Enantioselective synthesis of (-)-CP-55940 via ruthenium-catalyzed asymmetric hydrogenation of ketones

Article abstract of DOI:10.1002/adsc.201100898

A new and efficient catalytic asymmetric synthesis of the potent cannabinoid receptor agonist (-)-CP-55940 has been developed by using ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryl ketones via dynamic kinetic resolution (DKR) as a key step. With RuCl₂-SDPs/ diamine [SDPs=7,7'-bis(diarylphophino)-1,1'-spirobiindane] catalysts the asymmetric hydrogenation of racemic α-arylcyclohexanones via DKR provided the corresponding cis-β-arylcyclohexanols in high yields with up to 99.3% ee and >99:1 cis-selectivities. Both ethylene ketal group at the cyclohexane ring and ortho-methoxy group at the phenyl ring of the substrates 6 have little effect on the selectivity and reactivity of the hydrogenations. Based on this highly efficient asymmetric ketone hydrogenation, (-)-CP-55940 was synthesized in 13 steps (the longest linear steps) in 14.6% overall yield starting from commercially available 3-methoxybenzaldehyde and 1,4-cyclohexenedione monoethylene acetal. Copyright

Full text of DOI:10.1002/adsc.201100898

FULL PAPERS
DOI: 10.1002/adsc.201100898
Enantioselective Synthesis of (À)-CP-55940 via Ruthenium-
Catalyzed Asymmetric Hydrogenation of Ketones
Li-Jie Cheng,a Jian-Hua Xie,a,* Li-Xin Wang,a and Qi-Lin Zhoua,*
a
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-6177; e-mail: jhxie@nankai.edu.cn or qlzhou@nankai.edu.cn
Received: November 18, 2011; Published online: April 13, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100898.
Abstract: A new and efficient catalytic asymmetric
ACHTUNGTRENoNUNG xy group at the phenyl ring of the substrates 6 have
synthesis of the potent cannabinoid receptor agonist little effect on the selectivity and reactivity of the hy-
(À)-CP-55940 has been developed by using rutheni- drogenations. Based on this highly efficient asym-
um-catalyzed asymmetric hydrogenation of racemic metric ketone hydrogenation, (À)-CP-55940 was syn-
a-aryl ketones via dynamic kinetic resolution (DKR) thesized in 13 steps (the longest linear steps) in
as a key step. With RuCl2-SDPs/diamine [SDPs= 14.6% overall yield starting from commercially avail-
7,7’-bis(diarylphophino)-1,1’-spirobiindane] catalysts able 3-methoxybenzaldehyde and 1,4-cyclohex-
the asymmetric hydrogenation of racemic a-arylcy-
clohexanones via DKR provided the corresponding
cis-b-arylcyclohexanols in high yields with up to
ACHTUNGTNEReNUNG nedione monoethylene acetal.
99.3% ee and >99:1 cis-selectivities. Both ethylene Keywords: asymmetric synthesis; (À)-CP-55940; dy-
ketal group at the cyclohexane ring and ortho-meth- namic kinetic resolution; hydrogenation; ruthenium
Introduction
With 25 mol% of O-TBDPS-protected cis-4-d-proline
as catalyst, they obtained the key chiral intermediate
Chiral 2,5-disubstituted 1-arylcyclohexane is an im- of (À)-CP-55940 in moderate yield (68%) with high
portant structural motif that can be found in many enantioselectivity and diastereoselectivity (94% ee
natural products and biologically active molecules. and 99% de).
Examples of bioactive natural products containing
these structural units include Machaereol A and B,
which are antimalarial hexahydrodibenzopyran deriv- Results and Discussion
atives isolated from Machaerium multiflorum,[1] the
cannabinol-skeletal carbazole alkaloids Murrayamine Recently, we developed an efficient catalytic enantio-
O and P isolated from Murraya euchrestifolia,[2] and selective method for the synthesis of chiral b-substi-
the polycyclic cannabinoid Rubranine isolated from tuted cyclic alcohols by ruthenium-catalyzed asym-
Aniba rosaeodora[3] (Figure 1). Synthetic potent can- metric hydrogenation of racemic a-substituted cyclo-
nabinoid receptor agonists such as AM-2389,[4] AM- alkanones via dynamic kinetic resolution (DKR).[9]
4030[5] and CP-55940[6] also possess such trisubstituted This allowed us to design a catalytic enantioselective
chiral cyclohexanoid cores. Several asymmetric syn- approach to the construction of the chiral 2,5-disubsti-
thetic methods have been developed for the prepara- tuted 1-arylcyclohexanoid unit. As a model target
tion of chiral 2,5-disubstituted 1-arylcyclohexanoids molecule, (À)-CP-55940, a potent non-selective can-
and were applied to the synthesis of related natural nabinoid (CB) receptor agonist with Ki values of 0.58
or unnatural molecules.[7] However, the construction and 0.69 nM for human recombinant CB1 and CB2,
of this chiral core structure by catalytic asymmetric respectively,[6] was selected to demonstrate this highly
methods is scarce. In 2005, Iwabuchi et al. reported efficient catalytic method. The retro-synthetic analysis
an asymmetric synthesis of (À)-CP-55940 by using or- of (À)-CP-55940 is shown in Figure 2. We envisioned
ganocatalyzed intramolecular aldolization reaction.[8] that the hydroxy group directly linked to the cyclo-
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Figure 1. Selected bioactive molecules with chiral 2,5-disubstituted 1-arylcyclohexane unit.
Figure 2. Strategy for the enantioselective synthesis of (À)-CP-55940.
hexane ring of (À)-CP-55940 could be formed via the palladium-catalyzed Suzuki cross-coupling reaction
reduction of the corresponding ketone, and the g-hy- between 2-iodo-1,4-cyclohexanedione monoethylene
droxypropyl group at the 2-position of the ring could acetal 3 and arylboronic acid 4.
be introduced via allylic substitution, followed by hy-
Although the ruthenium-catalyzed asymmetric hy-
droboration-oxidation reaction. Thus, the chiral cis-3- drogenation of racemic a-arylcycloalkanones via
aryl-4-hydroxycyclohexanone ethylene acetal 1, which DKR has been demonstrated to be a highly efficient
can be easily obtained by ruthenium-catalyzed asym- approach to chiral cis-2-arylcycloalkanols by
metric hydrogenation of the corresponding racemic 2- Noyori[10] and us,[9f] the effects of a bulky ethylene
aryl-1,4-cyclohexanedione monoethylene acetal 2 via ketal group at the 4-position of the cyclohexane ring
DKR, will be an ideal chiral intermediate for the and the ortho-methoxy group at the phenyl ring of
enantioselective synthesis of (À)-CP-55940. And the the substrates on the selectivity and reactivity of the
racemic a-arylcyclohexanone 2 can be obtained by hydrogenation were unknown. We tested the asym-
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Enantioselective Synthesis of (À)-CP-55940 via Ruthenium-Catalyzed Asymmetric Hydrogenation
Table 1. Asymmetric hydrogenation of a-aryl-1,4-cyclohexanedione monoethylene acetals 6.[a]
Entry
Catalyst
X
7
Yield [%][b]
cis/trans[c]
ee [%][d]
1
2
3
4
5
N
H
H
7a
7a
7b
7c
7d
99
99
98
99
99
>99/1
>99/1
>99/1
>99/1
>99/1
97
97
96
99
2-MeO
3,4-(OCH2O)
3,5-(MeO)2
99.3
[a]
The reactions were performed at 0.2M of 6, under 50 atm of H2, at room temperature (25–308C) in i-PrOH containing
(Sa,RR)-5 (S/C=1000) and t-BuOK ([t-BuOK]=0.04M) unless otherwise stated. The conversion is 100%.
Isolated yield.
Determined by GC.
[b]
[c]
metric hydrogenation of several easily obtained race- dicated that both ethylene ketal group at the cyclo-
mic a-aryl-1,4-cyclohexanedione monoethylene ace- hexane ring and ortho-methoxy group at the phenyl
tals 6, which are analogues of 2, with RuCl2-SDPs/di- ring of the substrates have no negative effect on the
ACHTUNGTRENNUNG
amine catalysts 5[11] under the general hydrogenation selectivity and reactivity of the hydrogenation.
conditions.[9f] Both catalysts (Sa,RR)-5a and (Sa,RR)-
This finding encouraged us to synthesize (À)-CP-
5b gave high yield, high enantioselectivity (97% ee) 55940 by using ruthenium-catalyzed enantioselective
and excellent cis-selectivity (cis/trans >99:1) (Table 1, hydrogenation of compound 2. The racemic a-arylcy-
entries 1 and 2). With catalyst (Sa,RR)-5a, the sub- clohexanone 2 was prepared from arylboronic acid 4,
strates 6c and 6d with 3,4-(OCH2O) and 3,5-(MeO)2 which can be obtained easily from bromide 12
substituents on the phenyl ring were hydrogenated to (Scheme 1). Although the synthesis of aryl bromide
products 7c and 7d in 99% ee and 99.3% ee, respec- 12 has been reported,[8,12] the shortcoming of low
tively (entries 4 and 5). Furthermore, the 2-methoxy- yield of the previous methods prompted us to develop
substituted a-arylcyclohexanone 6b also gave the cor- an alternative route. Starting with 3-methoxybenzal-
responding cis-product 7b in excellent yield with 96% dehyde (8) we prepared aryl bromide 12 in 74% over-
ee and >99:1 cis-selectivity (entry 3). These results in- all yield in 4 steps including a direct geminal dialkyla-
Scheme 1. Synthesis of arylboronic acid 4.
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Scheme 2. Preparation and asymmetric hydrogenation of racemic a-arylcycloalkanone 2.
tion reaction.[13] The aryl bromide 12 was then treated coupling of iodo-substituted cyclohexenone 3 with ar-
[16]
with n-butyllithium (1.3 equiv.) in THF at À788C, fol- ylboronic acid 4 catalyzed by Pd
ACHTUNGTRENN(NUG PPh3)4 proceeded
lowed by triisopropyl borate (2.0 equiv.) and hydro- to afford a-arylcyclohexenone 14 in excellent yield
chloric acid (1N) to yield arylboronic acid 4 in 82% (98%). The a-arylcyclohexenone 14 was hydrogenat-
yield.[14]
ed over Pd-C to racemic a-arylcyclohexanone 2 in
With arylboronic acid 4 at hand, we tried to pre- 96% yield. Asymmetric hydrogenation of racemic a-
pare racemic a-arylcyclohexanone 2 (Scheme 2). The arylcyclohexanone 2 catalyzed by (Sa,RR)-5a under
commercially available 1,4-cyclohexenedione mono- 50 atm H2 produced alcohol (S,S)-1 in 99% yield with
ethylene acetal 13 was treated with iodine under basic 96% ee and >99:1 cis-selectivity.
conditions to yield the corresponding iodo-substituted
Having successfully realized the preparation and
cyclohexenone 3 in 84% yield.[15] The Suzuki cross- highly efficient asymmetric hydrogenation of racemic
Scheme 3. Synthesis of (À)-CP-55940.
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Enantioselective Synthesis of (À)-CP-55940 via Ruthenium-Catalyzed Asymmetric Hydrogenation
Table 2. Free radical allylation with allyltributyltin.[a]
Entry
X
R
SM[b]
Solvent
Conversion [%][c]
Selectivity[c] A/B
Yield [%][d]
1
2
3
4
5
6
7
U
SMe
OPh
OC6F5
Im[e]
SMe
SMe
SMe
15a
15b
15c
15d
15a
16
toluene
toluene
toluene
toluene
benzene
benzene
benzene
100
100
64
1/1.2
1/1.2
1/1.2
1/1.4
1.1/1
2.4/1
1.6/1
60
53
35
32
66
20
80
80
100
100
100
17
[a]
Reaction conditions: substrate/allyltributyltin/AIBN=1:5:0.5, 808C, 12 h.
SM=starting material.
Determined by H NMR.
Isolated yield.
Im=imidazole.
[b]
[c]
[d]
[e]
1
a-arylcycloalkanone 2, we next turned our attention of compound (S,S)-1 with allylmagnesium reagents,[21]
to the transformation of (S,S)-1 (96% ee) to (À)-CP- also gave unsatisfactory results. We finally found that
55940. Treatment of (S,S)-1 with NaH, CS2 and MeI the free radical allylic substitution of xanthate was
in THF at 08C to room temperature[17] for 2.5 h, fol- the method of choice for this transformation.[18] The
lowed by deprotection with hydrochloric acid and re- experiment results listed in Table 2 showed that the
duction with sodium borohydride afforded a single methyl xanthate 17 gave the best result (18a/18b, 1.6:
isomer of cis,cis-product 17 in good yield (84% yield 1, 80% yield, entry 7).
with three steps or 86% yield with two steps,
Scheme 3). Subsequent radical substitution of 17 with
allyltributyltin in benzene in the presence of azobis- Conclusions
ACHTUNGTRENNUNG(isobutyronitrile) (AIBN) at 808C for 12 h gave a mix-
ture of desired product 18a and deoxygenated product In summary, we have accomplished the efficient cata-
18b in 80% yield (18a/18b=1.6:1).[18] The separation lytic enantioselective synthesis of the potent cannabi-
of 18a and 18b was difficult. The mixture was reacted noid receptor agonist (À)-CP-55940, which contains
with borane (BH3·THF) at 08C to room temperature a chiral 2,5-disubsituted 1-arylcyclohexanoid unit, in
for 0.5 h, followed by treatment with 2 NNaOH and 14.6% overall yield over 13 steps (the longest linear
H2O2 (30%), affording the mixture of 19 and 18b. steps) from commercially available 3-methoxybenzal-
Compounds 19 and 18b were easily separated by dehyde via a ruthenium-catalyzed asymmetric ketone
column chromatography on silica gel, providing pure hydrogenation as a key step.
19 and 18b in 33% and 30% yields, respectively. Fi-
nally, demethylation of 19 by PrSLi in hexamethyl-
phosphoramide (HMPA)[19] yielded (À)-CP-55940 in
Experimental Section
1
89% yield. The H and 13C NMR spectra and the opti-
cal rotation of the synthesized (À)-CP-55940 were
General Remarks
identical to those described in the literature.[8]
All reactions and manipulations which are sensitive to mois-
ture or air were performed in an argon-filled glovebox
(VAC DRI-LAB HE 493) or by using standard Schlenk
techniques. Hydrogen gas (99.999%) was purchased from
Boc Gas Inc., Tianjin. Chemical reagents such as borane, di-
methylzinc and allyltributyltin were purchased from Aldrich
or Alfa Aesar chemical company. Anhydrous THF, Et2O,
Before completing the catalytic enantioselective
synthesis of (À)-CP-55940, we systematically studied
the allylic substitution reaction for the carbon-carbon
bond formation. Direct allylic substitution of the hy-
droxy group of (S,S)-1 with allylsilane catalyzed by
InCl3 according to Babaꢀs method[20] yielded only
a small amount of dehydroxylation product. Other
toluene and benzene was distilled from sodium benzophe-
methods including allylic substitution of the tosylate none ketyl. Anhydrous i-PrOH and CH2Cl2 were freshly dis-
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Li-Jie Cheng et al.
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tilled from calcium hydride. Melting points were measured
on a RY-I apparatus and uncorrected. NMR spectra were
recorded with a Bruker AV 400 spectrometer at 400 MHz
(1H NMR) and 100 MHz (13C NMR). Chemical shifts are re-
ported in ppm downfield from internal Me4Si. Optical rota-
tions were determined using a Perkin–Elmer 341 MC polar-
imeter. High resolution mass spectra (HR-MS) were record-
ed on an IonSpec FT-ICR mass spectrometer with an elec-
tron spray ionization (ESI) source. HPLC analyses were de-
termined using a Hewlett Packard Model HP 1100 Series
chromatography.
uene, 8 mL, 9.5 mmol) at À40 to À508C, and the obtained
orange solution was stirred at the same temperature for
45 min. A solution of 1-(3-methoxyphenyl)heptan-1-one (10)
(1.0 g, 4.5 mmol) in CH2Cl2 (18 mL) was slowly added at
À40 to À508C. After completion of the addition, the mix-
ture was allowed to slowly warm to À108C over a period of
2 h. The reaction mixture was quenched by slowly pouring
into an ice-cooled aqueous NH4Cl solution and extracted
with CH2Cl2 (3ꢂ20 mL). The combined organic extract was
washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate=20:1) to afford the product 11 as a colorless oil;
yield: 1.1 g (98%). 1H NMR (400 Hz, CDCl3): d=7.23 (t,
J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.89 (s ,1H), 6.72
(dd, J=8.0, 2.0 Hz, 1H), 3.82 (s, 3H), 1.60–1.56 (m, 2H),
1.28–1.20 (m, 12H), 1.05 (brs, 2H), 0.84 (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=159.3, 151.6, 128.8, 118.4,
112.6, 109.7, 55.0, 44.6, 37.7, 31.8, 30.0, 29.0, 24.7, 22.7, 14.1;
HR-MS (ESI): m/z=257.1878, calcd. for C16H26ONa ([M+
Na]+): 257.1876.
Preparation of Arylboronic Acid 4
1-(3-Methoxyphenyl)heptan-1-ol (9): A solution of 3-meth-
ACHTUNGTRENNUNGoxybenzaldehyde (20.0 g, 0.15 mol) in THF (80 mL) was
added slowly to a solution of hexylmagnesium bromide in
THF (350 mL) prepared in situ from 1-bromohexane (31.3 g,
0.19 mol) and magnesium turnings (4.6 g, 0.19 mol) at 08C.
After completing the addition, the mixture was allowed to
stir at room temperature for 3 h. The reaction mixture was
cooled to 08C again and treated slowly with hydrochloride
acid (1N, 100 mL). The organic layer was separated, and the
aqueous layer was extracted with ether (3ꢂ100 mL). The
combined organic extract was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure to yield
the crude product. The crude product was purified by distil-
lation to provide the product 9 as a colorless oil; yield:
29.4 g (90%); bp 1308C/0.5 mm Hg. 1H NMR (400 MHz,
CDCl3): d=7.26 (t, J=8.1 Hz, 1H), 6.92–6.90 (m, 2H),
6.82–6.80 (m, 1H) , 4.64 (t, J=6.6 Hz, 1H), 3.81 (s, 3H),
1.87 (brs, 1H), 1.83–1.64 (m, 2H), 1.50–1.15 (m, 8H), 0.87
(t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=159.6,
146.7, 129.3, 118.2, 112.7, 111.3, 74.4, 55.1, 39.0, 31.7, 29.1,
25.7, 22.5, 14.0; HR-MS (ESI): m/z=245.1516, calcd. for
C14H22O2Na ([M+Na]+): 245.1512.
1-Bromo-4-(1,1-dimethylheptyl)-2-methoxybenzene
(12):[8,12] To a stirred solution of 1-(1,1-dimethylheptyl)-3-
methoxybenzene (11) (4.5 g, 19.2 mmol) in AcOH (50 mL)
was slowly added bromine (3.1 g, 19.2 mmol) in AcOH
(10 mL) at room temperature and the reaction mixture was
stirred at the same temperature for 4 h. The reaction mix-
ture was quenched with H2O and extracted with Et2O (3ꢂ
150 mL). The combined organic extract was washed with
2N NaOH (50 mL) and brine, dried over MgSO4, and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (petroleum
ether/ethyl acetate=20:1) to afford 5.7 g products contain-
1
ing 12 (91%, determined by H NMR) and 1-bromo-2-(1,1-
dimethylheptyl)-4-methoxybenzene (9%), which are insepa-
rable.
12; 1H NMR (400 Hz, CDCl3): d=7.43 (d, J=8.0 Hz,
1H), 6.86 (s, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.90 (s, 3H),
1.59–1.55 (m, 2H), 1.28–1.03 (m, 14H), 0.84 (m, 3H);
13C NMR (100 MHz, CDCl3): d=155.3, 151.0, 132.5, 119.6,
110.0, 108.2, 56.0, 44.5, 37.9, 31.7, 29.9, 28.9, 24.6, 22.6, 14.1;
HR-MS (ESI): m/z=335.0975, calcd. for C16H26ONa ([M+
Na]+): 257.1876.
1-(3-Methoxyphenyl)heptan-1-one (10):
A solution of
CrO3 (16.0 g, 0.16 mol) and sulfuric acid (8.8 mL) in water
(32.4 mL) was added dropwise to a solution of 1-(3-meth-
ACHTUNGTRENNUNGoxyphenyl)heptan-1-ol (9) (28.0 g, 0.13 mmol) in acetone
(300 mL) at below 58C. After completion of the addition,
the reaction mixture was allowed to stir at room tempera-
ture for 3.0 h. The mixture was then filtered through a pad
of Florisil and the filtrate was concentrated under reduced
pressure. The residue was treated with 100 mL of ice-cooled
water and extracted with diethyl ether (3ꢂ200 mL). The
combined organic layer was washed with saturated sodium
bicarbonate solution and brine successively, dried over
MgSO4 and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel (petrole-
um ether/ethyl acetate=5:1) to provide the product 10 as
a pale yellow oil; yield: 27.7 g (98%). 1H NMR (400 Hz,
CDCl3): d=7.53 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.35 (t, J=
7.9 Hz, 1H), 7.08 (dd, J=8.2, 2.0 Hz, 1H), 3.84 (s, 3H), 2.94
(t, J=7.6 Hz, 2H), 1.72 (m, 2H), 1.39–1.31 (m, 6H), 0.89 (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=200.2,
159.7, 138.4, 129.4, 120.6, 119.1, 112.2, 55.2, 38.6, 31.6, 28.9,
24.3, 22.4, 13.9; HR-MS (ESI): m/z=243.1353, calcd. for
C14H20O2Na ([M+Na]+): 243.1356.
2-Methoxy-4-(2-methyloctan-2-yl)phenylboronic acid (4):
BuLi (2.4M in THF, 0.87 mL, 2.1 mmol) was added drop-
wise to a solution of aryl bromide 12 (550 mg, 91% pure,
1.6 mmol) in THF (20 mL) at À788C. The mixture was
stirred at the same temperature for 1 h and triisopropyl
borate (0.74 mL, 3.2 mmol) was added dropwise. The mix-
ture was stirred at À788C for 30 min and at À308C for 1 h.
The mixture was acidified with hydrochloric acid (1N,
15 mL) and extracted with ether (3ꢂ50 mL). The combined
organic extract was washed with brine, dried over Na2SO4
and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (petroleum
ether/ethyl acetate=5:1) to give 4 as a white solid; yield:
1
364 mg (82%); mp 98–1008C. H NMR (400 MHz, CDCl3):
d=7.74 (d, J=7.7 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.87 (s,
1H), 5.86–5.77 (m, 2H), 3.92 (s, 3H), 1.62–1.58 (m, 2H),
1.30–1.20 (m, 12H), 1.05 (brs, 2H), 0.84 (t, J=6.7 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=164.5, 155. 6, 136.3, 119.0,
107.7, 55.3, 44.4, 38.2, 31.7, 29.9, 28.8, 24.6, 22.6, 14.0;
1-(1,1-Dimethylheptyl)-3-methoxybenzene (11):[13b] To
a solution of TiCl4 (1.1 mL, 9.5 mmol) in CH2Cl2 (18 mL)
was added dropwise a solution of dimethylzinc (1.2M in tol-
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Enantioselective Synthesis of (À)-CP-55940 via Ruthenium-Catalyzed Asymmetric Hydrogenation
11B NMR (128 MHz, CDCl3): d=29.48; HR-MS (ESI):
m/z=277.1980, calcd. for C16H26BO3 ([MÀH]À): 277.1981.
28.9, 24.6, 22.6, 14.1; HR-MS (ESI): m/z=411.2501, calcd.
for C24H36O3Na ([M+Na]+): 411.2506.
Preparation of a-Arylcyclohexanone 2
Asymmetric Synthesis of (À)-CP-55940
ACHTUNGTRENNUNG
7-Iodo-1,4-dioxaspiro[4.5]dec-6-en-8-one (3): To a solution
G
of enone 13 (2.0 g, 13 mmol) in THF/H2O (60 mL, v/v=1/1)
was added K2CO3 (2.2 g, 16 mmol), I2 (5.0 g, 20 mmol,) and
DMAP (0.32 g, 2.6 mmol) successively. After stirring at
room temperature for 2 h, the mixture was diluted with
EtOAc (50 mL) and saturated Na2S2O3 solution (20 mL).
The organic layer was separated, and the aqueous layer was
extracted with EtOAc (3ꢂ50 mL). The combined organic
solution was washed with brine, dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl
acetate=3:1) to afford the product 3 as a white solid; yield:
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
drogenation vessel in a glove box under argon atmosphere.
Anhydrous i-PrOH (24.0 mL) was introduced with a syringe,
and the vessel was purged with hydrogen and pressurized to
20 atm for 5 min. After releasing the pressure, compound 2
(10 mmol in 12.0 mL i-PrOH) and a solution of t-BuOK in
i-PrOH (0.2 mmol/mL, 10.0 mL, 2 mmol) were added. The
vessel was purged with hydrogen and pressurized to 50 atm.
After stirring at room temperature for 12 h, the reaction
was stopped. The reaction mixture was concentrated and pu-
rified through a short silica gel column (petroleum ether/
ethyl acetate=2:1) to furnish alcohol (S,S)-1 as a colorless
oil; yield: 3.7 g (99%); [a]1D8: +40.9 (c 1.06, CHCl3); 96% ee.
SFC (Chiralpak AD-H column, 25 cmꢂ0.46 cm ID; 2-prop-
anol/CO2 =10:90; 408C; 100 bar; 2.0 mLminÀ1; 220 nm):
1
3.1 g (84%); mp 82–838C. H NMR (400 MHz, CDCl3): d=
7.40 (s, 1H), 4.08–4.00 (m, 4H), 2.82 (t, J=6.5 Hz, 2H), 2.24
(t, J=6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=191.3,
155.1, 107.2, 105.0, 65.0, 33.2, 33.0; HR-MS (ESI): m/z=
302.9487, calcd. for C8H9IO3Na ([M+Na]+): 302.9489.
7-(2-Methoxy-4-(2-methyloctan-2-yl)phenyl)-1,4-dioxa-
tRACTHNUTRGNEUNG
(major)=9.86 min; tR (minor)=11.82 min; 1H NMR
spiro
[4.5]dec-6-en-8-one (14): 2-Iodoenone
3
(67 mg,
(400 MHz, CDCl3): d=7.07 (d, J=8 Hz, 1H), 6.90 (dd, J=
8.0, 1.6 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 4.10–3.88 (m, 5H),
3.81 (s, 3H), 3.50 (d, J=13.2 Hz, 1H), 2.37 (t, J=13.2 Hz,
1H), 2.10–1.91 (m, 3H), 1.61–1.55 (m, 4H), 1.45 (s, 1H),
1.27–1.20 (m, 12H), 1.06 (brs, 2H), 0.84 (t, J=6.8 Hz, 3H);
13C NMR (100MHz, CDCl3): d=156.7, 149.9, 127.2, 126.7,
117.9, 109.6, 108.2, 67.0, 64.3, 64.2, 55.1, 44.5, 38.9, 37.7, 32.7,
31.7, 30.0, 29.7, 29.0, 28.9, 28.7, 24.6, 22.6, 14.1; HR-MS
(ESI): m/z=413.2666, calcd. C24H38O4Na ([M+Na]+):
413.2662.
0.24 mmol) was added to a mixture of arylboronic acid 4
(100 mg, 0.36 mmol), LiCl (30 mg, 0.72 mmol) and Na2CO3
(2M in water, 0.34 mL, 0.67 mmol) in 1,2-dimethoxyethane
(3 mL). The mixture was degassed three times and charged
with N2, and PdACHTUNGTRENNUNG(PPh3)4 (14 mg, 0.012 mmol) was added. The
reaction mixture was heated to 808C with vigorous stirring
for 12 h. The resulting reaction mixture was cooled to room
temperature and added to water (20 mL). The product was
extracted with EtOAc (3ꢂ10 mL). The combined organic
solution was washed with brine, dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified
by chromatography on silica gel (petroleum ether/ethyl ace-
tate=4:1) to afford the product 14 as a white solid; yield:
92 mg (98%); mp 82–848C. 1H NMR (400 MHz, CDCl3):
d=7.00 (d, J=7.8 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.84 (s,
1H), 6.53 (s, 1H), 4.05 (s, 4H), 3.74 (s, 3H), 2.78 (t, J=
6.6 Hz, 2H), 2.31 (t, J=6.6 Hz, 2H), 1.62–1.54 (m, 2H),
1.32–1.14 (m, 12H), 1.08 (brs, 2H), 0.85 (t, J=6.8 Hz, 3H);
13C NMR (100 MHz,): d=196.9, 156.7, 152.0, 142.9, 139.8,
129.7, 122.01, 118.1, 109.0, 104.7, 65.0, 55.6, 44.5, 37.9, 36.1,
33.4, 31.7, 30.0, 28.9, 24.6, 22.6, 14.0; HR-MS (ESI): m/z=
409.2346, calcd. for C24H34O4Na ([M+Na]+): 409.2349.
3-(2-Methoxy-4-(1,1-dimethylheptyl)phenyl)cyclohex-2-en-
one (2): To a solution of compound 14 (50 mg, 0.13 mmol)
of in ethanol (3 mL) was added 5% palladium on activated
carbon (27 mg, 0.013 mmol). The mixture was stirred under
atmospheric pressure of H2 for 3 h and was then filtered
through a pad of Florisil. The filtrate was concentrated
under reduced pressure and purified by chromatography on
silica gel (petroleum ether/ethyl acetate=4:1) to afford
product 2 as a white solid; yield: 48 mg (96%); mp 104–
1068C. 1H NMR (400 MHz, CDCl3): d=6.96 (d, J=8 Hz,
1H), 6.88 (d, J=8 Hz, 1H), 6.82 (s, 1H), 4.16–4.40 (m, 5H),
3.77 (s, 3H), 2.81 (td, J=14.0, 7.1 Hz, 1H), 2.54–2.43 (m,
2H), 2.19–2.11 (m, 3H), 1.60–1.54 (m, 2H), 1.27–1.07 (m,
14H), 0.84 (t, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=208.6, 156.7, 150.3, 128.2, 123.6, 118.0, 108.5, 107.7, 64.7,
64.6, 55.3, 47.7, 44.6, 39.5, 38.3, 37.7, 34.3, 31.7, 30.0, 28.9,
O-(7S,8S)-7-[2-Methoxy-4-(2-methyloctan-2-yl)phenyl]-
1,4-dioxaspiroACHTUNTRGNEUNG[4.5]decan-8-yl S-methyl carbonodithioate
(15): To a suspension of NaH (1.3 g, 53.3 mmol) in THF
(100 mL) was added a solution of (S,S)-1 (4.2 g, 10.7 mmol)
in THF (20 mL) at 08C. The mixture was stirred at room
temperature for 30 min, CS2 (0.96 mL, 16 mmol) was added
in one portion. The reaction mixture was continued to stir at
room temperature for 45 min. MeI (0.81 mL, 16 mmol) was
added to the mixture with stirring. After stirring for 45 min,
the reaction was quenched with aqueous NH4Cl until no hy-
drogen gas was evolved the organic layer was separated.
The aqueous layer was extracted with Et2O (3ꢂ100 mL),
the organic layers were combined and washed with brine,
dried over anhydrous MgSO4 and concentrated under re-
duced pressure. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate=10:1)
to afford the product 15 as a pale yellow oil; yield: 4.8 g
(94%); [a]2D0: +70.7 (c 1.03, CHCl3). 1H NMR (400 MHz,
CDCl3): d=7.02 (d, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H),
6.76 (s, 1H), 6.02 (s, 1H), 4.00 (m, 4H), 3.83 (s, 3H), 3.70
(d, J=13.2 Hz, 1H), 2.42 (s, 3H), 2.40–2.32 (m, 3H), 2.04–
1.71 (m, 4H), 1.57–1.53ACTHNUTRGENNU(G m, 2H), 1.27–1.02ACHTUNTGREN(NUNG m, 12H), 1.02
(brs, 2H), 0.84 (t, J=6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=214.7, 156.5, 149.6, 126.8, 125.4, 117.6, 108.9,
107.9, 80.4, 64.4, 64.3, 55.2, 44.6, 37.6, 36.8, 34.4, 31.7, 29.9,
29.7, 28.9, 28.9, 27.3, 24.5, 22.6, 18.4, 14.0; HR-MS (ESI):
m/z=503.2258, calcd. C26H40O4S2Na ([M + Na]+): 503.2260.
O-(1S,2S)-2-[2-Methoxy-4-(2-methyloctan-2-yl)phenyl]-4-
oxocyclohexyl S-methyl carbonodithioate (16): To a solution
Adv. Synth. Catal. 2012, 354, 1105 – 1113
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1111

Li-Jie Cheng et al.
FULL PAPERS
of ketal 15 (7.4 g, 15.5 mmol) in THF (200 mL) was added
aqueous HCl (10%, 200 mL) at room temperature. After
the reaction mixture had been stirred for 36 h, the organic
layer was separated, and the aqueous layer was extracted
with Et2O (3 ꢂ100 mL). The combined organic layer was
washed with brine, dried over anhydrous MgSO4 and con-
centrated under reduced pressure. The residue was purified
by chromatography on silica gel (petroleum ether/ethyl ace-
tate=8:1) to afford the product 16 as a pale yellow oil;
yield: 6.5 g (97%). The product 16 also could be obtained
directly from the treatment of the reaction mixture of the
synthesis of compound 15 with aqueous HCl for 36 h; yield:
luted with water and ether, and extracted with ether (3ꢂ
50 mL). The combined organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pres-
sure. The residue was purified by chromatography on silica
gel (petroleum ether/ethyl acetate=3:1–1:1) to offer the
product 19 as a colorless oil; yield: 676 mg (33% yield from
17); [a]17: À31.0 (c 0.50, CHCl3) [lit[8] [a]3D0: À33.6 (c 0.42,
CHCl3)]D. 1H NMR (400 MHz, CDCl3): d=7.01 (d, J=
7.3 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.79 (s, 1H), 3.78 (s,
3H), 3.73–3.68 (m, 1H), 3.44–3.39 (m, 2H), 2.84 (brs, 1H),
2.07–1.95 (m, 3H), 1.81–1.04 (m, 25H) ,0.97–0.88 (m, 1H),
0.83 (t, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
156.7, 148.8, 129.8, 126.2, 118.3, 108.7, 70.9, 63.1, 55.5, 44.6,
43.5, 40.5, 37.6, 35.5, 31.7, 30.0, 29.9, 29.9, 29.0, 28.9, 24.6,
22.6, 14.0; HR-MS (ESI): m/z=413.3028, calcd. C25H42O3Na
([M+Na]+): 413.3026.
1
96% yield. [a]1D8: +87.6 (c 1.0, CHCl3). H NMR (400 MHz,
CDCl3): d=7.03 (d, J=8.1 Hz, 1H), 6.85 (dd, J=8.0, 1.6 Hz,
1H), 6.78 (d, J=1.5 Hz, 1H), 6.15 (d, J=2.0 Hz, 1H), 3.86–
3.79 (m, 4H), 3.14 (t, J=14.0 Hz, 1H), 2.67–2.58 (m, 2H),
2.55–2.39 (m, 5H), 2.16–2.04 (m, 1H), 1.57–1.53 (m, 2H),
1.27–0.97 (m, 14H), 0.84 (t, J=6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=215.1, 210.0, 156.3, 150.3, 126.6,
124.1, 117.9, 108.1, 79.4, 55.2, 44.6, 41.6, 39.1, 37.7, 36.3, 31.7,
29.9, 29.0, 28.9, 24.5, 22.6, 18.8, 14.1; HR-MS (ESI): m/z=
459.2002, calcd. C24H36O3S2Na ([M+Na]+): 459.1998.
O-(1S,2S,4R)-4-Hydroxy-2-[2-methoxy-4-(2-methyloctan-
2-yl)phenyl]cyclohexyl S-methyl carbonodithioate (17):
NaBH4 (1.7 g, 44.7 mmol) was added to a solution of com-
pound 16 (6.5 g, 14.9 mmol) in CH3OH (120 mL) at À788C.
The mixture was stirred at À788C for 0.5 h and was warmed
to room temperature. After quenching with H2O the reac-
tion mixture was stirred at room temperature for 30 min and
extracted with Et2O (3 ꢂ100 mL). The organic layer was
washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by chro-
matography on silica gel (petroleum ether/ethyl acetate=
4:1) to afford the product 17 as a colorless oil; yield: 5.9 g
(90%); [a]1D8: +75.6 (c 1.0, CHCl3). 1HNMR (400 MHz,
CDCl3): d=7.08 (d, J=8.0 Hz, 1H), 6.84 (dd, J=8.0, 1.6 Hz,
1H), 6.76 (d, J=1.5 Hz, 1H), 5.96 (d, J=1.9 Hz, 1H), 3.95–
3.86 (m, 1H), 3.82 (s, 3H), 3.38 (dt, J=12.8, 2.4 Hz, 1H),
2.43 (s, 3H), 2.37–1.94 (m, 5H), 1.78–1.70 (m, 1H), 1.63–
(À)-CP 55,940: To
a solution of n-PrSH (3.5 mL,
38.4 mmol) in hexamethylphosphoric triamide (30.0 mL)
was added n-BuLi (2.4M in hexane, 10.7 mL, 25.6 mmol) at
08C. After stirring at 08C for 10 min and at room tempera-
ture for 10 min, the mixture was added to another flask con-
taining compound 19 (1.0 g, 2.6 mmol). The resulting mix-
ture was heated to 100–1208C for 5 h. After cooling to room
temperature, the reaction mixture was quenched with satu-
rated aqueous NH4Cl solution, extracted with ethyl acetate
(3ꢂ50 mL). The organic layer was washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate=1:1) to afford (À)-CP
55,940 as a white solid; yield: 850 mg (89%); mp 50–528C;
[a]3D3: À27.0 (c 0.2, CHCl3) [lit[8] [a]D29: À28.2 (c 0.15, CHCl3);
1
[a]3D3: À27.7 (c 0.2, CHCl3)]. H NMR (400 MHz, CD3OD):
d=6.93 (brs, 1H), 6.68 (brs, 2H), 3.55 (m, 1H), 3.29–3.23
(m, 2H), 2.81 (brs, 1H), 1.96–1.90 (m, 3H), 1.50–1.46 (m,
3H), 1.29–0.85 (m, 21H), 0.77 (t, J=6.4 Hz, 3H); 13C NMR
(100 MHz, CD3OD): d=155.5, 149.4, 129.5, 127.4, 118.5,
114.0, 71.7, 63.6, 45.8, 44.6, 42.5, 39.8, 38.2, 36.5, 33.0, 31.4,
31.2, 31.0, 30.6, 29.6, 25.8, 23.7, 14.5; HR-MS (ESI): m/z=
399.2878, calcd. C24H40O3Na ([M+Na]+): 399.2870.
1.53 (m, 3H), 1.27–1.00ACTHNUTRGNEU(GN m, 14H), 0.85 (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=214.7, 156.3, 149.6, 127.0,
125.5, 117.7, 107.8, 79.8, 70.2, 55.2, 44.6, 37.6, 37.4, 34.9, 31.7,
29.9, 28.9, 28.8, 27.9, 24.5, 22.6, 18.4, 14.01; HR-MS (ESI):
m/z=461.2156, calcd. C24H38O3S2Na ([M+Na]+): 461.2155.
Acknowledgements
ACHTUNGTRENNUNG(1R,3R,4R)-4-(3-Hydroxypropyl)-3-(2-methoxy-4-(2-
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China (973 Pro-
gram, No.2010CB833300, 2011CB808600), “111” Project of
the Ministry of Education of China (Grant No. B06005), and
Program for New Century Excellent Talents in University
(NCET-08-0292) for financial support.
methyloctan-2-yl)phenyl)cyclohexanol (19): A mixture of
thionocarbonate 17 (2.3 g, 5.3 mmol), allyltributyltin
(7.8 mL, 26.5 mmol), and AIBN (431 mg, 2.6 mmol) in ben-
zene (80 mL) was refluxed under nitrogen for 12 h. The so-
lution was concentrated and the residue was purified by
chromatography on silica gel (petroleum ether/ethyl ace-
tate=3:1) to afford an inseparable mixture of 18a and 18b
as a colorless oil; yield: 1.5 g (80%, 18a/18b=1.6:1).
The mixture of 18a and 18b was dissolved in dry THF
(80 mL) and cooled to 08C with ice bath. A solution of
borane in THF (1.0M, 4.7 mL, 4.7 mmol) was slowly added
over a period of 30 min, and the resulting mixture was
stirred at room temperature for 0.5 h. The reaction mixture
was cooled with ice again, and treated with aqueous NaOH
solution (2 N, 1.4 mL, 2.8 mmol,) and 30% aqueous hydro-
gen peroxide solution (0.5 mL, 5.8 mmol,). The resulting re-
action mixture was stirred at room temperature for 1 h, di-
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