Two new chiral nucleoside analogues: (4R,5R)-4-(4,6-dimethyl­pyrimidin-2-ylsulfan­yl)-5-[(2S,5R)-2-isoprop­yl-5-methyl­cyclo­hexyl­oxy]-2,3,4,5-tetra­hydro­furan-2-one and (4R,5R)-5-[(2S,5R)-isoprop­yl-5-methyl­cyclo­hexyl­oxy]-4-(4-methyl-1,3-thia­zol-2-ylamino)-2,3,4,5-tetra­hydro­furan-2-one

Synthesis and X-ray structural investigations have been carried out for the two title compounds, viz. C₂₀H₃₀N₂O₃S, (I), and C₁₈H₂₈N₂O₃S, (II). In both mol­ecules, the cyclo­hexyl­oxy moiety and the conjugated cyclic system are located on opposite sides of the tetra­hydro­furan-2-one ring. In the crystal structure of (II), there are two types of inter­molecular hydrogen bonds, viz. C—H...S and N—H...O, and the mol­ecules form a three-dimensional supramolecular architecture via the hydrogen bonds.

S1. Comment

The chemistry and biology of nucleoside analogues have been the subject of intensive study, since they possess many potent bioactivities, such as antiviral properties, for example against herpes simplex, AIDS-driven viral infections and the human immunodeficiency virus (Guillarme et al., 2003; Perbost et al., 1992; Wang et al., 2001; Remco et al., 2000). As part of our research work on nucleoside analogues, we synthesized the title compounds, (I) and (II), from 5-(R)-menthyloxy-2(5H)-furanone, (III), in order to evaluate their biological activity, and we report their structures here.

Compounds (I) and (II) are both composed of three sections, namely a cyclohexyloxy moiety, a tetrahydrofuran-2-one ring and a conjugated cyclic system, of which the first two almost have the same configuration in the two compounds, with similar bond distances and bond angles. Compounds (I) and (II) are not flat molecules (Figs. 1 and 2). The cyclohexyloxy section and the conjugated cyclic system are located on opposite sides of the tetrahydrofuran-2-one ring and the three rings are not coplanar with each other. In the cyclohexyloxy section, the six-membered ring adopts a chair conformation, with the isopropyl and methyl groups both located in the β-position, which is beneficial to the stability of the structure.

In the 4,6-dimethylpyrimidin-2-ylsulfanyl section of compound (I), all the non-H atoms of the group are coplanar, with a mean deviation of 0.013 (2) Å. The electrons of the ring are highly delocalized, with similar C—N and C—C bond distances (Table 1). The C15—S1 bond distance, which is shorter than C3—S1, arises from the conjugation of the electrons of atom S1 with the pyrimidinyl ring.

In the 4-methyl-1,3-thiazol-2-ylamino section of compound (II), all the non-H atoms of the group are coplanar, with a mean deviation of 0.009 (2) Å. The electrons on the ring are not as delocalized as those in (I). There are two obviously different C—N bond distances, C15—N2 and C16—N2. The C16—C17 bond distance is 1.332 (3) Å, characterizing a C═C double bond (Table 2). The short bond distances of C17—S1 and C15—S1 result from the conjugation of the electrons of atom S1 with atoms C15 and C17. The N1—C15 bond distance is shorter than the single bond C3—N1, but longer than that of the double bond C15—N2 [1.291 (3) Å], which can be attributed to the conjugation of the electrons of atom N1 with atoms C15 and N2.

Compound (II) contains one S atom, two N atoms and three O atoms, which are potential hydrogen-bond acceptors. One of the two N atoms (atom N1 of the NH group) is also a strong hydrogen-bond donor. However, the present results show that only two sites, one S atom (S1) and one O atom (O2), act as hydrogen-bond acceptors, and one N atom (N1) and one C atom (C10) act as hydrogen-bond donors, forming two types of intermolecular hydrogen bonds, C—H···S and N—H···O (Table 3). The C—H, H···S and C···S distances and the C—H···S angle indicate a weak hydrogen bond, while the N—H, H···O and N···O distances and the N—H···O angle indicate a strong hydrogen bond. Each molecule is connected to four adjacent ones through four intermolecular hydrogen bonds, two C—H···S hydrogen bonds and two N—H···O hydrogen bonds (Fig. 3). Through the action of these two types of hydrogen bonds, compound (II) forms a three-dimensional supramolecular architecture.

The crystal analysis shows the configuration of C3 is R in which compound?.

S2. Experimental

For the preparation of (I), triethylamine (404 mg, 4 mmol) was added at 298 K under nitrogen to a stirred mixture of 4,6-dimethylpyrimidine-2-thiol (280 mg, 2 mmol) and (III) (476 mg, 2 mmol) (Hui Huang et al., 1999) in dimethylformamide (8 ml). The mixture was stirred at room temperature. The completion of the reaction was monitored using thin-layer chromatography. CH₂Cl₂ was added to the mixture, which was then filtered. The filtrate was washed with H₂O, dried, and condensed in vacuo to give the crude product. Column chromatography gave colourless crystals of (I) (417 mg, 55%; m.p. 415.8–416.2 K). Recrystallization from petroleum–AcOEt (Ratio?) yielded crystals of (I) suitable for X-ray analysis. For the preparation of (II), to a mixture of 2-amino-4-methylthiazolyl (484 mg, 2 mmol), K₂CO₃ (1.11 g, 8 mmol) and tetrabutylammoniumbromide (322 mg, 1 mmol) was added CH₃CN (6 ml) and (III) (476 mg, 2 mmol). The reaction solution was stirred at room temperature for 2 d. AcOEt was added and the resulting mixture was washed with water and condensed in vacuo to provide the crude product, which was purified by flash chromatography, giving (II) as a light-yellow crystals (359 mg, 51%; m.p.466.5–468 K). Recrystallization from petroleum–AcOEt (Ratio?) yielded crystals of (II).

S3. Refinement

H atoms were generated goemetrically and allowed to ride on their parent C atoms, with C—H distances of 0.96 (CH₃), 0.97 (CH₂), 0.98 Å (CH) or 0.93 Å (unsaturated CH), and N—H distances of 0.86°, and with U_ico(H) = 1.2U_eq(C,N). Please check added text. The absolute structure was set by reference to the known chirality of the cyclohexyloxy moiety.

Computing details

For both compounds, data collection: SMART (Bruker, 1999); cell refinement: SMART; data reduction: SAINT (Bruker, 1999); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. The structure of (I), showing 30% probability displacement ellipsoids and the atom-numbering scheme.
	Fig. 2. The structure of (II), showing 30% probability displacement ellipsoids and the atom-numbering scheme.
	Fig. 3. A packing view for (II), showing the hydrogen bonding. Atoms labelled with the suffixes A–E are at the symmetry positions (x, y, z) (1/2 + x, 1/2 − y, −z), (x − 1/2, 1/2 − y, −z), (−x, −1/2 + y, 1/2 − z) and (−x, y − 1/2, 1/2 − z), respectively.

(I) (4R,5R)-4-(4,6-dimethylpyrimidin-2-ylsulfanyl)-5-[(2S,5R)-2-isopropyl- 5-methylcyclohexyloxy]-2,3,4,5-tetrahydrofuran-2-one

Crystal data

C20H30N2O3S	Dx = 1.162 Mg m^−3
Mr = 378.52	Melting point = 415.8–416.2 K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 956 reflections
a = 8.825 (4) Å	θ = 2.7–25.5°
b = 14.401 (6) Å	µ = 0.17 mm^−1
c = 17.033 (7) Å	T = 293 K
V = 2164.5 (15) Å^3	Prism, colourless
Z = 4	0.42 × 0.32 × 0.26 mm
F(000) = 816

Data collection

Bruker SMART CCD area-detector diffractometer	4425 independent reflections
Radiation source: fine-focus sealed tube	3686 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.029
ϕ and ω scans	θmax = 26.5°, θmin = 2.4°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −11→10
Tmin = 0.977, Tmax = 0.996	k = −17→17
12564 measured reflections	l = −21→10

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)] = 0.037	w = 1/[σ^2(Fo^2) + (0.0476P)^2 + 0.2336P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.097	(Δ/σ)max = 0.001
S = 1.06	Δρmax = 0.15 e Å^−3
4425 reflections	Δρmin = −0.15 e Å^−3
242 parameters	Extinction correction: SHELXL97 (Sheldrick, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.033 (2)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983), with how many Friedel pairs
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.00 (7)

Special details

Experimental. ¹H NMR (500 MHz, CDCl₃, δ, p.p.m.): 0.81 (3H, d, J = 6.9 Hz, H12), 0.92 (3H, d, J = 7.1 Hz, H14), 0.94 (3H, d, J = 6.6 Hz, H15), 0.97 (2H, m, H10), 1.01 (1H, m, H13), 1.29 (2H, m, H9), 1.69 (2H, m, H7), 2.13 (2H, m, H8, H11), 2.44 (6H, s, H8', H7'), 2.62 (1H, dd, J = 18.4, 2.6 Hz, H3), 3.26 (1H, dd, J = 18.4 and 9.0 Hz, H3), 3.56 (1H, dt, J = 10.7 and 4.1 Hz, H6), 4.15 (1H, dd, J = 8.8 and 1.0 Hz, H4), 5.73 (1H, s, H5), 6.79 (1H, s, H5'); ¹³C NMR (¹³⁵DEPT, 125 MHz, CDCl₃, δ, p.p.m.): 15.6 (C15), 20.9 (C14), 22.2 (C12), 3.1 (C10), 23.8 (C7',8'), 25.5 (t, C13), 31.3 (C8), 33.6 (C9), 34.3 (C3), 40.2 (C7), 44.4 (C11), 47.8 (C4), 77.6 (C6), 104.6 (C5), 116.6 (C5'), 167.6 (C4',6'), 169.1 (C2'), 175.0 (C2); IR (KBr, cm⁻¹): ν 1778(C=O).

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
S1	0.62843 (5)	0.48529 (3)	0.98734 (3)	0.05309 (16)
N1	0.33120 (17)	0.48972 (11)	0.96069 (10)	0.0516 (4)
N2	0.46554 (18)	0.63351 (11)	0.96853 (10)	0.0533 (4)
O1	0.69087 (15)	0.32620 (10)	0.84871 (8)	0.0520 (3)
O2	0.90826 (17)	0.26210 (14)	0.88812 (12)	0.0808 (5)
O3	0.45180 (15)	0.27066 (9)	0.87819 (7)	0.0470 (3)
C1	0.7869 (2)	0.29372 (14)	0.90440 (13)	0.0527 (5)
C2	0.7177 (2)	0.30465 (14)	0.98371 (12)	0.0525 (5)
H2A	0.7877	0.3347	1.0195	0.063*
H2B	0.6890	0.2448	1.0053	0.063*
C3	0.57801 (19)	0.36530 (13)	0.96988 (11)	0.0426 (4)
H3	0.4930	0.3459	1.0031	0.051*
C4	0.54515 (19)	0.34749 (13)	0.88331 (11)	0.0405 (4)
H4	0.4988	0.4019	0.8584	0.049*
C5	0.3968 (3)	0.25032 (15)	0.79984 (12)	0.0563 (6)
H5	0.4758	0.2660	0.7616	0.068*
C6	0.3671 (4)	0.14551 (19)	0.79691 (13)	0.0776 (8)
H6	0.2880	0.1326	0.8358	0.093*
C7	0.2994 (5)	0.1228 (3)	0.71627 (19)	0.1120 (13)
H7A	0.3752	0.1339	0.6761	0.134*
H7B	0.2727	0.0575	0.7146	0.134*
C8	0.1606 (5)	0.1802 (3)	0.69856 (19)	0.1225 (15)
H8A	0.0814	0.1642	0.7357	0.147*
H8B	0.1244	0.1647	0.6464	0.147*
C9	0.1900 (4)	0.2841 (3)	0.70275 (16)	0.0994 (10)
H9	0.2652	0.2997	0.6625	0.119*
C10	0.2582 (3)	0.3074 (2)	0.78310 (13)	0.0701 (7)
H10A	0.2847	0.3727	0.7846	0.084*
H10B	0.1832	0.2961	0.8236	0.084*
C11	0.5040 (5)	0.08683 (19)	0.81967 (18)	0.0943 (10)
H11	0.5419	0.1112	0.8696	0.113*
C12	0.6343 (4)	0.0926 (2)	0.7608 (2)	0.1152 (12)
H12A	0.6049	0.0629	0.7127	0.173*
H12B	0.7218	0.0620	0.7820	0.173*
H12C	0.6579	0.1566	0.7507	0.173*
C13	0.4601 (6)	−0.0152 (2)	0.8338 (2)	0.1445 (18)
H13A	0.3891	−0.0187	0.8764	0.217*
H13B	0.5492	−0.0503	0.8466	0.217*
H13C	0.4147	−0.0401	0.7871	0.217*
C14	0.0495 (4)	0.3430 (4)	0.6878 (2)	0.1458 (18)
H14A	0.0096	0.3291	0.6367	0.219*
H14B	0.0761	0.4076	0.6904	0.219*
H14C	−0.0256	0.3295	0.7269	0.219*
C15	0.4544 (2)	0.54139 (13)	0.97053 (11)	0.0457 (4)
C16	0.2026 (2)	0.53660 (16)	0.94678 (14)	0.0582 (5)
C17	0.2028 (2)	0.63179 (17)	0.94293 (15)	0.0647 (6)
H17	0.1136	0.6641	0.9331	0.078*
C18	0.3372 (3)	0.67880 (15)	0.95390 (13)	0.0595 (5)
C19	0.0622 (3)	0.4795 (2)	0.9355 (2)	0.0914 (9)
H19A	0.0545	0.4611	0.8815	0.137*
H19B	−0.0251	0.5156	0.9496	0.137*
H19C	0.0673	0.4252	0.9681	0.137*
C20	0.3451 (4)	0.78280 (18)	0.9474 (2)	0.0960 (9)
H20A	0.4491	0.8023	0.9487	0.144*
H20B	0.2914	0.8104	0.9906	0.144*
H20C	0.2998	0.8022	0.8989	0.144*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0396 (2)	0.0484 (3)	0.0713 (3)	−0.0008 (2)	−0.0143 (2)	−0.0077 (2)
N1	0.0377 (8)	0.0481 (9)	0.0691 (11)	−0.0005 (7)	−0.0016 (7)	−0.0031 (8)
N2	0.0527 (10)	0.0451 (9)	0.0622 (11)	0.0009 (8)	−0.0056 (8)	−0.0057 (8)
O1	0.0449 (7)	0.0633 (9)	0.0479 (8)	−0.0031 (7)	0.0055 (6)	0.0076 (6)
O2	0.0498 (9)	0.0977 (14)	0.0949 (13)	0.0181 (9)	0.0091 (9)	0.0041 (10)
O3	0.0532 (8)	0.0495 (7)	0.0385 (7)	−0.0144 (6)	0.0019 (6)	−0.0005 (6)
C1	0.0438 (11)	0.0499 (11)	0.0644 (14)	−0.0011 (9)	0.0006 (10)	0.0066 (10)
C2	0.0541 (11)	0.0511 (11)	0.0522 (11)	0.0065 (9)	−0.0086 (10)	0.0074 (9)
C3	0.0387 (9)	0.0438 (9)	0.0453 (10)	−0.0013 (7)	−0.0050 (8)	0.0034 (8)
C4	0.0374 (9)	0.0407 (10)	0.0433 (10)	−0.0037 (8)	−0.0019 (8)	0.0058 (8)
C5	0.0642 (14)	0.0692 (14)	0.0355 (11)	−0.0219 (11)	0.0056 (9)	−0.0056 (9)
C6	0.108 (2)	0.0790 (17)	0.0462 (12)	−0.0412 (17)	0.0197 (14)	−0.0183 (11)
C7	0.146 (3)	0.121 (3)	0.0694 (19)	−0.058 (3)	0.007 (2)	−0.0386 (18)
C8	0.126 (3)	0.175 (4)	0.0665 (19)	−0.069 (3)	−0.021 (2)	−0.025 (2)
C9	0.092 (2)	0.150 (3)	0.0555 (16)	−0.038 (2)	−0.0197 (15)	0.0054 (17)
C10	0.0602 (14)	0.0992 (19)	0.0511 (13)	−0.0207 (13)	−0.0109 (10)	0.0032 (12)
C11	0.149 (3)	0.0609 (15)	0.0731 (18)	−0.0034 (19)	0.0283 (19)	−0.0085 (13)
C12	0.141 (3)	0.086 (2)	0.119 (3)	0.009 (2)	0.037 (3)	−0.0099 (19)
C13	0.248 (5)	0.0610 (17)	0.124 (3)	−0.006 (3)	0.077 (3)	−0.0092 (18)
C14	0.094 (2)	0.252 (5)	0.091 (2)	−0.026 (3)	−0.050 (2)	0.034 (3)
C15	0.0438 (10)	0.0480 (10)	0.0454 (11)	0.0018 (8)	−0.0037 (9)	−0.0044 (8)
C16	0.0408 (10)	0.0645 (14)	0.0692 (14)	0.0028 (10)	0.0016 (10)	−0.0007 (11)
C17	0.0476 (12)	0.0628 (14)	0.0837 (16)	0.0145 (11)	−0.0034 (11)	−0.0003 (12)
C18	0.0598 (13)	0.0526 (12)	0.0661 (13)	0.0085 (10)	−0.0035 (11)	−0.0047 (10)
C19	0.0394 (11)	0.0879 (19)	0.147 (3)	−0.0045 (13)	−0.0064 (14)	0.0031 (19)
C20	0.095 (2)	0.0532 (14)	0.140 (3)	0.0088 (14)	−0.026 (2)	−0.0021 (15)

Geometric parameters (Å, º)

S1—C15	1.759 (2)	C8—H8B	0.9700
S1—C3	1.809 (2)	C9—C14	1.523 (5)
N1—C15	1.328 (2)	C9—C10	1.533 (3)
N1—C16	1.342 (3)	C9—H9	0.9800
N2—C18	1.330 (3)	C10—H10A	0.9700
N2—C15	1.331 (2)	C10—H10B	0.9700
O1—C1	1.355 (2)	C11—C12	1.528 (5)
O1—C4	1.447 (2)	C11—C13	1.538 (4)
O2—C1	1.196 (2)	C11—H11	0.9800
O3—C4	1.382 (2)	C12—H12A	0.9600
O3—C5	1.450 (2)	C12—H12B	0.9600
C1—C2	1.491 (3)	C12—H12C	0.9600
C2—C3	1.529 (2)	C13—H13A	0.9600
C2—H2A	0.9700	C13—H13B	0.9600
C2—H2B	0.9700	C13—H13C	0.9600
C3—C4	1.524 (3)	C14—H14A	0.9600
C3—H3	0.9800	C14—H14B	0.9600
C4—H4	0.9800	C14—H14C	0.9600
C5—C10	1.501 (3)	C16—C17	1.372 (3)
C5—C6	1.533 (3)	C16—C19	1.499 (3)
C5—H5	0.9800	C17—C18	1.378 (3)
C6—C11	1.524 (5)	C17—H17	0.9300
C6—C7	1.533 (4)	C18—C20	1.503 (3)
C6—H6	0.9800	C19—H19A	0.9600
C7—C8	1.508 (5)	C19—H19B	0.9600
C7—H7A	0.9700	C19—H19C	0.9600
C7—H7B	0.9700	C20—H20A	0.9600
C8—C9	1.521 (5)	C20—H20B	0.9600
C8—H8A	0.9700	C20—H20C	0.9600
C15—S1—C3	101.37 (9)	C10—C9—H9	107.9
C15—N1—C16	115.65 (17)	C5—C10—C9	111.7 (2)
C18—N2—C15	115.50 (17)	C5—C10—H10A	109.3
C1—O1—C4	110.11 (14)	C9—C10—H10A	109.3
C4—O3—C5	114.79 (14)	C5—C10—H10B	109.3
O2—C1—O1	121.9 (2)	C9—C10—H10B	109.3
O2—C1—C2	128.1 (2)	H10A—C10—H10B	107.9
O1—C1—C2	109.95 (16)	C6—C11—C12	113.5 (3)
C1—C2—C3	104.55 (16)	C6—C11—C13	111.7 (3)
C1—C2—H2A	110.8	C12—C11—C13	110.1 (3)
C3—C2—H2A	110.8	C6—C11—H11	107.0
C1—C2—H2B	110.8	C12—C11—H11	107.0
C3—C2—H2B	110.8	C13—C11—H11	107.0
H2A—C2—H2B	108.9	C11—C12—H12A	109.5
C4—C3—C2	101.90 (15)	C11—C12—H12B	109.5
C4—C3—S1	111.50 (13)	H12A—C12—H12B	109.5
C2—C3—S1	108.79 (13)	C11—C12—H12C	109.5
C4—C3—H3	111.4	H12A—C12—H12C	109.5
C2—C3—H3	111.4	H12B—C12—H12C	109.5
S1—C3—H3	111.4	C11—C13—H13A	109.5
O3—C4—O1	109.53 (15)	C11—C13—H13B	109.5
O3—C4—C3	108.01 (14)	H13A—C13—H13B	109.5
O1—C4—C3	105.10 (14)	C11—C13—H13C	109.5
O3—C4—H4	111.3	H13A—C13—H13C	109.5
O1—C4—H4	111.3	H13B—C13—H13C	109.5
C3—C4—H4	111.3	C9—C14—H14A	109.5
O3—C5—C10	109.69 (17)	C9—C14—H14B	109.5
O3—C5—C6	106.64 (17)	H14A—C14—H14B	109.5
C10—C5—C6	113.2 (2)	C9—C14—H14C	109.5
O3—C5—H5	109.1	H14A—C14—H14C	109.5
C10—C5—H5	109.1	H14B—C14—H14C	109.5
C6—C5—H5	109.1	N1—C15—N2	128.02 (18)
C11—C6—C5	113.7 (2)	N1—C15—S1	118.55 (14)
C11—C6—C7	114.7 (3)	N2—C15—S1	113.42 (14)
C5—C6—C7	107.8 (2)	N1—C16—C17	120.6 (2)
C11—C6—H6	106.7	N1—C16—C19	116.5 (2)
C5—C6—H6	106.7	C17—C16—C19	122.9 (2)
C7—C6—H6	106.7	C16—C17—C18	119.1 (2)
C8—C7—C6	112.2 (3)	C16—C17—H17	120.5
C8—C7—H7A	109.2	C18—C17—H17	120.5
C6—C7—H7A	109.2	N2—C18—C17	121.1 (2)
C8—C7—H7B	109.2	N2—C18—C20	117.6 (2)
C6—C7—H7B	109.2	C16—C19—H19A	109.5
H7A—C7—H7B	107.9	C16—C19—H19B	109.5
C7—C8—C9	113.1 (3)	H19A—C19—H19B	109.5
C7—C8—H8A	109.0	C16—C19—H19C	109.5
C9—C8—H8A	109.0	H19A—C19—H19C	109.5
C7—C8—H8B	109.0	H19B—C19—H19C	109.5
C9—C8—H8B	109.0	C18—C20—H20A	109.5
H8A—C8—H8B	107.8	C18—C20—H20B	109.5
C8—C9—C14	113.7 (3)	H20A—C20—H20B	109.5
C8—C9—C10	108.9 (3)	C18—C20—H20C	109.5
C14—C9—C10	110.3 (3)	H20A—C20—H20C	109.5
C8—C9—H9	107.9	H20B—C20—H20C	109.5
C14—C9—H9	107.9
C4—O1—C1—O2	171.7 (2)	C7—C8—C9—C14	−178.0 (3)
C4—O1—C1—C2	−8.6 (2)	C7—C8—C9—C10	−54.5 (4)
O2—C1—C2—C3	169.3 (2)	O3—C5—C10—C9	−176.5 (2)
O1—C1—C2—C3	−10.4 (2)	C6—C5—C10—C9	−57.6 (3)
C1—C2—C3—C4	23.61 (18)	C8—C9—C10—C5	54.4 (3)
C1—C2—C3—S1	−94.25 (16)	C14—C9—C10—C5	179.8 (3)
C15—S1—C3—C4	69.56 (14)	C5—C6—C11—C12	−67.5 (3)
C15—S1—C3—C2	−178.84 (13)	C7—C6—C11—C12	57.3 (3)
C5—O3—C4—O1	−72.27 (19)	C5—C6—C11—C13	167.3 (2)
C5—O3—C4—C3	173.77 (16)	C7—C6—C11—C13	−68.0 (3)
C1—O1—C4—O3	−91.68 (17)	C16—N1—C15—N2	0.3 (3)
C1—O1—C4—C3	24.14 (19)	C16—N1—C15—S1	−178.91 (16)
C2—C3—C4—O3	88.10 (17)	C18—N2—C15—N1	−0.9 (3)
S1—C3—C4—O3	−156.00 (12)	C18—N2—C15—S1	178.30 (16)
C2—C3—C4—O1	−28.76 (17)	C3—S1—C15—N1	8.52 (18)
S1—C3—C4—O1	87.14 (15)	C3—S1—C15—N2	−170.76 (15)
C4—O3—C5—C10	−84.5 (2)	C15—N1—C16—C17	0.3 (3)
C4—O3—C5—C6	152.61 (19)	C15—N1—C16—C19	180.0 (2)
O3—C5—C6—C11	−55.1 (3)	N1—C16—C17—C18	−0.3 (4)
C10—C5—C6—C11	−175.76 (19)	C19—C16—C17—C18	−179.9 (2)
O3—C5—C6—C7	176.5 (2)	C15—N2—C18—C17	0.9 (3)
C10—C5—C6—C7	55.9 (3)	C15—N2—C18—C20	−177.3 (2)
C11—C6—C7—C8	177.6 (3)	C16—C17—C18—N2	−0.4 (4)
C5—C6—C7—C8	−54.6 (3)	C16—C17—C18—C20	177.8 (2)
C6—C7—C8—C9	56.7 (4)

(II) (4R,5R)-5-[(2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-4-(4-methyl-1,3- thiazol-2-ylamino)-2,3,4,5-tetrahydrofuran-2-one

Crystal data

C18H28N2O3S	Dx = 1.200 Mg m^−3
Mr = 352.48	Melting point = 466.5–468.3 K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 826 reflections
a = 8.841 (3) Å	θ = 3.1–23.1°
b = 11.203 (3) Å	µ = 0.18 mm^−1
c = 19.692 (6) Å	T = 293 K
V = 1950.3 (10) Å^3	Prism, yellow
Z = 4	0.34 × 0.22 × 0.18 mm
F(000) = 760

Data collection

Bruker SMART CCD area-detector diffractometer	3997 independent reflections
Radiation source: fine-focus sealed tube	2992 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.031
ϕ and ω scans	θmax = 26.5°, θmin = 2.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −7→11
Tmin = 0.913, Tmax = 0.970	k = −13→14
11333 measured reflections	l = −24→17

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)] = 0.042	H-atom parameters constrained
wR(F^2) = 0.099	w = 1/[σ^2(Fo^2) + (0.0472P)^2 + 0.1182P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max = 0.013
3997 reflections	Δρmax = 0.16 e Å^−3
221 parameters	Δρmin = −0.17 e Å^−3
1 restraint	Absolute structure: Flack (1983), with how many Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.03 (8)

Special details

Experimental. ¹H NMR (500 MHz, CDCl₃, δ, p.p.m.): 0.79 (3H, d, J = 6.9 Hz, H12), 0.88 (H, m, H10), 0.90 (3H, d, J = 7.1 Hz, H14), 0.96 (3H, d, J = 6.5 Hz, H15), 1.02 (2H, m, H10, H13), 1.27 (2H, m, H9), 1.67 (2H, m, H7), 2.05 (1H, m, H11), 2.19 (1H, m, H8), 2.26 (3H, s, H6'), 2.50 (1H, d, J = 18.1 Hz, H3), 3.32 (1H, dd, J = 18.1 and 7.3 Hz, H3), 3.55 (1H, dt, J = 10.7 and 6.6 Hz, H6), 4.22 (1H, d, J = 6.9 Hz, H4), 5.73 (1H, s, H5), 6.17 (1H, s, H5'); ¹³C NMR (125 MHz, CDCl₃, δ, p.p.m): 15.6 (C15), 17.2 (C6'), 20.9 (C14), 23.1 (C10), 25.6 (C13), 31.4 (C8), 34.2 (C3, C9), 39.7 (C7), 47.6 (C11), 57.3 (C4), 77.7 (C6), 102.4 (C5), 103.7 (C5'), 138.3 (C2'), 166.6 (C5); IR (KBr, cm⁻¹): ν 1778 (C=O).

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
S1	−0.14879 (8)	0.22367 (6)	0.22496 (4)	0.0693 (2)
N1	0.0071 (2)	0.32833 (17)	0.12363 (9)	0.0540 (5)
H1	−0.0308	0.2749	0.0973	0.065*
N2	0.0458 (2)	0.39337 (16)	0.23518 (9)	0.0497 (4)
O1	0.32722 (17)	0.33004 (13)	0.05899 (8)	0.0572 (4)
O2	0.2752 (2)	0.30145 (18)	−0.05033 (9)	0.0882 (6)
O3	0.34001 (15)	0.50952 (11)	0.11756 (7)	0.0452 (3)
C1	0.2406 (3)	0.3434 (2)	0.00327 (12)	0.0560 (6)
C2	0.1045 (3)	0.4157 (2)	0.01931 (10)	0.0513 (5)
H2A	0.0139	0.3777	0.0019	0.062*
H2B	0.1127	0.4950	−0.0001	0.062*
C3	0.1008 (2)	0.42168 (19)	0.09624 (10)	0.0426 (5)
H3	0.0665	0.5003	0.1118	0.051*
C4	0.2669 (2)	0.40099 (18)	0.11472 (11)	0.0449 (5)
H4	0.2759	0.3582	0.1580	0.054*
C5	0.4856 (2)	0.50793 (18)	0.15171 (10)	0.0411 (5)
H5	0.5394	0.4342	0.1400	0.049*
C6	0.5742 (2)	0.6141 (2)	0.12578 (11)	0.0494 (5)
H6	0.5156	0.6853	0.1376	0.059*
C7	0.7230 (3)	0.6217 (3)	0.16558 (14)	0.0796 (8)
H7A	0.7842	0.5520	0.1555	0.095*
H7B	0.7787	0.6917	0.1509	0.095*
C8	0.6973 (4)	0.6288 (3)	0.24116 (13)	0.0850 (9)
H8A	0.6435	0.7019	0.2517	0.102*
H8B	0.7942	0.6314	0.2642	0.102*
C9	0.6075 (3)	0.5236 (2)	0.26728 (11)	0.0640 (6)
H9	0.6671	0.4513	0.2591	0.077*
C10	0.4604 (2)	0.5124 (2)	0.22740 (11)	0.0570 (6)
H10A	0.4082	0.4405	0.2416	0.068*
H10B	0.3959	0.5799	0.2380	0.068*
C11	0.5946 (3)	0.6162 (2)	0.04876 (12)	0.0617 (6)
H11	0.4945	0.6016	0.0290	0.074*
C12	0.6960 (4)	0.5201 (4)	0.02260 (15)	0.1237 (15)
H12A	0.6963	0.5216	−0.0261	0.186*
H12B	0.6601	0.4439	0.0380	0.186*
H12C	0.7969	0.5329	0.0391	0.186*
C13	0.6448 (6)	0.7383 (4)	0.02369 (15)	0.1303 (16)
H13A	0.7458	0.7541	0.0393	0.196*
H13B	0.5776	0.7983	0.0410	0.196*
H13C	0.6429	0.7397	−0.0251	0.196*
C14	0.5763 (4)	0.5313 (4)	0.34349 (13)	0.1102 (12)
H14A	0.5131	0.5991	0.3526	0.165*
H14B	0.6702	0.5397	0.3675	0.165*
H14C	0.5260	0.4599	0.3582	0.165*
C15	−0.0212 (2)	0.32530 (19)	0.19166 (11)	0.0479 (5)
C16	−0.0043 (3)	0.3657 (2)	0.30031 (11)	0.0546 (6)
C17	−0.1064 (3)	0.2785 (2)	0.30402 (13)	0.0653 (6)
H17	−0.1491	0.2509	0.3442	0.078*
C18	0.0602 (4)	0.4356 (3)	0.35836 (12)	0.0815 (9)
H18A	0.0235	0.5162	0.3565	0.122*
H18B	0.1686	0.4357	0.3553	0.122*
H18C	0.0298	0.3996	0.4005	0.122*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0646 (4)	0.0651 (4)	0.0783 (4)	−0.0231 (3)	0.0202 (3)	−0.0026 (3)
N1	0.0498 (11)	0.0667 (12)	0.0454 (10)	−0.0211 (10)	0.0031 (9)	−0.0102 (9)
N2	0.0503 (10)	0.0568 (10)	0.0418 (10)	−0.0091 (9)	0.0029 (8)	0.0002 (8)
O1	0.0433 (8)	0.0552 (9)	0.0733 (10)	0.0090 (7)	0.0017 (8)	−0.0080 (8)
O2	0.0916 (14)	0.1071 (15)	0.0658 (12)	0.0254 (12)	0.0211 (11)	−0.0296 (11)
O3	0.0340 (7)	0.0455 (8)	0.0562 (8)	−0.0017 (6)	−0.0077 (7)	0.0043 (7)
C1	0.0530 (14)	0.0582 (14)	0.0568 (14)	0.0021 (12)	0.0065 (13)	−0.0054 (12)
C2	0.0473 (12)	0.0646 (14)	0.0421 (12)	0.0068 (11)	0.0030 (10)	−0.0014 (10)
C3	0.0367 (10)	0.0521 (12)	0.0389 (11)	−0.0020 (9)	0.0019 (8)	−0.0029 (9)
C4	0.0395 (11)	0.0464 (11)	0.0487 (12)	−0.0028 (10)	−0.0008 (10)	0.0053 (10)
C5	0.0339 (10)	0.0433 (11)	0.0463 (11)	0.0039 (9)	−0.0041 (9)	0.0000 (9)
C6	0.0425 (12)	0.0519 (12)	0.0537 (13)	−0.0044 (10)	−0.0042 (10)	0.0000 (10)
C7	0.0581 (16)	0.110 (2)	0.0708 (17)	−0.0362 (16)	−0.0157 (14)	0.0111 (16)
C8	0.085 (2)	0.097 (2)	0.0740 (19)	−0.0230 (17)	−0.0324 (16)	−0.0075 (16)
C9	0.0639 (15)	0.0769 (16)	0.0511 (13)	0.0088 (14)	−0.0087 (12)	−0.0038 (12)
C10	0.0495 (13)	0.0745 (15)	0.0470 (12)	0.0027 (12)	0.0018 (11)	0.0004 (12)
C11	0.0524 (14)	0.0797 (16)	0.0531 (14)	−0.0112 (13)	−0.0006 (11)	0.0075 (12)
C12	0.105 (3)	0.196 (4)	0.070 (2)	0.060 (3)	0.0264 (19)	0.003 (2)
C13	0.173 (4)	0.138 (3)	0.080 (2)	−0.076 (3)	−0.007 (2)	0.038 (2)
C14	0.127 (3)	0.156 (3)	0.0478 (16)	0.008 (3)	−0.0198 (18)	−0.0037 (18)
C15	0.0389 (11)	0.0500 (12)	0.0548 (13)	−0.0058 (10)	0.0061 (10)	−0.0004 (10)
C16	0.0561 (13)	0.0581 (14)	0.0496 (13)	0.0041 (12)	0.0088 (11)	0.0081 (10)
C17	0.0657 (16)	0.0673 (15)	0.0630 (15)	0.0017 (14)	0.0214 (12)	0.0155 (13)
C18	0.106 (2)	0.096 (2)	0.0426 (14)	−0.0075 (18)	0.0019 (14)	0.0019 (13)

Geometric parameters (Å, º)

S1—C17	1.715 (3)	C7—H7B	0.9700
S1—C15	1.732 (2)	C8—C9	1.511 (4)
N1—C15	1.363 (3)	C8—H8A	0.9700
N1—C3	1.439 (3)	C8—H8B	0.9700
N1—H1	0.8600	C9—C10	1.524 (3)
N2—C15	1.291 (3)	C9—C14	1.528 (3)
N2—C16	1.392 (3)	C9—H9	0.9800
O1—C1	1.347 (3)	C10—H10A	0.9700
O1—C4	1.456 (3)	C10—H10B	0.9700
O2—C1	1.195 (3)	C11—C12	1.493 (4)
O3—C4	1.378 (2)	C11—C13	1.521 (4)
O3—C5	1.452 (2)	C11—H11	0.9800
C1—C2	1.484 (3)	C12—H12A	0.9600
C2—C3	1.517 (3)	C12—H12B	0.9600
C2—H2A	0.9700	C12—H12C	0.9600
C2—H2B	0.9700	C13—H13A	0.9600
C3—C4	1.531 (3)	C13—H13B	0.9600
C3—H3	0.9800	C13—H13C	0.9600
C4—H4	0.9800	C14—H14A	0.9600
C5—C10	1.508 (3)	C14—H14B	0.9600
C5—C6	1.513 (3)	C14—H14C	0.9600
C5—H5	0.9800	C16—C17	1.332 (3)
C6—C11	1.527 (3)	C16—C18	1.498 (3)
C6—C7	1.534 (3)	C17—H17	0.9300
C6—H6	0.9800	C18—H18A	0.9600
C7—C8	1.508 (4)	C18—H18B	0.9600
C7—H7A	0.9700	C18—H18C	0.9600
C17—S1—C15	88.06 (11)	C8—C9—C10	109.7 (2)
C15—N1—C3	119.47 (17)	C8—C9—C14	112.7 (2)
C15—N1—H1	120.0	C10—C9—C14	110.9 (2)
C3—N1—H1	120.0	C8—C9—H9	107.8
C15—N2—C16	109.52 (18)	C10—C9—H9	107.8
C1—O1—C4	110.18 (16)	C14—C9—H9	107.8
C4—O3—C5	115.06 (14)	C5—C10—C9	112.71 (18)
O2—C1—O1	122.0 (2)	C5—C10—H10A	109.1
O2—C1—C2	127.6 (2)	C9—C10—H10A	109.1
O1—C1—C2	110.39 (19)	C5—C10—H10B	109.1
C1—C2—C3	104.74 (18)	C9—C10—H10B	109.1
C1—C2—H2A	110.8	H10A—C10—H10B	107.8
C3—C2—H2A	110.8	C12—C11—C13	111.2 (3)
C1—C2—H2B	110.8	C12—C11—C6	113.7 (2)
C3—C2—H2B	110.8	C13—C11—C6	111.8 (2)
H2A—C2—H2B	108.9	C12—C11—H11	106.6
N1—C3—C2	110.78 (18)	C13—C11—H11	106.6
N1—C3—C4	110.69 (17)	C6—C11—H11	106.6
C2—C3—C4	102.12 (17)	C11—C12—H12A	109.5
N1—C3—H3	111.1	C11—C12—H12B	109.5
C2—C3—H3	111.1	H12A—C12—H12B	109.5
C4—C3—H3	111.1	C11—C12—H12C	109.5
O3—C4—O1	109.90 (16)	H12A—C12—H12C	109.5
O3—C4—C3	109.03 (17)	H12B—C12—H12C	109.5
O1—C4—C3	104.76 (16)	C11—C13—H13A	109.5
O3—C4—H4	111.0	C11—C13—H13B	109.5
O1—C4—H4	111.0	H13A—C13—H13B	109.5
C3—C4—H4	111.0	C11—C13—H13C	109.5
O3—C5—C10	109.11 (16)	H13A—C13—H13C	109.5
O3—C5—C6	107.03 (15)	H13B—C13—H13C	109.5
C10—C5—C6	112.57 (17)	C9—C14—H14A	109.5
O3—C5—H5	109.3	C9—C14—H14B	109.5
C10—C5—H5	109.3	H14A—C14—H14B	109.5
C6—C5—H5	109.3	C9—C14—H14C	109.5
C5—C6—C11	114.12 (18)	H14A—C14—H14C	109.5
C5—C6—C7	108.40 (18)	H14B—C14—H14C	109.5
C11—C6—C7	113.9 (2)	N2—C15—N1	123.60 (19)
C5—C6—H6	106.6	N2—C15—S1	115.84 (17)
C11—C6—H6	106.6	N1—C15—S1	120.53 (16)
C7—C6—H6	106.6	C17—C16—N2	115.4 (2)
C8—C7—C6	112.2 (2)	C17—C16—C18	126.8 (2)
C8—C7—H7A	109.2	N2—C16—C18	117.8 (2)
C6—C7—H7A	109.2	C16—C17—S1	111.15 (18)
C8—C7—H7B	109.2	C16—C17—H17	124.5
C6—C7—H7B	109.2	S1—C17—H17	124.5
H7A—C7—H7B	107.9	C16—C18—H18A	109.5
C7—C8—C9	112.0 (2)	C16—C18—H18B	109.5
C7—C8—H8A	109.2	H18A—C18—H18B	109.5
C9—C8—H8A	109.2	C16—C18—H18C	109.5
C7—C8—H8B	109.2	H18A—C18—H18C	109.5
C9—C8—H8B	109.2	H18B—C18—H18C	109.5
H8A—C8—H8B	107.9
C4—O1—C1—O2	173.7 (2)	C11—C6—C7—C8	175.6 (2)
C4—O1—C1—C2	−5.8 (2)	C6—C7—C8—C9	57.5 (3)
O2—C1—C2—C3	168.0 (3)	C7—C8—C9—C10	−54.2 (3)
O1—C1—C2—C3	−12.4 (2)	C7—C8—C9—C14	−178.3 (3)
C15—N1—C3—C2	−174.26 (19)	O3—C5—C10—C9	−174.29 (19)
C15—N1—C3—C4	73.2 (2)	C6—C5—C10—C9	−55.7 (3)
C1—C2—C3—N1	−93.8 (2)	C8—C9—C10—C5	53.4 (3)
C1—C2—C3—C4	24.1 (2)	C14—C9—C10—C5	178.5 (2)
C5—O3—C4—O1	−81.46 (19)	C5—C6—C11—C12	−68.7 (3)
C5—O3—C4—C3	164.24 (15)	C7—C6—C11—C12	56.5 (3)
C1—O1—C4—O3	−95.47 (19)	C5—C6—C11—C13	164.4 (3)
C1—O1—C4—C3	21.5 (2)	C7—C6—C11—C13	−70.3 (3)
N1—C3—C4—O3	−151.98 (16)	C16—N2—C15—N1	−178.0 (2)
C2—C3—C4—O3	90.1 (2)	C16—N2—C15—S1	0.1 (2)
N1—C3—C4—O1	90.43 (18)	C3—N1—C15—N2	−8.6 (3)
C2—C3—C4—O1	−27.5 (2)	C3—N1—C15—S1	173.32 (16)
C4—O3—C5—C10	−80.7 (2)	C17—S1—C15—N2	−0.16 (18)
C4—O3—C5—C6	157.22 (16)	C17—S1—C15—N1	178.03 (19)
O3—C5—C6—C11	−57.0 (2)	C15—N2—C16—C17	0.1 (3)
C10—C5—C6—C11	−176.81 (19)	C15—N2—C16—C18	−179.8 (2)
O3—C5—C6—C7	174.89 (19)	N2—C16—C17—S1	−0.2 (3)
C10—C5—C6—C7	55.1 (3)	C18—C16—C17—S1	179.7 (2)
C5—C6—C7—C8	−56.1 (3)	C15—S1—C17—C16	0.19 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2^i	0.86	2.13	2.898 (2)	149
C10—H10B···S1^ii	0.97	2.81	3.751 (3)	163

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