Engineering acyclic stereocontrol in the alkylation of vinylglycine- derived dianions: Asymmetric synthesis of higher α-vinyl amino acids

David B. Berkowitz, Jill M. McFadden, Marianne K. Sloss

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A generalizable synthesis of higher L-α-vinyl amino acids is presented. The strategy pursued here involves the introduction of the amino acid side chain via the alkylation of a chiral, vinylglycine-derived dianionic dienolate, bearing the (-)-8-(β-naphthyl)menthyl (d'Angelo) auxiliary. A model is presented that postulates a favored 'exo-entended' conformation for this dienolate, leading to C(α)-alkylation at the si face. The model invokes internal amidate chelation to control ester enolate geometry and soft-soft interactions between the polarizable β-naphthyl ring of the auxiliary and the extended π-system of the dienolate to shield the re face. Heats of formation for four conformers of this dianion were calculated for their semiempirical optimized geometries (PM3). The results support the notion that in these vinylglycine-derived dianionic dienolates, 'exo' conformations are considerable lower in energy than their 'endo' counterparts, with the 'exo- entended' conformation being most favorable. In fact, the d'Angelo auxiliary gives a greater degree of acyclic stereocontrol in this system when compared with the (-)-8-phenylmenthyl (Corey) and trans-2-(β-naphthyl)-cyclohexyl auxiliaries, using isobutyl iodide and benzyl bromide as model electrophiles. These dianions are generated from the corresponding dehydrobutyrine esters via sequential deprotonation with LDA and n-BuLi (2 equiv). When alkylations are carried out at -78 °C in THF-HMPA, they proceed in 65-81% yields, with both regiocontrol (deconjugative α-alkylation is preferred over γ- alkylation) and a great degree of acyclic stereocontrol [91:9 to ≥98:2 diastereomeric ratios (10 examples)]. The auxiliary may be recovered in high yield (generally 90%) using a modification of Gassman's 'anhydrous hydroxide' conditions, in which considerably higher temperatures are employed. Among the side chains introduced directly are those of butyrine, leucine, ornithine, phenylalanine, aspartate, valine, and norvaline. The lysine side chain is elaborated via a 4-step sequence from the alkylation product obtained with 1- chloro-4-iodobutane as electrophile. Importantly, to our knowledge, this work represents the first asymmetric synthesis of L-α-vinyl analogues of m- tyrosine, ornithine, and lysine, known time-dependent inhibitors for amino acid decarboxylases.

Original languageEnglish (US)
Pages (from-to)2907-2918
Number of pages12
JournalJournal of Organic Chemistry
Issue number10
StatePublished - May 19 2000

ASJC Scopus subject areas

  • Organic Chemistry


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