Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1996-09-12
1998-05-12
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C07C 3506
Patent
active
057508054
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to the rearrangement of epoxides of cyclic olefins, generally leading to allyl alcohols. It particularly relates to the preparation of cyclic allyl alcohols by means of an enantioselective rearrangement of an epoxide employing a chiral base.
BACKGROUND ART
Some examples of this are already known. For example Milne, D. and Murphy, P. J., J. Chem. Soc. Chem. Commun., (1993) 884-886 have recently disclosed the enantioselective rearrangement of a benzyloxy cyclopentene epoxide (1) using dilithiated (1R, 2S)-norephedrine: see Route A: ##STR2## The enantiomeric allyl alcohols (2) and (3) were produced in unequal amounts, the greatest selectivity being achieved by allowing the reactants to warm from -78.degree. C. to 0.degree. C. over 16 h, which afforded the isomer (3) in 86% enantiomeric excess ('e.e.). That is, of the total amount of both isomers produced, 93% was isomer (3) and 7% was isomer (2) so that the e.e. of isomer (3) was 93-7=86%.
DISCLOSURE OF THE INVENTION
We were interested in producing individual enantiomers of cis-4-(hydroxymethyl)cyclopent-2-ene-1-ol (4),(5) and therefore attempted to perform an analogue of Route A, namely Route B (R.sup.1 .dbd.--CH.sub.2 Ph): ##STR3##
However, there was no reaction when the benzyloxyepoxide (6,R.sup.1 .dbd.--CH.sub.2 Ph) was treated with dilithiated (1R,2S)-norephedrine. There was likewise no reaction with the corresponding trityloxy-epoxide (6, R.sup.1 .dbd.--CPh.sub.3).
But we have surprisingly found that the unprotected hydroxy-epoxide (6,R.sup.1 .dbd.H) reacts smoothly to give the desired allyl alcohols (4 and 5; R.sup.1 .dbd.R.sup.2 .dbd.H). Furthermore either isomer (4 or 5) is obtainable almost exclusively (up to 95% e.e. or more). The asymmetric induction is in the opposite sense from that found in the prior art (Route A).
Thus according to the invention there is provided a process for the base-catalysed rearrangement of an epoxide to an unsaturated alcohol, wherein the epoxide is an epoxide of a cyclic olefin which has a free hydroxy group and wherein the rearrangement produces a pair of enantiomers and the base is chiral, the relative proportions of the pair of products being dependent on the chiral form of the base. We are particularly interested in the rearrangement of meso-compounds, generating asymmetry. Thus the substrate will usually have an odd number of atoms in the cyclic olefin ring, most usually 5 or 7. The hydroxy-group may then be a substituent on the cycloolefin ring. Alternatively it may be in a side-chain, e.g. --CH.sub.2 OH. Preferred substrates include cis-3-cyclopentene epoxide 1-methanol and cis-4-cycloheptene epoxide 1-methanol.
The base is preferably a metallated (e.g. lithiated) chiral base, particularly a chiral amine base. Examples of chiral amine bases include bis ((1R)-1-phenylethyl) amine. Without being limited to any mechanism, it seems likely that highly selective reaction is produced by means of a base that can interact simultaneously with the hydroxy group and the epoxide group. Thus a difunctional base e.g. a metallated 1,2-aminoalcohol such as a dilithiated enantiomer of ephedrine, norephedrine, pseudoephedrine or norpseudoephedrine may be most effective.
Reaction can be carried out under experimentally convenient conditions, e.g. mild temperatures (e.g. 0.degree.-25.degree. C.).
Furthermore we have found that the reaction can be applied to the generation of an asymmetric tetrasubstituted carbon atom by desymmetrisation of a meso-epoxide, e.g. Route C, where R.sup.3 .noteq.H: ##STR4##
Thus in a preferred type of embodiment of the invention, the epoxide is an epoxide of a cycloolefin which is disubstituted at an atom located symmetrically with respect to the epoxide ring by (i) an interacting group such as a hydroxy group or a hydroxy-bearing group; and (ii) a second substituent which is not H. Thus a preferred substrate is (9), more preferably (10): ##STR5## where Z is OH or a hydroxy-bearing side chain e.g. hydroxy alkyl (e.g. C.sub.14 alkyl). R.sup.3 may be alkyl
REFERENCES:
Milne et al., Dilithiated Aminoalcohols as Homochiral Bases, J. Chem. Soc. Chem Commun., pp. 884-886, May 21, 1993.
Hodgson et al., Highly Enantioselective Rearrangement of a meso-Epoxide to an Allyl Alcohol for Carbocyclic Nucleoside Synthesis: an Internal Alkoxide Effect, Tet. Assym., pp. 337-338, Mar. 1994.
Hodgson et al., Concise Racemic and Highly Enantioselective Approaches to Key Intermediates for the Synthesis of Carbocyclic Nucleosides and pseudo-Ribofuranoses:Formal Synthesis of Carbovir, Chem. Soc. Perkin Trans 1, pp. 3373-3378, Dec. 7, 1994.
Asami, Tetrahedron Letters, vol. 26, No. 47, pp. 5803-5806, 1985.
Hodgson David Michael
Witherington Jason
Geist Gary
Puttlitz, Jr. Karl J.
The University of Reading
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