(+)-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…


6 Responses

  1. 1. I’ve seen Kocienski speak a couple of times. I particularly remember his Ionomycin work where they had to use /very/ specific solvent, order/rate of addition and coupling partners to get a good E/Z ratio. I’ve never done one, but it seemed even the man himself had to screen a lot of conditions.

    2. A very good postdoc in our group had terrible trouble doing a macrolactamisation of a (z)-a,b-unsaturated acid onto an aminoquinone. Macrolacton/lactam-isation of such acids can be a difficult if the nucleophile isn’t particularly reactive as the acid gets scrambled while waiting to react. Depending on the ring size the (z)-form is usually more stable after the macrocycle has been formed. In our case even just stirring the acid at rt with Hünig’s base caused isomerisation, DMAP and other coupling agents were not tolerated. I think the problem was eventually solved by reducing the quinone, making the NH2 a lot more nucleophilic and allowing some of the desired product to be obtained (along with a lot of isomerised material).

    3. Sure, I’ll take it as a compliment. I think it makes things easier to read, especially if you like to make random comments or go off on tangents. I stole the idea off Dylan’s (now defunct) Tenderblog and Totally Synthetic anyway.

  2. Hey, thanks for interest. I heard a talk of Kocienski some time ago and I think it was also on his Ionomycin work… What I remember most was his use of the underrepresented alkyne protection with Co2(CO)8. Pretty old school but as they started their work it was up to date 🙂

  3. Man Julia-Kocienski reactions can be a right pain to optimise: order of reagents, base counter ion, solvents, temperatures, additives such as HMPA or crown ethers, switching around the coupling partners and the heteroarlyl function of the sulfone all have massive effects on the yields and stereoselectivities….

  4. Sounds like you had similar problems… Can you recommend a paper or review which helped you to get the reaction done? I was wondering if there is some kind of easy way to solve the problems most people encounter earlier or later.

  5. A paper by Blakemore, J.Chem.Soc., Perkin Trans 1, 2002, 2563-2585 has a very comprehensive overview of the literature, I would recommend to choose the a system similar to yours and try their reaction conditions as a starting point

  6. Savvy comments – I learned a lot from the info – Does someone know if my business could grab a template a form version to fill in ?

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