(+)-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…


Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

Tyler J. Harrison, Stephen Ho, and James L. Leighton

DOI: http://dx.doi.org/10.1021/ja201467z

Usually I skip these polyketide syntheses but this one caught my eye. I really like these rapid assemblies, like those from the Krische group, of contiguous stereocenters without many “old-school” operations (e.g. Evans-Aldol). And as mentioned in the title the authors refer to this, in my eyes awesome, paper from Baran et al. on how total synthesis becomes more ideal.

The subject of this paper looks like this:

 Scheme 1

The synthesis of the first fragment starts with a Shi epoxidation of known olefin 1 which sets the critical stereocenter. Regioselective epoxide opening with in situ formed propynyl aluminate and some help from BF3-etherate formed alcohol 3 which was silylated to give 4. The resulting silane was used to form at least three more stereocenters and after Tamao-Fleming oxidation ketone 5. Compared to the rules from Baran et al., this starting point is 100% ideal because every stereocenter formed derived from a bond-forming step.

The cool Rhodium promoted rearrangement will be examined at the end of the synthesis.

 Scheme 2

Next ketone 5 was protected, reduced and the resulting diol protected again as the cyclic carbonate 6. Oxidative cleavage of the terminal olefin furnished aldehyde 7 which underwent stereoselective crotylation to give homoallyl alcohol 8.

 Scheme 3


Going on with the synthesis the newly formed terminal olefin was used to form again under Rhodium catalysis a tetrahydropyran ring. The free alcohol was acetylated to give 9 and reacted with the Nagao-Auxiliary shown under combined titanium and tin catalysis to give 10. Methanolysis of the amide bond, debenzylation, Mitsunobu reaction with 1, and oxidation of the sulphide formed key fragment 11.

 Scheme 4


The second half of Zincophorin also features a very nice crotylation reaction which set the first two stereocenters. Reaction of propionaldehyde with A in the presence of Sc(OTf)3 formed 12 which under a CM-reaction and tosylation gave 13. Another crotylation, this time catalysed by a bit more Sc(OTf)3 and silane B gave olefin 14. This cool crotylation will also be examined at the end of the story.

 Scheme 5


Alcohol 14 was protected as the PMB-ether and the unnecessary tosylated hydroxy functionality reductively removed. Oxidative cleavage of the terminal olefin gave at last fragment 16.

 Scheme 6


Both halves were combined through a highly selective Julia-Kocienski olefination to give 17. Global deprotection was started with PMB-group removal, followed by dioxanone cleavage and desilylation to give Zincophorin methyl ester.

Scheme 7

So at last as promised is the mechanistical background of the first Rhodium catalysed C-C-bond forming step. An older paper (JACS, 2000, 122, 8587-8588) gave some hints on how this chemistry works. If you disagree with my thoughts I would be very interested in your solution.

The first step should be an oxidative insertion reaction of Rhodium into the Si-H-bond. Next a metallosilylation reaction might proceed (a formal [2+2]-addition reaction) followed by a CO-insertion and reductive elimination of Rhodium to give the aldehyde shown. The homoallylic silane underwent a sigmatropic rearrangement which results in allylation of the aldehyde. Tamao-Fleming oxidation of the vinyl silane then produced an enol which tautomerized stereoselectively to ketone 5. Nice… this is a really impressive protocol.

 Scheme 8


The other crotylation strategy is discussed in detail in this paper (JACS, 2011, 133, 6517–6520). It starts with a silylation of the aldehyde and sigmatropic rearrangement through a chair-like transition state (Zimmerman-Traxler transition state) to give 12.

 Scheme 9


So that is it for the moment. Hope you enjoyed reading this and the cited literature as I did.

And as usual big thanks to Bobby for proofreading!

Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Joseph D.Panarese and Stephen P.Waters (this review)
DOI: http://dx.doi.org/10.1021/ol902154p

Tomohiro Nagasawa and Shigefumi Kuwahara (last 3 steps)
DOI: http://dx.doi.org/10.1021/ol802803x

Today I will present to you a short formal synthesis of Aspergillide C which makes use of a nice hetero DA followed by a Ferrier-type addition. The last 3 steps were taken from a synthesis published 9 months earlier. You should have a look in it.

I know there’s no KCN-like “never-used-before-in-total-synthesis”-chemistry in it but I were taken with how they accomplished this synthesis in only 9 steps as the longest linear sequence. Efficient and short as expected from a OL paper.

Let’s have a look at the retro:

Scheme 1


(I really like these paper with the retro already in it :))

As you can see they started with commercially available starting materials employing a DA, Ferrier alkylation and Pd(II)-catalysed lactonization. After installation of the side chain via Julia-Kocienski and macrolactonization they furnished Aspergillide C as described in the earlier synthesis from Nagasawa and Kuwahara.

Ok, before I forget it: the biological activity is again really interesting as Aspergillide C displays cytotoxicity against mouse lymphocytic leukaemia cells with a LD50 of 2µg/ml (don’t know why they did not use the IC50 value because as far as I know this is more significant…).

Scheme 2

Starting as mentioned above with a hetero DA catalysed by zinc chloride gave the desired γ-pyrone which was stereoselectively reduced under Luche conditions and acetylated. A lithium perchlorate mediated Ferrier-type alkylation followed by Pinnick oxidation furnished the carboxylic acid which was cyclised to the lactone by a Wacker-type oxidation (take a look at the double bond which moves around the ring; nice). Now we have our red fragment in hand.

The mechanism of the Ferrier-type alkylation might look like this:

Scheme 3


Lithium mediated vinylogue elimination of the acetate followed by anti selective addition of the TBS enol ether yields the product shown.

Next the preparation of the Julia fragment:

Scheme 4


They started with the commercially available hexenol which was protected, hydroborated and oxidised to the satured alcohol shown. Thioether formation under Mitsunobu conditions followed by ammonium heptamolybdate oxidation gave the green fragment in high yield.

The 2 fragments were combined after deprotection and diol cleavage of the red fragment under modified Julia-Kocienski conditions (normally it makes use of KHMDS).

Scheme 5


The rest of the synthesis was taken from the earlier published paper.

Hydrolysis, TBS protection and PMB ether cleavage yields the free acid which was cyclised under Yamaguchi conditions. A bit of TBAF then furnished the desired product in good overall yield.

Scheme 6


As mentioned earlier a very short and efficient synthesis again (17% yield over the longest linear sequence starting from protected glyceraldehyde) but hey, it serves the purpose.

I hope you enjoy reading this review though it is a bit shortspoken.

Ok, and next time I will feature a paper with this KCN-like chemistry, promised 🙂