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

2. 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 HO
HO 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

3. 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 Cl
MeO 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

4. 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 H
HO 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 NH2
O2C H O2C N O H N
H H H H H
O O O O
H2N Me Me
HO 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

5. 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 NMeBoc
HO2C NH O NH O
O O MeHN O O
H2N Me DdmHN Me
HO 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

6. 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 O
R 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 O
R 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

7. 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% yield
HO 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

8. 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
O
O2N
H
1) Boc2O; HCO2H, H2O2
2) LiOOH
Cl O
F NH2•TFA
MeHN
O Cl
O2N
O
O F
72% 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

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
! 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

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 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

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
! 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

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
! 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 H
F 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

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
! 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 Cl
F 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)

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
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 MeHN
MeHN
OMe HO
MeO OMe OH OH
44% yield
19:1 dr
see: Evans,JACS, 6426 1993

15. 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 O
MeHN 4) LDA, -78 °C
MeHN
5) LiOH, THF/MeOH
HO
BnO
OH OH
OBn OBn
65% yield

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
! 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 O
MeHN 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

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 Boc
MeHN
NHDdm CH2CHMe2 MeHN
O O
DdmHN Me
BnO
BnO Me
OBn OBn
OBn OBn
60% yield
5:1 dr

18. 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 Boc
MeHN
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

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
! 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
HO
MeHN 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

20. 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 Me
BnO 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

21. 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 NH2
HO2C HO
NH O NH HN NMeBoc
O O
H2N Me BnO
HO 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

22. 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)3
MeO OMe MeO OMe
MeO OMe
84% yield, 96% ee
49% yield
Cl
OBn OBn
NaOH, tBuOCl OBn
BnOCONH2 1) TBSOTf,
HO
(DHQD)2AQN lutidene TBSO
O 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

23. 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, N
Br 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, NaHCO3
HO 68% yield
NHBoc 70% yield TBSO
NH2 TBSO
O OH

24. Nicolaou's 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 O
Br 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

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
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 NHBoc
80% 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

26. 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 Br
TBSO THF, 0 °C
O
NH2 TBSO
EtO2C N O
H H
N
N EtO2C N NHBoc
N3 H
N O
N
N3
BnO Br Br
OMe
MeO OMe BnO
OMe
HO MeO OMe
NHBoc
O
90% yield

27. 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 Br
TBSO
O HO Cl
2) TBAF, -15 °C
H O
N 3) Et3P, MeCN/H2O H
EtO2C N NHBoc 4) LiOH, THF/H2O N
H HO2C N NHBoc
O H
N3 O
NH2
BnO
OMe BnO
OMe
MeO OMe
MeO OMe
46% yield
1:1 dr