Simvastatin

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.

S1. Comment

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.

S2. Experimental

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.

S3. Refinement

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.

Computing details

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).

Figures

Fig. 1. Structures of HMG-CoA. Fig. 2. An ORTEP-3 (Farrugia, 1997) drawing of (I), showing the atom-numbering scheme for non-H atoms and displacement ellipsoids at the 50% probability level. H atoms are shown as small circles of arbitrary radii. Fig. 3. The packing diagram of (I) (ORTEP-3; Farrugia, 1997) along the a axis. The b axis is to the right and the c axis is upwards. Fig. 4. A superposition of molecules of (I)–(IV) (fit based on fused rings to reveal differences in sidechains). (I) green, (II) blue, (III) red and (IV) grey.

(1S,3R,7S,8S,8aR)-3,7-dimethyl-8-{2-[(2R,4R)-4-hydroxy-6-oxo-3,4,5,6- tetrahydro-2H-pyran-2-yl]ethyl}-1,2,3,7,8,8a-hexahydronaphthalin-1-yl 2,2-dimethylbutanoate

Crystal data

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) Å^3	Needle, white
Z = 4	0.36 × 0.14 × 0.08 mm
F(000) = 912.000

Data collection

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

Refinement on F	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.072	H-atom parameters constrained
wR(F^2) = 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

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	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 (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

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