Wednesday, October 10, 2012

Synthesis of Cyanthiwigin U

Cyanthiwigin U is a challenging molecule to synthesize, and is the topic of tomorrow's synthesis seminar. Cyanthiwigin U is a diterpenoid which is isolated from both fungal and marine sources. It contains a cyclohepta[e]indene ring system, and has no less than 5 stereocenters, a real synthetic challenge.

In this paper, Phillips and Pfeiffer shows a very beautiful approach to synthesize Cyanthiwigin U. It all begins with the synthesis of an endo-acrylisoborneol. The authors used a synthetic strategy presented by Palomo et al. Lithiated methoxyallene is reacted with (1R)-(+)-camphor (1) using THF as solvent at -30 °C and TMEDA as metal ligand. The intermediate (2) is then hydrolyzed in 1M HCl, yielding the desired enones (3, 4 or 5 in the scheme 1 below).

Scheme 1. Taken from Palomo's publication

In  Phillips and Pfeiffer's paper, the endo-acrylisoborneol is then reacted with alkene 6 via a metathesis using Grubb's catalyst (7). The product is a substrate (8) which is next used as a Diels-Alder precursor.

Conditions: (1) 5 mol % Grubbs catalyst (7), 93%

The precursor 8 was then reacted with 1,4-dimethylcyclohexadiene in acidic media (2 equiv TfOH) at -78 °C provided the Diels-Alder product (9, a bicyclo[2.2.2]octene).

Conditions: (2) 1,4-dimethylcyclohexadiene, TfOH (2 equiv), -78 °C, 70%

The cyclization between 8 and 1,4-dimethylcyclohexadiene occurs through a Diels-Alder cyclization. 

Reacting product 9 with CAN (Cerium Ammonium Nitrate), removes the borneol group through a radical reaction. This procedure is also described by Palomo et al. in an earlier publication.

Conditions: (3) CAN, aqueous MeCN, 82%.
The carboxylic acid and pivalic ester are thereafter reduced to the alcohols using LiAlH4. The product is then  subjected to a Swern oxidation to yield the corresponding aldehydes.

Conditions: (4) a) LiAlH4, THF, reflux, 16h, 99%. b) (COCl)2, DMSO, Et3N, 84% 
The dialdehyde 11 is trated with vinylmagnesium bromide. The formed alcohols were re-oxidized
using Dess-Martin periodinane, providing the bis-enone 12. The bis-enone 12 was then exposed to Grubb's catalyst 7, under an atmosphere of ethylene, providing 13.

Conditions: (5) a) Vinylmagnesium bromide, CeCl3. b) Dess-Martin Periodinane. (6) 20 mol% 7, ethylene, Toluene

So, I did not quite get it at the beginning what was going on between 12 and 13, but I tried to make a drawing to understand it better. Here it is:

So the Grubbs catalyst open up the ring's alkene, and from there, it could either make the 7-membered ring first and then the 5-membered ring right after. It could also be the other way around. The important thing is that the alkene in the ring is opened first.

And it is very late right now so I will pause here and continue tomorrow or when I have some more time to write.

Peace & Luv

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