Modified synthesis of methyl (1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1- methylethyl)-cyclohexanecarboxylate from (R)-4-menthen-3-one

Article abstract of DOI:10.1007/s10600-012-0383-1

A modified stereospecific synthesis of potentially biologically and pharmacologically active methyl (1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1- methylethyl)cyclohexanecarboxylate from (R)-4-menthen-3-one was developed using sequential 1,4-conjugate addi

Full text of DOI:10.1007/s10600-012-0383-1

Chemistry of Natural Compounds, Vol. 48, No. 5, November, 2012 [Russian original No. 5, September–October, 2012]
MODIFIED SYNTHESIS OF METHYL (1R,2R,3E,5R)-
3-(HYDROXYIMINO)-5-METHYL-2-(1-METHYLETHYL)-
CYCLOHEXANECARBOXYLATE FROM (R)-4-MENTHEN-3-ONE
1,2*
2
2
2
G. Yu. Ishmuratov,
A. V. Bannova, E. R. Latypova,
UDC 542.943.5+542.957+547.596
1
2
R. R. Muslukhov, A. A. Smolꢀnikov, and R. F. Talipov
A modified stereospecific synthesis of potentially biologically and pharmacologically active methyl
(1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1-methylethyl)cyclohexanecarboxylate from (R)-4-menthen-
3-one was developed using sequential 1,4-conjugate addition of Norman reagent catalyzed by CuI–BF ·Et O–
3
2
CuCl and ozonolysis–reduction of the intermediate (R,R,R)-vinylmenthone by hydroxylamine hydrochloride
2
in MeOH.
Keywords: (R)-4-menthen-3-one, (R,R,R)-vinylmenthone, Norman reagent, ozonolysis–reduction, hydroxylamine
hydrochloride, synthesis.
The synthesis of methyl (1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1-methylethyl)cyclohexanecarboxylate (1),
a promising chiral synthon with potential pharmacological activity, from (R)-4-menthen-3-one (2) was reported earlier [1].
The scheme included sequential steps of catalyzed tandem CuI–BF ·Et O 1,4-addition of vinylmagnesiumbromide,
3
2
chromatographic isolation of (R,R,R)-vinylmenthone (3a) from the resulting mixture (18:1) with its stereoisomer (3b), ozonolytic
conversion in methanolic NaOH into the key ketoester (4), and final oximation in 19% overall yield.
a
b
c
d
48%
3a
+
64%
61%
O
O
MeO C
N
OH
O
MeO C
O
2
2
2
3a
3b
4
1
a. CH =CHMgBr, CuI-BF 4Et O, Et O-THF, –78ꢁC; b. SiO ; c. O /MeOH-CH Cl , NaOH, –78ꢁC; d. NH OH4HCl, Py, 20ꢁC
2
3
2
2
2
3
2
2
2
Herein we present a modified synthesis of 1 from the same cycloenone (2) that enables it to be obtained in greater
yield (39%) and fewer steps. For this, 1,4-conjugate addition of Norman reagent to (R)-4-menthen-3-one (2) was carried out
at –78°C in the presence of the same complex CuI–BF ·Et O with increased polarization of the conjugated enones through
3
2
interaction of added CuCl (1.33 eq) with the carbonyl O atom [2, 3]. This increased the enantioselectivity of the process [4,
2
5]. As a result, the single stereoisomer (R,R,R)-vinylmenthone (3a) was obtained in good yield (65%). Ozonolysis of 3a and
subsequent reduction of the peroxide products with an excess of hydroxylamine hydrochloride gave the desired 1. According
13
to C NMR data, the anti-isomer dominated [anti-syn 55:45 from the intensity ratio of anti- (57.79) and syn- (49.71) C-2
resonances].
a
b, c
65%
60%
O
O
MeO C
N
OH
2
3a
a. CH =CHMgBr, CuI-BF 4Et O, CuCl (1.33 eq.), THF, –78ꢁC; b. O , MeOH, 0ꢁC; c. NH OH4HCl, 20ꢁC
2
1
2
3
2
2
3
2
1) Institute of Organic Chemistry, Ufa Scientific Center, RussianAcademy of Sciences, 450054, Ufa, Prosp. Oktyabrya,
71, e-mail: insect@anrb.ru; 2) Bashkir State University, 450074, Ufa, Ul. Zaki Validi, 32, Russia, e-mail: lelvirar@mail.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2012, pp. 705–706. Original article submitted
May 22, 2012.
©
0009-3130/12/4805-0789 2012 Springer Science+Business Media New York
789

EXPERIMENTAL
IR spectra were recorded on a Prestige-21 IR instrument (Shimadzu) in thin layers. NMR spectra were recorded in
1
13
CDCl on an AM-300 spectrometer (Bruker) at operating frequency 300.13 MHz ( H) and 75.47 ( C). Resonances of
3
CD(H)Cl were used as standards, i.e., impurity protons in the deuterated solvent for PMR (ꢂ 7.27 ppm) and the average
3
13
CDCl resonance (ꢂ 77.00 ppm) for C NMR. Resonances were assigned using COSY (H–H) and COSY (C–H) spectra. The
3
H–H SSCC were determined using double resonance. Chromatographic analysis was performed in Chrom-5 [column length
1.2 m; stationary phase, silicone SE-30 (5%) + OV-225 (3%) on Chromaton N-AW-DMCS (0.16–0.20 mm), operating
temperature 50–200°C] and GC-9A (Shimadzu) [quartz capillary column, length 25 m, stationary phase DB-1 (0.25 ꢃm),
operating temperature 80–280°C] instruments with He carrier gas. Optical rotation was measured on a Perkin–Elmer 241-MC
polarimeter. Column chromatography was carried out over silica gel L (60–200 ꢃm) (Lancaster, England). TLC used Sorbfil
plates (Krasnodar). Solvents were dried using standard methods. THF was distilled from diisobutylaluminum hydride before
use; MeOH, from Na.
(2R,3R,5R)-3-Ethenyl-5-methyl-2-(1-methylethyl)cyclohexanone (3a). A stirred suspension prepared from Mg
(1.93 g, 79.2 mg-at) and CH =CHBr (8.47 g, 8.74 mL, 79.2 mmol) in anhydrous THF (80 mL, ꢄ, Ar) was treated with CuI
2
(7.55 g, 39.6 mmol, –30°C, Ar), stirred for 10 min, cooled to –78°C, treated dropwise with BF ·Et O (5.62 g, 39.6 mmol),
3
2
stirred for 5 min, treated with CuCl (7.13 g, 52.8 mmol), stirred for 5 min, treated dropwise with 2 (2.00 g, 13.2 mmol) in
2
anhydrous THF (5 mL), stirred for 7 h at –78°C, treated with saturated NH Cl solution (10 mL), stirred for 1.5 h, gradually
4
warmed to room temperature, and extracted with Et O (3 ꢅ 120 mL). The combined extracts were washed with saturated NaCl
2
solution (until pH 7), dried over MgSO , evaporated, and chromatographed over a column of SiO (petroleum ether eluent) to
4
2
21
–1
afford 3a (1.54 g, 65%), R 0.68 (petroleum ether:t-BuOMe, 3:1), [ ] +4.5° (c 3.69, CHCl ). IR spectrum (KBr, ꢆ, cm ):
f
D
3
3078 (CH =CHR), 3015 (CH =CHR), 1708 (C=O), 1654 (C=C), 915 (C=C).
2
2
PMR spectrum (300.13 MHz, CDCl , ꢂ, ppm, J/Hz): 0.73 and 0.82 [6H, d, J = 6.8, (CH ) CH], 0.91 (3H, d, J = 6.7,
3
3
3 2
2
3
CH C-5), 1.59 (1H, ddd, J = 12.0, J = 4.9, J = 9.8, H -4), 1.73–1.83 [1H, m, (CH ) CH], 1.85–1.94 (1H, m, H -4), 2.03–
3
a
3 2
3
e
3
3
2
2
2.12 (1H, m, H-5), 2.07 (1H, dd, J = 7.4, J = 5.1, H-2), 2.08 (1H, dd, J = 7.7, J = 12.4, H -6), 2.28 (1H, dd, J = 7.7,
a
3
2
3
3
3
2
3
J = 2.1, H -6), 3.03 (1H, ddd, J = 7.4, J = 5.7, J = 4.9, H-3), 4.98 (2H, dd, J = 16.7, J = 11.4, H-2ꢀ), 5.52 (1H, ddd,
e
3
4
J = 16.7, J = 11.4, J = 5.4, H-1ꢀ).
13
C NMR spectrum (75.47 MHz, CDCl , ꢂ, ppm): 20.18 (q, CH C-5), 20.87 and 21.92 [q, CH(CH ) ], 29.53 (d,
3
3
3 2
C-5), 27.94 [d, CH(CH ) ], 34.50 (t, C-4), 40.88 (d, C-3), 47.59 (t, C-6), 60.86 (d, C-2), 116.53 (t, C-2ꢀ), 136.87 (d, C-1ꢀ),
3 2
213.70 (s, C-1).
Methyl (1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1-methylethyl)cyclohexanecarboxylate (1). An O /O
3
2
mixture (ozonator production 35 mmol O /h) was passed through a solution of 3a (1.20 g, 6.7 mmol) in anhydrous MeOH
3
(30 mL) until the starting compound disappeared (TLC monitoring). The mixture was purged with Ar, cooled to 0°C, treated
with NH OH·HCl (3.26 g, 46.9 mmol), stirred for 48 h at room temperature, and evaporated in vacuo. The solid was treated
2
with Et O (300 mL), washed with saturated NaCl solution (until pH 7), dried over MgSO , and evaporated. The solid was
2
4
–1
washed with petroleum ether (70 mL) to afford 1 (0.90 g, 60%), R 0.42 (petroleum ether:t-BuOMe, 2:1). IR spectrum (ꢆ, cm ):
f
3260 (O–H), 1738 (C=O), 1654 (C=N), 970 (N–O).
3
3
PMR spectrum: 0.89 (3H, d, J = 6.1, CH C-5), 0.97 and 1.07 [6H, both d, J = 6.5, (CH ) C], 1.41–1.56 (1H, m,
3
3 2
H -6), 1.95–2.15 (3H, m, H-2, H-5, H -4), 2.93–3.00 (1H, m, H-3), 3.00–3.05 (2H, m, H -4, 6), 3.65 (3H, s, CH O).
a
a
e
3
13
C NMR spectrum: 20.50 (q, CH C-5), 20.91 and 22.44 [q, (CH ) C], 25.70 (d, HCC-2), 26.68 (t, C-6), 31.29 (d,
3
3 2
C-5), 31.13 (t, C-4), 42.85 (d, C-3), 49.71 (d, C -2), 51.38 (q, H CO), 51.79 (d, C -2), 158.94 (s, C-1), 174.20 (s, OCC-1).
syn
3
anti
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