New orthogonally functionalized synthetic blocks from R-(-)-carvone

Article abstract of DOI:10.1134/S107042801005012X

The intramolecular cyclization of (-)-cis-carveol under iodine treatment afforded (1R,5R,6S)-6-iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene that was subjected to allyl oxydation with the complex CrO₃DMP giving a synthetically valuable building block, (1R,5R,6S)-6-iodomethyl-2,6-dimethyl-7- oxabicyclo[3.2.1]oct-2-ene-4-one. In the latter the double bond was cleaved by ozonization to obtain the expected trioxo derivative, and the subsequent ozonolysis of its enol form provided a multiple functionalized tetrahydrofuran derivative. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S107042801005012X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 670−673. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © R.F. Valeev, L.S. Khasanova, M.S. Miftakhov, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 5,
pp. 643−645.
New Orthogonally Functionalized Synthetic Blocks
from R-(–)-Carvone
R. F. Valeev, L. S. Khasanova, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054, Russia
e-mail: bioreg@anrb.ru
Received October 15, 2008
Abstract—The intramolecular cyclization of (–)-cis-carveol under iodine treatment afforded (1R,5R,6S)-6-
iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene that was subjected to allyl oxydation with the complex
CrO3DMP giving a synthetically valuable building block, (1R,5R,6S)-6-iodomethyl-2,6-dimethyl-7-
oxabicyclo[3.2.1]oct-2-ene-4-one. In the latter the double bond was cleaved by ozonization to obtain the expected
trioxo derivative, and the subsequent ozonolysis of its enol form provided a multiple functionalized tetrahydrofuran
derivative.
DOI: 10.1134/S107042801005012X
Recently available and cheap R-(–)-carvone (I) found
extensive application as a chiral matrix to the targeted
synthesis of complex structures [1–10]. In the course of
development of the transition from the bicyclic compound
II [11] to unsaturated α-hydroxyketone III we obtained
several synthons IV–VIII of the general synthetic
interest and found an uncommon SiO2-promoted case
of the enolization of the α-ketoaldehyde fragment of
compound VI.
In keeping with the planned design of preparation of
hydroxyketone III a problem arose of the oxidative
cleavage of the double bond in compound II with the
oxidative “removal” of its two-carbon C3–C4. To this end
we first of all subjected compound II to allyl oxidation
with the complex CrO3·DMP (DMP is 1,5-
dimethylpyrazole) [12] and obtained cyclohexenone IV.
Cyclohexenone IV apart from the possibility to use it
in the main path of the designed synthesis is synthetically
Scheme 1.
O
_
(1) NaBH4 CeCl3 7H2O, MeOH
I
O
.
OH
O
(2) I2, NaHCO3, MeCN
2
5
1
6
3
4
R
5
II
III
I
Scheme 2.
O
.
CrO3 DMP
O
O
65%
O
O
O
6
O
I
I
II
V
IV
670

NEW ORTHOGONALLY FUNCTIONALIZED SYNTHETIC BLOCKS
671
attractive also as a inherently protected and stable 4-oxo
derivative of cis-carveol. We also used compound IV
for proving the structure of the basis bicycle II. The
S-configuration of the chiral center C6 in compound II
shown on the scheme was assumed on the grounds of
the data of chemical correlation with the preparation from
compound IV of lactone V by periodate cleavage
catalyzed with RuCl3. The latter process will be published
elsewhere.
repulsion of the all-cis oxo functions and the CH2I-sub-
stituent in compound VI. The enolization in the α-keto-
aldehyde fragment somewhat reduces the strain in the
system and is the driving force of the conversion of ketone
VI into enol VII.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer UR-
1
20 from thin films. H and 13C NMR spectra were
Further the oxidative cleavage of the double bond in
enone IV was investigated. The ozonization was per-
formed in MeOH at –78°C. In the process of chromato-
0graphic purification of the reduced ozonization product
ketoaldehyde VI detected in the reaction mixture by TLC
transformed into enol VII.According to the spectral data
enol VII is an isomerically pure compound, but we have
not proved the configuration of its double bond, and the
shown structure belongs to the preferred less hindered
E-isomer.
registered on a spectrometer Bruker AM-300 [300 (1H),
75.47 MHz (13C)] from solutions in CDCl3, internal
reference TMS. TLC analysis was performed on Silufol
plates. Rotation angles were measured on an instrument
Perkin-Elmer 241 MC. The purity of initial compounds
was checked by GLC on a chromatograph Chrom 5.
(1R,5R,6S)-6-Iodomethyl-2,6-dimethyl-7-
oxabicyclo[3.2.1]oct-2-ene (II). To a solution of 0.1 g
(0.67 mmol) of R-(–)-carvone (I) and 0.25 g (0.67 mmol)
of CeCl3·7H2O in 10 ml of MeOH was added at 20°C
0.025 g (0.67 mmol) of NaBH4, and the reaction mixture
was stirred for 5 min. The reaction mixture was diluted
with 20 ml of ethyl ether and 20 ml of H2O, the ether
layer was separated, the products were extracted from
the water layer with ether (3 × 10 ml), the combined
ether extracts were dried with Na2SO4 and filtered. The
filtrate was concentrated under a reduced pressure, the
residue was purified by column chromatography on SiO2
(petroleum ether–ethyl acetate, 5:1). Yield of (−)-cis-
carveol 0.09 g (90%), [α]D20 –23.6° (C 0.85, EtOH). IR
spectrum, ν, cm–1: 3331 (OH), 3082 (=CH), 1645 (C=C).
1H NMR spectrum, δ, ppm: 1.47–1.52 m (1H, H6), 1.72
s (3H, CH3), 1.74 d (3H, CH3, J 2 Hz), 1.85–2.30 m (5H,
H4,5,6, OH), 4.17 br.s (1H, H1), 4.71 s (2H, =CH2), 5.44 m
(1H, H3). 13C NMR spectrum, δ, ppm: 18.71 (CH3),
20.36 (CH3), 30.72 (C4), 37.60 (C6), 40.11 (C5), 70.61
The primary ozonization product VI was stirred in
EtOAc with the dispersion of SiO2 to convert it into enol
VII and then the latter was subjected to ozonization. Under
the conditions of the ozonization of enone IV (MeOH, –
78°C) enol VII did not react with ozone. Therefore the
enol ozonization was performed in MeOH at –40°C to
obtain furanones VIII and IX in the 1:1 ratio (1H NMR).
These compounds appeared on TLC as a single spot,
their chromatographic separation on SiO2 failed due to
the ready removal of the protective dimethylketal function
in compound IX. Therefore the formed mixture of
compounds VIII and IX was maintained in acid-water
medium till ketal IX completely converted into ketone
VIII.
The tendency of α-ketoaldehyde VI to enolization is
not quite understandable. One of probable reasons
consists in the sterical overloading and the electrostatic
Scheme 3.
MeO OMe
I
O
O
O
I
I
O
O
SiO2
O3
O
O
O
O3
IX
+
H3O+
I
O
EtOAc
O
O
OHC
OH
O
CHO
I
IV
VII
VI
VIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

VALEEV et al.
672
(C1), 108.86 (=CH2), 123.59 (C3), 135.84 (C2), 148.69
(=C=).
(2S,5R)-5-Acetyl-2-iodomethyl-2-methyl-
dihydrofuran-3-ylidenehydroxyacetaldehyde (VII).
Through a solution of 0.75 g (2.6 mmol) of ketone IV in
20 ml of MeOH was passed O3 at –78OC. When the
solution turned blue it was flushed with argon, 1 ml of
Me2S was added, the mixture was warmed to room
temperature and stirred for 3 h. Then the solvent was
distilled off, the residue was dissolved in 20 ml of EtOAc,
3 g of SiO2 was added, and the mixture was stirred for 6
h. Afterwards the solution was filtered, evaporated, and
the residue was subjected to column chromatography on
SiO2 (EtOAc–petroleum ether, 2:1). Yield 0.82 g (98%),
viscous light-yellow fluid, [α]D20 +57.3° (C 2.0, CHCl3).
IR spectrum, ν, cm–1: 3412 (OH), 1716, 1658 (2C=O).
1H NMR spectrum, δ, ppm: 1.64 s (3H, CH3), 2.43 s
(3H, CH3), 2.99–3.08 m (1H, H4), 3.27–3.35 m (1H, H4),
3.56 d (1H, CH2I, J 9 Hz), 3.93 d (1H, CH2I, J 9 Hz),
4.45–4.51 m (1H, H5), 6.04 br.s (1H, OH), 9.60 s (1H,
CHO). 13C NMR spectrum, δ, ppm: 13.40 (CH2I), 21.49
(CH3), 26.58 (CH3), 30.96 (C4), 81.71 (C5), 85.46 (C2),
136.44 (C3), 140.84 (=C=), 185.20 (CHO), 208.39 (C=O).
Mass spectrum (ACPI), m/z (Irel, %): 197 ([M –HI +
H]+, 127I) (100), 325 ([M + H]+, 127I) (1.25).
To a solution of 0.5 g (3.3 mmol) of (–)-carveol in
20 ml of acetonitrile at 0°C while stirring was added in
one portion 0.55 g (6.6 mmol) of NaHCO3. The mixture
was stirred for 15 min, then 0.84 g (3.3 mmol) of crystalline
I2 was added. The reaction mixture was stirred for 2 h at
room temperature till the disappearance of the initial
compound (TLC monitoring), the solution was evaporated,
and 15 ml of saturated solution of Na2S2O3 was added,
the reaction products were extracted with EtOAc (3 ×
10 ml). The combined organic solutions were dried with
MgSO4 and evaporated, the residue was subjected to
column chromatography on SiO2 (EtOAc–petroleum
ether, 1:10). Yield of compound II 0.66 g (73%). Light
yellow fluid, [α]D20 –17.5° (C 5.0, EtOH). IR spectrum,
ν, cm–1: 1088 (C–O–C). 1H NMR spectrum, δ, ppm:
1.45 s (3H, CH3), 1.70–1.72 m (3H, CH3), 1.91–1.95 m
(1H, H8), 2.23–2.38 m (3H, H4,5,8), 2.49–2.50 m (1H,
H4), 3.30 d (1H, CH2I, J 9 Hz), 3.37 d (1H, CH2I,
J 9 Hz), 4.13–4.15 m (1H, H1), 5.25–5.27 m (1H, H3).
13C NMR spectrum, δ, ppm: 14.22 (CH2I), 21.41 (CH3),
27.94 (CH3), 29.76 (C4), 35.10 (C8), 40.77 (C5), 77.53
(C1), 84.03 (C6), 120.72 (C3), 139.80 (C2).
(2S,5R)-5-Acetyl-2-iodomethyl-2-methyl-
dihydrofuran-3-one (VIII). Through a solution of 0.6 g
(1.86 mmol) of enol VII in 20 ml of MeOH was passed
O3 at –40°C to the ratio 3 mmol of O3 per 1 mmol of the
substrate. Then the reaction mixture was flushed with
argon, Me2S was added, the mixture was warmed to room
temperature, acidified with 10N water solution of HCl,
and stirred for 6 h.The solvent was distilled off, and the
residue was subjected to column chromatography on SiO2
(EtOAc–petroleum ether, 2:1). Yield 0.31 g (60%), light-
yellow fluid, [α]D20 +105.5° (C 2.35, CH2Cl2). IR
(1R,5R,6S)-6-Iodomethyl-2,6-dimethyl-7-
oxabicyclo[3.2.1]oct-2-ene-4-one (IV). To a solution
of 5.4 g (54.0 mmol) of CrO3 in 40 ml CH2Cl2 at –20°C
was added in one portion at stirring 5.2 g (54.0 mmol) of
1,5-dimethylpyrazole. The mixture was stirred for 15 min,
then 1 g (3.6 mmol) of compound II was added. The
reaction mixture was stirred for 4 h at –15°C, 20 ml of
20% aqueous NaOH was added, and the stirring was
continued for 1 h at 0°C. The organic layer was separated,
washed with 50% HCl solution for removing 1,5-di-
methylpyrazole, then with brine, dried with MgSO4, and
evaporated. The residue was subjected to column
chromatography on SiO2 (CHCl3–MeOH, 40:1). Yield
0.68 g (65%), light-yellow fluid. [α]D20 +350.3° (C 4.0,
1
spectrum, ν, cm–1: 1761, 1716 (2C=O). H NMR
spectrum, δ, ppm: 1.39 s (3H, CH3), 2.45 s (3H, CH3),
2.72–2.75 m (2H, H4), 3.26 d (1H, CH2I, J 9 Hz), 3.35 d
(1H, CH2I, J 9 Hz), 4.60–4.65 m (1H, H5). 13C NMR
spectrum, δ, ppm: 9.35 (CH2I), 20.86 (CH3), 26.47 (CH3),
37.49 (C4), 77.65 (C5), 82.39 (C2), 208.60 (2C=O).
1
CHCl3). IR spectrum, ν, cm–1: 1676 (C=O). H NMR
spectrum, δ, ppm: 1.55 s (3H, CH3), 2.08 s (3H, CH3),
2.36 d (1H, H8, J 12 Hz), 2.46–2.50 m (1H, H8), 3.10 m
(1H, H5), 3.12 d (1H, CH2I, J 9 Hz), 3.22 d (1H, CH2I,
J 9 Hz), 4.47–4.49 m (1H, H1), 5.78–5.79 m (1H, H3).
13C NMR spectrum, δ, ppm: 13.71 (CH2I), 22.16 (CH3),
28.23 (CH3), 39.96 (C8), 58.44 (C5), 78.27 (C1), 81.39
(C6), 125.70 (C3), 165.39 (C2), 199.02 (C=O). Mass
spectrum (ACPI), m/z (Irel, %): 293 ([M + H]+, 127I) (100),
165 ([M – HI + H]+, 127I) (42.4).
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