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.

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, 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.

Today, total synthesis of tetracyclic non-natural alkaloid (-)-Lycoricidine. Its enantiomer, (+)-Lycoricidine occurs in plants of the genus Amaryllidaceae (for example in the bulbs of narcissi):

The lycorine-type alkaloids exhibit wide spectrum of biological activities like carcinostatic and antiviral properties. The structure of (-)-Lycoricidine is shown below:

The plan of total synthesis includes application of certain cis-1,2-dihydrocatechols as starting material because of their microbiological availability. Retrosynthesis of target molecule is following:

The synthesis is very interesting, especially steps connected with conversion of stereochemistry in cyclohexene ring. Application of Overman rearrangement was tricky. It’s also interesting that the Suzuki-Miyaura cross-coupling and lactamization step occur nearly simultaneously.

For more information see: M. Matveenko, O. J. Kokas, M. G. Banwell, A. C. Wills, Organic Lett., 2007, 9, 3683.