Vijay N. Wakchaure

A New Structural Motif for Bifunctional Brønsted Acid/Base Organocatalysis

In recent years the concept of bifunctionality has enriched the field of asymmetric catalysis. Impressive progress has been made particularly in the area of enantioselective transitionmetal catalysis, but bifunctional organocatalysis is also being appreciated increasingly. Indeed, various acids and bases have been combined to generate powerful organocatalysts that effectively orient substrates in an enzymelike manner. Remarkably though, the vast majority of these structures are based on natural products, such as proline and the cinchona alkaloids, whilst fully synthetic catalysts are rare. Herein, we report the design and successful implementation of a new Brønsted acid/base motif for the highly enantioselective desymmetrization of meso anhydrides. The alcoholytic catalytic asymmetric desymmetrization of meso anhydrides is a powerful strategy for the preparation of enantiomerically pure hemiesters, which are valuable building blocks for the synthesis of various natural products and biologically active substances. Oda and Aitken pioneered a cinchona-alkaloid-catalyzed approach which furnished moderate enantioselectivities. 8] Bolm et al. developed a variant in which 110 mol% of either quinine or quinidine is utilized. This method generally provides excellent enantioselectivity (up to 99:1 e.r.) and is used frequently both in academic and industrial laboratories. Later, Deng et al. introduced commercially available modified cinchona-alkaloid-derived Sharpless ligands (DHQD)2AQN and its pseudoenantiomer (DHQ)2AQN as catalysts (5–20 mol%), which also give high enantioselectivity. More recently, Song et al. and Connon et al. observed highly enantioselective methanolyses of cyclic anhydrides catalyzed by cinchona-derived amine–thiourea bifunctional organocatalyst (10 mol%) at room temperature. 12] A remarkable breakthrough has been achieved very recently by Song et al.: they developed a robust cinchona-derived sulfonamide-based bifunctional organocatalyst, which shows unprecedented catalytic activity and excellent enantioselectivity in the methanolytic desymmetrization of meso cyclic anhydrides. Despite these important advances in bifunctional organocatalysis, modification of the cinchona alkaloids is limited, and access to both enatiomeric products with the same high enantioselectivity is not always ensured. Because of this and because new motifs for bifunctional organocatalysis are always needed, we became interested in exploring alternative fully synthetic structures. Our design is inspired by BINOLderived phosphoric acids, recently introduced to asymmetric catalysis by Akiyama and Terada. We were curious if it would be possible to incorporate a more basic site into such structures while retaining an acid functional group. We reasoned that this concept may be realized with structure A (Scheme 1), in which the base, which also has a Brønsted acidic site, is incorporated by means of a phosphoramide bond.

Catalytic Asymmetric Torgov Cyclization: A Concise Total Synthesis of (+)-Estrone

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.

Chiral Allenes via Alkynylogous Mukaiyama Aldol Reaction.

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.

Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines

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.

Divergent solid-phase synthesis of natural product-inspired bipartite cyclodepsipeptides : total synthesis of seragamide A

Macrocyclic natural products (NPs) and analogues thereof often show high affinity, selectivity, and metabolic stability, and methods for the synthesis of NP-like macrocycle collections are of major current interest. We report an efficient solid-phase/cyclorelease method for the synthesis of a collection of macrocyclic depsipeptides with bipartite peptide/polyketide structure inspired by the very potent F-actin stabilizing depsipeptides of the jasplakinolide/geodiamolide class. The method includes the assembly of an acyclic precursor chain on a polymeric carrier, terminated by olefins that constitute complementary fragments of the polyketide section and cyclization by means of a relay-ring-closing metathesis (RRCM). The method was validated in the first total synthesis of the actin-stabilizing cyclodepsipeptide seragamide A and the synthesis of a collection of structurally diverse bipartite depsipeptides.

Catalytic Asymmetric Reductive Condensation of N–H Imines: Synthesis of C2‐Symmetric Secondary Amines

A highly diastereoselective and enantioselective Brønsted acid catalyzed reductive condensation of N-H imines was developed. This reaction is catalyzed by a chiral disulfonimide (DSI), uses Hantzsch esters as a hydrogen source, and delivers useful C2 -symmetric secondary amines.

Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates

An acid inaccessible to aldol products The aldol reaction is a venerable and widely applicable method for making carbon-carbon bonds. Ironically, it is most challenged by the simplest substrates. The trouble is that the product looks a lot like one of the reactants, and so it can latch onto the coupling partner instead. Schreyer et al. report that a bulky phosphorus-based acid catalyst alleviates this problem. The acidic site is buried in a pocket that is too small to activate the product for further reaction. The chiral geometry of the catalyst also induces high enantioselectivity. Science, this issue p. 216 A phosphorus-based acid catalyst envelops its substrate to form just one carbon-carbon bond selectively. 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) and tert-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.