Rotamers or diastereomers? An overlooked NMR solution

Article abstract of DOI:10.1021/jo300734r

The existence of rotamers in a solution of analyte complicates ¹H NMR analysis, especially when the presence of diastereomers 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.

Full text of DOI:10.1021/jo300734r

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.
1
he appearance by H NMR spectroscopy of equilibrating
species such as rotamers due to protecting groups com-
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
T
plicates the analysis of reaction products. Equilibrating species
such as rotamers are most often distinguished from nonequilib-
rating diastereomers by techniques such as variable-temperature
(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.
HA proton in product 3 are observed.
Do these two peaks imply the existence of two rotamers due to
the protecting group (3 and 3′, Figure 2) or is the product of the
Figure 2. At first glance, the molecules present in the NMR sample may
be either rotamers 3 and 3′ or diastereomers 3 and 4.
To make clear the problem we wish to address, consider the
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.
1
Figure 1. H NMR spectrum of the crude mixture resulting from the
coupling of alcohol 1 and acid 2 under standard coupling conditions to give
depsipeptide 3 (see the Experimental Section) (5.2−4.1 ppm region only).
Received: April 12, 2012
Published: May 17, 2012
© 2012 American Chemical Society
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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
counterpart, the 1D gradient NOE experiment.14,15 In a standard
1D NOE difference experiment, a selected resonance is first
treated with a long saturating pulse before a nonselective 90°
pulse is applied, leading to the disappearance of peaks in the
targeted frequency region and a slight enhancement in intensity
of peaks (in the small molecule fast-tumbling regime) corre-
sponding to protons connected to those in the targeted fre-
quency region through space via the nuclear Overhauser effect.
1
Figure 5. (a) H NMR spectrum of a prepared sample deliberately
containing both 3 and 4. Four NMR resonances (I, II, III, and IV) are
observed corresponding to protons HA and HB in 3, 4, and their
respective rotamers. (b) 1D gradient NOE spectrum after selective
excitation of the resonance at 4.59 ppm (I) produces a single downfield
resonance in the same phase at 4.28 ppm (III), indicating that
resonances I and III belong to two rotamers of the same diastereomer
(3) and that resonances due to one diastereomer do not transfer spin
information via chemical exchange to the other. (c) 1D gradient NOE
spectrum after selective excitation of the diastereomeric peak at 4.52
ppm (II) also produces a single downfield peak in the same phase (IV),
indicating that resonances II and IV belong to two rotamers of the same
diastereomer (4). Only the 5.2−4.1 ppm region is shown for clarity.
1
The subtraction of a previously acquired standard H NMR
spectrum from the 1D NOE spectrum results in the NOE
difference spectrum, which will show a negative peak at the site of
irradiation and a positive peak at the sites of enhancement.16 If
the targeted peak at the site of irradiation corresponds to a
proton under significant chemical exchange with another proton
on the saturation time scale, the peak corresponding to the
second proton will also appear diminished due to saturation
transfer, resulting in a second negative peak in the difference
spectrum. The selective refocusing of a frequency in a 1D
gradient NOE experiment produces the same results through
inversion transfer. For our work therefore, irradiation of the peak
at 4.59 ppm using either a 1D NOE difference or 1D gradient
NOE experiment will result in a spectrum which shows two
negative peaks at 4.59 ppm and 4.28 ppm (see Figure 3), implying
chemical exchange and thus the existence of rotamers. Comparison
of the spectra of an intentionally prepared diastereomer 4 with 3
(Figure 4) supports this conclusion.
When a sample containing both diastereomers 3 and 4 (Figure 5)
is subject to the same experiment with a selective pulse at 4.59 ppm,
a negative peak again only appears at 4.28 ppm, confirming that
saturation/inversion transfer does not take place between
diastereomers. Thus, chemical-exchange experiments can also be
used to distinguish sets of rotamers in the presence of diastereomers
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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
identify peaks due to rotamers even in spectra in which peaks in
question are separated by as little as 0.06 ppm at 600 MHz, as
long as a proper control experiment is conducted.
Figure 6. 1H NMR spectrum of the column-chromatographed product
mixture (7) resulting from the coupling of 5 and 6 (only 5.3−4.2 ppm
region of interest shown). Resonances A−C are highlighted for clarity in
the following discussion. Assuming resonance B corresponds to a
proton in 7 or a combination of its rotamers due to its strong intensity, is
resonance A, which is of low intensity relative to other peaks, due to the
presence of an impurity or does it due to a proton in one of the many
possible rotamers of 7?
In principle, selective-excitation chemical-exchange NMR experi-
ments should be applicable to any scenario in which the simultaneous
possibility of interconverting compounds and the appearance of
new diastereomers or other nonexchanging impurities makes simple
1H NMR analysis inconclusive as long as the exchange is slow on the
chemical shift time scale such that the relevant peaks are distinct and
the exchange is sufficiently fast that there is significant inversion or
saturation transfer during the selective irradiation/mixing time.
While experiments to probe chemical exchange such as
saturation-transfer NMR sequences have been known and applied
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.
1H NMR spectrum, even though the column fractions appear
homogeneous by TLC. The question is again is: is peak A due to
a rotamer or due to a diastereomer or some other impurity?
The question as before is one of chemical exchange and can be
easily addressed by a 1D-selective chemical-exchange experi-
ment. Selective irradiation of peak B at 4.85 ppm (Figure 7)
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, all reactions were
conducted under anhydrous conditions under an atmosphere of argon.
1H NMR spectra were collected on a 600 MHz NMR spectrometer
using the deuterated solvent as an internal deuterium lock. Chemical
shift data are given in units δ calibrated with residual protic solvent (e.g.,
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)
are recorded to the nearest 0.1 Hz. 13C NMR spectra were collected on a
150 MHz spectrometer with broadband proton decoupling using the
deuterated solvent as an internal deuterium lock. Chemical shift data are
given in units δ calibrated with residual protic solvent (e.g., 77.23 ppm
for 13CHCl3). The 1D gradient NOE spectra in the manuscript were
obtained on a 600 MHz spectrometer using a 100 ms Gaussian selective
pulse and a 1.2 s mixing time with a standard 1D gradient NOE pulse
sequence.14 Only selected absorbances (νmax) are reported in the IR
spectra. Optical rotations were measured with the sample temperature
maintained at 25 °C. [α]D is reported in units of 10−1 deg g−1 cm2.
Concentration is quoted in units of 0.01 g cm−3.
Figure 7. Selective irradiation of peak B (see Figure 6) at 4.85 ppm in a
1D gradient NOE experiment provides a spectrum (shown) revealing
two negative peaks at frequencies 4.85 ppm (B) and 4.91 ppm (A).
results in the simultaneous appearance of an inverted peak A at
4.91 ppm. Because the saturating pulse does not have a perfect
square frequency profile, however, there is the risk that the
appearance of peak 4.91 ppm is actually due to overlap of an
irradiation tail with the peak and not chemical exchange. The
selectivity of the pulse, however, can be checked by irradiation of
peak A and observing its effect at the location symmetrical to the
location of peak B. Indeed, saturation of the peak at 4.91 ppm
(Figure 8) does not result in the appearance of the peak C to the
left (upfield) at 4.97 ppm but does result in the appearance of the
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Note
Synthesis of (S)-N-Butoxycarbonyl-N-methylvaline (1R)-2-
Methyl-1-[(phenylmethoxy)carbonyl]propyl Ester 3. To a
solution of phenylmethyl (2R)-2-hydroxy-3-methylbutanoate 1 (2.0 g,
9.6 mmol), N-methyl-N-Boc-valine 2 (2.3 g, 1.05 equiv), and 4-
dimethylaminopyridine (2.35 g, 2.0 equiv) in DCM (29 mL, 0.33M) at
0 °C was added solid HATU (4.0 g, 1.1 equiv) in several small portions.
The reaction mixture was allowed to stir for 4 h before dilution with
diethyl ether (100 mL) and water (50 mL). The organic layer was
separated and the solution washed sequentially with 1 M aq HCl (100
mL), H2O (50 mL), and half-satd aq Na2CO3 solution (2 × 100 mL,
mixing the layers vigorously for 10 min). The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo to afford depsipeptide 3
as a clean oil sufficiently pure for the next steps (2.83 g, 70% yield) and
immediately subjected to the NMR experiments described in the main
text. An analytical sample for complete characterization was obtained by
subjection of the product to silica gel flash column chromatography (3%
Synthesis of Amine 6. To depsipeptide 3 (440 mg, 1.05 mmol) was
added 2 mL of a solution of 4 M HCl in dioxane. The reaction was
allowed to stir overnight at room temperature before the mixture was
concentrated in vacuo. The liquid salt was taken up in Et2O (25 mL) and
washed with half-saturated aq Na2CO3 (2 × 25 mL). The aqueous layers
were back-extracted with Et2O (2 × 25 mL) and the combined organic
layers dried over MgSO4, filtered, and concentrated in vacuo to provide
amine 6 which was sufficiently pure for the next step (212 mg, 65%). 1H
NMR (400 MHz, CDCl3): 7.39−7.28 (m, 5H), 5.21 (d, 1H, J = 12.0 Hz),
5.15 (d, 1H, J = 12.0 Hz), 4.91 (d, 1H, J = 4.4 Hz), 3.01 (d, 1H, J =
6.0 Hz), 2.35 (s, 3H), 2.27 (m, 1H), 1.94 (m, 1H), 1.53 (s, 1H), 1.02−
0.92 (m, 12H). 13C NMR (100 MHz, CDCl3): 174.9, 169.5, 135.3,
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
(neat, cm−1): 2965.8, 2936.8, 2878.3, 1734.1, 1498.8, 1465.8, 1456.1,
1266.9, 1178.7, 1164.0, 1126.1, 1019.5, 749.0, 696.9. [α]25.5D: +28.2 (c =
2.15, CHCl3). HRMS (ESI-TOF) ([M + H+]): calcd for C18H28O4N
322.2013, found 322.2012.
1
EtOAc in 40−60 petroleum ether). H NMR (600 MHz, CDCl3):
Synthesis of Didepsipeptide 7. To a solution of acid 5 (500 mg,
1.5 mmol) in DCM (5 mL) at 0 °C was added Ghosez’s reagent (240 μL,
1.2 equiv). The solution was allowed to stir for 15 min before a solution
of amine 6 (480 mg, 1 equiv) and diisopropylethylamine (690 μL, 2.6
equiv) in DCM (5 mL) was added. The solution was allowed to warm to
room temperature overnight. The reaction mixture was diluted with
Et2O (50 mL), upon which N,N-dimethylisobutylamide crystallized out
of solution. The mixture was washed with 1 M aq HCl solution (25 mL),
H2O (25 mL), and half-saturated aq Na2CO3 solution (25 mL). The
organic layer was dried over MgSO4, filtered, and concentrated in vacuo
to provide a clean crude product which was further purified by flash
column chromatography (3% to 5% to 10% EtOAc/40−60 petroleum
ether) to provide didepsipeptide 7 which was homogeneous by TLC
analysis and subjected to the NMR experiments described in the main
text (404 mg, 43%). 1H NMR (600 MHz, CDCl3): (mixture of
rotamers) 7.34−7.27 (m, 5H), 5.22−3.98 (m, 4H), 3.01−2.76 (m, 6H),
2.42−2.02 (m, 4H), 1.44 (s, 9H), 1.06−0.76 (m, 24H). 13C NMR (150
MHz, CDCl3): (mixture of rotamers) 171.0, 170.8, 170.6, 170.3, 170.2,
169.8, 169.6, 169.6, 169.4, 169.2, 168.6, 156.4, 155.7, 135.4, 135.1, 128.6,
128.5, 128.4, 128.3, 80.0, 79.7, 77.5, 75.9, 75.5, 75.0, 74.9, 67.1, 66.8,
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,
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,
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,
16.6, 16.4. IR (neat, cm−1): 2968.1, 2935.9, 2877.3, 1738.7, 1694.1,
1668.7, 1468.4, 1390.5, 1367.3, 1238.5, 1184.3, 1147.7, 1126.5, 1020.4,
881.3, 751.9, 697.7, 665.3. [α]26.5D: −45.7 (c = 2.0, CHCl3). HRMS
(ESI-TOF) ([M + H+]): calcd for C34H55O9N2 635.3902, found
635.3905.
(mixture of rotamers) 7.37−7.28 (m, 5H), 5.18 (d, 1H, J = 12.0 Hz),
5.12 (d, 1H, J = 12.0 Hz), 4.86 (br s, 1H), 4.59 (d, 0.5H, J = 10.6 Hz),
4.28 (d, 0.5H, J = 10.6 Hz), 2.88 (s, 1.5H), 2.77 (s, 1.5H), 2.25 (br m,
1H), 2.18 (br m, 1H), 1.46 (s, 9H), 1.02−0.87 (m, 24H). 13C NMR (150
MHz, CDCl3): (mixture of rotamers) 171.0, 170.7, 169.2, 169.0, 156.3,
155.6, 135.3, 135.3, 128.5, 128.4, 128.3, 80.1, 79.8 66.9, 66.8, 64.7, 63.0,
30.6, 30.0, 28.3, 27.6, 27.4, 19.9, 19.1, 18.8, 18.8, 18.8, 17.0. IR (neat,
cm−1): 2968.9, 2935.1, 2878.2, 1740.9, 1694.5, 1455.8, 1390.2, 1366.6,
1307.4, 1258.6, 1182.8, 1146.6, 1125.4, 1024.5, 751.8, 697.1. [α]26.5
:
D
−33.3 (c = 1.28, CHCl3). HRMS (ESI-TOF) ([M + Na+]): calcd for
C23H35O6NNa 444.2356, found 444.2356.
Synthesis of (R)-N-Butoxycarbonyl-N-methylvaline (1S)-2-
Methyl-1-[(phenylmethoxy)carbonyl]propyl Ester 4. To a
solution of phenylmethyl (2S)-2-hydroxy-3-methyl-butanoate(100 mg,
0.48 mmol), N-methyl-N-Boc-valine 2 (122 mg, 1.1 equiv), and
4-dimethylaminopyridine (152 mg, 2.6 equiv) in DCM (1.5 mL, 0.33 M)
at 0 °C was added solid HATU (220 mg, 1.2 equiv) all at once. The
reaction mixture was allowed to stir for 4 h before dilution with diethyl
ether (10 mL) and water (5 mL). The organic layer was separated, and
the solution washed sequentially with 1 M aq HCl (10 mL), H2O (5
mL), and half-satd aq Na2CO3 solution (2 × 10 mL, mixing the layers
vigorously for 10 min). The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The product was subjected to silica
gel flash column chromatography (3% EtOAc in 40−60 petroleum
1
ether) to afford depsipeptide 4 as a clean oil (158 mg, 78% yield). H
NMR (600 MHz, CDCl3): (mixture of rotamers) 7.35−7.27 (m, 5H),
5.19 (d, 1H, J = 12.6 Hz), 5.12 (d, 1H, J = 12.6 Hz), 4.85 (app. S, 1H),
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,
156.0, 155.4, 135.3, 128.5, 128.4, 128.3, 80.2, 79.8, 77.0, 66.9, 66.8, 64.8,
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
(neat, cm−1): 2968.3, 2926.2, 2878.1, 1741.7, 1695.2, 1455.8, 1390.0,
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.
Synthesis of Acid 5. To a solution of depsipeptide 3 (1.4 g, 3.3
mmol) in THF (6.5 mL, 0.5 M) was carefully added Pd/C under Ar. The
solution was then purged with H2 gas and allowed to stir under H2 (1
atm, balloon) overnight. The reaction mixture was then purged with Ar,
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
of rotamers) 5.01 (br s, 0.66H), 4.89 (br s, 0.34H), 4.28 (d, 0.34H, J =
9.5 Hz), 4.17 (d, 0.66H, J = 10.0 Hz), 2.91 (s, 2H), 2.86 (s, 1H), 2.30 (br
m, 2H), 1.46 (s, 9H), 1.08−0.90 (br m, 12H). 13C NMR (150 MHz,
CDCl3): 173.96, 170.87, 170.65, 156.63, 155.85, 80.49, 80.33, 76.46,
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,
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+]):
calcd for C16H30O6N 332.2068, found 332.2066.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Full H and 13C spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: svl1000@cam.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the BP
Endowment (to S.V.L.) and the Winston Churchill Foundation
of the United States for a scholarship to D.X.H. We also thank
Dr. James Keeler and Dr. Matthew O’Brien of the Department of
Chemistry, Cambridge, for very helpful discussions regarding the
manuscript.
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Note
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tumbling regime will appear 180° relatively out of phase with the
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NMR or other techniques being used for qualitative identification of
rotamers with no mention of saturation transfer; for a few examples, see:
(a) Mizuta, S.; Onomura, O. RSC Advances 2012, 2, 2266−2269.
(b) Koning, C. B.; Otterlo, W. A. L.; Michael, J. P. Tetrahedron 2003, 59,
8337−8345. (c) Dransfield, P. J.; Gore, P. M.; Prokes, I.; Shipman, M.;
Slawin, A. M. Z. Org. Biomol. Chem. 2003, 1, 2723−2733. (d) Lewis, K.
C.; Maxwell, A. R.; McLean, S.; Reynolds, W. F.; Enriquez, R. G. Magn.
Reson. Chem. 2000, 38, 771−774. (e) Myers, A. G.; Yang, B. H.; Chen,
H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496−6511. (f) Patil, S. A.; Otter, B. A.; Klein, R. S. Nucleosides
Nucleotides 1990, 9, 937−956. (g) Al-Horani, R. A.; Desai, U. R.
Tetrahedron 2012, 68, 2027−2040. (h) Smith, A. B.; Chruma, J. J.; Han,
Q.; Barbosa, J. Bioorg. Med. Chem. Lett. 2004, 14, 1697−1702.
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