Gas extrusion in natural products total synthesis

Abstract

The thermodynamic driving force from the release of a gaseous molecule drives a broad range of synthetic transformations. This review focuses on gas expulsion in key reactions within natural products total syntheses, selected from the past two decades. The highlighted examples survey transformations that generate sulfur dioxide, carbon dioxide, carbonyl sulfide, or nitrogen through polar, radical, pericyclic, photochemical, or organometallic mechanisms. Of particular interest are applications wherein the gas extrusion enables formation of a synthetically challenging motif, such as an unusually hindered or strained bond.

Intramolecular Desulfitative Coupling: Nickel-Catalyzed Transformation of Diaryl Sulfones into Biaryls via Extrusion of SO2

“…The Ramberg–Bäcklund reaction is a well-known reaction specific to dialkyl sulfones and has been extensively studied since its discovery in 1940. , The reaction mechanism includes intramolecular S N 2 reaction of α-haloalkyl sulfones followed by extrusion of SO 2 from episulfones to provide alkenes (Scheme , eq 1). This intramolecular process represents fascinating replacement of the SO 2 unit by a C–C double bond.…”

Sulfite-Promoted Synthesis of N-Difluoromethylthioureas via the Reaction of Azoles with Bromodifluoroacetate and Elemental Sulfur

“…On the basis of the results of the control experiments and previous work, a plausible reaction mechanism is depicted in Scheme . First, compound 2a undergoes nucleophilic substitution with HOCH 2 SO 2 Na to produce a sulfone intermediate A , which is further decomposed to release difluorocarbene B . The electrophilic difluorocarbene B then reacts with benzimidazole 1a to afford an N -difluoromethyl benzimidazolium C .…”

Platform approach to diversification: bio-based methyl coumalate to functionalized aromatics via a Diels-Alder strategy

“…Negishi cross-coupling 46 with methyl 4-bromobenzoate (27) or the corresponding methyl 4-chlorobenzoate (Scheme 9). Alternatively, oxidation and esterification of (4isopropylphenyl)methanol could also furnish 40d.…”

“…Since its discovery in 1928, 24 the reaction has been regularly incorporated into numerous syntheses to construct sophisticated frameworks in academia 25,26 and industry. 27 Further advances have yielded variations from hetero-Diels-Alder 28 to transannular Diels-Alder 29 to inverse electrondemand Diels-Alder (IEDDA) 30,31 reactions as depicted in Scheme 1 which are a testament to its scope and utility. A critical aspect in controlling the regiochemistry of the reaction involves effectively matching an electron-deficient diene with an electronrich dienophile for optimal orbital overlap in the IEDDA reaction which is governed by the electronics of the Diels-Alder partners.…”

“…Subsequently, a retro-Diels-Alder reaction would expel carbon dioxide then alcohol elimination would complete the domino reaction with each conversion contingent on the previously formed in situ intermediate to furnish a targeted aromatic compound 22 (Scheme 5). Carbon dioxide extrusion likely occurred immediately after cycloadduct formation as loss of gaseous compounds is thermodynamically and entropically favorable and has beenstrategically used in natural product synthesis 27. After removal of carbon dioxide, the resulting diene 21 is primed for elimination to an aromatic system in the same pot, expedited by the alkoxide leaving group to avoid supplementary reagents.…”