Min Zhang

A visible-light-driven regioselective chlorodifluoromethylation of unactivated alkenes has been developed. In this process, readily available difluoroacetic acid serves as a difluoromethyl radical precursor and, upon activation with (diacetoxyiodo)benzene under visible-light irradiation, generates the CF2H radical species. Subsequent addition to terminal, di-, or trisubstituted alkenes, followed by trapping with N-chlorosuccinimide, furnishes the chlorodifluoromethylated products in good yields. Notably, the method has been used for the chlorodifluoromethylation of natural products and functional molecules, and the resulting C–Cl bond can undergo diverse derivatizations including replacement with heteroatoms.

Herein, we report an iridium-catalyzed direct asymmetric ring-opening allylation of cyclopropyl alcohols with free allyl alcohols. The catalytic system, consisting of [Ir(cod)Cl]₂, Carreira phosphoramidite ligand, and Fe(ClO₄)₂·xH₂O, enables efficient formation of β-allyl-substituted carbonyl compounds in good yields with excellent enantioselectivities (up to >99% ee). The method exhibits a broad substrate scope, tolerating diverse phenylvinylcarbinol derivatives and both aryl- and alkyl-substituted cyclopropanols.

A (3 + 2) annulation to access the structurally diverse polysubtituted cyclopentanones bearing two adjacent quaternary stereogenic centers is reported. This reaction is proposed to proceed through a domino Mukaiyama aldol/homoaldol reaction of silyl enol ethers with commercially available (1-ethoxycyclopropoxy)trimethylsilane, which serves as a cyclopropanone surrogate. The synthetic utilities of this methodology have been demonstrated by the diverse derivatizations of the annulated products and the synthesis of an analogue of natural product α-cuparenone.

An eco-friendly electrochemical oxidative dearomatization of anisole-based cyclopropyl alcohols has been developed for synthesizing spiro[4.5]diketones. The reaction involves the simultaneous C-C bond cleavage of cyclopropyl alcohols and spirocyclization with anisole under electrochemical conditions, eliminating the need for metal catalysts or additional oxidants. Via the efficient construction of five- and six-membered rings, this approach enables the synthesis of structurally diverse spirocyclic diketones with a broad substrate scope and compatibility with various functional groups. Notably, the method has been applied to the synthesis of anhydro-β-rotunol, a compound isolated from infected potato tubers and tobacco leaves.

ConspectusThe Mannich reaction, involving the nucleophilic addition of an enol(ate) intermediate to an imine or iminium ion, is one of the most widely used synthetic methods for the synthesis of β-amino carbonyl compounds. Nevertheless, the homo-Mannich reaction, which utilizes a homoenolate intermediate as the nucleophilic partner and provides straightforward access to the valuable γ-amino carbonyl compounds, remains underexplored. This can be largely attributed to the difficulties in generation and manipulation of the homoenolate species, despite various homoenolate equivalents that have been developed. Among the homoenolate equivalents developed, cyclopropanol stands out due to its intriguing reactivities endowed by the highly strained cyclopropane. Upon activation by a metal, cyclopropyl alcohol is prone to undergo an endocyclic C(sp³)-C(sp³) bond cleavage to give a homoenolate intermediate or a β-keto radical intermediate, which sets the stage for a diverse range of transformations. This account outlines our recent progress in the development of homo-Mannich reaction of cyclopropanol and its applications in natural product total synthesis. This new methodology can be classified into two subtypes: 1) the homo-Mannich reaction of cyclopropanol with imines or iminium ions and 2) the homo-Mannich-type reaction of cyclopropanol with heteroarenes. Through different ways to generate imines or iminium ions, tandem or sequential reactions of C-H oxidation/homo-Mannich, Bischler-Napieralski/homo-Mannich, and asymmetric allylation/homo-Mannich have been developed, leading to the rapid assembly of core scaffolds of sarpagine, koumine, ibophyllidine, Aspidosperma, Melodinus, and Kopsia alkaloids. Besides the reactions with imines or iminium ions, cyclopropyl alcohol can undergo ring-opening addition to indole and pyrrole rings to deliver core scaffolds of schizozygane and indolizidine alkaloids. Based on these methodology advancements, we have accomplished the asymmetric synthesis of 29 alkaloids belonging to 8 families. In this Account, we present a complete picture of our works concerning synthetic design, method development, and applications in natural product total synthesis. It is anticipated that the development of new methodologies of cyclopropyl alcohol will find broad applications in the realm of natural product synthesis.

The catalytic asymmetric propargylation of cyclopropanols has been developed using a new PyBox ligand, yielding cyclopentanones with an all-carbon quaternary stereogenic center and an adjacent quaternary gem-dimethyl carbon center.

A radical ring-opening arylation of cyclopropanol with 1,2,3-triazole has been achieved. This synthetic protocol provides straightforward access to a wide range of structurally diverse and chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridines with high efficiency from readily available chiral cyclopropanols.

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and N_a-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure−activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.