Organocatalytic Asymmetric α‐Selenenylation of Aldehydes

Abstract

Asymmetric organocatalysis has become a field of central importance for the stereoselective preparation of chiral, enantioenriched molecules. [1] In particular, chiral secondary amine catalysis has proven to be a powerful procedure for the enantioselective transformation of carbonyl compounds. Aminocatalysis has enabled the asymmetric a-, b-, and gfunctionalization of aldehydes and ketones with a wide range of electrophiles and nucleophiles by exploiting catalytic enamine, [2] SOMO (singly occupied molecular orbital), [3] iminium ion, [4] and dienamine [5] activation modes (Scheme 1). Within the realm of the non-inert elements classified as "non-metals" in the periodic table, only selenium-based compounds have yet to be stereoselectively incorporated into carbonyl compounds by organocatalysis.[6]Herein we report the exploitation of the enamine activation strategy in the first highly enantioselective aselenenylation of aldehydes catalyzed by a readily available chiral secondary amine. [7] This process provides access to highly attractive a-seleno aldehydes in high yield and with excellent enantiomeric excess (95-99 %) from commercially available starting materials under mild and simple reaction conditions. The synthetic utility of such intermediates [8] is demonstrated by their easy and rapid conversion into valuable chiral building blocks.The only access to chiral a-seleno aldehydes reported to date relies on a "chiral-pool" approach that involves multistep procedures.[9] To the best of our knowledge, no catalytic enantioselective processes are available for the preparation of these optically active building blocks. In light of this, and considering our recent efforts to expand the scope of asymmetric aminocatalysis, [10] we wondered whether the enamine activation concept might be extended to the highly enantioselective addition of selenium-based compounds to aldehydes.To assess the feasibility of such an asymmetric organocatalytic a-selenenylation strategy, we focused on air-stable, commercially available N-(phenylseleno)phthalimide (2) as the electrophilic selenium source.[11] Thus, treatment of propanal (1 a) with 2 in the presence of 10 mol % of l-proline in CH 2 Cl 2 (0.5 m) resulted in a clean but poorly selective selenenylation of the aldehyde (Table 1, entry 1). We then turned our attention to the use of imidazolidinone A [12] and the diarylprolinol silyl ethers B and C (TMS = trimethylsilyl), [13] which have recently emerged as potentially general enamine organocatalysts for a broad range of highly selective a-functionalizations of aldehydes.

Rationalization of an Unusual Solvent‐Induced Inversion of Enantiomeric Excess in Organocatalytic Selenylation of Aldehydes

“…[3] Scheme 2 shows how a bifurcation of the pathway after this step introduces the possibility of subsequent alteration of the stereoselectivity imparted in that step.Herein we report that downstream intermediates are further implicated in an intriguing and heretofore unexplained reversal of the sense of enantioselectivity as a function of solvent in the a-selenylation of aldehydes catalyzed by 4 a (see Scheme 3), [6] an effect that is difficult to rationalize by the model of Scheme 1. The current work extends our recent studies of other enamine-electrophile reactions [3] and suggests generality for this refined model which may inform further reaction optimization in organocatalysis.The a-selenylation reaction was reported previously by Melchiorre and co-workers [7] and by Cordova and co-workers, with excellent enantioselectivities in accordance with the steric model shown in Scheme 1. [6] In one example, however, Scheme 1.…”

“…The a-selenylation reaction was reported previously by Melchiorre and co-workers [7] and by Cordova and co-workers, with excellent enantioselectivities in accordance with the steric model shown in Scheme 1. [6] In one example, however, Scheme 1.…”

Asymmetric, Organocatalytic, Three-Step Synthesis of α-Hydroxy-(E)-β,γ-unsaturated Esters

“…α-Selenyl aldehydes 3a-e , prepared according to an Italian protocol,11 were immediately subjected in situ to a Wittig reaction to give the enantiomerically enriched compounds 5–11 (Scheme 1, A) in 48–83 % yields. Oxidation of the γ-seleneyl-( E )-α,β-unsaturated esters to the selenoxide using hydrogen peroxide caused spontaneous [2,3]-sigmatropic rearrangement to give the final enantioenriched α-hydroxy-( E )-β,γ-unsaturated esters (Scheme 1, B) in 63–90 % yields and excellent ee’s (≥94 %).…”

Die Diarylprolinolsilylether: zehn Jahre später

“…[37] Eine weitere bemerkenswerte Eigenschaft der Diarylprolinolsilylether ist ihre Verwendung für a-Funktionalisierungen auf der Basis von Substitutionsreaktionen, die zuvor nur in sehr geringer Zahl beschrieben worden waren. [38] Somit konnten EnaminZwischenstufen nun nicht nur Additionsreaktionen an polarisierte p-Systeme,s ondern auch Substitutionsreaktionen eingehen.…”