Asymmetric synthesis of chiral trifluoromethylated heliotridane via highly catalytic asymmetric Friedel-Crafts alkylation with β-trifluoromethylated acrylates and pyrroles

Article abstract of DOI:10.1039/c1nj20550a

Chiral Ph-dbfox (Ph-dbfox = (R,R)-4,6-dibenzofurandiyl-2,2′-bis(4- phenyloxazoline))/Zn(NTf₂)₂ catalyzed enantioselective Friedel-Crafts reactions of β-CF₃ acrylates with pyrroles and indoles have been investigated, which

Full text of DOI:10.1039/c1nj20550a

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PAPER
Asymmetric synthesis of chiral trifluoromethylated heliotridane via highly
catalytic asymmetric Friedel–Crafts alkylation with b-trifluoromethylated
acrylates and pyrroleswz
Yiyong Huang,ab Satoru Suzuki,a Guokai Liu,a Etsuko Tokunaga,a Motoo Shiroc
and Norio Shibata*a
Received (in Montpellier, France) 22nd June 2011, Accepted 15th August 2011
DOI: 10.1039/c1nj20550a
Chiral Ph-dbfox (Ph-dbfox = (R,R)-4,6-dibenzofurandiyl-2,20-bis(4-phenyloxazoline))/Zn(NTf2)2
catalyzed enantioselective Friedel–Crafts reactions of b-CF3 acrylates with pyrroles and indoles
have been investigated, which afforded the corresponding chiral trifluoromethyl pyrrole and
indole derivatives in high yields (90–99%) with a range of 66–99% ee values. With the aid of the
chiral adduct of the asymmetric Friedel–Crafts reaction, the chiral trifluoromethylated
heliotridane has been successfully constructed in good total yield.
Introduction
It is well known that fluorinated organic compounds have
some pharmaceutical superiority over their non-fluorinated
analogues.1 They have similar compatibility to the enzyme
receptor because of similarity in size and shape. On the other
hand, the C–F bond (485 kJ molꢀ1) is much stronger than the
C–H bond (416 kJ molꢀ1). So the fluorinated compounds
show higher metabolic stability. In addition, the incorporation
Fig. 1 9,10-Dehydro-dEpoB and its trifluoromethyl analogue.
of fluorine(s) into pharmaceuticals can increase lipophilicity
(especially with the trifluoromethyl group), membrane
permeability, and the binding capability to the target mole-
molecules of known bioactive compounds to improve their
cules. The importance can be reflected in that around 20% of
properties. Importantly, it is now a common practice in drug
new drugs contain fluorine(s) and more than 30% of crop
discovery to study fluoro-analogues of parent compounds
protection agents are organofluorine compounds.2 Further-
under development.4 For example, a remarkable CF3 group
more, according to a most up-to-date survey, 138 fluorine-
effect was observed when Danishefsky’s group sought for drug
containing drugs have received FDA approval for human
candidates. In Fig. 1, it was found that when the C12-methyl
diseases and 33 are currently in use for veterinary
group of compound 9,10-dehydro-dEpoB was replaced with a
applications.3 Therefore, recent investigations focus on the
trifluoromethyl functionality, termed fludelone, a dramatic
introduction of fluorine atoms and perfluoroalkyl groups into
improvement in terms of therapeutic index ensued. In addition,
fludelone is markedly less toxic than the parent compound.5
Among various types of organo-fluorine molecules,6 chiral
a Department of Frontier Materials, Graduate School of Engineering,
substances in which a trifluoromethyl (CF3) group and hetero-
atom are attached to an asymmetric carbon center have been
popularly studied and many strategies have been available to
construct them due to some unique biological and pharma-
ceutical activities in recent years.7 However, the work to
construct chiral trifluoromethylated compounds with a CF3
group at an all-C tertiary or quaternary chiral carbon center
without any heteroatom substituent remains challenging.8 In
Fig. 2, several of this type of important compounds of
biological interest are listed. Consequently, the development
of efficient and convenient synthetic methods for such
molecules has been highly required. In our previous studies,
Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan. E-mail: nozshiba@nitech.ac.jp;
Fax: +81 52-735-5442; Tel: +81 52-735-7543
b College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, China
c Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima,
Tokyo 196-8666, Japan
w We briefly communicated this work in 2010.23 In the present paper,
we describe in full the results of our highly catalytic asymmetric
Friedel–Crafts alkylation.
z Electronic supplementary information (ESI) available: General
experimental procedures, 1H, 13C and 19F NMR spectra for all crossed
products, characterisation data for all new products. CCDC 758056.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1nj20550a
c
2614 New J. Chem., 2011, 35, 2614–2621
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have been widely explored in the last few decades.13 In
particular, this methodology is a topic of great interest in
the application of selectively constructing enantioenriched
compounds bearing a CF3 group at stereogenic centers by
using prochiral trifluoromethylated substrates as building
blocks, which is an indirect asymmetric trifluoromethylation
strategy. Since Jørgensen’s group documented the novel
catalytic enantioselective Friedel–Crafts reactions of 3,3,3-
trifluoropyruvate with pyrroles, furans and thiophenes to
obtain various chiral hydroxy-trifluoromethyl ethyl esters in
2000,14 many groups in the world have devoted to the
asymmetric Friedel–Crafts reaction studies to construct
various chiral trifluoromethylated compounds.
Fig. 2 Chiral trifluoromethylated compounds of biological interest.
Fig. 3 Pyrrolizidine alkaloids.
Recently, employing chiral BINOL-derived phosphoric
acids as chiral Brønsted acid catalysts in the asymmetric
Friedel–Crafts reaction to obtain various enantioenriched
trifluoromethylated tertiary alcohols was reported by two
groups. Ma’s group15 utilized ethyl 4,4,4-trifluoroacetoacetate,
ethyl trifluoropyruvate and 2,2,2-trifluoroacetophenone as
electrophiles, but Akiyama’s group16 used methyl 3,3,3-tri-
fluoropyruvate. They both have obtained good results for the
asymmetric Friedel–Crafts reaction of indoles. However, when
they attempted to apply the optimized conditions to the
reaction with N–H pyrroles, a low level of enantioselectivity
was observed. Very recently, Bolm’s group developed a highly
chiral phosphoric acid catalyzed enantioselective Friedel–
Crafts reaction of N-Boc-protected ethyl trifluoropyruvate
imine with indoles to afford a wide variety of quaternary
indole-derived a-amino acids.17 In the meantime, organo-
metallic-catalyzed asymmetric Friedel–Crafts reactions based
on chiral trifluoromethylated products were also presented.
Pedro’s group developed the enantioselective Friedel–Crafts
reaction of b-trifluoromethyl-a,b-unsaturated ketones with
indoles by using chiral BINOL-type Zr(IV) complexes. Unfor-
tunately, the reaction didn’t work well with pyrrole
(55% ee).8k Feng’s group described the chiral N,N0-
dioxide–zinc(II) complexes catalyzed asymmetric Friedel–
Crafts alkylation between ethyl trifluoropyruvate and
indoles.18 In 2011, Lu’s group described an highly enantio-
selective alkylation of trifluoroethylidene malonates with
indoles catalyzed by copper(II)-bis (oxazoline) complexes, but
only 16% ee was obtained when reacting with N–H pyrrole.
Furthermore, they applied the chiral indole derivatives to the
transformation of some optically pure trifluoromethyl-
substituted alkylated indole derivatives with potentially inter-
esting bioactivities.8l Additionally, the chiral copper(I)19 and
Yb(III)20 catalysts were for the first time employed in the
asymmetric Friedel–Crafts reaction for the preparation of chiral
trifluoromethylated compounds by another two groups.
we reported enantioselective electrophilic trifluoromethylation
of b-keto esters with Umemoto’s reagent in the presence of a
stoichiometric amount of chiral non-racemic guanidines to
access trifluoromethylated products with a quaternary carbon
center.9 Continuing this work, we present herein a new strategy
to generate chiral compounds bearing a CF3 group at a
quaternary chiral carbon center without any heteroatom. Most
importantly, we can apply the chiral adduct to the synthesis of
chiral trifluoromethylated heterocyclic compounds.
Nitrogen-containing heterocycles are omnipresent in natural
products and biologically active compounds. Among them, the
pyrrolizidine alkaloids of heliotridane and pseudoheliotridane
represent a diverse group of natural products.10 Considerable
effort has been directed toward the synthesis of these com-
pounds because of their interesting pharmacological properties
(cytotoxic, antimitotic immunostimulatory, and anticancer).11
Fluorine-containing heterocyclic compounds play an important
role in drug and pesticide design. Though much attention
was drawn in the synthesis of fluorinated heterocycles,12 no
information on the synthesis of fluorinated heliotridane and
pseudoheliotridane is available in the literature. We assumed
that trifluoromethylated heliotridane or pseudoheliotridane
(Fig. 3) by alternating the CH3 group with a CF3 group would
have potentially interesting pharmacological properties.
In this context, a novel retrosynthetic proposal to access
chiral trifluoromethylated heliotridane and/or pseudohelio-
tridane is illustrated in Scheme 1. Our approach is based on
the catalytic asymmetric Friedel–Crafts reaction of N–H pyrrole
with the b-CF3 acrylate. Thus, the asymmetric Friedel–Crafts
reaction between pyrroles and b-CF3 acrylates needed to be fully
explored in the arena of total syntheses of the optically active
trifluoromethylated heliotridane or pseudoheliotridane.
The organo- and organometal-catalytic asymmetric Friedel–
Crafts reactions as a versatile C–C bond formation approach
Obviously, in the previous literature, most of the electro-
philes were focused on the trifluoroacetyl compounds7a or
their imine derivatives,21 whereas the use of trifluoromethy-
lated a,b-unsaturated carbonyl compounds as electrophiles is
less studied. In addition, while the indole nucleophiles have
been intensively investigated in the enantioselective Friedel–
Crafts reaction, the utility of pyrrole nucleophiles in this
context remains relatively unexplored and less successful.22
Bidentate Michael acceptors of compound 1 are b-trifluoro-
methylated acrylates bearing an achiral auxiliary as an alternative
Scheme 1 Retrosynthetic analysis of chiral trifluoromethylated helio-
tridane and pseudoheliotridane.
c
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acceptor moiety capable of chelating to a chiral metal complex
and can be transformed into the trifluoromethylated
carboxylic acid.23 We anticipated that compound 1 would be
excellent nucleophile acceptor candidates in the asymmetric
Friedel–Crafts reaction. Herein, we reported our full studies
on the chiral Lewis acid catalyzed enantioselective Friedel–
Crafts reaction of pyrroles and indoles with b-trifluoro-
methylated acrylates 1.w
or Zn(NTf2)2 (Table 1, entry 6). However, Zn(NTf2)2 shows
higher rate enhancement compared with Zn(ClO4)2ꢁ6H2O. So
Zn(NTf2)2 was used as the metal salt for further studies. The
use of bisoxazoline ligand L2 or L3 in combination with
Zn(NTf2)2 led to no further improvement of enantioselectivity
(Table 1, entries 7 and 8). The subsequent solvent screening
revealed that CH2Cl2 is the best choice of solvent. In order to
improve the ee value, the Friedel–Crafts reaction was carried
out at low temperatures. To our delight, lower temperature
afforded a higher ee value. The improvement of 89% ee was
observed at ꢀ40 1C, albeit a longer reaction time was needed
(Table 1, entry 12). Further improvement of the enantio-
selectivity excess to 96% was obtained at ꢀ60 1C (Table 1,
entry 13). The best ee up to 98% could be restored at ꢀ75 1C
at the expense of higher catalyst loading and concentration
(Table 1, entry 14).
Results and discussion
A chiral bisoxazoline ligand of Ph-dbfox (Ph-dbfox =
(R,R)-4,6-dibenzofurandiyl-2,20-bis(4-phenyloxazoline)) has
proven to be an excellent ligand in many asymmetric reactions
by our group.24 Thus, Ph-dbfox was chosen as the chiral
ligand in the preliminary studies.
According to the optimized conditions of entry 13 in
Table 1, we investigated the substrates scope of a wide variety
of pyrroles 2 (Table 2). The asymmetric Friedel–Crafts
reaction of N–H pyrrole 2b with 1a provided (S)-3b in 96%
yield and 98% ee (Table 2, entry 2). The ee value could be
further improved to 99% at ꢀ75 1C. To the best of our
knowledge, this has been so far the best ee value obtained
for the Friedel–Crafts reaction with N–H pyrrole.25 Various
protecting groups on the pyrrole nitrogen were well tolerated.
A decrease in enantiomeric excess was observed as the length
of the N-alkyl substituent of the pyrrole was increased
(Table 2, entries 3–5). It is probably due to an increase in
steric effects of the protecting group. Pyrrole 2e proceeded
with similar ee to pyrrole 2f for the same steric hindrance
(Table 2, entry 6). Additionally, the presence of electron-
withdrawing and high steric hindrance groups on the pyrrole
nitrogen resulted in a decrease in enantioselectivity and
Our investigation began by examining the Lewis acid
screening. The model reaction was performed in CH2Cl2 at
room temperature employing substrates 1a and N-methyl
pyrrole 2a. Surprisingly, no reaction occurred with either
Cu(OTf)2 or Cu(NTf2)2 as Lewis acids (Table 1, entries 1
and 2). Then we turned our attention to the zinc salts. The
reaction did not proceed in the presence of Zn(OAc)2
(Table 1, entry 3). Low yield and ee were observed when
Zn(OTf)2 was used (Table 1, entry 4). The ee could be
improved to 75% by using Zn(ClO4)2ꢁ6H2O (Table 1, entries 5)
Table 1 Optimization of the asymmetric Friedel–Crafts reaction
between b-CF3 acrylate 1a and N-methyl pyrrole 2aa
Table 2 Substrates scope of pyrrole nucleophilesa
Entry Lewis acid Ligand Solvent T/1C t/h Yield (%)b ee (%)c
Entry
R1
R2
2
3
t/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Cu(OTf)2 L1
Cu(NTf2)2 L1
Zn(OAc)2 L1
Zn(OTf)2 L1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene 20
Et2O
CHCl3
CH2Cl2 ꢀ40 12 98
CH2Cl2 ꢀ60 24 96
CH2Cl2 ꢀ75 24 96
20 24 Trace
20 24 Trace
20 24 Trace
20 24 40
ND
ND
ND
38
75
75
69
55
60
72
1
2
3
4
5
6
Me
H
Et
n-Pr
n-Bu
Allyl
Bn
Ph
H
H
H
H
H
H
H
H
H
Me
Et
Me
Et
Bn
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
24
24
24
24
36
48
48
48
24
24
24
24
48
96 (96)
96 (97)
97 (96)
95 (96)
95 (95)
94 (90)
93
96 (98)
98 (99)
94 (96)
93 (95)
94 (95)
98 (99)
85
e
Zn(ClO4)2 L1
20
20
20
20
4
2
2
2
6
6
2
86
96
92
90
93
91
90
Zn(NTf2)2 L1
Zn(NTf2)2 L2
Zn(NTf2)2 L3
Zn(NTf2)2 L1
Zn(NTf2)2 L1
Zn(NTf2)2 L1
Zn(NTf2)2 L1
Zn(NTf2)2 L1
Zn(NTf2)2 L1
7
9
8d
9
94
87
10
11
12
13
14d
20
20
96 (96)
96 (98)
97 (97)
99 (99)
95 (95)
88 (97)
84 (92)
87 (94)
70 (88)
66 (76)
70
89
96
98
10
11
12
13
H
2j
2k
2l
3j
3k
3l
Me
Me
Me
2m
3m
a
a
Unless noted, all reactions are performed at 0.10 M in substrate
1a and 0.50 M in substrate 2a, with 10 mol% catalyst loading in
Unless noted, all reactions are performed at 0.10 M in substrate 1a
and 0.50 M in substrate 2, with 10 mol% catalyst loading in 0.5 mL of
b
0.5 mL of solvent. Isolated yield after column chromatography.
b
solvent. Isolated yields. Data in brackets are obtained at ꢀ75 1C
c
d
Determined by chiral HPLC; ND = not determined. Reaction
c
with 20 mol% catalyst loading at 0.2 M. Determined by chiral
was performed at 0.20 M in substrate 1a, with 0.25 mL of solvent and
e
20 mol% catalyst was used. Hexahydrate was used.
HPLC. Data in brackets are obtained at ꢀ75 1C with 20 mol%
d
catalyst loading at 0.2 M. Reaction was performed at ꢀ20 1C.
c
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Table 3 Survey of nucleophile acceptorsa
Entry
Acceptor
3
t/h
Yield (%)b
ee (%)c
1
2
3
1b
1c
1d
3p
3q
3r
24
48
48
95
NR
97
79
ND
95
a
All reactions are performed at 0.10 M in substrates 1b–d and 0.50 M
b
in substrate 2b. Isolated yields. Determined by chiral HPLC.
c
Scheme 2 Asymmetric F–C reaction between b-CF3 acrylate 1a and
indoles.
(Table 3, entry 1). No reaction occurred even at RT by
changing the methyl groups of 1b to phenyl groups (Table 3,
entry 2). Compared to nucleophile acceptor 1a, 1d bearing
achiral auxiliary of thiazolidinone was also examined to
display 97% yield and 95% ee after 48 h (Table 3, entry 3).
These inferior results well proved that nucleophile acceptor 1a
was the best candidate in our studies.
reactivity (Table 2, entries 7 and 8). In the case of pyrrole 2h, a
higher temperature up to ꢀ20 1C was needed to complete the
reaction. The introduction of Me and Et groups at the
2-position of 2b resulted in lower ee of 88% and 84%
respectively (Table 2, entries 9 and 10). A similar sense of
asymmetric induction was disclosed by using N-methylpyrrole
2a and its 2-position derivatives. Increasing the steric require-
ments of the substituents at the 2-position of N-methylpyrrole
from H (96% ee, Table 2, entry 1) to Me (87% ee, Table 2,
entry 11), Et (70% ee, Table 2, entry 12), and Bn (66% ee,
Table 2, entry 13) resulted in gradual reduction of ee. Further-
more, as the results shown in brackets in Table 2, all ee values
could be improved by using the reaction conditions of entry 14
in Table 1, with a lower temperature to ꢀ75 1C albeit higher
catalyst loading (20%) and concentration (0.2 M). Especially
for the asymmetric Friedel–Crafts reactions of 2-substituted
pyrroles, the improvement of enantioselectivity was much
more obvious.
The plausible mechanism is illustrated in Fig. 4: initially,
1,4-addition of
a pyrrole nucleophile to a b-trifluoro-
methylated a,b-unsaturated carbonyl compound A, followed
by enantioselective protonation of the resulting transient
enolate B to generate product 3b and the chiral catalyst. The
absolute configuration of 3b was determined to be S by the
comparison of its optical rotation after derivatization to (S)-4
(Scheme 4). The sample of (R)-4 was synthesized in a different
way and its absolute stereochemistry was determined by X-ray
crystallographic analysis of 3s (CCDC 758056, Scheme 3). To
account for the stereochemistry of the asymmetric Friedel–
Crafts reaction, a plausible transition-state model is depicted
in Fig. 4. The acrylate coordinates in a bidentate fashion to the
catalyst metal center which adopts a six-member-planar
geometry and the nucleophilic pyrrole approaching the less
shielded Re face of the olefin b-carbon leads to the formation
of the major stereoisomer.
Subsequently, the optimized conditions of entry 14 in
Table 1 were utilized in the asymmetric Friedel–Crafts
reaction of 1a with indole and 4,7-dihydroindole. Whereas
the locus of nucleophilicity of pyrroles is at C-2, it resides at
C-3 for the indoles. Initial examination of the indole 2n was
encouraging. 3-Substituted indole 3n was furnished with
excellent levels of selectivity (99% ee) and in nearly quantita-
tive yield (Scheme 2, eqn (1)). Although C-2 substituted
indoles were impossible to be directly generated in this
Friedel–Crafts reaction, we solved this problem by using the
reported strategy: 4,7-dihydroindole 2o could be employed as
a 2,3-disubstituted pyrrole nucleophile, and easily transformed
into the corresponding indole product by aromatization with
p-benzoquinone (p-BQ) oxidation.26 Taking advantage of this
property, 2-substituted indole 3o was successfully accessed in
90% yield with 75% ee through two steps (Scheme 2, eqn (2)).
A subsequent survey of nucleophile acceptors revealed that
different substituents on the 4-position of the achiral template
play a key role in the reactivity and selectivity. When
the acceptor 1b with two methyl groups is introduced, the
reaction with N–H pyrrole completed in 79% ee after 24 h
To demonstrate the synthetic utility of this Friedel–Crafts
reaction methodology, we carried out the synthesis of
Fig. 4 Assumed catalytic cycle and working model for the stereo-
induction.
c
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trifluoromethylated heliotridane syn-8 was obtained in 54%
yield by using LiAlH4 reduction of syn-7 in ether, which was
finally fixed as picrate 9 by mixing with picric acid in ether.
The stereochemistry of the major isomer syn-7 was identified
by 19F NMR and 2D 1H NMR (1H-1H COSY) spectra (Fig. 5,
see also ESIz). In the case of 19F NMR spectra, the chemical
shift value of ꢀ71.1 ppm in a lower magnetic field for
compound syn-7 due to the steric deshielding effect indicates
a trans arrangement of C5-H and the CF3 group.27 However,
another diastereomer with –67.9 ppm belongs to the anti
isomer. It should be mentioned that these two diastereomers
of compound 7 could be separated by column chromatography.
The stereochemistry of compound syn-7 was further supported
by 2D 1H NMR (1H-1H COSY) spectra. For compound syn-7,
a strong cross peak was observed between the bridgehead
proton and the adjacent proton attached to the quaternary
carbon in the five-membered cyclic hexahydropyrrolizinone due
to the cis-substitution, while compound anti-7 showed a much
weaker cross peak between the corresponding protons.
Scheme 3 Total synthesis of trifluoromethylated heliotridane picrate 9.
Conclusions
In summary, we have developed a novel strategy to obtain
various chiral pyrroles, 2-substituted and 3-substituted indole
derivatives bearing a CF3 group at a quaternary chiral carbon
center without any heteroatom. This chiral Zn(NTf2)2-catalyzed
enantioselective Friedel–Crafts reaction not only showed high
reactivity and enantioselectivity for the commonly studied
indole and N-protected nucleophiles, but also for the challen-
ging N–H pyrrole substrates (up to 99% ee). To the best of our
knowledge, this is the best result for the asymmetric Friedel–
Crafts reaction with N–H pyrrole. The plausible reaction
mechanism and stereochemistry were illustrated. Significantly,
this methodology enabled the rapid total synthesis of
unreported chiral trifluoromethylated heliotridane. The struc-
tures of these compounds were intensively determined by using
NMR studies. The pharmacological properties of 8 and other
catalytic asymmetric reactions with b-trifluoromethylated
acrylates are currently being studied.
Scheme 4 Synthesis of (R)-4 from (S)-1e via (S, R)-3s (see ESIz for
details) and X-ray crystallographic analysis of (S, R)-3s (CCDC
758056).
unreported trifluoromethylated heliotridane by using the
Friedel–Crafts reaction adduct (S)-3b as an important chiral
building block (Scheme 4). The scale-up synthesis of com-
pound (S)-3b (1.0 g, 3.6 mmol) in the presence of 1 mol% of
the chiral Ph-dbfox/Zn(NTf2)2 catalyst at ꢀ60 1C was
achieved with the ee value up to 98%. With (S)-3b in hand,
the first transformation into the corresponding carboxylic acid
(S)-4 proceeded well in 80% yield. Rhodium-catalyzed hydro-
genation of (S)-4 afforded the diastereomeric mixture of
2-pyrrolidine carboxylic acid 5 (dr = 10 : 1) in quantitative
yield in the presence of H2 (10 atm) at room temperature.
Without further purification, 5 was successfully cyclized to the
trifluoromethylated hexahydropyrrolizin-3-one syn-7 (30%)
and anti-7 (5%) in the presence of tris(1,3-dihydro-2-
Experimental section
General
oxobenzoxazolin-3-yl) phosphine oxide
6 when heated
All reactions were performed in oven-dried glassware under a
nitrogen atmosphere, except where noted. Chemicals and
solvents were purchased from commercial suppliers and used
as received, except as follows. Dichloromethane, THF, ether,
and toluene were dried by passing through an activated
column. All reactions were monitored by TLC, or 19F
NMR. TLC analysis was performed by illumination with a
UV lamp (254 nm), staining with I2, or PMA [phospho-
molybdic acid (5 g) in ethanol (100 ml)] and heating. The
column of flash chromatography was packed with silica-gel
(60N spherical neutral size 63–210 mm) as the stationary phase.
1H NMR (600 MHz) spectra were recorded on a Bruker
Avance 600 instrument in CDCl3 (7.26), or CD2Cl2 (5.24),
and chemical shifts were measured relative to a residual
solvent peak. Chemical shifts (d) are expressed in ppm
under reflux in acetonitrile. The initial trial of DCC instead
of 6 as a cyclization reagent proved ineffective. A volatile
Fig. 5 NMR studies of compound 7.
c
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downfield from internal TMS. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublet, dt = doublet of
triplet, dq = doublet of quartet, m = multiplet, br = broad),
coupling constant(s) and integration. 13C NMR (150.9 MHz)
spectra were recorded on a Bruker Avance 600 instrument.
Chemical shifts are reported in parts per million (ppm) down-
field from TMS, using the middle resonance of CDCl3 (77.23),
or CD2Cl2 (53.73) as an internal standard. 19F NMR
(188 MHz) was recorded on a Varian Mercury 200 instrument
using CFCl3 (0) as an internal standard. HPLC analysis was
performed on a JASCO U-2080 plus using 4.6 ꢂ 250 mm
CHIRALPAK OD-H or CHIRALCEL AD-H column.
Optical rotations were measured on a HORIBA SEPA-300.
Infrared spectra were recorded on a JASCO FT/IR-200
spectrometer. Mass spectra were recorded on a SHIMADZU
GCMS-QP5050A or SHIMADZU LCMS-2010EV. High
resolution mass spectra (HRMS) (EI+) were obtained from
the Mass Spectrometry Laboratory, Nagoya Institute of
Technology, Nagoya.
926.6, 889.9, 797.4, 759.8, 736.7, 718.3, 687.5 cmꢀ1; mp =
+
123–124 1C; HRMS calcd. for C13H15F3N2O3 304.1035,
found 304.1005.
3-[4,4,4-Trifluoro-3-(1H-pyrrol-2-yl)-butyryl]-thiazolidin-2-one (3r)
Under a N2 atmosphere, to 10 mol% (0.005 mmol) of catalyst
complex Zn(NTf2)2/(R,R)-Ph-dbfox prepared as described
above in 0.2 mL CH2Cl2 was sequentially added 4 A MS
(15.0 mg), b-CF3 acrylates 1d (11.2 mg, 0.050 mmol), and the
solution of pyrrole 2a (17.0 mg, 0.250 mmol) in 0.05 mL
CH2Cl2. The mixture was stirred at ꢀ60 1C for 48 h, then
passed through a plug of silica gel using a 2 : 1 ratio of
petroleum ether and ethyl acetate to afford the title compound
(14.2 mg, 97%) as a white solid. The enantiomeric purity was
determined by HPLC analysis as 95% ee; Chiralcel AD-H,
n-hexane/i-PrOH = 80/20, flow rate 0.5 mL minꢀ1, l =
25
232 nm, tmaj = 25.8 min, tmin = 37.1 min; [a]D = ꢀ7.0
(c = 0.4, CHCl3); 1H NMR (CDCl3, 600 MHz): d = 8.41
(br s, 1H), 6.74 (t, J = 1.2 Hz, 1H), 6.16–6.15 (m, 2H),
4.16–4.00 (m, 1H), 4.11 (dt, J = 1.2 Hz, 7.2 Hz, 2H), 3.60
(ddd, J = 1.2 Hz, 10.2 Hz, 18.0 Hz, 1H), 3.38 (dd, J = 3.0 Hz,
18.0 Hz, 1H), 3.26 (dt, J = 1.2 Hz, 7.2 Hz, 2H); 13C NMR
(CDCl3, 150.9 MHz): d = 173.0, 169.5, 126.1 (q, J = 279.5
Hz), 124.1, 118.3, 108.7, 107.9, 46.9, 39.1 (q, J = 29.0 Hz),
36.7, 25.1; 19F NMR (CDCl3, 188 MHz): d = ꢀ70.1 (d, J =
9.0 Hz, 3F); IR (KBr): 3370.9, 1707.6, 1682.6, 1408.7, 1364.4,
General catalytic procedure for the Friedel–Crafts reactions
To a dried 10 mL test tube was added appropriate Lewis acid
and 1.1 equiv. of the (R,R)-Ph-dbfox ligand. Under a N2
atmosphere, dry solvent was introduced, followed by stirring
at RT for 1 h. 4 A MS and b-CF3 acrylates were added at RT,
then the solution of pyrroles in the same solvent was injected
by a syringe at the reaction temperature. While some Friedel–
Crafts products have the same polarity as the starting material
on TLC, the reaction would be monitored by 19F NMR. After
the starting material was consumed, the residue was directly
subjected to the silica-gel column chromatography to afford
the title product.
1309.4, 1259.3, 1162.9, 1131.1, 1110.8, 1098.3, 735.7 cmꢀ1
;
mp = 104–105 1C; HRMS calcd. for C11H11F3N2O2S+
292.0493, found 292.0468.
(S)-4,4,4-Trifluoro-3-(1H-pyrrol-2-yl)-butylic acid (4)
To a solution of (S)-3b (98% ee, 110.0 mg, 0.40 mmol) in THF
was added 1 N NaOH (aq., 0.80 mL, 0.80 mmol). After
stirring at RT for 1 h, 1 N HCl (aq.) was slowly added to
adjust the pH value of the reaction mixture to 1–2. Compound
(S)-4 (66.2 mg, 80%) was isolated as a solid by flash column
chromatography using a 3 : 1 ratio of petroleum ether and
4,4-Dimethyl-3-[4,4,4-trifluoro-3-(1H-pyrrol-2-yl)-butyryl]-
oxazolidin-2-one (3p)
Under a N2 atmosphere, to 10 mol% (0.005 mmol) of catalyst
complex Zn(NTf2)2/(R,R)-Ph-dbfox prepared as described
above in 0.2 mL CH2Cl2 was sequentially added 4 A MS
(15.0 mg), b-CF3 acrylate 1b (11.8 mg, 0.050 mmol), and the
solution of pyrrole 2a (17.0 mg, 0.250 mmol) in 0.05 mL
CH2Cl2. The mixture was stirred at ꢀ60 1C for 24 h, then
passed through a plug of silica gel using a 2 : 1 ratio of
petroleum ether and ethyl acetate to afford the title compound
(14.5 mg, 95%) as a white solid. The enantiomeric purity was
determined by HPLC analysis as 79% ee; Chiralcel OD-H,
n-hexane/i-PrOH = 70/30, flow rate 0.5 mL minꢀ1, l =
25
ethyl acetate as the eluent. [a]D = +17.3 (c = 0.8, CHCl3);
1H NMR (CDCl3, 600 MHz): d = 8.26 (br s, 1H), 6.76 (d, J =
2.4 Hz, 1H), 6.18–6.16 (m, 2H), 3.96–3.91 (m, 1H), 3.01 (dd,
J=4.2 Hz, 10.8 Hz, 1H), 2.88 (dd, J = 9.6 Hz, 10.8 Hz, 1H);
13C NMR (CDCl3, 150.9 MHz): d = 176.1, 125.8 (q, J =
279.5 Hz), 123.2, 118.8, 108.9, 108.1, 39.7 (q, J = 29.3 Hz),
33.8; 19F NMR (CDCl3, 188 MHz): d = ꢀ70.7 (s, 3F); IR
(KBr): 3470.3, 3119.3, 1719.2, 1660.4, 1560.1, 1418.4, 1363.4,
1293.0, 1272.8, 1181.2, 1164.8, 1035.6, 993.2, 930.5, 859.1,
810.9, 680.8 cmꢀ1; mp = 70–71 1C; HRMS calcd. for
+
25
C8H8F3NO2 207.0507, found 207.0513.
232 nm, tmin = 10.9 min, tmaj = 12.1 min; [a]D = +22.6
(c = 0.8, CHCl3); 1H NMR (CDCl3, 600 MHz): d = 8.43
(br s, 1H), 6.76–6.75 (m, 1H), 6.17–6.16 (m, 2H), 4.19–4.12
(m, 1H), 4.00 (ddd, J = 1.2 Hz, 8.4 Hz, 21.6 Hz, 1H), 3.67
(dd, J = 9.6 Hz, 16.8 Hz, 1H), 3.38 (dd, J = 4.8 Hz, 16.8 Hz, 1H),
1.54 (s, 3H), 1.44 (s, 3H); 13C NMR (CDCl3, 150.9 MHz): d =
170.6, 154.0, 126.1 (q, J = 279.3 Hz), 123.7, 118.4, 108.6,
108.2, 75.3, 60.7, 39.4 (q, J = 29.7 Hz), 36.5, 24.7, 24.5; 19F
NMR (CDCl3, 188 MHz): d = ꢀ70.2 (d, J = 9.2 Hz, 3F); IR
(KBr): 3383.5, 1772.3, 1695.1, 1397.2, 1350.9, 1327.8, 1279.5,
1263.2, 1244.8, 1185.0, 1163.8, 1127.2, 1102.1, 1076.1, 1033.7,
(4S,5aS)-4-Trifluoromethyl-hexahydropyrrolizin-2-one (syn-7)
To a 10 mL test tube was added 4 (66.0 mg, 0.40 mmol), 5% of
Rh–Al2O3 (8 mg), and 4 mL of EtOH. The resulting mixture
was put into an autoclave, and purged with H2 (10 atm). After
stirring at RT for 24 h, the solution was filtered through Celite,
and the solvent was evaporated in vacuo to provide the
2-pyrrolidine carboxylic acid as a white solid. Without further
purification, the compound obtained was heated under reflux
with the phosphine oxide 6 (186 mg, 0.41 mmol) and triethyl
c
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View Article Online
amine (0.2 mL, 1.43 mmol) in 10 mL acetonitrile. After 6 h, the
resulting solution was concentrated, then subjected to column
chromatography using ether as the eluent. The faster running
fraction of a colourless oil was determined as the syn isomer
(23.0 mg, 30%), while the lower fraction of a slightly yellow oil
1 mL ether. After stirring for 1 h at RT, the precipitate was
25
filtered as the target compound 9 (8.0 mg, 35% yield). [a]D
=
ꢀ5.8 (c = 0.6, CHCl3); 1H NMR (CDCl3, 600 MHz): d = 8.88
(s, 2H, Ar–H), 4.50–4.47 (m, 1H, 5-H), 4.15–4.12 (m, 1H,
2-H), 3.80 (dt, J = 12.0 Hz, 7.2 Hz, 1H, 8-H), 3.16–3.12
(m, 1H, 80-H), 3.06 (dt, J = 10.8 Hz, 6.0 Hz, 1H, 2-H),
2.81–2.75 (m, 1H, 4-H), 2.54–2.46 (m, 2H, 6-H, 3-H),
2.38–2.32 (m, 1H, 7-H), 2.21–2.14 (m, 1H, 70-H), 2.05–2.00
(m, 1H, 60-H); 13C NMR (CDCl3, 600 MHz): d = 162.3,
141.6, 128.6, 126.7, 125.2 (q, J = 277.7 Hz), 67.0 (d, J =
2.4 Hz), 55.6, 54.9, 48.7 (q, J = 29.5 Hz), 30.8, 26.7, 25.0;
19F NMR (CDCl3, 188 MHz): d = ꢀ70.0 (d, J = 6.6 Hz, 3F);
IR (KBr): 1716.3, 1637.3, 1557.2, 1489.7, 1434.8, 1329.7,
1276.7, 1162.9, 111.8 cmꢀ1; mp = 181–183 1C; MS (ESI, m/z):
212.200 (M + Na+); anal. calcd. (%) for C14H15F3N4O7 C,
41.18; H, 3.70; N, 13.72; found C, 41.22; H, 3.90; N, 13.60%.
25
was the anti isomer (4.0 mg, 5%). [a]D = +26.0 (c = 0.35,
1
CHCl3); H NMR (CDCl3, 600 MHz): d = 3.95 (dt, J = 6.6
Hz, 9.0 Hz, 1H, 5-H), 3.59 (dt, J = 8.4 Hz, 11.4 Hz, 1H, 8-H),
3.13–3.09 (m, 1H, 80-H), 2.91 (dd, J = 10.2 Hz, 16.2 Hz, 1H,
3-H), 2.87–2.79 (m, 1H, 4-H), 2.67 (dd, J = 9.0 Hz, 16.2 Hz,
1H, 30-H), 2.21–2.15 (m, 2H, 6-H, 7-H), 2.12–2.04 (m, 1H,
70-H), 1.50–1.43 (m, 1H, 60-H); 13C NMR (CDCl3, 600 MHz):
d = 171.1, 126.1 (q, J = 276.6 Hz), 60.9 (d, J = 3.2 Hz), 44.8
(q, J = 29.1Hz), 41.3, 35.2 (d, J = 2.26 Hz), 31.6, 26.6; 19F
NMR (CDCl3, 188 MHz): d = ꢀ71.1 (d, J = 6.6 Hz, 3F); IR
(neat): 2976.6, 2884.9, 1782.9, 1702.8, 1428.0, 1343.2, 1270.9,
1166.7, 1123.3, 1085.7, 688.5 cmꢀ1
; HRMS calcd. for
C8H10F3NO 193.0714, found 193.0756.
Acknowledgements
(4S,5aR)-4-Trifluoromethyl-hexahydropyrrolizin-2-one (anti-7)
This study was financially supported in part by Grants-in-Aid
for Scientific Research (21390030, 22106515, Project No. 2105:
Organic Synthesis Based on Reaction Integration). We also
thank the Asahi Glass Foundation.
25
[a]D = +24.0 (c = 0.3, CHCl3); 1H NMR (CDCl3,
600 MHz): d = 4.04–4.00 (m, 1H, 5-H), 3.57 (dt, J =
8.4 Hz, 11.4 Hz, 1H, 8-H), 3.23–3.15 (m, 1H, 4-H), 3.14–3.10
(m, 1H, 80-H), 2.93 (dd, J = 10.2 Hz, 17.4 Hz, 1H, 3-H), 2.64
(dd, J = 4.8 Hz, 17.4 Hz, 1H, 30-H), 2.22–2.17 (m, 1H, 7-H),
2.06–1.98 (m, 1H, 70-H), 1.96–1.92 (m, 1H, 6-H), 1.75–1.67
(m, 1H, 60-H); 13C NMR (CDCl3, 600 MHz): d = 172.0, 126.5
(q, J = 278.5 Hz), 61.1, 41.3, 38.3 (q, J = 28.5 Hz), 33.9, 29.7,
26.4; 19F NMR (CDCl3, 188 MHz): d = ꢀ67.8 (d, J = 6.6 Hz,
3F); IR (neat): 2926.5, 1779.0, 1684.4, 1484.0, 1428.0, 1392.4,
Notes and references
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MS (ESI, m/z): 216.100 (M + Na+); HRMS calcd. for
C8H10F3NO 193.0714, found 193.0698.
Trifluoromethylated heliotridane (8)
5 R. M. Wilson and S. J. Danishefsky, Angew. Chem., Int. Ed., 2010,
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8 (10.0 mg, 54% yield). [a]D = +20.3 (c = 0.3, Et2O);
1H NMR (CD2Cl2, 600 MHz): d = 3.41–3.38 (m, 1H, 5-H),
3.04–3.01 (m, 1H, 2-H), 2.83 (dt, J = 10.2 Hz, 6.6 Hz, 1H,
8-H), 2.54 (dt, J = 9.6 Hz, 6.6 Hz, 1H, 20-H), 2.46 (dt, J =
10.2 Hz, 6.6 Hz, 1H, 80-H), 2.35–2.29 (m, 1H, 4-H), 2.06–2.00
(m, 1H, 3-H), 1.96–1.85 (m, 2H, 6-H, 30-H), 1.80–1.73 (m, 1H,
7-H), 1.72–1.65 (m, 1H, 70-H), 1.54–1.49 (m, 1H, 60-H); 13C
NMR (CD2Cl2, 600 MHz): d = 128.1 (q, J = 277.2 Hz),
64.8(d, J = 2.3 Hz), 54.7, 54.1, 49.6 (q, J = 26.1 Hz), 32.2,
27.7 (d, J = 2.1 Hz), 26.1; 19F NMR (CD2Cl2, 188 MHz): d =
ꢀ70.1 (d, J = 9.2 Hz, 3F); HRMS calcd. for C8H12F3N
179.0922, found 179.0941.
Trifluoromethylated heliotridane picrate (9)
To a solution of 8 (10.0 mg, 0.056 mmol) in 1 mL ether was
added the solution of picric acid (20.0 mg, 0.056 mmol) in
c
2620 New J. Chem., 2011, 35, 2614–2621
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