Asymmetric synthesis of α- And β-amino acids by diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl) imines

Article abstract of DOI:10.1016/j.tetasy.2010.03.046

The diastereoselective addition of triorganozincates to (R)-N-(tert-butanesulfinyl)imines has been used as a key step to achieve the synthesis of highly enantiomerically enriched N-protected α- and β-amino acids. Desulfinylation of the addition products followed by benzoylation of the nitrogen atom of the obtained primary amines and oxidation of one of the substituents on the carbon atom connected to the nitrogen complete the sequence. Using the same configuration in the sulfinyl chiral auxiliary, α-amino acids with the (R) or the (S) configuration can be prepared by choosing the proper combination of imine and organozincate. α,α- Disubstituted α-amino esters with high enantiomeric purity can also be prepared when α-imino esters are the starting substrates.

Full text of DOI:10.1016/j.tetasy.2010.03.046

Tetrahedron: Asymmetry 21 (2010) 1421–1431
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of
a- and b-amino acids by diastereoselective addition
of triorganozincates to N-(tert-butanesulfinyl)imines
*
*
Raquel Almansa, Juan F. Collados, David Guijarro , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective addition of triorganozincates to (R)-N-(tert-butanesulfinyl)imines has been used as
a key step to achieve the synthesis of highly enantiomerically enriched N-protected a- and b-amino acids.
Desulfinylation of the addition products followed by benzoylation of the nitrogen atom of the obtained
primary amines and oxidation of one of the substituents on the carbon atom connected to the nitrogen
Received 2 March 2010
Accepted 31 March 2010
Available online 11 May 2010
complete the sequence. Using the same configuration in the sulfinyl chiral auxiliary,
the (R) or the (S) configuration can be prepared by choosing the proper combination of imine and organo-
zincate. -Disubstituted -amino esters with high enantiomeric purity can also be prepared when
-imino esters are the starting substrates.
a-amino acids with
This paper is dedicated to Professor Henri B.
Kagan on occasion of his 80th anniversary
a
,a
a
a
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
as Taxol, one of the most active antitumour agents.7a The method-
ologies for the asymmetric preparation of b-amino acids include
Due to the importance of
a
-amino acids1 as constituents of nat-
homologation of enantiopure
Mannich reactions, enzymatic resolution, Curtius rearrangement,
aminohydroxylation of ,b-unsaturated esters, stereoselective
hydrogenation of b-aminoacrylic acid derivatives, enolate addition
a-amino acids, enantioselective
urally occurring structures,2 such as peptides and proteins, their
asymmetric synthesis is still a very active research field in synthetic
a
organic chemistry. a-Amino acids have found applications as build-
ing blocks for the preparation of agrochemical and pharmaceutical
compounds2 and are also used as chiral auxiliaries and catalysts in a
variety of synthetic procedures.3 The numerous methods available
to chiral imines and conjugate addition of amines to
a,b-unsatu-
rated esters.7
We have recently reported the highly diastereoselective addi-
tion of triorganozincates to N-(tert-butanesulfinyl)imines,11 which
are very useful substrates for the preparation of chiral primary
amines.12 By using an excess of a previously formed triorganozin-
cate, good yields and diastereoselectivities were obtained in the
addition products, which could be easily transformed into the cor-
responding enantiomerically enriched amines by desulfinylation of
the nitrogen atom. We have improved this method by using only a
catalytic amount of a dialkylzinc to generate the organozincate,11c
which has led to higher yields and diastereoselectivities than in the
stoichiometric version. These results prompted us to apply our cat-
alytic methodology to the preparation of chiral primary amines
bearing oxidizable substituents, with the final aim of converting
these amines into amino acids.13 Herein, we report two different
approaches that have allowed us to effect the asymmetric synthe-
for the synthesis of optically active a-amino acids include several
of them which rely on the stereoselective addition of carboxylate
synthons to C@N bonds, such as the Strecker reaction or the Ugi
condensation.1a,b Some alkenyl,4 aryl5 and heteroaryl5d,6 substitu-
ents can be considered as synthetic equivalents for the carboxylic
acid, since they can be oxidatively cleaved to that functional group.
The addition of such oxidizable side chains to chiral imines
mediated by organometallic reagents4a,c,6b or their introduction as
substituents of the imine substrates4b,5d,6a,d–f is crucial in several
synthetic methodologies for the preparation of
found in the literature.
a-amino acids
On the other hand, the synthesis of b-amino acids7 has been the
subject of study of many researchers since the discovery that their
introduction into peptides enhances the stability of the latter
against proteolytic enzymes,8 which improves the metabolic labil-
ity of these peptides and allows their use as medicinal drugs. For
instance, several of these b-peptides have shown antifungal9 and
antibacterial10 activities. b-Amino acids are very useful as chiral
building blocks and as precursors of b-lactams.7b Functionalized
b-amino acids are components of several bioactive molecules, such
sis of a
- and b-amino acids.14
2. Results and discussion
We have verified that the catalytic generation of a triorganozin-
cate in the presence of a sulfinylimine generally gives a higher dia-
stereoselectivity than the addition of an excess of the previously
prepared triorganozincate to the imine.11c,14 Therefore, we decided
to use only the catalytic method to carry out this study. Since it is
* Corresponding author. Fax: +34 965903549.
E-mail addresses: dguijarro@ua.es, yus@ua.es (D. Guijarro).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.046

1422
R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
well known that the vinyl group can be oxidatively cleaved to the
corresponding carboxylic acid,4 we thought that the application of
enantiomer of the amino acid could be prepared by an appropriate
selection of the nucleophile.
our methodology to the synthesis of
(Scheme 1) would offer us the opportunity to prepare enantiome-
rically enriched -substituted -amino acids after the oxidation
a
-branched allylamines 2
Since the oxidation of the furyl group to a carboxylic acid is also
well documented in the literature,4c,5c,6 we tried an alternative ap-
proach to amino acids with the (R) absolute configuration. The
addition of primary and secondary alkyl groups to the heterocyclic
imine 1f (Scheme 2) through the corresponding alkyldimethylzin-
cates gave the expected sulfinamides in high diastereomeric ratios,
which were then converted into the corresponding primary amines
2. After benzoylation of the nitrogen, the obtained benzamides 3
were submitted to oxidation with NaIO4 catalyzed by RuCl3, which
transformed the furan ring into a carboxy group, leading to the ex-
pected N-benzoyl (R)-amino acids ent-4fa–fe in good yields and
with ee values between 92% and 96% (Scheme 2, Table 1, entries
6–10). Since in this case the substituent that was oxidatively
cleaved was not introduced in the nucleophilic addition step but
it already was in the starting imine, the absolute configuration of
the amino acid was opposite to the one obtained in our first ap-
proach (Scheme 1). Our methodology is complementary to other
a
a
step. Thus, the addition of the organozincate generated from
CH2@CHMgBr and a catalytic amount of Me2Zn to benzaldimine
1a gave the expected addition product, which was desulfinylated
by reaction with a solution of HCl in methanol15 and the obtained
free primary amine 2a was benzoylated with the aim of facilitating
the isolation of the final amino acid. Treatment of the benzamide
3a with NaIO4 in the presence of a catalytic amount of RuCl3 gave
N-benzoyl (S)-phenylglycine 4a with a 94% ee (Scheme 1, Table 1,
entry 1). An optimization of the experimental conditions revealed
that the best results were obtained performing the reaction in
THF at ꢀ78 °C. The same sequence applied to the aromatic imines
1b and 1c gave the expected protected amino acids 4b and 4c with
enantioselectivities of 92% and 88%, respectively (Scheme 1, Ta-
ble 1, entries 2 and 3). Aliphatic imines 1d and 1e were also tested
as substrates and afforded the expected amino acids 4d and 4e in
good yields (Scheme 1, Table 1, entries 4 and 5), although the ees
were lower than those obtained with the aromatic imines 1a–c.
It is worth noting that, since Me2(CH2@CH)ZnMgBr and
CH2@CHMgBr have shown opposite diastereoselectivities in their
addition to N-(tert-butanesulfinyl)benzaldimines,11a,b,16 either
reported approaches to a-amino acids involving the stereoselective
addition of organolithium6a or dialkylzinc6e reagents to imines de-
rived from furfural, since we obtain the opposite enantiomer of the
final amino acid.
We also tried to prepare
a-amino acids with a quaternary
stereogenic centre using
a-imino ester 5 (Scheme 3) as starting
O
O
O
S
NH2
i-iii
iv
v
N
t
-Bu
HN
R1
Ph
HN
R2
Ph
R1
R1
H
CO2H
1
2
3
4
a: R1 = R2 = Ph
b: R1 = R2 = 4-ClC6H4
1
2
c
: R = R = 4-MeOC6H4
d: R1 = R2 = Ph(CH2)2
e: R1 = R2 = Me(CH2)7
Scheme 1. Reagents and conditions: (i) CH2@CHMgBr (1.3 equiv), Me2Zn (0.15 equiv), THF, ꢀ78 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH; (iv) PhCOCl (2 equiv), 2 M NaOH (aq)
(34 equiv), CH2Cl2, 0–20 °C. (v) RuCl3 ꢁ H2O (5 mol %), NaIO4 (6 equiv), MeCN/H2O/CCl4 (3:3:2), 20 °C.
Table 1
Asymmetric synthesis of
a-amino acids via the diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines
Entry
Imine
Amine
Yieldb (%)
Benzamide
Yieldc (%)
a
-Amino acid
Yielde (%)
No.a
No.a
eed (%)
No.a
R2
eef (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1f
1f
1f
1f
5
2a
2b
2c
2d
2e
2fa
2fb
2fc
2fd
2fe
6a
6a
6b
6c
71
62
65
34
47
62
58
59
52
65
54
61
70
63
3a
3b
3c
3d
3e
3fa
3fb
3fc
3fd
3fe
7a
7a
7b
7c
87
92
83
81
96
60
99
99
85
69
96
96
74
84
96
92
88
60
60
94
96
92
94
95
86
92
80
62
4a
4b
4c
4d
Ph
94
89
96
90
77
75
98
77
90
88
—
94
92
88
58
60
92
96
92
92
92
—
4-ClC6H4
4-MeOC6H4
Ph(CH2)2
Me(CH2)7
Et
Me2CHCH2
Me(CH2)4
PhCH2
i-Pr
—
—
—
—
4e
ent-4fa
ent-4fb
ent-4fc
ent-4fd
ent-4fe
—
—
—
—
5g
5
—
—
—
—
—
—
5
a
b
c
Product number corresponding to the major enantiomer.
Overall isolated yield from the imine to the free amine based on the starting imine 1.
Isolated yield after column chromatography (hexane/ethyl acetate) based on the free amine 2. All isolated compounds were P95% pure (GC and/or 300 MHz 1H NMR).
d
Determined by HPLC using a ChiralCel OD-H column. The absolute configuration of the major enantiomer was deduced by comparison of the sign of the specific rotation
of the free primary amine 2 with the reported data.
e
Isolated yield based on the benzoylated amine 3. All isolated compounds were P95% pure (GC and/or 300 MHz 1H NMR).
Determined for the corresponding methyl ester by HPLC using a ChiralCel OD-H column.
The reaction was performed at ꢀ100 °C.
f
g

R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
1423
O
S
O
O
NH2
i-iii
iv
v
N
t
-Bu
HN
Ph
HN
HO2C
Ph
R2
H
R2
R2
O
O
O
1f
2
3
ent-4
fa: R2
= Et
fb: R2 = Me2CHCH2
fc: R2 = Me(CH2)4
fd: R2
fe: R2
= PhCH2
= i-Pr
Scheme 2. Reagents and conditions: (i) R2MgBr (1.3 equiv), Me2Zn (0.15 equiv), THF, ꢀ78 °C; (ii) NH4Cl (aq) (iii) HCl, MeOH; (iv) PhCOCl (2 equiv), 2 M NaOH (aq) (34 equiv),
CH2Cl2, 0–20 °C. (v) RuCl3 ꢁ H2O (5 mol %), NaIO4 (6 equiv), MeCN/H2O/CCl4 (3:3:2), 20 °C.
material. We first attempted the addition of EtMe2ZnMgBr to the
imino ester at ꢀ78 °C. We were glad to see that the ethylation
product was also obtained from the activated ketimine 5 and, after
desulfinylation and benzoylation, afforded the protected amino es-
ter 7a with an 86% ee (Scheme 3, Table 1, entry 11). In an attempt
to improve the stereoselectivity, the addition reaction was re-
peated at ꢀ100 °C, which led to the final amino ester with a 92%
ee (Scheme 3, Table 1, entry 12). An interesting point to remark
is that a reversal of the diastereoselectivity was observed when
EtMgBr was added to 5 instead of the trialkylzincate [70% ee for
the (S) enantiomer].11b Thus, both enantiomers of the final amino
ester could be prepared from the same imine substrate just by
changing the nucleophilic reagent. The addition of benzyl and iso-
propyl groups also proceeded very efficiently at ꢀ78 °C, giving the
expected N-protected amino esters 7b and 7c in good yields,
although with lower enantioselectivities than in the ethylation
reaction (80% and 62% ee, respectively; Scheme 3, Table 1, entries
13 and 14). No improvement was observed in these two cases
when the reaction was repeated at ꢀ100 °C. In all cases, the addi-
tion of the triorganozincate took place from the same face of the
imino ester as for the additions to the aldimines, giving the (R)
absolute configuration in the obtained a-amino esters 6 and 7.
Next, we examined the possibility of applying our strategy to
the synthesis of b-amino acids. Since the addition of the vinyl
group to imines 1 successfully led to the expected a-amino acids,
we thought that extending the chain of the nucleophile by one
more carbon would allow us to prepare the homologous series.
Thus, we tried to do the allylation of imine 1a by treating it with
the organozincate generated from CH2@CHCH2MgBr and a cata-
lytic amount of Me2Zn in THF at ꢀ78 °C. The expected amine ent-
2ga was obtained in good yield, but with a disappointing 44% ee.
We performed several experiments at different temperatures with
the aim of trying to improve the enantioselectivity and it increased
by raising the reaction temperature, the results being as follows:
72% ee (at ꢀ40 °C), 80% ee (at 0 °C) and 90% ee (at 20 °C). No further
improvement was obtained by setting up the reaction at 50 °C.
Therefore, we chose 20 °C as the optimum temperature. The addi-
tion of the allyl group to 1a at that temperature followed by desulf-
inylation yielded the expected homoallylamine ent-2ga, which was
then protected at the nitrogen atom with the benzoyl group afford-
ing benzamide ent-3ga with 90% ee (Scheme 4, Table 2, entry 1).
The oxidative cleavage of the terminal C@C bond was carried out
by reaction with NaIO4 catalyzed by RuCl3, giving the desired b-
amino acid 8a in 91% yield and with an 88% ee. Imine 1b could also
be transformed into the protected amino acid 8b with a 92% ee
(Scheme 4, Table 2, entry 2). However, when we submitted the
imine 8c, derived from 4-methoxybenzaldehyde, to the same reac-
tion sequence, amino aldehyde 9 (Fig. 1) was obtained with 92% ee
as the final product instead of the expected amino acid (Table 2,
entry 3). We tried to oxidize aldehyde 9 by treating it again with
the same oxidants as before, but decomposition was observed.
We do not have any good explanation for the different behaviour
of compound ent-3gc in the oxidation step. Finally, aliphatic imines
O
S
O
NH2
R2
i-iii
iv
N
t-Bu
HN
Ph
Ph
CO2Et
R2
CO2Et
Ph
CO2Et
Ph
5
6
7
a: R2 = Et
b: R2 = PhCH2
c: R2
= i-Pr
Scheme 3. Reagents and conditions: (i) EtMgBr (1.3 equiv), Me2Zn (0.15 equiv),
THF, ꢀ78 or ꢀ100 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH; (iv) PhCOCl (2 equiv), 2 M
NaOH (aq) (34 equiv), CH2Cl2, 0–20 °C.
O
O
O
NH2
S
i-iii
iv
v
N
t-Bu
HN
R1
Ph
HN
R2
Ph
R1
CO2H
R1
H
1
2g
ent-
3g
8
ent-
a: R1 = R2 = Ph
b: R1 = R2 = 4-ClC6H4
c: R1 = R2 = 4-MeOC6H4
d: R1 = R2 = Ph(CH2)2
e: R1 = R2 = Me(CH2)7
Scheme 4. Reagents and conditions: (i) CH2@CHCH2MgBr (1.3 equiv), Me2Zn (0.15 equiv), THF, 20 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH; (iv) PhCOCl (2 equiv), 2 M NaOH (aq)
(34 equiv), CH2Cl2, 0–20 °C. (v) RuCl3 ꢁ H2O (5 mol %), NaIO4 (6 equiv), MeCN/H2O/CCl4 (3:3:2), 20 °C.

1424
R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
Table 2
Asymmetric synthesis of b-amino acids via the diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines
Entry
Imine
Amine
Benzamide
Yieldc (%)
b-Amino acid
Yielde (%)
No.a
Yieldb (%)
No.a
eed (%)
No.a
R2
eef (%)
1
2
3
4
5
1a
1b
1c
1d
1e
ent-2ga
ent-2gb
ent-2gc
ent-2gd
ent-2ge
74
69
81
64
74
ent-3ga
ent-3gb
ent-3gc
ent-3gd
ent-3ge
99
87
90
87
80
90
92
94
70
72
8a
8b
9g
8d
8e
Ph
91
99
97
99
91
88
92
92
70
72
4-ClC6H4
4-MeOC6H4
Ph(CH2)2
Me(CH2)7
a
b
c
Product number corresponding to the major enantiomer.
Overall isolated yield from the imine to the free amine based on the starting imine 1.
Isolated yield after column chromatography (hexane/ethyl acetate) based on the free amine ent-2. All isolated compounds were P95% pure (GC and/or 300 MHz 1H NMR).
d
Determined by HPLC using a ChiralCel OD-H column. The absolute configuration of the major enantiomer was deduced by comparison of the sign of the specific rotation
of the free primary amine ent-2 with the reported data.
e
Isolated yield after column chromatography (hexane/ethyl acetate/methanol) based on the benzoylated amine ent-3. All isolated compounds were P95% pure (GC and/or
300 MHz 1H NMR).
f
Determined for the corresponding methyl ester by HPLC using a ChiralCel OD-H column.
The oxidation step did not give the expected b-amino acid, but the corresponding intermediate aldehyde 9 (see Fig. 1).
g
R
O
H
Ar
ZnMe2MgBr
H
O
ZnMe2MgBr
SO(t-Bu)
HN
Ph
N
CHO
N
Ar
MeO
A
B
9
Figure 2.
Figure 1.
calculations are in progress in order to establish the viability of
these proposals.
1d and 1e also led to the expected b-amino acids 8d and 8e in very
good yields, although in lower ees than in the reactions with benz-
aldimines 1a–c (Scheme 4, Table 2, entries 4 and 5). Although sev-
eral examples of the synthesis of b-amino acids by oxidative
cleavage of homoallylamines have been reported,17 to the best of
our knowledge this is the first time that the allylation of sulfinyli-
mines18 has been used as a key step for the preparation of those
amino acids.
3. Conclusions
In conclusion, the addition of triorganozincates to N-(tert-
butanesulfinyl)imines can be used as a key step in the asymmetric
synthesis of a- and b-amino acids and derivatives. Using the same
In all cases, as we had previously observed,11 the two diastere-
oisomers of the sulfinamides were the only products that could be
detected in the crude reaction mixtures after the addition of the
triorganozincates to imines 1 or 5. Therefore, they could be submit-
ted to the desulfinylation procedure without further purification,
affording the expected primary amines. By comparison of the sign
of their specific rotations with the data reported in the literature,
the absolute configuration of the amines 2, ent-2 and 6 could be
determined. The oxidation of the benzamides 3 and ent-3 was per-
formed following a literature procedure.19 The enantiomeric ex-
sulfinyl group on the nitrogen of the starting imine, the absolute
configuration of the final amino acid can be controlled by an appro-
priate choice of the way in which the synthetic equivalent of the
carboxy group is introduced. The methodology is also applicable
to the synthesis of
a,a
-disubstituted
a-amino acids with high
enantiomeric purity by using
a
-imino esters as substrates. Further
efforts to find more synthetic applications of this addition method-
ology are currently underway in our laboratories.
4. Experimental
4.1. General
cesses of the N-protected amino acids
4 and ent-4 were
determined for their corresponding methyl esters20 by HPLC anal-
ysis using a ChiralCel OD-H column. As it can be seen in Tables 1
and 2, in some cases there was a very slight loss of optical purity
(2% maximum) during the whole process from the imines to the
amino acids: the ee values of the final amino acids match very well
with the ee’s of the corresponding amines 2 or ent-2.
For general experimental information, see Ref. 22. When men-
tioned, an Rf value measured on deactivated silica gel means that
the TLC plate was eluted with a mixture of 5% triethylamine in hex-
ane and dried before applying the sample. Unless otherwise stated,
NMR samples were prepared using CDCl3 as solvent. All starting
materials needed for the synthesis of imines 1 and the solutions
of EtMgBr (1 M in THF, Aldrich), Me2CHCH2MgCl (2 M in THF, Al-
drich), Me(CH2)4MgBr (2 M in Et2O, Aldrich), PhCH2MgCl (1 M in
THF, Acros), i-PrMgBr (2 M in THF, Aldrich), CH2@CHMgBr (1 M
in THF, Aldrich), CH2@CHCH2MgBr (1 M in Et2O, Aldrich) and
Me2Zn (2 M in toluene, Aldrich) were commercially available and
were used as received. Optical rotations were measured on a Per-
kin–Elmer 341 polarimeter. HPLC analyses were performed at
25 °C on a JASCO apparatus, equipped with a PU-2089 Plus pump,
a MD-2010 Plus detector and an AS-2059 Plus automatic injector.
The stereochemical outcome of the addition reactions could be
rationalized assuming that they occur through the transition states
depicted in Figure 2. An alkyl or vinyl group would add to the
imine from the less sterically hindered Re-face through an open
transition state where the imine adopts the conformation shown
in Figure 2A, which is its preferred conformation according to the-
oretical calculations.21 In the case of the allylation reactions, the
addition of the nucleophile could take place from the Si-face of
the imine via a chair-like transition state like the one depicted in
Figure 2B through a SE20 mechanism. The coordination of the oxy-
gen atom of the sulfinyl group to the magnesium atom could pro-
vide further stabilization to both transition states. Theoretical

R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
1425
The HRMS (EI) were performed by the Technical Services of the
University of Alicante on a Finnigan MAT 95S apparatus.
(20), 134 (11), 132 (16), 131 (61), 115 (18), 103 (67), 102 (21),
77 (28), 63 (11), 51 (10).
4.2. Synthesis of imines 1
4.4.3. (S)-5-Phenylpent-1-en-3-amine 2d30
Colourless oil; Rf 0.28 (hexane/ethyl acetate: 1/1, deactivated
Imines 1 and 5 were prepared by reaction of the corresponding
aldehydes or ketone with (R)-tert-butanesulfinamide, according to
the literature procedures.23 Compounds 1a,23a 1b,24 1c,24 1d,25
1e,11b 1f26 and 511b were characterized by comparison of their
physical and spectroscopic data with those reported in the
literature.
silica gel); ½a 2D0
ꢂ
¼ þ4:0 (c 0.5, CHCl3, 60% ee);
m (film) 3092, 3072,
1609, 1449 (HC@C), 1261 cmꢀ1 (CN); dH 1.35 (br s, 2H, NH2),
1.75 (dt, 2H, J = 8.4, 7.4 Hz, CH2CH2CH), 2.67 (dd, 2H, J = 8.4,
7.4 Hz, CH2Ph), 3.32 (qt, 1H, J = 6.7, 0.9 Hz, CHN), 5.06 (ddd, 1H,
J = 10.3, 1.4, 1.1 Hz, 1 ꢁ CHH@C), 5.14 (dt, 1H, J = 17.2, 1.1 Hz,
1 ꢁ CHH@C), 5.82 (ddd, 1H, J = 17.2, 10.3, 6.8 Hz, CH@CH2), 7.18–
7.30 (m, 5H, ArH); dC 32.4 (CH2Ph), 39.1 (CH2CH2CH), 54.0 (CHN),
113.8 (CH2@C), 125.7, 128.3 (2C), 128.4 (2C), 142.1 (ArC), 143.2
(CH@CH2); m/z 161 (M+, 2%), 144 (21), 142 (12), 141 (11), 129
(20), 128 (11), 115 (12), 105 (11), 104 (39), 103 (20), 91 (30), 78
(17), 77 (17), 56 (100), 51 (16).
4.3. Addition of triorganozincates to imines 1: General
procedure
The addition of the catalytically generated organozincates to
imines 1 or 5 was carried out as previously described by us.11c
All the reactions used as the first step for the preparation of
a-ami-
4.4.4. (S)-Undec-1-en-3-amine 2e
no acids were performed at ꢀ78 °C (or ꢀ100 °C in the case of the
synthesis of amine 6a). The temperature of the addition reactions
that led to the homoallylic amines ent-2ga–ge was 20 °C. In all
cases, the obtained diastereomeric mixtures of sulfinamides were
submitted to the desulfinylation procedure without further
purification.
Colourless oil; Rf 0.20 (hexane/ethyl acetate: 1/1, deactivated
silica gel); ½a 2D0
ꢂ
¼ þ9:2 (c 1, CHCl3, 60% ee);
m (film) 3024 (HC@C),
1244 cmꢀ1 (CN); dH 0.88 (t, 3H, J = 6.7 Hz, Me), 1.22–1.44 [m, 14H,
(CH2)7], 3.27 (qd, 1H, J = 6.7, 1.1 Hz, CHN), 5.00 (ddd, 1H, J = 10.3,
1.5, 1.1 Hz, 1 ꢁ CHH@C), 5.09 (ddd, 1H, J = 17.2, 1.5, 1.1 Hz,
1 ꢁ CHH@C), 5.78 (ddd, 1H, J = 17.2, 10.3, 6.7 Hz, CH@CH2); dC
14.1 (Me), 22.6, 26.1, 29.3, 29.5, 29.6, 31.9, 37.6 [(CH2)7], 54.5
(CHN), 113.1 (CH2@C), 143.6 (CH@CH2); HRMS: M+ꢀC2H3 found
142.1633, C9H20N requires 142.1596.
4.4. Desulfinylation of the addition products. Isolation of
amines 2, ent-2 and 6: General procedure
The crude mixture of the addition reaction was dissolved in a
1.5 M solution of HCl in methanol (4 mL; prepared by dropwise
addition of SOCl2 to methanol at 0 °C) and stirred overnight at
room temperature. Then, the solvent was evaporated, a 2 M aque-
ous HCl solution (5 mL) was added and the mixture was extracted
with ethyl acetate (3 ꢁ 5 mL). The organic layers were discarded.
The aqueous layer was basified with a buffer solution of NH3
(1 M)/NH4Cl (1 M) and extracted with CH2Cl2 (3 ꢁ 10 mL). The
combined organic phases were dried (Na2SO4). After filtration
and evaporation of the solvent, pure amines 2, ent-2 and 6 were
obtained in the yields indicated in Tables 1 and 2. Amines 2a,27
2fa28 and 6a11b were characterized by comparison of their physical
and spectroscopic data with those reported in the literature. The
corresponding physical, spectroscopic and analytical data for the
other amines follow.
4.4.5. (R)-1-(2-Furyl)-3-methylbutan-1-amine 2fb31
Yellow oil; Rf 0.22 (hexane/ethyl acetate: 1/1, deactivated silica
gel); ½a 2D0
ꢂ
¼ þ46:0 (c 1, CHCl3, 96% ee);
m (film) 3386 (NH), 1649,
1555, 1461 (HC@C), 1142 cmꢀ1 (CN); dH 0.90, 0.92 (2d, 3H each,
J = 6.2 Hz each, Me2CH), 1.52–1.70 (m, 3H, CHMe2 and CH2), 1.40
(br s, 2H, NH2), 3.98 (t, 1H, J = 7.0 Hz, CHN), 6.11 (d, 1H,
J = 3.2 Hz, O–C@CH), 6.29 (dd, 1H, J = 3.2, 1.8 Hz, O–CH@CH), 7.33
(dd, 1H, J = 1.8, 0.8 Hz, O–CH); dC 22.3, 22.8 (2 ꢁ Me), 24.9 (CHMe),
45.3 (CH2), 47.8 (CHN), 104.2 (O–C@CCH), 110.0 (O–CH@CH), 141.2
(O–CH), 159.0 (O–C); m/z 153 (M+, <1%), 136 (14), 121 (20), 96
(100), 91 (10).
4.4.6. (R)-1-(2-Furyl)hexan-1-amine 2fc
Colourless oil; Rf 0.29 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢂ
¼ þ10:4 (c 1, CHCl3, 92% ee);
m (film) 3324 (NH), 1645, 1469
(HC@C), 1142 cmꢀ1 (CN); dH 0.80 (d, 3H, J = 6.7 Hz, Me), 1.16–
1.36 [m, 6H, (CH2)3Me], 1.53–1.77 (m, 2H, CH2CH), 1.82 (br s, 2H,
NH2), 3.03 (t, 1H, J = 6.9 Hz, CHN), 6.04 (d, 1H, J = 3.2 Hz, O–C@CH),
6.23 (dd, 1H, J = 3.2, 1.8 Hz, O–CH@CH), 7.26 (dd, 1H, J = 1.8, 0.8 Hz,
O–CH); dC 14.0 (Me), 22.5, 25.8, 31.7, 36.2 [(CH2)4], 49.8 (CHN),
104.2 (O–C@CH), 109.9 (O–CH@CH), 141.2 (O–CH), 159.0 (O–C);
m/z 167 (M+, <1%), 150 (19), 107 (36), 96 (100), 94 (35), 79 (22),
77 (18).
4.4.1. (R)-1-(4-Chlorophenyl)prop-2-en-1-amine 2b29
Colourless oil; Rf 0.15 (hexane/ethyl acetate: 4/1, deactivated
silica gel); ½a 2D0
ꢂ
¼ þ6:0 (c 0.2, CHCl3, 92% ee);
m (film) 3397 (NH),
3019 (HC@C), 1216 cmꢀ1 (CN); dH 2.35 (s, 2H, NH2), 4.51 (d, 1H,
J = 6.1 Hz, CHN), 5.12 (d, 1H, J = 10.3 Hz, 1 ꢁ CHH@C), 5.23 (d, 1H,
J = 17.0 Hz, 1 ꢁ CHH@C), 5.91–6.02 (m, 1H, CH@CH2), 7.29 (s, 4H,
ArH); dC 57.8 (CHN), 114.1 (CH2@C), 128.0 (2C), 128.6 (2C), 132.7,
142.8 (ArC), 141.8 (CH@CH2); m/z 167 (M+, 25%), 166 (80), 142
(29), 140 (100), 132 (62), 130 (31), 115 (53), 77 (36), 56 (30), 55
(30).
4.4.7. (R)-1-(2-Furyl)-2-phenylethanamine 2fd32
Orange oil; Rf 0.24 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢂ
¼ ꢀ10:5 (c 1, EtOH, 94% ee);
m (film) 3385 (NH), 3078, 3024,
4.4.2. (R)-1-(4-Methoxyphenyl)prop-2-en-1-amine 2c
1602, 1495, 1455 (HC@C), 1155 cmꢀ1 (CN); dH 2.07 (br s, 2H,
NH2), 2.90 (dd, 1H, J = 13.4, 8.3 Hz, 1 ꢁ CHH), 3.17 (dd, 1H,
J = 13.4, 5.3 Hz, 1 ꢁ CHH), 4.21 (dd, 1H, J = 8.3, 5.3 Hz, CHN), 6.10
(d, 1H, J = 3.2 Hz, O–C@CH), 6.30 (dd, 1H, J = 3.2, 1.8 Hz, O–CH@CH),
7.11–7.33 (m, 5H, ArH), 7.37 (dd, 1H, J = 1.8, 0.7 Hz, O–CH); dC 42.9
(CH2), 51.1 (CHN), 104.9 (O–C@CH), 110.0 (O–CH@CH), 126.5, 128.4
(2C), 129.3 (2C), 138.1 (ArC), 141.3 (O–CH), 157.8 (O–C); m/z 187
(M+, <1%), 170 (99), 169 (38), 142 (20), 141 (97), 115 (48), 96
(100), 91 (13).
Colourless oil; Rf 0.16 (hexane/ethyl acetate: 4/1, deactivated
silica gel); ½a 2D0
ꢂ
¼ ꢀ16:0 (c 0.2, CHCl3, 88% ee);
m (film) 3361
(NH), 1609 (HC@C), 1247 (CO), 1035 cmꢀ1 (CN); dH 1.60 (s, 2H,
NH2), 3.80 (s, 3H, Me), 4.49 (d, 1H, J = 6.1 Hz, CHN), 5.09 (dt, 1H,
J = 10.2, 1.5 Hz, 1 ꢁ CHH@C), 5.22 (dt, 1H, J = 17.1, 1.5 Hz,
1 ꢁ CHH@C), 6.00 (ddd, J = 17.1, 10.2, 6.1 Hz, CH@CH2), 6.87, 7.26
(2d, 2H each, J = 8.7 Hz each, ArH); dC 55.3 (Me), 57.7 (CHN),
113.4 (CH2@C), 113.9 (2C), 127.7 (2C), 136.6, 155.7 (ArC), 142.5
(CH@CH2); m/z 163 (M+, 10%), 162 (14), 147 (14), 146 (100), 136

1426
R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
4.4.8. (R)-1-(2-Furyl)-2-methylpropan-1-amine 2fe28
4.4.13. (R)-Dodec-1-en-4-amine ent-2ge35
Colourless oil; Rf 0.18 (ethyl acetate, deactivated silica gel);
Colourless oil; Rf 0.24 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢂ
¼ þ6:4 (c 0.6, CHCl3, 95% ee);
m
(film) 3113 (NH), 1644,
½
a 2D0
ꢂ
¼ ꢀ4:0 (c 0.5, CHCl3, 72% ee);
m (film) 1636, 1459 (HC@C),
1594, 1465 (HC@C), 1148 cmꢀ1 (CN); dH 0.87 0.94 (2d, 3H each,
J = 6.8 Hz each, Me2CH), 1.64 (br s, 2H, NH2), 2.00 (oct, 1H,
J = 6.8 Hz, CHMe2), 3.69 (d, 1H, J = 6.2 Hz, CHN), 6.12 (d, 1H,
J = 3.2 Hz, O–C@CH), 6.30 (dd, 1H, J = 3.2, 1.8 Hz, O–CH@CH), 7.33
(d, 1H, J = 1.8 Hz, O–CH); dC 18.3, 19.2 (Me2CH), 33.4 (CHMe2),
55.8 (CHN), 105.0 (O–C@CH), 109.8 (O–CH@CH), 141.0 (O–CH),
158.3 (O–C); m/z 122 (100), 109 (67), 104 (12).
1258 cmꢀ1 (CN); dH 0.88 (t, 3H, J = 6.6 Hz, Me), 1.22–1.32 [m, 12H,
(CH2)6Me], 1.97 (dtt, 1H, J = 13.7, 8.0, 0.9 Hz, 1 ꢁ CHHCH@CH2),
2.24 (dddt, J = 13.7, 6.2, 4.6, 1.3 Hz, 1 ꢁ CHHCH@CH2), 2.73–2.82
(m, 1H, CHN), 5.08 (d, 1H, J = 16.1 Hz, 1 ꢁ CHH@CH), 5.09 (d, 1H,
J = 16.1 Hz, 1 ꢁ CHH@CH), 5.72–5.86 (m, 1H, CH@CH2); dC 14.1
(Me), 22.7, 26.3, 29.3, 29.6, 29.8, 31.9, 40.5, 42.5 (8 ꢁ CH2), 50.6
(CHN), 117.3 (CH2@C), 136.0 (CH@CH2); m/z 167 (32), 150 (12),
149 (100), 71 (11), 70 (13), 57 (16).
4.4.9. (S)-1-Phenylbut-3-en-1-amine ent-2ga18a
4.4.14. (R)-Ethyl 2-amino-2,3-diphenylpropanoate 6b36
Yellow oil; Rf 0.50 (hexane/ethyl acetate: 1/1, deactivated silica
gel); ½a 2D0
ꢂ
¼ ꢀ25:3 (c 1, CHCl3, 90% ee);
m (film) 3379 (NH), 3065,
Yellow oil; Rf 0.47 (hexane/ethyl acetate: 1/1, deactivated silica
3026, 1639, 1492 cmꢀ1 (HC@C); dH 1.70 (br s, 2H, NH2), 2.29–
2.50 (m, 2H, CH2CN), 3.97 (dd, 1H, J = 8.1, 5.3 Hz, CHN), 5.06 (d,
1H, J = 10.2 Hz, 1 ꢁ CHH@C), 5.12 (d, 1H, J = 17.1 Hz, 1 ꢁ CHH@C),
5.74 (dddd, 1H, J = 17.2, 10.3, 8.1, 6.3 Hz, CH@CH2), 7.20–7.32 (m,
5H, ArH); dC 44.1 (CH2CN), 55.2 (CHN), 117.5 (CH2@C), 126.2
(2C), 126.8, 128.3 (2C), 145.7 (2C) (ArC), 135.3 (CH@CH2); m/z
106 (M+ꢀC3H5, 100%), 79 (27), 77 (20).
gel); ½a 2D0
ꢂ
¼ þ7:6 (c 0.5, CHCl3, 80% ee);
m (film) 3386 (NH), 3061,
3029 (HC@C), 1728 (C@O), 1195 cmꢀ1 (CN); dH 1.24 (t, 3H,
J = 7.1 Hz, Me), 2.37 (br s, 2H, NH2), 3.18, 3.64 (2d, 1H each,
J = 13.3 Hz each, CH2Ph), 4.19 (q, 1H, J = 7.1 Hz, CH2O), 7.11–7.60
(m, 10H, ArH); dC 14.0 (Me), 45.7 (CH2Ph), 61.6 (CH2O), 64.4
(CN), 125.6 (2C), 127.0 (2C), 127.6, 128.2 (2C), 128.3, 130.5 (2C),
136.0, 142.6 (ArC), 174.7 (C@O); m/z 240 (M+ꢀC2H5, <1%), 197
(14), 196 (88), 179 (16), 178 (100), 150 (11), 104 (56), 91 (15),
71 (10).
4.4.10. (S)-1-(4-Chlorophenyl)but-3-en-1-amine ent-2gb33
Colourless oil; Rf 0.29 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢂ
¼ ꢀ44:7 (c 1, CHCl3, 92% ee);
m (film) 3375 (NH), 3076, 1640
4.4.15. (R)-Ethyl 2-amino-3-methyl-2-phenylbutanoate 6c
Yellow oil; Rf 0.42 (hexane/ethyl acetate: 1/1, deactivated silica
(HC@C), 1091 cmꢀ1 (CN); dH 1.54 (br s, 2H, NH2), 2.32 (ddt, 1H,
J = 13.7, 7.9, 0.9 Hz, 1 ꢁ CHHCN), 2.42 (ddt, 1H, J = 13.7, 5.6,
1.2 Hz, 1 ꢁ CHHCN), 3.99 (dd, 1H, J = 7.9, 5.6 Hz, CHN), 5.09 (dq,
1H, J = 10.3, 1.0 Hz, 1 ꢁ CHH@CH), 5.11 (dq, 1H, J = 17.0, 1.6 Hz,
1 ꢁ CHH@CH), 5.72 (dddd, 1H, J = 17.0, 10.3, 7.9, 6.5 Hz, CH@CH2),
7.29 (s, 4H, 2 ꢁ ArH); dC 44.2 (CH2CN), 54.7 (CHN), 118.0 (CH2@C),
127.7 (2C), 128.4 (2C), 132.5, 144.2 (ArC), 135.0 (CH@CH2); m/z 181
(M+, <1%), 142 (32), 140 (100), 77 (16).
gel); ½a 2D0
ꢂ
¼ ꢀ12:1 (c 0.5, CHCl3, 62% ee);
m (film) 3400 (NH), 1726
(C@O), 1218 cmꢀ1 (CN); dH 0.67, 1.01 (2d, 3H each, J = 6.8 Hz each,
Me2CH), 1.23 (t, 3H, J = 7.1 Hz, MeCH2), 1.93 (br s, 2H, NH2), 2.76
(septet, 1H, J = 6.8 Hz, CHMe2), 4.15 (qd, 2H, J = 7.1, 0.9 Hz, CH2),
7.22–7.66 (m, 5H, ArH); dC 14.0 (MeCH2), 16.2, 17.9 (Me2CH),
35.3 (CHMe), 61.3 (CH2), 66.9 (CN), 125.9 (2C), 127.1, 128.1 (2C),
142.2 (ArC), 175.3 (C@O); m/z 221 (M+, <1%), 178 (49), 149 (12),
148 (100), 104 (39); HRMS: M+ꢀC3H7 found 178.0886, C10H12NO2
requires 178.0868.
4.4.11. (S)-1-(4-Methoxyphenyl)but-3-en-1-amine ent-2gc34
Yellow oil; Rf 0.36 (hexane/ethyl acetate: 1/1, deactivated silica
gel); ½a 2D0
ꢂ
¼ ꢀ37:5 (c 0.55, CHCl3, 94% ee);
m (film) 3321 (NH), 3069,
4.5. Benzoylation of the free amines. Isolation of compounds 3,
ent-3 and 7: General procedure
1609 (HC@C), 1250 (CO), 1178 cmꢀ1 (CN); dH 2.34 (dtdd, 1H,
J = 13.8, 8.0, 1.5, 1.0 Hz, 1 ꢁ CHHCN), 2.43 (ddddd, 1H, J = 13.8,
6.4, 5.4, 1.5, 1.0 Hz, 1 ꢁ CHHCN), 3.80 (s, 3H, MeO), 3.95 (dd, 1H,
J = 8.0, 5.4 Hz, CHN), 5.07 (ddt, 1H, J = 10.2, 2.0, 1.0 Hz,
1 ꢁ CHH@CH), 5.11 (ddt, 1H, J = 17.1, 2.0, 1.5 Hz, 1 ꢁ CHH@CH),
5.74 (dddd, 1H, J = 17.1, 10.2, 8.0, 6.4 Hz, CH@CH2), 6.87, 7.26
(2d, 2H each, J = 8.5 Hz each, ArC); dC 44.2 (CH2CN), 54.7 (CHN),
55.2 (Me), 117.5 (CH2@C), 113.7 (2C), 127.3 (2C), 137.9, 158.5
(ArC), 135.6 (CH@CH2); m/z 177 (M+, 13%), 176 (100), 161 (13),
146 (7), 91 (7), 77 (5).
An aqueous 2 M NaOH solution (10 mL) was added to a solution
of the corresponding amine (0.57 mmol) in CH2Cl2 (10 mL) at 0 °C
and the mixture was stirred for 5 min. Benzoyl chloride
(1.14 mmol) was added and the mixture was stirred overnight at
room temperature. Then, water (5 mL) was added and the mixture
was extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic lay-
ers were washed with brine (10 mL) and dried (Na2SO4). After fil-
tration and evaporation of the solvent, the pure benzamides 3,
ent-3 and 7 were obtained. These benzamides were analyzed by
HPLC on a ChiralCel OD-H column using a 254 nm UV detector,
10% i-PrOH in hexane as eluent and a flow rate of 0.5 mL/min.
The retention times were 18.5 (3a), 29.7 (ent-3a), 26.0 (3b), 38.3
(ent-3b), 33.9 (3c), 40.7 (ent-3c), 35.0 (3d), 43.2 (ent-3d), 15.3
(ent-3e), 19.3 (3e), 15.8 (3fa), 19.2 (ent-3fa), 12.8 (3fb), 16.1 (ent-
3fb), 13.2 (3fc), 18.9 (ent-3fc), 27.6 (3fd), 33.0 (ent-3fd), 14.4
(3fe), 15.7 (ent-3fe), 22.5 (3ga), 37.5 (ent-3ga), 23.8 (3gb), 31.7
(ent-3gb), 33.2 (3gc), 38.5 (ent-3gc), 34.1 (3gd), 43.5 (ent-3gd),
14.1 (ent-3ge), 19.2 (3ge), 13.3 (ent-7a; 5% i-PrOH in hexane as
eluent), 15.4 (7a; 5% i-PrOH in hexane as eluent), 33.3 (ent-7b;
2% i-PrOH in hexane as eluent), 35.6 (7b; 2% i-PrOH in hexane as
eluent), 61.0 (ent-7c; 1% i-PrOH in hexane as eluent), 71.0 (7c;
1% i-PrOH in hexane as eluent). The yields and enantiomeric ex-
cesses obtained are collected in Tables 1 and 2. Benzamides 3a,29
3fa,28 3fe,28 ent-3ga37 were characterized by comparison of their
physical and spectroscopic data with those reported in the
4.4.12. (R)-1-Phenylhex-5-en-3-amine ent-2gd34
Yellow oil; Rf 0.54 (hexane/ethyl acetate: 1/1, deactivated sil-
ica gel); ½a 2D0
ꢂ
¼ þ6:9 (c 0.7, CHCl3, 70% ee);
m (film) 3058, 3027,
1640, 1599, 1495, 1448 (HC@C), 1381 cmꢀ1 (CN); dH 1.37 (s, 2H,
NH2), 1.61 (dddd, 1H, J = 13.6, 10.1, 7.9, 5.7 Hz, 1 ꢁ CHCHHCH2),
1.76 (dddd, 1H, J = 13.6, 10.2, 6.2, 4.7 Hz, 1 ꢁ CHCHHCH2), 2.03
(dtt, 1H, J = 13.7, 7.9, 1.0 Hz, 1 ꢁ CHHCH@CH2), 2.27 (dddt, 1H,
J = 13.7, 6.3, 1.4 Hz, 1 ꢁ CHHCH@CH2), 2.64 (ddd, 1H, J = 13.7,
10.1, 6.2 Hz, 1 ꢁ CHHPh), 2.76 (ddd, 1H, J = 13.7, 10.2, 5.7 Hz,
1 ꢁ CHHPh), 2.82 (tt, 1H, J = 7.9, 4.7 Hz, CHN), 5.09 (ddt, 1H,
J = 10.7, 2.0, 1.0 Hz, 1 ꢁ CHH@CH), 5.10 (ddt, 1H, J = 16.3, 2.0,
1.4 Hz, 1 ꢁ CHH@CH), 5.79 (dddd, 1H, J = 16.3, 10.7, 8.1, 6.3 Hz,
CH@CH2), 7.30–7.16 (m, 5H, ArH); dC 32.6 (CH2Ph), 39.4
(CHCH2CH2), 42.6 (CH2CH@CH2), 50.1 (CHN), 117.5 (CH2@C),
125.7, 128.31 (2C), 128.34 (2C), 142.2 (ArC), 135.6 (CH@CH2);
m/z 134 (M+ꢀC3H5, 2%), 134 (81), 117 (24), 91 (100), 70 (16).

R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
1427
literature. The corresponding physical, spectroscopic and analytical
data for the other benzamides follow.
1 ꢁ CHH), 1.82 (dt, 1H, J = 13.5, 7.4 Hz, 1 ꢁ CHH), 5.41 (q, 1H,
J = 7.9 Hz, CHN), 6.25 (d, 1H, J = 3.2 Hz, O–C@CH), 6.32 (dd, 1H,
J = 3.2, 1.8 Hz, O–CH@CH), 7.36 (dd, 1H, J = 1.8, 0.7 Hz, O–CH),
7.42, 7.50, 7.78 (t, t and d, respectively, 2H, 1H and 2H, respec-
tively, J = 7.2 Hz each, ArH); dC 22.49, 22.51 (Me2CH), 25.0 (CHMe),
43.1 (CH2), 46.0 (CHN), 106.3 (O–C@CH), 110.0 (O–CH@CH), 126.9
(2C), 128.4 (2C), 130.2, 134.4 (ArC), 141.8 (O–CH), 154.6 (O–C),
166.5 (C@O); m/z 257 (M+, 15%), 200 (31), 136 (13), 121 (20),
105 (100), 77 (34).
4.5.1. (R)-N-[1-(4-Chlorophenyl)allyl]benzamide 3b14
Yellow oil; Rf 0.16 (hexane/ethyl acetate: 4/1); ½a D20
¼ þ36:0 (c
ꢂ
1, CHCl3, 92% ee);
m (film) 3295 (NH), 3091, 3058 (HC@C), 1636
(C@O), 1528 (N–C@O), 1342 cmꢀ1 (CN); dH 5.30 (ddd, 1H, J = 17.0,
1.7, 0.9 Hz, 1 ꢁ CHH@C), 5.34 (ddd, 1H, J = 10.4, 1.5, 0.9 Hz,
1 ꢁ CHH@C), 5.82 (dd, 1H, J = 8.0, 5.5 Hz, CHN), 6.09 (ddd, 1H,
J = 17.0, 10.4, 5.5 Hz, CH@CH2), 6.36 (d, 1H, J = 8.0 Hz, NH), 7.29–
7.54 (m, 9H, ArH); dC 54.9 (CHN), 116.9 (CH2@C), 126.9 (2C),
128.7 (4C), 128.9 (2C), 131.7, 133.6, 134.1, 139.0 (ArC), 136.7
(CH@CH2), 160.5 (C@O); m/z 271 (M+, 11%), 256 (14), 115 (38),
105 (100), 77 (48), 51 (15).
4.5.6. (R)-N-[1-(2-Furyl)hexyl]benzamide 3fc14
White solid; mp 65–66 °C; Rf 0.52 (hexane/ethyl acetate: 3/1);
½
a 2D0
ꢂ
¼ þ35:0 (c 1, CHCl3, 92% ee);
m (film) 3343 (NH), 1688 (HC@C),
1633 (C@O), 1525 (N–C@O), 1291 cmꢀ1 (CN); dH 0.87 (t, 3H,
J = 7.0 Hz, Me), 1.26–1.41 [m, 6H, (CH2)3Me], 1.84–1.98 (m, 2H,
CH2CN), 5.32 (dt, 1H, J = 8.4, 7.4 Hz, CHN), 6.24 (d, 1H, J = 3.3 Hz,
O–C@CH), 6.32 (dd, 1H, J = 3.3, 1.9 Hz, O–CH@CH), 6.38 (d, 1H,
J = 8.4 Hz, NH), 7.36 (dd, 1H, J = 1.9, 0.8 Hz, O–CH), 7.40–7.80 (m,
5H, ArH); dC 14.0 (Me), 22.5, 25.6, 31.4, 34.1 [(CH2)4], 47.6 (CHN),
106.4 (O–C@CH), 110.2 (O–CH@CH), 126.9 (2C), 128.5 (2C),
131.5, 134.4 (ArC), 141.8 (O–CH), 154.3 (O–C), 166.6 (C@O); m/z
271 (M+, 12%), 200 (43), 105 (100), 94 (12), 77 (33).
4.5.2. (R)-N-[1-(4-Methoxyphenyl)allyl]benzamide 3c14
Colourless oil; Rf 0.14 (hexane/ethyl acetate: 4/1); ½a D20
¼ þ43:6
ꢂ
(c 1, CHCl3, 88% ee);
m (film) 3314 (NH), 3078, 3052, 1628 (C@O),
1525 (N–C@O), 1249 (CO), 1238 cmꢀ1 (CN); dH 3.80 (s, 3H, Me),
5.29 (ddd, 1H, J = 17.4, 1.7, 1.1 Hz, 1 ꢁ CHH@C), 5.30 (ddd, 1H,
J = 10.2, 1.7, 1.1 Hz, 1 ꢁ CHH@C), 5.80 (ddt, 1H, J = 8.1, 5.1, 1.7 Hz,
CHN), 6.10 (ddd, 1H, J = 17.4, 10.2, 5.1 Hz, CH@CH2), 6.33 (d, 1H,
J = 8.1 Hz, NH), 6.90, 7.30 (2d, 2H each, J = 8.7 Hz each, 4 ꢁ ArH),
7.42, 7.49, 7.79 (t, t and d, respectively, 2H, 1H and 2H, respec-
tively, J = 7.3 Hz each, 5 ꢁ ArH); dC 54.9 (Me), 55.3 (CHN), 115.8
(CH2@C), 114.2 (2C), 128.6 (2C), 134.4, 159.2 (ArC), 137.3
(CH@CH2), 166.4 (C@O); m/z 267 (M+, 23%), 252 (25), 162 (16),
146 (58), 131 (44), 121 (24), 105 (100), 103 (76), 77 (92), 63
(15), 51 (36).
4.5.7. (R)-N-[1-(2-Furyl)-2-phenylethyl]benzamide 3fd28
Colourless oil; Rf 0.21 (hexane/ethyl acetate: 3/1); ½a D20
¼ þ1:7
ꢂ
(c 1, CHCl3, 94% ee);
m (film) 3225 (NH), 3063 (HC@C), 1640
(C@O), 1526 (N–C@O), 1155 cmꢀ1 (CN); dH 3.23 (dd, 1H, J = 13.5,
7.5 Hz, 1 ꢁ CHH), 3.29 (dd, 1H, J = 13.5, 6.2 Hz, 1 ꢁ CHH), 5.58
(ddd, 1H, J = 8.3, 7.5, 6.2 Hz, CHN), 6.08 (d, 1H, J = 3.2 Hz, O–C@CH),
6.28 (dd, 1H, J = 3.2, 1.8 Hz, O–CH@CH), 6.44 (d, 1H, J = 8.3 Hz, NH),
7.06–7.29 (m, 5H, 5 ꢁ ArH), 7.39 (dd, 1H, J = 1.8, 0.8 Hz, O–CH),
7.40–7.73 (m, 5H, 5 ꢁ ArH); dC 40.2 (CH2), 48.9 (CHN), 107.0 (O–
C@CH), 110.3 (O–CH@CH), 126.7, 126.9 (2C), 128.3 (2C), 128.6
(2C), 129.3 (2C), 131.6, 134.3, 136.9 (ArC), 141.8 (O–CH), 153.1
(O–C), 166.5 (C@O); m/z 291 (M+, <1%), 200 (73), 105 (100), 77 (28).
4.5.3. (S)-N-[1-(2-Phenylethyl)prop-2-enyl]benzamide 3d38
Colourless oil; Rf 0.36 (hexane/ethyl acetate: 4/1); ½a D20
¼ þ9:7
ꢂ
(c 0.7, CHCl3, 60% ee);
m (film) 3300 (NH), 3026 (HC@C), 1634
(C@O), 1537 (N–C@O), 1294 cmꢀ1 (CN); dH 1.97 (dq, 1H, J = 13.9,
7.6 Hz, 1 ꢁ CHHCH2Ph), 2.02 (dq, 1H, J = 13.9, 7.8 Hz,
1 ꢁ CHHCH2Ph), 2.74 (t, 2H, J = 7.8 Hz, CH2Ph), 4.76 (q, 1H,
J = 6.9 Hz, CHN), 5.19 (dt, 1H, J = 10.4, 1.3 Hz, 1 ꢁ CHH@C), 5.24
(dt, 1H, J = 17.2, 1.3 Hz, 1 ꢁ CHH@C), 5.90 (ddd, 1H, J = 17.2, 10.4,
5.5 Hz, CH@CH2), 6.05 (d, 1H, J = 7.4 Hz, NH), 7.12–7.69 (m, 10H,
ArH); dC 32.2 (CH2Ph), 36.3 (CH2CH2Ph), 51.6 (CHN), 115.4
(CH2@C), 126.0, 126.8 (2C), 128.4 (2C), 128.50 (2C), 128.55 (2C),
131.4, 134.5, 141.5 (ArC), 138.0 (CH@CH2), 166.7 (C@O); m/z 265
(M+, 2%), 161 (51), 105 (100), 77 (30).
4.5.8. (S)-N-[1-(4-Chlorophenyl)but-3-enyl)benzamide ent-3gb
White solid; mp 142–143 °C; Rf 0.36 (hexane/ethyl acetate: 4/
1); ½a 2D0
ꢂ
¼ ꢀ21:5 (c 0.4, CHCl3, 92% ee);
m (film) 3222 (NH), 3018
(HC@C), 1641 (C@O), 1515 (N–C@O), 1216 cmꢀ1 (CN); dH 2.66 (t,
2H, J = 7.0 Hz, CH2), 5.16 (dd, 1H, J = 10.1, 1.5 Hz, 1 ꢁ CHH@C),
5.20 (dd, 1H, J = 17.1, 1.5 Hz, 1 ꢁ CHH@C), 5.24 (q, 1H, J = 7.0 Hz,
CHN), 5.74 (ddt, 1H, J = 17.1, 10.1, 7.0 Hz, CH@CH2), 6.43 (d, 1H,
J = 7.0 Hz, NH), 7.27, 7.32 (2d, 2H each, J = 8.8 Hz each, 4 ꢁ ArH),
7.44–7.76 (m, 5H, 5 ꢁ ArH); dC 40.5 (CH2CN), 52.1 (CHN), 118.8
(CH2@C), 126.9 (2C), 127.8 (2C), 128.6 (2C), 128.7 (2C), 131.6,
133.0, 134.2, 140.2 (ArC), 133.6 (CH@CH2), 166.7 (C@O); m/z 285
(M+, <2%), 246 (12), 244 (34), 105 (100), 77 (29); HRMS:
M+ꢀC3H5, found 244.0544, C14H11ClNO requires 244.0529.
4.5.4. (S)-N-(1-Octylprop-2-enyl)benzamide 3e
White solid; mp 65–66 °C; Rf 0.56 (hexane/ethyl acetate: 4/1);
½
a 2D0
ꢂ
¼ þ11:0 (c 0.4, CHCl3, 60% ee);
m (film) 3383 (NH), 1634
(C@O), 1539 (N–C@O), 1114 cmꢀ1 (CN); dH 0.87 (t, 3H, J = 6.8 Hz,
Me), 1.17–1.45 [m, 12H, (CH2)6Me], 1.62 (dt, 1H, J = 14.6, 6.8 Hz,
1 ꢁ CHHCN), 1.64 (dt, 1H, J = 14.6, 6.7 Hz, 1 ꢁ CHHCN), 4.66 (quin-
tet, 1H, J = 7.0 Hz, CHN), 5.14 (d, 1H, J = 10.4 Hz, 1 ꢁ CHH@C), 5.23
(d, 1H, J = 17.2 Hz, 1 ꢁ CHH@C), 5.86 (ddd, 1H, J = 17.2, 10.4, 5.6 Hz,
CH@CH2), 6.04 (d, 1H, J = 7.9 Hz, NH), 7.40–7.81 (m, 5H, ArH); dC
14.1 (Me), 22.6, 25.8, 29.2, 29.42, 29.45, 31.8, 35.0 [(CH2)7], 51.7
(CHN), 114.9 (CH2@C), 126.8 (2C), 128.5 (2C), 131.4, 134.7, 138.4
(CH@CH2), 166.8 (C@O); m/z 273 (M+, <2%), 161 (15), 160 (48),
105 (100), 77 (23); HRMS: M+ found 273.2057, C18H27NO requires
273.2093.
4.5.9. (S)-N-[1-(4-Methoxyphenyl)but-3-enyl]benzamide ent-
3gc39
White solid; mp 150–151 °C; Rf 0.32 (hexane/ethyl acetate: 3/
1); ½a 2D0
ꢂ
¼ ꢀ25:2 (c 0.8, CHCl3, 94% ee);
m (film) 3342 (NH), 3004
(HC@C), 1632 (C@O), 1532 (N–C@O), 1290 (CN), 1249 cmꢀ1 (CO);
dH 2.68 (tt, 2H, J = 7.0, 1.2 Hz, CH2CN), 3.79 (s, 3H, Me), 5.11 (ddt,
1H, J = 10.1, 1.8, 1.2 Hz, 1 ꢁ CHH@C), 5.17 (ddt, 1H, J = 17.1, 1.8,
1.2 Hz, 1 ꢁ CHH@C), 5.24 (q, 1H, J = 7.0 Hz, CHN), 5.77 (ddt, 1H,
J = 17.1, 10.1, 7.0 Hz, CH@CH2), 6.88, 7.27 (2d, 2H each, J = 8.8 Hz
each, 4 ꢁ ArH), 7.42, 7.49, 7.76 (t, t and d, respectively, 2H, 1H
and 2H, respectively, J = 7.2 Hz each, 5 ꢁ ArH); dC 40.5 (CH2CN),
52.2 (Me), 55.3 (CHN), 114.0 (2C), 126.9 (2C), 127.6 (2C), 128.6
(2C), 131.5, 133.7, 134.6, 158.8 (ArC), 118.3 (CH2@C), 134.2
(CH@CH2), 166.6 (C@O); m/z 281 (M+, <1%), 240 (55), 160 (24),
159 (18), 144 (14), 129 (12), 115 (16), 105 (100), 77 (38).
4.5.5. (R)-N-[1-(2-Furyl)-3-methylbutyl]benzamide 3fb31
White solid; mp 89–90 °C; Rf 0.50 (hexane/ethyl acetate: 3/1);
½
a 2D0
ꢂ
¼ þ68:0 (c 1, CHCl3, 96% ee);
m (film) 3313 (NH), 3112,
3062, 3031 (HC@C), 1631 (C@O), 1539 (N–C@O), 1292 cmꢀ1
(CN); dH 0.96, 0.98 (2d, 3H each, J = 5.8 Hz each, Me2CH), 1.60
(non, 1H, J = 6.7 Hz, CHMe), 1.79 (ddd, 1H, J = 13.5, 7.9, 6.6 Hz,

1428
R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
4.5.10. (R)-N-[1-(2-Phenylethyl)but-3-enyl]benzamide ent-
3gd39
(33), 204 (11), 105 (100), 104 (12), 77 (26); HRMS: M+ꢀC3H7, found
282.1145, C17H16NO3 requires 282.1130.
White solid; mp 81–82 °C; Rf 0.41 (hexane/ethyl acetate: 3/1);
½
a 2D0
ꢂ
¼ ꢀ4:5 (c 1, CHCl3, 70% ee);
m
(film) 3310 (NH), 1682 (HC@C),
4.6. Oxidation of the benzamides. Isolation of the amino acids 4,
ent-4 and 8: General procedure
1634 (C@O), 1535 (N–C@O), 1283 cmꢀ1 (CN); dH 1.78–2.00 (m, 2H,
CH2CH2Ph), 2.34 (dd, 1H, J = 14.1, 7.2 Hz, 1 ꢁ CHHCH@CH2), 2.42
(dd, 1H, J = 14.1, 7.2 Hz, 1 ꢁ CHHCH@CH2), 2.72 (t, 2H, J = 8.0 Hz,
CH2Ph), 4.30 (ddt, 1H, J = 14.4, 8.6, 5.9 Hz, CHN), 5.11 (d, 1H,
J = 10.2 Hz, 1 ꢁ CHH@C), 5.12 (d, J = 16.7 Hz, 1 ꢁ CHH@C), 5.83
(ddt, 1H, J = 16.7, 10.2, 7.2 Hz, CH@CH2), 6.03 (br s, 1H, NH),
7.16–7.71 (m, 10H, ArH); dC 32.5 (CH2Ph), 36.1 (CH2CH2Ph), 39.2
(CH2CH@CH2), 48.9 (CHN), 118.2 (CH2@C), 125.9, 126.8 (2C),
128.3 (2C), 128.4 (2C), 128.5 (2C), 131.3, 134.8, 141.7 (ArC),
134.1 (CH@CH2), 167.0 (C@O); m/z 279 (M+, <1%), 238 (20), 122
(20), 117 (13), 105 (100), 91 (11), 77 (31).
The reductive cleavage of the terminal C@C bond of compounds
3a–e and ent-3ga–ge or the furyl group of compounds 3fa–fe was
carried out by treatment with NaIO4 in the presence of a catalytic
amount of RuCl3, following a literature procedure.19 The expected
amino acids 4, ent-4 and 8 were obtained in the yields indicated
in Tables 1 and 2. Their corresponding physical, spectroscopic
and analytical data follow.
4.6.1. (S)-2-Benzamido-2-phenylacetic acid 4a28
White solid; mp 199–200 °C; ½a D20
¼ þ58:0 (c 0.7, CHCl3, 94%
ꢂ
4.5.11. (R)-N-(1-Octylbut-3-enyl)benzamide ent-3ge
ee); m (film) 3400 (NH and OH), 3063 (HC@C), 1731 (C@O), 1643
White solid; mp 68–69 °C; Rf 0.44 (hexane/ethyl acetate: 4/1);
(C@O), 1524 (N–C@O), 1099 cmꢀ1 (CN); dH 5.78 (br s, 1H, CH),
7.33–7.60, 7.78–7.88 (2m, 9H and 2H, respectively, ArH and NH),
9.60 (s, 1H, CO2H); dC 64.0 (CHN), 127.2 (2C), 127.4, 128.1 (2C),
128.7 (2C), 129.0 (2C), 129.1, 129.5, 132.0 (ArC), 166.9 (CONH),
170.8 (CO2H); m/z 210 (M+ꢀCO2H, 38%), 193 (10), 105 (100), 77
(37).
½
a 2D0
ꢂ
¼ þ11:5 (c 0.5, CHCl3, 72% ee);
m (film) 3019 (HC@C), 1653
(C@O), 1517 (N–C@O), 1216 cmꢀ1 (CN); dH 0.87 (t, 3H, J = 6.9 Hz,
Me), 1.17–1.67 [m, 14H, (CH2)7], 2.27–2.45 (m, 2H, CH2CH@CH2),
4.22 (ddt, 1H, J = 14.0, 7.8, 6.3 Hz, CHN), 5.10 (d, 1H, J = 10.6 Hz,
1 ꢁ CHH@C), 5.12 (d, 1H, J = 16.6 Hz, 1 ꢁ CHH@C), 5.84 (ddt, 1H,
J = 16.6, 10.6, 7.3 Hz, CH@CH2), 7.39–7.77 (m, 5H, ArH); dC 14.1
(Me), 22.6, 26.0, 29.2, 29.46, 29.49, 31.8, 34.4 [(CH2)7], 39.1
(CH2CH@CH2), 48.9 (CHN), 117.9 (CH2@C), 126.7 (2C), 128.5 (2C),
131.2, 135.0 (ArC), 134.4 (CH@CH2), 167.0 (C@O); m/z 287 (M+,
<2%), 246 (40), 105 (100), 77 (17); HRMS: M+ found 287.2214,
4.6.2. (S)-2-Benzamido-2-(4-chlorophenyl)acetic acid 4b40
White solid; mp 181–182 °C; ½a D20
¼ þ49:0 (c 1, CHCl3, 92% ee);
ꢂ
m
(film) 3410 (NH and OH), 1728 (C@O), 1645 (C@O), 1522 (N–
C@O), 1092 cmꢀ1 (CN); dH 5.68 (d, 1H, J = 6.4 Hz, CHN), 7.24–
7.62, 7.66–7.85 (2m, 8H and 2H, respectively, ArH and NH), 9.30
(br s, 1H, CO2H); dC 56.4 (CHN), 127.2 (2C), 128.65 (2C), 128.73
(2C), 128.8, 129.0, 129.1 (2C), 132.2, 134.5 (ArC), 167.3 (CONH),
173.4 (CO2H); m/z 245 (M+ꢀCO2, 16%), 244 (28), 105, (100), 77
(49), 51 (15).
C
19H29NO requires 287.2249.
4.5.12. (R)-Ethyl 2-benzamido-2-phenylbutanoate 7a11b
Yellow oil; Rf 0.50 (hexane/ethyl acetate: 3/1); ½a D20
¼ ꢀ4:2 (c
ꢂ
0.8, CHCl3, 92% ee);
m (film) 3412 (NH), 3014 (HC@C), 1723
(C@O), 1667 (C@O), 1512 (N–C@O), 1244 (CO), 1217 cmꢀ1 (CN);
dH 0.93 (t, 3H, J = 7.3 Hz, MeCH2C), 1.19 (t, 3H, J = 7.1 Hz, MeCH2O),
2.61 (dq, 1H, J = 13.9, 7.1 Hz, 1 ꢁ CHHCN), 3.07 (dq, 1H, J = 13.9,
7.3 Hz, 1 ꢁ CHHCN), 4.13 (dq, 1H, J = 10.7, 7.1 Hz, 1 ꢁ CHHO),
4.26 (dq, 1H, J = 10.7, 7.1 Hz, 1 ꢁ CHHO), 7.24–7.87 (m, 11H, NH
and ArH); dC 8.6 (MeCH2C), 13.9 (MeCH2O), 25.5 (CH2C), 62.4
(CH2O), 66.5 (CN), 125.9 (2C), 127.0 (2C), 127.7, 128.4 (2C), 128.6
(2C), 131.6, 135.3, 139.8 (ArC), 165.3 (CONH), 175.6 (CO2Et); m/z
311 (M+, 1%), 239 (12), 238 (67), 105 (100), 77 (28).
4.6.3. (S)-2-Benzamido-2-(4-methoxyphenyl)acetic acid 4c41
Colourless oil; ½a D20
ꢂ
¼ þ31:0 (c 1, CHCl3, 88% ee);
m (film) 3417
(NH and OH), 1714 (C@O), 1639 (C@O), 1601 (N–C@O), 1244
(CO), 1108 cmꢀ1 (CN); dH 3.80 (s, 3H, Me), 5.72 (s, 1H, CHN),
6.88–8.10 (m, 10H, ArH and NH), 9.62 (br s, 1H, CO2H); dC 55.3
(Me), 63.3 (CHN), 114.9 (2C), 127.1 (2C), 128.58 (2C), 128.63,
128.7, 129.5 (2C), 132.0, 160.1, 166.8 (CONH), 170.0 (CO2H); m/z
251 (M+ꢀCO2, 26%), 240 (78), 105 (100), 103 (59), 77 (65), 76
(26), 51 (25).
4.5.13. (R)-Ethyl 2-benzamido-2,3-diphenylpropanoate 7b
Yellow oil; Rf 0.48 (hexane/ethyl acetate: 3/1); ½a D20
ꢂ
¼ þ40:1 (c
4.6.4. (S)-2-Benzamido-4-phenylbutanoic acid 4d42
1, CHCl3, 80% ee);
m
(film) 3411 (NH), 3013 (HC@C), 1728 (C@O),
Colourless oil; ½a D20
ꢂ
¼ þ7:2 (c 0.4, CHCl3, 58% ee);
m (film) 3321
1666 (C@O), 1510 (N–C@O), 1255 (CN), 1215 cmꢀ1 (CO); dH 1.22
(t, 3H, J = 7.1 Hz, Me), 3.94, 4.29 (2d, 1H each, J = 13.1 Hz each,
CH2Ph), 4.19, 4.20 (2qd, 1H each, J = 7.1, 3.7 Hz each, CH2O),
7.09–7.71 (m, 15H, ArH); dC 13.8 (Me), 38.0 (CH2Ph), 62.5 (CH2O),
66.7 (CN), 125.9 (2C), 126.9 (2C), 127.0, 127.8, 128.2 (2C), 128.50
(2C), 128.53 (2C), 130.0 (2C), 131.5, 134.9, 136.2, 139.7 (ArC),
166.0 (CONH), 172.4 (CO2Et); m/z 373 (M+, <1%), 282 (42), 252
(24), 105 (100), 77 (25); HRMS: M+ꢀC7H7, found 282.1108,
(NH and OH), 3024 (HC@C), 1727 (C@O), 1638 (C@O), 1520 (N–
C@O), 1216 cmꢀ1 (CN); dH 2.15–2.25, 2.32–2.42 (2m, 1H each,
CH2CN), 2.78 (t, 2H, J = 8.5 Hz, CH2Ph), 4.78 (td, 1H, J = 7.3, 5.2 Hz,
CHN), 6.73 (br s, 1H, NH), 7.18–7.70 (m, 10H, ArH); dC 31.7 (CH2Ph),
33.4 (CH2CN), 52.7 (CHN), 126.3, 127.1 (2C), 128.4 (2C), 128.60
(2C), 128.64 (2C), 132.0, 133.3, 140.6 (ArC), 167.7 (CONH), 176.1
(CO2H); m/z (DIP) 283 (M+, <1%), 179 (63), 161 (59), 105 (100),
91 (11), 77 (37).
C17H16NO3 requires 282.1130.
4.6.5. (S)-2-Benzamidodecanoic acid 4e43
4.5.14. (R)-Ethyl 2-benzamido-3-methyl-2-phenylbutanoate 7c
Colourless oil; ½a D20
ꢂ
¼ þ6:1 (c 0.4, MeOH, 60% ee);
m (film) 3429
Yellow oil; Rf 0.43 (hexane/ethyl acetate: 3/1); ½a D20
ꢂ
¼ ꢀ5:2 (c 1,
(NH and OH), 3019 (HC@C), 1720 (C@O), 1656 (C@O), 1519 (N–
C@O), 1215 cmꢀ1 (CN); dH 0.87 (t, 3H, J = 6.8 Hz, Me), 1.20–1.47
[m, 12H, (CH2)6Me], 1.77–1.88, 1.97–2.06 (2m, 1H each, CH2CN),
4.81 (td, 1H, J = 7.4, 5.6 Hz, CHN), 6.74 (d, 1H, J = 7.4 Hz, NH),
7.45, 7.53, 7.81 (t, t and d, respectively, 2H, 1H and 2H, respec-
tively, J = 7.5 Hz each, ArH); dC 14.1 (Me), 22.6, 25.3, 29.17, 29.22,
29.3, 31.8, 32.2 [(CH2)7], 52.8 (CHN), 127.1 (2C), 128.6 (2C),
132.0, 133.6 (ArC), 167.7 (CONH), 176.3 (CO2H); m/z (DIP) 291
(M+, 1%), 246 (10), 179 (26), 161 (17), 105 (100), 77 (20).
CHCl3, 62% ee); m (film) 3404 (NH), 3018 (HC@C), 1724 (C@O), 1671
(C@O), 1511 (N–C@O), 1287 (CO), 1216 cmꢀ1 (CN); dH 1.03, 1.05
(2d, 3H each, J = 6.9 Hz each, Me2CH), 1.20 (t, 3H, J = 7.1 Hz,
MeCH2), 3.27 (septet, 1H, J = 6.7 Hz, CHMe2), 4.15–4.29 (m, 2H,
CH2O), 7.25–7.85 (m, 10H, ArH); dC 14.0 (MeCH2), 18.48, 18.50
(Me2CH), 33.1 (CHMe), 62.1 (CH2), 69.5 (CN), 126.9 (2C), 127.1
(2C), 127.4, 128.0 (2C), 128.6 (2C), 131.5, 135.0, 137.6 (ArC),
165.9 (CONH), 172.7 (CO2Et); m/z 325 (M+, <1%), 282 (27), 252

R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
1429
4.6.6. (R)-2-Benzamidobutanoic acid ent-4fa44
4.6.12. (S)-3-Benzamido-3-(4-chlorophenyl)propanoic acid 8b49
Brown oil; ½a 2D0
ꢂ
¼ ꢀ14:0 (c 0.3, MeOH, 92% ee);
m
(film) 3309
White solid; mp 190–191 °C; ½a D20
¼ þ4:0 (c 0.5, MeOH, 92% ee);
ꢂ
(NH and OH), 1743 (C@O), 1622 (C@O), 1537 (N–C@O),
1183 cmꢀ1 (CN); dH (MeOH-d4) 1.03 (t, 3H, J = 7.4 Hz, Me), 1.80
(dq, 1H, J = 14.3, 7.1 Hz, 1 ꢁ CHH), 2.07 (dq, 1H, J = 14.3, 6.9 Hz,
1 ꢁ CHH), 4.48 (q, 1H, J = 6.5 Hz, CHN), 7.44, 7.56, 7.86 (t, t and d,
respectively, 2H, 1H and 2H, respectively, J = 7.3 Hz each, ArH);
dC (MeOH-d4) 10.9 (Me), 26.0 (CH2), 56.4 (CHN), 128.4 (2C), 129.5
(2C), 132.8, 135.4 (ArC), 170.3 (CONH), 176.9 (CO2H); m/z 207
(M+, <1%), 122 (21), 117 (13), 105 (100), 91 (10), 77 (29).
m
(film) 3328 (NH and OH), 1701 (C@O), 1638 (C@O), 1524 cmꢀ1
(N–C@O); dH 2.91, 2.97 (2dd, 1H each, J = 15.9, 6.4 Hz each, CH2),
4.34 (br s, 2H, NH and CO2H), 5.56 (t, 1H, J = 6.4 Hz, CHN), 7.30,
7.36 (2d, 2H each, J = 8.6 Hz each, 4 ꢁ ArH), 7.41–7.84 (m, 5H,
5 ꢁ ArH); dC 39.4 (CH2), 49.4 (CHN), 126.8 (2C), 127.5 (2C), 128.2
(2C), 128.4 (2C), 131.5, 132.9, 133.6, 139.4 (ArC), 167.4 (CONH),
173.1 (CO2H); m/z (DIP) 305 (M++2, <1%), 303 (M+, 2%), 200 (26),
198 (80), 138 (12), 105 (100), 77 (36).
4.6.7. (R)-2-Benzamido-4-methylpentanoic acid ent-4fb45
4.6.13. (R)-3-Benzamido-5-phenylpentanoic acid 8d
Dark oil; ½a 2D0
ꢂ
¼ ꢀ10:0 (c 0.3, MeOH, 96% ee);
m
(film) 1739
Yellowish solid; mp 139–140 °C; ½a D20
¼ þ10:8 (c 1, CHCl3, 70%
ꢂ
(C@O), 1627 (C@O), 1564 (N–C@O), 1163 cmꢀ1 (CN); dH (MeOH-
d4) 0.97, 0.99 (2d, 3H each, J = 6.2 Hz each, Me2CH), 1.69–1.88 (m,
3H, CH2CN), 4.69 (dd, 1H, J = 10.0, 4.6 Hz, CHN), 7.44 (dd, 2H,
J = 7.4, 7.0 Hz, 2 ꢁ ArH), 7.52 (t, 1H, J = 7.4 Hz, 1 ꢁ ArH), 7.86 (d,
2H, J = 7.0 Hz, 2 ꢁ ArH); dC (MeOH-d4) 21.8, 23.4 (Me2CH), 26.2
(CHN), 42.3 (CH2), 52.6 (CHN), 128.5 (2C), 129.4 (2C), 132.8,
135.3 (ArC), 170.4 (CONH), 176.2 (CO2H); m/z 235 (M+, <1%), 179
(28), 161 (17), 105 (100), 77 (29).
ee); m (film) 3301 (NH and OH), 1694 (C@O), 1638 (C@O), 1533
(N–C@O), 1250 cmꢀ1 (CN); dH 1.95 (dtd, 1H, J = 14.2, 8.3, 5.6 Hz,
1 ꢁ CH2CHHCN), 2.07 (dq, 1H, J = 14.2, 8.3 Hz, 1 ꢁ CH2CHHCN),
2.63 (dd, 1H, J = 15.8, 5.2 Hz, 1 ꢁ CHHCO2H), 2.68 (dd, 1H,
J = 15.8, 5.2 Hz, 1 ꢁ CHHCO2H), 2.72 (t, 2H, J = 8.0 Hz, CH2Ph),
4.04 (br s, 2H, NH and CO2H), 4.48 (dq, 1H, J = 8.8, 5.3 Hz, CHN),
7.13–7.77 (m, 10H, ArH); dC 32.5 (CH2Ph), 35.6 (CH2CH2Ph), 38.2
(CH2CO2H), 46.3 (CHN), 125.8, 126.8 (2C), 128.2 (2C), 128.3 (2C),
128.4 (2C), 131.5, 134.1, 141.2 (ArC), 167.5 (CONH), 174.1
(CO2H); m/z (DIP) 297 (M+, 8%), 193 (36), 105 (100), 88 (37), 77
(38).
4.6.8. (R)-2-Benzamidoheptanoic acid ent-4fc46
Dark oil; ½a 2D0
ꢂ
¼ ꢀ5:0 (c 0.5, MeOH, 92% ee);
m (film) 3349 (NH
and OH), 1641 (C@O), 1610 (C@O), 1575 (N–C@O), 1419 cmꢀ1
(CN); dH (MeOH-d4) 0.87 (t, 3H, J = 6.3 Hz, Me), 1.23–1.48 [m, 6H,
(CH2)3Me], 1.73–2.01 (m, 2H, CH2CN), 4.50 (dd, 1H, J = 8.3, 5.0 Hz,
CHN), 7.42, 7.51, 7.86 (t, t and d, respectively, 2H, 1H and 2H,
respectively, J = 7.2 Hz each, ArH); dC (MeOH-d4) 14.4 (Me), 23.6,
26.9, 32.7, 33.1 [(CH2)4], 56.0 (CHN), 128.5 (2C), 129.5 (2C),
132.7, 135.4 (ArC), 169.9 (CONH), 179.1 (CO2H); m/z 231 (10),
174 (15), 161 (11), 147 (41), 106 (10), 105 (100), 104 (12), 77 (35).
4.6.14. (R)-3-Benzamidoundecanoic acid 8e50
Yellow solid; mp 130–131 °C; ½a D20
¼ þ7:5 (c 0.5, MeOH, 72%
ꢂ
ee);
m (film) 3299 (NH and OH), 1699 (C@O), 1639 (C@O), 1537
(N–C@O), 1317 cmꢀ1 (CN); dH 0.86 (t, 3H, J = 6.7 Hz, Me), 1.19–
1.40 [m, 12H, (CH2)6Me], 1.57–1.74 (m, 2H, CH2CH2CN), 2.66 (dd,
1H, J = 16.2, 5.0 Hz, 1 ꢁ CHHCO2H), 2.73 (dd, 1H, J = 16.2, 4.9 Hz,
1 ꢁ CHHCO2H), 4.38–4.51 (m, 1H, CHN), 6.90 (d, 1H, J = 9.0 Hz,
NH), 7.38–7.79 (m, 5H, ArH); dC 14.1 (Me), 22.6, 26.3, 29.2, 29.3,
29.4, 31.8, 34.1 [(CH2)7], 38.3 (CH2CO2H), 46.4 (CHN), 126.9 (2C),
128.6 (2C), 131.6, 134.2 (ArC), 167.3 (CONH), 176.4 (CO2H); m/z
305 (M+, 4%), 200 (12), 193 (13), 192 (17), 122 (18), 105 (100),
77 (23).
4.6.9. (R)-2-Benzamido-3-phenylpropanoic acid ent-4fd28
Colourless oil; ½a D20
ꢂ
¼ ꢀ17:5 (c 0.5, MeOH, 92% ee);
m (film)
3091, 3058, 3016 (HC@C), 1720 (C@O), 1612 (C@O), 1537 (N–
C@O), 1227 cmꢀ1 (CN); dH 3.26, 3.37 (2dd, 1H each, J = 13.9,
5.6 Hz each, CH2), 5.08 (dt, 1H, J = 7.3, 5.6 Hz, CHN), 6.70 (d, 1H,
J = 7.3 Hz, NH), 7.16–7.71 (m, 10H, ArH); dC 37.3 (CH2), 53.6
(CHN), 127.1, 127.2 (2C), 128.6 (4C), 129.4 (2C), 131.9, 133.5,
135.7 (ArC), 167.6 (CONH), 175.0 (CO2H); m/z (DIP) 269 (M+, 2%),
148 (66), 147 (21), 105 (100), 91 (14), 77 (34).
4.6.15. (S)-N-[1-(4-Methoxyphenyl)-2-formylethyl]benzamide
951
Orange oil; Rf 0.50 (hexane/ethyl acetate: 3/1) ½a D20
¼ þ15:0 (c
ꢂ
1, CHCl3, 92% ee);
m (film) 3349 (NH), 1720 (C@O), 1662 (C@O),
1513 (N–C@O), 1098 cmꢀ1 (CN); dH 3.00 (ddd, 1H, J = 16.8, 6.2,
1.2 Hz, 1 ꢁ CHH), 3.17 (ddd, 1H, J = 16.8, 6.6, 2.3 Hz, 1 ꢁ CHH),
3.78 (s, 3H, Me), 5.65 (dt, 1H, J = 7.6, 6.5 Hz, CHN), 7.00 (d, 1H,
J = 7.6 Hz, NH), 6.83–7.76 (m, 9H, ArH), 9.78 (dd, 1H, J = 2.3,
1.2 Hz, CHO); dC 48.6 (CHN), 48.8 (CH2), 55.2 (Me), 114.2 (2C),
127.0 (2C), 127.7 (2C), 128.6 (2C), 131.7, 132.3, 133.9, 159.1
(ArC), 166.7 (CONH), 200.7 (CHO); m/z (DIP) 283 (M+, 1%), 240
(20), 149 (13), 135 (42), 134 (11), 105 (100), 85 (14), 83 (10), 77
(52), 72 (21), 71 (23), 69 (12), 58 (51), 57 (22), 55 (15), 43 (35),
41 (12).
4.6.10. (R)-2-Benzamido-3-methylbutanoic acid ent-4fe47
Yellow oil; Rf 0.48 (hexane/ethyl acetate: 3/1); ½a D20
¼ ꢀ27:6 (c
ꢂ
0.3, CHCl3, 92% ee);
m (film) 3452 (NH and OH), 1709 (C@O),
1642 (C@O), 1535 (N–C@O), 1248 cmꢀ1 (CN); dH 1.03, 1.05 (2d,
3H each, J = 7.1 Hz each, Me2CH), 2.30–2.41 (m, 1H, CHMe2), 4.78
(dd, 1H, J = 8.3, 4.8 Hz, CHN), 7.47, 7.52, 7.80 (t, t and d, respec-
tively, 2H, 1H and 2H, respectively, J = 7.2 Hz each, ArH), 8.08 (d,
1H, J = 8.3 Hz, NH); dC 17.8, 19.1 (Me2CH), 31.3 (CHMe2), 57.5
(CHN), 127.1 (2C), 128.7 (2C), 131.9, 133.8 (ArC), 167.9 (CONH),
175.9 (CO2H); m/z 221 (M+, <1%), 161 (56), 133 (18), 106 (21),
105 (100), 77 (47), 51 (13).
4.7. Determination of the enantiomeric excesses of amino acids
4, ent-4 and 8
K2CO3 (0.7 mmol) and MeI (0.7 mmol) were added to a solution
of the amino acid 4, ent-4 and 8 (0.4 mmol) in anhydrous DMF
(4.5 mL) at 0 °C. After stirring overnight at room temperature,
water (10 mL) was added and the mixture was extracted with
Et2O (2 ꢁ 10 mL). The combined organic layers were dried
(Na2SO4). After filtration and evaporation of the solvents, the ob-
tained amino esters were analyzed by HPLC on a ChiralCel OD-H
column using a 254 nm UV detector, 10% i-PrOH in hexane as elu-
ent and a flow rate of 0.5 mL/min. The retention times were 29.9
(4a methyl ester; 5% i-PrOH in hexane as eluent), 45.4 (ent-4a
4.6.11. (S)-3-Benzamido-3-phenylpropanoic acid 8a48
Yellow solid; mp 189–190 °C; ½a D20
¼ þ73:0 (c 1.5, CHCl3, 88%
ꢂ
ee);
m (film) 3347 (NH and OH), 1695 (C@O), 1637 (C@O), 1522
(N–C@O), 1282 cmꢀ1 (CN); dH (MeOH-d4) 2.95, 3.00 (2dd, 1H each,
J = 16.0, 5.9 Hz each, CH2), 5.61 (t, 1H, J = 5.9 Hz, CHN), 7.23–7.84
(m, 10H, ArH); dC (MeOH-d4) 41.5 (CH2), 52.1 (CHN), 127.6 (2C),
128.36 (2C), 128.42 (2C), 129.5 (2C), 129.6, 132.7, 135.7, 143.1
(ArC), 169.0 (CONH), 173.5 (CO2H); m/z (DIP) 269 (M+, <1%), 164
(88), 105 (100), 104 (17), 77 (42).

1430
R. Almansa et al. / Tetrahedron: Asymmetry 21 (2010) 1421–1431
8. (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015–2022; (b) Adessi, C.;
Soto, C. Curr. Med. Chem. 2002, 9, 963–978; (c) Ref. 7b, pp 611–614.
9. Karlsson, A. J.; Pomerantz, W. C.; Weisblum, B.; Gellman, S. H.; Palecek, S. P. J.
Am. Chem. Soc. 2006, 128, 12630–12631.
10. See, for instance: (a) Gademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew.
Chem., Int. Ed. 1999, 38, 1223–1226; (b) Hamuro, Y.; Schneider, J. P.; DeGrado,
W. F. J. Am. Chem. Soc. 1999, 121, 12200–12201; (c) Raguse, T. L.; Porter, E. A.;
Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 12774–12785; (d)
Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11516–
11519.
11. See, for instance: (a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry
2008, 19, 603–606; (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2008, 19, 2484–2491; (c) Almansa, R.; Guijarro, D.; Yus, M.
Tetrahedron Lett. 2009, 50, 3198–3201.
12. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995; (b)
Ellman, J. A. Pure Appl. Chem. 2003, 75, 39–46; (c) Zhou, P.; Chen, B.-C.; Davis, F.
A. Tetrahedron 2004, 60, 8003–8030; (d) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.;
Sun, X.-W. Acc. Chem. Res. 2008, 41, 831–840; (e) Ferreira, F.; Botuha, C.;
Chemla, F.; Pérez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162–1186.
13. For some other approaches to prepare amino acids from sulfinylimines, see Ref.
12e.
methyl ester; 5% i-PrOH in hexane as eluent), 29.7 (ent-4b methyl
ester), 37.1 (4b methyl ester), 35.6 (4c methyl ester), 42.1 (ent-4c
methyl ester), 37.0 (ent-4d methyl ester), 44.9 (4d methyl ester),
20.5 (ent-4e methyl ester), 22.1 (4e methyl ester), 9.4 (ent-4fa
methyl ester), 12.3 (4fa methyl ester), 8.2 (ent-4fb methyl ester;
flow rate 1.0 mL/min), 14.4 (4fb methyl ester; flow rate 1.0 mL/
min), 6.7 (ent-4fc methyl ester; flow rate 1.0 mL/min), 9.1 (4fc
methyl ester; flow rate 1.0 mL/min), 11.6 (ent-4fd methyl ester;
flow rate 1.0 mL/min), 16.6 (4fd methyl ester; flow rate 1.0 mL/
min), 6.9 (ent-4fe methyl ester; 2% i-PrOH in hexane as eluent, flow
rate 2.0 mL/min), 10.3 (4fe methyl ester; 2% i-PrOH in hexane as
eluent, flow rate 2.0 mL/min), 34.1 (ent-8a methyl ester), 48.2
(8a methyl ester), 33.9 (ent-8b methyl ester), 46.2 (8b methyl es-
ter), 23.9 (8d methyl ester), 36.7 (ent-8d methyl ester), 32.7 (ent-
8e methyl ester; 1% i-PrOH in hexane as eluent, flow rate 1.0 mL/
min), 47.7 (8e methyl ester; 1% i-PrOH in hexane as eluent, flow
rate 1.0 mL/min), 23.5 (9), 30.3 (ent-9). The enantiomeric excesses
obtained are collected in Tables 1 and 2.
14. Preliminary communication: Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron Lett.
2009, 50, 4188–4190.
15. The removal of the sulfinyl group was carried out following the procedure
previously described by us (see Ref. 11b).
16. Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–8904.
17. See, for instance: (a) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27,
4961–4964; (b) Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J. Org. Chem. 1990,
55, 215–223; (c) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883–5889; (d)
Expósito, A.; Fernández-Suárez, M.; Iglesias, T.; Muñoz, L.; Riguera, R. J. Org.
Chem. 2001, 66, 4206–4213; (e) Funabiki, K.; Nagamori, M.; Matsui, M. J.
Fluorine Chem. 2004, 125, 1347–1350; (f) Muñoz-Hernández, L.; Soderquist, J.
A. Org. Lett. 2009, 11, 2571–2574.
18. Some other examples of allylation of N-(tert-butanesulfinyl)imines: using
allylindium: (a) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 2004, 15, 3823–
3825; (b) Medjahdi, M.; González-Gómez, J. C.; Foubelo, F.; Yus, M. Heterocycles
2008, 76, 569–581; (c) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008,
10, 1259–1262; (d) González-Gómez, J. C.; Foubelo, F.; Yus, M. Synlett 2008,
2777–2780; Using allyltrifluoroborates: (e) Li, S.-W.; Batey, R. A. Chem.
Commun. 2004, 1382–1383; Using allylzinc bromide: (f) Sun, X.-W.; Xu, M.-
H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979–4982; Using allyl Grignard reagents: (g)
Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; Jiang, Y.-Z.; Mi, A.-Q.; Jong, T.-T.
J. Org. Chem. 1994, 59, 914–921; (h) Ref. 16.
Acknowledgements
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; grant no. CONSOLIDER INGENIO
2010, CSD2007-00006 and CTQ2007-65218) and the Generalitat
Valenciana (PROMETEO/2009/039 and GV/2007/036). R.A. thanks
the Spanish Ministerio de Educación y Ciencia for a predoctoral fel-
lowship. We also thank MEDALCHEMY S.L. for a gift of chemicals.
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