Oxepane Systems

The productive transformation of a macrocycle to a bicycle can also be executed simply by irradiating a bis(thiolactone). For example, irradiation of a solution of bis(thiolactone) 24 in toluene for 

On the basis of model studies, it appears that a preexisting ring(s) in the cyclization substrate (e. g. 39) is necessary for the success of this reaction type. Moreover, irradiation at elevated temperatures leads to cleaner reactions and higher yields, suggesting that thermal energy may be necessary to achieve the proper conformation for coupling to occur.22 

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

The assembly of medium-ring ethers using C-0 or C-C bond forming protocols can be a profitable enterprise 13 nevertheless, it was of interest to determine if medium-ring ethers could be derived 

Stepwise Formation of the Bis(oxepane) System The Third-Generation Strategy 

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The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

A Pd-catalyzed Michael-type cyclization (Equation 21) is described as a method for construction of a substituted oxepan system <1999TL1747>. 

Tandem RCM/allylstannane-aldehyde cyclizations are successfully used for the iterative synthesis of /ra/w-fused oxepane systems, particularly, three tricycles modeling different fragments in brevetoxins and ciguatoxins <2000S883>. Grubbs catalyst <1996JA100> was used on RCM step of the tandem while the procedure similar to that proposed by Yamamoto et al. <1991TL7069> was applied on the second step. 

Nicolaou and coworkers have not only used thioxocarboxylic esters as precursors of the first stable l,2-dithietane, ° but also as a photochemical approach to the oxepane system (equation 40), ° ° which could be useful in a total synthesis of brevetoxin... 

Saturated large rings may form nitrogen radicals by H abstraction from N, or abstraction may occur in the a- or /3-positions in nonnitrogen systems. Oxepane gives the radical in the 2-position, with subsequent cleavage and reclosure of the intermediate carbenoid to cyclohexanol (Section 5.17.2.1.5). In unsaturated large systems a variety of reactions, unexceptional in their nature, are found. Some azepines can be brominated by A -bromosuc-cinimide others decompose under similar conditions (Section 5.16.3.7). 

Scheme 8. Oxepane synthesis by photo-induced ring closure of dithioesters. The term dithioester is used in this chapter to describe compounds of type 39 even though such systems are sometimes referred to as dithionoesters or dithioxoesters.

In contrast to the IJK system 86, compound 87 (Scheme 17a) poses a much steeper synthetic challenge it is during the course of the synthesis of 87 that the diabolical bis(oxepane) problem would have to be dealt with. At this phase of the project, we had benefited from a good deal of experience with the bis(oxepane) problem, and this experience provided the foundation for a conservative solution. Starting from FG ring system 105, it was hoped that rings E, D, C, B, and A could be annulated sequentially and in that order (Scheme 17c). 

For the synthesis of the complex natural product, the terminus six-membered ketone 55 had to be transformed into an oxepane ring. For this necessary transformation, the authors were attracted by the single-carbon homologation of a pyr-anone (a sort of ring-expansion) because, in prindple, it could be used in an iterative sense at any stage of the 6-endo cydization in their poly-TH P-based synthetic approach for the synthesis of trans-fused 6,7,6 (THP-oxepane-THP) and 6,7,7 (THP-oxepane-oxepane) ring systems [28]. Treatment of ketone 55 with TMSCHN2... 

The cyclization of the homologous epoxide 36 under acidic conditions was also investigated (Table 9.5) [110]. As would be expected, compound 36a reacted by a 6-exo cyclization to give tetrahydropyran 38a (Entry 1). The a, 3-unsaturated hydroxy epoxide 36b gave a 1 3.5 mixture of oxepane 37b and tetrahydropyran 38b (Entry 2). Subjection of 36c and 36d, which both contain more electron-rich 71-systems, to the reaction conditions resulted in preferential 7-endo cyclization to give 37c and 37d, thus confirming the powerful regiodirecting effect of the vinyl moiety (Entries 3 and 4). 

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. 

In a related area, a novel 1,3-dipolar cycloaddition strategy involving 1,2-isopropylidene furanoside-fused oxepane derivatives and 4-0-allyl nitrone or nitrile oxide species to give chiral oxepinopyran and oxepinooxepane systems has been described <00TL10135>. 

However, these have not been the only approaches to the synthesis of these ring systems. For example, Sasaki et al. were able to use an intramolecular nucleophilic ring opening of an epoxide with sodium dimsylate to form the oxepane ring as illustrated in the conversion of 34 to 35 <99JOC9399>. 

Benzoannelation of the oxepane ring system leads to an increase in the barrier to ring inversion. Thus variable temperature NMR spectra on l,2,4,5-tetrahydro-3-benzoxepin (2) suggested that a chair conformation was preferred with a barrier to ring inversion of ca. 39.7 kJ mol"1. 

Oxepane (1), as a typical ether, is susceptible to oxidation and yields oxepan-2-one (78) as the initial product. Adipic acid was the product finally isolated after oxidation with Ru04 and NaI04 in a two-phase system (80SC205) or oxygen in the presence of a Pt catalyst (76CB3707) (Scheme 9). Oxidation of 2,3,6,7-tetrahydrooxepin (79) has been reported with peroxybenzoic acid or osmium tetroxide to yield the epoxide (80) or the cis diol (81) respectively (Scheme 10) (58JA3132). 

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