Total Synthesis of Oxazolomycin A

NO

O

NHHO

OH

MeO

NMe

O O

OHO

Oxazolomycin A

Eto, K.; Yoshino, M.; Takahashi K.; Ishihara, J.; Hatakeyama S.Org. Lett. 2011, 13, 5398

Dimas Paz Wipf group- Current Literature

October 8, 2011

Dimas Paz @ Wipf Group Page 1 of 14 12/28/2011

Oxazolomycin A - Isolation and Biological Active

• Oxazolomycin A was isolated from a strain Streptomyces togetherwith Neooxazolomycin in 1985 by Uemura at al.

• Oxazole polyene lactam-lactone

NO

O

NHHO

OH

MeO

NMe

O O

OHO

Oxazolomycin A

NO

O

NHHO

OHNMe

OHO

Neooxazolomycin

OO

OH

• They exhibit wide ranging and potent antibacterial and activities as well asin vivo antitumor activity.

a) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.; Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo,R.; Nakano, F.; Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1073. b) Takahashi, K.; Kawabata, M.;Uemura, D.; Iwadare, S.; Mitomo,R.; Nakano, F.; Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1077.

Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z. Curr. Drug. Discovery Technol. 2004, 1, 181

Dimas Paz @ Wipf Group Page 2 of 14 12/28/2011

Retrosynthesis

NO

O

NHHO

OH

MeO

NMe

O O

OHO

Oxazolomycin A

NO

O

NHHO

OH

MeO

NMe

O

OHO

HOHO

Nozaki-Hiyama-Kishi

Amidation

NO

O

OHHO

FmocHN I H

O

MeO

NMe

O

OPO

POPO

OBnNMe

OHO

OO

CO2Me

NMe

O

CO2MeCO2Me

OBn

Dihydroxylation

BnO

O

MeN

CO2Me

CO2Me

Conia-ene type cyclization

Dimas Paz @ Wipf Group Page 3 of 14 12/28/2011

Synthesis of the γ-LactoneOBn

NMe

OHO

OO

OH

Onyango, E. O.; Tsurumoto, J.; Imai, N.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem. Int. Ed.2007, 46, 6703.

TBDPSO

+OTfBnO

1. n-BuLi, DMPU/THF !78 °C

2. TBAF, THF81% (2 steps)

BnO

OH

1. H2CrO4, aq acetone, 0 °C2. SOCl2, CH2Cl2

3. toluene

MeHN CO2Me

CO2Me

BnO

O

MeN

CO2Me

CO2MeIn(OTf)3 (5 mol%)DBU (4.4 mol%)

toluene, reflux

63% (3 steps)

NMe

O

CO2MeCO2Me

OBn

91%

Dimas Paz @ Wipf Group Page 4 of 14 12/28/2011

Plausible mechanism - In(III)-catalyzed Conie-ene type cyclization

Endo, K.; Hatakeyama, T; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264

Dimas Paz @ Wipf Group Page 5 of 14 12/28/2011

Synthesis of the γ-Lactone

17 was supported by NOESY spectrum in [D8]THF/D2Oand also suggested to be energetically most stable by

Molecular mechanics calculation.

OBnNMe

OHO

OO

OH

OBnNMe

OHO

OO

CO2Me

1. LiOH, THF then HCl (1 M)

2. (COCl)2, DMF (cat.), CH2Cl2then NaBH4, THF-MeOH

!78 °C, 60%OBn

NMe

OHO

OO

OH

NMe

O

CO2MeCO2Me

OBnOsO4, NMO

THF-H2O100%

Dimas Paz @ Wipf Group Page 6 of 14 12/28/2011

Synthesis of the right-hand segment H

O

MeO

NMe

O

OPO

POPO

ZrCl4, i-PrOH

reflux OBnNMe

OHO

OH

OHMeO

On-C12H25SCH2OTIPS

CuBr2, n-Bu4NBr

Et3N, 4 Å MS, CH2Cl267% (5 steps) OBn

NMe

OHO

O

OHMeO

O

OTIPS

OBnNMe

OHO

OO

OH 1. MOMCl, i-Pr2EtN, CH2Cl2

2. NaBH4, THF-EtOH3. TBSOTf, 2,6-lutidine

CH2Cl2, !78 °C93% (3 steps)

OBnNMe

OHO

OTBS

OMOMOH

Me3O+BF4-

proton sponge

4 Å MS, CH2Cl295%

OBnNMe

OHO

OTBS

OMOMMeO

1. TBAF, THF2. H2CrO4, acetone, 0 °C

3. NaClO2, NaH2PO42-methyl-2-butene

t-BuOH-H2O

OBnNMe

OHO

OH

OMOMMeO

O

Dimas Paz @ Wipf Group Page 7 of 14 12/28/2011

Synthesis of the right-hand segment

Synthesis of the middle segment

H

O

MeO

NMe

O

OPO

POPO

H2NFmocCl

NaHCO3dioxane

96%

FmocHNacrolein

Hoveyda-Grubbs 2ndCH2Cl2, 85%

FmocHN CHOCrCl2, CHI3

THFFmocHN I

68% (E:Z = 8:1)

FmocHN I

OBnNMe

OHO

O

OHMeO

O

OTIPS

i-Pr2Si(OTf)2, 2,6-lutidine

ClCH2CH2Cl, reflux, 90%BnO

NMe

O

OMeO

O

OTIPS

OOSi

iPriPr

1. H2, Pd(OH)2, AcOEt

2. Dess-Martin periodinaneNaHCO3, CH2Cl2 O

NMe

O

OMeO

O

OTIPS

OOSi

iPriPr

H

92% (2 steps)

Dimas Paz @ Wipf Group Page 8 of 14 12/28/2011

Synthesis of the left-hand segment

TMSO

H

NO

N

OMeTMS

EtCOCl, LiClO4, i-Pr2EtNCH2Cl2-Et2O, -78 °C, 92%

TMSO

O

98% ee, >99% de

CO

HR1R3*N R1

O Lewis acid

(M) R3*N R1

OM

R2CHO

O OM

R3*N

R1

R2

H

O OM

R3*N

R1

R2

H

O

R2R1

O

NR3* + M

NR3* =N

O

N

OMeTMS

Plausible mechanism

Zhu, C.; Shen, X.; Nelson, S. C. J. Am. Chem. Soc. 2004, 126, 5352

NO

O

OHAcO

Dimas Paz @ Wipf Group Page 9 of 14 12/28/2011

Synthesis of the left-hand segmentN

O

O

OHAcO

TMSO

O

TMS

OHCO2Me

LDA, MeI

THF, !20 °C84%

TMS

OHCO2Me

1. NaOMe, MeOH

2. TBSOTf2,6-lutidine, CH2Cl20 °C, 98% (2 steps)

OTBSCO2Me

1. n-BuLi, I2, THF, !78 °C

2. o-(NO2)C6H4SO2NHNH2Et3N, i-PrOH-THF

OTBSCO2Me

I

Pd(PPh3)4, CuICsF, DMF

N

OSnBu3

NO

O

OMeTBSO

1. HF, MeCN2. LiOH, THF- MeOH

3. Ac2O, pyridineNaHCO3, MeOH

92% (2 steps)

83%88%

NO

O

OHAcO

NaOMeMeOH, 95%

Dimas Paz @ Wipf Group Page 10 of 14 12/28/2011

Synthesis of the left-hand segmentN

O

O

OHAcO

EtO OEt

HO

1. KSCN, HCl, MeCN, reflux

2. KH, n-BuI, THF79% (2 steps)

N

OBuS

t-BuLi, CuCN•2 LiCl THF, !78 °C

BrCH2CCSiMe3 !78 °C - rt, 94%

N

OBuS

TMS

1. Raney Ni, acetone: EtOHreflux, 92%

2. AgOTf, CH2Cl2/MeOH/H2O, 73%

N

O

n-Bu3SnH, AIBN

70 °C, 88%

N

OSnBu3

E/Z = 6:1

Dimas Paz @ Wipf Group Page 11 of 14 12/28/2011

Synthesis of Oxazolomycin A

ONMe

O

OMeO

O

OTIPS

OOSi

iPriPr

H

NO

O

OHAcO

FmocHN I

NO

O

NHHO

OH

MeO

NMe

O O

OHO

Dimas Paz @ Wipf Group Page 12 of 14 12/28/2011

Synthesis of Oxazolomycin A

ONMe

O

OMeO

O

OTIPS

OOSi

iPriPr

H

1. NiCl, CrCl2, THF-DMSO

FmocHN I

2. Dess-Martin periodinaneNaHCO3, CH2Cl2

3. L-selectride, THF, !78°C53% (3 steps)

HONMe

O

OMeO

O

OTIPS

OOSi

iPriPr

NHFmoc7R + 7S-epimer

4:1

1. Ac2O, pyridine, 91%

2. DBU, CH2Cl2then BOPCl, Et3N, CH2Cl2

NO

O

OHAcO

AcONMe

O

OMeO

O

OTIPS

OOSi

iPriPr

NH

O

AcO

NO

1. HF•pyridine, THF

2. LiOH, THF

NO

O

NHHO

OH

MeO

NMe

O

OHO

HOHO

NO

O

NHHO

OH

MeO

NMe

O O

OHO

Oxazolomycin A

HATU, i-Pr2EtN, THF

41% (3 steps)

68% (2 steps)

Dimas Paz @ Wipf Group Page 13 of 14 12/28/2011

Summary and Outlook

Oxazolomycin A was synthesized in 34 steps of the longest linear sequence in1.4% overall yield from methyl (S)-3-hydroxy-2-methylproprionate.

Key transformation include In(III)-catalyzed Conia-ene type cyclization, Cinchonaalkaloid-catalyzed cyclocondensation and asymmetric dihydroxylation.

NO

O

NHHO

OH

MeO

NMe

O O

OHO

Oxazolomycin A

Dimas Paz @ Wipf Group Page 14 of 14 12/28/2011