Synthesis of the promising chiral synthon isopropyl-4R-methyl-6- iodohexanoate from L-(-)-menthol

Article abstract of DOI:10.1007/s10600-005-0070-6

A synthesis of the promising optically pure synthon isopropyl-4R-methyl-6- iodohexanoate based on ozonolytic transformation of the product of regiospecific dehydratation of L-(-)-menthol, (R)-p-menth-3-ene, into 2,6R-dimethyl-8- hydroxyoctan-3-one was proposed. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-005-0070-6

Chemistry of Natural Compounds, Vol. 41, No. 1, 2005
SYNTHESIS OF THE PROMISING CHIRAL SYNTHON
ISOPROPYL-4R-METHYL-6-IODOHEXANOATE FROM L-(−)-MENTHOL
G. Yu. Ishmuratov,1 M. P. Yakovleva,1 V. A. Ganieva,2
R. R. Muslukhov,1 and G. A. Tolstikov1
UDC 542.943.5+547.48+547.596
Asynthesisofthepromisingopticallypuresynthonisopropyl-4R-methyl-6-iodohexanoatebasedonozonolytic
−
transformation of the product of regiospecific dehydratation of L-( )-menthol, (R)-p-menth-3-ene, into
2,6R-dimethyl-8-hydroxyoctan-3-one was proposed.
Key words: L-(−)-menthol, ozonolysis, ( )- -menth-3-ene, 2,6 -dimethyl-8-hydroxyoctan-3-one, 3 ,7-dimethyloctan-
R p
R
R
1,6 -diol,3 ,7-dimethyl-6-oxooctyl ester of3 ,7-dimethyl-6-oxooctanoicacid, 3 ,7-dimethyl-6-oxooctanoicacid, sodium -
tris
S
R
R
R
acetoxyborohydride.
We have expanded the synthetic potential of the readily available natural monoterpenoid L-(−)-menthol (1) by
synthesizing the promising optically pure synthon isopropyl-4 -methyl-6-iodohexanoate (6), which is a functional analog of
R
methyl-4 -methyl-6-iodohexanoate. The last compound is available from (+)-citronellic acid and is used to synthesize
R
biologically active compounds for medicine, agrochemistry, fragrances, and liquid crystals [1]. Furthermore, it was used to
synthesize sex pheromones of the smaller tea tortrix moth [2], German cockroach, and pine sawfly [3].
TsCl
Py
OTs
OH
1. O3 / CH2Cl2
NaI
I
MCPBA
OTs
O
O
[6]
2. NaBH(OAc)3
OH
i
i
CO2Pr
CO2Pr
4
1
6
5
3
2
[8]
O
O
NaClO
O
+
3
O
O
NaBH(OAc)3
NaClO
O
OH
OH
DIBAH
O
10
PCC
(NaClO)
O
CO2H
7
8
+
+
10
3
9
O
11
1) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, RF, 450054, Ufa, prospekt
Oktyabrya, 71, fax (3472) 35 60 66, e-mail: kharis@anrb.ru; 2) Birsk State Pedagogic Institute, RF, 452320, Birsk, ul.
Internatsional′naya, 10. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 33-36, January-February, 2005. Original
article submitted August 3, 2004.
0009-3130/05/4101-0041 ©2005 Springer Science + Business Media, Inc.
41

Thekeyintermediate in our proposedsynthesisis2,6R-dimethyl-8-hydroxyoctan-3-one(3), which waspreparedearlier
from (+)-citronellol by isomerization of its epoxide [4, 5].
The first approach to 3 was based on ozonolytic transformation of the product of regiospecific dehydratation of 1 by
the literature method [6], (R)-p-menth-3-ene (2), under the conditions of the method previously proposed by us for direct
reduction of the ozonolysis products of 1-alkylcycloalkenes into ketoalcohols [7].
Further selectivetransformationsof3 intothedesirediodoester 6includedprotection ofthehydroxyl, Baeyer—Villager
oxidation of the intermediate tosyloxyketone (4), and exchange of the p-toluenesulfonate for iodine.
Another longer and less effective approach to 3 was based on initial transformation of the menthollactone (7), which
is available from 1 [8], into the corresponding diol (8). Oxidation of 8 by sodium hypochlorite, which is widely used to oxidize
secondary alcohols in the presence of primary ones, by the literature method [9] at a reagent ratio 8:NaClO = 1:2.1 was
complicated by the formation of significant quantities of other products (according to GC of the resulting reaction mixture):
diketoester 10 (61%), the Tishchenko disproportionation product of the side product ketoaldehyde 9, and ketoacid 11 (23%),
from reoxidation of the same aldehyde. Performing the reaction by titration (very slow addition of the oxidant) with a reagent
ratio 8:NaClO = 1:1 produced only hydroxyketone 3 in 87% yield.
Furthermore, 8 underwent exhaustive Corey oxidation to 9, which was reduced without purification by sodium
tris-acetoxyborohydride, which selectively reduces an aldehyde in the presence of a ketone [10]. However, this reaction was
also accompanied by formation of significant quantities (up to 50%) of 10 according to GC.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument as thin layers. NMR spectra were recoded 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
impurity protons at δ 7.27 ppm in the deuterated solvent for PMR and the average CDCl signal at δ 77.00 ppm for C NMR.
3
Signals in the PMR spectra of 3 and 11 were assigned using homonuclear correlation spectroscopy (COSY 90). Spin—spin
coupling constants (SSCC) were determined by double resonance. GC was performed in 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, stationaryphase PEG-6000, working temperature 50-200°C] instruments with He carrier gas.
Column chromatography was carried out over silica gel L (40-100 µm, Czech Rep.). TLC used Silufol UV-254 plates (Czech
Rep.). Optical rotation was measured on a Perkin—Elmer-241-MC polarimeter. Elemental analyses of all compounds agreed
with those calculated. For chromatography used petroleum ether (40-70°C, PE). An aqueous solution (1 M) of NaClO
(Ufakhimprom, Bashkortostan Rep.) was used.
(R)-p-Menth-3-ene (2). Menthol (1, 2.50 g, 14.0 mmol) and triphenylphosphine (PPh , 4.20 g, 16.0 mmol) were
3
dissolved in dryCH CN (20 mL), heated to boiling, and treated dropwise with CCl (2.50 g, 16.0 mmol). The resulting mixture
3
4
was boiled until HCl was no longer evolved (~20 h) and then cooled. The resulting solid was filtered off. The solvent was
removed at atmospheric pressure using a fractionating column 0.2 m in length. The solid was chromatographed over SiO
2
20
(pentane) to afford 2 (1.16 g, 60%), [α]
+114.88°, lit. [11]. The IR spectrum is practically identical to that described
D
13
previously [12]; PMR and C NMR, [13].
2,6R-Dimethyl-8-hydroxyoctan-3-one (3). An ozone—oxygen mixture (ozonator productivity40.0 mmol O /h) was
3
bubbled through a solution of 2 (0.90 g, 6.5 mmol) and glacial AcOH (0.78 g, 13.0 mmol) in CH Cl (18 mL) with stirring at
2
2
-4 to-2°C until 6.7 mmol of ozone was absorbed. The reaction mixture was purged with Ar, diluted with CH Cl (9 mL), stirred
2
2
(10°C), and treated with a previously prepared suspension of NaBH(OAc) [prepared by adding a solution of glacial AcOH
3
(5.34 g, 89.0 mmol) in CH Cl (9 mL) to a suspension of NaBH (1.13 g, 29.7 mol) in CH Cl (45 mL) with subsequent stirring
2
2
4
2
2
for 2 h]. The reaction mixture was heated to room temperature, stirred for 3 h, cooled to 10°C, and treated with a solution of
NaOH (2.03 g) in water (45 mL). The organic layer was separated. The aqueous layer was extracted with CH Cl , successively
2
2
20
washed with saturated NH Cl solution and water, dried over Na SO , and evaporated to produce 3 (0.89 g, 78%), [α]
(c 0.3, CHCl ), R 0.42 (PE:ethylacetate = 7:3). IR spectrum (KBr, ν, cm ): 3200-3600, 1055 (OH), 1708 (C=O).
+8.64°
4
2
4
D
-1
f
3
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.89 (3H, d, J = 6.7, CH C-6), 1.06 (6H, d, J = 6.7, CH C-2, H-8), 1.40-1.55
3
3
3
3
(2H, m, H-4, H-7), 1.59-1.73 (2H, m, H-4, H-7), 1.75-1.92 (1H, m, H-6), 2.43-2.52 (2H, m, H-4), 2.53 (1H, septet, J = 6.9,
H-2), 4.07 (2H, dd, J = 9.1, J = 6.9, H-8).
2
3
42

13
C NMR spectrum (CDCl ): 18.27 (q, CH C-2), 19.08 (q, CH C-6), 27.67 (d, C-6), 30.03 (t, C-5), 37.80 (t, C-4),
3
3
3
40.61 (d, C-2), 41.61 (t, C-7), 62.49 (t, C-8), 214.38 (s, C-3).
3R,7-Dimethyloctan-1,6S-diol (8). A solution of 7 (23.5 mmol) prepared as before [8] in dry CH Cl (80 mL) was
2
2
treated dropwise (Ar, -15°C) with a toluene solution (12.5 mL, 73%) of diisobutylaluminium hydride (DIBAH) in dry CH Cl
2
2
(10 mL), stored (-15°C, 1 h; 20°C, 12 h), and treated successively with THF (11 mL) and H O (25 mL). The resulting solid
2
was filtered off with a sintered-glass filter. The organic layer was dried over MgSO , filtered, and evaporated to afford 8
4
20
-1
(3.33 g, 83%), R 0.10 (PE:ethylacetate = 7:3), [α]
-10.3° (c 2.43, CHCl ). IR spectrum (KBr, ν, cm ): 3200-3600, 1100,
3
f
D
1055 (OH).
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.75-0.95 (9H, ddd, J = 6.7, CH C-3, CH C-7, H-8), 1.10-1.70 (9H, m,
3
3
3
H-2—H-7), 2.50 (2H, br.s, OH), 3.50-3.75 (2H, m, H-1).
13
C NMR spectrum (CDCl ): 16.99 and 18.81 (q, CH C-7, C-8), 19.74 (q, CH C-3), 29.54 (d, C-3), 31.20 (t, C-5),
3
3
3
32.77 (t, C-4), 33.37 (d, C-7), 39.58 (t, C-2), 60.13 (t, C-1), 76.67 (d, C-6).
2,6R-Dimethyl-8-hydroxyoctan-3-one(3),3,7-Dimethyl-6-oxooctyl Ester of 3,7-Dimethyl-6-oxooctanoic Acid (10),
and 3R,7-Dimethyl-6-oxooctanoic Acid (11).
a. A solution of8 (1.18 g, 6.8 mmol) and glacial AcOH(5 mL) at room temperature was treated dropwise with aqueous
NaClO (7.2 mL, 1 M) and then after 30 min with another portion (7.2 mL) of the same solution, stirred for 12 h until the
peroxide disappeared (iodine—starch test), diluted with ethylacetate (50 mL), washed successively with saturated solutions of
NaHCO and NaCl, dried over Na SO , filtered, and evaporated to produce a mixture (1.01 g) consisting according to GC of
3
2
4
3 (16%), 10 (61%), and 11 (23%), which was separated chromatographically over SiO (PE:ethylacetate = 7:3).
2
b. A solution of 8 (1.00 g, 6.0 mmol) in glacial AcOH (3 mL) at room temperature was treated dropwise over 1 h with
aqueous NaClO (6.0 mL, 1 M, 6.0 mmol), extracted with CH Cl (3 × 30 mL), washed successively with saturated solutions
2
2
of NaHCO and NaCl, dried over Na SO , filtered, and evaporated to produce 3 (0.86 g, 87%).
3
2
4
c. A suspension ofpyridinium chlorochromate (PCC, 5.02 g, 23.3 mmol) in dryCH Cl (8 mL) (Ar, 20°C) was treated
2
2
dropwise with 8 (1.30 g, 7.5 mmol) in dry CH Cl (5 mL), stored for 2 h, diluted with Et O (20 mL), and filtered through SiO
2
2
2
2
(20 g) on a sintered-glass filter. The filtrate was evaporated. The solid 3R,7-dimethyloctan-6-on-1-al (9, 1.25 g, R 0.50,
f
PE:ethylacetate = 7:3) was dissolved in dry CH Cl (10 mL), stirred (10°C), and treated with a previouslyprepared suspension
2
2
of NaBH(OAc) [prepared by adding a solution of glacial AcOH (6.20 g, 103.0 mmol) in CH Cl (10 mL) to a suspension of
3
2
2
NaBH (1.30 g, 34.4 mmol) in CH Cl (50 mL) with subsequent stirring for 2 h]. The reaction mixture was heated to room
4
2
2
temperature, stirred for 3 h, cooled to 10°C, and treated with a solution of NaOH (2.34 g, 58.5 mmol) in water (50 mL). The
organic layer was separated. The aqueous layer was extracted with CH Cl (3 × 50 mL) washed successively with saturated
2
2
solutions of NH Cl and water, dried over Na SO , and evaporated to produce a mixture (1.15 g) consisting according to GC
4
2
4
of 3 (50%) and 10 (50%), which was separated chromatographically over SiO (PE:ethylacetate = 7:3).
2
13
The IR spectra, PMR spectra, and C NMR spectra of 3 prepared by methods a-c were practically identical to those
described above.
3R,7-Dimethyl-6-oxooctyl Ester of 3R,7-Dimethyl-6-oxooctanoic Acid (10), R 0.57 (PE:ethylacetate = 7:3),
f
20
-1
[α]
+13.6° (c 1.73, CHCl ). IR spectrum (KBr, ν, cm ): 1735, 1705 (C=O), 1030 (C–O–C).
D
3
3
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.98 (6H, d, J = 6.7, CH C-3, CH C-3′), 1.07 (12H, d, J = 7.0, CH C-7,
3
3
3
3
CH C-7′, H-8, H-8′), 1.33-1.49 (3H, m, H-2′, H-4, H-4′), 1.51-1.68 (3H, m, H-2′, H-4, H-4′), 1.90-2.25 (2H, m, H-3, H-3′), 2.09
3
2
3
2
3
(1H, dd, J = 15.2, J = 7.4, H-2), 2.25 (1H, dd, J = 15.2, J = 6.0, H-2), 2.40-2.48 (4H, m, H-5, H-5′), 2.60-2.75 (2H, m, H-7,
H-7′), 4.03 (2H, t, J = 6.6, H-1′).
13
C NMR spectrum (CDCl , δ, ppm): 18.10 (q, CH C-7, C-8, CH C-7′, C-8′), 18.95 (q, CH C-3), 19.29 (q, CH C-3′),
3
3
3
3
3
29.27 (d, C-3′), 29.74 (d, C-3), 30.02 (t, C-4), 30.26 (t, C-4′), 35.08 (t, C-7), 37.53 (t, C-2′, C-5′), 40.53 (d, C-7, C-7′), 42.25
(t, C-2), 62.27 (t, C-1′), 172.65 (s, C-1), 214.13 (s, C-6′), 214.42 (s, C-6).
20
3R,7-Dimethyl-6-oxooctanoic Acid (11), R 0.25 (PE:ethylacetate = 7:3), [α]
+9.90° (c 0.25, CHCl ). IRspectrum
f
D
3
-1
(KBr, ν, cm ): 1705, 1725 (C=O).
3
3
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.98 (3H, d, J = 6.7, CH C-3), 1.10 (6H, d, J = 7.0, CH C-7, H-8), 1.49 (1H,
3
3
3
3
2
3
3
2
3
dtd, J = 14.8, J = 5.7, J = 3.9, H-4), 1.67 (1H, dtd, J = 14.8, J = 7.7, J = 8.7, H-4), 1.90-2.20 (1H, m, H-3), 2.18 (1H, dd,
J = 15.1, J = 7.9, H-2), 2.34 (1H, dd, J = 15.1, J = 6.0, H-2), 2.43-2.52 (2H, m, H-5), 2.61 (1H, septet, J = 7.0, H-7), 8.9
(1H, br.s, OH).
2
3
2
3
3
43

13
C NMRspectrum (CDCl ): 18.30 (q, CH C-7, C-8), 18.87 (q, CH C-3), 29.61 (d, C-3), 30.07 (t, C-4), 37.60 (t, C-5),
3
3
3
40.67 (d, C-7), 41.16 (t, C-2), 178.40 (s, C-1), 214.69 (s, C-6).
3R,7-Dimethyl-1-tosyloxyoctan-6-one (4). A solution of p-toluenesulfonyl chloride (TsCl, 0.76 g, 3.96 mmol) in dry
Py (5 mL) (Ar, 0°C) was treated with 3 (0.57 g, 3.30 mmol), held at that temperature for 12 h, diluted with Et O (50 mL),
2
washed successivelywith HCl (10%) and saturated solutions ofNaHCO and NaCl, dried over MgSO , filtered, and evaporated
3
4
-1
to produce 4 (0.84 g, 78%). IR spectrum (KBr, ν, cm ): 1715 (C=O), 1600 (Ar), 1370, 1180 (S–O).
Isopropyl-4R-methyl-6-tosyloxyhexanoate (5). A suspension of m-chloroperbenzoic acid (MCPBA, 0.40 g, 50%)
in dry CHCl (1 mL) (20°C) was treated dropwise with a solution of 4 (0.40 g, 1.2 mmol) in dry CHCl (3 mL), stirred for
3
3
5 h, diluted with CH Cl (5 mL), washed successively with saturated solutions of Na S O and NaCl, dried over MgSO ,
2
2
2 2
3
4
-1
filtered, and evaporated to produce 5 (0.40 g, 96%). IR spectrum (KBr, ν, cm ): 1735 (C=O), 1590 (Ar), 1370, 1180 (S–O).
Isopropyl-4R-methyl-6-iodohexanoate (6). A solution of 5 (0.40 g, 1.1 mmol) and NaI (0.42 g, 2.8 mmol) in dry
acetone (4 mL) was boiled for 1.5 h, left in the dark for 24 h, diluted with icewater (3 mL), extracted with Et O (3 × 15 mL),
2
washed successively with saturated solutions of Na S O , NaHCO , and NaCl, dried over MgSO , filtered, and evaporated.
2 2
3
3
4
20
The solid was chromatographed over SiO (PE:ethylacetate = 5:1) to produce 6 (0.40 g, 92%), [α]
R 0.47 (PE:ethylacetate = 5:1). IR spectrum (KBr, ν, cm ): 1735 (C=O), 500 (C–J).
-6.1° (c 4.10, CHCl ),
3
2
D
-1
f
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.85 (3H, d, CH C-4, J = 6.2), 1.21 [6H, d, CH(CH ) , J = 6.3], 1.50-1.70 (2H,
3
3
3 2
m, H-5), 1.48-1.65 (2H, m, H-3), 1.65-1.80 (1H, m, H-4), 2.20-2.35 (2H, m, H-2), 3.13 (2H, t, H-6, J = 7.5), 4.96 [1H, st,
CH(CH ) , J = 6.3].
3 2
13
C NMR spectrum (CDCl ): 4.47 (t, C-6), 18.25 (q, CH C-4), 21.77 [q, CH(CH ) ], 31.02 (t, C-2), 32.08 (t, C-3),
3
3
3 2
40.43 (t, C-5), 67.41 [d, CH(CH ) ], 173.01 (s, C-1).
3 2
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