N-to- S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis

Abstract

The observation of thioester-mediated acyl transfer processes in nature has inspired the development of novel protein synthesis and functionalization methodologies. The chemoselective transfer of an acyl group from S-to-N is the basis of several powerful ligation strategies. In this work, we sought to apply the reverse process, the transfer of an acyl group from N-to-S, as a method to convert stable chiral amides into more reactive thioesters. To this end, we developed a novel cysteine-derived oxazolidinone that serves as both a chiral imide auxiliary and an acyl transfer agent. This auxiliary combines the desirable features of rigid chiral imides as templates for asymmetric transformations with the synthetic applicability of thioesters. We demonstrate that the auxiliary can be applied in a range of highly selective asymmetric transformations. Subsequent intramolecular N-to-S acyl transfer of the chiral product and in situ trapping of the resulting thioester provides access to diverse carboxylic acid derivatives under mild conditions. The oxazolidinone thioester products can also be isolated and used in Pd-mediated transformations to furnish highly valuable chiral scaffolds, such as noncanonical amino acids, cyclic ketones, tetrahydropyrones, and dihydroquinolinones. Finally, we demonstrate that the oxazolidinone thioesters can also serve as a surrogate for SNAC-thioesters, enabling their seamless use as non-native substrates in biocatalytic transformations.

Figure 1

(A) Novel methodologies inspired by the S-to-N acyl transfer reaction. (B) The application of imide auxiliaries in asymmetric synthesis. (C) The application of N-to-S acyl transfer in the synthesis of peptide thioesters. (D) A cysteine-derived chiral auxiliary that unites the desirable features of an imide auxiliary with the downstream functionality of a thioester.

Figure 2

(A) Synthesis of syn-aldol product 3. (B) Mass-selective (m/z = 346.11) LC-MS analysis of the conversion of 4 to 5 at 0 (top), 1 (middle), and 5 h (bottom).

Scheme 1. Synthesis and Derivatization of the anti-Aldol Product 7

Reagents and conditions: (a) MgCl₂, trimethylsilyl chloride (TMSCl), Et₃N, EtOAc, 23 °C; then TFA, MeOH, 23 °C, 88%; (b) (i) TFA, Et₃SiH, CH₂Cl₂, thenⁿPrOH-NaHCO₃, 23 °C, 93%; (ii) Pd(OAc)₂, Et₃SiH, MgSO₄, acetone, 23 °C, 72%; (c) TFA, Et₃SiH, CH₂Cl₂, then THF-NaHCO₃, 60 °C, 79%; (d) TFA, Et₃SiH, CH₂Cl₂, then EtOH-NaHCO₃, 60 °C, 80%; (e) TFA, Et₃SiH, CH₂Cl₂, then DMF-NaHCO₃, l-cysteine methyl ester, DL-dithiothreitol (DTT), 23 °C, 82%; (f) TFA, Et₃SiH, CH₂Cl₂, then Et₂O-Et₃N, benzylamine, silver trifluoroacetate (AgTFA), 23 °C, 83%.

Scheme 2. Synthesis and Derivatization of l- and d-Homophenylalanine; See the Supplementary Materials for Experimental Details

Scheme 3. Synthesis of Dihydropyrone 22 (A), Cyclic Ketone 26 (B), and Dihydroquinolinone 29 (C); See the Supplementary Materials for Experimental Details; Red, Oxygen; Blue, Nitrogen; Gray, Carbon; Yellow, Sulfur; White, Hydrogen

Figure 3

Chemoenzymatic synthesis of triketide lactone 34. (A) Synthesis of acyl-thioester feeding substrates (32 and 33); see the Supporting Information for experimental details. (B) Formation of triketide lactone 34 catalyzed by PKS modules (PikAIII/PikAIV) from the pikromycin (Pik) biosynthetic pathway; see the Supporting Information for experimental details. (C) LC/MS traces (ESI⁺) showing the production of 34 from all three feeding substrates (31–33).