Stereoselective α-Alkylation of New Chiral Auxiliaries: An Access to Enantiomerically Pure α- and α,β-Substituted β-Amino Acids

Abstract

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.

An Efficient Synthesis of Pyrimidines from β-Amino Alcohols

“…We present here an efficient access to acyclonucleosides 4 and 6 starting from β-amino alcohols 1 in three high-yielding steps. Reaction of the β-amino alcohol with cyanogen bromide followed by condensation of the resulting heterocycle 2 with ethyl propiolate or ethyl butynoate led to pyrimidinones 3 (Scheme ) 1 …”

An Efficient Synthesis of a New Series of Acyclonucleosides Starting from β-Amino Alcohols

“…We have already reported that synthons 2a react stereoselectively at the C-6 site of the uracil ring with different organocuprate reagents (Scheme ), leading to alkylated compounds 5 . These heterocycles eventually were transformed into pure β-amino acids 3 …”