john stephenson , christopher jones † , victor snieckus †
DESCRIPTION
Directed ortho Metalation (DoM) of 1,8-Naphthalene diethylamides: Research Towards Nerve Growth Factor Inhibitors. John Stephenson , Christopher Jones † , Victor Snieckus † † Department of Chemistry, Queen’s University, Kingston, ON, CANADA K7L 3N6. Nerve Growth Factor (NGF). - PowerPoint PPT PresentationTRANSCRIPT
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Directed Directed orthoortho Metalation (DoM) of Metalation (DoM) of
1,8-Naphthalene diethylamides:1,8-Naphthalene diethylamides:Research Towards Nerve Research Towards Nerve Growth Factor Inhibitors.Growth Factor Inhibitors.
John Stephenson, Christopher Jones†, Victor Snieckus†
†Department of Chemistry, Queen’s University, Kingston, ON, CANADA K7L 3N6
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Nerve Growth Factor (NGF)Nerve Growth Factor (NGF)
• Involved with the neuronal development in the Central Nervous System and Peripheral Nervous System.
• Nerve Growth Factor is implicated in Alzheimer’s, epilepsy, stroke and pain.
• Production of protein is stimulated in patients suffering from Arthritis pain.
• Inhibition of NGF causes reduction in pain levels.
Shamovsky, et al. J Am Chem Soc, 1999, 121, 9797-9806
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Previously Identified NGF InhibitorsPreviously Identified NGF Inhibitors
N
RO
O
O2N
R =
O
OH
NCP 205
HN
OHALE 540
N
O
O
Ar
Ar
EWG
Ar =
R1
Target Molecules
Marone, S. and Ross, G. 2000, World Patent No. WO0069829
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Mild Conditions
-78oC 0oC rtTHF or Et2O or DME
Regioselective E+ - Ar SubstComplement
Contiguous SubstitutionPatterns
FG
DMG DMG
DoM
E+
E+
DMG
E1+
E2+
DMG1
DMG2
E+
(m-DMG)
(p-DMG)
Iterative (ring - walk)
DMG1
DMG2
DMG3
(DMG2 > DMG1)
- -
---
--
-
Recent Work1. Kalinin, A.; Snieckus, V. et al. J Org Chem, 2003, 68, 59922. Chauder, B.; Snieckus, V. et al. Org Lett, 2002, 4, 815
Directed Directed orthoortho Metalation Metalation
OMe OMeRLi
Li
CO2
OMe
CO2H
Original Work1. Gilman et al. J. Am. Chem. Soc. 1939, 61, 106-109.2. Wittig et al. Chem. Ber. 1940, 73, 1197.
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DMG
E+
N-COR (R = Ot-Bu, t-Bu)
OCONEt2
O
N
Muchowski, Gschwend 1978
Snieckus, 1983
DMG
Meyers, Gschwend, 1975
CONEt2Beak, 1977
OMOM Christensen, 1975
SO2NR2Hauser, 1968
P(O)(t-Bu)2 Snieckus, 1998
CON--Cumyl
SO2N--Cumyl
OCON(Me)-Cumyl
Snieckus, 1999
DMG
Hartung, C, Snieckus, V. Modern Arene Chemistry, Wiley-VCH, Weinheim. 2002, p. 330
Directed Directed orthoortho Metalation (DoM) Reactions Metalation (DoM) Reactions in Organic Synthesisin Organic Synthesis
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Previous Work Involving 2,7-Disubstituted Previous Work Involving 2,7-Disubstituted 1,8-Naphthalene Systems1,8-Naphthalene Systems
Wuest, J. et al. Organometallics, 1996, 15, 1296
OCONEt2Et2NOCO OCONEt2Et2NOCO
tert-BuLi, THF
-95°C, TMSCl84% yield
Br2CCl487% yield
TMSTMS
OCONEt2Et2NOCO
BrBr
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Steric Interference With 1,8-Steric Interference With 1,8-bis(bis(diethylamide)diethylamide)Naphthalene SystemNaphthalene System
OONN
OO
1
TMSTMS <N
O
N
O
2
TMSTMS
X-ray structure of 2,7-bis(TMS)shows steric interference fromdiethylamide groups
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Previous Examples of DoM Chemistry Previous Examples of DoM Chemistry of Naphthalene 1,8-bis(diethylamide)of Naphthalene 1,8-bis(diethylamide)
1. sec-BuLi /TMEDA/ THF
-78°C 2. Electrophile
Et2NOC CONEt2Et2NOC CONEt2
EE
E+ E Equiv % Yield
4.4 50%
2.2 40%
Snieckus, V.; Jones, C., 2003, unpublished results.
(CH3)2N
H
O
H
O
Si(CH3)3Cl Si(CH3)3
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New Examples of DoM Chemistry New Examples of DoM Chemistry of Naphthalene 1,8-bis(diethylamide)of Naphthalene 1,8-bis(diethylamide)
E+ E Equiv % Yield
2.2 75%
4.4 86%
Snieckus, V.; Jones, C.; Stephenson, J., 2003, unpublished results.
MeS S
Me
CF3CH2I
SMe
I
1. sec-BuLi /TMEDA/ THF
-78°C 2. Electrophile
Et2NOC CONEt2Et2NOC CONEt2
EE
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Bromo Ipso-DesilylationBromo Ipso-Desilylation
Snieckus, V.; Jones, C.; Stephenson, J., 2003, unpublished results.
1. sec-BuLi /TMEDA/
THF / -78°C 2. (iPrO)3B3. NH4Cl(aq)/pinacol
Et2NOC CONEt2
BrBrEt2NOC CONEt2
BBO
OO
O
Metal-Halogen ExchangeMetal-Halogen Exchange
Br2/CH2Cl2
Reflux78% yield
Et2NOC CONEt2
TMSTMS
Et2NOC CONEt2
BrBr
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Research with Sulfonamide AnalogsResearch with Sulfonamide Analogs
1. NaNO2, H2SO4
2. SO2, Fe2+
NH2 SO3H HO3S SO2H
Cu2+, O2
HO3S SO3H
Desire to build a larger library of 2,7-substituted 1,8-naphthalene derivatives.
NH2 SO3H
NH S
1. (Boc)2O/THF
2. PCl5/DCM3. NHEt2/NEt3/DCM
N
O
OO
O
Research direction for New Year
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AcknowledgementsAcknowledgements
• Dr. Victor Snieckus• Chris Jones• Snieckus Group