Catalytic asymmetric michael reactions of α,β-unsaturated ketones with sulfonyl-containing nucleophiles: Chiral synthesis of (R)-muscone and (S)-celery ketone

Article abstract of DOI:10.1002/chem.201002418

An amine worth its salt: A highly enantioselective Michael addition reaction of α,β-unsaturated ketones with the sulfonyl-containing nucleophiles bis(phenylsulfonyl)methane and 1-(phenylsulfonyl)propan-2-one, catalyzed by a chiral primary amine salt, has been developed and gives excellent enantioselectivities (see scheme). The methodology has successfully demonstrated its synthetic utility in the chiral synthesis of (R)-muscone and (S)-celery ketone.

Full text of DOI:10.1002/chem.201002418

DOI: 10.1002/chem.201002418
Catalytic Asymmetric Michael Reactions of a,b-Unsaturated Ketones with
Sulfonyl-Containing Nucleophiles: Chiral Synthesis of (R)-Muscone and
(S)-Celery Ketone
Xiaomin Sun, Feng Yu, Tingting Ye, Xinmiao Liang, and Jinxing Ye*[a]
The chemistry of the sulfonyl group has found numerous
applications in organic and natural-product synthesis, with
one of the most important being its use as a protecting
group for amines.[1] Sulfones can be transformed into various
functionalities[2] or cleaved by reductive desulfonation.[3] Re-
cently, a few examples of catalytic asymmetric Michael reac-
tions have been reported by using sulfone-containing Mi-
chael acceptors and donors, and simple alkyl groups can be
introduced by reductive desulfonation.[4] The groups of
Alexakis,[5a–d] Palomo,[5e] and Lu[5f–h] have reported the
highly enantioselective Michael addition of aldehydes or ke-
tones to sulfone-containing Michael acceptors (vinyl sul-
fones) based on an enamine mechanism that uses a chiral
secondary or primary amine as the catalyst.
ers have developed an enantioselective conjugate addition
of FBSM to enones with a chiral phase-transfer catalyst.[6]
Kim and co-workers have reported an enantioselective con-
jugate addition of FBSM to enones with a 9-epi-amino cin-
chona alkaloid salt catalyst,[7] the conjugate-addition prod-
ucts of which are useful for the synthesis of chiral mono-
fluoromethylated compounds. Jørgensen and co-workers
have developed an elegant asymmetric conjugate addition
to cyclic a,b-unsaturated ketones with b-keto heterocyclic
sulfones, catalyzed by the 9-epi-amino cinchona alkaloid
salt, and the adducts can easily be transformed into optically
active alkynyl, alkenyl, and ketone products.[8] Rios, Wang,
and Cꢀrdova have reported the asymmetric Michael reac-
tions of enals with FBSM, catalyzed by diarylprolinol ether
in the absence or presence of an additive.[9a–c] Ruano and
Alemꢁn,[10a] Rios,[10b] and Palomo[10c] have accomplished the
asymmetric Michael reactions of enals with BSM, catalyzed
by diarylprolinol ether. It was also found that nonfluorinat-
ed BSM has rather poor reactivity in the allylic substitution
reaction.[6] These are the only examples of asymmetric Mi-
chael reactions that use BSM as the Michael donor. There-
fore, the development of catalytic asymmetric processes in
which bis(phenylsulfonyl)methane is used as a nucleophile
still remains a challenge. To the best of our knowledge,
there has been no report on the enantioselective Michael re-
action of a,b-unsaturated ketones with the less active BSM.
Herein, we report the discovery of a highly enantioselective
Michael addition of a,b-unsaturated ketones with BSM and
1-(phenylsulfonyl)propan-2-one (Scheme 2), catalyzed by a
chiral primary amine salt. The remarkable synthetic value of
the transformation has been successfully demonstrated by
the chiral synthesis of (R)-muscone and (S)-celery ketone.
The Michael reaction of 6a with bis(phenylsulfonyl)-
The Michael donors bis(phenylsulfonyl)methane (BSM)
and fluorobis(phenylsulfonyl)methane (FBSM) can be used
as methide and fluoromethide equivalents (Scheme 1).
Chiral methides are often present in medicinal intermedi-
ates, fragrances, and natural products. Shibata and co-work-
Scheme 1. BSM as a methide equivalent.
[a] X. Sun, F. Yu, T. Ye, Prof. Dr. X. Liang, Prof. Dr. J. Ye
Engineering Research Center of Pharmaceutical Process Chemistry
Ministry of Education, School of Pharmacy
East China University of Science and Technology
130 Meilong Road, Shanghai 200237 (P.R. China)
Fax : (+86)21-64251830
AHCTUNGTREGmNNUN ethane (7a) was examined as a model reaction (Table 1).
A variety of chiral primary amines (1–5), with or without
benzoic acid as an additive, were screened as catalysts in the
model reaction. Diaminocyclohexane (1) with benzoic acid
(2 equiv) provided the desired product in 72% conversion
and 73% ee (Table 1, entry 1). It is interesting to find that,
E-mail: yejx@ecust.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002418.
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Chem. Eur. J. 2011, 17, 430 – 434

COMMUNICATION
multifunctional catalyst 4, but with a moderate enantioselec-
tivity (Table 1, entry 4). The reaction proceeded smoothly
by using 9-aminoACTHNUTRGNEUNG
(9-deoxy)epiquinine 5[11,12] as the catalyst,
either with or without benzoic acid (Table 1, entries 5–7), al-
though the best enantioselectivity (97% ee) was obtained in
the presence of 2 equivalents of benzoic acid (Table 1,
entry 7).
Next, solvent effects were examined and it was found that
solvent did not affect the enantioselectivity but did affect
the conversion. Dichloromethane, acetonitrile, tetrahydro-
furan, 1,4-dioxane, 1,2-dichloroethane, chloroform, and eth-
anol were all found to be suitable solvents for this asymmet-
ric Michael reaction.
The reaction scope was explored and a variety of a,b-un-
saturated ketones were examined (Table 2). The reactions of
4-substituted 3-buten-2-ones (6a–h) with 7a afforded the de-
Scheme 2. Primiary amine catalyst.
Table 2. Scope of the asymmetric Michael reaction of 7a.[a]
Table 1. Screening of reaction conditions.[a]
Entry
R1
R2
Adduct
Time
[days]
Yield[b]
[%]
ee[c]
[%]
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18[d]
19
20
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Pr
Bu
Me
Pr
iPr
pentyl
hexyl
C2H4Ph
iBu
Me
Et
iBu
C2H4Ph
Et
iBu
C2H4Ph
Me
8a
8b
8c
8d
8e
8 f
8g
8h
8i
2
2
2
4
2
2
4
2
5
4
4
7
4
4
7
5
4
2
2
5
92
88
96
54
97
94
88
85
93
87
85
73
90
92
77
82
74
81
92
17
96
95
95
95
96
96
90
96
97
97
98
97
97
98
97
96
98
95
92
n.d.[e]
Entry
Catalyst
Solvent
Conversion
[%][b]
ee
[%][c]
1
2[d]
3[d]
4[d]
5[d]
6[e]
7
1
2
3
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
EtOAc
CH3CN
MeOH
Et2O
72
49
58
97
82
94
83
31
88
76
26
56
74
91
31
69
76
73
73
43
87
50
87
94
97
94
95
92
92
96
95
97
97
97
86
94
8j
8k
8l
8
9
8m
8n
8o
8p
8q
8r
8s
8t
10
11
12
13
14
15
16
17
18
Pr
Pr
Bu
THF
cyclopentadec-2-enone
cyclohex-2-enone
cyclohept-2-enone
1,4-dioxane
MeOtBu
1,2-DCE
CHCl3
Me
Ph
[a] All reactions were carried out by using enone 6 (1 equiv, 0.50 mmol,
1m), 7a (1.5 equiv), catalyst 5 (0.20 equiv), and benzoic acid (0.4 equiv)
in dioxane (0.5 mL). [b] Isolated yield. [c] Enantiomeric excess was deter-
mined by chiral HPLC. [d] The reaction was carried out at 48C. [e] n.d.=
not determined.
EtOH
[a] All reactions were carried out by using 6a (1 equiv, 0.10 mmol, 0.5m),
7a (1.5 equiv, 0.15 mmol), a chiral amine catalyst (0.02 mmol), and ben-
zoic acid (0.04 mmol). [b] Conversion was determined by GC. [c] Enan-
tiomeric excess was determined by chiral HPLC. [d] Without acid.
[e] With benzoic acid (10 mol%).
sired products in high yields and excellent enantioselectivi-
ties (Table 2, entries 1–8). The reactions between slightly
hindered 4-isopropyl-3-buten-2-one and BSM proceeded in
moderate yield with 95% enantioselectivity (Table 2,
entry 3). a,b-Unsaturated ketones 6i–p, which contain ethyl,
propyl, or butyl groups delivered the desired adducts in
good to excellent yields and excellent enantioselectivities
(Table 2, entries 9–16). Cyclic enones, such as cyclohex-2-
enone and cyclohept-2-enone, were also applicable to the
for 1,2-diphenylethylenediamine (2) and its primary amino-
thiourea equivalent 3 as catalysts, better results regarding
conversion and enantioselectivity were achieved in the ab-
sence of an acidic additive than those in the presence of an
acidic additive (Table 1, entries 2–3). Moderate conversion
and 87% ee were obtained by using primary aminothiourea
3 as the catalyst. The highest reactivity was observed with
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431

J. Ye et al.
Michael reaction and gave satisfactory yields with 92–
95% ee (Table 2, entries 18 and 19). It is delightful that a
74% yield and 98% enantioselectivity was obtained for
macrocyclic cyclopentadec-2-enone (Table 2, entry 17). Un-
fortunately, very low conversion was observed for benzylide-
neacetone (6t) and other 4-aryl-substituted 3-buten-2-ones
(Table 2, entry 20).
Another sulfonyl-containing nucleophile, 1-(phenylsulfo-
nyl)propan-2-one, was also tested under these optimized
conditions. It was interesting to find that a tandem Michael/
Aldol reaction occurred with this nucleophile. From com-
bined X-ray crystallographic and 1H NMR analyses, we
found that synthetically valuable cyclohex-2-enones were
generated. The reaction with 4-substituted 3-buten-2-ones
delivered products 9a–d (Table 3, entries 1–4), whereas 2-
Table 3. The scope of the asymmetric Michael reaction of 7b.[a]
Entry
R1
R2
Adduct
Time
[days]
Yield[b]
[%]
ee[c]
[%]
N
1[d]
2[d]
3[d]
4[d]
5[d]
Me
Me
Me
Me
Bu
Pr
Bu
Pent
C2H4Ph
Me
9a
9b
9c
9d
9e
5
4
4
6
4
56
83
84
87
45
95 (96:4)
95 (96:4)
95 (97:3)
94 (95:5)
91 (89:11)
Figure 1. X-ray crystallographic analysis of adducts 8a (top) and 9d
(bottom).
[a] All reactions were carried out by using enone 6 (1 equiv, 0.50 mmol,
1m), 7b (1.5 equiv), catalyst 5 (0.20 equiv), and benzoic acid (0.4 equiv)
in dioxane (0.5 mL). [b] Isolated yield. [c] Enantiomeric excess was deter-
mined by chiral HPLC. [d] Diastereoselectivity was determined by
1H NMR spectroscopy of the crude product.
octen-4-one gave product 9e (Table 3, entry 5). Good to ex-
cellent diastereoselectivities (8:1–25:1) and excellent enan-
tioselectivities (91–95% ee) were achieved for aliphatic a,b-
unsaturated ketones (Table 3).
Suitable single crystals of adducts 8a and 9d were ob-
tained for X-ray crystallographic analysis (Figure 1). The ab-
solute configuration of 8a was unambiguously determined
to be R, and the absolute configuration of 9d was 4S,5R.
The synthetic utility of this newly developed methodology
was further demonstrated by its use in the chiral synthesis of
natural-product ketones (R)-muscone and (S)-celery ketone
(Schemes 3 and 4, respectively). Natural (R)-muscone is ob-
tained in small quantities from the scent gland of the male
musk deer and has important applications in both perfumery
and medicine. Therefore, the efficient asymmetric synthesis
of optically active (R)-muscone has drawn much atten-
tion.[13] In our approach, the Michael adduct of macrocyclic
ketone cyclopentadec-2-enone 8q was protected with
ethane-1,2-dithiol in the presence of BF3·Et2O. Then, the
two phenylsulfonyl groups were reductively cleaved by acti-
vated magnesium in methanol and chiral 3-methyl thioacetal
Scheme 3. Chiral synthesis of (R)-muscone.
11 was obtained. Subsequent deprotection of the ketone was
carried out by using I2/NaHCO3 conditions and provided the
(R)-muscone target. The fragrant celery ketone (synthesized
by Livescone)[14] was also synthesized with our method
(Scheme 4). The tandem Michael/Aldol reaction adduct 9a
was protected with ethane-1,2-dithiol in the presence of
BF3·Et2O. Deprotection of thioacetal 12 was smoothly car-
ried out under nBu3SnH/AIBN conditions. The target (S)-
celery ketone was obtained through cleavage of thioacetal
13 with [bis(trifluoroacetoxy)iodo]benzene. These new total
syntheses of chiral ketones have the advantage of utilizing
commercially available starting materials, mild reaction con-
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Catalytic Asymmetric Micheal Reactions
COMMUNICATION
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and being easily scaled up.
In summary, a highly enantioselective Michael addition
reaction of a,b-unsaturated ketones with sulfonyl-containing
nucleophiles BSM and 1-(phenylsulfonyl)propan-2-one, cat-
alyzed by a chiral primary amine salt has been developed
with excellent enantioselectivities. The methodology has suc-
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Experimental Section
Catalytic asymmetric Michael addition of a,b-unsaturated ketones with
sulfonyl-containing nucleophiles: Catalyst 5 (0.10 mmol, 0.2 equiv), ben-
zoic acid (0.20 mmol, 0.4 equiv), and enone 6 (0.50 mmol, 1 equiv) were
added to a solution of 7 (0.75 mmol, 1.5 equiv) in dioxane (0.5 mL). The
reaction mixture was stirred at 358C for the time indicated, and then the
solvent was removed under vacuum. The residue was purified by silica
gel column chromatography to yield the desired addition product.
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Acknowledgements
We gratefully acknowledge the Fundamental Research Funds for the
Central Universities, the National Natural Science Foundation of China
(20902018), the Shanghai Pujiang Program (08J1403300), and the Shang-
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Keywords: asymmetric catalysis
reactions · organocatalysis · sulfur
·
ketones
·
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Received: August 20, 2010
Published online: November 30, 2010
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Chem. Eur. J. 2011, 17, 430 – 434