(2R,3R,4R)-Meth­yl 2-bromo-3,4-dihydr­oxy-3,4-O-isopropyl­idenetetra­hydro­furan-2-carboxyl­ate

Probert, M.R.; Watkin, D.J.; Stewart, A.J.; Storer, R.; Fleet, G.W.J.

doi:10.1107/S1600536805014467

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 61| Part 6| June 2005| Pages o1718-o1720

https://doi.org/10.1107/S1600536805014467

(2R,3R,4R)-Methyl 2-bromo-3,4-dihydroxy-3,4-O-isopropylidenetetrahydrofuran-2-carboxylate

Michael R. Probert,^a David J. Watkin,^a ^* Alistair J. Stewart,^b Richard Storer ^b and George W. J. Fleet ^c

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

(Received 21 April 2005; accepted 5 May 2005; online 14 May 2005)

The relative configuration of the quaternary C atom in the title bromide, C₉H₁₃BrO₅, prepared by bromination of the parent ester, has been determined by X-ray crystallographic analysis; the absolute configuration is known from the synthesis.

Comment

The bromination of tetrahydrofuran (THF) carboxylic acid esters to give α-bromoesters (Smith et al., 1999 ) is a key step in the synthesis of anomeric α-sugar amino acids (Estevez, Estevez et al., 1994 ; Estevez, Ardron et al., 1994 ). Such intermediates have also been used in the synthesis of biologically active spirohydantoins, such as the herbicide hydantocidin (3) (Fairbanks & Fleet, 1995 ; Fairbanks et al. 1993 ) and a powerful glycogen phosphorylase inhibitor (4) (Bichard et al., 1995 ; Krulle et al., 1997 ).

In a programme directed towards the synthesis of novel nucleosides of erythrose bearing a carbon substituent at the anomeric position, the protected THF ester (2) (Sanjayan et al., 2003 ) was treated with N-bromosuccinimide in trichloroethane in the presence of benzoyl peroxide; a single crystalline bromide was formed in 72% isolated yield. There is no reliable spectroscopic technique available in this case to allow the assignment of configuration of the quaternary C atom; X-ray crystallography firmly established the structure of the bromide as the β-anomer (1). The absolute configuration of (1) is determined by the use of D-ribose as the starting material for the synthesis.

The slightly large displacement parameters for atoms Br1, O3, O7, O9, C14 and C15 could be explained in terms of flexing of the two five-membered rings. Concerted rocking of the whole molecule is unlikely (R_TLS = 0.334). The crystal packing is unexceptional, apart from a short Br1⋯H152ⁱ contact of 2.92 Å [symmetry code: (i) −x + 1, y + $[{1\over 2}]$ , −z + $[{1\over 2}]$ ].

Figure 1
The molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level and H atoms with arbitrary radii.

Figure 2
Packing diagram of the title structure, viewed parallel to the a axis. The short Br1⋯H152ⁱ contact [symmetry code: (i) −x + 1, y + $[{1\over 2}]$ , −z + $[{1\over 2}]$ ] is shown as a dotted line.

Experimental

The title compound was crystallized from ethyl acetate/hexane. Full details of the synthesis will be published separately (Stewart et al., 2005 ).

Crystal data

C₉H₁₃BrO₅
M_r = 281.10
Orthorhombic, P 2₁ 2₁ 2₁
a = 6.6195 (2) Å
b = 10.4127 (3) Å
c = 16.3294 (7) Å
V = 1125.53 (7) Å³
Z = 4
D_x = 1.659 Mg m⁻³
Mo Kα radiation
Cell parameters from 1434 reflections
θ = 5–27°
μ = 3.65 mm⁻¹
T = 190 K
Plate, colourless
0.40 × 0.30 × 0.10 mm

Data collection

Nonius KappaCCD diffractometer
ω scans
Absorption correction: multi-scan(DENZO/SCALEPACK; Otwinowski & Minor, 1997 )T_min = 0.30, T_max = 0.69
8664 measured reflections
2490 independent reflections
2490 reflections with I > −3σ(I)
R_int = 0.051
θ_max = 27.5°
h = −8 → 8
k = −13 → 13
l = −20 → 21

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.050
wR(F²) = 0.097
S = 0.97
2490 reflections
137 parameters
H-atom parameters constrained
w = 1/[σ²(F²) + 0.02 + 2.65P] where P = [max(F_o²,0) + 2F_c²]/3
(Δ/σ)_max = 0.005
Δρ_max = 0.63 e Å⁻³
Δρ_min = −0.62 e Å⁻³
Absolute structure: Flack (1983 ), 902 Friedel pairs
Flack parameter: 0.049 (17)

Table 1
Selected geometric parameters (Å, °)

Br1—C2	2.007 (4)
C2—O3	1.368 (4)
C2—C6	1.530 (5)
C2—C10	1.517 (5)
O3—C4	1.451 (5)
C4—C5	1.503 (6)
C5—C6	1.530 (6)
C5—O9	1.433 (5)
C6—O7	1.409 (5)
O7—C8	1.430 (5)
C8—O9	1.417 (5)
C8—C14	1.483 (6)
C8—C15	1.491 (7)
C10—O11	1.189 (5)
C10—O12	1.330 (5)
O12—C13	1.444 (5)

Br1—C2—O3	109.4 (2)
Br1—C2—C6	107.9 (3)
O3—C2—C6	107.3 (3)
Br1—C2—C10	106.1 (2)
O3—C2—C10	109.6 (3)
C6—C2—C10	116.3 (3)
C2—O3—C4	106.5 (3)
O3—C4—C5	104.7 (3)
C4—C5—C6	105.0 (3)
C4—C5—O9	107.6 (4)
C6—C5—O9	105.3 (3)
C5—C6—C2	102.8 (3)
C5—C6—O7	105.1 (3)
C2—C6—O7	108.3 (3)
C6—O7—C8	109.8 (3)
O7—C8—O9	106.1 (3)
O7—C8—C14	109.7 (4)
O9—C8—C14	112.2 (4)
O7—C8—C15	109.0 (4)
O9—C8—C15	107.1 (4)
C14—C8—C15	112.5 (5)
C5—O9—C8	108.7 (3)
C2—C10—O11	124.6 (4)
C2—C10—O12	110.3 (3)
O11—C10—O12	125.0 (4)
C10—O12—C13	116.4 (3)

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 0.93–98 Å), with U_iso(H) in the range 1.2–1.5 times U_eq(C), after which they 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, 1. DOI: https://doi.org/10.1107/S1600536805014467/cf6424sup1.cif

Structure factors: contains datablock 1. DOI: https://doi.org/10.1107/S1600536805014467/cf64241sup2.hkl

Computing details top

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.

(2R,3R,4R)-Methyl 2-bromo-3,4-dihydroxy-3,4-O-isopropylidenetetrahydrofuran- 2-carboxylate top

Crystal data top

C₉H₁₃BrO₅	D_x = 1.659 Mg m⁻³
M_r = 281.10	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 1434 reflections
a = 6.6195 (2) Å	θ = 5–27°
b = 10.4127 (3) Å	µ = 3.65 mm⁻¹
c = 16.3294 (7) Å	T = 190 K
V = 1125.53 (7) Å³	Plate, colourless
Z = 4	0.40 × 0.30 × 0.10 mm
F(000) = 568

Data collection top

Nonius KappaCCD diffractometer	2490 reflections with I > −3σ(I)
Graphite monochromator	R_int = 0.051
ω scans	θ_max = 27.5°, θ_min = 5.2°
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997)	h = −8→8
T_min = 0.30, T_max = 0.69	k = −13→13
8664 measured reflections	l = −20→21
2490 independent reflections

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.050	w = 1/[σ²(F²) + 0.02 + 2.65P] where P = (max(F_o²,0) + 2F_c²)/3
wR(F²) = 0.097	(Δ/σ)_max = 0.005
S = 0.97	Δρ_max = 0.63 e Å⁻³
2490 reflections	Δρ_min = −0.62 e Å⁻³
137 parameters	Absolute structure: Flack (1983), 902 Friedel pairs
0 restraints	Absolute structure parameter: 0.049 (17)
Primary atom site location: structure-invariant direct methods

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

	x	y	z	U_iso*/U_eq
Br1	0.40041 (8)	0.26467 (5)	0.87830 (3)	0.0666
C2	0.3161 (6)	0.1256 (4)	0.8004 (2)	0.0334
O3	0.4825 (4)	0.0570 (3)	0.77676 (17)	0.0449
C4	0.5809 (7)	0.1316 (5)	0.7132 (3)	0.0516
C5	0.4105 (7)	0.1904 (4)	0.6652 (3)	0.0484
C6	0.2299 (6)	0.1897 (4)	0.7237 (2)	0.0397
O7	0.0891 (5)	0.1051 (4)	0.68791 (16)	0.0564
C8	0.1484 (6)	0.0765 (4)	0.6057 (2)	0.0414
O9	0.3581 (5)	0.1025 (5)	0.6012 (2)	0.0746
C10	0.1732 (6)	0.0392 (4)	0.8477 (2)	0.0358
O11	0.2036 (6)	−0.0710 (3)	0.8622 (2)	0.0615
O12	0.0096 (4)	0.1043 (3)	0.87037 (19)	0.0429
C13	−0.1357 (7)	0.0355 (5)	0.9197 (3)	0.0509
C14	0.0299 (9)	0.1562 (5)	0.5478 (3)	0.0605
C15	0.1220 (12)	−0.0637 (5)	0.5908 (4)	0.0836
H41	0.6604	0.1987	0.7370	0.0711*
H42	0.6639	0.0779	0.6791	0.0705*
H51	0.4451	0.2740	0.6450	0.0670*
H61	0.1786	0.2747	0.7346	0.0558*
H131	−0.2400	0.0937	0.9376	0.0930*
H132	−0.0653	−0.0017	0.9667	0.0928*
H133	−0.1956	−0.0312	0.8859	0.0925*
H141	0.0810	0.1434	0.4929	0.1087*
H142	0.0452	0.2435	0.5636	0.1090*
H143	−0.1104	0.1323	0.5512	0.1090*
H151	0.1609	−0.0850	0.5356	0.1530*
H152	0.2099	−0.1056	0.6296	0.1529*
H153	−0.0182	−0.0870	0.6009	0.1525*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Br1	0.0606 (3)	0.0705 (3)	0.0688 (3)	−0.0177 (3)	−0.0020 (3)	−0.0282 (3)
C2	0.0279 (17)	0.039 (2)	0.0328 (18)	0.0008 (15)	−0.0013 (15)	−0.0015 (16)
O3	0.0349 (14)	0.0595 (18)	0.0404 (15)	0.0086 (13)	0.0038 (12)	0.0044 (14)
C4	0.035 (2)	0.074 (3)	0.047 (2)	−0.009 (2)	0.009 (2)	0.000 (2)
C5	0.042 (2)	0.057 (2)	0.046 (2)	−0.009 (2)	0.008 (2)	0.0081 (19)
C6	0.035 (2)	0.048 (2)	0.036 (2)	−0.0019 (17)	0.0014 (16)	0.0114 (17)
O7	0.0287 (14)	0.112 (3)	0.0281 (13)	−0.0181 (18)	−0.0001 (12)	0.0057 (15)
C8	0.0295 (19)	0.061 (2)	0.033 (2)	0.0020 (17)	0.0039 (15)	0.0075 (17)
O9	0.0402 (18)	0.142 (4)	0.0415 (18)	−0.029 (2)	0.0120 (14)	−0.018 (2)
C10	0.0373 (19)	0.042 (2)	0.0276 (18)	−0.0001 (17)	0.0006 (15)	0.0000 (15)
O11	0.077 (2)	0.0389 (17)	0.068 (2)	0.0101 (15)	0.025 (2)	0.0120 (16)
O12	0.0361 (14)	0.0498 (15)	0.0427 (15)	0.0026 (12)	0.0082 (13)	0.0060 (14)
C13	0.043 (3)	0.069 (3)	0.040 (2)	−0.007 (2)	0.008 (2)	0.007 (2)
C14	0.081 (4)	0.065 (3)	0.035 (2)	0.027 (3)	−0.002 (2)	0.007 (2)
C15	0.086 (4)	0.051 (3)	0.115 (5)	0.020 (3)	0.040 (4)	0.016 (3)

Geometric parameters (Å, º) top

Br1—C2	2.007 (4)	C8—C14	1.483 (6)
C2—O3	1.368 (4)	C8—C15	1.491 (7)
C2—C6	1.530 (5)	C10—O11	1.189 (5)
C2—C10	1.517 (5)	C10—O12	1.330 (5)
O3—C4	1.451 (5)	O12—C13	1.444 (5)
C4—C5	1.503 (6)	C13—H131	0.964
C4—H41	0.957	C13—H132	0.977
C4—H42	0.962	C13—H133	0.972
C5—C6	1.530 (6)	C14—H141	0.967
C5—O9	1.433 (5)	C14—H142	0.951
C5—H51	0.959	C14—H143	0.963
C6—O7	1.409 (5)	C15—H151	0.964
C6—H61	0.964	C15—H152	0.964
O7—C8	1.430 (5)	C15—H153	0.973
C8—O9	1.417 (5)

Br1—C2—O3	109.4 (2)	O9—C8—C14	112.2 (4)
Br1—C2—C6	107.9 (3)	O7—C8—C15	109.0 (4)
O3—C2—C6	107.3 (3)	O9—C8—C15	107.1 (4)
Br1—C2—C10	106.1 (2)	C14—C8—C15	112.5 (5)
O3—C2—C10	109.6 (3)	C5—O9—C8	108.7 (3)
C6—C2—C10	116.3 (3)	C2—C10—O11	124.6 (4)
C2—O3—C4	106.5 (3)	C2—C10—O12	110.3 (3)
O3—C4—C5	104.7 (3)	O11—C10—O12	125.0 (4)
O3—C4—H41	110.3	C10—O12—C13	116.4 (3)
C5—C4—H41	109.1	O12—C13—H131	109.6
O3—C4—H42	111.0	O12—C13—H132	108.4
C5—C4—H42	111.3	H131—C13—H132	110.7
H41—C4—H42	110.2	O12—C13—H133	108.0
C4—C5—C6	105.0 (3)	H131—C13—H133	109.2
C4—C5—O9	107.6 (4)	H132—C13—H133	110.9
C6—C5—O9	105.3 (3)	C8—C14—H141	109.2
C4—C5—H51	111.7	C8—C14—H142	107.8
C6—C5—H51	113.9	H141—C14—H142	110.3
O9—C5—H51	112.8	C8—C14—H143	109.1
C5—C6—C2	102.8 (3)	H141—C14—H143	110.9
C5—C6—O7	105.1 (3)	H142—C14—H143	109.5
C2—C6—O7	108.3 (3)	C8—C15—H151	110.3
C5—C6—H61	112.7	C8—C15—H152	105.4
C2—C6—H61	112.4	H151—C15—H152	110.5
O7—C6—H61	114.7	C8—C15—H153	109.1
C6—O7—C8	109.8 (3)	H151—C15—H153	110.9
O7—C8—O9	106.1 (3)	H152—C15—H153	110.6
O7—C8—C14	109.7 (4)

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