Synthesis of chiral five-membered carbocyclic ring amino acids with an acetal moiety and helical conformations of its homo-chiral homopeptides

Article abstract of DOI:10.1002/bip.22769

Chiral five-membered carbocyclic ring amino acids bearing various diol acetal moieties were synthesized starting from l-malic acid, and homo-chiral homopeptides composed of cyclic amino acid (S)-Ac₅c^3EG bearing an ethylene glycol acetal, up to an octapeptide, were prepared. A conformational analysis revealed that (S)-Ac₅c^3EG homopeptides formed helical structures. (S)-Ac₅c^3EG homopeptides, up to hexapeptides, formed helical structures without controlling the helical screw direction, while (S)-Ac₅c^3EG hepta- and octapeptides formed helical structures with a preference for the left-handed (M) helical-screw direction.

Full text of DOI:10.1002/bip.22769

Synthesis of chiral five-membered carbocyclic ring amino acids with an acetal
moiety and helical conformations of its homo-chiral homopeptides
Yurie Koba,1 Yoko Hirata,1 Atsushi Ueda,1 Makoto Oba,1 Mitsunobu Doi,2 Yosuke Demizu,3
Masaaki Kurihara,3 Masakazu Tanaka1*
1Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-
8521, Japan
2Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
3Division of Organic Chemistry, National Institute of Health Sciences, Tokyo 158-8501, Japan
matanaka@nagasakiꢀu.ac.jp
Chiral five-membered carbocyclic ring amino acids bearing various diol acetal moieties were
synthesized starting from L-malic acid, and homo-chiral homopeptides composed of cyclic amino acid
(S)-Ac5c3EG bearing an ethylene glycol acetal, up to an octapeptide, were prepared. A conformational
analysis revealed that (S)-Ac5c3EG homopeptides formed helical structures. (S)-Ac5c3EG homopeptides,
up to hexapeptides, formed helical structures without controlling the helical screw direction, while (S)-
Ac5c3EG hepta- and octapeptides formed helical structures with a preference for the left-handed (M)
helical-screw direction.
Keywords: α,α-disubstituted amino acid; cyclic amino acid; conformation; helix; homopeptide
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INTRODUCTION
Peptides composed of nonꢀproteinogenic amino acids have attracted the attention of organic, peptide,
and medicinal chemists because they preferentially form a variety of stable secondary structures.1–3 Of
these, α,αꢀdisubstituted αꢀamino acidꢀcontaining peptides have been reported to form stable 310ꢀhelices,
αꢀhelices, and fully planar extended structures,4–9 which are capable of using the design of chiral
organocatalysts10–14 and cellꢀpenetrating peptides.15–18
We recently designed and synthesized the sixꢀmembered ring amino acid Ac6c4Bu with a changeable
chiral acetal moiety,19 as well as the cyclic amino acid Ac6c3,5Bu with two chiral acetal moieties
(FIGURE 1).20 In these sixꢀmembered ring amino acids, the αꢀcarbon atom was not a chiral center,
whereas the sideꢀchain acetal moiety had chiral centers. A conformational analysis of their homoꢀchiral
peptides revealed that, they formed helical secondary structures in solution and in a crystal state, and the
effects of the chiral centers of their homopeptides on helicalꢀscrew bias was very weak.
We designed a chiral fiveꢀmembered carbocyclic ring α,αꢀdisubstituted αꢀamino acid Ac5c3EG with an
acetal moiety, in which the αꢀcarbon atom was a chiral center.21 The acetal moiety at the γꢀposition may
be changeable and also removed to a carbonyl functional group. We also prepared its homoꢀchiral
homopeptides, up to an octapeptide, and examined their preferred secondary structures. We already
reported the preferred structures of chiral fiveꢀmembered carbocyclic ring amino acid homopeptides:
however, they had chiral centers at the αꢀcarbon atom and on the side chain,22 or exclusively on the side
chain.23–24 The chiral amino acid Ac5c3EG had a chiral center exclusively at the αꢀcarbon atom.
Furthermore, we investigated which type of intramolecular hydrogen bond, the N–H···O=C or N–H···–
O– (acetal) type, was formed.
[FIGURE 1; here]
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FIGURE 1 Chemical structures of chiral cyclic α,αꢀdisubstituted αꢀamino acids with acetal moieties.
RESULTS AND DISCUSSION
Synthesis of Chiral Five-membered Carbocyclic Ring Amino Acids with an Acetal Moiety
Both enantiomers of fiveꢀmembered carbocyclic ring amino acid (S)ꢀ and (R)ꢀAc5c3EG with an
ethylene glycol acetal were synthesized starting from Lꢀmalic acid, as shown in SCHEME 1. LꢀMalic
acid was converted into the MOMꢀprotected diester 1 in 83% yield by a treatment with SOCl2/MeOH,
and the subsequent protection of a secondary alcohol as a MOM ether.25 The diester 1 was then
converted into the diiodide 2 in 51% yield by reduction of the ester with LiAlH4, and substitution with
iodide using I2/PPh3. The alkylation of dimethyl malonate with 2 produced the cyclic diester 3 in 82%
yield. The monohydrolysis of 3 under alkaline conditions, followed by the Curtius rearrangement with
diphenylphosphoryl azide (DPPA) and a workꢀup with BnOH gave the amino acid 4 in 62% yield. The
amino acid 4 is a mixture of two diastereomers; however, we were unable to separate them using
preparative TLC or column chromatography on silica gel. Deprotection of the MOM ether in 4 with
ZrCl4 gave the alcohols 5 in 92% yield.26 The alcohols 5 were separated by column chromatography on
silica gel to give two diastereoisomers, 5a and 5b, in the ratio of 7 (more polar) to 3 (less polar). The
stereochemistry of 5a was unambiguously determined to be 1S,3S by an Xꢀray crystallographic
analysis.27 The alcohols 5a and 5b were oxidized by pyridinium dichromate (PDC) to give amino acids
(S)ꢀ6 (95%) and (R)ꢀ6 (85%), respectively, with a carbonyl functional group. The conversion of a
carbonyl functional group into an ethylene glycol acetal by ethylenedioxybis(trimethylsilane) and
TMSOTf gave Cbzꢀ{Ac5c3EG}ꢀOMe (S)ꢀ7 (84%) and (R)ꢀ7 (89%), respectively.
By using various kinds of alcohols, we synthesized chiral fiveꢀmembered carbocyclic ring amino acids
with different acetal moieties. For example, the reaction of (S)ꢀ6 with propaneꢀ1,3ꢀdiol gave a cyclic
amino acid (S)ꢀ8 with a propaneꢀ1,3ꢀdioxy moiety in 18% yield, while that with chiral (R,R)ꢀbutaneꢀ
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2,3ꢀdiol gave a cyclic amino acid (S)ꢀ9, in which chiral centers existed at the αꢀcarbon and side chain in
54% yield. Furthermore, in the reaction with trimethyl orthoacetate, the amino acid (S)ꢀ6 was converted
into the amino acid (S)ꢀ10 with a dimethyl acetal moiety in 66% yield.
[SCHEME 1; here]
SCHEME 1 Synthesis of the fiveꢀmembered carbocyclic ring amino acid (S)ꢀAc5c3EG and its
analogues.
Preparation of (S)-Ac5c3EG Homopeptides
(S)ꢀAc5c3EG homoꢀchiral homopeptides, up to an octapeptide, were synthesized by solutionꢀphase
methods, as follows. The Cꢀterminal free amino acid (S)ꢀ11 was prepared by alkaline hydrolysis of the
methyl ester in (S)ꢀ7, while the Nꢀterminal free amino acid (S)ꢀ12 was prepared by hydrogenolysis using
H2/PdꢀC.
Coupling between (S)ꢀ11 and (S)ꢀ12 using Oꢀ(7ꢀazabenzotriazolꢀ1ꢀyl)ꢀ1,1,3,3ꢀ
i
tetramethyluronium hexafluorophosphate (HATU), 1ꢀhydroxyꢀ7ꢀazabenzotriazole (HOAt), and Pr2NEt
produced the dipeptide (S)ꢀ13 in 95% yield. Deprotection of the Nꢀterminal Cbzꢀprotecting group in
(S)ꢀ14, followed by coupling with (S)ꢀ11 using HATU, HOAt, and iPr2NEt gave the tripeptide (S)ꢀ14 in
81% yield. Similarly, elongation of the peptide length by stepwise one amino acid residues produced
the tetrapeptide (S)ꢀ15 (76%), pentapeptide (S)ꢀ16 (37%), hexapeptide (S)ꢀ17 (59%), heptapeptide (S)ꢀ
18 (44%), and octapeptide (S)ꢀ19 (6%). Alternatively, the (S)ꢀAc5c3EG tetrapeptide (S)ꢀ15 was prepared
by coupling between the dipeptide acid and dipeptide amine derived from (S)ꢀ13; however, the yield was
moderate (37%). The spectroscopic data of homopeptides supported their structures.
[SCHEME 2; here]
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SCHEME 2 Preparation of (S)ꢀAc5c3EG homopeptides.
Conformational Analysis in Solution
The FTꢀIR absorption spectra of homopeptides Cbzꢀ{(S)ꢀAc5c3EG}nꢀOMe (7 and 13–19: n = 1–8) in
CDCl3 are shown in FIGURE 2. In the NꢀH stretching region (amide A) of peptides 14–19 (n = 3–8),
weak bands were observed at approximately 3420–3430 cmꢀ1 (free solvated NꢀH), whereas strong bands
were noted at 3310–3360 cm−1 and may have been derived from the peptide NH groups with N–
H···O=C intramolecular hydrogen bonds.28 No band at approximately 3390ꢀ3370 cm−1 was observed in
peptides 14–19. This band was attributed to the peptide NH group with intramolecular hydrogen bonds
between peptide N–H and acetal –O– (ether). This band was observed in the Ac6c3,5Bu homopeptides
having acetal moieties.20,29
[FIGURE 2; here]
FIGURE 2 FTꢀIR absorption spectra of homopeptides Cbzꢀ{(S)ꢀAc5c3EG}nꢀOMe (7 and 13–19: n = 1–
8) in CDCl3. Peptide concentration: 5 mM.
In the conformational analysis, distanceꢀgeometry methods in the ROESY NMR spectra could not be
applied to the (S)ꢀAc5c3EG homopeptides because they had no hydrogen atom at the αꢀcarbon of amino
acid residues. Instead, we used solvent perturbation experiments in the 1H NMR spectrum of (S)ꢀ17 by
adding the strong Hꢀbond acceptor solvent DMSOꢀd6 {0ꢀ10% (v/v)}, as shown in FIGURE 3. In the 1H
NMR spectrum of (S)ꢀ17, only the NH signal at the Nꢀterminus was unambiguously determined by its
highꢀfield position {δ 5.62 (br s, 1H)}, while the remaining five NH protons could not be assigned. Two
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NH signals were sensitive to the addition of DMSOꢀd6; one (n = 1) was very sensitive, while the other
was slightly sensitive (solventꢀexposed NH group), and the FTꢀIR absorption spectra and these results
suggested that a 310ꢀhelical structure was preferentially formed.23,24,28 1H NMR experiments by the
addition of the paramagnetic free radical 2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyloxyl {TEMPO; 0ꢀ5x10ꢀ2%
(w/v)} did not give clear results due to the overlapping of NH signals.
[FIGURE 3 here]
FIGURE 3 Plots of NꢀH chemical shifts in 1H NMR spectra of Cbzꢀ{(S)ꢀAc5c3EG}6ꢀOMe (S)ꢀ17, as a
function of the increasing percentage of DMSOꢀd6 (v/v) added to the CDCl3 solution. Peptide
concentration: 1.0 mM.
The CD spectra of peptides (S)ꢀ17–19 (n = 6–8) were measured in 2,2,2ꢀtrifluoroethanol (TFE)
solution.30,31 Up to hexapeptide (S)ꢀ17, no characteristic maxima (222 nm and 208 nm) for helical
structures were observed, and this may be attributed to the peptideꢀmain chain length not being
sufficiently long to control the helicalꢀscrew direction to oneꢀhandedness.22 In contrast, the CD spectra
of heptapeptide (S)ꢀ18 and octapeptide (S)ꢀ19 showed positive maxima at 222 nm and 208 nm, and a
much stronger negative maximum at 192 nm. These maxima of CD spectra were characteristic of a leftꢀ
handed (M) helical structure.22,31 The helicalꢀscrew direction may not have been perfectly controlled to
leftꢀhandedness because the intensities of the 222 nm and 208 nm maxima were weak. The results of
CD spectra depended on the peptide mainꢀchain length and were similar to those of homopeptides
composed of the chiral fiveꢀmembered carbocyclic ring amino acid (1S,3S)ꢀAc5cOM with a 3ꢀmethoxy
functional group.22
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[FIGURE 4; here]
FIGURE 4 CD spectra of (S)ꢀAc5c3EG homopeptides Cbzꢀ{(S)ꢀAc5c3EG}nꢀOMe (7 and 17–19: n = 1
and 6–8) in TFE solution (0.05 mM).
X-ray Crystallographic Analysis of the (R)-Ac5c3EG Dipeptide
The Cbzꢀ{(R)ꢀAc5c3EG}2ꢀOMe dipeptide (R)ꢀ13 provided suitable crystals for an Xꢀray
crystallographic analysis due to the slow evaporation of EtOH/H2O at room temperature. The crystal
and diffraction parameters of (R)ꢀ13 are summarized in TABLE 1. The molecular structure is shown in
FIGURE 5. The
corresponded to those of a rightꢀhanded (P) βꢀturn, whereas the Cꢀterminal residue torsion angles (
: +52.1° and −142.5°) were indicative of a semiꢀextended conformation. An intramolecular hydrogen
φ
and
ψ
torsion angles of the Nꢀterminal residue were −66.4° and −33.0°, which
φ
and
ψ
bond of the N–H···O=C or N–H···–O– (acetal) type was not observed, whereas an intermolecular
hydrogen bond was detected between N(1)–H and O(1’)=C(1’) (N···O distance: 2.86 Å; N–H···O angle:
167°).
The preferred structure of peptides composed of the sixꢀmembered ring amino acid (R,R)ꢀAc6c3,5Bu
bearing acetal moieties at the γꢀposition was a helical structure with the intramolecular hydrogen bonds
of the N(i)–H···–O– (i, acetal) type both in solution and a crystal state.20,29 On the other hand, peptides
composed of the fiveꢀmembered carbocyclic ring amino acid (R)ꢀAc5c3EG with a γꢀacetal moiety showed
no intramolecular hydrogen bond of the N(i)–H···–O– (i, ether) type. These differences in the
hydrogenꢀbond pattern may be attributed to the ring size difference of amino acids as well as the
conformational differences of rings.
TABLE 1 Crystal and diffraction parameters of the Cbzꢀ{(R)ꢀAc5c3EG}2ꢀOMe dipeptide (R)ꢀ13.
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[TABLE 1; here]
[FIGURE 5; here]
FIGURE 5 An ORTEP drawing of the Cbzꢀ{(R)ꢀAc5c3EG}2ꢀOMe dipeptide (R)ꢀ13.
CONCLUSION
Chiral fiveꢀmembered carbocyclic ring amino acids with various acetal moieties were synthesized
starting from Lꢀmalic acid. (S)ꢀAc5c3EG homoꢀchiral homopeptides, up to an octapeptide, were prepared.
A conformational analysis revealed that (S)ꢀAc5c3EG homopeptides formed helical structures. CD
spectra suggested that, up to a hexapeptide length, (S)ꢀAc5c3EG homopeptides might form both rightꢀ
handed (P) and leftꢀhanded (M) helical structures at almost equal amounts. However, elongation of the
peptide length to a heptapeptide and octapeptide resulted in the helicalꢀscrew direction being partially
controlled to leftꢀhandedness. Leftꢀhanded (M) helical structures were controlled exclusively by the
chiral αꢀcarbon atoms of fiveꢀmembered carbocyclic ring amino acids. We are now studying the
preferred structures of peptides with these fiveꢀmembered carbocyclic ring amino acids inserted into a Lꢀ
Leu sequence.
This work was supported in part by a GrantꢀinꢀAid for Young Scientists (A) (25713008) from JSPS
(M. O.), a GrantꢀinꢀAid for Scientific Research on Innovative Areas ‘Advanced Molecular
Transformations by Organocatalysts’ (26105745) from MEXT (M. T.), and Special Coordination Funds
for Promoting Science and Technology from JST (A. U.).
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MATERIALS AND METHODS
General Experimental Methodology
Optical rotations [α]D were measured using a 1.0 dm cell. Circular dichroism spectra (CD) were
measured using a 1.0ꢀmm path length cell. Infrared absorption spectra (IR) were recorded for
conventional measurements (KBr), and the solution (CDCl3) method using the 0.1ꢀmm path length of an
1
NaCl cell. H NMR spectra were determined at 400 or 500 MHz. HRMS(FAB) spectra were taken in
the dualꢀfocusing sector field mode, and HRMS(ESI) spectra were measured in the ToF mode.
Synthesis of Cyclic Amino Acids
Dimethyl (2S)-2-(Methoxymethoxy)succinate (1)25
A solution of Lꢀmalic acid (20.0 g, 149 mmol) and SOCl2 (24.0 mL, 328 mmol) in MeOH (360 mL)
was stirred at room temperature for 48 h. The solution was then neutralized with 1M aqueous NaOH
and evaporated. The aqueous solution was extracted with CHCl3 and dried over MgSO4. Removal of
the solvent gave a diester (21.5 g), which was used without purification. Methoxymethyl chloride
(MOMCl; 42.1 mL, 555 mmol) was added dropwise to the stirred solution of Lꢀmalic acid diester (21.5
g, 132 mmol) and iPr2NEt (75.1 mL, 431 mmol) in CH2Cl2 (240 mL) at 0°C, and the solution was then
stirred at room temperature for 24 h. The solution was diluted with saturated aqueous NH4Cl, extracted
with CHCl3, and dried over MgSO4. Removal of the solvent afforded an oily residue, which was
purified by short column chromatography on silica gel (30% EtOAc in nꢀhexane) to give 1 (25.6 g, 83%)
1
as a colorless oil: [α]31D −73.0 (c 1.16, CHCl3); IR (neat) 2957, 1740, 1215 cm−1; H NMR (400 MHz,
CDCl3): δ 4.70–4.77 (m, 2H), 4.56 (m, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.39 (s, 3H), 2.81–2.83 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 171.4, 170.2, 96.2, 71.6, 55.9, 52.1, 51.8, 37.5.
(2S)-1,4-Diiodo-2-(methoxymethoxy)butane (2)
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A solution of diester 1 (105 g, 509 mmol) was added dropwise to the stirred suspension of LiAlH4
(23.2 g, 611 mmol) in THF (800 mL) at 0°C, and the mixture was warmed to room temperature. After
being stirred for 24 h, the reaction was quenched with water, and the mixture was filtered through Celite.
Evaporation of the filtrate gave a crude diol (60.5 g, 79%), which was used without purification. A
mixture of crude diol (60.5 g, 403 mmol), PPh3 (317 g, 1.21 mol), imidazole (82.4 g, 1.21 mol), and I2
(307 g, 1.21 mol) in THF was stirred at 0°C, and the mixture was then warmed to room temperature.
After being stirred for 5 h, the mixture was diluted with EtOAc, washed with water, saturated aqueous
Na2S2O3, 1M aqueous HCl, 5% aqueous NaHCO3, brine and dried over MgSO4. Removal of the solvent
afforded an oily residue, which was purified by column chromatography on silica gel. The fraction
eluted with 5% EtOAc in nꢀhexane gave 2 (97.5 g, 65%) as a yellowish oil: [α]28 −39.3 (c 1.26,
D
CHCl3); IR (neat) 2947, 2889, 1145, 1096, 1032 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.74 (s, 2H), 3.54
(m, 1H), 3.45 (s, 3H), 3.25–3.41 (m, 4H), 2.04–2.22 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 96.5, 76.1,
56.3, 39.1, 10.0, 1.4; ESIꢀHRMS: m/z [M+] calcd for C6H12I2O2 369.8927, found 369.8955.
Dimethyl (3S)-3-(Methoxymethoxy)cyclopentane-1,1-dicarboxylate (3)
A mixture of 2 (18.2 g, 49.3 mmol), dimethyl malonate (5.60 mL, 49.0 mmol), and K2CO3 (17.0 g,
123 mmol) in DMF (150 mL) was stirred at 75°C under an Ar atmosphere. After being stirred for 50 h,
the mixture was diluted with EtOAc, and K2CO3 was filtered off. The filtrate was evaporated, and the
residue was purified by column chromatography on silica gel (30% EtOAc in nꢀhexane) to give 3 (9.92
1
g, 82%) as a colorless oil: [α]29D +6.21 (c 1.12, CHCl3); IR (neat) 2955, 1734, 1437, 1265 cm−1; H
NMR (400 MHz, CDCl3): δ 4.60 (q, J = 6.8 Hz, 2H), 4.21 (m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.34 (s,
3H), 2.45–2.52 (m, 2H), 2.37 (m, 1H), 2.13 (m, 1H), 1.76–1.96 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 172.8, 172.3, 95.0, 77.4, 58.6, 55.2, 52.7, 52.6, 40.4, 32.1, 31.8; ESIꢀHRMS: m/z [M+H]+
calcd for C11H19O6 247.1182, found 247.1179.
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Methyl (1RS,3S)-1-(Benzyloxycarbonyl)amino-3-(methoxymethoxy)cyclopentanecarboxylate (4)
A solution of 3 (49.3 g, 200 mmol) in MeOH (100 mL) and 0.5M aqueous NaOH (540 mL) was
stirred at 0°C, and then the solution was warmed to room temperature. After being stirred at room
temperature for 16 h, the solution was neutralized with 1M aqueous HCl, and MeOH was evaporated.
The aqueous solution was extracted with EtOAc, dried over MgSO4, and evaporated to give a crude
monocarboxylic acid (37.6 g), which was used for the next reaction without purification. A solution of
crude monocarboxylic acid (37.6 g), diphenylphosphoryl azide (DPPA; 38.4 mL, 178 mmol), and Et3N
(24.8 mL, 178 mmol) in toluene (500 mL) was refluxed for 1 h. Benzyl alcohol (18.5 mL, 178 mmol)
was then added to the solution, and the solution was refluxed for 6 h. After removal of the solvent, the
residue was diluted with EtOAc, washed with 1M aqueous HCl, 5% aqueous NaHCO3, brine and dried
over MgSO4. Removal of the solvent gave an oily residue, which was purified by column
chromatography on silica gel (25% EtOAc in nꢀhexane) to give 4 (41.9 g, 62%) as a colorless oil: IR
1
(neat) 3348 (br), 2953, 1724, 1719, 1522, 1246 cm−1; H NMR (400 MHz, CDCl3): δ 7.30–7.40 (m,
5H), 5.56 (br s, 0.2H), 5.30 (br s, 0.8H), 5.09 (s, 2H), 4.63 (s, 2H), 4.32 (m, 1H), 3.73 (br s, 3H), 3.35 (s,
2.0H), 3.33 (s, 1.0H), 2.28–2.44 (m, 3H), 2.10 (m, 1H), 1.70–2.20 (m, 2H); ESIꢀHRMS: m/z [M+H]+
calcd for C17H24NO6 338.1604, found 338.1588.
Methyl (1S,3S)- and (1R,3S)-1-(Benzyloxycarbonyl)amino-3-hydroxycyclopentanecarboxylate
(5a and 5b)
A mixture of 4 (990 mg, 2.93 mmol) and ZrCl4 (342 mg, 1.47 mmol) in MeOH (18 mL) was refluxed
under an Ar atmosphere for 3 h. The solution was then evaporated to give the residue, which was
purified by column chromatography on silica gel. The fraction eluted with 60% EtOAc in nꢀhexane
gave 5a (more polar, 558 mg, 65%) as colorless crystals and 5b (less polar, 230 mg, 27%) as a colorless
oil:
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1
5a: mp 59–62 °C; [α]21D −3.66 (c 0.95, CHCl3); IR (KBr) 3422, 3221, 3050, 1736, 1697 cm−1; H
NMR (400 MHz, CDCl3): δ 7.30–7.40 (m, 5H), 5.30 (br s, 1H), 5.09 (s, 2H), 4.47 (br s, 1H), 3.75 (br s,
13
3H), 2.37–2.56 (m, 3H), 2.28 (br m, 1H), 2.14 (m, 1H), 1.93 (br m, 1H), 1.88–1.78 (m, 1H); C NMR
(100 MHz, CDCl3): δ 175.7, 155.5, 136.2, 128.4, 128.1, 128.0, 72.8, 66.7, 65.0, 52.9, 46.7, 36.0, 34.7;
FABꢀHRMS: m/z [M+H]+ calcd for C15H20NO5 294.1341, found 294.1361; Xꢀray crystallographic
parameter: solvent: EtOAc/nꢀhexane; empirical formula: C15H19NO5; Mr: 337.36; crystal dimensions
[mm]: 0.15 x 0.10 x 0.02; crystal system: orthorhombic; a, b, c [Å]: 5.9160, 12.667, 22.091; V [Å3]:
1655.5; space group: P212121; Z: 4; D [g/cm3]: 1.354;
ꢀ
(MoK
α
) [cm−1]: 1.03; no. of observations (I
calc
> − 10.0 σI): 1884; no. of variables: 245; R1 0.0599; R 0.1646.
w
5b: [α]28D −7.02 (c 1.05, CHCl3); IR (neat) 3356 (br), 2954, 1700 (br), 1520 1262 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.30–7.40 (m, 5H), 6.10 (br s, 1H), 5.10 (s, 2H), 4.41 (br s, 1H), 4.21 (br s, 1H), 3.76
(br s, 3H), 2.52 (m, 1H), 2.41 (m, 1H), 1.90–2.15 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 175.0, 155.2,
136.0, 128.5, 128.2, 128.1, 73.1, 66.8, 64.9, 52.9, 46.7, 35.6, 34.9; FABꢀHRMS: m/z [M+H]+ calcd for
C15H20NO5 294.1341, found 294.1375.
Methyl (S)-1-(Benzyloxycarbonyl)amino-3-oxocyclopentanecarboxylate {(S)-6} and (R)-6
A mixture of 5a (200 mg, 0.682 mmol) and pyridinium dichromate (PDC; 641 mg, 1.70 mmol) in
CH2Cl2 (10 mL) was stirred under an Ar atmosphere at room temperature for 84 h. The mixture was
then filtered through Celite, and filtrate was evaporated. The residue was purified by column
chromatography on silica gel (50% EtOAc in nꢀhexane) to give (S)ꢀ6 (189 mg, 95%) as colorless
crystals: mp 113–115 °C; [α]21D +5.03 (c 0.96, CHCl3); IR (KBr) 3314 (br), 1744, 1717, 1528, 1273
1
cm−1; H NMR (400 MHz, CDCl3): δ 7.30–7.42 (m, 5H), 5.48 (br s, 1H), 5.10 (s, 2H), 3.76 (br s, 3H),
13
2.94 (d, J = 18.5 Hz, 1H), 2.82 (br d, J = 18.5 Hz, 1H), 2.38–2.55 (m, 4H); C NMR (100 MHz,
CDCl3): δ 214.0, 173.2, 155.4, 135.9, 128.5, 128.3, 128.1, 67.0, 62.5, 53.1, 47.8, 35.9, 32.6; ESIꢀ
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HRMS: m/z [M+H]+ calcd for C15H18NO5 292.1185, found 292.1204. Oxidation of 5b with PDC gave
(R)ꢀ6 in 85% yield.
(R)ꢀ6: mp 115–117 °C; [α]20D −4.56 (c 0.84, CHCl3).
Methyl (S)-1-(Benzyloxycarbonyl)amino-3,3-(ethylenedioxy)cyclopentanecarboxylate [Cbz-{(S)-
Ac5c3EG}-OMe; (S)-7] and (R)-7
Trimethylsilyl trifluoromethanesulfonate (TMSOTf; 80 ꢀL) was slowly added to the stirred solution of
ethylenedioxybis(trimethylsilane) (4.4 ml, 17.8 mmol) and (S)ꢀ6 (2.59 g, 8.89 mmol) in CH2Cl2 (60 mL)
at −35°C under an Ar atmosphere, and the solution was stirred for 35 h at the same temperature. The
solution was then diluted with 5% aqueous NaHCO3, extracted with CHCl3, and dried over MgSO4.
Removal of the solvent gave an oily residue, which was purified by column chromatography on silica
gel (60% EtOAc in nꢀhexane) to give (S)ꢀ7 (2.53 g, 84%) as a colorless oil: [α]26 +19.7 (c 0.98,
D
1
CHCl3); IR (neat) 3340 (br), 2955, 1736, 1716, 1261 cm−1; H NMR (400 MHz, CDCl3): δ 7.30–7.40
(m, 5H), 5.41 (br s, 1H), 5.10 (s, 2H), 3.86–3.94 (m, 4H), 3.74 (br s, 3H), 2.49 (d, J = 14.6 Hz, 1H) 2.40
13
(m, 1H), 1.90–2.20 (m, 4H); C NMR (100 MHz, CDCl3): δ 173.4, 155.3, 136.2, 128.3, 128.2, 128.0,
116.4, 66.6, 64.3, 64.2, 63.9, 52.5, 46.5, 34.6, 34.1; ESIꢀHRMS: m/z [M+H]+ calcd for C17H22NO6
336.1447, found 336.1472. The enantiomeric (R)ꢀ7 was also obtained from (R)ꢀ6 in 89% yield by the
same procedure as described above.
(R)ꢀ7: [α]26D −21.0 (c 1.02, CHCl3).
Methyl (R)-1-(Benzyloxycarbonyl)amino-3,3-(propane-1,3-dioxy)cyclopentanecarboxylate {(S)-
8}
A solution of (S)ꢀ6 (100 mg, 0.343 mmol), propaneꢀ1,3ꢀdiol (50 ꢀL, 0.692 mmol), and pyridinium pꢀ
toluenesulfonate (PPTS; 1.5 mg) in toluene (10 ml) was refluxed for 4 h, fixed with a DeanꢀStark
apparatus. The solution was then diluted with 5% aqueous NaHCO3, extracted with EtOAc, and dried
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over MgSO4. After evaporation of the solvent, the residue was purified by column chromatography on
silica gel (60% EtOAc in nꢀhexane) to give (S)ꢀ8 (22 mg, 18%) as a colorless oil: [α]22D +9.23 (c 1.00,
1
CHCl3); IR (neat) 3341 (br), 2955, 1717 (br), 1520, 1261 cm−1; H NMR (400 MHz, CDCl3): δ 7.25–
7.40 (m, 5H), 5.38 (br s, 1H), 5.05–5.13 (m, 2H), 3.80–3.95 (m, 4H), 3.73 (br s, 3H), 2.31–2.50 (m, 3H),
13
2.02–2.18 (m, 3H), 1.65–1.79 (m, 2H); C NMR (100 MHz, CDCl3): δ 173.3, 155.3, 136.2, 128.4,
128.1, 108.2, 66.7, 64.1, 61.9, 61.3, 52.6, 45.7, 33.9, 25.3; ESIꢀHRMS: m/z [M+H]+ calcd for
C18H24NO6 350.1604, found 350.1629.
Methyl
(S)-1-(Benzyloxycarbonyl)amino-3,3-{(2R,3R)-butane-2,3-
dioxy}cyclopentanecarboxylate {(S)-9}
A solution of (S)ꢀ6 (68.2 mg, 0.234 mmol), (2R,3R)ꢀbutaneꢀ2,3ꢀdiol (24 ꢀL, 0.263 mmol), pꢀTsOH
(4.6 mg, 0.024 mmol) in toluene (6 ml) was refluxed for 3 h, fixed with a DeanꢀStark apparatus. The
solution was then neutralized with Et3N, diluted with 5% aqueous NaHCO3, extracted with EtOAc, and
dried over MgSO4. Removal of the solvent afforded an oily residue, which was purified by column
chromatography on silica gel (60% EtOAc in nꢀhexane) to give (S)ꢀ9 (46 mg, 54%) as a colorless oil:
1
[α]28D +15.6 (c 1.15, CHCl3); IR (neat) 3348 (br), 2974, 1721, 1520, 1261 cm−1; H NMR (400 MHz,
CDCl3): δ 7.29–7.36 (m, 5H), 5.43 (br s, 1H), 5.11 (d, J = 12.2 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 3.72
(br s, 3H), 3.51–3.56 (m, 2H), 2.45 (d, J = 14.6 Hz, 1H), 2.38 (m, 1H), 2.00–2.16 (m, 4H), 1.23 (t, J =
5.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.3, 155.4, 136.3, 128.4, 128.1, 128.0, 115.6, 78.5, 78.4,
66.7, 64.2, 52.6, 48.2, 36.3, 33.9, 16.8, 16.7; ESIꢀHRMS: m/z [M+H]+ calcd for C19H26NO6 364.1760,
found 364.1773.
Methyl (S)-1-(Benzyloxycarbonyl)amino-3,3-(dimethoxy)cyclopentanecarboxylate {(S)-10}
Compound (S)ꢀ10 was prepared from (S)ꢀ6 and trimethyl orthoacetate in a manner similar to that
described for the preparation of (S)ꢀ9: 66%; a colorless oil; [α]28D +6.47 (c 1.04, CHCl3); IR (neat)
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1
3345 (br), 2951, 2820, 1724 (br), 1520, 1261 cm−1; H NMR (400 MHz, CDCl3): δ 7.27–7.39 (m, 5H),
5.36 (br s, 1H), 5.09 (s, 2H), 3.73 (br s, 3H), 3.20 (s, 3H), 3.17 (s, 3H), 2.35–2.48 (m, 2H), 2.18 (br d, J
13
= 14.2 Hz, 1H), 1.92–2.21 (m, 3H); C NMR (100 MHz, CDCl3): δ 173.5, 155.3, 134.2, 128.4, 128.0,
110.4, 66.7, 63.9, 52.6, 49.6, 49.0, 45.0, 34.2, 32.7; ESIꢀHRMS: m/z [M+Na]+ calcd for C17H23NNaO6,
360.1423 found 360.1425.
(S)-1-(Benzyloxycarbonyl)amino-3,3-(ethylenedioxy)cyclopentanecarboxylic Acid [Cbz-{(S)-
Ac5c3EG}-OH; (S)-11] and (R)-11
0.1M aqueous NaOH (20 mL) was added to the stirred solution of (S)ꢀ7 (310 mg, 0.925 mmol) in
MeOH (5 mL) at 0°C, and the solution was warmed to room temperature. After being stirred for 24 h,
the solution was acidified with citric acid, and evaporated. The residue was extracted with EtOAc, and
dried over MgSO4. Removal of the solvent gave a crude amino acid (S)ꢀ11 (309 mg, quantitative) as a
colorless oil, which was used for the next reaction without purification. [α]31D +21.5 (c 1.00, CHCl3);
IR (neat) 3327 (br), 3233, 1716 (br) cm−1; 1H NMR (400 MHz, CDCl3): δ 9.71 (br, 1H), 7.30–7.36 (m,
13
5H), 5.62 (br s, 1H), 5.11 (br s, 2H), 3.86–3.93 (m, 4H), 2.07–2.56 (m, 6H); C NMR (100 MHz,
CDCl3): δ 177.1, 155.8, 136.0, 128.5, 128.1, 128.0, 116.6, 67.0, 64.5, 64.4, 63.7, 46.2, 34.7, 34.1; FABꢀ
HRMS: m/z [M+H]+ calcd for C16H20NO6 322.1291, found 322.1306.
(R)ꢀ11: [α]30D −22.9 (c 1.00, CHCl3).
Methyl (S)-1-Amino-3,3-(ethylenedioxy)cyclopentanecarboxylate [H-{(S)-Ac5c3EG}-OMe; (S)-12]
and (R)-12
A mixture of (S)ꢀ7 (538 mg, 1.61 mmol) and 10% PdꢀC (130 mg) was rigorously stirred under a H2
atmosphere at room temperature for 5 h. The Pdꢀcatalyst was then filtered off, and the filtrate was
evaporated to give (S)ꢀ12 (313 mg, 97%), which was used for the next reaction without purification.
1
[α]28 +0.98 (c 0.95, CHCl3); IR (neat) 3368 (br), 2920, 1735, 1720 cm−1; H NMR (400 MHz,
D
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13
CDCl3): δ 6.55 (br s, 2H), 3.94–4.00 (m, 4H), 3.83 (s, 3H), 2.05–2.55 (m, 6H); C NMR (125 MHz,
CDCl3): δ 174.2, 116.6, 64.5, 64.4, 62.9, 53.0, 46.4, 35.3, 34.8; FABꢀHRMS: m/z [M+H]+ calcd for
C9H16NO4 202.1079, found 202.1107.
(R)ꢀ12: [α]22D −1.25 (c 1.02, CHCl3).
Synthesis of (S)-Ac5c3EG Homopeptides
(S)-Ac5c3EG Dipeptide [Cbz-{(S)-Ac5c3EG}2-OMe; (S)-13]
A solution of (S)ꢀ11 (1.20 g, 3.73 mmol), (S)ꢀ12 (633 mg, 3.14 mmol), Oꢀ(7ꢀazabenzotriazolꢀ1ꢀyl)ꢀ
1,1,3,3ꢀtetramethyluronium hexafluorophosphate (HATU; 1.43 g, 3.76 mmol), 1ꢀhydroxyꢀ7ꢀ
i
azabenzotriazole (HOAt; 512 mg, 3.76 mmol) and Pr2NEt (1.3 mL) in MeCN (10 mL) was stirred at
room temperature under a N2 atmosphere for 26 h. The solution was then evaporated, diluted with
EtOAc, washed with 5% aqueous NaHCO3, brine and dried over MgSO4. Removal of the solvent
afforded a white solid, which was purified by column chromatography on silica gel (80% EtOAc in nꢀ
hexane) to give (S)ꢀ13 (1.50 g, 95%) as colorless crystals: mp 126–128 °C; [α]26 +9.97 (c 1.30,
D
CHCl3); IR (KBr) 3391 (br), 3298, 2955, 1724, 1708, 1655, 1261 cm−1; 1H NMR (400 MHz, CDCl3): δ
7.76 (br s, 1H), 7.27–7.38 (m, 5H), 6.03 (br s, 1H), 5.04–5.15 (m, 2H), 3.80–4.00 (m, 8H), 3.70 (s, 3H),
2.31–2.55 (m, 6H), 1.95–2.15 (m, 6H); FABꢀHRMS: m/z [M+H]+ calcd for C25H33N2O9 505.2186,
found 505.2177.
(R)ꢀAc5c3EG Dipeptide (R)ꢀ13: mp 129–130 °C; [α]28D −12.2 (c 0.98, CHCl3).
(S)-Ac5c3EG Tripeptide [Cbz-{(S)-Ac5c3EG}3-OMe; (S)-14]
A mixture of (S)ꢀ13 (760 mg, 1.50 mmol) and 20% Pd(OH)2ꢀC (70 mg) in MeOH (20 mL) was
rigorously stirred under a H2 atmosphere at room temperature. The Pdꢀcatalyst was then filtered off, and
the filtrate was evaporated to give a crude amine (593 mg). A solution of the crude amine (593 mg), (S)ꢀ
11 (578 mg, 1.80 mmol), HATU (684 mg, 1.80 mmol), HOAt (245 mg, 1.80 mmol), and iPr2NEt (627
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ꢀL) in MeCN (20 mL) was stirred at room temperature under an Ar atmosphere. After being stirred for
22 h, the solution was evaporated, diluted with EtOAc, washed with 5% aqueous NaHCO3, brine, and
dried over MgSO4. Removal of the solvent afforded a white solid, which was purified by column
chromatography on silica gel. The fraction eluted with EtOAc gave (S)ꢀ14 (820 mg, 81%) as colorless
crystals: mp 70–72 °C; [α]22D +22.1 (c 0.85, CHCl3); IR (CDCl3) 3418 (br), 3360 (br), 2955, 1744,
1
1713, 1678, 1497 cm−1; H NMR (400 MHz, CDCl3): δ 7.63 (br s, 1H), 7.25–7.41 (m, 5H), 7.20 (br s,
1H), 5.91 (br s, 1H), 5.19 (d, J = 12.2 Hz, 1H), 5.05 (d, J = 12.2 Hz, 1H), 3.82–3.98 (m, 12H), 3.71 (s,
3H), 1.93–2.67 (m, 18H); ESIꢀHRMS: m/z [M+Na]+ calcd for C33H43N3NaO12 696.2744, found
696.2736.
(S)-Ac5c3EG Tetrapeptide [Cbz-{(S)-Ac5c3EG}4-OMe; (S)-15]
Tetrapeptide (S)ꢀ15 was prepared from tripeptide (S)ꢀ14 in a manner similar to that described for the
preparation of (S)ꢀ14: 76%; colorless crystals; mp 90–92 °C; [α]20D +10.0 (c 0.96, CHCl3); IR (CDCl3)
3422, 3337 (br), 2954, 1747, 1682 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.62 (br s, 1H), 7.48 (br s, 1H),
7.32–7.40 (m, 5H), 7.17 (br s, 1H), 6.05 (br s, 1H), 5.21 (d, J = 12.1 Hz, 1H), 5.09 (d, J = 12.1 Hz, 1H),
3.80–3.95 (m, 16H), 3.68 (s, 3H), 2.69 (d, J = 14.6 Hz, 1H), 2.50–2.59 (m, 3H), 2.20–2.49 (m, 8H),
1.85–2.18 (m, 12H); FABꢀHRMS: m/z [M+Na]+ calcd for C41H54N4NaO15 865.3483, found 865.3486.
(S)-Ac5c3EG Pentapeptide [Cbz-{(S)-Ac5c3EG}5-OMe; (S)-16]
Pentapeptide (S)ꢀ16 was prepared from tetrapeptide (S)ꢀ15 in a manner similar to that described for the
preparation of (S)ꢀ14: 37%; colorless crystals; mp 223–225 °C (decomp.); [α]28D −28.1 (c 1.00, CHCl3);
IR (KBr) 3333 (br), 2955, 2886, 1736, 1663, 1528 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.60 (br s, 1H),
7.56 (br s, 1H), 7.52 (br s, 1H), 7.32–7.42 (m, 5H), 7.03 (br s, 1H), 5.88 (br s, 1H), 5.15 (s, 2H), 3.75–
3.95 (m, 20H), 3.69 (s, 3H), 2.62–2.80 (m, 4H), 2.22–2.40 (m, 10H), 1.88–2.21 (m, 16H); FABꢀHRMS:
m/z [M+H]+ calcd for C49H66N5O18 1102.4403, found 1102.4406.
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(S)-Ac5c3EG Hexapeptide [Cbz-{(S)-Ac5c3EG}6-OMe; (S)-17]
Hexapeptide (S)ꢀ17 was prepared from pentapeptide (S)ꢀ16 in a manner similar to that described for
the preparation of (S)ꢀ14: 59%; colorless crystals; mp 129–132 °C (decomp.); [α]31D −54.2 (c 0.70,
CHCl3); IR (CDCl3) 3333 (br), 2955, 1744, 1670, 1524 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.79 (br s,
1H), 7.77 (br s, 1H), 7.70 (br s, 1H), 7.63 (br s, 1H), 7.30–7.42 (m, 5H), 7.04 (br s, 1H), 5.94 (br s, 1H),
5.18 (d, J = 12.2 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 3.76–3.95 (m, 24H), 3.71 (s, 3H), 1.90–2.66 (m,
36H); FABꢀHRMS: m/z [M+H]+ calcd for C57H77N6O21 1181.5142, found 1181.5159.
(S)-Ac5c3EG Heptapeptide [Cbz-{(S)-Ac5c3EG}7-OMe; (S)-18]
Heptapeptide (S)ꢀ18 was prepared from hexapeptide (S)ꢀ17 in a manner similar to that described for
the preparation of (S)ꢀ14: 44%; colorless crystals; mp 80–82 °C (decomp.); [α]29 −59.8 (c 1.27,
D
CHCl3); IR (CDCl3) 3314 (br), 2955, 1748, 1663, 1524 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.81 (br s,
1H), 7.78 (br s, 1H), 7.72 (br s, 1H), 7.67 (br s, 1H), 7.64 (br s, 1H), 7.32–7.42 (m, 5H), 6.93 (br s, 1H),
5.81 (br s, 1H), 5.16 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 12.2 Hz, 1H), 3.77–3.95 (m, 28H), 3.69 (s, 3H),
1.85–2.64 (m, 42H); FABꢀHRMS: m/z [M+Na]+ calcd for C65H87N7NaO24 1372.5700, found 1372.5699.
(S)-Ac5c3EG Octapeptide [Cbz-{(S)-Ac5c3EG}8-OMe; (S)-19]
Octapeptide (S)ꢀ19 was prepared from heptapeptide (S)ꢀ18 in a manner similar to that described for
the preparation of (S)ꢀ14: 6%; a white solid; [α]28D −62.1 (c 0.35, CHCl3); IR (CDCl3) 3310 (br), 2955,
1
1748, 1659, 1528 cm−1; H NMR (400 MHz, CDCl3): δ 7.75–7.84 (m, 4H), 7.65 (br s, 1H), 7.58 (br s,
1H), 7.31–7.42 (m, 5H), 6.81 (br s, 1H), 5.63 (br s, 1H), 5.22 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz,
1H), 3.76–3.96 (m, 32H), 3.69 (s, 3H), 1.89–2.65 (m, 48H); FABꢀHRMS: m/z [M+Na]+ calcd for
C73H98N8NaO27 1541.6439, found 1541.6423.
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29. Wolf, W. M.; Stasiak, M.; Leplawy, M. T.; Bianco, A.; Formaggio, F.; Crisma, M.; Toniolo, C. J.
Am. Chem. Soc. 1998, 120, 11558–11566.
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30. Toniolo, C.; Polese, A.; Formaggio, F.; Crisma, M.; Kamphuis, J. J. Am. Chem. Soc. 1996, 118,
2744–2745.
31. Yoder, G.; Polese, A.; Silva, R. A. G. D.; Formaggio, F.; Crisma, M.; Broxterman, Q. B.;
Kamphuis, J.; Toniolo, C.; Keiderling, T. A. J. Am. Chem. Soc. 1997, 119, 10278–10285.
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Biopolymers: Peptide Science
FIGURE 1 Chemical structures of chiral cyclic α,αꢀdisubstituted αꢀamino acids with acetal moieties.
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SCHEME 1 Synthesis of the fiveꢀmembered carbocyclic ring amino acid (S)ꢀAc5c3EG and its
analogues.
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Biopolymers: Peptide Science
SCHEME 2 Preparation of (S)ꢀAc5c3EG homopeptides.
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FIGURE 2 FTꢀIR absorption spectra of homopeptides Cbzꢀ{(S)ꢀAc5c3EG}nꢀOMe (7 and 13–19: n = 1–
8) in CDCl3. Peptide concentration: 5 mM.
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Biopolymers: Peptide Science
% DMSO-d6 in CDCl3
FIGURE 3 Plots of NꢀH chemical shifts in 1H NMR spectra of Cbzꢀ{(S)ꢀAc5c3EG}6ꢀOMe (S)ꢀ17, as a
function of the increasing percentage of DMSOꢀd6 (v/v) added to the CDCl3 solution. Peptide
concentration: 1.0 mM.
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FIGURE 4 CD spectra of (S)ꢀAc5c3EG homopeptides Cbzꢀ{(S)ꢀAc5c3EG}nꢀOMe (7 and 17–19: n = 1
and 6–8) in TFE solution (0.05 mM).
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Biopolymers: Peptide Science
FIGURE 5 An ORTEP drawing of the Cbzꢀ{(R)ꢀAc5c3EG}2ꢀOMe dipeptide (R)ꢀ13.
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TABLE 1 Crystal and diffraction parameters of the Cbzꢀ{(R)ꢀAc5c3EG}2ꢀOMe dipeptide (R)ꢀ13.
(R)ꢀAc5c3EG dipeptide (R)ꢀ13
empirical formula
Mr
C25H32N2O9
504.53
crystal dimensions [mm]
crystal system
lattice parameters:
a, b, c [Å]
0.24×0.06×0.01
monoclinic
5.942, 24.15, 8.588
90, 94.419, 90
1228.7
P21
α, β, γ [°]
V [Å3]
space group
Z value
2
Dcalc [g/cm3]
1.364
(MoKα
) [cm−1]
1.04
ꢀ
1849
no. of observations (I > − 10.0 σI)
no. of variables
325
R1, R
0.0739, 0.1709
EtOH/H2O
w
solvent
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