(4S)-3-[(2R,3S)-3-Hydr­oxy-2-methyl-3-phenyl­propion­yl]-4-isopropyl­oxazolidin-2-one

The mol­ecule of the title compound, C₁₆H₂₁NO₄, is chiral and has three asymmetric centres. The absolute configuration was not determined via diffraction measurements on the crystal, but was established from the known absolute configuration of the starting material. In the crystal structure, the mol­ecules assemble through inter­molecular hydrogen bonds into a macrostructure with helical channels.

S1. Comment

Chiral auxiliary-based aldol reactions have been the focus of much interest as the strategy of choice for accessing single isomers of β-hydroxy acid derivatives as chiral building blocks for bioactive compounds (Evans et al., 1981; Ager et al., 1996, 1997; Arya et al., 2000; Evans, Downey et al., 2002; Evans, Tedrow et al., 2002). We recently reported that the use of a new N-acyl phenyliminooxazolidine auxiliary resulted in high diastereoselectivity in alkylation reactions (Lee et al., 2002). During our ongoing studies of chiral auxiliary-based asymmetric reactions, the unexpected title compound, (I), was formed in an aldol reaction and its structure is reported here.

Compound (I) has three chiral C atoms and is one of eight possible stereoisomers. Crystallographically, the absolute configuration has not been established by anomalous dispersion effects, but the R and S configurations of the chiral centres could be assigned by reference to an unchanging asymmetric centre in the reaction procedure. Atoms C7, C8 and C13 have S, R and S configurations, respectively (Fig. 1).

In the crystal structure, molecules of (I) are assembled by two intermolecular hydrogen-bonding interactions, viz. O1—H1···O2ⁱ and C12—H12a···O4ⁱⁱ, with O1···O2ⁱ = 2.871 (3) Å and C12···O4ⁱⁱ = 3.369 (4) Å [symmetry codes: (i) 1 − x, 1/2 + y, −z; (ii) 1 − x, −1/2 + y, 1 − z]. Atom O1 of the alcohol group and atom C12 in the oxazolidinone ring act as hydrogen-bond donors, and atoms O2 and O4 of the ketone groups act as acceptors (Table 2). The molecules are extended via the hydrogen bonds into a macrostructure, with a left-handed helical chain (O1—H1···O2ⁱ; Fig. 2) and a right-handed helical chain (C12—H12A···O4ⁱⁱ; Fig. 3) along the b axis. The cavity of the channel in Fig. 2 has a minimum diameter of 2.816 Å. The molecules stack in layers along the b axis, and the distance between the layers is 6.175 Å. The side view of the hydrogen-bonded left-handed helical chain structure is shown in Fig. 4. The helices are packed in a hexagonal-based array.

Examination of the structure with PLATON (Spek, 2003) reveals a short ring–ring interaction (<6 Å) for oxazolidinone rings. The centroid–centroid distance between Cg1 (the centroid of the five-membered ring O3–C12) and Cg1ⁱⁱ [symmetry code: (ii) 1 − x, −1/2 + y, 1 − z] is 4.222 Å, and the dihedral angle between the ring planes is 35.9°. For phenyl rings, the shortest distance between Cg2 (the centroid of the phenyl ring C1–C6) and Cg2ⁱⁱⁱ [symmetry code: (iii) −x, −1/2 + y, −z] is 5.175 Å, and the dihedral angle is 42.2°.

S2. Experimental

The title compound was synthesized following an analogous procedure to that described by Evans, Downey et al. (2002) for related compounds. To a round-bottomed flask in a glove box was added MgBr₂·OEt₂ (36 mg, 0.5 equivalents). The flask was fitted with a septum cap and removed to an ambient atmosphere, where it was charged with N-acylated phenyliminooxazolidine (0.28 mmol, 72 mg, 1 equivalent), EtOAc (3 ml), benzaldehyde (0.30 mmol, 31 µl, 1.1 equivalents), Et₃N (0.55 mmol, 77 µl, 2 equivalents) and trimethylsilyl chloride (0.41 mmol, 53 µl, 1.5 equivalents). The reaction mixture was stirred for 26 h and then filtered directly through a plug of silica gel (5.5 cm × 4.0 cm) and eluted with Et₂O. The eluent was concentrated and dissolved in tetrahydrofuran (50 ml) and treated with 1.0 N HCl (10 ml). After stirring for 1 h, the mixture was diluted with Et₂O (100 ml) and water (100 ml). The organic layer was extracted with saturated NaHCO₃ (50 ml), dried, filtered and concentrated. Flash chromatography (EtOAc–hexane = 2:8) afforded pure compound (I) in 58% yield. Single crystals suitable for an X-ray diffraction study were obtained by slow evaporation of a toluene solution over a period of one week. Spectroscopic analysis: ¹H NMR (CDCl₃, δ, p.p.m.): 7.42–7.29 (m, 5H), 4.75 (bt, 1H, J = 6.3 Hz), 4.46–4.17 (m, 4H), 3.17 (bd, 1H, J = 6.6 Hz), 2.30–2.23 (m, 1H), 1.10 (d, 1H, J = 6.9 Hz), 0.87 (d, 1H, J = 7.1 Hz), 0.70 (d, 1H, J = 6.9 Hz); ¹³C NMR (CDCl₃, δ, p.p.m): 176.7, 154.2, 142.2, 128.5, 128.0, 126.5, 77.4, 63.2, 58.8, 43.9, 28.3, 17.9, 14.8, 14.3; MS (EI) m/z 291 (M⁺).

S3. Refinement

In the absence of significant anomalous scattering, Friedel opposites were merged. All H atoms were positioned geometrically and allowed to ride on their respective carrier atoms, with O1—H = 0.83 Å and U_iso(H) = 1.5U_eq(O1), and C—H = 0.94–0.99 Å and U_iso(H) = 1.2U_eq(C) or 1.5U_eq(C).

Computing details

Data collection: SMART (Bruker, 2000); cell refinement: SMART; data reduction: SAINT (Bruker, 2000); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The structure of (I), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are represented by circles of arbitrary size.
	Fig. 2. A view of the O1—H1···O2^i hydrogen-bond interactions (dashed lines) in the crystal structure of (I). [Symmetry code: (i) 1 − x, 1/2 + y, −z.]
	Fig. 3. A view of the C12—H12A···O4^ii hydrogen-bond interactions (dashed lines) in the crystal structure of (I). [Symmetry code: (ii) 1 − x, −1/2 + y, 1 − z.]
	Fig. 4. A side view of the hydrogen-bonded left-handed helical chain structure along the b axis. Dashed lines indicate hydrogen bonds. [Symmetry code: (i) 1 − x, 1/2 + y, −z.]

(4S)-3-[(2R,3S)-3-Hydroxy-2-methyl-3-phenylpropionyl]-4- isopropyloxazolidin-2-one

Crystal data

C16H21NO4	F(000) = 312
Mr = 291.34	Dx = 1.220 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 634 reflections
a = 11.6191 (10) Å	θ = 1.8–28.2°
b = 6.1749 (5) Å	µ = 0.09 mm^−1
c = 12.0431 (10) Å	T = 243 K
β = 113.394 (2)°	Block, colourless
V = 793.02 (11) Å^3	0.1 × 0.1 × 0.1 mm
Z = 2

Data collection

Bruker SMART 1000 area-detector CCD diffractometer	908 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.041
Graphite monochromator	θmax = 28.2°, θmin = 1.8°
ϕ and ω scans	h = −15→10
5052 measured reflections	k = −7→7
1976 independent reflections	l = −12→15

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.040	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.061	H-atom parameters constrained
S = 0.82	w = 1/[σ^2(Fo^2) + (0.0121P)^2] where P = (Fo^2 + 2Fc^2)/3
1976 reflections	(Δ/σ)max < 0.001
194 parameters	Δρmax = 0.10 e Å^−3
1 restraint	Δρmin = −0.11 e Å^−3

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	0.3867 (2)	0.5784 (3)	0.01675 (19)	0.0666 (7)
H1	0.3771	0.6181	−0.0522	0.100*
O2	0.59887 (19)	0.2834 (4)	0.19135 (19)	0.0580 (7)
O3	0.5394 (2)	0.5608 (4)	0.5043 (2)	0.0650 (7)
O4	0.3574 (2)	0.5237 (4)	0.3468 (2)	0.0702 (8)
N1	0.5480 (2)	0.4363 (4)	0.3336 (2)	0.0457 (7)
C1	0.2101 (3)	0.3282 (6)	−0.0618 (3)	0.0517 (9)
C2	0.1648 (3)	0.1345 (6)	−0.1206 (3)	0.0649 (11)
H2	0.2218	0.0247	−0.1180	0.078*
C3	0.0374 (4)	0.0980 (7)	−0.1833 (3)	0.0880 (15)
H3	0.0082	−0.0352	−0.2221	0.106*
C4	−0.0449 (4)	0.2597 (10)	−0.1877 (4)	0.0995 (18)
H4	−0.1315	0.2381	−0.2307	0.119*
C5	−0.0016 (4)	0.4551 (9)	−0.1293 (4)	0.0979 (15)
H5	−0.0588	0.5646	−0.1317	0.118*
C6	0.1252 (3)	0.4886 (6)	−0.0680 (3)	0.0721 (11)
H6	0.1542	0.6223	−0.0299	0.086*
C7	0.3484 (3)	0.3568 (5)	0.0130 (3)	0.0496 (9)
H7	0.3976	0.2642	−0.0192	0.059*
C8	0.3773 (3)	0.2981 (5)	0.1433 (3)	0.0483 (9)
H8	0.3247	0.3877	0.1729	0.058*
C9	0.3540 (3)	0.0572 (6)	0.1603 (3)	0.0721 (11)
H9A	0.4057	−0.0316	0.1319	0.108*
H9B	0.2663	0.0231	0.1144	0.108*
H9C	0.3755	0.0283	0.2454	0.108*
C10	0.5143 (3)	0.3415 (5)	0.2209 (3)	0.0501 (9)
C11	0.4686 (4)	0.5044 (5)	0.3881 (3)	0.0537 (10)
C12	0.6692 (3)	0.5064 (6)	0.5352 (3)	0.0700 (11)
H12A	0.6933	0.3806	0.5892	0.084*
H12B	0.7235	0.6284	0.5760	0.084*
C13	0.6814 (3)	0.4554 (5)	0.4176 (3)	0.0540 (10)
H13	0.7226	0.3127	0.4246	0.065*
C14	0.7530 (3)	0.6226 (6)	0.3781 (3)	0.0656 (11)
H14	0.7502	0.5765	0.2984	0.079*
C15	0.8895 (3)	0.6271 (6)	0.4650 (4)	0.1254 (19)
H15A	0.9388	0.6974	0.4266	0.188*
H15B	0.9193	0.4801	0.4869	0.188*
H15C	0.8978	0.7067	0.5373	0.188*
C16	0.6968 (4)	0.8484 (6)	0.3626 (4)	0.1024 (16)
H16A	0.6120	0.8455	0.3011	0.154*
H16B	0.7473	0.9474	0.3381	0.154*
H16C	0.6954	0.8966	0.4387	0.154*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0718 (16)	0.0637 (17)	0.0633 (16)	−0.0116 (15)	0.0256 (14)	0.0064 (14)
O2	0.0506 (15)	0.0655 (17)	0.0608 (16)	−0.0009 (14)	0.0250 (12)	−0.0111 (13)
O3	0.0760 (18)	0.0653 (16)	0.0523 (15)	−0.0091 (15)	0.0240 (13)	−0.0128 (14)
O4	0.0597 (16)	0.087 (2)	0.0664 (16)	0.0104 (17)	0.0270 (13)	−0.0065 (15)
N1	0.0475 (17)	0.0444 (18)	0.0429 (17)	0.0014 (14)	0.0158 (14)	−0.0008 (14)
C1	0.045 (2)	0.066 (3)	0.044 (2)	−0.003 (2)	0.0167 (17)	0.005 (2)
C2	0.057 (3)	0.081 (3)	0.054 (2)	−0.003 (2)	0.0191 (19)	−0.007 (2)
C3	0.071 (3)	0.099 (4)	0.072 (3)	−0.023 (3)	0.005 (2)	0.006 (3)
C4	0.053 (3)	0.131 (5)	0.087 (4)	−0.023 (3)	−0.001 (3)	0.034 (3)
C5	0.062 (3)	0.111 (4)	0.119 (4)	0.023 (3)	0.035 (3)	0.037 (3)
C6	0.056 (3)	0.067 (3)	0.091 (3)	0.002 (2)	0.027 (2)	0.007 (2)
C7	0.050 (2)	0.046 (2)	0.055 (2)	−0.003 (2)	0.0234 (18)	−0.0035 (19)
C8	0.043 (2)	0.058 (2)	0.046 (2)	0.002 (2)	0.0189 (16)	−0.0029 (19)
C9	0.070 (2)	0.075 (3)	0.061 (2)	−0.022 (2)	0.0162 (18)	0.014 (2)
C10	0.054 (2)	0.046 (2)	0.050 (2)	−0.005 (2)	0.0201 (19)	−0.0001 (19)
C11	0.067 (3)	0.042 (2)	0.052 (2)	−0.002 (2)	0.024 (2)	−0.0035 (19)
C12	0.067 (3)	0.078 (3)	0.054 (2)	−0.016 (2)	0.011 (2)	0.000 (2)
C13	0.051 (2)	0.041 (2)	0.057 (2)	0.0006 (18)	0.0083 (18)	−0.0027 (19)
C14	0.060 (2)	0.068 (3)	0.068 (3)	−0.018 (2)	0.025 (2)	−0.014 (2)
C15	0.051 (3)	0.108 (4)	0.188 (5)	−0.020 (3)	0.016 (3)	−0.016 (4)
C16	0.110 (4)	0.059 (3)	0.141 (4)	−0.011 (3)	0.053 (3)	0.029 (3)

Geometric parameters (Å, º)

O1—C7	1.434 (3)	C7—H7	0.9900
O1—H1	0.8300	C8—C10	1.517 (4)
O2—C10	1.224 (3)	C8—C9	1.540 (4)
O3—C11	1.357 (3)	C8—H8	0.9900
O3—C12	1.443 (3)	C9—H9A	0.9700
O4—C11	1.192 (3)	C9—H9B	0.9700
N1—C10	1.384 (4)	C9—H9C	0.9700
N1—C11	1.392 (4)	C12—C13	1.512 (4)
N1—C13	1.482 (4)	C12—H12A	0.9800
C1—C6	1.379 (4)	C12—H12B	0.9800
C1—C2	1.383 (4)	C13—C14	1.516 (4)
C1—C7	1.508 (4)	C13—H13	0.9900
C2—C3	1.387 (4)	C14—C15	1.514 (4)
C2—H2	0.9400	C14—C16	1.519 (4)
C3—C4	1.369 (5)	C14—H14	0.9900
C3—H3	0.9400	C15—H15A	0.9700
C4—C5	1.387 (6)	C15—H15B	0.9700
C4—H4	0.9400	C15—H15C	0.9700
C5—C6	1.376 (5)	C16—H16A	0.9700
C5—H5	0.9400	C16—H16B	0.9700
C6—H6	0.9400	C16—H16C	0.9700
C7—C8	1.512 (4)
C7—O1—H1	109.5	H9A—C9—H9C	109.5
C11—O3—C12	110.4 (3)	H9B—C9—H9C	109.5
C10—N1—C11	127.4 (3)	O2—C10—N1	117.5 (3)
C10—N1—C13	121.0 (3)	O2—C10—C8	122.4 (3)
C11—N1—C13	111.3 (3)	N1—C10—C8	119.9 (3)
C6—C1—C2	118.3 (3)	O4—C11—O3	121.1 (3)
C6—C1—C7	121.2 (3)	O4—C11—N1	130.2 (3)
C2—C1—C7	120.4 (3)	O3—C11—N1	108.7 (3)
C1—C2—C3	121.8 (4)	O3—C12—C13	106.5 (2)
C1—C2—H2	119.1	O3—C12—H12A	110.4
C3—C2—H2	119.1	C13—C12—H12A	110.4
C4—C3—C2	118.7 (4)	O3—C12—H12B	110.4
C4—C3—H3	120.7	C13—C12—H12B	110.4
C2—C3—H3	120.7	H12A—C12—H12B	108.6
C3—C4—C5	120.5 (4)	N1—C13—C12	101.2 (3)
C3—C4—H4	119.7	N1—C13—C14	113.4 (3)
C5—C4—H4	119.7	C12—C13—C14	114.8 (3)
C6—C5—C4	119.9 (5)	N1—C13—H13	109.1
C6—C5—H5	120.1	C12—C13—H13	109.1
C4—C5—H5	120.1	C14—C13—H13	109.1
C5—C6—C1	120.8 (4)	C15—C14—C13	110.5 (3)
C5—C6—H6	119.6	C15—C14—C16	110.4 (3)
C1—C6—H6	119.6	C13—C14—C16	113.6 (3)
O1—C7—C1	112.0 (3)	C15—C14—H14	107.3
O1—C7—C8	104.9 (3)	C13—C14—H14	107.3
C1—C7—C8	109.7 (3)	C16—C14—H14	107.3
O1—C7—H7	110.1	C14—C15—H15A	109.5
C1—C7—H7	110.1	C14—C15—H15B	109.5
C8—C7—H7	110.1	H15A—C15—H15B	109.5
C7—C8—C10	110.1 (3)	C14—C15—H15C	109.5
C7—C8—C9	113.1 (3)	H15A—C15—H15C	109.5
C10—C8—C9	106.6 (3)	H15B—C15—H15C	109.5
C7—C8—H8	109.0	C14—C16—H16A	109.5
C10—C8—H8	109.0	C14—C16—H16B	109.5
C9—C8—H8	109.0	H16A—C16—H16B	109.5
C8—C9—H9A	109.5	C14—C16—H16C	109.5
C8—C9—H9B	109.5	H16A—C16—H16C	109.5
H9A—C9—H9B	109.5	H16B—C16—H16C	109.5
C8—C9—H9C	109.5
C6—C1—C2—C3	−0.9 (5)	C9—C8—C10—O2	76.2 (4)
C7—C1—C2—C3	175.6 (3)	C7—C8—C10—N1	137.9 (3)
C1—C2—C3—C4	0.7 (6)	C9—C8—C10—N1	−99.1 (3)
C2—C3—C4—C5	−0.7 (7)	C12—O3—C11—O4	175.5 (3)
C3—C4—C5—C6	1.0 (7)	C12—O3—C11—N1	−6.9 (4)
C4—C5—C6—C1	−1.3 (6)	C10—N1—C11—O4	−10.9 (6)
C2—C1—C6—C5	1.2 (5)	C13—N1—C11—O4	175.2 (4)
C7—C1—C6—C5	−175.3 (3)	C10—N1—C11—O3	171.7 (3)
C6—C1—C7—O1	−32.2 (4)	C13—N1—C11—O3	−2.1 (4)
C2—C1—C7—O1	151.4 (3)	C11—O3—C12—C13	13.0 (4)
C6—C1—C7—C8	83.8 (4)	C10—N1—C13—C12	−164.8 (3)
C2—C1—C7—C8	−92.6 (4)	C11—N1—C13—C12	9.5 (4)
O1—C7—C8—C10	−55.6 (3)	C10—N1—C13—C14	71.8 (4)
C1—C7—C8—C10	−176.0 (3)	C11—N1—C13—C14	−113.9 (3)
O1—C7—C8—C9	−174.6 (3)	O3—C12—C13—N1	−13.0 (3)
C1—C7—C8—C9	65.0 (4)	O3—C12—C13—C14	109.4 (3)
C11—N1—C10—O2	−176.6 (3)	N1—C13—C14—C15	−177.7 (3)
C13—N1—C10—O2	−3.3 (4)	C12—C13—C14—C15	66.7 (4)
C11—N1—C10—C8	−1.1 (5)	N1—C13—C14—C16	57.5 (4)
C13—N1—C10—C8	172.3 (3)	C12—C13—C14—C16	−58.1 (4)
C7—C8—C10—O2	−46.8 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2^i	0.83	2.07	2.871 (3)	161
C12—H12A···O4^ii	0.98	2.48	3.369 (4)	150

Symmetry codes: (i) −x+1, y+1/2, −z; (ii) −x+1, y−1/2, −z+1.