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

 

Advertisements

Total Synthesis of (+)-Daphmanidin E

Total Synthesis of (+)-Daphmanidin E

Matthias E. Weiss and Erick M. Carreira

 DOI: http://dx.doi.org/10.1002/anie.201104681

It is pretty hard to decide these days which synthesis should be reviewed. Luckily the great accomplishment of the Fukuyama group (Gelsemoxonine) has recently been reviewed on B.R.S.M so I chose the exceptional work done by the Carreira group at the ETH. It features a densely functionalized compound found in some leaves called
(+)-Daphmanidin E. The biological profile is rather unspectacular which can be explained with low supply of material.

As usual the Carreira group used some very interesting chemistry to build this beasty:

 Scheme 1

 

The synthesis features as one of the key steps a very cool Cobalt catalyzed Heck cross coupling reaction of an alkyl iodide. If you are further interested, as I am, take a look into this review (Chem. Rev. 2010, 110, 1435–1462).

Starting from known building block 1 which is available in racemic form by some really old procedure the group used chemoenzymatic resolution to get enantioenriched 1. I think this citation might be the oldest one I used to date. It is only available in german… I like this old stuff and the nice language they use.

Scheme 2

 

Because the supporting information was not online while I wrote this review I cannot give you the yield of the resolution step (maybe later…).

Going on with the synthesis the group first desymmetrized the C2-symmetric building block by an acetal formation. Triflate formation using Comin’s reagent then gave fragment 2. In situ hydroboration of TBDPS-protected allyl alcohol and Suzuki coupling in the presence of Ph3As as the ligand added the first side chain which was later used for the crucial Heck reaction. Ph3As was essential for this step due to a de-triflation side reaction when phosphine based ligands were employed. Hydroboration/oxidation and subsequent global reduction was followed by diol protection/acetal cleavage and benzoylation of the second primary alcohol to furnish 3. O-alkylation of the corresponding enolate then produced enol ether 4.

 Scheme 3

 

The subsequent Claisen rearrangement gave ketone 5 which was again alkylated and rearranged to give ketone 6 with an extremely densely functionalized cyclohexane core, and three quaternary stereocenters. Selective hydroboration/oxidation of the least hindered methylene group was followed by acetylation and TBDPS removal. Selenation/oxidation/elimination according to Grieco’s protocol produced 7.

 Scheme 4

 

Selective removal of the acetonide was accomplished with a mixture of cerium trichloride and oxalic acid. Alcohol differentiation was achieved by protection of the primary alcohol with TMS, MOM-protection of the secondary one and desilylation. DMP oxidation then furnished aldehyde 8. Henry reaction with nitromethane was used to introduce the nitrogen atom into the system. After some efforts the group identified conditions to introduce the asymmetric methyl group by using one of the ligands published by Hoveyda et al with dimethylzinc as the nucleophile. Reduction of the nitro group and Boc-protection of the amine gave ketone 11.

 Scheme 5

 

Next both carbonyl groups were unmasked by ozonolytic cleavage of the methylene groups from which the aldehyde was chemoselectively reduced. A Finkelstein reaction of the corresponding mesylate gave iodide 13 from which the MOM-group of the pentanone ring was eliminated. Interestingly the iodide survived under the reaction conditions.

 Scheme 6

 

And here is the key step: By using catalyst B in a stoichometric amount, and after a lot of trials under different conditions, the group closed the seven-membered cycle. Some efforts later the group found that only a catalytic amount of B was necessary to get the reaction done, when DIPEA was added to the mixture. The scope of this remarkable key step will be part of a separate paper.

Scheme 7

 

The last steps of the synthesis include first a deacetylation (in the presence of the benzoyl protecting group). Oxidation and base catalyzed aldol condensation gave aldehyde 16. Ester formation under Corey’s conditions (MnO2 and NaCN in MeOH) was followed by protecting group exchange from benzoyl to acetyl to give 17. Boc-deprotection and simply heating the free amine in EtOH gave after MOM-removal Daphmanidin E in good yield.

 Scheme 8

 

Hell yeah… Really nice work, as usual. Interstingly only one co-author with respect to Prof. Carreira is mentioned in the title. The stage is open for discussions.

BTW.: Damn… B.R.S.M was a bit faster…

THX to Bobby for proofreading.
I selected this post to be featured on my blog’s page at Science Blogs.

Total Synthesis of (-)-Huperzine A

Total Synthesis of ()-Huperzine A

Takahiro Koshiba, Satoshi Yokoshima, and Tohru Fukuyama

DOI: http://dx.doi.org/10.1021/ol9022408

This time fresh work from the almighty Fukuyama group featuring a sweet compound with a really funny name: Huperzine A (at least in German it sounds funny…).

And it owes an interesting biological profile: “it was found to exhibit a potent, selective and reversible inhibitory activity against acetylcholinesterase” which could be used as a treatment for Alzheimer’s disease.

Retro:

They planned to install the 2-hydroxy pyridine at least; the exo-ethylidene then arises from vinyllithium addition and “alcohol” transposition. A Curtius rearrangement and a nice acid catalysed alkylation furnished the required intermediate.

So let’s do some synthesis…

Blue intermediate:

The commercially available anhydride shown was stereoselectively opened with benzyl alcohol in the presence of quinine following a procedure from Bolm. Chemoselective reduction and lactonization furnished one diastereoisomer in good yield with 93% ee. THF opening was followed by alkylation, alcohol directed epoxidation and Swern oxidation to give the blue fragment in high overall yield.

Key step:

The blue fragment was then exposed to a catalytic amount of TfOH in DCM at low temperature to give the tricyclic lactone.

The reaction was found by accident while trying to protect the alcohol as the TBS ether with TBSOTf which gave the product in low yield. After some screenings TfOH was identified to give the highest yields.

Red fragment:

MOM protection and base induced lactone opening with thiophenol set the stage for the Curtius rearrangement / carbamate protection (nice cascade which I did by myself but I had some problems with the purification). Oxidation to the sulfone and elimination gave an exo-methylene group which was used as a Michael acceptor for the sulfinylacetamide which cyclised to the pyrone at reflux in toluene. Amminolysis and methylation furnished the red intermediate.

Green product:

MOM deprotection and another Swern gave the required ketone which was exposed to vinyllithium followed by thionylchloride yielding the allylchloride shown. This was reductively removed with LiBHEt3 and after global deprotection with TMSI in MeOH the synthesis was done.

Some sweet chemistry in here especially the acid catalysed alkylation and the exo-ethylidene synthesis are my favourites.

What do you think?