The first total syntheses of newly isolated polyazole natural products azolemycins A–D, along with the synthesis of the tetra-oxazole non-natural analogue, are described

Anderson, Zoe J.

Fox, David J.

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Journal NameCite this: DOI: 10.1039/c0xx00000xwww.rsc.org/xxxxxxDynamic Article Links ►ARTICLE TYPEThis journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1Total Synthesis of the AzolemycinsZoe J. Anderson and David J. Fox†*Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XXDOI: 10.1039/b000000xThe first total syntheses of newly isolated polyazole natural products azolemycins A-D, along with the5synthesis of the tetra-oxazole non-natural analogue, are described.IntroductionAzolemycins A-D are compounds recently isolated from the soilbacterium, Streptomyces sp. FXJ1.264.1 A combination of massspectrometry and 1D and 2D NMR spectrometry identified the10structure as a modified heptapeptide, with four linked azoles andan N-terminal oxime. The major isolated azolemycins are the N-hydroxy derivative with the greater proportion as the E-oximegeometric isomer 1a, named azolemycin A and the lesserproportion as the Z- geometric isomer 1b, named azolemycin B15(Fig. 1). The minor isolated azolemycins differ only in containingan N-methoxy group and again were isolated as the E-isomer 2aand the Z-isomer 2b (azolemycins C and D respectively).20Figure 1 Azolemycins A-D.The biosynthesis of the azolemycins has been described,1 and isbelieved to involve the posttranslational modification of aribosomally-biosynthesised 7 amino-acid precursor. The oximefunctional group is believed to occur from a previously unknown25posttranslational modification, apparently utilizing a flavin-dependent monooxygenase to catalyse the oxidation of an N-terminal valine residue to the corresponding oxime.1 Oxime-containing natural products are unusual, and those reported,including caerulomycin A, althiomycin, collismycin A and30nocardicins A and B,2 result from nonribosomal peptidesynthesis.Until the 1980s, very few thiazole and oxazole-containingnatural products were known, but an increasing array have sincebeen identified, particularly derived from marine sources.3 These35products range from single oxazoles and thiazoles to morecomplicated linked chains or macrocycles of concatenated azoles.The combination of potent biological activity of many of theseazole products and the exciting synthetic challenges they pose hasmade them extremely attractive targets for total syntheses,4 and a40wide range of reagents have been developed to allow for this.5Polyazoles, or polyazole-containing, natural products made bytotal synthesis range from the relatively simple linked bis- andtriazole motifs, as found in the hennoxazoles,6 muscorides,7bleomycins,8 and myxothiazols,9 to more complicated45macrocyclic molecules such as the heptazole telomestatin, therelated YM-216391, IB-01211 and more recently, plantazolicin.104b, 11Synthetic StrategyOur chosen disconnection of the azolemycins involved a50convergent synthesis, with late stage formation of the centralthiazole, similar to the strategy used in the synthesis of YM-216391.11a The disconnection gave four distinct units: theisopropyl oxime 3, the left-hand mixed bisoxazole fragment 4,the right-hand methyl oxazole 5 and the isoleucine methyl ester 655(figure 2).Figure 2 Preliminary disconnections for the synthesis ofazolemycin AAs we planned to synthesise the thiazole from serine, the60tetraazole core could be divided into two repeating serine-threonine dimers, corresponding to a common threonine derivedoxazole 5. We therefore further disconnected the AB unit 4 intooxazole 8 and Boc-L-valine, 7 (figure 2). The protected oxazole2 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]building block 5 was synthesised from the diprotected Boc-serineacetonide 10. An HOBt/EDCI peptide coupling gave thethreonine dipeptide 11 in excellent yields. Oxidation of thethreonine residue using the Parikh-Doering conditions,12 andcyclodehydration using PPh3/I2/NEt3, as described by Wipf,7c5gave the oxazole 5 (scheme 1). In some reaction batches someunreacted alcohol 11 was carried through, with ketone 12, to thecyclodehydration step. In these cases, the elimination product 13was obtained and this was extremely difficult to separate fromoxazole 5. We therefore performed a Sharpless dihydroxylation10on the mixture of alkene 13 and oxazole 5.13 This chemoselectiveprocedure did not affect the oxazole but, as predicted, a simpleaqueous work-up afforded only the clean oxazole 5. We proposethat the alkene 13 formed an unstable diol that decomposed togive two non-isolated water soluble products, an amide and a15keto-ester.Scheme 1 (i) Dimethoxypropane, TsOH.H2O, CH2Cl2, 40 °C, 2h, 80 %; (ii) l-Thr.OMe.HCl, EDCI, cat. HOBt, EtOH, 0 °C to rt,18 h, 84 %; (iii) SO3.pyr, DMSO, iPr2EtN, CH2Cl2, 0 °C, 3 h; (iv)PPh3, I2, NEt3, CH2Cl2, 0 °C to rt, 18 h, 32 % over 2 steps; (v)20AcCl, MeOH, rt, 18h, quantThe AB unit was formed from the tripeptide 14, which wasmade by coupling Boc-valine 7 to the deblocked oxazole-amine 8(scheme 2). The serine residue was then cyclodehydrated usingDAST to give the crude oxazoline, as described by Williams et25al. in their synthesis of (-)-hennoxazole A.6a. Attempts to oxidisethis using standard conditions (e.g. BrCCl3 and DBU,5f orBrCCl3, CCl4 and pyridine14) were unsuccessful, presumably dueto the unactivated nature of the oxazoline. Though oxidations ofthis type of relatively unactivated oxazoline are not common in30the literature, examples do exist which use either MnO2 orNiO2,5i, 11c, 11d which are assumed to follow a similarmechanism.15 Despite being a widely used oxidising agent, manyprocedures do not state the provenance or preparation method ofMnO2, and the method of preparation has been shown to have a35significant effect on the oxidative ability of the reagent.16Yokokawa and Shioiri have reported that chemical manganesedioxide (CMD), manufactured for the production of dry batteries,is a superior oxidising agent than MnO2 prepared by othermethods.17 We therefore investigated a method of producing40activated MnO2 proposed by Ball, Goodwin and Morton, wherean aqueous solution of potassium permanganate is reacted withmanganese sulfate in neutral medium to give a precipitate ofMnO2.18 The MnO2 is then activated as required by azeotropicdrying with toluene, as described by Goldman.19 This provides a45source of MnO2 presumably similar in composition to the CMD,and indeed a similar technique using benzene-dried CMD wassuccessfully exploited by Shioiri and Yokokawa for the synthesisof a variety of thiazole-containing natural products. 20The oxazoline was treated with an excess of the freshly50activated MnO2 and, on completion, the residual MnO2 wasreduced using aqueous SO2. A simple aqueous work-up and silicachromatography gave the clean bisoxazole 4 in 27 % yield overtwo steps. It is likely that loss of the N-terminal Boc group duringthe reduction of the MnO2 cause the low yield for this step, and a55more resilient protecting group would undoubtedly haveimproved the yield. As this step provided us with sufficientmaterial to complete the synthesis however, we did not attempt tooptimise it further. One major concern was retaining thestereointegrity of the N-terminal valine during oxazole synthesis.60Previous work within the group had identified isoleucine as auseful residue to detect epimerization by 1H NMR in similarreactions. Boc-Ile-Ser-OMe was used as a model compound foroxazole, and we were encouraged to see no apparentepimerization of the N-terminal stereocentre (see ESI).65Scheme 2 (i) 7, EDCI, cat. HOBt, NMM, EtOH, rt, 18 h, 88 %;(ii) DAST, CH2Cl2, -78 °C to rt 2 h; then MnO2, toluene, 110 °C,6 h, 27 %.Methyl ester 4 was hydrolysed, and the resulting acid70underwent an EDCI/HOBt coupling with amine 8 to give thepentapeptide, 15. Protection of the pendant alcohol to give 16 wasrequired to prevent beta-elimination during the formation of thethioamide, which was achieved in excellent yields withLawesson’s reagent to give 17. Deprotection of the alcohol75provided 18, which underwent for a further DAST mediatedcyclodehydration to give the crude thiazoline. This was oxidisedusing CCl4 and pyridine to give thiazole 19 in a 27 % yield over 5steps (scheme 3).80Scheme 3 (i) LiOH, H2O, THF, rt, 4h, 99%; then 8, EDCI, cat.HOBt, NMM, EtOH, rt, 18 h, 73 %; (ii) TBDMSCl, imidazole,DMF, 0 °C, 3 h, 83 %; (ii) Lawesson's reagent, toluene, THF, 110°C, 44 h, 81 %; (iii) TBAF, THF, 0 °C, 1 h, 99 %; (iv) DAST,CH2Cl2, -78 °C to rt 1.5 h; then DBU, pyr., CCl4, MeCN, 0 °C to85rt, 18 h, 58 % over 2 steps.This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 3With the synthesis of the four azoles achieved, the completionof the natural products could be attempted. Saponification of themethyl ester 19 was more difficult than expected due to its lowsolubility, but long reaction times, high dilution and a mixture ofsolvents provided the hydrolysis product 20, which was readily5coupled to isoleucine methyl ester to give the hexapeptide 21.Removal of the Boc-protecting group allowed coupling 2-hydroxy-3-methylbutyric acid 22, made from L-valine accordingto the method of Bauer and Gajewiak,21 to give alcohol 23. Thisalcohol was oxidised to the ketone 24 which was reacted with10hydroxylamine to give azolemycin A, 1a (scheme 4; 21 steps, 16steps longest linear sequence, with an overall yield of 0.3 %).Reaction of ketone 24 with methoxyamine gave azolemycin D,2b, with a similar yield.15Scheme 4, MeOH, THF, CH2Cl2, H2O, rt, 26 h, 92 %; (ii) L-Ile-OMe.HCl, EDCI, cat. HOBt, NMM, EtOH, rt, 18 h, 84 %; (iii)NaNO2, H2SO4, H2O, 0 °C to rt, 18 h, 31 %; (iv)a) MeOH,AcCl,rt, 2 h; b) 22, EDCI, cat. HOBt, NMM, EtOH, 0 °C to rt, 18h, 90 % over 2 steps; (v) SO3.pyr., NEt3.DMSO, CH2Cl2, 0 °C, 320h, 65 %; (vi) NH2OH.HCl, pyridine, MeOH, CH2Cl2, rt, 24 h, 58%; (vii) NH2OMe.HCl, pyridine, MeOH, CH2Cl2, rt, 4h, 62 %.The 1H NMR spectra of the two synthesized natural productscorrelate well with the spectra of the naturally derived molecules.However, while the naturally derived azolemycins were isolated25separately as both the E- and Z- oxime isomers, a separation wasnot possible for the synthesized product, 1. The synthetic productconsisted mainly of the E-oxime 1a (azolemycin A), with onlytraces of the Z-isomer 1b (azolemycin B), based on the valine α-CH peaks in 1H NMR spectra. In contrast, the synthetic N-30methoxy azolemycins, 2, were obtained as primarily the Z-geometric oxime isomer (azolemycin D), but in CDCl3 showednear complete conversion to the E-isomer (azolemycin C) inaround 5 days.To extend this project, the synthesis of an azolemycin-like35tetra-oxazole natural product analogue 30 was attempted. It wasenvisaged that any activity shown by the natural productazolemycin A could be compared with this tetraoxazoleequivalent to observe the requirement, if any, for the C-ringthiazole. The synthesis of 30 was achieved in a straightforward40fashion by cyclisation and oxidation of serine-derived precursor15, forming the C-ring oxazole (scheme 5). This internal oxazolewas formed with comparative ease compared to the N-terminaloxazole A in the bisoxazole fragment 4. This supports ourhypothesis that, while an adjacent electron withdrawing group at45the 4-position is important for the oxidation of oxazolines, thereaction will still proceed in excellent yields if the formingbenefits from conjugation at the 2- and 4-positions withneighbouring azoles.50Scheme 5 (i) DAST, CH2Cl2 then DBU, pyr., CCl4, MeCN, 0 °Cto rt, 72 h, 89 %; (ii) LiOH, H2O, THF, CH2Cl2, 67%; (iii) L-Ile-OMe.HCl, EDCI, cat. HOBt, NMM, EtOH, 0 °C to rt, 18 h, 54%; (iv) MeOH, AcCl, rt, 2 h; then 22, EDCI, cat. HOBt, NMM,EtOH, 0 °C to rt, 18 h, 62 %; (v) SO3.pyr., NEt3.DMSO, CH2Cl2,550 °C, 6 h, 72 %; (vi) NH2OH.HCl, pyridine, MeOH, CHCl3, rt,18h, 33 %.NMR spectrometry suggests that oxime 30 was formed as amixture with the Z-isomer as the major isomer, with the majorpeak in the 1H spectrum for the CH adjacent to the oxime at 3.0060ppm, and the minor peak at 3.49 ppm (compare with 3.50 ppmfor E-1a, 3.00 ppm for Z-1b). Comparison of the 13C NMRspectra of the tetraoxazole 30 with the equivalent synthesizedazolemycin A 1 showed some distinctive differences. As well asthe obvious shift of the peak corresponding to C32 from 120.265ppm in 1 to 138.31 ppm in 30, the peaks corresponding to theother carbons of azole C, and those immediately surrounding it,were shifted significantly. In particular, in the thiazole 1 the peakcorresponding to B ring carbon C11, occurs at 130.9 ppm, but in4 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]the oxazole 30 the C11 peak appears at 125.7 ppm. This largedifference in chemical shift may facilitate the identification of therelative positions of oxazoles and thiazoles in new polyazolenatural products.5Figure 5 Numbering for azolemycin A, 1 and tetraoxazole 30.These syntheses produced azolemycin A and C and thetetraoxazole analogue 30, for initial biological testing.1 We arecontinuing assays in this area.Acknowledgements10We wish to thank the EPSRC for a DTA studentship (ZJA), DrLijiang Song for NMR data for the isolated naturally derivedazolemycins and Prof. Greg Challis for useful discussions. Dataare available at http://wrap.warwick.ac.uk/74514Notes and references15Department of Chemistry, University of Warwick, Gibbet HillRoad, Coventry, CV4 7AL, U.K. E-mail: d.j.fox@warwick.ac.uk† Electronic Supplementary Information (ESI) available:synthesis details and NMR spectra. See DOI: 10.1039/b000000x/1 N. Liu, L. Song, M. Liu, F. Shang, Z. Anderson, D. J. Fox, G.20L. Challis and Y. Huang, Chem. 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Total synthesis of the azolemycins

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Total synthesis of the azolemycins

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