Prochiral malonates

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Scheme 7.19 Maumy s [23] and Brunner s [24] copper-catalyzed EDP with prochiral malonic acids.

A limited number of prochiral malonates and glutarates are hydrolyzed by a-chymotrypsin to the corresponding monoesters with synthetically useful enantiose-lectivities(l-9) (Table 11.1-7). 

Scheme 2.25 Desymmetrization of prochiral malonates by porcine liver esterase and a-chymo-trypsin...

Schema 14 Lipase-catalyzed transesterification of monosubstituted prochiral malonates [116].

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

The antiviral agent virantmycin is an unusual chlorinated tetrahydroquinoline isolated from a strain of Streptomyces (Figure 6.10). Hydrolysis of a prochiral 2,2-disubstituted dimethyl malonate with PLE in DMSO-pH 8 phosphate buffer (1 4) was a key step in a stereodivergent synthesis of this natural product [57]. 

Enantioselective enzymatic ester hydrolyses of prochiral trimethylsilyl-substituted diesters of the malonate type have been applied for the synthesis of the related optically active monoesters68. As an example of this particular type of biotransformation, the enantioselective conversion of the diester 82 is illustrated in Scheme 17. Hydrolysis of compound 82 in phosphate buffer, catalyzed by porcine liver esterase (PLE E.C. 3.1.1.1) or horse liver acetonic powder (HLAP), gave the optically active monoester 83 (absolute configuration not reported) in 86% and 49% yield, respectively. The enantiomeric purities... 

The prochiral triene 16 (Figure 5) is a suitable precursor for the bicyclic core structure 17, and can be obtained in ten steps starting from dimethyl malonate. The intramolecular Diels-Alder cyclization to 17 proceeds with Me2AlCl catalysis in very good yield under mild conditions [12, 18],... 

The first example of absolute chiral recognition of a prochiral centre by a small molecule (cf. enzyme reactions) is the reaction of A( — )436-oc[(2S,9S)-2,9-diamino-4,7-diazadecanecobalt(m)]dichloride with a,a-aminomethylmalonate, which produces A( — )436-P2[(2S,9S)-2,9-diamino-4,7-diazadecanecobalt(in)-(R)-aminomethyl-malonate]+,401 and a crystal structure determination of the product has been performed.402... 

Glycine is the only a amino acid without a chiral centre, but replacing one of the two protons on the central carbon with, say, deuterium creates one the CH2 carbon is prochiral. Similarly, converting malonate derivate into its monoesler makes a chiral centre where there was none the central C is prochiral. ... 

Transition metal (such as Pd, Ir, Mo and W)-catalyzed asymmetric allylic substitutions with various nucleophiles are widely employed in organic synthesis and played an important role in the area of asymmetric C-C bond formation. Trost, Helmchen, Pfaltz and others have focused primarily on the direct allylation of malonates by prochiral electrophiles ... 

Fig. 5. Biosynthetic pathways for (I) 6-methylsalicylic acid and (II) the triacetic acid lactone. The structures of the intermediates have not been identified. The stereochemical course of the prochiral carbons (C-2 and C-4 in the triketide intermediate, C-3 and C-5 in 6-MSA) was investigated using R)- and (S)- [l- C,2- H]malonic acid extender substrate analogs in a coupled assay with 6-MSAS and succinyl-CoA transferase. The distinguishable hydrogens originating from the chiral malonyl CoA are labeled with H and H. Triacetic acid lactone synthesis is catalyzed by 6-MSAS in the absence NADPH...

MSA does not contain any chiral carbon centers. Before the aromatization of the six-membered ring occurs, two prochiral carbons (C-2 and C-4 in the six-carbon intermediate) evolve, each of which loses a hydrogen in the process of the dehydratization/aromatization steps. In addition, C-3 of the six-carbon intermediate forms a chiral center when the ketone is reduced to a hydroxyl by a ketoreductase activity (Fig. 5). The chirality of this hydroxyl carbon is unclear since the intermediate has not been isolated. It is also unknown if this carbon retains its chirality in an eight-carbon intermediate or whether the hydroxyl is eliminated by dehydration prior to the third condensation reaction. The stereospecificity at the prochiral C-2 and C-4 carbons in the reaction intermediates was addressed using chemically synthesized (] )- and (S)-[1- C, 2- H]malonate precursors which were enzymatically converted into CoA derivatives via succinyl CoA transferase [127,128]. Thus, the prochiral methylene in malonyl CoA was replaced by chiral, double-labeled (S)- or (J )-[1- C, 2- H]malonyl CoA substrates in the reaction mixture with 6-MSAS. The condensation is expected to occur with inversion of configuration and the intact methylene... 

The asymmetrization of prochiral disubstituted malonates has been enantioselectively realized in the presence of PLE (eq 2). ... 

There are also recent reports of the lipase-catalyzed enantioselective hydrolysis of prochiral diacid derivatives such as 2-substituted malonates, barbiturates, and highly substituted, sterically hindered 1,4-dihydropyridine derivatives using acy-loxymethyl groups to enhance the reaction rate. An example of a prochiral diester hydrolysis is illustrated in eq 10. ... 

Glusker, J. P., Carrell, H. L., Job, R., and Bruice, T. C. Mechanism for chiral recognition of a prochiral center, and for amino acid complexation to a Co(III) tetramine. The crystal structure, absolute configuration and circular dichro-ism of A(-)436-/ -[ (25 95)-2,9-diamino-4,7-diazadecanecobalt(III)aminomethyl-malonate] perchlorate monohydrate. J. Amer. Chem. Soc. 96, 5741-5751 (1974). 

Scheme 18 illustrates the proposed stages in 6-MSA biosynthesis in which the first and second condensation steps proceed with inversion to give the triketide (63). Ketoreduction gives the alcohol (64) and then elimination followed by a final malonyl condensation generates the tetraketide (65) which cyclises via an intramolecular condensation and enolises to give the aromatic nucleus of (66). In the first set of experiments (J )- and (S)-[l- C, H]nialonales were incubated separately with 6-MSA synthase purified from Penicillium patulum [56]. Isotope incorporations were determined by mass spectrometry. All the possible isotope patterns for retention or loss of the pro-J or pro-S hydrogens from C-3 and C-5 were permutated. Comparison with the actual spectra obtained demonstrated that opposite prochiral hydrogens were eliminated. The absolute stereochemistry was established in an analogous experiment [57] where the chiral malonates were incubated with acetoacetyl CoA rather than acetyl CoA. Subsequent mass spectral analysis showed that it is the Hr proton that is retained at C-3 of 6-MSA and so it can be deduced that the hydrogen at C-5 must be derived from the opposite prochiral hydrogen, Hg. The overall result is summarised in Scheme 18. In a recent collaborative study we have synthesised the triketide alcohol (64) as its NAC thioester and shown that it is indeed a precursor as, on incubation with 6-MSA synthase and malonyl CoA, 6-MSA production is observed [unpublished results]. Current work is aimed at synthesis of both enantiomers of (64) to study the overall stereochemistry of the ketoreduction and elimination reactions.

A similar stereochemical outcome to that observed for 6-MSA was found using orsellinate synthase isolated from Penicillium cyclopium [58]. The hydrogens retained at C-3 and C-5 of orsellinic acid (66, R=OH) are from opposite prochiral sites in malonate. This contrasts with a previous study [59] on... 

A limited number of acyclic and cyclic prochiral dicarboxylic acid diesters were found to be good substrates for hydrolysis catalyzed by lipases (Table 11.1-12). Notable examples which give a good illustration of the potential of hydrolases as well as of the trial and error approach one relies on to a certain extent are the dithio acetal derivative 9 and the fluoro alkyl malonates 1-8. The dithio monoester 9 is obtained with different lipases with high enantioselectivities and yields despite its remote chiral center. Candida cylindracea lipase is the enzyme of choice for the synthesis of fluoro alkyl malonates with small alkyl groups. An astonishing observation was... 

Facial selectivity induced by a stereogenic carbon atom in a-position to the radical center has been probed with acyclic and cyclic radicals [103], In the first cases, 2-substituted malonates 65-68 served as precursors for the prochiral radicals these were coupled in moderate yields with coradicals formed from acetic acid and the acids 34 and 35 (Eq. 9). 

The push toward enantiomerically-pure carbocyclic intermediates has led to the development of new methods for the enantiodifferentiation of inexpensive prochiral cyclic starting materials. For instance, Robert H. Morris of the University of Toronto recently reported (Organic Lett. 2005, 7, 1757) that a family of enantiomerically-pure Ru complexes originally developed for asymmetric transfer hydrogenation also mediate the enantioselective addition of malonate to cyclohexenone. 

Differentiation of the prochiral cyclopentadienyl system in 310 by intramolecular AHR generates 7r-allylpalladium 312, which was trapped intermolecularly with the malonate 311 in regio- and stereoselective maimer to provide the bicyclic system 313 with 87 % ee in the presence of NaBr in DMSO. The regio- and stereoselective anion capture can be understood by considering the steric effect as shown by 312. The total synthesis of c nellene 314 has been achieved from 313 [128],... 

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