Part 2: Enantioselective Total Synthesis of (−)-Citrinadin A and Revision of Its Stereochemical Structure

Part 2: Enantioselective Total Synthesis of (−)-Citrinadin A and Revision of Its Stereochemical Structure

 Zhiguo Bian, Christopher C. Marvin, and Stephen F. Martin


So folks, here it is. Took me a few days longer as promised but finally I made it. Though citrinadin A is closey related to citrinadin B the synthetic approach of the Martin group is much different from that of Wood et al.. Their retrosynthetic considerations are summarized in scheme 1. Interestingly the introduction of the epoxyketone utilizes almost the same chemistry under similar reaction conditions. Contrary to the Wood approach the spiro-oxindole is build up by an epoxidation / semipinacol rearrangement in a diastereoselective manner. This disconnection leads back to the bromoindole shown which in turn is introduced by a Fischer indole synthesis. The tertiary alcohol and amine are derived from selective epoxidation / epoxide opening to give a lactam which tracks back to a vinylogous Mannich reaction between 2 and A.

Scheme 1


 Dimethylcyclohexadione 1 is monoprotected and methoxycarbonylated with dimethylcarbonate. Subsequent triflation and copper-mediated introduction of another methylgroup then leads to ester 2. In the presence of LDA and in situ transmetallation with zinc chloride a vinylogous enolate is formed which reacts with in situ formed pyridinium ion A. After acidic hydrolysis ester 4 is formed which undergoes base mediated lactam formation to give 5.

 Scheme 2


Next TIPS cleavage sets the stage for the stereoselective introduction of a methyl group which had to be accomplished in a two-step sequence. After cuprate addition derived from PhMe2SiCH2MgCl and reduction of the ketone the silylgroup was removed under harsh conditions to provide alcohol 8. Epoxidation of the unsaturated lactam with peracid and ensuing opening with dimethylamine then leads to 10.

 Scheme 3


The dioxolane is then directly used in a Fischer indole synthesis with bromophenylhydrazine in aqueous sulfuric acid to give indole 11 in pretty good yield. Successive reduction of the lactam carbonyl was accomplished by combined alane / borohydride reduction which proved to give the best yields of 12. In situ protection of the sensitive amine moieties with PPTS and epoxidation with Davis oxaziridine yields an intermediate indoline which undergoes semipinacol rearrangement in the presence of acetic acid to give the core structure of the citrinadins with complete control of the quaternary carbon centre. Sonogashira coupling then provides alkyne 15.

 Scheme 4


All that remains was to transform the triple bond into the epoxyketone which was accomplished after amide formation with dimethylvaline utilizing again the Gold mediated oxygenation and subsequent Enders epoxidation protocol (cf. Wood et al.).

 Scheme 5


Pretty cool synthesis. It was very intriguing to me to see two almost completely different approaches of the Wood and Martin group which were also published back to back and ultimately corrected the proposed structure of the citrinadins.

Total Synthesis of (+)-Sieboldine A

Total Synthesis of (+)-Sieboldine A

Stephen M. Canham, David J. France, and Larry E. Overman


Unfortunately I was very busy the last weeks with studying but now the last exam is written so I took the advantage and finished to review this nice paper from Overman et al..

Sieboldine A presents in my eyes a classical Overman target because of the rigid alkaloid structure ready for cool rearrangement chemistry. The compound itself inhibits electric eel AChE with an IC50 value comparable to that of Huperzine A ( But the real interest for a synthetic chemist poses the unprecedented N-hydroxyazacyclononane ring which was unknown until the isolation and structure elucidation of Sieboldine A in 2003.

Scheme 1

Retrosynthetically spoken the first step cleaves the sensitive N,O-acetal. The precursor derives from a Diels-Alder product which in turn was produced by a sweet pinacol-terminated cyclization.

Scheme 2

The synthesis starts off with the known unsaturated lactone which was opened by diastereoselective Michael addition of methylcuprate and subsequent lactonization with iodine. Exhaustive reduction with LAH furnished a diol which was selectively monoprotected and oxidized to give the ketone shown.

The second intermediate was synthesized through a known route. Michael addition of tributyltin-cuprate complex on the alkyne and quenching the reaction with MeOH gave z-vinyl tributyltin ester. This was reduced with DIBAL-H, exposed to Mitsunobu conditions to produce the phenyl ether and converted to the iodide by halogen/metal exchange.

Scheme 3

Next both intermediates were combined by reacting the iodide with sec-BuLi, transmetallate the lithium species with cerium trichloride and add to this the ketone (all at -78°C). Protection of the resulting alcohol, Swern oxidation of the terminal silyl ether (which was deprotected under the reaction conditions) and Seyferth-Gilbert homologation utilizing the Ohira-Bestmann reagent yielded the terminal alkyne ready for the first key step.

Exposure of this to a bit of gold and silver produced two of the four rings needed in a nice tandem Prins/pinacol rearrangement reaction.

Scheme 4

The mechanism might look like this:

Mechanism 1

The gold attacks the terminal alkyne which in turn is attacked by the alkene through a 5-exo-dig cyclization. The resulting tertiary carbenium ion is neutralized by a pinacol type reaction of the TES-ether to give the vinylic gold intermediate which is protonated by i-PrOH.

Having most of the carbon skeleton in place the group turned their attention on the next key step. Ozonolysis of the exo-methylene group followed by neutral work—up with dimethylsulfide and subsequent phenolate elimination produced another exo-methylene group. This underwent a europium catalyzed Diels-Alder reaction with ethyl vinyl ether. Diastereoselective reduction of the ketone was followed by facial selective expoxidation with DMDO.

Scheme 5

The resulting epoxide was opened in the presence of ethanethiol with BF3-etherate in a sweet Overman style reaction. Desilylation, Mitsunobu reaction with double protected hydroxylamine and removal of the nosyl protecting group furnished an odd looking hemiacetal. Next some carbohydrate chemistry was utilized which is completely new to me to close the last ring (if someone has access to the paper, mail me). Oxidation of the remaining alcohol and MOM-cleavage yielded at least (+)-Sieboldine in 5% yield over 20 steps in the longest linear sequence.

Scheme 6

The Diels Alder reaction inspired me to propose the two mechanisms below. I am not sure which one is right but I favour the red one.

Mechanism 2

For a better understanding of the abbreviations some structures of the reagents possibly new to some readers:

Scheme 7

I loved the synthesis as usual when reading Overman’s work. Especially the pinacol-terminated cyclization, the Diels-Alder reaction and the ring opening/ring closing cascade.

If you have any questions do not hesitate to ask them…

Total Synthesis of (-)-Mersicarpine

Total Synthesis of (-)-Mersicarpine

Rie Nakajima, Tsuyoshi Ogino, Satoshi Yokoshima, and Tohru Fukuyama


Happy new year everybody out there…

This time I will present to you a very short synthesis from the Fukuyama group which took only about 12 steps from cyclohexanone to the product. No special biological profile or so was mentioned but the need for a stereoselective total synthesis drove the group on.

Key steps are a Eschenmoser-Tanabe fragmentation and an accidentally found cyclization/oxidation reaction.


I will not go into detail with the retro because it will be explained in the next 3 schemes but I present it for the sake of completeness.

Blue intermediate:

Starting from cheap cyclohexanone forming an imine which was alkylated then changed into a chiral imine with phenylethylamine which in turn undergoes an asymmetric addition on methyl acrylate. Oxidation with IBX in DMSO was followed by epoxidation with aqueous peroxide yielding the intermediate ready for the Eschenmoser-Tanabe fragmentation. This posed some problems to the authors but could be solved first by using a semicarbazide which was oxidized secondly with LTA to give the blue intermediate shown.

Red intermediate:

Aldehyde reduction and Sonogashira coupling of the alkyne was followed by a nice gold catalyzed indole formation. Diazo coupling with phenyldiazonium chloride yields the azo bridged indole which cyclized with the ester after deprotonation with NaH. Subsequent in situ mesylation of the alcohol furnished the last intermediate ready for the key step.

Key step:

After several attempts to optimize the conditions, this high yielding one pot procedure was developed giving Mersicarpine in almost quantitative yield.

The first step is the reduction of the azo bridge to the aminoindole. This undergoes a SN2 displacement of the mesylate forming the last ring needed. After tautomerization an autoxidation occurred which formed a hydroperoxide which was reduced with dimethylsulfide to yield the natural product.

Yeah… very short but elegant synthesis. Any suggestions or namely a good idea why the oxidation of the aminoindole occurres spontaneously? I worked with some aminoindoles too but never observed something like that…

Again I’m very busy but maybe I manage to review the incredible paper from the Fürstner group which came up last year.