CA2100821C - Stereocontrolled glycosidation - Google Patents
Stereocontrolled glycosidation Download PDFInfo
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- CA2100821C CA2100821C CA002100821A CA2100821A CA2100821C CA 2100821 C CA2100821 C CA 2100821C CA 002100821 A CA002100821 A CA 002100821A CA 2100821 A CA2100821 A CA 2100821A CA 2100821 C CA2100821 C CA 2100821C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
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Abstract
Novel glycosides containing novel leaving groups, pyridyloxy, pyrimidyloxy, methoxypyridyloxy, pyridyl carbonate and pyridyl thiocarbonate are utilized in many fertile syntheses of glycosides, disaccharides, trisaccharides, oligosaccharides, nucleosides and the like. These synthetic schemes are superior in stereospecificity, yield and speed of preparation of numerous novel compounds. Polymer supported syntheses may be utilized within the general scheme to provide enhanced product purity.
Description
rr.! ~"tølf'~~~
"~ .iy ~~; a STEREOCONTROLLED GLYCOSIDATION
The requirement to produce pure stereospeci.fic products is the core, pith and marrow of carbohydrate chemistry. Particularly essential is> the requirement to produce purer) alpha and beta anomers (C-1 anomers ire D-and L-sugars). Optimized yield of the compound and proportion of alpha anomer are both highly desirable, as those skilled in the art would appreciate, fox- practical and commercial reasons.
The present invention primarily relates to a. process of providing pure, or significantly higher proportion of alpha anomers in significantly improved yield. Specific donors, acceptors, promoters, and solvents are combined to produce specific anomers. The present invention secondarily provides novel compounds prepared by the process. Although the invention wil_L be described and referred to as it relates to processes of preparation of anomers from specific donors, acceptors, promoters, and solvents, and the resulting anomers, it will be understood that the principles of this invention are equally applicable to similar proces:~es and anomers and accordingly, it will be understood that the invention is not limited to such processes and anomers.
BACKGROUND AND PRIOR ART
The literature teaches the use of various glycosyl donors (sugar residues with a leaving group) with anomeric bromide and other functional groups to build an ultimate di-, tri-, or oligosaccharide.
O-protected beta bromo anomer is converted to the alpha disaccharide in 42% and 65% yield (Lemieux, J. Am.
Chem. Soc. 1975, 97, 4056), Table I.
~a ~ ~, fl !~ s3 _~ r,~
Similarly the alpha bromo 1,2-trans peracetyl glycoside anomer is converted to the equivalent beta (1,2-trans) glycoside in 47%, 64%, and 72% yield while the beta acetyl anomer was similarly converted in 71%, 72% and 80% yield (Hanessian, Carbohdr. Res., 53, C13 (1977) and 59, 261 (1977), Table II.
Activation of various anomeric donors has been heavily studied, using a variety of promoters, Table III.
Particularly of interest are those where the alpha: beta product ratio is known and can be improved, and where the overall yield is high, Table IV.
Previous work from applicant's laboratories has shown that glycosides can be prepared form glycosyl heterocyclic donors without protection of OH groups (S.
Hanessian et al. Carbohydrate Res. 80, C17 (1980)).
Speculation as to reaction mechanisms suggests metal complex formation with beta 2-pyridylthio donor leaving group, that is the activation is remote to the anomeric carbon, Table V, which applicant has termed "remote activation."
Extension of experimentation to a beta perbenzylated glycosyl 2-pyridinecarboxylate donor showed solvent dependence of anomeri.c product - ether-CHzCl2 giving primarily alpha while CH3CN gave primarily beta, Table VI.
Other extension based on applicant's original work can be found in Tetrahedron, 47, 6435, (1991).
It is a broad object of the invention to prepare specific anomeric compounds in improved yield and proportion, by selection of specific donors, selection of specific acceptors, ~~election of specific solvents, and selection of specific: promoters, in combination underselected specific process conditions. It is an rmst,r: t ~? (~ '~ ii i>r ~_ ~ i.~ ,_~ ~ ,r =:>
OBn Odn OBn Et~N-' Br- -~~ ROH Bno. o E3n0 ~ an0 pr ;, pit0 E3n0 BnO
ODn dr OBn OBn OR
O / \O
O O
O O
1 65% 42%
~o O
R. U. Len~icux, et al, J. Arn. Cf~em. Soc., 97, X1056(1975) onnt,r I z one ngOTr OAc nc0 O Ac0 -O
f~011 o' nc0 + nco (Me2N)zC0 . CF12C1zAc0 nc0 Br O
c n Ph~O O _ O--CI IZ-C-Me , Q Bn0'' ~ Bn0 '' I
l-~ Bn0 OMe Me OMe 6~
47% 72%
S. I-inNESSIAN el al. C13 (1977) , Carbolrydr. rtes.
, 5~ , .ono ono O SnCI,, nc0~~0 nco one + not-t ~-- nco-~-~~o~
nco or I2clz nco Aco n= Meu,yl (ao i ) , 2-r~ronyl (7 r i ) , Cyclonexyl (72'/ ) S. IInNESSIAN el al. , Carbohydr. files. , :59 . 261 (1977) ~i ~3 ~l ;'~ %'1 . a F: a. a,a (~ ;~_ .~
-D Cn 'T1 z ~ n ~ ~ ~ ~ O
a O °_' C7 c w z~
O w \ m cn o a ~.W ~ o ~ ~ o a~
c~ o ~ ~ ~" ---y- n (Q OD ~D C n .-~ ~ ~ ~' z C_7 cD -~-t~. r~ -~ COO D Z
O ~ "~ ~(D
_ ~ ZJ ''--. Cn D Z:
O \ ~ ~ ~ ~ ~ cn ~ cn Z O \
o \ O. C~~ ~ o p w~ O T ~' o o ~ ~ ~ = Cy ~
_..~ cn ~<
o~ ~ ~ ~ ~ N y~
o ;~ z a~ ~, _-- ~ \
N ~ O ~ ~ -s < ~ --.
CD
(D c~D W H
o~ ~ a cn -- r H
H
~
m cn ~ G) 'o~ n o \
cn ~ ~, ono m o \ -i ~. ~n ~ ~~ z ~ o o~ ~, " o ~o~< O w ~_ ~ ~o z ~° o c~ ~ ~~ s~ _ ° '~ ~ \ /
O m _ -J -. -.
°- cfl cn w o ~_ ~~ > o O
o 'D '~ ~~~
~
~i ~ n w O ~ c --icn 'c ~' ~ w =- cn rv O z Q7 ~ m Sv O
o CJ~ ~' O
cn ~
\
-I
~
~O
"~ .iy ~~; a STEREOCONTROLLED GLYCOSIDATION
The requirement to produce pure stereospeci.fic products is the core, pith and marrow of carbohydrate chemistry. Particularly essential is> the requirement to produce purer) alpha and beta anomers (C-1 anomers ire D-and L-sugars). Optimized yield of the compound and proportion of alpha anomer are both highly desirable, as those skilled in the art would appreciate, fox- practical and commercial reasons.
The present invention primarily relates to a. process of providing pure, or significantly higher proportion of alpha anomers in significantly improved yield. Specific donors, acceptors, promoters, and solvents are combined to produce specific anomers. The present invention secondarily provides novel compounds prepared by the process. Although the invention wil_L be described and referred to as it relates to processes of preparation of anomers from specific donors, acceptors, promoters, and solvents, and the resulting anomers, it will be understood that the principles of this invention are equally applicable to similar proces:~es and anomers and accordingly, it will be understood that the invention is not limited to such processes and anomers.
BACKGROUND AND PRIOR ART
The literature teaches the use of various glycosyl donors (sugar residues with a leaving group) with anomeric bromide and other functional groups to build an ultimate di-, tri-, or oligosaccharide.
O-protected beta bromo anomer is converted to the alpha disaccharide in 42% and 65% yield (Lemieux, J. Am.
Chem. Soc. 1975, 97, 4056), Table I.
~a ~ ~, fl !~ s3 _~ r,~
Similarly the alpha bromo 1,2-trans peracetyl glycoside anomer is converted to the equivalent beta (1,2-trans) glycoside in 47%, 64%, and 72% yield while the beta acetyl anomer was similarly converted in 71%, 72% and 80% yield (Hanessian, Carbohdr. Res., 53, C13 (1977) and 59, 261 (1977), Table II.
Activation of various anomeric donors has been heavily studied, using a variety of promoters, Table III.
Particularly of interest are those where the alpha: beta product ratio is known and can be improved, and where the overall yield is high, Table IV.
Previous work from applicant's laboratories has shown that glycosides can be prepared form glycosyl heterocyclic donors without protection of OH groups (S.
Hanessian et al. Carbohydrate Res. 80, C17 (1980)).
Speculation as to reaction mechanisms suggests metal complex formation with beta 2-pyridylthio donor leaving group, that is the activation is remote to the anomeric carbon, Table V, which applicant has termed "remote activation."
Extension of experimentation to a beta perbenzylated glycosyl 2-pyridinecarboxylate donor showed solvent dependence of anomeri.c product - ether-CHzCl2 giving primarily alpha while CH3CN gave primarily beta, Table VI.
Other extension based on applicant's original work can be found in Tetrahedron, 47, 6435, (1991).
It is a broad object of the invention to prepare specific anomeric compounds in improved yield and proportion, by selection of specific donors, selection of specific acceptors, ~~election of specific solvents, and selection of specific: promoters, in combination underselected specific process conditions. It is an rmst,r: t ~? (~ '~ ii i>r ~_ ~ i.~ ,_~ ~ ,r =:>
OBn Odn OBn Et~N-' Br- -~~ ROH Bno. o E3n0 ~ an0 pr ;, pit0 E3n0 BnO
ODn dr OBn OBn OR
O / \O
O O
O O
1 65% 42%
~o O
R. U. Len~icux, et al, J. Arn. Cf~em. Soc., 97, X1056(1975) onnt,r I z one ngOTr OAc nc0 O Ac0 -O
f~011 o' nc0 + nco (Me2N)zC0 . CF12C1zAc0 nc0 Br O
c n Ph~O O _ O--CI IZ-C-Me , Q Bn0'' ~ Bn0 '' I
l-~ Bn0 OMe Me OMe 6~
47% 72%
S. I-inNESSIAN el al. C13 (1977) , Carbolrydr. rtes.
, 5~ , .ono ono O SnCI,, nc0~~0 nco one + not-t ~-- nco-~-~~o~
nco or I2clz nco Aco n= Meu,yl (ao i ) , 2-r~ronyl (7 r i ) , Cyclonexyl (72'/ ) S. IInNESSIAN el al. , Carbohydr. files. , :59 . 261 (1977) ~i ~3 ~l ;'~ %'1 . a F: a. a,a (~ ;~_ .~
-D Cn 'T1 z ~ n ~ ~ ~ ~ O
a O °_' C7 c w z~
O w \ m cn o a ~.W ~ o ~ ~ o a~
c~ o ~ ~ ~" ---y- n (Q OD ~D C n .-~ ~ ~ ~' z C_7 cD -~-t~. r~ -~ COO D Z
O ~ "~ ~(D
_ ~ ZJ ''--. Cn D Z:
O \ ~ ~ ~ ~ ~ cn ~ cn Z O \
o \ O. C~~ ~ o p w~ O T ~' o o ~ ~ ~ = Cy ~
_..~ cn ~<
o~ ~ ~ ~ ~ N y~
o ;~ z a~ ~, _-- ~ \
N ~ O ~ ~ -s < ~ --.
CD
(D c~D W H
o~ ~ a cn -- r H
H
~
m cn ~ G) 'o~ n o \
cn ~ ~, ono m o \ -i ~. ~n ~ ~~ z ~ o o~ ~, " o ~o~< O w ~_ ~ ~o z ~° o c~ ~ ~~ s~ _ ° '~ ~ \ /
O m _ -J -. -.
°- cfl cn w o ~_ ~~ > o O
o 'D '~ ~~~
~
~i ~ n w O ~ c --icn 'c ~' ~ w =- cn rv O z Q7 ~ m Sv O
o CJ~ ~' O
cn ~
\
-I
~
~O
'I'AllI,l: I V
~ ~ r"1 ~~'9 ~ l C~ a I-a . a'. ~..~ i_~ I~ iu Of3n OE3n OBn ODn O
O I10 O Bn0 O
E3n0'=~ X -~ BnO~ '-- E3n0-~r~pn0 f3n0 OBr' OMe OBn~ Me Of3n Activator «~ ~ I~ Yield(°/~) O 3 : 1 88 ~~O~NII ( Scllmidt ) TfOSiMe3 on oci3 TBPq 1 : 2.1 84 ~~o~oEt ( Sinay ) on ( Nicolaou ) I3F3.E120 -- 65 on O ( Fraser-f3eid ) NDS 3 : 1 95 on S N
( Mereyala ) _ Mel major ~ 85 i TAISI,I: V
Activation -° ~ or dimes _os~~ -os.
I-I _ O~ N S
O f l ~.._ ' r O~N <)Fi ML
Oli R OI1 OI-i OI 1 I-IO o s N -ROf-1, Ng(ONOz)z Ino_ o ort rio oli \ PJIeCN, (ew min. rt lio oIi 35 - 95%
S. Hanessian, et al, Carbohydr. Res., 80, C17(1980) TAlrLls VI
t~ 1 ~1 !~ ~ .r w d.
!b ~. ,. _ 'J ~~.f -L
Otln OBn Of3n / CU(Ur()?, -50'~C ~ ~ ~ ~, f3n0'~ C~n0~0~
~ ~
+ ROI-I ---- -- onc> ''~ ~n ono~o ~rl or Sn(Ol!)2 ~1 o t3n0 Oftn O~ OOn OC!n p Eno r ci ce~cN
lZci2 cc : (1 a. : (i (Yield) (Yield) R = -(3111 71 : 29 19 : 81 (C>7 % (89 % ) ) OtW IO_ _.Mr.n f!n0 Oa ~ 83 : 17 9 : 91 (77 (97 % ) % ) Cln oo~~ rnP
otJn !)np ~O 9~ : 8 (70%)13 : 87 (92~) X
OOn OMo S. Kobayashi, et al., Telratiedron Lelt., 32, 7065(1991 ) !'Af)L1; VII
one OEI
I10 O 1. Promoter, rt Q
r! O N CI I.jNO~ / iso-PrOV-i (1:1 ) ~ ~ ~~~ -t- ~ - anOtllel~
one onl ~ , 2. Py / nc~0 Promoter (equiv.) Time a : (1 Yield(%) Hg(N03)? (1.0) 1 day No Reaction TMSOTf (1.0) 3.5hrs 6 ; 1 81 Me07 f (i. 1) 45rnin g ; f 7 t~-~ ~Y~~~s~-~
I-J _w. ~.: _ ~._I .I .:1.
ancillary object of the invention to identify specific donors, suitable for use in the invention. It is another ancillary object of the invention to identify specific acceptors, suitable for use in the invention. 7.t is another ancillary object of the invention to identify specific promoters, suitable for use in the invention.
It is another ancillary object of the: invention to identify specific solvents, suitable for use in the invention. It is a subsidiary object: of the invention to prepare novel anomeric compounds, utilizing unprotected and O-protected glycosyl donors. It is a fur_thebx~
subsidiary object of the invention to develc7p ~,ynt:hc~tic methods for the synthesis of glycosides, disaccharides, oligosaccharides and nucleosides, using glycosides including but not restricted to pyriclyloxy, methoxypyridyloxy, pyrimidyloxy, pyri.dylcarbonate, and pyridylthiocarbonate leaving groups, to provide said glycosides, disaccharides, oligosaccharides and nucleosides, including polymer supported oligosaccharide syntheses, in superior yield and stereospecificity, faster reaction times and shorter syntheses.
DESCRIPTION OF THE INVENTION
The appended summary tables after the general disclosure but before the claims are integral to the description of the present invention.
GLYCOSIDE SYNTHESIS WITH UNPROTECTED GLYCOSYL DONORS
Unprotected 2-pyridyloxy beta-D--glycosyl donor was treated with iPrOH (acceptor):CH3N02 (solvent) 1:1, at room temperature with Hg(NO3)Z, TMSOT:f and MeOTf (promoter), Table VII, followed by acetylation :in pyridine, Hg(N03)2 gave no reaction, TMSOTf 6:1 alpha:beta, 81%, MeOTf 9:1 alpha:beta, 78%.
lAllll: VI11 ~-,, ,~ :-y !', ~
F.. ~.. . 'n ;-,Onc ~. Maori, a - ~L,o Ilo- 1~~ so~~e~,n iso-o~o~ i ( ~ : I) n~oS-~ -~ (3 - anorner nco ' ~ I
I10 ,O N~ 2. Py/ nc~0 On () Solvent MeOTf (equiv.)rime a : Yield(/
(l ) ICS' Ct-1~N0~ 1.1 ~l5min 9 : 75 CI-1 CI t .0 ~l5min 5 : ~0 CH~CN 1.0 ~l5min 4 : a't ~ t-y 1 .o ~t5n lln /
~1,~
iso-Pr01-I 1.0 l5min 11 : B5 TAIll,l; IX
OI 1 ~OAc 1. MeOTI, tl ~O X CFi3N02/ iso-PrOli ( t : i) nc0~ -t- ~3 - anomer Ilo-~ --~ nco of I 2. r~y F nc2o one o~
~O I N~ 45 min, 7E3% ~O N 1 15 min, Ei!I%
a : (3 9 : 1 I i N cr. : (l 5 : 1 UNREACTIVE TO MeOTf:
~O ~S ~ ~S N~ .,-O fJ\ V~ ~'S N' N~
I / I / ' /
C~ISLF, x W .j ~. t; s~ ~ T,. -2.
one oFt t. Meort, ri CF13NOZ/ iso-fn Of i ( 1 : 1 ) nc0 '~
no-~X - nco ;-1 + (3 - anomer eo of t 2. f~y i nczo one o l MeOTf (equiv.) Tine a Yield( : (3 % ) Ii t.1 45rnin 9 : 1 7El ~O
N 0 <5rnin F3 : 1 79 ICS I .
~i' MeO
,O N~
1.0 2.5h a : 1 F3E3 OMe ' I'AFSI,Ii X1 OMe ~ ~OMe tJ~ OMe N~ N~
N
i pKa = 5.20 ~ 3.2n 4.8~~ 6.62 Reactivity:
., ~~ O N > ~~- O ~ > ~~ p N
OH O I ~ OH I OI-I
/ / /
Me OMe few min. 45 min >I2h j3CNMR(ppm) 97.81 (C-1 ) 98.21 (C-1 ) 98.71 (C-1 ) ~-~ ~~ C' :~: s E: _i t; Li l.1 ,~ ~.
Variation of solvent in the same process using MeOTf promoter, Table VIII, CH3N02, CH2Clz, CH3CN, THF, iPrOH (as solvent and acceptor) gave good yields (78-85%) and ratios (11:1 to 6:4).
Variation of leaving groups in t:he same process, Table IX, demonstrated that 2-pyridyloxy and 6-pyrimidinyloxy gave satisfactory yields and z°at.ios, while phenoxy, thiophenyl, 2-pyridylthio, .?-napht:hyrid.inyloxy, and 2-2-bipyridyl-2-thio were not reactive, under these conditions.
3-METHOXYPYRIDYL-2-OXY (MOP) GLYCOSYL DONORS
Further testing of 3- and 4-methoxypyridyl-2-oxy leaving groups, in the same process, Table X, grave excellent yields (78-88%) and ratios (8 to 9:1 or higher). The time factor was significantly less for the 3-methoxy radical (hereafter MOP) <5 minutes, as opposed to 2.5 hours for the 4-methoxy radical, while the 2-pyridyloxy radical took 45 minutes.
The donor results so far can be convincingly partially correlated with basicity (hKa) of the equivalent pyridine, the reactivity time, and the ~3CNMR
(ppm) of the anomeric carbon atom, Table XI.
Having established the superiority of the MOP donor, it was tested in the same process against a variety of promoters, Table XII. Time considerations militated against ZnClz, yields against ZnClz, PTS, ratios against NBS, PTS. ZnCl2, and especially Cu(OTf)z, BF3, and even more so MeOTf gave excellent results.
The proportion of MeOTf was varied in the same process, Tab7_e XIII, 1.0, 0.2 and 0.016 eq. gave closely similar results 76 to 79% yield ratio 8:1. Only 0.016 I'AI11,1: XIV ~'I ~ ~ ~' .w -~1 !., .~. 1.i ;~ ;~
On 1. MeOT(, rl one I 10 o Cf-1nN02 / 8011 ( 1 : 1 ) O
LI - _ n~o O ~ Nw ' nc0 oy~ ~?. Ac20 / Py one o r~
t Me ROH MeOTf (equiv.)Time a (3Yield(%) MeOH 0.2 <5lnin 10: 1 B2 Iso-PrOH 0.2 <5rnin 8 1 76 :
Mew/-doll 0.1 l0min 16: 1 77 Cyclohexanol0.2 30rnin 5 1 G2 :
IAI1LI: XV
I-10 OFI I Ip ' o MeOTI (0.2 eduiv.) OI 1 + ~_-W~OR
I10~~0 N yo~~o ~ CI-L RT
NO
, N N3 Z, ~
N~ Ori /
O
Me ROIH (equiv.) Time ~, : ij Yield(%) iso-PrOFi / CII~NO? (1 3 i~rs 12 : 1 : 1) O
IIO~o~ (34) 211rs 17: 1 70 NI-If~oc IIO~Or3n (30) 4 hrs 8 1 65 Me~OIi (2.1) 3 hrs 6 : 1 f~ '1 :'~) ~.P -"
TAlli,l; X I I 4r -n- Rv '~ :. .~' OAc OI i 1. Promoter, rt CI f 3N0z/ iso-PrOf f ( 1 : 1 ) nc0~ O
Flo- ° o N ,- -_~ n~~~ -~ (1 - anomer ! to '~ ~ a. r y / n~~o one ofi p M Je Promoter (equiv.)Tirne cx Yieid(~o) :
() MeOTf (1.0) <5rnin 8 : 79 PTS ( 1.0) 5min 1 : 65 BFI (1.0) 5rnin 8 : 77 Cu(OT()Z ( 1.0) 5rnin 7 : 82 ZnCl2 (1.0) 3days 4 : 61 NDS ( 1.0) <5min 6 : 78 I'AI?Lf; XI II
ono OF-I t. MeOTI, rt O CI-i3N0~1 iso-Pr01-1 ( 1 : t) ~ n O~=
eo-~ + (3 - anomer r i0 Ov N 1 2. Py / nc~0 C>nc O
Ofl O /
Me MeOT( (equiv.) Time a : (3 Yieid(°~o) 1 <5 min 8 : 1 79 0.2 < 5min 8 : 1 76 0.016 40min 8 : 1 78 ~ .g ~ ~, i' , ~ ;, ~~ '_i ~~,~ ..
eq. gave a longer time 40 min. as opposed to <5 min, which was felt to indicate catalytic rather than reactant nature of the MeOTf promoter.
The process was repeated using beta MOP D-glucopyranoside donor, with methanol,, isopropanol, transbut-2-en-1-ol, and cyclohexanol as acceptors, and 0.2 or 0.1 eq. of MeOTf, gave yields (62 to 820) and ratios (5 to 16:1) Table XIV.
A similar process was modified using beta MOP 2-azido-2-deoxy-D-galactopyranoside donor, iPrOH acceptor, benzyl glycolate, benzyl N-t-butoxycarbonylserine transbut-2-en-1-of in heavy equivalent excess gave reaction times of 2 to 4 hours with yields of 6.5 to 86%
and ratios of 6 to 17:1, Table XV, which are important as glycosides of 2-amino-2-deoxysugar derivatives.
In summary thus far superiority of yield, ratio, time, temperature, and promoter effectiveness has been conclusively demonstrated, with the MOP group. The effective application of the process to donors including unprotected hydroxyl groups has also been shown.
The MOP gluco- and galactopyranoside donors of Tables XIV and XV were prepared following Schemes I and II, which would be instantly intelligible to those skilled in the art of sugar or organic chemistry.
A tentative possible hypothetical mechanism is developed in Scheme III although thia is neither scientifically binding nor substantiated by kinetic experimentation.
The same process was applied to 2-acetamido-2-deoxy-beta-D-hexopyranoside MOP donors, with 0.1 eq. MeOTf in the gluco case and 0.2 eq. in the galacto case. Pure SOIII:Mfi 1 cz ~ k ~ 1~ :~i ;:r E.d .~:. .. ?. 1 .. . .. _ ._ nyo N
Onc O I ~ Onc .OII
nc0~ M° -~ ~1c0~ NaOMe tl0~ ~LO
nc0 TOIueno,110"C nc0~'O rJ fI~T~O ~ N\
MeOII / CFI?Ch ~ oll Onc ~, l5min, ?Il5'.o Onc ~ puant. yield /
O ~ O
M° Me ! IgDr2, Xylene 130"C, 5hrs, 4~
ono ~ol I
nc0 NaOMe FI o ~
nco ~-Onc o N MeOF-1 / CIi2Clz OL l o N
puant. yield O O
Mo Me IIO N
Onc ~ I / Onc .OII
~ (7 oqniv ) ~
nco~ t'~° _' nco-N-OJ,o N NaOMe / MeOFi tlii0 n~;o ~ nc ~o tJl me E3u~NE3r / Na01 I NI Inc ~ gC~ ~ rJl Inc I CIlzClz, rl, 30min O o M° M°
S(:IIEMP; II
ngo N
o ~ ~ n~o one Fro ol-I
nc0 Onc r (1.5 equiv.) ~, O NaOMe L O
O lute nc0~~0 N~ _ nc0 I-10~~0 N\
toluene, 11o~C N~ ~~ / Me0F1 N
N3 Br 45min p' J 3 O
Me Me 63"/
LiCI
ng0 N\
n~o ono ~ ~ n~o ono t-to olo O ~ (1.5 equiv.) nc0 O NaOMe FIO
nc0 CI Me -_ MeOFi Na toluene, 110"C N3 O N~
I r, r poi o I ~
r Me Me SCIII:!,lli II I
t1 ~ ~, '~ ', ::) ' ~4 i ~ rd -y-_o rt0! f, -rI'slfp pn 11p s~ pT
pl TIOr1 MeOTI + n 1 ,2 -ROI-1 1 bans p' 'r'' o w T(Qr1 Me Tf011 li f O N
O l .-O +
N 11p _._ Tlip ~~l ' pl1 ~
~
~ IZOIf p ~ sr~2 - iike pn , - Me ' Me Me 1,2 - cis nNOMCmznTioN
-riot-I
p ~r~o ~ p ~ ~ - on rlp--fl~
~ s T so _ __ rT O I-1 _ OI1 5~~2 _ olT
o O N like N ~~ ~
1 Jl ip ~J
p p 1,2 . - traps Me Me rnm.I: xv1 OEi OAc h-10'_~~ 1. MaOTf ( 0.1 equiv.) O
Ii0 O N\ , ~ ~ ~~~0 NI-IAc /~ CI-I~N02/ Iso-Pr01-t ~lyAc O / rt, 5min 2. Ac:zO / Py o~~ly ~3, 83%
Llo or I Ago one 1. NIeOTf ( 0.2 equiv.) ~ O
HO O N~ . Aco~~--o rreAc ~ c~yNO2/ISO-r~rol-~ Ne-IAA
't, 5min 2. Ac?o / Py only (3, 88%
I'nlll,l: XIX
l''p -~ :'1 ;'3 i'7 w3 y ,i f~ .~_ 5." ',.' ~~ :.F .SL
OII ~OAc (' OII ~OA_c to nc0-'N-", MeOTf (0.2 e<lulv.) IIO--r1-O nco~
110 LO N nc0-'~'~O N -s I10~-?~ ~- Ac0-~7~0 of o~ ~ Onc O~~ Cll,rlOz/lso-f rOli(1:1) 0l1 ~ one rt, 5mln M" ht" not observed Reactive Unreactive oll on~
rlo~ o~ n~o-~.~ 0 IWo rl n~o~-~-~-o F!
0l1 ~ ono / o /
Me Mo f10 OII Ac0 Onc ~O~ ~- O
I10~0 N AcO~'~O N
011 i Onc / /
(7~ O
Mo A1e IIO Ofl nc0 Onc I~< O' '< ,O
FIO~O N~ At0~7~~0Y N
F!~ I N~ 1I '1J
O
n Mn F.lc 1'n111,F: XX
TfOi-i (2.0 equiv.) DMF, rt, 15 - 20rniy on n~o ol-I ,~ one o do ° o tlh0'-'~O~ Nw -y nc0~~~0 N\ - I10 Nlinc nc0~~0 N\
NI inc ~ / N3 ~ / t'Ic O O O
Me Me Me 1.0 equiv. 10 equiv. 65 - 70°0 TfOi-I (2.0 equiv.) DMF, rt, 30min ola Ino on one flo oll nco O O N F nc0~~.0 N\ - - FiO~~ncO ~O
f 10 ~~ ~ ~ ~t I NHnc ' ~O N\
Nlinc ~ / ~ N
O O O
Me Me Me 1.0 equiv, 10 equ v. 61 TAIiI,rv XV I I ' ~~~ ~~~~114~
-r .,9. ;,~ xlt L~ .~,'~
Of I Onc .O
I IOC~O N MeOTf (0.2 equiv.) ' n~20~ / I'Y ~ ~~~ 19%
Nllnc I ~ C;I1~NOZ,r1,10min N O
p ~., f 13 i Me II tit O~ N
OI-I
O
Me MeOTf ( 0.2 equiv.) E 10 O nc2O / f'y II -IIN+ O
1' C rl3 R
R~-O ~OI-) ono R~
O R-t-O
o~,o n o~~ o ~0 0 / I i. Nllnc R, R = Cycloliexylidene I~IX~ , then nc?o / r'y R R
( 14 equiv.) 6d°~o 1AI1I,1~. XVIII
--t- 0 Ol i O~ O
(10 equiv.) O O
or-t ~ Necover the excess O f-1 HO O NO~.-O
FIC~O N\ I10 ~ O -~- ~ - anomer oIJ ~~ 1 MeOTf(0.2 equiv.) ce o CI-13N0?, rt, l5min o o M a 61 % ~O
4~ : ~1 ~° ~~ d~~ :'~ ~;~ :.n ,rt , ~ '~ !.
b. _u. ~,, ~! ;.i ~ a . .
beta products were obtained in 83 and 88o yield respectively, Table XVI.
DISACCHARIDE SYNTHESIS
The 2-acetamido-2-deoxy-beta-D-glucopyranosyJ. MOP
donor was treated first with MeOTf ( c) . 2 eq. ) in CH3NOz, at room temperature for 10 minutes, fol_Lowed addit.i.on of 14 eq, of 1,2-3,4 di-O-cyclohexylidenyl-D- galactopyranose acceptor with a free 6-hydroxyl, then acetic anhydride-pyridine, which gave 68% of the peracetylated ra~at~.a disaccharide, Table XVII. When the perhydr.~c~xy nluc:osyl beta MOP donor was similarly treated, with -the equivalent 1,2-3,4 di-O-isopropylidene-D- galactopyranose acceptor without subsequent peracetylation, t)ze reaction gave 610 yield of the disaccharide with 4:1 a_Lpha:beta ratio, Table XVIII.
In the absence of the acceptor -the oxazoline derivative can be isolated, Table XV:III.
Treating unprotected and peracetylated beta MOP
acceptors in the presence of MeOTf (~0.2 eq.) in CH3N02/iPrOH for 5 minutes, Table XIX, showed the unprotected gluco-, galacto- and 2-azido-2-deoxygalacto donors gave alpha products, while peracetylated donors gave no observable products, and were considered unreactive.
Gluco- and galacto- 2-acetamido-2-deoxypyranosyl beta MOP donors were each treated with 10 eq. of beta MOP, 2-azido-2-deoxy, 3,4, di-O-acetyl galacto-pyranoside acceptor with a free 6-hydroxyl, in the presence of 2.0 eq. TfOH, in DMF. 15-20 minutes at room temperature in the gluco case gave E.5-70% yield of pure beta 1,6-disaccharide, while 30 minutes in the galacto case gave 610 of pure beta 1,6-disaccharide, Table XX.
.., ,e -~ r ; :~ 1 ~ .c A a t,' v ~. ~ ;u -'.
Consideration of the results so far led to three proposed schemes for iterative oligosaccharide synthesis, Scheme IV, in which an active donor is coupled with an inactive donor as acceptor to give a disaccharide. The latent donor is then activated either by change c~f leaving group (1), activation of leaving group (3), or change of substituent (2), and the process repeated with another acceptor. As shown only beta linkages a-re present, although as those skilled in the az°t would understand alpha linkages can be generated routinely in such syntheses.
One such synthesis is indicated, Table XXI starting using the 2-acetamido--2-deoxy-D-glucopyranosyl MOP donor of Table XX, and forming the same beta disaccharide in 70% yield, which is then reduced peracetylated to its diacetamidohomolog, deprotected to form an active donor and coupled with l0 eq. of the same acceptor, in the presence of 2 eq. TfOH in DMF, for 20 minutes at room temperature, then peracetylated to give the beta trisaccharide in 34% yield, which can be further optimized.
In a close variation on the immediately preceding synthesis, the identi<~al disaccharide is prepared, deprotected and treated with 0.5 eq..MeOTf, CH3NOZ/iPrOH, at room temperature for 9 hours followed by peracetylation, to gi~,re the isopropyl derivative of the disaccharide in 66% yield, alpha: beta. 17:1, Table XXII.
ACTIVATION OF O-ACYL PROTECTED GLYCO~~YL MOP DONORS FOR
BETA-GLYCOSIDE SYNTHESIS - COPPER TRI:FLATE ACTIVATOR
O-acyl protected 1,2-trans MOP c~lycosyl donors are coupled with glycoside acceptors containing a single free hydroxyl, using Cu(OTf)z (2 eq.), CHZClz solvent at room temperature for 2 to 8 h, gave beta 1_inked D-glyco-w:af:n~e tv c~ .q t, r-3 ~) :~ .~
i .~. ~,. ~'~._7 ;j/ i J .~
n'livm° x ~n:,n9° Y la x ,.,..o ~~-o .r-o , o _ 1. no :.--~x no ~.% ~r -a._ '~~° o ~r _ no"~--,1~°'~'~-l,x no oorron nccEpron .v o FiO~~~Y ncllvnle X
E.'tC. ~_ _ _ _ _ _ _ _ nO ~O~--~O ~Y
ncllvoln donor ~O chsngo n' Io n ~O ~~ ~O~ ~
~.O ~O ~-O ~ --~- nD v~0 ~X
2. no :fix -F no ~-~-x --~ no :~-~° or"~'x ~ on o n' ooNOn nccsr~ron .v o Ilow~-~.'x ~ ocllvnledonor On O O O
BtC. -y- _ _ _ _ _ _ _ nOW.~ ~-x On OR
O ncllvnle X ~O oelivale Y O y0 110 ~Y nO v-~ y~0 ~Z
3. no ~ x ~ ~ w no :~°''~Y '~ i.- ~ o ." o ooNOn nccenTOn llo~'.--J-z etc.
I'nfll,fi XXI
TIOH(2.0 oquiv.) pM'', It, 15 - 20min of l nco of /of 1. tlZ, Pd / C. EtOF1 I10~ ~O' 'O'~ 2. ncp0 / Py ~~ O nc0 I O~O~ rJ ~~ O W 10 rJl Jnc nc0 '~O N
-' MTInc~ O I / N~ I / rJ~ O I /
O
Me ~I° Me 1.0 equiv. 10 equiv.
nc0 JFI
nc0~ O
~O~
Ns II
O /
Onc OI I 01.1 10 AqnIW Ma Onc O
nco~o- NaOMo l Me0li l~~p~/~o~,o N
nco Nllnc nco o N ~ Nnn' ~J -rJl Inc NI Inc ~I 1 TIOI-1 (2 equlv.) O ( / O/v DMf-, rl, 20m1n r.>, a rrt n one «nc ncO~o-~O Onc nc O / r nc ~ '~0 Y Nllnc n'(7. O
Nli~nc0 J) O rJ
N~
O /
M°
f ~rnnl,I: x x r W' ''~
~.r .S. ',J 1.' ~ i-J ..~
TtOH (2.0 equiv.) 011 Onc or{ nco on DMF, ri, 15 - 20rnin 11p-~I)--< n O
HO~O~ N + ncO~~p N\ -~- F-i0 NHnc n"O~O N
F 1 --~~ ~/ ''''''0 Nhinc ~ \ Na ~ / 70% N~
O / O O /
Me hfe Me 1.0 equiv. 10 equiv.
pr1 0~1 1. MeOTf (0.5 equiv.), rt ~~Onc Onc NaOMe / Me01-I h ~O~IiO CI-l3NOz/iso-PrOH, 9h nc02'~o o-~O nc0 T~
h1o Nhlnc h~o Lo - ~- iut~nc nco N~ ~ 2. n~?o / r~y N3 U
pY
rvie 66%
cx:(3=17:1 Tnllt,l: XXII I
Bz0' OBz Bz0 OBz ~ODn ~~O N Cu(OTf)z (2 equiv.) Bz0 w Bz0 OBz ~ / ROf! / CHZC12, rt E3h OBz BO~
O «?B~ COI Me Me E35%
Bz0 OBz Bz0 OBz O Cu(OTI)2 (2 equiv.) O ~OBn Bz0 ~~O N~ Bz0 ~~0~"O
flOf 1 / Ct hClz, rl, 2h OBz nll0 NI
OBz ~
~ OMe O
r Me 69%
OTBDMS OTBDMS
B O N Cu(OT()? (2 equiv.) ~d _ O
OBz ~ / f101i / CtI?CIz, rt, 2h OBzBBO~ O
r O OB~ Me Me 60%
lAlil.l? XXI\1 c3 ~ ~ ~~ ~ ;.a ;
h W
j , i ~ a l on on n0 ~n 2 edniv nO
) ~n rt Me0 i I (0 ~ rr . ~
, + (1- anorner . ~ on on C11~N0~/iso-i'r011() <y U i ~ 1 : 1 ht~
ol, Time a ; (1 Yield(%) o n oll ~ <5rnin 8 : 1 o hire ,01F,C)MS
_~~
-oa I~
~
~ 20rT~in 9 : 1 84 u' ~' I ~
rr, <o~rm r' ~
(~r o rr. 1 h 5 : 1 88 on I ~
M
<O~II
~~oo~o N 2h only a 95 on., ' o M r~
<O,D~n "~o~o 5h only a 85 rr' IT
~' o ' rae CAIILI: XXV
OBn OBn O gn0 ~O~
Oli gn0 O O N~ -t- ~ I O _ rvteOTt (0.2 equiV.)r pgn0~0 -t- ~) - anomer gn Oen ~~ , \~ Et?O, rt, 2hh O
O' J ° ° G6%
r ~ OXO
Me 1.5 equiv.
~ ~ r"1 ~~'9 ~ l C~ a I-a . a'. ~..~ i_~ I~ iu Of3n OE3n OBn ODn O
O I10 O Bn0 O
E3n0'=~ X -~ BnO~ '-- E3n0-~r~pn0 f3n0 OBr' OMe OBn~ Me Of3n Activator «~ ~ I~ Yield(°/~) O 3 : 1 88 ~~O~NII ( Scllmidt ) TfOSiMe3 on oci3 TBPq 1 : 2.1 84 ~~o~oEt ( Sinay ) on ( Nicolaou ) I3F3.E120 -- 65 on O ( Fraser-f3eid ) NDS 3 : 1 95 on S N
( Mereyala ) _ Mel major ~ 85 i TAISI,I: V
Activation -° ~ or dimes _os~~ -os.
I-I _ O~ N S
O f l ~.._ ' r O~N <)Fi ML
Oli R OI1 OI-i OI 1 I-IO o s N -ROf-1, Ng(ONOz)z Ino_ o ort rio oli \ PJIeCN, (ew min. rt lio oIi 35 - 95%
S. Hanessian, et al, Carbohydr. Res., 80, C17(1980) TAlrLls VI
t~ 1 ~1 !~ ~ .r w d.
!b ~. ,. _ 'J ~~.f -L
Otln OBn Of3n / CU(Ur()?, -50'~C ~ ~ ~ ~, f3n0'~ C~n0~0~
~ ~
+ ROI-I ---- -- onc> ''~ ~n ono~o ~rl or Sn(Ol!)2 ~1 o t3n0 Oftn O~ OOn OC!n p Eno r ci ce~cN
lZci2 cc : (1 a. : (i (Yield) (Yield) R = -(3111 71 : 29 19 : 81 (C>7 % (89 % ) ) OtW IO_ _.Mr.n f!n0 Oa ~ 83 : 17 9 : 91 (77 (97 % ) % ) Cln oo~~ rnP
otJn !)np ~O 9~ : 8 (70%)13 : 87 (92~) X
OOn OMo S. Kobayashi, et al., Telratiedron Lelt., 32, 7065(1991 ) !'Af)L1; VII
one OEI
I10 O 1. Promoter, rt Q
r! O N CI I.jNO~ / iso-PrOV-i (1:1 ) ~ ~ ~~~ -t- ~ - anOtllel~
one onl ~ , 2. Py / nc~0 Promoter (equiv.) Time a : (1 Yield(%) Hg(N03)? (1.0) 1 day No Reaction TMSOTf (1.0) 3.5hrs 6 ; 1 81 Me07 f (i. 1) 45rnin g ; f 7 t~-~ ~Y~~~s~-~
I-J _w. ~.: _ ~._I .I .:1.
ancillary object of the invention to identify specific donors, suitable for use in the invention. It is another ancillary object of the invention to identify specific acceptors, suitable for use in the invention. 7.t is another ancillary object of the invention to identify specific promoters, suitable for use in the invention.
It is another ancillary object of the: invention to identify specific solvents, suitable for use in the invention. It is a subsidiary object: of the invention to prepare novel anomeric compounds, utilizing unprotected and O-protected glycosyl donors. It is a fur_thebx~
subsidiary object of the invention to develc7p ~,ynt:hc~tic methods for the synthesis of glycosides, disaccharides, oligosaccharides and nucleosides, using glycosides including but not restricted to pyriclyloxy, methoxypyridyloxy, pyrimidyloxy, pyri.dylcarbonate, and pyridylthiocarbonate leaving groups, to provide said glycosides, disaccharides, oligosaccharides and nucleosides, including polymer supported oligosaccharide syntheses, in superior yield and stereospecificity, faster reaction times and shorter syntheses.
DESCRIPTION OF THE INVENTION
The appended summary tables after the general disclosure but before the claims are integral to the description of the present invention.
GLYCOSIDE SYNTHESIS WITH UNPROTECTED GLYCOSYL DONORS
Unprotected 2-pyridyloxy beta-D--glycosyl donor was treated with iPrOH (acceptor):CH3N02 (solvent) 1:1, at room temperature with Hg(NO3)Z, TMSOT:f and MeOTf (promoter), Table VII, followed by acetylation :in pyridine, Hg(N03)2 gave no reaction, TMSOTf 6:1 alpha:beta, 81%, MeOTf 9:1 alpha:beta, 78%.
lAllll: VI11 ~-,, ,~ :-y !', ~
F.. ~.. . 'n ;-,Onc ~. Maori, a - ~L,o Ilo- 1~~ so~~e~,n iso-o~o~ i ( ~ : I) n~oS-~ -~ (3 - anorner nco ' ~ I
I10 ,O N~ 2. Py/ nc~0 On () Solvent MeOTf (equiv.)rime a : Yield(/
(l ) ICS' Ct-1~N0~ 1.1 ~l5min 9 : 75 CI-1 CI t .0 ~l5min 5 : ~0 CH~CN 1.0 ~l5min 4 : a't ~ t-y 1 .o ~t5n lln /
~1,~
iso-Pr01-I 1.0 l5min 11 : B5 TAIll,l; IX
OI 1 ~OAc 1. MeOTI, tl ~O X CFi3N02/ iso-PrOli ( t : i) nc0~ -t- ~3 - anomer Ilo-~ --~ nco of I 2. r~y F nc2o one o~
~O I N~ 45 min, 7E3% ~O N 1 15 min, Ei!I%
a : (3 9 : 1 I i N cr. : (l 5 : 1 UNREACTIVE TO MeOTf:
~O ~S ~ ~S N~ .,-O fJ\ V~ ~'S N' N~
I / I / ' /
C~ISLF, x W .j ~. t; s~ ~ T,. -2.
one oFt t. Meort, ri CF13NOZ/ iso-fn Of i ( 1 : 1 ) nc0 '~
no-~X - nco ;-1 + (3 - anomer eo of t 2. f~y i nczo one o l MeOTf (equiv.) Tine a Yield( : (3 % ) Ii t.1 45rnin 9 : 1 7El ~O
N 0 <5rnin F3 : 1 79 ICS I .
~i' MeO
,O N~
1.0 2.5h a : 1 F3E3 OMe ' I'AFSI,Ii X1 OMe ~ ~OMe tJ~ OMe N~ N~
N
i pKa = 5.20 ~ 3.2n 4.8~~ 6.62 Reactivity:
., ~~ O N > ~~- O ~ > ~~ p N
OH O I ~ OH I OI-I
/ / /
Me OMe few min. 45 min >I2h j3CNMR(ppm) 97.81 (C-1 ) 98.21 (C-1 ) 98.71 (C-1 ) ~-~ ~~ C' :~: s E: _i t; Li l.1 ,~ ~.
Variation of solvent in the same process using MeOTf promoter, Table VIII, CH3N02, CH2Clz, CH3CN, THF, iPrOH (as solvent and acceptor) gave good yields (78-85%) and ratios (11:1 to 6:4).
Variation of leaving groups in t:he same process, Table IX, demonstrated that 2-pyridyloxy and 6-pyrimidinyloxy gave satisfactory yields and z°at.ios, while phenoxy, thiophenyl, 2-pyridylthio, .?-napht:hyrid.inyloxy, and 2-2-bipyridyl-2-thio were not reactive, under these conditions.
3-METHOXYPYRIDYL-2-OXY (MOP) GLYCOSYL DONORS
Further testing of 3- and 4-methoxypyridyl-2-oxy leaving groups, in the same process, Table X, grave excellent yields (78-88%) and ratios (8 to 9:1 or higher). The time factor was significantly less for the 3-methoxy radical (hereafter MOP) <5 minutes, as opposed to 2.5 hours for the 4-methoxy radical, while the 2-pyridyloxy radical took 45 minutes.
The donor results so far can be convincingly partially correlated with basicity (hKa) of the equivalent pyridine, the reactivity time, and the ~3CNMR
(ppm) of the anomeric carbon atom, Table XI.
Having established the superiority of the MOP donor, it was tested in the same process against a variety of promoters, Table XII. Time considerations militated against ZnClz, yields against ZnClz, PTS, ratios against NBS, PTS. ZnCl2, and especially Cu(OTf)z, BF3, and even more so MeOTf gave excellent results.
The proportion of MeOTf was varied in the same process, Tab7_e XIII, 1.0, 0.2 and 0.016 eq. gave closely similar results 76 to 79% yield ratio 8:1. Only 0.016 I'AI11,1: XIV ~'I ~ ~ ~' .w -~1 !., .~. 1.i ;~ ;~
On 1. MeOT(, rl one I 10 o Cf-1nN02 / 8011 ( 1 : 1 ) O
LI - _ n~o O ~ Nw ' nc0 oy~ ~?. Ac20 / Py one o r~
t Me ROH MeOTf (equiv.)Time a (3Yield(%) MeOH 0.2 <5lnin 10: 1 B2 Iso-PrOH 0.2 <5rnin 8 1 76 :
Mew/-doll 0.1 l0min 16: 1 77 Cyclohexanol0.2 30rnin 5 1 G2 :
IAI1LI: XV
I-10 OFI I Ip ' o MeOTI (0.2 eduiv.) OI 1 + ~_-W~OR
I10~~0 N yo~~o ~ CI-L RT
NO
, N N3 Z, ~
N~ Ori /
O
Me ROIH (equiv.) Time ~, : ij Yield(%) iso-PrOFi / CII~NO? (1 3 i~rs 12 : 1 : 1) O
IIO~o~ (34) 211rs 17: 1 70 NI-If~oc IIO~Or3n (30) 4 hrs 8 1 65 Me~OIi (2.1) 3 hrs 6 : 1 f~ '1 :'~) ~.P -"
TAlli,l; X I I 4r -n- Rv '~ :. .~' OAc OI i 1. Promoter, rt CI f 3N0z/ iso-PrOf f ( 1 : 1 ) nc0~ O
Flo- ° o N ,- -_~ n~~~ -~ (1 - anomer ! to '~ ~ a. r y / n~~o one ofi p M Je Promoter (equiv.)Tirne cx Yieid(~o) :
() MeOTf (1.0) <5rnin 8 : 79 PTS ( 1.0) 5min 1 : 65 BFI (1.0) 5rnin 8 : 77 Cu(OT()Z ( 1.0) 5rnin 7 : 82 ZnCl2 (1.0) 3days 4 : 61 NDS ( 1.0) <5min 6 : 78 I'AI?Lf; XI II
ono OF-I t. MeOTI, rt O CI-i3N0~1 iso-Pr01-1 ( 1 : t) ~ n O~=
eo-~ + (3 - anomer r i0 Ov N 1 2. Py / nc~0 C>nc O
Ofl O /
Me MeOT( (equiv.) Time a : (3 Yieid(°~o) 1 <5 min 8 : 1 79 0.2 < 5min 8 : 1 76 0.016 40min 8 : 1 78 ~ .g ~ ~, i' , ~ ;, ~~ '_i ~~,~ ..
eq. gave a longer time 40 min. as opposed to <5 min, which was felt to indicate catalytic rather than reactant nature of the MeOTf promoter.
The process was repeated using beta MOP D-glucopyranoside donor, with methanol,, isopropanol, transbut-2-en-1-ol, and cyclohexanol as acceptors, and 0.2 or 0.1 eq. of MeOTf, gave yields (62 to 820) and ratios (5 to 16:1) Table XIV.
A similar process was modified using beta MOP 2-azido-2-deoxy-D-galactopyranoside donor, iPrOH acceptor, benzyl glycolate, benzyl N-t-butoxycarbonylserine transbut-2-en-1-of in heavy equivalent excess gave reaction times of 2 to 4 hours with yields of 6.5 to 86%
and ratios of 6 to 17:1, Table XV, which are important as glycosides of 2-amino-2-deoxysugar derivatives.
In summary thus far superiority of yield, ratio, time, temperature, and promoter effectiveness has been conclusively demonstrated, with the MOP group. The effective application of the process to donors including unprotected hydroxyl groups has also been shown.
The MOP gluco- and galactopyranoside donors of Tables XIV and XV were prepared following Schemes I and II, which would be instantly intelligible to those skilled in the art of sugar or organic chemistry.
A tentative possible hypothetical mechanism is developed in Scheme III although thia is neither scientifically binding nor substantiated by kinetic experimentation.
The same process was applied to 2-acetamido-2-deoxy-beta-D-hexopyranoside MOP donors, with 0.1 eq. MeOTf in the gluco case and 0.2 eq. in the galacto case. Pure SOIII:Mfi 1 cz ~ k ~ 1~ :~i ;:r E.d .~:. .. ?. 1 .. . .. _ ._ nyo N
Onc O I ~ Onc .OII
nc0~ M° -~ ~1c0~ NaOMe tl0~ ~LO
nc0 TOIueno,110"C nc0~'O rJ fI~T~O ~ N\
MeOII / CFI?Ch ~ oll Onc ~, l5min, ?Il5'.o Onc ~ puant. yield /
O ~ O
M° Me ! IgDr2, Xylene 130"C, 5hrs, 4~
ono ~ol I
nc0 NaOMe FI o ~
nco ~-Onc o N MeOF-1 / CIi2Clz OL l o N
puant. yield O O
Mo Me IIO N
Onc ~ I / Onc .OII
~ (7 oqniv ) ~
nco~ t'~° _' nco-N-OJ,o N NaOMe / MeOFi tlii0 n~;o ~ nc ~o tJl me E3u~NE3r / Na01 I NI Inc ~ gC~ ~ rJl Inc I CIlzClz, rl, 30min O o M° M°
S(:IIEMP; II
ngo N
o ~ ~ n~o one Fro ol-I
nc0 Onc r (1.5 equiv.) ~, O NaOMe L O
O lute nc0~~0 N~ _ nc0 I-10~~0 N\
toluene, 11o~C N~ ~~ / Me0F1 N
N3 Br 45min p' J 3 O
Me Me 63"/
LiCI
ng0 N\
n~o ono ~ ~ n~o ono t-to olo O ~ (1.5 equiv.) nc0 O NaOMe FIO
nc0 CI Me -_ MeOFi Na toluene, 110"C N3 O N~
I r, r poi o I ~
r Me Me SCIII:!,lli II I
t1 ~ ~, '~ ', ::) ' ~4 i ~ rd -y-_o rt0! f, -rI'slfp pn 11p s~ pT
pl TIOr1 MeOTI + n 1 ,2 -ROI-1 1 bans p' 'r'' o w T(Qr1 Me Tf011 li f O N
O l .-O +
N 11p _._ Tlip ~~l ' pl1 ~
~
~ IZOIf p ~ sr~2 - iike pn , - Me ' Me Me 1,2 - cis nNOMCmznTioN
-riot-I
p ~r~o ~ p ~ ~ - on rlp--fl~
~ s T so _ __ rT O I-1 _ OI1 5~~2 _ olT
o O N like N ~~ ~
1 Jl ip ~J
p p 1,2 . - traps Me Me rnm.I: xv1 OEi OAc h-10'_~~ 1. MaOTf ( 0.1 equiv.) O
Ii0 O N\ , ~ ~ ~~~0 NI-IAc /~ CI-I~N02/ Iso-Pr01-t ~lyAc O / rt, 5min 2. Ac:zO / Py o~~ly ~3, 83%
Llo or I Ago one 1. NIeOTf ( 0.2 equiv.) ~ O
HO O N~ . Aco~~--o rreAc ~ c~yNO2/ISO-r~rol-~ Ne-IAA
't, 5min 2. Ac?o / Py only (3, 88%
I'nlll,l: XIX
l''p -~ :'1 ;'3 i'7 w3 y ,i f~ .~_ 5." ',.' ~~ :.F .SL
OII ~OAc (' OII ~OA_c to nc0-'N-", MeOTf (0.2 e<lulv.) IIO--r1-O nco~
110 LO N nc0-'~'~O N -s I10~-?~ ~- Ac0-~7~0 of o~ ~ Onc O~~ Cll,rlOz/lso-f rOli(1:1) 0l1 ~ one rt, 5mln M" ht" not observed Reactive Unreactive oll on~
rlo~ o~ n~o-~.~ 0 IWo rl n~o~-~-~-o F!
0l1 ~ ono / o /
Me Mo f10 OII Ac0 Onc ~O~ ~- O
I10~0 N AcO~'~O N
011 i Onc / /
(7~ O
Mo A1e IIO Ofl nc0 Onc I~< O' '< ,O
FIO~O N~ At0~7~~0Y N
F!~ I N~ 1I '1J
O
n Mn F.lc 1'n111,F: XX
TfOi-i (2.0 equiv.) DMF, rt, 15 - 20rniy on n~o ol-I ,~ one o do ° o tlh0'-'~O~ Nw -y nc0~~~0 N\ - I10 Nlinc nc0~~0 N\
NI inc ~ / N3 ~ / t'Ic O O O
Me Me Me 1.0 equiv. 10 equiv. 65 - 70°0 TfOi-I (2.0 equiv.) DMF, rt, 30min ola Ino on one flo oll nco O O N F nc0~~.0 N\ - - FiO~~ncO ~O
f 10 ~~ ~ ~ ~t I NHnc ' ~O N\
Nlinc ~ / ~ N
O O O
Me Me Me 1.0 equiv, 10 equ v. 61 TAIiI,rv XV I I ' ~~~ ~~~~114~
-r .,9. ;,~ xlt L~ .~,'~
Of I Onc .O
I IOC~O N MeOTf (0.2 equiv.) ' n~20~ / I'Y ~ ~~~ 19%
Nllnc I ~ C;I1~NOZ,r1,10min N O
p ~., f 13 i Me II tit O~ N
OI-I
O
Me MeOTf ( 0.2 equiv.) E 10 O nc2O / f'y II -IIN+ O
1' C rl3 R
R~-O ~OI-) ono R~
O R-t-O
o~,o n o~~ o ~0 0 / I i. Nllnc R, R = Cycloliexylidene I~IX~ , then nc?o / r'y R R
( 14 equiv.) 6d°~o 1AI1I,1~. XVIII
--t- 0 Ol i O~ O
(10 equiv.) O O
or-t ~ Necover the excess O f-1 HO O NO~.-O
FIC~O N\ I10 ~ O -~- ~ - anomer oIJ ~~ 1 MeOTf(0.2 equiv.) ce o CI-13N0?, rt, l5min o o M a 61 % ~O
4~ : ~1 ~° ~~ d~~ :'~ ~;~ :.n ,rt , ~ '~ !.
b. _u. ~,, ~! ;.i ~ a . .
beta products were obtained in 83 and 88o yield respectively, Table XVI.
DISACCHARIDE SYNTHESIS
The 2-acetamido-2-deoxy-beta-D-glucopyranosyJ. MOP
donor was treated first with MeOTf ( c) . 2 eq. ) in CH3NOz, at room temperature for 10 minutes, fol_Lowed addit.i.on of 14 eq, of 1,2-3,4 di-O-cyclohexylidenyl-D- galactopyranose acceptor with a free 6-hydroxyl, then acetic anhydride-pyridine, which gave 68% of the peracetylated ra~at~.a disaccharide, Table XVII. When the perhydr.~c~xy nluc:osyl beta MOP donor was similarly treated, with -the equivalent 1,2-3,4 di-O-isopropylidene-D- galactopyranose acceptor without subsequent peracetylation, t)ze reaction gave 610 yield of the disaccharide with 4:1 a_Lpha:beta ratio, Table XVIII.
In the absence of the acceptor -the oxazoline derivative can be isolated, Table XV:III.
Treating unprotected and peracetylated beta MOP
acceptors in the presence of MeOTf (~0.2 eq.) in CH3N02/iPrOH for 5 minutes, Table XIX, showed the unprotected gluco-, galacto- and 2-azido-2-deoxygalacto donors gave alpha products, while peracetylated donors gave no observable products, and were considered unreactive.
Gluco- and galacto- 2-acetamido-2-deoxypyranosyl beta MOP donors were each treated with 10 eq. of beta MOP, 2-azido-2-deoxy, 3,4, di-O-acetyl galacto-pyranoside acceptor with a free 6-hydroxyl, in the presence of 2.0 eq. TfOH, in DMF. 15-20 minutes at room temperature in the gluco case gave E.5-70% yield of pure beta 1,6-disaccharide, while 30 minutes in the galacto case gave 610 of pure beta 1,6-disaccharide, Table XX.
.., ,e -~ r ; :~ 1 ~ .c A a t,' v ~. ~ ;u -'.
Consideration of the results so far led to three proposed schemes for iterative oligosaccharide synthesis, Scheme IV, in which an active donor is coupled with an inactive donor as acceptor to give a disaccharide. The latent donor is then activated either by change c~f leaving group (1), activation of leaving group (3), or change of substituent (2), and the process repeated with another acceptor. As shown only beta linkages a-re present, although as those skilled in the az°t would understand alpha linkages can be generated routinely in such syntheses.
One such synthesis is indicated, Table XXI starting using the 2-acetamido--2-deoxy-D-glucopyranosyl MOP donor of Table XX, and forming the same beta disaccharide in 70% yield, which is then reduced peracetylated to its diacetamidohomolog, deprotected to form an active donor and coupled with l0 eq. of the same acceptor, in the presence of 2 eq. TfOH in DMF, for 20 minutes at room temperature, then peracetylated to give the beta trisaccharide in 34% yield, which can be further optimized.
In a close variation on the immediately preceding synthesis, the identi<~al disaccharide is prepared, deprotected and treated with 0.5 eq..MeOTf, CH3NOZ/iPrOH, at room temperature for 9 hours followed by peracetylation, to gi~,re the isopropyl derivative of the disaccharide in 66% yield, alpha: beta. 17:1, Table XXII.
ACTIVATION OF O-ACYL PROTECTED GLYCO~~YL MOP DONORS FOR
BETA-GLYCOSIDE SYNTHESIS - COPPER TRI:FLATE ACTIVATOR
O-acyl protected 1,2-trans MOP c~lycosyl donors are coupled with glycoside acceptors containing a single free hydroxyl, using Cu(OTf)z (2 eq.), CHZClz solvent at room temperature for 2 to 8 h, gave beta 1_inked D-glyco-w:af:n~e tv c~ .q t, r-3 ~) :~ .~
i .~. ~,. ~'~._7 ;j/ i J .~
n'livm° x ~n:,n9° Y la x ,.,..o ~~-o .r-o , o _ 1. no :.--~x no ~.% ~r -a._ '~~° o ~r _ no"~--,1~°'~'~-l,x no oorron nccEpron .v o FiO~~~Y ncllvnle X
E.'tC. ~_ _ _ _ _ _ _ _ nO ~O~--~O ~Y
ncllvoln donor ~O chsngo n' Io n ~O ~~ ~O~ ~
~.O ~O ~-O ~ --~- nD v~0 ~X
2. no :fix -F no ~-~-x --~ no :~-~° or"~'x ~ on o n' ooNOn nccsr~ron .v o Ilow~-~.'x ~ ocllvnledonor On O O O
BtC. -y- _ _ _ _ _ _ _ nOW.~ ~-x On OR
O ncllvnle X ~O oelivale Y O y0 110 ~Y nO v-~ y~0 ~Z
3. no ~ x ~ ~ w no :~°''~Y '~ i.- ~ o ." o ooNOn nccenTOn llo~'.--J-z etc.
I'nfll,fi XXI
TIOH(2.0 oquiv.) pM'', It, 15 - 20min of l nco of /of 1. tlZ, Pd / C. EtOF1 I10~ ~O' 'O'~ 2. ncp0 / Py ~~ O nc0 I O~O~ rJ ~~ O W 10 rJl Jnc nc0 '~O N
-' MTInc~ O I / N~ I / rJ~ O I /
O
Me ~I° Me 1.0 equiv. 10 equiv.
nc0 JFI
nc0~ O
~O~
Ns II
O /
Onc OI I 01.1 10 AqnIW Ma Onc O
nco~o- NaOMo l Me0li l~~p~/~o~,o N
nco Nllnc nco o N ~ Nnn' ~J -rJl Inc NI Inc ~I 1 TIOI-1 (2 equlv.) O ( / O/v DMf-, rl, 20m1n r.>, a rrt n one «nc ncO~o-~O Onc nc O / r nc ~ '~0 Y Nllnc n'(7. O
Nli~nc0 J) O rJ
N~
O /
M°
f ~rnnl,I: x x r W' ''~
~.r .S. ',J 1.' ~ i-J ..~
TtOH (2.0 equiv.) 011 Onc or{ nco on DMF, ri, 15 - 20rnin 11p-~I)--< n O
HO~O~ N + ncO~~p N\ -~- F-i0 NHnc n"O~O N
F 1 --~~ ~/ ''''''0 Nhinc ~ \ Na ~ / 70% N~
O / O O /
Me hfe Me 1.0 equiv. 10 equiv.
pr1 0~1 1. MeOTf (0.5 equiv.), rt ~~Onc Onc NaOMe / Me01-I h ~O~IiO CI-l3NOz/iso-PrOH, 9h nc02'~o o-~O nc0 T~
h1o Nhlnc h~o Lo - ~- iut~nc nco N~ ~ 2. n~?o / r~y N3 U
pY
rvie 66%
cx:(3=17:1 Tnllt,l: XXII I
Bz0' OBz Bz0 OBz ~ODn ~~O N Cu(OTf)z (2 equiv.) Bz0 w Bz0 OBz ~ / ROf! / CHZC12, rt E3h OBz BO~
O «?B~ COI Me Me E35%
Bz0 OBz Bz0 OBz O Cu(OTI)2 (2 equiv.) O ~OBn Bz0 ~~O N~ Bz0 ~~0~"O
flOf 1 / Ct hClz, rl, 2h OBz nll0 NI
OBz ~
~ OMe O
r Me 69%
OTBDMS OTBDMS
B O N Cu(OT()? (2 equiv.) ~d _ O
OBz ~ / f101i / CtI?CIz, rt, 2h OBzBBO~ O
r O OB~ Me Me 60%
lAlil.l? XXI\1 c3 ~ ~ ~~ ~ ;.a ;
h W
j , i ~ a l on on n0 ~n 2 edniv nO
) ~n rt Me0 i I (0 ~ rr . ~
, + (1- anorner . ~ on on C11~N0~/iso-i'r011() <y U i ~ 1 : 1 ht~
ol, Time a ; (1 Yield(%) o n oll ~ <5rnin 8 : 1 o hire ,01F,C)MS
_~~
-oa I~
~
~ 20rT~in 9 : 1 84 u' ~' I ~
rr, <o~rm r' ~
(~r o rr. 1 h 5 : 1 88 on I ~
M
<O~II
~~oo~o N 2h only a 95 on., ' o M r~
<O,D~n "~o~o 5h only a 85 rr' IT
~' o ' rae CAIILI: XXV
OBn OBn O gn0 ~O~
Oli gn0 O O N~ -t- ~ I O _ rvteOTt (0.2 equiV.)r pgn0~0 -t- ~) - anomer gn Oen ~~ , \~ Et?O, rt, 2hh O
O' J ° ° G6%
r ~ OXO
Me 1.5 equiv.
5.7 : 1 OBn OBn OI-I Bn0 O
Bno ° o ~~ o MeoTt (0.2 equiv.) osn~ .,. ~ - anomer BnC-'~ I N~ -F ~~ Et7O, rt, 20h O O
Ogn O~ O~c OMe 64%
Me O~c C)Me 1.5 equiv.
5.1 : 1 a ~i g~l''~:
i'-. _~_ ~J 1.~ ~~ ;.~ _?
rnnl.e xxvt ,oo~, on., nc of I ' u~,o X1.,-0 ~~,os B~~o~o N + n~o~~o N M~OTf (0.5 equiv.) _ o~n _ n~ -a- (~ - anorner E120.JrtQ 151t nc0(~O tJ
r tJ 7 Mo Mo (11 Me 1.5 eqnid.
4.5 : 1 OOn OI I ~n0 L
O~n ezoyo N MeOTf (0.5 equiv.) ,~o" + (3 - anomer r3no~o N ~ ~
Bn0 ~ + ~'o Opr I / EIzO / CF-IzCIZ(4:1 ) aio~0 N
OBn / rt, 3h ezo-~7''' 47% 013z Mo ' p Mo 0.5 equiv rnnt,e xxvtt 6 : 1 OEIn onn of I nno~C~
O o N + ~O Cu(OTf)2 (1.0 ecluiv.) t3n0- p~
o~,o~~~ ~ n':o~ 121, nro~'o + ~ - anorner Itno n,.o ~ EtzO, rt, OUn ~ / Onc OMo 75% n ~ Mo Mo 5.a : 1 or3n orm of O o N , c~(o-tf)2 (t.o ocJui~.) r~~,o"~o -+- cx - anomer ~ ~ r ono-B~~o~ , ncoy o~n n~o~~
r7n0 Onn I nc0~ ~ ~ ~ CFI~CN, ri, t5 rain nc0 Onc. OMo 67 % Onc OMo Mo 2.6 : i Of3n Of3i, Cu(orf), (t.o e~uiv.) ,~ , + (3 - anorner a"o o N -~- ~no en~ ~ E1~0, cl,oloslorol Bn0 OOn Br' ~ rt, 3.5h O
7E3'o Me 4 . 1 ~OBn OBn BnO~~''O
OI I Bn0 Br,o-~ ° + n~o ~° CrJ(oTf)2 (i.o e~ufv.) _ oe~ + (3 -anomer eno~T~ ~ ~
OBn nc nc0' ' =
O N one oMA ElzO, 4l1 MS, rt, 2larnln nc --''~~ ~_o 73% Onc~ Me i 4.3 : 1 Me ~ ~i 61 i~ C ~ P
(.J .k. ~.: ._~ v_i ~,t _...
pyranosyl disaccharides in 60-85o yie)_d, Table XXIII.
A number of D-glucopyranoside beta MOP donors unprotected, protected by 6-O-TBDMS, 3,4,6-O-benzyl, 2,3,4-O-benzyl and 2,3,4,6-O-benzyl were treated with MeOTf (0.2 eq) in CH3N02/iPrOH, at room temperature, the yields varied from 76-95%. with alpha: beta ratios from 5:1 to 1000 alpha. Reaction time and alpha proportion tended to increase with total bulk of protecting groups, Table XXIV.
GLYCOSIDE SYNTHESIS WITH O-ETHER PROTECTED GLYCOSYL MOP
DONORS
Perbenzylated glucopyranosyl beta MOP donor was treated in the presence MeOTf 0.2 eq., in ether at room temperature with 1.5 eq. of 6-hydroxy acceptors protected with isopropylidene, and acetyl groups, for 24 and 20 hours respectively to give 66% yield of 5.7:1 alpha: beta and 64% yield of 5:1 alpha: beta Table XXV.
Perbenzylated glucopyranosyl beta MOP donor was treated in the presence of MeOTf 0.5 eq., in ether at room temperature, 15 h, with 1.5 eq. of 6-hydrox.y diacetyl azidodeoxy glucopyranosyl beta MOP latent donor as acceptor, to give 55% yield of 4.5:1 alpha:beta. The same donor was treated in the presence MeOTf 0.5 eq., in ether/CHzCl2 at room temperature, 3 h, with 1.5 eq. of 6-hydroxy tribenzyl glucopyranosyl beta MOP latent donor as acceptor, to give 47% unoptimized yield of disaccharide alpha: beta 6:1 Table XXVI.
Perbenzylated glucopyranosyl beta MOP donor was treated in the presence of Cu(OTf)2 1.0 eq., in ether at room temperature, 12 h, with methyl 2;,3,4, tri-O-acetyl beta-D-glucopyranoside as acceptor, t:o give 75o yield of disaccharide, alpha:beta 5.8:1. The same reaction in a W ~ 'O
., .~ J ~J .~
CH3CN in 7_5 minutes gay%e 67% yield alpha: beta 1:2.6, favoring a beta-glycosidic linkage in this solvent.
Perbenzylated glucopyranosvl beta P~"IOl? donor was treated with Cu(OTt)2 1.0 eq., in ether at room temperal.ure, 3.5 h, with cholesterol acceptor, to givf= 78% yield, alpha : beta 4 : 1 . Perbenzylated gl_ucopyrano.sy7_ a.l.pha MOP
donor was treated with Cu(OTf)z 1.0 e~q., in ether at room temperature, 20 min, 4A MS , wi L:h methyl 2 , 3 , ~1-wt:zv. - U-acetyl-a1_pha-D-glucopyranoside as acceptor, to ~_l~_ve 73 yield of disaccharide alpha: beta 4.3:1, TaJal~ X:XV1I.
Perbenzylated 2-az ido-2-deoxy-galactopyrarr.!:»;y7_ beta MOP donor was treated with Cu (O'ff) 2 1.. 2 eq. , in C~3ZClz at room temperature, 6 h, with methyl 2,3,4--tri-O-acetyl-alpha-D-glucopyranoside acceptor, to give 90% yield of disaccharide, alpha: beta 3.2:1. The same reaction with Cu (OTf ) 2 2 . 2 eq. , in CH~CN i.n 12 h gave 60 0 ~,ri_eld c~f disaccharide, alpha: beta 1:2.6 Tab~.e XXZ'III.
Perbenzylated 2-azido-2.-deoxy-g:3lactopyranosyl alpha MOP donor was treated with Cu (OTf ) 2 1_ . 2 eq. , in CHzr~7.2 at room temperature, 30 min, with the following: 6-hydroxy, 3-hydroxy, 4-hydroxy, and 2-hydroxy methyl glycoside acceptors combining a variety of O a:nd N protective groups, Table XXIX, u.>hich gave respe~~tively 85% yield of disaccharide (alpha:~~eta 3:1), 53% yield (100% a~.ph~), 63o yield (alpha:bata. 6:i), and 48% yield (alpha: beta 4.2:7_) .
Per_benzylated glucopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room temperature, 8 h, with r:~,ethyl 3-O-ac«tyl--4,6-O-benzylidene-alpha-D-glucapyranoside as acceptor to give yield 45% of disaccharide, alpha: beta 2.4:1.
Per_benzylated glucopyra.r,osyl beta MOP donor ( 1.. 5 e;~ . ) was treated wi th Cu (OTf ) 2 1 eq. , in CH,C7.~/~ther ( I. : 4 ) at room temperature, 15 h, and methyl 2-O--Gcetyl-4,6-O-r benzylidene-alpha-D-glucopyranoside acceptor to give yield 60% of disaccharide, alpha: beta 10:1.
Perbenzylated glucopyranosyl beta MoP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHzCl2 at room temperature, 9 h, with methyl 2,3,6 tri-O-benzyl alpha-D-glucopyranoside acceptor to give yield 50% of disaccharide, alpha:beta 2:1, Table X:~X.
Perbenzylated galactopyranosyl b<~ta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room temperature, 6 h, with 3-0-acetyl 4,6-O-benzylidene-alpha-D-glucopyranoside acceptor to give yield 85% of disaccharide, alpha 1000. Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room temperature, 7 h, and methyl 2-O-acetyl-4,6-benzylidene-alpha-D-glucopyranoside acceptor to give yield 600 of disaccharide, alpha 100%. Perbenzylated galactopyranosyl beta MOP donor (1.5 ~eq.) was treated with Cu(OTf)z 1 eq., in CHZC12 at room temperature, 24 h, with methyl 2,3,6 tri-O-benzyl alpha-D-glucopyranoside as acceptor to give yield 60% of disaccharide, alpha 100%
Table XXXI. Perbenzylated galactopyranosyl beta MOP
donor (1.5 eq.) was treated with Cu(O'Tf)z 1 eq., in CHZCIz at room temperature, 9 h, and methyl 4,6-O-benzylidene-2-benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside acceptor to give yield 45% of disaccharide, alpha 100%.
Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf)z 1 eq., in CHZC12 at room temperature, 15 h, and methyl 2,3,4-tri-O-acetyl alpha-~D°-glucopyranoside acceptor to give yield 85% of the disaccharide, alpha: beta 3:1, Table XXXII. In the same table is shown treatment of the MOP 1,4 2,3,4,6-O-tetracetyl-beta-D-galactopyranosyl-4,6-O-isopropylidenyl-2-azido-2-deoxy-alpha-galactopyranoside with benzyl-N-benzoylserine, in CHzClz, 4A MS, in the presence of Cu(OTf)z to give 82% yield, alpha: beta 4:1.
2b i'~ '~ 3~i s !
r n a r, n x x v r 1 t s, :;. .. L, t.~ f"r .
~np .OBn ril,o or3n ~o olr O C - Cu(OTf)z (t.2 Bc)uiv.) C~nO
/° N~ v n~o~ __ ~ ry O -+- (3 - anorner nc0 Onc CHzCl7; rt, 6h nco'~'~' O
On ~~''110 ° OMe 90 % ncO
Me Onc Orvte 3.2 : t ftn0 OE3n ~n0 .OE3n Cn(OTr)2 (2.2 ec~uiv.) ono ° N + ° - ono ~°~ + a - anorner nco O
nc0 Oncl CH3CN, ri, 12h N, A OO
p OMe EO % ~ Me Ma 2.6 : 1 vnnLr; xxtx Bn0 OBn ~
Bn0 OBn OII Cn(OTI)z Bn0-'-N
O y (1.2 eynlv.)o i. ~i - ~norner ~
~ O '~ CI-lzClz, nc0~
tJ., Onc r1.30min !
OS" 0 o O~ pr~n , w / O!\c OMe O 3 . 1 hr"
Bn0 OBn f'h~O FI, OO
p ~ Cu(OTI)z O v (1.2 eqniv.)rJ
l NL
Bn0 to -- - O
I ItJL OMq CIiyClp, H
fl, 53 OMo % Bn0-rJ f -O
o O N Z
OnC
OBn /
only (7 MS
Bn0 OOn ~
~
B"O OBn /OBn Crl(Tr)? -O O (1.2 E?ytliv.)BnO
l 00 ' j ~ i- (~ - anomer ~ 0 0~-1 cl ycl,, u, sa %
No OBnOMo OBnOMe rr / 6 t Me Bn0 OBn Bn0 OBn of r Cn(Oli)z OBn B Ph~O~ O (1.2 eyniv.) O~ -E O'~ ~ r!
---n ~ o ~ , cl I,c:lz, F,,-~-O ~ +~ (3 - anomer 'T~1~ uMo rf. ~o~o rlo / ~ Mn Me 4.2 t t~ ~ 1~, I~ r1 a E .~
TnItI.I, XXx (.~ -~. ~ ~x E... ~:
Ph O
Ac0 Cu(0E1)z (1 equiv.) OgnO OMe Bn0 O N PI~~ ~ ~ Bn0 J
DoC~ ~ r. ~O 1 CII~CI~ , Ell. , r.l. B"~ O + ~- anomer ODn ~ / OII C,Me ~5°~ OBn O
Me 2.~1 : 1 (1.5 equiv.) OBn PrW ~ O
O
BnU'='~O N PIWO'~O Cu(OTI)Z (t equiv.) Bn0 OBnO Ac~
ar,o ~ F o~ oMe ogn ~ ~ Elo Aco ~ cn~Cl~m~o (l:n) Bno_l G GMA ,~h. , r.t. + (3- anomer ogn Me 60 (1.5 equiv.) l(~' 1 ~ : 1 OBn < ~ OBn Bn0'~~~O~N\ fi0~0 Cu(OTf)~ (1.5 equiv.~_ OBn Bno ''~ ''' ~ + y-- anomer Bno'~~
Ogn I / r Bn0 ~ CI IzCi~ , 91~. , r.l. pn0 go O Bn0 OMe 50 % OBn O O
i Me . gn (1.5 equiv.) E3nG OMe 2 : 1 rnm,l: xxxE
Phi ~O
Bn0 ODn Ac0 O Cu(OTr)z (tequiv.)~ Ogn~~OMe ~~~ r'Iy0 O - Bn0 Bn0 ~~O N~ r. O O
oBn I n~~~ Cr IzCh , sh. , r.L
0 0l f on>le °5'° Bno ogn Mo ONLY Ct (1.5 equiv.) Bn0 OBn Phi' l_< - p ~~O N PIyO'~O Cu(OTf)2 (1 ~quiv.) Ogre Ac0 Bn0 ~~ ''' ~ U --i.- BnO 7 OMe ODn O~~ v FIO-/1~~1 CrhCh , 7h. , r.t.
OMe 60 % Bn0 Ogn (1.5 equiv.) Me ONLY OC
Dn0 ODn O N OBn Cu(OT-I)~ (1.5 ec,uiv.) Bn0 ODn Bn0 I ~ l-f0-~ -w-ODn r- Bn0 Cr-IzCh , 2~1~. , r.l. Bn0 ~ OBn Dn0 OMe 60 % OBn O O
Me (1.5 equiv.) Dn0 Bn0 OMo ONLY (7:
4') ~! r'R t1 "'r . v a r: .J a 1'~.UI,I' XXXII
an0 Oan Ph''~O
O ---''~''// ''\~~' O O N Ph O Cu 01( 1 ecuiv. OanO~
an0 ~~ ~ ~ O ( )z ( I ),.- an0 1-INZ OMe OBn O ~ / r I-IC'~ CrIzClz , 9h. , r.t. an0 I INZ OMo 45'o Oan (1.5 ecJuiv.) M~
ONL',' a' an0 Oan Oan O N ~ OI-f Cn(OTI)z (J.2 equiv.) ano ~ n~o~~ -~ ,~~ + (3- anomer oar, ' , I eno nCo CI IzCIZ , IJ11. , f.l, anp O ~ ~~O OMe F35 ~ Oan (1.5 equiv.) Mo nc0 O
AcC
nc0 OMe 3 : 1 ' c-r .i ~ (l r) :::
E~~ !. ~,.' ~j ~. I~J
In summary the 2-(3-methoxy)-pyridyl MOP beta-D-hexopyranosides, exemplified by analogs in the D-gluco-, D-galacto- and their 2-azido-2-deoxy variants (~L,2-trans MOP glycosides) with hydroxyl acceptors, (alcohols and carbohydrates) in suitable solvents dive primarily alpha products (1,2-cis products) in the presence of MeOTf as promoter, in catalytic proportion, five other related leaving groups did not. MOP (3-methoxypyridyl-2-oxy) was shown superior (shorter) in reaction time to 2-oxypyridyl, and 4-methoxypyridyl-2-o}:y, although closely similar in yield and alpha proportion. The unprotected beta 2-acetamido MOP glycosides gave exclusively beta products under similar conditions. The peracetylated MOP
glycosides were unreactive as glycosyl donors. Ether protected equivalents were reactive as donors to give alpha products, in the presence of Cu(OTf)Z. Increasing degree of protection lengthened reaction time and increased alpha proportion. Perbenzylated beta MOP
glycosides gave alpha disaccharide products. Solvent dependency was noted, water miscible alcohols may be used as solvent and donor with excellent results, apart from this coincidence, the solvent is fairly critical CH3N02, CHzCl2, and ether, gave satisfactory to excellent results for alpha glycosides while CH3CN, favored the formation of beta-glycosides.
NUCLEOSIDE SYNTHESIS USING MOP GLYCOS YL DONORS
In a further development MOP leaving group? have been utilized to prepare nucleosides.. Clinically relevant nucleosides including AZT, used in the treatment of AIDS are shown in Table XXXIII. prior syntheses of 1,2 cis-pyrimidine nucleosides in Table XXXIV, using hemiacetal sugar acetates with trimei~hylsilyl substituted ethyl and butyl uracils, and of 1,2 i~rans-pyrimidine nucleosides in Table XXXV, where thymine derivatives are similarly prepared from thiophenyl hc~miacetals.
c3 ~ !.1 r ,! ,,~, : ~ '~
GN ~ l.° .r ~;~ ra .~
Perbenzylated galactopyranosyl beta MOP donor is allowed to react with trimethylsilyl uracil, thymine and cytosine in THF and toluene at room temperature using TMSOTf promoter, Table XXXVI, to give the expected beta-D-galactopyranosyl nucleosides in 55 to 95% yield with alpha: beta ratios of 6 to 9:91 to 94, showing excellent stereocontrol. Perbenzylated furanosyl nucleosides were prepared from trimethylsilyl thymine, Table XXXVII, uracil, Table XXXVIII, and cytosine, Table XXXIX, and MOP
perbenzylated furanosides, from inspection generally best yields and highest alpha proportion are obtained using toluene. Table XL shows a synthetic route to thymidines.
In a related development solid state oligosaccharides can prepared via MOP glycosides. The iterative process involves bonding of a MOP glycoside to a benzyl moiety on a resin support, the fixed glycoside is then allowed to react with an acetylated (inactive) MOP glycoside forming a stereospecific linkage. The acetate is then saponified and the process repeated, Table XLI. Details of the base strategy, Table XLII, first experiment, Table XLIII, and test recovery of unchanged MOP glycoside, Table XLIV are shown. Test effects using coupled glucopyranosyl MOP donor, CH3N02/iPrOH acceptor and MeOTf promoi~er, and changing the solvent are shown in Table XLV, yields vary from 40 to 100%, while alpha: beta ratios vary from 7.6 to 5:1.
Preparation of a disaccharide using a similar process is shown, Table XLVI. An enhanced coupling procedure using S-pyridyl thioester, is demonstrated, Table XLVII, while preparation of the resin-sugar linking precursor' is indicated, Table XLVIII.
The idea of using 2-pyridyl carbonate as donor, was tested, showing reasonable yields and. alpha-beta ratios, G~ -~ ~'3 ~ r? :" y q .i ~J v.' i J ..~.
while the equivalent phenyl carbonate was inactive under similar conditions, Table XLIX.
The concept of using the equivalent thiocarbonate is shown, Table L, the preparation of a number of such syntheses thiocarbonate donors, hereinafter TOPCAT, is shown, Table LI, these compounds are all crystalline, stable, 1,2 - trans isomers. TOPCAT perbenzyl alpha-D-glucopyranoside donor was tested with. methyl 2,3,4-tri-O-acetyl alpha-d-glucopyranose, using as promoters 1.2 eq.
Cu(OTf)2 and 2 eq. AgOTf in ether and CHZC12, and then reacted in excess (1.5 eq.) with various glycosides and AgOTf (3 eq.), Table LII, yields of 40 to 80% with alpha:beta ratios of 4:1 to 1.5:1 were noted. The concept was further explored using TOPCAT alpha--D-galactopyranosyl, alpha-L-fucopyrano~,yl, and 1,2-trans glycosyl donors, the promoter was AgOTf, the solvent CHZC12, effectuated by 4 A MS, yields from 46 to 83% were obtained with alpha: beta ratios of 8:1 to 100% alpha, Table LIII.
Pursuing the concept further, it: was demonstrated that it was possible to couple TOPCAT glycosyl donors, to a variety of MOP glycosyl donors, as acceptors, to produce potential disaccharide MOP donors, with AgOTf promoter, and either CHzCl2 or CHzClZ-~ather, yields from 54 to 74%, with alpha-beta ratios of 3:1. to 11:1, Table LIV.
The products can obviously be utilized both as themselves and as precursors in later syntheses.
A scheme for such synthetic is indicated, wherein PG
means protecting group, showing coupling of TOPCAT donor with MOP acceptor, and further reactions, specific details of oligosaccharides of interest are also shown, Table LV.
~a .~ ~ ~ , ". ; ~
,, Practical employment of such approaches are shown indicating preparation of TN-antigen type O-serine glycoside using TOPCAT and a related MOP synthesis, preparation of T-antigen type O-serine glycoside via a TOPCAT disaccharide, and a similar but different MOP
approach, for comparison the conventional approach is also shown, with its inferior qualitative yield, of alpha stereoisomer, Table LVI.
An additional development reacting trimethylsilyl pyrimidine acceptors with TOPCAT pyranosyl donors produces pyranosyl nucleosides, in good yield and alpha: beta ratios of 1:1 or better, Table LVII, and with a purine acceptor, Table LVIII. Arabinofuranosyl nucleoside preparation is detailed, Table LIX, while ribofuranosyl nucleoside preparation. is similarly detailed, Table LX. By inspection those skilled in the art can appreciate that both yields and stereospecificity are more than satisfactory.
A further demonstration of MOP and TOPCAT
versatility and elegance, is shown by the syntheses of Lex structures by MOP, Table LXI, and TOPCAT, Table LXII, both showing excellent yield and stE:reospecific:ity.
The overall synthetic scope of the invention is generally indicated, without such indication being restrictive or limiting in scope or application, Table LXIII.
In one broad aspect the invention is directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O--pyranosyl <~nd O-furanosyl glycosides, with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent. The improvement provides a donor is selected from the group consisting of glycosides substituted by y .~ G 1, 11 . 1 ~~
i _e_ 1J 0.r ~.r~ ld . ~?,.
leaving groups X of formula I and re7_ated heterocyclic bases:
., y (.1 !~ J
FORMULA I
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms. The promoter is selected from t~.he group consisting of MeOTf, TfOH, BF3, Cu(OTf)Z, ZnCl.?, and other acids, Lewis acids and chelating metals. ~rhE~ :~alvent a.s selected from the group consisting of CH3N02, and CHzCl2, EtzO, CH3CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
Preferably the donor is an O-pyranosyl gl.yc:ostde, the promoter is selected from the group consisting of MeOTf, TfOH, BF3, Cu(OTf)Z, and ZnClz, and trio solvent is selected from the group consisting of CH3NOZ, and CHzClz, EtzO, CH3CN, DMF and THF, and mixture~> thereof .
More preferably the donor is selected from the group consisting of glycosides of formula R.X wherein x: has formula I and related heterocyclic structures, and R has formula II, -~~,r--\~.
~~1- ~ ;.y, y FORMULA II
wherein R2 is azido, acyloxy of 2 to 6 carbon atoms, acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to ~'V .~ F ~ ,.7 ,:~ >
G. _',_ ~..~.._i ~_= .,a .:
carbon atoms, or a_Lkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are: independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R. The promoter is selected from the group consisting of MeOTf, TMSOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2, while the solvent is selected from the group consisting~~ of CH3N02, CHZClz, Et20, CH3CN, DMF, and THF and mixture; thereof .
Conveniently the the acceptor i~, selected i.'rom the group consisting of R'OH, wherein R' is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl of 1 to 27 carbon atoms, including N-substituted amino-~alcohols and S-substituted thio-alcohols, esters of alkanols of. 1 to 10 carbon atoms with hydroxyalkanoic acids of 2 to 6 carbon atoms, esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 7_0 carbon atoms, and glycosides of formula R"Y, wherein R" has formula III, ~cS
FORMULA III
containing at least one unprotected alcoholic hydroxyl, where Y is selected from the group cons~_st:ing of: alkoxy of 1 to 5 carbon atoms and X, R7 is a.zido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylc:arboxy of i' to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, alkenyloxy of 1 to 5 carbon atoms, ac:yloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of: 1 to 10 spy ~~;9~e I-. .; ~,.~ v_~ .r i..~
carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy o:~ 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of '7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and :R7 may together be alkylidenyldioxy of 3 to ~3 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms, or R8 and R9 may together be alkylidenyldioxy o:f 3 to 9 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms or R9 and R10 arylalkylidenyldioxy of 7 to 10 carbon atoms or R7, R8, R9, R.10 may be R or )2".
Most preferably X is 3-methoxy-pyridyl-2-oxy. The process may be considered as two distinct groups depending on whether the X group is alpha or beta on the pyranosyl ring. In the beta case R has formula IV, while in the alpha case R has the formula V.
v~ ) FORMULA IV (BETA) i ~ ~' ;, I': ~~ ' ~ /
r :-FORMULA V (ALPHA) In the alpha case, R2, is azido, arylalkoxy of 7 to carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms. The :promoter is Cu(OTf)z.
The solvent is selected from the group consisting of CHZClz, Et20, and mixtures thereof . The acceptor is selected from the group consisting of glycosides of formula R"Y, containing at least one unprotected :, ~9, .~
I~~mY ~ V ~ ~ YJ _~.
alcoholic hydroxyl, wherein Y is alko:xy of 1 to 5 carbon atoms, R7 is hydroxy, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of. 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, acyloxy of 2 to 6 carbon atoms arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of '7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 and R10 may together be aralkylidenyldioxy of 7 to 10 carbon atoms.
In another aspect the process may be applied to unprotected donors wherein R2, R3, and R4 are independently hydroxy, arylalkoxy of '7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, arylalkoxy of '7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or trialkylsiJ.oxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5 may be R, and at least one of R2, R3, R4 and R5 is hydroxyl. The promoter is selected from the group consisting of MeOTf, T1!~SOTf, BF3, Cu(OTf)Z, and ZnClz. The solvent is selected from the group consisting of CH3NOZ, CHzCl2, CH3CN, and THF and mixtures thereof. The acceptor may be selected from the group consisting of alkanols, alkenols and ~~ycloalkanols of 1 to 6 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y and R7 together are alkylid~snyldioxy of 3 to 9 carbon atoms, R8 and R9 together are alkylidenyldioxy of 3 to 9 carbon atoms. More preferably wherein R2, R3, R4 and R5 are hydroxyl, that it is the donor is unprotected.
In a further aspect protecting groups may be provided by ethers, in which case R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10 carbon atoms. The promoter is selected from the group consisting of MeOTf, and Cu(OTf)2. The solvent is ~~~ IAl~ll~~'a F. r_ ,. ,_ ;_3 a:~ n selected from the group consisting of CH3NOz, CHzCl2, EtZO, and CH3CN and mixtures thereof. PrefE:rably the acceptor is selected from the group consisting of alkanols of 1 to carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is selected from the group consisting of alkoxy of 1 to 5 carbon atoms and 3-methoxy-pyridyl-2-oxy, R7 is ,azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylca:rboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 t.o l0 carbon atoms, R8 is hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 'i to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R9 and R10 may together aralkylidenyldioxy of 7 to 10 carbon atoms.
In a further aspect the protecting groups may be esters, here R2, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy o:f 7 to 10 carbon atoms, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, and trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R. The promoter is Cu(OTf)2, and the solvent is CHzClz. In this case the acceptor is preferably a glycoside of formula R"Y, containing at least one unprotected alcoholic hydro:icyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is arylalkoxy of 7 to carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is alkenyloxy of 1 to 5 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is :hydroxyl, ~l s S > n, 'o s~
;.") ;,~
arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10 carbon atoms, R10 is hydroxyl, arylal:koxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms.
In a further aspect when an aminosugar or precursor is being prepared when the precursor function is acylamino, then R2 is acylamino of 2 to 5 carbon atoms, R3, R4 and R5 are hydroxyl. The promoter is selected from the group consisting of MeOTf, and TfOH. The solvent is selected from the group consisting of CH3NOz and DMF and mixtures thereof. Preferably the acceptor is selected from the group consisting of alkanols of 1 to carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is 3-methoxy-pyridyl-2-oxy, R7 is azido, R8 is acyloxy of 2 to 6 carbon atoms, R9 is acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms.
In a further aspect when an aminosugar or precursor is being prepared when the precursor function is azido, then R2 is azido, R3, is arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or R wherein R2, R3, R4, and R5 are acyloxy of 2 to 6 carbon atoms, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, or R4 and R5 together are alkylidenyldioxy of 3 to 9 carbon atoms. The promoter is Cu(OTf)2, while the solvent is selected from the group consisting of CHZC12, and CH3CN and mixtures thereof.
Preferably the acceptor is selected from the group consisting of esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is acyloxy of 2 to 6 i.. a. '_: a '_~% ~ r carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxyl, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or hydroxyl, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl or acyloxy of 2 to 6 carbon atoms, or R9 and R10 aralkylidenyldioxy of 7 to 10 carbon atoms.
The invention additionally encompasses an improved a process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including a trialkylsilyl ether of a pyrimidine, in the presence of a promoter and a solvent. The improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
~~~~.n FORMULA I
where A is N, or CH, and Rl is H or alkoxy of 1 to 5 carbon atoms. The promoter is TMSOTf, and other acids, Lewis acids and chelating metals. The solvent i.s selected from the group consisting of toluene, benzene, dioxane, CHZClz, Et20, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
Preferably the donor is an O-pyranosyl or O-furanosyl glycoside, of formulae II or VI, and the trialkyl silyl pyrimidine ether has formula VII.
~~ ~~ LT ~ J
n r7 / l_, ) i ~ ,I.
IO ,_ FORMULA II
i,~~
s./
\ ,,.,v~~ ~'~
\\ /
,.T
~, ~~ I 0 ~I~
FORMULA VI
~ ~ ~\
,c~~
;; _~~ v ~a_~~~
\- \ , /.___ FORMULA VII
wherein R2, R3, R4, and R5 are arylal.koxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms. Most preferably R2, R3, R4, R5, R11, R12 are benzyloxy, R11 is hydrogen or benzyloxy, R13 is trimethylsiloxy, R14 is trimethylsiloxy or benzamido, R15 is hydrogen or methyl.
The invention is further directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent.
The improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
'~''~ 4~ra'>"~
x Gr _d. ~~ "~,' '~ G,f ~J ..., i vl \
i, v '\ 1 FORMULA I
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms. The prcmoter is selectcad from the group consisting of MeOTf, 'ffOH, BF3, Cu(OTf)z, ZnClz, and other acids, Lewis acids and chelating meta:Ls. The solvent is selected from the group consisting of CH3NOZ, and CHzCl2, Et20, CH3CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof. The glycoside is coupled to a supporting resin by a coupling group integral to the resin, and a linking ~=_lement bonded to coupling group and the glycoside. Pr~=_ferably the coupling group is phenylenemethylamine, the linking element is a dicarboxylic acid residua forming an amido bond with the coupling group and an eater bond with the glycoside. More preferably the glycoside comprises a plurality of saccharide units.
In a further aspect the invention is directed to an improved process of glycoside synthesis comprising reaction of a donor selected from 0-pyranosyl and O-furanosyl glycosides, with an acceptor including an lcoholic hydroxyl, in the presence of a promoter and a solvent. The improvement comprising selecting the donor from the group consisting of glycosides substituted by leaving groups of formula VIII:
-iC~.~ ~~~ \
~J~
FORMULA VIII
where B is O or S. The promoter is selected from the group consisting of MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ~~ ~~t ~ ! 1 G' 't i , k f.i .a. '~ ': ._ ZnClz, and other acids, Lewis acids and chelating metals, The solvent is selected from the group consisting of CH3NOZ, and CHZC12, EtzO, CH3CN, DMF, THF, and other solvents of like polarity and dipole :moment and mixtures thereof. When the donor is an O-pyra:nosyl glycoside, the promoter is selected from the group consisting of AgOTf and Cu(OTf)z, the solvent is selected from the group consisting of CH3NOz, and CHzCl2, Et20, CH3CN, DMF and THF, and mixtures thereof. When the donor is selected from the group consisting of glycosides of formula IX wherein Z has formula VIII, T
3 w__~
i\ .~ L
FORMULA IX
then R2 is acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R. 'The promoter, is selected from the group consisting of AgOTf, and Cu(OTf)2.
The solvent is selected from the group consisting of CH3NOz, CHzClz, EtzO, CH3CN, DMF, and TF-(F and mixtures thereof.
When the donor is selected from the group consisting of glycosides of formula X wherein Z has formula VIII, c'~ .~ r'~ n :'o ~2 S / ' ~%'~~'L~-2;t y '~
FORMULA X
then R2, R3 and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5 is alkyl of 1 to 5 carbon atoms. Then the promoter is selected from the group consisting of AgOTf, and Cu(OTf)z, the solvent is selected from the group consisting of CH3NOz, CH2C12, Et20, CH3CN, DMF, and THh and mixtures thereof.
When the acceptor is selected from the group consisting of glycosides of formula RX wherein X has formula I and related heterocyclic structure, and R has the formula II
~,_n/.
U
i ~ , v,~i I
/ \ / ~, 1~ ~ , ,;
,w FORMULA I
/ /, c,, i;~v ~2? ' FORMULA II
then A is N, or CH, and R1 is H or alk.oxy of 1 to 5 carbon atoms, R2 is azido, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 t.o 10 carbon atoms, R3, and R4 are independently ydroxy, a.cyloxy of 2, to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atom~~, arylalkoxy of 7 to 10 carbon atoms, or' alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy.
~ ; ~~.'1,~~~
~.. ~. a ~ :J .~
In a further development the invention is directed to an improved process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including a trialkysilyl pyrimidine ether, in the presence of a promoter and a solvent, the improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups of formula VIII:
'7 ,% ~J \
(I
FORMULA VIII
where B is O or S. The promoter is selected from the group consisting of TriSOTf, MeOTf, TfOH, BF3, AgcJTf, Cu(OTf)2, ZnCl2, and other acids, Lewis acids and chelating metals. The solvent is selected from the group consisting of toluene, THF, and other solvents of like polarity and dipole moment and mixtures thereof. When the donor is an O-pyranosyl or O-furanosyl glycoside, of formulae IX, X, or XI, and the trialkyl silyl pyrimidine ether has formula VII
-.,1 C _~; /~ __ t ~ /' 11 ,-~ ~ __ 1 ~...1~;, FORMULA VII
/y LZ ~~,,,~~.,;r:~~~ ° ~~\
P~-, FORMULA IX
,_ \\ ,i~~~Li.jLil i / L.-_ _i' __ /; ~ o LG
FORMULA X
,~~., ,~ -~~=
_., r: . , ~'- ~~~ i ~ i ,.,, FORMULA XI
wherein R2, R3, R4, and R5 are arylalk:oxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atom:, R11 and R12 are arylal~:oxy of 7 to 10 carbon atoms, or alkoxy of 1 to .LO carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independent=ly of 1 to 5 carbon atoms, or acylamino of 7 t;o 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms,, and Z
has formula VIII.
In a further development the invention is directed to an improved process of nucleoside :synthesis comprising reaction of a donor: selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an acylated purine in the presence of bromine or a :like oxidiser, and a solvent, the improvement comprising the donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
__ ( ~ ., - , _, ' ~~ U l, ~ ~i FORMULA VIII
where B is O or S. The solvent is selected from the group consisting of DMF and other solvents of_ like polarity and dipole moment and mixtures thereof.
Preferably the purine is 6-benzoyl adenine.
EXPERIMENTAL DETAILS
The above noted examples and il7_ustrations are illustrative only in nature and not limiting.
The novel compounds of the present invention have utility as intermediates in the production of other compounds and as well have utility to those known glycosides but with improved results.
As those skilled in the art would realize these preferred illustrated details can be subjected to substantial variation, modification, change, alteration, and substitution without affecting o:r modifying the function of the illustrated embodiments.
This invention is not limited to the embodiments described above, and it will be apparent to persons skilled in the art that numerous modifications and variations form part of the present invention insofar as they do not depart from the spirit, nature and scope of the claimed and described invention.
Bno ° o ~~ o MeoTt (0.2 equiv.) osn~ .,. ~ - anomer BnC-'~ I N~ -F ~~ Et7O, rt, 20h O O
Ogn O~ O~c OMe 64%
Me O~c C)Me 1.5 equiv.
5.1 : 1 a ~i g~l''~:
i'-. _~_ ~J 1.~ ~~ ;.~ _?
rnnl.e xxvt ,oo~, on., nc of I ' u~,o X1.,-0 ~~,os B~~o~o N + n~o~~o N M~OTf (0.5 equiv.) _ o~n _ n~ -a- (~ - anorner E120.JrtQ 151t nc0(~O tJ
r tJ 7 Mo Mo (11 Me 1.5 eqnid.
4.5 : 1 OOn OI I ~n0 L
O~n ezoyo N MeOTf (0.5 equiv.) ,~o" + (3 - anomer r3no~o N ~ ~
Bn0 ~ + ~'o Opr I / EIzO / CF-IzCIZ(4:1 ) aio~0 N
OBn / rt, 3h ezo-~7''' 47% 013z Mo ' p Mo 0.5 equiv rnnt,e xxvtt 6 : 1 OEIn onn of I nno~C~
O o N + ~O Cu(OTf)2 (1.0 ecluiv.) t3n0- p~
o~,o~~~ ~ n':o~ 121, nro~'o + ~ - anorner Itno n,.o ~ EtzO, rt, OUn ~ / Onc OMo 75% n ~ Mo Mo 5.a : 1 or3n orm of O o N , c~(o-tf)2 (t.o ocJui~.) r~~,o"~o -+- cx - anomer ~ ~ r ono-B~~o~ , ncoy o~n n~o~~
r7n0 Onn I nc0~ ~ ~ ~ CFI~CN, ri, t5 rain nc0 Onc. OMo 67 % Onc OMo Mo 2.6 : i Of3n Of3i, Cu(orf), (t.o e~uiv.) ,~ , + (3 - anorner a"o o N -~- ~no en~ ~ E1~0, cl,oloslorol Bn0 OOn Br' ~ rt, 3.5h O
7E3'o Me 4 . 1 ~OBn OBn BnO~~''O
OI I Bn0 Br,o-~ ° + n~o ~° CrJ(oTf)2 (i.o e~ufv.) _ oe~ + (3 -anomer eno~T~ ~ ~
OBn nc nc0' ' =
O N one oMA ElzO, 4l1 MS, rt, 2larnln nc --''~~ ~_o 73% Onc~ Me i 4.3 : 1 Me ~ ~i 61 i~ C ~ P
(.J .k. ~.: ._~ v_i ~,t _...
pyranosyl disaccharides in 60-85o yie)_d, Table XXIII.
A number of D-glucopyranoside beta MOP donors unprotected, protected by 6-O-TBDMS, 3,4,6-O-benzyl, 2,3,4-O-benzyl and 2,3,4,6-O-benzyl were treated with MeOTf (0.2 eq) in CH3N02/iPrOH, at room temperature, the yields varied from 76-95%. with alpha: beta ratios from 5:1 to 1000 alpha. Reaction time and alpha proportion tended to increase with total bulk of protecting groups, Table XXIV.
GLYCOSIDE SYNTHESIS WITH O-ETHER PROTECTED GLYCOSYL MOP
DONORS
Perbenzylated glucopyranosyl beta MOP donor was treated in the presence MeOTf 0.2 eq., in ether at room temperature with 1.5 eq. of 6-hydroxy acceptors protected with isopropylidene, and acetyl groups, for 24 and 20 hours respectively to give 66% yield of 5.7:1 alpha: beta and 64% yield of 5:1 alpha: beta Table XXV.
Perbenzylated glucopyranosyl beta MOP donor was treated in the presence of MeOTf 0.5 eq., in ether at room temperature, 15 h, with 1.5 eq. of 6-hydrox.y diacetyl azidodeoxy glucopyranosyl beta MOP latent donor as acceptor, to give 55% yield of 4.5:1 alpha:beta. The same donor was treated in the presence MeOTf 0.5 eq., in ether/CHzCl2 at room temperature, 3 h, with 1.5 eq. of 6-hydroxy tribenzyl glucopyranosyl beta MOP latent donor as acceptor, to give 47% unoptimized yield of disaccharide alpha: beta 6:1 Table XXVI.
Perbenzylated glucopyranosyl beta MOP donor was treated in the presence of Cu(OTf)2 1.0 eq., in ether at room temperature, 12 h, with methyl 2;,3,4, tri-O-acetyl beta-D-glucopyranoside as acceptor, t:o give 75o yield of disaccharide, alpha:beta 5.8:1. The same reaction in a W ~ 'O
., .~ J ~J .~
CH3CN in 7_5 minutes gay%e 67% yield alpha: beta 1:2.6, favoring a beta-glycosidic linkage in this solvent.
Perbenzylated glucopyranosvl beta P~"IOl? donor was treated with Cu(OTt)2 1.0 eq., in ether at room temperal.ure, 3.5 h, with cholesterol acceptor, to givf= 78% yield, alpha : beta 4 : 1 . Perbenzylated gl_ucopyrano.sy7_ a.l.pha MOP
donor was treated with Cu(OTf)z 1.0 e~q., in ether at room temperature, 20 min, 4A MS , wi L:h methyl 2 , 3 , ~1-wt:zv. - U-acetyl-a1_pha-D-glucopyranoside as acceptor, to ~_l~_ve 73 yield of disaccharide alpha: beta 4.3:1, TaJal~ X:XV1I.
Perbenzylated 2-az ido-2-deoxy-galactopyrarr.!:»;y7_ beta MOP donor was treated with Cu (O'ff) 2 1.. 2 eq. , in C~3ZClz at room temperature, 6 h, with methyl 2,3,4--tri-O-acetyl-alpha-D-glucopyranoside acceptor, to give 90% yield of disaccharide, alpha: beta 3.2:1. The same reaction with Cu (OTf ) 2 2 . 2 eq. , in CH~CN i.n 12 h gave 60 0 ~,ri_eld c~f disaccharide, alpha: beta 1:2.6 Tab~.e XXZ'III.
Perbenzylated 2-azido-2.-deoxy-g:3lactopyranosyl alpha MOP donor was treated with Cu (OTf ) 2 1_ . 2 eq. , in CHzr~7.2 at room temperature, 30 min, with the following: 6-hydroxy, 3-hydroxy, 4-hydroxy, and 2-hydroxy methyl glycoside acceptors combining a variety of O a:nd N protective groups, Table XXIX, u.>hich gave respe~~tively 85% yield of disaccharide (alpha:~~eta 3:1), 53% yield (100% a~.ph~), 63o yield (alpha:bata. 6:i), and 48% yield (alpha: beta 4.2:7_) .
Per_benzylated glucopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room temperature, 8 h, with r:~,ethyl 3-O-ac«tyl--4,6-O-benzylidene-alpha-D-glucapyranoside as acceptor to give yield 45% of disaccharide, alpha: beta 2.4:1.
Per_benzylated glucopyra.r,osyl beta MOP donor ( 1.. 5 e;~ . ) was treated wi th Cu (OTf ) 2 1 eq. , in CH,C7.~/~ther ( I. : 4 ) at room temperature, 15 h, and methyl 2-O--Gcetyl-4,6-O-r benzylidene-alpha-D-glucopyranoside acceptor to give yield 60% of disaccharide, alpha: beta 10:1.
Perbenzylated glucopyranosyl beta MoP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHzCl2 at room temperature, 9 h, with methyl 2,3,6 tri-O-benzyl alpha-D-glucopyranoside acceptor to give yield 50% of disaccharide, alpha:beta 2:1, Table X:~X.
Perbenzylated galactopyranosyl b<~ta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room temperature, 6 h, with 3-0-acetyl 4,6-O-benzylidene-alpha-D-glucopyranoside acceptor to give yield 85% of disaccharide, alpha 1000. Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf)2 1 eq., in CHZClz at room temperature, 7 h, and methyl 2-O-acetyl-4,6-benzylidene-alpha-D-glucopyranoside acceptor to give yield 600 of disaccharide, alpha 100%. Perbenzylated galactopyranosyl beta MOP donor (1.5 ~eq.) was treated with Cu(OTf)z 1 eq., in CHZC12 at room temperature, 24 h, with methyl 2,3,6 tri-O-benzyl alpha-D-glucopyranoside as acceptor to give yield 60% of disaccharide, alpha 100%
Table XXXI. Perbenzylated galactopyranosyl beta MOP
donor (1.5 eq.) was treated with Cu(O'Tf)z 1 eq., in CHZCIz at room temperature, 9 h, and methyl 4,6-O-benzylidene-2-benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside acceptor to give yield 45% of disaccharide, alpha 100%.
Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf)z 1 eq., in CHZC12 at room temperature, 15 h, and methyl 2,3,4-tri-O-acetyl alpha-~D°-glucopyranoside acceptor to give yield 85% of the disaccharide, alpha: beta 3:1, Table XXXII. In the same table is shown treatment of the MOP 1,4 2,3,4,6-O-tetracetyl-beta-D-galactopyranosyl-4,6-O-isopropylidenyl-2-azido-2-deoxy-alpha-galactopyranoside with benzyl-N-benzoylserine, in CHzClz, 4A MS, in the presence of Cu(OTf)z to give 82% yield, alpha: beta 4:1.
2b i'~ '~ 3~i s !
r n a r, n x x v r 1 t s, :;. .. L, t.~ f"r .
~np .OBn ril,o or3n ~o olr O C - Cu(OTf)z (t.2 Bc)uiv.) C~nO
/° N~ v n~o~ __ ~ ry O -+- (3 - anorner nc0 Onc CHzCl7; rt, 6h nco'~'~' O
On ~~''110 ° OMe 90 % ncO
Me Onc Orvte 3.2 : t ftn0 OE3n ~n0 .OE3n Cn(OTr)2 (2.2 ec~uiv.) ono ° N + ° - ono ~°~ + a - anorner nco O
nc0 Oncl CH3CN, ri, 12h N, A OO
p OMe EO % ~ Me Ma 2.6 : 1 vnnLr; xxtx Bn0 OBn ~
Bn0 OBn OII Cn(OTI)z Bn0-'-N
O y (1.2 eynlv.)o i. ~i - ~norner ~
~ O '~ CI-lzClz, nc0~
tJ., Onc r1.30min !
OS" 0 o O~ pr~n , w / O!\c OMe O 3 . 1 hr"
Bn0 OBn f'h~O FI, OO
p ~ Cu(OTI)z O v (1.2 eqniv.)rJ
l NL
Bn0 to -- - O
I ItJL OMq CIiyClp, H
fl, 53 OMo % Bn0-rJ f -O
o O N Z
OnC
OBn /
only (7 MS
Bn0 OOn ~
~
B"O OBn /OBn Crl(Tr)? -O O (1.2 E?ytliv.)BnO
l 00 ' j ~ i- (~ - anomer ~ 0 0~-1 cl ycl,, u, sa %
No OBnOMo OBnOMe rr / 6 t Me Bn0 OBn Bn0 OBn of r Cn(Oli)z OBn B Ph~O~ O (1.2 eyniv.) O~ -E O'~ ~ r!
---n ~ o ~ , cl I,c:lz, F,,-~-O ~ +~ (3 - anomer 'T~1~ uMo rf. ~o~o rlo / ~ Mn Me 4.2 t t~ ~ 1~, I~ r1 a E .~
TnItI.I, XXx (.~ -~. ~ ~x E... ~:
Ph O
Ac0 Cu(0E1)z (1 equiv.) OgnO OMe Bn0 O N PI~~ ~ ~ Bn0 J
DoC~ ~ r. ~O 1 CII~CI~ , Ell. , r.l. B"~ O + ~- anomer ODn ~ / OII C,Me ~5°~ OBn O
Me 2.~1 : 1 (1.5 equiv.) OBn PrW ~ O
O
BnU'='~O N PIWO'~O Cu(OTI)Z (t equiv.) Bn0 OBnO Ac~
ar,o ~ F o~ oMe ogn ~ ~ Elo Aco ~ cn~Cl~m~o (l:n) Bno_l G GMA ,~h. , r.t. + (3- anomer ogn Me 60 (1.5 equiv.) l(~' 1 ~ : 1 OBn < ~ OBn Bn0'~~~O~N\ fi0~0 Cu(OTf)~ (1.5 equiv.~_ OBn Bno ''~ ''' ~ + y-- anomer Bno'~~
Ogn I / r Bn0 ~ CI IzCi~ , 91~. , r.l. pn0 go O Bn0 OMe 50 % OBn O O
i Me . gn (1.5 equiv.) E3nG OMe 2 : 1 rnm,l: xxxE
Phi ~O
Bn0 ODn Ac0 O Cu(OTr)z (tequiv.)~ Ogn~~OMe ~~~ r'Iy0 O - Bn0 Bn0 ~~O N~ r. O O
oBn I n~~~ Cr IzCh , sh. , r.L
0 0l f on>le °5'° Bno ogn Mo ONLY Ct (1.5 equiv.) Bn0 OBn Phi' l_< - p ~~O N PIyO'~O Cu(OTf)2 (1 ~quiv.) Ogre Ac0 Bn0 ~~ ''' ~ U --i.- BnO 7 OMe ODn O~~ v FIO-/1~~1 CrhCh , 7h. , r.t.
OMe 60 % Bn0 Ogn (1.5 equiv.) Me ONLY OC
Dn0 ODn O N OBn Cu(OT-I)~ (1.5 ec,uiv.) Bn0 ODn Bn0 I ~ l-f0-~ -w-ODn r- Bn0 Cr-IzCh , 2~1~. , r.l. Bn0 ~ OBn Dn0 OMe 60 % OBn O O
Me (1.5 equiv.) Dn0 Bn0 OMo ONLY (7:
4') ~! r'R t1 "'r . v a r: .J a 1'~.UI,I' XXXII
an0 Oan Ph''~O
O ---''~''// ''\~~' O O N Ph O Cu 01( 1 ecuiv. OanO~
an0 ~~ ~ ~ O ( )z ( I ),.- an0 1-INZ OMe OBn O ~ / r I-IC'~ CrIzClz , 9h. , r.t. an0 I INZ OMo 45'o Oan (1.5 ecJuiv.) M~
ONL',' a' an0 Oan Oan O N ~ OI-f Cn(OTI)z (J.2 equiv.) ano ~ n~o~~ -~ ,~~ + (3- anomer oar, ' , I eno nCo CI IzCIZ , IJ11. , f.l, anp O ~ ~~O OMe F35 ~ Oan (1.5 equiv.) Mo nc0 O
AcC
nc0 OMe 3 : 1 ' c-r .i ~ (l r) :::
E~~ !. ~,.' ~j ~. I~J
In summary the 2-(3-methoxy)-pyridyl MOP beta-D-hexopyranosides, exemplified by analogs in the D-gluco-, D-galacto- and their 2-azido-2-deoxy variants (~L,2-trans MOP glycosides) with hydroxyl acceptors, (alcohols and carbohydrates) in suitable solvents dive primarily alpha products (1,2-cis products) in the presence of MeOTf as promoter, in catalytic proportion, five other related leaving groups did not. MOP (3-methoxypyridyl-2-oxy) was shown superior (shorter) in reaction time to 2-oxypyridyl, and 4-methoxypyridyl-2-o}:y, although closely similar in yield and alpha proportion. The unprotected beta 2-acetamido MOP glycosides gave exclusively beta products under similar conditions. The peracetylated MOP
glycosides were unreactive as glycosyl donors. Ether protected equivalents were reactive as donors to give alpha products, in the presence of Cu(OTf)Z. Increasing degree of protection lengthened reaction time and increased alpha proportion. Perbenzylated beta MOP
glycosides gave alpha disaccharide products. Solvent dependency was noted, water miscible alcohols may be used as solvent and donor with excellent results, apart from this coincidence, the solvent is fairly critical CH3N02, CHzCl2, and ether, gave satisfactory to excellent results for alpha glycosides while CH3CN, favored the formation of beta-glycosides.
NUCLEOSIDE SYNTHESIS USING MOP GLYCOS YL DONORS
In a further development MOP leaving group? have been utilized to prepare nucleosides.. Clinically relevant nucleosides including AZT, used in the treatment of AIDS are shown in Table XXXIII. prior syntheses of 1,2 cis-pyrimidine nucleosides in Table XXXIV, using hemiacetal sugar acetates with trimei~hylsilyl substituted ethyl and butyl uracils, and of 1,2 i~rans-pyrimidine nucleosides in Table XXXV, where thymine derivatives are similarly prepared from thiophenyl hc~miacetals.
c3 ~ !.1 r ,! ,,~, : ~ '~
GN ~ l.° .r ~;~ ra .~
Perbenzylated galactopyranosyl beta MOP donor is allowed to react with trimethylsilyl uracil, thymine and cytosine in THF and toluene at room temperature using TMSOTf promoter, Table XXXVI, to give the expected beta-D-galactopyranosyl nucleosides in 55 to 95% yield with alpha: beta ratios of 6 to 9:91 to 94, showing excellent stereocontrol. Perbenzylated furanosyl nucleosides were prepared from trimethylsilyl thymine, Table XXXVII, uracil, Table XXXVIII, and cytosine, Table XXXIX, and MOP
perbenzylated furanosides, from inspection generally best yields and highest alpha proportion are obtained using toluene. Table XL shows a synthetic route to thymidines.
In a related development solid state oligosaccharides can prepared via MOP glycosides. The iterative process involves bonding of a MOP glycoside to a benzyl moiety on a resin support, the fixed glycoside is then allowed to react with an acetylated (inactive) MOP glycoside forming a stereospecific linkage. The acetate is then saponified and the process repeated, Table XLI. Details of the base strategy, Table XLII, first experiment, Table XLIII, and test recovery of unchanged MOP glycoside, Table XLIV are shown. Test effects using coupled glucopyranosyl MOP donor, CH3N02/iPrOH acceptor and MeOTf promoi~er, and changing the solvent are shown in Table XLV, yields vary from 40 to 100%, while alpha: beta ratios vary from 7.6 to 5:1.
Preparation of a disaccharide using a similar process is shown, Table XLVI. An enhanced coupling procedure using S-pyridyl thioester, is demonstrated, Table XLVII, while preparation of the resin-sugar linking precursor' is indicated, Table XLVIII.
The idea of using 2-pyridyl carbonate as donor, was tested, showing reasonable yields and. alpha-beta ratios, G~ -~ ~'3 ~ r? :" y q .i ~J v.' i J ..~.
while the equivalent phenyl carbonate was inactive under similar conditions, Table XLIX.
The concept of using the equivalent thiocarbonate is shown, Table L, the preparation of a number of such syntheses thiocarbonate donors, hereinafter TOPCAT, is shown, Table LI, these compounds are all crystalline, stable, 1,2 - trans isomers. TOPCAT perbenzyl alpha-D-glucopyranoside donor was tested with. methyl 2,3,4-tri-O-acetyl alpha-d-glucopyranose, using as promoters 1.2 eq.
Cu(OTf)2 and 2 eq. AgOTf in ether and CHZC12, and then reacted in excess (1.5 eq.) with various glycosides and AgOTf (3 eq.), Table LII, yields of 40 to 80% with alpha:beta ratios of 4:1 to 1.5:1 were noted. The concept was further explored using TOPCAT alpha--D-galactopyranosyl, alpha-L-fucopyrano~,yl, and 1,2-trans glycosyl donors, the promoter was AgOTf, the solvent CHZC12, effectuated by 4 A MS, yields from 46 to 83% were obtained with alpha: beta ratios of 8:1 to 100% alpha, Table LIII.
Pursuing the concept further, it: was demonstrated that it was possible to couple TOPCAT glycosyl donors, to a variety of MOP glycosyl donors, as acceptors, to produce potential disaccharide MOP donors, with AgOTf promoter, and either CHzCl2 or CHzClZ-~ather, yields from 54 to 74%, with alpha-beta ratios of 3:1. to 11:1, Table LIV.
The products can obviously be utilized both as themselves and as precursors in later syntheses.
A scheme for such synthetic is indicated, wherein PG
means protecting group, showing coupling of TOPCAT donor with MOP acceptor, and further reactions, specific details of oligosaccharides of interest are also shown, Table LV.
~a .~ ~ ~ , ". ; ~
,, Practical employment of such approaches are shown indicating preparation of TN-antigen type O-serine glycoside using TOPCAT and a related MOP synthesis, preparation of T-antigen type O-serine glycoside via a TOPCAT disaccharide, and a similar but different MOP
approach, for comparison the conventional approach is also shown, with its inferior qualitative yield, of alpha stereoisomer, Table LVI.
An additional development reacting trimethylsilyl pyrimidine acceptors with TOPCAT pyranosyl donors produces pyranosyl nucleosides, in good yield and alpha: beta ratios of 1:1 or better, Table LVII, and with a purine acceptor, Table LVIII. Arabinofuranosyl nucleoside preparation is detailed, Table LIX, while ribofuranosyl nucleoside preparation. is similarly detailed, Table LX. By inspection those skilled in the art can appreciate that both yields and stereospecificity are more than satisfactory.
A further demonstration of MOP and TOPCAT
versatility and elegance, is shown by the syntheses of Lex structures by MOP, Table LXI, and TOPCAT, Table LXII, both showing excellent yield and stE:reospecific:ity.
The overall synthetic scope of the invention is generally indicated, without such indication being restrictive or limiting in scope or application, Table LXIII.
In one broad aspect the invention is directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O--pyranosyl <~nd O-furanosyl glycosides, with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent. The improvement provides a donor is selected from the group consisting of glycosides substituted by y .~ G 1, 11 . 1 ~~
i _e_ 1J 0.r ~.r~ ld . ~?,.
leaving groups X of formula I and re7_ated heterocyclic bases:
., y (.1 !~ J
FORMULA I
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms. The promoter is selected from t~.he group consisting of MeOTf, TfOH, BF3, Cu(OTf)Z, ZnCl.?, and other acids, Lewis acids and chelating metals. ~rhE~ :~alvent a.s selected from the group consisting of CH3N02, and CHzCl2, EtzO, CH3CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
Preferably the donor is an O-pyranosyl gl.yc:ostde, the promoter is selected from the group consisting of MeOTf, TfOH, BF3, Cu(OTf)Z, and ZnClz, and trio solvent is selected from the group consisting of CH3NOZ, and CHzClz, EtzO, CH3CN, DMF and THF, and mixture~> thereof .
More preferably the donor is selected from the group consisting of glycosides of formula R.X wherein x: has formula I and related heterocyclic structures, and R has formula II, -~~,r--\~.
~~1- ~ ;.y, y FORMULA II
wherein R2 is azido, acyloxy of 2 to 6 carbon atoms, acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to ~'V .~ F ~ ,.7 ,:~ >
G. _',_ ~..~.._i ~_= .,a .:
carbon atoms, or a_Lkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are: independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R. The promoter is selected from the group consisting of MeOTf, TMSOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2, while the solvent is selected from the group consisting~~ of CH3N02, CHZClz, Et20, CH3CN, DMF, and THF and mixture; thereof .
Conveniently the the acceptor i~, selected i.'rom the group consisting of R'OH, wherein R' is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl of 1 to 27 carbon atoms, including N-substituted amino-~alcohols and S-substituted thio-alcohols, esters of alkanols of. 1 to 10 carbon atoms with hydroxyalkanoic acids of 2 to 6 carbon atoms, esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 7_0 carbon atoms, and glycosides of formula R"Y, wherein R" has formula III, ~cS
FORMULA III
containing at least one unprotected alcoholic hydroxyl, where Y is selected from the group cons~_st:ing of: alkoxy of 1 to 5 carbon atoms and X, R7 is a.zido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylc:arboxy of i' to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, alkenyloxy of 1 to 5 carbon atoms, ac:yloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of: 1 to 10 spy ~~;9~e I-. .; ~,.~ v_~ .r i..~
carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy o:~ 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of '7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and :R7 may together be alkylidenyldioxy of 3 to ~3 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms, or R8 and R9 may together be alkylidenyldioxy o:f 3 to 9 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms or R9 and R10 arylalkylidenyldioxy of 7 to 10 carbon atoms or R7, R8, R9, R.10 may be R or )2".
Most preferably X is 3-methoxy-pyridyl-2-oxy. The process may be considered as two distinct groups depending on whether the X group is alpha or beta on the pyranosyl ring. In the beta case R has formula IV, while in the alpha case R has the formula V.
v~ ) FORMULA IV (BETA) i ~ ~' ;, I': ~~ ' ~ /
r :-FORMULA V (ALPHA) In the alpha case, R2, is azido, arylalkoxy of 7 to carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms. The :promoter is Cu(OTf)z.
The solvent is selected from the group consisting of CHZClz, Et20, and mixtures thereof . The acceptor is selected from the group consisting of glycosides of formula R"Y, containing at least one unprotected :, ~9, .~
I~~mY ~ V ~ ~ YJ _~.
alcoholic hydroxyl, wherein Y is alko:xy of 1 to 5 carbon atoms, R7 is hydroxy, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of. 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, acyloxy of 2 to 6 carbon atoms arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of '7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 and R10 may together be aralkylidenyldioxy of 7 to 10 carbon atoms.
In another aspect the process may be applied to unprotected donors wherein R2, R3, and R4 are independently hydroxy, arylalkoxy of '7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, arylalkoxy of '7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or trialkylsiJ.oxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5 may be R, and at least one of R2, R3, R4 and R5 is hydroxyl. The promoter is selected from the group consisting of MeOTf, T1!~SOTf, BF3, Cu(OTf)Z, and ZnClz. The solvent is selected from the group consisting of CH3NOZ, CHzCl2, CH3CN, and THF and mixtures thereof. The acceptor may be selected from the group consisting of alkanols, alkenols and ~~ycloalkanols of 1 to 6 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y and R7 together are alkylid~snyldioxy of 3 to 9 carbon atoms, R8 and R9 together are alkylidenyldioxy of 3 to 9 carbon atoms. More preferably wherein R2, R3, R4 and R5 are hydroxyl, that it is the donor is unprotected.
In a further aspect protecting groups may be provided by ethers, in which case R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10 carbon atoms. The promoter is selected from the group consisting of MeOTf, and Cu(OTf)2. The solvent is ~~~ IAl~ll~~'a F. r_ ,. ,_ ;_3 a:~ n selected from the group consisting of CH3NOz, CHzCl2, EtZO, and CH3CN and mixtures thereof. PrefE:rably the acceptor is selected from the group consisting of alkanols of 1 to carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is selected from the group consisting of alkoxy of 1 to 5 carbon atoms and 3-methoxy-pyridyl-2-oxy, R7 is ,azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylca:rboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 t.o l0 carbon atoms, R8 is hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 'i to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R9 and R10 may together aralkylidenyldioxy of 7 to 10 carbon atoms.
In a further aspect the protecting groups may be esters, here R2, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy o:f 7 to 10 carbon atoms, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, and trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R. The promoter is Cu(OTf)2, and the solvent is CHzClz. In this case the acceptor is preferably a glycoside of formula R"Y, containing at least one unprotected alcoholic hydro:icyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is arylalkoxy of 7 to carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is alkenyloxy of 1 to 5 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is :hydroxyl, ~l s S > n, 'o s~
;.") ;,~
arylalkoxy of 7 to 10 carbon atoms, o:r alkoxy of 1 to 10 carbon atoms, R10 is hydroxyl, arylal:koxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms.
In a further aspect when an aminosugar or precursor is being prepared when the precursor function is acylamino, then R2 is acylamino of 2 to 5 carbon atoms, R3, R4 and R5 are hydroxyl. The promoter is selected from the group consisting of MeOTf, and TfOH. The solvent is selected from the group consisting of CH3NOz and DMF and mixtures thereof. Preferably the acceptor is selected from the group consisting of alkanols of 1 to carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is 3-methoxy-pyridyl-2-oxy, R7 is azido, R8 is acyloxy of 2 to 6 carbon atoms, R9 is acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms.
In a further aspect when an aminosugar or precursor is being prepared when the precursor function is azido, then R2 is azido, R3, is arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or R wherein R2, R3, R4, and R5 are acyloxy of 2 to 6 carbon atoms, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, or R4 and R5 together are alkylidenyldioxy of 3 to 9 carbon atoms. The promoter is Cu(OTf)2, while the solvent is selected from the group consisting of CHZC12, and CH3CN and mixtures thereof.
Preferably the acceptor is selected from the group consisting of esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is acyloxy of 2 to 6 i.. a. '_: a '_~% ~ r carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxyl, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or hydroxyl, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl or acyloxy of 2 to 6 carbon atoms, or R9 and R10 aralkylidenyldioxy of 7 to 10 carbon atoms.
The invention additionally encompasses an improved a process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including a trialkylsilyl ether of a pyrimidine, in the presence of a promoter and a solvent. The improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
~~~~.n FORMULA I
where A is N, or CH, and Rl is H or alkoxy of 1 to 5 carbon atoms. The promoter is TMSOTf, and other acids, Lewis acids and chelating metals. The solvent i.s selected from the group consisting of toluene, benzene, dioxane, CHZClz, Et20, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
Preferably the donor is an O-pyranosyl or O-furanosyl glycoside, of formulae II or VI, and the trialkyl silyl pyrimidine ether has formula VII.
~~ ~~ LT ~ J
n r7 / l_, ) i ~ ,I.
IO ,_ FORMULA II
i,~~
s./
\ ,,.,v~~ ~'~
\\ /
,.T
~, ~~ I 0 ~I~
FORMULA VI
~ ~ ~\
,c~~
;; _~~ v ~a_~~~
\- \ , /.___ FORMULA VII
wherein R2, R3, R4, and R5 are arylal.koxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms. Most preferably R2, R3, R4, R5, R11, R12 are benzyloxy, R11 is hydrogen or benzyloxy, R13 is trimethylsiloxy, R14 is trimethylsiloxy or benzamido, R15 is hydrogen or methyl.
The invention is further directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent.
The improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
'~''~ 4~ra'>"~
x Gr _d. ~~ "~,' '~ G,f ~J ..., i vl \
i, v '\ 1 FORMULA I
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms. The prcmoter is selectcad from the group consisting of MeOTf, 'ffOH, BF3, Cu(OTf)z, ZnClz, and other acids, Lewis acids and chelating meta:Ls. The solvent is selected from the group consisting of CH3NOZ, and CHzCl2, Et20, CH3CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof. The glycoside is coupled to a supporting resin by a coupling group integral to the resin, and a linking ~=_lement bonded to coupling group and the glycoside. Pr~=_ferably the coupling group is phenylenemethylamine, the linking element is a dicarboxylic acid residua forming an amido bond with the coupling group and an eater bond with the glycoside. More preferably the glycoside comprises a plurality of saccharide units.
In a further aspect the invention is directed to an improved process of glycoside synthesis comprising reaction of a donor selected from 0-pyranosyl and O-furanosyl glycosides, with an acceptor including an lcoholic hydroxyl, in the presence of a promoter and a solvent. The improvement comprising selecting the donor from the group consisting of glycosides substituted by leaving groups of formula VIII:
-iC~.~ ~~~ \
~J~
FORMULA VIII
where B is O or S. The promoter is selected from the group consisting of MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ~~ ~~t ~ ! 1 G' 't i , k f.i .a. '~ ': ._ ZnClz, and other acids, Lewis acids and chelating metals, The solvent is selected from the group consisting of CH3NOZ, and CHZC12, EtzO, CH3CN, DMF, THF, and other solvents of like polarity and dipole :moment and mixtures thereof. When the donor is an O-pyra:nosyl glycoside, the promoter is selected from the group consisting of AgOTf and Cu(OTf)z, the solvent is selected from the group consisting of CH3NOz, and CHzCl2, Et20, CH3CN, DMF and THF, and mixtures thereof. When the donor is selected from the group consisting of glycosides of formula IX wherein Z has formula VIII, T
3 w__~
i\ .~ L
FORMULA IX
then R2 is acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R. 'The promoter, is selected from the group consisting of AgOTf, and Cu(OTf)2.
The solvent is selected from the group consisting of CH3NOz, CHzClz, EtzO, CH3CN, DMF, and TF-(F and mixtures thereof.
When the donor is selected from the group consisting of glycosides of formula X wherein Z has formula VIII, c'~ .~ r'~ n :'o ~2 S / ' ~%'~~'L~-2;t y '~
FORMULA X
then R2, R3 and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5 is alkyl of 1 to 5 carbon atoms. Then the promoter is selected from the group consisting of AgOTf, and Cu(OTf)z, the solvent is selected from the group consisting of CH3NOz, CH2C12, Et20, CH3CN, DMF, and THh and mixtures thereof.
When the acceptor is selected from the group consisting of glycosides of formula RX wherein X has formula I and related heterocyclic structure, and R has the formula II
~,_n/.
U
i ~ , v,~i I
/ \ / ~, 1~ ~ , ,;
,w FORMULA I
/ /, c,, i;~v ~2? ' FORMULA II
then A is N, or CH, and R1 is H or alk.oxy of 1 to 5 carbon atoms, R2 is azido, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 t.o 10 carbon atoms, R3, and R4 are independently ydroxy, a.cyloxy of 2, to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atom~~, arylalkoxy of 7 to 10 carbon atoms, or' alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy.
~ ; ~~.'1,~~~
~.. ~. a ~ :J .~
In a further development the invention is directed to an improved process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including a trialkysilyl pyrimidine ether, in the presence of a promoter and a solvent, the improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups of formula VIII:
'7 ,% ~J \
(I
FORMULA VIII
where B is O or S. The promoter is selected from the group consisting of TriSOTf, MeOTf, TfOH, BF3, AgcJTf, Cu(OTf)2, ZnCl2, and other acids, Lewis acids and chelating metals. The solvent is selected from the group consisting of toluene, THF, and other solvents of like polarity and dipole moment and mixtures thereof. When the donor is an O-pyranosyl or O-furanosyl glycoside, of formulae IX, X, or XI, and the trialkyl silyl pyrimidine ether has formula VII
-.,1 C _~; /~ __ t ~ /' 11 ,-~ ~ __ 1 ~...1~;, FORMULA VII
/y LZ ~~,,,~~.,;r:~~~ ° ~~\
P~-, FORMULA IX
,_ \\ ,i~~~Li.jLil i / L.-_ _i' __ /; ~ o LG
FORMULA X
,~~., ,~ -~~=
_., r: . , ~'- ~~~ i ~ i ,.,, FORMULA XI
wherein R2, R3, R4, and R5 are arylalk:oxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atom:, R11 and R12 are arylal~:oxy of 7 to 10 carbon atoms, or alkoxy of 1 to .LO carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independent=ly of 1 to 5 carbon atoms, or acylamino of 7 t;o 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms,, and Z
has formula VIII.
In a further development the invention is directed to an improved process of nucleoside :synthesis comprising reaction of a donor: selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an acylated purine in the presence of bromine or a :like oxidiser, and a solvent, the improvement comprising the donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
__ ( ~ ., - , _, ' ~~ U l, ~ ~i FORMULA VIII
where B is O or S. The solvent is selected from the group consisting of DMF and other solvents of_ like polarity and dipole moment and mixtures thereof.
Preferably the purine is 6-benzoyl adenine.
EXPERIMENTAL DETAILS
The above noted examples and il7_ustrations are illustrative only in nature and not limiting.
The novel compounds of the present invention have utility as intermediates in the production of other compounds and as well have utility to those known glycosides but with improved results.
As those skilled in the art would realize these preferred illustrated details can be subjected to substantial variation, modification, change, alteration, and substitution without affecting o:r modifying the function of the illustrated embodiments.
This invention is not limited to the embodiments described above, and it will be apparent to persons skilled in the art that numerous modifications and variations form part of the present invention insofar as they do not depart from the spirit, nature and scope of the claimed and described invention.
Claims (47)
1. In a process of glycoside or nucleotide synthesis involving the reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor selected from alcoholic hydroxyl containing acceptors and trialkylsilyl ethers of a pyrimidine acceptors, in which the reaction is carried out in the presence of a promoter or solvent, the improvement wherein said donor is substituted by leaving groups X of formula I, or related heterocyclic bases, where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms,.
2. The process of claim 1 wherein said promoter is selected from the group consisting of MeOTf, TfnH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals.
3. The process of claim 1 or 2, wherein said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF and mixtures thereof.
4. The process of claim 1, wherein the promoter is TMSOTf, Lewis acids and chelating metals.
5. The process of claim 1 or 4, wherein said solvent is selected from the group consisting of toluene, benzene, dioxane, CH2Cl2, Et2O, THF and mixtures thereof .
6. The process of claim 1, wherein the promoter is selected from the group consisting of MeOTf, TfOH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals; said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof; and wherein the glycoside is coupled to a supporting resin by a coupling group integral to said resin, and a linking element bonded to coupling group and said glycoside.
7. In a process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an alcoholic hydroxyl acceptor, in the presence of a promoter and a solvent, the improvement comprising said donor is selected from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, said promoter is selected from the group consisting of MeOTf, TfOH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, said promoter is selected from the group consisting of MeOTf, TfOH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
8. A process of claim 7 wherein said donor is an O-pyranosyl glycoside, said promoter is selected from the group consisting of MeOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
9. A process of claim 7 wherein said donor is selected from the group consisting of glycosides of formula RX wherein X has formula I, and R has the formula II
wherein R2 is azido, acyloxy of 2 to 6 carbon atoms, acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
wherein R2 is azido, acyloxy of 2 to 6 carbon atoms, acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to
10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R, said promoter is selected from the group consisting of MeOTf, TMSOTf, TfOH, BF3, Cu(OTf)2, and ZnCl2, said solvent is selected from the group consisting of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures thereof.
10. A process of claim 9, wherein said acceptor is selected from the group consisting of R'OH, wherein R' is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl of 1 to 27 carbon atoms, N-substituted amino-alcohols and S-substituted thio-alcohols, esters of alkanols of 1 to 10 carbon atoms with hydroxyalkanoic acids of 2 to 6 carbon atoms, esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, wherein R" has formula III, containing at least one unprotected alcoholic hydroxyl, where Y is selected from the group consisting of alkoxy of 1 to 5 carbon atoms and X, R7 is azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, alkenyloxy of 1 to 5 carbon atoms, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms or R9 and R10 arylalkylidenyldioxy of 7 to 10 carbon atoms or R7, R8, R9, R10 may be R or R".
10. A process of claim 9, wherein said acceptor is selected from the group consisting of R'OH, wherein R' is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl of 1 to 27 carbon atoms, N-substituted amino-alcohols and S-substituted thio-alcohols, esters of alkanols of 1 to 10 carbon atoms with hydroxyalkanoic acids of 2 to 6 carbon atoms, esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, wherein R" has formula III, containing at least one unprotected alcoholic hydroxyl, where Y is selected from the group consisting of alkoxy of 1 to 5 carbon atoms and X, R7 is azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, alkenyloxy of 1 to 5 carbon atoms, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or cycloalkylidenyldioxy of 5 to 10 carbon atoms or R9 and R10 arylalkylidenyldioxy of 7 to 10 carbon atoms or R7, R8, R9, R10 may be R or R".
11. A process of claim 9 wherein X is 3-methoxy-pyridyl-2-oxy.
12. A process of claim 9 wherein R has formula IV
and wherein R2, R3, R4, R5 and X are as defined in claim 9.
and wherein R2, R3, R4, R5 and X are as defined in claim 9.
13. A process of claim 9 wherein R has formula V
where R2, is azido, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, said promoter is Cu(OTf)2 said solvent is selected from the group consisting of CH2Cl2, Et2O and mixtures thereof, said acceptor is selected from the group consisting of glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is hydroxy, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to carbon atoms or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 and R10 may togeher be aralkylidenyldioxy of 7 to 10 carbon atoms.
where R2, is azido, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, said promoter is Cu(OTf)2 said solvent is selected from the group consisting of CH2Cl2, Et2O and mixtures thereof, said acceptor is selected from the group consisting of glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is hydroxy, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to carbon atoms or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 and R10 may togeher be aralkylidenyldioxy of 7 to 10 carbon atoms.
14. A process of claim 10 wherein R2, R3 and R4 are independently hydroxy, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5 may be R, and at least one of R2, R3, R4 and R5 is hydroxyl, selecting said promoter from the group consisting of MeOTf, TMSOTf, BF3, Cu(OTf)2, and ZnCl2, selecting said solvent from the group consisting of CH3NO2, CH2Cl2, CH3CN, and THF and mixtures thereof.
15. A process of claim 14 wherein said acceptor is selected from the group consisting of alkanols, alkenols and cycloalkanols of 1 to 6 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y and R7 together are alkylidenyldioxy of 3 to 9 carbon atoms, R8 and R9 together are alkylidenyldioxy of 3 to 9 carbon atoms.
16. A process of claim 14 wherein R2, R3, R4 and R5 are hydroxyl.
17. A process of claim 11 wherein R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, said promoter is selected from the group consisting of MeOTf, and Cu(OTf)2, said solvent is selected from the group consisting of CH3NO2, CH2Cl2, Et2O, and CH3CN and mixtures thereof.
18. A process of claim 17 wherein said acceptor is selected from the group consisting of alkanols of 1 to 5 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is selected from the group consisting of alkoxy of 1 to 5 carbon atoms and 3-methoxy-pyridyl-2-oxy, R7 is azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to l0 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R9 and R10 may together aralkylidenyldioxy of 7 to 10 carbon atoms.
19. A process of claim 11 wherein R2, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, and trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R, said promoter is Cu(OTf)2, said solvent is CH2Cl2.
20. A process of claim 19 wherein said acceptor is a glycoside of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is alkenyloxy of 1 to 5 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10 is hydroxyl, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms.
21. the process of claim 11 wherein R2 is acylamino of 2 to 5 carbon atoms, R3, R4 and R5 are hydroxyl, said promoter is selected from the group consisting of MeOTf, and TfOH, said solvent is selected from the group consisting of CH3NO2 and DMF and mixtures thereof.
22. A process of claim 21 wherein said acceptor is selected from the group consisting of alkanols of 1 to 5 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is 3-methoxy-pyridyl-2-oxy, R7 is azido, R8 is acyloxy of 2 to 6 carbon atoms, R9 is acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl, Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms, or R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms.
23. A process of claim 11 wherein R2 is azido, R3, is arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or R wherein R2, R3, R4, and R5 are acyloxy of 2 to 6 carbon atoms, R4 and R5 are arylalkoxy of 7 to carbon atoms, or alkoxy of 1 to 10 carbon atoms, or R4 and R5 together are alkylidenyldioxy of 3 to 9 carbon atoms, said promoter is Cu(OTf)2, said solvent is selected from the group consisting of CH2Cl2, and CH3CN and mixtures thereof.
24. A process of claim 23 wherein said acceptor is selected from the group consisting of esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 5 carbon atoms, R7 is acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxyl, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or hydroxyl, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl or acyloxy of 2 to 6 carbon atoms, or R9 and R10 aralkylidenyldioxy of 7 to 10 carbon atoms.
25. In a process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor of trialkylsilyl ether of a pyrimidine, in the presence of a promoter and a solvent, the improvement comprising said donor is selected from the group consisting of glycosides substituted by leaving groups X of formula I:
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, said promoter is TMSOTf, Lewis acids and chelating metals, said solvent is selected from the group consisting of toluene, benzene, dioxane, CH2Cl2, Et2O, THF, and mixtures thereof.
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, said promoter is TMSOTf, Lewis acids and chelating metals, said solvent is selected from the group consisting of toluene, benzene, dioxane, CH2Cl2, Et2O, THF, and mixtures thereof.
26. A process of claim 25 wherein said donor is an O-pyranosyl or O-furanosyl glycoside, of formulae II or VI, and said trialkyl silyl pyrimidine ether has formula VII
wherein R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms.
wherein R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms.
27. A process of claim 26 wherein R2, R3, R4, R5, R11, R12 are benzyloxy, R11 is hydrogen or benzyloxy, R13 is trimethylsiloxy, R14 is trimethylsiloxy or benzamido, R15 is hydrogen or methyl.
28. In a process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an alcoholic hydroxy acceptor, in the presence of a promoter and a solvent, the improvement comprising said donor is selected from the group consisting of glycosides substituted by leaving groups X of formula I:
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, said promoter is selected from the group consisting of MeOTf, TfOH, BF3 Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof and said glycoside is coupled to a supporting resin by a coupling group integral to said resin, and a linking element bonded to coupling group and said glycoside.
where A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, said promoter is selected from the group consisting of MeOTf, TfOH, BF3 Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof and said glycoside is coupled to a supporting resin by a coupling group integral to said resin, and a linking element bonded to coupling group and said glycoside.
29. A process of claim 28, wherein said coupling group is phenylenemethylamine, said linking element is a dicarboxylic acid residue forming an amido bond with said coupling group and an ester bond with said glycoside.
30. A process of claim 29, wherein said glycoside comprises a plurality of saccharide units.
31. A novel glycoside wherein the glycoside has a substituent selected from the group consisting of wherein R1 and A are as defined in claim 1;
wherein R2 R3, R4 and R5 are as defined in claim 9;
wherein R7, R8, R9, R10 and Y are as defined in claim 10;
wherein R2, R3, R4 and R5 are as defined in claim 9;
wherein R2, R3, R4 and R5 areas defined in claim 13;
wherein R10, R11 and R12 are as defined in claim 26;
or wherein R13, R14 and R15 are as defined in claim 26.
wherein R2 R3, R4 and R5 are as defined in claim 9;
wherein R7, R8, R9, R10 and Y are as defined in claim 10;
wherein R2, R3, R4 and R5 are as defined in claim 9;
wherein R2, R3, R4 and R5 areas defined in claim 13;
wherein R10, R11 and R12 are as defined in claim 26;
or wherein R13, R14 and R15 are as defined in claim 26.
32. In a process of glycoside or nucleoside synthesis involving the reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor selected from alcoholic hydroxyl, trialkylsilyl pyrimidine ether and acylated purine, in which the reaction is carried out in the presence of a promotor or oxidizer and a solvent, the improvement wherein said donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
where B is O or S.
where B is O or S.
33. The process of claim 32 wherein said promoter is selected from the goup consisting of MeOTf, TfOH, BF3, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals.
34. The process of claim 32 or 33 wherein said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
35. The process of claim 32 wherein said promoter is selected from the group consisting of TMSOTf, MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2 ZnCl2, Lewis acids and chelating metals.
36. The process of claim 32 or 35 wherein said solvent is selected from the group consisting of toluene, THF, and mixtures thereof.
37. The process of claim 32 wherein said solvent is DMF, and said oxidizer is bromine.
38. In a process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an alcoholic hydroxy acceptor, in the presence of a promoter and a solvent, the improvement wherein said donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
where B is O or S, said promoter is selected from the group consisting of MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
where B is O or S, said promoter is selected from the group consisting of MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
39. A process of claim 38 wherein said donor is an O-pyranosyl glycoside, said promoter is selected from the group consisting of AgOTf and Cu(OTf)2, said solvent is selected from the group consisting of CH3NO2, and CH2Cl2, Et2O, CH3CN, DMF, THF, and mixtures thereof.
40. A process of claim 39 wherein said donor is selected from the group consisting of glycosides of formula IX wherein Z has formula VIII, wherein R2 is acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to carbon atoms, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R, said promoter is selected from the group consisting of AgOTf, and Cu(OTf)2, said solvent is selected from the group consisting of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures thereof.
41. A process of claim 39 wherein said donor is selected from the group consisting of glycosides of formula X
wherein Z has formula VIII, wherein R2, R3 and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5 is alkyl of 1 to 5 carbon atoms, said promoter is selected from the group consisting of AgOTf, and Cu(OTf)2, said solvent is selected from the group consisting of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures thereof.
wherein Z has formula VIII, wherein R2, R3 and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms, R5 is alkyl of 1 to 5 carbon atoms, said promoter is selected from the group consisting of AgOTf, and Cu(OTf)2, said solvent is selected from the group consisting of CH3NO2, CH2Cl2, Et2O, CH3CN, DMF, and THF and mixtures thereof.
42. A process of claim 38 wherein said acceptor is selected from the group consisting of glycosides of formula RX wherein X has formula I, and R has the formula II
wherein A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, R2 is azido, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy.
wherein A is N, or CH, and R1 is H or alkoxy of 1 to 5 carbon atoms, R2 is azido, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R5 is independently hydroxy.
43. In a process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with a trialkysilyl pyrimidine ether acceptor, in the presence of a promoter and a solvent, the improvement comprising said donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
where B is O or S, said promoter is selected from the group consisting of TMSOTf, MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of toluene, THF, and mixtures thereof.
where B is O or S, said promoter is selected from the group consisting of TMSOTf, MeOTf, TfOH, BF3, AgOTf, Cu(OTf)2, ZnCl2, Lewis acids and chelating metals, said solvent is selected from the group consisting of toluene, THF, and mixtures thereof.
44. A process of claim 43 wherein said donor is an O-pyranosyl or O-furanosyl glycoside, of formulae IX, X, or XI, and said trialkyl silyl pyrimidine ether has formula VII
wherein R2, R3, R4, and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms, and Z
has formula VIII.
wherein R2, R3, R4, and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10, is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R13 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, R14 is trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms, and Z
has formula VIII.
45. In a process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor of an acylated purine in the presence of bromine, and a solvent, the improvement comprising said donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
where B is O or S, said solvent is DMF.
where B is O or S, said solvent is DMF.
46. A process of claim 45, wherein said purine is 6-benzoyl adenine.
47. A novel glycoside wherein the glycoside has a substituent selected from the group consisting of wherein B is 0 or S:
wherein R2, R3, R4 and R5 are as defined in claim 40;
wherein R2, R3, R4 and R5 are as defined in claim 41;
or wherein R10, R11 and R12 are as defined in claim 44.
wherein R2, R3, R4 and R5 are as defined in claim 40;
wherein R2, R3, R4 and R5 are as defined in claim 41;
or wherein R10, R11 and R12 are as defined in claim 44.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002100821A CA2100821C (en) | 1993-07-19 | 1993-07-19 | Stereocontrolled glycosidation |
| AU72620/94A AU7262094A (en) | 1993-07-19 | 1994-07-19 | Solution and solid phase stereocontrolled glycosidation |
| PCT/CA1994/000396 WO1995003316A2 (en) | 1993-07-19 | 1994-07-19 | Solution and solid phase stereocontrolled glycosidation |
| US08/403,813 US5767256A (en) | 1993-07-19 | 1994-07-19 | Solution and solid phase stereocontrolled glycosidation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002100821A CA2100821C (en) | 1993-07-19 | 1993-07-19 | Stereocontrolled glycosidation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2100821A1 CA2100821A1 (en) | 1995-01-20 |
| CA2100821C true CA2100821C (en) | 2001-01-16 |
Family
ID=4151945
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002100821A Expired - Lifetime CA2100821C (en) | 1993-07-19 | 1993-07-19 | Stereocontrolled glycosidation |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2100821C (en) |
| WO (1) | WO1995003316A2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2423888T3 (en) | 2001-09-07 | 2013-09-25 | Alchemia Limited | Synthetic heparin pentasaccharides |
| WO2013091660A1 (en) * | 2011-12-23 | 2013-06-27 | Glycom A/S | A method for obtaining crystalline lacto-n-tetraose and lacto-n-neotetraose precursors and mixtures thereof |
| WO2014210397A1 (en) * | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
| KR101639160B1 (en) * | 2015-06-10 | 2016-07-12 | 건국대학교 산학협력단 | Benzyltriazole derivatized dextran for removing methyl violet dye |
| CN113926472B (en) * | 2021-07-29 | 2022-10-18 | 山东大学 | Glycosidation reaction catalyst, glycosidation method and application |
-
1993
- 1993-07-19 CA CA002100821A patent/CA2100821C/en not_active Expired - Lifetime
-
1994
- 1994-07-19 WO PCT/CA1994/000396 patent/WO1995003316A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995003316A3 (en) | 1995-03-30 |
| WO1995003316A2 (en) | 1995-02-02 |
| CA2100821A1 (en) | 1995-01-20 |
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