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 (±)-Communesin F via a Cycloaddition with Indol-2-one

Total Synthesis of (±)-Communesin F via a Cycloaddition with Indol-2-one

Johannes Belmar and Raymond L. Funk

 DOI: http://

It has been some time since my last entry. I was very busy with moving to the US and starting my master’s thesis. But as you can see after about 12 weeks I am back. I chose a rather short synthesis but there is still some work to be covered within the next weeks which should result in much more detailed write-ups.

The communesins are known to the synthetic community for quite a while and were the targets of extensive research and synthetic studies. The current paper utilized some nice methodology developed by the group and published in an earlier synthesis of perophoramidine. [1]

The synthesis begins with the union of azide 1 and bromooxindole 2. Because their initially reported conditions did not give any product at all it was found that the reaction proceeded smoothly in the presence of substoichiometric amounts of silver carbonate yielding 3. After tosylation the mixture was exposed to methanolysis to produce the backbone structure 4 of communesin F. Methylation with Meerweins’s salt, hydrogenolysis of the azide with subsequent Boc-protection and detosylation furnished amide 5.

 Scheme 1

The bromine was then used as a handle to introduce the prenyl sidechain with a Heck reaction to give an intermediate allylic alcohol. In the presence of mercury salts a cyclization took place constructing the crucial seven-membered amine ring. Deprotection of the amine under mild conditions using TBSOTf was followed by amide formation with some help from trimethylaluminium. The second side-chain was introduced in the usual sequence of deprotonation and subsequent alkylation with iodoacetonitrile.

 Scheme 2

The last ring was closed in a straightforward manner. Reduction of the nitrile to the aldehyde and the amide to the hemiaminal gave tetrahydrofuran 9. Reductive amination and acetylation finally produced communesin F in an overall yield of 6.7 %.

Scheme 3

The mechanism of the key step is pretty straightforward but nevertheless a nice one. After tosylating the oxindole nitrogen the resulting amide can be cleaved by methoxide to give an anilide anion which undergoes intramolecular attack on the indolenine 2 position to close the ring.

Scheme 4

[1] J. Am. Chem. Soc. 2004, 126, 5068

Yeah… that is it for the moment. I found some new interesting stuff to write-up, so I promise I will be up to date from now on J

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.



Synthesis of Dragmacidin D via Direct C-H Couplings

Synthesis of Dragmacidin D via Direct C-H Couplings

Debashis Mandal, Atsushi D. Yamaguchi, Junichiro Yamaguchi, and Kenichiro Itami


I thought about writing this review a few months ago but never found the time to get it done. But here it is and I hope you enjoy this cool paper as I did. I am a big fan of “flat” chemistry and C-H activation so naturally this piece had to be reviewed. Dragmacidin D itself shows some promising activity in the treatment of neurodegenerative diseases like Alzheimer’s or Parkinson’s disease. Only one total synthesis has been published by the Stoltz group in 2002 so there is still room for improvement. Retrosynthetically the group planned to stick all parts together via C-H activation/C-C coupling reactions.

 Scheme 1

The “sticky” –positions are marked in blue. As can be seen from this picture almost all crucial bonds can be formed through C-H activation (except the iodide).

Indole 1 was carboxylated to block the 3 position of the indole which would normally undergo iodination in the presence of NIS. Removal of the carboxyl group after halogenation gave indole 3. Tosylation was accomplished under standard conditions yielding the first coupling partner 4. Thiophene boronic acid 5 was oxidized to the corresponding alcohol to furnish after TIPS protection coupling partner 6. In the presence of PdII and silver(I) as the re-oxidant thiophene 7 formed in good yield on a gram scale. Desilylation and reductive desulfuration with Raney-Ni was followed by global deprotection and double MOM-protection to produce ketone 8. [1]

 Scheme 2

Next the 3 position of the indole moiety was again functionalized. This time pyrazine N-oxide was used in the presence of PdII to give 9. A TFAA mediated Polonovski-Potier rearrangement gave pyrazinone 10 which was used in a Friedel-Crafts-like acylation with 6-bromoindole to furnish 11 in good yield. Bromination of the ketone was accomplished via the TMS-enolate and NBS mediated bromination yielding 12. In the presence of Boc-guanidine Dragmacidin D was formed after deprotection.

 Scheme 3


Short and very efficient I would say. The only drawback might be that Dragmacidin D is formed in both enantiomeric forms. I was wondering how much silver the group stores in their laboratories J.

[1] Really a nice method to introduce the side chain on the indole. The net result is the reaction of an umpoled ketone with the aromatic ring.

A Concise and Versatile Double-Cyclization Strategy for the Highly Stereoselective Synthesis and Arylative Dimerization of Aspidosperma Alkaloids

A Concise and Versatile Double-Cyclization Strategy for the Highly Stereoselective Synthesis and Arylative Dimerization of Aspidosperma Alkaloids

Jonathan William Medley and Mohammad Movassaghi


The aspidosperma alkaloids belong to the family of monoterpene indole alkaloids which contains more than 2000 members. I think most of you are more or less familiar with their structures. Because of their broad structural diversity this family still challenges chemists to test new methodology. The Movassaghi group recently published this paper which contains an impressive Friedel-Crafts cyclization strategy to build up the framework in a concise manner. By the way three biogenetically related group members were synthesized and some analogous compounds.

Scheme 1


The group planned to access all three natural products through a common precursor which can be obtained via an interrupted Bischler-Napieralski reaction. Fragment 8 was synthesized utilizing Myers asymmetric alkylation strategy.

Scheme 2


Pseudophenamie 1 was acylated with crotonyl chloride to give amide 2 which in turn was deprotonated and alkylated to give 3. By doing so the endo-double bond was transformed into a terminal olefin. Another alkylation introduced the ethyl group while retaining the stereochemistry at the a-position. [1] TES protection of the auxiliary was necessary to overcome problems in the following alkylation/ring closing step. [2] Coupling partner 6 was obtained through methylation and chlorination of 5 in a straightforward manner. Alkylation of 6 with 4 was achieved with KH in the presence of TBAI to give acyclic precursor 7 in high yield.

Scheme 3


Next the nosyl group was removed with PhSH. In one pot the TES group was cleaved which resulted in the expected N à O acyl transfer. [3] The ester then easily formed lactam 8 with complete recovery of the auxiliary in almost quantitative yield. Triflation of lactam 8 in the presence of the slightly basic 3-cyanopyridine produced the key diiminium ion shown. Depending on the following steps a lot of derivatives can be accessed. [4] Employing first borohydride reduction and hydrogenation (-)-N-methylaspidospermidine was obtained. Using a buffered aqueous solution of TFA the diiminium salt was hydrolyzed, the double bond hydrogenated, and the carbonyl functionality reduced with LAH to give (+)-N-methylquebrachamine.

Scheme 4


Going half the way from the diiminium ion (which means leaving the double bond in place) coupling partners 12 and 13 were obtained. Again forming the diiminium ion from 13 in the presence of 12 iminium ion 14 was generated. Reduction with Red-Al and hydrogenation then gave (+)-dideepoxytabernaebovine.

Scheme 5


For clarity I put the mechanism of the Friedel-Crafts chemistry below. Triflate formation is straightforward. The following spirocyclization is controlled by the quaternary stereocenter. Most likely the ethyl side chain poses greater steric repulsion and the vinyl group might exhibit some sort of attractive secondary orbital interactions. The formed indoleninium ion then underwent aza-Prins cyclization to give after HCl elimination the diiminium ion used for further modifications.

Scheme 6


Extremely cool chemistry. I skipped to show all the analogs the group synthesized by the way but you really should have a look in the paper. It is highly recommended.

[1] Any guesses why the stereochemistry of the vinyl group is retained in this step? Normally it should be inverted I think…

[2] It was found that during the coupling step the resulting free amine after N àO acyl transfer underwent intramolecular alkylation with the chloride to close a lactone ring.

[3] The fast N à O acyl transfer can be explained when you look at the 3D model below:

Because of the large phenyl groups the amide nitrogen has almost no chance to overlap its non-bonding s-orbital with the antibonding p*-orbital of the carbonyl group. So the normally partial double bond character of the amide bond is weakened. On the other the free alcohol oxygen is very close to the amide carbonyl so that an acyl transfer should be really fast. I can only guess why this transfer is observed, maybe you have another explanation for that?

3D-model (click on the image to get an impression of the 3D structure):


[4] As nucleophiles the group employed for example Grignard reagents, allyl silanes, enol esters, or electron-rich arenes.

Big big thanks to Bobby for proofreading and additional question/suggestions.

Total Synthesis of (+)-Condylocarpine, (+)-Isocondylocarpine, (+)-Tubotaiwine and (-)-Actinophyllic Acid

Total Synthesis of (+)-Condylocarpine, (+)-Isocondylocarpine and (+)-Tubotaiwine

Connor L. Martin, Seiichi Nakamura, Ralf Otte, and Larry E. Overman


Total Synthesis of (±)- and (-)-Actinophyllic Acid

Connor L. Martin, Larry E. Overman, and Jason M. Rohde


This review summarizes two very interesting papers published more or less recently by the Overman group (he is still my favourite… ). I decided to combine both papers because a common intermediate was used to make all  four natural products and its synthesis makes use of some uncommon in situ Umpolung chemistry.

The first schemes were reproduced from the JACS paper while the last two schemes came from the OL paper.

Scheme 1

Starting with Boc-protected GABA 1 the free acid was transformed into the Weinreb amide and alkylated with a vinyl-Grignard to get 2. Enantioselective reduction of the resulting ketone with high ee was accomplished by using catalyst A in the presence of hydrogen (Noyori’s catalyst). Ozonolysis of the double bond and trapping of the alcohol and resulting aminal with acetic anhydride furnished piperidine 4.

The second main fragment was obtained in two steps from di-tert-butylmalonate. Deprotonation and acylation gave compound 6 which formed indole 7 after reduction of the nitro group with Pd on charcoal in the presence of vanadate.

Scheme 2

Then it is getting more interesting: the blue and red fragment were combined by using a bit of scandium triflate to form 8 with great diastereoselectivity. Reductive removal of the acetyl protecting group and Swern oxidation of the resulting free alcohol produced ketone 9. Next my favourite reaction of the whole paper was employed: first a double deprotonation of the ketone and the malonate and then combination of the two carbanions to form the critical bicyclic ring system. Although the yield is moderate it proceeds with high dr. [Fe(DMF)3Cl2][FeCl4] was prepared from dehydrated iron(III)chloride and DMF by simply mixing the reagents. Finally addition of vinyl-Grignard under Luche conditions to the ketone forms lactone 11.

Scheme 3

Going on with the synthesis the lactone and the remaining ester group were reduced to get bis-alcohol 12. At this stage Overman makes use of his almighty aza-Cope/Mannich reaction.

The t-Bu- and Boc-groups were cleaved off in the presence of dilute acid before formalin was added. For clarity I added the main stages of the following events:

First a Schiff base formed from formaldehyde and the secondary amine. This underwent an aza-Cope rearrangement (or some sort of Prins-reaction) with the allyl alcohol to form 13b. The newly formed enol then attacks the rearranged Schiff base in a Mannich reaction to give (-)-Actinophyllic acid 14 as its hydrochloride.

Scheme 4

Finally to the paper mentioned first. Starting from key intermediate 10 the ketone was reduced, the Boc group removed and the malonate decarboxylated/transesterified to give amine 15. Reductive amination with the dithioacetal aldehyde shown was followed by a DMTSF mediated alkylation to give 17. Reductive desulfuration with Raney Ni and oxidation of the remaining alcohol under Albright/Goldman conditions (Swern-oxidation) furnished 18.

Scheme 5

Wittig reaction of the keto group then produced (+)-condylocarpine (and (-)-isocondylocarpine respectively) which was reduced in the presence of platinum oxide to give (+)-tubotaiwine.

Scheme 6

Nice… I had the schemes finished a few days ago but also had to write my last serious exam so … What do you think? Any comments?

A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

Fa´tima Churruca, Manolis Fousteris, Yuichi Ishikawa, Margarete von Wantoch Rekowski, Candide Hounsou, Thomas Surrey, and Athanassios Giannis


As the title suggests it’s time for some sunlight chemistry… Ok only one step but the rest of the synthesis is also worth reading. The Terpendoles are a family of indoleterpenes which show weak activity as acyl-CoA:cholesterol acyltransferase inhibitors. Recently it was discovered that the terpendoles inhibit the kinesin spindle protein (KSP).

In this paper the synthesis of one member of this class is described. The retro is rather short as the paper is, too. We’re starting with some FGI and cut the molecule into two halves by using the above mentioned Nazarov cyclization strategy. As can easily be seen, the molecule should be accessible directly from the known Wieland-Miescher-ketone.


So here we go:

The scheme starts with a selective protection of the unconjugated carbonyl. Phenylthiomethylation (search for Kirk-Petrow-reaction for further information) which was followed by a SET reduction under Birch conditions and subsequent trapping of the anion with allylbromide then yields the allylated/methylated ketone. LAH reduction of the remaining ketone, boronation of the terminal olefin and oxidation results in lactone formation. Oxidation of the ketone lactone to an α-β-unsatured one was achieved under more or less unconventional conditions. Epoxidation with H2O2, epoxide opening with phenylselenide and protection of the resulting alcohol as the MOM ether closes the first scheme.

Scheme 1

Because the phenylthiomethylation looks a bit odd, here is the mechanism:

Mechanism 1

The first few steps should be clear. The Birch reduction step might involve an intermediate radical anion which is trapped by allylbromide and reprotonated under thermodynamic control.

Furthermore the dehydration dehydrogenation step with this to me unknown reagent:

Mechanism 2

This is only a proposal of what I think the mechanism might be… I’m open for better ideas or corrections.

With the blue intermediate in hand we can move on. Selective reduction of the lactone was achieved with DIBAL-H and the aldehyde olefinated. Epoxidation of the alkene with mCPBA was followed by Sc(III) mediated pyran formation, oxidation and epimerization of the isomeric ethers to give one single pyran ring. Grignard reaction with methylmagnesium chloride, PG interconversion and acetal cleavage sets the stage for the final few steps.

Scheme 2

The first step involves an aldol condensation/hydrogenation to link both halves of the molecule together. Methylation of the ketone, benzylic oxidation with DDQ, dehydration of the tertiary alcohol with Burgess reagent to the exocyclic alkene and isomerization of the latter one to the endocyclic alkene prepares the key intermediate for the Nazarov cyclization. This [2+2] cyclization was mediated by UV light and closes the ring in a disrotatory manner.

Scheme 3

Protecting group removal and complete reduction of the ketone then yields Terpendole E.

Scheme 4

Overall a nice synthesis but I would have preferred a bit more details in the paper. The authors only give the used reagents without any more information like conditions or eq’s. Nevertheless nice chemistry but there’s a little mistake in the published paper. Maybe you find it too…

Any comments?