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Filip Petronijevic Current Literature Presentation September, 4th 2010.
Total Synthesis of Sporolide B and 9-epi-Sporolide B
K.C.Nicolaou, Jianhua Wang, Yefeng Tang, and Lorenzo Botta J. Am. Chem. Soc. 2010, 132(32), 11350.
Filip Petronijevic @ Wipf Group Page 1 of 16 9/26/2010
Sporolide Isolation and Its Structural Determination
(a) Bunchan, G.O.; Williams, P.G.; Feling, R.H.; Kauffman, C.A.; Jensen, P.R.; Fenical, W. Org. Lett. 2005, 7, 2731. (b) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (c) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350. (d) http://www.aquapreneur.com/2008/01/11/scripps-jgi-sequence-marine-bacterium-s-tropica/comment
Salinospora tropica
OO
O Me
OHO
O
O
OH
MeO
OHOH
OHCl
Sporolide A!Sporolide B!
• no obvious biological activity • intriguing molecular architecture • 24-carbon polycyclic structre (cyclo penta[a]indene – cyclohexenone system) • 10 stereocenters • 13-membered ring
OO
O Me
OHO
O
O
OH
MeO
OHOH
OH
Cl
Filip Petronijevic @ Wipf Group Page 2 of 16 9/26/2010
Unraveling the Biosynthesis of Sporolide: From L-Tyrosine toward Sporolide
CO2H
NH2
OH
CO2H
O
OH
O-
O
OH
HO O-AMP
O
OH
HO
S-SpoT2
O
OH
HOS-SpoT2
O
OH
HO
HO
S-SpoT2
O
OH
HO
HO
OHS-SpoT2
O
OH
HO
O
O
S-SpoT2
O
OH
HO
O
O
CH3
S-SpoT2
O
OH
H3CO
O
O
CH3
S-SpoT2
O
OH
H3CO
O
O
CH3
O
Aminotransferase
SpoT1[ox]
SpoT2ATP
PPi
SpoT2
SpoT3[ox]
SpoT4[ox]
SpoT5[ox]
SpoT6SAM
SpoT7SAM SpoT8
SpoT9[ox]
p-HPPA(p-hydroxyphenylpyruvate)
(S)-p-HMA(p-hydroxymandelate)
L-TyrosineNonribosomal peptide
synthetase peptidyl carrierprotein
Phenol hydroxylaseMonooxygenaseAlcohol dehydrogenase
C-methyltransferase
O-methyltransferaseEpimerase
CYP450monooxygenase
OO
O Me
OHO
O
O
OH
MeO
OHOH
OH
Cl
sporolide B
(a) McGlinchey, R.P.; Nett, M.; Moore, B.S. J. Am. Chem. Soc. 2008, 130, 2406. (b) Nett, M.; Moore, B.S. Pure Appl. Chem.2009, 81, 1075.
Filip Petronijevic @ Wipf Group Page 3 of 16 9/26/2010
Unraveling the Biosynthesis of Sporolide: End Game
O
O
O
O
O
HO
OH
OH
O
SCoA
HO
O O
SCoASpoE2-E11 SpoF
S-SpoT2
OOH
H3CO
O
OCH3
O
"-OH"O
OO Me
OHO
O
O
OH
MeO
OHOH
OH OHO Me
O
O
MeO O
OH
O
O
O OH
OO
O Me
OHO
O
O
OH
MeO
OHOH
OH OO
O Me
OHO
O
O
OH
MeO
OHOH
OH
R1
R
R = Cl, R1 = H: Sporolide AR = H, R1 = Cl: Sporolide B
Cl-, then H+
presporolide
SpoT10
(a) McGlinchey, R.P.; Nett, M.; Moore, B.S. J. Am. Chem. Soc. 2008, 130, 2406. (b) Nett, M.; Moore, B.S. Pure Appl. Chem. 2009, 81, 1075. (c) Van Lanen, S.G.; Oh, T.J-.; Liu, W.; Pienkowski, E.W.; Shen, B. J. Am. Chem. Soc. 2007, 129, 13082. (d) Liu, W.; Christenson, S.D.; Standage, B.; Shen, B. Science 2002, 297, 1170.
Bergman cyclization
Filip Petronijevic @ Wipf Group Page 4 of 16 9/26/2010
Initial Retrosynthetic Considerations and Model Studies: Plan A or Plan B
OO
O Me
OHO
O
O
OH
MeO
OHOH
OH
Clmacrolactonization
[4+2] cycloadditionO
O
PgO MeO
HOOH
MeO
OPgOPg
OPg
Cl
O
O
PgO MeO
O
OH
MeO
OPgOPg
OPg
Cl
OH
hydroxy acido-quinone
OO
O Me
OHO
O
O
OH
MeO
macrolactonization
O
O
MeO
OEtO
BnOMe
OH
OO
O Me
OHO
O
O
MeO
O
O
MeO
OHO
BnOMe
OEt
HO
[4+2] cycloaddition
model systems
o-quinone fragment hydroxy indene fragment carboxylic acid -o-quinone fragment
hydroxy indene fragment
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350. (c) Aly, A.A.; Ehrhardt, S.; Hopf, H.; Dix, I.; Jones, P.G. Eur. J. Org. Chem. 2006, 335.
Filip Petronijevic @ Wipf Group Page 5 of 16 9/26/2010
MeOH
OO
1. MeMgBr; then
H
O
O
OEt
2. BnBr, Cs2CO3,NaI, DMF, 0 °C to rt; 92%
; 98%
3. TMSCHN2, HBF4,0 °C to rt; 81%
MeOBn
OO
CO2Et
OMe1. Pb(OAc)4, benzene, 80 °C
2. AcOH:THF:H2O (10:5:1), rt;95% over 2 steps
MeOBn
OO
CO2Et
OMe
3. Ag2O, CH2Cl2, rt; 94%
OO
MeBnOEtO
OMeO
O
O
MeBnOEtO
OMeO
HH NOE
O
O
MeBnOEtO
OOMe
H NOE82%
(ca. 1.5:1)
OO
MeBnOEtO
OMeO
O
O
BnO MeO
EtO
MeO
O
O
BnO MeO
OEt
MeO
57%(ca. 1:1)
OO
MeBnOEtO
OMeO
O80%
(ca. 10:1)O
O
MeBnOEtO
OMeO
O
MeO MeO
O
O
MeBnOEtO
OMeO
O
MeO
Synthesis of o-Quinone and Its Reaction with Indene Derivatives: [4+2] Cycloaddition
Filip Petronijevic @ Wipf Group Page 6 of 16 9/26/2010
MeBnO O
OCO2Et
MeO
OH
toluene, 115 °C, 3 h; 62% (ca. 1:1)
OO
MeBnOEtO
OMeO
HO
O
O
BnO MeO
EtO
MeO
HO
1. DMP, NaHCO3, CH2Cl2, rt; 88%
2. MePPh3Br, KHMDS, THF; 91%
O
O
BnO MeO
EtO
MeO
1. AD-mix-ß t-BuOH:H2O 0 °C; 93%
2. LiOH, dioxane:water, 80 °C; 98%O
O
BnO MeOOH
MeO
HO
HO H
O
O
BnO MeOO
MeO
HO H
Corey-NicolaouYamaguchicyanuric chlorideMikaiyama saltShiinaMitsunobu
X
Br
IHO2C
1. BH3•THF, rt; 80%
2. DHP, TsOH•H2O, CH2Cl2, 0 °C; 95%
Br
IOTHP
1. LDA, THF:HMPA, then O
2. CrCl2, NiCl2, DMF, 100 °C, 16 h; 76% OTHP HO
OH
p-TsOHbenzene
then MeOH82%
1. DMP, NaHCO3, rt; 95%2. MeOCH2PPh3Br, KHMDS, THF; 96%
3. HCl, THF, 60°C, 3 h; 88%4. NaBH4, THF:MeOH; 95%
HO
Construction of the Indene and Unsuccessful Macrolactonization
Preferred regiochemsitry
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
Filip Petronijevic @ Wipf Group Page 7 of 16 9/26/2010
MeOBn
HOOH
CO2Et
OMeMe
OBn
OO
CO2Et
OMe
EtO
CH(OEt)3TsOH•H2O
4Å MS, benzene,80 °C; 96%
LiOH, dioxane:water, 80 °C, 3 h; 99%
MeOBn
OO
CO2H
OMe
EtO
HO
DCC, DMAP,CH2Cl2, rt; 84%
OO
HO MeO
O
MeOOEt
1. TsOH, MeOH, rt; 98%
2. Ag2O, toluene, 120 °C, 1 h; 60%or a. Ag2O, CH2Cl2, rt; 99% b. toluene, 120 °C, 3 h; 50%
OO
MeBnOO
MeO
O
OO
BnO MeO
O
MeO
1. H2, Pd(OH)2/C, EtOH, rt; 85%2. PMBOH, PIFA, NaHCO3, CH3CN, 0 °C to rt; 87%
3. DDQ, CH2Cl2:water rt; 96%4. t-BuOOH, DBU, CH2Cl2, 40 °C; 60%
OO
O Me
OHO
O
O
MeO
The Proof of Concept: Successful Synthesis of Sporolide Model System
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
ester formation prior to [4+2] cycloaddtion
Filip Petronijevic @ Wipf Group Page 8 of 16 9/26/2010
OO
O Me
OHO
O
O
OH
MeO
OHOH
OH
Cl
O
O
OPgOMe
OO
OPg
PgO
OPgCl
OPgMe
[4+2] cycloaddition
O
OMeOPgMe
esterification
OH
OO
OPg
OPg
PgO
OPgCl
HO
cyclotrimerization
O
OMeOPgMe O
OO
OH
OBn
TBSO
OAcCl
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
“ … repeated attempts to construct hydroxy chloroindene through conventional methods were met with difficulties.”
Forays toward Sporolide B: Successful but not Successful
Filip Petronijevic @ Wipf Group Page 9 of 16 9/26/2010
H
OOBnMe
OO
1. MePPh3Br, KHMDS, THF, -78 °C to 0 °C; 98%
2. AD-mix ß, t-BuOH:H2O, rt; 96% (98% ee)3. TBSCl, Et3N, DMAP; 99% OHOBn
Me
OO
OTBS
1. t-BuOK, MeI, CH3CN, 0 °C to rt; 95%2. n-Bu4NF, THF, rt; 99%
3. DMP, NaHCO3, CH2Cl2, rt; 78 °C4. NaClO2, NaH2PO4•2H2O 2-methyl-2 butene; 96%
OMeOBnMe
OO
OH
O
HOOH
EDCI, DMAPCH2Cl2, rt; 73%
O
OMeOBnMe O
OO
OH
Pb(OAc)4, benzene75 °C; 89 %
O
OMeOBnMe O
OO
OH
AcO
Construction of the Cyclotrimerization Precursors: Toward the Indene Motif
IO
OTBS
1. NaBH4, CeCl3•7H2O, MeOH, - 78 °C2. NaH, BnBr, n-Bu4NI, THF, 0 °C to rt; 95%
3. Pd(PPh3)2Cl2, Et3N, CO, MeOH, 70 °C; 95%
OBn
OTBS
O
MeO
1. DIBAL-H, toluene, -78 °C to -10 °C; 95%2. DHP, TsOH•H2O, CH2Cl2, 0 °C
3. n-Bu4NF, THF, 25 °C4. DMP, NaHCO3, CH2Cl2, rt; 83% (overall)
OBn
O
OTHP1. I2, pyr:CH2Cl2 25 °C; 80%2. (S)-CBS-Me, BH3•THF -30 °C; 99%
3. TBSCl, imidazole, DMAP, CH2Cl2; 97%
OBn
OTBS
OTHP
I
TMSO H
O
HBn OTBS
HLi+
Cl
Li
Cl
Li
1. TMS-acetylene, Pd(PPh3)2Cl2, CuI, Et2NH, rt; 79%
2. Et2AlCl, CH2Cl2, -25 °C to rt3. DMP, NaHCO3, CH2Cl2, rt; 73% (overall)
OBn
OTBS
O
TMS
H
1. MeLi, cis-1,2-dichloroethene, Et2O, 0 °C; 79% (ca. 7:1 dr)2. K2CO3, MeOH, rt; 99%3. Ac2O, Et3N, DMAP; 93%
OBn
OTBS
OAc
Cl
ClCl
HH "Me- "ClH
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
Filip Petronijevic @ Wipf Group Page 10 of 16 9/26/2010
Toward Sporolide B: Successful but not Successful Attempts
O
OMeOBnMe O
OO
OH
AcOOBn
OTBS
OAc
Cl
O
OMeOBnMe O
OO
OH
AcO
OAcCl
OBn
TBSO
Cp*RuCl(COD), DCE, 25 °C30 min; 77%
1. Ac2O, Et3N, DMAP; 81%2. HF, CH3CN, then MeOH; 50%
O
OMeOBnMe O
OHHO
OAc
OAcCl
OBn
HO
1. Ag2O, CH2Cl2, rt; 89%
2. toluene, reflux (no reaction)O
O
BnO MeO
O
OAc
MeO
OAcOH
OBn
Cl
Sporolide BX
unfavorable interaction
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350. For Ru-catalyzed cyclotrimerization, see: (c) Yamamoto, Y.; Ogawa, R.; Itoh, K. Chem.Commun. 2000, 549. (d) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2003, 125, 12143.
Filip Petronijevic @ Wipf Group Page 11 of 16 9/26/2010
OBn
O
OTHP OBn
OTBS
OTHP
TMSI
1. NaBH4, CeCl3•7H2O, MeOH, -78 °C; 99%
2. TBSCl, imidazole, DMAP, CH2Cl2, rt; 95%3. TMS-acetylene, CuI, Pd(PPh3)2Cl2, Et2NH, rt; 98%
1. Et2AlCl, CH2Cl2, -25 °C to rt; 99%
2. DMP, NaHCO3, CH2Cl2; 79%
OBn
OTBS
O
TMS
H
1. MeLi, cis-1,2-dichloroethene, Et2O, 0 °C; (ca. 5:1 dr)
2. DMP, NaHCO3; 93% (overall)3. DIBAL-H, toluene, -78 °C; 81% (ca. 7:1 dr)
OBn
OTBS
OAc
Cl
1. K2CO3, MeOH, rt; 99%
2. Ac2O, Et3N, DMAP; 98%
OBn
OTBS
OH
Cl
TMS
TMS
O
H
O OTBS
HLi+
Cl
LiCl
Li
Bn
re faceattack
si faceattack
Toward epi-Sporolide B: Synthesis of 9-epi-Chloro Enediene
(a) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
Filip Petronijevic @ Wipf Group Page 12 of 16 9/26/2010
Synthesis of 9-epi-Sporolide B: “Almost There”
(a) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
O
OMeOBnMe O
OO
OH
AcOOBn
OTBS
OAc
Cl
O
OMeOBnMe O
OO
OH
AcO
OAcCl
OBn
TBSO
Cp*RuCl(COD), DCE, 25 °C30 min; 87%
O
OMeOBnMe O
OHHO
OAc
OAcCl
OBn
HO
1. Ac2O, Et3N, DMAP; 92%2. HF, CH3CN, then MeOH; 74%
1. Ag2O, CH2Cl2 rt; 89%
2. toluene, reflux 1.5 h; 20%
40% (based on50% recovered sm)
O
O
BnO MeO
O
OAc
MeO
OAcOH OBn
Cl
O
O
BnO MeO
O
OAc
MeO
OAcOH OBn
Cl
OO
O MeO
O
OH
MeO
OH
OHOH
Cl
OHO
9-epi-sporolide B
deprotection
functionalization of the phenyl ring
Filip Petronijevic @ Wipf Group Page 13 of 16 9/26/2010
1. Ac2O, Et3N, DMAP, CH2Cl2, 0 °C; 92%
2. H2 (balloon), Pd(OH)2, EtOAc, rt; 92%O
O
BnO MeO
O
OAc
MeO
OAcOH OBn
Cl
O
O
HO MeO
O
OAc
MeO
OAc
OAcOH
Cl
OO
O MeO
O
OAc
MeO
OAc
OAcOH
Cl
PIFA, H2O, NaHCO3, CH3CN, 0 °C; 66%
OH
1. DBU, CH2Cl2:MeOH, 40 °C, 4 h; 72%
2. t-BuOOH, DBU, CH2Cl2 40 °C, 3 h; 72%O
OO MeO
O
OH
MeO
OH
OHOH
Cl
OHO
9-epi-sporolide B
9
debenzylation
dearomatization
epoxydation
Synthesis of 9-epi-Sporolide B
(a) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
Filip Petronijevic @ Wipf Group Page 14 of 16 9/26/2010
O
O
BnO MeO
O
OAc
MeO
OAcOH OBn
Cl
1. TESOTf, Et3N, CH2Cl2, 0 °C; 95%
2. H2 (balloon), Pd(OH)2, EtOAc, rt; 92%3. PIFA, PMBOH, NaHCO3, CH3CN, 0 °C; 75%
OO
O MeO
O
OAc
MeO
OAc
OTESOH
Cl
OPMB
1. DMP, CH2Cl2, rt; 90%2. HF, CH3CN, rt; 85%3. Me4NBH(OAc)3, CH3CN, AcOH, rt; 85%
OO
O MeO
O
OAc
MeO
OAcOH
Cl
OPMB
OH
1. DDQ, CH2Cl2:H2O, rt; 70%
2. DBU, CH2Cl2:MeOH, 40 °C; 78%3. t-BuOOH, DBU, CH2Cl2, 40 °C; 63%
OO
O MeO
O
OH
MeO
OHOH
OH
Cl
OHO
sporolide B
debenzylationdearomatization
TES-protection
changing thestereochemistry
at C-9
selective epoxydation
Synthesis of Sporolide B: Mission Accomplished
(a) Nicolaou, K.C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449. (b) Nicolaou, K.C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350.
Filip Petronijevic @ Wipf Group Page 15 of 16 9/26/2010
Conclusions: Total Synthesis of Sporolide B and Its Epimer in a Nutshell
• A stereocontrolled total synthesis of Sporolide B and 9-epi-Sporolide B has been achieved
• Key step: intramolecular hetero [4+2] cycloaddition of o-quinone onto tetrasubstituted alkene
• Ruthenium-catalyzed [2+2+2] cyclization (cyclotrimerization) has been used for the construction of the highly substituted chlorinated indene system
OO
O Me
OHO
O
O
OH
MeO
OHOH
OH
Cl
sporolide B
OO
O Me
OHO
O
O
OH
MeO
OHOHOH
Cl
9-epi-sporolide B
9
O
O
BnO MeO
O
OAc
MeO
OAcOH OBn
Cl
O
O
BnO MeO
O
OAc
MeO
OAcOH OBn
Cl
heating in toluene
O
OMeOBnMe O
OO
OH
AcOOBn
OTBS
OAc
Cl
O
OMeOBnMe O
OO
OH
AcO
OAcCl
OBn
TBSO
Cp*RuCl(COD), DCE, 25 °C30 min; 77%
Filip Petronijevic @ Wipf Group Page 16 of 16 9/26/2010
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