Strategies for Enantioselective Synthesis

Tetsuaki Tanaka of Osaka University has reported (Tetrahedron Lett. 45 75, 2004) what appears to be a general route to alkylated quaternary centers, based on the Ti-mediated addition of allylmagnesium chloride to the Sharpless-derived epoxy ether 4. Remarkably, the conversion of 6 to 7 works equally well. 

Enantiomerically-pure sulfoxides are readily available. Ilan Marek of Technion-Israel Institute of Technology reports (J. Am. Chem. Soc. 125 11776, 2003) that alkyne-derived sulfoxides such as 8 can be used to direct the addition of an allylic organometallic, prepared in situ, to an aldehyde 9. Both the secondary alcohol, from the aldehyde, and the adjacent quaternary center of 10 are formed with 99% stereocontrol. 

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In summary, the C-H insertion chemistry of rhodium carbenoids is a very powerful method for transformation of C-H bonds. Highly regioselective and stereoselective reactions are possible and several classes of chiral catalyst are capable of very high asymmetric induction. The chemoselectivity in this chemistry is exceptional, as illustrated by the numerous intermolecular and intramolecular reactions described in this overview. Most notably, this chemistry offers new and practical strategies for enantioselective synthesis of a variety of natural products and pharmaceutical agents. 

Organotransition metal reagents have been used in both catalytic and stoichiometric dearomatization reaction sequences and provide mechanistically distinct pathways to alicyclic products. Additionally, metal-catalyzed asymmetric dearomatization is an attractive strategy for enantioselective synthesis [75],... 

Despite the structural relationship between ginkgolide B and bilobalide, retrosynthetic analysis of the latter produced a totally different collection of sequences. A successful synthesis of bilobalide was implemented using a plan which depended on stereochemical and FG-based strategies. A process for enantioselective synthesis was based on an initial enantioselective Diels-Alder step in combination with a novel annulation method. 

Unfortunately, the highest enantioselectivity so far obtained for the synthesis of styrene oxide by this route is only 57 % ee with Goodman s sulfide 30 [21]. Thus methylidene transfer is not yet an effective strategy for the synthesis of terminal epoxides. 

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

Two strategies for the synthesis of enantiomerically enriched diaryl methanols 27 are apparent first, asymmetric reductions of the corresponding diaryl ketones 36 [33], and, second, enantioselective aryl transfer reactions to the respective benzaldehyde derivatives 37 (Scheme 2.1.2.5) [34, 35]. 

Asymmetric epoxidation of prochiral olefins is a powerful strategy for the synthesis of enantiomericaUy enriched epoxidesJ Previously, we reported a fructose-derived catalyst (1) that gives high ee for a wide variety of trans- and trisubstituted olefins (Figure 6.5). " Recently, we discovered a new catalyst (2) derived from D-glucose that can epoxidize many c -olefins with high enantioselectivity and no c w/rran -isomerization. ... 

Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

The catalytic asymmetric epoxidation of alkenes offers a powerful strategy for the synthesis of enantiomerically enriched epoxides and enantioselective oxidation reactions in ionic liquids have been summarised previously.[39] Complexes based on chiral salen ligands - usually with manganese(III) as the coordinated metal - often afford excellent yields and enantioselectivities and the catalytic cycle for the reaction is depicted in Scheme 5.5 J40 ... 

A less common strategy for asymmetric synthesis, but one with considerable merit, is the enantioselective opening of meso epoxides (Fig. la) by achiral nucleophiles in the presence of a chiral catalyst. [5] Similarly, the kinetic resolution of racemic epoxides (Fig. lb), in the best cases, can deliver high enantiomeric excesses in the unreacted epoxide and ring-opened product. 

The hydrogenation of C=N double bonds is an important synthetic strategy for the synthesis of secondary amines. Chiral iridium catalysts allow the hydrogenation of prochiral imines to be carried out with high enantioselectivity in conventional liquid solvents. Such a process has already found industrial application in the preparation of (S)-metolaclor, a herbicide produced by Novartis in Switzerland [40]. Recent research at the Max Planck Institute for Coal Research has demonstrated that reactions of this type can be carried out in SCCO2 with the same level of enantioselectivity and with enhanced catalyst efficiency [12]. 

Viswanathan R, Prabhakaran EN, Plotkin MA, Johnston JN (2003) Free radical-mediated aryl amination and its use in a convergent 3-1-2 strategy for enantioselective indoline alpha-amino acid synthesis. J Am Chem Soc 125 163-168... 

The asymmetric a-hydroxylation of p-keto esters and p-keto amides is a useful strategy for the synthesis of a-hydroxy p-dicarbonyl compounds. Using TBHP 102 as the oxidant, the tV,A7 -dioxide magnesium catalyst was efficient for the enantioselective a-hydrojylation of p-keto esters 101 and p-keto amides, leading to a-hydro grdicarbonyl compounds 103 in high yields and with excellent enantioselectivities. Importantly, this reaction could be scaled up to gram scale (Scheme 3.31). ... 

S. (1999) Palladium in action domino coupling and atlylic substitution reactions for the efficient construction of complex organic molecules. J. Organomet. Chem., 576, 88-110 (d) Chapman, C.J. andProst, C.G. (2007) Tandem and domino catal3dic strategies for enantioselective S3mthesis. Synthesis, 1-21. 

Alternatively, enantioselective nucleophilic addition to imines followed by intramolecular trapping of the transient amino intermediate with creation of a new C-N bond constitutes a powerful strategy for the synthesis of various heterocycles of synthetic and biologic interest. In this field, the formation of six-membered rings largely leads the way, and one of the first examples was reported in 2(X)3 by Ohsawa s group [4a] for the direct synthesis of the 3-carboline core via a Mannich/aza-Michael cascade promoted by (5)-proline and subsequentiy applied to the total synthesis of e t-dihydrocorynantheol (Scheme 16.3) [4b]. 

The recent explosion in the development of asymmetric strategies for organic synthesis has fostered investigations into the discovery of methods for enantioselective and diastereoselective Diels-Alder reactions. Some early forays into this field focused on the use of chiral auxiliaries covalently attached to one of the reaction partners however, nearly all recent investigations have centered on developing chiral catalysts. The multitude of new catalysts spans the range of Lewis acids and Bronsted acids and bases as well as metal-based and organic molecules. 

Coates, G W. Waymouth, R. M. Enantioselective cyclopolymerization of 1,5-hexadiene catalyzed by chiral zirconocenes a novel strategy for the synthesis of optically active polymers with chirality in the main chain. J. Am. Chem. Soc. 1993,115, 91-98. 

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