Total Synthesis of Akuammiline Alkaloid (−)-Vincorine via Intramolecular Oxidative Coupling

Total Synthesis of Akuammiline Alkaloid (−)-Vincorine via Intramolecular Oxidative Coupling

Weiwei Zi, Weiqing Xie, and Dawei Ma


Vincorine is a rather young target for the synthetic community of which only a racemic synthesis has been published by the Qin group (J. Am. Chem. Soc., 2009, 131, 6013). Besides vincorine the akuammiline alkaloid family contains several interesting members like strictamine, scholarisine and aspidophylline. Total syntheses of most of the family members have been published within the last 20 years.

The group planned to access the crucial C-C bond marked in orange via an oxidative coupling. From the earlier synthesis of communisine A and B the group gained some experience with this kind of coupling reaction. [1] The remaining disconnections are straightforward leading to the key building blocks O-methyl-serotonin, a selenoaldehyde and ethyl acrylate.

 Scheme 1

First serotonin derivative 1 was double protected with Boc2O and oxidatively coupled to ethyl acrylate via a formal C-H activation under Pd(II) catalysis. [2] Hydrogenation of the

double bond and reduction of the ester gave alcohol 3 which was oxidized to the aldehyde and reacted with dimethyl malonate to give Michael acceptor 4. This was used in a highly stereoselective prolinol ether catalyzed Michael addition with the selenoaldehyde shown. Oxidation and base induced elimination furnished an exo-methylene group which shifted under the reaction conditions into conjugation but with the wrong geometry. Under UV-light irradiation the cis-double bond was changed into trans-configuration yielding key intermediate 6 in almost quantitative yield.

 Scheme 2


Going on with the synthesis the aldehyde was reduced, silylated, and the resulting ether heated on silica gel to remove selectively the indole Boc protecting group. In the presence of 2 equivalents of LHMDS and 1 equivalent of iodine the group was able to perform an awesome coupling reaction giving them almost the whole framework in one single step. Finally the least hindered methyl ester was removed under Krapcho’s decarboxylation conditions.

Scheme 3


The last ring was closed after direct conversion of the TBS ether into allyl chloride 10, Boc-removal with TMSOTf, and intramolecular alkylation to give 11. After reductive amination with formalin the group isolated (-)-Vincorine with an overall yield of 5 % over 18 steps in the longest linear sequence.

 Scheme 4


But how does the oxidative coupling work? The authors state that it might work through a radical mechanism as proposed in their communesin A and B syntheses. In the present publication no mechanism is given only some sort of transition state structure as is reproduced below. According to their postulation the doubly deprotonated starting material reacts through a Zimmermann-Traxler-like transition state stitching both ends together via intermediate radicals formed by two SET to iodine. In the last step the pyrrolidine ring is closed as usual.

 Scheme 5


During a group meeting we discussed the mechanistic rationale behind this reaction and came up with a mechanism like that shown below which is better harmonized with the usual reactivity observed in halogenation reactions with indoles. So after double deprotonation with LHMDS the indole 3-position is iodinated to form an indoline system which undergoes pyrrolo-indoline formation. The former indole nitrogen can then kicks out the iodide through a SN2’-type reaction. Now the malonate anion attacks the former 3-position of the indole and closes stereospecifically to give the expected product. The obvious problem is the source of stereocontrol.

 Scheme 6


If you perform a minimization of the starting material then you will recognize that the unsaturated side chain with the bulky TBS group shields the upper face of the indole. I would think that this bulkiness is responsible for the observed facial selectivity of the iodine addition. The remaining steps are now stereospecific and can only lead to the product.

 Scheme 7

Or can someone offer me a better explanation with respect to the stereoselectivity observed?



As Dave suggested a lithium aggregate might be respsonsible for the oberserved stereoselectivity of the iodine attack. So I created the following 3D model and minimized it with ChemDraw. Given that lithium couples the enolate and the deprotonated indole nitrogen and is additionally coordinated by two THF molecules then you get this prediction. Maybe this offers another explanation for the observed stereoselectivity though I am still not satisfied with both models. Nevertheless big thanks for this suggestion.

Scheme 8

 Big THX to Bobby for proofreading and questions.




Total Synthesis of the Galbulimima Alkaloid (-)-GB17

Total Synthesis of the Galbulimima Alkaloid ()-GB17

 Reed T. Larson, Michael D. Clift, and Regan J. Thomson


GB 17 belongs to the family of Galbulimima alkaloids which can be found in the bark of a rainforest tree with himbacine as a promising lead structure for muscarinic receptor antagonists. Himbacine-like compounds were tested for the treatment of Alzheimer’s disease as thrombin agonists.

Other family members including himandrine, GB13, himgaline, and GB16 have been synthesized. To date no synthesis of GB17 is known so the Thomson group accepted this last challenge. The retrosynthetic analysis is shown below. Nothing real spectacular but a nice access to the tetracyclic carbon skeleton is presented.

 Scheme 1


The first building block is readily available by a methodology developed by Lhommet et al. Reaction of ester 1 with (S)-phenylglycinol yielded oxazolidine 2 which was hydrogenated to give piperidine 3. The yields are not reported but considering the original publication about 40 % yield can be achieved.

The linchpin was synthesized starting from monoprotected diol 4 which was converted to iodide 5 and dithiane 6 which alkylation with 7 to give acetal 8. 5 and 8 were coupled and the aldehyde and alcohol were freed with dilute HCl in acetone. [3]

 Scheme 2

Treatment of ester 3 with lithiated phosphonate and Boc protection of the naked amine gave ketone 10 [4]. HWE reaction with linchpin 9 under Masamune-Roush conditions and subsequent DMP oxidation furnished aldehyde 11. After some model studies the group found that a TMS-prolinol catalyst gave highest yields and enantiomeric excess on a multigram scale. In a one-pot procedure the aldehyde was converted to unsaturated ester 12. Base induced cyclization, amine deprotection, and lactamization yielded tetracycle 13 in moderate yield. Nevertheless it was found that the wrong isomer had been formed together with complete inversion of the stereocenter next to the amine.

Scheme 3


Obviously the (E)-configured ester gave the wrong stereochemistry in the Michael addition step, so the group proceeded from 11a through a Still-Gennari modified HWE to give again under Masamune-Roush conditions ester 14. Boc deprotection and this time sodium methanolate induced cyclization did the job. Under these conditions the lactamization occurred to give 15. The keto group in 15 was removed under standard conditions by formation of the vinyl triflate which was reductively removed in the presence of Pd and formic acid as the hydrogen source. Stereoselective alkylation of the lactam was followed by dithiane removal, reduction, and oxidative cleavage of the exo-methylene group to give GB17.

Scheme 4


To explain the stereochemistry in the organocatalytic step I would propose the following transition state. Enamine formation of the prolinol ether should lead to the transition state with the least steric interactions. [5] McMillan’s catalyst or proline gave much lower ee values.

 Scheme 5


The outcome of the cyclization step can be explained considering the transition states shown below. In structure 12 steric interactions between the large Boc group and the ester force the double bond into an axial position. Alternatively without the Boc group and with a (Z)-double bond the ester group is equtorial so steric interactions can be minimized in the conformer shown.

 Scheme 6

And as usual THX to Bobby for proofreading.

[1] DOI:

The specificity of the reduction step can be explained by looking at the particular bonds which are reduced. 1) The enamine bond is reduced stereoselectively by facial differentiation from the Re face. 2) The aminal opens up to an imine which is again reduced to the amine. 3) The auxiliary is cleaved off.

[2] DOI:

[3] Have a look at BRSM’s blog for a sweet discusison on linchpins…

[4] Interestingly the group protected the amine after the BuLi chemistry which results in the usage of > 2 eq of lithiated phosphonate. Maybe earlier Boc-protection gave racemisation through DoM-chemistry with some help from the Boc group. Racemization was later found to occur in the presence of tBuOK.

[5] The group stated that the dithiane protecting group was essential for the reactivity of the substrate. Without this group almost no transformation was observed. Considering the great Thorpe-Ingold effect of this protecting group it might be an explanation.

Enantioselective Total Synthesis of (+)-Conicol via Cascade Three-Component Organocatalysis

Enantioselective Total Synthesis of (+)-Conicol via Cascade

Three-Component Organocatalysis

Bor-Cherng Hong, Prakash Kotame, Chih-Wei Tsai, and Ju-Hsiou Liao


This time some organocatalysis already published last year by a group based in Taiwan. Though not a spectacular paper I liked the first few steps and so reviewed it.

Conicol belongs to the class of meroterpenoids which were isolated from higher plants and recently from marine organisms. And as usually with these marine stuff it exhibits some cytotoxic effects against human cancer cells .

The key steps of the synthesis are a TMS-prolinol catalyzed enantioselective alkylation/Michael addition reaction followed by another Michael addition/aldol condensation to build the backbone of the whole molecule in almost 2 steps.

Additionally these two single pot sequences can be combined to one protocol giving the product in 55% yield with > 99% ee.

Scheme 1:

Scheme 2:

As mentioned above these sequences were combined to one very successful procedure. If you’re interested in the whole story have a look in here:

With all stereocenters and the carbon skeleton in hand only a few modifications were needed to give (+)-Conicol:

Scheme 3:

A decarbonylation reaction with Wilkinson catalyst was followed by double bond reduction with palladium on charcoal. Interestingly the nitro function is stable under these conditions.

Next the dimethylacetal was cleaved with hydrochloric acid, which results in elimination of the nitro function too, and an old school Wolff Kishner reduction gave Didehydroconicol.

Going on from the key intermediate the acetal was cleaved under milder conditions without causing elimination of the nitro function. This was done with DABCO, the aldehyde reduced, acetylated and eliminated under Birch conditions to give (+)-Conicol in 5% overall yield over 9 steps in the longest linear sequence.

Scheme 4:

I didn’t manage to publish this in january, sorry for that, but I’m just on the next paper so maybe I finish 3 reviews in February to keep my average of 2 reviews per month.