the use of nmr spectroscopy for chiral discrimination · assigning absolute stereochemistry...
TRANSCRIPT
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The Use of NMR Spectroscopy for Chiral Discrimination
Thomas J. Wenzel
Department of Chemistry
Bates College
Lewiston, Maine
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2007
“Using NMR Spectroscopic Methods to Determine Enantiomeric Purity and Assign Absolute Stereochemistry,” Wenzel, T.J.; Chisholm, C.D., Progress in NMR Spectroscopy, (DOI:10.1016/j.pnmrs.2010.07.003). “Assignment of Absolute Configuration Using Chiral Reagents and NMR Spectroscopy,” Wenzel, T.J.; Chisholm, C.D., Chirality, (DOI: 10.1002/chir.20889).
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Categories of Reagents
• Chiral Derivatizing Agents
• Chiral Solvating Agents
• Metal Complexes
• Liquid Crystals
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Chiral Derivatizing Agents Raban and Mislow (1965)
• Form a covalent bond between an optically pure reagent ((S)-CDA) and the compound of interest (Sub)
(S)-CDA + (R)-Sub = (S)-CDA-(R)-Sub (S)-CDA + (S)-Sub = (S)-CDA-(S)-Sub
• Resulting compounds are diastereomers
• Signals double in NMR spectrum (Chemical Shift Anisotropy) – areas proportional to percent of each enantiomer
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Chiral Derivatizing Agents: Key Criteria if Using to Determine
Enantiomeric Excess
• No racemization
• No kinetic resolution
• Need 100% enantiomeric purity of the reagent
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Chiral Solvating Agents (Pirkle – 1966) Metal Complexes (Whitesides and Lewis – 1970)
• Form non-covalent interactions between an optically pure reagent ((S)-CSA) and the compound of interest (Sub) (S)-CSA + (R)-Sub = (S)-CSA-(R)-Sub - KR (S)-CSA + (S)-Sub = (S)-CSA-(S)-Sub - KS
• Resulting compounds are diastereomers
• KR and KS are likely different – causes different
time-averaged solvation environments
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Chiral Solvating Agents and Metal Complexes
• Mix directly in an NMR tube
• Preferable to have fast exchange – NMR spectrum is a time average of bound and unbound forms (CSA + Sub = CSA-Sub)
• High concentration of CSA usually leads to larger discrimination
• Often see enhanced enantiomeric discrimination at lower temperatures
• CSA does not need to be 100% enantiomerically pure
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Assigning Absolute Stereochemistry
• Mechanism of discrimination is understood and characteristic changes in chemical shifts occur in the spectrum
– More common with certain families of chiral derivatizing agents
– Possible with some chiral solvating agents
• Empirical trend
– Best if use known model compounds as close as possible in structural features to the unknown
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L2
O
CF3
L1
H O
Ph OMe
(OMe) (Ph) (R)-MTPA
(S)-MTPA
Mosher Method: -methoxy- -trifluoromethylphenylacetic acid - MTPA (Dale and Mosher – 1973) • Prepare derivatives with (R)- and (S)-forms of the reagent (esters of secondary alcohols) • Syn-periplanar arrangement of HC-O-C(O)-C atoms (secondary alcohols) • Calculate RS values – negative for L1, positive for L2
C COH
CH3O
F3C
O
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10
RO
8 9
Me(10) Me(8) Me(9)
MTPA 0.07 -0.017 -0.04
MPA 0.05 -0.021 -0.26
RS
RS depends on: -Extent of conformational preference/how it influences the shielding -Degree of shielding (anthryl > naphthyl > phenyl)
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2,2,2-Trifluoro-1-(9-anthryl)ethanol (TFAE) (Pirkle’s Alcohol)
HCF3C OH
Versatile chiral solvating agent -Can determine optical purity -Can assign absolute configurations for certain classes of compounds
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Absolute Configurations - TFAE
O
H
C
O
Si-propyl
CH3
C6H5
CF3 H
O
H
C
O
SCH3
i-propyl
C6H5
CF3 H
(R, R) (R, S)
Sulfoxides
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Metal Complexes: Expand Coordination Number or Displace
Ligand (Donor/Acceptor Association)
• Lanthanides – Hard Lewis bases
– Nitrogen- and Oxygen-containing compounds
• Platinum, Palladium, Rhodium and Silver – Soft Lewis bases
– Alkenes, alkynes, aromatics, phosphorus-containing, sulfur-containing, alkyl halides
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Liquid Crystals Sackmann, Meiboom, Snyder (1968)
• Forms ordered material in a magnetic field
• Pair of enantiomers have different molecular orientations in the liquid crystal
• Three discrimination mechanisms
– Chemical shift anisotropy (least useful)
– Different dipolar coupling constants (1H-13C)
– Differences in quadrupolar splitting (2H) (most useful)
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Quadrupolar Splitting • Not observed in solution because of rapid
tumbling
• Observed in ordered media and extent of splitting depends on orientation relative to the applied magnetic field
2-2H-Propionic Acid Proton-decoupled deuterium NMR spectrum
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Poly( -benzyl-L-glutamate) – (PBLG) Incredible Versatility
• Only need different packing orders
• Do not need specific interactions between the substrate and the liquid crystal
• Effective for virtually any class of compound – Includes aliphatic hydrocarbons
• Especially effective for resonances of nuclei remote to the chiral center
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Deuterium Labeling
• Only need deuterium as a signal – better to use achiral reagents so no concern about kinetic resolution or racemization
– Convert -CO2H to -CO2CD3
– Add perdeutero benzoyl group (have o-, m- and p-protons as potential probes)
• Provides a single, strong signal (or a few easily assigned signals) for the analysis
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Crown Ethers
(18-crown-6)-2,3,11,12-tetracarboxylic acid
O
O
O
OO
O
HOOC
COOHHOOC
COOH
(1)
Commercially Available
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Association of Primary Amines
Wenzel, T. J.; Freeman, B. E.; Sek, D. C.; Zopf, J. J.; Nakamura, T.; Yongzhu, J.; Hirose, K.; Tobe, Y, Analytical and Bioanalytical Chemistry, 2004, 378, 1536-1547. Wenzel, T. J.; Thurston, J. E., Tetrahedron Letters, 2000, 41, 3769-3772. Wenzel, T. J.; Thurston, J. E., Journal of Organic Chemistry, 2000, 65, 1243-1248.
N
HH
O
O
O
O
COOH
COOHO
O
HOOC
HOOC
R
H
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Wenzel, T.J.; Bourne, C.E.; Clark, R.L., Tetrahedron: Asymmetry, 2009, 20, 2052-2060. Chisholm, C.D.; Fülöp, F.; Forró, E.; Wenzel, T.J., Tetrehedron: Asymmetry, 2010, 21, 2289-2294.
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Association of Secondary Amines
O
O
O
OO
O
H H
N
HOOC
HOOC COOH
O
O
R R'
In methanol
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The C-methyl and N-methyl resonances (400 MHz) of (a) 3 (10 mM) with increasing concentrations of 1 (0, 5, and 10 mM), (b) the hydrochloride salt of 3 (10 mM) with increasing concentrations of 1 (0, 20, and 40 mM), and (c) 3 (10 mM) with increasing concentrations of L-tartaric acid (0,5, and 10 mM)
Lovely, A.E.; Wenzel, T.J., Organic Letters, 2006, 8, 2823-2826.
NH
Dimethylbenzylamine
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NH
COOH
1H NMR spectrum (400 MHz) of the methine resonance of 8 (10 mM) in methanol-d4 with 1 at (b) 5 mM, (c) 10 mM, (d) 15 mM, (e) 20 mM, (f) 30 mM, (g) 40 mM.
Lovely, A.E.; Wenzel, T.J., Organic Letters, 2006, 8, 2823-2826.
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Pyrrolidines
NH
NH
NH
NH2
O
(11)(10) (12)
NH HO
NH
HO
NH
(2) (3) (4)
NH
HN
OH
NH
NH
NH2
(5) (6)
(7)
NH
O
NH
OH
(8) (9)
1 2
3
4
5
6
1 2
34
5
6
7
89
1
2 3
45
6 7
8
9
10
11
12 13
14
1
2 3
4
5
6
7
8
12
3
4
5
6
Lovely, A.E.; Wenzel, T.J., Tetrahedron Asymmetry, 2006, 17, 2642-48
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NH
HO
0.068
0.025
0.041
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(2) (3)
(4) (5)
(6)
NH
0.052 NH
0.015
0.2040.215
NH
OH
0.1910.253 NH
0.208
NH
N
0.1490.149
0.053
0.0330.062
NH
O
O
0.37
0.44
0.59
0.65
0.35
0.15
0.14
0.21
0.12
0.31
0.55
0.20
0.14
0.43
0.36 0.08
0.03
0.33
0.11
0.42
0.29
0.62
0.340.18
0.59
0.11
0.03
0.04
0.09
0.04
NH
OH
NH
OHNH
NH2
O
NH
OH
O
NH
OH
O
(7) (8)
(9) (10)
(11) (12)
NH
HN
(13) (14)
(15) (16)
0.048(0.120)
0.298 0.055
0.116
0.054
0.058
0.108
NH
N
NH
HN
NH
N
Piperidines and Piperazines
Lovely, A.E.; Wenzel, T.J., Journal of Organic Chemistry, 2006, 71, 9178-82.
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N
N
NHO
OH
N
O
N
OH
NOH
NO
ON
O
O
1514
19
16 17
18 2120
1
2
3
4
5
6 7
8
9
1
2
34
56 7 8
12
3
4
4
1
2 3
3
12
34
5
6
7
8
8
12
3
4
56
6 12
3
4
412
3
4
4
Tertiary Amines
1H – Discrimination usually small 13C – Baseline discrimination
Lovely, A.E.; Wenzel, T.J., Chirality, 2008, 20, 370-378
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Cyclodextrins
• Cyclic oligosaccharides
• Glucose units
– 6 –
– 7 –
– 8 –
• Water-soluble
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Carboxymethylated Cyclodextrins Synthetic Schemes
Dignam, C.F.; Randall, L.A.; Blacken, R.D.; Cunningham, P.R.; Lester, S.-K.G.; Brown, M.J.; French, S.C.; Aniagyei, S.E.; Wenzel, T.J., Tetrahedron Asymmetry, 2006, 17, 1199-1208. Wenzel, T. J.; Amonoo, E. P.; Shariff, S. S.; Aniagyei, S. E., Tetrahedron: Asymmetry, 2003, 14, 3099-3104. Smith, K. J.; Wilcox, J. D.; Mirick, G. E.; Wacker, L. S.; Ryan, N. S.; Vensel, D. A.; Readling, R.; Domush, H. L.; Amonoo, E. P.; Shariff, S. S.; Wenzel, T. J., Chirality, 2003, 15, S150-S158.
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Degree of CM Substitution
2-position 6-position Indiscriminate
-CD 3 2 7
-CD 4 1 9
-CD 4.5 2 8
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1H NMR (400 MHz, D2O) of (a) 10 mM chlorpheniramine with 10 mM (b) -CD, (c) -CDCM-Ind, (d) -CDCM-2 and (e) -CDCM-6.
7.47.67.88.08.28.4 ppm
H4’ H6’ H3’
H5’
(e)
(d)
(c)
(b)
(a)
N
CCH2CH2NH(CH3)2H
Cl
2
3
3'
4'
5'
6'
+
Native
Indiscriminate
2-position
6-position -CDCM
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1H NMR (400 MHz, D2O) of (a) 10 mM chlorpheniramine with 10 mM (b) β -CD, (c) β -CDCM-Ind, (d) β -CDCM-2 and (e) β -CDCM-6. Impurities marked by “x”
7.47.67.88.08.28.48.6 ppm
H6’
X
X
H4’ H3’
(e)
(d)
(c)
(b)
(a)
N
CCH2CH2NH(CH3)2H
Cl
2
3
3'
4'
5'
6'
+
Native
Indiscriminate
2-position
6-position β -CDCM
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-methylphenethyl- amine HCl (10 mM)
-CM-CD-Ind (20 mM) Yb(III) – (2-8 mM)
K.A. Provencher, T.J. Wenzel, Tetrahedron Asymmetry, 2008, 19, 1797-1803 Provencher, K.A.; Weber, M.A.; Randall, L.A.; Cunningham, P.R.; Dignam, C.F.; Wenzel, T.J., Chirality, 2010, 22, 336-346.
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Cationic Cyclodextrins
C.D. Chisholm, T.J. Wenzel, Tetrahedron Asymmetry, in press
DS = 0.7, 1.1, 1.5, 3.0 DS = 1.5 the best
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6.456.506.556.606.656.706.756.806.856.906.957.007.05 ppm2.62.72.82.93.03.13.23.33.4 ppm
Tyrosine with -CD-GTAC
1H NMR (400 MHz, D2O) (a) 10 mM tyrosine (L>D), with (b) 10 mM native α-CD, (c) 20 mM native α-CD, (d) 10 mM α-CD GTAC (DS = 1.5), and (e) 20 mM α-CD GTAC (DS = 1.5).
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Synthesis of Calix[4]resorcinarenes
Yanagihara, R.; Tominaga, M.; Aoyama, Y. J. Org. Chem., 1994, 59, 6865-6867. Dignam, C. F.; Zopf, J. J.; Richards, C. J.; Wenzel, T. J., Journal of Organic Chemistry, 2005, 70, 8071-8078. Dignam, C. F.; Richards, C. J.; Zopf, J. J.; Wacker, L. S.; Wenzel, T. J., Organic Letters, 2005, 7, 1773-1776.
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SCR-Pro
OH
OH
OHHO
HO
HO
HO OH
RR
R R
H H
HH
N
CO
O
NC
O
O
N
C O
O
NC
O
O
H
H
H
H
R =
H2
CCH2
SO3-
Water-soluble
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10 mM substrate with 2, 4, 6, 8, and 10 mM SCR-Pro
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Geometries of Complexes
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Association Constants
(R)-
enantiomer
(S)-enantiomer
1-Phenylethylamine HCl 68 97
1-(1-naphthyl)ethylamine HCl
361 595
Propranolol HCl 258 482
Tryptophan methyl ester HCl 59 113
Sodium tryptophan 67 40
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1H NMR spectra (400 MHz, D2O) of doxylamine (10 mM), (a) at 23° C, (b) with SCR-Pro (2 mM) at 23° C, (c) with SCR-Pro (40 mM) at 23° C and (d) with SCR-Pro (40 mM) at 50° C.
6.57.07.58.08.5 ppm
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Other Calix[4]resorcinarene Derivatives
NH
S-MOP
OCH3
NH
CH2OH
PyrMOH
NH
bis-MOP
OCH3CH3O
C.M. O’Farrell, J.M. Chudomel, J.M. Collins, D.F. Dignam, T.J. Wenzel, Journal of Organic Chemistry, 2008, 73, 2843-2851. C.M. O’Farrell, T.J. Wenzel, Tetrahedron Asymmetry, 2008, 19, 1790-1796. C.M. O’Farrell, K.A. Hagan, T.J. Wenzel, Chirality, 2009, 21, 911-921. Hagan,K.A.; O’Farrell, C.M.; Wenzel, T.J., European Journal of Organic Chemistry, 2009, 4825-4832.
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OH
NH
2-tert-butylamino-1-phenylethanol (10 mM) with 6, 8, and 10 mM of SCR-t4L
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Our Latest Calix[4]resorcinarene Systems
-methyl-L-proline ( MP)
L-pipecolinic acid (LPA)
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6.87.07.27.4 ppm
(c)
(b)
(a)
(a) 2/3-(S), 1/3-(R) (10 mM) (b) t3L (30 mM) (c) MP (30 mM)
6.66.87.07.27.4 ppm
(c)
(b)
(a)
(a) 2/3-L, 1/3-D (10 mM) (b) c4L (10 mM) (c) MP (8 mM)
N.H. Pham, T.J. Wenzel, Journal of Organic Chemistry, submitted.
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1.21.41.6 ppm
(d)
(c)
(b)
(a)
(a) N-benzyl-α-methylbenzylamine (10 mM) – CH3 (b) 20 mM t3L (c) 20 mM MP (d) 15 mM LPA
5.86.06.26.46.66.87.07.27.47.67.8 ppm
(a) 20 mM LPA (b) 2/3-D, 1/3-L (10 mM)
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Special Thanks To: • Catherine Dignam • Kayla Zomlefer • Jan Collins • Alice Brechting • Celeste Morin • Rebecca Miles • Daphney Frederique • Melissa Roan • Jeff Troughton • Beth Pond • Amanda Colby • Matt Bogyo • Estelle Lebeau • Lauren Randall • Renee Blacken • Patrick Cunningham • Shawna-Kaye Lester • Monique Brown • Susie French • Stella Aniagyei • Edwin Amonoo • Sonia Shariff • Ngoc Pham • Cora Chisholm
• Kristin Smith • James Wilcox • Gudrun Mirick • Lee Wacker • Nicole Ryan • David Vensel • Ginger Readling • Hilary Domush • Jason Zopf • Chris Richards • Bailey Freeman • David Sek • Jolene Thurston • Ann Lovely • Courtney O’Farrell • Katelyn Provencher • Madeline Weber • Brad Wenzel • Katie Hagan • Thao Nguyen • Chloe Bourne • Rebecca Clark • Ryan Rollo
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And To:
• National Science Foundation
• Research Corporation
• Camille and Henry Dreyfus Foundation
• Howard Hughes Medical Institute/Bates College
• Pfizer Pharmaceutical
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THREE YEARS OF s
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Pens and pencils are chiral (right-handed) because of the writing
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Be careful what you put on a pencil!