Straightforward synthesis of enantiopure (R)- and (S)-trifluoroalaninol

Article abstract of DOI:10.1039/c0ob00424c

Two efficient routes are reported for the synthesis of both enantiomers of trifluoroalaninol in enantiopure form. The first pathway involves a Strecker-type reaction performed from a chiral trifluoromethyloxazolidine (Fox). The second route, which is more

Full text of DOI:10.1039/c0ob00424c

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Straightforward synthesis of enantiopure (R)- and (S)-trifluoroalaninol†‡
Julien Pytkowicz, Olivier Ste´phany, Sinisa Marinkovic, Se´bastien Inagaki and Thierry Brigaud*
Received 14th July 2010, Accepted 11th August 2010
DOI: 10.1039/c0ob00424c
Two efficient routes are reported for the synthesis of both
enantiomers of trifluoroalaninol in enantiopure form. The
first pathway involves a Strecker-type reaction performed
from a chiral trifluoromethyloxazolidine (Fox). The second
route, which is more direct, involves, as a key step, the
reduction of chiral oxazolidines or imines derived from ethyl
trifluoropyruvate.
Enantiopure b-amino alcohols are very important natural or
synthetic pharmacologically active molecules.1 In addition 1,2-
amino alcohols and their derivatives are extensively used as chiral
ligands or auxiliaries.2 These compounds are very conveniently
obtained through the reduction of naturally occurring enantiopure
amino acids and several synthetic methods are reported in the
literature for their preparation.
It is now well documented that the introduction of trifluo-
romethyl groups into molecules significantly modifies their chem-
ical and biological properties and a growing number of synthetic
methods are reported for the synthesis of fluorinated compounds.3
b-Trifluoromethyl b-amino alcohols are very attractive molecules
as biologically active compounds4 and peptidomimetic units.5
Scheme 1 Retrosynthetic pathways for the synthesis of (R)- and
As the large scale synthesis of enantiopure Tfm-amino acids is
still a challenge,6 there are very few reports on the synthesis of
enantiopure b-trifluoromethyl b-amino alcohols resulting from
the reduction of the corresponding amino acids.7 For this reason
several strategies were adopted for the stereoselective elaboration
of the b-trifluoromethyl b-amino alcohol unit.8 Intriguingly de-
spite its interest and its apparent structural simplicity, to our
knowledge there are very few reports on the synthesis of chiral
trifluoroalaninol. Enantiopure (R)-trifluoroalaninol was prepared
from a multistep procedure involving the reduction of a chiral
a-trifluoromethyl-b-sulfinyl enamine followed by a nonoxidative
Pummerer rearrangement as key steps.9,10 However, this pro-
cedure does not appear to be easily scalable. Enantioenriched
(R)-trifluoroalaninol has also been obtained by enantioselective
reduction of an ethyl trifluoropyruvate oxime ether.11
In order to develop scalable methodologies for the synthesis
of both enantiomers of trifluoroalaninol in enantiopure form
we report here two diastereoselective strategies involving (R)-
phenylglycinol-based imines and oxazolidines (Scheme 1). We
chose as fluorinated starting materials the commonly available
fluoral ethyl hemiacetal and ethyl trifluoropyruvate. Both strate-
gies involve the same aminodiol as a key intermediate giving the
(S)-trifluoroalaninol.
target enantiopure trifluoroalaninols after removal of the (R)-
phenylglycinol side chain.
In a first approach the amino alcohols (R)-4 and (S)-4 were
conveniently obtained through a multistep procedure involving
a Strecker-type reaction on the oxazolidines 1, followed by the
methanolysis of the corresponding amino nitriles 2 and the
reduction of the amino esters 3 (Scheme 2). According to our
previous reports,12 the Lewis acid mediated Strecker-type reaction
performed on chiral Tfm-oxazolidines 1 gave the amino nitriles
(R)-2 and (S)-2 as a diastereomeric mixture. As the separation
of these two diastereomers was quite difficult, the following
methanolysis step was achieved from the diastereomeric mixture
to give the (R)-3 and (S)-3 methyl esters in 85% yield. A
partial epimerization of the C-2 centre of 3 occurred during this
transformation to give (R)-3 and (S)-3 as a 67 : 33 diastereomeric
mixture. The epimerization of a similar trifluoroalanine ester
through its enol form due to the high C–H acidity has already been
reported in the literature.13 In order to save a tedious separation,14
the diastereomeric (R)-3 and (S)-3 mixture was engaged in the
lithium aluminium hydride reduction step. At this stage the
expected amino diols 4 were conveniently separated by silica gel
chromatography to give (R)-4 and (S)-4 in 60% and 25% isolated
yield respectively.
Universite´ de Cergy-Pontoise, Laboratoire SOSCO, F-95000, Cergy-
Pontoise, France. E-mail: thierry.brigaud@u-cergy.fr; Fax: +33 (0)1 34
25 70 71; Tel: +33 (0)1 34 25 70 66
Although the Strecker pathway was efficient for the preparation
of diastereomerically pure amino alcohols 4, which are precursors
of the target enantiopure trifluoroalaninols, we investigated a more
direct route involving the reduction of imine and oxazolidines. The
chiral imine 5 and the diastereomeric mixture of oxazolidines 6
† This publication is part of the web themed issue on fluorine chemistry
‡ Electronic supplementary information (ESI) available: Procedures, syn-
thesis and characterization data of products 2–7, copies of 1H, 13C and19F
NMR spectra of compounds 3, 4 and 7. See DOI: 10.1039/c0ob00424c
4540 | Org. Biomol. Chem., 2010, 8, 4540–4542
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Scheme 4 The imine 5 reduction pathway for the synthesis of the amino
diols (S)-4 and (R)-4.
Table 1 The oxazolidine 6 reduction pathway for the synthesis of the
amino diols (R)-4 and (S)-4
Entry
Starting material
Yield of 4a
(R)-4/(S)-4 drb
1
2
3
6maj
6min
95
79
84c
72 : 28
50 : 50
69 : 31
6
maj/6min (83 : 17 dr)
Scheme 2 The Strecker pathway for the synthesis of the amino diols (R)-4
and (S)-4.
a Isolated yield. b Measured by 19F and 1H NMR. c After silica gel
separation, (R)-4 was isolated in 60% yield and (S)-4 was isolated in 24%
yield.
were conveniently prepared from ethyltrifluoropyruvate and (R)-
phenylglycinol according to our previously reported procedures
(Scheme 3).7,15–17 The main advantage of these intermediates is
that they already include the three carbon atoms of the target
trifluoroalaninols.18 It should be noticed that the imine 5 was
obtained in high yield (92%) without formation of haloform type
decomposition products frequently observed during the reaction
of trifluoropyruvate esters and amines.19
the diastereomerically pure 6 major diastereomer, (R)-4 and (S)-
4 were obtained in 95% yield as a 72 : 28 diastereomeric mixture
(Table 1, entry 1). Starting from the minor 6 diastereomer, (R)-4
and (S)-4 were obtained in 79% yield with a 50 : 50 diastereomeric
ratio (Table 1, entry 2). These results suggest that the reductions
of the oxazolidines 6 are not stereoselective. It is thus useless to
isolate both oxazolines 6 before the LAH reduction. Therefore
the reduction was performed on a 83 : 17 distereomeric mixture
of 6 to give the amino diols (R)-4 and (S)-4 in 84% yield as
a 69 : 31 diastereomeric mixture (Table 1, entry 3). The two
diastereomers were easily separated by silica gel chromatography
and diastereomerically pure (R)-4 and (S)-4 were obtained in 60%
and 24% isolated yield respectively. As for the Strecker pathway
and in contrast to the imine 5 reduction, the (R)-4 diastereomer
was the major.
The last step towards the synthesis of the enantiopure trifluo-
roalaninol was the removal of the (R)-phenylglycinol side chain of
(R)-4 and (S)-4 using the palladium catalyzed hydrogenolysis. This
reaction was performed in acidic medium in order to avoid the de-
activation of the Pearlman’s catalyst. Finally, the two enantiomers
of the targeted trifluoroalaninol 7 were conveniently isolated
in good yields as their hydrochloride salts (Scheme 5). As the
hydrogenolysis reactions were carried out from diastereomerically
pure isolated amino diols (R)-4 and (S)-4, the corresponding
trifluoroalaninols were likely to be enantiomerically pure.20 This
was confirmed by comparison of their optical rotations with
literature data.21
Scheme 3 Synthesis of ethyl trifluoropyruvate-based imine 5 and oxazo-
lidines 6.
The treatment of the imine 5 with lithium aluminium hydride
afforded the aminodiols (S)-4 and (R)-4 as a 72 : 28 diastereomeric
mixture in 73% yield. Under these conditions both the imine
and the ester function are reduced and we observe a complete
desilylation to yield (S)-4 as the major diastereomer (Scheme 4). In
contrast to the Strecker pathway giving the major (R) diastereomer
(Scheme 2), the major aminodiols obtained by reduction of the
imine 5 was the (S) one. This result is consistent with a major re
face attack of the imine 5.
In a similar manner, the treatment of oxazolidine 6 with lithium
aluminium hydride yielded the two amino diols (R)-4 and (S)-
4. The diastereomeric ratio of (R)-4 and (S)-4 were dependant
of the starting oxazolidines 6 diastereomeric ratio. Starting from
Conclusions
In conclusion, we developed two routes for the synthesis of both
enantiomers of trifluoroalaninol in enantiopure form starting
from (R)-phenylglycinol derived fluorinated oxazolidines (Fox) or
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Scheme 5 The synthesis of enantiopure (R)- and (S)-trifluoroalaninols.
imines. The first route relies on a Strecker type reaction whereas the
more straightforward second one uses ethyl trifluoropyruvate as
fluorinated starting material. The convenient separation of the two
diastereomers of the common intermediate amino diol 4 ensures
the achievement of trifluoroalaninols in enantiopure form. These
two routes use common and cheap reactants and can be scaled up
to gram quantities.
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4542 | Org. Biomol. Chem., 2010, 8, 4540–4542
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