chemical and biological studies of nakiterpiosin and ...ccc.chem.pitt.edu/wipf/current...
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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
Proposed Biosynthesis and Synthetic Plan
radical chlorinationnon-heme iron halogenase
bromoetherificationvanadium-dependent bromoperoxidase
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
6
8
20
21
25
Nakiterpiosin (1)
Nazarov Cyclization
OMe
O
OPg
Cl ClMeO
Br
MeOPgO
PgO
17Carbonylative Cross-Coupling Reaction
Br
MeOPgO
PgOOTf
18Intramolecular Diels-Alder
Reaction
OMe
O
OPg
Cl ClMe
M
Vinylogous Mukaiyama Aldol Reaction
19
Retrosynthesic Analysis of Nakiterpiosin
Gao, S. et al. J. Amer. Chem. Soc. ASAP
Filip Peteronijevic @ Wipf Group Page 7 of 17 12/28/2009
Synthesis of the Electrophilic Coupling Component 30
OO
O
O
AlCl3
CH2Cl2
O O
OHO
20 21 22
NH(OMe)Me•HCl
CDI, CH2Cl2, 23 °C74%
O O
NO23
Me
OMe
2 mol %Ru-[(S,S)-TsDPEN]
HCOONa, H2O, 40 °C87% (91% ee)
O O
NOH
24
Me
OMe
CH3
MgBr
THF0 to 23 °C
84%
O O
OH25
Me
Me2AlCl
CH2Cl2-78 to -30 °C
71%
OMeO
HO 6
DMAP(2-MeO2CC6H4)SO2Cl
CH2Cl2, 0 °C100%
OMeO
OS
CO2Me
O O
26 27
20% OsO4NMO
acetoneH2O, 23 °C
89%
OMeO
OS
CO2Me
O O
28
HO
HOLiBr
acetone60 °C62%
OMeOO
O
Br
Me
Me
29
OTfMeOO
O
Br
Me
Me
30
PhNTf2KHMDS
THF, -78 °C96%
O
R1R2
OH
R1R2
2 mol %Ru-[(S,S)-TsDPEN]
HCOOH, Et3N
TsN
NH2
RuCl
Ru-[(S,S)-TsDPEN](!6-mesytilene)
Noyori reduction
O
O
HOH
H3C
H H
Diels-Alder Reaction (exo vs. endo addition)
O O
OH25
Me
R3SiCl, DMF
imidazole, 23 °C
O O
OSiR3 Me
OMeO
R3SiO
Me2AlCl
CH2Cl2-78 to -30 °C
SiR3 = TBS, 56% (dr = 4:1)SiR3 = TES, 64% (dr = 100:0)SiR3 = TIPS, 60% (dr = 100:0)
- Ts or Ns less reactive - electron-deficient sulfonate is crucial for the SN2 reaction
Gao, S. et al. J. Amer. Chem. Soc. ASAP Fujii, A. et al. J. Amer. Chem. Soc. 1996, 118, 2521.
Filip Peteronijevic @ Wipf Group Page 8 of 17 12/28/2009
Synthesis of the Eastern Hemisphere of Nakiterpiosin: Yamamoto’s pinacol-type rearrangement
BrMe
COOH BH3•THF
THF, 23 °C
BrMe
OH
31 32
PCCsilica gel
CH2Cl2, 23 °C
BrMe
CHO
33
(EtO)2P(O)CH2CO2Et
NaH, THF, 0 °C
BrMe
34
CO2Et DIBAL
CH2Cl2, 0 °C89% (4 steps)
BrMe
35
OH
15 mol %Ti(OiPr)4/(–)-DETtBuOOH, 4A MS
CH2Cl2, -20 °C98% (92% ee)
BrMe
35
OHO TBSCl
imidazole
DMF, 23 °C97%
BrMe
36
OTBSO (4-Br-2,6-t-BuC6H2O)2AlMe
CH2Cl2, -78 °CCHO
Me OTBSMe
OTBS
38
20
Sn(OTf)23-Me-2-(TIPSO)furan
CH2Cl2, -78 °C80% (90% ee)
BrBr
OH
O
Me
39
Yamamoto’s rearrangement
Gao, S. et al. J. Amer. Chem. Soc. ASAP Maruoka, K. et al. J. Amer. Chem. Soc. 1989, 111, 6431.
Filip Peteronijevic @ Wipf Group Page 9 of 17 12/28/2009
Synthesis of the Eastern Hemisphere of Nakiterpiosin: Mukaiyama Aldol
O
H
O
O
H
Me O
HAr
SitBuMe2
Sn(OTf)2
Si-OTf
O
H
O
O
H
Me O
HAr
SitBuMe2
Sn(OTf)
MeOTBS
Br
OH
O
Me
39
CHO
Me OTBS
38
20Br
OOTIPS
CH3
Sn(OTf)2CH2Cl2, -78 °C
Gao, S. et al. J. Amer. Chem. Soc. ASAP Ollevier, T. et al. J. Org. Chem. 2008, 73, 331.
Filip Peteronijevic @ Wipf Group Page 10 of 17 12/28/2009
Synthesis of the Nucleophilic Component 47: Final Steps
MeOTBS
OBr
OH
O
Me
39
L-Selectride
THF, -78 °C92%
MeOTBS
OBr
OH
O
Me
40
25
Dess-Martinperiodinane, H2O
CH2Cl2, 23 °C98%
MeOTBS
OBr
O
O
Me
41
MeOTBS
OBr
OH
O
Me
42
NaBH4EtOH
THF, -78 °C93%
TBSOTf2,6-lutidine
CH2Cl2, 40 °C93%
MeOTBS
OBr
OTBS
O
Me
43
AcOH, H2O
THF, 60 °C76%
MeOH
OBr
OTBS
O
Me
44
Dess-Martinperiodinane, H2O
CH2Cl2, 23 °C91%
Me CHO OBr
OTBS
O
Me
45
20
Me OBr
OTBS
O
Me
46
20
Cl ClCl2, Et3NP(OPh)3
CH2Cl2, -78 °C83%
45 mol %Pd(PPh3)4
Me3SnSnMe3
dioxane, 110 °C50%
Me OMe3Sn
OTBS
O
Me
47
20
Cl ClMe O
Br
OH
O
Me
Cl Cl
PPhOPhOPhO
Cl
R
OR1
Cl-
RR1
O ClPOPhPhO
PhO Cl-
RR1
O
Cl
POPhPhO
PhO
Cl-
RR1
Cl Cl
C-21 gem-dichloride formation
Gao, S. et al. J. Amer. Chem. Soc. ASAP Spaggiari, A. et al. J. Org. Chem. 2007, 72, 2216.
Filip Peteronijevic @ Wipf Group Page 11 of 17 12/28/2009
Carbonylative Cross-Coupling Reaction: Optimization on the Model System 32b
OTfMeO
O
O
Br
Me
Me
30
Me3SnMe OTBS
32b
MeOO
O
Br
Me
MeO Me OTBS
TBS-49
MeOO
OMe
MeO Me OTBS
TBS-49a
Conditions
Gao, S. et al. J. Amer. Chem. Soc. ASAP
OTfMeO
O
O
Br
Me
Me
30
Me OMe3Sn
OTBS
O
Me
47
20
Cl Cl
Filip Peteronijevic @ Wipf Group Page 12 of 17 12/28/2009
Completion of the Synthesis of Nakiterpiosin
OTfMeO
O
O
Br
Me
Me
30
Me OMe3Sn
OTBS
O
Me
47
20
Cl ClCO, CuClPd(PPh3)4
DMSO, 55 °C62%
MeOO
O
Br
Me
MeO Me
51
O
OTBS
Cl Cl
Me
O
hν (350 nm)
CH3CN, 23 °C
OMe
O
OTBS
Cl ClMeO
HH
Br
Me
6
8
20
21
25
OO
OMeMe 52
iPr2NH
MeOH, 50 °C60% (2 steps)
OMe
O
OTBS
Cl ClMeO
HH
Br
Me9OO
OMeMe 53
TFA, H2O
CH2Cl2, 23 °C
OMe
O
OTBS
Cl ClMeO
HH
Br
Me9OHO
HO54
NaIO4
acetonepH 7.4 buffer
O
OMe
O
OTBS
Cl ClMeO
HH
Br
O
HO
MeHO
55
BF3•Et2O, Et3SiH
CH2Cl2, 0 °C44% (3 steps)
O
OMe
O
OTBS
Cl ClMeO
HH
Br
O
HO
Me
56
TBAF
THF, 23 °C79%
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
Nakiterpiosin (1)
OTfMeO
O
O
Br
Me
Me
30
Me3SnMe OH
48
MeOO
O
Br
Me
MeO Me OH
49
CO, CuCl (1.5 equiv.)Pd(PPh3)4 (1.5 equiv.)
DMSO, 55 °C66%
1. hν (350 nm) CH3CN, 23 °C
2. iPr2NH, MeOH 50 °C, 60% (2 steps)
MeO
HH
Br
MeOO
OMeMe 50
OH
Photo-Nazarov Cyclization: Model Studies
Gao, S. et al. J. Amer. Chem. Soc. ASAP Leitich, J. et al. Eur. J. Org. Chem. 2001, 2719.
Filip Peteronijevic @ Wipf Group Page 13 of 17 12/28/2009
An Improved Synthesis of Nakiterpiosin: Second Generation Approach
OMeO
O
O
Br
Me
Me
29
1. TFA, H2O CH2Cl2, 23 °C2. NaIO4, acetone pH 7.4 buffer, 23 °C
3. BF3•Et2O, Et3SiH CH2Cl2, 0 °C 52% (3 steps)
O
OMe
O
OH
Cl ClMeO
HH
Br
O
HO
Me
OO
Br
O
HO
Me
10
1. TESCl, imid. CH2Cl2, 23 °C
2. KHMDS, PhNTf2 THF, -78 °C 88% (2 steps)
OOTf
Br
O
TESO
Me
57
47, TBAFTHF, 23 °Cthen CO, CuCl
Pd(PPh3)4DMSO, 55 °C62% (2 steps)
Br
O Me
58
O
OH
Cl Cl
Me
OO MeO
TESO
1. hν (350 nm) CH3CN, 23 °C2. iPr2NH, MeOH, 50 °C
3. HF•py, CH3CN, 23 °C 55% (3 steps)
Nakiterpiosin (1)
Gao, S. et al. J. Amer. Chem. Soc. ASAP
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