Jacobsen epoxide resolution

Previously, it had been prepared by Jacobsen epoxide resolution however, a more efficient route was required. A collection of methodologies were tested, but these were surpassed by the method of Lepoittevin, which gave 15 in high enantiomeric excess and in large quantities, via the chlorohydrin 73, starting from epichlorohydrin as either enantiopode (Scheme 11). 

Scheme 8.28. Formally group-selection insertion of oxygen into enantiotopic C-H bonds, (a) An asymmetric Kharasch reaction [124], The catalyst is similar to that shown in Scheme 8.12, except that each oxazoline bears two methyl substituents at C-5. (b) Kinetic resolution of dihydronaphthalenes [125]. The reaction uses a Jacobsen epoxidation catalyst (Scheme 8.6, type A).

The product is, of course, racemic but, as it is an amine, resolution with an acid should be straightforward. Crystallization of its tartrate salt, for example, leads to the required single enantiomer in 99.9% ee. With such cheap starting materials, resolution is just about acceptable, even though it wastes half the material. It would be better to oxidize the indene enantio-selectively, and the solution here, as you saw in Chapter 41, is to use a Jacobsen epoxidation, which gives the epoxide in 79% yield and 84% ee. 

Dihydronaphthalene is often used as a model olefin in the study of epoxidation catalysts, and very often gives product epoxides in unusually high ee s. In 1994, Jacobsen discovered in his study on the epoxidation of 1,2-dihydronaphthalene that the ee of the epoxide increases at the expense of the minor enantiomeric epoxide.Further investigation led to the finding that certain epoxides, especially cyclic aromatically conjugated epoxides, undergo kinetic resolution via benzylic hydroxylation up to a krei of 28 (Scheme 1.4.9). 

The first application of the Jacobsen-Katsuki epoxidation reaction to kinetic resolution of prochiral olefins was nicely displayed in the total synthesis of (+)-teretifolione B by Jacobsen in 1995. 

Jacobsen has utilized [(salen)Co]-catalyzed kinetic resolutions of tenninal epoxides to prepare N-nosyl aziridines with high levels of enantioselectivity [72], A range of racemic aryl and aliphatic epoxides are thus converted into aziridines in a four-step process, by sequential treatment with water (0.55 equivalents), Ns-NH-BOC, TFA, Ms20, and carbonate (Scheme 4.49). Despite the apparently lengthy procedure, overall yields of the product aziridines are excellent and only one chromatographic purification is required in the entire sequence. 

Jacobsen demonstrated that the (salen)Cr system used to effect intermolecular, cooperative asymmetric azidolysis of meso-epoxides (Schemes 7.3 and 7.5) could be applied to sulfur-centered nucleophiles (Scheme 7.13). In order to overcome moderate enantioselectivity (<60% ee), a dithiol nucleophile was employed as part of a double resolution strategy in which the minor enantiomer of the monoaddition product reacts preferentially to form the meso- bis-addition product, thereby increasing the ee of the C2-symmetric bis-addition product. Enantiopure 1,2-mer-capto alcohols (>99% ee) were obtained from the meso-epoxide in ca. 50% overall yield by a burdensome (though effective) multistep sequence, [23]. 

Jacobsen also showed that 2,2-disubstituted epoxides underwent kinetic resolution catalyzed by (salen)Cr-N3 complex 3 under conditions virtually identical to those employed with monosubstituted epoxides (Scheme 7.34) [64]. Several epoxides in this difficult substrate class were obtained with high ees and in good yields, as were the associated ring-opened products. The kinetic resolution of TBS-... 

Two recent reports described addition of nitrogen-centered nucleophiles in usefully protected fonn. Jacobsen reported that N-Boc-protected sulfonamides undergo poorly selective (salen) Co-catalyzed addition to racemic epoxides. However, by performing a one-pot, indirect kinetic resolution with water first (HKR, vide infra, Table 7.1) and then sulfonamide, it was possible to obtain highly enantiomer-ically enriched addition products (Scheme 7.39) [71]. These products were transformed into enantioenriched terminal aziridines in straightforward manner. 

One way of overcoming these problems is by kinetic resolution of racemic epoxides. Jacobsen has been very successful in applying chiral Co-salen catalysts, such as 21, in the kinetic resolution of terminal epoxides (Scheme 9.18) [83]. One enantiomer of the epoxide is converted into the corresponding diol, whereas the other enantiomer can be recovered intact, usually with excellent ee. The strategy works for a variety of epoxides, including vinylepoxides. The major limitation of this strategy is that the maximum theoretical yield is 50%. 

The hydrolytic kinetic resolution (HKR) of terminal epoxides using Co-salen catalysts provides a convenient route to the synthesis of enantioemiched chiral compounds by selectively converting one enantiomer of the racemic mixture (with a maximum 50% yield and 100% ee) (1-3). The use of water as the nucleophile makes this reaction straightforward to perform at a relatively low cost. The homogeneous Co(III) salen catalyst developed by Jacobsen s group has been shown to provide high... 

S,12S)-2,12-Diacetoxytridecane (17) is a component of the female pheromone of pea midges (Contarinia pisi). Kitching synthesized 17 as shown in Scheme 28 by employing Jacobsen s hydrolytic kinetic resolution of terminal epoxides with a (salen)Co(OAc) complex, (S,S)-B [46]. By this reaction bis-... 

Jacobsen et al. reported enhanced catalytic activity by cooperative effects in the asymmetric ring opening (ARO) of epoxides.[38] Chiral Co-salen complexes (Figure 4.27) were used, which were bound to different generations of commercial PAMAM dendrimers. As a direct consequence of the second-order kinetic dependence on the [Co(salen)] complex concentration of the hydrolytic kinetic resolution (HKR), reduction of the catalyst loading using monomeric catalyst leads to a sharp decrease in overall reaction rate. 

M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Asymmetric Catalysis with Water Efficient Kinetic Resolution of Terminal Epoxides by Means of Catalytic Hydrolysis, Science 1997, 2T7, 936-938, and references cited therein. 

Scheme 20. Jacobsen s sequential use of catalytic asymmetric reactions, including his Cr-catalyzed kinetic resolution of epoxides in the total synthesis of taurospongin A (1998).

A very successful example for the use of dendritic polymeric supports in asymmetric synthesis was recently described by Breinbauer and Jacobsen [76]. PA-MAM-dendrimers with [Co(salen)]complexes were used for the hydrolytic kinetic resolution (HKR) of terminal epoxides. For such asymmetric ring opening reactions catalyzed by [Co(salen)]complexes, the proposed mechanism involves cooperative, bimetallic catalysis. For the study of this hypothesis, PAMAM dendrimers of different generation [G1-G3] were derivatized with a covalent salen Hgand through an amide bond (Fig. 7.22). The separation was achieved by precipitation and SEC. The catalytically active [Co "(salen)]dendrimer was subsequently obtained by quantitative oxidation with elemental iodine (Fig. 7.22). 

ARO reaction with phenols and alcohols as nucleophiles is a logical extension of HKR of epoxides to synthesize libraries of stereochemically defined ring-opened products in high optical purity. To this effect Annis and Jacobsen [69] used their polymer-supported Co(salen) complex 36 as catalyst for kinetic resolution of epoxides with phenols to give l-aiyloxy-2-alcohols in high yield, purity and ee (Scheme 17). Conducting the same reaction in the presence of tris(trifluoromethyl)methanol, a volatile, nonnucleophilic protic acid additive accelerates KR reaction with no compromise with enantioselectivity and yield. Presumably the additive helped in maintaining the Co(III) oxidation state of the catalyst. 

Tokimaga, M. Larrow, J. F. Kakiuchi, F. Jacobsen E. N. (1997) Asymmetric catalysis with water Efficient kinetic resolution of terminal epoxides by means of catalytic hydrolysis., Science, 111 936-938. 

Based on the landmark studies of Jacobsen and coworkers, who employed chiral (salen)CoX complexes for the asymmetric ring opening and kinetic resolution of aliphatic epoxides [18-20], Lu and coworkers synthesized highly isotactic copolymer from rac-propylene oxide and carbon dioxide (Scheme 5) [21]. 

In the realm of hydrolytic reactions, Jacobsen has applied his work with chiral salen complexes to advantage for the kinetic resolution of racemic epoxides. For example, the cobalt salen catalyst 59 gave the chiral bromohydrin 61 in excellent ee (>99%) and good yield (74%) from the racemic bromo-epoxide 60. The higher than 50% yield, unusual for a kinetic resolution, is attributed to a bromide-induced dynamic equilibrium with the dibromo alcohol 62, which allows for conversion of unused substrate into the active enantiomer <99JA6086>. Even the recalcitrant 2,2-disubstituted epoxides e.g., 64) succumbed to smooth kinetic resolution upon treatment with... 

Enantiomer-differentiating co-polymerization of terminal epoxides is achieved by chiral chromium and cobalt complexes. Jacobsen etal. reported the co-polymerization of 1-hexene oxide with GO2 by using complex 35a. The reaction proceeds with kinetic resolution at 90% conversion, the unreacted epoxide is found to be enriched in the (i )-enantiomer of 90% ee. Detailed information about the resultant polymer, however, is not described. As discussed in the previous section, chiral cobalt-salen complex 34c co-polymerizes PO and GO2 (Table 3). When 34c with /r<3 / j--(li ,2i )-diaminocyclohexane backbone is applied to the co-polymerization, (A)-PO is consumed preferentially over (i )-enantiomer with a of 2.8 to give optically active PPG (Equation (8)). In a similar manner, a binary catalyst system, 34d/Bu4NGl, preferentially consumes (A)-PO over R)-PO with = 2.8-3.5. ... 

The third investigation track demonstrated the immobilization of metal-salen complexes in mesoporous materials and their use in the hydrolytic kinetic resolution of meso and terminal epoxides. The best results were obtained over cobalt-Ja-cobsen catalysts. The catalytic activity of the (S,S)-Co(II)-Jacobsen complex immobilized on Al-MCM-41 was comparable with that of the homogeneous counterpart. Several other immobilization methods are still under investigation. 

Activated aziridines should be as useful as epoxides for carbon-carbon bond formation, with the advantage that the product will already incorporated the desired secondary aminated stercocentcr. To date, a general enantioselective method for the aziridination of alkcncs has not been developed. Eric Jacobsen of Harvard University (Angew. Chem. hit. Ed. 2004,43, 3952) has explored an interim solution, based on the resolution of racemic epoxides such as I. The cobalt catalyst that selectively hydrolyzes one enantiomer of the epoxide also promotes the addition of the imidc to the remaining enantiomerically-enriched epoxide. As expected, the aziridine 4 is opened smoothly with dialkyl cuprates. 

Jacobsen s cobalt and chromium salen complexes 69 and 70 have proven extremely successful in the enantioselective ring opening of meso-epoxides (and kinetic resolution of racemic epoxides). Recent accounts of these most efficient and practical catalysts can be found elsewhere [71-73]. 

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