8-Hydr­oxy-3,4,5-trimethyl-6-oxo-2,3,4,6-tetra­hydro­isoquinoline-7-carboxylic acid

In the natural product title compound, C₁₃H₁₅NO₄, intra­molecular O—H...O hydrogen bonds help to establish the conformation.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.008 Å
• R factor = 0.068
• wR factor = 0.231
• Data-to-parameter ratio = 8.1

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT111_ALERT_2_B ADDSYM Detects (Pseudo) Centre of Symmetry .....         94 PerFi

Alert level C
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical .          ?
PLAT113_ALERT_2_C ADDSYM Suggests Possible Pseudo/New Spacegroup .       Pnma
PLAT230_ALERT_2_C Hirshfeld Test Diff for    N1     -   C5      ..       5.32 su
PLAT340_ALERT_3_C Low Bond Precision on C-C Bonds (x 1000) Ang ...          8
PLAT420_ALERT_2_C D-H Without Acceptor       N1     -   H1A    ...          ?

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           26.00
           From the CIF: _reflns_number_total               1370
           Count of symmetry unique reflns         1372
           Completeness (_total/calc)             99.85%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no
PLAT199_ALERT_1_G Check the Reported _cell_measurement_temperature        293 K
PLAT200_ALERT_1_G Check the Reported _diffrn_ambient_temperature .        293 K
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C5     = .          S
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C10    = .          R

   0 ALERT level A = In general: serious problem
   1 ALERT level B = Potentially serious problem
   5 ALERT level C = Check and explain
   5 ALERT level G = General alerts; check

   5 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   4 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

---

S1. Comment

The title compound, (I) (Fig. 1), was isolated from the endophytic fungus Aspergillus terreus (Jiao et al., 2006; Shen et al., 2006).

There exist strong intramolecular hydrogen bonds (Table 1) between the hydroxyl group, carbonyl group and the neighboring carboxyl group. Conversely, the N—H group does not participate in an H bonding interaction.

Related literature

For background, see: Jiao et al. (2006); Shen et al. (2006).

S2. Experimental

The endophytic fungus Aspergillus terreus was cultured in modified Czapedox media at 298 K for 4 days. The fermentation broth (40 l) was extracted three times with an equal volume of ethyl acetate. The extract was concentrated in vacuo to give a dark brown residue (15 g). The extract was divided into three fractions by column chromatography on silica gel (gradient of chloroform and acetone from 1:0 to 0:1). Fraction 2 (3.1 g) was rechromatographed on silica gel CC (chloroform–acetone from 1:0 to 0:1) to give 3 fractions. Fraction 2–1 (0.6 g) was then subjected to gel filtration on Sephadex LH-20 with chloroform/acetone (1:1 v/v), followed by recrystallization in methanol to give colourless prisms of (I) (12 mg).

S3. Refinement

Amonalous dispersion was negligible and Friedel pairs were merged before refinement. The H atoms were geometrically placed (C—H = 0.96 Å, N—H = 0.86 Å, O—H = 0.82 Å) and refined as riding with U_iso(H) = 1.2U_eq(C) or 1.5U_eq(N, O).

Computing details

Data collection: SMART (Siemens, 1996); cell refinement: SMART (Siemens, 1996); data reduction: SAINT (Siemens, 1996); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997a); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997a); molecular graphics: SHELXTL (Sheldrick, 1997b); software used to prepare material for publication: SHELXTL (Sheldrick, 1997b).

Figures

Fig. 1. The molecular structure of (I), showing 30% probability displacement ellipsoids (arbitrary spheres for the H atoms). The H bonds are shown as double-dashed lines.

8-Hydroxy-3,4,5-trimethyl-6-oxo-2,3,4,6-tetrahydroisoquinoline-7-carboxylic acid

Crystal data

C13H15NO4	F(000) = 528
Mr = 249.26	Dx = 1.383 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 1842 reflections
a = 7.287 (1) Å	θ = 3.9–26.1°
b = 12.228 (2) Å	µ = 0.10 mm^−1
c = 13.431 (2) Å	T = 293 K
V = 1196.8 (3) Å^3	Prism, colourless
Z = 4	0.33 × 0.26 × 0.20 mm

Data collection

Bruker APEX CCD diffractometer	1370 independent reflections
Radiation source: fine-focus sealed tube	908 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.062
φ and ω scans	θmax = 26.0°, θmin = 3.0°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −8→0
Tmin = 0.967, Tmax = 0.980	k = −15→0
2616 measured reflections	l = −16→16

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.068	H-atom parameters constrained
wR(F^2) = 0.231	w = 1/[σ^2(Fo^2) + (0.122P)^2 + 0.2523P] where P = (Fo^2 + 2Fc^2)/3
S = 1.13	(Δ/σ)max < 0.001
1370 reflections	Δρmax = 0.23 e Å^−3
169 parameters	Δρmin = −0.27 e Å^−3
0 restraints	Extinction correction: SHELXTL (Sheldrick, 1997b), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.049 (10)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
O1	0.2486 (9)	0.0956 (5)	0.5965 (3)	0.0960 (17)
O2	0.2630 (9)	0.4173 (4)	0.5363 (3)	0.0953 (17)
O3	0.2521 (10)	0.2633 (5)	0.6536 (3)	0.0976 (17)
H3	0.2547	0.3259	0.6317	0.146*
O4	0.2366 (9)	0.0607 (3)	0.4115 (3)	0.0792 (14)
H4	0.2415	0.0459	0.4710	0.119*
N1	0.2007 (6)	0.1738 (4)	0.1281 (3)	0.0496 (12)
H1A	0.2084	0.1284	0.0794	0.060*
C1	0.2474 (10)	0.1954 (6)	0.5811 (4)	0.0717 (17)
C2	0.2599 (10)	0.3531 (5)	0.4628 (4)	0.0603 (14)
C3	0.2923 (12)	0.5152 (5)	0.3514 (6)	0.093 (3)
H3A	0.3051	0.5334	0.2822	0.140*
H3B	0.4002	0.5379	0.3869	0.140*
H3C	0.1870	0.5519	0.3783	0.140*
C4	−0.0359 (8)	0.3097 (7)	0.1240 (5)	0.080 (2)
H4A	−0.0711	0.2932	0.1913	0.120*
H4B	−0.1044	0.2645	0.0789	0.120*
H4C	−0.0611	0.3853	0.1102	0.120*
C5	0.1633 (8)	0.2883 (6)	0.1112 (4)	0.0622 (16)
H5	0.1943	0.3044	0.0418	0.075*
C6	0.2512 (9)	0.2392 (4)	0.4798 (3)	0.0488 (12)
C7	0.4873 (9)	0.3503 (6)	0.1487 (6)	0.082 (2)
H7A	0.5242	0.2750	0.1509	0.122*
H7B	0.5596	0.3918	0.1949	0.122*
H7C	0.5055	0.3783	0.0826	0.122*
C8	0.2225 (8)	0.1417 (4)	0.2208 (4)	0.0537 (14)
H8	0.2251	0.0669	0.2335	0.064*
C9	0.2687 (9)	0.3954 (4)	0.3621 (4)	0.0581 (14)
C10	0.2846 (8)	0.3595 (4)	0.1765 (4)	0.0544 (15)
H10	0.2463	0.4359	0.1690	0.065*
C11	0.2446 (9)	0.1666 (4)	0.3999 (4)	0.0497 (12)
C12	0.2417 (7)	0.2116 (4)	0.3000 (3)	0.0449 (11)
C13	0.2605 (8)	0.3260 (4)	0.2858 (3)	0.0493 (12)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.115 (4)	0.100 (4)	0.073 (3)	0.007 (4)	0.002 (4)	0.037 (3)
O2	0.122 (4)	0.098 (3)	0.066 (3)	0.004 (4)	−0.007 (3)	−0.034 (3)
O3	0.123 (4)	0.120 (4)	0.050 (2)	−0.003 (5)	−0.007 (3)	−0.004 (2)
O4	0.109 (4)	0.060 (2)	0.069 (2)	−0.011 (3)	0.003 (3)	0.0073 (19)
N1	0.061 (3)	0.056 (2)	0.032 (2)	0.009 (2)	−0.0030 (18)	−0.0085 (19)
C1	0.060 (4)	0.095 (5)	0.060 (3)	0.009 (5)	0.000 (4)	0.000 (3)
C2	0.053 (3)	0.067 (3)	0.061 (3)	−0.001 (4)	−0.007 (3)	−0.011 (3)
C3	0.130 (7)	0.044 (3)	0.105 (5)	−0.011 (4)	−0.009 (6)	0.000 (3)
C4	0.050 (3)	0.119 (6)	0.072 (4)	0.010 (4)	−0.009 (3)	0.011 (5)
C5	0.057 (3)	0.085 (4)	0.044 (3)	0.009 (3)	0.003 (3)	0.011 (3)
C6	0.047 (3)	0.056 (3)	0.044 (3)	0.000 (3)	−0.002 (3)	−0.002 (2)
C7	0.072 (4)	0.099 (5)	0.074 (4)	−0.020 (4)	0.008 (3)	0.025 (4)
C8	0.068 (4)	0.037 (2)	0.057 (3)	0.001 (3)	−0.003 (3)	−0.001 (2)
C9	0.070 (4)	0.042 (3)	0.063 (3)	−0.006 (3)	−0.005 (3)	0.000 (2)
C10	0.061 (4)	0.044 (3)	0.059 (3)	−0.004 (3)	−0.002 (3)	0.015 (2)
C11	0.050 (3)	0.046 (2)	0.053 (2)	0.001 (3)	−0.002 (3)	0.007 (2)
C12	0.040 (2)	0.042 (2)	0.053 (3)	−0.001 (3)	0.001 (3)	0.000 (2)
C13	0.042 (3)	0.050 (3)	0.056 (3)	0.002 (3)	0.001 (3)	0.010 (2)

Geometric parameters (Å, º)

O1—C1	1.238 (9)	C4—H4A	0.9600
O2—C2	1.262 (7)	C4—H4B	0.9600
O3—C1	1.280 (8)	C4—H4C	0.9600
O3—H3	0.8200	C5—C10	1.519 (8)
O4—C11	1.305 (6)	C5—H5	0.9800
O4—H4	0.8200	C6—C11	1.394 (7)
N1—C8	1.316 (6)	C7—C10	1.527 (9)
N1—C5	1.445 (8)	C7—H7A	0.9600
N1—H1A	0.8600	C7—H7B	0.9600
C1—C6	1.462 (8)	C7—H7C	0.9600
C2—C6	1.413 (8)	C8—C12	1.372 (7)
C2—C9	1.450 (8)	C8—H8	0.9300
C3—C9	1.482 (8)	C9—C13	1.331 (7)
C3—H3A	0.9600	C10—C13	1.534 (7)
C3—H3B	0.9600	C10—H10	0.9800
C3—H3C	0.9600	C11—C12	1.451 (7)
C4—C5	1.485 (8)	C12—C13	1.419 (7)
C1—O3—H3	109.5	C11—C6—C1	118.8 (5)
C11—O4—H4	109.5	C2—C6—C1	120.8 (5)
C8—N1—C5	117.4 (4)	C10—C7—H7A	109.5
C8—N1—H1A	121.3	C10—C7—H7B	109.5
C5—N1—H1A	121.3	H7A—C7—H7B	109.5
O1—C1—O3	120.8 (6)	C10—C7—H7C	109.5
O1—C1—C6	121.1 (6)	H7A—C7—H7C	109.5
O3—C1—C6	118.0 (6)	H7B—C7—H7C	109.5
O2—C2—C6	119.2 (5)	N1—C8—C12	124.1 (5)
O2—C2—C9	120.5 (5)	N1—C8—H8	118.0
C6—C2—C9	120.3 (5)	C12—C8—H8	118.0
C9—C3—H3A	109.5	C13—C9—C2	119.2 (5)
C9—C3—H3B	109.5	C13—C9—C3	124.1 (6)
H3A—C3—H3B	109.5	C2—C9—C3	116.6 (5)
C9—C3—H3C	109.5	C5—C10—C7	112.3 (5)
H3A—C3—H3C	109.5	C5—C10—C13	109.4 (4)
H3B—C3—H3C	109.5	C7—C10—C13	109.0 (5)
C5—C4—H4A	109.5	C5—C10—H10	108.7
C5—C4—H4B	109.5	C7—C10—H10	108.7
H4A—C4—H4B	109.5	C13—C10—H10	108.7
C5—C4—H4C	109.5	O4—C11—C6	122.8 (5)
H4A—C4—H4C	109.5	O4—C11—C12	119.1 (4)
H4B—C4—H4C	109.5	C6—C11—C12	118.1 (4)
N1—C5—C4	109.7 (6)	C8—C12—C13	121.3 (4)
N1—C5—C10	110.8 (4)	C8—C12—C11	118.8 (4)
C4—C5—C10	113.7 (6)	C13—C12—C11	119.8 (4)
N1—C5—H5	107.5	C9—C13—C12	121.9 (4)
C4—C5—H5	107.5	C9—C13—C10	124.1 (5)
C10—C5—H5	107.5	C12—C13—C10	113.8 (4)
C11—C6—C2	120.3 (4)
C8—N1—C5—C4	−83.5 (7)	C2—C6—C11—C12	−1.7 (9)
C8—N1—C5—C10	42.7 (7)	C1—C6—C11—C12	177.8 (6)
O2—C2—C6—C11	178.9 (6)	N1—C8—C12—C13	−7.4 (10)
C9—C2—C6—C11	−2.2 (10)	N1—C8—C12—C11	173.3 (6)
O2—C2—C6—C1	−0.5 (11)	O4—C11—C12—C8	2.8 (9)
C9—C2—C6—C1	178.3 (6)	C6—C11—C12—C8	−175.6 (6)
O1—C1—C6—C11	4.0 (11)	O4—C11—C12—C13	−176.5 (6)
O3—C1—C6—C11	−179.4 (7)	C6—C11—C12—C13	5.0 (8)
O1—C1—C6—C2	−176.5 (7)	C2—C9—C13—C12	0.6 (10)
O3—C1—C6—C2	0.0 (11)	C3—C9—C13—C12	178.6 (7)
C5—N1—C8—C12	−11.1 (9)	C2—C9—C13—C10	−174.6 (6)
O2—C2—C9—C13	−178.3 (7)	C3—C9—C13—C10	3.4 (11)
C6—C2—C9—C13	2.9 (10)	C8—C12—C13—C9	176.1 (6)
O2—C2—C9—C3	3.5 (10)	C11—C12—C13—C9	−4.6 (9)
C6—C2—C9—C3	−175.3 (7)	C8—C12—C13—C10	−8.3 (8)
N1—C5—C10—C7	66.1 (6)	C11—C12—C13—C10	171.1 (5)
C4—C5—C10—C7	−169.8 (5)	C5—C10—C13—C9	−146.2 (6)
N1—C5—C10—C13	−55.1 (6)	C7—C10—C13—C9	90.7 (7)
C4—C5—C10—C13	69.0 (7)	C5—C10—C13—C12	38.3 (7)
C2—C6—C11—O4	180.0 (6)	C7—C10—C13—C12	−84.9 (6)
C1—C6—C11—O4	−0.6 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O1	0.82	1.79	2.522 (6)	147
O3—H3···O2	0.82	1.70	2.456 (7)	152