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Total Synthesis of Coralloidolides A, B, C, and E
Kimbrough, T. J.; Roethle, P. A.; Mayer, P.; Trauner, D. Angew. Chem. Int. Ed. 2010, 49, 2619-2621
O
O
H
O
O
O
O
O
Coralloidolide A
OH
OH
OH
Coralloidolide B
O
H
O
O
Coralloidolide E
O O
O
O
O
Coralloidolide C
O
HO
O
O
H
O
Rubifolide
Melissa Sprachman Current Literature April 24, 2010
Melissa Sprachman @ Wipf Group Page 1 of 14 4/26/2010
Furanocembranoids and Related Compounds
O
O
O
(furano)cembrane skeleton
O
O
Opseudopterane skeleton
O
O
Ogersolane skeleton
Members of these classes are isolated from gorgonian corals; most are isolated from the Caribbean, but the coralloidolides were isolated from Alcyonium coralloides (by Pietra et al.), a Mediterranean Organism.
The coralloidolides are furanocembranes with the common structural feature of the 14-membered carbocyclic core.
Other common structural motifs of the furanocembranes are the furan and butenolide moeities; the coralloidolides feature these moeities intact (coralloidolide A) or further oxidized or hydrated.
Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298-317. D’Abrosio, M.; Fabbri, D.; Guerriero, A.; Pietra, F. Helv. Chim. Acta 1989, 70, 63-70.
http://en.wikipedia.org/wiki/Gorgonian
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“Regular” Furanocembranoids
Copied from Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298-317.
Melissa Sprachman @ Wipf Group Page 3 of 14 4/26/2010
“Oxidized” Furanocembranoids
Copied from Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298-317.
Melissa Sprachman @ Wipf Group Page 4 of 14 4/26/2010
“Furanocembranoid derivatives with complex polycyclic carbon skeletons”
Copied from Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298-317.
Melissa Sprachman @ Wipf Group Page 5 of 14 4/26/2010
Cembrane Biosynthesis and Proposals
OPP
-OPP H -H+
[O]O
O
H
O
R
R = H: RubifolideR = OH: Bipinnatin J
geranylgeranyl diphosphate
RodrÍguez, A. D.; Shi, J.-G. J. Org. Chem. 1998, 63, 420-421.
O
O
H
O
OH
O
O
H
O
[O]
h!O
O
O
OH
H
1. m-CPBA2. Ac2O, pyr, DMAP81% (2 steps)
3.
NH
DMSO, 150 oC
26%
40%
[1,3]
[5 + 2]
OHO
H
OO
kallolide A
intricarene
Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901-5904.
Also: Tang, B.; Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 6401-6404.
Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298-317.
m-CPBA88%
O
H
O
O O
isoepilophodione B
Melissa Sprachman @ Wipf Group Page 6 of 14 4/26/2010
Synthesis of Bipinnatin J
I
OH
1. Dess-Martin reagent2.
ICO2Et
OHOH
5% RuCp(MeCN)3PF6
CSA, THF/Me2CO
I
O
O
O
Ph3PH
O
I
O
O
CH2Cl271%
I
O
O
OH
OMe3SnO
Pd(PPh3)4, CuICsF, DMF
O
O
OH
O
O
92%
Ph3P, NBS (87%)
CrCl2, NiCl2 4 Å MSTHF (59%}
CO2EtLDA, THF
66% (2 steps(racemic)
I
OH CO2Et
OH52%
OH
NaBH4
99%
O
O
H
O
OH
O
On-BuLi
MeONHMe OLi
OLi
NOMe
Me3SnCl
then aq. NH4Cl OMe3Sn
O
Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345-347.
Melissa Sprachman @ Wipf Group Page 7 of 14 4/26/2010
Enantioselective Synthesis of Bipinnatin J
I
OH
1. Dess-Martin reagent2.
Li TMS
3. Dess-Martin reagentI
O
TMS
(S)-alpine borane
ITMS
OH
55% (4 steps)92% ee
1. K2CO3, MeOH2.TESOTf, lutidine
3. LiHMDS, ClCO2Et4. HF, H2O, MeCN I
CO2Et
OH
85% (4 steps)
OH
5% RuCp(MeCN)3PF6
CSA, THF/Me2CO52% I
O
O
O
Ph3POEt
O
I
O
O
EtO2C
CH2Cl284%
1. DIBAL-H2. PDC3. NaBH4
70% (3 steps)
I
O
O
OH
OMe3SnO
Pd(PPh3)4, CuICsF, DMF
O
O
OH
O
O
92%
Ph3P, NBS (87%) O
O
H
O
OH
CrCl2, 4 Å MSTHF (72%}
88% ee
Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901-5904.
Melissa Sprachman @ Wipf Group Page 8 of 14 4/26/2010
Other Approaches to Bipinnatin J
Br
SeO2, t-BuOOH
67%Br
HO
1. MOMCl, DIPEA, 91%
2. NaI, acetone, quant. I
MOMO O
OLi
THF/HMPA, 72%O
O
OMOM
1. LDA, PhSeCl, 86%O
O
OMOM2. H2O2, THF, 82%
LDA, TBSCl
quant.O
OTBS
OMOM
I
Br
AgO2CCF3
60%
O
O
OMOMI
Huang, Q.; Rawal, V. H. 2006, 8, 543-545.
Enantioselective route:
OOH
1. TMSn-BuLi, BF3•OEt2
2. K2CO3, MeOH/THF
97% (2 steps)
OH
OH
1. Cp2ZrCl2AlMe3, CH2Cl2reflux 3d
then I2, THF,
-30 oC to 0 oC
OH
OH
I
TsCl, ACN
48% (2 steps)
I
O1.
2. K2CO3, MeOH73%
MeO2C
SePh
OTBS
NaHMDS, THF,
-78 oC
then
I
OOTBS
OH
I
CO2Me
SePh
60%
BF3•OEt2
1. PTSA, CH2Cl2, rt
2. H2O2, THF
3. PPTS (cat), CH2Cl2/MeOH
62% (3 steps)
O
OI
OH
Common intermediate in Trauner's racemic synthesis (Rawal reported the correspondingracemic MOM ether)
(5 steps from commercialmaterial; 2 steps from reported material)
Tang, B.; Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 6401-6404.
Melissa Sprachman @ Wipf Group Page 9 of 14 4/26/2010
Synthesis of the Coralloidolides
Kimbrough, T. J.; Roethle, P. A.; Mayer, P.; Trauner, D. Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
O
O
H
O
rubifolide
O
O
H
O
bipinnatin J
OH
CF3COOH
Et3SiH
99%
H2O2, NaOH
95%
O
O
H
O
O
coralloidolide A
m-CPBA73%
O
H
O
O
coralloidolide E
O O
Sc(OTf)3•H2O
63%
O
O
O
OH
OH
OH
coralloidolide B
DBU
20%
O
O
O
coralloidolide C
O
HO
Melissa Sprachman @ Wipf Group Page 10 of 14 4/26/2010
Formation of Coralloidolide B
O
OO
O
OEO
OO
O
O
E+
H2O O
O
O
OH
OH
OH
(Not observed!high strain)
Via an oxocarbenium intermediate:
Stepwise hydrate formation followed by epoxide opening:
O
OO
O
O
H2O O
O
O
OH
OH
OH2
O
O
O
O
OH
OH
OH
coralloidolide Bconditions: Sc(OTf3) • xH2O, dioxane, rt, 3 h: 63% isolated
X-ray structure Of coralloidolide E:
Kimbrough, T. J.; Roethle, P. A.; Mayer, P.; Trauner, D. Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
Melissa Sprachman @ Wipf Group Page 11 of 14 4/26/2010
Transannular Aldol Additions
O
OO
O
O
O
H
O
O
O O
O
H
O
O
O OH
O
H
O
O
OH O
O
O
O
coralloidolide C
O
HO
O
O
O
H
O
OH
coralloidolide F
coralloidolide E
DBU
CH2Cl2, rt 12 h
20%
(not observed)
Kimbrough, T. J.; Roethle, P. A.; Mayer, P.; Trauner, D. Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
Melissa Sprachman @ Wipf Group Page 12 of 14 4/26/2010
Products from Other Aldol Attempts
O
H
O
O
O O
coralloidolide E
AcOH, rt 12 h
O
H
O
O
O O
HOAc
O
H
O
O
O O
OAc
23%
O
H
O
O
O
OAc
H2SO4
H2O, acetone26% O
H
O
O
O
OHTheauthorsspeculatethatthedouble‐bondprecursorisanaturalproductwhichexistsinorganismsthatproducecoralloidolides;theelectrophilicitywouldprecludesuccessfulisola:on.
Kimbrough, T. J.; Roethle, P. A.; Mayer, P.; Trauner, D. Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
Melissa Sprachman @ Wipf Group Page 13 of 14 4/26/2010
Summary and Outlook Trauner and coworkers have demonstrated the feasibility of preparing several coralloidolides from the common precursor rubifolide.
The nature of the transformation (oxidative and acidic conditions) support the hypothesis that rubifolide may serve as a biosynthetic precursor to the coralloidolides.
The asymmetric variant of the Trauner’s synthesis of bipinnatin J (rubifolide precursor) suffers from the need to add several additional FGI’s to install the correct stereocenters.
Is the synthesis of coralloidolide D from rubifolide also feasible?
O
O
O
OH
OH
OH
coralloidolide B
O
H
O
O
O O
coralloidolide E
O
H
O
O
coralloidolide E
O
O
H
O
O
rubifolide
[O] [O] H2O [1,3]
O
O
OH
OH
OO
O
O
O O
OH
HO
H+epoxide opening?
Melissa Sprachman @ Wipf Group Page 14 of 14 4/26/2010
