Sharpless model

Simultaneous deprotection and cyclization of diols 60a and 60b with 3 M HCl in MeOH followed by acetylation yielded the 2,3-trans- ( 50%) (61a and 61b) and for the first time 2,3-cw-flavan-3-ol methylether acetate derivatives ( 20%) (62a and 62b) in excellent enantiomeric excesses (>99%). The optical purity was assessed by H NMR using [Eu(hfc)3] as chiral shift reagent. The absolute configuration of the derivatives of the tram- and cii-flavan-3-ol derivatives was assigned by comparison of CD data with those of authentic samples in the catechin or epicatechin series flavan-3-ols. Thus, the absolute configuration of the flavan-3-ol methyl ether acetates confirms the assigned configuration of the diols as derived from the Sharpless model. 

Figure 3.3 The U-shaped (Corey model) and L-shaped (Sharpless model) binding pockets.

The key point of the Sharpless model is the two-step mechanism for the addition of osmium tetroxide to an alkene. The basis for this suggestion is the presence of inversion points in the Eyring plots (Sect. 4.1.1). The most viable proposal for this mechanism is outlined in Fig. 12. 

The development of Sharpless model was the result of a systematic investigation of the epoxidation reaction of a wide range of acyclic allylic alcohols [65], Two illustrative examples are shown below in Schemes 9.2 and 9.3. In the vanadium-catalyzed epoxidation of olefin 30, transition state 31 is believed to be favored. It includes an acute 0-C-C=C dihedral angle of 50° while at the same time, the dominant interactions are minimized (Scheme 9.2). In the epoxidation of 33 with a peracid, structure 34 incorporates an obtuse 0-C-C=C angle and concomitantly minimizes severe non-bonded A, j interactions (Scheme 9.3). 

Several structures of the transition state have been proposed (I. D. Williams, 1984 K. A. Jorgensen, 1987 E.J. Corey, 1990 C S. Takano, 1991). They are compatible with most data, such as the observed stereoselectivity, NMR measuiements (M.O. Finn, 1983), and X-ray structures of titanium complexes with tartaric acid derivatives (I.D. Williams, 1984). The models, e. g., Jorgensen s and Corey s, are, however, not compatible with each other. One may predict that there is no single dominant Sharpless transition state (as has been found in the similar case of the Wittig reaction see p. 29f.). 

A model for the catalytically active species in the Sharpless epoxidation reaction is formulated as a dimer 3, where two titanium centers are linked by two chiral tartrate bridges. At each titanium center two isopropoxide groups of the original tetraisopropoxytitanium-(IV) have been replaced by the chiral tartrate ligand ... 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Fig. 12.4. Successive models of the transition state for Sharpless epoxidation. (a) the hexacoordinate Ti core with uncoordinated alkene (b) Ti with methylhydroperoxide, allyl alcohol, and ethanediol as ligands (c) monomeric catalytic center incorporating t-butylhydroperoxide as oxidant (d) monomeric catalytic center with formyl groups added (e) dimeric transition state with chiral tartrate model (E = CH = O). Reproduced from J. Am. Chem. Soc., 117, 11327 (1995), by permission of the American Chemical Society. 

Visual models, additional information and exercises on Sharpless Epoxidation can be found in the Digital Resource available at Sprmger.com/carey-sundberg. 

Two model structures ((59) and (60)) for the enantiodifferentiating step in the [2 + 2] and [2 + 3] pathways have been given by the Sharpless and Corey groups, respectively (Figure 8). Both models can explain the stereochemistry observed in asymmetric dihydroxylation. 

Figure 8 Sharpless and Corey models for the enantiodifferentiating step in dihydroxylation.

Schreiber s model has also proved to be a general approach to a series of oxygenated metabolites of arachidonic acid, such as lipoxin A and lipoxin B.50 The family of linear oxygenated metabolites of arachidonic acid has been implicated in immediate hypersensitivity reactions, inflammation, and a number of other health problems. Among these metabolites, several compounds, such as lipoxin A, lipoxin B, 5,6-diHETE, and 14,15-diHETE possess 1-substituted (/ )-1 -alken-3.4-diol 84 as a common substructural moiety. Therefore, the car-binol 83 is an ideal substrate for generating compound 84 by applying Sharpless epoxidation reaction.50... 

Sharpless NE, DePinho RA (2006) The mighty mouse genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5 741-754... 

The Sharpless epoxidation is sensitive to preexisting chirality in selected substrate positions, so epoxidation in the absence or presence of molecular sieves allows easy kinetic resolution of open-chain, flexible allylic alcohols (Scheme 26) (52, 61). The relative rates, kf/ks, range from 16 to 700. The lower side-chain units of prostaglandins can be prepared in high ee and in reasonable yields (62). A doubly allylic alcohol with a meso structure can be converted to highly enantiomerically pure monoepoxy alcohol by using double asymmetric induction in the kinetic resolution (Scheme 26) (63). A mathematical model has been proposed to estimate the degree of the selectivity enhancement. 

A density functional study of the transition structures of Ti-catalyzed epoxidation of allylic alcohol was performed, which mimicked the dimeric mechanism proposed by Sharpless et al.5 Importance of the bulkiness of alkyl hydroperoxide to the stereoselectivity, the conformational features of tartrate esters in the epoxidation transition structure, and the loading of allylic alcohol in the dimeric transition structure model were pointed out. 

Asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aziridination reactions have been reviewed.62 The use of the Sharpless asymmetric epoxidation method for the desymmetrization of mesa compounds has been reviewed.63 The conformational flexibility of nine-membered ring allylic alcohols results in transepoxide stereochemistry from syn epoxidation using VO(acac)2-hydroperoxide systems in which the hydroxyl group still controls the facial stereoselectivity.64 The stereoselectivity of side-chain epoxidation of a series of 22-hydroxy-A23-sterols with C(19) side-chains incorporating allylic alcohols has been investigated, using m-CPBA or /-BuOOH in the presence of VO(acac)2 or Mo(CO)6-65 The erythro-threo distributions of the products were determined and the effect of substituents on the three positions of the double bond (gem to the OH or cis or trans at the remote carbon) partially rationalized by molecular modelling. 

Equatorially positioned methyl-branched derivatives may be obtained by reductive cleavage of spiro epoxides [94], Thus the Peterson olefination of 188gives the exocyclic 3 -methylene function in 189. By means of a Sharpless epoxidation the allylic 4"-hydroxy group should determine the chirality of the resulting epoxide. However, the Sharpless method does not show any reaction neither in a monosaccharide model system nor in this trisaccharide precursor [95]. Amazingly, the classical epoxidation with m-chloroperbenzoic acid is employed to give exclusively the desired (3"R) epoxide 190 in excellent yield. These results may be associated with a sufficient chiral induction of the stereochemical information at C-l", C-4", and C-5". A subsequent reduction furnishes the original E-D-C trisaccharide sequence 191 of mithramycin [95, 96]. 

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