Total Synthesis of (+)-Discodermolide

CHEM635

Kelsey RobertsGroup B

February 19, 2013

Patterson, I*; Florence, G. J.; Gerlach, K.; Scott, J. P. Agnew. Chem. Int. Ed. 2000, 39, 377-380.

Ian Paterson

• Born in 1954 in Dundee, Scottland• B.S. in Chemistry from U of Saint Andrews, 1976• PhD from Cambridge under Ian Flemming, 1979• NATO post-doctoral fellow with Gilbert Stork at Columbia• Lectureship at University College London• 1983-present Cambridge University Professor of Organic

Chemistry and Fellow of Jesus College• 237 Publications to date.• Research focuses on synthetic methods, synthesis and

structure determination of biologically active materials2

History of (+) Discodermolide

• First isolated in 1990 by Gunasekera in Florida from the Caribbean sponge Discodermia dissoluta.

• 13 Stereogenic centers, tetrasubstituted δ-lactone, on di and one tri-substituted Z-alkene, a carbamate, and a terminal Z-diene

• Acts as a antimitotic agent by stabilizing microtubules and promotes polymerization of tubulin

• Inhibits growth of breast cancer cells in vitro, resistant ovarian and colon cancer cells.

• Before Ian Paterson, 2 total synthesis of (+)-Discodermolide (Schreiber et al) and 3 of (-)-Discodermolide (Kobayashi, Myles, Johns)

• Schreiber et al determined absolute stereochemistry

3

Retrosynthesis

4

OO

OH

HO

OH O

OH H2N

O

O

OTBS

O

OH OTBSO

OTBS H2N

O

O

PMBO

OArO

TBSO O

H

OPMB

(+)-Discodermolide

+

2: C1-C6 5

+

3: C9-C16 4: C17-C24

Synthesis of 2

5

BnO

O

BnO

TBSO OTBS

HO

TBSO OH

HO

TBSO OO

BnO

TBSO OH

O

TBSO O

MeO

TBSO OO

BnO

OH OH

BnO

TBSO OTBS

HO

TBSO OH

HO

TBSO OO

1) (cy)2BCl, Et3N, Et2O,0°C, 3h; MeCHO,

-78°C to -27°C2) LiBH4, -78°C, 3h

3) H2O2/MeOH, NaOH, 0°CTBSOTf, 2,6-lutidine

CH2Cl2, -78°C, 2h

CSA, MeOH/CH2Cl20°C, 8h

20% Pd(OH)2/C, H2, EtOH

20°C, 20h

1) DMSO, (COCl)2CH2Cl2, -78°C, 1.5 h

2) Et3N-78°C to -20°C

20 min

NaClO2, NaH2PO4,2-methyl-2-butene

tBuOH, H2O, 20°C, 2h

CH2N2, Et2O,20°C, 5 min

2

Synthesis of 3

6

PMBO

O

PMBO

OH OCOEt

PMBO

O OH

PMBO

O O

PhSe

PMBO

OH OCOEt

OO

PMBO

MeMe

Me

1) (cy)2BCl, Et3N, Et2O,0°C, 3h

2) LiBH4, -78°C, 3h

3) H2O2/MeOH, NaOH, 0°CSmI2, EtCHO

THF, -10°C,2.5h

1)K2CO3, MeOH20°C, 3h

2) PhSeCH2CH(OEt)2toluene, cat PPTS,

reflux, 4.5h

NaIO4, NaHCO3

MeOH/H2O

20°C, 2h

Synthesis of 3 Continued

7

OO

PMBO

MeMe

Me

O

PMBO

O

PMBO

CO2Me

OTBS

OO

PMBO

MeMe

Me

PMBO

CO2Ar

OTBS

PMBO

CO2Me

OTBS

O

PMBO

O

1)NaOMe, MeOH0°C, 1h

2) TBSOTf, CH2Cl2,2,6-lutidine, -78°C,

1.5h

1)KOH (1M), MeOH,reflux, 1h

2) 2,6-dimethylphenol,DCC, 4-DMAP,CH2Cl2,

20°C, 16h

3

Synthesis of 4

8

O

OBzTSBO

CHO

TSBOOBz

OH O

TSBOOBz

PMBO O

TSBOOBz

PMBO O

TSBOOH

PMBO OH

TSBO

PMBO O

HSiMe3

Br

TSBO

PMBO

H

OPMBO

TSBO

PMBO

TSBOOBz

OH O

TSBO

PMBO O

H

+

1) (cy)2BCl, Et3N, Et2O,0°C, 3h

2) LiBH4, -78°C, 3h

3) H2O2/MeOH, NaOH, 0°C

PMBTCA, cat.

TfOH, THF, 20°C, 9h

LiAlH4, THF-78 to -27°C,

3h

NaIO4, MeOH,20°C, 30 min

+

1)CrCl2, THF,20°C, 16h

2) KH, THF,0°C, 1.5h

1) CSA, MeOH,20°C, 30 min

2) DMP, CH2Cl220°C, 15 min

4

Synthesis of 5

9

PMBO

CO2Ar

OTBS

PMBO

OTBS

OPMBOH

PMBO

ArO2C

OTBS

OPMBOH

H

OPMBO

PMBO

OTBS

OPMBOH

PMBOArO2C

OTBS

OPMBOH

HO

OTBS

OHOTBS

3

LiTMP, LiBr, THF, -100°C+

1) LiAlH4, THF, -30°C, 3h2) 2,4,6-Me3(C6H2)SO2Cl,Et3N, CH2Cl2, 20°C, 24 h

3) LiAlH4, THF, -30°C, 3h

1) TBSOTf, Et3N, CH2Cl2,20°C, 24h

2) DDQ, CH2Cl2/ pH 7buffer, 20°C, 16h

Synthesis of 5 Continued

10

HO

OTBS

OHOTBS

OTBS

OHOTBSMeO2C

OTBS

OHOTBSMeO2C

OTBS

OOTBS

O

H

H2N

O

1) cat. TEMPO, BAIB, CH2Cl220°C, 4h

2) (CF3CH2O)2P(O)CH2CO2Me,[18]c-6, K2CO3, PhMe,

-20 to 0°C, 2h

1)Cl3CC(O)NCO, CH2Cl2,20°C, 1 h

2) K3PO4, MeOH, 20°C, 1h3)DIBAL-H, CH2Cl2, -78°C, 1.5h

4) DMP, CH2Cl2, 20°C, 1H

5

Final Steps to (+)-Discodermolide

11

O

OTBS

O

O

H OTBSO

OTBS H2N

O

O

OTBSO

OTBS H2N

O

HO

O

OTBS

MeO2C

OTBSO

OTBS H2N

O

HO

O

OTBS

OOTBSO

OTBS H2N

O

HO

HO

OTBS

MeO2C

OO

OH

HO

OH O

OH H2N

O

(+)-Discodermolide

52

+

1) (+)-Ipc2BCl, Et3N, Et2O, 1.5h

2)H2O2/MeOH pH 7 buffer, 0°C, 1h

Me4NBH(OAc)3, MeCN/AcOH-25 to 20°C, 16h

+

HF pyr, THF, 20°C, 16h

Conclusion

• (+) Discodermolide synthesized in overall 7.7% yield

• 27 steps for longest linear sequence

12