Filip Petronijevic Current literature December 26 th , 2009. Chemical and Biological Studies of Nakiterpiosin and Nakiterpiosinone Shuanhu Gao, Qiaoling Wang, Lily Jun-Shen Huang, Lawrence Lum and Chuo Chen J. Amer. Chem. Soc. 2009, ASAP. O O Me O OH Cl Cl Me O H H Br O HO Me 6 8 20 21 25 O Me O OH Cl Cl Me O H H Br O Me O HO Nakiterpiosin (1) Nakiterpiosinone (2) Filip Peteronijevic @ Wipf Group Page 1 of 17 12/28/2009
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Filip Petronijevic Current literature December 26th, 2009.
Chemical and Biological Studies of Nakiterpiosin and Nakiterpiosinone
Shuanhu Gao, Qiaoling Wang, Lily Jun-Shen Huang, Lawrence Lum and Chuo Chen
J. Amer. Chem. Soc. 2009, ASAP.
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
6
8
20
21
25
OMe
O
OH
Cl ClMeO
HH
Br
OMe
O
HO
Nakiterpiosin (1) Nakiterpiosinone (2)
Filip Peteronijevic @ Wipf Group Page 1 of 17 12/28/2009
C-nor-D-homosteroids: Nakiterpiosin and Nakiterpiosinone
Terpios hoshinota
http://www.flmnh.ufl.edu/reefs/guamimg/porifera/Pages/Image81.html Teruya, T. et al. Tetrahedron, 2004, 60, 6989.
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
6
8
20
21
25
Nakiterpiosin
OMe
O
OH
Cl ClMeO
HH
Br
OMe
O
HO
Nakiterpiosinone
0.4 mg 0.1 mg
30 kg
A B
C D
steroid
A B
CD
C-nor-D-homosteroid
“Both compounds inhibited the growth of P388 mouse leukemia cells with a mean Inhibitory concentration (IC50) of 10 ng/mL.”
Filip Peteronijevic @ Wipf Group Page 2 of 17 12/28/2009
C-nor-D-homosteroids: Nakiterpiosin and Nakiterpiosinone
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
6
8
20
21
25
OMe
O
OH
Cl ClMeO
HH
Br
OMe
O
HO
Nakiterpiosin (1) Nakiterpiosinone (2)
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
6
8
20
21
25
Originally Proposed Nakiterpiosin (3)
OMe
O
OH
Cl ClMeO
HH
Br
OMe
O
HO
Originally Proposed Nakiteriosinpne (4)
Teruya, T. et al. Tetrahedron, 2004, 60, 6989. Gao, S. et al. J. Amer. Chem. Soc. ASAP
O NHMe
Me
H
H
Me
HO H
H
Me
H
Cyclopamine (5)
Me
H
Me
HO HHN
Me HHO
Me
Veratramine (6)
25
2520 20
- unusual stereochemistry at C-20 and C-25 - stereochemistry at C-6 and C-20 is arguable
Filip Peteronijevic @ Wipf Group Page 3 of 17 12/28/2009
Probing the C-6 Configuration of Nakiterpiosin(one)
OMeO
Br
O
OL-Selectride
THF, -78 °C95%
OHMeO
Br
O
O
85 (6S)-7
OMeO
Br
O
O
29
L-Selectride
THF, -78 °C89%
OHMeO
Br
O
O
(6R)-8
OMeO
Br
O
O
85
TFA, H2O
DCM, 23 °C
OMeO
Br
HO
HO
85a
NaIO4
acetonepH 7.4 buffer
OMe
Br
O
OHC
OHC
85b
BF3•Et2O, Et3SiH
CH2Cl2, 0 °C58% (3 steps)
OO
Br
O
HO
Me
(6S)-9
OMeO
Br
O
O
29
TFA, H2O
DCM, 23 °C
OMeO
Br
HO
HO
29a
NaIO4
acetonepH 7.4 buffer
29b
BF3•Et2O, Et3SiH
CH2Cl2, 0 °C52% (3 steps)
OO
Br
O
HO
Me
(6S)-10
OO
Br
O
HO
Me
HO
O
O
HH
Br
O
HO
Me
6
O
O
HH
Br
O
HO
Me
6
originally proposed
revised structure
Gao, S. et al. J. Amer. Chem. Soc. ASAP
Filip Peteronijevic @ Wipf Group Page 4 of 17 12/28/2009
Investigating the Stereochemistry at C-20
Gao, S. et al. J. Amer. Chem. Soc. ASAP
OO
OH
Cl ClMe
20
21
2223
11 (syn-syn)JH20-21 = 3.3 Hz
OO
OH
Cl ClMe
20
21
2223
12 (syn-anti)JH20-21 = 3.6 Hz
OO
OH
Cl ClMe
20
21
2223
13 (anti-syn)JH20-21 = 8.4 Hz
OO
OH
Cl ClMe
20
21
2223
14 (anti-anti)JH20-21 = 10.2 Hz
OMe
O
OH
Cl Cl
20
21
25
revised stereoshemistry atC20-C22-C23 of
Nakiterpiosin(one)
OMe
O
OH
Cl Cl
20
21
25
originally proposedNakiterpiosin(one)
(JH20-21 = 10.3 (10.1) Hz)
Filip Peteronijevic @ Wipf Group Page 5 of 17 12/28/2009
Studies of the C-25 Configuration of Nakiterpiosin(one)
OMe
O
OH
Cl Cl
20
21
25
CH3
HaHb
22 23 24
OMe
O
OH
Cl Cl
20
21
25
CH3
HaHb
22 23 24
25(S)
15 (anti-anti-cis) 16 (anti-anti-cis)
Gao, S. et al. J. Amer. Chem. Soc. ASAP
Filip Peteronijevic @ Wipf Group Page 6 of 17 12/28/2009
Filip Peteronijevic @ Wipf Group Page 14 of 17 12/28/2009
Synthesis of Nakiterpiosinone
OMeO
OS
CO2Me
O O
27
KHMDS, PhNTf2
THF, -78 °C, 70%
OTfMeO
OS
CO2Me
O O
74
9-BBN, THF
then NaOH, H2O223 to 50 °C, 97%
OTfMeO
OS
CO2Me
O O
75
HO
Dess-Martinperiodinane, H2O
CH2Cl2, 23 °C
OTfMeO
OS
CO2Me
O O
76
O
LiBr2-heptanone
120 °C64% (2 steps)
OTfMeO
Br77
O
PhI(OAc)2, KOH
MeOH, 0 to 23 °C75%
OTfMeO
Br78
MeO
HO
MeO
TFA, H2O
CH2Cl2, 23 °C100%
OTfMeO
Br79
HO
O
NaBH4
THF-MeOH, -78 °C
OTfMeO
Br80
HO
HO
TESOTf2,6-lutidine
CH2Cl2, 23 °C85% (2 steps)
OTfMeO
Br81
HO
TESO47, CO, CuCl
Pd(PPh3)4
DMSO, 55 °C41%
Me OMe3Sn
OTBS
O
Me
47
20
Cl Cl
MeOHO
TESO
Br
O Me
82
O
OTBS
Cl Cl
Me
O
hν (350 nm)
CH3CN, 23 °C69%
OMe
O
OTBS
Cl ClMeO
HH
Br
Me
6
8
20
21
25
OTESO
HO 83
OMe
O
OTBS
Cl ClMeO
HH
Br
MeOTESO
O 84
Dess-Martinperiodinane, H2O
CH2Cl2, 23 °C
TBAF
THF, 23 °C82% (2 steps)
OMe
O
OTBS
Cl ClMeO
HH
Br
MeOHO
ONakiterpiosinone (2)
Gao, S. et al. J. Amer. Chem. Soc. ASAP
- Selective oxidation of C-4 hydroxyl group of 28 or 54 is not possible - C-3 epimerization of 28 lead to considerable decomposition - Oxidation of diol 28 to diketone leads to diol cleavage
Filip Peteronijevic @ Wipf Group Page 15 of 17 12/28/2009
Biological Studies of Nakiterpiosin
SHH = Sonic hedgehog DISP = Dispatched protein PTCH = Patched protein SMO = Smoothened GLI = transcription factors
Hedgehog Patway
DNA-profile of Nakiterpiosin Treated HeLa Cells
Tubulin Polymerization Assay
Gao, S. et al. J. Amer. Chem. Soc. ASAP http://en.wikipedia.org/wiki/Hedgehog_signaling_pathway Chen, J. et al. Gen. and Develop. 2002, 16, 2743.
Filip Peteronijevic @ Wipf Group Page 16 of 17 12/28/2009
Conclusions
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
6
20
21
25
OMe
O
OH
Cl ClMeO
HH
Br
OMe
O
HO
Nakiterpiosin Nakiterpiosinone
Extesive spectroscopic and synthetic analysis led to revision of previoulsy missasaigned stereochemistry
Nakiterpiosin and Nakiterpiosinone were succesfully sinthesized(the rout towards Nakiterpiosin was improved - 21 step - 5% overall yield)
Preliminary biological studies showed that Nakiterpiosin is antimitoticagent; the mechanisam is different from other well-established antimitotic agents (Taxol)
Stereochemistry at C-6 was established through Noyori asymmetric hydrogenation
Lewis acid catalyzed exo-Diels-Alder furan cycloaddition used to establish A-ringSharpless Asymmetric Epoxydation followed by Yamamoto's pinacol type rearrangement
was used to establish stereochemistry at C-20
Vinylogous Mukaiyama Aldol reaction installed C-22 and C-23 stereocenters
Carbonylative cross-coupling - Nazarov cyclization connecteded two hemispheres of Nakiterpiosin and Nakiterpiosinone
Filip Peteronijevic @ Wipf Group Page 17 of 17 12/28/2009