Baran Group Meeting
10/5/05
Introduction
Aphidicolin
Mila Khoroosi
Biosynthetic Pathway
Oikawa, et. al. J. Am. Chem. Soc. 2001, 123, 5154-5155.
OH
HO
OPP
OPP
D
C
A
HO
B
H
H
OH
HO
(+)-Aphidicolin
H
Major
OH
HO
H
Isolated from the fungus Cephalosporium aphidicola. Structure determined by X-ray crystallography and
chemical degradation.
+
H
Minor
First shown to be active against DNA viruses, including Herpes simplex both in vitro and in the
rabbit eye.
HO
H
OH
H
Also inhibits DNA replication and growth of several human and murine neoplastic cells, with no
discernible toxicity, but both its insolubility in water and its deactivation in vivo by liver microsomal
oxidase limited its clinical potential.
Enhanced tumor activity of the 17-glycinate HCl salt and the 16-fluoro-derivative have revived interest.
H
Known degradation (during characterization) and reconversion by the isolation group
Synthetic challenges includes 8 stereocenters, especially the two adjacent chiral quaternary centers.
OH
HO
H
HO
H
OH
Isolation: Jarvis, J. A. J.; Neidle, S.; Brundet, K. M.; Dalziel, W.; Hesp, B. J. Chem. Soc., Chem. Commun. 1972, 1027.
H
HO
H
HO
H
OH
OH
Bioactivity: (a) Bucknall, R. A; Moores, J.; Simms, R.; Hesp, B, Antimicrob. Agents Chemother. 1973, 4, 294; (b) Spadari, S.;
Focher, F.; Kuenzle, C.; Corey, E. J.; Meyers, A. G.; Hardt, N.; Rebuizzini, A.; Ciarroccho, G.; Pedrali-Noy, G. Antiviral Res.,
1985, 5, 93; (c) Pedrali-Noy, G.; Mazza, G.; Focher, F.; Spadari, S. Biochem. Biophys. Res. Commun., 1980, 93, 1094.
Some figures in this presentation were taken from: Beaver, K. An Analysis of the total Syntheses of Aphidicolin: An Evans Group
Afternoon Seminar (March 20, 1998).
16
H
(+)-Aphidicolin
For a summary of total syntheses of aphidicolane and stemodane diterpenes from the late 1970s to 199: Toyota, M.; Masataka, I.
Tetrahedron 1999, 55, 5641-5679.
OH
HO
O
Aphidicolin
(diastereomeric
mixture about C16)
Smith
Rizzo, C. J.; Smith, A. B.; Tet. Lett. 1988, 29, 2793-2796.
Rizzo, C. J.; Smith, A. B.; J. Chem. Soc. Perkin Trans. 1 1991, 969-979.
Provides enantioselective synthetic routes from the ketone resulting from the degradation of (+)-Aphidicolin.
Baran Group Meeting
10/5/05
Aphidicolin
Mila Khoroosi
First Syntheses: Trost and McMurry
Trost: A vinyl-cyclopropane rearrangement
McMurry: A Robinson Annulation
Trost, B. M.; Nishimura, Y.; Yamamoto, K.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1328-1330.
McMurry, J. E.; Andrus, A.; Ksander, G. M.; Musser, J. H.; Johnson, M. A. J. Am. Chem. Soc. 1979, 101, 1330-1332.
O
O
O
1. HOCH2CH2OH, TsOH
1. LiAli-Bu2-t-BuH, -78 °C
2. Li/NH3; TMSCl
3. MeLi; CH2O
O
2. 3 N HCl
3. Me2CO, TsOH
O
O
O
HO
LDA;
1. OsO4; NaIO4
I
O
O
O
O
OTMS
O
O
O
Trost intermediate
1. PhSeSePh
NaBH4
SPh2
O
2. NaH
O
O
2. MeC(OTMS)=NTMS
Et3N
O
O
O
1. LAH
TMSO
H
3. Li/NH3
4. MeC(OTMS)=NTMS
1.
n-BuLi,
I
O
O
360 °C
2. EtOCH=CH2
O
1. 610 °C
2. Pd(OAc)2
CHO
O
O
O
2
H
O
O
O
BH
O
O
2. H2O2, NaBH4
O
O
CH2OTs
1. LAH
OH
OH
O
O
H
O
H
O
Na2Fe(CO)4
H
2. p-TsCl, py
O
1. DHP, TsOH
2. NH2NH2, KOH
PCC; KOH
O
O
O
3. Me2CO, TsOH
4. PCC
O
O
H
O
O
O
Baran Group Meeting
10/5/05
Aphidicolin
Mila Khoroosi
Corey
Corey
Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102, 1742-1744.
S
S
S
S
Me
O-
CO2Me
O-
Br
O
NaH, (EtO)2POCl
TBSO
1. TMSCN, ZnI2
O
t-Bu
Me
2. DIBAl-H, 0 °C
Me
O
OMe
S
Me
O
H
t-Bu
O
CHO
OTMS
S
1. LiSiMe3
Me
2. LDA; H+
Me
O
H
t-Bu
O
H
O
TBSO
O
CO2Me
OP(OEt)2
1. NaBH4
2. TBSCl
3. deprotection
CO2Me
Me
O
1. Hg(OCOCF3),
MeNO2, 0 °C
Me
ClHg
2. NaCl, H2O
TBSO
CO2Me
Me
O
1. HOCH2CH2OH, TsOH
2. NaBH4
Me
4. H2, Pd/C
5. (n-Bu)4NF
2. TsCl
H
3. PDC
4. (n-Bu)4NF
5. L-Selectride
O
t-Bu
CHO
Me
H
O
O
1.
O
t-Bu
H
O
O
H
t-Bu
O
TMSS
STMS
Li
1. ketalization
2. separation
OEt
H
2. HOAc, MeOH/H2O
HO
3. deprotection
H
O
t-Bu
HO
H
O
HO
Me
HO
O
H
H
H
(±)-Stemodinone
H
(+)-Aphidicolin
Applications to other natural products
ZnI2
H
HO
OH
Me
NH • HOAc
OH
HO
(±)-Aphidicolin
2.
O
OH
O
Me
H
Me
OH
1. MVK, DBU, K2CO3
Me
LiN(t-Bu)2, -120 °C
O
HO
Me
3. PCC
4. HClO4
H2O/acetone
OTs
O
O
t-Bu
1. t-BuCHO, TsOH
2. LAH
O
Me
Me
TBSO
O
H
(±)-Stemodin
Me
H
CHO
Baran Group Meeting
10/5/05
Aphidicolin
Mila Khoroosi
van Tamelen and Bettolo
Van Tamelen: A biogenetic approach
Bettolo: [2+2] cycloaddition
van Tamelen, E. E.; Zawacky, S. R.; Russell, R. K.; Carlson, J. G. J. Am. Chem. Soc. 1983, 105, 142-143.
Bettolo, R. M.; Tagliatesta, P.; Lupi, A.; Bravetti, D. Helv. Chim. Acta 1983, 66, 1922-1928.
OMe
O
OMe
1. NBS; K2CO3
2. LiN(Et)2
O
O
1. NaH; BnBr; H3O+
1. FeCl3
3. VO(acac)2
t-BuOOH
4. NaH, BnI
2. Li/NH3
3. Me2CO, TsOH
O
OBn
2. HCO2Et, NaH
3. MVK
HO
H
O
HO
H
O
O
O
O
O
HO
O
O
O
O
H
H
H
O
O
H
BnO
H
2. O3
3. NaBH4
BnO
BnO
BnO
O
O
H
1. HOCH2CH2OH,
TsOH
•
H
1. Trisylhydrazine
2. n-BuLi
O
H
BnO
BnO
O
1. m-CPBA
1. H2, PtO2
2. Pb(OAc)4
H
O
OH
O
conditions
unclear
1. NaH, MeI, CS2
2. Na
3. MsCl, py
H
OCSSCH3
OH
H
BnO
BnO
OMs
OH
Me2CO, H2O
H
O
!
H
O
H
O
H
O
O
1. CrO3• py2
H
BnO
BnO
O
OH
Me2CO, H2O
CrO3• py2
O
BnO
OMs
O
2. MsCl, Et3N
H
BnO
O
1. !
2. NaBH4
H
BnO
BnO
H
2. Li/NH3
O
O
Baran Group Meeting
10/5/05
Aphidicolin
Mila Khoroosi
Ireland and Iwata
Iwata
Ireland
Tanaka, T.; Okuda, O.; Murakami, K.; Yoshino, H.; Mikamiyama, H.; Kanda, A.; Kim, S-W.; Iwata, C. Chem. Pharm. Bull. 1995, 43
1407-1411.
Ireland, R. E.; Dow, W. C.; Godfrey, J. D.; Thaisrivongs, S. J. Org. Chem. 1984, 49, 1001-1013.
MeO
CH2
1.
O
CH2TMS
CO2Me
H
BnO
O
OBn
OBn
O
!
O
+
TMSOTf, -78 °C
3 steps
CH2SiMe3
O
O
OMe
CO2Et
BnO
OMs
OMs
BnO
O
CH2SiMe3
O
CH2SiMe3
1. H2, Pd/C
t-BuOK
O
1. n-BuLi, i-AmONO
2. NH2Cl
O
OMs
O
2. DIBAl-H
3. Ph3P=CH2
O
BnO
+
unwanted
diastereomer
2. Separation
N2
O
O
BnO
hv
O
CH2
O
O
O
SiO2
O
O
O
O
HO
O
TMS
2. Li,
O
O
O
EO
O
1. LDA, PhSeBr;
H2O2, pyr
O
O
Br
1. PCC
HO
2. Me2CuLi
O
O
8 steps
Provides a route to another natural product
O
O
O
CH3
H
HO
CH2
H
O
H
(previous work)
p-TsOH
O
HO
H
OH
O
OH
O
O
(±)-Aphidicolin
"-Chamigrene
(±)-Aphidicolin
OH
HO
OH
HO
Baran Group Meeting
10/5/05
Aphidicolin
Mila Khoroosi
Enantioselective Syntheses
Holton: First enantioselective synthesis
Tanis: Cationic Cyclization
Holton, R. A.; Kennedy, R. M.; Kim, H.-B.; Krafft, M. E.; J. Am. Chem. Soc. 1987, 109, 1597-1600.
Tanis, S. P.; Chuang, Y.-H.; Head, D. B. J. Org. Chem. 1988, 53, 4929-4938.
1. PhCOCl
2. SeO2, TBHP
O
+
TBSO
OLi
S(O)(Tol)
O
O
-78 °C
TBSO
O
2. HF
MgCl
O
O
S(O)(Tol)
S(O)(Tol)
O
O
NaOMe
O
3. L-DIPT, Ti(Oi-Pr)4
TBHP
4. PhCH2Br, NaH
S(O)(Tol)
O
1. CH2=CHLi
OH
4. LAH
5. TBSCl, DMAP, Et3N
6. CrO3, Py
Li2CuCl4
O
BnO
O
2. MgBr2; L-Selectride
3. LAH
3. HOCH2CH2OH, TsOH
4. Li/NH3; CH2O
O
1. Me2CO, H+
2. NBS, DMF
3. nBuLi; MeI
HO
O
HO
O
O
O
O
O
OH
HO
O
Me
OTBS
O
O
t-Bu
Corey
2. H2, Pd/C
H
H
HO
O
H
OH
O
H
O
10.7 % overall
from geraniol
HO
H
OH
(+)-Aphidicolin
(+)-Aphidicolin
OH
HO
McMurry
1. m-CPBA
Me
3 steps
HO
HO
Et3N, -78 °C
O
1. (COCl)2, Et3N,
DMSO
1. KOt-Bu
2. H2, Pd/C
O
O
BnO
O
OTBS
2. n-BuLi, p-TsOH
LiCl
BF3·Et2O
O
O
CHO
O
BnO
O
Note: These first three steps can be carried out in one pot in 45 % overall yield.
1. Zn, NH4Cl
2. HOCH2CH2OH, TsOH
3. O3; DMS
1. NaOMe, MeOH
n-Bu4NI
OCOPh
Baran Group Meeting
10/5/05
Aphidicolin
Mila Khoroosi
Enantioselective Syntheses
Toyota/Fukumoto: The Heck Reaction
Toyota: Palladium-catalyzed cycloalkenylation
Fukumoto, et. al. Tetrahedron 1994, 11153.
Fukumoto, et. al. Tetrahedron 1994, 10183.
Fukumoto, et. al. Tet. Lett. 1994, 6495.
Toyota, M.; Sasaki, M.; Ihara, M. Org. Lett. 2003, 5, 1193-1195.
O
O
O
O
O
LDA, THF
Bromoacrolein
1. Pd(OAc)2, P-(o-Tolyl)3
K2CO3, MeCN, ! (90%)
Br
(89%)
MOMO
OMOM
OMOM
O
2. HOCH2CH2OH, PPTS (89%)
O
OH
O
Diastereoselection 3:1
O
O
O
O
1. O3
230 °C
15 steps
O
2. LDA,
I
H
H
MOMO
TBSO
TBSO
O
O
O
1. CH2=CHOEt,
Hg(TFA)2
O
O
1. PCC, NaOAc (92%)
2. Ph2P(O)CH2CH2=CH2
n-BuLi, HMPA
1. O2, PdCl2, CuCl (70%)
2. H2, Pd-C (82%)
3. Ph3P=CH2 (81%)
2. Toluene, !,
then NaBH4 (82%)
OH
HO
O
Ireland
Bu4NF, CH2O
H
H
HO
HO
O
HO
H
H
OH
HO
(+)-Aphidicolin
Summary
O
1. methylene blue, 230 °C
O
O
2. O2, hv, porphyrin, pyr
3. NaI, AcOH
4. MnO2 (82%)
Iwata
Me
H
O
H
HO
H
OH
Longest Linear Sequence
Overall Yield
McMurry
18 steps
0.9% yield
Trost
23 steps
0.6% yield
van Tamelen
25 steps
0.03% yield
Bettolo/Lupi
24 steps
2.9% yield
Ireland
28 steps
0.93% yield
37 steps
0.96% yield
27 steps
2% yield
40 steps
0.19% yield
25 steps
2.3% yield
OH
HO
O
O
3. KOH
4. Me2CO, PPTS
2. Pd(OAc)2
OH
O
1. L-Selectride
2. Me2S+ (O)CH2-
1. LDA; TBSCl
Corey
Tanis
(+)-Aphidicolin
Iwata
Fukumoto
Holton
28 steps
1.65% yield
H