organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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

CROSSMARK_Color_square_no_text.svg

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].

3D view (loading...)
[Scheme 3D1]
Chemical scheme
[Scheme 1]

Structure description

Carbocyclic nucleosides are increasingly inter­esting compounds for their anti­viral and anti­tumor effects (Ji & Miller, 2010[Ji, C. & Miller, M. J. (2010). Tetrahedron Lett. 51, 3789-3791.]). 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[Crimmons, M. T. (1998). Tetrahedron, 54, 9229-9272.]; Altona & Sundaralingam, 1972[Altona, C. & Sundaralingam, M. (1972). J. Am. Chem. Soc. 94, 8205-8212.]). 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[link]) of cyclo­propanated 3-aza-2-oxabicylic I with an alcohol nucleophile thereby created the title fused bicyclic amino alcohol, II.

[Figure 1]
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[link]. 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[link], Table 1[link]), with adjacent mol­ecules related by translation.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA 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]
Figure 2
The mol­ecular structure of II, with displacement ellipsoids shown at the 30% probability level.
[Figure 3]
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[link].

Table 2
Experimental details

Crystal data
Chemical formula C15H27NO4
Mr 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)
V3) 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[Bruker (2014). APEX2 and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.])
Tmin, Tmax 0.669, 0.753
No. of measured, independent and observed [I > 2σ(I)] reflections 31096, 2841, 2438
Rint 0.046
(sin θ/λ)max−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
Δρmax, Δρmin (e Å−3) 0.17, −0.19
Computer programs: APEX2 and SAINT (Bruker, 2014[Bruker (2014). APEX2 and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL2016 (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]).

Structural data


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
C15H27NO4F(000) = 1248
Mr = 285.37Dx = 1.187 Mg m3
Monoclinic, C2/cCu Kα radiation, λ = 1.54178 Å
a = 30.4330 (8) ÅCell parameters from 8804 reflections
b = 6.0885 (2) Åθ = 3.3–66.5°
c = 19.3949 (5) ŵ = 0.69 mm1
β = 117.316 (1)°T = 150 K
V = 3192.97 (16) Å3Needle, colourless
Z = 80.20 × 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 opticsRint = 0.046
φ and ω scansθmax = 67.2°, θmin = 3.3°
Absorption correction: multi-scan
(SADABS; Bruker, 2014)
h = 3635
Tmin = 0.669, Tmax = 0.753k = 67
31096 measured reflectionsl = 2223
2841 independent reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.032H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.079 w = 1/[σ2(Fo2) + (0.0325P)2 + 2.2411P]
where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max = 0.001
2841 reflectionsΔρmax = 0.17 e Å3
191 parametersΔρmin = 0.19 e Å3
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 Uiso(H)=1.2Ueq(C) or 1.5Ueq(Cmethyl).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.62521 (3)0.04110 (15)0.55279 (5)0.0254 (2)
O20.61508 (3)0.12952 (16)0.72223 (5)0.0316 (2)
O30.57295 (3)0.08261 (14)0.61525 (5)0.0261 (2)
O40.66930 (3)0.69189 (13)0.51429 (4)0.0235 (2)
N10.64312 (4)0.08435 (17)0.63300 (5)0.0223 (2)
C10.66942 (5)0.47437 (19)0.54309 (7)0.0213 (3)
H1A0.6474440.3779480.4989160.026*
C20.71989 (5)0.3697 (2)0.58472 (7)0.0246 (3)
H2A0.7348640.3014100.5535120.030*
C30.75326 (5)0.4479 (3)0.66554 (8)0.0347 (3)
H3A0.7437550.5835470.6835210.042*
H3B0.7893090.4266980.6855900.042*
C40.72183 (5)0.2465 (2)0.65364 (7)0.0270 (3)
H4A0.7379510.0988130.6669750.032*
C50.67375 (4)0.2832 (2)0.65730 (7)0.0227 (3)
H5A0.6809310.3224900.7115310.027*
C60.64988 (5)0.4809 (2)0.60336 (7)0.0245 (3)
H6A0.6133780.4683120.5776680.029*
H6B0.6594430.6199790.6330650.029*
C70.60933 (4)0.0513 (2)0.66110 (7)0.0222 (3)
C80.53621 (5)0.1602 (2)0.63979 (7)0.0282 (3)
C90.50339 (6)0.3055 (3)0.57224 (9)0.0459 (4)
H9A0.4885270.2178130.5245720.069*
H9B0.4771890.3687440.5820860.069*
H9C0.5232260.4239110.5663580.069*
C100.50715 (6)0.0317 (3)0.64721 (10)0.0455 (4)
H10A0.5289270.1239140.6910530.068*
H10B0.4798650.0230940.6560270.068*
H10C0.4938230.1186150.5993640.068*
C110.56154 (6)0.2929 (3)0.71356 (8)0.0395 (4)
H11A0.5822980.1959490.7565850.059*
H11B0.5821920.4063120.7070370.059*
H11C0.5365580.3627100.7249080.059*
C120.65385 (4)0.71127 (19)0.43108 (6)0.0208 (3)
C130.60068 (5)0.6342 (2)0.38409 (8)0.0311 (3)
H13A0.5800480.6994600.4053810.047*
H13B0.5993800.4737370.3867300.047*
H13C0.5883550.6797360.3299010.047*
C140.65735 (5)0.9550 (2)0.41865 (7)0.0279 (3)
H14A0.6332971.0342790.4297880.042*
H14B0.6502320.9813870.3646830.042*
H14C0.6907731.0069780.4534510.042*
C150.68833 (5)0.5845 (2)0.40857 (7)0.0276 (3)
H15A0.7223590.6353270.4399640.041*
H15B0.6786170.6089280.3535050.041*
H15C0.6862510.4274090.4177220.041*
H1O0.6432 (7)0.081 (3)0.5493 (11)0.065 (6)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0354 (5)0.0249 (5)0.0201 (4)0.0002 (4)0.0165 (4)0.0015 (3)
O20.0402 (5)0.0366 (5)0.0260 (5)0.0080 (4)0.0220 (4)0.0063 (4)
O30.0281 (5)0.0296 (5)0.0254 (4)0.0057 (4)0.0165 (4)0.0027 (4)
O40.0380 (5)0.0170 (4)0.0191 (4)0.0015 (4)0.0162 (4)0.0003 (3)
N10.0294 (5)0.0227 (5)0.0188 (5)0.0017 (4)0.0144 (4)0.0003 (4)
C10.0290 (6)0.0165 (6)0.0216 (6)0.0002 (5)0.0145 (5)0.0012 (5)
C20.0275 (6)0.0257 (7)0.0249 (6)0.0004 (5)0.0156 (5)0.0023 (5)
C30.0276 (7)0.0472 (9)0.0280 (7)0.0095 (6)0.0115 (6)0.0013 (6)
C40.0257 (6)0.0311 (7)0.0246 (6)0.0018 (5)0.0119 (5)0.0064 (5)
C50.0276 (6)0.0229 (6)0.0193 (6)0.0028 (5)0.0122 (5)0.0000 (5)
C60.0320 (7)0.0205 (6)0.0270 (7)0.0008 (5)0.0188 (6)0.0010 (5)
C70.0264 (6)0.0207 (6)0.0217 (6)0.0017 (5)0.0130 (5)0.0022 (5)
C80.0276 (7)0.0311 (7)0.0319 (7)0.0032 (5)0.0188 (6)0.0026 (6)
C90.0402 (8)0.0558 (10)0.0426 (9)0.0205 (8)0.0198 (7)0.0073 (7)
C100.0408 (9)0.0434 (9)0.0669 (11)0.0069 (7)0.0372 (8)0.0076 (8)
C110.0424 (8)0.0388 (9)0.0404 (8)0.0043 (7)0.0218 (7)0.0098 (7)
C120.0274 (6)0.0205 (6)0.0162 (6)0.0009 (5)0.0116 (5)0.0007 (5)
C130.0283 (7)0.0310 (7)0.0309 (7)0.0002 (6)0.0109 (6)0.0024 (6)
C140.0422 (8)0.0215 (7)0.0245 (6)0.0000 (6)0.0190 (6)0.0020 (5)
C150.0338 (7)0.0281 (7)0.0259 (7)0.0049 (5)0.0179 (6)0.0018 (5)
Geometric parameters (Å, º) top
O1—N11.4172 (12)C8—C111.5108 (19)
O1—H1O0.94 (2)C8—C101.511 (2)
O2—C71.2135 (14)C8—C91.515 (2)
O3—C71.3333 (15)C9—H9A0.9800
O3—C81.4791 (14)C9—H9B0.9800
O4—C11.4367 (14)C9—H9C0.9800
O4—C121.4639 (13)C10—H10A0.9800
N1—C71.3818 (15)C10—H10B0.9800
N1—C51.4676 (15)C10—H10C0.9800
C1—C21.5097 (17)C11—H11A0.9800
C1—C61.5362 (16)C11—H11B0.9800
C1—H1A1.0000C11—H11C0.9800
C2—C31.5013 (18)C12—C141.5149 (17)
C2—C41.5098 (17)C12—C151.5192 (17)
C2—H2A1.0000C12—C131.5218 (17)
C3—C41.5061 (19)C13—H13A0.9800
C3—H3A0.9900C13—H13B0.9800
C3—H3B0.9900C13—H13C0.9800
C4—C51.5139 (17)C14—H14A0.9800
C4—H4A1.0000C14—H14B0.9800
C5—C61.5404 (17)C14—H14C0.9800
C5—H5A1.0000C15—H15A0.9800
C6—H6A0.9900C15—H15B0.9800
C6—H6B0.9900C15—H15C0.9800
N1—O1—H1O106.4 (11)C11—C8—C10112.95 (12)
C7—O3—C8119.98 (9)O3—C8—C9101.77 (10)
C1—O4—C12116.43 (9)C11—C8—C9110.72 (12)
C7—N1—O1115.14 (9)C10—C8—C9110.57 (13)
C7—N1—C5118.12 (10)C8—C9—H9A109.5
O1—N1—C5111.94 (9)C8—C9—H9B109.5
O4—C1—C2114.69 (10)H9A—C9—H9B109.5
O4—C1—C6109.83 (9)C8—C9—H9C109.5
C2—C1—C6104.95 (10)H9A—C9—H9C109.5
O4—C1—H1A109.1H9B—C9—H9C109.5
C2—C1—H1A109.1C8—C10—H10A109.5
C6—C1—H1A109.1C8—C10—H10B109.5
C3—C2—C1117.34 (11)H10A—C10—H10B109.5
C3—C2—C460.02 (9)C8—C10—H10C109.5
C1—C2—C4107.47 (10)H10A—C10—H10C109.5
C3—C2—H2A119.1H10B—C10—H10C109.5
C1—C2—H2A119.1C8—C11—H11A109.5
C4—C2—H2A119.1C8—C11—H11B109.5
C2—C3—C460.27 (8)H11A—C11—H11B109.5
C2—C3—H3A117.7C8—C11—H11C109.5
C4—C3—H3A117.7H11A—C11—H11C109.5
C2—C3—H3B117.7H11B—C11—H11C109.5
C4—C3—H3B117.7O4—C12—C14104.11 (9)
H3A—C3—H3B114.9O4—C12—C15111.16 (9)
C3—C4—C259.71 (8)C14—C12—C15110.11 (10)
C3—C4—C5115.60 (12)O4—C12—C13110.53 (10)
C2—C4—C5108.80 (10)C14—C12—C13109.87 (11)
C3—C4—H4A119.4C15—C12—C13110.86 (10)
C2—C4—H4A119.4C12—C13—H13A109.5
C5—C4—H4A119.4C12—C13—H13B109.5
N1—C5—C4110.37 (10)H13A—C13—H13B109.5
N1—C5—C6113.23 (10)C12—C13—H13C109.5
C4—C5—C6104.36 (10)H13A—C13—H13C109.5
N1—C5—H5A109.6H13B—C13—H13C109.5
C4—C5—H5A109.6C12—C14—H14A109.5
C6—C5—H5A109.6C12—C14—H14B109.5
C1—C6—C5105.68 (10)H14A—C14—H14B109.5
C1—C6—H6A110.6C12—C14—H14C109.5
C5—C6—H6A110.6H14A—C14—H14C109.5
C1—C6—H6B110.6H14B—C14—H14C109.5
C5—C6—H6B110.6C12—C15—H15A109.5
H6A—C6—H6B108.7C12—C15—H15B109.5
O2—C7—O3126.50 (11)H15A—C15—H15B109.5
O2—C7—N1121.89 (11)C12—C15—H15C109.5
O3—C7—N1111.51 (10)H15A—C15—H15C109.5
O3—C8—C11110.06 (10)H15B—C15—H15C109.5
O3—C8—C10110.21 (11)
C12—O4—C1—C2102.14 (12)C2—C4—C5—C615.46 (13)
C12—O4—C1—C6139.98 (10)O4—C1—C6—C5153.26 (10)
O4—C1—C2—C375.76 (13)C2—C1—C6—C529.48 (12)
C6—C1—C2—C344.85 (14)N1—C5—C6—C192.48 (12)
O4—C1—C2—C4140.48 (10)C4—C5—C6—C127.59 (12)
C6—C1—C2—C419.87 (13)C8—O3—C7—O23.74 (19)
C1—C2—C3—C495.27 (12)C8—O3—C7—N1172.72 (10)
C2—C3—C4—C597.70 (12)O1—N1—C7—O2162.08 (11)
C1—C2—C4—C3111.98 (12)C5—N1—C7—O226.13 (17)
C3—C2—C4—C5109.26 (12)O1—N1—C7—O321.27 (14)
C1—C2—C4—C52.72 (14)C5—N1—C7—O3157.22 (10)
C7—N1—C5—C4154.03 (10)C7—O3—C8—C1161.96 (15)
O1—N1—C5—C468.71 (12)C7—O3—C8—C1063.27 (15)
C7—N1—C5—C689.39 (12)C7—O3—C8—C9179.40 (11)
O1—N1—C5—C647.87 (13)C1—O4—C12—C14179.81 (10)
C3—C4—C5—N1171.18 (10)C1—O4—C12—C1561.67 (13)
C2—C4—C5—N1106.50 (11)C1—O4—C12—C1361.88 (13)
C3—C4—C5—C649.21 (13)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1O···O4i0.94 (2)1.87 (2)2.7926 (12)164.9 (17)
Symmetry code: (i) x, y1, z.
 

Funding information

AJL thanks NSERC Canada for funding.

References

First citationAltona, C. & Sundaralingam, M. (1972). J. Am. Chem. Soc. 94, 8205–8212.  CrossRef CAS PubMed Web of Science Google Scholar
First citationBruker (2014). APEX2 and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationCrimmons, M. T. (1998). Tetrahedron, 54, 9229–9272.  Google Scholar
First citationJi, C. & Miller, M. J. (2010). Tetrahedron Lett. 51, 3789–3791.  Web of Science CrossRef CAS PubMed Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationSheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
First citationSheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
First citationSpek, A. L. (2009). Acta Cryst. D65, 148–155.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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