A new synthesis of macrolactones bearing a cyclopropyl ring condensed to the macrocycle is reported via a cyclization-release strategy making use of solid-phase supported stabilized sulfur ylides

CARDULLO F

GENNARI C

LA PORTA E

PAIO A

PROVERA S

SENECI P

U. PIARULLI

E. La Porta

U. Piarulli

F. Cardullo

A. Paio

S. Provera

P. Seneci

C.M.A. Gennari

AIR Universita degli studi di Milano

Cyclative cleavage via solid-phase supported stabilized sulfur ylides: synthesis of macrocyclic lactones

GENNARI C.

PIARULLI, UMBERTO

Archivio istituzionale della ricerca - Università dell'Insubria

TETRAHEDRONLETTERSTetrahedron Letters 43 (2002) 761–766PergamonCyclative cleavage via solid-phase supported stabilized sulfurylides: synthesis of macrocyclic lactonesElena La Porta,a Umberto Piarulli,a,b Francesca Cardullo,c Alfredo Paio,c Stefano Provera,cPierfausto Senecid and Cesare Gennaria,*aDipartimento di Chimica Organica e Industriale, Universita` di Milano, Centro CNR per lo Studio delle Sostanze OrganicheNaturali, via G. Venezian 21, I-20133 Milano, ItalybDipartimento di Scienze Chimiche, Fis. e Mat., Universita` dell’Insubria, via Valleggio 11, I-22100 Como, ItalycGlaxo-SmithKline, Med. Res. Centre, via Fleming 4, I-37135 Verona, ItalydNucleotide Analog Design AG, Landsbergerstrasse 50, D-80339 Munich, GermanyReceived 31 October 2001; accepted 26 November 2001Abstract—A new synthesis of macrolactones bearing a cyclopropyl ring condensed to the macrocycle is reported via acyclization-release strategy making use of solid-phase supported stabilized sulfur ylides. © 2002 Elsevier Science Ltd. All rightsreserved.The convenient purification procedures and the otherknown advantages associated with solid-phase synthesismake it a powerful tool for the preparation of combina-torial libraries, a fundamental element of contemporarydrug discovery processes. In this context, cyclization-release techniques1 present distinct advantages overmore conventional approaches to solid-phase synthesis:(a) Most traditional solid-phase methods incorporate aheteroatom within a device that links the substrate tothe polymer support. Cleavage is achieved by ‘depro-tecting’ the heteroatom which, however, remains as avestigial stub on the final molecule. This is not aproblem in cyclative-cleavage approaches, where releasefrom the polymer support is obtained as a consequenceof the natural reactivity of the connecting functionality,leaving no traces on the target molecules.(b) Since detachment from the resin is a step associatedwith the correct reaction sequence, only substratesFigure 1. Synthesis of macrocyclic lactones via the cyclative release strategy, using solid-phase supported stabilized sulfur ylides.Keywords : solid-phase synthesis; macrocycles; cyclopropanes; sulfonium salts.* Corresponding author. Tel. +39-025835.4091; fax: +39-025835.4072; e-mail: cesare.gennari@unimi.it0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.PII: S0040 -4039 (01 )02258 -4E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766762which possess the correct functionality and react in theexpected way are released into the solution in highpurity, leaving all unreacted systems and by-productson the solid-phase.(c) The cyclization step takes place while the substrateis anchored on the polymer support, taking advantageof the functional group isolation granted by the resinand thus eliminating the risk of intermolecular reac-tions and the need of high dilution conditions. The ringclosing metathesis (RCM),1 the Wittig–Horner reac-tion,2 the Stille3 and Suzuki4 couplings have recentlybeen adapted to fit this scheme as carboncarbon bondforming cyclization processes in a cyclorelease from thesolid-phase.We recognized in sulfur ylides5 a functional arrange-ment with suitable characteristics for an originalcyclorelease strategy, featuring an activation phaseprior to the actual cyclization event, in a way reminis-cent of the principle of safety catch linkers. In particu-lar, we focused on sulfur ylides stabilized byelectron-withdrawing groups,6,7 which can be generatedunder extremely mild conditions8 and are thereforesuitable for intramolecular reactions. Following theanchoring of the ylide precursor onto the solid supportand elongation with a chain containing a Michaelacceptor terminal moiety (Fig. 1), the cyclative releasefrom the solid-phase is made possible by alkylation ofthe sulfur atom to the sulfonium salt, the immediateprecursor to ylide formation and reaction.Here we describe the application of this new cycliza-tion-release strategy to the synthesis of macrolactonesbearing a cyclopropyl system condensed to the macro-cyclic ring.9First of all, we investigated the preparation of resin-bound thioglycolic acid on Argogel® resin, the stabilityof the resin-bound sulfonium salt and the reactivity ofthe resin-bound ylide with aldehydes.6 Argogel®-Clresin was reacted with potassium thioacetate accordingto a published procedure,10 and the supported thioester1 was successfully reduced with LiBH4 in THF to giveArgogel®-SH resin 2, which was characterized byMAS–1H NMR and FT-IR (Scheme 1). Argogel®-SHresin 2 was then reacted with 13C-enriched (99%) ethylbromoacetate and triethylamine in DMF at room tem-perature. The supported ester 3 was characterized by13C-gel phase NMR (32.0 ppm) and FT-IR (CO,1730 cm−1). The ethyl ester was then saponified (NaOH,THF–H2O), and the resulting acid 4 was characterizedby MAS–1H NMR, FT-IR (CO 1720 cm−1), 13C-gelphase NMR (34.6 ppm) and transformed into the N-benzyl,N-methylamide 5 characterized by MAS–1HNMR, FT-IR (CO 1636 cm−1) and 13C-gel phaseScheme 1. Investigation on the stability of the resin-bound sulfonium salt 6 and on the reactivity of the resin-bound ylide withaldehydes.E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766 763NMR (33.9 ppm). Sulfonium salt 6 was synthesized bytreatment of sulfide 5 with 0.3 M MeOTf in DCM(room temperature, 1 h). The solid-supported sulfo-nium salt 6 was shown to be stable to washings andstorage, and characterized by MAS–1H NMR, FT-IR(CO 1646 cm−1) and 13C-gel phase NMR (48.5 ppm).Finally, it was reacted with DBU and protectedglyceraldehyde6 in CD2Cl2 at room temperature: thereaction was followed by 13C NMR in the gel phase-NMR tube (coaxial insert), by disappearance of thesulfonium–carbon peak at 48.5 ppm and appearance ofthe new epoxide–carbon peak at 52.4/52.7 ppm (twopeaks because of the tertiary amide present in 7). Thesame reaction was run successfully on a preparativescale employing different aldehydes (p-chlorobenzalde-hyde, propionaldehyde and protected glyceraldehyde)and solvents (DCM and CH3CN), as reported inScheme 1. Flash-chromatography of the crudes derivingfrom the washings of the resin allowed the isolation andcharacterization of the desired epoxyamides 7 (41%),(±)-8 (10%), and (±)-9 (20%).6 Overall yields were calcu-lated based on the initial loading of Argogel®-Cl resin(0.44 mmol/g).Having established the stability of the resin-bound sul-fonium salt and the reactivity of the resin-bound ylide,we turned our attention to the preparation of twodifferent resins bearing a thioglycolic acid unit. In thecase of Argogel® resin, a more straightforward routewas developed (Scheme 2) starting from methyl thiogly-colate and leading in two steps to the desired function-alized resin 10. In the case of Merrifield resin(chloromethylated polystyrene crosslinked with 1%divinylbenzene, 1.09 mmol/g), this was transformed tothe functionalized thiol resin 11, using a 1,4-butanediolspacer according to a published procedure.11 Thiol-resin 11 was then reacted with methyl bromoacetateand triethylamine in DMF. The supported ester 12 wascharacterized by MAS–1H NMR and FT-IR (CO,1739 cm−1) and then saponified (NaOH, THF–H2O) tothe desired functionalized resin 13 (CO, 1730 cm−1)(Scheme 2).Functionalized resins 10 or 13 were reacted with -hydroxy vinylketone 1412 using DCC and DMAP inDCM to give supported vinylketone 15 (Scheme 3). Thethioether of 15 was activated with MeOTf in DCM tothe corresponding resin bound sulfonium salt 16, whichwas purified by filtration and washings. Treatment of16 with DBU generated the stabilized sulfur ylide whichunderwent cyclative cleavage to give the macrocycliclactone (±)-17, bearing a cyclopropyl ring7 condensedto the macrocycle, in good yield and purity as a singlediastereoisomer (trans).15Scheme 2. Preparation of resins 10 and 13, functionalized as thioglycolic acid.Scheme 3. Solid-phase synthesis and cyclative release of macrocyclic lactone (±)-17.E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766764Scheme 4. Solid-phase synthesis and cyclative release ofmacrocyclic lactone (±)-22.cyclization precursor 26, which underwent cyclativecleavage under the usual conditions to give macrocycliclactones 27 and 28 (1:1)19 (Scheme 5).After optimization, this methodology will be employedfor the synthesis of a library of macrocyclic lactoneswith potential biological interest, bearing the uncom-mon ‘condensed-cyclopropyl’ functionality.9AcknowledgementsA graduate fellowship is gratefully acknowledged by E.La Porta (Glaxo-SmithKline, Verona, Italy). We thankDr. Sergio Lociuro (Glaxo-SmithKline) for support andhelpful discussions.References1. Nicolaou, K. C.; Vorloumis, D.; Li, T.; Pastor, J.;Winssinger, N.; He, Y.; Ninkovic, S.; Sarabia, F.; Vall-berg, H.; Roschangar, F.; King, N. P.; Finlay, R. M. V.;Giannakakou, P.; Verdier-Pinard, P.; Hamel, E. Angew.Chem. 1997, 109, 2181–2187; Angew. Chem., Int. Ed.Engl. 1997, 36, 2097–2103.2. Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F.J. Am. Chem. Soc. 1998, 120, 5132–5133.3. Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Murphy, F.Angew. Chem. 1998, 110, 2677–2680; Angew. Chem., Int.Ed. Engl. 1998, 37, 2534–2537.4. Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527–6530.5. Trost, B. M.; Melvin, L. S. Sulfur Ylides ; AcademicPress: New York, 1975.6. N,N-Dimethyl-2-(dimethylsulfuranilidene) acetamidereacts with chiral aldehydes and ketones with highstereoselectivity to form trans 2,3-epoxy-amides, see: (a)Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-Herrera, F. J. Tetrahedron 1990, 46, 7911–7922; (b)The scope of the cyclative cleavage reaction was investi-gated using propenylketones 18 (E)16 and 19 (Z),16following the same procedure described above forvinylketone 14. Macrocyclic lactone (±)-22 wasobtained as a single diastereoisomer from either E (20)or Z (21) resin-bound propenylketone in poor yield17(Scheme 4). Thus, the cyclization reaction seems quitesensitive to enone -substitution.Another point of interest regards the introduction of amore funtionalized chain in the macrocyclic ring. (+)-t-Butyl-(D)-lactate was coupled to Argogel® resin 10(DIC, 4-DMAP) to give resin-bound t-butylester 23which was hydrolized (TFA, DCM) to resin-bound acid24. Coupling with -hydroxy vinylketone 2518 gaveScheme 5. Solid-phase synthesis and cyclative release of macrocyclic lactones 27 and 28.E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–766 765Valpuesta, M.; Durante, P.; Lo´pez-Herrera, F. J. Tetra-hedron 1993, 49, 9547–9560; (c) Lo´pez-Herrera, F. J.;Sarabia-Garcia, F.; Pedraza-Cebrian, G. M.; Pino-Gon-zalez, M. S. Tetrahedron Lett. 1999, 40, 1379–1380; (d)Imashiro, R.; Yamanaka, T.; Seki, M. Tetrahedron:Asymmetry 1999, 10, 2845–2851; (e) For chiral sulfurylides, see: Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X.; Xia,L.-J.; Tang, M.-H. J. Chem. Soc., Perkin Trans. 1 1999,77–80.7. Dimethylsulfonium phenacylide and ethyl(dimethylsul-furanilidene)acetate (EDSA) are reported to react with avariety of Michael acceptors to form cyclopropyl deriva-tives, see: (a) Trost, B. M. J. Am. Chem. Soc. 1967, 89,138–142; (b) Payne, G. B. J. Am. Chem. Soc. 1965, 87,3351–3355; (c) Ma, D.; Cao, Y.; Yang, Y.; Cheng, D.Org. Lett. 1999, 1, 285–287; (d) Ma, D.; Cao, Y.; Wu,W.; Jiang, Y. Tetrahedron 2000, 56, 7447–7456; (e) Ma,D.; Jiang, Y. Tetrahedron: Asymmetry 2000, 11, 3727–3736.8. (a) Collado, I.; Dominguez, C.; Ezquerra, J.; Pedregal,C.; Monn, J. A. Tetrahedron Lett. 1997, 38, 2133–2136;(b) Nozaki, H.; Tunemoto, D.; Matubara, S.; Kondoˆ, K.Tetrahedron 1967, 23, 545–551.9. For a macrocyclic antibiotic containing an -ketocyclo-propyl functionality (tolypomicin), see: Bellomo, P.; Bru-fani, M.; Marchi, E.; Mascellani, G.; Melloni, W.;Montecchi, L.; Stanzani, L. J. Med. Chem. 1977, 20,1287–1291. For a review on cyclopropane containingnatural products, see: Donaldson, W. A. Tetrahedron2001, 57, 8589–8627.10. Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki, M.Tetrahedron Lett. 1996, 37, 2809–2812.11. Vanier, C.; Lorge´, F.; Wagner, A.; Mioskowski, C.Angew. Chem. 2000, 112, 1745–1749; Angew. Chem., Int.Ed. Engl. 2000, 39, 1679–1683. A modified procedure wasfollowed in one of the synthetic steps: PBr3, THF, 0°C tort was used instead of MsCl, Et3N, CH2Cl2, rt. We thankDr. Wagner for exchange of experimental procedures andhelpful discussions.12. -Hydroxy vinylketone 14 was prepared as follows: com-mercially available 12-hydroxylauric acid was protectedat the terminal hydroxy group (TBDPS-Cl, imidazole,DMF, rt, 1 h, 67%). The -OTBDPS-protected acid wastransformed into the Weinreb amide (N,O-dimethylhy-droxylamine hydrochloride, 1,1-carbonyldiimidazole,DCM, rt, 4 h, 91%) and subsequently reduced to alde-hyde (DIBAl-H, THF, 0°C, 45 min, 80%). The aldehydewas then treated with vinylmagnesium bromide (THF,−75 to 0°C, 1.5 h, 60%) to give the allylic alcohol, whichwas in turn oxidized to the vinylketone [Dess MartinPeriodinane (DMP),13 DCM, rt, 1 h, 92%]. The -OTB-DPS-protected vinylketone was deprotected (TBAF, p-TsOH–H2O, THF, 0°C to rt, 80 h, 80%)14 to give the-hydroxy vinylketone 14.13. Dess Martin Periodinane (DMP): (a) Dess, D. B.; Mar-tin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287; (b)Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899–2899.14. Hitchcock, S. A.; Houldsworth, S. J.; Pattenden, G.;Pryde, D. C.; Thomson, N. M.; Blake, A. J. J. Chem.Soc., Perkin Trans. 1 1998, 3181–3206.15. The loading of cyclization precursor 15 (0.35 mmol/g forArgogel® resin; 0.81 mmol/g for Merrifield resin) wascalculated from the original loading of the commercialresin (0.44 mmol/g for Argogel®-Cl resin; 1.09 mmol/gfor Merrifield resin) and considering a 100% yield foreach solid-phase synthetic step preceding the cyclization.The overall yield for the solid-phase synthesis of macro-cycle (±)-17 was calculated based on the above loadingvalues: 52% from Argogel® precursor 15 (31% after flashchromatography); 20% from Merrifield precursor 15(10% after flash chromatography). Lactone (±)-17 wasalso synthesized in solution-phase, following the samechemistry described in Scheme 3 but using S-ethyl thio-glycolic acid instead of resins 10 or 13. Sulfonium saltformation (1.5 equiv. MeOTf, DCM, rt, 1 h) and macro-cyclization (2 equiv. DBU) under high dilution conditions(10−3 M in DCM, rt, 20 h) gave lactone (±)-17, which waspurified by flash-chromatography (60% yield) and charac-terized as follows. 1H NMR (CDCl3, 400 MHz):  1.20–1.45 (14H, bs), 1.40–1.56 (2H, m), 1.60–1.75 (4H, m),2.10 (1H, ddd, J1=9.2 Hz, J2=5.9 Hz, J3=3.7 Hz), 2.35(1H, ddd, J1=14.1 Hz, J2=8.0 Hz, J3=6.3 Hz), 2.51(1H, ddd, J1=9.1 Hz, J2=5.7 Hz, J3=3.7 Hz), 2.70–2.80(1H, m), 3.85–3.95 (1H, m), 4.53 (1H, ddd, J1=11.1 Hz,J2=7.0 Hz, J3=4.2 Hz).13C NMR (CDCl3, 50.13 MHz): 16.2, 24.9, 28.7, 24.3–27.8 (7C), 44.1, 64.6, 209.0.HRMS [EI (70 eV)] calcd for [C16H26O3]+ 266.1882,found 266.1825.16. -Hydroxy propenylketones 18 and 19 were prepared asdescribed in Ref. 12 for -hydroxy vinylketone 14 butusing propenylmagnesium bromide instead of vinylmag-nesium bromide (THF, −75 to 0°C, 2.5 h, 70%). Theallylic alcohols (E+Z) were in turn oxidized to thepropenylketones [DMP,13 DCM, rt, 1.5 h, 77%]. The-OTBDPS-protected propenylketones were separated byflash-chromatography (E :Z=1:1) and deprotected(TBAF, p-TsOH–H2O, THF, 0°C to rt, 20 h, 84%)14 togive the -hydroxy propenylketones 18 and 19.17. The loading of cyclization precursor 20 or 21 (0.34 mmol/g for Argogel® resin; 0.81 mmol/g for Merrifield resin)was calculated from the original loading of the commer-cial resin (0.44 mmol/g for Argogel®-Cl resin; 1.09 mmol/g for Merrifield resin) and considering a 100% yield foreach solid-phase synthetic step preceding the cyclization.The overall yield for the solid-phase synthesis of macro-cycle (±)-22 was calculated based on the above loadingvalues: 15% from Argogel® precursor 20 or 21 (8% afterflash chromatography); 5% from Merrifield precursor 20or 21 (2% after flash chromatography). Lactone (±)-22was also synthesized in solution-phase, following thesame chemistry described in Scheme 4 but using S-ethylthioglycolic acid instead of resins 10 or 13. Sulfonium saltformation (1.5 equiv. MeOTf, DCM, rt, 1 h) and macro-cyclization (2 equiv. DBU) under high dilution conditions(10−3 M in DCM, rt, 20 h) gave lactone (±)-22 which waspurified by flash-chromatography (10% yield) and charac-terized as follows. 1H NMR (CDCl3, 400 MHz):  1.20–1.40 (17H, bs), 1.60–1.70 (4H, m), 1.91–2.03 (1H, m),2.20 (1H, dd, J1=9.5 Hz, J2=4.4 Hz), 2.33 (1H, ddd,J1=13.5 Hz, J2=8.1 Hz, J3=6.0 Hz), 2.47 (1H, dd,J1=5.8 Hz, J2=4.4 Hz), 2.75 (1H, ddd, J1=13.5 Hz,J2=7.3 Hz, J3=5.9 Hz), 3.87 (1H, ddd, J1=10.8 Hz,J2=6.8 Hz, J3=3.5 Hz), 4.59 (1H, ddd, J1=10.8 Hz,J2=7.4 Hz, J3=3.5 Hz). The relative stereochemistry wasassigned based on the coupling constants and on a COSYNMR spectrum (CDCl3, 400 MHz).E. La Porta et al. / Tetrahedron Letters 43 (2002) 761–76676618. Prepared from 1,10-decanediol via the following sequenceof reactions: (a) monoprotection (TBDPSCl, imidazole,DMF, rt, 24 h, 80%); (b) oxidation to aldehyde (DMP,DCM, rt, 1.5 h, 71%);13 (c) addition of vinylmagnesiumbromide (THF, 0°C, 1.5 h, 68%); (d) oxidation of theallylic alcohol to the vinylketone (DMP, DCM, rt, 1.5 h,92%);13 (e) TBDPS deprotection (TBAF, p-TsOH–H2O,THF, 0°C to rt, 70 h, 77%).1419. The loading (0.33 mmol/g) of Argogel® resin cyclizationprecursor 26 was calculated from the original loading ofcommercial Argogel®-Cl resin (0.44 mmol/g) and consid-ering a 100% yield for each solid-phase synthetic steppreceding the cyclization. The overall yield for the solid-phase synthesis of macrocycle 27 and 28 was calculatedbased on the above loading value: 33% (18% after flashchromatography). Lactones 27 and 28 were also synthe-sized in solution-phase, following the same chemistrydescribed in Scheme 5 but using S-ethyl thioglycolic acidinstead of resin 10. Sulfonium salt formation (1.5 equiv.MeOTf, DCM, rt, 1 h) and macrocyclization (2 equiv.DBU) under high dilution conditions (10−3 M in DCM,rt, 20 h) gave lactones 27 and 28 which were separated byflash-chromatography (63% combined yield) and charac-terized as follows. 1H NMR (CDCl3, 400 MHz) 27 (or28):  1.28–1.45 (10H, bs), 1.49 (3H, d, J=7.0 Hz),1.50–1.54 (2H, m), 1.61–1.71 (3H, m), 1.82–1.92 (1H, m),2.15 (1H, ddd, J1=10.3 Hz, J2=6.2 Hz, J3=3.9 Hz),2.39–2.49 (1H, m), 2.70–2.80 (2H, m), 4.14–4.28 (2H, m),5.07 (1H, q, J=7.0 Hz). 13C NMR DEPT (CDCl3, 100.6MHz):  16.4, 17.1, 24.4, 25.4, 24.6–28.1 (5C), 28.4, 29.0,43.3, 65.9, 69.8. 1H NMR (CDCl3, 400 MHz) 28 (or 27): 1.20–1.45 (10H, bs), 1.48–1.52 (2H, m), 1.53 (3H, d,J=7.0 Hz), 1.60–1.72 (3H, m), 1.85–1.95 (1H, m), 2.26(1H, ddd, J1=9.0 Hz, J2=5.7 Hz, J3=3.8 Hz), 2.44 (1H,ddd, J1=15.5 Hz, J2=8.1 Hz, J3=4.9 Hz), 2.60 (1H,ddd, J1=8.8 Hz, J2=5.9 Hz, J3=3.8 Hz), 2.75 (1H, ddd,J1=15.5 Hz, J2=8.5 Hz, J3=4.8 Hz), 4.10–4.29 (2H, m),5.27 (1H, q, J=7.0 Hz). HRMS [EI (70 eV)] calcd for[C17H26O5]+ 310.1780, found 310.1758.

Cyclative cleavage via solid-phase supported stabilized sulfur ylides: synthesis of macrocyclic lactones

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