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The Total Synthesis of Mitomycins
Bob Moreau
Organic Supergroup
April 25, 2007
Mitomycin A was isolated from the culture broth of Streptomyces caesipitosus in 1956 and mitomycin C in 1958.
Their gross structures as well as their relative and absolute stereochemistries were determined by X-ray crystallographic analysis in an effort that took about 20 years.
These mitomycins are active against Gram-positive and Gram-negative bacteria, and also show broad activity against tumor cells.
Mitomycin C has proven to be more potent and is a widely prescribed antitumor agent.
These molecules exert their powerful biological activity by crosslinking DNA strands.
N NH
O
O
Me
X OMe
OCONH2
Mitomycin A X = OMeMitomycin C X = NH2
Mechanism of Action
reduction -MeOH
alkylationof ds DNA
DNAcrosslinkingoxidation
N NH
O
O(H)
Me
H2N OMe
OCONH2
N NH
O
O(H)
Me
H2N
OCONH2
N
O
O(H)
Me
H2N
NH2
DNAN
O
O
Me
H2N
DNA
NH2
DNA
N
O
O(H)
Me
H2N
DNA
NH2
DNA
N NH
O
O
Me
H2N OMe
OCONH2
Mitomycin C
DNA
OCONH2
Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlak, J.; Verdine, G. L.; Nakanishi, K. Science 1987, 235, 1204.
Covalent Crosslink Adduct
Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlak, J.; Verdine, G. L.; Nakanishi, K. Science 1987, 235, 1204.
Molecular model of the Mitomycin C/DNA crosslinked complex showing the mitosene unit snugly fit into the minor grove. Based on this model, the mitosene unit protrudes less than 1 Å beyond the edges of the DNA backbone
Mitomycinoid Structures
N NH
O
O
Me
X OMe
OCONH2
N
O
O
Me
MeO OMe
OCONH2 O
O
Me
MeO
Mitomycin A X = OMeMitomycin C X = NH2
Isomitomycin AAlbomitomycin A
N
NHOMe
OCONH2
N
H
N NMe
O
O
Me
X OH
OCONH2
Mitomycin B X = OMeMitomycin D X = NH2
N NMe
O
O
Me
X OMe
OCONH2
Mitomycin F X = OMePorfiromycin X = NH2
N NMe
O
O
Me
X OR
Mitomycin G X = NH2, R = MeMitomycin H X = OMe, R = HMitomycin K X = OMe, R = Me
“The complexity of the problem arises from the need to accommodate highly interactive functionality in a rather compact matrix and to orchestrate the chemical progression such as to expose and maintain vulnerable structural elements as the synthesis unfolds. The synthesis of a mitomycin is the chemical equivalent of walking on egg shells.”
Danishefsky, S. J.; Scheryantz, J. M. Synlett. 1995, 475.
The Kishi Lab Approach
N NH
O
O
Me
MeO OMe
OCONH2
HN
MeO
Me
O
O
NH
OCONH2
O Me
HN
MeO
Me
O
O
NH
OCONH2
XOMe
MeO
Me
PO
PO
OPX
OMe
NH2
NH
MeO
Me
OMe
MeO
Me
PO
PO
Mitomycin A
Kishi’s Model System
N
O
O
Me
MeO OMe
HN
MeO
Me
O
O
O Me
HN
MeO
Me
O
O
XOMe
MeO
Me
PO
PO
XOMe
NH2
MeO
Me
OMe
MeO
Me
PO
PO
Synthesis of a Key Aromatic Intermediate
mCPBA
CH2Cl2, 0 °C
NaOMeMeOH, 0 °C
98%, 3 steps
MeO
Me
MeO
K2CO3
acetone, reflux
MeO
Me
MeO
O H
MeO
Me
MeO
O
O
HTiCl4
CH2Cl2, 0 °C
ClMeO
Cl
MeO
Me
MeO
OH
MeO
Me
MeO
O Br
PhNMe2, reflux
96%, 2 steps
MeO
Me
MeO
OH
Synthesis of a Key Aromatic Intermediate
Zn
AcOH, 0 °C
BnBr, K2CO3DME/DMF
reflux
67%, 3 steps
MeOH/dioxane
77%
HNO3
AcOH
MeO
Me
OBn
OBn1. LDA, CH3CN
-30 °C
2. CrO3, H2SO4aq. acetone
71%, 2 steps
MeO
Me
OMe
OH
MeO
Me
O
O
MeO
Me
OH
OH
MeO
Me
OBn
OBn
OPh O
NH
OHMeO
Me
OBn
OBn
O
CN
Medium Ring Formation
LAH
H2, Pd/CMeOH
O2
MeOH
MeOH, H+MeO
Me
OBn
OBn
O
CN
NC
MeO
Me
OBn
OBn
OMeOMe MeO
Me
OBn
OBn
OMeOMe
NH2
MeO
Me
OH
OH
OMeOMe
NH2
MeO
Me
O
O
OMeOMe
HN
MeO
Me
O
O
OMeOMe
NH2
40-50%, overall
Transannular Cyclizations
BF3.OEt2
MeSH, -45 °C
H+ in MeOH,SiO2, or heat
HN
MeO
Me
O
O
OMeOMe
HgCl2, Et3N
CH2Cl2
N
O
O
Me
MeO
N
O
O
Me
MeO OMe
HN
MeO
Me
O
O
SMeOMe
N
O
O
Me
MeO OMe
Transannular Cyclizations
BF3.OEt2
MeSH, -45 °C
H+ in MeOH,SiO2, or heat
HN
MeO
Me
O
O
OMeOMe
HgCl2, Et3N
CH2Cl2
N
O
O
Me
MeO
N
O
O
Me
MeO OMe
HN
MeO
Me
O
O
SMeOMe
N
O
O
Me
MeO OMe
Ketal Formation Problems
1. BH3 xylene reflux
2. H2O2
1. H2CO, NaOMe MeOH, 0 °C 69% (2. BnBr)
MeO
Me
OBn
OBn
O
CN
MeO
Me
BnO
BnO
CN
MeO OMe
MeO
Me
BnO
BnO
OH
CN
MeO OMe
MeO
Me
BnO
BnO
OR
CN
O
ketalformation
this compound wasobtained in only very
low yield
A Solution to the Ketal Formation Problems
Et3N, MeOH
71% overall
1. H2CO, NaOMe MeOH, 0 °C 69% 2. Ac2O
MeO
Me
OBn
OBn
O
CN MeO
Me
BnO
BnO
OAc
MeS SMe
NH
SMe
BF3.2AcOH
MeSH, -30 °C
MeO
Me
BnO
BnO
OAc
CN
MeS SMe
MeO
Me
BnO
BnO
OAc
CN
O
HgCl2, Et3N
MeOH/THF
85%, 3 steps
1. NaOMe MeOH/CH2Cl2 2. BnBr, KH DMF
MeO
Me
BnO
BnO
OBn
CN
MeS SMe
MeO
Me
BnO
BnO
OBn
CN
MeO OMe
Sidechain Functionalization
1. NaBH4 MeOH CH2Cl2, 0 °C2. Ac2O, py
66% overall
1. LDA; PhSeBr THF, -78 °C 2. 30% H2O2 EtOAc/THF
DIBAL
CH2Cl2, 0 °C
3 eq. OsO4
py/THF
87%
MeO
Me
BnO
BnO
OBn
CN
MeO OMe
MeO
Me
BnO
BnO
OBn
CN
MeO OMe
MeO
Me
BnO
BnO
OBn
MeO OMe
O
H
MeO
Me
BnO
BnO
OBn
MeO OMe
OAcMeO
Me
BnO
BnO
OBnOMe
OMe
OAc
MeO
Me
BnO
BnO
OBnOMe
OMe
OAc
OHOH
OHOH +
this reaction took over a week to go to completion
Installation of the Aziridine
steps
56% or 93%
MeO
Me
BnO
BnO
OBnOMe
OMe
OAc
MeO
Me
BnO
BnO
OBnOMe
OMe
OAc
OHOH
OHOH +MeO
Me
BnO
BnO
OBnOMe
OMe
OH
O
MeO
Me
BnO
BnO
OBnOMe
OMe
OMs
OMs
N3
1. LiN3, DMF 150 °C2. Ms2O, py
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
N P(OMe)2
O
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
OMs
N3
1. BnNH2 150 °C 2. BnBr, K2CO3 acetone reflux
51% overall
1. P(OMe)3 reflux 2. NaH, THF 81%, 2 steps
Advanced Medium Ring Formation
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
N P(OMe)2
O
MeI, K2CO3
acetone, reflux
LAH
Et2O, 0 °C
90%
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
NH
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
NMe
H2, Pd/CAcOH
MeO
Me
OH
OH
OHOMe
OMe
NH2
NMe
HN
MeO
Me
O
O
NMe
OHOMe
OMe
HN
MeO
Me
O
O
NMe
OHOMe
OMe O2
MeOH
32%, 3 steps
+
Reactivity of the Advanced Medium Ring
py, 0 °C
HN
MeO
Me
O
O
NMe
OCO2PhOMe
OMe
HN
MeO
Me
O
O
NMe
OCO2PhOMe
OMe
+
HN
MeO
Me
O
O
NMe
OHOMe
OMe
HN
MeO
Me
O
O
NMe
OHOMe
OMe
+
HN
MeO
Me
O
O
NMe
OPhOMe
OMe
CH2Cl2
MeO
Me
O
O
N NMe
OH
aq. HCl
MeOH
Cl OPh
O
Reactivity of the Advanced Medium Ring
py, 0 °C
HN
MeO
Me
O
O
NMe
OCO2PhOMe
OMe
HN
MeO
Me
O
O
NMe
OCO2PhOMe
OMe
+
HN
MeO
Me
O
O
NMe
OHOMe
OMe
HN
MeO
Me
O
O
NMe
OHOMe
OMe
+
HN
MeO
Me
O
O
NMe
OPhOMe
OMe
CH2Cl2
MeO
Me
O
O
N NMe
OH
aq. HCl
MeOH
Cl OPh
O
Failed Conditions from the Model System
COCl2, PhNMe2
CH2Cl2/PhCH3
HBF4
CH2Cl2
90%
NH3CH2Cl2PhCH3
0 °C
85%
HN
MeO
Me
O
O
NMe
OHSMe
OMe NH3
MeOH
HN
MeO
Me
O
O
NMe
OHOMe
OMe
BF3.OEt2
MeSH, -45 °Cx
N NMe
O
O
Me
MeO OMe
OH
N NMe
O
O
Me
MeO OMe
OCOCl
N NMe
O
O
Me
MeO OMe
OCONH2
N NMe
O
O
Me
H2N OMe
OCONH2
Porfiromycin
Completion of Porfiromycin
COCl2, PhNMe2
CH2Cl2/PhCH3
HBF4
CH2Cl2
90%
NH3CH2Cl2PhCH3
0 °C
85%
HN
MeO
Me
O
O
NMe
OHSMe
OMe NH3
MeOH
HN
MeO
Me
O
O
NMe
OHOMe
OMe
BF3.OEt2
MeSH, -45 °Cx
N NMe
O
O
Me
MeO OMe
OH
N NMe
O
O
Me
MeO OMe
OCOCl
N NMe
O
O
Me
MeO OMe
OCONH2
N NMe
O
O
Me
H2N OMe
OCONH2
Porfiromycin
Completion of Mitomycin A
1. H2, Pd/C AcOH 2. O2, MeOH
42%
1. acrolein CH2Cl22. BH3 THF/CH2Cl2 -78 °C to rt 3. Ac2O, py 78%
1. COCl2, PhNMe2 CH2Cl2
2. NH3 CH2Cl2, 0 °C
85%
HN
MeO
Me
O
O
NP
OHOMe
OMe
N NP
O
O
Me
MeO OMe
OH
N NH
O
O
Me
MeO OMe
OCONH2
Mitomycin A
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
NH
MeO
Me
BnO
BnO
OBnOMe
OMe
NBn2
NP
N NP
O
O
Me
MeO OMe
OCONH2
P = (CH2)3OAc
HBF4CH2Cl2
77%
1. NaOMe MeOH/CH2Cl22. DMSO, DCC TFA/py 3. HClO4, PhNMe2 CH2Cl2 35%
Nakatsubo, F.; Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 8116.Fukuyama, T.; Nakatsubo, F.; Cocuzza, A. J.; Kishi, Y Tetrahedron Lett. 1977, 49, 4295.Kishi, Y. J. Nat. Prod. 1979, 42, 549.
The Fukuyama Lab Approach
N NH
O
O
Me
H2N OMe
OCONH2
Mitomycin C
MeO
Me
O
O
N
NHH OMe
OCONH2
Isomitomycin A
N
O
O
Me
MeO OMe
OCONH2
N
H
MeO
Me
BnO
MeO
Ph
OTMS
N
OO
H SEtMeO
Me
BnO
MeO
Ph
OTMS
N3
OO
H SEtMeO
Me
MeO
Albomitomycin A
Intramolecular [3 +2] Cycloaddition
SnCl4CH2Cl2, -78 °C;
then py
95%, >20:1 dr
toluene110 °C
MeO
Me
BnO
MeO
Ph
O
N3
OEtS
OTMS
MeO
Me
BnO
MeO
Ph
OTMS
N3
OO
H SEt
MeO
Me
BnO
MeO
Ph
OTMS
N
OO
H SEt
NN
MeO
Me
BnO
MeO
Ph
OTMS
N
OO
H SEt
MeO
Me
MeO
13 steps
64% overall
H
86%
a triazoline
extrusionof N2
stereoselectivitylikely due to an endo Diels-Alder
Hydroxymethylene Installation
1. DIBALTHF, -78 °C
2. Ac2O, py
99%, 2 steps
MeO
Me
BnO
MeO
Ph
OTMS
N
OO
H SEtMeO
Me
BnO
MeO
Ph
OTMS
N
OOAc
H SEt
RuO2, NaIO41:1 EtOAc/H2O
84%
MeO
Me
BnO
MeO
N
OOAc
H SO2Et
H O
1. NaBH4, MeOH 97% 2.
CH2Cl2
MeO
Me
BnO
MeO
N
OOAc
H SO2Et
O NH
O
CCl3
O
N CCl3
O.O
Ozonolysis gavea complex mixture
Unveiling the Pyrrolidine
NH3
MeOH, rtMeO
Me
BnO
MeO
N
OO
H SO2Et
O NH
O
CCl3
O
MeO
Me
BnO
MeO
N
H
O NH2
O
OO
O
H
MeO
Me
BnO
MeO
N
NHOMe
H OH
O NH2
O
MeO
Me
BnO
MeO
N
NHH OH
O NH2
O
NaBH4
61% overall
NH3, -H2O
:NH3
the bridgeheadhemiaminal resistedreduction by NaBH4
Completion of Isomitomycin A
CSA
MeOH, rt
MeO
Me
BnO
MeO
N
NHH OH
OCONH2
1. H2 (1 atm) 10% Pd/C EtOH 2. DDQ, H2O acetone -78 °C
77%, 2 steps
MeO
Me
BnO
MeO
N
HN
H
OCONH2
MeO
Me
BnO
MeO
N
NHH OMe
OCONH2
MeO
Me
O
O
N
NHH OMe
OCONH2
60%
Isomitomycin A
Completion of Mitomycin C
NH3
MeOH, rt
85%
MeO
Me
O
O
N
NHH OMe
OCONH2
N NH
O
O
Me
H2N OMe
OCONH2
N
O
O
Me
H2N OMe
OCONH2
N
H
H2N
Me
O
O
N
NHH OMe
OCONH2
Al(OiPr)3
MeOH, rt
91%
Mitomycin C
Michael addition
β-elimination
Fukuyama, T.; Yang, L. J . Am. Chem. Soc. 1987, 109, 7881.Fukuyama, T.; Yang, L. J . Am. Chem. Soc. 1989, 111, 8303.
Completion of Mitomycin A
NH3
MeOH, rt
85%
MeO
Me
O
O
N
NHH OMe
OCONH2
N NH
O
O
Me
MeO OMe
OCONH2
N
O
O
Me
H2N OMe
OCONH2
N
H
H2N
Me
O
O
N
NHH OMe
OCONH2
Al(OiPr)3
MeOH, rt
91%
Mitomycin A
Michael addition
β-elimination
Fukuyama, T.; Yang, L. J . Am. Chem. Soc. 1987, 109, 7881.Fukuyama, T.; Yang, L. J . Am. Chem. Soc. 1989, 111, 8303.
Danishefsky’s Approach to FR-900482
NO
OH
H
O
OCONH2
OH
NH
FR-900482
NO
MeO
MeO
O
OMe
MeO
N
O
MeO
NRN
O
MeO
MeO
O
NR
OMeI
NO
MeO
MeO
O
OH
OMeI
O
IHO
OMe
intermolecularhetero
Diels-Alder
+
internalHeck arylation
An Intramolecular Approach to FR-900482
MeO
N
O
O
OMe
NO
OH
H
O
OCONH2
OH
NH
FR-900482
MeO O OMe
N
O
NO
MeO
MeO
O
OMeO
O
MeO
O
MeO
bridged mode
fused mode
MeO O OMe
N
OO
MeO
MeO
NO2
HO OMe
O
MeO
x
hν, 366 nm
MeOH
Inspiration for a Mitomycin Synthesis
MeO
N
O
O
OMe
NO
OH
H
O
OCONH2
OH
NH
FR-900482
MeO O OMe
N
O
NO
MeO
MeO
O
OMeO
O
MeO
O
MeO
bridged mode
fused mode
MeO O OMe
N
OO
MeO
MeO
NO2
HO OMe
O
MeO
x
hν, 366 nm
MeOH
The Danishefsky Lab Approach
MeO
Me
O
O
N
OMe
NMe
Mitomycin K
MeO
Me
MeO
MeO
N
O
OMe
NMe
MeO
Me
MeO
MeO
N
O
OMe
O
MeO
Me
MeO
MeO
N
O
O
OMeMeO
Me
MeO
MeONO2
HO OMeMeO
Me
MeO
intramolecularhetero
Diels-Alder
Hetero Diels-Alder
THF, -78 °C
80%
hν, 350 nmMeOH
MeO
Me
MeO
MeO
O
NO2
MeO
Me
MeO
MeO
MeO
Me
MeO
steps H
Li
OMe
NO2
HO OMe
MeO
Me
MeO
MeO
N
O
OMe
HO
+
45%
hν
MeO
Me
MeO
MeO
N
O
OOMe
15%
A Sequential Photolytic Redox Mechanism
hν, 350 nm
MeOH
MeO
Me
MeO
MeO
NO
H
O
HO OMe
MeO
Me
MeO
MeO
O OMe
N
O
MeO
Me
MeO
MeO
N
O
OOMe
MeO
Me
MeO
MeO
N
OOMe
HO
MeO
Me
MeO
MeONO2
HO OMe
1,5 H abstr.
-H2O
MeO
Me
MeO
MeO
N
O
OOMe
H
[4 + 2]
hν1,5 H abstr.
Aziridine Fragmentation
BnN3
PhH, 80 °C
85%
1. hν, 254 nm 76%2. L-Selectride THF, -78 °C 81%
PDC
CH2Cl2
65%
MeO
Me
MeO
MeO
N
OOMe
HO
MeO
Me
MeO
MeO
N
OOMe
O
MeO
Me
MeO
MeO
N
OOMe
O
NN
N
Bn
MeO
Me
MeO
MeO
N
OOMe
HO
Im
S
Im
DMAP
CH2Cl2
66%
NBn
MeO
Me
MeO
MeO
N
O
OMe
S
NBn
S
Im
MeO
Me
MeO
MeO
N
O
OMeNHBn
AIBNBu3SnH
PhH, 80 °C
Synthesis of a Deoxygenation Precursor
PhH, 80 °C
90%
L-SelectrideTHF, -78 °C
77%
PDC
CH2Cl2
65%
MeO
Me
MeO
MeO
N
O
OMe
HO
MeO
Me
MeO
MeO
N
O
OMe
O
MeO
Me
MeO
MeO
N
O
OMe
O
N3PhS
NN
N
SPh
MeO
Me
MeO
MeO
N
O
OMe
HO
NN
N
SPhMeO
Me
MeO
MeO
N
O
OMe
O
NN
N
SPh
Im
S
Im
S
Im
DMAP
CH2Cl2, 35 °C
65%
A Successful Deoxygenation
hν, 254 nmPhH
48%
AIBNBu3SnH
PhH, 80 °C
52%
MeO
Me
MeO
MeO
N
OOMe
NN
N
SPh
MeO
Me
MeO
MeO
N
OOMe
O
NN
N
SPh
Im
S
Raney Ni
acetone, 60 °C
70%
MeO
Me
MeO
MeO
N
OOMe
NH2+
13%
MeO
Me
MeO
MeO
N
OOMe
NSPh
MeO
Me
MeO
MeO
N
OOMe
NMe
extrusion of N2
Completion of Mitomycin K
NaOAcMeCN/H2O
8-16%
THF, -10 °C
90%
MeO
Me
MeO
MeO
N
O
OMe
NMe
MeO
Me
MeO
MeO
N
OMe
NMe
LiTMS OH
TMS
MeO
Me
O
O
N
OMe
NMe
OH
TMS
MeO
Me
O
O
N
OMe
NMe
PPTS
CH2Cl2
81%
N
Ag OOOO
Mitomycin K
Benbow, J. W.; Schulte, G. K.; Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1992, 31, 915.Benbow, J. W.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 12305.Danishefsky, S. J.; Scheryantz, J. M. Synlett. 1995, 475.
