3-[(R)-3,3-Dichloro-2-hydroxy­prop­yl]-8-hydr­oxy-6-meth­oxy-1H-isochromen-1-one

The title compound, C₁₃H₁₂Cl₂O₅, is an isocoumarin compound which has been isolated from the ethyl acetate extract of the fermentation broth of actinomycete Streptomyces sp. (V₄) from the South China Sea. There are intra- and inter­molecular hydrogen bonds and halogen bonds [Cl...Cl = 3.434 (2) Å; C—Cl...Cl = 121.6°]. The intermolecular O—H...O hydrogen bonds link mol­ecules into chains along the b axis.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.035
• wR factor = 0.096
• Data-to-parameter ratio = 13.7

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT115_ALERT_5_B ADDSYM Detects Noncrystallographic Inversion ...         95 PerFi

Alert level C
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for        C12
PLAT152_ALERT_1_C Supplied and Calc Volume s.u. Inconsistent .....          ?

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           27.06
           From the CIF: _reflns_number_total               2524
           Count of symmetry unique reflns         1593
           Completeness (_total/calc)            158.44%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured       931
           Fraction of Friedel pairs measured     0.584
           Are heavy atom types Z>Si present        yes
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_4_G Confirm the Absolute Configuration of C11    ...          R

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

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

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S1. Comment

As a kind of natural products from marine microorganisms, 3-((R)-3,3-dichloro-2-hydroxypropyl)-8-hydroxy-6-methoxy-1H- isochromen-1-one, is a isocoumarin-related dihydrodiaportin compound, from the fermentation broth of actinomycetes Streptomyces sp. (V4). In the primary biotest, the title compound showed weak activity inhibiting AchE in vitro (IC₅₀ = 3.9 uM/ml).

Larsen et al. also reported dichlorodiaportin (Larsen & Breinholt, 1999), but it was isolated from quite different microorganism, the typical cheese-associated isolates of Penicillium nalgiovense, and its structure was only elucidated based on spectral analysis, and the absolute configuration was depicted S by comparison with the optical rotation of those reported for several analogues of known absolute configuration. However, according to the optical rotation and our crystal structure, it is clear that Larsen's compound is the same compound as our dichlorodiaportin.

We report here the crystal structure of (I). Compound (I) crystallizes in space group P 2₁, and the 8-hydroxy-isochromen-1-one core rings in (I) is a planar conjugated ring system (Fig.1). In the crystal structure, there is an intra- molecular hydrogen bond [O···O = 2.624 (2) Å, and O—H···O = 144.6°] of O—H···O type between O3 and O5 hyroxyl groups in (I), and adjacent molecules form an infinite one-dimensional chain along b axis via O—H···O intermolecular hydrogen bonds [O···O = 2.913 (3)Å, and O—H···O = 149.0°] between the O3 and O5 hydroxyl groups (Fig.1 and Table 2).

Related literature

For related literature, see: Larsen & Breinholt (1999).

S2. Experimental

A strain of streptomyces sp. (V₄) was isolated from the South China Sea, has been deposited in the School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, P. R. China.

Culture conditions: soluble starch 10 g l^-1, Ca carbonate 2 g l^-1, ammorium sulfate 2 g l^-1, dipotassium hydrogen phosphate 1 g l^-1, magnesium sulfate hydrated 1 g l^-1, sodium chloride 1 g l^-1, yeast extract 10 g l^-1, pH 7.2 and incubation at 298 K for 6 d. For the extraction and separation of the metabolite, the cultures (100 L) of (I) were filtered through cheesecloth. The filtrate was concentrated to 5L below 323 K, then extracted three times by shaking with an equal volume of ethyl acetate. The extract was evaporated under reduced pressure. The combined organic extracts were subjected to silica-gel column chromatography, eluting with petroleum ether/ethyl (1:1 v/v) acetate, to yield (I).

Colorless block crystals of (I) were obtained by evaporation of a methanol solution.

The compound identity was confirmed by NMR spectroscopy, Elemental Analysis, IR, FAB-MS, melting point and optical rotation.

¹H-NMR in CDCl₃ (500 MHz): 6.59 (s, 1H), 6,57 (d, J = 2.0 1H), 3.01 (m, 1H), 2.95 (m, 1H), 4.42 (m, 1H), 6.20 (d, J = 3.0 1H), 3.92 (s, 3H), 11.10 (s, OH) and 5.20 (d, J = 6.0, OH).

¹³C-NMR in CDCl₃ (125 MHz): 166.8 (C), 154 (C), 107.4 (CH), 140.4 (C), 102.1 (CH), 168.0 (C), 101.2 (CH), 164.3 (C), 111.4 (C), 37.3 (CH₂), 73.1 (CH), 77.2 (CH) and 56.3 (CH₃).

Elemental Analysis: C 48.91, H 3.97, calc. (for C₁₃H₁₂O₅C_l2): C 48.93, H 3.79%.

IR (KBr): 3474, 3032, 2986, 1693, 1643, 1568, 1465, 1356, 1237, 1197, 1096, 853, 790, 690.

FAB-MS: 319 [M]⁺, 321 [M+2]⁺, 235 [M-CHCl₂]⁺, 107, 77.

M.p. 419–420 K.

[α]²⁰_D = +7.8 (c = 0.05, MeOH).

S3. Refinement

The H atoms were positioned geometrically and were treated as riding on their parent C atoms, with C—H distances in the range of 0.93–0.98 Å, with U_iso (H) = 1.2–1.5 times U_eq of the parent atom. H atoms attached to O3 and O5 (hydroxyl oxygen atoms) were located in difference Fourier maps and refined initially with distance restraints of 0.82 Å with U_iso (H) = 1.5 times U_eq (O).

Computing details

Data collection: SMART (Bruker, 1999); cell refinement: SMART (Bruker, 1999); data reduction: SAINT (Bruker, 1999); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures

	Fig. 1. View of the molecules in the asymmetric unit of (I), with anisotropic displacement parameters drawn at the 50% probability level.
	Fig. 2. A view of the hydrogen-bonded molecular chains (Dashed lines). The chains are aligned parallel to the crystallographic b axis. H atoms not involved in H-bonding have been omitted for clarity. Symmetry codes: (I) 1 - x,y - 1/2,-z; (II) 1 - x,1/2 + y,-z.
	Fig. 3. Supplementary figure.

3-[(R)-3,3-Dichloro-2-hydroxypropyl]-8-hydroxy-6-methoxy-1H-isochromen-1-one

Crystal data

C13H12Cl2O5	F(000) = 328
Mr = 319.13	Dx = 1.589 Mg m^−3
Monoclinic, P21	Melting point: 420 K
Hall symbol: P 2yb	Mo Kα radiation, λ = 0.71073 Å
a = 9.483 (3) Å	Cell parameters from 1002 reflections
b = 6.757 (2) Å	θ = 2.7–27.0°
c = 10.548 (3) Å	µ = 0.50 mm^−1
β = 99.217 (5)°	T = 293 K
V = 667.1 (4) Å^3	Block, colorless
Z = 2	0.50 × 0.34 × 0.21 mm

Data collection

Bruker SMART 1K area-detector diffractometer	2524 independent reflections
Radiation source: fine-focus sealed tube	2320 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.019
ϕ and ω scans	θmax = 27.1°, θmin = 2.0°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −12→11
Tmin = 0.787, Tmax = 0.902	k = −8→7
4190 measured reflections	l = −13→11

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.035	H-atom parameters constrained
wR(F^2) = 0.095	w = 1/[σ^2(Fo^2) + (0.0525P)^2 + 0.1606P] where P = (Fo^2 + 2Fc^2)/3
S = 1.07	(Δ/σ)max < 0.001
2524 reflections	Δρmax = 0.26 e Å^−3
184 parameters	Δρmin = −0.39 e Å^−3
1 restraint	Absolute structure: Flack (1983), 931 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.06 (8)

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
C1	0.54937 (19)	0.4698 (4)	−0.06308 (18)	0.0334 (4)
C2	0.55042 (19)	0.4661 (4)	0.07326 (17)	0.0317 (4)
C3	0.6821 (2)	0.4688 (4)	0.15853 (18)	0.0356 (4)
C4	0.6830 (2)	0.4614 (4)	0.28857 (19)	0.0387 (4)
H4	0.7694	0.4607	0.3446	0.046*
C5	0.5540 (2)	0.4548 (4)	0.33695 (18)	0.0361 (4)
C6	0.4234 (2)	0.4543 (4)	0.25529 (18)	0.0369 (4)
H6	0.3383	0.4501	0.2884	0.044*
C7	0.42213 (19)	0.4602 (4)	0.12326 (17)	0.0332 (4)
C8	0.29092 (19)	0.4610 (4)	0.03216 (18)	0.0358 (4)
H8	0.2038	0.4583	0.0619	0.043*
C9	0.29283 (18)	0.4657 (4)	−0.09298 (17)	0.0332 (4)
C10	0.17165 (19)	0.4676 (5)	−0.20293 (17)	0.0356 (4)
H10A	0.1783	0.3505	−0.2548	0.043*
H10B	0.1821	0.5820	−0.2562	0.043*
C11	0.02418 (19)	0.4735 (5)	−0.16418 (17)	0.0393 (5)
H11	0.0161	0.3586	−0.1091	0.047*
C12	−0.0964 (2)	0.4600 (5)	−0.2789 (2)	0.0471 (5)
H12	−0.1876	0.4740	−0.2473	0.057*
C13	0.4413 (3)	0.4492 (5)	0.5247 (2)	0.0502 (5)
H13A	0.3875	0.5677	0.5015	0.075*
H13B	0.4673	0.4429	0.6163	0.075*
H13C	0.3843	0.3359	0.4950	0.075*
Cl1	−0.08373 (8)	0.65243 (17)	−0.39091 (7)	0.0803 (3)
Cl2	−0.09425 (9)	0.22660 (16)	−0.35406 (9)	0.0829 (3)
O1	0.42041 (13)	0.4685 (3)	−0.14183 (12)	0.0349 (3)
O2	0.65509 (15)	0.4724 (3)	−0.11589 (14)	0.0452 (4)
O3	0.80850 (14)	0.4768 (3)	0.11445 (14)	0.0459 (4)
H3	0.7939	0.4940	0.0365	0.069*
O4	0.56832 (17)	0.4506 (3)	0.46640 (14)	0.0463 (4)
O5	0.00051 (18)	0.6449 (3)	−0.09336 (15)	0.0524 (5)
H5	0.0323	0.7420	−0.1259	0.079*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0317 (8)	0.0335 (10)	0.0355 (9)	0.0005 (10)	0.0067 (7)	−0.0017 (10)
C2	0.0315 (8)	0.0309 (9)	0.0325 (9)	0.0027 (10)	0.0044 (7)	0.0009 (9)
C3	0.0321 (9)	0.0324 (10)	0.0414 (10)	0.0010 (11)	0.0034 (7)	−0.0001 (10)
C4	0.0363 (9)	0.0401 (10)	0.0367 (10)	0.0003 (11)	−0.0033 (7)	−0.0017 (11)
C5	0.0442 (10)	0.0323 (10)	0.0305 (9)	−0.0006 (11)	0.0016 (7)	−0.0008 (10)
C6	0.0364 (9)	0.0434 (11)	0.0316 (9)	0.0011 (11)	0.0072 (7)	0.0010 (10)
C7	0.0323 (9)	0.0363 (10)	0.0309 (9)	−0.0008 (11)	0.0046 (7)	−0.0008 (10)
C8	0.0287 (8)	0.0461 (11)	0.0330 (9)	0.0007 (11)	0.0067 (7)	0.0016 (11)
C9	0.0297 (8)	0.0352 (10)	0.0354 (9)	−0.0024 (10)	0.0070 (7)	−0.0031 (10)
C10	0.0330 (8)	0.0470 (11)	0.0271 (8)	0.0013 (11)	0.0058 (6)	−0.0018 (10)
C11	0.0333 (9)	0.0568 (13)	0.0281 (9)	−0.0076 (11)	0.0060 (7)	−0.0016 (11)
C12	0.0311 (9)	0.0760 (16)	0.0349 (10)	−0.0087 (14)	0.0074 (7)	−0.0079 (13)
C13	0.0613 (13)	0.0601 (15)	0.0300 (10)	0.0009 (15)	0.0095 (9)	0.0023 (11)
Cl1	0.0525 (4)	0.1251 (9)	0.0574 (4)	−0.0046 (4)	−0.0090 (3)	0.0333 (5)
Cl2	0.0561 (4)	0.1063 (7)	0.0842 (5)	−0.0205 (4)	0.0046 (4)	−0.0486 (5)
O1	0.0296 (6)	0.0467 (8)	0.0291 (6)	0.0006 (8)	0.0062 (5)	−0.0002 (7)
O2	0.0332 (7)	0.0632 (10)	0.0413 (7)	0.0014 (9)	0.0126 (6)	0.0000 (9)
O3	0.0313 (6)	0.0623 (10)	0.0434 (8)	0.0011 (9)	0.0038 (5)	0.0036 (9)
O4	0.0511 (8)	0.0562 (9)	0.0298 (7)	0.0021 (10)	0.0011 (6)	0.0012 (8)
O5	0.0412 (8)	0.0737 (13)	0.0441 (8)	0.0008 (9)	0.0120 (6)	−0.0175 (9)

Geometric parameters (Å, º)

C1—O2	1.223 (2)	C9—C10	1.496 (2)
C1—O1	1.364 (2)	C10—C11	1.519 (2)
C1—C2	1.437 (3)	C10—H10A	0.9700
C2—C7	1.402 (2)	C10—H10B	0.9700
C2—C3	1.417 (2)	C11—O5	1.415 (3)
C3—O3	1.354 (2)	C11—C12	1.529 (3)
C3—C4	1.371 (3)	C11—H11	0.9800
C4—C5	1.400 (3)	C12—Cl2	1.766 (3)
C4—H4	0.9300	C12—Cl1	1.774 (3)
C5—O4	1.351 (2)	C12—H12	0.9800
C5—C6	1.390 (3)	C13—O4	1.437 (3)
C6—C7	1.391 (3)	C13—H13A	0.9600
C6—H6	0.9300	C13—H13B	0.9600
C7—C8	1.445 (2)	C13—H13C	0.9600
C8—C9	1.323 (3)	O3—H3	0.8200
C8—H8	0.9300	O5—H5	0.8200
C9—O1	1.389 (2)
O2—C1—O1	116.32 (17)	C9—C10—H10A	108.6
O2—C1—C2	125.56 (17)	C11—C10—H10A	108.6
O1—C1—C2	118.12 (16)	C9—C10—H10B	108.6
C7—C2—C3	119.41 (16)	C11—C10—H10B	108.6
C7—C2—C1	120.64 (16)	H10A—C10—H10B	107.6
C3—C2—C1	119.94 (16)	O5—C11—C10	113.2 (2)
O3—C3—C4	118.72 (17)	O5—C11—C12	107.8 (2)
O3—C3—C2	121.39 (17)	C10—C11—C12	112.93 (15)
C4—C3—C2	119.89 (17)	O5—C11—H11	107.6
C3—C4—C5	119.98 (17)	C10—C11—H11	107.6
C3—C4—H4	120.0	C12—C11—H11	107.6
C5—C4—H4	120.0	C11—C12—Cl2	110.3 (2)
O4—C5—C6	124.15 (19)	C11—C12—Cl1	111.17 (19)
O4—C5—C4	114.65 (17)	Cl2—C12—Cl1	110.42 (12)
C6—C5—C4	121.19 (17)	C11—C12—H12	108.3
C5—C6—C7	118.97 (18)	Cl2—C12—H12	108.3
C5—C6—H6	120.5	Cl1—C12—H12	108.3
C7—C6—H6	120.5	O4—C13—H13A	109.5
C6—C7—C2	120.54 (17)	O4—C13—H13B	109.5
C6—C7—C8	122.30 (17)	H13A—C13—H13B	109.5
C2—C7—C8	117.15 (16)	O4—C13—H13C	109.5
C9—C8—C7	121.02 (17)	H13A—C13—H13C	109.5
C9—C8—H8	119.5	H13B—C13—H13C	109.5
C7—C8—H8	119.5	C1—O1—C9	121.57 (14)
C8—C9—O1	121.48 (16)	C3—O3—H3	109.5
C8—C9—C10	129.93 (17)	C5—O4—C13	118.50 (15)
O1—C9—C10	108.59 (15)	C11—O5—H5	109.5
C9—C10—C11	114.68 (15)
O2—C1—C2—C7	−179.0 (3)	C1—C2—C7—C8	−0.9 (4)
O1—C1—C2—C7	0.4 (4)	C6—C7—C8—C9	−179.7 (3)
O2—C1—C2—C3	1.1 (4)	C2—C7—C8—C9	0.5 (4)
O1—C1—C2—C3	−179.5 (2)	C7—C8—C9—O1	0.4 (4)
C7—C2—C3—O3	−179.2 (2)	C7—C8—C9—C10	−179.9 (3)
C1—C2—C3—O3	0.7 (4)	C8—C9—C10—C11	2.8 (5)
C7—C2—C3—C4	1.4 (4)	O1—C9—C10—C11	−177.6 (2)
C1—C2—C3—C4	−178.7 (2)	C9—C10—C11—O5	61.4 (3)
O3—C3—C4—C5	179.4 (2)	C9—C10—C11—C12	−175.8 (3)
C2—C3—C4—C5	−1.2 (4)	O5—C11—C12—Cl2	−168.62 (15)
C3—C4—C5—O4	−179.1 (3)	C10—C11—C12—Cl2	65.6 (3)
C3—C4—C5—C6	0.4 (4)	O5—C11—C12—Cl1	68.5 (2)
O4—C5—C6—C7	179.6 (2)	C10—C11—C12—Cl1	−57.3 (3)
C4—C5—C6—C7	0.1 (4)	O2—C1—O1—C9	−180.0 (2)
C5—C6—C7—C2	0.1 (4)	C2—C1—O1—C9	0.6 (4)
C5—C6—C7—C8	−179.7 (3)	C8—C9—O1—C1	−1.0 (4)
C3—C2—C7—C6	−0.8 (4)	C10—C9—O1—C1	179.3 (2)
C1—C2—C7—C6	179.3 (3)	C6—C5—O4—C13	−1.2 (4)
C3—C2—C7—C8	179.0 (2)	C4—C5—O4—C13	178.3 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5···O3^i	0.82	2.18	2.913 (3)	149
O3—H3···O2	0.82	1.91	2.624 (2)	145

Symmetry code: (i) −x+1, y+1/2, −z.