Total Synthesis of Calicheamicin Type Enediyne Natural Products

17/09/02 Yuki Fujimoto

1 Contents

2 Enediyne Natural Products

SSS Me O OMe NHCO 2Me MeO O O H OH HO O N O O O OMe S O OH HO I OH O OMe O NHEt

I calicheamicin 1 (calicheamicin type) OMe O O O O CO 2H OH O HN O O OMe OH O O MeH N HO OH O OH O OH dynemicin A (dynemicin type) neocarzinostatin chromophore (chromoprotein type) 3 Bergman Cyclization

Jones, R. R.; Bergman, R. G . J. Am. Chem. Soc. 1972 , 94 , 660. 4 Distance of Diyne

a) Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988 , 110 , 4866. 5 b) Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. Engl. 1991 , 30 , 1387. Calicheamicin Type Action Mechanism

Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. Engl. 1991 , 30 , 1387 6 Contents

7 Introduction of Calicheamicin

SSS Me O OMe NHCO 2Me MeO O O H OH HO O N O O O OMe S O OH HO I OH O OMe NHEt I O calicheamicin 1 SSS Me Isolation O 1) NHCO 2Me bacterial strain Micromonospora echinospora ssp calichensis I Total synthesis of calicheamicin 1 HO OH Nicolaou, K. C. (1992, enantiomeric) 2) Danishefsky (1994, enantiomeric) 3)

Total synthesis of calicheamicinone Danishefsky, S. J. (1990, racemic) 4) Nicolaou, K. C. (1993, enantiomeric) 5) calicheamicinone Clive, D. L. J. (1996, racemic) 6) (calicheamicin aglycon) Magnus, P. (1998, racemic) 7)

1) Borders, D. B . et al J. Am. Chem. Soc. 1987 , 109 , 3464. 2) Nicolaou, K. C . et al J. Am. Chem. Soc . 1992 , 114 , 10082. 3) Danishefsky, S. J .; et al Angew. Chem. Int. Ed. Engl . 1994 , 33 , 858. 4) Danishefsky, S. J. et al J. Am. Chem. Soc. 1990 , 112 , 3253. 5) Nicolaou, K. C . et al J. Am. Chem. Soc . 1993 , 115 , 7612. 6) Clive, D. L. J. et al J. Am. Chem. Soc . 1996 , 118 , 4904. 8 7) Magnus, P. et al J. Am. Chem. Soc. 1998 , 120 , 3518. Strategy of Calicheamicin Synthesis

9 Danishefsky’s Approach

10 Danishefsky’s Approach 2

1) Harpp. D. N.; Ash, D. K. Int. J. Sulfur Chem., Part A 1971 , 1, 57. 11 Clive’s Approach

12 Clive’s Approach 2

13 Summary of Calicheamicinone Synthesis

14 Contents

15 Introduction of Shishijimicin OH

SSS Me O NHCO Me 2 N N H O HO OO O HO R1 OMe O NHR 2 shishijimicin A (R 1 = SMe, R2 = i- Pr) shishijimicin B (R1 = H, R2 = i-Pr) shishijimicin C (R 1 = SMe, R2 = Et) Isolation Total synthesis of shishijimicin A 2) lipophilic extract of the thin encrusting orange 1) Nicolaou K. C. (2015, enantiomeric) ascidian Didemnum proliferum (2003)

Biological activity antitumor (IC50 = 0.47 nM against P388 leukemia cells)

Structural features calicheamicinone aminosugar and thiosugar -carbolinyl

1) Oku, N.; Matsunaga, S.; Fusetani, N. J. Am. Chem. Soc . 2003 , 125 , 2044. 16 2) Nicolaou, K. C.; Lu, Z.; Li, R.; Woods, J. R.; Sohn, T. J. Am. Chem. Soc . 2015 , 137 , 8716 Retrosynthesis

17 1st Route toward Calicheamicin 1

18 1st Route toward Calicheamicin 2

19 1st Route toward Calicheamicin 3

O O O O O CO 2Me O CO 2Me NPhth NPhth NPhth MsCl, pyridine KN(TMS) 2 OH DMAP OMs TESO O TESO TESO toluene, -90 °C CH 2Cl 2 OMe 48 % enediyne addition O pyridine SiO 2 benzene 90 % (2 steps) OBz O O O NHCO 2Me O NPhth 3 steps I 5 steps calicheamicin 1 TESO OH TESO O O

20 Isoxazoline Synthesis

21 Introduction of Enediyne Unit

O O O O O O TMSCl N N N TIPS NaI O O O AcO MeCN AcO O LiN(TMS) 2 H LaCl 3 2LiCl H H OMEM THF, -78 °C; OMEM OH Ac 2O 90 % TIPS TIPS O O RLi H O (COCl) , DMSO MEMO 2 CH 2Cl 2, -78 °C; Et N N 3 O 85 % (2 steps) 1. K2CO 3 MeOH/THF 2. TBAF, THF O O O O (MeO) 2OP CO 2Me O O 0 °C N N N

O 3. TESOTf O LiN(TMS) 2 O TESO 2,6-lutidine AcO THF AcO CH 2Cl 2 -78 °C to rt 94 % (3 steps) 96 % O CO 2Me CO 2Me

TIPS TIPS

22 Synthesis of Shishijimicin Core

O O O O O CO 2Me O NPhth NR2 N LaCl 3 2LiCl O LiN(TMS) O Fe, NH 4Cl TESO 2 TESO TESO THF, -78 °C EtOH/H 2O O 60 °C, 83 % 85 % O CO 2Me reductive N-O bond cleavage PhthCl 1. MeNHNH 2 R2 = H,H pyridine benzene R2 = Phth MeNO 2 2. triphosgene 0 °C, 81 % pyridine CH 2Cl 2, 0 °C; MeOH 81 % (2 steps) SAc 1. PPh 3, DEAD OH 1. NaBH O Ac SH O 4 O O NHCO 2Me THF, 0 °C O NHCO 2Me CeCl 3 7H2O O NHCO 2Me 96 % (2 steps) MeOH, 92 %

TESO OH 2. HF Py/THF TESO OTMS 2. TMSCN; TESO AcOH 0 °C, 99 % O THF/H 2O, 0 °C O

23 Inversion of Stereoselectivity

24 Total Synthesis of Shishijimicin OTBS SAc SAc O O NHCO 2Me O O NHCO 2Me N N TESO OH O H TESO OO OTBS BF 3 OEt 2 O CH Cl , MS A HO 2 2 4 SMe -78 to -40 °C OMe 26 % (based on sugar) NAlloc i-Pr NH O N N KOH, MeOH, -5 °C; H AcOH; O Cl 3C O O O 1) HO O SMe N SS Me OMe O NAlloc i-Pr 0 °C O OH 50 % OTBS SSS Me SSS Me O NHCO Me O NHCO Me 2 N O 2 N N 1. HF Py /THF, 80 % N O H O H HO OO TES O OO HO O 2. Pd(PPh 3)4 (50 mol%) HO O SMe morpholine SMe THF, 0 °C, 91 % OMe OMe O NHi-Pr 3. p-TsOH O NAlloc i-Pr THF/acetone/H 2O shishijimicin A 73 %

1) Harpp. D. N.; Ash, D. K. Int. J. Sulfur Chem., Part A 1971 , 1, 57. 25 Summary

TMS Cl OBz O O NHCO 2Me TMS epimerization was needed calicheamicin TESO OH

O O O O N NPhth 21 steps 1.7 % yield O TESO O O H OMEM OMe SAc O O O NHCO 2Me

shishijimicin TESO OH stereoselective addition

TIPS 19 steps 21 % yield

26 appendix

27 DNA Cleavage Main Mechanism

Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. Engl. 1991 , 30 , 1387 28