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

 DOI: http://dx.doi.org/10.1002/anie.201200387

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.
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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.

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.

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

DOI: http://dx.doi.org/10.1021/ol102709s


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

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

DOI: http://dx.doi.org/10.1021/ja100178u

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?

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

_______________________________________________________________________________________

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.

A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural Products Spicifernin and Pulvilloric Acid

A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural Products Spicifernin and Pulvilloric Acid

Christopher F. Bender, Francis K. Yoshimoto, Christopher L. Paradise, and Jef K. De Brabander
DOI: http://dx.doi.org/ja905387r

Hey fellas,

really good stuff was published the last months and it was difficult to make a decision

… so I chose a synthesis from the De Brabander group published in July.

Though total syntheses from the Snider and Fürstner groups were published in 2008 and 2009 respectively there is always room for improvements because it shows some interesting biological activity:

Berkelic acid possesses selective activity against human ovarian cancer cells so a support of synthetic material is needed for further studies. Interestingly the true structure of berkelic acid was unknown until the synthesis from the Snider group in 2009.

Synthesis:

To shorten my review I will focus on the key step but discussions about specific reactions are welcome (I’m still trying to improve my style).

Retro:

retro_051109

The group recognised the fact that berkelic acid might be formed by a DA reaction of the already known compounds spicifernin and pulvilloric acid whose total syntheses were published some years ago.

Synthesis of the red fragment:

scheme_1_051109

A tBu-Valine enamine directed alkylation was followed after hydrolysis by a TiCl4 promoted aldol reaction giving the required α-β-unsatured ketone. A copper catalysed, anti-selective Michael addition with TMS-butyne, TMS and PMB-ether cleavage then gave the red fragment in good overall yield.

Synthesis of the blue fragment:

scheme_2_051109

A regioselective triflate formation/Suzuki-Miyaura reaction yields the symmetrical bis-hydroxy acid which was protected as the MOM-ether, epoxidized and hydrogenated at the benzylic position to give the racemic alcohol shown. Stereoselective Lipase catalysed acetylation of the R-alcohol and Mitsunobu reaction of the other enantiomer gave the required fully protected dihydroxy benzoic acid. Deprotection and exposure to TEOF/TFA yields the blue fragment through an oxo-Pictet-Spengler reaction again in an overall excellent yield.

Key step:

scheme_3_051109

Combining the 2 fragement in the presence of AgSbF6 produced berkelic acid methyl ester and additional diastereomers which could be separated after deprotection with (Bu3Sn)2O.

Mechanism:

mechanism_051109

3,5eq of AgSbF6 were required for the last transformation which can easily be seen from a mechanistic analysis:

The first equivalent produces the exo-methylene tetrahydrofuran, the second equivalent acts as a Lewis acid and oxidises the aromatic ring by cleaving the ethyl acetal. After formation of the required quinone methide the third equivalent catalyses the [4+2] addition yielding berkelic acid as the main diastereoisomer.

Nice work and sorry for the late review; I printed it some months ago but hm… it got lost 🙂