Total Syntheses of FR182877                                            MacMillan Group Meeting                            ...
FR182877 : Taxol-type                                                          HO                                         ...
A Proposed Biogenetic Synthesis of FR182877                                                                               ...
A Proposed Biogenetic Synthesis of FR182877                                                                               ...
The Pivotal Transformation: Endo vs. Exo                HO           H                  MeMe          B                   ...
Evans: A Diels-Alder Cascade Strategy                                                                        Suzuki       ...
Aldol Fragment Synthesis: Dibromide Fragment                                                                              ...
Aldol Fragment Synthesis: Boronic Acid Fragment                           OH         i. nBuLi, THF                        ...
Suzuki Coupling of the "Aldol" Fragments                                                              HO                  ...
Synthesis of the Pivotal Macrocycle                     O        OTBS                                                     ...
The Diels-Alder Cascade in Action                                                                                         ...
A Closer Look at the Cyclization Sequence                                                                   intermediate s...
Studying the Inherent Stereoselectivity of the TADA Cascade        ! Model IMDA study shows high endo selectivity with poo...
OMe                                               Me        OMeModeling the TADA Endo                         Me          ...
Analysis of the Transannular Hetero Diels-Alder Cycloaddition                                      ! Tricyclic intermediat...
HO                             HO           H                 Me                       MeMe                               ...
A Proposed Biogenetic Synthesis of FR182877                                                                               ...
Sorensen: Initial Retrosynthetic Strategy Towards (+)-FR182877                                   featuring a D-A / Knoeven...
Highlighted Issues in the Initial Strategy Towards (+)-FR182877                                              selectivity i...
Highlighted Issues in the Initial Strategy Towards (+)-FR182877                                            forming the !-k...
A Revised Retrosynthetic Strategy Towards (+)-FR182877                                       featuring a Knoevenagel / RCM...
Highlighted Issues in the Revised Strategy Towards (+)-FR182877                         unfruitful condensation reactions ...
Highlighted Issues in the Revised Strategy Towards (+)-FR182877                                                       an u...
A Re-revised Retrosynthetic Strategy Towards (+)-FR182877                                                                 ...
Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877                                                        ...
Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877                                               haunted b...
Sorensen: The Retrosynthetic Strategy that Worked                                                                   featur...
Synthesis of !-allyl Stille Coupling Fragment                                                                             ...
Fr182877
Fr182877
Fr182877
Fr182877
Fr182877
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Fr182877

  1. 1. Total Syntheses of FR182877 MacMillan Group Meeting October 5, 2005 Sandra LeeKey Articles:Isolation Papers: (a) Sato, B.; et. al. J. Antibiot. 2000, 53, 123; (b) Sato, B.; et. al. J. Antibiot. 2000, 53, 204;(c) Yoshimura, S.; et. al. J. Antibiot. 2000, 53, 615.Sorensen Synthesis: (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc. 2002, 124,4552; (b) Vanderwal, C. D.; Vosberg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393.Evans Synthesis: (a) Evans, D. A.; Starr, J. T. Angew. Chem. Int. Ed. 2002, 41, 1787; (b) Evans, D. A.; Starr, J.T. J. Am. Chem. Soc. 2003, 125, 13531.
  2. 2. FR182877 : Taxol-type HO H MeCytotoxicity and Antimitotic Activity A Me B! Isolation–Fujisawa Pharmaceutical Co. H H OH C O Isolated from the fermentation broth of Steptomyces 2 in 1998 with IC50 = 28-75 ng/mL cytotoxicity against DO several cell lines. Me 20 EO F H Structurally similar natural products: Hexacyclic Me Acid, Macquaimicin A, and Cochleamycin A! Synthetic challenges (a) 19-membered Hexacyclic carbomacrocycle featuring 12 stereocenters (b) Vinlogous carbonate embedded in a 6-6-7 fused ring system (c) Instability to air oxidation (C2-C21) to form a biologically inactive epoxide! Completed syntheses ! Ongoing synthetic efforts (+)-FR182877 by Sorensen in 2002 Armstrong in 2001: Model DF ring system (–)-FR182877 by Evans in 2002 Nakada in 2002: AB bicycle (+)-FR182877 by Sorensen in 2003 Roush in 2003: ABC tricycle Prunet in 2004: A ring Clarke in 2005: DEF ring system, B ring H O O H O Me Me O H H H H Me Me HO H OH HO H OH H H O O H VS. H H Me H H Me H Me Me (+)-FR182877 (–)-FR182877
  3. 3. A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OHsee Classics II, p. 490 Me
  4. 4. A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OHsee Classics II, p. 490 Me
  5. 5. The Pivotal Transformation: Endo vs. Exo HO H MeMe B CO2R OH HO OH H H OH H H Me OH O Cascade TADA Me B D O H H DO Me Me O H Endo-TS Me Me (–)-FR182877 Me OH OH Me Me O CO2R HO Me AcO H Me CO2R OH HO2C B HO OH H OH OH H H Me Me Cascade TADA H O D B O H H DO OH Me O H Exo-TS Me Me Me Hexacyclinic Acid
  6. 6. Evans: A Diels-Alder Cascade Strategy Suzuki HO H Me Br OR OR Transannular Me Diels-Alder OH reaction Me H H O Transannular Me O O hetero- !-ketoester alkylation Me O H Diels-Alder reaction CO2Et Me TBSO Me OR OR O O OH O OTBDPS OTBDPS OTBDPS(HO)2B O N H Me Me Bn O OR O O OH OMeO Me Me Me N O N H Me Me Br Me OTBS OTBS Bn Br
  7. 7. Aldol Fragment Synthesis: Dibromide Fragment O O i. , THF i. TBSCl, DMF, imid. Me MgBr Me H OH H OTBS ii. O3/O2; PPh3 ii. triethylorthoacetate, proprionic acid, 150°C OTBS 75% iii. DIBAL, –78 °C 73% O O OH i. MeNHOMe • HCl Bu2BOTf, TEA Me3Al, THF Me O O O N ii. TBSCl, DMF, imid. 88% Me OTBS iii. TsOH:nBu4NHSO4 (1:4) O N Bn MeOH, 0 °C Me 82% Bn O OTBS i. Dess-Martin O OTBSMeO Me Periodinane, NaHCO3 MeO Me N N Me ii. CBr4, PPh3, Me Br Me Me OH CH2Cl2, NaHCO3 70% Br
  8. 8. Aldol Fragment Synthesis: Boronic Acid Fragment OH i. nBuLi, THF TBDPSCl O Bu2BOTf, TEA OTBDPS HO H O O ii. SO3–Pyr, DMSO CH2Cl2, TEA 89% O N 59% Me Bn OH i. MeNHOMe • HCl O O O OH Me3Al, THF i. DIBAL, THF, –78 °CO N ii. HCCMgBr ii. TBSCl, DMF, imid. Me OTBDPS Me OTBDPS 75% >20:1 dr Bn 92% catechol-BH, OTBS OTBS Cy2BH (10 mol%) OTBS OTBS THF; 1N NaOH (HO)2B 97% Me OTBDPS Me OTBDPS
  9. 9. Suzuki Coupling of the "Aldol" Fragments HO H Me O OTBS MeO Me Me OH N H H O Me Me Br 5% Pd(PPh3)4 Tl2CO3 O Me O H Br THF:H2O (3:1), rt Me 84% desired pdt OTBS OTBS OTBDPS (HO)2B 8 Me O OTBS MeO Me N OTBS OTBS Me Me OTBDPS Br Me undesired double addition product! Highly Optimized Suzuki Coupling Conditions O OTBS The coupling was sensitive to the choice of base: MeO Me (1) strong bases (i.e. hydroxides, oxides) or less halophilic N OTBS OTBS cations resulted in slower rates and competitive Me Me OTBDP decomposition of SM via protodeborylation, oxidation, S elimination, etc. Me OTBS (2) silver bases completely decomposed products OTBDPS TBSO (3) carbonates had the best selectivity and only Tl2CO3 Me gave good reaction at rt
  10. 10. Synthesis of the Pivotal Macrocycle O OTBS O O OTBS MeO Me Me N EtO Me Me Me Br i. DIBAL, –78 °C Br ii. ethyldiazoacetate OTBS SnCl2 OTBS TBDPSO 70% TBDPSO OTBS OTBS Me Me O O OTBS Me O Me OTBS EtO EtO 2 Me Cs2CO3, *i. TBAF, AcOH, DMF THF (0.005M), rt O Me Brii. I2, PPh3, CH2Cl2 1:1 dr Me OTBS 64% (3 steps) I TBSO OTBS Br TBSO Me
  11. 11. The Diels-Alder Cascade in Action TBSO O Me OTBS Me OTBS H MeEtO EtO2C Br Ph2Se2O3, SO3-Pyr O Me OTBS O Me H H TEA, THF, rt; CO2Et Me hexanes, 50 °C Me TBSO 63% Me O H TBSO TBSO Br H TBSO Br TBSO Me single diastereomer HO HO H Me H Me i. HF-MeCN Me TMSOK, THF; Me OH OH H H H H ii. Pd(dppf)Cl (10 mol%) CO2Et NaHCO3, CH2Cl2 O Me3B3O3, Cs2CO3, O DMF:H2O (2:1), 100 °C HO Me H Cl 62% Me H O O N I 63% H Me Me Me Evans: [!]23D = -5 Fujisawa: [!]23D = -3.5
  12. 12. A Closer Look at the Cyclization Sequence intermediate species were not isolable TBSO Me OTBS TBSO Me OTBS H MeEtO2C H Me EtO2C Br B O Me [O] 15 H OTBS Br 3 O Me H H OTBS H H 4 14 Me " CO2Et 5 Me CO2Et 12 Me O TBSOTBSO 9 Me O H Br TBSO Me TBSO Br H TBSO Me OTBS ! NMR analysis shows 2H-pyran equilibrium O Z 1:1 X O ! Cyclization order? The Normal-demand DA (NDA) Y OH Me OTBS or inverse-demand hetero DA (HDA)? EtO2C Keq = FMO anaylsis using calculated (Spartan 5.1) Pz orbital 1-10 coefficients of the HOMO and LUMO predicts B-ring O Me cyclization to occur first. O OTBS OH Me HOMO LUMO X O Z TBSO Br Atom Pz Atom Pz Y best overlap C9 0.38 C5 0.51 best overlap C12 -0.48 C4 -0.26 C14 -0.07 C3 -0.56 C15 0.03 O1 -0.29Moorhoff (Syn 1997, 685): 6!-cyclization to pyran tautomer
  13. 13. Studying the Inherent Stereoselectivity of the TADA Cascade ! Model IMDA study shows high endo selectivity with poor diastereofacial selectivity Sorensens system, the enantiomer which differs only in silyl protecting groups and the Me @ C11, also observed high endo selectivity and the opposite dr 61:31 dr. This suggests that the C6-C8 stereotriad only modestly differentiates !-faces in the B-ring cyclization O OTBS TBSO TBSO MeO Me H Me H Me N 8 6 Me Me Br Br 11 OTBS OTBS Br 60 °C, CDCl3, 3h H H H H CHO CHO 37:63 dr OTBS Me O OMe Me O OMe O N N OTBS Me 18 19 Me Me TBSO Me TBSO Me desired cycloadduct! The high face-selectivity of the TADA cycloaddition is conjectured to arise from C18,C19 stereocenters
  14. 14. OMe Me OMeModeling the TADA Endo Me CO2Me Transition States H H O Me MeO H H Me HH H O OMe H MeO OMe MeO O H H H endo TS I Br Br Me Me Nine simplified macrocycles (varied Me OMe at C18 and C19) were energy- CO2Me minimized (PM3) with distance MeO H H MeO H H Me constraints (of 2.9-2.1 Å) leading to O Me MeO Me the observed natural product (via H H OMe Br O OMe O endo TS I) or its endo MeO Me H H diastereomer (via endo TS II). H Br endo TS II H Me For each macrocycle, five energy-minimized geometries were obtained and two energy curves were generated plotting the increasing energy penalty for !-face alignment of the approaching TS ( I and II). 18 19 Me OMe EtO2C EtO2C O Me OTBS Me O Me CHO Me Me TBSO Me MeO Br Br MeO MeO MeO Br 4.0-9.4 kcal/mol
  15. 15. Analysis of the Transannular Hetero Diels-Alder Cycloaddition ! Tricyclic intermediate has two low-energy conformations Me OMe Me OMe H CO2R Me H CO2R H !E = H Me MeO MeO H Me O OMe H OMe HO 2 kcal/mol H H Br H Br Me kinetic conformation from 1st D-A required conformation for 2nd D-A ! Application of transition state bond constraints energetically favors desired cyclization Me OMe Me OMe H CO2R H 3 Me CO2R H H 3 Me MeO MeO H Me O OMe H HO OMe X 15 14 RO RO H 14 H Me 15 H H Me Br H Br Me C3-C14: at 2.2 Å = –146 kcal/mol C3-C14: at 2.2 Å = –173 kcal/mol BrBr OR OR O-C15: at 2.4 A O-C15: at 2.4 A H H H H OR CO2R CO2R !!G = 27 kcal/mol RO Me Me O H Me O Experiment: R = TBS, R = Et H H Calculation: R, R = Me Me
  16. 16. HO HO H Me MeMe Me OH H OH H H O H O O O H H Me O H Me O Me Me (–)-FR182877 (+)-FR182877
  17. 17. A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OHsee Classics II, p. 490 Me
  18. 18. Sorensen: Initial Retrosynthetic Strategy Towards (+)-FR182877 featuring a D-A / Knoevenagel / D-A sequence RO H Me HO HO Me Me Me Transannular OR H H hetero- CHOMe Diels-Alder Me Knoevenagel H OH reaction H OH condenstation H O O O O Me H H H O Me O Me O Me O Me Me O RO RO H Me Me Y Me Me X OR Tandem Stille OR H H Claisen-Type Coupling- CHO Cyclization CHO IMDA Bn Bn Me O Me O N N O O X = SnBu3 or Br AcO Me O AcO Me O Y = SnBu3 or I
  19. 19. Highlighted Issues in the Initial Strategy Towards (+)-FR182877 selectivity in the tandem Stille/IMDA sequence TBSO TBSO Me Me Br Bu3Sn Pd2dba3 (5 mol%), MeMe OTBS OTBS Ph3As (20 mol%), THF, reflux IMDA CHO CHO Bn Bn or Me OMe O Cl2Pd(CN)2 DMF, rt N N O O AcO Me O AcO Me O TBSO TBSO H Me H Me Me Me OTBS OTBS H H H H CHO CHO Bn Bn Me O Me O N N O O AcO Me O AcO Me O undesired endo cycloadduct
  20. 20. Highlighted Issues in the Initial Strategy Towards (+)-FR182877 forming the !-keto lactone and Knoevenagel condensation TBSO TBSO H Me H Me Me Me OTBS 5 OTBS H H KHMDS ( 4 eq) H H CHO THF, –78 °C CHO Knoevenagel Bn Me O Me N O O AcO Me O Me O O HO ! Issues encountered in this approach: Me The desired !-keto lactone substrate was unstable to Stille coupling, as such the acetate imide was used. Me H OH The IMDA was not diastereoface-selective and gave 2 endo cycloadducts O O (separable by chromatography) H The Knoevenagel condensation to form the tetracycle ring was unsuccessful Me O Me revise strategy to an intermolecular Knoevenagel condensationSorensen: Org. Lett. 1999, 1, 645 + JACS 2003, 125, 5393
  21. 21. A Revised Retrosynthetic Strategy Towards (+)-FR182877 featuring a Knoevenagel / RCM approach HO HO Me Me TransannularMe hetero- Me H OH Diels-Alder H OH Ring-Closing H O reaction O Olefin Metathesis O O H H H Me O Me O Me Me RO H Me RO Me Me H OR H O Me CHO H OR Intermolecular H Condenstation O O O H O H O Me Me Me Me
  22. 22. Highlighted Issues in the Revised Strategy Towards (+)-FR182877 unfruitful condensation reactions are circumvented via a HWE TESO i. TBAF, THF TESO TESO Me ii. Dess-Martin H Me H Me Periodinane, NaHCO3Me Me Me OTES H OTES H OTES iii. NMP, rt H H OTES CHO CHO 1.9:1 dr 53% undesired product O O for IMDA rxn: Yamamotos BLA and MacMillans i. Et3N•3HF Me catalysts were also tried P ii. Ba(OH)2, THF, Me O O Br OMe iii. TESCl, N TEA, DMAP Me Me 6.5:1 Z:E Me TESO 65% H Me TESO H Me Me H OTES H Me Br H OTES H O O O O O O OMe Br OMe N N Me Me Me Me Me Me undesired product
  23. 23. Highlighted Issues in the Revised Strategy Towards (+)-FR182877 an unexpected olefin geometry in alkylidene formation TESO TESO H Me H MeMe Me t-BuLi, H OTES OTES THF, –78 °C H H H OR O Br >90% H O Li O O Br OMe E O O O N OMe Me Me transient lithium allenoate N Me Me Me Me TESO H Me ! Issues Encountered in this Approach: Me IMDA to form the first fragment was moderately diastereoface-selective (1.9:1 H OTES desired:undesired) H The desired !-keto lactone and the acyclic !-keto ester were not amenable to the O O Knoevenagel condensation O Isomerization to the needed E geometry of alkylidene ketolactone was not Me realized though various methods Me revise strategy to form E-geometry alkylidene dicarbonyl undesired Z-olefin geometry
  24. 24. A Re-revised Retrosynthetic Strategy Towards (+)-FR182877 OR Me Me OR H H HO RO Me Me CHO Transannular hetero- Diels-Alder H-W-E Me O OMeMe Me Condensation reaction H OH H OR N H O O O O Me O Me H H H Br Me O Me O O Me Me P OMe reductive C-acylation O OMe RO RO Me Me Intramolecular Me Diels-Alder Me OR OR reaction Me3Sn OTES CHO OAc !-allyl Stille coupling Me O OMe N Me O OMe Me N RO Me Me RO Me
  25. 25. Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877 IMDA and the HWE sequence TESO TESO O O Me Me MeO P OH MeOMe Me Br OTES OTES i. TBAF, THF, 0 °C H H i. DCC, NaHCO3 OTES CHO ii. MnO2, DMF, rt ii. Et3N•3HF, CH2Cl2Me O OMe Me O OMe 65% (2 steps) 77% N N Me 1.6:1dr Me acylation yielded 4 spots (chromatographic separation HO Me HO Me of desired endo product) HO TESO Me Me Me Me OH OTES H H i. Ba(OH)2, THF/H2O H CHO Me Br OMe H N ii. TESCl, imid., DMAP O Me O OMe Me O O N Me Me O Me Br O * P OMe O OMe
  26. 26. Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877 haunted by the formation of the E-alkylidene TESO TESO HO Me Me Me Me Me Me H OTES i. t-BuLi, THF, –78 °C H OTES H OH 1 Me Br OMe H OMe H H Me 19 O N ii. PPTS, MeOH N O OLi O Me O 64% (4 steps) Me O Me O O O Me Me Me undesired Z olefin geometry confirmed by X-ray ! Issues Encountered in this Approach: IMDA gave poor diastereofacial selectivity (1.6:1 of desired:undesided cycloadduct) Key reductive lithiation cyclization step resulted in the formation of an undesired Z alkylidene dicarbonyl tetracycle. It was conjectured that the geometrical constraints of the 12-membered ring would had favored the Z isomer revise strategy in forging the C1-C19 bond and forming the !-keto lactoneSorensen: Org. Lett. 2001, 3, 4307 + JACS 2003, 125, 5393
  27. 27. Sorensen: The Retrosynthetic Strategy that Worked featuring tandem TADA reactions RO OR HO Me Me lactonization Me O OMe Me OMe OR tandem RO OTMS O O H OH t-BuO TADAs H O TMSO O O OP H H Me Me Me H Me O Me O !-allyl Stille coupling Me Me Tsuji-Trost allylic alkylation OR Me OR OR O O OR Me OR OR O OO N OMe P RO HWE Me O OMe H I Bn Me SnMe3 Me OTMS O O TMSO O O AcO N AcO OMe O N Me Me Me Me Me Ph
  28. 28. Synthesis of !-allyl Stille Coupling Fragment MeNHOMe • HCl O O O OH Bu2BOTf, TEA Me3Al, THF OTBS OTBSH O N O O 75% (2 steps) Me(2 steps from diol) O N Bn Me Bn OTMS i. TMSCl, DMAP, O OH Me OTBS imid, CH2Cl2 MeO OTBS N ii. LiCH2P(O)(OMe)2, O Me Me THF, –78 °C OMe P O OMe OH OTES i. Ba(OH)2, THF; Me OH i. Et2BOMe, NaBH4 Me OTES THF/H2O, 0 °C THF/MeOH O ii. TESCl, DMAP, TESO I O imid., CH2Cl2 Me I Sn(Me3) Me iii. Me3SnSnMe3, Me ii. PPTS, MeOH, rt Pd(Ph3P)4, Hünigs, 79% (4 steps) PhH, 80 °C 83% (3 steps)
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