Review Article A Review on Platensimycin: A Selective FabF ...downloads.hindawi.com/archive/2016/9706753.pdfR 1 O 2 C OR 2 OR 2 26 :R1 = Me ,R 2 = MOM 1:R1 = R 2 = H: platensimycin

Review ArticleA Review on Platensimycin A Selective FabF Inhibitor

Manik Das Partha Sakha Ghosh and Kuntal Manna

Department of Pharmacy Tripura University (A Central University) Suryamaninagar Tripura 799022 India

Correspondence should be addressed to Kuntal Manna k manna2002yahoocom

Received 14 October 2015 Revised 25 December 2015 Accepted 31 December 2015

Academic Editor Maria Cristina Breschi

Copyright copy 2016 Manik Das et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Emerging resistance to existing antibiotics is an inevitable matter of concern in the treatment of bacterial infection Naturallyoccurring unique class of natural antibiotic platensimycin a secondary metabolite from Streptomyces platensis is an excellentbreakthrough in recent antibiotic research with unique structural pattern and significant antibacterial activity 120573-Ketoacyl-(acyl-carrier-protein (ACP)) synthase (FabF) whose Gram-positive bacteria need to biosynthesize cell membranes is the target ofinhibition of platensimycin So isolation retrosynthetic analysis synthesis of platensimycin and analogues of platensimycinsynthesized till today are the objectives of this review which may be helpful to further investigate and to reveal untouched areaon this molecule and to obtain a potential antibacterial lead with enhanced significant antibacterial activity

1 Introduction

Themajority of the ldquoillnessrdquo lies in the fact that when immunesystem is defeated it is in war with pathogens Developmentstarting from ethnic to modern synthetic approaches in drugdiscoverymainly provides better weapons to combat and sur-vive against pathogens In contrast to medical developmentpathogens also have acquired protection called ldquoresistancerdquoMore or less all classes of antibiotics are resistant to bacteriahence a novel process to the discovery of antibiotic with newmechanism of action is essential [1 2] Microbial and chemi-cal groups at Merck in the year 2006 have found three novelchemical classes using antisense technology from their oldermicrobial screening library [3] Two compounds platen-simycin and platencin were found as potent inhibitors of fattyacid biosynthesis Platensimycin selectively inhibits fatty acidacyl carrier protein synthase II (FabF) Platensin is a balanceddual inhibitor of both FabF and FabH (fatty acid acyl carrierprotein synthase III) [4] The third compound lucensimycinA was found to inhibit ribosomal protein synthesis FabF isone of the enzymes which catalyze the biosynthesis of fattyacids in bacteria It makes FabF an essential target for inhibit-ing bacterial growth in resistant bacteria Previously twoclasses of inhibitor cerulenin [5] and thiolactomycin [6ndash8]were reported but inhibitory activity was poor (IC

50ranges

within 13ndash13120583gmL) with poor antimicrobial activity (Strep-tococcus aurous MICmdash64 120583gmL) [9] On the other handplatensimycin had shown selective FabF inhibitory activityon S aurous and E coli with IC

50value of 48 nM and 68 nM

[3] The ability of this class of compounds to bind and inhibitFabF enzyme has given a new class of antibiotics Amongthem platensimycin and platencin are most promising andneed further investigation There might be an argument thatif fatty acid synthesis is an attractive target for antibacterialswhy there have notmany drugs or natural inhibitors targetingthis pathway been isolated One of the reasons may bethat the Streptomyces and related Actinomyces the organismsthat have delivered most of the existing antibiotics areconstrained in their ability to produce fatty acid synthesisinhibitors by the adjacent relationship between the syntheticpathways of fatty acids and polyketides These pathwaysshare many chemical mechanistic and structural featuresand thus fatty acid synthesis inhibitors recurrently inhibitpolyketide synthesis (eg cerulenin is a powerful inhibitorof polyketide synthesis) An organism producing a fatty acidsynthesis inhibitor must retain not only a resistant form ofthe fatty acid synthetic enzyme but also a resistant form ofthe antibiotic-producing polyketide synthase Furthermoreif several polyketides are needed for survival of the organismin its ecological niche then resistant forms of each of these

Hindawi Publishing CorporationInternational Journal of Medicinal ChemistryVolume 2016 Article ID 9706753 16 pageshttpdxdoiorg10115520169706753

2 International Journal of Medicinal Chemistry

O

OH OH

OH

NH

OMe

MeO O

1 platensimycin

Benzoic acidmoiety

Amidelinkage

Tetracyclic cage

Figure 1 Structure of platensimycin

pathways would be prerequisite Such precincts seem likelyto severely narrow the opportunities to evolve fatty acidsynthesis inhibitors and may account for the scarcenessof such antibiotics However various Streptomyces produceanalogues of thiolactomycin which has not been reportedto block polyketide synthesis thus demonstrating that devel-opment of fatty acid synthesis inhibitors by this organism isconceivable [10]

2 Isolation of Platensimycin

Platensimycin was isolated by Wang et al in 2006 at con-centration of 2 to 4mgL from fermentation broth of Splatensis (MA7327 and MA7331) using SephadexLH20 liquidchromatography medium by reversed-phase HPLC chro-matography [3] In a subsequent study three-step isolationwas modified by Singh et al and they established two-stepmethod eliminating the SephadexLH20 step [11] It was alsoisolated from Streptomyces platensis (MA7327) recoveredfrom soil samples collected in Eastern Cape South Africa[12]

3 Structure of Platensimycin

Platensimycin (Figure 1) consists of a benzoic acid moietysubstituted at ortho and para with hydroxyl group andin meta position is conjugated with a unique pentacyclicketolide by an amide linkage [13] The structure was estab-lished by combination ofDQ-COSY andTOCSY correlations(2DNMR) UV and IR spectroscopy and confirmed by X-raycrystallography [14]

4 Synthesis of Platensimycin

Platensimycin consists of an aromatic acid conjugated withaliphatic moiety by an amide linkage The effective syntheticstrategy is to synthesize the aromatic and aliphatic partsseparately and then combine them by amide linkage Manysynthetic methods are available for the synthesis of those twobuilding blocks

41 First Total Synthesis of Platensimycin Nicolaou et al inthe year 2006 first reported the total synthesis of platen-simycin [26]

411 Retrosynthetic Analysis of Platensimycin Using ret-rosynthetic analysis (Scheme 1) they separated the aromaticamine 2 and the carboxylic acid 3 by disconnection of amidelinkage The carboxylic acid was further simplified to asimplified enyne in successive three retrosynthetic stepsThisresulted in two target molecules to synthesize the tetracycliccarboxylic acid and the aromatic amine from simplifiedstarting material

412 Synthesis of Tetracyclic Cage The simplified enonegenerated from 3-ethoxycyclohex-2-enone which was usedas a starting material (Scheme 2) Allylic bromide 9 [27](LDA 92) and propargyl bromide (LDA 97) were used asreagents of choice to generate the bis-alkylated enone 10 from8 Reduction followed by acidic hydrolysis and reintroduc-tion of the TBS ether produced enone 11 from enone 10 (yield84) Spirocycle 12was generated by cycloisomerization of 11[28 29] Oxidation of 12 produced bis-enone 13 [30] whichupon acid hydrolysis gave desired aldehyde 6 Secondaryalcohol 14was prepared by addition of samarium(II) iodide ina dilute solution of aldehyde 6 HFIP in THFHMPA followedby NH

4Cl solution Esterification of 14 with TEA resulted

in the formation of cage-like structure 4 which on treatmentwith KHMDS and MeI followed by KHMDS and allyl iodideproduced olefin 16 Vinyl pinacol boronate and 16 reacted inpresence of the Grubbs second generation catalyst to producevinyl boronate 19 which on reacting with trimethylamine N-oxide gave 20 Following Pinnick protocol 20 was convertedto desired carboxylic acid 3

413 Synthesis of Aromatic Amine The synthesis of thearomatic amine 2 was started from 2-nitroresorcinol 21 byprotectingwithMOMether followed by catalytic hydrogena-tion 24 was formed (Scheme 3) Again protecting the aminogroup and followed by silylation lithiation and quenchingwith methyl cyanoformate 24 was carboxylated and byunprotecting amino group using thermolysis desired aniline2 was synthesized

414 Synthesis of Platensimycin Core The total synthesis ofplatensimycin was completed by the coupling of carboxylicacid 3 with aniline 2 which was achieved by treatment withHATU followed by hydrolysis with LiOH (Scheme 3)

42 Another Approach for Synthesizing Tetracyclic Cage byNicolaou et al After successfully reporting the first totalsynthetic strategy of platensimycin Nicolaou et al [31] reporta new synthetic strategy that starts from the readily availableand inexpensive (R)-(minus)-carvone to the tetracyclic enone 2

421 Retrosynthetic Strategy of Tetracyclic Enone A five-step retrosynthetic disconnection approach was shown togenerate commercially available (R)-(minus)-carvone 31 from 26(Scheme 4)

422 Synthesis of Tetracyclic Enone (R)-(minus)-carvone 31 onreaction with Grignardrsquos reagent 32 using CeCl

3[32] and by

oxidizing with PCC gave the corresponding enone 33 Enone

International Journal of Medicinal Chemistry 3

OH

OHOH

Me

Me

+

ONH

O

O O

Amide bond formation

1 platensimycin

OMOM

2

OMe

MeO

HO

O

Double alkylation 3

OMe

O

Ketyl radical cyclizationetherification

4

Me

O

O

5

O

O

Cycloisomerization6

O

7TBSO

MeO2C NH2

oplusoplus

⊖

Scheme 1 Retrosynthetic analysis of platensimycin

O

EtO

8

O

EtO

OTBS

10

O

TBSO11

O

TBSO

12

O

TBSO13

O

O6

O

OH

14

O

O

Me

O

O

16

O

O

Me

Me

Me

MeMe

Me MeMe

R

19

O

O

Me Me

MeMe

O

20

O

O

O

HO

3

OTBS

Br 9

(i)

(ii)

(iii)

(iv)

(v) (vi)(vii)

(viii)

(ix)(x)

(xi)

(xii)

N N MesMes

RuCl

Cl Ph

BO

O

(xiii)

(xiv)

Br

PCy3

R1

4 R1 = H

15 R1 = Me

Scheme 2 Synthesis of tetracyclic cage (i) LDA (ii) LDA (iii) DIBAL-H then HCl (iv) TBSCL (v) [CpRu(MeCN)3]PF6 (vi) LiHMDS

TMSCl (vii) Pd(OAc)2 (viii) HCl aq (ix) Sml

2 HFlP (x) TFA (xi) KHMDS MeI (xii) KHMDS (xiii) Me

3NO and (xiv) NaClO

2


OMOM

OMOM

2

OMe

OMeHO

O

3

HATU Et3N

OMe

OMeNH

O

LiOH then aq HCl

OR

NO2

OR

21 R = H22 R = MOM

(i)

(ii)

OMOM

NHR NHR

OMOM OMOM

23 R = H24 R = Boc(iii)

(iv)

OMOM

25 R = Boc2 R = H

(v)

CO2Me

MeO2C NH2

R1O2C

OR2

OR2

26 R1 = MeR2 = MOM1 R1 = R2 = H platensimycin

Scheme 3 Synthesis of aromatic amine and platensimycin (i) NaH MOMCL (ii) H2 PdC cat (iii) Boc

2O (iv) nBuLi and (v) 205∘C

33 was treated with Hg(OAc)2and later on with NaBH

4to

generate approximately 1 1 mixture of exo- and endotertiaryalcohol which on dehydration using Martinrsquos sulfuranereagent produced exocyclic alkene 35 which was treated withTMSCl and HMDS and followed by an electrophilic quenchwith PhSeCl and subsequent oxidative elimination (H

2O2) to

give enone 36 Enone 37 was treated with SmI2for radical

cyclization and by adding mentioned reagent (Scheme 5) insubsequent 8 steps of tetracyclic cage 26 was synthesized

43 Matsuorsquos Synthesis of Tetracyclic Cage

431 Retrosynthetic Analysis of Tetracyclic Cage Matsuo etal [33] offered another route for stereocontrolled synthesisof tetracyclic enone 4 They expected that the transannularradical cyclization of 44 will produce enone 4 A four-stepretrosynthetic analysis is producing enone 47 and siloxydiene48 The key feature of plan is that all stereocenters in4 are controlled by the stereochemistry presented in 47(Scheme 6)

432 Synthesis of Tetracyclic Cage O-TBS and O-benzoyl-protected enones 47a and 47b were prepared from 13-cyclohexadiene 49 through allylboration selective oxidation

and utilizing the Dess-Martin oxidation with the yield of(97) Diels-Alder reaction in between 47a and 47b andsiloxydienes produced two stereogenic mixtures 46a 46band 46c 46d The mixture of two inseparable diastereomers(46b and 46d) was employed in the next step FollowingNoyorirsquos procedure [26] followed by hydrolysis of the benzoylgroup and separation of diastereomers 53 was given whichupon catalytic oxidation using palladium(II) chloride andcopper(II) acetate produced 54a and 54b in 10 1 ratio Vinyltriflate 55 was produced from 54 and reduced to 56 whichwas transformed to 57 Transannular radical cyclization ofmonothioacetal 57 gave desired 4 (Scheme 7)

44 Kaliappanrsquos Synthesis of Tetracyclic Cage

441 Retrosynthetic Analysis of Tetracyclic Cage Kaliappanand Ravikumar [34] showed seven-step retrosynthetic anal-ysis using a 5-exo-trig radical cyclization strategy [35 36] togenerate Wieland-Miescher ketone 64 (Scheme 8)

442 Synthesis of Tetracyclic Cage Synthesis was startedfrom Wieland-Miescher ketone 64 [37] a chiral startingmaterial which on two-step reduction yielded an inseparablediastereomeric mixture of alcohols 66 [38] Corresponding


HO2C

OH

OH

NH

OMe

OMe

O

AlkylationO

Me

O

H

Etherification26

O

O

H

Sletter or radicalcyclization

27

O

O

28

O

O

O

Me OH

Me

Radical cyclization29

O

Me

O

O

Grignardaddition

30

O

Me

O

O

BrMg3231

+

OH

OH

NH

O

+HO2C

CH3

1 (minus)-platensimycin

(R)-(minus)-carvone


aldehyde 68 containing oxoethylene group was synthesizedfrom alcohols 66 by Mandai protocol [39] Using Ohira-Bestmann reagent 74 [40 41] enyne 69 was formed whichwas treated with AIBN in tert-BuOH and PPTS to initiatethe radical cyclization resulting formation of tetracyclic cage72 L-Selectride THF and TFACH

2Cl2were consecutively

added with 72 to produce the desired enone 58 (Scheme 9)

45 Coreyrsquos Synthetic Strategy

451 Synthesis of Tetracyclic Cage Lalic and Corey [42]used methoxy 120572-naphthol 75 as the starting material whichupon reaction with bistrifluoroacetoxyiodobenzene andethylene glycol in acetonitrile at 0∘C produced 6-methoxy-14-naphthoquinone-4-ethylene ketal 76 An enantioselectiveconjugation of 2-propenyl group to ketal 76 using 2-propenyltrifluoroborate Rh-BINAP BF

4catalyst and triethylamine

[43ndash45] produced the chiral ketone 77 cis-tetralin 78 wasgenerated from 77 by reduction of the carbonyl grouphydroxyl protection and reductive cleavage of the ethyleneketal subunit Demethylation of 78 produced phenol 79which was converted to tricyclic 80 by etherification followed

by reaction with Br2in CH

2Cl2 Heating with tetra-n-

butylammonium fluoride in THF at 130∘C tetracyclic cage81 was produced which on catalytic diastereoselective hydro-genation produced tetrahydro derivative 82 The saturatedketone82was transformed into the corresponding120572120573-enone4 using the 2-iodoxybenzoic acid sequence (Scheme 10) [4647]

46 Yamamotorsquos Synthetic Strategy

461 Retrosynthetic Analysis of Tetracyclic Core Li et al [47]used an intramolecular Robinson annulation approach [48]in the retrosynthetic analysis presented in (Scheme 11) Thebicyclic compound 84 to give the tetracyclic core structure4 is key step in the retrosynthesis by Robinson annulationevent

462 Synthesis of Tetracyclic Core The bicyclic ketone 84can be synthesized from known lactone 85 which couldbe generated from ketone 86 through a Baeyer-Villigeroxidationrearrangement sequence [49 50] and by uti-lizing Bronsted acid assisted chiral Lewis acid catalyzed


O

Me

31

O

OBrMg

32Me

O

OO

33

(iii)

HO Me

O

O

O

Me

34bMe

O

O

HO

Me

Me OH

O

O

O

Me

O

34a

(iv)

O

O

O

Me

35

O

O

O

(v)

(vi)

36

O

O

37

(vii)

(i)

(ii)

34ab

HO

O

H

39

(ix)

Ar(O)CO

O

H(x)

40

HO

O

H

41a

HO

O

H

41b

HO

Me

H

O

42

(xii)

(xiii)

O

Me

H

O

43

(xiv)

(xv)

O

Me

H

O

26

O

Me

O

44

+

(viii)

(xi) (xi)

(R)-(minus)-carvone34b998400

Scheme 5 Synthesis of tetracyclic cage (i) CeCl3 (ii) PCC and (iii) Hg(OAc)

2 then NaBH

4 (iv) Martinrsquos sulfurane (v) TMSCl Lil HMDS

and then PhSeCl (vi) H2O2 Py (vii) AcOHMW (ix) Sml

2 (x) DIADArCO

2H PPh

3 Ar=p-NO

2C6H4 (xi) KOH (xii) L-selectride (H

3O+)

(xiii) PCC (xiv) TMSCl Lil HMDS and (xv) IBX or Pd(OAc)2

Diels-Alder reaction and subsequent N-nitrosoaldol addi-tiondecarboxylation ketone 86 could be easily preparedfrom inexpensive commercially available starting materials(Scheme 12)

Diels-Alder reaction between methyl acrylate 87 andmethyl cyclopentadiene 88 produced adduct 89The reactionwas catalyzed by BLA and carbon-based Bronsted acid [51]Ketone 90 was obtained in one pot reaction from adduct89 using lithium enolate and lithium hydroxide in dioxaneBaeyer-Villiger oxidation in basic condition [52] of ketone 90gave lactone 85 Vinyl lactone 91 was obtained from lactone85 using cuprate reagent [53] and trifluoromethanesulfon-imide [54 55] DIBAL-H reduction followed by cyanation

produced cyanide92a92b whichwas reduced and subjectedto Wadsworth-Emmons conditions [56] to give enone 93ruthenium-catalyzed oxidation [57] produced aldehyde 84Using L-proline as the chiral control element followed bysodium hydroxide treatment gave the desired tetracyclic corestructure 4

5 Pharmacology of Platensimycin

Bacterial cell wall synthesis protein synthesis and DNAreplication are the predominant targets for widely usedantibiotics But the emergence of resistance to antibiotics


OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574

47a R = TBS47b R = Bz


46c R = TBS46d R = Bz

(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1

Scheme 7 Synthesis of tetracyclic cage (i) allylBBr2 thenHOOHNaOH (ii) t-BuOOHVO(sese)

2 (iii) Dess-Martin periodinane (iv) Silica

gel (v) TBSCl imidazoleBzCl Py (vi) PMSOTf (cat) (TMSOCH2)2 (vii) aqNaOH separation of diastereomers (viii) PdCl

2Cu(OAc)

2DMA

O2 (ix) KHMDS (x) Pd(OAc)

2(PPh3)2HCOOH Bu

3N (xi) PhSH (xii) Bu

3SnH AIBN toluene reflux and (xiii) 1N aq HCL


O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2

Scheme 9 Synthesis of tetracyclic cage (i) NaBH4 ETOH 00C 2 h (ii) TBSCI Im DMF rt 2 h (iii) DIBAL-H CH

2Cl2 (iv) NaH cat

KHTHF rt 12 h (v) Decalin 180∘C 5d (vi) K2CO3 MeOH (vii) TBAF THF reflux (viii) IBX PhFDMSO 65∘C (ix) TBTH AIBN t-

BuOH reflux 12 h (x) PPTS CH2Cl2 rt 6 h (xi) L-selectride THF minus78∘C to rt and (xii) TFACH

2Cl2 0∘C 2 h

demands new antibacterial targets Fatty acid synthase (FAS)pathway is now an attractive target for antibacterial agentsbecause as a new target FAS inhibition will not suffer frombacterial resistance immediately and biosynthesis pathway ofbacteria plants and parasites (FAS II in which componentproteins are dissociated) is different frommammals (FAS I inwhich component proteins are generally single-chain mul-tidomain homodimers or two-chain heterodimers carryingall proteins of the pathway) in subcellular organization of

components which demonstrate a target specificity for theFAS II inhibitors A general scheme for type II fatty acidbiosynthesis is shown in Figure 2[9] A recent developmentin finding inhibitors of fatty acid biosynthesis is the discov-ery of platensimycin which shows broad-spectrum Gram-positive antibacterial activity (Staphylococcus aureus (MRSA)and Enterococci (VRE) MIC lt 10 120583gmLminus1) by selectivelyinhibiting cellular lipid biosynthesis [58] The mechanismof action is the selective inhibition of elongation of FabF


OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O

Scheme 10 Synthesis of tetracyclic cage (i) PhI(O2CCF3)2 OHCH

2CH2OH MeCN 0∘C 2 h (ii) (S)-BINAP [Rh(cod)

2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH

4 MeOH (2) MEMCl 119894-Pr

2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH

2Cl2 minus20∘C (iv) PhSH Cs

2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2

minus78∘C (vi) n-Bu4NF THF D 130∘C (vii) [Rh(cod)

2]BF4 (RR)-DIOP H

2600 psi CH

2Cl2 16 h (viii) (1) TMSOTf Me

3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87


(a condensing enzyme) in the bacterial fatty acid syntheticpathway by intercalating with the malonyl binding site ofthe catalytic triad of FabF acyl enzyme intermediate Inversecorrelation of FabF expression levels with the sensitivityof S aureus to the drug platensimycin confirms that FabFis the useful target for antibacterial action Platensimycinexhibited an IC

50of 48 nM and 160 nM against FabF in S

aureus and E coli respectively But the drug shows weakinhibition against FabHwith an IC

50value of 67mM Further

studies have shown that in vitro binding of platensimycinwith FabF is relatively weak which leads to the discoveryof its binding with acyl-thioester intermediate of the FabFpathway From a crystal structure of a Cys-163-Gln FabFmutant which simulates acyl-thioester intermediate it was

found that platensimycin bind with the active site of FabFwith the carboxylic acid group lying in the malonate-bindingsite coplanar with the amide side chain of Gln163 [59]

Though Brinster et al [60] explained an alternativehypothesis that FAS II inhibition is not a suitable target forStreptococcus agalactiae (lactobacillales) The need for syn-thesized fatty acid by their own (streptococci pneumococcienterococci and staphylococci) reduces in the presence ofexogenous fatty acid in both in vitro and in vivo conditionsHuman serum has a high composition of fatty acids so FASII inhibitor may not affect at all Gram-positive pathogens invivo But the findings with S agalactiae can be reasonablyextended to all Gram-positive bacteria which has starteda vigorous debate Also there is no clear explanation how


COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93

Scheme 12 Synthesis of tetracyclic cage (i) CH2Cl2 minus78∘C 14 h (ii) LDA THF minus78∘C then PhNO minus78∘C 2 h and then LiOH dioxaneH

2O

30∘C 20 h (iii) H2O2NaOH Et

2OH2O 0∘C to rt 45min (iv) CuBrsdotMe

2S CH

2CMgBr THFMe

2S minus40∘C to rt (v) 45mol HNTf

2

CH2ClCH

2Cl 70∘C 45min (vi) DIBAL-H toluene minus78∘C 30min then Et

2AlCN BF

3sdotOET

2 20min (vii) DIBAL-Hn-BuLi minus78∘C to 0∘C

25min (viii) NaH CH3COCH

2P(O)(OET)

2 THF 0∘C 20min (ix) 202 eq NaIO

4 35mol RuCl

36 1 CH

3CNH

2O rt 3 h and (x) 1 eq

pyrrolidine-2-carboxylic acid DMF rt 5 days then 2N NaOH(aq) 0∘C to rt 40min

CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2

PlatencinPlatensimycin

Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP

120573-hydroxyacyl-ACP

Trans-2-enoyl-ACP

Figure 2 Fatty acid biosynthesis pathway of bacteria (FAS II)

bacteria incorporates exogenous fatty acids into their cell[61 62] Platensimycin exhibited antibacterial activity againstefflux-negative Escherichia coli (tolC) but not against wild-type E coli specifying that efflux mechanisms and notcompound specificity limit the effectiveness of platensimycinin E coli and possibly other Gram-negative bacteria [3]

6 Platensimycin Analogues

The major drawback to most natural products includingplatensimycin is poor pharmacokinetic properties and neg-ligible oral bioavailability Only the continuous infusion ofa high platensimycin dose showed effectiveness in mice


Table 1 Antimicrobial activity of synthesized platensimycin analogue

Slnumber Analogues name Analogues structure Antimicrobial activity Reference

1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O

Inhibits both FabF andFabH with similarpotency

[12]

2 7-PhenylplatensimycinOHH

N

HOO OPh

OMe

H

CO2H MIC against S aureus(MSSA) 025 120583gmL [15]

3 11-Methyl-7-phenylplatensimycin

OHHN

HOO OPh

OMe

Me

CO2H MIC against S aureus(MSSA) lt025 120583gmL [15]

4 Sulfonamide analoguesof platensimycin OHHO

O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]

5 Oxazinidinylplatensimycin

O

N O

Me

O

NH

OO

OH

OH

OH

MIC of 90 120583gmLagainst S aureus Sagalactiae and Bsubtilis

[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H

MIC against S aureus(MSSA) 04 120583gmL [18]

7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl

MIC against S aureus(MSSA) gt256 120583gmL [18]


Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl


9 Dehydrohomoplatencin

OH

HOOC

OHNH

O

O

OMIC against S aureus(MSSA) 04 120583gmL [19]

10 Isoplatensimycin

OHHN

HOO O

O CO2H MIC against S aureus(MSSA) 128120583gmL [20]

11 Carbaplatensimycin

Me

Me O

NH

OO

OH

OH

OH

MIC against S aureus04ndash11 120583gmL [21]

12 Platensimycin B1and B

3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]

14Homoplatensimide Aand homoplatensimideA methyl ester O

Me

Me OHN

O

O

Homoplatensimide A [R = H]Homoplatensimide A methyl ester [R = Me]

CO2R

H2N

Not tested [22]


Table 1 Continued


15

Dialkylamino-24-dihydroxybenzoic acidsanalogues ofPlatensimycin

OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4

Out of 18 Synthesizedderivatives fourderivatives which havethe substitution 1 2 3and 4 respectivelyhave shown potentialactivity against Bsubtilis (MIC2ndash8 120583gmL)

[23]

16 (minus)-nor-platencin

HN

HOCOOH

OH

OH

Me

O MIC against S aureus(MSSA) 5 120583gmL [24]

17 Adamantaplatensimycin HO

COOH

OO Me

OH

HOOC

OMe O

OH

OH

(minus)-Adamantaplatensimycin

(+)-Adamantaplatensimycin

MIC of (minus)-adamantaplatensimycinagainst S aureus(MSSA) 13ndash18 120583gmLMIC of (+)-adamantaplatensimycinagainst S aureus(MSSA) gt88 120583gmL

[25]

infected with S aureus [3] For the improvement of pharma-cokinetic profile many researchers have developed platen-simycin analogues (Table 1) however potent antimicrobialactivity than that of platensimycin is yet to get

7 Conclusion

Development of bacterial resistance to the existing antibioticsis an alarming situation in the 20th century Finding new tar-get for bacterial demolition is essential Platensimycin servingas a potential antibiotic interacting with FabF may bypassbacterial resistance It should be noted that starting from2006 till now a huge number of scientists providedmany syn-thetic strategies and derivatives which are very encouraging

Though some evidence like incorporation of exogenous fattyacid inside bacteria when supplied makes the hope regardingplatensimycin is uncertain overall isolation of platensimycinas a selective FabF inhibitor complex synthesis of tetracycliccage and enhancement of its pharmacokinetic properties byits derivative synthesis are the excellent works in the era ofmedicinal chemistry It is expected that this review might behelpful for the medicinal chemist

Abbreviations

Ac AcetylAIBN 221015840-Azobis(isobutyronitrile)


BINAP 221015840-Bis(diphenylphosphino)-110-binaphthalene

Boc tert-ButoxycarbonylBz BenzoylDIBALH Diisobutylaluminium hydrideDMF NN-DimethylformamideDMSO Dimethyl sulfoxideHATU O-(7-Azabenzotriazol-1-yl)-NNN1015840N1015840-

tetramethyluroniumhexafluorophosphate

HMPA Hexamethyl phosphoramideKHMDS Potassium hexamethyldisilazideLDA Lithium diisopropylamidePCC Pyridinium chlorochromate Piv pivaloylPPTS Pyridinium-p-toluenesulfonatePy PyridineTEA TriethylamineTf TrifluoromethanesulfonylTFA Trifluoroacetic acidTFE 222-TrifluoroethanolTHF TetrahydrofuranTMS Trimethylsilyl

Conflict of Interests

There is no conflict of interests

Acknowledgment

The authors are thankful to the Department of PharmacyTripura University (A Central University)

References

[1] C T Walsh ldquoWhere will new antibiotics come fromrdquo NatureReviews Microbiology vol 1 no 1 pp 65ndash70 2003

[2] S B Singh and J F Barrett ldquoEmpirical antibacterial drug dis-coverymdashfoundation in natural productsrdquo Biochemical Pharma-cology vol 71 no 7 pp 1006ndash1015 2006

[3] JWang S M Soisson K Young et al ldquoPlatensimycin is a selec-tive FabF inhibitor with potent antibiotic propertiesrdquo Naturevol 441 no 7091 pp 358ndash361 2006

[4] JWang S Kodali SH Lee et al ldquoDiscovery of platencin a dualFabF andFabH inhibitorwith in vivo antibiotic propertiesrdquoPro-ceedings of the National Academy of Sciences of the United Statesof America vol 104 no 18 pp 7612ndash7616 2007

[5] A Matsumae S Nomura and T Hata ldquoStudies on ceruleninIV Biological characteristics of ceruleninrdquo The Journal ofAntibiotics vol 17 pp 1ndash7 1964

[6] S Miyakawa K Suzuki T Noto Y Harada and H OkazakildquoThiolactomycin a new antibiotic IV Biological properties andchemotherapeutic activity in micerdquo The Journal of Antibioticsvol 35 no 4 pp 411ndash419 1982

[7] T Noto S Miyakawa H Oishi H Endo and H OkazakildquoThiolactomycin a new antibiotic III In vitro antibacterialactivityrdquo The Journal of Antibiotics vol 35 no 4 pp 401ndash4101982

[8] H Oishi T Noto H Sasaki et al ldquoThiolactomycin a newantibiotic I Taxonomy of the producing organism fermenta-tion andbiological propertiesrdquoTheJournal of Antibiotics vol 35no 4 pp 391ndash395 1982

[9] S Kodali A Galgoci K Young et al ldquoDetermination ofselectivity and efficacy of fatty acid synthesis inhibitorsrdquo TheJournal of Biological Chemistry vol 280 no 2 pp 1669ndash16772005

[10] J W Campbell and J E Cronan Jr ldquoBacterial fatty acidbiosynthesis targets for antibacterial drug discoveryrdquo AnnualReview of Microbiology vol 55 pp 305ndash332 2001

[11] S B Singh H Jayasuriya J G Ondeyka et al ldquoIsolation struc-ture and absolute stereochemistry of platensimycin a broadspectrum antibiotic discovered using an antisense differentialsensitivity strategyrdquo Journal of the American Chemical Societyvol 128 no 36 pp 11916ndash11920 2006

[12] C K Nicolaou S G Tria J D Edmonds and M Kar ldquoTotalsyntheses of (plusmn)-platencin and (minus)-platencinrdquo Journal of theAmerican Chemical Society vol 131 no 43 pp 15909ndash159172009

[13] D Habich and F Von Nussbaum ldquoPlatensimycin a new antibi-otic and lsquoSuperbug challengerrsquo from naturerdquo ChemMedChemvol 1 no 9 pp 951ndash954 2006

[14] M Saleem H Hussain I Ahmed T Van Ree and K KrohnldquoPlatensimycin and its relatives a recent story in the struggleto develop new naturally derived antibioticsrdquo Natural ProductReports vol 28 no 9 pp 1534ndash1579 2011

[15] K P Jang C H Kim S W Na et al ldquo7-Phenylplatensimycinand 11-methyl-7-phenylplatensimycin more potent analogs ofplatensimycinrdquo Bioorganic amp Medicinal Chemistry Letters vol20 no 7 pp 2156ndash2158 2010

[16] J McNulty J J Nair and A Capretta ldquoA synthesis of sul-fonamide analogs of platensimycin employing a palladium-mediated carbonylation strategyrdquo Tetrahedron Letters vol 50no 28 pp 4087ndash4091 2009

[17] J Wang V Lee and H O Sintim ldquoEfforts towards the identifi-cation of simpler platensimycin analogues-the total synthesis ofoxazinidinyl platensimycinrdquo ChemistrymdashA European Journalvol 15 no 12 pp 2747ndash2750 2009

[18] K Tiefenbacher A Gollner and J Mulzer ldquoSyntheses andantibacterial properties of iso-platencin Cl-iso-platencinand Cl-platencin identification of a new lead structurerdquoChemistrymdashA European Journal vol 16 no 31 pp 9616ndash96222010

[19] D C J Waalboer S H A M Leenders T Schulin-Casonato FL Van Delft and F P J T Rutjes ldquoTotal synthesis and antibioticactivity of dehydrohomoplatencinrdquo ChemistrymdashA EuropeanJournal vol 16 no 37 pp 11233ndash11236 2010

[20] K P Jang C H Kim S W Na H Kim H Kang and ELee ldquoIsoplatensimycin synthesis and biological evaluationrdquoBioorganic amp Medicinal Chemistry Letters vol 19 no 16 pp4601ndash4602 2009

[21] K C Nicolaou Y Tang J Wang A F Stepan A Li and AMontera ldquoTotal synthesis and antibacterial properties of car-baplatensimycinrdquo Journal of the American Chemical Society vol129 no 48 pp 14850ndash14851 2007

[22] K C Nicolaou A Li D J Edmonds G S Tria and S P ElleryldquoTotal synthesis of platensimycin and related natural productsrdquoJournal of the American Chemical Society vol 131 no 46 pp16905ndash16918 2009

[23] J Wang and H O Sintim ldquoDialkylamino-24-dihy-droxybenzoic acids as easily synthesized analogues of


platensimycin and platencin with comparable antibacterialpropertiesrdquo ChemistrymdashA European Journal vol 17 no 12 pp3352ndash3357 2011

[24] O V Barykina K L Rossi M J Rybak and B B SniderldquoSynthesis and antibacterial properties of (-minus)-nor-platencinrdquoOrganic Letters vol 11 no 22 pp 5334ndash5337 2009

[25] K C Nicolaou T Lister R M Denton A Montero and DJ Edmonds ldquoAdamantaplatensimycin a bioactive analogue ofplatensimycinrdquo Angewandte ChemiemdashInternational Editionvol 46 no 25 pp 4712ndash4714 2007

[26] K C Nicolaou A Li and D J Edmonds ldquoTotal synthesisof platensimycinrdquo Angewandte ChemiemdashInternational Editionvol 45 no 42 pp 7086ndash7090 2006

[27] M Sun YDeng E BatyrevaW Sha andRG Salomon ldquoNovelbioactive phospholipids practical total syntheses of productsfrom the oxidation of arachidonic and linoleic esters of 2-lysophosphatidylcholinerdquo The Journal of Organic Chemistryvol 67 no 11 pp 3575ndash3584 2002

[28] B M Trost and F D Toste ldquoRuthenium-catalyzed cycloiso-merizations of 16- and 17-enynesrdquo Journal of the AmericanChemical Society vol 122 no 4 pp 714ndash715 2000

[29] B M Trost J-P Surivet and F D Toste ldquoRuthenium-catalyzedenyne cycloisomerizations Effect of allylic silyl ether on regios-electivityrdquo Journal of the AmericanChemical Society vol 126 no47 pp 15592ndash15602 2004

[30] Y Ito T Hirao and T Saegusa ldquoSynthesis of 120572120573-unsaturatedcarbonyl compounds by palladium(II)-catalyzed dehydrosilyla-tion of silyl enol ethersrdquoThe Journal of Organic Chemistry vol43 no 5 pp 1011ndash1013 1978

[31] K C Nicolaou D Pappo K Y Tsang R Gibe and D Y-K Chen ldquoA chiral pool based synthesis of platensimycinrdquoAngewandte ChemiemdashInternational Edition vol 47 no 5 pp944ndash946 2008

[32] G A Molander ldquoApplication of lanthanide reagents in organicsynthesisrdquo Chemical Reviews vol 92 no 1 pp 29ndash68 1992

[33] J-I Matsuo K Takeuchi and H Ishibashi ldquoStereocontrolledformal synthesis of (plusmn)-platensimycinrdquo Organic Letters vol 10no 18 pp 4049ndash4052 2008

[34] K P Kaliappan and V Ravikumar ldquoAn expedient enantiose-lective strategy for the oxatetracyclic core of platensimycinrdquoOrganic Letters vol 9 no 12 pp 2417ndash2419 2007

[35] G Stork P C Tang M Casey B Goodman and M ToyotaldquoRegiospecific and stereoselective syntheses of (plusmn)-reserpineand (minus)-reserpinerdquo Journal of the American Chemical Societyvol 127 no 46 pp 16255ndash16262 2005

[36] S Janardhanam P Shanmugam and K Rajagopalan ldquoStereo-controlled synthesis of angularly fused tricyclic systems by Tin-mediated radical cyclizationrdquoThe Journal of Organic Chemistryvol 58 no 27 pp 7782ndash7788 1993

[37] N Harada T Sugioka H Uda and T Kuriki ldquoEfficientpreparation of optically pure Wieland-Miescher ketone andconfirmation of its absolute stereochemistry by the CD excitonchirality methodrdquo Synthesis vol 1990 no 1 pp 53ndash56 1990

[38] F-D Boyer and P-H Ducrot ldquoSynthesis of agarofuranantifeedants part II stereoselective construction of the tetrahy-drofuran ringrdquo Synthesis vol 2000 no 13 pp 1868ndash1877 2000

[39] T Mandai M Ueda S-I Hasegawa M Kawada J Tsuji andS Saito ldquoPreparation and rearrangement of 2-allyloxyethyl arylsulfoxides a mercury-free claisen sequencerdquo Tetrahedron Let-ters vol 31 no 28 pp 4041ndash4044 1990

[40] S Ohira ldquoMethanolysis of dimethyl (1-diazo-2-oxopropyl)phosphonate generation of dimethyl (diazomethyl) phospho-nate and reaction with carbonyl compoundsrdquo Synthetic Com-munications vol 19 no 3-4 pp 561ndash564 2006

[41] S Muller B Liepold G J Roth and H J Bestmann ldquoAnimproved one-pot procedure for the synthesis of alkynes fromaldehydesrdquo Synlett vol 1996 no 6 pp 521ndash522 1996

[42] G Lalic and E J Corey ldquoAn effective enantioselective route tothe platensimycin corerdquoOrganic Letters vol 9 no 23 pp 4921ndash4923 2007

[43] T Hayashi and K Yamasaki ldquoRhodium-catalyzed asymmetric14-addition and its related asymmetric reactionsrdquo ChemicalReviews vol 103 no 8 pp 2829ndash2844 2003

[44] M Pucheault S Darses and J-P Genet ldquoPotassium organotri-fluoroborates in rhodium-catalyzed asymmetric 14-additionsto enonesrdquo European Journal of Organic Chemistry vol 2002no 21 pp 3552ndash3557 2002

[45] GAMolander andN Ellis ldquoOrganotrifluoroborates protectedboronic acids that expand the versatility of the Suzuki couplingreactionrdquoAccounts of Chemical Research vol 40 no 4 pp 275ndash286 2007

[46] K C Nicolaou D L F Gray T Montagnon and S T HarrisonldquoOxidation of silyl enol ethers by using IBX and IBX N-oxidecomplexes a mild and selective reaction for the synthesis ofenonesrdquoAngewandte ChemiemdashInternational Edition vol 41 no6 pp 996ndash1000 2002

[47] P Li J N Payette and H Yamamoto ldquoEnantioselectiveroute to platensimycin an intramolecular robinson annulationapproachrdquo Journal of the American Chemical Society vol 129no 31 pp 9534ndash9535 2007

[48] G Stork C S Shiner and J DWinkler ldquoStereochemical controlof the internal Michael reaction A new construction of trans-hydrindane systemsrdquo Journal of the American Chemical Societyvol 104 no 1 pp 310ndash312 1982

[49] D P Curran and M-H Chen ldquoRadical-initiated polyolefiniccyclizations in condensed cyclopentanoid synthesis Total syn-thesis of (plusmn)-Δ9(12)-capnellenerdquo Tetrahedron Letters vol 26 no41 pp 4991ndash4994 1985

[50] E J Corey N M Weinshenker T K Schaaf and W HuberldquoStereo-controlled synthesis of prostaglandins F

2120572and E

2rdquo

Journal of the American Chemical Society vol 91 no 20 pp5675ndash5677 1969

[51] A Hasegawa T Ishikawa K Ishihara and H YamamotoldquoFacile synthesis of aryl- and alkyl-bis(trifluoromethylsul-fonyl)methanesrdquo Bulletin of the Chemical Society of Japan vol78 no 8 pp 1401ndash1410 2005

[52] N M Weinshenker and R J Stephenson ldquoBasic hydrogenperoxide cleavage of a bicyclic ketone A new procedure for aprostaglandin intermediaterdquoThe Journal of Organic Chemistryvol 37 no 23 article 3741 1972

[53] D P Curran M-H Chen D Leszczweski R L Elliottand D M Rakiewicz ldquoRegiocontrol in opening of 2H-cyclopenta[b]furanones with organocopper reagentsrdquoThe Jour-nal of Organic Chemistry vol 51 no 9 pp 1612ndash1614 1986

[54] C-G Yang N W Reich Z Shi and C He ldquoIntramolecularadditions of alcohols and carboxylic acids to inert olefinscatalyzed by silver(I) triflaterdquo Organic Letters vol 7 no 21 pp4553ndash4556 2005

[55] D C Rosenfeld S Shekhar A Takemiya M Utsunomiyaand J F Hartwig ldquoHydroamination and hydroalkoxylationcatalyzed by triflic acid Parallels to reactions initiated with


metal triflatesrdquo Organic Letters vol 8 no 19 pp 4179ndash41822006

[56] X Peng D Bondar and L A Paquette ldquoAlkoxide precoordina-tion to rhodium enables stereodirected catalytic hydrogenationof a dihydrofuranol precursor of the C29-40 FG sector ofpectenotoxin-2rdquo Tetrahedron vol 60 no 43 pp 9589ndash95982004

[57] D Yang and C Zhang ldquoRuthenium-catalyzed oxidative cleav-age of olefins to aldehydesrdquo The Journal of Organic Chemistryvol 66 no 14 pp 4814ndash4818 2001

[58] Y-M Zhang S WWhite and C O Rock ldquoInhibiting bacterialfatty acid synthesisrdquoTheJournal of Biological Chemistry vol 281no 26 pp 17541ndash17544 2006

[59] H T Wright and K A Reynolds ldquoAntibacterial targets in fattyacid biosynthesisrdquo Current Opinion in Microbiology vol 10 no5 pp 447ndash453 2007

[60] S Brinster G Lamberet B Staels P Trieu-Cuot A Gruss andC Poyart ldquoType II fatty acid synthesis is not a suitable antibiotictarget for Gram-positive pathogensrdquo Nature vol 458 no 7234pp 83ndash86 2009

[61] J B Parsons and C O Rock ldquoIs bacterial fatty acid synthesis avalid target for antibacterial drug discoveryrdquo Current Opinionin Microbiology vol 14 no 5 pp 544ndash549 2011

[62] H Jayasuriya K B Herath C Zhang et al ldquoIsolationand structure of platencin a FabH and FabF dual inhibitorwith potent broad-spectrum antibiotic activityrdquo AngewandteChemiemdashInternational Edition vol 46 no 25 pp 4684ndash46882007

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


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Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


O

OH OH

OH

NH

OMe

MeO O

1 platensimycin

Benzoic acidmoiety

Amidelinkage

Tetracyclic cage

Figure 1 Structure of platensimycin

pathways would be prerequisite Such precincts seem likelyto severely narrow the opportunities to evolve fatty acidsynthesis inhibitors and may account for the scarcenessof such antibiotics However various Streptomyces produceanalogues of thiolactomycin which has not been reportedto block polyketide synthesis thus demonstrating that devel-opment of fatty acid synthesis inhibitors by this organism isconceivable [10]

2 Isolation of Platensimycin

Platensimycin was isolated by Wang et al in 2006 at con-centration of 2 to 4mgL from fermentation broth of Splatensis (MA7327 and MA7331) using SephadexLH20 liquidchromatography medium by reversed-phase HPLC chro-matography [3] In a subsequent study three-step isolationwas modified by Singh et al and they established two-stepmethod eliminating the SephadexLH20 step [11] It was alsoisolated from Streptomyces platensis (MA7327) recoveredfrom soil samples collected in Eastern Cape South Africa[12]

3 Structure of Platensimycin

Platensimycin (Figure 1) consists of a benzoic acid moietysubstituted at ortho and para with hydroxyl group andin meta position is conjugated with a unique pentacyclicketolide by an amide linkage [13] The structure was estab-lished by combination ofDQ-COSY andTOCSY correlations(2DNMR) UV and IR spectroscopy and confirmed by X-raycrystallography [14]

4 Synthesis of Platensimycin

Platensimycin consists of an aromatic acid conjugated withaliphatic moiety by an amide linkage The effective syntheticstrategy is to synthesize the aromatic and aliphatic partsseparately and then combine them by amide linkage Manysynthetic methods are available for the synthesis of those twobuilding blocks

41 First Total Synthesis of Platensimycin Nicolaou et al inthe year 2006 first reported the total synthesis of platen-simycin [26]

411 Retrosynthetic Analysis of Platensimycin Using ret-rosynthetic analysis (Scheme 1) they separated the aromaticamine 2 and the carboxylic acid 3 by disconnection of amidelinkage The carboxylic acid was further simplified to asimplified enyne in successive three retrosynthetic stepsThisresulted in two target molecules to synthesize the tetracycliccarboxylic acid and the aromatic amine from simplifiedstarting material

412 Synthesis of Tetracyclic Cage The simplified enonegenerated from 3-ethoxycyclohex-2-enone which was usedas a starting material (Scheme 2) Allylic bromide 9 [27](LDA 92) and propargyl bromide (LDA 97) were used asreagents of choice to generate the bis-alkylated enone 10 from8 Reduction followed by acidic hydrolysis and reintroduc-tion of the TBS ether produced enone 11 from enone 10 (yield84) Spirocycle 12was generated by cycloisomerization of 11[28 29] Oxidation of 12 produced bis-enone 13 [30] whichupon acid hydrolysis gave desired aldehyde 6 Secondaryalcohol 14was prepared by addition of samarium(II) iodide ina dilute solution of aldehyde 6 HFIP in THFHMPA followedby NH

4Cl solution Esterification of 14 with TEA resulted

in the formation of cage-like structure 4 which on treatmentwith KHMDS and MeI followed by KHMDS and allyl iodideproduced olefin 16 Vinyl pinacol boronate and 16 reacted inpresence of the Grubbs second generation catalyst to producevinyl boronate 19 which on reacting with trimethylamine N-oxide gave 20 Following Pinnick protocol 20 was convertedto desired carboxylic acid 3

413 Synthesis of Aromatic Amine The synthesis of thearomatic amine 2 was started from 2-nitroresorcinol 21 byprotectingwithMOMether followed by catalytic hydrogena-tion 24 was formed (Scheme 3) Again protecting the aminogroup and followed by silylation lithiation and quenchingwith methyl cyanoformate 24 was carboxylated and byunprotecting amino group using thermolysis desired aniline2 was synthesized

414 Synthesis of Platensimycin Core The total synthesis ofplatensimycin was completed by the coupling of carboxylicacid 3 with aniline 2 which was achieved by treatment withHATU followed by hydrolysis with LiOH (Scheme 3)

42 Another Approach for Synthesizing Tetracyclic Cage byNicolaou et al After successfully reporting the first totalsynthetic strategy of platensimycin Nicolaou et al [31] reporta new synthetic strategy that starts from the readily availableand inexpensive (R)-(minus)-carvone to the tetracyclic enone 2

421 Retrosynthetic Strategy of Tetracyclic Enone A five-step retrosynthetic disconnection approach was shown togenerate commercially available (R)-(minus)-carvone 31 from 26(Scheme 4)

422 Synthesis of Tetracyclic Enone (R)-(minus)-carvone 31 onreaction with Grignardrsquos reagent 32 using CeCl

3[32] and by

oxidizing with PCC gave the corresponding enone 33 Enone


OH

OHOH

Me

Me

+

ONH

O

O O


1 platensimycin

OMOM

2

OMe

MeO

HO

O

Double alkylation 3

OMe

O


4

Me

O

O

5

O

O

Cycloisomerization6

O

7TBSO

MeO2C NH2

oplusoplus

⊖


O

EtO

8

O

EtO

OTBS

10

O

TBSO11

O

TBSO

12

O

TBSO13

O

O6

O

OH

14

O

O

Me

O

O

16

O

O

Me

Me

Me

MeMe

Me MeMe

R

19

O

O

Me Me

MeMe

O

20

O

O

O

HO

3

OTBS

Br 9

(i)

(ii)

(iii)

(iv)

(v) (vi)(vii)

(viii)

(ix)(x)

(xi)

(xii)

N N MesMes

RuCl

Cl Ph

BO

O

(xiii)

(xiv)

Br

PCy3

R1

4 R1 = H

15 R1 = Me




3NO and (xiv) NaClO

2


OMOM

OMOM

2

OMe

OMeHO

O

3

HATU Et3N

OMe

OMeNH

O

LiOH then aq HCl

OR

NO2

OR

21 R = H22 R = MOM

(i)

(ii)

OMOM

NHR NHR

OMOM OMOM

23 R = H24 R = Boc(iii)

(iv)

OMOM

25 R = Boc2 R = H

(v)

CO2Me

MeO2C NH2

R1O2C

OR2

OR2





4to


2O2) to











HO2C

OH

OH

NH

OMe

OMe

O

AlkylationO

Me

O

H

Etherification26

O

O

H


27

O

O

28

O

O

O

Me OH

Me


O

Me

O

O

Grignardaddition

30

O

Me

O

O

BrMg3231

+

OH

OH

NH

O

+HO2C

CH3


(R)-(minus)-carvone
















O

Me

31

O

OBrMg

32Me

O

OO

33

(iii)

HO Me

O

O

O

Me

34bMe

O

O

HO

Me

Me OH

O

O

O

Me

O

34a

(iv)

O

O

O

Me

35

O

O

O

(v)

(vi)

36

O

O

37

(vii)

(i)

(ii)

34ab

HO

O

H

39

(ix)

Ar(O)CO

O

H(x)

40

HO

O

H

41a

HO

O

H

41b

HO

Me

H

O

42

(xii)

(xiii)

O

Me

H

O

43

(xiv)

(xv)

O

Me

H

O

26

O

Me

O

44

+

(viii)

(xi) (xi)



2 then NaBH



2 (x) DIADArCO

2H PPh

3 Ar=p-NO


3O+)








OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574




(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1




2Cu(OAc)

2DMA


2(PPh3)2HCOOH Bu




O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


OH

OHOH

Me

Me

+

ONH

O

O O


1 platensimycin

OMOM

2

OMe

MeO

HO

O

Double alkylation 3

OMe

O


4

Me

O

O

5

O

O

Cycloisomerization6

O

7TBSO

MeO2C NH2

oplusoplus

⊖


O

EtO

8

O

EtO

OTBS

10

O

TBSO11

O

TBSO

12

O

TBSO13

O

O6

O

OH

14

O

O

Me

O

O

16

O

O

Me

Me

Me

MeMe

Me MeMe

R

19

O

O

Me Me

MeMe

O

20

O

O

O

HO

3

OTBS

Br 9

(i)

(ii)

(iii)

(iv)

(v) (vi)(vii)

(viii)

(ix)(x)

(xi)

(xii)

N N MesMes

RuCl

Cl Ph

BO

O

(xiii)

(xiv)

Br

PCy3

R1

4 R1 = H

15 R1 = Me




3NO and (xiv) NaClO

2


OMOM

OMOM

2

OMe

OMeHO

O

3

HATU Et3N

OMe

OMeNH

O

LiOH then aq HCl

OR

NO2

OR

21 R = H22 R = MOM

(i)

(ii)

OMOM

NHR NHR

OMOM OMOM

23 R = H24 R = Boc(iii)

(iv)

OMOM

25 R = Boc2 R = H

(v)

CO2Me

MeO2C NH2

R1O2C

OR2

OR2





4to


2O2) to











HO2C

OH

OH

NH

OMe

OMe

O

AlkylationO

Me

O

H

Etherification26

O

O

H


27

O

O

28

O

O

O

Me OH

Me


O

Me

O

O

Grignardaddition

30

O

Me

O

O

BrMg3231

+

OH

OH

NH

O

+HO2C

CH3


(R)-(minus)-carvone
















O

Me

31

O

OBrMg

32Me

O

OO

33

(iii)

HO Me

O

O

O

Me

34bMe

O

O

HO

Me

Me OH

O

O

O

Me

O

34a

(iv)

O

O

O

Me

35

O

O

O

(v)

(vi)

36

O

O

37

(vii)

(i)

(ii)

34ab

HO

O

H

39

(ix)

Ar(O)CO

O

H(x)

40

HO

O

H

41a

HO

O

H

41b

HO

Me

H

O

42

(xii)

(xiii)

O

Me

H

O

43

(xiv)

(xv)

O

Me

H

O

26

O

Me

O

44

+

(viii)

(xi) (xi)



2 then NaBH



2 (x) DIADArCO

2H PPh

3 Ar=p-NO


3O+)








OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574




(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1




2Cu(OAc)

2DMA


2(PPh3)2HCOOH Bu




O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


OMOM

OMOM

2

OMe

OMeHO

O

3

HATU Et3N

OMe

OMeNH

O

LiOH then aq HCl

OR

NO2

OR

21 R = H22 R = MOM

(i)

(ii)

OMOM

NHR NHR

OMOM OMOM

23 R = H24 R = Boc(iii)

(iv)

OMOM

25 R = Boc2 R = H

(v)

CO2Me

MeO2C NH2

R1O2C

OR2

OR2





4to


2O2) to











HO2C

OH

OH

NH

OMe

OMe

O

AlkylationO

Me

O

H

Etherification26

O

O

H


27

O

O

28

O

O

O

Me OH

Me


O

Me

O

O

Grignardaddition

30

O

Me

O

O

BrMg3231

+

OH

OH

NH

O

+HO2C

CH3


(R)-(minus)-carvone
















O

Me

31

O

OBrMg

32Me

O

OO

33

(iii)

HO Me

O

O

O

Me

34bMe

O

O

HO

Me

Me OH

O

O

O

Me

O

34a

(iv)

O

O

O

Me

35

O

O

O

(v)

(vi)

36

O

O

37

(vii)

(i)

(ii)

34ab

HO

O

H

39

(ix)

Ar(O)CO

O

H(x)

40

HO

O

H

41a

HO

O

H

41b

HO

Me

H

O

42

(xii)

(xiii)

O

Me

H

O

43

(xiv)

(xv)

O

Me

H

O

26

O

Me

O

44

+

(viii)

(xi) (xi)



2 then NaBH



2 (x) DIADArCO

2H PPh

3 Ar=p-NO


3O+)








OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574




(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1




2Cu(OAc)

2DMA


2(PPh3)2HCOOH Bu




O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


HO2C

OH

OH

NH

OMe

OMe

O

AlkylationO

Me

O

H

Etherification26

O

O

H


27

O

O

28

O

O

O

Me OH

Me


O

Me

O

O

Grignardaddition

30

O

Me

O

O

BrMg3231

+

OH

OH

NH

O

+HO2C

CH3


(R)-(minus)-carvone
















O

Me

31

O

OBrMg

32Me

O

OO

33

(iii)

HO Me

O

O

O

Me

34bMe

O

O

HO

Me

Me OH

O

O

O

Me

O

34a

(iv)

O

O

O

Me

35

O

O

O

(v)

(vi)

36

O

O

37

(vii)

(i)

(ii)

34ab

HO

O

H

39

(ix)

Ar(O)CO

O

H(x)

40

HO

O

H

41a

HO

O

H

41b

HO

Me

H

O

42

(xii)

(xiii)

O

Me

H

O

43

(xiv)

(xv)

O

Me

H

O

26

O

Me

O

44

+

(viii)

(xi) (xi)



2 then NaBH



2 (x) DIADArCO

2H PPh

3 Ar=p-NO


3O+)








OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574




(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1




2Cu(OAc)

2DMA


2(PPh3)2HCOOH Bu




O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

Me

31

O

OBrMg

32Me

O

OO

33

(iii)

HO Me

O

O

O

Me

34bMe

O

O

HO

Me

Me OH

O

O

O

Me

O

34a

(iv)

O

O

O

Me

35

O

O

O

(v)

(vi)

36

O

O

37

(vii)

(i)

(ii)

34ab

HO

O

H

39

(ix)

Ar(O)CO

O

H(x)

40

HO

O

H

41a

HO

O

H

41b

HO

Me

H

O

42

(xii)

(xiii)

O

Me

H

O

43

(xiv)

(xv)

O

Me

H

O

26

O

Me

O

44

+

(viii)

(xi) (xi)



2 then NaBH



2 (x) DIADArCO

2H PPh

3 Ar=p-NO


3O+)








OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574




(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1




2Cu(OAc)

2DMA


2(PPh3)2HCOOH Bu




O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


OH

NH

OH

O O

O Me

O

O Me

OO

O

Me

OO

OMe

O

O

HPGO

O

O

OPG

+OMe

1 4 46

45

48 47

44

∙

HO2C

R3SiO


OH

O

OH O

OH

O

OR

(i) (ii) (iii)(iv)

O

HRO

O

O

HRO

O

+

49 50 51 52

OO

HHO

O

OO

O

Me

O+

OO

O

O

53

54a 54b

OO

O

OTf

OO

O

OTf

55

56

OO

O

MeSPh

O

OMe

574




(v)

(vi)

(vii)(viii)

(ix)

(x)

(xi)(xii)

10 1

10 1

= 46b 46d 11 1




2Cu(OAc)

2DMA


2(PPh3)2HCOOH Bu




O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

HNHO

OHO

1 platensimycin

O4

O O

O58

O59

OH

60

HOH

61

TBSOH

CHO

62

OH

O

63

OH

O

64

CO2H


O

O

(i)(ii)

TBSO

O

TBSO

OH

(iii) SOPh

(iv)

TBSO

O

PhSO

TBSO

(v)

OP

OMe

OMeO O

(vi)HOHO (vii) TBSO

+

O O

(viii)

+

(viii)

O(xi) HO

HO

(xii)

64 65 66 67

6869

70b70a

71a71b

72 5873

74

(x)

(ix)

H3C

H3C

N2


2Cl2 (iv) NaH cat



2Cl2 0∘C 2 h




OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


OH

OMe

O

OMe

O O

O

OMe

O OMe

OMEM

OMe

O OMe

OMEM

OH

Me

OMe

BrOTIPS

OMe

OTIPS

OMe

O

O

75

76 77 78

79 80 8182

4

(i) (ii) (iii) (iv)

(v) (vi) (vii)

(viii)O



2]BF4 C7H8 H2O

Et3N CH

3-CH(BF

3K)=CH

2 (iii) (1) NaBH


2NEt CH

2Cl2 (3) TsOHMe

2CO 0∘C (4) i-Bu

2AIH CH

2Cl2 0∘C (5)

Et3SiH (CF

3CO)2O CH


2CO3 DMF D 170∘ (v) (1) i-Pr

3SiCl imidazole CH

2Cl2 23∘C 12 h and (2) Br

2 CH2Cl2


2]BF4 (RR)-DIOP H

2600 psi CH


3N CH

2Cl2and (2)

IBX MPO DMSO

O

O

NH

OO

+

OH

OH

OH O

O

O

O

CHO

OCHO

OOO

O

COOMe

1 platensimycin 483

84858688 87










COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


COOMe

88 87 COOMe OO

O

85

OO

91

ONC

ONC

OO

OCHO

O84

O

O

4

O

4aO

N

+

+

+

+

B OPh

Ph

Ph

F

F

F

F

F

HTf

Tf

NH

COOH

MgBr

(i)

(ii)

(v)

(vi)

(iv)

(vii)

(viii)

(iii)

(ix)

(x)

89 90

92a92b93


2O



2S CH

2CMgBr THFMe


2

CH2ClCH


2AlCN BF

3sdotOET



2P(O)(OET)


4 35mol RuCl

36 1 CH

3CNH



CO

CoA

Acetyl-CoA

CO

CHO

HO

CO

S CoAMalonyl CoA

Accase (ABCD)

FabDACP-SH

CO

C CO

S ACPMalonyl-ACP

HS-CoA + CO2

FABHC

O

C CO

S ACP

CH

C CO

S ACP

OH

NADP2H

NADP

FabG

CH

CH

CO

S ACP

FabA

FabZ

CO

S ACP

Acyl-ACP

NAD2H

NAD

Fabl (KL)

CO

CHO CO

S ACPMalonyl-ACP

ACP-SH + CO2


Decynoyl-NAC

Triclosanisoniazid

FabFFabBHS-CoA

H2

H2

H2

H2

H2

H3CH3C

H3C

H3C

H3C

H2O

(CH2)2n

(CH2)2n

(CH2)2n

(CH2)2n

120573-ketoacyl-ACP


Trans-2-enoyl-ACP








1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




1 (minus)-Platencin

OH

HOOC

OH

NH

OMe O


[12]


N

HOO OPh

OMe

H



OHHN

HOO OPh

OMe

Me



O

OH

NHSR

OO

O

O

R = Or

Or

Not tested [16]


O

N O

Me

O

NH

OO

OH

OH

OH


[17]

6 Isoplatencin

OH

HOOC

OHNH

O

Me

O

Me

H


7 Cl-iso-platencin

OH

HOOC

OHNH

O

Me

O

Me

H

Cl



Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table 1 Continued


8 Cl-platencin

OH

HOOC

OHNH

O

Me

O

H

Cl



OH

HOOC

OHNH

O

O


10 Isoplatensimycin

OHHN

HOO O



Me

Me O

NH

OO

OH

OH

OH



3

O

OH

OHOMe

O Me

HN

O

OH

HN O

O

O

OH

OH

H2N

1 B1

2 B2 3 B3

Not tested [22]

13 Platensimide AO

Me

Me OHN

O

HNAc

CO2H

Not tested [22]


Me

Me OHN

O

O


CO2R

H2N

Not tested [22]


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table 1 Continued


15


OH

HOOC

OH

NH

O

NnN

N N N

1

2 3 4

R1

R2

R2 = H or R1 R1 = 1 or 2 or 3 or 4


[23]


HN

HOCOOH

OH

OH

Me



COOH

OO Me

OH

HOOC

OMe O

OH

OH




[25]


7 Conclusion



Abbreviations









Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of








Acknowledgment


References





















































2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






























2120572and E

2rdquo

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Review Article A Review on Platensimycin: A Selective FabF ...downloads.hindawi.com/archive/2016/9706753.pdfR 1 O 2 C OR 2 OR 2 26 :R1 = Me ,R 2 = MOM 1:R1 = R 2 = H: platensimycin