The First Asymmetric Reduction

The first example of the asymmetric reduction by an NAD(P)H model compound was reported in 1975 (Ohnishi et al. 1975a). By means of 

The metal ion in this system may be regarded as a mimetic apo-enzyme in the sense that it not only accelerates the reduction but also provides an asymmetric field as does the enzyme in biological reactions. 

The effect of the bivalent metal ion on the reduction with a 1,4--dihydropyridine derivative as a model of NAD(P)H, particularly on the induction of chirality, was thus found to be quite large. The increase in the stereospecificity is, here, associated with an increase in the reactivity, which is not common in organic reactions. Thus, it will be necessary to discuss the role of the metal ion in the model system before we discuss the mechanism for the induction of asymmetry. 

---

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

Morken and coworkers [39b] developed the first asymmetric reductive aldol reaction with silanes as reductants in combination with a chiral rhodium catalyst. a,P-Unsaturated esters were reacted with several aldehydes to provide the corresponding aldol products 79 in good yields and enantio- and diastereoselectivities (Scheme 8.23). Both aliphatic and aromatic aldehydes could be converted into aldol products 79 under these conditions. Furthermore, the group reported an iridium-catalyzed asymmetric version that tolerated various protected hydroxyaldehydes [39aj. On the basis of this precedence, a highly enantio- and diastereoselective... 

Asymmetric reductions of other iminium salts (Baba et al. 1976) and olefins are also reported. The first asymmetric reduction of an olefinic double bond by a chiral NAD(P)H model was reported by Ohnishi et al. (1976a). a-Methylbenzylidenemalononitrile was reduced by i -PNPH in the presence of magnesium perchlorate in 8 e.e. (Scheme 16). Again Mg(II) was indispensable for the asymmetric induction in this system. 

As mentioned, Matsumura published the first asymmetric reduction of ketimines with a proline formamide activator A 1 and trichlorosilane. The yield and selectivities were only moderate, but it paved the way for further developments. They showed that it was possible to reduce imines selectively in the presence of ketones without affecting the latter. Additionally, a transition state explaining the stereoinduction was hypothesized (Figure 32.6). Transition state TS 1 is preferred over TS 2 because of the steric phenyl-phenyl repulsion of the activator and the substrate. This explains the need of aryl imines for successfid stereoinduction. 

Reductive amination is a well-known methodology in organic synthesis as is evident from the literature reviews. There are a large number of reports available in the literature that deal with the asymmetric imine reduction, but there are few reports available on asymmetric reductive amination. The asymmetric version of this brilliant methodology was introduced in 1999 when Blaser et al. reported on the first asymmetric reductive amination for the synthesis of metolachlor. ... 

The first asymmetric synthesis of (-l-)-abresoline was achieved from the chiral piperidine derivative 153, which upon treatment of its hydroxy side-chain substituent with carbon tetrabromide, triphenylphosphine, and triethyl-amine cyclized to the frarcr-quinazolidine 154. Deketalization and silyl protection of the phenolic group, followed by stereoselective reduction with lithium tri-t -butylborohydride (L-Selectride ), gave an alcohol, which after acylation and deprotection furnished (-l-)-abresoline 155 (Scheme 25) <2005TL2669>. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Given the importance of chiral amines to synthetic chemistry as well as other fields asymmetric hydrogenation of imines has attracted wide interest but limited success compared to C=C and C=0 bond reduction. The first asymmetric hydrogenation of imines was carried out in the seventies with mthenium- and rhodium-based catalysts, followed later by titanium and zirconium systems [82]. Buchwald found that... 

In 2007, AntiUa and coworkers disclosed the first asymmetric organocatalytic reduction of acyclic a-imino esters (Scheme 23) [39], Chiral VAPOL phosphate (5)-16 (5 mol%) served as a catalyst for the transfer hydrogenation of the latter (62) employing commercially available dihydropyridine 44a to give both aromatic and aliphatic a-amino esters 63 in very high yields (85-98%) and enantioselectivities (94-99% ee). 

Two strategies for the synthesis of enantiomerically enriched diaryl methanols 27 are apparent first, asymmetric reductions of the corresponding diaryl ketones 36 [33], and, second, enantioselective aryl transfer reactions to the respective benzaldehyde derivatives 37 (Scheme 2.1.2.5) [34, 35]. 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

Recently, the first asymmetric cell-free application of styrene monooxygenase (StyAB) from Pseudomonas sp. VLB 120 was reported [294]. StyAB catalyses the enantiospecific epoxidation of styrene-type substrates and requires the presence of flavin and NADH as cofactor. This two-component system enzyme consists of the actual oxygenase subunit (StyA) and a reductase (StyB). In this case, the reaction could be made catalytic with respect to NADH when formate together with oxygen were used as the actual oxidant and sacrificial reductant respectively. The whole sequence is shown in Fig. 4.106. The total turnover number on StyA enzyme was around 2000, whereas the turnover number relative to NADH ranged from 66 to 87. Results for individual substrates are also given in Fig. 4.106. Excellent enantioselectivities are obtained for a- and -styrene derivatives. 

The efficient synthesis of racemic triphyophilline (60) paved the way for the first asymmetric total synthesis of the 5,1-linked napthylisoquinoline alkaloid (-)-ancistrocladine (1) (ref. 47). The approach once again relied on the successful intramolecular strategy used previously and required the development of asymmetric synthesis of the tetrahydroisoquinoline portion of 1. The route to isoquinoline segment 79 began with the synthesis of homochiral amphetamine derivative 83 via a reductive methylation protocol (Scheme 10) (ref. 54, 55) Thus, condensation of ketone 80 with (S)-... 

In this short synthesis of (-)-PGEj two of the four stereogenic centres are installed by microbial reduction. The substrate for the first asymmetric step is cyclopentanetrione (92), which is prepared in one step by a double Dieckmann condensation. 

Cheng has published a convenient and synthetically useful alternative method to the NHK reaction for the arylation of aromatic aldehydes in a mild and selective way with nickel(ll) bromide/zinc/dppe mediated protocol for the synthesis of diaryl carbinols. Durandetti reported an electrochemical coupling of aryl halides with aldehydes for the synthesis of diaryl carbinols which was catalytic in chromium and nickel salts. Comins utilized the NHK reaction to prepare 5-(l-hydroxyalkyl)-2,3-dihydro-4-pyridones, which were then explored in reductive, oxidative and substitutive reactions. " The first asymmetric catalytic synthesis of 5y -alk-l-ene-3,4-diols was developed the regio-, diastereo- and enantioselective addition of 3-chloropropenyl pivaloate to aldehydes was made possible by exploiting Salen r(II) species in a catalytic version of the NHK reaction. ... 

As mentioned. List et al. used TRIP derivative 31 in combination with a Hantzsch ester to perform the first asymmetric, oiganocatalytic reductive amination. Acetophenone was stirred for 9 hours at room temperature with anisi-dine in the presence of 4 A molecular sieves to first form the imine. Subsequently, 5 mol% 31 and 1.4 equivalents... 

---