1.3- Diketones, stereoselective reduction

Edegger, K., Stampfer, W., Seisser, B. et al. (2006) Regio- and stereoselective reduction of diketones and oxidation of diols by biocatalytic hydrogen transfer. European Journal of Organic Chemistry, (8), 1904—1909. 

Table 9.1 Enzyme-catalysed stereoselective reduction of diketones/keto esters to keto alcohols/hydroxy esters...

Kalaitzakis, D., Rozzell, J.D., Kambourakis, and S. Smonou, L, Highly stereoselective reductions of a-alky 1-1,3-diketones and a-alkyl-/3-keto esters catalyzed by isolated NADPH-depen-dent ketoreductases. Org. Lett., 2005, 7, 4799-4801. 

Stereoselective reduction of a 2-chloro-1,3-diketone. The reduction of I (nonenolizable) proceeds predominately anti with respect to the C—Cl bond. The chlorine atom in the product can be removed by zinc dust reduction of the methoxymethyl ether. 

So far, most microorganisms and enzymes derived therefrom have been used in the reduction of a single keto group of p-keto or a-keto compounds [68-71], Recently, Patel et al. [72] have demonstrated the stereoselective reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester (41), to (3,S, 5R)-dihydroxy-6-(benzyloxy)hexanoic acid, ethyl ester (42a) (Fig. 14). The compound (42a) is a key chiral intermediate required for the chemical synthesis of [4-[4a,6P(E)]]-6-[4,4-bis(4-fluorophenyl)-3-(l-methyl-lH-tetrazol-5-yl)-l,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one, compound R-( + )-(43), a new anticholesterol drug that acts by inhibition of HMG CoA reductase [73], Among various microbial cultures evaluated for the stereoselective reduction of diketone (41), cell suspensions of Aci-... 

Recently, a series of studies of the stereoselective reduction of 1,3-diketones has been reported which expands upon this methodology. When 1,3-diphenyl-1,3-propanedione was reduced with three equivalents of NaBH4 in the presence of (S,S)-15,THFA,and ethanol in CHCI3 at -20°C, (S,S)- 1,3-diphenyl- 1,3-propanediol was obtained quantitatively in 97% ee (Scheme 9) [54], The anti syn ratio of the product was 84 16. Diketones with electron-donating and electron-withdrawing substituents on their phenyl rings were also reduced with high enanti-oselectivity and diastereoselectivity. 

Lactone. Various fungi, including Bakers yeast and Geotrichum candi-dum, have been shown to produce optically active lactones, useful chiral synthon, via the stereoselective reduction of suitable unsaturated precursors (42). Figure 15 shows the production scheme for a chiral, substituted diketone, a synthon for optically active carotenoids. 

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. 

The control of chemical selectivity is a classical problem in organic chemistry and an antibody s ability to route reactions via disfavored pathways, as in the asymmetric Diels-Ald reaction, has important practical ramifications. Not surprisingly, extension of this approach to the catalysis of other unselective or energetically demanding reactions has become an important focus of research. Syn eliminations [45], cationic olefin cycliza-tions [46], and enol ether hydrolyses [47] are among the processes that have been investigated. For the purposes of the current discussion, however, the regio- and stereoselective reduction of the diketone 21 [48] illustrates what... 

The regio- and stereoselective reductions of 2-substituted-l,3-diketones were extensively studied by Smonou and her coworkers [55]. In this work, the corresponding optically pure hydroxy ketones and diols were synthesized utilizing isolated NADPH-dependent ketoreductases (KRED). Although most... 

D. Kalaitzakis,. D. Rozzell, S. Kambourakis, L. Smonou, Highly Stereoselective Reductions of a-alkyl-1,3-diketones and a- alkyl-b-keto esters catalyzed by isolated NADPH-dependent Ketoreductases, Org. Lett. 22 (2005) 4799-4801. 

Several of these products [189-191] have been prepared and used for the total synthesis of natural products [185-187]. The formation of by-products was observed quite often during these reductions. This might be due to the slow rates of the reaction. Hence, the addition of activators has been suggested [191]. These "activators" (most often a,p-imsaturated alcohols, ketones, or nitriles) seem to act as suicide substrates for several oxidoreductases [192, 193], whereas, for the reduction of cyclopentanoid 1,3-diketones, stereoselectivity was high, and most often [194] low selectivity was observed for cyclohexanoid 1,3-diketones [184, 194-197]. 

Kat, M, Sarvary I, Frejd T, Hahn-Hagerdal B, Gorwa-Grauslund MF. An improved stereoselective reduction of a bicyclic diketone by Saccharomyces cerevisiae combining process optimization and strain engineering. Appl. Microbiol. Biotechnol. 2002 59 641-648. 

Stereoselective hydride reduction of 1,2,5-thiadiazoline 1,1-dioxides 60 generates unsymmetrical 1,2,5-thiadiazol-idine 1,1-dioxides 61 <1998SL623> that can be readily converted to unsymmetrical vicinal diamines 62 with HBr in the presence of phenol (Scheme 5) <1996TL2859, 1998SL623>. The unsymmetrical thiadiazolidine 1,1-dioxides 63 can also be converted into 1,2-diketones 64 on treatment with selenium dioxide followed by alkaline hydrolysis (Equation 7) <1997SL671>. 

Intramolecular coupling Some aromatic diketones have been stereoselectively cy-clized under various electrolysis conditions, which, together with the substrate structure, strongly influence the stereochemistry of the formed cyclic diol. Reductive cyclization of 1,8-diaroylnaphthalenes led to trans-diols, 2,2 -diaroylbiphenyls and a, )-diaroylalkanes yielded cis-diols with different stereoselectivities depending on substrate structure and electrolysis conditions (pH, cosolvent) (Fig. 57) [310-312]. 

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]. 

Nitrogen-coordinated pentacoordinate complexes have been used as stereoselective reducing agents in the preparation of erythro-(meso)- 1,2-diols from diketones and a-hydroxyketones109. The reducing agent was the (l-naphthylamino-8)trihydridosilane 92e. After formation of the dioxo chelate from the diketone (equation 32), the diol was obtained from the pentacoordinate silicon complex by reduction with LiAlILt. 29 Si NMR spectroscopy was used for the product-ratio analysis in this reaction, which was found to yield primarily the erythro diols. 

Reduction of 1,4-diketones with thexylborane (1 equiv.) is also stereoselective, with anti-selectivity of 17-47 1. Reduction of 1,5- and 1,6-diketones shows no stereoselectivity, but reduction of 1,3-diketones can show modest anti-stereoselectivity. 

It is much more difficult to pass stereochemical information from one ring to the other in spirocyclic compounds because each ring is orthogonal to the other. Nonetheless, some reactions are surprisingly stereoselective—one such is the reduction of the spirocyclic diketone that we made a moment ago. Treatm it with 1-iAllI4 gives one diastereoisomer of the spirocyclic diol. 

Reduction of diketone 169 with sodium boro hydride proceeded stereoselectively to give diol 170, as a single isomer in 83% yield (Scheme 33) <1999T7471>. 

Generally, reduction of diketones 12 (or in some cases their hexacarbonyldicobalt complexes) yields better stereoselectivities than the related ethylenic diketones 11, especially when R is a sterically demanding group. In addition, the propargylic diols obtained can be easily transformed not only into the saturated... 

Treatment of the aldehyde 148 with lithium phenylacetylide yielded another versatile intermediate (149), which could be transformed, after stereoselective partial reduction to the corresponding tram allylic alcohol (150), either by simple deprotection to racemic 36 or first by oxidation and then deprotection to the diketone 39. Elimination of water from the ketol 36 gave 8, which could be reduced with diisobutyl aluminum hydride without affecting the double bond to the dienol 48. ... 

A more versatile reducing agent is samarium diiodide, which promotes chemoselective cyclizations of functionalized keto aldehydes in a stereodefined manner to form 2,3-dihydrocyclopentane carboxylate derivatives in good yields and with diastereoselectivities of up to 200 1 (equation 38)7 The reaction proceeds via selective one-electron reduction of the aldehyde component and subsequent nucleophilic attack on the ketone moiety. Stereochemical control is established by chelation of the developing diol (19) with Sm " " which thereby selectively furnishes cis diols (equation 39). The stereoselective M/-cyclization of 1,5-diketones to cis cyclopentane-1,2-diols using TiCU/Zn has been used to prepare stereodefined sterically hindered acyclic 1,2-diols when a removable heteroatom, such as sulfur or selenium, is included in the linking chain (equation 40). 

The reduction of the 1,3-diketones 3.122 and 3.123 to diols can also be stereoselective and can lead to either syn,syn 1,3-diols or to syruanti 1,3-diols, depending... 

Diamine 264 is made from the a-diketone benzil by a simple but multiple cyclisation to give the heterocycle 265. Stereoselective dissolving metal reduction gives anti-266 and hence racemic 264 on aminal hydrolysis. Resolution with tartaric acid brings down crystals of the tartrate of one enantiomer. With l-(+)-tartaric acid, the salt with (.S, .S )-264 is less soluble while (R,R)-264 requires treatment with d-(—)-tartaric acid. One important application is the asymmetric Lewis acid46 267. 

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