“Click” Chemistry, a New Approach to Familiar Reactions · “Click” Chemistry, a New...
Transcript of “Click” Chemistry, a New Approach to Familiar Reactions · “Click” Chemistry, a New...
“Click” Chemistry, a New Approach to Familiar Reactions
Andrea MolengraftJanuary 26, 2005
“Click” Chemistry?
• As defined by K. B. Sharpless
– “‘Click’ chemistry…a set of powerful, virtually 100% reliable, selective reactions for the rapid synthesis of new compounds via heteroatom links (C-X-C)…Click chemistry is integral now to all research within theSharpless Lab.”
Borman, S. C & En. 2002, 80(6), 29.
“Click” Chemistry?• “Strategy for the rapid and efficient assembly of molecules with
diverse functionality…enabled by a few nearly perfect reactions, it guarantees reliable synthesis of the desired products in high yield and purity…”
– Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. Olson, A.; Fokin, V.; Sharpless, B.; Wong, H. Chem. Bio. Chem. 2003, 4, 1246.
• “Designing powerful and selective reactions for an efficient synthesis of interesting compounds and combinatorial librariesthrough heteroatom links…” The Huisgen 1,3-dipolar cycloaddition of azides and alkynes is regarded as the ‘cream of the crop’ of concerted reactions…”
– Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753.
• “Synthetic appeal…high yields, simple reaction conditions, tolerance of oxygen and water, and simple product isolation...”
– Helms, B.; Mynar, J; Hawker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126, 15020.
Classes of “Click” Reactions
• Nucleophilic opening of highly strained rings– SN2 ring opening reactions– Epoxides, aziridines, cyclic sulfates, cyclic sulfamidates, aziridinium
ions
• “Protecting Group” Reactions– Reversible carbonyl chemistry– Acetals, ketals and their aza-analogs
• Cycloaddition Reactions– Hetero Diels-Alder, 1,3 dipolar cycloadditions involving heteroatoms
R
N3
R
N NN
R'
R'
R
N NNR'
H
H
H
+
1,4 triazole 1,5 triazole
+
Kolb, H.; Finn, M.; Sharpless, B. Angew. Chem. Int. Ed. 2001, 40, 2004.
Applications of Triazoles
• Agricultural– Fungicides– Herbicides– Antimicrobial
• Medicinal– Cytostatic– Virostatic– Antiinflamatory
• Industrial– Photostabilizers– Fluorescent whiteners– Optical brightening agents– Corrosion retardants
• Macromolecules– Drug delivery– Nanoscale electronics– Oligonucleotides
Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
Huisgen’s [1,3] Dipolar Cycloaddition
• Cycloaddition between azides and acetylenes to formtriazoles
R
N N N
R
N NN
R'
R'
R
N NNR'H
H
∆
H
R
NN
NR'
HR
NN
NH
R'
+
1,4 triazole 1,5 triazole
+
1 2
34
1 2
34
5
1:1
1 2 3
12
3
4
12 3
or
5
5
45
Huisgen, R. 1984. 1,3-dipolar cycloaddition- Introduction, survey, mechanism. In: Padwa, A.; ed. 1,3-dipolar Cycloaddition Chemistry (Vol. 1). Wiley. P. 1-176.
Regioselectivity of “Click” Chemistry
• Addition of Cu(I)-catalyst– “the champion “click” process…”
• Alkyne activation
Rostovtsev, V., Green, L., Fokin, V. Sharpless. B. Angew. Chem Int. Ed. 2002, 41, 2596. Li, Z.; Seo, T.; Ju, J. Tetrahedron. Lett. 2004, 45, 3143.
R
N N N
R
N NNR'
R'
H
H+
1,4 triazole
1 2 34
5 1 2
34
5[Cu]
Proposed catalytic cycle for Cu(I)-catalyzed ligation
Rostovtsev, V.; Green, L.;Fokin, V;Sharpless. B. Angew. Chem Int. Ed. 2002, 41, 2596.Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
NN
N
R1
R2
NN
N
R1
R2CuLn
CuLn
NR2 CuLnR1
N N NR2
NN
NCuLn
R1
R1 HR1
III
III
IV
NN
[CuLn]+DirectStepwise
V 1,4 triazoleR2
Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, 2596.
Regioselectivity using Cu(I)
NN
N NNN
O
H
CuSO4 H2O (1mol%) Na ascorbate (5mol%) H2O: tBuOH (2:1), r.t., 8 hr
O H
91 %
+
12
3
45
1,4 substituted triazole
Cu catalyzed:
NN
N
O
H
neat, 92oC, 18 h
+NN
N
O H
12
3
45
NNN
HO
12
34
5
(1,4) (1,5)1.6 : 1
+
Thermal:
12
3
12
3
45
45
Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, 2596.
Functional Group ToleranceNN
N PhO
O
NNN Ph
NNN Ph
OH
NN
N
Ph
NNN
NN
N NH
SO2NH2
NNN
NNN
OH
OOPh
NNN OH
Ph
NNN N
PhO
O
NNN
PhNEt2
NN N
OH
HO
HONNN
Ph
NHHN
NH2
NH
NH2HN
OHHO OH
H
H
H
R
NN
N
R'
H
92 %
93%
82%
84 %
91 %
88 %
88 %
84 %
88 %
90 %
94 %
4
+
[0.25-0.5] M
CuSO4 (1mol%)Na ascorbate (10 mol%)H2O: tBuOH12-24 hr.
12
3
5
Regioselectivity of “Click” Chemistry
• Addition of Cu(I)-catalyst– “the champion “click” process…”
• Alkyne activation
Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, 2596. Li, Z.; Seo, T.; Ju, J. Tetrahedron Lett. 2004, 45, 3143.
R
N N N
R
N NNR'
R'
H
H+
1,4 triazole
1 2 34
5 1 2
34
5[Cu]
Li, Z.; Seo, T.; Ju, J. Tetrahedron Lett. 2004, 45, 3143.
Regioselectivity by Alkyne Activation
N3EtO
O
R' O
NNN
EtO
O
EtO
OEt
OO
NNN
EtO
O 94%
82%
NNN
EtO
O
OEt
O
NNN
EtO
OOMe
O
O SO
O
67%
+ H2O, rt, 6-12 h
OR''O
90%
85%
N/A
N/A
no [Cu] CuCl (0.1eq.), 1 h
81%
“Click” Applications in Macromolecules
• Dendrimer Synthesis
• Solid Support Chemistry– SPOS– SPPS
• DNA functionalization
Dendrimer Synthesis
Divergent-Growth
Convergent-Growth
Tomalia, I. Polymer J. 1985, 17, 117.Frechet, J.; Hawker, C. J. Amer. Chem. Soc. 1990, 112, 7638.
Dendrimer Synthesis
Wu, P.; Feldman, A.; Nugent, A.; Hawker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V.Angew. Chem. Int. Ed. 2004, 43, 3928.
RN
NX
Cl
NN
NR
X
Cl
NNN
R NN
NR
X
N3
NNN
R
X
Cl
N
+ 1. CuSO4 (5 mol %) Na ascorbate (10 mol %) H2O/tBuOH (1:1)
2. 1.5 equiv NaN3, acetone/H2O (4:1) 60oC, 1-3 h
[G-1]
2 equiv.+
3rd Generation [G-3]
1st Generation [G-1]
NN
N
X
N3
NNN
NN
NR
XNNN
RNN
NR
XNNN
R
NN
N
X
N3
NNN
2nd Generation [G-2]
NN
N
XNNN
NN
NR
XNNN
RNN
NR
XNNN
R
NN
N
XNNN
NN
NR
XNNN
RNN
NR
XNNN
R
1. CuSO4 (5 mol %) Na ascorbate (10 mol %) H2O/tBuOH (1:1)2. 1.5 equiv NaN3, acetone/H2O (4:1) 60oC, 1-3 h
> 95%
> 90%
Dendrimer Synthesis
ClO
O
NCl
O
Cl
SN
OO
N3HO
N3
O
ButO NH
N3
O
N3HO
N3O
ON3
Azides:
Alkynes:
OO
O
O
O
O
N
N
O O
OO
N
N
N
O
OO
branching "cores"
Central "cores"
Dendrimer Synthesis
• 4th generation dendrimer synthesis
Wu, P.; Feldman, A.; Nugent, A.; Hawker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V.Angew. Chem. Int. Ed. 2004, 43, 3928.
N3 NCl
O
N
N
N
O
OO
NN
N
X
N3
NNN
NN
N
XNNN
NN
NR
X
NNN
RNN
NR
XNNN
R
NN
N
XNNN
NN
NR
XNNN
RNN
NR
X
NNN
R
+
3rd Generation [G-3]
Cu(I)r.t., 30 h
Wu, P.; Feldman, A.; Nugent, A.; Hawker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V.Angew. Chem. Int. Ed. 2004, 43, 3928.
92 % yield
NN NO
N NN
ON
NN
N
O
N
NN
NO
N
N NN
NO
NNN
NNN
NN
N
NNN
NN N
O N
N NN
O
N
NNN
N
O
N NNN
N N
NNN
N NN
OO
NNN
O
NN
N NO
N
N NN
O
N
NNN
N
O
N NN
NN N
NNN
N NN
NNN
ONN
N N
ON NNN
NO
NNN
NNN
N NN
NN
N
NNN O
N
NNN
ONN
N N
ON
NNN
NO
NNN
NNN
N NN
NN
N
NN
N
O
N
NNN
ON
NN N
NO
NNN
NN
N
NN
N
NNN
Dendronized linear polymers
• Three main pathways– I “grafting-to”
– II “grafting-from”
– III incorporate dendrons into the monomer
Helms, B.; Mynar,J; Hawker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126, 15020.
+
Ochiai, B.; Tomalia, I.; Endo, T. Macromol. Chem. Phys. 2001, 202, 3099.Helms, B.; Mynar, J.; Hawker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126, 15020.
Dendronized linear polymers
BrTMS
H TMS TMS
KOH, H2OTHF, MeOH
H
H
OO
N3O
O
N NN
+AIBN60oC, 24 h
n nPd/Cl2(PPh3)2CuI, Et3N
poly vinylacetylene(PV acet)
+
1st generation dendrimer
CuSO4 5H2O (5 mol %) Na ascorbate (10 mol %)1:1 THF/H2O
n n
PV acet
Quantitative yield
“Click” Applications in Macromolecules
• Dendrimer Synthesis
• Solid Support Chemistry– SPOS– SPPS
• DNA functionalization
“Click” Chemistry Using a Solid Support
• Solid Phase Organic Synthesis (SPOS)
• Solid Phase Peptide Synthesis (SPPS)
N3
Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753.
SPOS: Solid Phase Organic Synthesis
NH2 HO2C
CHOAr N
H
CHOAr
O
N3
CHOAr
NCHO
Ar
N N
+
+
BAL Resin:
"Click" Resin
SPOS: Library of Tertiary Amines
Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.
N3
NN N
O
OO
O
ArCHO
NN N
ArCHO
= polystyrene
(Backbone Amide Linker)
(Regenerative Michael Acceptor)
Library of amides
Library of tertiary amines
"click"
"click"
REM
BAL
Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.
SPOS: Library of Tertiary Amines• Triazolylmethyl acrylate (TMA) Resin
Cl N3 NN N
O
O
NN N
O
ON
BnCl
Cl N
O
O
NaN3, DMSO, 70oC, 48 h CuI,DMF, THF,DIPEA
35oC, 10 h
benzylmethylamineDMFrt, 16 h
1. DMSO, rt, 16h2. TEA, DMF,rt, 16 h
TMA Resin
Cl
ClBr
68%
+TMA Resin
66%
• Parallel synthesis: TMA & REM Resins
47 (>90)53 (91)p-NitrobenzylN-Phenyl-piperazinee
75 (>90)79 (93)AllylN-Phenyl-piperazined
73 (>90)75 (92)CH2CO2MeTetrahydro-isochinolinec
63 (>90)77 (92)p-NitrobenzylTetrahydro-isochinolineb
88 (>90)82 (95)AllylTetrahydro-isochinolinea
REMyield (purity)
TMA yield (purity)
R’’NRR’
Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.
NN N
O
O
O
O
NH
tetrahydro-isochinoline
NHN
N-phenyl piperazine
NN N
O
O
NN N
O
O
NRR'H-NRR' NRR'R''1. R''Br2. cleavage
a-eTMA Resin
SPOS: Selective Receptor Ligands
Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753.
N3 ArCHO
NN N
ArCHO
= polystyrene
SPOS by BAL
Library of lead amides
"click"
CHO
O
R
R'N
N N
N
CHO
NN N
FAMT FIMT
FAMT: Formyl Aryloxy Methyl Triazole
FIMT: Formyl Indole Methyl Triazole
Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753.
SPOS: Selective Receptor Ligands
CHO
R'
R
OH
CHO
O
R
R'
CHO
O
R
R'N
N N
N3
N
N
N
CHO N
CHO
NN N
Br
Br
DMF, K2CO3,70oC, 24 h
THF, DIPEA,CuI35oC, 16 h
1. THF, rt to 60oC, 1 h2. NaOH, H2O rt, 0.5 h
FAMT
FIMT
+
+ THF, DIPEA,CuI35oC, 16 h
Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753.
SPOS: Selective Receptor Ligands
O
CHOO
a
CHOO
b
OCHO
c
O
OO
O
CHOO
O
d
O
CHO
e
O
O
6 (>95) 67 (>95)9 (>95)94 (>95)9 (>95)
f
94 (>95)
N
CHO
Yield (purity) of g
CHO
O
R
R'N
N N
N
CHO
NN N
NN N
ArN
NBn
OS
HN
NBn
OS
f
1. 4-amino-1-benzylpiperdine, Na(OAc)3BH2. benzothiophene-2-carboxylic acid DIC, HOAt, DIPEA, DMF, rt, 16 h
TFA (2% in CH2Cl2)rt, 2 h
a-e
g
Preparation of Amide Library using FIMT Resins
74% (99%)
60% (99%)
90% (99%)
60% (97%)
A5
72% (95%)
53% (96%)
90% (96%)
53% (90%)
A4
78% (95%)
93% (93%)
93% (93%)
58% (90%)
A3
74% (91%)
88% (97%)
91% (98%)
50% (77%)
A2
73% (85%)
90% (94%)
92% (94%)
55% (85%)
A1B4B3B2B1
50-93 % yield77-99 % purity
N N
CN
NEt N
N
N N S
MeO
OMe
R =
R' =A1 A2 A3 A4 A5
B1 B2 B3 B4
N
CHO
NN N
N NN
N
N
R'
R
O
R' NH
RO1. A(1-5)-NH2, Na(OAc)2BH,
CH2Cl2, rt, 16 h2. B(1-4)-CO2H, TFFH, DIPEA, DMF, rt, 24 h
TFA (2% in CH2Cl2)rt, 16 h
f
“Click” Applications in Macromolecules
• Dendrimer Synthesis
• Solid Support Chemistry– SPOS– SPPS
• DNA functionalization
Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
SPPS: Cu(I) catalysis on Solid Support
FGFG
O
FmocHN
FGFG
O
FGFG=Phe-Gly-Phe-Gly = HMBA-PEGA800
CHCNCH2Cl2 THF tolueneN,N-dimethylformamide N-ethyldiisopropylamine
Solvents:
Quantitative conversions & purities: 75-95%
Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
SPPS: Cu(I) catalysis on Solid Support
All conversions > 95%*
FGFG
OFmocHN
FGFG
OFmocHN
NN N
ROH
1. R-N3, DIPEA,Cu(I) 20% piperidine/DMF2. 0.1 M NaOH (aq)
a-e
FGFG=Phe-Gly-Phe-Gly = HMBA-PEGA800
H2N N3
FmocHN N3
OH
O
N3 N3SGAL
NR90% 79% 78% 75%
a b c d e
Si
SPPS:Cu(I) catalysis on Solid Support
Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
O 1. RN3DIPEA,Cu(I)2. 0.1M NaOH (aq.)
FGFG
O
NN N
HO
O OH
> 95% conversion> 75-95 % purity
OH
O
N3
OH
O
OH
O
OH
ON3
N3
OH
O
N3
OH
O
N3N3OH
ON3
OH
O
N3
OH
ON3
NH2N3
N3
NH2
NH2N3
SN3
N3
93 % 90 %
84 %HN
NH
NH2
NH2N3
OH
O
N3
75 %
95 %
NR
Si N3
SPPS: Cu(I) catalysis on Solid Support
• Peptide Protecting Group Compatibility
88Arg(Pmc)90Asn(Trt)
> 95Trp(Boc)> 95Asp (tBu)
> 95Lys(Boc)> 95Tyr (tBu)
85Met> 95Thr(tBu)
81Cys(Trt)> 95Pro
80His(Trt)> 95Ala
% purityXxx% purityXxx
Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
> 95% conversion
Triphenylmethyl (Trt)
O
O
t-Butyloxycarbonyl (Boc)
OSO
O
2,2,5,7,8-pentamethyl-chroman-6-sulphonyl (Pmc)
O1.
DIPEA,Cu(I)2. 0.1M NaOH (aq.)
Xxx FG
OHN3
O
O
Xxx FG OHNN N
HO
O
Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
SPPS: Cu(I) catalysis on Solid Support
• Scale Up
NH
HN
O
O
O
O
HN
OPh
H2N
NN N
NH
HN
OH
HO
O
O
O
O
Ph
NN N
NH
HN
OH
O
O
OPh
N3
HON3
DIPEA,CuI0.1M NaOH (aq)
DIPEA,CuI0.1M NaOH (aq)
79% 87%
O
“Click” Applications in Macromolecules
• Dendrimer Synthesis
• Solid Support Chemistry– SPOS– SPPS
• DNA functionalization
“Click” Chemistry in Biology
• Construction of fluorescent oligonucleotides for DNA sequencing
• Biological Inhibitors
• In-situ “Click” approach
DNA Sequencing
• Modified Oligonucleotides• Introducing additional functional groups
in DNA– Staudinger reaction
– Limitations: aqueous conditions required hydrolyze intermediate aza-ylide
Seo, T.; Li, Z.; Ruparel H.; Ju J. J. Org Chem. 2003, 68, 609.Saxon, E.; Bertozzi C. Science, 2002, 287, 2007.
R3P: N3 R' R3P N R' H2O H2N R'OP
R3+ +
Seo, T.; Li, Z.; Ruparel H.; J. Org Chem. 2003, 68, 609.
DNA Sequencing
• Fluorescent ss DNA sequencing
Br OEt
O
N3 OH
O
N3 O
ON
O
O
HNN3
O
H2N
GTT TTC CCA GTC ACG ACG-3'
GTT TTC CCA GTC ACG ACG-3'
EDC, CH2Cl2
96%
Azide labeled DNA
1. NaN3, DMSO2. NaOH, MeOH, H2O3. HCl
OO NHO
DNA Sequencing
Seo, T.; Li, Z.; Ruparel H.; J. Org Chem. 2003, 68, 609.
HNN3
O
O O
ON
O
OO
OH
HO2C H2N
O O
HN
O
OH
O2C
O O
ONH
O
OH
O2C
NN N N
H
OO O
ONH
O
OH
O2C
NN
N NH
O
GTT TTC CCA GTC ACG ACG-3'
+
DMSO/ H2O80'C, 72 h
GTT TTC CCA GTC ACG ACG-3'
GTT TTC CCA GTC ACG ACG-3'
+
DMFNaHCO3
91%
Biological Inhibitors
Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. Olson, A.; Fokin, V.; Sharpless, B.; Wong, H. Chem. Bio. Chem. 2003, 4, 1246.
• HIV-1 protease (HIV-1 PR)
OHN
O
O
OHN
O
NOH
SO
O
O
OHN
O
OH
N3 OHN
O
OH
N3O
NaN3, EtOH/H2O 60oC, 2 h
1. 4 N HCl/dioxane2. (S)-3-tetrahydrofuranyl N-oxysuccinimidyl carbonate, Et3N
1. 4 N HCl/dioxane2. TfN3, H2O/CH2Cl2/MeOH, rt.
1. i-BuNH2, MeOH2. p-methoxybenenesulfonyl chloride,K2CO3, CH3CN, 3 h.
83%
76%
N3 NOH
SO
O
O
Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. Olson, A.; Fokin, V.; Sharpless, B.; Wong, H. Chem. Bio. Chem.2003, 4, 1246.
Biological Inhibitors
OH
NH
OO
R=
HN
O
NH
Boc
HN O
OO
0N H
N
O
1 2
3 4
17 +/- 139 +/- 1G48V
52 +/- 246 +/- 2V82A
24 +/- 119 +/- 1V82F
13 +/- 0.56 +/- 0.5HIV PR
21Enzyme
IC50 [nM]
N3 NOH
SO
O
O
OHN
O
OH
N3O O
HN
O
OH
NON N
R
N N
OHSO
O
O
NNR
R H
R H
1.H2O,tBuOH (1:1) Cu+/Cu++
1.H2O,tBuOH (1:1) Cu+/Cu++
In Situ “Click” Chemistry
PERFECT FIT Model of acetylcholinesterase inhibitor.
Lewis, W.; Green, L.; Grynszpan, F.; Radic, Z.; Carlier, P.; Taylor, P.; Finn, M.; Sharpless, B. Angew chemie. Int. Ed, 2002, 41, 1054.
In-Situ “Click” Chemistry
Lewis, W.; Green, L.; Grynszpan, F.; Radic, Z.; Carlier, P.; Taylor, P.; Finn, M.; Sharpless, B. Angew chemie. Int. Ed, 2002, 41, 1054.
N
HNN3
HCl
N
HN
HCl
NN3
H2N NH2
N
H2N NH2
H
H
n
1 (n=2-6)
3 (n=1-3) 4 (m=6-8)
2 (m=2-6)
m
nm
• Enzyme Templating– Inhibitor for acetylcholinesterase
80oC6 days
N
H2N NH2
NN
N
NH
N
N
H2N NH2
NN
N
NH
N
(1,5) (1,4)
Why “Click” Chemistry?
• Functional group tolerance• Aqueous conditions• Shorter reaction time• High yield• High purity• Regiospecificity
Acknowledgments
• Dr. Jackson• Dr. Borhan• Dr. Odom• Jackson & Miller Research Group