Chiral malonates

The chiral center would be installed from either Unear carbamate 15 or branched carbamate 16 via the asymmetric addition of malonate anion to the 7i-allyl Mo complex reported by Trost et al. [11] to afford the branched chiral malonate derivative 17. Decarboxylation of 17 should provide the mono-carboxylic acid 18. Masa-mune homologation with 18 affords our common precursor 14. Linear carbamate 15 was obtained from the corresponding cinnamic acid, and branched 16 was prepared in one pot from the corresponding aldehyde. 

A similar dealkoxycarbonylation reaction utilizing the Krapcho conditions was used by Moberg and coworkers in the synthesis of (R)-badofen (Scheme 6.161b) from a chiral malonate precursor (see Scheme 6.52) [108],... 

Dioxo-l,3-dioxanes ring-open under basic conditions. Cleavage of the 5,5-disubstituted derivatives in the presence of quininium or quinidinium alkoxides produces chiral malonic hemi-esters (ee 30-40%) in high yield [11]. The addition of cetyltrimethylammonium bromide promotes the base-catalysed cleavage of p-keto esters to form ketones under sonication [12]. 

Systematic investigations of twofold additions of malonates to C70 revealed that the second addition takes place at one of the five a-bonds of the unfunctionalized pole [17, 26], With achiral, C2v-symmerical malonate addends, three constitutionally isomeric bisadducts are formed An achiral one (C2v-symmetrical 1), and two chiral ones (C2-symmetrical 2 and 3), which are obtained as pairs of enantiomers with an inherently chiral addition pattern (Figure 13.5). Twofold addition of chiral malonates leads to the formation of five optically active isomers, two constitutionally isomeric pairs of C2-symmetrical diastereomers and a third constitutional C2-symmetrical isomer (Figure 13.5). Twofold additions of azides to C70 lead to diazabis[70]homo-fullerenes, which served as starting material for the synthesis of bis-(aza[70]-fullerenyl) (Cg9N)2 (Chapter 12) [27]. As further bisadditions, addition reaction to C70 [2+2]cycloaddition of electron-rich bis(diethylamino)ethyne and 1-alkylthio-2-(diethylamino)ethynes [28] and the addition of transition metal fragments have been reported [29-32],... 

The natural products as- and fra t-whisky lactones 95 have been prepared from the furanones 94 (92-93% yield), which were themselves obtained from ak-3-phenyl-6-butyl-3,6-dihydro-l,2-dioxin 92 and a chiral malonate ester 93 in 54% yield <20060L463> chromatographic separation on silica gel provided the pure (3R,43, 53)- and (33, 4i ,5R)-diastereomers of 94 which were converted into two nature-identical and two non-natural isomers of 95. 

No discussion of studies on the stereochemical outcome of polyketide biosynthesis would be adequate without mention of the seminal studies of Jordan and Spencer [56-58] using chiral malonates to determine the stereospecificity of the elimination and enolisation reactions occurring during 6-MSA (66, R = H) and orsellinic acid (66, R = OH) biosynthesis. Early experiments by Abell and... 

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.

In the following sections we discuss the methods that have been developed to study the steric course of reactions at proprochiral and proproprochiral centers on carbon and phosphorus, and some of the biochemical applications of these methods. Specifically, we consider chiral methyl groups, chiral malonic acid, chiral phosphate monoesters, and chiral inorganic phosphate. 

Chiral malonate esters have been used successfully in asymmetric cyclopropanations, as shown by the example in Scheme 6.39, part of a total synthesis of steroids such as estrone [143,144]. The key step in this sequence is an intramolecular Sn2 alkylation of the monosubstituted malonate. The rationale for the diastereoselec-tivity is shown in the illustrated transition structure. Note that the enolate has C2 symmetry, so it doesn t matter which face of the enolate is considered. The illustrated conformation has the ester residues syn to the enolate oxygens to relieve Al>3 strain, with the enolate oxygens and the carbinol methines eclipsed. The allyl halide moiety is oriented away from the dimethylphenyl substituent, exposing the alkene Re face to the enolate. The crude selectivity is about 90% as determined by conversion to the dimethyl ester and comparison of optical rotations [143], but a single diastereomer may be isolated in 67% yield by preparative HPLC [144], This reaction deserves special note because it was conducted on a reasonably large scale ... 

Use of chiral malonic esters in the reaction with 1,4-dibromo-2-butene to provide (+) 126. About 80% optical enrichment was achieved. 

Efficient asymmetric carbopalladation occurred in the reaction of the racemic allene 441 with iodobenzene and malonate using BPPFOAc (Xl-14) as a chiral ligand. The chiral malonate derivative 442 with 95 % ee was obtained in 77 % yield [167],... 

Fadel, A. and Vandromme, L. (1999) Total synthesis of (—)-sporochnol A, the fish deterrent, from a chiral malonate. Tetrahedron Asymmetry, 10,1153-1162. 

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