Let me add that aplysamine 6 is a natural product (of course) isolated from sponge Pseudoceratina sp.

Well, that’s not very complex target and the retrosynthesis and also total synthesis should be quite easy. My idea to disconnect this stuff is something like that:

Everything should by clear. All starting materials could be prepared from phenole or from commercialy avaiable anisaldehyde.

People who did the synthesis used very simmilar approach, so I didn’t draw retrosynthesis again. One important difference is use of Perkin condensation instead of something I labeled ‘Wittig-like’ reaction Let’s see how they completed whole total synthesis.

As you can see they started with p-anisaldehyde and they brominated it in first step. Ok, reaction is slow (there’s no Lewis acid), but more interesting is that aldehyde functional group isn’t oxidizied under such conditions. Coversion 3->4 is of course mentioned Perkin condensation (well, authors wrote that is Doebner-Knovenagel condensation… ok, probably it is ). Last step in this scheme is conversion of carboxylic acid to corresponding acyl chloride.

Now, second building block is prepared. They use p-hydroxy benzyl alcohol (can be obtained from p-anisaldehyde by its reduction) as second precursor. Next substitution oh hydroxyl group is performed to give 7. It’s a question why they didn’t convert -OH to better leaving group such as tosylate and so forth. 7 is reduced on palladium catalyst to amine hydrochloride 8, which in turn is brominated to 9 (again without any Lewis acid).

In next step two building blocks 5 and 9 are coupled and amide 10 is formed. OH group from aromatic ring of 9 isn’t acylated.

10 is a core of aplysamine 6. In next two steps primary amine moiety is attached to this structural core. This is achived by use of Williamson reaction (ether formation) with 1,3-dibromopropane to form derivative 11. 11 is converted to aplysamine 6 by well-known Sn2 reaction.

For more pieces of information please see:

N. Ullah, K. M. Arafeh, Tetrahedron Lett., 2009, 158-160.

Dideoxypetrosynol A is linear, polyacetylenic target molecule which consist 30 carbon atoms. It’s also C₂-symmetric molecule what is important to planning synthesis, of course. Let’s see structure of dideoxypetrosynol A:

It looks so simple but its spectrum of biological activities is very wide. Dideoxypetrosynol A was isolated from marine sponge (Petrosia sp.) found in Komun islands, Korea. It exhibit anticancer activity aganist ovarian and skin cancer cells. It can also inhibit DNA replication. So, biological properties are interesting but – unfortunately – concentration of dideoxypetrosynol in dry natural source is very poor (just about 23 mg in 14.5 kg dry source). Development of synthesis this target in larger scale is obvious.

There are also some compounds (with interesting biological activity) related to dideoxypetrosynol, for example: duryne 2, petrosynol 3:

Synthesis of such quite simple compounds shouldn’t be very complicated… maybe boring, but in fact – it’s not. Just look at retrosynthesis chart:

Benefits from presence of C₂ symmetry axis are clear. Grignard and Wittig key steps are obvious, but what is the ‘Oxidative coupling of Wittig reagent’? Let’s look at the synthesis to answer this question.

Synthesis starts with 4, TBS-protected terminal alkynol, which is deprotonated by butyllithium in first step and reacted with oxirane in the presence of Me3Al as Lewis acid to give diol 5. Now, free OH group is exchanged to Br and then, by adding triphenylphosphine, phosphonium salt 6 is formed. It’s quite clear. In next step buthyllithium is added again and in next few hours by acting of oxygen from the atmosphere – product 7 is forming. It’s oxidative coupling. Nice reaction.

Next steps are:

and they include deprotection and oxidation to form 8, Wittig olefination to form 9, and Grignard reagent addition to form racemic dideoxypetrosynol 1. Well, racemic.

Finally, racemic product was resolved by enzyme lipase AK:

There are also one feature in this synthesis: why don’t they start their synthesis from 1,4-dichlorobut-2-ene and undergo S_N2 reaction with Grignard reagent derived from corresponding alkyne? Well, actually they wanted to do it in such way but only side products were forming:

For more see:

B. W. Gung, A. O. Omollo, Eur. J. Org. Chem, 2008.

When I was preparing to my summer Natural Product Exam and when I was admiring how Nature ‘do’ such big molecules by biosynthetic routes I just wanted to know how R. B. Woodward could synthesize such complex molecule like cholesterol. Well, it was more complicated than I expected. By the way – articles from 1950s are so difficult to read… there are no chemical equations and no schemes in some of them.

But let’s see how Woodward did his synthesis, but first let’s remind designation of steroids fused-ring system:

The first interesting thing is that Woodward started his synthesis with ring designated as C. Next he built something like pre-ring D and then he constructed rings B and A respectively. Then he converted pre-ring D into true ring D. Let’s see some steps:

As you can see, synthesis starts with some quinone derivatives 1 which is converted to 3 in Diels-Alder reaction. Stereochemistry of resulting bicyclic molecule is cis and switching it into trans is possible by forming enolate 4. Protolysis of 4 gives desired product 5 (configuration trans).

Next steps involve reduction quinone moiety, hydrolysis and de-hydroxylation α-hydroxy ketone. Seems to be quite obvious.

Here, we have formation of ring B. It’s interesting that intermediate 9b is favoured product of first step (Woodward wrote nothing about 9a, but it’s very likely that 9a and 9b exist in equlibrium although – 9a occur in very small amount). Conversion 9b -> 12 involve Michael reaction, cyclization and deformylation reactions. I’d like to know what is mechanism of deformylation (free radical?… in such solvent?). And what was first: cyclization or deformylation?

In next stages, Woodward underwent cis-dihydroxylation (osmium tetraoxide-mediated) reaction. Resulting two isomers converted to isomeric acetonides which one of them was stable and was used in following steps.

These steps involve formation of A ring. To achive this goal Woodward prepared adduct with N-methylaniline, to protect the most sensitive on base attack centre. In spite of this – there was still three active sites of molcules, but attack of acrylonitrile was succesful… In such way 19 was formed.

19 was then converted into β-enol lactone 20 and by acting methylmagnesium bromide on it 21 was formed with established ring A. Mechanism of this transformation is simple. First methylmagnesium bromide attack lactone carbonyl group and lactone ring opens. Then intramolecular aldol-like reaction occurs.

Next acetonide moiety is deprotected and six-membered pre-D ring is oxidized to two aldehyde groups. Then Dieckmann-like reaction happens and five-membered ring D is formed.

Steroid fused ring system is finished. Now, in few steps cholestanol was prepared. And because route form cholestanol to cholesterol was previously known, Woodward could say: total synthesis is done.

For more see:

R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, W. M. MacLamore, J. Am. Chem. Soc., 1952, 74, 4223.

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/2007/09/aplysiallene/ http://www.totalsynthesis.eu/2007/09/aplysiallene/#comments Mon, 03 Sep 2007 15:40:43 +0000 Natural Product http://www.total.synthesis.chemicalforum.eu/?p=3

Hello

First, some nice Total Synthesis of (-)-Aplysiallene published in Organic Letters.

This compound was found in red alga Laurencia okamurai Yamada (in 1985) and in sea hare Aplysia kurodai (in 2001). Retrosynthetc Analysis of (-)-Aplysiallene is presented below. Initially stereochemistry of (-)-Aplysiallene was opposite to stereochemistry presented above. Structure of that target was revised thanks to NMR.

And the way in which real structure of (-)-Aplysiallene was synthesized is shown:

It’s very interesting to me the use of oxygen as oxidant supported by cobalt-based Mukaiyama catalyst. I’m wondernig about mechanism of that oxidation…

For more information see: J. Wang, B. Pagenkopf, Organic Lett., 2007, 9, 3703.