Total Synthesis Blog

Today, very interesting total synthesis of natural products 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.