Design of oxa-spirocyclic PHOX ligands for the asymmetric synthesis of lorcaserin via iridium-catalyzed asymmetric hydrogenation.

Phosphine-oxazoline (PHOX) ligands are a very important class of privileged ligands in asymmetric catalysis. A series of highly rigid oxa-spiro phosphine-oxazoline (O-SIPHOX) ligands based on O-SPINOL was synthesized efficiently, and their iridium complexes were synthesized by coordination of the O-SIPHOX ligands to [Ir(cod)Cl]2 in the presence of sodium tetrakis-3,5-bis(trifluoromethyl)phenylborate (NaBArF). The cationic iridium complexes showed high reactivity and excellent enantioselectivity in the asymmetric hydrogenation of 1-methylene-tetrahydro-benzo[d]azepin-2-ones (up to 99% yield and up to 99% ee). A key intermediate of the anti-obesity drug lorcaserin could be efficiently synthesized using this protocol.

Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: an efficient entry to key intermediates of HIV protease inhibitors.

A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α'-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(iii) catalyst system, a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99 : 1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(iii) catalyst.

One-Pot Reductive 1,3-Dipolar Cycloaddition of Secondary Amides: A Two-Step Transformation of Primary Amides.

The one-pot reductive 1,3-dipolar cycloaddition of secondary aromatic N-(trimethylsilylmethyl)amides with reactive dipolarophiles is reported. The method relies on the in situ generation of nonstabilized NH azomethine ylide dipoles via amide activation with triflic anhydride, partial reduction with 1,1,3,3-tetramethyldisiloxane (TMDS), and desilylation with cesium fluoride (CsF). Running under mild conditions, the reaction tolerated several sensitive functional groups and provided cycloadducts in 71-93% yields. The use of less reactive dipolarophile methyl acrylate led to the cycloadduct in only 40% yield. A (Z) geometric intermediate of NH-azomethine 1,3-dipole was postulated to account for the observed higher yields and higher cis diastereoselectivity for the substrates bearing an electron-withdrawing group. This model features an unconventional cyclic transition state via carbanion-aryl ring interaction. Because the starting secondary amides can be prepared from common primary amides, the current method also constitutes a two-step transformation of primary amides.

Mild Metal-Free Hydrosilylation of Secondary Amides to Amines.

The combination of amide activation by Tf2O with B(C6F5)3-catalyzed hydrosilylation with TMDS constitutes a method for the one-pot reduction of secondary amides to amines under mild conditions. The method displays a broad applicability for the reduction of many types of substrates, and shows good compatibility and excellent chemoselectivity for many sensitive functional groups. Reductions of a multifunctionalized α,ß-unsaturated amide obtained from another synthetic methodology, and a C-H functionalization product produced the corresponding amines in good to excellent yield. Chemoselective reduction of enantiomeric pure (ee >99%) tetrahydro-5-oxo-2-furaneamides yielded 5-(aminomethyl)dihydrofuran-2(3H)-ones in a racemization-free manner. The latter were converted in one pot to N-protected 5-hydroxypiperidin-2-ones, which are building blocks for the synthesis of many natural products. Further elaboration of an intermediate led to a concise four-step synthesis of (-)-epi-pseudoconhydrine.

Direct reductive coupling of secondary amides: chemoselective formation of vicinal diamines and vicinal amino alcohols.

We report the first one-pot reductive homocoupling reaction of secondary amides and cross-coupling reaction of secondary amides with ketones to give secondary vicinal diamines and amino alcohols. This method relies on the direct generation of α-amino carbon radicals from secondary amides by activation with trifluoromethanesulfonic anhydride, partial reduction with triethylsilane and samarium diiodide-mediated single-electron transfer. The reactions were run under mild conditions and tolerated several functional groups.