2′-Deoxy-7-propynyl-7-deaza­adenosine: a DNA duplex-stabilizing nucleoside

In the title compound, 2′-deoxy-7-propynyl-7-deaza­adenosine, C₁₄H₁₆N₄O₃, the torsion angle of the N-glycosylic bond is anti [χ = −130.7 (2)°]. The sugar pucker of the 2′-deoxy­ribo­furanosyl moiety is C2′-endo–C3′-exo, ²T₃ (S-type), with P = 185.9 (2)° and τ_m = 39.1 (1)°, and the orientation of the exocyclic C4′—C5′ bond is −ap (trans). The 7-substituted propynyl group is nearly coplanar with the heterocyclic base moiety. Mol­ecules of the nucleoside form a layered network in which the heterocyclic bases are stacked head-to-tail with a closest distance of 3.197 (1) Å. The crystal structure of the nucleoside is stabilized by three inter­molecular hydrogen bonds of types N—H... O, O—H... N and O—H... O.

S1. Comment

7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides occur naturally and have been isolated as monomers and as constituents of nucleic acids (Suhadolnik, 1970, 1979). Among them are ribonucleosides such as tubercidin, (IIa), isolated from Streptomyces tubercidicus (Nakamura, 1961), as well as its 7-substituted derivatives toyocamycin, (IIb), and sangivamycin, (IIc), which are produced by Streptomyces toyocaensis or other Streptomyces strains (Nishimura et al., 1956; Ohkuma, 1961) (see scheme; unless otherwise stated, purine numbering is used throughout this discussion). The natural occurrence and extraordinary biological and pharmacological properties of 7-deazapurine nucleosides have been the reasons for active study of their synthesis, their biochemical and physical properties, and their incorporation into nucleic acids. 7-Deazapurine 2'-deoxyribonucleosides are used as biochemical probes (Mizusawa et al., 1986; Prober et al., 1987; Seela et al., 1993; Murchie & Lilley, 1994), in nucleic acid diagnostics (Bailly & Waring, 1998) and in antisense technology (Lamm et al., 1991; Uhlmann et al., 2000).

Among the various modifications carried out on purine and pyrimidine nucleosides to stabilize duplex and triplex DNA, the propynyl group has attracted particular attention. This group has been introduced into the 5-position of pyrimidine nucleosides (Froehler et al., 1992; Sági et al., 1993; Barnes & Turner, 2001a,b; Gutierrez et al., 1997; Ahmadian et al., 1998; Graham et al., 1998) and the 7-position of 7-deazapurine or 8-aza-7-deazapurine nucleosides (Buhr et al., 1996; He & Seela, 2002a,b; Seela & Shaikh, 2005). Our laboratory has shown that a propynyl group introduced into the 7-position of 8-aza-7-deazapurine exerts a stronger stabilizing effect on DNA duplexes (He & Seela, 2002a,b) than do the pyrimidine bases.

The introduction of the propynyl group at the 7-position of 7-deazaadenosine, (IIIa) (Seela & Thomas, 1995), lowers the pK_a value. The title compound, (I), shows a pK_a of 4.5, while the non-fuctionalized nucleoside (IIIa) has a pK_a value of 4.9. The incorporation of (I) into oligonucleotides significantly increases the stability of the Watson–Crick base pair dA–dT and the tandem base pair dA–dG in DNA (Seela, Budow et al., 2005). The 7-propynyl residue of (I) also stabilizes DNA–RNA duplexes (Buhr et al., 1996). Against this background, we became interested in undertaking a single-crystal X-ray analysis of compound (I) and present the results here.

Compound (I) was synthesized from (IIIb) (Buhr et al., 1996). The three-dimensional structure of (I) (7-(2-deoxy-β-D-erythro-pentofuranosyl)-5-(prop-1-ynyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine) is shown in Fig. 1 and selected geometric parameters are listed in Table 1. The orientation of the nucleobase relative to the sugar moiety (syn/anti) is defined, in analogy with the purine nucleosides, by the torsion angle χ (O4'—C1'—N9—C4) (purine numbering; IUPAC–IUB Joint Commission on Biochemical Nomenclature, 1983); the preferred conformation around the N-glycosylic bond for natural purine 2'-deoxyribonucleosides is usually in the anti range. In the crystalline state of (I), the glycosylic bond torsion angle is anti [χ = −130.7 (2)°], which is similar to that of 2'-deoxy-7-iodotubercidin, (IIIb) [χ = −147.1 (8)°; Seela et al., 1996] as well as that of 7-deaza-2'-deoxy-7-propynylguanosine (χ = −117.1 (5)°; Seela et al., 2004), while for 2'-deoxytubercidin, (IIIa), and 2'-deoxy-7-fluorotubercidin the glycosylic bond torsion angles are χ = −104.4 (2) and −101.1 (3)°, respectively, which are in the range of the high-anti conformation (Zabel et al., 1987; Seela, Xu & Eickmeier, 2005).

The sugar moiety of (I) exhibits a pseudorotational phase angle P = 185.9 (2)° with an amplitude τ_m = 39.1 (1)°, indicating an S-type sugar pucker (2'-endo-3'-exo, ²T₃) (Rao et al., 1981). This type of sugar conformation is also found for 2'-deoxytubercidin (Zabel et al., 1987), while 2'-deoxy-7-iodotubercidin shows an envelope sugar ring conformation (₃E) (Seela et al., 1996). The torsion angle γ [O5'—C5'—C4'—C3' = −172.7 (3)°] describing the orientation of the 5'-hydroxyl group relative to the sugar ring shows that the C4'—C5' bond is in an -ap (trans) orientation (Saenger, 1984). The S-type sugar puckering of compound (I) in the solid state is similar to the preferred conformation found in solution (71% S). The conformational analysis was carried out on the basis of ¹H NMR vicinal [¹H, ¹H] coupling constants using the program PSEUROT6.3 (Van Wijk et al., 1999).

The base moiety of (I) is almost planar, the r.m.s. deviation of ring atoms from their calculated least-squares planes being 0.0095 Å. The propynyl group of (I) is slightly inclined by 1.6° with respect to the aromatic ring of the molecule. This is smaller than the angles observed for 7-deaza-7-propynyl-2'-deoxyguanosine (4.6°; Seela et al., 2004) and 8-aza-7-deaza-7-propynyladenosine (4.0°; Lin et al., 2005). The group is almost linear, with dihedral bond angles C7—C7A—C7B = 178.5 (3)° and C7A—C7B—C7C = 178.2 (4)°. The triple-bond length of (I) is 1.185 (3) Å, which is within the range of non-conjugated triple bonds (Reference?).

The structure of nucleoside (I) is stabilized by three intermolecular hydrogen bonds (N6—H6··· O4', O3'—H3'···N1 and O5'-H5'···O3'), leading to the formation of a layered network (Fig. 2 and Table 2) with head-to-tail stacking of the nucleobases, which is different from the head-to-head stacking of 7-deaza-2'-deoxy-7-propynylguanosine (Seela et al., 2004). The shortest distance between the stacked bases for nucleoside (I) is 3.197 (1) Å, which is less than the average base-pair stacking distance in B-DNA (3.5 Å). It is also smaller than that observed for the related 7-deaza-2'-deoxy-7-propynylguanosine [3.728 (1) Å; Seela et al., 2004].

S2. Experimental

Compound (I) was synthesized from (IIIb) as described previously by Buhr et al. (1996) and was crystallized slowly from double-distilled water as colourless crystals (m.p. 479–480 K). For the diffraction experiment, a single-crystal was fixed at the top of a Lindemann capillary with epoxy resin.

S3. Refinement

In the absence of suitable anomalous scattering, the Flack (1983) parameter could not be used to determine the absolute structure. Therefore, 508 Friedel equivalents were merged before the final refinement. The known configuration of the parent molecule was used to define the enantiomer employed in the refined model. All H atoms were initially found in a difference Fourier synthesis. In order to maximize the data/parameter ratio, the H atoms were placed in geometrically idealized positions, with C—H = 0.93–0.98 Å and N—H = 0.86 Å, and constrained to ride on their parent atoms, with U_iso(H) = 1.2U_eq(C,N). The OH groups were refined as a rotating group, with O—H = 0.82 Å [Please clarify - CIF data show their positions were refined] and U_iso(H) = 1.5U_eq(O).

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: SHELXTL (Sheldrick, 1997); program(s) used to solve structure: SHELXTL; program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2003).

Figures

	Fig. 1. A perspective view of (I), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary size.
	Fig. 2. Details of the layered network, showing the hydrogen bonds (dashed lines) within the layers and the stacking of the nucleobases.

2'-Deoxy-7-propynyl-7-deazaadenosine

Crystal data

C14H16N4O3	F(000) = 608
Mr = 288.31	Dx = 1.441 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 63 reflections
a = 6.5812 (11) Å	θ = 4.9–14.0°
b = 10.5084 (13) Å	µ = 0.10 mm^−1
c = 19.216 (2) Å	T = 293 K
V = 1328.9 (3) Å^3	Block, colourless
Z = 4	0.5 × 0.3 × 0.3 mm

Data collection

Bruker P4 diffractometer	Rint = 0.037
Radiation source: fine-focus sealed tube	θmax = 30.0°, θmin = 2.1°
Graphite monochromator	h = −9→1
2θ/ω scans	k = −14→1
2918 measured reflections	l = −27→1
2214 independent reflections	3 standard reflections every 97 reflections
1852 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.052	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.146	w = 1/[σ^2(Fo^2) + (0.0951P)^2 + 0.1584P] where P = (Fo^2 + 2Fc^2)/3
S = 1.03	(Δ/σ)max = 0.001
2214 reflections	Δρmax = 0.40 e Å^−3
197 parameters	Δρmin = −0.30 e Å^−3
2 restraints	Absolute structure: established by known chemical absolute configuration
Primary atom site location: structure-invariant direct methods

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
N1	0.7891 (3)	0.19520 (19)	0.41491 (9)	0.0251 (4)
C2	0.7834 (4)	0.0893 (2)	0.45434 (12)	0.0275 (5)
H2A	0.7854	0.0129	0.4300	0.033*
N3	0.7753 (4)	0.07896 (17)	0.52299 (10)	0.0244 (4)
C4	0.7771 (4)	0.1931 (2)	0.55401 (10)	0.0198 (4)
C5	0.7872 (4)	0.31155 (19)	0.52130 (10)	0.0198 (4)
C6	0.7916 (4)	0.3085 (2)	0.44775 (11)	0.0209 (4)
N6	0.7970 (4)	0.4155 (2)	0.40838 (11)	0.0307 (5)
H6A	0.7988	0.4098	0.3637	0.037*
H6B	0.7987	0.4890	0.4280	0.037*
C7	0.7874 (4)	0.4065 (2)	0.57526 (12)	0.0223 (4)
C7A	0.7989 (5)	0.5414 (2)	0.56718 (13)	0.0273 (5)
C7B	0.8110 (6)	0.6529 (3)	0.55909 (15)	0.0381 (7)
C7C	0.8216 (7)	0.7918 (3)	0.5508 (2)	0.0571 (10)
H7C1	0.8267	0.8312	0.5959	0.086*
H7C2	0.7036	0.8211	0.5262	0.086*
H7C3	0.9415	0.8137	0.5250	0.086*
C8	0.7755 (4)	0.34148 (19)	0.63713 (11)	0.0239 (5)
H8A	0.7724	0.3789	0.6810	0.029*
N9	0.7689 (3)	0.21201 (16)	0.62443 (9)	0.0215 (4)
C1'	0.7348 (4)	0.1104 (2)	0.67468 (11)	0.0224 (4)
H1'	0.6884	0.0346	0.6496	0.027*
C2'	0.9155 (4)	0.0739 (3)	0.71961 (13)	0.0313 (5)
H2'A	1.0029	0.1465	0.7283	0.038*
H2'B	0.9946	0.0066	0.6982	0.038*
C3'	0.8131 (4)	0.0283 (2)	0.78641 (12)	0.0285 (5)
H3'A	0.9050	0.0349	0.8264	0.034*
O3'	0.7446 (4)	−0.09864 (17)	0.77677 (10)	0.0380 (5)
H3'B	0.744 (6)	−0.140 (4)	0.815 (2)	0.057*
O4'	0.5776 (3)	0.14999 (17)	0.72107 (9)	0.0274 (4)
C4'	0.6376 (4)	0.1225 (2)	0.79213 (12)	0.0277 (5)
H4'A	0.5241	0.0834	0.8173	0.033*
C5'	0.7019 (6)	0.2450 (3)	0.82831 (15)	0.0449 (8)
H5'A	0.7360	0.2255	0.8763	0.054*
H5'B	0.8239	0.2768	0.8060	0.054*
O5'	0.5549 (6)	0.3412 (3)	0.82777 (15)	0.0737 (11)
H5'C	0.469 (8)	0.336 (6)	0.792 (3)	0.088*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0289 (10)	0.0262 (9)	0.0201 (8)	−0.0012 (9)	0.0000 (8)	−0.0013 (7)
C2	0.0361 (13)	0.0229 (10)	0.0233 (9)	−0.0031 (11)	−0.0002 (10)	−0.0039 (9)
N3	0.0341 (11)	0.0162 (7)	0.0228 (8)	0.0000 (8)	0.0004 (9)	−0.0011 (7)
C4	0.0247 (10)	0.0158 (8)	0.0187 (9)	−0.0010 (9)	−0.0003 (8)	0.0005 (7)
C5	0.0233 (10)	0.0166 (8)	0.0193 (8)	−0.0006 (8)	−0.0007 (9)	0.0025 (8)
C6	0.0193 (9)	0.0226 (9)	0.0207 (9)	−0.0025 (9)	−0.0009 (8)	0.0055 (8)
N6	0.0397 (12)	0.0267 (9)	0.0256 (9)	0.0002 (10)	−0.0005 (9)	0.0103 (8)
C7	0.0284 (11)	0.0144 (8)	0.0240 (9)	−0.0018 (9)	0.0000 (9)	0.0005 (8)
C7A	0.0351 (13)	0.0181 (9)	0.0286 (10)	0.0006 (10)	−0.0004 (11)	0.0010 (9)
C7B	0.0511 (18)	0.0203 (11)	0.0429 (14)	0.0002 (12)	0.0007 (14)	0.0028 (11)
C7C	0.076 (3)	0.0179 (12)	0.078 (2)	−0.0001 (15)	0.004 (2)	0.0126 (14)
C8	0.0334 (12)	0.0155 (8)	0.0229 (9)	−0.0007 (9)	−0.0006 (10)	−0.0013 (8)
N9	0.0339 (10)	0.0144 (7)	0.0164 (7)	−0.0007 (8)	0.0004 (7)	0.0019 (6)
C1'	0.0309 (11)	0.0174 (8)	0.0190 (8)	−0.0012 (9)	0.0023 (8)	0.0047 (8)
C2'	0.0318 (12)	0.0329 (12)	0.0291 (11)	0.0029 (10)	0.0011 (11)	0.0095 (11)
C3'	0.0389 (14)	0.0248 (10)	0.0218 (9)	0.0024 (10)	−0.0030 (10)	0.0070 (9)
O3'	0.0651 (14)	0.0217 (8)	0.0272 (8)	−0.0007 (10)	−0.0008 (9)	0.0061 (7)
O4'	0.0299 (9)	0.0310 (8)	0.0212 (7)	0.0035 (7)	0.0021 (7)	0.0050 (7)
C4'	0.0388 (13)	0.0263 (11)	0.0179 (9)	0.0012 (10)	0.0031 (9)	0.0036 (9)
C5'	0.068 (2)	0.0321 (12)	0.0345 (13)	0.0079 (15)	−0.0109 (16)	−0.0094 (12)
O5'	0.112 (3)	0.0491 (13)	0.0596 (16)	0.0358 (17)	−0.0289 (18)	−0.0261 (14)

Geometric parameters (Å, º)

N1—C2	1.346 (3)	C8—H8A	0.9300
N1—C6	1.347 (3)	N9—C1'	1.457 (3)
C2—N3	1.325 (3)	C1'—O4'	1.427 (3)
C2—H2A	0.9300	C1'—C2'	1.519 (3)
N3—C4	1.339 (3)	C1'—H1'	0.9800
C4—N9	1.369 (3)	C2'—C3'	1.527 (3)
C4—C5	1.396 (3)	C2'—H2'A	0.9700
C5—C6	1.414 (3)	C2'—H2'B	0.9700
C5—C7	1.439 (3)	C3'—O3'	1.420 (3)
C6—N6	1.356 (3)	C3'—C4'	1.525 (4)
N6—H6A	0.8600	C3'—H3'A	0.9800
N6—H6B	0.8600	O3'—H3'B	0.86 (4)
C7—C8	1.374 (3)	O4'—C4'	1.450 (3)
C7—C7A	1.427 (3)	C4'—C5'	1.523 (4)
C7A—C7B	1.185 (3)	C4'—H4'A	0.9800
C7B—C7C	1.470 (4)	C5'—O5'	1.400 (4)
C7C—H7C1	0.9600	C5'—H5'A	0.9700
C7C—H7C2	0.9600	C5'—H5'B	0.9700
C7C—H7C3	0.9600	O5'—H5'C	0.90 (5)
C8—N9	1.383 (3)
C2—N1—C6	117.82 (18)	O4'—C1'—N9	108.19 (18)
N3—C2—N1	129.0 (2)	O4'—C1'—C2'	106.61 (18)
N3—C2—H2A	115.5	N9—C1'—C2'	116.1 (2)
N1—C2—H2A	115.5	O4'—C1'—H1'	108.6
C2—N3—C4	111.66 (19)	N9—C1'—H1'	108.6
N3—C4—N9	124.75 (19)	C2'—C1'—H1'	108.6
N3—C4—C5	126.77 (18)	C1'—C2'—C3'	102.2 (2)
N9—C4—C5	108.49 (18)	C1'—C2'—H2'A	111.3
C4—C5—C6	115.50 (19)	C3'—C2'—H2'A	111.3
C4—C5—C7	107.10 (18)	C1'—C2'—H2'B	111.3
C6—C5—C7	137.4 (2)	C3'—C2'—H2'B	111.3
N1—C6—N6	118.14 (19)	H2'A—C2'—H2'B	109.2
N1—C6—C5	119.21 (19)	O3'—C3'—C4'	112.2 (2)
N6—C6—C5	122.6 (2)	O3'—C3'—C2'	109.0 (2)
C6—N6—H6A	120.0	C4'—C3'—C2'	101.00 (19)
C6—N6—H6B	120.0	O3'—C3'—H3'A	111.4
H6A—N6—H6B	120.0	C4'—C3'—H3'A	111.4
C8—C7—C7A	126.2 (2)	C2'—C3'—H3'A	111.4
C8—C7—C5	106.17 (18)	C3'—O3'—H3'B	112 (3)
C7A—C7—C5	127.6 (2)	C1'—O4'—C4'	109.42 (19)
C7B—C7A—C7	178.5 (3)	O4'—C4'—C5'	109.7 (2)
C7A—C7B—C7C	178.2 (4)	O4'—C4'—C3'	105.53 (18)
C7B—C7C—H7C1	109.5	C5'—C4'—C3'	111.8 (2)
C7B—C7C—H7C2	109.5	O4'—C4'—H4'A	109.9
H7C1—C7C—H7C2	109.5	C5'—C4'—H4'A	109.9
C7B—C7C—H7C3	109.5	C3'—C4'—H4'A	109.9
H7C1—C7C—H7C3	109.5	O5'—C5'—C4'	114.5 (3)
H7C2—C7C—H7C3	109.5	O5'—C5'—H5'A	108.6
C7—C8—N9	109.79 (19)	C4'—C5'—H5'A	108.6
C7—C8—H8A	125.1	O5'—C5'—H5'B	108.6
N9—C8—H8A	125.1	C4'—C5'—H5'B	108.6
C4—N9—C8	108.44 (17)	H5'A—C5'—H5'B	107.6
C4—N9—C1'	123.67 (18)	C5'—O5'—H5'C	113 (4)
C8—N9—C1'	127.51 (18)
C6—N1—C2—N3	1.6 (4)	N3—C4—N9—C1'	−7.0 (4)
N1—C2—N3—C4	−1.2 (4)	C5—C4—N9—C1'	173.0 (2)
C2—N3—C4—N9	179.6 (3)	C7—C8—N9—C4	0.2 (3)
C2—N3—C4—C5	−0.4 (4)	C7—C8—N9—C1'	−173.0 (2)
N3—C4—C5—C6	1.4 (4)	C4—N9—C1'—O4'	−130.7 (2)
N9—C4—C5—C6	−178.5 (2)	C8—N9—C1'—O4'	41.5 (3)
N3—C4—C5—C7	−179.4 (3)	C4—N9—C1'—C2'	109.6 (3)
N9—C4—C5—C7	0.7 (3)	C8—N9—C1'—C2'	−78.3 (3)
C2—N1—C6—N6	−179.9 (3)	O4'—C1'—C2'—C3'	29.7 (2)
C2—N1—C6—C5	−0.3 (3)	N9—C1'—C2'—C3'	150.3 (2)
C4—C5—C6—N1	−1.0 (3)	C1'—C2'—C3'—O3'	80.4 (2)
C7—C5—C6—N1	−179.9 (3)	C1'—C2'—C3'—C4'	−38.0 (2)
C4—C5—C6—N6	178.6 (2)	N9—C1'—O4'—C4'	−134.14 (19)
C7—C5—C6—N6	−0.3 (5)	C2'—C1'—O4'—C4'	−8.5 (2)
C4—C5—C7—C8	−0.6 (3)	C1'—O4'—C4'—C5'	104.2 (2)
C6—C5—C7—C8	178.4 (3)	C1'—O4'—C4'—C3'	−16.4 (3)
C4—C5—C7—C7A	179.0 (3)	O3'—C3'—C4'—O4'	−82.0 (2)
C6—C5—C7—C7A	−2.0 (5)	C2'—C3'—C4'—O4'	33.9 (2)
C7A—C7—C8—N9	−179.3 (3)	O3'—C3'—C4'—C5'	158.8 (2)
C5—C7—C8—N9	0.3 (3)	C2'—C3'—C4'—C5'	−85.3 (2)
N3—C4—N9—C8	179.5 (2)	O4'—C4'—C5'—O5'	56.0 (3)
C5—C4—N9—C8	−0.5 (3)	C3'—C4'—C5'—O5'	172.7 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6A···O4′^i	0.86	2.53	3.173 (3)	132
O3′—H3′B···N1^ii	0.86 (4)	2.02 (4)	2.851 (3)	165 (4)
O5′—H5′C···O3′^iii	0.90 (5)	2.05 (5)	2.884 (4)	155 (5)

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