Organocatalytic Atroposelective Aldol Condensation: Synthesis of Axially Chiral Biaryls by Arene Formation

Abstract

Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri-ortho-substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides.

Symmetry in Cascade Chirality-Transfer Processes: A Catalytic Atroposelective Direct Arylation Approach to BINOL Derivatives

“…Unfortunately, although moderate to good isolated yields were achieved, the level of enantioinduction was very poor (3–10% enantiomeric excess, ee ), which we partially attributed to interference by the MeOH liberated during the formation of the mixed-acetal intermediate ( 1 + 2 → 3 ; Figure 2A); 6b addition of 3 Å molecular sieves (MS) did not improve the ee . We observed similar interference by proton donors (i.e., H 2 O) during the catalytic synthesis of BINAM derivatives; 5h in that case the addition of 4 Å MS was advantageous.…”

“…In contrast, a 1,4-addition mechanism was recently proposed by Tan and co-workers for a related reaction (Figure 2C). 5k We were pleased to observe that a 10 mol % loading of chiral phosphoric acid 7b catalyzed the coupling of 6a with 2a under mild conditions and led to the formation of functionalized biaryl 9a in excellent isolated yield with 49% ee . Encouraged by this initial result, we conducted a survey of structurally diverse BINOL-derived chiral phosphoric acid catalysts 2d,9 and solvents to find the optimum conditions that maximize the enantiomeric excess of the product (Table 1; see the Supporting Information (SI) for details).…”

“…3 In view of the importance of biaryls, it is surprising that relatively few methods are available for their atroposelective synthesis in an operationally simple and scalable fashion. 4 Current strategies 5 include classical resolution of racemic biaryls, desymmetrization of preformed prochiral biaryls, dynamic kinetic resolution of rapidly racemizing preformed chiral biaryls, 5c,i transition-metal-catalyzed aryl–aryl coupling, 4b,5d de novo construction of an aromatic ring, 5b,j and central-to-axial chirality exchange 5f,h,k (Figure 1B). …”

“…As part of an ongoing program in the Kürti group to develop new and practical transition-metal-free direct arylation methods for the preparation of highly functionalized symmetrical and unsymmetrical biaryls, 6a,5h,6b we recently successfully exploited quinone and iminoquinone monoacetals as arylating agents to access both BINOL- and NOBIN-type functionalized biaryls that are atropoisomeric but non- C 2 -symmetric from phenols and naphthols under organocatalytic conditions ( 1 + 2 → 5 ; Figure 2A). 6b We also briefly explored the possibility of using chiral BINOL-derived phosphoric acids as catalysts to obtain the biaryl products in an enantiomerically enriched form.…”

Stereoselective Arene‐Forming Aldol Condensation: Synthesis of Axially Chiral Aromatic Amides

“…[8] By considering the formation of anew aromatic ring of the ortho-substituted arylglyoxylic amides 1,webecame intrigued by the possibility of complementing these methods by the chiral amine-catalyzed atroposelective aldol condensation developed in our group (Scheme 1b). [9] In particular,i ft he stereochemical information of the amine catalyst is transferred into the axially chiral product, the process would provide the enantioenriched aromatic amide 2 with restricted rotation about the ArÀCO bond.To validate this notion, the naphthyl glyoxylic amide 1a was prepared as an exploratory substrate (Scheme 2). The esterification of 2-naphtol (3a)w ith oxalyl chloride was followed by aF riedel-Crafts acylation to form naphthofurandione 4a in 92 %y ield.…”