Simvastatin, or (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxo-3,4,5,6-tetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate, C25H38O5, is almost isostructural with lovastatin, and the general conformational features are closely related to those of other reported crystal structures of statins. The only hydrogen bond present facilitates the formation of infinite chains of molecules along the b axis.
Supporting information
CCDC reference: 219566
To a solution of simvastatin (1.1 g) in acetone (3.5 ml) was added n-heptane (6.5 ml). The mixture was allowed to stand overnight, and the resulting crystals were washed with n-heptane and adjusted for measurement.
The flexible acid residue is disordered and is modelled as two optional rotated parts, namely C22/C23/C24/C25 (occupany 2/3) and C32/C33/C34/C35 (occupancy 1/3). Restrains of 1.550 (5) Å were applied to the interatomic distances of the minor disordered form. Atom H531, which is involved in the hydrogen-bond network, was found from Fourier maps and was refined with a fixed position. The remaining H atoms were placed in calculated positions and refined as riding on their attached C atoms, with C—H distances of 1.0 Å.
Data collection: COLLECT (Nonius BV, 1997); cell refinement: DENZO/SCALEPACK (Otwinowski & Minor, 1996); data reduction: DENZO/SCALEPACK (Otwinowski & Minor, 1996); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Watkin et al. 2001); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: CRYSTALS (Watkin et al. 2001).
(1
S,3
R,7
S,8S,8aR)-3,7-dimethyl-8-{2-[(2
R,4
R)-4-hydroxy-6-oxo-3,4,5,6- tetrahydro-2
H-pyran-2-yl]ethyl}-1,2,3,7,8,8a-hexahydronaphthalin-1-yl 2,2-dimethylbutanoate
top
Crystal data top
C25H38O5 | Dx = 1.167 Mg m−3 |
Mr = 418.57 | Melting point: not measured K |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 10477 reflections |
a = 6.1283 (3) Å | θ = 1–25° |
b = 17.2964 (7) Å | µ = 0.08 mm−1 |
c = 22.4659 (6) Å | T = 293 K |
V = 2381.33 (16) Å3 | Needle, white |
Z = 4 | 0.36 × 0.14 × 0.08 mm |
F(000) = 912.000 | |
Data collection top
Enraf Nonius Kappa CCD diffractometer | Rint = 0.03 |
Graphite monochromator | θmax = 26.0°, θmin = 3.5° |
ϕ & ω scans | h = −7→7 |
4673 measured reflections | k = −21→21 |
2692 independent reflections | l = −27→27 |
2281 reflections with I > 1.96σ(I) | |
Refinement top
Refinement on F | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.072 | H-atom parameters constrained |
wR(F2) = 0.084 | Method = Prince modified Chebychev polynomial, (Watkin, 1994)
W = [weight] * [1-(deltaF/6*sigmaF)2]2 2.18 2.29 1.53 |
S = 1.12 | (Δ/σ)max = 0.000079 |
2281 reflections | Δρmax = 0.44 e Å−3 |
267 parameters | Δρmin = −0.28 e Å−3 |
Crystal data top
C25H38O5 | V = 2381.33 (16) Å3 |
Mr = 418.57 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 6.1283 (3) Å | µ = 0.08 mm−1 |
b = 17.2964 (7) Å | T = 293 K |
c = 22.4659 (6) Å | 0.36 × 0.14 × 0.08 mm |
Data collection top
Enraf Nonius Kappa CCD diffractometer | 2281 reflections with I > 1.96σ(I) |
4673 measured reflections | Rint = 0.03 |
2692 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.072 | 267 parameters |
wR(F2) = 0.084 | H-atom parameters constrained |
S = 1.12 | Δρmax = 0.44 e Å−3 |
2281 reflections | Δρmin = −0.28 e Å−3 |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | Occ. (<1) |
O1 | 0.5595 (5) | 0.11553 (13) | 0.05082 (11) | 0.0754 | |
O2 | 0.8000 (6) | 0.16046 (19) | −0.01074 (15) | 0.1044 | |
O3 | 0.7347 (8) | 0.2115 (2) | 0.17234 (16) | 0.1212 | |
O4 | −0.0096 (3) | −0.12402 (11) | 0.17925 (8) | 0.0571 | |
O5 | 0.2245 (7) | −0.1493 (2) | 0.25228 (13) | 0.1049 | |
C1 | 0.6978 (5) | 0.17134 (18) | 0.03373 (17) | 0.0697 | |
C2 | 0.7162 (6) | 0.24488 (19) | 0.0688 (2) | 0.0820 | |
C3 | 0.6028 (7) | 0.2463 (2) | 0.12742 (16) | 0.0756 | |
C4 | 0.3878 (6) | 0.2037 (2) | 0.12196 (17) | 0.0718 | |
C5 | 0.4261 (6) | 0.12054 (17) | 0.10414 (13) | 0.0625 | |
C6 | 0.2180 (6) | 0.07748 (17) | 0.08998 (15) | 0.0663 | |
C7 | 0.2472 (5) | −0.01037 (16) | 0.08735 (14) | 0.0594 | |
C8 | 0.1255 (4) | −0.16670 (15) | 0.13711 (12) | 0.0536 | |
C9 | 0.1025 (5) | −0.25354 (17) | 0.14498 (16) | 0.0663 | |
C10 | −0.1287 (6) | −0.2845 (2) | 0.13494 (18) | 0.0754 | |
C11 | −0.2375 (5) | −0.24305 (17) | 0.08441 (15) | 0.0651 | |
C12 | −0.1623 (4) | −0.17995 (16) | 0.05789 (13) | 0.0562 | |
C13 | −0.2809 (5) | −0.1443 (2) | 0.00835 (14) | 0.0668 | |
C14 | −0.2226 (6) | −0.0792 (2) | −0.01641 (15) | 0.0708 | |
C15 | −0.0320 (5) | −0.03139 (18) | 0.00339 (13) | 0.0619 | |
C16 | 0.0363 (5) | −0.05243 (15) | 0.06710 (12) | 0.0533 | |
C17 | 0.0522 (4) | −0.14154 (16) | 0.07523 (11) | 0.0515 | |
C18 | 0.1550 (7) | −0.0353 (3) | −0.04323 (16) | 0.0811 | |
C19 | −0.2744 (9) | −0.2817 (3) | 0.1906 (2) | 0.1006 | |
C20 | 0.0649 (7) | −0.1162 (2) | 0.23439 (15) | 0.0728 | |
C21 | −0.0688 (9) | −0.0627 (3) | 0.27170 (17) | 0.0925 | |
C22 | −0.187 (2) | −0.0040 (8) | 0.2371 (5) | 0.141 (3)* | 0.6670 |
C23 | −0.332 (4) | 0.043 (1) | 0.2748 (7) | 0.181 (6)* | 0.6670 |
C24 | 0.092 (3) | −0.025 (1) | 0.3166 (7) | 0.184 (5)* | 0.6670 |
C25 | −0.192 (3) | −0.1114 (8) | 0.3151 (7) | 0.160 (4)* | 0.6670 |
C32 | −0.040 (3) | −0.0832 (13) | 0.3384 (4) | 0.128 (6)* | 0.3330 |
C33 | −0.267 (5) | −0.078 (3) | 0.3686 (12) | 0.25 (2)* | 0.3330 |
C34 | −0.3106 (19) | −0.0602 (18) | 0.2513 (13) | 0.17 (1)* | 0.3330 |
C35 | 0.015 (7) | 0.0194 (12) | 0.2561 (17) | 0.210 (16)* | 0.3330 |
H21 | 0.8746 | 0.25465 | 0.0765 | 0.1001* | |
H22 | 0.6555 | 0.28758 | 0.0438 | 0.1001* | |
H31 | 0.5737 | 0.3013 | 0.13881 | 0.0934* | |
H41 | 0.3116 | 0.2049 | 0.16131 | 0.0887* | |
H42 | 0.2948 | 0.2296 | 0.09129 | 0.0887* | |
H51 | 0.4990 | 0.09703 | 0.13961 | 0.0733* | |
H61 | 0.1073 | 0.08982 | 0.12128 | 0.0795* | |
H62 | 0.1636 | 0.09551 | 0.05037 | 0.0795* | |
H71 | 0.2881 | −0.02925 | 0.12791 | 0.0710* | |
H72 | 0.3669 | −0.02272 | 0.05866 | 0.0710* | |
H81 | 0.2840 | −0.15577 | 0.14344 | 0.0643* | |
H91 | 0.1462 | −0.26667 | 0.18666 | 0.0780* | |
H92 | 0.2030 | −0.27982 | 0.11637 | 0.0780* | |
H101 | −0.1101 | −0.3402 | 0.12419 | 0.0875* | |
H111 | −0.3783 | −0.26492 | 0.06950 | 0.0784* | |
H131 | −0.4147 | −0.1707 | −0.00695 | 0.0786* | |
H141 | −0.3086 | −0.0606 | −0.05142 | 0.0854* | |
H151 | −0.0749 | 0.02432 | 0.00558 | 0.0750* | |
H161 | −0.0818 | −0.03389 | 0.09428 | 0.0630* | |
H171 | 0.1704 | −0.15893 | 0.04761 | 0.0630* | |
H181 | 0.0968 | −0.0206 | −0.08325 | 0.1003* | |
H182 | 0.2132 | −0.0893 | −0.04478 | 0.1003* | |
H183 | 0.2747 | 0.0010 | −0.03176 | 0.1003* | |
H191 | −0.4225 | −0.3024 | 0.1808 | 0.1198* | |
H192 | −0.2073 | −0.3138 | 0.2228 | 0.1198* | |
H193 | −0.2876 | −0.2270 | 0.2045 | 0.1198* | |
H221 | −0.313 | −0.0391 | 0.2291 | 0.1554* | 0.6670 |
H222 | −0.127 | 0.0155 | 0.1985 | 0.1554* | 0.6670 |
H231 | −0.448 | 0.074 | 0.2546 | 0.2198* | 0.6670 |
H232 | −0.389 | 0.023 | 0.3133 | 0.2198* | 0.6670 |
H233 | −0.203 | 0.077 | 0.2827 | 0.2198* | 0.6670 |
H241 | 0.008 | 0.011 | 0.3427 | 0.2363* | 0.6670 |
H242 | 0.154 | −0.068 | 0.3413 | 0.2363* | 0.6670 |
H243 | 0.213 | 0.004 | 0.2965 | 0.2363* | 0.6670 |
H251 | −0.284 | −0.0780 | 0.3414 | 0.1740* | 0.6670 |
H252 | −0.090 | −0.1427 | 0.3402 | 0.1740* | 0.6670 |
H253 | −0.288 | −0.1467 | 0.2916 | 0.1740* | 0.6670 |
H321 | 0.093 | −0.0613 | 0.3579 | 0.1541* | 0.3330 |
H322 | −0.031 | −0.1410 | 0.3383 | 0.1541* | 0.3330 |
H331 | −0.259 | −0.097 | 0.4106 | 0.3364* | 0.3330 |
H332 | −0.276 | −0.020 | 0.3684 | 0.3364* | 0.3330 |
H333 | −0.399 | −0.100 | 0.3488 | 0.3364* | 0.3330 |
H341 | −0.3587 | −0.0444 | 0.2106 | 0.1811* | 0.3330 |
H342 | −0.3959 | −0.0307 | 0.2818 | 0.1811* | 0.3330 |
H343 | −0.3362 | −0.1168 | 0.2568 | 0.1811* | 0.3330 |
H531 | 0.7578 | 0.2515 | 0.20230 | 0.2824* | |
H351 | 0.176 | 0.0258 | 0.2616 | 0.3674* | 0.3330 |
H352 | −0.064 | 0.0512 | 0.2863 | 0.3674* | 0.3330 |
H353 | −0.027 | 0.0368 | 0.2152 | 0.3674* | 0.3330 |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0729 (14) | 0.0649 (12) | 0.0885 (14) | −0.0053 (11) | 0.0197 (13) | −0.004 (1) |
O2 | 0.102 (2) | 0.0968 (19) | 0.114 (2) | 0.0097 (18) | 0.045 (2) | 0.0238 (16) |
O3 | 0.147 (3) | 0.108 (2) | 0.109 (2) | −0.014 (2) | −0.061 (3) | −0.0054 (18) |
O4 | 0.055 (1) | 0.0635 (11) | 0.053 (1) | −0.0007 (8) | −0.0036 (8) | −0.0075 (8) |
O5 | 0.109 (2) | 0.130 (2) | 0.0757 (15) | 0.027 (2) | −0.0298 (17) | −0.0010 (15) |
C1 | 0.0603 (16) | 0.0630 (16) | 0.086 (2) | 0.0082 (14) | 0.0088 (16) | 0.0173 (15) |
C2 | 0.0639 (17) | 0.0663 (17) | 0.116 (3) | −0.0079 (16) | −0.0094 (19) | 0.0156 (19) |
C3 | 0.083 (2) | 0.0618 (16) | 0.082 (2) | −0.0055 (17) | −0.0145 (18) | −0.0045 (15) |
C4 | 0.071 (2) | 0.0647 (16) | 0.0795 (19) | −0.0056 (16) | 0.0101 (17) | −0.0084 (15) |
C5 | 0.0670 (16) | 0.0579 (14) | 0.0626 (15) | −0.0008 (14) | 0.0042 (13) | 0.0051 (12) |
C6 | 0.0613 (16) | 0.0601 (15) | 0.0775 (19) | −0.0037 (13) | 0.0029 (15) | −0.0018 (13) |
C7 | 0.0552 (14) | 0.0573 (13) | 0.0658 (16) | 0.0003 (12) | −0.0028 (13) | −0.0020 (11) |
C8 | 0.0444 (12) | 0.0544 (13) | 0.0620 (14) | 0.0040 (11) | −0.004 (1) | −0.0026 (11) |
C9 | 0.0656 (16) | 0.0551 (14) | 0.0782 (18) | 0.0048 (14) | −0.0052 (15) | −0.0011 (13) |
C10 | 0.074 (2) | 0.0591 (16) | 0.093 (2) | −0.0078 (15) | 0.0006 (17) | 0.0012 (16) |
C11 | 0.0549 (14) | 0.0614 (15) | 0.0789 (18) | −0.0072 (13) | −0.0008 (14) | −0.0143 (13) |
C12 | 0.0466 (12) | 0.0586 (14) | 0.0633 (15) | 0.0020 (11) | −0.0016 (11) | −0.0166 (11) |
C13 | 0.0535 (14) | 0.0809 (19) | 0.0659 (16) | 0.0002 (14) | −0.0121 (13) | −0.0094 (15) |
C14 | 0.0627 (17) | 0.087 (2) | 0.0623 (15) | 0.0055 (16) | −0.0104 (14) | −0.0074 (15) |
C15 | 0.0587 (15) | 0.0673 (17) | 0.0597 (14) | 0.0055 (14) | −0.0030 (13) | 0.0023 (12) |
C16 | 0.0471 (12) | 0.0558 (13) | 0.0570 (13) | 0.0023 (11) | 0.0018 (11) | −0.0024 (11) |
C17 | 0.0439 (11) | 0.0577 (13) | 0.0529 (12) | 0.0028 (11) | −0.0019 (11) | −0.005 (1) |
C18 | 0.081 (2) | 0.100 (3) | 0.0623 (17) | 0.007 (2) | 0.0101 (17) | 0.0060 (17) |
C19 | 0.090 (3) | 0.114 (3) | 0.098 (3) | −0.025 (3) | 0.008 (2) | 0.021 (2) |
C20 | 0.075 (2) | 0.079 (2) | 0.0646 (17) | −0.0108 (17) | −0.0081 (16) | −0.0018 (14) |
C21 | 0.101 (3) | 0.108 (3) | 0.0686 (19) | −0.002 (3) | 0.012 (2) | −0.0203 (19) |
Geometric parameters (Å, º) top
O1—C1 | 1.341 (4) | C15—C18 | 1.554 (5) |
O1—C5 | 1.453 (4) | C15—H151 | 1.000 |
O2—C1 | 1.194 (4) | C16—C17 | 1.555 (4) |
O3—C3 | 1.427 (5) | C16—H161 | 1.000 |
O3—H531 | 0.976 | C17—H171 | 1.000 |
O4—C8 | 1.458 (3) | C18—H181 | 1.000 |
O4—C20 | 1.327 (4) | C18—H182 | 1.000 |
O5—C20 | 1.204 (6) | C18—H183 | 1.000 |
C1—C2 | 1.500 (5) | C19—H191 | 1.000 |
C2—C3 | 1.490 (6) | C19—H192 | 1.000 |
C2—H21 | 1.000 | C19—H193 | 1.000 |
C2—H22 | 1.000 | C20—C21 | 1.493 (6) |
C3—C4 | 1.515 (6) | C21—C22 | 1.469 (14) |
C3—H31 | 1.000 | C21—C24 | 1.553 (5) |
C4—C5 | 1.511 (4) | C21—C25 | 1.493 (15) |
C4—H41 | 1.000 | C21—C32 | 1.550 (5) |
C4—H42 | 1.000 | C21—C34 | 1.551 (5) |
C5—C6 | 1.511 (5) | C21—C35 | 1.550 (5) |
C5—H51 | 1.000 | C22—C23 | 1.48 (2) |
C6—C7 | 1.531 (4) | C22—H221 | 1.000 |
C6—H61 | 1.000 | C22—H222 | 1.000 |
C6—H62 | 1.000 | C23—H231 | 1.000 |
C7—C16 | 1.551 (4) | C23—H232 | 1.000 |
C7—H71 | 1.000 | C23—H233 | 1.000 |
C7—H72 | 1.000 | C24—H241 | 1.000 |
C8—C9 | 1.519 (4) | C24—H242 | 1.000 |
C8—C17 | 1.524 (4) | C24—H243 | 1.000 |
C8—H81 | 1.000 | C25—H251 | 1.000 |
C9—C10 | 1.531 (5) | C25—H252 | 1.000 |
C9—H91 | 1.000 | C25—H253 | 1.000 |
C9—H92 | 1.000 | C32—C33 | 1.55 (1) |
C10—C11 | 1.499 (5) | C32—H321 | 1.000 |
C10—C19 | 1.538 (6) | C32—H322 | 1.000 |
C10—H101 | 1.000 | C33—H331 | 1.000 |
C11—C12 | 1.326 (4) | C33—H332 | 1.000 |
C11—H111 | 1.000 | C33—H333 | 1.000 |
C12—C13 | 1.465 (4) | C34—H341 | 1.000 |
C12—C17 | 1.524 (3) | C34—H342 | 1.000 |
C13—C14 | 1.306 (5) | C34—H343 | 1.000 |
C13—H131 | 1.000 | C35—H351 | 1.000 |
C14—C15 | 1.499 (5) | C35—H352 | 1.000 |
C14—H141 | 1.000 | C35—H353 | 1.000 |
C15—C16 | 1.535 (4) | | |
| | | |
C1—O1—C5 | 123.3 (3) | C8—C17—H171 | 105.46 |
C3—O3—H531 | 105.7 | C12—C17—H171 | 109.58 |
C8—O4—C20 | 117.6 (3) | C16—C17—H171 | 105.70 |
O1—C1—O2 | 117.2 (3) | C15—C18—H181 | 109.42 |
O1—C1—C2 | 120.5 (3) | C15—C18—H182 | 109.09 |
O2—C1—C2 | 122.2 (3) | H181—C18—H182 | 109.475 |
C1—C2—C3 | 116.3 (3) | C15—C18—H183 | 109.89 |
C1—C2—H21 | 107.86 | H181—C18—H183 | 109.475 |
C3—C2—H21 | 107.3 | H182—C18—H183 | 109.476 |
C1—C2—H22 | 107.6 | C10—C19—H191 | 109.7 |
C3—C2—H22 | 108.1 | C10—C19—H192 | 109.4 |
H21—C2—H22 | 109.466 | H191—C19—H192 | 109.475 |
O3—C3—C2 | 110.7 (4) | C10—C19—H193 | 109.4 |
O3—C3—C4 | 110.1 (3) | H191—C19—H193 | 109.476 |
C2—C3—C4 | 109.0 (3) | H192—C19—H193 | 109.476 |
O3—C3—H31 | 108.8 | O4—C20—O5 | 122.8 (4) |
C2—C3—H31 | 108.99 | O4—C20—C21 | 113.5 (3) |
C4—C3—H31 | 109.16 | O5—C20—C21 | 123.6 (3) |
C3—C4—C5 | 110.5 (3) | C20—C21—C22 | 113.7 (6) |
C3—C4—H41 | 108.9 | C20—C21—C24 | 106.1 (8) |
C5—C4—H41 | 109.09 | C22—C21—C24 | 111.4 (10) |
C3—C4—H42 | 109.5 | C20—C21—C25 | 107.1 (7) |
C5—C4—H42 | 109.4 | C22—C21—C25 | 119.1 (10) |
H41—C4—H42 | 109.466 | C24—C21—C25 | 97.6 (9) |
O1—C5—C4 | 111.3 (2) | C20—C21—C32 | 109.8 (9) |
O1—C5—C6 | 105.8 (2) | C22—C21—C32 | 136.5 (10) |
C4—C5—C6 | 113.2 (3) | C24—C21—C32 | 52.9 (11) |
O1—C5—H51 | 112.42 | C25—C21—C32 | 45.2 (10) |
C4—C5—H51 | 104.2 | C20—C21—C34 | 112.1 (12) |
C6—C5—H51 | 110.14 | C22—C21—C34 | 49.8 (13) |
C5—C6—C7 | 113.5 (3) | C24—C21—C34 | 141.7 (14) |
C5—C6—H61 | 108.62 | C25—C21—C34 | 74.1 (12) |
C7—C6—H61 | 108.56 | C32—C21—C34 | 113.5 (14) |
C5—C6—H62 | 108.34 | C20—C21—C35 | 105.0 (17) |
C7—C6—H62 | 108.31 | C22—C21—C35 | 53.9 (16) |
H61—C6—H62 | 109.466 | C24—C21—C35 | 63.4 (16) |
C6—C7—C16 | 112.3 (2) | C25—C21—C35 | 146.3 (17) |
C6—C7—H71 | 108.56 | C32—C21—C35 | 113.1 (16) |
C16—C7—H71 | 108.86 | C34—C21—C35 | 102.9 (19) |
C6—C7—H72 | 108.83 | C21—C22—C23 | 112.1 (11) |
C16—C7—H72 | 108.79 | C21—C22—H221 | 93.2 |
H71—C7—H72 | 109.468 | C23—C22—H221 | 88.6 |
O4—C8—C9 | 111.9 (2) | C21—C22—H222 | 120.7 |
O4—C8—C17 | 106.3 (2) | C23—C22—H222 | 122.1 |
C9—C8—C17 | 111.2 (2) | H221—C22—H222 | 109.467 |
O4—C8—H81 | 111.30 | C22—C23—H231 | 117.8 |
C9—C8—H81 | 105.10 | C22—C23—H232 | 120.5 |
C17—C8—H81 | 111.23 | H231—C23—H232 | 109.476 |
C8—C9—C10 | 114.5 (3) | C22—C23—H233 | 87.2 |
C8—C9—H91 | 107.99 | H231—C23—H233 | 109.476 |
C10—C9—H91 | 107.9 | H232—C23—H233 | 109.476 |
C8—C9—H92 | 108.51 | C21—C24—H241 | 108.8 |
C10—C9—H92 | 108.45 | C21—C24—H242 | 107.1 |
H91—C9—H92 | 109.466 | H241—C24—H242 | 109.475 |
C9—C10—C11 | 110.8 (3) | C21—C24—H243 | 112.5 |
C9—C10—C19 | 114.0 (3) | H241—C24—H243 | 109.475 |
C11—C10—C19 | 110.0 (3) | H242—C24—H243 | 109.475 |
C9—C10—H101 | 105.51 | C21—C25—H251 | 110.3 |
C11—C10—H101 | 109.20 | C21—C25—H252 | 110.9 |
C19—C10—H101 | 107.0 | H251—C25—H252 | 109.476 |
C10—C11—C12 | 125.4 (3) | C21—C25—H253 | 107.2 |
C10—C11—H111 | 117.16 | H251—C25—H253 | 109.475 |
C12—C11—H111 | 117.43 | H252—C25—H253 | 109.475 |
C11—C12—C13 | 121.0 (3) | C21—C32—C33 | 108.0 (9) |
C11—C12—C17 | 122.9 (3) | C21—C32—H321 | 115.4 |
C13—C12—C17 | 116.0 (3) | C33—C32—H321 | 120.9 |
C12—C13—C14 | 123.4 (3) | C21—C32—H322 | 103.5 |
C12—C13—H131 | 118.37 | C33—C32—H322 | 96.6 |
C14—C13—H131 | 118.2 | H321—C32—H322 | 109.467 |
C13—C14—C15 | 124.2 (3) | C32—C33—H331 | 110.5 |
C13—C14—H141 | 117.9 | C32—C33—H332 | 96.3 |
C15—C14—H141 | 117.83 | H331—C33—H332 | 109.476 |
C14—C15—C16 | 111.0 (3) | C32—C33—H333 | 120.5 |
C14—C15—C18 | 110.5 (3) | H331—C33—H333 | 109.476 |
C16—C15—C18 | 114.7 (3) | H332—C33—H333 | 109.476 |
C14—C15—H151 | 109.95 | C21—C34—H341 | 124.0 |
C16—C15—H151 | 104.73 | C21—C34—H342 | 108.2 (12) |
C18—C15—H151 | 105.61 | H341—C34—H342 | 109.476 |
C7—C16—C15 | 112.9 (3) | C21—C34—H343 | 94.9 (12) |
C7—C16—C17 | 112.2 (2) | H341—C34—H343 | 109.476 |
C15—C16—C17 | 111.2 (2) | H342—C34—H343 | 109.476 |
C7—C16—H161 | 105.88 | C21—C35—H351 | 113.5 (17) |
C15—C16—H161 | 107.21 | C21—C35—H352 | 100.9 (17) |
C17—C16—H161 | 106.94 | H351—C35—H352 | 109.476 |
C8—C17—C12 | 111.3 (2) | C21—C35—H353 | 113.6 (15) |
C8—C17—C16 | 114.1 (2) | H351—C35—H353 | 109.476 |
C12—C17—C16 | 110.4 (2) | H352—C35—H353 | 109.476 |
Experimental details
Crystal data |
Chemical formula | C25H38O5 |
Mr | 418.57 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 293 |
a, b, c (Å) | 6.1283 (3), 17.2964 (7), 22.4659 (6) |
V (Å3) | 2381.33 (16) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.36 × 0.14 × 0.08 |
|
Data collection |
Diffractometer | Enraf Nonius Kappa CCD diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 1.96σ(I)] reflections | 4673, 2692, 2281 |
Rint | 0.03 |
(sin θ/λ)max (Å−1) | 0.617 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.072, 0.084, 1.12 |
No. of reflections | 2281 |
No. of parameters | 267 |
No. of restraints | ? |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.44, −0.28 |
Cremer and Pople's puckering parameters for the rings A (C8 C9 C10 C11 C12 C17) and B (C12 C13 C14 C15 C16 C17) topcompound | | ring A | | | ring B | |
| ϕ[°] | θ[°] | Q[Å] | ϕ[°] | θ[°] | Q[Å] |
I | 19.4 (5) | 48.7 (4) | 0.440 (3) | -103.3 (4) | 52.9 (3) | 0.468 (3) |
II | 18.9 | 49.0 | 0.447 | -108.0 | 51.5 | 0.475 |
III | 22.4 | 48.3 | 0.468 | 111.3 | 51.6 | 0.473 |
IV | 19.9 | 47.2 | 0.443 | -109.1 | 53.1 | 0.480 |
Notes: I this work; II Sato et al., 1984 III Brown et al., 1976 IV Haruyama et al., 1986 |
Torsion angles of flexible residues topcompound | C17/C8/O4/C20 [°] | C17/C16/C7/C6 [°] |
I | -159.2 | -170.3 |
II | -154.4 | -173.5 |
III | -141.4 | 178.8 |
IV | -141.8 | 178.4 |
Notes: I this work; II Sato et al., 1984 III Brown et al., 1976 IV Haruyama et al., 1986 |
Hypercholesteromia is known to be a primary risk factor for coronary artery disease. In humans, 50% or more of the total body cholesterol is derived from de novo synthesis, and the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) catalyzing a rate-limiting step in cholesterol biosynthesis is, therefore, a prime target for pharmacological intervention. Originally, the potent competitive inhibitors of HMG-CoA reductase were isolated from various fungi, for example, lovastatin (mevinolin or Monacolin K) or mevastatin (ML 236B or compactin) (Fig. 1), but at the present time a number of semisynthetic or synthetic derivatives are also available (Endo & Hasumi, 1993). The aim of the present work is to compare the structure of the novel semisynthetic derivative simvastatin, (I) (Fig. 1), with the structures of three related HMG-CoA reductase inhibitors, namely lovastatin, (II) (Sato et al., 1984), mevastatin, (III) (Brown et al., 1976), and mevastatin metabolite, (IV) (which corresponds to pravastatin in its lactone form; Haruyama et al., 1986). Besides these compounds, the structures of 6(S)-epi-mevinolin-4-p-nitrobenzoate (Stokker et al., 1986) and dihydromevinolin (Albers-Schönberg et al., 1981) have also been reported.
A view of (I), with the atomic numbering scheme, is shown in Fig. 2. The molecular packing (Fig. 3) is based on only one hydrogen bond, viz. O3—H531···O5(1 − x,y + 1/2,1/2 − z), which facilitates the formation of infinite chains along the b axis.
In order to investigate the chemical relationship of (I)–(IV), we have compared (I) with the three previously known related structures. Despite the expected effect of an additional methyl group on the side chain, (I) and (II) are isostructural. Surprisingly, (III) is not isostructural with (I) and (II) but is isostructural with (IV). Conformational analysis of the fused rings has revealed that there are only subtle differences in conformation. The C8–C12/C17 rings adopt approximate 1H2 half-chair conformations and the C12–C17 rings adopt approximate 5H6 half-chair conformations. Another interesting part of the analysis concerns the flexible chains. Despite the expected differences in the directions of the side chains, the molecules are very similar to one another (Fig. 4). The values of the torsion angles characterizing the directions vary in the range 141.4–159.2° for C17—C8—O4—C20 and −170.3–178.4° for C17—C16—C7—C6.