Access to Enantio-enriched Substituted α-Trifluoromethyl Azepanes from l -Proline

Article abstract of DOI:10.1021/acs.orglett.8b02167

4-Substituted α-trifluoromethyl azepanes C were synthesized via the ring expansion of trifluoromethyl pyrrolidines A, which were synthesized from l-proline via a regioselective ring-opening of a bicyclic azetidinium intermediate B by various nucleophiles.

Full text of DOI:10.1021/acs.orglett.8b02167

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Access to Enantio-enriched Substituted α‑Trifluoromethyl Azepanes
from L‑Proline
Guillaume Masson, Sarah Rioton, Domingo Gomez Pardo,* and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), UMR 8231, ESPCI Paris/CNRS, PSL
University, 10 rue Vauquelin, Paris 75231 Cedex 05, France
*
S Supporting Information
ABSTRACT: 4-Substituted α-trifluoromethyl azepanes C were synthesized via the ring expansion of trifluoromethyl
pyrrolidines A, which were synthesized from L-proline via a regioselective ring-opening of a bicyclic azetidinium intermediate B
by various nucleophiles. The regioselectivity of the ring expansion is induced by the presence of a trifluoromethyl group. The
chirality of the starting material was transferred to the azepanes with high enantiomeric excess.
7
8
zepanes constitute the core of many natural and bioactive
metathesis, lactamization of α-trifluoromethyl amines,
1
,2
9
A
molecules (Figure 1) and are one of the 100 most
addition of nucleophiles on trifluoromethyl imines, addition
3
10
present ring systems in small drug molecules. As a
consequence, various methods to access azepanes has been
of TMSCF on cyclic imines, or intramolecular [2 + 2]-
3
11
cycloaddition of ω-acetylenic allenes (Scheme 1). However,
in most cases, only a few examples were reported, especially for
highly enantio-enriched azepanes, which would be important
for the discovery of new bioactive compounds. Therefore, here,
we report a general method to access highly enantio-enriched
α-trifluoromethyl azepanes.
In the context of our ring-expansion program, the
synthesis of substituted α-trifluoromethyl azepanes A was
envisioned from pyrrolidine D via an azetidinium intermediate
4
developed. The incorporation of F atoms can influence the
biological activity of a molecule by influencing its con-
5
formation, metabolic stability, lipophilicity, or pKa. In
particular the introduction of a trifluoromethyl group in the
α-position of an amino group is very interesting as the
presence of a CF in such position is decreasing the basicity of
12
3
the amine while maintaining its hydrogen bond donor
property. Therefore, such α-trifluoromethyl amines can be
6
very good amide isosteres.
Previous syntheses allowing the preparation of α-trifluor-
omethyl azepanes were reported by using ring-closing
Scheme 1. Previous Syntheses of α-Trifluoromethyl
Azepanes
Received: July 11, 2018
Figure 1. Bioactive molecules containing azepane rings.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02167
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
B (Scheme 2). This type of bicyclic azetidinium intermediate
Scheme 4. Determination of the Relative Configuration of
(S,R)-4 and (S,S)-4 by NOE
as already been employed to access azepanes, but with
4i,13
regioselectivity problems during the ring opening.
In our
case, the presence of the trifluoromethyl group should render
12d,14
the nucleophilic attack regioselective.
Scheme 2. Strategy To Access α-Trifluoromethyl Azepanes
by GC-MS and TLC after 5 h. The temperature had to be
increased to 40 °C to observe the complete disappearance of
the triflate C by TLC, after 5 h. This observation allowed us to
assume that an azetidinium intermediate was formed.
Nucleophiles (2.5 equiv) were then added to the reaction
mixture at room temperature.
Pyrrolidines D were prepared from L-proline by realizing a
one-carbon Arndt−Eistert homologation. Initially, (S)-N-Cbz-
proline 1 was treated with oxalyl chloride to produce the
corresponding acid chloride, which was treated with
trimethylsilyldiazomethane to form, after 5 h at 0 °C,
When ethanol or benzyl alcohol were added to 5, the
corresponding azepanes were not formed (see Table 1, entries
diazoketone 2 (Et N, THF/MeCN = 1:1, 80%). When
3
diazoketone 2 was treated with AgOBz, Et N in MeOH, a
3
2
and 3), even after heating the reaction mixture at 40 °C
Wolff rearrangement occurred to produce the desired methyl
15
(
Table 1, entries 4 and 5). However, using the corresponding
ester 3 (90%, >99% enantiomeric excess (ee)). The addition
sodium ethoxide and benzyloxide, which are more nucleophilic
than the alcohols, azepanes 9a and 9b were formed with an
excellent diastereoselectivity and they were isolated in good
yields of 86% and 95%, respectively (Table 1, entries 6 and 7).
of TMSCF to 3, in the presence of a catalytic amount of
3
16
TBAF (toluene, −78 °C), under Prakash’s conditions, led to
a ketone intermediate that was not isolated but directly
reduced with NaBH to produce two separable diastereomers:
4
pyrrolidines (S,S)-4 and (S,R)-4 in 45% and 28% yields,
respectively. Subsequently, the N-Cbz protecting group of
compounds (S,S)-4 and (S,R)-4 was replaced by a N-benzyl
group in order to make the nitrogen lone pair available for the
formation of the azetidinium intermediate B (Scheme 3).
Table 1. Ring-Expansion Conditions
Scheme 3. Synthesis of Trifluoromethyl Pyrrolidines
entry
nucleophile
t1
t2
yield (%)
1
2
3
4
5
6
7
rt
a
EtOH
BnOH
EtOH
BnOH
EtONa
BnONa
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
rt
rt
a
40 °C
40 °C
a
rt
86 (dr > 98:2)
95 (dr > 98:2)
a
rt
a
Room temperature.
We were pleased to find that the reaction is general, because
various nucleophiles can be used. The use of sodium
phenoxide and tetrabutylammonium acetate respectively led
to 9c (77%) and 9d (87%) (Scheme 5). When other
nucleophiles such as amines, which are more nucleophilic
than alcohols, were utilized the corresponding 2-trifluoro-
methyl-4-amino azepanes 9e−9i were isolated in good yields
(
79%−95%). Benzhydrazine and tetrabutylammonium azide
The relative stereochemistry of compounds 4 was
determined by NOE experiments on the bicyclic compounds
and 8 which were prepared from (S,R)-4 and (S,S)-4,
respectively, by treatment with DAST (Scheme 4).
With 5 and 6 in hand, the formation of the bicyclic
azetidinium intermediates B as well as their ring opening with
different nucleophiles was evaluated. When 5 was treated at
were also used as nucleophiles and led to the corresponding
substituted azepanes 9j and 9k. It is worth mentioning that
sodium trifluoromethyl acetimidate allowed the formation of
the corresponding azepanes 9l in 73% yield with an excellent
diastereoselectivity and an excellent enantiomeric excess (ee
>99%). Since azepane 9l was crystalline, an X-ray diffraction
(XRD) of the compound was realized and the relative and
absolute configuration of the stereogenic centers at C2 and C4
was confirmed (Figure 2). Other nucleophiles, such as
thiophenol and tetrabutylammonium borohydride also showed
7
room temperature with Tf O (1.1 equiv), in the presence of
2
1
,8-bis(dimethylamino)naphthalene (proton-sponge) (2.0
equiv) in CH Cl , only the triflate intermediate C was detected
2
2
B
DOI: 10.1021/acs.orglett.8b02167
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Ring Expansion of 6 with Various Nucleophiles
Figure 2. X-ray diffraction (XRD) of 9l and 10f
their ability to open the bicyclic azetidiniums, giving the
corresponding azepanes 9m and 9n, respectively. Carbon
nucleophiles such as cyanide, sodium malonate, and cuprate
led to the formation of the corresponding substituted azepanes
9
o−9q from pyrrolidines 5 in moderate to good yields (see
Scheme 5).
Scheme 5. Ring Expansion of 5 with Various Nucleophiles
deprotected azepanes 11 and 12, respectively, with excellent
yields and without any epimerization of the stereogenic centers
(
Scheme 7).
Scheme 7. Debenzylation of 9c and 10b
In conclusion, the ring expansion of pyrrolidines D to
azepanes A via bicyclic azetidinium intermediates B showed an
excellent regioselectivity and a complete chirality transfer from
the L-proline to the azepanes. This method allows easy access
to 2-trifluoromethyl-4-substituted azepanes in highly diaster-
eomeric and enantiomeric excess, and should be of interest to
medicinal chemists.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02167.
The diastereomer 6, was also treated under the same
conditions as 5 and, whatever the nucleophiles, e.g., alcoholate,
phenolate, acetate, amines, trifluoromethylacetamide, or
cyanide, the corresponding azepanes 10a−10g were obtained
in good yields (73%−96%) (Scheme 6). It is worth mentioning
that the 2-trifluoromethyl-4-trifluoromethylacetamide azepanes
Experimental procedures, 1H, 13C and 19F NMR spectra
of isolated compounds, supercritical fluid chromatog-
raphy (SFC) chromatograms (PDF)
Accession Codes
1
0f was crystalline, allowing us to perform an XRD analysis
CCDC 1850085 and CCDC 1850086 contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_ request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
that confirmed the relative and absolute configuration of the
stereogenic centers at C2 and C4 (Figure 2).
We were able to perform the debenzylation (Pd/C, H2,
MeOH) of the diastereomers 9c and 10b, which produced the
C
DOI: 10.1021/acs.orglett.8b02167
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(8) (a) García Ruano, J. L.; de Haro, T.; Singh, R.; Cid, M. B. J. Org.
Chem. 2008, 73, 1150−1153. (b) Wan, W.; Hou, J.; Jiang, H.; Yuan,
Z.; Ma, G.; Zhao, G.; Hao, J. Eur. J. Org. Chem. 2010, 2010, 1778−
336033.
1786.
AUTHOR INFORMATION
Corresponding Authors
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(
9) (a) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.;
Roschenthaler, G.-V.; Nenajdenko, V. G. Synlett 2009, 403−406.
b) Shevchenko, N. E.; Balenkova, E. S.; Roschenthaler, G.-V.;
Nenajdenko, V. G. Synthesis 2010, 120−126. (c) Shmatova, O. I.;
Nenajdenko, V. G. Eur. J. Org. Chem. 2013, 6397−6403.
̈
(
̈
*
E-mail: domingo.gomez-pardo@espci.fr (D. Gomez Pardo).
E-mail: janine.cossy@espci.fr (J. Cossy).
*
ORCID
(
d) Shevchenko, N. E.; Shmatova, O. I.; Balenkova, E. S.;
Ro
237−2245. (e) Shmatova, O. I.; Shevchenko, N. E.; Balenkova, E. S.;
Roschenthaler, G.-V.; Nenajdenko, V. G. Eur. J. Org. Chem. 2013,
3049−3058. (f) Shmatova, O. I.; Shevchenko, N. E.; Balenkova, E. S.;
Roschenthaler, G.-V.; Nenajdenko, V. G. Mendeleev Commun. 2013,
3, 92−93.
10) (a) Nenajdenko, V. G.; Zakurdaev, E. P.; Prusov, E. V.;
Balenkova, E. S. Tetrahedron 2004, 60, 11719−11724. (b) Shevchen-
ko, N. E.; Vlasov, K.; Nenajdenko, V. G.; Roschenthaler, G.-V.
̈
schenthaler, G.-V.; Nenajdenko, V. G. Eur. J. Org. Chem. 2013,
Domingo Gomez Pardo: 0000-0003-0540-0321
Janine Cossy: 0000-0001-8746-9239
Notes
2
̈
̈
The authors declare no competing financial interest.
2
(
ACKNOWLEDGMENTS
■
One of the authors (S.R.) thanks GlaxoSmithKline for a grant.
̈
Tetrahedron 2011, 67, 69−74. (c) Zhao, W.-B.; Nakagawa, S.; Kato,
A.; Adachi, I.; Jia, Y.-M.; Hu, X.-G.; Fleet, G. W. J.; Wilson, F. X.;
Horne, G.; Yoshihara, A.; Izumori, K.; Yu, C.-Y. J. Org. Chem. 2013,
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DOI: 10.1021/acs.orglett.8b02167
Org. Lett. XXXX, XXX, XXX−XXX