One-pot synthesis of β-amino acid derivatives from α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2006.10.007

The one-pot transformation of α-amino acid into β-amino acid derivatives is described. The application of this method to the synthesis of modified dipeptides was also illustrated.

Full text of DOI:10.1016/j.tetlet.2006.10.007

Tetrahedron Letters 47 (2006) 8757–8760
One-pot synthesis of b-amino acid derivatives from a-amino acids
a
a,
a,
b
*
*
´
Carlos J. Saavedra, Rosendo Hern a´ ndez, Alicia Boto and Eleuterio Alvarez
a
Instituto de Productos Naturales y Agrobiolog ı´ a del CSIC, Avda. Astrof ı´ sico Francisco S a´ nchez, 3, 38206-La Laguna, Spain
b
Instituto de Investigaciones Qu ı´ micas CSIC, Avda. Am e´ rico Vespucio, 49, Isla de la Cartuja, 41092 Sevilla, Spain
Received 24 August 2006; revised 29 September 2006; accepted 2 October 2006
Available online 20 October 2006
Abstract—The one-pot transformation of a-amino acid into b-amino acid derivatives is described. The application of this method to
the synthesis of modified dipeptides was also illustrated.
ꢀ
2006 Published by Elsevier Ltd.
1
The synthesis of b-amino acids and peptides containing
2
them has arisen great interest, due to the promising
biological activities shown by many of these compounds.
For instance, b-amino acid 1 (methylphenidate or
ꢁ
Ritalin , Fig. 1) is clinically used as a treatment for
3
the attention deficit disorder in children, and dipeptide 2
ꢁ
(
bestatine or Ubenimex ) is an immunological response
4
modifier.
In previous articles, we have reported the syntheses of
alkaloids and a-amino phosphonates from a-amino
acids 3 (Scheme 1) using a tandem radical fragmenta-
5
tion–addition of nucleophiles reaction. When sub-
strates 3 were treated with (diacetoxyiodo)benzene
(
DIB) and iodine, under irradiation with visible light,
an O-radical 4 was generated, which underwent b-scis-
6
sion, generating a C-radical 5. This intermediate was
oxidized in the reaction mixture to an acyliminium ion
Scheme 1. b-Scission in amino acid derivatives.
6
,7,8 which was trapped by oxygen, nitrogen, phospho-
rous or carbon nucleophiles. We reasoned that the addi-
tion of enolsilylethers to the acyliminium ion could
generate b-amino acid derivatives 7 or modified peptides
(
when Z = [aa] ). The feasibility of this strategy is dis-
n
cussed herein.
In order to study the fragmentation–addition reaction,
different amino acid derivatives 8–12 (Scheme 2) were
prepared, in good yields, by the acylation or carbamoyl-
ation of commercial precursors. Substrates 8–11 were
treated with DIB and iodine at room temperature and
under irradiation with visible light (Table 1, entries
1–8). The reaction mixture was then cooled to 0 ꢂC
and the enolsilylether and BF ÆOEt were added,
Figure 1. Bioactive b-amino acid derivatives.
Keywords: Radicals; b-Amino acids; Dipeptides; Fragmentation;
Acyliminium ions; Nucleophilic addition.
*
Corresponding authors. Tel.: +34 922 251004; fax: +34 922 260135;
e-mail addresses: rhernandez@ipna.csic.es; alicia@ipna.csic.es
3
2
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.10.007

8758
C. J. Saavedra et al. / Tetrahedron Letters 47 (2006) 8757–8760
Table 1. One-pot b-fragmentation–alkylation reaction
a,b,c,d
e
Entry
Substrate
Conditions
Products (%)
a
1
2
3
4
5
6
7
8
9
8
8
A
B
13 (50)
14 (41)
15 (55)
16 (67)
17 (50)
18 (55)
19 (85)
20 (77)
21 (69)
22 (56)
b
9
A
B
A
B
A
B
9
10
10
11
11
12
12
c
C
d
1
0
D
a
Method A. The substrate (1 mmol) in dry dichloromethane (15 mL)
was treated with DIB (2.5 mmol) and iodine (1 mmol) and irradiated
with visible light (100 W tungsten-filament lamp). The reaction
mixture was stirred at room temperature under nitrogen until no
starting material was observed by TLC analysis (about 3 h). It was
then cooled to 0 ꢂC and BF
5 equiv) were added. The reaction mixture was allowed to reach rt
and stirred for 4 h, and afterwards it was poured into aqueous
NaHCO –10% Na and extracted with CH Cl
C@C(OTMS)OMe as the
3 2 2
ÆOEt (2 equiv) and CH @C(OTBS)OMe
(
3
2
S
O
2 3
2
2
.
b
c
Method B. As Method A, but using Me
nucleophile.
2
Method C. The substrate (1 mmol) in dry acetonitrile (15 mL) was
treated with DIB (2.5 mmol) and iodine (2 mmol) and irradiated with
visible light (100 W tungsten-filament lamp). The reaction mixture
was stirred at room temperature under nitrogen until no starting
material was observed by TLC analysis (about 3 h). Dry methanol
was then added and the mixture was poured into aqueous 10%
Na
and evaporated, and the crude product was solved in dry acetonitrile,
cooled to 0 ꢂC, and treated with BF ÆOEt (2 equiv) and
CH @C(OTBS)OMe (5 equiv). The reaction mixture was allowed to
reach rt and stirred for 4 h, and afterwards it was poured into
aqueous NaHCO and extracted with CH Cl
2 2 3 2 2
S O and extracted with CH Cl . The organic layer was dried
3
2
2
3
2
2
.
d
e
Method D. As Method C, but using Me
nucleophile.
2
C@C(OTMS)OMe as
Yields are given for products purified by chromatography on silica
gel.
used as components of glycine reuptake inhibitors in
1
0
the CNS.
The fragmentation–alkylation of methyl carbamate 12
using methods A or B gave a complex mixture of prod-
ucts, so different conditions were tried (methods C or
1
1
D, entries 9 and 10). In the first step, a tandem fragmen-
tation–b-iodination–addition of methanol reaction took
place. The crude product was then treated with the Lewis
acid and the nucleophile to give the iodinated b-amino
acid derivatives (± )-21 or (± )-22 in good yields. The
introduction of iodine in a previously non-functionalized
position is specially interesting, since these iodinated
pyrrolidines could be valuable intermediates in the syn-
Scheme 2. One-pot transformation of a-amino acid into b-amino acid
derivatives.
affording b-amino acid derivatives 13–20. In spite of
their different volume, both nucleophiles gave similar
product yields. In this way, a-amino acids were trans-
formed in one step into the corresponding b-analogues.
1
2
thesis of alkaloids and bactericidal iminoglyco acids.
The biological activities of amino acids 13–20 are under
study. Thus, the derivatives of b-homophenylalanine
Another interesting application of the scission–alkyl-
ation reaction would be the preparation of modified
peptides, which is a rapidly growing field in medicinal
(
related to compounds 17 and 18) have been reported
9
2
as a new treatment for type II diabetes. Moreover, their
insertion into more complex structures could also be of
interest. For example, related b-amino acids are units of
aminopeptidase inhibitors such as bestatine 2 or amasta-
chemistry. Starting from bioactive peptides, the modifi-
cation of the C-terminal residue could afford derivatives
1
3
with different biological activity, potency or selectivity.
Since the modified residue would be attached to chiral
amino acid units, the reaction was expected to be
stereoselective.
2
d
tine, and several b-amino acids with lipophilic side
chains (such as compounds 13, 15 and 17) have been

C. J. Saavedra et al. / Tetrahedron Letters 47 (2006) 8757–8760
8759
References and notes
1
. For recent reviews on the synthesis or uses of b-amino
acids, see: (a) Liljeblad, A.; Kanerva, L. T. Tetrahedron
2
006, 62, 5831–5854; (b) Enantioselective Synthesis of b-
amino Acids; Juaristi, E., Soloshonok, V. A., Eds.; Wiley-
VCH: New York, 2005; (c) Viso, A.; Fern a´ ndez de la
Pradilla, R.; Garc ´ı a, A.; Flores, A. Chem. Rev. 2005, 105,
3167–3196; (d) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem.
2005, 633–639; (e) Cordova, A. Acc. Chem. Res. 2004, 37,
102–112; (f) Davies, S. G.; Smith, A. D.; Price, P. D.
Tetrahedron: Asymmetry 2005, 16, 2833–2891; (g) France,
S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem.
Res. 2004, 37, 592–600; (h) Ma, J.-A. Angew. Chem., Int.
Ed. 2003, 42, 4290–4299; (i) Taggi, A. E.; Hafez, A. M.;
Lectka, T. Acc. Chem. Res. 2003, 36, 10–19; (j) Sewald, N.
Angew. Chem., Int. Ed. 2003, 42, 5794–5795; (k) Liu, M.;
Sibi, M. P. Tetrahedron 2002, 58, 7991–8035; (l) Ellman, J.
A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
Scheme 3. Reagents and conditions: (i) DIB, I
2 2 2
, hm, CH Cl , then 0 ꢂC,
BF ÆOEt , Me C@C(OTMS)OMe, 58%, 24:25 5:2.
3
2
2
984–995; (m) Park, K.-H.; Kurth, M. J. Tetrahedron 2002,
58, 8629–8659; (n) F u¨ lop, F. Chem. Rev. 2001, 101, 2181–
2204.
2
. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180; (b)
Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15; (c)
Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
2
001, 101, 3219–3232; (d) Bauvois, B.; Dauzonne, D. Med.
Res. Rev. 2006, 26, 88–130.
3
4
5
. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.;
Maki, T. Tetrahedron 2000, 56, 7411–7422, and references
cited therein.
. (a) Pearson, W. H.; Hines, J. V. J. Org. Chem. 1989, 54,
4
235–4237; (b) Suda, H.; Takita, T.; Aoyagi, T.; Umez-
awa, H. J. Antibiot. 1976, 29, 600–601.
. For examples on the decarboxylation of amino acids, see:
(
a) Boto, A.; Gallardo, J. A.; Hern a´ ndez, R.; Saavedra, C.
J. Tetrahedron Lett. 2005, 46, 7807–7811; (b) Boto, A.; de
Le o´ n, Y.; Gallardo, J. A.; Hern a´ ndez, R. Eur. J. Org.
Chem. 2005, 3461–3468; (c) Boto, A.; Hern a´ ndez, R.;
Su a´ rez, E. J. Org. Chem. 2000, 64, 4930–4937.
Figure 2. X-ray analysis of dipeptide 24.
6
. For reviews on b-scission, see: (a) Hartung, J.; Gottwald,
T.; Spehar, K. Synthesis 2002, 1469–1498; (b) Zhdankin,
V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584; (c)
Togo, H.; Katohgi, M. Synlett 2001, 565–581; (d) Su a´ rez,
E.; Rodr ´ı guez, M. S. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 2, pp 440–454; For recent references on the b-
fragmentation reaction, see: (e) Boto, A.; Hern a´ ndez, D.;
Hern a´ ndez, R.; Su a´ rez, E. J. Org. Chem. 2003, 68, 5310–
The reaction was studied with the Leu-Ala derivative
3, using Me C@C(OTMS)OMe as the nucleophile.
2
2
The scission–alkylation afforded modified dipeptides
1
4
2
4
and 25 (Scheme 3), which could be separated by
chromatography and crystallization. The configuration
1
5
of 24 was determined by X-ray analysis (Fig. 2). As
expected, the reaction was diastereoselective (24:25,
5
:2). However, the isolation of the two possible diaste-
5
319.
reomers is also interesting, in order to determine the
influence of the configuration into the biological activity.
7
. For a discussion on the mechanism of the oxidation step,
see: Boto, A.; Hern a´ ndez, R.; Le o´ n, Y.; Murgu ´ı a, J. R.;
Rodr ´ı guez-Afonso, A. Eur. J. Org. Chem. 2005, 673–
In summary, the one-pot fragmentation–alkylation reac-
tion is a versatile and efficient pathway to obtain many
different b-amino acid derivatives from readily available
precursors. The synthesis of modified peptides is another
interesting application of this reaction.
6
82.
8
. For recent reviews on acyliminium ions, see: (a) Marya-
noff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–1628; (b)
Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104,
2
311–2352.
9
. (a) Kubryk, M.; Hansen, K.-B. Tetrahedron: Asymmetry
2
4
006, 17, 205–209; (b) Weber, A. J. Med. Chem. 2004, 48,
135–4141.
Acknowledgements
1
1
0. Wolin, R. L.; Santill a´ n, A., Jr.; Barclay, T.; Tang, L.;
Venkatesan, H.; Wilson, S.; Lee, D. H.; Lovenberg, T. W.
Bioorg. Med. Chem. 2004, 12, 4493–4509.
1. Boto, A.; Hern a´ ndez, R.; Le o´ n, Y.; Su a´ rez, E. J. Org.
Chem. 2001, 66, 7796–7803.
12. (a) La Ferla, B.; Bugada, P.; Cipolla, L.; Peri, F.; Nicotra,
F. Eur. J. Org. Chem. 2004, 2451–2470; (b) Schweizer, F.
Angew. Chem., Int. Ed. 2002, 41, 230–253.
This work was supported by the Research Programme
PPQ2003-01379 of the Plan Nacional de Investigaci o´ n
Cient ´ı fica, Desarrollo e Innovaci o´ n Tecnol o´ gica, Minis-
terios de Ciencia y Tecnolog ´ı a y de Educaci o´ n y Ciencia,
Spain. We also acknowledge financial support from
FEDER funds. C.J.S. thanks the CSIC for an I3P
fellowship.

8760
C. J. Saavedra et al. / Tetrahedron Letters 47 (2006) 8757–8760
1
3
1
1
3. For an electrochemical decarboxylation of peptides, see:
7.79 (2H, d, J = 7.0 Hz); C NMR (125.7 MHz, CDCl
16.9 (CH ), 22.3 (CH ), 22.9 (2 · CH ), 23.2 (CH ), 25.0
(CH), 41.4 (CH ), 46.0 (C), 51.3 (CH), 51.9 (CH ), 52.3
3
) d
Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl.
3
3
3
3
1
986, 25, 843–844.
2
3
1
4. All the compounds were completely characterized by H
(CH), 127.0 (2 · CH), 128.6 (2 · CH), 131.7 (CH), 134.0
(C), 167.3 (C), 171.2 (C), 177.0 (C). Anal. Calcd for
C H N O : C, 66.27; H, 8.34; N, 7.73. Found: C, 66.25;
20 30 2 4
13
and C NMR, MS, HRMS, IR and elemental analysis.
D-COSY, HSQC and NOESY experiments were also
2
1
carried out. Selected data for compound 24: H NMR
500 MHz, CDCl ) d 0.97 (6H, d, J = 5.8 Hz), 1.04 (3H, d,
J = 6.8 Hz), 1.20 (6H, s), 1.67–1.98 (3H, m), 3.67 (3H, s),
.08 (1H, dddd, J = 7.1, 7.1, 7.1, 10.2 Hz), 4.67 (1H, ddd,
H, 8.47; N, 7.92.
(
3
15. Crystal data for 24: C20
H
30
N
2
O
4
, M
r
= 362.46, colourless
Cl /n-hexane,
trigonal, space group P6 (no. 170), a = b = 11.7280(10) A,
3
needle (0.55 · 0.11 · 0.10 mm ) from CH
2
2
˚
4
5
˚
˚
3
J = 6.0, 8.3, 8.3 Hz), 6.87 (2H, br b, 2 · NH), 7.40 (2H,
c = 26.998(5) A, a = b = 90ꢂ, c = 120ꢂ, V = 3216.0(7) A ,
Z = 6. qcalcd = 1.123 g cm , k (Mo Ka) = 0.71073 A,
F(000) = 1176, l = 0.078 mm , T = 100(2) K. 26186
À3
˚
dd, J = 7.2, 7.9 Hz), 7.48 (1H, dd, J = 7.0, 7.8 Hz), 7.79
1
3
À1
(
2H, d, J = 7.5 Hz); C NMR (125.7 MHz, CDCl
3
) d 16.7
(
CH ), 22.3 (CH ), 22.7 (CH ), 22.8 (CH ), 23.2 (CH ),
reflections measured for the range 3.45ꢂ < h < 26.37ꢂ.
3
3
3
3
3
2
5
1
5.0 (CH), 41.8 (CH
2
), 46.0 (C), 51.3 (CH), 51.9 (CH
3
),
Final refinement with 2240 [Rint = 0.0802] unique reflec-
2.5 (CH), 127.1 (2 · CH), 128.5 (2 · CH), 131.7 (CH),
34.0 (C), 167.3 (C), 171.6 (C), 176.9 (C). Anal. Calcd for
tions and 317 parameters gave, R
1
= 0.0774, wR
2
= 0.1858
[for 1336 reflections with I > 2r(I)],
1
R = 0.1434,
C H N O : C, 66.27; H, 8.34; N, 7.73. Found: C, 66.13;
wR = 0.2375 (all data) (S = 1.092). The X-ray crystallo-
20
30
2
4
2
1
H, 8.26; N, 7.76. Selected data for compound 25: H NMR
500 MHz, CDCl ) d 0.98 (3H, d, J = 6.3 Hz), 0.99 (3H, d,
J = 6.3 Hz), 1.12 (3H, d, J = 6.6 Hz), 1.17 (6H, s), 1.65–
graphic file, in CIF format, has been deposited with the
Cambridge Crystallographic Data Centre, CCDC No.
618736 for 24. Copy of this information may be obtained
free of charge from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or
http://www.ccdc.cam.ac.uk/conts/retrieving.html.
(
3
1
6
.81 (3H, m), 3.67 (3H, s), 4.09 (1H, dddd, J = 6.8, 6.8,
.9, 9.7 Hz), 4.65 (1H, ddd, J = 6.0, 8.3, 8.3 Hz), 6.70 (1H,
d, J = 8.2 Hz, NH), 6.85 (1H, d, J = 9.6 Hz, NH), 7.43
2H, dd, J = 7.2, 7.8 Hz), 7.50 (1H, dd, J = 7.3, 7.5 Hz),
(