Asymmetric fumarates

The utility of the asymmetric fumarate/butadiene addition in synthesis is highlighted by the conversion of the (f ./ )-cyclohexene (313a) (derived from (+)-( 5)-menthol) to enantiomerically pure (-)-bilobalide (317) (Scheme 78). This conversion involves particularly the annulation of a cyclopentenone ring to (313a) at the acylated centers which govern the topicity of the acylation (313a) - (314) and internal Michael reaction (314) (315). Ozonolysis of the cyclohexene moiety sets the stage for the formation... 

Optically inactive starting materials can give optically active products only if they are treated with an optically active reagent or if the reaction is catalyzed by an optically active substance The best examples are found m biochemical processes Most bio chemical reactions are catalyzed by enzymes Enzymes are chiral and enantiomerically homogeneous they provide an asymmetric environment m which chemical reaction can take place Ordinarily enzyme catalyzed reactions occur with such a high level of stereo selectivity that one enantiomer of a substance is formed exclusively even when the sub strate is achiral The enzyme fumarase for example catalyzes hydration of the double bond of fumaric acid to malic acid m apples and other fruits Only the S enantiomer of malic acid is formed m this reaction... 

Charlton121 has recently reported the asymmetric induction in the reaction of dimethyl fumarate and l,3-dihydrobenzo[c]thiophene 2,2-dioxide (198) containing a chiral a-alkoxy group at the 2-position (equation 128). A diastereomeric excess of 2.8 1 of 199 to 200 is achieved by using 198 derived from optically active a-methylbenzyl alcohol. 

Subsequently, stoichiometric asymmetric aminohydroxylation was reported.78 Recently, it was found by Sharpless79 that through the combination of chloramine-T/Os04 catalyst with phthalazine ligands used in the asymmetric dihydroxylation reaction, catalytic asymmetric aminohydroxylation of olefins was realized in aqueous acetonitrile or tert-butanol (Scheme 3.3). The use of aqueous rerr-butanol is advantageous when the reaction product is not soluble. In this case, essentially pure products can be isolated by a simple filtration and the toluenesulfonamide byproduct remains in the mother liquor. A variety of olefins can be aminohydroxylated in this way (Table 3.1). The reaction is not only performed in aqueous medium but it is also not sensitive to oxygen. Electron-deficient olefins such as fumarate reacted similarly with high ee values. 

An important competing process with significant practical consequences is the catalytic dimerization of diazoacetate to form maleate and fumarate esters. Most catalysts suffer from this side reaction, leading to the use of the alkene as solvent in order to accelerate the productive pathway and the slow addition of diazo compound in order to minimize dimerization. Since this problem is generally shared across most catalyst architectures, it will be mentioned in discussions of individual asymmetric catalyst systems only in those instances where these precautions prove to be unnecessary. 

When the reaction is conducted in the presence of added fumarate, the yield of pyrrolidine (130) increases at the expense of the aziridine. Jacobsen suggests that the aziridines and pyrrolidines arise from a common intermediate, azo-methine ylide (132), Scheme 6, which may also be partly responsible for the poor levels of asymmetric induction in this reaction. Electrocyclic ring closure of the azo-methine while still within the coordination sphere of the metal (131) may provide aziridine with some induction, while decomplexation (132) will lead to the formation of racemic aziridine and pyrrolidine. 

Fumaric and maleic compounds are also suitable substrates in the rhodium-catalyzed asymmetric 1,4-addition reactions. While phosphorus-based chiral ligands, such as (/f)-binap, provide low enantioselectivity for these substrates (<51% ee), chiral diene ligands 38 and 45 are particularly effective for achieving high ee (Figures 3.39 and 3.40). 

Figure 3.39. Scope of Rh/chiral diene-catalyzed asymmetric 1,4-addition of arylboronic acids to di-rert-butyl fumarate.

A special case of asymmetric enantiomer-differentiating polymerization is the isoselective copolymerization of optically active 3-methyl-1-pentene with racemic 3,7-dimethyl-1-octene by TiCl4 and diisobutylzinc [Ciardelli et al., 1969]. The copolymer is optically active with respect to both comonomer units as the incorporated optically active 3-methyl-l-pentene directs the preferential entry of only one enantiomer of the racemic monomer. The directing effect of a chiral center in one monomer unit on the second monomer, referred to as asymmetric induction, is also observed in radical and ionic copolymerizations. The radical copolymerization of optically active a-methylbenzyl methacrylate with maleic anhydride yields a copolymer that is optically active even after hydrolytic cleavage of the optically active a-methylbenzyl group from the polymer [Kurokawa and Minoura, 1979]. Similar results were obtained in the copolymerizations of mono- and di-/-menthyl fumarate and (—)-3-(P-styryloxy)menthane with styrene [Kurokawa et al., 1982],... 

By far, the best asymmetric synthesis is done in nature by enzymes7). These have also found industrial application8, e.g. the stereospecific amination of fumaric acid (10) to (S)-aspartic acid (11) ... 

Asymmetric ethylidene transfer has been achieved in the reactions of 1-cyclohexenyl ethers carrying a chiral auxiliary with 1,1-diodoethane/diethylzinc 39. Asymmetric induction in the reaction of diazofluorene with fumaric esters bearing chiral alcohol moieties has been investigated (equation 84)140,141. Kinetics of intramolecular cyclopropanation in... 

Chiral Ti complex, derived from hydrobenzoin dilithium salt and TiCl4, can be used for the asymmetric Diels-Alder reaction of several dienes with fumarate [53] (Eq. 8A.30). However, attempted use of acrylate as dienophile resulted in low enantioselectivity. 

Photochemical (4 + 2) cycloaddition of anthracene and dimethyl fumarate or maleate have been reported by Kaupp [301], The reaction requires a high concentration of dimethyl fumarate or maleate owing to the short lifetime of the excited singlet state of anthracene and its facile dimerization. However, irradiation of a benzene solution of (9-anthryl)methyl methyl fumarate or maleate resulted in the intramolecular (4 + 2) photocycloaddition efficiently [302], Asymmetric induction in this intramolecular photocycloaddition of 291b-c was also investigated (Scheme 83). 

Scheme 27 Asymmetric IRDARs of furfuryl fumarates 91 under thermal and high-pressure conditions [65]...

Asymmetric IRDARs of optically active furfuryl fumarates 91 were investigated under thermal and high-pressure conditions. The diastereoselectivities observed increased with the size of the tether substituents, achieving up to 86% in the case of R = f-Bu, though in the case of R = neo-Pen only 38% de was obtained. It is concluded the diastereoselectivity observed was thermodynamically controlled (Scheme 27) [65]. An IRDA ring-expansion approach toward taxinine (a carbocylic compound) [66] utilizing both Lewis acids and high pressure has been reported [67]. 

Asymmetric Diels-Alder reactions.1 Both the acrylate and the fumarate of aethyl (R)-mandelate undergo cycloaddition with a-hydroxy-o-quinonedimethane to five l-hydroxy-l,2,3,4-tetrahydronaphthalenes in >95% de. 

The thermal asymmetric hDA (AHDA) reaction between 2,4-diaryl-l-thiabuta-l,3-dienes and di-(—)-menthyl fumarate proceeds in excellent yield to afford a mixture of four diastereomers with only moderate Jt-facial diastereo-selectivity (Equation 126). The reaction is accelerated by Lewis acids without influencing the endo selectivity, although overall yields are lower. Chromatographic separation of the cis and trans adducts followed by recrystallization enabled the diastereomers to be obtained in a stereochemically pure state. Removal of the chiral auxiliary by reaction with LiAlH4 from both cis adducts gave the enantiomers of various 2,3-bis(hydroxymethyl)-3,4-dihydro-277-thiopyr-ans and desulfurization provides a route to optically pure diols < 1996J(P1) 1897 >. 

The use of a chiral fumarate ester allows for asymmetric induction irrespective to the approach of the dienophile to the diene. In particular, dimenthyl fumarate (6) has been advocated for large scale because of its ready availability, low cost, excellent yields, and high asymmetric induction.35128129 203-208 Although other more exotic chiral auxiliaries may be used,32 the use of 5 coupled with a homogeneous Lewis acid catalyst at low temperatures allows for remarkably high diastereo-selectivity with a number of dienes (Scheme 26.5).125 164-209... 

Aminoquinazolinone derivatives were oxidized with the optically active oxidant lead tetra-(S)-2-methylbutanoate in the presence of excess styrene, E)-, 2-diphenylethylene and dimethyl fumarate. The aziridine was obtained with asymmetric induction only from ( )- 1,2-diphenyl-ethylene, but the enantiomeric excess was not reported31. 

Control of absolute asymmetry is a relatively untouched area for [2 + 2] photochemical cycloaddition reactions despite the recent advances in the field of asymmetric synthesis. The first example of the use of a removable chiral auxiliary was reported by Tolbert, who obtained impressive enantioselectivity in the photocycloaddition of bomyl fumarate to stilbenes (equation 37). More recently, Lange has shown that menthyl cyclohexenonecarboxylates are useful in control of absolute stereochemistry (equation 38). Baldwin and Meyers have also obtained excellent facial selectivity in systems where the stereogenic center which controls the diastereoselectivity can be excised to afford products of high enantiomeric purity (equations 39,40). 

Although (maleic acid)Fe(C0)4 has a symmetry plane perpendicular to the plane of the double bond, (fumaric acid)Fe(C0)4 is clearly asymmetric and should thus be capable of resolution into its enantiomers (457). Accordingly, addition of the complex to a solution of brucine in acetone and crystallization of the diastereoisomeric salts followed by decomposition with hydrochloric acid yielded the two enantiomers having optical activities [a]ff —593 (acetone C, 0.848) and [a] f - -587 (acetone C, 0.921). Analyses and infrared spectra of individual enantiomers were identical to those of the racemic mixture. 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

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