Danishefsky Taxol total synthesis
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The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.
Danishefsky's route to Taxol has many similarities with that of Nicolaou. Both are examples of convergent synthesis with a coupling of the A and the C ring from two precursors. The main characteristic of the Danishefsky variant is the completion of the oxetane D ring onto the cyclohexanol C ring prior to the construction of the 8-membered B ring. The most prominent starting material is the Wieland-Miescher ketone. This compound is commercially available as a single enantiomer and the single chiral group present in this molecule is able to drive the entire sequence of organic reactions to a single optically active Taxol endproduct. The final step, the tail addition is identical to that of Nicolaou and is based on Ojima chemistry .
In terms of raw material shopping, this taxol molecule consists of the aforementioned Wieland-Miescher ketone, 2-methyl-3-pentanone, lithium aluminium hydride, osmium tetroxide, phenyllithium, pyridinium chlorochromate, the Corey-Chaykovsky reagent and acryloyl chloride. Key chemical transformations are the Johnson-Corey-Chaykovsky reaction and the Heck reaction.
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[edit] Synthesis D ring
Scheme 1 shows the synthesis of the oxetane D ring from the C ring starting from the Wieland-Miescher ketone 1.1 Organic reduction of this ketone with sodium borohydride provides the alcohol 1.2 which is protected as an acyl group in 1.3 with acetic anhydride, DMAP and pyridine. The ketone group is also protected as the acetal 1.4 with glycol catalyzed by naphtalenesulfonic acid. The acetyl group is replaced by a TBS group by first deprotection with sodium ethoxide in ethanol and reprotection with tert-butyldimethylsilyltriflate and lutidine accompanied by an alkene isomerization. The double bond in 1.4 is activated to a hydroxyl group in 1.5 by a hydroboration reaction followed by oxidation with hydrogen peroxide. The hydroxyl group is then oxidized to ketone 1.6 by action of pyridinium dichromate. With all the sensitive functional groups disabled, the methylene group required for the oxetane ring D can now be provided by the Corey-Chaykovsky reagent which converts the carbonyl group to the oxirane 1.7. Aluminium isopropoxide opens the epoxide ring and forms the allyl alcohol 1.8 after elimination of water. Two more hydroxyl groups are generated by oxidation of the newly formed double bond with osmium tetroxide and N-Methylmorpholine N-oxide as re-oxidant. This reaction lacks stereospecifity and the yield of triol 1.9 with the correct stereochemistry is therefore reduced. The primary alcohol is then converted into the silyl ether 1.10 with trimethylsilyl chloride in pyridine and the secondary alcohol is modified to the triflate 1.11 with triflic anhydride. A good nucleophile and a good leaving group are now in place in the correct anti-conformation for the final oxetane ring formation step to 1.12 in ethylene glycol at reflux temperature.
[edit] Synthesis C ring
In the next phase starting from the WM ketone the C ring is modified by a ring-opening procedure from which two anchoring points are formed for fusion with the A ring. In scheme 2 the alcohol 2.1 is protected by a benzyl group with benzyl bromide, sodium hydride and a quaternary ammonium salt as phase transfer catalyst. In 2.2 the acetal protecting group is removed from the ketone with p-toluenesulfonic acid. This ketone (2.3) forms the silyl enol ether 2.4 by reaction with trimethylsilyltriflate and a Rubottom oxidation introduces an acyloin group in 2.5 . Ring opening by oxidative cleavage with lead tetraacetate in methanol generates a methyl ester group and an aldehyde group in 2.6. In the next step the aldehyde is protected as an acetal with methanol and collidine p-toluenesulfonate (CPTS) and the ester is reduced to the primary alcohol 2.7 with Lithium aluminium hydride. The hydroxyl group is converted in a Grieco elimination to the selenide in 2.8 which on oxidation with hydrogen peroxide gives the alkene 2.9. Ozonolysis with ozone and triphenylphosphine provides the aldehyde 2.10.
[edit] Synthesis A ring
The A ring is a cyclohexane ring with two functional groups, a vinyl lithium group and a masked enolate for hooking up with the C ring forming the 8 membered B ring similar to the Nicolaou effort. Starting materials for this synthesis in scheme 3 are ethyl isopropyl ketone 3.1 which forms enamine 3.3 with morpholine 3.2. This enamine reacts with acryloyl chloride 3.4 in a combined nucleophilic conjugate addition and nucleophilic acyl substitution to the cyclohexanone 3.5. In the next step the morpholine group is removed by hydrolysis to the dione 3.6. reaction with hydrazine in triethylamine and ethanol affords the hydrazone 3.7 and reaction with iodine and DBN gives the iodide 3.9 in a hydrazone iodination. This reaction step is complicated because not the mono-ene 3.9 is isolated but the diene 3.10 in an unexpected dehydrogenation. The ketone group is converted into the cyanohydrin 3.10 with trimethylsilyl cyanide, potassium cyanide and a crown ether and in the last step iodine is replaced by lithium in the vinyl lithium 3.11 by reaction with tert-butyllithium in THF at -78 °C.
[edit] Synthesis B ring
The bottom part of the taxol B ring synthesis is a nucleophilic addition of the vinyl lithium 4.1 group of ring A with the ring C aldehyde group of 4.2. In 4.3 the ketone group is deprotected by action of TBAF which removes the trimethylsilyl group in 4.2. In the next step the double bond is oxidized with MCPBA to the epoxide 4.4 . This epoxide is then hydrogenated with hydrogen over palladium on carbon to the diol 4.5 which is protected in the next step as the cyclic carbonate ester 4.6 by reaction with carbonyl diimidazole and sodium hydride in dimethylformamide. These two alcohol groups are part of the final taxol molecule.
The alkene reduction of 4.6 to 4.7 with L-Selectride corrects the unexpected outcome of the A ring hydrazone iodinization. The ketone is converted into the vinyl triflate 4.8 when reacted with phenyl triflimide and potassium hexamethyldisilazide in THF at -78°C. This is one of the functional groups taking part in the Heck reaction. For the generation of the other reactive group the acetal group is deprotected with pyridinium tosylate to the carbonyl group in 4.9 which is subsequently converted to the terminal alkene 4.10 in a Wittig reaction with methylenetriphenylphosphorane. The intramolecular Heck reaction of 4.10 to 4.11 with Tetrakis(triphenylphosphine)palladium(0) and potassium carbonate in acetonitrile at reflux completes the second ring closing reaction for the B ring.
The second part of the B ring synthesis (scheme 5) is concerned with correct chemistry for the newly formed ethylene bridge connecting the A and C rings. This bridge currently has an exocyclic methylene group but in the ultimate taxol molecule this bridge is an α-acyl ketone. The required conversion is accomplished in the next 10 steps.
The TBS protecting group in 5.1 is not compatible with future functional groups and replaced by a TES (triethylsilyl) group in 5.2 through the intermediate hydroxyl group. Next the A ring double bond is converted into an oxirane 5.3 with MCPBA. The oxirane also serves as a protecting group in preparation for modifications of the exocyclic alkene. In the next two steps the benzyl protecting group in 5.3 has served its purpose and is replaced by an acyl group (acetic anhydride, DMAP and pyridine) in 5.5 through the intermediate alcohol 5.4 (hydrogenation over palladium on carbon). The carbonate ester in 5.5 is opened by reaction with phenyllithium to the α-hydroxybenzoate ester 5.6. The cleavage of the exocyclic double bond is accomplished by formation of the osmate ester 5.7 with osmium tetraoxide and pyridine and subsequent oxidative cleavage with lead tetraacetate to the ketone 5.8. the epoxide protecting group is now removed with samarium iodide and acetic anhydride in THF at -78°C to 5.9. The reaction of 5.9 with potassium tert-butoxide forms the enolate and subsequent reaction with phenylseleninic anhydride yields the hydroxy ketone 5.10. This oxidation step is comparable to allylic oxidation with selenium dioxide. In the final step the hydroxyl group is acylated to 5.11.
[edit] Tail addition
The tail addition step in this synthesis (scheme 7) is identical to that in the Nicolaou tail addition and based on Oijama chemistry. The A ring is functionalized with a hydroxyl group through PCC oxidation of 7.1. to 7.2 and subsequent reduction to alcohol 7.3 with sodium borohydride. Reaction of 7.3 with the Oijama lactam 7.4 and a concluding silyl deprotection step at two TES positions gives Taxol 7.6. Because the correct stereochemistry was already introduced in the WM-ketone this synthetic Taxol has the same optical rotation as the natural compound.
[edit] References
- ↑ Total Synthesis of Baccatin III and Taxol Samuel J. Danishefsky, John J. Masters, Wendy B. Young, J. T. Link, Lawrence B. Snyder, Thomas V. Magee, David K. Jung, Richard C. A. Isaacs, William G. Bornmann, Cheryl A. Alaimo, Craig A. Coburn, and Martin J. Di Grandi J. Am. Chem. Soc.; 1996; 118(12) pp 2843 - 2859 DOI Abstract
- ↑ New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of lactam synthon method Iwao Ojima, Ivan Habus, Mangzhu Zhao, Martine Zucco, Young Hoon Park, Chung Ming Sun and Thierry Brigaud Tetrahedron Volume 48, Issue 34 , 1992, Pages 6985-7012 Abstract
