Noyori studies

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

Kitamura and Noyori have reported mechanistic studies on the highly diastere-omeric dialkylzinc addition to aryl aldehydes in the presence of (-)-i-exo-(dimethylamino)isoborneol (DAIB) [33]. They stated that DAIB (a chiral (i-amino alcohol) formed a dimeric complex 57 with dialkylzinc. The dimeric complex is not reactive toward aldehydes but a monomeric complex 58, which exists through equilibrium with the dimer 57, reacts with aldehydes via bimetallic complex 59. The initially formed adduct 60 is transformed into tetramer 61 by reaction with either dialkylzinc or aldehydes and regenerates active intermediates. The high enantiomeric excess is attributed to the facial selectivity achieved by clear steric differentiation of complex 59, as shown in Scheme 1.22. 

Noyori et al. recently used ESI-MS to characterize species present in catalytically active solutions during the hydrogenation of aryl-alkyl ketones using their base-free catalyst precursors trans-[Ru((R)-tol-BINAP)((R, RJ-dpenJfHXf/ -BH ] (tol-BI-NAP = 2,2 -bis(ditolylphosphino) -1, T-binaphthyl dpen = 1,2-diphenylethylenedia-mine) in 2-propanol [9b]. Based upon ESI-MS observations, deuterium-labeling studies, kinetics, NMR observations, and other results, the authors proposed that the cationic dihydrogen complex trans-[Ru((R)-tol-BINAP)((R, R)-dpen)(H)( 2-H2)]+ is an intermediate in hydrogenations carried out in the absence of base. 

From the seminal studies of Sabatier [43] and Adams [44] to the more recent studies of Knowles [45] and Noyori [46], catalytic hydrogenation has been regarded as a method of reduction. The results herein demonstrate the feasibility of transforming catalytic hydrogenation into a powerful and atom-economical method for reductive C-C bond formation. Given the profound socioeconomic impact of al-kene hydroformylation, the development of catalysts for the hydrogen-mediated... 

Two technical applications of C = N-X substrates have been reported. Noyori s Ru-PP-NN catalyst system was successfully applied in a feasibility study by Dow Chirotech for the hydrogenation of a sulfonyl amidine [77], while Avecia showed the commercial viability of its CATHy catalyst based on a pentamethyl cyclopentadienyl Rh complex for the reduction of phosphinyl imines [78] (Fig. 34.11). 

The reports by Noyori sparked intense academic and industrial interest in this area, and these studies led ultimately to a plethora of reports describing investigations into new catalysts [1]. In this respect, a variety of metals have been employed, including cobalt, nickel, palladium, platinum and zinc, though the best catalysts have employed ruthenium [11], rhodium [14, 15] and iridium [14, 16, 17]. 

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]. 

Vedejs et al. reported catalyst inhibition during a study on the enantioselective transfer hydrogenation of dihydro-isoquinolines using Noyori s catalyst (Scheme 44.2) [27]. Here, the problem is caused by the bidentate nature of the substrate. Whereas the bromo compound 1 a could be rapidly reduced, the tosylamide-sub-stituted compound lb could not be reduced, and although the problem could be alleviated somewhat by alkylation of the sulfmamide to 1 c, hydrogenation of this was still sluggish. Although the authors propose this to be a case of product... 

After extensive developmental studies, [35] the final crucial element in our most recent synthesis of epothilone B involves an asymmetric catalytic reduction of the C3 ketone of 67 proceeding via a modified Noyori procedure (Scheme 2.8, 67—>68). In the event, Noyori reduction of ketone 67 afforded the desired diol 68 with excellent diasteresdectivity (>95 5). The ability to successftdly control the desired C3 stereochemistry of the late stage intermediate 68 permitted us to introduce the Cl-C7 fragment into the synthesis as an achiral building block. 

A more recent isotope study has been conducted with the use of the actual Noyori catalyst by Casey and Johnson [41], They studied the kinetic isotope effect by H NMR spectroscopy at -10 to -30 °C for the reaction of d, d-i (CH/OD and CD/OH), < s isotopically substituted propan-2-ol and 4-phenylbut-3-yn-2-none. The catalyst and the reaction are shown in Figure 4.31. 

Example 5 Hayakawa and Noyori group in their studies on new activators for phosphoroamidite coupling reactions have applied the most effective member of the group of acid/azole complexes AT-(phenyl)imidazolium tri-flate (N-PhIMT) in the efficient synthesis of biologically important compounds [20j]. A noteworthy example is synthesis of cytidine-5 -monophos-pho-AT-acetylneuraminic acid. This compound is a source of sialic acid in the sialyltransferase-catalysed biosynthesis of sialyl oligosaccharides [25]. 

These deviations from linearity indicate the existence of an oligomeric distribution of chiral ligands. Noyori proposed a rationale as follows Due to the different dissociability (stability) of homochiral and heterochiral dimer, the enantiopurity of the remaining reactive catalyst (monomer) is improved as compared with that of the submitted chiral ligand 6 (Scheme 9.5) [11]. Heterochiral dimer is thermodynamically more stable than homochiral dimer, which is consistent with Noyori s rationale mentioned above [12a]. An ab initio molecular orbital study was also reported in a simplified model reaction between formaldehyde and dimethylzinc catalyzed by achiral 2-aminoethanol [12b]. 

The reduction of e.w-c/./i-unsaturated lactones in high e.e.s has recently been reported to be achievable by the use of Ru/BINAP combinations (Scheme 22)138. Some extensive studies, reported in a detailed full paper by Noyori, have been carried out to identify which factors control the enantioselectivity of the reaction. That the carbonyl group is closely involved in directing the reaction is clearly demonstrated by the observation that... 

Carbon dioxide, either as an expanded liquid or as a supercritical fluid, may be a viable replacement for a variety of conventional organic solvents in reaction systems. Numerous studies have shown that many reactions can be conducted in liquid or supercritical C02 (sc C02) and, in some cases, rates and selectivities can be achieved that are greater than those possible in normal liquid- or gas-phase reactions (other chapters in this book Noyori, 1999 Savage et al., 1995). Nonetheless, commercial exploitation of this technology has been limited. 

The most fully understood system in this class of reactions, however, is the DAIB-catalyzed addition of diethylzinc to aldehydes, due to the very detailed mechanistic studies performed by Noyori et al.32-37 They were able to determine the structure of several intermediates involved in the reaction and established the kinetic law. Part of the catalytic cycle is depicted in Scheme 13. The origin of the asymmetric amplification lies in the formation of dimers of DAIB-zinc alkoxides. The heterochiral dimer is quite stable in the concentration range of the experiment (2 x 10 1 to 5 x 10 1 M in toluene for DAIB), whereas the homodimers are prone to dissociation and react further with diethylzinc to give a di-zinc complex that is the active species in the catalytic cycle. They react with benzaldehyde and give rise to the asymmetric transfer of the ethyl group. The final product, as a zinc alkoxide, does not interfere with the reaction (and hence there is no autoinduction), since it... 

Although the Rh-catalyzed asymmetric hydrogenations of prochiral enamides have been extensively studied and excellent results have been frequently achieved, the catalytic asymmetric hydrogenations of 2-arylacrylic acids have been less successful. Until recently most catalyst systems gave only moderate optical yields for the 2-arylpropionic acid products (77). An important breakthrough in the study of these reactions was reported by Noyori et al. By using Ru(BINAP)(OAc)2 as a catalyst precursor, these researchers obtained excellent optical yields in the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid (72). 

Noyori also observed that under high pressure of H2, the solvolysis of the ruthenium-alkyl species was less important for the product formation. In our study of the Ru(H)-catalyzed hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid in CH3OD, we found the deuterium labelling in the naproxen product to be similar to those reported on the hydrogenation of tiglic acid ... 

---