name and it’s molecular

structure is really

interesting. Let me

introduce you spiro-

noraristeromycin:

Spiro-noraristeromycin is an analog of naturally occuring aristeromycin. That one was isolated from Streptomyces citricolor bacteria and exhibits antiviral activity.

Let’s see how spiro-noraristeromycin has been synthesised.

Core compound 5 can be synthesised by alkylation of cyclopentadiene anion with dichloride 3 wich in turn can be obtained from commercially avaiable amine 2.

Diene 5 is used in hetero-Diels-Alder reaction where acyl nitroso compound 7 is a dienophile. Compound 7 is unstable but it can be prepared in situ by oxidation of Boc-protected hydroxylamine 6. Such an oxidation of hydroxamic acids (Boc-NHOH has hydroxamic acid motif) is well-known reaction. Anyway – hetero-Diels-Alder reaction leads to adduct 8.

Now, bicyclic system can be cleavaged by molybdenum hexacarbonyl in the presence of reducing agent – sodium borohydride. This allows to get syn-amino alcohol 9 in 90% yield. Hydroxyl group of compund 9 is then protected as acetate ester and in next step Boc group is removed under standard conditions (TFA) which leads to compound 11.

Free NH2 group of amine 11 can be now utilized in aromatic nucleophilic substitution reaction with pyrimidine 12. The yield is high and only one chlorine atom is substituted by an amine. Nitro group of compound 13 is reduced to amine 14 in the presence of indium metal in acidic environment. Now, synthesis of purine can be acomplished. Reaction with ethyl orthoformate and camphorosulphonic acid leads to compound 15.

In next step, UpJohn dihydroxylation is undergone and diol 16 is formed. Diol 16 reacts with ammonia in sealed tube and chlorine atom is substituted and also – acetate hydrolyses. In this way triol 17 is formed. Hydrogenolysis of compound 17 leads to spiro-noraristeromycin 1.

For more – please see here.

Ortho strategy has been chosen to construct such trisubstituted pyridines. 4-substituted pyridine seems to be a good starting material in such strategy. Let’s see strategic disconnection in retrosynthetic plan:

Total synthesis should be quick.

As you can see it starts with 4-cyanopyridine 2. First and second step are of course halogenations steps which go through ortho-lithiations. In first step bromine is introduced into molecule (through nucleophilic attack on CBr₄) and in second step – iodine. LTMP is lithium 2,2,6,6-tetramethylpiperide, a strong and sterically hindered base:

Next steps allow to construct five-membered ring:

Conversion 5 to unsaturated ester 6 is Heck reaction. Unsaturated ester 6 can be then hydrogenated on Adam’s catalyst to 7. 7 in turn is cyclized to 8 under basic conditions (enolisation and nucleophilic attack on CN group) and subsequent hydrolysis.

From ketone 8 both louisianins can be prepared under Stille coupling reaction conditions.

The only difference between those two reactions is adition of base (DBU = 1,8-diazabicycloundec-7-ene) which causes isomerisation to more stable (trans and disubstituted) alkene.

That’s all. Happy New Year and see:

Chang, C. -Y. et al., Tetrahedron (2009), doi:10.1016/j.tet.2008.11.075

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.

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/2007/11/andrachcinidine/ http://www.totalsynthesis.eu/2007/11/andrachcinidine/#comments Fri, 02 Nov 2007 18:26:14 +0000 Natural Product http://www.totalsynthesis.eu/2007/11/02/andrachcinidine/
Today, some target which seems to be quite easy to synthesise – (-)-Andrachcinidine:

That 2,6-disubstituted piperidine-derived alkaloid was isolated from plant Andrachne aspera (picture taken from http://www.teline.fr/:

Yes… target seems to be easy to synthesise, but its synthesis is quite complicated. Retrosynthesis of (-)-andrachcinidine is shown below:

As you can see intramolecular Sn2 cyclization and olefin-cross metathesis are key reactions for this synthesis.

Let’s see synthesis of compound 3:

First step leading form 5 to 7 is epoxide ring opening by hydride anion form Red-Al. Alkoxide anion is generated in such way which in turn reacts with benzaldehyde acetal – giving another acetal. That one is reduced to corresponding ether 7 by LiAlH4-AlCl3. Next, 7 is oxidised under Swern condition and formed aldehyde is stereoselectively allylated.

Also synthesis of 4 is drawn below:

Here, we have Wittig olefination of Garner’s aldehyde 6 and followed hydroboration which gives 8. Next, 8 is TBDPS-protected and then ring opening occurs in presence of copper chloride hydrate. Then, Swern oxidation and Wittig olefination of 9 are undergone to form 4.

Having synthesised 3 and 4 olefin cross-metathesis could be done.

There were a few transformations after metathesis to get final product…

For more information see:

P. R. Krishna, G. Dayaker, Tetrahedron Lett., 2007, 48, 7279.