Note

pubs.acs.org/joc

Rotamers or Diastereomers? An Overlooked NMR Solution

Dennis X. Hu, Peter Grice, and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
*
S Supporting Information

ABSTRACT: The existence of rotamers in a solution of analyte

complicates 1H NMR analysis, especially when the presence of dia-
stereomers is also possible. Organic chemists have often responded
to this problem by conducting variable-temperature (VT) NMR
experiments, changing NMR solvents, or adding complexing agents.
Here, with specific examples, we illustrate the use of simple yet widely
overlooked chemical-exchange NMR experiments which allow the
nonintrusive rapid distinguishment of rapidly equilibrating small
molecules such as rotamers from nonequilibrating diastereomers.

T he appearance by 1H NMR spectroscopy of equilibrating

species such as rotamers due to protecting groups com-
plicates the analysis of reaction products. Equilibrating species
the 1H NMR spectrum (CDCl3) of the crude reaction mixture, two
peaks at 4.59 and 4.28 ppm of equal intensities corresponding to the
HA proton in product 3 are observed.
such as rotamers are most often distinguished from nonequilib- Do these two peaks imply the existence of two rotamers due to
rating diastereomers by techniques such as variable-temperature the protecting group (3 and 3′, Figure 2) or is the product of the
(VT) NMR, solvent switching,1,2 or the introduction of a com-
plexing agent.3−5 These techniques are generally inconvenient,
especially when the analyzed substrate is precious and must be
recovered. When only qualitative information about the identity of
constituents in a sample is required, chemical-exchange NMR ex-
periments serve as far simpler alternatives. Chemical-exchange
NMR experiments such as saturation transfer have been used in
organometallic chemistry to identify isomers due to ligand
movement and in biochemistry to study protein receptor−ligand
interactions but are often ignored or forgotten by synthetic chemists.
In this paper, we illustrate the use of 1D selective chemical-exchange
NMR experiments to distinguish rotamers from diastereomers in
circumstances where the possibilities of both isomers exist. Figure 2. At first glance, the molecules present in the NMR sample may
To make clear the problem we wish to address, consider the be either rotamers 3 and 3′ or diastereomers 3 and 4.
HATU6 coupling of (R)-α-hydroxyvaline7 (1) and (R)-N-Me-Boc-
Val-OH8 (2) to give depsipeptide 3 (Figure 1). Upon inspection of reaction a complete mixture of diastereomers due to the epimeri-
zation of 2 after activation, as is very common in peptide coupling
due to oxazolone or ketene formation?9−12 Usually, the rate of
carbamate rotameric exchange is sufficiently fast and the rate of
epimerization in neutral chloroform is negligible so that we can
reduce the question of rotamers vs diastereomers to a question of
detecting the chemical exchange.13 If the proton responsible for
the peak at 4.59 ppm and the proton responsible for the peak at
4.28 ppm behave spectroscopically as if they are under chemical
exchange, then the two compounds in solution are not
diastereomers, whereas if the two protons are not under chemical
exchange, the two compounds are likely to be diastereomers. It is
possible to answer the chemical-exchange question with a 1D-
selective chemical-exchange NMR experiment without the need
for further work.
Figure 1. 1H NMR spectrum of the crude mixture resulting from the
coupling of alcohol 1 and acid 2 under standard coupling conditions to give Received: April 12, 2012
depsipeptide 3 (see the Experimental Section) (5.2−4.1 ppm region only). Published: May 17, 2012

© 2012 American Chemical Society 5198 dx.doi.org/10.1021/jo300734r | J. Org. Chem. 2012, 77, 5198−5202
The Journal of Organic Chemistry Note

Figure 3. 1D gradient NOE spectrum of crude compound 3 (see Figure 1)

with an initial selective pulse at 4.59 ppm creates a peak at 4.59 ppm as
well as a new peak of the same phase at 4.28 ppm due to rotameric
chemical exchange. In contrast, normal NOE enhancements appear in
the opposite phase from the selective pulse peak.

Figure 4. Direct comparison of an NMR sample of 3 with an NMR

sample of synthetic 4 supports the conclusion about the identity of the
two compounds in the described reaction mixture as rotamers.

A convenient method to conduct a 1D-selective chemical-

exchange experiment is to simply use the pulse sequence of the
commonly used 1D NOE difference experiment or its modern Figure 5. (a) 1H NMR spectrum of a prepared sample deliberately
counterpart, the 1D gradient NOE experiment.14,15 In a standard containing both 3 and 4. Four NMR resonances (I, II, III, and IV) are
1D NOE difference experiment, a selected resonance is first observed corresponding to protons HA and HB in 3, 4, and their
respective rotamers. (b) 1D gradient NOE spectrum after selective
treated with a long saturating pulse before a nonselective 90°
excitation of the resonance at 4.59 ppm (I) produces a single downfield
pulse is applied, leading to the disappearance of peaks in the resonance in the same phase at 4.28 ppm (III), indicating that
targeted frequency region and a slight enhancement in intensity resonances I and III belong to two rotamers of the same diastereomer
of peaks (in the small molecule fast-tumbling regime) corre- (3) and that resonances due to one diastereomer do not transfer spin
sponding to protons connected to those in the targeted fre- information via chemical exchange to the other. (c) 1D gradient NOE
quency region through space via the nuclear Overhauser effect. spectrum after selective excitation of the diastereomeric peak at 4.52
The subtraction of a previously acquired standard 1H NMR ppm (II) also produces a single downfield peak in the same phase (IV),
spectrum from the 1D NOE spectrum results in the NOE indicating that resonances II and IV belong to two rotamers of the same
difference spectrum, which will show a negative peak at the site of diastereomer (4). Only the 5.2−4.1 ppm region is shown for clarity.
irradiation and a positive peak at the sites of enhancement.16 If
the targeted peak at the site of irradiation corresponds to a negative peaks at 4.59 ppm and 4.28 ppm (see Figure 3), implying
proton under significant chemical exchange with another proton chemical exchange and thus the existence of rotamers. Comparison
on the saturation time scale, the peak corresponding to the of the spectra of an intentionally prepared diastereomer 4 with 3
second proton will also appear diminished due to saturation (Figure 4) supports this conclusion.
transfer, resulting in a second negative peak in the difference When a sample containing both diastereomers 3 and 4 (Figure 5)
spectrum. The selective refocusing of a frequency in a 1D is subject to the same experiment with a selective pulse at 4.59 ppm,
gradient NOE experiment produces the same results through a negative peak again only appears at 4.28 ppm, confirming that
inversion transfer. For our work therefore, irradiation of the peak saturation/inversion transfer does not take place between
at 4.59 ppm using either a 1D NOE difference or 1D gradient diastereomers. Thus, chemical-exchange experiments can also be
NOE experiment will result in a spectrum which shows two used to distinguish sets of rotamers in the presence of diastereomers
5199 dx.doi.org/10.1021/jo300734r | J. Org. Chem. 2012, 77, 5198−5202
The Journal of Organic Chemistry Note

so long as the excited peak is well resolved from the other

peaks.
In a second experiment to illustrate the precision of the
method, the 1H NMR spectrum of the purified product mixture
resulting from the coupling of depsipeptides 5 and 6 to give
tetradepsipeptide 7 (Figure 6) shows an even more complicated

Figure 8. Selective irradiation of peak A (see Figure 6) at 4.91 ppm in a

1D gradient NOE experiment provides a spectrum (shown) revealing
two negative peaks at frequencies 4.91 (A) and 4.85 ppm (B), but
notably no peak (C) at 4.97 ppm.

peak B to the right (downfield) at 4.85 ppm, confirming that the

appearance of peak 4.91 ppm with the first irradiation at 4.85
ppm was not due to broadness of the irradiation window. Thus,
the selective chemical-exchange NMR technique can be used to
Figure 6. 1H NMR spectrum of the column-chromatographed product identify peaks due to rotamers even in spectra in which peaks in
mixture (7) resulting from the coupling of 5 and 6 (only 5.3−4.2 ppm
question are separated by as little as 0.06 ppm at 600 MHz, as
region of interest shown). Resonances A−C are highlighted for clarity in
the following discussion. Assuming resonance B corresponds to a long as a proper control experiment is conducted.
proton in 7 or a combination of its rotamers due to its strong intensity, is In principle, selective-excitation chemical-exchange NMR experi-
resonance A, which is of low intensity relative to other peaks, due to the ments should be applicable to any scenario in which the simultaneous
presence of an impurity or does it due to a proton in one of the many possibility of interconverting compounds and the appearance of
possible rotamers of 7? new diastereomers or other nonexchanging impurities makes simple
1
H NMR analysis inconclusive as long as the exchange is slow on the
1
H NMR spectrum, even though the column fractions appear chemical shift time scale such that the relevant peaks are distinct and
homogeneous by TLC. The question is again is: is peak A due to the exchange is sufficiently fast that there is significant inversion or
a rotamer or due to a diastereomer or some other impurity? saturation transfer during the selective irradiation/mixing time.
The question as before is one of chemical exchange and can be While experiments to probe chemical exchange such as
easily addressed by a 1D-selective chemical-exchange experi- saturation-transfer NMR sequences have been known and applied
ment. Selective irradiation of peak B at 4.85 ppm (Figure 7) for many years,17 they have been largely overlooked18 by organic
chemists in common problems such as distinguishing rotamers from
diastereomers. Here, we have illustrated that selective chemical-
exchange NMR experiments are trivial, useful methods specifically
for distinguishing rapidly equilibrating rotamers from nonequilibrat-
ing diastereomers. The techniques described can also be generally
applied to other problems involving chemical exchange. We believe
application of these methods avoids the use of traditional VT-NMR
methods and greatly speeds up accurate product analyses.

■ EXPERIMENTAL SECTION
General Methods. Unless otherwise stated, all reactions were
conducted under anhydrous conditions under an atmosphere of argon.
1
H NMR spectra were collected on a 600 MHz NMR spectrometer
Figure 7. Selective irradiation of peak B (see Figure 6) at 4.85 ppm in a using the deuterated solvent as an internal deuterium lock. Chemical
1D gradient NOE experiment provides a spectrum (shown) revealing shift data are given in units δ calibrated with residual protic solvent (e.g.,
two negative peaks at frequencies 4.85 ppm (B) and 4.91 ppm (A). CHCl3 at 7.26 ppm). The multiplicity of a signal is indicated as follows:
br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doublet of doublets; dt, doublet of triplets; etc. Coupling constants (J)
results in the simultaneous appearance of an inverted peak A at are recorded to the nearest 0.1 Hz. 13C NMR spectra were collected on a
4.91 ppm. Because the saturating pulse does not have a perfect 150 MHz spectrometer with broadband proton decoupling using the
square frequency profile, however, there is the risk that the deuterated solvent as an internal deuterium lock. Chemical shift data are
appearance of peak 4.91 ppm is actually due to overlap of an given in units δ calibrated with residual protic solvent (e.g., 77.23 ppm
irradiation tail with the peak and not chemical exchange. The for 13CHCl3). The 1D gradient NOE spectra in the manuscript were
obtained on a 600 MHz spectrometer using a 100 ms Gaussian selective
selectivity of the pulse, however, can be checked by irradiation of pulse and a 1.2 s mixing time with a standard 1D gradient NOE pulse
peak A and observing its effect at the location symmetrical to the sequence.14 Only selected absorbances (νmax) are reported in the IR
location of peak B. Indeed, saturation of the peak at 4.91 ppm spectra. Optical rotations were measured with the sample temperature
(Figure 8) does not result in the appearance of the peak C to the maintained at 25 °C. [α]D is reported in units of 10−1 deg g−1 cm2.
left (upfield) at 4.97 ppm but does result in the appearance of the Concentration is quoted in units of 0.01 g cm−3.

5200 dx.doi.org/10.1021/jo300734r | J. Org. Chem. 2012, 77, 5198−5202

The Journal of Organic Chemistry Note

Synthesis of (S)-N-Butoxycarbonyl-N-methylvaline (1R)-2- Synthesis of Amine 6. To depsipeptide 3 (440 mg, 1.05 mmol) was
Methyl-1-[(phenylmethoxy)carbonyl]propyl Ester 3. To a added 2 mL of a solution of 4 M HCl in dioxane. The reaction was
solution of phenylmethyl (2R)-2-hydroxy-3-methylbutanoate 1 (2.0 g, allowed to stir overnight at room temperature before the mixture was
9.6 mmol), N-methyl-N-Boc-valine 2 (2.3 g, 1.05 equiv), and 4- concentrated in vacuo. The liquid salt was taken up in Et2O (25 mL) and
dimethylaminopyridine (2.35 g, 2.0 equiv) in DCM (29 mL, 0.33M) at washed with half-saturated aq Na2CO3 (2 × 25 mL). The aqueous layers
0 °C was added solid HATU (4.0 g, 1.1 equiv) in several small portions. were back-extracted with Et2O (2 × 25 mL) and the combined organic
The reaction mixture was allowed to stir for 4 h before dilution with layers dried over MgSO4, filtered, and concentrated in vacuo to provide
diethyl ether (100 mL) and water (50 mL). The organic layer was amine 6 which was sufficiently pure for the next step (212 mg, 65%). 1H
separated and the solution washed sequentially with 1 M aq HCl (100 NMR (400 MHz, CDCl3): 7.39−7.28 (m, 5H), 5.21 (d, 1H, J = 12.0 Hz),
mL), H2O (50 mL), and half-satd aq Na2CO3 solution (2 × 100 mL, 5.15 (d, 1H, J = 12.0 Hz), 4.91 (d, 1H, J = 4.4 Hz), 3.01 (d, 1H, J =
mixing the layers vigorously for 10 min). The organic layer was dried 6.0 Hz), 2.35 (s, 3H), 2.27 (m, 1H), 1.94 (m, 1H), 1.53 (s, 1H), 1.02−
over MgSO4, filtered, and concentrated in vacuo to afford depsipeptide 3 0.92 (m, 12H). 13C NMR (100 MHz, CDCl3): 174.9, 169.5, 135.3,
as a clean oil sufficiently pure for the next steps (2.83 g, 70% yield) and 128.5, 128.4, 76.9, 69.2, 66.9, 35.2, 31.5, 30.0, 19.2, 18.9, 18.6, 17.2. IR
immediately subjected to the NMR experiments described in the main (neat, cm−1): 2965.8, 2936.8, 2878.3, 1734.1, 1498.8, 1465.8, 1456.1,
text. An analytical sample for complete characterization was obtained by 1266.9, 1178.7, 1164.0, 1126.1, 1019.5, 749.0, 696.9. [α]25.5D: +28.2 (c =
subjection of the product to silica gel flash column chromatography (3% 2.15, CHCl3). HRMS (ESI-TOF) ([M + H+]): calcd for C18H28O4N
EtOAc in 40−60 petroleum ether). 1H NMR (600 MHz, CDCl3): 322.2013, found 322.2012.
(mixture of rotamers) 7.37−7.28 (m, 5H), 5.18 (d, 1H, J = 12.0 Hz), Synthesis of Didepsipeptide 7. To a solution of acid 5 (500 mg,
5.12 (d, 1H, J = 12.0 Hz), 4.86 (br s, 1H), 4.59 (d, 0.5H, J = 10.6 Hz), 1.5 mmol) in DCM (5 mL) at 0 °C was added Ghosez’s reagent (240 μL,
4.28 (d, 0.5H, J = 10.6 Hz), 2.88 (s, 1.5H), 2.77 (s, 1.5H), 2.25 (br m, 1.2 equiv). The solution was allowed to stir for 15 min before a solution
1H), 2.18 (br m, 1H), 1.46 (s, 9H), 1.02−0.87 (m, 24H). 13C NMR (150 of amine 6 (480 mg, 1 equiv) and diisopropylethylamine (690 μL, 2.6
MHz, CDCl3): (mixture of rotamers) 171.0, 170.7, 169.2, 169.0, 156.3, equiv) in DCM (5 mL) was added. The solution was allowed to warm to
155.6, 135.3, 135.3, 128.5, 128.4, 128.3, 80.1, 79.8 66.9, 66.8, 64.7, 63.0, room temperature overnight. The reaction mixture was diluted with
30.6, 30.0, 28.3, 27.6, 27.4, 19.9, 19.1, 18.8, 18.8, 18.8, 17.0. IR (neat, Et2O (50 mL), upon which N,N-dimethylisobutylamide crystallized out
cm−1): 2968.9, 2935.1, 2878.2, 1740.9, 1694.5, 1455.8, 1390.2, 1366.6, of solution. The mixture was washed with 1 M aq HCl solution (25 mL),
1307.4, 1258.6, 1182.8, 1146.6, 1125.4, 1024.5, 751.8, 697.1. [α]26.5D: H2O (25 mL), and half-saturated aq Na2CO3 solution (25 mL). The
−33.3 (c = 1.28, CHCl3). HRMS (ESI-TOF) ([M + Na+]): calcd for organic layer was dried over MgSO4, filtered, and concentrated in vacuo
C23H35O6NNa 444.2356, found 444.2356. to provide a clean crude product which was further purified by flash
Synthesis of (R)-N-Butoxycarbonyl-N-methylvaline (1S)-2- column chromatography (3% to 5% to 10% EtOAc/40−60 petroleum
Methyl-1-[(phenylmethoxy)carbonyl]propyl Ester 4. To a ether) to provide didepsipeptide 7 which was homogeneous by TLC
solution of phenylmethyl (2S)-2-hydroxy-3-methyl-butanoate(100 mg, analysis and subjected to the NMR experiments described in the main
0.48 mmol), N-methyl-N-Boc-valine 2 (122 mg, 1.1 equiv), and text (404 mg, 43%). 1H NMR (600 MHz, CDCl3): (mixture of
4-dimethylaminopyridine (152 mg, 2.6 equiv) in DCM (1.5 mL, 0.33 M) rotamers) 7.34−7.27 (m, 5H), 5.22−3.98 (m, 4H), 3.01−2.76 (m, 6H),
at 0 °C was added solid HATU (220 mg, 1.2 equiv) all at once. The 2.42−2.02 (m, 4H), 1.44 (s, 9H), 1.06−0.76 (m, 24H). 13C NMR (150
reaction mixture was allowed to stir for 4 h before dilution with diethyl MHz, CDCl3): (mixture of rotamers) 171.0, 170.8, 170.6, 170.3, 170.2,
ether (10 mL) and water (5 mL). The organic layer was separated, and 169.8, 169.6, 169.6, 169.4, 169.2, 168.6, 156.4, 155.7, 135.4, 135.1, 128.6,
the solution washed sequentially with 1 M aq HCl (10 mL), H2O (5 128.5, 128.4, 128.3, 80.0, 79.7, 77.5, 75.9, 75.5, 75.0, 74.9, 67.1, 66.8,
mL), and half-satd aq Na2CO3 solution (2 × 10 mL, mixing the layers 65.7, 64.9, 64.7, 63.3, 63.0, 61.7, 61.6, 31.8, 31.7, 31.0, 30.7, 30.3, 30.0,
vigorously for 10 min). The organic layer was dried over MgSO4, 29.9, 29.6, 29.4, 29.4, 28.6, 28.3, 28.3, 28.0, 27.7, 27.3, 27.3, 20.1, 19.9,
filtered, and concentrated in vacuo. The product was subjected to silica 19.6, 19.5, 19.4, 19.3, 19.1, 19.0, 18.9, 18.9, 18.8, 18.6, 17.1, 17.0, 16.9,
gel flash column chromatography (3% EtOAc in 40−60 petroleum 16.6, 16.4. IR (neat, cm−1): 2968.1, 2935.9, 2877.3, 1738.7, 1694.1,
ether) to afford depsipeptide 4 as a clean oil (158 mg, 78% yield). 1H 1668.7, 1468.4, 1390.5, 1367.3, 1238.5, 1184.3, 1147.7, 1126.5, 1020.4,
NMR (600 MHz, CDCl3): (mixture of rotamers) 7.35−7.27 (m, 5H), 881.3, 751.9, 697.7, 665.3. [α]26.5D: −45.7 (c = 2.0, CHCl3). HRMS
5.19 (d, 1H, J = 12.6 Hz), 5.12 (d, 1H, J = 12.6 Hz), 4.85 (app. S, 1H), (ESI-TOF) ([M + H+]): calcd for C34H55O9N2 635.3902, found
635.3905.

■
4.51 (d, 0.5 H, J = 9.9 Hz), 4.20 (d, 0.5H, J = 9.9 Hz), 2.83 (s, 1.5H), 2.79
(s, 1.5H), 2.30−2.12 (m, 2H), 1.44 (s, 9H), 1.06−0.82 (m, 12H). 13C
NMR (150 MHz, CDCl3): (mixture of rotamers) 171.1, 170.6, 169.2, ASSOCIATED CONTENT
156.0, 155.4, 135.3, 128.5, 128.4, 128.3, 80.2, 79.8, 77.0, 66.9, 66.8, 64.8, *
S Supporting Information
63.2, 30.7, 30.5, 30.1, 28.3, 27.6, 19.8, 19.6, 18.8, 18.8, 18.8, 18.7, 17.0. IR Full 1H and 13C spectra of new compounds. This material is
(neat, cm−1): 2968.3, 2926.2, 2878.1, 1741.7, 1695.2, 1455.8, 1390.0,
available free of charge via the Internet at http://pubs.acs.org.

■
1366.6, 1294.3, 1258.8, 1181.4, 1145.3, 1124.7, 1024.5, 935.6, 880.6,
750.5, 697.3. [α]26.5D: −70.9 (c = 1.63, CHCl3). HRMS (ESI-TOF)
([M + Na+]): calcd for C23H35O6NNa 444.2356, found 444.2364. AUTHOR INFORMATION
Synthesis of Acid 5. To a solution of depsipeptide 3 (1.4 g, 3.3 Corresponding Author
mmol) in THF (6.5 mL, 0.5 M) was carefully added Pd/C under Ar. The *E-mail: [email protected].
solution was then purged with H2 gas and allowed to stir under H2 (1
Notes
atm, balloon) overnight. The reaction mixture was then purged with Ar,
The authors declare no competing financial interest.

■
filtered over a pad of Celite over silica with EtOAc (100 mL), and
concentrated in vacuo to afford acid 4 which was sufficiently pure for the
next step (1.08 g, quantitative). 1H NMR (400 MHz, CDCl3): (mixture ACKNOWLEDGMENTS
of rotamers) 5.01 (br s, 0.66H), 4.89 (br s, 0.34H), 4.28 (d, 0.34H, J = We gratefully acknowledge financial support from the BP
9.5 Hz), 4.17 (d, 0.66H, J = 10.0 Hz), 2.91 (s, 2H), 2.86 (s, 1H), 2.30 (br Endowment (to S.V.L.) and the Winston Churchill Foundation
m, 2H), 1.46 (s, 9H), 1.08−0.90 (br m, 12H). 13C NMR (150 MHz, of the United States for a scholarship to D.X.H. We also thank
CDCl3): 173.96, 170.87, 170.65, 156.63, 155.85, 80.49, 80.33, 76.46, Dr. James Keeler and Dr. Matthew O’Brien of the Department of
66.13, 64.66, 63.49, 31.13, 30.07, 29.99, 29.95, 29.83, 28.30, 27.52, 27.45,
19.89, 19.80, 19.09, 18.87, 18.79, 17.19, 16.96, 16.88, 16.09. IR (neat,
Chemistry, Cambridge, for very helpful discussions regarding the
manuscript.

■
cm−1): 2969.7, 2935.7, 2878.6, 1741.5, 1696.4, 1657.4, 1657.4, 1469.9,
1448.7, 1392.2, 1368.6, 1309.7, 1198.5, 1149.8, 1126.6, 1022.3, 752.9.
[α]26.5D: −49.0 (c = 4.03, CHCl3). HRMS (ESI-TOF) ([M + H+]): REFERENCES
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The Journal of Organic Chemistry Note

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