An intermediate in a new synthesis approach to β-substituted β-hydroxy­aspartame

The crystal and molecular structure of 1-tert-butyl 4-ethyl (2′R,3′R,5′R,2S,3S)-3-bromo­methyl-3-hydroxy-2-[(2′-hydroxy-2′,6′,6′-tri­methyl­bi­cyclo­[3.1.1]­hept-3′-yl­idene)­amino]­succinate, C₂₁H₃₄BrNO₆, is presented. This compound is an intermediate in the new synthetic route to β-substituted β-hydroxy­aspartates, which are blockers of glutamate transport.

S1. Comment

L-Glutamate is the major exitatory neurotransmitter in the mammalian central nervous system. The glutamate uptake system consists of at least five different transporter proteins called excitatory amino acid transporters (EAATs), EAAT1–5, which have been cloned from mammalian tissues. It was reported that from some derivatives of DL-threo-β-hydoxyaspartate, the L-threo-β-benzyloxyaspartate (L-TBOA) was the most potent blocker for human EAAT3, while the D isomer revealed a difference in the pharmacophores between EAAT1 and EAAT3. Synthesis of various analogues of β-hydoxyaspartate and especially β-hydroxy-β-substituted aspartates will give indispensable tools for the investigation of the physiological roles of glutamate transporters (Wehbe et al., 2003). For the synthesis of β-hydroxy-β-substituted α-aminoacids, and in particular β-hydroxy aspartates (Lebrun et al., 1997; Shimamoto et al., 1998), we have explored a new strategy using the enolate of the Schiff base prepared from (+)-(1R,2R,5R)-2-hydroxypinan-3-one and tert-butylglycinate (El Achkar et al., 1988), (I). This strategy is outlined in the reaction scheme below.

The products are the epoxides (III) and (IV), which are versatile intermediates in organic chemistry (Hauser et al., 1986) and would be good precursors for the synthesis of diversely β-substituted β-hydroxy aspartates and their derivatives. In order to determine unambiguously the configuration of the different asymetric C atoms at different synthesis steps, the structures of the key intermediate (IIb) was studied by X-ray diffraction.

Fig. 1 shows the molecular structure of (IIb). From the known R configuration of atoms C2', C3' and C5', we found an S configuration for atoms C2 and C3. The bicyclo system from (+)-(1R,2R,5R)-2-hydroxypinan-3-one consists of a six-membered ring (C1'—C2'—C3'—C4'—C5'—C6') bridged between atoms C3' and C5' with two methyl groups attached on atom C8' and a methyl and a hydroxyl group attached on atom C'2. The N atom of the future amine function is involved in a Schiff bases with an E configuration for the C1'=N1 bond. This E configuration was found in the X-ray structure of several similar Shiff bases (Laue et al., 2000; Thieme et al., 2000; Katagiri et al. 2001). As shown by the C2—N1—C1'—C2' and C2—N1—C1'—C6' torsion angles [175.9 (3) and −0.1 (5)°, respectively], the geometry of the double bond is slightly distorted.

The packing shown in Fig. 2 is characterized by the establishment of intermolecular and intramolecular hydrogen bonds. Atom O3 in the reference molecule acts as a hydrogen-bond donor, via atom H3, to atoms O4' and O2' in the molecule at (-x, y − 1/2, −z). Atom O2' also acts as a hydrogen-bond donor, via atom H2', to atom N1. These two short intramolecular hydrogen bonds, O3—H3···O4' [O···O = 2.729 (4) Å] and O2'—H2'···N1 [O···N = 2.877 (4) Å], hold the molecule in a rigid conformation by forming two pseudo-five-membered rings. The intermolecular O3—H3···O2' hydrogen bond [O···O = 2.768 (4) Å], and propagation of this bond from the molecule at (-x, y − 1/2, −z) to the molecule at (x, y − 1, z), generates an infinite chain running parallel to the [010] direction.

S2. Experimental

Potassium hexamethyldisilazane (KHMDS) gave the best result in obtaining the potassium Schiff base enolate. Alkylation by ethyl bromopyruvate as prochiral keton (Soloshonok et al., 1997) afforded only the β-hydroxy compound, (IIa) and (IIb), in 74% yield as a mixture of two diastereoisomers (d.r. = 88/12), which were separated by silica-gel column chromatography. For the X-ray diffraction analysis, pure (IIb) (m.p. 365–366 K) was dissolved in the required amount of anhydrous Et₂O. Single crystals were grown from the solution by slow evaporation at room temperature. Compound (IIb) was easily transformed into epoxide (III) by action of CsF in tetrahydrofuran/CH₃CN (1/1) in 76% yield. After cleavage of the chiral auxiliary group, the aminoester epoxyde (IV) was obtained in 50% yield.

S3. Refinement

Atoms H3 and H2', which are involved in hydrogen bonds, were located in difference Fourrier maps. The remaining H atoms were introduced at calculated positions and refined as riding atoms (O—H = 0.82 Å, and C—H = 0.96, 0.97 and 0.98 Å) with displacement parameters equal to 1.2 (OH, CH and CH₂) or 1.5 (CH₃) times that of the parent atom. It was clear early in the refinement that there was some disorder in the structure. Some 35% of the atomic site for atom C7 from the methyl group of the ethyl ester function is occupied by a second position. The ethyl ester was then refined as a disordered group. Atom C10 from the terbutyl group displays an elongated ellipsoid axis; however, because of the close interactions between the methyl group and methyl atom C7A of a symmetry-related molecule (1 − x, y + 1/2, 1 − z) and methyl atom C11 of a symmetry-related molecule at (1 − x, y + 1/2, − z), no chemically sensible disordered model could be obtained. As discussed above, the absolute configuration of atoms C2 and C3 was established from the known absolute configuration of atoms C2', C3' and C5'; it was therefore not imperative to determine it from the anomalous dispersion of the Br atom, and no Friedel pairs were collected.

Computing details

Data collection: KappaCCD Software (Nonius, 1997); cell refinement: HKL SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO (Otwinowski & Minor, 1997) and SCALEPACK; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976), PLATON (Spek, 2001); software used to prepare material for publication: maXus (Mackay et al., 1999).

Figures

	Fig. 1. An ORTEPII (Johnson,1976) wiew of the molecular structure of (IIb), showing the labelling of all non-H atoms. Displacement ellipsoids are shown at the 50% probability level and H atoms are shown as circles of arbitrary radii.
	Fig. 2. A PLATON (Spek, 2003) view of the intra- and intermolecular hydrogen-bonded motif of (IIb). Only atoms involved in hydrogen bonding are labelled. Atoms C, O, N and H are shown as spheres of arbitrary radii and hydrogen bonds are shown as dotted lines. [Symmetry codes: (i) −x, y − 1/2, −z; (ii) −x, y + 1/2, −z; (iii) x, y − 1, z.]

(2'R,3'R,5'R,2S,3S)-3-bromomethyl-3-hydroxy-2-[(2'-hydroxy-2',6',6'- trimethylbicyclo[3.1.1]hept-3'-ylidene)amino]succinic acid

Crystal data

C21H34BrNO6	F(000) = 500
Mr = 476.39	Dx = 1.297 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 24309 reflections
a = 11.546 (2) Å	θ = 3.5–28.6°
b = 10.321 (3) Å	µ = 1.72 mm^−1
c = 11.594 (4) Å	T = 293 K
β = 118.031 (5)°	Prism, colourless
V = 1219.6 (6) Å^3	0.50 × 0.40 × 0.20 mm
Z = 2

Data collection

Nonius KappaCCD area-detector diffractometer	2981 reflections with I > 2σ(I)
Radiation source: X-ray tube	Rint = 0.046
ϕ–scan	θmax = 28.6°, θmin = 3.5°
Absorption correction: multi-scan (SORTAV; Blessing, 1995)	h = −15→14
Tmin = 0.487, Tmax = 0.709	k = −13→13
24309 measured reflections	l = −14→15
3231 independent reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.046	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.119	H-atom parameters constrained
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0432P)^2 + 0.5864P] where P = (Fo^2 + 2Fc^2)/3
2981 reflections	(Δ/σ)max < 0.001
281 parameters	Δρmax = 0.71 e Å^−3
28 restraints	Δρmin = −0.57 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
Br1	0.46929 (4)	0.35065 (4)	0.34258 (4)	0.07121 (14)
O1	0.2960 (2)	0.8565 (3)	0.0505 (2)	0.0631 (6)
O1'	0.4913 (3)	0.7588 (3)	0.1672 (3)	0.0775 (8)
O2'	−0.0179 (3)	0.9508 (4)	0.0322 (3)	0.0954 (12)
O3	0.2718 (2)	0.5413 (2)	0.1127 (2)	0.0529 (5)
O4'	0.1510 (3)	0.4845 (3)	0.2600 (3)	0.0655 (7)
O4	0.3036 (3)	0.5950 (3)	0.4301 (2)	0.0668 (7)
N1	0.1942 (3)	0.7818 (2)	0.1962 (2)	0.0430 (6)
C1	0.3818 (3)	0.7859 (3)	0.1468 (3)	0.0488 (7)
C2	0.3284 (3)	0.7398 (3)	0.2381 (3)	0.0397 (6)
C3	0.3275 (3)	0.5890 (3)	0.2400 (3)	0.0397 (6)
C4	0.2473 (3)	0.5483 (3)	0.3078 (3)	0.0482 (7)
C5	0.4674 (3)	0.5370 (3)	0.3151 (3)	0.0505 (7)
C6	0.2391 (6)	0.5669 (8)	0.5098 (5)	0.1033 (19)
C7A	0.315 (3)	0.555 (3)	0.6349 (18)	0.112 (8)	0.35 (2)
C7B	0.3148 (15)	0.4756 (15)	0.6052 (12)	0.124 (4)	0.65 (2)
C8	0.3264 (5)	0.9142 (4)	−0.0489 (4)	0.0744 (11)
C9	0.1991 (9)	0.9843 (9)	−0.1348 (8)	0.149 (3)
C10	0.4398 (10)	1.0038 (8)	0.0131 (7)	0.168 (4)
C11	0.3439 (7)	0.8097 (6)	−0.1271 (5)	0.0999 (17)
C1'	0.1708 (3)	0.8921 (3)	0.2279 (3)	0.0424 (6)
C2'	0.0248 (3)	0.9288 (4)	0.1696 (3)	0.0552 (8)
C3'	0.0106 (4)	1.0581 (3)	0.2231 (4)	0.0586 (8)
C4'	0.1005 (5)	1.1583 (4)	0.2046 (5)	0.0736 (11)
C5'	0.2103 (4)	1.1110 (4)	0.3351 (4)	0.0637 (9)
C6'	0.2723 (4)	0.9926 (3)	0.3099 (4)	0.0547 (8)
C7'	−0.0560 (4)	0.8230 (4)	0.1845 (6)	0.0889 (16)
C8'	0.1027 (4)	1.0727 (4)	0.3735 (4)	0.0587 (8)
C9'	0.0594 (6)	1.1891 (5)	0.4268 (6)	0.0919 (15)
C10'	0.1331 (5)	0.9586 (5)	0.4670 (4)	0.0805 (12)
H3	0.1946	0.5230	0.0883	0.064*
H2	0.3851	0.7721	0.3266	0.048*
H2'	0.0126	0.8944	0.0045	0.114*
H5A	0.5119	0.5803	0.3991	0.061*
H5B	0.5147	0.5563	0.2668	0.061*
H6A	0.1765	0.6355	0.4960	0.124*	0.35 (2)
H6B	0.1898	0.4871	0.4780	0.124*	0.35 (2)
H6C	0.2310	0.6456	0.5511	0.124*	0.65 (2)
H6D	0.1519	0.5327	0.4552	0.124*	0.65 (2)
H7A	0.2622	0.5441	0.6781	0.168*	0.35 (2)
H7B	0.3679	0.6315	0.6676	0.168*	0.35 (2)
H7C	0.3708	0.4809	0.6513	0.168*	0.35 (2)
H7D	0.2672	0.4461	0.6494	0.186*	0.65 (2)
H7E	0.3956	0.5149	0.6673	0.186*	0.65 (2)
H7F	0.3335	0.4034	0.5644	0.186*	0.65 (2)
H9A	0.2098	1.0357	−0.1982	0.178*
H9B	0.1765	1.0395	−0.0818	0.178*
H9C	0.1305	0.9220	−0.1789	0.178*
H10A	0.4374	1.0645	−0.0508	0.202*
H10B	0.5200	0.9550	0.0472	0.202*
H10C	0.4356	1.0498	0.0830	0.202*
H11A	0.3583	0.8473	−0.1950	0.120*
H11B	0.2666	0.7566	−0.1654	0.120*
H11C	0.4181	0.7575	−0.0715	0.120*
H3'	−0.0801	1.0867	0.1928	0.070*
H4'A	0.1154	1.1409	0.1304	0.088*
H4'B	0.0752	1.2478	0.2053	0.088*
H5'	0.2719	1.1778	0.3898	0.076*
H6'A	0.3334	0.9542	0.3928	0.066*
H6'B	0.3216	1.0187	0.2652	0.066*
H7'A	−0.0351	0.8154	0.2747	0.133*
H7'B	−0.0372	0.7425	0.1551	0.133*
H7'C	−0.1474	0.8431	0.1331	0.133*
H9'A	0.1302	1.2148	0.5095	0.138*
H9'B	−0.0151	1.1651	0.4379	0.138*
H9'C	0.0361	1.2599	0.3664	0.138*
H10'A	0.2028	0.9819	0.5513	0.121*
H10'B	0.1595	0.8854	0.4338	0.121*
H10'C	0.0562	0.9368	0.4747	0.121*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br1	0.0715 (2)	0.05031 (17)	0.0944 (3)	0.01552 (19)	0.04102 (19)	0.0159 (2)
O1	0.0804 (15)	0.0627 (13)	0.0592 (12)	0.0179 (16)	0.0437 (12)	0.0188 (14)
O1'	0.0601 (16)	0.096 (2)	0.092 (2)	0.0021 (15)	0.0481 (15)	0.0252 (17)
O2'	0.085 (2)	0.123 (3)	0.0471 (14)	0.052 (2)	0.0050 (14)	−0.0038 (16)
O3	0.0524 (12)	0.0588 (13)	0.0441 (11)	−0.0047 (11)	0.0198 (10)	−0.0097 (10)
O4'	0.0556 (14)	0.0652 (16)	0.0780 (17)	−0.0142 (12)	0.0333 (13)	0.0026 (13)
O4	0.0679 (15)	0.093 (2)	0.0472 (12)	−0.0072 (14)	0.0334 (12)	0.0025 (13)
N1	0.0427 (13)	0.0390 (13)	0.0431 (13)	0.0035 (10)	0.0166 (11)	−0.0004 (10)
C1	0.0528 (18)	0.0434 (15)	0.0554 (17)	−0.0037 (13)	0.0297 (15)	0.0004 (13)
C2	0.0391 (14)	0.0387 (13)	0.0393 (13)	−0.0012 (11)	0.0168 (11)	−0.0006 (11)
C3	0.0402 (14)	0.0407 (14)	0.0386 (13)	−0.0001 (11)	0.0187 (11)	0.0001 (11)
C4	0.0489 (16)	0.0474 (16)	0.0514 (16)	0.0016 (13)	0.0262 (14)	0.0061 (13)
C5	0.0453 (16)	0.0469 (16)	0.0579 (17)	0.0033 (13)	0.0231 (14)	0.0084 (14)
C6	0.108 (4)	0.148 (5)	0.086 (3)	0.018 (4)	0.073 (3)	0.033 (3)
C7A	0.143 (14)	0.16 (2)	0.063 (6)	−0.044 (17)	0.075 (8)	−0.020 (11)
C7B	0.138 (9)	0.143 (11)	0.088 (8)	0.001 (9)	0.051 (7)	0.041 (7)
C8	0.113 (3)	0.066 (2)	0.064 (2)	0.002 (2)	0.057 (2)	0.0169 (18)
C9	0.194 (6)	0.173 (7)	0.124 (5)	0.100 (6)	0.112 (5)	0.098 (5)
C10	0.262 (8)	0.145 (6)	0.093 (4)	−0.120 (7)	0.080 (5)	0.005 (4)
C11	0.144 (5)	0.099 (4)	0.087 (3)	0.010 (3)	0.079 (3)	0.005 (3)
C1'	0.0441 (15)	0.0437 (14)	0.0370 (13)	0.0015 (11)	0.0170 (12)	0.0033 (11)
C2'	0.0475 (17)	0.0560 (19)	0.0508 (16)	0.0125 (14)	0.0138 (14)	−0.0057 (14)
C3'	0.065 (2)	0.0505 (18)	0.0636 (19)	0.0176 (16)	0.0330 (17)	0.0077 (15)
C4'	0.106 (3)	0.0460 (19)	0.086 (3)	0.013 (2)	0.060 (3)	0.0139 (19)
C5'	0.082 (3)	0.0424 (17)	0.083 (3)	−0.0118 (17)	0.052 (2)	−0.0136 (17)
C6'	0.0570 (18)	0.0478 (17)	0.0640 (19)	−0.0081 (14)	0.0322 (16)	−0.0106 (14)
C7'	0.053 (2)	0.068 (3)	0.139 (4)	−0.0111 (18)	0.039 (2)	−0.030 (3)
C8'	0.071 (2)	0.0536 (19)	0.0646 (19)	−0.0008 (16)	0.0428 (18)	−0.0064 (15)
C9'	0.109 (4)	0.081 (3)	0.112 (4)	−0.002 (3)	0.074 (3)	−0.028 (3)
C10'	0.101 (3)	0.091 (3)	0.063 (2)	−0.004 (3)	0.051 (2)	0.012 (2)

Geometric parameters (Å, º)

Br1—C5	1.948 (3)	C5—H5B	0.9700
O1—C1	1.312 (4)	C6—H6A	0.9700
O1—C8	1.479 (4)	C6—H6B	0.9700
O1'—C1	1.204 (4)	C6—H6C	0.9700
O3—C3	1.393 (3)	C6—H6D	0.9700
O4'—C4	1.183 (4)	C7A—H7A	0.9600
O4—C4	1.341 (4)	C7A—H7B	0.9600
O4—C6	1.463 (5)	C7A—H7C	0.9600
O2'—C2'	1.448 (5)	C7B—H7D	0.9600
N1—C1'	1.263 (4)	C7B—H7E	0.9600
N1—C2	1.455 (4)	C7B—H7F	0.9600
C1—C2	1.530 (4)	C9—H9A	0.9600
C2—C3	1.557 (4)	C9—H9B	0.9600
C3—C5	1.527 (4)	C9—H9C	0.9600
C3—C4	1.528 (4)	C10—H10A	0.9600
C6—C7A	1.30 (2)	C10—H10B	0.9600
C6—C7B	1.403 (14)	C10—H10C	0.9600
C8—C11	1.483 (7)	C11—H11A	0.9600
C8—C10	1.484 (9)	C11—H11B	0.9600
C8—C9	1.516 (8)	C11—H11C	0.9600
C1'—C6'	1.519 (4)	C3'—H3'	0.9800
C1'—C2'	1.541 (4)	C4'—H4'A	0.9700
C2'—C7'	1.497 (6)	C4'—H4'B	0.9700
C2'—C3'	1.513 (5)	C5'—H5'	0.9800
C3'—C4'	1.550 (6)	C6'—H6'A	0.9700
C3'—C8'	1.566 (5)	C6'—H6'B	0.9700
C4'—C5'	1.528 (7)	C7'—H7'A	0.9600
C5'—C6'	1.513 (5)	C7'—H7'B	0.9600
C5'—C8'	1.555 (5)	C7'—H7'C	0.9600
C8'—C10'	1.526 (6)	C9'—H9'A	0.9600
C8'—C9'	1.538 (6)	C9'—H9'B	0.9600
O3—H3	0.8200	C9'—H9'C	0.9600
O2'—H2'	0.8200	C10'—H10'A	0.9600
C2—H2	0.9800	C10'—H10'B	0.9600
C5—H5A	0.9700	C10'—H10'C	0.9600
C1—O1—C8	121.7 (3)	C7B—C6—H6C	110.0
C4—O4—C6	117.3 (4)	O4—C6—H6C	110.0
C1'—N1—C2	120.7 (3)	C7A—C6—H6D	129.9
O1'—C1—O1	126.9 (3)	C7B—C6—H6D	110.0
O1'—C1—C2	121.2 (3)	O4—C6—H6D	110.0
O1—C1—C2	111.8 (3)	H6C—C6—H6D	108.4
N1—C2—C1	112.9 (2)	C6—C7A—H7A	109.5
N1—C2—C3	106.8 (2)	C6—C7A—H7B	109.5
C1—C2—C3	109.1 (2)	C6—C7A—H7C	109.5
O3—C3—C5	108.6 (2)	C6—C7B—H7D	109.5
O3—C3—C4	111.0 (2)	C6—C7B—H7E	109.5
C5—C3—C4	110.1 (2)	H7D—C7B—H7E	109.5
O3—C3—C2	109.9 (2)	C6—C7B—H7F	109.5
C5—C3—C2	110.3 (2)	H7D—C7B—H7F	109.5
C4—C3—C2	107.0 (2)	H7E—C7B—H7F	109.5
O4'—C4—O4	125.3 (3)	C8—C9—H9A	109.5
O4'—C4—C3	125.1 (3)	C8—C9—H9B	109.5
O4—C4—C3	109.6 (3)	H9A—C9—H9B	109.5
C3—C5—Br1	111.6 (2)	C8—C9—H9C	109.5
C7A—C6—O4	116.6 (11)	H9A—C9—H9C	109.5
C7B—C6—O4	108.6 (7)	H9B—C9—H9C	109.5
O1—C8—C11	109.5 (4)	C8—C10—H10A	109.5
O1—C8—C10	110.6 (4)	C8—C10—H10B	109.5
C11—C8—C10	114.0 (6)	H10A—C10—H10B	109.5
O1—C8—C9	101.1 (4)	C8—C10—H10C	109.5
C11—C8—C9	108.3 (5)	H10A—C10—H10C	109.5
C10—C8—C9	112.6 (6)	H10B—C10—H10C	109.5
N1—C1'—C6'	126.2 (3)	C8—C11—H11A	109.5
N1—C1'—C2'	115.7 (3)	C8—C11—H11B	109.5
C6'—C1'—C2'	118.1 (3)	H11A—C11—H11B	109.5
O2'—C2'—C7'	109.4 (4)	C8—C11—H11C	109.5
O2'—C2'—C3'	105.4 (3)	H11A—C11—H11C	109.5
C7'—C2'—C3'	113.8 (3)	H11B—C11—H11C	109.5
O2'—C2'—C1'	104.9 (3)	C2'—C3'—H3'	115.0
C7'—C2'—C1'	112.5 (3)	C4'—C3'—H3'	115.0
C3'—C2'—C1'	110.1 (3)	C8'—C3'—H3'	115.0
C2'—C3'—C4'	108.9 (3)	C5'—C4'—H4'A	114.2
C2'—C3'—C8'	113.2 (3)	C3'—C4'—H4'A	114.2
C4'—C3'—C8'	86.7 (3)	C5'—C4'—H4'B	114.2
C5'—C4'—C3'	87.0 (3)	C3'—C4'—H4'B	114.2
C6'—C5'—C4'	108.4 (3)	H4'A—C4'—H4'B	111.3
C6'—C5'—C8'	111.4 (3)	C6'—C5'—H5'	115.4
C4'—C5'—C8'	87.8 (3)	C4'—C5'—H5'	115.4
C5'—C6'—C1'	112.1 (3)	C8'—C5'—H5'	115.4
C10'—C8'—C9'	109.1 (4)	C5'—C6'—H6'A	109.2
C10'—C8'—C5'	116.8 (4)	C1'—C6'—H6'A	109.2
C9'—C8'—C5'	111.8 (3)	C5'—C6'—H6'B	109.2
C10'—C8'—C3'	121.8 (3)	C1'—C6'—H6'B	109.2
C9'—C8'—C3'	110.1 (4)	H6'A—C6'—H6'B	107.9
C5'—C8'—C3'	85.5 (3)	C2'—C7'—H7'A	109.5
C3—O3—H3	109.5	C2'—C7'—H7'B	109.5
C2'—O2'—H2'	109.5	H7'A—C7'—H7'B	109.5
N1—C2—H2	109.3	C2'—C7'—H7'C	109.5
C1—C2—H2	109.3	H7'A—C7'—H7'C	109.5
C3—C2—H2	109.3	H7'B—C7'—H7'C	109.5
C3—C5—H5A	109.3	C8'—C9'—H9'A	109.5
Br1—C5—H5A	109.3	C8'—C9'—H9'B	109.5
C3—C5—H5B	109.3	H9'A—C9'—H9'B	109.5
Br1—C5—H5B	109.3	C8'—C9'—H9'C	109.5
H5A—C5—H5B	108.0	H9'A—C9'—H9'C	109.5
C7A—C6—H6A	108.1	H9'B—C9'—H9'C	109.5
C7B—C6—H6A	139.5	C8'—C10'—H10'A	109.5
O4—C6—H6A	108.1	C8'—C10'—H10'B	109.5
C7A—C6—H6B	108.1	H10'A—C10'—H10'B	109.5
C7B—C6—H6B	76.5	C8'—C10'—H10'C	109.5
O4—C6—H6B	108.1	H10'A—C10'—H10'C	109.5
H6A—C6—H6B	107.3	H10'B—C10'—H10'C	109.5
C7A—C6—H6C	72.4
C8—O1—C1—O1'	−0.1 (6)	N1—C1'—C2'—O2'	−71.2 (4)
C8—O1—C1—C2	178.7 (3)	C6'—C1'—C2'—O2'	105.2 (3)
C1'—N1—C2—C1	−85.2 (3)	N1—C1'—C2'—C7'	47.8 (4)
C1'—N1—C2—C3	154.9 (3)	C6'—C1'—C2'—C7'	−135.9 (4)
O1'—C1—C2—N1	−179.6 (3)	N1—C1'—C2'—C3'	175.8 (3)
O1—C1—C2—N1	1.4 (4)	C6'—C1'—C2'—C3'	−7.8 (4)
O1'—C1—C2—C3	−61.0 (4)	O2'—C2'—C3'—C4'	−61.2 (4)
O1—C1—C2—C3	120.0 (3)	C7'—C2'—C3'—C4'	178.9 (4)
N1—C2—C3—O3	74.8 (3)	C1'—C2'—C3'—C4'	51.5 (4)
C1—C2—C3—O3	−47.5 (3)	O2'—C2'—C3'—C8'	−155.7 (3)
N1—C2—C3—C5	−165.5 (2)	C7'—C2'—C3'—C8'	84.4 (4)
C1—C2—C3—C5	72.1 (3)	C1'—C2'—C3'—C8'	−43.0 (4)
N1—C2—C3—C4	−45.8 (3)	C2'—C3'—C4'—C5'	−86.5 (3)
C1—C2—C3—C4	−168.1 (2)	C8'—C3'—C4'—C5'	26.9 (3)
C6—O4—C4—O4'	−1.2 (6)	C3'—C4'—C5'—C6'	84.8 (3)
C6—O4—C4—C3	179.3 (4)	C3'—C4'—C5'—C8'	−27.1 (3)
O3—C3—C4—O4'	0.3 (5)	C4'—C5'—C6'—C1'	−50.7 (4)
C5—C3—C4—O4'	−120.0 (4)	C8'—C5'—C6'—C1'	44.3 (4)
C2—C3—C4—O4'	120.2 (4)	N1—C1'—C6'—C5'	−176.9 (3)
O3—C3—C4—O4	179.7 (3)	C2'—C1'—C6'—C5'	7.2 (4)
C5—C3—C4—O4	59.5 (4)	C6'—C5'—C8'—C10'	41.5 (5)
C2—C3—C4—O4	−60.4 (3)	C4'—C5'—C8'—C10'	150.3 (4)
O3—C3—C5—Br1	−68.2 (3)	C6'—C5'—C8'—C9'	168.1 (4)
C4—C3—C5—Br1	53.6 (3)	C4'—C5'—C8'—C9'	−83.1 (4)
C2—C3—C5—Br1	171.37 (19)	C6'—C5'—C8'—C3'	−82.0 (3)
C4—O4—C6—C7A	148.5 (14)	C4'—C5'—C8'—C3'	26.8 (3)
C4—O4—C6—C7B	107.9 (8)	C2'—C3'—C8'—C10'	−36.3 (5)
C1—O1—C8—C11	66.0 (6)	C4'—C3'—C8'—C10'	−145.4 (4)
C1—O1—C8—C10	−60.4 (7)	C2'—C3'—C8'—C9'	−165.8 (4)
C1—O1—C8—C9	−179.9 (5)	C4'—C3'—C8'—C9'	85.1 (4)
C2—N1—C1'—C6'	−0.1 (5)	C2'—C3'—C8'—C5'	82.7 (3)
C2—N1—C1'—C2'	175.9 (3)	C4'—C3'—C8'—C5'	−26.4 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O4′	0.82	2.31	2.729 (4)	113
O2′—H2′···N1	0.82	2.51	2.877 (4)	108
O3—H3···O2′^i	0.82	2.00	2.768 (4)	156

Symmetry code: (i) −x, y−1/2, −z.