Stereoconvergent route to chiral cyclohexenone building blocks: Formal synthesis of (-)-dysidiolide

Article abstract of DOI:10.1039/c2ob26532j

A stereoconvergent access to chiral carbocyclic building blocks is reported. 6-(3′-Hydroxy-4′-methylpent-4′-enyl)-3-methoxy cyclohex-2-enone (1) that consists of four stereoisomers, i.e., racemic ca. 1:1 diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent strategy has allowed the formal synthesis of bioactive (-)-dysidiolide.

Full text of DOI:10.1039/c2ob26532j

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PAPER
Stereoconvergent route to chiral cyclohexenone building blocks: formal
synthesis of (−)-dysidiolide†
Gamal A. I. Moustafa, Yasumasa Kamada, Tetsuaki Tanaka and Takehiko Yoshimitsu*
Received 3rd August 2012, Accepted 12th September 2012
DOI: 10.1039/c2ob26532j
A stereoconvergent access to chiral carbocyclic building blocks is reported. 6-(3′-Hydroxy-4′-methylpent-
4′-enyl)-3-methoxy cyclohex-2-enone (1) that consists of four stereoisomers, i.e., racemic ca. 1 : 1
diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective
catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent
strategy has allowed the formal synthesis of bioactive (−)-dysidiolide.
enable chiral induction at the side chain of 1. We initially
attempted the metal–enzyme combocatalysis of racemic diastereo-
Introduction
Carbocycles bearing a quaternary carbon constitute important
motifs in bioactive natural products.1 Their ubiquity has stimu-
lated considerable efforts to establish methods for the asym-
metric construction of the quaternary carbon centers. One of the
most recent approaches developed for this purpose includes
palladium-catalyzed asymmetric quaternization of 3-alkoxy or
3-thioalkyl cycloalk-2-enones, which has successfully enabled
asymmetric syntheses of carbocyclic natural compounds.2
We recently discovered that alkoxydienolates derived from
5- and 6-(3′-hydroxy-4′-alkenyl)-3-methoxycycloalk-2-enones
underwent highly diastereoselective alkylation to furnish quater-
nized cyclic enones.3 We envisioned that application of the
remote-stereocontrolled alkylative quaternization to the carbo-
cyclic system having a single asymmetric stereocenter would
provide facile access to chiral building blocks bearing a quatern-
ary carbon, which are relevant to natural terpenes.4,5 The present
study demonstrates a successful stereoconvergent strategy in
which a single enantiomer of such carbocycles can be produced
from racemic two diastereomers of 1, i.e., four stereoisomers,
through a regioselective catalytic asymmetric reduction followed
by the remote alkylative stereoinduction.
meric alcohol 1 to enzymatically acquire the requisite chirality
(Table 1). It is well recognized that successful metal–enzyme
Table 1 Attempted chiral induction of alcohol 1 by metal–enzyme
combocatalysis
Entry Enzyme
Catalyst Temp./time
Yield of 2 eed,e
1
2
3
4
5
PS-IM
AK
4b
4b
80 °C/72 h
40 °C/140 h 68%
70 °C/96 h
70 °C/84 h
rt/72 h
69%
33% (S)
40% (R)
76% (S)
14% (S)
0% (—)
Novozyme 4b
Novozyme 5b
27%
13%
6%
PS-C II
3c
Results and discussion
In our strategy to establish stereoconvergent routes, it was envi-
saged that either metal–enzyme combocatalysis ‘dynamic kinetic
resolution (DKR)’6 or oxidation–asymmetric reduction would
a Enzyme (150 mg mmol−1) and isopropenyl acetate (1.5 equiv.) were
used. b 5 mol% of catalyst activated with 5 mol% t-BuOK was
employed. c Dichloromethane was the reaction solvent and p-CIPhOAc
(1.5 equiv.) was the acyl donor. d Determined by 1H NMR analysis of
the Mosher ester of corresponding quaternized material 8. e Absolute
configuration was determined by comparison with those of the authentic
alcohol 7 obtained by CBS reduction protocol.
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6
Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: yoshimit@phs.osaka-u.ac.jp; Fax: +81-6-6879-8214;
Tel: +81-6-6879-8213
1
†Electronic supplementary information (ESI) available: Copies of H &
13C NMR. See DOI: 10.1039/c2ob26532j
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Scheme 2 Determination of absolute configuration of alcohol 7.
(>99% ee) of the material 7 obtained by this protocol was deter-
mined by 1H NMR analysis of Mosher esters derived from
known quaternized compound 8. Thus, alcohol 7 was alkylated
with 2,3-dibromopropene by the previously-reported protocol to
afford quaternized enone 8 ([α]2D0 −20.9 (c 0.09, CHCl3)) with
high 1,4-stereoinduction (dr = 96 : 4), which was subsequently
transformed into the Mosher esters. It is also worth mentioning
that the production of enone 8 would lead to an enantioselective
access to (−)-platencin.11
The absolute configuration of the newly-introduced 3′ stereo-
center at the side chain was unambiguously determined by the
conversion of alcohol 7 to known alcohol 12 via three steps
(Scheme 2). Alcohol 7 was first quaternized with MeI via remote
stereoinduction to give alcohol 10 in 50% yield with dr =
86 : 14. Although the separation of diastereomers generated in
the alkylative quaternization process was quite difficult as
described in our previous paper,3 we were pleased to find, after
many trials, that single desired isomer 10 ([α]2D0 −6.9 (c 0.15,
CHCl3)) was separable from its minor diastereomer by careful
flash silica gel column chromatography eluting with Et2O–pet-
roleum ether (1 : 2 v/v) (for details, see Experimental section).
Then, alcohol 10 was subjected to Lemieux–Johnson oxidative
cleavage to provide aldehyde 11 in 91% yield, which, upon treat-
ment with BH3·Me2S in CH2Cl2 at −60 °C, provided the known
alcohol 12 in 74% yield. The value of optical rotation, [α]D20
+17.6 (c 0.08, CHCl3), obtained for 12 was in good agreement
with the value [α]2D3 +18.49 (c 0.114, CHCl3) (>99% ee) reported
by Trost and co-workers,12 indicating that the absolute configur-
ation of the originally-introduced 3′-allylic center was S, which
exactly matched with that predicted by the empirical rule for the
CBS reduction.13
Further application of the stereoconvergent strategy to natural
product synthesis has culminated in the formal synthesis of
(−)-dysidiolide (18), a marine natural phosphatase inhibitor
(Scheme 3).14,15 The quaternized compound ent-10 ([α]1D9 +7.0
(c 0.15, CHCl3)), which was analogously prepared with (S)-
MeCBS catalyst by the protocol utilized for the synthesis of its
enantiomer 10, was initially converted to acetate 13 by treatment
with Ac2O and DMAP.16 A subsequent deacetoxylation of
acetate 13 with palladium catalyst–ammonium formate cleanly
afforded enone 14.17 It should be mentioned that our initial
efforts to convert alcohol ent-10 to enone 14 under either
Barton–McCombie or halogenation–dehalogenation conditions
led to an inseparable mixture of enone 14 and its alkenyl regio-
isomer. With compound 14 in hand, further manipulations were
Scheme 1 Preparation of optically pure alcohol 7 and its conversion to
key intermediate 8 in (−)-platencin synthesis.
catalysis requires compatibility of both a racemization catalyst
and an enzyme. In our screening of the reagent systems, ruthe-
nium complexes 3,7 4,8 and 5,9 the most commonly used cata-
lysts for this purpose, were examined.
Ruthenium catalyst 3 is known to exert remarkable reactivity
toward allylic alcohols, particularly at room temperature in com-
bination with Amano PS-C II lipase and p-ClPhOAc as the acyl
donor. Likewise, catalyst 4 has been successfully applied for the
metal–enzyme catalysis of allylic alcohols in combination with
Novozyme or Amano lipases at elevated temperature using iso-
propenyl acetate as the acyl donor. Among various popular
lipases, Novozyme (Candida antarctica lipase B; CALB) and
Pseudomonas cepacia lipase (PS-IM, PS-C II) are frequently
used because they have broad substrate scope and provide high
enantioselectivity, in addition to their thermal stability. With
these combinations, the metal–enzyme catalysis of allylic
alcohol 1 was evaluated, revealing that the degree of stereo-
control was only moderate to low. Thus, among the reagents
tested, PS-IM in combination with 5 mol% of Ru(II) catalyst 4
and t-BuOK was found to moderately promote the reaction,
affording (3′S)-acetate 2 with 33% ee in 69% yield. Interestingly,
with a combination of AK (Pseudomonas fluorescens) and cata-
lyst 4, (3′R)-acetate ent-2 was obtained in 68% yield in a slightly
increased ee (40% ee) with an opposite absolute configuration.
However, all other reaction conditions, including Novozyme–cat-
alyst 4 at 70 °C, Novozyme–catalyst 5 at 70 °C, and PS-C II–cat-
alyst
3 with p-ClPhOAc at rt, afforded no meaningful
improvements in the yields and ees.
Therefore, we turned our attention to an alternative method to
construct the requisite chiral center; i.e., an oxidation–catalytic
asymmetric reduction protocol. Thus, alcohol 1 was initially oxi-
dized with Dess–Martin periodinane to provide the correspond-
ing ketone 6 quantitatively (Scheme 1). The ketone 6 was
regioselectively reduced with BH3·SMe2 in the presence of
(R)-MeCBS catalyst,10 giving rise to alcohol 7 (>99% ee regard-
ing the 3′-allylic stereocenter) in 73% yield consisting of ca.
1 : 1 diastereomeric mixture. The high enantiomeric excess
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shifts are reported in ppm relative to the internal solvent signal
[chloroform-d: 7.26 ppm (1H NMR), 77.0 ppm (13C NMR)] or
to tetramethylsilane (0 ppm) as an internal standard. FT-IR
spectra were recorded for samples loaded as neat films on NaCl
plates. Mass spectra were obtained according to the specified
technique. Analytical thin layer chromatography (TLC) was per-
formed using Kieselgel 60 F254. Compounds were visualized
with UV light and stained with anisaldehyde solution.
3-Methoxy-6-(4-methyl-3-oxopent-4-enyl)cyclohex-2-enone (6).
To a solution of racemic alcohol 1 (300 mg, 1.34 mmol) in
CH2Cl2 (15 mL) was added Dess–Martin periodinane (853 mg,
2.01 mmol) at room temperature. After being stirred for 30 min,
the mixture was treated with sat. NaHCO3 and sat. Na2S2O3. The
whole mixture was then poured into a separatory funnel where it
was extracted with EtOAc. The phases were separated and the
organic phase was washed with brine, dried over MgSO4,
filtered, and concentrated. The residue was purified by flash
silica gel column chromatography (EtOAc–n-hexane 2 : 3) to
yield ketone 6 (295 mg, quant.) as a colorless solid. Ketone 6:
Colorless needles of mp 88–90 °C (Et2O); IR (neat) ν 1666,
1633 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.02 (s, 1H), 5.77 (s,
1H), 5.31 (s, 1H), 3.68 (s, 3H), 2.89–2.79 (m, 2H), 2.45 (t, 2H,
J = 6.8 Hz), 2.29–2.22 (m, 1H), 2.11–1.98 (m, 2H), 1.87 (s,
3H), 1.83–1.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 202.0,
201.2, 177.6, 144.1, 124.9, 101.7, 55.6, 44.3, 35.1, 27.7, 27.0,
24.8, 17.6; MS m/z: 222 (M+), 126 (100%); HRMS (EI) calcd
for C13H18O3 (M+): 222.1256, found: 222.1251.
Scheme 3 Formal synthesis of (−)-dysidiolide.
carried out to produce compound 17a.15i,j,l Thus, vinylation of
the carbonyl functionality of enone 14 with vinyl magnesium
bromide followed by treatment of the resultant alcohol with sat.
NH4Cl furnished trienone 15 in good yield. The carbonyl group
of trienone 15 was then removed via a three-step protocol:18,19
DIBAL reduction of 15, sulfation of the resultant allylic alcohol
16 with SO3·Py, and again, reduction of the sulfate intermediate
with LAH successfully provided the known triene 17a ([α]D20
+14.0 (c 0.12, CHCl3); ref. 15j ([α]2D5 +13 (c 0.25, CHCl3)), a
key intermediate in the asymmetric total synthesis of (−)-dysi-
diolide (18).
Preparation of optically pure alcohol 7 by asymmetric
reduction of ketone 6 with (R)-MeCBS–BH3·Me2S. To a stirred
solution of (R)-MeCBS catalyst (1.0 M in toluene, 0.45 mL,
0.45 mmol) in CH2Cl2 (2 mL) was added BH3·Me2S (10.0 M,
0.1 mL, 1.0 mmol), and the solution was stirred for 30 min at
room temperature and then cooled to −78 °C. A solution of
ketone 6 (200 mg, 0.9 mmol) in CH2Cl2 (7 mL) was added via a
cannula over 45 min, and the mixture was stirred at −70 °C for
10 h. The reaction was then quenched by slow addition of
methanol at −70 °C. After being stirred for 30 min, the mixture
was poured into a separatory funnel where it was partitioned
between Et2O and water. The phases were separated and the
organic phase was dried over MgSO4, filtered, and concentrated.
The residue was purified by flash silica gel column chromato-
graphy (EtOAc–n-hexane 2 : 3) to yield optically pure alcohol 7
(148 mg, 73%) as a colorless oil. Compound 7: (1 : 1 diastereo-
Conclusions
In conclusion, we have demonstrated
a stereoconvergent
meric mixture) IR (neat) ν 3418, 1645 cm−1
;
1H NMR
approach to enantiomerically pure quaternary carbocycles
through the sequence of asymmetric side chain construction fol-
lowed by remote stereoinduction. Further application of the
present strategy to the chemical synthesis of bioactive complex
natural products will be disclosed in due course.
(500 MHz, CDCl3) δ 5.34 (s, 1H), 4.96 (s, 1H), 4.84–4.82 (m,
1H), 4.03–4.08 (m, 1H), 3.68 (s, 3H), 2.45–2.43 (m, 2H),
2.29–2.21 (m, 1H), 2.11 (brs, 0.5H), 2.10–2.04 (m, 1H), 1.96
(brs, 0.5H), 1.89–1.74 (m, 2H), 1.73 (s, 3H), 1.68–1.44 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 201.7, 201.5, 177.74, 177.68,
147.5, 147.2, 111.1, 110.8, 101.83, 101.79, 75.59, 75.57, 55.6,
44.9, 44.8, 32.7, 32.0, 27.9, 27.7, 26.6, 26.4, 25.8, 25.2, 17.7,
17.6 (these peaks originate from a 1 : 1 diastereomeric mixture);
MS m/z: 225 [M + H]+, 69 (100%); HRMS (FAB) calcd for
C13H21O3 [M + H]+ 225.1491, found: 225.1496. The above-
mentioned data are in good agreement with those reported by
our group.11 Determination of ee of alcohol 7: alcohol 7
obtained by the above-mentioned CBS protocol was converted
Experimental
General experimental
Melting points are uncorrected. All reagents were used as
1
received from commercial suppliers unless otherwise noted. H
NMR spectra (400 or 300 MHz) and 13C NMR spectra (100 or
75 MHz) were measured in the specified solvents. Chemical
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to enone 8 by the previously-reported procedure.11 The quater-
nized enone 8 was then esterified with (R)- and (S)-MTPA,
DCC, and DMAP in CH2Cl2 at room temperature to give corre-
sponding (R)- and (S)-Mosher esters. The enantiomeric excess
treated with MeOH at −60 °C. After being stirred for 30 min,
the mixture was poured into a separatory funnel where it was
partitioned between EtOAc and water. The phases were separated
and the organic phase was dried over MgSO4, filtered, and con-
centrated. The residue was purified by flash silica gel column
chromatography (EtOAc–n-hexane 2 : 1) to yield alcohol 12
(6 mg, 74%) as a colorless oil. Alcohol 12: [α]2D0 +17.6 (c 0.08,
CHCl3); lit. [α]2D3 +18.49 (c 0.114, CHCl3) (>99% ee);12 IR
(neat) ν 3470 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.28 (s, 1H),
3.68 (s, 3H), 3.62–3.58 (m, 2H), 2.44 (t, 2H, J = 6.4 Hz),
1.98–1.91 (m, 1H), 1.76–1.68 (m, 2H), 1.60–1.45 (m, 3H), 1.10
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 204.1, 176.4, 101.0,
63.4, 55.6, 43.3, 33.0, 32.1, 27.2, 25.8, 22.3. The above-men-
tioned spectroscopic data are in good agreement with those
reported in the literature.12
1
was determined by H NMR analysis of the esters to be >99%
ee (for the 1H NMR spectra, see ESI†).
(S)-6-((S)-3-Hydroxy-4-methylpent-4-enyl)-3-methoxy-6-methyl-
cyclohex-2-enone (10). To a stirred solution of LDA (2.0 M in
heptane–THF–ethylbenzene; 400 μL, 0.80 mmol) in THF
(2 mL) at −78 °C was added a solution of enone 7 (60 mg,
0.27 mmol, >99% ee) in THF (4 mL) over a period of 5 min.
Then the mixture was stirred at the same temperature for
additional 30 min. Following dropwise addition of methyl iodide
(50 μL, 0.8 mmol), the whole mixture was allowed to warm to
0 °C and stirring was continued for further 2 h. Upon addition of
sat. NH4Cl, the mixture was transferred to a separatory funnel
where it was extracted with Et2O. The phases were separated and
the organic phase was washed with brine, dried over MgSO4,
filtered, and concentrated. The residue was carefully purified by
flash silica gel column chromatography (ϕ 2.5 × 27 cm SiO2,*
Et2O–petroleum ether 1 : 2) to yield a pale yellow oil of alcohol
syn-10 (25 mg, 39%) as a single diastereomer. Further elution
gave 6.8 mg (11%) of a mixture of the two diastereomers (syn-
isomer 10 : anti-isomer = 1 : 2), indicating that the diastereomeric
ratio of the quaternized products was 86 : 14 which is consistent
with our previously reported data.3 Further elution gave
unreacted enone 7 (15 mg, 17% recovered). Alcohol 10: [α]D20
−6.9 (c 0.15, CHCl3) (>99% ee); IR (neat) 3416, 1645 cm−1; 1H
NMR (300 MHz, CD3OD) δ 5.28 (s, 1H), 4.89 (s, 1H), 4.80 (s,
1H), 3.93 (dd, 1H, J = 6.0, 5.7 Hz), 3.72 (s, 3H), 2.47 (t, 2H, J
= 6.3 Hz), 2.00–1.91 (m, 1H), 1.77–1.70 (m, 1H), 1.68 (s, 3H),
1.54–1.41 (m, 4H), 1.06 (s, 3H), 13C NMR (125 MHz, CDCl3) δ
204.9, 177.5, 148.1, 112.1, 101.9, 77.6, 56.5, 43.9, 33.5, 32.9,
30.4, 26.7, 23.6, 18.5; HRMS (EI) calcd for C14H22O3 (M+)
238.1569, found 238.1573. The above-mentioned data are in
good agreement with those reported by our group.3 *For ensur-
ing efficient separation, this size of column was used.
Procedure for dynamic kinetic resolution (DKR) of alcohol 1
(Table 1, entry 1). To a suspension of t-BuOK (3.8 mg,
0.0335 mmol) in toluene (0.5 ml) was added Ru-catalyst 4
(21.4 mg, 0.0335 mmol) and the mixture was stirred under argon
atmosphere for 6 min. Then, Na2CO3 (71 mg, 0.67 mmol),
lipase Amano PS-IM (100.5 mg, 150 mg mmol−1 alcoholic sub-
strate), isopropenyl acetate (110 μL, 1.005 mmol), and a solution
of alcohol 1 (150 mg, 0.67 mmol) in toluene (3 mL) were added
sequentially. After being stirred for 72 h at 80 °C, the reaction
mixture was filtered through a pad of Celite and concentrated.
Purification by flash silica gel column chromatography (EtOAc–
n-hexane 1 : 1) afforded (3′S)-acetate 2 (124 mg, 69%) as a col-
orless oil. The enantiomerically enriched acetate 2 obtained
above was then subjected to methanolysis followed by remote
alkylative quaternization with 2,3-dibromopropene to furnish the
corresponding quaternized material 8. The enantiomeric excess
of compound 2 was thus determined by Mosher analysis of 8 to
be 33% ee. Acetate 2 (1 : 1 diastereomeric mixture): colorless
oil; IR (neat) ν 1736, 1654 cm−1; 1H NMR (400 MHz, CDCl3) δ
5.31 (s, 1H), 5.16–5.12 (m, 1H), 4.93 (s, 1H), 4.87 (s, 1H), 3.67
(s, 3H), 2.41 (t, 2H, J = 6.4 Hz), 2.20–2.15 (m, 1H), 2.09–2.03
(m, 1H), 2.04 (s, 3H), 1.84–1.65 (m, 4H), 1.71 (s, 3H),
1.38–1.31 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 200.92,
200.85, 177.49, 177.47, 170.33, 170.32, 142.85, 142.81, 113.02,
112.82, 77.27, 77.22, 55.63, 44.80, 44.63, 30.09, 29.80, 27.78,
27.74, 26.43, 26.33, 25.28, 25.21, 21.20, 21.19, 18.11, 17.99
(These signals originate from a 1 : 1 diastereomeric mixture.);
MS m/z: 266 (M+), 126 (100%); HRMS (EI) calcd for C15H22O4
(M+): 266.1518, found: 266.1539. A representative procedure
for methanolysis of acetate 2: to a solution of acetate 2 (60 mg,
0.225 mmol) in MeOH–H2O (3 mL; 4 : 1 v/v) was added
K2CO3 (62.2 mg, 0.45 mmol). After being stirred for 4 h at
room temperature, the mixture was filtered through a pad of
Celite, concentrated under reduced pressure, and extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by
flash silica gel column chromatography (EtOAc–n-hexane 2 : 1)
to give alcohol 7 (51 mg, quant.) as a colorless oil.
(R)-3-(4-Methoxy-1-methyl-2-oxocyclohex-3-enyl)propanal (11).
To a stirred solution of alcohol 10 (13 mg, 0.0545 mmol, >99%
ee) in t-BuOH–H2O (3 mL; 1 : 1 v/v) were added NaHCO3
(23 mg, 0.27 mmol), OsO4 (4% in water, 10 μL, 0.0014 mmol),
and NaIO4 (35 mg, 0.164) sequentially. The reaction mixture
was stirred at room temperature for 1 h and then quenched with
sat. Na2S2O3. After being stirred for 30 min, the mixture was
extracted with EtOAc and washed with water and with brine.
The organic layer was separated, dried over MgSO4, filtered, and
concentrated. The residue was purified by flash silica gel column
chromatography (EtOAc–n-hexane 1 : 1) to give aldehyde 11
1
(9.7 mg, 91%) as a colorless oil. H NMR (400 MHz, CDCl3) δ
9.76 (s, 1H), 5.27 (s, 1H), 3.68 (s, 3H), 2.84–2.42 (m, 4H),
1
1.92–1.72 (m, 4H), 1.10 (s, 3H). The H NMR data is in good
agreement with that reported in the literature.12
(S)-6-(3-Hydroxypropyl)-3-methoxy-6-methylcyclohex-2-enone
(12). A solution of aldehyde 11 (8 mg, 0.041 mmol, >99% ee)
in CH2Cl2 (1.5 mL) was cooled to −78 °C and then treated with
BH3·Me2S (1.0 M in CH2Cl2, 41 μL, 0.041 mmol). After being
stirred for 18 h at −60 °C, the reaction mixture was slowly
Table 1, entry 2. Following the procedure described for entry
1, (3′R)-acetate ent-2 was obtained in 68% yield/40% ee with
lipase Amano AK at 40 °C for 140 h.
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been reported by our group.3 *For ensuring efficient separation,
this size of column was used.
Table 1, entry 3. Following the procedure described for entry
1, (3′S)-acetate 2 was obtained in 27% yield/76% ee with Novo-
zyme at 70 °C for 96 h.
(R)-5-((R)-4-Methoxy-1-methyl-2-oxocyclohex-3-enyl)-2-methyl-
pent-1-en-3-yl acetate (13). To a solution of alcohol ent-10
(37 mg, 0.155 mmol) in CH2Cl2 (3 mL) were added DMAP
(3.8 mg, 0.031 mmol) and acetic anhydride (21 μL,
0.202 mmol). After being stirred at room temperature for 1 h, the
mixture was treated with NaHCO3, diluted with CH2Cl2, and
poured into a separatory funnel where it was washed with water
and then with brine. The organic layer was separated, dried over
MgSO4, filtered, and concentrated. The residue was purified by
flash silica gel column chromatography (EtOAc–n-hexane 1 : 4)
to give acetate 13 (43 mg, 99%) as a colorless oil. [α]2D0 −14.2 (c
Table 1, entry 4. Following the procedure described for entry
1, (3′S)-acetate 2 was obtained in 13% yield/14% ee with Novo-
zyme and Ru-catalyst 5 at 70 °C for 84 h.
Table 1, entry 5. A suspension containing alcohol 1 (100 mg,
0.45 mmol), Ru-catalyst 3 (10.8 mg, 0.018 mmol), lipase
Amano PS-C II (67.5 mg, 150 mg mmol−1), p-ClPhOAc
(115 mg, 0.68 mmol), and Et3N (95 μL, 0.68 mmol) in CH2Cl2
(4 mL) was stirred at room temperature under argon atmosphere.
After 72 h, the reaction mixture was filtered through a pad of
Celite and concentrated. Purification of the residue by flash silica
gel column chromatography (EtOAc–n-hexane 1 : 1) afforded
acetate 2 (7 mg, 6% yield, 0% ee).
0.21, CHCl3); IR (neat) ν 1735, 1654 cm−1
;
1H NMR
(300 MHz, CDCl3) δ 5.24 (s, 1H), 5.09 (t, 1H, J = 6.6 Hz), 4.92
(s, 1H), 4.87 (s, 1H), 3.66 (s, 3H), 2.40 (t, 2H, J = 6.6 Hz), 2.03
(s, 3H), 1.95–1.85 (m, 1H), 1.75–1.66 (m, 2H), 1.69 (s, 3H),
1.59–1.52 (m, 2H), 1.49–1.35 (m, 1H), 1.06 (s, 3H),; 13C NMR
(75 MHz, CDCl3) δ 203.5, 176.4, 170.3, 142.7, 113.2, 101.0,
77.6, 55.6, 42.9, 32.3, 32.0, 26.9, 25.7, 22.4, 21.2, 17.9; MS
m/z: 280 (M+), 221 (100%); HRMS (FAB) calcd for C16H25O4
(M + H)+: 281.1753, found: 281.1762.
Preparation of alcohol ent-7 by asymmetric reduction of
ketone 6 with (S)-MeCBS–BH3·Me2S. To a stirred solution of
(S)-MeCBS catalyst (155.2 mg, 0.56 mmol) in toluene–CH2Cl2
(0.6 mL : 2 mL) was added BH3·Me2S (123 μL, 1.23 mmol),
and the solution was stirred for 30 min at room temperature and
then cooled to −78 °C. A solution of ketone 6 (250 mg,
1.12 mmol) in CH2Cl2 (8 mL) was then added through a
cannula over 45 min, and the mixture was stirred at −70 °C for
further 10 h. The reaction was quenched by slow addition of
MeOH at −70 °C. After being stirred for 30 min, the mixture
was poured into a separatory funnel where it was partitioned
between Et2O and water. The phases were separated and the
organic phase was dried over MgSO4, filtered, and concentrated.
The residue was purified by flash silica gel column chromato-
graphy (EtOAc–n-hexane 2 : 3) to yield alcohol ent-7 (179 mg,
71%) as a colorless oil. The enantiomeric excess (>99% ee) was
determined by 1H NMR analysis of the Mosher esters of the cor-
responding quaternized material ent-8.
(R)-3-Methoxy-6-methyl-6-(4-methylpent-4-enyl)cyclohex-2-
enone (14). To a stirred solution of acetate 13 (43 mg,
0.153 mmol) in 1,4-dioxane (3 mL) were added
Pd2(dba)3·CHCl3 (8 mg, 0.0077 mmol), n-Bu3P (10 μL,
0.0383 mmol), and HCO2NH4 (19 mg, 0.306 mmol). After
being stirred for 30 min at 90 °C, the mixture was cooled to
room temperature, and transferred to a separatory funnel where it
was partitioned between Et2O and water. The organic phase was
separated, dried over MgSO4, filtered, and concentrated. The
residue was purified by flash silica gel column chromatography
(EtOAc–n-hexane 1 : 15) to yield enone 14 (32 mg, 94%) as a
colorless oil. [α]1D9 −22.8 (c 0.17, CHCl3); IR (neat) ν
1654 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.26 (s, 1H), 4.68 (s,
1H), 4.65 (s, 1H), 3.67 (s, 3H), 2.45–2.33 (m, 2H), 2.00–1.88
(m, 3H), 1.77–1.63 (m, 2H), 1.69 (s, 3H), 1.58–1.29 (m, 3H),
1.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 204.2, 176.4, 154.7,
110.0, 101.0, 55.6, 43.3, 38.2, 36.4, 32.1, 25.8, 22.34, 22.31,
21.9; MS m/z: 222 (M+), 222 (100%); HRMS (FAB) calcd for
C14H23O2 (M + H)+: 223.1698, found: 223.1698.
(R)-6-((R)-3-Hydroxy-4-methylpent-4-enyl)-3-methoxy-6-methyl-
cyclohex-2-enone (ent-10). To a stirred solution of LDA (2.0 M
in heptane–THF–ethylbenzene; 795 μL, 1.59 mmol) in THF
(3 mL) at −78 °C was added a solution of enone ent-7 (120 mg,
0.53 mmol) in THF (5 mL) over a period of 5 min. Then the
mixture was stirred at the same temperature for an additional
30 min. Following dropwise addition of methyl iodide (99 μL,
1.59 mmol), the whole mixture was allowed to warm to 0 °C
and stirring was continued for further 2 h. Upon addition of sat.
NH4Cl, the mixture was transferred to a separatory funnel where
it was extracted with Et2O. The phases were separated and the
organic phase was washed with brine, dried over MgSO4,
filtered, and concentrated. The residue was carefully purified by
flash silica gel column chromatography (ϕ 2.5 × 35 cm SiO2,*
Et2O–petroleum ether 1 : 2) to yield a pale yellow oil of alcohol
syn-ent-10 (50.7 mg, 40%) as a single diastereomer. Further
elution gave 12.4 mg (10%) of a mixture of the two diastereo-
mers (syn-isomer ent-10 : anti-isomer = 1 : 2.2), indicating that
the diastereomeric ratio of the quaternized products was 86 : 14
which is consistent with our previously reported data.3 Further
elution gave unreacted enone ent-7 (19 mg, 16% recovered).
Alcohol ent-10: [α]1D9 +7.0 (c 0.15, CHCl3) (>99% ee). The
spectroscopic and analytical data of this material have previously
(R)-4-Methyl-4-(4-methylpent-4-enyl)-3-vinylcyclohex-2-enone
(15). To a stirred solution of enone 14 (24 mg, 0.107 mmol) in
THF (3 mL) was added vinyl magnesium bromide (1.0 M in
THF, 0.535 mL, 0.535 mmol) at 0 °C. Then the mixture was
warmed to room temperature and stirred for 1 h. Sat. NH4Cl was
then added and stirring was continued for an additional 30 min.
The whole mixture was diluted with Et2O and transferred to a
separatory funnel. The organic layer was separated, washed with
brine, dried over MgSO4, and concentrated. The residue was
purified by flash silica gel column chromatography (EtOAc–n-
hexane 1 : 20) to yield trienone 15 (19.1 mg, 81%) as a colorless
oil. [α]1D9 +37.7 (c 0.11, CHCl3); IR (neat) ν 1670 cm−1 1H
;
NMR (300 MHz, CDCl3) δ 6.43 (dd, 1H, J = 17.1, 10.8 Hz),
6.09 (s, 1H), 5.69 (dd, 1H, J = 17.1, 1.5 Hz), 5.35 (dd, 1H, J =
10.8, 1.5 Hz), 4.71 (s, 1H), 4.65 (s, 1H), 2.47–2.41 (m, 2H),
2.11–1.96 (m, 3H), 1.76–1.67 (m, 2H), 1.69 (s, 3H), 1.58–1.28
This journal is © The Royal Society of Chemistry 2012
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(m, 3H), 1.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 199.8,
166.2, 145.3, 134.1, 123.4, 120.1, 110.3, 38.7, 38.2, 37.5, 34.1,
33.4, 24.8, 22.3, 21.9; MS m/z: 218 (M+), 91 (100%); HRMS
(EI) calcd for C15H22O (M+): 218.1671, found: 218.1689.
δ 6.38 (d, 1H, J = 9.9 Hz), 5.79–5.72 (m, 1H), 5.34 (q, 1H, J =
6.9 Hz), 4.69 (s, 1H), 4.66 (s, 1H), 2.23–2.10 (m, 2H), 1.97 (t,
2H, J = 6.6 Hz), 1.72 (d, 3H, J = 7.2 Hz), 1.71 (s, 3H),
1.63–1.51 (m, 2H), 1.50–1.31 (m, 4H), 1.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 146.3, 141.2, 127.5, 123.3, 117.6, 109.6,
38.5, 38.1, 36.7, 34.6, 25.7, 22.9, 22.4, 21.9, 12.7; HRMS (EI)
calcd for C15H24 (M+): 204.1878, found: 204.1877.
(R)-4-Methyl-4-(4-methylpent-4-enyl)-3-vinylcyclohex-2-enol
(16). To a stirred solution of trienone 15 (13 mg, 0.0595 mmol)
in CH2Cl2 (2 mL) at −78 °C was added DIBAL (1.04 M in
n-hexane; 115 μL, 0.119 mmol). The mixture was warmed to
0 °C and stirred for 30 min. Following quenching with water,
stirring was continued for additional 15 min. Then Celite was
added, and the mixture was stirred at room temperature for
further 15 min. After filtration of the mixture through a pad of
Celite, the filtrate was concentrated. The residue was purified by
flash silica gel column chromatography (EtOAc–n-hexane 1 : 20)
to yield trienol 16 (11.5 mg, 88%) as a colorless oil (1 : 1 diastereo-
Acknowledgements
G. A. I. M. acknowledges scholarship awarded by the Egyptian
Ministry of Higher Education for his graduate study. This work
was partially supported by Hoansha Foundation, the Program for
Promotion of Fundamental Sciences in Health Sciences of the
National Institute of Biomedical Innovation (NIBIO), and a
Grant-in-Aid for Scientific Research on Innovative Areas [no.
22136006] from the Ministry of Education, Culture, Sports,
Science and Technology of Japan (MEXT).
1
meric mixture). IR (neat) ν 3260 cm−1; H NMR (300 MHz,
CDCl3) δ 6.28 (dd, 0.5H, J = 17.1, 10.8 Hz), 6.24 (dd, 0.5H, J =
17.1, 10.8 Hz), 5.83 (d, 0.5H, J = 17.1 Hz), 5.81 (d, 0.5H, J =
17.1 Hz), 5.39 (dd, 0.5H, J = 17.1, 1.8 Hz), 5.38 (dd, 0.5H, J =
17.1, 1.8 Hz), 5.02 (dd, 0.5H, J = 10.8, 1.8 Hz), 4.98 (dd, 0.5H,
J = 10.8, 1.8 Hz), 4.68 (s, 1H), 4.64 (s, 1H), 4.20 (m, 1H),
1.98–1.88 (m, 3H), 1.85–1.78 (m, 1H), 1.68 (s, 3H), 1.67–1.50
(m, 2H), 1.49–1.20 (m, 4H), 1.07 (s, 1.5H), 1.00 (s, 1.5H); 13C
NMR (75 MHz, CDCl3) δ 147.54, 145.96, 145.86, 145.79,
135.88, 126.60, 124.61, 115.02, 114.73, 109.95, 109.86, 67.44,
65.58, 39.82, 39.34, 38.39, 38.35, 36.46, 36.38, 31.96, 30.30,
29.05, 28.24, 26.36, 25.85, 22.28, 22.02, 21.74 (These peaks
originate from a 1 : 1 diastereomeric mixture); MS m/z: 220
(M+), 96 (100%); HRMS (EI) calcd for C15H24O (M+):
220.1827, found: 220.1841.
Notes and references
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(S)-6-Methyl-6-(4-methylpent-4-enyl)-1-vinylcyclohex-1-ene
(17a) and (R)-3-ethylidene-4-methyl-4-(4-methylpent-4-enyl)-
cyclohex-1-ene (17b). To a stirred solution of alcohol 16 (8 mg,
0.0363 mmol) in THF (2 mL) at 0 °C was added SO3·Py
(11.6 mg, 0.073 mmol). After 1 h, complete conversion of
alcohol 16 to the corresponding pyridinium sulfate monoester
was confirmed by TLC analysis. LiAlH4 (4.1 mg, 0.109 mmol)
was then added at 0 °C, and the mixture was stirred for 1 h at
0 °C and 2 h at room temperature. Water was added at 0 °C to
quench the reaction and stirring was continued for 15 min. Then
Celite was added, and the mixture was stirred at room temp-
erature for a further 15 min. After filtration of the mixture through
a pad of Celite, the filtrate was concentrated and the residue was
purified by flash silica gel column chromatography (n-hexane) to
yield less polar triene 17a (2.4 mg, 32%) as a colorless oil and
more polar regioisomeric triene 17b (2.2 mg, 30%) as a colorless
oil. Triene 17a: [α]D20 +14.0 (c 0.12, CHCl3) (>99% ee); lit. [α]D25
+13.0 (c 0.25, CHCl3) (95% ee);15j 1H NMR (300 MHz, CDCl3)
δ 6.26 (dd, 1H, J = 17.1, 11.1 Hz), 5.83 (t, 1H, J = 3.9 Hz), 5.27
(dd, 1H, J = 17.1, 1.8 Hz), 4.89 (dd, 1H, J = 10.8, 1.8 Hz), 4.68
(s, 1H), 4.65 (s, 1H), 2.06–1.93 (m, 4H), 1.69 (s, 3H), 1.61–1.29
(m, 8H), 1.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.3,
143.8, 137.1, 124.3, 112.9, 109.6, 40.4, 38.5, 36.4, 35.1, 27.1,
26.1, 22.4, 21.8, 19.0; HRMS (EI) calcd for C15H24 (M+):
204.1878, found: 204.1851. The above-mentioned data are in
good agreement with those reported in the literature.15i,j,l Triene
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17b: [α]1D9 +20.0 (c 0.10, CHCl3); H NMR (300 MHz, CDCl3)
8614 | Org. Biomol. Chem., 2012, 10, 8609–8615
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acetate predominantly afforded regioisomeric triene 17b.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8609–8615 | 8615