tert-Butyl N-[(1R*,2R*,4R*,5S*)-rel-4-tert-but­oxy­bicyclo­[3.1.0]hex-2-yl]-N-hy­droxy­carbamate

Lough, A.J.; Tait, K.; Horvath, A.; Tam, W.

doi:10.1107/S2414314617014195

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 2| Part 10| October 2017| x171419

https://doi.org/10.1107/S2414314617014195

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tert-Butyl N-[(1R,2R,4R,5S)-rel-4-tert-butoxybicyclo[3.1.0]hex-2-yl]-N-hydroxycarbamate

Alan J. Lough,^a ^* Katrina Tait,^b Alysia Horvath ^b and William Tam ^b

^aDepartment of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada, and ^bDepartment of Chemistry, University of Guelph, Guelph, Ontario, N1G 2W1, Canada
^*Correspondence e-mail: alough@chem.utoronto.ca

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 29 September 2017; accepted 2 October 2017; online 6 October 2017)

In the title compound, C₁₅H₂₇NO₄, the cyclopentane ring adopts an envelope conformation with the methylene group as the flap. The dihedral angle between the cyclopropane ring and the cyclopentane ring (all atoms) is 77.54 (13)°. In the crystal, molecules are linked via O—H⋯O hydrogen bonds, forming C(7) chains propagating along [010].

Keywords: crystal structure; carbocyclic nucleosides; hydrogen bonding.

CCDC reference: 1577701

Structure description

Carbocyclic nucleosides are increasingly interesting compounds for their antiviral and antitumor effects (Ji & Miller, 2010 ). Replacing the oxygen atom of the parent furanose ring with a methylene unit increases stability towards certain cleaving enzymes but also decreases structural rigidity, which lowers bioactivity (Crimmons, 1998 ; Altona & Sundaralingam, 1972 ). The creation of structurally rigid carbocyclic nucleoside analogs are therefore synthetically useful targets. The cyclopropanation of 3-aza-2-oxabicyclic alkenes adds increased structural rigidity upon ring opening while creating new stereocenters to make diverse organic frameworks. The acid-catalysed ring-opening reaction (Fig. 1) of cyclopropanated 3-aza-2-oxabicylic I with an alcohol nucleophile thereby created the title fused bicyclic amino alcohol, II.

Figure 1
Acid-catalysed nucleophilic ring opening of cyclopropanated 3-aza-2-oxabicyclic substrate I with an alcohol.

The molecular structure of II is shown in Fig. 2. In the arbitrarily chosen asymmetric molecule of the racemic crystal the stereogenic centres are as follows: C1 R; C2 S; C4 R; C5 R. The conformation of the cyclopentane ring is well described as an envelope on C6 (the methylene group), which lies to the same side of the C1/C2/C4/C5 plane as does C3. The dihedral angle between the cyclopropane ring (C2/C3/C4) and the cyclopentane ring (all atoms) is 77.54 (13)°. In the crystal, O—H⋯O hydrogen bonds link the molecules, forming C(7) chains propagating along [010] (Fig. 3, Table 1), with adjacent molecules related by translation.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1O⋯O4ⁱ	0.94 (2)	1.87 (2)	2.7926 (12)	164.9 (17)
Symmetry code: (i) x, y-1, z.

Figure 2
The molecular structure of II, with displacement ellipsoids shown at the 30% probability level.

Figure 3
Part of the crystal structure of (II), with O—H⋯O hydrogen bonds shown as dashed lines.

Synthesis and crystallization

In a small screw-cap vial containing a stir bar, the catalyst pyridinium p-toluenesulfonate (PPTS) (4.4 mg, 0.018 mmol, 0.10 equiv) was added. The cyclopropanated 3-aza-2-oxabicyclic substrate I (35.1 mg, 0.166 mmol, 1.0 equiv) was added to the same vial and reagents were dissolved in the nucleophile tert-butyl alcohol (0.5 ml). The vial was sealed and heated to 90°C with continuous stirring for 47 h. The crude product was purified by column chromatography using a gradient (EtOAc:hexanes = 1:9 to 1:1), followed by recrystallization using slow evaporation of mixed solvents of 1:3 EtOAc:hexanes to give clear, colourless crystals of II.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₅H₂₇NO₄
M_r	285.37
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	150
a, b, c (Å)	30.4330 (8), 6.0885 (2), 19.3949 (5)
β (°)	117.316 (1)
V (Å³)	3192.97 (16)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	0.69
Crystal size (mm)	0.20 × 0.02 × 0.02

Data collection
Diffractometer	Bruker Kappa APEX DUO CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2014 )
T_min, T_max	0.669, 0.753
No. of measured, independent and observed [I > 2σ(I)] reflections	31096, 2841, 2438
R_int	0.046
(sin θ/λ)_max (Å⁻¹)	0.598

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.032, 0.079, 1.04
No. of reflections	2841
No. of parameters	191
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.19
Computer programs: APEX2 and SAINT (Bruker, 2014), SHELXT (Sheldrick, 2015a ), SHELXL2016 (Sheldrick, 2015b ), PLATON (Spek, 2009 ) and SHELXTL (Sheldrick, 2008 ).

Structural data

CCDC reference: 1577701

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314617014195/hb4175sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314617014195/hb4175Isup2.hkl

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2014); cell refinement: APEX2 (Bruker, 2014); data reduction: SAINT (Bruker, 2014); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

tert-Butyl N-[(1R*,2R*,4R*,5S*)-rel-4-tert-butoxybicyclo[3.1.0]hex-2-yl]-N-hydroxycarbamate top

Crystal data top

C₁₅H₂₇NO₄	F(000) = 1248
M_r = 285.37	D_x = 1.187 Mg m⁻³
Monoclinic, C2/c	Cu Kα radiation, λ = 1.54178 Å
a = 30.4330 (8) Å	Cell parameters from 8804 reflections
b = 6.0885 (2) Å	θ = 3.3–66.5°
c = 19.3949 (5) Å	µ = 0.69 mm⁻¹
β = 117.316 (1)°	T = 150 K
V = 3192.97 (16) Å³	Needle, colourless
Z = 8	0.20 × 0.02 × 0.02 mm

Data collection top

Bruker Kappa APEX DUO CCD diffractometer	2438 reflections with I > 2σ(I)
Radiation source: Bruker ImuS with multi-layer optics	R_int = 0.046
φ and ω scans	θ_max = 67.2°, θ_min = 3.3°
Absorption correction: multi-scan (SADABS; Bruker, 2014)	h = −36→35
T_min = 0.669, T_max = 0.753	k = −6→7
31096 measured reflections	l = −22→23
2841 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.032	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.079	w = 1/[σ²(F_o²) + (0.0325P)² + 2.2411P] where P = (F_o² + 2F_c²)/3
S = 1.04	(Δ/σ)_max = 0.001
2841 reflections	Δρ_max = 0.17 e Å⁻³
191 parameters	Δρ_min = −0.19 e Å⁻³
0 restraints

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. H atoms were placed in calculated positions with C–H = 0.95–1.00\%A and included in the refinement with U_iso(H)=1.2U_eq(C) or 1.5U_eq(C_methyl).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.62521 (3)	0.04110 (15)	0.55279 (5)	0.0254 (2)
O2	0.61508 (3)	0.12952 (16)	0.72223 (5)	0.0316 (2)
O3	0.57295 (3)	−0.08261 (14)	0.61525 (5)	0.0261 (2)
O4	0.66930 (3)	0.69189 (13)	0.51429 (4)	0.0235 (2)
N1	0.64312 (4)	0.08435 (17)	0.63300 (5)	0.0223 (2)
C1	0.66942 (5)	0.47437 (19)	0.54309 (7)	0.0213 (3)
H1A	0.647444	0.377948	0.498916	0.026*
C2	0.71989 (5)	0.3697 (2)	0.58472 (7)	0.0246 (3)
H2A	0.734864	0.301410	0.553512	0.030*
C3	0.75326 (5)	0.4479 (3)	0.66554 (8)	0.0347 (3)
H3A	0.743755	0.583547	0.683521	0.042*
H3B	0.789309	0.426698	0.685590	0.042*
C4	0.72183 (5)	0.2465 (2)	0.65364 (7)	0.0270 (3)
H4A	0.737951	0.098813	0.666975	0.032*
C5	0.67375 (4)	0.2832 (2)	0.65730 (7)	0.0227 (3)
H5A	0.680931	0.322490	0.711531	0.027*
C6	0.64988 (5)	0.4809 (2)	0.60336 (7)	0.0245 (3)
H6A	0.613378	0.468312	0.577668	0.029*
H6B	0.659443	0.619979	0.633065	0.029*
C7	0.60933 (4)	0.0513 (2)	0.66110 (7)	0.0222 (3)
C8	0.53621 (5)	−0.1602 (2)	0.63979 (7)	0.0282 (3)
C9	0.50339 (6)	−0.3055 (3)	0.57224 (9)	0.0459 (4)
H9A	0.488527	−0.217813	0.524572	0.069*
H9B	0.477189	−0.368744	0.582086	0.069*
H9C	0.523226	−0.423911	0.566358	0.069*
C10	0.50715 (6)	0.0317 (3)	0.64721 (10)	0.0455 (4)
H10A	0.528927	0.123914	0.691053	0.068*
H10B	0.479865	−0.023094	0.656027	0.068*
H10C	0.493823	0.118615	0.599364	0.068*
C11	0.56154 (6)	−0.2929 (3)	0.71356 (8)	0.0395 (4)
H11A	0.582298	−0.195949	0.756585	0.059*
H11B	0.582192	−0.406312	0.707037	0.059*
H11C	0.536558	−0.362710	0.724908	0.059*
C12	0.65385 (4)	0.71127 (19)	0.43108 (6)	0.0208 (3)
C13	0.60068 (5)	0.6342 (2)	0.38409 (8)	0.0311 (3)
H13A	0.580048	0.699460	0.405381	0.047*
H13B	0.599380	0.473737	0.386730	0.047*
H13C	0.588355	0.679736	0.329901	0.047*
C14	0.65735 (5)	0.9550 (2)	0.41865 (7)	0.0279 (3)
H14A	0.633297	1.034279	0.429788	0.042*
H14B	0.650232	0.981387	0.364683	0.042*
H14C	0.690773	1.006978	0.453451	0.042*
C15	0.68833 (5)	0.5845 (2)	0.40857 (7)	0.0276 (3)
H15A	0.722359	0.635327	0.439964	0.041*
H15B	0.678617	0.608928	0.353505	0.041*
H15C	0.686251	0.427409	0.417722	0.041*
H1O	0.6432 (7)	−0.081 (3)	0.5493 (11)	0.065 (6)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0354 (5)	0.0249 (5)	0.0201 (4)	0.0002 (4)	0.0165 (4)	−0.0015 (3)
O2	0.0402 (5)	0.0366 (5)	0.0260 (5)	−0.0080 (4)	0.0220 (4)	−0.0063 (4)
O3	0.0281 (5)	0.0296 (5)	0.0254 (4)	−0.0057 (4)	0.0165 (4)	−0.0027 (4)
O4	0.0380 (5)	0.0170 (4)	0.0191 (4)	−0.0015 (4)	0.0162 (4)	0.0003 (3)
N1	0.0294 (5)	0.0227 (5)	0.0188 (5)	−0.0017 (4)	0.0144 (4)	−0.0003 (4)
C1	0.0290 (6)	0.0165 (6)	0.0216 (6)	0.0002 (5)	0.0145 (5)	0.0012 (5)
C2	0.0275 (6)	0.0257 (7)	0.0249 (6)	0.0004 (5)	0.0156 (5)	0.0023 (5)
C3	0.0276 (7)	0.0472 (9)	0.0280 (7)	−0.0095 (6)	0.0115 (6)	0.0013 (6)
C4	0.0257 (6)	0.0311 (7)	0.0246 (6)	0.0018 (5)	0.0119 (5)	0.0064 (5)
C5	0.0276 (6)	0.0229 (6)	0.0193 (6)	−0.0028 (5)	0.0122 (5)	0.0000 (5)
C6	0.0320 (7)	0.0205 (6)	0.0270 (7)	0.0008 (5)	0.0188 (6)	0.0010 (5)
C7	0.0264 (6)	0.0207 (6)	0.0217 (6)	0.0017 (5)	0.0130 (5)	0.0022 (5)
C8	0.0276 (7)	0.0311 (7)	0.0319 (7)	−0.0032 (5)	0.0188 (6)	0.0026 (6)
C9	0.0402 (8)	0.0558 (10)	0.0426 (9)	−0.0205 (8)	0.0198 (7)	−0.0073 (7)
C10	0.0408 (9)	0.0434 (9)	0.0669 (11)	0.0069 (7)	0.0372 (8)	0.0076 (8)
C11	0.0424 (8)	0.0388 (9)	0.0404 (8)	−0.0043 (7)	0.0218 (7)	0.0098 (7)
C12	0.0274 (6)	0.0205 (6)	0.0162 (6)	0.0009 (5)	0.0116 (5)	0.0007 (5)
C13	0.0283 (7)	0.0310 (7)	0.0309 (7)	0.0002 (6)	0.0109 (6)	0.0024 (6)
C14	0.0422 (8)	0.0215 (7)	0.0245 (6)	0.0000 (6)	0.0190 (6)	0.0020 (5)
C15	0.0338 (7)	0.0281 (7)	0.0259 (7)	0.0049 (5)	0.0179 (6)	0.0018 (5)

Geometric parameters (Å, º) top

O1—N1	1.4172 (12)	C8—C11	1.5108 (19)
O1—H1O	0.94 (2)	C8—C10	1.511 (2)
O2—C7	1.2135 (14)	C8—C9	1.515 (2)
O3—C7	1.3333 (15)	C9—H9A	0.9800
O3—C8	1.4791 (14)	C9—H9B	0.9800
O4—C1	1.4367 (14)	C9—H9C	0.9800
O4—C12	1.4639 (13)	C10—H10A	0.9800
N1—C7	1.3818 (15)	C10—H10B	0.9800
N1—C5	1.4676 (15)	C10—H10C	0.9800
C1—C2	1.5097 (17)	C11—H11A	0.9800
C1—C6	1.5362 (16)	C11—H11B	0.9800
C1—H1A	1.0000	C11—H11C	0.9800
C2—C3	1.5013 (18)	C12—C14	1.5149 (17)
C2—C4	1.5098 (17)	C12—C15	1.5192 (17)
C2—H2A	1.0000	C12—C13	1.5218 (17)
C3—C4	1.5061 (19)	C13—H13A	0.9800
C3—H3A	0.9900	C13—H13B	0.9800
C3—H3B	0.9900	C13—H13C	0.9800
C4—C5	1.5139 (17)	C14—H14A	0.9800
C4—H4A	1.0000	C14—H14B	0.9800
C5—C6	1.5404 (17)	C14—H14C	0.9800
C5—H5A	1.0000	C15—H15A	0.9800
C6—H6A	0.9900	C15—H15B	0.9800
C6—H6B	0.9900	C15—H15C	0.9800

N1—O1—H1O	106.4 (11)	C11—C8—C10	112.95 (12)
C7—O3—C8	119.98 (9)	O3—C8—C9	101.77 (10)
C1—O4—C12	116.43 (9)	C11—C8—C9	110.72 (12)
C7—N1—O1	115.14 (9)	C10—C8—C9	110.57 (13)
C7—N1—C5	118.12 (10)	C8—C9—H9A	109.5
O1—N1—C5	111.94 (9)	C8—C9—H9B	109.5
O4—C1—C2	114.69 (10)	H9A—C9—H9B	109.5
O4—C1—C6	109.83 (9)	C8—C9—H9C	109.5
C2—C1—C6	104.95 (10)	H9A—C9—H9C	109.5
O4—C1—H1A	109.1	H9B—C9—H9C	109.5
C2—C1—H1A	109.1	C8—C10—H10A	109.5
C6—C1—H1A	109.1	C8—C10—H10B	109.5
C3—C2—C1	117.34 (11)	H10A—C10—H10B	109.5
C3—C2—C4	60.02 (9)	C8—C10—H10C	109.5
C1—C2—C4	107.47 (10)	H10A—C10—H10C	109.5
C3—C2—H2A	119.1	H10B—C10—H10C	109.5
C1—C2—H2A	119.1	C8—C11—H11A	109.5
C4—C2—H2A	119.1	C8—C11—H11B	109.5
C2—C3—C4	60.27 (8)	H11A—C11—H11B	109.5
C2—C3—H3A	117.7	C8—C11—H11C	109.5
C4—C3—H3A	117.7	H11A—C11—H11C	109.5
C2—C3—H3B	117.7	H11B—C11—H11C	109.5
C4—C3—H3B	117.7	O4—C12—C14	104.11 (9)
H3A—C3—H3B	114.9	O4—C12—C15	111.16 (9)
C3—C4—C2	59.71 (8)	C14—C12—C15	110.11 (10)
C3—C4—C5	115.60 (12)	O4—C12—C13	110.53 (10)
C2—C4—C5	108.80 (10)	C14—C12—C13	109.87 (11)
C3—C4—H4A	119.4	C15—C12—C13	110.86 (10)
C2—C4—H4A	119.4	C12—C13—H13A	109.5
C5—C4—H4A	119.4	C12—C13—H13B	109.5
N1—C5—C4	110.37 (10)	H13A—C13—H13B	109.5
N1—C5—C6	113.23 (10)	C12—C13—H13C	109.5
C4—C5—C6	104.36 (10)	H13A—C13—H13C	109.5
N1—C5—H5A	109.6	H13B—C13—H13C	109.5
C4—C5—H5A	109.6	C12—C14—H14A	109.5
C6—C5—H5A	109.6	C12—C14—H14B	109.5
C1—C6—C5	105.68 (10)	H14A—C14—H14B	109.5
C1—C6—H6A	110.6	C12—C14—H14C	109.5
C5—C6—H6A	110.6	H14A—C14—H14C	109.5
C1—C6—H6B	110.6	H14B—C14—H14C	109.5
C5—C6—H6B	110.6	C12—C15—H15A	109.5
H6A—C6—H6B	108.7	C12—C15—H15B	109.5
O2—C7—O3	126.50 (11)	H15A—C15—H15B	109.5
O2—C7—N1	121.89 (11)	C12—C15—H15C	109.5
O3—C7—N1	111.51 (10)	H15A—C15—H15C	109.5
O3—C8—C11	110.06 (10)	H15B—C15—H15C	109.5
O3—C8—C10	110.21 (11)

C12—O4—C1—C2	102.14 (12)	C2—C4—C5—C6	−15.46 (13)
C12—O4—C1—C6	−139.98 (10)	O4—C1—C6—C5	−153.26 (10)
O4—C1—C2—C3	75.76 (13)	C2—C1—C6—C5	−29.48 (12)
C6—C1—C2—C3	−44.85 (14)	N1—C5—C6—C1	−92.48 (12)
O4—C1—C2—C4	140.48 (10)	C4—C5—C6—C1	27.59 (12)
C6—C1—C2—C4	19.87 (13)	C8—O3—C7—O2	−3.74 (19)
C1—C2—C3—C4	95.27 (12)	C8—O3—C7—N1	172.72 (10)
C2—C3—C4—C5	−97.70 (12)	O1—N1—C7—O2	−162.08 (11)
C1—C2—C4—C3	−111.98 (12)	C5—N1—C7—O2	−26.13 (17)
C3—C2—C4—C5	109.26 (12)	O1—N1—C7—O3	21.27 (14)
C1—C2—C4—C5	−2.72 (14)	C5—N1—C7—O3	157.22 (10)
C7—N1—C5—C4	154.03 (10)	C7—O3—C8—C11	−61.96 (15)
O1—N1—C5—C4	−68.71 (12)	C7—O3—C8—C10	63.27 (15)
C7—N1—C5—C6	−89.39 (12)	C7—O3—C8—C9	−179.40 (11)
O1—N1—C5—C6	47.87 (13)	C1—O4—C12—C14	179.81 (10)
C3—C4—C5—N1	171.18 (10)	C1—O4—C12—C15	−61.67 (13)
C2—C4—C5—N1	106.50 (11)	C1—O4—C12—C13	61.88 (13)
C3—C4—C5—C6	49.21 (13)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O4ⁱ	0.94 (2)	1.87 (2)	2.7926 (12)	164.9 (17)

Symmetry code: (i) x, y−1, z.

Funding information

AJL thanks NSERC Canada for funding.

References

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