Epoxides natural products synthesis

The Sharpless epoxidation is one of the most important of the newer organic reactions. Although limited to allylic alcohols, it has found wide application in natural product synthesis. 

Mori et al. have demonstrated the most dramatic uses of lithiated epoxides in natural product synthesis [62]. By employing the chemistry developed by Jackson, and subsequently performing a Lewis acid-catalyzed (BF3 OEt2) cyclisation, tetra-hydrofuran, tetrahydropyran, and oxepane rings are readily accessed this strategy is demonstrated by the synthesis of the marine epoxy lipid 173 (Scheme 5.40) [63]. 

Most often, the application of cyanohydrin acetonide couplings to a natural product synthesis calls for coupling with a primary alkyl halide. This has proven successful in every instance. However, on occasion, alkylations of more hindered epoxides or hindered alkyl halides are desirable. These reactions are less dependable. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

In conjunction with work in natural products synthesis, the controlled installation of stereocenters alpha to indole C2 remains of significant interest. In their approach to Clausena alkaloids, e.g., (-)-(5R, 6S)-balasubramide, Wang and co-workers employed an intramolecular 8-CMc/o-epoxide-arene cyclization for installation of a C2-C3 8-membered lactam moiety with excellent enantioselectivity <07OL1387>. The Chen group has reported a diastereoselective reaction between 2-lithioindoles and chiral A -terf-but ane sulfinyl... 

Apart from the processes based on the homolytic epoxide opening summarized above, other synthetic transformations employing Cp2TiCl have been reported by several authors. These reactions, however, have received scarce application for natural product synthesis so far and, therefore, we only present a short resume of them. 

There are two especially relevant cases where Cp2TiCl-promoted epoxide deoxygenations have been demonstrated to conform to the requirements of selectivity, mildness, and wide functional group tolerance desirable in natural product synthesis the chemical correlation between cryptophycin-23 and cryptophycin-45 and the synthesis of anhydrovinblastine, the key intermediate in the synthesis of the anticancer drug Navelbine, from leurosine (Scheme 14) [91-93]. 

Palladium on barium sulfate has been used in the hydrogenolysis of epoxides in natural product synthesis. The reaction in equation (25) illustrates its high level of functional group compatibility. 

Deoxygenation via iodohydrin intermediates using chlorosilane/sodium iodideand p-toluenesul-fonic acid/sodium iodidehas also been reported. In a natural product synthesis, an epoxide has been deoxygenated with a large excess of triethylsilane at 300 C for 30 h (equation 51). 

The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-10mol%) if molecular sieves are present. Polymer-supported catalysts have also been reported.Both (-I-) and (—) diethyl tartrate are readily available, so either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, including substrates where the double bond is mono-, di-, tri-, and tetrasubstituted, " and is highly useful in natural product synthesis. 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 f-BuOOH.i 2 ... 

Epoxy-ene cyclizations have been used as key steps in natural products synthesis. The preparations of pseudopterosin, a potent antiflammatory agent and analgesic <88JOCl584>, and (+)-aphidicolin <85TL6147,88JOC4929), (+ )-9,10-jyn- and (+)-9,10-an/i-copalol <92JOC4598> are representative examples of the synthetic utility of Lewis acid-catalyzed epoxide cyclizations. 

Since the first report by Katsuki and Sharpless in 1980 [21], the asymmetric epoxidation of allylic alcohols has been widely applied to the synthesis of various compounds [22]. Among several asymmetric epoxidations developed, the Sharpless asymmetric epoxidation (AE) is undoubtedly the most popular and versatile method, which has greatly contributed to the progress of natural product synthesis. 

Several a,j5-unsaturated (5-lactones are produced by higher plants, and it is speculated that they originate biogenetically from the respective 1,3-polyhydroxylated acids. The synthesis of (— )-tarchonanthuslactone (615) exemplifies the utility of asymmetric 1,3-polyols in natural product synthesis (Scheme 90) [145]. All- y -epoxide 606 is transformed into the natural product 615 in good overall yield using only standard synthetic operations. 

The DBU promoted epoxide opening reaction through an ElcB process has been applied to natural product synthesis. Trudeau and Morken reported a synthesis of fraxinellone (113) [34] (Scheme 7.24). Treatment of epoxide 111 with DBU in benzene gave allylic alcohol 112, which was led to the natural product by oxidation of the resulting alcohol with TEAR... 

The asymmetric epoxidation of functionalized alkenes still attracts considerable attention. Synthetic chemists continue to be in search of new and improved routes to epoxides, since they provide versatile intermediates for natural product synthesis. The topic of preparative techniques for chiral epoxides is seldom broached without the mention of the Sharpless epoxidation. Indeed, the impact of this protocol cannot be overestimated, as new applications continue to be reported. For example, linear poly(tartrate ester) ligands have been used this past year to generate a solid-supported Sharpless-type catalyst <97CC123>. 

Note added in proof. ktotA synthesis of (-)-xialenon A using bicyclic alcohol 77 [Eq. (26)] represents the first application of enantioselective a-hthiation transannular C-H insertion of epoxides in natural product synthesis [78]. The first enantioselective generation - intermo-lecular nucleophile trapping of a lithium carbenoid has been described, via enantioselective a-deprotonation of the epoxides of oxa- and aza-bicyclic alkenes [e.g. 93 Eq. (30)] using alkyl-lithiums in the presence of (-)-sparteine or bisoxazoline 5 [Eq. (3)] [79]. Insertion of a second... 

The third section of the chapter describes recently developed anion relay chemistry (ARC) involving threefold domino Sj -Brook rearrangement/ reactions, discovered by Tietze and extensively explored by Amos Smith 111 and his group. These reactions are also initiated by nucleophihc ring opening of epoxides, usually by silyl-substituted dithiane anions, and find useful apphcation in natural product synthesis. 

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