Selective Oxidations in the Synthesis of Complex Natural ent-Kauranes and ent-Beyeranes.

Syntheses of two natural products derived from the ent-kaurene kaurenoic acid are described for the first time using regio- and diastereoselective oxidations. Palladium- and manganese-mediated oxidations were used to accomplish the syntheses of two ent-beyerane metabolites. The use of the White-Gormisky-Zhao catalyst Mn(CF3-PDP) enabled the first application of a nondirected metal-catalyzed oxidation in an unactivated C-H bond in a total synthesis.

Chemoselective methylene oxidation in aromatic molecules.

Despite significant progress in the development of site-selective aliphatic C-H oxidations over the past decade, the ability to oxidize strong methylene C-H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late-stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Here, we report a simple manganese small-molecule catalyst Mn(CF3-PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic and biaryl moieties. Late-stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C-H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.

Enantioselective Synthesis of Phthalides and Isochromanones via Heck-Matsuda Arylation of Dihydrofurans.

In this communication, the enantioselective synthesis of phthalides and isochromanones is described through a new palladium-catalyzed Heck-Matsuda arylation/NaBH4 -reduction/lactonization sequence of 2,3- and 2,5-dihydrofurans in good overall yields and excellent enantioselectivities (up to 98:2 er). This expeditious synthesis of chiral Heck lactol intermediates allowed the diversification of the strategy to obtain medicinally relevant chiral lactones, amines, and olefins. The natural product 3-butylphthalide was obtained in three steps with an overall yield of 33 % yield in 98:2 er.

Remote, Late-Stage Oxidation of Aliphatic C-H Bonds in Amide-Containing Molecules.

Amide-containing molecules are ubiquitous in natural products, pharmaceuticals, and materials science. Due to their intermediate electron-richness, they are not amenable to any of the previously developed N-protection strategies known to enable remote aliphatic C-H oxidations. Using information gleaned from a systematic study of the main features that makes remote oxidations of amides in peptide settings possible, we developed an imidate salt protecting strategy that employs methyl trifluoromethanesulfonate as a reversible alkylating agent. The imidate salt strategy enables, for the first time, remote, nondirected, site-selective C(sp3)-H oxidation with Fe(PDP) and Fe(CF3PDP) catalysis in the presence of a broad scope of tertiary amides, anilide, 2-pyridone, and carbamate functionality. Secondary and primary amides can be masked as N-Ns amides to undergo remote oxidation. This novel imidate strategy facilitates late-stage oxidations in a broader scope of medicinally important molecules and may find use in other C-H oxidations and metal-mediated reactions that do not tolerate amide functionality.

Total Synthesis of (-)-Marinisporolide C.

The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.

Total Synthesis of the Oxopolyene Macrolide (-)-Marinisporolide C.

The first total synthesis of (-)-marinisporolide C was performed in 25 steps (longest linear sequence) and an overall yield of 1%. Due to the high degree of convergence and robustness, the C9-C35 fragment that corresponds to the polyol portion was obtained in gram quantity. Highlights of this synthesis include five highly stereoselective aldol reactions responsible for the construction of five C-C bonds and six stereogenic centers. Additionally, a very efficient Julia-Kocienski reaction was used to install a C22-C23 double bond, and the macrocyclic ring was closed using an intramolecular Horner-Wadsworth-Emmons olefination.

The role of ß-bulky substituents in aldol reactions of boron enolates of methylketones with aldehydes: experimental and theoretical studies by DFT analysis.

In this work, we show the influence of the volume of the ß-substituents on the levels of 1,5-stereoselectivities of aldol reactions of boron enolates generated from ß-alkoxy methylketones with aldehydes. Excellent levels of 1,5-syn stereoinduction were obtained when the ß-protecting group is a silicon ether. This remarkable selectivity is attributed to the volume of the ß-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of ß-alkyl-ß-alkoxy methylketones.

Influence of ß-substituents in aldol reactions of boron enolates of ß-alkoxy methylketones.

Moderate to good levels of substrate-based 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of ß-tert-butyl methylketones with achiral aldehydes, independent of the nature of the ß-alkoxy protecting group (P = PMB or TBS). The analysis of the relative energies of the transition structures by theoretical calculations using the density functional B3LYP shows relative energies favoring the corresponding OUT-1,5-SYN transition structures, explaining the observed 1,5-syn stereoinduction.