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A general method for the preparation of syn -2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings from 2-mercaptoethanols and quinone ketals is presented. This ring system is produced by Michael addition of a 2-mercaptoethanol to a quinone ketal, followed by cyclization of the initial Michael adduct, and subsequent aromatization to afford a syn -2,3-disubstituted-1,4-benzoxathiin in fair to good chemical yield. Several chiral syn -2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings were prepared with this method from enantioenriched 2-mercaptoethanols. No loss of enantiopurity was observed.

A highly stereoselective aldol reaction was observed on chromane carboxylate ester 1 via the corresponding diisopinocampheyl boron-enolate using commercially available (−)-DIP-Cl reagent. The aldol product 2c was obtained in 89% yield with 48 dr and 92% ee. Further studies indicate that stereoselective formation of the enolate and proper chiral ligand on boron are responsible for the exceptional diastereo- and enantioselectivity in the aldol reaction.

An efficient synthesis of a structurally unique, novel M(3) antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl(2)-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.

Bromopyridine 4 was converted into aminopyridine 5 under Cu2O catalysis with an ethylene glycol solution of ammonia in excellent yield (90%). The amination reaction features low (0.5 mol%) catalyst loading, mild reaction temperature (80°C) and low reaction pressure (50 psi). This protocol is further studied in the amination of a variety of aryl halides.

Bromocyclopentitols and amino (or amido) bromocyclopentitols having a CBr bond trans to two different vicinal hydroxyl groups show selectivity in base-promoted epoxide formation. The role of adjacent polar substituents in directing bromohydrin cyclization is discussed.

Potent inhibitors of trehalase, such as trehazolin and its congeners, represent an attractive approach to the design of effective new insect control agents. In this report, enantioselective total syntheses of (−)-6-epitrehazolin and (+)-trehazolin were achieved using the asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene and the acylnitroso compound arising from in situ oxidation of (S)-mandelohydroxamic acid with tetrabutylammonium periodate. Further functionalization of the resulting 3,4,5-trisubstituted cyclopentene, either involving osmylation or epoxidation of the double bond, efficiently created pentasubstituted cyclopentanes. Introduction of the quaternary carbon in both synthesis targets was achieved via stereoselective osmylation of an intermediate 2,3,4,5-substituted 1-methylenecyclopentane.

Dimethyl sulfomycinamate (1), a methanolysis product from the natural antibiotic sulfomycin I, is synthesized in 11 steps (Scheme 19). The chemistry of various pyridine, thiazole, and oxazole heterocycles and their coupling reactions under palladium catalysis are examined. The key transformations in the synthesis are the selective palladium-catalyzed coupling reactions on doubly activated pyridine 62 and the condensation reaction between bromo ketone 69 and amide 28 to form the oxazole moiety 76. The first preparation of oxazole triflates is described, as are some of their chemical properties.

A novel rearrangement was discovered during an investigation of the lithium-bromine exchange reactions of bromothiazole derivatives and their subsequent reactions with various electrophiles.

The total synthesis of both michellamine A (1a) and B (1b), by consecutive construction first of the inner (non-stereogenic) axis and subsequently the two outer (stereogenic) axes in a highly convergent manner, is described. The michellamines are of considerable interest due to their pronounced anti-HIV activity.

Potent inhibitors of trehalase, such as trehazolin and its congeners, represent an attractive approach to the design of effective new insect control agents. In this report, enantioselective total syntheses of (−)-6-epitrehazolin and (+)-trehazolin were achieved using the asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene and the acylnitroso compound arising from in situ oxidation of (S)-mandelohydroxamic acid with tetrabutylammonium periodate. Further functionalization of the resulting 3,4,5-trisubstituted cyclopentene, either involving osmylation or epoxidation of the double bond, efficiently created pentasubstituted cyclopentanes. Introduction of the quaternary carbon in both synthesis targets was achieved via stereoselective osmylation of an intermediate 2,3,4,5-substituted 1-methylenecyclopentane.

Bromopyridine 4 was converted into aminopyridine 5 under Cu2O catalysis with an ethylene glycol solution of ammonia in excellent yield (90%). The amination reaction features low (0.5 mol%) catalyst loading, mild reaction temperature (80°C) and low reaction pressure (50 psi). This protocol is further studied in the amination of a variety of aryl halides.

An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an α,β-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols.

A practical and convenient synthesis of azetidine-3-carboxylic acid (1) that proceeded in 55% overall yield from commercially available diethylbis(hydroxymethyl)malonate (3) is reported. Azetidine ring-formation was achieved in high yield by cyclization of bistrifiate of the diol (3) and benzylamine. Decarboxylation under carefully pH-controlled conditions gave the mono acid azetidine that was hydrogenated to give the title compound.