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Comparative syntheses of Vancomycin

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Ian Mangion …

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

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  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  • 26. OH Cl Closure of 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 ! Ether formation proceeds without atropdiastereoselectivity H2N Me HO Me OH OH N N N Cl N N N OH Br Br 1) CuBr, K2CO3 MeCN, 82 °C O BrTBSO O HO Cl 2) TBAF, -15 °C H O N 3) Et3P, MeCN/H2O HEtO2C N NHBoc 4) LiOH, THF/H2O N H HO2C N NHBoc O H N3 O NH2BnO OMe BnO OMe MeO OMe MeO OMe 46% yield 1:1 dr
  • 27. OH Cl Amide Formation and Deprotection Cl O O H HO N O H O O OH N Me O N NH H NH HN NH HO2C O O O ! Completion of the left half achieved via lactamization H2N Me HO Me OH OH N N N N N N O Br 1) FDPP, DIPEA O Br HO Cl DMF, 0-> 25 °C Cl O H H 2) TBSOTf, HO N O N HHO2C N NHBoc lutidene N H 3) TMSOTf, O NH2 O lutidene NH NH2 O BnOBnO OMe F OMe MeO MeO F F O OMe OMe 70% yield PhO P PhO O F F FDPP
  • 28. 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 N N N N N N O Br O Br OH Cl Cl H EDCI, HOBt, THF, 0 °C H TBSOTBSO N O TBSO N O O Cl H H H N N N O NH2 OH O N NH H NH O NH O O O NMeBoc TBSO OBnO Cl BnO H NHDdm CH2CHMe2 HO2C N NHMeO MeO O O NMeBoc OMe OMe O OMe OMe NHDdm CH2CHMe2 86% yield For synthesis of tripeptide, see Nicolaou Classics II, p. 268
  • 29. 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 ! Triazene-activated ether formation favors unnatural O O H2N Me atropisomer; thermal equilibration is possible HO Me OH OH N N N N N N Cl O Br OH O O Cl H TBSO ClTBSO N O O Cl CuBr, K2CO3 H H H TBSO N O N N H O O OTBS O N NH MeCN, 82 °C N H O N NH O O O NMeBoc H NH NMeBoc O NH O HNBnO NHDdm CH2CHMe2 BnO O OMeO DdmHN Me MeO OMe OMe Me OMe OMe 74% yield ! Heating unnatural isomer at 140 °C provides 2:3 mix in 80-85% yield 1:3 dr
  • 30. OH Final Functionalizations O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Triazene proves difficult to functionalize as phenol O O H2N Me HO Me OH OH N N NH2 N Cl Cl O O O O Cl Cl 1) Raney Ni, MeOH H H TBSO N OTBSO N O 2) H2, Pd(OH)2 H O O OTBS H O O OTBS N N O N O N H NH HN H NH O NMeBoc NH O NH HN NMeBoc HOBnO O O O O Me DdmHN DdmHN Me MeOMeO Me Me OMe OMe OMe OMe
  • 31. OH Final Functionalizations O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Triazene proves difficult to functionalize as phenol O O H2N Me HO Me OH OH N N I N Cl Cl O O O O Cl Cl 1) Raney Ni, MeOH H H TBSO N OTBSO N O 2) H2, Pd(OH)2 H O O OTBS H O O OTBS N N O N O N 3) HBF4, iPrONO H NH HN H NH O NMeBoc NH O NH HN NMeBoc 4) KI, 25 °C HOBnO O O O O Me DdmHN DdmHN Me MeOMeO Me Me OMe OMe OMe OMe
  • 32. OH Final Functionalizations O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Triazene proves difficult to functionalize as phenol O O H2N Me HO Me OH OH N N OH N Cl Cl O O O O Cl Cl 1) Raney Ni, MeOH H H TBSO N OTBSO N O 2) H2, Pd(OH)2 H O O OTBS H O O OTBS N N O N O N 3) HBF4, iPrONO H NH HN H NH O NMeBoc NH O NH HN NMeBoc 4) KI, 25 °C HOBnO 5) MeMgBr (30 eq) O O O O iPrMgBr (30 eq); Me DdmHN DdmHN Me B(OMe)3 (100 eq); MeOMeO Me Me H2O2 OMe OMe OMe OMe 32% yield
  • 33. OH Final Functionalizations O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Phenol protection and introduction of methyl ester O O H2N Me HO Me OH OH OH Cl OMe Cl O O O O Cl Cl H O 1) Cs2CO3, MeI HTBSO N TBSO O H O O OTBS 2) Dess-Martin N H O O OTBS N N O N O N H NH NMeBoc H NH O HN 3) KMnO4 NH O NH HN NMeBoc 4) CH2N2 MeO2CHO O O O O DdmHN Me DdmHN MeMeO Me MeO Me OMe OMe OMe OMe 74% yield
  • 34. OH Completion of the Natural Product O O Cl Cl H HO N O H O O OH N Me O N NH H NH HN NH HO2C O ! Desilylation is followed by global deprotection O O H2N Me HO Me OH OH OMe Cl OH Cl O O O O Cl Cl H HTBSO N O HO O H O O OTBS 1) HF•pyr, N H O O OH N pyridine N O N O N H NH HN NMeBoc HMeO2C NH O NH O NH HN NHMe 2) AlBr3, EtSH HO2C O O O O DdmHN Me Me H2NMeO Me HO Me OMe OMe OH OH 62% yield Nicolaou, Takayanagi, Jain, Natarajan, Koumbis, Bando, Ramanjulu, ACIEE, 1998, 2717
  • 35. Conclusions! While synthesis is not an issue in the supply of Vancomycin, fascinating chemistry has been discovered in pursuit of an expedient synthesis N Oallyl N N O OH F O Br HO HO Cl O NO2 O H H N N N NH HO2C N NHBoc H H O O NH2 BnO OMe MeO OMe N Oallyl N Cl N O O O Br Cl H HO N O O O OH H N N O NH2 H NH HN NH O BnO Evans - 36 steps MeO Nicolaou - 36 steps 0.2% overall yield OMe OMe 0.13% overall yield 84% average 82% average! Control over the wide variety of stereocenters in the context of a complex synthesis is most notable