synthesis and medicinal chemistry of selected antitubercular natural products and natural product...

RSC Advances

REVIEW

Synthesis and me

AhNsSsadcsdjT

doctoral studies with Professor Kextensively worked on synthesis ooration with (a) AuTEK-Biomed AdAfrica, (b) NRF, South Africa anproject. At present, he is working aStya Research Foundation, Gurgao

aResearch Scientist/Group Leader, Research

University, Institutional area, Sector-32, PlobDepartment of Chemistry and Biochemis

NamibiacInstitute of Infectious Disease and Molecu

Private Bag, Rondebosch 7701, South AfricadDepartment of Chemistry, Guru Nanak D

E-mail: [email protected]; Fax: +91-

ext. 3320

Cite this: RSC Adv., 2014, 4, 15180

Received 25th October 2013Accepted 10th March 2014

DOI: 10.1039/c3ra46124f

www.rsc.org/advances

15180 | RSC Adv., 2014, 4, 15180–1521

dicinal chemistry of selectedantitubercular natural products and naturalproduct derivatives

Aman Mahajan,a Renate Hans,b Kelly Chibaleac and Vipan Kumar*d

Despite advances in molecular methods for the diagnosis of tuberculosis (TB) and its resistant forms, it

remains more prevalent in the world today than at any other time in human history. Of equal concern is

the slow moving antitubercular drug development pipeline which calls for research efforts to be

intensified and directed towards the discovery of new molecular scaffolds and/or the remodelling of

some old TB drug families. In support of the latter, this review highlights synthetic methodologies and

structure activity relationships (SARs) elaborated for natural products and/or natural product derivatives

with promising antitubercular activity. It further attests to the enormous potential of natural products in

the antitubercular drug discovery process.

man Mahajan Ph.D, obtainedis Ph.D in 2005 from Guruanak Dev university under theupervision of Prof Kamaljitingh where he explored theynthesis, and structural char-cterization of hetarylazoisperse dyes based on diazoomponents and regioselectivecaffold decoration of 3,4-dihy-ropyrimidin-2(1H)-ones. Heoined the University of Capeown, South-Africa for his post-elly Chibale (2006–2011) andf drug-like molecules in collab-vance Materials Division, Southd (c) European union antimals a research scientist in Apeejayn, India.

and Development Centre, Apeejay Stya

t 23, Gurgaon, India

try, University of Namibia, Windhoek,

lar Medicine, University of Cape Town,

ev University, Amritsar-143005, India.

183-2258819-20; Tel: +91-183-2258802

5

Introduction

The prevalence of TB in resource-poor settings, the everincreasing pace at which resistance develops against clinicallyused drugs, and the existence of unfavourable drug–druginteractions for the treatment of TB–HIV coinfection, areevidence of the urgent need for new, cheaper and more effectiveantitubercular drugs. Advances made in synthetic andcombinatorial chemistry have contributed signicantly towardsthe development of new antitubercular drugs.1 The role andimportance of natural products in antitubercular

Renate Hans Ph.D, received herMSc in Natural Product Chem-istry from the University of Bot-swana in 2002, where shestudied the isolation and struc-ture elucidation of majormetabolites from traditionallyused medicinal plants. Sheobtained her Ph.D in 2009 fromthe University of Cape Townunder the supervision of Prof.Kelly Chibale were she designed,synthesized and elaborated

structure–activity relationships of antimalarial and antitubercularagents modeled on natural products. She has taken up a lecture-ship at the University of Namibia and her current research inter-ests revolve around the isolation and structure elucidation ofnatural products from medicinal plants and their use as scaffoldsin the design and synthesis of novel anti-infective agents.

This journal is © The Royal Society of Chemistry 2014

Review RSC Advances

chemotheraphy cannot be overstated as evidenced by thenumber of reviews published on this topic. Historically, naturalproducts contributed signicantly towards the arsenal of anti-tubercular drugs. The aminoglycoside streptomycin 1, from theactinobacterium Streptomyces griseus was the rst antibioticwith bactericidal activity.2 Rifamycin (2a, Fig. 1), a polyketideproduced by cultures of Amycolatopsis mediterranei3 is animportant anti-TB drug lead which aided the discovery of thesemisynthetic rst-line drug, rifampin 2b. Other semisyntheticderivatives of 2a with enhanced anti-TB activity and pharma-cological properties include rifapentine 2c, rifametane 2d andrifabutine 2e.4 The latter deserves special mention, for itscompatibility with antiretrovirals has made it invaluable in thetreatment of HIV-related TB.4 Infection by MDR-TB strainsrequires treatment with second line drugs such as kanamycin 3,amikacin 4, and capreomycin 5.3,5 Another streptomycete-derived natural product is the D-alanine mimic, cycloserine 6which exerts its mechanism of action by inhibiting cell wallbiosynthesis in Mycobacterium tuberculosis. It is produced bycultures of Streptomyces orchidaceus and is used clinically as asecond-line antitubercular agent.3

This review serves to complement other comprehensivereviews on antitubercular compounds.6–9 Themain focus will beon reviewing various synthesis strategies reported for selectednatural product and natural product-derived antitubercularagents. This includes compounds which are undergoing clinicaltrials, used clinically and those reported to inhibit the growth ofmycobateria. Reference will also be made to key structureactivity relationship (SAR) data for some of the compounds. Thecompounds herein discussed are listed below according to theirchemical and biosynthetic classication:

1. Thiolactones, lactones, and macrolides2. Alkaloids

Kelly Chibale has been a fullProfessor of Organic Chemistryat the University of Cape Town(UCT) since 2007. In 2008 hewas awarded a Tier 1 SouthAfrica Research Chair in DrugDiscovery under the South AfricaResearch Chairs Initiative(SARChI) of the Department ofScience and Technology (DST)and administered through theNational Research Foundation(NRF). In 2009 he became the

founding Director of the Medical Research Council (MRC) DrugDiscovery and Development Research Unit at UCT. In the sameyear (2009) he was elected a Life Fellow of UCT and a Fellow of theRoyal Society of South Africa. In 2010 he became the Founder andDirector of the UCT Drug Discovery and Development Centre (H3-D). His research has been in the eld of drug discovery and hasbeen underpinned by (Hit to Lead and Lead Optimization)medicinal chemistry.


3. Terpenes4. Miscellaneous

1. Thiolactones, lactones andmacrolides1.1 Thiolactomycin and analogues

The naturally occurring broad-spectrum antibiotic, (5R)-thio-lactomycin (S,E)-4-hydroxy-3,5-dimethyl-5-(2-methylbuta-1,3-dienyl)thiophen-2(5H)-one, (TLM, 7, Fig. 2) was rst isolated inJapan in 1982 from the fermentation broth of the soil bacteriaNorcardia.10 Interest in 7 was prompted by its favourable attri-butes such as good bioavailability and toxicity prole in amouse model10 and more importantly, its ability to selectivelyand reversibly inhibit the condensing enzyme of dissociabletype II fatty acid synthase (FAS).10 Thiolactomycin andanalogues reportedly inhibit Gram negative and Gram positivebacteria,10 Plasmodium falciparum,11 African trypanosomiasis,11

and Toxoplasma gondii.11 Of interest, is their inhibitory activityagainst fatty acid and mycolic acid biosynthesis in M.tuberculosis.12

In 1913, prior to the isolation and structure elucidation of 7,Benary described the synthesis of the thiolactone ring system,the key intermediate of 7.13 This synthesis protocol was utilizedby Wang and Salvino,14 in developing the rst racemic synthesisof 7. As shown in Scheme 1 it involves an initial selective a-bromination of methyl a-propionylpropionate 8 (ref. 15) withpyridinium tribromide in acetic acid to yield the bromoketoneester 9. Nucleophilic substitution of 9 with thioacetic acid in thepresence of a base afforded the thioester 10 which underwent abase-catalyzed cyclization to yield thiolactone 11, as a racemate.The key step in the synthesis was the reaction of the dianion 12,generated in situ by the reaction of 11with NaH and n-BuLi, with

Vipan kumar Ph.D, has beenworking as an AssistantProfessor in the Department ofChemistry, Guru Nanak DevUniversity, Amritsar since 2009.He obtained his Ph.D with Prof.MP Mahajan, in the Departmentof Applied Chemistry, GNDU. In2007, he moved to the Universityof Cape Town (UCT), SouthAfrica to pursue his post-doctoral studies with Prof. KellyChibale and extensively worked

on molecular hybridization protocols for the preparation ofmolecular conjugates intended for HIV–malaria co-infections. Hisresearch interests include the development of diverse syntheticprotocols for synthesis of novel molecular frameworks targetingtropical infections. He has also been engaged in the utilization ofb-lactam synthon protocols for the synthesis of functionally deco-rated and biologically relevant heterocycles with medicinalpotential.

RSC Adv., 2014, 4, 15180–15215 | 15181

Fig. 1 First- and second-line natural product and natural product-derived antitubercular drugs.

Fig. 2 (5R)-Thiolactomycin 7.

Scheme 1

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the isoprene equivalent, 3-ethoxy-2-methyl-2-propenal. This wasfollowed by the acid hydrolysis and subsequent Wittig reactionof the synthesized aldehyde 13 to furnish 7 as a racemate.

Thomas and co-workers developed an asymmetric synthesisfor non-natural (5S)-thiolactomycin ent-7 (Scheme 2).16 Themethodology involves the conversion of (S)-lactate 14 to theallylic alcohol 15 through a series of reactions which includesilylation, DIBAL reduction of the ester functionality, Wittigcondensation of the aldehyde with Ph3PC(Me)CO2Et and desi-lylation to yield the corresponding a,b-unsaturated ester 15withthe expected E-geometry at the double bond. The stereoselective[3,3] sigmatropic rearrangement of allylic xanthate 16, preparedby base catalyzed reaction of 15 with CS2/CH3I, affordeddithiocarbonate 17.16,17 Selective replacement of the dithiocar-bonate group with p-methoxybenzyl chloride afforded 18 whichwas subjected to ozonolysis to yield the corresponding aldehyde19.18 Aldehyde 19 was then converted to an a,b-unsaturatedaldehyde 20 via treatment with lithiated 2-triethylsilylpropanal


Scheme 2

Review RSC Advances

N-t-butylimine followed by acid hydrolysis.17 Reaction of thealdehyde 20 with triphenylphosphonium methylide yielded thediene 21 which underwent a hydroboration–oxidation reactionto yield the primary alcohol 22. Treatment of the latter with4-chlorophenylselenocyanate in the presence of tributyl phos-phine afforded a terminal selenite 23 which aer base hydro-lysis and reaction with N,N0-carbonyl di-imidazole formed theacyl imidazolite 25.18 Reaction of the imidazolide with theenolate of methyl propionate afforded a diastereomeric mixtureof keto-ester 26. Follow up treatment of 26 with triuoroaceticacid–mercuric acetate–hydrogen sulde generated the thiol 27which underwent a base-mediated cyclization to yield the thi-otetronic acid 28 aer acidication.19 Removal of the arylsele-nide group by treatment of 28 with trimethyloxoniumtetrauoroborate yielded the selenonium salt 29 which uponreaction with KOH in THF-DMSO afforded ent-7.20

McFadden and coworkers21 developed an asymmetricsynthesis of naturally occurring thiolactomycin 7, using theSeebach self-regeneration of chirality approach (Scheme 3).22 In

Scheme 3


this synthesis, the Kellog's method was used to convert(2R)-alanine 30 via diazotization–chlorination to (2R)-chlor-opropionic acid 31. Deacetylation of 32, an intermediate fromthe reaction of 31 with cesium thioacetate, led to (2S)-thiolacticacid 33. The acid-catalyzed reaction of 33 with pivalaldehydeafforded a cis/transmixture (2.5 : 1) of (S)-oxathiolanones whichwas separated by means of fractional crystallization. The cis-(S)-oxathiolanones 34 so obtained was treated with LDA followed bycondensation with tiglic aldehyde 35, to give a (2 : 1) mixture ofthe diastereomeric alcohol 36. A method developed by Reichand Wollowitz was used in the conversion of the allylic alcohol36 to the 1,3-diene 37.23 Ethanolysis of 37 in the presence ofCs2CO3 gave 38, which was acylated with propionyl chloride toyield the thioester 39. Upon treatment with LiHMDS, 39underwent a thio-Dieckman condensation to yield 7 with highoptical purity.

Ohata and Terashima24 reported an asymmetric synthesis,which utilizes the chiral auxiliary strategy to afford the enan-tiomeric pairs 7 and ent-7 and their 3-dimethyl derivatives. Theauthors moreover demonstrated the efficiency of this protocolby successfully applying it in the synthesis of enantiomeric pairsof 5-vinylthiolactomycin derivatives. Scheme 4, outlines thesynthesis strategy which starts with the Horner–Wadsworth–Emmons25 reaction of tiglic aldehyde 35 with an a-branchedphosphonate followed by hydrolysis of the ester functionalitywith NaOH. The resulting hexadienoic acid 40 was reacted withpivaloyl chloride and (R)-4-benzyl-2-oxazolidinone to afford thechiral 2-oxazolidinone 44.26 A key step in this synthesis was thede-conjugative asymmetric a-sulfenylation of the chiral 2-oxa-zolidinone which involved deprotonation of 41 with NaHMDSin the presence of HMPA yielded the trienolate 42, which uponaddition of the sulfenylating agent 43 gave a diastereomericmixture (8 : 1). Separation of the mixture was achieved bypreparative HPLC and afforded pure 44 which aer treatmentwith Ti(OiPr)4 in benzyl alcohol resulted in the benzyl ester 45.27

Conversion of the benzyl ester 45 to the a-propionylthioester 47was achieved by removal of the ketal group followed by treat-ment of the intermediate 46 with Cs2CO3. Reaction of thecesium thiolate so formed with propionyl chloride in the

Scheme 4

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Scheme 6

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presence of Et3N gave the a-propionylthioester 47. Dieckmanncyclization of 47 was mediated by LiHMDS and led to theformation of 7.21

The development of synthesis methodologies for 7 andanalogues gained considerable momentum in early 2000.Takabe and co-workers28 developed a 12-step chemoenzymaticsynthesis of 7 of which the rst part involved the synthesis ofthe racemic acid precursor 49. This was achieved by an initialprotection of the hydroxyl group of 11 via chemoselectivemethylation with Bu4N

+OH� and (CH3)2SO4 to yield an aniso-meric mixture of 4-methoxy and 2-methoxy derivatives in theratio 82 : 18. Aer separation, the desired 4-methoxy isomer 48underwent formylation to give the racemic thiotetronic acidintermediate 49. Chirazyme® L-2 (Candida antarctica or lipaseB) was selected as the enzyme to catalyse the enantioselectiveacetylation of 49 with vinyl acetate at 25 �C. It afforded the(R)-alcohol 50 with 78% enantiomeric excess.

The authors made several attempts to extend the C-5 sidechain of the aldehyde 51, which was obtained from 50 underSwern oxidation conditions, but were unsuccessful. This wasascribed to the stabilization of the anion by the adjacentsulphur atom and tautomerization.28 However, treatment of 51with crotyl tributylstannane in the presence of the Lewis acidBF3$OEt2 afforded the allylic alcohol 52. The alcohol 52 wasthen brominated and the bromide derivative 53, so obtained,underwent a base-mediated elimination to afford 54 as aninseparable trans/cis mixture (9 : 1). Deprotection of 54 withlithium thiolate afforded 7 in good yields (Scheme 5).

Dormann and Bruckner29 developed a catalytic, asymmetricsynthesis of 7 which comprises a 7-step reaction sequence. Themethodology involves an initial Wittig condensation of thealdehyde 55 with phosphorane 56 followed by ethanolysisleading to the formation of 57 (Scheme 6).30 Conversion of 57 tothe silylated vinyl epoxide 58 involves a catalytic Sharplessasymmetric epoxidation,31,32 followed by in situ protection of theepoxy-alcohol 58 to yield vinyl epoxide 59 with 93% ee. Thiolysisof 59 with thiopropionic acid in the presence of the Lewis acid,Me3Al at �78 �C followed by the addition of vinyl epoxideresulted in the formation of 60 which was desilylated with theHF/Pyridine complex to yield 61. A reductive vic-didesoxygena-tion synthesis methodology developed by Garegg andSamuelsson33 and which utilizes PPh3, imidazole and I2,

Scheme 5

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promoted the conversion of 61 to the diester/diene 62. Die-ckmann condensation of 62 in the presence of LiHMDS21 led tothe formation of 7.

Thiolactomycin 7 represents an attractive lead for anti-mycobacterial research12 and has become the focus of variousstudies. Additionally, the elucidation of the crystal structure of 7bound to E. coli's FabB revealed important interactions between7 and the enzyme's active site; one such being the accommo-dation of the isoprene group at C-5 in an incompletely lledhydrophobic pocket.34 Particular attention has therefore beengiven to structural modication at the C-5 position. Forexample, Douglas and coworkers12 investigated the anti-tuber-cular activity of racemic thiolactomycin analogues withaliphatic substituents at the C-5 position. Optimization of thesynthesis, started with investigating the ability of differentbases (NaH, lithium bis(trimethylsilyl)amide (LiHMDS), t-BuLi),and base combinations (NaH/t-BuLi, NaHMDS/t-BuLi) todeprotonate the precursor, thiolactone 11. Most of theanalogues 63 were obtained by treatment of 11 with the basecombination NaH/t-BuLi and various alkylating agents (Scheme7). The analogue with a 5-tetrahydrogeranyl substituent provedto be the most potent of the test compounds with an MIC90 forM. tuberculosis of 29 mM and 92% mycolate inhibition in

Scheme 7


Review RSC Advances

extracts of M. smegmatis. The Structure–Activity Relationship(SAR) in the present case revealed that the modication of TLMcan provide analogues with enhanced activity againstM. tuberculosis andmycolic acid synthases fromM. smegmatis. Itwas argued that the planarity of the side chain is the crucialfactor for successful binding with FAS-II enzyme.

Thiolactomycin 7, is furthermore reported to exert its modeof action by targeting the b-ketoacyl-acyl-carrier protein syn-thases: mtKas A, mtKas B,12 and to a lesser extend mtFabH12

which are all members of the type II Fas system. Senior andcoworkers12 synthesized analogues with biphenyl substituentsat the C-5 position which were screened for inhibitory activityagainst recombinantmtFabH. Selection of the biphenyl motif inanalogue design and synthesis was reportedly based on therigidity and stability it imparts. Synthesis of these biphenylanalogues proceeded via intermediate 64 (Scheme 8). Treat-ment of 64 with various arylboronic acids under Suzukicoupling conditions afforded analogues 65. The most activecompound in this series reportedly showed a 4-fold increase inactivity compared to 7.

In continuing the search for analogues of 7 with enhanced invitro inhibitory activity against mtFabH, Senior and coworkers,as a follow-up on the synthesis of biphenyl-based analogues,12

described the synthesis of aromatic acetylenic analogues 67.12

The latter were obtained via Sonogashira coupling of a prop-argyl substituted intermediate 66 with variously substituted aryliodides, as shown in Scheme 9.

The most active compound in this series showed an 18-foldincrease in activity compared to 7 against mtFabH, andpossessed an acetyl group at the para-position on theacetylenic aromatic side-chain. A structural comparison of the

Scheme 8

Scheme 9


biphenyl- and acetylenic TLM analogues with the best mtFabHactivity revealed the need for a “linear p rich system” with anhydrogen-bond acceptor at the para position of the aromaticring.12 From the activity data, it was concluded that acetylenebased compounds are signicantly better than the biphenylanalogues. For instance, compound 67a displayed IC50 value of4 � 0.4 mM whereas the best of biphenyl analogue exhibited anIC50 of 17 � 1.3 mM. In an independent study, Bhowruth andcoworkers investigated the activity of C-5 biphenyl-basedanalogues (Fig. 3) for growth inhibitory activity of M. tubercu-losis BCG and activity against mtFabH.12 A modied version ofthe Wang and Salvino14 method afforded the thiolactone ring11. Conditions similar to those employed by Senior andcoworkers12 afforded 15 biphenyl and biphenyl-based racemicTLM analogues (Fig. 3). The most active analogue showed a25-fold increase in mtFabH inhibitory activity compared to 7with an IC50 value of 3 mM.

As mentioned earlier, most of the synthesis of thio-lactomycin analogues focussed on replacing and/or modifyingthe C-5 substituent. Kamal and coworkers, however, synthe-sized analogues of 7 by etherication of the C-4 hydroxyl groupof thiolactone 11.12 As shown in Scheme 10, potential anti-TBderivatives were prepared by the O-alkylation of 11 with variousdibromoalkanes in the presence of K2CO3. This was followed bythe reaction of the bromo-ethers 68 so obtained with methylthioglycolate, 1-methyl piperazine and morpholine to givecompounds 69, 70 and 71, respectively. The anti-tubercularprole was shown to depend upon the spacer length with themost potent of the tested compounds having an octyl chain andmethyl glycolate as linker displayed an IC50 of 1.0–4.0 mg mL�1.

Kim and coworkers studied the effect of modication of theisopreniod chain on antimycobacterial activity.12 One of the

Fig. 3 Biphenyl and biphenyl-based racemic TLM analogues.

Scheme 10

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series of compounds synthesized are the racemic C-5 thio-lactomycin analogues 72 prepared by introducing differentsubstituents at the C-5 position of 11 using the method devel-oped by Douglas and coworkers12 (Scheme 11). Structure–activity relationship studies revealed the presence of isoprenoidside chain as absolutely important for activity against KasA,KasB and FabB. Interestingly, the improved activity ofanalogues against whole cells did not correlate with the enzymeinhibition activity, for example, the compound with an MIC of25 mM against E. coli has no activity against FabB, the knownTLM target. These results strongly suggest that the TLManalogues must be evaluated with respect to their activity interms of IC50 against a specic condensing enzyme as well as interms of growth-inhibitory potential to avoid confusing SARresulting from effects on multiple enzyme targets.

Investigation of the importance of each double bond in theisoprene side chain was achieved by assessing the anti-myco-bacterial activity of a second series of analogues obtained bythe systematic reduction of the double bonds. As outlined inScheme 12 chiral 7, obtained by fermentation, was treatedwith a diimide excess and afforded compounds 73 and 74by varying the reaction duration. Diimide was prepared bythe reaction of NH2NH2$H2O with aqueous 30% H2O2 in

Scheme 12

Scheme 11

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EtOH.35 A batch of 7 underwent hydroboration–oxidation toafford the alcohol 75, which in turn was treated with excessdiimide to effect the reduction of the internal double bond ofthe C-5 substituent and thus yielded 76. Mesylation of 76 gavethe dimesylate 77 and was followed by substitution of theprimary mesyl group with iodide to yield 78.35 The latter wasthen subjected to a one-pot dehydroiodination and demesy-lation procedure to afforded 79 as a mixture of diastereomersin 50% yield.

The racemic butadiene analogue 86 was selected to study theeffect of the methyl group in the isoprene side chain on anti-mycobacterial activity. The synthesis of 86 is shown in Scheme13. The rst step involved protection of the C-4 hydroxyl groupof 11 using MOMCl and DIPEA in dichloromethane. Hydrox-ymethylation at position C-5 of 80 involved the treatment withLiHMDS and subsequent reaction with paraformaldehyde toafford 81 which underwent oxidation with Dess–Martin peri-odinane to furnish the aldehyde 82.36,41 Olenation of 82 underHorner–Wadsworth–Emmons reaction conditions required theuse of a more stable ylide, diethyl 2-oxopropylphosphonate andfurnished 83 as well as the deformylated product.37 Chemo-selective reduction of 83 with NaBH4 in the presence ofCeCl3$7H2O afforded the alcohol 84.38 Treatment of the allylicalcohol 84 with Burgess reagent yielded the butadiene 85.Analogue 86 was obtained aer reacting 85 with NaHSO4$SiO2

in dichloromethane at room temperature.Compound 89, which contains an additional methyl group

on the isoprene chain provided further information for delin-eating SAR for this series of analogues. Synthesis of 89 waspreceded by protection of the C-4 hydroxyl group in 7 as a MOMether to yield ent-89, which underwent a olen cross metathesisreaction with Grubbs' second generation catalyst and trans-2-butene to yield derivative ent-88.38 Deprotection of ent-88involved reaction with the polymer supported TsOH and silicagel in dichloromethane at room temperature to yield 89(Scheme 14).

1.2 Passioricin

Polyhydroxylated pyrones known as passioricins andanalogues of passioricin lactone are reported to exhibit anti-TB properties (Fig. 4).39 Conjugated lactone 90 was found to be

Scheme 13


Scheme 14

Fig. 4 Passifloricin and its analogues.

Scheme 15

Scheme 16

Review RSC Advances

active in the Artemia salina test, whereas the unconjugatedlactones 91 and 92 showed no activity.39d

Conjugated lactone 90 was found to be active in the Artemiasalina test, whereas the unconjugated lactones 91 and 92showed no activity.39d The stereoselective syntheses of thed-lactones of (2Z,5S,7R,9S,11S)-tetrahydrooxyhexacos-2-enoicacid, (passioricin A, 90) and its (5R)-epimer 5R-epi-90 (107)were described by Marco et al.39 It involves a three-step reactionsequence, which include asymmetric allylation using Brown'schiral boranes, hydroxyl protection and oxidative cleavage of thecarbon–carbon double bond to create new stereogenic centresin each cycle (Scheme 15).40,41

The n-hexadecenal 93 was reacted with b-allyl diisopino-campheyborane (allylIBIpc2) – prepared from allyl magnesiumbromide and diisopinocampheylborane chloride ((+)-DIPCl) toyield the homoallyl alcohol 94 as a 96 : 4 enantiomericmixture.42 Protection of the hydroxyl group as the tert-butyldi-methylsilyl derivative 95 followed by ozonolysis of the olenicbond yielded an intermediate b-silyloxy aldehyde.43 The latterwas subjected to asymmetric allylation to give homoallyl alcohol96 with the desired syn conguration of the two oxygen func-tionalities.44 Silylation of 98b and oxidative cleavage of theolenic bond was followed by asymmetric allylation of theintermediate b-silyloxyaldehyde. Allylation afforded the pro-tected triol 99 with the desired (S)-conguration at the newstereogenic carbon. Compound 99 was silylated to yield 100which in turn was subjected to another round of ozonolysis,allylation and protection to yield the alcohol 101. The cinna-mate 102, was obtained by treatment of 101 with cinnamoylchloride.45 No reaction occurred when the ester 102 was


subjected to RCM with standard ruthenium complex A. Thedesired lactone 103was obtained by replacing the latter with thesecond generation ruthenium catalyst B.41 Acid-catalyzedcleavage of all silyl protecting groups of 103, gave the lactone 90,in good yield.46 Disappointingly, the NMR data of the synthe-sized 90 proved to be distinctly different from those publishedfor the natural product. For the synthesis of the C-5-epimer of90 (Scheme 16), the b-oxygenated aldehyde resulting from theoxidative cleavage of the compound 100 was allylated using areagent derived from (+)-DIPCl and allyl magnesium bromide.The resulting alcohol 104 was reacted with cinnamoyl chlorideto yield cinnamate 105 which was subjected to RCM usingcatalyst B, followed by deprotection to yield 107, the C-5-epimerof 90. According to the data published by Echeverri andco-workers,47 only the diastereomeric structures 90 and 5R-epi-90 should be possible for passioricin A. However, the datapresented by Echeverri and co-workers is partly erroneous and

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the structure proposed for natural lactone is incorrect especiallywith regard to the conguration of some of the stereogeniccenters as evidenced from the works of Marco and co-workers.39

1.3 Erythromycin

One practical approach for expeditious TB drug discovery is toconsider current antibiotic classes that already possess accept-able pharmacological and toxicological proles, and then tooptimize for potency against M. tuberculosis. Erythromycin (108and 109, Fig. 5), the rst generation prototypical macrolide, is anatural product produced by Streptomyces erythreus. Thecompound inhibits protein synthesis by binding to the 50Ssubunit of 70S ribosomes near the peptidyl transferase center,thus blocking the movement of nascent peptides through theexit tunnel. Erythromycin has a short serum half-life as well asacid lability, the acid degradation product of which results ingastric motility-based discomfort. In addition, activity wasrestricted to Gram-positive bacteria and no activity wasobserved against M. tuberculosis. The second generation mac-rolides clarithromycin (CAM, 110), roxithromycin (RXM, 111),dirithromycin (DRM, 112) and azithromycin (AZM, 113, Fig. 5)48

were therefore developed to have superior acid stability andserum half-life. CAM and AZM were, along with rifabutin 2e, themost active clinical agents against M. avium.49,50 With theexception of AZM (an azalide which possesses a differentspectrum of activity than other macrolides), these compoundswere also found to possess potent activity against M. leprae inaxenic media51,52 in macrophages,53 mice54,55 and ultimately inman.56–58 CAM is currently recommended by the WHO fortreatment of leprosy in cases of rifampin resistance orintolerance.59

Isolated and discovered in the early 1950s in the fermenta-tion broth of the fungus Saccharopolyspora erythraea,60 eryth-romycin A 108 and erythromycin B 109 are the best knownmembers of the clinically important macrolide class of antibi-otics.61 Indeed, 108 and several of its derivatives remain theantibiotics of choice for the clinical treatment of numerouspathogenic bacteria. Erythromycin A and B differ by a hydroxylgroup at C(11) and are bis-glycosylated macrocyclic lactones

Fig. 5 Antitubercular antibiotics.

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bearing a desosamine residue on the hydroxyl group at C(5) anda cladinose group on the hydroxyl function at C(3).

Given the unusual combination of powerful antibioticactivity and stereochemically complex architecture, it is notsurprising that the erythromycins have been popular targets forsynthesis. As such, they have provided fertile testing ground fordeveloping new strategies and methods for the stereoselectiveformation of carbon–carbon bonds and introduction of func-tional groups. Despite the numerous synthetic efforts directedtoward the erythromycins,62 the only total synthesis of 108 wasreported by the Woodward group in 1981.63 This landmarkachievement was followed by the singular report of a formaltotal synthesis of 108 by Oishi and co-workers in 1988.64

Recently Martin et al.65 reported the total synthesis of 109 usingtwo different strategies. One of the strategies followed theclassical approach in which the desosamine and cladinoseresidues were sequentially appended to a macrocyclic lactone,which was formed by cyclization of a seco acid derivative, to givea bis-glycosylated macrolide intermediate which is then con-verted to 109. The second strategy features an abiotic approachin which a seco acid bearing a desosamine residue is cyclized togive a monoglycosylated macrocyclic lactone that is thentransformed into 109 via a sequence of steps involving refunc-tionalizations and a glycosylation to introduce the cladinosemoiety.

Accordingly, the primary alcohol group in 115, which wasavailable in six steps from 114 following reported procedures,66

was selectively protected to give 116 (Scheme 17). Conversion of116 into the protected ketone 117 was achieved by sequentialcarbonate formation and hydrolysis of the thioacetal. Lithiumenolate generated by deprotonation of the ketone 117 usinglithium hexamethyldisilazide underwent a highly stereo-selective aldol reaction with the protected aldehyde 118 to give119, thereby completing the synthesis of a portion of theerythromycin B backbone. The carbonyl group at C(9) of 119wasstereoselectively reduced with Me4NBH(OAc)3 to give the anti-diol which was protected as a cyclic mesitylene acetal to give121.67,68 Deprotection of the primary alcohol group of 121 fol-lowed by Swern oxidation and reaction of the aldehyde soformed with tri-n-butylcrotylstannane in the presence ofBF3$OEt2, furnished 122 together with minor quantities ofdiastereomeric adducts. Attempts to introduce a cladinoseresidue onto the C(3) hydroxyl group of 122 even in the presence

Scheme 17


Review RSC Advances

of a number activators gave at best miniscule quantities of thedesired cladinose derivative.

An alternative approach was then utilized which involved theinitial appendage of desosamine to a precursor of a seco acid.The rst step of this approach involved the synthesis of a cyclicp-methoxybenzylidene acetal involving the primary andsecondary alcohol groups at C(3) and C(5) of 115 with subse-quent silylation of the tertiary alcohol at C(6) to give 123.Reductive cleavage of the acetal moiety in 123 with BH3$THF inthe presence of AlCl3 in Et2O affected the selective release of theless hindered primary hydroxyl group to furnish 124. Subse-quent protection of the hydroxyl group at C(3) of 124 as its TBSether followed by hydrolysis of the thioacetal in the presence ofHg(ClO4)2 and in aqueous THF saturated with CaCO3 delivered125. Addition of an enolate generated from 125 to the protectedaldehyde 118 furnished 126 with excellent syn and anti Felkin–Anh stereoselectivity. The reduction of hydroxyketone 126 soobtained with Me4NBH(OAc)3 proceeded stereoselectively (ca.10 : 1) to give the C(9)–C(11) anti-diol that was protected as acyclic mesitylene acetal to provide 127. Oxidative removal of thePMB protecting group from 127 using DDQ delivered 128. Anumber of attempts to glycosylate the free hydroxyl group atC(5) of 128 with 129 were unsuccessful (Scheme 18).

Despite the signicant disappointment of being unable tointroduce a desosamine group on 128, compound 127 wasconsidered to be a viable intermediate in the synthesis of eryth-romycin B via the well established approach involving glycosyl-ation of a macrocyclic lactone. The selective deprotection of theprimary alcohol of 127 followed by oxidation with the Dess–Martin periodinane gave the aldehyde 130. Reaction of 130 withtri-n-butylcrotylstannate in the presence of BF3$OEt2 delivered aseparablemixtureof all fourpossiblediastereomerichomoallylic

Scheme 18


alcohols with the major product being the syn isomer arisingfrom the nucleophilic attack as per the Felkin–Anh model. Thefree hydroxyl group at C(3) of the major adduct was then incor-porated into a cyclic p-methoxy-phenyl (PMP) acetal by oxidativecyclization of 131. A two step oxidative cleavage of the carbon–carbon double bond in 131 and removal of the C(13) hydroxylprotecting group by hydrogenolysis furnished the seco acidderivative 132. Macrolactonization of 132 following the Yama-guchi protocol proceeded with high efficiency to give the eryth-ronolide B derivative 133. Fluoride-induced deprotection of theC(6) tertiary hydroxyl group proceeded smoothly to yield 134.Hydrolytic removal of the cyclic C(3)–C(5) protecting groupresulted in the isolation of triol 135 along with (9S)-dihydroery-thronolide 136. The reaction of 135 with pyrimidyl thioglycoside129 in the presence of silver nitrate furnished 137 as a singleisomer. 137 on subsequent treatment with 138 in the presence ofa mixture of copper(II) triate and copper(II) oxide provided 139.Selective hydrolysis of the mesitylene acetal in 139 followed byuoride-induced removal of the silyl protecting group on the L-cladinosinemoiety gave the tetraol140. Theoxidationof140with1 equiv. of the Dess–Martin periodinane reagent proceededexclusively at the C(9) hydroxyl group to deliver 109 (Scheme 19).

The 6-O-alkyl derivatives of erythromycin, namely its methylderivative clarithromycin (110; Fig. 5), are 14-membered

Scheme 19

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macrolide antibiotics which are active in vitro against clinicallyimportant Gram-positive and Gram-negative bacteria.69

Numerous methods of regioselective alkylation at the 6-OH oferythromycin have been described in the literature.70 The mostimportant ones comprise the direct protection of the highlyreactive OH groups at C-2 and C-4 positions and indirectblocking of hydroxyl groups at the 11 and 12 positions byderivatization of the 9-carbonyl group via O-substituted oximesbearing relatively bulky substituents.71 Brunet et al.72 recentlyreported the preparation of 110 through the highly regiose-lective O-methylation at C(6)–OH of the novel derivative 9-pyr-imidyloxime erythromycin A. The whole process is outlined inScheme 20 and involved derivatization of erythromycin A oxime141 by reaction with 2-chloro-pyrimidine in basic solution.72

The corresponding erythromycin A 9-O-(2-pyrimidyl)-oxime 142was quantitatively silylated at the 2 and 4 positions using amixture of trimethylsilylchloride and trimethylsilyl-imidazole indichloromethane. The key methylation at the 6-OH was per-formed on the resulting 2,4-O-bistrimethylsilyl erythromycin A9-O-(2-pyrimidyl)oxime 142 with 1.5 equiv. of methyl iodide in asolution of 1.5–2.0 equiv. of potassium hydroxide in DMSO atroom temperature. Deprotection of 2- and 4-OH groups and9-carbonyl can be performed stepwise by treatment of 144 withformic acid in water–ethanol leading to 9-O-(2-pyrimidyl)oximeof clarithromycin 145 which was then easily transformed intoclarithromycin 110 by treatment with sodium hydrogen sulteethanol–water solution at 80 �C for 6 h.

Ma et al.73 have recently reported the synthesis and evalua-tion proles of clarithromycin derivatives with C-4 elongated

Scheme 20

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arylalkyl groups against resistant bacterial strains. Thesederivatives have been reported to show excellent activity againsterythromycin-susceptible Streptococcus pneumoniae, Strepto-coccus aureus or Streptococcus pyogenes and some of themexhibited greatly improved activity against erythromycin-resis-tant strains. The synthesis of 4-O-arylalkylcarbamoyl clari-thromycin derivatives began with the conversion ofclarithromycin 110 as a starting material to 4-O-acylimidazolideintermediate 146, as a common intermediate to introducevarious functional groups at the C-4 position as shown inScheme 21. This was carried out by acetylation of the20-hydroxyl group of CAM with acetic anhydride followed bytransformation of the 4-hydroxyl group to the acyl imidazoleutilizing 1,10-carbonyldiimidazole and triethylamine. Subse-quent condensation of intermediate 146 with the correspond-ing arylalkylamine in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 60 �C followed by selective removal of the20-O-acetyl group by heating in methanol, gave the targetderivatives 147. Compound 147c was the most effective (0.06 mgmL�1) against S. pneumonia encoded by the erm gene whilecompound 147a had the most potent activity (0.25 mg mL�1)against S. pneumonia encoded by the erm and mef genes.

Azithromycin 113, a semi-synthetic 15-membered macrolideantibiotic, is derived from erythromycin A by a sequence ofoximation, Beckmann rearrangement, reduction, and N-meth-ylation.74 Azithromycin is the rst azalide on the market and itdisplays the best antibacterial activity among its familymembers. In comparison with erythromycins, its benecialproperties stem from its improved acid stability, increased oralbioavailability, longer half-life, higher intracellular concentra-tion, and broader antibacterial activity.75 Kang et al.76 haverecently reported the rst asymmetric total synthesis of 113. Theapproach involved the retrosynthetic disconnection of 113 atthe lactone linkage and the C9–N9a bond to provide the westernamine alcohol chain 148 and the eastern hydroxy carboxylicacid chain 149 (Scheme 22). The timing of the glycosylationsteps appear to be critical to achieve more effective glycosyla-tions and macrolactonization, and thus obviate extra protec-tion/deprotection manipulation. Based on the retrosynthetic

Scheme 21


Scheme 22

Review RSC Advances

analysis, it was proposed to append desosamine during theeastern chain construction and cladinose aer formation of themacrolide.

Synthesis of 113 was initiated with the preparation of 148through the desymmetrization method, asymmetric ethyladdition, and regioselective epoxide openings. Accordingly,the triol 150 was desymmetrized enantioselectively in thepresence of the imine catalyst 151 to furnish the mono-benzoate 153 with 91% ee in nearly quantitative yield(Scheme 23).77 Aer conversion of 153 into the correspondingepoxide through mesylation in a one-pot process, the gener-ated epoxy benzoate was hydrolyzed, oxidized and treatedwith Et2Zn with the aid of the aminoalcohol ligand 154 togive an 11 : 1 separable mixture of the desired R-alcohol 155and its diastereomeric S-alcohol.78,79 The epoxy alcohol 155was derivatized into the diastereomeric epoxide 156 byreduction of the epoxy group with red-Al, silylation of thesecondary hydroxyl group, and hydroxy-directing epoxidation.The epoxy group of 156 was amenable to regioselectivesubstitution using NaN3 in the presence of MgSO4 in2-methoxyethanol.80 The prepared hydroxyl azide was pro-tected as a TBS ether, reduced to an amine, and desilylated togive the western amine segment 148 in 59% overall yieldfrom 156.

Eastern carboxylic acid moiety 149 was constructed byemploying the desymmetrization protocol for the quaternarycarbon center, crotylation reactions for the C2–C5 stereogeniccenters, and the known chiral building block 157 for the methylsubstituent at C8.81 The desymmetrization substrate 159 wasprepared from 157 via a sequence of transmetalation, additionof the generated alkyllithium to the ketone 158, and hydrolysis

Scheme 23


of the acetonide group (Scheme 24).82 Diastereoselectivedesymmetrization in the presence of the imine catalyst 152afforded the monobenzoate 160 in 94% yield along with 4% ofits diastereomer.76 Intermediate 160 was converted into thecorresponding epoxy alcohol and was subsequently oxidizedand then treated with crotylborane reagent 161 yielding a 9 : 1separable mixture of the epoxy alcohol 162 and its diaste-reomer.83 The epoxy group of 162 was reductively cleaved andthe resultant diol was chemoselectively glycosylated at thesecondary hydroxy group using 5 equiv. of pyrimidyl thio-desosaminide 163 (ref. 84) in the presence of AgOTf85 deliveringthe desired stereoisomeric b-glycoside 164. For the requisitestereochemical installation of the substituents at C2 and C3, theFelkin–Anh model utilizing the crotylation reagent 165 (ref. 86)has been employed.87 Ozonolysis of 164 and subsequent croty-lation gave alkene 166, which had all the requisite functional-ities installed followed by olenic double bond cleavage byoxidation88 and desilylation of the resulting carboxylic acid toform 149.

Aer completing the synthesis of 148 and 149, primaryhydroxy group of 149 was chemoselectively oxidized withDess–Martin periodinane,89 and the resultant aldehyde wascoupled with 148 by reductive amination under hydrogena-tion conditions with subsequent combination with formal-dehyde in the presence of Pd/C. The one-pot couplingprocess on removal of the carbonate group in the sugar ringgave the monoglycosylated seco-acid 167. Macrocyclization of167 under the reaction conditions developed by Yamaguchiand coworkers90 gave the 15-membered lactone 168. Thebranched neutral sugar was attached to 168 using 2-thio-pyridyl cladinoside 169 (ref. 91) in the presence of Cu(OTf)2/CuO and gave a 6 : 1 separable anomeric mixture of theTBS-protected azalides, in favor of the desired b-anomer170 which upon purication was desilylated to give 113(Scheme 25).

Scheme 24

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Scheme 25

Scheme 26

Scheme 27

RSC Advances Review

2. Alkaloids2.1 Berberine

Berberine 171 is characterized by a dibenzo [a,g]quinolizidinering system (Fig. 6). This alkaloid is present in a number ofclinically-important medicinal plants which includes thetraditional Chinese herb Huanglian, Coptischinensis.92 Accord-ing to reports, 171 acts as a membrane poison which reducesthe infectiousness of bacteria, fungi and protozoa in animalsand humans by inhibiting adherence of microorganisms to thehost cells.93–96 It is also reported to display immunostimulatoryactivity by promoting the protective action of the spleen viaincreased blood supply and by releasing immunepotentiatingcompounds.97 SAR revealed that for these quaternary salts, thearomatic C ring and 2,3-methylenedioxy moiety are essentialcomponents for antibacterial activity.98–100

In 2006, He et al.101 described the synthesis of protoberberinederivatives which utilizes 171 as an intermediate. Compound171 was prepared via a synthetic route which employed homo-piperonylamine 172 and variously substituted aromatic alde-hydes 173 as starting materials (Scheme 26). The amine 172 andaldehyde 173 was heated at 110 �C for 1 h to give Schiff base 174which was reduced to 175with NaBH4 inmethanol under reux.Cyclisation of compound 175 to berberine chloride 171 wasachieved using dialdehydeglyoxal.

In 1969, Kametani et al.102 reported the total synthesis ofberberine iodide. Condensation of 3,4-methylenediox-yphenethylamine 177 with 5-benzyloxy-2-bromo-4-methoxyphenylacetate 178 afforded the amide 179. Cyclization of 179with phosphoryl chloride gave 3,4-dihydro-isoquinoline 180,which was reduced with NaBH4 to yield 1,2,3,4-tetrahy-droisoquinoline 181. Debenzylation of 181 gave the expected

Fig. 6 Berberine.

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phenolic base 182. Construction of the ‘berberine bridge’ in 183involved a Mannich reaction of the in situ generated iminiumion. Debromination of 183 with zinc powder in sodiumhydroxide solution afforded (�)-nandinine 184 which in turnwas methylated to give (�)-canadine 185. Dehydrogenation of185 with iodine afforded berberine iodide 171 in good yield(Scheme 27).

2.2 Chelerythrine

Chelerythrine 186 is a benzo[c]phenanthridine alkaloid extrac-ted from Chelidonium majus (Fig. 7).103 Bioassay-guided frac-tionation led to the isolation of 186 from another source, theroots of Sanguinaria canadensis. It displayed signicant anti-mycobacterial activity against M. aurum and M. smegmatis with

Fig. 7 Chelerythrine and norchelerythrine.


Scheme 29

Review RSC Advances

IC50s of 7.30 mg mL�1 and 29.0 mg mL�1, respectively,104,105 andinhibits the growth ofM. tuberculosis H37Rv by$94% at 12.5 mgmL�1.106,107 SAR studies revealed that alkoxy substituents eitherin the form of methoxy or methylenedioxy functional groups,play an important role in the antitubercular potency of thisfamily of alkaloids.108

Most of the synthetic approaches to the benzo[c]phenan-thridine nucleus involve the construction of either the B or Cring in the nal or semi-nal stages of the synthesis. In 2011,Hibino et al.109 described the total synthesis of this class ofalkaloids based on a microwave assisted electrocyclic reactionof the aza 6p-electron system. The aim of synthetic plan was toconstruct the 11,12-dihydrobenzo[c]phenanthridine framework187. The latter could be derived from a 2-cyclo-alkenylbenzaldoxime methylether 188 through new bondformation between the C4b and N5-positions in the tetracyclicbenzo[c]phenanthridine, via a microwave-assisted electrocyclicreaction as shown in Scheme 28. An appropriately substituted2-cycloalkenylbenzaldoxime methylether 188 and its precursor189 was obtained by the Suzuki–Miyaura coupling reaction110

between 6-bromo-2,3-dimethoxybenzaldehyde 190 and3,4-dihydro-6,7-methylenedioxynaphthylboronic acid pinacolester 191. This design was applied in the preparation of tet-raoxygenated benzo[c]phenanthridines 186b.

The rst stage of the synthesis entailed the formation ofpinacol borate 191, as shown in Scheme 29. Treatment of 2-allyl-4,5-methylenedioxy phenol 193 (ref. 110) with tri-uoromethanesulfonic anhydride (Tf2O) and pyridine affordedthe O-triate 194 which was subjected to the Stille crosscoupling reaction with allyltributyltin in the presence ofPdCl2(PPh3)2 to give the diallylbenzene 195. Olen metathesisof diallylbenzene 195with the Grubbs I catalyst afforded the 1,4-dihydronaphthalene 196 which was subjected to an oxidative-hydroboration to yield 2-hydroxytetrahydronaphthalene 197.Oxidation of the alcohol 197 with pyridinium chlorochromate(PCC) in CH2Cl2 afforded the known b-tetralone 192.111 Theunstable b-tetralone 192 was immediately treated with N-phe-nylbis(triuoromethanesulfonamide) (Tf2NPh) and LDA toproduce the triate 198, which in turn was converted to pinacolborate 191 with bis(pinacolato)diborane and PdCl2(dppf).112

Scheme 28


The 2,3,7,8-tetraoxygenated benzo[c]phenanththridines (186aand186b)113weresynthesizedas shown inScheme30.TheSuzuki–Miyaura reaction of 6-bromo-2,3-dimethoxybenzaldehyde 190(ref. 114) with pinacol borate 191 in the presence of PdCl2(PPh3)2or PdCl2(dppf) afforded the 2-cycloalkenylbenzaldehyde 189 in75% yield. The aldehyde 189 was then converted into the corre-sponding oxime ether 188 in 95% yield. The oxime ether 188 wassubjected to a microwave-assisted electrocyclic reaction at 180 �Cto give the desired 11,12-dihydrobenzo[c]phenanthridine 187 in84% yield. Subsequent dehydrogenation of 187 with 10% Pd–Cafforded benzo[c]phenanthridines 186b. The norchelerythrine186b was then converted to chelerythrine 186a.115

2.3 Manzamine

The manzamines are complex polycyclic marine-derived alka-loids from the Okinawan sponge, Haliclona.116 They possess afused and bridged tetra- or pentacyclic ring system, which isattached to a b-carboline moiety. Since the rst report ofmanzamine A (199, Fig. 8), several manzamine-type alkaloids

Scheme 30

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have been isolated from 16 sponge species belonging to theChalinidae, Niphatidae, Petrosidae, Thorectidae, and Irciniidaefamilies.117,118 Manzamines exhibit a diverse range of bioactiv-ities which includes cytotoxicity,116 insecticidal, antibacterial,antileishmaniasis, antimalarial,119 and anti-inammatoryactivity.120 According to reports, manzamines also show potentactivity against HIV-1 and several AIDS opportunistic infection(OI) pathogens, for example, Cryptosporidium parvum, Toxo-plasma gondii, and M. tuberculosis.120,121

With regard to antitubercular activity, reports have shownthat most manzamines display a 98–99% inhibition of M.tuberculosis growth at an MIC < 12.5 mg mL�1.120,122 Noteworthyexamples include, iricinal A (200, Fig. 9), 12,34-oxamanzamines201 and 202, 204, hydroxymanzamine A 203, and manando-manzamine A 205.120 SAR studies moreover revealed that theb-carboline unit is not essential for antitubercular activity.120

The rst total synthesis of 199 entails a 17-step synthesiswith 206 acting as precursor. Employed in this synthesis, are avinylogous amide photoaddition, fragmentation and Mannichclosure sequences. The stereochemistry of 199 was establishedfrom the single stereogenic center in 206 and serves as evidenceof the remarkable level of stereochemical control afforded bythe photochemical cascade employed in this synthesis. As a rst

Fig. 8 Structure of manzamine A.

Fig. 9 Anti-tubercular manzamine alkaloids.

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step, the secondary amine 206 was reacted with the acetylenicketone 207 to give the vinylogous amide photosubstrate 208.The latter underwent photoaddition to yield 209, as shown inScheme 31. A retro-Mannich fragmentation via O-closure of theketoiminium intermediate 210 yielded the aminal 211.123

Compound 211 isomerised via iminium ion 212 in the presenceof pyridinium acetate, to yield the manzamine tetracycle 213 asa single stereoisomer. The B-ring was modied by carboxylationof the enolate derived from 214 to give the keto ester 215. Thenext steps involved the reduction of the C-11 ketone followed byelimination of the derived mesylate with DBU in reuxingbenzene which yielded a mixture of a,b- and b,g-unsaturatedcompounds 216 and 217, respectively.

Selenation of 216 and 217 with PhSeCl in the presence ofLiTMP resulted in the formation of a-selenated product 218.Oxidation of selenide 218 resulted in the formation of C-12a-alcohol 219, which underwent deprotection and tosylation togive 221. Removal of the Boc-group and exposure of secondaryamine to Hunigs base led to the formation of methyl ircinate222 in low yields (Scheme 32). Base-catalyzed cyclization of theacetylinic substrate 223 resulted in the formation of a macro-cyclic product which aer Lindlar reduction gave 222. Reduc-tion of the a,b-unsaturated ester 222 with DIBAL–H yieldedircinol A 224, which aer oxidation with Dess–Martin's reagentgave iricinal A 200. Using the procedure of Kobayashi, couplingof 200 with tryptamine in the presence of triuoroacetic acidgave manzamine D, 225 which aer oxidation with DDQprovided manzamine A, 199.123

Scheme 31


Scheme 32

Scheme 33

Scheme 34

Review RSC Advances

2.4 Stemona alkaloids

Extracts of Stemona which includes metabolites such as ste-monine124 226 and parvistemonine125 227 (Fig. 10), respectively,have been used in Chinese and Japanese folk medicine asinsecticides as well as drugs for the treatment of respiratorydiseases such as bronchitis, pertussis and tuberculosis.Synthesis of the polycyclic core of these natural products provedchallenging. However, in recent years an impressive series ofstrategies have culminated in several total syntheses of theseanalogues.

In 1999, Wipf et al.126 reported the formation of nine-membered lactams by oxidative ring expansion. The method-ology involved the formation of nine-membered lactams bystepwise conversion of the aromatic amino acid tyrosine intothe saturated medium ring core system of the tuberostemononealkaloid. As shown in Scheme 33, the oxidative cyclization ofCBz-tyrosine 228 yielded 229 which underwent a copper(I)catalyzed conjugate addition of MeMgBr to give 230 as amixtureof diastereomers.127 Treatment of 230 with iodobenzene diac-etate and iodine initiated a formal alkoxy fragmentation whichled to 231 as a separable 1.2 : 1 mixture of epimers.128

For the synthesis of 236 (Scheme 34), the enone 229 wassubjected to successive ketone and alkene reduction followed byselective silylation of the secondary hydroxyl group to generate232. Exposure of 232 to a mixture of iodobenzene diacetate andiodine in methylene chloride provided the azonane 233 as asingle isomer, which was then treated with silver acetate toyield 234. Peroxidation of 234 withm-chloroperbenzoic acid and

Fig. 10 Stemona alkaloids.


BF3-etherate led to the peroxy acetal 235 which was treated withpyridine to yield the desired ketolactam 236.

Another approach for the synthesis of nine membered lac-tams involves the Eschenmoser Claisen129 rearrangement of 229to yield the amide 237. Epoxidation of 237 followed by ringopening with methyl cuprate led to a 2 : 1 mixture of silyl ethers239 and 240. Lactone 239 was desilylated using HF/pyridine andsubjected to radical fragmentation conditions to yield ninemembered heterocycle 241. Peracid-mediated oxidation ofthe mixed acetal moiety provided 242 in 86% yields aer apyridine-mediated decomposition of the peroxide intermediate(Scheme 35).

2.5 Tryptanthrin analogs

Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) 243(Scheme 36) is an indoloquinazoline alkaloid isolated from anumber of plants such as Isatis,130 Calanthe,131 Wrightia,132

Couroupota,133 and Strobilanthes.134 It can also be produced byCandida lipolytica when grown in media containing an excess oftryptophan, hence the name tryptanthrin.135 It has been repor-ted to display various biological activities, such as antibacterial,antifungal, and antileishmanial,132,134,136 and found to be apotent dual inhibitor of COX-2 and 5-LOX.137 In recent years,243 has attracted much attention as an arylhydrocarbonreceptor (AHR) and anticancer agent.138,139 Subsequent studiesextended the spectrum of antimicrobial activity to includeactivity against M. tuberculosis.140 The synthesis of 243 waspursued intensively due to its attractive in vitro properties andsimple structure. An efficient synthesis strategy for tryptanthrininvolves a regioselective lithiation of 2-unsubstituted

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Scheme 36

Scheme 35

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quinazolinone at C-2 together with the subsequent reactionwith an electrophile in an intramolecular fashion to affordcyclized product (Scheme 37).141 The synthesis of 243 wasinitiated by the formation of methyl 2-(4-oxoquinazolin-3(4H)-yl)benzoate 247. The latter was obtained by condensinganthranilic acid 244 with methyl anthranilate 246 and triethy-lorthoformate 245 in the ionic liquid, 1-n-butylimadazoliumtetraouroborate ([Hbim] BF4). This condensation reaction waspromoted by the Bronsted acidity of the ionic liquid whichplayed the dual role of reaction medium and promoter. Regio-selective lithiation of 247 with lithium diisopropylamide (LDA)afforded the lithiated anion 248 which underwent intra-molecular cyclization to yield 243.

3. Terpenes3.1 Pleuromutilins

Pleuromutilin (249, Fig. 11) possesses an unusual tricyclicditerpenoid structure. This antimicrobial natural compoundexerts its activity against pathogenic bacteria by inhibition ofbacterial protein synthesis.142 To date, no pleuromutulinderivatives have been developed for use in humans. However,

15196 | RSC Adv., 2014, 4, 15180–15215

the Global Alliance for TB Drug Development is focussing onthe synthesis and evaluation of new analogues of pleuro-mutulins.142,143 A series of mutilin 14-carbamates have beendiscovered based on SAR studies of naturally occurring pleu-romutulin 249. These novel mutilin 14-carbamates have shownpotent antibacterial activity and display a spectrum of activitywhich encompasses the major respiratory tract pathogens.

Pleuromutilins 249 represents a challenging scaffold for thedevelopment of methodology to construct the eight-memberedring system.144 The synthetic route outline in Scheme 37, makeuse of a novel approach to construct the tricyclic framework andto introduce stereogenic centers on the eight membered ring ofpleuromutilin 249 over 25 steps.144 Construction of 258 wasachieved via a key sterically demanding oxy-cope rearrangementof the tricyclic vinyl carbinol 257 which could arise via a stereo-electronically controlled 1,6-addition or alkylation of a suitabledienone derivative 254. The synthesis of 257 was started bycondensation of the cross-conjugated enolate derived fromenone 250 with 3-penten-2-one to afford a (5 : 1) mixture ofdiketones 251 and 252 (Scheme 37). Diketone 251 was cyclizedvia a pyrrolidine–enamine to yield the desired dienone 253.Desilylation of 253 followed by tosylation of the resulting alcoholfurnished dienone tosylate 254 for the conjugate addition–alkylation sequence. Treatment of 254with LiCu(CH3)2 in THF at�78 �C followedby additionofHMPAafforded thebicyclic enone255.145,146 The addition of CH2]CHMgBr to 255 yielded a 1 : 1mixture of alcohols 256 and 257. Treatment of this mixture withPhSCl/P(OEt)3 resulted in a shi of equilibrium towards 257which can be easily recovered in good yields.147 Elaboration of258 to (�)259 was initiated by epoxidation of 258 with mCPBAandketalization of the resulting singlediastereomeric epoxide inthe presence of BF3$Et3O to yield the crystalline ketal 259. Theresidual carbonyl group in 259was converted to benzyl ether 260using standard methods. Introduction of the three remainingstereogenic centers on the eight membered ring was envisionedto proceed via initial introduction of C13–C14 unsaturation.Treatment of 260 with PyH+Br� gave the equatorial bromo ketal261 which underwent syn dehydrohalogenation with tert-BuO�K+ to provide the transketal olen 262. Further stereo-selective 1,4 addition and hydrolysis of the ketal occurred aerexposure of 262 to p-TsOHunder reux, to give a single ketol 263.AerC14 hydroxyl groupprotection, the resultingMOMketolwasconverted regiospecically to a single TMS enol ether, oxidizedusing mCPBA and subjected to TBAF deprotection to afford therequired C11 a-hydroxyketone 264.148,149 Protection of 264 affor-ded the bis-MOM ether 265 (Scheme 38). Introduction of theremaining C12 quaternary centre proceeded from 265 in threesteps by (i) addition of CH2]CHMgBr, (ii) conversion of theresulting tertiary carbinol to the primary allylic chloride, and (iii)SN20 g-alkylation with CH3CuB(CH3)3, to give 266 (5 : 1, g/a).150

Conversion of 266 to (�)249was achieved over two steps by usinga method reported by Gibbons.151

3.2 Pseudopteroxazole

Pseudopteroxazole (268, Fig. 12) was isolated from the sea whipPseudopterogorgia elisabethae as part of a bioassay-guided


Scheme 37

!

Fig. 11 Diterpenoid pleuromutilin.


Review RSC Advances

evaluation of extracts from this organism and has shown potentinhibitory activity (97% at 12.5 mg mL�1) against M. tuberculosisH37Rv.152 The presence of benzoxazole functionality in thestructure of 268 was highlighted due to its rare occurrence innatural products.

Harmata et al.153 developed a succinct route to a potentialprecursor of pseudopteroxazole 268 which proceed via a selec-tive, intramolecular addition of a sulfoximine-stabilized carb-anion to an a,b-unsaturated ester, followed by functional groupmanipulations.152–154 The ester 269 (ref. 152) was reacted with(R)-sulfoximine 270 to afford 271 (Scheme 39).155,156

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Scheme 38

Fig. 12 Structure of anti-tubercular pseudopteroxazole.

Scheme 39

Scheme 40

Scheme 41

Fig. 13 Possible approaches of the allylic cation to the benzene ring.

RSC Advances Review

Treatment of 271 with LDA followed by a protic quenchafforded the benzothiazine 272 as 10 : 1 mixture of diastereo-mers. In explaining the stereochemistry of the major product ofthe reaction, a model of 274 shows that the enolate interme-diate will adopt a conformation in which one face of the enolateis signicantly more congested than the other. Unfortunately272 had the wrong stereochemistry at the methyl-bearingcarbon, at least with respect to a projected pseudopteroxazolesynthesis.

The reduction and Swern oxidation of 272 afforded thealdehydes 273 and 274 in 1.6 : 1 ratio (Scheme 40). Treatment of273 and 274 with the Wittig reagent 275 gave 276 and 277 assingle stereoisomers, respectively. Each stereoisomer wastreated with methanesulfonic acid154 and diene 276 afforded278 while 277 yielded 279.

Corey and co-workers demostrated the stereochemicaldivergence in the reaction of 280 and 281 with

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methanesulfonic acid (Scheme 41).157 While compound 280afforded 283 and 285 with a diastereoselectivity of 25 : 1,281 afforded the corresponding compounds in a ratioof 1 : 8.

In case of 280, the benzyloxy group served to direct thecyclization and minimization of untoward steric interactions,which favored an approach of the allylic cation to the benzenering as shown in Scheme 41. In the case of 281, the –OTBSgroup served to direct the regiochemistry of the allylic cationattack. Applying these concepts to 278 and assuming themethoxy group is a better directing group than the sulfox-imine group, two possible approaches of the allylic cation tothe benzene ring are 286 and 287 as shown in Fig. 13. Theformer suffers from steric interactions between the allyliccation and the sulfoximine phenyl substituent. The latterapproach should thus be preferred, and this in fact leads to284.


Scheme 44

Review RSC Advances

4. Miscellaneous4.1 S-Adenosyl-L-methionine

In 2004, Ploux et al.158 described the synthesis and evaluation ofS-adenosyl-L-methionine analogues as inhibitors of puriedE. coli cyclopropane fatty acid (CFA) synthases. The latter servesas a model for theM. tuberculosis cyclopropane synthases whichhave been identied as potential targets for antituberculardrugs.159 Of all the different ways that the cyclopropane ring canbe biosynthesized in nature, the most interesting is the directmethylenation of the double bonds catalyzed by cyclopropanesynthase.160,161 The methylenation reaction proceed by transferof a methylene group from the activated methyl group ofS-adenosyl-L-methionine – (S-AdoMet) to the (Z)-double bond ofan unsaturated fatty acid chain, resulting in the formation of acyclopropane ring 291 on the alkyl chain (Scheme 42).

Shown in Scheme 43 is the step which preceded the enzyme-catalyzed reaction above. It involved the preparation of thesulfonium salts 293 (ref. 162) and 295 (ref. 163) by methylationof corresponding suldes 292 and 294, respectively. The enzy-matic reaction which followed was monitored using HPLC.However, the authors found that none of the two sulfoniumsalts were converted to their corresponding suldes andconcluded that 293 and 295 are poor competitive inhibitors.158

To ascertain if epimerization could account for the poorinhibiting properties of the sulfonium salts, an alternativesynthesis was employed which utilizes D,L-S homocysteine thi-olactone 296 as starting material and led to a 80 : 20 diaste-reomeric mixture of D,L-S-AdoHcy 298, (Scheme 44).164

An unseparable diastereomeric mixture (50 : 50) of 50-desoxy-50-methylthioadenosine (MTA) sulfoxide 299 as well as the MTA

Scheme 43

Scheme 42


sulfone 300,158 were obtained by treatment of 294 with H2O2 inaqueous acetic acid.165 Subjecting L-S-AdoHcy 289 to similarreaction conditions (Scheme 45) yielded a 45 : 55 diastereo-meric mixture of sulfoxide 301.158 L-S-AdoHcy sulfone 302 wasoriginally obtained by a complex oxidation protocol.165 Thisstudy revealed that the adenosine unit was essential for strongbinding and that the best inhibitors of E. coli cyclopropanesynthase are S-adenosyl-L-homocysteine and its sulfoxides.158

4.2 Amamistatin B and analogs

Amamistatins A 303 and B 304, (Fig. 14) are a pair of naturalproducts that were isolated from the actinomycete, Nocardiaasteroides.166 They are structurally similar to mycobacterialsiderophores and contain a hydroxyphenyloxazole as well as

Scheme 45

Fig. 14 Natural products isolated from Nocardia asteroids.

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Scheme 46

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both linear and cyclic forms of 3-N-hydroxylysine. AmamistatinB 304 has been reported to moderately inhibit the growth of M.tuberculosis with an MIC of 47 mM.

In 2008 Miller et al.167 described the synthesis of Amamis-tatin B 304 along with its analogs. The synthesis of 303 and 304began with the preparation of its four primary componentswhich include a hydroxyl phenyl oxazole, linear and cyclichydroxamic acids derived from lysine and b-hydroxy acid(Fig. 15).167 These fragments were coupled in stepwise fashion toproduce 304. Synthesis of hydroxyl phenyl oxazole fragments305 and 306, (Fig. 16) and the protected linear hydroxamate 307from CBz-D-lysine was done according to a reported proce-dure.167 The b-hydroxy acid 308 was prosecuted using theMukaiyama aldol reaction.168

The synthesis of cyclic hydroxamate 313 includes an initialconversion of CBz-lysine 309 to CBz-hydroxynorleucine 310a byusing nitroferricyanide according to a reported procedure(Scheme 46).169 Produced as a byproduct in this reaction is thecorresponding dehydration product 310b. EDC-mediatedcoupling with O-benzyl hydroxylamine gave benzyl hydrox-amates 311a and 311b which upon mesylation led to theformation of 312. On treatment with t-BuOK in DMF, mesylate312 gave the desired benzyl hydroxamate 313a along with theO-cyclized hydroximate isomer 314b in a 3 : 1 ratio.

Deprotection of the CBz group of 313a with HBr gave amine313 as a hydrobromide salt. EDC-mediated coupling betweenb-hydroxy acid 308 and cyclic hydroxamate 313 resulted in theformation of b-hydroxylamide 314 (Scheme 47). Ester formationbetween 314 and linear hydroxamate 307 was carried out usingDCC and catalytic 4-pyrrolidinopyridine to yield 315. Depro-tection of the ester S-315 was achieved by hydrogenolysis to thegive amine R-316 with two free hydroxamic acids.

Hydroxyphenyloxazole 305 was converted to NHS-ester 317and coupled with R-316 to yield amamistatin B R-304 (Scheme48). This same synthetic sequence was repeated using theopposite enantiomer of linear hydroxamate 307 to give S-304, adiastereomer of amamistatin B.

Scheme 47

Fig. 15 Precursors for the synthesis of amamistatin B.

Fig. 16 Hydroxy phenyl oxazole, protected hydroxamate and b-hydroxyacid fragments.

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A similar method was used for the synthesis of 318, an ama-mistatin analog lacking two of themetal binding sites present inthe parent compound as shown in Scheme 49. Commerciallyavailable L-(�)-a-amino-3-caprolactam HCl 319 was coupled tob-hydroxy acid 308, and the resulting b-hydroxylamide 320 wasesteried with S-312 using DCC and catalytic 4-pyrrolidinopyr-idine.170Removal of the CBz-group of 321was done using 33wt%HBr/AcOH. Coupling of amine 322 so obtained to phenyl oxazole305 followed by deprotection of the benzyl hydroxamate withhydrogenolysis afforded amamistatin analog 318.

4.3 Caprazamycin

In 2003, the caprazamycins (CPZs; 324, Fig. 17) were isolatedfrom a culture broth of the Actinomycete strain Streptomyces sp.


Scheme 48

Scheme 49

Fig. 17 Anti-tubercular caprazamycins.

Fig. 18 Stereochemical structure of caprazol.

Review RSC Advances

MK730-62F2. The CPZs have shown excellent in vitro anti-mycobacterial activity against drug-susceptible and multidrug-resistant M. tuberculosis strains without signicant toxicity inmice.171


Matsuda et al.172 have recently reported the total synthesis ofcaprazol, the core structure of caprazamycin antibiotics. Thestereochemical structure of caprazol (325, Fig. 18) was recentlyrevealed through X-ray crystal structure analysis; it consists of auridine, an aminoribose, and a characteristic diazepanoneunit.172

The synthesis methodology proposed involved oxidation of20,30-O-isopropylideneuridine 326 with IBX173 followed by a two-carbon elongation with Ph3P]CHCO2Me and benzoylox-ymethyl (BOM) protection of the NH group at position 3 of theuracil moiety to give 327 (trans/cis ¼ 37 : 1) (Scheme 50).Sharpless aminohydroxylation174 of 327 with (DHQD)2AQN as achiral ligand, afforded 328 with a 50S,60S/50R,60R ratio of 86 : 14.When the ribosyl uoride 329a protected with an iso-propylidene group was activated with BF3$Et2O,175 the corre-sponding ribosides were obtained with 27 : 73 (a/b)stereoselectivity at the anomeric position. Treatment of 328with the ribosyl uoride 329b, which possesses a more stericallyhindered 3-pentylidene group, afforded the desired azide 330with good b selectivity (a/b ¼ 4 : 96) when activation was con-ducted with BF3$Et2O. The azide group in 330 was reduced tothe corresponding amine, which was Boc-protected to give 331.Basic hydrolysis of themethyl ester in 331with Ba(OH)2 gave thedesired carboxylic acid 332, which in turn was coupled with thesecondary amine 333 using DEPBT176 to deliver the amide 334.Compound 334 was then treated with OsO4, and the resultingdiastereomeric mixture of diols was oxidatively cleaved to givealdehyde 335. The desired diazepanone 336 was obtained from335 using NaBH(OAc)3. Compound 336 was methylated byusing (CH2O)n and NaBH(OAc)3 to give 337. Treatment of 337with NH4F in MeOH resulted in selective cleavage of the TBDPSprotecting group at the primary hydroxy group to form 338,which was then transformed into carboxylic acid 339 by a two-step sequence with Dess–Martin periodinane and NaOCloxidation.177 Finally, global deprotection of 339 with aqueousHF provided (+)-325.

4.4 Capreomycins

The capreomycins are known for their effectiveness againstmultidrug-resistant strains of M. tuberculosis. These cyclicpeptide antibiotics capreomycins IA, IB, IIA, and IIB (Fig. 19)have been isolated from Streptomyces capreolus.178,179 It is a

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Scheme 50

Fig. 19 Cyclic peptide antibiotics capreomycins.

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second line agent employed in combination with other antitu-bercular drugs. Moreover, it may be used to treat streptomycin-resistant strains of M. tuberculosis.179

In 2003, Williams et al. described the asymmetric synthesisof (2S,3R)-capreomycidine and 340 (Fig. 19).180 The synthesis ofcapreomycin IB began with a novel enolate–aldimine reactionbetween chiral glycinate (�)-343 and benzyl imine 342.180 Thelatter was prepared by the reaction of 3-tert-butyldimethylsiloxy-

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propanal 341 with benzyl amine on alumina (Scheme 51).Treatment of (�)-343 with LHMDS followed by transmetalationwith dimethylaluminum chloride provided the desiredaluminium enolate which on reaction with imine 342 yieldedthe Mannich products 344a and 344b as an inseparable mixtureof diastereomers.

Guanidinylation of Mannich product 344 was achieved byreaction with triethylamine, mercuric chloride and N,N0-di-tert-butoxy carbonyl-S-methyl-isothiourea. A sequence of steps asshown in Scheme 52 led to the synthesis of (2S,3R)-capreomycidin.180

Titanium enolate chemistry was used in the synthesis ofenantiomerically pure a-formylglycine diethyl acetal 349.180

Formation of the titanium enolate of (+)-343 was followed byaddition of triethylorthoformate to yield diethyl acetal 348.Hydrogenolysis of 348 provided R-a-formylglycine dimethylacetalin 349. Reuxing 349 in 3 N EtOH$HCl afforded the ethylester hydrochloride salt 350, (Scheme 53), which was used insubsequent peptide couplings.

Another important precursor for the synthesis of capreo-mycin 1B 340 is diaminopropanoic acid b-lysine dipeptide. Theappropriately protected diaminopropanoic acid 351 was


Scheme 51

Scheme 52

Scheme 53

Scheme 54

Scheme 55

Scheme 56

Review RSC Advances

prepared from an oxidative Hofmann rearrangement of N-CBz-asparagine (Scheme 54). Coupling of 351 with N-hydroxyl-succinimidyl ester of bis(tert-butoxy carbonyl)-b-lysine180 352 inthe presence of N-methyl morpholine provided the dipeptide353 (Scheme 54).

Base hydrolysis of the methyl ester 353 afforded thecarboxylic acid 354 in quantitative yield (Scheme 55). Couplingof 354 with the R-a-formylglycine diethyl acetal ethyl esterhydrochloride salt 350 in the presence of EDC$HCl and HOBtprovided the desired tripeptide 355.

Removal of the carbobenzyloxy-group was accomplishedwith hydrogen in the presence of Pearlman's catalyst to provide


the amine 356, which was used immediately in the subsequentcoupling reaction, that is, to avoid a possible N,N-acyl migra-tion. In an attempt to make the synthesis of capreomycin IB 340as convergent as possible, the dipeptide fragment of aspara-gines and alanine 359 was prepared.181 Coupling of tripeptide356 and 357 with diisopropyl carbodiimide and HOBt resultedin pentapeptide 358, (Scheme 56). Hofmann rearrangement of358 with bis(triuoroacetoxy)iodosobenzene and pyridineprovided the primary amine 359.

Scheme 57 shows how treatment of the dihydrochloride saltof 340 with benzyl chloroformate and aqueous sodiumhydroxide afforded the N-a-CBz capreomycidine 360, which wasused in crude form in the subsequent coupling reaction withpentapeptide 358 resulting in the synthesis of advanced inter-mediate 361 followed by the removal of the CBz-group of 361 viahydrogenolysis followed by hydrolysis of the ester.

Treatment of the desalted amino acid with coupling reagentsEDCI and HOAt provided 362 as a single diastereomer. Removal

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Scheme 57

Scheme 58

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of the Boc group was achieved using 99% formic acid, whereasdeketalization required reuxing with HCl. The intermediate soobtained was then treated with urea to yield capreomycin IB340.

4.5 D-Cycloserine

Cycloserine (Fig. 20) is an analogue of amino acid D-alanine andwas found to inhibit alanine racemase and alanine ligaseenzymes. Both these enzymes are essential in the synthesis ofpeptidoglycans as well as cell wall biosynthesis and mainte-nance. In M. smegmatis inactivation of these enzymes, report-edly, leads to increased sensitivity to cycloserine whereasoverexpression leads to the development of resistance.182–186

In 1957, Stammer et al.187 described the synthesis of cyclo-serine and its methyl analog. The methodology involved theinitial synthesis of 3-isoxazolidone 363 by the cyclization of b-chloropropionohydroxamic acid 364 which in turn wassynthesized from the corresponding ester 365, (Scheme 58). DL-serine methyl ester hydrochloride 366 was converted to DL-4-carbomethoxy-2-phenyl-2-oxazoline 367 using a procedurereported by Elliott.188 DL-4-carbomethoxy-2-phenyl-2-oxazoline367 was then converted to the corresponding hydroxamic acid368 by treatment with hydroxylamine and sodiummethoxide inmethanol at room temperature. Ring opening of 368 in thepresence of dry HCl led to the formation of b-chlor-opropionohydroxamic acid 369, which in presence of aqueous

Fig. 20 Structure of cycloserine.

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alkali formed the corresponding isooxazolidone 370. Boilingethanol saturated with hydrogen chloride removed the benzoylgroup and also opened the isoxazolidone ring giving thehydrochloride of DL-b-amino oxyalanine ethyl ester 371. Thelatter was reacted with potassium hydroxide followed by treat-ment with HCl to give the hydrochloride of DL-cycloserine.

4.6 Hirsutellones

Hirsutellones,189 pyrrospirones,190 and pyrrocidines191 belong toa growing class of fungal secondary metabolites possessingantifungal and antibiotic activities. Particularly impressive arethe activities of hirsutellones A and B (372a and 372b, Fig. 21)189

against M. tuberculosis.192 Isolated from the insect pathogenicfungus Hirsutella nivea BCC 2594, the hirsutellones share anumber of unique structural features, including a 6,5,6-fusedtricyclic core, a g-lactam- or succinimide-containing moiety, a12- or 13-membered p-cyclophane structural motif whichencompasses an aryl ether linkage, and ten stereogenic centers.

Recently Nicolaou et al.193 have reported the total synthesis ofhirsutellone B 372b in its enantiomerically pure form through astrategy that features a number of novel cascade sequences andchemoselective reactions. Scheme 59 presents, in retrosyntheticformat, the devised synthetic strategy for 372b. As shown, thehydroxy g-lactam moiety was expected to be formed spontane-ously from the corresponding keto amide, whose origin wastraced back to the styrene-containing p-cyclophane 373. Thelatter compound was retrosynthetically expanded to the lessstrained 14-membered sulfone ring 374 through a Ramberg–Backlund reaction. Disassembly of cyclic sulfone 374 withexcision of the sulfur atom led to diol 375, whose furtherdisconnection generated tricyclic core 376 as its possible

Fig. 21 Anti-tubercular hirsutellones A and B.


Scheme 59

Review RSC Advances

precursor. Finally, rupture of the three indicated carbon–carbonbonds within 376, through a [4 + 2] cycloaddition/ring formingepoxide opening, revealed the TMS-epoxy tetraene 377 as alikely precursor. The latter compound was expected to undergothe designed sequential ring closures upon activation with asuitable Lewis acid to afford stereoselectively the desired [6,5,6]-tricyclic core 376.

The enantioselective construction of the hirsutellone tri-cyclic core 376 commenced with (R)-(+)-citronellal 378 andproceeded as shown in Scheme 60. Thus, Stork–Zhao olena-tion of 378 with phosphorane Ph3P]CHI furnished the cor-responding Z-olenic iodide, which was subjected to selectiveozonolysis to afford iodo aldehyde 379.194 Reaction of 379 withthe stabilized phosphorane Ph3P]CHCHO and subsequentJørgensen asymmetric epoxidation195 of the resultinga,b-unsaturated aldehyde, with H2O2 in the presence ofproline-derived catalyst 380, resulted in the formation of theepoxy aldehyde, whose condensation with Ph3P]CHCO2Mefurnished epoxy ester iodide 381. Coupling of olenic iodide381 with the stannane TMS derivative 382 in the presence ofCuTC 383 (ref. 196) led to the cyclization precursor 377. Theintramolecular epoxide opening/Diels–Alder reaction inducedby Et2AlCl afforded the tricyclic core 376 as a single diaste-reoisomer. The reaction is assumed to proceed through speciesI, leading to intermediate II which then undergoes cyclizationreaction to yield 376.

Scheme 60


Scheme 61 details the conversion of 376 into 374 through asequence that involved a Barton etherication,197 a cascade-based selective functionalization of a diol, and a macro-cyclization. Thus, hydroxy methyl ester 376 was reacted withp-Tol4BiF in the presence of Cy2NEt and catalytic amounts ofCu(OAc)2. The resulting aryl ether methyl ester was reducedwith LiAlH4 to afford, aer oxidation with PhI(OAc)2–TEMPO,aldehyde 385. Extension of the carbonyl side chain of 385 wasaccomplished by addition of TBSO(CH2)3MgBr 384 and subse-quent oxidation of the resulting secondary alcohol with DMPgave ketone 386 Functionalization of the aryl methyl group in386 to give the desired dihydroxy compound 375 was thencarried out with CAN in aqueous MeCN (oxidation/desilylation)and subsequent reduction of the resulting aldehyde with NaB-H(OAc)3. Diol 375 was then exposed to the action of ZnI2 andAcSH facilitating its chemoselective conversion into iodo thio-acetate 387, presumably through the cascade involving reactivespecies III–VI, as shown in Scheme 61. Treatment of the iodothioacetate 387 with NaOMe at ambient temperature andsubsequent oxidation of the resulting macrocyclic sulde withH2O2 and Na2WO4 furnished targeted macrocyclicsulfone 374.

Treatment of sulfone 374 with alumina-impregnated KOH inthe presence of CF2Br2 led to the corresponding olen through aRamberg–Backlund reaction (Scheme 62).198 Diastereoselectivecarboxymethylation of this product furnished keto ester 373.From the three olenic bonds of tetracycle 373, the one residingwithin the strained 13-membered p-cyclophane ring proved themost reactive towards AD-mix-b,199 allowing efficient generationof diol 388. The benzylic nature of the C30 hydroxy group of 388facilitated its selective removal through Barton deoxygenation(nBu3SnH, AIBN) of its thionocarbonate, leading to hydroxyester 389. Oxidation of alcohol 389 with DMP proceeded

Scheme 61

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Scheme 62

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smoothly to afford keto ester 390 which upon heating with NH3

in MeOH/H2O led to 372b.

Scheme 63

4.7 Kahalalide A

Kahalalide A (391, Fig. 22) is a cyclic depsipeptide whichemerged as a promising lead. It reportedly inhibits the growthof M. tuberculosis by 83% at 12.5 mg mL�1.200

In 2005, Ganesan et al.200 described the total, solid phasesynthesis of 391 and its analogues. Synthesis of 391 began withthe attachment of Fmoc-D-Phe to the commercially availablesulfonamide resin to give 392, as shown in Scheme 63. This stepwas repeated to ensure high loading, aer which peptidecoupling with Fmoc-D-Leu, Fmoc-L-Thr(t-Bu), Fmoc-D-Phe andamine deprotection yielded the tetrapeptide 393. Addition ofthe S-enantiomer of chiral 2-methylbutyric acid afforded asingle diastereomer of kahalalide A 391 whereas addition ofracemic 2-methylbutyrate gave a racemic mixture of 391 and itsMeBu diastereomer. Deprotection of the threonine side chain in394 was followed by ester formation with Fmoc-L-Ser (t-Bu). Adouble coupling was employed to drive this reaction tocompletion. Further peptide extension afforded the key linearheptapeptide 395. Sulfonamide alkylation with iodoacetonitrilefollowed by removal of the trityl-group resulted in macrolytic

Fig. 22 Cyclic depsipeptide-kahalalide A.

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cleavage of depsipeptide 396. Acidic cleavage of the tert-butylethers completed the synthesis of (S-MeBu)-kahalalide A and(�-MeBu)-kahalalide A.

4.8 Kanamycin

4.8.1 Kanamycin A. Kanamycin A 397 is the majorcompound of the kanamycins, a group of aminoglycoside anti-biotics discovered by Umezawa et al. in cultures of Streptomyceskanamyceticus.201 Cleavage products of 397 include 3-amino-3-deoxy-D-glucose (kanosamine), 6-amino-6-deoxy-D-glucose and2-deoxystreptamine. In 1969, Umezawa202 described the totalsynthesis of 397. One of the two synthesis routes proposed,proceeds via a masked derivative of 6-O-(3-amino-3-amino-3-deoxy-a-D-glucopyranosyl)-2-deoxystreptamine (398, 3AD) andthe other utilizes amasked derivative of 4-O-(6-amino-6-deoxy-a-D-glucopyranosyl)-2-deoxystreptamine (6AD). For the totalsynthesis of 397, the former route was chosen as 398 can bereadily obtained compared to the later derivative. The synthesisstarted with the reaction of 398with benzyl chloroformate whichafforded a tri-N-carbobenzoxy derivative 400 as a colorless solidin 84% yield (Scheme 64).203 Acetonation of 399 in the presenceof p-toluenesulfonic acid afforded the diisopropylidene deriva-tive 400 in quantitative yield. This was followed by the benzyla-tion of 400 in the presence of pulverized barium oxide andbarium hydroxide to give the benzyl derivative 401 which aertreatment with acetic acid gave the deacetonated product 402.Preferential acetonation of the C-4 and C-6 hydroxyl groups ofthe 3-amino-3-deoxy-D-glucose moiety in 402 was achieved by


Scheme 64

Scheme 65

Review RSC Advances

treatment of the latter with 2,2-dimethoxypropane followed byneutralization with amberlite IRA-400b. The mono-isopropylidene derivative 403, was then reuxed with dry 6-(N-benzylacetamido)-2,3,4-tri-O-benzyl-6-deoxy-a-D-glucopyranosylchloride 404 in the presence of pulverized mercuric cyanide,followed by the removal of the isopropylidene group.204 A seriesof deprotection steps yielded a ninhydrin-positive productwhich was reacted with 2,4-dinitrouorobenzene and acetylatedto give product 405 as yellow needles. Hydrolysis of 405 withmethanolic ammonia followed by treatment with an excess ofDowex 1� 2 (OH�) resin afforded a free base which was puriedby chromatography on a column of Dowex 1� 2 (OH�) resin andrecrystallized from aqueous methanol–ethanol to afford 397.

4.8.2 Kanamycin B. Umezawa et al.205 also described thetotal synthesis of kanamycin B 406, which comprises of2-deoxystreptamine, 3-amino-3-deoxy-D-glucose, and 2,6-di-amino-2,6-dideoxy-D-glucose.206–208 The starting material, nea-mine 407 was synthesized from paromamine which in turn canbe synthesized from glucosamine and 2-deoxystreptamine.209,210

Compound 407 was converted to tetra-N-carbobenzoxy-neamine408 via treatment with 30 wt% carbobenzoxychloride solution(Scheme 65). Treatment of 408 with 2,2-dimethoxypropane inthe presence of p-toluenesulfonic acid gave a mixture of mon-oisopropylidene derivatives 409 in 41% yield. The mixture wasbenzylated to afford 4-O-(3,4-di-O-benzyl-2,6-dicarbobenzoxy-amino-2,6-dideoxy-a-D-glucopyranosyl)-N,N0-dicarbobenzoxy-


5,6-O-isopropylidene-2-deoxystreptamine 410 which aerdeacetonation gave 4-O-(3,4-di-O-benzyl-2,6-dicarbobenzooxy-amino-2,6-dideoxy-a-D-glucopyranosyl)-N,N-dicarbobenzoxy-2-deoxystreptamine 411 in 86% yield.

The compound 411 was condensed with 3-acetamido-2,4,6-tri-O-benzyl-3-deoxy-a-D-glucopyranosyl chloride in thepresence of pulverized mercuric cyanide. Similar to thesynthesis of kanamycin A 397, a series of deprotection stepsyielded a ninhydrin-positive product. However, for the removalof O-benzyl and N-carbobenzoxy groups it was found thattreatment of the condensation product with sodium in liquidammonia instead of palladium black gave a better overall yieldof 412. Ammonolysis and hydrolysis of 412 afforded the freebase which was identied as natural kanamycin B 406.

4.9 Mycobactin analogs

The mycobacterial cell wall comprises large amounts of lipidsand mycolic acids. Moreover, its impermeability has beenimplicated as a contributor to drug resistance in the Mtb strain.The tight packing and subsequent low uidity of the cell walllimits the penetration of therapeutic agents and may impair thegrowth and development of microbes by restricting nutrient,including iron, acquisition. Microbial iron chelators, alsoknown as siderophores, are known for their ability to sequesteriron from the host. The affinity and specicity of siderophoresfor Fe(III) has been attributed to the nature of the iron chelatinggroup which is usually catecholate or hydroxamic acidresidues.211,212 Mycobactins, a structurally complex family of

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siderophores, were rst isolated and characterized by Snow andcoworkers.213 Members of this family display a similar carbonskeleton with variations in the conguration of the chiralcenters and the peripheral groups (Fig. 23).

The rst total synthesis of mycobactin S2 an analogue ofnatural mycobactin S (Fig. 23) was accomplished by Milleret al.212 In 1998, the same author214 described the total synthesisof four different mycobactin analogues using a minimal pro-tecting group strategy. Retrosynthetically, the mycobactins canbe constructed by coupling the mycobactic acid 417 (portion I)and the cobactin 418 (portion II), (Fig. 24). Mycobactic acid 417in turn, can be generated from coupling oxazoline 419 andamino acid 420. The cobactins 418 can be easily produced bythe coupling of amine 422 with acid 421. Construction of lysinederivative 420 can be achieved by dimethyldioxirane (DMD)oxidation of the 3-amino group of the appropriate R-protectedlysine ester. Oxazoline derivative 419 can be prepared by apreviously reported methodology.211 Cyclolysine 422 can bederived from lysine by direct DMD oxidation followed byintramolecular amidation.

Treatment of cyclic hydroxamate 423 (ref. 211) with 10 wt%Pd on carbon in methanol afforded the free amine 424 in

Fig. 23 Structure of mycobactins with peripheral groups.

Fig. 24 Retrosynthetic approach for the synthesis of mycobactins.

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quantitative yield (Scheme 66). Cross-coupling of 424 with CBz-protected threonine and serine using DCC and DMAP, gave onlymoderate yields of the desired products, 425 and 426, respec-tively. The major byproducts produced in this reaction aredimeric and oligomeric esters which result from the self-coupling of the CBz-protected b-hydroxy amino acids. However,coupling of amine 424 with CBz-protected threonine in thepresence of HOAt afforded amide 425 without detectablecompetitive ester formation (Scheme 66). Similar reactionconditions were used in the preparation of the serine-basedcobactin analogue 426.

Synthesis of the mycobactic acid component commencedwith the preparation of hydroxamate intermediate 430 (Scheme67). Treatment of hydroxylamine 427 with excess palmitoylchloride in the presence of NaHCO3 resulted in N- and O-acyl-ation of the hydroxylamine moiety. Subsequent removal of theO-palmitoyl hydroxamate group afforded hydroxamic acid 428.Reaction of 428 with SEMCl provided O-protected hydroxamate429. The desired hydroxamate 430 was produced by hydroge-nation of 429 followed by EDC-mediated coupling with oxazo-line derivative 419. Saponication of 430 yielded thecorresponding acid 431 which was subsequently coupled withmodied cobactins 425 and 426 to give desired protectedmycobactin analogues 432a and 432b, respectively.

Scheme 66

Scheme 67


Review RSC Advances

All attempts to remove the protecting groups resulted in thedecomposition of the products because of the presence of weakinternal ester bonds. The methodology was subsequentlymodied in order to synthesize the desired scaffolds. Thus,treatment of oxazoline 419 with amine 429 in the presence ofEDC$HCl resulted in the formation of mycobactin analogue430, (Scheme 68).

Oxazoline derivative 419 was coupled with the amine 420,which contain a free hydroxamic acid to yield the desiredproduct 417. Under similar conditions, the free cobactinanalogue 418 was prepared by coupling CBz-protected L-serineand cyclolysine 422. The CBz protected serine was treated with422 in the presence of EDC$HCl and HOAt to provide thedesired mycobactin analogue 413. The threonine analogue 414was produced in a similar manner as shown in Scheme 69.

The synthesis of b-alanine analogue 415 commenced withthe coupling of amine 424 with CBz-protected b-alanine in the

Scheme 68

Scheme 69

Scheme 70

Scheme 71


presence of EDC$HCl and HOAt to give 433a (Scheme 70).Reductive removal of the CBz protecting group followed by theEDC$HCl/HOAt mediated coupling with 417a resulted in thedesired product 434. The treatment of 434 with tetrabutylammonium uoride in acetic acid gave mycobactin analogue415. Synthesis of 416, another mycobactin analogue, startedwith the treatment of Boc-protected serine with O-benzyl-hydroxylamine to give hydroxamate 435 (Scheme 71). Intra-molecular cyclization in the presence of triphenylphosphineand carbon tetrachloride gave b-lactam 436, which underwentsaponication to produce the desired 2,3-diamino propionicacid derivative 437. Cobactin analogue 438a was easily preparedby EDC mediated coupling of acid 437 and cyclolysine 424.Conversion of benzyl-protected hydroxylamine moiety to thecorresponding free amine 438b, was accomplished by simplepalladium-catalyzed hydrogenation. Subsequent coupling of417b with unprotected mycobactic acid 438b afforded themycobactin analogue 416.

Conclusions

There is consensus, that advances in antimycobacterialscreening technologies and organic synthesis can expediteantitubercular drug discovery efforts. The examples cited in this

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review, summarizes both the achievements and contribution oforganic synthesis in antitubercular drug discovery. Noteworthy,is the agging of erroneous assignment of stereochemistry,errors in proposed structures and the remarkable control ofstereoselectivity demonstrated in some synthesis. Because ofthe treacherous link between tuberculosis and poverty,simplicity and cost-effectiveness should emerge as an impor-tant criterion when assessing the efficiency of syntheses. Thisreview also showed that the most typical leads in tuberculosischemotherapy are natural products and or derivatives thereof.With the aid of genomic information, molecular remedies cantherefore be sourced from simple natural products that allowfor chemical derivatization around a minimum structuralrequirement (bioactiphore or pharmacophore) to enhanceantitubercular activity.

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