Total Synthesis of Branimycin: An Evolutionary Approach

Total Synthesis of Branimycin: An Evolutionary Approach

Valentin S. Enev, Wolfgang Felzmann, Alexey Gromov, Stefan Marchart, and Johann Mulzer

DOI: http://dx.doi.org/10.1002/chem.201200257

As the title suggests this full account features a collection of approaches towards the central core of branimycin. All those who are interested in a great story of evolutionary chemical design really should have a look at the full paper. I will focus in this short write-up only on the longest linear sequence.

Scheme 1

As can be seen from scheme 1 the synthesis focusses mainly on three fragments where green fragment 1 and blue fragment 2 constitute the main part of the molecule. The synthesis of fragment 1 is described in a previous paper but also featured in the following. The evolutionary design is limited to the synthesis of 2 and fragment 3 is commercially available dimethyl malonate.

The first route to allylalcohol 7 started from (R,R)-dimethyltartrate which was protected and reduced to diol 5. Methylation, tosylation, Finkelstein reaction, and reductive acetonide cleavage then furnished 7 in low yield. A more direct access from glycidol 6 is also presented. After methylation of the hydroxy function the epoxide was opened under Corey-Chaykovsky conditions to give 7. TIPS protection and ozonolysis of the olefin produced aldehyde 8.

Scheme 2

Next aldehyde 8 underwent a Marshall reaction with a chiral silylallene to give in high yield and stereoselectivity alkyne 9. Aqueous ammonium chloride was necessary for in situ deprotection of the resulting TMS ether. MOM protection of the alcohol and Schwartz reaction with subsequent iodine quench was used to arrive at vinyl iodide 10. Protection group switch from TIPS to the more convergent cleavage TBS group is straightforward giving green fragment 1.

 Scheme 3

The synthesis of the blue fragment began with Diels Alder reaction between two equivalents of furan and methyl propiolate. With ester 11 in hand the surplus ester group was removed following Barton’s protocol. Saponification and esterification with HPT produced thiohydroxamate ester 12 which loses CO2 under reductive radical reaction conditions yielding 13. Opening of one of the dihydrofurans gives a racemic mixture of alcohols 14 which were in turn protected. The silyl group was used as a handle in a Tamao-Fleming oxidation to introduce the terminal alcohol to give after methylation rac15.

Scheme 4

The next step in the synthesis is an interesting chiral resolution strategy by a “chiral hydride”. This is transferred from a Ni-(R)-BINAP complex with DiBAl-H as the hydride source. Never saw this kind of strategy in a total synthesis before but it is really a pretty neat solution. Although half of the material got lost in this step it provides rapid access to the blue fragment 2. If you are interested in this step you should have a look into this one [1]. So with enantiomerically pure 16 in hand the alcohol was oxidized and the PMB group replaced with a TBS group. After chemo- and stereoselective epoxidation (maybe guided by the methoxy group?) the blue fragment 2 was ready for the crucial coupling step.

 Scheme 5

Metal/halogen exchange of 1 with tBuLi and quench with 2 generated an alcoholate which immediately opens the epoxide in a 5-exo-tet reaction to give 19. This advanced intermediate was protected as a TBS ether and exposed to Cr(VI) which is known to promote allylic oxidation/rearrangement/oxidation to give in the end an unsaturated ketone. An attempted Claisen rearrangement to introduce the side chain did not give any positive results so the group had to pursue a different route. Michael addition of dimethylmalonate, triflation of the ketone, and reduction saved the day giving 21 in good overall yield.

 Scheme 6

Global reduction with LiBEt3H, selective monomethylation and MOM-deprotection produced diol 22. Chemoselective TEMPO oxidation (primary vs. secondary alcohol) to the aldehyde and Pinnick oxidation gave seco-acid 23. Some macrolactonization conditions were screened but the rather old school Corey-Nicolaou reaction proved to be successful to furnish after desilylation branimycin. As can be seen from scheme 7 it was not possible to control the stereochemistry a to the ester functionality. The preceding methylation to differentiate the hydroxy functionalities did not result in any chiral resolution so this stereocenter remains racemic giving at last two diastereomers of branimycin. Nevertheless the absolute of this stereocenter could be unambiguously resolved which remained unclear at the beginning of the story.

 Scheme 7

Sorry for the long delay of posting but I am really busy with finishing my exams and planning my move to the US.

 

[1] http://dx.doi.org/10.1016/S0040-4020(97)10211-3

 

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