Asymmetric synthesis of quaternary α-amino acid derivatives and their fluorinated analogues

Article abstract of DOI:10.1007/s00726-011-0881-7

In this work, we describe the asymmetric synthesis of a series of fluorinated and non-fluorinated quaternary α-amino acid derivatives. This methodology involves the diastereoselective addition of chiral 2-p-tolylsulfinyl benzylcarbanions to either imines containing a 2-furyl moiety or trifluoromethyl α-imino esters. Synthetic practicality of this method is demonstrated by short (two-steps) and convenient preparation of 2-(trifluoromethyl)indoline-2-carboxylates.

Full text of DOI:10.1007/s00726-011-0881-7

Amino Acids (2011) 41:559–573
DOI 10.1007/s00726-011-0881-7
ORIGINAL ARTICLE
Asymmetric synthesis of quaternary a-amino acid derivatives
and their fluorinated analogues
•
Santos Fustero Marıa Sanchez-Rosello
•
´
´
Claribel Baez Carlos del Pozo Jose L. Garcıa Ruano
´
•
•
•
´
´
Jose Aleman Leyre Marzo Alejandro Parra
´
•
•
´
´
Received: 25 January 2011 / Accepted: 4 March 2011 / Published online: 22 March 2011
Ó Springer-Verlag 2011
Abstract In this work, we describe the asymmetric
synthesis of a series of fluorinated and non-fluorinated
quaternary a-amino acid derivatives. This methodology
involves the diastereoselective addition of chiral 2-p-tol-
ylsulfinyl benzylcarbanions to either imines containing a
2-furyl moiety or trifluoromethyl a-imino esters. Synthetic
practicality of this method is demonstrated by short
(two-steps) and convenient preparation of 2-(trifluoro-
methyl)indoline-2-carboxylates.
It is well known that conformational changes in the
chains of peptides and proteins provoke significant altera-
tions in their secondary and tertiary structures, seriously
affecting their properties. In this sense, the synthesis and
incorporation of non-natural amino acids into peptidic
´
chains has been extensively studied (Felix 2004). Specifi-
cally, a,a-disubstituted quaternary a-amino acids (Fig. 1b)
are important since they increase the stability of proteins
and restrict their conformational flexibility, giving rise to
peptidomimetics with higher resistance against proteases as
well as increased levels of lipophilicity and bioavailability.
For these reasons, the development of efficient methodol-
ogies for the asymmetric synthesis of these type of amino
acids has attracted a great deal of interest in organic syn-
Keywords Asymmetric synthesis ꢀ Sulfinylcarbanion ꢀ
a,a-Disubstituted (quaternary)-a-amino acids ꢀ a,b-Dialkyl-
a-amino acids ꢀ Trifluoromethylated a-amino acids ꢀ
Sterically constrained amino acids
´
thesis (Cativiela and Dıaz-de-Villegas 1998, 2000; Park
¨
and Kurth 2002; Ohfune and Shinada 2005; Vogt and Brase
´
2007; Najera and Sansano 2007; Soloshonok and Soro-
Introduction
chinsky 2010).
a-Amino acids play a central role in biochemistry and are
essential for life. Indeed, they are the building blocks of
biologically relevant molecules, such as peptides and pro-
teins, among many others.
However, the synthesis of even more constrained amino
acids bearing additional chiral centers and their incorpo-
ration into peptides have been less explored (Balaram and
Ramaseshan 1991; Hruby et al. 1997; Gibson et al. 1999;
Abell 1999; DeGrado 2001), particularlya,b-dialkyl-a-
amino acids (Fig. 1c) which would permit the control of
the dihedral angles /, w and x, hence allowing for the
organization of amino acid chains by controlling the tor-
sional angles and the position of the side-chains (Solos-
honok 2002). Despite their potential, there are only a few
reports concerning the synthesis of these compounds in
enantiomerically pure form, thus their biological studies
are seriously limited (Soloshonok et al. 2001; Qiu et al.
2000).
´
S. Fustero ꢀ C. Baez ꢀ C. del Pozo
´
Departamento de Quımica Organica, Universidad de Valencia
Burjassot, 46100 Valencia, Spain
´
´
´
S. Fustero (&) ꢀ M. Sanchez-Rosello
´ ´ ´
Laboratorio de Moleculas Organicas, Centro de Investigacion
´
Prıncipe Felipe, 46012 Valencia, Spain
e-mail: santos.fustero@uv.es; sfustero@cipf.es
´
´
J. L. Garcıa Ruano (&) ꢀ J. Aleman ꢀ L. Marzo ꢀ A. Parra
Soloshonok et al. (2008) described the preparation of
a,b-dialkyl-a-amino acids by using chiral Nickel (II)
complexes, although with low diastereoisomeric ratio in
´
Departamento de Quımica Organica (C-I), Universidad
Autonoma de Madrid, Cantoblanco 28049 Madrid, Spain
´
´
e-mail: joseluis.garcia.ruano@uam.es
123

560
S. Fustero et al.
R5
R6
Fig. 1 Standard and modified
peptidic chains
(a)
(b)
(c)
O
O
*
R3
O
O
O
R4
R2
O
R4
H
N
H
N
H
N
N
H
N
H
N
H
N
N
N
R1
R2 *
H
R1 R2
H
H
R1
O
O
O
R3
Modified peptide bearing
quaternary -amino acids
Modified peptide bearing
α,β−dialkyl-α-amino acids
Standard peptidic chain
α
most cases. In addition, several organocatalytic approaches
substituted, spurred our interest in the development of a
new strategy for their asymmetric synthesis, as well as in
fluorine-containing derivatives. This new approach would
be based on the methodology previously developed by our
research groups involving the reaction of 2-(p-tolylsulfinyl)
benzylcarbanions with aldimines and ketimines, which
took place with almost complete control of the configura-
tion at the two adjacent stereogenic centers simultaneously
by addition of azlactones to a,b-unsaturated aldehydes
´
(Cabrera et al. 2008) or nitroalkenes (Aleman et al. 2008)
have been described in the last 2 years.
On the other hand, the presence of fluorine atoms in
a-amino acids often induces significant changes in the
physical properties, biological activities and metabolic
profiles of the peptides containing them (Kukhar 2009;
´
created (Garcıa Ruano et al. 2003, 2005a, b, c).
¨
Sorochinsky and Soloshonok 2010; Jackel and Kocksch
2005; Qiu et al. 2004; Purser et al. 2008; Mu¨ller et al.
2007). Thus, fluorinated amino acids have recently
emerged as valuable building blocks for designing hyper-
stable protein folds as well as for directing highly specific
We hypothesized that N-protected imines containing a
2-furyl moiety [one of the most classical ways to mask the
acid functionality is the use of the furan ring (Kobayashi
et al. 1997; Fustero et al. 2008a, b, c; Hasbullah and Jones
2010)] could react with benzylcarbanions stabilized by a
remote p-tolylsulfinyl group in order to obtain a,a-disub-
stituted-a-amino acid derivatives. We would also be able to
obtain a,b-dialkyl-a-amino acids by choosing the appro-
priate sulfinylbenzylcarbanion. In this manner, the stereo-
chemistry at the quaternary a-amino acid stereocenter and
the benzylic one could be controlled in a single step.
In this paper, we report the results obtained in the
reaction of 2-p-tolylsulfinyl benzylcarbanions derived from
1 with N-p-tolylsulfinylimines and N-p-methoxyphenyl
(PMP) fluorinated imines 2 bearing a 2-furyl substituent.
The application of these reactions to the preparation of
enantiomerically pure quaternary a-amino acid derivatives
through the oxidative elaboration of the furan ring is also
described (Fig. 2).
¨
protein–protein interactions (Jackelet al. 2004; Hodges
and Raines 2005; Golbiket al. 2005). Moreover, some
a-trifluoromethyl a-amino acids exhibit anticancer, anti-
bacterial and antihypertensive properties and also the
ability of acting as suicide inhibitors of pyridoxalpho-
sphate-dependent enzymes (Sewald et al. 1994; Asensio
¨
et al. 2001; Jackel and Kocksch 2005; Qiu et al. 2004;
Purser et al. 2008; Mu¨ller et al. 2007).
In this context, we described the asymmetric synthesis
of a particular class of a,b-dialkyl-a-amino acids a few
years ago. Specifically, we developed a method for the
asymmetric synthesis of cyclic b,b-difluorinated-a-amino
acid derivatives bearing a quaternary stereocenter. The
process relied on the chemo- and diastereoselective addi-
tion of allylic organometallic reagents to fluorinated
a-imino esters followed by a ring closing metathesis
reaction. We were able to achieve complete selectivity in
the nucleophilic addition when (R)-phenylglycinol methyl
ether was employed as chiral auxiliary (Fustero et al. 2006,
2008a, b, c).
Materials and methods
NMR spectra were obtained on a Bruker 300 spectrometer,
1
The above-mentioned biological relevance of a,a-
disubstituted a-amino acids, in particular those a,b-dialkyl-
running at 300 and 75 MHz for H and 13C, respectively.
Chemical shifts (d) are reported in ppm relative to residual
Fig. 2 Initial proposal for the
synthesis of a,a-disubstituted-a-
amino acids
PG
N
O
R2
R2
*
R1
R2
*
R1
NH-PG
O
NH-PG
CO2H
*
SOTol
R1
2
*
TolOS
LDA
3
1
α
quaternary -amino acids
R1 = H, Me, Bn, Allyl
R2 = H, Me, CF3
123

Asymmetric synthesis of quaternary a-amino acid derivatives and their fluorinated analogues
561
1
solvent signals (CHCl3, 7.26 ppm for H NMR, CDCl3,
77.0 ppm for 13C NMR). 13C NMR spectra were acquired
on a broad-band decoupled mode. Optical rotations were
measured by a Perkin–Elmer 241 polarimeter. All reactions
were carried out in anhydrous solvents and under argon
atmosphere. THF and Et2O were distilled from sodium-
benzophenone under argon, and CH2Cl2 was distilled from
P2O5. Flash column chromatography was performed using
silica gel Merk-60 (230–400 mesh). n-BuLi (2.5 M solu-
tion in hexanes) was purchased from Aldrich.
(dd, J = 1.5, 7.6 Hz, 1H), 7.50–7.47 (m, 2H), 7.39 (dd,
J = 1.3, 7.6 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.26, (d,
J = 1.1 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.82 (d, J =
8.0 Hz, 2H), 6.63 (d, J = 8.1 Hz, 2H), 6.15 (dd, J = 1.9,
3.2 Hz, 1H), 5.98 (d, J = 3.2 Hz, 1H), 4.38 (dd, J = 8.9,
10.8 Hz, 1H), 3.79 (d, J = 8.8 Hz, 1H), 3.68 (dq, J = 10.9,
6.8 Hz, 1H), 2.26 (s, 3H), 2.11 (s, 3H), 0.84 (d, J = 6.8 Hz,
3H). 13C NMR (CDCl3, 75 MHz): d 153.7, 143.1, 142.7,
141.8, 141.7, 141.6, 141.2, 140.5, 131.9, 129.7, 128.9 m
127.6 m 127.4, 126.0, 125.9, 125.3, 110.2, 107.6, 57.3, 38.4,
21.2, 21.1, 19.4. MS (ESI?): [M ? Na]?calcd for
C27H27NO3S2Na 500.1324; found 500.1306.
Commercially available starting materials and solvents
were used without further purification. Sulfoxides 1
´
(Garcıa Ruano et al. 2003, 2005a, b, c), imines (S)-2a
(Jiang et al. 2005), (S)-2b (Leverett et al. 2006) and (S)-2d
N-{(2S,3S)-2-(Furan-2-yl)-3-[2-((S)-(p-tolylsulfinyl)
phenyl]butan-2-yl}(S)-p-tolylsulfinamide (3b)
´
´
(Garcıa Ruano et al. 2008), addition product 3g (Garcıa
Ruano et al. 2008) and trifluoromethyl a-imino ester 8
(Watanabe et al. 1982a, b) had previously been described.
By means of the general procedure described above,
compound 3b was obtained as yellow oil in 51% yield.
[a]2D0 = ?44.8 (c 1.0, CH2Cl2). 1H NMR (CDCl3,
300 MHz): d 7.70 (dd, J = 1.5, 7.6 Hz, 1H), 7.52 (dt,
J = 1.4, 7.5 Hz, 1H), 7.45–7.39 (m, 2H), 7.32 (d, J =
7.8 Hz, 1H), 7.25 (d, J = 9.4 Hz, 2H), 7.07, (d,
J = 8.5 Hz, 4H), 6.94 (d, J = 8.2 Hz, 2H), 6.30 (dd,
J = 1.9, 3.3 Hz, 1H), 6.24 (d, J = 3.3 Hz, 1H), 5.99 (s,
1H), 4.09 (q, J = 7.0 Hz, 1H), 2.33 (s, 3H), 2.27 (s, 3H),
1.73 (s, 3H), 0.72 (d, J = 7.1 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 158.4, 143.9, 143.5, 143.0, 141.7, 140.8,
140.3, 131.8, 130.0, 129.6, 129.1, 128.9, 127.1, 125.7,
125.1, 110.3, 106.7, 60.0, 41.8, 21.3, 18.1, 15.9.MS (ESI?):
[M ? H]?calcd for C28H30NO3S2 492.1667; found
492.1653.
(S)-4-Methyl N-(2,2,2-trifluoro-1-(furan-2-yl)
ethylidene) benzenesulfinamide [(S)-2c]
[a]2D5 = ?146.3 (c 1.0, CHCl3).1H NMR (CDCl3,
300 MHz): d 7.86 (dd, J = 0.6, 1.7 Hz, 1H), 7.76 (dd,
J = 1.7, 6.6 Hz, 2H), 7.33–7.28 (m, 3H), 6.68 (dd, J = 1.9,
3.8 Hz, 1H), 2.40 (s, 3H). 13C NMR (CDCl3, 75 MHz):
2
d 148.9, 146.1 (q, JCF = 35.7 Hz), 144.0, 142.9, 142.8,
4
1
130.0, 125.4, 121.9 (q, JCF = 2.9 Hz), 118.7 (q, JCF
=
281.2 Hz), 113.5, 21.5. 19F NMR (CDCl3, 282.4 MHz):
d -66.94 (s, 3F). HRMS (EI?): m/z calcd for C13H10F3NO2S
[M]?301.0384, found: 301.0389.
General procedure for the synthesis of addition
products 3 and 9
N-{(2S)-2-(Furan-2-yl)-1-[2-((S)-(p-tolylsulfinyl)
phenyl]propan-2-yl}(S)-p-tolylsulfinamide(3c/3c0)
A solution of n-BuLi (0.49 mmol, 2.5 M in hexane) was
added dropwise to i-Pr2NH (0.74 mmol) in THF (2 mL) at
0°C. After stirring for 10 min, the mixture was cooled at
–78°C and then a solution of sulfoxide 1 (0.41 mmol) in
THF (2 mL) was added. After 10 min, the corresponding
imine (2 or 8) (0.45 mmol) dissolved in THF (2 mL) was
added at –78°C. When the reaction was completed (the
reaction was followed by TLC), the mixture was hydro-
lyzed (2 mL aqueous saturated NH4Cl), extracted
(3x10 mL Et2O), washed (2 9 10 mL NaCl sat), dried
(MgSO4) and the solvent evaporated. The residue was
purified by flash column chromatography.
By means of the general procedure described above,
compounds 3c/3c0 were obtained as yellow oil in 50% yield
and a 60:40 mixture of diastereoisomers. Minor diaste-
1
reoisomer: H NMR (CDCl3, 300 MHz): d 7.79–6.88 (m,
13H), 6.38 (d, J = 1.9 Hz, 1H), 6.22 (d, J = 3.1 Hz, 1H),
4.75 (s, 1H), 4.05 (d, J = 17.2 Hz, 1H), 3.89 (d,
J = 17.2 Hz, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 2.11 (s, 3H).
13C NMR (CDCl3, 75 MHz): d 155.5, 145.0, 143.0, 142.4,
142.0, 140.9, 134.7, 131.7, 131.5, 130.5, 130.0, 130.0,
128.2, 126.7, 125.8, 125.7, 110.7, 108.7, 59.0, 46.6, 29.7,
5.1, 21.3. Major diastereoisomer: 1H NMR (CDCl3,
300 MHz):
d 7.90 (d, J = 7.9 Hz, 1H), 7.55 (d,
N-{(1S,2S)-1-(Furan-2-yl)-2-[2-((S)-(p-tolylsulfinyl)
phenyl]propyl} (S)-p-tolylsulfinamide(3a)
J = 8.1 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.44 (d, J =
8.3 Hz, 2H), 7.37 (t, J = 6.9 Hz, 1H), 7.27 (d, J = 6.8 Hz,
2H), 7.20 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 7.6 Hz, 1H),
6.35 (dd, J = 1.7, 3.1 Hz, 1H), 6.15 (d, J = 3.1 Hz, 1H),
4.80 (s, 1H), 3.51 (d, J = 13.6 Hz, 1H), 3.32 (d,
J = 13.6 Hz, 1H), 2.39 (s, 3H), 2.33 (s, 3H), 1.88 (s, 3H);
By means of the general procedure described above, com-
pound 3a was obtained as yellow oil in 82% yield. [a]D20
=
-37.0 (c 0.5, CH2Cl2). 1H NMR (CDCl3, 300 MHz): d 7.98
123

562
S. Fustero et al.
13C NMR (CDCl3, 75 MHz): d 155.0, 144.9, 142.9, 142.2,
141.8, 141.6, 141.3, 134.2, 131.5, 130.5, 130.0, 129.6,
128.2, 125.6, 125.5, 124.8, 110.7, 109.1, 59.5, 43.7, 24.7,
21.5, 21.4. MS (TOF ES?): [M ? Na]?calcdfor
C27H27NO3S2Na500.1324; found 500.1320.
7.37(dd, J = 1.3, 7.5 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H),
7.10 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 7.9 HZ, 2H), 6.95 (d,
J = 8.2 Hz, 2H), 6.36 (dd, J = 1.8, 3.3 Hz, 1H), 6.30 (dd,
J = 0.8, 3.3 Hz, 1H), 60.70 (s, 1H), 4.57–4.34 (m, 4H),
4.11–4.06 (m 2H), 2.37 (s, 3H), 2.30 (s, 3H), 1.75 (s, 3H).
13C NMR (CDCl3, 75 MHz): d 158.3, 144.3, 142.9, 141.7,
141.4, 140.3, 134.7, 131.5, 129.9, 129.7, 129.0, 128.7,
127.1, 125.7, 125.4, 116.2, 110.4, 106.9, 59.8, 47.1, 35.5,
21.3, 21.3, 18.2.MS (TOF ES?): [M ? H]?calcd for
C30H32NO3S2518.1824; found 518.1830.
N-{(2R,3S)-2-(Furan-2-yl)-3-[2-((S)-p-tolylsulfinyl)
phenyl]butan-2-yl}(R)-p-tolylsulfinamide (Epi-3b)
By means of the general procedure described above, com-
pound epi-3b was obtained as yellow oil in 46% yield.
[a]2D0 = -13.3 (c 0.8, CH2Cl2). 1H NMR (CDCl3,
300 MHz): d 7.51–7.47 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H)
7.38 (dd, J = 1.4,7.5 Hz, 1H), 7.32 (dd, J = 1.4, 7.6 Hz,
1H), 7.26 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H),
7.19 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.03 (d,
J = 7.7 Hz, 1H), 6.40 (dd, J = 1.9, 3.3 Hz, 1H), 6.37 (d,
J = 3.2 Hz, 1H), 5.00 (s, 1H), 4.28 (q, J = 7.1 Hz, 1H),
2.36 (s, 3H), 2.35 (s, 3H), 1.68 (s, 3H), 1.04 (d, J = 7.1 Hz,
3H) 13C NMR (CDCl3, 75 MHz): d 156.2, 144.2, 143.2,
142.9, 142.3, 14.9, 140.8, 140.3, 131.7, 129.7, 129.6, 129.4,
128.4, 127.8, 125.5, 125.4, 110.3, 109.5, 61.6 (2C), 22.2,
21.3 (2C), 17.3.MS (TOF ES?): [M ? H]?calcd for
C28H30NO3S2 492.1667; found 492.1671.
4-Methoxy-N-[(2S)-1,1,1-trifluoro-2-(furan-2-yl)-3-(2-(S)-
(phenylsulfinyl)phenyl)propan-2-yl) aniline (3f)
By means of the general procedure described above,
compound 3f was obtained as yellow oil in 73% yield.
[a]2D5 = ?28.9 (c 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): d 7.69 (dd, J = 1.3, 7.7 Hz, 1H), 7.30–7.26 (m,
4H), 7.15–7.13 (m, 3H), 6.52–6.45 (m, 4H), 6.32 (dd,
J = 1.7, 3.4 Hz, 1H), 6.27–6.24 (m, 2H), 5.90 (br s, 1H),
3.61 (d, J = 14.0 Hz, 1H), 3.58 (s, 3H), 3.00 (d,
J = 13.9 Hz, 1H), 2.27 (s, 3H). 13C NMR (CDCl3,
75 MHz): d 153.0, 148.4, 143.8, 142.2, 140.9, 140.9,
138.4, 134.4, 133.7, 131.2, 129.9, 128.3, 128.1, 128.0 (q,
1JCF = 292.1 Hz), 124.7, 118.4, 113.8, 111.2, 110.8, 64.6
2
N-{(2S,3S)-2-(Furan-2-yl)-3-[2-(methylsulfinyl) phenyl]-4-
benzylbutan-2-yl}(S)-p-tolylsulfinamide (3d)
(q, JCF = 26.0 Hz), 55.4, 36.8, 21.2. 19F NMR (CDCl3,
282.4 MHz): d -81.96 (s, 3F). HRMS (EI?): m/z calcd for
C27H25F3NO3S [M ? H]?500.1507, found: 500.1505.
By means of the general procedure described above,
compound 3d was obtained as yellow oil in 60% yield.
[a]2D0 = -14.8 (c 1.0, CH2Cl2). 1H NMR (CDCl3,
300 MHz): d 7.82 (d, J = 7.5 Hz, 1H), 7.58–7.43 (m, 5H),
7.22 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 7.02,
(d, J = 6.7 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 6.82 (d,
J = 8.2 Hz, 2H), 6.65 (d, J = 7.6 Hz, 2H), 6.41 (dd,
J = 1.9, 2.7 Hz, 1H), 6.34 (d, J = 3.3 Hz, 1H), 4.55
(s, 1H), 4.21 (dd, J = 2.9, 10.8 Hz, 1H), 3.05 (dd, J = 2.9,
13.3 Hz, 1H), 2.88 (dd, J = 10.9, 13.1 Hz, 1H), 2.38
(s, 3H), 2.22 (s, 3H), 1.79 (s, 3H). 13C NMR (CDCl3,
75 MHz): d 157.9, 144.9, 142.6, 141.9, 141.9, 140.6,
140.3, 140.0, 138.7, 130.7, 129.9, 129.2, 128.8, 128.2,
127.8, 126.2, 126.2, 126.1, 125.7, 110.6, 107.6, 60.5, 50.3,
38.6, 21.5, 21.3, 19.7, 14.2. MS (ESI?): [M ? Na]?calcd
for C34H33NO3S2Na 590.1794; found 590.1804.
(2S,3S)-Ethyl 2-(4-methoxyphenylamino)-3-[2-(S)-
(p-tolylsulfinyl)phenyl]-2-(trifluoromethyl) butanoate (9a)
By means of the general procedure described above, com-
pound 9a was obtained as a light yellow solid in 62% yield.
Mp = 39–41°C. [a]D25 = ?5.8 (c 1.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 7.66–7.61 (m, 2H), 7.42–7.33 (m, 4H),
7.21–7.16 (m, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.65 (d,
J = 9.2 Hz, 2H), 4.88 (br s, 1H), 4.37 (q, J = 7.2 Hz, 1H),
4.06–3.89 (m, 2H), 3.67 (s, 3H), 2.30 (s, 3H), 1.14 (d,
J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): d 167.9, 154.4, 144.2, 141.1, 140.5, 140.2,
137.9, 131.9, 131.2, 129.7, 128.5, 128.4, 125.1, 125.2 (q,
2
1JCF = 290.9 Hz), 120.4, 114.0, 71.1 (q, JCF = 24.7 Hz),
61.9, 55.5, 39.9, 21.3, 18.0, 13.7. 19F NMR(CDCl3,
282.4 MHz): d -73.84 (s, 3F). HRMS (EI?): m/z calcd for
C27H29F3NO4S [M ? H]?520.1769, found: 520.1766.
N-{(2S,3S)-2-(Furan-2-yl)-3-[2-(methylsulfinyl)phenyl]-4-
allylbutan-2-yl}(S)-p-tolylsulfinamide (3e)
(2R,3S)-Ethyl 2-(4-methoxyphenylamino)-3-[2-(S)-
(p-tolylsulfinyl)phenyl]-2-(trifluoromethyl) butanoate (9a0)
By means of the general procedure described above, com-
pound 3e was obtained as yellow oil in 42% yield. [a]D20
=
-23.0 (c 1.0, CH2Cl2). 1H NMR (CDCl3, 300 MHz): d 7.78
(dd, J = 1.5, 7.6 Hz, 1H), 7.59–7.54 (m, 1H), 7.49 (dd,
J = 1.4, 7.5 Hz, 1H), 7.46 (dd, J = 0.8, 1.8 Hz, 1H),
By means of the general procedure described above,
compound 9a0 was obtained as a light yellow solid in 20%
1
yield. Mp = 48–50°C. [a]2D5 = ?24.4 (c 1.0, CHCl3). H
123

Asymmetric synthesis of quaternary a-amino acid derivatives and their fluorinated analogues
563
NMR (CDCl3, 300 MHz): d 7.71 (d, J = 7.2 Hz, 1H),
7.45–7.36 (m, 5H), 7.22–7.19 (m, 2H), 6.59–6.47 (m, 4H),
4.90 (br s, 1H), 4.33–4.18 (m, 2H), 4.25 (q, J = 7.2 Hz,
1H), 3.63 (s, 3H), 2.32 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H),
1.05 (d, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d 167.3, 153.7, 143.4, 141.3, 141.0, 140.9, 138.1, 132.0,
130.9, 129.9, 129.1, 128.2, 125.6 (q, JCF = 291.6 Hz),
2
124.8, 119.3, 113.8, 70.8 (q, JCF = 24.7 Hz), 62.0, 55.5,
38.2, 21.3, 17.9, 13.8. 19F NMR (CDCl3, 282.4 MHz):
6.71–6.63 (m, 4H), 4.95–4.87 (m, 1H), 4.75–4.63 (m, 3H),
4.41 (dd, J = 5.2, 9.1 Hz, 1H), 4.15–3.98 (m, 2H), 3.67 (s,
3H), 2.64–2.58 (m, 2H), 2.28 (s, 3H), 1.07 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3, 75 MHz): d 167.8, 154.5, 145.9,
141.3, 140.2, 137.4, 137.3, 133.8, 131.5, 130.9, 129.8,
1
128.9, 129.1, 125.4, 125.1 (q, JCF = 290.5 Hz), 120.6,
2
114.0, 118.0, 71.8 (q, JCF = 24.7 Hz), 62.2, 55.5, 44.9,
36.7, 21.3, 13.7. 19F NMR (CDCl3, 282.4 MHz): d -73.96
(s, 3F). HRMS (EI?): m/z calcd for C29H31F3NO4S
[M ? 1]?546.1926, found: 546.1918.
1
d
-67.47 (s, 3F). HRMS (EI?): m/z calcd for
C27H29F3NO4S [M ? H]?520.1769, found: 520.1749.
(2S,3R)-Ethyl 2-(4-methoxyphenylamino)-3-[2-(S)-
(p-tolylsulfinyl)phenyl)-2-(trifluoromethyl]hex-5-enoate
(9c0)
(2S)-Ethyl 3,3,3-trifluoro-2-(4-methoxyphenylamino)-
2-[2-(S)-(p-tolylsulfinyl)benzyl]propanoate (9b)
By means of the general procedure described above,
compound 9b was obtained as yellow oil in 38% yield.
[a]2D5 = -5.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d 7.80 (dd, J = 1.4, 7.8 Hz, 1H), 7.44, 7.37 (m, 3H),
7.36–7.25 (m, 2H), 7.19–7.16 (m, 2H), 6.67–6.59 (m, 4H),
4.67 (br s, 1H), 3.96–4.06 (m, 2H), 3.66 (s, 3H), 3.51 (dd,
J = 16.5, 45.5 Hz, 2H), 2.30 (s, 3H), 0.86 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3, 75 MHz): d 167.6, 154.5, 143.8,
141.8, 140.7, 136.2, 133.3, 131.2, 130.1, 128.2, 125.9,
By means of the general procedure described above,
compound 9c0 was obtained as yellow oil in 12% yield.
[a]2D5 = -0.9 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d 774 (dd, J = 1.7, 9.2 Hz, 1H), 7.59 (dd, J = 1.3, 7.9 Hz,
1H), 7.47–7.38 (m, 4H), 7.21–7.18 (m, 2H), 6.56 (d,
J = 9.1 Hz, 2H), 6.42 (d, J = 9.0 Hz, 2H), 4.68–4.49 (m,
3H), 4.29 (dq, J = 1.0, 7.2 Hz, 2H), 4.19 (dd, J = 3.3,
11.9 Hz, 1H), 3.62 (s, 3H), 2.78–2.70 (m, 1H), 2.33–2.20
(m, 1H), 2.31 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): d 167.4, 154.1, 145.4, 141.3, 140.6,
137.7, 137.6, 133.6, 132.3, 131.8, 130.0, 128.7, 128.4,
1
125.7, 124.6 (q, JCF = 292.1 Hz), 121.2, 114.3, 68.4 (q,
2JCF = 25.6 Hz), 63.1, 55.4, 29.9, 21.3, 13.5. 19F NMR
(CDCl3, 282.4 MHz): d -73.25 (s, 3F). HRMS (EI?): m/z
calcd for C26H26F3NO4S [M]?505.1535, found: 505.1535.
1
125.7 (q, JCF = 291.6 Hz), 125.2, 120.0, 117.6, 113.9,
70.7 (q, 2JCF = 24.7 Hz), 62.3, 55.5, 43.4, 36.7, 21.3, 13.9.
19F NMR (CDCl3, 282.4 MHz): d -67.84 (s, 3F). HRMS
(EI?): m/z calcd for C29H31F3NO4S [M ? 1]?546.1926,
found: 546.1907.
(2R)-Ethyl 3,3,3-trifluoro-2-(4-methoxyphenylamino)-2-
[2-(S)-(p-tolylsulfinyl)benzyl]propanoate (9b0)
By means of the general procedure described above,
compound 9b0 was obtained as yellow oil in 13% yield.
[a]2D5 = -35.4 (c 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): d 7.89 (dd, J = 1.7, 7.9 Hz, 1H), 7.41–7.30 (m,
5H), 7.19–7.14 (m, 2H), 6.63–6.56 (m, 4H), 5.09 (br s, 1H),
4.12–4.05 (m, 2H), 3.64 (s 3H), 3.40 (dd, J = 15.6,
49.0 Hz, 2H), 2.30 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): d 168.0, 155.2, 144.0, 141.9,
140.8, 135.7, 133.3, 130.9, 130.0, 129.1, 128.1, 128.2 (q,
1JCF = 276.2 Hz),126.1, 125.1, 122.5, 114.3, 68.2 (q,
2JCF = 25.4 Hz), 62.9, 55.5, 29.9, 21.4, 13.4. 19F NMR
(CDCl3, 282.4 MHz): d -72.43 (s, 3F). HRMS (EI?): m/z
calcd for C26H26F3NO4S [M]?505.1535, found: 505.1520.
General procedure for the synthesis of N-acetyla-amino
acid derivatives 4
To a solution of the corresponding compound 3 (0.41 mmol)
in MeOH (5 ml), TFA (1.23 mmol) was added. The solution
was stirred for about 2 h, and thereafter (followed by TLC)
the residue was purified by strong cation exchange (SCX)
chromatography. Then, to a solution of the yellow amine
residue (0.41 mmol) in THF (2 ml) acetic anhydride
(0.656 mmol) and Et3N (1.23 mmol) were added and stirred
for 12 h. When the reaction was completed (followed by
TLC), the reaction mixture was extracted (3 9 10 mL Et2O),
washed (2 9 10 mL H2O), dried (MgSO4) and the sol-
vent evaporated. Then, the corresponding residue was
solved in a mixture of CH3CN/H2O/CCl4 (4/4/4 ml), NaIO4
(0.656 mmol) and RuCl3 (0.041 mmol) were added at room
temperature. The solution was stirred overnight, and fol-
lowed by TLC. When the reaction was completed the product
was extracted with AcOEt (4 ml), dried (MgSO4), and the
solvent evaporated. Finally, the obtained yellow oil was
solved in MeOH (5 ml) and trimethylsilyldiazomethane was
(2S,3S)-Ethyl 2-(4-methoxyphenylamino)-3-[2-(S)-
(p-tolylsulfinyl)phenyl)-2-(trifluoromethyl]hex-5-enoate (9c)
By means of the general procedure described above, com-
pound 9c was obtained as yellow oil in 38% yield. [a]D25
=
-43.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d 7.63–7.57 (m, 2H), 7.48–7.31 (m, 4H), 7.19–7.14 (m, 2H),
123

564
S. Fustero et al.
slowly added (1.23 mmol). When the reaction was com-
pleted (followed by TLC) the solvent was evaporated and the
residue was purified by flash column chromatography.
300 MHz): d 7.43 (d, J = 0.8 Hz, 1H), 7.42–7.15 (m, 3H),
6.96–6.93 (m, 2H), 6.58 (dd, J = 2.3, 6.7 Hz, 2H), 6.32
(dd, J = 2.5, 6.4 Hz, 4H), 3.82 (br s, 1H), 3.64 (s, 3H),
3.43 (dd, J = 14.3, 18.5 Hz, 2H). 13C NMR (CDCl3,
75 MHz): d 154.1, 148.9, 142.5, 137.3, 134.1, 130.7,
(2S, 3S)-Methyl-3-[2-(p-tolylsulfonyl)phenyl]-2-
acetamidobutanoate (4a)
1
128.1, 127.2, 125.6 (q, JCF = 289.4 Hz), 119.9, 114.2,
2
111.0, 110.9, 64.6 (q, JCF = 25.8 Hz), 55.4, 40.3. 19F
By means of the general procedure described above,
NMR (CDCl3, 282.4 MHz): d -101.4 (s, 3F). HRMS
(EI?): m/z calcd for C20H19F3NO2[M ? H]?362.1368,
found: 362.1378.
compound 4a was obtained as yellow oil in 55% yield
1
(three steps). [a]D20 = ?55.9 (c 0.93, CH2Cl2). H NMR
(CDCl3, 300 MHz): d 8.11 (d, J = 8.0 Hz, 1H), 7.54 (dt,
J = 1.3, 8.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.27
(d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.2 Hz, 2), 4.50 (dd,
J = 8.3, 11.2 Hz, 1H), 3.82 (qd, J = 6.9, 11.3 Hz, 1H),
3.71 (s, 3H), 2.36 (s, 3H), 1.62 (s, 3H), 0.77 (d, J = 6.9 Hz,
3H). 13C NMR (CDCl3, 75 MHz): d 172.0, 169.7, 144.5,
142.3, 139.3, 138.6, 134.4, 130.0, 128.8, 128.7, 127.6,
127.4, 58.4, 52.2, 36.1, 22.6, 21.6, 18.1. MS (ESI?):
[M ? Na]?calcd for C20H23NO5SNa 412.1189; found
412.1172.
4-Methoxy-N-[(2S,3S)-1,1,1-trifluoro-2-(furan-2-yl)-3-
phenylbutan-2-yl]aniline (5b)
By means of the general procedure described above, com-
pound 5b was obtained as colorless oil in 96% yield.
[a]2D5 = ?57.3 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d 7.45 (d, J = 1.8 Hz, 1H), 7.34–7.25 (m, 5H), 6.66–6.60
(m, 2H), 6.54–6.53 (m, 1H), 6.49 (dd, J = 1.8, 3.3 Hz, 1H),
6.39–6.34 (m, 2H), 3.84 (br s, 1H), 3.65 (q, J = 7.2 Hz, 1H),
3.64 (s, 3H), 1.27 (d, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 153.5, 148.8, 142.0, 140.2, 138.0, 129.3, 128.4,
(2S,3S)-Methyl 2-(acetylamino)-2-methyl-3-
[2-(p-tolylsulfonyl)phenyl]butanoate (4b)
1
127.6, 126.3 (q, JCF = 292.1 Hz), 118.8, 113.9, 111.1 (q,
2
4JCF = 2.2 Hz), 110.7, 67.0 (q, JCF = 25.1 Hz), 55.4,
By means of the general procedure described above,
compound 4b was obtained as yellow oil in 42% yield
(three steps). [a]2D0 = ?60.2 (c 0.4, CH2Cl2). 1H NMR
(CDCl3, 300 MHz): d 8.29 (dd, J = 1.4, 7.9 Hz, 1H), 7.72
(d, J = 8.3 Hz, 2H), 7.64 (s, 1H), 7.60 (dd, J = 1.4,
7.6 Hz, 1H), 7.52–7.45 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H),
3.89 (q, J = 7.0 Hz, 1H), 3.77 (s, 3H), 2.41 (s, 3H), 1.89 (s,
3H), 1.58 (s, 3H), 0.67 (d, J = 7.1 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): d 158.3, 143.8, 143.3, 142.7, 141.7,
140.9, 140.6, 140.4, 131.9, 130.0, 129.6, 129.1, 129.0,
127.1, 125.7, 125.0, 110.2, 106.7, 59.9, 50.6, 41.7, 21.3,
18.0, 15.8. MS (ESI?): [M ? Na]?calcd for
C21H25NO5SNa 426.1351; found 426.1340.
46.3, 17.4. 19F NMR (CDCl3, 282.4 MHz): d -67.76 (s, 3F).
HRMS (EI?): m/z calcd for C21H20F3NO2[M]?375.1446,
found: 375.1453.
(2S,3S)-Ethyl 2-(4-methoxyphenylamino)-3-phenyl-2-
(trifluoromethyl)butanoate (10a)
By means of the general procedure described above, com-
pound 10a was obtained as colorless oil in 70% yield.
[a]2D5 = ?28.39 (c 0.8, CHCl3). 1H NMR (CDCl3,
300 MHz): d7.37–7.32 (m, 5H), 6.79–6.70 (m, 4H),
4.18–4.07 (m, 2H), 3.89 (br s, 1H), 3.74 (s, 3H), 3.68 (q,
J = 7.2 Hz, 1H), 1.55 (d, J = 7.4 Hz, 3H), 1.14 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d 168.2,
154.5, 139.2, 137.2, 129.1, 128.4, 127.9, 125.0 (q,
General procedure for the Nickel–Raney
desulfinylation reaction
2
1JCF = 291.0 Hz), 121.0, 114.0, 71.8 (q, JCF = 24.3 Hz),
62.1, 55.5, 45.1, 16.0, 13.7. 19F NMR (CDCl3, 282.4 MHz):
A solution of the corresponding sulfoxide 3f, g or
9/90(0.50 mmol) in THF (5 mL) was added to a suspension
of Ni–Raney (2.5 g) in THF (5 mL). The reaction was
stirred for 2 h, filtered through a Celite pad, and the residue
was purified by flash column chromatography.
d
-74.20 (s, 3F). HRMS (EI?): m/z calcd for
C20H22F3NO3[M]?381.1552, found: 381.1540.
(2R,3S)-Ethyl 2-(4-methoxyphenylamino)-3-phenyl-2-
(trifluoromethyl)butanoate (10a0)
(S)-4-Methoxy-N-(1,1,1-trifluoro-2-(furan-2-yl)-3-
phenylpropan-2-yl)aniline (5a)
By means of the general procedure described above, com-
pound 10a0 was obtained as colorless oil in 72% yield.
[a]2D5 = -9.96 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d7.39–7.32 (m, 5H), 6.75–6.59 (m, 4H), 4.38–4.25 (m, 2H),
3.71 (s, 3H), 3.76–3.71 (m, 2H), 1.49 (d, J = 7.1 Hz, 3H),
1.30 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
By means of the general procedure described above,
compound 5a was obtained as colorless oil in 89% yield.
[a]2D5 = ?56.5 (c 1.0, CHCl3). 1H NMR (CDCl3,
123

Asymmetric synthesis of quaternary a-amino acid derivatives and their fluorinated analogues
565
(2S,3S)-Ethyl 2-(4-methoxyphenylamino)-3-phenyl-2-
(trifluoromethyl)hex-5-enoate (10d)
d 167.8, 154.2, 138.7, 137.5, 129.4, 128.6, 128.1, 125.2 (q,
2
1JCF = 290.5 Hz), 120.0, 114.0, 71.5 (q, JCF = 24.7 Hz),
62.2, 55.5, 43.2, 17.2, 13.9. 19F NMR (CDCl3, 282.4 MHz):
d
-76.19 (s, 3F). HRMS (EI?): m/z calcd for
By means of the general procedure described above, com-
pound 10d was obtained as colorless oil in 62% yield.
[a]2D5 = -7.5 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d736–7.32 (m, 5H), 6.79–6.71 (m, 4H), 5.48–5.37 (m, 1H),
4.99–4.86 (m, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.96 (br s, 1H),
3.74 (s, 3H), 3.52 (dd, J = 3.5, 11.6 Hz, 1H), 2.82–2.71 (m,
2H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d 167.9, 154.6, 137.0, 136.3, 135.3, 130.1, 128.3, 128.0,
C20H22F3NO3[M]?381.1552, found: 381.1544.
(S)-Ethyl 2-benzyl-3,3,3-trifluoro-2-
(4-methoxyphenylamino)propanoate (10b)
By means of the general procedure described above, com-
1
pound 10b was obtained as a white solid in 77% yield.
1
125.0 (q, JCF = 291.0 Hz), 121.0, 117.2, 114.1, 71.9 (q,
Mp = 45–47°C. [a]D25 = ?18.4 (c 1.0, CHCl3). H NMR
2JCF = 24.5 Hz), 62.2, 55.5, 51.0, 33.9, 13.7. 19F NMR
(CDCl3, 282.4 MHz): d -74.24 (s, 3F). HRMS (EI?): m/z
calcd for C22H24F3NO3[M]?407.1708, found: 407.1710.
(CDCl3, 300 MHz): d7.22–7.20 (m, 3H), 7.09–7.06 (m, 2H),
6.82–6.75 (m, 4H), 4.48 (br s, 1H), 4.28–4.15 (m, 2H), 3.76
(s, 3H), 3.53 (dd, J = 14.5, 83.2 Hz, 2H), 1.22 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d 168.0,
154.3, 136.9, 133.7, 130.1, 128.2, 127.3, 124.8 (q,
(2R,3S)-Ethyl 2-(4-methoxyphenylamino)-3-phenyl-2-
(trifluoromethyl)hex-5-enoate (10d0)
2
1JCF = 289.9 Hz), 120.6, 114.4, 68.8 (q, JCF = 26.2 Hz),
62.9, 55.5, 35.1, 13.7. 19F NMR (CDCl3, 282.4 MHz): d
-81.65 (s, 3F). HRMS (EI?): m/z calcd for
C19H20F3NO3[M]?367.1395, found: 367.1385.
By means of the general procedure described above, com-
pound 10d0 was obtained as colorless oil in 70% yield.
[a]2D5 = ?32.8 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
d7.39–7.35 (m, 5H), 6.69–6.58 (m, 4H), 5.48–5.37 (m, 1H),
5.00–4.86 (m, 2H), 4.36–4.24 (m, 2H), 3.71 (s, 3H), 3.59
(dd, J = 4.0, 11.7 Hz, 1H), 2.79–2.59 (m, 2H), 1.28 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d 167.7,
(2S,3S)-Ethyl 2-(4-methoxyphenylamino)-3-phenyl-2-
(trifluoromethyl)hexanoate (10c)
154.3, 137.4, 136.0, 135.3, 130.3, 128.6, 128.3, 125.1 (q,
By means of the general procedure described above,
2
1JCF = 289.9 Hz), 120.2, 117.2, 114.0, 71.4 (q, JCF
=
compound 10c was obtained as a white solid in 74% yield.
1
25.4 Hz), 62.2, 55.5, 49.5, 34.9, 13.9. 19F NMR (CDCl3,
282.4 MHz): d -76.97 (s, 3F). HRMS (EI?): m/z calcd for
C22H24F3NO3[M]?407.1708, found: 407.1706.
Mp = 71–73°C. [a]D25 = -28.5 (c 1.0, CHCl3). H NMR
(CDCl3, 300 MHz): d7.33–7.31 (m, 5H), 6.76–6.69 (m,
4H), 4.11 (q, J = 7.1 Hz, 2H), 3.95 (br s, 1H), 3.73 (s, 3H),
3.45 (dd, J = 2.6, 12.2 Hz, 1H), 2.04–2.00 (m, 1H),
1.85–1.80 (m, 1H), 1.16–0.96 (m, 2H), 1.14 (t, J = 7.2 Hz,
3H), 0.83 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 168.0, 154.4, 137.2, 136.9, 129.9, 128.3,
General procedure for the synthesis of N-Boc-a-amino
acid derivatives 7
N-PMP protected amines 5 (0.15 mmol) were dissolved in
CH3CN/CCl4/H2O (3: 1.5: 1.5 mL) under brisk stirring.
Then, NaIO4 (0.18 mmol) and RuCl3ꢀ3H2O (0.015 mmol)
were added. After stirring at room temperature for 2 h, the
reaction salts were filtered off and washed with CH2Cl2.
The organic layer was washed with saturated aqueous
NaHCO3, dried over anhydrous Na2SO4 and the solvents
removed under reduced pressure. The crude reaction mix-
ture was then dissolved in MeOH (1.5 mL) and added to a
stirred solution of p-toluenesulfonic acid (0.33 mmol) and
Girard T (0.33 mmol). The reaction mixture was stirred for
10 min and next, methanol was removed under reduced
pressure. The resulting residue was dissolved in AcOEt
(10 mL), quenched with 1 M K2HPO4, and extracted with
AcOEt (4 9 10 mL). The combined organic layers were
washed with brine (3 9 10 mL), dried over anhydrous
Na2SO4 and concentrated in vacuum. The resulting crude
reaction mixture was diluted with CH2Cl2 (2.5 mL), and
1
127.9, 125.1 (q, JCF = 290.5 Hz), 120.4, 114.1, 72.0 (q,
2JCF = 24.2 Hz), 62.1, 55.5, 50.9, 31.3, 20.9, 13.7, 13.6.
19F NMR (CDCl3, 282.4 MHz): d -73.99 (s, 3F). HRMS
(EI?): m/z calcd for C22H26F3NO3[M]?409.1865, found:
409.1865.
General procedure for the tert-BuLi desulfinylation
reaction
A solution of t-BuLi (0.22 mmol, 1.7 M in hexane) was
added dropwise to a solution of the corresponding sulfox-
ide 9c or 9c0 (0.1 mmol) in THF (2 mL) at –78°C. After
10 min stirring, the mixture was hydrolyzed (2 mL satu-
rated NH4Cl), extracted (3 9 10 mL AcOEt), washed
(2 9 10 mL NaCl sat), dried (MgSO4) and the solvent
evaporated. The residue was purified by flash column
chromatography.
123

566
S. Fustero et al.
2
(Boc)2O (0.75 mmol) and K2CO3 (0.45 mmol) were added
at 0°C. After stirring for 4 h, the reaction was quenched
with H2O and the aqueous layer was extracted with EtOAc
(3 9 10 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4 and the solvents
removed under reduced pressure. The crude reaction mix-
ture was purified by means of flash column chromatogra-
phy on silica gel.
(q, JCF = 25.8 Hz), 46.4, 27.7, 17.5. 19F NMR (CDCl3,
282.4 MHz): d -68.47 (s, 3F). HRMS (EI?): m/z calcd for
C19H22F3NO3[M]?369.1552, found: 369.1537.
General procedure for the synthesis of indolines 11
To a solution of the corresponding amine 100(0.2 mmol) in
THF (0.1 M) at 0 C a solution of KHDMS (0.3 mmol,
0.5 M in toluene) was added under argon atmosphere, and
the temperature was raised to room temperature. The
reaction was followed by TLC and once the reaction was
completed, the mixture was treated with a saturated solu-
tion of NaHCO3 (10 mL) and extracted with CH2Cl2
(3 9 10 mL). The organic phase was dried with anhydrous
Na2SO4, and the solvent was eliminated under reduced
pressure. Finally, compounds 11 were purified by means of
flash column chromatography.
4-[(2S,3S)-1,1,1-Trifluoro-2-(furan-2-yl)-3-phenylbutan-2-
ylimino]cyclohexa-2,5-dienone (6b)
By means of the general procedure described above, after
the oxidation step compound 6b was obtained by crystal-
lization with Et2O as a brown solid. Mp = 114–116°C.
[a]2D0 = ?13.9 (C 0.27, CH2Cl2). 1H NMR (CDCl3,
300 MHz): d 7.47 (s, 1H), 7.53–7.23 (m, 5H), 6.60 (dd,
J = 3.3, 10.7 Hz, 1H), 6.55–6.51 (m, 3H), 6.04 (dd,
J = 2.2, 10.4, 1H), 5.68 (dd, J = 2.4, 10.6 Hz, 1H), 3.84
(q, J = 7.2 Hz, 1H), 1.63 (d, J = 6.6 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): d 187.1, 160.8, 148.8, 143.8, 142.4,
(2R,3S)-Ethyl 1-(4-methoxyphenyl)-3-methyl-2-
(trifluoromethyl)indoline-2-carboxylate (11a)
1
140.5, 131.9, 131.1, 130.2, 128.8 (q, JCF = 240.0 Hz),
By means of the general procedure described above,
128.3, 127.8, 111.2, 111.0, 73.2 (q, 2JCF = 96.7 Hz), 26.5,
17.1. MS (ESI?): [M ? Na]?calcd for C20H16NO2F3Na
382.1030; found 382.1025.
compound 11a was obtained as a white solid in 51% yield.
1
Mp = 66–68°C. [a]D25 = ?9.2 (c 1.0, CHCl3). H NMR
(CDCl3, 300 MHz): d7.34 (d, J = 8.9 Hz, 2H), 7.05–6.98
(m, 2H), 6.92–6.89 (m, 2H), 6.77–6.72 (m, 1H), 6.18 (d,
J = 7.9 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 4.01 (q,
J = 7.1 Hz, 1H), 3.83 (s, 3H), 1.45 (d, J = 7.2 Hz, 3H),
1.24 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d
165.8, 158.6, 151.0, 132.6, 129.1, 130.8, 128.1, 124.8 (q,
1JCF = 284.4 Hz), 122.6, 118.6, 114.4, 107.4, 81.1 (q,
2JCF = 26.4 Hz), 61.7, 55.4, 43.2, 15.6, 14.1. 19F NMR
(CDCl3, 282.4 MHz): d -81.28 (s, 3F). HRMS (EI?): m/z
calcd for C20H20F3NO3[M]?379.1395, found: 379.1394.
(S)-tert-Butyl 1,1,1-trifluoro-2-(furan-2-yl)-3-
phenylpropan-2-ylcarbamate (7a)
By means of the general procedure described above,
compound 7a was obtained as yellow oil in 48% yield
(three steps). [a]D25 = ?17.6 (c 1.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): d7.40 (d, J = 1.3 Hz, 1H), 7.18–7.16
(m, 3H), 6.93–6.91 (m, 2H), 6.90–6.78 (m, 2H), 4.05 (br s,
1H), 3.43 (dd, J = 14.0, 23.3 Hz, 2H), 1.45 (s, 9H). 13C
NMR (CDCl3, 75 MHz): d 152.2, 144.3, 142.7, 141.7,
(2R,3S)-Ethyl 3-allyl-1-(4-methoxyphenyl)-2-
(trifluoromethyl)indoline-2-carboxylate (11b)
1
130.7, 128.2, 127.4, 125.3 (q, JCF = 288.8 Hz), 111.2,
110.9, 83.2, 64.0 (q, 2JCF = 26.4 Hz), 40.3, 27.7. 19F NMR
(CDCl3, 282.4 MHz): d -82.38 (s, 3F). HRMS (EI?):
m/z calcd for C18H20F3NO3[M]?355.1395, found: 355.1323.
By means of the general procedure described above, com-
pound 11b was obtained as a white solid in 64% yield.
Mp = 50–52°C. [a]D25 = ?14.6 (c 1.0, CHCl3). H NMR
1
tert-Butyl (2S,3S)-1,1,1-trifluoro-2-(furan-2-yl)-3-
phenylbutan-2-ylcarbamate (7b)
(CDCl3, 300 MHz): d 7.33 (d, J = 8.9 Hz, 2H), 7.21 (d,
J = 7.3 Hz, 1H), 7.04–6.98 (m, 1H), 6.92–6.89 (m, 2H),
6.71 (dt, J = 1.0, 7.4 Hz, 1H), 6.17 (d, J = 7.7 Hz, 1H),
6.04–5.90 (m, 1H), 5.22–5.16 (m, 2H), 4.23–4.15 (m, 2H),
3.97 (dd, J = 5.5, 8.4 Hz, 1H), 3.83 (s, 3H), 2.63–2.56 (m,
2H), 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d 165.7, 158.6, 151.0, 135.5, 132.6, 130.9, 130.9, 128.2,
By means of the general procedure described above,
compound 7b was obtained as yellow oil in 55% yield
(three steps). [a]D25 = ?35.6 (c 1.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): d7.45 (dd, J = 0.8, 1.8 Hz, 1H),
7.36–7.31 (m, 3H), 7.26–7.23 (m, 2H), 6.78 (dd, J = 2.3,
6.8 Hz, 2H), 4.05 (br s, 1H), 3.64 (q, J = 7.2 Hz, 1H), 1.51
(s, 9H), 1.26 (d, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 152.3, 143.8, 142.2, 140.0, 129.2, 128.6,
127.8, 126.3 (q, 1JCF = 291.6 Hz), 111.3, 110.7, 83.1, 66.3
1
124.8 (q, JCF = 285.5 Hz), 123.8, 118.5, 117.5, 114.4,
107.7, 80.2 (q, 2JCF = 26.4 Hz), 61.8, 55.4, 47.3, 36.4, 13.9.
19F NMR (CDCl3, 282.4 MHz): d -81.89 (s, 3F). HRMS
(EI?): m/z calcd for C22H22F3NO3[M]?405.1552, found:
405.1552.
123

Asymmetric synthesis of quaternary a-amino acid derivatives and their fluorinated analogues
567
Results and discussion
substitutions at the benzylic center were also tolerated, thus
obtaining benzyl derivative 3d and allyl derivative 3e both
as unique diastereoisomers (Table 1, entries 5–6).
First, we prepared the starting materials, i.e. the ortho-
sulfinylbenzyl derivatives 1 and the N-protected 2-furyl
imines 2. The former ones were obtained according to
Regarding the trifluoromethyl-substituted imines, when
N-sulfinylketimine (S)-2c was reacted with the sulfinyl-
carbanion (S)-1a under the same conditions, we observed a
complex mixture of products (Table 1, entry 7). Therefore,
we changed the nitrogen protecting group from the p-tolu-
enesulfinyl to the p-methoxyphenyl (PMP) group1
´
literature protocols (Garcıa Ruano et al. 2003, 2005a, b, c).
N-Sulfinylimines 2a, b were synthesized through a con-
densation reaction between the corresponding carbonylic
compound and (S)-p-toluenesulfonamide in the presence of
´
Ti(OEt)4 as a water scavenger (Davis et al. 1993; Garcıa
´
(Garcıa Ruano et al. 2008). In this way, N-PMP tri-
Ruano et al. 2005a, b, c), thus obtained pure products in good
yields after column chromatography purification (Fig. 3a),
while trifluoromethylimine 2d was prepared by the Stau-
dinger (aza-Wittig) reaction of furyltrifluoromethylketone
(Soloshonok et al. 1986, 1987, 1988; Kerdesky and Basha
1991) with N-PMP iminophosphorane (Stauffer et al. 2000)
(Fig. 3b).
fluoromethylfurylimine 2d took part in a mono-induction
process, in which only the sulfinyl group of 1 would induce
asymmetry in the formation of the new chiral centers. To our
delight, both sulfinylcarbanions (S)-1a and (S)-1b led to the
corresponding addition products 3f and 3g as single diaste-
reoisomers in good yields (Table 1, entries 8, 9).
The next step in our study comprised the transformation of
adducts 3 into the corresponding quaternary a-amino acid
derivatives. In the case of the non-fluorinated compounds it
involved the desulfinylation of the nitrogen and the oxidative
elaboration of the furane moiety. To illustrate this process, 3a
and 3b were treated with TFA (hydrogenolysis of the N–S
bonds) and the resulting amino sulfoxides (purified by SCX
column) were then acetylated. Further oxidation (of both, the
sulfoxide and the furan ring) with NaIO4/RuCl3 followed by
esterification with trimethylsilyldiazomethane afforded
a-amino esters 4 in good yields (Fig. 4).
We also tried to exemplify the synthesis of a-trifluoro-
methyl a-amino acid derivatives by using an analogous
sequence. Thus, starting from compounds 3f and 3g, we
removed the p-toluenesulfinyl group by treatment with Ni
Raney in THF/H2O to give desulfinylated products 5 in
very good yields. Then, in order to release the amino group
under oxidative conditions (RuCl3/NaIO4), we observed
the formation of quinonimine intermediates 6, which
proved to be very difficult to hydrolyze Different attempts
with H2O, 10% aqueous HCl or H2SO4 either at room or
high (100°C) temperature gave only starting material or
complex mixtures. Fortunately, we could hydrolyze these
intermediates by using a Girard reagent in a polar protic
solvent (Girard and Sandulesco 1936). These reagents are
quaternary ammonium salts bearing an acetylhydrazine
functionality and they have been widely used to extract
carbonylic compounds from natural product mixtures
(Wheeler et al. 1961, 1962; Watanabe et al. 1982a, b).
Thus, the treatment of a solution of intermediates 6 in
MeOH with Girard T in the presence of p-toluenesulfonic
acid followed by addition of a K2HPO4 solution and an
extractive work up (del Pozo et al. 2001) led to the
With imines 2 in hand, we went on to deal with the
nucleophilic addition of stabilized c-sulfinylcarbanions
derived from sulfoxides 1. The reaction of (S)-1a with
N-sulfinylated 2-furyl aldimine (S)-2a yielded compound
3a as the only isomer in 82% yield (Table 1, entry 1). The
same reaction with N-sulfinylketimine (S)-2b yielded a
single diastereoisomer anti-3b although in moderate yield
(Table 1, entry 2), probably as a consequence of the eno-
lization of this methyl-substituted ketimine. As we had
previously observed with other N-sulfinylketimines, when
the carbanion derived from (S)-2-p-tolylsulfinyl toluene
(1b) reacted with ketimine (S)-2b, a 60:40 mixture of
diastereoisomers 3c and 3c0 was detected in the crude
reaction mixture (Table 1, entry 3). Interestingly, the
reaction of the sulfinylcarbanion derived from (S)-1a with
N-sulfinylketimine (R)-2b gave syn-amine derivative epi-
3b (Table 1, entry 4). Comparison of the results in entries 2
and 4 suggests that this methodology allows for the syn-
thesis of all possible diastereoisomers by choosing the
appropriate configuration at both sulfinyl groups. Other
:
O
:
O
(a)
S
S
O
N
p-Tol
p- Tol
H2N
O
O
R
R
Ti(EtO)4
Δ
CH2Cl2,
(S)-2a (R = H, 78%)
2b
(S)-
(R = Me, 63%)
(S)-2c (R = CF3, 70%)
R
N
(b)
O
Ph3P N R
O
O
CF3
CF3
Δ
Toluene,
1
2d (R = PMP, 84%)
Our research groups’ previous results showed that these fluorinated
PMP-derived imines reacted with p-tolyl sulfinyl carbanions in good
´
yields and selectivities (see Garcıa-Ruano et al. 2008).
Fig. 3 Synthesis of 2-furyl imines 2
123

568
S. Fustero et al.
Table 1 Reaction of sulfinylcarbanions of 1 with 2-furyl imines 2
O
PG
S
N
LDA
R2
Tol
NH-PG
O
O
+
R2
THF, –78°C
R1
TolOS
R1
1
2
3
Entry
(S)-1 (R1)
2
R2
PG
3
dra
% Yieldb
1
2
3
4
5
6
7
8
9
a
1a (Me)
1a (Me)
1b (H)
(S)-2a
(S)-2b
(S)-2b
(R)-2b
(S)-2b
(S)-2b
(S)-2c
2d
H
(S)-SOTol
(S)-SOTol
(S)-SOTol
(R)-SOTol
(S)-SOTol
(S)-SOTol
(S)-SOTol
MeOC6H4
MeOC6H4
3a
3b
3c/3c0
[98:2
82
51
50c
46
60
42
–
Me
Me
Me
Me
Me
CF3
CF3
CF3
[98:2
60:40
[98:2
[98:2
[98:2
–
1a (Me)
1c (Bn)
1d (Allyl)
1a (Me)
1b (H)
epi-3bd
3d
3e
C.Me
3f
[98:2
[98:2
73
71
1a (Me)
2d
3 g
1
Diastereoisomeric ratio determined by H-NMR analysis of the crude mixture
Isolated yields after flash column chromatography
Combined yield of the two diastereoisomers
b
c
d
e
Opposite configuration at the a-carbon quaternary stereocenter
Complex mixture
Fig. 4 Synthesis of b-methyl
a-amino acids 4
1. TFA, MeOH
R
NH-SOTol
O
R
NH-Ac
2. Ac2O, Et3N, DMAP
Ar
CO2Me
3. NaIO4, RuCl3
TMSCH2N2
TolOS
Me
Me
3a (R = H)
3b (R = Me)
4a (R = H, 55%, 3 steps)
4b (R = Me, 42%, 3 steps)
corresponding free amine intermediates which, without
further purification, were protected as N-Boc carbamates 7
under standard conditions. Although this protocol allowed
us to isolate both N-Boc protected amines 7 in good yields
from PMP derivatives 5, we were not able to oxidize the
furane ring, and we obtained complex mixtures of products
after trying various conditions (Fig. 5).
this hindered conformation and the relatively stable p-p
stacking, the hydrolysis of these quinone-type intermedi-
ates was difficult to achieve.3
However, not being able to oxidize the furane ring in the
fluorinated derivatives, we decided to slightly change our
strategy for the preparation of quaternary fluorinated
a-amino acids. This new approach consisted of the addition
of our 2-p-tolylsulfinylbenzylcarbanions of (S)-1 to fluori-
nated a-imino esters, which are interesting synthetic inter-
mediates for the preparation of b-fluorinated a-amino acids
(Fustero et al. 2006, 2008a, b, c). Thus, the N-PMP imino
ester derived from commercially available ethyl trifluoro-
pyruvate was easily obtained by means of an aza-Wittig
reaction, and it was used as electrophile in the reaction with
In this context, we were able to obtain crystals of
compound 6b suitable for X-ray analysis,2 which allowed
us to confirm the relative configuration of this type of
derivatives. Interestingly, this X-ray structure showed a
p-stacking interaction between the quinonimine ring and
the phenyl group at the b-position, with a typical distance
´
˚
connecting the rings (4.0 A) (Fig. 6). It is likely that due to
2
´
The authors have deposited atomic coordinates for 6b and 9a with
3
the Cambridge Crystallographic data Centre (deposition numbers
CCDC 805405 & 805406). The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge Cb2 1EZ, UK.
The stability of products 6 can be attributed to the strong electron
withdrawing effect of the CF3 group as well as its strong stereocon-
trolling effect. In certain cases it can act as a bigger group than the
tert-butyl one (see, for example Soloshonok et al. 1996).
123

Asymmetric synthesis of quaternary a-amino acid derivatives and their fluorinated analogues
Fig. 5 Transformations for
569
RuCl3 (10 mol%)
NaIO4 (1.2 equiv)
F3C
F3C
R
NH-PMP
NH-PMP
O
obtaining a-trifluoromethyl
amino acid derivatives
Ni Raney
O
THF/ H2O
CH3CN/ CCl4/ H2O
TolOS
R
5a (R = H, 89%)
3f (R = H, 73%)
3g
5b (R = Me, 96%)
(R = Me, 71%)
O
Boc
1. Girard T, p-TsOH
F3C
N
F3C
HN
MeOH
O
O
2. K2CO3, (Boc)2O
CH2Cl2
R
R
6a
7a
(R = H, 48%, 3 steps)
(R = H)
6b (R = Me)
7b (R = Me, 55%, 3 steps)
Fig. 6 Two different views of the structure of 6b highlighting the p-stacking interaction and determination of the absolute stereochemistry of 6b
by X-ray experiments (right)
Table 2 Reaction of sulfinylcarbanions of 1 with the trifluoromethyla-imino ester 8
O
PMP
PMP
PMP
S
N
LDA
HN
HN
Tol
+
+
CF3
CO2Et
CO2Et
CF3
F3
C
CO2Et
THF, 78°C
R
TolOS
R
TolOS
R
1
8
9
9´
Entry
(S)-1 (R1)
9
dra
% Yieldb, c
1
2
3
a
1a (Me)
1b (H)
9a/9a0
9b/9b0
9c/9c0
75:25
82
51
50
75:25
75:25
1d (Allyl)
Diastereoisomeric ratio determined by 19F-NMR analysis of the crude mixture
Isolated yields after flash column chromatography
b
c
Combined yields of the two diastereoisomers
different stabilized sulfinylcarbanions. These reactions took
substitution at the benzylic position (Table 2). However, the
diastereoisomers could easily be separated by column
chromatography.
place in good yields although a 3/1 diastereoisomeric mix-
ture was obtained in all cases independently of the
123

570
S. Fustero et al.
The absolute configuration of compounds 9 was deter-
compound 9c, the reaction with Ni Raney caused the
hydrogenation of the double bond, thus obtaining the
b-propyl substituted product 10c in 74% yield (Table 3,
entry 5). In order to avoid reductive conditions, compounds
9c and 9c0 were desulfinylated by using t-BuLi at –78°C. In
this manner, the allyl substitution at the benzylic position
was also obtained in good yields (Table 3, entries 6, 7).
Another strategy for removing the sulfinyl group was
mined related to the known (SS) stereochemistry of the
chiral auxiliary by analysis of the X-ray diffraction pattern
of a suitable crystal obtained by slow evaporation of a
solution of the minor diastereoisomer 9a0 in hexanes/die-
thyl ether (Fig. 7).2
Once compounds 9 and 90 had been obtained as single
diastereoisomers, the sulfoxide group was removed to
obtain the desired a-trifluoromethyl a-amino acid deriva-
tives. Therefore, we carried out the desulfinylation of either
diastereoisomer 9 and 90 separately by treatment with either
Ni Raney or t-BuLi. These reactions proceeded in good
yields (Table 3). In the case of the b-allyl substituted
´
developed by our research groups in 2008 (Garcıa Ruano
et al. 2008), which involved an anionic-anionic asymmetric
tandem process including an intramolecular-nucleophilic
aromatic substitution of the p-tolylsulfinyl group by the
nitrogen atom. This process gave rise to optically pure
fluorinated indolines. Likewise, if an appropriate base is
added to addition products 9/90, fluorinated a-amino acid
derivatives inserted into an indoline skeleton (Horton et al.
2003; Anas and Kagan 2009; Liu et al. 2010) were
obtained. These kind of compounds, e.g. 2-(alkyl)indoline-
2-carboxylates, have been explored for the treatment of
anxiety and depression (Kondo et al. 2006, 2008), and they
have also been studied for the prevention and treatment of
PMP
PMP
N
KHMDS, THF
rt, 2 h
HN
CF3
CF3
CO2Et
CO2Et
R
TolOS
R
11a
11b
9a´ (R = Me)
(R = Me, 51%)
(R = Allyl, 64%)
9d´
(R = Allyl)
Fig. 7 Determination of the absolute stereochemistry of (R, S, SS)-
9a0 by X-ray experiments
Fig. 8 Synthesis of fluorine-containing indolinecarboxylate deriva-
tives 11
Table 3 Elimination of the sulfoxide in compounds 9 and 90
PMP
PMP
PMP
Method A
or
HN
*
HN
HN
CO2Et
CF3
CF3
CO2Et
CF3
+
Method B
CO2Et
TolOS
R
R
R
9 or 9´
10
10´
Entry
9/90
Methoda
R
10/100
% Yieldb
1
2
3
4
5
6
7
a
9a
9a0
9b
9b0
9c
A
A
A
A
A
B
B
Me
Me
H
10a
10a0
10b
10b0
10c
70
72
77
83
74
62
70
H
n-Pr
Allyl
Allyl
9c
9c0
10d
10d0
Method A = Ni Raney, THF. Method B = t-BuLi, THF, -78°C
Isolated yields after flash column chromatography
b
123

Asymmetric synthesis of quaternary a-amino acid derivatives and their fluorinated analogues
571
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carboxylates 11 in good yields without epimerization of the
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functionality with stabilized ortho-sulfinylbenzylcarba-
nions 1 and the subsequent nitrogen deprotection and furan
oxidation. The nucleophilic addition was highly selective
and led to the corresponding amines with two vicinal ste-
reogenic centers, one of them quaternary. For the prepa-
ration of fluorinated analogues of a-amino acids, the
reaction of the sulfinylcarbanions with a trifluoromethyl
a-imino ester (8) allowed for the attainment of the final
a-amino acid derivatives 10 just after a desulfinylation step.
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a-amino acids, namely 2-(trifluoromethyl)indoline-2-car-
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synthesis of b, b-difluorinated 1-amino-1-cyclopentane carbox-
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Fustero S, Roman R, Sanz-Cervera JF, Simon-Fuentes A, Cun˜at AC,
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´
pyrazole formation through the use of fluorinated alcohols as
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Acknowledgments We would like to thank the Spanish Ministerio
´
e Innovacion (CTQ2010-19774, CTQ-2009-12168),
Generalitat Valenciana (PROMETEO/2010/061) and Comunidad de
Madrid (‘‘programa AVANCAT CS2009/PPQ-1634’’) for their
financial support. M. S.-R. and J. A. would like to express their
de Ciencia
´
´
Garcıa Ruano JL, Aleman (2003) Stereocontrolled reactions mediated
by a remote sulfoxide group: synthesis of optically pure anti-b-
amino alcohols. Org Lett 5:4513–4516
´
gratitude for a Juan de la Cierva and Ramon y Cajal contract,
respectively, and L.M. and C.B. for their predoctoral fellowships.
´
´
Garcıa Ruano JL, Aleman J, Soriano F (2003) Facile synthesis of
optically pure 1, 2-diaryl (and 1-alkyl-2-aryl) ethyl and propyl-
amines. Org Lett 5:677–680
´
´
Garcıa Ruano JL, Aleman, Parra A (2005a) Highly stereoselective-
benzylation of N-sulfinylketimines. J Am Chem Soc 127:
13048–13054 (references cited therein)
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