Sharpless’ asymmetric epoxidation

Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-/so-propoxide, and optically pure diethyl tartrate. 

Johnson, R. A. Sharpless, K. B. In Comprehensive Organic Synthesis, Trost, B. M., Ed, Pergamon Press New York, 1991 Vol. 7, Chapter 3.2. (Review). 

Palucki, M. Sharpless-Katsuki Epoxidation In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 50-62. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 234, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 250, Springer International Publishing Switzerland 2014 

Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the presence of cinchona alkaloid ligands. 

A stepwise mechanism involving osmaoxetane seems to be more consistent with the experimental data than the corresponding concerted [3 + 2] mechanism  

The catalytic cycle is shown on the next page (the secondary cycle is shut off by maintaining a low concentration of olefin) page 371. 

Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (Review, Nobel Prize Address). 

Sharpless Asymmetric Epoxidation. The epoxidation reactions described heretofore generated racemic products even when they were highly diastereoselective. The reagents presented simply did not 

When the previously cited transition structure 193 is applied to the asymmetric epoxidation of allylic alcohols, it must be modified to include binding of the peroxide, the allylic alcohol, and also the chiral tartrate. The metal in the new model is titanium rather than vanadium, and tetraisopropoxy titanium was found to react with 2 equivalents of diethyl tartrate to form a species such as 212, where OR = 0/-Pr and CO2R = CO2Et.3i7.3i8 The tartrate can bind to titanium from either the bottom or the top face.3i8 The nature of the 

OR and E groups will determine the facial preference and, thereby, the selectivity of the epoxidation. When 212 reacted with TBHP and an allylic alcohol, 2 equivalents of 2-propanol were displaced to generate 213. The peroxide linkage and the allylic alcohol in 213 are closely related to the orientation described in 193 (see above). Backside attack of the alkene moiety along the axis of the O—O bond will lead to the epoxide. The titanium metal, serves as a template for the reaction and the presence of the chiral tartrate converts 213 into a 

Sharpless provided an empirical model that enables one to predict the stereochemistry of the epoxide formed in this reaction. When using the natural L-(+)- (2/ , 3R) tartrate, the allylic alcohol should be oriented as shown for 214, with the hydroxyl group in the plane of the double bond and to the right.316c with this 

104 times faster than 221 with (L)-(-t)-DIPT due to the consonance with the (5)-enantiomer (and the corresponding dissonance of this tartrate with the (/ )-enantiomer). This led to kinetic resolution (one enantiomer reacts faster to give a predominance of that epoxide) of the allylic alcohols.316c general, the 

The enantioselective total synthesis of the annonacenous acetogenin (+)-parviflorin was accomplished by T.R. Hoye and co-workers. The b/s-tetrahydrofuran backbone of the natural product was constructed using a sequential double Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation. The bis allylic alcohol was epoxidized using L-(+)-DET to give the essentially enantiopure bis epoxide in 87% yield. 

In the laboratory of D.P. Curran, the asymmetric total synthesis of (20R)-homocamptothecin was achieved using the Stale coupling and the SAE as key steps. The SAE was used to install the key C20 stereocenter. The ( )-allylic alcohol was epoxidized rapidly in the presence of stoichiometric amounts of L-(+)-DET and TBHP at -20 °C to afford the corresponding epoxide in 93% ee. Interestingly, the (Z)-allylic alcohol reacted with D-(-)-DET sluggishly and gave the epoxide in very iow yieid and with only 31% ee. 

The last and key step during the total synthesis of (-)-laulimalide by I. Paterson et al. was the Sharpless asymmetric epoxidation. The success of the total synthesis relied on the efficient kinetic differentiation of the Cis and C20 allylic alcohols during the epoxidation step. When the macrocyclic diol was oxidized in the presence of (+)-DIPT at -27 °C for 15h, only the C16-C17 epoxide was formed. 

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Fig. 8. Use of Sharpless asymmetric epoxidation for the preparation of an intermediate in the synthesis of FK-506 (105), where represents the chiral...

Figure 1. Stereofacial selectivity rule for the Sharpless asymmetric epoxidation.

The essential features of the Masamune-Sharpless hexose synthesis strategy are outlined in a general way in Scheme 4. The strategy is based on the reiterative- application of a two-carbon extension cycle. One cycle comprises the following four key transformations (I) homologation of an aldehyde to an allylic alcohol (II) Sharpless asymmetric epoxidation of the allylic alcohol ... 

Scheme 4. The Sharpless asymmetric epoxidation in the J.T. Baker Company s commercial synthesis of (7/ ,8S)-disparlure (15).

The construction of key intermediate 18 can be conducted along similar lines. Sharpless asymmetric epoxidation of allylic alcohol 22 using (+)-DET furnishes epoxy alcohol 52b (Scheme 11). Subjection of the latter substance to the same six-step reaction sequence as that leading to 54a provides allylic alcohol 54b and sets the stage for a second SAE reaction. With (+)-DET as the... 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

SAE reaction see Sharpless asymmetric epoxidation Saegusa oxidation 390 samarium diiodide 496, 633, 638 saponification 49, 207 sativene 382 f. 

DIPT diisopropyl tartrate SAE Sharpless Asymmetric Epoxidation... 

The development of Sharpless asymmetric epoxidation (SAE) of allylic alcohols in 1980 constitutes a breakthrough in asymmetric synthesis, and to date this method remains the most widely applied asymmetric epoxidation technique [34, 44]. A wide range of substrates can be used in the reaction ( ) -allylic alcohols generally give high enantioselectivity, whereas the reaction is more substrate-dependent with (Z)-allylic alcohols [34]. 

Sesquinorbornatrienes 949 Sharpless asymmetric epoxidation 826 Sharpless reagent 73, 289, 291 Shift reagents, coordination of sulphoxides with 573... 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Although the Sharpless asymmetric epoxidation is an elegant method to introduce a specific defined chirality in epoxy alcohols and thus, in functionalized aziridines (see Sect. 2.1), it is restricted to the use of allylic alcohols as the starting materials. To overcome this limitation, cyclic sulfites and sulfates derived from enantiopure vfc-diols can be used as synthetic equivalents of epoxides (Scheme 5) [12,13]. 

The epoxidation of allylic alcohols can also be effected by /-butyl hydroperoxide and titanium tetraisopropoxide. When enantiomerically pure tartrate ligands are included, the reaction is highly enantioselective. This reaction is called the Sharpless asymmetric epoxidation.55 Either the (+) or (—) tartrate ester can be used, so either enantiomer of the desired product can be obtained. 

The synthesis shown in Scheme 13.66 starts with the Sharpless asymmetric epoxidation product of geraniol. The epoxide was opened with inversion of configuration by NaBHjCN-BFj. The double bond was cleaved by ozonolysis and converted to the corresponding primary bromide. The terminal alkyne was introduced by alkylation of... 

Posticlure [(6Z,9Z,llS,12S)-ll,12-epoxy-6,9-henicosadiene, 14] is the female sex pheromone of the tussock moth, Orgyia postica. Wakamura s first synthesis of 14 was achieved by employing Sharpless asymmetric epoxidation, and the final product was of 59% ee [38]. Mori prepared 14 of high purity as shown in Scheme 25 basing on asymmetric dihydroxylation (AD) [39]. Kumar also published an AD-based synthesis of 14 [40], which was more lengthy and less efficient than Mori s [39]. 

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