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

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2-De­­oxy-2-fluoro-2-C-methyl-D-ribono-1,4-lactone (fluoro­methyl­rib)

aDepartment of Chemical Crystallography, Chemical Research Laboratory, Mansfield Road, Oxford OX1 3TA, England, bIdenix Pharmaceuticals, 60 Hampshire Street, Cambridge, MA 02139, USA, and cDepartment of Organic Chemistry, Chemical Research Laboratory, Mansfield Road, Oxford OX1 3TA, England
*Correspondence e-mail: samuel.parker@magd.ox.ac.uk

(Received 7 February 2006; accepted 20 February 2006; online 3 March 2006)

The relative stereochemistry of the fluoro substituent (as ribo) and the ring size of the lactone (as five) in the title compound, C6H9FO4, have been established by X-ray crystallographic analysis.

Comment

Until recently, carbohydrate building blocks with branched carbon chains have not been readily available in large quanti­ties (Bols, 1996[Bols, M. (1996). Carbohydrate Building Blocks. New York: Wiley.]; Lichtenthaler & Peters, 2004[Lichtenthaler, F. W. & Peters, S. (2004). C. R. Chim. 7, 65-90.]). The Kiliani reaction of ketoses with cyanide, followed by acetonation (Hotchkiss et al., 2004[Hotchkiss, D., Soengas, R., Simone, M. I., van Ameijde, J., Hunter, S., Cowley, A. R. & Fleet, G. W. J. (2004). Tetrahedron Lett. 45, 9461-9464.]; Soengas et al., 2005[Soengas, R., Izumori, K., Simone, M. I., Watkin, D. J., Skytte, U. P., Soetaert, W. & Fleet, G. W. J. (2005). Tetrahedron Lett. 46, 5755-5759.]), provides access to a novel class of carbohydrate scaffold which contains a branched hydroxy­methyl carbon chain. Branched sugars bearing a C-2 alkyl group are also available from the Kiliani reaction of cyanide with 1-deoxy­ketoses, themselves prepared by addition of organometallic reagents to sugar lactones. Thus, reaction of cyanide with a protected 1-de­oxy-D-ribulose afforded the isopropyl­idene derivative of arabinono-1,5-lactone (1) (Hotchkiss et al., 2006[Hotchkiss, D. J., Jenkinson, S. F., Storer, R., Heinz, T. & Fleet, G. W. J. (2006). Tetrahedron Lett. 47, 315-318.]), shown to crystallize in a boat conformation (Punzo, Watkin, Jenkinson & Fleet, 2005[Punzo, F., Watkin, D. J., Jenkinson, S. F. & Fleet, G. W. J. (2005). Acta Cryst. E61, o127-129.]).

[Scheme 1]

Protected sugar lactones such as (1) allow modification of the tertiary alcohol group to introduce other functional groups at the quaternary centre; hitherto, there have been very few strategies for the synthesis of branched carbohydrates with a non-oxygen functional group at a quaternary position. Esterification of the free hydroxyl group in (1) with triflic anhydride in pyridine afforded the trifluoro­methane­sulfonate (2). Reaction of (2) with sodium azide in dimethyl­formamide gave the ribo-azide (3) as the major product in good yield, even though the overall reaction is a nucleophilic displacement at a very hindered position; this reaction is very unlikely to be an SN2 reaction, so the stereochemistry at C-2 of the azide (3) was established by X-ray crystallographic analysis (Punzo, Watkin, Jenkinson, Cruz & Fleet, 2005[Punzo, F., Watkin, D. J., Jenkinson, S. F., Cruz, F. P. & Fleet, G. W. J. (2005). Acta Cryst. E61, o511-o512.]), showing that the reaction proceeded with inversion of configuration to give the ribono­lactone (3) in a boat conformation with the C-2 methyl group in a hindered flagpole position. A minor product was also formed during the azide displacement reaction and was proven by X-ray analysis to have the ribo-configuration (4) (Punzo et al., 2006[Punzo, F., Watkin, D. J., Jenkinson, S. F., Cruz, F. P. & Fleet, G. W. J. (2006). Acta Cryst. E62, o321-o323.]). It is noteworthy that the 1,5-lactones (1), (3) and (4) all adopt a boat conformation in the solid state.

When the trifluoro­methane­sulfonate (2) was treated with tris­(dimethyl­amino)sulfur trimethyl­silyl difluoride – an excellent source of nucleophilic fluoride – fluoro­lactone (5) was isolated as the major product. Removal of the isopropyl­idene protecting group by treatment with aqueous acid gave the title unprotected fluoro­lactone, (6). The crystal structure reported in this paper (Fig. 1[link]) establishes the relative ribo-stereochemistry in both (5) and (6), and also shows that deprotection of the ketal (5) is accompanied by contraction of the six-ring lactone in (5) to give a five-ring lactone in (6). The quaternary fluoride (6) is likely to be a powerful inter­mediate for the synthesis of a novel class of carbohydrate in which a F atom is attached to a quaternary centre. The absolute configuration of (6) was established by the use of D-erythrono­lactone as the starting material for the preparation of (1).

The crystal structure consists of pleated sheets lying perpendicular to c, with mol­ecules linked by hydrogen bonds (Fig. 2[link]). There is a short contact between adjacent sheets [2.86 Å for O9⋯C5([{1\over 2}] + x, [{1\over 2}-y], 1 − z)].

[Figure 1]
Figure 1
The mol­ecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level. H atoms are shown as spheres of arbitary radius.
[Figure 2]
Figure 2
A c-axis projection. The mol­ecules are linked by hydrogen bonds (dashed lines) into pleated sheets perpendicular to c.

Experimental

The fluoro­lactone (6) (Mayes et al., 2006[Mayes, B. A., Storer, R., Watkin, D. J., Jenkinson, S. F. & Fleet, G. W. J. (2006). In preparation.]) was crystallized from ethyl acetate:heptane (8:1), m.p. 415–416 K; [α]D20 +129.3° (c = 0.9 in CH3CN).

Crystal data
  • C6H9FO4

  • Mr = 164.13

  • Orthorhombic, P 21 21 21

  • a = 7.3570 (2) Å

  • b = 8.2864 (2) Å

  • c = 11.7886 (3) Å

  • V = 718.67 (3) Å3

  • Z = 4

  • Dx = 1.517 Mg m−3

  • Mo Kα radiation

  • Cell parameters from 900 reflections

  • θ = 1–27°

  • μ = 0.14 mm−1

  • T = 150 K

  • Block, colourless

  • 0.60 × 0.40 × 0.40 mm

Data collection
  • Nonius KappaCCD diffractometer

  • ω scans

  • Absorption correction: multi-scan(DENZO/SCALEPACK; Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.])Tmin = 0.64, Tmax = 0.94

  • 1612 measured reflections

  • 964 independent reflections

  • 958 reflections with I > −3σ(I)

  • Rint = 0.008

  • θmax = 27.5°

  • h = −9 → 9

  • k = −10 → 10

  • l = −14 → 14

Refinement
  • Refinement on F2

  • R[F2 > 2σ(F2)] = 0.030

  • wR(F2) = 0.098

  • S = 0.91

  • 958 reflections

  • 100 parameters

  • H-atom parameters constrained

  • w = 1/[σ2(F2) + (0.1P)2] where P = [max(Fo2,0) + 2Fc2]/3

  • (Δ/σ)max < 0.001

  • Δρmax = 0.22 e Å−3

  • Δρmin = −0.18 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)[link]

D—H⋯A D—H H⋯A DA D—H⋯A
O9—H6⋯O8i 0.82 1.90 2.701 (2) 165
O8—H7⋯O6ii 0.84 2.01 2.804 (2) 157
Symmetry codes: (i) [x-{\script{1\over 2}}, -y-{\script{1\over 2}}, -z+2]; (ii) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+2].

The H atoms were all located in a difference map, but those attached to C atoms were repositioned geometrically. The H atoms were initially refined with soft restraints on the bond lengths and angles to regularize their geometry (C—H in the range 0.93–0.98, O—H = 0.82 Å) and Uiso(H) (in the range 1.2–1.5 times Ueq of the parent atom), after which the positions were refined with riding constraints.

Data collection: COLLECT (Nonius, 2001[Nonius (2001). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: DENZO/SCALEPACK (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO/SCALEPACK; program(s) used to solve structure: SIR92 (Altomare et al., 1994[Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M. C., Polidori, G. & Camalli, M. (1994). J. Appl. Cryst. 27, 435.]); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003[Betteridge, P. W., Carruthers, J. R., Cooper, R. I., Prout, K. & Watkin, D. J. (2003). J. Appl. Cryst. 36, 1487.]); molecular graphics: CAMERON (Watkin et al., 1996[Watkin, D. J., Prout, C. K. & Pearce, L. J. (1996). CAMERON. Chemical Crystallography Laboratory, Oxford, England.]); software used to prepare material for publication: CRYSTALS.

Supporting information


Computing details top

Data collection: COLLECT (Nonius, 2001); cell refinement: DENZO/SCALEPACK; data reduction: DENZO/SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003); molecular graphics: CAMERON (Watkin et al., 1996); software used to prepare material for publication: CRYSTALS.

2-Deoxy-2-fluoro-2-C-methyl-D-ribono-1,4-lactone top
Crystal data top
C6H9FO4Dx = 1.517 Mg m3
Mr = 164.13Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121Cell parameters from 900 reflections
a = 7.3570 (2) Åθ = 1–27°
b = 8.2864 (2) ŵ = 0.14 mm1
c = 11.7886 (3) ÅT = 150 K
V = 718.67 (3) Å3Block, colourless
Z = 40.60 × 0.40 × 0.40 mm
F(000) = 344
Data collection top
Nonius KappaCCD
diffractometer
958 reflections with I > 3σ(I)
Graphite monochromatorRint = 0.008
ω scansθmax = 27.5°, θmin = 3.0°
Absorption correction: multi-scan
(DENZO/SCALEPACK; Otwinowski & Minor, 1997)
h = 99
Tmin = 0.64, Tmax = 0.94k = 1010
1612 measured reflectionsl = 1414
964 independent reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.030H-atom parameters constrained
wR(F2) = 0.098 w = 1/[σ2(F2) + (0.1P)2]
where P = [max(Fo2,0) + 2Fc2]/3
S = 0.91(Δ/σ)max < 0.001
958 reflectionsΔρmax = 0.22 e Å3
100 parametersΔρmin = 0.18 e Å3
0 restraints
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.26615 (19)0.06271 (16)0.80936 (11)0.0189
C20.45465 (18)0.13941 (14)0.81193 (11)0.0165
C30.53478 (17)0.07250 (16)0.92219 (11)0.0174
O40.44849 (12)0.08566 (11)0.93581 (9)0.0193
C50.30033 (19)0.09816 (14)0.87060 (11)0.0184
O60.20970 (13)0.21809 (11)0.86637 (9)0.0266
C70.7384 (2)0.04800 (18)0.91928 (13)0.0223
O80.81162 (14)0.00656 (11)1.02682 (10)0.0284
O90.45498 (14)0.30961 (9)0.80642 (8)0.0214
F100.15671 (11)0.15009 (10)0.88691 (8)0.0270
C110.1703 (2)0.05096 (18)0.69793 (13)0.0289
H210.52190.09600.74830.0171*
H310.49970.14180.98670.0184*
H710.79130.15020.89710.0248*
H720.76570.03750.86150.0253*
H1110.05680.00940.71000.0416*
H60.39930.35100.85890.0318*
H70.77030.08661.04030.0405*
H10.14480.15910.67210.0420*
H20.24520.00730.64510.0406*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0190 (7)0.0156 (5)0.0222 (7)0.0029 (5)0.0005 (5)0.0018 (5)
C20.0179 (7)0.0144 (5)0.0172 (6)0.0005 (5)0.0018 (5)0.0002 (4)
C30.0202 (6)0.0129 (5)0.0192 (6)0.0046 (5)0.0004 (5)0.0008 (5)
O40.0221 (5)0.0150 (4)0.0209 (5)0.0043 (4)0.0017 (4)0.0037 (4)
C50.0193 (6)0.0169 (6)0.0189 (7)0.0003 (5)0.0023 (5)0.0007 (5)
O60.0258 (6)0.0207 (5)0.0333 (7)0.0078 (4)0.0012 (5)0.0014 (4)
C70.0197 (6)0.0229 (6)0.0244 (8)0.0022 (5)0.0035 (5)0.0001 (5)
O80.0311 (5)0.0206 (4)0.0334 (6)0.0043 (4)0.0154 (5)0.0012 (4)
O90.0281 (6)0.0128 (4)0.0231 (5)0.0017 (4)0.0076 (4)0.0012 (4)
F100.0202 (4)0.0260 (5)0.0347 (5)0.0024 (4)0.0068 (4)0.0059 (4)
C110.0315 (8)0.0240 (7)0.0313 (9)0.0023 (7)0.0107 (7)0.0007 (6)
Geometric parameters (Å, º) top
C1—C21.5258 (19)O4—C51.3378 (16)
C1—C51.5367 (17)C5—O61.1978 (17)
C1—F101.4171 (15)C7—O81.4195 (18)
C1—C111.4941 (17)C7—H710.968
C2—C31.5311 (18)C7—H721.003
C2—O91.4118 (13)O8—H70.845
C2—H210.968O9—H60.818
C3—O41.4651 (16)C11—H1110.984
C3—C71.512 (2)C11—H10.964
C3—H310.987C11—H20.961
C2—C1—C5101.73 (10)C3—O4—C5111.06 (10)
C2—C1—F10106.90 (10)C1—C5—O4109.64 (10)
C5—C1—F10103.48 (10)C1—C5—O6127.52 (12)
C2—C1—C11118.26 (12)O4—C5—O6122.80 (12)
C5—C1—C11115.71 (11)C3—C7—O8112.83 (12)
F10—C1—C11109.41 (11)C3—C7—H71106.7
C1—C2—C3102.47 (10)O8—C7—H71107.5
C1—C2—O9114.63 (11)C3—C7—H72107.9
C3—C2—O9113.59 (11)O8—C7—H72111.1
C1—C2—H21107.1H71—C7—H72110.8
C3—C2—H21109.1C7—O8—H7104.6
O9—C2—H21109.5C2—O9—H6112.5
C2—C3—O4104.49 (10)C1—C11—H111107.9
C2—C3—C7114.26 (12)C1—C11—H1108.0
O4—C3—C7108.16 (11)H111—C11—H1110.7
C2—C3—H31110.1C1—C11—H2109.4
O4—C3—H31108.8H111—C11—H2108.9
C7—C3—H31110.8H1—C11—H2112.0
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O9—H6···O8i0.821.902.701 (2)165
O8—H7···O6ii0.842.012.804 (2)157
Symmetry codes: (i) x1/2, y1/2, z+2; (ii) x+1/2, y+1/2, z+2.
 

References

First citationAltomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M. C., Polidori, G. & Camalli, M. (1994). J. Appl. Cryst. 27, 435.  CrossRef Web of Science IUCr Journals Google Scholar
First citationBetteridge, P. W., Carruthers, J. R., Cooper, R. I., Prout, K. & Watkin, D. J. (2003). J. Appl. Cryst. 36, 1487.  Web of Science CrossRef IUCr Journals Google Scholar
First citationBols, M. (1996). Carbohydrate Building Blocks. New York: Wiley.  Google Scholar
First citationHotchkiss, D. J., Jenkinson, S. F., Storer, R., Heinz, T. & Fleet, G. W. J. (2006). Tetrahedron Lett. 47, 315–318.  Web of Science CrossRef CAS Google Scholar
First citationHotchkiss, D., Soengas, R., Simone, M. I., van Ameijde, J., Hunter, S., Cowley, A. R. & Fleet, G. W. J. (2004). Tetrahedron Lett. 45, 9461–9464.  Web of Science CrossRef CAS Google Scholar
First citationLichtenthaler, F. W. & Peters, S. (2004). C. R. Chim. 7, 65–90.  Web of Science CrossRef CAS Google Scholar
First citationMayes, B. A., Storer, R., Watkin, D. J., Jenkinson, S. F. & Fleet, G. W. J. (2006). In preparation.  Google Scholar
First citationNonius (2001). COLLECT. Nonius BV, Delft, The Netherlands.  Google Scholar
First citationOtwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press.  Google Scholar
First citationPunzo, F., Watkin, D. J., Jenkinson, S. F., Cruz, F. P. & Fleet, G. W. J. (2005). Acta Cryst. E61, o511–o512.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationPunzo, F., Watkin, D. J., Jenkinson, S. F., Cruz, F. P. & Fleet, G. W. J. (2006). Acta Cryst. E62, o321–o323.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationPunzo, F., Watkin, D. J., Jenkinson, S. F. & Fleet, G. W. J. (2005). Acta Cryst. E61, o127–129.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationSoengas, R., Izumori, K., Simone, M. I., Watkin, D. J., Skytte, U. P., Soetaert, W. & Fleet, G. W. J. (2005). Tetrahedron Lett. 46, 5755–5759.  Web of Science CrossRef CAS Google Scholar
First citationWatkin, D. J., Prout, C. K. & Pearce, L. J. (1996). CAMERON. Chemical Crystallography Laboratory, Oxford, England.  Google Scholar

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