Asymmetric synthesis of enantioenriched α-allyl esters through Pd(BINAPHANE)-catalysed allylation of disubstituted ketenes.

Pd2dba3·CHCl3 (2.5 mol%)-BINAPHANE (5 mol%) was used to promote the first catalytic enantioselective allylation of disubstituted ketenes to give α-allyl esters. The ester products were formed in good to excellent yields (61-93% yield for 13 examples, 16 examples in all), with moderate to good enantioselectivity (68-80% ee for 7 examples).

Asymmetric Synthesis of Bicyclic Pyrazolidinones through Alkaloid-Catalyzed [3+2]-Cycloadditions of Ketenes and Azomethine Imines.

A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid-catalyzed formal [3+2]- and [3+2+2]-cycloadditions of ketenes with azomethine imines is described. The methodology was found to be tolerant of ketene and a variety of monosubstituted ketenes (R=alkyl, OAc). The products were formed in good to excellent yields (71-99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (≥93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a [3+2+2]-cycloaddition to form structurally interesting bicyclic pyrazolo-oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.

Asymmetric synthesis of cyclopentanones through dual Lewis acid-catalysed [3+2]-cycloaddition of donor-acceptor cyclopropanes with ketenes.

When InBr3-EtAlCl2 (15-30 mol%) was used as a dual Lewis acid system to promote the formal [3+2]-cycloaddition of enantioenriched donor-acceptor cyclopropanes with ketenes, cyclopentanones were formed in good to excellent yields (84-99%, 18 examples), and with excellent transfer of chirality (15 examples, 90% ee to >99% ee).

Asymmetric Synthesis of Tetrahydrofurans through Palladium(0)-Catalyzed [3 + 2]-Cycloaddition of Vinylcyclopropanes with Ketenes.

In this article we describe a new asymmetric synthesis of highly substituted tetrahydrofurans through a Pd(PPh3)4-catalyzed formal [3 + 2]-cycloaddition of donor-acceptor cyclopropanes and ketenes. The desired structural motif was formed in moderate to excellent yields (42-84% for 16 examples), with excellent Z:E isomer diastereoselectivity (≥19:1 for 16 examples), and with good to excellent enantioselectivity in all cases examined (83-97% ee for 6 examples). The synthetic utility of the products was illustrated by a number of diastereoselective transformations into reduced tetrahydrofurans and spirocyclic tetrahydrofuran-barbiturate derivatives.

Recent Developments in Vinylsulfonium and Vinylsulfoxonium Salt Chemistry.

This review describes advances in the literature since 2000 in the area of reactions of vinylsulfonium and vinylsulfoxonium salts, with a particular emphasis on stereoselective examples. Although the chemistry of vinylsulfonium salts was first explored back in the 1950s, and that of vinylsulfoxonium salts in the early 1970s, there has been renewed interest in these compounds since the turn of the century. This has been largely due to an increased appreciation for the many synthetic possibilities associated with these valuable electrophiles. The development of improved routes to vinylsulfonium salts allowing for their in situ generation has played a part in accelerating their study. In general, reactions of the two sulfur salt classes follow a similar mechanistic pathway: initial conjugate addition of a nucleophile to the ß-position, followed by protonation of an ylide intermediate, and cyclization of tethered anion to afford monocyclic or bicyclic product (e.g., cyclopropane, aziridine, oxazole, oxazolidinone, γ-lactam or γ-lactone). Alternatively, reactions involve formation of an ylide intermediate followed by intramolecular Johnson-Corey-Chaykovsky reaction (epoxidation or cyclopropanation), and subsequent cyclization to afford the desired bicyclic product (e.g., fused bicyclic epoxide or cyclopropane).

Asymmetric Synthesis of γ-Lactones through Koga Amine-Controlled Addition of Enediolates to α,ß-Unsaturated Sulfoxonium Salts.

A chiral Koga amine-controlled asymmetric synthesis of cis-γ-lactones through a formal [3 + 2] cycloaddition of enediolates with α,ß-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).

Asymmetric Synthesis of Dipropionate Derivatives through Catalytic Hydrogenation of Enantioenriched E-Ketene Heterodimers.

A highly diastereoselective approach to dipropionate derivatives through Pd/C-catalyzed hydrogenation of enantioenriched E-ketene heterodimers is described. Catalytic hydrogenation of the E-isomer of ketene heterodimer ß-lactones (12 examples) provides access to syn,anti-ß-lactones (dipropionate derivatives) bearing up to three stereogenic centers (dr up to 49:1), and with excellent transfer of chirality (ee up to >99%).

Alkaloid-Catalyzed Enantioselective [3 + 2] Cycloaddition of Ketenes and Azomethine Imines.

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.

Catalytic Asymmetric Synthesis of Ketene Heterodimer ß-Lactones: Scope and Limitations.

In this article we describe extensive studies of the catalytic asymmetric heterodimerization of ketenes to give ketene heterodimer ß-lactones. The optimal catalytic system was determined to be a cinchona alkaloid derivative (TMS-quinine or Me-quinidine). The desired ketene heterodimer ß-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).

Asymmetric Synthesis of Deoxypropionate Derivatives via Catalytic Hydrogenolysis of Enantioenriched Z-Ketene Heterodimers.

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).

Phosphine-Catalyzed Diastereoselective Synthesis of ß-Lactones from Disubstituted Ketenes and α-Chiral Oxyaldehydes.

In this article we describe a catalytic procedure for the diastereoselective synthesis of ß-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 ß-lactone formation. The major isomer of the ß-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 (31)P NMR spectroscopy. The utility of the methodology is demonstrated by a short synthesis of a (+)-peloruside A synthon.

Diastereoselective synthesis of γ-lactones through reaction of enediolates with α,ß-unsaturated sulfoxonium salts.

Studies of the reaction of lithium enediolates with α,ß-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.

Phosphine-catalyzed asymmetric synthesis of ß-lactones from disubstituted ketenes and aldehydes.

In this article we describe a general catalytic procedure for the formation of ß-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 ß-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 ß-lactone formation. Evidence for the involvement of phosphonium enolate intermediates in the reaction mechanism was obtained through reaction monitoring by (31)P NMR spectroscopy and by comparison with previously characterized intermediates observed in the phosphine-catalyzed ketene homodimerization reaction.

Diastereoselective reaction of sulfoxonium ylides, aldehydes and ketenes: an approach to trans-γ-lactones.

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).

BINAPHANE-catalyzed asymmetric synthesis of trans-ß-lactams from disubstituted ketenes and N-tosyl arylimines.

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 ß-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).

Catalytic asymmetric heterodimerization of ketenes.

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 ß-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.

Josiphos-catalyzed asymmetric homodimerization of ketoketenes.

In this paper the development of a chiral phosphine-catalyzed homodimerization of ketoketenes that provides access to a variety of highly substituted ketoketene dimer ß-lactones (11 examples) is reported. The Josiphos catalytic system displays good to excellent enantioselectivity (up to 96% ee). Ring-opening reactions of the enantioenriched ketoketene dimers were also carried out to access 1,3-diketones, enol esters, and ß-hydroxyketones with good diastereoselectivity.

Phosphine-catalyzed asymmetric synthesis of beta-lactones from arylketoketenes and aromatic aldehydes.

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 beta-lactones (14 examples) is reported. The BINAPHANE catalytic system displays excellent enantioselectivity (seven examples with ee >or=90%) and high diastereoselectivity favoring formation of the trans-diastereomer (nine examples with dr >or=90:10).

Organocatalytic dimerization of ketoketenes.

A general method for the catalytic dimerization of ketoketenes is described. Tri-n-butylphosphine was found to be the optimal organocatalyst for the racemic reaction. When lithium iodide was used as an additive, the reaction was rendered selective for dimer formation (dimer/trimer > or = 16:1). Ring-opening reactions of the ketoketene dimers as well as preliminary studies toward the development of an asymmetric variant are also reported.

Development of a solid-phase 'asymmetric resin-capture-release' process: application of an ephedrine chiral resin in an approach to gamma-butyrolactones.

The potential of a solid-phase asymmetric resin-capture-release strategy for high-throughput synthesis has been evaluated. Fukuzawa's Sm(ii)-mediated, asymmetric approach to gamma-butyrolactones was selected to illustrate the feasibility of such a process. Alpha,beta-unsaturated esters immobilised on an ephedrine chiral resin have been applied in an asymmetric approach to gamma-butyrolactones. Lactone products are obtained in moderate isolated yields with selectivities up to 96% ee. In addition, we have shown that the ephedrine resin can be conveniently recovered and recycled although in some cases lower yields were obtained on reuse of the chiral resin. A short synthesis of a moderate DNA-binding microbial metabolite using asymmetric resin-capture-release is also described.