OA10327A - Process for epoxidising prochiral olefins and a catalyst therefor and intermediates for making the catalyst - Google Patents

Description

010327 7 » //

PROCESS FOR EPOXIDISING PROCHIRAL OLEFINS AND A CATALYST TKEREFOR ANDINTERMEDIATES FOR MAKING THE CATALYST

This invention relates to a novel proccss ior preparing epoxides from olefins5 and in particular chiraïly cnriched epoxides, certain novel catalysts used in such process and contpounds associatcd with Liie process. WO 91/14694 dcsciibcs certain catalysts of the following formula (I):

in v/hich M is a transition métal ion, A is an anion, and n is eilher 0, 1 or 2. At leastone of or Xp selected from tlie group consisting of silyls, aryls, secondaryalkvls and teriiary alkyls; and at least one of X3 or X4 is selected from the same 15 group. Y|, Y2, Y3, Y4, Y5 and Y/, arc independently selected from the groupconsisting of hydrogen, halides, alkyls, aryl groups, silyl groups, and alkyl groupsbcaring heteroatoms such as alkoxy and halide. Also, at least one of Rj, R2, R 3 andt<4 is selected from a first group consisting of H, CH3, C2H5 and primary alkyls.Fuithennore, if is selected from said fitst group, lhen R2 and R3 are selected from 20 a second group consisting of aryl groups, heteroatom-bearing aromatic gioups, secondary alkyls and teriiary alkyls. If R2 is selected from said first group, Lhen Rjand R4 aie selected from said second group. If R3 is selected from said first group,then Rj and R4 are selected from said second group. If R4 is selected from said firstgroup, then R2 and R3 are selected from said second group. Such catalysts are 25 described as being uscful in enanlioselectiveîy epoxidising a prochiral olefin.

In addition WO 91/14694 describcs certain catalysts of the formula siiown below,herein referred to as formula (IA): 010327

Y

Y 4 x '2

X X.

X ‘3 4 (IA) where M is defined as a transition métal ion and A is an anion; where n is either 3,4,5or 6; where at least one of X| or X2 is selected front the group consisting of aryls, 5 primary alkyls, secondary alkyls, tertiary alkyls, and hetero atoms; where at least oneof X3 or X4 is selected front the group consisting of aryls, primary alkyls, secondaryalkyls, tertiary alkyls, and hetero atoms; where at least one of Y j or Y2 is selectedfrom the group consisting of aryls, primary alkyls, secondary alkyls, tertiary alkyls,and hetero atouts; where at least one of Y4 or Y5 is selected from the group 10 consisting of aryls, primary alkyls, secondary alkyls, tertiary alkyls, and hetero atoms;where Y3, and Yg are independently selected from the group consisting of hydrogenand primary alkyl groups; where R j and R4 are trans to eaclt other and at least one ofR j and R4 is selected from the group consisting of primary alkyls and hydrogen; andwhere the carbons in the (C)n portion hâve substituents selected from Lite group 15 consisting of hydrogen, alkyl, aryl, and heteroatoms.

Such catalysts are described as being useful in enaniioselectively epoxidising a prochiral olefin. Thèse catalysts belong to the class of catalysts known in tlie art as’salen catalysts'.

Co-pcnding International Patent Application Number PCT/GB93/01666 (now 20 International Patent Application, Publication Nurnber WO 94/03271 ) also discloses asériés of salen catalysts, structurally distinct from tlie catalysts of formula (I) andhaving the general formula (II): 3 0Î0327

B imn v (CHR )t

FV

(ii) in which M is a transition métal 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 hydrogenor an organic group; B and E are independently oxygen, CH2, NR^ in which is alkyl, hydrogen,alkylcarbonyl, or arylcarbonyl or SOn where n is Ü or an integer 1 or 2, with theproviso that B and E are not simultaneously CH2 and that when B is oxygen, NR^ orSOn, then r cannot be 0, and when E is oxygen, NRd or SOn, then t cannot be 0;

Rj, R2. R3, R4, R5, Rg, R7, Rg, R9 and Rjq are independently hydrogen,alkyl or alkoxy.

The compounds of formula (II) also catalyse Üic enantioselectivecxpoxidiation of certain prochiral olefins.

It bas been suggcsted in the art that the use of compounds such as pyridineoxide and 2-melhyl imidazole in combination with certain chiral (salen) manganèse(TU) complex catalysts improves the Chemical yield such reactions (Syn. Lett. April1991, 265-266), although the effect upon the enantioselectivity of the catalysedreactions is currently not clear (Tetrahedron Vol. 50, No 15, p. 4323 -4334, 1994). Inthis context pyridine oxide and 2-metliyl imidazole are referred to as 'donor ligands’as they are considered to donor-bond to the metallic ion of the salen catalyst.

One particular problem associated with the use of such donor ligands is tirecomplété removal of the donor ligand from the final epoxide product, espccially inlarge scale reactions and most espccially when two phase reaction Systems are used. lt has now been discovercd tirât one particular compound, isoquinoline N-oxide, previously unrcported as a donor ligand, is particularly efficient as a donorligand in that it advantageously enhances catalyst turnover and in addition it possessesvery good solubility characteristics for use as a donor ligand, enabling it to be used inthe métal salen complex catalysed epoxidation réactions and subsequently 10 bereadily rcmoved from the epoxide products of Lire reaction. Il has also been τ 010327 discovered that a particular group of salen catalysts are especially suited lo use wilhdonor ligands in that the présence of the donor ligands consistently produccs noi onlyan increase in réaction rate but also an increase in the enantioselective specificity ofthe epoxidaticn reactions.

In addition a further sériés of salen catalysts which are structurally distinctfrom those of formulae fl), (IA) and (II) has now been prepared which surprisinglyaie also able to catalyse the enantioselective expoxidation of certain prochiral olefins.

Accordingly, in a first aspect, tlie invention provides a process forenantioselectively epoxidising a prochiral olefin, which process comprises reactingtlie prochiral olefin wilh a source of oxygen in the presence of a salen catalyst and asource of an électron donating ligand, characterised in that the donor ligand isisoquinoline N-oxide or a compound having donor ligand activity and havingsubstantially the same solubility characteristics as isoquinoline N-oxide. A suitable salen catalyst is a compound of formula (I), (ΙΑ), (Π) or acompound of formula (III) (which compound of formula (ΠΙ) is defined hereinafter).

The invention also provides isoquinoline N-oxide or a compound havingdonor ligand activity and having substantially the same solubility characteristics asisoquinoline N-oxide, for use as a donor ligand.

In a furLher aspect tlie invention provides a process for enantioselectivelyepoxidising a prochiral olefin, which process comprises reacting the prochiral olefinwilh a source of oxygen in the presence of a salen catalyst and a source of an électrondonating ligand, characterised in that the salen catalyst is a compound of formula (II). A source of an électron donating ligand is suitably provided by a compoundwhich is capable of forming a donor bond wilh the transition métal M of the saidsalen catalyst, such tliat in use tlie rate of the epoxidation reaction is increased and theenantioselective specificity of the resulting product may also be increased. A source of électron donating ligand is suitably provided by a compoundwhich is capable of forming a donor bond with the transition métal M of the salencatalyst such that in use the enantioselective specificity of the compound of formula(I) is increased. A suitable source of an électron donating ligand may be selected from the listconsisting of: ''pyridine N-oxide, 2-methyl pyridine N-oxide, 4-methyl pyridine N-oxide, 4-phcnyl pyridine N-oxide or isoquinoline N-oxide, especially isoquinoline N-oxidc.

In tlie compounds of formula (I) and (IA):

Preferred values for Μ,Α,η,Χρ X2, X3, X4, Yμ Y2, Y3, Y4, Y5, Υβ, RpR2, R3 and R4 are as defined in WO 91/14694.

Suitable catalysts are those of formula (IA) as defined above. A prefeired sub-gioup of catalysts are those of formula (IB) as defined below: 5 010327 'Z—f

in which Yj and Y4 arc the sanie and are sclectcd frorn üic group consisüng of methyli-butyl or methoxy and R2 and R3 are cither boüi phenyl or together with die carbonatoms to which they arc attached form a hexyl ring.

Most preferably, in catalysts of formula (IB), Y j and Y4 are botli i-butyl andR2 and R3 together with the carbon atoms to which they are attached form a hexylring.

In the conipounds of formula (II):

The suitable, favoured and preferred values of the variables A, B, E, Ra, R^,Rc, Rd, R' R}, R2, R3, R4, R5, Rô- R7. R8> Rç> r10· n> B s t are as described inWO 94/03271 unless otherwise stated herein.

Suitable organic groups R' include alkyl, alkylcarbonyl, arylcarbonyl or aryldérivatives.

Particular examples of R' include substiluted alkyl groups.

One example of R' is a triphenylmethyl group.

Preferably s and t are zéro, r is 1 and Ra is hydrogen, B is oxygen and E isCHo- or r, s and t are 1, Ra, R b and Rc are hydrogen and B and E are both oxygen; ors is zéro, r and t are both 1, Ra is hydrogen or triphcnylmethyloxymethylcne and Rcis hydrogen, B is oxygen and E is -CH2-; or r and t are both 1, s is zéro, Ra and Rcare hydrogen, B is NR^ where R^ is phenyl carbonyl and E is 0¾.

Suitably, R2, R4, R5 and R7 each independently represent hydrogen.

Suitably R μ R3, Rg and R g each independently represent Ομ^ alkyl.

Favourably Rj and Rg represent branched alkyl groups such as tertiary alkylgroups. .. R3 and R5 also advantageously represent branched alkyl groups.

N

One preferred example for each of and Rg is tertiary butyl.

Particular examples of R3 and R 5 are tertiary butyl and methyl.

Exemples of R2. R4, R5 and R7 are hydrogen.

Examples of the compounds of formula (II) include those exemplified in WO94/03271 and particularly include those compounds referred to herein.

As stated above a further aspect of the invention is the discove.ry of a novelsériés of salen catalysis: -é 0 ί 03

Accordingly, in a furihcr aspect lhe présent invention provides a compound of formula (J1I):

in which M is a transition métal ion; A is a counter-ion if required; B, B', E and E' are independently selected from the group consisting ofhydrogen aryl, Cj.g alkyl, silyl or aryl-Cj.5 alkyl in which any aryl or alkyl moietyis optionally substituted or B’ and B or E' and E together form a C2-6 polymethylenelink; with lire proviso that only one of the carbons marked with an asterisk is a chiralcentre; R|, R2, R3, R4. R5, R(j, R7, Rg, R9 and are independently hydrogen,alkyl or alkoxy.

In the compounds of formula (III):

Suitably, R2, R4, R5 and R 7 each independently represent hydrogen.

Suitably Rj, R3, Rg and Rg each independently represent Cj.g alkyl.

Favourably R] and Rg represent branched alkyl groups such as tertiary alkyl groups. R3 and R(5 also advantageously represent branched alkyl groups.

One preferred example for each of Rj and Rg is tertiary butyl.

Particular examples of R3 and R$ are tertiary butyl and methyl.

Examples of R2, R4, R5 and R7 are hydrogen.

Preferably one of B and E is phenyl, methyl or isopropyl and the other ishydrogen. Most preferably one of B and E is phenyl and the other is hydrogen.

The compounds of formula (III) are also suitable salen catalysts for use in theprocess of the invention.

In lhe compounds of formula (I), (IA), (ÏB), (II) and (III);

The bond between M and A bas varying degrees of ionic character depending on the aiûon used.

Suitable transition métal ions, M, include Mn, Cr, Fe, Ni, Co, Ti, V, Ru and

Os in an appropriatc oxidation siale.

Pieferably the transition métal ion, M, is Mn in oxidation State (II) or (III). 7 01032?

It sliould be appveciated that in some cases for example when M is Μη (II), acounlcr-ion is not rcquired.

Suitable counter-ions, A, includc those anions meniioned in WO 91/14694and WO 94/03271.

Preferably, A is chloride.

In the process of tlie invention:

Suitable prochiral olefins includc compounds which comprise the followinggroups as part of lheir structure, cyclobexcnc, 5,6-dihydro-2H-pyran, 1,2,5,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine and 5,6-dihydro-2H-thiopyran.

Favoured prochiral olefins includc those compounds which comprise thefollowing groups as part of tlieir 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.

Preferred prochiral olefins include those mentioned in EP-A-0 376 524, suchas the compounds of formula (XIV) therein, and in particular 2,2-dimethyl-6-pentafluoroethyl-2H-l-benzopyran.

Preferred prochiral olefins include 6-aceîyl-2,2-dimethyl-2H-l-benzopyran.

Suitable oxygen sources includc oxidising agents such as sodiumhypochlorite.

The epoxidation reaction may be carried out using any suitable procedurewherein the prochiral olefm, the source of oxygen, the compound of formula (I) andthe source of the électron donating ligand arc allowed to rcact to providc the requiredepoxide.

Suitably, lire réaction is carried out in a two phase System, especially whenthe source of oxygen and/or one of the reaction components is soluble in water, andespecially when the source of oxygen is sodium hypochlorite.

Suitable two phase Systems are those used conventionally in tire art takinginto account the nature of the particular reactants, an example is melhylene chlorideand water. 1 he salen catalyst such as a compound of formula (I), (ΙΑ), (II) or (III), theprochiral olefin and the source of the électron donating ligand in an inert, waterimmiscible solvent such as dichlorometbane may be reacted witli the source ofoxygen in water.

Gcneraïiy tire reaction takes place at a pH in the range of between 10 and 13,preferably between 10.5 and 12, most preferably between 11 and 11.5, convenientlythe pH is controlled by tlie presence of a buffer such as sodium dihydrogenphosphate.

The réaction may be carried oui at any suitable température providing a convcnicnt iaie of foimalion of the required product. Becatise of the increase in rate ° 010327 of the réaction caused by the prcsence of tlie source of the électron donating ligandthe réaction inay be carricd out at a lower température than without the said ligand,such as in the range of between 0°C and 40°C.

Gencrally it is carried out at ambient or at a slightly elevated température butpreferably at ambient température.

Suitably the mole pcrcentage ratio of the compound of formula (I) to theprochiral olefin is in the range of 0.01 to 10, preferably in tire range of 0.1 to 0.5, 0.5to 5, 1 to 5, 1 to 3, 0.5 to 2 most preferably in the range of 0.2 to 2.

Suitably tlie mole ratio of the source of tlie électron donating ligand toprochiral olefin is in the range of 0.05 to 3, such as 0.1 to 2.0 or 1 to 2, preferably intire range of 0.1 to 2. For example a suitable mole ratio range for N-pyridine oxide is0.5 to 2. An example of a suitable mole ratio range for isoquinoline N-oxide is 0.1 to0.5.

The présent invention also extends to the préparation of ail epoxides which areprecursors to those compounds of formula (I) in EP-A-0376524, especially thespécifie examples thereof.

The présent invention also extends to the préparation of ail epoxides which areprecursors to those compounds of formula (I) in WO 92/22293, especially the spécifieexamples thereof.

The présent invention also extends to the subséquent conversion of each of thesaid epoxides into tire respective compounds of formula (I) of EP-A-0 376 524, inparticular to the conversion of the relevant precursor epoxide into the respectivespécifie exemple of ΕΡ-Λ-0 376 524, and especially to the conversation of 2,2-dimethyl-6-pentafluoroethyl-3,4-epoxy-2H-1-benzopyran into (-)trans-3,4-dihydro-2,2-dimetliyl-4-(2-oxopiperidin-l-yl)-6-pentafluoroethyl-2H-l-benzopyran-3-ol ortlie (+) trans isomer thereof.

Tire présent invention also extends to the subséquent conversion of each of thesaid epoxides into the respective compounds of formula (I) of WO 92/22293, inparticular to the conversion of tlie relevant precursor epoxide into the respectivespecific^example of WO 92/22293 and in particular to the conversion of (3R,4R) 6-acetyl-2,2-dimelhyl-3,4-epoxy-2H- 1-benzopyran into trans-6-acetvl-4S-(4-fluorobcnzoylamino)-3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3R-ol or the 3S, 4Risomer thereof: 'Rie présent invention also extends to the product formed between tire salen catalyst, such as tlie compound of formula (I), (IA), (IB), (Π) or (ΙΠ) and the électron donating ligand,

When used hcrcin tlie tenu 'chiral salen catalyst' refers to salen catalysts which bave a prédominance of onc particular cnantionier and which in use providc a 3 010327 prédominance of one parlicular enantiomer of the product epoxide from the prochiral olefin substrate.

The lerin 'alkyl' when used alone or when forming part of othergroups (forexample alkoxy groups or alkycarbonyl groups) includes straight- or branched-chainalkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examplesinclude melhyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.

When used herein the terni 'aryl' includes phcnyl and naphthyl optionallysubstituted with up to five, prefcrably up to three, groups selected from halogen,alkyl, phenyl, alkoxy, haloalkyl, alkylcarbonyl 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 alkyl groups include those mentioned herein for arylgroups, phenyl is a parlicular example.

Il should bc appreciated that the carbon atoms marked with an asterisk arechiral centres and the présent invention extends to each individual enantiomer and anymixtures thereof.

The compounds of formula (I), (IA) and (IB) may be prepared according tothe procedures in described in WO 91/14694 or by procedures analogous to them.

The compounds of formula (II) may be prepared according to the proceduresdiscîosed in International Application, Publication Number WO 91/14694 orprocedures analogous the them.

The contents of WO 91/14694 and WO 94/03271, including the spécifiedescriptions and examples therein, arc incorporated herein by référencé.

For the compounds of formula (III), the présent invention also provides aprocess for the préparation of compounds of formula (IH) which comprises forming atransition métal complex of the following compound of formula (IV): 010327 4θ

R, 6

R2 R R, ‘a

R '7 where variables Rj, R2, R3, Rq, R5, Rg, R7, Rg, R9 and Rjq, B, B', E and E' are asdefined in relation to formula (III), wherein only one of the carbons marked with anasterisk is a chiral centre, and thereafter if necessary separating any enantiomers.

Suitably the transition métal ion complex may be formed by the addition of asuitable transition métal sait, such as manganèse (II) or (ΠΙ) acetate, preferablymanganèse (III) acetate, to a compound of formula (IV) in a suitable solvent such aséthanol or methylene dichloride, at elevated température. The optional replacementor interconversion of the counter ion may be effected by the addition of a suitablesource of the desired counter-ion such as an alkali métal sait, for example LiCl.

The séparation of any enantiomers may be carried oui by conventionaltechniques, such as crystallisation of dérivatives or chromatography, However, itshould be appreciated thaï it is preferred that séparation of enantiomers is carried outbefore formir.g a transition métal complex.

The invention further provides a process for the préparation of compounds offormula (IV) which comprises condcnsing scquentially, in any order, a compound offormula (V):

-E'

NHR 12 (V) where B, B', E and E’ are as defined in formula (III) and Rjj and R ]2 independentlyrepresent hydrogen or an amine protecting group, providing at least one of Rj j andRj2 is hydrogen, with: (i) a compound of formula (VI); 44 010327 ο

(VI) wherein R ], I<2, R3, Rq and R9 arc as dcfincd in relation to formula (III); and (ii) a compound of formula (VII),

wherein R5, Rg, R7, Rg and Rjq are as defïned in relation to formula (ΙΠ); andthereaftcr as required removing any protecting group R π or Rj2, isolating therequired compound including if necessary separating any enantiomers.

It is preferred tliat the compound of formula (IV) is prepared from optically10 pure compounds of formula (V) which are preferably prepared themselves from optically pure slarting materials. Altcmatively, racemates or mixtures of enantiomersof formula (VI) or (VII) may themselves be rcsolvcd using conventional techniques inthe art such as crystallisation of dérivatives, or chromatography.

When compounds of formula (IV) are required in which one or more of R μ15 R2, R3, R4 and R9 are not the same as one or more of Rg, R7, Rg, R5 and Rjq respectively, then compounds of formula (V) may be sequentially condensed withcompounds of formula (VI) and formula (VII), in any order, by heating a suitablyprotected compound of formula (V) with a compound of formula (VI) or (VII) (in a1:1 mole ratio) in an inert solvent such as éthanol, if necessary, purifying the resulting 20 interrncdi'âte compound of formula (VIII) or (IX): 42. 010327

B

E

R

R (VIII) (IX) whcrein variables Rj to R12- E, E'. B and B’ are as defined in relation to formula (V), (VI) or (VII) using conventional séparation techniques, such as chromatography;removing any protecting group Rj j or R12 and then as required repeating thereaction using a compound of formula (VI) or (VII).

Suitable protecting groups R j j or Rj2 include conventional amine protectinggroups the insertion and removal of which are compatible with the nature of themolécules being protected, such as benzyl groups, silyl groups or acyl groups such asbcnzoyl groups, prefcrably silyl groups.

The removal of Rj j or R12 wlicn representing protecting groups tnay becarricd out using conventional techniques in the art depending upon the nature of theprotecting group.

Il should be appreciated tirât when each of Rj, R2, R3, R4 and R9 is the sameas each of Rg, R7, R(p R5 and Rjq respeclively the conrpounds of formula (VI) and (VII) are the same, thcrefore, conrpounds of formula (V) in which Rj j and Rj2 ishydrogen are preferably uscd and two moles of a compound of formula (VI) or (VII)are utilised.

Suitably, the reaction is carried out in an inert solvent, such as éthanol, atelevated température, for example at reflux température of the chosen solvent.

Compounds of formula (V) are either known compounds or may be preparedaccording to known methods or analogously to known methods or analogously to themcthods.described hcrein.

Compounds of formula (VI) and (VII) are either commercially available, are known compounds or may be prepared according to known methods or analogouslyto known methods for examples such as tliese described by G.Casiraghi et al J. ChemSoc. Perkin Transactions I. 19S0 p!862 - 1865.

Novel compounds of formula (IV), (VI), (VII), (VIII) and (IX) form an aspect of the présent invention.

As stated above the compounds of formula (II) herein may be prepared using the methods disclosed in co-pending International Patent Application Nuinber >13 010327 PCT/GB93/01666 (now International Patent Application, Publication Numbcr WO94/03271). For tbe avoidancc of doubl these mcthods involve the following:

The compounds of formula (II) may be prepared by fonning a transition métalcomplex of tbe following compound of formula (X):

B E

I I (CHR )r (CHRc)t

(X) wliere variables Rj to Rjq, B, E, r, s, t Ra, Rb and Rc are as dcfined in relation toformula (II), and thereafter if necessary scparating any enantiomers.

Suitably the transition métal ion complex may be formed by the addition of asuitable transition métal sait such as manganèse (II) or (ΠΙ) acetate, preferablymanganèse (III) acetate, to a compound of formula (Π) in a suitable solvent such aséthanol or mcthylene dichloride. at elevated température. The optional replacementor interconversion of the countcr ion may be cffectcd by the addition of a suitablesource of the desired counter-ion such as an alkali métal sait, for example LiCl.

The séparation of any enantiomers may be carried out by conventionaltechniques, such as crystaliisation of dérivatives or chromatography. However, itshould be appreciated tirât is is preferred that séparation of enantiomers is carried outbefore fonning a transition métal complex.

The compounds of formula (X) may also be prepared by condensing sequentially, in any order, a compound of formula (XI): (CHRb)sZ \

B E (CHRa)r ÇHnc)t

RnHN NHR1? 12 (XI) whcre r, s, t, Ra, Rb and Rc E, B arc. as defined in formula (II) and Rp and Rj2 indcpcndcntly represent hydrogen or an amine protccting group, providing ai least one of 12 ] j and R ] 2 is hydrogen, wilh a compound of the above defined formulae C1 η 327 (VI) and (VII). 'Πιε reaction conditions arc analogous to tliose mentioned above inrelation to the réaction between the cotnpound of formula (V) and lhe compounds offonnulae (VI) and (VII).

It is preferred that the compound of formula (X) is prepared from optically5 pure compounds of formula (XI) which are preferably prepared themselves from optically pure starting matcrials. Altcmatively, racemates or mixtures of enantiomersof formula (X) or (XI) may themselves be resoived using convenlional techniques inthe art such as crystallisation of dérivatives, or chromatography.

When compounds of formula (X) are required in which one or more of R μ10 R-2. R3, R4 and R9 are not the same as one or more of Rg, R7, Rg, R 5 and Rjq respectively, then compounds of formula (XI) may be sequentially condensed withcompounds of formula (VI) and formula (VII), in any order, by heating a suitablyprotected compound of formula (XI) with a compound of formula (VI) or (VII) (in a1:1 mole ratio) in an inert solvent such as éthanol, if necessary, purifying the resulting 15 intermediate compound of formula (XII) or (XHI): /(Clk)^

B E

(XIII) ycH2)S\

B E

20 wherein variables Rj to R ^2’ r> s> E Ra> R^, Rc, E and B are as defined in to formula(XI), (VI) and (VII) using conventional techniques such as chromatography removingany Rjq or R12 protecting groups and then repeating the reaction using a compoundof formula fVI) or (VII) as required.

Suitable protecting groups Rj j and R j2 and the methods for lhe removal ofsuch groups are as described above.

It should be appreciated that when each of Rj, R2, R3, R4 and R9 is the same as each of Rg, R7, Rg, R 5 and Rjq respectively the compounds of formula (VI) and (VII) are tire same, therefore, compounds of formula (XI) in which Rj j and R12 is hydrogen are preferably used and two moles of a compound of formula (VI) or (VII) 25 010327 arc utiliscd, in an incrt solvent, such as éthanol, at elevated température, for exampleai reflux.

Compounds of formula (XI) arc either known compounds or may be preparedaccording to known methods or analogously to known methods or analogously to the 5 methods described herein, for example when a compound of formula (XI) is 3,4-diaminotetrahydrofuran, such a compound may bc prepared according to thefollowing scheme, for example, as described in descriptions 1 and 2.

10 Altematively, (S.S)trans 3,4-diaminotetrahydrofuran may be prepared according to the following scheme, for cxample, as described in descriptions 4 to 6.

The 5R, 6R-diamino-l,3-dioxepanc may be prepared according to theprocedures, rts described in descriptions 8 to 13. 15 The 3R, 4S-diamino tetrahydropyran may be prepared according to the procedures as described in descriptions 15 to 17.

The 3R,4S-diamino-(2S)(triphenylmethoxymethyl)tetrahydropyran may be prepared according to the procedures as described in descriptions 21 to 24. ' 010327

The (±) traits-l-bcnzoyl-3,4-diaminopiperidine may be prepared according to the procedures as dcscribcd in descriptions 25 to 27.

The catalysts, of formula (III) are preferably prepared in a chiral form by using a resolved compound of formula (XI) which may be resolved using 5 conventional techniques. The compound of formula (XI) may itself be prepared fromsuitable precusor compounds such as these outlined in hercinbefore which may beresolved using conventional techniques or may be purchased in a resolved form.Alternativcly, the couplcd compound of formula (X) may be resolved usingconventional techniques. 10 The présent invention also provides a process for preparing compounds of formula (A) (as defined in WO 93 17026) or, where appropriate, a pharmaceuticallyacceptable sali thereof, or a pharmaceutically acceptable solvaté thereof whichcomprises reacting a compound of formula (I), a source of oxygen, a compound offormula (C) and a source of the électron donating ligand, and thereafter converting 15 Ute resulting compound of formula (B) into a compound of formula (A) or, whereappropriate, a pharmaceutically acceptable sait thereof, or a pharmaceuticallyacceptable solvaté thereof.

The présent invention also extends to the product formed between thecompound of formula (1) and the électron donating ligand provided by tire above 20 mentioned source.

Compounds of formula (C) are commercially available or may be preparedaccording to the procedures icferred to or outlined in EP-A-0 376 524.

The following descriptions and cxamples illustrate the présent invention. 010327 (Λ) Exaiuplcs Using (lie Calalysls of WO 91/14694

Example 1: The préparation of (3R,4R)-6-acetyl-2,2-diniethyl-3,4-epoxy-2H-l-benzopyran, using pyridine N-oxide as eîectron donating ligand. A solution of sodium hypochlorite (54ml, 13.7% w/v), 0.05M NaiîPO4(50ml) and water (70 ml) were adjustcd to pli 11.3 with 8N NaOH. 6-Acctyl-2,2-dimethyl chromene (10g 0.049 mol) and E,R-[l,2-bis (3,5-di-tert- butylsalicylideamino)cyclo-hexane]manganese (311) chloride catalyst (320mg 1mol%), pyridine N-oxide (9.5g, 2eq) and dichloromcthane (50ml) were mixedtogetherand thc mixture was stirred for 1 hour.

The solution was diluted witli DCM (200ml) and filtered through celite andthe layers separated. The aqueous layer was re-extracted with DCM (200ml) then theorganic layers combined. The organic phase was washed with water (2 x 400ml) andevaporated to dryness to give a brown oil 12g, ee 95% (chiral hplc). The oil wascrystallised from IPE (2½ volumes) seeded with epoxide to give the tille compoundas an off-white/brown solid (6.45g, 60%) ee>99%.

The saine réaction wilhoul an électron donating ligand added, such as pyridine N-oxide, typically requîtes 1 mole% of catalyst to achieve complété conversion at roomtempérature in about 4 hrs (crade epoxide e.e. 92%).

Example 2: llie Préparation of (3R,4R)-2,2-diinelhyl-3,4-epoxy-6- pcntanuorocthyî-2II-l-benzopyran, using isoquinoline N-oxide as électrondonating ligand. A solution of sodium hypochlorite (44 ml, 17% w/v), water (70 ml) and0.05M NaH2PC>4 (50 ml) was adjusted to pH 11.3 with dilute orthophosphoric acid.2,2-DiinethyI-6-pentafluoroethyl-2H-l-benzopyran (13.6g, 50 mmol), dichloromethane (100 ml), isoquinoline N-oxide (0.725g, 10 mole%) and R,R-[1,2-bis(3,5-di-tcrt-butylsalicylideamino)cyclohexane]manganese (III) chloride (64 mg, 0.2 mole%) were added and the mixture stirred rapidly at room température. After 2hrs HPLC analysis indicated 95% conversion of chromene to epoxide. The reactionmixture was ajlowed to stir at room température for anolher 3 hrs but no furtherconversion of chromene to epoxide occurred. The e.e. of the crade (3R,4R)-epoxidewas ineasured as 92.5% according to chiral HPLC. The mixture was diluted withdichloromethane (200 ml) and filtered through celite, and the layers separated. Theorganic phase was washed with water (3 x 100 ml) then evaporated to dryness to givethe crade titlc compound (15.0g), as a vellow solid. The crade product wasrccrystalliscd from hcxanc (3 volumes) to give the pure Lille compound (8.0g, 54%)as colon; less needles (e.e. > 9998). .48 010327

The sarne réaction wilhout an électron donaling ligand, such as isoquinoline N-oxide, typically rcquires 2 ntole% of calalyst to givc complété conversion.

Exaniple 3: The préparation of (3R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-l-benzopyran, using isoquinoiine N-oxide as électron donating ligand.

The procedure of Example 1 was repeated using 10 mole% of isoquinoline N-oxide insiead of pyridine N-oxide. The amouni of catalyst was also reduced to 0.1inole%. Complète conversion to the required epoxide (e.e. 96%) was achieved in lesstitan 15 mins

Exaniple 4: The préparation of (3R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-8-iodo-2H-l-benzopyran, using isoquinoline N-oxide as électron donating ligand.

The procedure of Example 1 was repeated using 0.2 equiv of isoquinoline N-oxide instead of pyridine N-oxide. The amouni of catalyst was reduced to 0.2mole%. Complété conversion to the epoxide (e.e. 98%) was observed after 2hrs. Thecrude produel was recrystaîlised front 1PE (3 volumes) to give Lhe enantiomericallypure liîle compound, rn.p. 123.6 - 125.4 deg. C. in a yield of 72%. (R) Examples Using the Catalysts of WO 94/03271

Exaniple 5: Préparation of (3R,4R)-6-Acctyl-2,2-diinethyl-3,4-epoxy-2II-l-benzopyran, using pyridine N-oxide as électron donating ligand. . Sodium hypoclilorile (21.5 ml, 17.3% w/v), water (34 ml) and 0.05MNa2HPC>4 (25 ml) were adjusted to pPI 13 with 8 N NaOIT 6-Acetyl-2,2-diniethyl-2H-l-benzopyran (5.0g, 25 mmoles), pyridine N-oxide (5.0g, 52 mmoles) and theS,S-Mn Saîen catalyst (3S,4S)-bis-(3,5-di-tert-butylsalicylideamino)tetrahydrofuran-ntanganese (III) chloridc (D34, 152 mg, 1 mole %) were added with dichloromelhane(50 ml) and the mixture stirred at room température. After 2 hrs the reaction wascomplété according to 1IPLC analysis. The mixture was diluted withdichloromctliane and filtered through celite. The two phases were separated and theorganic phase washed with water (200 ml), then evaporated to dryness under reducedpressure to give the crude title compound as a brown oil (5.0g). This was shown bychiral HPLC to hâve an e.e. of 94%.

The title compound was obtained enantioinercial.ly pure (e.e. >99.8%) byrecrystallization of lhe crude product from diisopropyl ether in a recovery of 44%. 010327 J3

Exan,pie 6: Préparation of (3S,4S)-6-AcetyI-2,2-dimethyl-3,4-cpoxy-2II-l- benzopyran without use of an électron donating ligand.

Sodium hypochlorite solution (8.0 ml, 17.3% w/v), water (14 ml) and 0.05MNa2HPC»4 (10 ml) was adjusted to pH 13 with 8N NaOH. 6-AcetyI-2,2-dimethyl-2H-l-benzopyran (2.0g, 10 mmoles) and R,R-Mn Salen catalyst (R,R)-5,6-bis-(3,5-di-teri-butylsalicylidcamjno)-l,3-dioxcpane]-inanganese (III) chloride (D31, 63 mg, 1mol %) werc addcd with dichloromethane (20 ml) and lhe mixture stirred at roomtempérature overnight. IIPLC analysis indicatcd that about 13% of the chromenestill remained.

The mixture was diluted with dichloromethane (50 ml) and filtered throughcelite. The organic phase was separated then washed with water (100 ml) andevaporated to dryness to give the crude title compound as an oil (2.1g, 96% wt.yicld). Analysis of tins sample by chiral HPLC indicated an e.e. of 86%.

Example 7: Préparation of (3S,4S)-6-Acetyi-2,2-dimethyI-3,4-epoxy-2H-l-benzopyran, using pyridine N-oxide as électron donating ligand.

The procedure of Example 6 was repeated but with the addition of pyridine N-oxide (1.9g, 20 mmoles). HPLC analysis indicated complété reaction after stirringovernight at room température. The crude product was isolated in the same way togivc 2.3g of the title compound with an e.e. of 95%. The tille compound wasobiained cnantioinerically pure (e.e. >99.8%) by rccrystallization of die crude productfrom diisopropyl ether in a rccovery of 50%.

Example 8: Préparation of (3R,4R)-6-Acetyl-2,2-dimethyi-3,4-epoxy-2H-l-benzopyran, using isoquinoline-N-oxide as électron donating ligand.

The procedure of Example 5 was repeated but with the addition ofisoquinoline-N-oxide (1.74g, 12 mmoles) instead of pyridine N-oxide. HPLCanalysis indicated complété reaction within 30 mins., after stirring at roomtempérature. The crude product was isolated in the same way to give the crude titlecompound as a brown oil (5.1g). This was shown by chiral HPLC to hâve an e.e. of94%. The titfe compound was obiained enantiomerically pure (e.e. >99.8%) byrecrystallization from diisopropyl ether in a rccovery of 48%.

Example 9: Préparation of (3S,4S)-6-Acetyl-2,2-dimethyl-3,4-epoxy-2II-l- benzopyran

Sodium hypochlorite (31 ml, 12.1% w/v, 50 mmoles), water (34 ml) and 0.05M Nt^IIPOq (25 ml) were adjusted to ρί J 13 with 8N NaOH. 6-Acctyl-2,2- dimcdiyl-2H-l-benzopyran (5.0g, 25 mmoles), isoquinoline N-oxidc (0.362g, 5

JO 010327 mmoles, 0.2 equiv) and (3R,4S)-bis-(3,5-di tert-butylsalicylideamino)tetrahydropyranmanganèse (III) chloridc (0.032g, 0.05 mmole, 0.2 mole%) were added wiihdichloromethane (50 ml) and the mixture stirred al 15 - 20 deg. C. After 4 hrs thereaction was complété according to HPLC analysis. The mixture was diluted wilhdichloromethane and filtered through cclite. The îwo phases were separated and tlieorganic phase washed with water (2 x 200 ml), then evaporated to dryness underrcduccd pressure to give the crude litle compound as a pale brown oil (5.3g). Thiswas shown by chiral HPLC to hâve an e.e. of 92%.

The litle compound was obtained enantiomercially pure (e.e. >99.8%), m.p.51°C, by rccrystallization of the crude product from diisopropyl ether in a recovery of41%.

Exarnple 10: Préparation of (3S,4S)-6-Cyano-2,2-dimelhyl-3,4-epoxy-2H-l-benzopyran

Tire procedure described in Exarnple 9 was repeated using 6-cyano-2,2-dimethyl-2H-1-benzopyran (4.63g, 25 mmoles) as the chromene substate. The crude (3S,4S)epoxide formed was shown to hâve an e.e. of 93%. Ibis was recrystallised from 2-propanol to give tlie litle compound (e.e. >99%), m.p. 144-145 deg. C, in a recovery7of75%.

Example 11: Préparation of (3S,4S)-6-Bronro-2,2-dimethyI-3,4-epoxy-2H-l-benzopyran

The procedure described in Exarnple 9 was repeated using 6-bromo-2,2-dimethyl-2H-1-benzopyran (5.98g, 25 mmoles) as the chromene substrate. The crude (3S.4S)epoxide formed was shown to hâve an e.e. of 95%. This was recrystallised fromhcxane/ethyl acetate to give tlie tille compound (e.e. >99%), m.p. 101-102 deg. C, ina recovery' of 65%. (C) Examples Using The Compound of Formula (ΙΠ) as Catalyst

Exarnple 12: (R)-l-Phenyl-l,2-bis(3-icri-butyl-S-methylsalicylideamino)ethane -manganèse (III) cbîoride (E12). (R)-l-Phenyl-l,2-bis(3-zerf-buiyl-5-methylsalicylideamino)ethane (D37,2.42g, 5.0mmo!) was dissolved in éthanol (50ml) and solid manganèse (Π) acetatetetrahydrate (2.45g, lO.Ommoî) was added. The solution was refluxed for 2 hoursthen lithium chlpride (anhydrous) 0.64g, 15.0mmol) was added and the solution wasrefluxed for a further 30 min. After cooling water (1ml) was added to lhe stirringsolution. The precipitate was temoved by filtration, washed with 90% aqueous

U 010327 éthanol (10ml) thcn dticd in vacuo ovcr IbOg lo afford lhe tille compound as a brown solid, 2.73g, 95% yicld.

Example 13: Πιε Chiral epoxidalion of 2,2-dimethyl-6- penlafluoroelhylchromene using E12 lo give 2,2-diniethyl-6-penlanuoroethyl-lH-benzopyran-(3R,4R)-epoxidc.

Aqueous sodium hypochlorite solution (8.5% w/v, 17.5ml, 20.0 mmol) wasdilutcd lo 25ml wilh water followed by the addition of 0.05M Nal^PCty (aq) (10ml).The pH was adjusted to 11.3 and the solution cooled lo 0°C, then added to a solutionof 2,2-dimethyI-6-pcntafluoroethyl chromene (2.78g. 10.0 mmol) and (El2) (0.115g,0.20mmol) in methylcnc chloride (10ml) at 0°C. The reaction was stirred for 1 hourat 0°C thcn at room température overnight.

Hexane (100ml) and water (50ml) were added and the organic layerpartitioned off. The aqueous layer was extracted wilh a further portion of hexane(100ml) and the combined organic layer was dried over MgSC>4 and the solventremoved in vacuo to give the tiüe compound as a brown oil. 2.7g (94% yield).

The oil was purified by flash chromatography (silica gel 60, MERCK 9385,230-400 mesh) (30g) eluiing wilh 0-5% diethylelher in hexane lo give the titlecompound as a pale yellow, partially crystalline solid, 2.11g, 72% yield, identical (JHNMR, TLC, HPLC) with an authentic sample, e.e. - 63% by chiral HPLC.

Example 14: (R)-l’Pbenyl-l,2-bis(3,5-di-Zert-butyIsalicyIideamino)eÜiane -manganèse (ÎIÎ) chloride (E14). (R)-l-Phenyl-l,2-bis(3,5-di-feri-butylsaIicylideamino)ethane (D38, 1.70g,3.0minol) was dissolved in éthanol (30ml) and manganèse (II) acetate tetrahydrate(1.47g, 6.0mmol) was added. The solution was refiuxed for 16 hours then lithiumchloride (0.38g, 9.0mmo!) was added, the réaction refiuxed for a further 30 min thenallowed to cool to room température. Water (1ml) was added to the stirring solutionand the resulting precipitate was removed by filtration to give the product as a brownsolid which was dried tri vacuo ovcr P2O5 to afford 2.56g of the tille compound, 78%yield.

Exainple 15: The Chiral epoxidation of 2,2-dimethyI-6- penlanuoroelhylcliromene using E14 to give 2,2-diniethyl-6-pentanuoroethyl-lII-benzopyran-(3R,4R)-epoxide.

Aqueous sodium hypochlorite solution (8.5% w/v, 17.5ml, 20.0 mmol) was dilutcd to 25ml with water followed by the addition of 0.05M Nal^POq (aq) (10ml). 'lhe pli was adjusted to 11.3 and lhe solution coolcd to 0°C, then added to a solution 0ir 2,2-dimcthyI-6-pentafiuorocthyl chromene (2.78g, 10.0 mmol) and (R)-l-phenyl- 010327 1,2-bis(3,5-di-?cr/-butyl-salicylideamino)ethane - manganèse (Ι1Ί) chloride (E14)(0.131g, 0.20mmol) in methylene chloride (10ml) al 0°C. The réaction was stirredfor 2 hours ai 0°C lhen at room température overnight.

Hexane (100ml) and water (50ml) were added and lhe organic layerpartitioned off. The squeous layer was extracted witli a further portion of hexane(100ml), and the combincd organic layeis was dried over MgSÛ4 and the solventlemovcd in vacuo to givc the title compound as a yellow oil, 2.91g (99% yicld).

The oil was purified by flash chiomatography (silica gel 60, MERCK, 230-400 mesh) (40g) eluting with 0-5% diethyl ether in hexane to give the title compoundas a pale yellow crystalline solid, 1.81g, 62% yield, identical (^H NMR, TLC, HPLC)with an authentic sample, c.e. = 68% by chiral HPLC.

ExampJe 16: (S)-l-MclIiyl-l, 2-bis (3-tert-butyl-5-meihylsaIicylidcamino)etliàne - manganèse (ΠΙ) chloride (El6) (S)-1 -Me‘hy'1-1, 2-bis(3-tert-butyl-5-methylsalicylideamino)ethane (D39)(338mg, 0.8 mmol) was dissolved in EtOH (8ml) and manganèse (H) acetatetetrahydratc (392 mg, 1.6 mmol) was added. The mixture was rcfluxcd for 2h lhenlithium chloride (102 mg, 2.4 mmol) was added and, after a further lh at reflux, themixture was cooled to ambient. A few drops of water were added and the resultingprecipitate filtered and dried in vacuo over P2O5 to afford the title compound as abrown powder, 270 mg (66% yield).

Example 17: The chiral epoxidation of 2, 2-diinethyl-6-pentafluorethylchroniene using E16 to give 2, 2-diinelhyI-6-pentanuoroethylcliroinene-(3S, 4S)-epoxide.

Aqueous sodium hypochlorite solution (16.75% w7v, 8.9 ml, 20 mmol) was diluted to 25ml with water followed by the addition of 0.05m NaH2PC>4 (aq)(10ml).

Oie pli was adjusted to 11.3 and lhe solution cooled to 0°C, then added to a solution of 2, 2-dimethyl-6-pentafluoreihyl chromene (2.78g, 10 mmol) and (S)-l-melhyl-l, 2-bis (3-tert-butyl-5-mcthylsalicylideamino) ethanc - manganèse (ΠΊ) chloride (E16, », 102 mg, 0.20 mmol) in methylene chloride ( 10ml) at 0°C. The reaction was stirred at0°C for lh theh at room température overnight.

Hexane (100ml) and water (50ml) were added and the organic layerpartitioned off. The aqueous layer was extracted with a further portion of hexane(100ml) and the combincd organic layers w’ere dried over MgSC>4 and the solventremoved in vacuo to give the crude title compound as a brown oil, 2.78g (95% yield),Quantitative analysis (HPLC) showed this to contain 2.27g (77% yield) of the titlecompound, identical (TLC, HPLC) with an authentic sample, ce = 32% by chiralHPLC. 010327

Example 18: (S)-I-Isopropyi-l, 2-bis (3-ler t-butyI-5-metliylsalicyclidcamino)ethane-mangancsc (III) chloride. (E18) (S)-l-isoPropyl-l. 2-bis (3-tert-butyl-5-methylsalicylideamino) ethane (D40, 5 240 mg, 0.53 mmol) was dissolved in éthanol (10ml) and manganèse (ΙΠ) acetate diliydratc (0.14g, 0.53 mmol) was added. The mixture was refluxcd for 2h thenlithium chloride (34mg, 0.8 mmol) was added. After a futlher lh al reflux thesolution was coolcd, solvent was rcrnovcd in vacuo and the residue chromatographedon silica (Merck 9385, 20g, eluling with 0-6% methanol in chlorofonn) to afford the 10 title compound as a brown powder, 60ing (21% yield).

Example 19: The chiral epoxidation of 2, 2-dimethyI-6-pentafIuoretliylchromene using El8 to give 2, 2-dinicthyI-6-pentafluoroetIiylchromene- (3S, 4S)-epoxide 15 Açueous sodium hypochlorile solution (15.24% w/v, 2 ml, 4 mmol) was made up to 5 ml with water. 0.05 M NaH2PC>4(aq)(2 ml) was added and the pH adjusted to 11.3. The solution was cooled to O°C‘ then added to a solution of (0.56g, 2mmol)and the catalyst (S)-l-isopropyl-l, 2-bis (3-tert-butyl-5-methylsalicyclideamino)ethane-manganese (III) chloride. (El8, 21.5 mg, 0.04 mmol) in methylene chloride 20 (6ml). The mixture was stirred at O°C for lh then at room température ovemight.

Hexane (20ml) and water (10ml) were added and the organic layer separated.

The aqucous phase was extracted with further hexane (20ml) and the combinedorganic phase was dricd (MgSOq) and the solvent removed in vacuo to afford the titlecompound as a yellow oil (0.51g). Quantitative analysis (HPLC) showed this to 25 contain 0.42g (71% yield) of the title compound, identical (TLC, HPLC) with anauthentic sample, ee = 23% by chiral IIPLC.

Example 20: The chiral epoxidation of 6-acetyl-2,2-dimethyl chromene usingE14 to give 6-acetvl-2,2-dimethyl chromene-(3R, 4R) epoxide. 30 A solution of sodium hypochlorile (8.6ml, 17.3%w/v), water (14ml) and

Na2HPC>4 (0.05M, 10ml) was adjusted to pH 11.3 with 8N NaOH. 6-Acetyl-2,2-dimethyl chromene (2g) and E14 (65.6 mg 1 moi %) and dichloromethane (20ml) wasadded and üie mixture stirred rapidly at room température overnight.

The mixture was diluted with dichloromethane (50ml) and filtered through 35 ceîite. The two layers were separated and the organic phase washed with water(100ml) the evaporatcd to dryness to give the title compound (2.0g 92%), ee = 67%by chiral IIPLC. 010327

Exainpie 21 The durai epoxidaiion of 6-acetyI-2, 2-dimethyl chromcne usingE14 to give 6-acetvl-2, 2-dimethyl chromcne-(3R, 4R) epoxide, using pyridine-N-oxide as électron donating catalyst

The réaction of Example 20 was repeated with the addition of pyridine N- 5 oxide (1.9 g, 2eq). The ee of the title product was found to be 79% using chiralHPLC.

Descriptions of Inierinrdiates for the Préparation of Compounds of Formula (II)(as descrihed in WO 94/03271) 10 Description 1 (±) 2,5-Dihydro-3-nitrofuran (Dl) A mixture of (±) irons 3-chloromercurio-4-nitro-2,5-dihydrofuran^ (38.54g,109.6 mmol) and Et3N (11.07g, 109.6 mmol) in CH2CI2 (2.2L) at 25°C was stirredfor 1.25h. 5% aqueous citric acid (1.1L) was added and stirring was continued for 5 15 min. The mixture was fïltered through celite, separated and the organic phase washedwith 5% aqueous citric acid (220 ml), dried over Na2SO4 and concentrated in vacuo.Chrornatography of the rcsidue on silica (Merck 9385, 300g) eluting with CHCI3-Hexane (1:1 -> 1:0) afforded (Dl) as a pale yellow oil which crystallised in tliefreezer, 5.45g (43.2%). 20 δ (CDC13) 4.95 (4H,S) and 7.10 (JH,S) 1. P. Bitha and Y -1. Lin, J. IJcterocyclic Chem.. 1988, 25. 1035-1036.

Description 2 (±) 3,4-Diaminotetrahydrofuran (D2) 25 A solution of (±) 4-amino-3-nitrotetrahydrofuran, prepared from (Dl) via Lite method of Bitha and Lin (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 for65h at 20°C. The suspension was fïltered, the solids washed with EtOH (100 ml) andthe combined filtrate evaporated in vacuo to afford (±) (D2) as a colourless oil, 3.26g 30 (S 1.5%) o'(CDCl3) 1.40 (4H,bs), 3.20 (2H. m), 3.50 (2H,dd) and 4.08 (2H,dd). -»

Description 3 (±) 3,4-bis (3-/erf-ButyI-5-methylsaîicylideannno)tetrahydrofuran (D3) 35 A solution of the racemie diamine (D2) (855 mg, 8.38 mmol) and 3-teri-butyI· 5-methyIsalicaldehydc (3.22g, 16.76 mmol) in EtOH (50 ml) was heated at reflux for1.5h. The solvent was removed in vacuo and the rcsidue chromatographed on silica(Merck 9385. 300g) using CIICI3 as chient to afford (±) (D3) as pale yellow necdles.1.35g, (35.8%). 010327 δ (CDC13) 1.42 (18H,s), 2.25 (6II,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(inclliancsuIphonyJoxy)telraliydrofuran (D4) A solution of 1,4-anbydro-L-tlncitol (2.45g, 23.5 mmol ex Aldrich Chemicalcompany) in a mixture of THF (75 ml) and Et2Û (75 ml) at 0°C was treatedsequentially witli trielhylamine (7.2 ml, 51.7 mmol, 2.2 eq) and methanesulphonylchloride (3.82 ml, 49.35 mmol, 2.1 cq). The mixture was stirred for4h thcn stored at0°C ovcmight (-16h).

The reaction was filtered and the solids washed with THF (20 ml). Thecombined filtrate was evaporated invacuo and partitioned between 10% aqueouscitric acid (60 ml) and EtOAc (150 ml). The organic phase was dried (MgSC>4) andevaporated to afford (D4) as a colourless oil, 5.82g (95%). δ (CDC13) 3.12 (6H,s) 4.00 (2H,dd), 4.18 (2H,dd) and 5.25 (2H,dd).

Description 5 (S,S) trans 3,4-Diazidoteirabydrofuran (D5) A mixture of the dimesylate (D4) (5.80 g, 22.3 mmol) and lithium azide (5.46, 111.5 mmol, 2.5 eq) in DMSO (60 ml) was heaied at 100-110°C for 40h. Aftercooling to ambient the réaction was diluted with water (IL) and extracted with EtOAc(IL, 2 x O.75L). The combined organic phase was washed with water (0.5L) andbrinc (0.5L), dried over MgSOq and evaporated in vacuo to a pale yellow oil of thelitle compound, 2.18g (61.5%). δ (CDC13) 3.75 (2H,dd) and 3.90 - 4.05 (4H,m).

Description 6 (S,S) irons 3,4-Diannnotetrahydrofuran

To lithium aluminium hydride (2.05g, 54 mmol) in dry THF (150 ml) at 0°Cwas added the diazide (D5) (2.08g, 13.5 mmol) in THF (50 ml) dropwise over 10min. After 15 min the solution was allowed to warm to ambient, then stirred for 16h.

The inaction mixture was re-cooled to 0°C and quenched sequentially withII2O (2 ml), 15% aqueous NaOH (2 ml) and furiher H2O (6 ml) and warmed toambient. After stirring for Ih the mixture was filtered through celite, rinsed withTHF (2 x 150 mî) and Lire combined filtrate evaporated in vacuo to afford (D6) as apale yellow oil, 1.28g (93%). δ (CDCI3) 1.30 (4H,bs), 3.20 (2Il,dd), 3.50 (2H,dd) and 4.08 (2H,dd).

Description 7 010327 (S,S) traits 3,4-bis(3-iert-Butyl-5-inethylsalicylideamino)tetrahydrofuran (D7) A solution of the (S,S)-diamine (D6) (1.26g, 12.35 mniol) and 3-tert-butyl-5-mcthylsalicaldchyde (4.74g, 24.70 mntol) in EtOH (75 ml) was heated at reflux for3.5h. The solution was cooled and solvent removed in vacuo to afford crude (5) as ayellow oil, 5.50g (99%). A sample of thc crude matcrial (4.55g) was chroniatographed on silica (Merck9385, gradient of CIICI3 in hexane) to afford pure (197) as a yellow foam, 4.39g(95.5% yield). δ (CDC!3) 1.42 (18H,s), 2.25 (6H,s), 3.95 - 4.10 (4H,m) 4.33 (2H,q), 6.90(2H,d), 7.15 (2H,d), 8.30 (2H,s) and 13.15 (2H,bs).

Description 8 (2R.3R)-l,4-Dibcnzyloxy-2,3-dhnetlianesuIfonyIox7butane

To a solution of (2R,3R)-(+)-l,4-dibenzyîoxy-2,3-butanediol (25.3g, S3.7mmol ex Aldrich Chemical Company) in dichloromethane (165ml), cooled in anice bâtir, was added methanesulfonyl chloride (13.0ml, 167.4 inmol), followed byslow addition of bielhylamine (23.3ml, 167.4mrnol) stich that thc température did nolrise above 5°C. Once lhe addition was complété tire reaction was allowcd to stir withice-bath cooling for 3 hours. Water (600ml) was then added and the organic phaseseparated. The aqueous phase was re-extracted with dichloromethane (200nrl) andthe combined organic phases washed with water (400ml) and brine (400ml), dried(MgSOq), and the solvent evaporated to afford a pale yellow solid. Trituration withdiethyl ether afforded thc title compound (28.2g, 74%) as colourless crystals m.p. 72-73°C. ' 1h n.m.r. (CDCl3):ô 3.03 (s,6H,2xCH3), 3.76 (m,4H,2xCH2O),4.48(d,2II,CH2Ph), 4.57 (d,2H,CH2Ph), 5.00 (m,2H,2xCH), 7.27-7.39 (m,10H,2xPh) 13c n.m.r. (CDC13):ô 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). C2oH260gS2 requires: C: 52.39, H:5.72%. found : C: 52.36, H:5.59%.

H

Description 9 (2R,3R)-DirnelhanesulfonyIoxybutane-l,4-diûi (2R,3R)-l,4-Dibenzyloxy-2,3-dimethanesulfonyloxybutane (27.6g, 60.3mmol) (D8) was dissolved in aeelone (500ml), a suspension of 10% Pd/C (29.9g)in acetone (300ml) added, and the mixture hydrogenated at 1 atm. pressure for 2hours at ambient tcmpcrlure. The mixture was then filtercd three times through a pad 010327 of silica and Ccliic, and thc solvent evaporated to give lhe title compound as a straw-coloured oil (14.7g, 87%), which solidificd on standing. lH n.m.r. (DMSO-d6):ô 3.24 (s,6H,2xCH3), 3.69 (m,4H,2xCH2),4.76(m,2H,2xCH), 5.33 (t.2H,2xOH). 5 13C n.m.r. (DMSO-d6):ô 38.1 (2xCH3), 59.7 (2xCH2), 80.3 (2xCH). EI-MS:in/e 279 (MI1+), 261 (MI1+-II2O), 183 (M+-OMs), 165 (M+- OMs,IJ2O). » Μ η ,· 01 0327

Description 10 (6R,7R)-DimethanesuIfonyloxy-2,4,9,lî-tetraoxadodecane (2R,3R)-Dimethanesulfonyloxybutane-l,4-diol (14.7g, 52.9 mmol) (D9) wasdissolved in dimethoxymethane (89.5ml) and dichloromethane (30ml) at 40°C.Lithium bromide (0.91g) and p-toluenesulfonic acid monohydrate (1.01g, 5.29mmol)were added, and lhe mixture heated under reflux for 3 hours. The reaction wasallowed to cool to ambicnt température, and then poured into saturated sodiumbicarbonate solution (200ml), extracted with ethyl acetate (2x200ml), dried (MgSO4)and evaporated to give a colourless oil. This was purified by column chromatographyon silica, eluting with 0-1% methanol in dichloromethane, to afford the titlecompound as a colourless oil (8.2g, 42%). lH n.m.r. (CDC13):Ô 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. (CDC13):8 38.8 (2xSCH3), 55.8 (2xOCH3), 66.1 (2xCH2), 78.4(2xCH), 96.8 (2xOCH2O) CI-MS:m/e 384 (MNH4+). ^10^22^10^2 tequires: C: 32.78, H:6.05%. found : C: 32.22, H:5.62%.

Description 11 (5R,6R)-Dimethanesulîonyloxy-l,3-dioxepane A solution of (6R,7R)-dimethanesulfonyloxy-2,4,9,11-tetraoxadodecane(8.2g, 22.4mmol) (D10) and p-toluenesulfonic acid monohydrate (0.26g, 1.34mmol)in tol'uene (165ml) was heated under reflux ovemight. The solvent was evaporatedand the brown residue triturated with diethyl ether to afford the title compound as anoff-white solid (5.9g, 91%) m.p. 133-134°C. lH n m.r. (CDCl3):ô 3.13 (s,6H,2xCH3), 3.84 (m,2H,CH2),4.06 (m,2H,CH2),4.77 (s,2H,OCH2O), 4.81 (m,2H,2xCH). 13c n.m.r. (CDC13):Ô 38.8 (2xCH3), 64.1 (2xCH2) 78.3 (2xCH), 94.6(OCH2O) EI-MS:m/e 291 (MNH+),195 (M+-OMs). C7Hj40gS2 requires: C: 28.96, H:4.86%. found : C: 29.22, H:4.61%.

Description 12 (5R,6R)-Diazido-13-dioxepane A mixture of (5R,6R)-dimethanesulfonyloxy-l,3-dioxepane (5.0g, 17.2mmol) DI 1 and lithium azide (4.2g, 86mmol) in dimethylsulphoxide (60ml) was stirred and heated to 110-120°C ovemight. The reaction mixture was then cooled, poured into 49 010327 water (200ml), and extracted wilh eihyl acetate (2x 150 ml). The combined organic phases were washed with water (2x150ml) and brine (150ml), dried (MgSC>4) and evaporated to give the tille compound as a brown oil (2.7g, 85%). *H n.m.r. (CDC13):5 3.49 (m,2H,2xCH), 3.74 (m,2H,2xCH2), 3.93 5 (m,2H,CH2), 4.73 (s,2H,OCH2O). 13C n.m.r. (CDC13):Ô 64.3 (2xCH), 64.6 (2xCH2) 94.3 (OCH2O). EI-MS:m/e 185 (MH+), 157 (MH+-N2), 142 (M+-N3). C5HsN6O2 requires: C: 32.61, H:4.38, N:45.63%. found : C: 32.33, H:4.67, N:45.38%. 10

Description 13 (5R,6R)-Diamino-l,3-dÎoxepane

To a slurry of lithium aluminium hydride (2.1g, 55.3mmol) in dry tetrahydrofuran (70ml) at 0°C under an argon atmosphère was added dropwise a 15 solution of (5R, 6R)-diazido-l,3-dioxepane (2.6g, 14.1mmol) (D12) in dry tetrahydrofuran (50ml). During the addition the reaction température was maintainedbelow 10°C with an ice-salt bath. One completion, the reaction mixture was allowedto warm to ambient température, and stined for a further 1.5 hours. It was then re-cooled and the reaction quenched by addition of water (2ml), 2M NaOH (2ml), and 20 water (4ml), tiie température again being maintained below 10°C by means of an ice-salt bâtir. The quenched reaction mixture was allowed to warm to ambienttempérature, stirred for a further 2 hours, then filtered through Celite, and the fil terpad washed well with tetrahydrofuran. The combined filtrâtes were evaporated toafford'the title compound as a pale yellow oil (1.3g, 70%). 25 n.m.r. (CDC13):5 1.56 (brs,4H,2xNH3), 2.62 (m,2H,2xCH),3.58 (m,2H,CH2), 3.77 (m,2H,2xCH2), 4.72 (s,2H,OCH2O) 13C n.m.r. (CDC13):Ô 57.9 (2xCH), 67.5 (2xCH2) 93.8 (OCH2O).C5rii2N2O2 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)+. 30

Description 14 01 032 7

Préparation of (5R,6R)-Di-(3,5-di-tert-butyl) salicylideamino-l,3-dioxepane (5R,6R)-Diamino-l,3-dioxepane (1.0g, 7.6mmoî) (D13) and 3,5-di-tert- butylsalicaldehyde (3.6g, 15.4mmol, 2eq.) were dissolved in éthanol (100ml), and thesolution stirred under reflux for 3 hours. The réaction mixture was then allowed tocool, the solvent was cvaporatcd, and the residue purified by column chromatographyon silica, eluting with 4% diethyl ether in hexane. This afforded the title compoundas a bright yellow foam (3.5g, 82%). lH n.m.r. (CDC13):Ô 1.23 (s,18H,6xCH3), 1.41 (s,18H,6xCH3),3.85(m,2H,CH2), 4.07 (m,2H,CH2), 4.87 (s,2H,OCH2O), 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):Ô 29.4 (6xCH3), 31.4 (6xCH3) 34.1 (2x£CH3), 35.0(2x£CH3),.67.7 (2xCH), 73.8 (2xCH2), 94.2 (OCH2O), 117.6, 126.4, 127.4, 136.6,140.3, 157.9 (Ar), 168.4 (2xC=N) C35H52N2O4 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)-Diacetoxytetraîiydropyran (D15) A solution of 3,4-di-O-acetyl-D-Xylal3 (11.16g) in 50% aqueous éthanol(400ml) containing PtO2 (400mg) was hydrogenated at atmospheric pressure for 3.5hours at 25°C. The suspension was filtered through celite, washed with 50% aqueouséthanol (50ml) and water (50ml), and the combined filtrate evaporated in vacuo toafford the title compound as a colourless oil, 9.6g (85%). δ (CDC13): 1.30-1.50 (lH,m), 2.10 (6H,S), 2.10-2.20 (lH.m), 3.35-3.60 (2H,m). 3.80-4.00 (2H,m) and 4.80-5.00 (2H,m). 2. Dictionaiy of Organic Compounds, 5th Edition, 1982, Chapman &amp; Hall,London, 579 and references therein.

Description'dô (3R,4R)-Dimethanesulfonyloxytetrahydropyran(D16)

Sodium (~50mg) was dissolved in methanol (100ml) at ambient. To theresulting solution was added a solution of the diester (D15) (9.56g, 47.3mmol) inmethanol (100ml) 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 à colourless oil. This was dissolved in a mixture oftetrahydrofuran (220ml) and diethyl ether (220ml). Triethylamine (10.86g, 31 010327 107.5inmol,) was added and the solution cooled to 0°C. Meihanesulphonyl chloride (11.76g, 102.7mmol) was added dropwise at 0°C, the solution was stirred fora fuither hour then stored at 4°C for 16 hours. Tire resulting suspension was filtered and the solids washed with tetrahydrofuran (2x95ml) and diethyl ether (2x 180ml).

The combined filtrate was evaporated in vacuo and the residue partitioned betweencthyl acétate (200ml) and 10% atjueous citric acid (200ml). The organic phase wasdricd (MgSOzj), filtered and concentrated in vacuo to a colourless foam to afford tiretitle compound, 12.07g (93%). δ (CDCI3): 3.10 (6H,s), 2.00-2.40 (2H,m), 3.40-4.20 (4H,m), 4.55-4.65(III,m) and 4.70-4.85 (III,in).

Description 17 (3R,4S)-Diaminotetrahydropyran (D17)

The dimesylate (D16) (12.07g, 44 mmol) was dissolved indimethylsulphoxide (88ml) and treated with lithium azide (10.8g, 220mmol). Themixture was heated at 100°C for 40 hours, then cooled to ambient and poured intowater (1.03L) and extracted with ethyl acetate (1.03L, 2 x 0.59L). The combinedorganic phase was washed with water (300ml) and brine (300ml), dried over MgSÛ4and concentrated in vacuo to give the crude diazide as a brown oil, 3.7g. This wasdissolved in tetrahydrofuran (45ml), and added dropwise 10 acold (0°C) suspensionof lithium aluminium hydride (3.34g, 88mmol) in tetrahydrofuran (220ml),maintaining the température below +10°C. After completion of addition thesuspension was stirred al 0°C for 0.5 hours then warmed to ambient and stirred for 16hours:

The mixture was recooled to 0°C and queriched sequentially with water(3.34ml) in tetrahydrofuran (5ml), 15% aqueous sodium hydroxide (3.34ml) andfurther water (10ml). The mixture was allowed to warm to ambient, stirred for onehour then filtered through celite, rinsing with tetrahydrofuran (2x400ml). Thecombined filtrate was concentrated in vacuo to give the title diamine as a colourlessoil, 2.62g (51%). δ (CDCI3): 1.20-1.90 (6H,m), 2.40-2.50 (2H,m), 2.90-3.40 (2H,m) and3.80-4.00 (2H,m). 010327 iZ,

Description 18 (3R,4S)-bis-(3,5-Di-tert-ButylsalÎcylideamino)tetrahydropyran, (D18) Το the diarnine (D17) (2.55g, 22mmol) in éthanol (220ml) was added 3,5-di-tcrt-butylsalicaldehyde (10.3g, 44mmol). The mixture was heated at reflux for 2hours, cooled to ambient filtered, and the crystalline product dried in vacuo to affordthe title compound as yellow crystals, 4.81g, (40%). Ô (CDC13): 1.20 (1811,s), 1.40 (1811,s), 1.50-2.20 (211,m), 3.50-3.70 (411,ni), 4.00-4.15 (2H,m), 7.00 (21I,bs), 7.35 (2H,bs), 8.33 (lH,s), 8.37 (lH,s) and13.20 (2H,bs).

Description 19 (3R,4S)-bis (3-icri-Buty’l-5-met]iylsalicylideamino) tetrahydropyran (D19) A solution of the diarnine (D17) (0.62g, 5.35mmol) and 3-tert-butyl-5-methylsalicaldehyde (2.05g, 10.7mmmol) in éthanol (40ml) was heated at reflux for 2hours. The solution was cooled then stored at 4°C for 70 hours to afford a yellowprecipitate. This was filtered, washcd wilh cold 95% aqueous éthanol (5ml) and driedin vacuo to afford the title compound, 1.22g (49%). δ (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 20 (3S,4S)-bis (3,5-di-terl-Butylsalicylideaniino) letrahydrofuran (D20) A solution of (S.S)-diamine (D6) (0.96g, 9.4mmol) and 3,5-di-tert-butylsaiicaldehyde (4.4g, 18.8mmol) in éthanol (90ml) was heated at reflux for 2hours. The mixture was cooled to 0°C, filtered and the solids washed with coldéthanol and dried to afford the title compound as yellow crystals, 3.07g (61%). δ (CDC13): 1.27 (18H,s), 1.45 (18H,s), 3.95-4.10 (4H,m), 4.30-4.40 (2H,m), 7.05 (2H,d), 7.40 (2H,d), 8.35 (2H,s) and 13.20 (2H,s).

Description 21 (3S,4R)-DiiTydroxy-(2R)-(hydroxymelhyl)tetrahydropyran (D21) A solution of D-GlucaP (16.0g, 0.11 mole) in 50% aqueous éthanol (500ml)was treated with platinum oxide (0.75g) and hydrogenated at ambient at atmosphericpressure for 5 hours. Tire suspension was treated with charcoal (50g) filtered throughcelite (200g) and the solids washed with 50% aqueous éthanol (300ml). Thecombined filtered was evaporatcd in vacuo and dried over ?2θ5 to afford the titlecompound as a colourlcss oil, 16.0g (99%). 010327 δ (CD3OD): 1.50-1.70 (ΙΙΙ,ιη), 1.80-2.20 (ΙΗ,ηι), 3.00-3.20 (211,m), 3.30- 3.70 (31I,m), 3.80-4.00 (2H,m) and 4.90 (3H,bs) 3. Dictionary of Organic Compounds, 5th Edition, 1982, Chapman and Hall,

London. 2754, and références therein.

Description 22 (3S,4R)-DiIi7droxy-(2E)-(triplienyinietlioxyr.iethyl) tetrahydropyran (D22) A solution of the triol (D21) (1.76g, 11.9mmol) in pyridine (20ml) was treatedwith Lrityl chloridc (3.31g, 11.9mmol) and 4-(dimethylamino)pyridine (50mg).Diisopropylethylaminc (1.92g, 14.8mmol, 1.25eq) was added and the solution slirredfor 4 hour at ambient température.

The mixture was poured into water (200ml) and extracted with diethyl ether(2x200ml). The combined organic phase was washed with 10% aqueous citric acid(100ml) and brine (100ml), dried over MgSOq and concentrated in vacuo to an oil.The residue was chromatographed on silica (eluentrgradient of methanol inchloroform) to afford the title compound as a colourless foam, 3.70g (79.7%). δ (CDC13): 1.60-1.80 (lH,m), 1.90-2.00 (lH,m), 2.70 (2H,bs,D2O exch), 3.25-3.50 (5H,m), 3.60-3.70 (lH,m), 3.90-4.00 (lH,m) and 7.20-7.50 (15H,m).

Description 23 (3E,4R)-Diinethancsuîphonyloxy-(2R)- (tripbenylnieîhoxyinethyl)tctrahydropyran (D23)

To the diol (D22) (3.10g, 7.95mmol) in a mixture of diethyl ether andtetrahÿdrofuran (2:1, 150ml) was added triethylamine (1.76g, 17.5mmol). Themixture was cooled to 0°C and methanesulphonyl chloride (1.91g, 16.7mmol) added.After 2 hours the suspension was filtered and the filtraie concentrated in vacuo, thenredissolved in cthyl acetate (200ml). The solution was washed with 10% aqueouscitric acid (100ml) and brine (50ml), then dried over MgSO4. Solvent was removedin vacuo and the residue dried to afford (12) as a colourless solid, 4.26g (95%). δ (CDC13): 2.20-2.50 (2H,m), 2.50 (3H,s), 3.10 (3H,s), 3.20-3.30 (lH,m), 3.40-3.60 (311,m). 3.95-4.10 (lH,m), 4.70-4.80 (2H,m) and 7.20-7.50 (15H,m).

Description 24 (3R,4S)-bis(3,5-Oi-teri-butylsaIicvIideamino)-(2S)-(triphenyl niellioxyinetliyl)tetrahydropyran (D24) A mixture of the dimesylate (D23) (2.85g, 5.22mmol) and lithium azide (1.28g, 26.1inmol) indimethyl sulphoxidc (20ml) was heated at 100-110°C for 24hour. The solution was cooled, poured into water (200inl) and extracted with etliylacetate (2x300ml). The combined organic phase was washed with water (2x300ml) 34 010327 and brinc (300ml), and dried over MgSOq. Removal of the solvent afforded lheintermediate diazide as a yellow foam (1.52g). A 1.40g portion of the diazide in tetrahydrofuran (10ml) was added to asuspension of lithium aluminium hydride (470mg, 12.4mmol) in tetrahydrofuran(30ml) ai (ÏJC. After stirring al 0°C for 1 hour the mixture was allowcd lo warm toambient and stirred for 16 hours. The suspension was rccoolcd to 0°C and qucnchedsequentially wiüi water (0.5inl), 15% aqueous sodium hydroxide (0.5inI) and furtherwater ( 1.5ml). After warmingthe ambient and stirring for 1 hour the mixture wasfiltered, the solids washed with tetrahydrofuran (2x20ml) and the combined filtrateevaporated to afford tire 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 éthanol (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 tille compound as a yellow powder,210mg, in 8.4% overall yield front (D23). δ (CDCI3): 1.25 (9Il,m), 1.30-1.60 (2H,m), 1.32 (9H,s) 1.40 (9H,s), 1.50(911,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(IH.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 (1H,s) and 13.50 (1H,s).

Description 25 (±Xrfln5-l-Benzoyl-3,4-bis(njctbanesulpl)onyloxy)piperidine (D25) (±)rrans-l-Benzoylpiperidine-3,4-diol^ (3g, 13.6mmol) was suspended indichloromethane (70ml) and Iriethylamine (5.74ml, 43mmol) was added. Themixture was cooled to -10°C and methanesulphonyl chloride (2.6ml, 34mmol) addedover 5 min. After a further 15 min the mixture was poured into ice-water (50ml) andthe organic layer washed with 5% aqueous citric acid (30ml). The solution was driedover MgSOq and concentrated in vacuo to a foam, 5.3g (100%). δΗ (CDC13):1.95 (2H,m), 2.30 (2H,rn),3.15 (6H,s), 4.70 (2H,m), 4.85 (2H.m)and-7.45 (5H,m). 4. V. Pctrow and O. Stephenson, J Pharin, Pharmacol, 1962, 14. 306-314.

Description 26 (±)/ra/LS-l-Benzoyl-3,4-diazidopiperidine (D26) A mixture of the dimesylate (D25) (5.3g, 14mmol) and lithium azide (3.4g,69mmol) in dimethylsulphoxide (36ml) was heated at 100°C for 18 hours. Aftercooling the réaction mixture was partitioned between dichloromethane (200ml) andwater (50ml). The aqueous phase was separated and further extracted withdichloromethane (100ml, 50ml) and the combined organic extracts washed with water 010327 (3x50ml), dricd (NagSO/j) and concenlratcd in vacuo. The residue was chromatographed on silica (eluent: gradient of methanol in dichloromethane) toafford the title compound as a colourless solid, 900mg (24%). δΗ (CDCl3):1.60 (2Il,m), 2.10 (2Il,m),3.05 (2H,m), 3.20 (2H,m) and 7.40(5H, ni).

Description 27 (±)ZrfiHS-l-Benzoyl-3,4-dianiinopîperidine (D27) A solution of the diazidc (D26) (450mg, 1.7mmol) in éthanol (30ml) wastreated with Lindlar catalyst (5%Pd/ CaCO3, 250mg) and stirred under hydrogen (1atm) for 24 hour. Tire mixture was filtercd and solvent removed in vacuo to affordthe title compound as oil, 350mg (94%). δΗ (DMSO):1.20 (lH,m), 1.65-1.80 (2H,nr),2.20 (2H,m), 2.70 (lH,m), 3.00(Jïî.m), 3.30 (lH,m), 4.40 (lH,m) and 7.40 (5H,m).

Description 28 (-)Zr«r.’s-l-Bcnzoyl-3,4-bis(3,5-dÎ-tert-butylsancylideainino)piperidine (D28) A solution of tire amine (D27) (350mg, l.ômmol) and 3,5-di-tert-butylsalicaldehyde (960mg, 4.Immol) in éthanol (40ml) was heated at reflux for 3hours. The mixture was cooled and filtered to afford the racemic bis-inzine, 652mg(63% Ι- Α lOOtng sample was separated by chiral Irplc (CI1IRALPAK AD, eluent 2%25 éthanol in hexane) to afford the tille compound as a single enantiomer, |αΐ° ' - 228°(c=O.13,CHCi3). δΗ (CDC13):1.2O (18H,s), 1.45 (18H,s), 2.00 (2H,m), 3.25 (2H,m), 3.45(ΙΗ,ηι), 3.55 (lH.rn), 4.35 (2H,nr), 6.95 (2H,s), 7.40 (7H,m), 8.30 (2H,s) and 13.15(2II,bs).

Description 29 (±) 3,4-bis (3-/ert-Butyl-5-methylsalicyiideainino) tetrahydrofuran manganèse(III) cbloride (D29) A suspension of the racemic ligand (D3) (690 mg, 1.53 mmol) in ElOH(25 ml) was heated with Mn(OAc)2-4H2O (750 nrg, 3.06 mmol) at reflux for 18h.LiCl (195 nrg, 4.49 mmol) was added and reflux continued for a further 0.5h.

Solvent was removed in vacuo and tire residue chromatographed on silica (Merck 9385, 100g) cluting with a gradient of McOIi in CHC13, to afford the title compound as a brown powder (90 mg, 11%) together with unreactcd (D3), 420 mg (61% rccovcry).

010327

Description 30 (S,S) trans 3,4-bis (3-rcri-IJutyl-5-niethylsalicyh'deamino)tetraIiydrofuranmanganèse (III) chloride (D30)

Metliod Λ (using manganèse (II) acetaïc) Λ solution of (D7) (0.95g, 2.11 mmol) and Mn(OAc)2-4H2O (1.03g, 4.22mmol) in EtOH (40 inl) was hcatcd at reflux for 17h. Lithium chloride (268 mg, 6.33mmol) was added and reflux continued for a further 0.5h. After cooling to ambientthe solvent was removed in vacuo and the residue chromatographed on silica (Merck9385, gradient of MeOH in CHCI3) to afford (E3) as a brown powder, 26 mg (2.3%),together with unreacted (D7), 683 mg (72%).

Method B (using manganèse (III) acetate)^. A solution of (D7) (1.53g, 3.4 mmol) in a mixture of CH2CI2 (17 ml) andMeOII (17 ml) was treated with Mn(OAc)3.2Il2O (0.01g, 3.4 mmol). The mixturewas heated at reflux for 3h, cooled 10 ambient and treated with lithium chloride(0.21g, 5.1 mmol). After sdrring for 16h the solvent was reduccd in vacuo to ca. 8ml, Et20 (70 ml) was added and the suspension slirred for lh. The mixture wasfiltered and tire solids washed with Et2Û (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.

Description 31

Préparation of (R,R)-5,6-bis-(3,5-di-tert-buiylsalicylideamino)-l,3-dioxepane]-mangenese (ΠΙ) chloride (D31) (5R,6R)-Di-(3,5-di-tert-butyl)saIicylideamino-l,3-dioxepane (1.0g, 1.77mmoî) (D14) and manganèse (II) acetate tetrahydrate (2.17g, 8.87mmol) weresuspended in 95% éthanol (50ml), and the mixture stirred under reflux ovemight.Lithium chloride (0.38g, 8.96mmol) was then added and heating continued for afurther 30 minutes. The reaction mixture was then cooled, water (60ml) added, andfiltered tirough Celite. The dark precipitate was washed well with water, thendissoived in dichloromcthane (80ml), dried (MgSOzj), and the solvent evaporated togive the titlc compound as a dark brown solid (0.9g, 78%). c35H50N2°4MnC1 requires: C:64.36, IT7.72, N:4.29%. found: C: 64.57, H: 7.57, N: 4.09% CI-MS: m/e 565 (MII-Mn,Cl)+, 235 (3,5-di-tert-butylsalicaJdehydeIl)+.

Description 32 37 010327 (3R,4S)-bis-(3,5-ili-lcrt-bulylsalicylidcaniino)tctrahydropyran-inanganese (III) chloride (D32) Λ solution of thc ligand (DIS) (4.SIg, S.Smmol) in dichloromethane-methanol(1:1, 88ml) was treated wilh manganèse iriacetate dihydrate (2.35g, 8.8mmol) and ihemixture heated at reflux for 4 hours. Lithium chloride (0.56g, 13.2mmol) was addedand heating at reflux continued for a iurlher 1 hour. Tire mixture was cooled,concentrated in vacuo and the residuc uiturated with dicthyl ether (220ml). The solidproduct was filtered, washed with dicthyl ether (2 x 65ml) and dried to afford (5) as abrown powder, 5.3g (94%).

Description 33 (3R,4S)-bis-(3-tert-buty]-5-methylsaIicyIideaniino)tetrahydropyran-manganese(ΙΠ) chloride (D33) A solution of the ligand (D19) (928mg, 2mmol) in dichloromethane-methanol(1:1, 20ml) was treated wilh manganèse triacetate dihydrate (536mg, 2mmol) andheated at reflux for 3 hours. The mixture was cooled to ambient, lithium chloride(128mg, 3mmol) was added and the solution stirred for 1 hour. The reaction mixturewas concentrated in vacuo and the residue triturated with diethyl ether (40ml). Thesolid product was filtered, washed wilh diethyl ether (2x15ml) and dried in vacuo toafford the tiüe conipound as a brown powder, 1.09g (98%).

Description 34 (3S,4S)-bis-(3,S-di-tert-ButyIsaIicylideamino)tetrahydrofuran-manganese (III)chloride (D34) A solution of the ligand (D20) (1.07g, 2mmol) and manganèse triacetatedihydrate (536mg, 2mmol) in a mixture of dichloromethane and methanol (1:1,20ml)was heated at reflux for 6.5 hour. The solution was cooled to ambient, lithiumchloride (128mg, 3mmol) was added and the mixture stirred for 16 hours. Thereaction mixture was concentrated in vacuo and the residue triturated wilh diethylether (50ml). The solid product was filtered, washed with diethyl ether (2x15ml) anddried in vacuo to afford thc title compound as a brown powder, 1.12g (89%).

Description 35 (3R,4S)-bis-(3,5-Di-tert-ButylsaIicyIideamino)-(2R)- (triphcnylmethoxynîethyl)tetrahydropyran-manganese (Ht) chloride (D35)

To the ligand (D24) (160mg, 195mmol) in dichloromethane-methanol (3:2,5ml) was added NaOIÎ- (0.93ml of 0.417 moîar in methanol, 390 mmol) andmanganèse triacetatedibydrate (52.5mg, 195 mmoi). The solution was heated at $ 010327 reflux for 3 bours. lithium chloridc ( 12.5tng, 300 ininol) added and the mixture stirred for 15 bours.

Solvent was removed in vacuo and the residue triturated with dietliyl ether(10ml). The solid product was filtered, washed with diethyl ether (2x2ml) and driedwith afford the tille compound as a brown powder, 136mg (77%).

Description 36 (-)trans-l-Benzoyl-3,4-bis(3,5-di-iertbutylsalicylideanuno) piperidine-manganese(ΙΠ) chloride (D36) A mixture of the (-) ligand (D28) (20mg, 0.013mmol) and manganèsetriacetate dihydrate (lOmg, 0.037mmol) in diehlorornetbane-methanol (3:2, 5ml) washeated at reflux for 4 hour. Lithium chloride (1.6mg, 0.038mmol) was added andreflux continued for a further 1 hour.

Solvent was removed in vacuo and the residue chromatographed on silica(eluent: 10% methanol in dichloromethane) to afford the title compound as a brownpowder, 22m g (97%).

Descriptions of Intcrmediates for the Préparation of Compounds Of Formulaan)

Description 37: (R)~l-Phenvî-l,2-bis(3-/rr/-butyl-5- incihylsalicyfideamino)<.'thane (D37) (R)-l ,2-Diamino-l-phenylethane (prepared from (R)-2-aminôphenylacetamide^ via réduction to the diamine by the method of Brown andHeim^) (1.36g, 10.0 mmol) was dissoîved in éthanol (50ml) and solid 2-hydroxy-3-tert-butyl-5-methylbenzaldehyde (prepared from 2-tert-butyI-4-methyl-phenol by themethod of Casiraghi et al$) (3.84g, 20.0mrnol) was added. After a 90 min at refluxtire réaction was cooled and water (Iml) was added. The yellow solid formed wasremoved by filtration, washed with 95% aqueous éthanol (10ml) and dried in vacuoover P2O5 to givc the tille compound as yellow solid, 3.33g, 69% yield. 5(CDC13) 1.41 (9H,s), 1.43(9H,s), 2.22(3H,s), 2.23(311,s), 3.93 (IH,dd), 4.12(III,dd), 4.68 (1 H,dd), 6.84 (2II,d), 7.09 (2H,s), 7.30-7.50(511,m), 8.25(111,s), 8.37(1 H,s), and 13.50(2H,bs). 6. C.G. Nielson and D.F. Ewing, J, Chem. Soc. (C), 1966, pp 393-397. 7. II.C. Brown and P. Heim, J, Qrg. Chem.. 1973, 38. p.p. 912-916.

Description 38: (R)-l-î'bci))!-L2-bis(3,5-di-/r,-i-bii1yl-salicylîdcaniino)e(h3ne (D38) 39 010327 (R)-1,2-Diamino· 1-phenylcüianc (0.68g, 5.0 mmol) was dissolved in éthanol(50ml) and 2-hydroxY-3,5-di-rerz-butyl-benzaldehyde (prepared from 2,4-à\-tcrt-butylphenol by Lhe mctbod of Casiraghi et afî) (2.34g, lO.Ommol) was added. Thereaction was refluxed for 2 hours, cooled to room température and water (1ml) was 5 added to the stirring solution. The product was isolated by filtration, washcd with95% aqueous éthanol (5ml) and di ied in vacuo over P2O5 to give lhe tille compoundas yellow solid, 2.11 g, 74% yield. ô(CDCl3) 1.24 (9H,s), î.27(9Il,s), 1.41(9H,s), 1.45(9H,s), 3.95 (IH.dd), 4.15(lH,dd), 4.70 (IH.dd), 7.05 (2H,bs), 7.30-7.50(7H,m), 8.34(1H,S), 8.42(lH,s), and 10 13.60(211,bs). 8. G. Casiraghi, G. Casnati, G. Puglia, G. Sartori and G. Terenghi, J. Chem. Soc.Perkin J, 1980, p.p. 1862-1865. 15 Description 39: (S)-l-Methyl-l, 2-bis(3-tcrt-butyl-5-ine(hylsalicylideaniino)cthane (D39). A suspension of (S)-l, 2-diaminopropane dihydrochloride (290 mg, 2mmol)in ElOH (5ml) was treated witli IM ethanolic NaOH (4ml, 4mmol). 2-Hydroxy-5-tert-butyl-3-metbylbenzaldehyde (770 mg, 4mmol) was added and the mixture heated 20 at reflux for 1.5h. The suspension was filtered, partially evaporated and a small quantity of water added to precipitatc the tille compound as yellow solid. This wasfiltered, washcd with 95% aqueous EtOIl and dried in vacuo over P2O5» ιθ afford thefile compound 730 mg (86% yield). δ (CDC13), 1.33 (3H, s), 1.36 (18H, d), 2.25 (6H, s), 3.62 (2H, m), 3.76 (1H, m), 25 6.80 (2H, s), 7.03 (2H, s), 8.20 (IH, s), 8.25 (1H, s), 13.50 (2H, bs)

Description 40: (S)-l-Isopropyl-l, 2-bis (3-tert-butyJ-5-methy!salicylideaniino)ethnne (D40).

To sodium borohydride (1.13g, 30 mmol) in glyme (30 ml) under nitrogen 30 was added (S)-Valinamide hydrochloride (1.53g, 10 mmol) suspended in glyme (35ml) witii stirring. The solution was cooled to 10°C and boron trifluoride etherate (4.9ml, 40 mrnoty in glyme (10 ml) was added dropwise over 20 min, then the mixturewas heated at reflux for 16 h. After cooling to ambient water (7.5 ml), followed by3M NaOH (15 ml), was added and the resulting clear solution refluxed for 2h. 35 Solvent was removed in vacuo to afford a white solid which was extracted with chloroform (3 x 10ml), the combined exiract being evaporated to afford the diaminc (0.34g). This was dissolved in éthanol (15 ml) and treated with 2-hydroxy-3-terl- bulyl-5-methyl benzaldehyde (1.28g, 6.6 mmol). The solution was heated at reflux for 2b, cooled, concentrated in vacuo and the residuc chromatographcd on silica 40 010327 (Merck 9385, eluling with 0-6% McOH in chlorofonn) to afford the title cornpound,0.73g (16% yield). δ (CDC13), 1.04 (6H, m), 1.39 (18H, 2s), 2.10 (1H, m), 2.24 (6H, s). 3.3 - 4.0 (3H,bm), 6.S5 (2H, m), 7.09 (2H, ni), 8.24 (211, s), 13.60 (2H, bs).

Claims (14)

41 010327 Claims:

1. A process for enantiosclcctivclv epoxidising a prochiral olefin, which processcomprises rcacling the prochiral olefin vvitli a source of oxygen in the présence of asalcn catalyst and a source of an électron donating ligand, characterised in that thedonor ligand is isoquinolinc N-oxide or a compound having donor ligand activitv andhaving substantially the sanie soluhility charactenstics as isoquinoline N-oxide.

2. A process according to claim 1, whcrein the salen catalyst is: (i) a compound of formula (I):

in which M is a transition métal ion, A is an anion, and n is either 0, 1 or 2. At leastone of Xj or Xg is selcctcd from the group consisting of silyls, aryls, secondaryalkyls and tertiary alkyls; and at least one of X3 or X4 is selected from the samegroup. Y1, Y2, Y3, Y4, Y5 and Y 5 are independently selected from the groupconsisting of hydrogen, halides, alkyls, aryl groups, silyl groups, and alky 1 groupsbearing heteroatoms such as alkoxy and halide; at least one of Rj, R2, R3 and R4 isselected from a First group consisting of H, CH3, C2H5 and primary alkyls; if R j isselected from said frrst group, then R2 and R3 are selected from a second groupconsisting of aryl groups, heteroatom-bcaring aromatic groups, secondary alkyls andtertiary alkyls; if R2 is selected from said first group, then R j and R4 are selectedFrom said second group; if R3 is selected from said First group, then R{ and R4 areselcctcd from said second group; if R4 is selected from said First group, then R2 andPs.3 are selcctcd from said second group; (ii) a compound of formula (IA): 010327 4-2-

3. Λ process according to daim 1 or daim 2, whercin lhe salcn catalystis:selectcd from the list consisiing of: R,R-[ 1,2-bis 3,5-di-tcrt-butylsalicylidencam’.no)cyclo-hexane]mangancse (III)chloridc; (3S,4S)-bis-(3,5-di teit butylsalicylideamino)ictrahydiOfuran-manganese (1Π)chloride; (R,R)-5,6-bis-(3,5-di-tert-butylsalicy]idenamino)-l,3-dioxepane]-manganese (ΙΠ)chloride; (R)-l-phenyl-l,2-bis(3-zerî-butyl-5-methylsalicylideamino)ethane - manganèse (III)chloride; (R) -l-phenyl-l,2-bis(3,5-di-rerf-butyl-saJicylideamino)ethane - manganèse (ΙΠ)chloride; (S) -l-methyl-l, 2-bis (3-ten-butyl-5-mcthylsalicylideamino) ethane - manganèse (ΙΠ)chloridc; and (S)-l-isopropyl-l, 2-bis (3-tert-buiyI-5-meihylsalicyclideamino) ethane-manganese(III) chloride

4. A process according to any one of daims 1 to 3, whercin the prochiral olefinis a compound which comprises the following groups as part of iis structure:cyclohexene, 5,6-dihydro-2II-pyran, 1,2,5,6-lctrahydropyridine, 1,2,3,4-tetrahydropyridinc and 5,6-dihydro-2II-thiopyran.

5. A process according to any one of daims 1 to 4, wherein the prochiral olefinis a compound which comprise the following groups as part of ils structure:: 1,2-dihydronaphthalcne, 2H-chromene, 1,2-dihydroquinoline, 1,2-dihydroisoquinolineand 2H-thiochromene.

6. A process according to any one of daims 1 to 5, wherein the prochiral olefinis 2,2-dimcthyi-6-pentafluorocihyl-2ll-l-bcnzopyran or 6-acetyl-2,2-dimcthvl-2H-l-bcnzopyran.

7. A process according to any one of daims 1 to 6, wherein the oxygen issodium hypocblorite.

8. A process for enantioselcclively epoxidising a prochiral olefin, which processcomprises rcaciing lhe prochiral olefin with a source of oxygen in the présence of asalcn catalysi and a source of an électron donating ligand, charactcrised in that thesalen catalyst is a compound of formula (II). té 010327

9. Λ proccss according to daim 8, wherein the source of électron donating ligandis isoquinoline N-oxide.

10. Λ compound of fonnuîa (111): E 13

(III) in which M is a transition métal ion; A is a cormier-ion if requircd; B, B’, E and E’ are indepcndently selected froin the group consisting ofhydrogen aryl, Cp.5 alkyl, silyl or aiyl-Cj.g alkyl in which any aryl or alkyl moietyis optionally substituted or B' and B or E' and E together form a C2-6 polymethylenelink; with the proviso tlaat only one of the carbons marked with an asterisk is a chiralcentre; R], R2, R3, R4, R5, R<p R7, ^9 and ^10 are independently hydrogen, alkyl or alkoxy.

10 where M is defined as a transition métal ion and A is an anion; where n is either 3,4,5or 6; where at least one of X | or X2 is selected from the group consisting of aryls,primary alkyls, secondary alkyls, tertiary alkyls, and hetero atoms; where at least oneof X3 or X4 is selected from the group consisting of aryls, primary alkyls, secondaryalkyls, tertiary alkyls, and hetero atoms; where at least one of Y j or Y2 is selectedfrom the group consisting of aryls, primary alkyls, secondary alkyls, tertiary alkyls,and hetero atoms; where at least one of Y4 or Y5 is selected from the groupconsisting of aryls, primary alkyls, secondary' alkyls, tertiary alkyls, and hetero atoms;where Y3, and Y 5 are indcpcndently selected from the group consisting of hydrogenand primary' alkyl groups; where Rj and R4 are trans to each other and at least one ofRj and R4 is selected from the group consisting of primary’ alkyls and hydrogen; andwhere the carbons in the (C)n portion bave substituents selected from the groupconsisting cf hydrogen, alkyl, aryl, and heteroatoms; 15 (iii) a compound of formula (IB):

20 in which Y1 and Y4 are the same and are selected from the group consisting of methylt-butyl or methoxy and R2 and R3 are either both phenyl or together wilh the carbonatoms to which they arc atiachcd fonn a hexyl ring; (iv) a compound of formula (II): 43 010327 /{CH R

in which M is a transition métal 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, Rc are each independently hydrogen or CH2OR' where R' is hydrogen or anorganic group; B and E are independently oxygen, Cib, NR.d jn which is alkyl, hydrogen,alkylcarbonyl, or arylcarbonyl or SOn where n is 0 or an integer 1 or 2, with theproviso tirât B and E are not simultaneously CH2 and that when B is oxygen, NR^ orSOn, tlien r cannot be 0, and when E is oxygen, NR^ or SOn, then t cannot be 0; Rj, R2, R3, R4, R5, R(S, R7, Rg, R9 and Rjq are independently hydrogen, alkyl oralkoxy; or

in which M is a transition métal ion; A is a counter-ion if required; B, B', E and E' are independently selected from the group consisting of hydrogen aryl,alkyl, siiyl or aryl-Cq.g alkyl in which any aryl or alkyl moiety is optionally substituted or B1 and B or E' and E together form a C2-6 polymethylene link; w-ith the proviso that onlÿ onc of the carbons marked with an asterisk is a chiral centre; R], 1<2, R3, R4, R5, R^, R7, Rg, R9 and Rjq are independently hydrogen, alkyl or alkoxy. 44 010327

11. A compound according to claim 10, wherein, R2, R4, R5 and R7 eachindependently represent hydrogen and Rp R3, Rg and Rg each independentlyrepresent Cpg alkyl.

12. A compound according to claim 10 or claim 11, wherein,one of B and E isphenyl, methyl or isopropyl and the other is hydrogen.

13. A compound according 10 claim 10 selected from the list consisting of:(R)-i~phenyl-l,2-bis(3-fe7ï-butyI-5-mcthylsalicylideamino)ethane - manganèse (III)chloride; (R) -1-phenyl-l,2-bis(3,5-di-rerz-butyl-salicyîideamino)ethane - manganèse (ΙΠ)chloride; (S) -1-methyl-1, 2-bis (3-tcrt-butyl-5-methylsalicylideamino) ethane - manganèse (ΙΠ)chloride; and (S)-1-isopropyl-1,2-bls (3-tert-buiyl-5-incthylsalicyclideamino) ethane-manganese(III) chloride

14. Λ process for the préparation of coinpounds of formula (III) wliich comprises: 010327 (a) forming s. transition métal cornplcx of the following compound of formula(IV):

where variables R], Rj, R3, R4, R5, Rg, R7, Rg, R9 and Rjq, B, B', E and E’ are asdefined in relation lo formula (ΙΠ), and thereafter if necessary separating anyenantiomers.; 10 (b) first forming a compound of formula (IV) by condensing sequcntially, in anyorder, a compound of formula (V): B E B-V--V E. 15 RuHN NHR12 (y) where B, B’, E and E’ are as defined in formula (III) and Rjy and R12 independentlyrepresent hydrogen or an amine protecting group, providing at least one of Rp andR12 is hydrogen, with:

wherein R ], I<2, R3, R4 and R9 are as defined in relation to formula (III); and 20 (ii) a compound of formula (VII), 47 010327

(VII) whercin R5, R5, R7, Rg and Rjq are as defincd in relation to formula (III); andthercafter as rcquired removing any protecting group j or Rj2’ isolating therequired compound including if necessary separating any enantiomers.; and 5 thereaftcr forming the transition métal complex as described in reaction (a) above.

14. An intermediate compound of formula (IV), (VI), (VII), (VIII) or (IX). *·