Application of Two-Directional Carbonyl Ene Reaction to The Synthesis of Complex Tetrahydropyrans, and Studies Toward the Synthesis of C26-C39 Subunit of Spirastrellolide B.

The use of exocyclic enol ethers as nucleophiles in carbon-carbon bond forming reactions has been underutilized in organic synthesis. This work describes the use of 6-iodomethyl-2-methylenetetrahydropyran as a bis-exocyclic enol ether equivalent for the synthesis of pyran derivatives. Use of this linchpin allows for bidirectional elaboration of the pyran core by two directional carbonyl ene. The development of a convergent, modular synthesis of 2,6-disubstituted-4H-pyrans in a three-step sequence starting from 6-iodomethyl-2-methylenetetrahydropyran is described. Initial carbonyl ene reaction of 6-iodomethyl-2-methylenetetrahydropyran with aldehydes or activated ketones was followed by elimination of iodide to give cross oriented bis-enol ethers that contain both endocyclic and an exocyclic enol ethers. A second carbonyl ene reaction then resulted in formation of the target 2,6-disubstituted-4H-pyrans. This approach provided 2,6-disubstituted-4H-pyrans in synthetically useful yields and allows for rapid diversification about the central pyran core. Studies to evaluate the scope of the second carbonyl ene reaction revealed that the use of electron deficient aldehydes is required. The extended conjugation present in the cross oriented exocyclic enol ethers is thought to reduce their reactivity. Several strategies were explored to reduce conjugation in the cross-oriented substrates to enhance the reactivity of the exocyclic enol ether in the second carbonyl ene reaction. Functionalization of the endocyclic bond by spiroketalization, reduction, and nucleophilic addition resulted in higher product yields and expanded scope in the subsequent carbonyl ene reactions. These modifications also provided for a rapid increase in complexity in the pyran products available by this two directional sequence. Application of the bidirectional carbonyl ene methodology toward the synthesis of the C26-C39 bis-spiroketal of spirastrellolide B is also described. This work has resulted in the enantioselective preparation of starting materials and their use in the synthesis of an advanced spiroketal intermediate via a carbonyl ene/spiroketalization/elimination sequence; the second carbonyl ene reaction was also carried out, though initial attempts to convert the resulting ene product to the desired bis-spiroketal skeleton were not successful. This work demonstrates the utility of exocyclic enol ethers as neutral nucleophiles for the formation of carbon-carbon bonds. Application of this chemistry using the bi-directional carbonyl ene methodology provides access to functionally complex pyran derivatives that can be utilized as intermediates for the preparation of biologically active natural products.