mitomycin family of antitumor antibiotics · 4 rings 4 stereogenic centers 1 aziridine 1 quinone 1...
TRANSCRIPT
N NR2
OMe
O
O
R1
Me
OCONH2
Mitomycin C
R1 R2NH2 H
Mitomycin A OMe H
Mitomycin F OMe Me
Porifomycin NH2 Me
N NR2
OH
O
O
R1
Me
OCONH2
Mitomycin B
R1OMe
Mitomycin E NH2
Mitomycin M MeNH H
Mitomycin I
R2H
Me
Me
Me
H
NH
CONH2Mitomycin J Me
Mitomycin L MeNH
Mitomycin D NH2 H
N NMe
OR2
O
O
R1
Me
Mitomycin G
R1
NH2Mitomycin H OMe
R2
MeH
Mitomycin K OMe Me
O
O
MeO
Me N
NOMe H
OCONH2
Isomitomycin A
N
O
O
MeO
Me
OCONH2OMe
H
N
Albomitomycin A
Mitomycin Family of Antitumor Antibiotics
Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches. Bass, P.; Gubler, D.A.; Judd, T.C.; Williams, R.M. Chem. Rev. 2013, 113, 6816-6863
N NH
OMe
O
O
H2N
Me
OCONH2
4 rings4 stereogenic centers1 aziridine1 quinone1 hemi-amino ketal2 basic N's1 urethane
14 points = 28 steps
Funk Analysis
OH
N OOHC
OCONH2
NH
OH
N NH
OCONH2O
O
OMeH2N
MeH H
HH
Mitomycin C
OH
N O
OCONH2
NH
OH
H
H
OAc
N OOHC
OCONH2
NAc
OAc
H
H
FK973 (Phase I: dropeed due to VLS)
OMe
N OOHC
OCONH2
NAc
OAc
H
H
FK973 (Phase II: noVLS)
OMe
N OOHC
OCONH2
NR
OH
H
H
FR70496 R = AcFR157471 R = H
(active metabolites of FK317)
OHFR900482 FR66979
FR Family of Antitumor Antibiotics
OH
N OOHC
OCONH2
NH
OH
H
H
FR900482
4 rings4 stereogenic centers1 aziridine1 hydroxylamine hemi-ketal1 urethane1 basic N
12 points = 24 steps
Funk Analysis
FR-900482 & FR-66979: MASKED MITOSENES
Fukuyama, T.; Goto, S., Tetrahedron Lett., 1989, 30, 6491Williams, R.M.; Rajski, S.; Rollins, S.B., Chem. & Biol., 1997, 4, 127
Mitomycin C: Non-specific Host Toxicity is (Likely) a Manifestation of Redox Cycling
FR-900482 Family: No Redox Cycling (2 e- versus 1 e- activation)No Oxidative Damage to DNA
Review: Tomasz, M., Chem. Biol., 1995, 2, 575
O
HO
HO
HO OUDP
CH2OH
O
HO
O
HO OUDP
CH2OH
O
HO
H2N
HO OUDP
CH2OH
O
HO
H2N
HO OH
CH2OH
O
HO
H2N
HO OH
CH2OPi
O
HO
H2NHO OH
CH2OPiHO
NH
HOOPi
OPi CO2H
OHOH
OPi
HO2C
O NH2 OHO
HO2CHO
NH2
MitP
NAD+MmcF
mitGNAD(P)+
mitA
Gln
mitS
mitJ
isomerase
RifHhomolog
transketolase
UDP-glucose kanosamine
K6P
amino-DAHP amino-DHQ
R5P S7P
OHO
NH2HO2C
OH
NH2HO2CMitA
amino-DHS AHBA
Biosynthesis: AHBA
OH
NH
HOOH
CH2OH
OHNHAc
ACP
O
OH
NH
POOH
OHNHAc
ACP
O
OH
OH
NH
OOH
OHNHAc
ACP
O
OH
N
OHOH
NHACP
O HO
OH
NOHC
OCONH2OH
NHO
OH
NH
OHOH
NHACP
O
O
NH
OHOH
NHACP
O O
N NH
OMe
O
O
H2N
Me
OCONH2
OH
NH2HO2C
O
HO
HO
AcHN OUDP
CH2OH
MitB
OH
NH
OOH
CH2OH
OHNHAc
OH
NH2ACP
O
ACP
O
reductase
NAD(P)H
kinaseATP
a, MitC
FR900482 Mitomycin C
[O]
MitE
OH
NH2AMP
O
(MitF)
MitC
AHBA
100
101
OH
NH
OHOH
OH
NHAcACP
O
OH
HN
OHOH
OH
NHAcACP
O
OH
NH
OHNHAc
ACP
O
c d
HOO
c
Paynerearrangementd
N NH
OH
O
O
H2N
Me
OCONH2
Mitomycin D
MitC
b
ba
“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.”
Sam Danishefsky
S. J. Danishefsky, J. M. Schkeryantz, Synlett 1995, 475.
MeO
MeOMe
13 stepsMeO
MeOBn
OBnOAc
10 stepsO
CN
BnO
BnOMe
MeO
OBn
OAc
MeO OMeOH
OH
13 steps
BnO
BnOMe
MeO
OBn
N
OMeOMe
N(CH2)3OAc
Bn Bn
O
O
MeO
Me NH
OH
N(CH2)3OAc
OMeOMe
O
O
MeO
Me N
OH
N(CH2)3OAc
OMe 5 steps
O
O
R
Me N
OCONH2
NH
OMe
Mitomycin A, R = OMe
Mitomycin C, R = NH2
NH3MeOH75%
HBF4CH2Cl2
77%42% (2 steps)2. O2, MeOH1. Pd/C, H2
Kishi: First Synthesis of MMC
Y. Kishi, J. Nat. Prod. 1979, 42, 549. F. Nakatsubo, A. J. Cocuzza, D. E. Keeley, Y. Kishi, J. Am. Chem. Soc. 1977, 99, 4835.F. Nakatsubo, T. Fukuyama, A. J. Cocuzza, Y. Kishi, J. Am. Chem. Soc. 1977, 99, 8115.T. Fukuyama, F. Nakatsubo, A. J. Cocuzza, Y. Kishi, Tetrahedron Lett. 1977, 4295.
O
O
MeO
Me N
OH
NMe
OH
O
O
MeO
Me N
OCONH2
NMe
OH
Mitomycin B
1.H2, Pd/C, pyr.O
O
MeO
Me NH
OH
NMe
OMeOMe
OH
OH
MeO
Me N
OH
NMe
OMeOMe
Cbz
1. H2, Pd/C
5% (overall)
1. Cl3CCONCO2. K2CO3, MeOH
55% (two steps)
2. BnOCOCl, pyr.3. 3N HCl, CH2Cl2
2. O2, MeOH
Kishi: MMB
HBF4CH2Cl2
77%
O
O
MeO
Me N
OH
NMe
OMe 3 steps
60%
O
O
H2N
Me N
OCONH2
NMe
OMe
Porfiromycin
1. K2CO3, MeI2. Pd/C, H23. O2, MeOH
32% (Three steps)
O
O
MeO
Me NH
OH
NMe
OMeOMe
O
O
MeO
Me
OH
NH
OMeOMe
NBn Bn
Kishi: Porfiromycin
O
O
MeO
Me N
OCONH2
NH
OH
Mitomycin AO
O
MeO
Me N
OCONH2OMe
Albomitomycin
H
N
O
O
MeO
Me N
N
OCONH2OMe
H
Isomitomycin A
O
O
MeO
Me N
N
OCONH2OMe
H
Isomitomycin A
MeOMe
MeO13
stepsMe
OMe
MeOOBn
Ph
O
+O
SEt
OTMS
SnCl4, pyr.
95%
MeOMe
MeOOBn
Ph
O
OTMS
O
SEt toluenereflux
86%
OBn
OMe
MeO
Me N
O
OCONH2SEt
O9
steps
O
O
H2N
Me N
OCONH2
NH
OMe
Mitomycin C
NH3
N3
N3
T. Fukuyama, L. Yang, Tetrahedron Lett. 1986, 27, 6299. T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1987, 109, 7881.
Fukuyama: Isomitomycin C to MMC
MeO
Me
OMe
OMe
CHO
NO2
+ Li
OMeTHF
- 78 °C
MeO
Me
OMe
OMeNO2
OH OMe
h!350 nm
OMeMeO
MeOMe
NO
OOMe
45%
OMeMeO
MeOMe
N
OOMe
HO
5steps
OMeMeO
MeOMe
N
OOMe
SN
NN
SPh
S
Im
OMeMeO
MeOMe
N
OOMe1. Bu3SnH, AIBN, 63%
2. hv, 48%
3steps
NSPh
OMeO
MeO
N
OMe
NMe
OHSiMe3 O
MeO
MeO
N
OMe
NMe
PPTS
99%
MMK
Danishefsky: MMK
J. W. Benbow, G. K. Schulte, S. J. Danishefsky, Angew. Chem. Int. Ed. Engl. 1992, 31, 915.J. W. Benbow, K. F. McClure, S. J. Danishefsky, J. Am. Chem. Soc. 1993, 115, 12305.
OTBSMeO
Me N
OTBS
N3
OMs
OOMe
OMeO
Me N
O
OMe
NMe
Mitomycin K
1. (CO2Me)2 KOtBu 4 steps
1. DMDO AcOH2. Me2SO4 NaH
4 steps
NO2MeO
Me
Me
NO2
2. Zn, HCl
47%
NH2MeO
Me NH
CO2Me
OTBSMeO
Me NH
CHO
OTBS
S(CH3)21. NaH, then N32. MsCl
65% (two steps)
OTBSMeO
Me N
OTBS
N3
OMs
65%
Z. Wang, L. S. Jimenez, Tetrahedron Lett. 1996, 37, 6049. V. J. Colandrea, S. Rajaraman, L. S. Jimenez, Org. Lett. 2003, 5, 785.
Jimenez: MMK
OH
Me
CO2Et
NHBn
9 steps
BnOCO2Et
N3OPMB
+O OTMS
BnO
NH2OPMB
O
SPh
OH
DIBAL
1. SnCI4, -78 oC then HCI, 23 oC, 96%. 2. PhSH, Et3N, CH2Cl2, 3. Ac2O, Py, 23 oC 4. Et3SiH, BF3 Et2O, 23 oC 5. Zn, AcOH, 23 oC 45%
BnO
NH2OPMB
O
SPh
OHH
BnO
OPMBN
OH
SPh NaCNBH382%
(2 steps)
BnO
OPMBNH
OH
SPh
BnO
OPMBN
O
Ac
O
1. Ac2O, Py, 60 oC2. m-CPBA, 0 oC then PhH, sealed tube, 170 oC , 7 h3. NaOH, MeOH, 23 oC4. m-CPBA, 23 oC 5. Swern oxidation 65%
BnO
OPMBN
O
OAc
O
OTBS
BnO
OPMBN
O O
O
OMe
Me
1. HCHO, LiOH, 0 oC2. NaBH, EtOH, -78 to 23 oC3. TBSCI, im., DMAP, 23 oC4. DIBAL, PhH, -78 oC5. m-CPBA, 23 oC6. Ac2O, 23 oC7. Swern oxidation 35%.
1. NH2NH2, 23 oC2. n-Bu4NF, 23 oC3. Me2C(OMe)2, CSA, 23 oC 96%.
1. NaN3, 125 oC, 6 h2. MsCl, Et3N, 23 oC3. TFA, 23 oC, 10 min4. COCl2, Py, 23 oC5. CAN, 23 oC 65%
BnO
OHN
O
O
O O
N3
OMs
BnO
OMeN
O NH
O
O
MeO
O1. PCC, MgSO4, 23 oC2. CH(OMe)3, CSA, 23 oC3. Ph3P, i-Pr2NEt, 60 oC 54%
OH
OHC NO NH
OH
OCONH2
FR900482
1. H2 (1 atm), Pd-C 23 oC, 2h2. HClO4 (0.05 equiv), 23 oC, 2h3 NH3, 23 oC, 2h 91%
Fukuyama: FR900482
T. Fukuyama, L. Xu, S. Goto, J. Am. Chem. Soc. 1992, 114, 383. 43 steps
BnO
MeO2C
I
NO
HOOMOM
+PhH0 oC80%
BnO
MeO2C
I
NO
OMOMOHBnO
MeO2C
I
NO2
BnO
MeO2C
I
NO
OMOM
OAc
OH
OH
SmI2, -78 oC;
then Oxone0 oC (85%)
1. Ac2O, py
2. OsO4 Me3NO-H2O 65%
BnO
MeO2C
I
NO
OMOM
NCO2Me
(Ph3P)4PdEt3N90 oC93%
BnO
MeO2C NO
OMOM
NCO2Me
BnO
MeO2C
I
NO
OMOM
OAc
NCO2Me
1. Tf2O, py2. Bu4NN3
3. Tf2O, py4. Ph3P; NH4OH5. MeCO2Cl, py 53%
1. K2CO3, MeOH2. Swern [ox]
3. Ph3PCH3Br, NaHMDS,-20 oC 75%
BnO
MeO2C NO
OMOM
NCO2Me
O TIPSO
MeO2C NO
OMOM
NCO2Me
OTIPS
1. OsO4, NMO
2. DIAD, Ph3P THF, rt 77%
1. SmI2 Me2NOH -78 oC
2. H2, Pd-C, EtOH3. TIPSOTf, 0 oC (i-pr)2NEt 85%
1. DIBAL-H, -78 oC
2. N-((methoxycarbonyl) oxy)succinimide, py3. MnO2, CH2Cl2 74%
TIPSO
OHC NO
OMOM
NCO2Me
OTIPS OH
OHC NO
OH
NH
OCONH2
(±)-FR900482
1. TBAF, THF2. PhOCOCl (i-pr)2NEt
3. Ph3CBF4 di-t-butylpyr.4. NH3, CH2Cl2 i-PrOH5. K2CO3 MeOH/H2O 46%
Danishefsky: FR900482
34 steps
J. M. Schkeryantz, S. J. Danishefsky, J. Am. Chem. Soc. 1995, 117, 4722.
OTBS
OTf
O
N MeMe
TrocNaH
>99%
OBn
OBOM
OTBS
NAlloc
OTBS
O
NMeMe
Troc
OBn
OBOM
OTBS
NHAlloc
+
1. Zn, AcOH2. TsCI, Et3N
3. MsCI, Et3N 72%
1. NaH, im., THF,!2. (HF)n Py, Py3. DMP
4. LiHMDS; then NaBH4-H2O 43%
OBn
OBOM
OTBS
NAlloc
OTBS
OMs
NHTs
L-diethyl tartrate
15 steps
5-hydroxyisophthalate
15 steps
BnO
OBOMN
Alloc
OHOH
NTsK2CO3
89%MeOH
1. TBDPSCI2. DMP3. (HF)n py, py
4. DBU5. NaBH4. 38%
1. TBDPSCI22. Pd(PPh3)43. m-CPBA
4. Ac2O, NaHCO35. DMP6. (HF)n Py, Py 21%
BnO
OBOMN
Alloc
OHOH
NTs
BnO
OBOMN
OAc
OOH
NTs
OH
OHC NO
OH
NH
OCONH2
(+)-FR900482
OBn
OBOMN
OHOH
NTsO
1. CI3COCOCI, py2. NH3, THF3. Ac2O, Py, DMAP4. sodium naphth.
DME5. H2, 10% Pd-C6. Swern [ox]7. NH3, MeOH 25%
Terashima: (+)-FR900482
T. I. (a) Katoh, E.; Yoshino, T.; Terashima, S., Tetrahedron Lett. 1996, 37, 3471Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.; Terashima, S., Tetrahedron Lett. 1996, 37, 3478;Katoh, T.; Yoshino, T.; Nagata, Y.; Nakatani, S.; Terashima, S., Tetrahedron Lett. 1996, 37, 3479Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S., Tetrahedron 1997, 53, 10229Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.; Terashima, S., Tetrahedron 1997, 53, 10239Katoh, T.; Nagata, Y.; Yoshino, T.; Nakatani, S.; Terashima, S., Tetrahedron 1997, 53, 10253 Katoh, T.; Terashima, S., J. Synth. Org. Chem., Jpn. 1997, 55, 946.
57 steps
MeO
OHC
OH
NO2
9 steps
BnO
NO2OBn
OTIPS
OMPMBnO
OBnN
OMPMOH
Troc
Grubbs 1PhH, 65 oC
0.005 M78%
BnO
OBnN
OMPMOH
Troc
1. Raney Ni, H22. TrocCl, K2CO33. KH, Ally bromide
4. HF-py5. Swern [ox]; vinylMgBr 53%
OH
OHC NO
OH
NH
OCONH2
(±)-FR900482
BnO
(Fukuyama's intermediate)
OPMBN
OTBSOH
O
OAc
15 steps
(Fukuyama)
1. Zn, AcOH2. MCPBA3. Ac2O4. m-CPBA
5. CF3CO2H6. TBSCl, Im, DMAP7. H2, Pd-C8. pMBOH PPh3, DEAD 9%
Martin: Formal Total Synthesis (+/-)-FR900482
Martin, S.F., et al., J. Am. Chem. Soc. 2000, 122, 10781
38 steps
OTBS
OO
MeMe
+
R
BnOOTf
NO2R
BnO
NO2
OTBS
OO
MeMe
Pd(OAc)2
75%
R = CO2Me
pyrrolidine;
then AcOH
50%
R
BnO
NO2
OTBS
O
O MeMe
O
1. Zn(BH4)2, -30 oC2. TIPSOTf, 2,6-lutidine3. AcOH/H2O (5:1 v/v)
4. TBSCl, NEt3, DMAP 5. TsCl, DABCO6. NaH, DMF7. CSA, MeOH 44%
5 stepsL-Tartaric Acid
R
BnO
NO2
OTIPS
O
OH
1. DMP2. H2, Pt-C 89% R
BnO
NOH
O
OTIPS
R
BnO
NO
O
O
OMe
Me Me
HCHO
LiOH;then HCl
BnO
R NO
OH
O
OH
1. 2-methoxypropene TsOH H2O
2. TBAF 3. Swern oxidation 70%
OH
OHC NO
OH
NH
OCONH2
(+)-FR900482
BnO
NO
O
O MeMe
OMP
OMs
N3
BnO
NO
O
O MeMe
OMe
MeO NH
1. 2-methoxypropene, PPTS2. DIBAL3. 4-methoxyphenol, PPh3, DEAD4. LiN3, DMF/H2O, 120 oC 5. MsCl, NEt3 36% 5 steps
1. TFA2. (Cl3CO)2C=O3. CAN
4. PCC, MgSO45. CSA, CH(OMe)36. PPh3, iPr2NEt 53%
1. H2 , Pd/C
2. 1% HClO43. NH3 89 %
Fukuyama: (+)-FR900482
M. Suzuki, M. Kambe, H. Tokuyama, T. Fukuyama, Angew. Chem. Int. Ed. 2002, 41, 4686.
>34 steps
Ciufolini: (+/-)-FR900482
OBn
N3
CHO
OBn Ti(Oi-Pr)4
TMS
Li
87%
OBn
N3
TMSOH
OBnBnO
tol., !
99%NN N
OBnOH
TMS
h"68%
BnO
N
OBnOH
TMS
H
Bu4NOH
50%
OBn OBn OBn
OBn
BnO
HN
OHOBn
BnO
N
OOBn
OBn OBn OAc
O
OH
N
OH
OH
OH
O O
1. N2H2 H2O2. H2 Pd/C97%
1. 2-methoxypropene PPTS2. LiN3, 100 oC
3. Ac2O, K2CO34. MsCl, Et3N5. TFA6. COCl2, Et3N, 0 oC 9% overall
1. MCPBA, 0 oC2. Ac2O
3. m-CPBA, NaHCO34. TPAP, NMO 4Å MS 51 %
OH
N
OH
OCONH2
OH
O NH
AcO
N
O
O
OAc
O
O
OMs
N3(±)-FR66979
1. PPh3, iPr2NEt THF/H2O
2. NH3, MeOH31%
11 steps
5-nitrovanillin
OMeOH
NO2OHC
Ducray, R.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2002, 41, 4688.
31 steps
Judd, T.C.; Williams, R.M., Angew. Chem. Int. Ed. 2002, 41, 4683
NH
NCO2Me
ODEIPSMOMO
MeO2C
H
H
MOMOMe
MeO2C NO2
NCO2Me
OHC
OpMB
NaOMeMOMO
MeO2C NO2NCO2Me
OpMB
OH+
90%
1. DEIPSCl 2. DDQ3. Dess-Martin [ox] 65% overall
MOMO
MeO2C NO2NCO2Me
O
ODEIPS
H
1. H2, Pd-C2. MgSO4, 4A
CH2Cl23. NaCNBH3, TFA
75%
H
HH
H
H
H
HOHO
NO2Me
HO2C NO2
10 steps25% overall
4 steps28% overall
Williams: (+)-FR900482
NH
NCO2Me
ODEIPSMOMO
MeO2C
H
H
NNCO2Me
OMOMO
MeO2CpMb
OTBS
H
H
NNCO2Me
MOMO
MeO2CpMb
OH
H
NNCO2Me
OMOMO
MeO2CpMb
OH
H
H
NNCO2Me
OMOMO
MeO2CpMb
OH
H
H
1. p-OMeBnBr
DIPEA, CH2Cl22. TASF, DMF-H2O3. Dess-Martin ox.
70% (3 steps)
1. LDA, -45 oC
DMF2. H2CO/ THF
50% (1:1) + 45% sm
DBU, tol.
(70% + 30% sm)
TBSOTf, CH2Cl2
2,6-lut.96%
+
Total Synthesis of (+)-FR66979 and (+)-FR900482DMDO-mediated construction of the hydroxylamine hemi-ketal
Judd, T.C.; Williams, R.M., Angew. Chem. Int. Ed. 2002, 41, 4683
3433
N
OTBSMOMO
MeO2CNCO2Me
pMB
OH
H
O O
Me Me
CH2Cl2K2CO330~50%
N
OTBSMOMO
MeO2CNCO2Me
OH
H
OMe
OHO -ArCHON
O
MOMO
MeO2CNCO2Me
OH
OTBS
H
H
1. TBAF, THF (92%)2. Cl3CCONCO, CH2Cl2;
SiO2, MeOH (86%)3. TMSBr, CH2Cl2 -45 oC (60%)
NO
HO
MeO2CNCO2Me
OH
OCONH2
H
HLiBH4, MeOH
THF (78%) NO
HO
NH
OH
OCONH2
H
H
OHFR6697932 steps
Swern ox.
33% NO
HO
OHCNH
OH
OCONH2
H
H
FR90048233 steps from:
HOHO
NO2
HO2C NO2
Me
Aldrich
MOMOMe
NH2
CO2MeO
CO2Me
NHCbz
MOMO
MeNH
CO2Me
OHCO2Me
CbzHN
MOMO
MeN
CO2Me
MeO2CNPf
BsMOMO
NMeO2CNPf
Bs
O1. H2, Pd-C2. PfBr3. MeOH cat. HCl
KHMDS (72%)
Mg(ClO4)290%
4. Bs2O 62%
MOMO
N
NPf
Bs
O
EtO
OEt
MOMO
N
NPf
Bs
OH
EtO
OEt
OCONH2
MOMO
N
NPf
O
EtO
OEt
OCONH2
AcO
1. TBHP, Triton B 2. H2, Pd-C, py
1. LiAlH4, THF2. Swern
3. HC(OEt)3, p-TsOH4. (H2CO)n, Triton B 82%
3. Cl3CCONCO4. NaBH4 55%
1. 2e-
2. Davis’ ox.3. Ac2O
NaOAc4. DMP 48%
MOMO
N NPf
OH
EtO
OEt
OCONH2
O
AcO
NOHC NAc
OAcOCONH2
O
FK973
1. TFA, Et3SiH
2. Ac2O py 52%
97%
NH2NH2
Rapoport: Formal Total Synthesis of FR900482
Paleo, M. R.; Aurrecoechea, N.; Jung, K.-Y.; Rapoport, H. J. Org. Chem. 2002, 68, 130.
FR900482:A New Approach to "Pro-Mitosenes"
MOMO
MeO2C NNCO2Me
O
NVOC
OHMOMO
MeO2C NNCO2Me
O
NVOC
MOMO
MeO2C NH
NCO2Me
ODEIPS MOMO
MeO2C NNCO2Me
ODEIPS
NVOC
NVOCCl
DIPEA75%
1. TBAF THF
2. Dess-Martin60%
LDA, H2C=O
DMF, -45 oC1:1 Mix Diast.
58%
X-ray(desired isomer crystallizes)
H
H
H
H
H
H
H
H
The First Photo-triggered Pro-Mitosene
Judd, T.C.; Williams, R.M., Org. Lett. 2002, 4, 3711
Efficient Photo-triggeredCross-linking of DNA! (~103x FR)
Judd, T.C.; Williams, R.M., Org. Lett. 2002, 4, 3711
5' * 3'
TTTATTAACGTAATGCTTAATCGCAATGGGATT
AAATAATTGCATTACGAATTAGCGTTACCCTAA3' 5'
1 2 3 4 5 6