General Synthetic Approach to Diverse Taxane Cores

Abstract

Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvonederived fragments, facilitated by Pd-catalyzed C−C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visiblelight induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

“…Among them, bicyclo[3.1.1]­heptane (BCH) has recently been employed as an effective 3D bioisostere of benzene . In fact, BCH-containing natural products, such as α-pinene and massarinolin A, have long been investigated either directly or as key synthetic intermediates for biomedical purposes . However, there have been only a few synthetic methods toward BCH derivatives (Scheme C).…”

Practical and General Alcohol Deoxygenation Protocol

“…Despite the drawbacks of trialkyl tin reagents, the limitations of all alternative methods still regularly force the use of tin-based deoxygenation protocols, from academic settings to large-scale industrial processes. [41][42][43][44][45][46][47] Overall, introduction of a general, nontoxic, and practical method to deoxygenate alcohols would enable broader implementation of alcohol deletion approaches in synthesis.…”

“…While effective in some cases, these alternative methods suffer the synthetic limitations endemic to standard substitution chemistry; S N 1 requires readily ionizable alcohols and S N 2 proceeds only with unhindered alcohols. Despite the drawbacks of trialkyl tin reagents, the limitations of all alternative methods still regularly force the use of tin‐based deoxygenation protocols, from academic settings to large‐scale industrial processes [41–47] . Overall, introduction of a general, nontoxic, and practical method to deoxygenate alcohols would enable broader implementation of alcohol deletion approaches in synthesis.…”

Skeletal diversification by C–C cleavage to access bicyclic frameworks from a common tricyclooctane intermediate

“…[16][17][18][19] Through selective cleavage of different bonds in a single polycyclic scaffold, a variety of substructures bearing unique topology can be accessed. While our group has explored this approach for structural diversification in the remodeling of bicyclic cyclobutanols derived from carvone, [20][21][22][23][24][25][26][27] these developments have been inherently limited. Here, we describe C-C cleavage tactics to access new chemical space using topologically complex-yet simple to synthesize-molecules that feature a cyclobutane.…”

“…Using mono-protected diol 26, we explored the selective formation of an alkoxy radical from the C2 alcohol group, which could undergo beta-scission to yield desired [3.2.0] bicycle 28. Use of an iridium photocatalyst and phosphonate base presumably effected the selective activation of the O-H bond through proton coupled electron transfer (PCET) 42 to form the corresponding alkoxy radical (27) which underwent the b-scission to generate the tertiary alkyl radical followed by trapping with TRIP-thiol to give [3.2.0] bicyclic aldehyde. However, the resulting aldehyde group was found to be unstable during isolation and so one-pot reduction with NaBH 4 was undertaken.…”