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The asymmetric unit of the title compound, C
22H
31N
3O
4·H
2O, incorporates one water molecule, which is hydrogen bonded to the 3-oxo O atom of the indolizidinone system. The two rings of the peptidomimetic molecule are
trans-fused, with the six-membered ring having a slightly distorted half-chair conformation and the five-membered ring having a perfect envelope conformation. The structure is stabilized by intermolecular O—H
O interactions between the water and adjacent peptide molecules, and by N—H
O interactions between the peptide molecules, which link the molecules into infinite chains.
Supporting information
CCDC reference: 193442
The title compound was synthesized according to a previously reported procedure
(Angiolini et al., 2000) followed by protective group manipulation.
Suitable single crystals of (I) were obtained by recrystallization from
diethyl ether.
Due to the absence of any significant anomalous scatterers in the compound, the
absolute configuration could not be determined and Friedel opposites were
merged before the final refinement. The absolute configuration of the model
was assigned to match the configuration of the chiral centres known from the
synthesis. Atoms H1W and H2W were located from difference Fourier maps and
refined isotropically. All remaining H atoms were treated as riding atoms
(C—H = 0.95–1.00 Å), with Uiso(H) = 1.2Ueq(parent
atom).
Data collection: SMART (Siemens, 1996); cell refinement: SAINT (Siemens, 1996); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996); software used to prepare material for publication: SHELXL97.
tert-Butyl
(3
S,6
R,9
R)-(5-oxo-3-{
N-[1(
R)-phenylethyl]carbamoyl}- 1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl)carbamate monohydrate
top
Crystal data top
C22H31N3O4·H2O | F(000) = 904 |
Mr = 419.51 | Dx = 1.211 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 4199 reflections |
a = 8.520 (2) Å | θ = 2.4–20.6° |
b = 12.095 (2) Å | µ = 0.09 mm−1 |
c = 22.323 (5) Å | T = 95 K |
V = 2300.4 (8) Å3 | Prism, colourless |
Z = 4 | 0.55 × 0.10 × 0.06 mm |
Data collection top
Bruker SMART CCD area-detector diffractometer | 2933 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.047 |
Graphite monochromator | θmax = 27.5°, θmin = 1.8° |
ω scans | h = −11→11 |
23342 measured reflections | k = −15→15 |
2992 independent reflections | l = −29→29 |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.048 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.109 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.15 | w = 1/[σ2(Fo2) + (0.0371P)2 + 1.2606P] where P = (Fo2 + 2Fc2)/3 |
2992 reflections | (Δ/σ)max = 0.001 |
293 parameters | Δρmax = 0.34 e Å−3 |
0 restraints | Δρmin = −0.22 e Å−3 |
Crystal data top
C22H31N3O4·H2O | V = 2300.4 (8) Å3 |
Mr = 419.51 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 8.520 (2) Å | µ = 0.09 mm−1 |
b = 12.095 (2) Å | T = 95 K |
c = 22.323 (5) Å | 0.55 × 0.10 × 0.06 mm |
Data collection top
Bruker SMART CCD area-detector diffractometer | 2933 reflections with I > 2σ(I) |
23342 measured reflections | Rint = 0.047 |
2992 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.048 | 0 restraints |
wR(F2) = 0.109 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.15 | Δρmax = 0.34 e Å−3 |
2992 reflections | Δρmin = −0.22 e Å−3 |
293 parameters | |
Special details top
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell e.s.d.'s are taken
into account individually in the estimation of e.s.d.'s in distances, angles
and torsion angles; correlations between e.s.d.'s in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s.
planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor
wR and goodness of fit S are based on F2, conventional
R-factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 >
σ(F2) is used only for calculating R-factors(gt) etc.
and is not relevant to the choice of reflections for refinement.
R-factors based on F2 are statistically about twice as large
as those based on F, and R- factors based on ALL data will be
even larger. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1W | 0.5635 (3) | 0.8447 (2) | 0.62571 (10) | 0.0391 (6) | |
H1W | 0.530 (5) | 0.829 (3) | 0.5923 (19) | 0.039 (11)* | |
H2W | 0.632 (7) | 0.796 (5) | 0.635 (2) | 0.087 (18)* | |
N1 | 0.4972 (2) | 0.95998 (16) | 0.38705 (9) | 0.0136 (4) | |
H1 | 0.5986 | 0.9727 | 0.3839 | 0.020* | |
N2 | 0.5453 (2) | 0.67431 (16) | 0.42135 (9) | 0.0140 (4) | |
N3 | 0.5147 (3) | 0.58712 (17) | 0.57343 (9) | 0.0151 (4) | |
H3 | 0.6041 | 0.6215 | 0.5800 | 0.023* | |
O1 | 0.3110 (2) | 0.82555 (14) | 0.39133 (8) | 0.0172 (4) | |
O2 | 0.5352 (2) | 0.77803 (14) | 0.50429 (7) | 0.0192 (4) | |
O3 | 0.3180 (2) | 0.48716 (15) | 0.61571 (8) | 0.0182 (4) | |
O4 | 0.5353 (2) | 0.54085 (15) | 0.66798 (7) | 0.0188 (4) | |
C1 | 0.4920 (3) | 0.6150 (2) | 0.32452 (11) | 0.0187 (5) | |
H1A | 0.3786 | 0.6318 | 0.3211 | 0.028* | |
H1B | 0.5214 | 0.5613 | 0.2930 | 0.028* | |
C3 | 0.5821 (3) | 0.7700 (2) | 0.38392 (10) | 0.0139 (5) | |
H3A | 0.6849 | 0.8034 | 0.3958 | 0.021* | |
C2 | 0.5910 (3) | 0.7205 (2) | 0.32018 (11) | 0.0192 (5) | |
H2A | 0.5468 | 0.7721 | 0.2902 | 0.029* | |
H2B | 0.7008 | 0.7030 | 0.3091 | 0.029* | |
C4 | 0.4493 (3) | 0.85503 (19) | 0.38888 (10) | 0.0123 (4) | |
C5 | 0.5158 (3) | 0.6883 (2) | 0.47978 (11) | 0.0141 (5) | |
C6 | 0.4467 (3) | 0.58923 (19) | 0.51374 (10) | 0.0149 (5) | |
H6 | 0.3315 | 0.6025 | 0.5183 | 0.022* | |
C7 | 0.4671 (4) | 0.4802 (2) | 0.48117 (11) | 0.0213 (5) | |
H7A | 0.4021 | 0.4227 | 0.5007 | 0.032* | |
H7B | 0.5782 | 0.4566 | 0.4833 | 0.032* | |
C8 | 0.4181 (4) | 0.4922 (2) | 0.41572 (11) | 0.0224 (6) | |
H8A | 0.4213 | 0.4194 | 0.3954 | 0.034* | |
H8B | 0.3098 | 0.5215 | 0.4131 | 0.034* | |
C9 | 0.5319 (3) | 0.57118 (19) | 0.38627 (11) | 0.0173 (5) | |
H9 | 0.6374 | 0.5352 | 0.3845 | 0.026* | |
C10 | 0.4445 (3) | 0.5341 (2) | 0.61869 (11) | 0.0148 (5) | |
C11 | 0.4874 (3) | 0.4905 (2) | 0.72518 (11) | 0.0181 (5) | |
C12 | 0.4694 (4) | 0.3660 (2) | 0.71804 (12) | 0.0292 (7) | |
H12A | 0.3759 | 0.3501 | 0.6939 | 0.044* | |
H12B | 0.4581 | 0.3318 | 0.7576 | 0.044* | |
H12C | 0.5624 | 0.3359 | 0.6980 | 0.044* | |
C13 | 0.3390 (3) | 0.5452 (2) | 0.74875 (12) | 0.0228 (6) | |
H13A | 0.3530 | 0.6256 | 0.7491 | 0.034* | |
H13B | 0.3181 | 0.5191 | 0.7895 | 0.034* | |
H13C | 0.2504 | 0.5261 | 0.7228 | 0.034* | |
C14 | 0.6265 (3) | 0.5177 (3) | 0.76509 (12) | 0.0253 (6) | |
H14A | 0.6352 | 0.5981 | 0.7695 | 0.038* | |
H14B | 0.7228 | 0.4887 | 0.7470 | 0.038* | |
H14C | 0.6111 | 0.4839 | 0.8046 | 0.038* | |
C15 | 0.3920 (3) | 1.0549 (2) | 0.39002 (11) | 0.0159 (5) | |
H15 | 0.2869 | 1.0319 | 0.3745 | 0.024* | |
C16 | 0.4570 (3) | 1.1449 (2) | 0.34893 (11) | 0.0203 (5) | |
H16A | 0.4684 | 1.1154 | 0.3083 | 0.030* | |
H16B | 0.5596 | 1.1691 | 0.3638 | 0.030* | |
H16C | 0.3846 | 1.2079 | 0.3484 | 0.030* | |
C17 | 0.3719 (3) | 1.0968 (2) | 0.45395 (11) | 0.0160 (5) | |
C18 | 0.2770 (3) | 1.1893 (2) | 0.46445 (13) | 0.0203 (5) | |
H18 | 0.2246 | 1.2239 | 0.4319 | 0.030* | |
C19 | 0.2587 (3) | 1.2311 (2) | 0.52195 (14) | 0.0251 (6) | |
H19 | 0.1939 | 1.2939 | 0.5285 | 0.038* | |
C20 | 0.3344 (4) | 1.1816 (2) | 0.56971 (13) | 0.0266 (6) | |
H20 | 0.3228 | 1.2108 | 0.6090 | 0.040* | |
C21 | 0.4271 (3) | 1.0896 (2) | 0.56009 (12) | 0.0247 (6) | |
H21 | 0.4785 | 1.0551 | 0.5929 | 0.037* | |
C22 | 0.4456 (3) | 1.0470 (2) | 0.50242 (11) | 0.0191 (5) | |
H22 | 0.5091 | 0.9834 | 0.4963 | 0.029* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1W | 0.0586 (16) | 0.0380 (13) | 0.0208 (11) | 0.0226 (13) | −0.0072 (11) | −0.0116 (9) |
N1 | 0.0115 (9) | 0.0139 (9) | 0.0155 (9) | 0.0013 (8) | 0.0007 (8) | 0.0006 (8) |
N2 | 0.0152 (10) | 0.0124 (9) | 0.0144 (9) | −0.0002 (8) | 0.0012 (8) | 0.0013 (8) |
N3 | 0.0147 (10) | 0.0183 (10) | 0.0125 (9) | −0.0026 (9) | −0.0034 (8) | 0.0042 (8) |
O1 | 0.0155 (8) | 0.0152 (8) | 0.0209 (9) | 0.0004 (7) | 0.0010 (7) | 0.0016 (7) |
O2 | 0.0327 (10) | 0.0141 (8) | 0.0108 (7) | −0.0016 (8) | −0.0009 (8) | 0.0002 (7) |
O3 | 0.0139 (8) | 0.0224 (9) | 0.0182 (8) | −0.0003 (7) | 0.0012 (7) | 0.0052 (7) |
O4 | 0.0152 (8) | 0.0282 (9) | 0.0130 (8) | −0.0010 (8) | −0.0015 (7) | 0.0062 (7) |
C1 | 0.0250 (13) | 0.0174 (11) | 0.0137 (11) | −0.0012 (11) | 0.0019 (10) | −0.0036 (9) |
C3 | 0.0140 (11) | 0.0149 (10) | 0.0128 (11) | 0.0016 (9) | 0.0016 (9) | 0.0017 (9) |
C2 | 0.0261 (14) | 0.0189 (12) | 0.0125 (11) | 0.0012 (11) | 0.0037 (10) | −0.0014 (10) |
C4 | 0.0147 (11) | 0.0149 (10) | 0.0072 (9) | 0.0012 (9) | 0.0009 (9) | 0.0007 (8) |
C5 | 0.0124 (11) | 0.0160 (11) | 0.0137 (10) | 0.0020 (9) | −0.0025 (9) | 0.0022 (9) |
C6 | 0.0131 (11) | 0.0165 (11) | 0.0149 (11) | 0.0005 (10) | −0.0024 (9) | 0.0032 (9) |
C7 | 0.0311 (14) | 0.0140 (11) | 0.0189 (11) | −0.0043 (11) | −0.0003 (11) | 0.0032 (9) |
C8 | 0.0324 (15) | 0.0177 (12) | 0.0170 (12) | −0.0093 (12) | −0.0009 (11) | −0.0012 (10) |
C9 | 0.0220 (12) | 0.0132 (11) | 0.0166 (11) | 0.0028 (10) | 0.0007 (10) | −0.0021 (9) |
C10 | 0.0141 (11) | 0.0146 (11) | 0.0158 (11) | 0.0042 (9) | −0.0008 (9) | 0.0019 (9) |
C11 | 0.0213 (12) | 0.0217 (12) | 0.0114 (10) | 0.0010 (11) | 0.0013 (10) | 0.0049 (9) |
C12 | 0.0480 (19) | 0.0208 (13) | 0.0187 (12) | 0.0071 (14) | 0.0003 (13) | 0.0031 (10) |
C13 | 0.0237 (14) | 0.0255 (13) | 0.0192 (12) | 0.0001 (12) | 0.0042 (11) | −0.0012 (11) |
C14 | 0.0235 (14) | 0.0361 (16) | 0.0162 (12) | 0.0030 (13) | −0.0034 (11) | 0.0051 (11) |
C15 | 0.0160 (11) | 0.0129 (11) | 0.0189 (12) | −0.0004 (9) | −0.0029 (10) | 0.0005 (10) |
C16 | 0.0277 (14) | 0.0157 (11) | 0.0176 (12) | 0.0001 (11) | −0.0001 (11) | 0.0021 (9) |
C17 | 0.0167 (12) | 0.0116 (11) | 0.0197 (12) | −0.0037 (10) | 0.0040 (10) | −0.0012 (9) |
C18 | 0.0196 (12) | 0.0139 (11) | 0.0275 (14) | −0.0014 (11) | 0.0045 (11) | 0.0036 (10) |
C19 | 0.0269 (14) | 0.0132 (11) | 0.0353 (15) | −0.0007 (11) | 0.0115 (12) | −0.0036 (11) |
C20 | 0.0327 (15) | 0.0249 (13) | 0.0222 (13) | −0.0049 (13) | 0.0087 (12) | −0.0101 (11) |
C21 | 0.0274 (15) | 0.0254 (13) | 0.0214 (13) | −0.0014 (12) | 0.0013 (11) | 0.0009 (11) |
C22 | 0.0213 (13) | 0.0157 (11) | 0.0203 (12) | 0.0019 (10) | 0.0036 (11) | −0.0016 (10) |
Geometric parameters (Å, º) top
O1W—H1W | 0.82 (4) | C8—H8A | 0.9900 |
O1W—H2W | 0.86 (6) | C8—H8B | 0.9900 |
N1—C4 | 1.334 (3) | C9—H9 | 1.0000 |
N1—C15 | 1.458 (3) | C11—C14 | 1.518 (4) |
N1—H1 | 0.8800 | C11—C13 | 1.521 (4) |
N2—C5 | 1.339 (3) | C11—C12 | 1.523 (4) |
N2—C3 | 1.462 (3) | C12—H12A | 0.9800 |
N2—C9 | 1.477 (3) | C12—H12B | 0.9800 |
N3—C10 | 1.337 (3) | C12—H12C | 0.9800 |
N3—C6 | 1.453 (3) | C13—H13A | 0.9800 |
N3—H3 | 0.8800 | C13—H13B | 0.9800 |
O1—C4 | 1.232 (3) | C13—H13C | 0.9800 |
O2—C5 | 1.226 (3) | C14—H14A | 0.9800 |
O3—C10 | 1.221 (3) | C14—H14B | 0.9800 |
O4—C10 | 1.347 (3) | C14—H14C | 0.9800 |
O4—C11 | 1.472 (3) | C15—C17 | 1.524 (3) |
C1—C9 | 1.515 (3) | C15—C16 | 1.527 (3) |
C1—C2 | 1.533 (4) | C15—H15 | 1.0000 |
C1—H1A | 0.9900 | C16—H16A | 0.9800 |
C1—H1B | 0.9900 | C16—H16B | 0.9800 |
C3—C4 | 1.532 (3) | C16—H16C | 0.9800 |
C3—C2 | 1.546 (3) | C17—C22 | 1.389 (4) |
C3—H3A | 1.0000 | C17—C18 | 1.400 (4) |
C2—H2A | 0.9900 | C18—C19 | 1.388 (4) |
C2—H2B | 0.9900 | C18—H18 | 0.9500 |
C5—C6 | 1.536 (3) | C19—C20 | 1.382 (4) |
C6—C7 | 1.516 (3) | C19—H19 | 0.9500 |
C6—H6 | 1.0000 | C20—C21 | 1.381 (4) |
C7—C8 | 1.526 (4) | C20—H20 | 0.9500 |
C7—H7A | 0.9900 | C21—C22 | 1.396 (4) |
C7—H7B | 0.9900 | C21—H21 | 0.9500 |
C8—C9 | 1.512 (4) | C22—H22 | 0.9500 |
| | | |
H1W—O1W—H2W | 107 (4) | C1—C9—H9 | 108.6 |
C4—N1—C15 | 124.1 (2) | O3—C10—N3 | 125.2 (2) |
C4—N1—H1 | 118.0 | O3—C10—O4 | 125.4 (2) |
C15—N1—H1 | 118.0 | N3—C10—O4 | 109.4 (2) |
C5—N2—C3 | 119.8 (2) | O4—C11—C14 | 101.7 (2) |
C5—N2—C9 | 127.5 (2) | O4—C11—C13 | 110.5 (2) |
C3—N2—C9 | 112.48 (18) | C14—C11—C13 | 110.6 (2) |
C10—N3—C6 | 121.5 (2) | O4—C11—C12 | 110.3 (2) |
C10—N3—H3 | 119.2 | C14—C11—C12 | 110.8 (2) |
C6—N3—H3 | 119.2 | C13—C11—C12 | 112.5 (3) |
C10—O4—C11 | 121.6 (2) | C11—C12—H12A | 109.5 |
C9—C1—C2 | 103.0 (2) | C11—C12—H12B | 109.5 |
C9—C1—H1A | 111.2 | H12A—C12—H12B | 109.5 |
C2—C1—H1A | 111.2 | C11—C12—H12C | 109.5 |
C9—C1—H1B | 111.2 | H12A—C12—H12C | 109.5 |
C2—C1—H1B | 111.2 | H12B—C12—H12C | 109.5 |
H1A—C1—H1B | 109.1 | C11—C13—H13A | 109.5 |
N2—C3—C4 | 109.38 (19) | C11—C13—H13B | 109.5 |
N2—C3—C2 | 103.26 (19) | H13A—C13—H13B | 109.5 |
C4—C3—C2 | 111.3 (2) | C11—C13—H13C | 109.5 |
N2—C3—H3A | 110.9 | H13A—C13—H13C | 109.5 |
C4—C3—H3A | 110.9 | H13B—C13—H13C | 109.5 |
C2—C3—H3A | 110.9 | C11—C14—H14A | 109.5 |
C1—C2—C3 | 103.74 (19) | C11—C14—H14B | 109.5 |
C1—C2—H2A | 111.0 | H14A—C14—H14B | 109.5 |
C3—C2—H2A | 111.0 | C11—C14—H14C | 109.5 |
C1—C2—H2B | 111.0 | H14A—C14—H14C | 109.5 |
C3—C2—H2B | 111.0 | H14B—C14—H14C | 109.5 |
H2A—C2—H2B | 109.0 | N1—C15—C17 | 111.9 (2) |
O1—C4—N1 | 124.7 (2) | N1—C15—C16 | 108.1 (2) |
O1—C4—C3 | 121.0 (2) | C17—C15—C16 | 111.5 (2) |
N1—C4—C3 | 114.2 (2) | N1—C15—H15 | 108.4 |
O2—C5—N2 | 121.5 (2) | C17—C15—H15 | 108.4 |
O2—C5—C6 | 121.5 (2) | C16—C15—H15 | 108.4 |
N2—C5—C6 | 117.0 (2) | C15—C16—H16A | 109.5 |
N3—C6—C7 | 112.3 (2) | C15—C16—H16B | 109.5 |
N3—C6—C5 | 108.26 (19) | H16A—C16—H16B | 109.5 |
C7—C6—C5 | 113.5 (2) | C15—C16—H16C | 109.5 |
N3—C6—H6 | 107.5 | H16A—C16—H16C | 109.5 |
C7—C6—H6 | 107.5 | H16B—C16—H16C | 109.5 |
C5—C6—H6 | 107.5 | C22—C17—C18 | 118.6 (2) |
C6—C7—C8 | 110.2 (2) | C22—C17—C15 | 122.3 (2) |
C6—C7—H7A | 109.6 | C18—C17—C15 | 119.2 (2) |
C8—C7—H7A | 109.6 | C19—C18—C17 | 120.7 (3) |
C6—C7—H7B | 109.6 | C19—C18—H18 | 119.7 |
C8—C7—H7B | 109.6 | C17—C18—H18 | 119.7 |
H7A—C7—H7B | 108.1 | C20—C19—C18 | 120.2 (3) |
C9—C8—C7 | 107.5 (2) | C20—C19—H19 | 119.9 |
C9—C8—H8A | 110.2 | C18—C19—H19 | 119.9 |
C7—C8—H8A | 110.2 | C21—C20—C19 | 119.7 (3) |
C9—C8—H8B | 110.2 | C21—C20—H20 | 120.1 |
C7—C8—H8B | 110.2 | C19—C20—H20 | 120.1 |
H8A—C8—H8B | 108.5 | C20—C21—C22 | 120.4 (3) |
N2—C9—C8 | 110.7 (2) | C20—C21—H21 | 119.8 |
N2—C9—C1 | 101.79 (19) | C22—C21—H21 | 119.8 |
C8—C9—C1 | 118.2 (2) | C17—C22—C21 | 120.4 (2) |
N2—C9—H9 | 108.6 | C17—C22—H22 | 119.8 |
C8—C9—H9 | 108.6 | C21—C22—H22 | 119.8 |
| | | |
C5—N2—C3—C4 | −56.0 (3) | C5—N2—C9—C1 | 150.4 (2) |
C9—N2—C3—C4 | 118.9 (2) | C3—N2—C9—C1 | −23.9 (3) |
C5—N2—C3—C2 | −174.5 (2) | C7—C8—C9—N2 | −51.6 (3) |
C9—N2—C3—C2 | 0.3 (3) | C7—C8—C9—C1 | −168.3 (2) |
C9—C1—C2—C3 | −38.2 (2) | C2—C1—C9—N2 | 37.4 (2) |
N2—C3—C2—C1 | 23.4 (2) | C2—C1—C9—C8 | 158.8 (2) |
C4—C3—C2—C1 | −93.9 (2) | C6—N3—C10—O3 | −2.8 (4) |
C15—N1—C4—O1 | 2.5 (4) | C6—N3—C10—O4 | 177.2 (2) |
C15—N1—C4—C3 | 179.0 (2) | C11—O4—C10—O3 | −0.4 (4) |
N2—C3—C4—O1 | −38.8 (3) | C11—O4—C10—N3 | 179.6 (2) |
C2—C3—C4—O1 | 74.7 (3) | C10—O4—C11—C14 | 178.8 (2) |
N2—C3—C4—N1 | 144.5 (2) | C10—O4—C11—C13 | −63.8 (3) |
C2—C3—C4—N1 | −102.0 (2) | C10—O4—C11—C12 | 61.2 (3) |
C3—N2—C5—O2 | −7.9 (4) | C4—N1—C15—C17 | 93.3 (3) |
C9—N2—C5—O2 | 178.1 (2) | C4—N1—C15—C16 | −143.5 (2) |
C3—N2—C5—C6 | 168.2 (2) | N1—C15—C17—C22 | −0.8 (3) |
C9—N2—C5—C6 | −5.7 (4) | C16—C15—C17—C22 | −122.1 (3) |
C10—N3—C6—C7 | −75.2 (3) | N1—C15—C17—C18 | 178.6 (2) |
C10—N3—C6—C5 | 158.7 (2) | C16—C15—C17—C18 | 57.4 (3) |
O2—C5—C6—N3 | −41.1 (3) | C22—C17—C18—C19 | 0.8 (4) |
N2—C5—C6—N3 | 142.8 (2) | C15—C17—C18—C19 | −178.7 (2) |
O2—C5—C6—C7 | −166.4 (2) | C17—C18—C19—C20 | 0.0 (4) |
N2—C5—C6—C7 | 17.5 (3) | C18—C19—C20—C21 | −0.7 (4) |
N3—C6—C7—C8 | −170.9 (2) | C19—C20—C21—C22 | 0.5 (4) |
C5—C6—C7—C8 | −47.7 (3) | C18—C17—C22—C21 | −1.0 (4) |
C6—C7—C8—C9 | 65.4 (3) | C15—C17—C22—C21 | 178.4 (2) |
C5—N2—C9—C8 | 23.9 (3) | C20—C21—C22—C17 | 0.4 (4) |
C3—N2—C9—C8 | −150.4 (2) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1W—H1W···O2 | 0.82 (4) | 2.06 (4) | 2.838 (2) | 158 (3) |
O1W—H2W···O1i | 0.86 (5) | 2.19 (5) | 2.972 (3) | 151 (4) |
N3—H3···O1i | 0.88 | 1.98 | 2.847 (2) | 167 |
N1—H1···O3i | 0.88 | 1.93 | 2.807 (2) | 173 |
C15—H15···O4ii | 1.00 | 2.50 | 3.502 (3) | 175 |
Symmetry codes: (i) x+1/2, −y+3/2, −z+1; (ii) x−1/2, −y+3/2, −z+1. |
Experimental details
Crystal data |
Chemical formula | C22H31N3O4·H2O |
Mr | 419.51 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 95 |
a, b, c (Å) | 8.520 (2), 12.095 (2), 22.323 (5) |
V (Å3) | 2300.4 (8) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.09 |
Crystal size (mm) | 0.55 × 0.10 × 0.06 |
|
Data collection |
Diffractometer | Bruker SMART CCD area-detector diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 23342, 2992, 2933 |
Rint | 0.047 |
(sin θ/λ)max (Å−1) | 0.650 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.048, 0.109, 1.15 |
No. of reflections | 2992 |
No. of parameters | 293 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.34, −0.22 |
Selected geometric parameters (Å, º) topN1—C4 | 1.334 (3) | N2—C9 | 1.477 (3) |
N1—C15 | 1.458 (3) | N3—C10 | 1.337 (3) |
N2—C5 | 1.339 (3) | N3—C6 | 1.453 (3) |
N2—C3 | 1.462 (3) | | |
| | | |
C4—N1—C15 | 124.1 (2) | C10—N3—C6 | 121.5 (2) |
C5—N2—C3 | 119.8 (2) | O2—C5—N2 | 121.5 (2) |
C5—N2—C9 | 127.5 (2) | O2—C5—C6 | 121.5 (2) |
C3—N2—C9 | 112.48 (18) | N2—C5—C6 | 117.0 (2) |
| | | |
C15—N1—C4—O1 | 2.5 (4) | C5—C6—C7—C8 | −47.7 (3) |
C9—N2—C5—O2 | 178.1 (2) | C5—N2—C9—C8 | 23.9 (3) |
C9—N2—C5—C6 | −5.7 (4) | C3—N2—C9—C1 | −23.9 (3) |
N2—C5—C6—C7 | 17.5 (3) | C6—N3—C10—O3 | −2.8 (4) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1W—H1W···O2 | 0.82 (4) | 2.06 (4) | 2.838 (2) | 158 (3) |
O1W—H2W···O1i | 0.86 (5) | 2.19 (5) | 2.972 (3) | 151 (4) |
N3—H3···O1i | 0.88 | 1.98 | 2.847 (2) | 167 |
N1—H1···O3i | 0.88 | 1.93 | 2.807 (2) | 173 |
C15—H15···O4ii | 1.00 | 2.50 | 3.502 (3) | 175 |
Symmetry codes: (i) x+1/2, −y+3/2, −z+1; (ii) x−1/2, −y+3/2, −z+1. |
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Indolizidinone-type 6,5-fused bicyclic lactams are of considerable pharmaceutical interest, since they can act as dipeptide mimics (Kim et al., 1996; Colombo et al., 1998; Angiolini et al., 2000). The synthesis of so-called peptidomimetic molecules has been a very active and productive field of research in drug design (Hanessian et al., 1997). The rationale for the development of peptide analogues is that these molecules have the same biological effects as natural peptides but, at the same time, are metabolically more stable. Of particular interest has been the replacement of reverse-turn dipeptide motifs with constrained molecules that reproduce their conformational features (Kahn, 1993). 6,5- and 7,5-fused 2-oxo-1-azabicyclo[X.3.0]alkane amino acids can be regarded as conformationally resticted substitutes for Ala-Pro and Phe-Pro dipeptide units; their conformations, studied using a combination of computer modelling with 1H NMR and FT–IR spectroscopy (Belvisi et al., 2000), have been shown to meet specific criteria, so they can be used to replace the central (i+1 and i+2) residues of β-turns.
To validate the conformational information obtained by these methods, the structure determination of the title compound, (I), a synthetic derivative of a 6,5-fused bicyclic lactam whose crystallinity allows an X-ray crystallographic analysis, has been undertaken. A preliminary data collection at room temperature showed that the crystal had a very low diffracting power. To increase the percentage of significant data, the temperature of the experiment was reduced to 95 K. The asymmetric unit of (I) comprises one molecule of tert-butyl (3S,6R,9R)-(5-oxo-3-{[1(R)-phenylethyl]carbamoyl}- 1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl)carbamate and one water molecule (Fig. 1), which interact through an O—H···O hydrogen bond. The absolute configuration of (I) was based on the known configuration of the starting material (Angiolini et al., 2000).
The six-membered ring of the indolizidinone system has a quite distorted half-chair conformation, with puckering parameters (Cremer & Pople, 1975) Q = 0.522 (2) Å, θ = 46.2 (3)° and ϕ = 216.4 (4)° for the atom sequence N2—C5—C6—C7—C8—C9. Atoms C7 and C8 are 0.325 (4) and -0.467 (4) Å, respectively, from the mean plane defined by atoms C9, N2, C5 and C6, and the r.m.s. deviation of these latter four atoms from their plane is 0.024 Å. The amido substituent at C6 (6R) is oriented equatorially, in agreement with the orientation reported for another bicyclic lactam (Kim et al., 1996). The same authors also indicate that the six-membered ring of the bicycle adopts a pseudo-chair conformation, while Hua et al. (1995) found that the six-membered lactam ring in a derivative of an octahydro-5-indolizinone could be described as having a distorted envelope conformation. However, we calculated the puckering parameters for the six-membered ring in these two literature structures and found them to be quite similar [Q = 0.479 and 0.531 (6) Å; θ = 40.5 and 55.3 (5)°; ϕ = 229.2 and 215.6 (8)°, respectively] to those for the title compound, which are close to the ideal values for a half-chair conformation (Cremer & Pople, 1975). Hua et al. (1995) state that `normally, the six-membered lactam ring assumes a distorted chair conformation owing to the tendency of the amide bond to be planar' and this is in agreement with the perfect chair conformation reported for different indolizidine moieties (Koh et al., 1993; Fleming et al., 1996; Mukhopadhyyay, 1998). The five-membered ring adopts an almost perfect envelope conformation for the atom sequence C9—C1—C2—C3—N2; the puckering parameters are q = 0.388 (2) Å and ϕ = 217.1 (4)° (the nearest ideal value for an envelope amounts to ϕ = 216°), and atom C1 is 0.596 (4) Å from the mean plane defined by atoms C2, C3, N2 and C9 (the r.m.s. deviation of these four atoms from the plane is 0.002 Å). The same conformation has been found both in indolizidinone (Hua et al., 1995) and indolizidine (Koh et al., 1993; Fleming et al., 1996; Garofano et al., 1998; Mukhopadhyyay, 1998) systems. The two rings are trans-fused (Table 1).
The observed bond distances and angles for the three amide bonds in the molecule are within the expected range derived from previously reported data (Allen et al., 1987). The value found for the N2—C9 distance is in good agreement with other values reported for this bond in the same environment, which range from 1.469 (2) (Garofano et al., 1998) to 1.479 (3) Å (Koh et al., 1993).
The geometric parameters of the hydrogen bonds are given in Table 2. Intermolecular O—H···O and N—H···O hydrogen bonds link the molecules into extended chains, which run parallel to the a axis, as shown in Fig. 2. Within the chain, adjacent peptide molecules are parallel but in a head-to-tail arrangement, as each N—H interacts with the amide O at the opposite end of the next molecule. The water molecule also links ajacent peptide molecules within the chain. In addition, one weaker C—H···O interaction is present.