A chiral Koga amine-controlled asymmetric synthesis of cis-γ-lactones through a formal [3 + 2] cycloaddition of enediolates with α,β-unsaturated sulfoxonium salts is described. The desired structural motif was formed in moderate to good yields (50–71% for 13 examples), with good to very good diastereoselectivity (dr 5:1 to 10:1 for 20 examples), favoring the cis-isomer, and good to excellent enantioselectivity (70–91% ee for 13 examples).

A new asymmetric synthesis of bicyclic pyrazolidinones through an alkaloid-catalyzed formal [3 + 2] cycloaddition of in situ generated ketenes and azomethine imines is described. The products were formed in good to excellent yields (52–99% for 17 examples), with good to excellent diastereoselectivity (dr 5:1 to 27:1 for 11 examples), and with excellent enantioselectivity in all cases (≥96% ee). This method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.

In this article we describe extensive studies of the catalytic asymmetric heterodimerization of ketenes to give ketene heterodimer β-lactones. The optimal catalytic system was determined to be a cinchona alkaloid derivative (TMS-quinine or Me-quinidine). The desired ketene heterodimer β-lactones were obtained in good to excellent yields (up to 90%), with excellent levels of enantioselectivity (≥90% ee for 33 Z and E isomer examples), good to excellent (Z)-olefin isomer selectivity (≥90:10 for 20 examples), and excellent regioselectivity (only one regioisomer formed). Full details of catalyst development studies, catalyst loading investigations, substrate scope exploration, protocol innovations (including double in situ ketene generation for 7 examples), and an application to a cinnabaramide A intermediate are described. The addition of lithium perchlorate (1–2 equiv) as an additive to the alkaloid catalyst system was found to favor formation of the E isomer of the ketene heterodimer. Ten examples were formed with moderate to excellent (E)-olefin isomer selectivity (74:25 to 97:3) and with excellent enantioselectivity (84–98% ee).

A diastereoselective approach to deoxypropionate derivatives through Pd/C-catalyzed hydrogenolysis of enantioenriched ketene heterodimers is described. Catalytic hydrogenolysis of the Z-isomer of ketene heterodimers facilitates access to anti-deoxypropionate derivatives (10 examples with dr 7:1 to >20:1). Transfer of chirality from the Z-ketene heterodimer to an acid product was good to excellent in most cases (78–99% ee for 12 examples).

Studies of the reaction of lithium enediolates with α,β-unsaturated sulfoxonium salts are described. γ-Lactones were formed in very good to excellent yields (82% → 99% for 11 examples) and with very good to excellent diastereoselectivity (dr >90:10 for 10 examples), favoring the trans-diastereomer.

In this Letter we describe a catalytic procedure for the diastereoselective synthesis of β-lactones bearing up to three stereogenic centers, from disubstituted ketenes and chiral β-oxyaldehydes. Tri-n-butylphosphine was determined to be the best catalyst with yields of up to 95% and moderate to good diastereoselectivity (dr up to 4:1) obtained in the formation of highly substituted β-lactones.

In this article we describe a catalytic procedure for the diastereoselective synthesis of β-lactones bearing two stereogenic centers, from disubstituted ketenes and α-chiral oxyaldehydes. Tri-n-butylphosphine was found to be the optimal catalyst in terms of effecting both good yield and diastereoselectivity (dr from 3:1 to 32:1 for 8 examples) in β-lactone formation. The major isomer of the β-lactone products was determined to be the anti-diastereomer, and its formation was rationalized by a polar Felkin–Anh model. Involvement of phosphonium enolate intermediates in the reaction mechanism was indicated through reaction monitoring by 31P NMR spectroscopy. The utility of the methodology is demonstrated by a short synthesis of a (+)-peloruside A synthon.

A method for the enantioselective synthesis of γ-lactones through the reaction of enantioenriched sulfoxonium ylides, aldehydes, and ketenes was developed. Enantioenriched (98% ee) aminosulfoxonium ylide was subjected to reaction with a variety of aldehydes (both aromatic and aliphatic) and disubstituted ketenes, leading to the formation of α,β-substituted γ-lactones in moderate to very good diastereoselectivity (dr up to 95:5) and with enantiomeric excesses of up to 79% ee. Best levels of enantioselectivity were observed in the reactions of enantioenriched aminosulfoxonium ylide with isobutyraldehyde and various alkylarylketenes.A method for the enantioselective synthesis of γ-lactones through the reaction of enantioenriched sulfoxonium ylides, aldehydes, and ketenes was developed. Enantioenriched (98% ee) aminosulfoxonium ylide was subjected to reaction with a variety of aldehydes (both aromatic and aliphatic) and disubstituted ketenes, leading to the formation of α,β-substituted γ-lactones in moderate to very good diastereoselectivity (dr up to 95:5) and with enantiomeric excesses of up to 79% ee.

In this article we describe a general catalytic procedure for the formation of β-lactones bearing two stereogenic centers, from disubstituted ketenes and achiral aldehydes. BINAPHANE was found to display excellent enantioselectivity (≥90% ee for eight examples) and good diastereoselectivity (≥90:10 for 13 examples) in catalyzing the formation of β-lactones bearing two stereogenic centers from achiral aldehydes (both aromatic and aliphatic) and alkylarylketenes or dialkylketenes. A preference for formation of the trans diastereomer was observed in these reactions. For those reactions where BINAPHANE failed as a catalyst, tri-n-butylphosphine was found to be an effective achiral nucleophilic catalyst, effecting good yield and diastereoselectivity in racemic β-lactone formation. Evidence for the involvement of phosphonium enolate intermediates in the reaction mechanism was obtained through reaction monitoring by 31P NMR spectroscopy and by comparison with previously characterized intermediates observed in the phosphine-catalyzed ketene homodimerization reaction.

A general method for the diastereoselective formation of β-hydroxyketones by the reduction of ketene dimers was developed. The reduction of ketene homodimers, derived from alkylarylketenes and dimethylketene, and ketene heterodimers, derived from methylketene and ethylphenylketene or diphenylketene, was investigated. Methylphenylketene dimer was reduced with optimal diastereoselectivity (dr = 6:1) using LiBH4. However, more generally, LiAlH4 was found to be the most effective reducing system with respect to diastereoselectivity (dr up to >99:1) and yield (62–>99% for 10 examples).A general method for the diastereoselective formation of β-hydroxyketones by the reduction of ketene dimers was developed. Methylphenylketene dimer was reduced with optimal diastereoselectivity (dr up to 6:1) using LiBH4. However, more generally LiAlH4 was found to be the most effective reducing system with respect to diastereoselectivity (dr up to >99:1) and yield (62–>99% for 10 examples).

In this paper, a novel approach to γ-lactones from the reaction of sulfoxonium ylides, aldehydes, and ketenes is described. The new ylide-based method provides access to γ-lactones from disubstituted ketenes, in good yields, and with good diastereoselectivity favoring the trans-diastereomer (11 examples with dr ≥ 82:18, dr up to 92:8).

In this Communication we describe an unprecedented catalytic asymmetric heterodimerization of ketenes of wide substrate scope. The alkaloid-catalyzed method provides access to ketene heterodimer β-lactones and allows even two different monosubstituted ketenes to be cross-dimerized, with excellent enantioselectivity (17 examples with ≥90% ee) and excellent heterodimer regioselectivity observed in all cases.

The development of a BINAPHANE-catalyzed formal [2 + 2]-cycloaddition of disubstituted ketenes and inexpensive N-tosyl arylimines that provides access to a variety of highly substituted β-lactams (16 examples) is described. The BINAPHANE catalytic system displays moderate to excellent enantioselectivity (up to 98% ee) and high diastereoselectivity in most cases, favoring formation of the trans-diastereomer (13 examples with dr ≥ 90:10).

In this paper, the development of a chiral phosphine-catalyzed formal [2 + 2] cycloaddition of aldehydes and ketoketenes that provides access to a variety of highly substituted β-lactones (14 examples) is reported. The BINAPHANE catalytic system displays excellent enantioselectivity (seven examples with ee ≥90%) and high diastereoselectivity favoring formation of the trans-diastereomer (nine examples with dr ≥90:10).

The mechanism of PBu3-catalyzed homodimerization of ketoketenes has been explored and compared with that of the previously reported trialkylphosphite-mediated reactions. NMR studies of the PBu3-catalyzed reaction implicated the involvement of tetravalent phosphonium intermediates. Phosphonium intermediates in the catalytic cycle were trapped through reaction with trimethylsilyl chloride and 4-chlorobenzaldehyde, and the resulting products were characterized. A method for the stoichiometric generation of phosphonium enolates was developed as a result of these studies. No evidence was obtained for the involvement of pentacovalent phosphorane intermediates in trialkylphosphine-catalyzed ketoketene homodimerization reactions, in contrast with the mechanism of the trialkylphosphite-mediated homodimerization of dimethylketene. An X-ray crystal structure analysis of methylphenylketene dimer showed that it possesses Z-geometry about the exocyclic olefin.The mechanism of the PBu3-catalyzed homodimerization of ketoketenes has been investigated and compared with that of the previously reported P(OMe)3-mediated homodimerization of dimethylketene. NMR studies and intermediate trapping experiments of the PBu3-catalyzed reaction implicated the involvement of tetravalent phosphonium enolate intermediates.