Synthesis and Evaluation of -Diaminophosphoryl Aminothioureas as Bifunctional Catalysts for Vinylogous Aldol Reactions of Isatins and 2(3)-Furanones.

The organocatalytic asymmetric direct vinylogous aldol reaction of -methylisatins and γ-butenolides to provide 3-hydroxy-2-oxindole derivatives was investigated. A series of -diaminophosphoryl aminothiourea catalysts was synthesized, and their utility for the stereoselective formation of was examined.

Biomimetic Organocatalytic Approach to 4-Arylquinolizidine Alkaloids and Application in the Synthesis of (-)-Lasubine II and (+)-Subcosine II.

An enantioselective, biomimetic organocatalytic synthesis of 4-arylquinolizidin-2-ones, key intermediates in the synthesis of several Lythraceae alkaloids, was developed. The methodology features -proline-mediated Mannich/aza-Michael reactions of readily available arylideneacetones and Δ-piperideine. The total syntheses of (-)-lasubine II and (+)-subcosine II as well as the formal syntheses of structurally related Lythraceae alkaloids were achieved.

Stereoselective synthesis of E-3-(arylmethylidene)-5-(alkyl/aryl)-2(3H)-furanones by sequential hydroacyloxylation-Mizoroki-Heck reactions of iodoalkynes.

A modular, stereoselective synthesis of E-3-(arylidene)-5-(alkyl/aryl)-2(3H)-furanones was developed. The methodology features regioselective addition of β-aryl acrylic acids to iodoacetylenes to furnish the Z-acyloxy iodoalkenes. A stereoselective 5-exo-trig Mizoroki-Heck reaction of the acyloxy iodoalkenes generates the target E-2(3H)-furanones.

Functionalization of diazotetronic acid and application in a stereoselective modular synthesis of pulvinone, aspulvinones A-E, G, Q and their analogues.

A modular synthesis of aspulvinones A, B, C, D, E, G and the recently isolated aspulvinone Q was developed. The methodology features a highly stereoselective aldol condensation of diazotetronic acid with aldehydes to provide 5-arylidene diazotetronates. Subsequent catalytic intermolecular C-H insertion reactions of the arylidene tetronates with arenes provide a series of naturally occurring aspulvinones including aspulvinones C, D and Q which have not been synthesized before.

Catalytic Undirected Intermolecular C-H Functionalization of Arenes with 3-Diazofuran-2,4-dione: Synthesis of 3-Aryl Tetronic Acids, Vulpinic Acid, Pinastric Acid, and Methyl Isoxerocomate.

A variety of 3-aryl tetronic acids have been synthesized by an undirected, intermolecular C-H functionalization of arenes with 3-diazofuran-2,4-dione. This methodology featured as a key step in the synthesis of a series of naturally occurring 3-aryl-5-arylidene tetronic acids (pulvinates) from commercially available tetronic acid. Salient features of the pulvinic acid synthesis include a one-step, stereoselective synthesis of the C5 arylidene group and a single step introduction of the C3 aryl substituent.

Formal Synthesis of (+)-Lasubine II and (-)-Subcosine II via Organocatalytic Michael Addition of a Ketone to an α-Nitrostyrene.

The first examples of an organocatalytic Michael addition of a ketone to in situ generated α-nitrostyrenes are reported. A suitably functionalized γ-nitroketone obtained from the organocatalyzed Michael addition was converted into (+)-2-epi-lasubine II, the immediate synthetic precursor of (+)-lasubine II and (-)-subcosine II (enantiomers of the natural quinolizidine alkaloids). Two of the three stereocenters in (+)-2-epi-lasubine II are set by the Michael reaction.

Enantioselective approach to functionalized quinolizidines: synthesis of (+)-julandine and (+)-cryptopleurine.

An efficient synthesis of functionalized quinolizidines was developed from an enantiomerically enriched γ-nitroketone, which is easily prepared by an organocatalytic ketone-nitroalkene Michael addition. Oxidative ring expansion of the nitroketone followed by reductive ring-opening leads to a suitably functionalized nitrodiol which is an intermediate to the title compounds.

Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-hydroxypipecolic acid: application of an organocatalytic direct vinylogous aldol reaction.

The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ-crotonolactone and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.

The organocatalytic vinylogous aldol reaction: recent advances.

Over the past decade, organocatalysis has emerged as a powerful tool for stereoselective carbon-carbon bond formation under exceptionally mild conditions. The organocatalytic versions of a large number of traditional synthetic transformations are now well established and the quest for new applications of the basic concepts of organocatalysis continues. This review addresses the emergent interest in the organocatalytic vinylogous aldol reaction.

Organocatalytic asymmetric direct vinylogous aldol reactions of γ-crotonolactone with aromatic aldehydes.

The direct aldol reaction of γ-crotonolactone and various aromatic aldehydes is catalyzed by bifunctional aminothiourea and aminosquaramide organocatalysts to provide diastereomerically and enantiomerically enriched 5-substituted 2(5H) furanones (γ-butenolides). The reaction is a simple alternative to the classical vinylogous aldol reaction of silyloxy furans.

Stereoselective synthesis of 3-aryloctahydroindoles and application in a formal synthesis of (-)-pancracine.

A stereoselective synthesis of 3-aryloctahydroindoles from enantiomerically enriched gamma-nitroketones has been developed. Reduction of imines derived form the nitroketones provides the trans-fused octhaydroindole motif selectively. The cis-octahydroindole skeleton is accessible by an invertive cyclization strategy involving a diastereomerically pure nitromesylate intermediate.

Synthesis and evaluation of guanidinyl pyrrolidines as bifunctional catalysts for enantioselective conjugate additions to cyclic enones.

Guanidinyl pyrrolidines derived from 'S'-proline are effective catalysts for the enantioselective conjugate addition of malonate, nitroalkane and other carbon and heteroatom nucleophiles to cyclohexenone and cyclopentenone in the absence of basic additives. The stereoselectivity is strongly dependent on catalyst loading as well as reaction concentration.

An enantioselective approach to (+)-laurencin.

A convergent enantioselective route to an advanced intermediate for the synthesis of the marine natural product (+)-laurencin has been developed. The methodology employs ring-opening of an ephedrine-based spiro-epoxide with a chiral secondary alcohol, hemiacetal allylation and ring closing metathesis as the key steps for elaboration of the functionalized medium-ring ether moiety in laurencin.

Enantioselective synthesis of functionalized medium-sized oxacycles.

Enantioselective routes to functionalized, seven-, eight-, and nine-membered oxacycles that are amenable to further elaboration have been developed. Salient features of the methodology include highly diastereoselective and regioselective transformations of an ephedrine-derived epoxy morpholinone to functionalized precursors of the oxacycles. The ephedrine scaffold exerts remote stereocontrol in the functionalization of the appended oxacycle.

Simple diamine- and triamine-protonic acid catalysts for the enantioselective Michael addition of cyclic ketones to nitroalkenes.

Simple, chiral, pyrrolidine-based diamine and triamine derivatives that incorporate the secondary-secondary diamine motif are efficient catalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to 2-nitrovinyl arenes. The highest selectivities are obtained when these catalysts are used in conjunction with protonic acids. Steric factors in the substrate and the size of the acid additive play an important role in stereoselection.

A concise, enantioselective approach to (-)-quinic acid.

[reaction: see text] An expedient, enantioselective synthesis of a key precursor to (-)-quinic acid has been achieved from an ephedrine-derived morpholine-dione. The salient features of this approach are a highly diastereoselective conversion of the dione to a dialkenyl morpholinone and a subsequent ring-closing metathesis reaction. Removal of the ephedrine portion generates an enantiomerically enriched hydroxycyclohexene carboxamide that is readily converted to the quinic acid precursor.

Combinatorial optimization of isatin-beta-thiosemicarbazones as anti-poxvirus agents.

Novel strategies are required to combat pox virus infections, whether caused by escape of viruses such as monkeypox from indigenous areas or intentional release of smallpox. Anti-smallpox drugs with a unique mode of antiviral action, inhibition of transcription termination, were known but not therapeutically useful. Using a combinatorial method, variants of the basic isatin-beta-thiosemicarbazone structure were prepared and examined for cytotoxicity and antiviral activity in vaccinia virus- and cowpox virus-infected human cells.