Prochiral diketones

Similar reduction of a prochiral diketone C with another yeast, Pichia terricola afforded D, which was converted to JH I,28 JH II,28 JH 029 and 4-methyl JH I.30 In the case of (+)-4-methyl JH I, asymmetric hydrolysis of dimethyl 3-methylglutarate with pig-liver esterase (PLE) was also employed for its... 

Our synthesis started from hydroxy ketone B (Figure 5.31), which was obtained by asymmetric reduction of prochiral diketone A with fermenting baker s yeast.38 The key step in the present synthesis was the ring formation by intramolecular alkylation of C to give D. To obtain C, the enfifo-hydroxy group of B was first epimerized via retro-aldol/aldol by treatment with p-toluenesulfonic acid in carbon tetrachloride. The tricyclic intermediate D was converted to (+)-pinthunamide (146), mp 187-189°C, [a]D215 = +60 (EtOH), which was identical with the natural product. Its absolute configuration was thus determined as depicted in 146.39... 

Asymmetric reduction of diketone is one of the easiest ways to obtain chiral di-ols. Bisoxazaborolidine having two catalytic centers seems to be especially good at catalyzing the enantioselective reduction of prochiral diketones. 1,6-Diphe-... 

Prochiral diketones or racemic ketones, like enol esters, are also amenable to a hydrolase-catalyzed asymmetric transformation. The enol acetates and ketones 63 and 64, respectively, may be obtained by Pseudomonas cepacia lipase-catalyzed and Candida cylindracea lipase-catalyzed hydrolysis of the corresponding racemic enol esters or prochiral bis enol ester, respectively, with high enantioselectivity and yield. 

Every kinetic resolution of bi- and polycyclic ketones suffers from mie particular drawback because the bridgehead carbon atoms make it impossible to recycle the undesired wrong enantiomer via racemization. Hence the desymmetrizatiOTi of prochiral diketones, making use of the enantioface- or enantiotopos-specificity of HLADH, is of advantage. For instance, both the cis- and tran -forms of the decali-nediones shown in Scheme 2.117 were reduced to give (5)-alcohols with excellent optical purity. Similar results were obtained with unsamrated derivatives [743, 795]. 

Scheme 2.117 Desymmetrization of prochiral diketones using HLADH...

As illustrated by the conversion of 8 to 13, organocatalysis can be used to effect the enantioselective construction of polycarbocyclic products. The initial ring prepared in enantiomerically-pure form by organocatalysis can also set the chirality of a polycyclic system. Professor Corey has reported (/. Am. Chem. Soc. 2007, 129, 10346) that Itsimo-Corey reduction of the prochiral diketone 25 led to the ketone 27. Cyclization followed by oxidation and reduction then delivered estrone methyl ether 28. 

Fig. 8.40 One-pot reactions sequence, including hydrogenation of prochiral diketone 1,2-indanedione (I) with chemoenzymatic dynamic kinetic resolution of the resulting rac-2-hydroxy-l-indanone by racemization of (S)-2-hydroxy-l-indanone into (ff)-2-hydroxy-l-indanone and acylation of the latter to (ff)-2-acetoxy-l-indanone. (From O. Langvik, T. Sandberg, J. Wdrnd, D.Yu. Murzin, R. Leino, One-pot synthesis of (R)-2-acetoxy-l-indanone from 1,2-indanedione combining metai cataiyzed hydrogenation and chemoenzymatic dynamic kinetic resoiution, dynamic kinetic resoiution, Catai. Sci. Technoi 5 (2015) 150—160. Copyright the Royai Society of Chemistry).

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

It has already been mentioned that prochirality of the olefin is not necessary for successful enantioselective cyclopropanation with an alkyl diazoacetate in the presence of catalysts 207. What happens if a prochiral olefin and a non-prochiral diazo compound are combined Only one result provides an answer to date The cyclopropane derived from styrene and dicyanodiazomethane shows only very low optical induction (4.6 % e.e. of the (25) enantiomer, catalyst 207a) 9S). Thus, it can be concluded that with the cobalt chelate catalysts 207, enantioface selectivity at the olefin is generally unimportant and that a prochiral diazo compound is needed for efficient optical induction. As the results with chiral copper 1,3-diketonates 205 and 2-diazodi-medone show, such a statement can not be generalized, of course. 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

Double Hydrogenation of 1,3- and 1,2-Diketones. Scheme 57 illustrates another example of highly enantioselective formation of alcoholic products. The BINAP-Ru(II)-catalyzed hydrogenation of prochiral 1,3-diketones produces diastereomeric 1,3-diols, for which the dl or anti isomers are always dominant and ee values are uniformly high (92,105). For example, the reaction of 2,4-pentanedione catalyzed by an (R)-BINAP-Ru complex produces a 99 1 mixture of almost enantiomer-... 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

Indium trichloride mediates the intramolecular cyclization of the prochiral allylstannyl diketone to afford the desymmetrized cis-cis cyclohexanol predominantly (Equation (36)). The use of TiCU in place of InCl3 gives the cis-trans diastereomer.213... 

Reduction of symmetrical and prochiral 1,3-diketones with yeast gives optically active 3 hydroxy ketones, which are useful chiral building blocks in organic synthesis. 

Until recently, the preparation of the bicyclic ene-diones (47a,b), which are important intermediates in steroid total synthesis, has led only to racemic mixtures This deficiency has now been met as follows. Michael addition of the vinyl ketone (44) to the cyclic diketones (45a) and (45b) afforded the triketo-intermediates (46a) and (46b) in high yield, each containing a prochiral centre. Optically active amines and amino-acids were used as chiral reagents to... 

In 1985, we reported that reduction of a prochiral 1,3-diketone A (Figure 3.6) with fermenting baker s yeast (Saccharomyces cerevisiae) was enantioselective to give (5)-hydroxy ketone B of 98-99% ee.26 I noticed that the Baeyer-Villiger oxidation of B would furnish (S)-hydroxylactone, a building block synthetically equivalent to the terminal epoxide moiety of (+)-JH III. This idea was used for the synthesis of (+)- and (-)-JH III in 1987.27... 

Figure 3.9 summarizes our synthesis of the enantiomers of JH I in 1988.28 If we want to employ the same strategy as used for the synthesis of JH III, the synthesis of JH I demands the execution of the diastereo-and enantioselective reduction of a prochiral 1,3-diketone A. Unfortunately, reduction of A with fermenting baker s yeast was nondiastereoselective, giving both B and C. After extensive screening of yeasts, Pichia terricola KI 0117 donated by Kirin Brewery Co. was found to achieve highly stereoselective reduction to give >99% of B with 99% ee. Since both of the 3,5-dinitrobenzoates D and E were crystalline, these could be purified by recrystallization, and 100% pure E was secured. Conversion of E to F was achieved by methanolysis followed by acetonide formation. The enantiomeric purity of F was proved to be ca. 100% ee by HPLC analysis of bis-MTPA ester G derived from F. 

Reduction of prochiral 1,3-diketone A with baker s yeast gives hydroxy ketone B of 99% ee.10 The ketone B was converted to unsaturated ketone C, which was treated with (Z)-l-propenylmagnesium bromide in the presence of cerium(III) chloride to give a mixture of D and E. This mixture was directly subjected to oxy-Cope rearrangement to give F from D. The exo-isomer E was recovered unchanged. 

In a further example, a biocatalytic route for the production of optically pure 3-substituted cyclohexylamine derivatives from prochiral bicychc P-diketones was established by employing three biocatalytic reaction steps (Scheme 4.16) [53]. The sequence combined the stereoselective hydrolysis of a C-C bond catalyzed by a P-diketone hydrolase [54] (6-oxocamphor hydrolase (OCH) from Rhodococcus sp. [55]), followed by an Upase-catalyzed esterification [Candida antarctica lipase B (CAL-B), Novozyme 435], and a subsequent asymmetric amination by either an (S)-or (1 )-selective m-TA [V.fluvialis [27] or a variant of the Arthrobacter sp. TA [16a] (ArRmutll)]. 

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