Diastereoselective conjugate reduction with samarium diiodide: asymmetric synthesis of methyl (2S,3R)- N -acetyl-2-amino-2,3- dideuterio-3-phenylpropionate Stephen G. Davies,* Humberto Rodrı ´guez-Solla, Juan A. Tamayo, A. Christopher Garner and Andrew D. Smith The Department of Organic Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, UK OX1 3TA. E-mail: steve.davies@chem.ox.ac.uk Received (in Cambridge, UK) 2nd June 2004, Accepted 28th June 2004 First published as an Advance Article on the web 8th September 2004 A highly diastereoselective conjugate reduction using SmI 2 and D 2 O has been demonstrated on a homochiral benzylidene diketopiperazine template, giving methyl (2S,3R)- N-acetyl-2-amino-2,3-dideuterio-3-phenylpropionate 12 in 93% de and 90% ee after deprotection, hydrolysis and N-acetylation. Samarium diiodide (SmI 2 ) is a versatile reagent in synthetic organic chemistry. 1 First introduced by Kagan, 2 SmI 2 has been used to effect a range of organic transformations, including the chemose- lective reduction of a wide variety of functional groups such as organic halides, carbonyls and epoxides. This versatile reagent also promotes reductions of the CLC double bond of a,b-unsaturated esters and amides, and, while additives such as N,N-dimethylace- tamide 3 or HMPA 4 are typically required to facilitate this reaction, Concello´n et al. have recently shown that conjugate reductions can be carried out using SmI 2 and either H 2 O or D 2 O. 5,6 The diastereoselective conjugate reduction of a,b-unsaturated carbonyl systems using this methodology has received only minimal attention. 5c,7 SmI 2 has also been employed in various other enantioselective processes. 1h,8 Previous work from this laboratory has demonstrated that protonation of metallated bis-N-4-methoxybenzyl-diketopiperazine enolates 1, prepared by conjugate addition to the methylene diketopiperazine 2 or deprotonation of a substituted diketopiper- azine 3, proceed with high levels of diastereoselectivity and may be used for the asymmetric synthesis of either (R)- or (S)-a-amino acids depending upon the enantiomer of auxiliary utilised. 9 The excellent protonation selectivity observed using this template led us to investigate the diastereoselectivity upon protonation of the analogous samarium enolate, which it was envisaged could be generated by the SmI 2 promoted conjugate reduction of a 3-alkylidene substituted diketopiperazine template 4 (Fig. 1). We report herein our preliminary results in this area, in which protonation of the samarium enolate proceeds with high levels of diastereoselectivity under the stereocontrol of the chiral auxiliary and with excellent stereoselectivity in the formation of an exocyclic stereogenic centre, facilitating the first highly stereoselective SmI 2 promoted asymmetric synthesis of (2S,3R)-2,3-dideuterio-pheny- lalanine derivatives. Initial investigations were concerned with the SmI 2 promoted reduction of the (3E,6S)-5 and (3Z,6S)-6 diastereoisomers of template 4. Treatment of (3E,6S)-5 with SmI 2 in THF and subsequent addition of deoxygenated H 2 O led to clean reduction of the a,b-unsaturated enamide to afford the known cis-(3S,6S)-7 in 95% de, 9c,e and in 93% isolated yield. The effect of enamide geometry upon the diastereoselectivity of this reduction was next examined, with the diastereoisomeric benzylidene (3Z,6S)-6 also giving cis-(3S,6S)-7 in 96% de and 89% isolated yield (Scheme 1). Encouraged by the high levels of cis-selectivity afforded by these reductions, consistent with the expected protonation selectivity for an intermediate samarium enolate, the mechanism and stereo- chemical course of these transformations was probed further through the incorporation of deuterium in these reactions. While the reduction of (E)- and (Z)-benzylidenes 5 and 6 with SmI 2 in THF–H 2 O affords a single new stereogenic centre at C(6), the reductive deuteration of these substrates potentially generates, stereoselectively, two new stereogenic centres, at C(6) and C(1’). Treatment of either (3E,6S)-5, (3Z,6S)-6, or a 7 : 1 mixture of (3E,6S)-5 : (3Z,6S)-6 with a solution of SmI 2 in THF–D 2 O gave C(1’),C(6)-dideuterated-diketopiperazine (3S,6S,1’R)-8 with w99% incorporation of two deuterium atoms. Examination of the 1 H NMR spectrum of the crude material indicated a 92 : 8 ratio of (3S,6S,1’R)-8 and combined diastereoisomers (3S,6S,1’S)-9, (3S,6R,1’R)-10 and (3S,6R,1’S)-11, respectively and a 95.5 : 4.5 ratio of cis-(3S,6S) 8 1 9 to trans-(3S,6R) 10 1 11 diastereoisomers respectively, in all reductions investigated. Chromatographic removal of the samarium residues afforded 8 (92 : 8 mixture of 8 and minor diastereoisomers 9–11) in 96% yield (Scheme 2). The (3S,6S,1’R)-configuration within dideutero 8 was estab- lished by conversion to the known methyl (2S,3R)-N-acetyl-2- amino-2,3-dideuterio-3-phenylpropionate 12. 10 N-Debenzylation of 8 with ceric ammonium nitrate afforded (3S,6S,1’R)-dideuterio- diketopiperazine 13 in 90% yield. Subsequent hydrolysis followed by esterification yielded a mixture of methyl (2S,3R)-2-amino-2,3- dideuterio-3-phenylpropionate 14 and (S)-valine methyl ester 15 as their hydrochloride salts which were separated by distillation of the free amino esters to afford (2S,3R)-2,3-dideutero-phenylalanine methyl ester 14 in 93% d.e and 90% ee 11 [consistent within experimental error with the 95.5 : 4.5 ratio of cis (8 1 9)/trans (10 1 11) diastereoisomers from the diketopiperazine reduction]. N-acetylation of 14 afforded, after chromatographic purification, N-acetyl (2S,3R)-12 in 71% overall yield (Scheme 3). The relative configuration within 12 was identified unambigu- ously by comparison with an authentic 1 : 1.4 mixture of racemic dideutero (2SR,3RS)-12 and dideutero epimer (2SR,3SR)-16, derived from the D 2 O promoted SmI 2 reduction of methyl (Z)- a-acetamido-cinnamate, and comparison with the 1 H NMR Fig. 1 Scheme 1 Reagents and conditions: (i) SmI 2 , THF, H 2 O, rt. DOI: 10.1039/b408257e 2502 Chem. Commun. , 2004, 2502–2503 This journal is ß The Royal Society of Chemistry 2004 Published on 08 September 2004. Downloaded by University of Western Ontario on 26/10/2014 04:27:40. View Article Online / Journal Homepage / Table of Contents for this issue