Isothiourea‐Catalyzed Enantioselective Carboxy Group Transfer

Abstract

The rational design and mechanistic understanding of catalytic systems capable of generating quaternary stereocenters in an asymmetric fashion is a recognized challenge in synthesis. [1] A number of asymmetric Lewis base mediated processes have been developed within this area, [2] in which enantiomerically pure derivatives of 4-(pyrrolidino)pyridine (PPY) and 4-dimethylaminopyridine (DMAP) are elegantly employed by the Fu, [3] Vedejs, [4] and Richards groups, [5] as asymmetric catalysts for the rearrangement of 5-oxazolyl carbonates into 4-carboxyazlactones (Scheme 1). [6] This process delivers C-carboxyazlactones bearing a quaternary stereocenter with excellent enantiocontrol. [7] Among the recent developments in Lewis base catalysis, the ability of isothioureas to efficiently promote alcohol acylation has been demonstrated. Birman and Li first showed that tetramisole and its benzannulated analogue BTM could catalyze effective kinetic resolution [8] and desymmetrization protocols (Scheme 2). [9] Independent studies by Kobayashi and Okamoto, and Birman et al. subsequently introduced DHPB, [10] before Birman and Li developed HBTM (1) for the kinetic resolution of aryl cycloalkanols. [11] Building upon these studies, [12,13] Dietz and Gröger have utilized tetramisole (32 mol %) to promote a modestly enantioselective rearrangement of an oxazolyl acetate (63 % ee at 80 % conversion), [14] and we have shown that DHPB represents the optimal catalyst substructure for the carboxyl group transfer reaction of oxazolyl carbonates in the racemic series. [15] As part of a research program concerned with utilizing Lewis bases as catalysts, [16] we hoped to build upon these precedents by using chiral isothioureas, such as 1, to promote the Steglich rearrangement with high enantioselectivity. The incorporation of a stereodirecting group at C4, adjacent to the nucleophilic nitrogen atom, is imperative in these catalyst architectures; this contrasts the recognized derogatory effect of the 2-substitution of DMAP or PPY derivatives upon catalytic turnover in acylation reactions. [4a, 17] Upon formation of an N-carboxy derivative within the Steglich reaction, this stereodirecting group was predicted to adopt a pseudoaxial conformation. [18] It was anticipated that asymmetric induction would arise from discrimination between the prochiral faces of an azlactone enolate upon addition to this intermediate, preferably anti to the C4 stereodirecting unit, with the axial C3 À H aiding differentiation between the planar aromatic and aliphatic quadrants (Figure 1).Initial studies evaluated isothiourea 1 to promote the asymmetric O-to C-carboxyl group transfer of a range of alkyl and aryl oxazolyl carbonates 2-4, with the transfer of the Scheme 1. The asymmetric Steglich rearrangement. Scheme 2. Evolution of isothiourea catalysts.Figure 1. Proposed stereodefined N-carboxy intermediate. The stereodirecting unit at C4 is imperative; the stereodefined N-carboxy intermediate has a pseudoaxial directing substituent; and discrimination between the...

Isothiourea‐Catalysed Asymmetric C‐Acylation of Silyl Ketene Acetals

“…[18] By analogy to our previous transition state modelling for this C-carboxylation reaction (preferred transition state 50 shown schematically in Scheme 7), combined with the modelling studies from Birman and Houk on the origin of amidine (CF 3 [26] a simplistic model to account for the enantioselectivity of the C-acylation of silyl ketene acetals is outlined below. We envisage that the N-propionyl group of the N-acylated isothiourea lies approximately coplanar with the tetrahydropyrimidine unit of the heterocycle, with the syn rotamer (C=O group syn to C=N) preferred.…”

“…Among the recent developments in asymmetric acyl or carboxyl transfer processes with Lewis bases, the use of isothioureas of the generic structures 11 and 12 (Scheme 2), initially introduced by Birman and co-workers, is particularly notable. [14] These bench-and air-stable catalyst architectures are either commercially available or are prepared in a few simple steps from readily available materials and have been used in a range of asymmetric acylation protocols including kinetic resolutions, [15] dynamic kinetic resolutions [16] desymmetrisations [17] and O-to C-carboxyl [18] and acyl transfer processes.…”

Application of a Palladium‐Catalyzed C−H Functionalization/Indolization Method to Syntheses of cis‐Trikentrin A and Herbindole B

“…[17] For the preparation of 2, aryl triflate 9 was subjected to hydrogenolysis with H 2 under high pressure to give 10 b in 89 % yield. [21] Our preliminary studies to overcome these existing challenges have focused on the use of quinine derivatives, [22] peptides, [21a, 23] and chiral isothioureas [24] as catalysts. When triflamide 18 b was subjected to our newly developed indolization reaction, the corresponding indole Given that the monotriflation of 5 to give 8 (Scheme 2) is the enantiodetermining step for the syntheses described herein, we investigated several strategies to render this step enantioselective.…”

ChemInform Abstract: Application of a Palladium‐Catalyzed C—H Functionalization/Indolization Method to Syntheses of cis‐Trikentrin A and Herbindole B.

“…[17] Fort he preparation of 2,aryl triflate 9 was subjected to hydrogenolysis with H 2 under high pressure to give 10 b in 89 %yield. [21] Our preliminary studies to overcome these existing challenges have focused on the use of quinine derivatives, [22] peptides, [21a, 23] and chiral isothioureas [24] as catalysts.A dditional challenges inherent to the use of hydroquinone 5 as as ubstrate include its ready oxidation to the corresponding quinone as well as oversulfonation. Of these catalysts,o rganocatalysts have proven to be the most general.…”