我先来一个吧起到抛砖引玉的作用：
The total synthesis of Oseltamivir

这些年来对于Oseltamivir的合成吸引着一大群牛人，从E.J Corey,到Shibasaki,Trost,Chi-Huey Wong,Fukuyama,再到2009年的Hayashi.前面几个都是响当当的任务，就是Hayashi相对来说弱一点。但是工作做得最好的却是Hayashi( 个人观点).不过Hayashi也是Corey的post Dr，在oseltamivir的合成上可谓是青出于蓝。最初Oseltamivir是Gilead Sciences 先合成出来的，但不晓得什么原因居然被F. Hoffman-La Roche 公司先申请了专利，据说还打官司了。F. Hoffman-La Roche 公司靠oseltamivir不晓得赚了多少钱呢。其实oseltamivir的分子式并不是很难（对于全合成来说），但是为什么会引起这么多牛人的兴趣，主要是该化合物的药用。
Oseltamivir INN , an antiviral drug, slows the spread of influenza (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day.The drug is marketed under the trade name Tamiflu, and is taken orally in capsules or as a suspension. It has been used to treat and prevent influenza A virus and influenza B virus infection in over 50 million people since 1999.

Oseltamivir is a prodrug, a (relatively) inactive chemical which is converted into its active form by metabolic process after it is taken into the body. It was the first orally active neuraminidase inhibitor commercially developed. It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences,and is marketed by Genentech. In Japan, it is marketed by Chugai Pharmaceutical Co.As of December 15, 2010 , the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.

这里我们主要来看看Hayashi的Angew. Chem. Int. Ed. 2009, 48, 1 – 5这篇关于oseltamivir的合成。



首先是硝基烯烃和醛在脯氨酸衍生物催化下一个micheal addition生成化合物8,然后再和化合物5再一个micheal addition，然后再接着一个Horner-Wadsworth-Emmons reaction，合成了一个六元环，带有三个手性中心。所得到的化合物9有R,S构型，再用tolSH转化下，就得到了想要的S构型化合物6.整个过程one  pot,产率不错70%。当然其中也有副反应产物10和11，但作者用retro-micheal addition和retro-aldol转化回去了。(其实这里类似2006年Enders发的那篇nature，醛形成烯胺，先和硝基烯烃作用，然后生成化合物5发生micheal addition,最后Horner-Wadsworth-Emmons reaction就完成了关环.估计作者看了Enders的文章，受到了启发，用类似的方法合成六元环结构。)

然后化合物6在TFA作用下脱保护，再用草酰氯转化为酰氯，和叠氮化钠作用生成酰基叠氮化物，这几步不用后处理。然后直接发生Curtius rearrangement，生成酰胺。再用Zn还原硝基为氨基。最后再来个retro-micheal addition，最终得到oseltamivir.从化合物6到最后产率为82%。总共9步反应，产率达到惊人的57.4%=70%×82%,不是绝后的，至少也是空前的。

Oseltamivir total synthesis
Commercial production
The current production method is based on the first scalable synthesis developed by Gilead Sciences  starting from naturally occurring quinic acid or shikimic acid. Due to lower yields and the extra steps required (because of the additional dehydration), the quinic acid route was dropped in favour of the one based on shikimic acid, which received further improvements by Hoffmann-La Roche. The current industrial synthesis is summarised below:


Karpf / Trussardi synthesis
The current production method includes two reaction steps with potentially hazardous azides. A reported azide-free Roche synthesis of tamiflu is summarised graphically below :

The synthesis commences from naturally available (− ) -shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with p-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions[5] in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (− ) -shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to oseltamivir that do not involve the use of (− ) -shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

Corey synthesis
In 2006 the group of E.J. Corey published a novel route bypassing shikimic acid starting from butadiene and acrylic acid . The inventors chose not to patent this procedure which is described below:

Butadiene 1 reacts in an asymmetric Diels-Alder reaction with the esterfication product of acrylic acid and 2,2,2-Trifluoroethanol 2 catalysed by the CBS catalyst. The ester 3 is converted into an amide in 4 by reaction with ammonia and the next step to lactam 5 is an iodolactamization with iodine initiated by trimethylsilyltriflate. The amide group is fitted with a BOC protective group by reaction with Boc anhydride in 6 and the iodine substituent is removed in an elimination reaction with DBU to the alkene 7. Bromine is introduced in 8 by an allylic bromination with NBS and the amide group is cleaved with ethanol and caesium carbonate accompanied by elimination of bromide to the diene ethyl ester 9. The newly formed double bond is functionalized with N-bromoacetamide 10 catalyzed with Tin(IV) bromide with complete control of stereochemistry. In the next step the bromine atom in 11 is displaced by the nitrogen atom in the amide group with the strong base KHMDS to the aziridine 12 which in turn is opened by reaction with 3-pentanol 13 to the ether 14. In the final step the BOC group is removed with phosphoric acid and the oseltamivir phosphate 15 is formed.

Shibasaki synthesis


An improved method published in 2007 starts with the enantioselective desymmetrization of aziridine 1 with trimethylsilyl azide (TMSN3) and a chiral catalyst to the azide 2. The amide group is protected as a BOC group with Boc anhydride and DMAP in 3 and iodolactamization with iodine and potassium carbonate first gives the unstable intermediate 4 and then stable cyclic carbamate 5 after elimination of hydrogen iodide with DBU.

The amide group is reprotected as BOC 6 and the azide group converted to the amide 7 by reductive acylation with thioacetic acid and 2,6-lutidine. Caesium carbonate accomplishes the hydrolysis of the carbamate group to the alcohol 8 which is subsequently oxidized to ketone 9 with Dess-Martin periodinane. Cyanophosphorylation with diethyl phosphorocyanidate (DEPC) modifies the ketone group to the cyanophosphate 10 paving the way for an intramolecular allylic rearrangement to unstable β-allyl phosphate 11 (toluene, sealed tube) which is hydrolyzed to alcohol 12 with ammonium chloride. This hydroxyl group has the wrong stereochemistry and is therefore inverted in a Mitsunobu reaction with p-nitrobenzoic acid followed by hydrolysis of the p-nitrobenzoate to 13.

A second Mitsunobu reaction then forms the aziridine 14 available for ring-opening reaction with 3-pentanol catalyzed by boron trifluoride to ether 15. In the final step the BOC group is removed (HCl) and phosphoric acid added to objective 16.

Fukuyama synthesis


Pyridine (1) is reduced with sodium borohydride in presence of benzyl chloroformate to the Cbz protected dihydropyridine 2. The asymmetric Diels-Alder reaction with acrolein 3 is carried out with the McMillan catalyst to the aldehyde 4 as the endo isomer which is oxidized to the carboxylic acid 5 with sodium chlorite, Monopotassium phosphate and 2-methyl-2-butene. Addition of bromine gives halolactonization product 6 and after replacement of the Cbz protective group by a BOC protective group in 7 (hydrogenolysis in the presence of Di-tert-butyl dicarbonate) a carbonyl group is introduced in intermediate 8 by catalytic ruthenium(IV) oxide and sacrificial catalyst sodium periodate. Addition of ammonia cleaves the ester group to form amide 9 the alcohol group of which is mesylated to compound 10. In the next step iodobenzene diacetate is added, converting the amide in a Hofmann rearrangement to the allyl carbamate 12 after capturing the intermediate isocyanate with allyl alcohol 11. On addition of sodium ethoxide in ethanol three reactions take place simultaneously: cleavage of the amide to form new an ethyl ester group, displacement of the mesyl group by newly formed BOC protected amine to an aziridine group and an elimination reaction forming the alkene group in 13 with liberation of HBr. In the final two steps the aziridine ring is opened by 3-pentanol 14 and boron trifluoride to aminoether 15 with the BOC group replaced by an acyl group and on removal of the other amine protecting group (Pd/C, Ph3P, and 1,3-dimethylbarbituric acid in ethanol) and addition of phosphoric acid oseltamivir 16 is obtained.

Trost synthesis
In 2008 the group of Barry M. Trost of Stanford University published the shortest synthetic route to date
[ Last edited by Flyingdragon on 2012-4-10 at 22:51 ]，

貌似楼主那个文献综述是wiki上扒的，囧。https://en.wikipedia.org/wiki/Oseltamivir_total_synthesis

其实Oseltamivir全合成文献总结的最全的还算chem8上那篇文献探讨的文章。

这些结构比较难弄纯呀。。。。。  太厉害了 。。。。