Total Synthesis of (–)-ExiguolideFuwa, H.; Sasaki, M. Org. Lett. 2010, 12, 584-587.

Short Literature Presentation 3/9/2010

Erika A. Crane

Total Synthesis of (–)-ExiguolideCook, C.; Guinchard, X.; Liron, F.; Roulland, E. Org. Lett. 2010, 12, 744-747.

(–)-exiguolide

Isolated in 2006 by Ohta, Ikegami and coworkers from the marine sponge

Geodia exigua

Ohta, S.; Uy, M. M.; Yanai, M.; Ohta, E.; Hirata, T.; Ikegami, S.Tetrahedron Lett. 2006, 47, 1957-1960.

16-membered macrolide

two cis-2,6-disubstituted tetrahydropyran rings

exocyclic enoate moiety and triene side chain

7 stereogenic centers

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

Biological Activity of (–)-exiguolide

Inhibit sea urchin gamete (Hemicentrotus pulcherrimus) fertilization at a 20 μM concentration

A concentration of 100 μM did not affect the development of the already

fertilized eggs up to gastrula stage

Ohta, S.; Uy, M. M.; Yanai, M.; Ohta, E.; Hirata, T.; Ikegami, S. Tetrahedron Lett. 2006, 47, 1957-1960.

Cossy, J.C. R. Chemie, 2008, 11, 1477-1482.

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

Biological Activity of (–)-exiguolide

bryostatin core (–)-exiguolide

Cossy, J.C. R. Chemie. 2008, 11, 1477-1482.

This combined with the biological activity presents exiguolide with great potential to possess antitumor activity

O O

O

O

ORMeMe

HOO

MeO2C

MeMe

OH H

OH

RO OHMe

CO2Me

O O

O

O Me

MeO2C

MeMe

MeO2C

H

Also, exiguolide is very structurally similar to the bryostatins, a class of complex molecules

with potent antitumor activity

O O

O

OOMeO2C

MeMe

OH H

OH

O OH

CO2MeOC7H15bryologue

Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. J. Am. Chem. Soc. 2008, 130, 6658-6659.

Fuwa and Sasakiʼs Retrosynthesis

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

Suzuki-Miyaura coupling

O

H

O

OO

H

H

H

Me

Me

H

HH

Julia-Kocienskiolefination

O

H

OOHC

H

H

Me

HH

oxa-conjugate addition

B

Me

MeO2C OO

Me MeMe

Me

IYamaguchi macrolactonization

TBDPSO

I

OMPM

MeS

N NN

NO O Ph

cross-methathesisreductive etherification

OH

TIPSO

OOTES

Me

OBnOTBDPS

OH

TIPSO

OOTES

Me

OBn

OTBDPS

TIPSO

MeO2C

H

Fuwa and Sasakiʼs Forward Synthesis

6 stepsfrom the Roche ester

asymmetric Brown allylation

cross-metathesis

chelate-controlled allylation

OH

TIPSO

OTBDPS

OH

OTBDPS

OMPM

OTBDPS

OH

1.) MPMOC(=NH)CCl3, Sc(OTf)3, toluene, rt

2.) OsO4, NMO, THF/ H2O, rt; NaIO4 69% (over 2 steps)

1.) allylSiMe3, MgBr2•OEt2, CH2Cl2, 0 °C 84%, > 20:1 dr

2.) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C3.) DDQ, pH 7 buffer, CH2Cl2, rt 97% (over 2 steps)

OOTES

Me

OBn

CHOMe

OBnMe

OBn

HO

CO2Me

Me

OBn

TESO

O NMe

OMe

1.)(+)-Ipc2BOMe, allylMgBr, Et2O, –78 °C

2.) methyl acrylate, G-II, CH2Cl2, 35 °C 72% (over 2 steps)

1.) H2, Pd/C, EtOAc, rt

2.) MeONHMe•HCl, AlMe3, CH2Cl2, 0 °C3.) TESCl, NEt3, DMAP, CH2Cl2, rt 92% yield (over 3 steps)

tetra(vinyl)tin,MeLi, Et2O

–80 °C96%

Fuwa and Sasakiʼs Forward Synthesis

available in 10 stepsfrom the Roche ester

reductive etherification

cross-metathesis oxa-conjugate additionOH

TIPSO

OTBDPS

OOTES

Me

OBnOH

TIPSO

OOTES

Me

OBnOTBDPS

O

H

TESO

O

H

Me

HH

TBDPSOHG-II, CH2Cl235 °C

93%, > 20:1 dr

O

H

OOHC

H

H

Me

HH

TBDPSO

BnOKOt-Bu, THF, 0 °C

95% > 20:1 dr

1.) BF3•OEt2, Et3SiH, CH2Cl2, –60 to –25 °C 98%, 10:1 dr2.) H2, Pd/C, EtOAc, MeOH, rt, 90%3.) DMP, CH2Cl2, rt, 97%

I

OMPM

MeS

N NN

NO O Ph

TIPSO

TIPSO

LiHMDS, THF, HMPA,–78 °C to rt, 63%

O

H

O

H

H

Me

HHTIPSO

MPMO

MeTBDPSO

IJulia-Kocienski olefination

Fuwa and Sasakiʼs Forward Synthesis

asymmetric Horner-Wadsworth-Emmons

yamaguchi macrolactonization

O

H

O

OO

H

H

H

Me

Me

H

HH

I

TIPSO

O

H

O

H

H

Me

HHTIPSO

MPMO

MeTBDPSO

I1.) 10% KOH/MeOH, THF, 60 °C, 94%2.) DMP, CH2Cl2, rt

3.) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, rt4.) TMSCHN2, MeOH, C6H6, rt 94% (over 2 steps)

O

H

O

MeO2C

H

H

Me

HHTIPSO

MPMO

Me

I

1.) BF3•OEt2, Et3SiH, CH2Cl2, 0 °C, 89%2.) TMSOK, THF, rt3.) 2,4,6-trichlorobenzoyl chloride, NEt3, THF; DMAP, toluene, 80 °C, 94% (over 2 steps)

O

H

O

OO

H

H

H

Me

Me

H

HH

I

MeO2C

1.) HF•pyr, THF, rt2.) DMP, CH2Cl2, rt 100% (over 2 steps)

3.) NaHMDS, THF,

–40 °C, 94% 5:1 Z:E

OO P

OCO2Me

B

Me

MeO2C OO

Me MeMe

MePd2(dba)3, Ph3As,Ag2O, THF, rt, 73% (–)-exiguolide

Suzuki-Miyaura coupling

Roulland et al. Retrosynthesis

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

Sonogashira coupling

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

I

Yamaguchi macrolactonization

ene-yne cross coupling reaction/oxa-conjugate addition

Me

MeO2C

O

H

MeO2C

H

O

HO2C

H

H

Me

HH

HO Me

HHPrOi

O

OH

TMS

OTBS

Me

Me

TBSO

O

Roulland et al. Forward Synthesis

SN2ʼ reaction of activated phosphate

Jacobsen hydrolytic kinetic resolution

must be Z-allylic alcohol in order to get anti attack and full transfer of chirality

OTBS

Me

Me

TBSO

O

OTBDPS OTBDPSO

OTBDPSOTBSOTBDPSOTBS

OH

Me

OTBS

OTBS

Me

TBSO

TBDPSO

Me

1.) mCPBA, CH2Cl2, rt 99%

2.) (S,S)-CoII-salen, AcOH, air, toluene; H2O, 0 °C to rt 47%, 99.5% ee

1.) TMS acetylene, n-BuLi, BF3•OEt2, THF, 75%

2.) K2CO3, MeOH, rt, 95%3.) TBSCl, imidazole, DMF, rt, 94%

1.) n-BuLi,

THF, –78 °C to rt, 95%

2.) NaBH4, CeCl3•7H2O, EtOH

–78 to 15 °C, 99%, 96:4 dr

OTBS

MeN

O

Me

OMe

1.) H2, Lindlar's, quinoline, EtOAc, rt, 100%2.) KHMDS, Et2O, -78 °C; ClPO(OEt)2; –40 °C, MeCuLi, 96% 95:5 dr

1.) NaOH, MeOH, reflux, 92%2.) (COCl)2, DMSO, CH2Cl2, –78°C; NEt3

3.) allyl bromide, Zn, NH4Cl, THF, H2O, rt, 1;1 dr 99% (over 2 steps)4.) DMP, CH2Cl2, rt, 100%

Roulland et al. Forward Synthesis

Trostʼs ene-yne coupling/oxa-conjugate addition

Jacobsen hydrolytic kinetic resolution

OTBS

Me

Me

TBSO

O

1.) iPrOH, NEt3, 0 °C to rt2.) mCPBA, CH2Cl2, rt 55% (over 2 steps)

2.) (S,S)-CoII-salen, AcOH, air, toluene; H2O, 0 °C to rt 44%

TMS acetylene, n-BuLi,THF; Et2AlCl, 0 °C to rt

Me

O

Cl

O

iPr-O

O80%, 99.5% ee

PrOi

O

OH

TMS

RuMeCNMeCN

MeCNPF6

7 mol %

5 mol % AcOH, acetone,rt, 47%, 8:1 dr

OTMS

H

TBSO

iPrO2C

O

H

Me

HH

TBSO Me

HH

1.) NIS, MeCN, 0 °C, 94%2.) CSA, 2,2-dimethoxypropane, MeOH, reflux; Et3SiH, BF3•OEt2, CH2Cl2, – 40 °C 82% > 20:1 dr

OI

H

O

iPrO2C

H

H

Me

HH

HO Me

HH O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

1.) NaOH, MeOH, H2O, rt 89%2.) PdCl2(dppf), Et3N, CO, MeOH, reflux, 83% 92:8 Z:E

3.) 2,4,6-trichlorobenzoyl chloride, NEt3, THF, rt; DMAP, toluene, 60 °C, 75% Yamaguchi macrolactonization

reductive etherification

Roulland et al. Forward Synthesis

Trostʼs ene-yne coupling/oxa-conjugate addition

Jacobsen hydrolytic kinetic resolution

OTBS

Me

Me

TBSO

O

1.) iPrOH, NEt3, 0 °C to rt2.) mCPBA, CH2Cl2, rt 55% (over 2 steps)

2.) (S,S)-CoII-salen, AcOH, air, toluene; H2O, 0 °C to rt 44%

TMS acetylene, n-BuLi,THF; Et2AlCl, 0 °C to rt

Me

O

Cl

O

iPr-O

O80%, 99.5% ee

PrOi

O

OH

TMS

RuMeCNMeCN

MeCNPF6

7 mol %

5 mol % AcOH, acetone,rt, 47%, 8:1 dr

OTMS

H

TBSO

iPrO2C

O

H

Me

HH

TBSO Me

HH

1.) NIS, MeCN, 0 °C, 94%2.) CSA, 2,2-dimethoxypropane, MeOH, reflux; Et3SiH, BF3•OEt2, CH2Cl2, – 40 °C 82% > 20:1 dr

OI

H

O

iPrO2C

H

H

Me

HH

HO Me

HH O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

1.) NaOH, MeOH, H2O, rt 89%2.) PdCl2(dppf), Et3N, CO, MeOH, reflux, 83% 92:8 Z:E

3.) 2,4,6-trichlorobenzoyl chloride, NEt3, THF, rt; DMAP, toluene, 60 °C, 75% Yamaguchi macrolactonization

reductive etherification

Roulland et al. Forward Synthesis

Takai-Utimoto olefination

Sonogashira coupling

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

O

H

MeO2C

H

O

OO

H

H

H

Me

Me

H

HH

I

OMeO2C

H

O

OO

H

H

H

Me

Me

H

HH

Me

MeO2C

1.) OsO4, NMO, acetone, H2O; Pb(OAc)4, benzene 20% (31% recov.)

2.) CHI3, CrCl2, THF, rt 94%

1.) Pd(PPh3)4, CuI, NEt3, THF, rt, 51%

2.) H2, Lindlar's, quinoline, EtOAc, rt, 62%

(–)-exiguolide

originally wanted to do a cross-methathesis to append triene side-chain but could not get to work