Stoichiometric racemic catalysts

The first use of a metal catalyst in the DKR of secondary alcohols was reported by Williams et al. [7]. In this work, various rhodium, iridium, ruthenium and aluminum complexes were tested. Among them, only Rh2(OAc)4 and [Rh(cod)Cl]2 showed reasonable activity as the racemization catalyst in the DKR of 1-phenylethanol. The racemization occurred through transfer-hydrogenation reactions and required stoichiometric amounts of ketone as hydrogen acceptor. The DKR of 1-phenylethanol performed with Rh2(OAc)4 and Pseudomonas Jluore-scens lipase gave (R)-l-phenylethyl acetate of 98%e.e. at 60% conversion after 72 h. 

The Williams group reported the DKR of 1-phenylethanol as the first metalloenzy-matic DKR [9]. This DKR employed Pseudomonas fluorescens lipase (PPL) as the resolution enzyme, a rhodium complex as the racemization catalyst, and vinyl acetate as the acyl donor in cyclohexane, but the reaction required a stoichiometric amoxmt of acetophenone for hydrogen transfer and stopped at 60% conversion (Scheme 5.6). 

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

The application of a chiral auxiliary or catalyst, in either stoichiometric or catalytic fashion, has been a common practice in asymmetric synthesis, and most of such auxiliaries are available in homochiral form. Some processes of enantiodifferentiation arise from diastereomeric interactions in racemic mixtures and thus cause enhanced enantioselectivity in the reaction. In other words, there can be a nonlinear relationship between the optical purity of the chiral auxiliary and the enantiomeric excess of the product. One may expect that a chiral ligand, not necessarily in enantiomerically pure form, can lead to high levels of asymmetric induction via enantiodiscrimination. In such cases, a nonlinear relationship (NLE) between the ee of the product and the ee of the chiral ligand may be observed. 

In practice, any of these four approaches might be the most effective for a given synthesis. If they are judged on the basis of absolute efficiency in the use of chiral material, the ranking is resolution < natural source < chiral auxiliary < enantioselective catalyst. A resolution process inherently employs only half of the original racemic material. A starting material from a natural source can, in principle, be used with 100% efficiency, but it is consumed and cannot be reused. A chiral auxiliary can, in principle, be recovered and reused, but it must be used in stoichiometric amount. A chiral catalyst can, in principle, produce an unlimited amount of an enantiomerically pure material. 

Another method for the asymmetric version of the Baeyer-Villiger reaction was presented by Lopp and coworkers in 1996 . By employing overstoichiometric quantities of Ti(OPr-t)4/DET/TBHP (1.5 eq./1.8 eq./1.5 eq.), racemic andprochiral cyclobutanones were converted to enantiomerically enriched lactones with ee values up to 75% and moderate conversions up to 40% (Scheme 171). Bolm and Beckmann used a combination of axially chiral C2-symmetric diols of the BINOL type as ligands in the zirconium-mediated Baeyer-Villiger reaction of cyclobutanone derivatives in the presence of TBHP (or CHP) as oxidant (Scheme 172) . With the in situ formed catalysts 233a-d the regioisomeric lactones were produced with moderate asymmetric inductions (6-84%). The main drawback of this method is the need of stoichiometric amounts of zirconium catalyst. 

Widenhoefer and co-workers have developed an effective Pd-catalyzed protocol for the asymmetric cyclization/ hydrosilylation of functionalized 1,6-dienes that employed chiral, non-racemic pyridine-oxazoline ligands." " " Optimization studies probed the effect of both the G(4) substituent of the pyridine-oxazoline ligand (Table 7, entries 1-6) and the nature of the silane (Table 7, entries 6-15) on the yield and enantioselectivity of the cyclization/ hydrosilylation of dimethyl diallylmalonate. These studies revealed that employment of isopropyl-substituted catalyst (N-N)Pd(Me)Gl [N-N = (i )-( )-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(i )-43f and a stoichiometric amount of benzhydryldimethylsilane provided the best combination of asymmetric induction and chemical yield, giving the corresponding silylated cyclopentane in 98% yield as a single diastereomer with 93% ee (Table 7, entry 15). 

The advantage of asymmetric activation of the racemic BINOL-Ti(OPr )2 complex ( 2) is highlighted in a catalytic version (Table 8C.3, entry 5) wherein high enantioselectivity (80.0% ee) is obtained by adding less than the stoichiometric amount (0.25 molar amount) of (R)-BI-NOL [42a], A similar phenomenon has been observed in the aldol [42c] and (hetero) Diels-Al-der [44] reactions catalyzed by the racemic BINOL-Ti(OPr )2 catalyst (+2). 

The same group subsequently discovered that the loading of the chiral diamine catalyst can be reduced substantially if triethylamine is added in stoichiometric amounts as an achiral proton acceptor [37b]. As shown at the top of Scheme 13.23, as little as 0.5 mol% catalyst 45 was sufficient to achieve yields and ee comparable with the stoichiometric variant (application of the Oriyama catalysts 44 and 45 in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). Oriyama et al. have also reported that 1,3-diols can efficiently be desymme-trized by use of catalysts 44 or 45. For best performance n-butyronitrile was used as solvent and 4-tert-butylbenzoyl chloride as acylating agent (Scheme 13.23, bottom) [38]. 

One of the first effective chiral PPY derivatives to be developed for asymmetric acyl transfer was catalyst 7, which was shown by Fuji and Kawabata in 1997 to be effective for the acylative KR of various racemic mono-benzoylated ds-diol derivatives [76]. Subsequently, it was also successfully applied in the KR of N-protected cyclic ds-amino alcohols [77]. Using 5 mol% of PPY 7 in the presence of a stoichiometric amount of collidine in CHCI3 at rt, a variety of cyclic ds-amino alcohol derivatives were resolved with moderate selectivities (s = 10-21) (Table 8.6). 

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