molecules

Review Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity

Pedro Laborda, Su-Yan Wang and Josef Voglmeir *

Glycomics and Glycan Bioengineering Research Center, College of Food Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China; [email protected] (P.L.); [email protected] (S.-Y.W.) * Correspondence: [email protected]; Tel.: +86-25-8439-9512; Fax: +86-25-8439-9553

Academic Editor: Vito Ferro Received: 17 October 2016; Accepted: 3 November 2016; Published: 11 November 2016

Abstract: Despite being a common viral disease, influenza has very negative consequences, causing the death of around half a million people each year. A neuraminidase located on the surface of the virus plays an important role in viral reproduction by contributing to the release of viruses from infected host cells. The treatment of influenza is mainly based on the administration of neuraminidase inhibitors. The neuraminidase inhibitors zanamivir, laninamivir, oseltamivir and peramivir have been commercialized and have been demonstrated to be potent influenza viral neuraminidase inhibitors against most influenza strains. In order to create more potent neuraminidase inhibitors and fight against the surge in resistance resulting from naturally-occurring mutations, these anti-influenza drugs have been used as templates for the development of new neuraminidase inhibitors through structure-activity relationship studies. Here, we review the synthetic routes to these commercial drugs, the modifications which have been performed on these structures and the effects of these modifications on their inhibitory activity.

Keywords: influenza treatment; neuraminidase inhibitors; organic synthesis; total synthesis; sialic acid analogues

1. Introduction Influenza is a serious viral illness which can lead to hospitalization and death, especially in the elderly [1–3]. Influenza spreads around the world in yearly outbreaks, resulting in about three to five million cases of severe illness and approximately 250,000 to 500,000 deaths [3,4]. Newly mutated forms of the flu virus appear every year and some of them show high levels of resistance to the standard antiviral drugs [5–7]. Furthermore, during the last century four influenza pandemics have occurred: “Spanish influenza” in 1918, “Asian influenza” in 1958, “Hong Kong influenza” in 1968, and “avian influenza” in 2004 [8]. Influenza is an RNA virus and is subdivided into three genera: influenza A, influenza B and influenza C. Influenza A is the most virulent virus and has provoked the devastating pandemics of the past. Influenza A can be divided into different serotypes based on the antibody response to these viruses. The most famous serotypes are H1N1, which caused the “Spanish influenza” and the 2009 pandemic, H2N2, which caused the “Asian influenza”, H3N2, which caused the “Hong Kong influenza”, and H5N1, which caused the “avian influenza”. Influenza type B and C are much less common than influenza A. The two glycoproteins found on the influenza virus surface envelope are hemagglutinin and neuraminidase (EC 3.2.1.18) (Figure1)[ 9–12]. Hemagglutinin is responsible for viral attachment to the cell surface receptor, which is a terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) residue usually linked to a galactose in a α-(2,3) or α-(2,6) glyosidic linkage [9]. The functional neuraminidase, on the other hand, is anchored to the viral membrane by a hydrophobic sequence near the N-terminus [13–17].

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[13–17].It has been It has shown been in shown tissue culturein tissue that culture neuraminidase that neuraminidase activity is required activity tois required destroy viral to destroy receptors viral by receptorsremoving by the removing sialic acid the of the sialic hemagglutinin-sialic acid of the hemagg acidlutinin-sialic linkage, thereby acid linkag contributinge, thereby to thecontributing release of progenyto the release viruses of progeny from infected viruse cellss from [18 infected–20]. cells [18–20].

Figure 1. Influenza virus replication pathway and the effect of neuraminidase inhibitors. (A) The Figure 1. Influenza virus replication pathway and the effect of neuraminidase inhibitors. (A) The virus virus is linked to the host cell via hemagglutinin employing the terminal Neu5Ac residue of the surface is linked to the host cell via hemagglutinin employing the terminal Neu5Ac residue of the surface receptor. Then, Then, the the endocyto endocytosissis of ofthe the virus virus occurs; occurs; (B) Viral (B) Viral RNA RNA is released is released into the into cytoplasm the cytoplasm where whereis transferred is transferred to the host to the cell host nucleus; cell nucleus; (C) Viral (C )RNA Viral replication RNA replication and mRNA and mRNA synthesis synthesis occurs occursinside theinside nucleus. the nucleus. The RNA The is RNA then isre thenleased released into the into cytoplasm; the cytoplasm; (D) Viral (D )proteins Viral proteins are synthetized are synthetized using mRNAusing mRNA and directed and directed to the to cell the cellmembrane membrane for forvirus virus assembly. assembly. After After incorporation incorporation of of the the genome fragments, virusvirus budding budding begins; begins; (E )(E After) After budding, budding, the virusthe virus surface surfac is attachede is attached at the Neu5Ac at the Neu5Ac receptor. receptor.The neuraminidase The neuraminidase is able to hydrolyze is able to Neu5Ac hydrolyze allowing Neu5Ac the releaseallowing of the virus;release (F )of Neuraminidase the virus; (F) Neuraminidaseactivity is inhibited activity in presence is inhibited of neuraminidasein presence of neuraminidase inhibitors preventing inhibitors the pr releaseeventing of thethe virusrelease and of thereducing virus and pathogenicity. reducing pathogenicity.

Medical treatment treatment of ofinfluenza influenza is generally is generally based based on the onadministration the administration of neuraminidase of neuraminidase inhibitors [21–26].inhibitors 2,3-Didehydro-2-deoxy- [21–26]. 2,3-Didehydro-2-deoxy-N-acetylneuraminicN-acetylneuraminic acid, also calle acid,d DANA, also calledwas the DANA, first influenza was the neuraminidasefirst influenza inhibitor neuraminidase reported inhibitor (Figure reported2) [27]. While (Figure DANA2)[ 27 has]. never While been DANA commercialized, has never been its structurecommercialized, has been its used structure as a template has been for usedthe discov as aery template of inhibitors for the which discovery are both of inhibitorsmore potent which and betterare both tolerated more potent by humans. and better Of tolerated these, zanamivir, by humans. oseltamivir, Of these, zanamivir, laninamivir oseltamivir, and peramivir laninamivir have emergedand peramivir as promising have emerged long-acting as promising neuraminidase long-acting inhibitors neuraminidase for the treatment inhibitors and for prophylaxis the treatment of humanand prophylaxis influenza ofvirus human infection influenza (Figure virus 2) infection[28–35]. However, (Figure2)[ severa28–35l ].naturally However, occurring several naturallyinfluenza neuraminidaseoccurring influenza mutations, neuraminidase such as mutations,H274Y mutations such as in H274Y H1N1 mutations and H5N1 in H1N1influenza and H5N1A strains, influenza have Ademonstrated strains, have significant demonstrated resistance significant towards resistance the abov towardse drugs [5,36,37]. the above For drugs this [reason,5,36,37 ].the For development this reason, ofthe antiviral development drugs of which antiviral are drugseffective which against are effectivenew strains against of influenza new strains virus of influenzathrough the virus creation through of novelthe creation influenza of novelneuraminidase influenza inhibitors neuraminidase or by improving inhibitors the or inhibitory by improving activity the of inhibitory existing antiviral activity drugsof existing is a vibrant antiviral research drugs field is a [38]. vibrant Nowadays, research the field development [38]. Nowadays, of new theneuraminidase development inhibitors of new isneuraminidase generally based inhibitors on the is synthesis generally of based derivatives on the synthesis of the previously of derivatives mentioned of the previously commercial mentioned drugs. Here,commercial we review drugs. all Here,the synthetic we review strategies all the which synthetic have strategies been reported which for have the been production reported of for these the productioncompounds, of the these modifications compounds, perf theormed modifications on their structures, performed and on their the effects structures, of these and modification the effects of onthese their modification biological activities. on their biological activities.

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Figure 2. Retrosynthetic analysis of the evolution of influenza neuraminidase inhibitors. Figure 2. Retrosynthetic analysis of the evolution of influenza neuraminidase inhibitors. 2. Zanamivir,2. Zanamivir,Figure Laninamivir Laninamivir 2. Retrosynthetic and and Other Otheranalysis DerivativesDerivatives of the evolution of influenza neuraminidase inhibitors. Zanamivir, commercialized under the name Relenza, received regulatory approval as a 2.Zanamivir, Zanamivir, Laninamivir commercialized and Other under Derivatives the name Relenza, received regulatory approval as a neuraminidase-targeting anti-influenza drug in 1999 [32]. Although originally only suitable for neuraminidase-targeting anti-influenza drug in 1999 [32]. Although originally only suitable for parenteralZanamivir, (subcutaneous commercialized or intravenous) under administration,the name Relenza, zanamivir received was developed regulatory for approvaloral inhalation, as a parenteralneuraminidase-targetingtargeting (subcutaneous the upper respiratory or anti-influ intravenous) tractenza [32]. administration,drug Zanamivi in 1999r was [32]. zanamivirderived Although from was DANAoriginally developed by theonly forintroduction oralsuitable inhalation, for of targetingparenterala guanidine the upper(subcutaneous group respiratory linked or intravenous)to tract C-4 [32[3,39,40].]. Zanamiviradministration, This modification was zanamivir derived resulted from was DANAdeveloped in significantly by for the oral introduction inhalation,increased of a guanidinetargetinginhibitory group the activity. upper linked The respiratory to followin C-4 [3, 39tractg ,synthetic40 ].[32]. This Zanamivi routes modification tor wasproduce derived resulted zanamivir from in significantly DANA have beenby the increasedreported. introduction inhibitory of activity.a guanidine The following group linked synthetic to C-4 routes [3,39,40]. to produce This zanamivirmodification have resulted been reported.in significantly increased inhibitory2.1. Synthesis activity. of Zanamivir The followin g synthetic routes to produce zanamivir have been reported. 2.1. Synthesis of Zanamivir Zanamivir was first synthesized by von Itzstein and coworkers [41] using sialic acid Neu5Ac as 2.1. Synthesis of Zanamivir theZanamivir starting material was first (Scheme synthesized 1). Neu5Ac by von was Itzstein first converted and coworkers to the ethylester [41] using 1, which sialic was acid treated Neu5Ac as thewith starting Zanamiviracetic anhydride material was first in (Scheme acetic synthesized acid1). containing Neu5Ac by von Itzsteina wascatalytic first and amount convertedcoworkers of concentrated [41] to theusing ethylester sialicsulfuric acid acid 1Neu5Ac, whichgiving as2 was. treatedtheThe starting withring-opening acetic material anhydride reaction (Scheme with in 1). acetic Neu5Actrimethylsilyl acid was containing first azide converted occurs a catalytic to by the a amountethylester backside of 1nucleophilic, concentrated which was treatedattack. sulfuric acidwithAfter giving acetic hydrogenation,2. anhydride The ring-opening inthe acetic amine acid reaction product containing with4 was a trimethylsilyl catalyticconverted amount to the azide ofguanidine concentrated occurs derivative by asulfuric backside 6 acidby nucleophilictreatment giving 2. attack.Thewith After ring-opening1,3-bis(tert-butoxycarbonyl)-2-methylthiopseudourea hydrogenation, reaction thewith amine trimethylsilyl product azide4 was occurs converted (5) usingby ato HgClbackside the2guanidine as thenucleophilic promoter. derivative attack. After6 by Aftersaponification hydrogenation, and removal the amine of tert product-butoxycarbonyl 4 was converted (Boc) usingto the trifluguanidineoroacetic derivative acid (TFA), 6 by zanamivirtreatment treatment with 1,3-bis(tert-butoxycarbonyl)-2-methylthiopseudourea (5) using HgCl2 as the promoter. withwas isolated 1,3-bis(tert-butoxycarbonyl)-2-methylthiopseudourea in 30%–50% yields. This synthetic strategy was (later5) using improved HgCl 2with as theminor promoter. modifications After After saponification and removal of tert-butoxycarbonyl (Boc) using trifluoroacetic acid (TFA), saponificationby Scheigetz and and coworkers removal of [42] tert and-butoxycarbonyl by Chandler (Boc) and coworkersusing triflu [43]oroacetic allowing acid the(TFA), production zanamivir of zanamivir was isolated in 30%–50% yields. This synthetic strategy was later improved with minor waszanamivir isolated on in a 30%–50%large scale. yields. This synthetic strategy was later improved with minor modifications modifications by Scheigetz and coworkers [42] and by Chandler and coworkers [43] allowing the by Scheigetz and coworkers [42] and by Chandler and coworkers [43] allowing the production of productionzanamivir of on zanamivir a large scale. on a large scale.

Scheme 1. The strategy for the synthesis of zanamivir developed by von Itzstein and coworkers [41].

Scheme 1. The strategy for the synthesis of zanamivir developed by von Itzstein and coworkers [41]. Scheme 1. The strategy for the synthesis of zanamivir developed by von Itzstein and coworkers [41].

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SinceSince 1994, 1994, three three further further synthetic synthetic routes routes for the for production the production of zanamivir of zanamivir have been have reported been reported[44–46]. Yao[44– 46and]. Yaocoworkers and coworkers reported reported the synthesis the synthesis of zanamivir of zanamivir using D using-glucono-D-glucono-δ-lactoneδ-lactone (8) as the (8) asstarting the starting material material (Scheme (Scheme 2) [44], 2which)[ 44], was which easily was converted easily converted into 9 after into protection9 after protection steps and stepsreduction and reductionof the carboxylic of the carboxylic acid to aldehyde acid to [47,48]. aldehyde 9 was [47 ,allowed48]. 9 was to allowedreact with to chiral react withhydroxylamine chiral hydroxylamine 7, which was7, whichprepared was from prepared D-mannose, from D -mannose,leading to leadingnitrone to10 nitrone. The 1,3-dipolar10. The 1,3-dipolar cycloaddition cycloaddition of 9 with of methyl9 with methylacrylate acrylate was accomplished was accomplished in a stereoselective in a stereoselective manner, and manner, the chiral and auxiliary the chiral (R*) auxiliary was removed (R*) was by removedtransamination by transamination with hydroxylamine with hydroxylamine to obtain the to isoxazolidine obtain the isoxazolidine 13. After hydrogenolysis13. After hydrogenolysis of the N-O ofbond the N-Oand protection bond and protectionas a Boc carbamate, as a Boc carbamate, the alcohol the group alcohol of group compound of compound 14 was14 oxidizedwas oxidized using usingDess-Martin Dess-Martin periodinane. periodinane. The Boc The protecting Boc protecting group group was then was selectively then selectively removed removed by treatment by treatment with with1 M methanolic 1 M methanolic HCl and HCl the and resulting the resulting amine aminewas treated was treatedwith acetic with anhydride acetic anhydride containing containing 10% v/v 10%sulfuricv/v sulfuricacid and acid to andgive to compound give compound 15. The15. Theremaining remaining steps steps were were carried carried out out under under similarsimilar conditionsconditions toto thosethose reportedreported byby vonvon ItzsteinItzstein andand coworkerscoworkers [[41].41].

Scheme 2. Synthetic route to zanamivir developeddeveloped byby YaoYao andand coworkerscoworkers [[44].44].

Nitabaru,Nitabaru, Kumagai and Shibasaki reported a synthesissynthesis of zanamivirzanamivir using (E)-4-methoxy-)-4-methoxy- benzyloxy-2-butanalbenzyloxy-2-butanal asas the the starting starting material material (Scheme (Scheme3)[ 45 3)]. An[45]. asymmetric An asymmetric Henry reactionHenry betweenreaction 4-nitro-1-butenebetween 4-nitro-1-butene (16) and ((E16)-4-methoxybenzyloxy-2-butanal) and (E)-4-methoxybenzyloxy-2-butanal (17) using (17 an) organometallicusing an organometallic complex complex prepared by combining Nd5O(OiPr)13 and sodium bis(trimethylsilyl)amide (NaHMDS) with prepared by combining Nd5O(OiPr)13 and sodium bis(trimethylsilyl)amide (NaHMDS) with chiral ligandchiral ligand18 was 18 performed was performed to obtain tothe obtain desired the anti-adductdesired anti-adduct19 with high19 with enantioselectivity high enantioselectivity (94% ee). The(94% compound ee). The compound19 nitro group19 nitro was group then was reduced then reduced with zinc with in zi thenc presencein the presence of hydrochloric of hydrochloric acid, andacid, the and amine the amine was protected was protected with Boc with to give Boc compound to give compound20. After protection20. After protection of the vicinal of the carbamate vicinal andcarbamate alcohol and moieties alcohol as moieties an N,O-acetal as an andN,O-acetal removal and of theremovalp-methoxybenzyloxy of the p-methoxybenzyloxy (PMB) protecting (PMB) group,protecting21 wasgroup, subjected 21 was subjected to a Katsuki-Sharpless to a Katsuki-Sharpless asymmetric asymmetric allylic epoxidationallylic epoxidation by treatment by treatment with with tert-butylhydroperoxide, Ti(OiPr)4 and (+)-diethyl tartrate (DET) to achieve 22. Oxirane 22 was tert-butylhydroperoxide, Ti(OiPr)4 and (+)-diethyl tartrate (DET) to achieve 22. Oxirane 22 was then ring-openedthen ring-opened by treatment by treatment with with aqueous aqueous tetrabutylammonium tetrabutylammonium fluoride fluoride (TBAF) (TBAF) and and the the resultingresulting alcoholsalcohols werewere subjected subjected to to perbenzylation. perbenzylation. The The resulting resulting compound compound23 was 23 was treated treated with acidwithin acid order in toorder remove to remove the Boc the group. Boc group. Hydrolysis Hydrolysis of the oxazolidine,of the oxazolidine, followed followed by acetylation by acetylation of the aminoof the groupamino andgroup silylation and silylation of the hydroxyl of the hydroxyl group was gr carriedoup was out carried to give out compound to give 24compound. The terminal 24. The double terminal bond double bond of 24 was hydroxylated by treatment with OsO4, followed by cleavage with sodium periodate, to give the corresponding aldehyde which was subjected to a Wittig reaction with 25 to

Molecules 2016, 21, 1513 5 of 40 of 24 was hydroxylated by treatment with OsO , followed by cleavage with sodium periodate, to give Molecules 2016, 21, 1513 4 5 of 40 the corresponding aldehyde which was subjected to a Wittig reaction with 25 to afford compound 26afford. After compound deprotection 26. After of the deprotection tert-butyldimethylsilyl of the tert-butyldimethylsilyl group (TBS) with group TBAF-AcOH, (TBS) with26 TBAF-AcOH,was treated with26 was BF treated3·OEt2 towith obtain BF3·OEt tetrahydropyranyl2 to obtain tetrahydropyranyl hemiketal 27. The hemiketal benzyl 27 groups. The benzyl (Bn) were groups then (Bn) removed were underthen removed hydrogen under atmosphere hydrogen in the atmosphere presence ofin Pd/C,the presence and acetic of Pd/C, anhydride and acetic was used anhydride for protection was used of thefor hydroxylprotection groups of the ashydroxyl acetates. groups A benzoate as acetat groupes. A was benzoate introduced group into was the introduced C-2 position into of the28 by C-2 a copper-mediatedposition of 28 by a oxidation copper-mediated with tert-butyl oxidation perbenzoate, with tert-butyl giving perbenzoate,29. The subsequent giving 29. The treatment subsequent with Htreatment2SO4/Ac with2O/AcOH H2SO4/Ac led2 toO/AcOH oxazoline led30 to. oxazoline The synthesis 30. The of zanamivir synthesis wasof zanamivir completed was according completed to conditionsaccording to reported conditions by von reported Itzstein by and von coworkers Itzstein and [41 coworkers] in Scheme [41]1. in Scheme 1.

Scheme 3.3. Synthetic strategy to zanamivir developeddeveloped byby NitabaruNitabaru andand coworkerscoworkers [[45].45].

MaMa andand co-workersco-workers reportedreported aa syntheticsynthetic routeroute beginningbeginning fromfrom tert-butyl tert-butyl (2-nitrovinyl)carbamate(2-nitrovinyl)carbamate ((3131)) (Scheme(Scheme4 4))[ [46].46]. ThisThis compoundcompound waswas usedused asas thethe substratesubstrate forfor aa MichaelMichael additionaddition reactionreaction withwith acetoneacetone usingusing catalyticcatalytic amountsamounts of thiourea-basedthiourea-based complex 32,, whichwhich waswas previouslypreviously describeddescribed byby HuangHuang and Jacobsen [49]. [49]. Compound Compound 3333 waswas obtained obtained with with 98% 98% ee andee and 72% 72% yield. yield. Compound Compound 33 was33 then subjected to a Henry reaction with aldehyde 34 by treatment with CuBr2 in presence of ligand 35 was then subjected to a Henry reaction with aldehyde 34 by treatment with CuBr2 in presence of ligand[50]. The35 nitro[50]. group The nitro of compound group of compound36 was reduced36 was using reduced Zn/AcOH using and Zn/AcOH then protected and then with protected an acetyl group (Ac). SeO2 was used for the selective oxidation of C-1 to achieve acid 38. After deprotection of with an acetyl group (Ac). SeO2 was used for the selective oxidation of C-1 to achieve acid 38. the methoxymethyl acetal (MOM) and Boc protecting groups by treatment with hydrochloric acid and formation of the guanidine group by addition of compound 39, zanamivir was obtained with an overall yield of 18%. This strategy was performed on a multigram scale (30 g) demonstrating the potential of this 8-step synthetic route. Although great efforts have been made to enhance the synthetic

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After deprotection of the methoxymethyl acetal (MOM) and Boc protecting groups by treatment with hydrochloric acid and formation of the guanidine group by addition of compound 39, zanamivir was obtained with an overall yield of 18%. This strategy was performed on a multigram scale (30 g) Molecules 2016, 21, 1513 6 of 40 demonstrating the potential of this 8-step synthetic route. Although great efforts have been made to routeenhance of von the Itzstein synthetic and route coworkers of von [41], Itzstein both and high coworkers yields (30%–50%), [41], both a highlow number yields (30%–50%), of synthetic asteps low (anumber 6-stepof route) synthetic and stepsthe low (a 6-stepprice of route) the starting and the material low price (Neu5Ac) of the starting makes material this industrial (Neu5Ac) pathway makes difficultthis industrial to improve pathway upon. difficult to improve upon.

Scheme 4. The synthetic route to zanamivir described by Ma and coworkers [[46].46].

2.2. C-1 Modifications Modifications Among the reported modifications modifications to zanamivir, derivatization at the C-1 of the pyranose ring are particularly significant.significant. Both Both esterification esterification of of the the carboxylic acid, and the substitution of this functional group forfor phosphonatephosphonate havehave been been reported. reported. Vasella Vasella and and Wyler Wyler reported reported the the first first synthesis synthesis of ofa phosphonic a phosphonic acid acid analogue analogue of DANAof DANA [51 [51],], while, while Shie, Shie and and co-workers co-workers later later reported reported the the synthesis synthesis of ofzanamivir zanamivir phosphonate phosphonate (44), (44 also), also called called zanaphosphor, zanaphosphor, using sialicusing acid sialic Neu5Ac acid Neu5Ac as the starting as the materialstarting (Schemematerial 5(SchemeA) [ 52]. 5A) This [52]. sialic This acid sialic was acid protected was protec withted acetic with anhydride acetic anhydride in presence in presence of pyridine of pyridine (py) at 100(py)◦ C,at with100 °C, concomitant with concomitant decarboxylation decarboxylation to obtain to compound obtain compound41. The substitution 41. The substitution of the anomeric of the anomericacetate was acetate carried was out carried using trimethylsilyl out using trimethyls diethyl phosphiteilyl diethyl as phosphite the nucleophile as the and nucleophile trimethylsilyl and trimethylsilyltrifluoromethylsulfonate trifluoromethylsulfonate (TMSOTf) as (TMSOTf) a promoter as to a givepromoter the phosphonate to give the phosphonate compound 42 compoundas a mixture 42 asof αa andmixtureβ anomers of α and (2:3). β anomers The Dehydration (2:3). The wasDehydration performed was using performedN-bromosuccinimide using N-bromosuccinimide (NBS) under photochemical(NBS) under photochemical conditions to conditions afford compound to afford43 compound. Finally, similar 43. Finally, conditions similar as conditions those reported as those by vonreported Itzstein by von and Itzstein co-workers and [co-workers41] were used [41] for were the used introduction for the introduction of the guanidine of the groupguanidine at C-4 group and atdeprotection C-4 and deprotection steps. Zanamivir steps. phosphonateZanamivir phosphonate showed stronger showed inhibitory stronger activities inhibitory against activities H1N1, against H3N2 H1N1,and H5N1 H3N2 influenza and H5N1 neuraminidases influenza neuraminidases in comparison in with comparison zanamivir with and zanamivir against H1N1 and inagainst comparison H1N1 within comparison oseltamivir. with Bren oseltamivir. and coworkers Bren and have coworkers performed have binding performed energy binding calculations energy for calculations zanamivir, foroseltamivir zanamivir, and oseltamivir peramivir and derivatives peramivir bearing derivatives a C-1 linked bearing sulfonate a C-1 linked group sulfonate in place group of the in carboxylic place of theacid carboxylic moiety [53 ],acid which moiety predict [53], that which zanamivir predict sulfonate, that zanamivir oseltamivir sulfonate, sulfonate oseltamivir and peramivir sulfonate sulfonate and peramivirshould all exhibitsulfonate stronger should binding all exhibit to avian stronger influenza binding neuraminidase to avian influenza H5N1 than neuraminidase their carboxylate H5N1 and phosphatethan their carboxylate analogues. and phosphate analogues. Li et al. have reported a straightforward methodology for the synthesis of zanamivir alkoxyalkyl ester derivatives 45a–c (Scheme 5B) [54]. This method was based on treating zanamivir with alkoxyalkyl bromides in presence of dimethylsulfoxide (DMSO) and triethyamine at 80 °C. These compounds demonstrated improved bioavaility when orally administered. However, all derivatives displayed lower inhibitory activity against H1N1 and H3N2 influenza neuraminidases in comparison to zanamivir.

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Li et al. have reported a straightforward methodology for the synthesis of zanamivir alkoxyalkyl ester derivatives 45a–c (Scheme5B) [ 54]. This method was based on treating zanamivir with alkoxyalkyl bromides in presence of dimethylsulfoxide (DMSO) and triethyamine at 80 ◦C. These compounds demonstrated improved bioavaility when orally administered. However, all derivatives displayed lower inhibitory activity against H1N1 and H3N2 influenza neuraminidases in comparison Moleculesto zanamivir. 2016, 21, 1513 7 of 40

Scheme 5. Synthesis of C-1 modifiedmodified zanamivir analogues. (A) Synthetic strategy for zanaphosphor (44) developeddeveloped by by Shie Shie and and coworkers coworkers [52 ];[52]; (B) Synthetic(B) Synthetic strategy strategy for zanamivir for zanamivir ester derivatives ester derivatives (45a–c) (developed45a–c) developed by Li and by coworkersLi and coworkers [54]. [54].

2.3. C-4 Modifications Modifications Gervay-Hage and and Lu Lu reported reported the synthesis the synthesis of C-4 triazole of C-4 analogues triazole analogues of zanamivir of 49 zanamivir (Scheme 6A)49 (Scheme[55]. Acetylated6A) [ 55 Neu5Ac]. Acetylated (46) was Neu5Ac used (46as) the was starting used as material. the starting This material. compound This was compound treated with was TMSOTftreated with followed TMSOTf by followedreaction with by reaction trimethylsylil with trimethylsylil azide (TMSN azide3) to (TMSNobtain 3a) tozanamivir obtain a zanamivirderivative bearingderivative a C-4 bearing linked a azido C-4 linked group azido(47). A group series ( 47of). protected A series triazole of protected compounds triazole (49 compounds) were afforded (49) wereby Cu(I)-catalyzed afforded by Cu(I)-catalyzed 1,3-dipolar addition 1,3-dipolar with additiondifferent withalkynes. different Finally, alkynes. deprotection Finally, of deprotection the acetate groupsof the acetatewas carried groups out was using carried NaOMe/MeOH out using NaOMe/MeOHto produce C-4 triazole to produce zanamivir C-4 triazole analogues zanamivir 50a–i. Theanalogues same methodology50a–i. The same was used methodology by Shen and was coworkers used by Shenfor the and synthesis coworkers of C-4 for and the C-8 synthesis modified of zanamivirC-4 and C-8 analogues modified [56]. zanamivir Yao and coworkers analogues reported [56]. Yao the andsynthesis coworkers of C-4 reportedthiocarbamide the synthesis derivatives of fromC-4 thiocarbamide zanamivir intermediate derivatives 15 from (Scheme zanamivir 6B) [44]. intermediate A number 15of (Schemedifferent6 B)thiocarbamates [ 44]. A number reacted of smoothlydifferent thiocarbamates with 15 to afford reacted the corresponding smoothly with carbamides15 to afford the51a correspondingand 51b. The acetyl carbamides deprotection51a and was51b. Thecarried acetyl out deprotection by treatment was with carried 1 N NaOH out by treatmentsolution in with methanol 1 N NaOH to afford solution 52. Ikeda in methanol and coworkers to afford developed52. Ikeda and a coworkerssynthetic strategy developed based a synthetic on the strategy selective based O-4-alkylation on the selective of 53O-4-alkylation by treatment of 53withby iodomethanetreatment with or iodomethane alkyl bromides or alkylin the bromides presence in of the Ag presence2O and tetra- of Agn-butylammonium2O and tetra-n-butylammonium iodide (TBAI) oriodide in presence (TBAI) of or NaH in presence to access of C-4 NaH modified to access zana C-4mivir modified analogues zanamivir bearing analogues different bearing aliphatic different chains (aliphatic55a–e, Scheme chains 6C) (55a [57].–e, SchemeCompounds6C) [ 5755a].– Compoundse showed inhibitory55a–e showed activity inhibitory against the activity neuraminidase against the of parainfluenzaneuraminidase virus of parainfluenza type 1 with the virus ethylated type 1 withanalogue the ethylateddisplaying analogue the greatest displaying efficacy. the However, greatest theseefficacy. results However, were not these compared results were to the not inhibitory compared activity to the of inhibitory commercial activity drugs. of commercialLin and coworkers drugs. reportedLin and coworkersthe synthesis reported of acyl theguanidine synthesis zanamivir of acylguanidine derivatives zanamivir 57 (Scheme derivatives 6D) [58].57 The(Scheme synthetic6D) route [ 58]. Theconsisted synthetic of the route reaction consisted of different of the acylguanidine reaction of different derivatives acylguanidine and amine derivatives 4 to obtain andcompounds amine 4 56to. Deprotectedobtain compounds by treatment56. Deprotected with TFA/CH by2 treatmentCl2 followed with by TFA/CH K2CO3 afforded2Cl2 followed derivatives by K 257CO which3 afforded were evaluatedderivatives against57 which H1N1 were and evaluated H3N2 againstinfluenza H1N1 neuraminidases, and H3N2 influenza but showed neuraminidases, much lower but inhibitory showed activitiesmuch lower in comparison inhibitory activities with zanamivir. in comparison with zanamivir.

Molecules 2016, 21, 1513 8 of 40 Molecules 2016, 21, 1513 8 of 40

Scheme 6. Synthesis of C-4 modified zanamivir analogues bearing triazole groups 50a–l (A) [55]; Scheme 6. Synthesis of C-4 modified zanamivir analogues bearing triazole groups 50a–l (A)[55]; thiocarbamates 52a,b (B) [44]; alkyl chains 55a–e (C) [57] or acylguanidines 57 (D) [58]. thiocarbamates 52a,b (B)[44]; alkyl chains 55a–e (C)[57] or acylguanidines 57 (D)[58]. Liu and coworkers reported the synthesis of a wide range of C-4 modified zanamivir analogues usingLiu compounds and coworkers 46 and reported 58 as starting the synthesis materials of [59]. a wide The range introduction of C-4 modifiedof amino acids zanamivir was performed analogues usingby coupling compounds of Boc-protected46 and 58 as amino starting acids materials with 58 [by59 ].treatment The introduction with 1-hydroxybenzotriazole of amino acids was (HOBt) performed in bypresence coupling of of N Boc-protected,N-diisopropylethylamine amino acids with(DIPEA)58 by and treatment subsequent with Ac 1-hydroxybenzotriazole and Boc deprotection (HOBt)with in presenceNaOH/MeOH of N ,andN-diisopropylethylamine TFA/CH2Cl2, respectively (DIPEA) (Scheme and 7A). subsequent The direct reaction Ac and of Boc 46 deprotectionwith substituted with NaOH/MeOHisothiocyanates and and TFA/CH isocyanates2Cl2, respectivelywas also performed (Scheme 7inA). a Thesimilar direct manner reaction as reported of 46 with by substitutedYao and isothiocyanatescoworkers [44], and using isocyanates 46 instead wasof 15 also as the performed starting material. in a similar The re manneraction was as reportedcarried out by at Yao room and coworkerstemperature [44], (rt) using without46 instead addition of 15of asany the catalyst starting. Liu material. and coworkers The reaction described was the carried introduction out at room of

Molecules 2016, 21, 1513 9 of 40

Molecules 2016, 21, 1513 9 of 40 temperature (rt) without addition of any catalyst. Liu and coworkers described the introduction of cyclic secondary amines from acetylated Neu5Ac using pyridine as catalyst (cat.) [60] [60] (Scheme 77B).B). Acetylation,Acetylation, treatment withwith TMSOTf,TMSOTf, andand deprotectiondeprotection usingusing NaOH/MeOHNaOH/MeOH resulted in C-4C-4 substitutedsubstituted zanamivir analogues 62.. Furthermore, Liu Liu and coworkers studied the inhibitory activity of allall thethe synthetized zanamivir analoguesanalogues [[59].59]. The The C-4 derivatization of zanamivir with thiocarbamates, α-amino-amino acids or or cyclic cyclic secondary secondary amines amines led led to todecr decreasedeased inhibitory inhibitory activities activities against against both both H3N2 H3N2 and andH5N1 H5N1 influenza influenza virus virus neuraminidases. neuraminidases. The The best best results results were were obtained obtained with with a a zanamivir zanamivir analogue bearing an LL-asparagine moiety which showed 400- andand 200-fold200-fold lowerlower inhibitoryinhibitory activityactivity towardstowards H3N2 and H5N1H5N1 neuraminidases,neuraminidases, respectively,respectively, thanthan zanamivir.zanamivir.

Scheme 7.7. SynthesisSynthesis of of C-4 C-4 modified modified zanamivir zanamivir analogues analogues (A) ( bearingA) bearing amino amino acids acids (60)[ 59(60]) or [59] (B) or cyclic (B) secondarycyclic secondary amines amines (62)[60 (62]. ) [60].

2.4. C-5 ModificationsModifications Von Itztein, Smith and coworkers developed a synthetic procedure for the synthesis of Von Itztein, Smith and coworkers developed a synthetic procedure for the synthesis of zanamivir zanamivir derivatives bearing different substituents through substitution of the N-acetyl group [61]. derivatives bearing different substituents through substitution of the N-acetyl group [61]. The N-Boc The N-Boc protected derivative was synthesized by reacting 47 with Boc anhydride followed by protected derivative was synthesized by reacting 47 with Boc anhydride followed by deprotection using deprotection using NaOMe/MeOH and NaOH. The reduction of the azide with triphenylphosphine NaOMe/MeOH and NaOH. The reduction of the azide with triphenylphosphine and guanylation and guanylation led to the formation of N-Boc protected zanamivir which was treated with methyl led to the formation of N-Boc protected zanamivir which was treated with methyl trifluoroacetate to trifluoroacetate to obtain the corresponding amine as a suitable intermediate for derivatization at C-5. obtain the corresponding amine as a suitable intermediate for derivatization at C-5. However, none of However, none of these C-5 modifications of zanamivir showed enhanced inhibition against influenza these C-5 modifications of zanamivir showed enhanced inhibition against influenza A (serotype is not A (serotype is not described) and influenza B. described) and influenza B.

Molecules 2016, 21, 1513 10 of 40 Molecules 2016, 21, 1513 10 of 40

2.5. C-6 ModificationsModifications Von ItzsteinItzstein andand coworkerscoworkers reportedreported thethe synthesissynthesis of thethe thioetherthioether zanamivir derivative 67 (Scheme(Scheme8 8).). ToTo achieveachieve thisthis goal,goal, 63 was used as the starting material [[62],62], and was treatedtreated withwith · oxalacetic acid in thethe presencepresence ofof Ni(OAc)Ni(OAc)22·(H(H2O)O)44 andand NaOH NaOH to to produce 64, which was thenthen decarboxylated to to give give 6565. .After After protection protection of ofthe the carboxylic carboxylic acid acid by bytreatment treatment with with MeOH MeOH in the in thepresence presence of acid, of acid,the corresponding the corresponding ester was ester acetylated was acetylated to give tothe give bicyclic the compound bicyclic compound 66. The rest66. Theof the rest procedure of the procedure was carried was out carried in an analogous out in an ma analogousnner to the manner reactions to described the reactions in Scheme described 1 [41]. in SchemeThe thioether1[ 41]. Thederivative thioether was derivative found to was have found inhibitory to have effects inhibitory against effects influenza against influenzavirus sialidase virus sialidasecomparable comparable to its oxy-analogue. to its oxy-analogue.

Scheme 8. Synthetic strategy for the production of zanamivir C-6 thioether analogues 67 reported by von Itzstein and coworkers [[62].62].

2.6. C-7 ModificationsModifications (Laninamivir) Andrews and coworkers reported the synthesis of C-7 carbamate zanamivir analogues [63]. [63]. Two differentdifferent syntheticsynthetic methodologiesmethodologies were employed to produce these derivatives. The first first (route A, Scheme 99A):A): beganbegan withwith thethe protectionprotection ofof compoundcompound 68 waswas byby treatmenttreatment withwith carbamoylcarbamoyl chloridechloride in presence ofof 4-dimethylaminopyridine4-dimethylaminopyridine (DMAP)(DMAP) toto obtainobtain 69.. 69 was then allowed to react with the appropriate isocyanate, synthesized according to co conditionsnditions reported by Zbiral and coworkers [64], [64], and DMAP toto yieldyield 7070.. After After reduction of the azidoazido groupgroup withwith triphenylphosphine,triphenylphosphine, thethe cycliccyclic carbonate waswas hydrolyzed hydrolyzed in aqueousin aqueous triethylamine triethylamine at 40 at◦C 40 to give°C to71 .give The formation71. The formation of the guanidine of the moietyguanidine was moiety accomplished was accomplished through the through standard the techniquestandard technique [41]. In the [41]. second In the approach second approach (route B, Scheme(route B,9B), Scheme68 was 9B), treated 68 was with treated 1.2 equivalents with 1.2 equivalents of 4-nitrophenyl of 4-nitrophenyl chloroformate chloroformate in dry pyridine in dry to yieldpyridine compound to yield 73compound. Treatment 73. ofTreatment73 withsuitable of 73 with primary suitable and primary secondary and aminessecondary resulted amines in resulted a panel ofin C7-carbamatesa panel of C7-carbamates74. The rest 74 of. The the synthesisrest of the was synthesis carried was out carried as described out as in described route A. C-7in route carbamates A. C-7 werecarbamates obtained were with obtained a higher with yield a (40%–67%)higher yield using (40%–67%) route B. using Furthermore, route B. routeFurthermore, B permitted route the B synthesispermitted ofthe a moresynthesis diverse of a range more of diverse analogues. range Inhibitory of analogues. activity Inhibitory screening activity revealed screening that none revealed of the compoundsthat none of describedthe compounds were asdescribed potent as were zanamivir as pote fornt as the zanamivir inhibition for of the influenza inhibition A and of influenza influenza A B neuraminidasesand influenza B neuraminidases (the serotype of (the influenza serotype A was of in notfluenza stated). A was Klibanov not stated). and coworkers Klibanov and have coworkers reported thehave binding reported of the zanamivir binding toof poly(iso-butylene-alt-maleiczanamivir to poly(iso-butylene-alt-maleic anhydride) through anhydride) a C-7 through linkage a [C-765], utilizinglinkage [65], the method utilizing reported the method by Andrews reported and coworkersby Andrews [63 ].and Although coworkers the functionalization [63]. Although withthe afunctionalization monofunctional with polymer a monofunctional could not improve polymer the inhibitory could not activity improve of zanamivir, the inhibitory the bifunctional activity of naturezanamivir, of the the polymer bifunctional allowed nature the attachment of the polymer of either allowed zanamivir the attachment or Neu5Ac showedof either in zanamivir each case anor Neu5Ac showed in each case an increased inhibitory activity against H3N2 influenza neuraminidase in the order of two magnitudes when compared to zanamivir.

Molecules 2016, 21, 1513 11 of 40 increased inhibitory activity against H3N2 influenza neuraminidase in the order of two magnitudes whenMolecules compared 2016, 21, 1513 to zanamivir. 11 of 40

Scheme 9. SyntheticSynthetic routes routes to C-7 modified modified zanamivir analogues ( 72) reported by Andrews and coworkers [[63].63]. ( A)) Synthetic approach approach for the synthesi synthesiss of mono-substituted carbamates; (B) Synthetic approach for the synthesis of carbamates viavia activationactivation withwith 4-nitrophenyl4-nitrophenyl chloroformate.chloroformate.

Honda and and coworkers coworkers developed developed a chemo-enzymatic a chemo-enzymatic route, route,outlined outlined in Scheme in 10, Scheme to obtain 10, toC-7 obtain substituted C-7 substituted zanamivir zanamiviranalogues analogues[66]. Epoxide [66]. Epoxide75 was subjected75 was subjected to treatment to treatment with either with Bu4NFH2F3-potassium bifluoride, methanol, ethanol or sodium azide to obtain bicyclic compounds either Bu4NFH2F3-potassium bifluoride, methanol, ethanol or sodium azide to obtain bicyclic compounds76a–d with 28%,76a– 95%,d with 82% 28%, and 95%, 72% 82%yield, and respective 72% yield,ly. Acid respectively. treatment using Acid treatmentTFA followed using by TFA3 N followedhydrochloric by 3 acid N hydrochloric allowed the acid formation allowed of the mannose formation analogues of mannose 77a analogues–d. These77a mannose–d. These derivatives mannose derivatives77a–d were 77athen–d reactedwere then with reacted pyruvate with in pyruvatepresence of in Neu5Ac presence aldolase of Neu5Ac at pH aldolase 7.5 to atproduce pH 7.5 the to produceNeu5Ac analogues the Neu5Ac 78a analogues–d. After protection78a–d. After of protectionthe hydroxyl of and the hydroxylcarboxylic and acid carboxylic groups, the acid protected groups, thesialic protected acids reacted sialic with acids sodium reacted azide with in sodium the pres azideence inof theDowex presence 50W allowing of Dowex the 50W incorporation allowing the of incorporationthe azide at C-4 of to the afford azide 79a at C-4–d. toThe afford rest 79aof the–d .synthesis The rest of to the zanamivir synthesis analogues to zanamivir was analoguesaccomplished was accomplishedaccording to the according previously to the repo previouslyrted methodology reportedmethodology [62]. Compound [62]. 80b Compound, laninamivir,80b, laninamivir,showed an showedinhibitory an activity inhibitory against activity influenza against B influenza neuraminidase B neuraminidase twice as high twice as asthat high of aszanamivir. that of zanamivir. In 2010, Inlaninamivir 2010, laninamivir was approved was approved for influenza for influenza treatment treatment in Japan in and Japan is marketed and is marketed under the under name the Inavir name Inavir[67]. Laninamivir [67]. Laninamivir is administered is administered by nasal by nasal inhalation inhalation [67]. [67 A]. Asimilar similar synthetic synthetic strategy strategy to to obtain laninamivir was later reported by Sugai andand coworkerscoworkers [[68].68]. Honda and coworkers also reported direct C-7 alkylation to obtain zanamivir analogues Honda and coworkers also reported direct C-7 alkylation to obtain zanamivir analogues modified modified with longer side-chains or alcohol, amino, N-acetyl, azido or phenyl functionalities. To with longer side-chains or alcohol, amino, N-acetyl, azido or phenyl functionalities. To achieve this, achieve this, starting material 80 (Scheme 10) was treated with a variety of dialkylsulfates in the starting material 80 (Scheme 10) was treated with a variety of dialkylsulfates in the presence of NaH in presence of NaH in N,N-dimethylformamide (DMF) to afford the corresponding alkyl ethers in N,N-dimethylformamide (DMF) to afford the corresponding alkyl ethers in moderate yield. The rest of moderate yield. The rest of the procedure to achieve the zanamivir derivatives was carried out the procedure to achieve the zanamivir derivatives was carried out according to conditions described according to conditions described above.[62] Neither elongation of the O-alkyl chain, nor terminal above. [62] Neither elongation of the O-alkyl chain, nor terminal functionalization of the O-alkyl chain functionalization of the O-alkyl chain with NH2, OH, N3 and NHAc groups could enhance inhibitory activity against influenza A virus sialidase (serotype is not mentioned).

Molecules 2016, 21, 1513 12 of 40

with NH2, OH, N3 and NHAc groups could enhance inhibitory activity against influenza A virus sialidase (serotype is not mentioned). Molecules 2016, 21, 1513 12 of 40

Scheme 10. Synthetic route to laninamivir and other zanamivir analogues 79a–d reported by Honda Scheme 10. Synthetic route to laninamivir and other zanamivir analogues 79a–d reported by Honda and coworkers [66]. and coworkers [66]. A direct alkylation methodology was also employed by Honda and coworkers [69] for the A direct alkylation methodology was also employed by Honda and coworkers [69] for synthesis of glutamic acid polymers bearing zanamivir analogues via an alkyl ether spacer linked to thethe synthesis C-7 position. of glutamic Polyglutamic acid polymersacid (M. W. bearing 50,000–70,000) zanamivir was analogues activated viawith an HOBt. alkyl Subsequent ether spacer linkedcondensation to the C-7 with position. the terminal Polyglutamic amine linker acid of (M.zanamivir W. 50,000–70,000) analogues was was afforded activated the zanamivir- with HOBt. Subsequentderivatized condensation macromolecules with (e.g., the 81 terminal, Scheme amine10). The linker efficacy of zanamivirof intranasally analogues administered was affordedpolymeric the zanamivir-derivatizedsialidase inhibitor 81 macromoleculeswas tested in vivo (e.g., using81 ,an Scheme infected 10 mouse). The efficacymodel on of the intranasally basis of the administered survival polymericrate. The sialidase inhibitor inhibitor was administered81 was tested intranasallyin vivo usingonce an24 infectedh prior to mouse infection. model It onwas the found basis that of the survivalcompound rate. 81 The was inhibitor a much wasmore administered effective prophylactic intranasally than once zanamivir, 24 h prior with to a infection.survival rate It wasof 100% found thatamong compound the mice81 treatedwas a muchwith this more compound, effective prophylacticwhile none of thanthe mice zanamivir, treated withwith azanamivir survival survived. rate of 100% amongSharpless the mice treatedand coworkers with this reported compound, [70] the while synthesis none of of the 1,4-triazole mice treated linked with zanamivir zanamivir analogues survived. dimersSharpless (89) (Scheme and coworkers 11). Carboxylic reported acids [70 bearing] the synthesis alkyne functionality of 1,4-triazole (82 linked) were treated zanamivir with analogues thionyl dimerschloride (89 )and (Scheme trimethylsilyl 11). Carboxylic azide to acidsgive the bearing corresponding alkyne functionality acyl azides (which82) were were treated not isolated with thionyl but chlorideimmediately and trimethylsilyl heated to reflux azide in totoluene, give the induci correspondingng Curtius rearrangement acyl azides which to form were isocyanates not isolated (83). but immediatelyThe isocyanates heated thus to refluxobtained in toluene,were reacted inducing with Curtiusprotected rearrangement zanamivir. Meanwhile, to form isocyanates treatment of (83 ). Thecarboxylic isocyanates acids thus 85 with obtained sodium were azide reacted in acetone/water with protected gave the zanamivir. corresponding Meanwhile, acid azides treatment which of carboxylicwere treated acids with85 withthionyl sodium chloride azide and in trimethylsilyl acetone/water azide gave to provide the corresponding acyl azides. These acid azides were then which converted via a Curtius rearrangement to the corresponding isocyanates and then allowed to react were treated with thionyl chloride and trimethylsilyl azide to provide acyl azides. These were then with protected zanamivir. A 1,-3-dipolar addition reaction between the alkyne-bearing zanamivir converted via a Curtius rearrangement to the corresponding isocyanates and then allowed to react derivatives and their azide-bearing counterparts resulted in the formation of dimers 88 which were with protected zanamivir. A 1,-3-dipolar addition reaction between the alkyne-bearing zanamivir then deprotected by treatment with TFA. The best conditions for the 1,3-dipolar reaction were found derivatives and their azide-bearing counterparts resulted in the formation of dimers 88 which were to be CuSO4 (0.3 equivalents), ascorbic acid (1.5 equivalents) in a 1:2 H2O/tBuOH mixture (v/v) at thenroom deprotected temperature. by treatment In vitro screening with TFA. of The inhibitory best conditions activity forrevealed the 1,3-dipolar that most reaction 1,4-triazole were linked found to bezanamivir CuSO4 (0.3 dimers equivalents), are significantly ascorbic acidmore (1.5 potent equivalents) inhibitors in than a 1:2 zanamivir H2O/tBuOH and mixtureoseltamivir (v/ vagainst) at room temperature.neuraminidaseIn vitro of influenzascreening A (Sydney/5/97, of inhibitory activityH3N2) and revealed influenza that B most neuraminidase 1,4-triazole (Harbin/7/94). linked zanamivir dimers are significantly more potent inhibitors than zanamivir and oseltamivir against neuraminidase of influenza A (Sydney/5/97, H3N2) and influenza B neuraminidase (Harbin/7/94).

Molecules 2016, 21, 1513 13 of 40

Molecules 2016, 21, 1513 13 of 40

SchemeScheme 11. 11. SynthesisSynthesis of 1,4-triazole of 1,4-triazole linked zanamivir linked zanamivir dimers (89 dimers) reported (89 by) reported Sharpless byand Sharpless coworkers and [70]. coworkers [70]. 2.7. C-9 Modifications 2.7. C-9Zanamivir Modifications analogues bearing 9-cyclopropanecarbonylamino and 9-butanecarbonylamino groups (95a and 95b, respectively) have been developed by Suzuki, Kiso, Tokiwa, and coworkers [71] (Scheme Zanamivir analogues bearing 9-cyclopropanecarbonylamino and 9-butanecarbonylamino groups 12). Compound 47 was used as the starting material for their synthetic route. Hydrogenolysis of the (95a and 95b, respectively) have been developed by Suzuki, Kiso, Tokiwa, and coworkers [71] azido group of 47 with hydrogen and Lindlar catalyst yielded the corresponding amine derivative (Scheme 12). Compound 47 was used as the starting material for their synthetic route. Hydrogenolysis which was protected with Boc anhydride resulting in compound 90. Deprotection of the acetate of the azido group of 47 with hydrogen and Lindlar catalyst yielded the corresponding amine derivative groups was carried out in NaOMe/MeOH to afford 91. The C-9 hydroxyl group was selectively whichactivated was protected with p-toluenesulfonyl with Boc anhydride chloride resulting (TsCl) to in compoundobtain 92, which90. Deprotection was substituted of the with acetate azide groups to wasobtain carried 93. out93 was in NaOMe/MeOH then subjected to to a affordStaudinger91. The reductio C-9 hydroxyln using trimethyl group was phosphine selectively to generate activated the with p-toluenesulfonylintermediate amine chloride which (TsCl) was toconverted obtain 92 to, whichcompounds was substituted 94a and 94b with using azide the toappropriate obtain 93. NHS93 was thenester. subjected After removal to a Staudinger of protecti reductionng groups using and trimethyl guanylation phosphine with N to,N′ generate-bis-(tert-butoxycarbonyl)-1 the intermediate amineH- whichpyrazole-1-carboxamidine was converted to compounds (bis-BocPCH),94a and 95a94b andusing 95b were the appropriate obtained. These NHS zanamivir ester. After analogues removal of 0 protectingwere tested groups against and H1N1 guanylation and H3N2 with influenzaN,N -bis-(tert-butoxycarbonyl)-1 virus neuraminidases, however,H-pyrazole-1-carboxamidine they displayed lower (bis-BocPCH),levels of inhibitory95a and activity95b were in comparison obtained. Theseto zanamivir zanamivir itself. analogues were tested against H1N1 and

Molecules 2016, 21, 1513 14 of 40

H3N2 influenza virus neuraminidases, however, they displayed lower levels of inhibitory activity in comparisonMolecules 2016 to, 21 zanamivir, 1513 itself. 14 of 40

SchemeScheme 12. 12.Synthetic Synthetic strategy strategy to affordto afford C-9 modifiedC-9 modified zanamivir zanamivir analogues analogues95a– b95areported–b reported by Suzuki, by Suzuki, Kiso, Tokiwa and coworkers [71]. Kiso, Tokiwa and coworkers [71].

2.8.2.8. Other Other Modifications Modifications Bamford and coworkers reported the synthesis of zanamivir analogues with truncated Bamford and coworkers reported the synthesis of zanamivir analogues with truncated C-6-glycerol side-chains (102, 104 and 108) [72]. A zanamivir analogue lacking any side-chain (102) C-6-glycerol side-chains (102, 104 and 108)[72]. A zanamivir analogue lacking any side-chain was obtained using N-acetylglucosamine, GlcNAc (96), as the starting material (Scheme 13A). From (102) was obtained using N-acetylglucosamine, GlcNAc (96), as the starting material (Scheme 13A). 96, the tri-O-acetyl-1-chloro derivative 97 was prepared through treatment with acetyl chloride. From 96, the tri-O-acetyl-1-chloro derivative 97 was prepared through treatment with acetyl chloride. Azobisisobutyronitrile (AIBN) and Bu3SnH were used for the free-radical-initiated dehalogenation Azobisisobutyronitrileto give 98. After removal (AIBN) of the and acetyl Bu3SnH protecting were usedgroups for using the free-radical-initiated NaOMe/MeOH, the dehalogenationprimary alcohol to givewas98 .selectively After removal oxidized of the under acetyl oxygen protecting atmosphere groups using in presence NaOMe/MeOH, of Pt to theobtain primary acid alcohol99. After was selectivelyesterification oxidized of 99 underwith methanol, oxygen atmosphere the hydroxyl in groups presence of the of Ptcorresponding to obtain acid ester99. were After protected esterification as of acetates99 with using methanol, acetic anhydride. the hydroxyl An elimination groups of thereaction corresponding was carried esterout on were the protected protected compound as acetates usingthrough acetic treatment anhydride. with An 1,8-diazabicyclo(5.4.0)undec-7-ene elimination reaction was carried (DBU) out on in the CHCl protected3 at reflux compound to yield through 100, treatmentwhich was with reacted 1,8-diazabicyclo(5.4.0)undec-7-ene with TMSOTf followed by TMSN (DBU)3 to in obtain CHCl azide3 at reflux 101. After to yield reduction100, which of the was reactedazide withunder TMSOTf an atmosphere followed of hydrogen by TMSN in3 presenceto obtain of azide Pd/C,101 the. resulting After reduction amine was of theguanylated azide under to angive atmosphere zanamivir ofderivative hydrogen 102 in. The presence synthesis of of Pd/C, the single the carbon resulting side-chain amine analogue was guanylated 104 was carried to give zanamivirout using derivative zanamivir102 as. the The starting synthesis material. of the singleTreatment carbon with side-chain sodium periodate analogue (2104 equivalents,was carried outScheme using 13B) zanamivir yielded asaldehyde the starting 103, which material. was directly Treatment reduced with with sodium sodium periodate borohydride (2 equivalents, to obtain Scheme104, after 13B) purification yielded aldehyde by anion-ex103,change which waschromatography. directly reduced The with2 carbon sodium side-chain borohydride analogue to obtainwas 104obtained, after purification from 105 which by anion-exchange was treated with chromatography. diazodiphenylmethane The 2(DDM) carbon to side-chaingive the DPM analogue ester 106 was obtained(Scheme from 13C).105 The whichoxidation/reduction was treated withmethodology diazodiphenylmethane described for the (DDM)synthesis to of give the single the DPM carbon ester 106side-chain(Scheme analogue13C). The was oxidation/reduction then employed using methodology 1.1 equivalents described of sodium for the periodate synthesis instead of the of single 2 equivalents to afford 107. Boc and DPM protecting groups were removed using TFA, and subsequent carbon side-chain analogue was then employed using 1.1 equivalents of sodium periodate instead of 2 guanylation in presence of aminoiminomethanesulfinic acid (AIMSA) afforded zanamivir analogue equivalents to afford 107. Boc and DPM protecting groups were removed using TFA, and subsequent 108. Inhibitory activity screening revealed that compounds, 102, 104 and 108, show lower inhibitory guanylation in presence of aminoiminomethanesulfinic acid (AIMSA) afforded zanamivir analogue activity in comparison with zanamivir against influenza A and influenza B neuraminidases 108. Inhibitory activity screening revealed that compounds, 102, 104 and 108, show lower inhibitory (subtypes are not identified). The highest inhibitory activity was achieved when the two carbon activityside-chain in comparison analogue was with used. zanamivir against influenza A and influenza B neuraminidases (subtypes are not identified). The highest inhibitory activity was achieved when the two carbon side-chain analogue was used.

Molecules 2016, 21, 1513 15 of 40 Molecules 2016, 21, 1513 15 of 40

Scheme 13. Synthetic strategy reported by Bamford and coworkers [72] to obtain zanamivir analogues Scheme 13. Synthetic strategy reported by Bamford and coworkers [72] to obtain zanamivir analogues wherein the C-6-glycerol side-chain is truncated. (A) Synthetic route to zanamivir analogue 102; wherein the C-6-glycerol side-chain is truncated. (A) Synthetic route to zanamivir analogue 102; (B) Synthetic route to zanamivir analogue 104; (C) Synthetic route to zanamivir analogue 108. (B) Synthetic route to zanamivir analogue 104;(C) Synthetic route to zanamivir analogue 108. Honda and coworkers described a synthetic route to bicyclic ether, namely tetrahydrofuran- 2-yl,Honda tetrahydropyran-2-yl and coworkers describedand oxepan-2-yl a synthetic derivatives route to bicyclicof zanamivir ether, namely[73]. The tetrahydrofuran-2-yl, synthesis of the tetrahydropyran-2-yltetrahydrofuran-2-yl, andtetrahydropy oxepan-2-ylran-2-yl, derivatives and oxepan-2-yl of zanamivir derivatives [73 substituted]. The synthesis by diols at of the the tetrahydrofuran-2-yl,C-3′ and C-4′ positions tetrahydropyran-2-yl, (113a–d) was achieved and using oxepan-2-yl 80 as the starting derivatives material substituted (Scheme by14A). diols 80 was at the 0 0 C-3alkylatedand C-4 withpositions toluene-4-sulfonic (113a–d) was acid achieved 2-(2,2-diethyl-(1,3)dioxolan-4-yl)-ethyl using 80 as the starting material ester, (Schemeallyl iodide, 14A). 80 trifluoromethanesulfonicwas alkylated with toluene-4-sulfonic acid 2,2-difluoro-but-3-enyl acid 2-(2,2-diethyl-(1,3)dioxolan-4-yl)-ethyl ester, or 5-iodo-pent-1-ene in ester,the presence allyl iodide, of trifluoromethanesulfonicNaH in DMF to give the acid corresponding 2,2-difluoro-but-3-enyl compounds ester, 108a or, 5-iodo-pent-1-ene108b, 108c or 108d in, respectively. the presence After of NaH in DMFremoval to giveof the the TBDMS corresponding protecting compounds group with108a TBAF, 108b and, subsequent108c or 108d protection, respectively. of the After C-4 hydroxyl removal of thegroup TBDMS with protecting an acetyl group group, with the TBAF acetonide and subsequent group was protectiondeprotected of thewith C-4 acetic hydroxyl acid. groupCompounds with an acetyl109a group,–d were the then acetonide afforded groupthrough was formation deprotected of the with thiocarbonates acetic acid. with Compounds thiophosgene109a and–d wereDMAP. then affordedThe thiocarbonates through formation were reduced of the thiocarbonates using methyl phosphite with thiophosgene at 120 °C to and give DMAP. compounds The thiocarbonates 110a–d. A werering-closing reduced using metathesis methyl reaction phosphites with at 120Grubbs’◦C to catalyst give compounds was accomplished110a–d. A to ring-closing obtain compounds metathesis reactions111a–d. with Osmium Grubbs’ tetraoxide catalyst and was N accomplished-methylmorpholine- to obtainN-oxide compounds (NMO)111a were–d used. Osmium to selectively tetraoxide andoxidizeN-methylmorpholine- the double bond ofN -oxide111a–d (NMO)to provide were diols used 112a to–d selectivelyas single diastereomers. oxidize the doubleThe diols bond thus of 111aobtained–d to provide were converted diols 112a to– dcompoundsas single diastereomers.113a–d under the The same diols conditions thus obtained as those were previously converted to compoundsdescribed in Scheme113a–d 10under [66]. Tetrahydropyran-2-yl the same conditions de asrivatives those previously substituted described by hydroxyl in Schemegroups at 10 the[ 66 ]. C-4′ and C-5′ positions (114a–d, Scheme 14B) were achieved using a similar synthetic strategy. A Tetrahydropyran-2-yl derivatives substituted by hydroxyl groups at the C-40 and C-50 positions (114a–d, sialidase inhibitory assay showed that these zanamivir derivatives exhibited inhibition of A/PR/8/34 Scheme 14B) were achieved using a similar synthetic strategy. A sialidase inhibitory assay showed

Molecules 2016, 21, 1513 16 of 40

Molecules 2016, 21, 1513 16 of 40 that these zanamivir derivatives exhibited inhibition of A/PR/8/34 comparable to that of zanamivir. comparable to that of zanamivir. On the other hand, the movement of the hydroxyl groups from C-3′ On the other hand, the movement of the hydroxyl groups from C-30 and C-40 (113a–d) to C-40 and C-50 and C-4′ (113a–d) to C-4′ and C-5′ (114a–d) decreased the inhibitory activity, as did the absence of (114a–d) decreased the inhibitory activity, as did the absence of hydroxyl groups at these positions. hydroxyl groups at these positions.

SchemeScheme 14. 14. The synthetic synthetic route route reported reported by byHonda Honda and andcoworkers coworkers [73] to [ 73achieve] to achieve bicyclic bicyclicether derivatives of zanamivir. (A) Synthetic route to zanamivir analogues 113a–d; (B) Zanamivir analogues ether derivatives of zanamivir. (A) Synthetic route to zanamivir analogues 113a–d;(B) Zanamivir 114a–d. analogues 114a–d. Smith and coworkers explored a different synthetic approach to obtain C-6 ether modified Smith and coworkers explored a different synthetic approach to obtain C-6 ether modified 4-amino zanamivir analogues (121) [74] (Scheme 15). Initial chloroacetylation of 96 with acetyl 4-aminochloride zanamivir and subsequent analogues cyclization (121)[74 with] (Scheme tetraethylammonium 15). Initial chloroacetylation chloride formed ofthe96 tri-withO-acetyl acetyl chlorideoxazoline and glycoside subsequent 115 which cyclization was opened with by tetraethylammonium treatment with 3-pentanol chloride in the formed presence the of tri-p-tolueneO-acetyl oxazolinesulfonamide glycoside (pTSA)115 towhich form was116 exclusively. opened bytreatment The secondary with 3-pentanolalcohol groups in the were presence then selectively of p-toluene sulfonamideprotected in (pTSA) three simple to form protecting116 exclusively. group manipulations The secondary to alcoholafford 117 groups, the unprotected were then selectivelyprimary protectedalcohol of in which three was simple then protecting oxidized with group SO3-py manipulations and NH2SO3H to to afford afford117 the, α the,β-unsaturated unprotected acid primary 118. alcoholThis acid of whichwas then was converted then oxidized into its withmethyl SO ester.3-py Treatment and NH2 ofSO the3H ester to afford with 2-(1 theHα-benzotriazole-,β-unsaturated acid1-yl)-1,1,3,3-tetramethyluronium118. This acid was then tetrafluoroborat converted intoe (TBTU) its methyl and TMSOTf ester. Treatment produced the of theoxazoline ester 119 with 2-(1whichH-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium was opened with TMSN3 to produce azide 120. tetrafluoroborateReduction of the azide (TBTU) with and SnCl TMSOTf2 and hydrolysis produced theof oxazoline the methyl119 esterwhich led wasto zanamivir opened with analogue TMSN 1213 to. Using produce a similar azide 120synthetic. Reduction route, Smith of the and azide

Molecules 2016, 21, 1513 17 of 40 with SnCl and hydrolysis of the methyl ester led to zanamivir analogue 121. Using a similar Molecules 20162 , 21, 1513 17 of 40 synthetic route, Smith and coworkers reported the synthesis of a C-6 ketone, 4-amino zanamivir analoguecoworkers122 reportedand its reducedthe synthesis derivative of a C-6123 ketone,[74] (Figure 4-amino3A). Smithzanamivir and coworkers analogue later122 and described its reduced [ 75] thederivative synthesis 123 of[74] oxadiazoles (Figure 3A). (124 Smith) and and 4-aminozanamivir coworkers later described analogues [75] possessing the synthesis triazole of oxadiazoles moieties (125124,) Figureand 4-aminozanamivir3B). Both 124 and analogues125 derivatives possessing showed triazole decreased moieties inhibitory (125, Figure activities 3B). Both with 124 respect and 125 to zanamivir.derivatives Wyattshowed and decreased coworkers inhibitory reported activities [76] a synthetic with respect approach to zanamivir. to C-4 and Wyatt C-5, 6-carboxamideand coworkers modifiedreported [76] zanamivir a synthetic analogues approach (126 to, FigureC-4 and3C). C- In5, contrast6-carboxamide to zanamivir, modified these zanamivir analogues analogues were found (126, toFigure be potent 3C). In inhibitors contrast to of zanamiv influenzair, these A neuraminidase analogues were (serotype found to not be specified)potent inhibitors when theof influenza guanidine A groupneuraminidase was replaced (serotype by amine,not specified) hydroxyl when or the even gu deleted.anidine group While was the replaced synthesis by ofamine, C-5 modifiedhydroxyl zanamiviror even deleted. analogues While was the also synthesis performed, of C-5 they modified showed zanamivir decreased analogues inhibitory was activities also performed, in comparison they withshowed zanamivir decreased analogues inhibitory bearing activities an acetylin compar groupison in with this position.zanamivir Inhibitory analogues activities bearing werean acetyl not comparedgroup in this with position. zanamivir Inhibitory itself, oractivities with other were commercialnot compared drugs. with Onzanamivir the other itself, hand, or with Beau other and coworkerscommercial described drugs. On [77 the] a shortother synthetic hand, Beau route and to C-4coworkers zanamivir described congeners [77]127 a shortand 128syntheticwith truncated route to side-chainsC-4 zanamivir (Figure congeners3D) through 127 and a128 Petasis-borono with truncated Mannich side-chains reaction. (Figure No 3D) inhibitory through a activities Petasis-borono were reportedMannich forreaction. derivatives No inhibitory121, 122 ,activi123, ties127 wereand 128 reported. for derivatives 121, 122, 123, 127 and 128.

Scheme 15. Synthetic strategy reported by Smith and coworkers [[74]74] for the synthesissynthesis of zanamivirzanamivir analogue 121.

Molecules 2016, 21, 1513 18 of 40 Molecules 2016, 21, 1513 18 of 40

Figure 3. Complex zanamivir analogues. (A) Zanamivir analogues 122 and 123 synthetized by Smith Figure 3. Complex zanamivir analogues. (A) Zanamivir analogues 122 and 123 synthetized by Smith and coworkers [74]; (B) Zanamivir analogues 124 and 125 synthetized by Smith and coworkers [75]; and coworkers [74]; (B) Zanamivir analogues 124 and 125 synthetized by Smith and coworkers [75]; (C) Zanamivir analogue 126 synthetized by Wyatt and coworkers [76]; (D) Zanamivir analogues 127 (C) Zanamivir analogue 126 synthetized by Wyatt and coworkers [76]; (D) Zanamivir analogues 127 and 128 synthetized by Beau and coworkers [77]. and 128 synthetized by Beau and coworkers [77]. 3. Oseltamivir 3. Oseltamivir Oseltamivir, commercialized in its phosphate form under the name Tamiflu, was approved in Oseltamivir, commercialized in its phosphate form under the name Tamiflu, was approved in 2002 as an orally administered drug for the treatment of influenza A and B. Oseltamivir is not itself 2002effective as an orallyagainst administered viral neuraminidases, drug for thebut treatmentis rapidly ofconverted influenza by A hepatic and B. Oseltamivircarboxylases isinto not the itself effectivepotent neuraminidase against viral neuraminidases, inhibitor oseltamivir but carboxylate. is rapidly converted Although Scicinski by hepatic and carboxylases coworkers studied into the potentseveral neuraminidase carbocyclic analogues inhibitor of oseltamivirzanamivir [78], carboxylate. oseltamivirAlthough itself was discovered Scicinski and by Bischofberger coworkers studied and severalcoworkers carbocyclic and patented analogues in 1995 of zanamivir [79]. Oseltamivir [78], oseltamivir displays improved itself was inhibitory discovered activity by Bischofberger over zanamivir and coworkersagainst influenza and patented H2N2, in H3N2 1995 [and79]. H6N2 Oseltamivir neuraminidas displayses improved[24]. The development inhibitory activity of efficient over synthetic zanamivir againstroutes influenza to this compound H2N2, H3N2 has been and a H6N2 highly neuraminidases active area of research [24]. The in developmentthe last two decades of efficient [80]. synthetic routes to this compound has been a highly active area of research in the last two decades [80]. 3.1. Synthesis of Oseltamivir 3.1. Synthesis of Oseltamivir Several synthetic routes for the synthesis of oseltamivir have been reported and can be broadly dividedSeveral into synthetic five different routes forretrosyn the synthesisthetic strategies: of oseltamivir synthesis have from been ( reported−)-shikimic and acid can or be broadlyother divided6-membered into five rings different (Scheme retrosynthetic16a), through a strategies:Diels-Alder synthesisreaction with from acrylic (−)-shikimic acid as the acid dienophile or other 6-membered(Scheme 16b), rings by (Schemeconstruction 16a), of througha cyclohexane a Diels-Alder ring through reaction an intramolecular with acrylic acidmetathesis as the dienophilereaction, (Schemevia a Horner-Wadsworth-Emmons 16b), by construction of a cyclohexane reaction or aldol ring throughcondensation an intramolecular (Scheme 16c); metathesisfrom nitroalkenes reaction, viaby a Horner-Wadsworth-EmmonsCurtius rearrangement (Scheme reaction 16d) or orfrom aldol D-glucal condensation by Claisen (Scheme rearrangement 16c); from (Scheme nitroalkenes 16e). by Curtius rearrangement (Scheme 16d) or from D-glucal by Claisen rearrangement (Scheme 16e).

Molecules 2016, 21, 1513 19 of 40 Molecules 2016, 21, 1513 19 of 40

SchemeScheme 16. 16. RetrosyntheticRetrosynthetic analysis of the sy synthesisnthesis routes routes to to oseltamivir. oseltamivir. (a ()a )synthesis synthesis from from (−)-shikimic acid or other 6-membered rings; (b) through a Diels-Alder reaction with acrylic acid as (−)-shikimic acid or other 6-membered rings; (b) through a Diels-Alder reaction with acrylic acid as the dienophile; (c) by construction of a cyclohexane ring through an intramolecular metathesis reaction, the dienophile; (c) by construction of a cyclohexane ring through an intramolecular metathesis reaction, via a Horner-Wadsworth-Emmons reaction or aldol condensation; (d) from nitroalkenes by Curtius via a Horner-Wadsworth-Emmons reaction or aldol condensation; (d) from nitroalkenes by Curtius rearrangement or (e) from D-glucal by Claisen rearrangement. rearrangement or (e) from D-glucal by Claisen rearrangement. Rohloff and coworkers reported the first synthetic route to oseltamivir starting from the relativelyRohloff inexpensive and coworkers (−)-shikimic reported (Scheme the first 17) and synthetic (−)-quinic route acids to [81]. oseltamivir This methodology, starting from with the relativelyminor modifications, inexpensive has (− )-shikimicbeen used for (Scheme the industrial 17) and production (−)-quinic of oseltamivir acids [81]. on This a multiton methodology, scale. withThe minor synthesis modifications, of acetonide 130 has from been shikimic used foracid thewas industrialaccomplished production by treatment of oseltamivirwith TsOH and on a multiton3-pentanone, scale. Thewhile synthesis the free ofhydroxyl acetonide group130 fromwas protected shikimic acidas a wasmesylate accomplished (Ms). Trimethylsilyl by treatment withtrifluoromethanesulfonate TsOH and 3-pentanone, (TMS whileOTf) the and free borane-methyl hydroxyl group sulfide was complex protected were as aused mesylate for the (Ms). Trimethylsilylsynthesis of epoxide trifluoromethanesulfonate 131. The epoxide was (TMSOTf) opened by and azide borane-methyl to obtain compounds sulfide complex 132a and were 132b used. The for theintramolecular synthesis of epoxide reductive131 cyclization. The epoxide of 132a was and opened 132b bywas azide carried to obtainout with compounds trimethylphosphine132a and 132bin . Theanhydrous intramolecular acetonitrile reductive at 35 cyclization °C to give ofaziridine132a and 133132b whichwas was carried opened out with sodium trimethylphosphine azide and inammonium anhydrous acetonitrilechloride in dimethylformamide at 35 ◦C to give aziridine to yield133 azidoacetamidewhich was opened 134 after with acetylation sodium azide of the and ammoniumamine. Compound chloride 134 in dimethylformamidewas then treated with toRaney yield nickel azidoacetamide (Ra-Ni) under134 a hydrogenafter acetylation atmosphere, of the amine.yielding Compound oseltamivir134 withwas a thentotal treatedyield of with35%–40%. Raney Since nickel 1999 (Ra-Ni) several under groups a hydrogenhave improved atmosphere, upon yieldingthe original oseltamivir synthesis, with increasing a total yield the ofoverall 35%–40%. yield [82–89]. Since 1999 Other several research groups groups have have improved developed upon thesynthetic original strategies synthesis, starting increasing from the other overall 6-membered yield [82– 89rings.]. Other In two research examples groups of this have approach, developed syntheticHudickly strategies et al. [90] starting and Kann from and other coworkers 6-membered [91] rings.describe Ind two synthetic examples routes of this to approach,oseltamivir Hudickly using inexpensive ethyl benzoate as the starting material, and Zutter and coworkers accomplished the et al. [90] and Kann and coworkers [91] described synthetic routes to oseltamivir using inexpensive synthesis of oseltamivir starting from 2,6-dimethoxyphenol [92]. Raghavan et al. and Rohloff et al. ethyl benzoate as the starting material, and Zutter and coworkers accomplished the synthesis of reported synthetic approaches to oseltamivir using 3-cyclohexene carboxylic acid as the starting oseltamivir starting from 2,6-dimethoxyphenol [92]. Raghavan et al. and Rohloff et al. reported material [81,93], whereas a cis-1,2-dihydrodiol bromoarene was employed in the synthetic route synthetic approaches to oseltamivir using 3-cyclohexene carboxylic acid as the starting material [81,93], reported by Fang and coworkers [94]. Trost and Zhang [95] used a bicyclic lactone 135 (Scheme 17) whereaswhich acouldcis-1,2-dihydrodiol be asymmetrically bromoarene alkylated wasthrough employed the use in of the a syntheticcatalytic palladium route reported complex by Fangto andprovide coworkers a chiral [94 intermediate]. Trost and product Zhang for [95 the] usedsynthesis a bicyclic of oseltamivir. lactone 135 (Scheme 17) which could be asymmetricallyCorey and coworkers alkylated developed through a the synthetic use of route a catalytic based on palladium a Diels-Alder complex reaction. to provideThe procedure a chiral intermediatebegan with producta [4 + 2] cycloaddi for the synthesistion between of oseltamivir. 1,3-butadiene (136) and trifluoroethyl acrylate (137) using anCorey S-proline-derived and coworkers Lewis-acid developed catalyst a synthetic (138) obtaining route based 139on [96] a Diels-Alder(Scheme 18). reaction. Ammonolysis The procedure of the beganester with group a [4 of + 139 2] cycloadditionwas accomplished between by treatment 1,3-butadiene with (a136mmonia) and trifluoroethylin presence of acrylateTFA. Compound (137) using an141S-proline-derived was then produced Lewis-acid by reaction catalyst of 140 (138 with) obtaining iodine. After139 [ 96protection] (Scheme of 18 the). Ammonolysisamine with Boc, of a the esterdehydroiodination group of 139 was reaction accomplished was carried by out treatment with DBU with to give ammonia 142, which in presence was allylically of TFA. brominated Compound 141usingwas N then-bromosuccinimide produced by to reaction generate of 143140. Treatmentwith iodine. of 143 Afterwith cesium protection carbonate of the in ethanol amine withyielded Boc, a dehydroiodinationcompound 144, which reaction was was subjected carried outto a with SnBr DBU4-catalyzed to give 142bromoacetamidation, which was allylically reaction brominated using usingN-bromoacetamideN-bromosuccinimide (NBA) in to acetonitrile generate 143 at .−40 Treatment °C to obtain of 143145. withThe construction cesium carbonate of the aziridine in ethanol was performed using tetra-n-butylammonium hexamethyldisilazane and provided bicyclic product yielded compound 144, which was subjected to a SnBr4-catalyzed bromoacetamidation reaction

Molecules 2016, 21, 1513 20 of 40 using N-bromoacetamide (NBA) in acetonitrile at −40 ◦C to obtain 145. The construction of the aziridineMolecules was 2016 performed, 21, 1513 using tetra-n-butylammonium hexamethyldisilazane and provided20 of bicyclic 40 product 146. After treatment with cupric triflate and 3-pentanol at 0 ◦C, and removal of the Boc protecting146Molecules. After group, 2016 treatment, 21, oseltamivir1513 with cupric was trif afforded.late and Other3-pentanol Diels-Alder-based at 0 °C, and removal approaches of the Boc to protecting this20 molecule of 40 group, oseltamivir was afforded. Other Diels-Alder-based approaches to this molecule include that include146. that After of treatment Fukuyama with and cupric coworkers, triflate and who 3-pentanol subjected at 0 pyridine°C, and removal to a Diels-Alder of the Boc protecting reaction with of Fukuyama and coworkers, who subjected pyridine to a Diels-Alder reaction with acrylic acid acrylicgroup, acid oseltamivir derivatives was using afforded. McMillans Other Diels-Alder- catalyst [97based], while approaches Wu and to this coworkers molecule haveinclude reported that a derivatives using McMillans catalyst [97], while Wu and coworkers have reported a synthetic strategy syntheticof Fukuyama strategy and which coworkers, starts from who the subjected Diels-Alder pyridine cycloaddition to a Diels-Alder between reactionN-Boc with pyrrol acrylic andacid ethyl which starts from the Diels-Alder cycloaddition between N-Boc pyrrol and ethyl 3-bromopropyolate 3-bromopropyolatederivatives using [McMillans98], and Shibasakicatalyst [97], and while coworkers Wu and coworkers have reported have report theed synthesis a synthetic of strategy oseltamivir [98], and Shibasaki and coworkers have reported the synthesis of oseltamivir starting from fumaryl which starts from the Diels-Alder cycloadditiont between N-Boc pyrrol and ethyl 3-bromopropyolate startingchloride from and fumaryl 1-(t-butyldimethylsolix)-1,3-butadiene chloride and 1-( -butyldimethylsolix)-1,3-butadiene [99,100]. [99,100]. [98], and Shibasaki and coworkers have reported the synthesis of oseltamivir starting from fumaryl chloride and 1-(t-butyldimethylsolix)-1,3-butadiene [99,100].

Scheme 17. The synthetic approach to (−)-shikimic acid developed by Rohloff and coworkers for the Scheme 17. The synthetic approach to (−)-shikimic acid developed by Rohloff and coworkers for the synthesis of oseltamivir [81]. synthesisScheme of oseltamivir17. The synthetic [81]. approach to (−)-shikimic acid developed by Rohloff and coworkers for the synthesis of oseltamivir [81].

Scheme 18. Synthetic strategy for the synthesis of oseltamivir developed by Corey and coworkers [96]. Another approach to the synthesis of oseltamivir is based on a ring formation by a metatesis SchemeScheme 18. Synthetic 18. Synthetic strategy strategy for forthe the synthesissynthesis of of oseltamivir oseltamivir develope developedd by Corey by Corey and coworkers and coworkers [96]. [96]. reaction. This strategy was applied by Sudalai and coworkers using cis-1,4-butene diol (147) as the Another approach to the synthesis of oseltamivir is based on a ring formation by a metatesis

reaction. This strategy was applied by Sudalai and coworkers using cis-1,4-butene diol (147) as the

Molecules 2016, 21, 1513 21 of 40

Another approach to the synthesis of oseltamivir is based on a ring formation by a metatesis reaction. This strategy was applied by Sudalai and coworkers using cis-1,4-butene diol (147)Molecules as the 2016 starting, 21, 1513 material (Scheme 19)[101]. 147 was monosilylated with TBSCl21 and of 40 then treated with tert-butyl hydroperoxide (TBHP) in presence of (−)-DET to give the epoxide 148. 2,2,6,6-tetramethylpiperidinyloxystarting material (Scheme 19) [101]. (TEMPO) 147 was monosilylated was used for with the selectiveTBSCl and oxidation then treated of with the freetert-butyl hydroxyl hydroperoxide (TBHP) in presence of (−)-DET to give the epoxide 148. 2,2,6,6-tetramethylpiperidinyloxy group to yield aldehyde 149, which was subjected to allylation with ethyl 2-(bromomethyl)acrylate (TEMPO) was used for the selective oxidation of the free hydroxyl group to yield aldehyde 149, (150) and zinc to obtain 151. The hydroxyl group of 151 was then protected with MOMCl and the which was subjected to allylation with ethyl 2-(bromomethyl)acrylate (150) and zinc to obtain 151. TBS groupThe hydroxyl removed group to of yield 151 was152 then, which protected was with oxidized MOMCl with and 2-iodoxybenzoic the TBS group removed acid to (IBX) yield to 152 obtain, the aldehydewhich was153 oxidized. A Seyferth-Gilbert with 2-iodoxybenzoi homologationc acid (IBX) to was obtain performed the aldehyde to achieve153. A Seyferth-Gilbert154 and then the triplehomologation bond was reduced was performed to a double to achieve bond 154 under and then a hydrogen the triple atmosphere bond was reduced in the to presence a double ofbond Lindlar catalyst.under The a hydrogen cyclohexene atmosphere core 156 in thewas presence then constructed of Lindlar catalyst. via a metathesis The cyclohexene reaction core using156 was Grubbs’ then II catalyst.constructed Finally, via oseltamivir a metathesis was reaction achieved using using Grubbs similar’ II catalyst. conditions Finally, than oseltamivir those reported was achieved by Rohloff and coworkersusing similar [81 conditio] andns Nie than and those coworkers reported [by84 Rohloff]. A similar and co syntheticworkers [81] approach and Nie wasand coworkers reported [84]. by Kang and OhA similar [102] using syntheticcis-2,3-bis(hydroxymethyl)aziridine approach was reported by Kang and instead Oh [102] of theusing epoxide cis-2,3-bis(hydroxymethyl) derivative 148. Yao and aziridine instead of the epoxide derivative 148. Yao and Cong developed a synthetic strategy starting Cong developed a synthetic strategy starting from L-serine [103] whereas protected (S)-glutamic acid from L-serine [103] whereas protected (S)-glutamic acid was used in the synthesis of oseltamivir was used in the synthesis of oseltamivir proposed by Saicic and coworkers [104]. proposed by Saicic and coworkers [104].

SchemeScheme 19. Synthetic 19. Synthetic route route from fromcis cis-1,4-butenediol-1,4-butenediol 147 proposedproposed by by Sudalai Sudalai and and coworkers coworkers [101] [ 101for ] for the synthesisthe synthesis of oseltamivir of oseltamivir based based on on the the formation formation of the ring ring by by a ametathesis metathesis reaction. reaction.

Chai and coworkers reported a synthetic route to oseltamivir from D-ribose (157) the key step of Chai and coworkers reported a synthetic route to oseltamivir from D-ribose (157) the key step of which consists of an intramolecular metathesis reaction to afford the six-member ring (Scheme 20) [105]. whichAfter consists protection of an of intramolecular D-ribose with methanol metathesis and reaction 3-pentanone, to afford compound the six-member 158 was treated ring (Scheme with iodine 20)[ 105]. Afterin protection the presence of D of-ribose imidazole with and methanol PPh3 to and afford 3-pentanone, 159. Zn-mediated compound elimination-allylation158 was treated withof 159 iodine in theprovided presence 160 of, which imidazole was subjected and PPh to 3a metathesisto afford 159reaction. Zn-mediated using a Grubbs’ elimination-allylation II catalyst to afford 161 of. 159 providedAfter 160opening, which of the was acetonide subjected ring to with a metathesis aluminium reaction chloride, usingthe hydroxyl a Grubbs’ group II catalystlinked to toC-4 afford was 161. Afterselectively opening ofmesylated the acetonide to give ring162. withTreatment aluminium of 162 with chloride, trifluoromethanesulfonic the hydroxyl group anhydride linked toin C-4the was selectivelypresence mesylated of pyridine to allowed give 162 the. Treatmentformation of of 163162. Afterwith the trifluoromethanesulfonic introduction of an azide at anhydrideC-5, aziridine in the presence165 was of pyridine obtained allowed by reduction the formation of the azide of 163 to .the After corresponding the introduction amine ofvia an Staudinger azide at C-5, reaction aziridine followed by trimethylamine-mediated cyclization. Finally, oseltamivir was afforded according to 165 was obtained by reduction of the azide to the corresponding amine via Staudinger reaction followed conditions reported by Rohloff and coworkers [81]. A similar synthetic strategy from ribose was also by trimethylamine-mediated cyclization. Finally, oseltamivir was afforded according to conditions reported by Kongkathip and coworkers shortly after [106]. Recently, Kongkathip and coworkers have reportedagain by described Rohloff a andsynthetic coworkers route with [81 minor]. A similarmodifications synthetic using strategyD-glucose fromas the ribosestarting was material also [107]. reported

Molecules 2016, 21, 1513 22 of 40 by Kongkathip and coworkers shortly after [106]. Recently, Kongkathip and coworkers have again described a synthetic route with minor modifications using D-glucose as the starting material [107]. Molecules 2016, 21, 1513 22 of 40 Molecules 2016, 21, 1513 22 of 40

Scheme 20. Synthetic route from D-ribose (157) proposed by Chai and coworkers [105] for the synthesis Scheme 20. Synthetic route from D-ribose (157) proposed by Chai and coworkers [105] for the synthesis Schemeof oseltamivir, 20. Synthetic the key route step fromof which D-ribose consists (157 of) proposedthe formation by Chai of the and ring coworkers by a metathesis [105] for reaction. the synthesis of oseltamivir, the key step of which consists of the formation of the ring by a metathesis reaction. of oseltamivir, the key step of which consists of the formation of the ring by a metathesis reaction.

Scheme 21. Synthetic route proposed by Shie and coworkers [108] for the synthesis of oseltamivir using mannitol as the starting material and constructing the ring via a Horner-Wadsworth-Emmons SchemeSchemereaction. 21. Synthetic21. Synthetic route route proposed proposed by by Shie Shie and and coworkers coworkers [108 [108]] for for the the synthesis synthesis of oseltamivirof oseltamivir using using mannitol as the starting material and constructing the ring via a Horner-Wadsworth-Emmons mannitol as the starting material and constructing the ring via a Horner-Wadsworth-Emmons reaction. reaction.

Molecules 2016, 21, 1513 23 of 40

Shie and coworkers developed a synthetic approach based on the construction of the carbocyclic ring viaMolecules the 2016 Horner-Wadsworth–Emmons, 21, 1513 reaction [108] (Scheme 21). 1,2-Di-O-isopropylidene-23 of 40 α-D- xylofuranose (166) was treated with NH OH·HCl and pyridinium dichromate (PDC) followed by Shie and coworkers developed a synthetic2 approach based on the construction of the carbocyclic LiAlH to obtain 167, which was protected with acetic anhydride, 2,20-dimethoxypropane and ring4 via the Horner-Wadsworth–Emmons reaction [108] (Scheme 21). 1,2-Di-O-isopropylidene-α-D- benzylxylofuranose alcohol. (166) was treated with NH2OH·HCl and pyridinium dichromate (PDC) followed by LiAlH4 Theto obtain primary 167, which hydroxyl was protected group ofwith168 aceticwas anhydride, then replaced 2,2′-dimethoxypropane by ethoxycarbonylmethanephosphonic and benzyl alcohol. acid diethylThe primary ester in hydroxyl using group NaH of and 168 awas 15-crown-5 then replaced catalyst by ethoxycarbonylmethanephosphonic to give 169. An intramolecular Horner-Wadsworth-Emmonsacid diethyl ester in using reaction NaH and was a then15-crown-5 carried catalyst out to to yield give the 169 cyclohexene. An intramolecular carboxylate 170.Horner-Wadsworth-Emmons After introduction of the azidoreaction group was then in C-4,carried the out acetal to yield protecting the cyclohexene group carboxylate was removed 170. and After introduction of the azido group in C-4, the acetal protecting group was removed and C-6 was C-6 was epimerized to afford 172. 172 was reacted with Cl3C(=NH)OCHEt2 and the compound 173 epimerized to afford 172. 172 was reacted with Cl3C(=NH)OCHEt2 and the compound 173 azide was azide was reduced under a hydrogen atmosphere in presence of Lindlar catalyst to obtain oseltamivir. reduced under a hydrogen atmosphere in presence of Lindlar catalyst to obtain oseltamivir. Later, Kongkathip and coworkers [109] and Fang and coworkers [110] succeeded in performing Later, Kongkathip and coworkers [109] and Fang and coworkers [110] succeeded in performing the the ringring closureclosure byby anan intramolecularintramolecular Horner-W Horner-Wadsworth-Emmonsadsworth-Emmons reaction reaction using using mannose mannose and and N-acetylglucosamineN-acetylglucosamine as startingas starting materials, materials, respectively. respectively.

Scheme 22. Synthetic route from mannitol (174) to oseltamivir reported by Mandai and coworkers Scheme 22. Synthetic route from mannitol (174) to oseltamivir reported by Mandai and coworkers [111] [111] performing the construction of the ring via aldol condensation. performing the construction of the ring via aldol condensation. Mandai and coworkers described a synthetic route based on the same retrosynthetic analysis Mandaibut in this and case coworkers performing describedthe construction a synthetic of the ring route via basedan aldo onl condensation the same retrosynthetic [111] (Scheme 22). analysis but inMannitol this case (174 performing) was used as the the construction starting material, of the and ring transformed via an aldol into condensation the aldehyde form [111 175] (Scheme using 22). Mannitolperiodate-based (174) was usedoxidation as the [112]. starting 175 was material, treated andwith transformedvinylmagnesium into bromide the aldehyde to give form176, which175 using periodate-basedwas subjected oxidation to Claisen [112 rear].rangement175 was treated to produce with ester vinylmagnesium 177. The ester bromide was reduced to give to a176 hydroxyl, which was subjectedgroup towith Claisen DIBAL, rearrangement which was then toprotected produce with ester a 2tetrahydropyranyl177. The ester wasgroup reduced (THP) to to give a hydroxyl178. groupAD-mix- with DIBAL,β was used which to dihydroxylate was then protected 178 followed with by a 2tetrahydropyranylmesylation of the hydroxyl group groups (THP) to toobtain give 178. AD-mix-179. βThewas mesylated used to alcohols dihydroxylate were substituted178 followed for azides, by mesylationwhich were reduced of the hydroxyl to amines groupsby treatment to obtain 179. Thewith mesylatedlithium aluminium alcohols hydride were substituted (LiAlH4) to for give azides, 180. Amines which werewere reducedprotected toregioselectively amines by treatment by treatment with N-ethoxycarbonylphthalimide (PhthNCO2Et) and acetic anhydride to provide 181 with lithium aluminium hydride (LiAlH4) to give 180. Amines were protected regioselectively by treatment with N-ethoxycarbonylphthalimide (PhthNCO2Et) and acetic anhydride to provide 181 after deprotection of the THP groups. Hydroxyl groups were then oxidized to aldehydes using TEMPO. Molecules 2016, 21, 1513 24 of 40

Ring-closure was performed via an aldol condensation in presence of Bn2NH·TFA to afford 183. Finally,Molecules deprotection 2016, 21, 1513 led to oseltamivir. Later, a similar synthetic approach was reported by24the of 40 same research group using methionine as the starting material [113]. The Ko research team simplified the mannitol-basedafter deprotection synthesis of the by THP protecting groups. theHydroxyl carboxylic groups acid were of 117thenas oxidized a lactone to [aldehydes114]. A Dieckmann using condensationTEMPO. Ring-closure was used bywas Shibasaki performed andvia an coworkers aldol condensation for the in construction presence of Bn of2NH·TFA the oseltamivir to afford ring 183. Finally, deprotection led to oseltamivir. Later, a similar synthetic approach was reported by the intermediate 144 [115], which was also reported by Corey and coworkers [96]. same research group using methionine as the starting material [113]. The Ko research team simplified Ma and coworkers reported a synthetic methodology to obtain oseltamivir with ring construction the mannitol-based synthesis by protecting the carboxylic acid of 117 as a lactone [114]. A Dieckmann via Curtiuscondensation rearrangement was used by [116 Shibasaki] (Scheme and 23 coworker). (Z)-2-Nitroethenamines for the construction184 of wasthe oseltamivir treated with ring acetic anhydrideintermediate and DMAP 144 [115], yielding which was the also enamide reported185 by, Corey which and was coworkers subjected [96]. to Michael addition with 2-(pentan-3-yloxy)acetaldehydeMa and coworkers reported (186 a synthetic) using a methodology proline derivative to obtain as oseltamivir a catalyst. with Curtius ring construction rearrangement was carriedvia Curtius out rearrangemen by additiont of[116] vinylphosphonate (Scheme 23). (Z)-2-Nitroethenamine and Cs2CO3 to 184 give was188 treated, which with was acetic directly treatedanhydride with p -toluenethioland DMAP yielding to provide the enamide the corresponding 185, which was ester subjected189. to189 Michaelwas thenaddition transformed with 2-(pentan-3-yloxy)acetaldehyde (186) using a proline derivative as a catalyst. Curtius rearrangement into oseltamivir after reduction with Zn and K2CO3 treatment. Later, Šebesta and coworkers [117], Hayashiwas andcarried coworkers out by addition [118,119 of ]vinylphosphonate and Lu and coworkers and Cs2CO [1203 to] give reported 188, which similar was synthetic directly treated strategies with p-toluenethiol to provide the corresponding ester 189. 189 was then transformed into oseltamivir to obtain oseltamivir using Curtius rearrangements as key steps for the construction of ring. It is after reduction with Zn and K2CO3 treatment. Later, Šebesta and coworkers [117], Hayashi and worth mentioning that Hayashi and coworkers performed the synthesis to oseltamivir in a one-pot coworkers [118,119] and Lu and coworkers [120] reported similar synthetic strategies to obtain synthesisoseltamivir [119]. using Liu and Curtius coworkers rearrangements explored as a key synthetic steps for approach the construction using a Claisenof ring. rearrangementIt is worth for thementioning construction that Hayashi of the and oseltamivir coworkers performed ring using theD synthesis-glucal to (190 oseltamivir) as the in starting a one-pot material synthesis [121] (Scheme[119]. 24 Liu). Itand was coworkers reported explored that 190 awas synthetic synthetized approach from using glucose a Claisen although rearrangement reaction for conditions the of thisconstruction transformation of the oseltamivir are not mentioned. ring using D-glucal Fully (190 protected) as the startingD-glucal material was [121] achieved (Scheme by 24). formation It was of a 4,6-benzylidenereported that 190 acetal was synthetized in presence from of pyridiniumglucose althoughp-toluenesulfonate reaction conditions (PPTS) of this transformation and silylation are of the 3-hydroxylnot mentioned. group, followedFully protected by treatment D-glucal withwas achieved diisobutylaluminium by formation of hydride a 4,6-benzylidene (DIBAL-H) acetal to free in the primarypresence alcohol of pyridinium191. The primaryp-toluenesulfonate hydroxyl (P groupPTS) and of silylation191 was of oxidized the 3-hydroxyl to the group, aldehyde followed by using by treatment with diisobutylaluminium hydride (DIBAL-H) to free the primary alcohol 191. The Dess-Martin periodinane and then subjected to Wittig methylenation to provide terminal olefin primary hydroxyl group of 191 was oxidized to the aldehyde by using Dess-Martin periodinane and 192. The Claisen rearrangement reaction was performed at 210 ◦C in diphenyl ether to yield 193. then subjected to Wittig methylenation to provide terminal olefin 192. The Claisen rearrangement The oxidationreaction was of 193performedto ethyl at ester 210 °C194 inwas diphenyl carried ether out to by yield using 193 NaClO. The oxidation2/NaH 2ofPO 1934 in to theethyl presence ester of 2-methyl-2-butene,194 was carried followed out by using by esterification NaClO2/NaH with2PO4 ethylin the iodide.presence 2,3-Dichloro-5,6-dicyanobenzoquinone of 2-methyl-2-butene, followed by (DDQ)esterification was used towith selectively ethyl removeiodide. the2,3-Dichloro PMB protecting-5,6-dicyanobenzoquinone group to provide 195(DDQ). Then, was transformation used to into compoundselectively remove196 was the carried PMB protecting out with trichloroacetylgroup to provide isocyanate 195. Then, and transformation potassium into carbonate. compound196 was treated196 with was (CuOTf)carried out2-toluene with trichloroacetyl and TMSN isocyanate3 to give 197 and. Treatmentpotassium carbonate. of 197 with 196 DBU was treated followed with by the (CuOTf)2-toluene and TMSN3 to give 197. Treatment of 197 with DBU followed by the addition of addition of Cs2CO3 provided compound 199 which was subjected to treatment with Dess-Martin Cs2CO3 provided compound 199 which was subjected to treatment with Dess-Martin periodinane and periodinane and then LiAlH(OtBu)3 to promote inversion of configuration at C-3. 201 was generated then LiAlH(OtBu)3 to promote inversion of configuration at C-3. 201 was generated by treatment with by treatment with MsCl/Et3N followed by 3-pentanol/BF3·Et2O. Finally, oseltamivir was obtained MsCl/Et3N followed by 3-pentanol/BF3·Et2O. Finally, oseltamivir was obtained after reduction of the after reduction of the azido group with PPh3 in tetrahydrofuran (THF)/H2O. azido group with PPh3 in tetrahydrofuran (THF)/H2O.

Scheme 23. Synthetic route to oseltamivir based on ring construction via a Curtius rearrangement Scheme 23. Synthetic route to oseltamivir based on ring construction via a Curtius rearrangement reported by Ma and coworkers [116]. reported by Ma and coworkers [116].

Molecules 2016, 21, 1513 25 of 40

Molecules 2016, 21, 1513 25 of 40

Scheme 24. Synthetic route to oseltamivir by Liu and coworkers [121]. The oseltamivir ring was Scheme 24. Synthetic route to oseltamivir by Liu and coworkers [121]. The oseltamivir ring was afforded by a Claisen rearrangement. afforded by a Claisen rearrangement. 3.2. C-1 Modifications 3.2. C-1 Modifications Oseltamivir phosphonate (202, Figure 4A), also called tamiphosphor, was synthesized by Shie Oseltamivirand coworkers phosphonate using the same (202, Figuresynthetic4A), strategy also called reported tamiphosphor, for the synthesis was synthesized of oseltamivir by Shie via and coworkersintramolecular using the Horner-Wadsworth-Emmons same synthetic strategy reported reaction for [108], the synthesis with the ofsole oseltamivir difference viabeing intramolecular that the Horner-Wadsworth-Emmonsprimary alcohol is substituted reaction with CH [1082(PO(OEt)], with2 the)2 rather sole differencethan(EtO2CCH being2PO(OEt) that the2), resulting primary in alcohol a is substitutedphosphonate with ester CH in2(PO(OEt) place of the2)2 carboxylaterather than(EtO ester. Inhibitory2CCH2PO(OEt) activity2 ),screening resulting revealed in a phosphonate that the esterphosphonate in place of theanalogue carboxylate is a more ester. potent Inhibitory inhibitor activity against screeningH1N1 and revealedH5N1 neuraminidases that the phosphonate than analogueoseltamivir is a more [108]. potent Gunasekera inhibitor [122] against and H1N1Streiche andr [123] H5N1 have neuraminidases both reported than the oseltamivirsynthesis of [ 108]. tamiphosphor from oseltamivir. Lesnikowski and coworkers reported a synthetic approach to Gunasekera [122] and Streicher [123] have both reported the synthesis of tamiphosphor from achieve an oseltamivir derivative bearing a boron cluster on C-1 (203) [124] (Figure 4B). After the oseltamivir. Lesnikowski and coworkers reported a synthetic approach to achieve an oseltamivir ester hydrolysis of compound 134, the acid was treated with 1-(3hydroxypropyl)-1,12-dicarba-closo- derivative bearing a boron cluster on C-1 (203)[124] (Figure4B). After the ester hydrolysis of compound dodecaborane in the presence of DCC, and the resulting azide reduced with PPh3 to provide the 134, thedesired acid derivative was treated 203. withKanai 1-(3hydroxypropyl)-1,12-dicarba-closo-dodecaborane and Saito reported the synthesis of a bicyclic oseltamivir analogue in the 204 presence [125] of DCC,(Figure and the 4C), resulting which was azide achieved reduced after with functionalization PPh3 to provide of the the C-7-H desired bond derivative with a Ru203 catalyst. Kanai and and the Saito reportedsubsequent the synthesis addition of of a olefins. bicyclic Stankova oseltamivir and cowo analoguerkers explored204 [125 the] (Figure synthesis4C), of whichoseltamivir was esters achieved after functionalizationof amino acids 4-F-phenylalanine of the C-7-H ( bondR,S) and with glycine a Ru [126]. catalyst The and resulting the subsequent oseltamivir additionderivative ofwith olefins. Stankova4-F-phenylalanine and coworkers (R) ( explored205, Figure the 4D) synthesis could successfully of oseltamivir inhibit the esters influenza of amino virus acids in a cell 4- Fbased-phenylalanine assay. (R,S) and glycine [126]. The resulting oseltamivir derivative with 4-F-phenylalanine (R)(205, Figure4D) could successfully inhibit the influenza virus in a cell based assay.

Molecules 2016, 21, 1513 26 of 40 Molecules 2016, 21, 1513 26 of 40

Molecules 2016, 21, 1513 26 of 40

Figure 4. C-1 modified oseltamivir analogues. (A) Tamiphosphor (202) [108]; (B) Oseltamivir bearing a Figure 4. C-1 modified oseltamivir analogues. (A) Tamiphosphor (202)[108]; (B) Oseltamivir bearing boron cluster reported by Lesnikowski and coworkers [124] (203); (C) A bicyclic derivative of oseltamivir a boronFigure cluster4. C-1 modified reported oseltamivir by Lesnikowski analogues. and (A coworkers) Tamiphosphor [124 ]((202203) [108];); (C )(B A) Oseltamivir bicyclic derivative bearing a of synthesized by Kanai and Saito [125] (204); (D) A 4-F-phenylalanine (R) derived oseltamivir analogue oseltamivirboron cluster synthesized reported by Lesn Kanaiikowski and Saito and [coworkers125](204); [124] (D) A(203 4-);F -phenylalanine(C) A bicyclic derivative (R) derived of oseltamivir oseltamivir (205). analoguesynthesized (205 ).by Kanai and Saito [125] (204); (D) A 4-F-phenylalanine (R) derived oseltamivir analogue (205). 3.3. C-4 Modifications 3.3. C-4 Modifications 3.3. C-4Lederkremer Modifications and coworkers described the enzymatic synthesis of oseltamivir C-4 lactose Lederkremer and coworkers described the enzymatic synthesis of oseltamivir C-4 lactose analogues [127]. Two different approaches were used to link the amino group of oseltamivir to analoguesLederkremer [127]. Two and different coworkers approaches described were the enzy usedmatic to link synthesis the amino of os groupeltamivir of oseltamivirC-4 lactose to lactose and lactobionolactone. The linkage with lactose was performed by reductive amination of its lactoseanalogues and lactobionolactone. [127]. Two different The approaches linkage with were lactose used wasto link performed the amino by reductivegroup of oseltamivir amination ofto its lactosereducing and end lactobionolactone. with oseltamivir Thein the linkage presence with of lactose NaBH 3wasCN toperformed provide 206by reductive(Scheme 25A). amination The amide of its reducingformation end between with oseltamivir the carboxyl in thegroup presence of lactobio of NaBHnolactone3CN and to provide the amino206 group(Scheme of oseltamivir 25A). The amidewas reducing end with oseltamivir in the presence of NaBH3CN to provide 206 (Scheme 25A). The amide formation between the carboxyl group of lactobionolactone and the amino group of oseltamivir formationperformed between at 120 °C the (pH carboxyl 7) to yield group 207 of (Scheme lactobio nolactone25B). The andtrans the-sialidase amino ofgroup the protozoanof oseltamivir parasite was was performed at 120 ◦C (pH 7) to yield 207 (Scheme 25B). The trans-sialidase of the protozoan performedTrypanosoma at cruzi 120 , °Cwhich (pH allows7) to yield the enzymatic 207 (Scheme addition 25B). ofThe α (2,3)-linkedtrans-sialidase sialyl of residuesthe protozoan to the terminalparasite parasite Trypanosoma cruzi, which allows the enzymatic addition of α(2,3)-linked sialyl residues to TrypanosomaD-galactopyranosyl cruzi, which units allows of mucins, the enzymatic was used addition to study of αthe(2,3)-linked inhibitory sialyl activity residues of the to theoseltamivir terminal theanalogues. terminal DBoth-galactopyranosyl 206 and 207 demonstrated units of mucins, to be was stronger used to inhibitors study the than inhibitory oseltamivir activity against of the D-galactopyranosyl units of mucins, was used to study the inhibitory activity of the oseltamivir 206 207 oseltamiviranalogues.Trypanosoma analogues. Both cruzi 206neuraminidase, and Both 207 demonstratedand while thedemonstrated inhibitory to be strongeractivities to be inhibitors strongerof 206 and inhibitors than207 were oseltamivir inferior than oseltamivir toagainst those againstTrypanosomashownTrypanosoma by lactitol cruzi andneuraminidase, cruzi lactobionolactone.neuraminidase, while whilethe inhibitory the inhibitory activities activities of 206 and of 206 207and were207 inferiorwere inferiorto those to thoseshown shown by lactitol by lactitol and andlactobionolactone. lactobionolactone.

Scheme 25. The synthetic approach described by Lederkremer and coworkers to access oseltamivir C-4 lactose analogues [127]. (A) Synthetic route to oseltamivir analogue 206. (B) Synthetic route to Scheme 25. The synthetic approach described by Lederkremer and coworkers to access oseltamivir oseltamivir analogue 207. SchemeC-4 lactose 25. The analogues synthetic [127]. approach (A) Synthetic described route by to Lederkremer oseltamivir analogue and coworkers 206. (B) to Synthetic access oseltamivir route to C-4oseltamivir lactose analogues analogue [207127.]. (A) Synthetic route to oseltamivir analogue 206.(B) Synthetic route to oseltamivirChochkova analogue and coworkers207. reported a synthetic approach to obtain oseltamivir amino acids conjugatesChochkova using andAc-Cys-OH, coworkers Fmoc-Tyr( reportedt Bu)-OHa synthetic and approachBoc-His(DNP)-OH to obtain asoseltamivir building blaminoocks [128].acids conjugatesTheChochkova C-termini using andof Ac-Cys-OH, coworkersthese compounds Fmoc-Tyr( reported weretBu)-OH a synthetic amid andated approachBoc-His(DNP)-OH with the to obtainamine as oseltamivir ofbuilding oseltamivir blocks amino using[128]. acids conjugatesThe(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide C-termini using Ac-Cys-OH,of these compounds Fmoc-Tyr( weretBu)-OH amid (E andDC)/HOBt.ated Boc-His(DNP)-OH with Martinthe amine and ascoworkersof buildingoseltamivir reported blocks using [an128 ]. The(1-ethyl-3-(3-dimethylaminopropyl)carbodiimideeasy C-termini synthetic approach of these to compounds C-4 guanidine were (210, Scheme amidated (EDC)/HOBt. 26A) with and MartinN the-substituted amine and coworkers guanidine of oseltamivir reported oseltamivir usingan analogues (213a–h, Scheme 26B) starting from oseltamivir in a similar approach [129]. The (1-ethyl-3-(3-dimethylaminopropyl)carbodiimideeasy synthetic approach to C-4 guanidine (210, Scheme (EDC)/HOBt. 26A) and N-substituted Martin and guanidine coworkers oseltamivir reported analogues (213a–h, Scheme 26B) starting from oseltamivir in a similar approach [129]. The

Molecules 2016, 21, 1513 27 of 40 an easy synthetic approach to C-4 guanidine (210, Scheme 26A) and N-substituted guanidine oseltamivir analogues (213a–h, Scheme 26B) starting from oseltamivir in a similar approach [129]. Molecules 2016, 21, 1513 27 of 40 The unsubstituted oseltamivir analogue 210 was obtained after reaction of oseltamivir with 208 and the subsequentunsubstituted deprotection oseltamivir analogue of the guanidine 210 was obtained and carboxylic after reaction groups. of oseltamivir For the synthesiswith 208 and of the213a –h, oseltamivirsubsequent was deprotection treated with ofN the-benzyloxycarbonyl guanidine and carboxylic isothiocyanate groups. (CbzNCS)For the synthesis to yield of thiourea213a–h, 211. The reactionoseltamivir between was treated211 and with different N-benzyloxycarbonyl amines and isothiocyanate subsequentdeprotection (CbzNCS) to yield of the thiourea guanidine 211. and carboxylicThe reaction acid groups between provided 211 and differentN-substituted amines and guanidine subsequent oseltamivir deprotection analogues of the guanidine213a–h. and210 was showncarboxylic to be capableacid groups of provided enhanced N-substituted the inhibitory guanidine activity oseltamivir against analogues H1N1 213a (A/California/04/2009),–h. 210 was shown H1N1tomutant be capable H274Y of enhanced (A/California/04/2009), the inhibitory activity H5N1 against (A/Anhui/1/2005) H1N1 (A/California/04/2009), and H5N1 H1N1 mutant mutant H274Y (A/Anhui/1/2005).H274Y (A/California/04/2009), This result H5N1 mirrors (A/Anhui/1/2005) the effect ofand the H5N1 guanidine mutant H274Y modification (A/Anhui/1/2005). observed in This result mirrors the effect of the guanidine modification observed in zanamivir [3,39,40]. While zanamivir [3,39,40]. While N-substituted guanidine oseltamivir analogues 213a and 213h showed N-substituted guanidine oseltamivir analogues 213a and 213h showed enhanced inhibitory activity enhancedin comparison inhibitory with activity oseltamivir in comparison against the with above oseltamivir mentioned againstinfluenza the virus above strains, mentioned they showed influenza virusless strains, inhibitory they showedactivity than less compound inhibitory 210 activity. than compound 210.

Scheme 26. Synthetic routes to oseltamivir analogues bearing a guanidine group linked to C-4. Scheme 26. Synthetic routes to oseltamivir analogues bearing a guanidine group linked to (A) Synthetic approach to C-4 guanidine (210). (B) N-substituted guanidine oseltamivir analogues C-4. (A) Synthetic approach to C-4 guanidine (210); (B) N-substituted guanidine oseltamivir (213a–h) starting from oseltamivir reported by Martin and coworkers [129]. analogues (213a–h) starting from oseltamivir reported by Martin and coworkers [129]. 3.4. C-5 Modifications 3.4. C-5 Modifications Zanardi and coworkers reported a synthetic strategy for the synthesis of 5-epi-oseltamivir 225 [130] Zanardi(Scheme 27). and Pyrrole coworkers 214, D-mannitol-derived reported a synthetic glyceraldehyde strategy 215 for andthe O-anisidine synthesis 216 ofwere 5-epi-oseltamivir used for the 225 [130production] (Scheme of compound 27). Pyrrole 217 through214, D a-mannitol-derived Mukaiyama-Mannich glyceraldehyde reaction performed215 at 30and °C Oin-anisidine water. 217 216 werewas used subjected for the productionto catalytic hydrog of compoundenolysis over217 Pd/C,through and a the Mukaiyama-Mannich resulting compound was reaction protected performed by at 30treatment◦C in water. with 3-pentanone217 was subjected and camphorsulfonic to catalytic acid hydrogenolysis (CSA) to provide over 218. Pd/C,After protection and the of resulting the compoundamide waswith protecteda benzyl group, by treatment ring-opening with 3-pentanoneof the ketal was and achieved camphorsulfonic using BH3·Me acid2SO/TMSOTf (CSA) to provide in THF. The primary alcohol of 219 was oxidized by treatment with Dess-Martin periodinane to obtain 218. After protection of the amide with a benzyl group, ring-opening of the ketal was achieved using 220, which was subjected to an intramolecular aldol cyclization in the presence of TBSOTf/iPr2EtN to BH ·Me SO/TMSOTf in THF. The primary alcohol of 219 was oxidized by treatment with Dess-Martin 3 produce2 221. After removal of the amine protecting groups by treatment with sodium in ammonia and periodinanewith trichloroisocyanuric to obtain 220, which acid (TCCA) was subjected and subsequent to an intramolecularprotection as acetate aldol and cyclization Boc, fluoride-promoted in the presence of TBSOTf/O-desilylationiPr2EtN and to producemesylation221 transformed. After removal 223 into of the lactam amine 224 protecting. Finally, treatment groups by with treatment lithium with sodiumhydroxide in ammonia led to a and monocyclic with trichloroisocyanuric carboxylate, and removal acid (TCCA) of the Boc and protecting subsequent group protection and elimination as acetate and Boc,gave fluoride-promoted 225. This compoundO -desilylationshowed a much and lower mesylation inhibitory transformed activity against223 into H1N1 lactam and224 H3N2. Finally, treatmentinfluenza with neuraminidases lithium hydroxide than ledoseltamivir. to a monocyclic De-Eknamkul carboxylate, and coworkers and removal developed of the a Boc synthetic protecting groupapproach and elimination to 5-amino gave derivatives225. This from compound quinic acid showed[131], following a much the lower synthetic inhibitory strategy activity described against H1N1by and Rolhoff H3N2 and influenza coworkers neuraminidases [81]. Azide 134 than was oseltamivir.acylated with De-Eknamkul acrylic acid or and crotonic coworkers acid and developed the azido group was reduced to amino group. These compounds showed similar inhibitory activities a synthetic approach to 5-amino derivatives from quinic acid [131], following the synthetic strategy compared to oseltamivir. described by Rolhoff and coworkers [81]. Azide 134 was acylated with acrylic acid or crotonic acid and

Molecules 2016, 21, 1513 28 of 40 the azido group was reduced to amino group. These compounds showed similar inhibitory activities compared to oseltamivir. Molecules 2016, 21, 1513 28 of 40

Scheme 27. The synthetic route to 5-epi-oseltamivir (225) reported by Zanardi and coworkers [130]. Scheme 27. The synthetic route to 5-epi-oseltamivir (225) reported by Zanardi and coworkers [130].

3.5. C-63.5. C-6 Modifications Modifications Šebesta and coworkers described the synthesis of oseltamivir bearing a benzyloxy group or a Šebesta and coworkers described the synthesis of oseltamivir bearing a benzyloxy group or a p-methoxybenzyloxy group at the C-6 position [117]. The synthetic approach used was similar to p-methoxybenzyloxy group at the C-6 position [117]. The synthetic approach used was similar to that reported by Ma and coworkers, i.e., via a Curtius rearrangement but using the benzyloxy and thatp reported-methoxybenzyloxy by Ma and deri coworkers,vatives of aldehyde i.e., via a 186 Curtius [116]. rearrangement but using the benzyloxy and p-methoxybenzyloxy derivatives of aldehyde 186 [116]. 4. Peramivir 4. Peramivir Peramivir, also known by its trade names Rapivab, Rapiacta or Peramiflu, is the latest commercializedPeramivir, also drug known for the by treatment its trade of influenza. names Rapivab, Peramivir Rapiactais administered or Peramiflu, intravenously is the[21]. latestIt commercializedwas developed drug by forstructure-activity the treatment ofrelationship influenza. (SAR) Peramivir studies is administeredof oseltamivir, intravenously which led to[ 21]. It wasmodifications developed including by structure-activity contraction of the relationship 6-membered (SAR)ring to studies a 5-membered of oseltamivir, ring [132]. whichInhibitory led to modificationsstudies have including revealed that contraction peramivir ofshowes the 6-membered higher inhibition ring towards to a 5-membered H1N1 influenza ring neuraminidase [132]. Inhibitory studiesin comparison have revealed to thatzanamivir peramivir andshowes oseltamivir higher [133–136]. inhibition As towards this compound H1N1 influenza was only neuraminidase recently in comparisonapproved in to the zanamivir USA (2014) and and oseltamivir in Japan and [133 South–136]. Korea As this (2015), compound few synthetic was only routes recently to peramivir approved in theor its USA derivatives (2014) and have in been Japan reported and Southto date. Korea (2015), few synthetic routes to peramivir or its derivatives have been reported to date. 4.1. Synthesis of Peramivir 4.1. SynthesisAll reported of Peramivir synthetic routes are based on the same retrosynthetic approach, using (−)-(1R,4S)-2- azabicyclo(2.2.1)hept-5-en-3-one (226) or derivative 232 as precursors. Babu and coworkers described the All reported synthetic routes are based on the same retrosynthetic approach, using (−)-(1R,4S)-2- first synthetic route to peramivir (Scheme 28) [132]. The opening of lactam ring 226 was achieved azabicyclo(2.2.1)hept-5-en-3-onethrough hydrochloric acid treatment. (226) or After derivative protection232 ofas the precursors. amine with Babu Boc, and227 was coworkers subjected described to a the first[3 + 2] synthetic cycloaddition route with to peramivir 2-ethyl-1-nitrobutane (Scheme 28)[ in132 presence]. The of opening phenyl ofisocyanate lactam ring to obtain226 was 228. achieved PtO2

Molecules 2016, 21, 1513 29 of 40 through hydrochloric acid treatment. After protection of the amine with Boc, 227 was subjected to a [3 +Molecules 2]Molecules cycloaddition 2016 2016, 21, ,21 1513, 1513 with 2-ethyl-1-nitrobutane in presence of phenyl isocyanate to obtain29228 of29 40 of. PtO 40 2 catalyzed hydrogenolysis and subsequent protection using acetic anhydride yielded compound 229. catalyzed hydrogenolysis and subsequent protection using acetic anhydride yielded compound 229. Aftercatalyzed removal hydrogenolysis of Boc, the corresponding and subsequent amine protection was furtherusing acet reactedic anhydride with pyrazolecarboxamide yielded compound 229 and. After removal of Boc, the corresponding amine was further reacted with pyrazolecarboxamide and thenAfter hydrolysed removal inof presenceBoc, the corresponding of NaOH to give amine peramivir was further with areacted 21% total with yield. pyrazolecarboxamide Later, Jia and coworkers and thenthen hydrolysed hydrolysed in in presence presence ofof NaOHNaOH toto givegive peramivir withwith aa 21%21% total total yield. yield. Later, Later, Jia Jiaand and improved this synthetic route, increasing the overall yield to 34% [137]. coworkerscoworkers improved improved this this synt synthetichetic route, route, increasingincreasing the overalloverall yield yield to to 34% 34% [137]. [137].

Scheme 28. The synthetic route to peramivir using lactam 226 as the starting material reported by Scheme 28. The synthetic route to peramivir using lactam 226 as the starting material reported by Babu and coworkers [132]. BabuScheme and coworkers28. The synthetic [132]. route to peramivir using lactam 226 as the starting material reported by Babu and coworkers [132]. Miller and Mineno developed a synthetic approach starting from Boc-protected hydroxylamine Miller(230) which and was Mineno subjected developed to a Diels-Alder a synthetic reaction approach with cyclopentadiene starting from (231 Boc-protected) to give 232 (Scheme hydroxylamine 29) Miller and Mineno developed a synthetic approach starting from Boc-protected hydroxylamine (230)[138]. which After was ring subjected opening of to lactam a Diels-Alder 232 via Mo(CO) reaction6 treatment, with cyclopentadienethe resulting compound (231) 233 to givewas 232 (230) which was subjected to a Diels-Alder reaction with cyclopentadiene (231) to give 232 (Scheme 29) (Schemereacted 29)[ with138 ].ethyl After chloroformate ring opening to ofyield lactam 234. 232Thisvia was Mo(CO) then treated6 treatment, with MeNO the resulting2 and a catalytic compound [138]. After ring opening of lactam 232 via Mo(CO)6 treatment, the resulting compound 233 was 233 wasquantity reacted of Pd(0) with to ethyl obtain chloroformate nitro compound to 235 yield, which234 was. This transformed was then into treated the carboxylic with MeNO acid 2byand a reacted with ethyl chloroformate to yield 234. This was then treated with MeNO2 and a catalytic catalyticemploying quantity a mixture of Pd(0) of toNaNO obtain2 and nitro AcOH compound in DMF, followed235, which by wastreatment transformed with a catalytic into the amount carboxylic quantityof TMSCl of Pd(0)in MeOH to obtain to give nitro compound compound 236. The 235 remaining, which was steps transformed were carried into out the in acarboxylic similar manner acid by acid by employing a mixture of NaNO2 and AcOH in DMF, followed by treatment with a catalytic employingto that described a mixture by ofBabu NaNO and 2co andworkers AcOH to inyield DMF, peramivir followed [132]. by treatment with a catalytic amount amountof TMSCl of TMSCl in MeOH in MeOHto give tocompound give compound 236. The236 remaining. The remaining steps were steps carried were out carried in a similar out in manner a similar mannerto that to described that described by Babu by and Babu coworkers and coworkers to yield toperamivir yield peramivir [132]. [132].

Scheme 29. Synthetic route to peramivir using a lactam (232) precursor, as reported by Miller and Mineno [138].

Scheme Scheme 29. 29.Synthetic Synthetic route routeto toperamivir peramivir using a lactam ( (232232) )precursor, precursor, as as reported reported by by Miller Miller and and MinenoMineno [138 [138].].

Molecules 2016, 21, 1513 30 of 40

4.2. C-4 Modifications Wulff and coworkers carried out a study on the inhibitory activity of de-guanidinylated peramivir analogue [139], with the results suggesting that the lack of the guanidine group in the peramivir structure had no effect on the inhibitory activity against H1N1 neuraminidases. The synthesis of the de-guanidinylated analogue was carried out according to conditions reported by Mineno and coworkers [138].

4.3. C-5 Modifications Chand and coworkers reported a synthetic approach allowing access to C-5 and C-6 modified peramivir derivatives (Scheme 30)[140]. The synthesis began with 4-bromocyclopenten-2-one (237), which was converted to 238 using sodium azide. Reaction of 238 with the sodium salt of diethyl acetamidomalonate in ethanol at −40 ◦C gave the 1,4-adduct 239. The azido group of 239 was then converted into the Boc-protected amine 240. Treatment of 240 with trimethysilyl 1,3-dithiane and n-butyllithium resulted in the formation of compound 241. After hydrolysis of the ester groups, compound 242 was treated with ethyl chloroformate and triethylamine and then allowed to react with N,O-dimethylhydroxylamine to give methylamide 243. Reduction of this compound with lithium tri-tert-butoxyaluminohydride (LTBA) gave aldehyde 244, which was subjected to a Wittig reaction using propyltriphenylphosphonium bromide and sodium hexamethyl disilane (NaHMDS) to give 245. After deprotection with methanolic HCl and TFA, the resulting amine was treated with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (5) in the presence of HgCl2 to give 247. Hydrolysis of the methyl ester was followed by removal of the Boc groups to obtain 248. The hydrogenation of the double bond of 248 in the presence of platinum (IV) oxide led to peramivir analogue 249. Inhibitory activity studies revealed that the inhibitory activity of 249 was no greater than that of oseltamivir or zanamivir towards influenza A and influenza B neuraminidases (serotypes not specified). A synthesis of the trisubstituted cyclopentane 255 starting from 4β-acetyloxy-3β- carboxycyclopentane-1β-carboxylate (250) was reported by Hronowski and Szarek (Scheme 31)[141]. The carboxyl group of 250 was reduced to hydroxymethyl with sodium borohydride and the acetate group was removed with sodium methoxide in methanol. After hydrolysis of the methyl ester, both hydroxyl groups of 251 were replaced with azide groups using hydrazoic acid, diethyl azodicarboxylate (DEAD) and tetraphenylprofyrin (TPP) to give the methyl ester 253. The reduction of the azido group was performed under hydrogen atmosphere in presence of a catalytic amount of palladium on carbon to provide the corresponding amine. The selective acetylation of the aminomethyl group was carried out by treatment with acetic anhydride at 0 ◦C leading to compound 254. Guanylation and subsequent Boc deprotection was achieved as described above in Scheme 30 to obtain 255. This compound showed low inhibitory activities in comparison with zanamivir and olsetamivir against influenza A and influenza B neuraminidases (serotypes not specified). A stereodivergent synthesis to C-2, C-5 and C-6 modified peramivir derivatives was reported in another work by Chand and coworkers [142], using cyclopentanone 240 as starting material. For the synthesis of derivatives 260a and 260b (Scheme 32), attack by deprotonated tris(methylthio)methane on 240 yielded compound 256, which was then converted to 257 by treatment with NaOH. The formation of the amide was carried out using either diethylamide or dipropylamide to obtain compounds 258a and 258b, respectively, which were then converted to the methyl esters 259a and 259b by treatment with methanol and mercury (II) chloride. After removal of the Boc groups with TFA, guanylation and ester hydrolysis were performed as described before (Scheme 30) to yield peramivir analogues 260a and 260b. The C-2 diastereoisomer of compound 260b was synthesized by changing the order of the guanylation and tris(methylthio)methane addition steps. The screening of the inhibitory activities revealed that the introduction of an N,N-substituted amide on the C-5 side-chain as well as the introduction of a hydroxyl group in C-2 has an adverse effect on the inhibitory activity against influenza A neuraminidase. Molecules 2016, 21, 1513 31 of 40

Molecules 2016, 21, 1513 31 of 40 Molecules 2016, 21, 1513 31 of 40

Scheme 30. Synthetic route for peramivir analogue 249 reported by Chand and coworkers [140]. Scheme 30. Synthetic route for peramivir analogue 249 reported by Chand and coworkers [140]. Scheme 30. Synthetic route for peramivir analogue 249 reported by Chand and coworkers [140].

Scheme 31. Synthetic route to peramivir analogue 255 reported by Hronowski and Szarek [141]. Scheme 31. Synthetic route to peramivir analogue 255 reported by Hronowski and Szarek [141]. Scheme 31. Synthetic route to peramivir analogue 255 reported by Hronowski and Szarek [141].

Molecules 2016, 21, 1513 32 of 40

Molecules 2016, 21, 1513 32 of 40

Molecules 2016, 21, 1513 32 of 40

Scheme 32. Synthetic route to peramivir analogues 261a and 261b reported by Chand and coworkers [142]. Scheme 32. Synthetic route to peramivir analogues 261a and 261b reported by Chand and coworkersChand [142 and]. coworkers described another synthetic route to C-5 modified peramivir analogues using an ethylated compound 227 (261) as starting material (Scheme 33A) [134]. The synthesis was Scheme 32. Synthetic route to peramivir analogues 261a and 261b reported by Chand and coworkers [142]. Chandperformed and in coworkers a similar way described to that anotherreported syntheticby Babu and route coworkers to C-5 modified [132]. Compound peramivir 261 analogues was usingallowed anChand ethylated to reactand compoundcoworkerswith 1-nitro-3- described227n-propylpentane(261 )another as starting syntheti to afford materialc route 262. (Scheme Thisto C-5 was modified then33A) stirred [134 peramivir]. under The synthesishydrogenanalogues was performedusingatmosphere an in ethylated a similar in the compound way presence to that 227of reported (platinum261) as by starting Babu(IV) andoxidematerial coworkers to (Schemeyield [263132 33A), ].which Compound [134]. was The treatedsynthesis261 was with allowedwas performedthiocarbonyldiimidazole in a similar way to provide to that 264 reported. by Babu and coworkers [132]. Compound 261 was to react with 1-nitro-3-n-propylpentane to afford 262. This was then stirred under hydrogen atmosphere allowed to react with 1-nitro-3-n-propylpentane to afford 262. This was then stirred under hydrogen in the presence of platinum (IV) oxide to yield 263, which was treated with thiocarbonyldiimidazole to atmosphere in the presence of platinum (IV) oxide to yield 263, which was treated with provide 264. thiocarbonyldiimidazole to provide 264.

Scheme 33. Synthesis of C-5 modified peramivir analogues. (A) The synthetic route to peramivir analogue 266 reported by Chand and coworkers [134]; (B) Peramivir derivative 267 synthetized by Chand and coworkers [134]; (C) Peramivir derivative 268 studied by Smee and coworkers [136].

Scheme 33. Synthesis of C-5 modified peramivir analogues. (A) The synthetic route to peramivir Scheme 33. Synthesis of C-5 modified peramivir analogues. (A) The synthetic route to peramivir analogue 266 reported by Chand and coworkers [134]; (B) Peramivir derivative 267 synthetized by analogue 266 reported by Chand and coworkers [134]; (B) Peramivir derivative 267 synthetized by Chand and coworkers [134]; (C) Peramivir derivative 268 studied by Smee and coworkers [136]. Chand and coworkers [134]; (C) Peramivir derivative 268 studied by Smee and coworkers [136].

Molecules 2016, 21, 1513 33 of 40

Compound 264 was then subjected to a free radical reaction with (nBu)3SnH and AIBN to give 265. After deprotection, peramivir analogue 266 was obtained. Peramivir derivative 267 (Scheme 33B) was synthetized using the same synthetic strategy but maintaining the C-5 linked hydroxyl group. In vivo inhibitory activity tests of compounds 266 and 267 had similar or better inhibitory efficacy in comparison with zanamivir and oseltamivir when given orally or intranasally. In another study, Smee and coworkers studied [136] the inhibitory activity of cyclopentane derivatives 266, 267 and 268 (Scheme 33C) [136]. All analogues showed similar inhibitory activities in comparison to peramivir and displayed greater inhibitory activity than oseltamivir or zanamivir.

5. Conclusions Neuraminidase inhibitors have evolved from DANA to zanamivir through the introduction of a guanidine group to the C-4 position; from zanamivir to laninamivir by methylation of the C-7 hydroxyl group; to oseltamivir by modifying the heterocycle to a carbocycle; and from oseltamivir to peramivir by contraction of the 6-membered ring to 5-membered ring. Several of the derivatives described here showed increased inhibitory potential in comparison to their predecessor compounds. The synthesis of zanamivir has been performed either starting from a pyranose ring structure such as Neu5Ac or D-glucono-δ-lactone, or by formation of the pyranose ring through a Henry reaction or nucleophilic substitution. Among the modifications to the zanamivir core, the replacement of the carboxylic acid moiety for a phosphonate group has been demonstrated to increase inhibitory activity against H1N1, H3N2 and H5N1 influenza neuraminidases whereas the esterification of the carboxylic acid has in every case resulted in reduced inhibitory potential. To our knowledge, modifications at C-2 and C-3 have never been studied. Inhibitory activity could not be enhanced by performing modifications on C-4, C-5, C-6 or C-9, while modifications at C-7 have been shown to be capable of enhancing the inhibitory activity of zanamivir. The C-7 methoxy zanamivir derivative laninamivir showed much higher inhibitory activity against influenza B neuraminidase than zanamivir. Linking zanamivir to polymers or the formation of C-7 linked zanamivir dimers has resulted in interesting compounds with higher inhibitory activity in comparison with zanamivir. Lower inhibitory activities were detected in derivatives with modifications to the C-6-glycerol side-chain. The synthesis of oseltamivir has been thoroughly studied and five different retrosynthetic analyses have been explored. Among the derivatives of oseltamivir which have been synthesized, oseltamivir phosphonate has been demonstrated to be a significantly more potent inhibitor against H1N1 and H5N1 neuraminidases than oseltamivir. No modifications on C-2, C-3 and C-7 of the oseltamivir structure have yet been reported. The introduction of a guanidine group at the C-4 position of the hydrolyzed oseltamivir structure significantly enhanced its inhibitory activity whereas no modifications at C-5 resulted in any improvement. While C-6 modified oseltamivir analogues were synthetized, no inhibition studies of these compounds have yet been performed. Only one retrosynthetic analysis based on the use of the bicyclic compounds 226 and 232 as precursors has been developed for the synthesis of peramivir. None of the modifications performed on the peramivir scaffold could improve its inhibitory activity over peramivir itself. In contrast to zanamivir, it was reported that the lack of a guanidyl group in the peramivir structure showed little effect on its inhibitory activity. The high number of recent publications in the field of neuraminidase inhibitor synthesis reflects the huge ongoing effort to find yet more potent neuraminidase inhibitors.

Acknowledgments: This work was supported in part by the Natural Science Foundation of China (grant numbers 31471703, A0201300537 and 31671854), and the 100 Foreign Talents Plan (grant number JSB2014012). The authors would like to thank Louis Conway (GGBRC, Nanjing) for language editing of this manuscript. Conflicts of Interest: The authors declare no conflicts of interest. Molecules 2016, 21, 1513 34 of 40

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