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.

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

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.

Nice structure and nice name (however, I prefer snow ). (+)-Sundiversifolide exhibits some interesting biological properties. For example it can inhibit root growth of some plants. Also it can inhibit (in small concentrations – about 100 μM) germination of some fungi species and therefore it can be used as natural herbicide.

Below I’ve shown my retrosynthetic approach to (+)-Sundiversifolide:

(Click on image to enlarge it)

The key steps involve Diels-Alder cyclization, ring expansion (with use diazo compound) and TPAP-promoted cyclization (see also Total Synthesis of Bruguierol C for other application of that key reaction). I’m waiting for your opinions.

The real retrosynthesis of (+)-Sundiversifolide is shown below:

(Click on image to enlarge it)

As you can see, intramolecular acylation with use of organolithium compound was taken advantage here to construct seven-membered carbon-framework of (+)-Sundiversifolide (with correct configurations on three stereogenic centers).

Complete synthesis of target molecule is drawn below.

(Click on image to enlarge it).

Synthesis starts with homopropargylic alcohol 2 which, first, is TBDPS-protected and then combined with paraform. In such way monoprotected unsaturated diol 3 is formed. Then triple carbon-carbon bond is reduced by Red-Al in ether to form alkene 4 in E configuration. In next step -OH functional group is exchanged to iodine which allow to alkylate 6 diastereoselectively with iodo-derivative 5 in presence of stron base (LDA). 7 is then dihydroxylated with AD-mix-β to generate 8 in situ, which undergo intramolecular reaction to form lactone 9. Free -OH functional group is then protected with TBSCl which allow to selective deprotecion of primary OH functional group with TBAF. Released OH group is exchanged to iodine under standart conditions to form iodo-derivative 12 which is used in next step.

(Click on image to enlarge it)

Organolithium compound 13 is generated in situ from iodo-derivative 12 and then intramolecular acylation reaction happens. Hemiacetale 14 which is in equilibrium with ketone 15 is result of this reaction. To shift equlibrium to ketone 15 reaction with TBDPSCl is performed.

(Click on image to enlarge it)

Then Grignard reaction occured to form 17 and TBS-protected alcohol was deprotected to release OH functional group. Newly formed -OH group was then oxidised and hemiacetale 19 (in equilibrium with corresponding ketone) was created. Next, deprotection of 19 occured followed by reaction with phosphorus ylide. Result of this reaction was forming 23 which contain fused seven- and – fivemembered rings. Next, exo ethylene group of 23 was converted to corresponding epoxide. That step allowed to stereoselective saturation double carbon-carbon in ring by “nickel borides”. Then dehydratation under kinetic control could be undergone to form 26. The last step involved reaction with ZnI₂ and NaBH₃CN (regioselective reduction of epoxide ring) and (+)-Sundiversifolide was in that way synthesised.

For more see:

M.Shindo et al., Organic Lett., 2008, 10, 1247.

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.