Rapid Construction of the Aza-Propellane Core of Acutumine via a Photochemical [2 + 2] Cycloaddition Reaction

Synthetic efforts toward the chlorinated aza-propellane alkaloid acutumine (<b>1</b>) are described. The key vicinal quaternary centers were constructed by a photochemical [2 + 2] cycloaddition reaction of a furanyl-tetrahydroindolone. Dihydroxylation of the [2 + 2] product enabled a tandem retro-aldol/intramolecular ketalization reaction, which revealed the aza-propellane core of <b>1</b> while generating an unusual, caged, pentacyclic hemiketal product

α‑Diazo-β-ketonitriles: Uniquely Reactive Substrates for Arene and Alkene Cyclopropanation

An investigation of the intramolecular cyclopropanation reactions of α-diazo-β-ketonitriles is reported. These studies reveal that α-diazo-β-ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor–acceptor-substituted diazo substrates instead produce mixtures of C–H insertion and dimerization products. α-Diazo-β-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the α-cyano-α-ketocyclopropane products are demonstrated to serve as substrates for S_N2, S_N2′, and aldehyde cycloaddition reactions

Enantioselective Synthesis of Tryptophan Derivatives by a Tandem Friedel–Crafts Conjugate Addition/Asymmetric Protonation Reaction

The tandem Friedel–Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate is reported. The reaction is catalyzed by (<i>R</i>)-3,3′-dibromo-BINOL in the presence of stoichiometric SnCl₄, and is the first example of a tandem conjugate addition/asymmetric protonation reaction using a BINOL·SnCl₄ complex as the catalyst. A range of indoles furnished synthetic tryptophan derivatives in good yields and high levels of enantioselectivity, even on a preparative scale. The convergent nature of this transformation should lend itself to the preparation of unnatural tryptophan derivatives for use in a broad array of synthetic and biological applications

Copper-Catalyzed Diastereoselective Arylation of Tryptophan Derivatives: Total Synthesis of (+)-Naseseazines A and B

A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B

Copper-Catalyzed Diastereoselective Arylation of Tryptophan Derivatives: Total Synthesis of (+)-Naseseazines A and B

A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B

Enantioselective Synthesis of Tryptophan Derivatives by a Tandem Friedel–Crafts Conjugate Addition/Asymmetric Protonation Reaction

The tandem Friedel–Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate is reported. The reaction is catalyzed by (<i>R</i>)-3,3′-dibromo-BINOL in the presence of stoichiometric SnCl₄, and is the first example of a tandem conjugate addition/asymmetric protonation reaction using a BINOL·SnCl₄ complex as the catalyst. A range of indoles furnished synthetic tryptophan derivatives in good yields and high levels of enantioselectivity, even on a preparative scale. The convergent nature of this transformation should lend itself to the preparation of unnatural tryptophan derivatives for use in a broad array of synthetic and biological applications

Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic α,α-Disubstituted Ketones

The first enantioselective Ni-catalyzed reductive acyl cross-coupling has been developed. Treatment of acid chlorides and racemic secondary benzyl chlorides with a Ni^II/bis­(oxazoline) catalyst in the presence of Mn⁰ as a stoichiometric reductant generates acyclic α,α-disubstituted ketones in good yields and high enantioselectivity without requiring stoichiometric chiral auxiliaries or pregeneration of organometallic reagents. The mild, base-free reaction conditions are tolerant of a variety of functional groups on both coupling partners

Enantioselective Total Synthesis of (−)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (−)-acetylaranotin (<b>1</b>) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (−)-<b>1</b> in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family

Enantioselective Total Synthesis of (−)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (−)-acetylaranotin (<b>1</b>) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (−)-<b>1</b> in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family

Enantioselective Total Synthesis of (−)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (−)-acetylaranotin (<b>1</b>) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (−)-<b>1</b> in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family