A functionalized enol lactone containing a protected α-amino acid

Giuseppe Bruno; Francesco Nicoló; Massimiliano Cordaro; Giovanni Grassi; Francesco Risitano

doi:10.1107/S1600536810043709

. 2010 Nov 30;66(Pt 12):o3356. doi: 10.1107/S1600536810043709

A functionalized enol lactone containing a protected α-amino acid

Giuseppe Bruno ^a, Francesco Nicoló ^a,^*, Massimiliano Cordaro ^b, Giovanni Grassi ^b, Francesco Risitano ^b

PMCID: PMC3011768 PMID: 21589625

Abstract

The crystal structure of N-(3,9-dimethyl-4-phenyl-2,5-dioxo-3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-3-yl)-N-methylbenzamide methanol monosolvate, C₂₈H₂₃NO₅·CH₃OH, has been determined at room temperature by X-ray diffraction. Structural parameters are discussed with reference to ab initio calculations.

Related literature

For structures containing enol lactone fragments, see: Murray et al. (1982 ▶); Harborne & Baxter (1999 ▶); Qabaja et al. (2000 ▶). For related structures containing a coumarin fragment, see: Yu et al. (2003 ▶). For a phenylfuro[3,2-c]chromen-4-one structure, see: Bruno et al. (2001 ▶). For related furan-5-one structures, see: Grassi et al. (2002 ▶). For the Cambridge Structural Database, see: Allen (2002 ▶). For the GAUSSIAN98 software used for the ab initio calculations, see: Frisch et al. (1998 ▶). For the synthetic process used, see: Grassi et al. (2003 ▶). For background to O—C—O bond-angle asymmetry, see: Kokila et al. (1996 ▶).

Experimental

Crystal data

C₂₈H₂₃NO₅·CH₄O
M _r = 485.52
Monoclinic,
a = 10.7435 (14) Å
b = 9.9056 (17) Å
c = 23.298 (3) Å
β = 94.817 (7)°
V = 2470.7 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 298 K
0.58 × 0.38 × 0.36 mm

Data collection

Siemens P4 diffractometer
Absorption correction: ψ scan (Kopfmann & Huber, 1968 ▶) T _min = 0.870, T _max = 0.968
9535 measured reflections
4347 independent reflections
2843 reflections with I > 2σ(I)
R _int = 0.036
3 standard reflections every 197 reflections intensity decay: none

Refinement

R[F ² > 2σ(F ²)] = 0.049
wR(F ²) = 0.132
S = 1.01
4347 reflections
331 parameters
H-atom parameters constrained
Δρ_max = 0.18 e Å⁻³
Δρ_min = −0.31 e Å⁻³

Data collection: XSCANS (Bruker, 1999 ▶); cell refinement: XSCANS; data reduction: SHELXTL (Sheldrick, 2008 ▶); program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XPW (Siemens, 1996 ▶); software used to prepare material for publication: PARST97 (Nardelli, 1995 ▶) and SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810043709/jh2217sup1.cif

e-66-o3356-sup1.cif^{(26.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810043709/jh2217Isup2.hkl

e-66-o3356-Isup2.hkl^{(208.7KB, 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
O35—H35⋯O27	0.82	1.99	2.784 (3)	163
C9—H9⋯O35ⁱ	0.93	2.46	3.320 (4)	153
C19—H19⋯O11ⁱⁱ	0.93	2.60	3.403 (3)	144

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

supplementary crystallographic information

Comment

Highly functionalized enol lactones constitute an attractive class of compounds not only because of their molecular architecture but also because of the interesting biopharmacological activity often shown by compounds possessing this subunit in their molecular skeleton (Murray et al., 1982; Harborne & Baxter, 1999; Qabaja et al., 2000).

The molecule 3 is mainly constituted by a cumarine system which is further [3,2-c]-fused with a 3,4-dihydro-pyran-2-one ring carrying at posistion 3 a methyl and a methyllbenzamide group while a phenyl moiety is placed at 4. Then these C atoms at 3 and 4 are chiral centers showing the same configuration. Due to the P2₁/n centric space group, both the S,R and R,S diastereomers are present in the solid state and the crystals represent a perfect racemic mixture. The methyl cumarin fragment is planar within experimental error; bonds distances and angles of this moiety are in good agreement with the corresponding values reported for such fragments (Yu et al., 2003). The methylbenzamide fragment is not planar and shows the usual bond geometry values: the phenyl ring is rotated by 60.9 (3)° with respect to the amide moiety. The three carbonyl groups have very different C═O bond distances and their O atoms are involved in several intra- and intermolecular hydrogen interactions. The significant elongation of C(26)—O(27) bond might be related to the strongest hydrogen interaction of its O atom with the co-crystallized methanol molecule: O(27)···H(35) and O(27)···O(35) are 1.99 and 2.784 (3) Å, respectively, while O(35)—H(35)···O(27) is 163°. The sum of the valence angles around N(24) is 357.7 (2)° and evidences the not significant pyramidalization of the nitrogen. Therefore the nitrogen geometry appears planar and might be related to its sp² hybridization caused by the delocalization of its lone-pair over the carbonyl fragments as also suggested by the length of the bonds involving the N(24) atom. Phenyl group bonded to C(26) is rotated with respect to this system (the N(24)—C(26)—C(28)—C(29) torsion angle is 60.5 (3)°) and does not participate to the possible π-electronic delocalization as evidenced by the C(28)—C(26) single-bond length value [1.491 (3) Å]. In the crystal lattice, each pair of molecules related by an inversion centre shows a π-interaction of 3.4 (1) Å between their planar furo[3,2-c]coumarin fragments. The substituent phenyl rings, despite their out-of-plane rotation, are directed far from the flat central molecular bulk and do not obstacle the strong π-stacking in the formation of the centrosymmetric couple, remaing at its surface as the co-crystallized methanol. Therefore crystal packing is constituted by dimeric units interconnected by several weak hydrogen bonds involving the O atoms.

Here, as well as already found in the phenyl-furo[3,2-c]chromen-4-one (Bruno et al., 2001) and in other related coumarin compounds reported in the October 2004 (Version 5.27) release of CSD (Allen, 2002), an important asymmetry in the O—C—O bond angles has been detected [β = O(1)—C(2)—O(11), 117.4 (2)° and α = C(3)—C(2)—O(11), 125.1 (2)°] Δ(α-β) = 7.7 (2)°. Even more similar significant differences have been observed in other molecules containing the furan-5-one fragment, as we have already reported (Grassi et al., 2002).

Ab initio and DFT calculations on some models have been performed in order to clarify the relevant observed asymmetry in the O—C—O bond angles of the cumarinic fragment. From these results we can conclude that the observed and calculated carbonyl distortion arises exclusively from electronic rather than steric factors. However further statistical and theoretical study are necessary to better clarify the real nature of this asymmetry.

Experimental

Fig. 2.

We recently described a novel kind of cyclo-condensation process that converts two equivalents of a münchnone and a 1,3-dicarbonyl compound into a functionalized enol lactone containing a protected α-amino acid (Grassi et al., 2003). Here we report structural characterization of the enol lactone 3 synthesized by 4,5-dimethyl-2-phenyl-1,3-oxazolium-5-late (DMPO) 2 and 4-hydroxy-6-methylcoumarin 1 (an unsymmetrical enolisable dicarbonyl substrate). Single crystals of 3 suitable for X-ray analysis were obtained by slow evaporation from a methanole solution.

In trying to get some insight regarding this important asymmetry in the O—C—O bond angle of the cumarinic fragment an ab initio and DFT calculations on some model compounds, such as the bicyclic 3,4-dyhidro-pyrano[4,3-b]pyran-2,5-dione, a series of 3-substituted pyran-2-one, the cumarine and 3-methyl-cumarine, were performed by using the basis set 6-31+G(d,p) in GAUSSIAN98 (Frisch et al., 1998). At all level of calculations this controversial asymmetry (Kokila et al., 1996) around carbonilic C atom is consistent with the X-ray structural observations.