A Unified Strategy to ent-Kauranoid Natural Products: Total Syntheses of ���
(–)-Trichorabdal A and (–)-Longikaurin E
John T. S. Yeoman, Victor W. Mak, and Sarah E. Reisman. J. Am. Chem. Soc. 2013, 135, 11764.
Kara George Rosenker Wipf Group - Current Literature
24 August 2013
MeH
OHMe
O
O
O
OH(–)-trichorabdal A
MeH
Me
O
OAcOOH
OH
(–)-longikaurin E
MeH
TBSOMe
O O
Kara Rosenker @ Wipf Group Page 1 of 15 8/24/2013
The ent-Kaurenes (Diterpenoids)
H
H
ent-kaurene
• Isodon species have a long tradi1on in Chinese folk medicine for their cura1ve proper1es
• Over 600 known Isodon diterpenoids (mainly ent-‐kaurenoids) • Classified into 11 groups and 5 subgroups based on the
different oxygena1on and cleavage paEerns • Many of these compounds exhibit potent an1bacterial, an1-‐
inflammatory, and an1cancer proper1es
Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673. Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach. 3rd ed.; Wiley: Great Britain, 2008.
ent-kaurene
H
H
(–)-copalyl diphosphate
H
H
OPPOPP
geranylgeranyl diphosphate(GGDP)
CPS KS
Kara Rosenker @ Wipf Group Page 2 of 15 8/24/2013
H
H
ent-kaurene
The ent-Kaurenes (Diterpenoids)
MeH
MeO O
OAcHO
maoecrystal Z
OH
O
OMe
HO
MeMe O
O
maoecrystal V
Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673.
MeH
OH O
O
O
OHtrichorabdal A (R = H)
trichorabdal B (R= OAc)
MeH
Me
O
OAcOOH
OH
longikaurin E
MeH
OHO O
O
O
OHR
shikodonin
• Isodon species have a long tradi1on in Chinese folk medicine for their cura1ve proper1es
• Over 600 known Isodon diterpenoids (mainly ent-‐kaurenoids) • Classified into 11 groups and 5 subgroups based on the
different oxygena1on and cleavage paEerns • Many of these compounds exhibit potent an1bacterial, an1-‐
inflammatory, and an1cancer proper1es
Kara Rosenker @ Wipf Group Page 3 of 15 8/24/2013
H
H
ent-kaurene
• (–)-‐Longikaurin E was isolated in 1981 from Rabdosia longituba - In vitro growth inhibi1on against 5 human cancer cells lines
(IC50s < 10 µM; HL-‐60, SMMC-‐7721, A-‐549, MCF-‐7, SW-‐480) • (–)-‐Trichorabdal A was isolated in 1981 from Rabdosia
trichocarpa - Potent in vivo an1tumor ac1vity, IC50 = 548 nM (HeLa cells) - Modest an1bacterial ac1vity against H. pylori
The ent-Kaurenoids: (–)-Trichorabdal A and (–)-Longikaurin E
1
2
34
5
67
8
9
10
11
1213
14
15
16
17
18 19
20
MeH
OHMe
O
O
O
OH(–)-trichorabdal A
O
H
6,7-seco-ent-kaurene
OR7
20
6
8910
5
Fujita, E.; Fuji, K.; Sai, M.; Node, M.; Watson, W. H.; Zabel, V. J. Chem. Soc. Chem. Commun. 1981, 899.; Fuji, K.; Node, M.; Sai, M.; Fujita, Takeda, S.; Unemi, N. Chem. Pharm. Bull. 1989, 37, 1472.; Kadota, S.; Basnet, P.; Ishii, E.; Tamura, T.; Namba, T. Zbl. Bakt. 1997, 286, 63. Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles 1981, 16, 227.Zhao, W.; Pu, J.-X.; Du, X.; Su, J.; Li, X.-N.; Yang, J.-H.; Xue, Y.-B.; Li, Y.; Xiao, W.-L.; Sun, H.-D. J. Nat. Prod. 2011, 74, 1213.
MeH
Me
O
OAcOOH
OH
(–)-longikaurin EH
H
OOHO
R
R
6
7
20
7,20-epoxy-ent-kaurane
510 8
9
Kara Rosenker @ Wipf Group Page 4 of 15 8/24/2013
Synthesis of 6,7-seco-ent-Karanoids
• In 1986 Mander and co-workers reported a 33-step synthesis of 15-desoxyeffusin
Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Letters 1986, 27, 3923. Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Letters 1986, 27, 3927.
O OMe
EtO2CH O
MeO OMe
CO2H 11 steps
H
H O
OO
O
3 steps
O
H O
O
O
MOM MOM MOM8 steps
O
H
OO HH
H
OHO
OHAcO 15-desoxyeffusin
6,7-seco-ent-kaurene7,20-epoxy-ent-kaurane
6
7
20
AcO
MeH
OH O
OAcO15
15-desoxyeffusin
H5IO610 steps
Kara Rosenker @ Wipf Group Page 5 of 15 8/24/2013
Synthesis of 6,7-seco-ent-Karanoids
• 12 years later this group completed a 29-step semisynthesis of longirabdolactone
Adamson, G.; Mander, L. N. Aust. J. Chem. 2003, 56, 805.
OHH
CO2HHHO
O
OC
gibberellic acid(commercial)
OHH
OHH
CO
O
CHO
KH
H
H
OO
CO
OMe
H
OOO O86%
O
H
O
MeO2C
O HH
H
OHO
OO 6,7-seco-ent-kaurene
7,20-epoxy-ent-kauranes
6
7
20
76
MeH
OO O
O
O
longirabdolactone
MeH
OHO O O
3 steps 4 steps
Kara Rosenker @ Wipf Group Page 6 of 15 8/24/2013
Total Synthesis of (–)-Maoecrystal Z
MeH
OMe O O
H
O HH
MeH
MeO O
OHHO
SmI2, LiBrt-BuOH
THF, -78 °C
54%
MeH
OMe O O
H
OH
2 rings4 stereogenic centers
SmIII
(–)-maoecrystal Z
Cha, J. Y.; Yeoman, J. R. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. Szostak, M.; Procter, D. J. Angew. Chem. Int. Ed. 2012, 51, 9238.
MeH
MeO O
OAcHO
(–)-maoecrystal Z
OH
– TiIII-mediated reductive epoxide coupling– SmII-mediated reductive cascade cyclization
• First total synthesis of maoecrystal Z was reported in 2011 by Reisman and co-workers – 12 steps from (–)-γ-cyclogeraniol
OTBSMeMe
2 steps fromγ-cyclogeraniol
MeH
TBSOMe
O O
O Cp2TiCl2, Zn0
2,4,6-collidine⋅HClTHF, 23 °C
74%
CO2CH2CF3
MeH
TBSOMe
OCH2CF3
O
O TiIV
single diastereomer
Kara Rosenker @ Wipf Group Page 7 of 15 8/24/2013
A Unified Strategy to ent-Kauranoid Natural Products
MeH
OH O
O
O
OHtrichorabdal A (R = H)
trichorabdal B (R= OAc)
MeH
Me
O
OAcOOH
OH
longikaurin E
MeH
OHO O
O
O
OHR
shikodonin
MeH
MeO O
OAcHO
maoecrystal Z
OH
O
OMe
HO
MeMe O
O
maoecrystal V
OTBSMeMe
2 steps fromγ-cyclogeraniol
O MeH
TBSOMe
O O
Cha, J. Y.; Yeoman, J. R. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
Kara Rosenker @ Wipf Group Page 8 of 15 8/24/2013
Title Paper: Retrosynthetic Design for ���Trichorabdal A and Longikaurin E
Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
MeH
Me
O
OAcOOH
OH
(–)-longikaurin E
MeH
TBSOMe
O
O OR
MeH
OHMe
O
O
O
OH(–)-trichorabdal A
Sm-mediatedreductivecyclization
Pd-mediatedoxidativecyclization Me
H
TBSOMe O ORO
SiR'3
MeH
TBSOMe O O
H
O HMe
H
TBSOMe O O
TBSO
OHMeMe
Sm-mediatedreductivecyclization
intermediate in the synthesis of maoecrystal Z
(–)- γ-cyclogeraniol
Kara Rosenker @ Wipf Group Page 9 of 15 8/24/2013
Synthesis of Common Intermediate
OHMeMe
(–)- γ-cyclogeraniol
OTBSMeMe
O
3:1 anti:syn
1. TBSCl, imidazole CH2Cl2
2. m-CPBA, NaHCO3 CH2Cl2
91% (2 steps)
Cp2TiCl2, Zn0
2,4,6-collidine⋅HClTHF, 23 °C
CO2CH2CF3
MeH
TBSOMe
OCH2CF3
O
O TiIV
Cha, J. Y.; Yeoman, J. R. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
NMe
OTBS
OPh
Me
OHNMe
OPh
Me
OHHO
O PivCl, NEt3
THF; then (R,R)-pseudoephedrine
82%
I OTBS
LDA, LiClTHF
1. BH3⋅NH3 LDA, THF
2. I2, PPh3, im. CH2Cl2
85% (2 steps)92%
A
O
TBSO
OTBSO
MeMe
MeH
TBSOMe
O O74%
single diastereomer
TBSO
ILHMDS, 4:1 THF/HMPA
0 to 23 °C
63%intermediate in the synthesis
of maoecrystal Z
A
Kara Rosenker @ Wipf Group Page 10 of 15 8/24/2013
Synthesis of Oxidative Cyclization Substrate
MeH
TBSOMe O OMOMO
TBS
KHMDSTBSCl, DMPU
THF, -78 °C
85%
Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
O
TBSO
OTBSO
MeMe
O
O
OTBSO
MeMe
1. n-Bu4NHSO4 p-TsOH MeOH, 0 °C
2. DMP, DCM77% (2 steps)
SmI2, LiBrt-BuOH
THF, -78 °C
57%
MeH
TBSOMe O O
O
H H
SmIII
MeH
TBSOMe O O
MOMO
H
HMOMCl
n-Bu4NI, DIPEA
DMF, 45 °C
91%
MeH
TBSOMe O O
HO
H
HMe
H
TBSOMe O O
H
O SmIII
single diastereomer
Kara Rosenker @ Wipf Group Page 11 of 15 8/24/2013
Reaction Optimization: ��� Pd-Mediated Oxidative Cyclization
MeH
TBSOMe O OMOMO
TBS
MeH
TBSOMe
O
O OMOM
PdII
DMSO, 45 °Cair
• Little difference observed when the reaction was conducted under an air or oxygen atmosphere
• Entry 3 conducted in MeCN gives lower yield and increased side product formation
• All other solvents tested gave only trace quantities of product (toluene, glyme, dioxane, t-BuOH, DMF)
Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
entry Pd source addi/ve yield (%)
1 Pd(OAc)2 (0.1) – 7
2 Pd(OAc)2 (1.0) – 35
3 Pd(OAc)2 (1.0) – 28*
4 Pd(TFA)2 (1.0) – 19
5 PdCl2 (1.0) AgBF4 (2.0) 5
6 PdCl2 (1.0) – 0
7 Pd(OAc)2 (1.0) H2O (5.0) 38
8 Pd(OAc)2 (1.0) K2CO3 (5.0) 0
9 Pd(OAc)2 (1.0) AcOH (0.5) 56
10 Pd(OAc)2 (0.1) AcOH (0.5) 7
11 Pd(OAc)2 (1.0) AcOH (1.0) 31
12 Pd(OAc)2 (1.0) p-‐TsOH (0.5) 46
13 Pd(OAc)2 (1.0) BzOH (0.5) 32
14 Pd(OAc)2 (1.0) PivOH (0.5) 40
First example of a Pd-mediated oxidative cyclization of a silyl ketene
acetal to generate an all-carbon quaternary center
Kara Rosenker @ Wipf Group Page 12 of 15 8/24/2013
Total Synthesis of (–)-Trichorabdal A
MeH
TBSOMe
O
O OMOM
O3, DCM-94 °C;
then PPh3
69%
MeH
TBSOMe
O
O
O
OMOM
MeH
TBSOMe
O
O
O
OMOM
Me2NCH2NMe2Ac2O
DMF, 95 °C
82%
MeH
OHMe
O
O
O
OH(–)-trichorabdal A
1. 6 M aq. HCl dioxane, 45 °C
2. TEMPO, PhI(OAc)2 DCM
73% (2 steps)
15 steps from (–)-γ-cyclogeraniol
Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
Kara Rosenker @ Wipf Group Page 13 of 15 8/24/2013
Total Synthesis of (–)-Longikaurin E
MeH
TBSOMe
O
O OMOM
6 M aq. HCl
dioxane, 45 °C
89%
MeH
HOMe
O
O OH
1. TEMPO PhI(OAc)2
2. Ac2O DMAP58% (2 steps)
MeH
OMe
O
O OAcH
MeH
MeOAcOOH
OH MeH
Me
O
OAcOOH
OH
(–)-longikaurin E
SmI2
THF, 23 °C
55%(75% BRSM)
1. O3, DCM, -94 °C; then PPh3
2. Me2NCH2NMe2 Ac2O, DMF, 95 °C
44% (2 steps)
17 steps from (–)-γ-cyclogeraniol
Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
Kara Rosenker @ Wipf Group Page 14 of 15 8/24/2013
Conclusions and Outlook
• A unified synthetic strategy has been applied to the first total syntheses of (–)-trichorabdal A and (–)-lonikaurin E – 15 and 17 steps, respectively from (–)-γ-cyclogeraniol
• PdII-mediated oxidative cyclization reaction was employed to generate the an all-carbon quaternary center and build the bicyclo[3.2.1]octane core
• Three architecturally distinct ent-kauranoids were prepared from a common spirolactone intermediate
MeH
OHMe
O
O
O
OH(–)-trichorabdal A
MeH
Me
O
OAcOOH
OH
(–)-longikaurin E
MeH
MeO O
OAcHO
(–)-maoecrystal Z
OH
O
TBSO
OTBSO
MeMe
Kara Rosenker @ Wipf Group Page 15 of 15 8/24/2013