The chiral phosphoric acid TRIP, a useful Brønsted acid catalyst, easily becomes contaminated with metal impurities in the form of phosphate salts during synthesis. This significantly reduces the content of free acid in the product which can hamper the catalytic activity. Methods to easily judge whether TRIP contains mainly the free acid or phosphate salts are presented, using 1 H NMR spectroscopy or a simple pH test. An improved synthetic protocol for TRIP was established that reliably produces the free acid.In recent years, relatively strong chiral Brønsted acids have emerged as powerful catalysts for many asymmetric transformations. 1 Particularly effective are phosphoric acids 1 with an axially chiral binaphthyl backbone bearing sterically demanding substituents in the 3-positions, first introduced as catalysts by Akiyama and Terada 2 ( Figure 1). Among the many differently substituted binaphthyl-phosphoric acids, 3,3¢-bis(2,4,6-triisopropylphenyl)-1,1¢-binaphthyl-2,2¢-diyl hydrogenphosphate (2, abbreviated TRIP), emerged as a particularly powerful one in terms of activity and stereoselectivity. 3 Figure 1 Chiral binaphthyl phosphoric acids: general structure 1 and TRIP 2TRIP was first introduced for the asymmetric transfer hydrogenation of imines. 4 Other notable applications in which TRIP turned out to be the best asymmetric Brøn-sted acid catalyst include the reductive amination of abranched aldehydes, 5 an aldol conjugate reduction-reductive amination cascade, 6 Friedel-Crafts and PictetSpengler reactions 7 and cycloadditions. 8In the aforementioned reactions, asymmetry was introduced by the conjugate base of TRIP 2. The chiral phosphate can also effect stereoselectivity if employed in the form of salts in reactions with cationic intermediates, 9 a strategy also termed asymmetric counteranion directed catalysis (ACDC). 10 The TRIP anion has proven to induce high levels of stereoselectivity in combination with organic counterions, for example, in the transfer hydrogenation and epoxidation of a,b-unsatured aldehydes 10,11 and ketones, 12 respectively. The use of the TRIP anion in otherwise achiral transition-metal complexes enabled asymmetric gold-catalyzed allene cyclizations 13 and palladium-catalyzed allylic alkylations 14 with high levels of stereoselectivity. Furthermore, TRIP was also the catalyst of choice in combinations of Brønsted acid and transitionmetal catalysis. 15 Interestingly, alkali or alkaline earth salts of chiral phosphates 1 can also be efficient catalysts. 16 Feng and coworkers reported the use of sodium salts of 1 in an enantioselective Strecker reaction 16b and Ishihara and coworkers reported the use of alkali or alkaline earth salts for an enantioselective cyanosilylation of ketones 16a and a Mannich reaction. 16c In all these cases, the chiral induction was dependent on the metal counterion and the mode of preparation of the salts.Lately, Ishihara pointed out the possible salt formation and contamination of BINOL-derived phosphoric acids 1 during purification on silica gel and...

A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2 O has been developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross-coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.

Branching out: An organocatalytic reductive amination of α‐branched ketones using dynamic kinetic resolution is reported. The cis‐2‐substituted cyclohexyl amines were obtained in high diastereoselectivity and enantioselectivity from the corresponding ketones.

Reactions that form a product with the same reactive functionality as that of one of the starting compounds frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) andtert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliphatic and aromatic acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-molecule catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mole % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.

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Herein we describe the development of a catalytic enantioselective alkynylogous Mukaiyama aldol reaction. The reaction is catalyzed by a newly designed chiral disulfonimide and delivers chiral allenoates in high yields and with excellent regio-, diastereo-, and enantioselectivity. Our process tolerates a broad range of aldehydes in combination with diverse alkynyl-substituted ketene acetals. The reaction products can be readily derivatized to furnish a variety of highly substituted enantiomerically enriched building blocks.

A two-step procedure for producing optically active, high value primary amines has been developed. The first and key step is the asymmetric reductive amination of a prochiral alkyl alkyl (acyclic or cyclic) or aryl alkyl (acyclic or cyclic) ketone with (R)-or (S)-a-methylbenzylamine (a-MBA). The normally stepwise excessive procedures of chiral auxiliary approaches are avoided by simultaneously incorporating the auxiliary and a new stereogenic center at the former carbonyl carbon of the ketone during step one. Specifically, step one is the hydrogenation (4-8 bar) of a prochiral ketone substrate in the presence of a-MBA, a Lewis acid 4 ], and a heterogeneous hydrogenation catalyst (Raney-Ni, Pt-C, Pd-C, Ru-C, or Rh-C), providing the amine diastereomers 2 in good to excellent yield and diastereoselectivity. Depending on the ketone examined (acyclic vs. cyclic, alkyl alkyl vs. aryl alkyl, sterically encumbered vs. unencumbered), the correct combination of heterogeneous hydrogenation catalyst, solvent, and temperature is crucial for allowing high yield and de with practical reaction times (generally 6-20 h). Performing the reaction in the absence of one of the indicated Lewis acids results in the formation of large amounts of alcohol by-product (> 25 %).Step two, hydrogenolysis, allows smooth removal of the chiral auxiliary providing a-chiral primary amines in good overall yield (5 examples 71-78 %, 1 example 64 %) and in 66-98 % enantiomeric excess. This two-step strategy is noteworthy because: 1) it is yield and stepwise efficient; 2) all the reagents are inexpensive and already used by the pharmaceutical industry; 3) a broad range of ketone substrates are suitable; 4) either enantiomeric form of the a-chiral amine product can be produced; 5) the reaction conditions are mild; and 6) the process is amenable to scale-up.

An asymmetric Torgov cyclization, catalyzed by a novel, highly Brønsted acidic dinitro-substituted disulfonimide, is described. The reaction delivers the Torgov diene and various analogues with excellent yields and enantioselectivity. This method was applied in a very short synthesis of (+)-estrone.