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.

Synthesis of Undecachlorosulfolipid A: Re-evaluation of the Nominal Structure

Synthesis of Undecachlorosulfolipid A: Re-evaluation of the Nominal Structure

Christian Nilewski, Nicholas R. Deprez, Thomas C. Fessard, Dong Bo Li, Roger W. Geisser, and Erick M. Carreira

 DOI: http://dx.doi.org/10.1002/anie.201102521

This time I will present to you a real beasty of a molecule. It belongs to the class of the chlorosulfolipids which gained some synthetic interest in the last few years. Their biological profiles combined with the low supply of material drives researchers to produce some quantities for biological evaluation. Nevertheless from a synthetic point of view the development of asymmetric halogenation reactions is a growing field which can be further examined during the synthesis of such complex tasks.

The most complex member of the chlorosulfolipids looks like this:

 Scheme 1

As can be seen from the structure it contains no less than 15 stereocenters of which 9 are contiguous and 9 are chiral chlorine atoms. In the light that only a handful of tactics for asymmetric chlorination reactions are known to date this is an extremely challenging task.

We start off with two precursor molecules whose syntheses are described in the supporting material which I highly recommend for reading because it contains a lot of useful information about NMR analysis of chiral chlorine bearing carbon atoms.

 Scheme 2


The first intermediate stems from commercially available (S)-1,2,4-butanetriol 1 which was protected as the acetonide, coupled under Mitsunobu conditions with phenyltetrazolylsulfide which in turn was oxidized to the sulfone. Julia-Kocienski olefination gave a mixture of E/Z-isomers which were isomerized to the major E-isomer under photolytic conditions to give 4.

The more reactive g,d-olefin was dichlorinated with tetraethylammonium trichloride with a d.r. of about 1.8 / 1 which can be further enhanced after epoxidation because of the easier separation of diastereomers. DiBAl-H reduction of the ester was followed by acetylation of the alcohol, stereoselective Sharpless dihydroxylation, and regioselective epoxide formation upon treatment with triflic anhydride. The overall yield of this sequence is only 9 % but during these five steps four of the fifteen stereocenters are formed.

5 was subjected to acetonide cleavage conditions and the resulting diol was protected as the bis-TBS ether of which the primary alcohol was again set free with HF – pyridine to give 6. Oxidation of the terminal alcohol to the aldehyde and Wittig olefination with phosphonium salt 12 gave 13 whose double bond was again dichlorinated to give after deacetylation compound 14.

 Scheme 3


Fragment 12 stems from two commercially available building blocks. On one hand ethyl lactate was protected and selectively reduced to aldehyde 7 while on the other hand propanediol was monoprotected and iodinated under Appel conditions to give iodide 8. Diastereoselective alkylation with the lithium reagent derived from 8 then furnished alcohol 9 which in turn was benzylated, and converted after selective monodeprotection into iodide 11 which gave Wittig salt 12 in the presence of triphenylphosphine.

 Scheme 4


The second half of the molecule derived from pentanediol. Monoprotection, Ley oxidation and dichlorination with NCS produced aldehyde 15. Next asymmetric alkynylation under Carreira’s conditions gave 16 with excellent enantioselectivity. Semireduction of the alkyne and hydroxy directed epoxidation of the trans-alkene necessitated DMP oxidation of the alcohol because no suitable conditions for selective epoxide opening could be identified. Thus ZrCl4 mediated epoxide opening of 16a and stereoselective reduction of the ketone gave diol 17.

To the end the diol was protected as an acetonide, the TBDPS group removed, the terminal alcohol oxidized, and reacted with Still-Gennari modified HWE reagent A to yield 18.

 Scheme 5


Going on with the synthesis ester 18 was successively reduced and the resulting allylic alcohol exposed to Sharpless asymmetric epoxidation reaction conditions. The epoxide was then regioselectively opened to give diol 19. Acetonide formation and debenzylation was followed by Mitsunobu coupling and oxidation to yield sulfone 21.

 Scheme 6


Fragments 14 and 21 were coupled under Julia-Kocienski conditions after prior DMP oxidation of the terminal alcohol of 14. Subsequently the epoxide of the intermediate was opened with PPh3Cl2 to give alcohol 22. Stereoselective dichlorination of the double bond then gave 23.

 Scheme 7


To the end 23 was debenzylated and the resulting alcohol used as a handle to introduce a double bond with Martin sulfurane. TBS removal and selective esterification with palmitoyl chloride gave protected Undecachlorosulfolipid 25.

Scheme 8

Conversion of 25 into Undecachlorosulfolipid was then accomplished first by sulfate introduction with SO3 in DMF followed by acetonide cleavage with TFA.

Scheme 9

With a few µg of Undecachlorosulfolipid A in hand the group compared the analytical data of their lab work to the reported data and noticed that the compounds were not identical. Especially the assignment of the ester bearing hydroxy group caused some problems. It was assumed that the stereochemistry should be R instead of S.

Well… nevertheless congratulations to the group to get this synthesis to work. Hopefully there will be a full account of this work showing all their tactics.

THX to Bobby for proofreading!

Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin

Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin

Scott A. Snyder, Zhen-Yu Tang, and Ritu Gupta

DOI: http://dx.doi.org/10.1021/ja9014716

Hello again! It’s almost a month ago since my last post so I decided to dig out this short synthesis with some nice new chemistry in it as mentioned in the headline.

This time an interesting halogenated natural product (chosen to demonstrate their powerful method) with only 3 stereocenters of which 2 were captured by chlorine. This class of Napyradiomycins exhibit antibacterial activity against methicillin- and vancomycin-resistant strains and some anti tumour activity (some infos about MRSA can be found here: http://en.wikipedia.org/wiki/Antibiotic_resistance).

Only one total synthesis is known which yielded only a racemic mixture of Napyradiomycin A1 so here comes the second one. The retro looks like this:

Scheme 1


They planned to use the isolated olefin for their asymmetric chlorination, install the alcohol and rearrange it to build up the allylic chain on the benzoquinone ring system. It was further planned to cyclise the bis-unsatured chain to get Napyradiomycin B4 but these results will be presented in a follow up publication.

The basis of the synthesis is flavion which was synthesised earlier by other groups in a relatively long 8 step reaction sequence. They shortened it by heating the sulfonic acid salt in an alkali fusion and let the air do the rest.

Scheme 2


The resulting flavion was reacted with methyl crotonaldehyd under acid catalysis to give the ABC-ring system via a tandem Knoevenagel/6-π-electrocyclization followed by protection of the non-conjugated hydroxy function. The resulting tetrahydropyran fused ring system was exposed to the chlorination conditions which yielded the expected product in 87% yield with 93% e.e. after crystallisation. The conjugated chlorine was changed to an acetate with retention of configuration and after protection of the other hydroxy function and acetate cleavage, the second key intermediate was readily prepared.

The key step in this scheme is the asymmetric chlorination of the olefin:

4 eq of the previously synthesised ligand were reacted in THF with BH3 and AcOH. After solvent removal, the intermediate was added in THF, followed by chlorine which was bubbled through the solution. A transition state was formulated which look like this:

Scheme 33_070509

Details can be found in the supporting information. Then they installed the hydroxy function with retention of configuration:

Scheme 4


The adjacent carbonyl function may act as an electron pair acceptor throughout the whole addition/elimination reaction. The in situ formed SmI2 acts as a Lewis acid and removes selectively the acetyl protecting group.

The second half of the synthesis starts with a Johnson-Claisen rearrangement followed by a conjugate reduction with KHBPh3 as the reducing agent. It’s the first time I met a reagent for this kind of reduction without making use of a copper containing reagent.

After ester reduction and re-oxidation with Dess-Martin periodinane the resulting aldehyde was used for a Wittig-olefination.

The second chlorine was introduced stereoselectively with NCS and the protecting groups cleaved with MgI2 and PPTS to give enantiomerically pure Napyradiomycin A1.

Scheme 5


The supporting information also features a synthesis of the ligand used in the asymmetric chlorination if you’re interested in trying it by yourself.

So that’s it for the moment. Suggestions are welcome.