A Diels-Alder approach to the enantioselective construction of fluoromethylated stereogenic carbon centers

Article abstract of DOI:10.1039/c1cc15889a

Highly enantioselective Diels-Alder reactions of β- fluoromethylacrylates were carried out in the presence of a Lewis acid activated chiral oxazaborolidine catalyst. These reactions yielded fluoromethylated cyclohexenes, including trifluoromethyl-, difluo

Full text of DOI:10.1039/c1cc15889a

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COMMUNICATION
A Diels–Alder approach to the enantioselective construction of
fluoromethylated stereogenic carbon centersw
Kazutaka Shibatomi,* Fumito Kobayashi, Akira Narayama, Ikuhide Fujisawa and Seiji Iwasa
Received 22nd September 2011, Accepted 18th October 2011
DOI: 10.1039/c1cc15889a
Highly enantioselective Diels–Alder reactions of b-fluoromethyl-
acrylates were carried out in the presence of a Lewis acid activated
chiral oxazaborolidine catalyst. These reactions yielded fluoromethyl-
ated cyclohexenes, including trifluoromethyl-, difluoromethyl-, and
monofluoromethyl cyclohexenes, as nearly pure enantiomers. The
resulting fluoromethyl cyclohexenes were converted into potential
synthetic intermediates for bioactive compounds.
Scheme 1 Synthetic strategy for chiral fluoromethyl cyclohexenes.
oxazaborolidine 1, which was developed by Yamamoto
et al.10,11 The reaction proceeded smoothly at À78 1C to yield
Selective incorporation of fluorine-containing substituents into
organic molecules is a highly valuable process in drug discovery.1
the desired product 4a with good exo selectivity12 (Table 1,
Fluoromethyl groups (tri-, di-, and monofluoromethyl groups)
entry 1). To our delight, both diastereomers were obtained as a
have been widely used for modifying the biological properties of
nearly single enantiomer (99% ee).13 It is noteworthy that the
drug candidates because the corresponding fluoromethylated
non-fluorinated dienophile (ethyl crotonate) did not react at
molecules often have higher lipophilicity, metabolic stability,
all under the same reaction conditions (entry 3). This indicates
and bioavailability than do their parent compounds. However,
that the strong electron withdrawing effect of a trifluoromethyl
developing methods for the highly enantioselective construction
group accelerates the reaction. We then used furans as dienes.
of fluoromethylated stereogenic centers remains a challenging
task;2–5 in particular, there are only few known catalytic methods
As shown in entry 4, the reactions in the presence of 30 mol%
of 1 yielded the corresponding adducts with excellent enantio-
for introducing di- and monofluoromethyl groups in an enantio-
selective manner.4,5
selectivity. The diastereoselectivity in this reaction was virtually
the same as that in the reaction with cyclopentadiene (exo selective,
Diels–Alder reaction using fluoromethylolefins as the dienophile
entry 1 vs. 4). In contrast, the reactions of ethyl (Z)-b-trifluoro-
methylacrylate [(Z)-2] yielded the desired adducts 4c and 5b with
high endo selectivity (entries 5 and 6). Subsequently, substituted
furans were used as dienes. Interestingly, when 3-substituted furans
were used, endo adducts were preferentially formed with high
diastereoselectivity (5c and 5d in entries 7 and 8, respectively).14
On the other hand, the exo adduct was formed exclusively
when using a 2-substituted furan (5e in entry 9). Nearly
optically pure products were obtained in all cases.
is an attractive approach for the formation of fluoromethylated
stereogenic carbon centers. The resulting fluoromethylcyclohexenes
are pharmaceutically attractive building blocks since the cyclo-
hexene backbone is an important framework in drug design.
Thus, significant efforts for this reaction have been made over
the past six decades.6–8 However, there is no published report on
the enantioselective version of the Diels–Alder reaction with
fluoromethylolefins.9 In this communication, we describe a new
catalytic route to enantioenriched fluoromethyl cyclohexenes,
including tri-, di-, and monofluoromethylated cyclohexenes, via
the asymmetric Diels–Alder reaction of b-fluoromethylacrylates
(Scheme 1).
Next, we shifted our focus to the synthesis of difluoromethyl-
cyclohexenes from the dienophile ethyl (E)-b-difluoromethyl-
acrylate (6), which was synthesized according to a reported
procedure.15 The results are summarized in Table 2. The reaction
of 6 with unsubstituted cyclopentadiene or furan proceeded
smoothly to yield the corresponding product (7 or 8a, respectively)
as a nearly 1 : 1 diastereomixture with excellent enantioselectivity
(entries 1 and 2). On the other hand, high diastereoselectivity was
achieved when using substituted furans (entries 3–5), as in the case
of the reaction with (E)-2 (see Table 1, entries 7–9).
Initially, we focused on the Diels–Alder reaction of ethyl
(E)-b-trifluoromethylacrylate [(E)-2] with cyclopentadiene in
the presence of 10 mol% of Lewis acid activated chiral
Department of Environmental and Life Sciences, Toyohashi University
of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580,
Japan. E-mail: shiba@ens.tut.ac.jp; Fax: +81 532 48 5833;
Tel: +81 532 44 6810
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization of all new compounds. CCDC 822839.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc15889a
The Diels–Alder reaction of monofluoromethylacrylates
was also examined. (E)-b-Monofluoromethylacrylate (9) was
synthesized in good yield by using a modified literature
procedure15 (see ESIw for details). The Diels–Alder reaction
c
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Chem. Commun., 2012, 48, 413–415 413

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Table 2 Asymmetric Diels–Alder reaction of b-CHF2-acrylatesa
Table 1 Asymmetric Diels–Alder reaction of b-CF3-acrylatesa
Yieldb (%) eec (%)
(exo/endo) (exo, endo)
Yieldb (%) eec (%)
(exo/endo) (exo, endo)
Major product
Entry
Major product
Entry Dienophile
1
2
(E)-2
(E)-3
4a: R=Et 81 (78/22) 99, 99
4b: R=Me 78 (76/24) 99, 99
1d
2
7: X = CH2 90 (57/43) 99, 99
8a: X = O 99 (53/47) 99, 99
Ethyl
crotonate
3
0
—, —
3e
4f
8b: R = Br 68 (1/99) nd, 99
8c: R = Me 87 (1/99) nd, 99
4d
(E)-2
5a
94 (76/24) 99, 99
75 (1/99) nd, 99
5g,h
8d
74 (99/1) 99, nd
4c:
X=CH2
5b: X=O 67 (1/99) nd, 99
5
(Z)-2
(Z)-2
6d
a
All reactions were carried out for 24 h with 30 mol% of 1, unless
b
otherwise noted. Isolated yield. Determined by chiral HPLC or
c
7d,e (E)-2
8d,f (E)-2
5c: R=Br 89 (1/99) nd, 99
5d: R=Me 88 (9/91) nd, 99
d
GC analysis. Reactions were carried out for 8 h with 10 mol% of 1.
e
f
3-Bromofuran was used. 3-Methylfuran was used. 2-Methylfuran
g
h
was used. Reaction was carried out for 48 h.
9d,g (E)-2
5e
99 (99/1) 99, nd
a
All reactions were carried out for 8 h with 10 mol% of 1, unless
b
otherwise noted. Isolated yield. Determined by chiral GC analysis.
d
c
e
Reactions were carried out for 24 h with 30 mol% of 1. 3-Bromo-
furan was used. The absolute configuration of 5c was determined by
f
X-ray crystallographic analysis (see Scheme 5). 3-Methylfuran was
g
used. 2-Methylfuran was used.
Scheme 2 Asymmetric Diels–Alder reaction of b-CH2F-acrylates.
of 9 with cyclopentadiene in the presence of 50 mol% of 1
afforded the desired adduct 10 in high yield, with good endo
selectivity and excellent enantioselectivity, although the reac-
tion was sluggish (Scheme 2).
We then attempt to convert the fluoromethylated cyclo-
adducts into potential synthetic intermediates for bioactive
compounds. First, the optically pure trifluoromethyl cyclo-
adduct 5b was converted into 6-trifluoromethyl-shikimate 13
via the reported procedure (Scheme 3).16 Treatment of 5b with
lithium hexamethyldisilazide (LiHMDS) resulted in b-elimination
of the bridgehead oxygen to yield cyclohexadienol 11. After the
protection of the hydroxy group of 11 with t-butyldimethylsilyl
trifluoromethanesulfonate (TBDMSOTf), the resulting silyl ether
was osmylated with osmium tetroxide and subsequently reduced
with sodium bisulfate to afford the diol 12. Deprotection with
tetrabutylammonium fluoride (TBAF) yielded 13, and thus, the
first asymmetric synthesis of 6-CF3-shikimate was accomplished.
Next, the difluoromethylated cycloadduct endo-7 was con-
verted to a bicyclic enone 17 via the procedure developed by
Scheme 3 Synthesis of 6-trifluoromethylshikimate 13. Reaction
conditions: (a) LiHMDS, THF, À78 1C to rt, 2 h; (b) TBDMSOTf,
2,6-lutidine, CH2Cl2, rt, 1 h; (c) OsO4, pyridine, rt, 8 h, then Na2S2O5,
pyridine, rt, 20 min; (d) TBAF, THF, rt, 6 h.
Grubbs catalyst yielded the desired bicyclic diene 17 with a
difluoromethyl function (Scheme 4).
Aube 17
´
.
He reported the synthesis of a similar non-fluorinated
Finally, to establish the stereochemistry of these Diels–Alder
adducts, we synthesized 4-phenylbenzoate 18 from 5c by a simple
two-step transformation (Scheme 5). Single-crystal X-ray crystal-
lographic analysis of 18 revealed the absolute and relative
stereochemistry and regiochemistry, as shown in the ORTEP
drawing.19
enone and its conversion to dendrobatid alkaloid 251F.18
Weinreb amide 15 was synthesized in good yield by the hydrolysis
of endo-7 and subsequent condensation with N,O-dimethyl-
hydroxylamine. Treatment of 15 with a vinyl Grignard reagent
and subsequent olefin metathesis with the first-generation
c
414 Chem. Commun., 2012, 48, 413–415
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(a) C. Ni, F. Wang and J. Hu, Beilstein J. Org. Chem., 2008,
4(21), DOI: 10.3762/bjoc.4.21; (b) C. Ni and J. Hu, Synlett, 2011,
770; (c) J. Hu, W. Zhang and F. Wang, Chem. Commun., 2009,
7465; (d) G. K. S. Prakash and J. Hu, Acc. Chem. Res., 2007,
40, 921; (e) See also ref. 3c.
5 For the enantioselective monofluoromethylation using a-fluoro-
(phenylsulfonyl)methane (FSM) derivatives as a synthetic equiva-
lent of a monofluoromethide, see: (a) T. Fukuzumi, N. Shibata,
M. Sugiura, H. Yasui, S. Nakamura and T. Toru, Angew. Chem.,
Int. Ed., 2006, 45, 4973; (b) S. Mizuta, N. Shibata, Y. Goto,
T. Furukawa, S. Nakamura and T. Toru, J. Am. Chem. Soc.,
2007, 129, 6394; (c) T. Furukawa, N. Shibata, S. Mizuta,
S. Nakamura, T. Toru and M. Shiro, Angew. Chem., Int. Ed.,
2008, 47, 8051; (d) W.-B. Liu, S.-C. Zheng, H. He, X.-M. Zhao,
L.-X. Dai and S.-L. You, Chem. Commun., 2009, 6604; (e) S. Zhang,
Y. Zhang, Y. Ji, H. Li and W. Wang, Chem. Commun., 2009, 4886;
Scheme 4 Derivatization of endo-7 to bicyclic enone 17. Reaction
conditions: (a) 10% aq. NaOH, reflux, h; (b) BOP, Et3N,
2
HNMe(OMe)ÁHCl, CH2Cl2, rt, 24 h; (c) CH2QCHMgBr, Et2O,
(f) A.-N. Alba, X. Companyo
2009, 15, 7035; (g) F. Ullah, G.-L. Zhao, L. Deiana, M. Zhu,
P. Dziedzic, I. Ibrahem, P. Hammar, J. Sun and A. Cordova,
´
, A. Moyano and R. Rios, Chem.–Eur. J.,
rt, 1.5 h; (d) Grubbs cat. (5 mol%), ethylene, CH2Cl2, rt, 20 h.
´
Chem.–Eur. J., 2009, 15, 10013; (h) H. W. Moon, M. J. Cho and
D. Y. Kim, Tetrahedron Lett., 2009, 50, 4896; (i) For pioneering
studies on the nucleophilic fluoromethylation with FSM deriva-
tives, see ref. 4b–d.
6 For early studies on the Diels–Alder reaction of fluoromethyl-
olefins, see: (a) E. T. McBee, C. G. Hsu, O. R. Pierce and
C. W. Roberts, J. Am. Chem. Soc., 1955, 77, 915; (b) E. T.
McBee, C. G. Hsu and C. W. Roberts, J. Am. Chem. Soc., 1956,
78, 3389; (c) E. T. McBee, C. W. Roberts and C. G. Hsu, J. Am.
Chem. Soc., 1956, 78, 3393.
7 For recent reports and reviews, see: (a) Y.-H. Lam, S. J. Stanway
and V. Gouverneur, Tetrahedron, 2009, 65, 9905; (b) T. Hanamoto,
R. Anno, K. Yamada, K. Ryu, R. Maeda, K. Aoi and H. Furuno,
Tetrahedron, 2009, 65, 2757; (c) V. G. Nenajdenko, V. M. Muzalevskiy,
A. V. Shastin, E. S. Balenkova and G. Haufe, J. Fluorine Chem., 2007,
128, 818; (d) T. Billard, Chem.–Eur. J., 2006, 12, 974; (e) J. Leuger,
Scheme 5 X-Ray crystallographic analysis.
In conclusion, we have accomplished the highly enantio-
selective Diels–Alder reaction of b-fluoromethylacrylates with
cyclic dienes in the presence of a Lewis acid activated chiral
oxazaborolidine catalyst. The reaction successfully afforded
fluoromethylated cyclohexenes, including tri-, di-, and mono-
fluoromethylcyclohexenes. The most striking feature of this
reaction is that the cycloadducts are obtained as nearly pure
enantiomers.
G. Blond, R. Frohlich, T. Billard, G. Haufe and B. R. Langlois, J. Org.
¨
Chem., 2006, 71, 2735, and earlier references cited therein.
8 The results of our preliminary study on the Diels–Alder reaction of
2 with achiral Lewis acid are shown in ESIw.
9 For an example of the diastereoselective reaction, see: B. Linclau,
P. J. Clarke and M. E. Light, Tetrahedron Lett., 2009, 50, 7144.
10 (a) K. Futatsugi and H. Yamamoto, Angew. Chem., Int. Ed., 2005,
44, 1484; (b) K. Shibatomi, K. Futatsugi, F. Kobayashi, S. Iwasa
and H. Yamamoto, J. Am. Chem. Soc., 2010, 132, 5625.
11 For other reports on the asymmetric Diels–Alder reaction with
Lewis acid activated chiral oxazaborolidine, see: (a) S. Mukherjee
and E. J. Corey, Org. Lett., 2010, 12, 632; (b) D. Liu, E. Canales
and E. J. Corey, J. Am. Chem. Soc., 2007, 129, 1498.
We thank Prof. H. Yamamoto (The University of Chicago)
for helpful discussions. This study was supported by the Asahi
Glass Foundation and KAKENHI (23750111) from MEXT.
The partial support from Takeda Science Foundation is also
acknowledged. We also thank the Instrument Center of the
Institute for Molecular Science for permission and advice on
the usage of their X-ray diffractometer equipment.
12 Endo/exo nomenclature is related to the stereochemistry of the
carbonyl substituent.
13 We confirmed that the optical purity of 4a and 5a does not change
even after chromatographic purification using achiral silica gel or
solvent evaporation (samples with an ee of 90% were used for
checking). For the self-disproportionation effect of the enantiomers of
perfluorinated compounds, see: (a) V. A. Soloshonok, Angew. Chem.,
Int. Ed., 2006, 45, 766; (b) V. A. Soloshonok, H. Ueki, M. Yasumoto,
S. Mekala, J. S. Hirschi and D. A. Singleton, J. Am. Chem. Soc., 2007,
129, 12112; (c) H. Ueki, M. Yasumoto and V. A. Soloshonok, Tetra-
hedron: Asymmetry, 2010, 21, 1396.
14 The origin of the diastereoselection is discussed in ESIw.
15 (a) K. Tamura, T. Yamazaki, T. Kitazume and T. Kubota, J. Fluorine
Chem., 2005, 126, 918; (b) M. Jagodzinska, F. Huguenot and
M. Zanda, Tetrahedron, 2007, 63, 2042.
Notes and references
1 (a) Fluorine in medicinal chemistry and chemical biology,
ed. I. Ojima, Wiley & Sons, New York, 2009; (b) J.-P. Begue and
´ ´
D. Bonnet-Delphon, Bioorganic and Medicinal Chemistry of Fluorine,
Wiley & Sons, Hoboken, 2008.
2 For reviews on the asymmetric construction of trifluoromethylated
stereogenic centers from prochiral trifluoromethylated substrates,
see: (a) J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev.,
2011, 111, 455; (b) K. Mikami, Y. Itoh and M. Yamanaka, Chem.
Rev., 2004, 104, 1.
16 For non-asymmetric synthesis of t-butyl 6-trifluoromethylshikimate,
see: J. Leroy, N. Fischer and C. Wakselman, J. Chem. Soc., Perkin
Trans. 1, 1990, 1281.
3 For reviews on enantioselective trifluoromethylation, see: (a) G. Valero,
X. Companyo and R. Rios, Chem.–Eur. J., 2011, 17, 2018; (b) J.-A. Ma
´
´
17 A. Wrobleski, K. Sahasrabudhe and J. Aube, J. Am. Chem. Soc.,
2002, 124, 9974.
and D. Cahard, Chem. Rev., 2008, 108, PR1; (c) N. Shibata,
S. Mizuta and H. Kawai, Tetrahedron: Asymmetry, 2008, 19, 2633;
(d) T. Billard and B. R. Langlois, Eur. J. Org. Chem., 2007, 891.
4 For an example of the enantioselective difluoromethylation
and related reviews on the diastereoselective reaction, see:
18 T. F. Spande, H. M. Garraffo, H. J. C. Yeh, Q.-L. Pu, L. K.
Pannell and J. W. Daly, J. Nat. Prod., 1992, 55, 707.
19 One of the two molecules in the asymmetric unit is shown for
clarity.
c
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Chem. Commun., 2012, 48, 413–415 415