Keto diastereoselective reduction

Diastereoselective reduction of p-keto esters.1 Reduction of p-keto esters (3) of the chiral a-naphthylborneol (2)2 is stereoselective because one face of the carbonyl group is blocked by the naphthyl group. Chelation of the keto ester with... 

Diastereoselective reduction of chiral -keto sulfoxides (11,291-292). Chiral p-keto sulfoxides 1, prepared by reaction of p-(tolylsulfinyl)methyllithium with esters, are reduced by DIBAH in THF diastereoselectively to (R,S)-2. In the presence of ZnCl2, the opposite diastereoselectivity obtains. The paper includes a new method for conversion of these p-hydroxy sulfoxides into chiral epoxides.1... 

Diastereoselective reduction of chiral p-keto sulfoxides.1 The chiral /i-keto sulfoxides (I) are reduced by LiAH4 and several borohydrides mainly to 2. The stereoselectivity is increased as the temperature is lowered. In contrast, DIBAH and diborane reduction results mainly in the alcohol 3. 

Diastereoselective reduction of chiral fl-keto sulfoxides1 (13, 115-116). This reaction, which can be controlled to provide either diastereomer of a chiral P hydroxy sulfoxide, has been used to obtain (R)- or (S)-4-hydroxy-2-cyclohexenones from the monoketal (2) of 1,4-cyclohexanedione. Sulfinylation of 2 with (S)-( —)-... 

Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by Wittig-Horner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-C16 bond, the onti-aldol 41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boron enolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted, diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(m) bis(trifluoroacetate) [16], As in Nicolaou s synthesis, the N12-C13 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 him) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). 

P-Keto sulfoximines 300 undergo diastereoselective reductions at -78 °C with sodium borohydride or diborane to give mixtures of diastereomeric P-hydroxy sulfoximines. The product diastereoselection increases as the steric demand of the substituent R of 300 increases (Table 19). Reductive removal of the P-sulfoximine group of the diastereomeric mixture of P-hydroxy sulfoximines gives secondary alcohols with the (S)-configuration.125... 

This reaction type has also been used for the diastereoselective reduction of a variety of structurally related o -amino-/3-keto esters (equations 9 and 10). Treatment of rac-73 with a substoichiometric amount of chiral mediator 72, using formic acid and triethylamine as the hydrogen source, gave the enantiomerically pure a-amino-/ -hydroxy ester (R,S)-syn-74 in 100% yield with 95 5 dr and 99% ee (equation 9), via the diastereoselective reduction of (S)-73. The unreacted R)-73 efficiently racemizes through tautomerization under these reaction conditions. 

Furthermore, they demonstrated that the optically active a-hydroxy-P-keto esters 105 obtained undergo diastereoselective reduction giving anti-a,P-diols. 

Fig. 2.5 (a) En antioselective keto-group reduction using oxazaborolidine en route to MK-0417. (b) Commercial manufacture ofMK-0507 (Trusopt ) incorporates a biocatalytic reduction step using an alcohol dehydrogenase [Neurospora crassa) and operates in a diastereoselective manner as the 5-methyl group is in a fixed (S)-configuration. 

Enantio and diastereoselective reduction (dynamic resolution) of keto esters and ketones can be achieved using yeast and other microorganisms[55, 70> 74, 245 253l. As shown in Fig. 15-43, when the racemization rate of the keto ester is faster than that for the yeast reduction, and the product hydroxyester is not racemized under the reaction conditions, then the yeast reduction may proceed enantioselectively and... 

Figure 15-44. Diastereoselective reduction of cyclic keto esters 24S. ...

Enantio- and diastereoselective reduction of cyclic keto esters are also achieved using various microorganisms (Fig. 15-44) 245]. By selecting a suitable organism, syn-and anti-hydroxyesters may be synthesized enantio- and diastereoselectively. 

Diastereoselective reduction of 4-keto-2-alkylborate esters (1). This reaction can be effected with several rcductants, but the highest diastercoselectivity (anti) is obtained with BHrTHF at -78° in THF. ... 

Diastereoselective reduction of the keto function can be tailored to produce either 3,5-syn (121) or anti (122) dihydroxy esters simply by choosing the appropriate reducing agent. 

The relative and absolute configuration of 35,125-dihydroxypalmitic acid, a constituent of the Ipomea operculata M. resin, was confirmed by synthesis starting with dimethyl L-malate (35). An efficient synfliesis of (55)-hydroxy-20 4(6 ,8Z,l 1Z,14Z) was accomplished by the coupling of two readily accessible synthons, methyl (55)-hydroxy-7-iodo-heptanoate and 4Z,7Z- tridecadien-l-yne (36). A highly stereoselective synthesis of P-dimorphecolic acid, (95)-hydroxy-18 2(10.E,12 ), has been reported the synthesis features a diastereoselective reduction of a keto intermediate [4] in which the tricarbonyliron lactone tether induces a 1,5-transfer of chirality followed by a stereoselective decarboxylation to create all of the stereochemical ele-... 

The enantiomerically pure 2,3-unsaturated aldonic lactone 2 was prepared following Sharpless asymmetric dihydroxylation of 2-vinylfuran to give 1 (Scheme 1). The chain-extended aldonolactones 4 and 5 were prepared from the P-keto ester 3 by use of a diastereoselective reduction with either d- or L-tartaric acid in conjuction with sodium borohydride (Scheme 2). Reaction of Meldrum s acid (5a) with D-aldopentoses and hexoses gave 3,6-anhydro-2-deoxy-aldono-... 

In 2005, Kambourakis et al. reported the biocatalytic reduction of a-alkyl-1,3-diketones and a-alkyl-/l-ketoesters by employing isolated NADPH-dependent ketoreductases (KREDs). The corresponding optically pure single keto alcohols and hydroxy esters were obtained in quantitative yields (Scheme 3.9). The same group had previously reported the total synthesis of a new class of triterpene derivatives with anti-HIV activity, statin and statin analogues, based on a diastereoselective reduction of a 2-alkyl-substituted 3-ketoglutarate by a KRED. The results are summarised in Scheme 3.9. 

Another of the arylalanines, L-tryptophan, was used at the same laboratories [81] for the synthesis of novel benzazepines (56) as dual inhibitors of ACE and thromboxane synthase (Scheme 5.25). Ozonolysis of 7V-acetyl l-tryptophan to effect scission of the indole ring followed by 7V-protection gave the 4-keto acid (57) as a cyclization precursor. Downstream transformations included diastereoselective reduction of the ketone functionality and reductive alkylation of the amine substituent with ethyl 2-oxo-4-phenyl-butanoate. 

Diastereoselective Reduction of Ketone Carbonyl Group of 1,3-Keto Ester... 

Professor Fraga reported the study of diastereoselective reduction In cyclic 1,3-keto ester substrates in 2004 [1], using CaCU as additive to form complexation with 1,3-keto esters substrates to control the reduction. Sodium borohydride was added to the mixture and the selective reduction of ketone carbonyl group happened with 90 % diastereoselectivity. The transition state proposed is shown in Fig. 3.5. 

Table 3.1 Condition screening for the diastereoselective reduction of 1,3-keto ester...

So far, the diastereoselective reduction of 1,3-the keto ester was successftdly realized to form compound 3.6. The same substrate with different experimental conditions can obtain cfr-product and tranr-product with high diastereoselectivity, respectively, which lays the foundation for the further development of various strategies for total synthesis. 

Fraga CAM, Teixeira LHP, Menezes CMOS et al (2004) Studies on diastereoselective reduction of cyclic J -keto esters with boron hydrides. Part 4 the reductive profile of functionalized cyclohexanone derivatives. Tetrahedron 60 2745-2755... 

Scheme 3.15 Asymmetric synthesis of the both enantiomers of a-hydroxy acids by the diastereoselective reduction of a-keto amides.

The baker s yeast reduction of (3-keto esters has been extensively studied in the past [36]. Green cell suspension cultures obtained from bryophytes were studied by Speicher et al. in bioconversions for the enantio- or diastereoselective reduction of simple ketones, (3-keto esters, and a,(3-unsaturated carbonyl compounds [37]. These bioreductions proceed according to the Prelog s rule. It has been confirmed that bryophyte cell cultures are generally capable of ADH reductions in reactions with various substrates. One of the four possible stereoisomers was formed from the (3-keto ester 20, the anti-(2S,3S)-20b product, due to the diastereoselective reduction with concomitant DKR through in situ racemization of the substrate via enolization (Scheme 12.17). The ds-(li ,2S)-2-hydroxycyclohexane carboxylate 3a was obtained with Metrosideros polymorpha with 90-94% de and up to 90% ee [37]. 

Scheme 12.17 Diastereoselective reductions of (3-keto esters 20 and 3 with bryophyte whole cells...

Figure 13.12 Diastereoselective reduction of2-keto-3-(N-benzoylamino)-3-phenylpropionic acid ethyl ester to chiral C-13 paclitaxel side-chain synthon.

Shimoda K, Kubota N, Hamada H, Hamada H. Diastereoselective reduction of p-keto carbonyl compounds by cultured plant cells. Tetrahedron Lett. 2006 47 1541-1544. 

Enantiomerically pure /J-keto sulfoxides are prepared easily via condensation of a-lithiosulfinyl carbanions with esters. Reduction of the carbonyl group in such /J-keto sulfoxides leads to diastereomeric /J-hydroxysulfoxides. The major recent advance in this area has been the discovery that non-chelating hydride donors (e.g., diisobutylaluminium hydride, DIBAL) tend to form one /J-hydroxysulfoxide while chelating hydride donors [e.g., lithium aluminium hydride (LAH), or DIBAL in the presence of divalent zinc ions] tend to produce the diastereomeric /J-hydroxysulfoxide. The level of diastereoselectivity is often very high. For example, enantiomerically pure /J-ketosulfoxide 32 is reduced by LAH in diethyl ether to give mainly the (RR)-diastereomer whereas DIBAL produces exclusively the (.S R)-diastereomer (equation 30)53-69. A second example is shown in... 

Scheme 65 summarizes Mori s synthesis of 44 [97]. Reduction of keto ester A with baker s yeast gave hydroxy ester B of about 98% ee. Methylation of the dianion derived from B diastereoselectively gave C, which was converted to 44. This process enabled the preparation of about 10 g of (lS,5R)-44. 

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