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

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

“…Using caesium carbonate, carbamoyl sulfones were converted into the corresponding N -Boc-protected imines 2 that were immediately submitted to List's organocatalytic Mannich reaction [29–30]. The resulting aldehydes 3 were not isolated (also in view of their known stereochemical lability) but directly reduced to alcohols 4 [32–33]. Purification was carried out through chromatography and, in some cases, by additional crystallization, affording these key intermediates in high ee and de ( syn relative configuration, see Supporting Information File 1).…”

Isothiourea‐Mediated One‐Pot Synthesis of Functionalized Pyridines

“…[2] Despite many recent advances, novel methods for the synthesis of highly functionalized pyridines in a selective and high yielding manner from accessible starting materials remains an important goal within the synthetic community. [3] Following the demonstration by Romo and co-workers of generating ammonium enolates [4] from carboxylic acids, [5] we have shown that isothioureas [6,7] catalyze the intermolecular Michael addition/lactonization/lactamization of arylacetic acids and electron-deficient Michael acceptors. [8] To expand this mode of activation, we questioned whether this methodology could be used to access functionalized pyridines.…”

Isothiourea‐Mediated Asymmetric O‐ to C‐Carboxyl Transfer of Oxazolyl Carbonates: Structure–Selectivity Profiles and Mechanistic Studies

“…[20] Building upon these precedents, and as part of our existing research programme focusing upon Lewis base catalysis, [21] we have shown that isothioureas such as HBTM 11 and 13 promote the asymmetric O-to C-carboxyl rearrangement of oxazolyl carbonates with high enantioselectivity (up to 94 % ee). [22,23] Notably, recent work by Okamoto has probed the ability of a C(4)-stereodirecting unit within tetrahydropyrimidine-derived isothioureas to promote the asymmetric Steglich rearrangement, [24] whereas Grçger and Dietz have utilised isothioureas for related asymmetric O-to Cacetyl transfer processes. [25] To understand the origins of asymmetric induction in the O-to C-carboxyl transfer process using HBTM 11 we have previously carried out molecular modelling calculations, allowing a simple model for asymmetric induction in this process to be developed ( Figure 1).…”

“…C(2)-phenyl substitution (isothiourea 11) leads to optimal reactivity in this series, allowing the reaction temperature to be lowered to À50 8C to achieve optimal product ee values (91 % ee, Further investigations probed the effect of 2,3-disubstitution within the isothiourea catalyst structure (Table 1, entries 18-34). In comparison to HBTM 11, the incorporation of an additional syn-configured C(3)-iPr substituent (isothiourea 13) leads to marginally increased stereoselectivities under optimised conditions (Table 1, entries [18][19][20][21][22], with the incorporation of an electronegative Cl atom within the benzothiazole unit (isothiourea 18) giving negligible change in stereoselectivity ( Table 1, entry 23). The inclusion of alternative C(2)-2-naphthyl or C(3)-methyl units (within 19 and HBTM 2 12 respectively) gave slightly lower enantioselectivities than 13 ( Table 1, entries [24][25][26][27][28].…”