(2 S,4 R)-4-hydroxyproline(4-nitrobenzoate): Strong induction of stereoelectronic effects via a readily synthesized proline derivative. Crystallographic observation of a correlation between torsion angle and bond length in a hyperconjugative interaction

Article abstract of DOI:10.1021/jo500367d

(2S,4R)-4-Hydroxyproline(4-nitrobenzoate) was synthesized. The crystal structure revealed an exo ring pucker, with the nitrobenzoate pseudoaxial on the pyrrolidine envelope and antiperiplanar to C^β and C ^δ C-H bonds. The unit cell exhibited variation in C ^δ-H/C^γ-O and C^β-H/C ^γ-O torsion angles, with a 15° increase in torsion angle (148° to 163°) observed to result in a 0.018 A decrease in C ^δ-H/C^γ-O bond length, consistent with favorable σ_C-H → σ*_C-O hyperconjugative interactions increasing with greater orbital overlap.

Full text of DOI:10.1021/jo500367d

Note
pubs.acs.org/joc
(2S,4R)‑4-Hydroxyproline(4-nitrobenzoate): Strong Induction of
Stereoelectronic Effects via a Readily Synthesized Proline Derivative.
Crystallographic Observation of a Correlation between Torsion
Angle and Bond Length in a Hyperconjugative Interaction
Anil K. Pandey, Glenn P. A. Yap,* and Neal J. Zondlo*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: (2S,4R)-4-Hydroxyproline(4-nitrobenzoate) was synthesized. The crystal structure revealed an exo ring pucker,
with the nitrobenzoate pseudoaxial on the pyrrolidine envelope and antiperiplanar to Cβ and Cδ C−H bonds. The unit cell
exhibited variation in Cδ−H/Cγ−O and Cβ−H/Cγ−O torsion angles, with a 15° increase in torsion angle (148° to 163°)
observed to result in a 0.018 Å decrease in Cδ−H/Cγ−O bond length, consistent with favorable σC−H → σ*C−O hyperconjugative
interactions increasing with greater orbital overlap.
modulate both reaction rate and stereoselectivity.21−23,25−27
roline is a unique amino acid due to its cyclic structure,
Pwhich in proteins limits its conformation to the torsion For example, Chandler and List demonstrated in transannular
angle ϕ = −65° 25°.1,2 4-Substituted prolines, including the
intramolecular aldol reactions that (2S,4R)-4-fluoroproline
exhibited substantially greater enantioselectivity and reaction
rate than either (2S)-proline or the (2S,4S)-4-fluoroproline
diastereomer and applied (2S,4R)-4-fluoroproline as a catalyst
in the asymmetric total synthesis of (+)-hirsutene.28
collagen constituent (2S,4R)-4-hydroxyproline, provide en-
hanced conformational control compared to proline via their
relative preferences for the Cγ-exo versus Cγ-endo pyrrolidine
ring puckers.3,4 In (2S,4R)-4-hydroxyproline, the pyrrolidine
ring preferentially adopts an exo ring pucker, which in general
leads to a greater preference for more compact conformations
of proline and for a trans amide bond (Figure 1). Because
proline side-chain conformation couples to the protein main
chain, 4-substituted prolines can allow selective control of local
peptide and protein structure and protein stability.3,5−18
Because of both conformational restriction of proline and the
ability to readily incorporate additional functionality into
proline amino acids using the hydroxyl group of the inexpensive
amino acid (2S,4R)-4-hydroxyproline as a reactive handle, 4-
substituted prolines have been widely employed in medicinal
chemistry and in peptide and protein design.
We have investigated the incorporation of 4-substituted
prolines into peptides and miniproteins to control structure and
function.9−11 In that work, we found that the nitrobenzoate of
(4R)-hydroxyproline induced a particular conformation re-
striction (Figure 1, Table 1) that was greater than that of (4R)-
hydroxyproline and similar to that of (4R)-fluoroproline. In the
trp cage miniprotein, replacement of proline 12 with the 4-
nitrobenzoate ester of (4R)-hydroxyproline resulted in a 13 °C
increase in thermal stability compared to proline and a 10 °C
increase in thermal stability compared to (4R)-hydroxypro-
line.10 Within model Ac-TYProxN-NH2 tetrapeptides (Prox =
proline derivative), the proline derivative that most favored the
trans amide bond, which is usually associated with exo ring
pucker preference, was the 4-nitrobenzoate of (4R)-hydrox-
In addition, proline and proline-derived molecules have
recently emerged as effective catalysts for a series of carbonyl
addition reactions, including aldol, Michael, and Mannich
reactions.19−27 The incorporation of groups that can stabilize
the structure of proline-based catalysts can substantially
Received: February 14, 2014
Published: April 10, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
data are consistent with the nitrobenzoate inducing strong
stereoelectronic effects that are comparable to those of fluorine
and greater than those of hydroxyl. However, in the absence of
crystallographic data, it is possible that the effects observed for
the 4-nitrobenzoate of (4R)-hydroxyproline could be due to
unforeseen structural effects of the nitrobenzoate. Therefore,
we sought independent determination of the effects of the
hydroxyproline nitrobenzoate on proline structure.
While the (4S)-hydroxyproline nitrobenzoates are common
intermediates in the synthesis of proline derivatives,29,30 via
Mitsunobu reaction of (4R)-hydroxyproline with 4-nitro-
benzoic acid, the 4R derivative had never previously been
described. In our previous work, we demonstrated the facile
incorporation of this amino acid within fully synthesized
peptides using a method termed proline editing, in which a
selectively deprotected (4R)-hydroxyproline-containing peptide
was converted to contain one of over 120 diverse proline amino
acids in high yield via practical chemistry on the solid
phase.9−11
The peptides synthesized via proline editing were readily
analyzed by NMR spectroscopy. However, these peptides were
not amenable to crystallization. Therefore, we embarked upon
the synthesis of the free amino acid, which could potentially be
crystalline. The nitrobenzoate was readily synthesized (Scheme
1) by esterification of the hydroxyl group on the methyl ester of
Boc-(2S,4R)-4-hydroxyproline, a compound that is commer-
cially available or synthesized in 1 step from inexpensive Boc-
(2S,4R)-4-hydroxyproline. This product was subjected to acidic
deprotection, which generated the crystalline free amino acid.
X-ray diffraction revealed the structure of the zwitterionic
form of this amino acid (Figures 2−4, Table 2), with four
Figure 1. Left: (2S,4R)-4-hydroxyproline(4-nitrobenzoate) exo and
endo ring puckers and the conformational preferences observed for
proline residues with these ring puckers.6−8,11,18 Right: nomenclature
of proline Hβ and Hδ hydrogens, with hydrogens capable of engaging
in hyperconjugative interactions (as the σ of Cβ−Hβ3 or Cδ−Hδ2
bonds), via overlap with the σ* of the Cγ-nitrobenzoate, indicated in
bold.
Table 1. NMR-Derived Data from Peptides with Proline and
a
4R-Substituted Prolines
Ac-TYXN-NH2,
X =
ΔG
ΔΔG
Ktrans/cis
(kcal mol−1
)
(kcal mol−1
)
ref
Hyp(4-NO2-Bz)
8.2
7.0
5.6
2.7
−1.25
−1.15
−1.02
−0.59
−0.66
−0.56
−0.43
0.00
10, 11
9, 11
9, 11
9, 11
Flp
Hyp
Pro
a
ΔGtrans/cis = −RT ln Ktrans/cis. ΔΔGtrans/cis = ΔGtrans/cis (peptide with
proline derivative) − ΔGtrans/cis (peptide with proline), which indicates
the magnitude of the structural effect. Experiments were conducted in
90% H2O/10% D2O with 5 mM phosphate buffer pH 4 and 25 mM
NaCl. Hyp(4-NO2-Bz): the 4-nitrobenzoate ester of (2S,4R)-4-
hydroxyproline; Flp: (2S,4R)-4-fluoroproline; Hyp: (2S,4R)-4-hydrox-
yproline; Pro: 2S-proline.
yproline.10,11 Overall comparison of the effects of substituents
on amide cis−trans isomerism (Ktrans/cis), via quantification of
the effects on Ktrans/cis in the 4R versus 4S diastereomers of a
substituent, revealed a total of 0.90 kcal/mol modulation of
ΔΔGtrans/cis in Ac-TYProxN-NH2 peptides and 0.82 kcal/mol in
Ac-TAProxN-NH2 peptides for the 4-nitrobenzoates of 4-
hydroxyproline, compared to 0.91 and 0.87 kcal/mol for
fluorine substitution (i.e., 4-fluoroprolines) and 0.43 and 0.56
kcal/mol for hydroxyl substitution (i.e., 4-hydroxyprolines).
Moreover, analysis of the NMR spectra of these peptides
revealed greater overall amide chemical shift dispersion and
greater dispersion of proline ring hydrogen chemical shifts for
(4R)-hydroxyproline(4-nitrobenzoate) than for 4R-hydroxypro-
line or proline (Figures S1, S2, Supporting Information),
indicating greater conformational restriction for nitrobenzoate
substitution than hydroxyl substitution.11 Collectively, these
Figure 2. Crystallographically determined structure of one molecule of
(2S,4R)-4-hydroxyproline(4-nitrobenzoate). (a,b) Overall molecular
structure. (c) View with nonenvelope proline carbons in a plane
perpendicular to the page, demonstrating the envelope pseudoaxial
conformation of the nitrobenzoate. (d) View down the Cδ-Cγ bond,
showing the antiperiplanar relationship of the Cδ−Hδ2 bond and Cγ−
O bond and the gauche relationship of the Cγ−O bond with the Cδ−N
and Cβ−Cα bonds. Entry (c) also shows the antiperiplanar relationship
of the Cβ−Hβ3 and Cγ−O bonds. The ammonium hydrogens in the
crystal are the deuterium isotope of hydrogen.
Scheme 1. Synthesis of (2S,4R)-4-Hydroxyproline(4-nitrobenzoate)
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The amino acid adopted a structure consistent with a strong
stereoelectronic effect induced by the nitrobenzoate, as had
been suggested by peptide NMR data. The proline ring
adopted a Cγ-exo ring pucker (Figure 2c), with the nitro-
benzoate at the pseudoaxial position of the envelope of the
pyrrolidine ring. This conformation is sterically unfavorable due
to gauche interactions with the ring and due to the
nitrobenzoate being on the concave (inward) face of the
pyrrolidine envelope. The magnitude of this latter interaction is
reduced by rotation of the Cγ−O bond to place the
nonconjugated oxygen lone pair into the envelope and the
carbonyl away from the envelope. The plane of the aromatic
ring is overall nearly orthogonal to the plane of the pyrrolidine
ring, with the nitrobenzoate extending far above the proline
ring. These data suggest that the observed strong conforma-
tional preferences of the hydroxyproline nitrobenzoate were
probably not due to specific interactions of the aromatic
nitrobenzoate group, but rather due to the electron-with-
drawing nature of the nitrobenzoate group resulting in a strong
preference for the exo ring pucker.
Figure 3. . Crystallographic data of (2S,4R)-4-hydroxyproline(4-
nitrobenzoate): (a) unit cell topology, with 4 molecules in the unit
cell; (b) thermal ellipsoids (50% probability).
Closer analysis of the crystal structure indicates that (2S,4R)-
4-hydroxyproline(4-nitrobenzoate) adopts a structure in the
proline ring that is nearly identical to that of Ac-(2S,4R)-4-
fluoroproline-OMe (Ac-Flp-OMe) (CSD code: RISDEC),
which exhibits strong stereoelectronic effects due to the highly
electron-withdrawing nature of fluorine.3,33 The Cγ−O bond
exhibits gauche relationships with both the Cβ−Cα and Cδ−N
bonds (Table 2), in opposition to the expectations of sterics. In
contrast, the nitrobenzoate Cγ−O bond is close to antiper-
iplanar with the Cδ−Hδ2 (163.1°, 162.7°, 148.3°, and 163.7°)
and Cβ−Hβ3 (162.0°, 161.4°, 159.4°, and 150.3°) bonds. These
results are consistent with a typical gauche effect and, in
particular, are very similar to the gauche effect observed for
(4R)-fluoroproline or (4R)-acetoxyproline.
Interestingly, the molecule with the largest deviation from an
antiperiplanar arrangement between the Cγ−O and Cδ−Hδ2
bonds (148.3°) had a longer Cγ−Cδ bond (1.523 Å) than the
other Cγ−Cδ bonds (1.505, 1.509, 1.510 Å), consistent with the
expected contraction of the C−C bond due to hyper-
conjugation in the latter molecules (Figure 4, Table 2).
Similarly, the molecule with the largest deviation from an
antiperiplanar arrangement of the Cγ−O and Cβ−Hβ3 bonds
(150.3°) had the longest Cβ−Cγ bond (1.520 Å, versus 1.507 Å
(162.0°), 1.510 Å (161.4°), and 1.513 Å (159.4°)).
Considering all potential hyperconjugative interactions with
the nitrobenzoate, we observed a correlation between the C−
H/C−O torsion angle and the bond lengths of those C−C
bonds (Figure 5). These data suggest that the bond contraction
observed was specifically due to favorable hyperconjugative
interactions induced by the highly electron-withdrawing
nitrobenzoate group.
Figure 4. Comparison of two molecules in the unit cell exhibiting
divergent Hδ2−Cδ−Cγ−O torsion angles (top) and Cδ−Cγ bond
lengths (bottom).
symmetry-unique molecules in the asymmetric unit. The
molecules pair such that two distinct hydrogen-bonded
polymers are formed by water bridging an ammonium donor
to two carboxylate acceptors (Figure S3, Supporting
Information). The two polymers differ in the identity of the
linking carboxylate. In polymer A, both carboxylate acceptors
are from two symmetry equivalent molecules while in polymer
B the acceptors are from two symmetry-unique molecules.
Crystal packing resulted from a slip-stack alignment of ABA
polymers with the aromatic groups in parallel-displaced planes
3.5 Å apart, which allowed favorable interactions between the
positively and negatively charged components of the aromatic
rings, similar to other cases displaying π−π interactions.31,32
a
Table 2. Torsion Angles (deg) and Bond Lengths (Å) for Bonds Associated with Cγ from Different Molecules in the Unit Cell
molecule
Hδ2−Cδ−Cγ−O (deg)
Cδ−Cγ (Å)
Hβ3−Cβ−Cγ−O (deg)
Cβ−Cγ (Å)
Cγ−O (Å)
Cα−Cβ−Cγ−O (deg)
N−Cδ−Cγ−O (deg)
A
B
162.7(3)
163.1(3)
148.3(3)
163.7(3)
1.510(4)
1.505(4)
1.523(4)
1.509(5)
161.4(3)
162.0(3)
159.4(3)
150.3(3)
1.510(4)
1.507(4)
1.513(4)
1.520(5)
1.459(4)
1.459(4)
1.453(4)
1.459(4)
−79.1(3)
−78.5(3)
−81.3(3)
−89.9(3)
−78.0(3)
−77.5(3)
−92.1(3)
−77.2(3)
C
D
a
Numbers in parentheses are the standard errors of the last digit. Hδ2−Cδ−Cγ−O torsion angles are negative in sign and are reported here as the
absolute value of the torsion angle for comparison to Hβ3−Cβ−Cγ−O.
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Note
longer exo bonds to the axial substituent compared to the
equatorial substituent) or alternatively due to shortened endo
O−C bonds in a series of molecules with more electron-
withdrawing axial substituents (and longer exo bonds to the
most electron-withdrawing substituents). In both of these
classes of examples, the highly compelling data supporting the
importance of stereoelectronic effects are obtained by
comparison between stereoisomers or among nonisomeric
compounds. In addition, these examples all are conducted with
axial substituents that allow near-perfect (∼180°) antiperiplanar
arrangements of the groups, and thus near-perfect orbital
overlap of the donor and acceptor orbitals. In contrast, the
complementary data herein are obtained within different
crystallographically observed conformations of a single
molecule. These data reveal C−C bond contraction, indicative
of greater bond strength, due to increased orbital overlap as a
function of torsion angle. These results are expected but are
challenging to observe experimentally and more typical of the
results found via calculations. The work herein thus provides
direct experimental evidence supporting the fundamental
concept that the extent of orbital overlap in a stereoelectronic
effect correlates with strengthening of the hyperconjugative
interaction.
Figure 5. Association of torsion angle with orbital overlap and bond
length. (a) Orbital overlap of σ*C−O with the σC−H orbital (Cδ−Hδ2
bond) for the Cδ−Cγ bonds in molecule B (left) and molecule C
(right). The larger torsion angle (left) exhibits better orbital overlap of
the donor σC−H with the acceptor σ*C−O and a shorter C−C bond. (b)
Comparison of C−C bond length as a function of H−C−C−O torsion
angle across all Cβ−Cγ (Hβ−Cβ−Cγ−O) and Cδ−Cγ (Hδ2−Cδ−Cγ−
O) bonds in the unit cell.
We have described the synthesis of the amino acid (2S,4R)-4-
hydroxyproline(4-nitrobenzoate). This amino acid had pre-
viously been incorporated within peptides via proline editing,
with the nitrobenzoate observed to induce one of the largest
stereoelectronic effects of 4-substituted prolines. Here, we
demonstrate the facile solution-phase synthesis of this amino
acid in two steps from commercially available starting materials.
(2S,4R)-4-Hydroxyproline(4-nitrobenzoate) exhibits stereoe-
lectronic effects similar to those of (2S,4R)-4-fluoroproline
but may be synthesized without requiring double inversion at
the C4 stereocenter of the common starting material (2S,4R)-4-
hydroxyproline.34−36 Combined with our previous demonstra-
tion of the incorporation of this amino acid within a peptide
during solid-phase peptide synthesis, (2S,4R)-4-hydroxyproline-
(4-nitrobenzoate) represents the easiest entry to a 4R-
substituted proline derivative with a greater conformational
preference than Hyp.
The crystal structure of (2S,4R)-4-hydroxyproline(4-nitro-
benzoate) confirmed data in peptides that the 4-nitrobenzoate
of hydroxyproline induces a strong stereoelectronic effect, with
a Cγ-exo ring pucker observed. Interestingly, the four molecules
in the unit cell did not exhibit identical geometries. In two of
the molecules, a classical stereoelectronic effect was observed,
with strong overlap (torsion angle 159.4°−163.7°) of one Cδ−
Hδ and one Cβ−Hβ bond with the σ* of the Cγ−O bond. In the
other two molecules, one of the bonds to Cγ exhibited this
effect. However, the other C−C bond in these molecules (Cγ−
Cδ in molecule C; Cγ−Cβ in molecule D) exhibited a significant
deviation (torsion angle 148.3°−150.3°) from these torsion
angles, resulting in worse overlap of that C−H σ with the C−O
σ*.32,37 The observation of a smaller H−C−C−O torsion angle
was associated with a significantly longer C−C bond. These
data provide direct evidence supporting stabilizing hyper-
conjugative interactions leading to a contraction of the C−C
bond length, compared to molecules of identical composition
in a slightly different conformation (13°−15° deviation in
torsion angle) lacking this stabilizing interaction.
EXPERIMENTAL SECTION
■
Synthesis and Characterization. (2S,4R)-1-tert-Butyl 2-Methyl
4-((4-Nitrobenzoyl)oxy)pyrrolidine-1,2-dicarboxylate (1). (2S,4R)-1-
tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (5.00 g,
20.4 mmol) was dissolved in anhydrous CH2Cl2 (200 mL) at room
temperature under N2. To the solution were added 4-nitrobenzoic acid
(3.41 g, 20.4 mmol) and dicyclohexylcarbodiimide (DCC) (5.06 g,
24.5 mmol). A catalytic amount of N,N-(dimethylamino)pyridine
(DMAP) (125 mg, 1.0 mmol) was added to the reaction mixture, and
the resulting mixture was stirred vigorously for 12 h. The white
precipitate was filtered, and the solvent was removed in vacuo. The
resulting crude oil was purified by silica gel column chromatography
(0−2% CH3OH/CH2Cl2 v/v) to yield compound 1 (6.1 g) as a
colorless oil (76% yield). The NMR data represent the major
rotational isomer (trans). The minor cis rotational isomer was
distinctly observed for a few resonances: 1H NMR (600 MHz,
CDCl3) δ 8.32−8.30 (d, J = 8.8 Hz, 2H), 8.20−8.18 (d, J = 8.7 Hz,
2H), 5.58−5.57 (m, 1H), 4.56−4.52 (t, J = 7.8 Hz, minor), 4.47−4.43
(t, J = 8.1 Hz, major) (sum of major and minor =1H), 3.91−3.85 (m,
1H), 3.79 (s, minor), 3.78 (s, major) (sum of major and minor =3H),
3.73−3.70 (m, 1H), 2.61−2.58 (m, 1H), 2.40−2.32 (m, 1H), 1.47 (s,
minor), and 1.44 (s, major) (sum of major and minor = 9H); 13C
NMR (151 MHz, CDCl3) δ 173.0, 164.4, 153.9, 151.1, 135.2, 131.2,
124.0, 81.2, 74.7, 74.0, 58.2, 52.7, 36.9, and 28.6; ESI MS: [M + Na]+
calcd for C18H22N2O8Na 417.1, found 417.0; HRMS (LIFDI-TOF)
m/z [M]+ calcd for C18H22N2O8 394.1376; fragments observed: [M −
C7H5NO4]•+ calcd for C11H17NO4 227.1158, found 227.1146 (loss of
nitrobenzoate); [M − C7H3NO3]•+ calcd for C11H19NO5 245.1263,
found 245.1234 (loss of nitrobenzoyl) (major fragment); [M−
C5H8O2]•+ calcd for C13H14N2O6 294.0852, found 294.0865 (loss of
Boc) (second most prominent fragment).
(2S,4R)-4-((4-Nitrobenzoyl)oxy)pyrrolidine-2-carboxylic Acid (2).
Compound 1 (3.4 g, 8.6 mmol) was dissolved in anhydrous CH2Cl2
(20 mL) under a nitrogen atmosphere. Trifluoroacetic acid
(CF3COOH) (20 mL) was added to the solution, and the resulting
reaction mixture was stirred at room temperature for 6 h. The solvent
was removed in vacuo. The crude oil thus obtained was washed with
cold ether (3 × 15 mL) to obtain compound 2 (1.8 g) as a white solid
The association of a greater extent of hyperconjugation with
a shorter bond length is well-known in studies on the anomeric
effect in glycosides and acetals.38−40 In these cases, strong
evidence of hyperconjugation is obtained via the observation of
shorter O−C endo bonds on molecules with axial electron-
withdrawing substituents compared to stereoisomers which
have equatorial electron-withdrawing substituents (as well as
1
(74% yield): H NMR (600 MHz, D2O) δ 8.46−8.37 (d, J = 7.2 Hz,
2H), 8.34−8.28 (d, J = 7.1 Hz, 2H), 5.77 (m, 1H), 4.87−4.82 (m,
1H), 4.61−4.54 (m, 1H), 3.90−3.74 (m, 2H), 2.90−2.84 (m, 1H), and
2.68−2.64 (m, 1H); 13C NMR (151 MHz, D2O/DMSO-d6 (9:1)) δ
171.2, 162.2, 153.1, 137.4, 133.9, 126.3, 76.8, 60.1, 55.8, 53.2, and 36.7;
4177
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Note
HRMS (LIFDI-TOF) m/z [M + H]+ calcd for C12H13N2O6 281.0774,
found 281.0763.
X-ray Crystallography. Crystals were obtained from the slow
evaporation of a solution of approximately 10 mg of compound 2 in
500 μL of D2O (Table 3). The systematic absences in the diffraction
*E-mail: zondlo@udel.edu. Tel: +1-302-831-0197. Fax: +1-
302-831-6335.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NIH (GM93225 and RR17716) and the
University of Delaware for funding.
■
Table 3. Crystallographic Data and Refinement Details
empirical formula
formula weight
C12H14N2O7
298.25
T (K)
200(2)
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■
412.
wavelength (Å)
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)
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1248
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1.011
final R indices [I > 2σ(I)]
R indices (all data)
R = 0.0437, wR2 = 0.0906
R = 0.0712, wR2 = 0.1039
−0.3(3)
absolute structure parameter
largest diff peak and hole (e/Å3) 0.286 and −0.192
(14) Kim, W.; Hardcastle, K. I.; Conticello, V. P. Angew. Chem., Int.
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data are consistent with P21 and P21/m. The noncentrosymmetric
space group option is consistent with the enatiomerically resolved
sample. The absolute structure parameter refined to nil indicating the
true hand of the data had been determined41 consistent with known
chiral centers. The data set was treated with multiscan absorption
corrections.42 The structure was solved using direct methods and
refined with full-matrix, least-squares procedures on F2. All non-
hydrogen atoms were refined with anisotropic displacement
parameters. Four symmetry unique molecules of the zwitterion and
four water molecules of hydration were located in the asymmetric unit.
The water and ammonium H atoms were located from the difference
map and treated with X−H and H−H geometrical restraints. All other
hydrogen atoms were treated as idealized contributions with
geometrically calculated positions and with Uiso equal to 1.2, or 1.5
for methyl, Ueq of the attached atom. The methylene H atom torsion
angles were derived from the refined C−C bond positions and
assuming idealized tetrahedral sp3 geometry. Atomic scattering factors
are contained in the SHELXL 2013 program library.43 Structural
information has been deposited with the Cambridge Crystallographic
Data Centre under deposition no. CCDC 986367.
(18) For an example of an endo ring pucker leading to a stronger
preference for a trans amide bond, due to an intramolecular hydrogen
bond, see: Kuemin, M.; Nagel, Y. A.; Schweizer, S.; Monnard, F. W.;
Ochsenfeld, C.; Wennemers, H. Angew. Chem., Int. Ed. 2010, 49,
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S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632−649.
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(26) Albrecht, L.; Jiang, H.; Jørgensen, K. A. Chem.Eur. J. 2014, 20,
358−368.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional crystallographic data, CIF file, and 1H and 13C NMR
spectra of 1 and 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
(27) Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed.
2011, 50, 11860−11871.
(28) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130, 6737−
6739.
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(30) Gomez-Vidal, J. A.; Forrester, M. T.; Silverman, R. B. Org. Lett.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: gpyap@udel.edu. Tel: +1-302-831-4441.
■
2001, 3, 2477−2479.
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(33) The 4R-acetoxyproline exhibited similar effects on ring pucker,
although no effect on Ktrans/cis compared to 4R-hydroxyproline was
observed: Jenkins, C. L.; McCloskey, A. I.; Guzei, I. A.; Eberhardt, E.
S.; Raines, R. T. Biopolymers 2005, 80, 1−8.
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(37) The observation of different structures within the unit cell is
potentially due to crystal-packing effects, in which the competition
between π-π interactions and stereoelectronic effects leads to structural
distortion. For an example of structures exhibiting the competition
between crystal packing effects and stereoelectronic effects, see:
Alabugin, I. V.; Manoharan, M.; Buck, M.; Clark, R. J. THEOCHEM
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4179
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