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Stereoselective cyclization of zincated α-N-homoallylamino nitriles has been developed. Following treatment with lithium diisopropylamide (LDA) and transmetalation with zinc bromide, α-N-(1-phenylethyl)-N-homoallylamino nitriles lead to 2,3-methanopyrrolidines in moderate to good yields (up to 66 %) and excellent selectivities (up to >98:2). With substrates derived from α-branched homoallylic amines, a stereospecific inversion of the homoallylic stereogenic center was observed. To account for this, a mechanistic rationale involving the formation of zincioiminium ions from zincated α-amino nitriles is put forward. 2,3-Methanopyrrolidines should then arise from a sequence involving an aza-Cope rearrangement providing a configurationally stable (2-azoniaallyl)zinc species that then undergoes a [3+2] cycloaddition reaction.

A new bicyclic heterocycle 3, which is potentially useful for the synthesis of b-amino acids, has been obtained from a reaction between (S)-phenylglycinol and cyanogen bromide followed by a condensation with methyl propiolate. Conjugate additions of different organocuprate reagents to this chiral Michael acceptor occurred with complete diastereoselectivity. An optically pure b amino acid was obtained in excellent yield from the masked chiral derivative 4a.

New bicyclic heterocycles 5, which are potentially useful for the enantioselective synthesis of substituted b-amino acids, have been synthesized. A study on the a-alkylation of these chiral auxiliaries is presented. An optically pure b-amino acid was obtained in excellent yield from its masked chiral derivative 6a.The asymmetric synthesis of b-amino acids 1 has attracted much attention in recent years 2 owing especially to their use as building blocks for the synthesis of b-lactam antibiotics. 3 We recently published 4 the synthesis of a new chiral auxiliary 1 derived from (2S)-phenylglycinol which provides an enantioselective access to b-substituted bamino acids 3 via intermediates 2 (Scheme 1). Scheme 1These intermediates result from a diastereoselective alkylation of the bicyclic enone 1 and we wish to present here the outcome of a further alkylation involving these intermediates 2.Chiral intermediates 5a and 5b were synthesized by the following two-step sequence: (i) reaction between (2S)-phenylglycinol and cyanogen bromide 5 affording compound 4, (ii) condensation of this product with ethyl acrylate 6 or ethyl crotonate to form adducts 5a and 5b respectively (Scheme 2). a) methyl acrylate, EtOH, reflux, 97%. b) ethyl crotonate, EtOH, reflux, 25%. Scheme 2On the other hand, chiral bicyclic auxiliaries 5b and 5d were obtained by diastereoselective alkylation of 1 with organocuprate reagents 4 in the same way as reported in Scheme 1.Enolates derived from products 5 were generated by treatment with LiHMDS for 15 min at -10°C in THF. The electrophile was added at -10°C or at -50°C and the reaction mixture was stirred for 2 h at this temperature and further hydrolyzed with a saturated NH 4 Cl aqueous solution 7 (Table 1).The overall yields of alkylation range from 88% to 96% when the reactions were performed at -10°C. At -50°C, the yield drops due to incomplete conversion. The major isomer obtained in every case resulted from the alkylation of the apparently most hindered b side of the enolate intermediate. The S absolute configuration of the a center in adducts 6 was established by NOE 1 H NMR experiments in the case of a,b-dialkylated 6b-d compounds. Adduct 6a led to the known (S)-3-amino-2-methylpropanoic acid 8 8 by using the chemical sequence described in Scheme 3. 9Hydrogenation (Pd/C catalyst) of adduct 6a gave the reduced product 7. 10 The experimental conditions of basecatalysed hydrolysis 11 which were used in the synthesis of b-amino acids, 4 gave rise, in the present case, to epimerisation of the created stereocenter which is now a to a carbonyl group. However, strong acidic conditions afforded Downloaded by: Rice University. Copyrighted material.