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.

Total Synthesis of Tulearin C

Total Synthesis of Tulearin C

Konrad Lehr, Ronaldo Mariz, Lucie Leseurre, Barbara Gabor, and Alois Fürstner

 DOI: http://dx.doi.org/10.1002/anie.201106117

Tulearin C is at first sight a rather simple polyketide natural product. Only seven stereocenters of which only four are contiguous and none of them is quaternary. Nevertheless no useful route to this compound has been established to date despite some potential antiproliferative action against human leukaemia cell lines.

The group around Fürstner built their synthesis upon a RCAM (ring-closing alkyne metathesis) with subsequent trans-selective hydrosilylation/protodesilylation to get the trans alkene. This critical feature was the major problem of earlier approaches which relied on a trans selective RCM which instead gave a mixture of trans and cis alkenes of virtually 2 : 1.

 Scheme 1


Breaking down the molecule into two halves the group reduced the problem to the common starting unit 1. This glutarate monoester is available in large quantities from dimethyl-3-methylglutarate.

Desymmetrizing saponification of one of the ester groups with a pig liver esterase (PLE) and further enhancing ee by crystallization of the crude acid with cinchonidine gave ester 1. You should have a look in the SI how they did this interesting saponification. After formation of the lithium salt the ester was reduced to the alcohol and cyclized to give lactone 2. Wittig reaction then furnished dichloride 3 which was reacted with excess methyl lithium to give alcohol 4 and after DMP oxidation aldehyde 5.

The key transformation of this scheme is detailed at the end.

Scheme 2

Aldehyde 5 then underwent stereoselective alkynylation under Carreira’s conditions to give diyne 6. Regioselective reduction of the internal alkyne and quench with iodine was followed by silylation of the free alcohol. The excellent regiocontrol can be ascribed to the alcohol function which guides the Red-Al to the correct end of the triple bond. Palladium catalyzed methylation and subsequent desilylation then furnished the green fragment. Direct introduction of the methyl group in the hydrometallation step with Red-Al did not produce any product at all.

Scheme 3

As mentioned above the synthesis of the second fragment commenced with key intermediate 2. Claisen reaction with ethyl acetate and reduction of the resulting dicarbonyl compound gave diol 9. Protection of the primary alcohol was necessary to get the following methylation done. MOM-protection of the secondary alcohol produced ester 10. After desilylation of the TBDPS group an Appel reaction of the free alcohol furnished iodide 11

Scheme 4

The second half of the red fragment was synthesized from butynol. Hydrozirconation with Schwartz’ reagent in the presence of DiBAl-H and iodine quench was followed by triflation and alkynylation to get iodide 12.

Scheme 5

Both parts were combined by first generating the alkylzinc species from 11 which underwent a Negishi coupling with iodide 12. Sharpless dihydroxylation and subsequent MOM cleavage was followed by global TBS protection and saponification of the ester grouping.

Scheme 6

Esterification of 15 with 8 was accomplished with EDC in almost quantitative yield. RCAM with catalyst C was done in toluene in excellent yield although some heating was necessary. Trans-selective hydrosilylation gave lactone 17 from which the siloxy group was removed with AgF. TBS removal under standard conditions then produced Tulearin C.

Scheme 7

And here are the details concerning the formation of key fragment 4. It is some kind of Grob fragmentation and I would compare it to the well known Eschenmoser fragmentation. Two possible reaction pathways are shown in the paper of which the left one is preferred.

As can easily be seen from the scheme the first step is a metal-halogen exchange to give a carbenoid-like carbon atom. The next step might on the one hand be an intramolecular E2-reaction to give the acetylenic chloride which undergoes another metal-halogen exchange and subsequent alkylation with in situ formed MeCl (blue arrows).

Or alternatively the vinyl-lithium species is alkylated with in situ formed MeCl before the second chloride atom undergoes a metal-halogen exchange and further fragmentation (green arrows).

Independent of the intermediates the same product is formed in good yield. In the original paper some applications of this transformation are shown and a detailed investigation of the mechanism and further application are underway. Also two examples are shown in which allenes instead of alkynes are formed.

Scheme 8

As usual exceptionally good stuff from the Fürstner group.

And big thanx to Bobby for proofreading.

Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Allen Y. Hong, Michael R. Krout, Thomas Jensen, Nathan B. Bennett, Andrew M. Harned, and Brian M. Stoltz

DOI: http://dx.doi.org/10.1002/anie.201007814

Recently a very cool methodology was published developed by the Stoltz group for the synthesis of acylcyclopentenes . As given in the paper a lot of natural products are related to this motif so there is a need for an easy and rapid access.

Scheme 1

As can be seen from the structures given these natural products mainly derive from the MVP-pathway. Nevertheless this method should also prove useful in the synthesis of alkaloids or polyketides.

Before I present to you the main part of the paper have a brief look at the synthesis of the main precursor:

Scheme 2

Cyclopentanone 1 was enolized, protected as the TMS ether, and reacted with in situ generated dichloroketene to give cyclobutanone 3. Reductive dechlorination and Grob fragmentation/ether formation produced ketone 5 in good yield on a multigram scale.

This was then decorated with different organic residues in two steps to give ketoester 6 in moderate to good yield. Pd-catalyzed enantioselective decarboxylation/allylation was followed by reduction of the keto group to give 8. Depending on the residues three different reducing conditions are described. At last the critical contraction reaction from 8 to 9 was carried out with LiOH in THF in the presence of TFE in excellent yield.

Scheme 3

A lot of residues are described; I only added just a few to give a brief insight. For detailed information have a look in the more than 250 (!) pages thick supporting information.

The mechanism of the contraction step might look like this: the green proton leaves first and kicks out the red hydroxy group to produce directly the cyclobutanone-intermediate. This opens up with extrusion of the acetyl group to give after reprotonation and tautomerization the expected product.

If you think about the second possibility of first removing the blue proton followed by a Michael-type self-addition of the enolate, generated from deprotonation of the ketone, then you are missing the Baldwin rules (as I did at first sight).

Scheme 4

One of the many special examples which I picked out from the supporting information is the synthesis of the Hamigeran C core structure. Starting from cyclopentene 9 the terminal olefin was elongated with iodophenol in a Heck reaction to give 10. Chemoselective reduction of the styrene double bond and triflate formation was followed by another Heck reaction employing Herrmann’s catalyst to give tricyclic compound 13. First time I have seen Herrmann’s catalyst, funny German name.

Scheme 5

Nice methodology as usual from the Stoltz group. Any comments?

And special thanks to Bobby for proofreading my post in advance!

Total Synthesis of Cyathin A3 and Cyathin B2

Total Synthesis of Cyathin A3 and Cyathin B2

Part II – Retro schemes from Snider and Trost

As requested (from krest17) here are the two retro schemes from the Snider and Trost groups.

If you are interested in getting further details you find the links to the syntheses in the header.

(I prefer the one from the Trost group, again very cool transition metal chemistry)

Snider’s synthesis : http://dx.doi.org/10.1021/ja9615379


Trost’s synthesis: http://dx.doi.org/10.1021/ja0435586


I skipped the details but if you want to we can discuss them here…

Total Synthesis of Cyathin A3 and Cyathin B2

Keunho Kim and Jin Kun Cha

DOI: http://dx.doi.org/10.1002/ange.200901669


This time two diterpene natural products which were first isolated in the 1970’s by Ayers and co-workers and subjected to a number of total syntheses. If you’re interested, some older syntheses can be found from the Snider and Trost group during which the starting material for this approach was synthesied.
Before you ask why they did another synthesis of these two molecules one should remember the significant biological properties which lay in the stimulation of nerve growth factors and can therefore be used as models for synthetic analogues.
And because it’s another cool approach…

So let’s begin with the retro (I do like paper were they put in their retro… less work for me):


They planned as the key step a Prins-pinacol like tandem reaction (a reaction sequence used extensively by the Overman group) followed by a RCM reaction. The starting cyclopropanol originates from a known ester, synthesised from the Snider group in their earlier approach through a Kulinkovich reaction. This named reaction was new to me but is obviously a very useful manipulation.
So here the first scheme:

Scheme 1


We start with the above mentioned Kulinkovich reaction (the mechanism can be found in detail under the link) followed by TMSCl addition to give the cyclopropanol-TMS ether. This was reacted with dimethoxy-2-bromoethane to give after reductive elimination the intermediate cyclobutanone product. The interesting sequence here is the Prins-pinacol tandem sequence which I will present to you right now:


I suppose that the stereochemistry is fully controlled by the remote methyl group.

Next on a LHMDS induced aldolreaction with two various aldehydes was done followed by a Ti(iPrO)4 catalysed reaction similar to a Turbo-Grignard with the allylbromide shown. The resulting triene was used for a RCM to give the tetracyclic intermediate, ready for the second key step.

Scheme 2


They commenced with a radical thionylation ensued by a PPh3 * Br2 induced Grob fragmentation of the cyclobutanol to give the seven-membered unsatured ketone.
A mechanism is not given so here’s my proposal:


The styrene like double-bond was selectively dihydroxylated, cleaved with lead(IV)acetate and after decarbonylation using Wilkinson’s catalyst, realeased the quarternary methyl group.
Interestingly the PMB group cleavage gave better results than the Ph residue.

The sulfur was then oxidised using Davis oxaziridine and exposed to Pummerer rearrangement conditions (TFAA). This gives a mixture of products which were reacted without separation with acetic anhydride and mercury(II)trifluoroacetate to give in an overall yield of about 65% Cyathin B2.

Scheme 3


This could be converted to Cyathin A3 in 7 steps using standard chemistry which need no further explanation. Here the scheme:

Scheme 4


All in all another cool approach although not very atom economic. My favourites are the two presented key steps and the introduction of the methyl group through the styrene cleavage.
I would be thankful for every comment or suggestion. I’m looking forward to move this page to real .com-domain because it’s difficult to find this page with Google…

And if you’re interested in helping me with publishing reviews please send an eMail to synthetic.chemistry@googlemail.com. Help is always appreciated…

Development of a Formal [4 + 1] Cycloaddition: Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation and MgI2-Promoted VCP-CP rearrangement

Development of a Formal [4 + 1] Cycloaddition:

Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation of 1,3-Dienyl-Keto Esters and MgI2-Promoted Vinylcyclopropane – Cyclopentene Rearrangement

Rockford W. Coscia, and Tristan H. Lambert

DOI: http://dx.doi.org/10.1021/ja809226x

About half a year ago this interesting paper was published and is still in the list of the most viewed papers of the JACS so I decided to put in my two cents and give you a short overview. The overall reaction looks like this:

Scheme 1


As mentioned above the first step is a palladium catalysed cyclopropanation, which is the main investigation in this paper, followed by a vinylcyclopropane/cyclopentene rearrangement (VCP-CP) to give the cis-fused 5/6 ring system.

The first step involves a Mg(ClO4)2 induced enolisation with a simultaneously Pd(II) coordination to the 1,3-diene unit. The formed enol attacks the palladium complex to give the 6-membered ring. After another enolisation a fused cyclopropane is formed with concomitant reduction of the Pd(II) to Pd(0) which is reoxidised with the copper additive. While using Cu(OAc)2 as the oxidant a reductive elimination and a Saegusa type oxidation is observed due to a ligand exchange on the Pd(II) source, which can be overcome by changing the anion from acetate to iPrCO2. The reaction cycle is shown below:

Scheme 2


Some compounds which were produced during the investigation are given in the next scheme:

Scheme 3


The main drawback with this methodology is the need for a double substituted α-C to increase the yield and to prevent the above mentioned oxidation. Without these substituents the yield dropped to 52% (compound 3) but with complex starting materials the yield is still moderate (compound 4).

With these vinylcyclopropanes in hand a MgI2 induced ring opening/ring closure reaction was used to convert the cyclopropane to a cyclopentene.

The proposed mechanism is shown here:

Scheme 4


The Lewis acidic MgI2 attacks the acetyl acetate moiety and releases an iodide. This opens the cyclopropane on reaction with the terminal alkene in a concerted or stepwise manner to give the allyl iodide. A SN2 reaction of the enolate closes the ring again to give this time the thermodynamically favoured cyclopentene. This process gives generally good yields in contrast to the varying yield of the first step.

Some examples were produced to test again the scope of the methodology.

Currently the authors are working on a more general route to 1) extend the strategy to other nucleophilic moieties, 2) remove the need for gem-dimethyl blocking group, and 3) running the two reactions in one pot.

Maybe by using a chiral Lewis acid it should be possible to increase the diastereomeric ratio? In conclusion I think that this methodology has a great potential and I am interested to see its first application in a total synthesis.