organic papers (1S*,2S*,4S*)-3,3-Difluoro-2,4-dihydroxy- 5,5-dimethylcyclooct-5(Z)-en-1-yl N,N-diethylcarbamate Comment Experimental

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1 organic papers Acta Crystallographica Section E Structure Reports Online ISSN (1S*,2S*,4S*)-3,3-Difluoro-2,4-dihydroxy- 5,5-dimethylcyclooct-5(Z)-en-1-yl N,N-diethylcarbamate John Fawcett, a Jonathan M Percy, a Stéphane Pintat, b Clive A Smith c and Emi Uneyama a * a Department of Chemistry, University of Leicester, Leicester LE1 7RH, England, b GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, England, and c Chroma Therapeutics Ltd, 93 Milton Park, Abingdon, Oxon OX14 4RY, England Correspondence jmp29@leicester.ac.uk Key indicators Single-crystal X-ray study T = 150 K Mean (C C) = Å R factor = wr factor = Data-to-parameter ratio = 6.9 For details of how these key indicators were automatically derived from the article, see The structure of the title compound, C 15 H 25 F 2 NO 4, is reported and reveals a pseudorotational relationship between the ring conformation of this compound and that of an isomeric byproduct reported in the following paper. Comment Conformational equilibria in eight-membered carbocycles occur via two main processes, pseudorotation and ring inversion. The latter exchanges substituent groups between equatorial and axial environments in a pseudo-enantiomeric relationship. Ring inversion is usually the more energetically demanding process; barriers to inversion exchange of kcal mol 1 have been reported, with smaller barriers (ca 5 kcal mol 1 ) (Servis & Noe, 1973) for the pseudorotation. [For early attempts to apply variable-temperature NMR to these phenomena, see Anderson et al. (1969) and St Jacques et al. (1966).] Recent work from our group has attempted to define these processes for a trio of difluorinated cyclooctenyl systems (Fawcett, Griffith et al., 2005). We were interested in observing a pseudorotational relationship between the ring conformations in the pair of reduction products (1) and (2), obtained upon treatment of a precursor ketone with sodium borohydride. Received 11 July 2005 Accepted 3 August 2005 Online 21 September 2005 Product (1) (the major product) arises from the opposite sense of hydride attack, with the N,N-diethylcarbamoyl group retaining its original location (Fig. 1). Product (2), reported in the following paper (Fawcett, Percy et al., 2005), arises from reagent attack on the ring face which bears the hydroxyl group, followed by migration of the N,N-diethylcarbamoyl group on to the newly formed hydroxyl group (Balnaves et al., 1999). A comparison of the two molecules is shown in Fig. 2. O HO hydrogen bonding links molecules of (1) into chains along the b axis (Table 1). # 2005 International Union of Crystallography Printed in Great Britain all rights reserved Experimental The precursor ketone was prepared as described in the literature (Fawcett, Griffith et al., 2005). Sodium borohydride (1.8 mmol, 70 mg) was added in five portions to a cold (273 K) solution of the ketone (1.8 mmol, 0.59 g) in ethanol (10 ml). After completion of the addition, the reaction mixture was allowed to warm to room doi: /s Fawcett et al. C 15 H 25 F 2 NO 4 o3319

2 organic papers Figure 1 The molecular structure of (1), showing the atom-numbering scheme and 50% displacement ellipsoids. H atoms have been omitted for clarity. filtered and concentrated under reduced pressure to leave a white solid (0.51 g). Purification by column chromatography (40% ethyl acetate in light petroleum) afforded the desired diol (1) as a white solid (0.43 g, 72%). R F (40% ethyl acetate in light petroleum) 0.29; m.p K (found: C 56.17, H 7.71, N 4.29%; C 15 H 25 F 2 NO 4 requires: C 56.06, H 7.84, N, 4.36%); max (KBr)/cm (s br,o H), 3356 (s br, O H), 2977 (m, C H), 2877 (m, C H), 1671 (s, C O); 1 H NMR (250 MHz, CDCl 3 ): 5.83 (1H, dd, J = 18.5, 9.0 Hz, H-5), 5.53 (1H, t, J = 9.0, 9.0 Hz, H-4), 4.84 (1H, ddd, 3 J HF = 21.3, 8.0, 4.1 Hz, H-3), 4.48 (1H, d, J = 5.7 Hz, H-8), (1H, m, H-1), [5H, m, OH and N(CH 2 CH 3 ) 2 ], 2.45 (1H, dd, J gem = 13.8, J = 8.5 Hz, H-6a), 2.17 (1H, br s, OH), 1.77 (1H, dd, J gem = 13.8 Hz, J = 8.3 Hz, H-6b), [12H, m, N(CH 2 CH 3 ) 2 and 2 CH 3 ]; 13 C NMR (63 MHz, CDCl 3 ): 157.4, 131.4, (d, 3 J CF = 6.6 Hz), (dd, 1 J CF = 253.1, Hz), 87.4 (d, 3 J CF = 9.2 Hz), 70.8 (dd, 2 J CF = 23.9, 19.8 Hz), 68.4 (dd, 2 J CF = 23.9, 20.9 Hz), 42.8, 42.0, 39.8, 34.9, 30.4, 24.3, 14.5, 13.4; 19 F NMR (235 MHz, CDCl 3 ): (1F, dddd, J gem = 241.5, 3 J HF = 21.2, 10.6, 4 J FH = 6.6 Hz), (1F, dd, J gem = 241.5, 3 J FH = 16.6 Hz); [HRMS (FAB, [M+H] + ) Found: , calculated for C 15 H 26 F 2 NO 4 : ]; m/z (FAB): 322 (100%, [M+H] + ). An analytical sample was recrystallized by vapour diffusion (ethyl acetate/light petroleum) to afford colourless needles. Crystal data C 15 H 25 F 2 NO 4 M r = Monoclinic, Pn a = (14) Å b = (12) Å c = (3) Å = (3) V = (2) Å 3 Z =2 Data collection Bruker APEX CCD area-detector diffractometer and! scans Absorption correction: none 5283 measured reflections 1403 independent reflections Refinement Refinement on F 2 R[F 2 >2(F 2 )] = wr(f 2 ) = S = reflections 203 parameters H-atom parameters constrained D x = Mg m 3 Mo K radiation Cell parameters from 2104 reflections = = 0.11 mm 1 T = 150 (2) K Block cut from needle, colourless mm 1332 reflections with I > 2(I) R int = max = 25.0 h = 9! 9 k = 7! 7 l = 18! 18 w = 1/[ 2 (F o 2 ) + (0.1065P) P] where P =(F o 2 +2F c 2 )/3 (/) max = max = 0.37 e Å 3 min = 0.45 e Å 3 Table 1 Hydrogen-bond geometry (Å, ). D HA D H HA DA D HA Figure 2 An overlay showing the relationship between the structures of compounds (1) and (2). temperature, stirred for 2 h at this temperature and poured over a mixture of ice and water (25 ml). HCl (10 ml of a 1 N solution) was added cautiously and the mixture was extracted with diethyl ether (3 25 ml). The combined organic extracts were dried (MgSO 4 ), O1 H1O2 i (10) 133 Symmetry code: (i) x; y þ 1; z. H atoms were positioned geometrically, with C H = Å and O H = 0.84 Å, and treated as riding, with U iso (H) = 1.2 or 1.5 (methyl and OH) times U eq of the parent atom. Data collection: SMART (Bruker, 1997); cell refinement: SAINT (Bruker, 1999); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine o3320 Fawcett et al. C 15 H 25 F 2 NO 4

3 organic papers structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Sheldrick, 2000); software used to prepare material for publication: SHELXTL. The authors thank the Universities of Birmingham and Leicester, the EPSRC (project grant GR/K84882 for SP), GlaxoSmithKline (CASE studentship for SP) and Universities UK (ORS Award for EU). References Anderson, J. E., Glazer, E. S., Griffith, D. L., Knorr, R. & Roberts, J. D. (1969). J. Am. Chem. Soc. 91, Balnaves, A. S., Gelbrich, T., Hursthouse, M. B., Light, M. E., Palmer, M. J. & Percy, J. M. (1999). J. Chem. Soc. Perkin Trans. 1, pp Bruker (1997). SMART. Version Bruker AXS Inc., Madison, Wisconsin, USA. Bruker (1999). SAINT. Version Bruker AXS Inc., Madison, Wisconsin, USA. Fawcett, J., Griffith, G. A., Percy, J. M., Pintat, S., Smith, C. A. & Uneyama, E. (2005). Org. Biomol. Chem. 3, Fawcett, J., Percy, J. M., Pintat, S., Smith, C. A. & Uneyama, E. (2005). Acta Cryst. E61, o3322 o3323. Servis, K. L. & Noe, E. A. (1973). J. Am. Chem. Soc. 95, Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany. Sheldrick, G. M. (2000). SHELXTL. Version Bruker AXS Inc., Madison, Wisconsin, USA. St Jacques, M., Brown, M. A. & Anet, F. A. L. (1966). Tetrahedron Lett. pp Fawcett et al. C 15 H 25 F 2 NO 4 o3321

4 supporting information [doi: /s ] (1S*,2S*,4S*)-3,3-Difluoro-2,4-dihydroxy-5,5-dimethylcyclooct-5(Z)-en-1-yl N,N-diethylcarbamate John Fawcett, Jonathan M Percy, Stéphane Pintat, Clive A Smith and Emi Uneyama S1. Comment Conformational equilibria in eight-membered carbocycles occur via two main processes, pseudorotation and ring inversion. The latter exchanges substituent groups between equatorial and axial environments in a pseudo-enantiomeric relationship. Ring inversion is usually the more energetically demanding process; barriers to inversion exchange of kcal mol 1 have been reported, with smaller barriers (ca 5 kcal mol 1 ) (Servis & Noe, 1973) for the pseudorotation. [For early attempts to apply variable-temperature NMR to these phenomena, see Anderson et al. (1969) and St Jacques et al. (1966).] Recent work from our group has attempted to define these processes for a trio of difluorinated cyclooctenyl systems (Griffith et al., 2005). We were interested to observe a pseudorotational relationship between the ring conformations in the pair of reduction products (1) and (2), obtained upon treatment of a precursor ketone with sodium borohydride. Product (1) (the major product) arises from the opposite sense of hydride attack, with the N,N-diethylcarbamoyl group retaining its original location (Fig. 1). Product (2), reported in the following paper (Fawcett, Percy et al., 2005), arises from reagent attack on the ring face which bears the hydroxyl group, followed by migration of the N,N-diethylcarbamoyl group on to the newly formed hydroxyl group (Balnaves et al., 1999). A comparison of the two molecules is shown in Fig. 2. O H O hydrogen bonding links molecules of (1) into chains along the b axis (Table 1). S2. Experimental The precursor ketone was prepared as described in the literature (Fawcett, Griffith et al., 2005). Sodium borohydride (1.8 mmol, 70 mg) was added in five portions to a cold (273 K) solution of the ketone (1.8 mmol, 0.59 g) in ethanol (10 ml). After completion of the addition, the reaction mixture was allowed to warm to room temperature, stirred for 2 h at this temperature and poured over a mixture of ice and water (25 ml). HCl (10 ml of a 1 N solution) was added cautiously and the mixture was extracted with diethyl ether (3 25 ml). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure to leave a white solid (0.51 g). Purification by column chromatography (40% ethyl acetate in light petroleum) afforded the desired diol (1) as a white solid (0.43 g, 72%). R F (40% ethyl acetate in light petroleum) 0.29; m.p K (found: C 56.17, H 7.71, N 4.29%; C 15 H 25 F 2 NO 4 requires: C 56.06, H 7.84, N, 4.36%); ν max (KBr)/cm (s br, O H), 3356 (s br, O H), 2977 (m, C H), 2877 (m, C H), 1671 (s, C O); 1 H NMR (250 MHz, CDCl 3 ): δ 5.83 (1H, dd, J = 18.5, 9.0 Hz, H-5), 5.53 (1H, t, J = 9.0, 9.0 Hz, H-4), 4.84 (1H, ddd, 3 J HF = 21.3, 8.0, 4.1 Hz, H-3), 4.48 (1H, d, J = 5.7 Hz, H-8), (1H, m, H-1), [5H, m, OH and N(CH 2 CH 3 ) 2 ], 2.45 (1H, dd, J gem = 13.8, J = 8.5 Hz, H-6a), 2.17 (1H, br s, OH), 1.77 (1H, dd, J gem = 13.8 Hz, J = 8.3 Hz, H-6 b), [12H, m, N(CH 2 CH 3 ) 2 and 2 CH 3 ]; 13 C NMR (63 MHz, CDCl 3 ): δ 157.4, 131.4, (d, 3 J CF = 6.6 Hz), (dd, 1 J CF = 253.1, Hz), 87.4 (d, 3 J CF = 9.2 Hz), 70.8 (dd, 2 J CF = 23.9, 19.8 Hz), 68.4 (dd, 2 J CF = 23.9, 20.9 Hz), 42.8, 42.0, 39.8, 34.9, 30.4, 24.3, 14.5, 13.4; 15 F NMR (235 MHz, CDCl 3 ): δ (1 F, dddd, J gem = 241.5, 3 J HF = 21.2, 10.6, 4 J FH = sup-1

5 6.6 Hz), (1 F, dd, J gem = 241.5, 3 J FH = 16.6 Hz); [HRMS (FAB, [M+H] + ) Found: , calculated for C 15 H 26 F 2 NO 4 : ]; m/z (FAB): 322 (100%, [M+H] + ). An analytical sample was recrystallized by vapour diffusion (ethyl acetate/light petroleum) to afford colourless needles. S3. Refinement H atoms were positioned geometrically, with C H = Å and O H = 0.84 Å, and treated as riding, with U iso (H) = 1.2 or 1.5 (methyl and OH) times U eq of the parent atom. Figure 1 The molecular structure of (1), showing the atom-numbering scheme and 50% displacement ellipsoids. H atoms have been omitted for clarity. sup-2

6 Figure 2 An overlay showing the relationship between the structures of compounds (1) and (2). (1S*,2S*,4S*)-3,3-Difluoro-2,4-dihydroxy-5,5-dimethylcyclooct-5(Z)-en-1-yl N,N-diethylcarbamate Crystal data C 15 H 25 F 2 NO 4 M r = Monoclinic, Pn Hall symbol: P -2yac a = (14) Å b = (12) Å c = (3) Å β = (3) V = (2) Å 3 Z = 2 F(000) = 344 D x = Mg m 3 Mo Kα radiation, λ = Å Cell parameters from 2104 reflections θ = µ = 0.11 mm 1 T = 150 K Block, colourless mm sup-3

7 Data collection Bruker APEX CCD area-detector diffractometer Radiation source: fine-focus sealed tube Graphite monochromator φ and ω scans 5283 measured reflections 1403 independent reflections Refinement Refinement on F 2 Least-squares matrix: full R[F 2 > 2σ(F 2 )] = wr(f 2 ) = S = reflections 203 parameters 2 restraints Primary atom site location: structure-invariant direct methods 1332 reflections with I > 2σ(I) R int = θ max = 25.0, θ min = 2.6 h = 9 9 k = 7 7 l = Secondary atom site location: difference Fourier map Hydrogen site location: inferred from neighbouring sites H-atom parameters constrained w = 1/[σ 2 (F o2 ) + (0.1065P) P] where P = (F o 2 + 2F c2 )/3 (Δ/σ) max = Δρ max = 0.37 e Å 3 Δρ min = 0.45 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 F 2 against ALL reflections. The weighted R-factor wr and goodness of fit S are based on F 2, conventional R-factors R are based on F, with F set to zero for negative F 2. The threshold expression of F 2 > σ(f 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 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 (Å 2 ) x y z U iso */U eq F (7) (9) (4) (14) F (6) (8) (4) (12) O (8) (10) (4) (15) H * O (8) (10) (4) (15) H * O (8) (9) (4) (14) O (8) (9) (4) (14) N (9) (11) (5) (16) C (11) (14) (6) (19) H1A * C (12) (15) (6) (2) C (11) (14) (6) (2) H * C (11) (13) (6) (19) H * C (11) (14) (6) (19) sup-4

8 C (12) (15) (7) (2) H * H * H * C5" (12) (16) (7) (2) H5" * H5" * H5" * C (11) (15) (7) (2) H6A * H6B * C (12) (14) (6) (2) H * C (12) (14) (6) (2) H * C (11) (15) (5) (19) C (11) (17) (6) (2) H10C * H10D * C (11) (14) (6) (2) H10A * H10B * C (12) (16) (6) (2) H11D * H11E * H11F * C (13) (2) (8) (3) H11A * H11B * H11C * Atomic displacement parameters (Å 2 ) U 11 U 22 U 33 U 12 U 13 U 23 F (3) (3) (3) (3) (2) (2) F (2) (3) (3) (2) (2) (3) O (4) (3) (3) (3) (3) (3) O (3) (3) (4) (3) (3) (3) O (3) (3) (3) (3) (3) (3) O (3) (3) (3) (3) (3) (3) N (4) (4) (4) (3) (3) (3) C (5) (4) (4) (4) (4) (4) C (5) (5) (5) (4) (4) (4) C (5) (5) (5) (4) (4) (4) C (4) (4) (5) (3) (4) (4) C (4) (4) (4) (4) (4) (4) C (5) (5) (6) (4) (4) (4) C5" (5) (5) (5) (4) (4) (4) sup-5

9 C (4) (5) (6) (4) (4) (4) C (5) (4) (5) (4) (4) (4) C (5) (5) (5) (4) (4) (4) C (4) (5) (4) (4) (3) (4) C (4) (6) (4) (4) (4) (4) C (5) (5) (5) (4) (4) (4) C (5) (5) (5) (4) (4) (4) C (5) (7) (6) (5) (5) (5) Geometric parameters (Å, º) F1 C (11) C5 H F2 C (11) C5 H O1 C (10) C5" H5" O1 H C5" H5" O2 C (11) C5" H5" O2 H C6 C (13) O3 C (11) C6 H6A O3 C (10) C6 H6B O4 C (11) C7 C (14) N1 C (12) C7 H N1 C (12) C8 H N1 C (11) C10 C (13) C1 C (13) C10 H10C C1 C (13) C10 H10D C1 H1A C10 C (14) C2 C (12) C10 H10A C3 C (13) C10 H10B C3 H C11 H11D C4 C (12) C11 H11E C4 H C11 H11F C5 C5" (13) C11 H11A C5 C (12) C11 H11B C5 C (13) C11 H11C C5 H C1 O1 H H5"1 C5" H5" C3 O2 H C5 C5" H5" C9 O3 C (7) H5"1 C5" H5" C9 N1 C (7) H5"2 C5" H5" C9 N1 C (8) C7 C6 C (8) C10 N1 C (7) C7 C6 H6A O1 C1 C (7) C5 C6 H6A O1 C1 C (7) C7 C6 H6B C8 C1 C (8) C5 C6 H6B O1 C1 H1A H6A C6 H6B C8 C1 H1A C8 C7 C (8) C2 C1 H1A C8 C7 H sup-6

10 F2 C2 F (7) C6 C7 H F2 C2 C (7) C7 C8 C (8) F1 C2 C (7) C7 C8 H F2 C2 C (7) C1 C8 H F1 C2 C (7) O4 C9 N (8) C1 C2 C (7) O4 C9 O (8) O2 C3 C (7) N1 C9 O (8) O2 C3 C (7) N1 C10 C (8) C2 C3 C (8) N1 C10 H10C O2 C3 H C11 C10 H10C C2 C3 H N1 C10 H10D C4 C3 H C11 C10 H10D O3 C4 C (7) H10C C10 H10D O3 C4 C (7) N1 C10 C (8) C5 C4 C (7) N1 C10 H10A O3 C4 H C11 C10 H10A C5 C4 H N1 C10 H10B C3 C4 H C11 C10 H10B C4 C5 C5" (7) H10A C10 H10B C4 C5 C (7) C10 C11 H11D C5" C5 C (8) C10 C11 H11E C4 C5 C (7) H11D C11 H11E C5" C5 C (7) C10 C11 H11F C5 C5 C (8) H11D C11 H11F C5 C5 H H11E C11 H11F C5 C5 H C10 C11 H11A H5 1 C5 H C10 C11 H11B C5 C5 H H11A C11 H11B H5 1 C5 H C10 C11 H11C H5 2 C5 H H11A C11 H11C C5 C5" H5" H11B C11 H11C C5 C5" H5" O1 C1 C2 F (9) C3 C4 C5 C (11) C8 C1 C2 F (7) O3 C4 C5 C (9) O1 C1 C2 F (9) C3 C4 C5 C (11) C8 C1 C2 F (9) C4 C5 C6 C (10) O1 C1 C2 C (7) C5" C5 C6 C (8) C8 C1 C2 C (10) C5 C5 C6 C (10) F2 C2 C3 O (9) C5 C6 C7 C (12) F1 C2 C3 O (9) C6 C7 C8 C1 7.2 (15) C1 C2 C3 O (7) O1 C1 C8 C (9) F2 C2 C3 C (10) C2 C1 C8 C (10) F1 C2 C3 C (7) C10 N1 C9 O (9) C1 C2 C3 C (11) C10 N1 C9 O4 8.3 (13) C9 O3 C4 C (7) C10 N1 C9 O3 5.7 (12) C9 O3 C4 C (9) C10 N1 C9 O (7) O2 C3 C4 O (8) C4 O3 C9 O4 2.5 (12) sup-7

11 C2 C3 C4 O (11) C4 O3 C9 N (7) O2 C3 C4 C (8) C9 N1 C10 C (10) C2 C3 C4 C (10) C10 N1 C10 C (10) O3 C4 C5 C5" 57.0 (9) C9 N1 C10 C (11) C3 C4 C5 C5" (8) C10 N1 C10 C (10) O3 C4 C5 C (7) Hydrogen-bond geometry (Å, º) D H A D H H A D A D H A O1 H1 O2 i (10) 133 Symmetry code: (i) x, y+1, z. sup-8