Platensimycin

By Talitha Pahs, Patrick Müller and Isabella Mladenova

Introduction

Platensimycin is a recently discovered antibiotic with a new mechanism of action, produced by the

bacterium Streptomyces platensis which was first isolated out of a South African soil sample by MSD

Sharp & Dohme, due to a Substance screening project. They have been searching for a target which is

able to inhibit Proteins like FabF being involved in the fatty acid synthesis, as they were successfully

detected by an Antisense RNA-Method to be necessary for the biosynthesis of the bacterial cell

membrane. The first chemical racemic total synthesis of Platensimycin was completed in 2006 by

MSD Sharp & Dohme1.[1]

1. MSD Sharp & Dohme is called Merck & Co., Inc. in Canada and USA [2]

The relevance of Platensimycin

Platensimycin (Fig.1) is a promising antibiotic against

several multi resistant gram-positive bacteria without

any cross-resistances observed concerning other

antibiotics like Vancomycin. It is assumed that fewer

bacteria build a resistance against Platensimycin,

which provides Platensimycin to be a possible reserve

antibiotic. Other points for Platensimycin being a

relevant antibiotic, is the selectivity as well as no

toxicity being observed in a murine model.

Furthermore Platensimycin might be a potent drug against Diabetes and related metabolic diseases.

Due to the extrusion mechanism of gram-negative bacteria which is pumping the target out of the

cell membrane, Platensimycin is not a suitable antibiotic against gram-negative bacteria as long as

the extrusion mechanism is not disturbed. [1]

The Synthesis of Platensimycin

The first total synthesis of racemic Platensimycin was reported in 2006 by Nicolaou and coworkers. Since then different Syntheses of the core substructure were developed by various groups in quite a short time. There are racemic and enantiopure synthesis. [3] Now there are more than 21 Syntheses for the core substructure. [3]

Synthesis in general

(Graphics: Information concerning the Mechanism [7] structures [8])

Synthesis of the aromatic fragment

There are two ways of making the aromatic fragment.

Nicolaou and co-worker start with a 2-Nitroresorcin which then gets two times a MOM

(Methoxymethyl) protection group. The next step is the reduction to an Amin that afterwards is

transformed to N-Boc (tert-Butoxycarbonyl)- Derivate. The carboxylic acid was made after an In-situ

Silylieration of the Carbamate through ortho-metallation. The removal of the Boc-protection group

made the Amin [8] that is needed for the Synthesis of Platensimycin. [6]

(Graphics: https://publikationen.uni-

tuebingen.de/xmlui/bitstream/handle/10900/49592/pdf/Dissertation_Max_Wohland_Endversion.pdf?sequence=1&isAllowed=y)

Giannis has in a not regioselective method Methyl-2,4-dihydroxybenzoat nitrated in a 1:1

assortment. The Isomers are easy to separate and there are two more reactions steps necessary to

get the final product. Because of that the Synthesis seems very efficient.

(Graphics:

https://publikationen.unituebingen.de/xmlui/bitstream/handle/10900/49592/pdf/Dissertation_Max_Wohland_Endversion.pdf?sequence=1

&isAllowed=y)

The Nicolaou Synthesis

Nicolaou and coworkers started with (R)-carvone, which was converted to branch derivate A. Thus, a

1-2 addition of a Grignard reagent in the present of Ce3Cl2 followed by allylic oxidation of the

resulting tertiary alcohol with transposition of the double bond gave [A]. [A] made a oxymercuration-

carbocyclization with Hg(OAc)2 and NaBH4 gave the bicyclic product [B] as a mixture of epimers. Then

an elimination with Martin’s sulfurane reagent led to the exocyclic olefin [C] which was converted to

the aldehyde [D] through the cleavage of the acetal. [D]was treated with SmI2 to give the tricyclic

product [E] as a single stereoisomer in a 57% yield. Subsequent occurred an inversion of

configuration by a Mitsunobu reaction, followed by treatment with base led to [F] in a 1:1 mixture of

diastereoisomers. Stereoselective reduction of the ketone, followed by an acidic work-up and then

an oxidation with PCC gave ketone [G]. This substrate was transformed into enone [H] and its

regioisomer in a 2:1 ratio. Double alkylation led to [I], which can be used to make Platensimycin. [3]

This mechanism led to cyclic ether as an intermediate which has been the pivotal „relay compound

for most of the subsequent formal syntheses of Platensimycin. [3]

(Graphics: http://ccc.chem.pitt.edu/wipf/courses/2320_08_files/HO/Nicolaou%20(Platensimycin,%202008).pdf structure of Platensimycin

[8] )

The Gosh Synthesis

The Gosh Synthesis started with an (S)-carvone [A]and was first reported in 2007 by Gosh and Xi.

Their strategy was based on the conversion of (S)-carvone into the known oxabicycle[3.3.0]octane

ketone [B]. [3]

[B] was made of [A] with an oxidation under Bayer-Villiger conditions in excellent yield. Then further

oxidation of the methyl ketone appendage gave the corresponding alcohol [C]. In the following step a

protection group as TBS ether was made and then an olefination according to Petasis, followed by

hydroboration which gave product [D] as a 2:1 mixture of isomers [6]. Deprotection of the TBS ether

with DDQ gave the corresponding secondary alcohol which following oxidized to the ketone. The

ketone was treated with chiral phosphonoacetate and gave product [E] in a seperavle 3.2:1 mixture

of E-/Z- esters. The reduction of product [E] led to the alcohol [F], which was prepared for the Diels-

Alder reaction. First a transformation led to the methoxydiene [H] and a following thermal

intramolceluar Diels-Alder reaction afforded the core substructure [I] as the O-methyl ether.

The core substructure is closely related to Nikolaou’s key intermediate, but does not make a formal

synthesis yet. [6]

(Graphics: http://onlinelibrary.wiley.com/doi/10.1002/anie.200705303/full)

Comparison with Nicolaou Synthesis

Both synthesises started with carvone but they use different enantiomers

Crucial for the conception of the synthesis plan was a similar radical carbon cycle closure

In the step of bicyclic ketone , the synthesis pathways differ : The product A was isolated in the

Gosh synthesis of its epimer [3]

Nikolaou’s two asymmetric syntheses

The first total synthesis of racemic

Platensimycin by Nicolaou and coworkers

was soon changed into an asymmetric

synthesis due to an enantioselective

cycloisomerization or diastereoselective

alkylation.

The enantioselective cycloisomerization

reaction started with substrate [A]which

react to the spirocyclic product [B] (in a

91% yield and high enantiomeric excess)

due to a Ru(II) catalyst according to

Zhang. The residual carboxylate function

needed to be removed, which was made

using the Barton’s method. During this

reaction there happened a 1,3 Hydrid

shift. Follwed by a hydrolysis of the acetal

group and the treatment of SmI2 led to

product [E]. [E] was treated with TFA and

react to the core substructure. [3] (Graphics [3],[8])

In the second asymmetric synthesis was an oxidative cycloaromatization of the key amid [B] due to

an acylation of (S , S) -pseudoephedrine with the carboxylic acid [A]. Following by an asymmetric

Myer- alkylation with benzyl bromide and LDA led to product [C]. In 4 steps the substrate [ D ] was

made. This is needed for the oxidative cyclodearomatzation, which is the key reaction. Substrate [E]

reacts in three steps to the optic active core substructure Platensimycin. [3]

( Graphics: http://www.unc.edu/depts/mtcgroup/litmeetings/platensimycin.pdf)

Yamamoto’s asymmetric synthesis

A profitable Synthesis of the core substructure of Platensimycin was developed in 2007 by Yamamoto

and coworkers. Substrate [B]was made by an asymmetric Diels-Alder reaction of

methylcyclopentadiene and methyl acrylate in a 92% yield and 99% ee. An N-nitrose aldol addition-

decarboxylation sequences led to the enantiomerically pure ketone [C]. Afterwards a Bayer-Villiger

oxidation with H2O2 under basic conditions, followed by hydrolysis and dehydrative lactonization led

to the bycicle lactone [D]. A following SN2 addition of a vinyl group and a lactonization of the

intermediate cyclopentane with triflourmethansulfonimide as organic solvent. These rections gave

product [E] that is further elaborated to F and F’. Substrate [F] is necessary for the following reaction.

[F‘] can be recycelt. The enone [F] was extended through a critical L-proline- mediated Robinson

annulation. The resulting product is furnished a stoichiometric amount of L-proline in DMF which

effected an intramolecular Michael addition and led to product [G]. The treatment of [G] with NaOh

led to an aldol condensation and the formation of the core substructure with a good

diastereoselctivity (dr = 5:1) [3].

(Graphics: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553032/figure/F3/)

Corey’s entioselective synthesis

Lalic and Corey found a new synthesis in 2007. The synthesis started with 6-methoxy – α-naphtol [A].

In a one-step reaction 6-methoxy – α-naphtol [A]was converted to 1,4-naphthoqinone [B] by

oxidative ketalization with bis-trifouroacetoxyiodobenzene. For the following reactions

trimethylamine is an essential compound. [B] react in a enantioselective conjugate addition to [C] in

the presence of Ru-BINAP catalyst and trimethylamine. In five stepts [B] react to [C]. [C] got a

protection group to protect the reactive phenolic hydroxyl group. Then a treatment with bromine in

CH2Cl2 led to tricyclic bromide [D]. A following treatment with TBAF led to quinone [E]. [E] was

hydrogenated in a stereoselective manner in the presence of chiral rhodium phosphine catalyst to

build ketone [F]. The last step is the formation of the TMS silyl enol ether, followed by oxidation with

IBX. The product is the core substructure. [3]

(Graphics: http://repositories.lib.utexas.edu/bitstream/handle/2152/17858/heckere.pdf?sequence=2)

Snider’s formal synthesis of (±)-Platensimycin

The synthesis pathway of Snider’s and co-workers synthesis started with a four step conversion of

the 5-methoxytetraloe [A] to the enone [B] in a mixture of cis- and trans- decalines. The mixure of

decalines were separated and equilibrated to a 6:4 ratio. For the further synthesis the necessarily cis-

decalin [B] was treated with tributyltin hydride and AIBN what led to a reductively cyclization which

formed tricycle [C]. This dione was treated with L-Selectride which gave the diol [D] in a mixture of

axial and equatorial isomers. [4] The axial isomer could react directly in an elimination reaction to

alkene [E] while the equatorial isomer needed to be treated with 1M HCl or silicia gel to form the

alkene. The last steps included an allylic oxidation with SeO2 under microwave irradiation followed by

an oxidation with MnO2 to form the core substructure, which can react to Platensimycin. [6]

(Graphics:http://repositories.lib.utexas.edu/bitstream/handle/2152/17858/heckere.pdf?sequence=2)

A Bismuth(III)-Catalyzed Friedel−Crafts Cyclization and stereocontrolled Organocatalytic Approach

to (−)-Platensimycin

Stanley T.-C. Eey and Martin J. Lear have developed this synthetic pathway for the core substructure

2010. The synthesis pathway started with the allylic alcohol [A] which was treated with L-(+) DIPT to

form the epoxy alcohol [B] in 98% yield and 91% ee. The desired stereocenter at C12 were made by

the opening of regioselective epoxide with allylic magnesium chloride. The following treatment with

Martinelli’s regeoselctive catalytic monotosylation led to product [C] which reacted to the cis-tosyl

lactol [D] in a 85% yield through oxidative double bond cleavage. By a new catalytic combination of 5

mol % Bi(OTf3) with 3 equiv of LiClO4 as a cocatalyst a Friedel Crafts intramolecular cyclization led to

[E] in a 94% yield within 3,5h. The Reduction with H2/Pd/C led to the benzyl deprotected tosyl-phenol

[F]. The treatment of [F] with TBAF in xylene at 130°C gave the desired dieone caged core [G] in 86%

yield over two steps. A chemo- and stereocontrolled conjugated reduction led to the enone [H1]

which gave [J] after a treatment with H2/Pd/C in a 3:1 diastereomirc ratio. The treatment with of [J]

with AlCl3 / TBAl gave [K]. By mesylation of [K] and heating with LiBr/Li2CO3 in DMSO gave the

targeted core substructure. [5]

(Graphics: http://pubs.acs.org/doi/full/10.1021/ol102390t)

Mechanism of Action

Platensimycin shows antibacterial

activity against gram-positive

bacteria, for example S. aureus

(MRSA). The characteristic difference

is the inhibition of the fatty acid

synthesis II (FAS II) of bacteria. [1][9]

FAS II carries out the bacterial fatty

acid synthesis. The ketoacyl-ACP

carrier Protein (elongation of the

fatty acid chain) is inhibited by

Platensimycin by catalysis of the

FabF- enzyme. The FAS II is necessary

for the biosynthesis of the bacterial

cell membrane. [1][9][10]

Platensimycin did not affect the DNA,

RNA, protein or cell wall biosynthesis

of the mammals. [9] (Graphics: http://dx.doi.org/10.1016/j.chembiol.2014.01.005)

This Graphic does show the most important interactions between Platensimycin and FabF.

(Graphics: http://www.scipharm.at/download.asp?id=1506)

Relations – Platensimycin and Analogs

1.) Platencin

Platencin (Fig. 2) has a similar structure then

Platensimycin, which provides a similar mechanism of

action. The only component missing is the ether-ring.

Two advantages of Platencin are inhibiting FabH as

well, which is thought to be responsible for a lower risk

of bacteria building resistance and Platencin being

effective against gram-negative bacteria. But there is a

conflict between the inhabitation of FabH and FabF. Platencins effect against FabF is six times less

effective than Platensimycin and for times better against FabH. But together it provides a good

antibiotic [1].

2.) Structural diversifications

Scientists tried to modify Platensimycin to increase its antibiotic effect and to promote the synthesis.

There have been found two suitable analogs, 7-Phenylplatensimycin (Fig. 3) and 11–Methyl 7-

Phenylplatensimycin (Fig. 4). Both do promote the cyclic addition and show higher activity against

gram-positive bacteria then Platensimycin does [1].

3.) Inspiration for Bioorganic Metals

Platensimycin has been an inspiration for a few bioorganic Metals where 3-(4-

[acetylferrocenoyl]butanamido)-2,4-dihydroxybenzoic acid (Fig. 5) established itself for being

effective against Aureus selective [1].

References

[1] Adil M Allahverdiyev (2013). The use of platensimycin and platencin to fight antibiotic resistance.

Infection and Drug Resistance 2013:6 99–114 [Access: 15. June 2015]

[2] http://www.msd.de/msd/unsere-geschichte/ [Access: 17.06.2015]

[3]Hanessian, S. (2013). Design and Strategy in Organic Synthesis . Wiley-VCH. 484-499

[4]Hecker, E. (2008): "Studies toward the Total Synthesis of (±)-Chartelline and (–)-Platensimycin"

http://repositories.lib.utexas.edu/bitstream/handle/2152/17858/heckere.pdf?sequence=2

[Access: 20. May 2015]

[5]Lear, S. T.-C. (2010, Oktober 29). A Bismuth(III)-Catalyzed Friedel−Crafts Cyclization and

Stereocontrolled Organocatalytic Approach to (−)-Platensimycin. Organic Letters.

http://pubs.acs.org/doi/full/10.1021/ol102390t [Access: 01. June 2015]

[6]Tiefenacher, K. Mulzer, J. (2008, March 2007). Synthesis of Platensimycin. Angewandte Chemie .

http://onlinelibrary.wiley.com/doi/10.1002/anie.200705303/full [Access: 20. Mai 2015]

[7] Stanley Eey(2013)Total Synthesis of the Potent Antibiotic Platensimycin

http://www.scs.illinois.edu/denmark/presentations/2013/gm-2013-9-10.pdf [Access: 18.06.2015]

[8] ACD/Chemsketch, version 14.01, Advanced Chemistry Development, Inc., Toronto, On, Canada,

www.acdlabs.com, 2012.

[9] Jun Wang, (18.May 2006) Platensimycin is a selective FabF Inhibitor with potent antibiotic

properties, Nature 441 358 – 361

http://www.nature.com/nature/journal/v441/n7091/pdf/nature04784.pdf [Access: 19.06.2015]

[10] Peterson, M.R., (20. March 2014) Mechanisms of Self-Resistance in the Platensimycin and

Platencin-Producing Streptomyces platensis MA7327 and MA7339 Strains, Chemistry & Biology 21,

389-397,March 20, 2014 – http://dx.doi.org/10.1016/j.chembiol.2014.01.005 [Access: 19.06.2015]