Ozonolytic transformation of (S)-(-)-limonene in hcl-isopropanol

Article abstract of DOI:10.1007/s10600-015-1206-y

Partial ozonolysis of (S)-(-)-limonene (ee 50%) in cyclohexane:isopropanol at 2-4°C formed the 1,2,4-trioxolane as a mixture of diastereomers in a 3:2 ratio. A solution of HCl in i-PrOH acted as a cleaving agent during decomposition of the peroxides and a

Full text of DOI:10.1007/s10600-015-1206-y

DOI 10.1007/s10600-015-1206-y
Chemistry of Natural Compounds, Vol. 51, No. 1, January, 2015
OZONOLYTIC TRANSFORMATION OF (S)-(–)-LIMONENE
IN HCl–ISOPROPANOL
1*
1
1
G. Yu. Ishmuratov, Yu. V. Legostaeva, L. R. Garifullina,
1
1
2
R. R. Muslukhov, L. P. Botsman, and G. G. Kozlova
Partial ozonolysis of (S)-(–)-limonene (ee 50%) in cyclohexane:isopropanol at 2–4°C formed the
1,2,4-trioxolane as a mixture of diastereomers in a 3:2 ratio. A solution of HCl in i-PrOH acted as a
cleaving agent during decomposition of the peroxides and a cyclizing agent during formation of the
diastereomeric 1,2,4-substituted cyclohexanes.
Keywords: (S)-(–)-limonene, ozonolysis, isopropanol, HCl.
Monoterpenes are important constituents of essential oils from higher plants. Thus, limonene is broadly distributed
in essential oils of many plants but most of all in citrus and turpentine isolated from conifer sap [1]. The exo- and endocyclic
double bonds in its structure are responsible for its high synthetic potential, e.g., in ozonolytic transformations. However, only
several examples of ozonation of this diene and transformation of its peroxide ozonolysis products were reported. We reported
previously [2] that (S)-(–)-limonene (1) (ee 50%) under partial ozonolysis conditions in cyclohexane:MeOH at 2–4°C formed
ozonides 2a and 2b as a mixture (2:3) of diastereomers that were 30% transformed into a hemiketal (3) after 6 d at room
temperature. Furthermore, it was observed that methyl[(1S)-2,4-dimethoxy-2,4-dimethylcyclohexyl]acetate (4) was formed
in 70% yield after 48 h as a single diastereomeric pair in a 3:1 ratio by treating the peroxides (2a and 2b) with semicarbazide
hydrochloride. The presence of the hemiketal in 3 explained unambiguously the C-4 methoxy in cyclohexane derivative 4 [2]
OH
O
(Scheme 1).
O
O
a, b
a, c
OMe
a, b
O
O
O
+
S
O
6 d
2a
3
2b
1
a, c
d
OMe
6 d
O
5
3
OMe
1
OH
i
OPr
CO Me
2
5 (70%)
4 (70%)
a. 0.9 eq. O , 2–4ꢁC; b. MeOH–cyclohexane; c. i-PrOH–cyclohexane; d. NH C(O)NHNH 4HCl
3
2
2
Scheme 1
Herein we present results for the replacement of MeOH by i-PrOH during partial ozonolysis of 1, which produced the
same ozonides 2a and 2b in a 3:2 ratio. However, their transformation in i-PrOH was different. The peroxides (2a and 2b)
were converted (70%) after 6 d at room temperature into the ketohemiacetal (5) (Scheme 1).
The different behavior of the intermediate ozonides (2a and 2b) in MeOH and i-PrOH apparently had a decisive
influence on the structure of the non-peroxide ozonolysis products that were formed by the HCl solution in MeOH or i-PrOH.
1) Institute of Organic Chemistry, Ufa Scientific Center, RussianAcademy of Sciences, 450054, Ufa, Prosp. Oktyabrya, 71,
e-mail: insect@anrb.ru; 2) Birsk Filial, Bashkir State University, 452453, Birsk, Ul. Internatsionalꢀnaya, 10. Translated from
Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2015, pp. 63–65. Original article submitted June 20, 2014.
©
0009-3130/15/5101-0071 2015 Springer Science+Business Media New York
71

Cyclic ester 4 was formed in 60% yield in HCl–MeOH and was entirely identical to that obtained by treatment of the
ozonides (2a and 2b) with semicarbazide hydrochloride. However, analogous work up in i-PrOH gave a mixture (3:1) of
diastereomers of the tri-substituted cyclohexanol (6) in 50% yield instead of the proposed isopropyl analog (7) of the trimethoxy
compound (4). The ester of 6 was selectively reduced by DIBAH to give the corresponding primary-tertiary diol (8) in order
to establish unambiguously the position of the hydroxyl (Scheme 2).
ꢃ+ ꢃ-
HCl
ꢃ- ꢃ+
O
i-PrOH
OH
OPr
OH
OPr
i
i
i-Bu AlH, 0 ꢁC
2
CO R
2
9, 10
i
CH OH
CO Pr
6 (50%)
2
HCl i-PrOH
HCl
i-PrOH
2
8 (70%)
HCl
MeOH
4
2a, b
i
OPr
OPr
i
R = H (9), Pr (10)
i
CO Pr
2
7
Scheme 2
We propose that 6 formed according to Scheme 2 upon work up of the ozonides (2a and 2b) with HCl in i-PrOH.
Initially, unsaturated ketoacid 9 formed upon treatment with HCl and converted to the corresponding isopropyl ester (10).
Then, the carbonyl was activated by the HCl proton and was attacked by the double bond with simultaneous stabilization by
i-PrOH.
Thus, (S)-(–)-limonene behaved differently during ozonolysis in i-PrOH and MeOH both during transformation into
non-peroxide products at room temperature and during treatment with HCl.
EXPERIMENTAL
We used equipment at the Khimiya Center for Collective Use, IOC, USC, RAS. IR spectra were recorded from thin
layers on an IR Prestige-21 Fourier Transform Spectrophotometer (Shimadzu). NMR spectra were recorded in CDCl with
3
TMS internal standard on high-resolution AM-300 and Avance III 500 spectrometers (operating frequencies 300 and 500 MHz
1
13
for H and 75.47 MHz for C) (Bruker). Resonances in PMR spectra were assigned and SSCC were determined using double
resonance and 2D homo- and heteronuclear COSY (H–H), HSQC, HMBC, and NOESY correlation spectroscopy. Mass
spectra were recorded using direct sample introduction into the ion source of a high-resolution MAT 95 XP GC-MS (Thermo
13
Finnigan). The temperature was programmed from 50 to 270°C at 25°C/min and ionizing potential 70 eV. C NMR spectra
were recorded with broad-band proton decoupling and in JMOD mode. GC was performed on Chrom-5 [column length 1.2 m,
silicone SE-30 (5%) stationary phase on Chromaton N-AW-DMCS (0.16–0.20 mm), operating temperature 50–300°C] and
Chrom-41 (column length 2.4 m, PEG-6000 stationary phase, operating temperature 50–200°C) instruments using He carrier
gas. TLC monitoring used Sorbfil SiO (Russia), hexane–MTBE eluent, and H SO –anisaldehyde detection. Column
2
2
4
chromatography used SiO (70–230) (Lancaster, Great Britain). Optical rotation was measured on a 241-MC polarimeter
2
20
(PerkinElmer). We used (S)-(–)-limonene {97%, ee 50%, [ꢂ] –94° (neat)}. Elemental analyses of all compounds corresponded
D
with those calculated. The ozonator output was 40 mmol O per hour.
3
Ozonolysis of (S)-(–)-limonene (1). A solution of 1 (1.1 g, 8.09 mmol, ee 50%) in a mixture of distilled cyclohexane
(20 mL) and anhydrous alcohol [14.70 mmol, MeOH (0.6 mL) or i-PrOH (1.12 mL)] at 2–4°C was purged with an O /O
3
2
mixture until 7.4 mmol of O was absorbed. The mixture was purged with Ar. The cyclohexane layer was decanted.
3
Stability of Ozonide (2a and 2b). A solution of ozonide (2a and 2b) in i-PrOH was held at room temperature for 6 d.
C NMR spectra were recorded daily. The ozonide (2a and 2b) was converted (70%) to the hemiacetal (5) in 6 d.
13
72

13
(4S)-4-Isopropenyl-1-methyl-7,8,9-trioxabicyclo[4.2.1]nonane (2a and 2b). The C NMR spectrum was identical
to that published earlier [2].
13
(5S)-5-(2-Hydroxy-2-isopropoxyethyl)-6-methylhept-6-en-2-one (5). C NMR spectrum (75.47 MHz, i-PrÎÍ,
Ñ D , ꢃ, ppm): 17.82 (17.95) (q, CÍ ), 26.25 (26.02) (t, Ñ-4), 29.31 (q, C-1), 40.48 (40.42) (t, CÍ ), 41.32 (40.89) (t, C-3), 43.24
6
6
3
2
i
(43.08) (d, C-5), 67.69 (67.41) (d, ÎCH(ÑÍ ) ), 99.68 (99.63) (s, C(ÎÍ)ÎPr ), 113.54 (t, Ñ-7, CH =C), 146.15 (145.77) (s,
3 2
2
Ñ-6, CH =C), 208.73 (s, Ñ-2, Ñ=Î).
2
Treatment of Ozonides (2a and 2b) with Alcoholic HCl. A solution of the ozonides (2a and 2b) was stirred (0°C),
treated with alcoholic HCl [25 mL, prepared by bubbling HCl obtained from NaCl (64 g) and H SO (conc., 30 mL) through
2
4
anhydrous MeOH or i-PrOH (50 mL)], stirred at room temperature for 24 h, and evaporated. The residue was dissolved in
CHCl (100 mL), washed with H O (to pH ꢄ 7), dried over Na SO , and evaporated.
3
2
2
4
Methyl [(1S)-2,4-dimethoxy-2,4-dimethylcyclohexyl]acetate (4). R 0.53 (hexane–MTBE, 2:1), a 3:1 pair of
f
13
diastereomers (according to C NMR). The IR and NMR spectra were identical to those reported earlier [2].
Isopropyl [(1S)- (6a) and (1R)- (6b) -4-hydroxy-2-isopropoxy-2,4-dimethylcyclohexyl]acetates were obtained as
a mixture (3:1) of diastereomers (6a and 6b) (1.05 g, 50%) and were separated by chromatography (SiO , hexane–MTBE,
2
+
4:1). Light-yellow viscous mass. Mass spectrum, m/z (I , %): 286 (M , 0.1), 252 (2), 225 (5), 169 (60), 167 (20), 165 (10).
rel
–1
i
IR spectrum (KBr, ꢅ, cm ): 3475 (ÎÍ), 1729 (ÑÎ Pr ), 1080 (іΖÑ).
2
1
Compound (6a). Yield 0.79 g (37%), R 0.25 (hexane–MTBE, 2:1). Í NMR spectrum (500 MHz, CDCl , ꢃ, ppm,
f
3
J/Hz): 1.08 (3Í, s, CH ), 1.19 (3Í, s, CH ), 1.22 (12H, d, J = 6.6, 4CH ), 1.38–1.44 (1Í, m, Í-5), 1.43–1.46 (1Í, m, Íà-6),
3
3
3
1.58 (1Í, d, J = 15.06, Íà-3), 1.56–1.61 (1Í, m, Íå-6), 1.62 (1Í, d, J = 13.7, Íå-5), 1.79 (1H, dd, J = 15.06, 3.76, Hå-3),
i
i
1.80–1.92 (1Í, m, Í-1), 1.93 (1Í, dd, J = 12.5, 2.1, ÑÍå ÑÎ Pr ), 2.72 (1Í, d, J = 12.5, ÑÍà ÑÎ Pr ), 3.81 (1Í, sept, J = 6.6,
2
2
2
2
13
ÑÍ(CH ) ), 4.7 (1Í, br.s, ÎÍ), 5.0 (1H, sept, ÑO ÑÍ(CH ) ). C NMR spectrum (75.47 MHz, CDCl , ꢃ, ppm): 21.88 (q,
3 2
2
3 2
3
i
2CÍ ), 21.97 (q, 2CÍ ), 25.25 (q, CÍ ), 25.28 (t, C-6), 32.88 (q, ÑÍ ), 35.28 (t, CH CO Pr ), 38.56 (t, C-5), 41.95 (d, Ñ-1),
3
3
3
3
2
2
i
49.24 (t, C-3), 62.51 (d, ÎÑÍ(ÑÍ ) ), 67.37 (d, ÑÎ ÑÍ(ÑÍ ) ), 71.25 (s, Ñ-4), 76.75 (s, Ñ-2), 173.55 (s, CO Pr ).
3 2
2
3 2
2
20
1
Compound (6b). Yield 0.26 g (12%), R 0.22 (hexane–MTBE, 2:1). [ꢂ] +4.6ꢁ (CH Cl , 1.15). Í NMR spectrum
f
D
2
2
(500 MHz, CDCl , ꢃ, ppm, J/Hz): 1.03 (3Í, s, CH ), 1.18 (12H, d, J = 6.6, 4CH ), 1.25 (3Í, s, CH ), 1.30 (1Í, dd, J = 9.5, 3.0,
3
3
3
3
Íà-5), 1.40 (1Í, d, J =14.1, Íà-3), 1.41–1.45 (1Í, m, Íà-6), 1.54–1.59 (1Í, m, Íå-6), 1.58 (1Í, d, J = 9.5, Íå-5), 1.74 (1H,
i
d, J = 14.1, Hå-3), 1.80–1.92 (1Í, m, Í-1), 2.03 (1Í, ddd, J = 15.5, 9.3, 1.3, ÑÍå ÑÎ Pr ), 2.52 (1Í, dd, J = 15.5, 4.1,
2
2
i
13
ÑÍà ÑÎ Pr ), 3.76 (1Í, sept, J = 6.6, ÑÍ(CH ) ), 4.7 (1Í, br.s, ÎÍ), 4.92 (1H, sept, ÑO ÑÍ(CH ) ). C NMR spectrum
2
2
3 2
2
3 2
(75.47 MHz, CDCl , ꢃ, ppm): 21.79 (q, 2CÍ ), 21.88 (q, 2CÍ ), 24.79 (q, CÍ ), 25.09 (t, C-6), 25.88 (q, ÑÍ ), 34.78 (t,
3
3
3
3
3
i
CH CO Pr ), 38.14 (t, C-5), 43.18 (d, Ñ-1), 47.86 (t, C-3), 63.44 (d, ÎÑÍ(ÑÍ ) ), 67.32 (d, ÑÎ ÑÍ(ÑÍ ) ), 70.80 (s, Ñ-4),
75.78 (s, Ñ-2), 173.46 (s, CO Pr ).
2
2
3 2
2
3 2
i
2
(4S)-4-(2-Hydroxyethyl)-3-isopropoxy-1,3-dimethylcyclohexanol (8). A solution of 6 (0.14 g, 0.5 mmol) in
anhydrous CH Cl (20 mL) at 0°C was stirred, treated with i-Bu AlH (73%, 1.0 mL) in toluene, stirred at room temperature
2
2
2
for 2 h (TLC monitoring), treated with H O (2 mL, 0°C), and filtered. The filtrate was dried over Na SO and evaporated to
2
2
4
13
afford diastereomers (3:1) 8 (0.80 g, 70%) (according to GC and C NMR) as a light-yellow viscous mass, R 0.10 (hexane–
f
20
–1
1
MTBE, 2:1), [ꢂ]
+11.4ꢁ (CH Cl , 0.523). IR spectrum (ꢅ, cm ): 3359 (ÎÍ), 1073 (іΖÑ). Í NMR spectrum
D
2 2
(300 MHz, CDCl , ꢃ, ppm, J/Hz): 1.15 (6H, d, J = 4.8, 2CH ), 1.25 (3H, s, CH ), 1.28 (3Í, s, ÑÍ ), 1.30–1.36 (1H, m, Íà-6),
3
3
3
3
1.36–1.39 (1Í, m, Íà-5), 1.39 (2Í, m, ÑÍ ÑÍ ÎÍ), 1.40–1.49 (1Í, m, Íå-6), 1.44–1.52 (1Í, m, Í-1), 1.71–1.79 (1Í, m,
2
2
Íå-5), 1.95 (1Í, dd, J = 13.5, 2.3, Í-3), 2.10 (1Í, dd, J = 13.5, 2.2, Í-3), 3.50–3.62 (1H, m, ÑÍ ÎÍ), 3.69–3.78 (1H, m,
2
13
ÑÍ ÎÍ), 3.96 (1Í, sept, OÑÍ(CH ) ), 4.40 (1Í, br.s, ÎÍ), 4.80 (1Í, br.s, ÎÍ). C NMR spectrum (75.47, CDCl , ꢃ, ppm):
2
3 2
3
19.09 (18.88) (q, CÍ ), 25.86 (24.84) (q, ÑÍ ), 27.30 (25.86) (t, C-6), 32.72 (30.79) (q, ÑÍ ), 34.55 (32.72) (t, CH CÍ ÎH),
3
3
3
2
2
38.98 (38.93) (t, C-5), 44.01 (44.54) (d, C-1), 49.74 (53.42) (t, C-3), 61.39 (61.83) (t, ÑÍ ÎÍ), 63.03 (63.71) (d, ÑÍ(ÑÍ ) ),
2
3 2
70.72 (70.59) (s, Ñ-4), 78.29 (76.88) (s, Ñ-2).
REFERENCES
1.
2.
V. V. Plemenkov, Introduction to the Chemistry of Natural Compounds [in Russian], Kazan, 2001, 378 pp.
G. Yu. Ishmuratov, Yu. V. Legostaeva, L. P. Botsman, G. V. Nasibullina, R. R. Muslukhov, D. V. Kazakov,
and G. A. Tolstikov, Zh. Org. Khim., 48, 26 (2012).
73