Enantioselective malonic acid synthesis

The first enantioselective formal total synthesis of paeonilactone A was reported by J.E. Backvall who used a palladium(ll)-catalyzed 1,4-oxylactonization of a conjugated diene as the key step. The lactonization precursor diene acid was obtained from an enantiopure dimethyl malonate derivative via sequential Krapcho decarboxylation and ester hydrolysis. 

The first enantioselective total synthesis of (+)-macbecin I was accomplished by R. Baker and co-workers. A key vinyl iodide precursor was prepared stereoselectively using the malonic ester synthesis. Diethyl methylmalonate was treated with in situ generated diiodocarbene in ether at reflux to afford diiodomethylmethylmalonate in good yield. This dialkylated malonic ester then was converted to ( )-3-iodo-2-methyl-2-propenoic acid by reacting it with aqueous KOH. The saponification was accompanied by a concomitant decarboxylation. 

Decarboxylation of malonic acid derivatives is a well studied process in the biosynthesis of biomolecules such as long-chain fatty acids and polyketides. A decarboxylase that exhibits enantioselectivity for substituted malonates would be useful for producing ophcally active carboxylic acids, hi fact, malonyl-CoA decarboxylase does catalyze an enantioselective decarboxylation (Figure 3.2) [5], but malonyl-CoA is an unsuitable precursor for optically active substances. Instead, we focused on the prochiral-activated compoimd arylmalonate, an intermediate of malonic ester synthesis, to develop a method for enantioselective decarboxylation. Malonates are stable at room temperature but readily decompose to arylacetate and CO2 at high temperatures. This suggests that the decarboxylation of arylmalonate may occur naturally if arylmalonate acts as a substrate for a decarboxylase. 

From an extensive screening of microorganisms, we first developed such a biocatalyst, Alcallgenes bronchlsepticus, in 1989 [Eq. (11)] [12]. (/ )-Phenylpropionic acid (21a) was obtained from a-methyl-a-phenylmaloiiic acid (22a), and the yield and e.e. of the products were exteemely high. Indeed, this is a new type of biotransformation that can be performed on a preparative scale since the substrates, disubstituted malonates, are readily available via the well-established malonate ester synthesis. To date, all of the attempts for enantioselective decarboxylation of malonates by a chemical asymmetric synthesis resulted in only low to moderate e.e. of the products. In order to understand the mechanism of this enzyme-mediated decarboxylation we embarked on the isolation of the enzyme and further study of its characteristics. 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

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... 

By substituting (S)-(-)-l-amino-2-(dimethylmethoxymethyl)pyrrolidine (S)-(83) for (S)-(4), Enders has developed an efficient and enantioselective Hantzsch synthesis (Scheme 4). In this synthesis, the more-hindered hydrazone formed from (83) was condensed with an acetoacetic acid ester. Deprotonation of the hydrazone so-formed (the major tautomer present was an enehydrazine) followed by addition of an arylidene malonate derivative yielded (85), which could be closed with mild acid to yield optically active... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

Since oxazolidines and oxazolidinones are fiindamental structural classes in organic chemistry (chiral auxiliaries) and in medicinal chemistry (e.g., Linezolid) and since they mask P-hydroxy-a-amino acids, which are widespread in various biologically active compounds and in natural products, the enantioselective synthesis of oxazolidinones is a challenging topic. Indeed, a new method for the direct synthesis of chiral 4-carboxyl oxazolidinones 168 by the catalytic asymmetric aldol reaction of isocyanato-malonate diesters 166 with aldehydes 167 in the presence of a thiourea catalyst (TUC) was developed. Since the resulting chiral 4-carboxy oxazolidinones are the equivalent of P-hydroxy-a-amino acids, this procedure... 

The (R,/J)-Ph-DBFOX/Zn(OAc)2 combination is an effective catalyst to give optically pure 2-fluorinated malonates in a process similar to desymmetrization (Scheme 44.21). Although the malonates are nearly symmetrical and less acidic, the enantioselectivities observed in the desymmetrization-like fluorination reaction are high and superior to the corresponding enzymatic methods. This synthetically useful method was applied to the synthesis of pharmaceutically attractive molecules that include a-ben-zyl- 3-alanine, fiuorinated -lactams, fiuoro-alacepril, and a HIV-1 protease inhibitor. ... 

A practical and highly enantioselective Michael addition of malonates to enones catalysed by bifunctional primary amine-thiourea (5) derived from 1,2-diaminocyclohexane has been reported. The addition of weak acids and elevated temperature improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol%) of catalysts. A related bifunctional cinchona-thiourea catalyst has been involved in asymmetric organocatalysed conjugate addition reactions of monoth-iomalonates to nitroolefins. ... 

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