Mechanisms asymmetric reduction

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

To date, synthetically useful enantioselective hydroalumination is limited to the asymmetric reductive ring-opening reaction of bicycHc ethers. In spite of the fact that further studies are necessary to get a detailed understanding of the reaction mechanism, this reaction provides a new route to various cycloalkenol derivatives, which are useful intermediates in the preparation of biologically active compounds. 

In many studies of asymmetric reductions no attempts were made to rationalize either the extent or the sense of the observed asymmetric induction, that is, the absolute configuration of the predominant enantiomer. It is believed that it is premature in certain cases to attempt to construct a model of the transition state of the key reaction step, given the present state of knowledge about the mechanism of these reduction processes. The complexity of many of the reducing systems developed is shown by the fact that the enantiomeric excess or even the sense of asymmetric induction may depend not only on the nature of the reducing agent and substrate, but also on temperature, solvent, concentration, stoichiometry of the reaction, and in some cases the age of the reagent. 

Despite the uncertainties of mechanism and of the identity of reactive species, attempts have been made to analyze stereochemical control in asymmetric reductions in terms of a model of the transition state in which steric or other interactions can be assessed. These models could prove useful in suggesting modifications for improving the design of selective reducing agents or for predictive purposes. However, it should be kept in mind that there are only two possible outcomes in the direction of asymmetric induction at a prochiral unit undergoing reaction, and confidence in the predictive usefulness of a given model can only be obtained after a considerable number of examples have been examined. 

T. Matsuda, T. Harada, N. Nakajima, and K. Nakamura, Mechanism for improving stereoselectivity for asymmetric reduction using acetone powder of microorganism, Tetrahedron Lett. 2000, 41, 4135 4138. 

The boron atom dominates the reactivity of the boracyclic compounds because of its inherent Lewis acidity. Consequently, there have been very few reports on the reactivity of substituents attached to the ring carbon atoms in the five-membered boronated cyclic systems. Singaram and co-workers developed a novel catalyst 31 based on dicarboxylic acid derivative of 1,3,2-dioxaborolane for the asymmetric reduction of prochiral ketones 32. This catalyst reduces a wide variety of ketones enantioselectively in the presence of a co-reductant such as LiBH4. The mechanism involves the coordination of ketone 32 with the chiral boronate 31 and the conjugation of borohydride with carboxylic acid to furnish the chiral borohydride complex 34. Subsequent transfer of hydride from the least hindered face of the ketone yields the corresponding alcohol 35 in high ee (Scheme 3) <20060PD949>. 

Asymmetric reduction of activated olefins has been performed using prochiral cumarin derivatives [414—416]. A maximum asymmetric yield reported was 17%, as in Eq. (62) [415], and an asymmetry induction mechanism has also been discussed [416]. Later, Schafer and coworkers carried out similar enantioselective electroreduction of various 4-substituted cumarins by systematic variation of the electrolysis conditions, and they obtained optical yields as high as 67% [Eq. (62)] [417-419]. Computational chemistry using semiempirical AMI demonstrates that ri-protonation of the intermediate anion by protonated yohimbine to form the (i )-isomer is energetically favored [418,419]. 

The cyclic mechanism, in which the concertedness of the reaction is so clearly depicted, has found applications in several other instances in organomagnesium chemistry. This is particularly true for the reduction reaction with the aid of Grignard compounds. It was reported in 1950, in a paper on the asymmetric reduction of ketones with the aid of chiral Grignard reagents [58], that Whitmore had already presented the idea of a cyclic mechanism (Scheme 23) at an American Chemical Society meeting in 1943 [59] ... 

Enantioselective reduction of simple ketone carbonyls is possible, but catalysts that deliver consistently high selectivities in such reactions have been elusive [61-64]. More success has been recorded in the asymmetric reduction of functionalized ketones and imines (reviews [65,66]). Two types of stoichiometric reductants are used dihydrogen and dihydrosilanes (reviews ref. [67,68]), but as the mechanism of hydrosilylation is highly controversial [68], we will discuss only the former. 

These examples were followed with a continuous stream of ligands (that continues to this day cf. ref. [66,105,107,108,118-120]) that were tested with rhodium and other metals in asymmetric reductions and other reactions catalyzed by transition metals [102-104,121]. Simultaneously, studies of the mechanism of the asymmetric hydrogenation were pursued, most agressively in the labs of Halpem... 

The great utility of this asymmetric reduction system is a result of the detailed and systematic analysis of its mechanism by the Corey group at Harvard and others.16 6- 7 Using the Itsuno conditions as a starting point, the Corey laboratories obtained pure (after sublimation) oxazaborolidine 10 from the reaction of amino alcohol 9 with two equivalents of BH3-THF... 

Further, in contrast to heterogeneous catalysis, where scattering of deuterium throughout the molecule usually results, selective addition of D2 to a double bond occurs. Finally, asymmetric hydrogenation has been achieved by use of complexes with phosphines that are optically active either at the phosphorus atom or at a carbon atom on the group attached to P.53 The mechanism of reduction probably involves the following steps ... 

Scheme 5. Mechanism of the asymmetric reduction of carbonyl compounds (e. g. 25) with borane and chiral oxazaborolidine catalysts (e. g. 26).

As the essential features of enzymatic mechanisms are unraveled, there should be simultaneous utilization of this information in nonenzymatic chemistry. Modern synthetic methods enable subtle, but powerful, electronic and steric forces, such as must exist at the active site in enzymatic reactions, to be brought to bear on functional groups in simple models. The chemist interested in asymmetric reductions and other asymmetric syntheses now faces this interesting challenge. 

The catalytic mechanism of the asymmetric reduction of alkenes catalyzed by ene-reductases has been studied in great detail [977] and it has been shown that a hydride (derived from a reduced flavin cofactor) is stereoselectively transferred onto Cp, while a Tyr-residue adds a proton (which is ultimately derived from the solvent) onto Cot from the opposite side (Scheme 2.134). As a consequence of the stereochemistry of this mechanism, the overall addition of [H2] proceeds in a trans-fashion with absolute stereospecificity [978]. This reaction is generally denoted as the oxidative half reaction . The catalytic cycle is completed by the so-called reductive half reaction via reduction of the oxidized flavin cofactor at the expense of NAD(P)H, which is ultimately derived from an external H-source via another... 

Discussion in the previous section raises the question, how the 1,4-dihydropyridine moiety releases a negative species, "hydride , after being coordinated by a metal ion that has an electron-withdrawing property. To answer the question and to consider the molecular arrangement in the transition state of the asymmetric reduction we must deal with the mechanism of the reduction by 1,4-dihydropyridine derivatives. 

Allylic alcohols also provide a suitably activated substrate for hydrogenation. Ryoji Noyori s asymmetric reduction of the prochiral geraniol (E-double bond geometry) and nerol (Z-double bond geometry) to enantiomerically pure citronel-lol in the presence of Ru(OAc)2 BINAP is a well-known example. The nonallylic olefin is not reduced appreciably, which indicates the importance that the allylic alcohol functionality plays in this reduction. (Homoallylic alcohols are also reduced by this system, but when the olefin in question is three or more bonds distant from the alcohol moiety, the compound is inert.) Either enantiomer of cit-ronellol is accessible regardless of which substrate is used depending on the chirality of the Ru-BINAP catalyst used (8). This type of relationship implies that the reaction s mechanism possesses high facial selectivity. 

First, for reasons of clarity, the currently-accepted mechanism of transition-metal complex catalyzed-hydrosilylation reactions will be described briefly. Furthermore, consideration of selective, if not asymmetric, reduction of certain carbonyl compounds by way of rhodium(I)-catalyzed hydrosilylation (Section 4) is included in this review because the catalytic process and stereochemical course of this reaction correlate closely with those of their asymmetric reduction under similar conditions that will be described in the succeeding section. 

Asymmetric reduction of ketones by hydrosilylation in the presence of a chiral catalyst followed by hydrolysis has been studied by several research groups independently. In this Section, results so far obtained are properly compiled and plausible mechanisms of the asymmetric hydrosilylation of prochiral ketones are discussed. 

---