Alcohols oxidative kinetic resolution

SCHEME 34.35. Structure of (—(-aurantioclavine 133 and details of the secondary alcohol oxidation kinetic resolution step. 

SCHEME 34.37. Structure of (-l-)-amurensinine 141 and details of the asymmetric secondary alcohol oxidative kinetic resolution step. 

SCHEME 34.41. Asymmetric secondary alcohol oxidation kinetic resolution step in the synthesis of human neurokinin receptor antagonist h-NKl 156. 

The complex Pd-(-)-sparteine was also used as catalyst in an important reaction. Two groups have simultaneously and independently reported a closely related aerobic oxidative kinetic resolution of secondary alcohols. The oxidation of secondary alcohols is one of the most common and well-studied reactions in chemistry. Although excellent catalytic enantioselective methods exist for a variety of oxidation processes, such as epoxidation, dihydroxy-lation, and aziridination, there are relatively few catalytic enantioselective examples of alcohol oxidation. The two research teams were interested in the metal-catalyzed aerobic oxidation of alcohols to aldehydes and ketones and became involved in extending the scopes of these oxidations to asymmetric catalysis. 

In an effort to develop more active catalyst systems for the oxidative kinetic resolution of non-activated alcohols, Stoltz et al. discovered a modified set of conditions that accomplishes similar resolutions in a fraction of the time [43]. 

Sigman et al. have optimized their system too [45]. A study of different solvents showed that the best solvent was f-BuOH instead of 1,2-dichloroethane, which increased the conversion and the ee. To ensure that the best conditions were selected, several other reaction variables were evaluated. Reducing the catalyst loading to 2.5 mol % led to a slower conversion, and varying temperature from 50 °C to 70 °C had little effect on the selectivity factor s. Overall, the optimal conditions for this oxidative kinetic resolution were 5 mol % of Pd[(-)-sparteine]Cl2, 20 mol % of (-)-sparteine, 0.25 M alcohol in f-BuOH, molecular sieves (3 A) at 65 °C under a balloon pressure of O2. 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Interestingly, the scope of the reaction using this catalyst can be extended to oxidative kinetic resolution of secondary alcohols by using (-)-sparteine as a base (Table 10.2) [25]. The best enantiomeric excess of the alcohol was obtained when a chiral enantiopure base and an achiral catalyst were used. The use of chiral enantiopure catalyst bearing ligand 17 led to low enantioselectivity. 

Scheme 10.6 Mechanism of aerobic oxidation catalysed by complex 13 [23] Table 10.2 Oxidative kinetic resolution of alcohols using (-)-sparteine [25]...

Axially chiral Pd-NHC complexes reported by Shi and co-workers [26-28] have shown high selectivity in the oxidative kinetic resolution of alcohols without the need of addition of a chiral base. Enantiomeric excesses of up to 99% were obtained (Scheme 10.7). 

Scheme 10.7 Oxidative kinetic resolution of alcohols using chiral bis-NHC hgands [26-28] 10.3.1.2 Anaerobic Oxidation...

The empirical observation that (—)-sparteine 55 is necessary for catalysis implicates a base-promoted pathway in the mechanism. In the first step, a palladium alk-oxide is formed after alcohol binding, followed by p-hydride elimination of the alkoxide to yield a ketone product. On the basis of a kinetic study of the enantio-selective oxidation of 1-phenylethanol, it was revealed that (—)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on palladium and an exogeneous base " ... 

The groups of Sigman and Stoltz have concurrently published the palladium-catalyzed oxidative kinetic resolution of secondary alcohols using molecular oxygen as the stoichiometric oxidant. Both communications also described a single example of a diol desymmetrization using a palladium catalyst in the presence of (—(-sparteine [Eqs. (10.42) ° and (10.43) ] ... 

Oxidative kinetic resolution of secondary alcohols mediated with a catalytic amount of optically active binaphthyl-type iV-oxyl has been performed with high selectivity". Also, it has mediated oxidative asymmetric desymmetrization of primary alcohols with good selectivity (equation 25)". ... 

As already reported in Section II.A.2, the enzymes chloroperoxidase (CPO) and Copri-nus peroxidase (CiP) catalyze the enantioselective oxidation of aryl alkyl sulfides. If a racemic mixture of a chiral secondary hydroperoxide is used as oxidant, kinetic resolution takes place and enantiomerically enriched hydroperoxides and the corresponding alcohols can be obtained together with the enantiomerically enriched sulfoxides. An overview of the results obtained in this reaction published by Wong and coworkers, Hoft and... 

Even more interesting is the oxidative kinetic resolution of alcohols under aerobic conditions. The system Pd(lI)/sparteine/02 was reported to convert a racemic alcohol with high selectivity into the ketone and the alcohol [97-99]. This has also been shown to work with palladium carbene complexes (Scheme 16). 

Scheme 16 Aerobic oxidative kinetic resolution of secondary alcohols...

The allylic alcohol binds to the remaining axial coordination site, where stereochemical and stcrcoelectronic effects dictate the conformation shown in Figure 6A.9 [6]. The structural model of catalyst, oxidant, and substrate shown in Figure 6A.9 illustrates a detailed version of the formalized rule presented in Figure 6A. 1. Ideally, all observed stereochemistry of epoxy alcohol and kinetic resolution products can be rationalized according to the compatibility of their binding with the stereochemistry and stereoelectronic requirements imposed by this site [6]. A... 

In principle, oxidative kinetic resolution of racemic alcohols can be achieved by using chiral oxidation catalysts such as TEMPO derivatives or dioxiranes. The selectivity achieved by use of these methods is, however, less than that observed in acylation reactions (Section 12.1). 

Pd(II) catalysts have been widely used for aerobic oxidation of alcohols. The catalytic systems Pd(OAc)2-(CH3)2SO [14] and Pd(OAc)2-pyridine [15] oxidize allylic and benzylic alcohols to the corresponding aldehydes and ketones. Secondary aliphatic alcohols, with relatively high water solubility, have been oxidized to the corresponding ketones by air at high pressure, at 100 °C in water, by using a water-soluble bathophenanthroline disulfonate palladium complex [PhenS Pd(OAc)2] [5d]. The Pd catalyst has also been successfully used for aerobic oxidative kinetic resolution of secondary alcohols, using (-)-sparteine [16]. 

Several other systems have been discovered for the aerobic oxidative kinetic resolution of secondary alcohols. Katsuki has shown that (nitroso)Ru-salen complexes such as 1 can successfully resolve alcohols under photolytic conditions in the presence of dry air (Scheme 4) [9]. A related Ru complex was also able to achieve... 

Fig. 12.14 Chiral nitroxyl radical 34 for oxidative kinetic resolution of alcohols.

In 1998 evidence for the existence of a commonly invoked intermediate for a variety of oxygen transfer reactions involving the ]0 = Mn ] moiety was obtained by interception of an ]0 = Mn (salen)(OIPh)] complex (Fig. lA) and a binu-clear [pi-0(Mn (salen)(0IPh))2] complex (Fig. IB) [36]. Later, an ESI-MS study on the Mn-catalyzed oxidative kinetic resolution of secondary alcohols by PhI(OAc)2 reported the observation of a similar manganese salen intermediate [MnV(salen)(PhIO)(OCH(CH3)Ph]+ (Fig. 1C) [6]. This, along with the observation of [Mn "(salen)(PhI(OAc)2)] (Fig. ID), allowed the proposal of a possible catalytic cycle for the kinetic resolution of secondary alcohols by this system. 

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