Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species.

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc-mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N-heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol-derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring-opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate-determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

A Homo-Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids.

We report here a homo-Mannich reaction of cyclopropanol with an iminium ion, generated by an asymmetric allylic dearomatization of indole, to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this approach, an all-carbon quaternary stereogenic center as well as an allyl and a ketone group were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five-, six-, and seven-membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families.

Catalytic Net Oxidative C-C Activation and Silylation of Cyclopropanols with a Traceless Acetal Directing Group.

Redox-neutral carbon-carbon (C-C) bond activation and functionalization strategies of cyclopropanols that give metallo homoenolate have offered merits to construct a range of useful ß-functionalized ketones in an inverse-polarity fashion. Discovery and identification of oxidative C-C activation reactions of cyclopropanols that generate metallo enolate-homoenolate would provide an opportunity to afford α,ß-difunctionalized ketones. We report catalytic, net oxidative C-C activation, and silylation of cyclopropanols with traceless acetal directing groups under consecutive Ir and Rh catalysis in regio-, stereo-, and chemo-selective fashion. In detail, Ir-catalyzed hydrosilylation of cyclopropyl acetates provides the acetal directing group in quantitative yield. Rh-catalyzed proximal C-C silylation of the resulting cyclopropyl silyl acetal produces the metallo enolate-homoenolate equivalent, dioxasilepine, which uniquely holds an interconnected ß-silyl moiety and Z-vinyl acetal. Upon sequential treatment of a silaphile that removes the acetal directing group and electrophile, the seven-membered silicon-containing heterocycle, serving as the ketone α,ß-dianion equivalent, delivers α,ß-difunctionalized ketones. Scope of the hitherto unexplored reactivity of cyclopropanols toward net oxidative C-C silylation and the versatility of the resulting dioxasilepines were demonstrated. These include late-stage, net oxidative C-C silylation of biologically relevant molecules and facile production of a range of α,ß-difunctionalized ketones. Preliminary mechanistic studies suggest that the C-C activation harnessing the electron-rich Wilkinson-type catalyst is likely the turnover-determining step and a Rh-π interaction is the key to the efficient metal insertion to the proximal C-C bond in cyclopropanols.

Asymmetric Cyclopropanation and Epoxidation via a Catalytically Formed Chiral Auxiliary.

For the enantioselective diversification of a single starting material, a different chiral catalyst is usually required for each transformation. Herein, we extend the concept of catalytically formed chiral auxiliary from hydrogenation to the asymmetric cyclopropanation and epoxidation of tetra-substituted olefins, alleviating the need for different chiral catalysts in the alkene functionalization step. The chiral auxiliary is catalytically constructed from propargylic amines in a Pd-catalyzed enantioselective carboetherification step using a commercially available trifluoroacetaldehyde hemiacetal tether. The installed auxiliary is then controlling the stereochemistry of the cyclopropanation and the epoxidation using standard highly reactive reagents to give enantioenriched spirocyclic aminomethylcyclopropanols and α-amino-α-hydroxy ketones.

Visible-Light-Induced C4-Selective Functionalization of Pyridinium Salts with Cyclopropanols.

The site-selective C-H functionalization of heteroarenes is of considerable importance for streamlining the rapid modification of bioactive molecules. Herein, we report a general strategy for visible-light-induced ß-carbonyl alkylation at the C4 position of pyridines with high site selectivity using various cyclopropanols and N-amidopyridinium salts. In this process, hydrogen-atom transfer between the generated sulfonamidyl radicals and O-H bonds of cyclopropanols generates ß-carbonyl radicals, providing efficient access to synthetically valuable ß-pyridylated (aryl)ketones, aldehydes, and esters with broad functional-group tolerance. In addition, the mild method serves as an effective tool for the site-selective late-stage functionalization of complex and medicinally relevant molecules.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids.

We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na -methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.

Diastereo- and enantioselective preparation of cyclopropanol derivatives.

The diastereoselective carbocupration reaction of alkoxy-functionalized cyclopropene derivatives, followed by a subsequent trapping of the resulting cyclopropylmetal species with an electrophilic source of oxygen (oxenoid) afforded various tetrasubstituted cyclopropanol derivatives in high diastereo- and enantiomeric ratios. Similarly, the enantioselective copper-catalyzed carbomagnesiation/oxidation (or amination) sequence on achiral nonfunctionalized cyclopropenes provided the desired cyclopropanol (and cyclopropylamine) derivatives in excellent diastereo- and enantiomeric excesses.

Copper-Catalyzed Aerobic Oxidative Cyclization Cascade to Construct Bridged Skeletons: Total Synthesis of (-)-Suaveoline.

Based on the discovery of copper-catalyzed cyclopropanol ring-opening addition to iminium ions, an unprecedented catalytic aerobic C-H oxidation/cyclopropanol cyclization cascade using CuCl2 as the multifunctional catalyst and air as the oxidant was developed to construct the azabicyclo[3.3.1]nonane skeleton, which is widespread in natural products and medicines. Using this method, concise asymmetric total synthesis of the indole alkaloid (-)-suaveoline was achieved. This study not only provides an efficient, low-cost, and environmentally benign method for constructing such bridged frameworks, but also enriches the realm of cyclopropanol chemistry and C-H functionalization.

Hemoprotein-Catalyzed Cyclopropanation En Route to the Chiral Cyclopropanol Fragment of Grazoprevir.

Reactions that were once the exclusive province of synthetic catalysts can increasingly be addressed using biocatalysis. Through discovery of unnatural enzyme reactions, biochemists have significantly expanded the reach of enzymatic catalysis to include carbene transfer chemistries including olefin cyclopropanation. Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti-hepatitis C drug grazoprevir.

Pd-Catalyzed Selective Remote Ring Opening of Polysubstituted Cyclopropanols.

The distant functionalization of ω-ene cyclopropanols is induced by a Pd-catalyzed Heck reaction triggering a "metal-walk" and selective ring-opening of the three-membered ring. This approach provides a new class of acyclic aldehydes possessing concomitantly a stereodefined double bond and a quaternary carbon stereocenter α to the carbonyl group.

Immobilization of Methylosinus trichosporium OB3b for methanol production.

Due to the natural gas boom in North America, there is renewed interest in the production of other chemical products from methane. We investigated the feasibility of immobilizing the obligate methanotrophic bacterium Methylosinus trichosporium OB3b in alginate beads, and selectively inactivating methanol dehydrogenase (MDH) with cyclopropane to produce methanol. In batch cultures and in semi-continuous flow columns, the exposure of alginate-immobilized cells to cyclopropane or cyclopropanol resulted in the loss of the majority of MDH activity (> 80%), allowing methanol to accumulate to significant concentrations while retaining all of M. trichosporium OB3b's methane monooxygenase capacity. Thereafter, the efficiency of methanol production fell due to recovery of most of the MDH activity; however, subsequent inhibition periods resulted in renewed methanol production efficiency, and immobilized cells retained methane-oxidizing activity for at least 14 days.

Catalytic Cyclopropanol Ring Opening for Divergent Syntheses of γ-Butyrolactones and δ-Ketoesters Containing All-Carbon Quaternary Centers.

Catalytic ring opening cross coupling reactions of strained cyclopropanols have been useful for the syntheses of various ß-substituted carbonyl products. Among these ring opening cross coupling reactions, the formation of α,ß-unsaturated enone byproducts often competes with the desired cross coupling processes and has been a challenging synthetic problem to be addressed. Herein, we describe our efforts in developing divergent syntheses of a wide range of γ-butyrolactones and δ-ketoesters containing all-carbon quaternary centers via copper-catalyzed cyclopropanol ring opening cross couplings with 2-bromo-2,2-dialkyl esters. Our mechanistic studies reveal that unlike the previously reported cases, the formation of α,ß-unsaturated enone intermediates is actually essential for the γ-butyrolactone synthesis and also contributes to the formation of the δ-ketoester product. The γ-butyrolactone synthesis is proposed to go through an intermolecular radical conjugate addition to the in situ generated α,ß-unsaturated enone followed by an intramolecular radical cyclization to the ester carbonyl double bond. The reactions are effective to build all-carbon quaternary centers and have broad substrate scope.

Radical Cyclopropanol Ring Opening Initiated Tandem Cyclizations for Efficient Synthesis of Phenanthridines and Oxindoles.

ß-Keto radicals can be readily generated from single-electron oxidation and ring opening of cyclopropanols. Herein, we report new ways of trapping ß-keto radicals derived from Mn(III)-mediated oxidative cyclopropanol ring opening with biaryl isonitriles and N-aryl acrylamides derived from anilines. Through tandem radical cyclization processes, substituted phenanthridines and oxindoles can be synthesized in one step and good to excellent yield. These new synthetic methods feature broad substrate scope and mild reaction conditions, efficiently form two carbon-carbon bonds, and use cheap and commercially available manganese salts as oxidants. Concomitant installation of ketone functionality in the final products provides a handle for further functionalization of these important and biologically relevant scaffolds.

Copper(II)-salt-promoted oxidative ring-opening reactions of bicyclic cyclopropanol derivatives via radical pathways.

Copper(II)-salt-promoted oxidative ring-opening reactions of bicyclic cyclopropanol derivatives were investigated. The regioselectivities of these processes were found to be influenced by the structure of cyclopropanols as well as the counter anion of the copper(II) salts. A mechanism involving rearrangement reactions of radical intermediates and their competitive trapping by copper ions is proposed.