Conformational Design Principles in Total Synthesis

Abstract

Conformation is one of the most fundamental concepts in organic chemistry for chemists to visualize a molecule as a three‐dimensional object in addition to its constitution and configuration. Conformational factors significantly affect the physical properties, chemical reactivities, and biological activities of a molecule. The significance of conformational design has been generally recognized since its successful application in the total synthesis of complex natural products, such as vitamin B12 and erythronolide. Conformational analysis, especially intentional control of conformational preferences by conformational design, could play a critical role in the synthesis of complex organic molecules by guiding the formation of bonds, stereocenters, or rings. This Minireview highlights selected examples of conformational design in natural‐product synthesis, with particular emphasis on the applications and new insights advanced in the last 20 years. The examples discussed herein are divided into three categories by structural features of the substrates: open‐chain type, cyclohexane type, and medium‐ and large‐ring type.

Role of Macrocyclic Conformational Steering in a Kinetic Route toward Bielschowskysin

“…The syntheses described herein highlight the importance of conformational analysis in macrocycles to fully exploit the inherent reactivity of these strained molecules and uncover potential synthetic strategies. 37 As highlighted by Stoltz in a recent review article, only a single de novo synthesis of polycyclic FBC natural products has been reported since the 1990s. 2c Given the remaining synthetic challenges associated with this family of natural products (e.g., verrilin, plumarellide, and mandapamate), we anticipate that both strategies of macrocyclic E-alkene epoxidation and kinetic/thermodynamic dearomatization reported herein will find applications to the synthesis of a large number of molecules in this class.…”

Total Synthesis of Ritterazine B

“…22 Conformational analysis of the disfavored species 23 and 24 revealed the existence of synpentane-like interactions between the C20/C20ʹ-b-Me and the axial C13/C13ʹ-Me groups. 5,23 These interactions are not present with the a-disposed C20-Me groups, which appear less sterically encumbered.…”

Nickel-Catalyzed Kumada Cross-Coupling Reactions of Benzylic Sulfonamides

“…Furthermore, we demonstrate that sulfonamides undergo stereospecific XC reactions, in contrast to the stereoablative reactivity typically observed with styrenyl aziridines and Katritzky salts [ 22 , 36 , 37 , 38 , 39 , 40 , 51 , 52 , 53 , 54 ]. This stereospecific manifold allows for rapid diastereoselective construction of acyclic fragments bearing 1,3-substitution [ 55 , 56 ].…”