Discodermolide A Synthetic Challenge Me Me Me HO Me O O OH O NH2 Me Me OH O Me Me OH Nicole Goodwin MacMillan Group Meeting April 21, 2004 Me Me Me HO Discodermolide Me O O OH O NH2 Isolation and Biological Activity Me Me OH O Me Me OH ! Isolated in 1990 by the Harbor Branch Oceanographic Institution from the Caribbean deep-sea sponge Discodermia dissoluta ! Not practical to produce discodermolide from biological sources ! 0.002% (by mass) isolation from frozen sponge ! must be deep-sea harvested at a depth in excess of 33 m ! Causes cell-cycle arrest at the G2/M phase boundary and cell death by apoptosis ! Member of an elite group of natural products that act as microtubule-stabilizing agent and mitotic spindle poisons ! Taxol, epothilones A and B, sarcodictyin A, eleutherobin, laulimalide, FR182877, peloruside A, dictyostatin ! Effective in Taxol-resistant carcinoma cells ! presence of a small concentration of Taxol amplified discodermolide's toxicity by 20-fold ! potential synergies with the combination of discodermolide with Taxol and other anticancer drugs ! Licensed by Novartis from HBOI in 1998 as a new-generation anticancer drug 1 Cell Apoptosis M - Mitosis G0 Discodermolide disrupts the G2/M phases of the cell cycle. Resting Discodermolide, like Taxol, inhibits microtubule depolymerization by binding G1 - Gap 1 to tubulin. G2 - Gap 2 cells increase in size, cell growth control checkpoint no microtubules = no spindle fiber new proteins formation S - Synthesis DNA replication Me Me Me HO Discodermolide Me O O OH O NH2 Isolation and Biological Activity Me Me OH O Me Me OH ! Considerable synthetic effort to produce discodermolide because of dearth of biological supply ! Taxol is semi-synthesized from an intermediate extracted from the European Yew tree ! the epothilones are obtained from fermentation ! Several total syntheses and numerous fragment syntheses ! 1993 - Schrieber ! 1995 - Smith 1998 - Smith, second generation ! 1997 - Myles (UCLA) ! 1998 - Marshall (UVa) ! 2000 - Paterson ! Novartis synthesis is a combination these total synthesis ! Smith - fragment syntheses from a common precursor (CP) ! Marshall - !-alkyl Suzuki coupling of C14 to C15 ! Paterson - endgame 2 Discodermolide A Synthetic Challenge (Z)-olefin Me Me Me 8 HO 9 22 Me 7 14 O O OH O NH2 terminal (Z)-diene Me 13 Me OH O Me Me OH tri-substituted (Z)-olefin ! Repeating stereotriad from common precursor (CP) Me Me Me 20 HO 18 Me 19 OMe Me Me 10 12 O O OH O NH2 N OPMB Me 11 Me Me 2 4 OH O O OH Me 3 Me CP OH Me Mee Mee HO Mee 18 20 Discodermolide 10 Outline O O OH O NNHH22 Mee 12 Me OH O Me 2 4 Mee OH ! Paterson Synthesis (1998, 2001) ! selectivity from intrinsic bias of molecule ! boron-mediated anti Aldols ! Claisen rearrangement to set C13 olefin ! Nozaki-Hiyama/Petersen elimination - diene formation ! selective reductions at C7 or C5 ! Smith Synthesis (1995, 2003) ! stereotriad from a common precursor (CP) - Evans aldol ! Negishi coupling at C14 ! Yamamoto diene formation ! Wittig olefination at C8 - first and second generation ! Marshall Synthesis (1998) ! Allenylstannane additions to chiral aldehydes for stereotriads ! !-alkyl Suzuki coupling with vinyl iodide ! Novartis synthesis - over 60 g produced! 3 Paterson 2001 Retrosynthesis 24 Me Me Me 8 HO Me O O OH O NH2 Me Me 1 13 OH O Me Me OH CO Ar 2 24 Me Me 6 PMBO 16 Me Me 9 Me Me H 17 MeO2C 1 Me Me OTBS O O OPMB OTBS Boron -mediated Anti Aldols Me Me Me Me Me Me BnO PMBO OBz O O O Me HO ethyl (S)-lactate CO2Me Me Me Me HO Paterson 2001 Me O O OH O NH2 Preparation of C1 to C6 Fragment Me Me OH O Me Me OH Me Me Me Me Me Cy2BCl MeCHO HO BnO BnO CO2Me Et3N O O BCy2 H BnO BnO H Cy Cy Cy H minimize H LiBH Me B Cy Me 4 O Me B B Me Me O Cy Me O Cy O Me A1,3 Me 1,3 syn reduction O O BnO H Me H O Me Me 5 steps* Me Me 2 2 6 BnO Me Me 86% yield MeO2C 76% yield 1 >97% d.s. OH OH OTBS O * 1. TBSOTf 2. CSA, MeOH/CH2Cl2. 3. Pd(OH)2/C, H2, EtOH. 4. Swern. 5. i. NaClO2. ii. CH2N2. 4 Me Me Me HO Paterson 2001 Me O O OH O NH2 Preparation of C9 to C18 Fragment Me Me OH O Me Me OH O Me Me Me Me H Me Me Me Cy2BCl i. HO PMBO PMBO CO2Me Et3N ii. H2O2 O 95% yield, >97% d.s. O OH Me Me Me Me Me Me Me4NBH(OAc)3 PhSeCH CH(OEt) PMBO 2 2 PMBO or PPTs, PhMe 1. SmI2, EtCHO OH OH 94% yield O O 2. K2CO3, MeOH CH2SePh Me Me Me PMBO O Me NaIO4 Me H Me Et OPMB Holmes protocol O O O Sm O Me Me Me HO Paterson 2001 Me O O OH O NH2 Ring Expansion Claisen Rearrangement Me Me OH O Me Me OH Me Me Me Me Me Me H PMBO PMBO Me Me NaIO4 O O O Holmes O O O PMBO Me CH2SePh Me Me H Me Claisen Me PMBO 3 steps* O Me 82% yield O O 86% yield PMBO Me O Me O O PMBO 16 Z olefin geometry set 9 Me Me without other isomer present! Me Me OTBS Holmes, et al. J. Am. Chem. Soc. 1997, 119, 7483 * 1. KOH, MeOH. 2. 2,6-Me2phenol, DCC, DMAP. 3. TBSOTf 5 Me Me Me HO Paterson 2001 Me O O OH O NH2 C17 to C24 Fragment Me Me OH O Me Me OH Me TBSO H Me Me Me Me Me Me Me BCy Cl (S)-ethyl 2 O TBSO lactate OBz OBz OBz Me2NEt 99% yield O O >97% d.s. OH O Cy2B 1. PMBO(C=NH)CCl3 Me Me 2. NaBH ; K CO , MeOH 4 2 3 TBSO H 3. NaIO4 H PMBO O R H H CrL O n TMS Me TMS CrCl2 LnCr TMS THF Br H Me Me TMS Me Me 24 R H KH H OH TBSO TBSO TMS 98% yield 17 Me PMBO OH from diol OPMB Me Me Me HO Paterson 2001 Me O O OH O NH2 C17 to C24 and C9 to C16 Fragment Union Me Me by a syn Aldol OH O Me Me OH Me O O ArO OLi 16 LiTMP, LiBr Me Me 24 PMBO 9 -100 °C PMBO Me Me Me H 17 Heathcock conditions Me Me to give (E)-enolate Me Me O OPMB OTBS OTBS ArO C Me Me H 2 R OAr PMBO LiAlH H Li Me 4 O R O OR OPMB -30 °C Me Me Me 88% yield OTBS R = H, !-elim. of OAr, epimerizes C18 HO R = Li, no epimerization, in situ reduction Me Me PMBO Me OH OPMB Me Me OTBS Clark, D. L.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5878. Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 9571. 6 Me Me Me Paterson 2001 HO Me Alternate Syn Aldol Approach is Unsuccessful O O OH O NH2 Me Me OH O Me Me OH Me Me Me Me PMBO LiTMP, LiBr PMBO Me Me -100 °C H O Me O Me O OPMB O LiO Me Me OH OPMB OH OPMB H H Me Me Me Me Me Me O O O O Me Me 55% yield 39% yield PMBO PMBO 3 steps Me Me Me PMBO 5 steps, 17% overall yield from lactone Me or OTBS OPMB 7 steps, 42% yield fromacyclic aldol route Me Me OTBS Me Me Me HO Paterson 2001 Me O O OH O NH2 Finishing the C9 to C24 Fragment Me Me OH O Me Me OH HO Me Me Me Me Me PMBO 1. MesSO2Cl, Et3N PMBO Me Me 2. LiAlH4, -10°C OH OPMB OH OPMB Me Me Me Me OTBS OTBS Me Me Me 1. TBSOTf HO Me 2. DDQ OTBS OH Me Me OTBS ArO2SO Me Me O OPMB PMBO PMBO Me Super-Hydride Me OH OPMB Me Me Me Me 66% yield Me Me OTBS OTBS 7 Me Me Me HO Paterson 2001 Me O O OH O NH2 Final Coupling at C7 Me Me OH O Me Me OH Me Me Me Me Me Me HO 1. TEMPO MeO Me Me OTBS OH 2. Still-Gennari HWE O OTBS OH Me Me OC F Me Me MeO 2 5 P OC F OTBS 2 5 OTBS O O O Me Me Me Cl C N chiral boron reagent control 3 C 1. O ; K2CO3 O of a mismatched case Me 2. DIBAL OTBS OBL2 3. DMP OTBS O NH2 Me Me MeO2C OTBS O Me Me Me Me Me HO Me * O OTBS O NH2 1. Me4NBH(OAc)4 (+)-Discodermolide MeO2C Me Me OH O 2. HF pyr or 10.3% overall yield Me Me 3N HCl/MeOH 23 steps (longest linear) OTBS Me Me Me HO Me Paterson 2001 * O O OH O NH2 Chiral Boron Reagent Addition Me Me OH O Me Me OH Me Me Me OTBS OBL 2 O Me MeO2C + OTBS OH Me Me Me Me OTBS Me Me Me Me Me Me HO HO Me Me + O OH O NH2 O OH O NH2 MeO2C Me Me MeO2C Me Me OH O OH O Me Me Me Me OH OH R S yield nu Me Cy2BCl 88 12 67 O H H Me (+)-Ipc2BCl 16 84 87 RL O (—)-Ipc2BCl* 97 3 88 H H RL nu “..the first example of a chiral boron reagent overturning the intrinsic stereoselectivity of a complex aldol coupling between chiral carbonyl compounds” 8 Me Me Me HO Paterson 2003, Second Generation Me O O OH O NH2 Tri-substituted olefin Me Me OH O Me Me OH 1.