Synthesis of enantiopure trans-2,5-disubstituted trifluoromethylpyrrolidines and (2S,5R)-5-trifluoromethylproline

Article abstract of DOI:10.1021/jo502885v

Enantiopure trans-2,5-disubstituted trifluoromethylpyrrolidines were prepared on a several gram scale starting from a readily available chiral fluorinated oxazolidine (Fox). A pure oxazolopyrrolidine intermediate could be obtained after an efficient separ

Full text of DOI:10.1021/jo502885v

Article
pubs.acs.org/joc
Synthesis of Enantiopure trans-2,5-Disubstituted
Trifluoromethylpyrrolidines and (2S,5R)‑5-Trifluoromethylproline
Hodney Lubin, Julien Pytkowicz,* Gregory Chaume, Gwenaelle Sizun-Thome, and Thierry Brigaud*
́
́
̈
́
Laboratoire de Chimie Biologique (LCB), Universite de Cergy-Pontoise, 5 Mail Gay-Lussac, 95000 Cergy-Pontoise cedex, France
S
* Supporting Information
ABSTRACT: Enantiopure trans-2,5-disubstituted trifluoro-
methylpyrrolidines were prepared on a several gram scale
starting from a readily available chiral fluorinated oxazolidine
(Fox). A pure oxazolopyrrolidine intermediate could be
obtained after an efficient separation by selective diastereomer
destruction. The addition of various Grignard reagents on this
oxazolopyrrolidine provided disubstituted pyrrolidines with
moderate to complete trans diastereoselectivity. The highly
valuable compound (2S,5R)-5-trifluoromethylproline could be
synthesized from the same oxazolopyrrolidine intermediate via
a Strecker-type reaction.
been obtained through an enantioselective cycloaddition
reaction.23 Other syntheses of diversely substituted trifluor-
omethylprolines have also been published. Dipeptides incor-
porating racemic 2-trifluoromethylproline can be directly
prepared using the Ugi reaction.24 Our group reported the
synthesis of both enantiomers of 2-trifluoromethylproline
involving a chiral trifluoromethylated allylmorpholinone as
the key intermediate.25 Such a 2-trifluoromethylproline has
recently been incorporated into a tripeptide that presents an
interesting analgesic biological activity.26 Haufe and co-
workers27 reported the addition of an isocyanoacetate on a
trifluoromethyl alkoxyenone to obtain a trifluoromethylpyrrole.
The catalytic hydrogenation of this pyrrole provided the first
example of a racemic synthesis of cis-5-trifluoromethylproline.
Recently, Meffre and co-workers28 described the synthesis of
cis-5-trifluoromethylproline starting from L-glutamic acid but
reported racemization of the final compound. We report herein
a stereoselective strategy for the synthesis of enantiopure
(2R,5R)-5-trifluoromethylproline as well as enantiopure 2,5-
disubstituted trifluoromethylpyrrolidines.
Over the past several years, we have developed efficient
methods for the synthesis of enantiopure α-trifluoromethyl-
substituted amino acids (α-Tfm-AAs),29,30 amino alcohols,31
and diamines29 starting from readily available fluorinated
oxazolidine (Fox) compounds.32 Considering the very few
examples of asymmetric syntheses of trifluoromethylated
pyrrolidines reported in the literature, we turned our attention
to the nonfluorinated series and were inspired by the early work
of Husson33 and, more recently, by Kadouri-Puchot’s and
Mangeney’s synthesis of 2,5-disubstituted pyrrolidines and 5-
substituted proline involving chiral oxazolidines.34 We decided
INTRODUCTION
■
2,5-Disubstituted pyrrolidines constitute important motifs
found in natural alkaloids,1 and 5-substituted prolines are
conformationally constrained unnatural amino acids.2 Both can
be considered as compounds with high biological interest.3
They also have been used for asymmetric synthesis as chiral
auxiliaries,4,5 chiral ligands,6 and organocatalysts.7 The
fluorinated fragments can deeply modify physicochemical
properties of organic compounds and sometimes change their
biological features significantly.8−10 Among them, the powerful
electron-withdrawing trifluoromethyl group has been used to
modulate the pKa of neighboring functions,11 promote specific
conformations,12 and increase the lipophilicity13 and the
metabolic stability14 of molecules of biological interest.
Several trifluoromethylpyrrolidines have already been
synthesized in the literature, mostly in their racemic forms.
Since the first example of pyrrolidine synthesis published by
Burger et al.,15 the [3 + 2] cycloaddition of an azomethine ylide
and a dipolarophile has often been used to reach β-
substituted13,16 or α-substituted17,18 trifluoromethylpyrroli-
dines. Highly functionalized trifluoromethylpyrrolidines can
also be synthesized from a Michael-type addition/annulation
sequence on a CF3-substituted vinylsulfonium salt,19 intra-
molecular cyclization of fluorinated homoallylamines, and one-
pot intramolecular cyclization of aminoalkynes followed by
nucleophilic addition of the Ruppert reagent.20 However, very
few methods giving an access to optically active compounds
have been published. Fustero et al.21 described a tandem cross-
metathesis intramolecular aza-Michael reaction of an enantio-
merically enriched aminoalkene, and Li et al.22 obtained good
enantioselectivities in their copper-catalyzed asymmetric 1,3-
dipolar cycloaddition. Several racemic and stereoselective
syntheses of trifluoromethylprolines are also found in the
literature. Highly substituted 3-trifluoromethylprolines have
Received: December 19, 2014
© XXXX American Chemical Society
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to investigate this strategy in the fluorinated series. Our target
chiral pyrrolidines and proline should be obtained from a
common trifluoromethylated oxazolopyrrolidine intermediate 1
via an organometallic addition or a Strecker-type reaction
(Scheme 1). Compound 1 should be obtained by the
oxazolidine imine-type cyclic transition state involving chelation
of the lithium metal by both the imine and the phenylglycinol
residue (Scheme 2).35
Since the two diastereomers (R)-2 and (S)-2 were not easily
separable, the aldehydes were generated from the mixture
under aqueous acidic conditions, and the two corresponding
oxazolopyrrolidines (R)-1 and (S)-1 were obtained in 66%
yield with a similar diastereomeric ratio (84:16 dr) (Scheme 3).
Scheme 1. Retrosynthetic Plan
Scheme 3. Synthesis of Oxazolopyrrolidines (R)-1 and (S)-1
It should be noted that the cyclization is completely
diastereoselective, giving only the trans-oxazolidine relative
configuration. Unfortunately, the two diastereomers could not
be separated either at this step.
intramolecular condensation under acidic conditions of the
amino alcohol 2, which in turn should be obtained from the
addition of an aldehyde precursor lithium reagent on the
fluorinated oxazolidine (Fox). This retrosynthetic pathway
should provide an asymmetric, robust and scalable synthesis of
trifluoromethylpyrrolidines (Scheme 1).
In order to obtain 2,5-disubstituted pyrrolidines, addition of
organometallic reagents on the diastereomeric mixture of
oxazolopyrrolidines 1 was investigated. The addition of 2 equiv
of phenyl Grignard reagent on the mixture of oxazolopyrroli-
dines 1 resulted in the formation of the two addition products
(R,R)-3 and (S)-3 arising from (R)-1 and (S)-1 along with
nonreacted oxazolopyrrolidine (R)-1 (Scheme 4). Three
important reaction features could be deduced from this result:
(i) under these experimental conditions, oxazolopyrrolidine
(S)-1 reacted more rapidly than oxazolopyrrolidine (R)-1; (ii)
the addition on (R)-1 was completely selective, furnishing
trans-pyrrolidine (R,R)-3; (iii) the addition on (S)-1 was not
selective, giving a mixture of undetermined cis- and trans-
pyrrolidine (S)-3. Moreover, the nonreacted oxazolopyrrolidine
RESULTS AND DISCUSSION
■
Synthesis of Oxazolopyrrolidine 1. The condensation of
fluoral with (R)-phenylglycinol gave the corresponding
fluorinated oxazolidine (Fox) as a 68:32 mixture of two
inseparable diastereomers.32 The reaction of the allyllithium
reagent with the mixture of oxazolidines proceeded mostly
through γ-addition but was not completely diastereoselective
and led to the major formation of the diastereomer (R)-2
(84:16 dr). Considering that the same diastereoselectivity was
obtained starting from pure trans-Fox, we propose an open-
Scheme 2. Synthesis of Amino Alcohols (R)-2 and (S)-2
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Grignard reagents (entries 3−6), and the reaction did not
proceed at all with organolithium reagents (entries 7−9).
To rationalize this good trans stereoselectivity, we propose an
iminium-based open transition state with the benzylic proton of
the phenylglycinol moiety close to the trifluoromethyl group.
The transition state leading to the cis-pyrrolidine would be
higher in energy because of the sterically unfavorable proximity
of the phenyl and trifluoromethyl groups (Figure 2). According
to this transition state, the better diastereoselectivity observed
for hindered Grignard reagents can be explained by the fact that
their steric hindrance reinforces the repulsion between the CF3
group and the phenyl group of the chiral auxiliary. Organo-
lithium reagents are known to attack trifluoromethylated
oxazolidines directly, mainly with retention of configuration.32
The lower Lewis acidities of the organolithium reagents seem,
in our case, to prevent the formation of the iminium. If this is
true, then the absence of reactivity could be explained by the
sterically hindered approach of the organolithium reagent to
oxazolopyrrolidine (R)-1 (Figure 2). All attempts to increase
the reactivity of (R)-1 toward organolithium reagents failed. No
reaction occurred even upon increasing the number of
equivalents of nucleophile, using organolithium in the presence
of lithium bromide, increasing the temperature from 0 °C to
room temperature, or preopening the oxazolopyrrolidine (R)-1
by treatment with a Lewis acid (BF3·OEt2).
The last step required for the synthesis of the target
trifluoromethylated pyrrolidines consisted of the removal of the
phenylethanol moiety. In the case of the phenyl-substituted
pyrrolidine (R,R)-3, this cleavage could not be performed by
hydrogenolysis because of an unselective cleavage of the two
benzylic positions. However, the target pyrrolidine (R,R)-9
could be obtained in enantiomerically pure form in 74% yield
by oxidative cleavage of the phenylglycinol side chain promoted
by cerium(IV) ammonium nitrate (CAN) (Scheme 6).
To demonstrate the efficiency of our strategy, a scaled-up
procedure without any chromatographic purification was
achieved starting from 10 g of Fox to give 1.93 g of pure
pyrrolidine (R,R)-9. An overall yield of 21% was obtained for
this procedure involving only two purification steps: distillation
of oxazolopyrrolidine (R)-1 and distillation of the final
pyrrolidine (R,R)-9.
Scheme 4. Addition of Phenyl Grignard Reagent on
Oxazolopyrrolidines 1
(R)-1 could be recovered from the mixture by a simple
distillation (Scheme 4).
Considering that the stereoselective synthesis of trifluor-
omethylpyrrolidines requires starting from pure oxazolopyrro-
lidine (R)-1, we intended to take advantage of the kinetic
difference between the Grignard reagent addition reactions on
(R)-1 and (S)-1 to perform a separation based on the selective
consumption of the undesired diastereomer.
To test the feasibility of such a resolution, substoichiometric
portions of phenyl Grignard reagent were sequentially added to
the diastereomeric mixture of oxazolopyrrolidines (R)-1 and
(S)-1, and the reaction was monitored by fluorine NMR
spectroscopy to track the total consumption of the more
reactive diastereomer (S)-1 (Figure 1). From this study, it
appeared that the addition of 0.7 equiv of Grignard reagent was
the best compromise to transform the entire amount of
undesired compound (S)-1 and preserve the maximum amount
of oxazolopyrrolidine (R)-1 in the mixture (Figure 1). At a
preparative scale, the treatment of the oxazolopyrrolidine
mixture 1 with 0.7 equiv of phenyl Grignard reagent allowed
the isolation of pure oxazolopyrrolidine (R)-1 by distillation in
69% yield. This resolution is scalable, and pure oxazolopyrro-
lidine (R)-1 could be obtained on a scale of more than 9 g
according to this procedure (Scheme 5).
Synthesis of 2,5-Trifluoromethylpyrrolidines. The
addition of various Grignard and organolithium reagents was
tested on pure isolated (R)-1. Good results were observed with
hindered Grignard reagents such as PhMgBr and i-PrMgBr,
since the addition reaction was completely diastereoselective to
give only the trans-pyrrolidines (R,R)-3 and (R,R)-4,
respectively (Table 1, entries 1 and 2). The selectivity
decreased for less hindered reagents such as n-butyl or methyl
Synthesis of 5-Trifluoromethylproline (R,S)-13. A
straightforward synthesis of 5-trifluoromethylproline (R,S)-13
Figure 1. Monitoring of the addition reaction by 19F NMR spectroscopy.
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Scheme 5. Separation of (R)-1 from (S)-1 by Selective Diastereomer Destruction
Table 1. Addition of Organometallics on (R)-1
Scheme 6. Synthesis of Pyrrolidine (R,R)-9
a
entry
RM
equiv
yield (%)
de (%)
product
1
2
3
4
5
6
7
8
9
PhMgBr
i-PrMgBr
allyl-MgBr
MeMgBr
vinyl-MgBr
n-BuMgBr
MeLi
2
4
97
61
73
95
52
66
0
>98
>98
(R,R)-3
Scheme 7. Strecker-Type Reaction on (R)-1
(R,R)-4
b
4
84
5
6
7
8
3.3
4
70
68
52
12
2
n-BuLi
2
0
PhLi
2
0
a
Determined by 1H and 19F NMR analysis of the crude mixture.
>98% de after silica gel purification.
b
was envisioned through a three-step procedure involving a
Strecker-type reaction on oxazolopyrrolidine (R)-1 followed by
hydrolysis of the corresponding aminonitrile and removal of the
phenylglycinol side chain. This strategy has already been
successfully employed for the preparation of several Tfm-amino
acids.29,30 The Strecker-type addition reaction on (R)-1 was
performed using trimethylsilyl cyanide as the cyanide donor in
the presence of boron trifluoride diethyl etherate to promote
the formation of the iminium intermediate (Scheme 7). Under
these conditions, a diastereomeric mixture of amino nitriles 10
(70% de) was obtained in fairly good yield. In this case, a
nonchelate transition state should lead to the major formation
of the cis adduct (R,S)-10. Fortunately the two diastereomers
were easily separated by silica gel chromatography to give the
major amino nitrile (R,S)-10 in 57% isolated yield and the
minor isomer (R,R)-10 in 11% yield. One-pot hydrolysis of the
cyano group/removal of the phenylethanol moiety was tested
on the enantiopure amino nitrile (R,S)-10 in strongly acidic
aqueous solution, but this resulted in partial epimerization of
the target 5-trifluoromethylproline (Scheme 7).
To achieve the synthesis of the target enantiopure 5-
trifluoromethylproline, the cyano group of amino nitrile (R,S)-
10 was converted into methyl ester (R,S)-11 in 74% yield
under acidic conditions without any epimerization (Scheme 8).
In opposition to the results obtained in the nonfluorinated
series,34 we did not observe any formation of a bicyclic lactone.
After saponification of the ester in the presence of LiOH and
hydrogenolysis of the phenylethanol moiety, the expected
(2S,5R)-5-trifluoromethylproline (R,S)-13 was obtained in
Figure 2. Proposed transition state.
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Scheme 8. Synthesis of (2S,5R)-5-Trifluoromethylproline
(R,S)-13
Scheme 9. Synthesis of (2R,5R)-5-Trifluoromethylproline
(R,R)-13
enantiopure form in 79% yield (Scheme 8). The cis relative
configuration of (R,S)-13 was deduced from the NMR data of
the corresponding hydrochloride, which were rigorously
identical to those recently reported by others in the racemic
series.27,28
mined by X-ray crystallography (cf. the Supporting Informa-
tion). The palladium-catalyzed hydrogenolysis of a small
quantity of lactone (R,R)-14 afforded an analytical quantity
of (R,R)-13 hydrochloride presenting a trans configuration
(Scheme 9).36
Determination of Absolute and Relative Configura-
tions. As none of the new compounds synthesized were solids,
X-ray crystallography could not be used to assign the absolute
configurations of the trifluoromethylpyrrolidines. The absolute
configuration of oxazolopyrrolidine (R)-1 and pyrrolidine
(R,R)-9 could be assigned by NOE difference NMR experi-
ments. For oxazolopyrrolidine (R)-1, the strong correlation
between the proton at the α position of the phenyl group (H3)
and the proton at the α position of the trifluoromethyl group
(H5) clearly indicated the (R) configuration of the correspond-
ing carbon (C5). A similar correlation between the proton of
the ring junction (H8) and the pro-S proton of the
phenylglycinol methylene (H2′) allowed us to assign the (S)
configuration to the ring junction. Using the same methodology
on pyrrolidine (R,R)-9, we observed correlations between two
sets of three protons corresponding to the two faces of the five-
membered ring, confirming the trans configuration of the
phenyl and trifluoromethyl groups (Figure 3).
CONCLUSIONS
■
We have shown that the chiral fluorinated oxazolopyrrolidine
(R)-1 could be readily synthesized on a multigram scale starting
from a fluorinated oxazolidine (Fox) using an organometallic-
addition-based kinetic resolution. The addition of the Grignard
reagent on (R)-1 was diastereoselective, with hindered reagents
leading to the trans adduct as the major product. Surprisingly,
no addition reaction could be performed with organolithium
reagents. The synthetic potential of this methodology was
demonstrated by the scalable synthesis of enantiopure (2R,5R)-
2-phenyl-5-trifluoromethylpyrrolidine (R,R)-9. Similarly, highly
valuable enantiopure (2S,5R)-5-trifluoromethylproline (R,S)-13
was synthesized in a few steps from the same oxazolopyrro-
lidine (R)-1 via a Strecker-type reaction.
EXPERIMENTAL SECTION
■
(R)-2-[(1R)-(Z)-1-Trifluoromethyl-4-methoxybut-3-enylami-
no]-2-phenylethanol (2). To a solution of allyl methyl ether (20.2 g,
280.5 mmol, 3.0 equiv) in THF (220 mL) under an argon atmosphere
at −78 °C was added dropwise a solution of s-BuLi (251.7 mL, 1.3 M
in hexanes, 327.2 mmol, 3.5 equiv). The reaction mixture was stirred at
−78 °C for 45 min. A solution of the diastereomeric Fox mixture (20.3
g, 93.5 mmol, 1.0 equiv) in THF (220 mL) was then added dropwise
over a period of 30 min, and the reaction mixture was stirred at −78
°C for 2 h. The reaction was quenched at −78 °C with a saturated
NH4Cl solution, and the aqueous layer was extracted with ethyl acetate
(3 × 100 mL). The organic layers were combined, washed with water
and brine, dried over MgSO4, filtered, and concentrated under reduced
pressure to afford the crude product (33.9 g) as yellow oil. The desired
amino alcohol 2 was obtained as a mixture of two diastereomers
(84:16 dr). The crude mixture was employed in the next step without
any purification. For characterization purposes, the reaction was
performed starting from a small quantity of oxazolidine (0.434 g, 2
mmol) to give after purification by silica gel chromatography
(cyclohexane/ethyl acetate 90:10 to 95:5) a diastereomeric mixture
of (R)-2 and (S)-2 (0.383 g, 66%). A pure analytical sample of the
major diastereomer (R)-2 could be obtained. [α]D −52.2 (c = 1.0,
CHCl3); IR 3341, 2935, 1665, 1454, 1397, 1264, 1224, 1129, 1105,
1025, 931, 758, 700 cm−1; 1H NMR (400 MHz) δ 2.16 (bs, 2H, NH),
2.26−2.34 (ddd, 1H, J = 14.1, 13.5, 6.6 Hz), 2.59 (ddd, 1H, J = 14.1,
8.5, 5.3 Hz), 3.04 (ddq, 1H, J = 13.5, 5.3 Hz, JH−F = 8.0 Hz), 3.55 (dd,
1H, J = 10.9, 8.1 Hz), 3.63 (s, 3H), 3.70 (dd, 1H, J = 10.9, 4.4 Hz),
4.03 (dd, 1H, J = 8.1, 4.4 Hz), 4.44 (ddd, 1H, J = 8.5, 6.6, 6.2 Hz), 6.09
(d, 1H, J = 6.2 Hz), 7.22−7.39 (m, 5H); 13C NMR (100.5 MHz) δ
Figure 3. NOE experiments on (R)-1 and (R,R)-9.
The configurations of pyrrolidines 4−11 were determined by
1
comparison with H NMR data for (R,R)-3 according to the
coupling constants and the chemical shifts of the cyclic protons.
Further confirmation of the cis configuration of the major
amino nitrile (R,S)-10 and the final 5-trifluoromethylproline
(R,S)-13 was given indirectly by the synthesis of an analytical
sample of (2R,5R)-5-trifluoromethylproline (R,R)-13 and
comparison of its NMR data with those for (R,S)-13. When
the minor amino nitrile (R,R)-10 was treated with an acidic
methanol solution, trans-bicyclic lactone (R,R)-14 was formed
together with amino ester (R,S)-11 (Scheme 9). The structure
of trans-bicyclic lactone (R,R)-14 was unambiguously deter-
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23.0, 56.6 (q, JC−F = 27.8 Hz), 59.8, 62.5, 67.4, 100.4, 126.5 (q, JC−F
=
δ −76.2 (d, 3F, JH−F = 7.8 Hz); HRMS (EI+, direct inlet probe) m/z
[M+] calcd for C19H20F3NO 335.1497, found 335.1497.
282.1 Hz), 127.8, 127.9, 128.7, 140.1, 149.4; 19F NMR (376.2 MHz) δ
−77.7 (d, 3F, JH−F = 8.0 Hz); HRMS (EI+, direct inlet probe) m/z
[M+] calcd for C14H18F3NO2 289.1290, found 289.1290.
(R)-2-[(2R,5R)-2-Isopropyl-5-trifluoromethylpyrrolidin-1-yl]-2-
phenylethanol ((R,R)-4). Obtained from (R)-1 (1.5 g, 5.8 mmol, 1.0
equiv) in THF (15 mL) following the general procedure using two
additions of i-PrMgBr (2 × 3.9 mL, 3.0 M in THF, 2 × 11.7 mmol, 4.0
equiv). The crude material was purified by silica gel chromatography
(cyclohexane/ethyl acetate 100:0 to 75:25) to provide the pure
pyrrolidine (R,R)-4 (1.1 g, 3.5 mmol, 61%, >98% de) as a colorless oil.
[α]D −20.2 (c = 1.0, CHCl3); IR 3416, 2960, 2875, 1471, 1451, 1389,
(3R,5R,7aS)-3-Phenyl-5-(trifluoromethyl)hexahydropyrrolo-
[2,1-b]oxazole ((R)-1). To a solution of crude amino alcohol 3 (13.3
g, 46.04 mmol, 1.0 equiv) in diethyl ether (175 mL) was slowly added
a sulfuric acid aqueous solution over 15 min (172.65 mL, 2 M, 345.3
mmol, 7.5 equiv). After 2 min of vigorous stirring, the aqueous layer
was extracted with diethyl ether (3 × 75 mL). The organic layers were
combined, washed with water, dried over MgSO4, filtered, and
concentrated under reduced pressure to afford the desired bicyclic
oxazolidines 1 as a mixture of two diastereomers (84:16 dr).
Purification by silica gel chromatography afforded the pure bicyclic
oxazolidines (7.8 g, 30.4 mmol, 66%) as an inseparable mixture of two
diastereoisomers (R)-1 and (S)-1 (84:16 dr). To the mixture of
bicyclic oxazolidines 1 (7.8 g, 30.3 mmol, 1.0 equiv) in THF (150 mL)
under an argon atmosphere at 0 °C was added dropwise a solution of
PhMgCl over 5 min (3.2 mL, 25% in THF, 6.1 mmol, 0.2 equiv). The
reaction mixture was stirred at room temperature for 16 h. Aliquots
were taken at regular intervals and worked up, and the evolution of the
reaction was monitored by 19F NMR spectroscopy. After 16 h of
stirring, an additional amount of PhMgCl solution (8.0 mL, 25% in
THF, 15.2 mmol, 0.5 equiv) was added to allow the completion of the
reaction after 3 h of stirring. The reaction was quenched at 0 °C with a
saturated NH4Cl solution (75 mL). The aqueous layer was extracted
with DCM (3 × 100 mL). The organic layers were combined, washed
with water and brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude mixture was purified by silica gel
chromatography (cyclohexane/ethyl acetate 100:0 to 90:10) to
provide the diastereomerically pure bicyclic oxazolidine (R)-1 as a
colorless oil (5.348 g, 20.79 mmol, 69%, >98% de). Alternatively, the
crude reaction mixture could also be purified by distillation under
vacuum to give (R)-1 as a colorless oil (bp 110 °C, 1 mbar). [α]D
−52.2 (c = 1.0, CHCl3); IR 2872, 1497, 1451, 1396, 1376, 1282, 1183,
1
1370, 1270, 1162, 1129, 1091, 1035, 945, 762, 701 cm−1; H NMR
(400 MHz) δ 0.91 (d, 3H, J = 6.6 Hz), 1.05 (d, 3H, J = 6.4 Hz), 1.13−
1.20 (m, 1H), 1.44−1.54 (m, 1H), 1.67 (ddd, 1H, J = 8.6, 5.7, 2.9 Hz),
3
1.70−1.78 (m, 1H), 2.16 (dqq, 1H, J = 7.3, 6.6, 6.4 Hz), 2.70 (bs,
1H), 3.02 (q, 1H, J = 7.3 Hz), 3.76 (dd, 1H, J = 11.0, 5.9 Hz), 3.77
(quint d, 1H, J = 8.8, 2.5 Hz), 3.93 (dd, 1H, J = 11.0, 9.3 Hz), 4.34
(dd, 1H, J = 9.3, 5.9 Hz), 7.23−7.37 (m, 5H); 13C NMR (100.5 MHz)
δ 19.0, 21.0, 24.9, 27.5, 28.8, 59.6, 59.7 (q, JC−F = 28.8 Hz), 62.6, 69.0,
124.8 (q, JC−F = 291.4 Hz), 127.9, 128.7, 128.9, 138.5; 19F NMR
(376.2 MHz) δ −76.8 (bs, 3F); HRMS (EI+, direct inlet probe) m/z
[M+] calcd for C16H22F3NO 301.1653, found 301.1644.
(R)-2-[(2R,5R)-2-Allyl-5-trifluoromethylpyrrolidin-1-yl]-2-phenyle-
thanol (5). Obtained from (R)-1 (0.26 g, 1.0 mmol, 1.0 equiv) in THF
(3 mL) following the general procedure using two additions of allyl-
MgBr (2 × 2.0 mL, 1.0 M in diethyl ether, 2 × 2.0 mmol, 4.0 equiv).
The crude product (0.3 g, 84% de) was purified by silica gel
chromatography (cyclohexane/ethyl acetate 100:0 to 95:5) to provide
the pure major pyrrolidine 5 (0.22 g, 0.73 mmol, 73%, >98% de) as a
colorless oil. The minor diastereoisomer could not be isolated. [α]D
−93.0 (c = 1.28, CHCl3); IR 3423, 2980, 2903, 1640, 1495, 1451,
1
1379, 1281, 1156, 1131, 1073, 1055, 1026, 914, 848, 763 cm−1; H
NMR (400 MHz) δ 1.17 (ddt, 1H, J = 13.5, 12.4, 8.4 Hz), 1.59 (dddd,
1H, J = 12.8, 12.6, 8.4, 6.9 Hz), 1.78 (dd, 1H, J = 13.5, 6.9 Hz), 1.82
(dd, 1H, J = 12.8, 6.9 Hz), 2.20 (dt, 1H, J = 14.7, 7.4 Hz), 2.57 (dddd,
3
1H, J = 14.7, 6.9, 5.0, 1.4 Hz), 2.72 (bs, 1H), 3.35 (ddt, 1H, J = 8.4,
1
1153, 1123, 1024, 986, 890, 755, 698 cm−1; H NMR (400 MHz) δ
7.4, 5.0 Hz), 3.47 (dq, 1H, JH−F = 8.6 Hz, J = 8.4 Hz), 3.71 (dd, 1H, J
= 10.2, 3.2 Hz), 3.96 (dd, 1H, J = 10.8, 10.2 Hz), 4.01 (dd, 1H, J =
10.2, 3.9 Hz), 5.08 (dt, 1H, J = 10.2, 0.9 Hz), 5.14 (ddd, 1H, J = 17.3,
1.96−2.13 (m, 2H), 2.17−2.32 (m, 2H), 3.42 (ddq, 1H, J = 8.0, 3.7
Hz, JH−F = 7.6 Hz), 3.59 (dd, 1H, J = 8.2, 6.6 Hz), 4.28−4.37 (m, 2H),
4.96 (d, 1H, J = 4.1 Hz), 7.23−7.27 (m, 1H), 7.31−7.39 (m, 4H); 13C
NMR (100.5 MHz) δ 24.0, 29.9, 68.2 (q, JC−F = 29.7 Hz), 70.6, 73.3,
98.9, 126.3, 126.4 (q, JC−F = 278.9 Hz), 127.3, 128.6, 141.5; 19F NMR
(376.2 MHz) δ −79.7 (d, 3F, JH−F = 7.6 Hz); HRMS (EI+, direct inlet
probe) m/z [M+] calcd for C13H14F3NO 257.1027, found 257.1025.
General Procedure for the Synthesis of Trifluoromethylated
Pyrrolidines 3−8. To a solution of bicyclic oxazolidine (R)-1 (1.0
equiv) in THF under argon at 0 °C was added dropwise a solution of
the Grignard reagent over 5 min. The reaction mixture was stirred at
room temperature for 2 h, and the evolution of the reaction was
monitored by 19F NMR spectroscopy. If necessary, a second portion of
the organometallic reagent, identical to the first one, was added. After
8 h of stirring at room temperature, the reaction was quenched with a
saturated NH4Cl solution. The aqueous layer was extracted three times
with ethyl acetate. The organic layers were combined, dried over
MgSO4, filtered, and concentrated. The crude product was purified by
silica gel chromatography to provide the pure pyrrolidine.
(R)-2-Phenyl-2-[(2R,5R)-5-trifluoromethyl-2-phenylpyrrolidin-1-
yl]ethanol ((R,R)-3). Obtained from (R)-1 (3.9 g, 15.0 mmol, 1.0
equiv) in THF (75 mL) following the general procedure using
PhMgCl (15.8 mL, 25% in THF, 30.0 mmol, 2.0 equiv). The crude
product was purified by silica gel chromatography (cyclohexane/ethyl
acetate 100:0 to 75:25) to provide the pure pyrrolidine (R,R)-3 (4.9 g,
14.5 mmol, 97%, >98% de) as a colorless oil. [α]D −48.9 (c = 1.15,
CHCl3); IR 3374, 2888, 1493, 1452, 1380, 1269, 1129, 1108, 1077,
1022, 869, 797, 759, 698 cm−1; 1H NMR (400 MHz) δ 1.66−1.72 (m,
1H), 1.95−2.05 (m, 2H), 2.17 (tt, 1H, J = 11.0, 8.5 Hz), 2.34 (tt, 1H, J
= 13.2, 8.5 Hz), 3.67 (dd, 1H, J = 11.0, 7.3 Hz), 3.80−3.88 (m, 2H),
4.20 (t, 1H, J = 7.3 Hz), 4.42 (dd, 1H, J = 8.0, 3.4 Hz), 7.01−7.06 (m,
2H), 7.17−7.37 (m, 8H); 13C NMR (100.5 MHz) δ 25.5, 32.5, 60.3
(q, JC−F = 29.7 Hz), 61.4, 63.0, 65.8, 127.5 (q, JC−F = 286.6 Hz), 127.6,
127.8, 127.8, 128.5, 128.7, 129.2, 137.6, 144.5; 19F NMR (376.2 MHz)
3
1.4, 0.9 Hz), 5.84 (dddd, 1H, J = 17.3, 10.2, 7.4, 6.9 Hz), 7.21−7.40
2
(m, 5H); 13C NMR (100.5 MHz) δ 26.4, 29.9, 40.2, 59.1 (q, JC−F
=
1
29.7 Hz), 62.4, 65.0, 65.9, 117.3, 126.9 (q, JC−F = 280.8 Hz), 128.5,
128.7, 128.9, 135.3, 136.3; 19F NMR (376.2 MHz) δ −78.2 (d, 3F,
JH−F = 8.6 Hz); HRMS (EI+, direct inlet probe) m/z [M+] calcd for
C16H20F3NO 299.1497, found 299.1494.
(R)-2-[(2S,5R)-2-Methyl-5-trifluoromethylpyrrolidin-1-yl]-2-phe-
nylethanol (6). Obtained from (R)-1 (0.26 g, 1.0 mmol, 1.0 equiv) in
THF (3 mL) following the general procedure using two additions of
MeMgBr (0.34 mL + 0.7 mL, 3.2 M in MeTHF, 1.1 + 2.2 mmol, 1.1 +
2.2 equiv). The crude material (0.26 g, 0.95 mmol, 95%, 70% de) was
purified by silica gel chromatography (cyclohexane/ethyl acetate 100:0
to 95:5) to provide the pyrrolidines 9 as a mixture of two
diastereomers (0.17 g, 0.64 mmol, 6%, 70% de) as a colorless oil.
Separation of the two diastereoisomers could not be achieved by silica
gel chromatography. The NMR data for the major trans
diastereoisomer 6 were determined from the mixture. IR 3390,
2964, 2897, 1496, 1451, 1380, 1280, 1186, 1127, 1072, 1031, 942, 899,
852, 762, 699 cm−1; 1H NMR (400 MHz) δ 1.28 (d, 1H, 3J = 6.6 Hz),
1.24−1.35 (m, 1H), 1.71−1.86 (m, 2H), 1.96−2.05 (m, 1H), 3.52 (qd,
1H, JH−F = 8.0 Hz, J = 3.0 Hz), 3.60 (sext, 1H, J = 6.6 Hz), 3.75 (dd,
1H, J = 10.8, 5.8 Hz), 3.94 (dd, 1H, J = 10.8, 9.4 Hz), 4.33 (dd, 1H, J =
9.4, 5.8 Hz), 7.22−7.43 (m, 5H); 13C NMR (100.5 MHz) δ 19.2, 24.9,
32.2, 58.8 (q, 2JC−F = 29.7 Hz), 59.2, 60.8, 63.3, 127.2 (q, 1JC−F = 283
Hz), 127.9, 128.2, 128.8, 128.9, 137.9; 19F NMR (376.2 MHz) δ
−78.85 (d, 3F, JH−F = 8.0 Hz); HRMS (EI+, direct inlet probe) m/z
[M+] calcd for C14H18F3NO 273.1340, found 273.1341.
(R)-2-Phenyl-2-[(2R,5R)-2-trifluoromethyl-5-vinylpyrrolidin-1-yl]-
ethanol (7). Obtained from (R)-1 (1.5 g, 5.9 mmol, 1.0 equiv) in THF
(10 mL) following the general procedure using two equal additions of
vinyl-MgBr (2 × 16.7 mL, 0.7 M in THF, 2 × 11.7 mmol, 4.0 equiv).
The crude product (1.3 g) was purified by silica gel chromatography
F
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(cyclohexane/ethyl acetate 100:0 to 90:10) to provide an inseparable
mixture of pyrrolidines 7 (0.9 g, 3.0 mmol, 52%, 68% de) as a yellow
oil. IR 3368, 2873, 1714, 1700, 1455, 1403, 1373, 1267, 1131, 1083,
1028, 877, 737, 723, 701 cm−1; 1H NMR (400 MHz) δ 1.28−1.35 (m,
1H), 1.45−1.69 (m, 1H), 1.80−1.91 (m, 1H), 2.00−2.27 (m, 1H),
2.89−3.28 (m, 1H), 3.31−3.62 (m, 1H), 3.62−4.07 (m, 2H), 4.17−
4.44 (m, 1H), 4.79−5.40 (m, 2H), 5.42−5.71 (m, 0.16H), 5.83 (ddd,
0.8H, J = 16.5, 10.3, 9.4), 7.26−7.36 (m, 5H); 13C NMR (100.5 MHz)
under reduced pressure. Purification of the crude product (3.7 g, 70%
de) by silica gel chromatography (cyclohexane/ethyl acetate 100/0 to
60/40) afforded the pure pyrrolidines (R,S)-10 (2.4 g, 57%, >98% de)
and (R,R)-10 (0.5 g, 11%) as yellow oils. (R,S)-10: [α]D −82.5 (c =
2.9, CHCl3); IR 3459, 2887, 1495, 1452, 1381, 1278, 1154, 1117,
1146, 942, 882, 829, 763, 735, 700, 654 cm−1; 1H NMR (400 MHz) δ
1.74 (dq, 1H, J = 13.5, 8.9 Hz), 2.00−2.06 (m, 1H), 2.21 (dd, 2H, J =
14.0, 7.5 Hz), 2.67 (bs, 1H), 3.82 (quint d, 1H, J = 8.0, 2.6 Hz), 3.95
(dd, 1H, J = 11.5, 5.3 Hz), 4.07 (dd, 1H, J = 11.5, 8.6 Hz), 4.12 (t, 1H,
J = 7.5 Hz), 4.19 (dd, 1H, J = 8.6, 5.3 Hz), 7.29−7.40 (m, 5H). 13C
NMR (100.5 MHz) δ 26.0, 30.1, 52.0, 61.4 (q, JC−F = 29.7 Hz), 62.0,
2
δ 25.0, 29.7 (minor), 30.4, 52.3 (minor), 58.2 (q, JC−F = 29.7 Hz),
61.4, 62.3 (minor), 63.0, 66.7 (minor), 67.6, 98.6 (minor), 117.4,
1
126.8 (q, JC−F = 282.7 Hz), 127.7, 128.2, 128.5, 129.0, 137.2, 139.9;
66.0, 120.2, 126.2 (q, 1JC−F = 280.8 Hz), 128.1, 128.5, 128.9, 136.5; 19
F
19F NMR (376.2 MHz) δ −78.03 (d, 2.52F, JH−F = 7.8), −79.70 (d,
0.48F, JH−F = 7.8 Hz); HRMS (ESI) m/z [M + H]+ calcd for
C15H19F3NO 286.1419, found 286.1420.
NMR (376.2 MHz) δ −78.6 (d, 3F, JH−F = 8.0 Hz); HRMS (EI+,
direct inlet probe) m/z [M+] calcd for C14H15F3N2O 284.1136, found
284.1133. (R,R)-10: [α]D +0.1 (c = 2.7, CHCl3); IR 3459, 2887, 1495,
1452, 1381, 1278, 1154, 1117, 1146, 942, 882, 829, 763, 735, 700, 654
cm−1; 1H NMR (400 MHz) δ 2.03−2.33 (m, 5H, OH), 3.83 (quint d,
1H, J = 7.4, 1.0 Hz), 4.02 (d, 1H, J = 6.6 Hz), 4.13 (dd, 1H, J = 11.0,
5.9 Hz), 4.43 (dd, 1H, J = 11.0, 8.9 Hz), 4.59 (dd, 1H, J = 8.9, 5.9 Hz),
7.27−7.41 (m, 5H); 13C NMR (100.5 MHz) δ 26.1, 30.0, 52.0, 59.3
(q, JC−F = 29.7 Hz), 62.3, 62.8, 121.7, 126.4 (q, JC−F = 282.8 Hz),
128.4, 128.5, 129.1, 136.5; 19F NMR (376.2 MHz) δ −78.5 (d, 3F,
JH−F = 7.4 Hz); HRMS (EI+, direct inlet probe) m/z [M+] calcd for
C14H15F3N2O 284.1136, found 284.1150.
(2S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-2-methoxycarbon-
yl-5-trifluoromethylpyrrolidine ((R,S)-11). Amino nitrile (R,S)-10
(1.3 g, 4.7 mmol, 1.0 equiv) was dissolved in methanol saturated with
gaseous hydrogen chloride (25 mL) and stirred overnight at room
temperature. The reaction was quenched by careful addition of a
saturated solution of NaHCO3 (50 mL), and the mixture was extracted
with DCM (3 × 50 mL). The combined organic phases were dried
over magnesium sulfate, filtered, and concentrated under reduced
pressure. Purification of the crude product (1.4 g) by silica gel
chromatography (cyclohexane/ethyl acetate 100:0 to 70:30) afforded
the pure methyl ester (R,S)-11 (1.1 g, 74%, >98% de) as a colorless oil.
[α]D −107.8 (c = 1.1, CHCl3); IR 3435, 2954, 1734, 1282, 1154, 1116,
1044, 763, 701 cm−1; 1H NMR (400 MHz) δ 1.30−1.45 (m, 1H), 1.73
(bs, 1H), 1.88 (dd, 1H, J = 13.3, 6.9 Hz), 2.01 (ddd, 1H, J = 14.6, 8.2,
6.9 Hz), 2.18 (dt, 1H, J = 14.6, 8.0 Hz), 3.44 (quint, 1H, J = 8.2 Hz),
3.71−3.83 (m, 1H), 3.78 (s, 3H), 3.97 (bd, 1H, J = 9.6 Hz), 4.04 (dd,
1H, J = 12.3, 9.6 Hz), 4.12 (dd, 1H, J = 8.2, 8.0 Hz), 7.20−7.29 (m,
2H), 7.31−7.45 (m, 3H); 13C NMR (100.5 MHz) δ 26.8, 28.5, 52.4,
59.2 (JC−F = 30.7 Hz), 62.4, 67.3, 67.8, 126.3 (JC−F = 281.8 Hz), 128.1
(2C), 128.5, 128.9 (2C), 135.9, 174.6; 19F NMR (376.2 MHz) δ
−78.2 (d, 3F, JH−F = 7.9 Hz); HRMS (EI+, direct inlet probe) m/z
[M+] calcd for C15H18F3NO3 317.1239, found 317.1249.
(R)-2-[(5R)-2-Butyl-5-trifluoromethylpyrrolidin-1-yl]-2-phenyle-
thanol (8). Obtained from (R)-1 (0.26 g, 1.0 mmol, 1.0 equiv) in THF
(3 mL) following the general procedure using two additions of n-
BuMgCl (1.2 + 5.9 mL, 20% in THF and toluene, 2.0 + 10 mmol, 2 +
10 equiv). The crude product (0.32 g) was purified by silica gel
chromatography (cyclohexane/ethyl acetate 100:0 to 96:4) to provide
an inseparable mixture of pyrrolidines 8 (0.2 g, 0.7 mmol, 66%, 52%
de) as a colorless oil. 1H NMR (400 MHz) δ 0.94 (t, 3H, J = 7.1 Hz),
1.19−1.50 (m, 6H), 1.58−1.67 (m, 1H), 1.70−1.79 (m, 1H), 1.82−
1.96 (m, 2H), 2.69 (bs, 1H), 3.20−3.27 (m, 0.2H) (minor), 3.28−3.36
(m, 0.8H) (major), 3.43 (p, 0.2H, J = 8.9 Hz) (minor), 3.55−3.63 (m,
0.8H) (major), 3.68−3.77 (m, 1H), 3.89−4.0 (m, 1.2H), 4.32 (dd,
0.8H, J = 9.6, 5.5 Hz) (major), 7.20−7.39 (m, 5H); 13C NMR (100.5
MHz) δ 14.1, 22.9, 24.5, 26.4 (minor), 26.9 (major), 28.8 (minor),
29.6, 30.0, 32.0 (major), 35.7 (minor), 58.7 (q, J = 28.7 Hz) (minor),
58.9 (q, J = 28.7 Hz) (major), 60.1, 62.1 (minor), 62.9 (major), 64.1,
65.5, 126.7 (q, J = 280.8 Hz) (minor), 127.1 (q, J = 270.3 Hz)
(major), 127.8 (major), 128.2 (minor), 128.6 (2C), 128.7 (2C), 136.1
(minor), 138.2 (major); 19F NMR (376.2 MHz) δ −77.6 (d, 3F, J =
8.6 Hz) (major), −78.4 (d, 3F, J = 8.6 Hz) (minor); HRMS (ESI) m/z
[M + H]+ calcd for C17H25F3NO 316.1888, found 316.1888.
(2R,5R)-2-Phenyl-5-trifluoromethylpyrrolidine ((R,R)-9). To a
solution of pyrrolidine (R,R)-3 (4.1 g, 12.1 mmol, 1.0 equiv) in a 1:1
mixture of acetonitrile and water (120 mL) at room temperature was
added CAN (14.6 g, 26.7 mmol, 2.2 equiv). The reaction mixture
became black and was stirred at room temperature for 3 min. K2CO3
was added, and the reaction mixture was stirred for 10 min at room
temperature. The aqueous layer was extracted with ethyl acetate (3 ×
25 mL), and the organic layer was washed with water, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
mixture (3.511 g) was distilled under reduced pressure (75 °C, 2 ×
10−1 mbar), and the desired pyrrolidine (R,R)-9 (1.9 g, 9.0 mmol,
74%) was obtained as a colorless liquid. [α]D +34.9 (c = 1.0, CHCl3);
IR 3365, 3030, 2971, 1603, 1493, 1452, 1373, 1273, 1145, 1109, 1028,
(2S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-5-trifluoromethyl-
pyrrolidine-2-carboxylic Acid ((R,S)-12). (R,S)-11 (1.0 g, 3.2
mmol, 1 equiv) was dissolved in THF (17 mL), and a solution of
LiOH (3.5 mL, 1 M in H2O, 1.1 equiv) was added dropwise at 0 °C.
The resulting yellow solution was stirred overnight at room
temperature, diluted with water (10 mL), acidified with 1 N HCl
solution (pH ≈ 1), and extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were dried over magnesium sulfate and
concentrated under reduced pressure, and the crude product was
purified by silica gel chromatography (cyclohexane/ethyl acetate 100:0
to 90:10) to give (R,S)-12 (0.8 g, 83%, >98% de) as a white solid. Mp
= 126−127 °C; [α]D −93.1 (c = 0.61, CHCl3); IR 2976, 2161, 2030,
1
943, 877, 757, 698 cm−1; H NMR (400 MHz) δ 1.76 (dq, 1H, J =
12.2, 8.2 Hz), 2.00 (dddd, 1H, J = 13.3, 8.2, 6.2, 5.7 Hz), 2.10 (bs,
1H), 2.20 (dtd, 1H, J = 13.3, 8.2, 5.0 Hz), 2.31 (dq, 1H, J = 12.2, 6.2
Hz), 3.93 (qdd, 1H, 3JH−F = 8.2 Hz, J = 8.2, 5.7 Hz), 4.37 (dd, 1H, J =
8.2, 6.2 Hz), 7.23−7.36 (m, 5H); 13C NMR (100.5 MHz) δ 25.5, 34.3,
2
1
59.0 (q, JC−F = 29.7 Hz), 62.2, 126.3, 127.2 (q, JC−F = 281.8 Hz),
124.4, 128.7, 143.9; 19F NMR (376.2 MHz) δ −80.04 (d, 3F, JH−F
=
3
8.2 Hz); HRMS (EI+, direct inlet probe) m/z [M+] calcd for
C11H12F3N 215.0922, found 215.0929.
(2S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-2-cyano-5-trifluoro-
methylpyrrolidine ((R,S)-10) and (2R,5R)-1-[(R)-2-Hydroxy-1-
phenylethyl]-2-cyano-5-trifluoromethylpyrrolidine ((R,R)-10).
To a solution of pure (R)-1 (3.9 g, 15.0 mmol, 1.0 equiv) in DCM
(45 mL) under an argon atmosphere at 0 °C was slowly added boron
trifluoride etherate (3.8 mL, 30 mmol, 2.0 equiv). The reaction
mixture was stirred at 0 °C for 15 min, and then TMSCN (4.0 mL, 30
mmol, 2.0 equiv) was added dropwise over 5 min. The reaction
mixture was slowly allowed to warm to room temperature and stirred
overnight. The reaction was quenched at 0 °C with a saturated
solution of NaHCO3 (50 mL). The aqueous layer was extracted with
DCM (3 × 50 mL). The organic layers were combined, washed with 2
M NaOH and water, dried over MgSO4, filtered, and concentrated
1
1588, 1365, 1292, 1165, 1089, 1052, 820, 778, 702, 663 cm−1; H
NMR (400 MHz) δ 1.41−1.54 (m, 1H), 1.86−1.95 (m, 1H), 2.02−
2.13 (m, 1H), 2.24−2.33 (m, 1H), 3.52−3.62 (m, 1H), 3.88−3.94 (m,
1H), 4.08−4.22 (m, 3H), 7.20−7.25 (m, 2H), 7.34−7.42 (m, 3H); 13C
NMR (100.5 MHz) δ 27.0, 28.7, 60.1 (q, JC−F = 29.7 Hz), 62.2, 67.2,
67.5, 125.9 (q, JC−F = 206.1 Hz), 128.0 (2C), 128.8, 129.1 (2C), 135.3,
176.2; 19F NMR (376.2 MHz) δ −77.9 (d, 3F, JH−F = 7.6 Hz); HRMS
(EI+, direct inlet probe) m/z [M+] calcd for C14H16F3NO3 303.1082,
found 303.1074.
(2S,5R)-5-Trifluoromethylproline ((R,S)-13). (R,S)-12 (0.7 g,
2.2 mmol, 1 equiv) was dissolved in MeOH (22 mL), and a catalytic
amount of palladium stabilized over charcoal (0.2 g, 10 wt %, 0.2
G
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mmol, 0.1 equiv) was carefully added. The heterogeneous mixture was
stirred for 1 h under a H2 atmosphere (gas balloon), filtered over
Celite, and concentrated under reduced pressure. The crude product
was crystallized in a minimum (2 mL) of a 1:1 pentane/Et2O mixture
to give (R,S)-13 (0.315 g, 79%) as a white solid. Mp 80−81 °C; [α]D
−63.2 (c = 1.0, CHCl3); IR 2976, 2161, 2030, 1588, 1365, 1292, 1165,
(3) Fournie-Zaluski, M. C.; Coric, P.; Thery, V.; Gonzalez, W.;
Meudal, H.; Turcaud, S.; Michel, J. B.; Roques, B. P. J. Med. Chem.
1996, 39, 2594−2608.
(4) Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1977, 42, 1663−
1664.
(5) Kim, B. H.; Lee, H. B.; Hwang, J. K.; Kim, Y. G. Tetrahedron:
Asymmetry 2005, 16, 1215−1220.
(6) Hoen, R.; van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; de
Vries, J. G.; Feringa, B. L. Org. Lett. 2004, 6, 1433−1436.
(7) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen,
K. A. J. Am. Chem. Soc. 2004, 126, 4790−4791.
(8) Bioorganic and Medicinal Chemistry of Fluorine; Begue, J.-P.,
Bonnet-Delpon, D., Eds.; Wiley: Hoboken, NJ, 2008.
(9) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I.,
Ed.; Wiley-Blackwell: Hoboken, NJ, 2009.
1
1089, 1052, 820, 778, 702, 663 cm−1; H NMR (400 MHz) δ 1.96
(dtd, 1H, J = 13.3, 7.3, 5.9 Hz), 2.15 (dq, 1H, J = 13.3, 7.3 Hz), 2.19−
2.33 (m, 1H), 3.90 (sext, 1H, J = 7.3 Hz), 4.01−4.09 (m, 1H), 7.37
(bs, 2H); 13C NMR (100.5 MHz) δ 25.7, 29.6, 59.8 (q, 3F, JC−F = 30.7
Hz), 60.2, 125.8 (q, JC−F = 277.9 Hz), 177.4; 19F NMR (376.2 MHz) δ
−79.2 (d, 3F, JH−F = 7.3 Hz); HRMS (EI+, direct inlet probe) m/z
[M+] calcd for C6H8F3NO2 183.0507, found 183.0507.
(4R,6R,8aR)-4-Phenyl-6-(trifluoromethyl)hexahydropyrrolo-
[2,1-c][1,4]oxazin-1-one ((R,R)-14). A solution of (R,R)-10 (0.4 g,
1.4 mmol, 1 equiv) was dissolved in methanol saturated with gaseous
hydrogen chloride (7 mL), and the solution was stirred at room
temperature until completion of the reaction (48 h). The reaction was
quenched with NaHCO3 (5 mL), and the aqueous layer was extracted
with dichloromethane (3 × 10 mL). The organic layers were
combined, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude mixture was purified by silica gel
chromatography (cyclohexane/ethyl acetate 100/0 to 70/30). The
trans-lactone (R,R)-14 (0.2 g, 0.6 mmol, 74%) was obtained as a white
solid. Mp 104−105 °C; [α]D +33.8 (c = 1.0, CHCl3); IR 2161, 2030,
1750, 1281, 1156, 1113, 1025, 763, 701 cm−1; 1H NMR (400 MHz) δ
1.97−2.03 (m, 1H), 2.07−2.13 (m, 1H), 2.21−2.29 (m, 1H), 2.54−
2.60 (m, 1H), 3.31−3.39 (m, 1H), 4.02−4.07 (m, 1H), 4.22−4.29 (m,
3H), 7.30−7.39 (m, 5H); 13C NMR (100.5 MHz) δ 24.3, 26.4, 60.5,
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2
1
64.4, 66.7 (q, JC−F = 30.7 Hz), 70.9, 125.8 (q, JC−F = 280.8 Hz),
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The methyl ester (R,S)-11 (0.05 g, 0.14 mmol, 10%) resulting from
the epimerization was also recovered.
ASSOCIATED CONTENT
* Supporting Information
■
S
General information, NMR spectra of all new compounds, and
ORTEP/X-ray and CIF data for single-crystal X-ray analyses of
compound (R,R)-14 (CCDC 1046816). This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Fustero, S.; Jimen
Am. Chem. Soc. 2007, 129, 6700−6701.
́ ́
ez, D.; Sanchez-Rosello, M.; Del Pozo, C. J.
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(23) Li, Q.; Ding, C.-H.; Li, X.-H.; Weissensteiner, W.; Hou, X.-L.
Synthesis 2012, 44, 265−271.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: thierry.brigaud@u-cergy.fr.
*E-mail: julien.pytkowicz@u-cergy.fr.
■
(24) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.;
Roschenthaler, G.-V.; Nenajdenko, V. G. Synlett 2009, 403−406.
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2009, 11, 209−212.
Notes
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Hadjiolova, R.; Bocheva, A.; Brigaud, T. Eur. J. Med. Chem. 2013, 62,
122−129.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(27) Kondratov, I. S.; Dolovanyuk, V. G.; Tolmachova, N. A.; Gerus,
We thank the French Ministry of Research for awarding a
research fellowship to H.L. and Central Glass Company for
financial support and the gift of trifluoroacetaldehyde hemi-
acetal. We also thank the French Fluorine Network.
I. I.; Bergander, K.; Frohlich, R.; Haufe, G. Org. Biomol. Chem. 2012,
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10, 8778−8785.
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(28) Ortial, S.; Dave, R.; Benfodda, Z.; Benimelis, D.; Meffre, P.
Synlett 2014, 25, 569−573.
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(31) Pytkowicz, J.; Stephany, O.; Marinkovic, S.; Inagaki, S.; Brigaud,
T. Org. Biomol. Chem. 2010, 8, 4540−4542.
DEDICATION
■
This article is dedicated to Professor Iwao Ojima (State
University of New York at Stony Brook) on the occasion of his
70th birthday.
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H
DOI: 10.1021/jo502885v
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The Journal of Organic Chemistry
Article
(36) The NMR data for trans (R,R)-13 hydrochloride were different
from those reported for cis-(R,S)-13 by others in the racemic series
(see refs 27 and 28).
I
DOI: 10.1021/jo502885v
J. Org. Chem. XXXX, XXX, XXX−XXX