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.

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.

You can read here today about total synthesis of (+)-Isofregenedol and, in my opinion, this is the very total synthesis which looks like a magic. In one aspect, at least.

Let’s see our current target molecule:

It looks interestingly. Only one chiral carbon atom, but five-substituted aromatic ring – in other hand. This stuff is a diterpene which was isolated from chilean flower Haplopappus parvifolius by Niemeyer in 1991. (+)-Isofregenedol exhibits important biological activites. It’s – for example – methionine aminopeptidase-2 reversible inhibitor, agonist of glucocorticoid receptor and agonist of serotonin 5-HT₇ receptor. Sounds seriously.

Before you’ll see how this molecule were prepared, I’ll show you my approach to its organic synthesis. First – retrosynthesis:

As you can see, my synthesis would be start with bromoxylene. However, I know that there could be some problems with regioselectivity during Friedel-Crafts acylation step. But see:

I think it can work.

Ok, let’s leave this and deal with real organic synthesis of (+)-Isofregenedol done by authors of paper. Their total synthesis has a few more steps than my, but theirs really was done So let’s look at retrosynthetic plan:

Lots of disconnections. And one of more important disconnection here is gold(I)-catalyzed benzannulation. This is that magic about which I write. Some details are shown below:

Initially authors wanted to complete synthesis in very effective way. They wanted to perform benzannulation of highly substituted cyclohexane ring (obtained from geraniol as chiral building block), but unfortuantely such reaction gave no product. So plans had to change. Modified approach is shown below in all its details:

Total synthesis of (+)-Isofregenedol starts with cyclohexene epoxide 2. 2 is undergone epoxide ring opening reaction with vinyl Grignard reagent and followed by Swern oxidation to give 3. Next, addition of alkynyl Grignard reagent to ketone 3 occurs and tertiary propargyl alcohol 4 is formed. Everything is ready to carry out gold(I)-catalyzed benzannulation reaction:

Yield of the reaction is 69%, but in this step aromatic ring with four substituent is created. But how it really works? One of possible mechanisms is drawn below:

When I look at this mechanism then everything becomes so clear

Ok, so we have already tetrahydronaphtalene core 5 of (+)-Isofregenedol, now we have to link to it all lacking substituents.

Conversion of 5 to 7 maybe very elegant. Probably regioselctivity of benzylic oxidation isn’ very good. But addition of dimethylzinc in the presence of TiCl₄ as a Lewis acid looks nice. And in such way we have dimethyl derivative 7 as major product (under standard condition we rather would expect tertiary alcohol). Now, 7 is converted with high yield (excellent regioselectivity) to 8 and then Stille coupling is performed (some microwave chemistry aspect) and vinylbenzene 9 is formed. In next step double bond of 9 reacts with 9-BBN in hydroboration reaction to give intermediate 10.

This intermediate is combined with iododerivative 11 under Suzuki coupling conditions. Compound 12 is formed and it’s reduced with DIBAL-H to give allylic alcohol 13. In next step enantioselective Sharpless epoxidation is undergone (with excellent yield and high enantiomeric excess) and epoxide 14 is formed. In next two steps which include formation of iododerivative and epoxide ring opening (+)-Isofregenedol is obtained. And total synthesis (consisting of 13 steps and where no protecting groups was needed) is completed.

Fore more – as always see:

M. Riou, L. Barriault, J. Org. Chem., 2008, 73, 7436.

Deja vu? Maybe yes because (+)-Dodoneine is also – similary to hyptolide – α,β-unsaturated δ-lactone. Just look at the structure of (+)-Dodoneine:

It’s not so complicated (it has only two chiral carbon atoms, hyptolide – four) as hyptolide, but synthetic approach to this target is quite different than to previous one.

But now, let’s say something about its biological properties.

(+)-Dodoneine was isolated from methanolic extract from plant called ‘african mistletoe’ with very nice-sounded latin name Tapinathus dodoneifolius. This plants grow somwhere in West Africa. Authors of paper wrote that ‘african mistletoe’ is applied in treatment of wide spectrum of diseases, including cardiovascular and respiratory. It’s also used as remedy aganist cholera, diarrhoea, stomach ache and wounds. It’s possible that (+)-dodoneine could find interesting medical applications.

In my opinion, (+)-Dodoneine can be synthesized analogically like hyptolide. Proposition of retrosynthesis is shown below:

Authors have chosen other synthetic route:

As you can see – only two olefinations and only two stereoselective aldol condesations. Full retrosynthetic analysis is shown below:

Ok. As you can see, total synthesis starts with p-hydroxybenzaldehyde (2) which is undergone some kind of Wittig-type reaction to give α,β-unsaturated ethyl ester 3. Then phenolic -OH group is protected. In next step 4 is first reduced by LiAlH₄ and then oxidized to form aldehyde 5. It’s interesting that LiAlH₄ can reduce ester functional group and carbon-carbon double bond.

Now, stereoselective Crimmins aldol reaction can be carried out. I’ve never heard about this reaction before, but it looks promisingly. Reagent 6 can be divided into two parts: real reagent which is blue (or something like that;) ) and chiral auxiliary (which is, say, red;) ). Diastereselectivity of the reaction isn’t very high, but I think that is acceptable. Diasteroisomers 7a and 7b could be easily separated.

Hydroxy group of 7a was then TBS-protected (in the presence of base called 2,6-lutidine which is of course 2,6-dimethylpiridine) to give 8. Now, chiral auxiliary is removed by using reducing agent – DIBAL-H. Released aldehyde 9 combines with Crimmins reagent (6) again to give diasteroisomers 10a and 10b.

Following two steps are protection and removal of chiral auxiliary. Now, aldehyde 12 is undergone olefination reaction. Do you remember reagent 13, that nice modified phosphonate? Well, people who done total synthesis of hyptolide talked about Still olefination. Now – the same reaction is called Horner-Wadsworth-Emmons olefination. Well, I’ll be saying just “Wittig-like”

One-pot removal of all protecting groups from 14 gives desired target (+)-Dodoneine, 1:

Final product does not forms purely because there are significant amounts of (+)-Dodoneine ‘internal adduct’ (formed in internal Michael reaction):

Forming of 15 critically depends on hydrolytic conditions.

For more of course see:

P. Srihari, G. Rajendar, R. Srinivasa Rao, J. S. Yadar, Tetrahedron Lett., 2008, 49, 5590.

Today, total synthesis of hyptolide which was published in Tetrahedron Letters. Structure of target molecule is drawn below (click on images to enlarge them ):

Authors wrote about some “important biological activities” and “interesting pharmacological properties” and they wrote nothing more So, what do we have here? Well, four stereocentres, two double bonds and α,β-unsaturated δ-lactone ring makes hyptolide really nice target molecule.

Hyptolide is present in plants from family called Lamiaceae, especially in genera Hyptis and Syncolostemon. There are several compounds related to hyptolide: spicigerolide, anamarine and synrotolide. Their are shown below.

I’ve tried to plan the synthesis of hyptolide and my proposition of retrosynthesis is presented at next images.

I hope that everything is clear (P means some protecting groups)

The real retrosynthesis of hyptolide:

As you can see I’ve labeled the picture with three reactions but key transformations are connected to epoxide chemistry.

Synthesis starts with racemic allylic alcohol 5 which undergo kinetic resolution under Sharpless conditions (Sharpless epoxidation). In next few steps, involving protection/deprotection reactions, oxirane 6 is formed which in turn is converted (Swern oxidation) to α,β-unsaturated aldehyde 7:

It seems to me that mechanism of conversion 6 to 7 involve standard oxidation of primary -OH and then attack of base on α-hydrogen. Developing carboanion leads to opening of epoxide ring. That’s my theory

Let’s return to synthesis. In few next steps second epoxide 9 is generated stereoselectively. And this epoxide is reduced by titanocene-like complex. Unfortuanelly, author didn’t write anything about stereo- and regioselectivity. But 10 was obtained in 85% yield, so stereoselectivities probably were high.

Resulting 1,3-diol 10 is next protected by conversion to its acetonide 12 (in the presence of CSA – camphorsulfonic acid). Deprotection of 12 with TBAF (tetrabutylammonium fluoride) gives 13. Only primary TBDPS-protected hydroxy group was removed.

Next steps ivolve construction of Z double bond. To achive this goal Still olefination (another modification of Wittig-Horner-and so forth;)) was chosen as key reaction. Z : E selectivity of formed product was good.

Conversion of 16 to 18 is also interesting. Direct reduction of ester 16 with DIBAL-H gives allylic alcohol 17, not desired aldehyde. So, there is necessity of introduction additional step – Dess-Martin oxidation.

With 18 in hand final steps could be undergone. Allylboration of 18 gives alcohol 19 which, in turn, is converted to its acrylate. Now, everything is ready to do ring-closing metathesis (RCM) reaction and obtain framework of hyptolide 22. 22 is deprotected then and transformed to its triacetylated form – hyptolide.

As always – for more see:

T. K. Chakraborty, S. Purkait, Tetrahedron Lett., 2008, 49, 5502.