Total Synthesis of (+)-Daphmanidin E

Total Synthesis of (+)-Daphmanidin E

Matthias E. Weiss and Erick M. Carreira


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.
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