CA2141790A1 - Chiral catalysts and epoxidation reactions catalyzed thereby - Google Patents

Chiral catalysts and epoxidation reactions catalyzed thereby

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Publication number
CA2141790A1
CA2141790A1 CA002141790A CA2141790A CA2141790A1 CA 2141790 A1 CA2141790 A1 CA 2141790A1 CA 002141790 A CA002141790 A CA 002141790A CA 2141790 A CA2141790 A CA 2141790A CA 2141790 A1 CA2141790 A1 CA 2141790A1
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Prior art keywords
formula
hydrogen
compound
chloride
bis
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CA002141790A
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French (fr)
Inventor
David Bell
David Miller
Robin P. Attrill
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SmithKline Beecham Ltd
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Individual
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Priority claimed from GB929216662A external-priority patent/GB9216662D0/en
Priority claimed from GB939308968A external-priority patent/GB9308968D0/en
Application filed by Individual filed Critical Individual
Publication of CA2141790A1 publication Critical patent/CA2141790A1/en
Abandoned legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B01J31/2243—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/22—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings
    • C07D321/04—Seven-membered rings not condensed with other rings
    • C07D321/06—1,3-Dioxepines; Hydrogenated 1,3-dioxepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
    • B01J2231/72—Epoxidation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B01J2531/0252—Salen ligands or analogues, e.g. derived from ethylenediamine and salicylaldehyde
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/70—Complexes comprising metals of Group VII (VIIB) as the central metal
    • B01J2531/72—Manganese

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Catalysts (AREA)

Abstract

A compound of formula (I), in which M is a transition metal ion;
A is a counter-ion if required; r, s and t are independently 0 to 3 such that r+s+t is in the range of 1 to 3; Ra, Rb, Rc are each independently hydrogen or CH2OR' where R' is hydrogen or an organic group; B and E are independently oxygen, CH2, NRd in which Rd is alkyl, hydrogen, alkylcarbonyl, or arylcarbonyl or SOn where n is 0 or an integer 1 or 2, with the proviso that B and E are not simultaneously CH2 and that when B is oxygen, NRd or SOn, then r cannot be 0, and when E is oxygen, NRd or SOn, then t cannot be 0; R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, alkyl or alkoxy.

Description

W o 94/03271 21 417 9 0 PCT/CB93/01666 CHIRAL ~ATALYSTS AND EPOXIDATION REACTIONS CATALYZED THEREBY
This invention relates to novel catalysts and their use in the conversion of certain ole~lns into chirally enriched epoxides.
WO/91/14694 describes certain catalysts of the following formula (A):

R1 (Cn) R4 `

y ~ ~ Y4 (A) in which M is a transition metal ion, A is an anion, and n is either 0, 1 or 2. At least 10 one of Xl or X2 is selected from the group consisting of silyls, aryls, secondary aL~,v!s and tertiary alkyls; and at least one of X3 or X4 is selected from the same grou~. Y1, Y2, Y3, Y4, Ys and Y6 are indcpendently selected from the group ~- ; consisdng of hydrogen, halides, alkyls, aryl groups, silyl groups, and alkyl groups bearing heteroatoms such æ aL~coxy and halide. Also, at least one of Rl, R2, R3 and 15 R4 is~selected ~rom a first group consisting of H, CH3, C2Hs and primary aL~cyls.
Furthermore, if Rl is selected from said first group, then R2 and R3 are selected from a second group consisting of aryl groups, heteroatom-bearing aromatic groups, secondary alkyls and tcrtiary alkyls. If R2 is selected f~m said first group, then R
and R4 are selectcd from said second group. If R3 is selccted from said first group, 20 then Rl and R4 are selected from said second group. If R4 is selccted from said first group, then R2 and R3 are selected from said second group.
Such catalysts are descnbed as being useful in enantioselectively epoxidising a prochiralolefin.
Structurally distinct catalysts have now been prepared which surprisingly 25 possess the ability to catalyse the enantioselective expoxidiation of certain prochiral olefins.
Accorc'dngly, the present invendon providcs a compound of formula a~ :

~ I

wo 94/03271 pcr/GB93/ol666 b ~CHR ~
B E
I C

)r (CHR ~t R4 r ~ Rs R3 ~ A ~ R6 (~

F~2 R, R~, R7 in which M is a transition metal ion;
S A is a counter-ion if required; -r, s and t are independently 0 to 3 such that r+s+t is in the range of 1 to 3;
Ra, Rb, Rc are each independendy hydrogen or CH2OR' where R' is hydrogen or an organic group;
B and E are independently oxygen, CH2, NRd in which Rd is allcyl, hydrogen, -~10 allcylcarbonyl, or arylcarbonyl or Sn where n is 0 or an integer 1 or 2, with the proviso that B and E are not simultaneously CH2 and that when B is oxygen, NRd or SOn, then r cannot be 0, and when E~ is oxygen, NRd or SOn, then t cannot be û;
Rl, R2, R3, R4, Rs, R6, R7, Rg, Rg and Rlo are independently hydrogen, alkyl or alkoxy.
Suitable transition metal ions, M, include Mn, Cr, Fe, Ni, Co, rl, V, Ru and Os in an appropriate oxidaion state.
Aeferably the transition metal ion, M, is Mn in oxidation sta~e (II~ or (III).
It should be appreciated that in some cases for example when M is Mn (II), a -counter-ion is not required.
20 Suitable counter^ions, A, include those anions mentioned in WO 9l/l4694.
Preferably, A is chlo~ide.
Suitable organic groups R' include alkyl, aLkylcarbonyl, arylcarbonyl or aryl derivatives.
Par;ticular examples of R' include substituted alkyl groups.
2~ One example of R' is triphenylmethyl.
Preferably s and t are zero, r is 1 and Ra is hydrogen, B is oxygen and E is CH2; or r, s and t are l, Ra, Rb and RC are hydrogen and B and E are both oxygen; or s is zero, r and t are both l, Ra is hydrogen or tIiphenylmethyloxymethylene and RC

WO ~4/03271 21 417 9 0 PCT/GB93/0l666 is hydrogen, B is oxygen a:nd E is -CH2-; or r and t are both 1, s is zero, Ra and Rc are hydrogen, B is NRd where Rd is phenyl carbonyl and E is CH2.
Suitably, R2, R4, Rs and R7 each independently represent hydrogen.
Suitably R 1, R3, R6 and RB each independently represent C 1-6 alkyl.
S Favourably Rl and R8 represent branched alkyl groups such as tertia y alkyl groups.
R3 and R6 also advantageously represent branched alkyl groups.
One preferred example for each of R 1 and R8 is ter~ary butyl.
Particular examples of R3 and R6 are tertiary butyl and methyl.
Examples of R2, R4, R5 and R7 are hydrogen.
The term 'aLkyl' when used alone or when forming part of other groups (for example alkoxy groups or alkycarbonyl groups) includes straight- or branched~hain aLkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples `
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
When used herein the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, aL~cyl, phenyl, alkoxy, haloalkyl, alkylcar~onyl and phenylcarbonyl.
A preferred aryl group is a substituted or unsubstituted phenyl group.
Transition metals M include those having oxidation states of (II) or more.
Suitable substituents for aryl include alkyl, halogen and alkoxy~
Optional substituents for aL~cyl groups include those mentioned herein for aryl groups, phenyl is a particular example.
It should be appreciated that the carbon atoms marked with an asterisk are chiral centres and the present invention extends to each individual enantiomer and any mixtures thereof. `
The present invention also provides a process for the preparation of compounds of forrnula (I) which compriæs forming a transition metal complex of the following compound of formula (II):
.:.

WO 94/0327~ ;3 PCI/GB93/01666 (CHP~ ~

C
(CHR )r (CHR )t \ ^ .1 t ~ R~o ~OH OH~

R2 R, R8 R7 where variables Rl to Rlo, B, E, r, s, t Ra, Rb and Rc are as defined in relation to forrnula (I), and thereafter if necessary separating any enantiomers.
Suitably the transition metal ion complex may be formed by the addition of a S suitable transition metal salt such as rnanganese (II) or (III) acetate, preferably manganese (m) acetate, to a compound of forrnula (II) in a suitable solvent such as ethanol or methylene dichloride, at elevatcd temperature. 111G optional replacement or interconversion of the counter ion may be effected by the addition of an aL~cali metal salt containing the desired counter-ion such as LiCl.
The separation of any enantiomers may be camed out by conventional -techniques, such as crystallisation of derivatives or chromatography. However, it should be appreciated that is is preferred that separation of enantiomers is carried out before fo ming a eransition metal complex.
The nvention further provides a process for the p~;eparation of compounds of 15 formula (II) which comprises condensing sequentially, in any ordert a compound of forrnula (III): b /(CHR
B E
I c (111) (~HR )t R"~N NHR,2 where r, s, t, Ra, Rb and RC E, B are as defined in formula (I) and R l l and Rl2 independently represent hydrogen or an arnine protecting group, providing at least 20 one of Rl 1 and R12 is hydrogen, with a compound of formula (IV);

wo 94/~3271 2 1 4 1 7 9 0 PCl/(~1~93/01666 . ' ~

R4 C--Rg (IV) ~ ~
R2 P'1 :
and a compound of forrnula (V), removing any protecting group R 1 1 or R 12 as necessary;
//
R5 \ ~G--R1 0 R6 ~OH

R7 R~ (V) 5 wherein Rl to Rlo are as defined in relation to formula (I3, and thereafter as required isolating the required compound including if necessary separating any enantiorners.
It is prefe~red that the compound of formula (II) is prepared from op~ically pure compounds of formula (~I) which are preferably prepared themselves from optically pure star~ng materials. Altematively, racemates or mixtures of enantiomers 10 of formula (II) or (III3 may themselves be resolved using conventional techniques in the art such as crystallisation of derivatives, or chromatography.
When compounds of fosmula (II) are required in which one or more of Rl, R2, R3, R4 and Rg are not the same as one or rnore of Rg, R7, R6, Rs and Rlo respectively, then compounds of fonnula (III) may be sequentially condensed with15 compounds of forrnula (IV) and formula (V), in any order, by heating a suitably protected c~mpound of formula (III) with a compound of formula (IV) or (V) (in a1:1 mole ratio) in an inert solvent such as ethanol, if necessary, purifying the resulting intennediate compound of formula (VI) or (VII):

wo 94/o327~ 41L7t 9 PCltGB93/01666 ,~(CH2)~

(C~CH2)( (C~ R~o 4 \ ~)CN NHR,2 . N~R5 R3 ~OH HO ~ R6 Rz R, (Vl) R~ R (Vll) wherein variables Rl to R12, r, s, t, Ra, Rb, RCt E and B are as de~lned in to formula (III), (TV) and (V) using conventional techniques such as chromatography removing 5 any R1 1 or Rl~ protecting groups and then repeating the reacaon using a compound of ~orrnula (IV) or (~) as required.
Suitable protecting groups Rl 1 or R12 include conventional arnine pr~tec~ng groups such as benzyl groups, silyl groups or acyl groups such as benzoyl groups.
The removal of Rl 1 or R12 when represen~ing protecting groups may be 10 carried out using conventional techniques in the art depending upon the nanlre of ~e protecting group. -It should be appreciated that when each of R1, R2, R3, R4 and Rg is the same -~
as each of R~, R7, R6, Rs and Rlo respectively the compounds of formula (IV) and(V) are the same, ~herefore, compounds of ~ormula (III) in which Rl 1 and R12 is15 hydrogen are preferably used and two moles of a compound of formula (IV) or (V) are utilised, in an inert solvent, such as ethanol, at elevated temperature, for example at reflux.
Compounds of formula (m) are either known compounds or may be prepared according to known methods or analogously to known methods or analogously to the ~
methods described herein~ for example when a compound of formula (m) is: 3,~ `:
diaminotetrahydrofuran, such a compound may be prepared according to the following scheme, for example, as des~ibed in descriptions 1 and 2. ;

- 6 - ~

21~1790 WO 94/0i271 PCr/C~B93/01666 :` NO2 NH2 NO2 (~/ H I> THF
~5 C
( ) H2, Pd/C
tOH
NH N~2 (~ :
Alternatively, 3,4~iaminotetrahydrofuran may be prepared according to the following scheme, for example, as described in descriptions 4 to 6.
HO OH CH302S, Qso2cH3 , Et3N

,~ THo-C L20 LJN3 lDMSO O ~:

~` LiAH4 THF
0C ~ room terlp The 5R, 6R-diamno-1,3-dioxepane may be prepared according to the procedures, as described in descriptions 8 to 13.
The 3R, 4S-dian~ino tetrahydropyran may be prepared according to the pr~cedures as described in descriptions 15 to 17.
The 3R,4R-diamino-(2R)(triphenyl methoxymethyl)tetrahydrofuran may be prepared according to the procedures as described in descriptions 21 to 24.
The (~:) ~ans-1-'oenzoyl-3,4-diarninopiperidine may be prepared according to the procedures as described in descriptions 25 to 27.
Compounds of forrnula (IV) and (V) are either comrlnercially available, are known compounds or may 'oe prepared according to known methods or analogously lS to known methods for exarnples such as these described by G.Casiraghi et al J. Chem Soc. Perkin Transactions l. 1980 P1862 - 186S~
NoYei compounds of forrnula (II), (IIT). (IV), (V), (VI) and (VII) form an aspect of the present invention.

W 0 94/03271 ~ ~ PCT/GB93/01666 It should be appreciated that the term chiral catalyst refers to catalysts of formula (I) which have a predominance of one particular enantiomer and thereforeare useful in forming a predominance of one particular enantiomer of the resulting epoxide produced from a prochiral olefin. , S It should be appreciated that the catalysts, of forrnula (I) are preferably prepared in a chiral form by using a resolved compound of formula ~III) which may ;
be resolved using conventional techniques. The compound of formula (lII) may itself `
be prepared from suitable precusor compounds such as these outlined in hereinbefore which may be resolved using conventional techniques or may be purchased in a resolved form. Alternatively, the coupled compound of formula (Il) may be resolved using conventional techniques. `
The invention further provides a process for enantioselectively epoxidising a prochiral olefin in the presence of an oxygen source and a chiral catalyst of formula -Suitable prochiral olefins include compounds which comprise the following groups as part of their structure, cyclohexene, 5,6-dihydro-2H-pyran, 1,2,5,6-tetrahydropyridine,1,2,3,4-tetrahydropyridine and 5,6 dihydro-2H-thiopyran.
Favoured prochiral olefins include those compounds which comprise the following groups as part of their structure form: 1,2-dihydronaphthalene, 2H-chromene, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline and 2H-thiochromene.
Such compounds are well known in the potassium channel activator field.
Preferably, prochiral olefins include those mentioned in EP-A-0 376 524, such as the compounds of formula (XIV) therein, and in particular 2,2-dimethyl-6- I` `
pentafluoroethyl-2H-l-benzopyran.
It should be appreciated that the present invention pamcularly extends to the preparation of all epoxide precursors to those compounds of foranula (I) in EP-A-0 376 524 and especially the specific examples thereof using the herein ' described process.
The present invention also particularly extends to the subsequent conversion of all epoxide precursors to all specific examples in EP-A-0 376 524, to those specific examples in particular to the preparation of (-)trans-3,~dihydro-2,2-dimethyl4-(2-oxopiperidin-l-yl)-~pentafluoroethyl-2H-l-benzopyran-3-ol.
Suitable oxygen sources include sodium hypochlorite. `
It should be appreciated that only one enantiomer of a catalyst of formula ~I) is required to produce the 3S,4S enantiomer of the epoxide precursor to compounds describcd in EP-A- 0 376 524 which in turn produce the 3S,4R configuration in the compounds of forrnula (I) as describcd in EP-A-0 376 524. Conversely, the 3R, 4Renantiomers of the epoxide precursors produce the 3R, 4S configuration in the compounds of forrnula (I) as described in EP-A-0376 524.

WO ~4/03271 21 417 9 0 PCl /GB93/01666 The following descriplions and examples illus~ate the present inven~ion.

wo 94/03271 ~ 4~rl PCr/CB93/0l666 Description 1 (i:) 2,5-Dihydro-3 nitrofuran (Dlj A mixture of (i) ~rans 3-chloromercurio~nitro-2,5~ihydrofuran~ (38.54g, 109.6 mmol) and Et3N (11.07g,109.6 mmol) in CH2Cl2 (2.2L) at 25C was stirred S for 1.25h. S% aqueous citric acid (l.lL) was added and stirring was continued for S
min. The mixture was filtered thr~ugh celite. separated and the organic phase washed with 5% aqueous citric acid (220 ml), dried over Na2SO4 and concentrated in vacuo. -Chromatography of the residue on silica (Merck 9385, 300g) eluting with CHC13- -Hexane (1:1 -> 1:0) afforded (Dl) as a pale yellow oil which c~ystallised in the freczer,5.4Sg (43.2%). -(CDC13) 4.95 (4H,S) and 7.10 (lH,S) 1. P. Bitha and Y - I. Lin, J. Heterocyclic Chem., 1988, ~, 1035-1036. `
:'.'~' Description 2 (+) 3,4-Diaminotetrahydrofuran (D2) --`
A solution of (+) 4-amino-3-nitrotetrahydrofuran, prepared from (Dl) via the method of Bitha and Lin1, (4.66g,35.3 mmol) in EtOH (100 ml) containing 10%
palladium on carbon (2.5g) was hydrogenated on a Parr shaker apparatus at 35 psi for 65h at 20C. The suspension was filtaed, the solids washed with EtOH (100 ml) and the combined filtrate evaporated in uacuo to afford (i) (D2) as a colourless oil, 3.26g (81.5%) ,`
~ (CDC13) 1.40 (4H,bs), 3.20 (2H, m),3.50 (2H,dd) and 4.08 (2H,dd).

Description 3 (:~) 3,4-bis (3-tert-Butyl-5-meth91sa1icylideamino)tetrahydrofuran (W) A solution of the raccmic diamine (D2) (855 mg, 8.38 mmol) and 3-tert-butyl-5-methylsalicaldehyde (3.22g,16.76 mmol) in EtOH (50 ml) was heated at reflux for ;
l.5h. The solvent was removed in vacuo and the residue chromatographcd on silica(Merck 9385,300g) using CHC13 as eluent to afford (:~) (D3) as pale yellow needles, 1.35g, (35.8%).
~ (CDCl3) 1.42 (18H,s),2.25 (6H,s), 3.95-4.10 (2H,m), 4.43 (2H,q), 6.90 (2H,d),7.15 (2H,d), 8.30 (2H,s) and 13.10 (2H,bs).

Description 4 (S,S) trans 3;4-bis(methanesulphonyloxy)tetrahydrofuran (D4) A solution of 1,4-anhydr~L-threitol (2.45g, 23.S mmol ex Aldrich Chemical company) in a mixture of THF (75 ml) and Et20 (75 ml) at 0C was treated sequentially with triethylamine (7.2 ml,51.7 mmol, 2.2 eq) and methanesulphonyl 21 4~7~(3 WO 94/03271 pcr/GB93/o1666 chloride (3.~2 ml,49.35 mmol,2.1 eq). The rnixture was s~rred for 4h then stored at 0C overnight (~16h).
The reaction was filtered and the solids washed with T~ (20 ml). The ;
combined filtrate was evaporated in vacuo and partitioned between 10% aqueous S citric acid (60 ml) and EtOAc (150 ml). The organic phase was dried (MgSO4) and evaporated to afford (D4) as a colourless oil, 5.82g (95%).
o (CDC13) 3.12 (6H,s) 4.00 (2H,dd)t 4.18 (2H,dd) and 5.25 ~2H,dd).

Description S `
(S,S) trans 3,4-Diazidotetrahydrofuran (D5) A mixture of the dimesylate (D4) (5.80g, 22.3 mmol) and lithium azide (5.46, ~
111.5 rnmol. 2.5 eq) in DMSO (60 rnl) was heated at 100-110C for 40h. After -cooling to ambient the reaction was diluted with water (IL) and extracted with EtOAc (IL,2 x 0.75L). The combined organic phase was washed with water (0.SL) and brine (0.SL). dried over MgSO4 and evaporated in vacuo to a pale yellow oil of the title compound, 2.18g (61.5%).
o (FDCl3) 3.75 (2H,dd) and 3.90 - 4.05 (4H,m3.
:.,, Description 6 (S,S) trans 3,4-Diaminotetrahydrofuran `
To lithium aluminium hydride (2.0Sg, 54 rnmol) in dry T~ (150 ml) at 0C
was added the diazide (D5) (2.08g,13.5 mrnol) in THF (50 ml) dropwisc over 10 min. After 15 min the soluion was allowed to warm to ambient, then stirrcd for 16h.
The reacion mixture was re-cooled to 0C and quenched sequentially with H20 (2 ml), 15% aqueous NaOH (2 ml) and further H20 (6 ml) and warmed to ambient. After stilTing for lh the mixture was filtered through celite, rinsed with THF (2 x 150 ml) and the combined filtrate evaporated in vacuo to afford (D6) as a -pale yellow oil, 1.28g (93%).
~ (CDC13) 1.30 (4H,bs), 3.20 (2H,dd), 3.50 (2H,dd) and 4~08 (2H,dd).
Description 7 (S,S) tralts 3,4-bis(3-tert-Butyl-5-methylsalicylideamino)tetl ahydrofuran (D7) A solution of the (S,S)-diamine (l~O (1.26g, 12.35 mmol) and 3-tert-butyl-5-methylsalicaldehyde (4.74g,24.70 mmol) in EtOH (75 ml) was heated at reflux for 3.5h. The solution was cooled and solvent removed in vacuo to afford crude (5) as a yellow oil,5.S0g (99%).
A sample of the crude material (4.55g) was chromatographed on silica (Merck 9385, gradient of CHC13 in hexane) tO afford pure (D7) as a yellow foam, 4.39g (95.5% yield).

WO 94/0327l ~ 9 ~ Pcr/ GB93/01666 r~
~ (CDC13) 1.42 (18H,s), 2.25 (6H,s), 3.95 - 4.10 (4H,m) 4.33 (2H,q), 6.90 -~
(2H,d), 7.1~ (2H,d), 8.30 (2H,s) and 13.15 ~2H,bs~.

Description 8 (2R,3~)-1,4-Dibenzyloxy-2,3-dimethanesulfonyloxybutane To a soluhon of (2R,3R)-(~)-l,Wbenzyloxy-2,3-butanediol (25.3g, 83.7mrnol ex Aldrich Chernical Company) in dichloromethane (165ml), cooled in an -~
ice bath, was added methanesulfonyl chloride (13.0ml, 167.4 mmol), followed by slow addition of triethylamine (23.3ml, 167.4mmol) such that the temperature did not rise above 5C. Once the addition was complete the reaction was allowed to stir with ice-bath cooling for 3 hours. Water (600ml) was then added and the organic phaseseparated. The aqueous phase was re-extracted with dichloromethane (200rnl) and ~-the combined organic phases washed with water (400ml) and brine (400rnl), dried (MgSO4), and the solvent evaporated to afford a pale yellow solid. Trin~tion with diethyl ether afforded the title compound (28.2g, 74%) as colourless crystals m.p. 72- -73C. `
lH n.m.r. (CDC13):o 3.03 (s,6H,2xCH3), 3.76 (m,4H,2xCH20),4.48 `~
(d,2H,CH2Ph), 4.57 (d,2H,CH2Ph), 5.00 (m,2H,2xCH),7.27-7.39 (m,lOH,2xPh) 13C n.m.r. (CDC13):~ 38.8 (2xCH3), 68.7 (2xCH2) 73.7 (2xCH2), 78.7 `
(2xCH), 128.1, 128.2, 128.6, 137.0 (2xPh).
EI-MS:m/e 459 (MH+), 367 (M+-CH2Ph).
C20H2608S2 requires: C: 52.39, H:5.72%.
found : C: 52.36, H:5.59%.

Description 9 (2R,3R)-Dimethanesulfonyloxybutane-1,4-diol (2R,3R)-l,~Dibcnzyloxy-2,3~imethanesulfonyloxybutane (27.6g, 60.3mmol) (D8) was dissolvcd in acetone (500ml), a suspension of 10% Pd/C (29.9g) in acetone (300ml) added, and the n~ixture hydrogenated at 1 a~n. pressure for 2hours at ambient tempernIre. The mixture was then filtered three times through a pad of silica and Celite, and the solvent evaporated to give the title compound as a s~aw-coloured oil (14.7g, 87%), which solidified on standing.
lH n.m.r. (DMSO-d6):~ 3.24 (s,6H,2xCH3), 3.69 (m,4H,2xCH2),4.76 (m,2H,2xCH), 5.33 (t,2H.2xOH).
13C n.m.r. (DMSO-d6):~ 38.1 (2xCH3), 59.7 (2xCH2), 80.3 (2xCH).
EI-MS~ le 279 (MH+), 261 tMH+-H2o)~ 183 (M+-OMs), 165 (M+-OMs.H20)-wo 94/03271 21417 9 f~ pcr/GB93/ol666 Description 10 (6R,7R)-Dimethanesulfonyloxy-2,4,9,11-tetraoxadodecane . .:
(2R,3R)-Dimethanesulfonyloxybutane-1,4-diol (14.7g, 52.9 mmol) (D9) was dissolved in dimcthoxymethane (89.5ml) and dichloromethane (30ml) at 40C.
Lithium bromide (0.91g) and p-toluenesulfonic acid monohydrate ~1.01g, 5.29mmol)were added, and the mixture heated under reflux for 3 hours. The reaction was allowed to cool to ambient temperature, and then poured into saturated sodium bicarbonate solution (200ml), cxtracted with ethyl acetate (2x200ml), dried (MgSO4) and cvaporated to give a colourless oil. This was purified by column chromatography on silica, cluting with 0-1% methanol in dichloromethane, to afford the title compound as a colourless oil (8.2g, 42%).
lH n.m.r. (CDC13):~ 3.13 (s,6H,2xCH3), 3.39 (s,6H,2xOCH3), 3.87 (m,4H?2xCH2),4.66 (m,4H,2xOCH2O), 5.02 (m,2H,2xCH).
13C n.m.r. (CDCl3):~ 38.8 (2xSCH3), 55.8 (2xOCH3), 66.1 (2xCH2), 78.4 ~(2xCH), 96.8 (2xOCH2O) ;
CI-MS:m/e 384 (MNH4+). ~',r' Cl0H2210S2 requires: C: 32.78, H:6.05%.
found : C: 32.22, H:5.62%.
.'` .
Description 11 -(5R,6R)-Dimethanesulfonyloxy-1,3-dioxepane ;`
A solution of (6R,7R)-dimcthanesulfonyloxy-2,4,9,1 l -tetraoxadodecanc , - (8.2g, 22.Ammol) (D10~ and ~tolucncsulfonic acid monohydrate (0.26g, 1.34mmol) in tolucnc (165ml) was hcatcd under reflux overnight. The solvent was evaporatcd -and thc brown rcsiduc trituratcd with dicthyl cther to afford the titlc compound as an off-white solid (5.9g, 91%) m.p. 133-134C.
H n.m.r. (CDCl3):~ 3.13 (s,6H,2xCH3), 3.84 (m,2H,CH2),4.06 (m,2H,CH2), 4.77 (s,2H,OCH20), 4.81 (m,2H,2xCH).
13C n.m.r. (CDCl3):o 38.8 (2xCH3), 64.1 (2xCH2) 78.3 (2xCH), 94.6 (OCH20) EI-MS:m/e 291 (MNH+).195 (M+-OMs). ~-qH14OgS2 requires: C: 28.96, H:4.86%.
found : C: 29.22, H:4.619to.

Description 12 (SR,6R)-Dia~ido-1,3-dioxepane l~
A mixmIe of (SR,6R)-dimethanesulfonyloxy-1,3-dioxepane (5.0g, 17.2mmol) Dl 1 and lithium azide (4.2g, 86mmol) in dimethylsulphoxide (60rnl) was sti~red and ` `
heated to 110-120C overnight. The reaction mixture was then cooled, poured into - 13-wo 94/03271 ~4 PCr/GB93/01666 water (200ml), and extracted with ethyl acetate (2xl50ml) The combined organic phases were washed with water (2x150ml) and brine (150ml), dried (MgS04) and evaporated tO give the title compound as a brown oil (2.7g, 85%) lH n.m.r. (CDCl3):~ 3.49 (m,2H,2xCH~, 3.74 (m,2H,2xCH2), 3.93 , (mt2H,CH2),4.73 (s,2H,OCH20).
13C n.m.r. (CDC13):~ 64.3 (2xCH), 64.6 (2xCH2) 94.3 (OCH2O). ~-EI-MS:rn/e 185 (MH+), 157 (MH+-N2), 142 (M+-N3).
CsH~N6O2 requires: C: 32.61, H:4.38, N:45.63%.
found : C; 32.33, H:4.67, N:45.38%. -:~-Description 13 (~R,6R)-Diamino~ dioxepane To a slurry of lithium aluminium hydride (2.1g, 55.3mmol) in dry tetrahydrofuran (70ml) at 0C under an argon atmosphere was added dropwise a solution of (SR, 6R)-Diazido-1,3-dioxepane (2.6g,14.1mmol) (D12) in dry tetrahydrofuran (50ml). During the addition the reaction ~emperature was maintained below 10C with an ice-salt bath. Onc completion, the reaction mixture was allowed to warm to ambient temperature, and st*ed for a further 1.5 hours. It was then re-cooled and the reaction quenched by addition of water (2ml)t 2M NaOH (2ml), and water (4ml), the temperature again being maintained below 10C by means of an ice-salt bath. The quenchcd reaction mixture was allowed ~o warrn to ambient temperature, s~red for a further 2 hours, then filtered through Celite, and the filter pad washed well with tetrahydrofuran. The combined filtrates were evaporated to afford the title compound as a pale yellow oil (1.3g,70%).
lH n.m.r. (CDC13):~ 1.56 (brs,4H,2xNH3), 2.62 (m,2H,2xCH),3.58 (mt2H,CH2),3.77 (m,2H,2xCH2), 4.72 (s,2H,OCH20) 13C n.m.r. (CDC13):~ 57.9 (2xCH), 67.5 (2xCH2) 93.8 (OCH20).
CsH12N2O2 requires: C: 45.44, H:9.15, N:21.20%.
found : C: 45.13, H:8.76, N: 19.58%.
EI-MS:m/e 133 (MH+), 116 (M+-NH2)+,90 (M-2NH2)+.

.. .

wo 94/0327l 2141 7 ~ ~3 pcr/GB93/o1666 Description 14 Preparation of (5R,6R)-Di-(3,5-di-tert-butyl) salicylidenamino-1,3-dioxepane (SR,6R)-Diamino-1,3~ioxepane (l.Og,7~6mrnol) (D13) and 3,5-di-tert-S butylsalicaldehyde (3.6g, 15.4mmol, 2eq.) were dissolved in ethanol (lOOml), and the -solution stirred under retlux for 3 hours. The reaction mixture was then alrowed to cool, the solvent was evaporated, and the residue puIifled by column chromatogIaphy on silica. eluting with 4% diethyl ether in hexane. This afforded the title compound as a bright yellow foam (3.5g,82%). ---lo lH n.m.r. (CDC13);o 1.23 (s,18H,6xCH3), 1.41 (s,18H,6xCH3),3.85 (m~2H,CH2),4.07 (m,2H,CH2),4.87 (s,2H,OCH20), 6.99 (d,2H,Ar), 7.33 ~-(d,2H,Ar), 8.33 (s,2H,2xCH=N), 13.20 (brs, 2H,2xOH). ;
13C n.m.r. (CDC13):~ 29.4 (6xCH3), 31.4 (6xCH3) 34.1 (2xCCH3), 35.0 ;
(2x~CH3),.67.7 (2xCH),73.8 (2xCH2),94.2 (OCH20), 117.6,126.4, 127.4, 136.6, 140.3, 157.9 (Ar), 168.4 (2xC=N) `
C3sHs2N204 requires: C: 74.43, H:9.28, N:4.96%.
found : C: 74.56, H:9.15, N: 4.92%.
CI-MS:m/e 565 (MH+).
:
Description 15 (3R, 4R)-Diacetoxytetrahydropyran (D15) A solution of 3,4-di-~acetyl-D-Xylal (11.16g) in 50% aqueous ethanol (400ml) containing PtO2 (400rng) was hydrogenated at atmospheric pressure for 3.5 hours at 25C. The suspension was filtered through celite, washed with 50% aqueous `
ethanol (SOml) and water (SOml), and the combined filtrate evaporated in acuo to afford the title compound as a colourless oil,9.6g (85%).
~ (CDCl3): 1.30-1.50 (lH,m), 2.10 (6H,S),2.1~2.20 (lH,m),3.35-3.60 (2H,m). 3.804.00 (2H,m) and 4.80-5.00 (2H,m).
2. Dictionary of Organic Compounds, 5th Edition, 1982, Chapman & Hall, London, 579 and references therein.

Description 16 (3R,4R)-Dimethanesulfonyloxytetrahydropyran(D16) Sodium (~SOmg) was dissolved in methanol (lOOml) at ambient. To the resulting solution was added a solution of the diester (D15) (9.56g, 47.3mmol) in methanol (lOOml) and the mixture stirred for 72 hours. Amberlite IR 120H+ resin (20g) was added and the mixture filtered. Concentration of the filtrate in vacuoafforded the diol as a colourless oil. This was dissolved in a mixture of tetrahydrofuran (220ml) and diethyl ether (220ml). Triethylamine (10.86g, Wo 94/03271 ~ pcr/Gss3/ol666 107.5mmol,) was added and the solution cooled to 0C. Methanesulphonyl chloride ' -(11.76g, 102.7mmol) was added dropwise at 0C, the solution was stilTed for a further hour then stored at 4C for 16 hours. The resulting suspension was filtered and the solids washed with tetrahydrofuran (2x95ml) and diethy1 ether (2x180ml).The combined filtrate was evaporated in vacuo and the residue partitioned betwecn -ethyl acetate (200ml) and 10% aqueous citric acid (200ml). The organic phase wasdried (MgSO4), filtered and concentrated in vacuo to a colourless foam to afford the title compound, 12.07g (93%).
~ (CDC13): 3.10 (6H~s), 2.0~2.40 (2H,m), 3.40-4.20 (4H,m),4.55-4.65 (lH,m) and 4.70-4.85 (lH,m).

Description 17 (3R,4S)-Diaminotetrahydropyran (D17) The dimesylate (D16) (12.07g,44 mmol) was dissolved in dimethylsulphoxide (88ml) and treated with lithium azide (10.8g,220mmol). The mixture was hcated at 100C for 40 hours~ then cooled to ambient and poured intowater (1.03L) and extracted with ethyl acetate (1.03L,2 x 0.59L). The combined organic phase was washcd with water (300ml) and brine (300ml), dried over MgSO4 n and concentratcd in ~acuo to give the crudc diazide as a brown oil, 3.7g. This was dissolved in tetrahydrofuran (45ml), and added dropwise to a cold (0C) suspension of lithium alùminium hydride (3.34g, 88mmol) in tetrahydrofuran (220ml), maintauning thc temperature below +10C. After completion of addition the suspension was stirred at 0C for 0.5 hours then warmed to ambient and stirred for 16 hours.
The mixture was recooled to 0C and quenched sequentially with water (3.34ml) in tetrahydrofuran (5ml),15% aqueous sodium hydroxide (3.34ml) and further water (lOml). The mixture was allowed to warm to ambient, stirred for one hour then filtered through celite, rinsing with tetrahydrofuran (2x400ml). The combined filtrate was concentrated in vacuo to give the title diamine (3) as a colourless oil, 2.62g (51%).
(CDC13): 1.2~1.90 (6H,m), 2.40-2.50 (2H,m), 2.9~3.40 (2H,m) and 3.80-4.00 (2H,m).

wo 94/03271 21417 ~ ~) pcr/GB93/ol666 Description 18 -(3R,4S)-bis-(3,5-Di-t~rt-Butyls~licylideamino)tetrahydropyran, (Dl8) To the diamine (D17) (2.55g, 22mrnol) in ethanol (220ml) was added 3,5 di~
tertbutylsalicaldehyde (10.3g,44mmol). The mixture was heated at reflux for 2 S hours, cooled to ambient filtered, and the crystalline product dried in vacuo to afford the title compound as yellow clystals, 4.81g, (4û%). `
o (CDC13): 1.20 (18H,s), 1.40 (18H,s),1.50-2.20 (2H~m), 3.5~3.70 (4H,m), 4.00 4.15 (2H,m), 7.00 (2H,bs), 7.35 (2H,bs), 8.33 (lH,s), 8.37 (1H,s) and 13.20 (2H,bs).

Description 19 (3R,4S)-bis (3-te-t~Butyl-5-methylsalicylideamino) tetrahydropyran (Dl9) A solution of the diamine (D17) (0.62g,5.35mmol) and 3-tenbutyl-5-methylsalicaldehyde (2.05g,10.7mrnmol) in ethanol (40rnl) was heated at reflux for 2 hours. The solution was cooled then s~ored at 4C for 70 hours to afford a yellow precipitate. This was filtered, washed with cold 95% aqueous ethanol (5ml) and dried `
in ~acuo to afford the title compound, 1.22g (49%).
~ (CDC13): 1.40 (18H,s),1.80-2.20 (2H,m), 2.20 (6H,s), 3.40-3.70 (4H,m), 4.00 4.20 (2H,m),-6.80 (2H,bs~,7.05 (2H,bs),8.27 (lH,s), 8.30 (lH,s) and 13.30 (2H,bs).
, Description 2û
(3S,4S)-bis (3,5-di-tert-Butylsalicylideamino) tetrahydrofuran (D20) A soluion of (S,S)~iamine (D6) (0.9og, 9.4mrnol) and 3,5~i-tertbutylsalicaldehyde (4.4g, 18.8mrnol) in ethanol (9Oml) was heated at reflux for 2 hours. The mixture was cooled to 0C, filtered and the solids washed with cold ethanol and dried to afford the title compound as yellow crystals, 3.07g (61%).
~ (CDC13): 1.27 (18H,s), 1.45 (18H,s),3.95-4.10 (4H,m), 4.3~4.40 (2H,m), 7.05 (2H,d),7.40 (2H,d), 8.35 (2H,s) and 13.20 (2H,s).
Description 21 (3S,4R)-Dihydroxy-(2R)-(hydroxymethyl)tetrahydropyran (D21) A solution of D-Glucal (16.0g, 0.11 mole) in 50% aqueous ethanol (SOOml) was treated with platinum oxide (0.75g) and hydrogenated at ambient at atmospheric pressure for 5 hours. The suspension was treated with charcoal (50g) filtered through celite (200g3 and the solids washed with 50% aqueous ethanol ~300ml). The combined filte~d was evaporated in vacuo and dried over P ~Os to afford the title compound as a colourless oil, 16.0g (99%)~

WO94/03271 ~4 pcr/Gss3/ol666 ~ (CD30D): 1.5~1.70 (lH,m), 1.8~2.20 (lH,m), 3.00-3.20 (2H?m), 3.30-3.70 (3H,m), 3.~0-4.00 (2H,m) and 4.90 (3H,bs) 3. Dictionary of Organic Compounds,5th Edi~ion, 1982, Chapman and Hall, London, 2754, and references therein.
Description 22 (3S,4R)-Dihydroxy-(2R)-(triphenylmethoxymethyl) tetrahydropyran (D22) A solution of the triol (D21) (1.76g, 11.9mrnol) in pyridine (20ml) was treated with trityl chloride (3.31g,11.9mmol) and 4-(dimethylarnino)pyridine (50mg).
10 Diisopropylethylamine (1.92g,14.8mmol, 1.25eq) was added and the soluion stirred for 4 hour at ambient tcmperature.
The mixhlre was poured into water (200ml) and extracted with diethyl ether (2x200ml). The combined organic phase was washed with 10% aqueous citnc acid (lOOrsll) and bnne (100ml), dried over MgSO4 and cencentrated in vacuo to an oil.
15 The residue was chromatographed on silica (eluent:gradient of methanol in chloroform) to afford the title compound as a colourless foam, 3.70g (79.7%).
~ (CDCl3): 1.60 1.80 (1H,m),1.90^2.00 (lH,m),2.70 (2H,bs,D20 exch), 3.25-3.50 (SH,m), 3.60 3.70 (lH,m),3.90-4.00 (lH,m) and 7.20-7,50 (lSH,m).

Description 23 ~ `
(3R,4R)-Dimethanesulphonyloxy-(2R)-(triphenylmethoxymethyl)tetrahydropyran (D23) To the diol (D22) (3.10g,7.95mrnol) in a mixture of diethyl ether and tetrahydrofuran (2:1,150ml) was added triethylamine (1.76g, 17.5mmol). The rnixture was cooled to 0C and methanesulphonyl chloride ~1.9lg,16.7mmol) added.After 2 hours the suspension was filtered and the filtrate concen~ated in ~acuo, then r~dissolved in ethyl acetate (200ml). The solution was washed with 10% aqueous citric acid (100ml) and brine (SOml), then dried over MgSO4. Solvent was removedin ~acuo and the residue dried to afford (12) as a colourless solid, 4.26g (95%).
~ (CDCl3): 2.2~2.50 (2H,m), 2.50 (3H,s), 3.10 (3H,s), 3.20-3.30 (lH,m), 3.40-3.60 (3H,m), 3.95-4.10 (lH,m),4.70~.80 (2H,m) and 7.20-7.50 (1SH,m).

Description 24 (3S,4S)-bis(3,5-Di-tert-butylsalicylideamino)-(2R)-(triphenyl methoxy nethyl)tetrahydropyran (D24) A mixture of the dimesylate (D23) (2.gSg,5.22mmol) and lithium azide (1.28g, 26.1 mmol) in dimethyl sulphoxide (20ml) was heated at 100 110C for 24 hour. The solution was cooled. pou~ into water (200m1) and extracted with ethyl acetate (2x300ml). The combined organic phase was washed with water (2x300m1) W O 94/03271 2 i 41 7 9 ~ PC~r/G B93/01666 ~
and brine (300ml), and dried over MgS04. Removal of the solvent afforded the interrnediate diazide as a yellow foarn (1.52g).
A 1.40g portion of the diazide in tetrahydrofuran (lOml) was added to a ~-~
suspension of lithium aluminium hydride (470mg, 12.4nunol) in tetrahydrofuran 5 (30ml) at 0C. After stirring at 0C for 1 hour the mixture was allowed to warm to ambient and stirred for 16 hours. The suspension was recooled to 0C and quenched sequentially with water (O.Sml),15% aqueous sodium hydroxide (O.Sml) and furtherwater ( l.Sml3~ After wam~ing the ambient and sti~ing for 1 hour the mixture wasfiltered, the solids washed with tetrahydrofuran (2x20ml) and the combined filtrate evaporated to afford the crude diamine as a foam (1.28g). ;
A portion of the diamine (1.18g) and 3,5-di-tert butylsalicaldehyde (1.42g, 6.08mmol) in ethanol (30ml) was heated at reflux for 4 hour then cooled to ambient. -Solvent was removed in vacuo and the residue chromatographed on silica (eluent:
gradient of chloroform in hexane) to afford the title compound as a yellow powder, -~
210mg, in 8.4% overall yield from (D23).
o (CDC13): 1.25 (9H,m), 1.30-1.60 (2H,m), 1.32 (9H,s) 1.40 (9H,s), 1.50 (9H,s), 2.40-2.55 (lH,s),2.70-2.80 (lH,s), 3.30-3.60 (2H,m), 3.90-4.30 (3H,m), 6.85 (lH,bs), 7.00-7.35 (16H,m),7.38 (lH,bs), 7.45 (lH,bs), 8.30 (lH,s), 8.50 (lH,s).13.25 (lH,s) and 13.50 (lH,s~.
Description 25 )trans-l-Benzoyl-3,4-bis~methanesulphonyloxy)piperidine (D25) (i:)trans-l-Benzoylpiperidine-3,4-diol (3g, 13.6mmol) was suspended in dichloromcthane (70ml) and triethylamine (5.74ml, 43mmol) was added. The mix~ure was cooled to -10C and methanesulphonyl chloride (2.6ml, 34mmol) added I
over S min. Aftera further 15 min the mixnlre was poured into ice-water (50ml) and the organic layer washed with 5% aqueous citric acid (30ml). The solution was dried I ~
over MgS04 and concentrated in ~acuo to a foam, 5.3g (100%).
H (CI)C13):1.95 (2H,m), 2.30 (2H,m),3.15 (6H,s), 4.70 (2H,m), 4.85 (2H,m) and 7.45 (5H,m).
4. V. Petrow and 0. Stepehnson, J Pharm. Pharmacol, 1962,14, 306-314.
:
Description 26 - (+)trans-l-Benzoyl-3,4-diazidopiperid;ne (D26) A mixture of the dimesylate (D25) (S.3g, 14mmol) and lithium azide (3.4g, 69mmol) in ~imethylsulphoxide (36ml) was heated at 100C for 18 hours. Afur cooling the reaction mixture was partitioned between dichloromethane (200ml) andwater (SOml). The aqueous phase was separated and further extracted with dichloromethane (lOOml,50ml) and the combined organic extracts washed with water - 19-wO 94/0327l ~,~ 4~ ~ 9 ~ PCI/GB93/01666 (3x50ml dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica (eluent: gradient of methanol in dichloromethane) to afford the title compound as a colourless solid,9OOmg ~24%).
~H (CDC13):1.60 (2H,m), 2.10 (2H,m),3.05 (2H,m), 3.20 (2H,m) and 7.40 (5H, m).

Description 27 (+)trans-1-Benzoyl-3,4-diaminopiperidine (D27) A solution of the dia~ide a)26) (450mg, 1.7rnmol) in ethanol (30ml) was treated with Lindlar catalyst (5%Pd/ CaC03, 250rng) and stirred under hydrogen (1 ~`
atm) for ~4 hour. The rnixture was filtered and solvent removed in vacuo to afford the title compound as oil, 350mg (94%).
H (DMSO) 1.20 (lH,m),1.65-1.80 (2H,m),2.20 (2H,m),2.70 (lH,m), 3.00 (lH,m), 3.30 (lH,m),4.40 (lH,m) and 7.40 (SH,m).
~:
Description 28 (-)trans-1-Benzoyl~3,4-bis(3,5-di-tert-butylsalicylideamino)piperidine (D28) A solution of the arnine (D27) (350rng,1.6mmol) and 3,5-di-tertbutylsalicaldehyde (960mg, 4.1mrnol) in ethanol (40ml) was h~ated at reflux for 3 hours. The rnixture was cooled and filtered to afford the racemic bis-imine, 652mg ~;
(63%).
A 100rng sample was separa~ed by chiral hplc (CHIRALPAK AD, eluent 2%
ethanol in hexane) to afford the title compound as a single enan~iomer, [ ]D = 228 (c=0.13, CHC13).
~H (CDC13):1.20 (18H,s),1.45 (18H,s), 2.00 (2H,m),3.25 (2H,m), 3.45 (lH,m), 3.55 (lH,m), 4.35 (2H,m), 6.95 (2H,s), 7.40 (;'H,m), 8.30 (2H,s) and 13.15 (2H,bs).

WO94/03271 21~179 ~ pcr/Gss3/ol666 Example 1 (i) 3,4-bis (3-teff Butyl-5-methylsalicylideamino) tetrahydrofuran manganese (III) chloride (E1) S A suspension of the racem~ic ligand (D3) (690 mg, 1.53 mmol) in EtOH
(25 ml) was heated with Mn(OAc)2.4H20 (750 mg, 3.06 mmol) at reflux for 18h.
LiCI (195 mg, 4.49 mmol) was added and reflux continued for a further 0.5h.
Solvent was removed in vacuo and the residue chromatographed on silica (Merck 9385, 100g) eluting with a gradient of MeOH in CHC13, to afford the title compound ;;
as a brown powder (90 mg, 11%) together with unreacted (D3), 420 mg (61%
recovery).

Example 2 , The epoxidation of 2,~-dimethyl-6-pentafluoroethyl-2H-l-benzopyran using (E1) to give (~) 2,2-dimethyl-3,4-epoxy~pentatluoroethyl-2H-l-benzopyran (E2) Aqueous sodium hypochloride solution (16.75% w/v, 4.44 ml, 2 eq) was diluted to 12.5 ml with H20. 0.05M Na2HP04 (aq) (S ml) was added and th pH .
adjus:ted to 11.3. Thc rcsulting solution was cooled to 0C and added to a solution of 2,2 dimethyl-~pentafluoroethyl-2H-l-benzopyran (1.39g, 5 mmol) and the catalyst (El) (45 mg, 0.1 mmol, 2 mol%) in CH2C12 (5 ml). The ~ixture was sdrred at 0C for lh thcn allowed to warm to room temperature and , sdrred for a fur~her 16h.
Hexane (50 ml) and H2O (25 ml) were added and the organic layer separated. ~The aqueous phase was washed with hexane (50 ml) and the combined organic phase :
dried over MgSO4 and concentrated in vacuo to give a pale yellow oil, 1.42g.
.
Ouantitive hplc analysis showed this to contain 1.08g (74%) of the desired epoxide (E2) togcther with a trace (<5% recovery) of starting material both compounds idendcal (IH nmr) with authentic samples.
Example 3 (S,s) trans 3,4-bis (3-tert Butyl-5-methylsalicylideamino)tetrahydrofuran manganese (III) chloride (E3) ~` Method A (using manganese (I~) acetate) A solution of (D7) (0.95g, 2.11 mmol) and Mn(OAc)2.4H2O (1.03g, 4.22 `
mmol) in EtOH (40 ml) was heated at reflux for 17h. Uthium chloride (268 mg, 6.33 n~nol) was added and reflux continued for a further 0.5h. After cooling to ambient the solvent was removed in vacuo and the residue chromatographed on silica (Merck 4 ~. r ~

Wo 94/03271 pcr/GB93/o1666 9385, gradient of MeOH in CHCl3) to afford (E3) as a brown powder, 26 mg (2.3%),together with unreacted (D7), 683 mg (72%).
Method B (using manganese (III) acetate)S.
A solution of (D7) (1.53g, 3.4 mrnol) in a mixture of CH2C12 (17 ml) and MeOH (17 ml) was treated with Mn(OAc)3.2H20 (0.01g, 3.4 mmol). The mixture `
was heated at reflux for 3h, cooled to ambient and treated with lithium chloride(0.21g, S.l mmol). After stirring for 16h the solvent was reduced in vacuo to ca 8 ml, Et20 (70 ml) was added and thc suspension stimed for lh. The mixture was filtcred and the solids washed with Et20 (3 x 20 ml) and dried in vacuo to afford (E3) as a brown powder, 1.57g (86%).
5 T. Matsushita and T. Shono, Bull. Chem. Soc. Japan, 1981, 54, ~ `~
3743-3748.
. .
-Example 4 The chiral epoxidat;on of 2,2-dimethyl-6 pentatluoroethyl-2H-1-benzopyran using (E3) to give (3R,4R)-2,2-dimethyl-3,4-epoxy-6-pentalluoroethyl-2H-l-benzopyran (E4) Aqueous sodium hypochlorite solution (16.75% w/v, 8.9 rnl 20.0 mmol) was diluted to 25 ml with H2O. 0.05M NaH2PO4 (aq) (10 rnl) was addcd and the pH
adjustcd to 11.3. Thc rcsulting solution was coolcd to 0C and added to a solution of `
2,2~imethyl-~pentafluoroethyl-2H-I-benzopyran (2.78g, 10.0 mrnol) and the catalyst (E3) (0.108g, 0.2 rnmol, 2 mol%) in methylene chloride (10 ml). The mixtùre wæ stirred at 0C for Ih then allowcd to warm to room temperaturc and stirred for a further 20h.
Hexanc (100 ml) and H20 (50 rnl) were added and the organic layer - separated. The aqueous phase was washed with hexane (100 ml) and the combined organic plsase dried over MgSO4 and concentrated in vacuo to give a pale yellow oil, 2.86g.
; Quandtadvc hplc analysis showed this to contain 2.09g, (71%) of the desired epoxide (E4) and a small quantity (about 10%) of starting material, both compounds identical (lH NMR, TLC, HPLC) with authentic samples, e.e. = 66% by chiral HPLC.

Example 5 Preparation of (R,R)-5,6~bis-(3,5-di-tert-butylsalicylidenamino)-1,3.dioxepane].mangenese ~'III) chloride (SR,6R)-Di-(3,5-di-tert-buql)salicylidenamin~1,3-dioxepane (l.Og, 1.77mmol) (D14) and manganese (II) acetate tetrahydrate (2.17g, 8.87mmol) were suspended in 95~ ethanol (S0ml), and the mixture stirred under rellux overnight. - 22-wo 94/0327l 21 ~ 1 7 g ~ PCT/GB93/01666 ~;
Lithium chlonde (0.38g, 8.96mmol) was then added and heating continued for a further 30 minutes. The reaction mixture was then cooled, water (60ml) added, and filtered through Celite. The dark precipitate was washed well with water, then dissolved in dichloromethane (80ml), dried (MgS04), and the solvent evaporated tO
give the title compound as a dar~c brown solid (0.9g,78%).
C3sHsoN204MnCl requires: C:64.36, H:7.72, N:4.29%.
found: C: 64.S7, H: 7.57, N: 4.09%
CI-MS: m/e 565 (MH-Mn,CI)+, 235 (3,5-di-tert-butylsalicaldehydeH)+.

Example 6 Preparation of (3S,4S)-2-2-dimethyl-3,4-epoxy-6-pent~tluoroethyl-2H-l-benzopyran by oxidation of 2,2-dimethyl-6-pentafluoroethyl-2H-l-benzopyran using sodium hypochlorite catalysed by (R,R)-5~6-bis-(3,5-di-tert-butylsalicylideamino)-1,3-dioxepane~-manganese (III) chloride Sodium hypochlorite solution (11.4% w/v, 13.1ml,2eq.) was diluted to 2 with water, followed by the addition of 0.05 molar sodium dihydrogen phosphate (lOml). The pH of this solution was adjusted tO 11.3 with 2 molar aqueous sodiumhydroxide, and it was then ad~ed to a solution of 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran (2.78g, 10mmol), and (R.R)-11,2-bis-(3,5-di-tert- `-butylsalicylidenamino)-1,3-dioxepane]-manganese (III) chloride (0.131g, 2mol%) in dichloromethane (10ml), which had been cooled in an ice bath. The reaction mixture was allowed to wann to ambient temperature and stirred for 22 hours, by which time the reaction was essentially complete.
The reaction mixture was diluted with water (SO~T1I) and hexane (lOOml), filtered through Celite, the organic phase separated and the aqueous extracted with a further portion of hexane (100ml). llle combined organic phases were dried (MgS04) and evaporated to give the title compound as a yellowish solid (2.6g, 88%).
Hplc determination of the chiral purity of the crude product gave an e.e. of 86.0%.
The crude product was recrystallised from hexane to afford colourless crystals, m.p.
72-73C.
lH n.m.r.(CDC13):~1.29 (s,3H,CH3), 1.59 (s,3H,CH3), 3.53 (d,lH,H-3), 3.94 ,~
(d,lH,H-4), 6.90 (dd,lH,H-8), 7.46 (dd,lH,H-7),7.s? (dd,lH,H-5).
13C n.m.r. (CDC13): ~ 22.9 (CH3), 25.5 (CH3),50.4 (C-3), 62.5 (C-4), 74.1 (C-2), 113.4(tq,CF3), 118.4(C-8)~ 119.1 (qt,CF2), 120.4(C-4'), 121.1 (t,C-6), 128.1, 128.6 (2xt,C-5,7), 155.7(C-8').
EI-MS:m/e 294 M+, 279 (M-CH3)+.
C13Hl 1FsO2 requires: C:53.07, H: 3.77%.
found: C:52.69,H: 3.82%.

W O 94/03271 2~ 4~ 9 PCT/GB93/01666 Exam ple 7 (3R,4S)-bis-(3,5-di-tert-butylsalicylideamino)tetrahydropyran-manganese (III) chloride(E7) S A solution of the ligand (D18) (4.81g, 8.8mmol) in dichloramethane-methanol (1:1, 88ml) was treated with maganese triactate dihydrate (2.35g, 8.8mrnol)~and the mixture heated at reflux for 4 hours. Lithium chloride (0.56g, 13.2mmol) was added and heating at reflux continued for a further 1 hour. The mixture was cooled, concentrated in ~acuo and the residue triturated with diethyl ether (220ml). The solid 10 product was filtered, washed with diethyl ether (2 x 65ml) and dried to afford (5) as a brown powder,5.3g (94%).

Example ~
The chiral epoxidation o~ 2,2-dimethyl 6-pentafluoroethyl-2H-1-benzopyran 15 using (E7) to give (3S,4S)-2j2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H-l-benzopyran (E8) ~queous sodium hypochloritc (15.24% w/v,9.8ml,20mmol) was diluted to 25ml with H20Ø05M NaH2P04(aq) (lOml) was added and the pH adjusted to 11.3.
; The resulting solution was cooled to 0C and added to a solution of 2,2-dimethyl-~
20 pentafluoroethyl-2H-I-benzopyran (2.78g, lOmmol), and the catalyst (E7) (127mg, - 0.2mol%) in dichloromethane (lOml). The mixture was stirred at 0C for 1 hour thcn allowed to warm to ambient and stirred for a further 18 hours.
Hexane (lOOml) and water (50rnl) were added and the organic layer separated.
- The aqueous phase was washed with hcxane (lOOrnl) and the combined organic phase 25 dried over MgS04 and concentrated in ~acuo to afford a yellow solid (2.60g).
Quantitative hplc analysis showed this to contain 2.47g (84%) of the desired ; ~ ~ epoxide (E8), identical (lH nmr, tlc, hplc) with an authentic sample, ee=88.4% by :~
chiral hplc.
~-Example 9 (3R,4S)-bis-(3-tert-butyl-5-methylsalicylidenamino)tetrahydropyran-manganese (III) chloride (E9) A solution of the ligand (D 19) (928mg, 2mrnol) in dichloromethane-methanol (1:1, 20ml) was treated with manganese triacctate dihydrate (536mg,2mmol) and heated at reflux for 3 hours. The mixture was coolcd to ambient, lithium chloride (128mg,3mn~ol) was added and thc solution stirred for 1 hour. The reaction mixture was concentrated in ~acuo and the residue triturated with diethyl ether (40ml). The solid product was filtered, washed with diethyl ethcr (2xlSml) and dried in vacuo to afford the title compound as a brown powder, l.O9g (98%).

wo 94/03271 21417 ~3 0 PCI/GB93J01666 Example 10 The chiral epoxidation of 2,2-dimethyl-6-pentatluoroethyl-2H-1-benzopyran using (E9) to give (3S,4S)-2,2-dimethyl-3,4-epoxy-6-pentatluoroethyl-2H-l- , S benzopyran (E8) Aqueous sodium hypochlorite (15.24% w/v, 9.8ml, 20mmol) was di~uted to `
25ml with H20. 0.05M NaH2P04(aq) (lOml) was added and the pH adjusted to 11.3.
The resulting solution was cooled to 0C and added to a solution of 2,2-dimethyl-~
pentafluoroethyl-2H-1-benzopyran (2.78g, lOmmol) and the catalyst (E9) (lllmg, 0.2mrnol, 2mol~) in dichloromethane (lOml). The mixture was stirred at 0C for 1hour then allowed to warm to ambient and stirred for a further 18 hour. -Hexane (lOOml) and water (SOml) were added and the organic layer separated.
The aqueous phase was washed with hexane (lOOml) and the combined organic phase dricd over MgS04 and concentrated in vacuo to give (E8) as a yellow oil (2.72g, 93%), identical (lH nmr, tlc, hplc) with an authentic sample, ee='73% by chiral hplc. ~ -Example 11 (3S,4S)-bis-(3,5-di-tert-Butylsalicylideamino)tetrahydrofuran-manganese (III) chloride (E11) A solution of the ligand (D20) (1.07g, 2mmol) and manganese triacetate dihydrate (536mg, 2mmol) in a rnixture of dichloromethane and methanol (1: 1, 20ml) was hea~ed at reflux for 6.5 hour. Thc solution was cooled to arnbient, lithium `
chloride (128mg, 3mmol) was added and the n~ixture stilTed for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated with diethyl ~ ~-ether (SOml). The solid product was filtered, washed with diethyl ether (2xlSml) and dried in vacuo to afford the title compound as a brown powder, 1.12g (89%).
~ `
Example 12 The chiral epoxidation of 2,2-dimethyl-6-pentafluoroethyl-2H-l-benzopyran using (E11) to give (3R,4R)-2,2-dimethyl-3,4-epoxy-6-pentatluoroethyl-2H.l.
benzopyran (E4) Aqueous sodium hypochlorite (15.24% w/v, 9.8ml, 20mmol) was diluted to 25ml with H20. O.OSM NaH2P04(aq) (lOml) was added and the pH adjusted to 11.3.
The resulting solution was cooled to 0C and added to a solution of 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran (2.78g, lOmmol) and the catalyst (E11~ (124.5mg, 0.2mmol, 2tnol%) in dichloromethane (lOml). The mixture was stirred at 0C for 1hour then allowed to wann to ambient and stirred overnight.

wo 9~/03271 ~ 1 pcr/GBg3/ol666 ~-~
Hexane (100ml) and water (50ml) were added and the organic layer separated. ~
The aqueous phase was washed with hexane (100ml) and the combined organic phase dried over MgSO4 and concentrated in vacuo tO a yellow oil, 2.73g.
Quantitative hplc analysis showed this to contain 2.47g (84%) of the desired 5 expoxide (E4), identical (lH nmr, tlc, hplc) with an authentic sample, ee=85.6% by chiral hplc.

Example 13 (3R,4S~bis-(3,5-Di-tert-Butylsalicylidenamino)-(2R)-10 (triphenylmethoxg nethyl)tetrahydropyran-nunganese (III) chloride (E13) To the ligand (D24) (16~ng, 195~1mol) in dichloromcthane-mcthanol (3:2, 5ml) was added NaOH (0.93ml of 0.417 molar in methanol,390 ~mol) and manganese triacetate dihydrate (52.5mg,195 ~lmol). The solution was heated at reflux for 3 hours, lithium chloride (12.5mg, 300 ~mol) addcd and the mLlcture stirred 15 for 15 hours.
Solvent was removed in vacuo and thc residue triturated with diethyl ether (lOml). l'he solid product was filtetcd, washed with diethyl ether (2x2ml) and dned with afford the title compound as a brown powder, 136mg C77%) 20 ~ Example 14 The chiral epoxidation of 2,2-dimethgl-~-pentafluoroethyl-2H-l-benzopgran using (E13) to give (3S,4S)-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H-l-~; benzopyran (E8) Aqueous sodium hypochlorite (11.4% w/v, 2.6ml, 4mmol) was diluted to Sml with water. 0.05M NaH2PO4(aq) was added and the pH adjustcd to 11.3. The resulting solution was cooled to 0C and addcd to a solution of 2,2-dimcthyl-6-pcntafluoroethyl-2H-1-bcnzopyran (560mg, 2mmol) and the catalyst (E13) (36mg, 0.04mmol) in dichloromethane (2ml) at 0C. The reaction was stirred for 1 hour at 0 C then at room tcmpcrature overnight.
Hcxane (20ml) and water (lOml) were added and the organic layer separated.
The aqueous phase was extracted with further hexane (20ml) and the combined organic phase dried (MgSO4) and the solvent removed in vacuo to afford (E8) as aycllow oil (0.55g).
Quantitative hplc analysis showed this to contain 0.496g (84%) of thc desired cpoxide (E8), idcntical (lH nmr, tlc, hplc) with an authentic sample, ee=84% by chiral hplc., I;~

Example 15 .

wo 94J03271 21 41 7 9 0 PCT/GB93/01666 (-)trans-l-Ben~oyl-3,4-bis(3,5-di-tertbutylsalicylideamino) piperidine-manganese(III) chloride (E15) A mixture of the (-) ligand (D28) (20mg, 0.013mmol) and manganese triacetate dihydrate (lOmg, 0.037rrunol) in dichloromethane-methanol (3:2, Sml) was -S heated at reflux for 4 hour. Lithium chloride (1.6mg, 0.038n~nol) was added and `
reflux con.inued for a fur~her 1 hour. .^ ` -Solvent was removed in ~racuo and the residue chromatographed on silica (eluent: 10% methanol in dichloromethane) tO afford the title compound as a brown powder, 22mg (97%).
Example 16 The chiral epoxidation of 2,~-dimethyl-6-pentalluoroethyl-2H-l-benzopyran using (E15) to give (3R,4R)-2,2-dimethyl-3,4-epoxy-6-pentatluoroethyl-2H~
benzopyran (E4) A solution of 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran (560rng, `~
2mmol) and the catalyst (E15) (22mg, 0.03mmol) in dichloromethane (2ml) was ~ -cooled to 0C. A mixture of aqueous sodium hypochlori~e solution (2.6ml of 11.4%w/v, 4mmol) and O.O5M NaH2PO4(aq) (2rnl, adjusted to pH 11.3) was added, the mixturc ssirred at 0C for 1 hour, then allowed to warm to ambient and sti~ed overnigh;.
The rnixture was diluted with water (lOrnl) and extracted with hexane -(4x20ml). The combined organic phase was washed with water (lOml), dried over Na2SO4 and evaporated to afford the desired epoxide, 492mg (83%). Analysis by chiral hplc showed an ee of 77%.

` .:

Claims (14)

WO 94/03271 PCT/GB93/01666
1. A compound of formula (I):
(I) n which M is a transition metal ion;
A is a counter-ion if required;
r, s and t are independently 0 to 3 such that r+s+t is in the range of 1 to 3;
Ra, Rb, Rc are each independently hydrogen or CH2OR' where R' is hydrogen or an organic group;
B and E are independently oxygen, CH2, NRd in which Rd is alkyl, hydrogen, alkylcarbonyl, or arylcarbonyl or SOn where n is 0 or an integer 1 or 2, with the proviso that B and E are not simultaneously CH2 and that when B is oxygen, NRd or SOn, then r cannot be 0, and when E is oxygen, NRd or SOn, then t cannot be 0;
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, alkyl or alkoxy.
2. A compound according in claim 1 in which M is Mn.
3. A compound according to claim 2 in which Mn is in an oxidation state (II) or (III).
4. A compound according to claim 1 in which A is chlorine.
5. A compound according to any one of claims 1 to 4 in which s and t are zero, ris 1 and Ra is hydrogen, B is oxygen and E is CH2; or r, s and t are 1, Ra, Rb and Rc are hydrogen and B and E are both oxygen; or s is zero, r and t are both 1, Ra is hydrogen or triphenylmethyloxymethylene and Rc is hydrogen, B is oxygen and E is -CH2-; or r and t are both 1, s is zero, Ra and Rc are hydrogen, B is NRd where Rd is phenyl carbonyl and E is CH2.
6. A compound according to any one of claims 1 to 5 in which R l and R8 are tertiary butyl, R3 and R6 are tertiary butyl or methyl and R2, R4, R5 and R7 arehydrogen.
7. A compound selected from (?) 3,4-bis (3- tert Butyl-5-methylsalicylideamino ) tetrahydrofuran manganese (III) chloride;
(S,S) trans 3,4-bis (3-tert Butyl-5-methylsalicylideamino)tetrahydrofuran manganese (III) chloride;
Preparation of (R,R)-5,6-bis-(3,5-di-tert-butylsalicylidenamino)-1,3-dioxepane]-mangenese (m) chloride;
(3R,4S)-bis-(3,5-di-tert-butylsalicylideamino)tetrahydropyran-manganese (m) chloride;
(3R,4S)-bis-(3-tert-butyl-5-methylsalicylidenamino)tetrahydropyran-manganese chloride;
(3S,4S)-bis-(3,5-di-tert-Butylsalicylideamino)tetrahydrofuran-manganese (III) chloride;
(3R,4S)-bis-(3,5-Di-tert-Butylsalicylidenamino)-(2R)-(triphenylmethoxymethyl)tetrahydropyran-manganese (III) chloride and (-)trans-1-Benzoyl-3,4-bis(3,5-di-tertbutylsalicylideamino) piperidine-manganese(III) chloride.
8. A process for the preparation of compounds of formula (I), as defined in claim 1 which comprises forming a transition metal complex of the following compound of formula (II):

(II) where variables R1 to R10, B, E, r, s, t Ra, Rb and RC are as defined in relation to formula (I), in claim 1 and thereafter if necessary separating any enantiomers.
9. A process for the preparation of compounds of formula (II), in claim 1 which comprises condensing sequentially, in any order, a compound of formula (III):
(III) where r, s, t, Ra, Rb and Rc E, B are as defined in formula (I) and R11 and R12 independently represent hydrogen or an amine protecting group, providing at least one of R11 and R12 is hydrogen, with a compound of formula (IV);
(IV) and a compound of formula (V), removing any protecting group R11 or R12 as necessary;

(V) wherein R1 to R10 are as defined in relation to formula (I), and thereafter as required isolating the required compound including if necessary separating any enantiomers.
10. A process for enantioselectively epoxidising a prochiral olefin in the presence of an oxygen source and a chiral catalyst of formula (I) as defined in claim 1.
11. A process according to claim 10 in which the prochiral olefin comprises one of the following list of groups as part of its structure: cyclohexene, 5,6-dihydro-2H-pyran, 1,2,5,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine and 5,6-dihydro-2H-thiopyran.
12. A process according to claim 10 or 11 in which the prochiral olefin comprises one of the following list of groups as part of its structure: 1,2-dihydronaphthalene, 2H-chromene, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline and 2H-thiochromene.
13. A process according to any one of claims 10 to 12 in which the prochiral olefin is 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran.
14. A process according to claim 13 in which the 2,2-dimethyl-pentafluoroethyl-chromene (3S,4S)-epoxide product is subsequently converted to trans-6-pentafluoroethyl-3,4-dihydro-2,2-dimethyl-4R-(pipendin-2-on-1-yl)-2H-1-benzopyran-3S-ol.
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