Stereodivergent Dual Catalytic α‐Allylation of Protected α‐Amino‐ and α‐Hydroxyacetaldehydes

Abstract

Fully stereodivergent dual-catalytic a-allylation of protected a-amino-and a-hydroxyacetaldehydes is achieved through iridium-and amine-catalyzed substitution of racemic allylic alcohols with chiral enamines generated in situ. The operationally simple method furnishes useful aldehyde building blocks in good yields,m ore than 99 %e e, and with d.r.values greater than 20:1 in some cases.A dditionally,t he g,d-unsaturated products can be further functionalizedi n as tereodivergent fashion with high selectivity and with preservation of stereochemical integrity at the C a position.Formation of multiple stereogenic centers in asingle chemical transformation with complete control of absolute and relative configuration represents as ignificant challenge in asymmetric synthesis.[1] We recently described the concept of stereodivergent dual catalysis,w hereby two distinct chiral catalysts operate concurrently,yet independently,topromote bond formation with full control over the configuration of two new stereogenic centers.[2] Simultaneous use of ac hiral Ir(P,olefin) complex and achiral amine allowed implementation of this concept in the stereodivergent a-allylation of branched and linear alkanals as well as g-allylation of cyclic a,b-unsaturated aldehydes.[3] Herein, we report the enantioand diastereodivergent a-allylation of protected a-aminoand a-hydroxyacetaldehydes through dual iridium/amine catalysis (Scheme 1). Ther esulting a-N/O-substituted unsaturated aldehyde products are amenable to further elaboration under mild conditions with high selectivity.Aldehydes have been examined as substrates in amine/ transition-metal catalyzed a-allylation reactions to furnish general and useful approaches to optically active adducts. [4] Most prominently featured in these studies are a-alkylsubstituted branched and linear aldehydes.H owever,n oticeably absent is the use of protected a-amino-and a-hydroxyacetaldehydes.[5] There are merely four reactions reported to date,w hich involve Pd-catalyzed allylation to afford g,dunsaturated adducts in racemic form [5a,b] or at best 46 % ee.[5c]Theuse of asuitably protected a-aminoacetaldehyde in adual catalytic process of the type shown in Scheme 1could result in afully stereodivergent synthesis of b,b'-disubstituted a-amino acid derivatives.T he sustained interest in this class of compounds as synthetic intermediates and conformational constraints in the development of peptidomimetics continues to stimulate the development of methods for their synthesis. [6,7] Currently available routes to these structures typically give only one of the two possible diastereomers in high enantio-and diastereoselectivity. [8] In those processes that enable synthesis of the complementary diastereomer,the switch in the sense of diastereoselectivity is usually the result of ac hange in the catalyst [9] or substrate, [10] or stems from ad hoc adjustment of the reaction conditions.[11] In contrast to these approaches,a tt he outset of this study we sought to identify one-step,f ully stereodivergent a...

Stereodivergent Catalysis

“…415 This diastereodivergent dual catalysis has been applied to α-amino and α-hydroxyacetaldehyde. 416 For linear aldehydes a secondary amine diarylsilylprolinol 475 was used in the diastereodivergent α-allylation of n-hexanal in the presence of dimethyl hydrogenephosphate, giving the corresponding stereoisomers 476 in high ee (>99%) and de >90% (Scheme 172). 417 This methodology has been applied to a concise synthesis of the selective serotonin reuptake inhibitor (−)-paroxetine, commonly used in the treatment of depression, obsessive compulsive disorders, and panic disorders.…”

Advances in Asymmetric Diastereodivergent Catalysis

“…Carreira's group recently further expanded the substrate scope for the aldehydes. The more challenging protected α‐amino‐ and α‐hydroxyacetaldehydes were successful applied in this diastereodivergent catalysis, and the corresponding α‐amino and α‐hydroxy β‐substituted γ,δ‐unsaturated aldehydes were obtained in good yields with excellent diastereo‐ and enantioselectivities …”

Stereodivergent Propargylic Alkylation of Enals via Cooperative NHC and Copper Catalysis

“…All possible stereoisomers of the product were obtained by the orthogonal permutation of chiral amine and iridium complex of chiral phosphoramidite. Since this seminal work, substantial progress has been made on catalytic stereodivergent synthesis [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] based on the cooperative action of different catalytic principles. In particular, the asymmetric coupling event of transient nucleophiles bonded with either chiral organocatalysts or Lewis acids with electrophilic π-allyl Ir [14][15][16][17][18][19][20][21][22][23][25][26][27][28][29] /Rh 24 /Pd [30][31][32] intermediates has been intensively investigated and turns out to be the most general platform to establish stereodivergent synthesis (Fig.…”