Novel tetrahydrofuran-epoxide compounds are described as intermediates for the preparation of non-adjacent bis-THF-acetogenins of pharmaceutical interest. Also described is a novel stereocontrolled synthesis for preparing such intermediates starting with commercially available enantiomers of glycidyl benzylether.

FIELD OF THE INVENTION 
The invention relates to novel intermediates, particularly a 
tetrahydrofuran (THF) epoxide prepared according to a stereocontrolled 
method which can be used to prepare therapeutically active mono-THF and 
bis-THF acetogenins. 
BACKGROUND OF THE INVENTION 
Since the first discovery of uvaricin in 1982.sup.1, more than 220 
annonaceous acetogenins have been reported. Considerable attention has 
been paid to this class of naturally occurring polyketide-derived fatty 
acids due to their pleiotropic biological activities.sup.2, including 
their immunosuppressive and anti-neoplastic properties. Acetogenins are 
optically pure compounds frequently containing 1-3 tetrahydrofliran (THF) 
rings in the center of a long hydrocarbon chain. The stereochemistry of 
the THF rings may affect the activity of acetogenins since it has been 
noticed that different stereoisomers of acetogenins display strikingly 
different biological activity profiles. However, very little is known 
about the structure-activity relationships contributing to these 
differences. 
FNT .sup.1 Jolad, S. D.; Hoffman, J. J.; Schram, K. H.; Tempesta, M. S.; Kriek, 
G. R.; Bates, R. B.; Cole, J. R. J. Org. Chem. 1982, 47, 3151. 
FNT .sup.2 Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. -M.; He, K.; 
McLaughlin, J. L. Natural Product Reports, 1996, 275 and references cited 
therein. 
Earlier reports described schemes for total synthesis of mono-THF and 
bis-THF acetogenins..sup.3 However, very few synthetic strategies yielding 
the central core THF-unit of mono-THF containing acetogenins are 
stereoselective and therefore require chromatographic separation of the 
key intermediates..sup.4 We have now developed an efficient and 
stereocontrolled approach to synthesize the central core THF-unit of 
mono-THF containing acetogenins which allows each stereogenic center 
around the THF ring to be controlled. 
FNT .sup.3 a) Figadere, B.; Peyrat, J. -F.; Cave, A. J. Org. Chem. 1997, 62, 
3248 and references cited therein. b) Hoye, T. R.; Ye, Z. J. Am. Chem. 
Soc. 1996, 118, 180 1. c) Figadere, B. Acc. Chem. Res. 1995, 28, 359 and 
references cited therein. 
FNT .sup.4 a) Gesson, J. -P.; Bertrand, P. Tetrahedron Lett. 1992, 33, 5177. b) 
Harmange, J. -C.; Figadere, B. Cave, A. Tetrahedron Lett. 1992, 33, 5749. 
c) Makabe, H.; Tanaks, A.; Oritani, T. J. Chem. Soc. Perkin Trans. I, 
1994,1975. d) Wu, Y. -L.; Yao, Z. -J. Tetrahedron Lett. 1994, 35, 157. e) 
Wu, Y. -L.; Yao, Z. -J. J. Org. Chem. 1995, 60, 1170. 
SUMMARY OF THE INVENTION 
Accordingly the present invention is directed to a stereocontrolled 
synthesis of a central core tetrahydrofuran (THF)-unit of mono-THF 
containing acetogenins. The invention also includes novel intermediates 
which are key in the synthesis of the therapeutically active mono-THF 
acetogenins, particularly, for example, corossolone, and (10RS) 
corossoline. 
The present invention includes as a novel intermediate for the synthesis of 
the above acetogenins a stereoisomeric compound of the formula 
##STR1## 
wherein Ar is phenyl or substituted phenyl. 
A particular compound of choice in this case is the compound of the formula 
I where Ar is phenyl. 
Another novel intermediate of the present invention is a stereoisomeric 
compound of the formula 
##STR2## 
wherein Ar is phenyl or substituted phenyl, R is lower acetyl, and n is 1 
or 2. The preferred compound in this instance is the compound of the 
formula II where Ar is phenyl; R is methyl and n is 1. 
The present invention also includes a process for preparing the 
intermediate of the formula I which includes the steps of: 
(a) reacting a stereoisomeric compound of the formula 
##STR3## 
wherein P is an acid labile protective group with an aromatic carboxylic 
acid halide or anhydride, or an aromatic sulfonyl halide to form a 
stereoisomeric compound of the formula 
##STR4## 
(b) reacting the resulting aromatic ester of formula IV with an acidic 
resin in an alcohol solvent to afford a stereoisomeric compound of the 
formula 
##STR5## 
(c) reacting the product of step (b) of formula V with a methane sulfonyl 
halide or aryl-sulfonyl halide followed by an alkali metal alkoxide or 
carbonate in an alcohol solvent to afford the product of the above formula 
I. 
DETAILED DESCRIPTION 
The following terms used throughout the present application have the 
following meanings: 
The term "stereoisomeric" compound means the compound depicted by its 
respective formula existing in any of 8 possible optical isomers. The 
compounds of Formulae I through V have three asymmetric carbon atoms or 
chiral centers and each center containing the asymmetric carbon atoms 
connected to four different groups exist either in the R configuration or 
S configuration. 
By way of illustration the asymmetric carbon atoms or chiral centers of the 
compounds of Formula I and II are designed with an asterisk as follows: 
##STR6## 
The term "Ar" stands for an aromatic group and is particularly a phenyl or 
a substituted phenyl group wherein the substituents are those that are 
typically used in organic chemistry or an aromatic ring such as, for 
example, alkyl, alkoxy, halo or nitro. 
The term "alkyl" denotes a straight or branched hydrocarbon chain and with 
the term "lower" includes such straight or branched hydrocarbon chain 
having from 1 to 7 carbon atoms. As a preferred embodiment, chains from 1 
to 4 carbon atoms are included. These include as examples, methyl, ethyl, 
propyl, isopropyl, butyl, secondary butyl, t-butyl, and the like. 
The term "alkoxy" refers to an alkyl moiety connected to an oxygen atom 
depicted by the formula OR, where R is an alkyl chain as defined above. 
Preferred alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the 
corresponding branched chain alkoxy groups of the propoxy and butoxy 
groups. 
The term "halo" includes the halogen family and particularly fluoro, 
chloro, bromo, and iodo. A preferred halo substituent is chloro. 
The term "acid labile protective" group means any group capable of 
protecting a hydroxyl group and capable of being easily removed under 
acidic conditions without affecting other functional groups in the 
compound. These include groups having an oxygen atom located off a carbon 
atom attached to the oxygen atom of the hydroxy group, e.g. 
##STR7## 
Such groups include, for example, methoxymethyl, 1-ethoxyethyl, 
tetrahydropyranyl and the like. 
The synthesis of the novel intermediates of the present invention by a 
stereocontrolled method is illustrated by way of example in Schemes 1 and 
2 and begin with a commercially available glycidyl benzyl ether, which is 
commercially available in both enantiomeric forms. Thus the synthesis 
shown in the schemes and described below are for the synthesis of a 
particular stereoisomer but the synthesis can be used to prepare all 
possible stereoisomers. 
The epoxide, for example, (S-glycidyl benzylether) is first opened with 
allyl magnesium bromide using a cuprous halide catalyst, particularly, for 
example, cuprous bromide to provide a single regioisomer of homoallylic 
alcohol 1. The reaction is carried out in tetrahydrofuran as a solvent at 
preferably 0.degree. C. 
The hydroxyl group is then protected as the corresponding ethoxy ethyl 
ether by known methods, for example, an acid medium in methylene chloride 
solvent, and the terminal double bond is transformed to the aldehyde 2 
under oxidative cleavage conditions. By way of example, the oxidation may 
be carried out with osmium tetroxide catalyst, N-methyl morpholine-N-oxide 
(NMO), then sodium periodate, NaIO.sub.4 in an aqueous tetrahydrofuran 
medium. The aldehyde is converted to the pure 
(E)-.alpha.-.beta.-unsaturated ester 3 via the Wittig-Homer reaction (as 
described in Krief, A.; Dumont, W.; Lecomte, P. Tetrahedron 1989, 45, 
3039). The ester group is then reduced to the corresponding allylic 
alcohol using diisobutylaluminum hydride. Sharpless asymmetric epoxidation 
(as described in Hanson, R. M.; Sharpless, K. B. J. Org Chem. 1986, 51, 
1922) using (L)-(+)-diisopropyl tartrate provides the corresponding epoxy 
alcohol 5 as the only diastereomer which can be detected by NMR 
spectroscopy. The hydroxy group is then converted to a (p)-nitrobenzoate 6 
by treating a hydroxyl compound with a p-nitrobenzoylchloride, in the 
presence of triethylamine and methylene chloride solvent. The next step, 
one of the key steps in the overall process, is the one-step removal of 
the epoxy ethyl ether protective group as well as ring-closing to the 
tetrahydrofuran compound 7 as a single isomer. This step is carried out by 
using an acidic resin, particularly a Dowex resin, in methanol. Epoxide 
formation is then accomplished by first transforming the secondary 
hydroxyl group into a mesylate or tosylate by treating compound 7 with 
methane sulfonyl chloride or p-toluenesulfonyl chloride in the presence of 
triethylamine in methylene chloride solvent at about 0.degree. C. The 
intermediary benzoate-mesylate compound is then treated with an alkali 
metal alkoxide or in an alcohol solvent, particularly, for example, sodium 
methoxide or potassium carbonate in methanol to yield the THF-epoxide 
compound 8, which is the preferred compound of the novel intermediates of 
formula I of the present invention. 
##STR8## 
The novel intermediate of formula I, and particularly compound 8, is used 
as a key intermediate as the epoxide can be easily opened by different 
nucleophiles to lead to structures with a fixed stereochemical 
relationship around the THF-ring unit. For example, as shown in Scheme 2, 
compounds 9 and 10 have been prepared using undecylmagnesium bromide and 
methyl phenyl sulfone as nucleophiles. Compound 10 represents the 
preferred embodiment of the novel intermediates of formula II. 
By way of example, the transformation of compound 8 to 9 takes place by 
treating 8 with undecylmagnesium bromide in tetrahydrofuran using a 
cuprous halide such as, for example, cuprous bromide at about 0.degree. C. 
The hydroxyl group is then protected with a methoxy methyl group (MOM). 
Conversion of compound 8 to compound 10 is also illustrated in Scheme 2 to 
take place in a two-step synthesis. 
##STR9## 
Compound 9 is the key intermediate used in the total synthesis of 
corossolone and corossoline (as described in Wu, Y. -L; Yao, Z. -J. J. Org 
Chem. 1995, 60, 1170). 
Thus, for example, stereospecific compound 9 prepared by the method of the 
present invention may be used directly in the synthesis of corossolone as 
reported by Wu, id., and as shown in Schemes 3, 4, 5 and 6. Compound 9 as 
prepared by the present invention eliminates the need for separating the 
different isomers formed in the synthesis shown by Wu, id. 
Compound 9 of the present invention where the hydroxyl group is protected 
by a tertiary-butyldimethyl silyl group (TBS or TBDMS) is propargylated by 
treatment with the enantiomerically pure allenylboronic ester, 
2-allenyl-1,3-dioxa-2-borolane-(4S,5S)-dicarboxylic acid 
bis(1'-methylethyl) ester, prepared from an allenylboric acid and 
diisopropyl D-tartrate in the presence of powdered 4 .ANG.molecular 
sieves. The reagent-controlled asymmetric propargylation is performed at 
-78.degree. C. for 24 h and gives a stereoselective product. The THF 
segment 13 with the desired chiral centers is obtained after silylation of 
homopropargyl alcohol 12 (Scheme 1). 
##STR10## 
The remaining part of the synthesis is illustrated by schemes 4, 5 and 6 
and is carried out as described by Wu, id. 
##STR11## 
In addition, the use of intermediates 9 and 10 through coupling of these 
compounds may be used to prepare non-adjacent bis-THF acetogenins. 
Thus, the present invention provides an efficient procedure for the 
stereocontrolled synthesis of THF-epoxide. This synthetic approach offers 
several advantages over previously described strategies. First, both 
enantiomers of glycidyl benzyl ether are commercially available and the 
stereochemical outcome in the Sharpless asymmetric epoxidation step can be 
selected by the use of either enantiomer of diisopropyl tartrate. 
Furthermore, the stereochemical outcome for the final epoxidation can also 
be varied by derivatizing either the primary or the secondary hydroxyl 
group into a leaving group. This approach can yield 8 stereoisomeric 
THF-epoxides and thereby provide the opportunity to generate large 
chemical libraries of mono-THF containing acetogenins.