56
The Chemistry of Nine-Membered Enediyne Natural Products Zhang Wang MacMillan Group Meeting April 17, 2013
The Chemistry of Nine-Membered
Enediyne Natural Products
Zhang Wang
MacMillan Group Meeting
April 17, 2013
Natural Products Sharing a Unique Structure
Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024.Buchanan, G. O.; Williams, P. G.; Feling R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731-2734.
NC
Cl
HO
O
OH
HO
OOH
MeMe
NC
H
ClO
O
OH
HO
OOH
MeMe
cyanosporaside A
cyanosporaside B
OO
Me
OHO
MeO
O
OH
Cl
HO
O
OH
H OH
H
OH
OO
Me
OHO
MeO
O
OH
H
ClO
O
OH
H OH
H
OH
sporolide A
sporolide B
R1
R2
R1 = H, R2 = Clor R1 = Cl, R2 = H
[O]
[O][O]
R
H
Natural Products Sharing a Unique Structure
Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024.Buchanan, G. O.; Williams, P. G.; Feling R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731-2734.
NC
Cl
HO
O
OH
HO
OOH
MeMe
NC
H
ClO
O
OH
HO
OOH
MeMe
cyanosporaside A
cyanosporaside B
OO
Me
OHO
MeO
O
OH
Cl
HO
O
OH
H OH
H
OH
OO
Me
OHO
MeO
O
OH
H
ClO
O
OH
H OH
H
OH
sporolide A
sporolide B
R
+ "magic"
+ "HCl"
Examples of Nine-Membered Enediynes
OO
O
O
O
O
OOH
Me
OMeO
Me
OHOHMeHN
OHHO
O
O
OOH
OMe
HO
Cl
O
OH
NH
O
ClMeO
HOMeH
HO OOHO
H
OH
Me NH
O Me
HOMe
neocarzinostatin chromophore N1999A2
maduropeptinchromophore
Examples of Nine-Membered Enediynes
O
HO
HO
N
OOH
Me
HOMe Cl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore
OClHO
O
O
O
O
HNO
OMe
O
O
OH2N
Me
Me
HO OH
NMe2
C-1027 chromophore
Two Types of Nine-Membered Enediynes
OHHO
O
O
OOH
OMe
HO
Cl
N1999A2
O
O
HO
HO
N
OOH
Me
HOMe Cl
HN
O
OOH
MeNMe2
O
O
Ar
O
proposed kedarcidin chromophore
[O]
Bergman cyclization Myers cyclization
Ten-Membered Enediyne Natural Products
MeSSS
OHO
H
OO
O
O
NH
OOS
O
O
O
Me
NHCOOMe
EtHNMeO
OH
MeMeI
OMeOMe
MeHO
MeO OH
HO
calicheamicin !1I
HNOH
OH
O
O OH
COOH
OMe
Me
O
dynemicin A
MeSSS
OHO
H
OO
O
O
Me
NHCOOMe
i-PrHNMeO
HO
MeS
O
N
NHHO
shishijimicin A
HNO
O OH
Me
OOH
OH
uncialamycin
Bergman Cyclization
Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660-661.
H
H
D
D
D
D
H
H
200 oC
D
D
D
D
! p-Benzyne diradical intermediate
MeOH, 200 oCOH+ no
OMe
H
HCCl4
Cl
Clheat
Bergman Cyclization
Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866-4868.
! Nicolaou's distance theory based on calculation and experiments
CompoundRingsize
c…d distance ° stability
CH2
c
d
9 2.84
A
unknown,should cyclize
(CH2)2 10 3.25 cyclize at 25 oC
(CH2)3 11 3.61 stable at 25 oC
4.12stable at 25 oCt1/2 = 30 s at 200 oC
Bergman Cyclization
Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630-7632.Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 4986-4987.
! Magnus-Snyder least motion/strain energy theory
TBSO
O
c
d
TBSO
O
c...d distance °A
3.391
3.368 (oxime)
relative rate of Bergman cyclization at 124 oC
650
1
Global strain energy of starting material and productshould be considered for complex molecules
strain energy releaseafter cyclization kcal
6.0
-1.5
(cyclohexanone adopts achair conformer in product)
Bergman Cyclization
Perrin, C. L.; Rodgers, B. L.; O'Connor, J. M. J. Am. Chem. Soc. 2007, 129, 4795-4799.
H
H
D
D
D
D
H
H
200 oC
! Nucleophiles can react with p-benzyne diradical, producing phenyl anion
LiX, HOAc
DMSO, 37 oCX X
H
!G = -80 to -100 kJ/mol
can be treated as towards halides
Bergman Cyclization
Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024.
! Cyanosporasides from enediyne precursor
NC
Cl
HO
O
OH
HO
OOH
MeMe
NC
H
ClO
O
OH
HO
OOH
MeMe
cyanosporaside A
cyanosporaside B
NC
OH
OO Me
Me
OHO
HO
pre-cyanosporaside
Bergmancyclization
NC
OO
OH
HO
OOH
MeMe +
in seawater
Bergman Cyclization
! Bergman cyclization of calicheamicin
S
OHO
H
OSugar
NHCOOMe
Nu:
SS
MeS-
OHO
OSugar
NHCOOMe
OHO
OSugar
NHCH2OOMeS
OHO
OSugar
NHCH2OOMeS
Bergman Cyclization
! Bergman cyclization of dynemicin
HNOH
OH
O
O OH
COOH
OMe
Me
O
dynemicin A
HNOH
OH
OH
OH OH
COOH
OMe
Me
O
HNOH
OH
O
OH OH
COOH
OMe
Me
HO
Nu:
HNOH
OH
OH
OH OH
COOH
OMe
Me
HO
Nu
Bergman Cyclization
! Bergman cyclization of dynemicin
HNOH
OH
OH
OH OH
COOH
OMe
Me
HO
Nu
HNOH
OH
OH
OH OH
COOH
OMe
Me
HO
Nu
Myers Cyclization
Myers, A. G. Tetrahedron Lett. 1987, 28, 4493-4496.
OO
O
O
O
O
ArO
OMe
OHOHMeHN
Nu:
OO
O
ArCOO
O
OH
OMe
OHOHMeHN
Nu
ArCOO
OO
Me
OHOHMeHN
Nu
OO
OH
O
DNA Cleavage with Diradical
OO
O
O
O
O
OOH
Me
OMeO
Me
OHOHMeHN
neocarzinostatin chromophore
binds DNAminor groove
favors T, A rich sequences
Naphthoate parallels DNA base pairs
positively charged amino sugar interactswith phosphate
DNA Cleavage with Diradical
OO
O
O
O
O
ArO
OMe
OHOHMeHN
Nu:
ArCOO
OO
Me
OHOHMeHN
Nu
OO
OH
O
O
O
P
ThymineO
HH
P
O
O
P
ThymineO
P
O2O
O
P
ThymineO
P
OO
downstreamreactions
DNA cleavage
Goldberg, I. H. Acc. Chem. Res. 1991, 24, 191-198.
Enediyne Natural Products Are Polyketides
OO
O
O
O
O
OOH
Me
OMeO
Me
OHOHMeHN
neocarzinostatin chromophore
HNOH
OH
O
O OH
COOH
OMe
Me
O
dynemicin A
cleaved
Liang, Z.-X. Nat. Prod. Rep. 2010, 27, 499-528.
Apoprotein of Nine-Membered Enediynes
Baker, J. R.; Woolfson, D. N.; Muskett, F. W.; Stoneman, R. G.; Urbaniak, M. D.; Caddick, S. ChemBioChem 2007, 8, 704-717.
• Nine-membered enediynes isolated with apoproteins except N1999A2
• Apoproteins protect and transport enediynes
• Apoproteins have about 110 amino acids
• Structural features of apoproteins avoid:
external nucleophile attack,
electrophile activation of epoxides,
H-abstraction of diradical intermediatesneocarzinostatin
OHHO
O
O
OOH
OMe
HO
Cl N1999A2
OO
O
O
O
O
OOH
Me
OMeO
Me
OHOHMeHN
neocarzinostatin chromophore
Neocarzinostatin Chromophore
OO
O
O
O
O
OOH
Me
OMeO
Me
OHOHMeHN
neocarzinostatin chromophore
1957 isolation of carzinostatin
1965 isolation of neocarzinostatin
1972 Bergman cyclization
1979 1:1 noncovalent complex of a protein and chromophore was identified
1985 gross structure of neocarzinostatin chromophore was identified
1987 ten-membered enediynes were found Myers cyclization proposed
1988 relative and absolute stereochemistry of neocarzinostatin chromophore was determined
1996 the aglycon was synthesized
1998 neocarzinostatin chromophore synthesized
Nan Ji, PhD thesis, Harvard University 2006.
Maduropeptin Chromophore
Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T. W. J. Am. Chem. Soc. 1994, 116, 9351-9352.
O
OH
NH
O
ClMeO
HRH
HO OOHO
H
OH
Me NH
O Me
HOMe
Tris•HCl and MeOH R = OMe, Cl, OH
isolation condition product composition
without Cl-, and MeOH R = OMe, OH
use EtOH instead of MeOH R = OEt
DNA cleaving ability
R = Cl > R = OMe
enhanced ability in basic media
no DNA scission upon adding thiol
Maduropeptin Chromophore
Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T. W. J. Am. Chem. Soc. 1994, 116, 9351-9352.
O
N
O
ClMeO
H
HO OOHO
H
OH
Me NH
O Me
HOMe
OH
O
N
O
ClMeO
H
HO OOHO
H
OH
Me NH
O Me
HOMe
C-1027 Chromophore
Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M. Tetrohedron Lett. 1994, 35, 5253-5256.
OClHO
O
O
O
O
HNO
OMe
O
O
OH2N
Me
Me
HO OH
NMe2
OClHO
O
O
O
O
HNO
OMe
O
O
OH2N
Me
Me
HO OH
NMe2
in apoprotein
H
H
kH/kD = 3.8
EtOH
C-1027 Chromophore
Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M. Tetrohedron Lett. 1994, 35, 5253-5256.
°bond order: 1.21, 1.44 A°bond order: 1.35, 1.41 AR1
R2
R3
C-1027 Chromophore
Hirama, M. et. al. J. Am. Chem. Soc. 2000, 122, 720-721.
OClHO
O
O
O
O
HNO
OMe
O
O
OH2N
Me
Me
HO OH
NMe2
OClHO
O
O
O
O
HNO
OMe
O
O
OH2N
Me
Me
HO OH
NMe2
in apoprotein
H-abstraction pdt.
slow
Drugs from Enediynes ---- Mylotarg
S
OHO
H
OO
O
O
NH
OOS
O
O
O
Me
NHCOOMe
EtHNMeO
OH
MeMeI
OMeOMe
MeHO
MeO OH
HO
SNH
ON
MeMe Me
OO
NH
hP67.6
By Wyeth, and later Pfizer
For treatment of acute myeloid leukemia
2000 to 2010
Withdrawn by Pfizer in 2010 due to side effects
Drugs from Enediynes ---- Mylotarg
http://www.biology.iupui.edu/biocourses/Biol540/6secondwavequestionCSS.html
Drugs from Enediynes ---- SMANCS
Maeda, H. Advanced Drug Delivery Reviews 2001, 46, 169-185.
Drugs from Enediynes ---- SMANCS
Maeda, H. Advanced Drug Delivery Reviews 2001, 46, 169-185.
Total Synthesis of Nine-Membered Enediynes
O
HO
HO
N
OOH
Me
HOMe Cl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore
O
OH
NH
O
ClMeO
HOMeH
HO OOHO
H
OH
Me NH
O Me
HOMe
maduropeptin chromophore
Fast synthesis of fragments
Correct sequence to assemble
Mild reaction conditions in late stage
Courage, prudence and persistance
Total Synthesis of Nine-Membered Enediynes
Professor Andrew G. Myers
Harvard University
Professor Masahiro Hirama
Tohoku University
Total Synthesis of Proposed Kedarcidin Chromophore
O
HH
O
NCl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (1997)
O
HO
HO
N
OOH
Me
HOMe Cl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (2007)
O
OOH
MeHO
Me
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
Total Synthesis of Proposed Kedarcidin Chromophore
O
HH
O
NCl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (1997)
O
OOH
MeHO
Me
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
etherification
glycosylation
lactonization
peptide coupling
Enediyne core should be synthetizedat a relatively late stage
Correct protecting groups
Powerful while mild conditions
Total Synthesis of Proposed Kedarcidin Chromophore
Myers, A. G.; Horiguchi, Y. Tetrahedron Lett. 1997, 38, 4363-4366.
! Naphthoate synthesis
OO
HO
O
1. PPh3, DEAD, i-PrOH
2. aq. NaOH, 93%
iPrO
HOOH
1. CH(OEt)3, SnCl4
2. MeI, K2CO3, 79%
iPrO
MeOOMe
CHO
EtOO O
OEt91%
HOAc, piperidine
iPrO
MeOOMe
OEtO
O
OEt
E/Z = 1:1
1. KHMDS, TESCl
2. dilute with PhH, then h!
iPrO
MeOOMe
OTES
O
OEt
1, NaOH
2. PivCl, py
38% - 64%
iPrO
MeOOMe
OPiv
O
OH
Total Synthesis of Proposed Kedarcidin Chromophore
Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41, 1062-1067.Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Chloropyridine synthesis
N
HO
Cl
formalin
NaHCO3, 81% N
HO
ClOH
1. MOMCl, 81%
2. Swern [O], 92% N
MOMO
Cl CHO
S+H2N
O-
Me
NCl
MOMO
NS+
O-
Me
OMe
OTi(Oi-Pr)3
Ti(OEt)4
93%
-78 oC, 94%, 91 deNCl
MOMO
HNS+
O-
MeCOOMe
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Chloropyridine synthesis
NCl
MOMO
HNS+
O-
MeCOOMe
MeOH, AcCl
93%
NCl
HO
NH2•HClCOOMe
Boc2O, NEt3
84%
NCl
HO
NHBocCOOMe
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Core synthesis
O
OO
MeMe
O
DIBAL
96% O
OO
MeMe
HO
LDA, TMSCHN2
81%
OO
MeMe
OH
LHMDS, TESCl;LHMDS, TESCl
OO
MeMe
OTES
TES
1. 3HF•NEt3
2. Swern [O]
OO
MeMe
CHO
TES
PPh3, CBr4
NEt3, 78%
OO
MeMe
TES
Br
Br
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Core synthesis
OO
MeMe
TES
Br
Br HF, H2O, 98%
SO2Cl2, NEt3,DMAP, 63%
OSO
OO
TES
Br
Br
NCl
HO
NHBocCOOMe
1. KHMDS
2. H2SO4, H2O3. TBSCl, Imidazole 82% overall
NCl
O
BocHN COOMe
BrBr
TES
TBSO
1. LiOH, H2O2
2. FmOH, DMAP, 93%Me
NO2
O
O O
Me
NO2
NCl
O
BocHN COOFm
BrBr
TES
TBSO
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Core synthesis
NCl
O
BocHN COOFm
BrBr
TES
TBSO
TMSOTf
lutidine
NCl
O
H2N COOFm
BrBr
TES
TBSO
iPrO
MeOOMe
OPiv
O
OH
EDC
HOBt
iPrO
MeOOMe
OPiv
O
OBt
NaHCO3
97%
NCl
O
HN COOFm
BrBr
TES
TBSO
iPrO
MeOOMe
OPiv
O
Total Synthesis of Proposed Kedarcidin Chromophore
O
HH
O
NCl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (1997)
O
OOH
MeHO
Me
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Core synthesis
OO
CHO
Me Me1. LiTMS
2. PDC, 86%
OO
Me Me
OH
TMS
OO
Me Me
TMS
O
MgBr
HgCl2, 64%, 4:1 dr
LHMDS,TESCl, 97%
OO
Me Me
OTES
TMSTES
1. HF, H2O
2. K2CO3, MeOH
93%
OHHO
OH
TES
AcCl, py
82%
OHAcO
OH
TES
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. Org. Lett. 2007, 9, 1923-1925.
! Suger synthesis
HO Me
O
NH2
OH 1. HCl, MeOH
2. paraformaldehyde MgSO4, H2, Pd/C 90%
MeO Me
O
NMe2
OH AcCl, py
93%MeO Me
O
NMe2
OAc
LHMDSthen MOMBr78%
O
MeNMe2
MOMO
OH2, Pd(OH)2
TFE, 82%
O
MeNMe2
MOMO
O1. AcCl, TFE2. DBU
3. DEIPSCl, Im. 76%
O
MeNMe2
DEIPSO
O
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. Org. Lett. 2007, 9, 1923-1925.
! Core synthesis
O
MeNMe2
DEIPSO
ODIBAL
88%
O
MeNMe2
DEIPSO
OHDAST
O
MeNMe2
DEIPSO
F
Cp2HfCl2,
AgClO4
OH
TES
OAc
O
ONMe2
ODEIPS
Me
K2CO3, MeOH
50% overallOH
TES
OH
O
ONMe2
ODEIPS
Me
OH
TES
OAc
OH
Total Synthesis of Proposed Kedarcidin Chromophore
O
HH
O
NCl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (1997)
O
OOH
MeHO
Me
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Core synthesis
OH
TES
OH
O
ONMe2
ODEIPS
Me
NCl
O
HN COOFm
BrBr
TES
TBSO
iPrO
MeOOMe
OPiv
O
Sonogashira, 61%
NCl
O
HN COOFm
Br
R
TBSO
iPrO
MeOOMe
OPiv
O
OH
R
OH
O
ONMe2
ODEIPS
Me
R = TES
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Core synthesis
NCl
O
HN COOFm
Br
R
TBSO
iPrO
MeOOMe
OPiv
O
OH
R
OH
O
ONMe2
ODEIPS
Me
R = TES
1. NEt3, 2. DMAPMe
NO2
O
O O
Me
NO2
NCl
O
HN
Br
R
TBSO
iPrO
MeO
OMe
OPiv
O
OH
R
O
O
ONMe2
ODEIPS
MeO
66%
R = TES1.7 : 1 atropisomersin C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Glaser coupling
NCl
O
HN
Br
R
TBSO
iPrO
MeO
OMe
OPiv
O
OH
R
O
O
ONMe2
ODEIPS
Me
R = TES1.7 : 1 atropisomersin C6D6
O
1. AgNO3, 73%2. Cu(OAc)2, CuI, py, 59%
NCl
O
HN
iPrO
MeO
OMe
OPiv
O
OH
O
O
ONMe2
ODEIPS
MeO
BrH
HH
TBSO
9 : 1 atropisomers in C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Transannular cyclization
LHMDS, then t-BuLi,quenched with HOAc immediately (< 3 s)
52%N
Cl
O
HN
iPrO
MeO
OMe
OPiv
O
OH
O
O
ONMe2
ODEIPS
MeO
BrH
HH
TBSO
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
TBSOOH
9 : 1 atropisomersin C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Advanced stage
1. TBAF, o-nitrophenol
2. PivCl, NEt3, 76%
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
TBSOOH
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
HOOH
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Advanced stage
Ph2MeCOOH, VO(acac)2
28%
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
HOOH
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
HOOH
O
1.5 : 1 atropisomersin C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Advanced stage
AgPF6, DTBMP
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
HOOH
1.5 : 1 atropisomersin C6D6
O
O SPhMe
TESOHO Me
O
HH
O
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
O
OOH
MeTESO
Me
OH
59%
1.5 : 1 atropisomersin C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! Advanced stage
Martin's sulfurane
65%
O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
OOH
1 : 1 atropisomersin C6D6
O
O
HH
O
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
O
OOH
MeTESO
MeO
OHMe
TESOMe 1.5 : 1 atropisomers
in C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
! End game
TBAF, o-nitrophenol
then 3HF•NEt3, 50%O
HH
NCl
HN
O
OODEIPS
MeNMe2
O
OO
OPiv
MeO
MeOOiPr
O
1.2 : 1 atropisomersin C6D6
O
O
HH
O
NCl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOOiPr
O
OOH
MeHO
MeO
OHMe
TESOMe 1 : 1 atropisomers
in C6D6
Total Synthesis of Proposed Kedarcidin Chromophore
O
HH
O
NCl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (1997)
O
HO
HO
N
OOH
Me
HOMe Cl
HN
O
OOH
MeNMe2
O
OO
OH
MeO
MeOO Me
Me
proposed kedarcidin chromophore (2007)
O
OOH
MeHO
Me
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383.
Unfinishable Mission?
OClHO
O
O
O
O
HNO
OMe
O
O
OH2N
Me
Me
HO OH
NMe2
C-1027 chromophore
O
N
O
ClMeO
H
HO OOHO
H
OH
Me NH
O Me
HOMe
OH
real maduropeptin chromophore?
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