Total Synthesis of Oxazolomycin Accc.chem.pitt.edu/wipf/Current Literature/Dimas_2.pdf · 2011, 13,...
Transcript of Total Synthesis of Oxazolomycin Accc.chem.pitt.edu/wipf/Current Literature/Dimas_2.pdf · 2011, 13,...
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
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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