04/30/05Ruth Nunes @ Wipf Group 1

Total Synthesis of Antascomincin BDominic E. A. Brittain, Dr., Charlotte M. Griffiths-Jones, Dr.,

Michael R. Linder, Dr., Martin D. Smith, Dr., Catherine McCusker,Dr., Jaqueline S. Barlow, Dr., Ryo Akiyama, Dr., Kosuke Yasuda,

Dr., Steven V. Ley, Professor Dr. *Angewandte Chemie International Edition

Volume 44, Issue 18, Pages 2732-2737Published Online: 1 Apr 2005

HO

HO

HO

O

N

O

OO

O

HO

O

26

30

61

11

16

1

N

Fmoc

61CO2H

fragment IO

O

MOMO

O

26

30

MeO

MeO

fragment II

TBSO OPMB

OTBS OTBS10 24

fragment III

Ruth Nunes @ Wipf Group 1 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 2

Antascomincin A - E and the FKBP12

• Isolated from a strain of Micromonospora (China), 1996;J. Antibiot. 1996, 49, 230.

• Immunophilin FKBP12, main target of rapamycin andFK506, used as binding to evaluate more than 12000 strainsof Actinomycetes;

• FKBP’s known as peptydil prolyl cis-trans isomerases;• Ligand-FKBP12 complex determines the

immunosuppressant effect;Science, 1990, 250, 556.JACS, 1991, 113, 8045.

• The new family presented same degree of bindingto the FKBP12 as rapamycin and FK506, but noimmunosuppressive property;

• Antascomincins antagonize bothimmunosuppressants;

• FKBP12 found in high quantities in the brain;Nature,1992, 358, 584.

R2O

HO

R1

On(H2C)

N

O

OO

O

HO

O

R3

Ruth Nunes @ Wipf Group 2 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 3

Immunosuppressive mechanismrapamycin, FK506, ascomycin andmeridamycin.

Calcineriunand RAFT

FKBP

12

Drug Calcineriun

and RAFTFKBP

12

FKBP

12

Drug

Drug

The Immunosuppressive Drug Action:

The Non-Immunosuppressive Ligand:

FKBP

12

FKBP ligands

FKBP

12 FKBP ligands

• Ligand-FKBP neurotropic non-immunosuppressant complexes: clinical use.• Independent mechanisms.• Attention returned to the strong FKBP’s ligands with no immunosuppression activity.

Ruth Nunes @ Wipf Group 3 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 4

First Synthesis of an Antascomincin Member

HO

HO

HO

O

N

O

OO

O

HO

O

26

30

61

11

16

1

N

Fmoc

61CO2H

fragment IO

O

MOMO

O

26

30

MeO

MeO

fragment II

TBSO OPMB

OTBS OTBS10 24

fragment III

Ruth Nunes @ Wipf Group 4 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 5

Fragment II

O

O

MOMO

O

26

30

MeO

MeO

fragment II

O

O

MOMO

BnO

MeO

MeO

OBn2

O

O

O

MeO

MeOOTBS

H3

BnO

BnO

SnBu3

4

HO

H

HO

H

CO2MeCO2Me

5

OO

OMe

CO2MeCO2Me

OMe

6

MeCOCOMe, CSA

CH(OMe)3, MeOH,68%

OO

OMe

OMe

7

OH

OTBSa. LAH, THF, 99%

b. NaH, TBSCl, 87%

OO

OMe

OMe

O

OTBS(COCl)2, DMSO,

DCM, TEA3

J. Chem. Soc. Perkin Trans. 1, 1999, 1627, 1631Chem Rev. 2001, 101, 53.

Ruth Nunes @ Wipf Group 5 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 6

O

O

MOMO

O

26

30

MeO

MeO

fragment II

OBn

OBnBu3Sn

4

HOBn

O

8

1) a. (E)-butene, KOtBu,

n-BuLi, THF -78°C; b. (+)-(Ipc)2BOMe, Et2O, BF3.OEt, -78°C;2) BnBr, NaH, DMF, 62%

OBn

OBn

9

a. O3, DCM, -78°C

then PPh3;b. NaBH4, MeOH, 90%

OBn

OBn

10

HO

OBn

OBn

11

I

I2, im., PPh3,

DCM, 90%

allylpyridylsulfide, tBuLi

THF, -78°C, 95%

OBn

OBn

12SPy

Bu3SnLi, CuBr, THF

-78°C, 98%

Ruth Nunes @ Wipf Group 6 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 7

O

O

O

MeO

MeOOTBS

H3

BnO

BnO

SnBu3

4

+

ZnI2, DCM, -78°C to rt, 85%O

O

HO

BnO

MeO

MeO

OBn

OTBS

13

O

O

MOMO

BnO

MeO

MeO

OBn

OH

a. MOMCl, DIPEA

DCM;b. TBAF, THF, 89%

O

O

MOMO

BnO

MeO

MeO

OBn

14

2

1) (COCl)2, DMSO, TEA, DCM;2) MePPh3Br, BuLi THF, -78°C to rt 87%

1) Grubbs 2nd gener.

toluene, reflux, 75%;

2) H2, Pd/C, EtOH, 96%

O

O

MOMO

HO

MeO

MeO

OH

syn/anti 6:1 at C29-C30

30 29

NaH, THF, 88% O

O

MOMO

O

26

30

MeO

MeO

fragment II

2-(2,4,6-triisopropylbenzenesulfonyl)imidazole

Ruth Nunes @ Wipf Group 7 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 8

Fragment III

TBSO OPMB

TBSO OTBS10 24

fragment III

TBSO

TBSO O10

16

OPMB

2417

16

17

asymmetric Aldol

8 steps

10 steps

hydrozirconation

1) [Zr(Cp)2(H)(Cl)] DCM, -78°C to 0°C2) 16, AgClO4, DCM 96%

TBSO OPMB

TBSO OH

28

1) separation;

2) TBSCl, im., 93%

separated diastereomersof fragment III

Ruth Nunes @ Wipf Group 8 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 9

Fragment III + Fragment II

TBSO OPMB

TBSO OTBS

fragment III

1) DDQ, DCM, H2O;

2) PhSSPh, PBu3, py, 95%3) PhSeSePh, H2O2, Et2O 88%

TBSO SO2Ph

TBSO OTBS

O

O

MOMO

O

MeO

MeO

1) BuLi, HMPA, THF, -78°C, then fragment II at -20°C, 70%2) lithium 4,4-di-t-butylbiphenol 78%

fragment II

O

O

MOMO

HO

MeO

MeO

24

25

OTBSTBSO

TBSO

24

25

29

30

Ruth Nunes @ Wipf Group 9 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 10

24

25

30

O

MOMO

O

MeO

MeO

OH

OTBSTBSO

TBSO

31

O

MOMO

O

MeO

MeO

O

OTBSTBSO

HO

N

FmocO

32

O

MOMO

O

MeO

MeO

O

OTBSTBSO

HO

N

HO

O

33

O

MOMO

O

MeO

MeO

O

OTBSTBSO

HO

NO

O

O

OH

O

34

O

MOMO

O

MeO

MeO

O

OTBS

NO

O

OO

OTBSO

1) EDCI, frg I, 95%

2) CSA, MeOH, 62%

1) a. TPAP, NMO

b. NaClO2, NaH2PO4 2-methlbut-2-ene, 75%2) piperidine, DMF;

benzo[1,4]dioxin-2-one DMAP, 87%

EDCI, DCM, 71%

Ruth Nunes @ Wipf Group 10 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 11

34

O

MOMO

O

MeO

MeO

O

OTBS

NO

O

OO

OTBSO

LHMDS, THF, 68%

35

O

MOMO

O

MeO

MeO

O

OTBS

NO

O

OO

OTBS

36

O

MOMO

O

MeO

MeO

O

OTBS

NO

O

OO

OTBS

OH

HO

HO

HO

O

O

NO

O

OO

HO

Antascomicin B

Dess-Martin, H2O, DCMpy, 80%

1) HF.py, py, THF, 4 days;

2) Dess-Martin, DCM, py;3) TFA, H2O, 10 min 13%

Ruth Nunes @ Wipf Group 11 5/2/2005

04/30/05Ruth Nunes @ Wipf Group 12

Conclusion• First total synthesis of antascomicin family member;• Butanediacetal as protecting stereodirecting group;• Transannular Dieckmann condensation - oxidation;• Related approach used by Ohtsuka in 1983, in 1999 for a taxane skeleton;• Vicinal tricarbonyls;• 52 total steps from commercially available materials;• Longest linear sequence of 23 steps;

Ruth Nunes @ Wipf Group 12 5/2/2005