3 Reductions, asymmetric

the absence of electronic repulsion would make transition state A preferred to 

giving the (S)-enantiomer as the major product. However, there is a delicate balance between electronic and steric factors. Hence, the decrease in enantiose-lectivity seen in the reduction of tert-butyl phenyl ketone reflects greater steric interactions in transition state A between the Al-O bond and the tert-butyl group. 

aromatic substituent for aromatic ketones and tertiary alkyl group for 

Mulzer and Berger used the Midland reduction en route to the total synthesis of the boron-containing macrodiolide antibiotic tartrolon B (90), which acts 

Many other reagents have been used in place of DCC. The most common is oxalyl chloride (Swcrn). 

Analogously, the conversion of amines into imines was realized and indolines were converted into indoles in good yields [239]. 

The sulfinyl chirality has shown [86] considerable utility in asymmetric synthesis, particularly for carbon-carbon bond formation (see Sections 

2 and 4.2.8). Its use as the chiial souice in a NADII mimic has been reported [240]. Reduction of methyl benzoyl formate by enantiopure 1 -propyl-(5)-3-(/ )-tolyl)suIfinyl-l, 4-dihydropyridine yielded the (/ )-mandelate with 96% e.e. 

The asymmetric reduction ot ketones with borane or with NaBH4/Me,SiCl, catalysed by (3-hydroxysulfoximines, afforded secondary alcohols in high yields with good enantioselectivities [241,242]. 

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Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents Review Synthesis 1992, 605. 

Chiral aluminium hydride for the asymmetric reduction of prochiral ketones... 

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

In this thiamine pyrophosphate-mediated process, ben2aldehyde (29), added to fermenting yeast, reacts with acetaldehyde (qv) (30), generated from glucose by the biocatalyst, to yield (R)-l-phen5l-l-hydroxy-2-propanone (31). The en2ymatically induced chiral center of (31) helps in the asymmetric reductive (chemical) condensation with methylamine to yield (lR,23)-ephedrine [299-42-3] (32). Substituted ben2aldehyde derivatives react in the same manner (80). 

Optically Active PO. The synthesis of optically pure PO has been accompHshed by microbial asymmetric reduction of chloroacetone [78-95-5] (90). (3)-2-Meth5loxirane [16088-62-3] (PO) can be prepared in 90% optical purity from ethyl (3)-lactate in 44% overall yield (91). This method gives good optical purity from inexpensive reagents without the need for chromatography or a fermentation step. (3)-PO is available from Aldrich Chemical Company, having a specific rotation [0 ] ° 7.2 (c = 1, CHCl ). 

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiendy reduces all simple four- to nine-membered cycHc ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aUphatic acycHc ketones (C-4—C-10) (103,104) can be efficiendy achieved by alcohol dehydrogenase isolated from Thermoanaerohium hrockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse Hver and T. hrockii... 

J -Dehydroquinolizidine reacts with the enantiomeric (—)- and (-l-)-menthyl chloroformates forming (—)- and (-l-)-menthoxycarbonyl- -dehydroquinolizidines. These can be reduced as such or in the form of their immonium salts with sodium borohydride to (—)- and (+)-l-menthoxy-carbonylquinolizidines, which give (+)- and (-)-lupinin, respectively, on reduction with lithium aluminum hydride (243). The optical yield of the asymmetric reduction is about 10%. 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

Biomimetic oxidation and asymmetric reduction with coenzyme NAD analogs 99YGK512. 

General procedure for the asymmetric reduction of e,/l-unsaturated ketones [32]... 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

The synthesis of 10 features the SN2 displacement of the allylic acetate with migration of R2 from the ate complex6. Precursors 9 are prepared by the hydroboration of 3-acetoxy-l-alkynes that are available with very high enantiomeric purity via the asymmetric reduction of the corresponding l-alkyn-3-ones, and a substantial degree of asymmetric induction occurs in the conversion of 9 to 10. Best results, based on the enantioselectivity of reactions of 10 with aldehydes, are obtained when R2 is a bulky group such as isopinocampheyl (79 85 % ee)6. The yields of reactions of 10 with aldehydes are 62-76%. 

Optically active 1-alkoxyallylstannanes are more readily available by asymmetric reduction of acylstannanes using either ( + )-(/J)-BINAL-Il105 106 or LiAlH4-Darvon alcohol [(2S,3/ )-4-dimethylamino-3-mcthy]-1,2-diphenyl-2-butanol] 06 followed by O-alkylation. The stereoselectivity of the BINAL-H reductions differs from that usually observed, and has been attributed to a tin-oxygen hypervalent interaction107, l08. 

Alkoxyallylstannanes are also available by boron trifluoride-diethyl ether complex induced isomerization of their 1-alkoxy isomers. This isomerization proceeds in an antarafacial manner with excellent stereoselectivity to give (Z)-3-alkoxyallylstannanes possibly via an intermolecu-lar exchange process119. Coupled with the asymmetric reduction of acylstannanes (see Section 1.3.3.3.2.3.1) this provides access to 1-alkyl-3-alkoxyallylstannanes of useful optical purity106. 

Enantiomerically pure alkylboranes arc known to be excellent reagents for asymmetric reduction but they can also be used to generate enantiomerically pure /V-borylimines by partial reduction of nitriles. Addition of organolithium and Grignard reagents to these compounds affords secondary carbinamines in moderate to good yield but low enantioselectivity13,14. The best results reported so far are shown below. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

Aryl vinyl sulphones, reactions of 646 Aryl vinyl sulphoxides 620 optical resolution of 287 reactions of 354, 355, 360, 361, 621 Asscher-Vofsi reaction 189 Asymmetric induction 625 Asymmetric oxidation 72-78 Asymmetric reduction 78, 79 Asymmetric synthesis 824-846 Atomic orbitals 2, 3 Azetidinones 790, 791 ot-Azidoaldehydes, synthesis of 811 Azidosulphones, photolysis of 883, 884 Azosulphones, photolysis of 879 Azoxysulphones, photolysis of 879 1-Azulyl sulphoxides, synthesis of 265... 

The results cited in this section indeed appear very promising and encouraging, but there are still many problems to solve. Chemical and optical yields are extremely sensitive to experimental conditions such as current density and electrolyte composition Some experimental details in the asymmetric reduction of citraconic acid are indeed puzzling, such as a temperature maximum of the optical yield, and the fact the same product enantiomer is formed regardless if D or l polyvaline was used... 

O Water absorbing polymer Figure 8.26 Asymmetric reduction of ketones in CO2 by Geotrichum candidum immobilized whole cell [20], (a) Time course for the reduction of o-fluoroacetophenone (b) substrate specificity (c) apparatus for C. candidum-cata yzed reduction with semiflow process using scC02. 

Resting cell of G. candidum, as well as dried cell, has been shown to be an effective catalyst for the asymmetric reduction. Both enantiomers of secondary alcohols were prepared by reduction of the corresponding ketones with a single microbe [23]. Reduction of aromatic ketones with G. candidum IFO 5 767 afforded the corresponding (S)-alcohols in an excellent enantioselectivity when amberlite XAD-7, a hydro-phobic polymer, was added to the reaction system, and the reduction with the same microbe afforded (R)-alcohols, also in an excellent enantioselectivity, when the reaction was conducted under aerobic conditions (Figure 8.31). 

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]. 

Asymmetric reduction with very high ee values has also been achieved with achiral reducing agents and optically active catalysts. The two most important... 

In the above cases, an optically active reducing agent or catalyst interacts with a prochiral substrate. Asymmetric reduction of ketones has also been achieved with an achiral reducing agent, if the ketone is complexed to an optically active transition metal Lewis acid. ... 

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