Synthetic Enchantment with Mitomycinoids · 2017-01-12 · Synthetic Enchantment with Mitomycinoids...
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O O N 9a NH OMe O Me H 2 N O NH 2 Monday, August 16th, 2004 Jeremy May, Dan Caspi, Neil Garg, Jenny Roizen and G. Sekar Synthetic Enchantment with Mitomycinoids Mitomycin C S y n t h e t i c C h a l l e n g e s : • Complex stereochemistry • Avoiding aromatization to pyrrole, indole, or hydroquinone • Sensitive aziridine and quinone • Hemiaminal ether linkage at C(9a) • Originally isolated and characterized by Japanese and American pharmaceutical companies as a consequence of antibiotic screens. • Mitomycins A and B were isolated in 1956, followed by Mitomycin C in 1958. • Mapping the structures engaged the interests of chemists and crystallographers for 20 years. • Early on it was discovered that mitomycins are potent antibiotics (gram positive and gram negative bacteria, and mycobateria) and cytotoxic agents. • Mitomycin C (Mutamycin®) is the most potent of the family, and is also a widely prescribed antitumor agent marketed by Bristol-Myers Squibb Oncology. • Elucidation of the detailed biological mechanism was very challenging, and the original proposal in 1963 by Iyer and Szybalski has been experimentally verified with few changes. • Mitomycin C is also among the first bioreductively activated drugs, and it is selective for hypoxic (O 2 -deficient cells). "The synthesis of a mitomycin is the chemical equivalent of walking on egg shells" History of the Mitomycins Biosynthesis and mechanisms of action: Boger, D. L. Chem. Rev. 2002, 102, 2477. Herbert, R. B. Nat. Prod. Rep. 2003, 20, 494. Synthetic studies: Danishefsky, S. J. Synlett 1995, 475. Kono, M. Synlett 1992, 778. -S. Danishefsky
Transcript of Synthetic Enchantment with Mitomycinoids · 2017-01-12 · Synthetic Enchantment with Mitomycinoids...
O
O
N
9a
NH
OMe
O
Me
H2N
ONH2
Monday, August 16th, 2004
Jeremy May, Dan Caspi, Neil Garg, Jenny Roizen and G. Sekar
Synthetic Enchantment with Mitomycinoids
Mitomycin C
Synthetic Challenges:
• Complex stereochemistry
• Avoiding aromatization to pyrrole, indole, or hydroquinone
• Sensitive aziridine and quinone
• Hemiaminal ether linkage at C(9a)
• Originally isolated and characterized by Japanese and American pharmaceutical companies as a consequence of antibiotic screens.
• Mitomycins A and B were isolated in 1956, followed by Mitomycin C in 1958.
• Mapping the structures engaged the interests of chemists and crystallographers for 20 years.
• Early on it was discovered that mitomycins are potent antibiotics (gram positive and gram negative bacteria, and mycobateria) and cytotoxic agents.
• Mitomycin C (Mutamycin®) is the most potent of the family, and is also a widely prescribed antitumor agent marketed by Bristol-Myers Squibb Oncology.
• Elucidation of the detailed biological mechanism was very challenging, and the original proposal in 1963 by Iyer and Szybalski has been experimentally verified with few changes.
• Mitomycin C is also among the first bioreductively activated drugs, and it is selective for hypoxic (O2-deficient cells).
"The synthesis of a mitomycin is the chemical equivalent of walking on egg shells"
History of the Mitomycins
Biosynthesis and mechanisms of action:
Boger, D. L. Chem. Rev. 2002, 102, 2477.Herbert, R. B. Nat. Prod. Rep. 2003, 20, 494.
Synthetic studies:
Danishefsky, S. J. Synlett 1995, 475.Kono, M. Synlett 1992, 778.
-S. Danishefsky
Isomitomycin A
O
O
N
OMe
O
Me
MeO Albomitomycin A
X R HMitomycin B OMe H !Mitomycin D NH2 H !Mitomycin F OMe Me "Porifiromycin NH2 Me "
O
O
N NMe
OR
Me
X
OH
X NO
OH
O
NH2O
NH
NH2
O
H
N
X Mitomycin A OMeMitomycin C NH2
The Mitomycinoid FamilyKey Structural Types
X FR-900482 CHOFR-66979 CH2OH
7
65
5a
8a8
O
O
N4
9a
9
32
1
NH
OMe
10 O
Me
X
O
O
Me
MeO
O
O
N NMe
OR
O
Me
X
N
NOMe
O
H
H
ONH2
NH2O
NH2
O
X R Mitomycin G NH2 Me Mitomycin H OMe H Mitomycin K OMe Me
•
Biosynthesis of Mitomycin
7
65
5a
8a
8
NH2
OH
O
HO
3
2
NH2
1 OH
9aHO
9
HO10
OH
O
D-glucosamine
• Studies in the 1970's and 1980's revealed that 3-amino-5-hydroxy-benzoic acid (AHBA), D-glucosamine, carbamoyl phosphate and S-adenosyl methionine are involved in the convergent assembly of these natural products.
• The basic building blocks have been known for some time, but the specific order of assembly has remained undefined.
• Mutant strains of S. lavendulae allow for the isolation of biosynthetic intermediates (complete set of genes for mitomycin biosynthesis has been identified and characterized).
Sherman, D. H. J. Am. Chem. Soc. 2001, 123, 6712.Sherman, D. H. Chem. Biol. 1999, 6, 251.Sherman, D. H. J. Bacteriol. 1999, 181, 2199.
H
P
OO
ROOR
H2N
O
carbamoyl phosphate
(from L-citrulline or L-arginine)AHBA
7
65 5a
8a8
O
O
N4
9a
9
32
1
NH
OMe
10 O
Me
H2N
ONH2
Reductive Activation of Mitomycin C
O
O
N NH
OMe
O
Me
H2N
ONH2
enzymaticor
chemicalreduction
OH
OH
N NH
OMe
O
Me
H2N
ONH2
OH
OH
N NH
O
Me
H2N
ONH2
- CH3OH
O
OH
N
NH2
O
Me
H2N
ONH2
DNA!-attack
H+
Quinone Methide
• N2 and N7 atoms of guanines in the minor groove of DNA are
primary alkylation sites.
• Alkylation always proceeds in the order shown.
• !-attack is also observed with the unnatural enantiomer of MC,
potentially accounting for the lower cytotoxicity (50%).
• Completely unreactive with DNA at pH 7-8, but in the presence of
reductants, cross-linking occurs in < 1 min.
N
NNH2N
HN
O
guanine
dR
OH
OH
N
NH2
O
Me
H2N
ONH2
DNA
OH
OH
N
NH2
Me
H2NDNA
DNA
reduced mitocene
N2
N7
DNA
Rebek's Stepwise Approach
N
COOH
R
OMeO2C
N
MeO2CCO2MeCO2Me
R
N
CO2Me
R
MeO2CO
Ac2O
KO-t-Bu
N
H2NO
O
OCONH2
NH2
OMe
J. Rebek, Jr. J. Org. Chem. 1984, 49, 5164
N
O
O
XOCONH2
OMe
X = OMe: Mitomycin AX = NH2: Mitomycin C
CO2MeMeO2C
NHFranck's meta Photo-Fries Rearrangement Approach
O
N
O
NH2
h!
O
N
O
NH2
O
NH2
N
O
NH2
N
O
OH
R. W. Franck J. Org. Chem. 1977, 42, 105
14%
MeO MeO MeO MeO
Huisgen pyrrole synthesis
65%
82%
Enantiopure SM
One-step Bicycloannulation Approach
NH
NPhNaH
COOMe
Br
N
NPh
COOMe
60%
NNPh
COOMe
Br
NNPh
COOMe
Br
N
Br
NPh
COOMe
R. M. Cory Chem. Commun. 1983, 1244
NH
O
THF, 0°C
NaH
SMe2
72%THF, 0°C
IN
O
SMe2
H
N
O
L. S. Jimenez J. Am. Chem. Soc. 1994, 116, 4977
N
NH
O
O
MeO
N
NMe
O
O
MeO
OMe
J. Org. Chem. 1996, 61, 818 Tetrahedron Lett. 1996, 37, 6049
N
O
O
XOCONH2
OMe
X = OMe: Mitomycin AX = NH2: Mitomycin C
NH
N
NH
OH
O
(±)-Mitomycin-K
2-imidoyl indole
2-formyl indole
Intramolecular Radical Cyclization
N
OBn
OMe
MeO CH2OH
NBOC
Br
N
NBOC
OBn
OMe
MeO CH2OH
HBu3SnH
AcCN, toluene reflux 55%
N
NH
O
O
MeO CH2OCONH2
H
F. E. Ziegler J. Org. Chem. 1997, 62, 1083 Tetrahedron Lett. 1998, 39, 2455
N
COOEt
NCPh3
Li
D N
NCPh3
COOEt
N
COOEt
NCPh3
SnBu3
D
MeLi
- 65 °C
PhSeCl
80%
E. Vedejs J. Am. Chem. Soc. 2002, 124, 749
N
NCPh3
COOEt
D
Li
N
OMeBr COOEt
OMeO
Bu3SnH, AIBN
toluene, heat
N
OMeH COOEt
OMeO
OMe
OMe
N
O
COOEt
A. F. Parsons Synlett. 2002, 1431
44%
N
O
O
XOCONH2
OMe
X = OMe: Mitomycin AX = NH2: Mitomycin C
NH
(+)-Demethoxymitomycin A
Anionic Cyclization
Enantiopure SM
H
7.3 : 1
N
O
O
O
BOC
O
Miller's Transannular Cyclization
5 mol% HNO3
MeOH, 135°C 81% N O
OMe
N NH
OMe
O
S. J. Miller J. Org. Chem. 2003, 68, 2728
N
O
O
N
O
O
TiO-i-Pr
O-i-Pr
N
O
Ti
O
O-i-Pr
O-i-Pr
MeO MeO OMe
N
OH
OH
OOMe
c-C5H9MgClClTi(O-i-Pr)3
O2 workup
60%
Jin Kun Cha J. Am. Chem. Soc. 1997, 119, 8127
Cyclization Through TitanacyclopropaneN
O
O
XOCONH2
OMe
X = OMe: Mitomycin AX = NH2: Mitomycin C
O
NH
Total Synthesis of FR66979 and FR900482
S. F. Martin J. Am. Chem. Soc. 2000, 122, 10781R. M. Williams Angew. Chem. Int. Ed. 2002, 41, 4883M. A. Ciufolini Angew. Chem. Int. Ed. 2002, 41, 4888
Synthetic efforts before 1977 Y. Kishi J. Am. Chem. Soc. 1977, 99, 4835 (references cited therein)
enantiopure SM
Danishefsky's AttemptsActivated Cyclopropanes
N NH
OMe
O
O
Me
X
OCONH2
X=OMe Mitomycin AX=NH2 Mitomycin C
O
Me
O
O
NPhth
OCO2Me
O
N2
O
Me
O
O
NPhth
O
CO2Me
O
5:1 drFrom Claisen and
Diazomalonate formation.
NH2NH2Rh(II)
O
O
O
Me NH
OH
•O
CO2Me
O
O
O
Me N
OH
OCO2Me
O
Me
O
O
NPhth
CO2Me
CO2Me
OH
CSAMeOH
NH2NH2
(CONHNH2)
+
N
<25% yield
H
H
(87% yield)
(42% yield)
(47% yield)
OBnOAc
O
O
Me NH2
Br
OAc
O
O
Me NH
H
OBn
Br
SePh
OAc
O
O
Me N
H
OBn
SePh
SePh
NPhth
OBn
O
O
Me N
H
OBn
NMe
O
O
O
Me N
H
OBn
NMe
OBnOAc
O
O
Me NH2
OTBS
BrHg(OAc)2
OAc
O
O
Me NH
OBn
OTBS
Tandem Ring Formation
N NH
OMe
O
O
Me
X
OCONH2
X=OMe Mitomycin AX=NH2 Mitomycin C
Oxidation at C9a Needed!
Indole formation a continual problem.
31% yield from Claisen precursor to selenide elimination product.
From a Claisen rearrangement:
(51% yield)
Oxidation at C9a
N NH
OMe
O
O
Me
X
OCONH2
X=OMe Mitomycin AX=NH2 Mitomycin C
N NP
O
O
Me
X
OP
H
N NP
O
O
Me
X
OP
OR?
Looking at these sorts of compounds led to bioactivity studies.
OBn
O
O
Me N
H
OBn
OAc
OAc
OBn
O
O
Me N
H
OBn
OAc
OAcO
mCPBA
OBn
O
O
Me N
OBn
OAc
OAc
Ac2O
PolonovskyReaction
OBn
O
O
Me N
OBn OBn
O
O
Me N
OBn
OAc
OAc
OBn
O
O
Me N
H
OBn
OAc
OAcOAc
OBn
O
O
N
H
OBn
OAc
OAcOAc
11% 25% 26% 18%
R'
R
either R or R'is OAc
Imine formation here is possible.
Oxidation of C9a is not straightforward.
Oxidation at C9-C9a
N NH
OR
O
O
Me
O
R=H Mitomycin HR=Me Mitomycin K
OTMS
O
OTMS
Me N
OTBS
OAc
OAc
OsO4
OTMS
O
OTMS
Me N
TBSO
OAc
OAc
O
OsO
O
OH2S
OTMS
O
OTMS
Me N
TBSO
OAc
OAc
OH
OH
OBn
O
O
Me N
O
NMe
HOBn
O
O
Me N NMe
O
OsO
O
O
Nuc
O OBn
O
O
Me N NMe
OH
O
OBn
O
O
Me N NMe
OH
OsO4
PetersonOlefination Amazingly, this intermediate could not
be equilibrated to Mitomycin H or K.
Mitomycin H and K
Hetero Diels-Alder ReactionsOH
X NO
OH
O
NH2O
NH
FR-900482 X=CHOFR-66979 X=CH2OH
The FR Series of Mitomycinoids
OBn
I
MeO2C NO
OMOM
HO
OBn
I
MeO2C NO
OHOMOM
1) OsO4
2) Aziridine Installation
!
1) Olefin formation(77% yield)
2) Heck reaction (90% yield)
OBn
I
MeO2C NO
OAcOMOM
NAc
OBn
MeO2C NO
OMOM
NAc
OTIPS
MeO2C NO
OMOM
NAc
OTIPS
1) epoxidation (76% yield)
2) SmI2 (90% yield)3) TIPS incorporation (92% yield)
1) DIBAL (93% yield)
2) MnO2 (85% yield)
OTIPS
NO
OMOM
NAc
OTIPS
O
H
OH
NO
OH
O
NH2O
NHH
OFR-900482
70% yield
Intramolecular Hetero Diels-Alder
N NH
OR
O
O
Me
O
R=H Mitomycin HR=Me Mitomycin K
Mitomycin K
H
OO
O
O
Me
OMe
Li
NO2
OHO
O
O
Me NO2
OMe
h!
O
O
O
Me N
OMe
OO
O
O
Me N
O
O
OMe
O
O
O
Me N
OMe
O
HO
1) PDC (65%)2) PhSCH2N3 (90%)
3) L-Selectride (77%)4)
O
O
O
Me N NMe
OMe
O
N
N
NSPh
SIm
S
Im
S
Im
1) AIBN, SnHBu3 (52%)
2) h! (48% yield)3) Ra-Ni (70% yield)
1) TMSCH2Li (90% yield)
2) Ag(II) (16% yield)3) PPTS (81% yield)
N NH
OMe
O
O
Me
O
Mitomycin K
Use of Bn causes aziridine opening in the presence of radicals.
(65%)
(80% yield)(45% yield)
X
O
O
N NH
OMe
O
NH2
O
MeO
OBn
OBn
a) H2, Pd/C
MeOH
MeO
O
O
HN
b) O2
MeOH
OH
OMeOMe
40-50%H2N
OHOMe
OMeMeO
OH
OH
H2N
OHOMe
OMe
1. PhO2CCl, Pyr., CH2Cl2
2. MeSH, cat. BCl3•OEt2, –45 °C
MeO
O
O
HN
OCO2Ph
OMeSMe
HgCl2, NEt3
CH2Cl2
67%
MeO
O
O
N
OMe
OCO2Ph
NH3
90%
MeO
O
O
N
OMe
OCONH2
Al2O3
30-35%
MeO
O
O
N
OMe
OCONH2
Deiminomitomycin A (trans) Kishi, Y. JACS 1977, 99(14), 4835-4836
Kishi's Route to Deiminomitomycin A:Michael Addition / Trans-annular Cyclization
1:1 cis:trans
X = OMe Mitomycin AX = NH2 Mitomycin C
cis decomposes
MeO
OBn
OBn
a) H2, Pd/C, MeOH
b) O2, CH3OH
MeO
O
O
HN
OH
OMeOMe
H2N
OBn
OMe
OMe
NR NR
HBF4
CH2Cl2, rt77%
MeO
O
O
N NR
OMe
OH
Kishi, Y. TL 1977, 49, 4295-4298Kishi, Y. JACS 1977, 99(14), 8115-8116
Kishi's Route to Mitomycin A:Michael Addition / Trans-annular Cyclization X
O
O
N NH
OMe
O
NH2
O
X = OMe Mitomycin AX = NH2 Mitomycin C
R = (CH2)3OAc or Me
R = (CH2)3OAc
TrBF4
CH2Cl2, rt90 %
R = Me
O
O
CH2OHNR
O
O
NH
85%
MeO
O
O
N NR
OMe
OCONH2
1. NaOCH3, CH3OH, CH2Cl22. DMSO-DCC, TFA-Pyr, rt
3. HClO4, C6H5N(CH3)2 CH2Cl2, rt
1. COCl2, C6H5N(CH3)2 toluene, CH2Cl2, rt
2. NH3, CH2Cl2, toluene 0 °C
MeO
O
O
N NH
OMe
OCONH2
Mitomycin A
NH3
MeOH
H2N
O
O
N NH
OMe
OCONH2
Mitomycin C
CH3I, NaHCO3MeO
O
O
N NMe
OMe
OCONH2
N-Methyl Mitomycin A
NH3
MeOH
H2N
O
O
N NMe
OMe
OCONH2
Porfiromycin
Lancaster, J. JACS 1962, 3185-3187
X
O
O
N NH
OMe
O
NH2
O
X = OMe Mitomycin AX = NH2 Mitomycin C
Kishi's Route to Mitomycins A and C, and Porfiromycin:End Game
If R = (CH2)3OAc
MeO
O
O
N NR
OMe
OH
Isomitomycin A
X Mitomycin A OMeMitomycin C NH2
The Fukuyama Approach
7
6
8
O
O
N
9
32
1
NH
OMe
10 O
Me
X
O
O
Me
MeO
N
NH
OMe
O
ONH2
NH2O
1
2
3
Fukuyama Total Synthesis Efforts:
JACS 1987, 109, 7881-7882; 1st generation synthesis
JACS 1987, 111, 8303-8304; 2nd generation synthesis
Problems to consider:
reactive quinonereactive aziridinemethanol elimination
Fukuyama's Solution:
Prepare Isomitomycin A
and perform 'Mitomycin
Rearrangement'
9a
9a
Isomitomycin A
O
O
N
OMe
O
Me
MeO
Albomitomycin A
NH2
O
H
N
Mitomycin A
The Mitomycin Rearrangement
7
6
8
O
O
N
9
32
1
NH
OMe
10 O
Me
MeOO
O
Me
MeO
N
NOMe
O
H
ONH2NH2O
JACS 1987, 109, 7224-7225
7
O
O
N NH
OMe
O
Me
MeO
ONH2
7
O
O
N NH
OMe
O
Me
H2N
ONH2
NH3
MeOH
Mitomycin C
Mitomycin A
Access to Both Mitomycins A & C
JACS 1962, 84, 3185
• Mixture isolated from fermentation broth of streptomyces caespitosus• Mitomycin A is heavily favored
Isomitomycin A
Fukuyama's Route to Isomitomycin A:Assembling the Carbon Framework
O
O
Me
MeO
N
NHOMe
O
NH2O
OBn
MeO
Me
OMe
N3
Ph
O
• masked quinonemoiety
OBn
MeO
Me
OMe
N
O
O
SEtOTMS
Ph
OBn
MeO
Me
OMe
N3
O
O
SEtOTMS
Ph
O
OTMS
EtS
+SnCl4 (0.1 equiv)
CH2Cl2, pyr, -78 °C
95% yield
toluene
110 °C, 3h
86% yield
OBn
MeO
Me
OMe
N
O
O
SEtOTMS
Ph
N N
-N2
• High diastereoselectivity? Possibly endo Diels-Alder reaction, then retro aldol.
JOC 1981, 46, 3970-3977• aziridine seems pretty robust
OBn
MeO
Me
OMe
N
O
OAc
SO2Et
O
HNO CCl3
O
9
9
Isomitomycin A
Fukuyama's Route to Isomitomycin A:Late-Stage Manipulations O
O
Me
MeO
N
NHOMe
O
NH2O
OBn
MeO
Me
OMe
N
O
OAc
SO2Et
O
HNO CCl3
O
NH3
MeOH
OBn
MeO
Me
OMe
N
O
NH2O
O
O
OBn
MeO
Me
OMe
N
O
OH
SO2Et
O
NH2O
OBn
MeO
Me
OMe
N
NH
OMe
OH
O
NH2O
OBn
MeO
Me
OMe
N
NHOH
O
NH2O
NaBH4
61% yield 9a
• bridgehead hemiaminal (9a) stable to reaction conditions!
The Total Synthesis of Isomitomycin A, Isomitomycin C,Mitomycin A, and Mitomycin C
OBn
MeO
Me
OMe
N
NHOH
O
NH2O
9a
OBn
MeO
Me
OMe
N
NH
O
NH2O
9aCSA
MeOH
60% yield
• highly strained iminium ion formed under carefully controlled acidic conditions
OBn
MeO
Me
OMe
N
NHOMe
O
NH2O
1. H2, Pd/C, EtOH
2. DDQ
77% yield
O
X
Me
O
N
NHOMe
O
NH2O
Isomytomycin A
Al(O-iPr)3
MeOH, 23 °C
91% yield
O
O
N
OMe
O
Me
MeO
Albomitomycin A
NH2
O
H
N Mitomycin A X=OMe
O
O
N NH
OMe
O
Me
X
ONH2
Mitomycin C X=NH2
NH3MeOH
Isomitomycin CX=NH2
X=OMe
NH3
MeOH 85% yield
Mytomycin Synthetic Challenges and Solutions - Summary
X Mitomycin A OMeMitomycin C NH2
7
6
8
O
O
N
9
32
1
NH
OMe
10 O
Me
X
ONH2
9a
Problems Solutions to date
• quinone reactivity -aromatization -Michael acceptor
• install at late stage• carry as aromatic derivative
• C(9a) reactivity -loss of OMe
• install functionality at C(9a) early• install C(9a) OMe at late stage
• reactive aziridine •!install at late stage
• stereocontrol -no asymmetric synthesis to date
• make more rigid system to enhance diastereoselectivity
Team 1
Team 2
Team 3
Team 4
New Solutions?
