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

 DOI: http://dx.doi.org/10.1021/ja303602f

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?

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Addendum:

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.

[1] http://dx.doi.org/10.1002/anie.201106205

[2] http://dx.doi.org/10.1002/anie.200500468

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Total Synthesis of (-)-Dendrobine

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/SN2 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 SN2 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 the Galbulimima Alkaloid (-)-GB17

Total Synthesis of the Galbulimima Alkaloid ()-GB17

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

 DOI: http://dx.doi.org/10.1002/anie.201108227

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: http://dx.doi.org/10.1016/j.tet.2005.05.079

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: http://dx.doi.org/10.1021/ja055740s

[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.

Natural product–inspired cascade synthesis yields modulators of centrosome integrity

Natural product–inspired cascade synthesis yields modulators of centrosome integrity

Heiko Dückert, Verena Pries, Vivek Khedkar, Sascha Menninger, Hanna Bruss, Alexander W Bird, Zoltan Maliga, Andreas Brockmeyer, Petra Janning, Anthony Hyman, Stefan Grimme, Markus Schürmann, Hans Preut, Katja Hübel, Slava Ziegler, Kamal Kumar & Herbert Waldmann
DOI: http://dx.doi.org/10.1038/NChemBio.758
I will start this write-up with a question to all readers: what is the longest cascade reaction you can think of? I mean how many separate steps occur while the compounds react and rearrange and form new bonds. [1] The longest one I thought is the Ugi-4CR with some concomitant steps e.g. condensation to form heterocycles. But all in all with a maximum of 8 reaction steps.

So have a look at this one:

Scheme 1

If you have some spare time try to figure out what happens. For all the others here is the solution the authors offer. [2]
The first step is the Michael addition of PPh3 into the triple bond of the acetylenic ester. Vinylogous aldol addition of the so formed ester enolate and subsequent Michael addition of the newly formed enolate into the unsaturated ester gave a tricyclic compound after elimination of triphenylphosphine. Then tryptamine was added followed by 1.5 eq of CSA. Tryptamine attacks the unsaturated ketone which results in elimination of the phenolate. The formed 2H-pyrane undergoes an electrocyclic ring opening which closes again to a dihydropyridine ring system.

Scheme 2


Next the dihydropyridine eliminates again the phenolate forming a pyridinium ion which is attacked again by the phenolate to give a rearranged dihydropyridine. Electrocyclic ring opening yields an imine which undergoes a Pictet-Spengler reaction with the 2-position of the indole ring. The last two steps contain another Michael addition of the tetrahydro-β-carboline nitrogen atom onto the unsaturated ketone and subsequent eliminiation of phenolate to give at last the indoloquinolizine skeleton.

Scheme 3

The yields ranged from 20 % up to 91 % in a single pot reaction and the procedure is rather simple: just mix PPh3, the aldehyde, and the acetylenic ester in hot PhMe. After about 5 minutes add the tryptamine followed by CSA and heat the mixture for another 5 to 30 minutes.

[1] For all of you admiring cascade reactions I must recommend this review by Nicolaou (for all those who did not read it yet): DOI: http://dx.doi.org/10.1002/anie.200601872
[2] The authors state that even they did not expect the last steps to happen. But some of the substances they got are very active in interfering with the mitosis of cancer cells.

Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B

Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B

John C. Jewett and Viresh H. Rawal

DOI: http://dx.doi.org/10.1002/anie.201003361

Further read: DOI: http://dx.doi.org/10.1002/anie.200701677

and                 DOI: http://dx.doi.org/10.1021/ja050728l

Sorry for the long delay but now I am back into business. This time with a nice synthesis from Rawal et al. who already synthesized this sweety but only in a racemic fashion. Obviously they accomplished the stereoselective synthesis in the last few months by applying an interesting methodology which made it possible to retain the stereochemistry at the carbon center marked with a little star.

Scheme 1

By virtually cutting the molecule into two halves one gets the known natural product pederic acid and the so called mycalamine. Rawal et al. already published a total synthesis of pederic acid which I will refer to later. Mycalamine is not natural product by itself but named after the parent compound.

For the biologists out there: mycalamide B displays some antiproliferative activities against various cancer cell lines which make it an interesting target for many working groups.

I will start this brief review with the synthesis of pederic acid which was published some years ago. It starts with an esterification of the known alcohol shown and protected glyceric acid in the presence of EDC/DMAP. Petasis methylenation then furnished the required exo-methylene group ready for a nice Wacker-type cyclization which closes the THP-ring. The benzylidene protection group was removed under Birch conditions, the more acidic primary alcohol protected as a TES-ether and the remaining one as a benzoylester. PDC oxidation furnished the benzoylpederic acid which was transformed into the acid chloride under standard conditions in quantitative yield.

Scheme 2

Next the second half of the molecule, mycalamine, has to be synthesized. They started with a copper mediated epoxide ring opening, TIPS protection of the free alcohol and oxidative cleavage of the methylene group to the aldehyde. A stereoselective Diels-Alder reaction under Yamamoto’s conditions was done by employing MAD as the catalyst which was prepared in situ from AlMe3 and the corresponding alcohol. During work-up the TIPS was cleaved off and the alcohol methylated. Then my favourite reaction took place:

A Mukaiyama/Michael reaction of the silylketene acetal with the unsaturated ketone in the presence of TBSOTf gave a TBS protected enol which was directly epoxidized with mCPBA (Rubottom oxidation). The MOM group was cleaved, the epoxide opened and both connected in a 1,3-dioxane ring.

Scheme 3

The coupling partner of the above mentioned Diels-Alder reaction is available in two steps from methyl formate and iso-pentanone as showed below.

Scheme 4

Next the ketone was reduced by employing the very old-school Meerwein-Ponndorf-Verley reduction. Other reduction systems gave mainly the alcohol with the wrong stereochemistry. The alcohol was methylated in methyliodide in the presence of silver oxide.

Scheme 5

Debenzylation, saponification and subsequent Curtius rearrangement gave the cyclic carbamate by trapping of the intermediary isocyanate with the free alcohol. And this cyclic carbamate gave the group the opportunity to couple both halves without racemization of the stereocenter marked. The carbamate was deprotonated and reacted with pederic acid chloride to give after selective debenzoylation and carbamtate cleavage mycalamide b in 14 steps in the longest linear sequence and with 3% overall yield.

Dude, what a nice synthesis… And if I counted right 11 named reactions were used… So if you have any questions or suggestions feel free to ask. THX for reading my stuff…

Catalytic Enantioselective Total Syntheses of Bakkenolides I, J, and S: Application of a Carbene-Catalyzed Desymmetrization

Catalytic Enantioselective Total Syntheses of Bakkenolides I, J, and S: Application of a Carbene-Catalyzed Desymmetrization

Eric M. Phillips, John M. Roberts, and Karl A. Scheidt

DOI: http://dx.doi.org/10.1021/ol100938j

“The bakkanes are a large class of sesquiterpene natural products containing a characteristic cis-fused 6,5-bicyclic core”. They possess a wide variety of biological activity for example antifeedant effects, platelet aggregation inhibition and presumably some activity against various cancer cell lines. Some total syntheses were published to date but this one catched my eye because of the nice methodology presented here. As you might know, NHC (N-heterocyclic carbene) catalyzed reactions can be used in analogy to nature’s TPP-catalyzed aldol reactions, e.g. in the Strecker reaction. Further examples are the use of NHC’s as ligands in metathesis reactions, Suzuki- and Buchwald-cross couplings or, as presented here, in an enantioselective synthesis of β-lactones.

It’s a rather short synthesis but with two cool key steps presented separately. First the three guys which were synthesized:

Scheme 1

As you can see with the core of Bakkenolide S in hand the remaining two are easily made.

The synthesis starts off with a Tsuji-Trost reaction giving them the allylic alcohol which was oxidized with BAIB in the presence of TEMPO to the unsatured aldehyde (why didn’t they use manganese dioxide?). This was cyclised to the β-lactone employing the group’s own chemistry with a good yield and excellent enantio- and diastereoselectivity.

Scheme 2

The mechanism looks like this:

Scheme 3

As in the Strecker reaction the NH-carbene (in situ produced with Hünig’s base) attacks the aldehyde and forms after loss of the α-proton an unsaturated enolate. This is re-protonated with enol formation and reformation of the positively charged NH-ligand. Subsequent enantio- and diastereoselective aldol reaction gave the tertiary alcohol which reacts with the strongly activated ketone to give the β-lactone under catalyst recovery. NICE…

With the key intermediate in hand the group removed the lactone in the presence of silica gel to give the olefin and carbon dioxide. Dioxolane formation was followed by stereoselective boronation/oxidation to the alcohol followed by deprotection of the ketone and TBS ether formation. Wittig reaction to the terminal olefin and isomerization with Crabtree’s catalyst gave the trisubstituted internal alkene.

Scheme 4

Reduction of the alkene, de-silylation and DMP-oxidation then furnished the ketone shown. Deprotonation was accomplished with LDA, the resulting enol reacted with Mander’s reagent and the methyl ester transesterified with propargyl alcohol. The prepended isomerization of the terminal olefin proved to be necessary because direct reduction under various conditions didn’t produce the expected product.

The following step presents again a nice methodology which I will present to you separately.

Originally the group planned to produce the δ-lactone via a Conia-ene reaction (http://www.organic-chemistry.org/namedreactions/conia-ene-reaction.shtm) but this attempt was unsuccessful. Nevertheless by reacting the propargyl ester with Mn3+ the lactone was formed in very good yield with excellent diastereoselectivity.

Reduction of the ketone and subsequent isomerization of the lactone then produced Bakkenolide S.

Scheme 5

The mechanism of the lactone formation might be this one:

Scheme 6

First a SET oxidation by manganese to give the strongly stabilized radical which reacts after rotation of the ester group with the alkyne moiety to give the 5-exo-dig radical.

Further info about this kind of reactions can be found here: Chem. Rev. 1996, 96, 339-363

To the end, ester formation with the corresponding acid chloride gave Bakkenolide I and J.

Scheme 7

Overall a nice synthesis in which a lot of interesting methodology was employed. If you’re interested in further reactions catalyzed by this NHC’s have a look in the references.

THX for reading my stuff J

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I received a question on the isomerization step so here’s the mechanism for this transformation:

Scheme 8

The TBAF acts as a base and deprotonates the alcohol. This undergoes a retro aldol reaction followed by bond rotation of the latone and reverse aldol reaction to give the final product.

Stereoselective Phosphine-Catalyzed Synthesis of Highly Functionalized Diquinanes

Stereoselective Phosphine-Catalyzed Synthesis of HighlyFunctionalized Diquinanes

Jonathan E. Wilson, Jianwei Sun, and Gregory C. Fu

DOI: http://dx.doi.org/10.1002/anie.200905125

While reviewing a nice paper from Overman I found this sweet one from Greg Fu and decided to present this to you first.

What we got here is a subsequent investigation of a procedure already published by Tomita et al. featuring a novel Baylis-Hillmann-like cyclization cascade:

The blue compounds represent the paper from Tomita et al., the red ones the paper featured in this review.

The reaction sequence is induced by the addition of about 20 mol% of tributylphopshine in a DCM/ethyl acetate mixture at room temperature to the starting material.

First a Michael addition of the phosphine to the alkyne yields an allenyl enolate which rapidly tautomerizes to an α-β-unsatured enolate. Next a Michael addition to the unsatured ester gives an ester enolate which reacts with the vinyl phosphine cation to from an ylide. This in turn yields after some tautomerization and catalyst regeneration the product:

The diastereoselectivity can easily be seen from the transition state:

Having established the right reaction conditions the group prepared some derivatives with the yields varying from 54% up to 89% respectively. Also the first formed 5 membered ring could be expanded to a 6 membered one without significant loss in yield.

And some studies towards further reactions of the produced diquinanes were employed featuring a Grignard reaction, Luche-reduction and Pd catalysed hydrogenation all in excellent diastereoselectivity:

Attempts to develop enantioselective reaction conditions by using a chiral phosphine gave very promising results:

On balance a nice reaction with some potential in natural product synthesis. What do you think?