Total Synthesis of Jiadifenolide

Total Synthesis of Jiadifenolide

Ian Paterson,* Mengyang Xuan, and Stephen M. Dalby*

DOI: http://dx.doi.org/10.1002/anie.201404224

As promised months ago here is the write-up of the second Jiadifenolide synthesis published this year. The main features of this synthesis from the Paterson group consist of a boron-aldol reaction and a neat SmI2 mediated radical cyclization. Though a racemic synthesis (like in the good old days) this route provides an efficient and highly selective access to Jiadifenolide.

The synthesis started with Luche reduction of cyclopentenone 1 which in turn was treated with mCPBA followed by TBS protection to give oxirane 2. In the presence of BF3 the epoxide rearranged to the corresponding ketone with excellent diastereocontrol. HWE reaction, LiAlH4 reduction and acylation then delivered allyl acetate 5. Silylketene acetal formation and subsequent heating in benzene resulted in Ireland-Claisen rearrangement to yield after another LiAlH4 reduction alcohol 6 in moderate yield. Hydrolysis of the TBS ether and global Swern oxidation finally furnished 7.

Scheme 1

 scheme_1_17102014

The remaining carbon skeleton was attached utilizing the boron enolate of lactone 8 followed by TES protection. Upon treatment with samarium diiodide the last quaternary center was formed giving tricycle 10 in good yield. A possible transition state is depicted below. Deprotection and PCC oxidation then delivered ketone 11. The hydroxyl group at the ring junction was then introduced by a Rubottom oxidation, the ketone subsequently reduced and protected. All that remained was dihydroxylation of the double bond, oxidation to the pyruvate and deprotection of the TES group to complete the synthesis.

 

Scheme 2

 scheme_2_17102014

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Total Synthesis of (-)-Dendrobine

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/SN2 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 SN2 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.

Total Synthesis of (+)-Daphmanidin E

Total Synthesis of (+)-Daphmanidin E

Matthias E. Weiss and Erick M. Carreira

 DOI: http://dx.doi.org/10.1002/anie.201104681

It is pretty hard to decide these days which synthesis should be reviewed. Luckily the great accomplishment of the Fukuyama group (Gelsemoxonine) has recently been reviewed on B.R.S.M so I chose the exceptional work done by the Carreira group at the ETH. It features a densely functionalized compound found in some leaves called
(+)-Daphmanidin E. The biological profile is rather unspectacular which can be explained with low supply of material.

As usual the Carreira group used some very interesting chemistry to build this beasty:

 Scheme 1

 

The synthesis features as one of the key steps a very cool Cobalt catalyzed Heck cross coupling reaction of an alkyl iodide. If you are further interested, as I am, take a look into this review (Chem. Rev. 2010, 110, 1435–1462).

Starting from known building block 1 which is available in racemic form by some really old procedure the group used chemoenzymatic resolution to get enantioenriched 1. I think this citation might be the oldest one I used to date. It is only available in german… I like this old stuff and the nice language they use.

Scheme 2

 

Because the supporting information was not online while I wrote this review I cannot give you the yield of the resolution step (maybe later…).

Going on with the synthesis the group first desymmetrized the C2-symmetric building block by an acetal formation. Triflate formation using Comin’s reagent then gave fragment 2. In situ hydroboration of TBDPS-protected allyl alcohol and Suzuki coupling in the presence of Ph3As as the ligand added the first side chain which was later used for the crucial Heck reaction. Ph3As was essential for this step due to a de-triflation side reaction when phosphine based ligands were employed. Hydroboration/oxidation and subsequent global reduction was followed by diol protection/acetal cleavage and benzoylation of the second primary alcohol to furnish 3. O-alkylation of the corresponding enolate then produced enol ether 4.

 Scheme 3

 

The subsequent Claisen rearrangement gave ketone 5 which was again alkylated and rearranged to give ketone 6 with an extremely densely functionalized cyclohexane core, and three quaternary stereocenters. Selective hydroboration/oxidation of the least hindered methylene group was followed by acetylation and TBDPS removal. Selenation/oxidation/elimination according to Grieco’s protocol produced 7.

 Scheme 4

 

Selective removal of the acetonide was accomplished with a mixture of cerium trichloride and oxalic acid. Alcohol differentiation was achieved by protection of the primary alcohol with TMS, MOM-protection of the secondary one and desilylation. DMP oxidation then furnished aldehyde 8. Henry reaction with nitromethane was used to introduce the nitrogen atom into the system. After some efforts the group identified conditions to introduce the asymmetric methyl group by using one of the ligands published by Hoveyda et al with dimethylzinc as the nucleophile. Reduction of the nitro group and Boc-protection of the amine gave ketone 11.

 Scheme 5

 

Next both carbonyl groups were unmasked by ozonolytic cleavage of the methylene groups from which the aldehyde was chemoselectively reduced. A Finkelstein reaction of the corresponding mesylate gave iodide 13 from which the MOM-group of the pentanone ring was eliminated. Interestingly the iodide survived under the reaction conditions.

 Scheme 6

 

And here is the key step: By using catalyst B in a stoichometric amount, and after a lot of trials under different conditions, the group closed the seven-membered cycle. Some efforts later the group found that only a catalytic amount of B was necessary to get the reaction done, when DIPEA was added to the mixture. The scope of this remarkable key step will be part of a separate paper.

Scheme 7

 

The last steps of the synthesis include first a deacetylation (in the presence of the benzoyl protecting group). Oxidation and base catalyzed aldol condensation gave aldehyde 16. Ester formation under Corey’s conditions (MnO2 and NaCN in MeOH) was followed by protecting group exchange from benzoyl to acetyl to give 17. Boc-deprotection and simply heating the free amine in EtOH gave after MOM-removal Daphmanidin E in good yield.

 Scheme 8

 

Hell yeah… Really nice work, as usual. Interstingly only one co-author with respect to Prof. Carreira is mentioned in the title. The stage is open for discussions.

BTW.: Damn… B.R.S.M was a bit faster…

THX to Bobby for proofreading.
I selected this post to be featured on my blog’s page at Science Blogs.

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.

A General Approach to the Basiliolide/Transtaganolide Natural Products: Total Syntheses of Basiliolide B, epi-8-Basiliolide B, Transtaganolide C, and Transtaganolide D

A General Approach to the Basiliolide/Transtaganolide Natural Products: Total Syntheses of Basiliolide B, epi-8-Basiliolide B, Transtaganolide C, and Transtaganolide D

Hosea M. Nelson, Kei Murakami, Scott C. Virgil, and Brian M. Stoltz

DOI: http://dx.doi.org/10.1002/anie.201008003

This time a rather short synthesis but with some cool chemistry in it. As can be seen from the papers cited by the Stoltz group, a lot of working groups are currently working on this subject. The main problem of all approaches is the endgame of the synthesis and not the impressive IMDA reaction utilized by most groups to build the core structure.

So here is the subject:

 Scheme 1

 

Because all stereocenters came from one step which is done without any chiral control, the synthesis yields an epimeric mixture of the natural product.

The paper only cites the synthesis of the first fragment so I added it for the sake of completeness.

The synthesis of the green fragment starts from commercially available geranyl acetate. This was oxidized to the ester through a sequence of allylic oxidation and manganese dioxide mediated two step oxidation to give ester 3. Removal of the acetate then yields alcohol 4.

Scheme 2

 

The blue fragment was synthesized from methyl propiolate which was iodinated under acid catalysis to give selectively the Z-product. This was exposed to standard Sonogashira conditions and coupled with butynol to give 7. Lactonization with iodine monochloride and subsequent oxidation furnished crude acid 9 which was used without further purification.

 Scheme 3

 

To test in principle the crucial Claisen/IMDA step, the blue fragment was coupled with geraniol 10 under standard conditions and exposed to well known conditions to form first the enol ester and rearrange this to tricyclic compound 12. Although the yield is pretty good, the reaction took 18 (!) days to reach completeness. Nevertheless Sonogashira coupling under standard conditions after protection of the ester furnished Transganolide C and D in moderate yield.

 Scheme 4

For the preparation of the Basiliolides the synthesis was optimized. First both fragments were coupled in the presence of DCC which set the stage for the Claisen/IMDA reaction as before. By adding two equivalents of BTSA and a catalytic amount of TEA to a solution of 10, tricyclic compound 11 forms in excellent yield and high diastereomeric purity in only 2 (!) days . TBS protection of the acid proved crucial for the final step. Stille coupling with the ethinyl stannane shown produced directly an epimeric mixture of Basiliolide B albeit in low yield.

 Scheme 5

 

So at last here is the cool Claisen/IMDA-reaction step. First BTSA forms the TMS enol ester which undergoes a Claisen-Ireland rearrangement. Now with all double bonds in the right place Diels-Alder reaction forms the remaining two bonds to give the core structure of Basiliolide B.

 Scheme 6

 

I am very busy these days but hopefully I get a second review done this month. THX for reading my stuff.

And THX to Bobby for proofreading in advance.

Enantioselective Total Synthesis of (+)-Salvileucalin B

Enantioselective Total Synthesis of (+)-Salvileucalin B

Sergiy Levin, Roger R. Nani, and Sarah E. Reisman

DOI: http://dx.doi.org/10.1021/ja110192b

Happy new year fellas… hope you rushed in well.

Today’s molecule is from the past 2010 but a goody! The structure is a bit odd because of the cyclopropane ring breaking the aromatic system of the phthalide. By the way this structure motif is called a norcaradiene ring. Kindly the authors added a retro to the paper so less work for me:

Scheme 1

The authors planned to construct the cyclopropane motif at last by employing a nice copper catalyzed cyclopropanation. The phtalan moiety was constructed through a ruthenium catalyzed cycloisomerization and the chain extended by an Arndt-Eistert homologation.

So here we start from the very beginning.

The alcohol shown was oxidized under standard conditions and reacted with pseudoephedrine to give amide 1.

Scheme 2

The second main fragment was synthesized through a stereoselective alkynylation using a mandelamide ligand and dimethylzinc. The corresponding alcohol was propargylated, desilylated and exposed after mesylation to Finkelstein conditions to give bromide 2.

Next fragment 1 was enolized with LHMDS and reacted with 2 to give triyne 3. The reaction conditions were developed by the Myer’s group (J. Am. Chem. Soc. 1997, 119, 6496-6511), nice paper btw.

Scheme 3

Now it’s getting really cool. The triyne was cyclised to the phthalan ring after deprotection of the TMS group employing TBAF. Really nice but I could not figure out exactly which protocol they followed, nothing is said in the paper or supporting info. If anyone of you has an idea you are welcome to forward me the DOI.

The auxiliary was cleaved off and acid 4 extended by one CH2 under Arndt-Eistert conditions to give 5. The resulting methylester was reacted with the sodium salt of acetonitrile to give a cyanoacetate which was converted to diazo compound 6. Exposing this to a bit of copper(II) for only one minute in a microwave the cyclopropane ring formed in good yield to give 7.

Scheme 4

The ketone was then transformed into the enol triflate. Reduction of the nitrile was not that trivial: the corresponding in situ formed aldehyde underwent a retro-Claisen rearrangement and opened the cyclopropane ring. After some experimentation it was possible to rapidly reduce the nitrile to alcohol 8. Carbonylation under standard conditions furnished lactone 9 which was exposed to Cr(VI) to give a mixture of products containing substantial amounts of (+)-Salvileucalin B.

Scheme 5

Short but very effective. I liked the way how the norcaradiene core was built. And especially the cycloisomerization reaction catched my eye.

Comments?

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

1_0705091

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

2_070509

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

4_070509

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

5_070509

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.