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