Total Synthesis of (-)-Dendrobine

Lukas M. Kreis and Erick M. Carreira

DOI: http://dx.doi.org/10.1002/anie.201108564

Dendrobine is the most abundant alkaloid isolated from an orchid which is used in traditional chinese medicine. The caged structure of this natural product is responsible for the interest of organic chemists in its synthesis. Retrosynthetically the synthesis is almost straightforward. Opening of the lactone and intramolecular amination give a precursor which is easily built up through an Ireland-Claisen rearrangement and enamine induced Michael addition.

 Scheme 1

Ester 1 which is easily accessible from commercially available material underwent a nice Michael addition with iPrNO₂ to give after removal of the nitro group the cis-configured ester 2. The stereochemical outcome can be explained by using the Cornforth model. Excessive reduction with LiAlH₄ was followed by benzoylation, acetonide cleavage, double TBS protection, selective mono-deprotection, and Swern oxidation of the primary alcohol to give aldehyde 3. Parallel to the latter synthesis the second fragment commenced with alcohol 4. Silylation, methylation of the alkyne, and iodination after hydrozirconation employing Schwartz’s reagent yielded iodide 5. Both fragments were combined after halogen—metal exchange with tBuLi and one-pot deprotection of the benzoyl protecting group with ethyl Grignard to furnish advanced intermediate 6.

 Scheme 2

 

Selective oxidation of the primary alcohol produced lactone 7 most likely through transitional lactol formation. After converting the ester group into the TMS-ester enolate the mixture was refluxed and underwent the crucial Ireland-Claisen rearrangement. The naked acid which resulted after work-up was protected as the methyl ester 8. Global desilylation was accomplished with HF in pyridine and followed by PCC oxidation. Aldehyde 9 was then condensed with benzylmethylamine and the resulting Michael adduct reduced with palladium on charcoal and hydrogen to give 10. N-C bond formation was accomplished by bromination/S_N2 displacement and stereoselective reduction of the ketone then formed in situ dendrobine. [1]

 Scheme 3

The mechanistic rational of the enamine induced Michael addition is shown below. After formation of the enamine the unsaturated ketone is attacked from the bottom face to give presumably after some proton shifts another enamine. Reduction from the Re face delivered amine 10 while the benzyl group is cleaved off at the end of this sequence.

Scheme 4

The C-N bond formation was induced by PHT, a commercially available mild brominating reagent. It was hypothesized that the nitrogen is brominated first and delivers the bromine to the a-position of the ketone. DMAP was essential in this step because it epimerized this position and left the bromine in an ideal position for a S_N2 displacement by the nearby nitrogen.

 Scheme 5

 Luckily BRSM took the Indoxamycin B synthesis from Carreira. Check it out…

[1] Big thanks to Bobby for correcting the presumed structure of PHT: it is believed known that the tribromide ion forms an ion pair with a protonated pyrrolidinone. Makes sense compared to pyridinium tribromide. Here is the corrected link to the crystal structure: ftp://ftp.oldenbourg.de/pub/download/frei/ncs/224-4/1267-2622.pdf

Big THX to Bobby for proofreading and corrections.

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.

A General Strategy for the Stereocontrolled Preparation of Diverse 8- and 9-Membered Laurencia-Type Bromoethers

Scott A. Snyder, Daniel S. Treitler, Alexandria P. Brucks, and Wesley Sattler

DOI: http://dx.doi.org/10.1021/ja2069449

DOi: http://dx.doi.org/10.1002/anie.200903834

This time some cool methodology from the Snyder group involving the use of a recently reported new reagent: BDSB. It is formed by the reaction of diethylsulfide, SbCl₅ and bromine:

Scheme 1

With this reagent a lot of bromonium ion induced cyclization reactions are possible which do not work well with the common reagents e.g. NBS or TBCO. In a communication from 2009 the group used this reagent quite efficiently to produce fused cyclohexane systems.

Scheme 2

All these reactions were conducted with BDSB in nitromethane. No or very low yields of the products were obtained using common reagents. Encouraged by these results the group conducted some experiments to form larger ring systems in a biomimetic manner:

Scheme 3

As can be seen from scheme 3 some quite interesting motifs can be produced in a highly selective and efficient way. Recently the group reported an extension of this methodology which prompted me to write this little review.

They used BDSB to convert tetrahydropyrans into oxocane ring systems through an interesting biomimetic rearrangement reaction.

Scheme 4

By exposing the substituted THP-rings to BDSB a bromonium ion induced cyclization occurred which opens the five membered ring to an eight membered one. And all this in a stereoselective manner with high ee’s. Following this approach some members of the lauroxocane group of natural products were produced.

Scheme 5

Depending on the tetrahydropyran used a lot of diastereomers can easily be synthesized. In a representative example the group started from pentenol and methoxypropene to produce via a Claisen rearrangement 5-octenone. The second fragment derived from hexanal which was stereoselectively chlorinated using NCS and L-proline. An aldol reaction combined both halves and the resulting aldol product was exposed to anti selective reduction conditions. Cyclization to the tetrahydropyran was accomplished under high pressure in methanol.

Scheme 6

I think this is a very useful methodology to form medium sized rings otherwise not so easy to access. Because of the ease of preparing BDSB it will hopefully find more applications in literature and total synthesis.

THX to Bobby for the helpful corrections.