Anhydrides, enantioselective desymmetrization

Enantioselective desymmetrization of meso-succinic anhydrides with diphenylzinc is catalyzed by Pd(OAc)2/chiral diphosphine 209 (Equation (113)).470... 

A-Boc-leucinal may react with allyl- and alkenyhnagnesium hahdes giving syn- and awf/-products in ca 9 1 ratio. This method was used for the asymmetric synthesis of important amino acids like statine and norstatine. An enantioselective desymmetrization of anhydrides was reported. Arylmagnesium chlorides react in toluene in the presence of (—)-sparteine (1 equiv.) with 3-substituted glutaric anhydrides 215, giving aryl ketones with 87-92% ee (equation 145). ... 

Scheme 8. Catalytic enantioselective desymmetrizations of anhydrides using cinchona alkaloid catalysts...

In a further demonstration of the broad scope of nickel(0) oxidative additions to C-0 bonds, cyclic anhydrides were illustrated to be versatile substrates in crosscoupling processes. For example, enantioselective desymmetrizations with diethylzinc and cyclic anhydrides provide efficient access to functionalized 1,4-dicarbonyl products. The enantioselectivity-detemuning step in this process is the oxidative addition of nickel(O) to anhydride C-0 bond. Several other functionalization processes derived fi-om oxidative addition of nickel(O) to anhydrides were previously described. ... 

Seebach and coworker have reported the enantioselective desymmetrization of meso esters, anhydrides and sulfonylimides using TADDOL-Ti reagents [334]. In the desymmetrization of anhydrides, a catalytic amount of the chiral TADDOL-Ti... 

Asymmetric synthesis of unnatural j8-amino acids derivatives based on azide chemistry is known. Enantioselective desymmetrization of mera-anhydride 293 mediated by cinchona alkaloids gives optically active monomethylester 294. This compound was converted into the acyl azide, which underwent Curtius degradation followed by alcoholysis of the intermediate isocyanate affording 8-amino acid derivative 295 in high enantiomeric excess. The authors observed that Grubbs catalyst was able to polymerize norbomene-type monomer 295 affording the corresponding polymer 296 in quantitative yield (Scheme 3.45). 

Initial studies indicated that this ruthenium complex is an effective chiral catalyst for enantioselective metathesis. For example, desymmetrization of the anhydride 68 (Scheme 43) in the presence of 10 mol % of 65 and 10... 

More recently, we have discovered that Pd-JOSIPHOS complexes effectively desymmetrize a variety of succinic anhydrides in excellent yield and enantio-selectivity [Eq. (10.54)]. The reaction proceeds at ambient temperature in some cases and can deliver aryl and alkylzinc reagents with equal facility. For reasons that are unclear, the latter protocol requires a styrenic additive for high enantioselectivity ... 

A very efficient and practical process for desymmetrization of meso-anhydrides was reported by Bolm et al. in 1999 and in subsequent publications (Scheme 13.3) [9, 10]. In their approach, which is a further development and improvement in the use of alkaloids as catalysts, (—)-quinine (2) or (+)-quinidine (3) in this case, low reaction temperature and solvent optimization proved crucial to achieving optimum enantioselectivity. Under their conditions methanolysis of several meso anhydrides (8a-g, 9a-g, Scheme 13.3) can be achieved in good yields and with excellent enantiomeric excesses in the presence of equimolar amounts of the inexpensive and readily available alkaloids 2 and 3 [9, 10]. 

The field of organocatalytic enantioselective anhydride transformations has seen tremendous progress during recent years. For example, the alcoholytic desymmetrization of meso anhydrides, effected by stoichiometric quantities of inexpensive and readily available cinchona alkaloids, has been developed to a very practical level, and several applications, e.g. for the synthesis of enantiomerically pure... 

Quite recently, we also observed that quinine-based thiourea derivatives showed dramatic concentration and temperature effects on the enantioselectivity in the alcoholytic desymmetrization ofmeso-cyclic anhydrides, which can also be attributed to the self-association of the catalyst [23]. Of course, the possibility that the variation in... 

Shortly thereafter, Aiken and coworkers also reported that quinine (4) could be used as a catalyst (50mol%) to promote the methanolytic desymmetrization of the meso-epoxy anhydride 8a to give the lactone 9a in 57% yield and 76% ee (Scheme 11.6) [4]. Lowering the reaction temperature to 0 or —30 °C did not result in any increase in selectivity. meso-Aziridine anhydride 8b was also tested under similar reaction conditions, but a lower enantioselectivity (40% ee) was obtained (Scheme 11.6). 

However, highly interestingly, unusual concentration and temperature effects on the enantioselectivity were observed by Song and coworkers [11a]. As shown in Figure 11.2, the enantioselectivity in the methanolytic desymmetrization reaction of the meso-cyclic anhydride IS increases with increasing dilution of the reaction mixture and on raising the reaction temperature from —20 to 20 °C. 

Kinetic resolutions. Baylis-Hillman adducts are deracemized by exploiting their reactivity toward Pd(0)-catalyzed substitution, using chiral ligand 2. Both the planar chiral DMAP derivative 3 and the axially chiral analogue (4) ° and 5" have been developed as catalysts for enantioselective acylation. Benzylic alcohols undergo enantioselective acylation with the aid of 6. Methanolysis of meio-anhydrides in the presence of a cinchona alkaloids is a good way to desymmetrize such compounds. ... 

Nishiyama and co-workers reported that iPr-PYBOX-Rh(III) catalyst promotes the highly enantioselective hydrosilylation of ketones (234). Asymmetric desymmetrization reactions of glutaric anhydride derivative were carried out by using Rh(I)-PHOX complexes (235). 

The desymmetrization of prochiral cyclic anhydrides promoted by cinchona alkaloid derivatives is archetypal of this reaction class. First investigated by the groups of Oda and Aitken using cinchonine and quinine respectively, Bolm subsequently showed that cinchona alkaloids could desymmetrize prochiral anhydrides with exquisite enantioselectivities, with the pseudoenantiomeric... 

The diol 4 had never been described in the literature before we used it in the synthesis of 1. Initially, we tried to synthesize it using an enantioselective Diels-Alder reaction between a chiral fumarate equivalent 5 (Scheme 10.1) and butadiene 6, followed by double-bond dihydroxylation [41]. However, a more effective protocol for large-scale synthesis could finally be based on the procedure shown in Scheme 10.2, leading to enantiomericaUy pure (lS,2S)-cyclohex-4-ene-1,2-dicarboxylic acid 7 [42]. Here, a Bolm desymmetrization of tetrahydrophthahc anhydride 8 using quinine leads to monoester 9 in 89% ee. The monoester 9, in turn, can be epimerized to the trans isomer 10 which is hydrolyzed to obtain 7, after crystallization. This intermediate is the starting material for the synthesis of 4 and of other conformationally constrained DCCHD to be used as monosaccharide mimics [43, 44]. Our current best protocol for the large-scale synthesis of 7 is reported at the end of this chapter. 

Chen and coworkers have developed a bifunctional quinine-derived squaramide-promoted enantioselective alcoholysis of meso-succinic anhydride 36 [116]. Whereas modest enantioselectivity can be obtained in the presence of a catalytic amount of squaramide 22, high enantioselectivity was realized when more than 1 equivalent of squaramide was utQized (Scheme 10.36). The utility of the squaramide-catalyzed desymmetrization was nicely illustrated by carrying out an efficient synthesis of (-f)-biotin from the enantioenriched hemiester 37, which, in turn, was obtained by desymmetrization of 36. 

Y. Chen, S. Tian, L. Deng, A highly enantioselective catalytic desymmetrization of cyclic anhydrides with modified cinchona alkaloids, J. Am. Chem. Soc. 122 (39) (2000) 9542-9543. 

Later, Bolm and coworkers reported excellent enantioselectivities (85-99%) for the desymmetrization of me o-anhydrides by an optimized reaction protocol... 

In 2007, Furukawa et al. described large-scale applications of the alkaloid derived catalysts 75 (Fig. 7.7) for the kinetic resolution of urethane-protected a-amino acid A -carboxyanhydrides and the desymmetrization of cyclic me. o-anhydrides [81]. The 0-propargylquinidine (OPQD) 75b and quinine (OPQ) catalyst 75a were described as highly enantioselective (70-97%) and practical, e.g. in the synthesis of (5)-iV-Boc-propargylglycine, a key intermediate for a commercial P-amino acid (BAY 10-8888/PFD-118). 

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