Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

Abstract

In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol™ (1) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E (2) and taxabaccatin III (3) have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The route to these natural products is enabled by a strategy that holistically mimics Nature's approach (two-phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox-isomerization to set the key trans-diol present in 2 and 3. This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion thus empowering a medicinal chemistry campaign that is not wedded to semi-synthesis.

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…175 While this topic is beyond the purview of this Review , one example is presented here that eloquently demonstrates the utility of the selective C–H oxidations of late-stage intermediates. 237 As shown in Figure 27, nature often utilizes a two-pronged approach in the synthesis of complex molecules. First, a cyclase phase assembles the complex ring structures and carbon-based framework of the molecule.…”

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

“…The structure and the extremely hindered nature of the C9,C10 olefin was verified by X-ray crystallography. [51] Despite several hundred experiments on 25 and derivatives thereof we were unable to oxidize this olefin in either the presence or absence of oxygen at either C2, C13, or C5 (26). While frustrating, this spectacular failure bolsters the original design of 7 as the ideal synthetic cyclase phase endpoint.…”

“…Instead, the C2 alcohol interfered and produced a cyclic ether (SI-10; see the Supporting Information for details) which could not be utilized further in the synthesis. A simple workaround approach was pursued by Sharpless vanadium-catalyzed epoxidation to deliver 10, with immediate exposure to hydroxide, thus affording the crystalline triol 11 in 67 % yield (gram-scale, structure confirmed by X-ray crystallography) [51] . Acetylation of the secondary alcohols (Ac 2 O, 89 %, gram-scale) set the stage of 12 for chromium(V)-mediated installation of the C13 oxygenation.…”

“…Acetylation of the secondary alcohols (Ac 2 O, 89 %, gram-scale) set the stage of 12 for chromium(V)-mediated installation of the C13 oxygenation. This CÀH oxidation, invented specifically for this oxidation but finding utility in related contexts, [26] could be used to robustly access the enone 14 (50 % yield, gram-scale) along with 13 [51] (29 %, structure verified by X-ray crystallography). As with the synthesis of 14, this reagent [43] proved essential and was unique in its ability to enable access to C13 oxidized taxane intermediates.…”

“…Over a short period of time in CH 2 Cl 2 this compound fortuitously isomerized into the ahydroxy ketone 21, a species which could be isolated and crystallized (structure verified by X-ray crystallography). [51] In the optimized route 21 was carried forward in the same flask and exposed to sodium amalgam [47] at room temperature to produce the coveted trans-diol 22 in 72 % yield from 19. It is worth reflecting on the fact that this taxane 22, bearing an additional layer of complexity (C2 oxidation) relative to 4, could be procured in only 16 steps from 8.…”