Asymmetric -Hydride Transfer Reactions

Asymmetric [l,5]-hydride transfer reactions have recently emerged as being an important method to realize the asymmetric functionalization of C(sp )—H bonds. Both transition metal complexes and small molecule organocatalysts are found to be capable of catalyzing these reactions. This chapter aims at providing a concise description of the state-of-the-art of this promising area. 

2 Asymmetric [l,5]-Hydride Transfer Catalyzed by Lewis Acid 

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This type of asymmetric a-aUcylation of aldehydes was combined with an asymmetric hydride transfer reaction to a,P-unsaturated aldehydes. Thus, when used with iminium and enamine activation, access to a-alkylated aldehydes is given. The yields and enantioselectivities observed are better than those described for the enamine catalysis (Scheme 4.17) [49]. 

Aqueous alkali hydroxides can be used to replace flammable bases of sodium metal, sodium hydride, sodamide, and other alkoxides. The reaction temperature is lowered while the reaction rate improves because the increased reactivity of anions in the nonpolar solvent (Goldberg, 1989 Dehmlow and Dehm-low, 1993 Starks et al., 1994) as have asymmetric phase-transfer reactions (O Donnell, 1993). 

Hydride-transfer reactions suffer from the several shortcomings. First, a conventional optical resolution must usually be performed to obtain an optically active carbinol, which is then converted to the halide when the Grignard method is to be used. The actual reduction is generally not the only reaction pathway hence carbinol by-product is produced. More undesirable, however, is the fact that the asymmetric center of the organometallic reagent is sacrificed when the new chiral center is created. Unless the reaction is stereospecific, which is rarely the case, a net overall decrease in chirality results. 

In 2009, Seidel and co-workers reported a Lewis acid-catalyzed [l,5]-hydride transfer reaction for the synthesis of polycyclic tetrahydroquinolines. It was found that the gadolinium triflate could efficiently accelerate the reaction (Scheme 4.4a). Preliminary attempts to realize asymmetric catalysis revealed that when a chiral magnesium bisoxazoline was utilized as the catalyst, the desired product 6a could be obtained in 74% yield and 30% ee, which was the first example of a catalytic asymmetric [l,5]-hydride transfer reaction by a chiral Lewis acid (Scheme 4.4b). The reason for the relatively low enanti-oselectivity was attributed to the reversibility of the ring-closure step in the presence of a strong Lewis acid catalyst. 

The Kim group envisioned that the saturated aldehydes 19 might also be used as viable substrates for asymmetrie [l,5]-hydride transfer/cyelization reactions by coupling the in situ generation of the o,p-unsaturated imin-ium intermediate 22 by oxidation (Seheme 4.11a). IBX (2.0 equiv.) was found to be the suitable organie oxidant compatible with the established catalytic system (20 mol% of C3 and 20 mol% of DNBS) for the asymmetric [l,5]-hydride transfer reactions. This novel cascade reaction also allows the efficient synthesis of ring-fused tetrahydroquinoline products with high enantioseleetivity. 

Scheme 4.9 Organoeatalytic asymmetric [l,5]-hydride transfer reaction reported by Kim.

This chapter highlights the recent advances in the area of catalytic asymmetric [l,5]-hydride transfer reactions which have recently emerged as an alternative mediod for the direct functionalization of the C(sp )—H bonds. The intramolecular hydride transfer nature renders the reaction to be a redox-neutral process, thus preventing the use of an external oxidant. The readily occurrence of... 

Hughes M, Prince RH, Wyeth P (1978) Metal ion function in alcohol dehydrogenases-II. The metal binding sites of pyridine carbaldehyde and N-benzyldihydronicotinamide. J Inorg Nucl Chem 40 713-718 Huskey WP, Schowen RL (1983) Reaction coordinate tunneling in hydride-transfer reactions. J Am Chem Soc 105 5704-5706 Inouye Y, Oda J, Baba N (1983) Reduction with chiral dihydropyridine reagents. In Morrison JD (ed) Asymmetric synthesis, vol 2. Academic Press, New York, p91... 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

Mazet et al. have reported an efficient asymmetric isomerization reaction of allylic alcohols [60, 61]. In a preliminary report they utilized the BArp analog of Crabtree s complex to efficiently catalyze a hydride transfer from the a position of the allylic alcohol to the p position of the olefin with a concomitant formation of a formyl group. A subsequent report detailed a remarkable enantioselective variant of this process catalyzed with Ir(12g) and (12h) (Scheme 12). 

The reversible formation of a N,N-dibenzyl iminium intermediate, which is reduced by hydride capture from the Hantzsch ester 1 was proposed. Subsequent hydrolysis regenerates catalyst 2 and releases the saturated aldehyde. The transition state A has been suggested for the hydride transfer. An example of the asymmetric version of this reaction was also realized, by using a chiral imidazolidi-none catalyst (the McMillan imidazolidinium salt 3 [13]) (see Scheme 11.4). 

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