Synthesis of Oxacyclic Natural Products

Alkenyl and aryl radicals are also useful for expedient synthesis of oxacyclic natural products. For example, the hexahydrobenzofuran subunit 12 for avermectin synthesis was obtained from the bromopropenyl ether 11 [13] (Scheme 6). A formal synthesis of morphine (15) was reported by Parker utilizing tandem radical cyclizations initiated by the aryl radical from the bromoaryl ether 13 [14] (Scheme 7). A closely related example for the morphine skeleton synthesis also employed aryl radical cyclization [15]. 

Carbon-nitrogen multiple bonds serve as intramolecular radical acceptors for oxacycle synthesis. Many oxacyclic natural products are synthesized via carbocycle-forming radical reactions of oxacyclic substrates. Oxygen-centered radicals play an important role in oxacycle synthesis, which frequently involves initial hydrogen abstraction and subsequent displacement reactions. Many different kinds of inter-molecular radical reactions are also of considerable practical value in the synthesis of a plethora of oxacyclic natural products. 

A number of oxacyclic natural products were synthesized via carbocycle-forming radical reaction of oxacyclic intermediates. An early example is the synthesis of (-)-dihydroagarofuran (170) by Biichi [109] (Scheme 58). The bridgehead chloride 168 obtained from the corresponding hydroxy ketone was amenable to radical cycliza-tion, and the tricyclic ether 169 was duly obtained. The aplysin synthesis [110] provides another example, and (—)-karahana ether (173) was synthesized via radical cyclization of the substrate 171 [111] (Scheme 59). Lactonic natural products (-1-)-eremantholide A [112], alliacolide [113], and (-)-anastrephin [114] were prepared via a variety of carbocycle-forming radical cyclization reactions. In the total synthesis of spongian-16-one (176) [115] (Scheme 60), the butenolide moiety in the substrate 174 served as the final radical acceptor for three consecutive 6-endo-. rig cyclizations. 

When Wacker-type reactions are performed under a CO atmosphere, the (3-H elimination pathway can be suppressed in favor of CO insertion and subsequent nucleophilic cleavage of the acyl metal species.399 This alkoxycarbonylation process has found widespread utility, particularly in the synthesis of five- and six-membered oxacyclic natural products. For example, the THF core of tetronomycin was prepared by the Pd-catalyzed alkoxycarbonylation of 4-alkenol derivatives (Equations (117) and (118)), where stereocontrol was achieved by utilizing either the directing ability of a free hydroxyl or the conformational bias imposed by a bulky silyl ether.420 Additional examples making... 

For mechanistic discussions and many early examples of radical reactions in the synthesis of oxacyclic and other natural products, see C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237. 

Total synthesis of oxacyclic macrodiolide natural products 05CRV4348. 

Total synthesis of structurally complex marine oxacyclic natural products. Fuwa, H. (2010), Bull. Chem. Soc.Jpn, 83, 1401-1420. 

Boron trifluoride etherate promotes the fWt/a-selcctivc oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The oxacyclization transformations may mimic ringforming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products <2002JOC2515>. 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

McDonald and co-workers have published a partial synthesis of thyrsiferol (1) and venustatriol (2) [30]. They focused upon the regio-and stereoselective oxacyclizations [57] to approach the ABC framework, a structural feature that is common to both natural products. 

Early investigations by Pirmng and Johnson demonstrated the power of rearrangement reactions of oxonium ylides for rapid assembly of oxacyclic structures [115]. An impressive application of such rearrangements in natural products synthesis has been documented by Clark (Scheme 16.29) [116]. In the experiment, treatment of diazoketone 219 with a Cu catalyst generated an oxonium ylide 220, which underwent rearrangement to give... 

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