7-Azaindoline Auxiliary: A Versatile Attachment Facilitating Enantioselective­ C–C Bond-Forming Catalysis

Abstract

This short review provides an overview of 7-azaindoline auxiliaries in asymmetric catalysis. 7-Azaindoline serves as a useful attachment to carboxylic acids, and the thus-formed 7-azaindoline amides are amenable to atom-economical C-C bond-forming reactions with high stereoselectivity. The attachment is used for the sake of gaining traction in promoting the reaction of interest and can be easily removed after enantioselective reactions. Both nucleophilic and electrophilic catalyses are realized with broad tolerance for functional groups, showcasing the usefulness of 7-azaindoline auxiliaries for practical and streamlined synthesis of a wide range of acyclic chiral building blocks.

The Fascinating Chemistry of α‐Haloamides

“…α‐Halogenated 7‐azaindoline amides are particularly useful in direct enolization chemistry due to their facilitated enolization in soft Lewis acid/Brønsted base cooperative catalysis allowing for direct aldol and Mannich‐type reactions with chiral Cu(I) catalysts in a highly stereoselective manner …”

Recent Advances in Catalytic Enantioselective Synthesis of Fluorinated α‐ and β‐Amino Acids

“…In 2014, Shibasaki and Kumagai designed and synthesized a kind of α-fluorinated 7-azaindoline acetamide 124 for constructing optically active fluorine-containing compounds with structural diversity. [76] A highly asymmetric direct Mannich-type reaction of N-Boc aldimines 113 with α-CF 3 -7-azaindoline acetamide 124 a was achieved by using a combined soft Lewis acid/ Brønsted base system comprising chiral Cu(I) complex and Barton's base, which provided enantioenriched α-CF 3 -β-amino amides 128 in up to 96% yield, > 20:1 dr and 99% ee (Scheme 28). [77a] Soon after, they found that α-fluoroalkyl substituted 7-azaindoline acetamides 124 b could also work well with N-Boc aldimines 113, giving the α-fluoroalkyl-β-amino amides 129 in 92-99% ee by replacing 125 with (R)-xyl-segphos 126.…”

“…[77b] By using a similar cooperative acid/base catalyst system, a highly enantioselective Mannich-type reaction of N-Boc (or Cbz) aldimines 113 with α-fluoro or α-F-α-CF 3 substituted 7-azaindoline acetamides 124 c or 124 d was developed, to deliver a variety of optically pure fluorinated β-amino acid derivatives bearing α-fluorine atom or α-fluoro-α-CF 3 functionality in excellent stereoselectivities. [76,77] Mechanism studies demonstrated that chiral Cu complex firstly coordinated with N and O atom of 7-azaindoline acetamide to aid its deprotonative activation by Barton's base, whilst the resulting intermediate interacted with aldimine 113, as shown in Scheme 28. Recently, this strategy was extended to a highly stereoselective Mannich-type reaction of isatin derived ketimines with α-CF 3 -7-azaindoline acetamide 124 a.…”

Direct anti Glycolate Aldol Reaction of Protected Chiral N‐Hydroxyacetyl Thiazolidinethiones with Acetals Catalyzed by a Nickel(II) Complex

“…Further improvements utilized other aryl α‐hydroxymethyl ketones or amides and were applied to the synthesis of natural products, but few significant advances have been reported since then. Interestingly, Shibasaki described a related enantioselective aldol addition of α‐sulfanyl 7‐azaindolinylamide catalyzed by a copper(I) complex,, whereas Aoki has recently reported that direct aldol reactions of a protected dihydroxyacetone with aromatic aldehydes catalyzed by zinc complexes containing histidine produce syn aldol adducts with good yields and enantioselectivities . In view of the lack of methods to prepare anti glycolate adducts and taking advantage of our experience with stoichiometric reactions of titanium(IV) enolates with acetals, and direct and highly stereoselective carbon‐carbon bond forming reactions from chiral N ‐acyl‐1,3‐thiazolidene‐2‐thiones catalyzed by nickel(II) complexes,, we envisaged that Lewis acid‐mediated glycolate aldol‐like additions to dialkyl acetals might proceed in a highly efficient manner.…”