Val‐Ala Dipeptide Isosteres by Hydrocyanation of α′‐Amino α,β‐Unsaturated Ketones − Control of Stereoselectivity by the N‐Protecting Group

Abstract

Three diastereoisomeric hydroxyethylene isosters of the Val‐Ala dipeptide were synthesized from α,β‐unsaturated ketones 1 derived from N‐Boc‐ and N,N‐dibenzyl‐L‐valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β‐cyano ketones with the stereoselectivity depending on the protecting group. N‐Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N‐dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N‐Boc and N,N‐dibenzyl compounds. The cyano alcohols thus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val‐Ala dipeptide. In the first series the hydroxy group and the N‐terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C‐terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4‐hydroxy‐5‐amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach. (© Wiley‐VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003)

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

“…Compound 9 was obtained as a 9:1 mixture of diastereomers, the syn ( S , S ) diastereomer being the major one. The selectivity of the reduction is in agreement with previous results and is consistent with the Cram model for a chelation controlled reduction [ 16 – 18 ]. Both OH groups of compound 9 were oxidized by PCC to obtain aldehyde 10 .…”

Diastereoselective synthesis of vicinal amino alcohols

“…The corresponding Boc-protected compounds (158 and 160) showed the opposite stereochemical outcome with high dependence on the stereochemistry at the β-position. 51 Reduction of α,β-unsaturated ketones. Enones are generally synthesized from amino acid derived β-ketophosphonates via Horner-Wadsworth-Emmons reaction with the desired aldehyde.…”

Nitrilases Catalyze Key Step to Conformationally Constrained GABA Analogous γ-Amino Acids in High Optical Purity

“…Michael addition of cyanide to α,β-unsaturated cyclic ketones gave 3-oxo-cyclopentanecarbonitrile (±)- 9 and 3-oxo-cyclohexanecarbonitrile (±)- 10 . We made considerable improvements (see Supporting Information) compared with the poor yields achieved by the literature procedures for both five- and six-membered ketonitriles. − Subsequent NaBH 4 reduction of the ketones afforded epimeric hydroxy nitriles in a cis:trans -isomer ratio of 88:12 for six-membered 24 (±)- 16 and (±)- 18 as well as 61:39 for five-membered rings (±)- 15 and (±)- 17 , determined by GC/MS analysis. Displacement of the mesylates of (±)- 15 −(±)- 18 by azide, reduction, and final protection gave the desired amino nitriles in Scheme .…”