Structural Features of Vancomycin Type Glycopeptide Antibiotics! Generally characterized by an aryl-rich polypeptide backb...
Proposed Biosynthesis of Vancomycin-Type Glycopeptides ! Remarkably, genes and proteins responsible for the biosynthesis o...
Biological Activity (Gram-Positive Bacteria)! Vancomycin inhibits cell wall cross-linking through tight binding, eventuall...
The Evans Design     ! Chiral auxiliary technology will be used to create most amino acid stereocenters                   ...
Oxazolidinone-Based Amino Acid Synthesis    ! Chiral auxiliary approach creates labile arylglycine stereocenters in contro...
Oxazolidinone-Based Amino Acid Synthesis! The auxiliary approach proves unsuccessful for the central resorcinol-type arylg...
Synthesis of the Left Macrocycle  ! Oxazolidinone methodology is employed to stereoselectively access a protected amino al...
OH   Synthesis of the Left Macrocycle                                                             O               O       ...
OH    Synthesis of the Left Macrocycle                                                              O             O       ...
OH   Synthesis of the Left Macrocycle                                                                            O        ...
OH          Synthesis of the Left Macrocycle                                                                  O           ...
OH            Synthesis of the Left Macrocycle                                                        O             O     ...
OH       Synthesis of the Left Macrocycle                                                            O             O      ...
OH       Synthesis of the Left Macrocycle                                                   O               O             ...
OH        Synthesis of the Right Macrocycle                                                                    O          ...
OH          Synthesis of the Right Macrocycle                                                                             ...
OH          Synthesis of the Right Macrocycle                                                                             ...
OH              Completion of Vancomycin                                                                                  ...
OH                Completion of Vancomycin                                                                                ...
The Nicolaou Design     ! Sharpless asymmetric catalysis will be used to create most amino acid stereocenters             ...
Dihydroxylation/Aminohydroxylation Based Approach      ! Sharpless methodology used to create aryl amino acid stereocenter...
Dihydroxylation/Aminohydroxylation Based Approach     ! As in the Evans synthesis, creating the central fragment is challe...
Nicolaous Triazene-Driven Ether Synthesis! Triazene serves to activate aryl ring for SNAr and acts as functional handle fo...
OH            Cl            Approach to the Left Macrocycle                                                               ...
OH            Cl         Approach to the Left Macrocycle                                             Cl                   ...
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
Comparative syntheses of Vancomycin
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Comparative syntheses of Vancomycin

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Ian Mangion
MacMillan Group Meeting
September 28, 2005
http://www.princeton.edu/chemistry/macmillan/

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Comparative syntheses of Vancomycin

  1. 1. Structural Features of Vancomycin Type Glycopeptide Antibiotics! Generally characterized by an aryl-rich polypeptide backbone with varying crosslinking and glycosidation patterns Me HO HO HO HO HO H2N O Me OH O OH N O O O H O O HO Cl Y HO OH O O O O H2N O Cl X H H O N O HO N O H O O OH H O O OH N N Me O N O N H NH H HO2C NH O NH NH O NH HN NH2 O2C NH2 O O O H2N Me HO HOHO Me O OH O OH OH O HO OH X = Y = Cl; Vancomycin HO OH X = H, Y = Cl; Eremomycin OH X = Y = H; Orienticin C Teicoplanin! Useful references Hubbard, B. K.; Walsh, C. T. Angew. Chem. Int. Ed., 2003, 42, 730 Kahne, D.; Leimkuhler, C.; Lu, W.; Walsh, C. Chem. Rev., 2005, 105, 425 Evans, D.; Wood, M. R.; rotter, W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem. Int. Ed., 1998, 37, 2700 Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winsigger, N.; Hughes, R.; Bando, T. Angew. Chem. Int. Ed., 1999, 38, 240 Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc., 1999, 121, 10004
  2. 2. Proposed Biosynthesis of Vancomycin-Type Glycopeptides ! Remarkably, genes and proteins responsible for the biosynthesis of these molecules have been characterized ! Biosynthesis can be reduced to peptide elongation and post-translational modification Cl OH OH ClMeO OMe O Me OH HO OH OH HO H2N HO Me NHMe OH OH H2N OH OH OH H2N OH H2N H2N H2N H2N O H2N O O O O O O OH OH Cl OR Cl OR Cl HO OH O O H Cl HO N O H H O O OH HO N O N [O] H O O OH O N Me N O N Me H NH HN NH2 O2C NH O H NH HN NH2 O2C NH O O O O O H2N Me HO H2N Me Me HO OH OH Me OH OH ! The challenge to the synthetic chemist is immense: biosynthesis entails 35 total steps
  3. 3. Biological Activity (Gram-Positive Bacteria)! Vancomycin inhibits cell wall cross-linking through tight binding, eventually leading to cell lysis OR Cl OR Cl O O O O Cl Cl H HHO N O HO O H O O OH N H N O O OH O N Me N Me O N N O H N N NH2 N NH2O2C H O2C N O H N H H H H H O O O O H2N Me MeHO H2N Me HO Me OH OH OH OH O Me H O O Me O N O N O N O H H O Me O Me Alanine dimer - normally linked (resistance) to glycan outer wall of cell! Disruption of just one of the five hydrogen bonds leads to a 1000-fold loss in activity
  4. 4. The Evans Design ! Chiral auxiliary technology will be used to create most amino acid stereocenters OH Cl Oallyl O O O OH F Cl Cl H H HO HO N O HO N O H O O OH H O O NO2 N Me N O N O O N H NH HN NH H NH HN NMeBocHO2C NH O NH O O O MeHN O O H2N Me DdmHN MeHO Me BnO Me OH OH OBn OBn Oallyl Oallyl O OH HO OMs O2N Cl OH H H HO N O F O H N H N N O NH2 Cl O O NHBoc HO2C NH O NH O MeHN HO BnO OH OH OBn OBn ! This strategy relies on atropdiastereoselective macrocyclizations
  5. 5. Oxazolidinone-Based Amino Acid Synthesis ! Chiral auxiliary approach creates labile arylglycine stereocenters in controlled fashion X = tetramethyl guanidinium Bu Bu O O B O O O O O OR NBS R XN3 R N O R N O N O N O -78 °C Br N3 Bn Bn Bn Bn dr 91:9 - >99:1 O O K O O O O O OR KHMDS TrisN3; SnCl2; R R R N O N O N O N O HOAc Boc2O N3 BocHN Bn Bn Bn Bn dr 91:9 - >99:1 Tris = 2,4,6-triisopropyl phenyl ! This strategy is applied to all arylglycines in the Evans synthesis Evans, JACS, 4011, 1990
  6. 6. Oxazolidinone-Based Amino Acid Synthesis! The auxiliary approach proves unsuccessful for the central resorcinol-type arylglycine OH Oallyl MeO OMe TBSO OMs BnO NHMe H2N OH OH BocHN BocHN O O 1 O OH Oallyl Oallyl Br Br Br OH 1) Br2 1) BuOCOCl, NMM, 2) Boc2O MeNH2 74% yieldHO 3) NaH, HO NH2 2) MeMgCl; tBuLi; MeHN AllylBr NHBoc NHBoc B(OMe)3; H2O2 O O O 70% yield Oallyl Oallyl 1) TBSCl HO OTBS 2) MeMgCl; tBuLi; MsO OH 1) MsCl 1) LiOOH B(OMe)3; H2O2 1 2) Boc2O 2) TBSCl Boc 3) HF•pyr MeN MeHN NHBoc NHBoc O O
  7. 7. Synthesis of the Left Macrocycle ! Oxazolidinone methodology is employed to stereoselectively access a protected amino alcohol O O Cl TfO OTf F NCS O N Sn O O O Sn(OTf)2, NMP O2N Bn NCS S 19:1 dr O N O THF, -78 °C N Cl H Bn O N F Bn O OO2N H 1) Boc2O; HCO2H, H2O2 2) LiOOH Cl O F NH2•TFA MeHN O Cl O2N O O F72% yield O N 46% from MeO OMe Boc benzaldehyde NH O MeHN O2N O EDCI•HCl, HOBt, 0 °C O N OH Boc MeO OMe
  8. 8. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O! Functional group adjustment and amino acid coupling O O H2N Me HO Me OH OH Cl F Cl F 1) Li2CO3, MeOH O O2N 2) TFA, DMS, CH2Cl2; OH O O2N O O O N EDCI•HCl, HOBt, 0 °C O NHBoc NH Boc O N MeHN O H NH OBn NHBoc MeHN HO OBn MeO OMe OMe MeO OMe OMe 82% yield
  9. 9. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O! Oxidative coupling provides undesired atropisomer O O H2N Me HO Me OH OH Cl F O2N OH OH H O2N O F N O 1) TFA, DMS; TFAA O NHBoc NHTFA O N O O H 2) VOF3, BF3•Et2O, Cl OH NH OBn AgBF4, TFA/CH2Cl2; NH MeHN NaBH(OAc)3 MeHN OMe OMe MeO OMe MeO OMe 65% yield, 19:1 dr! Vanadium serves as oxidant, BF3 as trap for oxygen nucleophiles, silver as trap for chloride ion impurities, TFA as part of solvent mixture, NaBH(OAc)3 as reductive quench see: Evans,JACS, 6426 1993
  10. 10. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O! Oxidative coupling proceeds via radical cation O O H2N Me HO Me OH OH Cl F O2N OH OH H O2N O F N O 1) TFA, DMS; TFAA O NHBoc NHTFA O N O O H 2) VOF3, BF3•Et2O, Cl OH NH OBn AgBF4, TFA/CH2Cl2; NH MeHN NaBH(OAc)3 MeHN OMe OMe MeO OMe MeO OMe O H O N O NHBoc NHTFA O N O O H OBn NH OBn NH MeHN MeHN OMe OMe MeO OMe MeO OMe see: Evans,JACS, 6426 1993
  11. 11. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Careful coupling introduces the central aryl fragment O O H2N Me HO Me OH OH Oallyl O2N TBSO OMs O2N OH 1) NaHCO3, MeOH, 6 d OH H O HF N F O N 2) HATU, HOAt, collidine H NHTFA N O O CH2Cl2/DMF, -20 °C O NHBoc Cl OH Cl O NH NH OH Oallyl O MeHN TBSO OMs MeHN OMe OMe 65% yield MeO OMe MeO OMe HO2C NHBoc N N Me N N HATU N Me O HOAt N Me Me
  12. 12. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Macrocyclization occurs with good selectivity O O H2N Me HO Me OH OH Oallyl Oallyl TBSO OMs O2N O OMs OH H 1) HF•pyridine ClF N O H H 2) Na2CO3, DMSO; HO O N N H PhNTf2 O O NHBoc N Cl O NHBoc OH O NH O 3) Zn0, AcOH OTf O NH 4) NaNO2, H3PO2, MeHN cat. Cu2O MeHN OMe OMe MeO OMe MeO OMe 62% yield 5:1 dr (10:1 dr w/o Cl)
  13. 13. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Thermal equilibration provides the desired atropisomer O O H2N Me HO Me OH OH OPiv Oallyl O OMs O OMs 1) Pd(dppf)Cl2, HCOH, DMF, 75 °C Cl Cl H H 2) Piv Cl HO N O HO N O H H 3) TFA, DMS; TFAA N N O O NHBoc O O NHTFA OTf O 4) AlBr3, EtSH NH O NH 5) MeOH, 55 °C MeHNMeHN OMe HOMeO OMe OH OH 44% yield 19:1 dr see: Evans,JACS, 6426 1993
  14. 14. OH Synthesis of the Left Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Thermal equilibration provides the desired atropisomer O O H2N Me HO Me OH OH OPiv OPiv O OMs O OH Cl Cl H O HO N H H 1) BnBr, Cs2CO3 HO N O N 2) LiSEt, THF, 0 °C H N O O NHTFA O O NH2 NH O 3) allyl-Br, Cs2CO3 NH OMeHN 4) LDA, -78 °C MeHN 5) LiOH, THF/MeOH HO BnO OH OH OBn OBn 65% yield
  15. 15. OH Synthesis of the Right Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Fragment coupling completes the peptide chain O O H2N Me HO Me OH OH OPiv OPiv O OH O OH F Cl Cl H EDCI, HOAt, THF, 0 °C H HO HO N O HO N O O NO2 H H H N N N F O O NH2 O O N H NH NH O NH O O O NMeBoc HO OMeHN NO2 MeHN H NHDdm CH2CHMe2 HO2C N NH BnO BnO O O NMeBoc OBn OBn O OBn OBn NHDdm CH2CHMe2 86% yield MeO OMe For synthesis of tripeptide, see Nicolaou Classics II, p. 290 Ddm
  16. 16. OH Synthesis of the Right Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Closure of the second macrocycle proceeds O O H2N Me with the desired atropdiastereoselectivity HO Me OH OH Oallyl Oallyl Cl O OH F O O Cl 1) CsF, DMSO Cl H HO H HO N O O NO2 HO N O H H 2) Zn0, AcOH H O O OH N N N O O N NH 3) HBF4, tBuONO, O O N H H NH O O O NMeBoc MeCN; CuCl/CuCl2 NH O NH HN NMe O BocMeHN NHDdm CH2CHMe2 MeHN O O DdmHN Me BnO BnO Me OBn OBn OBn OBn 60% yield 5:1 dr
  17. 17. OH Synthesis of the Right Macrocycle O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Closure of the second macrocycle proceeds O O H2N Me with the desired atropdiastereoselectivity HO Me OH OH Oallyl Oallyl Cl O OH F O O Cl 1) CsF, DMSO Cl H HO H HO N O O NO2 HO N O H H 2) Zn0, AcOH H O O OH N N N O O N NH 3) HBF4, tBuONO, O O N H H NH O O O NMeBoc MeCN; CuCl/CuCl2 NH O NH HN NMe O BocMeHN NHDdm CH2CHMe2 MeHN O O DdmHN Me BnO BnO Me OBn OBn OBn OBn Mechanism for Sandmeyer reaction not fully known, but may be as follows: 60% yield 5:1 dr ArN2+ X- + CuX Ar + N2 + CuX2 Ar + CuX2 ArX + CuX
  18. 18. OH Completion of Vancomycin O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! An unusual mild deprotection reveals a carboxylic acid O O H2N Me HO Me OH OH Oallyl Cl Oallyl Cl O O O O Cl Cl H H HO N O HO N O 1) N2O4, NaOAc H OH H OH O O O O N N O O N O O N 2) H2O2, LiOH H NH NMe H NH NMe NH O HN NH O HN Boc Boc HOMeHN O O O O DdmHN Me DdmHN Me BnO Me BnO Me OBn OBn OBn OBn 68% yield ! Nitrosation in the presence of seven amide functionalities
  19. 19. OH Completion of Vancomycin O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Final deprotection proves uneventful O O H2N Me HO Me OH OH Oallyl OH Cl Cl O O O O Cl Cl H H O HO N O HO N H O O OH H O O OH N 1) Pd(PPh3)4 N O O N O O N H H NH NMe NH O NH HN NMe NH O HN Boc 2) Pd/C, EtOH,HO 1,4-cyclohexadiene HO O O O O 3) TFA, DMS, CH2Cl2 DdmHN Me H2N MeBnO Me HO Me OBn OBn OH OH 62% yield ! Completion of vancomycin aglycon in 40 linear steps Evans, Wood, Trotter, Richardson, Barrow, Katz ACIEE, 1998, 2700
  20. 20. The Nicolaou Design ! Sharpless asymmetric catalysis will be used to create most amino acid stereocenters N OH Cl N O O N Cl O Br H OH HO N O Cl H O O OH H N TBSO N O TBSO O N Me H H N O O Cl NH O NH HN NH O NH2HO2C HO NH O NH HN NMeBoc O O H2N Me BnOHO O O Me Me OH OH DdmHN MeO Me OMe OMe OH Cl N H O TBSO N O MeO N N O NH2 NHBoc Br Br NH OH BnO BnO HO MeO NH2 MeO OMe OMe O OMe OMe ! Atropdiastereoselctivity left unaddressed in the design
  21. 21. Dihydroxylation/Aminohydroxylation Based Approach ! Sharpless methodology used to create aryl amino acid stereocenters O H OH HO 1) (n-Bu)2SnO, O 1) Ph2P=CH2 BnBr, TBAI, 70 °C BnO B OH 2) AD-mix-! 2) n-BuLi; B(OMe)3MeO OMe MeO OMe MeO OMe 84% yield, 96% ee 49% yield Cl OBn OBn NaOH, tBuOCl OBn BnOCONH2 1) TBSOTf, HO (DHQD)2AQN lutidene TBSOO O K2OsO2(OH)4 NHCbz 2) H2, Pd/C O nPrOH/H2O NH2 OEt OEt 3) SO2Cl2 (2 steps) OEt 45% yield, 87% ee 78% yield ! Enantioenrichment attained through amino acid coupling
  22. 22. Dihydroxylation/Aminohydroxylation Based Approach ! As in the Evans synthesis, creating the central fragment is challenging N NH2 NH2 N 1) LAH, THF, 0 °C N 1) SOCl2, MeOH Br Br 2) NaNO2, 6 M HCl, Br Br 71% yield 2) Br2, AcOH AcOH/H2O, 0 °C; KOH, pyrrolidine O OH O OMe HO 98% yield 1) PCC, CH2Cl2 O 2) Ph3P=CH2, THF PhO P 3) AD-mix-!, PhO N3 tBuOH/H2O 4) TBSCl, imidazole DPPA N N N N N N 1) Boc2O, TEA N 1) PPh3, DEAD, NBr Br 2) TBAF, THF DPPA, 0 °C N Br Br Br Br 72% yield 3) TEMPO, NaOCl, 2) PPh3, H2O, 60 °C 95% ee KBr, NaHCO3HO 68% yield NHBoc 70% yield TBSO NH2 TBSO O OH
  23. 23. Nicolaous Triazene-Driven Ether Synthesis! Triazene serves to activate aryl ring for SNAr and acts as functional handle for phenol N N K+ N N Cu N N OBr Br OH K2CO3 Br Br CuBr•Me2S O pyridine O H H N N N NHBoc N NHBoc H H Me O Me O -KBr OH Br O N N N O Br O H aq. HCl N 54% yield N NHBoc H Me O O H N N NHBoc H Nicolaou, JACS, 119, 1997, 3421 Me O
  24. 24. OH Cl Approach to the Left Macrocycle Cl O O H HO N O H O O OH N Me O N NH H NH HN NH O ! A Suzuki coupling builds the biaryl bond HO2C O O H2N Me HO Me OH OH O O NHBoc NHBoc BnO O MeO MeO B OH Pd(PPh3)4 OH 87% yield Toluene/H2O 2:1 dr MeO OMe I 90 °C BnO OMe OMe MeO OMe 1) DPPA, DEAD Cl Ph3P, THF, -20 °C OH Cl 2) LiOH, THF/H2O OH TBSO O O TBSO NH2 NHBoc80% yield EtO2C N HO H EtO2C NH2 N3 N3 94% yield 1) EDC, HOAt BnO THF, -30-> -10 °C BnO OMe OMe 2) TMSOTf, lutidene OMe MeO OMe MeO
  25. 25. OH Cl Approach to the Left Macrocycle Cl O O H HO N O H O O OH N Me O N NH H NH HN NH HO2C O O O! Peptide coupling sets up biaryl ether synthesis H2N Me HO Me OH OH Cl N OH N Cl N EDC, HOAt OH Br BrTBSO THF, 0 °C O NH2 TBSOEtO2C N O H H N N EtO2C N NHBoc N3 H N O N N3BnO Br Br OMe MeO OMe BnO OMe HO MeO OMe NHBoc O 90% yield
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