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end credits紫杉醇的全合成路线
2008 九月 12
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Danishefsky Taxol total synthesis From Wikipedia, the free encyclopedia
intheflesh>venthheavenThe Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996[1]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.
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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 prent in this molecule is able to drive the entire quence of organic reactions to a single optically active Taxol endproduct. The final step, the tail addition is identical to that of Nicolaou and is bad on Ojima chemistry.[2]
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.
Contents
∙ 1 Synthesis D ring
∙ 2 Synthesis C ring
∙ 3 Synthesis A ring
∙ 4 Synthesis B ring
∙ 5 Tail addition
wsk>lengthwi∙ 6 See also
∙7 References
[edit] Synthesis D ring草莓的英文
第一张图显示D环的合成由Wieland-Miescher 酮开始。1. 硼氢化钠将羰基还原为醇2并且用乙酰氯，DMAP和吡啶酰基化为3。接着，羰基被乙二醇在萘磺酸催化下保护为缩酮（同时伴随着双键移位）。然后，乙酰基被叔丁基二甲基硅基（TBDMS）取代。被活化的双键经过硼氢化-氧化反应得到醇5。然后，吡啶·铬酐把羟基氧化为酮6。在所有官能团都被钝化之后，氧杂四元环所需的亚甲基可以经由Cor
ey-Chaykovsky 反应得到环氧化物7. 异丙醇铝将环氧键打开，消除得到烯丙基醇8。两个顺式羟基由四氧化锇和N-甲基-N-氧化吗啉氧化双键得到。 This reaction lacks stereospecifity and the yield of triol 9 with the correct stereochemistry is therefore reduced. 一级醇被三甲基氯硅烷转化为硅醚10，而二级醇则经由三氟甲磺酸酐转换为磺酸酯。一个好的亲核试剂以及离去基团的构建方便了产生12的亲核取代反应。
[edit] Synthesis C ring
In the next pha 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 2the alcohol12is protected by a benzyl group with benzyl bromide, sodium hydride and a quaternary ammonium salt as pha transfer catalyst. In 13the acetal protecting group is removed from the ketone with p-toluenesulfonic acid. This ketone (14) forms the silyl enol ether15by reaction with trimethylsilyltriflate and a Rubottom oxidation introduces an acyloin group in 16. Ring opening by oxidative cleavage with lead tetraacetate in methanol generates a methyl ester group and an aldehyde group in 17. 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 18 with Lithium aluminium hydride. The hydroxyl group is converted in a Grieco elimination to the lenide in 19which on oxidation with hydrogen peroxide gives the alkene
when there was me and you20. Ozonolysis with ozone and triphenylphosphine provides the aldehyde
21.
[edit] Synthesis A ring
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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 3are ethyl isopropyl ketone22which forms enamine23 with morpholine. This enamine reacts with acryloyl chloride in a combined nucleophilic conjugate addition and nucleophilic acyl substitution to the cyclohexene 24. In the next step the morpholine group is removed by hydrolysis to the dione 25. Reaction with hydrazine in triethylamine and ethanol affords the hydrazone26 and reaction with iodine and DBN gives the iodide 27in a hydrazone iodination. This reaction step is complicated becau not the mono-ene is isolated but the diene 28 in an unexpected dehydrogenation. The ketone group is converted into the cyanohydrin29with trimethylsilyl cyanide, potassium cyanide and a crown ether and in the last step iodine is replaced by lithium in the vinyl lithium 30 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 30 group of ring A with the ring C aldehyde group of 21. In 30the ketone group is deprotected by action of TBAF which removes the trimethylsilyl group in 31. In the next step the double bond is oxidized with MCPBA to the epoxide 32. This epoxide is then hydrogenated with hydrogen over palladium on carbon to the diol 33which is protected in the next step as the cyclic carbonate ester34by reaction with carbonyl diimidazole and sodium hydride in dimethylformamide. The two alcohol groups are part of the final taxol molecule.
The alkene reduction of 34to 35with L-Selectride corrects the unexpected outcome of the A ring hydrazone iodinization. The ketone is converted into the vinyl triflate36 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 37which is subquently converted to the terminal alkene38 in a Wittig reaction with methylenetriphenylphosphorane. The intramolecular Heck reaction of 38 to 39 with
Tetrakis(triphenylphosphine)palladium(0) and potassium carbonate in acetonitrile at reflux completes the cond ring closing reaction for the B ring.
