Substrate-Modified Functional Group Reactivity: Hasubanan and Acutumine Alkaloid Syntheses

Abstract

Functional group taxonomy provides a powerful conceptual framework to classify and predict the chemical reactivity of molecular structures. These principals are most effective in monofunctional settings, wherein individual functional groups can be analyzed without complications. In more complex settings, the predictive value of these analyses decreases as alternative reaction pathways, promoted by neighboring substituents and aggregate molecular properties, emerge. We refer to this phenomenon as substrate-modified functional group reactivity. In this Perspective, we explain how substrate-modified functional group reactivity molded our synthetic routes to the hasubanan and acutumine alkaloids. These investigations underscore the potential for discovery and insight that can only be gained by studying the reactivity of complex multifunctional structures.

Mn-, Fe-, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins

“…194,195,196 Specifically, treatment of 67 with stoichiometric Co(acac) 2 in isopropanol at 75 °C hydrated the styrenyl alkene, and conjugate addition occured upon treatment with excess formic acid to yield (+)-periglaucine B ( 68 ) in 55% over 2 steps. The hydration reaction proceeded with 2.2:1 diastereoselectivity in favor of the desired isomer.…”

“…In 2011, Herzon et al employed Mukiayama’s early hydration conditions (which do not employ PhSiH 3 ) in their synthesis of hasubanan alkaloids, including (+)-periglaucine B ( 68 ) (Figure ). − Specifically, treatment of 67 with stoichiometric Co­(acac) 2 in isopropanol at 75 °C hydrated the styrenyl alkene, and conjugate addition occurred upon treatment with excess formic acid to yield (+)-periglaucine B ( 68 ) in 55% over two steps. The hydration reaction proceeded with 2.2:1 diastereoselectivity in favor of the desired isomer.…”

Developments in the Synthesis of Hasubanan Alkaloids

“…Grignard addition to chiral sufinyl imine Chiral auxiliary Herzon, 2011; [1] 2014 [3] (À )-hasubanonine; (À )-runanine; (À )-delavayine;…”

“…Herzon's collective synthesis of hasubanan alkaloids is also based on electrophilic cyclization (Scheme 17). [1][2][3]15] If total synthesis could be considered the art, this work with no exaggeration should be one of the masterpieces, and it has reserved its place in history. The developed strategy was based on the attachment of rings on the "bottom" cycle, similar to Reisman's approach but fully functionalized.…”

“…Their polycyclic cage skeleton has inspired several original approaches from different research groups, in particular, groups of Profs. Herzon, [1–3] Reisman, [4] Trauner, [5,6] Castle, [7,8] and very recently Zhu [9] and Nagasawa [10,11] . Origins of such intensive research interest are apparently caused not by bioactivity of hasubanan alkaloids itself, which is scarcely reported, [12] but of their derivatives and more complex structural analogs.…”