(2R,4S,5S)-5-Meth­oxy-4-methyl-3-oxohept-6-en-2-yl benzoate

The title compound was synthesized in the course of the total synthesis of fusaequisin A in order to verify and confirm the configurations of the stereogenic centers and to exclude the possibility of epimerization during the methyl­ation process. The absolute configuration was determined by anomalous dispersion and agrees with the configuration of the allylic alcohol used in the synthesis.

Abstract

The title compound, C₁₆H₂₀O₄, was synthesized in the course of the total synthesis of fusaequisin A in order to verify and confirm the configurations of the stereogenic centers and to exclude the possibility of epimerization during the methyl­ation process. The crystal structure of the title compound at 100 K has ortho­rhom­bic (P2₁2₁2₁) symmetry. The absolute configuration was determined by anomalous dispersion and agrees with the configuration of the allylic alcohol used in the synthesis.

Structure description

The title compound, C₁₆H₂₀O₄ (Fig. 1 ▸), was obtained during the synthesis of the Western fragment of fusaequisin A. Background to fusaequisin A is given by Shiono et al. (2013 ▸). The asymmetric synthesis of the Western fragment is based on Paterson’s anti aldol chemistry (Paterson et al., 1994 ▸; Paterson, 1998 ▸). In the course of the total synthesis of curvicollide C (Che et al., 2004 ▸) the precursor of the title compound (I) was prepared (von Kiedrowski et al., 2017 ▸) and provided potential for further investigations regarding the total synthesis of fusaequisin A. The methyl­ation process is shown in Fig. 2 ▸.

Figure 1.

The mol­ecular structure of I showing displacement ellipsoids at the 50% probability level

Figure 2.

Methyl­ation of O-desmethyl­fusaequisin A.

The title compound crystallizes in the ortho­rhom­bic space group P2₁2₁2₁ with four mol­ecules in the unit cell with H1A and H3A almost in plane (H1A—C1⋯C3—H3A pseudo torsion angle = −1°) and H2A and H3A in an anti­periplanar arrangement (H2A—C2—C3—H3A = 179°), which minimizes 1,3-allylic strain. Furthermore, the C8 methyl group and the O1 atom of the ether group are also in an anti­periplanar arrangement with a C8—C4—C3—O1 torsion angle of 177.32 (10)°. The ester moiety shows the most stable and expected s–cis-conformation. In the crystal, a weak C—H⋯O inter­action arising from the aromatic C—H grouping para to the side chain links the mol­ecules into C(10) chains propagating in the [010] direction (Table 1 ▸).

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C14—H14A⋯O2i	0.95	2.54	3.2838 (18)	135

Symmetry code: (i) .

Synthesis and crystallization

The reaction (Fig. 3 ▸) was carried out under an argon atmosphere. To an ice-cooled solution of the allylic alcohol (C₁₅H₁₈O₄, 262.31 g mol⁻¹, 300 mg, 1.10 mmol, 1 equiv.) in CH₂Cl₂ were successively added dried (0.1 mbar, 250°C, 2 h) 3 Å mol­ecular sieves (200 mg), 1,8-bis­(di­methyl­amino)­naphthalene (proton sponge^®, C₁₄H₁₈N₂, 214.31 g mol⁻¹, 943 mg, 4.40 mmol, 4 equiv.) and tri­methyl­oxonium tetra­fluoro­borate (Me₃OBF₄, C₃H₉BF₄O, 147.91 g mol⁻¹, 651 mg, 4.40 mmol, 4 equiv.). The opaque, orange solution was warmed to room temperature. The reaction mixture was stirred at room temperature for 4 h and was then diluted by the addition of aqueous phosphate pH 7 buffer. The phases were separated and the aqueous layer was extracted three times with CH₂Cl₂. The combined organic layers were dried (MgSO₄) and all volatiles were removed under reduced pressure. The light yellow residue was purified by flash chromatography (cyclo­hexane-ethyl acetate, 20:1 to 10:1) to afford the title methyl ether (I) (C₁₆H₂₀O₄, 276.33 g mol⁻¹, 238 mg, 0.86 mmol, 78%) as a white solid. Colourless crystals of I suitable for X-ray crystallographic analysis were obtained under air by slow evaporation from the mixed solvents of diethyl ether and n-pentane. R _f = 0.56 (cyclo­hexa­ne–ethyl acetate, 5:1); m.p. = 80–83°C; [ a ]_D ²⁰ = −8.3° (c = 0.5 g ml⁻¹ in CHCl₃) ; ¹H NMR (500 MHz, CDCl₃) δ 1.06 (d, J = 7.1 Hz, 3H, 3-CH₃), 1.55 (d, J = 7.0 Hz, 3H, 1-CH₃), 2.93 (dq, J = 9.7, 7.1 Hz, 1H, 3-CH), 3.15 (s, 3H, 4-OCH₃), 3.70 (dd, J = 10.1, 9.3 Hz, 1H, 4-CH), 5.24–5.35 (m, 2H, 6-CH₂), 5.41 (q, J = 7.0 Hz, 1H, 1-CH), 5.56 (ddd, J = 17.1, 10.1, 8.5 Hz, 1H, 5-CH), 7.43–7.48 (m, 2H, aryl-CH), 7.55–7.60 (m, 1H, aryl-CH), 8.05–8.12 (m, 2H, aryl-CH); ¹³C NMR (126 MHz, CDCl₃) δ 14.1 (3-CH₃), 15.3 (1-CH₃), 47.0 (3-CH), 56.6 (4-OCH₃), 75.5 (1-CH), 85.4 (4-CH), 120.2 (6-CH₂), 128.5 (aryl-CH), 129.8 (aryl-CH), 129.9 (aryl-CH), 133.3 (aryl-CH), 136.0 (5-CH), 166.0 (aryl-C), 210.1 (2-C); IR ν = 3075 (w), 2985 (w), 2935 (w), 2825 (w), 1720 (s), 1065 (w), 1450 (m), 1420 (w), 1375 (m), 1315 (m), 1265 (s), 1205 (w), 1175 (w), 1115 (s), 1090 (s), 1070 (m), 1025 (m), 1010 (m), 965 (m), 935 (m), 715 (s), 685 (w) cm⁻¹; HRMS (ESI): m/z [M + H]⁺ calculated for C₁₆H₂₁O₄: 277.1434; found: 277.1342.

Figure 3.

Reaction conditions for the methyl­ation of the allylic alcohol.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸.

Table 2. Experimental details.

Crystal data
Chemical formula	C16H20O4
M r	276.32
Crystal system, space group	Orthorhombic, P212121
Temperature (K)	100
a, b, c (Å)	8.1297 (4), 11.8232 (6), 15.7213 (9)
V (Å3)	1511.12 (14)
Z	4
Radiation type	Cu Kα
μ (mm−1)	0.71
Crystal size (mm)	0.12 × 0.10 × 0.06
Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS;Bruker, 2016 ▸)
T min, T max	0.700, 0.754
No. of measured, independent and observed [I > 2σ(I)] reflections	28627, 3078, 3054
R int	0.027
(sin θ/λ)max (Å−1)	0.625
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.023, 0.060, 1.07
No. of reflections	3078
No. of parameters	184
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.18, −0.12
Absolute structure	Flack x determined using 1293 quotients [(I +)−(I −)]/[(I +)+(I −)] (Parsons et al., 2013 ▸)
Absolute structure parameter	0.03 (2)

Computer programs: APEX3 and SAINT (Bruker, 2016 ▸), SHELXT2014/5 (Sheldrick, 2015a ▸), SHELXL2018/3 (Sheldrick, 2015b ▸), XP (Sheldrick, 2008 ▸) and OLEX2 (Dolomanov et al., 2009 ▸).

Supplementary Material

CCDC reference: 2109383

Additional supporting information: crystallographic information; 3D view; checkCIF report

full crystallographic data

Crystal data

C16H20O4	Dx = 1.215 Mg m−3
Mr = 276.32	Melting point = 353–356 K
Orthorhombic, P212121	Cu Kα radiation, λ = 1.54178 Å
a = 8.1297 (4) Å	Cell parameters from 9807 reflections
b = 11.8232 (6) Å	θ = 6.1–74.6°
c = 15.7213 (9) Å	µ = 0.71 mm−1
V = 1511.12 (14) Å3	T = 100 K
Z = 4	Block, colourless
F(000) = 592	0.12 × 0.10 × 0.06 mm

Data collection

Bruker APEXII CCD diffractometer	3054 reflections with I > 2σ(I)
φ and ω scans	Rint = 0.027
Absorption correction: multi-scan (SADABS;Bruker, 2016)	θmax = 74.5°, θmin = 4.7°
Tmin = 0.700, Tmax = 0.754	h = −10→10
28627 measured reflections	k = −14→14
3078 independent reflections	l = −18→19

Refinement

Refinement on F2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F2 > 2σ(F2)] = 0.023	w = 1/[σ2(Fo2) + (0.0308P)2 + 0.2127P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.060	(Δ/σ)max < 0.001
S = 1.07	Δρmax = 0.18 e Å−3
3078 reflections	Δρmin = −0.12 e Å−3
184 parameters	Absolute structure: Flack x determined using 1293 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
0 restraints	Absolute structure parameter: 0.03 (2)
Primary atom site location: dual

Special details

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

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

	x	y	z	Uiso*/Ueq
C1	0.09507 (18)	0.29265 (12)	0.39623 (10)	0.0306 (3)
H1A	0.080921	0.309404	0.337584	0.037*
H1B	0.010147	0.255322	0.426807	0.037*
O1	0.52090 (11)	0.31350 (8)	0.40027 (6)	0.0257 (2)
C2	0.23199 (17)	0.32109 (12)	0.43502 (9)	0.0260 (3)
H2A	0.241816	0.302998	0.493680	0.031*
O2	0.57315 (12)	0.55222 (8)	0.31396 (6)	0.0257 (2)
C3	0.37402 (15)	0.38013 (10)	0.39331 (8)	0.0210 (3)
H3A	0.348192	0.392678	0.331840	0.025*
O3	0.79670 (11)	0.67523 (7)	0.40634 (6)	0.02254 (19)
C4	0.41493 (15)	0.49330 (10)	0.43492 (8)	0.0200 (2)
H4A	0.442788	0.480340	0.496105	0.024*
O4	0.58296 (11)	0.79534 (7)	0.39300 (6)	0.0255 (2)
C5	0.56184 (15)	0.54690 (10)	0.39052 (8)	0.0195 (2)
C6	0.69017 (16)	0.59668 (11)	0.45003 (8)	0.0214 (3)
H6A	0.633436	0.636762	0.497741	0.026*
C7	0.5209 (2)	0.22018 (12)	0.34321 (10)	0.0346 (3)
H7A	0.624899	0.178862	0.348492	0.052*
H7B	0.508591	0.247754	0.284770	0.052*
H7C	0.429206	0.169617	0.357046	0.052*
C8	0.27180 (16)	0.57771 (12)	0.42921 (10)	0.0279 (3)
H8A	0.180721	0.551481	0.464968	0.042*
H8B	0.234674	0.583387	0.370058	0.042*
H8C	0.308649	0.652131	0.448962	0.042*
C9	0.80093 (17)	0.50522 (12)	0.48637 (10)	0.0298 (3)
H9A	0.733683	0.448423	0.515567	0.045*
H9B	0.878182	0.539103	0.526875	0.045*
H9C	0.862385	0.469110	0.440132	0.045*
C10	0.72720 (16)	0.77408 (10)	0.38331 (7)	0.0204 (3)
C11	0.85150 (16)	0.85390 (10)	0.34781 (8)	0.0206 (3)
C12	0.79937 (18)	0.96224 (11)	0.32518 (8)	0.0237 (3)
H12A	0.686828	0.982661	0.330513	0.028*
C13	0.91308 (19)	1.04000 (11)	0.29482 (9)	0.0286 (3)
H13A	0.878073	1.114116	0.280093	0.034*
C14	1.07716 (19)	1.01054 (12)	0.28578 (9)	0.0303 (3)
H14A	1.153904	1.064064	0.264420	0.036*
C15	1.12937 (17)	0.90223 (13)	0.30810 (9)	0.0294 (3)
H15A	1.241701	0.881748	0.301761	0.035*
C16	1.01703 (17)	0.82427 (11)	0.33962 (8)	0.0243 (3)
H16A	1.052798	0.750788	0.355613	0.029*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C1	0.0290 (7)	0.0303 (7)	0.0325 (7)	−0.0065 (6)	0.0030 (6)	0.0020 (6)
O1	0.0265 (4)	0.0206 (4)	0.0298 (5)	0.0050 (4)	−0.0010 (4)	−0.0022 (4)
C2	0.0284 (7)	0.0248 (6)	0.0249 (6)	−0.0012 (5)	0.0023 (5)	0.0032 (5)
O2	0.0317 (5)	0.0244 (4)	0.0211 (4)	−0.0027 (4)	0.0034 (4)	−0.0001 (3)
C3	0.0220 (6)	0.0199 (6)	0.0210 (6)	0.0009 (5)	0.0000 (5)	0.0011 (5)
O3	0.0210 (4)	0.0178 (4)	0.0289 (5)	−0.0008 (4)	0.0021 (4)	0.0021 (4)
C4	0.0197 (5)	0.0207 (6)	0.0197 (5)	0.0004 (5)	0.0012 (5)	−0.0017 (5)
O4	0.0226 (4)	0.0211 (4)	0.0326 (5)	0.0007 (4)	0.0033 (4)	−0.0017 (4)
C5	0.0215 (6)	0.0146 (5)	0.0224 (6)	0.0040 (5)	0.0012 (5)	0.0001 (5)
C6	0.0210 (6)	0.0199 (6)	0.0234 (6)	−0.0018 (5)	0.0013 (5)	0.0028 (5)
C7	0.0377 (8)	0.0236 (6)	0.0426 (8)	0.0051 (6)	0.0039 (7)	−0.0090 (6)
C8	0.0234 (6)	0.0264 (7)	0.0339 (7)	0.0053 (5)	0.0006 (6)	−0.0059 (5)
C9	0.0233 (6)	0.0279 (7)	0.0382 (7)	−0.0005 (6)	−0.0036 (6)	0.0095 (6)
C10	0.0244 (6)	0.0174 (5)	0.0196 (6)	−0.0006 (5)	−0.0008 (5)	−0.0030 (5)
C11	0.0245 (6)	0.0192 (6)	0.0180 (6)	−0.0020 (5)	0.0002 (5)	−0.0034 (5)
C12	0.0277 (7)	0.0209 (6)	0.0226 (6)	0.0005 (5)	0.0004 (5)	−0.0015 (5)
C13	0.0389 (7)	0.0214 (6)	0.0256 (6)	−0.0034 (6)	0.0022 (6)	0.0009 (5)
C14	0.0354 (7)	0.0296 (7)	0.0260 (6)	−0.0119 (6)	0.0064 (6)	−0.0015 (5)
C15	0.0252 (7)	0.0340 (7)	0.0291 (7)	−0.0038 (6)	0.0038 (5)	−0.0049 (6)
C16	0.0257 (6)	0.0236 (6)	0.0235 (6)	−0.0003 (5)	0.0003 (5)	−0.0026 (5)

Geometric parameters (Å, º)

C1—C2	1.313 (2)	C7—H7B	0.9800
C1—H1A	0.9500	C7—H7C	0.9800
C1—H1B	0.9500	C8—H8A	0.9800
O1—C7	1.4220 (17)	C8—H8B	0.9800
O1—C3	1.4347 (15)	C8—H8C	0.9800
C2—C3	1.5001 (18)	C9—H9A	0.9800
C2—H2A	0.9500	C9—H9B	0.9800
O2—C5	1.2087 (16)	C9—H9C	0.9800
C3—C4	1.5261 (17)	C10—C11	1.4911 (18)
C3—H3A	1.0000	C11—C12	1.3953 (18)
O3—C10	1.3477 (15)	C11—C16	1.3965 (19)
O3—C6	1.4438 (15)	C12—C13	1.3883 (19)
C4—C5	1.5215 (17)	C12—H12A	0.9500
C4—C8	1.5357 (17)	C13—C14	1.386 (2)
C4—H4A	1.0000	C13—H13A	0.9500
O4—C10	1.2089 (16)	C14—C15	1.394 (2)
C5—C6	1.5199 (17)	C14—H14A	0.9500
C6—C9	1.5188 (18)	C15—C16	1.389 (2)
C6—H6A	1.0000	C15—H15A	0.9500
C7—H7A	0.9800	C16—H16A	0.9500
C2—C1—H1A	120.0	H7B—C7—H7C	109.5
C2—C1—H1B	120.0	C4—C8—H8A	109.5
H1A—C1—H1B	120.0	C4—C8—H8B	109.5
C7—O1—C3	112.20 (11)	H8A—C8—H8B	109.5
C1—C2—C3	124.65 (12)	C4—C8—H8C	109.5
C1—C2—H2A	117.7	H8A—C8—H8C	109.5
C3—C2—H2A	117.7	H8B—C8—H8C	109.5
O1—C3—C2	110.60 (10)	C6—C9—H9A	109.5
O1—C3—C4	105.50 (10)	C6—C9—H9B	109.5
C2—C3—C4	112.85 (10)	H9A—C9—H9B	109.5
O1—C3—H3A	109.3	C6—C9—H9C	109.5
C2—C3—H3A	109.3	H9A—C9—H9C	109.5
C4—C3—H3A	109.3	H9B—C9—H9C	109.5
C10—O3—C6	115.73 (10)	O4—C10—O3	123.58 (12)
C5—C4—C3	109.85 (10)	O4—C10—C11	124.96 (12)
C5—C4—C8	107.29 (10)	O3—C10—C11	111.42 (11)
C3—C4—C8	112.31 (10)	C12—C11—C16	119.97 (12)
C5—C4—H4A	109.1	C12—C11—C10	118.07 (12)
C3—C4—H4A	109.1	C16—C11—C10	121.92 (12)
C8—C4—H4A	109.1	C13—C12—C11	119.56 (13)
O2—C5—C6	122.72 (12)	C13—C12—H12A	120.2
O2—C5—C4	122.56 (12)	C11—C12—H12A	120.2
C6—C5—C4	114.69 (10)	C14—C13—C12	120.64 (13)
O3—C6—C9	106.34 (10)	C14—C13—H13A	119.7
O3—C6—C5	111.60 (10)	C12—C13—H13A	119.7
C9—C6—C5	111.27 (11)	C13—C14—C15	119.88 (13)
O3—C6—H6A	109.2	C13—C14—H14A	120.1
C9—C6—H6A	109.2	C15—C14—H14A	120.1
C5—C6—H6A	109.2	C16—C15—C14	119.95 (13)
O1—C7—H7A	109.5	C16—C15—H15A	120.0
O1—C7—H7B	109.5	C14—C15—H15A	120.0
H7A—C7—H7B	109.5	C15—C16—C11	120.00 (13)
O1—C7—H7C	109.5	C15—C16—H16A	120.0
H7A—C7—H7C	109.5	C11—C16—H16A	120.0
C7—O1—C3—C2	75.42 (14)	O2—C5—C6—C9	−102.56 (14)
C7—O1—C3—C4	−162.25 (11)	C4—C5—C6—C9	79.43 (13)
C1—C2—C3—O1	−121.33 (15)	C6—O3—C10—O4	−4.44 (17)
C1—C2—C3—C4	120.75 (15)	C6—O3—C10—C11	173.50 (10)
O1—C3—C4—C5	58.00 (12)	O4—C10—C11—C12	1.17 (19)
C2—C3—C4—C5	178.86 (10)	O3—C10—C11—C12	−176.74 (11)
O1—C3—C4—C8	177.32 (10)	O4—C10—C11—C16	178.96 (13)
C2—C3—C4—C8	−61.81 (14)	O3—C10—C11—C16	1.06 (16)
C3—C4—C5—O2	46.33 (16)	C16—C11—C12—C13	−0.16 (19)
C8—C4—C5—O2	−76.02 (15)	C10—C11—C12—C13	177.67 (11)
C3—C4—C5—C6	−135.66 (10)	C11—C12—C13—C14	0.8 (2)
C8—C4—C5—C6	101.99 (12)	C12—C13—C14—C15	−0.6 (2)
C10—O3—C6—C9	−167.80 (11)	C13—C14—C15—C16	−0.2 (2)
C10—O3—C6—C5	70.68 (13)	C14—C15—C16—C11	0.9 (2)
O2—C5—C6—O3	16.05 (17)	C12—C11—C16—C15	−0.70 (19)
C4—C5—C6—O3	−161.96 (10)	C10—C11—C16—C15	−178.45 (12)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C14—H14A···O2i	0.95	2.54	3.2838 (18)	135

Symmetry code: (i) −x+2, y+1/2, −z+1/2.

Funding Statement

The TU Dortmund and the DFG are gratefully acknowledged for financial support.