A Mild and Chemoselective Photoredox-Catalyzed Reduction of Aromatic Ketones.

A mild, chemoselective reduction of aromatic ketones was discovered and investigated. The combination of photoredox and Lewis acid catalysis with an organic hydrogen source reduced aromatic ketones in good to high yield. Optimization found 2-phenylbenzothiazoline to be a sufficiently strong source of hydrogen in combination with an iridium photosensitizer and lanthanum triflate.

Photoredox-Catalyzed Oxidation of Anions for the Atom-Economical Hydro-, Amido-, and Dialkylation of Alkenes.

Photoredox catalysis has become a powerful method to generate free radical intermediates in organic synthesis. This report describes the use of photoredox catalysis to directly oxidize common nucleophilic anions to access electrophilic 1,3-dicarbonyl and amidyl radical intermediates. First, conjugate bases of 1,3-dicarbonyls were oxidized to neutral radical species for intramolecular hydro- and dialkylation of alkenes.

Diastereoselective Synthesis of Unnatural Amino Acids by Alkylation of α- tert-Butanesulfinamide Auxiliary-Bound Enolates.

A new chiral auxiliary for the diastereoselective alkylation of amino ester enolates that takes advantage of chiral information stored on the enolate side of the amino ester substrate has been developed. Chiral α-sulfinamido esters were alkylated under basic conditions in good yields (up to 90%) and good to high diastereoselectivities (generally >6:1) to provide unnatural mono- and α,α-disubstituted amino acid derivatives. This auxiliary allowed for the ready conversion of ester functionality without the need for esoteric reagents.

Dual Lewis Acid/Photoredox-Catalyzed Addition of Ketyl Radicals to Vinylogous Carbonates in the Synthesis of 2,6-Dioxabicyclo[3.3.0]octan-3-ones.

A combined Lewis acid/photoredox catalyst system enabled the intramolecular umpolung addition of ketyl radicals to vinylogous carbonates in the synthesis of 2,6-dioxabicyclo[3.3.0]octan-3-ones.

A Nitrone Dipolar Cycloaddition Strategy toward an Enantioselective Synthesis of Massadine.

An enantioselective route to the C,D-bicycle of massadine is reported. Enantiopure intermediates were generated by a single stereoselective reduction using the Corey-Bakshi-Shibata reagent. This initial stereoinduction was translated into the five contiguous stereocenters of the massadine D-ring by a synthetic route that features a diastereoselective and stereospecific Ireland-Claisen rearrangement of a trianionic enolate followed by a diastereoselective nitrone dipolar cycloaddition of a highly electron-poor oxime.

Palladium(II)-Catalyzed Enantioselective Reactions Using COP Catalysts.

Allylic amides, amines, and esters are key synthetic building blocks. Their enantioselective syntheses under mild conditions is a continuing pursuit of organic synthesis methods development. One opportunity for the synthesis of these building blocks is by functionalization of prochiral double bonds using palladium(II) catalysis.

Z-Selective Cross-Metathesis and Homodimerization of 3E-1,3-Dienes: Reaction Optimization, Computational Analysis, and Synthetic Applications.

Olefin metathesis reactions with 3E-1,3-dienes using Z-selective cyclometalated ruthenium benzylidene catalysts are described. In particular, a procedure for employing 3E-1,3-dienes in Z-selective homodimerization and cross-metathesis with terminal alkenes is detailed. The reaction takes advantage of the pronounced chemoselectivity of a recently reported ruthenium-based catalyst containing a cyclometalated NHC ligand for terminal alkenes in the presence of internal E-alkenes.

Carboxylate-assisted C(sp³)-H activation in olefin metathesis-relevant ruthenium complexes.

The mechanism of C-H activation at metathesis-relevant ruthenium(II) benzylidene complexes was studied both experimentally and computationally. Synthesis of a ruthenium dicarboxylate at a low temperature allowed for direct observation of the C-H activation step, independent of the initial anionic ligand-exchange reactions. A first-order reaction supports an intramolecular concerted metalation-deprotonation mechanism with ΔG(‡)(298K) = 22.

Alkene chemoselectivity in ruthenium-catalyzed Z-selective olefin metathesis.

Chelated ruthenium catalysts have achieved highly chemoselective olefin metathesis reactions. Terminal and internal olefins were selectively reacted in the presence of internal olefins. Products were produced in good yield and high stereoselectivity for formation of a new olefin.

Is there no end to the total syntheses of strychnine? Lessons learned in strategy and tactics in total synthesis.

From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this Review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.

Palladium(II)-catalyzed enantioselective synthesis of 2-vinyl oxygen heterocycles.

2-Vinylchromanes (1), 2-vinyl-1,4-benzodioxanes (2), and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazines (3) can be prepared in high yields (90-98%) and excellent enantiomeric purities (87-98% ee) by [COP-OAc](2)-catalyzed cyclization of phenolic (E)-allylic trichloroacetimidate precursors. Deuterium-labeling and computational experiments are consistent with these cyclization reactions taking place by an anti-oxypalladation/syn-deoxypalladation mechanism. 2-Vinylchromanes can also be prepared in good yields and high enantiomeric purities from analogous (E)-allylic acetate precursors, which constitutes the first report that acetate is a competent leaving group in COP-catalyzed enantioselective S(N)2' substitution reactions.

Palladacyclic imidazoline-naphthalene complexes: synthesis and catalytic performance in Pd(II)-catalyzed enantioselective reactions of allylic trichloroacetimidates.

A new family of air- and moisture-stable enantiopure C,N-palladacycles (PIN-acac complexes) were prepared in good overall yield in three steps from 2-iodo-1-naphthoic acid and enantiopure β-amino alcohols. Three of these PIN complexes were characterized by single-crystal X-ray analysis. As anticipated, the naphthalene and imidazoline rings of PIN-acac complexes 18a and 18b were canted significantly from planarity and projected the imidazoline substituents R(1) and R(2) on opposite faces of the palladium square plane.

Mechanism of the cobalt oxazoline palladacycle (COP)-catalyzed asymmetric synthesis of allylic esters.

The catalytic enantioselective S(N)2' displacement of (Z)-allylic trichloroacetimidates catalyzed by the palladium(II) complex [COP-OAc](2) is a broadly useful method for the asymmetric synthesis of chiral branched allylic esters. A variety of experiments aimed at elucidating the nature of the catalytic mechanism and its rate- and enantiodetermining steps are reported. Key findings include the following: (a) the demonstration that a variety of bridged-dipalladium complexes are present and constitute resting states of the COP catalyst (however, monomeric palladium(II) complexes are likely involved in the catalytic cycle); (b) labeling experiments establishing that the reaction proceeds in an overall antarafacial fashion; (c) secondary deuterium kinetic isotope effects that suggest substantial rehybridization at both C1 and C3 in the rate-limiting step; and (d) DFT computational studies (B3-LYP/def2-TZVP) that provide evidence for bidentate substrate-bound intermediates and an anti-oxypalladation/syn-deoxypalladation pathway.

Catalytic asymmetric synthesis of chiral allylic esters.

A broadly useful catalytic enantioselective synthesis of branched allylic esters from prochiral (Z)-2-alkene-1-ols has been developed. The starting allylic alcohol is converted to its trichloroacetimidate intermediate by reaction with trichloroacetonitrile, either in situ or in a separate step, and this intermediate undergoes clean enantioselective S(N)2' substitution with a variety of carboxylic acids in the presence of the palladium(II) catalyst (R(p),S)-di-μ-acetatobis[(η(5)-2-(2'-(4'-methylethyl)oxazolinyl)cyclopentadienyl-1-C,3'-N)(η(4)-tetraphenylcyclobutadiene)cobalt]dipalladium, (R(p),S)-[COP-OAc](2), or its enantiomer. The scope and limitations of this useful catalytic asymmetric allylic esterification are defined.