Asymmetric Tandem Conjugate Addition–Aldol Condensation with N‐Acryloyloxazolidines Derived from 2‐Phenylglycinol

Abstract

The tandem 1,4‐addition–aldol condensation reaction of diethylzinc, α,β‐unsaturated chiral enantiopure oxazolidines derived from 2‐phenylglycinol, and carbonyl compounds is disclosed. The reaction proceeds through a radical‐polar crossover mechanism involving the aldol condensation of a trisubstituted zinc enolate through a Zimmerman–Traxler transition state. Installation of a 2‐pyridine moiety at the hemiaminal position of the chiral auxiliary allows obtaining both excellent asymmetric induction and diastereoselectivity (up to >90 % de). The developed protocol is suitable for aromatic and aliphatic aldehydes, as well as ketones.

Highly Stereoselective Aldol Reactions by Memory of Chirality: Synthesis of Quaternary β‐Hydroxy α‐Amino Acids

“…However, this does not seem significant to us, as the diastereomeric ratio is close to 1 : 1. Thus, when 2‐pyridinecarboxaldehyde is used, there is probably complexation of the potassium enolate by the pyridine nitrogen (pyridine, a good complexing agent, is regularly used to achieve a better control of the stereoselectivity [31] ) as in transition state II ( Scheme 2). More surprisingly, the crystallographic structure of the acetylated compound Ac‐5a is different from that observed for the major diastereomer in the reaction with the alanine derivative.…”

Diastereoselective Functionalization of Chiral N‐Acyl‐1,3‐oxazolidines and Their Applications in the Synthesis of Bioactive Molecules

“…Experiments for a second alkylation of 31 c were conducted at a higher temperature, however, only a mixture of the starting material and a degradation product (32) were found. The mechanism offered as explanation for the formation of enamide 32 involves deprotonation of the benzylic position in the oxazolidine ring, followed by hydrolysis of trifluoroacetone.…”

“…The combined efforts of the Pérez‐Luna and Terán groups, resulted in the successful development of 1,3‐oxazolidine chiral auxiliary 101 , able to impart selectivity in both steps through an active volume in a privileged step of the transition state by installing a pyridine ring in the C‐2 position of the heterocyclic ring [32] . Reaction of this new system with benzaldehyde afforded 102 as 88 : 12 mixture of only two diastereoisomers.…”

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

“…While simple, this reaction offers attractive features: 1) it proceeds under mild conditions in the absence of any transition-metal catalyst; 2) the 1,4-addition step can be combined with condensation reactions of the zinc enolate with electrophiles in protocols wherein all the reactive partners can be introduced from the start, given that dialkylzinc reagents offer a large functional group tolerance; and 3) the radical character of the process allows for the use of alkyl iodides as alkyl source in multicomponent reactions. Trialkylboranes can react in a similar way with enones [3] whereas, distinctively, suitable acceptors for the reaction with dialkylzinc reagents also include α,β-unsaturated carboxylic acid derivatives such as α,β-unsaturated (di)esters [4,5], N-enoyloxazolidinones [6,7], N-enoyloxazolidines [8], or alkylidenemalonates [9][10][11]. These reactions follow a free-radical chain process wherein alkyl radicals (R • ) add across the C-C double bond of the 1,4-acceptor, activated by complexation with the dialkylzinc, to deliver an enoxyl radical that undergoes homolytic substitution at zinc (S H 2) to produce a zinc enolate and a new R • that propagates the radical chain (Scheme 1).…”