Sequential kinetic resolution

Scheme 7.22 Mechanism of the sequential kinetic resolution of trans-cyclohexane-1,2-diamine.

Majeric Elenkov, M., Tang, L., Hauer, B. and Janssen, D.B., Sequential kinetic resolution catalyzed by halohydrin dehalogenase. Org. Lett., 2006, 8, 4227. 

It has been shown that the maximum overall selectivity (Ftot) of a sequential kinetic resolution can be related to the individual selectivities (Fj, 2) of each of the steps [60]. tot represents the enantioselectivity that a hypothetical single-step resolution would need to yield the enantiomeric purity of the two-step resolution. 

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. 

Alternatively, epoxides can be formed with concomitant formation of a C-C bond. Reactions between aldehydes and various carbon nucleophiles are an efficient route to epoxides, although the cis. trans selectivity can be problematic (see Section 9.1.4). Kinetic resolution (see Section 9.1.5.2) or dihydroxylation with sequential ring-closure to epoxides (see Section 9.1.1.3) can be employed when asymmetric epoxidation methods are unsatisfactory. 

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of exocyc-lic allylic ethers is demonstrated by the example provided in Scheme 6.9. The optically pure starting allylic ether, obtained by the aforementioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford the desired chromene in >99% ee [20], Unlike the unsaturated pyrans discussed above, chiral 2-substituted chromenes are not readily resolved by the Zr-catalyzed protocol. Optically pure styrenyl ethers, such as that shown in Scheme 6.9, are obtained by means of the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

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).

Trisubstituted cyclic alkenes have been kinetically resolved via a chiral dioxirane (4), generated in situ from the ketone and Oxone. A sequential desymmetrization and kinetic resolution of cyclohexa-1,4-dienes has also been achieved. The observed stereochemical results have been rationalized on the basis of a spiro-planar transition state model.93... 

In order to obtain levoglucosenone 1 in both enantiomeric forms by employing lipase-mediated kinetic resolution, we used acrolein dimer 2 as the starting material.4 2 was first transformed to the bicyclic ketone ( )-6 by sequential four steps of reactions via 3-5. Racemic levoglucosenone ( )-l was obtained from 6 via the silyl ether 7 by employing the Saegusa reaction. To carry out lipase-mediated resolution, ( )-l was transformed into the e/wfo-alcohol ( )-8 and the acetate ( )-9 (Scheme 1). 

The results for our kinetic resolutions are shown in Table III. The biphasic procedure was used to synthesize enantiomerically pure aldols by kinetic resolution on a scale of miligrams to grams, with amounts of antibody binding sites ranging from 0.0086 to 0.12 mol %. To illustrate the potential for catalyst recycling, we chose to synthesize (S)-47 via three sequential resolutions of aldol rac-47 with the same 84G3 catalyst. 

Halldorsson, A., Thordarson, R, Kristinsson, B., Magnusson, C. D., and Haraldsson, G. G. 2004. Lipase-catalysed kinetic resolution of 1-O-alkylglycedrols by sequential transesterification. Tetrahedron Asymm., 15, 2893-2899. 

It is worth mentioning the emergence of sequential catalytic processes involving a ruthenium-catalyzed step followed by a catalytic enzymatic transformation. This strategy has been developed by the groups of J.E. Backvall, and M.-J. Kim and J. Park especially for the dynamic kinetic resolution of alcohols (Scheme 50) [107-109]. 

An additional strategy employed by Sih and co-workers involved sequential enzyme-catalyzed reactions. Pseudomonas lipases were found to tolerate a wide range of substrates although the enantioselectivity was generally only moderate. However, by first performing a methanolysis of the oxazolinone followed by a separate enzyme-catalyzed hydrolysis under kinetic resolution conditions, a highly enantio-merically enriched product could be obtained, as shown in Fig. 9-211491. 

Information about the degree of configurational stability of allenyltitanium compounds has been provided by Hoffmann and Hoppe (Scheme 35). Racemic allenyltitanium reagent (3) is prepared by sequential treatment of 3-methoxy-1,2-butadiene (2) with n-butyllithium and titanium tetraisopropoxide. In the reaction of the racemate with one equivalent of (S)-(4) or its racemate, products (5)-(8) are formed in 70-90% total yield in the ratios shown in Scheme 35. Since the product ratios from the two experiments are different, the equilibrium between the enantiomers of (3) must be slow compared to the rate of reaction of (3) with (4). Thus, (S)-(3) leads to (5) + (6) and (R)-(3) leads to (7) + (8) (i.e. 51 49). From experiment B, the combinations (S)-(3) + (S)-(4) and (/ )-(3) -t- (/ )-(4) are shown to react considerably more rapidly than that of the (R)/(.S) pairs (mutual kinetic resolution). ... 

Fig. 2.7 Sequential enzymatic kinetic resolution via hydrolysis and esterification...

Fig. 2.8 Mechanism of concurrent sequential enzymatic kinetic resolution via hydrolysis-esterification in aqueous-organic solvent...

Finally, the sequential iminium-enamine asymmetric catalysis was notably exploited by Roy and Chen in the kinetic resolution of nitroallyhc acetates 203 (Scheme 2.68) [92],... 

S. Roy, K. Chen, Org. Lett. 2012,14, 2496-2499. Three-component organocascade kinetic resolution of racemic nitroal-lylic acetates via sequential iminium/enatnine asymmetric catalysis. 

In 2007, the same authors reported the deracemisation of secondary ben lic alcohols on the basis of a two-step process with the combination of two different chiral ruthenium catalysts (Scheme 3.12). The initial step of this sequential process was a kinetic resolution of the starting secondary alcohol by the selective oxidation of the S-alcohol to the corresponding ketone catalysed by a first chiral ruthenium complex. This ketone intermediate was then selectively reduced to the I -alcohol by the second chiral ruthenium catalyst. As compared with kinetic resolution, this two chiral ruthenium system provided a convenient and efficient approach for the synthesis of chiral alcohols in high yields and excellent enantioselectivities of up to 92% ee, as shown in Scheme 3.12. 

Another example of allylic alkylation of cycloalkenediols diacetates was performed using a chiral alkyl phosphane bearing a carboxyl group. An interesting level of selectivity was observed through a sequential asymmetric allylic alkylation—kinetic resolution process (eq 69). ... 

Rowe BJ, Spilling CD. The synthesis of l-hydrox3fphospho-nates of high enantiomeric excess using sequential asymmetric reactions titanium alkoxide-catalyzed P—C bond formation and kinetic resolution. Tetrahedron Asymm. 2001 12 1701-1708. 

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