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 S_N2’-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

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

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/S_N2 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 S_N2 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.