Progress toward the Total Synthesis of Nogalamycin Using a Benzyne Cycloaddition Strategy.

Nogalamycin (NOG) is a member of the anthracycline glycoside natural products; no total syntheses have yet been reported, and there is minimal understanding of how the aglycone substitution pattern and identities of the A- and D-ring sugars impact the anticancer activity and toxicity. This paper reports progress toward a modular approach to NOG that could enable systematic structure-activity relationship studies. Key steps include a regioselective benzyne cycloaddition and reductive ring-opening to assemble a versatile AB core for analogue synthesis.

Pd-Catalyzed Heck-Type Reactions of Allenes for Stereoselective Syntheses of Substituted 1,3-Dienes.

A highly stereoselective Pd-catalyzed Heck-type reaction of allenes in which the stereochemistry of both olefins is set simultaneously was developed. The ligand CyJohnPhos was crucial to achieving stereoselectivity, while minimizing isomerization of the starting material through hydropalladation. The stereodetermining factors were proposed to be A1,3 strain between the catalyst and allene substituent, which influences the σ-π-σ equilibrium of the coupled allene intermediate, as well as eclipsing interactions of R groups in the ß-hydride elimination. Good functional group tolerance and stereoselectivities for formation of the Z,E isomer were demonstrated. The methodology was further expanded to include the regioselective formation of 2,4-dienoates and 2,4-dienamides with a variety of substitution patterns, albeit in reduced stereoselectivities favoring the E,E isomer. A plausible mechanism is proposed to account for the observed selectivities and substituent effects.

Scope and mechanistic investigations of Pd-catalyzed coupling/cyclizations and cycloisomerizations of allenyl malonates.

Pd-catalyzed transformations of allenyl malonates provide convenient access to functionalized carbocycles, but the influence of the ligand, solvent, base, and reaction conditions on the mechanism, regioselectivity, and product outcome of the cyclization are not well-understood. Additionally, from the perspective of synthetic utility, access to either fully substituted or enantioenriched cyclopentane building blocks has not yet been achieved. This work describes how targeted changes to the reaction conditions enable predictable control over the mechanism of Pd-catalyzed allene cross-coupling/cyclization and cycloisomerization, irrespective of the allene substitution pattern. Both enantioenriched cyclopropanes and cyclopentenes can be obtained through axis-to-center chirality transfer from the allene precursor at room temperature, which is not possible using reported Pd-catalyzed methods that result in racemization of the allene. Finally, the ability to divert the reactivity of the allenyl malonate from cross-coupling/cyclization to cycloisomerization by a simple switch of the ligand on Pd from a bidentate phosphine to an electron-poor triphenylphosphite is demonstrated.

Stereodivergent Metal-Catalyzed Allene Cycloisomerizations.

Metal-catalyzed allene cycloisomerizations provide rapid entry into five-membered carbocyclic frameworks, a common motif in natural products and pharmaceuticals. While both Au(I) and Pd(0)-catalyzed allene cycloisomerizations give 5-endo-dig cyclization, Pd prefers the syn diastereomer in contrast to the anti isomer observed with Au. The change in stereoselectivity is proposed to arise from buildup of A1,3 strain during the key carbopalladation step to furnish the cycloisomerized products in moderate to good dr with yields comparable to Au(I) catalysts.