Development of a Concise Synthesis of Ouabagenin and Hydroxylated Corticosteroid Analogues

Abstract

The natural product ouabagenin is a complex cardiotonic steroid with a highly oxygenated skeleton. This full account describes the development of a concise synthesis of ouabagenin, including the evolution of synthetic strategy to access hydroxylation at the C19 position of a steroid skeleton. In addition, approaches to install the requisite butenolide moiety at the C17 position are discussed. Lastly, methodology developed in this synthesis has been applied in the generation of novel analogues of corticosteroid drugs bearing a hydroxyl group at the C19 position.

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

“…207,208 Baran’s team found that Mukaiyama’s hydration 105 procedure could install the C-14 tertiary alcohol 94 from the trisubstituted alkene 93 in 86% yield and 8:1 diastereoselectivity. Use of dioxane as solvent improved the diastereoselectivity of the nascent alcohol.…”

“…Consequently, we do not discuss these numerous reactions further except to state that a number of groups have found uses for this reaction in complex molecule and natural product syntheses. 207,208,386,387,388,389,390,391 …”

Recent Progress in Steroid Synthesis Triggered by the Emergence of New Catalytic Methods

“…Subsequently, the Baran group successfully implemented this strategy in the synthesis of polyoxygenated cardiotonic steroid ouabagenin from progesterone . As progesterone does not contain the β‐C14 hydroxyl group, Baran and co‐workers installed this moiety using Δ 14 ‐alkene‐containing intermediate 66 (Scheme ).…”

Recent Accomplishments in the Total Synthesis of Natural Products Through C–H Functionalization Strategies

“…Shortly afterward, they published a full account describing the synthesis of 2 and the approach toward C-19-hydroxylated corticosteroid analogs [36,37]. Shortly afterward, they published a full account describing the synthesis of 2 and the approach toward C-19-hydroxylated corticosteroid analogs [36,37].…”