In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction. These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature's catalysts, enzymes. In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners. For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles. Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increases the reaction rates and yields, without any detectable influence on the outstanding enantioselectivities inherent to these reactions. To place our results in perspective, many important contributions to this emerging field are highlighted and our own reports are chronicled. PAULL et al.

The catalytic, enantioselective, [4 + 2] cycloaddition reaction of ortho-quinone methides with silyl ketene acetals is described. This mechanistically interesting reaction, initiated by a chiral cinchona alkaloid-derived ammonium fluoride “precatalyst” complex, affords a variety of alkyl- and aryl-substituted 3,4-dihydrocoumarin products in excellent yield and with good enantioselectivity.

An examination into the derivatization of various natural products using newly developed α-fluorination methodology is disclosed. An activated ketene enolate, generated from an acid chloride, is allowed to react with an electrophilic fluorine source (NFSi). Quenching the reaction with a nucleophilic natural product produces biologically relevant α-fluorinated carbonyl derivatives of select chemotherapeutics, antibiotics, and other pharmaceuticals.

In this Communication, we disclose a catalytic, highly enantioselective (up to >99% ee) α-fluorination of acid chlorides to produce a variety of optically active carboxylic acid derivatives from readily accessible and commercially available starting materials. The reaction depends on dually activated ketene enolates generated from two discrete catalysts -a chiral nucleophile and an achiral transition metal complex working in tandem. The active, putative α-fluorobis(sulfonimide) intermediates readily transacylate in situ under mild conditions upon addition of a wide variety of nucleophiles, including complex natural products. As a consequence, the power of this method is witnessed by the broad range of α-fluorinated products that can be accessed efficiently depending on the work up conditions. In many ways, medicinal chemistry has entered the "age of fluorine." The number of drugs and drug candidates that contain fluorine has increased exponentially over the past few years, making its installation in a stereoselective (especially an enantioselective) manner of vital importance to the synthetic chemist. 1 Along these lines, several impressive examples of catalytic, enantioselective fluorination have recently appeared in which β-keto esters, imides, and aldehydes serve as substrates to produce products in high enantioselectivity and yield. 2 However, one very important complementary piece of the puzzle would be an enantioselective α-fluorination of ketene enolates that could produce simple, optically enriched α-fluorinated carboxylic acid derivatives directly. 3 In this communication, we report a catalytic, highly enantioselective α-fluorination of acid chlorides to produce products of broad scope and in excellent yield. This new reaction exploits a recently developed "dual activation" strategy from our labs in which a chiral nucleophile is combined with a transition metal-based Lewis acid cocatalyst to access metal-coordinated, chiral ketene enolates. 4 In this instance, these catalytically generated, dually-activated enolates are efficiently fluorinated with commercially available N-fluorodibenzene-sulfonimide (NFSi) 5 to produce configurationally stable α-fluorinated carboxylic acid derivatives in high enantiomeric excess (ee) (eq 1). The power of this new method is demonstrated in the broad range of different derivatives that can be lectka@jhu.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript synthesized depending on the work up conditions; fluorinated carboxylic acids, amides, esters, and even peptides are all accessible depending on the nucleophile employed to quench the reaction.(1)Our interest in catalytic, enantioselective halogenation extends back over several years. 6 We originally reported an enantioselective chlorination and bromination of acid chlorides using cinchona alkaloid derivatives as catalysts, and polyhalogenated quinones as mild sources of halogen in conjunction with a variety of stoichiometric bases. Unfortunately, we could never adequ...

A catalytic, asymmetric process for the synthesis of 1,4-benzoxazinones from o-benzoquinone imides and ketene enolates is reported. Addition of Lewis acids (Zn(OTf)2, In(OTf)3, and in particular Sc(OTf)3) creates a bifunctional catalytic system that dramatically increases the reaction rate and the yield of these non-natural amino acid precursors while preserving the remarkable enantioselectivity inherent to the reaction. Cocatalyst Sc(OTf)3 increases the yield by up to 42% while producing products in >99% ee.