A folded conformation of an ascidiacycl­amide derivative: 3-methoxy­sulfoxide-(2R,3R)-threoninyl desoxazoline-ascidiacycl­amide

Ascidiacycl­amide, cyclo(-Ile-Oxz-D-Val-Thz-)₂, has two methyl-oxazoline (Oxz) residues, and each Oxz residue has two chiral C atoms. In the present work, C₃₈H₆₀N₈O₁₂S₄, a chiral modification of these atoms was attempted. A total of ten diastereomers were considered, of which seven were synthesized. For the three remaining diastereomers, the reaction was incomplete or very much slowed down. These diastereomers had the D configuration for both Oxz residues. This result appeared to be related to the conformation of the reaction intermediates. Therefore, the intermediates were converted into stable forms and then isolated to confirm their structures. Crystals were obtained from one derivative and its structure was found to be of the folded form. In this form, the activated atoms were separated from the target atoms. It is suggested that this folded conformation hinders the completion of the reaction.

Key indicators

• Single-crystal synchrotron study
• T = 100 K
• Mean [sigma](C-C) = 0.009 Å
• R factor = 0.075
• wR factor = 0.201
• Data-to-parameter ratio = 8.9

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



DIFMX_01  Alert C The maximum difference density is > 0.1*ZMAX*0.75
          _refine_diff_density_max given =      1.314
          Test value =      1.200

DIFMX_02  Alert C The minimum difference density is > 0.1*ZMAX*0.75
          The relevant atom site should be identified.

STRVAL_01
         From the CIF: _refine_ls_abs_structure_Flack    0.380
         From the CIF: _refine_ls_abs_structure_Flack_su    0.150
           Alert C Flack test results are ambiguous.

PLAT_320  Alert C Check Hybridisation of  S(29)  in main residue          ?

PLAT_320  Alert C Check Hybridisation of  S(60)  in main residue          ?

PLAT_360  Alert C Short  C(sp3)-C(sp3) Bond  C(22)  -   C(23)  =       1.39 Ang.

PLAT_601  Alert C Structure Contains Solvent Accessible VOIDS of      59.00 A   3

PLAT_703  Alert C Torsion Calc    -71.0(6), Rep    -70.3(6), Dev.      1.17 Sigma
                     N1  -C2  -C3  -C5     1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc    167.1(5), Rep    167.7(5), Dev.      1.20 Sigma
                     C7  -C2  -C3  -C5     1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc    164.0(6), Rep    164.9(6), Dev.      1.50 Sigma
                     C2  -C3  -C5  -C6     1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc   -114.5(7), Rep   -113.3(6), Dev.      1.71 Sigma
                     C18 -N20 -C21 -C22    1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc    175.0(6), Rep    174.0(5), Dev.      1.67 Sigma
                     N32 -C33 -C34 -C35    1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc     53.1(8), Rep     51.8(6), Dev.      1.62 Sigma
                     C38 -C33 -C34 -C35    1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc    -70.8(8), Rep    -69.4(8), Dev.      1.75 Sigma
                     C35 -C34 -C36 -C37    1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc     56.3(6), Rep     57.0(6), Dev.      1.17 Sigma
                     C42 -C41 -C49 -O50    1.555   1.555   1.555   1.555

PLAT_703  Alert C Torsion Calc    118.1(5), Rep    118.7(5), Dev.      1.20 Sigma
                     C49 -N51 -C52 -C56    1.555   1.555   1.555   1.555

General Notes



ABSMU_01  Radiation type not identified. Calculation of
          _exptl_absorpt_correction_mu not performed.

REFLT_03
         From the CIF: _diffrn_reflns_theta_max           30.60
         From the CIF: _reflns_number_total               4973
         Count of symmetry unique reflns         5005
         Completeness (_total/calc)             99.36%
         TEST3: Check Friedels for noncentro structure
         Estimate of Friedel pairs measured         0
         Fraction of Friedel pairs measured     0.000
         Are heavy atom types Z>Si present          yes
          WARNING: Large fraction of Friedel related reflns may
                   be needed to determine absolute structure


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 16 Alert Level C = Please check

---

S1. Comment

Ascidiacyclamide (ASC), (3), is a symmetric cyclic peptide (Fig. 1) containing unusual amino acids, such as oxazoline (Oxz) and thiazole (Thz) (Hamamoto et al., 1983). Two major conformations and their conformational equilibrium have been suggested for ASC (Ishida et al., 1988; In et al., 1993). In our series of studies, the relationships between ASC conformation and symmetry of the chemical structure have been examined; additionally, we have studied the asymmetric modifications which disturb the C₂ symmetry of ASC and how this affects the ASC structures in both the solid state and in solution (Doi et al., 1999; Asano et al., 2001). Here, we extend the asymmetric modifications by substituting the Oxz residues with their diastereomers.

ASC is synthesized from a cyclic hexapeptide, (1), using thionyl chloride (Hamada et al., 1987), as shown in Fig. 1. Oxz rings are formed from the threonine residues via the chlorosulfoxide intermediate (2) after reacting for 1–2 d at 273–277 K. For the synthesis of the ASC diastereomers, the threonine residues of (1) are replaced by the following threonine diastereomers: Thr, allo-threonine (aThr), D-Thr and D-aThr. A total of ten diastereomers of (1) were synthesized and their configurations at positions (10,11,41,42) are (S,S,S,S), (S,S,S,R), (S,S,R,R), (S,S,R,S), (S,R,S,R), (S,R,R,R), (S,R,R,S), (R,R,R,R), (R,R,R,S) and (R,S,R,S). Natural ASC is synthesized from (S,S,S,S)-(1). For seven of the ten diastereomers, the reaction of Oxz formation was completed under the reported conditions. However, this reaction did not complete or was very much slowed down for the three diastereomers having (R,R,R,R), (R,R,R,S) and (R,S,R,S) configurations. These configurations imply that residues 2 and 6 are D-amino acids (Cα at positions 10 and 41). We presume that a particular conformation, which hinders the completion of the reaction, is present in the intermediates (2) derived from these three diastereomers. Such a conformation is interesting because it is stable, even in thionyl chloride solution. To clarify this conformation, three methyl sulfoxide derivatives of 4 were isolated, by the addition of methanol to intermediates (2), and the structure of (R,R,R,R)-(4) was analyzed.

The structure of (R,R,R,R)-(4) is shown in Fig. 2. The configuration (R,R,R,R) is confirmed for atoms C10, C11, C41 and C42 in the structure. The molecule is folded and four intramolecular hydrogen bonds are formed to stabilize the folded conformation: N1···O39 2.983 (6), N20···O62 3.017 (6), N32···O8 2.950 (6) and N51···O31 3.112 (6) Å. This structure is very similar to the folded forms of ASC and its derivatives (Doi et al., 1999). The Thz rings (C25—N26—C27—C28—S29 and C56—N57—C58—C59—S60) face each other with an angle of 15.3° between the ring planes. The distance between the thiazole rings indicates π–π electron stacking [e.g. C27···C58 3.414 (8) Å]. This feature is an important characteristic of the folded ascidiacyclamide.

In the reaction for Oxz ring formation, the activated Cβ atoms of D-Thr residues (C11 and C42) are necessary for contact with the carbonyl O atoms of Ile (O8 and O39) (Fig. 1). However, the C11 (or C42) atom is well separated from the O8 (or O39) atom in this folded structure (Fig. 2). It seems that such spatial arrangements cause incompletion or slow down of the reaction.

S2. Experimental

The compound (R,R,R,R)-(4) was crystallized from chloroform solution as clusters of blocks. These crystals were crushed in 100% glycerol and a single-crystal was mounted on a nylon loop under a nitrogen stream at 100 K. Data were measured on a Rigaku R-AXIS-IV using synchrotron radiation. A total of 42 images were collected for each 4° oscillation angle and these were integrated to 35905 reflections by MOSFLM (Leslie, 1999). They were successively processed yielding 17501 reflections with R_sym = 0.054 and R_merg = 0.076, using SCALA (Evans, 1997) of the CCP4 Suite (Collaborative Computational Project, Number 4, 1994). In the refinement the R value increased in the high-resolution shell greater than 0.82 Å. Therefore, reflections from this shell were omitted from the refinement. The absolute configuration agreed with the L– and D-configurations of the materials (amino acids), and the Flack x parameter was 0.38 (15). In the final refinement, a peak with 1.31 e A^-3 was observed at a distance of 0.92 Å from atom S45.

Computing details

Data collection: PROCESS (Higashi, 1996); cell refinement: MOSFLM (Leslie, 1999); data reduction: MOSFLM; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 1998); software used to prepare material for publication: PLATON.

Figures

Fig. 1. The structure of (R,R,R,R)-(4). Dashed lines indicate intramolecular hydrogen bonds. [Please check that this is the correct figure]

Diastereomer 8 of desoxazolin-ascidiacyclamide derivatives cyclo(–Ile-D-allo-MsThr-D-Val-Thz-Ile-D-allo-MsThr-D-Val-Thz-) Ms=methoxysufonyl

Crystal data

C38H60N8O12S4	Dx = 1.325 Mg m^−3
Mr = 949.18	Synchrotron radiation, λ = 0.83600 Å
Orthorhombic, P212121	Cell parameters from 6840 reflections
a = 10.7820 (3) Å	θ = 1.2–31.0°
b = 19.6026 (4) Å	µ = 0.27 mm^−1
c = 22.5181 (7) Å	T = 100 K
V = 4759.3 (2) Å^3	Block, colorless
Z = 4	0.08 × 0.08 × 0.08 mm
F(000) = 2016

Data collection

Rigaku R-AXIS-IV diffractometer	4759 reflections with I > 2σ(I)
Radiation source: double monochromated beam	Rint = 0.055
Diamond monochromator	θmax = 30.6°, θmin = 1.6°
Detector resolution: 10 pixels mm^-1	h = −13→13
oscillation scans	k = −23→23
16269 measured reflections	l = 0→27
4973 independent reflections

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.075	w = 1/[σ^2(Fo^2) + (0.1152P)^2 + 7.3374P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.201	(Δ/σ)max = 0.042
S = 1.05	Δρmax = 1.31 e Å^−3
4973 reflections	Δρmin = −0.67 e Å^−3
560 parameters	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0085 (10)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983)
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.38 (15)

Special details

Geometry. Mean-plane data from final SHELXL refinement run:-

Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane)

10.1950 x - 4.8495 y + 4.7622 z = 1.8307

* 0.0000 C25 * -0.0006 N26 * 0.0010 C27 * -0.0008 C28 * 0.0004 S29

Rms deviation of fitted atoms = 0.0007

10.5402 x - 4.0126 y - 1.1132 z = 0.7556

Angle to previous plane = 15.30

* 0.0034 C56 * -0.0063 N57 * 0.0065 C58 * -0.0039 C59 * 0.0003 S60

Rms deviation of fitted atoms = 0.0047

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 (Ų)

	x	y	z	Uiso*/Ueq
N1	0.4046 (4)	0.6583 (2)	0.75546 (19)	0.0272 (9)
H1	0.3890	0.6161	0.7482	0.041*
C2	0.4189 (5)	0.7065 (3)	0.7065 (2)	0.0274 (10)
H2	0.4917	0.7350	0.7147	0.041*
C3	0.4404 (5)	0.6693 (3)	0.6476 (2)	0.0332 (12)
H3	0.3784	0.6331	0.6430	0.050*
C4	0.4295 (7)	0.7200 (4)	0.5953 (3)	0.0490 (16)
H4A	0.4437	0.6963	0.5586	0.049*
H4B	0.4902	0.7555	0.5999	0.049*
H4C	0.3480	0.7396	0.5950	0.049*
C5	0.5714 (7)	0.6377 (4)	0.6483 (3)	0.0521 (17)
H5A	0.6323	0.6735	0.6427	0.063*
H5B	0.5861	0.6171	0.6868	0.063*
C6	0.5885 (8)	0.5841 (5)	0.6005 (4)	0.069 (2)
H6A	0.6700	0.5647	0.6037	0.069*
H6B	0.5790	0.6048	0.5621	0.069*
H6C	0.5275	0.5489	0.6054	0.069*
C7	0.3045 (5)	0.7528 (3)	0.7051 (2)	0.0296 (11)
O8	0.1980 (3)	0.73054 (19)	0.69896 (19)	0.0335 (9)
N9	0.3288 (4)	0.8200 (2)	0.7116 (2)	0.0299 (10)
H9	0.4043	0.8339	0.7131	0.045*
C10	0.2276 (5)	0.8691 (3)	0.7162 (3)	0.0323 (12)
H10	0.1627	0.8542	0.6887	0.048*
C11	0.2698 (6)	0.9408 (3)	0.6956 (3)	0.0417 (14)
H11	0.1964	0.9695	0.6899	0.063*
C12	0.3572 (6)	0.9761 (3)	0.7384 (4)	0.0476 (16)
H12A	0.3166	0.9819	0.7761	0.048*
H12B	0.3798	1.0199	0.7228	0.048*
H12C	0.4303	0.9488	0.7436	0.048*
O13	0.3327 (4)	0.9332 (3)	0.6389 (2)	0.0491 (11)
S14	0.2687 (2)	0.96181 (14)	0.57976 (10)	0.0720 (6)
O15	0.3601 (6)	0.9473 (4)	0.5354 (3)	0.0767 (17)
O16	0.1545 (6)	0.9161 (4)	0.5695 (4)	0.094 (2)
C17	0.1761 (10)	0.8445 (5)	0.5531 (5)	0.082 (3)
H17A	0.0979	0.8220	0.5472	0.074*
H17B	0.2209	0.8220	0.5844	0.074*
H17C	0.2235	0.8426	0.5171	0.074*
C18	0.1689 (5)	0.8733 (3)	0.7774 (3)	0.0332 (12)
O19	0.0790 (4)	0.9108 (2)	0.7849 (2)	0.0422 (10)
N20	0.2190 (4)	0.8355 (2)	0.8215 (2)	0.0332 (10)
H20	0.2901	0.8165	0.8161	0.050*
C21	0.1551 (7)	0.8262 (3)	0.8777 (3)	0.0425 (14)
H21	0.0756	0.8500	0.8739	0.064*
C22	0.2198 (11)	0.8578 (5)	0.9309 (4)	0.078 (3)
H22	0.1645	0.8507	0.9649	0.070*
C23	0.3310 (10)	0.8259 (6)	0.9453 (5)	0.087 (3)
H22A	0.3669	0.8477	0.9794	0.070*
H22B	0.3872	0.8293	0.9124	0.070*
H22C	0.3158	0.7787	0.9540	0.070*
C24	0.2285 (14)	0.9331 (6)	0.9224 (6)	0.112 (5)
H24A	0.2233	0.9447	0.8814	0.101*
H24B	0.3032	0.9495	0.9394	0.101*
H24C	0.1584	0.9550	0.9430	0.101*
C25	0.1239 (5)	0.7508 (3)	0.8838 (2)	0.0305 (11)
N26	0.1254 (4)	0.7094 (2)	0.8382 (2)	0.0307 (10)
C27	0.0868 (5)	0.6447 (3)	0.8554 (2)	0.0307 (11)
C28	0.0561 (6)	0.6383 (3)	0.9142 (3)	0.0416 (14)
H28	0.0285	0.5983	0.9321	0.062*
S29	0.07597 (18)	0.71455 (9)	0.94953 (7)	0.0473 (4)
C30	0.0796 (5)	0.5885 (3)	0.8123 (2)	0.0286 (11)
O31	0.0529 (4)	0.5298 (2)	0.82810 (18)	0.0364 (9)
N32	0.0989 (4)	0.6059 (2)	0.75495 (19)	0.0281 (9)
H32	0.1177	0.6472	0.7458	0.042*
C33	0.0878 (5)	0.5541 (3)	0.7088 (2)	0.0296 (11)
H33	0.0139	0.5266	0.7172	0.044*
C34	0.0725 (6)	0.5864 (3)	0.6469 (2)	0.0352 (12)
H34	0.1431	0.6167	0.6396	0.053*
C35	0.0728 (11)	0.5304 (4)	0.5999 (3)	0.073 (3)
H35A	0.1593	0.5200	0.5902	0.073*
H35B	0.0338	0.5472	0.5644	0.073*
H35C	0.0334	0.4911	0.6140	0.073*
C36	−0.0474 (7)	0.6288 (4)	0.6444 (3)	0.0480 (16)
H36A	−0.1178	0.5980	0.6448	0.058*
H36B	−0.0523	0.6567	0.6799	0.058*
C37	−0.0579 (10)	0.6750 (4)	0.5903 (4)	0.071 (2)
H37A	−0.1341	0.7003	0.5923	0.071*
H37B	−0.0571	0.6477	0.5549	0.071*
H37C	0.0108	0.7061	0.5896	0.071*
C38	0.2012 (5)	0.5074 (3)	0.7116 (2)	0.0288 (11)
O39	0.3079 (4)	0.52856 (19)	0.70402 (18)	0.0319 (8)
N40	0.1754 (4)	0.4411 (2)	0.7236 (2)	0.0272 (9)
H40	0.0994	0.4283	0.7272	0.041*
C41	0.2738 (5)	0.3915 (3)	0.7307 (2)	0.0267 (10)
H41	0.3406	0.4052	0.7037	0.040*
C42	0.2343 (6)	0.3193 (3)	0.7120 (2)	0.0335 (12)
H42	0.3080	0.2903	0.7089	0.050*
C43	0.1419 (6)	0.2860 (3)	0.7536 (3)	0.0416 (14)
H43A	0.1218	0.2412	0.7391	0.042*
H43B	0.0679	0.3131	0.7553	0.042*
H43C	0.1774	0.2824	0.7925	0.042*
O44	0.1755 (4)	0.3242 (2)	0.65409 (19)	0.0411 (10)
S45	0.2563 (2)	0.29921 (13)	0.59711 (8)	0.0643 (6)
O46	0.1698 (6)	0.3149 (3)	0.5498 (3)	0.0733 (18)
O47	0.3745 (6)	0.3455 (3)	0.5962 (2)	0.0642 (14)
C48	0.3564 (9)	0.4146 (4)	0.5765 (4)	0.065 (2)
H48A	0.4344	0.4382	0.5768	0.058*
H48B	0.2995	0.4373	0.6027	0.058*
H48C	0.3233	0.4144	0.5370	0.058*
C49	0.3297 (4)	0.3897 (3)	0.7932 (2)	0.0252 (10)
O50	0.4182 (3)	0.3519 (2)	0.80324 (17)	0.0323 (8)
N51	0.2783 (4)	0.4309 (2)	0.83433 (18)	0.0254 (9)
H51	0.2065	0.4484	0.8277	0.038*
C52	0.3422 (5)	0.4465 (3)	0.8900 (2)	0.0282 (11)
H52	0.4234	0.4242	0.8883	0.042*
C53	0.2747 (6)	0.4183 (3)	0.9449 (3)	0.0351 (12)
H53	0.3184	0.4358	0.9799	0.053*
C54	0.1412 (6)	0.4424 (4)	0.9494 (3)	0.0494 (16)
H54A	0.1388	0.4913	0.9475	0.049*
H54B	0.1065	0.4275	0.9865	0.049*
H54C	0.0940	0.4237	0.9172	0.049*
C55	0.2831 (8)	0.3411 (3)	0.9472 (3)	0.0538 (18)
H55A	0.2409	0.3247	0.9819	0.054*
H55B	0.3687	0.3276	0.9488	0.054*
H55C	0.2452	0.3221	0.9123	0.054*
C56	0.3652 (5)	0.5227 (3)	0.8918 (2)	0.0279 (11)
N57	0.3736 (4)	0.5605 (2)	0.84380 (18)	0.0270 (9)
C58	0.4018 (5)	0.6272 (3)	0.8587 (2)	0.0272 (10)
C59	0.4119 (6)	0.6400 (3)	0.9182 (3)	0.0378 (13)
H59	0.4291	0.6825	0.9348	0.057*
S60	0.38869 (17)	0.56700 (7)	0.95752 (6)	0.0400 (4)
C61	0.4156 (5)	0.6798 (3)	0.8121 (2)	0.0274 (10)
O62	0.4385 (4)	0.7401 (2)	0.82502 (17)	0.0330 (9)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.023 (2)	0.029 (2)	0.029 (2)	0.0002 (18)	0.0034 (17)	0.0018 (17)
C2	0.021 (2)	0.029 (2)	0.033 (3)	0.001 (2)	0.003 (2)	0.003 (2)
C3	0.032 (3)	0.038 (3)	0.030 (3)	−0.007 (2)	0.002 (2)	0.005 (2)
C4	0.062 (4)	0.053 (4)	0.033 (3)	−0.005 (4)	0.005 (3)	0.004 (3)
C5	0.048 (4)	0.061 (4)	0.046 (4)	0.011 (3)	0.002 (3)	−0.011 (3)
C6	0.055 (4)	0.083 (6)	0.069 (5)	0.016 (4)	0.005 (4)	−0.024 (5)
C7	0.026 (3)	0.032 (3)	0.031 (3)	−0.002 (2)	−0.001 (2)	0.007 (2)
O8	0.0231 (18)	0.0295 (19)	0.048 (2)	−0.0036 (15)	−0.0042 (17)	0.0061 (17)
N9	0.021 (2)	0.028 (2)	0.040 (2)	−0.0026 (18)	−0.0004 (19)	0.0044 (19)
C10	0.020 (2)	0.035 (3)	0.041 (3)	0.004 (2)	−0.002 (2)	0.008 (2)
C11	0.039 (3)	0.027 (3)	0.059 (4)	−0.002 (3)	−0.002 (3)	0.013 (3)
C12	0.036 (3)	0.038 (3)	0.069 (4)	−0.008 (3)	−0.003 (3)	−0.003 (3)
O13	0.036 (2)	0.054 (3)	0.057 (3)	−0.001 (2)	0.000 (2)	0.021 (2)
S14	0.0617 (12)	0.0923 (16)	0.0619 (12)	0.0161 (12)	−0.0103 (10)	0.0114 (11)
O15	0.070 (4)	0.095 (5)	0.065 (4)	−0.002 (4)	0.000 (3)	0.014 (3)
O16	0.062 (4)	0.109 (6)	0.111 (6)	0.006 (4)	−0.023 (4)	0.015 (5)
C17	0.070 (6)	0.087 (7)	0.091 (7)	−0.011 (5)	−0.019 (5)	0.003 (6)
C18	0.021 (2)	0.030 (3)	0.048 (3)	−0.002 (2)	−0.005 (2)	0.001 (2)
O19	0.0254 (19)	0.036 (2)	0.065 (3)	0.0026 (17)	−0.001 (2)	0.002 (2)
N20	0.025 (2)	0.035 (2)	0.039 (2)	0.002 (2)	−0.003 (2)	−0.003 (2)
C21	0.046 (3)	0.046 (3)	0.036 (3)	0.000 (3)	−0.001 (3)	−0.003 (3)
C22	0.108 (8)	0.081 (6)	0.045 (4)	−0.039 (6)	−0.002 (5)	−0.022 (4)
C23	0.080 (6)	0.109 (8)	0.073 (6)	0.001 (6)	−0.006 (5)	−0.029 (6)
C24	0.143 (11)	0.072 (6)	0.123 (10)	−0.012 (8)	−0.036 (9)	−0.037 (7)
C25	0.027 (3)	0.034 (3)	0.030 (3)	0.006 (2)	−0.004 (2)	−0.007 (2)
N26	0.026 (2)	0.035 (2)	0.031 (2)	0.007 (2)	−0.0001 (19)	−0.0008 (19)
C27	0.026 (2)	0.032 (3)	0.034 (3)	0.003 (2)	0.004 (2)	−0.001 (2)
C28	0.047 (3)	0.044 (3)	0.034 (3)	0.006 (3)	0.011 (3)	0.005 (3)
S29	0.0652 (10)	0.0462 (8)	0.0304 (7)	0.0086 (8)	0.0076 (7)	−0.0042 (6)
C30	0.020 (2)	0.036 (3)	0.030 (2)	0.006 (2)	0.001 (2)	0.000 (2)
O31	0.036 (2)	0.039 (2)	0.034 (2)	−0.0009 (18)	0.0069 (17)	0.0054 (17)
N32	0.023 (2)	0.030 (2)	0.031 (2)	0.0030 (18)	−0.0016 (18)	−0.0034 (18)
C33	0.033 (3)	0.027 (2)	0.028 (2)	0.005 (2)	−0.001 (2)	−0.001 (2)
C34	0.041 (3)	0.033 (3)	0.032 (3)	0.002 (3)	−0.003 (2)	0.000 (2)
C35	0.128 (8)	0.057 (4)	0.034 (3)	0.037 (5)	−0.012 (4)	−0.007 (3)
C36	0.055 (4)	0.046 (3)	0.042 (3)	0.011 (3)	−0.016 (3)	−0.004 (3)
C37	0.085 (6)	0.061 (5)	0.067 (5)	0.030 (5)	−0.016 (5)	0.010 (4)
C38	0.034 (3)	0.028 (2)	0.024 (2)	0.000 (2)	−0.003 (2)	−0.003 (2)
O39	0.0294 (19)	0.0281 (18)	0.038 (2)	−0.0047 (16)	0.0033 (16)	−0.0009 (16)
N40	0.0215 (19)	0.027 (2)	0.033 (2)	0.0002 (18)	−0.0012 (18)	0.0026 (18)
C41	0.022 (2)	0.027 (2)	0.031 (2)	0.004 (2)	−0.001 (2)	−0.002 (2)
C42	0.034 (3)	0.030 (3)	0.036 (3)	0.002 (2)	−0.007 (2)	−0.004 (2)
C43	0.042 (3)	0.031 (3)	0.052 (3)	−0.008 (3)	−0.009 (3)	0.014 (3)
O44	0.039 (2)	0.045 (2)	0.039 (2)	0.0089 (19)	−0.0116 (19)	−0.0099 (19)
S45	0.0608 (12)	0.0955 (15)	0.0365 (8)	−0.0210 (12)	0.0043 (8)	−0.0025 (9)
O46	0.089 (4)	0.079 (4)	0.052 (3)	−0.033 (4)	−0.021 (3)	0.009 (3)
O47	0.066 (3)	0.069 (3)	0.058 (3)	0.002 (3)	0.002 (3)	0.003 (3)
C48	0.070 (5)	0.060 (5)	0.065 (5)	−0.009 (4)	−0.006 (4)	0.010 (4)
C49	0.018 (2)	0.028 (2)	0.030 (2)	−0.001 (2)	0.001 (2)	−0.001 (2)
O50	0.0228 (18)	0.0370 (19)	0.037 (2)	0.0070 (17)	−0.0026 (16)	−0.0024 (17)
N51	0.0199 (18)	0.029 (2)	0.027 (2)	0.0049 (18)	0.0015 (17)	−0.0004 (17)
C52	0.027 (2)	0.029 (2)	0.028 (2)	0.005 (2)	−0.002 (2)	0.002 (2)
C53	0.037 (3)	0.039 (3)	0.030 (3)	0.002 (3)	0.000 (2)	0.006 (2)
C54	0.039 (3)	0.064 (4)	0.046 (3)	0.003 (3)	0.017 (3)	0.014 (3)
C55	0.079 (5)	0.034 (3)	0.049 (4)	0.001 (3)	0.017 (4)	0.014 (3)
C56	0.024 (2)	0.031 (3)	0.029 (2)	0.008 (2)	−0.001 (2)	0.000 (2)
N57	0.023 (2)	0.033 (2)	0.025 (2)	0.0015 (18)	0.0012 (17)	0.0003 (17)
C58	0.024 (2)	0.026 (2)	0.032 (3)	0.005 (2)	−0.004 (2)	0.001 (2)
C59	0.040 (3)	0.037 (3)	0.037 (3)	0.003 (3)	−0.006 (3)	−0.002 (2)
S60	0.0593 (9)	0.0365 (7)	0.0242 (6)	0.0003 (7)	−0.0033 (6)	0.0001 (5)
C61	0.016 (2)	0.034 (3)	0.032 (3)	0.002 (2)	−0.002 (2)	0.003 (2)
O62	0.0307 (19)	0.0334 (19)	0.035 (2)	0.0009 (17)	−0.0036 (16)	−0.0048 (16)

Geometric parameters (Å, º)

N1—C61	1.348 (7)	C30—N32	1.351 (7)
N1—C2	1.460 (6)	N32—C33	1.457 (6)
C2—C7	1.532 (7)	C33—C38	1.530 (7)
C2—C3	1.532 (7)	C33—C34	1.540 (7)
C3—C5	1.543 (9)	C34—C35	1.524 (9)
C3—C4	1.544 (8)	C34—C36	1.538 (9)
C5—C6	1.514 (10)	C36—C37	1.522 (10)
C7—O8	1.236 (7)	C38—O39	1.235 (7)
C7—N9	1.351 (7)	C38—N40	1.356 (7)
N9—C10	1.459 (7)	N40—C41	1.448 (6)
C10—C18	1.519 (8)	C41—C49	1.533 (7)
C10—C11	1.547 (7)	C41—C42	1.537 (7)
C11—O13	1.453 (8)	C42—O44	1.454 (7)
C11—C12	1.516 (9)	C42—C43	1.514 (9)
O13—S14	1.602 (5)	O44—S45	1.627 (5)
S14—O15	1.431 (7)	S45—O46	1.449 (6)
S14—O16	1.540 (8)	S45—O47	1.565 (6)
O16—C17	1.470 (13)	O47—C48	1.438 (10)
C18—O19	1.229 (7)	C49—O50	1.229 (6)
C18—N20	1.351 (8)	C49—N51	1.348 (7)
N20—C21	1.454 (8)	N51—C52	1.462 (7)
C21—C22	1.519 (10)	C52—C56	1.515 (7)
C21—C25	1.521 (9)	C52—C53	1.537 (7)
C22—C23	1.391 (15)	C53—C55	1.518 (8)
C22—C24	1.492 (15)	C53—C54	1.518 (9)
C25—N26	1.310 (7)	C56—N57	1.315 (7)
C25—S29	1.722 (6)	C56—S60	1.734 (5)
N26—C27	1.390 (7)	N57—C58	1.383 (7)
C27—C28	1.371 (8)	C58—C59	1.369 (8)
C27—C30	1.469 (8)	C58—C61	1.479 (7)
C28—S29	1.708 (7)	C59—S60	1.701 (6)
C30—O31	1.240 (7)	C61—O62	1.241 (7)
C61—N1—C2	120.1 (4)	C30—N32—C33	119.5 (4)
N1—C2—C7	108.2 (4)	N32—C33—C38	108.8 (4)
N1—C2—C3	111.2 (4)	N32—C33—C34	111.6 (4)
C7—C2—C3	112.7 (4)	C38—C33—C34	111.6 (4)
C2—C3—C5	108.7 (5)	C35—C34—C36	111.4 (6)
C2—C3—C4	110.1 (5)	C35—C34—C33	109.4 (5)
C5—C3—C4	109.6 (5)	C36—C34—C33	110.2 (5)
C6—C5—C3	112.5 (6)	C37—C36—C34	114.4 (7)
O8—C7—N9	122.4 (5)	O39—C38—N40	122.8 (5)
O8—C7—C2	122.8 (5)	O39—C38—C33	122.5 (5)
N9—C7—C2	114.8 (5)	N40—C38—C33	114.7 (5)
C7—N9—C10	120.4 (5)	C38—N40—C41	121.0 (4)
N9—C10—C18	114.2 (4)	N40—C41—C49	113.8 (4)
N9—C10—C11	111.0 (5)	N40—C41—C42	112.7 (4)
C18—C10—C11	110.3 (5)	C49—C41—C42	109.8 (4)
O13—C11—C12	108.4 (5)	O44—C42—C43	107.3 (5)
O13—C11—C10	107.9 (5)	O44—C42—C41	107.7 (4)
C12—C11—C10	114.0 (5)	C43—C42—C41	114.3 (5)
C11—O13—S14	119.5 (4)	C42—O44—S45	117.0 (4)
O15—S14—O16	109.3 (5)	O46—S45—O47	113.1 (3)
O15—S14—O13	102.3 (3)	O46—S45—O44	99.8 (3)
O16—S14—O13	105.4 (4)	O47—S45—O44	105.7 (3)
C17—O16—S14	117.8 (6)	C48—O47—S45	116.1 (6)
O19—C18—N20	122.9 (6)	O50—C49—N51	123.7 (5)
O19—C18—C10	119.0 (5)	O50—C49—C41	119.2 (5)
N20—C18—C10	118.1 (5)	N51—C49—C41	117.1 (4)
C18—N20—C21	121.3 (5)	C49—N51—C52	121.3 (4)
N20—C21—C22	114.8 (6)	N51—C52—C56	107.8 (4)
N20—C21—C25	107.7 (5)	N51—C52—C53	113.0 (4)
C22—C21—C25	115.3 (6)	C56—C52—C53	114.2 (4)
C23—C22—C24	114.8 (11)	C55—C53—C54	111.4 (6)
C23—C22—C21	113.3 (8)	C55—C53—C52	110.9 (5)
C24—C22—C21	109.3 (9)	C54—C53—C52	113.0 (5)
N26—C25—C21	122.0 (5)	N57—C56—C52	123.0 (5)
N26—C25—S29	114.9 (4)	N57—C56—S60	114.1 (4)
C21—C25—S29	123.0 (4)	C52—C56—S60	122.8 (4)
C25—N26—C27	110.2 (5)	C56—N57—C58	110.5 (4)
C28—C27—N26	115.1 (5)	C59—C58—N57	115.4 (5)
C28—C27—C30	123.8 (5)	C59—C58—C61	123.9 (5)
N26—C27—C30	121.1 (5)	N57—C58—C61	120.7 (5)
C27—C28—S29	109.9 (5)	C58—C59—S60	110.1 (4)
C28—S29—C25	89.9 (3)	C59—S60—C56	90.0 (3)
O31—C30—N32	123.0 (5)	O62—C61—N1	122.5 (5)
O31—C30—C27	121.2 (5)	O62—C61—C58	121.2 (5)
N32—C30—C27	115.7 (5)	N1—C61—C58	116.3 (5)
C61—N1—C2—C3	163.9 (4)	C27—C30—N32—C33	−177.3 (4)
C61—N1—C2—C7	−71.7 (6)	O31—C30—N32—C33	0.4 (7)
C2—N1—C61—C58	−179.0 (4)	C30—N32—C33—C34	162.1 (4)
C2—N1—C61—O62	−0.9 (7)	C30—N32—C33—C38	−74.1 (6)
N1—C2—C3—C4	168.8 (4)	N32—C33—C34—C35	174.0 (5)
N1—C2—C3—C5	−70.3 (6)	N32—C33—C34—C36	−62.0 (6)
C7—C2—C3—C4	46.8 (6)	C38—C33—C34—C35	51.8 (6)
C7—C2—C3—C5	167.7 (5)	C38—C33—C34—C36	175.8 (5)
N1—C2—C7—O8	−59.1 (6)	N32—C33—C38—O39	−61.2 (6)
N1—C2—C7—N9	120.6 (5)	N32—C33—C38—N40	118.2 (5)
C3—C2—C7—O8	64.6 (7)	C34—C33—C38—O39	62.4 (7)
C3—C2—C7—N9	−115.8 (5)	C34—C33—C38—N40	−118.2 (5)
C2—C3—C5—C6	164.9 (6)	C33—C34—C36—C37	168.0 (6)
C4—C3—C5—C6	−75.7 (7)	C35—C34—C36—C37	−69.4 (8)
C2—C7—N9—C10	−174.9 (4)	C33—C38—N40—C41	−176.6 (4)
O8—C7—N9—C10	4.8 (8)	O39—C38—N40—C41	2.7 (8)
C7—N9—C10—C11	−155.1 (5)	C38—N40—C41—C42	−150.5 (5)
C7—N9—C10—C18	79.6 (6)	C38—N40—C41—C49	83.9 (6)
N9—C10—C11—C12	−71.8 (6)	N40—C41—C42—C43	−69.9 (6)
N9—C10—C11—O13	48.4 (6)	N40—C41—C42—O44	49.0 (6)
C18—C10—C11—C12	55.4 (7)	C49—C41—C42—C43	57.8 (6)
C18—C10—C11—O13	175.6 (4)	C49—C41—C42—O44	176.7 (4)
N9—C10—C18—O19	−176.3 (5)	N40—C41—C49—O50	−176.0 (4)
N9—C10—C18—N20	4.2 (7)	N40—C41—C49—N51	2.8 (6)
C11—C10—C18—O19	57.9 (7)	C42—C41—C49—O50	57.0 (6)
C11—C10—C18—N20	−121.6 (5)	C42—C41—C49—N51	−124.2 (5)
C10—C11—O13—S14	110.1 (5)	C41—C42—O44—S45	103.7 (4)
C12—C11—O13—S14	−126.2 (5)	C43—C42—O44—S45	−132.9 (4)
C11—O13—S14—O15	177.9 (5)	C42—O44—S45—O46	−177.8 (4)
C11—O13—S14—O16	−67.7 (5)	C42—O44—S45—O47	−60.2 (4)
O13—S14—O16—C17	−67.8 (7)	O44—S45—O47—C48	−74.3 (6)
O15—S14—O16—C17	41.7 (8)	O46—S45—O47—C48	34.2 (6)
C10—C18—N20—C21	−167.8 (5)	C41—C49—N51—C52	−164.2 (4)
O19—C18—N20—C21	12.8 (8)	O50—C49—N51—C52	14.6 (8)
C18—N20—C21—C22	−113.3 (6)	C49—N51—C52—C53	−114.2 (5)
C18—N20—C21—C25	115.2 (6)	C49—N51—C52—C56	118.7 (5)
N20—C21—C22—C23	−68.8 (7)	N51—C52—C53—C54	−56.1 (6)
N20—C21—C22—C24	61.4 (7)	N51—C52—C53—C55	70.7 (6)
C25—C21—C22—C23	58.4 (7)	C56—C52—C53—C54	67.5 (6)
C25—C21—C22—C24	−171.5 (6)	C56—C52—C53—C55	−165.7 (5)
N20—C21—C25—N26	−17.0 (7)	N51—C52—C56—N57	−25.2 (7)
N20—C21—C25—S29	166.8 (4)	N51—C52—C56—S60	157.5 (4)
C22—C21—C25—N26	−147.3 (5)	C53—C52—C56—N57	−151.6 (5)
C22—C21—C25—S29	36.5 (7)	C53—C52—C56—S60	31.1 (6)
C21—C25—N26—C27	−176.8 (5)	C52—C56—N57—C58	−176.1 (5)
S29—C25—N26—C27	−0.3 (6)	S60—C56—N57—C58	1.4 (6)
C21—C25—S29—C28	176.3 (5)	C52—C56—S60—C59	176.9 (5)
N26—C25—S29—C28	−0.2 (5)	N57—C56—S60—C59	−0.6 (4)
C25—N26—C27—C28	0.8 (7)	C56—N57—C58—C59	−1.7 (6)
C25—N26—C27—C30	179.8 (5)	C56—N57—C58—C61	−179.7 (5)
N26—C27—C28—S29	−0.9 (7)	N57—C58—C59—S60	1.3 (6)
C30—C27—C28—S29	−179.8 (4)	C61—C58—C59—S60	179.2 (4)
N26—C27—C30—O31	175.4 (5)	N57—C58—C61—N1	−3.5 (7)
N26—C27—C30—N32	−6.9 (7)	N57—C58—C61—O62	178.4 (5)
C28—C27—C30—O31	−5.8 (8)	C59—C58—C61—N1	178.8 (5)
C28—C27—C30—N32	171.9 (5)	C59—C58—C61—O62	0.6 (8)
C27—C28—S29—C25	0.6 (5)	C58—C59—S60—C56	−0.4 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O39	0.86	2.17	2.983 (6)	158
N9—H9···O50^i	0.86	1.98	2.818 (5)	165
N20—H20···O62	0.86	2.20	3.017 (6)	158
N32—H32···O8	0.86	2.13	2.950 (6)	160
N40—H40···O19^ii	0.86	1.97	2.813 (6)	165
N51—H51···O31	0.86	2.30	3.112 (6)	158

Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x, y−1/2, −z+3/2.