Synthesis of Dragmacidin D via Direct C-H Couplings

Synthesis of Dragmacidin D via Direct C-H Couplings

Debashis Mandal, Atsushi D. Yamaguchi, Junichiro Yamaguchi, and Kenichiro Itami

DOI: http://dx.doi.org/10.1021/ja209945x

I thought about writing this review a few months ago but never found the time to get it done. But here it is and I hope you enjoy this cool paper as I did. I am a big fan of “flat” chemistry and C-H activation so naturally this piece had to be reviewed. Dragmacidin D itself shows some promising activity in the treatment of neurodegenerative diseases like Alzheimer’s or Parkinson’s disease. Only one total synthesis has been published by the Stoltz group in 2002 so there is still room for improvement. Retrosynthetically the group planned to stick all parts together via C-H activation/C-C coupling reactions.

 Scheme 1

The “sticky” –positions are marked in blue. As can be seen from this picture almost all crucial bonds can be formed through C-H activation (except the iodide).

Indole 1 was carboxylated to block the 3 position of the indole which would normally undergo iodination in the presence of NIS. Removal of the carboxyl group after halogenation gave indole 3. Tosylation was accomplished under standard conditions yielding the first coupling partner 4. Thiophene boronic acid 5 was oxidized to the corresponding alcohol to furnish after TIPS protection coupling partner 6. In the presence of PdII and silver(I) as the re-oxidant thiophene 7 formed in good yield on a gram scale. Desilylation and reductive desulfuration with Raney-Ni was followed by global deprotection and double MOM-protection to produce ketone 8. [1]

 Scheme 2

Next the 3 position of the indole moiety was again functionalized. This time pyrazine N-oxide was used in the presence of PdII to give 9. A TFAA mediated Polonovski-Potier rearrangement gave pyrazinone 10 which was used in a Friedel-Crafts-like acylation with 6-bromoindole to furnish 11 in good yield. Bromination of the ketone was accomplished via the TMS-enolate and NBS mediated bromination yielding 12. In the presence of Boc-guanidine Dragmacidin D was formed after deprotection.

 Scheme 3

 

Short and very efficient I would say. The only drawback might be that Dragmacidin D is formed in both enantiomeric forms. I was wondering how much silver the group stores in their laboratories J.

[1] Really a nice method to introduce the side chain on the indole. The net result is the reaction of an umpoled ketone with the aromatic ring.

Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor

Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor

Thomas Schmidt and Andreas Kirschning

DOI: http://dx.doi.org/10.1002/anie.201106762

Happy new year everybody… I start this year with a nice synthesis from my university done by a very smart student. In this paper a lot of cool metal mediated chemistry is employed which reminds me a bit of the work done by the Fürstner group at the MPI.

Some methodology needs as usual special attention and will be examined at the end of this short write-up.

As the title says Carolacton is a potent biofilm inhibitor which is nowadays a very interesting field to establish new drugs and natural products as biofilms play a major role in clinical treatments.

Retrosynthetically Carolacton was divided in two fragments of almost the same complexity. Beside the crucial macrolactonization step the linear precursor was envisaged to be formed by a stereoselective Nozaki-Hiyama-Kishi reaction. The key steps in the formation of fragment 1 contain an alkyl Negishi coupling and a cool aldol reaction developed by the Ley group. The second fragment was formed among others by a Marshall reaction and an underrepresented Duthaler-Hafner acetate aldol reaction.

Scheme 1

Starting from commercially available lactic acid 3 which was transformed into triflate 4 in a four step sequence through acetylation, ester formation, deacetylation, and triflate formation a zinc mediated SN2 coupling of triflate 4 with homoallyl Grignard formed ester 5. Thorough reduction of the ester group furnished after TIPS protection silyl ether 6. Ozonolysis of the terminal double bond was followed by reductive work-up and Appel reaction to give bromide 7.

Scheme 2

Ester 8, which was obtained by a short protocol developed by Fu et al., was coupled with the corresponding zinc organyl of 7 in the presence of PyBOX-ligand A and a pinch of nickel. Ester 9 is obtained with great diastereoselectivity regarding the red colored methyl group. It was found that it was necessary to grind the added sodium chloride to get good results. [1]

After reduction and manganese dioxide oxidation to aldehyde 10 the above mentioned Ley aldol reaction with ester 15 was employed. Aldol product 11 was obtained in good yield and excellent diastereoselectivity.

Scheme 3

Fragment 15 can easily be prepared through a three step sequence which is shown in detail below. Commercially available diol 12 was first protected as the dioxane ether 13. The 1,2-dimethoxy protecting group is used as a chiral memory unit because the stereochemical information at position 2 is lost during enolization. Chloride elimination and Ozonolysis of the resulting double bond gave after neutral workup ester 15.

Enolization with LHMDS then produces an enolate which reacts in a Zimmermann-Traxler boat conformation transition state with aldehyde 10. The whole story of this methodology can be looked up in the article which is cited above.

Scheme 4

The second half of the synthesis started from propargyl alcohol 16. Oxidation and hydride-transfer reduction with isopropanol catalyzed by Noyori’s catalyst gave enantiomerically pure alcohol 17. Mesylation formed the first partner for the Marshall reaction. The aldehyde partner was obtained from Roche ester 19 which was protected, excessively reduced and again oxidized. Next an anti-selective Marshall reaction mediated by indium(I)iodide and catalyzed by Pd(0) was used to give homo-propargyl alcohol 21. Desilylation with TBAF, acetal formation and chemoselective reduction then furnished after Swern oxidation aldehyde 22. This underwent another interesting reaction: a Duthaler-Hafner titanium mediated aldol reaction with t-butylacetate. This step will be detailed at the end of this post.

After reaction with Meerwein’s salt fragment 2 was almost ready for the Nozaki-Hiyama-Kishi reaction.

Scheme 5

First fragment 11 was freed from the chiral memory unit and the resulting diol protected as the acetonide. During protection the TIPS group was lost and the free alcohol then oxidized to give aldehyde 23.

On the other hand fragment 2 was exposed to Schwartz’s reagent and quenched with iodine to give vinyl iodide 24. In the presence of Cr(II), in situ formed Ni(0), and ligand B both halves were combined to give 25 and 26 as a mixture of diastereomers (~ 1 : 5). [2] Besides carrying the synthesis on with 26, it was tried using the wrong diastereomer 25 in a Mitsunobu process to close the macrolactone. Instead of closing the ring a SN2’ reaction was observed to give the vinylogous macrolactone.

Scheme 6

At last the acyclic precursor 26 was converted into the 12-membered lactone after saponification of the methyl ester and reaction with MNBA. Because of the delicate framework the t-butyl ester was transesterified with TESOTf and desilylated to give 27. PMB removal was followed by Dess-Martin oxidation and acetonide cleavage to yield Carolacton in good yield. [3]

Scheme 7

And as promised here is the mechanistic rationale for the Duthaler-Hafner reaction. Under standard aldol conditions i.e. LDA deprotonation of the acetate and subsequent reaction with aldehyde the diastereoselectivity can be predicted using the Felkin-Anh model. Here the wrong diastereomer is preferred. To overcome this substrate controlled reaction, the enolate is made chiral by using a stoichiometric amount of this furanose modified titanium reagent. After transmetallation of the enolate a Zimmermann-Traxler transition state can be formulated which is inherently controlled by the chiral ligands. This time the correct diastereomer is formed. [4]

Scheme 8


Nice work and worth a read.
[1] Interestingly the Negishi cross coupling can be conducted employing a racemic mixture of the chloride. Only one diastereomer is formed. The authors of this article (DOI: http://dx.doio.org/10.1039/B805648J) therefore propose a radical pathway.

[2] More about this cool stereoselective Nozaki-Hiyama-Kishi reaction can be found here: DOI: http://dx.doi.org/10.1021/ol0269805

[3] Interestingly the last deprotection step took 6 days. Pretty tough this acetonide…

[4] If you want to read more about this have a look in here,
DOI: http://dx.doi.org/10.1002/anie.198904951
Because the paper did not state exactly how the stereochemistry observed can be explained I tried it by myself. If anyone has a better explanation I really would like to hear it.

(+)-Sorangicin A: evolution of a viable synthetic strategy

(+)-Sorangicin A: evolution of a viable synthetic strategy

Amos B. Smith III., Shuzhi Dong, Richard J. Fox, Jehrod B. Brenneman, John A. Vanecko, Tomohiro Maegawa

 DOI: http://dx.doi.org/10.1016/j.tet.2011.09.035

Sorangicin A is an extremely potent antibiotic acting against Gram-positive and Gram-negative bacteria with a MIC ranging from 0.3 to 25 µg/ml, respectively. It inhibits the RNA polymerase of bacterial cells leaving eukaryotic cells unaffected.

Besides a dioxabicyclo[3.2.1]octane, 15 stereogenic centers, and a tetrahydro- and dihydropyran ring, this 31-membered macrocycle contains a E,Z,Z-ester motif. The whole story of structure elucidation (and correction) is featured in the cited article. Because the whole is beyond the scope of this write-up interested readers should really have a look at it.

The completion of the synthesis was accomplished in 2009 but recently this full account appeared containing a lot of improvements. So here it is:

Scheme 1

 

This giant beastie is cut into four fragments. The two main fragments, blue and green, are of almost the same and much higher complexity compared to red and orange. It was planned to connect all fragments via two Julia-Kocienski, one Stille, and one Mukaiyama macrolactonization reaction. Synthesis of fragments 7, 21, and 33 will be presented separately before all were connected to form 36.

At the outset of the synthesis the acetonide of glyceraldehyde underwent a Cr-catalyzed Diels-Alder reaction with Danishefsky’s diene to give after addition of TFA dihydropyranone 2. Enantioselective Michael addition of in situ formed styryl cuprate and quench with methyl iodide furnished tetrahydropyranone 3. The temporary transmetallation with dimethyl zinc was necessary to suppress double ortho methylation of the resulting enolate. Selective ketone reduction from the less hindered face was followed by acetonide cleavage and trisylation to form alcohol 4.

 Scheme 2

 

In the presence of KHMDS epoxide formation was induced. Subsequent intramolecular epoxide opening produced the delicate dioxabicyclo[3.2.1]octane in high yield. Parikh-Doering oxidation and Takai-Utimoto olefination gave vinyl iodide 6 which was transformed into 7 by means of a dihydroxylation/periodate diol cleavage. Dihydroxylation is chemoselective with respect to the more electron rich double bond.

Scheme 3

 

The synthesis of the blue fragment started off with commercially available lactone 8 which was benzylated to give fragment 9. After elective monoreduction transformation of the resulting lactol into alkyne 10 was accomplished with TMS-diazomethane. The alkyne was used to introduce selectively a trans double bond through hydrozirconation. After some experimentation the group found that prior to in situ formation of Cp2Zr(H)Cl (Schwartz’s reagent) in the presence of lithium triethylborohydride the latter one should be added first to form the alcoholate which no longer interferes with the hydrometallation step. Quenching of the metallate species with NIS then gave iodide 11. Parikh-Doering oxidation, reaction of methyl Grignard under Luche conditions, and another oxidation then produced ketone 12.

Scheme 4

 

The coupling partner of 12 was synthesized in four steps from amide 13. Aldol reaction of the boron enolate of 13 with the aldehyde shown gave aldol 14 which was transformed into Weinreb amide 15 prior to protection of the free alcohol with TBS and monoreduction with DiBAl-H to give 16.

 Scheme 5

 

Fragments 12 and 16 were combined through boron enolate chemistry to give aldol 17 in high yield but as a 1 : 1 mixture of diastereomers. Because separation of the diastereomers was easily accomplished both were transformed into pyran 19 through different routes. Desilylation with buffered HF was followed by BF3 promoted thioacetal formation in the presence of ethyl mercaptan to give from diol 18a/b pyran 19 in high yield. In the case of 18b a two step oxidation/reduction protocol was necessary to invert the stereochemistry of the free alcohol.

 Scheme 6

Moving on with the synthesis vinyl iodide 19 was coupled in a neat alkyl Suzuki reaction with a 9-BBN boronate derivative to give olefin 20. Desulfuration of the thioacetal was followed by MOM protection of the free alcohol; triple debenzylation and selective mesylation of the resulting primary alcohol then gave mesylate 21. Acetonide protection of the vicinal diol and replacement of the mesylate with phenyltetrazolyl mercaptane produced after oxidation fragment 22.

 Scheme 7

 

The third and last main fragment was synthesized from known ephedrine derivative 23. Under Myers conditions amide 24 was produced in almost quantitative yield and excellent diastereomeric ratio. Reductive removal of the auxiliary and subsequent alkynylation under Corey-Fuchs conditions with concomitant methylation gave alkyne 25. Hydrometallation and bromination then furnished vinyl bromide 26 which was combined with dihydropyranone 27. The latter one was synthesized using again the chromium catalyst previously shown in scheme 2 through a Diels-Alder reaction with Danishefsky’s diene. In situ protection of the enolate with TES provided dihydropyran 28.

 Scheme 8

The TES enolate was used in a Rubottom oxidation to yield after deprotection/TBS protection ketone 29. Removal of the unwanted oxygen function was done through triflate formation with Comins reagent and palladium mediated reduction to give dihydropyran 30. PMB removal was then followed by two step oxidation of the free alcohol to the acid and tert-butylation to yield ester 31. Later on the group found out that the stereochemistry determined for the highlighted alcohol functionality was wrong. So an intermezzo of deprotection, oxidation/reduction, and global TBS protection was necessary to get the diastereomeric product. Selective TBS removal, Mitsunobu thiolation and oxidation then gave at last fragment 33.

Scheme 9

 

Assembling of fragments 7 and 22 via Julia-Kocienski olefination proved to be problematic. Considerable efforts were needed to get the reaction done. Optimal results were obtained by using tBuLi in the presence of HMPA as the base to give after several cycles product 34 in useful yield. Desilylation with buffered HF was followed by Dess-Martin oxidation to aldehyde 35 which was subjected to another Julia-Kocienski olefination. This time optimum results were obtained with KHMDS as a base to give after TBS removal ester 36 in good yield.

Scheme 10

 

Interestingly the group first planned to connect fragments 34 and 33 in the reverse direction by means of reacting the aldehyde of 33 with the sulfone of 34. Using the latter starting materials the group got besides a yield of 30 % a 1 : 1 mixture of olefins. [1]

Stille coupling of vinyl iodide 36 with stannane 37 which was obtained in one step following a known protocol gave after chemoselective saponification acid 38.

 Scheme 11

 

Macrolactonization proved difficult but after some experimentation the group found that good yield could be achieved using Mukaiyama’s modified conditions. [2] Deprotection of the tert-butyl ester was also problematic so the group first transformed it into a TBS ester. This was necessary because under standard acidic or Lewis acidic conditions the trienoate linkage was harmed. Global deprotection was done with hydrochloric acid to furnish in the end Sorangicin A as a single diastereomer.

 Scheme 12

 

This is really a huge achievement and with a yield of 3.2 % over 30 steps in the longest linear sequence not so bad J. It features some interesting chemistry namely the cool Diels-Alder reaction, the neat formation of the dioxabicyclo[3.2.1]octane, and the alkyl Suzuki coupling. Although the group first got the wrong diastereomer and proved later on that the original published structure was wrong the synthesis is straightforward.

THX for reading and comments are as usual welcome.

[1] I have never run a Julia-Kocienski olefination to date but I am sure this is only a matter of trial and error. Or does anyone have a good explanation concerning these results i.e. 30 % y, 1 : 1 versus 86 % y, only E?

[2] By employing standard Yamaguchi or modified conditions the sensitive trienoate linkage isomerized to some extent by a Michael addition of DMAP. Using a Mukaiyama reagent modified by Evans, the group worried about the iodide counterion which might react in a similar manner. Did anyone of you ran into similar problems during macrolactonization chemistry?

[3] Hopefully B.R.S.M. takes it as a compliment that I copy his style of putting marks in my text to direct you to the comments above…

And big big thanks to Bobby for reading all this more than twice. I promise this will be the last big one this year…

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.

Total Synthesis of (±)-Streptonigrin: De Novo Construction of a Pentasubstituted Pyridine using Ring-Closing Metathesis

Total Synthesis of (±)-Streptonigrin: De Novo Construction of a Pentasubstituted Pyridine using Ring-Closing Metathesis

Timothy J. Donohoe, Christopher R. Jones, and Luiz C. A. Barbosa

DOI: http://dx.doi.org/10.1021/ja207835w

Streptonigrin is a rather interesting natural product because of its axial chirality between rings C and D which was determined to be M. It contains a highly substituted quinoline dione system connected to a pentasubstituted pyridine ring. Only a handful of total syntheses are known to date and none of them, as it is true for this one, devises an enantioselective route towards the target compound. Nevertheless, compared to the previously described routes this one furnished (±)-Streptonigrin in a respectable yield of 11% over 14 steps (LLS).

The problem was reduced as shown below:

Scheme 1

The group planned an iterative route in which the main fragments were coupled using standard palladium chemistry. By using this approach three fragments are retrosynthetically received.

The synthesis of the green fragment commenced with benzaldehyde 1 which was nitrated ipso with respect to the carbonyl and reduced to give aniline 2. Acylation and subsequent cyclization was followed by chlorination to give quinoline 4. After some experimentation the group found stannane 5 to be the most reliable intermediate for the crucial C-C-bond forming step. The resulting stannane was used without further purification.

 Scheme 2

 

Next the orange fragment was synthesized starting from ethyl glyoxalate 6. Oxime formation was followed by regioselective crotylated to give methoxyamino ester 7. Amidation with phthalimide A after acid chloride formation gave amide 8. RCM employing Hoveyda-Grubbs II worked uneventfully to give pyridone 9. The presence of benzoquinone was necessary to prevent isomerization of the double bond by quenching the Ru-H species formed in situ. After elimination of methanol and triflate formation the resulting pyridine was brominated with NBS to give 11.

 Scheme 3

The last fragment was completed within 3 steps. Bromination of phenol 12 with NBS was followed by benzylation and boronate formation to give 14.

 Scheme 4

 

Fragments 5 and 11 were then coupled under old school conditions using tetrakis to give 15 which was reacted with 14 to give 16 again in the presence of tetrakis. Oxidation of the quinoline fragment then gave quinoline dione 17 in very good yield.

 Scheme 5

 

All previous syntheses relied on the endgame of the Weinreb paper published in 1980 going on from intermediate 17. Nevertheless the Donohoe group decided to construct their own endgame.

 Scheme 6

 

Bromination of 17 produced a dibrominated product 18 which was directly reacted with sodium azide to give compound 19 which in turn was converted into pyridine 20 through hydrogenation with palladium on charcoal. In the latter step the azide was reduced to the amine, the bromine reductively removed, and the benzyl protecting group cleaved off. After saponification racemic Streptonigrin was obtained.

Very nice stuff and no polyketides anywhere.

THX to Bobby for proofreading.

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.

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!