Enantioselectivity hydride transfer

A crystalline inclusion complex of 10-(4-f-butylphenyl)-3-(2-ethyl-phenyl)-pyrimido[4,5-fc]quinoline-2,4(3H,10H)-dione/urea/EtOH obtained. X-ray analysis showed that the urea is doubly H-bonded to the pyrimidinone (96TL8905). The proximity of the chiral axis might give interesting applications in chiral recognition. The enantiomers were involved in an enantioselective hydride transfer reaction (Figure 25). 

The direct asymmetric reduction of unprotected l//-indoles to chiral indolines with up to 93% ee progressed via electrophilic indolenium ions formed by C(3) protonation by in situ generated HCl the chiral Lewis base (149) then mediated enantioselective hydride transfer from HSiCl3. ... 

Polbom and Severin studies have been reported that describe the use of MlPs in the reduction of ketones." This research was related closely to the work of Lemaire et al. on enantioselective hydride-transfer reactions using a catalytic Rh(l) complex" (see below), but, beneficially, an achiral catalyst and the catalytically more active Ru(ll) center was used. The MIP was prepared from a six-membered TSA for the reduction of benzophenone (Figure 2) and exhibited a sevenfold increase in hydrogenation rate relative to the control polymer. Impressive substrate selectivity was also observed with this imprinted catalyst because benzophenone was reduced preferentially with respect to acetophenone and in stark contrast use of the control polymer afforded the opposite selectivity. The 2-point connection of the catalyst to the polymer (Figure 2) was shown to improve the activity and selectivity over the analogous MIP with a single recognition site. 

The Lemaire research group has performed pioneering studies in this area. For example, enantioselective hydride-transfer reaction has been investigated using a catalytic rhodium complex incorporated into an organic cross-linked... 

Scheme 18 The MIP-catalyzed enantioselective hydride transfer to acetophenone. Reagents and conditions (i) Propan-2-ol and (ii) 5mol% Rh(I) polymer, KOH, i-PrOH, 60 °C, one day.

In the presence of achiral or racemic aluminum complexes, enantioselective hydride transfer of chiral secondary alcohols to carbonyl compounds was well... 

SCHEME 1.85 Catalytic enantioselective hydride-transferring closure. 

In the same study, several ligands variously functional on both the nitrogen and the sulfur atoms have been developed, providing a new class of cyclo-hexylamino sulfide ligands derived from cyclohexene oxide. All the ligands depicted in Scheme 9.7 were evaluated for the Ir-catalysed hydride-transfer reduction of acetophenone in the presence of i-PrOH as the hydrogen donor, providing enantioselectivities of up to 70% ee. 

New chiral oxazaborolidines that have been prepared from both enantiomers of optically active inexpensive a-pinene have also given quite good results in the asymmetric borane reduction of prochiral ketones.92 Borane and aromatic ketone coordinate to this structurally rigid oxazaborolidine (+)- or (—)-94, forming a six-membered cyclic chair-like transition state (Scheme 6-41). Following the mechanism shown in Scheme 6-37, intramolecular hydride transfer occurs to yield the product with high enantioselectivity. With aliphatic ketones, poor ee is normally obtained (see Table 6-9). 

A case of the addition of an allylstannane to aldehydes has been reported by Tagliavini to proceed with appreciable enantioselectivity (Scheme 6.15) [40]. A notable feature of the Zr-catalyzed transformations is that they proceed more rapidly than the corresponding Ti-catalyzed processes reported by the same research team (see Scheme 6.16). Furthermore, C—C bond formation is significantly more efficient when the reactions are carried out in the presence of 4 A molecular sieves the mechanistic rationale for this effect is not known. It should be noted that alkylations involving aliphatic aldehydes are relatively low-yielding, presumably as the result of competitive hydride transfer and formation of the reduced primary alcohol. 

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). 

Due to the extensively represented oxidative behaviour of the carbenium ions as hydride abstractor or one-electron oxidant [157], attempts were made to employ the carbocations as reagents. Recently the enantioselective outcome in a hydride transfer reaction was reported [158, 159]. The abstraction of the exo hydrogen atoms from the tricarbonyliron complex 57 resulted in a yield up to 70% and enantiose-lectivity of 53% (Scheme 62) [158]. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

In the phase-transfer processes discussed in Section 11.2 it is assumed that the anionic hydride source, i.e. borohydride or a hypervalent hydrosilicate, forms an ion-pair with the chiral cationic phase-transfer catalyst. As a consequence, hydride transfer becomes enantioselective. An alternative is that the nucleophilic activator needed to effect hydride transfer from a hydrosilane can act as the chiral inducer itself (Scheme 11.6). 

In 1988, Hosomi et al. established that hydride transfer from hydrosilanes can be rendered enantioselective by using chiral anionic activators such as the dilithium salts of the diol 15 or of phenylalaninol 16 (Scheme 11.6) [22], In the presence of stoichiometric amounts of the dilithium salt of 15, isobutyrophenone was reduced by trialkoxysilanes with 69% ee, whereas 40 mol% of the corresponding salt of 16 was sufficient to effect reduction of acetophenone with 49% ee [23],... 

There are a number of different approaches to performing enantioselective reductions of ketones within the flow domain, using either a borane-derived hydride transfer agent such as that described previously or modified transition metal hydrogenations an example of the latter involved a column of Pt/Al203 modified with O-methyl cinchonidine (21) to induce chirality in the product (Scheme 4.64). Continuous monitoring showed that a 30 min induction period was required before the optimal reaction rate and ee could be obtained. This was ascribed to the need for... 

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