Total Synthesis of Branimycin: An Evolutionary Approach

Total Synthesis of Branimycin: An Evolutionary Approach

Valentin S. Enev, Wolfgang Felzmann, Alexey Gromov, Stefan Marchart, and Johann Mulzer

DOI: http://dx.doi.org/10.1002/chem.201200257

As the title suggests this full account features a collection of approaches towards the central core of branimycin. All those who are interested in a great story of evolutionary chemical design really should have a look at the full paper. I will focus in this short write-up only on the longest linear sequence.

Scheme 1

As can be seen from scheme 1 the synthesis focusses mainly on three fragments where green fragment 1 and blue fragment 2 constitute the main part of the molecule. The synthesis of fragment 1 is described in a previous paper but also featured in the following. The evolutionary design is limited to the synthesis of 2 and fragment 3 is commercially available dimethyl malonate.

The first route to allylalcohol 7 started from (R,R)-dimethyltartrate which was protected and reduced to diol 5. Methylation, tosylation, Finkelstein reaction, and reductive acetonide cleavage then furnished 7 in low yield. A more direct access from glycidol 6 is also presented. After methylation of the hydroxy function the epoxide was opened under Corey-Chaykovsky conditions to give 7. TIPS protection and ozonolysis of the olefin produced aldehyde 8.

Scheme 2

Next aldehyde 8 underwent a Marshall reaction with a chiral silylallene to give in high yield and stereoselectivity alkyne 9. Aqueous ammonium chloride was necessary for in situ deprotection of the resulting TMS ether. MOM protection of the alcohol and Schwartz reaction with subsequent iodine quench was used to arrive at vinyl iodide 10. Protection group switch from TIPS to the more convergent cleavage TBS group is straightforward giving green fragment 1.

 Scheme 3

The synthesis of the blue fragment began with Diels Alder reaction between two equivalents of furan and methyl propiolate. With ester 11 in hand the surplus ester group was removed following Barton’s protocol. Saponification and esterification with HPT produced thiohydroxamate ester 12 which loses CO2 under reductive radical reaction conditions yielding 13. Opening of one of the dihydrofurans gives a racemic mixture of alcohols 14 which were in turn protected. The silyl group was used as a handle in a Tamao-Fleming oxidation to introduce the terminal alcohol to give after methylation rac15.

Scheme 4

The next step in the synthesis is an interesting chiral resolution strategy by a “chiral hydride”. This is transferred from a Ni-(R)-BINAP complex with DiBAl-H as the hydride source. Never saw this kind of strategy in a total synthesis before but it is really a pretty neat solution. Although half of the material got lost in this step it provides rapid access to the blue fragment 2. If you are interested in this step you should have a look into this one [1]. So with enantiomerically pure 16 in hand the alcohol was oxidized and the PMB group replaced with a TBS group. After chemo- and stereoselective epoxidation (maybe guided by the methoxy group?) the blue fragment 2 was ready for the crucial coupling step.

 Scheme 5

Metal/halogen exchange of 1 with tBuLi and quench with 2 generated an alcoholate which immediately opens the epoxide in a 5-exo-tet reaction to give 19. This advanced intermediate was protected as a TBS ether and exposed to Cr(VI) which is known to promote allylic oxidation/rearrangement/oxidation to give in the end an unsaturated ketone. An attempted Claisen rearrangement to introduce the side chain did not give any positive results so the group had to pursue a different route. Michael addition of dimethylmalonate, triflation of the ketone, and reduction saved the day giving 21 in good overall yield.

 Scheme 6

Global reduction with LiBEt3H, selective monomethylation and MOM-deprotection produced diol 22. Chemoselective TEMPO oxidation (primary vs. secondary alcohol) to the aldehyde and Pinnick oxidation gave seco-acid 23. Some macrolactonization conditions were screened but the rather old school Corey-Nicolaou reaction proved to be successful to furnish after desilylation branimycin. As can be seen from scheme 7 it was not possible to control the stereochemistry a to the ester functionality. The preceding methylation to differentiate the hydroxy functionalities did not result in any chiral resolution so this stereocenter remains racemic giving at last two diastereomers of branimycin. Nevertheless the absolute of this stereocenter could be unambiguously resolved which remained unclear at the beginning of the story.

 Scheme 7

Sorry for the long delay of posting but I am really busy with finishing my exams and planning my move to the US.

 

[1] http://dx.doi.org/10.1016/S0040-4020(97)10211-3

 

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 Tulearin C

Total Synthesis of Tulearin C

Konrad Lehr, Ronaldo Mariz, Lucie Leseurre, Barbara Gabor, and Alois Fürstner

 DOI: http://dx.doi.org/10.1002/anie.201106117

Tulearin C is at first sight a rather simple polyketide natural product. Only seven stereocenters of which only four are contiguous and none of them is quaternary. Nevertheless no useful route to this compound has been established to date despite some potential antiproliferative action against human leukaemia cell lines.

The group around Fürstner built their synthesis upon a RCAM (ring-closing alkyne metathesis) with subsequent trans-selective hydrosilylation/protodesilylation to get the trans alkene. This critical feature was the major problem of earlier approaches which relied on a trans selective RCM which instead gave a mixture of trans and cis alkenes of virtually 2 : 1.

 Scheme 1

 

Breaking down the molecule into two halves the group reduced the problem to the common starting unit 1. This glutarate monoester is available in large quantities from dimethyl-3-methylglutarate.

Desymmetrizing saponification of one of the ester groups with a pig liver esterase (PLE) and further enhancing ee by crystallization of the crude acid with cinchonidine gave ester 1. You should have a look in the SI how they did this interesting saponification. After formation of the lithium salt the ester was reduced to the alcohol and cyclized to give lactone 2. Wittig reaction then furnished dichloride 3 which was reacted with excess methyl lithium to give alcohol 4 and after DMP oxidation aldehyde 5.

The key transformation of this scheme is detailed at the end.

Scheme 2

Aldehyde 5 then underwent stereoselective alkynylation under Carreira’s conditions to give diyne 6. Regioselective reduction of the internal alkyne and quench with iodine was followed by silylation of the free alcohol. The excellent regiocontrol can be ascribed to the alcohol function which guides the Red-Al to the correct end of the triple bond. Palladium catalyzed methylation and subsequent desilylation then furnished the green fragment. Direct introduction of the methyl group in the hydrometallation step with Red-Al did not produce any product at all.

Scheme 3

As mentioned above the synthesis of the second fragment commenced with key intermediate 2. Claisen reaction with ethyl acetate and reduction of the resulting dicarbonyl compound gave diol 9. Protection of the primary alcohol was necessary to get the following methylation done. MOM-protection of the secondary alcohol produced ester 10. After desilylation of the TBDPS group an Appel reaction of the free alcohol furnished iodide 11

Scheme 4

The second half of the red fragment was synthesized from butynol. Hydrozirconation with Schwartz’ reagent in the presence of DiBAl-H and iodine quench was followed by triflation and alkynylation to get iodide 12.

Scheme 5

Both parts were combined by first generating the alkylzinc species from 11 which underwent a Negishi coupling with iodide 12. Sharpless dihydroxylation and subsequent MOM cleavage was followed by global TBS protection and saponification of the ester grouping.

Scheme 6

Esterification of 15 with 8 was accomplished with EDC in almost quantitative yield. RCAM with catalyst C was done in toluene in excellent yield although some heating was necessary. Trans-selective hydrosilylation gave lactone 17 from which the siloxy group was removed with AgF. TBS removal under standard conditions then produced Tulearin C.

Scheme 7

And here are the details concerning the formation of key fragment 4. It is some kind of Grob fragmentation and I would compare it to the well known Eschenmoser fragmentation. Two possible reaction pathways are shown in the paper of which the left one is preferred.

As can easily be seen from the scheme the first step is a metal-halogen exchange to give a carbenoid-like carbon atom. The next step might on the one hand be an intramolecular E2-reaction to give the acetylenic chloride which undergoes another metal-halogen exchange and subsequent alkylation with in situ formed MeCl (blue arrows).

Or alternatively the vinyl-lithium species is alkylated with in situ formed MeCl before the second chloride atom undergoes a metal-halogen exchange and further fragmentation (green arrows).

Independent of the intermediates the same product is formed in good yield. In the original paper some applications of this transformation are shown and a detailed investigation of the mechanism and further application are underway. Also two examples are shown in which allenes instead of alkynes are formed.

Scheme 8

As usual exceptionally good stuff from the Fürstner group.

And big thanx to Bobby for proofreading.

Total Synthesis of Bryostatin 1

Total Synthesis of Bryostatin 1

Gary E. Keck, Yam B. Poudel, Thomas J. Cummins, Arnab Rudra, and Jonathan A. Covel

DOI: http://dx.doi.org/10.1021/ja110198y

[1] http://doi:10.1016/j.tetlet.2006.09.094, Tetrahedron Letters 47 (2006) 8267–8270

[2] http://dx.doi.org/10.1021/ol050511w, ORGANIC LETTERS, 2005, 2149-2152

As promised here is my first review of the month:

I finished almost all of my exams so I decided to review this huge contribution to the field of organic and total synthesis. Although some members of the family of the Bryostatins were readily synthesized the total synthesis of Bryostatin 1 has never been disclosed to day. And here it is:

Scheme 1

O yeah, what a beauty J The current paper deals only with the last 24 steps so a closer look in the literature and supporting information unveiled the remaining “few” steps. If you want to read more stuff about the whole story you should have a look in the many references mentioned in the original paper.

So what’s it all about with these Bryostatins? As mentioned in the paper Bryostatin 1 for example exhibits some action against diabetes, stroke, cancer and Alzheimer’s disease. It is assumed that this action is a result of the strong interaction with protein kinase C isozymes. Again, more details can be found in the references.

I will start my review with the syntheses of some key fragments which are later used in the main paper mentioned above.

The blue fragment was available in four simple steps from ester 16: Allylation was followed by a Wohl-Ziegler bromination, a modified Williamson ether synthesis and simple saponification of the ester to give acid 1.

Scheme 2

The second half was synthesized starting from isobutyl lactate 34. BOM-protection and DiBAl-H reduction gave aldehyde 35. Stereoselective allylation, PMB-protection and ozonolysis furnished aldehyde 36 which in turn was allylated to give fragment 2 in about 80% overall yield.

Scheme 3

Fragment 1 and 2 were combined under standard Esterification conditions to give 3. The olefin was extended by a three step protocol involving oxidative boronation, Parrikh-Doering oxidation and Wittig methylenation to furnish 4. This underwent a nice Rainier metathesis reaction, which I presented to you last month, to close the pyran ring and gave 5. Epoxidation with MMPP (a more soluble substitute for the more familiar mCBPA) and in situ opening of the epoxide with methanol was followed by Ley oxidation and aldol condensation with methyl glyoxalate to give ketone 7.

Scheme 4

Luche reduction of the ketone and immediate trapping of the alcohol with acetic acid anhydride produced 8. TBS cleavage with HF and Ley oxidation with TPAP yielded aldehyde 9 which was reacted with homoallyl alcohol 10 in the presence of TMSOTf to give 11.

Scheme 5

The synthesis of the green fragment is discussed next before we move on with the synthesis.

Ester 20 was alkylated and isomerized with tBuOK to give 22. Complete DiBAl-H reduction gave alcohol 23 which was deprotonated / mesylated / stannylated in a one pot reaction to give 24.

Scheme 6

The second half of the fragment was synthesized starting with aldehyde 25. A stereoselective Mukaiyama aldol reaction was followed by PMB-protection of the free alcohol to give 26. Deprotection of the silylated alcohol and Parrikh-Doering oxidation was followed by another nice substrate controlled Mukaiyama aldol reaction to give 28. Silylation, dihydroxylation and lead mediated diol cleavage (Criegee oxidation) gave 29.

Scheme 7

Next Me2AlCl mediated allylation of aldehyde 29 with allyl stannane 24 gave alcohol 30 as a single diastereomer. Acetylation and PMB-cleavage under standard conditions was followed by ozonolysis to give 32. The hemiacetal was converted to a full acetal with methanol / CSA while the TBS group was cleaved off, the free alcohol oxidized and allylated to give the red / green fragment 10.

Scheme 8

The BPS-group (better known as TBDPS) was cleaved off with HF, the thiolester hydrolysed in the presence of H2O2 and the free alcohol trapped as the TES ether 12. PMB-cleavage was followed by Yamaguchi macrolactonization to give lactone 13 whose exo-methylene group was dihydroxylated and oxidized to ketone 14.

Scheme 9

The ketone was used to introduce the last ester group by employing a HWE-reaction with Fuji’s chiral phosphonate A to give 15. Selective acetate cleavage, esterification and global deprotection with LiBF4 then produced Bryostatin 1 as a single diastereomer.

Scheme 10

Man, what a long synthesis but extremely cool. Hope you enjoyed reading this and hopefully you have some suggestions and comments for me… It really took me some time to get an overlook and find all the widespread papers.

Bis die Tage…

Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries, and Premetalated Nucleophiles in Polyketide Construction

Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer
Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries,
and Premetalated Nucleophiles in Polyketide Construction

Soo Bong Han, Abbas Hassan, In Su Kim, and Michael J. Krische

DOI: http://dx.doi.org/10.1021/ja1082798

Additional information (DOI’s):

http://dx.doi.org/10.1021/ol901096d

http://dx.doi.org/10.1021/ja805722e

http://dx.doi.org/10.1039/b917243m

http://dx.doi.org/10.1021/ja802001b

This time some chemistry for all the transition metal fans out there: a very nice synthesis of (+)-Roxaticin from Krische et al. which demonstrates the outstanding potential of their stereoselective allylation chemistry. By employing the strategy developed by the Krische lab the otherwise painful synthesis of this beastie was extremely simplified. If you are interested in syntheses from other labs have a look in the supporting information of the original paper which contains an useful overview.

Or if you are equally enthusiastic about the chemistry you should have a look in the paper which I linked above under additional information.

So let’s have a brief look at our target:

Scheme 1

Obviously the molecule is perfectly suited with respect to the allylation chemistry which was employed. Before I get started with pointing out the individual steps first the syntheses of the main catalysts used:

Scheme 2

The first one was synthesized by mixing [Ir(cod)Cl]2, the BIPHEP ligand, chloro-nitro-benzoic acid and the base in the presence of allyl acetate. This in situ formed catalyst was used as such with remarkable results.

The second one was synthesized in a similar manner:

Scheme 3

As you will see in the ongoing synthesis the enantiomer of the (R)-I-Cat. was used, too.

The synthesis begins with propanediol which was converted to the bishomoallyl alcohol under standard conditions in good yield and extremely high ee and dr. Protection as the acetonide was followed by ozonolysis and reductive work-up to give the next diol. This was again converted into the bishomoallyl alcohol, protected as the TBS ether and reacted with ozone/sodium borohydride to give another diol. Allylation, conversion of the TBS ether into the acetonide and ozonolysis/reduction furnished the last diol.

Scheme 4

In only nine steps the whole “alcoholic”-part of the target was finished! Nice…

Next the C2-symmetric molecule was selectively converted on one side into the alkene by employing some Mukaiyama chemistry. First one alcohol was converted into a selenide which was oxidized and eliminated to give the terminal alkene in moderate yield. Olefin metathesis with the PMB protected homoallyl alcohol shown was followed by another allylation step of the remaining alcohol with methylallyl acetate. This time the second catalyst (S)-II was used and not less than two stereogenic centers were set up.

Scheme 5

Another olefin metathesis was employed again with Grubbs-Hoveyda-II but this time with acrolein as the chain extension. Protection of the free alcohol as the TES ether and oxidative PMB removal produced again a homoallyl alcohol. HWE-reaction of the terminal aldehyde and saponification of the ester then furnished protected (+)-Roxaticin in its open form.

Scheme 6

Yamaguchi ring macrolactonization and global deprotection with DOWEX-50 finished the synthesis in only 20 steps in the longest linear sequence.

Scheme 7

For all those who are interested in the mechanism and have to time to look in the reference, here is the mechanism of this cool allylation step:

The in situ formed catalyst first oxidizes the alcohol to the aldehyde and forms a hydrido-iridium-species. It should be noted that the reaction can also be done with the aldehyde oxidation level but in this case they were too unstable to be used.

Next fresh allyl acetate reacts with the reduced form of the catalyst to give again the allyl coordinated iridium which in turn inserts itself into the double bond an in situ formed aldehyde. By reacting with another molecule of alcohol the homoallyl alcohol was set free and the reaction cycle goes on. For clearance I skipped some intermediates but this should be sufficient to get a brief overview.

Scheme 8

I really like this sort of chemistry. Seems not applicable for multigram synthesis but for quick access to a lot of analogues it is the perfect method I think.

Comments?

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

AspergillideC_retro_17.10.09

(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
scheme_2_171009

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

mechanism_171009

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

scheme_3_171009

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

scheme_4_171009

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

scheme_5_171009

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 🙂

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