Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11ß-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

Diastereoselective syntheses of substituted cis-hydrindanones featuring sequential inter- and intramolecular Michael reactions.

The hydrindane (bicyclo[4.3.0]nonane) structural motif (1) and related cis-1-hydrindanone skeleton (2) are common substructures in many natural products. Herein, we describe efficient access to substituted cis-1-hydrindanones enabled by a sequence of Michael reactions. A copper-catalyzed intermolecular Michael addition of a cyclic silyl ketene acetal to a ß-substituted-α-alkoxycarbonyl-cyclopentenone enables construction of a quaternary center and is followed, after incorporation of an additional Michael acceptor, by a second, intramolecular addition of a nucleophilic ß-ketoester. This strategy affords stereoselective access to substituted bicyclic cis-hydrindanone ring systems containing up to three contiguous stereocenters.

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.

Efficient asymmetric synthesis of structurally diverse P-stereogenic phosphinamides for catalyst design.

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

Carbamoyl anion addition to N-sulfinyl imines: highly diastereoselective synthesis of α-amino amides.

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.

A concise and convergent synthesis of PA-824.

An efficient four-step synthesis of PA-824, a promising antituberculosis drug candidate, has been developed. This concise approach offers significant improvements over the synthetic route currently used for large-scale production.

Diastereoselective syntheses of chroman spiroketals via [4 + 2] cycloaddition of enol ethers and o-quinone methides.

A variety of chroman spiroketals are synthesized via inverse-demand [4 + 2] cycloaddition of enol ethers and ortho-quinone methides (o-QMs). Low temperature o-QM generation in situ allows for the kinetic, diastereoselective construction of these motifs, providing entry to a number of unusual chroman spiroketal natural products.

Synthesis of resorcinol derived spironitronates.

Syntheses of several unique spironitronates are reported. The key transformation involves the first known example of an ipso oxidative cyclization of nitro functionality. Oxidation proceeds from both o- and p-phenols. Reductions of these compounds provide novel spiroisoxazoline derivatives.

Total synthesis of (+/-)-mitorubrinic acid.

[reaction: see text] (+/-)-Mitorubrinic acid, a member of the azaphilone family of natural products, has been constructed in 12 steps. Key aspects of the synthesis include elaboration and oxidative dearomatization of an isocoumarin intermediate to provide the azaphilone nucleus with a disubstituted, unsaturated carboxylic acid side chain.

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.

Diastereoselective Synthesis of α-Quaternary Aziridine-2-carboxylates via Aza-Corey-Chaykovsky Aziridination of N-tert-Butanesulfinyl Ketimino Esters.

A general, scalable, and highly diastereoselective aziridination of N-tert-butanesulfinyl ketimino esters is described. The methodology has been utilized to provide straightforward access to previously unobtainable, biologically relevant α-quaternary amino esters and derivatives starting from readily available precursors.

A diastereoselective formal synthesis of berkelic acid.

A formal synthesis of berkelic acid is reported. The strategy employs the combination of a chiral exocyclic enol ether and an achiral isochromanone to afford the chroman spiroketal core via a base-triggered generation and cycloaddition of an o-quinone methide intermediate. Other key steps include equilibration of the spiroketal, intramolecular benzylic oxidation, and lactone addition/hemiketal reduction; all occur with good diastereoselectivity.

Chemoselective reactions of 3-benzyloxy-1,2-o-quinone with organometallic reagents.

Chemoselective additions of organometallic reagents to 3-benzyloxy-1,2-o-quinone are described. Various nucleophiles are shown to undergo selective 1,2-addition, 1,4-addition, and etherification. Selective 1,2-additions provide stable, nondimerizing o-quinols as a novel alternative to oxidative dearomatization.