Oxacyclic Substrates

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. 

It has been demonstrated that group 6 Fischer-type metal carbene complexes can in principle undergo carbene transfer reactions in the presence of suitable transition metals [122]. It was therefore interesting to test the compatibility of ruthenium-based metathesis catalysts and electrophilic metal carbene functionalities. A series of examples of the formation of oxacyclic carbene complexes by metathesis (e.g., 128, 129, Scheme 26) was published by Dotz et al. [123]. These include substrates where double bonds conjugated to the pentacarbonyl metal moiety participate in the metathesis reaction. Evidence is... 

Based on a transformation described by Catellani and coworkers [61], the Lautens group [62] developed a three-component domino reaction catalyzed by palladium for the synthesis of benzo annulated oxacycles 6/1-114 (Scheme 6/1.30). As substrates, these authors used a m-iodoaryl iodoalkyl ether 6/1-113, an alkene substi-... 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

Use of aldehyde substrates for radical cyclization of y5-alkoxyacrylates presents opportunities for construction of fused oxacyclic systems. Under the tributylstan-... 

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. 

Schmidt and Biernat have successfully applied the sequentially Ru-catalyzed RCM-isomerization reaction in the synthesis of six- to eight-membered oxacycles, which can be regarded as glycals of 3-deoxyheptoses with variable ring size (Scheme 12.11). Interestingly, in this study, the same precursor was transformed in a divergent manner to furnish the corresponding substrate for... 

Palladium-catalyzed C-H olefination is also a very useful protocol to synthesize oxygen-containing heterocycles, since it allows to functionalize the substrates with an unsaturated olefinic moiety which would constitute a Jt-conjugated structure or be elaborated further. Two pathways are often encountered in this approach (i) addition of the resulted arylpalladium complex to alkynes and subsequent protonation or transformation and (ii) addition of the arylpalladium complex to olefins and following palladium hydride elimination [7b, 20]. The current methods are mainly focused on the functionalization of aromatic C-H bonds to form benzo-oxacycles. 

Phenol and its derivatives are the most common substrates for the construction of oxacycles in this approach. In 2000, Fujiwara and coworkers reported a palladium-catalyzed intramolecular addition reaction of aryl alkynoates to construct coumarins in a mixture of trrfluoroacetic acid and CH2CI2 at room temperature (Scheme 3.6) [21]. This method is simple and efficient to give the desired oxygen-containing heterocycles in high yields. However, this palladium-catalyzed C-H olefination reaction is only constrained to the electron-rich aromatic compounds owing to the inherent limitation of electrophilic metalation process. 

Advances in applying these studies to stereoselective oxacycle synthesis have been critically dependent upon the development of enantioselective epoxidation methods. Extensive research into designing these reactions has resulted in a wide range of structurally distinct epoxides being available in enantiomerically pure form through experimentally facile methods that utilize easily accessible catalysts. These enabling methods assure that substrate synthesis will not limit further exploration in epoxide-based cyclization reaction development. 

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