Today, some interesting tricyclic target, Alboatrin:

Alboatrin has characteristic cis tetrahydofurane-benzenopyrane system. Also, there is ketal moiety present in this molecule what (in my opinion) can be taken advantage in planning of synthesis of Alboatrin (well, in my retrosynthesis I’ve taken advantage of this fact ).

Let’s say something about properties of our target. Well, Alboatrin was isolated from Verticillium alboatrum (some fungi specie, I guess). It exhibits phytotoxic activity, for example – it inhibits the root growth.

Retrosynthesis is shown below:

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There are four key reactions used in this total synthesis: Claisen rearrangement, intramolecular ketene-alkene cycloaddition, oxidative ring enlargement and stereoselective alkilation in exo position. Synthesis is shown below:

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Synthesis starts with oricnol, 2, which can be obtained from many species of lichens. 2 is converted to 3 under Williamson’s ethers synthesis conditions. Then, 3 in high temperature undergo [3,3]-sigmatropic Claisen rearrangement to give mixture of 4a and 4b in 2:1 ratio. Desired regioisomer 4a was isolated by column chromatography. Next, 4a was converted to 5 in a Williamson-like reaction. Then 5 underwent reaction with p-TsCl and triethylamine and keten moiety was generated in situ. Next, ketene-alkene cycloaddition occured and cyclobutanone 7 was formed. Next, oxidative enlargement of ring was performed to give 8. Then, in few steps (one of them involve stereoselective alkilation of lactone in exo position) Alboatrin 1 was accomplished.

My proposition of retrosynthesis of Alboatrin is presented below. As I wrote above, I tried to take advatage of presence of ketal moiety in target molecule. So, I’ve proposed some tandem-like cyclisation. Oricnol is the starting material in my synthesis, too. I’m waiting for your opinions

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For more pieces of information see:

B. Biswas et al., Tetrahedron, 2008, 64, 3212.

Today, in the end of the year , some new total synthesis – (+)-Kalafungin. The structure of this target is shown below:

(+)-Kalafungin was isolated for the first time in 1968 from Streptomyces tanashiensis fungi and it exhibits some antibiotic properties. Retrosynthesis of that target is shown below:

As you can see, there are some interesting conversions in the retrosynthetic plan. In my opinion tandem Michael-Dieckmann and intramolecular tranesterification steps are very tricky (and look very very nice ). Also undergone isomerisation and oxidation by atmospheric oxygen have great synthetic utility.

The whole synthesis was completed as shown below:

Transformation of starting material, (S)-aspartic acid (1) starts with diazotization of amine group followed by exchanging diazonium group to bromine (with inversion of configuration – S_N2 mechanism). Next reduction of carboxylic groups occurs and converting of bromohydrine to corresponding epoxide can be completed. By treatment TBSCl on such epoxy-alcohol, TBS-protected epoxy-alcohol 2 is formed.

Transformation of 2 to 4 (throug epoxide-ring opening) is undergone under standard conditions. Cyclization of 4 to lactone 5 occurs in the presence of methanolic solution of sodium methoxide. This is very interesting step. I’ve wondered a lot about mechanism of thar conversion… I’ve published my try on the next page, I think it can be possible (I hope so).

Next, we have second interesting step in that synthesis. Tandem Michael-Dieckmann reaction ! Nice! My own mechanism of that step is also drawn on the next page. I just wonder about acidity of hydrogen atom in methyl group in 6. Nice way to complete substituted anthracene-like systems, by the way.

Conversion of 7 to 8 includes Grignard addition to carbonyl group of lactone an deprotection of TBS, That’s interesting that phenolic -OH group can be present while Grignard addition occurs

8 is then oxidized by NBS and cerium-ammonium nitrate (CAN) to form 9. Then methoxy group in 9 is deprotected to OH on the presence of Lewis acid, AlCl₃. Next, side chain is oxidized to carboxylic group and then, in the presence of atmospheric oxygen, oxidation and lactonizaton take place. The last step in which (+)-kalafungin, 13, is formed, occurs in the presence of sulfuric acid.

But, fortunately, I always find time to publish some nice total synthesis. Today – one of an ergot alkaloid – (-)-cis-Clavicipitic Acid:

Nice tricyclic structure, isn’t it? This compound was isolated from Clavicepis fusiformis (some kind of fungis, I guess) and SD58. Biological activity of (-)-cis-Clavicipitic Acid is still under investigation (and total synthesis of that target is part of the program). But, let’ see some retrosynthetic analysis…

The key reaction is Pd(II)-catalyzed aminocyclization. Synthesis is shown below:

Thallium-mediated iodination is the first step of that synthesis. Next – Boc-protection, catalyzed by DMAP. Transformation 5 to 7 is interesting stereoselective phase transfer catalyzed alkylation. The PTC is naturally-derived quartenary-ammonium salt 6. Looks pretty nice

Next, from 7 to 9, is paladium-catalyzed Heck reaction. Interesting step is aminocylization. Stereoselectivity of that transformation is 5:1 (cis:trans isomer) and preferable transition state (for cis isomer formation) is believed to look just like below:

Also, the last step is really interesting to me: zinc bromide-mediated deprotection 12 to desired target. There’s no epimerization (-)-cis-Clavicipitic Acid here. Nice trick.

For more information of course see to paper:

J. Ku, B. Jeong, S. Jew, H. Park, J. Org. Chem., 2007, 72, 8115.

Oh… There’s one mistake in picture: of course indole-nitrogen atom in 12 sill bears Boc group