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Acta Crystallogr C. 2009 April 15; 65(Pt 4): o179–o182.
Published online 2009 March 28. doi:  10.1107/S0108270109009792
PMCID: PMC2724995

Diastereomers (R C,S P)- and (R C,R P)-S-methyl P-(3-azido­prop­yl)-N-[(1R)-1-phenyl­ethyl]phospho­namido­thio­ate

Abstract

Diastereoisomers of the title organophospho­rus compound, C12H19N4OPS, denoted R C S P, (I), and R C R P, (II), were structurally characterized and compared. Asymmetric phosphorus compounds are of interest with regard to the use of these systems as possible protein probes via the stereoselective delivery of an azide group tethered to the P atom into key protein regions. The diastereomers were produced in a 1:1 mixture and isolated by chromatography. Although both isomers crystallize in the same space group with superficially similar cell constants, conformational and packing differences are pronounced. Despite the conformational differences, strong inter­molecular hydrogen bonding links both isomers into chains parallel to the a axis [N(...)O = 2.8609 (18) and 2.966 (3) Å in (I) and (II), respectively], with C—H(...)π inter­chain inter­actions of ca 3.5 Å.

Comment

Organophosphates (OPs) are a well known class of com­pounds with particular utility as insecticides and increasing involvement in protein mechanisms as inhibitors, substrates, transition state analogs and isosteres (Rye & Baell, 2005 [triangle]). One of the key structural features of OPs is the potential to bear a stereogenic center at phospho­rus. This important variable allows researchers to investigate the role of stereoisomerism in studies with biological targets. For example, asymmetric phospho­rus esters inter­act stereospecifically with enzymes, receptors and transporters (Thompson et al., 1992 [triangle], 1993 [triangle]; Berkman et al., 1993 [triangle]). Numerous routes to asymmetric OP compounds are known but few have been structurally assigned. Our current inter­est in asymmetric phospho­rus compounds resides in their possible application as probes of proteins in which an azide group tethered to the P atom can be stereoselectively delivered into key protein regions, e.g. the ‘gorge’ in acetyl­cholinesterases (Sussman et al., 1991 [triangle]; Ordentlich et al., 1993 [triangle]).

Our goal was to prepare the stereoisomeric forms of azide-tethered OPs [structures R C S P, (I), and R C P P, (II)] for use as photoaffinity probes. Pure phosphonamide diastereomers were produced by the reaction of (R)-(+)-α-methyl­benzyl­amine with a racemic mixture of O-methyl 3-azido­propyl thio­phosphonyl chloride followed by S-to-O isomerization to afford the corresponding diastereomers in a 1:1 ratio. Attempts at isolation by crystallization result in small quantities of noncrystalline precipitate in a diethyl ether/minimal methanol mix. This material was difficult to isolate and clean well enough to identify whether it was a single diastereomer or a mixture. Separation by chromatography was clean and more predicta­ble than direct separation by crystallization/cocrys­tallization and was used to isolate each isomer. This method, used previously to isolate stereoisomers (Bortoluzzi et al., 2004 [triangle]), provided good yields of both (I) and (II), which readily crystallized from diethyl ether and methanol/diethyl ether solutions.

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Object name is c-65-0o179-scheme1.jpg

Both compounds crystallize in the space group P212121, and the chirality was determined by refinement of the Flack (1983 [triangle]) parameter in conjunction with the known chiral carbon center. The cell parameters are similar for each compound, but with significant differences evident in the a and c axial lengths (differences of ca 0.26 and 1.37 Å, respectively), with compound (I), the R C S P isomer, having the larger cell.

The mol­ecular species are shown in Fig. 1 [triangle] and selected geometric parameters are given in Table 1 [triangle]. The bonding patterns within the two systems are very similar around each stereocenter, the largest difference of ca 0.02 Å being in the P1—N8 and N8—C9 bonds. Conformational differences are much more pronounced and are reflected in the differences in the torsion angles between the two compounds. Compound (I), the R C S P isomer, shown in Fig. 1 [triangle](a), is in a more ‘relaxed’ conformation, with the aliphatic chain forming a straight backbone with respect to the N8—C9 vector. The azide, –SMe and C10 groups are on the same side of this chain, and the phenyl group and the oxide occupy the other side. Compound (II), the R C R P isomer, shown in Fig. 1 [triangle](b), is twisted, with the azide curling back towards the phenyl group. The phenyl, –SMe and azide groups are on the same side of the chain, with the sulfur in the –SMe group ca 3.2 Å from the phenyl ring plane. The conformational differences – relaxed and twisted forms – have also been seen previously in other stereoisomers (Bortoluzzi et al., 2004 [triangle]).

Figure 1
The mol­ecular structures of (a) (I) and (b) (II). Displacement ellipsoids are shown at the 30% probability level and H atoms are shown as spheres of arbitrary radii.
Table 1
Selected bond lengths (Å) and torsion angles (°)

Changes in conformation are reflected in the packing of each system. Each phosphine oxide acts as a hydrogen-bond acceptor for the amine group (N8; see Table 2 [triangle]), which generates a strong inter­molecular hydrogen bond linking the mol­ecules into chains parallel to the a axis. The twofold axis in both (I) and (II) dicta­tes the placement of the azide group; however, the conformational differences between the structures result in the azide groups wrapping around each other in (I) and facing each other in (II), both in alternating patterns (see Fig. 2 [triangle]). The inter­molecular distances between the terminal azide N atoms in (I) and (II) are ca 3.5 and 3.2 Å, respectively. In both (I) and (II) there is also a close inter­molecular contact between atom C7 (thio­meth­yl) and an adjacent phenyl group, with a C—H(...)π plane distance of ca 3.5 Å.

Figure 2
The packing of (a) (I) and (b) (II), viewed approximately parallel to the a axis in each case. Cell axes are labeled and H atoms have been omitted for clarity. Hydrogen bonds are drawn with dashed lines.
Table 2
Hydrogen-bond geometry (Å, °)

Two closely related phosphon­amido­thio­ates, both S C S P, namely S-(9-anthracenylmeth­yl) N-(1-phenyl­ethyl)(ethoxy­vinyl)thio­phosphon­amidate (Lee et al., 1992 [triangle]) and (S P,S C)-S-[2-(4-nitro­phen­yl)]-2-oxoethyl N,P-dimethyl-N-(1-phenyl­ethyl)­phosphon­amido­thio­ate (McQueney et al., 1991 [triangle]), have been reported. These mol­ecules have similar bonding patterns to (I) and (II) but have very different inter­molecular inter­actions. The former compound displays a similar hydrogen-bonding synthon (e.g. N(...)O = ca 2.96 Å) and the S atom is ca. 3.5 Å from the phenyl ring substituent, as seen in (I) and (II). The latter compound is much more complex with many hydrogen-bonding inter­actions, unlike (I) or (II).

Experimental

The title compounds were prepared by treating O-methyl (3-azo­prop­yl)thio­phosphonyl chloride (0.49 g, 2.3 mmol) with (R)-(+)-α-methyl­benzyl­amine (1.2 ml, 9.2 mmol). Following chromatography (20% ether/hexane), methyl iodide (10 equivalents) was added and the solution was refluxed for 2 d. The solution was concentrated under reduced pressure to give a crude diastereomeric mixture of (I) and (II) (0.48 g, 1.6 mmol) in 70% yield and a diastereomeric ratio of 50:50. Silica-gel chromatography (1–5% MeOH/CHCl3) separated pure fractions of the two diastereomers, which were subsequently recrystallized successively prior to diffraction analysis using diethyl ether and methanol/diethyl ether, respectively.

Isomer (I) was the faster eluting fraction and was recrystallized from diethyl ether: m.p. 368.7–369.0 K; [α]D 20 = +23.6° (CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.23–7.33 (5H, m), 4.46–4.56 (1H, m), 3.31 (2H, t, J = 6.5 Hz), 3.16 (1H, t, J = 10.2 Hz), 2.17 (3H, d, J = 12.6 Hz), 1.90–1.97 (2H, m), 1.81–1.87 (2H, m), 1.52 (3H, d, J = 6.7 Hz); 31P NMR (161.9 MHz, CDCl3): δ 49.5 (s).

Isomer (II) was collected as the slower eluting fraction and was dissolved in a minimal amount of methanol and crystallized by the slow addition of dieth­yl ether: m.p. 361.7–362.0 K; [α]D 20 = +60.1° (CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.22–7.33 (5H, m), 4.46–4.56 (1H, m), 3.31 (2H, t, J = 6.5 Hz), 3.23 (1H, t, J = 9.1 Hz), 2.16 (3H, d, J = 12.6 Hz), 1.81–1.87 (2H, m), 1.68–1.78 (2H, m), 1.52 (3H, d, J = 6.7 Hz); 31P NMR (161.9 MHz, CDCl3): δ 50.9 (s).

Composition analysis of the racemate [(I)/(II)]: νmax (KBr, cm−1): 2099.25 (–N3); HRMS calculated m/z 299.1095, found m/z 299.1093 (M + H)+; analysis calculated for C12H19N4OPS: C 48.31, H 6.42, N 18.78%; found: C 48.30, H 6.44, N 18.68%.

Compound (I)

Crystal data

  • C12H19N4OPS
  • M r = 298.34
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is c-65-0o179-efi1.jpg
  • a = 5.1896 (2) Å
  • b = 12.1755 (4) Å
  • c = 23.6534 (8) Å
  • V = 1494.56 (9) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.32 mm−1
  • T = 90 K
  • 0.39 × 0.19 × 0.17 mm

Data collection

  • Bruker SMART APEX diffractometer
  • Absorption correction: multi-scan (SADABS; Bruker, 2007 [triangle]) T min = 0.885, T max = 0.947
  • 22210 measured reflections
  • 3437 independent reflections
  • 3317 reflections with I > 2σ(I)
  • R int = 0.030

Refinement

  • R[F 2 > 2σ(F 2)] = 0.027
  • wR(F 2) = 0.065
  • S = 0.99
  • 3437 reflections
  • 178 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.39 e Å−3
  • Δρmin = −0.17 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1418 Friedel pairs
  • Flack parameter: −0.01 (7)

Compound (II)

Crystal data

  • C12H19N4OPS
  • M r = 298.34
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is c-65-0o179-efi1.jpg
  • a = 5.4509 (3) Å
  • b = 12.0987 (6) Å
  • c = 22.2882 (11) Å
  • V = 1469.88 (13) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.33 mm−1
  • T = 90 K
  • 0.48 × 0.08 × 0.05 mm

Data collection

  • Bruker SMART APEX diffractometer
  • Absorption correction: multi-scan (SADABS; Bruker, 2007 [triangle]) T min = 0.859, T max = 0.984
  • 21644 measured reflections
  • 3372 independent reflections
  • 2858 reflections with I > 2σ(I)
  • R int = 0.074

Refinement

  • R[F 2 > 2σ(F 2)] = 0.041
  • wR(F 2) = 0.089
  • S = 1.02
  • 3372 reflections
  • 174 parameters
  • H-atoms treated by a mixture of constrained and independent refinement
  • Δρmax = 0.50 e Å−3
  • Δρmin = −0.24 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1397 Friedel pairs
  • Flack parameter: 0.05 (10)

Atom H8 was located via difference electron-density maps in both (I) and (II), and the positional and displacement parameters were refined freely in (I), while the displacement parameter was initially refined and finally fixed in (II). All other H atoms were placed in idealized positions and refined using a riding model, with U iso(H) values constrained to be 1.2U eq (for CH and CH2 H atoms; C—H = 0.95–1.00 Å) and 1.5U eq (for CH3; C—H = 0.98 Å) of the carrier atom.

For both compounds, data collection: SMART (Bruker, 2006 [triangle]); cell refinement: SAINT-Plus (Bruker, 2006 [triangle]); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: XP in SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: publCIF (Westrip, 2009 [triangle]).

Supplementary Material

Crystal structure: contains datablocks global, I, II. DOI: 10.1107/S0108270109009792/em3024sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S0108270109009792/em3024Isup2.hkl

Structure factors: contains datablocks II. DOI: 10.1107/S0108270109009792/em3024IIsup3.hkl

Acknowledgments

This work was supported by NIEHS UO1 ES016102 and NCRR COBRE RR15583. The diffraction facility was established at the University of Idaho with the assistance of the NSF–EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver, WA, USA.

Footnotes

Supplementary data for this paper are available from the IUCr electronic archives (Reference: EM3024). Services for accessing these data are described at the back of the journal.

References

  • Berkman, C. E., Ryu, S., Quinn, D. A. & Thompson, C. M. (1993). Chem. Res. Toxicol.6, 28–32. [PubMed]
  • Bortoluzzi, A. J., Andrade, E. S. & Nunes, R. J. (2004). Acta Cryst. C60, o614–o616. [PubMed]
  • Bruker (2006). SMART (Version 5.632) and SAINT-Plus (Version 7.23a). Bruker AXS Inc., Madison, Wisconsin, USA.
  • Bruker (2007). SADABS. Version 2007/4. Bruker AXS Inc., Madison, Wisconsin, USA.
  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  • Lee, S.-L., Hepburn, T. W., Swarz, W. H., Ammon, H. L., Mariano, P. S. & Dunaway-Mariano, D. (1992). J. Am. Chem. Soc.114, 7346–7354.
  • McQueney, M. S., Lee, S.-L., Swartz, W. H., Ammon, H. L., Mariano, P. S. & Dunaway-Mariano, D. (1991). J. Org. Chem.56, 7121–7130.
  • Ordentlich, A., Barak, D., Kronman, C., Flashner, Y., Leitner, M., Segall, Y., Ariel, N., Cohen, S., Velan, B. & Shafferman, A. (1993). J. Biol. Chem.268, 17083–17095. [PubMed]
  • Rye, C. S. & Baell, J. B. (2005). Curr. Med. Chem.12, 3127–3141. [PubMed]
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Sussman, J. L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L. & Silman, I. (1991). Science, 253, 872–879. [PubMed]
  • Thompson, C. M., Berkman, C. E., Ryu, S., Jackson, J. A., Quinn, D. A. & Larson, A. (1993). In Reviews in Pesticide Toxicology, Vol. 2, edited by R. M. Roe & R. J. Kuhr. Raleigh: Toxicology Communications.
  • Thompson, C. M., Ryu, S. & Berkman, C. E. (1992). J. Am. Chem. Soc.114, 10710–10715.
  • Westrip, S. P. (2009). publCIF. In preparation.

Articles from Acta Crystallographica Section C: Crystal Structure Communications are provided here courtesy of International Union of Crystallography