Carl A. Busacca

Reduction of Tertiary Phosphine Oxides with DIBAL-H

The reduction of tertiary phosphine oxides (TPOs) and sulfides with diisobutylaluminum hydride (DIBAL-H) has been studied in detail. An extensive solvent screen has revealed that hindered aliphatic ethers, such as MTBE, are optimum for this reaction at ambient temperature. Many TPOs undergo considerable reduction at ambient temperature and then stall due to inhibition. 31P and 13C NMR studies using isotopically labeled substrates as well as competition studies have revealed that the source of this inhibition is tetraisobutyldialuminoxane (TIBAO), which builds up as the reaction proceeds. TIBAO selectively coordinates the TPO starting material, preventing further reduction. Several strategies have been found to circumvent this inhibition and obtain full conversion with this extremely inexpensive reducing agent for the first time. Practical reduction protocols for these critical targets have been developed.

RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061.

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.

The Reaction of Grignard Reagents with Bunte Salts: A Thiol-Free Synthesis of Sulfides

S-Alkyl, S-aryl, and S-vinyl thiosulfate sodium salts (Bunte salts) react with Grignard reagents to give sulfides in good yields. The S-alkyl Bunte salts are prepared from odorless sodium thiosulfate by an SN2 reaction with alkyl halides. A Cu-catalyzed coupling of sodium thiosulfate with aryl and vinyl halides was developed to access S-aryl and S-vinyl Bunte salts. The reaction is amenable to a broad structural array of Bunte salts and Grignard reagents. Importantly, this route to sulfides avoids the use of malodorous thiol starting materials or byproducts.

Cross coupling of vinyl triflates and alkyl Grignard reagents catalyzed by nickel(0)-complexes

Abstract The scope and limitations of the Nickel(0)-catalyzed cross coupling of vinyl triflates with alkyl Grignard reagents have been studied. The effect of triflate substitution, solvent, and especially ligands have been examined. Ligands which are successful for sp2 and sp Grignard reagents fail for sp3 Grignard reagents.

Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis

An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct.

A one step synthesis of thiazolines from esters

Abstract Condensation of the triisobutylaluminum complex of cysteamine HCl with a variety of carboxylic esters furnishes thiazolines in one step. This new method has been applied to chiral α-aminoesters to give α-amino thiazolines of high optical purity, yet N-benzyl protection of the amine is required.

Ambient Temperature Hydrophosphination of Internal, Unactivated Alkynes and Allenyl Phosphineoxides with Phosphine Borane Complexes

Phosphine boranes have been found to hydrophosphinate internal, unactivated alkynes at room temperature under basic conditions without the need for catalysts or radical initiators. The use of air-sensitive secondary phosphines is avoided in this facile process. Broad scope in both the phosphine borane and alkyne partners leads to excellent diversity in the phosphine products. Asymmetric hydrogenation of these species then provides one of the shortest possible routes to chiral monodentate phosphines. Hydrophosphination of allenyl phosphine oxides under similar conditions followed by hydrogenation of the exomethylene moiety yields a wide variety of bis-phosphine derivatives.

A General Method for Imine Formation Using B(OCH2CF3)3

Tris(2,2,2-trifluoroethyl)borate [B(OCH2CF3)3] was found to be a mild and general reagent for the formation of a variety of imines by condensation of amides or amines with carbonyl compounds. N-Sulfinyl, N-toluenesulfonyl, N-(dimethylamino)sulfamoyl, N-diphenylphosphinoyl, N-(α-methylbenzyl), and N-(4-methoxyphenyl) aldimines are all accessible using this reagent at room temperature. The reactions are operationally simple, and the products are obtained without special workup or isolation procedures.

A facile synthesis of 4-aryl-2,3-dihydropyrroles

Abstract A combination of Heck arylation of N-allylsulfonamide and subsequent hydroformylation provides a simple and flexible entry into the title compounds.

Large-Scale Asymmetric Synthesis of a Cathepsin S Inhibitor

A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.