Two-Phase Synthesis of (−)-Taxuyunnanine D

Abstract

The first successful effort to replicate the beginning of the Taxol oxidase phase in the laboratory is reported, culminating in the total synthesis of taxuyunnanine D, itself a natural product. Through a combination of computational modeling, reagent screening, and oxidation sequence analysis, the first three of eight C–H oxidations (at the allylic sites corresponding to C-5, C-10, and C-13) required to reach Taxol from taxadiene were accomplished. This work lays a foundation for an eventual total synthesis of Taxol capable of delivering not only the natural product but also analogs inaccessible via bioengineering.

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

“…As illustrated in Figure 1, Taxol™ can be viewed as a "level 11" taxane due to the presence of 9 oxidized carbon atoms and two degrees of unsaturation; over 100 natural products at this oxidation state have been isolated. Similarly, decinnamoyltaxinine E ( 2 ) 29 , taxabaccatin III ( 3 ) 30 , taxusin ( 4 ) 31–36 , taxuyunnanine D ( 5 ) 37,38 , and taxadiene ( 6 ) 39–41 can be viewed as level 3–5 taxanes and represent over 100 additional natural products. In this report, the first enantioselective total syntheses of decinnamoyltaxinine E ( 2 ) and taxabaccatin III ( 3 ) are presented.…”

“…Based on prior studies 38 , it was expected that Pd-catalysed allylic oxidation would take place smoothly to install the C–5 oxygenation. Instead, the C–2 alcohol interfered and produced a cyclic ether ( SI-10 ) that could not be utilized further in the synthesis (see SI for details).…”

CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation

“…The lack of C3 oxidation when using SeO 2 allowed access to analogues 10 and 12 , which are devoid of the C3,C4,C5‐hydroxy triad that is so prominent in ingenol ( 1 ). Finally, transformation of cyclase‐phase endpoint 17 into ingenol analogue 14 led to another curious finding in oxidation chemistry ( Path E ): although 14 did not react under Pd(OH) 2 /TBHP conditions, it was successfully oxidized at C3 when using our recently developed Cr V ‐based allylic oxidation,13 giving ingenane 26 with an inverted stereocenter at C3. This inversion of stereochemistry did not obstruct the synthetic plan, since it 26 was easily converted into analogues 11 and 9 in 1 and 2 steps, respectively.…”

CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation

“…Tw o-phase terpene synthesis can both enable scalable access to the parent natural product and constitute atemplate for preparation of analogues with deepseated changes. [10] In the case of 1,the latter cannot be rapidly obtained through semisynthesis or synthetic biology.I nt his work, an exploratory oxidase phase ( Figure 1B)featuring 13 CÀHoxidations is used to systematically evaluate the role of the four hydroxy groups in the biological activity of ingenol (1).…”

“…Thereafter, in ad iverging pathway, 16 was transformed into C4-deoxy analogues 6 and 8 (Path B). The" allylic oxidation panel" previously developed during our synthesis of taxuyunnanine D [13] was employed throughout this work. After extensive experimentation, ak ey Pd(OH) 2 /TBHP step [14] (20!21)w as found to be critical to the success of this reaction sequence,s ince the allylic oxidation at C3 was only possible using these conditions.The product of this oxidation reaction, 21,w as structurally confirmed by X-ray analysis to establish the relative stereochemistry of the generated analogues 6 and 8 (see the Supporting Information for details).…”