Epoxide fragmentation

The following syntheses of five-membered carbocyclic systems involve radical-induced epoxide fragmentation with radical translocation and cyclization. The resulting bicyclic alcohols are formed as a mixture of two epimeric esters with cw-fused rings.[71]... 

The route of the Pd-catalyzed cyclization of the substituted oxirane 75, including the involvement of epoxide fragment in the cyclization step (Scheme 35), is highly dependent on the hydrogen-bonding properties of the solvent <1994AGE2182>. 

Cyclization via epoxide fragmentation. Treatment of the epoxythionoimidaz-olide 1 with Bu3SnH and AIBN generates an alkoxy radical by fragmentation of the epoxy group with cyclization to a ds-fused bicyclic system (2). 

Two representative examples are provided in Scheme 10. The allyloxyl radical is generated, in the first step, by a C-radical-induced epoxide fragmentation [20b[. A ring expansion reaction occurs subsequently to give the ten-membered enedione system (Eq. 33) [60]. Nishida et al. show in the second example (Eq. 34) [61] another interesting case of a double ring expansion reaction induced by alkoxyl radicals similar to the one previously reported by the same authors (Eq. 31) [59]. 

Again we found ourselves one simple reaction away from completing the total synthesis of myriaporone 1. A variety of desilylation conditions were screened, but none provided the desired product. Either no reaction was observed, or decomposition products, characterized by epoxide fragmentation and/or consumption of the enone, were recovered. After spending several months attempting final deprotection conditions (Scheme 12) and final reductions (Scheme 11), it was painfully clear that a new strategy would be required. At this point Brian and Jeff successfully defended their Ph.D. theses and Kristen took the lead. Her attempt to overcome the instability of our advanced synthetic intermediates would rely on a late-stage epoxidation, the stereochemical outcome of which was far from certain. 

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

The (partial) description of the synthesis and coupling of the five fragments starts with the cyclohexyl moiety C —C. The first step involved the enantio- and diastereoselective harpless epoxidation of l,4-pentadien-3-ol described on p. 126f. The epoxide was converted in four steps to a d-vinyl d-lactone which gave a 3-cyclohexenecarboxylate via Ireland-CIaisen rearrangement (cf. p. 87). Uncatalysed hydroboration and oxidation (cf. p. 131) yielded the desired trans-2-methoxycyclohexanol which was protected as a silyl ether. The methyl car-... 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Construction of the A ring fragment starts with epoxidation of chiral d-carvone (114) to afford epoxide 115. 

A retrosynthetic analysis of fragment 152 can be completed through cleavage of the C16-C17 bond in enone 155, the projected precursor of epoxide 152. This retrosynthetic maneuver furnishes intermediates 156 and 157 as potential building blocks. In the forward sense, acylation of a vinyl metal species derived from 156 with Weinreb amide 157 could accomplish the construction of enone 155. Iodide 153, on the other hand, can be traced retrosynthetically to the commercially available, optically active building block methyl (S)-(+)-3-hydroxy-2-methyIpropionate (154). 

For the construction of the I ring, the vinylic group introduced to activate the y-hydroxy epoxide moiety of 28 towards cyclization is an acrylic ester residue, which concomitantly allows cyclization on the allylic position, with formation of the tricyclic compound 29 containing the IJK fragment of the natural product, and fur-... 

The multicomponent linchpin coupling of silyl dithianes with epoxides was very efficiently used to access both the AB and CD spiroketal fragments of spongistatin. 

Scheme 8.52 Retro-aldol fragmentation of an epoxide-derived hemiacetal.

A retroaldol fragmentation subsequent to the addition of p-TsOI I and a small amount of water to epoxide 206, obtained by oxidation of enol ether 205 with DMDO, resulted in the direct formation of dialdehyde hydrate 208, possessing the spirostructure necessary for the construction of the fused-rings core of ( )-ginkoli-de B. Apparently, hydrolysis of the epoxide produces the hemiacetal 207, which undergoes retroaldol fragmentation of the cydobutane to afford the dialdehyde, which forms the stable hydrate 208 (Scheme 8.52) [94]. 

The outcomes of intramolecular cyclizations of hydroxy vinylepoxides in more complicated systems can be difficult to predict. In a study of the synthesis of the JKLM ring fragment of dguatoxin, epoxide 44 was prepared and subjected to acid-mediated cydization conditions (Scheme 9.24) [114]. Somewhat surprisingly, the expected oxepane 45 was not formed, but instead a mixture of tetrahydropyran 46 and tetrahydrofuran 47 was obtained, both compounds products of attack of the C6 and C5 benzyl ether oxygens, respectively, on the allylic oxirane position (C3). Repetition of the reaction with dimsylpotassium gave a low yield of the desired 45 along with considerable amounts of tetrahydropyran 48. 

When hydrogenolysis of vinylepoxides is used sequentially, it allows for the controlled formation of 1,3-polyols. In the synthesis of the C11-C23 fragment 92 of preswinholide A, hydrogenolysis of ( ) olefin 93 gave the syn isomer 94 (Scheme 9.37) [159]. Methylation, reduction, epoxidation, oxidation, and olefmation of this material then gave vinylepoxide 95, which was subjected to hydrogenolysis to afford 96 in excellent yield. Repetition of this sequence ultimately afforded the desired derivative 94. 

Very recently, the Shipman group have made a further step towards a comprehensive structure/activity profile for noncovalent interactions between azinomycin B and DNA [152]. They synthesized simplified azinomycin analogues 69 and 96-98 (Scheme 11.13), retaining both the epoxide and aziridine alkylating functionalities, with systematically altered substitution on the naphthoate fragment, and analyzed their DNA crosslinking by gel electrophoresis. They found that cross-... 

The N-aminoaziridine version7 of the a,/3-epoxyketone->alkynone fragmentation is a possible alternative in situations where the simple tosylhydrazone version6-9 fails. The tosylhydrazone method often gives good yields at low reaction temperatures, but it tends to be unsuccessful with the epoxides of enones that are not cyclic or are not fully substituted at the /5-carbon atom. For example, it has been reported9 that 2,3-epoxycyclohexanone docs not produce 5-hexynal by the tosylhydrazone route. The A-aminoaziridine method can also be recommended for the preparation of acetylenic aldehydes as well as ketones. 

---