Novel synthesis of (4R)-4-methylpentanolide from (L)-(-)-menthol

Article abstract of DOI:10.1007/s10600-005-0033-y

A novel synthesis of the promising optically pure chiral (4R)-4-methylpentanolide that is based on several regiospecific oxidative transformations of (4R)-2,4-dimethyl-1-(1-methylethyl)-1-cyclohexene, the product of addition of (-)-menthone and methylmagn

Full text of DOI:10.1007/s10600-005-0033-y

Chemistry of Natural Compounds, Vol. 40, No. 6, 2004
NOVEL SYNTHESIS OF (4R)-4-METHYLPENTANOLIDE
FROM (L)-(-)-MENTHOL
G. Yu. Ishmuratov, M. P. Yakovleva, G. V. Zaripova,
L. P. Botsman, R. R. Muslukhov, and G. A. Tolstikov
UDC 542.943.5+547.48+547.596
A novel synthesis of the promising optically pure chiral (4R)-4-methylpentanolide that is based on several
regiospecific oxidative transformations of (4R)-2,4-dimethyl-1-(1-methylethyl)-1-cyclohexene, the product
of addition of (-)-menthone and methylmagnesium iodide followed by acid dehydration, was proposed.
Key words: L-(-)-Menthol, (-)-menthone, (4 )-4-methylpentanolide, chiral synthon, (1 ,2 ,5 )- and (1 ,2 ,5 )-1,5-
S S R R S R
R
dimethyl-2-(1-methylethyl)cyclohexan-1-ols,(4 )-2,4-dimethyl-1-(1-methylethyl)-1-cyclohexene, (4 )-4,8-dimethylnonan-2,7-
R
R
dione, isopropyl-(4 )-5-acetoxy-4-methylpentanoate.
R
In continuation of research on functionalization of the common natural monoterpenoid L-(-)-menthol ( ~ 100%),
ee
we developed a synthesis of (4 )-4-methylpentanolide (1), a potentially useful chiral synthon.
R
Lactone 1 was previously prepared as the racemate by oxidation of 3-methyltetrahydropyran with sodium bromate [1]
or dimethyl- or methyltrifluoromethyldioxiranes [2]. It was isolated in the opticallyactive form from side products of industrial
production of dehydropregnenolone acetate from diosgenin [3-5] and cyclization of 5-amino-4 -methylpentanoic acid [6].
R
MeMgI
Et O, ∆
SiO
2
OH
3a
+
OH
2
O
3a
3b
2
+
H O
3
O
1. O /CH Cl
2
3
2
O
2. NaBH(OAc)
H SO
2
O
3
5
O
4
5
1
MCPBA
OAc
+
1
O
i
OPr
H O = (CO H) , or H PO , or H SO
4
6
+
3
2
2
3
4
2
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya, 71,
fax (3472) 35 60 66, e-mail: kharis@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 451-453, November-
December, 2004. Original article submitted August 3, 2004.
0009-3130/04/4006-0548 ©2004 Springer Science + Business Media, Inc.
548

According to the literature [7, 8], Grignard addition of methylmagnesium iodide to (1R,4S)-(-)-menthone (2) in THF
at room temperature occurs stereoselectively and produces a mixture of (1S,2S,5R)- (3a) and (1R,2S,5R)-1,5-dimethyl-2-
(1-methylethyl)cyclohexan-1-ol (3b) with primarily the former (90%) and 65% yield without catalyst [7] and 69% yield with
CeCl catalyst [8]. Carrying out the reaction with boiling in Et O enabled the overall yield of the desired alcohols to be
3
2
increased to 96% and the stereoselectivity to reach 94:6 (3a:3b).
Acid dehydration of the mixture ofalcohols (3a and -b) occurs over 24 h toproduce the thermodynamicallymore stable
(4R)-2,4-dimethyl-1-(1-methylethyl)-1-cyclohexene (4), the structure of which was indirectly confirmed by ozonolytic
decomposition of its double bond. After reduction of the peroxide ozonolysis products with sodium trisacetoxyborohydride,
which converts1-methylcycloalkenesintohydroxyketoneswithout affectingtheketoneformed[9], (4R)-4,8-dimethylnonan-2,7-
dione (5) was obtained as the only product.
Exhaustive oxidation of diketone 5 byCaro acid according to Baeyer and Villiger [10, 11] occurs regiospecificallyand
gives the desired optically active lactone 1 with rotation angle 16.8° (+14.3°, o.p. 85% [3] and +16.8°, o.p. 100% [4]). Lactone
1 spontaneouslyconverts on storage for a month from an oil into a crystalline substance owing to formation of linear polyesters
21
20
[4, 5]. This is accompanied by a decrease in the rotation angle to +4.7° ([α]
+8.1° [4] and [α]
+5.3° [5]).
D
D
13
Formation of lactone 1 through the intermediate diester 6 was confirmed by spectral analysis ( C NMR) of the
chromatographically unseparated mixture (1:1) of these compounds that was formed upon oxidation of dione 5 by
metachloroperbenzoic acid.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument in thin layers. NMR spectra were recorded on a Bruker AM-300
13
spectrometer (working frequency 300.13 MHz for PMR and 75.47 MHz for C NMR) in CDCl . The internal standards were
3
13
the impurity protons in CDCl with δ 7.27 ppm in the PMR; the average signal of CDCl at δ 77.00 ppm in the C NMR.
3
3
Signals in the PMR were assigned using double resonance and two-dimensional homonuclear correlation spectroscopy COSY
H—H. GC was performed on Chrom-5 [column length 1.2 m, stationary phase silicone SE-30 (5%) on Chromaton N-AW-
DMCS (0.16-0.20 mm), working temperature 50-300°C] and Chrom-41 [column length 2.4 m, stationary phase PEG-6000,
working temperature 50-200°C] instruments with He carrier gas. Column chromatography was carried out on silica gel L
(Czech Rep., 40-100 µm). TLC was performed on Silufol UV-254 (Czech Rep.) plates. Optical rotation was measured on a
Perkin—Elmer 241-MC polarimeter. Starting menthone was synthesized as before [12]. Elemental analyses of all compounds
agreed with those calculated.
(1S,2S,5R)- and (1R,2S,5R)-1,5-Dimethyl-2-(1-methylethyl)cyclohexan-1-ols (3). Grignard reagent was prepared
from Mg (1.84 g, 77.0 mg-at) and methyliodide (10.86 g, 77.0 mmol) in absolute Et O (38 mL) and treated dropwise with
2
menthone (2, 10.00 g, 65.0 mmol) at 0°C under Ar. The mixture was boiled for 1 h, held for 12 h at room temperature, cooled
to 0°C, treated with H O (10 mL), and stirred for 1 h at room temperature. The solid was filtered off and washed on a Schott
2
filter with Et O (50 mL). The combined organic extracts were dried over MgSO , filtered, and evaporated to afford a mixture
2
4
(94:6) of 3a and 3b (10.61 g, 96%), the main component of which (3a) was isolated by column chromatography over SiO
2
20
-1
(hexane:Et O, 7:3), R 0.47 (hexane:Et O, 7:3), [α]
-2.44 (c 2.5, CHCl ). IR spectrum (KBr, ν, cm ): 3600-3350 (OH).
3
f
2
2
D
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.84 (3H, d, J = 2, CH C-5), 0.88 and 0.89 [6H, both d, J = 2, (CH ) CH], 1.01-
3
3
3 2
1.05 (1H, m, H -6), 1.04-1.08 (1H, m, H-2), 1.05-1.09 (1H, m, H -3), 1.18-1.27 (1H, m, H -3), 1.22 (3H, s, CH C-1), 1.30-1.39
a
a
e
3
(1H, m, H -6), 1.34-1.40 (1H, m, H -4), 1.45-1.50 (1H, m, H-5), 1.60-1.78 [1H, m, (CH ) CH], 1.75-1.80 (1H, m, H -4), 3.20
e
a
3 2
e
(1H, br.s, OH), [8].
13
C NMR spectrum, 3a epimer (CDCl ): 19.17 (q, CH C-5), 22.03 and 22.30 [both q, (CH ) C], 24.58 (d, C-5), 24.58
3
3
3 2
13
(t, C-3), 25.41 [d, (CH ) C], 30.67 (q, CH C-1), 35.20 (t, C-4), 52.91 (t, C-6), 53.14 (d, C-2), 74.08 (s, C-1). C NMR, 3b
3 2
3
epimer (from a mixture of 3a and 3b) (CDCl ): 18.18 (q, CH C-5), 20.84 (t, C-3), 22.24 and 23.75 [both q, (CH ) C], 26.08
3
3
3 2
(d, C-5), 28.81 (q, CH C-1), 28.85 [d, (CH ) C], 35.18 (t, C-4), 50.45 (d, C-2), 50.69 (t, C-6), 72.98 (s, C-1).
3
3 2
(4R)-2,4-Dimethyl-1-(1-methylethyl)-1-cyclohexene (4). a. A mixture of 3a and 3b (2.00 g, 12.0 mmol) and oxalic
acid (1.62 g, 18.0 mmol) was held for 24 h at 100°C, cooled, diluted with hexane (20 mL), washed successively with saturated
20
NaHCO and NaCl solutions, dried over MgSO , and evaporated to afford 4 (1.64 g, 90%), [α]
+9.0° (c 2.5, CHCl ).
3
3
4
D
549

-1
IR spectrum (KBr, ν, cm ): 1645 (C=C).
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.89 (3H, d, J = 6.7, CH C-4), 0.92 [6H, d, J = 6.9, (CH ) C], 1.28 (1H, dd,
3
3
3
3
3 2
2
2
3
2
3
J = 7.3, J = 6.7, H -5), 1.61 (3H, s, CH C-2), 1.60-1.69 (1H, m, H -5), 1.88 (1H, dd, J = 6.4, J = 2.0, H -6), 1.94 (1H, dd,
a
3
e
a
3
2
J = 6.5, J = 10.5, H -3), 1.90-1.98 (1H, m, H -4), 1.92-2.02 (1H, m, H -6), 2.29 (1H, d, J = 6.5, H -3), 2.82 [1H, s,
a
a
e
e
(CH ) CH].
3 2
13
C NMR spectrum (CDCl ): 18.60 (q, CH C-4), 20.27 and 21.91 [both q, (CH ) C], 23.31 (t, C-6), 29.18 (d, C-4),
3
3
3 2
29.46 [d, (CH ) C], 31.78 (t, C-5), 41.24 (t, C-3), 123.97 (s, C-2), 134.37 (s, C-1), 207.6 (q, CH C-2).
3 2
3
b. A mixture of 3a and 3b (2.00 g, 12.0 mmol) and H PO (0.45 mL, 85%) was worked up as described in a. to afford
3
4
4 (1.64 g, 90%) that had identical spectral data as the product from that experiment.
c. A solution of 3a and 3b (2.00 g, 12.0 mmol) and conc. H SO (1 mL) in H O (10 mL) and the method described
2
4
2
in a. afforded 4 (1.66 g, 91%) that was identical to the product from a.
(4R)-4,8-Dimethyl-2,7-nonanedione (5). An ozone—oxygen mixture (ozonator production 40.0 mmol O /h) was
3
passed through a solution of 4 (5.00 g, 33.0 mmol) and glacial acetic acid (3.93 g, 66.0 mmol) in CH Cl (91 mL) with stirring
2
2
at -4 to -2°C until 34.0 mmol of ozone had been absorbed. The reaction mixture was purged with Ar, diluted with CH Cl
2
2
(46 mL), stirred (10 C), treated with a previously prepared suspension of NaBH(OAc) [prepared by adding glacial acetic acid
3
(27.14 g, 452.0 mmol) in CH Cl (46 mL) to a suspension of NaBH (5.74 g, 151.0 mmol) in CH Cl (228 mL) with stirring
2
2
4
2
2
for 2 h], heated to room temperature, stirred for 3 h, cooled to 10°C, and treated with NaOH solution (10.31 g in 229 mL H O).
2
The organic layer was separated, washed successively with saturated NH Cl solution and water, dried over Na SO , and
4
2
4
20
evaporated to afford 5 (4.75 g, 79%), [α]
+8.88° (c 2.5, CHCl ).
3
D
-1
IR spectrum (KBr, ν, cm ): 1712 (C=O).
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.88 (3H, d, J = 2.0, CH C-4), 1.08 [6H, d, J = 2.0 (CH ) C], 2.11 (3H, s, H-1),
3
3
3 2
0.93-1.00 (2H, m, H-5), 1.15-1.65 (1H, m, H-4), 2.15-2.65 [5H, m, H-3, H-6, (CH ) CH].
3 2
13
C NMR spectrum (CDCl ): 18.33 [q, (CH ) C], 19.64 (d, CH C-4), 28.86 (q, C-1), 30.41 (d, C-4), 30.58 (t, C-5),
3
3 2
3
37.91 (t, C-6), 40.87 (d, C-8), 51.07 (t, C-3), 208.53 (s, C-2), 214.55 (s, C-7).
(4R)-4-Methylpentanolide (1). Concentrated H SO (8.1 mL) was added to water (2.7 mL). The mixture was cooled
2
4
to 5°C, treated with K S O (5.67 g, 21.0 mmol), adjusted to 15°C, treated successively with water (8.8 mL) and 5 (1 g,
2 2
8
5.4 mmol), stirred at room temperature for 35 h, poured into cold water (50 mL), and extracted with CH Cl (3 × 50 mL). The
2
2
extract was washed successively with saturated NaHCO and NaCl solutions, dried over MgSO , and evaporated to afford
3
4
20
lactone 1 (0.41 g, 66%), [α]
+16.8° (c 1.0, CHCl ).
D
3
-1
IR spectrum (KBr, ν, cm ): 1748 (C=O).
2
3
3
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.89 (3H, d, J = 6.6, CH C-5), 1.44 (1H, ddt, J = 12.8, J = 13.4, J = 7.1,
H -4), 1.83-1.89 (1H, m, H -3), 1.90-1.94 (1H, m, H-4), 2.38 (1H, ddd, J = 15.7, J = 13.4, J = 7.1, H -3), 2.51 (1H, ddd,
J = 15.7, J = 4.3, J = 7.0, H -3), 3.80 (1H, dd, J = 12.7, J = 13.7, H -5), 4.19 (1H, ddd, J = 12.7, J = 4.0, J = 1.1, H -5).
3
3
3
2
3
3
a
e
e
2
3
3
2
3
2
3
3
a
a
e
13
C NMR spectrum (CDCl ): 16.02 (q, CH -5), 25.58 (t, C-4), 27.32 (d, C-5), 29.91 (t, C-3), 170.84 (s, C-2).
3
3
(4R)-4-Methylpentanolide (1) and Isopropyl-(4R)-4-methyl-5-acetoxypentanoate (6). A suspension of
m-chloroperbenzoic acid (1.41 g, 8.2 mol, 50%) in dry CHCl (7.5 mL) was treated with diketone 5 (0.5 g, 2.7 mol) in dry
3
CHCl (2.3 mL); stirred at room temperature for 3 d; diluted with CHCl (100 mL); washed with saturated Na S O , NaHCO ,
3
3
2 2
3
3
and NaCl solutions; dried over Na SO , and evaporated to afford a mixture (1:1, 0.7 g) of the (R)-4-methylpentanolide (1) and
2
4
isopropyl-(R)-4-methyl-5-acetoxypentanoate (6).
-1
IR spectrum (KBr, ν, cm ): 1748 (C=O).
13
C NMR spectrum, 6: (from a mixture of 1 and 6) (CDCl ): 16.40 (q, CH -4), 20.83 (q, CH COO), 21.74 [q,
3
3
3
(CH ) C], 28.42 (t, C-3), 32.03 (d, C-4), 32.61 (t, C-2), 67.50 [d, (CH ) C], 68.77 (t, C-5), 171.07 (s, CH COO), 172.95
3 2
3 2
3
(s, C-1).
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2.
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