Ripostatin B

 

 

Ripostatin B

Angew. Chem. Int. Ed. 2012, 51, 3396

P. Winter, W. Hiller, & M. Christmann*

The retrosynthesis of Ripostatin B begins with a deprotection of the protected secondary hydroxyl groups and the oxidation of the primary alcohol group to the acid.  It is interesting to note that the two secondary hydroxyl groups were differently protected – one as a TBS group and the other as an ester group.  It is rather unusual to see the final stage deprotection using LiBEt₃, but worked in this case quite selectively, without harming the conjugated lactone functionality.  The isolated double bond in 14 was installed by a RCM reaction using Grela’s catalyst on substrate 13.  The allyl group was installed by a Stille coupling on vinyl iodide 12, which in turn was derived from a Yamaguchi esterification of acid 11 with alcohol 10.  The alcohol group in 10 was derived by an Evans-Tischchenko reduction of the ketone, which was present as it dithiane derivative in 9.  The preparation of compound 9 was the showcase event in this total synthesis – the coupling of a silylated dithane with two different epoxides – and this required some optimization with regards to the order of addition (i.e. after anion formation, epoxide 4 was added followed by epoxide 7).  It is also important to note that this step gave mono-protected TBS ether.  The other elegant strategy was the preparation of both epoxides 4 and 7 from geranyl acetate.  Epoxide 7 was derived from aldehyde 6 (stereselective epoxide formation with the increase of one carbon atom via a Corey-Chaykovsky procedure followed by Jacobsen resolution), which came from epoxide 5 by sodium periodate mediated oxidative cleavage.  Epoxide 5 was derived a lithium cupurate addition on geranyl acetate.  In contrast epoxide 4 (which has the same carbon count at geranyl acetate), came by an internal attack of the hydroxide on a chiral “Cl” atom – which was installed in stereospecific manner by using the Jorgensen/MacMillan protocol.  The terminal hydroxyl group came from the reduction of aldehyde 3 which was prepared as before from epoxide 2 (sodium periodate oxidation).  Epoxide 2 was prepared by vinyl Grignard substitution on geranyl acetate. 

So, overall a very nice semi-convergent synthesis with some interesting transformations by the group of my former colleague, Mathias Christmann.

Ripostatin A

 

Ripostatin A

Org. Letters 2012, 14, 4690

W. Tang & E. V. Prusov*

The retrosynthesis of Ripostatin A begins with a deprotection of the protected methyl acetal which quite sensitive.  This was achieved by a mild neutral aqueous hydrolysis.  The terminal acid functionality was derived from oxidation of the primary alcohol by Dess-Martin periodinane oxidation followed by Pinnick Oxidation (sodium perchlorate).  The alcohol was originally in its TBS-protected form in 8.  Predictably, the central alkene group in 8 was formed by a ring-closing-metathesis reaction using Grubb’s second generation catalyst. The double allyl groups required for the RCM reaction were neatly installed by a double Stille reaction between allyl stannane 5 and double-vinyl-iodide compound 6.  Conceptually, this is really interesting as it reduces the need to install the two carbon-carbon-double-bond groups separately.  The ester group of compound 6 is the next disconnection giving rise to acid 5 and alcohol 4.  The ketal group of 4 comes from the open ketone 3, which is prepared by an Patterson Aldol reaction between methyl ketone 2 and aldehyde 1.  The syntheses of both 1 and 2 have been described by the authors in their previous publication Angew. Chem. Int. Ed. 2012, 51, 3401–3404.