N,N′-[(8-endo,11-endo-Dihy­droxy­penta­cyclo­[5.4.0.02,6.03,10.05,9]undecane-8,11-di­yl)bis­(methyl­enecarbon­yl)]di-l-phenyl­alanine

Rajshekhar Karpoormath; Patrick Govender; Hendrik G Kruger; Thavendran Govender; Glenn E M Maguire

doi:10.1107/S1600536810035956

. 2010 Sep 11;66(Pt 10):o2537–o2538. doi: 10.1107/S1600536810035956

N,N′-[(8-endo,11-endo-Dihydroxypentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane-8,11-diyl)bis(methylenecarbonyl)]di-l-phenylalanine

Rajshekhar Karpoormath ^a, Patrick Govender ^b, Hendrik G Kruger ^a, Thavendran Govender ^c, Glenn E M Maguire ^a,^*

PMCID: PMC2983209 PMID: 21587528

Abstract

The title compound, C₃₃H₃₆N₂O₈, is the first example of a disubstituted peptidic pentacycloundecane (PCU) diol. The structure displays an array of inter- and intramolecular hydrogen bonding by both amide and alcohol functional groups. This hydrogen-bonding system connects the molecules into a three-dimensional network.

Related literature

For examples of PCU cage structures which exhibit C—C bond lengths that deviate from the norm, see: Flippen-Anderson et al. (1991 ▶); Linden et al. (2005 ▶); Kruger et al. (2005 ▶, 2006 ▶). For analogous PCU cage structures and their packing, see: Kruger et al. (2006); Boyle et al. (2007a ▶,b ▶); Vasquez et al. (2002 ▶); Anderson et al. (2007 ▶). For different cage crystal structures, see: Bott et al. (1998 ▶).

Experimental

Crystal data

C₃₃H₃₆N₂O₈
M _r = 588.64
Orthorhombic,
a = 10.6230 (5) Å
b = 14.7773 (6) Å
c = 18.2819 (8) Å
V = 2869.9 (2) Å³
Z = 4
Cu Kα radiation
μ = 0.80 mm⁻¹
T = 100 K
0.33 × 0.28 × 0.18 mm

Data collection

Bruker Kappa DUO APEXII diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1997 ▶) T _min = 0.678, T _max = 0.875
17910 measured reflections
4968 independent reflections
4892 reflections with I > 2σ(I)
R _int = 0.018

Refinement

R[F ² > 2σ(F ²)] = 0.032
wR(F ²) = 0.085
S = 1.06
4968 reflections
412 parameters
6 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.63 e Å⁻³
Δρ_min = −0.19 e Å⁻³
Absolute structure: Flack (1983 ▶), 2058 Friedel pairs
Flack parameter: −0.02 (14)

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: X-SEED (Barbour, 2001 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810035956/gw2085sup1.cif

e-66-o2537-sup1.cif^{(30KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810035956/gw2085Isup2.hkl

e-66-o2537-Isup2.hkl^{(243.4KB, hkl)}

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1N⋯O6ⁱ	0.95 (1)	1.90 (1)	2.8399 (18)	172 (2)
N2—H2N⋯O5	0.96 (1)	2.01 (2)	2.7579 (18)	134 (2)
O1—H1O⋯O2	0.96 (1)	1.79 (2)	2.6649 (16)	150 (2)
O5—H5O⋯O1	0.95 (1)	1.58 (1)	2.4886 (16)	158 (3)
O4—H4O⋯O7ⁱⁱ	0.96 (1)	1.84 (2)	2.7425 (18)	154 (2)
O8—H8O⋯O5ⁱⁱⁱ	0.97 (1)	1.68 (1)	2.6501 (17)	177 (3)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

The authors would like to thank Dr Hong Su (The University of Capetown) for the data collection and structure refinement.

supplementary crystallographic information

Comment

The novel compound (I) was synthesized as a part of an ongoing project looking into the biological activity of cage compounds and their derivatives. It can be converted to a diacid and coupled to desired peptides as a potential HIV-1 protease inhibitor. The title compound (I) consists of a large apolar (lipophilic) hydrocarbon skeleton with polar amide and hydroxy units (Fig.1). (I) crystallized with four molecules in the asymmetric unit all of which show shortening and elongation of specific C—C bonds in the cage moiety as observed by previous authors (Flippen-Anderson et al., 1991; Linden et al., 2005; Kruger et al., 2005; Kruger et al., 2006, Boyle et al., 2007a,b). The shortest C—C bond lengths in the cage occur between C1—C7, C1—C2, C4—C5 and C9—C10, with the values ranging between 1.499–1.533 Å. The longest C—C bond length is between C6—C11 with a value of 1.616 (3) Å. This is the first example of a bis-amino acid substituted pentacyloundecane diol reported. We believe it to be the primary example of a PCU diol with aromatic residues positioned close to the cage. As the phenylalanine derivative it is interesting to see that there are no obvious π-stacking contributions to the overall structure. A striking aspect of the structure is its hydrogen bonding arrangements. In previous examples PCU diols were reported as being hydrogen bonded in both intra and intermolecular fashion giving rise to two-dimensional crystal planes (Vasquez et al., 2002). In (I) there are several possibly sites for hydrogen bonding to occur and all of the centers do in fact take an active part. The hydrogen bonding arrangements can be seen in Fig. 2. Intramolecular hydrogen bonding occurs between the amide N(2)–H···O5, the alcohol group O(5)–H···O(1) and the next alcohol O(1)–H···O(2). This is a similar arrangement to that found by Anderson et al., 2007 when three and four alcohol groups respectively were reported. In the case of intermolecular bonding a far more intricate arrangement occurs than previously reported examples. An intermolecular hydrogen bond is generated by the amide group N(1)–H···O(6) (symmetry code; -x + 1, y - 1/2, -z + 1/2). All of the other intermolecular bonds are formed by the carboxylic residues in two distinct arrangements. First, by O(8)–H···O(5) on the PCU cage (symmetry code; -x, y + 1/2, -z + 1/2). Second by O(4)–H···O(7) at the terminals of the two molecules (symmetry code; -x + 1/2, -y + 2, z - 1/2). These interactions create the interlocking arrangements rendering the three dimensional expansion of the structure.

Experimental

A solution of PCU cage diol diacid (0.50 g, 1.7 mmol) in dry DCM (15 ml) was stirred at room temperature for 5 min. To this mixture was added tert-butyl 2-amino-3-phenylpropanoate (1.50 g, 6.8 mmol) and cooled in ice water bath and stirred for 5 min. To the above cooled mixture was added HATU (3.24 g, 8.5 mmol) followed by DIPEA (2.4 ml, 13.6 mmol) as a base. The solution was then slowly brought to room temperature and stirred for 6 h. The crude reaction mixtures was washed with water (100 ml) and then with 10% HCL (100 ml). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄) and filtered. The crude product was evaporated to dryness under vacuum using a teflon pump at 40 °C to obtain thick yellow oil. This crude oily product was further dissolved in DCM and TFA (1:1) solvent mixture and stirred overnight. TFA was removed by bubbling air through the peptide and the remaining DCM was removed under vacuum at 30°C. The product was obtained as a yellow oil which was purified by preparative HPLC and solid phase extraction. Crystallization of the product was carried out by dissolving the pure compound in DCM and TFA (1:1, 3 ml) and was stored at 20 °C. The percentage yield of the pure final compound was 67% (0.67 g).

1H NMR (MeOD, 600 MHz): δH 1.05 (1H, d, J = 10.68), 1.39 (1H, d, J = 10.56), 1.67 (1H, d, J = 8.84 Hz), 1.90 (1H, d, J = 8.88 Hz), 2.20–2.36 (7H, m), 2.45–2.46 (2H, m), 2.91–2.99 (2H, m), 3.24–3.29 (2H, m), 4.69–4.71 (1H, m), 4.77–4.87 (1H, m), 7.13–7.16 (1H, m), 7.21–7.30 (9H, m).

IR (film) v_max: 3261.55 cm^-1, 2957.06 cm^-1, 1758.52 cm^-1, 1638.17 cm^-1, 1522.71 cm^-1, 1191.53 cm^-1, 758.74 cm^-1, 701.36 cm^-1, 489.06 cm^-1.

Melting point: 414–415 K. HR ESI m/z: Calc. for C33H36N2O8: [M+H]+ m/z 589.2544. Found: [M+H]+ m/z 589.2541.