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

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

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[Smith, M. D., Long, D. D., Martin, A,, Campbell, N., Bleriot, Y. & Fleet, G. W. J. (1999). Synlett, pp. 1151-1153.]) is a key step in the synthesis of anomeric α-sugar amino acids (Estevez, Estevez et al., 1994[Estevez, J. C., Estevez, R. J., Ardron, H., Wormald, M. R., Brown, D. & Fleet, G. W. J. (1994). Tetrahedron Lett. 35, 8885-8888.]; Estevez, Ardron et al., 1994[Estevez, J. C., Ardron, H., Wormald, M. R., Brown, D. & Fleet, G. W. J. (1994). Tetrahedron Lett. 35, 8889-8890.]). Such inter­mediates have also been used in the synthesis of biologically active spiro­hydantoins, such as the herbicide hydantocidin (3)[link] (Fairbanks & Fleet, 1995[Fairbanks, A. J. & Fleet, G. W. J. (1995). Tetrahedron, 51, 3881-3894.]; Fairbanks et al. 1993[Fairbanks, A. J., Ford, P. S., Watkin, D. J. & Fleet, G. W. J. (1993). Tetrahedron Lett. 34, 3327-3330.]) and a powerful glycogen phospho­rylase inhibitor (4)[link] (Bichard et al., 1995[Bichard, C. J. F., Mitchell, E. P., Wormald, M. R., Watson, K. A., Johnson, L. N., Zographos, S. E., Koutra, D. D., Oikonomakos, N. G. & Fleet, G. W. J. (1995). Tetrahedron Lett. 36, 2145-2148.]; Krulle et al., 1997[Krulle, T. M., de la Fuente, C., Watson, K. A., Gregoriou, M., Johnson, L. N., Tsitsanou, K. E., Zographos, S. E., Oikonomakos, N. G. & Fleet, G. W. J. (1997). Synlett, pp. 211-213.]).

[Scheme 1]

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)[link] (Sanjayan et al., 2003[Sanjayan, G. J., Stewart, A. J., Hachisu, S., Gonzalez, R., Watterson, M. P. & Fleet, G. W. J. (2003). Tetrahedron Lett. 44, 5847-5852.]) 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)[link]. The absolute configuration of (1)[link] 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 (RTLS = 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]
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]
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[Stewart, A. J., Storer, R., Watkin, D. J. & Fleet, G. W. J. (2005). Tetrahedron Asymmetry. In preparation.]).

Crystal data
  • C9H13BrO5

  • Mr = 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

  • Dx = 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[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 = 0.30, Tmax = 0.69

  • 8664 measured reflections

  • 2490 independent reflections

  • 2490 reflections with I > −3σ(I)

  • Rint = 0.051

  • θmax = 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(Fo2,0) + 2Fc2]/3

  • (Δ/σ)max = 0.005

  • Δρmax = 0.63 e Å−3

  • Δρmin = −0.62 e Å−3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), 902 Friedel pairs

  • Flack parameter: 0.049 (17)

Table 1
Selected geometric parameters (Å, °)[link]

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 Uiso(H) in the range 1.2–1.5 times Ueq(C), after which they 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, G., 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 (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
C9H13BrO5Dx = 1.659 Mg m3
Mr = 281.10Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121Cell parameters from 1434 reflections
a = 6.6195 (2) Åθ = 5–27°
b = 10.4127 (3) ŵ = 3.65 mm1
c = 16.3294 (7) ÅT = 190 K
V = 1125.53 (7) Å3Plate, colourless
Z = 40.40 × 0.30 × 0.10 mm
F(000) = 568
Data collection top
Nonius KappaCCD
diffractometer
2490 reflections with I > 3σ(I)
Graphite monochromatorRint = 0.051
ω scansθmax = 27.5°, θmin = 5.2°
Absorption correction: multi-scan
(DENZO/SCALEPACK; Otwinowski & Minor, 1997)
h = 88
Tmin = 0.30, Tmax = 0.69k = 1313
8664 measured reflectionsl = 2021
2490 independent reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.050 w = 1/[σ2(F2) + 0.02 + 2.65P]
where P = (max(Fo2,0) + 2Fc2)/3
wR(F2) = 0.097(Δ/σ)max = 0.005
S = 0.97Δρmax = 0.63 e Å3
2490 reflectionsΔρmin = 0.62 e Å3
137 parametersAbsolute structure: Flack (1983), 902 Friedel pairs
0 restraintsAbsolute 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
xyzUiso*/Ueq
Br10.40041 (8)0.26467 (5)0.87830 (3)0.0666
C20.3161 (6)0.1256 (4)0.8004 (2)0.0334
O30.4825 (4)0.0570 (3)0.77676 (17)0.0449
C40.5809 (7)0.1316 (5)0.7132 (3)0.0516
C50.4105 (7)0.1904 (4)0.6652 (3)0.0484
C60.2299 (6)0.1897 (4)0.7237 (2)0.0397
O70.0891 (5)0.1051 (4)0.68791 (16)0.0564
C80.1484 (6)0.0765 (4)0.6057 (2)0.0414
O90.3581 (5)0.1025 (5)0.6012 (2)0.0746
C100.1732 (6)0.0392 (4)0.8477 (2)0.0358
O110.2036 (6)0.0710 (3)0.8622 (2)0.0615
O120.0096 (4)0.1043 (3)0.87037 (19)0.0429
C130.1357 (7)0.0355 (5)0.9197 (3)0.0509
C140.0299 (9)0.1562 (5)0.5478 (3)0.0605
C150.1220 (12)0.0637 (5)0.5908 (4)0.0836
H410.66040.19870.73700.0711*
H420.66390.07790.67910.0705*
H510.44510.27400.64500.0670*
H610.17860.27470.73460.0558*
H1310.24000.09370.93760.0930*
H1320.06530.00170.96670.0928*
H1330.19560.03120.88590.0925*
H1410.08100.14340.49290.1087*
H1420.04520.24350.56360.1090*
H1430.11040.13230.55120.1090*
H1510.16090.08500.53560.1530*
H1520.20990.10560.62960.1529*
H1530.01820.08700.60090.1525*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Br10.0606 (3)0.0705 (3)0.0688 (3)0.0177 (3)0.0020 (3)0.0282 (3)
C20.0279 (17)0.039 (2)0.0328 (18)0.0008 (15)0.0013 (15)0.0015 (16)
O30.0349 (14)0.0595 (18)0.0404 (15)0.0086 (13)0.0038 (12)0.0044 (14)
C40.035 (2)0.074 (3)0.047 (2)0.009 (2)0.009 (2)0.000 (2)
C50.042 (2)0.057 (2)0.046 (2)0.009 (2)0.008 (2)0.0081 (19)
C60.035 (2)0.048 (2)0.036 (2)0.0019 (17)0.0014 (16)0.0114 (17)
O70.0287 (14)0.112 (3)0.0281 (13)0.0181 (18)0.0001 (12)0.0057 (15)
C80.0295 (19)0.061 (2)0.033 (2)0.0020 (17)0.0039 (15)0.0075 (17)
O90.0402 (18)0.142 (4)0.0415 (18)0.029 (2)0.0120 (14)0.018 (2)
C100.0373 (19)0.042 (2)0.0276 (18)0.0001 (17)0.0006 (15)0.0000 (15)
O110.077 (2)0.0389 (17)0.068 (2)0.0101 (15)0.025 (2)0.0120 (16)
O120.0361 (14)0.0498 (15)0.0427 (15)0.0026 (12)0.0082 (13)0.0060 (14)
C130.043 (3)0.069 (3)0.040 (2)0.007 (2)0.008 (2)0.007 (2)
C140.081 (4)0.065 (3)0.035 (2)0.027 (3)0.002 (2)0.007 (2)
C150.086 (4)0.051 (3)0.115 (5)0.020 (3)0.040 (4)0.016 (3)
Geometric parameters (Å, º) top
Br1—C22.007 (4)C8—C141.483 (6)
C2—O31.368 (4)C8—C151.491 (7)
C2—C61.530 (5)C10—O111.189 (5)
C2—C101.517 (5)C10—O121.330 (5)
O3—C41.451 (5)O12—C131.444 (5)
C4—C51.503 (6)C13—H1310.964
C4—H410.957C13—H1320.977
C4—H420.962C13—H1330.972
C5—C61.530 (6)C14—H1410.967
C5—O91.433 (5)C14—H1420.951
C5—H510.959C14—H1430.963
C6—O71.409 (5)C15—H1510.964
C6—H610.964C15—H1520.964
O7—C81.430 (5)C15—H1530.973
C8—O91.417 (5)
Br1—C2—O3109.4 (2)O9—C8—C14112.2 (4)
Br1—C2—C6107.9 (3)O7—C8—C15109.0 (4)
O3—C2—C6107.3 (3)O9—C8—C15107.1 (4)
Br1—C2—C10106.1 (2)C14—C8—C15112.5 (5)
O3—C2—C10109.6 (3)C5—O9—C8108.7 (3)
C6—C2—C10116.3 (3)C2—C10—O11124.6 (4)
C2—O3—C4106.5 (3)C2—C10—O12110.3 (3)
O3—C4—C5104.7 (3)O11—C10—O12125.0 (4)
O3—C4—H41110.3C10—O12—C13116.4 (3)
C5—C4—H41109.1O12—C13—H131109.6
O3—C4—H42111.0O12—C13—H132108.4
C5—C4—H42111.3H131—C13—H132110.7
H41—C4—H42110.2O12—C13—H133108.0
C4—C5—C6105.0 (3)H131—C13—H133109.2
C4—C5—O9107.6 (4)H132—C13—H133110.9
C6—C5—O9105.3 (3)C8—C14—H141109.2
C4—C5—H51111.7C8—C14—H142107.8
C6—C5—H51113.9H141—C14—H142110.3
O9—C5—H51112.8C8—C14—H143109.1
C5—C6—C2102.8 (3)H141—C14—H143110.9
C5—C6—O7105.1 (3)H142—C14—H143109.5
C2—C6—O7108.3 (3)C8—C15—H151110.3
C5—C6—H61112.7C8—C15—H152105.4
C2—C6—H61112.4H151—C15—H152110.5
O7—C6—H61114.7C8—C15—H153109.1
C6—O7—C8109.8 (3)H151—C15—H153110.9
O7—C8—O9106.1 (3)H152—C15—H153110.6
O7—C8—C14109.7 (4)
 

References

First citationAltomare, A., Cascarano, G., Giacovazzo, G., 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 citationBichard, C. J. F., Mitchell, E. P., Wormald, M. R., Watson, K. A., Johnson, L. N., Zographos, S. E., Koutra, D. D., Oikonomakos, N. G. & Fleet, G. W. J. (1995). Tetrahedron Lett. 36, 2145–2148.  CrossRef CAS Web of Science Google Scholar
First citationEstevez, J. C., Ardron, H., Wormald, M. R., Brown, D. & Fleet, G. W. J. (1994). Tetrahedron Lett. 35, 8889–8890.  CrossRef CAS Web of Science Google Scholar
First citationEstevez, J. C., Estevez, R. J., Ardron, H., Wormald, M. R., Brown, D. & Fleet, G. W. J. (1994). Tetrahedron Lett. 35, 8885–8888.  CrossRef CAS Web of Science Google Scholar
First citationFairbanks, A. J., Ford, P. S., Watkin, D. J. & Fleet, G. W. J. (1993). Tetrahedron Lett. 34, 3327–3330.  CSD CrossRef CAS Web of Science Google Scholar
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First citationKrulle, T. M., de la Fuente, C., Watson, K. A., Gregoriou, M., Johnson, L. N., Tsitsanou, K. E., Zographos, S. E., Oikonomakos, N. G. & Fleet, G. W. J. (1997). Synlett, pp. 211–213.  CrossRef Google Scholar
First citationNonius (2001). COLLECT. Nonius BV, Delft, The Netherlands.  Google Scholar
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First citationSanjayan, G. J., Stewart, A. J., Hachisu, S., Gonzalez, R., Watterson, M. P. & Fleet, G. W. J. (2003). Tetrahedron Lett. 44, 5847–5852.  Web of Science CrossRef CAS Google Scholar
First citationSmith, M. D., Long, D. D., Martin, A,, Campbell, N., Bleriot, Y. & Fleet, G. W. J. (1999). Synlett, pp. 1151–1153.  Google Scholar
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First citationWatkin, D. J., Prout, C. K. & Pearce, L. J. (1996). CAMERON. Chemical Crystallography Laboratory, Oxford, England.  Google Scholar

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