Asymmetric Synthesis of α-Trifluoromethylthio-β-Amino Acids under Phase Transfer Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b04195

The first asymmetric α-trifluoromethylthiolation of 2-substituted isoxazolidin-5-ones was developed using Maruoka type N-spiro ammonium catalysts under phase-transfer conditions. The resulting products, containing a trifluoromethylthiolated quaternary chiral carbon, were obtained in moderate to good yields and up to 98:2 enantiomeric ratio. Moreover, the easy N-O bond cleavage provided access to undescribed α-trifluoromethylthio-β^2,2-amino acids, with promising applications in biochemistry and medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.9b04195

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of α‑Trifluoromethylthio-β-Amino Acids
under Phase Transfer Catalysis
Vito Capaccio,‡ Marina Sicignano,† Ricardo I. Rodríguez,‡ Giorgio Della Sala,*,†
,‡
́
́
and Jose Aleman*
†
̀
Dipartimento di Chimica e Biologia “A. Zambelli”, Universita degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA,
Italy
‡
́
́
Organic Chemistry Department, Modulo 1, Universidad Autonoma de Madrid, 28049 Madrid, Spain
S
* Supporting Information
ABSTRACT: The first asymmetric α-trifluoromethylthiolation of
2-substituted isoxazolidin-5-ones was developed using Maruoka
type N-spiro ammonium catalysts under phase-transfer con-
ditions. The resulting products, containing a trifluoromethylthio-
lated quaternary chiral carbon, were obtained in moderate to good
yields and up to 98:2 enantiomeric ratio. Moreover, the easy N−
O bond cleavage provided access to undescribed α-trifluorome-
thylthio-β2,2-amino acids, with promising applications in bio-
chemistry and medicinal chemistry.
n light of the biomedical significance regarding β-amino
Iacid motifs, its catalytic asymmetric synthesis has been
imposed in pharmaceutical, biological, and materials chemistry
as a trending research topic worldwide. β-Amino acid scaffolds
behave as constituent elements of peptide derivatives and
foldamers exhibiting unique well-defined secondary structures
and enhanced metabolic stability.1 A well-known strategy for
modulating physical and chemical properties of amino acids
and proteins relies on the incorporation of fluorinated
substituents, resulting in a broad range of advantages such as
proteolytic and folding stability, improved pharmacokinetics,
modulation of binding affinity with proteins and membranes,
allowing the application of 19F NMR in biochemistry and
medicinal chemistry and the implementation of 18F-based
imaging techniques.2 Considering the great interest aroused by
the applications of fluorinated β-amino acids and β-peptides,3
it is not surprising that continuous efforts were devoted to the
synthesis of these compounds in enantioenriched forms during
the past years.3a,4 More specifically, the presence of a SCF3
group into a molecule is well-known to be desirable from a
bioactivity point of view, based on the fact that the
combination of a considerable electron-withdrawing power
with outstanding lipophilicity5 confers to the pharmaceuticals
improved bioavailability and metabolic stability.6 These are
some of the reasons that several drugs that include the SCF3
moiety have been developed in the past decade (see examples,
Figure 1a).7 Despite this, the enantioselective synthesis of
trifluoromethylthiolated β-amino acids has never been
described hitherto.
Figure 1. Synthesis of β2,2-amino acids by α-reaction of α-substituted
isoxazolidin-5-ones with electrophiles.
lective reaction at C-4 in the presence of an electrophilic
species, followed by (2) a reductive cleavage of the N−O bond
(Figure 1b).8−11 Such substrates usually show good levels of
On the other hand, 4-substituted-isoxazolidin-5-ones have
recently proven to be ideal precursors of enantioenriched β2,2-
amino acids containing a quaternary chiral center, through a
two-step synthetic sequence consisting of (1) an enantiose-
Received: November 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04195
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
enantioselectivity in Michael additions,9 SN2′ allylation with
Morita−Baylis−Hillman carbonates,10 α-amination,9 and α-
sulfenylation.11 However, the trifluoromethylthiolation of
isoxazolidin-5-ones that would give access to enantioenriched
β-trifluoromethylthio-amino acids has not been achieved.12
In this work, we describe the asymmetric trifluoromethylth-
iolation of isoxazolidinone derivatives through phase-transfer
catalyzed conditions using Maruoka’s catalyst.13 In addition,
we describe the N−O bond cleavage, achieving the final 2-
trifluoromethylthio-β2,2-amino acid derivative.
We began our studies choosing 1a as the model substrate,
TBAB as the phase transfer catalyst, and the shelf-stable N-
(trifluoromethylthio)phthalimide 2 as a SCF3 source.11,14
Among the different bases and solvents surveyed, only solid
K2CO3 in diethyl ether furnished the anticipated product 3a in
acceptable yield at room temperature, whereas stronger bases
brought about the rapid decomposition of reagent 2.15 With
these conditions in hand, we proceeded to the chiral catalysts
screening (Table 1 with the catalysts outlined in Figure 2).
Figure 2. Phase-transfer catalysts screened in the trifluoromethylth-
iolation of isoxazolidin-5-one 1a.
with the 3,5-bis(trifluoromethyl)phenyl substituted N-spiro
quaternary ammonium salt 11 (entry 8). The catalyst loading
was reduced to 5 mol % without losing enantioselectivity and
only a small erosion of conversion (entry 10). Aiming to
explore the smallest possible amount of the catalyst, we found
that 2 mol % led to significant decline of conversion and a
small decrease of e.r. (entry 11). Any attempt to improve the
enantioselectivity by changing solvent (entries 12−15) and
decreasing temperature (entry 16) proved unsuccessful.
Although a minimal increase of e.r. was obtained by using
toluene, the conversion was rather low even after 72 h (entry
13).
Having defined the optimal reaction conditions (entry 10,
Table 1), we moved to extend the methodology to various 4-
substituted isoxazolidin-5-ones 1 (Scheme 1). Consistently
good enantiomeric ratios (from 82:18 to 98:2) were achieved
with variously substituted arylmethyl and heteroarylmethyl
substrates 1a−n. On the other hand, the electronic nature of
the aryl group largely influenced the reactivity. Therefore,
moderate to good isolated yields (48−87%) were achieved for
isoxazolidinones containing phenyl (3a,b) or aromatic ring
with EWGs (3c−j). However, isoxazolidinones with EDGs on
the aryl moiety reacted in general with moderate conversions
(products 3k,l) due to the poorer acidity of the hydrogen at α-
carbonyl position. Interestingly, the reaction was also
compatible with heteroaromatic derivatives (products 3m
and 3n). Seeking proof of the above hypothesis, we studied the
reaction protocol on more acidic α-aryl substrates 1o,p.
Indeed, we obtained 3o and 3p in high yields and in only 10−
20 min with good enantiomeric ratio and good yields. With
these substrates catalyst 10 proved to be more enantioselective
than 11.
a
Table 1. Screening of Catalysts and Reaction Conditions
catalyst
(mol %)
t
yield
b
e.r.
c
entry
solvent
(h)
(%)
(optical rotation)
1
2
3
4
5
6
7
8
4 (10)
5 (10)
6 (10)
7 (10)
8 (10)
9 (10)
10 (10)
11 (10)
12 (10)
11 (5)
11 (2)
11 (5)
11 (5)
11 (5)
11 (5)
11 (5)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
toluene
CH2Cl2
MTBE
Et2O
48
48
48
48
48
48
48
48
48
48
48
72
72
72
72
96
24
26
64
80
71
64
34
67
43
60
33
21
29
0
62:38 (−)
55:45 (−)
60:40 (−)
62:38 (−)
60:40 (−)
61:39 (−)
89:11 (+)
93:7 (+)
69:31 (+)
93:7 (+)
90:10 (+)
78:22 (+)
95:5 (+)
−
9
10
11
12
13
14
15
20
55
91:9 (+)
92:8 (+)
d
16
a
Reaction conditions: 1a (0.10 mmol), 2a (0.20 mmol), K2CO3 (0.20
b
mmol), catalyst (x mmol), solvent (1.0 mL). NMR yields on the
crude product using terephthalaldehyde as an internal standard.
c
Determined by chiral HPLC (see Supporting Information).
Reaction performed at 4 °C.
d
The facial selectivity of this asymmetric trifluoromethylth-
iolation was unequivocally determined by X-ray crystal analysis
of product 3e, which showed (S) configuration,16 in agreement
with previously reported PTC reactions with a closely related
(R,R)-Maruoka’s catalyst.9,11 We assumed the same stereo-
chemical course of the reaction for the rest of the compounds.
The enantioselective phase-transfer catalyzed trifluorome-
thylthiolation has been successfully scaled up to 1.0 mmol of
substrate 1a, leading to 3a with virtually unaltered yield and
enantiomeric ratio (48% yield, 92:8 e.r.).17
We first examined the performance of diverse cinchoninium
and quinidinium catalysts (entries 1−6, Table 1). The O-
alkylated derivatives 6-9 (entries 3−6) led to product 3a with
better conversion than catalysts containing a free hydroxyl
group (entries 1−2). However, uniformly low level of
enantioselectivity was observed with cinchona alkaloid derived
salts, regardless of the nature of O-alkyl and N-benzyl
substituents. To our delight, Maruoka’s catalysts 10−12
turned out to be much more suitable (entries 7−9), obtaining
good conversions and e.r.’s. The best enantioselectivity and
conversion in the trifluoromethylthiolation of 1a were achieved
At the final stage, pursuing the synthesis of enantioenriched
2-trifluoromethylthio-β2,2-amino acids, we carried out the N−
O cleavage reaction using 3a as representative product.
B
DOI: 10.1021/acs.orglett.9b04195
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Pleasingly, N-Boc protected β-amino acid 4 was obtained in
high yield by hydrogenolysis with ammonium formate and Pd/
C (Scheme 2).
Scheme 1. Scope of the Trifluoromethylthiolation of
Isoxazolidin-5-ones
a b c
, ,
Scheme 2. Synthesis of 2-Trifluoromethylthio-β2,2-Amino
Acid 4
In summary, we developed an asymmetric phase-transfer
catalyzed α-trifluoromethylthiolation of α-substituted isoxazo-
lidin-5-ones with good enantioselectivity and overall good
yields. The obtained products proved to be easily transformed
into the corresponding enantioenriched α-trifluoromethylthio-
β2,2-amino acids, previously undescribed compounds for which
intriguing applications in several areas, such as medicinal
chemistry, materials chemistry, bioengineering, and materials
science, could reasonably be envisaged.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04195.
Table of optimization, experimental procedures, charac-
terization data of the unknown compounds, copies of
NMR spectra and HPLC traces (PDF)
Accession Codes
CCDC 1959946−1959947 contain the supplementary crys-
tallographic 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 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gdsala@unisa.it.
*E-mail: jose.aleman@uam.es.
ORCID
Vito Capaccio: 0000-0001-7987-3848
Marina Sicignano: 0000-0002-9382-2622
Ricardo I. Rodríguez: 0000-0003-3846-8154
Giorgio Della Sala: 0000-0001-5020-8502
́
́
Jose Aleman: 0000-0003-0164-1777
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Spanish Government (CTQ2015-
64561-R and RTI2018-095038-B-I00), “Comunidad de
Madrid” and European Structural Funds (S2018/NMT-
a
The following reaction conditions were applied unless otherwise
specified: 1 (0.10 mmol), 2 (0.20 mmol), K2CO3 (0.20 mmol), 11
b
c
́
4367). R.I.R thanks Fundacion Carolina for a graduate
fellowship. G.D.S and M.S. thank the University of Salerno
(0.005 mmol), Et2O (1.0 mL). Isolated yields. Determined by chiral
d
HPLC (see Supporting Information). Catalyst 10 (2 mol %, 0.002
mmol) was used.
for financial support (FARB).
C
DOI: 10.1021/acs.orglett.9b04195
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(14) Compound 2 was prepared as described in the literature: Kang,
K.; Xu, C.; Shen, Q. Copper-catalyzed trifluoromethylthiolation of
aryl and vinyl boronic acids with a shelf-stable electrophilic
trifluoromethylthiolating reagent. Org. Chem. Front. 2014, 1, 294.
Crystals of 2, obtained by slow evaporation of an hexane/2-propanol
1:1 solution, were submitted to X-ray analysis. This is the first crystal
structure reported for compound 2 (CCDC: 1959946; see Supporting
Information for more details).
(15) See Supporting Information for optimization tables.
(16) CCDC 1959947 contains the supplementary crystallographic
data for compound 3e. These data are provided free of charge by The
Cambridge Crystallographic Data Centre. See Supporting Information
for details.
(17) See Supporting Information for the detailed procedure.
E
DOI: 10.1021/acs.orglett.9b04195
Org. Lett. XXXX, XXX, XXX−XXX