Two key chiral intermediates in a new 4-hydroxy­isoleucine synthesis

We present the crystal and molecular structure of two key compounds of a new synthesis strategy for isomers of natural (2S,3R,4S)-4-hydroxyisoleucines, 2,3,5,6,7,8-hexa­hydro-3-(1-hydroxy-1-methyl-2-oxo­propyl)-6,8-methano-7,7,8a-tri­meth­yl-5H-1,4-benzoxazin-2-one, C₁₆H₂₃NO₄, and 2,3,5,6,7,8-hexa­hydro-3-(1-methyl-2-oxo­propyl)-6,8-methano-7,7,8a-tri­meth­yl-5H-1,4-benzoxazin-2-one, C₁₆H₂₃NO₃. A new optically pure chiral oxazinone auxiliary derived from (1R,2R,5R)-2-hydroxy­pinan-3-one was used.

S1. Comment

As a part of an ongoing study aimed at synthesizing γ-hydroxy α-aminoacids (Jacob et al., 1997) and in particular 4-hydroxyisoleucine, we explored a new strategy using as starting material the oxazinone (El Achkar et al., 1988) derived from (1R,2R,5R)-2-hydroxypinan-3-one. The natural isomer (2S,3R,4S)-4-hydroxyisoleucine extracted from fenugrek seeds known in traditional medicine for its antidiabetic properties was recently characterized as a new insulinotropic compound (Sauvaire et al., 1998). For structure-activity studies it was necessary to prepare enantiomerically pure isomers of 4-hydroxyisoleucine and their precursors (Kassem et al., 2000). To unambiguously know the configuration of the different asymetric carbons at different synthesis steps, the structures of two key intermediates, (II) and (IV), were studied by X-ray diffraction. From the known R configuration of C7, C10 and C12 we found R configuration for C2 and S for C3 in compound (II) and R configuration for the C2 and C3 in compound (IV). The strategy used is outlined in the reaction scheme below. \sch

Compounds (II) and (IV) have similar structures except the O3 hydroxyl group attached to the C3-atom in (II), replaced by an hydrogen in compound (IV). They are composed of the six-membered ring (C1—C2—N1—C8—C7—O1) of the oxazinone sharing one side (C7—C8) with the bicyclo system from the (1R,2R,5R)-2-hydroxypinan-3-one and on C2 the future amino-acid side chain (C3—C4—C5). The C1—C2—N1—C8—C7—O1 ring can be described with a boat conformation more distorted for compound (IV) than for (II). The C2 and C7 are respectively 0.387 (6) and 0.507 (5) Å above the mean plane of the other four atoms (r.m.s. Δ = 0.090 Å) for compound (II). However, for compound (IV), C2 and C7 are, respectively, 0.526 (6) and 0.517 (6) Å out of the same mean plane (r.m.s. Δ = 0.099 Å). This is also indicated by the torsion angle O1—C1—C2—N1 of 29.2 (1) and 43.0 (1)°, respectively. The bicyclo system including a six-membered ring (C7—C8—C9—C10—C11—C12) is bridged between C12 and C10 with C13. Two methyl groups are attached to this bicyclo system on C13 and on C7.

S2. Experimental

The enantioselective condensation of butan-2,3-dione on the (1'R,2'R,5'R)-oxazinone (I) resulted in the alcohol (II). After a deshydration step, a stereoselective hydrogenation of the double bond of coumpound (III) gave the second optically pure intermediate (IV). After a reduction step, the final cleavage of the chiral auxiliary produced two pure isomers of 4-hydroxyisoleucine. For the X-ray diffraction analysis pure (II) (m.p. 375–377 K) and (IV) (m.p. 382–384 K) were dissolved in the required amount of anhydrous Et₂O. Single crystals grew from the solution by slow evaporation at room temperature.

S3. Refinement

For both structures the H atoms were introduced at calculated positions and refined as riding with an isotropic displacement parameter U(H)_eq = U_eq + 0.02 of the parent atoms [parent + option of maXus (Mackay et al., 1999)].

Computing details

For both compounds, data collection: KappaCCD (Nonius, 1998); data reduction: DENZO and Scalepak (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: maXus (Mackay et al., 1999); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: maXus.

Figures

	Fig. 1. An ORTEPII (Johnson, 1976) view of the molecular structure of (II) showing the labelling of all non-H atoms. Displacement ellipsoids are shown at the 50% probability level and H atoms are drawn as circles of arbitrary radius.
	Fig. 2. An ORTEPII (Johnson, 1976) view of the molecular structure of (IV) showing the labelling of all non-H atoms. Displacement ellipsoids are shown at the 50% probability level and H atoms are drawn as circles of arbitrary radius.

(II)

Crystal data

C16H23NO4	Dx = 1.258 Mg m^−3
Mr = 293.36	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 9594 reflections
a = 11.0434 (5) Å	θ = 1.0–26.2°
b = 11.0028 (3) Å	µ = 0.09 mm^−1
c = 12.7460 (6) Å	T = 298 K
V = 1548.70 (10) Å^3	Prism, colourless
Z = 4	0.40 × 0.30 × 0.20 mm
F(000) = 632

Data collection

Kappa CCD area-detector diffractometer	Rint = 0.062
ϕ–scan	θmax = 26.2°
9422 measured reflections	h = −13→13
1719 independent reflections	k = −12→12
1576 reflections with I > 3σ(I)	l = −14→15

Refinement

Refinement on F^2	190 parameters
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.041	Calculated w = 1/[σ^2(Fo^2) + 0.03Fo^2)]
wR(F^2) = 0.058	(Δ/σ)max = 0.005
S = 1.32	Δρmax = 0.14 e Å^−3
1576 reflections	Δρmin = −0.16 e Å^−3

Special details

Geometry. All standard uncertainties (except dihedral angles between l.s. planes) are estimated using the full covariance matrix. The standard uncertainties in cell dimensions are are used in calculating the standard uncertainties of bond distances, angles and torsion angles. Angles between l.s. planes have standard uncertainties calculated from atomic positional standard uncertainties; the errors in cell dimensions are not used in this case.

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

	x	y	z	Uiso*/Ueq
O1	0.80675 (4)	0.35476 (3)	0.21678 (3)	0.0454 (2)
O2	0.79030 (4)	0.43003 (4)	0.05802 (3)	0.0531 (2)
O3	1.02965 (3)	0.31680 (4)	−0.01746 (3)	0.0458 (2)
O4	0.74352 (4)	0.25746 (4)	−0.12923 (3)	0.0682 (3)
N1	0.94190 (4)	0.16070 (4)	0.14153 (4)	0.0403 (3)
C1	0.81495 (5)	0.34393 (5)	0.11209 (4)	0.0394 (3)
C2	0.85985 (5)	0.22308 (5)	0.07032 (4)	0.0354 (3)
C3	0.92549 (4)	0.24173 (5)	−0.03478 (4)	0.0372 (3)
C4	0.84108 (5)	0.30457 (6)	−0.11267 (4)	0.0435 (3)
C5	0.88272 (6)	0.41535 (6)	−0.17025 (5)	0.0526 (4)
C6	0.96583 (6)	0.12218 (6)	−0.08264 (5)	0.0527 (4)
C7	0.81782 (4)	0.24540 (5)	0.28220 (4)	0.0358 (3)
C8	0.92169 (4)	0.17113 (5)	0.23934 (4)	0.0349 (3)
C9	1.01064 (5)	0.11875 (6)	0.31786 (5)	0.0488 (3)
C10	1.01181 (5)	0.19512 (6)	0.41786 (5)	0.0486 (3)
C11	0.98768 (6)	0.32829 (6)	0.38611 (5)	0.0567 (4)
C12	0.85161 (5)	0.29493 (5)	0.38928 (4)	0.0435 (3)
C13	0.88557 (5)	0.19499 (6)	0.47131 (4)	0.0417 (3)
C14	0.88872 (7)	0.25258 (8)	0.58073 (5)	0.0682 (5)
C15	0.81863 (6)	0.07469 (6)	0.48100 (5)	0.0552 (4)
C16	0.69496 (6)	0.18218 (8)	0.27725 (5)	0.0594 (4)
H2	0.789655	0.172897	0.060137	0.055054*
H3	1.086861	0.274144	0.031634	0.064080*
H5A	0.818946	0.443908	−0.214066	0.072486*
H5B	0.952193	0.394827	−0.211819	0.072486*
H5C	0.904571	0.477024	−0.120220	0.072486*
H6A	1.019013	0.079571	−0.035249	0.071377*
H6B	1.007233	0.138122	−0.146912	0.071377*
H6C	0.895823	0.072345	−0.096054	0.071377*
H9A	1.090191	0.118931	0.287221	0.069343*
H9B	0.987583	0.037246	0.334680	0.069343*
H10	1.080778	0.175240	0.459295	0.068900*
H11A	1.008392	0.353761	0.316296	0.077001*
H11B	1.004831	0.392641	0.434582	0.077001*
H12	0.791950	0.353332	0.410708	0.061869*
H14A	0.929820	0.329083	0.577722	0.083805*
H14B	0.931335	0.198899	0.627686	0.083805*
H14C	0.807674	0.263939	0.605398	0.083805*
H15A	0.815119	0.037199	0.412832	0.076024*
H15B	0.737792	0.088085	0.506159	0.076024*
H15C	0.861454	0.023045	0.528446	0.076024*
H16A	0.682090	0.153401	0.207517	0.076153*
H16B	0.632343	0.238472	0.296269	0.076153*
H16C	0.694916	0.115135	0.325470	0.076153*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0540 (2)	0.0419 (2)	0.0402 (2)	0.0178 (2)	0.0002 (2)	0.0014 (2)
O2	0.0627 (3)	0.0482 (3)	0.0484 (2)	0.0192 (2)	−0.0005 (2)	0.0083 (2)
O3	0.0324 (2)	0.0466 (3)	0.0584 (3)	−0.0092 (2)	−0.0039 (2)	0.0082 (2)
O4	0.0445 (2)	0.0962 (4)	0.0640 (3)	−0.0136 (3)	−0.0147 (2)	0.0057 (3)
N1	0.0392 (3)	0.0384 (3)	0.0433 (3)	0.0068 (2)	0.0018 (2)	0.0011 (2)
C1	0.0309 (3)	0.0437 (4)	0.0434 (3)	0.0045 (3)	−0.0003 (3)	−0.0004 (3)
C2	0.0305 (3)	0.0355 (4)	0.0401 (3)	−0.0005 (2)	−0.0018 (2)	−0.0019 (3)
C3	0.0295 (3)	0.0367 (3)	0.0453 (3)	−0.0040 (3)	0.0019 (3)	−0.0002 (3)
C4	0.0376 (3)	0.0528 (4)	0.0401 (3)	0.0013 (3)	0.0021 (3)	−0.0006 (3)
C5	0.0500 (4)	0.0559 (4)	0.0521 (4)	0.0068 (3)	0.0009 (3)	0.0084 (4)
C6	0.0515 (4)	0.0485 (4)	0.0581 (4)	−0.0016 (3)	0.0123 (4)	−0.0062 (3)
C7	0.0315 (3)	0.0375 (3)	0.0384 (3)	0.0051 (3)	−0.0022 (2)	0.0027 (3)
C8	0.0282 (3)	0.0293 (3)	0.0471 (3)	0.0013 (2)	−0.0005 (2)	−0.0006 (3)
C9	0.0382 (3)	0.0588 (4)	0.0493 (4)	0.0185 (3)	−0.0024 (3)	0.0058 (3)
C10	0.0323 (3)	0.0615 (4)	0.0519 (4)	0.0016 (3)	−0.0133 (3)	0.0015 (3)
C11	0.0604 (4)	0.0536 (4)	0.0561 (4)	−0.0218 (3)	−0.0127 (3)	−0.0021 (4)
C12	0.0473 (3)	0.0398 (4)	0.0432 (3)	0.0106 (3)	−0.0045 (3)	−0.0053 (3)
C13	0.0394 (3)	0.0467 (4)	0.0390 (3)	0.0041 (3)	−0.0062 (3)	−0.0016 (3)
C14	0.0725 (5)	0.0864 (6)	0.0457 (4)	0.0108 (5)	−0.0112 (4)	−0.0052 (4)
C15	0.0503 (4)	0.0564 (4)	0.0590 (4)	−0.0039 (3)	−0.0064 (3)	0.0115 (4)
C16	0.0314 (3)	0.0943 (6)	0.0527 (4)	−0.0119 (4)	−0.0045 (3)	0.0048 (4)

Geometric parameters (Å, º)

O1—C1	1.3427 (6)	C7—C8	1.5106 (7)
O1—C7	1.4691 (6)	C7—C12	1.5162 (7)
O2—C1	1.2028 (6)	C7—C16	1.5260 (8)
O3—C3	1.4332 (6)	C8—C9	1.5161 (7)
O4—C4	1.2141 (6)	C9—C10	1.5268 (8)
N1—C2	1.4546 (6)	C10—C11	1.5432 (9)
N1—C8	1.2716 (6)	C10—C13	1.5517 (7)
C1—C2	1.5158 (7)	C11—C12	1.5474 (8)
C2—C3	1.5370 (7)	C12—C13	1.5631 (7)
C3—C4	1.5273 (7)	C13—C14	1.5322 (8)
C3—C6	1.5168 (8)	C13—C15	1.5211 (8)
C4—C5	1.4952 (8)
C1—O1—C7	119.1 (1)	C8—C7—C12	109.5 (1)
C2—N1—C8	117.4 (1)	C8—C7—C16	114.4 (1)
O1—C1—O2	119.0 (1)	C12—C7—C16	114.8 (1)
O1—C1—C2	116.7 (1)	N1—C8—C7	122.5 (1)
O2—C1—C2	124.3 (1)	N1—C8—C9	119.9 (1)
N1—C2—C1	113.5 (1)	C7—C8—C9	117.3 (1)
N1—C2—C3	108.2 (1)	C8—C9—C10	110.3 (1)
C1—C2—C3	110.1 (1)	C9—C10—C11	107.6 (1)
O3—C3—C2	108.7 (1)	C9—C10—C13	111.0 (1)
O3—C3—C4	109.2 (1)	C11—C10—C13	87.8 (1)
O3—C3—C6	109.0 (1)	C10—C11—C12	86.3 (1)
C2—C3—C4	109.8 (1)	C7—C12—C11	107.5 (1)
C2—C3—C6	111.9 (1)	C7—C12—C13	114.1 (1)
C4—C3—C6	108.1 (1)	C11—C12—C13	87.2 (1)
O4—C4—C3	117.5 (1)	C10—C13—C12	85.5 (1)
O4—C4—C5	122.4 (1)	C10—C13—C14	112.3 (1)
C3—C4—C5	120.0 (1)	C10—C13—C15	118.2 (1)
O1—C7—C8	107.5 (1)	C12—C13—C14	108.9 (1)
O1—C7—C12	103.7 (1)	C12—C13—C15	123.4 (1)
O1—C7—C16	106.0 (1)	C14—C13—C15	107.3 (1)
C7—O1—C1—O2	170.4 (1)	C12—C7—C8—N1	−150.6 (1)
C7—O1—C1—C2	−11.8 (1)	C12—C7—C8—C9	23.2 (1)
C1—O1—C7—C8	43.5 (1)	C8—C7—C12—C11	36.9 (1)
C1—O1—C7—C12	159.4 (1)	C8—C7—C12—C13	−57.9 (1)
C1—O1—C7—C16	−79.3 (1)	C16—C7—C8—N1	78.9 (1)
C8—N1—C2—C1	35.4 (1)	C16—C7—C8—C9	−107.3 (1)
C8—N1—C2—C3	157.9 (1)	C16—C7—C12—C11	167.2 (1)
C2—N1—C8—C7	−0.4 (1)	C16—C7—C12—C13	72.4 (1)
C2—N1—C8—C9	−174.0 (1)	N1—C8—C9—C10	148.6 (1)
O1—C1—C2—N1	−29.2 (1)	C7—C8—C9—C10	−25.4 (1)
O1—C1—C2—C3	−150.7 (1)	C8—C9—C10—C11	−32.9 (1)
O2—C1—C2—N1	148.4 (1)	C8—C9—C10—C13	61.6 (1)
O2—C1—C2—C3	27.0 (1)	C9—C10—C11—C12	84.1 (1)
N1—C2—C3—O3	−61.8 (1)	C9—C10—C13—C12	−81.0 (1)
N1—C2—C3—C4	178.7 (1)	C9—C10—C13—C14	170.4 (1)
N1—C2—C3—C6	58.7 (1)	C9—C10—C13—C15	44.7 (1)
C1—C2—C3—O3	62.7 (1)	C13—C10—C11—C12	−27.2 (1)
C1—C2—C3—C4	−56.7 (1)	C11—C10—C13—C12	27.0 (1)
C1—C2—C3—C6	−176.8 (1)	C11—C10—C13—C14	−81.6 (1)
O3—C3—C4—O4	−174.0 (1)	C11—C10—C13—C15	152.7 (1)
O3—C3—C4—C5	9.8 (1)	C10—C11—C12—C7	−87.4 (1)
C2—C3—C4—O4	−54.8 (1)	C10—C11—C12—C13	27.0 (1)
C2—C3—C4—C5	129.0 (1)	C7—C12—C13—C10	81.0 (1)
C6—C3—C4—O4	67.5 (1)	C7—C12—C13—C14	−166.9 (1)
C6—C3—C4—C5	−108.7 (1)	C7—C12—C13—C15	−40.0 (1)
O1—C7—C8—N1	−38.5 (1)	C11—C12—C13—C10	−26.9 (1)
O1—C7—C8—C9	135.3 (1)	C11—C12—C13—C14	85.1 (1)
O1—C7—C12—C11	−77.6 (1)	C11—C12—C13—C15	−148.0 (1)
O1—C7—C12—C13	−172.4 (1)

(IV)

Crystal data

C16H23NO3	Dx = 1.193 Mg m^−3
Mr = 277.36	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 11140 reflections
a = 8.2610 (3) Å	θ = 1.0–26.4°
b = 12.5168 (5) Å	µ = 0.08 mm^−1
c = 14.9291 (3) Å	T = 298 K
V = 1543.69 (9) Å^3	Prism, colourless
Z = 4	0.40 × 0.30 × 0.20 mm
F(000) = 600

Data collection

Kappa CCD area-detector diffractometer	Rint = 0.028
ϕ–scan	θmax = 26.4°
10011 measured reflections	h = −10→10
1793 independent reflections	k = −14→15
1630 reflections with I > 3σ(I)	l = −18→18

Refinement

Refinement on F^2	181 parameters
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.039	Calculated w = 1/[σ^2(Fo^2) + 0.03Fo^2)]
wR(F^2) = 0.060	(Δ/σ)max = 0.001
S = 1.31	Δρmax = 0.17 e Å^−3
1630 reflections	Δρmin = −0.31 e Å^−3

Special details

Geometry. All standard uncertainties (except dihedral angles between l.s. planes) are estimated using the full covariance matrix. The standard uncertainties in cell dimensions are are used in calculating the standard uncertainties of bond distances, angles and torsion angles. Angles between l.s. planes have standard uncertainties calculated from atomic positional standard uncertainties; the errors in cell dimensions are not used in this case.

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

	x	y	z	Uiso*/Ueq
O1	0.84959 (5)	0.37220 (3)	0.77036 (2)	0.0410 (2)
O2	0.86251 (5)	0.54706 (3)	0.78450 (3)	0.0531 (2)
O3	1.02798 (6)	0.60814 (4)	0.97029 (3)	0.0733 (3)
N1	0.66951 (6)	0.36927 (4)	0.92778 (3)	0.0432 (3)
C1	0.84195 (7)	0.46150 (4)	0.81984 (3)	0.0365 (3)
C2	0.80140 (7)	0.44768 (4)	0.91804 (3)	0.0363 (3)
C3	0.75404 (7)	0.55366 (4)	0.96073 (4)	0.0405 (3)
C4	0.88997 (8)	0.63417 (5)	0.95388 (4)	0.0499 (4)
C5	0.8458 (1)	0.74627 (5)	0.93186 (6)	0.0815 (5)
C6	0.71612 (9)	0.53928 (6)	1.05987 (4)	0.0679 (4)
C7	0.82091 (7)	0.26836 (4)	0.81462 (3)	0.0359 (3)
C8	0.68062 (7)	0.28621 (4)	0.87948 (4)	0.0403 (3)
C9	0.54188 (8)	0.20840 (5)	0.87675 (5)	0.0596 (4)
C10	0.53561 (8)	0.15005 (5)	0.78696 (5)	0.0571 (4)
C11	0.58995 (8)	0.22898 (5)	0.71260 (5)	0.0553 (4)
C12	0.76450 (7)	0.19647 (4)	0.73793 (4)	0.0417 (3)
C13	0.69283 (7)	0.08731 (4)	0.77030 (4)	0.0506 (3)
C14	0.6789 (1)	0.01124 (5)	0.69040 (5)	0.0752 (5)
C15	0.7632 (1)	0.02463 (5)	0.84758 (5)	0.0745 (5)
C16	0.98016 (8)	0.23392 (5)	0.85619 (4)	0.0524 (4)
H2	0.895698	0.421476	0.948537	0.055864*
H12	0.847900	0.194369	0.693132	0.060903*
H3	0.660136	0.581655	0.931029	0.060233*
H10	0.429805	0.122954	0.773059	0.076141*
H16A	1.059359	0.223717	0.809893	0.071199*
H16B	0.965759	0.168317	0.888593	0.071199*
H16C	1.016460	0.288617	0.896493	0.071199*
H11A	0.545850	0.206181	0.656304	0.074133*
H11B	0.552050	0.299681	0.726004	0.074133*
H9A	0.442577	0.246401	0.886650	0.078735*
H9B	0.556677	0.156501	0.923350	0.078735*
H6A	0.629518	0.488680	1.066470	0.085913*
H6B	0.684218	0.606580	1.085170	0.085913*
H6C	0.810518	0.513380	1.090370	0.085913*
H15A	0.774128	0.070929	0.898481	0.092678*
H15B	0.867628	−0.002871	0.831281	0.092678*
H15C	0.692428	−0.033571	0.862280	0.092678*
H5A	0.942068	0.789070	0.928755	0.099180*
H5B	0.775368	0.774070	0.977355	0.099180*
H5C	0.791368	0.747970	0.875055	0.099180*
H14A	0.634738	0.048144	0.639597	0.093213*
H14B	0.608838	−0.046856	0.706497	0.093213*
H14C	0.784038	−0.016156	0.675497	0.093213*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0556 (2)	0.0347 (2)	0.0326 (2)	−0.0069 (2)	0.0083 (2)	0.0013 (2)
O2	0.0781 (3)	0.0368 (2)	0.0443 (2)	−0.0085 (2)	0.0069 (2)	0.0085 (2)
O3	0.0525 (3)	0.0817 (3)	0.0858 (3)	−0.0037 (3)	−0.0124 (3)	−0.0150 (3)
N1	0.0519 (3)	0.0398 (3)	0.0379 (3)	−0.0034 (3)	0.0113 (2)	0.0030 (2)
C1	0.0389 (3)	0.0346 (3)	0.0361 (3)	−0.0023 (3)	0.0030 (3)	0.0019 (3)
C2	0.0437 (3)	0.0331 (3)	0.0321 (3)	0.0046 (3)	0.0022 (2)	0.0016 (2)
C3	0.0428 (3)	0.0380 (3)	0.0408 (3)	0.0083 (3)	0.0008 (3)	−0.0039 (3)
C4	0.0540 (4)	0.0488 (4)	0.0469 (4)	−0.0002 (3)	0.0051 (3)	−0.0119 (3)
C5	0.0864 (6)	0.0384 (4)	0.1198 (7)	−0.0025 (4)	0.0269 (5)	−0.0088 (4)
C6	0.0882 (6)	0.0626 (4)	0.0529 (4)	−0.0023 (4)	0.0241 (4)	−0.0125 (3)
C7	0.0417 (3)	0.0307 (3)	0.0354 (3)	−0.0026 (3)	0.0018 (3)	0.0033 (2)
C8	0.0428 (3)	0.0403 (3)	0.0378 (3)	−0.0041 (3)	0.0048 (3)	0.0081 (3)
C9	0.0543 (4)	0.0520 (4)	0.0724 (5)	−0.0150 (3)	0.0201 (4)	0.0008 (3)
C10	0.0434 (4)	0.0534 (4)	0.0745 (5)	−0.0138 (3)	0.0031 (3)	−0.0053 (4)
C11	0.0506 (4)	0.0559 (4)	0.0593 (4)	−0.0023 (3)	−0.0129 (3)	−0.0047 (3)
C12	0.0422 (3)	0.0399 (3)	0.0429 (3)	−0.0047 (3)	0.0037 (3)	−0.0030 (3)
C13	0.0491 (4)	0.0380 (3)	0.0648 (4)	−0.0086 (3)	0.0029 (3)	−0.0006 (3)
C14	0.0686 (5)	0.0547 (4)	0.1023 (6)	−0.0197 (4)	0.0043 (5)	−0.0225 (4)
C15	0.0819 (5)	0.0417 (4)	0.0998 (6)	−0.0056 (4)	0.0014 (5)	0.0193 (4)
C16	0.0511 (4)	0.0470 (4)	0.0591 (4)	0.0035 (3)	−0.0090 (3)	−0.0060 (3)

Geometric parameters (Å, º)

O1—C1	1.3412 (6)	C7—C8	1.5266 (8)
O1—C7	1.4772 (6)	C7—C12	1.5290 (7)
O2—C1	1.2059 (6)	C7—C16	1.5171 (8)
O3—C4	1.2108 (7)	C8—C9	1.5046 (8)
N1—C2	1.4736 (7)	C9—C10	1.527 (1)
N1—C8	1.2687 (6)	C10—C11	1.5523 (9)
C1—C2	1.5138 (7)	C10—C13	1.5381 (9)
C2—C3	1.5228 (7)	C11—C12	1.5453 (8)
C3—C4	1.5124 (8)	C12—C13	1.5655 (7)
C3—C6	1.5235 (9)	C13—C14	1.5305 (9)
C4—C5	1.4867 (9)	C13—C15	1.5116 (9)
C1—O1—C7	118.6 (1)	C12—C7—C16	113.8 (1)
C2—N1—C8	115.9 (1)	N1—C8—C7	122.4 (1)
O1—C1—O2	119.5 (1)	N1—C8—C9	119.4 (1)
O1—C1—C2	116.6 (1)	C7—C8—C9	117.8 (1)
O2—C1—C2	123.8 (1)	C8—C9—C10	111.0 (1)
N1—C2—C1	109.6 (1)	C9—C10—C11	108.3 (1)
N1—C2—C3	110.4 (1)	C9—C10—C13	110.9 (1)
C1—C2—C3	111.3 (1)	C11—C10—C13	88.0 (1)
C2—C3—C4	111.2 (1)	C10—C11—C12	85.8 (1)
C2—C3—C6	110.9 (1)	C7—C12—C11	108.2 (1)
C4—C3—C6	107.3 (1)	C7—C12—C13	113.4 (1)
O3—C4—C3	120.4 (1)	C11—C12—C13	87.3 (1)
O3—C4—C5	122.0 (1)	C10—C13—C12	85.6 (1)
C3—C4—C5	117.5 (1)	C10—C13—C14	112.4 (1)
O1—C7—C8	106.1 (1)	C10—C13—C15	117.8 (1)
O1—C7—C12	103.4 (1)	C12—C13—C14	109.3 (1)
O1—C7—C16	107.1 (1)	C12—C13—C15	122.9 (1)
C8—C7—C12	109.2 (1)	C14—C13—C15	107.5 (1)
C8—C7—C16	116.1 (1)
C7—O1—C1—O2	−178.8 (1)	C8—C7—C12—C11	39.2 (1)
C7—O1—C1—C2	−0.9 (1)	C8—C7—C12—C13	−55.8 (1)
C1—O1—C7—C8	40.7 (1)	C16—C7—C8—N1	76.8 (1)
C1—O1—C7—C12	155.6 (1)	C16—C7—C8—C9	−110.8 (1)
C1—O1—C7—C16	−83.9 (1)	C16—C7—C12—C11	170.8 (1)
C8—N1—C2—C1	43.1 (1)	C16—C7—C12—C13	75.7 (1)
C8—N1—C2—C3	166.0 (1)	N1—C8—C9—C10	151.1 (1)
C2—N1—C8—C7	−0.4 (1)	C7—C8—C9—C10	−21.5 (1)
C2—N1—C8—C9	−172.7 (1)	C8—C9—C10—C11	−35.1 (1)
O1—C1—C2—N1	−43.0 (1)	C8—C9—C10—C13	59.9 (1)
O1—C1—C2—C3	−165.4 (1)	C9—C10—C11—C12	84.1 (1)
O2—C1—C2—N1	134.9 (1)	C9—C10—C13—C12	−81.9 (1)
O2—C1—C2—C3	12.5 (1)	C9—C10—C13—C14	169.0 (1)
N1—C2—C3—C4	178.3 (1)	C9—C10—C13—C15	43.3 (1)
N1—C2—C3—C6	59.0 (1)	C13—C10—C11—C12	−27.3 (1)
C1—C2—C3—C4	−59.8 (1)	C11—C10—C13—C12	27.0 (1)
C1—C2—C3—C6	−179.1 (1)	C11—C10—C13—C14	−82.1 (1)
C2—C3—C4—O3	−44.4 (1)	C11—C10—C13—C15	152.1 (1)
C2—C3—C4—C5	139.2 (1)	C10—C11—C12—C7	−87.0 (1)
C6—C3—C4—O3	77.0 (1)	C10—C11—C12—C13	26.8 (1)
C6—C3—C4—C5	−99.4 (1)	C7—C12—C13—C10	81.6 (1)
O1—C7—C8—N1	−42.0 (1)	C7—C12—C13—C14	−166.2 (1)
O1—C7—C8—C9	130.4 (1)	C7—C12—C13—C15	−38.9 (1)
O1—C7—C12—C11	−73.4 (1)	C11—C12—C13—C10	−27.1 (1)
O1—C7—C12—C13	−168.5 (1)	C11—C12—C13—C14	85.1 (1)
C12—C7—C8—N1	−152.8 (1)	C11—C12—C13—C15	−147.6 (1)
C12—C7—C8—C9	19.5 (1)