total synthesis of natural

product isolated from

liverwort Radula perrottetii and Radula

variabilis – Radulanin H.

Its structure is shown below:

Radulanin H exhibits inhibitory activity aganist cyclooxygenase. It has no stereocentres but contains seven-membered heterocyclic ring with trisubstituted double bond and highly-substituted aromatic ring. Concise synthesis of this aromatic ring is the challange.

So how this synthesis was planned?

It’s not a surprise that ring-closing metathesis was used in contruction of heterocyclic ring. This simplification reveals compound A which can be prepared from phenol B by introduction of two allyl groups in Claisen and Williamson reactions. Now, question arises – in which way aromatic ring B (with all substituents on their places) can be synthesised? Well, for such complex system authors of paper have chosen synthesis from acyclic substrates:

It’s not very obvious how this can be done by using ethyl acetoacetate and benzyl bromide – so let’s see how this synthesis has been acomplished.

The answer is – dianions! They acted on ethyl acetoacetate 2 with a little bit more than 1 eq NaH and they got of course anion 2a. For this moment it sounds like simple synthesis from acetoacetates. But they didn’t add to reaction mixture  electrophile but another equivalent of strong base instead! In this way they got dianion 2b. When in next step they added benzyl bromide more reactive anion reacted with electrophile and ketoester 3 was formed. That’s not standard procedure of alkylate ethyl acetoacetate Ketoester 3 was in next step protected as acetal 4. Yield after two steps is good.

Well, next step involves also dianion strategy but this time dianion 2b is acylated with previously formed ketoester 4 (that’s why carbonyl group in 3 had to be protected) and we have compound 5.

Ok, now 5 should make some aromatic ring It can be done by deprotection of acetal 5 to polycarbonyl compound 5a which forms 5c by some aldol-like intramolecular reaction. Now – by using weak base sodium perchlorate – 5c is converted to 6. Yield is only 48% but in one step you get highly-substituted aromatic ring.

Now 6 is converted to its allyl ethers mixture 7a and 7b. These compounds aren’t isolated and in high temperature, under Claisen rearrangement reaction conditions, allylbenzene 8 is formed.

Next step is second Williamson reaction and in this way allyl ether 9 is formed. Regioselectivity of this reaction is quite obvious because other OH group between two substituent is of course less reactive. Cyclisation of 9 to 10 probably is not very easy because paper’s authors used 20% mol Grubbs’ catalyst. It’s a quite big amount, but yield after two steps (RCM and deprotection step) was very good.

For more details see: M. Yoshida, K. Nakatani, K. Shishido, Tetrahedron, 2009, 65, 5702–5708.

For Polish version of this post please see here.

Do you know snowdrops? It’s well-known that bulbs of these flowers (latin name is Galanthus nivalis) contain many alkaloids and galantamine (or galanthamine) is one of them:

This is an important natural product because of its biological properties and phamacological applications – it’s used in treatment of mild Alzheimer’s disease. So there are many approaches to total synthesis of galantamine and here I’ll try to show most recent of them (I think so).

Authors of the paper on which I base developed new interesting reaction: DMCRC – what means Double Michael-Claisen Reaction Cascade. The reaction allows to synthesise quickly highly substituted cyclohexenones which can be used in total syntheses of many ’sterically congested’ natural products and galantamine is only one of several examples mentioned in paper (the others are aspidospermidone, lycoramine and  mesembrine).

Let’s look at retrosynthetic analysis:

As you can see, that organic synthesis of galantamine starts with arylated acetone. Now, let’s see how it was acomplished:

Mentioned before acetone 2 was undergone DMCRC (yeah, exercise that name one more time – Double Michael-Claisen Reaction Cascade) reaction with tert-butyl ester of acrylic acid. The mechanism of this conversion isn’t so obvious and you can find full explanation (with some calculations of transition states) in paper. The most important thing is that termodynamic enolate of 2 reacts faster with acrylic ester than kinetic enolate of 2. This is the secret of this reaction

Let’s get back to synthetic route. Formed 1,3-dienone 3 is converted in next step to enol ether 4 which is next reduced to enone 5. Enone 5 is then protected (self-protected) by primary alcohol moiety in Michael-type reaction and this allows to selective removal benzyl group to give 7 without any saturation on carbon-carbon double bond.

Then released phenolic -OH group participates in five-membered fused ring and 8 is formed. Next, two oxidations were performed to oxidise primary -OH group to carboxylic acid. Transformation 9 to 10 is a Curtius rearrangement and DPPA (DiPhenyl PhosporoAzidate) is a donor of azides here. Now, Pictet-Spengler cyclization occurs to give 11, and mechanism of this reaction is drawn below:

Synthesis of galantamine is completed in such way:

There is nice method of conversion cyclohexanone 11 to cyclohexenone 13 in palladium-catalyzed process. Mechanism is:

β-elimination of organopalladium compound can only occur at one side of carbon-oxygen double bond.

In last step 13 is reduced by L-Selectride (stereoselective reduction of carbonyl group) and LiAlH₄ (reduction of ester moiety) and galantamine 1 is formed.

For more pieces of information of course see:

T. Ishikawa, S. Saito et al., J. Org. Chem., 2008, 7498.

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.

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