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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Scalable Total Synthesis of (-)-Berkelic Acid Using a Protecting-Group-Free Strategy

Scalable Total Synthesis of (-)-Berkelic Acid Using a Protecting-Group-Free Strategy[1]

Francisco J. Fananás, Abraham Mendoza, Tamara Arto, Baris Temelli, and Felix Rodriguez

 DOI: dx.doi.org/10.1002/anie.201109076

Berkelic acid is a rather old target to the synthetic community and three total syntheses have been published to date. Interestingly the material provided by synthesis produced contradictory biological results compared to earlier studies. So besides showing the power of their methodology the group planned to provide enough material for refined studies.

 Scheme 1

As can be seen from scheme 1 the group planned to construct almost the whole framework in one single step after disconnection of the side. It should be noted that the group has some experience with this kind of cascade transformations of which they can rely on. Nevertheless instead of employing palladium catalysts the group turned their attention to silver catalysis. With this cascade reaction in mind they hoped that the stereogenic methyl group would control the stereoselectivity of the whole transformation.

The three key building blocks were prepared in a straightforward manner. Starting from commercially available butynol 1 the hydroxy functionality was mesylated and replaced by diethylmalonate to give after complete reduction diol 2. Starting from ester 3 the second fragment was prepared by triflation of the least hindered hydroxy group followed by Suzuki cross coupling with the trifluoroborate of heptyne. Hydroxy-directed reaction with formaldehyde and subsequent oxidation produced ester 4. The last building block stems from dimethyl malate which was doubly alkylated in the first place. Then the a-hydroxy ester was used for a periodate cleavage followed by cyanohydrin formation which was catalyzed by PNPCl.[2]

 Scheme 2

 

Combination of the red fragment 2 and orange fragment 4 was accomplished in the presence of 5 mol% silver(II). Subsequent hydrogenation of the resulting double bond yielded 7 in good yield and diastereoselectivity favoring the desired one. Appel reaction under standard conditions was followed by cyanohydrin alkylation and unmasking of the ketone to give protected Berkelic acid 9. Small amounts of Berkelic acid can be produced in good yield by selective saponification of the more active ester. This was only done when material was needed for testing or analysis as the natural product is a short-lived compound.

 Scheme 3

 

The mechanism of the cool key step is presented below. On one hand the red fragment underwent a 5-exo-dig cyclization thus desymmetrizing the propanediol moiety to give after protodemetallation a tetrahydrofuran ring. On the other hand the carbonyl of the orange fragment underwent a 6-endo-dig cyclization. Supported by keto-enol tautomerism of the hydroxy functionality an ortho-quinone methide is formed. Michael addition of the enol ether from the red fragment onto the quinone methide was followed by acetal formation by the phenol. Hydrogenation of the newly formed double bond then gave intermediate 7.[3]

 Scheme 4

 

[1] I was pointed to the title which says “[…] protecting-group-FREE strategy”… I am not particularly sure how they got the title but I see almost two protecting groups: the TES-cyanohydrin and one of the methyl esters. Maybe the title refers to the neat cascade reaction in which no protecting groups are necessary…

[2] It is the first time I ever saw this reagent in action. It is usually used for halogenation reactions. The cited paper in this step found that in the presence of PNPCl the cyanohydrin formation is much faster which was ascribed to an activation of the carbonyl oxygen by the high oxophilicity of phosphorous.

[3] At first sight one might think of a Diels-Alder reaction. But brief examination of the stereochemistry on the newly formed pyran ring shows that only a stepwise mechanism can form this particular anti-substitution pattern.

Addendum: If you are interested in earlier studies of the group you should have a look into these two papers

Big THX to Bobby for proofreading.

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.

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

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.

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.

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

DOI: http://dx.doi.org/10.1021/ol902840x

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: http://dx.doi.org/10.1016/j.tetlet.2008.11.106

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.