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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A Concise Total Synthesis of (-)-Maoecrystal Z

A Concise Total Synthesis of (-)-Maoecrystal Z

Jacob Y. Cha, John T. S. Yeoman, and Sarah E. Reisman

DOI: http://dx.doi.org/10.1021/ja2073356

Recently I stumbled onto this excellent paper from the Reisman group. While reading the paper I wondered if I ever reviewed one of their total syntheses because of the very appealing tactics employed by the group. By checking my archive I found the review of salvileucalin B … Nevertheless here is another excellent piece of work from this young research group featuring the total synthesis of Maoecrystal Z.

The retro is shown below.

Scheme 1

 

Some functional group manipulations led to a diol which was disconnected with respect to a radical cyclization cascade of the corresponing bisaldehyde. This in turn derived from a spirocyclic precursor which can easily be synthesized from a known cyclohexane derivative.

Though the paper starts from 3 the synthesis of this intermediate can be found in two older publications. The synthesis begins with the condensation of methylmalonate and mesityl oxide followed by conversion of one of the resulting ketones into a vinyl chloride with PCl3 and reduction of this into cyclohexanone 1. Wittig olefination, mild ester hydrolysis and resolution with (R)-phenylethylamine gave acid 2. Esterification with diazomethane and reduction with LAH then gave (-)-γ-cyclogeraniol 3 in good overall yield.

Scheme 2

 

Going on with the synthesis the alcohol was silylated and the exo methylene group epoxidized with mCPBA. Now to the first key step of the synthesis: a nice lactone formation through a radical promoted cyclization employing a protocol devised by the Gansäuer group. The mechanistic details are discussed at the end. According to the paper the use of the trifluoroethyl ester was required in contrast to the normally employed ordinary alkyl esters.

 Scheme 3

With fragment 5 in hand the group turned their attention onto the synthesis of alkylating agent 9. Pentenoic acid was reacted with pseudoephedrine, and alkylated under Myer’s conditions to give 8 in high yield and dr. Reductive removal of the auxiliary and Appel iodinaton then gave 9.

 Scheme 4

 

Both fragments were combined via enolization of 5 with LDA in the presence of HMPA followed by the addition of 9. Next a double bond was introduced through selenation/selenoxide elimination. Global desilylation with H2SiF6 and Dess-Martin oxidation then gave bisaldehyde 11. This cyclizes with some help from SmI2 (Kagan’s reagent) to give 12 in good yield. Remarkably during this process two new rings and four stereocenters were formed in a highly selective manner. Again the mechanistic rationale is discussed later in this review.

 Scheme 5

 

Protection of the free hydroxy groups with acetic anhydride catalyzed by TMSOTf furnished lactone 13. To the end ozonolysis of the terminal olefin, exo-methylene introduction with Eschenmoser’s salt and selective mono-deprotection produced Maoecrystal Z in moderate yield. The major problem the end of the synthesis posed was the selective acetylation of 12. Acetylation was not possible under various conditions without rearrangement processes or different monoacetylation products.

 Scheme 6

 

As promised here is the mechanistic understanding of the lactonization process: reductive opening of the epoxide gave a tertiary radical which attacks the acrylic acid ester. The resulting ester then cyclizes spontaneously under the reaction conditions.

 Scheme 7

 

The latter cyclization of the bisaldehyde can be explained with the scheme shown below. As usual SmI2 produces a ketyl radical from the less sterically hindered carbonyl functionality. 6-endo-trig cyclization closes the first ring and provides an enoyl radical which is reduced by a second equivalent of SmI2 to give the corresponding enolate. Aldol reaction with the remaining aldehyde closes the second ring to give 12.

 Scheme 8

Very nice work… And very straightforward. I really like the two key steps because of their efficiency and their rareness.

THX to Bobby for proofreading.

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.

Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Stephen Hanessian, Nicolas Boyer, Gone Jayapal Reddy, and

Benoıˆt Descheˆnes-Simard

DOI: http://dx.doi.org/10.1021/ol901896c

Another sweet paper from the Hanessian group published in August featuring a bunch of nice biological active compounds. Especially Oidiolactone B exhibits an impressive activity against interleukin-1β which could potentially be used for treatment of inflammatory diseases (http://en.wikipedia.org/wiki/Interleukin).

Only a handful of syntheses have been published yet each featuring only one target, this paper disloses the syntheses of 7 members of this class of compounds starting from one common precursor. Pretty amazing I think and very atom economic…

They planned to install the C ring at least and decorating the starting decaline core with some well established methods for example a sweet Reformatzky and Baylis-Hillmann reaction, both a bit underdeveloped in total synthesis.

Scheme 1

scheme_1_061009

So let’s get started with this:

Scheme 2

scheme_2_061009

First some protection and then a nice radical conjugate reduction under Birch conditions quenched with Mander’s reagent to give the methoxycarbonyl side chain in good yield and dr (which is unimportant because it is destroyed in the next step). Triflate formation and Stille like reduction gave them the unsatured ester which was again reduced with single electron transfer as I suppose (or maybe by facial selective hydrogen addition?), followed by alkylation and deprotection. A highly efficient IBX mediated dehydrogenation was followed by deprotection of the ester to give the blue intermediate. Didn’t know the IBX dehydrogenation method, I would have used a Saegusa type reaction but this one seems to be more practical.

With this intermediate in hand they were able to prepare the key intermediate shown above in only 5 more steps:

Scheme 3

scheme_3_061009

A highly efficient phosphine catalysed Baylis-Hillmann reaction with formaldehyde was followed by a bromolactonization to close the D ring lactone through the shown transition state. TES protection and a nice catalytic Reformatzky reaction furnished the key intermediate in an impressive overall yield of 17% over 14 steps.

The biggest problem poses the dehydration to form the exomethylen ester group. This problem was solved employing Burgess reagent to dehydrate the hydroxy function off the ring.

Scheme 4

scheme_4_061009

After having the dehydration problem solved they commenced with HF mediated deprotection/ in situ lactonisation followed by DMDO epoxidation to give Oidiolactone C.

To improve the yield they switched the order of events and got the product in a much better yield. With the epoxidated decaline in hand a mild TES deprotection by CSA, DMP oxidation and strong acid catalysed lactolisation gave then a mixture of epimers of Oidiolactone D.

This was methylated to give Oidiolactone A.

Having these three in hand only 3 more to go:

Scheme 5

scheme_5_061009

Starting with the already employed CSA mediated deprotection and DMP oxidation, followed by Burgess dehydration and acidic lactolisation to give the fourth natural product in this paper. A described access to Nagilactone F through isopropylgrignard addition gave only low yield and moderate diastereoselectivity, so they worked their way through a more commonly isopropylengrignard reaction reaction followed by a modified Wilkinson reduction to give Nagilactone F in a much better yield and diastereoselectivity. Oidiolactone B, the most potent member of this class, was easily accessible by methyl acetal formartion and separation of the desired major isomer.

Overall a nice paper which discloses a bunch of total syntheses in only 4 pages 😉

You are advised to have a look in it. I enjoyed most the smooth preparation of the key intermediate.

Any comments?