Holton Taxol total synthesis
The Holton Taxol total synthesis, published by
The Holton
Other raw materials required for this synthesis include 4-pentenal,
Retrosynthesis
It was envisaged that Taxol (51) could be accessed through tail addition of the Ojima lactam 48 to alcohol 47. Of the four rings of Taxol, the D ring was formed last, the result of a simple intramolecular SN2 reaction of hydroxytosylate 38, which could be synthesized from hydroxyketone 27. Formation of the six-membered C ring took place through a Dieckmann condensation of lactone 23, which could be obtained through a Chan rearrangement of carbonate ester 15. Substrate 15 could be derived from ketone 6, which, after several oxidations and rearrangements, could be furnished from commercially available patchoulene oxide 1.
AB ring synthesis
As shown in Scheme 1, the first steps in the synthesis created the bicyclo[5.3.1]undecane AB ring system of Taxol. Reaction of epoxide 1 with
C ring preparation
As shown in Scheme 2, the next phase involved addition of the carbon atoms required for the formation of the C ring. Ketone 7 was treated with magnesium bromide diisopropylamide and underwent an
C ring synthesis
As shown in Scheme 3,
D ring synthesis and AB ring elaboration
In this section of the Holton Taxol synthesis (Scheme 4), the oxetane D ring was completed and ring B was functionalized with the correct substituents. Allylic alcohol 34, obtained from deprotection of
Tail addition
In the final stages of the synthesis (Scheme 5), the hydroxyl group in 46 was deprotected to give alcohol 47. Reaction of the lithium alkoxide of 47 with the
Precursor synthesis
Patchoulene oxide (1) could be accessed from terpene
Protecting groups
The total synthesis makes use of multiple protecting groups as follows:
| Protecting group | Protection reagents and conditions | Deprotection reagents and conditions | Use in synthesis |
|---|---|---|---|
| BOM (benzyloxymethyl) | benzyloxymethyl chloride, N,N-diisopropylethanamine, tetrabutylammonium iodide, in refluxing dichloromethane, 32 h | H2, Pd/C | Alcohol 27 (Scheme 3) was protected as the BOM ether, a more robust protecting group than MOP (see below). |
| Carbonate (asymmetric) | phosgene, pyridine, ethanol in dichloromethane, -23 to -10 °C | sodium bis(2-methoxyethoxy)aluminumhydride ( Red-Al )
|
The secondary alcohol in the 4-pentenal product of the aldol reaction, 9, was protected as an asymmetric carbonate ester. This group was removed in conjunction with the Red-Al reduction of ketone 12 (Scheme 2). |
| Carbonate (cyclic) [1] | phosgene, pyridine, dichloromethane, -78 °C to room temperature, 1 h | deprotected through Chan rearrangement (treatment with lithiumtetramethylpiperidide) | The cyclic carbonate ester was removed as a result of the Chan rearrangement in 15, which created a carbon-carbon bond that was part of the Taxol framework (Scheme 2). |
| Carbonate (cyclic) [2] | phosgene, pyridine, -78 to -23 °C, 0.5 h | phenyllithium in tetrahydrofuran at -78 °C. | Diol 19 (Scheme 3) was protected as a cyclic carbonate ester. This carbonate ester was cleaved by phenyllithium in tetrahydrofuran at -78 °C to give hydroxybenzoate 42 (Scheme 4). |
| MOP (2-methoxy-2-propyl) | 2-methoxypropene
|
tetrabutylammonium fluoride (1 mol eq., THF, -1 °C, 6 h)
|
The hydroxyl group in hydroxyester 24 (Scheme 3) was protected as a MOP ether in order to decarboxylate the β-ketoester group. |
| TBS (tert-butyldimethylsilyl) | butyllithium, tetrahydrofuran, tert-butyldimethylsilyl chloride | tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) | After Grob fragmentation (Scheme 1), the resultant alcohol 6 was protected as a TBS ether 7, which is kept in place until the final addition of the tail (Scheme 5). |
| TES (triethylsilyl) [1] | triethylsilyl chloride, 4-(dimethylamino)pyridine, pyridine | hydrogen fluoride/pyridine complex in acetonitrile | The secondary hydroxyl group in diol 4 (Scheme 1) was protected as a TES ether in order to prevent its participation in the Grob fragmentation. The TES was cleaved in 37 (Scheme 4) and returned to the alcohol. |
| TES (triethylsilyl) [2] | see Ojima lactam | hydrogen fluoride, pyridine, acetonitrile, 0 °C, 1 h | The secondary alcohol of 48 (Scheme 5) needed to be protected until addition of the tail to the secondary hydroxyl group in ring A was complete. |
| TMS (trimethylsilyl) [1] | lithium diisopropylamide, trimethylsilyl chloride | hydrofluoric acid, pyridine, acetonitrile. | Ketone 25 (Scheme 3) was protected as the TMS enol ether and subsequently was oxidized with m-chloroperoxybenzoic acid. In the process the TMS group migrated to the 2-hydroxyl group. |
| TMS (trimethylsilyl) [2] | trimethylsilyl chloride | hydrofluoric acid, pyridine, acetonitrile | The primary hydroxyl group in triol 35 (Scheme 4) was protected as a TMS ether allowing activation of the secondary hydroxyl group as a tosylate leaving group. |
See also
- Paclitaxel total synthesis
- Danishefsky Taxol total synthesis
- Kuwajima Taxol total synthesis
- Mukaiyama Taxol total synthesis
- Nicolaou Taxol total synthesis
- Wender Taxol total synthesis