IIIUSOO5789605A United States Patent (19) 11 Patent Number: 5,789,605 Smith, I et al. 45) Date of Patent: Aug. 4, 1998 54 SYNTHETICTECHNIQUES AND Jacquesy et al., "Metabromation Du Dimethyl-2, 6 Phenol INTERMEDIATES FOR POLYHYDROXY, Et De Son Ether Methylique En Milieu Superacide", Tetra DENYL LACTONES AND MIMCS hedron, 1981, 37, 747-751. THEREOF Kim et al., "Conversion of Acetals into Monothioacetals, O-Alkoxyazides and O-Alkoxyalkyl Thioacetates with 75) Inventors: Amos B. Smith, III. Merion; Yuping Magnesium Bromide". Tetra, lett, 1989, 30(48), Qiu; Michael Kaufman, both of 6697-6700. Philadelphia; Hirokaza Arimoto, Longley et al., "Discodermolide-A New, Marine-Derived Drexel Hill, all of Pa.; David R. Jones, Immunosuppressive Compound". Transplantation, 1991. Milford, Ohio; Kaoru Kobayashi, 52(4) 650-656. Osaka, Japan Longley et al., "Discodermolide-A New, Marine-Derived Immunosuppressive Compound". Transplantation, 1991. 73 Assignee: Trustees of the University of 52(4), 657-661. Pennsylvania, Philadelphia, Pa. Longley et al., "Immunosuppression by Discodermolide". Ann. N.Y. Acad. Sci., 1993. 696, 94-107. (21) Appl. No.:759,817 Nerenburg et al., "Total Synthesis of the Immunosuppres 22 Filed: Dec. 3, 1996 sive Agent (-)-Discodermolide". J. Am. Chem, Soc., 1993, 115, 12621-12622. (51) Int. Cl. ................. C07D407/06; C07D 319/06; Paterson, I. et al., "Studies Towards the Total Synthesis of CO7D 309/10 the Marine-derived Immunosuppressant Discodermolide; (52) U.S. Cl. .......................... 549/370; 549/374; 549/417 Asymmetric Synthesis of a C-Cö-Lactone Subunit". J. (58) Field of Search ..................................... 549/370,374, Chen. Soc. Chen, Commun., 1993, 1790-1792. 549/417 Paterson, I. et al., "Studies Towards the Total Synthesis of the Marine-derived Immunosuppresant Discodermolide; 56 References Cited Asymmetric Synthesis of a C-C Subunit". Synlett, 1995. Remington's Pharmaceutical Sciences, Mack Publishing FOREIGN PATENT DOCUMENTS Company. Easton, PA, 1980. 2280677 2/1995 United Kingdom. Roush et al., "Acyclic Diastereoselective Synthesis Using Tartrate Ester Modified Crotylboronates. Double Asymmet OTHER PUBLICATIONS ric Reactions with ol-Methyl Chiral Aldehydes and Synthe Clark. D.L. et al., "Studies on the Alkylation of Chiral sis of the C(19) -CO29) Segment of Rifamycin S". J. Am. Enolates: Application toward the Total Synthesis of Disco Chen. Soc., 1990, 112, 6348-6359. dermolide". J. Org. Chem, 1993. 58, 5878-5879. Smith et al., "Total Synthesis of (-)-Discodermolide", J. Evans. P.L. et al., "The Synthesis of a C-C Lactone Am. Chem. Soc., 1995, 117, 12011-12012. Fragment of Discodermolide". Tetra, Lett, 1993, 34(50), Smith, A. B. et al., "Total Synthesis of (-)-Discodermolide 8163-8166, Exploiting a Common Precursor". J. Am. Chem. Soc., (Sub Golec, J.M.C. et al., "The Synthesis of a C-CLactone mission Copy), 1-60. Fragment of Discodermolide", Tetra. Lett, 1993, 34 (50), 8159-8162. Solladie et al., "Asymmetric Synthesis of Polyhydroxylated Golec, J.M.C. et al., "An Approach to the Synthesis of a Natural Products II. The C-1/C-12 Unit of Amphotericin C-CFragment of Discodermolide", Tetra. Lett, 1993, B", Tetra. Lett, 1987, 28(7), 797-800. 34(50), 8167-8.168. ter Haar et al., “Discodermolide, A Cytotoxic Marine Agent Golec, J.M.C. et al., "Total synthesis of discodermolide", that Stabilizes Microtubules More Potently than Taxol", Chemical Abstracts, 1995, 123, 831, Abstract No. 32864j. Biochen., 1996, 35, 243-250. Greene and Wuts. Protective Groups in Organic Synthesis, Yang. G. et al., "the Synthsis of the C-9 to C-21 Sector of 2d Edition, John Wiley & Sons, New York, 1991. Discodermolide: An Efficient Route to the C13-14 Gunasekera et al., "Discodermolide: A New Bioactive Poly Z-Trisubstituted Alkene". Tetra. Lett, 1994, 35(16), hydroxylated Lactone from the Marine Sponge Discodernia 2503-2504. dissoluta”, J. Org. Chem, 1990. 55, 4912–4915. Yang. G. et al., "An Alkylative Strategy to the C-13 to C-21 Gunasekera et al., "Discodermolide: A New Bioactive Poly Sector of Discodermolide', Tetra. Lett, 1994, 35(9), hydroxylated Lactone from the Marine Sponge Discodermia 1313-1316. dissoluta. Additions and Corrections", J. Org. Chem, 1991, 56(3), 1346. Primary Examiner-Alan L. Rotman Hodges et al., "Reactions to Lithiooxazole”. J. Org. Chen, Assistant Examiner-Charanjit S. Aulakh 1991, 56, 449-452. Attorney, Agent, or Firm-Woodcock Washburn Kurtz Hung et al., "Distinct binding and cellular properties of Mackiewicz & Norris LLP synthetic (+)-and (-)-discodermolides". Chem, & Biol, 1994, 1(1), 67-71. 57 ABSTRACT Hung et al., "(+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding Synthetic methods for lactone-containing compounds such and results in mitotic arrest", Chem. & Biol., 1996, 3(4), as the discodermolides are provided, as are compounds 287-293. which mimic the chemical and/or biological activity thereof, Hung, D.T. et al., "Syntheses of Discodermolides Useful for and methods and intermediates useful in their preparation. Investigating Microtubule Binding and Stabilization", J. Am. Chem. Soc., 1996, 118, 11054-11080. 9 Claims, 31 Drawing Sheets U.S. Patent Aug. 4, 1998 Sheet 1 of 31 5,789,605 Figure 1 ÖTBs PMP A(2) Common Precursor (5) Denote the repeating stereochemical triad Figure 2 NH l to-co. "EGO"1) PMBO1 CC, PPTS PMBO -- OH (-)-6 2) LiAlH, THF (74%, 2 steps) (-)-8 Bn 1) soSwern (O) Pouli O 2) "- 5- O 1. (+)-9 (+)-10 n-BuBOTf, EtN, CH2Cl2 (89%, 2 steps) HN(Me)OMeeHC AIMe, THF (89%) OH O Common Precursor (+)-5 U.S. Patent Aug. 4, 1998 Sheet 2 of 31 5,789,605 Figure 3 i: Me MeN s Pouls. DDC, CHCa YOMe iAlH. THF CHO ÖH 5 (76%) olo o (80%) on-o Common Precursor (+)-6 FMP (-)-11 FMP (-12 TBSO, 2,6-ut n-BuBOTT, EN CHC (100%) CHCl2 (80%) OH TsC, py Og LiBH, EtOH (100%) THF (81%) 6.6 ÖTes i (-)-15 PMP PhP, la, imid. N (95%)(1:2) O Fup Fragment (-)-A(2) U.S. Patent Aug. 4, 1998 Sheet 3 of 31 5,789,605 ewo) (%98) #eun61-I OHO,! salg ew OBWd(el=N'Rosw U.S. Patent Aug. 4, 1998 Sheet 4 of 31 5,789,605 Figure 5 a) -Buli (2 equiv) THF, -78 C; b) MgBr os-o OTBS c) PMBO Br PMP 1 N= (-)-A(2) (-)-22 OTBs PaCl2(dppf), EtO, RT (14%) Figure 6 PMBO ÖTBsis ----6TBs (22 DDQ (1.0 equiv) (-25 (83%) CH2Cl2, H2O OH (), d dTBs (-)-15 PMP (86% recovery) U.S. Patent Aug. 4, 1998 Sheet 5 of 31 5,789,605 ?WO QQSBL KOHO Ou8 U.S. Patent 5,789,605 (£)E-(-) U.S. Patent Aug. 4, 1998 Sheet 7 of 31 5,789,605 |?einfil salg w-(-) (pex?uJeug)?louz+ O d wd O~ U.S. Patent Aug. 4, 1998 Sheet 8 of 31 5,789,605 SELO U.S. Patent Aug. 4, 1998 Sheet 9 of 31 5,789,605 eleinfil Saigcs-(+) Oo08 (%96) U.S. Patent Aug. 4, 1998 Sheet 10 of 31 5,789,605 (%89) y!einfil U.S. Patent Aug. 4, 1998 Sheet 11 of 31 5,789,605 SB19 saloº saloº ”OSEL 09-(-) gawd saloº saloº (%56) U.S. Patent Aug. 4, 1998 Sheet 12 of 31 5,789,605 20] 91eun61-I 10! 3:0|| |91-8) U.S. Patent Aug. 4, 1998 Sheet 13 of 31 5,789,605 HO SELLO A01 NOBIA/-IH90,8; U.S. Patent Aug. 4, 1998 Sheet 14 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 15 of 31 5,789,605 Salg U.S. Patent Aug. 4, 1998 Sheet 16 of 31 5,789,605 Ozein61-3 U.S. Patent Aug. 4, 1998 Sheet 17 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 18 of 31 5,789,605 ZZ?un61-) OEWd U.S. Patent Aug. 4, 1998 Sheet 19 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 20 of 31 5,789,605 Figure 24 BL EtO Eoul- Pd(PPh), 1) NaHMDS, THF --Orls-as-s- SO2 TBSOCHO 1 n TBSO OS c 1) DOC so C Xs OPMB B 2) PPha so4 - x = PPPh midazole SE OPMB 3) PPhi-Print EEO THF 2) DMSO, AcO 3) PPTS/MeOH EDC 501 U.S. Patent Aug. 4, 1998 Sheet 21 of 31 5,789,605 Figure 25 OTBS CHO 602 15 63 2) DiBAL CHCl2 1) TsC, Pyr. OPMBOTBS OTBS 1) PPTS/MeOH 2) Praculif Eto 2) MnO2 Phh OPMEOTBS OTBS 1) DDC / CHCHO 2) HF f MeCN U.S. Patent Aug. 4, 1998 Sheet 22 of 31 5,789,605 Figure 26 s DBAL-H -- El2 -- CH2Cl2 on-o OTBS Y O OTBS -raisera-e- PMB A PMB PPh s PPh. s PH 2 refix OH OPMBOTBS OPMBOTBS 703 : R Ph3P* I OPMBOTBs 2) t 705 O Q-lis 706 OPMBOTBS 707 80% ACOH OTs room temp. OPMBOTBS 709 K2CO3 MeOH DOC CH2C2-H2O OPMBOTBS OH OTBS CCCONCO (CICH2)2,MeOH K2CO HF / CHCN st-e-arreal-e- U.S. Patent Aug. 4, 1998 Sheet 23 of 31 5,789,605 Figure 27 OH OPMBOTBS PPh PPh 2 : Ph 16 inidazole R reflux TBSO OPMBOTBS O2 SEt 80% AcOH R room temp. PhP OPMBOTBS 2) t 803 du OPMBOTBS CHO 805 K2CO MeOH OPMBOTBS OPMBOBS 808 807 OPMBOBS SE U.S. Patent Aug. 4, 1998 Sheet 25 of 31 5,789,605 Figure 29 2) DiBAL, CHC 1) Sospyr, DMSO, EN 2 OTBS 1) PPTS/MeOH 2)glycosy bromide (Ooe) s: 3:) Hger CHC U.S. Patent Aug. 4, 1998 Sheet 26 of 31 5,789,605 'ULOSELL(£ [×] U.S. Patent Aug. 4, 1998 Sheet 27 of 31 5,789,605 U.S. Patent Aug. 4, 1998 Sheet 28 of 31 5,789,605 U.S.