A two-step practical synthesis of dehydroalanine derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.01.122

A two-step practical synthesis of dehydroalanine derivatives from commercially available starting materials is reported. The approach comprises an Ugi four-component reaction using 2-benzoylacetaldehyde, followed by an elimination process of the benzoate group. This protocol provided access to several dehydroalanine derivatives modified with diverse functional groups, which might be useful for further transformations in the construction of more complex molecules.

Full text of DOI:10.1016/j.tetlet.2011.01.122

Tetrahedron Letters 52 (2011) 1635–1638
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Tetrahedron Letters
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A two-step practical synthesis of dehydroalanine derivatives
Karell Pérez-Labrada a,b, Edwin Flórez-López a, Evelyn Paz-Morales a, Luis D. Miranda a, , Daniel G. Rivera c,
⇑
⇑
a Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, México D.F. 04510, Mexico
b Department of Chemistry, Institute of Pharmacy and Food, University of Havana, San Lázaro y L, Vedado 10400, Ciudad de La Habana, Cuba
c Center for Natural Products Study, Faculty of Chemistry, University of Havana, Zapata y G, Vedado 10400, Ciudad de La Habana, Cuba
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step practical synthesis of dehydroalanine derivatives from commercially available starting mate-
rials is reported. The approach comprises an Ugi four-component reaction using 2-benzoylacetaldehyde,
followed by an elimination process of the benzoate group. This protocol provided access to several dehy-
droalanine derivatives modified with diverse functional groups, which might be useful for further trans-
formations in the construction of more complex molecules.
Received 15 October 2010
Revised 24 January 2011
Accepted 26 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dehydroalanine amides 1 (Scheme 1) are important structural
motifs found in several natural products, including epidermin,1
microcystins,2 lantibiotics,3 thiostrepton,4 and nocathiacins5 deriv-
reaction with sequential secondary transformations has become a
powerful approach to reach high molecular complexity in a few
steps, usually from readily available starting materials.12 Herein,
we report a two-step approach for the synthesis of dehydroalanine
derivatives1 using a Ugi-4CR/elimination sequential reaction pro-
tocol (Scheme 1).
atives. This
a,b-unsaturated amino acid has been also reported to
play an important catalytic role in the active sites in yeast and bac-
terial enzymes.6 Due to their good balance between stability and
reactivity, dehydroalanine derivatives represent a valuable syn-
thetic precursor to natural and unnatural amino acids and also in
the construction of more complex molecules. The captodative dou-
ble bond in dehydroalanine could be potentially useful in metal-
catalyzed cross-coupling processes,7 Michael-type additions,8 and
asymmetric catalytic transformations,9 etc. Notably, dehydroala-
nine derivatives 1have been typically prepared starting from the
amino acid serine by a sequence of peptide couplings and then
an elimination process, a protocol which normally encompasses
Our approach was based in the use of a substituted acetalde-
hyde at C-2 with an appropriate leaving group (6), in the aldehyde
input in the four-component set of the Ugi reaction. In a straight-
forward manner, the Ugi adduct 2 might be transformed into the
dehydroalanine derivative 1 by a base-mediated elimination pro-
cess (Scheme 1). 2-Acetyl- and 2-benzoyl acetaldehydes 6b and
6a were examined, with the benzoyl group being better for our
purposes than the acetyl group. 2-Benzoyl acetaldehyde 6a was
synthesized in two steps according to a reported procedure.13
Initially, the Ugi reaction was optimized using microwave
irradiation14,15 at 50 °C by mixing equimolar amounts of the four
components in methanol.16 We confirmed that in this case imine
pre-formation time was not an important consideration for
improvement of the yield. Under these optimized conditions, most
of the examined reactions were completed within a few minutes.
Accordingly, the model Ugi four-component set of 2-bromobenzyl-
amine (7), acetic acid (8), tert-butyl isocyanide and aldehyde 6
afforded the expected adduct in gratifying 82% yield after column
chromatography purification (Table 1, entry 1). In all further exper-
iments the t-butyl isocyanide was used as a model reagent.
Dimethoxyphenethylamine 12 and benzylamines 7 and 13 gave
good yields of the desired products. Chloroacetic acid (9), benzoic
acid (14), and phenylacetic acid (15) also provided the correspond-
ing Ugi adducts in good yields.
undesirable protection/deprotection sequences.10 Therefore,
a
direct entry to these kinds of enamides still remains as an impor-
tant synthetic challenge. On the other hand, the Ugi reaction
(Ugi-4CR) is a versatile chemical process to rapidly construct
molecular diversity in peptide and heterocyclic platforms,11 a goal
widely desired in diversity-oriented and combinatorial synthesis
programs. The programmed combination of this multi-component
R1COOH (3)
LG
O
H
N
O
R2NH2
R3NC
(4)
(5)
H
N
R1
N
R3
R1
N
R3
R2
O
LG
CHO
R2
O
2
1
6a, LG = OBz
6b, LG = OAc
LG = Leaving group
Then we focused our attention on the reaction conditions to
eliminate the benzoate group. After examining different condi-
tions, we found that the corresponding dehydroalanine derivatives
were efficiently produced when a benzene solution of the Ugi ad-
ducts 2a–h was mixed with an aqueous solution of KOH, under
Scheme 1. Retrosynthetic analysis.
⇑
Corresponding authors. Tel.: +52 55 56 22 44 40; fax: +52 55 56 16 22 17.
E-mail address: lmiranda@unam.mx (L.D. Miranda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.122

1636
K. Pérez-Labrada et al. / Tetrahedron Letters 52 (2011) 1635–1638
Table 1
Results of the two-step synthesis of dehydroalanines
Entry Amine
Acid
Ugi producta
Yieldc Enamideb
(%)
Yieldc
(%)
Br
NH HCl
1
82
94
96
7
Br
Br
NH HCl
2
88
7
NH HCl
7
3
86
95
O
O
Br
NH HCl
4
89
93
11
5
6
81
89
96
97
7
8
81
79
94
95
a
b
c
Conditions: 2-Benzoyl acetaldehyde (6a),MeOH, 50 °C,
Conditions: Benzene, KOH(aq), Bu4NI.
Isolated yield after purification by column chromatography.
lw.
phase-transfer conditions, using Bu4NI. Under these conditions, the
starting material was totally consumed in 2 h and the desired ena-
mides 1a–h were obtained in fairly good yields after column chro-
matography. Under the same conditions, the Ugi adducts 2b and 2f
underwent elimination of the benzoate group with the simulta-
neous substitution of the chloride substituent by a hydroxyl group.

K. Pérez-Labrada et al. / Tetrahedron Letters 52 (2011) 1635–1638
1637
Berthiol, F.; Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem., Int. Ed. 2007,
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Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 33–75. Chapter 2.
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Figure 1. Single-crystal X-ray analysis of 1a. Hydrogen atoms were eliminated for
clarity.
14. Microwave reactions were conducted using a CEM Discover Synthesis™ Unit
(CEM Corp., Matthews, NC). http://www.cem.com/page176.html.
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The structures of alldehydroalanine derivatives were determined
by spectroscopic data, and the structure of product 1a was further
confirmed through single-crystal X-ray analysis (Fig. 1).
The data collected in Table 1 convincingly show that various
dehydroalanines, containing diverse reactive functionalities, were
useful for further transformations and could be prepared using this
two-step protocol.
In closing, we have developed a protocol for the preparation of
several dehydroalanines, using a programmed combination of a
Ugi reaction and a subsequent elimination process. This two-step
synthetic route allowed the construction of a variety of dehydro-
alanine derivatives modified with synthetically useful functional
groups from readily accessible starting materials. Currently, we
are examining other leaving groups along with further transforma-
tions of the dehydroalanine adducts, and the publication of these
results is forthcoming.
16. General procedure for the Ugi four-component reaction. In a 100 mL round
bottom flask the corresponding amine (1 mol) (only when amine
hydrochloride was used, 1 mmol of Et3Nwas added), the 2-
benzoylacetaldehyde (1 mol), the corresponding carboxylic acid (1 mol) and
the tert-butyl isocyanide (1 mol) were dissolved in 3 ml of MeOH and stirred at
room temperature. Then the flask was connected to a condenser and placed
into the microwave cavity under an argon atmosphere and the reaction
mixture was irradiated with 50 W for 10 min at 50 °C and then allowed to cool
to room temperature. The reaction solvent was evaporated and the crude
product was purified by silica gel flash column chromatography.
General procedure for the elimination reaction. To
a solution of the
corresponding Ugi derivative (1.3 mmol) in benzene (10 mL) an aqueous
solution of KOH (50%, 10 mL) was added, followed by Bu4NI (0.39 mmol). The
reaction mixture was stirred at room temperature and monitored by TLC.
When the starting material was totally consumed, the organic layer was
diluted with dichloromethane (10 mL) and washed with water (5 Â 10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography to afford the
corresponding dehydroalanine in good yields.
Selected spectral data: Dehydroalanine (1a): Yield 94% as white crystals; mp
97–98 °C, Rf = 0.32 (n-hexane/ethyl acetate 2:1); 1H NMR (CDCl3/TMS,
300 MHz) d: 1.19 (s, 9H), 2.06 (s, 3H), 4.93 (s, 2H), 5.46 (s, 1H, J = 5.2 Hz),
5.69 (s, 1H), 6.35 (s, 1H), 7.17 (td, 1H, J = 7.7, 1.7 Hz), 7.29 (t, 1H, J = 7.5 Hz),
7.43 (dd, 1H, J = 7.7, 1.7 Hz), 7.56 (dd, 1H, J = 8.3/1.4 Hz); 13C NMR (CDCl3,
75.5 MHz): d 22.1, 28.2, 51.4, 122.4, 124.5, 128.0, 129.7, 132.0, 133.0, 135.9,
Acknowledgements
Financial support from the CONACYT (No. 82643) is gratefully
acknowledged. We also thank R. Patiño, A. Peña, E. Huerta E. Gar-
cía-Rios, L. Velasco, and J. Pérez for technical support. K.P.L. was
a ‘‘Red de Macrouniversidades de América Latina y el Caribe’’ grad-
uate scholarship holder and EPM is a DGAPA-UNAM postgraduate
scholarship holder.
143.4, 162.1, 170.6; FTIR (KBr, cmÀ1
) mmax: 3403, 3331, 2969, 1671, 1625, 1389;
MS (EI) m/z: 353 (M+H); HRMS m/z calcd for C16H22BrN2O2 [M+H] 353.0865,
found: 353.0872. Dehydroalanine (1b): Yield 96% as a clear oil; Rf = 0.45 (n-
hexane/ethyl acetate 1:1); 1H NMR (CDCl3/TMS, 300 MHz) d: 1.53 (s, 9H), 4.27
(s, 2H), 4.66 (d, 1H, J = 1.5 Hz), 5.02 (s, 2H), 5.75 (d, 1H, J = 1.5 Hz), 6.96 (dd, 1H,
J = 7.7, 1.4 Hz), 7.13 (td, 1H, J = 7.5, 1.6 Hz), 7.25 (td, 1H, J = 7.2, 1.2 Hz), 7.58
(dd, 1H, J = 7.8, 1.2 Hz); 13C NMR (CDCl3, 75.5 MHz): d 27.6, 47.0, 47.1, 58.3,
104.0, 122.5, 126.7, 127.7, 128.9, 133.0, 133.3, 137.0, 158.5, 163.3; FTIR (KBr,
References and notes
cmÀ1
) mmax: 3346, 3063, 1687, 1612; MS (EI) m/z: 351 (MÀ18); HRMS m/z calcd
for C16H22BrN2O3 [M+H] 369.0814, found: 369.0829. Dehydroalanine (1c):
Yield 95% as a clear oil; Rf = 0.32 (n-hexane/EtOAc, 1:1); 1H NMR (CDCl3/TMS,
300 MHz) d: 1.13 (s, 9H), 3.61 (s, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 4.92 (s, 2H), 5.37
(s, 1H), 5.53 (s, 1H), 6.39 (s, 1H), 6.77 (m, 2H), 6.85 (d, 1H, J = 1.5 Hz), 7.16 (td,
1H, J = 7.8, 1.8 Hz), 7.26 (td, 1H, J = 7.5, 1.2 Hz), 7.40 (dd, 1H, J = 7.7, 1.7 Hz),
7.54 (dd, 1H, J = 7.7, 1.4 Hz); 13C NMR (CDCl3, 75.5 MHz): d 28.1,40.4, 51.3, 51.5,
55.8, 111.2, 112.1, 121.2, 123.6, 124.6, 126.9, 127.9, 129.6, 131.8, 133.0, 135.8,
1. Allgaier, H.; Jung, G.; Werner, R. G.; Schneider, U.; Zahner, H. Angew. Chem., Int.
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142.7, 148.1, 149.0, 161.9, 171.4; FTIR (KBr, cmÀ1
) mmax: 3352.45, 3061.24,
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2966.55; 2934.26, 1671.98, 1625.95, 1514.87, 1456.65, 1263.76, 1234.96; MS
(EI) m/z: 490 (M+H); HRMS m/z calcd for C24H30BrN2O4 [M+H] 489.1389,
found: 489.1378. Dehydroalanine (1d): Yield 93% as white crystals; mp 130–
131 °C; Rf = 0.29 (n-hexane/EtOAc, 2:1); 1H NMR (CDCl3, 300 MHz) d: 1.25 (s,
9H), 2.04 (s, 3H) 4.84 (s, 2H), 5.44 (s, 1H), 5.70 (s, 1H), 5.97 (s, 2H), 6.36 (s,1H),
6.96 (s, 1H), 6.99 (s, 1H); 13C NMR (CDCl3, 75.5 MHz) d: 22.2, 28.3 51.1, 51.4,
102.0, 111.3, 112.7, 115.3, 122.7, 129.1, 143.2, 147.8, 148.3, 162.1, 170.7; FTIR
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(b) Wickner, R. B. J. Biol. Chem. 1969, 244, 6550–6552.
(KBr, cmÀ1
HRMS m/z calcd for
)
m
max: 3316, 2973, 1669, 1619, 1475, 1231; MS (EI) m/z: 397 (M+H);
17H22BrN2O4 [M+H] 397.0763, found: 397.0756.
7. (a) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. Org. Lett.
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C
Dehydroalanine (1e): Yield 96% as white crystals; mp 119–120 °C, Rf = 0.34
(n-hexane/EtOAc, 2:3); 1H NMR (CDCl3/TMS, 300 MHz) d:1.32 (s, 9H), 2.03 (s,
3H), 2.85 (t, 2H, J = 7.7 Hz), 3.72 (m, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 5.37 (s, 1H),
5.78 (s, 1H), 6.38 (s, 1H), 6.7 (m, 3H); 13C NMR (CDCl3, 75.5 MHz) d: 22.2, 28.4,
33.0, 48.8, 51.5, 55.8, 111.4, 111.8, 120.5, 121.9, 130.5, 143.0, 147.7, 149.0,
162.2, 170.6; IR (KBr, cmÀ1
) mmax: 3338, 2964, 2934, 1664, 1623, 1516, 1452,
1396.09; MS (EI) m/z: 348 (M+H); HRMS m/z calcd for C19H28N2O4 [M+H]
348.2049, found: 348.2047. Dehydroalanine (1f): Yield 97% as white crystals;
mp 98–99 °C, Rf = 0.28 (n-hexane/EtOAc, 2:1); 1H NMR (CDCl3/TMS, 300 MHz)
d: 1.45 (s, 9H), 2.81 (m, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 3.89 (m, 2H), 4.04 (s, 2H),
4.91 (d, 1H, J = 1.2 Hz), 5.83 (d, 1H, J = 1.2 Hz), 6.75 (m, 3H); 13C NMR (CDCl3,
75.5 MHz) d: 27.5, 31.4, 44.2, 46.8, 55.8, 58.0, 101.9, 111.2, 111.8, 120.5, 130.3,

1638
K. Pérez-Labrada et al. / Tetrahedron Letters 52 (2011) 1635–1638
137.0, 147.7, 148.9, 158.5, 162.5; FTIR (KBr, cmÀ1
1608, 1515, 1419, 1262 MS (EI) m/z: 346 (M+H); HRMS m/z calcd for
)
m
max: 2960, 2935, 1682,
463.0883, found: 463.0870. Dehydroalanine (1h): Yield 95% as a clear oil;
Rf = 0.25 (n-hexane/EtOAc, 3:1); 1H NMR (CDCl3/TMS, 300 MHz) d: 1.15 (s, 9H),
3.71 (s, 2H), 4.78 (s, 2H), 5.48 (s, 1H), 5.59 (s, 1H), 6.48 (s, 1H), 6.96 (td, 1H,
J = 7.6, 1.8 Hz), 7.22–7.41 (m, 6H), 7.83 (dd, 1H, J = 7.7, 1.1 Hz). 13C NMR (CDCl3,
75.5 MHz) d: 28.2, 46.2, 51.4, 53.0, 101.3, 123.7, 128.1, 128.2, 128.4, 128.8,
128.9, 129.0, 129.5, 130.7, 137.0, 138.5, 139.3, 143.0, 161.9, 169.9; FTIR (KBr,
;
C
19H26N2O4 [M+H] 346.1893, found: 346.1894. Dehydroalanine (1g): Yield 97%
as white crystals; mp 138–139 °C, Rf = 0.29 (n-hexane/EtOAc, 3:1); 1H NMR
(CDCl3/TMS, 300 MHz) d: 1.16 (s, 9H), 4.95 (s, 2H), 5.45 (s, 1H), 5.78 (s, 1H),
6.97–7.49 (m, 8H), 7.76 (d, 1H, J = 8.1 Hz); 13C NMR (CDCl3, 75.5 MHz) d: 28.3,
51.5, 52.2, 94.1, 121.2, 127.6, 128.0, 128.1, 128.8, 129.4, 130.4, 136.8, 139.4,
cmÀ1
) mmax: 3403, 3343, 2967, 2927, 1673, 1623, 1513, 1391; MS (EI)
141.3, 142.8, 162.5, 169.8; FTIR (KBr, cmÀ1
)
m
max: 3346, 2969, 1666, 1625,
m/z: 476 (M+H) HRMS m/z calcd for C22H26IN2O2 [M+H] 477.1039, found:
1518, 1392; MS (EI) m/z: 462 (MÀH); HRMS m/z calcd for C21H24IN2O2 [M+H]
477.1046.