Synthesis and Biological Activity of Platensimycin

Synthesis and Biological Activity of Platensimycin
Presented by Marie-Christine Brochu First Seminar University of Ottawa April 3rd 2008 Good afternoon everyone. It is a pleasure for me to present you this litterature research about Platensimycin. I hope you’ll enjoy this presentation as I enjoyed preparing it and that you’ll learn as much as I learned.

Presentation Outline 2) 10 Synthesis of Platensimycin
Platensimycin Biological Activity 2) 10 Synthesis of Platensimycin 1- Nicolaou (racemic) 6- Kaliappan (enantioselective) 2- Nicolaou (enantioselective) 7- Mulzer (racemic) 3- Snider (racemic) 8- Corey (enantioselective) 4- Nicolaou (racemic) 9 - Ghosh (enantioselective) 5- Yamamoto (enantioselective) 10- Nicolaou (enantispecific) 3) Brief overview of different strategies to access the cage like structure of Platensimycin In this presentation, I’ll explain briefly the mechanism of action of Platensimycin. In the main part of my talk, I’ll present different synthetic strategies used to date to access the cage like core of Platensimycin. Finally, I’ll give a brief overview of what we are about to see during the talk.

Introduction Isolated from a strain of a Streptomyces Platensis (a soil bacterium collected in South-Africa) by a Merck research group in New Jersey Platensimycin represents a new class of antibiotics because it operates through a new mechanism of action It is a selective inhibitor of FabF, an elongation-condensing enzyme involved in the bacterial fatty acid biosynthesis This is the structure of Platensimycin. It was isolated from a strain of Streptomyces Platensis by a research group at Merck in NewJersey. Many reseach group are interested in the total synthesis of Platensimycin. One reason is that Platensimycin possess a lypophilic and compact pentacyclic core that reprents an interresting synthetic challenge. However, what makes Platensimycin a very important molecule is its biological activity. It is a selective and potent inhibitor of FabF, an elongation-condensing enzyme involve in the bacterial fatty acid biosynthesis. Platensimycin is receiving a lot of attention from the scientific community because it represents a new class of antibiotics that operate through a new mechanim of action. New structural class of antibiotics that address novel targets are urgently needed as more and more bacteria are acquiring resistance to the known antibacterial agents. Wang et al. Nature 2006, 441, 358.

Platensimycin biological activity
Fatty acid biosynthesis is an essential metabolic process for all leaving organism since the cell membrane is composed of fatty acids. Fatty acids biosynthesis is organized differently in bacteria than in humans. Therefore, it is an attractive target for antibacterial drug discovery. Many different enzymes are involved in the bacterial fatty acid biosynthesis that is ilustrated in this slide. FabF is involved in the elongation-condensation step. Let see more in details what’s happening during this step. Häbich, D., Nussbaum, F. V. ChemMedChem 2006, 1, 951.

Platensimycin biological activity
First of all, The ACP transfers the growing fatty acid to the cysteine presents in tha active site of FabF, building an acyl-enzyme intermediate. By forming this intermediate, FabF swings from a close to an open conformation that open the malonyl binding subsite. Another ACP can than transfer yhe malonyl fragment into the pocket. Decarboxylation and insertion of a 2 carbones fragment into the acyl-enzyme intermediate leads to of the elongated beta-ketoacyl-ACP and FabF returns to its close conformation. Platensimycin compete for the malonyl binding site and block the formation of the beta-ketoacyl-ACP. Häbich, D., Nussbaum, F. V. ChemMedChem 2006, 1, 951.

Nicolaou’s First Racemic Total Synthesis Retrosynthetic Analysis
Starting from now, we’ll talk about different strategies reported in the litterature to synthesize Platensimycin. All synthesis are reported in chronological order. Here is illustrate the retrosynthetic ansalysis of the first total synthesis of Platensimysin reported by Nicolaou. They first envisaged to disconnect this amide bond leading to 2 fragments, this substituted aniline and this carboxylic acid. The more syntheticly challenging carboxylic acid can be obtained via bis alkylation of this enone that we’ll call Nicolaou’s intermediate. All other synthesis of Platensimycin reported in the litterature are actually formal synthesis and present different ways to prepare this key intermediate. So, Nicolaou evisaged to access the cage like structure of intermediate 4 through intramolecular addition of this alcohol to this alkene. Alcohol 5 would be obtain through intramolecular radical cyclization of this aldehyde to this enone. Spirocyclic cyclohexadienone 6 should be obtained via cycloisomerization of enone 7 that should come from this ethoxycyclohexenone. Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Nicolaou’s First Racemic Total Synthesis
Nicolaou started from ethoxycyclohexenone that was bisalkylated in good yield. Reduction with DIBAL-H followed by acidic hydrolysis and reprotection of the allylic alcohol with a TBS group leads to enone 7 in 84% yield. Cycloisomerization using the method developed by Trost affords spirocyclic enone 11 in excellent yield as a 1:1 mixture of diastereoisomers. Dienone 6 was generated through the oxidation of the corresponding silyl enol ether from compound 7. Finally, aldehyde deprotection affords intermediate 6 in good yield. Lets see more the details what is happening during the cycloisomerization reaction. Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Ru-Catalyzed Enyne Cycloisomerization
In this slide is illustrated the mechanism proposed by Trost rof the ruthenium catalyzed cycloisomerization of enynes. It starts from coordinatively unsaturated cyclopentadienylruthenium that first biscoordinate with the substrate to form complexe 13. Tautomerization of the enyne from an internal redox process provides metallacycle 14. Beta hydride elimination forms vinylruthenium hydride 15 wich finally undergoes reductive elimination to regenerate the Ru(II) catalyst and provides the desired cyclic product. Trost, B. H., Surivet, J.-P., Toste, F. D. J. Am. Chem. Soc., 2004, 126,

Treatment of aldehyd 6 with samarium iodide leads to the formation of the ketyl radical 16 that undergoes congugate addition to the enone yielding to alcohol 5 in 46% yield as a 2:1 mixture of diastereoisomers. They were not able to separate both diastereoisomers so they treated the mixture with TFA and only the alcohol having the desired stereochemistry undergoes acidic etherification. The selectivity of this reaction is explained by the proximity the hydroxy group to the alkene in the compound possessing the right stereochemistry. So, the cage like structure of Platensimycin was obtained in 27% overall yield starting from aldehyde 6. They were able to access intermediate 4 via the same startegy in a one pot fashion by quenching the SmI2 radical cyclization with oxygen at -78°C and by adding TFA to the mixture. The one pot procedure leads to intermediate 4 in 25% yield. Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Bisalkylation of enone 4 leads to compound 17 in good yield with excellent diastereoselectivity. The rigid cage structure shield the top face of the enone so the alkyl can only come from the bottom of the molecule. This reason explain the excellent stereocontrol observed for this alkylation sequence. They finally convert the terminal olefine through a carboxilic acid in a 3 steps sequence. First, olefine cross-metathesis between 17 and vinyl pinacol boronate leads to compound 18, that was first oxydized to the aldehyde using trimethyl N-oxide and further oxydized to the carboxylic acid under Pinnick protocol. Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Synthesis of the substituted aromatic amine started from 2-nitroresorcinol. Both alcohol were simultaniously protected as a MOM ether in 82% yield. Reduction of the nitro group affords aniline 22 that was than protected with a Boc. In situ silylation of the carbamate, ortho lithiation of the aromatic ring and final quench with methyl cyanoformate leads to aryl 24 in 54% overall yield. Aniline 24 was finally deprotected thermally to affords the desired coupling partner 2 in 83% yield. Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

The total synthesis of Platensimycin was completed by coupling carboxylic acid 3 with aniline 2 using HATU as coupling agent in 85% yield. Hydrolysis of the ester followed by acidic cleavage of MOM groups afforded the racemic Platensimycin in excellent yield. NMR data of the synthetic Platensimycin were consistent with data reported earlier by the Merck group for the natural Platensimycin. Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Nicolaou’s First Racemic Total Synthesis An Overview
First total Synthesis of Platensimycin ever reported (paper published on September 29th 2006, 4.5 months after Merck published in Nature) They access the core of Platensimycin via radical cyclization followed by etherification in acidic condition There is a brief resume of what we’ve seen so far. So, Nicolaou’s group were the first to report the total synthesis of Platensimycin in 2006, 4.5 mounth after Merck’s group research reported its isolation and its interresting biological activity. They access the core of Platensimycin via radical cyclization of aldehyde 6 followed by acidic etherification. They access the core in 10 steps and 11% overall yield. 10 steps 11% overall yield Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Nicolaou’s First Enantioselective Formal Synthesis Retrosynthesis Analysis
2 strategies: asymmetric cycloisomerization cyclodearomatization Nicolaou’s group reported the first enantioselective total synthesis of Platensimycin. There approach is the same as what we described previously. They envisge preparing the aldehyde key intermediate 6 as a sole enantiomer. They propose 2 different strategies to access the optically active aldehyde 6. The first approach is to prepare 6 via asymetric cycloisomerization. The second approach is to prepare 6 via cyclodearomatization of phenol 28 that should be obtain from 29. Chiral ketone 29 would be formed via asymetric alkyklation. Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.

Nicolaou’s First Enantioselective Formal Synthesis 1st Approach: Asymmetric Cycloisomerization
The first approach to access the chiral aldehyde precursor 6 use an asymetric version of the Trost ruthenium catalyzed cycloisomerization. This asymetric version of the reaction was developed by Zhang. Nicolaou’s group tried the reaction first with 2 derivatives of compound 27 without success. They tried the reaction with the terminal acetylene derivative and the correspounding TMS-acetylene derivative. Both failed to give the desired product. The problem was overcame by preparing compound 27 starting from enone 7 that we described the synthesis previously in the talk. Enone 7 was first protected as a silyl enol ether and this ester group was introduced by deprotonation of the terminal alkyne and reaction of the resulting anion with Mander’s reagent. The silyl enol ether was than oxydized to the enone with IBX and the allylic alcohol was finally deprotected under acidic conditions. Cycloisomerization precursor was prepared starting from 7 in 61% overall yield in 4 steps. Enantioselective cycloisomerization steps leads to the chiral aldehyde 28 in excellent yield and with ee gratter than 95%. The aldehyde fonctionnality was first protected as an acetal and the carboxylate group was remove via Barton radical decarboxylation. The mechanism of this reaction will be explain in the next slide. Finally, the acetal was cleave under acidic conditions. Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.

Nicolaou’s First Enantioselective Formal Synthesis 2nd Approach: Cyclodearomatization
The second enantioselective approach proposed by Nicolaou in is paper pass through an asymetric alkylation and a cyclodearomatization. Carboxylic acic 40 was coupled with a chiral auxiliary and than alkylated with benzylic bromide 43 in 87% yield and 85% diastereoisomeric excess. Diastereomerically pure 44 was obtained by a single recristallization. The chiral auxiliary was cleaved with methyl lithium, leading to ketone 29. Enantiomeric excess of ketone 29 was determined by chiral HPLC and appeared to be gratter than 98%. Ketone 29 was converted to enol triflate 45 using Comin’s reagent and the allylsylane moiety was introduced via Kumada cross coupling reaction. The TBS protecting group was removed under acidic conditions. Many different conditions were tried for the dearomative cyclization step and it appeared that best results were obtained using diacetoxyiodobenzene in trifluoroethanol at -10°C. Finally, the aldehyde moiety was release under acidic conditions. Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.

Cyclodearomatization mechanism
The Nicolaou’s intermediate was obtained in the same manner as described previously: samarium iodide promoted radical cyclization followed by acidic etherification. In summary, the Nicolaou intermediate was obtained as its enantioenriched form in 9 steps and 10% overall yield.

Nicolaou’s First Enantioselective Formal Synthesis
Compound 34 undergoes the same reaction sequence as its exocyclic isomer leading to Nicolaou’s intermediate in 34% overall yield. It is interesting to note that alcohol 35 is obtain this time as a single diastereoisomer in contrast to the reaction with the exocyclic compound that lead to a 2:1 diastereomeric ratio. This excellent stereocontrol permit to access Nicolaou’s intermediate in grater yield. In summary, this secound strategy leads to the enantioenriched Nicolaou intermediate in about 5% overall yield in 12 steps. 12 steps 6% overall yield 10 steps 10 % overall yield Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.

Snider’s and Nicolaou’s Racemic Formal Synthesis
We have described so far the first general approach used by Nicolaou to access the core of Platensimycin. He starts from spiroaldehyde 6 that undergoes intramolecular radical conjugate addition to lead to alcohol 5 that undergoes etherification under acidic condition. Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett. 2007, 9 (9), 1825.

Snider’s Racemic Formal Synthesis
Snider strategy was inspired by the work of Marinovic published in TL in Snider synthesis starts from 5-methoxy-1-tetralone that undergo reductive alkylation with 2,3-dibromopropene to give enone 46 in 86% yield with a 10 to 7 diastereoisomeric ratio. Both diastereoisomers can be separated. The major one is the desired one. The undesired trans product can be equilibrated under acidic conditions. At the equilibrum, there is a 4:3 mixture of diastereoisomers, the major one being the desired one again. So, they did the first reaction, and they treated the undesired diastereoisomer under acidic condition to recuperate some material. They obtained 70% overall yield of the compound 46a. 7 steps 23% overall yield Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett. 2007, 9 (9), 1825.

Snider’s Racemic Formal Synthesis
Snider strategy was inspired by the work of Marinovic published in TL in Snider synthesis starts from 5-methoxy-1-tetralone that undergo reductive alkylation with 2,3-dibromopropene to give enone 46 in 86% yield with a 10 to 7 diastereoisomeric ratio. Both diastereoisomers can be separated. The major one is the desired one. The undesired trans product can be equilibrated under acidic conditions. At the equilibrum, there is a 4:3 mixture of diastereoisomers, the major one being the desired one again. So, they did the first reaction, and they treated the undesired diastereoisomer under acidic condition to recuperate some material. They obtained 70% overall yield of the compound 46a. Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett. 2007, 9 (9), 1825.

Nicolaou’s Racemic Formal Synthesis
The radical cyclization precursor 47a was obtained via this route. First, bis alkylation of ethoxycyclohexenone afford compound 58 in moderate yield. Reduction with DIBAL-H followed by treatment of the resulting allylic alcohol under acidic conditions leads to enone 59 in excellent yield. Oxydation of the silyl enole ether derived from 59 affords dienone 60 in 77% yield over 2 steps. Alcohol deprotection followed by oxidation gives aldehyde 61 in 90% yield. Finally, Stetter reaction foremed the bicylo diketone 47a as a single diastereoisomer in 64% yield. Nicolaou, K. C., Tang, Y., Wang, Chem. Commun. 2007, 1922.

Stetter’s reaction mechanism
The radical cyclization precursor 47a was obtained via this route. First, bis alkylation of ethoxycyclohexenone afford compound 58 in moderate yield. Reduction with DIBAL-H followed by treatment of the resulting allylic alcohol under acidic conditions leads to enone 59 in excellent yield. Oxydation of the silyl enole ether derived from 59 affords dienone 60 in 77% yield over 2 steps. Alcohol deprotection followed by oxidation gives aldehyde 61 in 90% yield. Finally, Stetter reaction foremed the bicylo diketone 47a as a single diastereoisomer in 64% yield.

Snider’s and Nicolaou’s Racemic Formal Synthesis
7 steps 23 % overall yield They selectivly protected the enone carbonyl of compound 47a as a thioacetal in 80% yield. IBX oxydation of silyl enol ether derived from 62 afforded enone undergoes radical conjugate addition in good yield. Reduction of ketone 50 was problematic and most conditions tried leads to the formation of the undesired equatorial alcohol isomer. Best results were obtained with L-selectride. The undesired diastereoisomer can be recuperate by oxydation with DMP to reforme ketone 50 that can be reduced again. Alcohol 63a undergoes etherification under acidic conditions to afford 51 in 90% yield. Finally, deprotection of the enone was performed under oxydative conditions. This approach gives access to the Nicolaou’s intermediate in 15 steps with an overall yield of 5%. Nicolaou 15 steps 8 % overall yield

Yamamoto’s Enantioselective Formal Synthesis Retrosynthetic Analysis
The next synthesis expose a completly different strategy for the preparation of the Nicalaou’s intermediate. Yamamoto’s group endvisaged to prepare 4 via diastereoselective Robinson annulation. The Robinson annulation precursor can be redrawn in 2D and would come from lactone 66. Lactone 66 would be obtain through BV oxydative rearrangment of ketone 67 that can be obtained as a single enantiomer using an enantioselective Diels-Alder reaction developped in Yamamoto’s laboratory. Li, P., Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.

Yamamoto’s Enantioselective Formal Synthesis
The synthesis starts by enantioselective Diels-Alder reaction catalyzed by a Bronsted acid assited chiral lewis acid. I’ll talk more in details about this reaction in the next slide. Ester 70 was converted to ketone 67 in good yield by formation of the nitroso adduct that was hydrolysed under basic conditions. Baeyer-Villiger oxidation of ketone 67 under basic conditions gave lactone 66 in moderate yield through hydrolysis of the first Baeyer-Villiger product followed by dehydrative lactonization. Addition of vinyl cuprate reagent to lactone 66 leads to the carboxylic acid that was than relactonize. Reduction of the lactone 71 with DIBAL-H followed by LA mediated cyanation afford compound 72 without any stereocontrol control at the new form chiral center. Both compounds are separable and the undesired diastereoisomer can be epimerized to recuperate some of the desired material. Li, P., Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.

Yamamoto’s Enantioselective Diels-Alder Reaction
This slide illustrates the transition states of the enantioselective Diels-Alder reaction developped in Yamamoto’s laboratory. As we all know, monosubstituted cyclopentadiene existe as a mixture of regioisomers because it undergoes a facile [1,5]-sigmatropic rearrangment at temperature under 0°C. The Yamamoto’s approach to access enantioselective Diels-Alder adducts is highly regioselective and enantioselective. The dienophile first complexe with the chiral catalyst. As we can see in this sheme, one face of the dienophile is shield by the phenyl group at the back, so the diene approach is only possible from front. Both regioisomers of the diene are present in the reaction mixture. In the case of the 1 substituted cyclopentadiene, the endo approach is not possible because the steric hinderence between the substituant and the phenyl group drawn in red that is pointing in front of us. Those, this regioisomer do not react. However, 2-substituted cyclopentadiene is oriented in the TS in a way that the R substituant is pointing away from the catalyst-dienophile complexe resulting in a much lower energy transition state. TS disfavored Steric interaction between R and phenyl in red TS favored Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9536.

The synthesis starts by enantioselective Diels-Alder reaction catalyzed by a Bronsted acid assited chiral lewis acid. I’ll talk more in details about this reaction in the next slide. Ester 70 was converted to ketone 67 in good yield by formation of the nitroso adduct that was hydrolysed under basic conditions. Baeyer-Villiger oxidation of ketone 67 under basic conditions gave lactone 66 in moderate yield through hydrolysis of the first Baeyer-Villiger product followed by dehydrative lactonization. Addition of vinyl cuprate reagent to lactone 66 leads to the carboxylic acid that was than relactonize. Reduction of the lactone 71 with DIBAL-H followed by LA mediated cyanation afford compound 72 without any stereocontrol control at the new form chiral center. Both compounds are separable and the undesired diastereoisomer can be epimerized to recuperate some of the desired material. Li, P., Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.

Cyanide 72a was reduced to the corresponding aldehyde wich was subjected to Wadsworth-Emmons conditions to give enone 74 in 65% yield over 2 steps. Ruthenium catalyzed oxidative cleavage of the terminal olefin gave aldehyde 64 in 59% yield. The reaction didn’t go to completion and 27% of starting material was recovered. The final key Robinson annulation event was accomplished one pot using L-proline as a chiral control element to mediate the initial intramolecular Michael addition. Addition of aqueous sodium hydroxide promote the dehydration of the beta hydroxy ketone resulting from the previous aldol reaction. To summarize, Nicolaou’s intermediate was obtain as a single diastereoisomer in 10 steps and 5% overall yield using the Yamamoto’s approach. 10 steps 5 % overall yield Li, P., P. J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.

Kaliappan’s Enantioselective Formal Synthesis Model Study Preparation
The next synthesis is the work of a group research from Austria. They access the core of Platensimycin from compound 78, that they prepared according to a methode previously described in the litterature. This methode is described below and strats from 6-methoxy-1-tetralone. 79 was first reduce to the alcohol using NaBH4. Vilsmeier reaction followed by oxydation with Silver oxide leads to carboxylic acid 80 in 54% yield over 3 steps. Compound 80 was reduced under catalytic hydrogenation conditions to afford compound 81 in quantitative yield. Carboxylic acid 81 was converted to the correspounding acid chloride and treated with TMS diazomethane to afford the correspounding diazoketone that was cyclized under acidic conditions to afford intermediate 78 in 59% yield over 3 steps. 12 steps 3% overall yield Kaliappan, K. P., Ravikumar, V. Org. Lett. 2007, 9, 2417.

Mulzer’s Racemic Formal Synthesis Retrosynthetic Analysis
The next synthesis is the work of a group research from Austria. They access the core of Platensimycin from compound 78, that they prepared according to a methode previously described in the litterature. This methode is described below and strats from 6-methoxy-1-tetralone. 79 was first reduce to the alcohol using NaBH4. Vilsmeier reaction followed by oxydation with Silver oxide leads to carboxylic acid 80 in 54% yield over 3 steps. Compound 80 was reduced under catalytic hydrogenation conditions to afford compound 81 in quantitative yield. Carboxylic acid 81 was converted to the correspounding acid chloride and treated with TMS diazomethane to afford the correspounding diazoketone that was cyclized under acidic conditions to afford intermediate 78 in 59% yield over 3 steps. Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed. 2007, 46, 8074. * References cited in the previous paper

Mechanism The next synthesis I’ll present to you use a different strategy from what we have seen so far. Corey’s group endvisage to access the core of Platensimycin via bromination of this terminal double bond that should lead to bromo ether 84. Phenol deprotection should form the last ring by bromide displace and afford dienone 76 that would be monoreduced to give Nicolaou’intermediate. They envisage obtaining phenol intermediate 85 as a single enantiomer from methoxy alpha naphtol using enantioselective conjugate addition methodology.

Mulzer’s Racemic Formal Synthesis
The next synthesis is the work of a group research from Austria. They access the core of Platensimycin from compound 78, that they prepared according to a methode previously described in the litterature. This methode is described below and strats from 6-methoxy-1-tetralone. 79 was first reduce to the alcohol using NaBH4. Vilsmeier reaction followed by oxydation with Silver oxide leads to carboxylic acid 80 in 54% yield over 3 steps. Compound 80 was reduced under catalytic hydrogenation conditions to afford compound 81 in quantitative yield. Carboxylic acid 81 was converted to the correspounding acid chloride and treated with TMS diazomethane to afford the correspounding diazoketone that was cyclized under acidic conditions to afford intermediate 78 in 59% yield over 3 steps. Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed. 2007, 46, 8074. * References cited in the previous paper

Corey’s Enantioselective Formal Synthesis Retrosynthetic Analysis
The next synthesis I’ll present to you use a different strategy from what we have seen so far. Corey’s group endvisage to access the core of Platensimycin via bromination of this terminal double bond that should lead to bromo ether 84. Phenol deprotection should form the last ring by bromide displace and afford dienone 76 that would be monoreduced to give Nicolaou’intermediate. They envisage obtaining phenol intermediate 85 as a single enantiomer from methoxy alpha naphtol using enantioselective conjugate addition methodology. Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921.

Corey’s Enantioselective Formal Synthesis
The synthesis strats from methoxy alpha naphtol. Oxidative ketalisation of compound 88 leads to monoprotected napthoquinone 87 in 80% yield. Enantioselective propenyl conjugate addition on enone 96 affords compound 86 in excellent yield an excellent enantioselectivity. They said in the paper that it is important to use triethylamine in this reaction because it accelerate the reaction, so it can be done at lower temperature. 2-propenyl rhodium intermediate is unstable at high temperature and undergoes beta hydride elimination that generate the 1-propenyl conjugate adduct. Diastereoselective reduction of the ketone followed by protection of the resulting alcohol with a MEM group gives compound 89. Acetal 89 was deprotected and the resulting ketone was reduced with DIBAL-H to the corrspounding alcohol that was finally deoxygenated. Compound 90 was prepared in 79% overall yield starting from 86. Phenol was finally deprotected under mild conditions. 12 steps 26 % overall yield enantioenriched Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921.

Corey’s Enantioselective Formal Synthesis
The synthesis strats from methoxy alpha naphtol. Oxidative ketalisation of compound 88 leads to monoprotected napthoquinone 87 in 80% yield. Enantioselective propenyl conjugate addition on enone 96 affords compound 86 in excellent yield an excellent enantioselectivity. They said in the paper that it is important to use triethylamine in this reaction because it accelerate the reaction, so it can be done at lower temperature. 2-propenyl rhodium intermediate is unstable at high temperature and undergoes beta hydride elimination that generate the 1-propenyl conjugate adduct. Diastereoselective reduction of the ketone followed by protection of the resulting alcohol with a MEM group gives compound 89. Acetal 89 was deprotected and the resulting ketone was reduced with DIBAL-H to the corrspounding alcohol that was finally deoxygenated. Compound 90 was prepared in 79% overall yield starting from 86. Phenol was finally deprotected under mild conditions.

Ghosh’s Enantiospecific Formal Synthesis Retrosynthetic Analysis
Ghosh approach is based upon an intramolecular Diels-Alder that would construct the tetracyclic core of Platensimycin in a stereocontrolled manner. So, ester 91a should come from the Diels-Alder precursor 92 that would come from bicyclic ketone 94. Bicyclic ketone 94 would come from carvone that is commercially available in both enantiomeric form. Ghosh, A., Xi, K. Org. Lett. 2007, 9, 4013.

Ghosh’s Enantiospecific Formal Synthesis
Lactone 101 was prepared using a method previously described in the litterature form carvone 95. Oxymercuration/Reductive-Alkylation of 95 leads to keto alcohol 96. Keto alcohol 96 was oxydized using mCPBA to give bicyclo latone 101 possessing a methyl ketone substituant. In the paper they cited, oxydation of the keto alcohol 96 with mCPBA leads the lactone possessing a methyl ester instead of a methyl ketone. They proposed in the primary litterature that first BV product 98 is formed. The 7-member ring lactone can open and form an other 5-member ring lactone that is more favored thermodynamicly. Under oxydative condition, the secondary alcohol can be converted to the corresponding ketone that finally undergoes a secong BV reaction. They said in Ghosh paper that BV oxydation of lactone 101 with mCPBA is difficult and yield to 97 in only 20%. So, they choose to stop the reaction at the keto lactone 101. Ghosh, A. K., Xi, K. Org. Lett. 2007, 9, 4013.

Oxymercuration/Reductive-Alkylation Mechanism
First, addition of mercury acetate to the terminal alkene under aqueous conditions results in selective Markovnikov oxymercuration. The alkyl mercury acetate is then reduced to the alkyl mercury hydride using NaBH4. Alkyl mercury hydrides are unstable intermediates which forms alkyl radical at room temperature. The primary radical formed can now undergoes intramolecular conjugate addition to the enone to form keto alcohol 116.

Ghosh’s Enantiospecific Formal Synthesis
They finally heated the isomeric mixture of compound 92 at 200°C in chlorobenzene for the final Diels-Alder key step. Only the E isomer undergoes Diels-Alder reaction to afford methoxy ester 91a in 39% yield, that is pretty good considering the fact that only 50% of the starting material is reacting. The Z isomer does not react and 38% of compound 92b was recovered at the end of the reaction. The Diels-Alder TS in the case of the Z isomer is probably pretty high in energy due to the steric interraction between the methoxy group and the bycyclic ether here so the reaction doesn’t occur. Even if the last steps of this synthesis are not optimal, I like this approach because it is different from what people have tried so far. 20 steps 4% overall yield Ghosh, A. K., Xi, K. Org. Lett. 2007, 9, 4013.

Nicolaou’s Enantiospecific Formal Synthesis
The next step is the formation of the 6 member ring ketone at the back. Stetter reaction of aldehyde 113 leads to an inseparable mixture of epimeric diketone 111 as a 1:5 mixture, the undesired epimer being favored. Interrestingly, when they treated aldehyde 113 with samarium iodide, they observed they observed the formation of a single stereoisomer of alkoxy ketone 121. The stereocontrol of the reaction can be explain by the formation of a chelate transition state. Nicolaou, K. C., Li, A., Edmons, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Nicolaou’s Enantiospecific Formal Synthesis
The next step is the formation of the 6 member ring ketone at the back. Stetter reaction of aldehyde 113 leads to an inseparable mixture of epimeric diketone 111 as a 1:5 mixture, the undesired epimer being favored. Interrestingly, when they treated aldehyde 113 with samarium iodide, they observed they observed the formation of a single stereoisomer of alkoxy ketone 121. The stereocontrol of the reaction can be explain by the formation of a chelate transition state. 14 steps 1.3 % overall yield Nicolaou, K. C., Li, A., Edmons, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.

Conclusion

Anknowledgment Group members: Pr. Louis Barriault Steve Arns
Francis Barabé Éric Beaulieu Anik Chartrand Anna Chkrebtii Christiane Grisé Geneviève L. Bétournay Patrick Lévesque Daniel Newbury Jason Poulin Maxime Riou Catherine Séguin

Cyanide 72a was reduced to the corresponding aldehyde wich was subjected to Wadsworth-Emmons conditions to give enone 74 in 65% yield over 2 steps. Ruthenium catalyzed oxidative cleavage of the terminal olefin gave aldehyde 64 in 59% yield. The reaction didn’t go to completion and 27% of starting material was recovered. The final key Robinson annulation event was accomplished one pot using L-proline as a chiral control element to mediate the initial intramolecular Michael addition. Addition of aqueous sodium hydroxide promote the dehydration of the beta hydroxy ketone resulting from the previous aldol reaction. To summarize, Nicolaou’s intermediate was obtain as a single diastereoisomer in 10 steps and 5% overall yield using the Yamamoto’s approach. Li, P., P. J. N., Yamamoto, H. J. Am. Chem. Soc., 2007, 129, 9534

Antibacterial Agents Introduction
5 main mechanisms of action: Inhibition of cell metabolism Inhibition of bacterial cell wall synthesis Interactions with the plasma membrane Disruption of protein synthesis Inhibition of nucleic acid transcription and replication There is fve main mechanism of action by which antibacterial agents act (énumération). I’ll explain them in more details in the next slides. Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp

Inhibition of cell metabolism
This is some example of sulfonamides drugs. Notice that acylation of the aniline is tolerate because the amide bond can be metabilized in the body. This permit to release the antibiotics were we want it to act because it is metabolized in the intestin. Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp

Inhibition of cell metabolism
An important class of compound that acts as anti-metabolite are sulfonamides. There is an example here at the bottom. Many sulfonamides are used to treat differents types of infections. Most structural modifications occurs at this part of the molecule. Sulfonamides are inhibitors of dihydropteroate synthetase and block the biosynthesis of tetrahydrofolate. Tetrahydrofolate is necessary for the replication of bacterial cells because it is involved in the synthesis of the pyrimidine nucleic acid bases required for DNA synthesis. Sulfonamides are bacteriostatic angents because they prevent cells to grow and multiply. This allows enough time to the immune system to kill bacteria. Another antimetabolite called trimethoprim block the biosynthesis of tetrahydrofolate to by inhibiting another ezyme called dihydrofolate reductase. It is used in conjuction with sulfamethoxazole for the treatment of malaria. Sulfones are other inhibitors of dihydroteroate synthetase and are used for the treatment of leprosis. Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp

Inhibition of cell metabolism Resistance
Sulfonamides are reversible inhibitor of dihydropteroate synthetase, so resistance by synthesizing more PABA - Resistance by mutations, modifications of the dihydropteroate synthetase which result in less affinity for sulfonamides or modifications of the cell membrane which result in less permeability to the sulfonamides Some bacteria gained resistance to sulfonamides. Sulfonimides are reversible inhibitor of dihydropteroate synthetase so the bacteria can react by synthesizing more PABA. There is bacteria that mutate and that has dihydropteroate synthetase that presents less affinity for sulfonamides. Mutation can leads to bacteria that presents a cell membrane with less permeability to the sulfonamides. Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp

Barton Radical Decarboxylation Mechanism
Barton ester 31 was prepared in 2 steps starting from the correspounding methyl ester. The methyl ester was first hydrolyse and the resulting carboxylic acid was couple with 2-mercaptopyridine N-oxide. Treatement of 31 with tributyl tin hydride and light starts the radical sequence illustrate here. They evisage that radical 33 will be quench by tributyl tin hydride and generate expected product 34. It appears that radical 33 undergoes a 1,3 hydride shift before being quench by HSnBu3 at the less indered primary end leading to compound 30 possessing an endocyclic double bound.

Nicolaou First Enantioselective Total Synthesis 1st Approach: Asymmetric Cycloisomerization
The first approach to access the chiral aldehyde precursor 6 use an asymetric version of the Trost ruthenium catalyzed cycloisomerization. This asymetric version of the reaction was developed by Zhang. Nicolaou’s group tried the reaction first with 2 derivatives of compound 27 without success. They tried the reaction with the terminal acetylene derivative and the correspounding TMS-acetylene derivative. Both failed to give the desired product. The problem was overcame by preparing compound 27 starting from enone 7 that we described the synthesis previously in the talk. Enone 7 was first protected as a silyl enol ether and this ester group was introduced by deprotonation of the terminal alkyne and reaction of the resulting anion with Mander’s reagent. The silyl enol ether was than oxydized to the enone with IBX and the allylic alcohol was finally deprotected under acidic conditions. Cycloisomerization precursor was prepared starting from 7 in 61% overall yield in 4 steps. Enantioselective cycloisomerization steps leads to the chiral aldehyde 28 in excellent yield and with ee gratter than 95%. The aldehyde fonctionnality was first protected as an acetal and the carboxylate group was remove via Barton radical decarboxylation. The mechanism of this reaction will be explain in the next slide. Finally, the acetal was cleave under acidic conditions. Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942

Nicolaou First Enantioselective Total Synthesis Asymmetric Cycloisomerization Approach
Compound 34 undergoes the same reaction sequence as its exocyclic isomer leading to Nicolaou’s intermediate in 34% overall yield. It is interesting to note that alcohol 35 is obtain this time as a single diastereoisomer in contrast to the reaction with the exocyclic compound that lead to a 2:1 diastereomeric ratio. This excellent stereocontrol permit to access Nicolaou’s intermediate in grater yield. In summary, this secound strategy leads to the enantioenriched Nicolaou intermediate in about 5% overall yield in 12 steps. 12 steps 5.6% overall yield enantioenriched Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942

Nicolaou First Enantioselective Total Synthesis Cyclodearomatization Approach
The second enantioselective approach proposed by Nicolaou in is paper pass through an asymetric alkylation and a cyclodearomatization. Carboxylic acic 40 was coupled with a chiral auxiliary and than alkylated with benzylic bromide 43 in 87% yield and 85% diastereoisomeric excess. Diastereomerically pure 44 was obtained by a single recristallization. The chiral auxiliary was cleaved with methyl lithium, leading to ketone 29. Enantiomeric excess of ketone 29 was determined by chiral HPLC and appeared to be gratter than 98%. Ketone 29 was converted to enol triflate 45 using Comin’s reagent and the allylsylane moiety was introduced via Kumada cross coupling reaction. The TBS protecting group was removed under acidic conditions. Many different conditions were tried for the dearomative cyclization step and it appeared that best results were obtained using diacetoxyiodobenzene in trifluoroethanol at -10°C. Finally, the aldehyde moiety was release under acidic conditions. Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942

Nicolaou First Enantioselective Total Synthesis Cyclodearomatization Approach
The Nicolaou’s intermediate was obtained in the same manner as described previously: samarium iodide promoted radical cyclization followed by acidic etherification. In summary, the Nicolaou intermediate was obtained as its enantioenriched form in 9 steps and 10% overall yield. 9 steps 10.5 % overall yield enantioenriched Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942

Snider Racemic Formal Synthesis
Snider strategy was inspired by the work of Marinovic published in TL in Snider synthesis starts from 5-methoxy-1-tetralone that undergo reductive alkylation with 2,3-dibromopropene to give enone 46 in 86% yield with a 10 to 7 diastereoisomeric ratio. Both diastereoisomers can be separated. The major one is the desired one. The undesired trans product can be equilibrated under acidic conditions. At the equilibrum, there is a 4:3 mixture of diastereoisomers, the major one being the desired one again. So, they did the first reaction, and they treated the undesired diastereoisomer under acidic condition to recuperate some material. They obtained 70% overall yield of the compound 46a. Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825

They submit compound 46a through radical cyclization conditions and tricyclic compound 47a was obtained in 84% yield. The trans isomer 46b can undergo radical cyclization under the same conditions. The tried to epimerize at this stage but this time, it is the undesired trans product that is favored at the equilibrum. Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825

Let just redraw compound 47a in 3D so it will be easier to understand the next reactions. Dione 47a was reduced using L-selectride. The less hindered ketone was reduced at -78°C and no selectivity was observed at this center. The more hindered ketone was reduced at rt and a 12:1 selectivity for the alcohol at the axial position was observed. Those compound cannot be separated, so the mixture was submited to Nicolaou’s acidic etherification conditions to afford alcohols 48a and 48b 81% yield as a 1:1 mixture. Those diastereoisomers can be separated. Alcohol 48a was converted to the corresponding triflate which did undergo E2 elimination under basic condition to afford compound 55 in 90% yield. They treated the equatorial alcohol under the same conditions and they observed no elimination because there is no hydrogen antiperiplanar to the triflate. They treated the triflate under conditions that promote E1 elimination and obtain compound 55 in 84% yield. Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825

They tried differents conditions for the allylic oxidation step. First, they try with chromium oxide dimethylpyrazole and they obtain the desired product with his regioisomer as a 4:1 unseparable mixture. Using 8 equiv of SeO2, they observed major formation of undesired dienone 58. They found that by reducing the number of equivalent of SeO2 and by reducing the reaction time, they avoid the formation of the overoxidized product 58. Allylic alcohol 56 can be converted to Nocolaou’s intermediate by smooth oxydation with MnO2 in excellent yield. To resume, Snider’s group was able to synthesize Nicolaou’s intermediate in 7 steps and 32% overall yield. This final results account for 2 recuperation steps, were the undesired diastereoisomer is epimerized into the desired one. 7 steps (+ 2 recuperation steps) 32 % overall yield racemic Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825

Nicolaou Racemic Formal Synthesis
The radical cyclization precursor 47a was obtained via this route. First, bis alkylation of ethoxycyclohexenone afford compound 58 in moderate yield. Reduction with DIBAL-H followed by treatment of the resulting allylic alcohol under acidic conditions leads to enone 59 in excellent yield. Oxydation of the silyl enole ether derived from 59 affords dienone 60 in 77% yield over 2 steps. Alcohol deprotection followed by oxidation gives aldehyde 61 in 90% yield. Finally, Stetter reaction foremed the bicylo diketone 47a as a single diastereoisomer in 64% yield. Nicolaou, K. C., Tang, Y., Wang, J. Chem. Commun., 2007, 1922

Nicolaou Racemic Formal Synthesis
They selectivly protected the enone carbonyl of compound 47a as a thioacetal in 80% yield. IBX oxydation of silyl enol ether derived from 62 afforded enone undergoes radical conjugate addition in good yield. Reduction of ketone 50 was problematic and most conditions tried leads to the formation of the undesired equatorial alcohol isomer. Best results were obtained with L-selectride. The undesired diastereoisomer can be recuperate by oxydation with DMP to reforme ketone 50 that can be reduced again. Alcohol 63a undergoes etherification under acidic conditions to afford 51 in 90% yield. Finally, deprotection of the enone was performed under oxydative conditions. This approach gives access to the Nicolaou’s intermediate in 15 steps with an overall yield of 5%. 15 steps 5 % overall yield racemic Nicolaou, K. C., Tang, Y., Wang, J. Chem. Commun., 2007, 1922

Mulzer Racemic Formal Synthesis Retrosynthetic Analysis
The next synthesis is the work of a group research from Austria. They access the core of Platensimycin from compound 78, that they prepared according to a methode previously described in the litterature. This methode is described below and strats from 6-methoxy-1-tetralone. 79 was first reduce to the alcohol using NaBH4. Vilsmeier reaction followed by oxydation with Silver oxide leads to carboxylic acid 80 in 54% yield over 3 steps. Compound 80 was reduced under catalytic hydrogenation conditions to afford compound 81 in quantitative yield. Carboxylic acid 81 was converted to the correspounding acid chloride and treated with TMS diazomethane to afford the correspounding diazoketone that was cyclized under acidic conditions to afford intermediate 78 in 59% yield over 3 steps. Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed., 2007, 46, 8074 * References cited in the previous paper

Mulzer Racemic Formal Synthesis
Diastereoselective Grignard methylation followed by allylic bromination leads to bromo alcohol 77 that cylized under basic conditions to give dienone 76 in good yield. Finally, complete reduction of 76 affords ketone 83 as a 2:1 dr. Ketone 76 was reoxydized to the mono enone in moderate yield. 12 steps 7 % overall yield enantioenriched Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed., 2007, 46, 8074

Corey Enantioselective Synthesis of the Core Retrosynthetic Analysis
The next synthesis I’ll present to you use a different strategy from what we have seen so far. Corey’s group endvisage to access the core of Platensimycin via bromination of this terminal double bond that should lead to bromo ether 84. Phenol deprotection should form the last ring by bromide displace and afford dienone 76 that would be monoreduced to give Nicolaou’intermediate. They envisage obtaining phenol intermediate 85 as a single enantiomer from methoxy alpha naphtol using enantioselective conjugate addition methodology. Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921

Corey Enantioselective Synthesis of the Core
The synthesis strats from methoxy alpha naphtol. Oxidative ketalisation of compound 88 leads to monoprotected napthoquinone 87 in 80% yield. Enantioselective propenyl conjugate addition on enone 96 affords compound 86 in excellent yield an excellent enantioselectivity. They said in the paper that it is important to use triethylamine in this reaction because it accelerate the reaction, so it can be done at lower temperature. 2-propenyl rhodium intermediate is unstable at high temperature and undergoes beta hydride elimination that generate the 1-propenyl conjugate adduct. Diastereoselective reduction of the ketone followed by protection of the resulting alcohol with a MEM group gives compound 89. Acetal 89 was deprotected and the resulting ketone was reduced with DIBAL-H to the corrspounding alcohol that was finally deoxygenated. Compound 90 was prepared in 79% overall yield starting from 86. Phenol was finally deprotected under mild conditions. Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921

Corey Enantioselective Synthesis of the Core
The phenol group was reprotected with a silyl group. Reaction of the terminal alkene with bromine affords the bicyclic bromo ether 84 in 84% with excellent diastereoselectivity. Deprotection of the phenol group with TBAF complete the formation of the cage like structure. Diastereoselective bishydrogenation using a chiral ruthenium complexe affords ketone 90 in good yield. Finally, ketone 90 was converted to the corresponding silyl enol ether and oxydized to the enone to give Nicolaou’s intermediate in 80% yield. Corey’s approach is prelly efficient as it leads to the Nicolaou’s intermediate as a single enantiomer in 26% overall yield in 12 steps starting from achiral alpha methoxy naphthol. 12 steps 26 % overall yield enantioenriched Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921

Ghosh Enantiospecific Formal Synthesis Retrosynthetic Analysis
Ghosh approach is based upon an intramolecular Diels-Alder that would construct the tetracyclic core of Platensimycin in a stereocontrolled manner. So, ester 91a should come from the Diels-Alder precursor 92 that would come from bicyclic ketone 94. Bicyclic ketone 94 would come from carvone that is commercially available in both enantiomeric form.

Ghosh Enantiospecific Formal Synthesis
Lactone 101 was prepared using a method previously described in the litterature form carvone 95. Oxymercuration/Reductive-Alkylation of 95 leads to keto alcohol 96. Keto alcohol 96 was oxydized using mCPBA to give bicyclo latone 101 possessing a methyl ketone substituant. In the paper they cited, oxydation of the keto alcohol 96 with mCPBA leads the lactone possessing a methyl ester instead of a methyl ketone. They proposed in the primary litterature that first BV product 98 is formed. The 7-member ring lactone can open and form an other 5-member ring lactone that is more favored thermodynamicly. Under oxydative condition, the secondary alcohol can be converted to the corresponding ketone that finally undergoes a secong BV reaction. They said in Ghosh paper that BV oxydation of lactone 101 with mCPBA is difficult and yield to 97 in only 20%. So, they choose to stop the reaction at the keto lactone 101.

They obtain gratter amount of the ester derivative of 101 using those conditions. The ester was hydrolysed to alcohol 102 in good yield. The alcohol was protected with a TBS group and the lactone was subjected to Petasis olefination to give enol ether 103. Hydroboration of enol ether 103 leads to primary alcohol 104 in 81% yield as a 2:1 mixture of diastereoisomers. The major primary alcohol 104a was protected with TBDPS group and the secondary alcohol was selectivly deprotected using a catalytic amount of DDQ. Swern oxydation of alcohol 105 affords ketone 94 in excellent yield.

Petasis Olefination Mechanism

Horner-Emmons olefination using this chiral phosphonoacetate leads olephine 107 in a 3.2 to 1 mixture of E/Z isomers that can be separated by flash chromatography. Other conditions tried for this reaction provides only poor E/Z selectivity because the steric differentiation on each side of the carbonyl group in marginal. The ester 107a was reduced to allylic alcohol 108 using DIBAL in 86% yield. Allylic alcohol 108 was protected with a THP and the primary alcohol was unprotected using TBAF yielding to monoprotected alcohol 109 in excellent yield.

Alcohol 109 was oxidized under Swern conditions and the resulting aldehyde was submitted to Horner-Emmons olephination conditions to furnished the dienophile moiety with good E/Z selectivity. The THP protecting group was removed under acidic conditions to give allylic alcohol 110 in 65% yield over 3 steps. Dess-Martin oxydation followed by Witig olefination finally affords the Diels-Alder precursor 92 in 77% yield as a 1:1 mixture of E/Z isomers. Both isomers cannot be separated by flash chromatography.

They finally heated the isomeric mixture of compound 92 at 200°C in chlorobenzene for the final Diels-Alder key step. Only the E isomer undergoes Diels-Alder reaction to afford methoxy ester 91a in 39% yield, that is pretty good considering the fact that only 50% of the starting material is reacting. The Z isomer does not react and 38% of compound 92b was recovered at the end of the reaction. The Diels-Alder TS in the case of the Z isomer is probably pretty high in energy due to the steric interraction between the methoxy group and the bycyclic ether here so the reaction doesn’t occur. Even if the last steps of this synthesis are not optimal, I like this approach because it is different from what people have tried so far.

Nicolaou Enantiospecific Formal Synthesis Retrosynthetic Analysis
This is the latest synthesis of Platensimycin and it was published by Nicolaou recently. They andvisaged to prepare intermediate 4 via reduction etherification of bisketone 111. They planed to form the 6 member ring at the back via Stetter reaction or radical cyclization. Aldehyde 112 can be redrawn in this perspective and would come from compound 114 via radical cyclization to form this bond. Compound 114 would be prepared from carvone that is commercially available enantiomericly pur.

Nicolaou Enantiospecific Formal Synthesis
The synthesis starts from (R)-carvone. Fisrt, 1,2 griganrd addition using Luche conditions followed by oxydative rearrangment using PCC leads to enone 114 in 90% yield. Enone 114 than undergoes intramolecular radical cyclisation to give the desired bicyclic product 116 in 61% yield as a 1:1 mixture of exo and endo products. 20% of starting material was recovered. It was observed that the endo product exists predominantly as its hemiketal form. Lets examine more in details what happens during the intramolecular radical cyclization step.

Oxymercuration/Reductive-Alkylation Mechanism
First, addition of mercury acetate to the terminal alkene under aqueous conditions results in selective Markovnikov oxymercuration. The alkyl mercury acetate is then reduced to the alkyl mercury hydride using NaBH4. Alkyl mercury hydrides are unstable intermediates which forms alkyl radical at room temperature. The primary radical formed can now undergoes intramolecular conjugate addition to the enone to form keto alcohol 116.

Dehydration of the exo/endo mixture of 116 using Martin’s sulfurane (the structure of this reagent is drawn here) leads to the exocyclic alkene 114. They reported in the paper that among several dehydration protocols they tried, the only one that provided exclusively the exocyclic olefin is the one that use Martin’s sulfurane. Regioselective enone formation via selenoxyde elimination leads to compound 117 in 36% overall yield starting from 116. Finally, aldehyde deprotection in acidic conditions leads to the key step precursor 113 in good yield. Let see in more details whats happens during the conversion of 114 to 117.

Martin’s Sulfurane Dehydration Mechanism
Martin, J. C., Arhart, R. J. J. Amer. Chem. Soc. 1971, 93, 4327

Conversion of Ketones to Enones by Selenoxyde Syn Elimination
First, the most substituted silyl enol ether is formed under thermodynamic conditions. The nucleophilic protected enolate reacts with the electrophilic phenyl selenium chloride to give the alpha phenylseleno ketone that is than oxydixed with aqueous hydrogen peroxyde. Finally, the resulting selenoxide undergoes syn elimination to afford the desired alpha,beta unsaturated ketone.

The next step is the formation of the 6 member ring ketone at the back. Stetter reaction of aldehyde 113 leads to an inseparable mixture of epimeric diketone 111 as a 1:5 mixture, the undesired epimer being favored. Interrestingly, when they treated aldehyde 113 with samarium iodide, they observed they observed the formation of a single stereoisomer of alkoxy ketone 121. The stereocontrol of the reaction can be explain by the formation of a chelate transition state.

They tried to epimerize diketone 111 under basic conditions but it appears to be unstable. So they tried to epimerize keto alcohol under the same conditions and it appears to be resistant to epimerization. They found that if the alcohol 121a possess the reverse stereochemistry at this position it is possible to epimerize at the other position alpha to the carbonyl group.

Iversion of the hydroxy was performed under Mitsunobu conditions affords ester 122 in 67% yield. Hydrolysis of 122 under basic conditions leads to alcohol 123a that undergo epimerization alpha to the ketone under thoses conditions. Epimers 123a and 123b can be separated by flash chromatography. Reduction of the ketone followed by acidic etherification leads to tetracyclic alcohol 124 in 80% yield. Oxydation with PCC gives ketone 111 in excellent yield. Finally, Nicolaou’s key intermediate was obtained by selective monooxydization of ketone 111 via by Saegusa oxydation.

Synthesis and Biological Activity of Platensimycin

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