(+)-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…

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Philip Garner, H. Umit Kaniskan, Charles M. Keyari, and Laksiri Weerasinghe

DOI: http://dx.doi.org/10.1021/jo200553g

Sorry for the long delay but I was a bit busy with my relocation. This piece of work was published a few weeks ago and deals with some interesting chemistry. I am not very familiar with this unusual [3 + 2] or formal [2 + 2 + 1]-cycloaddition reaction.

Let’s take a look at the retro:

Scheme 1


They make use of some old school and some modern chemistry. The bicyclic moiety is accessible by a Strecker reaction. A Pictet-Spengler reaction was used to produce the tetrahydroisoquinoline ring using starting material from a lactamization step. The proline-like motif in turn was formed through this odd cycloaddition step.

 Scheme 2

The aromatic part of Cyanocycline A was synthesized using some well known chemistry. Starting from anisol 1 a Friedel-Crafts acylation and subsequent Baeyer-Villiger oxidation formed 2. Regioselective bromination and saponification yielded phenol 3 which was protected as the benzyl ether 4.

Now to the first cool chemistry used in this paper: a stereoselective Grignard reaction with a D-serine-derived nitrone. The mechanistic rationale is explained at the end of this review. Hydroxylamine reduction was accomplished under Clemmensen conditions followed by Cbz-protection of the free amine to give 6. Acetonide removal and Dess-Martin oxidation then gave aldehyde 7.

Scheme 3


Next the formal [3 + 2]-cycloaddition is used to make three more stereocenters. Condensation of 7 with amine 8 was followed by the addition of silver acetate and methyl acrylate to give 10. Again the mechanism is discussed later on. Removal of both Cbz-groups and benzyl-groups forms the lactam ring and subsequent protection of the pyrrolidinyl nitrogen with Cbz gave 11. Boc-deprotection with TFA and a Pictet-Spengler reaction in acetic acid produced after benzylation of the free alcohol 12.

Scheme 4


Reduction of the Cbz group to a methyl group and cleavage of the chiral auxiliary with LAH in the presence of the amide worked fine. Oxidation of the terminal alcohol of 13 and subsequent Strecker reaction with TMSCN formed 14. Thioamide formation with Lawesson’s reagent and reductive desulfuration then gave imine 15.

 Scheme 5

Heating 15 in MeOH with some equivalents of ethylene oxide in a sealed tube formed 16. Selective debenzylation was accomplished with boron trichloride followed by benzoquinone formation with Mn3+ to give Cyanocycline A.

Scheme 6

And for those who want to know how the key steps might work, here is the mechanistic rationale. First the Grignard reaction:

Scheme 7

The authors explain the outcome of the reaction with an open transition state in which the Grignard reagent attacks the least hindered face of the nitrone. This is probably stabilized by a magnesium ion (when Grignard reagents are used). The reaction proceeds with high diastereoselectivity.

The second key step is somewhat more complicated. First the amide undergoes an imine formation with the aldehyde. Next one of the glycine protons is lost in the presence of silver which forms a tight complex with the imine nitrogen. The result is a positive charge on the nitrogen and a negative charge on one of the two vicinal carbon atoms. Moreover the silver cation forms a second complex with the acrylate which undergoes the cycloaddition and attacks the 1,3-dipole from the least hindered face to give 10.

Scheme 8

Nice chemistry don’t you think? And a really complex target. Comments?

And thx to Bobby for proofreading 😉

Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B

Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B

John C. Jewett and Viresh H. Rawal

DOI: http://dx.doi.org/10.1002/anie.201003361

Further read: DOI: http://dx.doi.org/10.1002/anie.200701677

and                 DOI: http://dx.doi.org/10.1021/ja050728l

Sorry for the long delay but now I am back into business. This time with a nice synthesis from Rawal et al. who already synthesized this sweety but only in a racemic fashion. Obviously they accomplished the stereoselective synthesis in the last few months by applying an interesting methodology which made it possible to retain the stereochemistry at the carbon center marked with a little star.

Scheme 1

By virtually cutting the molecule into two halves one gets the known natural product pederic acid and the so called mycalamine. Rawal et al. already published a total synthesis of pederic acid which I will refer to later. Mycalamine is not natural product by itself but named after the parent compound.

For the biologists out there: mycalamide B displays some antiproliferative activities against various cancer cell lines which make it an interesting target for many working groups.

I will start this brief review with the synthesis of pederic acid which was published some years ago. It starts with an esterification of the known alcohol shown and protected glyceric acid in the presence of EDC/DMAP. Petasis methylenation then furnished the required exo-methylene group ready for a nice Wacker-type cyclization which closes the THP-ring. The benzylidene protection group was removed under Birch conditions, the more acidic primary alcohol protected as a TES-ether and the remaining one as a benzoylester. PDC oxidation furnished the benzoylpederic acid which was transformed into the acid chloride under standard conditions in quantitative yield.

Scheme 2

Next the second half of the molecule, mycalamine, has to be synthesized. They started with a copper mediated epoxide ring opening, TIPS protection of the free alcohol and oxidative cleavage of the methylene group to the aldehyde. A stereoselective Diels-Alder reaction under Yamamoto’s conditions was done by employing MAD as the catalyst which was prepared in situ from AlMe3 and the corresponding alcohol. During work-up the TIPS was cleaved off and the alcohol methylated. Then my favourite reaction took place:

A Mukaiyama/Michael reaction of the silylketene acetal with the unsaturated ketone in the presence of TBSOTf gave a TBS protected enol which was directly epoxidized with mCPBA (Rubottom oxidation). The MOM group was cleaved, the epoxide opened and both connected in a 1,3-dioxane ring.

Scheme 3

The coupling partner of the above mentioned Diels-Alder reaction is available in two steps from methyl formate and iso-pentanone as showed below.

Scheme 4

Next the ketone was reduced by employing the very old-school Meerwein-Ponndorf-Verley reduction. Other reduction systems gave mainly the alcohol with the wrong stereochemistry. The alcohol was methylated in methyliodide in the presence of silver oxide.

Scheme 5

Debenzylation, saponification and subsequent Curtius rearrangement gave the cyclic carbamate by trapping of the intermediary isocyanate with the free alcohol. And this cyclic carbamate gave the group the opportunity to couple both halves without racemization of the stereocenter marked. The carbamate was deprotonated and reacted with pederic acid chloride to give after selective debenzoylation and carbamtate cleavage mycalamide b in 14 steps in the longest linear sequence and with 3% overall yield.

Dude, what a nice synthesis… And if I counted right 11 named reactions were used… So if you have any questions or suggestions feel free to ask. THX for reading my stuff…

Total Synthesis of (+)-Sieboldine A

Total Synthesis of (+)-Sieboldine A

Stephen M. Canham, David J. France, and Larry E. Overman

DOI: http://dx.doi.org/10.1021/ja103666n

Unfortunately I was very busy the last weeks with studying but now the last exam is written so I took the advantage and finished to review this nice paper from Overman et al..

Sieboldine A presents in my eyes a classical Overman target because of the rigid alkaloid structure ready for cool rearrangement chemistry. The compound itself inhibits electric eel AChE with an IC50 value comparable to that of Huperzine A (https://syntheticnature.wordpress.com/2009/11/23/total-synthesis-of-huperzine-a/). But the real interest for a synthetic chemist poses the unprecedented N-hydroxyazacyclononane ring which was unknown until the isolation and structure elucidation of Sieboldine A in 2003.

Scheme 1

Retrosynthetically spoken the first step cleaves the sensitive N,O-acetal. The precursor derives from a Diels-Alder product which in turn was produced by a sweet pinacol-terminated cyclization.

Scheme 2

The synthesis starts off with the known unsaturated lactone which was opened by diastereoselective Michael addition of methylcuprate and subsequent lactonization with iodine. Exhaustive reduction with LAH furnished a diol which was selectively monoprotected and oxidized to give the ketone shown.

The second intermediate was synthesized through a known route. Michael addition of tributyltin-cuprate complex on the alkyne and quenching the reaction with MeOH gave z-vinyl tributyltin ester. This was reduced with DIBAL-H, exposed to Mitsunobu conditions to produce the phenyl ether and converted to the iodide by halogen/metal exchange.

Scheme 3

Next both intermediates were combined by reacting the iodide with sec-BuLi, transmetallate the lithium species with cerium trichloride and add to this the ketone (all at -78°C). Protection of the resulting alcohol, Swern oxidation of the terminal silyl ether (which was deprotected under the reaction conditions) and Seyferth-Gilbert homologation utilizing the Ohira-Bestmann reagent yielded the terminal alkyne ready for the first key step.

Exposure of this to a bit of gold and silver produced two of the four rings needed in a nice tandem Prins/pinacol rearrangement reaction.

Scheme 4

The mechanism might look like this:

Mechanism 1

The gold attacks the terminal alkyne which in turn is attacked by the alkene through a 5-exo-dig cyclization. The resulting tertiary carbenium ion is neutralized by a pinacol type reaction of the TES-ether to give the vinylic gold intermediate which is protonated by i-PrOH.

Having most of the carbon skeleton in place the group turned their attention on the next key step. Ozonolysis of the exo-methylene group followed by neutral work—up with dimethylsulfide and subsequent phenolate elimination produced another exo-methylene group. This underwent a europium catalyzed Diels-Alder reaction with ethyl vinyl ether. Diastereoselective reduction of the ketone was followed by facial selective expoxidation with DMDO.

Scheme 5

The resulting epoxide was opened in the presence of ethanethiol with BF3-etherate in a sweet Overman style reaction. Desilylation, Mitsunobu reaction with double protected hydroxylamine and removal of the nosyl protecting group furnished an odd looking hemiacetal. Next some carbohydrate chemistry was utilized which is completely new to me to close the last ring (if someone has access to the paper, mail me). Oxidation of the remaining alcohol and MOM-cleavage yielded at least (+)-Sieboldine in 5% yield over 20 steps in the longest linear sequence.

Scheme 6

The Diels Alder reaction inspired me to propose the two mechanisms below. I am not sure which one is right but I favour the red one.

Mechanism 2

For a better understanding of the abbreviations some structures of the reagents possibly new to some readers:

Scheme 7

I loved the synthesis as usual when reading Overman’s work. Especially the pinacol-terminated cyclization, the Diels-Alder reaction and the ring opening/ring closing cascade.

If you have any questions do not hesitate to ask them…

Construction of Fused Heterocyclic Architectures by Formal [4+1]/[3+2] Cycloaddition Cascade of Sulfur Ylides and Nitroolefins

Construction of Fused Heterocyclic Architectures by Formal
[4+1]/[3+2] Cycloaddition Cascade of Sulfur Ylides and Nitroolefins

Liang-Qiu Lu, Fang Li, Jing An, Ji-Ji Zhang, Xiao-Lei An, Qiu-Lin Hua, and Wen-Jing Xiao

DOI: http://dx.doi.org/10.1002/anie.200904766

It’s methodology time as can be seen from the title. A short paper featuring a nice cascade reaction for the construction of these highly functionalized heterocycles (don’t know the trivial name, if there is one, for these kind of structures; the names generated from ChemDraw are… useless….)



A formal [4 + 1] addition of the ylide is followed by an intramolecular [3 + 2] cycloaddition of the formed nitronate to give this odd looking heterocycle.

After some efforts to improve the yield, CHCl3 was identified to be the best solvent. During the studies 10 derivatives were made including different substitution patterns on the phenyl moiety, a thiophenol, a naphthalene and one acyclic derivative (referring to the starting ether).

Also 12 derivatives were made varying the residue on the ylide. The yields are generally above 75%, in some cases up to 99% (!).

Additionally the d.r. is really high (in all cases 95 : 5 minimum) with respect to the one diastereomer represented above.

So what’s the mechanism? It might look like this:



The ylide attacks the nitro group via Michael addition followed by a SN2 displacement of dimethylsulfide. The formed nitronate then acts as a 1,3-dipole and reacts in a cycloaddition with the olefin of the α-β-unsatured ester to give the product.

It can easily be seen that after formation of the first stereocenter the following four are formed stereospecifically.

The products of this reaction sequence can be hydrogenated in the presence of Raney Ni to give fused pyrroline rings:



And at long last it was tried to improve the ee by adding a symmetric urea in half stoichiometric quantities (which leaves room for some improvements) but does the job very well:



I think my shortest piece to date… Maybe when they discover a suitable natural product owing this kind of framework then this methodology could show its full potential.

Nice work!

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.