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Ian Mangion MacMillan Group Meeting September 28, 2005 http://www.princeton.edu/chemistry/macmillan/
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Structural Features of Vancomycin Type Glycopeptide Antibiotics
! Useful references
Hubbard, B. K.; Walsh, C. T. Angew. Chem. Int. Ed., 2003, 42, 730
! Generally characterized by an aryl-rich polypeptide backbone with varying crosslinking and glycosidation patterns
O
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NH2
Me
O
H2N
HN O
OH
NH
OH
HO
O
O2C
X
HO
Y
OH
O
OH
HOHO
O
O
MeHO
MeH2N
O
O O
HN
O
NH
O
NH
O
HN O
OH
NH
O
O
O
HO2C
Cl
HO
Cl
OH
O
OH
HOHO
NH
X = Y = Cl; VancomycinX = H, Y = Cl; EremomycinX = Y = H; Orienticin C
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
NH
ONH2
HO
OH
O
O
OOHHO
HO
H2N
OHO
HO
OHOH
Teicoplanin
Proposed Biosynthesis of Vancomycin-Type Glycopeptides
! The challenge to the synthetic chemist is immense: biosynthesis entails 35 total steps
! 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
OMeMeO
H2NNHMe
O
Cl
OH
H2NOH
O
HO
H2NOH
O
OH
H2NOH
O
OH
HO OH
H2N
O
H2NOH
O
Me
H2NOH
O
Me
OR
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH2
Me
O
H2N
HN O
OH
NH
OH
HO
O
O2C
HO
OH
Cl
ClOR
HN
O
NH
O
NH
O
HN
OMe
Me
NH2
Me
O
H2N
HN O
OH
NH
OH
HO
O
O2C
HO
OH
Cl
OH
H2NOH
O
HO
HO OH
OH
ClOH
Cl
[O]
Biological Activity (Gram-Positive Bacteria)
! Disruption of just one of the five hydrogen bonds leads to a 1000-fold loss in activity
! Vancomycin inhibits cell wall cross-linking through tight binding, eventually leading to cell lysis
OR
O O
HN
O
N
O
N
O
N
OMe
Me
NH2
Me
O
H2N
HN O
OH
N
OH
HO
O
O2C
HO
OH
Cl
Cl
O
NH
O
Me
N
Me
O
O
H
HH
H H
OR
O O
HN
O
N
O
N
O
N
OMe
Me
NH2
Me
O
H2N
HN O
OH
N
OH
HO
O
O2C
HO
OH
Cl
Cl
O
NH
O
Me
O
Me
O
O
HH
H H
(resistance)Alanine dimer - normally linkedto glycan outer wall of cell
The Evans Design
! This strategy relies on atropdiastereoselective macrocyclizations
! Chiral auxiliary technology will be used to create most amino acid stereocenters
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl Oallyl
O
HN
O
NH
O
NH
O
HN
OMe
Me
NMeBoc
O
DdmHN
HN O
OBn
NH
OBn
HO
O
BnO
Cl
O
MeHN
HO
F
NO2
OH
Oallyl
O
HN
O
NH2
HN O
OH
NH
OH
HO
O
HO2C
HO
Cl
OHOallyl
HO
HN
O
NHBoc
HN O
OBn
NH
OBn
O
BnO
O
MeHN
OMs
OH
F
O2N
Cl
Oxazolidinone-Based Amino Acid Synthesis
! This strategy is applied to all arylglycines in the Evans synthesis
! Chiral auxiliary approach creates labile arylglycine stereocenters in controlled fashion
N O
O
Bn
O
R
N O
O
Bn
O
R
B
Bu Bu
N O
O
Bn
O
R
Br
NBS
-78 °C
XN3
X = tetramethyl guanidinium
N O
O
Bn
O
R
N3
dr 91:9 - >99:1
TrisN3;
HOAc
Tris = 2,4,6-triisopropyl phenyl
N O
O
Bn
O
R
N3
N O
O
Bn
O
R KHMDS
N O
O
Bn
O
R
K
dr 91:9 - >99:1
SnCl2;
Boc2O
N O
O
Bn
O
R
BocHN
Evans, JACS, 4011, 1990
Oxazolidinone-Based Amino Acid Synthesis
! The auxiliary approach proves unsuccessful for the central resorcinol-type arylglycine
OMeMeO
H2NNHMe
OBocHN
OH
O
OH
BocHNOH
O
Oallyl
TBSO OMs
BnO
NH2
HO
O
OH
1) Br2
2) Boc2O
3) NaH,AllylBr NHBoc
HO
O
Oallyl
BrBr
1) BuOCOCl, NMM, MeNH2
2) MeMgCl; tBuLi; B(OMe)3; H2O2
70% yield
NHBocMeHN
O
Oallyl
OHBr
74% yield
1) TBSCl2) MeMgCl; tBuLi; B(OMe)3; H2O2
NHBocMeHN
O
Oallyl
OTBSHO1) MsCl2) Boc2O
3) HF•pyr
NHBocMeN
O
Oallyl
OHMsO
Boc
1
1
1) LiOOH
2) TBSCl
Synthesis of the Left Macrocycle
! Oxazolidinone methodology is employed to stereoselectively access a protected amino alcohol
1) Boc2O; HCO2H, H2O2
2) LiOOH
NO
O
Bn
O
NCS
Cl
F
O2N
H
O
Sn(OTf)2, NMP
THF, -78 °CNO
O
Bn
O
NCS
Sn
TfO OTf
N
O
O
Bn
ONH
O
Cl
F
O2NS 19:1 dr
OH
ON
O
Cl
F
O2NO
46% frombenzaldehyde
MeO OMe
NH2•TFA
O
MeHN
EDCI•HCl, HOBt, 0 °C
MeO OMe
NH
O
MeHN
ON
O
Cl
F
O2NO
72% yield
Boc
Boc
Synthesis of the Left Macrocycle
! Functional group adjustment and amino acid coupling
NHBoc
O
HO
EDCI•HCl, HOBt, 0 °C
MeO OMe
NH
O
MeHN
ON
O
Cl
F
O2NO
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
OMe
OBn
2) TFA, DMS, CH2Cl2;
1) Li2CO3, MeOH
Boc
MeO OMe
NH
O
MeHN
O
Cl
F
O2NOH
NH
NHBoc
O
OMe
OBn
82% yield
Synthesis of the Left Macrocycle
! Oxidative coupling provides undesired atropisomer
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) TFA, DMS; TFAA
MeO OMe
NH
O
MeHN
O
Cl
F
O2NOH
NH
NHBoc
O
OMe
OBn
65% yield, 19:1 dr
2) VOF3, BF3•Et2O, AgBF4, TFA/CH2Cl2; NaBH(OAc)3
! 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
NHTFA
HN O
NH
OO
MeHN
OH
F
O2N
Cl
see: Evans,JACS, 6426 1993
MeO OMe
OH
OMe
Synthesis of the Left Macrocycle
! Oxidative coupling proceeds via radical cation
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) TFA, DMS; TFAA
MeO OMe
NH
O
MeHN
O
Cl
F
O2NOH
NH
NHBoc
O
OMe
OBn2) VOF3, BF3•Et2O, AgBF4, TFA/CH2Cl2; NaBH(OAc)3
NHTFA
HN O
NH
OO
MeHN
OH
F
O2N
Cl
see: Evans,JACS, 6426 1993
MeO OMe
OH
OMe
MeO OMe
NH
O
MeHN
ONH
NHBoc
O
OMe
OBn
NHTFA
HN O
NH
OO
MeHN
MeO OMe
OBn
OMe
Synthesis of the Left Macrocycle
! Careful coupling introduces the central aryl fragment
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) NaHCO3, MeOH, 6 d
NHTFA
HN O
NH
OO
MeHN
OH
F
O2N
Cl
MeO OMe
OH
OMe
2) HATU, HOAt, collidine CH2Cl2/DMF, -20 °C
N N
N
N
ON
N
Me
Me
MeMe
HATU
HOAt
TBSO
Oallyl
OMs
HO2C NHBoc
HN
HN O
NH
OO
MeHN
OH
F
O2N
Cl
MeO OMe
OH
OMe
TBSO
Oallyl
OMs
NHBoc
O
65% yield
Synthesis of the Left Macrocycle
! Macrocyclization occurs with good selectivity
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) HF•pyridine2) Na2CO3, DMSO; PhNTf2
3) Zn0, AcOH
4) NaNO2, H3PO2,
cat. Cu2O
HN
HN O
NH
OO
MeHN
OH
F
O2N
Cl
MeO OMe
OH
OMe
TBSO
Oallyl
OMs
NHBoc
O
62% yield5:1 dr
(10:1 dr w/o Cl)
HN
HN O
NH
OO
MeHN
MeO OMe
OTf
OMe
O
Oallyl
OMs
NHBoc
O
HO
Cl
Synthesis of the Left Macrocycle
! Thermal equilibration provides the desired atropisomer
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) Pd(dppf)Cl2, HCOH, DMF, 75 °C
4) AlBr3, EtSH5) MeOH, 55 °C
44% yield19:1 dr
HN
HN O
NH
OO
MeHN
MeO OMe
OTf
OMe
O
Oallyl
OMs
NHBoc
O
HO
Cl2) Piv Cl3) TFA, DMS; TFAA
OPiv
O
HN
O
NHTFA
HN O
OH
NH
OH
HO
O
HO
Cl
see: Evans,JACS, 6426 1993
OMs
MeHN
O
Synthesis of the Left Macrocycle
! Thermal equilibration provides the desired atropisomer
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) BnBr, Cs2CO3
2) LiSEt, THF, 0 °C
3) allyl-Br, Cs2CO3
4) LDA, -78 °C5) LiOH, THF/MeOH
65% yield
OPiv
O
HN
O
NHTFA
HN O
OH
NH
OH
HO
O
HO
Cl
OMs
MeHN
O
OPiv
O
HN
O
NH2
HN O
OBn
NH
OBn
HO
O
BnO
Cl
OH
MeHN
O
Synthesis of the Right Macrocycle
! Fragment coupling completes the peptide chain
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
EDCI, HOAt, THF, 0 °C
OPiv
O
HN
O
NH2
HN O
OBn
NH
OBn
HO
O
BnO
Cl
OH
MeHN
O
For synthesis of tripeptide, see Nicolaou Classics II, p. 290Ddm
OMeMeO
HO2CHN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
HO
F
NO2
OPiv
O
HN
O
NH
HN O
OBn
NH
OBn
HO
O
BnO
Cl
OH
MeHN
O
HN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
HO
F
NO2O
86% yield
Synthesis of the Right Macrocycle
! Closure of the second macrocycle proceeds with the desired atropdiastereoselectivity
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) CsF, DMSO
2) Zn0, AcOH
3) HBF4, tBuONO,
MeCN; CuCl/CuCl2
Oallyl
O
HN
O
NH
HN O
OBn
NH
OBn
HO
O
BnO
Cl
OH
MeHN
O
HN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
HO
F
NO2O
60% yield5:1 dr
Oallyl
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OBn
NH
OBn
HO
O
BnO
OH
Cl
Cl
MeHN
O
Synthesis of the Right Macrocycle
! Closure of the second macrocycle proceeds with the desired atropdiastereoselectivity
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) CsF, DMSO
2) Zn0, AcOH
3) HBF4, tBuONO,
MeCN; CuCl/CuCl2
Oallyl
O
HN
O
NH
HN O
OBn
NH
OBn
HO
O
BnO
Cl
OH
MeHN
O
HN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
HO
F
NO2O
60% yield5:1 dr
Oallyl
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OBn
NH
OBn
HO
O
BnO
OH
Cl
Cl
MeHN
O
Mechanism for Sandmeyer reaction not fully known, but may be as follows:
ArN2+ X-
+ CuX Ar + N2 + CuX2
Ar + CuX2 ArX + CuX
Completion of Vancomycin
! An unusual mild deprotection reveals a carboxylic acid
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) N2O4, NaOAc
2) H2O2, LiOH
68% yield
Oallyl
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OBn
NH
OBn
HO
O
BnO
OH
Cl
Cl
MeHN
O
! Nitrosation in the presence of seven amide functionalities
Oallyl
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OBn
NH
OBn
HO
O
BnO
OH
Cl
Cl
HO
O
Completion of Vancomycin
! Final deprotection proves uneventful
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) Pd(PPh3)4
2) Pd/C, EtOH,1,4-cyclohexadiene3) TFA, DMS, CH2Cl2
62% yield
! Completion of vancomycin aglycon in 40 linear steps
Oallyl
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OBn
NH
OBn
HO
O
BnO
OH
Cl
Cl
HO
O
OH
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMe
O
H2N
HN O
OH
NH
OH
HO
O
HO
OH
Cl
Cl
HO
O
Evans, Wood, Trotter, Richardson, Barrow, Katz ACIEE, 1998, 2700
The Nicolaou Design
! Atropdiastereoselctivity left unaddressed in the design
! Sharpless asymmetric catalysis will be used to create most amino acid stereocenters
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
ClN
O
HN
O
NH2
O
NH
O
HN
OMe
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
Cl
BnO
TBSO
OH
Cl
Br
N
N
HO
N
Br
HO
O
NH2
HN O
OMe
NH
OMe
TBSO
O
MeO
Cl
BnO
Br
N
N
OH
NH2
MeO O
OMe
OH
OMe
MeO
BnO
NHBoc
Dihydroxylation/Aminohydroxylation Based Approach
! Enantioenrichment attained through amino acid coupling
! Sharpless methodology used to create aryl amino acid stereocenters
MeO OMe
O H
1) Ph2P=CH2
2) AD-mix-!
MeO OMe
HOOH
84% yield, 96% ee
1) (n-Bu)2SnO, BnBr, TBAI, 70 °C
2) n-BuLi; B(OMe)3
MeO OMe
BnOO
B OH
49% yield
OBn
OEt
O
(2 steps)
NaOH, tBuOCl BnOCONH2
(DHQD)2AQN
K2OsO2(OH)4
nPrOH/H2O
OBn
OEt
O
HO
NHCbz
1) TBSOTf, lutidene
2) H2, Pd/C3) SO2Cl2
OBn
OEt
O
TBSO
NH2
45% yield, 87% ee78% yield
Cl
Dihydroxylation/Aminohydroxylation Based Approach
! As in the Evans synthesis, creating the central fragment is challenging
NH2
1) SOCl2, MeOH
2) Br2, AcOH
98% yield
1) LAH, THF, 0 °C2) NaNO2, 6 M HCl,
AcOH/H2O, 0 °C;KOH, pyrrolidine
OHO
NH2
OMeO
BrBr
71% yield
N
HO
BrBr
N
N
1) PCC, CH2Cl22) Ph3P=CH2, THF3) AD-mix-!, tBuOH/H2O4) TBSCl, imidazole
N
BrBr
N
N
TBSOOH
72% yield95% ee
1) PPh3, DEAD, DPPA, 0 °C
2) PPh3, H2O, 60 °C
N
BrBr
N
N
TBSONH2
P
O
N3
PhOPhO
DPPA
1) Boc2O, TEA2) TBAF, THF
3) TEMPO, NaOCl, KBr, NaHCO3
N
BrBr
N
N
HONHBoc
O
68% yield70% yield
Nicolaou's Triazene-Driven Ether Synthesis
! Triazene serves to activate aryl ring for SNAr and acts as functional handle for phenol
N
BrBr
N
N
NH
O
Me
HN
O
OH
NHBoc
K2CO3
CuBr•Me2Spyridine
N
BrBr
N
N
NH
O
Me
HN
O
NHBoc
OCu
-KBr
K+
N
Br
N
N
NH
O
Me
HN
O
O
NHBoc
54% yieldaq. HCl
OH
Br
NH
O
Me
HN
O
O
NHBoc
Nicolaou, JACS, 119, 1997, 3421
Approach to the Left Macrocycle
! A Suzuki coupling builds the biaryl bond
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
BnO
MeO OMe
O
B OH
O
MeONHBoc
I
OMe
Pd(PPh3)4
Toluene/H2O90 °C
BnO
OH
OMe
OMe
MeO
MeO
O
NHBoc
87% yield2:1 dr
1) DPPA, DEAD Ph3P, THF, -20 °C2) LiOH, THF/H2O
BnO
N3
OMe
OMe
MeO
HO
O
NHBoc
94% yield
1) EDC, HOAt THF, -30-> -10 °C
NH
EtO2C
TBSO
Cl
OH
NH2EtO2C
TBSO
Cl
OH
BnO
N3
OMe
OMe
MeO
O
NH280% yield
2) TMSOTf, lutidene
Approach to the Left Macrocycle
! Peptide coupling sets up biaryl ether synthesis
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
NH
EtO2C
TBSO
Cl
OH
BnO
N3
OMe
OMe
MeO
O
NH2
EDC, HOAtTHF, 0 °C
NN
N
BrBr
O
HONHBoc
NH
EtO2C
TBSO
Cl
OH
BnO
N3
OMe
OMe
MeO
OHN
NN
N
BrBr
O
NHBoc
90% yield
Closure of the Left Macrocycle
! Ether formation proceeds without atropdiastereoselectivity
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) CuBr, K2CO3
MeCN, 82 °C
2) TBAF, -15 °C3) Et3P, MeCN/H2O4) LiOH, THF/H2ON
HEtO2C
TBSO
Cl
OH
BnO
N3
OMe
OMe
MeO
OHN
NN
N
BrBr
O
NHBoc
46% yield1:1 dr
NH
HO2C
HO
BnO
NH2
OMe
OMe
MeO
OHN
NN
N
Br
O
NHBoc
O
Cl
Amide Formation and Deprotection
! Completion of the left half achieved via lactamization
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) FDPP, DIPEADMF, 0-> 25 °C
70% yield
NH
HO2C
HO
BnO
NH2
OMe
OMe
MeO
OHN
NN
N
Br
O
NHBoc
O
2) TBSOTf, lutidene3) TMSOTf, lutidene
N
O
HN
O
NH2
HN O
OMe
NH
OMe
HO
O
MeO
Cl
Br
BnO
Cl
N
N
O
PPhO
PhO O
F
F
F
F
FFDPP
Synthesis of the Right Macrocycle
! Fragment coupling completes the peptide chain
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
EDCI, HOBt, THF, 0 °C
N
O
HN
O
NH2
HN O
OMe
NH
OMe
TBSO
O
MeO
Cl
Br
BnO
For synthesis of tripeptide, see Nicolaou Classics II, p. 268
HO2CHN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
TBSO
OH
Cl
N
O
HN
O
NH
HN O
OMe
NH
OMe
TBSO
O
MeO
Cl
Br
BnO
HN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
TBSO
OH
ClO
86% yield
N
N
N
N
Synthesis of the Right Macrocycle
! Triazene-activated ether formation favors unnatural atropisomer; thermal equilibration is possible
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
N
O
HN
O
NH
HN O
OMe
NH
OMe
TBSO
O
MeO
Cl
Br
BnO
HN
O
NH
NHDdm
OO
CH2CHMe2
NMeBoc
TBSO
OH
ClO
74% yield1:3 dr
N
N
N
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
N
N
BnO
CuBr, K2CO3
MeCN, 82 °C
! Heating unnatural isomer at 140 °C provides 2:3 mix in 80-85% yield
Final Functionalizations
! Triazene proves difficult to functionalize as phenol
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
N
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
N
N
BnO
1) Raney Ni, MeOH2) H2, Pd(OH)2
NH2
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
HO
Final Functionalizations
! Triazene proves difficult to functionalize as phenol
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
N
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
N
N
BnO
1) Raney Ni, MeOH2) H2, Pd(OH)2
I
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
HO
3) HBF4, iPrONO4) KI, 25 °C
Final Functionalizations
! Triazene proves difficult to functionalize as phenol
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
N
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
N
N
BnO
1) Raney Ni, MeOH2) H2, Pd(OH)2
OH
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
HO
3) HBF4, iPrONO4) KI, 25 °C5) MeMgBr (30 eq) iPrMgBr (30 eq); B(OMe)3 (100 eq); H2O2
32% yield
Final Functionalizations
! Phenol protection and introduction of methyl ester
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) Cs2CO3, MeI2) Dess-Martin
OMe
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO2C
MeO
OTBS
Cl
Cl
3) KMnO4
4) CH2N2
74% yield
OH
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO
OTBS
Cl
Cl
HO
Completion of the Natural Product
! Desilylation is followed by global deprotection
OH
O O
HN
O
NH
O
NH
O
HN
OMe
Me
NH
Me
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
1) HF•pyr, pyridine
OMe
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NMeBoc
O
DdmHN
HN O
OMe
NH
OMe
TBSO
O
MeO2C
MeO
OTBS
Cl
Cl
2) AlBr3, EtSH
62% yield
OH
O O
HN
O
NH
O
NH
O
HN
O
Me
Me
NHMe
O
H2N
HN O
OH
NH
OH
HO
O
HO2C
HO
OH
Cl
Cl
Nicolaou, Takayanagi, Jain, Natarajan, Koumbis, Bando, Ramanjulu, ACIEE, 1998, 2717
Conclusions
! While synthesis is not an issue in the supply of Vancomycin, fascinating chemistry has been discovered in pursuit of an expedient synthesis
! Control over the wide variety of stereocenters in the context of a complex synthesis is most notable
Oallyl
O
NH
OH
HN
NH
HO
F
NO2O
O
Oallyl
O O
NH
O
NH
O
HN
OH
Cl
Evans - 36 steps0.2% overall yield
84% average
NH
HO2C
HO
BnO
NH2
OMeOMe
MeO
OHN
NN
N
Br
O
NHBoc
O
Cl
N
O
HN
O
NH2
HN O
OMe
NH
OMe
HO
O
MeO
Cl
Br
BnO
N
N
Nicolaou - 36 steps 0.13% overall yield
82% average
