Diastereoselective Conjugate Addition to Chiral α,β‐Unsaturated Carbonyl Systems in Aqueous Media: An Enantioselective Entry to α‐ and γ‐Hydroxy Acids and α‐Amino Acids

Abstract

The stereoselectivity of the ultrasonically induced zinc--copper conjugate addition of iodides to chiral alpha,beta-unsaturated carbonyl systems under aqueous conditions was studied. Alkyl iodides add diastereoselectively to methylenedioxolanone 1 and methyleneoxazolidinone 2 to afford the 1,4-addition products in good yields (38-95 %) and with high diastereomeric excess (44-90 % de). The 1,4-addition to chiral gamma,delta-dioxolanyl-alpha,beta-unsaturated esters 3-5 also proceeds with good yields (51-99 %). The diastereoselectivity is dependent on the geometry of the olefin: the Z isomer 3 gives high diastereoselectivity, while the reactions with the E isomer 4 are nonstereoselective. The reaction proceeds with excellent chemoselectivity and allows the use of iodides bearing ester, hydroxy, and amino groups. Since the 1,4-addition products can be readily hydrolyzed, this methodology constitutes a novel entry for the enantioselective synthesis of alpha- and gamma-hydroxy acids and alpha-amino acids in aqueous media. The results obtained support the radical mechanism proposed by Luche, and represent one of the few examples of a radical stereoselective conjugate addition in aqueous medium.

Reactivity of Polar Organometallic Compounds in Unconventional Reaction Media: Challenges and Opportunities

“…Conjugate 1,4‐addition of alkyl halides (R–X) to α,β‐unsaturated aldehydes, ketones, esters, amides71 or nitriles72 can be mediated in EtOH/H 2 O or THF/H 2 O mixtures by the combination of Zn and Cu under sonication conditions. It is worth noting that this methodology has been fruitfully applied to the synthesis of: (i) a variety of vitamin D 3 derivatives,73 (ii) dioxolanes,73d (iii) oxazolidinones73h and (iv) sinefungin analogues 74. Finally, the intramolecular version of this 1,4‐addition reaction mediated by Zn/CuI allowed the straightforward synthesis of the lupinine analogues 45 (Scheme ) 75,76.…”

Advances in Asymmetric Amino Acid Synthesis Enabled by Radical Chemistry

“…While the pioneering works in this field were based on the use of harmful radical initiators such as Et 3 B, Bu 3 SnH, and AIBN, [86][87][88][89][90][91][92][93][94][95]97,[144][145][146][147] later the chemists found that the less toxic zinc, indium and copper are also capable as reductants to generate radicals from more hard reagents. [96,97,148,151,152,[162][163][164] In the past 5 years, a new round of development in the asymmetric synthesis of non-proteinogenic AAs has been begun by photoredox chemistry. Eco-friendly and green approaches were elaborated by applying readily accessible feedstock carboxylic acids and amines for straightforward radical coupling under mild conditions.…”

Desenvolvimento sustentável e química verde

“…O efeito de ultra-som é importante principalmente em reações Luche e colaboradores demonstraram que haletos de alquila reagem com aldeídos e cetonas α,β-insaturados, levando aos produtos de adição quando na presença de zinco-cobre em água ou solventes duplos sobre ação de ultra-som [68][69][70] . Recentemente, Suárez e colaboradores reportaram alguns exemplos de adições conjugadas estereosseletivas de iodetos induzidas por zinco-cobre a sistemas carbonílicos α,β-insaturados quirais (Esquema 22) 71 .…”