Synthesis of a new family of 2-ethylidene-γ-unsaturated δ-amino esters via microwave activated Stille coupling

Article abstract of DOI:10.1007/s00726-009-0392-y

A simple approach to a new family of enantiomerically enriched polyunsaturated t-Boc-protected-δ-amino esters is described, via microwave promoted Stille coupling of (Z)-methyl-2-bromobutenoate with stannylated allylamines. The reaction conditions are mild and selective and disclose a simple way to 1-substituted butenoates of defined geometry.

Full text of DOI:10.1007/s00726-009-0392-y

Amino Acids (2010) 39:175–180
DOI 10.1007/s00726-009-0392-y
ORIGINAL ARTICLE
Synthesis of a new family of 2-ethylidene-c-unsaturated d-amino
esters via microwave activated Stille coupling
•
Gabriella Barozzino Consiglio Francesca Gaggini
•
•
Alessandro Mordini Gianna Reginato
Received: 24 July 2009 / Accepted: 11 November 2009 / Published online: 26 November 2009
Ó Springer-Verlag 2009
Abstract A simple approach to a new family of enanti-
omerically enriched polyunsaturated t-Boc-protected-d-
amino esters is described, via microwave promoted Stille
coupling of (Z)-methyl-2-bromobutenoate with stannylated
allylamines. The reaction conditions are mild and selective
and disclose a simple way to 1-substituted butenoates of
defined geometry.
enzyme inhibitors or antibiotics (Wipf et al. 2005; Garbe
et al. 2004; Tamamura et al. 2003; Yang et al. 1999).
Basically, in many cases, the isosteric replacement of a
dipeptide unit requires the preparation of a d-amino acid.
Very recently, this class of compounds has stimulated a
great interest since, as in the homologous b- and c-pep-
tides, conformational analysis of d-peptides revealed a
considerable potential of secondary structure formation
(Sengupta et al. 2006; Baldauf et al. 2006; Ananda et al.
2005; Baldauf et al. 2004). In particular, it has been shown
that the elongation of the backbone of the amino acid
constituents might enrich the field of folded structures and
for this reason d-peptides and d-amino acids are considered
a useful tool also in peptides and foldamers design and in
material sciences (Hill et al. 2001; Baldauf et al. 2005). For
these reasons, we envisaged unsaturated d-amino acids as
those reported in Fig. 1, bearing an ethylidenic conjugated
double bond, as an interesting class of new molecules that
could be exploited, for instance, as rigid spacers (Chen
et al. 1995; Georgsson et al. 2005; Douat-Casassus et al.
2007) and as Michael acceptor-binding sites for the design
of new enzyme inhibitors (Johnson et al. 2002; Steindl
et al. 2005). To the best of our knowledge, this class of
compounds has not been reported so far.
Keywords Amino acids ꢀ d-Amino esters ꢀ
Stille coupling ꢀ Acrylates ꢀ Microwave
Introduction
Peptidomimetics are valuable tools for conformational
investigations of bioactive peptides and proteins, and for
the development of peptide leads for pharmaceuticals
(Olson et al. 1993; Bursavich and Rich 2002; Hanessian
et al. 1997). In particular, the replacement of the peptide
amidic moiety with a chemically more resistant and in vivo
stable functionality is an important research area in
medicinal chemistry. In recent years, many non-hydroly-
sable mimetics have been developed and among the others
the relatively rigid tri-substituted (E)-alkene W [(E)–
C(R) = CH)] isosters have been used in a number of
Results and discussion
G. Barozzino Consiglio ꢀ F. Gaggini
Dipartimento di Chimica Organica ‘‘Ugo Schiff’’,
University of Florence, via della Lastruccia 13,
50019 Sesto Fiorentino (Firenze), Italy
Stemming from our interest in the use of naturally occur-
ring amino acids as building blocks for organic synthesis
(Reginato et al. 1999; 2005a, b; Ciardi et al. 2007; Regi-
nato et al. 2007) we were particularly attracted by the
possibility of designing a new and flexible method to
prepare orthogonally protected polyunsaturated-d-amino
esters such as 3 (Scheme 1). Key intermediates in our
A. Mordini ꢀ G. Reginato (&)
Istituto di Chimica dei Composti Organometallici
(ICCOM-CNR), Via Madonna del Piano 10,
50019 Sesto Fiorentino (Firenze), Italy
e-mail: gianna.reginato@iccom.cnr.it
123

176
G. Barozzino Consiglio et al.
Fig. 1 2-ethylidene-gamma-
unsaturated delta-amino esters
reactions have been achieved in solution as well as on solid
phase (Larhed et al. 2002; Maleczka et al. 2000). Thus, to
improve the yields and find milder reaction conditions, we
decided to investigate the effect of microwave irradiation
on our coupling process, and we were pleased to find that
under optimized conditions, namely at 80°C, with a 200 W
microwave source for 30 min in toluene, the reaction led to
NH2
COOH
R'
R
approach were chiral t-Boc-protected stannylallylamines 1,
which are easily accessible from amino acids using stan-
dard procedures developed in our laboratories (Reginato
et al. 1996). This compounds are versatile synthons, and
can be coupled with several electrophiles under Pd catal-
ysis (Stille conditions) to afford a wide range of c-substi-
tuted allylamines 4 (Reginato et al. 1996), or dienylamines
5 (Reginato et al. 2005a, b) (Scheme 1). This protocol is
mild, stereospecific, highly chemoselective and suitable for
chiral substrates (Reginato et al. 1997, 1998, 2000).
Accordingly, we envisaged that d-amino esters 3 could
be simply obtained using 2-bromo-alkenoates 2 as coupling
partners. Although 1-alkenyl halides are probably the most
widely used organic electrophiles in Stille coupling (Farina
et al. 1998), to our knowledge 2-bromoalkenoates have
never been employed before, thus, to select the best
experimental conditions, we decided to perform some
model reactions. We used stannylallylamine 1a and the
commercially available (E)-methyl-2-bromobutenoate 2a
as coupling partners (Scheme 2). The reaction was per-
formed in DMF with the commonly used Pd(PPh3)4 as
catalyst and the anticipated amino ester 3a was actually
recovered in 55% yield after 24 h at 80°C. The use of a
different catalyst such as Pd(AsPh3)4 (Reginato et al.
2005a, b) or a higher reaction temperature did not improve
the final yield.
1
quantitative conversion of stannane 1a. H NMR analysis
of the crude mixtures showed that no isomerization of the
double bonds occurred as exclusively the anticipated iso-
mer 3 having E, Z geometry was recovered and, after
workup and chromatography, isolated in 76% yield.
Substituted acrylate fragments are valuable building
blocks in organic chemistry participating in many asym-
metric transformations; however, few good routes exist to
prepare even simple 1-substituted species (Biswas et al.
2005; Mani et al. 2006). To exploit the generality of this
reaction, three different stannanes (6–8) were used and
the results obtained clearly show that the formation of
1-substituted butenoates (9–11) always occurs smoothly
(Table 1, entries 1–3). Finally, the same reaction condi-
tions were applied to a range of three different chiral non-
racemic stannylallylamines (1b–d) derived, respectively,
from phenylalanine, valine and leucine and the corre-
sponding d-amino esters (3a–d) were recovered in good
yields after purification (Table 1, entries 4–6).
It is known that the synthetic elaboration of dipeptides
can be challenging because of their sensitivity (Diaz and
Ferreira 2001). To verify if our reaction condition were
mild enough to be used also with such substrates, we
prepared dipeptido stannane 12 according to a reported
procedure (Reginato et al. 2005a, b). Once again the
expected coupling compound 13 (Scheme 3) was obtained
in good yield, after purification.
Over the past few years, the efficiency of microwave
flash heating in accelerating cross-coupling reactions has
been successfully demonstrated and very fast Stille
It is remarkable that compound 13 was obtained as a
1
single diastereoisomer as both H and 13C NMR spectra
showed no peaks due to epimerization at the d-carbon of
the amino ester moiety, thus confirming that no racemi-
zation of the starting material or isomerization of the
double bond occurred. Finally, to demonstrate that d-amino
esters 3 are capable of undergoing typical reactions asso-
ciated with peptide synthesis, t-Boc-aminoester 3a was
NHBoc
R
R
E
4
E
Pd(0)
COOMe
NHBoc
R'
NHBoc
Br
SnBu3
2
COOMe
R'
R
COOMe
AA
Pd(0)
3
1
NHBoc
NHBoc
Br
Br
2
R
COOMe
76%
SnBu3
Pd(0)
Pd[PPh3]4
Toluene
1a
3a
NHBoc
MW 80°C, 200 W, 30 min
R
R
5
Scheme 2 Optimized conditions for the coupling of stannylallyl-
amine 1 with methyl-2-bromo-butenoate
Scheme 1 Stille coupling of stannylallylamines with electrophiles
123

Synthesis of a new family of 2-ethylidene-c-unsaturated d-amino esters
Table 1 MW activated coupling of 2 with stannanes
177
or dipeptides to obtain a novel family of polyunsaturated
d-amino esters which were previously unreported.
Entry
Stannanea)
Product
Isolated yield
SnBu3
Experimental
COOMe
75%
1
General
6
9
COOMe
Stannanes 1a–d (Reginato et al. 1996) 8 (Dabdoub et al.
2001) and 12 (Reginato et al. 2005a, b) were synthesized
according to the published procedure. [Pd(PPh3)4] was
freshly prepared and stored under nitrogen atmosphere.
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without purification. All
air-sensitive reactions were performed using Schlenk
techniques. Tetrahydrofuran was freshly distilled immedi-
ately prior to use from sodium/benzophenone. Toluene and
DMSO were dried over sodium and stored under nitrogen
SnBu3
S
S
68%
72%
2
3
b)
7
SnBu3
COOMe
11
8
NHBoc
NHBoc
COOMe
SnBu3
66%
4
˚
over 4-A molecular sieves. Petroleum ether, unless speci-
fied, is 40–60°C boiling fraction. Reactions were moni-
tored by TLC on SiO2 plates, detection was made using a
KMnO4 basic solution. Flash column chromatography was
performed using glass columns (10–50 mm wide) and SiO2
(230–400 mesh). 1H-NMR spectra were recorded with 200
or 400 MHz spectrometers. 13C-NMR spectra were recor-
ded at 50.3 or 100.6 MHz. Chemical shifts were deter-
mined relative to the residual solvent peak (CHCl3, d
7.26 ppm for 1H-NMR; CHCl3, d 77.0 ppm for 13C-NMR).
Coupling constants (J) were reported in Hertz. Polarimetric
measurements were performed in CHCl3 solution at
k = 589 nm, the temperature was specified case by case.
The mass spectra were recorded under electronic impact
conditions (EIMS) at 70 eV ionizing potential.
3b
1b
NHBoc
NHBoc
COOMe
COOMe
SnBu3
SnBu3
81%
70%
5
6
1c
3c
NHBoc
NHBoc
3d
1d
a
Reaction conditions: toluene, [Pd(PPh3)4] cat; MW, 80°C, 200 W,
30 min
b
Reaction time: 50 min
All microwave irradiation experiments were carried out
using a CEM Focused MicrowaveTM Synthesis System,
Model Discover microwave oven equipped with an infrared
temperature control system. All microwave reactions were
performed in sealed 10 mL microwave vials.
deprotected with TFA and the free amine 14 was
coupled with t-Boc-phenylalanine using DEPC/DIEA
(diethylcyano-phosphonate/diisopropylethylamine) proce-
dure. After purification, the expected dipeptide 15 was
indeed obtained in 79% yield (Scheme 4).
General procedure for cross-coupling reaction
with methyl 2-bromo-but-2-enoic carboxylate
In summary, we have shown that organostannanes can
be coupled with the commercially available (E)-methyl-2-
bromobutenoate in mild conditions under MW activation.
The procedure discloses an easy access to (Z)-1-substituted
butenoates and has been applied to chiral stannylated
allylamines derived from naturally occurring amino acids
Methyl-2-bromo-but-2-enoic carboxylate 2 (2 eq) was
dissolved in toluene together with a catalytic amount of
Pd(PPh3)4 (0.05 eq). Stannane 1a–d (1 eq) was then added
and the mixture heated to 80°C by microwave irradiation at
Scheme 3 Coupling of
dipeptido stannane 12 with
methyl-2-bromo-butenoate
O
O
BocHN
COOMe
BocHN
2a
MW
N
N
SnBu3
H
H
13
12
80°C 200W
45'
69%
123

178
G. Barozzino Consiglio et al.
Scheme 4 Deprotection and
coupling with Boc-PHE-OH of
delta-amino ester
O
COOMe
Boc-PHE-OH
BocHN
COOMe
H2N
3a
N
H
TFA
DIA
DEPC
14
15
79%
200 W (value previously settled on the Microwave oven)
for 30 min or 1 h depending on the substrate. The solution
was diluted with ether and treated with a NaOH (1 M)
solution. The mixture was filtered, extracted with ether and
the organic phase washed with brine and dried. The crude
product obtained after evaporation was purified by flash
chromatography.
7.90; N, 4.01. Calc. for C20H27NO4: C, 69.54; H, 7.88; N,
4.05 [a]2D3 = -5.1 (c = 0.84, CHCl3).
(5S)-(E)-5-tert-butoxycarbonylamino-2-eth-(Z)-ylidene-7-
methyl-oct-3-enoic acid methyl ester 3c
Methyl-2-bromo-but-2-enoic carboxylate
2
(133 mg,
0.7 mmol) was dissolved into toluene (2 mL) together with
Pd(PPh3)4 (30 mg, 0.025 mmol) and stannane 1c (250 mg,
0.5 mmol). The mixture was heated to 80°C by microwave
irradiation for 45 min. After work-up and purification
(petroleum ether–AcOEt = 5:1), 126 mg of pure 3c were
obtained as a pale yellow oil (yield 81%). 1H NMR
(200 MHz, CDCl3): d 6.81 (q, 1H, J = 7.4 Hz); 6.29–6.22
(E)-5-tert-Butoxycarbonylamino-2-eth-(Z)-ylidene-
pent-3-enoic acid methyl ester 3a
Methyl-2-bromo-but-2-enoic carboxylate
2
(70 mg,
0.4 mmol) was dissolved into toluene (1 mL) together with
Pd(PPh3)4 (23 mg, 0.02 mmol) and stannane 1a (115 mg,
0.3 mmol). The mixture was heated to 80°C by microwave
irradiation for 30 min. After work-up and purification
(petroleum ether–AcOEt = 4:1), 58 mg of pure 3a were
obtained as a colorless oil (yield 76%). 1H NMR (200 MHz,
CDCl3): d 6.82 (q, 1H, J = 7.3 Hz); 6.30–6.22 (dapp, 1H,
JAB = 16.4 Hz); 6.09–5.98 (dtapp, 1H, JAB = 16.4 Hz,
J = 5.9 Hz); 4.63 (bs, 1H); 3.88–3.80 (m, 2H); 3.74 (s, 3H);
1.85 (d, 3H, J = 7.3 Hz); 1.42 (s, 9H). 13C NMR
(50.3 MHz, CDCl3) d: 166.7; 155.7; 148.1; 132.2; 128.9;
122.5; 79.9; 51.9; 42.5; 28.2; 14.6. MS m/z 199 (29);
57(100). Elemental analysis: found: C, 61.22; H, 8.26; N,
5.51. Calc. for C13H21NO4: C, 61.16; H, 8.29; N 5.49.
(dapp, 1H, JAB = 15.9 Hz); 6.01–5.90 (ddapp, 1H, JAB
=
15.9 Hz, J = 6.2 Hz); 4.42 (bs, 1H); 4.26–4.07 (m, 1H);
3.74 (s, 3H); 1.89(d, 3H, J = 7.4 Hz); 1.79–1.52 (m, 2H);
1.44–1.33 (m, 1H); 1.43 (s, 9H); 0.92 (d, 3H, J = 6.6 Hz);
0.91 (d, 3H, J = 6.6 Hz). 13C NMR (50.3 MHz, CDCl3) d:
167.5; 155.3; 138.2; 136.2; 130.3; 121.1; 79.3; 51.6; 51.4;
44.8; 28.4; 24.8; 22.6; 22.5; 14.7. MS m/z 198 (6); 57(100).
Elemental analysis: found: C, 65.60; H, 9.41; N, 4.37. Calc.
for C17H29NO4: C, 65.57; H, 9.39; N, 4.50. [a]2D3 = -20.8
(c = 0.77, CHCl3).
(5S)-(E)-tert-butoxycarbonylamino-2-eth-(Z)-ylidene-6-
methyl-hept-3-enoic acid methyl ester 3d
(5S)-(E)-5-tert-butoxycarbonylamino-2-eth-(Z)-ylidene-6-
phenyl-hex-3-enoic acid methyl ester 3b
Methyl-2-bromo-but-2-enoic carboxylate
2
(186 mg,
1.0 mmol) was dissolved into toluene (2 mL) together with
Pd(PPh3)4 (35 mg, 0.03 mmol) and stannane 1d (352 mg,
0.7 mmol). The mixture was heated to 80°C by microwave
irradiation for 45 min. After work-up and purification
(petroleum ether–AcOEt = 6:1), 144 mg of pure 3d were
obtained as a pale yellow oil (yield 70%). 1H NMR
(200 MHz, CDCl3): d 6.80 (q, 1H, J = 7.4 Hz); 6.27–
6.19 (dapp, 1H, JAB = 16.0 Hz); 6.01–5.90 (ddapp, 1H,
JAB = 16.0 Hz, J = 6.4 Hz); 4.53 (bs, 1H); 4.11–3.94
(m, 1H); 3.73 (s, 3H); 1.88(d, 3H, J = 7.4 Hz); 1.87–1.70
(m, 1H); 1.44 (s, 9H); 0.93 (d, 3H, J = 2.19 Hz); 0.89
(d, 3H, J = 2.19 Hz). 13C NMR (50.3 MHz, CDCl3) d:
167.5; 155.5; 138.1; 134.3; 130.4; 122.4; 79.3; 58.3; 51.6;
32.7; 28.4; 18.7; 18.3; 14.6. MS m/z 198 (38); 57(100).
Elemental analysis: found: C, 64.57; H, 9.11; N, 4.69. Calc.
for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. [a]2D3 = -9.0
(c = 1.25, CHCl3).
Methyl-2-bromo-but-2-enoic carboxylate
2
(270 mg,
1.5 mmol) was dissolved into toluene (3 mL) together with
Pd(PPh3)4 (60 mg, 0.05 mmol) and stannane 1b (527 mg,
1.0 mmol). The mixture was heated to 80°C by microwave
irradiation for 45 min. After work-up and purification
(petroleum ether–AcOEt = 5:1), 228 mg of pure 3b were
obtained as a pale yellow oil (yield 66%). 1H NMR
(200 MHz, CDCl3): d 7.41–7.10 (m, 5H); 6.78 (q, 1H,
J = 7.4 Hz); 6.21–6.13 (dapp, 1H, JAB = 16.0 Hz); 6.07–
5.96 (ddapp, 1H, JAB = 16.0 Hz, J = 5.4 Hz); 4.61–4.38
(m, 2H); 3.72 (s, 3H); 2.88–2.84 (m, 2H); 1.81(d, 3H,
J = 7.4 Hz); 1.40 (s, 9H). 13C NMR (50.3 MHz, CDCl3)
d: 166.4; 155.1; 138.5; 137.3; 134.8; 130.1; 129.6; 128.2;
126.4; 122.0; 79.4; 53.9; 51.6; 41.7; 28.3; 14.6. MS m/z
289 (3); 57(100). Elemental analysis: found: C, 69.57; H,
123

Synthesis of a new family of 2-ethylidene-c-unsaturated d-amino esters
(Z)-2-phenyl-but-2-enoic acid methyl ester 9
179
0.2 mmol). The mixture was heated to 80°C by microwave
irradiation for 45 min. After work-up and purification
(petroleum ether–AcOEt = 6:1) 63 mg of pure 13 were
Methyl-2-bromo-but-2-enoic carboxylate
2
(85 mg,
1
0.5 mmol) was dissolved into toluene (1 mL) together with
Pd(PPh3)4 (21 mg, 0.02 mmol) and stannane 6 (110 mg,
0.3 mmol). The mixture was heated to 80°C by microwave
irradiation for 30 min. After work-up and purification
(petroleum ether–AcOEt = 5:1) 41 mg of pure 9 were
obtained as a colorless oil (yield 75%). Spectroscopic data
were in agreement with those reported in the literature
(Mani et al. 2006).
obtained as a pale yellow oil (69%). H NMR (400 MHz,
CDCl3): d 7.22–7.12 (m, 5H); 6.73 (q, 1H, J = 7.3 Hz);
6.42 (bs, 1H); 6.12 (d, 1H, JAB = 16.0 Hz); 6.14–6.10
(ddapp, 1H, JAB = 16.0 Hz, J = 6.8 Hz); 5.03–4.90 (m,
1H); 4.20–3.90 (m, 1H); 4.32–4.15 (m, 1H); 3.66 (s, 3H);
3.01-2.96 (m, 2H); 1.78 (d, 3H, J = 7.2 Hz); 1.71–1.63 (m,
1H); 1.33 (s, 9H); 0.82 (d, 3H, J = 6.5 Hz); 0.91 (d, 3H,
J = 6.5 Hz). 13C NMR (50.3 MHz, CDCl3) d: 170.3;
166.3; 155.4; 138.5; 136.7; 134.8; 132.9; 129.3; 128.6;
123.4; 80.2; 56.9; 56.3; 51.7; 38.2; 32.4; 28.3; 18.7; 18.2;
14.7. MS m/z 388 (2); 91 (76), 57(100). Elemental analysis:
found: C, 67.58; H, 8.21; N, 6.27. Calc. for C25H36N2O5:
C, 67.54; H, 8.16; N, 6.30. [a]2D3 = -13.0 (c = 1.25,
CHCl3).
(E)-2-thiophen-2-yl-but-2-enoic acid methyl ester 10
Methyl-2-bromo-but-2-enoic carboxylate
2
(70 mg,
0.4 mmol) was dissolved into toluene (1 mL) together with
Pd(PPh3)4 (25 mg, 0.02 mmol) and stannane 7 (150 mg,
0.4 mmol). The mixture was heated to 80°C by microwave
irradiation for 50 min. After work-up and purification
(petroleum ether–AcOEt = 5:1) 51 mg of pure 10 was
obtained as a pale yellow oil (yield 68%). 1H NMR
(200 MHz, CDCl3): d 7.37 (d, 1H, J = 5.1 Hz); 7.23 (q,
1H, J = 7.3 Hz); 7.07–7.03 (m, 1H); 6.97 (d, 1H,
J = 3.7 Hz); 3.77 (s, 3H); 1.91 (d, 3H, J = 7.3 Hz). 13C
NMR (50.3 MHz, CDCl3) d: 167.1; 142.0; 135.2; 128.3;
127.8; 126.1; 126.3; 52.2; 15.9.. MS m/z 182 (90); 123
(100). Elemental analysis: found: C, 59.37; H, 5.57. Calc.
for C9H10O2S, C, 59.32; H, 5.53.
(E)-5-[(2S)-2-tert-butoxycarbonylamino-3-phenyl-
propionylamino)]-2-eth-(Z)-ylidene-pent-3-enoic acid
methyl ester 15
Amino ester 3a (50 mg, 0.22 mmol) was dissolved into
CH2Cl2 (2 mL) and, after cooling at -10°C, reacted with
TFA (0.5 mL). After 15 min, the solvent was evaporated to
give the deprotected amino acid 14 which was immediately
reacted with Boc-Phe-OH (58 mg, 022 mmol) and diiso-
propylamine (67 mg, 0.7 mmol) and diethylcyanophosph-
onate (54 mg, 0.33 mmol). The reaction mixture was stirred
overnight, then diluted with ethyl acetate (5 mL) and an
NH4Cl saturated solution (5 mL). After extraction, evapo-
ration and purification (petroleum ether–AcOEt = 5:1)
76 mg of 15 were obtained (yield 79%). 1H NMR (200 MHz,
CDCl3): d 7.30–7.26 (m, 2H); 7.23–7.19 (m, 3H); 6.82
(q, 1H, J = 7.4 Hz); 6.21–6.17 (dapp, 1H, JAB = 16.0 Hz);
5.98–5.89 (m, 1H ? 1H); 5.04 (bs, 1H); 4.35–4.27 (m, 1H);
3.92–3.88 (m, 2H); 3.74 (s, 3H); 3.10–3.01 (m, 2H); 1.86
(d, 3H, J = 7.0 Hz); 1.39 (m, 9H). 13C NMR (50.3 MHz,
CDCl3) d: 170.8; 167.2; 155.3; 138.9; 136.6; 130.2; 129.8;
129.2; 128.6; 126.9; 123.9; 80.2; 56.1; 51.8; 41.8; 38.7; 28.3;
14.8. MS m/z 402 (1); 346 (3); 57(100). Elemental analysis:
found: C, 65.70; H, 7.49; N, 6.98. Calc. for C22H30N2O5: C,
65.65; H, 7.51; N, 6.96. [a]2D3 = -0.32 (c = 1.05, CHCl3).
(E)-2-ethylidene-dec-3-ynoic acid methyl ester 11
Methyl-2-bromo-but-2-enoic carboxylate
2
(70 mg,
0.4 mmol) was dissolved into toluene (1 mL) together with
Pd(PPh3)4 (25 mg, 0.02 mmol) and stannane 8 (80 mg,
0.2 mmol). The mixture was heated to 80°C by microwave
irradiation for 30 min. After work-up and purification
(petroleum ether–AcOEt = 30:1) 31 mg of pure 11 were
obtained as a pale yellow oil (yield 72%). 1H NMR
(200 MHz, CDCl3): d 7.22 (q, 1H, J = 7.1 Hz); 3.77
(s, 3H,); 2.42 (t, 2H, J = 6.7 Hz); 2.00 (d, 3H,
J = 7.1 Hz); 1.34–1.17 (m, 8 H); 0.92 (t, 5H, J = 6.2 Hz).
13C NMR (50.3 MHz, CDCl3) d: 166.1; 147.3; 130.9;
118.2; 98.0; 51.2; 31.3; 29.4; 28.7; 22.7; 19.7; 16.6; 14.1.
Elemental analysis: found: C, 75.02; H, 9.91. Calc. for
C13H20O2, C, 74.96; H, 9.68.
(5S)-(E)-[(2S)-2-tert-butoxycarbonylamino-3-phenyl-
propionylamino)]-2-eth-(Z)-ylidene-6-methyl-hept-3-enoic
acid methyl ester 13
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