Biocatalytic Thionation of Epoxides for Enantioselective Synthesis of Thiiranes

Abstract

Expanding the enzymatic toolbox for the green synthesis of valuable molecules is still of high interest in synthetic chemistry and the pharmaceutical industry. Chiral thiiranes are valuable sulfur-containing heterocyclic compounds, but relevant methods for their enantioselective synthesis are limited. Herein, we report a biocatalytic thionation strategy for the enantioselective synthesis of thiiranes, which was developed based on the halohydrin dehalogenase (HHDH)-catalyzed enantioselective ring-opening reaction of epoxides with thiocyanate and a subsequent nonenzymatic rearrangement process. A novel HHDH was identified and engineered for enantioselective biocatalytic thionation of various aryl-and alkyl-substituted epoxides on a preparative scale, affording the corresponding thiiranes in up to 43 % isolated yield and 98 % ee. Large-scale synthesis and useful transformations of chiral thiiranes were also performed to demonstrate the utility and scalability of the biocatalytic thionation strategy.

Flipping the Substrate Creates a Highly Selective Halohydrin Dehalogenase for the Synthesis of Chiral 4-Aryl-2-oxazolidinones from Readily Available Epoxides

“…In the reverse epoxide ring-opening reaction, the enzyme can take other nucleophiles, such as azide, cyanide, nitrite, cyanate, or thiocyanate, to form new C−N, C−O, C− C, and C−S bonds. 33,34 In recent years, based on the two specific sequence motifs "T-X 4 -F/Y-X-G" and "S-X 12 -Y-X 3 -R", which were derived from multiple sequence alignments of the known HHDHs, a large number of haloalcohol dehalogenases have been discovered and divided into A−G subgroups. 35 ArHheC, one of the subfamily C HHDHs, showed good βattack preference and stereoselectivity in the ring opening of alkyl epoxide using cyanate as a nucleophile to produce 5substituted oxazolidinones, 36 while low stereoselectivity and regioselectivity were observed when styrene oxide was used as the substrate (34:66 α/β) (Scheme 1e).…”

“…4.5.1.-) catalyze the reversible dehalogenation of α-halo alcohols to form epoxides. In the reverse epoxide ring-opening reaction, the enzyme can take other nucleophiles, such as azide, cyanide, nitrite, cyanate, or thiocyanate, to form new C–N, C–O, C–C, and C–S bonds. , In recent years, based on the two specific sequence motifs “T-X 4 -F/Y-X-G” and “S-X 12 -Y-X 3 -R”, which were derived from multiple sequence alignments of the known HHDHs, a large number of haloalcohol dehalogenases have been discovered and divided into A–G subgroups while low stereoselectivity and regioselectivity were observed when styrene oxide was used as the substrate (34:66 α/β) (Scheme e) .…”

“…The extremely low reaction temperature and the formation of different binding conformations of nucleophile nitrite in the halide-binding site were the main reasons for the success of the reaction. When thiocyanate was used as the nucleophile in the ring opening of epoxides catalyzed by HHDHapb 34 and its mutant M4, chiral thiiranes were obtained with high ee by the enzymatic ring opening of epoxides and a subsequent non-enzymatic rearrangement. The isolation of reaction intermediates revealed that thiocyanate could attack either the C α or C β of epoxides.…”

Biocatalytic Enantioselective Synthesis of Chiral β-Hydroxy Nitriles Using Cyanohydrins as Cyano Sources

“…HHDHs can catalyze not only the formation of epoxides through dehalogenation of vicinal halohydrins but also the generation of β-substituted alcohols or its derivatives through the ring-opening of epoxides in the presence of several anionic nucleophiles, such as cyanide, azide, cyanate, nitrite, and thiocyanate (Figure S1). , Many HHDHs have been identified and engineered for the synthesis of various chiral compounds, such as epoxides, − β-halohydrins, − β-hydroxy nitriles, − β-azidoalcohols, − oxazolidinones, − β-nitroalcohols, and thiiranes . In particular, chiral β-hydroxy nitriles are a ubiquitous class of cyano-containing compounds present in many pharmaceuticals (Scheme a). − For instance, the chiral β-hydroxy nitrile moiety is a crucial component of remdesivir (GS-5734), which is a nucleoside analogue with potent antiviral activity .…”

Biocatalytic Synthesis of Metaxalone and Its Analogues

“…Halohydrin dehalogenases (HHDHs) have the ability to catalyze the dehalogenation of vicinal halohydrins to epoxides, releasing protons and halide ions in the process . In addition, HHDHs can also catalyze ring-opening reactions of epoxides in the presence of several anionic nucleophiles, such as cyanide, nitrite, azide, thiocyanate, and cyanate, resulting in the generation of β-substituted alcohols or their derivatives. In particular, the enzymatic ring-opening reaction of epoxides with cyanate (OCN – ) generates unstable isocyanates and cyanate adducts, which can be easily converted to oxazolidinones by undergoing a spontaneous cyclization reaction .…”