The Chemistry of Nine-Membered

Enediyne Natural Products

Zhang Wang MacMillan Group Meeting

April 17, 2013 Natural Products Sharing a Unique Structure

OH

O O H H OH O Me O MeO Cl OH HO O Me Cl O Me O O O H OH OH NC H OH [O] OH R2 cyanosporaside A R sporolide A H

1 [O] R OH [O] O O Cl O Me R1 = H, R2 = Cl Cl MeO H OH or R1 = Cl, R2 = H OH O O HO O O Me O H H Me OH O H OH OH NC OH

cyanosporaside B sporolide B

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. Natural Products Sharing a Unique Structure

OH

O O H H OH O Me O MeO Cl OH HO O Me Cl O Me O O O H OH OH NC H OH OH cyanosporaside A R sporolide A

OH

O O + "magic" Cl + "HCl" O Me Cl OH MeO H OH O O HO O O Me O H H Me OH O H OH OH NC OH

cyanosporaside B sporolide B

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. Examples of Nine-Membered Enediynes

O OH O HO O O O OH OH O O HO O O Me Me O O Cl OMe OMe OH MeHN OH

neocarzinostatin chromophore N1999A2 OH O

Cl NH MeO O H H OMe

HO O OH HO O O Me

H Me N maduropeptin H chromophore HO Me Examples of Nine-Membered Enediynes

Me

O Me H2N O MeO O MeO HO Cl

OH O O OMe O HN O O HO Me N O Cl HN Me O HO OH Me OH O O O O O Me O NMe2 H O H OH O O Me NMe2

proposed kedarcidin chromophore C-1027 chromophore Two Types of Nine-Membered Enediynes

Ar OH HO O HN O HO O Me Cl N OH Me O OH O O O O HO O H O H OH O O Me Cl OMe NMe2

proposed kedarcidin chromophore N1999A2

O

[O]

Bergman cyclization Myers cyclization Ten-Membered Enediyne Natural Products

O HO MeSSS NHCOOMe Me O Me Me I O Me H COOH O S O OH O HN N O O H HO O OMe OH O OMe OMe Me O O HO EtHN MeO MeO OH O OH OH

I dynemicin A calicheamicin !1

O HO MeSSS NHCOOMe Me N MeS Me H O HN OH O O O OH HO HO NH O O

O i-PrHN O OH MeO shishijimicin A uncialamycin Bergman Cyclization

D H o H 200 C D

H D D H

D D

D D

! p-Benzyne diradical intermediate

MeOH, 200 oC O + OH Me no

H

Cl H CCl4

heat Cl

Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660-661. Bergman Cyclization

! Nicolaou's distance theory based on calculation and experiments

Ring c…d distance Compound size A° stability

c unknown, 9 2.84 CH2 should cyclize

d

3.25 cyclize at 25 oC (CH2)2 10

3.61 stable at 25 oC (CH2)3 11

stable at 25 oC 4.12 o t1/2 = 30 s at 200 C

Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866-4868. Bergman Cyclization

! Magnus-Snyder least motion/strain energy theory

c...d distance relative rate of Bergman strain energy release ° cyclization at 124 oC after cyclization A kcal O

TBSO c 3.391 650 6.0 (cyclohexanone adopts a d chair conformer in product)

O

TBSO 3.368 (oxime) 1 -1.5

Global strain energy of starting material and product should be considered for complex molecules

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. Bergman Cyclization

D H o H 200 C D

H D D H

! Nucleophiles can react with p-benzyne diradical, producing phenyl anion

H

LiX, HOAc

DMSO, 37 oC X X

!G = -80 to -100 kJ/mol

can be treated as towards halides

Perrin, C. L.; Rodgers, B. L.; O'Connor, J. M. J. Am. Chem. Soc. 2007, 129, 4795-4799. Bergman Cyclization

! Cyanosporasides from enediyne precursor

H OH O HO O Me Cl Me O NC OH OH Bergman cyanosporaside A O cyclization OH in seawater HO O Me O Me HO O Me + O Me OH O NC OH NC Cl OH O pre-cyanosporaside HO O Me H Me O NC OH

cyanosporaside B

Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021-1024. Bergman Cyclization

! Bergman cyclization of calicheamicin

O O HO HO S S NHCOOMe NHCOOMe Me S H S-

O O Nu: Sugar Sugar

O O HO HO NHCH2OOMe NHCH2OOMe S S

O O Sugar Sugar Bergman Cyclization

! Bergman cyclization of dynemicin

Me Me COOH COOH OH O HN OH OH HN O O OMe OMe

OH O OH OH OH OH

dynemicin A

Me Me COOH COOH OH OH HN OH O HN HO HO OMe OMe Nu

Nu: OH OH OH OH OH OH Bergman Cyclization

! Bergman cyclization of dynemicin

Me Me COOH OH OH HN COOH HO OH OH HN HO OMe Nu OMe Nu

OH OH OH OH OH OH Myers Cyclization

O O O O O O Nu: O OH

O Nu Ar O ArCOO Me Me O O O O OH OH MeHN MeHN OH OH

O O O OH Nu

ArCOO Me O O OH MeHN OH

Myers, A. G. Tetrahedron Lett. 1987, 28, 4493-4496. DNA Cleavage with Diradical

favors T, A rich sequences

Naphthoate parallels DNA base pairs

positively charged amino sugar interacts with phosphate

O O O

O OH O binds DNA minor groove O Me Me O O OMe OH MeHN OH

neocarzinostatin chromophore DNA Cleavage with Diradical

O O O O O O Nu: O OH P Nu O O H Thymine Ar ArCOO H O O Me O Me O O O O OH MeHN OH OH MeHN P OH

P P

downstream O O Thymine reactions O Thymine O2 O O DNA cleavage O

O O

P P

Goldberg, I. H. Acc. Chem. Res. 1991, 24, 191-198. Enediyne Natural Products Are Polyketides

O O O

O Me OH COOH O OH O HN O OMe O Me Me O O OH O OH OMe OH MeHN OH

neocarzinostatin chromophore dynemicin A

cleaved

Liang, Z.-X. Nat. Prod. Rep. 2010, 27, 499-528. Apoprotein of Nine-Membered Enediynes

O OH O HO O O O OH OH O O HO O O Me Me O N1999A2 O Cl OMe OMe OH MeHN OH • Nine-membered enediynes isolated with neocarzinostatin chromophore 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 intermediates neocarzinostatin

Baker, J. R.; Woolfson, D. N.; Muskett, F. W.; Stoneman, R. G.; Urbaniak, M. D.; Caddick, S. ChemBioChem 2007, 8, 704-717. Neocarzinostatin Chromophore

1957 isolation of carzinostatin O 1965 isolation of neocarzinostatin O O 1972 Bergman cyclization

O 1979 1:1 noncovalent complex of a protein and chromophore OH was identified O 1985 gross structure of neocarzinostatin chromophore was identified O Me Me 1987 ten-membered enediynes were found O O Myers cyclization proposed OMe OH MeHN 1988 relative and absolute stereochemistry of neocarzinostatin OH chromophore was determined neocarzinostatin chromophore 1996 the aglycon was synthesized

1998 neocarzinostatin chromophore synthesized

Nan Ji, PhD thesis, Harvard University 2006. Maduropeptin Chromophore

isolation condition product composition

OH O Tris•HCl and MeOH R = OMe, Cl, OH Cl NH MeO without Cl-, and MeOH R = OMe, OH O H use EtOH instead of MeOH R = OEt H R

HO O OH HO O O Me

H Me N H DNA cleaving ability HO Me R = Cl > R = OMe

enhanced ability in basic media

no DNA scission upon adding thiol

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. Maduropeptin Chromophore

OH O O

N Cl N Cl MeO MeO O O

H H

HO O HO O OH HO OH HO O O Me O O Me

H H Me N Me N H H HO HO Me Me

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. C-1027 Chromophore

H N H2N O 2 O

O O

HO Cl EtOH HO Cl O H O O O OMe OMe O H O O O HN HN Me HO OH Me HO OH O O O O O O Me Me NMe NMe2 2

in apoprotein

kH/kD = 3.8

Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M. Tetrohedron Lett. 1994, 35, 5253-5256. C-1027 Chromophore

3 R bond order: 1.21, 1.44 A°

R1 bond order: 1.35, 1.41 A° R2

Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M. Tetrohedron Lett. 1994, 35, 5253-5256. C-1027 Chromophore

H N H2N O 2 O

O O

HO Cl HO Cl O O O O OMe OMe O O O O HN HN Me HO OH Me HO OH O O O O O O Me Me NMe NMe2 2

in apoprotein slow

H-abstraction pdt.

Hirama, M. et. al. J. Am. Chem. Soc. 2000, 122, 720-721. Drugs from Enediynes ---- Mylotarg

hP67.6

NH O O Me O Me Me N O N S H HO S NHCOOMe Me O Me I O Me H O S O N O H HO O OMe OH O OMe Me O O HO EtHN MeO MeO OH

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

Me OH O O Me MeO Cl NH MeO O MeO H H OMe OH HO O O OH HN O HO O O Me HO Me Cl N H Me N Me O H OH O O HO O Me H O H OH O O maduropeptin chromophore Me NMe2

proposed kedarcidin 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 Professor Masahiro Hirama

Harvard University Tohoku University Total Synthesis of Proposed Kedarcidin Chromophore

Me Me

O Me O Me MeO MeO

MeO MeO

OH OH

O O HN O HN O HO Cl N Me Cl N O Me O OH O O O H O O H O H O OH H OH OH O O O O Me Me O Me HO NMe2 NMe2 Me proposed kedarcidin chromophore (1997) proposed kedarcidin chromophore (2007)

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

Me

O Me MeO

MeO

peptide coupling OH

O etherification HN O lactonization Cl N O O glycosylation H H O Enediyne core should be synthetized at a relatively late stage O OH OH O O Me O Me Correct protecting groups HO NMe2 Me Powerful while mild conditions proposed kedarcidin chromophore (1997)

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

! Naphthoate synthesis

HO iPrO iPrO 1. PPh3, DEAD, i-PrOH 1. CH(OEt)3, SnCl4

O HO MeO CHO 2. aq. NaOH, 93% 2. MeI, K2CO3, 79% O OH OMe O

O O EtO 91% OEt HOAc, piperidine

OEt i i iPrO O PrO OPiv 1, NaOH PrO OTES 1. KHMDS, TESCl

O O O MeO MeO MeO 2. PivCl, py 2. dilute with PhH, OMe OH OMe OEt then h! OMe OEt 38% - 64% E/Z = 1:1

Myers, A. G.; Horiguchi, Y. Tetrahedron Lett. 1997, 38, 4363-4366. Total Synthesis of Proposed Kedarcidin Chromophore

! Chloropyridine synthesis

HO formalin HO 1. MOMCl, 81% MOMO

OH Cl N Cl N CHO Cl N NaHCO3, 81% 2. Swern [O], 92%

O- S+ Ti(OEt)4 H2N 93% Me

- O- OTi(Oi-Pr)3 O S+ S+ HN OMe N N Cl N Cl Me Me -78 oC, 94%, 91 de COOMe MOMO MOMO

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. Total Synthesis of Proposed Kedarcidin Chromophore

! Chloropyridine synthesis

O- S+ NH2•HCl HN MeOH, AcCl Cl N COOMe Cl N Me 93% COOMe HO MOMO

Boc2O, NEt3

84%

NHBoc Cl N COOMe

HO

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

! Core synthesis

Me Me Me Me Me Me O O O DIBAL LDA, TMSCHN2 O O O OH

O 96% O 81% O HO

LHMDS, TESCl; LHMDS, TESCl

Me Me Me Me Me Me O Br PPh , CBr O O 3 4 1. 3HF•NEt3 O O O OTES Br CHO

NEt3, 78% 2. Swern [O]

TES TES TES

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

! Core synthesis NHBoc Cl N COOMe Me O 1. KHMDS Me O S O Br O Br HF, H2O, 98% HO O O Br Br 2. H SO , H O SO2Cl2, NEt3, 2 4 2 DMAP, 63% 3. TBSCl, Imidazole 82% overall TES TES

BocHN COOFm BocHN COOMe

N N 1. LiOH, H2O2 Cl Cl

O 2. FmOH, DMAP, 93% O Me Me TBSO Br TBSO Br Br O Br

TES NO2 O O NO2 TES

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

! Core synthesis

iPrO OPiv iPrO OPiv EDC

O O iPrO OPiv MeO MeO HOBt OMe OH OMe OBt O MeO OMe HN COOFm

NaHCO3 N Cl 97% BocHN COOFm H2N COOFm O

N N Br Cl Cl TBSO TMSOTf Br O O TES lutidine TBSO Br TBSO Br Br Br

TES TES

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

Me

O Me MeO

MeO

OH

O HN O Cl N O O H H O O OH OH O O Me O Me HO NMe2 Me

proposed kedarcidin chromophore (1997) Total Synthesis of Proposed Kedarcidin Chromophore

! Core synthesis

Me Me Me Me MgBr Me Me O O O O 1. TMS Li O O OH O

CHO 2. PDC, 86% HgCl2, 64%, 4:1 dr

TMS TMS

LHMDS, TESCl, 97%

Me Me AcO OH HO OH AcCl, py 1. HF, H2O O O OH OH OTES

82% 2. K2CO3, MeOH

93% TES TES TMS TES

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

! Suger synthesis

O OH 1. HCl, MeOH O OH AcCl, py O OAc

HO Me MeO Me MeO Me 93% NH2 2. paraformaldehyde NMe2 NMe2 MgSO4, H2, Pd/C 90% LHMDS then MOMBr 78%

O 1. AcCl, TFE O O 2. DBU H2, Pd(OH)2 O O O

DEIPSO Me 3. DEIPSCl, Im. MOMO Me TFE, 82% MOMO Me 76% NMe2 NMe2 NMe2

Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. Org. Lett. 2007, 9, 1923-1925. Total Synthesis of Proposed Kedarcidin Chromophore

! Core synthesis

O OH F DIBAL DAST O O O

DEIPSO Me 88% DEIPSO Me DEIPSO Me

NMe2 NMe2 NMe2

OAc

OH Cp2HfCl2,

OH AgClO4

TES

NMe2 NMe2 Me Me O O OAc OH ODEIPS K2CO3, MeOH ODEIPS

O O 50% overall OH OH

TES TES

Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. Org. Lett. 2007, 9, 1923-1925. Total Synthesis of Proposed Kedarcidin Chromophore

Me

O Me MeO

MeO

OH

O HN O Cl N O O H H O O OH OH O O Me O Me HO NMe2 Me

proposed kedarcidin chromophore (1997) Total Synthesis of Proposed Kedarcidin Chromophore

! Core synthesis

i PrO OPiv NMe2 iPrO OPiv Me O O OH ODEIPS O MeO MeO O OMe HN COOFm OMe HN COOFm

OH N N NMe2 Cl Me Cl O OH TES ODEIPS O O O

TBSO Br TBSO Sonogashira, 61% OH Br Br

TES R = TES R R

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

! Core synthesis

iPrO OPiv Me Me 66% O 1. NEt3, 2. DMAP MeO O OMe HN COOFm NO2 O O NO2

N NMe2 Me Cl O OH ODEIPS iPrO OPiv O O O MeO TBSO OH Br OMe HN

N O R R = TES NMe2 R Cl Me O O ODEIPS O O

TBSO OH Br R = TES 1.7 : 1 atropisomers R R in C6D6

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

! Glaser coupling iPrO OPiv

O 1. AgNO , 73% MeO 3 2. Cu(OAc)2, CuI, py, 59% OMe HN

N O NMe2 Cl Me O O ODEIPS O iPrO OPiv O O TBSO OH MeO Br OMe HN R = TES R R N O NMe2 1.7 : 1 atropisomers Cl Me in C6D6 O O ODEIPS O H O H H Br OH TBSO

9 : 1 atropisomers in C6D6

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

! Transannular cyclization

iPrO OPiv

O LHMDS, then t-BuLi, MeO quenched with HOAc immediately (< 3 s) OMe HN 52% OiPr N O NMe2 Cl Me O MeO O ODEIPS O H O MeO H OPiv H Br OH TBSO O HN O 9 : 1 atropisomers Cl N O in C6D6 O H H O OH TBSO ODEIPS O Me NMe2

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

! Advanced stage

OiPr OiPr MeO MeO

MeO MeO

OPiv 1. TBAF, o-nitrophenol OPiv

O O HN O HN O 2. PivCl, NEt3, 76% Cl N Cl N O O O O H H O H H O OH OH TBSO ODEIPS HO ODEIPS O O Me Me NMe2 NMe2

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

! Advanced stage

OiPr OiPr MeO MeO

MeO MeO

OPiv OPiv Ph2MeCOOH, VO(acac)2 O O HN O HN O 28% Cl N Cl N O O O O H H O H H O OH OH HO ODEIPS HO ODEIPS O O O Me Me NMe2 NMe2 1.5 : 1 atropisomers in C6D6

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

! Advanced stage

OiPr OiPr MeO MeO

MeO MeO OPiv OPiv AgPF6, DTBMP O O HN O HN O Cl N Cl N Me O SPh O O O O 59% TESO H H O HO Me H H O OH OH O ODEIPS HO ODEIPS OH O O O O Me O Me Me TESO NMe2 NMe2 Me 1.5 : 1 atropisomers 1.5 : 1 atropisomers in C6D6 in C6D6

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

! Advanced stage

OiPr OiPr MeO MeO

MeO MeO

OPiv OPiv Martin's sulfurane O O HN O HN O Cl N Cl N 65% O O O O H H H O H O OH O ODEIPS O ODEIPS OH O O OH O O Me Me Me Me O O TESO NMe2 TESO NMe2 Me Me 1.5 : 1 atropisomers 1 : 1 atropisomers in C6D6 in C6D6

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

! End game

OiPr OiPr MeO MeO

MeO MeO

OH OPiv TBAF, o-nitrophenol O O HN O HN O Cl N Cl N then 3HF•NEt , 50% O O 3 O O H H H O H O O OH O ODEIPS OH O O OH O O Me Me Me Me O O HO NMe2 TESO NMe2 Me Me 1 : 1 atropisomers 1.2 : 1 atropisomers in C6D6 in C6D6

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

Me Me

O Me O Me MeO MeO

MeO MeO

OH OH

O O HN O HN O HO Cl N Me Cl N O Me O OH O O O H O O H O H O OH H OH OH O O O O Me Me O Me HO NMe2 NMe2 Me proposed kedarcidin chromophore (1997) proposed kedarcidin chromophore (2007)

Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 5381-5383. Unfinishable Mission?

OH H2N O O

O Cl N MeO HO Cl O O O H OMe O HO O OH O HO O O Me HN HO OH Me H O O Me N O H Me NMe2 HO Me

C-1027 chromophore real maduropeptin chromophore?