Synthesis of optically active 5-alkoxy-6-methylcyclohex-2-en-1-ones and 4-alkoxy-5-methylcyclopent-1-enyl benzoate

Article abstract of DOI:10.1021/jo801981c

(Chemical Equation Presented) The reaction of (-)-(1E,3Z)-2-methyl-1-((1S)- 1-phenylethoxy)penta-1,3-dien-3-ol benzoate with allyltrimethylsilane in SO ₂ and in the presence of a catalytic amount of Tf₂NTMS gives a silyl sulfinate in

Full text of DOI:10.1021/jo801981c

their synthesis have been proposed.16,17 The two 5-siloxycy-
clohex-2-enones 1 and 218 and bicyclic compounds 319 and 420
are the only enantiomerically enriched 6-alkyl-substituted 5-hy-
droxycyclohex-2-enone derivatives reported thus far.
Synthesis of Optically Active
5-Alkoxy-6-methylcyclohex-2-en-1-ones and
4-Alkoxy-5-methylcyclopent-1-enyl Benzoate
Mjaris Turks† and Pierre Vogel*
Laboratory of Glycochemistry and Asymmetric Synthesis
(LGSA), Swiss Federal Institute of Technology (EPFL),
Batochime, CH-1015 Lausanne, Switzerland
pierre.Vogel@epfl.ch
ReceiVed September 20, 2008
The synthesis of 5-hydroxy-, 5-alkoxy-, and 5-siloxycyclohex-
2-enones is a challenge because these compounds are prone to
ꢀ-eliminations generating the corresponding phenols, under basic
or acidic conditions. We present here an original approach to
the synthesis of enantiomerically enriched 6-alkyl-5-alkoxycy-
clohex-2-enones. The method is illustrated for the preparation
of derivative 5. We disclose also the synthesis of the enantio-
merically enriched cyclopentanone enol benzoate 6, a yet
unknown compound. Apart from their potential as synthetic
intermediates, both 5 and 6 are of interest for the perfume
industry.21-32
The reaction of (-)-(1E,3Z)-2-methyl-1-((1S)-1-phenylethox-
y)penta-1,3-dien-3-ol benzoate with allyltrimethylsilane in
SO2 and in the presence of a catalytic amount of Tf2NTMS
gives a silyl sulfinate intermediate that furnishes (-)-
(6Z,1′S,4S,5S)-5-methyl-4-(1′-phenylethoxy)octa-1,6-dien-6-
yl benzoate after acidic workup. The latter undergoes ring-
closing metathesis producing (-)-(2S,3S)-2-methyl-3-((1S)-
1-phenylethoxy)cyclopent-5-en-1-yl benzoate. It has been
converted also into the corresponding trimethylsilyl enol
ether. After oxidation, an enone is obtained that undergoes
ring-closing metathesis giving (-)-(5S,6S)-6-methyl-5-((1S)-
1-phenylethoxy)cyclohex-2-en-1-one.
In 2004, we reported that the reactions of 1-alkoxy-1,3-dien-
3-ol esters (7) with sulfur dioxide and allylsilanes (10) generate
enol esters of type 13 with high stereoselectivity. The reactions
imply equilibrium of dienes 7 + SO2 with corresponding
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† Present Address: Faculty of Material Science and Applied Chemistry, Riga
Technical University, Riga LV-1048, Latvia.
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10.1021/jo801981c CCC: $40.75
Published on Web 11/14/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 435–437 435

SCHEME 1
SCHEME 2
17 was obtained in 82% yield (based on 16) and was then
submitted to oxidation with an excess of 2-iodoxybenzoic acid
(IBX) and 4-methoxypyridine N-oxide (MPO) in DMSO (25
°C, 16 h)46,47 to produce enone 18 in 64% yield. In the presence
of 10 mol % of Grubbs’ II catalyst in dry benzene (80 °C, 30
min), ring-closing alkene metathesis furnished cyclohexenone
5 in 85% yield. Because of the neutral conditions used for the
latter reaction, heating of 5 did not induce ꢀ-elimination of
1-phenylethanol.
We believe that the chemistry disclosed here can be applied
to the synthesis to further enantiomerically enriched 5-alkoxy-
6-alkylcyclohex-2-enone derivatives starting from dienes of type
7 (R1 * Me). As both enantiomeric forms of the chiral auxiliary
(1-phenylethanol) are commercially available, the cyclohex-
enones can be obtained in both their enantiomeric forms.
unstable sultines 8 that, in the presence of a protic or Lewis
acid catalyst, are isomerized into zwitterionic species 9 that are
allylated by the allylsilanes 10 producing silyl sulfinates 11.
After acidic workup, the corresponding ꢀ,γ-unsaturated sulfinic
acids 12 undergo stereoselective retro-ene eliminations of SO2
with formation of 13 (Scheme 1).33
In this process, sulfur dioxide permits the Umpolung of the
electron-rich dienes 7 generating oxyallyl cationic intermediates
(9) that are quenched by electron-rich alkenes such as
allylsilanes.34,35 Compounds 13 undergo ring-closing me-
tathesis36-38 catalyzed by the second-generation Grubbs’
catalyst.39-42 An example is given with enol benzoate 16 (ee
97%) obtained by reaction of (-)-(1E,3Z)-2-methyl-1-((1S)-1-
phenylethoxy)-penta-1,3-dien-3-ol benzoate (14, ee 97%) with
SO2 and allyltrimethylsilane (15) in the presence of a catalytic
amount of (CF3SO2)2NSiMe3 at -78 °C.43 Thus, in the presence
of 0.1 equiv of Grubbs’ II catalyst (dry benzene, 80 °C, 30 min),
cyclopentenyl benzoate 6 was obtained in 75% yield. To our
knowledge, this is the first example of ring-closing metathesis
involving an enol ester and an alkene (Scheme 2), although
several examples of ring-closing alkene metatheses involving
enol ethers or enoxysilanes with alkenes have been presented.44,45
Enol benzoate 16 was converted into its silyl enol ether 17
by reaction with MeLi ·LiBr in Et2O at -78 °C to generate the
corresponding ethyl ketone that was not purified but used
directly in the silylation step with Me3SiOTf/Et3N. Enoxysilane
Experimental Section
Preparation of (-)-(2S,3S)-2-Methyl-3-((1S)-1-phenylethoxy)-
cyclopent-5-en-1-yl Benzoate (6). To a solution of Grubbs’ second-
generation catalyst (31 mg, 0.036 mmol, 0.1 equiv) in dry benzene
(70 mL) under argon atmosphere was added a solution of 16 (0.133
g, 0.36 mmol, 1 equiv).43 The resulting solution was heated under
reflux for 0.5 h. Solvent was evaporated in vacuo and the residue
purified by FC (PE/EtOAc ) 95:5): 88 mg (75%), colorless oil;
1
[R]25 ) -176 (c ) 1.40, CHCl3); H NMR (CD2Cl2, 400 MHz)
D
8.07 (d, 2H, J ) 8.0 Hz), 7.60 (t, 1H, J ) 7.0), 7.47 (t, 2H, J )
7.7), 7.36-7.25 (m, 5H), 5.44 (ddd, 1H, J ) 2.5, 2, 1.1), 4.46 (q,
1H, J ) 6.4), 4.13 (dt, 1H, J ) 7.4, 6.8), 3.00 (dqt, 1H, J ) 7.4,
6.8, 1.5), 2.42 (ddd, 1H, J ) 16.0, 7.4, 3.2), 2.34 (dddd, 1H, J )
16.0, 6.8, 2.5), 1.43 (d, 3H, J ) 6.4), 1.18 (d, 3H, J ) 7.0); 13C
NMR (CD2Cl2, 100.6 MHz) 164.2, 152.8, 144.5, 133.4, 129.8,
128.6, 128.4, 127.4, 126.4, 126.3, 109.3, 76.9, 76.1, 40.5, 34.4,
24.0, 11.2; MALDI-HRMS calcd. for C21H22O3Na+ 345.1467, found
345.1480.
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(34) Vogel, P.; Turks, M.; Bouchez, L. C.; Markovic, D.; Varela-Alvarez,
A.; Sordo, J. A. Acc. Chem. Res. 2007, 40, 931–942.
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M. C.; Fonquerne, F.; Didier, C.; Flowers, C. Pure Appl. Chem. 2008, 80, 791–
805.
(+)-(4S,5S)-4-Methyl-5-((1S)-1-phenylethoxy)octa-1,7-dien-3-
one (18). A solution of 16 (3.32 g, 9.1 mmol, 1 equiv) in Et2O (50
mL) was added at -78 °C to a solution of MeLi ·LiBr (2.2 M,
10.3 mL, 22.7 mmol, 2.5 equiv) in Et2O (24 mL). The reaction
mixture was stirred at -78 °C overnight and afterward poured
slowly into a saturated aqueous solution of NH4Cl (200 mL). The
aqueous phase was extracted with Et2O (3 × 50 mL), washed with
brine, dried (Na2SO4), and evaporated in vacuo. The resulting ethyl
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436 J. Org. Chem. Vol. 74, No. 1, 2009

ketone (2.23 g, ∼94%) was dried under reduced pressure (0.06 Torr,
12 h) and used without further purification. To a solution of the
ethyl ketone (2.23 g, 8.56 mmol, 1 equiv) in CH2Cl2 (40 mL) at
-20 °C was added NEt3 (3.58 mL, 25.7 mmol, 3 equiv) followed
by Me3SiOSO2CF3 (2.01 mL, 11.1 mmol, 1.3 equiv). The reaction
mixture was allowed to reach 20 °C in 2 h. Cold pentane (300 mL
(-50 °C)) was added, and the resulting suspension was filtered
through a small pad of silica gel (suspended in pentane containing
2% of NEt3). The organic phase was sequentially washed with 15%
aqueous solution of citric acid (3 × 70 mL), saturated aqueous
solution of NaHCO3 (3 × 50 mL), and brine (2 × 50 mL), dried
(Na2SO4), and evaporated in vacuo. The resulting oil (17) was dried
under reduced pressure (0.06 Torr, 12 h): yield 2.49 g (82% over
two steps from 16), colorless oil. Analytical data for (2S,3S)-(1-
ethylidene-2-methyl-3-((1S)-1-phenylethoxy)hex-5-enyloxy)trimeth-
1.2), 5.78 (dd, 1H, J ) 10.5, 1.2), 5.74 (ddt, 1H, J ) 17.2, 10.4,
7.4), 4.99 (dm, 1H, J ) 10.4), 4.96 (dm, 1H, J ) 17.2), 4.43 (q,
1H, J ) 6.2), 3.72 (dt, 1H, J ) 8.0, 4.9), 3.21 (dq, 1H, J ) 8.0,
6.8), 2.13 - 2.06 (m, 2H), 1.32 (d, 3H, J ) 6.2), 1.03 (d, 3H, J )
6.8); 13C NMR (CDCl3, 100.6 MHz) 203.5, 144.2, 136.5, 134.1,
128.3, 128.1, 127.5, 126.6, 117.3, 78.5, 46.2, 35.5, 23.6, 12.2; ESI-
HRMS calcd for [C17H22O2 + H]+ 259.1698, found 259.1692.
(-)-(5S,6S)-6-Methyl-5-((1S)-1-phenylethoxy)cyclohex-2-en-
1-one (5). To a solution of Grubb’s second-generation catalyst (98
mg, 0.116 mmol, 0.1 equiv) in dry benzene (240 mL) under argon
atmosphere was added a solution of 18 (0.30 g, 1.16 mmol, 1 equiv).
The resulting solution was heated under reflux for 0.5 h. Solvent
was evaporated in vacuo, and the residue was purified by FC (PE/
EtOAc ) 9:1): yield 0.227 mg (85%); colorless oil; [R]25D ) -130
1
(c ) 0.55, CHCl3); H NMR (CDCl3, 400 MHz) 7.37-7.25 (m,
1
5H), 6.69 (dt, 1H, J ) 10.2, 3.8), 6.25 (dt, 1H, J ) 10.2, 1.9), 4.49
(q, 1H, J ) 7.0), 3.85 (dt, 1H, J ) 7.0, 4.5), 2.76 (dq, 1H, J ) 7.0,
3.8), 2.39 (dddd, 1H, J ) 19.0, 6.0, 3.2, 1.9), 2.34 (dddd, 1H, J )
19.0, 5.1, 1.9, 1.9), 1.42 (d, 3H, J ) 6.4), 1.23 (d, 3H, J ) 7.0);
13C NMR (CDCl3, 100.6 MHz) 198.1, 146.1, 144.1, 129.1, 128.5,
127.6, 126.2, 76.4, 75.1, 45.9, 30.0, 24.5, 10.5; MALDI-HRMS
calcd for C15H18O2Na+ 253.1204, found 253.1209.
ylsilane (17): H NMR (CDCl3, 400 MHz) 7.36-7.25 (m, 5H),
5.65 (ddt, 1H, J ) 17.3, 10.2, 7.0), 4.96 (dm, 1H, J ) 17.3), 4.92
(dm, 1H, J ) 10.2), 4.62 (q, 1H, J ) 6.4), 4.52 (q, 1H, J ) 6.4),
3.53 (dt, 1H, J ) 7.0, 3.8), 2.52 (dq, 1H, J ) 7.0, J ) 6.4),
2.18-2.03 (m, 2H), 1.53 (dd, 3H, 3J ) 7.0, 1.3), 1.42 (d, 3H, J )
6.4), 1.02 (d, 3H, J ) 7.0), 0.19 (s, 9H). To a solution of IBX
(0.252 g, 0.90 mmol, 3 equiv) in DMSO (1.0 mL) was added
MPO·H2O (0.112 g, 0.90 mmol, 3 equiv) at 25 °C. The resulting
mixture was allowed to stay for 30 min. Then a solution of 17
(0.10 g, 0.30 mmol, 1 equiv) in DMSO (0.5 mL) was added, and
the resulting mixture was stirred at 25 °C for 16 h. A saturated
aqueous solution of NaHCO3 (10 mL) was added, and the product
was isolated by extraction with Et2O (3 × 7 mL). The collected
organic layers were washed with brine (3 × 6 mL), dried (Na2SO4),
filtered, and evaporated. The residue was purified by FC (PE/EtOAc
Acknowledgment. We are grateful to the Swiss National
Science Foundation for financial support and to Mr. M. Rey,
F. Sepulveda, Dr. S. R. Dubbaka, Ms. C. Exner, and Mr. S.
Laclef for their technical help.
Supporting Information Available: Analytical details for
products 6, 5, 17, and 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
) 95:5) yielding 50 mg (64% from 17): colorless oil; [R]25
)
D
1
+73 (c ) 0.45, CHCl3); H NMR (CDCl3, 400 MHz) 7.35-7.24
(m, 5H), 6.44 (dd, 1H, J ) 17.2, 10.5), 6.25 (dd, 1H, J ) 17.2,
JO801981C
J. Org. Chem. Vol. 74, No. 1, 2009 437