Chiral auxiliaries

Details Chiral auxiliaries Chiral auxiliaries

1996-06-24

1998-09-01

Gerstl, Robert

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548230, C07D26320

Patent

active

058012494

DESCRIPTION:

BRIEF SUMMARY
This invention relates to new chiral auxiliaries and derivatives thereof useful in the synthesis of chiral molecules, in particular to new chiral auxiliaries containing an oxazolidinone ring structure or a thia or aza analogue thereof.
The use of chiral auxiliaries in the selective synthesis of single enantiomers of chiral molecules is now well known--see, for example, EP-A-0457469 and the references described therein. Such auxiliaries typically comprise (i) a reactive part carrying or to which may be coupled a moiety having a prochiral centre, and (ii) a chiral part which influences the stereochemical course of reactions at the prochiral centre, thereby encouraging the generation of substantially enantiomerically pure products. The auxiliary is preferably such that the desired single enantiomeric product can thereafter be uncoupled and recovered, with simultaneous regeneration of the reactive part of the auxiliary, thereby permitting a succession of subsequent sequences of coupling, stereoselective synthesis and uncoupling reaction stages using the same auxiliary.
A representative class of auxiliaries currently used in this way comprises 4-monosubstituted oxazolidin-2-ones of formula ##STR2## (where R represents an organic group and the asterisk denotes that this group is predominantly in the R- or S-configuration such that the compound (A) is in substantially enantiomerically pure form). Here the 3-position amino group represents the reactive part (i) to which may be coupled a moiety, e.g. an acyl group, having a prochiral centre; the group R at the 4-position represents the chiral part (ii) which will direct the stereochemical course of reactions at such a prochiral centre.
An important requirement of such auxiliaries is that their basic structure should be substantially completely stable under the various reaction conditions employed, in particular that the structure should not be degraded under the conditions used for uncoupling of the desired stereoselective product. Similarly it is critical that uncoupling may be effected under conditions which are sufficiently mild not to induce racemisation of the desired substantially enantiomerically pure product.
A problem encountered with the above-described auxiliaries (A) is that the oxazolidinone ring may not exhibit sufficient stability during uncoupling reactions. Thus, for example, removal of an acyl group from the 3-position amino group, e.g. by acid- or base-catalysed hydrolysis, may also be accompanied by substantial degradation of the oxazolidinone ring, as illustrated in the following sequence: ##STR3## (where R and the asterisk are as hereinbefore defined and R' represents an acyl group). In this sequence path 1 is the desired uncoupling reaction (product cleavage) and path 2 represents unwanted degradation of the auxiliary (oxazolidinone cleavage). It will be appreciated that such degradation reduces both the yield of the desired product and the level of recovery of the auxiliary and thus has substantial adverse effects on operating costs, particularly for large-scale processes.
This problem is currently ameliorated by using hydroperoxides as cleavage agents in conjunction with oxazolidinone chiral auxiliaries, these directing the cleavage reaction predominantly along the desired product cleavage path 1. Such peroxide-based materials are hazardous to use, however, and there is thus a continuing need for chiral auxiliaries with improved stability under e.g. hydrolysing conditions and which permit stereoselective syntheses involving a wide range of prochiral centre-containing moieties.
The present invention is based on our finding that 4-asymmetrically substituted oxazolidin-2-ones and thia and aza analogues thereof may be stabilised against unwanted oxazolidinone cleavage if the 5-position of the ring is symmetrically disubstituted, whereby a wide range of e.g. acyl groups containing prochiral centres may be readily and reversibly coupled to the 3-position amino group. Most surprisingly, the presence of such substituents at the 5-position does not

REFERENCES:
patent: 5461162 (1995-10-01), Ho

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