This is a sesquiterpene isolated from the roots of Psacalium decompositum and it exhibit some interesting biological properties including antihyperglycemic, anti-inflammatory, antimicrobial and antioxidant activities. Authors of paper didn’t mention anything about biological activity of single enantiomers of Cacalol.

Retrosynthesis chart (not very good-looking…) is shown below:

Synthesis of target molecule isn’t more complicated than retrosynthesis.

As you can see, total synthesis starts with p-methylanisole 2 which is converted to its organolithium derivative 3 by ortho-lithiation reaction. 3 is then alkylated by 5-iodo-pent-1-ene. In next step intramolecular Friedel-Crafts reaction occur which provides bicyclic product 6. Next, we have formylation which gives two regioisomers 8a and 8b (and 8a is main product). These regioisomers seemed to be inseparable by flesh chromatogrphy. So, Baeyer-Villiger oxidation followed by hydrolysis were undergone and resulting phenols 9a and 9b could by purified by chromatography.

9a was converted to 11 in reaction with chloroacetone under Williamson conditions. By acting of concentrated sulfuric acid on 11, tricyclic product 12 was formed. Deprotection of 12 gives racemic Cacalol.

For more see:

B. L. Kadrowski, R. W. Hoppe, J. Chem. Org., 2008, 73, 5177.

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:

(Click on image to enlarge it)

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:

(Click on images to enlarge them)

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

(Click on image to enlarge it)

For more pieces of information see:

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

Today, some nice total synthesis – Barrenazines A and B. Structure of these C₂-symmetrical molecules is shown below:

These Barrenazines were isolated in 2003 by Kashman from some (according to authors of article) unidentified tunicates from Barren Islands (Madagascar). They exhibit mild cytotoxic activity against certain tumor cells. The retrosynthetic analysis is shown below:

I can only say that concept of that synthesis is very tricky. I’ve tried predict some step myself utilizing C₂-symmetry of target molecule, but I haven’t thought that central pyrazine ring can be done in such way. Oh, maybe I just have to learn more !

Following retrosynthetic steps are drwan below:

Pyridinium cation ! Nice starting material for that total synthesis ! It’s really interesting that organomagnesium halide addition can be completed to such system. Here, carbonyl group seems to be unreactive.

Synthesis of both (-)-Barrenazine A and B is drawn below:

In first step, to disubstituted pyridine chiral auxiliary was introduced and next completely stereoselective addition of Grignard reagent was undergone. Next, methyl ether was cleavaged to form corresponding ketone. That ketone was undergone reaction with trifluoroacetic acid in chloroform to unprotect tri-i-propylsillyl protecting group. In next step, removal of chiral auxiliary group occured, but later in the same place Boc-protecting group was directed. Next, we have reduction of ketone by using L-selectride reducing agent:

Next, we have free radical azidation in the presence of cerium ammonium nitrate (CAN). Formed in such way azidoketone can dimerize under Staudinger condition. In that step, skeleton of Barrenazines was created. Boc-deprotection gave (-)-Barrenazine B and following hydrogenation gave (-)-Barrenazine A.

For more pieces of informations see:

M. M. Martinez, L. A. Sarandeses, J. P. Sestelo, Tetrahedron Lett., 2007, 48, 8536.

]]> http://www.totalsynthesis.eu/2007/11/total-synthesis-of-barrenazines/feed/ 1 http://www.totalsynthesis.eu/2007/10/clavicipitic-acid/ http://www.totalsynthesis.eu/2007/10/clavicipitic-acid/#comments Tue, 23 Oct 2007 17:31:18 +0000 Natural Product http://www.totalsynthesis.eu/2007/10/23/clavicipitic-acid/
To little time, to many tasks to do…

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

Today, some interesting target – (+)-Bruguierol C:

This natural product was first isolated in 2005 from the stem of Bruguiera gymmorrhiza mangrove tree. Bruguierol C has interesting biological properties – for example exhibits modest antimicrobial activities (probably because of meta hydroxy substituted aromatic ring) including antimicrobial activity aganist Enterococcus faecalis (which shows resistance to popular antibiotics).

Retrosynthetic analysis is shown below:

The key simplification is first conversion – intramolecular Friedel-Crafts reaction depending on capture of in situ generated oxocarbenium cation.

Complete synthesis is drawn below:

Reduction of starting ester with DIBAL directly to aldehyde wasn’t selective so team decided to use LiAlH4 and they oxidized formed alcohol in next step. Also, utilizing of TPAP (tetra-n-propylammonium perruthenate) in lactonization is interesting.

For more information see:

D. M. Solorio, M. P. Jennings, J. Org. Chem., 2007, 72, 6621.