Highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids from chiral imines of trifluoropyruvate

Article abstract of DOI:10.1039/c0cc02408b

An efficient method for highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids was developed via indium mediated allylation of (R)-phenylglycinol methyl ether based imines of trifluoropyruvate in good yields with high diastereos

Full text of DOI:10.1039/c0cc02408b

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Highly diastereoselective synthesis of quaternary a-trifluoromethyl
a-amino acids from chiral imines of trifluoropyruvatewz
Qiao-Qiao Min,b Chun-Yang He,a Haibing Zhoub and Xingang Zhang*a
Received 7th July 2010, Accepted 1st September 2010
DOI: 10.1039/c0cc02408b
An efficient method for highly diastereoselective synthesis of
quaternary a-trifluoromethyl a-amino acids was developed via
indium mediated allylation of (R)-phenylglycinol methyl ether
based imines of trifluoropyruvate in good yields with high
diastereoselectivities at room temperature; to illustrate the
application of this method in organic synthesis, 2-allyl-2-(tri-
fluoromethyl) aziridine was prepared in an efficient manner.
construction of quaternary chiral center with a CF3 group
still poses a significant synthetic challenge.
Herein, we disclose a new and effective method for highly
diastereoselective synthesis of quaternary a-allyl a-Tfm-AAs
through the coupling of allylindium generated in situ with
chiral imines of trifluoropyruvate at room temperature in
moderate to excellent yields with high diastereoselectivities
(dr = 18 : 1 to single), which provides a useful and operationally
convenient protocol to a series of non-racemic quaternary
a-Tfm-AAs and related derivatives. Actually, due to its
relatively low reduction potential, indium is a selective reagent,
and differs from most other elements (zinc, magnesium and tin)
used as reagents in Barbier-type additions.8 As a result, the
employment of indium promotes the allylation of chiral
ketimines under mild conditions without specific activation
and pre-paration of allylindium. As far as we know, this is the
first example of stereoselective addition of allyindium to
ketimines.9
Fluorine-containing amino acids possess enormous potential
for practical applications, and the related chemistry is a
developing area of interdisciplinary interest.1 In particular,
a-trifluoromethyl a-amino acids (a-Tfm-AAs), a type of
quaternary a-amino acids,2 are promising pharmaceutical
candidates and powerful bioorganic tools because they could
greatly influence the bioavailability of peptides by improving
enzymatic stability and enhancing the lipophilicity which
promotes permeability through the body barriers.3 In
addition, CF3 has been used as a reporting group for in vivo
studies through 19F NMR.4 Hence, to develop an efficient
method to prepare this type of valuable fluorinated amino
acids is of great importance.
Initially, we started the synthesis of nonracemic quaternary
a-allyl a-Tfm-AAs by coupling of allylindium, generated
in situ by allyl bromide 2a and In(0), with chiral imino ester
1a in which the (R)-phenylglycinol methyl ether was used as
chiral auxiliary due to its low expense and commercial
availability. In addition, it has been demonstrated that indium
can chelate well with N/O atoms in ligands;9d thus, we
envisioned that a rigid chelated transition state might be
formed when (R)-phenylglycinol methyl ether was used as
the chiral auxiliary, and as a result a high diastereoselectivity
would be observed (eqn (1)).
To the best of our knowledge, so far only a few synthetic
methods to prepare non-racemic quaternary a-Tfm-AAs have
been described and they are all based on chiral auxiliaries.1a,5
Especially for the asymmetric synthesis of a-allyl a-Tfm-AAs,
an important building block to prepare various a-Tfm-AAs
derivatives by simple functionalization of alkene moiety,1a
only two examples have been reported to date, with dr values
ranging from 1.9 : 1 to 5.7 : 1.6 Recently, another example of
highly diastereoselective synthesis of a-allyl b,b-difluorinated
quaternary a-amino acids has been reported via the addition
of pre-prepared allylzinc bromide to chiral difluorinated imino
esters at low temperature (ꢀ40 1C).7 From the viewpoint of
synthetic convenience, however, the reaction carried out at
room temperature without pre-requirement of preparation of
moisture-sensitive allylmetal reagents would be more useful
for general organic synthesis. Therefore, despite the progress
in asymmetric synthesis, the highly stereoselective
ð1Þ
Although it has been demonstrated that the reactions of
trifluoropyruvate esters with amines result in substantial
amounts of haloform type decomposition products,10 the
preparation of imino ester 1a by condensation of ethyl tri-
fluoropyruvate with (R)-phenylglycinol methyl ether in the
presence of catalytic amount of PPTS still afforded 88% yield.
Imino esters 1b–e were prepared according to Uneyama’s
procedure,11 due to the fact that the corresponding trifluoro-
pyruvates of 1b–e are not commerically available (see ESIz).
To our delight, after a survey of the reaction conditions, we
found that the reaction carried out with 1a (1.0 equiv.), 2a
(2.2 equiv.), and In (2.0 equiv.) in THF at room temperature for
19 h provided 3a in excellent yield (98%) with high diastereo-
selectivity (dr >20 : 1) (Table 1, entry 1). Under the standard
reaction conditions, the indium-mediated coupling of 2a with
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China. E-mail: xgzhang@mail.sioc.ac.cn;
Fax: (+86)-21-6416-6128; Tel: (+86)-21-5492-5333
b State Key Laboratory of Virology, College of Pharmacy, Wuhan
University, Wuhan, 430071, China
w This publication is part of the web themed issue on fluorine
chemistry.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures, analytical data for all new compounds and
crystallographic data for 4j (CIF). CCDC 782838. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc02408b
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8029–8031 8029

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Table
1
Indium-mediated diastereoselective coupling of allylic
Table
2
Indium mediated diastereoselective coupling of allylic
bromide 2 with chiral imino ester 1a
bromide 2 with imino ester 1a
a
Reaction was carried out with 1a (0.30 mmol), 2a (0.66 mmol) and
In (0.6 mmol) in THF (3 mL) at rt. b Isolated yield. c Determined by
19F NMR before column chromatography. d Using 2.8 equiv. In and
3.2 equiv. of 2f
diastereoisomers were observed (Table 2, entry 1). However,
for substrate 2f containing an electron-withdrawing ester
group, 60% yield of 3k with high diastereoselectivity were
afforded under standard conditions (Table 3, entry 3). The
resulting moderate yield of 3k is probably due to the low
reactivity of 2f.
a
Reaction was carried out with 1a (0.30 mmol), 2a (0.66 mmol) and In
(0.6 mmol) in THF (3 mL) at rt. b Isolated yield. c Determined by 19F
NMR before column chromatography.
The absolute configurations of a-allyl a-Tfm-AAs 3 were
1
assigned by comparing H and 13C NMR of (3R,5R)-4b with
different imino esters 1b–e were tested (Table 1, entries 2–4).
Excellent yields (94–98%) and high diastereoselectivities ranging
from 18 : 1 to >20 : 1 were obtained for 2-trimethylsilylethyl
(TMSE), allyl and propargyl imino esters 1b–d (Table 1, entries
2–4). A moderate yield (45%) was obtained for benzyl imino
ester 1e, but high dr value was still observed (Table 1, entry 5),
suggesting that the steric effect plays a minor role in diastereo-
selectivity. It is noteworthy that these functional groups, TMSE,
allyl and propargyl, in a-Tfm-AAs 3b–e can subsequently be
applied for further functionalization, providing opportunities to
access diverse a-Tfm-AAs derivatives. Gratifyingly, branched
allyl bromide 2b underwent reaction smoothly and provided
the desired products in high yields with excellent diastereo-
literature.6b This was further confirmed by X-ray crystallo-
graphic analysis of optically pure 4j (see ESIz). As depicted in
Scheme 1, (3R,5R)-4b was synthesized from 3b (dr >20 : 1) in
two steps (88% overall yield) and 4j was prepared from 3j in a
similar way. Interestingly, this R configuration generated
through our method by the addition of allyindium to 1 is
different from Brigaud’s method,6b in which an opposite S
configuration was observed as the major product. Probably,
different transition states were involved in these two reactions,
as a result the different stereoselectivities were observed.12
The high diastereoselectivity of the reaction may be
explained by the coordination of indium with substrates in a
highly restricted chair transition state in which R3 is at the
energy favored equatorial position, and indium coordinates
selectivities (Table 1, entries
6 and 7). Moreover, ethyl
2-(bromomethyl)acrylate 2c also worked well in high efficiency
and diastereoselectivity, thus allowing for further transformation
through Michael addition (Table 1, entry 8).
Most importantly, 1-substituted linear allyl bromides 2d–f
were also suitable substrates for the coupling of imino ester 1a,
and moderate to high yields with high diastereoselectivities
were also provided (Table 2). To the best of our knowledge,
there is no report related to diastereoselective construction of
two contiguous quaternary and tertiary stereocenters in a-allyl
a-Tfm-AAs; the results in Table 2 represent the first three
examples of this type. The yields and diastereoselectivities of
the reactions depend on the nature of the group R3. The bulky
group, such as phenyl, afforded 3j in high yield with single
isomer (Table 2, entry 2); while a smaller group, such as
methyl, provided 3i in good yield with high dr value, but four
Scheme 1 Synthesis of (3R,5R)-4b and 4j.
c
8030 Chem. Commun., 2010, 46, 8029–8031
This journal is The Royal Society of Chemistry 2010

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Scheme 3 Synthesis of optically active quaternary (R)-a-Tfm-Leu 5
and aziridine 7.
with CQN and MeO of imine and carbonyl group of ester,
which induces the allylindium to attack the steric less hindered
Si face of imino ester to generate R (R3 = H) or R,R
(R3 = Ph, CO2Et) or R,S (R3 = Me) configuration stereo-
selectively (Scheme 2).
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The chiral auxiliary in 3 could be efficiently removed by
hydrogenolysis. As shown in Scheme 3 eqn (1), hydrogenation
of 3g in the presence of Pd(OH)2/C afforded enantioenriched
(R)-a-Tfm-Leu 5 in 80% yield. From the viewpoint of
synthetic application of 3, a versatile synthetic building block,
2-allyl-2-(trifluoromethyl)aziridine 7 was easily prepared via
two steps from 3a in high yield (89% overall yield, two steps)
(Scheme 3 eqn (2)). To our knowledge, there have been no
existing catalytic asymmetric aziridination protocols13 that
can access this important optically active structure so far.
In conclusion, we developed an effective and operationally
convenient method for highly diastereoselective synthesis of
quaternary a-Tfm-AAs through indium-mediated allylation of
(R)-phenylglycinol methyl ether based imines of trifluoro-
pyruvate in good yields with high diastereoselectivities at room
temperature without pre-requirement of preparation of moisture
sensitive allylmetal reagents.
8 For reviews, see: (a) J. Auge, N. Lubin-Germain and J. Uziel,
´
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The NSFC (Nos 20852003 and 20902100), the Shanghai
Rising-Star Program (09QA1406900) and SIOC are greatly
acknowledged for funding this work.
10 H. Ohkura, D. O. Berbasov and V. A. Soloshonok, Tetrahedron,
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11 H. Amii, Y. Kishikawa, K. Kageyama and K. Uneyama, J. Org.
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Notes and references
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and B. Koksch, Chem. Soc. Rev., 2008, 37, 1727; (b) T. Brigaud,
G. Chaume, J. Pytkowicz and F. Huguenot, Chim. Oggi, 2007, 25,
8; (c) X.-L. Qiu, W.-D. Meng and F.-L. Qing, Tetrahedron, 2004,
60, 6711; (d) M. Zanda, New J. Chem., 2004, 28, 1401. For selected
papers, see: (e) P. Bravo, A. Farina, V. P. Kukhar,
A. L. Markovsky, S. V. Meille, V. A. Soloshonok,
12 For the proposed transition state of Brigaud’s method, please
see ESIz.
13 (a) Y. Yamauchi, T. Kawate, H. Itahashi, T. Katagiri and
K.
Uneyama,
Tetrahedron
Lett.,
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44,
6319;
(b) Y. Yamauchi, T. Kawate, T. Katagiri and K. Uneyama,
Tetrahedron, 2003, 59, 9839.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8029–8031 8031