Holton Taxol total synthesis

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Holton Taxol total synthesis overview from raw material perspective

The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol (generic name: paclitaxel).[1][2]

The Holton Taxol total synthesis is a good example of a linear synthesis starting from commercially available natural compound patchoulene oxide.[3] This epoxide can be obtained in two steps from the terpene patchoulol and also from borneol. The reaction sequence is also enantioselective, synthesizing (+)-Taxol from (-)-patchoulene oxide or (-)-Taxol from (-)-borneol with a reported specific rotation of +- 47° (c=0.19 / MeOH). The Holton sequence to Taxol is relatively short compared to that of the other groups with an estimated 37 step not counting the addition of the amide tail. One of the reasons is that the patchoulol starting compound already contains 15 of the 20 carbon atoms required for the Taxol ABCD ring framework.

Other raw materials required for this synthesis include 4-pentenal, m-chloroperoxybenzoic acid, methyl magnesium bromide and phosgene. Two key chemical transformations in this sequence are a Chan rearrangement and a sulfonyloxaziridine enolate oxidation.

Retrosynthesis[edit]

Holton's total synthesis of Taxol was derived from the natural product patchoulene oxide (1). The final stage of the synthesis was the formation of the tail by addition of the Ojima lactam 42 to alcohol 41. Of the four rings of Taxol, the D ring was formed last, the result of a simple intramolecular SN2 reaction of hydroxytosylate 33. Formation of the C ring took place through the Dieckmann condensation of ketone 20, with a Grignard reagent adding the final carbon for the ring system. Preparation for the C ring synthesis took place through a Chan rearrangement of carbonate ester 13 and subsequent oxidation and reduction reactions. The AB ring synthesis involved multiple rearrangements starting from epoxide 1 (patchoulene oxide).

Holton taxol total synthesis retrosynthesis
Retrosynthesis

AB Ring synthesis[edit]

As shown in Scheme 1, starting from patchoulene oxide (1), the first steps created the bicyclo[5.3.1]undecane AB ring system of Taxol. Reaction of epoxide 1 with tert-butyllithium removed the acidic α-epoxide proton, leading to an elimination reaction and ring-opening of the epoxide to give allylic alcohol 2. The allylic alcohol was epoxidized to epoxyalcohol 3 using tert-butyl hydroperoxide and titanium(IV)tetraisopropoxide. In the subsequent reaction, the Lewis acid boron trifluoride catalyzed the ring opening of the epoxide followed by skeletal rearrangement of the isopropyl bridge and an elimination reaction to give unsaturated diol 4. The newly created hydroxyl group was protected as the triethylsilyl ether, and the double bond was epoxidized by reaction with meta-chloroperbenzoic acid. Acid-catalization Grob fragmentation of epoxide 6 gave ketone 7 in over 90% yield. The hydroxyl group was protected as the tert-butyldimethylsilyl ether. In the next phase, the carbon atoms required for the formation of the C ring were added. The ketone group in 7 was converted into magnesium enolate 8 by action of lithium diisopropylamide and methylmagnesium bromide. This enolate was reacted with 4-pentenal in an aldol reaction to give β-hydroxyketone 9. The hydroxyl group was protected as the asymmetric carbonate ester (10). Oxydation of the enolate of ketone 10 with (+)-camphorsulfonyl oxaziridine gave α-hydroxyketone 11 in 85% yield. Reduction of the ketone group with 20 equivalents of Red-Al gave a triol which was immediately converted to carbonate 12 using phosgene.

Ring AB synthesis Scheme 1
Scheme 1

C Ring preparation[edit]

As shown in Scheme 2, Swern oxidation of alcohol 12 gave ketone 13. The carbonyl group was used to set the functionality of the B ring in preparation for formation of the C ring. The first step in this sequence was a Chan rearrangement of the carbonate ester using lithium tetramethylpiperidide, which gave α-hydroxyester 14. The hydroxyl group was reductively removed using samarium(II) iodide to give stable enol 15. Chromatography of this enol on silica gel gave the cis diastereomer 16 predominantly, along with a small amount of the trans isomer, which could be recycled. Treatment of this ketone with lithium tetramethylpiperidide and (+)-camphorsulfonyl oxaziridine gave α-hydroxyketone 17. Reduction of the ketone using Red-Al resulted also in epimerization to give the required trans-fused lactone 18.

Ring C preparation scheme 2
Scheme 2

C Ring synthesis[edit]

As shown in Scheme 3, diol 18 was protected with phosgene as a carbonate ester (19). The terminal alkene group of 19 was next converted to a methyl ester using ozonolysis followed by oxidation with potassium permanganate and esterification with diazomethane. The second C-C bond formation step in the cyclohexane C ring synthesis involved a Dieckman condensation of lactone 20 using lithium diisopropylamide as a base at -78°C to give enol ester 21. Decarboxylation of 21 required protection of the hydroxyl group as the 2-methoxy-2-propyl (MOP) ether (22). With the protecting group in place, decarboxylation was effected with potassium thiophenolate in dimethylformamide to give protected hydroxy ketone 23. In the next two steps the MOP protecting group was removed by acid, and alcohol 24 was reprotected with another, more robust, ether protecting group, benzyloxymethyl (25). The ketone was converted to the trimethylsilyl enol ether 26, which was subsequently oxidized in a Rubottom oxidation using m-chloroperbezoic acid to give the trimethylsilyl protected acyloin 27. At this stage the final missing carbon atom in the Taxol ring framework was introduced in a Grignard reaction of ketone 27 using a 10-fold excess of methylmagnesium bromide to give tertiary alcohol 28. Treatment of tertiary alcohol 28 with the Burgess reagent gave the exocyclic alkene. Acidic workup gave allylic alcohol 29.

Ring C synthesis scheme 3
Scheme 3

D Ring synthesis and AB ring elaboration[edit]

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 29 was oxidized with osmium tetroxide in pyridine to give triol 30. The three hydroxyl groups were modified in the next five reaction steps. After protection of the primary hydroxyl group, the secondary hydroxyl group in 32 was converted to a good leaving group using p-toluenesulfonyl chloride. Tosylate 33 underwent cyclization to give oxetane 34 by nucleophilic displacement with inversion of the tosyl group by the primary hydroxyl group. The remaining tertiary alcohol was acylated, and the silyl group was removed to give allylic alcohol 36. The carbonate ester was cleaved by reaction with phenyllithium in tetrahydrofuran at -78°C to give alcohol 37, which completed the lower part of the B ring. In the upper part of the B ring, the hydroxyl group was oxidized to ketone 38 using tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO). This ketone was depronated with potassium tert-butoxide in tetrahydrofuran at low temperature and further oxidized by reaction with benzeneseleninic anhydride to give α-hydroxyketone 39, which was subsequently acylated to give α-acetoxyketone 40.

Holton Taxol total synthesis scheme 4
Scheme 4

Tail addition[edit]

The tail addition step in this synthesis (Scheme 5) is identical to that in the Nicolaou tail addition and based on the Ojima lactam. The hydroxyl group in 40 was deprotected to give alcohol 41. Reaction of the lithium alkoxide of 41 with the Ojima lactam 42 adds the tail in 43. Deprotection gave (-)-Taxol 45.

Scheme 5 Holton Taxol total synthesis Tail Addition
Scheme 5

Precursor synthesis[edit]

The synthesis of patchoulene oxide (1) started from tricyclic compound patchoulol (45) and involved carbocation rearrangement followed by elimination in the presence of a protic acid. The driving force for the rearrangement is relief of ring strain. Zaitsev's rule applies in the elimination. Epoxidization gave patchoulene oxide 1.

Taxol total synthesis by Holton pre.svg

Protecting Groups[edit]

BOM (benzyloxymethyl)[edit]

Protection Reagents: Benzyloxymethyl chloride, N,N-diisopropylethanamine, tetrabutylammonium iodide, reflux 32 h

Deprotection Reagents: H2, Pd/C

Alcohol 25 (Scheme 3) was protected as the BOM ether, a more robust protecting group than MOP (see below).

Carbonate (asymmetric)[edit]

Protection Reagents: Phosgene, pyridine in dichloromethane followed by ethanol

Deprotection Reagents: Sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al)

The secondary alcohol in the 4-pentenal product of the aldol reaction, 10 (Scheme 1), was protected by the asymmetric carbonate ester. This group was removed in conjunction with the Red-Al reduction of ketone 11 (Scheme 1).

Carbonate (cyclic) [1][edit]

Protection Reagent: Phosgene, pyridine, dichloromethane, -78°C-25°C, 1 h

Deprotection Reagents: Chan rearrangement with lithiumtetramethylpiperidide

Red-Al was used to completely reduce ketone 11 (Scheme 1) which caused carbonate rearrangement with elimination of ethanol. The cyclic carbonate ester was removed as a result of the Chan rearrangement in 13 which created a carbon-carbon bond that was part of Taxol.

Carbonate (cyclic) [2][edit]

Protection Reagent: Phosgene, pyridine, dichloromethane, -23°C, 0.5 h

Deprotection Reagents: 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 36 (Scheme 4).

MOP (2-methoxy-2-propyl)[edit]

Protection Reagents: p-Toluenesulfonic acid and 2-methoxypropene

Deprotection Reagents: Tetrabutylammonium fluoride (1 mol eq., THF, -1°C, 6 h)

The hydroxyl group in hydroxyester 21 (Scheme 3) was protected as a MOP ether in order to decarboxylate the β-ketoester group.

TBS (tert-butyldimethylsilyl)[edit]

Protection Reagents: Butyllithium, tetrahydrofuran, tert-butyldimethylsilyl chloride

Deprotection Reagents: Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)

After Grob fragmentation of β-epoxyalcohol 6 (Scheme 1), the resultant alcohol was protected as a TBS ether, which is kept in place until the final addition of the tail (Scheme 5).

TES (triethylsilyl) [1][edit]

Protection Reagents: Triethylsilyl chloride, 4-(dimethylamino)pyridine, pyridine

Deprotection Reagents: 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 of β-epoxyalcohol 6. The TES was cleaved in 36 (Scheme 4) and returned to the alcohol.

TES (triethylsilyl) [2][edit]

Protection Reagents: See Ojima lactam

Deprotection Reagents: Hydrogen fluoride, pyridine, acetonitrile, 0°C, 1 h

The secondary alcohol on the tail of Taxol 43 (Scheme 5) needed to be protected until addition of the tail to the secondary hydroxyl group in ring A was complete.

TMS (trimethylsilyl) [1][edit]

Protection Reagents: Lithium diisopropylamide, trimethylsilyl chloride

Deprotection Reagents: Burgess reagent, acidic workup

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][edit]

Protection Reagents: Trimethylsilyl chloride

Deprotection Reagents: Acetic acid

The primary hydroxyl group in triol 30 (Scheme 4) was protected as a TMS ether allowing activation of the secondary hydroxyl group as a tosylate leaving group.

See also[edit]

References[edit]

  1. ^ Robert A. Holton, Carmen Somoza, Hyeong Baik Kim, Feng Liang, Ronald J. Biediger, P. Douglas Boatman, Mitsuru Shindo, Chase C. Smith, Soekchan Kim, Hossain Nadizadeh, Yukio Suzuki, Chunlin Tao, Phong Vu, Suhan Tang, Pingsheng Zhang, Krishna K. Murthi, Lisa N. Gentile, and Jyanwei H. Liu (1994). "First total synthesis of taxol. 1. Functionalization of the B ring". J. Am. Chem. Soc. 116 (4): 1597–1598. doi:10.1021/ja00083a066. 
  2. ^ Robert A. Holton, Hyeong-Baik Kim, Carmen Somoza, Feng Liang, Ronald J. Biediger, P. Douglas Boatman, Mitsuru Shindo, Chase C. Smith, Soekchan Kim, Hossain Nadizadeh, Yukio Suzuki, Chunlin Tao, Phong Vu, Suhan Tang, Pingsheng Zhang, Krishna K. Murthi, Lisa N. Gentile, and Jyanwei H. Liu (1994). "First Total Synthesis of Taxol. 2. Completion of the C and D Rings". J. Am. Chem. Soc. 116 (4): 1599–1600. doi:10.1021/ja00083a067. 
  3. ^ Robert A. Holton, R. R. Juo, Hyeong B. Kim, Andrew D. Williams, Shinya. Harusawa, Richard E. Lowenthal, and Sadamu. Yogai (1988). "A synthesis of taxusin". J. Am. Chem. Soc. 110 (19): 6558–6560. doi:10.1021/ja00227a043. 

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