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. 2013 Jul 8;69(27-28):5685-5701.
doi: 10.1016/j.tet.2013.04.028.

Total synthesis of taxane terpenes: cyclase phase

Yoshihiro Ishihara  1 , Abraham Mendoza, Phil S Baran
Affiliations

Total synthesis of taxane terpenes: cyclase phase

Yoshihiro Ishihara et al. Tetrahedron. .

Abstract

A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural taxane, dubbed "taxadienone", was synthesized as our first entry into the taxane family of diterpenes. The final synthetic sequence illustrates a seven-step, gram-scale and enantioselective route to this tricyclic compound in 18% overall yield. This product was then modified further to give (+)-taxadiene, the lowest oxidized member of the taxane family of natural products.

Keywords: Cyclase phase; Taxadiene; Taxane; Terpene; Total synthesis.

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Figures

Figure 1
Figure 1
A two-phase biosynthesis versus terpene synthesis in the eudesmane and taxane families of natural products. [O] = oxidation.
Figure 2
Figure 2
Early retrosynthetic disconnections for taxadienone (10).
Figure 3
Figure 3
A) Dienes that have been used in various taxane core syntheses.,7a–7s B) Potentially useful cyclohexane starting materials to serve as the taxane C ring. The reported minimum number of steps to make these dienes and cyclohexanes are listed for comparison. Note: aDiene 12 can be made in 1 step from tetramethylallene and formaldehyde using a thermal ene reaction, but tetramethylallene is prohibitively expensive at >$200/gram (Sigma–Aldrich, April 2013). bCommercially available as of April 2013.
Figure 4
Figure 4
Selected examples of A-ring/C-ring coupled compounds in initial studies.
Figure 5
Figure 5
Initial synthetic investigations toward the synthesis of taxadienone (10). Disconnection A: a ring-closing metathesis (RCM) approach would require many steps to even reach the key intermediate 54. Disconnection B: the required aldol closure from 55 simply did not proceed. Disconnection C: the required reductive aldol closure from 47 or 48 did not proceed. Disconnection D: without a suitable dienophile (i.e., using an electronically neutral olefin), the Diels–Alder reaction did not proceed under thermal or radical cation conditions. Disconnection E: with sp2 carbons at C3 and C8, the Diels–Alder reaction did not proceed even under radical cation conditions, and conjugate addition at C8 to install the methyl unit did not proceed because only the undesired conjugate addition onto C14 occurred. Disconnection F: a Shapiro reaction with an acrolein trap, followed by oxidation and Diels–Alder reaction, would not lead to an enantioselective synthesis of 10 because the stereochemistry at C8 could not be set selectively.
Figure 6
Figure 6
A scalable 1,6-addition reaction resulting in a compound bearing both an A-ring precursor and a C ring, which then became the focal point of this research project.
Figure 7
Figure 7
Revised strategy for the synthesis of the taxane tricyclic framework. [O] = oxidation, [H] = reduction.
Figure 8
Figure 8
Limited utility of kinetic enolate 58, rearrangement to thermodynamic enolate 62, and failure to allylate at C3.
Figure 9
Figure 9
Failure to oxidize allylated ketone 50 at the C2 position via allylic C–H oxidation methods.
Figure 10
Figure 10
Failure to functionalize the C3 position of 44, 58 and 65 using acrolein, acryloyl chloride or benzaldehyde.
Figure 11
Figure 11
Attempting to make use of hydrolyzed ketone 43: synthesis of a TMS enol ether from 43 resulting primarily in Δ, enol ether 66, as well as formation of enone 67.
Figure 12
Figure 12
A) A cyclopropanation strategy that was B) inefficient during the cyclopropane synthesis step and that C) failed at cyclopropane C3 functionalization.
Figure 13
Figure 13
The elusive aldol reaction at C3, requiring the unexpected additive: water.
Figure 14
Figure 14
Completion of racemic taxadienone (10).
Figure 15
Figure 15
A summary of the nine-step, first-generation racemic synthesis of taxadienone (10), with possible areas of improvement marked with *.
Figure 16
Figure 16
Plan of action for testing the enantioselectivity and absolute configuration of the asymmetric addition step. Note: the desired enantiomeric series of products are displayed.
Figure 17
Figure 17
Synthesis of (+)-44, (−)-43, (−)-61 and (−)-10, with X-ray structures of the latter two compounds displaying the wrong absolute configuration.
Figure 18
Figure 18
X-ray structure of enantiomerically enriched (+)-taxadienone (10) with the correct absolute configuration and deoxygenation from (+)-taxadienone (10) to taxadiene (8).
Figure 19
Figure 19
The nine-step, first-generation racemic synthesis of taxadienone (10; shown in black) as well as its seven-step, second-generation enantioselective synthesis (shown in blue).
Figure 20
Figure 20
Optimization of most of the steps in the enantioselective synthesis of (+)-taxadienone (10), resulting in more efficient reaction conditions and even going through different synthetic intermediates.
Figure 20
Figure 20
Optimization of most of the steps in the enantioselective synthesis of (+)-taxadienone (10), resulting in more efficient reaction conditions and even going through different synthetic intermediates.
Figure 21
Figure 21
Gram-scale synthesis of (+)-taxadiene (8) from (+)-taxadienone (10).
Figure 22
Figure 22
Summary of the taxane cyclase phase.
Figure 23
Figure 23
Nature’s presumed oxidation sequence from taxadiene (8) and a planned propagation of oxidative information from the three functional groups of taxadienone (10). [O] = oxidation.
Figure 24
Figure 24
Strategic advantage of having an over-oxidized functional group at C2: generating a series of natural and unnatural taxanes. [O] = oxidation.
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