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Acta Crystallogr Sect E Struct Rep Online. 2010 November 1; 66(Pt 11): o2750–o2751.
Published online 2010 October 9. doi:  10.1107/S1600536810039589
PMCID: PMC3009327

(3R,4R,5R)-5-(Acetamido­meth­yl)-N-benzyl-3,4-dihy­droxy­tetra­hydro­furan-3-carboxamide

Abstract

X-ray crystallographic analysis with Cu Kα radiation established the relative configurations of the stereogenic centers in the title compound, C15H20N2O5, and clarified mechanistic ambiguities in the synthesis. The conformation of the five-membered ring approximates twisted, about a C—O bond. The absolute configuration of this carbon-branched dipeptide isostere was known based on the use of d-ribose as the starting material. Refinement of the Flack parameter gave an ambiguous result but the refined Hooft parameter is in agreement with the assumed (d-ribose) absolute structure. The crystal structure consists of N—H(...)O and O—H(...)O hydrogen-bonded bi-layers, with the terminal methyl and phenyl groups forming a hydro­phobic inter-layer inter­face. Some weak C—H(...)O inter­actions are also present.

Related literature

For reviews of sugar amino acids, see: Risseeuw et al. (2007 [triangle]); Smith & Fleet (1999 [triangle]). For investigations of peptidomimetics, see: Smith et al. (1998 [triangle]); Long et al. (1998 [triangle], 1999 [triangle]); Claridge et al. (1999 [triangle]); Brittain et al. (2000 [triangle]); Hungerford et al. (2000 [triangle]); Raunkjr et al. (2004 [triangle]); Jockusch et al. (2006 [triangle]); Tuin et al. (2009 [triangle]). For crossed-aldol reactions of carbohydrates with formaldehyde, see: Ho (1985 [triangle]); Simone et al. (2005 [triangle], 2008 [triangle]); Best et al. (2010 [triangle]). For more strategies for the synthesis of branched carbohydrates, see: Hotchkiss et al. (2004 [triangle]); Soengas et al. (2005 [triangle]); Booth et al. (2008 [triangle]). For a related structure, see: Punzo et al. (2005 [triangle]). For the treatment of hydrogen atoms in CRYSTALS, see: Cooper et al. (2010 [triangle]). For the determination of absolute configuration, see: Hooft et al. (2008 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o2750-scheme1.jpg

Experimental

Crystal data

  • C15H20N2O5
  • M r = 308.33
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-66-o2750-efi1.jpg
  • a = 5.4130 (2) Å
  • b = 8.5082 (2) Å
  • c = 32.6501 (4) Å
  • V = 1503.70 (7) Å3
  • Z = 4
  • Cu Kα radiation
  • μ = 0.86 mm−1
  • T = 150 K
  • 0.35 × 0.20 × 0.04 mm

Data collection

  • Oxford Diffraction Gemini diffractometer
  • Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2002 [triangle]) T min = 0.95, T max = 0.97
  • 12797 measured reflections
  • 1805 independent reflections
  • 1371 reflections with I > 2.0σ(I)
  • R int = 0.038
  • θmax = 54.3°

Refinement

  • R[F 2 > 2σ(F 2)] = 0.033
  • wR(F 2) = 0.061
  • S = 0.99
  • 1796 reflections
  • 200 parameters
  • H-atom parameters constrained
  • Δρmax = 0.21 e Å−3
  • Δρmin = −0.28 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 681 Friedel pairs
  • Flack parameter: 0.0 (3)

Data collection: Gemini (Oxford Diffraction, 2006 [triangle]); cell refinement: CrysAlis RED (Oxford Diffraction, 2002 [triangle]); data reduction: CrysAlis RED; program(s) used to solve structure: SIR92 (Altomare et al., 1994 [triangle]); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003 [triangle]); molecular graphics: CAMERON (Watkin et al., 1996 [triangle]); software used to prepare material for publication: CRYSTALS.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810039589/hb5639sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810039589/hb5639Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

Financial support to MIS provided through the European Community’s Human Potential Programme under contract HPRN-CT-2002–00173 is gratefully acknowledged.

supplementary crystallographic information

Comment

δ-Tetrahydrofuran sugar amino acids (THF SAAs) (Risseeuw et al., 2007; Smith and Fleet, 1999) have been extensively used as dipeptide isosteres (Long et al., 1998; Brittain et al., 2000) and incorporated into peptidomimetics (Smith et al., 1998; Hungerford et al., 2000; Raunkjr et al., 2004). The secondary structural preferences induced by THF SAAs upon their incorporation into peptidomimetics have been investigated in a wide variety of systems (Long et al., 1999; Tuin et al., 2009). All these studies have been reported on linear carbon chains, however a number of approaches to branched carbohydrates have been developed (Soengas et al., 2005; Hotchkiss et al., 2004; Booth et al., 2008). This will allow the synthesis of THF SAAs with a branched carbon chain and allow a new family of foldamers to be created.

Compound (4) is a dipeptide isostere bearing a branching carbon substituent at position C-3 of the THF scaffold. The branched peptidomimetic (4) was synthesized in a number of steps from the suitably protected D-ribose derivative (1). A crossed aldol reaction of (1) with formaldehyde (Ho, 1985) gave the resulting lactol which was then further modified to give the carbon-branched lactone trifluoromethanesulfonate (2). Reaction of (2) in acidic methanol (Simone et al., 2008) afforded the branched δ-THF SAA (3). The dipeptide isostere (4) was synthesized from SAA scaffold (3) in four synthetic steps. The crystal structure of an isomeric branched peptidomimetic has been published previously (Punzo et al., 2005). The crystal structure of (4) removes mechanistic ambiguities arising from the Ho crossed aldol condensation and successive modifications of the THF scaffold. Furthermore the crystal structure may provide information about the conformational preference of the scaffold (4) and its corresponding ability to induce any secondary structural features when incorporated into peptidomimetics. The use of D-ribose as the starting material enabled the determination of the absolute configuration of this carbon-branched dipeptide isostere (4).

Experimental

Compound (4) was dissolved in methanol, ethyl acetate and cyclohexane and then crystallized as the solvent (methanol) evaporated slowly to give crystals of (I) as very thin fragile colourless plates, which readily delaminated on handling. M.p. 428.2–429.2 K; [α]D23 +0.64 (c, 0.70 in methanol) (Simone et al., 2005).

Refinement

Refinement of the Flack (1983) parameter was inconclusive, 0.0 (3), but the Hooft parameter, 0.01 (6) was in agreement with the known absolute configuration (Hooft et al., 2008).

The H atoms were all located in a difference map, but those attached to carbon 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, N—H = 0.86, 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 (Cooper et al., 2010).

Figures

Fig. 1.
The title compound with displacement ellipsoids drawn at the 50% probability level. H atoms are shown as spheres of arbitary radius.
Fig. 2.
The hydrogen bonded bi-layer viewed along the 'a' axis. The hydrophobic faces to the layers explains why the thin platey crystals were extremely fragile.
Fig. 3.
Preparation of the title compound.

Crystal data

C15H20N2O5Dx = 1.362 Mg m3
Mr = 308.33Cu Kα radiation, λ = 1.54180 Å
Orthorhombic, P212121Cell parameters from 6490 reflections
a = 5.4130 (2) Åθ = 2–50°
b = 8.5082 (2) ŵ = 0.86 mm1
c = 32.6501 (4) ÅT = 150 K
V = 1503.70 (7) Å3Plate, colourless
Z = 40.35 × 0.20 × 0.04 mm
F(000) = 656

Data collection

Oxford Diffraction Gemini diffractometer1371 reflections with I > 2.0σ(I)
graphiteRint = 0.038
ω scansθmax = 54.3°, θmin = 5.4°
Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2002)h = −5→5
Tmin = 0.95, Tmax = 0.97k = −8→8
12797 measured reflectionsl = −33→34
1805 independent reflections

Refinement

Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.033 Method = Modified Sheldrick w = 1/[σ2(F2) + ( 0.1P)2 + 0.0P] , where P = (max(Fo2,0) + 2Fc2)/3
wR(F2) = 0.061(Δ/σ)max = 0.0003
S = 0.99Δρmax = 0.21 e Å3
1796 reflectionsΔρmin = −0.28 e Å3
200 parametersAbsolute structure: Flack (1983), 681 Friedel pairs
0 restraintsFlack parameter: 0.0 (3)
Primary atom site location: structure-invariant direct methods

Special details

Experimental. The crystal was placed in the cold stream of an Oxford Cryosystems open-flow nitrogen cryostat (Cosier & Glazer, 1986) with a nominal stability of 0.1 K.Cosier, J. & Glazer, A.M., 1986. J. Appl. Cryst. 105 107.The 9 missing reflections are all low-angle and in the penumbra of the beam trap. Their indices are 1 0 1 0 1 1 0 1 2 0 1 3 0 0 4 0 1 4 0 1 5 0 0 6

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

xyzUiso*/Ueq
O10.5384 (3)0.54901 (19)0.24407 (4)0.0310
C20.5370 (4)0.5114 (3)0.28721 (7)0.0285
C30.2641 (4)0.5070 (3)0.29786 (7)0.0260
C40.1541 (4)0.4286 (3)0.25891 (7)0.0254
C50.3580 (4)0.4433 (3)0.22659 (7)0.0292
O60.1751 (3)0.6640 (2)0.30274 (4)0.0326
O70.0770 (3)0.27045 (18)0.26442 (4)0.0315
C80.2035 (5)0.4123 (4)0.33591 (8)0.0282
O90.3097 (3)0.2865 (2)0.34244 (5)0.0385
N100.0228 (4)0.4687 (2)0.35927 (6)0.0333
C11−0.0761 (5)0.3862 (3)0.39501 (7)0.0386
C120.0572 (5)0.4266 (4)0.43394 (8)0.0357
C130.2683 (6)0.3472 (4)0.44544 (9)0.0475
C140.3884 (6)0.3856 (4)0.48131 (11)0.0609
C150.3030 (7)0.5041 (5)0.50564 (9)0.0650
C160.0949 (7)0.5856 (4)0.49430 (9)0.0609
C17−0.0278 (5)0.5475 (4)0.45838 (8)0.0465
C180.2707 (4)0.5031 (3)0.18519 (7)0.0335
N190.4531 (4)0.4865 (2)0.15327 (6)0.0334
C200.4739 (5)0.3543 (4)0.13069 (8)0.0327
O210.3280 (4)0.2440 (2)0.13419 (5)0.0418
C220.6860 (5)0.3518 (3)0.10127 (8)0.0482
H610.12230.69450.28140.0479*
H710.19690.21860.26940.0465*
H101−0.03170.55820.35380.0384*
H1910.55860.56380.14970.0387*
H220.63020.59040.30290.0333*
H210.61240.40780.29130.0332*
H410.00660.48760.24990.0266*
H510.43040.33720.22250.0326*
H111−0.24740.41420.39830.0447*
H112−0.06310.27060.38880.0441*
H1310.33260.26590.42870.0566*
H1410.53000.32720.48830.0728*
H1510.38640.52820.53070.0784*
H1610.02780.66520.51110.0716*
H171−0.16950.60310.45050.0557*
H1810.22600.61670.18690.0395*
H1820.12390.44460.17780.0396*
H2230.67190.26780.08200.0701*
H2220.84020.34750.11500.0711*
H2210.68890.44460.08540.0713*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0310 (9)0.0329 (11)0.0290 (10)−0.0035 (9)−0.0004 (8)0.0013 (9)
C20.0288 (17)0.0261 (19)0.0305 (16)0.0022 (15)−0.0051 (13)0.0002 (13)
C30.0303 (17)0.0240 (19)0.0237 (16)0.0006 (15)0.0003 (12)0.0029 (14)
C40.0291 (14)0.0156 (18)0.0313 (16)0.0013 (13)−0.0048 (14)0.0002 (14)
C50.0299 (15)0.0260 (18)0.0316 (16)−0.0019 (16)0.0001 (13)−0.0043 (15)
O60.0433 (11)0.0236 (13)0.0309 (11)0.0047 (10)−0.0042 (9)−0.0010 (9)
O70.0303 (11)0.0251 (12)0.0390 (10)−0.0027 (9)−0.0010 (8)−0.0005 (9)
C80.0280 (17)0.028 (2)0.0287 (18)−0.0011 (17)−0.0022 (15)−0.0061 (16)
O90.0453 (12)0.0285 (12)0.0417 (12)0.0080 (11)0.0038 (10)0.0052 (10)
N100.0378 (13)0.0288 (15)0.0334 (13)0.0078 (13)−0.0003 (12)0.0038 (11)
C110.0394 (18)0.044 (2)0.0322 (17)−0.0018 (16)0.0059 (15)0.0031 (15)
C120.0366 (18)0.042 (2)0.0282 (17)−0.0039 (18)0.0041 (16)0.0094 (17)
C130.048 (2)0.054 (2)0.041 (2)−0.003 (2)0.0050 (18)0.0083 (18)
C140.046 (2)0.077 (3)0.059 (2)−0.009 (2)−0.008 (2)0.021 (2)
C150.072 (3)0.081 (3)0.042 (2)−0.022 (3)−0.010 (2)0.005 (2)
C160.072 (3)0.066 (3)0.044 (2)−0.007 (2)0.007 (2)−0.0091 (19)
C170.0511 (19)0.050 (2)0.0382 (18)0.0005 (19)0.0049 (18)0.0023 (17)
C180.0340 (16)0.032 (2)0.0346 (17)−0.0018 (15)0.0013 (14)−0.0018 (15)
N190.0367 (13)0.0319 (16)0.0318 (13)−0.0115 (13)0.0074 (12)−0.0025 (12)
C200.0385 (19)0.034 (2)0.0254 (16)0.0013 (19)−0.0072 (17)0.0015 (17)
O210.0472 (13)0.0319 (14)0.0462 (12)−0.0103 (11)0.0017 (11)−0.0039 (10)
C220.052 (2)0.054 (2)0.0389 (18)0.0002 (18)0.0118 (17)−0.0006 (16)

Geometric parameters (Å, °)

O1—C21.444 (2)C12—C131.379 (3)
O1—C51.445 (3)C12—C171.381 (4)
C2—C31.518 (3)C13—C141.379 (4)
C2—H220.983C13—H1310.948
C2—H210.981C14—C151.364 (4)
C3—C41.555 (3)C14—H1410.941
C3—O61.429 (3)C15—C161.373 (4)
C3—C81.517 (3)C15—H1510.956
C4—C51.532 (3)C16—C171.386 (3)
C4—O71.420 (2)C16—H1610.945
C4—H410.988C17—H1710.937
C5—C181.520 (3)C18—N191.443 (3)
C5—H510.993C18—H1810.998
O6—H610.796C18—H1820.968
O7—H710.801N19—C201.350 (3)
C8—O91.234 (3)N19—H1910.879
C8—N101.330 (3)C20—O211.232 (3)
N10—C111.463 (3)C20—C221.497 (3)
N10—H1010.836C22—H2230.956
C11—C121.501 (3)C22—H2220.947
C11—H1110.963C22—H2210.945
C11—H1121.007
C2—O1—C5104.10 (17)H111—C11—H112109.4
O1—C2—C3103.53 (17)C11—C12—C13121.1 (3)
O1—C2—H22110.7C11—C12—C17120.0 (3)
C3—C2—H22113.4C13—C12—C17118.9 (3)
O1—C2—H21109.3C12—C13—C14120.4 (3)
C3—C2—H21110.6C12—C13—H131120.3
H22—C2—H21109.2C14—C13—H131119.3
C2—C3—C4101.29 (19)C13—C14—C15120.7 (3)
C2—C3—O6109.3 (2)C13—C14—H141117.6
C4—C3—O6111.3 (2)C15—C14—H141121.7
C2—C3—C8114.3 (2)C14—C15—C16119.6 (3)
C4—C3—C8111.0 (2)C14—C15—H151119.8
O6—C3—C8109.4 (2)C16—C15—H151120.6
C3—C4—C5104.63 (19)C15—C16—C17120.2 (3)
C3—C4—O7114.56 (19)C15—C16—H161121.4
C5—C4—O7112.09 (19)C17—C16—H161118.3
C3—C4—H41109.5C16—C17—C12120.2 (3)
C5—C4—H41109.7C16—C17—H171120.5
O7—C4—H41106.4C12—C17—H171119.3
C4—C5—O1105.40 (17)C5—C18—N19113.39 (19)
C4—C5—C18114.6 (2)C5—C18—H181110.5
O1—C5—C18110.66 (19)N19—C18—H181107.5
C4—C5—H51107.7C5—C18—H182107.8
O1—C5—H51110.6N19—C18—H182109.3
C18—C5—H51107.9H181—C18—H182108.2
C3—O6—H61109.1C18—N19—C20122.2 (2)
C4—O7—H71108.0C18—N19—H191117.8
C3—C8—O9120.1 (2)C20—N19—H191119.9
C3—C8—N10115.9 (3)N19—C20—O21122.1 (2)
O9—C8—N10123.8 (2)N19—C20—C22115.2 (3)
C8—N10—C11123.6 (2)O21—C20—C22122.7 (3)
C8—N10—H101117.8C20—C22—H223111.9
C11—N10—H101118.5C20—C22—H222111.9
N10—C11—C12112.9 (2)H223—C22—H222110.6
N10—C11—H111108.9C20—C22—H221110.7
C12—C11—H111108.1H223—C22—H221105.3
N10—C11—H112106.4H222—C22—H221106.0
C12—C11—H112111.2

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O6—H61···O7i0.801.952.737 (4)167
O7—H71···O1ii0.802.082.821 (4)154
N10—H101···O21i0.842.293.023 (4)147
N19—H191···O9iii0.882.042.861 (4)155
C2—H22···O21iii0.982.453.322 (4)148
C4—H41···O1iv0.992.593.520 (4)156
C4—H41···O7i0.992.493.257 (4)134

Symmetry codes: (i) −x, y+1/2, −z+1/2; (ii) −x+1, y−1/2, −z+1/2; (iii) −x+1, y+1/2, −z+1/2; (iv) x−1, y, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: HB5639).

References

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