Trisubstituted Alkenes through Stereoretentive Cross-Metathesis for Natural Product Synthesis
Chapter One: Stereoretentive Cross-Metathesis of Trisubstituted Olefins The development of stereoretentive olefin metathesis catalysts has solved a long-standing problem in the field, allowing for trisubstituted alkenes to be synthesized in high stereochemical purity and under kinetic control. E- as well as Z-isomers of trisubstituted alkenyl halides, nitriles, and allylic alcohols can be accessed through cross-metathesis of commercially available and easily accessible alkenes. Through the use of the same strategy, macrocyclic trisubstituted alkenes have been accessed in either isomeric form through stereoretentive ring-closing metathesis of the corresponding diene starting materials. Thus, for the first time, a wide range of E- and Z-trisubstituted alkenes can be obtained selectively through olefin metathesis, regardless of the underlying thermodynamic preferences. Chapter Two: Development of Catalytic Stereoretentive Cross-Metathesis of Trisubstituted Alkenyl Bromides We have introduced a general and widely applicable strategy for the synthesis of E- and Z-trisubstituted alkenyl bromides through cross-metathesis. The reaction is applicable to terminal, disubstituted, and trisubstituted olefins bearing a variety of functional groups including alkenes with α-, or β-branches. The requisite stereodefined cross-partners, E- and Z-2-bromo-2-butene are commercially available and can be synthesized with ease in one step from abundant starting materials. This represents a notable improvement over our previous approach, where the non-halogenated alkene starting material had to be prepared through cross-coupling in high stereochemical purity to ensure high stereoretention in the subsequent cross-metathesis. Catalysts derived from Mo monoaryloxide pyrrolide complexes, some of which are commercially available, are optimal for this transformation. The applicability of the approach is underscored through the formal synthesis of phomactin A with improved overall yield and step count. Chapter Three: Total Synthesis of Ambrein We have completed a total synthesis of ambrein, a terpenoid isolated from whale secretion, a much sought perfume ingredient. The approach involved joining two fragments through formation of the central trisubstituted alkene. Our route entailed a sequence of cross-metathesis of alkenyl bromides and cross-coupling, providing access to a previously difficult-to-access trisubstituted olefin with high efficiency and selectivity. One fragment was generated from a readily accessible enantiomerically enriched compound, sclareolide, and the other from inexpensive methylcyclohexenone. The stereogenic center of the latter was established through a NHC-Cu-catalyzed enantioselective allylic substitution, which was followed by differentiation of these alkenes through site-selective epoxidation. The total synthesis is more efficient and offers a more practical route to ambrein. Chapter Four: Stereoretentive Cross-Metathesis of Trisubstituted α,β-Unsaturated Carbonyl Compounds We have developed a strategy for the synthesis of Z- and E-Trisubstituted α,β-unsaturated carbonyl compounds through stereoretentive CM involving commercially available or easily accessible alkene substrates. The method is applicable to a variety of α,β-unsaturated esters, thioesters, and acyl fluorides. Furthermore, mono-, di-, and trisubstituted alkenes can be used as starting materials. Transformations may be carried out on gram scale and, in some cases, with commercially available Mo catalysts. The utility of the catalytic approach was highlighted through synthesis of previously accessed intermediates more directly and with improved efficiency.