Chiral acyl acceptors

Scheme 3 A Lipase-catalyzed resolution of a chiral acyl acceptor. B The scheme shows the competition tetween two enantiomeric alcohols (HOR and HOS) and water for the acyl enzyme (RiCOO-Enz). The nucleophile (HOR2) released from the acyl donor is supposed to tautomerize, evaporate, or otherwise leave the system. The substrates competing for the enzyme (HO-Enz) are the acyl donor (R1COOR2), the products formed during the catalysis (R,COOR and R,COOS), and any formed acid (RjCOOH). The enantiomeric alcohol moieties R and S are shown in boldface.

Numerous examples exist on the kinetic resolution of chiral acyl acceptors. Among other compounds primary and secondary alcohols, various amines, and peroxides have been resolved. Representative examples are shown in Scheme 7. The secondary alcohol 2-octanol was resolved using S-ethyl octanethioate as acyl donor and C. antarctica lipase B [12]. The alkyl peroxide was acylated with isopropenyl acetate using P. cepacia lipase [87]. The primary amine was resolved by C. antarctica lipase B-catalyzed acylation of ethyl octanoate at reduced pressure [88]. The primary alcohol was successfully resolved by acylation of vinyl acetate at — 40 C [89]. 

ScheniB 7 Examples of lipase-catalyzed kinetic resolution by deacylation of an acyl enzyme (RiCOO-Enz). The chiral acyl acceptors are a secondary alcohol [12], a j roxide [87], a primary amine [88], and a primary alcohol [89]. The fast-reacting enantiomers are shown. 

Annelations via Friedel-Crafts acylation were applied to racemic syntheses of [njhelicenes with n up to 6. The 12-step synthesis of [6]helicene (1) by Newman and Lednicer employed stepwise diannelation, followed by oxidative aromatiza-tion and then resolution with the complex of a chiral n-acceptor, a-2,4,5,7-tetrani-tro-9-fhiorohdeneaminooxypropionic acid (TAPA) and 1 [25]. The one-step diannelation was ubiquitously applied to syntheses of triarylamine [4]helicenes,... 

The chiral acyl oxazolidinones developed by Evans have been demonstrated to function successfully in conjugate addition reactions of titanium enolates to acceptor olefins [99]. A noteworthy example is the addition of 96 to acrylonitrile (Equation 16). Interestingly, although the starting substrate 96 includes both ester and imide groups bearing acidic a-protons, the deprotonation selectively gives the imide-derived enolate. Adduct 98... 

Chiral acyl oxazolidinones also proved effective as auxiliaries on the acceptor component in asymmetric conjugate additions (Equation 17) [100]. Hruby reported a Cu-catalyzed 1,4-addition to phenyl-substituted acceptor 99 that proceeds with high diastereofacial selectivity to furnish 101 in 98 2 dr and 91 % yield. In these studies, low diastereomeric ratios were observed for the corresponding benzyl-substituted oxazolidinones. 

Unsaturated acyl derivatives of oxazolidinones can be used as acceptors, and these reactions are enantioselective in the presence of chiral to-oxazoline catalysts.321 Silyl ketene acetals of thiol esters are good reactants and the stereochemistry depends on the ketene acetal configuration. The Z-isomer gives higher diastereoselectivity than the Zf-isomer. 

Friestad and co-workers recently demonstrated that N-acyl hydrazones were excellent radical acceptors in the presence of a chiral Lewis acid [84], Valerolactam-derived hydrazone 117 proved to be the optimal substrate for enantioselective radical additions. Upon further optimization it was found that Cu(OTf )i and f-bulyl bisoxazoline ligand 96 gave the best yields and ee s (Scheme 31). Interestingly, a mixed solvent system (benzene dichloromethane in a 2 1 ratio, respectively) in the presence of molecular sieves (4 A) were necessary to achieve high yields and selectivities. 

The same group subsequently discovered that the loading of the chiral diamine catalyst can be reduced substantially if triethylamine is added in stoichiometric amounts as an achiral proton acceptor [37b]. As shown at the top of Scheme 13.23, as little as 0.5 mol% catalyst 45 was sufficient to achieve yields and ee comparable with the stoichiometric variant (application of the Oriyama catalysts 44 and 45 in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). Oriyama et al. have also reported that 1,3-diols can efficiently be desymme-trized by use of catalysts 44 or 45. For best performance n-butyronitrile was used as solvent and 4-tert-butylbenzoyl chloride as acylating agent (Scheme 13.23, bottom) [38]. 

Few examples exist in the literature concerning the stereoselective addition of acyl radicals to a radical acceptor in an acyclic manner. Equation (13.1) shows the efficient 1,2-asymmetric induction in the addition of aliphatic or aromatic acyl radicals to chiral acyclic alkenes 1 [7]. The corresponding a-hydroxy ketones 3 were produced with high syn selectivity (Table 13-1). This acyl radical addition is very exothermic, and it is hypothesized that Hammond s postulate can be invoked to predict a transition state that is very close in energy to the starting alkene 1. The X-ray structure of 1 was then used to rationalize the stereochemical outcome of this radical addition by determination of the least sterically hindered path for the approaching radical. 

In 2008, the Scheldt group reported a direct electrophilic amination via homoenolates catalyzed by N-heterocyclic carbenes using l-acyl-2-aryldiazenes as the electrophilic acceptors, which further increased the versatility of the homoenolate chemistry. It is worthwhile to note that only electron-rich substituents on the aryl component of the diazene could result in product formation (up to 84% yield), while electron-poor aryl substituents gave a lowyield (25%). An example of an asymmetric version of this new ami-nation reaction was achieved with the utilization of the chiral triazolium salt developed in their own group, providing the pyrazolidinone product in good yield (61%) and excellent enantioselectivity (90% ee) (Scheme 7.51). 

In 2013, the Chi group realized an NHC-catalyzed asymmetric p-functional-ization reaction of aldehydes via the transformation of saturated aldehydes to formal Michael acceptors via double oxidation. By using the catalyst derived from the chiral amino indanol triazolium salt in combination with quinone as the oxidant, the p-aryl substituted saturated aldehydes were converted to the o,p-unsaturated acyl azolium intermediates which further reacted with 1,3-dicarbonyl compounds or p-keto esters to generate the corresponding 5-lactones. It was found the use of LiCl and 4 A MS as additives was beneficial to improve the ee s of the products. Notably, the p-alkyl substituted saturated aldehydes were not viable substrates, probably due to the reduced acidity of the p-C—H bonds (Scheme 7.118). 

The Friedel-Crafts alkylation is one of the oldest synthetic methodologies known. The catalytic asymmetric version of the reaction [311] enables the preparation of important chiral building blocks. Electron-rich aromatic and heteroaromatic compounds have been productively used in organocatalyzed enantioselective inter- and intramolecular Friedel-Craft-[312] type conjugate additions over different Michael acceptors such as, a,p-unsaturated aldehydes, a,P-unsaturated ketones, nitroole-fins, and a,p-unsaturated acyl phosphonates. 

Jprgensen s group has very recaitly d onstrated the usefulness of o,P-unsaturated acyl phosphonates as hydrogen-bond acceptors in the enantioselective Hiedel-Crafts reaction with indoles [341]. Since the acyl phosphonate moiety is a powerful ester and amide surrogate, this reaction is an interesting approach towards the synthesis of optically active p-(3-indolyl)esters and amides as represented in Scheme 2.119 for selected examples. The reaction is catalyzed by chiral thiourea-based catalyst ent-191 that activates the nucleophile and the electrophile through hydrogen-bond interactions. 

---