A-Alkyl-p-keto esters

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Dynamic kinetic resolution of a-alkyl-P-keto ester was conducted successfully using biocatalysts. For example, baker s yeast gave selectively syn(2R, 3S)-product [29a] and the selectivity was enhanced by using selective inhibitor [29b] or heat treatment of the yeast [29c]. Organic solvent was used for stereochemical control of G. candidum [29d]. Plant cell cultures were used for reduction of 2-methyl-3-oxobu-tanoate and afforded antialcohol with Marchantia [29e,f] and syn-isomer with Glycine max [29f]. 

Asymmetric alkylation of a-alkyl-P-keto esters. The sense of asymmetric alkylation of the chiral enamines prepared from (S)-valine /-butyl ester with a-alkyl-P-keto esters is markedly controlled by the solvent. Thus alkylation of the anion 1, prepared with LDA in toluene, with CH,I in the presence of HMPT (1 equiv.) results in (R)-2 in 99% ee, whereas alkylation in THF (2 equiv.) results in (S)-2 in 92% ee. The effect of HMPT is general for a variety of electrophiles depending on the electrophile, dioxolane... 

Reductions. iyn-Selective reduction of 1,3-diketones and a-alkyl-p-keto esters is observed with borane-pyridine in the presence of TiCl4. On the other hand, anti-products predominate in the reduction with LiBHEt -CeCli. 

Scheme 12.15 Dynamic kinetic resolution in the bioreduction of a-alkyl-P-keto esters by Recombinant E. co//expressing Gcylp or Cre3p.

The same enzymes were also applied to the DKR of a-alkyl-P-keto esters, such as 20, 21, 43, and 44, for the preparation of the corresponding hydroxy esters with excellent chemical and optical purity, as shown in Scheme 12.22 [55a,57j. In this case, substrate 43 was selected for the asymmetric chemoenzymatic synthesis of the aggregation pheromone 45 (sitophilate) of the granary weevil Sitophilus granarius (Scheme 12.23) [57]. 

Scheme 12.22 Dynamic kinetic resolution of a-alkyl-P-keto esters 20, 21, 43, and 44 catalyzed by ketoreductases.

Kalaitzakis D, Rozzell JD, Kambourakis S, Smonou I. Highly stereoselective reductions of a-alkyl-l,3-diketones and a-alkyl-p-keto esters catalyzed by isolated NADPH-dependent ketoreductases. Org. Lett. 2005 7 4799-4801. 

Another improvement was reported by Leonard et al. in their preparation of a promising antimalarial, Endochin. The improvement was the alkylation of intermediate enamino-ester 28 by reaction with NaOEt followed by alkylation with an alkyl bromide, rather than forming 29 by reaction of 27 and a suitable P-keto-ester. This provided the important intermediate 29 required for cyclization to Endochin (30). Endochin was first reported by German scientists but was not publicly disclosed until the Department of Commerce made this information available after World War II.Leonard was able to improve upon the chemistry reported by Andersag and Salzer in 1940 and isolated Endochin in 40% overall yield from m-anisidine (27). 

Application of the Ritter reaction conditions on y-hydroxy-a,P-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or y-A-acylamino-P-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The y-A-acylamino-P-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCI3 <06TL4385>. 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

Chiral 3,3-disubstituted cyclopentanones. Taber et al have extended a synthesis of cyclopentanones by a rhodium catalyzed intramolecular C—H insertion (11,459) to a synthesis of (+ )-a-cuparenone (3), which contains a chiral quaternary center. Thus the chiral a-diazo-p-keto ester 1, prepared by alkylation of a chiral oxazolidone (11, 379-381) on treatment with Rh2(OAc)4 is converted into 2 in 67% yield. This product is converted in several steps into (+ )-3. 

Access to enantioenriched carbonyl compounds of high value which possess quaternary a-carbon stereocenters containing hetero-functionalities represents one of the most challenging tasks in phase-transfer-catalyzed asymmetric alkylation. In due course, Maruoka and coworkers devised the asymmetric alkylation of cyclic a-amino-P-keto esters 67 with C2-symmetric phase-transfer catalyst lh as a means of obtaining aza-cyclic amino acids with quaternary stereocenters (Scheme 5.32) [33]. 

The alternative alkylation product could be obtained by using a different P-keto ester ... 

In their synthesis of Baylis-Hillman adducts as potential alkylating agents, Lawrence et al. attempted the oxidation of diol 56 under standard Swem conditions, with unexpected results.41 Instead of the required a-methylene-P-keto ester, the formation of an allylic chloride 57 was detected. The substitution is thought to take place via a conjugate-elimination process through enolate 59 involving the ester group, which is clearly implicated since the Swem oxidation of related alcohols such as 60 proceeds as expected. 

One of the limitations of the intramolecular Barbier reaction of a>-haloalkyl p-keto ester substrates, as developed in our laboratory, was the inability to utilize secondary alkyl halides. Under the aprotic conditions utilized, a retroaldol reaction transpired that led to undesired transformations of the intermediate generated (Eq. 2). 

In numerous synthetic studies it has been demonstrated that DMP can be used for a selective oxidation of alcohols containing sensitive functional groups, such as unsaturated alcohols [297,1215-1218], carbohydrates and polyhydroxy derivatives [1216, 1219-1221], silyl ethers [1222,1223], amines and amides [1224-1227], various nucleoside derivatives [1228-1231], selenides [1232], tellurides [1233], phosphine oxides [1234], homoallylic and homopropargylic alcohols [1235], fluoroalcohols [1236-1239] and boronate esters [1240]. Several representative examples of these oxidations are shown below in Schemes 3.349-3.354. Specifically, the functionalized allylic alcohols 870, the Baylis-Hillman adducts of aryl aldehydes and alkyl acrylates, are efficiently oxidized with DMP to the corresponding a-methylene-p-keto esters 871 (Scheme 3.349) [1217]. The attempted Swern oxidation of the same adducts 870 resulted in substitution of the allylic hydroxyl group by chloride. 

It is not clear why the Mn(in)-mediated electrochemical cyclization of 20 and 22 was completely unsuccessful. It should be noted that the rate determining step in the cyclization of a-unsubstituted P-keto esters is the addition of the alkene to the Mn(ni) enolate with loss of Mn(II) while the rate determining step in the oxidation of a-alkyl substituted P-keto esters is the formation of the Mn(III) enolate, which rapidly loses Mn(II) to form the free a-keto radical (57, 40). Mn(III)-mediated electrochemical oxidation was somewhat successful for a-alkyl substituted P-keto esters, but failed for a-unsubstituted P-keto esters. 

Owing to the importance of optically active amino acid derivatives and the lack of successful systems for catalytic asymmetric CDC reactions of glycine derivatives with p-keto esters, Wang and co orkers embarked on the study of enantioselective CDC reactions of secondary and tertiary amines for the synthesis of optically active a-alkyl a-amino acids. In the presence of a catalytic amount of Cu(OTf)2 and BOX ligand L2 as the chiral catalyst, in combination with DDQ as the stoichiometric oxidant, the reactions of glycine esters 47 with a-substituted p-keto esters 48 underwent smoothly to afford the desired products 49 in satisfactory yields, moderate dr and excellent ee (Scheme 2.17). 

Keto esters represent interesting substrates that permit ready and various opportunities for further stmctural manipulation, but until 2002 only limited asymmetric a-alkylation procedures were developed [85]. In 2002, Dehmlow et al. [86] demonstrated the use of cinchonidinium bromide Ic in asymmetric a-alkylation of p-ketoester 24 when the corresponding benzylated product 29 (Scheme 8.11, entry 1) was obtained in excellent yield (97%), satisfying 46% ee. Better results in terms of enantioselectivity (up to 97% ee) were reported by Kim and co-workers [87], who showed the effectiveness of bulky cinchonine-derived catalysts IL in asymmetric a-alkylation of P-ketoesters(Scheme 8.11, entry 2). An asymmetric a-alkylation procedure with broad generahty in terms of the stmcture of P-ketoesters 25 and alkyl hahdes under PTC with C2-symmetric PTC L was developed by Maruoka and co-workers [88] (Scheme 8.11, entry 3). Further optimization led to the development of a reliable route for the asymmetric synthesis of not only a,a-dialkyl-P-hydroxy and p-amino esters, but also functionalized aza-cyclic a-amino esters [89], a-alkylated ketolactones [90], and functionalized a-benzoyloxy-P-ketoesters [91]. Shghtly changed catalyst XXV (Scheme 8.12) was also successfully used for the constmction of enantiomerically enriched various a-alkyl-a-fluoro-P-keto esters... 

Water has been used as the medium for the synthesis of Qxs in good yields from 1,3-diketones/esters/ketoesters via tandem one-pot procedure (Scheme 2.11). The synthesis proceeds through in situ formation of intermediate a-halo-P-keto esters using N-bromosuccinimide (NBS), which undergo tandem A -alkylation-condensa-tion-dehydrogenation with the 1,2-diamines to form the Qx [87]. 

The Schmidt rearrangement of optically active a,a-bisalkylated p-keto esters (161) regioseiectively proceeds to give IV-acyl oc-alkylated a-amino acid esters (162) with retention of configuration and little or no racemization." Acid hydrolysis of (162), followed by treatment with propylene oxide, affords a-alkylated a-amino acids (163) in high yield and optical purity (equation 48). 

After alkylation, hytholysis in aqueous base and acidification, followed by heating, leads to decarboxylation. The alkylated p-keto ester yields a ketone the alkylated malonic ester gives a carboxylic acid. 

In 2000, the group of Stewart in Florida reported the asymmetric synthesis of P-hydroxy esters and a-alkyl-P-hydroxy esters by recombinant E. cdi expressing enzymes from baker s yeast [32]. In all cases, a single diastereomer was produced (Scheme 12.15). Both strains yielded the syn-(3S)-alcohols 20a, 21a, 23a, and 28a, with high ee values and in moderate chemical yields. When racemic a-substituted P-keto esters 20, 21, 23, and 28 were employed as substrates, DKRs resulted in almost complete conversion of the substrate, due to facile racemization at the a-position. 

Another approach has recently been described by Cuetos et al. for the dynamic kinetic resolution of a-substituted p-amino esters [77]. Several ra-transaminases and acyclic alkyl-p-keto esters were tested, leading to high conversion rates and high ee and de values. With this result in mind it seems feasible that novel transaminases will be designed to create enantiomeric pure molecules under mild and economically feasible conditions. 

A highly stereoselective synthetic strategy for disubstituted piperidines 247 with cis appendages was reported recently. A one-pot intermolecular imino aldol reaction of a-arylmethylidine 244 or a-alkylidine p-keto ester 248 with aldimine 246 followed by intramolecular aza-Michael reaction (alkylative cyclization) in a domino fashion afforded the corresponding piperidines 247 in high yields and excellent stereoselectivity (er, dr >99%) (Scheme 40.54). ... 

The anion of a p keto ester may be alkylated at carbon with an alkyl halide and the product of this reaction subjected to ester hydrolysis and decarboxylation to give a ketone... 

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