The First General Enantioselective Catalytic Diels−Alder Reaction with Simple α,β-Unsaturated Ketones

210

Like molecules of life (e.g., proteins and DNA), many pharmaceutical drugs are also asymmetric (chiral); they are not superimposable on their mirror images. One mirror image form (enantiomer) of a drug can have desirable activity, the other not. Consequently, the development of methods for the selective synthesis of one enantiomer is of great scientific and economic importance. We report here that a simple, commercially available chiral alcohol, ␣,␣,␣ ,␣ -tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), catalyzes the all-carbon Diels-Alder reactions of aminosiloxydienes and substituted acroleins to afford the products in good yields and high enantioselectivities (up to 92% enantiomeric excess). It is remarkable that the reactions are promoted by hydrogen bonding, the ubiquitous ''glue'' that helps to keep water molecules together and holds up the 3D structures of proteins. Hydrogen bond catalysis is little used in chemical synthesis, wherein most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. As it does for enzymes, hydrogen bonding not only organizes TADDOL into a well defined conformation, but, functioning as a Brønsted acid catalyst, it also activates the dienophile toward reaction with the diene. The gross structure of the TADDOL has been found to have a profound influence on both the rate and the enantioselectivity of the cycloadditions. These structure-function effects are rationalized by evaluating the conformation adopted by the TADDOLs in the crystal state. It is suggested that , -stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.M ost biomolecules are asymmetric (chiral), that is, they are not superimposable on their mirror image. Likewise, small molecules that might be used to modulate the response of the biomolecule are also frequently chiral. One mirrorimage form (enantiomer) of the small molecule may elicit a desirable response, such as stimulation or inhibition of a particular function, whereas the other image might produce no response or a completely different response. It is, in part, for this reason that a tremendous effort has been put into the development of methods for the selective synthesis of one enantiomer. In 2002, single enantiomer drugs comprised 37% ($152 billion) of the total market of Ϸ$400 billion. This number is projected to increase steadily, such that chiral drugs will constitute a market of Ͼ$200 billion by 2008. The growing economic importance of chiral compounds has spurred major research efforts from many laboratories, academic and industrial, directed at the selective preparation of chiral compounds. In this report, we describe our results on the hydrogenbonding-mediated catalysis of the all-carbon Diels-Alder reaction.The premier process for forming functionalized cyclohexenes, with up to four new stereogenic centers (1), the Diels-Alder reaction plays a pivotal strategic role in the synthesis of numerous complex natural products (2). The steady evolution of this reaction...

Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

Enantioselective Diels–Alder reactions catalyzed by hydrogen bonding

Thadani

Stankovic²,

Rawal³

2004

210

“…Despite the superficial similarities between aldehydes and ketones, these carbonyl families exhibit largely different steric and electronic properties with respect to catalyst interactions. As a consequence, the translation of enantioselective activation modes between these carbonyl subclasses is often difficult (if not unattainable in many cases) (21,22). Herein, we describe the invention of a previously undisclosed family of organocatalysts that enable cyclic ketones to successfully function within the SOMO-activation platform while being chemically robust to oxidative reagents.…”

mentioning

confidence: 99%

Direct and enantioselective α-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis

Mastracchio

Warkentin

Walji

et al. 2010

Self Cite

111

The first enantioselective organocatalytic α-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation. Moreover, three new oxidatively stable imidazolidinone catalysts have been developed that allow cyclic ketones to successfully participate in this transformation. The new catalyst platform has also been exploited in the first catalytic enantioselective α-enolation and α-carbooxidation of ketones.asymmetric synthesis | organocatalysis T he enantioselective catalytic α-alkylation of simple ketones remains a fundamental goal in chemical synthesis (1-4). Seminal work from Doyle and Jacobsen (5), Trost and co-workers (6-8), Stoltz and co-workers (9, 10), Braun and co-workers (11,12), and Hartwig and co-workers (13, 14) has introduced valuable previously undescribed technologies for (i) the enantioselective alkylation of preformed or in situ generated metal enolates (5,6,(11)(12)(13)(14)(15)(16)(17) and (ii) the asymmetric and decarboxylative conversion of allyl keto carbonates to α-allylated ketones (7-10). With these key advances in place, a goal now for asymmetric catalysis has become the direct α-allylation of simple ketone substrates (18,19), an elusive yet potentially powerful bond construction (Scheme 1).Recently, we questioned whether the catalytic principles of singly occupied molecular orbital (SOMO) activation (20) might be translated to ketonic systems, thereby providing an unreported mechanism for direct and enantioselective α-carbonyl alkylation. Despite the superficial similarities between aldehydes and ketones, these carbonyl families exhibit largely different steric and electronic properties with respect to catalyst interactions. As a consequence, the translation of enantioselective activation modes between these carbonyl subclasses is often difficult (if not unattainable in many cases) (21,22). Herein, we describe the invention of a previously undisclosed family of organocatalysts that enable cyclic ketones to successfully function within the SOMO-activation platform while being chemically robust to oxidative reagents. Moreover, we document the introduction of a previously undescribed catalytic α-ketone alkylation reaction that is immediately amenable to asymmetric induction. Enantioselective SOMO CatalysisOver the last decade, the field of enantioselective synthesis has witnessed tremendous progress in the successful implementation of small organic molecules as asymmetric catalysts. In particular, two modes of carbonyl activation by chiral secondary amines have led to the discovery of a large number of previously undescribed reactions (Scheme 2): (i) Iminium catalysis (23), wherein lowest unoccupied molecular orbital (LUMO) lowering a...

“…This catalysis concept was founded on the mechanistic hypothesis that the reversible formation of iminium ions from ␣,␤-unsaturated aldehydes and amines (Scheme 2) might emulate the equilibrium dynamics and -orbital electronics that are inherent to Lewis acid catalysis (Scheme 1). This new catalysis strategy has subsequently been applied to the development of a variety of enantioselective chemical processes, including cycloadditions (46,47,50), Mukaiyama-Michael additions (53), Friedel-Crafts alkylations (48,49,52), heteroconjugate additions, hydrogenations, and cascade reactions.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B

Austin

Kim

Sinz

et al. 2004

Self Cite

442

117

Pyrroloindoline and bispyrroloindoline are a subclass of alkaloid structural motifs that commonly exhibit biological activity. An enantioselective organocatalytic approach to the synthesis of pyrroloindoline architecture is described. The addition-cyclization of tryptamines with ␣,␤-unsaturated aldehydes in the presence of imidazolidinone catalysts 1 and 8 provides pyrroloindoline adducts in high yield and excellent enantioselectivities. This transformation is successful for a wide range of tryptamine and ␣,␤-unsaturated aldehyde substrates. This amine-catalyzed sequence has been extended to the enantioselective construction of furanoindoline frameworks. Application of this pyrroloindoline-forming reaction to natural product synthesis has been accomplished in the context of the enantioselective synthesis of (؊)-flustramine B.