Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1996-08-12
2000-03-14
O'Sullivan, Peter
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
540200, 544172, 548215, 549494, 560 38, 560 39, 560 41, C07C20968, C07C21126
Patent
active
060374985
DESCRIPTION:
BRIEF SUMMARY
This invention is concerned with new chiral lithium amides and their use in the synthesis of chiral .beta.-amino acids, .beta.-lactams and the like.
Compounds such as (R)- and (S)-.alpha.-methylbenzylamine are known to be useful starting materials in the synthesis of a range of chiral molecules. Thus, for example, N-allyl derivatives thereof have been described in connection with stereoselective syntheses by Bailey et al. in Tet. Lett. 30(39), pp. 5341-5344 (1989) and by Cardillo et al. in Tet. 47(12/13), pp. 2263-2272 (1991).
The present invention is based on our finding that lithio derivatives of such substantially enantiomerically pure N-allylated .alpha.-methylbenzylamines and analogues thereof are particularly useful reagents acting as sources of chiral nucleophiles.
Thus according to one aspect of the invention there are provided compounds of general formula (I) ##STR2## (wherein R represents a carbocyclic aryl group, R.sup.1 represents an organic group, R.sup.2 represents a hydrogen atom or an organic group, and the asterisk denotes that the group R.sup.1 is predominantly in the R- or S-configuration such that the compound (I) is in substantially enantiomerically pure form).
The term substantially enantiomerically pure as used herein denotes compounds containing at least 80%, advantageously at least 90%, and preferably at least 95% of the desired enantiomer.
Carbocyclic aryl groups R may, for example, contain 6-20 carbon atoms, e.g. as in phenyl or naphthyl, and may if desired be substituted, for example by one or more of halo (e.g. chloro, bromo, or iodo), hydroxy, lower (e.g. C.sub.1-4) alkoxy (e.g. methoxy or ethoxy), lower alkylthio (e.g. methylthio), lower alkylsulphonyl (e.g. methylsulphonyl), amino, substituted amino (e.g. mono- or di-(lower alkyl)amino such as methylamino or dimethylamino), carboxy, cyano, lower alkoxycarbonyl (e.g. methoxycarbonyl), carbamoyloxy, sulphamoyl and sulphoxy. Preferred R groups include phenyl and 3,4-dimethoxyphenyl.
The groups R.sup.1 can be selected from a wide range of organic groupings, including, for example, aliphatic, cycloaliphatic and araliphatic groups, e.g. containing up to 20 carbon atoms and optionally carrying one or more substituents. R.sup.1 may thus, for example, represent a group selected from C.sub.1-10 alkyl such as methyl or ethyl; C.sub.2-10 alkenyl such as vinyl or propenyl; C.sub.3-10 cycloalkyl such as cyclopentyl or cyclohexyl; C.sub.3-10 cycloalkyl--C.sub.1-4 alkyl such as cyclopentylmethyl; C.sub.6-12 aryl--C.sub.1-4 alkyl such as benzyl; and substituted versions of any of the preceding groups, e.g. carrying substituents as described above for R.
One preferred class of compounds (I), by virtue of ease of availability of starting materials therefor, are those in which R represents optionally substituted phenyl and R.sup.1 represents methyl.
Where R.sup.2 in formula (I) represents an organic group this may, for example, be a lower alkyl group containing 1-10, e.g. 1-6 carbon atoms, as in methyl, ethyl, propyl and butyl groups; a lower (e.g. C.sub.2-10) alkenyl group such as vinyl; a carbocyclic aryl group, e.g. containing 6-20 carbon atoms, such as phenyl or naphthyl; or a heterocyclic group, e.g. having one or more 5- and/or 6-membered rings and containing one or more heteratoms selected from O, N and S as in, for example, furyl, thienyl, pyrrolyl, pyridyl, benzothienyl, indolyl, imidazolidinyl or piperidinyl.
As noted above, compounds (I) according to the invention are a useful source of chiral nucleophiles, capable of undertaking highly stereoselective reactions. Thus, for example, they may undergo Michael addition to .alpha.,.beta.-unsaturated carboxylic acid derivatives such as esters, thioesters, amides, thioamides and oxazolidinones, with high diastereoselectivity, e.g. as represented by the following sequences in the case of addition to an .alpha.,.beta.-unsaturated ester: ##STR3## (where R, R.sup.1 and R.sup.2 are as hereinbefore defined; R.sup.3 represents an organic group; R.sup.4 represents an esterifying group such as a low
REFERENCES:
patent: 5773610 (1998-06-01), McWhorter et al.
Martin et al., "Total Synthesis of Racemic Lycoramine," J. Org. Chem., 46, 3567-3568, 1981.
Bailey et al., Tetrahedron Letters, vol. 30, No. 39, 1989, 5341-5344.
Cardillo et al., Tetrahedron Letters, vol. 47, No. 12, 1991, 2263-2272.
Davies Stephen Graham
Fenwick David Roy
Polywka Mario Eugenio Cosamino
Reed Frank
O'Sullivan Peter
Oxford Asymmetry International PLC
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