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The title dipeptide, 1-(
tert-butoxycarbonyl-
D-alanyl)-
N-isopropyl-
L-pipecolamide or Boc-
D-Ala-
L-Pip-NH
iPr (H-Pip-OH is pipecolic acid or piperidine-2-carboxylic acid), C
17H
31N
3O
4, with a
D–
L heterochiral sequence, adopts a type II′ β-turn conformation, with all-
trans amide functions, where the C-terminal amide NH group interacts with the Boc carbonyl O atom to form a classical
i+3
i intramolecular hydrogen bond. The C
α substituent takes an axial position [H
α (Pip) equatorial] and the
trans pipecolamide function is nearly planar.
Supporting information
CCDC reference: 192976
The synthesis of Boc-D-Ala-L-Pip-NHiPr was carried out as follows. The
classical DIC/AtOH/DIEA (1/1/1) method was applied, starting from Boc-D-Ala-OH
and enantiomerically pure H—L-Pip-NHiPr, obtained after elimination
of the Boc protective group (HCl/AcOEt, ~3 N) of
Boc-L-Pip-NHiPr, which was previously obtained by reaction of
optically pure Boc-L-Pip-OH (BA 14202, Neosystem, Strasbourg, France)
with isopropylamine according to the DIC/BtOH/DIEA (1/1/1) method. The crude
dipeptide was chromatographed on silica gel using pure AcOEt as eluting
solvent, to give Boc-D-Ala-L-Pip-NHiPr, (I), as a white solid. Single
crystals of (I) were grown from a dilute ethyl acetate solution by slow
evaporation at room temperature (F = m.p.? 444 K; yield 80%) Thin layer
chromatography: Rf = 0.43, AcOEt/Hexanes 1/1. Spectroscopic analysis: [α]D
= -78.2 (c = 1.0, CHCl3, at 299 K); 1H NMR (CDCl3, δ, p.p.m.): 6.28 [d,
bd, 1H, NH(iPr)], 5.3–5.1 [m, 2H, NH(Ala) CHα(Pip)], 4.53 [m, 1H,
CHα(Ala)], 4.09 [m, 1H, CH(iPr)], 3.80 (d, J = 13.8 Hz, 1H, Hεeq),
3.11 (m, 1H, Hεax), 2.42 (d, J = 12.4 Hz, 1H, Hβeq), 1.8–1.4 (m, 5H,
Hβax, H2γ, H2δ), 1.43 (s, 9H, tBu), 1.32 [d, J = 7.4 Hz,
3H, Me(Ala)], 1.2–1.0 [m, 6H, Me2(iPr)].
Because of the lack of any significant anomalous dispersion effects, the
absolute conformation could not be determined from the diffraction experiment.
Friedel pairs were merged prior to refinement. The C-terminal isopropyl group
was found to be disordered and was modelled over two sites [occupancy factors
0.48 (2):0.52 (2)]. All non-H atoms were refined anisotropically, except the C
atoms of the two methyl groups of the C-terminal isopropyl group. The H atoms
of the disordered methyl group were not placed. Other H atoms connected to C
atoms were placed at calculated positions using a riding model, with C—H =
0.96–0.98 Å. The positions of H atoms attached to N atoms were located from
a difference map and the N—H bond distance was restrained to 1.03 (1) Å
(Taylor & Kennard, 1983). All H atoms were refined with their isotropic
displacement parameters fixed at 1.3 times that of the parent atom.
Data collection: COLLECT (Nonius, 1998); cell refinement: COLLECT; data reduction: HKL suite (Otwinoski & Minor, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997).
1-(
tert-butoxycarbonyl-
D-alanyl)-
N-isopropyl-
L-pipecolamide
top
Crystal data top
C17H31N3O4 | F(000) = 372 |
Mr = 341.45 | Dx = 1.132 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71070 Å |
Hall symbol: P 2yb | Cell parameters from 6016 reflections |
a = 9.3630 (2) Å | θ = 3.3–25.7° |
b = 9.9720 (5) Å | µ = 0.08 mm−1 |
c = 11.1270 (5) Å | T = 293 K |
β = 105.330 (3)° | Prismatic, colourless |
V = 1001.94 (7) Å3 | 0.4 × 0.3 × 0.2 mm |
Z = 2 | |
Data collection top
Nonius KappaCCD area-detector diffractometer | 1616 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.029 |
Graphite monochromator | θmax = 25.7°, θmin = 3.3° |
oscillation scans | h = −11→11 |
6016 measured reflections | k = −12→12 |
1978 independent reflections | l = −13→13 |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.054 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.150 | w = 1/[σ2(Fo2) + (0.0932P)2 + 0.135P] where P = (Fo2 + 2Fc2)/3 |
S = 1.06 | (Δ/σ)max = 0.005 |
1978 reflections | Δρmax = 0.41 e Å−3 |
232 parameters | Δρmin = −0.19 e Å−3 |
9 restraints | Extinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.15 (2) |
Crystal data top
C17H31N3O4 | V = 1001.94 (7) Å3 |
Mr = 341.45 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 9.3630 (2) Å | µ = 0.08 mm−1 |
b = 9.9720 (5) Å | T = 293 K |
c = 11.1270 (5) Å | 0.4 × 0.3 × 0.2 mm |
β = 105.330 (3)° | |
Data collection top
Nonius KappaCCD area-detector diffractometer | 1616 reflections with I > 2σ(I) |
6016 measured reflections | Rint = 0.029 |
1978 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.054 | 9 restraints |
wR(F2) = 0.150 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.06 | Δρmax = 0.41 e Å−3 |
1978 reflections | Δρmin = −0.19 e Å−3 |
232 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 | Occ. (<1) |
C1 | 1.0553 (4) | −0.0759 (5) | 0.6436 (4) | 0.0691 (11) | |
C2 | 0.9631 (5) | −0.1461 (6) | 0.7142 (5) | 0.0879 (14) | |
H2A | 0.8775 | −0.0927 | 0.7134 | 0.114* | |
H2B | 1.0201 | −0.1596 | 0.7987 | 0.114* | |
H2C | 0.9321 | −0.2314 | 0.6761 | 0.114* | |
C3 | 0.9625 (8) | −0.0412 (7) | 0.5114 (5) | 0.111 (2) | |
H3A | 0.8765 | 0.0087 | 0.5163 | 0.145* | |
H3B | 0.9323 | −0.1224 | 0.4654 | 0.145* | |
H3C | 1.0208 | 0.0118 | 0.4701 | 0.145* | |
C4 | 1.1887 (6) | −0.1566 (7) | 0.6423 (8) | 0.128 (3) | |
H4A | 1.2401 | −0.1808 | 0.7261 | 0.166* | |
H4B | 1.2531 | −0.1047 | 0.6062 | 0.166* | |
H4C | 1.1589 | −0.2364 | 0.5939 | 0.166* | |
O1 | 1.1195 (3) | 0.0476 (3) | 0.7071 (3) | 0.0714 (8) | |
C5 | 1.0326 (4) | 0.1490 (4) | 0.7269 (3) | 0.0544 (8) | |
O2 | 0.8992 (2) | 0.1546 (3) | 0.6887 (2) | 0.0668 (7) | |
N1 | 1.1166 (3) | 0.2456 (3) | 0.7958 (3) | 0.0564 (8) | |
H1 | 1.2291 (13) | 0.236 (5) | 0.821 (4) | 0.073* | |
C6 | 1.0471 (3) | 0.3662 (4) | 0.8254 (3) | 0.0533 (8) | |
H6 | 0.9983 | 0.4130 | 0.7479 | 0.069* | |
C7 | 1.1613 (4) | 0.4584 (5) | 0.9072 (5) | 0.0851 (15) | |
H7A | 1.1134 | 0.5381 | 0.9253 | 0.111* | |
H7B | 1.2344 | 0.4821 | 0.8645 | 0.111* | |
H7C | 1.2085 | 0.4133 | 0.9836 | 0.111* | |
C8 | 0.9307 (3) | 0.3290 (3) | 0.8948 (3) | 0.0456 (7) | |
O3 | 0.9578 (2) | 0.2407 (3) | 0.9737 (2) | 0.0637 (7) | |
N2 | 0.8009 (3) | 0.3980 (3) | 0.8678 (2) | 0.0462 (7) | |
C9 | 0.6863 (3) | 0.3581 (4) | 0.9290 (3) | 0.0515 (8) | |
H9 | 0.7338 | 0.3013 | 1.0002 | 0.067* | |
C10 | 0.6225 (4) | 0.4811 (5) | 0.9800 (4) | 0.0679 (11) | |
H10A | 0.5397 | 0.4532 | 1.0112 | 0.088* | |
H10B | 0.6976 | 0.5186 | 1.0492 | 0.088* | |
C11 | 0.5713 (4) | 0.5871 (5) | 0.8824 (4) | 0.0742 (12) | |
H11A | 0.5371 | 0.6649 | 0.9192 | 0.096* | |
H11B | 0.4891 | 0.5531 | 0.8170 | 0.096* | |
C12 | 0.6972 (4) | 0.6276 (4) | 0.8271 (5) | 0.0731 (11) | |
H12A | 0.7758 | 0.6690 | 0.8910 | 0.095* | |
H12B | 0.6616 | 0.6928 | 0.7612 | 0.095* | |
C13 | 0.7573 (4) | 0.5049 (4) | 0.7747 (4) | 0.0595 (9) | |
H13A | 0.6821 | 0.4710 | 0.7036 | 0.077* | |
H13B | 0.8424 | 0.5311 | 0.7459 | 0.077* | |
C14 | 0.5632 (3) | 0.2752 (4) | 0.8427 (3) | 0.0529 (8) | |
O4 | 0.4396 (3) | 0.2722 (3) | 0.8605 (3) | 0.0752 (9) | |
N3 | 0.5991 (3) | 0.2034 (3) | 0.7534 (3) | 0.0636 (9) | |
H3 | 0.698 (3) | 0.209 (5) | 0.731 (4) | 0.083* | |
C15A | 0.4988 (15) | 0.1104 (10) | 0.6726 (13) | 0.089 (8) | 0.517 (17) |
H15A | 0.4037 | 0.1102 | 0.6938 | 0.116* | 0.517 (17) |
C16A | 0.476 (3) | 0.160 (3) | 0.5407 (17) | 0.187 (9)* | 0.517 (17) |
C17A | 0.5687 (12) | −0.0270 (12) | 0.6970 (13) | 0.094 (4)* | 0.517 (17) |
C15B | 0.4891 (12) | 0.1228 (8) | 0.6671 (11) | 0.058 (6) | 0.483 (17) |
H15B | 0.4247 | 0.0861 | 0.7156 | 0.075* | 0.483 (17) |
C16B | 0.3901 (11) | 0.2051 (11) | 0.5647 (8) | 0.084 (4)* | 0.483 (17) |
C17B | 0.5570 (12) | 0.0034 (11) | 0.6199 (12) | 0.086 (4)* | 0.483 (17) |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.069 (2) | 0.064 (3) | 0.078 (2) | −0.0136 (19) | 0.0270 (19) | −0.022 (2) |
C2 | 0.084 (3) | 0.082 (3) | 0.098 (3) | −0.007 (3) | 0.024 (2) | 0.013 (3) |
C3 | 0.163 (6) | 0.102 (5) | 0.075 (3) | −0.033 (4) | 0.042 (3) | −0.033 (3) |
C4 | 0.090 (3) | 0.086 (4) | 0.225 (7) | −0.017 (3) | 0.073 (4) | −0.079 (5) |
O1 | 0.0528 (13) | 0.0653 (18) | 0.101 (2) | −0.0087 (13) | 0.0291 (13) | −0.0319 (15) |
C5 | 0.0508 (18) | 0.058 (2) | 0.0583 (18) | −0.0051 (17) | 0.0220 (14) | −0.0075 (16) |
O2 | 0.0449 (12) | 0.0794 (18) | 0.0719 (15) | −0.0037 (13) | 0.0083 (10) | −0.0130 (14) |
N1 | 0.0404 (13) | 0.0544 (17) | 0.0761 (18) | −0.0035 (13) | 0.0186 (12) | −0.0140 (15) |
C6 | 0.0468 (16) | 0.0446 (18) | 0.074 (2) | 0.0013 (14) | 0.0260 (15) | 0.0020 (16) |
C7 | 0.055 (2) | 0.061 (3) | 0.147 (4) | −0.0160 (19) | 0.040 (2) | −0.040 (3) |
C8 | 0.0427 (16) | 0.0429 (18) | 0.0506 (17) | −0.0022 (13) | 0.0111 (12) | −0.0007 (15) |
O3 | 0.0561 (14) | 0.0656 (17) | 0.0701 (15) | 0.0096 (12) | 0.0178 (11) | 0.0187 (14) |
N2 | 0.0368 (12) | 0.0474 (16) | 0.0559 (14) | −0.0008 (11) | 0.0149 (10) | 0.0027 (12) |
C9 | 0.0405 (15) | 0.064 (2) | 0.0525 (17) | −0.0038 (15) | 0.0161 (13) | 0.0012 (16) |
C10 | 0.058 (2) | 0.081 (3) | 0.070 (2) | −0.005 (2) | 0.0263 (18) | −0.021 (2) |
C11 | 0.059 (2) | 0.066 (3) | 0.098 (3) | 0.0130 (19) | 0.022 (2) | −0.017 (2) |
C12 | 0.058 (2) | 0.057 (2) | 0.101 (3) | 0.0049 (19) | 0.0128 (19) | 0.000 (2) |
C13 | 0.0558 (19) | 0.055 (2) | 0.072 (2) | 0.0068 (16) | 0.0240 (17) | 0.0129 (18) |
C14 | 0.0443 (16) | 0.049 (2) | 0.068 (2) | −0.0023 (14) | 0.0182 (15) | 0.0031 (16) |
O4 | 0.0446 (12) | 0.084 (2) | 0.104 (2) | −0.0117 (13) | 0.0313 (13) | −0.0115 (17) |
N3 | 0.0434 (15) | 0.065 (2) | 0.082 (2) | −0.0060 (14) | 0.0159 (14) | −0.0205 (18) |
C15A | 0.085 (13) | 0.076 (12) | 0.114 (16) | −0.010 (11) | 0.042 (11) | −0.017 (12) |
C15B | 0.040 (7) | 0.055 (9) | 0.067 (10) | −0.008 (7) | −0.006 (7) | −0.019 (7) |
Geometric parameters (Å, º) top
C1—O1 | 1.468 (5) | N2—C9 | 1.469 (4) |
C1—C2 | 1.488 (6) | C9—C14 | 1.533 (5) |
C1—C4 | 1.489 (7) | C9—C10 | 1.537 (5) |
C1—C3 | 1.536 (8) | C9—H9 | 0.9800 |
C2—H2A | 0.9600 | C10—C11 | 1.501 (7) |
C2—H2B | 0.9600 | C10—H10A | 0.9700 |
C2—H2C | 0.9600 | C10—H10B | 0.9700 |
C3—H3A | 0.9600 | C11—C12 | 1.521 (6) |
C3—H3B | 0.9600 | C11—H11A | 0.9700 |
C3—H3C | 0.9600 | C11—H11B | 0.9700 |
C4—H4A | 0.9600 | C12—C13 | 1.526 (6) |
C4—H4B | 0.9600 | C12—H12A | 0.9700 |
C4—H4C | 0.9600 | C12—H12B | 0.9700 |
O1—C5 | 1.351 (5) | C13—H13A | 0.9700 |
C5—O2 | 1.210 (4) | C13—H13B | 0.9700 |
C5—N1 | 1.348 (5) | C14—O4 | 1.225 (4) |
N1—C6 | 1.446 (4) | C14—N3 | 1.338 (5) |
N1—H1 | 1.020 (10) | N3—C15A | 1.450 (5) |
C6—C7 | 1.518 (5) | N3—C15B | 1.451 (5) |
C6—C8 | 1.538 (4) | N3—H3 | 1.023 (10) |
C6—H6 | 0.9800 | C15A—C16A | 1.510 (5) |
C7—H7A | 0.9600 | C15A—C17A | 1.512 (5) |
C7—H7B | 0.9600 | C15A—H15A | 0.9800 |
C7—H7C | 0.9600 | C15B—C16B | 1.508 (5) |
C8—O3 | 1.221 (4) | C15B—C17B | 1.509 (5) |
C8—N2 | 1.360 (4) | C15B—H15B | 0.9800 |
N2—C13 | 1.468 (5) | | |
| | | |
O1—C1—C2 | 111.2 (4) | N2—C9—C10 | 111.0 (3) |
O1—C1—C4 | 102.7 (3) | C14—C9—C10 | 111.1 (3) |
C2—C1—C4 | 110.9 (5) | N2—C9—H9 | 107.5 |
O1—C1—C3 | 109.1 (4) | C14—C9—H9 | 107.5 |
C2—C1—C3 | 110.6 (4) | C10—C9—H9 | 107.5 |
C4—C1—C3 | 112.1 (5) | C11—C10—C9 | 112.0 (3) |
C1—C2—H2A | 109.5 | C11—C10—H10A | 109.2 |
C1—C2—H2B | 109.5 | C9—C10—H10A | 109.2 |
H2A—C2—H2B | 109.5 | C11—C10—H10B | 109.2 |
C1—C2—H2C | 109.5 | C9—C10—H10B | 109.2 |
H2A—C2—H2C | 109.5 | H10A—C10—H10B | 107.9 |
H2B—C2—H2C | 109.5 | C10—C11—C12 | 110.3 (3) |
C1—C3—H3A | 109.5 | C10—C11—H11A | 109.6 |
C1—C3—H3B | 109.5 | C12—C11—H11A | 109.6 |
H3A—C3—H3B | 109.5 | C10—C11—H11B | 109.6 |
C1—C3—H3C | 109.5 | C12—C11—H11B | 109.6 |
H3A—C3—H3C | 109.5 | H11A—C11—H11B | 108.1 |
H3B—C3—H3C | 109.5 | C11—C12—C13 | 110.2 (3) |
C1—C4—H4A | 109.5 | C11—C12—H12A | 109.6 |
C1—C4—H4B | 109.5 | C13—C12—H12A | 109.6 |
H4A—C4—H4B | 109.5 | C11—C12—H12B | 109.6 |
C1—C4—H4C | 109.5 | C13—C12—H12B | 109.6 |
H4A—C4—H4C | 109.5 | H12A—C12—H12B | 108.1 |
H4B—C4—H4C | 109.5 | N2—C13—C12 | 112.0 (3) |
C5—O1—C1 | 121.2 (3) | N2—C13—H13A | 109.2 |
O2—C5—N1 | 124.1 (3) | C12—C13—H13A | 109.2 |
O2—C5—O1 | 126.0 (3) | N2—C13—H13B | 109.2 |
N1—C5—O1 | 110.0 (3) | C12—C13—H13B | 109.2 |
C5—N1—C6 | 119.6 (3) | H13A—C13—H13B | 107.9 |
C5—N1—H1 | 120 (3) | O4—C14—N3 | 122.7 (3) |
C6—N1—H1 | 120 (3) | O4—C14—C9 | 119.9 (3) |
N1—C6—C7 | 110.6 (3) | N3—C14—C9 | 117.3 (3) |
N1—C6—C8 | 109.5 (3) | C14—N3—C15A | 123.6 (8) |
C7—C6—C8 | 109.0 (3) | C14—N3—C15B | 120.9 (7) |
N1—C6—H6 | 109.2 | C15A—N3—C15B | 6.2 (7) |
C7—C6—H6 | 109.2 | C14—N3—H3 | 125 (3) |
C8—C6—H6 | 109.2 | C15A—N3—H3 | 111 (3) |
C6—C7—H7A | 109.5 | C15B—N3—H3 | 114 (3) |
C6—C7—H7B | 109.5 | N3—C15A—C16A | 107.2 (13) |
H7A—C7—H7B | 109.5 | N3—C15A—C17A | 106.8 (8) |
C6—C7—H7C | 109.5 | C16A—C15A—C17A | 114.4 (16) |
H7A—C7—H7C | 109.5 | N3—C15A—H15A | 109.4 |
H7B—C7—H7C | 109.5 | C16A—C15A—H15A | 109.4 |
O3—C8—N2 | 121.8 (3) | C17A—C15A—H15A | 109.4 |
O3—C8—C6 | 119.7 (3) | N3—C15B—C16B | 112.7 (7) |
N2—C8—C6 | 118.5 (3) | N3—C15B—C17B | 112.1 (8) |
C8—N2—C13 | 126.1 (3) | C16B—C15B—C17B | 113.4 (10) |
C8—N2—C9 | 118.7 (3) | N3—C15B—H15B | 106.0 |
C13—N2—C9 | 115.0 (3) | C16B—C15B—H15B | 106.0 |
N2—C9—C14 | 112.1 (3) | C17B—C15B—H15B | 106.0 |
| | | |
C2—C1—O1—C5 | −61.5 (5) | N2—C9—C14—O4 | −155.5 (3) |
C4—C1—O1—C5 | 179.8 (5) | C10—C9—C14—O4 | −30.7 (5) |
C3—C1—O1—C5 | 60.7 (5) | C10—C9—C14—N3 | 152.4 (3) |
C1—O1—C5—O2 | −5.7 (6) | O4—C14—N3—C15A | −2.9 (8) |
O2—C5—N1—C6 | −1.5 (5) | O4—C14—N3—C15B | 3.6 (8) |
C5—N1—C6—C7 | 178.0 (4) | C14—N3—C15A—C16A | 119.0 (14) |
N1—C6—C8—O3 | 40.6 (4) | C15B—N3—C15A—C16A | 53 (13) |
C7—C6—C8—O3 | −80.6 (4) | C14—N3—C15A—C17A | −117.9 (11) |
C7—C6—C8—N2 | 98.1 (4) | C15B—N3—C15A—C17A | 176 (14) |
O3—C8—N2—C13 | −179.6 (3) | C14—N3—C15B—C16B | 78.8 (13) |
C6—C8—N2—C13 | 1.7 (5) | C15A—N3—C15B—C16B | −163 (14) |
O3—C8—N2—C9 | −4.6 (5) | C14—N3—C15B—C17B | −151.7 (9) |
C13—N2—C9—C14 | 73.9 (4) | C15A—N3—C15B—C17B | −34 (12) |
C8—N2—C9—C10 | 133.4 (3) | C1—O1—C5—N1 | 174.7 (3) |
C13—N2—C9—C10 | −51.0 (4) | O1—C5—N1—C6 | 178.1 (3) |
N2—C9—C10—C11 | 52.4 (4) | C5—N1—C6—C8 | 57.9 (4) |
C14—C9—C10—C11 | −73.0 (4) | N1—C6—C8—N2 | −140.7 (3) |
C9—C10—C11—C12 | −56.0 (4) | C6—C8—N2—C9 | 176.8 (3) |
C10—C11—C12—C13 | 56.4 (4) | C8—N2—C9—C14 | −101.7 (3) |
C8—N2—C13—C12 | −131.9 (3) | N2—C9—C14—N3 | 27.6 (5) |
C9—N2—C13—C12 | 52.9 (4) | C9—C14—N3—C15A | 173.9 (7) |
C11—C12—C13—N2 | −54.3 (4) | C9—C14—N3—C15B | −179.6 (6) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O4i | 1.02 (1) | 1.94 (2) | 2.929 (3) | 164 (4) |
N3—H3···O2 | 1.02 (1) | 2.13 (2) | 3.118 (4) | 162 (4) |
Symmetry code: (i) x+1, y, z. |
Experimental details
Crystal data |
Chemical formula | C17H31N3O4 |
Mr | 341.45 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 293 |
a, b, c (Å) | 9.3630 (2), 9.9720 (5), 11.1270 (5) |
β (°) | 105.330 (3) |
V (Å3) | 1001.94 (7) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.4 × 0.3 × 0.2 |
|
Data collection |
Diffractometer | Nonius KappaCCD area-detector diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 6016, 1978, 1616 |
Rint | 0.029 |
(sin θ/λ)max (Å−1) | 0.610 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.054, 0.150, 1.06 |
No. of reflections | 1978 |
No. of parameters | 232 |
No. of restraints | 9 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.41, −0.19 |
Selected torsion angles (º) topC1—O1—C5—N1 | 174.7 (3) | C8—N2—C9—C14 | −101.7 (3) |
O1—C5—N1—C6 | 178.1 (3) | N2—C9—C14—N3 | 27.6 (5) |
C5—N1—C6—C8 | 57.9 (4) | C9—C14—N3—C15A | 173.9 (7) |
N1—C6—C8—N2 | −140.7 (3) | C9—C14—N3—C15B | −179.6 (6) |
C6—C8—N2—C9 | 176.8 (3) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O4i | 1.020 (10) | 1.936 (17) | 2.929 (3) | 164 (4) |
N3—H3···O2 | 1.023 (10) | 2.127 (19) | 3.118 (4) | 162 (4) |
Symmetry code: (i) x+1, y, z. |
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With the advent of the post-genomic era, a larger number either of peptides or peptidomimetics will be designed as available drugs for studying their role in the development and care of diseases. In addition, with sequences of natural amino acids, those with different topologies containing non-coded building blocks will be mandatory to face this challenge.
Of the three main types of structural motifs (β-sheets, helices and turns of loops), the β-turn, which is often involved in molecular recognition processes, offers the significant advantage that it is compact and of such a size that it can readily be encountered in the totally amidated dipeptide sequence R—CO-Xaa-Yaa-NH—R'.
The widespread naturally occurring non-proteinogenic amino acid, pipecolic acid, H-Pip-OH (also known as homoproline or piperidine-2-carboxylic acid), is a proline analogue with a six-membered piperidine ring and which is found in many biologically active compounds. It is a component of several antibiotics, immunosuppressants and inhibitors of HIV protease, and has been extensively used as a proline substitute in numerous syntheses of peptidomimetics studied in structure-activity relationships.
As part of an overall conformational analysis project aimed at exploring local perturbations induced by the substitution either of Pip or AzPip (AzPip is the homologue of Pip in which an Nα atom has been substituted for the Pip Cα atom), we recently reported the crystal structures of Boc-L-Ala-(S)AzPip-NHiPr and of Piv-L/DPip-NHMe (Didierjean et al., 2000), and in this paper, we present the molecular crystal-structure resolution of Boc-D-Ala-L-Pip-NHiPr, (I), for the purpose of giving prominence to conformational bias. \sch
A view of the molecule of (I) with the atom-numbering scheme is shown in Fig. 1. Selected torsion angles and hydrogen bonds with their geometry and symmetry geometry are given in Tables 1 and 2, respectively. The bond lengths and angles are in agreement with literature data on the geometry of the Pip residue (Bhattacharjee & Chacko, 1979; Rae et al., 1980; Bardi et al., 1992; Didierjean et al., 2000) and Boc urethane derivatives (Benedetti et al., 1980). A type b of this latter N-protecting group is assumed by the trans arrangement of both C1—O1 versus C5—N1 and the CONH amide bond of the urethane group. The C-terminal isopropyl group is disordered and was modelled over two positions with restrained distances and angles.
The piperidine ring adopts a chair (4C1) conformation with the Hα atom in the equatorial disposition, as expected from calculations (Toniolo et al., 1989) and as also found in Piv-D/LPip-NHMe (Didierjean et al., 2000). The piperidyl imide link is trans [ω = 176.8 (3)°] and atom N2 exhibits a very low displacement [0.033 (3) Å] from the plane defined by its three substituents.
The molecule of (I) is folded by a type-II' β-bend conformation, with D-Ala as i+1 and L-Pip as i+2 corner residues. The 4 → 1 intramolecular hydrogen bond takes place between the donor (NHiPr) C-terminal amide group and the (Boc)urethane carbonyl acceptor sites (Fig. 1, Table 2).
Concerning the molecular packing, an intermolecular N—H···O═C hydrogen-bonding network occurs along the a axis, involving the urethane (D-Ala)N—H as donor and the amide (Pip)C═O as acceptor (Fig. 2, Table 2). The crystal can be described as forming infinite chains, where each chain forms weak van der Waals interactions with neighbouring chains.
If we compare the conformation of (I) with that of Boc-L-Ala-(S)AzPip-NHiPr (Didierjean et al., 2000), the two prominent changes are a cis disposition for the median AzPip imide bond and type-VI β-turn-like folding. Thus, local modification of the three-dimensional structure can be achieved by using the Pip/AzPip couple, and this should be of great interest when designing new building blocks for peptidomimetics.