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

Parker, S.; Watkin, D.; Mayes, B.; Storer, R.; Jenkinson, S.; Fleet, G.

doi:10.1107/S1600536806006337

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 62| Part 4| April 2006| Pages o1208-o1210

https://doi.org/10.1107/S1600536806006337

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

Samuel Parker,^a ^* David Watkin,^a Benjamin Mayes,^b Richard Storer,^b Sarah Jenkinson ^c and George Fleet ^c

^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 ; Lichtenthaler & Peters, 2004 ). The Kiliani reaction of ketoses with cyanide, followed by acetonation (Hotchkiss et al., 2004 ; Soengas et al., 2005 ), 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 ), shown to crystallize in a boat conformation (Punzo, Watkin, Jenkinson & Fleet, 2005 ).

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 S_N2 reaction, so the stereochemistry at C-2 of the azide (3) was established by X-ray crystallographic analysis (Punzo, Watkin, Jenkinson, Cruz & Fleet, 2005 ), 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 ). 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) 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). 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
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
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 ) 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
M_r = 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
D_x = 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 )T_min = 0.64, T_max = 0.94
1612 measured reflections
964 independent reflections
958 reflections with I > −3σ(I)
R_int = 0.008
θ_max = 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(F_o²,0) + 2F_c²]/3
(Δ/σ)_max < 0.001
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	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 U_iso(H) (in the range 1.2–1.5 times U_eq of the parent atom), after which the positions were refined with riding constraints.

Data collection: COLLECT (Nonius, 2001 ); cell refinement: DENZO/SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO/SCALEPACK; 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.

Supporting information

Crystal structure: contains datablocks global, 6. DOI: https://doi.org/10.1107/S1600536806006337/cf2007sup1.cif

Structure factors: contains datablock 6. DOI: https://doi.org/10.1107/S1600536806006337/cf20076sup2.hkl

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

C₆H₉FO₄	D_x = 1.517 Mg m⁻³
M_r = 164.13	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 900 reflections
a = 7.3570 (2) Å	θ = 1–27°
b = 8.2864 (2) Å	µ = 0.14 mm⁻¹
c = 11.7886 (3) Å	T = 150 K
V = 718.67 (3) Å³	Block, colourless
Z = 4	0.60 × 0.40 × 0.40 mm
F(000) = 344

Data collection top

Nonius KappaCCD diffractometer	958 reflections with I > −3σ(I)
Graphite monochromator	R_int = 0.008
ω scans	θ_max = 27.5°, θ_min = 3.0°
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997)	h = −9→9
T_min = 0.64, T_max = 0.94	k = −10→10
1612 measured reflections	l = −14→14
964 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.030	H-atom parameters constrained
wR(F²) = 0.098	w = 1/[σ²(F²) + (0.1P)²] where P = [max(F_o²,0) + 2F_c²]/3
S = 0.91	(Δ/σ)_max < 0.001
958 reflections	Δρ_max = 0.22 e Å⁻³
100 parameters	Δρ_min = −0.18 e Å⁻³
0 restraints

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

	x	y	z	U_iso*/U_eq
C1	0.26615 (19)	−0.06271 (16)	0.80936 (11)	0.0189
C2	0.45465 (18)	−0.13941 (14)	0.81193 (11)	0.0165
C3	0.53478 (17)	−0.07250 (16)	0.92219 (11)	0.0174
O4	0.44849 (12)	0.08566 (11)	0.93581 (9)	0.0193
C5	0.30033 (19)	0.09816 (14)	0.87060 (11)	0.0184
O6	0.20970 (13)	0.21809 (11)	0.86637 (9)	0.0266
C7	0.7384 (2)	−0.04800 (18)	0.91928 (13)	0.0223
O8	0.81162 (14)	−0.00656 (11)	1.02682 (10)	0.0284
O9	0.45498 (14)	−0.30961 (9)	0.80642 (8)	0.0214
F10	0.15671 (11)	−0.15009 (10)	0.88691 (8)	0.0270
C11	0.1703 (2)	−0.05096 (18)	0.69793 (13)	0.0289
H21	0.5219	−0.0960	0.7483	0.0171*
H31	0.4997	−0.1418	0.9867	0.0184*
H71	0.7913	−0.1502	0.8971	0.0248*
H72	0.7657	0.0375	0.8615	0.0253*
H111	0.0568	0.0094	0.7100	0.0416*
H6	0.3993	−0.3510	0.8589	0.0318*
H7	0.7703	0.0866	1.0403	0.0405*
H1	0.1448	−0.1591	0.6721	0.0420*
H2	0.2452	0.0073	0.6451	0.0406*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0190 (7)	0.0156 (5)	0.0222 (7)	−0.0029 (5)	0.0005 (5)	0.0018 (5)
C2	0.0179 (7)	0.0144 (5)	0.0172 (6)	−0.0005 (5)	0.0018 (5)	0.0002 (4)
C3	0.0202 (6)	0.0129 (5)	0.0192 (6)	0.0046 (5)	−0.0004 (5)	0.0008 (5)
O4	0.0221 (5)	0.0150 (4)	0.0209 (5)	0.0043 (4)	−0.0017 (4)	−0.0037 (4)
C5	0.0193 (6)	0.0169 (6)	0.0189 (7)	−0.0003 (5)	0.0023 (5)	0.0007 (5)
O6	0.0258 (6)	0.0207 (5)	0.0333 (7)	0.0078 (4)	0.0012 (5)	−0.0014 (4)
C7	0.0197 (6)	0.0229 (6)	0.0244 (8)	0.0022 (5)	−0.0035 (5)	−0.0001 (5)
O8	0.0311 (5)	0.0206 (4)	0.0334 (6)	0.0043 (4)	−0.0154 (5)	−0.0012 (4)
O9	0.0281 (6)	0.0128 (4)	0.0231 (5)	0.0017 (4)	0.0076 (4)	−0.0012 (4)
F10	0.0202 (4)	0.0260 (5)	0.0347 (5)	−0.0024 (4)	0.0068 (4)	0.0059 (4)
C11	0.0315 (8)	0.0240 (7)	0.0313 (9)	−0.0023 (7)	−0.0107 (7)	0.0007 (6)

Geometric parameters (Å, º) top

C1—C2	1.5258 (19)	O4—C5	1.3378 (16)
C1—C5	1.5367 (17)	C5—O6	1.1978 (17)
C1—F10	1.4171 (15)	C7—O8	1.4195 (18)
C1—C11	1.4941 (17)	C7—H71	0.968
C2—C3	1.5311 (18)	C7—H72	1.003
C2—O9	1.4118 (13)	O8—H7	0.845
C2—H21	0.968	O9—H6	0.818
C3—O4	1.4651 (16)	C11—H111	0.984
C3—C7	1.512 (2)	C11—H1	0.964
C3—H31	0.987	C11—H2	0.961

C2—C1—C5	101.73 (10)	C3—O4—C5	111.06 (10)
C2—C1—F10	106.90 (10)	C1—C5—O4	109.64 (10)
C5—C1—F10	103.48 (10)	C1—C5—O6	127.52 (12)
C2—C1—C11	118.26 (12)	O4—C5—O6	122.80 (12)
C5—C1—C11	115.71 (11)	C3—C7—O8	112.83 (12)
F10—C1—C11	109.41 (11)	C3—C7—H71	106.7
C1—C2—C3	102.47 (10)	O8—C7—H71	107.5
C1—C2—O9	114.63 (11)	C3—C7—H72	107.9
C3—C2—O9	113.59 (11)	O8—C7—H72	111.1
C1—C2—H21	107.1	H71—C7—H72	110.8
C3—C2—H21	109.1	C7—O8—H7	104.6
O9—C2—H21	109.5	C2—O9—H6	112.5
C2—C3—O4	104.49 (10)	C1—C11—H111	107.9
C2—C3—C7	114.26 (12)	C1—C11—H1	108.0
O4—C3—C7	108.16 (11)	H111—C11—H1	110.7
C2—C3—H31	110.1	C1—C11—H2	109.4
O4—C3—H31	108.8	H111—C11—H2	108.9
C7—C3—H31	110.8	H1—C11—H2	112.0

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	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−1/2, −y−1/2, −z+2; (ii) x+1/2, −y+1/2, −z+2.

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