Allyl alcohols from Sharpless epoxidation

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

The second compound could be made by a Wittig reaction with a stabilized ylid and the required diol ikdehyde derived from an epoxy-alcohol and hence from an allylic alcohol by Sharpless epoxidation. 

In 1980, Katsuki and Sharpless described the first really efficient asymmetric epoxidation of allylic alcohols with very high enantioselectivities (ee 90-95%), employing a combination of Ti(OPr-/)4-diethyl tartrate (DET) as chiral catalyst and TBHP as oxidant Stoichiometric conditions were originally described for this system, however the addition of molecular sieves (which trap water traces) to the reaction allows the epoxidation to proceed under catalytic conditions. The stereochemical course of the reaction may be predicted by the empirical rule shown in equations 40 and 41. With (—)-DET, the oxidant approaches the allylic alcohol from the top side of the plane, whereas the bottom side is open for the (-l-)-DET based reagent, giving rise to the opposite optically active epoxide. Various aspects of this reaction including the mechanism, theoretical investigations and synthetic applications of the epoxy alcohol products have been reviewed and details may be found in the specific literature . 

Another method, where a different reduction methodology is employed, can be used to generate secondary and tertiary allylic alcohols from primary ones, and when this method is used in combination with Sharpless asymmetric epoxidation enantioselectivity may even be achieved (Scheme 11). ... 

It s no surprise that when chemists from Bristol Myers Squibb needed the epoxide beiow, they turned to asymmetric dihydroxyiation rather than either of the epoxidation methods we have shown you. Sharpless epoxidation works only with allylic alcohols, and Jacobsen epoxidation performs poorly here, giving oniy 70-74% ee (mainly because the substrate is not a cis alkene). However, asymmetric dihydroxyiation saves the day with 98% ee and around 90% yield, and a variant of the reaction we have just shown you gives the epoxide, also in 90% yield—well worth the extra step. 

In a continuation of his studies on asymmetric P-lactam synthesis, Evans [42] utilized a,P-epoxyaldehydes 49a and 49b, prepared in two steps from achiral allylic alcohols via Sharpless asymmetric epoxidation and Swern oxidation, as chiral glyoxal synthons for the ketene-imine cycloaddition. Diastereosel-ection was excellent, ranging from 90 10 to 97 3 with overall yield of 50 up to 84% (for Schiff base formation and cycloaddition) after recrystallization or chromatographic purification of the major diastereomer. The sense of asymmetric induction correlated with that obtained in the analogous glyceraldehyde reaction, as established by periodic acid cleavage to aldehydes 51. 

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

In 1980, Katsuki and Sharpless communicated that the epoxidation of a variety of allylic alcohols was achieved in exceptionally high enantioselectivity with a catalyst derived from titanium(IV) isopropoxide and chiral diethyl tartrate. This seminal contribution described an asymmetric catalytic system that not only provided the product epoxide in remarkable enantioselectivity, but showed the immediate generality of the reaction by examining 5 of the 8 possible substitution patterns of allylic alcohols all of which were epoxidized in >90% ee. Shortly thereafter. Sharpless and others began to illustrate the... 

A careful analysis of this problem led to the identification of an exceedingly simple solution (see Scheme 10). The Masamune-Sharpless solution to the threo 2,3-diol problem actually takes advantage of the ready availability of the erythro 2,3-diol diastereoisomer. As we have seen in Scheme 9, erythro 2,3-diols such as 20 can be conveniently assembled from trans allylic alcohols via sequential SAE and Payne rearrangement/epoxide opening reac-... 

The Sharpless-Katsuki asymmetric epoxidation (AE) procedure for the enantiose-lective formation of epoxides from allylic alcohols is a milestone in asymmetric catalysis [9]. This classical asymmetric transformation uses TBHP as the terminal oxidant, and the reaction has been widely used in various synthetic applications. There are several excellent reviews covering the scope and utility of the AE reaction... 

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. ... 

The stereochemistry of the first step was ascertained by an X-ray analysis [8] of an isolated oxazaphospholidine 3 (R = Ph). The overall sequence from oxi-rane to aziridine takes place with an excellent retention of chiral integrity. As the stereochemistry of the oxirane esters is determined by the chiral inductor during the Sharpless epoxidation, both enantiomers of aziridine esters can be readily obtained by choosing the desired antipodal tartrate inductor during the epoxidation reaction. It is relevant to note that the required starting allylic alcohols are conveniently prepared by chain elongation of propargyl alcohol as a C3 synthon followed by an appropriate reduction of the triple bond, e. g., with lithium aluminum hydride [6b]. 

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]. 

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. 

An effective deoxygenation using enantiomerically pure epoxides from primary allylic alcohols ( Sharpless epoxides ) [44] to give enantiomerically pure secondary allylic alcohols was described by Yadav [45]. This approach circumvented a kinetic resolution of secondary allylic alcohols that implies a maximum yield of 50% ( Scheme 5). 

A major advantage that nonenzymic chiral catalysts might have over enzymes, then, is their potential ability to accept substrates of different structures by contrast, an enzyme will select only its substrate from a mixture. Striking examples are the chiral phosphine-rhodium catalysts, which catalyze die hydrogenation of double bonds to produce chiral amino acids (10-12), and the titanium isopropoxide-tartrate complex of Sharpless (11,13,14), which catalyzes the epoxidation of numerous allylic alcohols. Since the enantiomeric purities of the products from these reactions are exceedingly high (>90%), we might conclude... 

Although it was also Henbest who reported as early as 1965 the first asymmetric epoxidation by using a chiral peracid, without doubt, one of the methods of enantioselective synthesis most frequently used in the past few years has been the "asymmetric epoxidation" reported in 1980 by K.B. Sharpless [3] which meets almost all the requirements for being an "ideal" reaction. That is to say, complete stereofacial selectivities are achieved under catalytic conditions and working at the multigram scale. The method, which is summarised in Fig. 10.1, involves the titanium (IV)-catalysed epoxidation of allylic alcohols in the presence of tartaric esters as chiral ligands. The reagents for this asyimnetric epoxidation of primary allylic alcohols are L-(+)- or D-(-)-diethyl (DET) or diisopropyl (DIPT) tartrate,27 titanium tetraisopropoxide and water free solutions of fert-butyl hydroperoxide. The natural and unnatural diethyl tartrates, as well as titanium tetraisopropoxide are commercially available, and the required water-free solution of tert-bnty hydroperoxide is easily prepared from the commercially available isooctane solutions. 

More than a decade of experience on Sharpless asymmetric epoxidation has confirmed that the method allows a great structural diversity in allylic alcohols and no exceptions to the face-selectivity rules shown in Fig. 10.1 have been reported to date. The scheme can be used with absolute confidence to predict and assign absolute configurations to the epoxides obtained from prochiral allylic alcohols. However, when allylic alcohols have chiral substituents at C(l), C(2) and/or C(3), the assignment of stereochemistry to the newly introduced epoxide group must be done with considerably more care. 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

Asymmetric epoxidation of olefins is an effective approach for the synthesis of enan-tiomerically enriched epoxides. A variety of efficient methods have been developed [1, 2], including Sharpless epoxidation of allylic alcohols [3, 4], metal-catalyzed epoxidation of unfunctionalized olefins [5-10], and nucleophilic epoxidation of electron-deficient olefins [11-14], Dioxiranes and oxazirdinium salts have been proven to be effective oxidation reagents [15-21], Chiral dioxiranes [22-28] and oxaziridinium salts [19] generated in situ with Oxone from ketones and iminium salts, respectively, have been extensively investigated in numerous laboratories and have been shown to be useful toward the asymmetric epoxidation of alkenes. In these epoxidation reactions, only a catalytic amount of ketone or iminium salt is required since they are regenerated upon epoxidation of alkenes (Scheme 1). 

Asymmetric synthesis of stavudine and cordycepin, anti-HIV agents, and several 3 -amino-3 -deoxy-P-nudeosides was achieved utilizing this cycloisomerization of 3-butynols to dihydrofuran derivatives [16]. For example, Mo(CO)6-TMNO-promoted cyclization of the optically active alkynyl alcohol 42, prepared utilizing Sharpless asymmetric epoxidation, afforded dihydrofuran 43 in good yield. Iodine-mediated introduction of a thymine moiety followed by dehydroiodination and hydrolysis of the pivaloate gave stavudine in only six steps starting from allyl alcohol (Scheme 5.13). 

---