New synthesis of optically pure α-branched aliphatic carboxylic acids from amidines

Article abstract of DOI:10.1055/s-2004-822335

A range of amidines containing amino acid function was easily prepared in good yields from simple starting materials. Starting from L- or D- proline and linear symmetric ketones, optically pure amidines were prepared. Hydrolysis of these amidines afforded optically pure branched aliphatic carboxylic acids.

Full text of DOI:10.1055/s-2004-822335

PAPER
1041
New Synthesis of Optically Pure a-Branched Aliphatic Carboxylic Acids from
Amidines
Synthesisof
O
l
pticall
a
yPure
a
-B
r
v
anche
d
A
liph
i
atic
C
o
A
cids Cassani, Giuseppe Celentano, Emanuela Erba,* Donato Pocar
Istituto di Chimica Organica ‘Alessandro Marchesini’ e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Etero-e Carbociclici, Università degli Studi di Milano, Via G. Venezian, 21, 20133 Milano, Italy
Fax +39(02)50314476; E-mail: emanuela.erba@unimi.it
Received 16 February 2004; revised 11 March 2004
substituent from 5 to 4 position, furnishes the desired
Abstract: A range of amidines containing amino acid function was
amidines (Scheme 1). In this way many amidines, vari-
ously substituted, were obtained easily in a one-pot reac-
tion.
easily prepared in good yields from simple starting materials. Start-
ing from L- or D- proline and linear symmetric ketones, optically
pure amidines were prepared. Hydrolysis of these amidines afford-
ed optically pure branched aliphatic carboxylic acids.
As shown in Scheme 1, starting from enamine bearing dif-
ferent substituents, a stereogenic center is formed. This
work was devoted to investigating the stereochemical im-
plication of this reaction in order to produce optically pure
aliphatic acids.
Key words: amidine, aliphatic carboxylic acid, valproic acid (2-
propylpentanoic acid), circular dichroism
Amidines are versatile starting materials in several syn-
thetic schemes. By far the largest part of which deals with
the preparation of heterocyclic compounds.1 Moreover
the amidines could be considered as precursors of acid
functions.
In order to investigate the stereochemical course of the re-
action, we need to start from a reagent containing a chiral
centre. At first we considered the possibility of using a
primary amine containing an asymmetric carbon. In fact,
the synthesis of triazolines from aryl azides and imines
was previously described. In this case the Schiff base re-
acts in its enamino form with an aryl azide and an amino-
triazoline was obtained. In the same way starting from
tosyl azide, an amidine was directly obtained3
(Scheme 2).
Previous research from this laboratory was devoted to the
investigation of the reactivity of amidines in the construc-
tion of heterocyclic rings.2 Amidines are easily obtained
by heterocyclic transformation. In fact, the cycloaddition
of aromatic azides with enamines supplies a 4,5-dihydro-
triazole, which by nitrogen loss and transposition of the
R2
R1
R2
R1
R2
R3
R1
N
*
N
Ar N3
N
N
N
R3
N
Ar
R4 R3
N
R4
Ar
R4
Scheme 1
X
X
X
X
NH2
Z
+
O
N
NH
Z
X
X
Z
TosN3
ArN3
NH
Z
X
N
Tos
X
X
N
N
N
X
HN
Z
Ar
Scheme 2
SYNTHESIS 2004, No. 7, pp 1041–1046
x
x
.
x
x
.2
0
0
4
Advanced online publication: 14.04.2004
DOI: 10.1055/s-2004-822335; Art ID: Z03104SS
© Georg Thieme Verlag Stuttgart · New York

1042
F. Cassani et al.
PAPER
Amino acid methyl esters 1a–c (L-phenylalanine methyl
ester, L-proline methyl ester and D-proline methyl ester)
were reacted with symmetrical linear ketones 2a–c or a 4-
substituted-cyclohexyl ketone 2d or 2e in an inert solvent
in the presence of molecular sieves. The amidines 3a–l
were easily obtained when an equivalent amount of tosyl
azide was added to this solution. When the reaction was
complete (2–72 h, see Table 1), the amidine, containing
the whole amino acid function, was isolated (Scheme 3).
O
R1
R2
R3
TosN3
N
N
+
N
R1
N
R1 R1
H
N
Tos
R2
R3
3b,4a: R1=CH3, R2=H, R3=COOCH3
3c,4b: R1=CH3, R2=COOCH3, R3=H
3d,4c: R1=C2H5, R2=H, R3=COOCH3
3e,4d: R1=C2H5, R2=COOCH3, R3=H
3f,4e: R1=C3H7, R2=H, R3=COOCH3
3g,4f: R1=C3H7, R2=COOCH3, R3=H
O
R1 COOCH3
R1 COOCH3
R4
+
N
Tos
R2
R2
N
R4
R5
R2
N
H
R3
R5
R3
R1
N
R3
1a-c
2a-e
TosN3
R1
N
Tos
R2
R3
1a: R1=H, R2=CH2Ph, R3=H
1b: R1=H, R2R3=(CH2)3
1c: R2=H, R1R3=(CH2)3
2a: R4=R5=CH3
R4
R1
N
N
R5
R3
4a-f
N
N
N
3b-g
2b: R4=R5=C2H5
H3COOC
R2
Tos
R1
Scheme 4
2c: R4=R5=C3H7
2d: R4R5=CH2CH(CH3)CH2
2e: R4R5=CH2C(OCH2CH2O)CH2
H
Table 1 Amidines 3a–n Prepared
R5
Tos
R4
R3
Amidine
(–) Isomersa
(%)
(+) Isomersa
(%)
Reaction
Time (h)
N
N
R4
H
H3COOC
R2
R5
Tos
R1
3a
3b
3c
3d
3e
3f
60
97
1
40
3
50
62
62
60
60
60
60
36
2
R3
N
N
H3COOC
R2
3a,b,d,g,h-l
R1
99
5
3a: R1=H, R2=CH2Ph, R3=H, R4=R5=CH3
3b: R1=H, R2R3=(CH2)3, R4=R5=CH3
3a',c,e,f,h'-l'
95
5
3c: R2=H, R1R3=(CH2)3, R4=R5=CH3
3d: R1=H, R2R3=(CH2)3, R4=R5=C2H5
3e: R2=H, R1R3=(CH2)3, R4=R5=C2H5
3f: R1=H, R2R3=(CH2)3, R4=R5=C3H7
3g: R2=H, R1R3=(CH2)3, R4=R5=C3H7
3h: R1=H, R2R3=(CH2)3, R4R5CH2CH(CH3)CH2
3i: R1=H, R2R3=(CH2)3, R4R5=CH2C(OCH2CH2O)CH2
95
2
98
3
3g
3h
3i
97
3l: R1=H, R2=CH2Ph, R3=H, R4R5=CH2C(OCH2CH2O)CH2
25:25:25:25
Scheme 3 Reaction conditions: Amino acid ester (6 mmol), ketone
(6 mmol), molecular sieves 4Å (7 g), TosN3 (6 mmol), r.t.
50
50
50
53
50
50
50
47
3l
60
2
3m
3n
The reaction with a linear ketone has been already de-
scribed.4 The triazoline intermediate reacted in two differ-
ent reaction pathways: with loss of nitrogen and formation
of desired amidine or with loss of a diazoalkane. In the lat-
ter case the linear amidines 4a–f were obtained
(Scheme 4).
72
a Percentage of isomers was estimated by HPLC analysis.
The products 3a–l were examined by HPLC using chiral
column (Chiralcell OD, eluent: hexane–propan-2-ol, 7:3).
The amidines 3b–g showed the presence of a predominant
diastereomer (ee = 95–99%; see Table 1).
was irrelevant for the reaction course. In fact, L-proline es-
terified with propan-2-ol5 or with (–)-menthol6 was react-
ed with cyclohexane-1,4-dione mono ethylene ketal (2e)
and tosyl azide yielding a mixture of diastereoisomers in
equivalent amounts (see Table 1, entries 3m,n).
These results were obtained when the starting materials
were L- or D-proline methyl ester and linear ketones. Start-
ing from L-phenylalanine as amine or cyclic ketones as
carbonyl compound (Table 1, entry 3a,h–l), the enantio-
meric excess was poor or nil. The esterification of the L-
proline with a bulky alcohol [propan-2-ol or (–)-menthol]
The aim of this work was the selective production of the
aliphatic acid containing an asymmetric carbon. The opti-
mization of hydrolysis of the amidine function was the
main point considering its resistance to hydrolysis condi-
Synthesis 2004, No. 7, 1041–1046 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Pure a-Branched Aliphatic Carboxylic Acids
1043
was performed with HP 1050, DAD, pump Merck-Hitachi L 7100,
injector Rhedyne loop 20mL, column Chiralcell OD, 1 mL/min,
hexane–propan-2-ol (7:3).
tions. Under mild conditions (10% HCl, reflux, 12 h), the
amidine was recovered unaltered. Harsh conditions (37%
HCl, reflux, 8 h) bring to a complete transformation with-
out formation of secondary products (Scheme 5).
Amidines 3a–n; General Procedure
Amino acid ester hydrochloride 1a–c (6 mmol) was suspended in
CH2Cl2 (20 mL) and Et3N (606 mg, 6 mmol) was added. After 30
min, ketone 2a–e (6 mmol), molecular sieves 4Å (7 g) and tosyl
azide (6 mmol) were added. The mixture was stirred at r.t. until the
disappearance of the starting material (20–60 h). The suspension
was filtered and evaporated. The crude was chromatographed with
EtOAc–cycloexane (1:1) as eluent.
NH2
O2S
R
H
+
COOH
3b,d,g
R
5a,c,f
CH3
2-[2-Methyl-1-(toluene-4-sulfonylimino)butylamino]-3-phenyl-
propionic Acid Methyl Esters (3a and 3a¢)
Yield: 21%; colorless oil.
IR: 1740 cm–1 (C=O).
NH2
O2S
R
H
+
1H NMR (200 MHz): d = 0.80–0.95 (m, 3 H, CH3), 1.12 and 1.19 (2
d, 3 H, J = 7.3 Hz, CH3), 1.10–1.40 (m, 2 H, CH2), 2.43 (s, 3 H, Ar-
CH3), 2.95–3.32 (m, 2 H, CH2Ph), 3.55–3.80 (m, 1 H, CHCH3),
3.71 and 3.74 (2 s, 3 H, CH3O), 4.75–4.84 (m, 1 H, CHCOO), 5.80–
5.97 (m, 1 H, NH), 6.98–7.90 (m, 9 H, ArH).
13C NMR (75 MHz): d = 11.58, 11.77 (CH3), 18.20, 18.51 (CH3),
21.67 (CH3), 28.33, 28.36 (CH), 38.90, 37.15 (CH), 38.95, 39.01
(CH), 52.70 (CH3), 54.67, 54.91 (CH), 126.56 (CH), 127.56 (CH),
128.87 (CH), 129.33 (CH), 129.46 (CH), 135.40 (C), 135.55 (C),
3c,e,f
COOH
5b,d,e
R
CH3
3b,5a,3c,5b: R = CH3
3d,5c,3e,5d: R = C2H5
3f,5e,3g,5f: R = C3H7
Scheme 5 Reaction conditions: 37% HCl, reflux, 8 h.
By prolonged extraction of the crude with dichlo- 141.20 (C), 142.35 (C), 171.62 (C), 172.00 (C).
romethane, we obtained an equimolar mixture of aliphatic
acid and tosyl amide in good yield (70%), from which the
pure acid can be distilled out. Starting from amidine 3b,
(R)-(–)-2-methylbutyric acid (5a) was obtained. Hydroly-
sis of 3c furnishes (S)-(+)-2-methylbutyric acid (5b). Both
acids were compared with the authentic samples. Hydrol-
ysis of the amidines 3d–g under the same conditions
Anal. Calcd for C22H28N2O4S: C, 63.44; H, 6.78; N, 6.73. Found: C,
63.24; H, 6.89; N, 6.52.
(1S)-[(2R)-Methyl-1-(toluene-4-sulfonylimino)butyl]pyrroli-
dine-2-carboxylic Acid Methyl Ester (3b)
Yield: 30%; colorless oil; [a]D –127.0.
IR: 1739 cm–1 (C=O).
yields two enantiomeric pairs of acids. Starting from ami- 1H NMR (200 MHz): d = 1.02 (t, 3 H, J = 7.3 Hz, CH3), 1.37 (d, 3
H, J = 7.32 Hz, CH3), 1.78–2.22 (m, 6 H, 3 CH3), 2.40 (s, 3 H, Ar-
dine 3d, the (R)-(–)-2-ethylpentanoic acid (5c) was
obtained7 and the other isomer 5d was formed from 3e.
CH3), 3.45 (s, 3 H, CH3O), 3.58–3.87 (m, 3 H, CH and CH2N),
4.42–4.58 (m, 1 H, CHCOO), 7.25 and 7.78 (AA¢BB¢ system, 4 H,
J = 8.06 Hz, ArH).
The optically pure 2-propylhexanoic acid has not been de-
scribed earlier. The hydrolysis course of 3f and 3g was the
13C NMR (75 MHz): d = 11.93 (CH3), 15.68 (CH3), 21.12 (CH3),
same as the other amidines. Starting from amidine 3f, the
25.24 (CH2), 25.48 (CH2), 28.08 (CH2), 39.84 (CH), 48.49 (CH2),
51.94 (CH3), 62.45 (CH), 126.28 (CH), 128.90 (CH), 141.61 (C),
143.609 (C), 169.62 (C), 172.0 (C).
acid 5e was obtained, whereas from amidine 3g, the (+)-
acid 5f was obtained. The circular dichroism spectra of
(S)-(+)-2-methylbutyric (5b) and (–)-2-propylhexanoic
Anal. Calcd for C18H26N2O4S: C, 58.99; H, 7.15; N, 7.64. Found C,
acid (5e) show a similar course. This result allowed us to
58.77; H, 7.34; N, 7.60.
assign a S-configuration to 5e. Acid 5f shows a circular
dichroism spectrum having opposite signs of 5e and hence
its configuration is R.
(1S)-[1-(Toluene-4-sulfonylimino)propyl]pyrrolidine-2-carbox-
ylic Acid Methyl Ester (4a)
Yield: 34%; mp 72 °C; white crystals from i-Pr2O; [a]D –106.6.
IR: 1750 cm–1 (C=O).
This new procedure results in optically pure aliphatic,
branched carboxylic acids containing a stereogenic cen-
ter. This class of acids may be correlated to the valproic 1H NMR (200 MHz): d = 1.35 (t, 3 H, J = 7.3 Hz, CH3), 1.95–2.25
acid (2-propylpentanoic acid) and its metabolites.8 More-
(m, 4 H, 2 CH2), 2.40 (s, 3 H, Ar-CH3), 2.86–3.05 (m, 2 H, CH2),
3.49 (s, 3 H, CH3O), 3.50–3.81 (m, 2 H, CH2N), 4.12–4.55 (m, 1 H,
CHCOO), 7.24–7.78 (AA¢BB¢ system, 4 H, J = 8.1 Hz, ArH).
13C NMR (75 MHz): d = 10.83 (CH3), 21.64 (CH3), 24.79 (CH2),
25.92 (CH2), 29.29 (CH2), 47.89 (CH2), 52.23 (CH3), 61.02 (CH),
over, an easy method to obtain amidines containing the
amino acid function was performed.
Mps were determined using a Büchi 510 (capillary) apparatus. [a]D
Values were measured with Perkin-Elmer 343 plus polarimeter (c =
10% in CHCl3; 20 °C). IR spectra were recorded on a JASCO IR
Report 100 instrument (Nujol; cm–1). NMR spectra were obtained
with Bruker Advance 300, Bruker AC 200 and Varian Gemini 200
instruments. J values are given in Hz for solutions in CDCl3. HPLC
126.37 (CH), 129.14 (CH), 141.44 (C), 142.01 (C), 168.31 (C),
172.07 (C).
Anal. Calcd for C16H22N2O4S: C, 56.78; H, 6.55; N, 8.28. Found: C,
56.54; H, 6.75; N, 8.12.
Synthesis 2004, No. 7, 1041–1046 © Thieme Stuttgart · New York

1044
F. Cassani et al.
PAPER
(1R)-[(2S)-Methyl-1-(toluene-4-sulfonylimino)butyl]pyrroli-
dine-2-carboxylic Acid Methyl Ester (3c)
Anal. Calcd for C20H30N2O4S: C, 60.89; H, 7.66; N, 7.10. Found: C,
60.82; H, 7.74; N, 7.02.
Yield: 31%; colorless oil; [a]D +127.0.
IR: 1739 cm–1 (C=O).
(1R)-[1-(Toluene-4-sulfonylimino)butyl]pyrrolidine-2-carboxy-
lic Acid Methyl Ester (4d)
Yield: 21%; mp 72 °C; white crystals from i-Pr2O; [a]D +111.8.
1H NMR (200 MHz): d = 1.02 (t, 3 H, J = 7.3 Hz, CH3), 1.33 (d, 3
H, J = 7.32 Hz, CH3), 1.78–2.22 (m, 6 H, 3 CH3), 2.40 (s, 3 H, Ar-
CH3), 3.43 (s, 3 H, CH3O), 3.58–3.87 (m, 3 H, CH and CH2N),
4.42–4.58 (m, 1 H, CHCOO), 7.25 and 7.78 (AA¢BB¢ system, 4 H,
J = 8.1 Hz, ArH).
13C NMR (75 MHz): d = 12.08 (CH3), 16.02 (CH3), 21.26 (CH),
25.62 (CH2), 26.21 (CH2), 28.22 (CH2), 39.38 (CH), 48.64 (CH2),
52.06 (CH3), 62.59 (CH), 126.45 (CH), 129.05 (CH), 141.83 (C),
143.50 (C), 169.76 (C), 172.19 (C).
(1S)-[(2S)-Propyl-1-(toluene-4-sulfonylimino)hexyl]pyrroli-
dine-2-carboxylic Acid Methyl Ester (3f)
Yield: 25%; yellow oil; [a]D –99.8.
IR: 1741 cm–1 (C=O).
1H NMR (200 MHz): d = 0.88–1.00 (m, 6 H, 2 CH3), 1.24–2.28 (m,
14 H, 7 CH2), 2.40 (s, 3 H, Ar-CH3), 3.47 (s, 3 H, OCH3), 3.68–3.78
(m, 2 H, CH2N), 3.86–4.54 (m, 1 H, CHC=N), 4.47–4.54 (m, 1 H,
CHCOO), 7.24 and 7.78 (AA¢ BB¢ system, 4 H, J = 8.1 Hz, ArH).
13C NMR (75 MHz): d = 13.92 (CH3), 14.26 (CH3), 21.14 (CH2),
21.38 (CH3), 23.15 (CH2), 25.54 (CH2), 27.83 (CH2), 29.27 (CH2),
31.22 (CH2), 33.67 (CH2), 43.55 (CH), 48.41 (CH2), 51.79 (CH3),
62.48 (CH), 126.28 (CH), 128.78 (CH), 141.59 (C), 143.58 (C),
169.25 (C), 171.99 (C).
Anal. Calcd for C18H26N2O4S: C, 58.99; H, 7.15; N, 7.64. Found: C,
58.69; H, 7.44; N, 7.57.
(1R)-[1-(Toluene-4-sulfonylimino)propyl]pyrrolidine-2-car-
boxylic Acid Methyl Ester (4b)
Yield: 33%; mp 72 °C; white crystals from i-Pr2O; [a]D +106.6.
(1S)-[(2R)-Ethyl-1-(toluene-4-sulfonylimino)pentyl]pyrroli-
dine-2-carboxylic Acid Methyl Ester (3d)
Anal. Calcd for C22H34N2O4S: C, 62.53; H, 8.11; N, 6.63. Found: C,
62.34; H, 8.25; N, 6.52.
Yield: 42%; mp 88 °C; white crystals from i-Pr2O; [a]D –88.2.
IR: 1739 cm–1 (C=O).
(1S)-[1-(Toluene-4-sulfonylimino)pentyl]pyrrolidine-2-carbox-
ylic Acid Methyl Ester (4e)
Yield: 30%; mp 88 °C; white crystals from i-Pr2O; [a]D –103.5.
IR: 1739 cm–1 (C=O).
1H NMR (200 MHz): d = 0.97 (t, 3 H, J = 7.32 Hz, CH3), 1.42–2.30
(m, 8 H, 4 CH2), 2.42 (s, 3 H, CH3), 2.80–3.04 (m, 2 H, CH2C=N),
3.48 (s, 3 H, OCH3), 3.58–3.78 (m, 2 H, CH2N), 4.48–4.56 (m, 1 H,
CHCOO), 7.24 and 7.78 (AA¢BB¢ system, 4 H, J = 8.0 Hz, ArH).
13C NMR (75 MHz): d = 13.82 (CH3), 21.60 (CH3), 23.20 (CH2),
24.78 (CH2), 28.53 (CH2), 29.28 (CH2), 32.33 (CH2), 48.01 (CH2),
52.19 (CH3), 61.01 (CH), 126.38 (CH), 129.09 (CH), 141.53 (C),
141.92 (C), 167.39 (C), 172.07 (C).
1H NMR (200 MHz): d = 0.53 and 1.05 (2 t, 6 H, J = 7.20 Hz, 2
CH3), 1.27–2.19 (m, 10 H, 5 CH2), 2.40 (s, 3 H, Ar-CH3), 3.44 (s, 3
H, OCH3), 3.62–3.81 (m, 2 H, CH2N), 3.85–4.02 (m, 1 H, CHC=N),
4.44–4.58 (m, 1 H, CHCOO), 7.24 and 7.79 (AA¢BB¢ system, 4 H,
J = 8.1 Hz, ArH).
13C NMR (75 MHz): d = 12.56 (CH3), 14.60 (CH3), 21.65 (CH3),
24.64 (CH2), 24.87 (CH2) 25.77 (CH2), 28.06 (CH2), 33.79 (CH2),
45.39 (CH), 48.66 (CH2), 52.07 (OCH3), 62.60 (CH), 126.45 (CH),
129.03 (CH), 141.79 (C), 143.86 (C), 169.20 (C), 172.25 (C).
Anal. Calcd for C20H30N2O4S: C, 60.89; H, 7.66; N, 7.10. Found: C,
60.74; H, 7.82; N, 6.98.
Anal. Calcd for C18H26N2O4S: C, 58.99; H, 7.15; N, 7.64. Found: C,
58.84; H, 7.28; N, 7.64.
(1S)-[1-(Toluene-4-sulfonylimino)butyl]pyrrolidine-2-carboxy-
lic Acid Methyl Ester (4c)
Yield: 10%; mp 72 °C; white crystals from i-Pr2O; [a]D –111.8.
(1R)-[(2R)-Propyl-1-(toluene-4-sulfonylimino)hexyl]pyrroli-
dine-2-carboxylic Acid Methyl Ester (3g)
Yield: 27%; yellow oil; [a]D +101.0.
IR: 1740 cm–1 (C=O).
1H NMR (200 MHz): d = 0.86–1.02 (m, 6 H, 2 CH3), 1.26–2.28 (m,
14 H, 7 CH2), 2.40 (s, 3 H, Ar-CH3), 3.48 (s, 3 H, OCH3), 3.68–3.80
(m, 2 H, CH2N), 3.85–4.07 (m, 1 H, CHC=N), 4.47–4.54 (m, 1 H,
CHCOO), 7.22 and 7.76 (AA¢BB¢ system, 4 H, J = 8.40 Hz).
13C NMR (75 MHz): d = 17.02 (CH3), 17.20 (CH3), 20.88 (CH3),
21.00 (CH2), 21.50 (CH2), 24.02 (CH2), 24.98 (CH2), 26.00 (CH2),
27.96 (CH2), 42.08 (CH), 44.22 (CH2), 46.00 (CH3), 61.40 (CH),
123.1 (CH), 125.2 (CH), 140.80 (C), 143.00 (C), 169.80 (C), 171.20
(C).
1H NMR (200 MHz): d = 1.12 (t, 1 H, J = 7.2 Hz, CH3), 1.71–2.36
(m, 4 H, 2 CH2), 3.42 (s, 3 H, Ar-CH3), 2.80–3.04 (m, 2 H, CH2N),
3.42 (s, 3 H, CH3O), 3.43–3.80 (m, 2 H, CH2C=N), 4.48–4.57 (m, 1
H, CHCOO), 7.22 and 7.77 (AA¢ BB¢ system, 4 H, J = 8.1 Hz, ArH).
13C NMR (75 MHz): d = 14.51 (CH3), 20.31 (CH2), 21.61 (CH3),
24.80 (CH2), 29.29 (CH2), 34.34 (CH2), 48.08 (CH2), 51.18 (CH3),
61.02 (CH), 126.37 (CH), 129.10 (CH), 141.51 (C), 141.92 (C),
167.16 (C), 172.07 (C).
Anal. Calcd for C17H24N2O4S: C, 57.93; H, 6.86; N, 7.95. Found C,
57.82; H, 6.94; N 7.87.
(1R)-[(2S)-Ethyl-1-(toluene-4-sulfonylimino)pentyl]pyrroli-
dine-2-carboxylic Acid Methyl Ester (3e)
Yield: 60%; mp 88 °C; white crystals from i-Pr2O; [a]D +88.2.
1H NMR (300 MHz): d = 0.50 and 1.00 (2 t, 6 H, J = 7.20 Hz, 2
CH3), 1.27–2.19 (m, 10 H, 5 CH2), 2.40 (s, 3 H, Ar-CH3), 3.43 (s, 3
H, OCH3), 3.62–3.81 (m, 2 H, CH2N), 3.85–4.02 (m, 1 H, CHC=N),
4.44–4.58 (m, 1 H, CHCOO), 7.24 and 7.79 (AA¢BB¢ system, 4 H,
J = 8.1 Hz, ArH).
Anal. Calcd for C22H34N2O4S: C, 62.53; H, 8.11; N, 6.63. Found: C,
62.49; H, 8.32; N, 6.54.
(1R)-[1-(Toluene-4-sulfonylimino)pentyl]pyrrolidine-2-carbox-
ylic Acid Methyl Ester (4f)
Yield: 31%; mp 88 °C; white crystals from i-Pr2O; [a]D +103.5.
1-[(3-Methylcyclopentyl)-1-(toluene-4-sulfonylimino)meth-
yl]pyrrolidine-2-carboxylic Acid Methyl Esters (3h and 3h¢)
Yield: 52%; colorless oil.
IR: 1740 cm–1 (C=O).
13C NMR (75 MHz): d = 12.43 (CH3), 14.47 (CH3), 21.25 (CH2),
21.51 (CH3), 25.51 (CH2), 25.60 (CH2), 27.99 (CH2), 30.65 (CH2),
45.29 (CH), 48.64 (CH2), 51.92 (CH3), 62.56 (CH), 126.29 (CH),
128.93 (CH), 141.70 (C), 142.96 (C), 169.11 (C), 172.08 (C).
Synthesis 2004, No. 7, 1041–1046 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Pure a-Branched Aliphatic Carboxylic Acids
Hydrolysis of Amidines 3b–g,i; General Procedure
1045
1H NMR (200 MHz): d = 1.01–1.15 (m, 3 H, CH3), 1.80–2.35 (m,
11 H, 6 CH2 and CH), 2.40 (s, 3 H, Ar-CH3), 3.44 (s, 3 H, CH3O),
3.65–3.80 (m, 2 H, CH2N), 3.85–415 (m, 1 H, CHC=N), 4.44–4.59
(m, 1 H, CHCOO), 7.25 and 7.77 (AA¢BB¢ system, 4 H, J = 8.43 Hz,
ArH).
13C NMR (75 MHz): d = 21.56 (CH3), 25.39 (CH2), 27.71, 27.83
(CH2), 30.06 (CH2), 34.55, 34.98 (CH2), 35.84, 35.93 (CH2), 36.25,
36.30 (CH), 48.71, 48.78 (CH2), 52.04 (CH3), 62.40 (CH), 126.53
(CH), 129.01 (CH), 141.76 (C), 143.12 (C), 169.11, 169.31 (C),
172.14 (C). Anal. Calcd for C20H28N2O4S: C, 61.20; H, 7.19; N,
7.14. Found: C, 61.01; H, 7.31; N, 6.98.
The appropriate amidine 3b–g,i (2 mmol) was suspended in 37%
HCl (40 mL) and the mixture was refluxed for 8 h. The resulting so-
lution was extracted with CH2Cl2 (100 mL) with a continuous liq-
uid/liquid extractor. The organic layer, dried (Na2SO4) was
evaporated. The composition of the resulting white powder was an
equimolar mixture of acid and tosyl amide (yield of acid: 70–80%).
The white powder was dissolved in H2O (250 mL) and 200 mL of
water containing the acid was distilled. This distillate was extracted
with CH2Cl2 (200 mL) with a continuous liquid/liquid extractor.
The organic layer, dried (Na2SO4) and evaporated afforded the pure
acid.
1-[(1,4-Dioxaspiro[4.4]non-7-yl)-1-(toluene-4-sulfonylimi-
no)methyl]pyrrolidine-2-carboxylic Acid Methyl Esters (3i and
(R)-(–)-2-Methylbutyric Acid (5a)
Yield: 56%; colorless oil; [a]D –19 {(Lit.9 [a]D –19}.
3i¢)
Yield: 42%; colorless oil.
1H NMR (200 MHz): d = 0.96 (t, 3 H, J = 7.33 Hz, CH3), 1.20 (d, 3
H, J = 6.8 Hz, CH3), 1.47–1.73 (m, 2 H, CH2), 2.40–2.44 (m, 1 H,
CH), 11.00 (br s, 1 H, CO2H).
13C NMR (50 MHz): d = 10.93 (CH3), 14.63 (CH3), 24.75 (CH2),
43.38 (CH), 179.61 (C).
IR: 1745 cm–1 (C=O).
1H NMR (200 MHz): d = 1.82–2.38 (m, 10 H, 5 CH2), 2.40 (s, 3 H,
Ar-CH3), 3.42 and 3.45 (2 s, 3 H, OCH3), 3.75–4.19 [m, 7 H,
O(CH2)2O, CH2N and CHC=N], 4.49–4.55 (m, 1 H, CHCOO), 7.24
and 7.78 (AA¢BB¢ system, 4 H, J = 8.41 Hz, ArH).
(S)-(+)-2-Methylbutyric Acid (5b)
Yield: 52%; colorless oil; [a]D +19.
Anal. Calcd for C21H28N2O6S: C, 57.78; H, 6.47; N, 6.42. Found: C,
57.62; H, 6.51; N, 6.33.
(R)-(–)-2-Ethylpentanoic Acid (5c)
Yield: 55%; colorless oil; [a]D – 6 {Lit.7 [a]D –6.05}.
2-{[(1,4-Dioxaspiro[4.4]non-7-yl)-1-(toluene-4-sulfonylimi-
no)methyl]amino}-3-phenylpropionic Acid Methyl Esters (3l
and 3l¢)
1H NMR (200 MHz): d = 0.84–1.45 (m, 8 H, 2 CH3 and CH2), 2.60–
2.79 (m, 4 H, 2 CH2), 2.38–2.42 (m, 1 H, CH), 11.00 (br s, 1 H,
CO2H).
13C NMR (50 MHz): d = 11.18 (CH3), 14.03 (CH3), 20.3 (CH2),
22.58 (CH2), 31.67 (CH2), 46.71 (CH), 181.03 (C).
Yield: 68%; colorless oil.
IR: 1473 cm–1 (C=O).
1H NMR (300 MHz): d = 1.58–2.04 (m, 6 H, 3 CH2), 2.43 (s, 3 H,
Ar-CH3), 2.92–3.27 (m, 2 H, CH2Ph), 3.69 and 3.27 (2 s, 3 H,
CH3O), 3.82–3.02 [m, 4 H, O(CH2)2O], 4.20–4.26 (m, 1 H,
CHC=N), 4.73–4.89 (m, 1 H, CHCOO), 7.02–7.82 (9 H, m, ArH).
(S)-(+)-2-Ethylpentanoic Acid (5d)
Yield: 49%; colorless oil; [a]D +6.05.
Anal. Calcd for C25H30N2O6S: C, 61.71; H, 6.21; N, 5.76. Found: C,
61.54; H, 6.40; N, 5.62.
(S)-(–)-2-Propylhexanoic Acid (5e)
Yield: 45%; colorless oil; [a]D –3.09.
IR: 1705 cm–1 (C=O).
1H NMR (200 MHz): d = 0.80–1.05 (m, 6 H, 2 CH3), 1.28–1.77 (m,
10 H, 5 CH2), 2.19–2.43 (m, 1 H, CH), 11.00 (br s, 1 H, CO2H).
13C NMR (50 MHz): d = 14.12 (2 CH3), 20.34 (CH2), 23.20 (CH2),
29.53 (CH2), 29.72 (CH2), 32.1 (CH2), 44.42 (CH), 181.02 (C=O).
1-[(1,4-Dioxaspiro[4.4]non-7-yl)-1-(toluene-4-sulfonylimi-
no)methyl]pyrrolidin-2-carboxylic Acid Isopropyl Ester (3m
and 3m¢)
Yield: 37%; colorless oil.
IR: 1430 cm–1 (C=O).
1H NMR (200 MHz): d = 1.03 and 1.16 (2 d, 6 H, J = 7.3 Hz, 2 CH3),
1.82–2.36 (m, 10 H, 5 CH2), 2.40 (s, 3 H, Ar-CH3), 3.76–3.87 (m, 2
H, CH2N), 3.91–3.95 [m, 4 H, O(CH2)2O], 4.05–4.22 (m, 1 H,
CHC=N), 4.51–4.56 (m, 1 H, OCH), 4.74–4.86 (m, 1 H, CHCOO),
7.26 and 7.78 (AA¢BB¢ system, 4 H, J = 8.1 Hz, ArH).
Anal. Calcd for C9H18O2: C, 68.31; H, 11.47. Found: C, 68.22; H,
11.62.
(R)-(+)-2-Propylhexanoic Acid (5f)
Yield: 48%; colorless oil; [a]D +3.09.
Anal. Calcd for C23H32N2O6S: C, 59.46; H, 6.94; N, 6.03. Found: C,
59.34; H, 7.02; N, 5.97.
Acknowledgment
1-[(1,4-Dioxaspiro[4.4]non-7-yl)-1- (toluene-4-sulfonylimi-
no)methyl]pyrrolidin-2-carboxylic Acid Menthyl Esters (3n
and 3n¢)
We thank Ministero dell’Istruzione, dell’Università e della Ricerca
(MIUR) for financial support.
Yield: 45%; colorless oil.
IR: 1442 cm–1 (C=O).
References
1H NMR (200 MHz): d = 0.67–0.95 (m, 9 H, 3 CH3), 1.25–2.14 (m,
20 H, 8 CH2 and 4 CH), 2.40 (s, 3 H, Ar-CH3), 3.72–3.81 (m, 2 H,
CH2N), 3.94–3.96 [m, 4 H, O(CH2)2O], 4.02–4.21 (m, 1 H,
CHCOO), 4.68–4.76 (m, 1 H, CH-menthol), 7.26 and 7.79 (AA¢BB¢
system, 4 H, J = 6.9 Hz, ArH).
(1) Boyd, G. V. In The Chemistry of Amidines and Imidates;
Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1991,
Chap. 8, 367.
(2) (a) Clerici, F.; Erba, E.; Pocar, D. Tetrahedron 2003, 59,
1667. (b) Erba, E.; Gelmi, M. L.; Pocar, D. Tetrahedron
2000, 56, 9991. (c) Erba, E.; Pocar, D.; Valle, M. J. Chem.
Soc., Perkin Trans. 1 1999, 421.
Anal. Calcd for C30H44N2O6S: C, 64.26; H, 7.91; N, 5.00. Found: C,
64.14; H, 8.02; N, 4.97.
Synthesis 2004, No. 7, 1041–1046 © Thieme Stuttgart · New York

1046
F. Cassani et al.
PAPER
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Synthesis 2004, No. 7, 1041–1046 © Thieme Stuttgart · New York