Catalytic enantioselective Michael addition of 1-fluoro-bis (phenylsulfonyl)methane to α,β-unsaturated ketones catalyzed by cinchona alkaloids

Article abstract of DOI:10.1002/anie.200802904

(Chemical Equation Presented) A catalyst worth its salt: The ammonium salts of cinchona alkaloids possessing sterically demanding substituents effectively catalyzed the enantioselective 1,4-conjugate addition of 1-fluorobis(phenyl- sulfonyl) methane to α,β-unsaturated ketones to furnish the Michael adducts in high yield with excellent enantioselectivity (see scheme). The adducts are useful for the synthesis of chiral monofluoromethylated molecules.

Full text of DOI:10.1002/anie.200802904

Angewandte
Chemie
DOI: 10.1002/anie.200802904
Synthetic Methods
Catalytic Enantioselective Michael Addition of 1-Fluoro-
bis(phenylsulfonyl)methane to a,b-Unsaturated Ketones Catalyzed by
Cinchona Alkaloids**
Tatsuya Furukawa, Norio Shibata,* Satoshi Mizuta, Shuichi Nakamura, Takeshi Toru, and
Motoo Shiro
There is a high demand in both academia and industry for
enantiopure fluorine-containing organic molecules because of
their unique pharmacological properties.[1] Although their
occurrence in natural systems is rare,[2] monofluorinated
analogues of biologically active compounds are often eval-
uated as bioisosteres of the parent molecules.[1,3] Compounds
with monofluoromethyl groups are also important in biolog-
ical systems.[4] The current state-of-the-art asymmetric catal-
ysis uses organocatalysts or ligand–metal complexes that
allow access to the chiral monofluorinated organic com-
pounds with high enantiocontrol.[5] However, most of the
recent innovations in this area are based on the enantiose-
lective fluorination reactions developed by us and others.[5,6]
In comparison, the enantioselective fluoromethylation reac-
tions still need to be investigated.[7] In 2006, we disclosed 1-
fluorobis(phenylsulfonyl)methane (FBSM) as a synthetic
equivalent of a monofluoromethide species under the palla-
dium-catalyzed Tsuji–Trost allylic alkylation conditions,
which provided the first asymmetric allylic monofluorome-
thylation with high enantiocontrol.[8a] Hu and co-workers, and
Prakash, Olah, and co-workers demonstrated the effective-
ness of FBSM for achieving monofluoromethylation in the
non-asymmetric epoxide ring-opening and Mitsunobu reac-
tions.[9] Recently, we reported the FBSM-based catalytic
um salts of cinchona alkaloids possessing sterically demand-
ing substituents effectively catalyzed the conjugate addition
reaction to furnish Michael adducts in high yield with
excellent enantioselectivity.
The catalytic asymmetric Michael addition reaction is one
of the most powerful tools for carbon–carbon bond-forming
reactions.[10] Either chiral quaternary ammonium salts or
chiral Lewis acids can be successfully used as catalysts for
achieving high enantiocontrol. There are many reports of the
catalytic asymmetric conjugate addition of nucleophiles to a
Michael acceptor; however, it has not been extended to
asymmetric fluoromethylations.[11,15] On the basis of our work
on asymmetric monofluoromethylations, FBSM was envi-
sioned to function as a Michael-type donor under suitable
conditions. This assumption was first tested on the reaction of
FBSM with chalcone (1a) under our best conditions for
asymmetric Mannich-type fluoromethylation,[8b] which
employed benzylquinidinium chloride (QD-3a; X = Cl) as a
catalyst (10 mol%) in the presence excess CsOH·H2O
(3.0 equiv) in CH2Cl2 at low temperature. The initial results
were quite discouraging as the reaction produced Michael
adduct 2a in a 62% yield with a low ee value (Table 1,
entry 1). The ee value was improved to 44% when the
reaction was performed in the presence of K2CO3 (Table 1,
entry 2). After screening various bases and solvents (Table 1,
entries 3–8), a catalytic amount of QD-3a (X = Cl) and
3 equivalents of Cs2CO3 in CH2Cl2 provided (S)-2a with the
highest enantioselectivity (Table 1, entry 4). Attempts to
improve the enantioselectivity of the product by using catalyst
QD-4 failed, providing 2a in a low yield with 27% ee
(Table 1, entry 9). This finding indicated that the free hydroxy
group of the cinchona alkaloid is indispensable for achieving
high enantiocontrol. Ammonium salts, CN-3a and CD-3a,
derived from cinchonine and cinchonidine, respectively, were
less effective (Table 1, entries 11 and 12). An extensive
screening of cinchona alkaloids was performed under the
same conditions (Table 1, entries 10–17), and we found that
the quinidinium chloride (QD-3 f; X = Br), bearing a steri-
cally demanding benzyl substituent, was effective at providing
2a in high yield with an excellent ee value of 97% (Table 1,
entry 17). We also discovered that by using the analogous
ammonium bromide derived from quinine (QN-3 f; X = Br), a
similar enantioselectivity was obtained for 2a, albeit with the
opposite (R) stereochemistry (Table 1, entry 18).[12] Notably,
for the reaction of 1a with FBSM at low catalyst loading
(5 mol%), the same high ee value of (S)-2a was obtained
(Table 1, entry 19).
enantioselective
Mannich-type
monofluoromethylation
which provided chiral a-fluoromethylamines with excellent
enantioselectivities.[8b] On the basis of this concept we used
FBSM as a potential monofluoromethide equivalent, and
report herein the first catalytic, asymmetric 1,4-conjugate
addition of FBSM to a,b-unsaturated ketones. The ammoni-
[*] T. Furukawa, Prof. N. Shibata, Prof. S. Mizuta, Dr. S. Nakamura,
Prof. T. Toru
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya, 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: nozshiba@nitech.ac.jp
Dr. M. Shiro
Rigaku Corporation
3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666 (Japan)
[**] Support was provided by a Grant-in-Aid for Scientific Research(B)
(19390029) for Scientific Researchon Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science, and Technology Japan
(19020024).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802904.
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Table 1: Optimization of 1,4-conjugate addition reaction.[a]
Table 2: Substrate scope for 1,4-addition reaction.[a]
Entry
1
Ar
R
2[b]
S)-2a
(S)-2b
(S)-2c
(S)-2d
Yield[c] [%] ee [%]
1
2
3
4
5
6
7
8
1a PhP(h
80
76
85
86
77
52
82
32
91
69
58
64
77
90
90
68
56
97
97
98
97
94
91
95
95
85
90
96
96
82
94
89
93
84
1b Ph4-ClC
1c Ph3-ClC
1d Ph4-BrC
1e Ph4-MeC
6H4
6H4
6H4
6H4 (S)-2e
S)-2f
1f
4-ClC6H4
Ph(
Ph(
1g 4-BrC6H4
1h 4-BocOC6H4 4-BrC6H4
1i
1j
S)-2g
(S)-2h
R)-2i
9
PhMe
PhEt
(
(
10
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
17[d]
R)-2j
1a PhP(h
R)-2a
(R)-2b
(R)-2c
(R)-2d
R)-2f
R)-2g
S)-2j
1b Ph4-ClC
1c Ph3-ClC
1d Ph4-BrC
1f
1g 4-BrC6H4
1j PhEt
6H4
6H4
6H4
Entry Cat.
Base
Solvent
Yield[b] [%] ee [%]
4-ClC6H4
Ph(
Ph(
(
1
2
3
4
5
6
7
8
QD-3a[c] CsOH·H2O
QD-3a[c] K2CO3
CH2Cl2
CH2Cl2
CH2Cl2
62
81
81
82
53
58
52
2
21
73
33
54
60
59
67
50
78
56
80
8
44
44
72
41
55
36
28
27
62[f]
57
37[f]
60
67
34
21[f]
97
96[f]
97
QD-3a[c] K2CO3
[e]
QD-3a[c] Cs2CO3
QD-3a[c] Cs2CO3
QD-3a[c] Cs2CO3
QD-3a[c] Cs2CO3
QD-3a[c] Cs2CO3
CH2Cl2
[a] Reactions were carried out using FBSM (1.0 equiv), 1 (1.1 equiv),
Cs2CO3 (3.0 equiv), and QD-3 f (X=Br; 5 mol%) in CH2Cl2 at ꢀ408C for
1–2 d. Yields were calculated based on FBSM unless otherwise noted.
[b] The absolute stereochemistry of (S)-2a was determined by X-ray
crystallographic analysis and all other products were tentatively assigned
by analogy. [c] Yield of isolated product. [d] QN-3 f (X=Br; 5 mol%) was
used as a catalyst.
toluene
CH2Cl2/toluene (7:3)
THF
tBuOMe
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
QD-4
Cs2CO3
10
11
12
13
14
15
16
17
18
QN-3a[c] Cs2CO3
CN-3a[c] Cs2CO3
CD-3a[c] Cs2CO3
QD-3b[d] Cs2CO3
QD-3c[d] Cs2CO3
QD-3d[c] Cs2CO3
QD-3e[d] Cs2CO3
QD-3f[d] Cs2CO3
QN-3f[d] Cs2CO3
other products are tentatively assigned by analogy to that of
2a. Compound QN-3 f (X = Br) was also found to be a
general catalyst, furnishing the antipode of 2 in high yield with
excellent enantioselectivity (Table 2, entries 11–17).
CH2Cl2
CH2Cl2
CH2Cl2
To understand the high enantioselectivity observed for the
conjugate addition catalyzed by the cinchona alkaloids QD-
3 f (X = Br) and QN-3 f (X = Br), both of which have a bulky
benzyl substituent on the quaternary nitrogen atom, we
postulated a transition-state structure for the production of
(R)-2a catalyzed by QN-3 f (Figure 1). The three-dimensional
molecular structure of QN-3 f was generated by the PM3
method of the MOPACprogram together with the X-ray
crystallographic data reported for the QN-3a·Cl/malonic acid
complex,[13] which indicated that QN-3 f exists in an open
conformation[14] (Figure 1a). The free hydroxy group in QN-
3 f captures substrate 1a, presumably by intermolecular
hydrogen-bond formation to the carbonyl oxygen atom in
1a (Figure 1b). This hypothesis would be consistent with
participation of the chloride in a hydrogen bond with the OH
group of QN-3 f as observed in the calculated structure in
Figure 1a. The aromatic p–p interactions between 1a and
QN-3 f additionally stabilize the transition-state structure in
which the FBSM approaches from the Re face of 1a; the
Si face is effectively blocked by the bulky parts of the benzyl
substituent in QN-3 f (Figure 1b).
19[g] QD-3f[d] Cs2CO3
[a] Reactions were carried out withFBSM (1.0 equiv), 1a (1.1 equiv),
base (3.0 equiv), and catalyst (10 mol%) in solvent at ꢀ408C for 1 d
unless otherwise noted. Yields were calculated based on FBSM. [b] Yield
of isolated product. [c] X=Cl. [d] X=Br. [e] 10 equiv of K2CO3 was used.
[f] (R)-2a was obtained. [g] 5 mol% of QD-3 f was used.
With optimal conditions in hand, the scope of the FBSM-
based Michael addition reaction was explored with a variety
of substrates to establish the generality of the process. By
using a catalytic amount of QD-3 f (X = Br; 5 mol%), all
substrates afforded products in good to excellent yield and
high to excellent enantioselectivity (Table 2). A series of
chalcone derivatives (1a–h) with a variety of substituents,
such as bromo, chloro, methyl, and O-Boc groups, on their
aromatic rings were nicely converted into products 2a–h in
good yields with ee values ranging from 91 to 98% (Table 2,
entries 1–8). Enolizable enones 1i and 1j were also compat-
ible with the same reaction conditions and afforded products
2i and 2j in good yield with ee values of 85% and 90%,
respectively (Table 2, entries 9 and 10). The absolute stereo-
chemistry of (S)-2a was determined by an X-ray crystallo-
graphic analysis (see the Supporting Information) and all the
The conjugate addition adducts (2) can be readily
converted into the respective monofluoromethylated deriva-
tives (6) by a sequence of steps without racemization
(Scheme 1): 1) NaBH4-reduction of the carbonyl group of
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Experimental Section
1a (0.385 mmol, 80.2 mg) was added to a stirred mixture of FBSM
(0.350 mmol, 110.0 mg), QD-3 f (0.0175 mmol, 16.1 mg), and Cs2CO3
(1.05 mmol, 342.1 mg) in dry CH2Cl2 (1.0 mL) at ꢀ408C. After
completion of the reaction (1–2 days, monitored by TLC), the
reaction mixture was diluted with CH2Cl2 and then washed with
water and brine. The organic layer was dried over Na2SO4 and the
solvent was then removed under reduced pressure. After purification
by chromatography on silica gel eluting with acetone in hexane (2:8),
2a was obtained as a colorless solid (145.7 mg, 80%). The ee value
was determined to be 97% by using HPLCanalysis (DAICEL
CHIRAL CEL AD-H column; iPrOH/hexane 3:7).
Figure 1. a) Three-dimensional structure of QN-3 f (X=Cl; calculated).
b) A proposed transition-state assembly for the enantioselective
Michael addition of FBSM to 1a catalyzed by QN-3 f (X=Br) to give
(R)-2a.
Received: June 18, 2008
Revised: August 4, 2008
Published online: September 22, 2008
Keywords: asymmetric catalysis · cinchona alkaloids · fluorine ·
.
Michael addition
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Scheme 1. Conversions of 1,4-addition products into monofluorome-
thylated compounds. a) NaBH4 (1.2 equiv), THF/MeOH (8:1), RT, 1 h,
98% for 4a, 98% for 4b; b) Mg (10 equiv), THF/MeOH (1:4), 08C!
RT, 1 h, 50% for 5a, 72% for 5b, 50% for 8a, 54% for 8b; c) PCC
(2.0 mol%), H5IO6 (1.05 equiv), MeCN, 97% for 6a, 70% for 6b;
d) MeMgBr (5.0 equiv), THF, ꢀ60!ꢀ408C, 83%, d.r. 13:1, for 7a;
e) p-TolMgBr (5.0 equiv), THF, ꢀ20!08C, 70%, d.r. >99:1, for 7b.
PCC=pyridinium chlorochromate.
2a and b to alcohols 4a and b, respectively, 2) reductive
desulfonylation to 5a and b using Mg/MeOH, and 3) PCC
oxidation of 5a and b. Notably, an additional stereocenter can
be constructed with high diastereoselectivity by the addition
of a methyl or tolyl Grignard reagent to 2a (d.r. 13:1 for
MeMgBr, d.r. > 99:1 for p-TolMgBr) and subsequent desul-
fonylation using Mg/MeOH to afford monofluorinated deriv-
atives 8a, b in good yields without any loss of the chiral
information at the benzylic positions. The absolute stereo-
chemistry at the newly generated quaternary carbon center of
8 was not determined.
In summary, we have used the ammonium salts of
sterically demanding cinchona alkaloids QD-3 f and QN-3 f
to promote the first asymmetric conjugate addition of FBSM
to a,b-unsaturated ketones, providing versatile and enantio-
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level of enantioselectivity, and the flexibility to generate
either enantiomer of the product have been achieved. The
conjugate addition adducts are useful for the synthesis of
chiral monofluoromethylated molecules. Additional investi-
gations of the full scope of this conjugate addition reaction
and applications to the synthesis of biologically interesting
targets are underway in our laboratory.
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