Amide Enolate Additions to Acylsilanes: In Situ Generation of Unusual and Stereoselective Homoenolate Equivalents

Abstract

The synthesis of beta-hydroxy carbonyl compounds is an important goal due to their prevalence in bioactive molecules. A novel approach to construct these structural motifs involves the multicomponent reaction of acylsilanes, amides, and electrophiles. The addition of amide enolates to acylsilanes generates beta-silyloxy homoenolate reactivity by undergoing a 1,2-Brook rearrangement. These unique nucleophiles formed in situ can then undergo addition to alkyl halides, aldehydes, ketones, and imines. The gamma-amino-beta-hydroxy amide products derived from the addition of these homoenolates to N-diphenylphosphinyl imines are generated with excellent diastereoselectivity (> or = 20:1) and can be efficiently converted to highly valuable gamma-lactams. Finally, the use of optically active amide enolates delivers beta-hydroxy amide products with high levels of diastereoselectivity (> or = 10:1).

Ammonia synthons for the multicomponent assembly of complex γ-lactams

“…Although this useful building block has found many applications as a member of the "chiral pool," it is a poor starting point for the diverse synthesis of lactams given the limited opportunities for introducing substituents at the carbon centers of the ring. Recently reported methods address this gap in synthesis technology by allowing the rapid assembly of polysubstituted γ-lactams (7)(8)(9).…”

Advances toward the Synthesis of Functionalized γ-Lactams

“…40 The synthesis of the stable homoenolate started with treatment of compound A with lithium diisopropylamide (LDA), followed by quenching it with compound B, which readily underwent Brook rearrangement (Scheme 30). The reaction intermediate reacted with N-diphenylphosphinyl imine 127 to provide compound 128.…”

“…The N-diphenylphosphinyl prosthetic group on the imine group was an optimal choice for this reaction due to its electron-withdrawing and acid sensitive properties, which favored the final cyclization reaction to form g-lactam 129. 40 Another stereoselective approach to substituted g-lactams was developed from a three-component reaction, namely an aldehyde, an imine and a cyclic anhydride. 41 The reaction required the formation of the iminium species under dehydrating conditions, followed by addition of the asymmetric succinic anhydride (Scheme 31).…”

Alternaric acid: formal synthesis and related studies

“…In this context, streamlined one-pot transformations, cascade reactions, and multicomponent couplings have emerged as enabling tools for the synthesis of complex molecules [1–2]. Our laboratory [3–16] and others have developed [17] and employed [18–19] silyl glyoxylates 1 in a variety of synthetic endeavors, both in natural-product synthesis and synthetic methodologies [20]. Key to their use in a variety of contexts is the ability of silyl glyoxylates to function as linchpin synthons for geminal coupling of nucleophile/electrophile pairs at a glycolic acid subunit (Scheme 1), which allows the rapid build-up of molecular complexity.…”