Flash vacuum pyrolysis of stabilised phosphorus ylides. Part 17. Preparation of aliphatic amino acid derived γ-alkoxycarbonyl-amino-β-oxo ylides and pyrolysis to give α,β-acetylenic γ-amino acid and GABA analogues

Article abstract of DOI:10.1039/b110243e

A series of eleven α-aminoacyl stabilised phosphorus ylides 9-19 have been prepared by condensation of N-alkoxycarbonyl protected amino acids with Ph₃P = CHCO₂Et using a carbodiimide peptide coupling reagent. Upon flash vacuum pyrolysis at 600 °C, these undergo extrusion of Ph₃PO to give the corresponding α,β-acetylenic γ-amino esters 21-29, 33 and 34 in moderate yield. In two cases the terminal alkynes 30 and 31 are also formed. The β-aminoacyl ylide 20 from β-alanine similarly gives the α,β-acetylenic δ-amino ester 35 upon pyrolysis. Regioselective addition of HBr to the triple bond of one acetylenic ester 25 was observed giving a mixture of E and Z α-bromoacrylates 36. Hydrogenation of the N-Cbz acetylenic esters 21-23 and 33 results in N-deprotection and hydrogenation of the triple bond to afford the chiral GABA analogues 37-40 in 70 ->95% ee as determined by ¹⁹F NMR of their Mosher amides. Fully assigned ¹³C NMR spectra of all the ylides and acetylenic ester derivatives are presented.

Full text of DOI:10.1039/b110243e

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Flash vacuum pyrolysis of stabilised phosphorus ylides. Part 17.1
Preparation of aliphatic amino acid derived ꢀ-alkoxycarbonyl-
amino-ꢁ-oxo ylides and pyrolysis to give ꢂ,ꢁ-acetylenic ꢀ-amino
acid and GABA analogues
1
R. Alan Aitken,*a Nazira Karodia,a Tracy Massila and Robert J. Youngb
a School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, Fife,
UK KY16 9ST
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK SG1 2NY
Received (in Cambridge, UK) 12th November 2001, Accepted 19th December 2001
First published as an Advance Article on the web 21st January 2002
A series of eleven α-aminoacyl stabilised phosphorus ylides 9–19 have been prepared by condensation of
N-alkoxycarbonyl protected amino acids with Ph P᎐CHCO Et using a carbodiimide peptide coupling reagent.
᎐
3
2
Upon flash vacuum pyrolysis at 600 ЊC, these undergo extrusion of Ph3PO to give the corresponding α,β-acetylenic
γ-amino esters 21–29, 33 and 34 in moderate yield. In two cases the terminal alkynes 30 and 31 are also formed.
The β-aminoacyl ylide 20 from β-alanine similarly gives the α,β-acetylenic δ-amino ester 35 upon pyrolysis.
Regioselective addition of HBr to the triple bond of one acetylenic ester 25 was observed giving a mixture
of E and Z α-bromoacrylates 36. Hydrogenation of the N-Cbz acetylenic esters 21–23 and 33 results in
N-deprotection and hydrogenation of the triple bond to afford the chiral GABA analogues 37–40 in
70 –>95% ee as determined by 19F NMR of their Mosher amides. Fully assigned 13C NMR spectra
of all the ylides and acetylenic ester derivatives are presented.
In previous Parts of this series we have shown that flash vacuum
pyrolysis (FVP) of oxo stabilised phosphorus ylides provides a
useful route for synthesis of a wide variety of alkynes.2 Since
the ylides are readily formed by acylation with an acid chloride
or the equivalent we were interested to extend the method to
ylides 1 derived from amino acids. As shown, this is expected to
give chiral amino acid analogues in which the acid group is
Relatively few compounds of structure 2 and 3 have been
prepared before,5 but they are of considerable importance as
potential mechanism-based inhibitors of medicinally important
enzymes.6 In particular, 2 (R2 = H) and a number of N-
substituted analogues have been shown to be effective GABA
mimics,7 and related compounds have been proposed for the
therapeutic treatment of alcoholism and as anti-tumour
agents.8 The propargylamine (prop-2-ynylamine) 3 (R2 = (CH2)3-
NH2) and analogues have been shown to be selective irreversible
inhibitors of ornithine decarboxylase and thus to have poten-
tial anti-tumour activity,9 while 3 (R2 = (CH2)2CO2H) and
related compounds effectively inhibit GABA aminotransferase
and may be used for the treatment of epilepsy.10
᎐
either spaced out from the α-centre by a C᎐C unit as in
᎐
2 or, using our previous discovery that higher temperature
3
᎐
FVP results in loss of the ester group, replaced by C᎐CH
᎐
as in 3. In Part 7, we described the synthesis of aminoacyl
ylides 4 with nitrogen protected in the form of the thermally
robust phthalimide but these underwent loss of Ph3PO in an
unexpected way upon FVP to give the pyrroloisoindolediones
5.4
We describe here the synthesis of aminoacyl ylides with the
amino function protected by apparently more labile alkoxy-
carbonyl groups and their successful transformation using FVP
into a range of acetylenic amino ester products.11
Results and discussion
Using the method developed by Wasserman,12 a range of N-
benzoxycarbonyl and N-ethoxycarbonyl amino acids 6–8 were
reacted with (ethoxycarbonylmethylene)triphenylphosphorane
and the peptide coupling reagent 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) in the presence of
a catalytic quantity of DMAP. Standard work-up followed by
chromatographic purification afforded the desired ylides 9–20
in moderate yield (Table 1). As expected these were stable crys-
talline solids which gave satisfactory analytical data and 31P
NMR signals in the range δP ϩ17–18. The 1H and particularly
13C NMR spectra were rather complex both due to phosphorus
coupling and, in the cases of 16, 18 and 19, the presence of
rotamers due to restricted rotation about the carbamate func-
tion. The fully assigned spectra of the starting N-protected
DOI: 10.1039/b110243e
J. Chem. Soc., Perkin Trans. 1, 2002, 533–541
This journal is © The Royal Society of Chemistry 2002
533

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Table 1 Preparation and properties of ylides 9–20
Amino acid
R1
R2
Yield (%)
Mp/ЊC
δP
[α]D
9
10
11
12
13
14
15
16
17
18
19
20
Ala
Val
Leu
Gly
Ala
Val
Leu
Ile
Ala
Pro
Pro
β-Ala
Bn
Bn
Bn
Et
Et
Et
Me
Pri
Bui
H
Me
Pri
Bui
Bus
Me
—
46
49
44
51
50
45
45
48
45
49
44
52
140–142
88–91
152–154
147–149
68–69
128–129
105–107
148–149
103–104
129–130
112–114
94–95
ϩ17.5
ϩ17.8
ϩ17.5
ϩ17.8
ϩ18.0
ϩ17.8
ϩ17.9
ϩ18.7/18.6
ϩ18.0
ϩ20.3
ϩ28.7
ϩ21.7
—
ϩ17.5
ϩ22.6
ϩ17.1
ϩ5.9
ϩ13.8
Ϫ45.0
Ϫ33.8
—
Et
Et
Bui
Bn
Et
ϩ17.6/17.4
ϩ17.4/17.2
ϩ18.1
—
—
—
amino acids, some of which are reported here for the first time,
were of considerable assistance in allowing complete assign-
ment of the 13C NMR data for the new ylides 9–20 (Table 2). As
we have noted previously, the low value (≤3 Hz) for 2JP–keto C(᎐O)
bodes well for the successful extrusion of Ph3PO. As shown ᎐in
Tables 1 and 2, both the isoleucine derived ylide 16 and the two
proline derived ylides 18 and 19 showed separate 31P and 13C
NMR signals for the two carbamate rotamers. For ylides 16
and 19 variable temperature 31P NMR studies gave activation
energies ∆G‡ of 74.8 and 70.9 kJ molϪ1, respectively, for the
rotation processes.
pyrolysis product 28 where an additional stereogenic centre is
present the absence of diastereomer signals in the NMR spectra
indicated that no significant degree of racemisation had
occurred. An alternative to the method reported here is
provided by the work of Reetz and coworkers13 who treated
suitably protected α-amino aldehydes with CBr4–Ph3P fol-
lowed by BuLi in the so-called Corey–Fuchs procedure and
then intercepted the aminoalkynyllithiums with CO2 to give
α,β-acetylenic γ-amino acids after deprotection.
The ylides were now subjected to FVP at 600 ЊC and 1–5 ×
10Ϫ2 Torr in a conventional flow system and this led to the
desired extrusion of Ph3PO to give the acetylenic esters 21–29
and 33–35 in moderate yield after chromatographic separation
from the Ph3PO (Table 3). These gave the expected analytical
and spectroscopic data and in the majority of cases separate 13
C
NMR signals were observed for the two carbamate rotamers
(Table 4). For 9 and 10 additional minor products were
obtained from the chromatography which proved to be the
terminal alkynes 30 and 31 resulting from the known3 loss of
the ethoxycarbonyl group under these conditions. Attempts to
increase the proportion of these products by performing the
pyrolyses at higher temperatures were frustrated by an increas-
ing degree of decomposition to give intractable products. The
rather interesting functionalised 1,3-diene product 32 was also
obtained as a minor product from 10 and its formation is prob-
ably explained by two consecutive 1,3-hydrogen shifts in the
primary product 22.
With the acetylenic products in hand, we were anxious to
examine the further reactivity of these potentially versatile syn-
thetic intermediates. Treatment of 25 with HBr in acetic acid
resulted in clean regioselective addition of HBr across the triple
bond to give the α-bromoacrylate 36 as a 1 : 1 mixture of E and
Z isomers. It seems likely that a wide variety of other additions
to the triple bond could be carried out and this is currently
being examined. In order to obtain GABA analogues, we sub-
jected the Cbz protected compounds 21–23 and 33 to catalytic
hydrogenation. This resulted in removal of the Cbz group and
complete hydrogenation of the triple bond to give the chiral
γ-amino esters 37–40 in 70–80% yield. These again showed
significant optical rotations and the ee could now be deter-
mined by conversion to the corresponding Mosher amides14
which gave good separation of 19F NMR signals in each case
leading to values for the ee of 76% (37), 85% (38), >85% (39)
As noted in Tables 1 and 3, both the chiral acetylenic esters
and their ylide precursors showed substantial optical rotations.
However no satisfactory method for direct determination of the
ee of these compounds has yet been found. For 16 and its
534
J. Chem. Soc., Perkin Trans. 1, 2002, 533–541

Table 2 13C NMR spectra of ylides 9–20, δC (JP–C
)
NCO2R1 signalsb
P-Phenyl
C-1
CHN
P᎐C
᎐
COCN
CO2Et
CO
R1
C-2
C-3
C-4
R2 signals
9
10
11
12
13
14
15
16a
52.5 (8)
60.4 (8)
55.1 (8)
49.2 (8)
52.4 (8)
60.3 (8)
54.9 (8)
60.5 (8)
57.2 (8)
51.9 (8)
62.9 (8)
62.4 (8)
62.7 (8)
62.4 (8)
—
68.8 (111)
69.8 (111)
69.3 (111)
68.9 (112)
68.8 (111)
70.0(110)
69.2 (110)
70.3 (110)
69.8 (110)
68.4 (110)
69.2 (111)
68.9 (111)
69.3 (110)
68.9 (111)
71.4 (111)
194.8
194.1
195.2
190.6
195.1
194.4
195.4
194.5
166.7 (14), 58.7, 13.8
166.8 (14), 58.6, 13.8
166.8 (15), 58.7, 13.9
167.4 (15), 58.7, 13.9
166.8 (15), 58.7, 13.8
166.9 (15), 58.8, 13.9
166.8 (15), 58.7, 13.9
166.8 (14), 58.7, 13.8
166.7 (14)
166.4 (14), 58.2, 13.3
167.51 (15), 58.4, 13.7
167.46 (15), 58.3
167.54 (15), 58.4, 13.8
167.49 (15), 58.3, 13.7
167.9 (15), 58.5, 13.7
155.5
156.6
156.6
156.6
155.9
157.0
156.6
156.9
137.1 (4ry), 128.3, 127.7 (3C), 65.9
137.1 (4ry), 128.2, 127.6 (3C), 66.0
137.1 (4ry), 128.3, 127.7 (3C), 66.1
60.4, 14.7
60.2, 14.7
60.4, 14.6
126.0 (93)
126.0 (94)
126.2 (94)
125.9 (94)
126.2 (94)
126.1 (94)
126.3 (94)
126.2 (93)
126.15 (93)
125.5 (93)
126.4 (93)
126.2 (94)
126.7 (94)
133.0 (10)
133.0 (10)
133.1 (10)
133.2 (10)
133.1 (10)
133.2 (10)
133.1 (10)
133.1 (10)
128.6 (12)
128.5 (12)
128.5 (12)
128.6 (13)
128.6 (13)
128.5 (13)
128.5 (13)
128.5 (12)
131.8 (<2)
131.8 (<2)
131.8 (2)
131.9 (2)
131.8 (2)
131.8 (2)
131.7 (2)
131.6 (<2)
20.4
32.3, 20.7, 15.9
43.6, 25.1, 21.9, 21.8
—
20.5
32.3, 20.7, 15.9
43.7, 25.1, 24.0, 21.8
39.4, 27.8, 16.8, 12.1
38.8, 22.8
20.6
46.9, 30.7, 23.8
47.4, 31.8, 23.0
47.2, 31.7, 22.9
46.9, 30.7, 23.8
40.0 (6), 37.4
60.3, 14.6
60.3, 14.6
12.9
17
194.5
155.5
154.54
154.51
155.0
154.9
156.6
69.9, 27.5, 18.6 (2C)
137.4 (4ry), 128.2, 127.6 (3C), 66.3
66.0
60.6, 14.8
60.5
132.5 (10)
133.3 (10)
132.9 (10)
133.4 (10)
133.1 (10)
133.0 (10)
128.1 (13)
128.8 (13)
131.5 (<2)
131.6 (4)
131.5 (4)
131.6 (2)
131.5 (<2)
131.7 (2)
18a
195.6(3)
195.1(3)
195.5
195.4
196.0
19a
128.5 (13)
128.4 (13)
128.6 (12)
20
60.2, 14.8
126.5 (94)
a For 16, 18 and 19 the signals for both carbamate rotamers are given where they differ. b 4ry refers to quaternary carbon atoms.

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Table 4 13C NMR spectra of alkyne products 21–31 and 33–35, δC (JP–C). The signals for both carbamate rotamers are given where they differ
R2
NCO2R1
R1 signals
᎐
–C᎐O
᎐
C–CO2Et
CHN
21
30
22
74.4, 86.8
70.6, 84.1
76.0, 85.2
75.8, 81.6
72.1, 81.6
75.0, 86.5
71.2, 83.4
75.1, 83.5
75.0, 83.3
74.2, 87.1
75.9, 85.6
75.2, 86.9
74.8, 86.9
74.4, 88.2
75.6, 86.1
76.0, 85.3
74.3, 87.1
74.3, 87.0
70.3, 86.8
74.1, 81.1
70.1
14.0, 62.2, 155.0
—
14.0, 62.1, 155.5
38.8
38.9
49.2
21.6
22.5
17.9, 18.6, 33.0
153.2
155.2
153.3
67.2, 128.2 (2C), 128.3, 128.6 (2C), 136.0 (4ry)
67.0, 128.1 (2C), 128.2, 128.5 (2C), 136.2 (4ry)
67.3, 128.2 (2C), 128.3, 128.6 (2C), 136.1 (4ry)
31
23
—
49.1
41.8
17.5, 18.6, 32.8
22.1, 22.4, 24.9, 44.3
155.5
153.3
67.0, 125.5, 128.2 (2C), 128.5 (2C), 136.2 (4ry)
67.2, 128.2 (2C), 128.3, 128.6 (2C), 136.1 (4ry)
14.0, 62.1, 155.3
24
14.0, 62.2, 156.0
30.7
29.8
38.6
49.7
47.7
40.2
41.6
47.6
47.8
38.7
48.4
47.9
47.7
48.2
38.9
—
153.2
14.6, 61.5
25
26
14.0, 62.1, 155.3
14.0, 62.1, 156.0
14.0, 62.0, 156.6
14.0, 62.1, 155.7
60.0, 156.0
14.0, 62.1, 155.9
62.0, 155.7
21.6
153.3
153.4
153.6
153.4
153.6
153.4
153.3
153.3
153.4
154.1
153.5
14.5, 61.4
14.5, 60.1
14.5, 61.4
14.5, 61.9
61.4
14.5, 61.9
62.0
18.0, 18.6, 33.2
17.8, 18.8, 33.3
22.1, 22.3, 24.8, 44.3
22.1, 22.5, 24.9, 44.6
11.5, 15.1, 25.2, 39.4
11.4, 14.7, 25.8, 39.6
21.6
24.6, 33.2, 46.3
23.8, 33.2, 45.9
23.8, 33.2, 46.1
24.6, 32.4, 45.8
20.3
27
28
29
33
14.0, 62.1, 155.5
14.0, 62.0, 154.4
19.0 (2C), 28.0, 71.6
67.0, 127.9, 128.0, 128.4 (2C), 136.5(4ry)
34
35
14.0, 62.0, 154.7
154.5
14.0, 62.0, 156.5
14.7, 61.5
14.6, 61.1
74.3, 86.1
74.2, 87.1
153.5
MS-902 spectrometer using electron impact at 70 eV or on a
VG Autospec using chemical ionisation with isobutane as the
ionising gas. Optical rotations were measured on an Optical
Activity AA1000 polarimeter and are given in units of 10Ϫ1 deg
cm2 gϪ1. Dry CH2Cl2 was prepared by storage over P2O5.
Ethyl
(4S)-4-benzoxycarbonylamino-5-methyl-3-oxo-2-tri-
phenylphosphoranylidenehexanoate 10. From N-benzoxycarb-
onyl-(S)-valine as colourless crystals (1.48 g, 49%), mp
88–91 ЊC (Found: C, 72.4; H, 6.4; N, 2.35. C35H36NO5P requires
C, 72.3; H, 6.2; N, 2.4%); [α]2D0 ϩ28.7 (c 0.995 in CH2Cl2);
νmax/cmϪ1 3390, 1710, 1640, 1550, 1275, 1220, 1090, 1065, 1000,
740, 710 and 680; δH 7.80–7.63 (5 H, m, Ph), 7.51–7.40 (10 H,
m, Ph), 7.39–7.20 (5 H, m, Ph), 5.68 (1 H, d, J 9, NH), 5.54
(1 H, m, CHNH), 5.06 (2 H, s, OCH2Ph), 3.74 (2 H, m, OCH2),
2.44 (1 H, br m, CH), 1.09 (3 H, d, J 6, CHMe), 0.72 (3 H, t, J 7,
CH2Me) and 0.68 (3 H, d, J 7, CHMe); δC see Table 2; δP ϩ17.8;
m/z (FAB) 582 (M ϩ Hϩ, 16%), 492 (5), 375 (100), 303 (39), 262
(14) and 183 (14).
Preparation of N-protected amino acids
To a stirred solution of the appropriate amino acid (10.0 g) in
2 M NaOH (1.0 equiv.) at 0 ЊC were added simultaneously
benzyl or ethyl chloroformate (1.0 equiv.) and 2 M NaOH
(1.0 equiv.) dropwise. The mixture was stirred at 0 ЊC for 3 h
then washed with ether (20 cm3). The aqueous phase was acidi-
fied with 2 M HCl and extracted with ethyl acetate (3 × 50 cm3).
The combined organic phase was dried and the solvent evapor-
ated to furnish the product. Properties of the products are
summarised in Table 5.
Ethyl
(4S)-4-benzoxycarbonylamino-6-methyl-3-oxo-2-tri-
phenylphosphoranylideneheptanoate 11. From N-benzoxycarb-
onyl-(S)-leucine as colourless crystals (1.36 g, 44%), mp
152–154 ЊC (Found: C, 72.8; H, 6.5; N, 2.3. C34H34NO5P
requires C, 72.6; H, 6.4; N, 2.4%); [α]2D0 ϩ21.7 (c 0.975 in
CH2Cl2); νmax/cmϪ1 3390, 3300, 1695, 1655, 1535, 1500, 1290,
1250, 1094, 1080, 1045, 730 and 680; δH 7.67–7.61 (5 H, m, Ph),
7.64–7.44 (10 H, m, Ph), 7.30–7.26 (5 H, m, Ph), 5.61 (2 H, m,
NH and CH), 5.07 (2 H, s, OCH2Ph), 3.81 (2 H, m, OCH2), 1.77
(2 H, m, CH2CH), 1.36 (1 H, m, CH2CH ), 1.12 (3 H, d, J 6,
CHMe), 0.94 (3 H, d, J 6, CHMe) and 0.72 (3 H, t, J 7,
CH2Me); δC see Table 2; δP ϩ17.5; m/z (CI) 596 (M ϩ Hϩ,
100%), 550 (44), 506 (6), 488 (19), 416 (30), 375 (23), 319 (7),
292 (12), 279 (17), 263 (41), 225 (36), 187 (11), 156 (12) and 91
(19).
Preparation of ꢁ-aminoacyl phosphorus ylides
To a stirred solution of (ethoxycarbonylmethylene)triphenyl-
phosphorane (1.82 g, 5.2 mmol) and the appropriate N-
protected amino acid (5.2 mmol) in dry CH2Cl2 (25 cm3) at
0 ЊC was added EDCI (1.0 g, 5.2 mmol) and DMAP (0.03 g,
0.26 mmol). The mixture was stirred at this temperature for
30 min then allowed to warm up to RT. Once all the starting
material was consumed (indicated by TLC) the mixture was
poured into brine, extracted with CH2Cl2 (3 × 20 cm3) and the
combined organic extracts dried and evaporated. The crude
product was purified by chromatography (SiO2, ethyl acetate–
hexane, 1 : 2) followed by recrystallisation from ethyl acetate.
Ethyl 4-ethoxycarbonylamino-3-oxo-2-triphenylphosphoranyl-
idenebutyrate 12. From N-ethoxycarbonylglycine as colourless
crystals (1.27 g, 51%), mp 147–149 ЊC (Found: C, 68.2; H, 6.0;
N, 2.8. C27H28NO5P requires C, 67.9; H, 5.9; N, 2.9%);
νmax/cmϪ1 3400, 1700, 1650, 1570, 1510, 1300, 1235, 1170, 1105,
1090, 770 and 690; δH 7.70–7.61 (6 H, m, Ph), 7.60–7.50 (3 H,
m, Ph), 7.49–7.43 (6 H, m, Ph), 5.68 (1 H, br m, NH), 4.56 (2 H,
d, J 3, CH2), 4.09 (2 H, m, OCH2), 3.78 (2H, m, OCH2), 1.17
(3 H, t, J 7, Me) and 0.76 (3 H, t, J 7, Me); δC see Table 2; δP
ϩ17.8; m/z (CI) 478 (M ϩ Hϩ, 100%), 432 (52), 386 (8), 375
(19), 365 (11), 319 (6), 279 (26), 263 (29), 218 (14), 187 (9), 172
(20) and 47 (8).
Ethyl (4S)-4-benzoxycarbonylamino-3-oxo-2-triphenylphos-
phoranylidenepentanoate 9. From N-benzoxycarbonyl-(S)-
alanine as colourless crystals (1.21 g, 46%), mp 140–142 ЊC
(Found: C, 71.9; H, 5.7; N, 2.5. C33H32NO5P requires C, 71.6;
H, 5.7; N, 2.5%); [α]2D0 ϩ20.3 (c 1.005 in CH2Cl2); νmax/cmϪ1
3450, 1700, 1645, 1560, 1475, 1270, 1220, 1090, 1080, 1040, 750
and 690; δH 7.78–7.61 (5 H, m, Ph), 7.55–7.41 (10 H, m, Ph),
7.41–7.25 (5 H, m, Ph), 5.88 (1 H, d, J 7, NH), 5.51 (1 H, m,
CH), 5.05 (2 H, s, OCH2Ph), 3.79 (2 H, m, OCH2), 1.54 (3 H, d,
J 6, CHCH3) and 0.74 (3 H, t, J 7, Me); δC see Table 2; δP ϩ17.5;
m/z (CI) 554 (M ϩ Hϩ, 100%), 508 (20), 446 (18), 375 (31), 279
(11), 263 (17), 184 (8) and 91 (10).
Ethyl
(4S)-4-ethoxycarbonylamino-3-oxo-2-triphenylphos-
The racemic compound was prepared using N-benzoxy-
carbonyl-( )-alanine and had mp 142–143 ЊC.
phoranylidenepentanoate 13. From N-ethoxycarbonyl-(S)-
alanine as colourless crystals (1.09 g, 50%), mp 68–69 ЊC
536
J. Chem. Soc., Perkin Trans. 1, 2002, 533–541

Table 5 Properties of N-protected amino acids 6–8 The signals for both carbamate rotamers are given where they differ
δH
δH
R1 R2 Yield (%)
Bn Me 68
Mp/ЊC
82–84
Lit. mp/ЊC
83–84
Ref.
17
OH
NH
CHN
4.41
R1 signals
7.38, 5.17
R2 signals
0.74
CO2H
NCO
155.9
CHN
49.4
R1 signals
R2 signals
18.2
6
10.84
5.58
6.69
177.5
136.0, 128.5, 128.2, 128.0, 67.1
6a
6
Bn Me 68
Bn Pri 58
114–115
60–62
114–115
66–67
18
19
10.90
10.15
9.66
5.60
6.64
5.28
6.33
5.50
6.85
5.58
6.77
4.43
4.22
4.43
4.25
4.33
7.41, 5.18
7.34, 5.11
2.18, 1.12, 0.98
1.61, 0.94, 0.93
—
176.4
178.0
156.5
156.2
157.2
156.5
58.8
52.3
136.0, 128.4, 128.2, 128.1, 67.2
136.0, 128.5, 128.2, 128.1, 67.1
31.0, 19.0, 17.3
6
6
6
Bn Bui 61
(Oil)
(Oil)
(Oil)
(Oil)
67–69
(Oil)
19
20
21
41.4, 24.7, 22.8, 21.7
Et
H
70
4.15, 1.25
4.00
4.07, 1.19
174.4
173.7
177.2
42.6
43.2
49.4
61.8, 14.6
62.4
61.4, 14.5
—
Et Me 71
10.26
4.33
1.40
18.4
6a
6
Et Me 71
Et Pri 70
80–82
(Oil)
84
37
22
23
10.80
11.11
9.47
5.52
6.54
5.31
6.38
5.32
6.36
5.45
7.01
—
4.33
4.37
4.36
4.25
4.35
4.24
3.46
4.16, 1.25
4.13, 1.25
4.13, 1.26
3.91, 1.94b
2.23, 1.00, 0.94
1.64, 0.96
176.3
178.0
176.7
157.0
156.6
156.6
58.8
52.3
58.2
61.5, 14.5
61.4, 14.5
61.4, 14.5
31.1, 19.0, 17.4
41.4, 24.7, 22.9, 21.7
37.8, 24.8, 15.5, 11.6
18.9
6
6
6
7
7
8
Et Bui 69
Et Bus 72
Bui Me 69
(Oil)
(Oil)
—
24
—
—
19
25
26
(Oil)
1.95, 1.49, 0.98, 0.93
1.48
83–85
60–61
59–60
57–59
—
10.15
10.01
10.68
10.88
177.3
177.9
176.7
176.3
177.0
176.4
177.2
156.9
157.9
155.4
154.7
155.9
155.1
157.4
50.5
49.9
59.1
58.7
59.1
58.7
36.7
72.6, 28.2, 19.4
72.0
67.3, 136.3, 128.4, 127.9, 127.8
67.2
61.8, 14.7
61.7, 14.6
61.5, 14.9
Bn
Et
—
—
—
—
77
77
62
77
7.31, 5.09
7.26
4.07, 1.13
3.46, 2.05
46.6, 30.7, 24.1
128.3,127.5
57–58
57–59
—
3.39, 2.11, 1.80
46.8, 30.9, 24.3
46.5, 29.7, 23.5
c
c
6.42
7.17
4.14, 1.28
—
—
a Data for racemic compound. b Additional signal at δH 0.96 (6 H). c Additional signal at δH 2.52 and δC 34.6 (CH2CO).

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(Found: C, 68.4; H, 5.8; N, 2.8. C28H30NO5P requires C,
68.4; H, 6.2; N, 2.9%); [α]2D0 ϩ17.5 (c 0.98 in CH2Cl2); νmax/cmϪ1
3400, 1710, 1650, 1570, 1340, 1280, 1230, 1100, 1070 and 690;
δH 7.81–7.62 (6 H, m, Ph), 7.60–7.53 (3 H, m, Ph), 7.53–7.42
(6 H, m, Ph), 5.66 (1 H, br d, J 9, NH), 5.48 (1 H, br m, CHN),
4.06 (2 H, q, J 7, OCH2), 3.79 (2 H, m, OCH2), 1.45 (3 H, d, J 6,
CHMe), 1.16 (3 H, t, J 7, CH2Me) and 0.75 (3 H, t, J 7,
CH2Me); δC see Table 2; δP ϩ18.0; m/z (CI) 492 (M ϩ Hϩ,
100%), 446 (76), 375 (54), 303 (8), 279 (9), 263 (34), 232 (8), 186
(21), 116 (8) and 47 (11).
(N-Benzoxycarbonyl-(S)-prolinoyl(ethoxycarbonyl)methyl-
ene)triphenylphosphorane 18. From N-benzoxycarbonyl-(S)-
proline as colourless crystals (1.40 g, 49%), mp 129–130 ЊC
(Found: C, 72.5; H, 6.15; N, 2.3. C34H34NO5P requires C, 72.5;
H, 5.9; N, 2.4%); [α]2D0 Ϫ45.0 (c 1.03 in CH2Cl2); νmax/cmϪ1 3350,
1675, 1650, 1580, 1440, 1295, 1100, 760 and 690; δH 7.88–7.14
(20 H, m, Ph), 5.71 and 5.64* (1 H, dd, J 9, 3, CH), 5.08 (2 H,
m, OCH2Ph), 3.72 (2 H, m, OCH2), 3.49 (2 H, m, CH2), 2.40
and 2.04 (2 H, 2 × m, CH2), 1.73 (2 H, m, CH2) and 0.66 (3 H, t,
J 7, Me); δC see Table 2; δP ϩ17.6 and 17.4*; m/z 567 (Mϩ,
0.7%), 553 (2.8), 525 (8), 465 (2.3), 375 (27), 279 (20), 181 (23),
149 (25), 105 (29) and 91 (100).
The racemic compound was prepared using N-ethoxy-
carbonyl-( )-alanine and had mp 80–82 ЊC.
(N-Ethoxycarbonyl-(S)-prolinoyl(ethoxycarbonyl)methylene)-
triphenylphosphorane 19. From N-ethoxycarbonyl-(S)-proline
as colourless crystals (1.19 g, 44%), mp 112–114 ЊC (Found: C,
69.8; H, 6.5; N, 2.4. C30H32NO5P requires C, 69.6; H, 6.2; N,
2.7%); [α]2D0 Ϫ33.8 (c 0.96 in CH2Cl2); νmax/cmϪ1 1650, 1560,
1440, 1290, 1095, 1080, 750 and 690; δH 7.68–7.55 (6 H, m, Ph),
7.55–7.38 (9 H, m, Ph), 5.52 and 5.61 (1 H, ddd, J 13, 9, 2, CH),
4.04 (2 H, m, OCH2), 3.72 (2 H, m, OCH2), 3.40 (2 H, m, CH2),
2.36 and 2.04 (2 H, 2 × m, CH2), 1.71 (2 H, m, CH2), 1.18 (3 H,
m, Me) and 0.68 (3 H, t, J 7, Me); δC see Table 2; δP ϩ17.4 and
17.2*; m/z (CI) 518 (M ϩ Hϩ, 100%), 472 (95), 449 (9), 400 (42),
375 (71), 319 (9), 290 (58), 279 (73), 244 (14), 212 (49), 187 (32),
142 (52) and 47 (16).
Ethyl (4S)-4-ethoxycarbonylamino-5-methyl-3-oxo-2-triphen-
ylphosphoranylidenehexanoate 14. From N-ethoxycarbonyl-(S)-
valine as colourless crystals (1.23 g, 45%), mp 128–129 ЊC
(Found: C, 69.3; H, 6.5; N, 2.6. C30H34NO5P requires C, 69.4;
H, 6.6; N, 2.7%); [α]2D0 ϩ22.6 (c 0.975 in CH2Cl2); νmax/cmϪ1
3385, 1730, 1660, 1575, 1380, 1290, 1220, 1100, 1070 and 690;
δH 7.74–7.61 (6 H, m, Ph), 7.59–7.51 (3 H, m, Ph), 7.49–7.42
(6 H, m, Ph), 5.69 (1 H, br d, NH), 5.17 (1 H, br m, CHNH),
4.06 (2 H, q, J 7, OCH2), 3.79 (2 H, m, OCH2), 2.41 (1 H, br s,
CHMe2), 1.18 (3 H, t, J 7, CH2Me), 1.06 (3H, d, J 7, CHMe),
0.75 (3 H, t, J 7, CH2Me) and 0.62 (3 H, d, J 7, CHMe); δC see
Table 2; δP ϩ17.8; m/z (CI) 520 (M ϩ Hϩ, 100%), 474 (31), 375
(34) and 263 (31).
Ethyl 5-ethoxycarbonylamino-3-oxo-2-triphenylphosphoranyl-
idenepentanoate 20. From N-ethoxycarbonyl-β-alanine as
colourless crystals (1.34 g, 52%), mp 94–95 ЊC (Found: C, 68.1;
H, 6.1; N, 2.8. C28H30NO5P requires C, 68.4; H, 6.2; N, 2.9%);
νmax/cmϪ1 3230, 1700, 1650, 1535, 1320, 1255, 1230, 1120, 1105,
1100, 1080, 1030, 750 and 690; δH 7.80–7.42 (15 H, m, Ph), 5.31
(1 H, br m, NH), 4.08 (2 H, q, J 7, OCH2), 3.72 (2 H, q, J 7,
OCH2), 3.42 (2 H, m, CH2N), 3.12 (2 H, t, J 7, CH2), 1.25 (3 H,
t, J 7, Me) and 0.69 (3 H, t, J 7, Me); δC see Table 2; δP ϩ18.1;
m/z (CI) 492 (M ϩ Hϩ, 100%), 446 (12), 391 (29), 279 (39) and
263 (5).
Ethyl (4S)-4-ethoxycarbonylamino-6-methyl-3-oxo-2-triphen-
ylphosphoranylideneheptanoate 15. From N-ethoxycarbonyl-
(S)-leucine as colourless crystals (1.23 g, 45%), mp 105–107 ЊC
(Found: C, 69.6; H, 7.0; N, 2.5. C30H34NO5P requires C, 69.8;
H, 6.8; N, 2.6%); [α]2D0 ϩ17.1 (c 0.935 in CH2Cl2); νmax/cmϪ1
3360, 3260, 1720, 1670, 1580, 1260, 1100, 1050 and 690;
δH 7.75–7.61 (6 H, m, Ph), 7.56–7.50 (3 H, m, Ph), 7.48–7.42
(6 H, m, Ph), 5.56 (1 H, m, NH), 5.41 (1 H, m, CHNH), 4.04
(2 H, q, J 7, OCH2), 3.72 (2 H, m, OCH2), 1.78 (2 H, m,
CH2CH), 1.34 (1 H, m, CHMe2), 1.17 (3 H, t, J 7, CH2Me), 1.11
(3 H, d, J 5, CHMe), 0.93 (3 H, d, J 6, CHMe) and 0.73 (3 H, t,
J 7, CH2Me); δC see Table 2; δP ϩ17.9; m/z (CI) 534 (M ϩ Hϩ,
100%), 488 (93), 431 (14), 412 (7), 375 (30), 319 (5), 274 (20),
263 (39), 228 (28), 185 (8), 158 (8) and 47 (9).
Flash vacuum pyrolysis of ylides
The apparatus used was as described previously.27 All pyrolyses
were conducted at 600 ЊC and at pressures in the range 1–5 ×
10Ϫ2 Torr. Under these conditions the contact time in the hot
zone was estimated to be ∼10 ms. In each case a mixture of solid
and oil collected at the furnace exit which was shown by 1H and
31P NMR to be a mixture of Ph3PO and the desired product.
Chromatography on silica (diethyl ether–hexane, 1 : 2) gave the
pure products as follows.
Ethyl (4S,5S)-4-ethoxycarbonylamino-5-methyl-3-oxo-2-tri-
phenylphosphoranylideneheptanoate 16. From N-ethoxycarb-
onyl-(S,S)-isoleucine as colourless crystals (1.34 g, 48%), mp
148–149 ЊC (Found: C, 69.4; H, 6.8; N, 2.5. C31H36NO5P
requires C, 69.8; H, 6.8; N, 2.6%); [α]2D0 ϩ5.9 (c 1.0 in CH2Cl2);
νmax/cmϪ1 3390, 1695, 1650, 1580, 1470, 1440, 1340, 1298, 1280,
1220, 1098, 1065, 750 and 690; δH 7.78–7.61 (6 H, m, Ph), 7.59–
7.50 (3 H, m, Ph), 7.47–7.31 (6 H, m, Ph), 5.55 (1 H, m, NH),
5.46 (1 H, m, CHN), 4.03 (3 H, q, J 7, OCH2), 3.78 (2 H, m,
OCH2), 1.68 (1 H, m, CH), 1.17 (3 H, t, J 7, OCH2Me), 1.10–
0.91 (3 H, m, CH2Me), 0.87 (2 H, m, CHCH2), 0.74 (3 H, t, J 7,
OCH2Me) and 0.58 (3 H, d, J 7, CHMe); δC see Table 2; δP
ϩ18.7, 18.6*; m/z (CI) 534 (M ϩ Hϩ, 75%), 458 (9), 412 (6), 375
(11), 326 (17), 312 (11), 294 (5), 281 (22), 266 (23), 215 (48) and
236 (100).
Ethyl (4S)-4-(benzoxycarbonylamino)pent-2-ynoate 21. FVP
of the ylide 9 (500 mg) gave the title compound (72 mg, 29%) as
a yellow oil (Found: C, 65.7; H, 6.6; N, 5.4; M ϩ Hϩ, 276.1226.
C15H17NO4 requires C, 65.4; H, 6.2; N, 5.1%; M ϩ H,
276.1236); [α]2D3 Ϫ30.3 (c 0.615 in CH2Cl2); νmax/cmϪ1 3318, 2983,
2245, 1709, 1526, 1254, 1064, 770 and 708; δH 7.38 (5 H, s, Ph),
5.11 (2 H, s, OCH2Ph), 4.99 (1 H, br d, NH ), 4.70 (1 H, m,
CH ), 4.22 (2 H, q, J 7, OCH2), 1.47 (3 H, d, J 7, CHMe) and
1.30 (3 H, t, J 7, Me); δC see Table 4; m/z (CI) 276 (M ϩ Hϩ,
26%), 232 (100), 147 (8) and 91 (9).
Ethyl (4S)-4-isobutoxycarbonylamino-3-oxo-2-triphenylphos-
phoranylidenepentanoate 17. From N-isobutyloxycarbonyl-(S)-
alanine as colourless crystals (1.2 g, 45%), mp 103–104 ЊC
(Found: C, 69.1; H, 6.5; N, 2.7. C30H34NO5P requires C, 69.4;
H, 6.6; N, 2.7%); [α]2D0 ϩ13.8 (c 0.5 in CH2Cl2); νmax/cmϪ1 3490,
1710, 1650, 1545, 1320, 1255, 1230, 1120, 1105, 1100, 1090,
1050, 750 and 690; δH 7.81–7.62 (6 H, m, Ph), 7.57–7.52 (3 H,
m, Ph), 7.49–7.42 (6 H, m, Ph), 5.76 (1 H, br d, J 7, NH), 5.46
(1 H, m, CH), 3.77 (4 H, m, 2 × CH2), 1.83 (1 H, m, CH), 1.46
(3 H, d, J 7, CHMe), 0.85 (6 H, d, J 6, CHMe2) and 0.75 (3 H, t,
J 7, Me); δC see Table 2; δP ϩ18.0; m/z (CI) 520 (M ϩ Hϩ,
100%), 474 (10), 444 (13), 375 (12), 263 (19) and 187 (15).
An additional minor product obtained from the chrom-
atography was compound 30.
(3S)-3-(Benzoxycarbonylamino)but-1-yne 30. Compound 30
as a yellow oil (28 mg, 15%) (Found: Mϩ, 203.0954. C12H13NO2
requires Mϩ, 203.0946); [α]2D2 Ϫ3.43 (c 0.84 in CH2Cl2); νmax
/
cmϪ1 3405, 2926, 2253, 1708, 1525, 1224, 1049, 752 and 698;
δH 7.40 (5 H, s, Ph), 5.14 (2 H, s, OCH2Ph), 5.06 (1 H, br d,
NH), 4.72 (1 H, m, NHCH ), 2.62 (1 H, d, J 2, –CH) and 1.48
(3 H, d, J 7, CHMe); δC see Table 4; m/z (EI) 203 (Mϩ, 8%), 149
(9), 112 (5), 108 (80), 91 (100), 79 (16) and 65 (14).
538
J. Chem. Soc., Perkin Trans. 1, 2002, 533–541

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Ethyl
(4S)-4-benzoxycarbonylamino-5-methylhex-2-ynoate
Ethyl (4S)-4-ethoxycarbonylamino-5-methylhex-2-ynoate 26.
22. FVP of the ylide 10 (300 mg) gave the title compound
(91 mg, 58%) as colourless crystals, mp 60–62 ЊC (Found: M ϩ
Hϩ, 304.1551. C17H21NO4 requires M ϩ H, 304.1549); [α]2D3
Ϫ34.4 (c 0.545 in CH2Cl2); νmax/cmϪ1 3330, 2970, 2240, 1715,
1535, 1302, 1260, 1050, 750 and 690; δH 7.38 (5 H, s, Ph), 5.14
(2 H, s, OCH2Ph), 5.02 (1 H, br d, NH), 4.55 (1 H, m, NHCH ),
4.24 (2 H, q, J 7, OCH2), 1.99 (1 H, m, CHMe2), 1.33 (3 H, t,
J 7, Me) and 1.03 (6 H, d, J 7, CHMe2); δC see Table 4; m/z (CI)
304 (M ϩ Hϩ, 51%), 260 (92), 232 (100), 188 (14) and 171 (16).
Additional minor products obtained from the chrom-
atography were as follows.
FVP of the ylide 14 (500 mg) gave the title compound (79 mg,
34%) as a yellow oil (Found: M ϩ Hϩ, 242.1400. C12H19NO4
requires M ϩ H, 242.1392); [α]2D0 Ϫ49.5 (c 0.91 in CH2Cl2);
νmax/cmϪ1 3350, 2960, 2240, 1700, 1540, 1460, 1360, 1240, 1090,
1030 and 740; δH 4.92 (1 H, br d, J 8, NHCH), 4.51 (1 H, m,
NHCH ), 4.22 (2 H, q, J 7, OCH2), 4.14 (2 H, q, J 7, OCH2),
1.96 (1 H, m, CH), 1.31 (3 H, t, J 7, Me), 1.26 (3 H, t, J 7, Me)
and 1.02 (6 H, d, J 7, CHMe2); δC see Table 4; m/z (CI) 242
(M ϩ Hϩ, 92%), 224 (9), 213 (21), 196 (100), 170 (27), 153 (21)
and 57 (44).
Ethyl (4S)-4-ethoxycarbonylamino-6-methylhept-2-ynoate 27.
FVP of the ylide 15 (450 mg) gave the title compound (77 mg,
36%) as a yellow oil (Found: M ϩ Hϩ, 256.1556. C13H21NO4
requires M ϩ H, 256.1549); [α]2D0 Ϫ74.5 (c 0.865 in CH2Cl2);
νmax/cmϪ1 3340, 2460, 2240, 1700, 1530, 1370, 1245, 1050 and
760; δH 5.15 and 5.31 (1 H, 2 × br d, NHCH), 4.64 and 4.81
(1 H, m, NHCH ), 4.22 (2 H, q, J 7, OCH2), 4.17 (2 H, q, J 7,
OCH2), 1.78 (1 H, m, CH2CH ), 1.48 (2 H, t, J 7, CH2), 1.31
(3 H, t, J 7, Me), 1.26 (3 H, t, J 7, Me) and 0.95 (6 H, d, J 7,
CHMe2); δC see Table 4; m/z (CI) 256 (M ϩ Hϩ, 98%), 228 (11),
210 (100), 198 (12), 167 (15) and 57 (23).
(3S)-3-Benzoxycarbonylamino-4-methylpent-1-yne 31. Com-
pound 31 was isolated as a colourless oil (13 mg, 10%) (Found:
Mϩ, 231.1253. C14H17NO2 requires M, 231.1259); [α]2D2 Ϫ2.7
(c 0.25 in CH2Cl2); νmax/cmϪ1 3307, 2963, 2243, 1708, 1526,
1467, 1238, 1028, 754 and 697; δH 7.37 (5 H, s, Ph), 5.11 (2 H, s,
OCH2), 4.92 (1 H, br s, NH), 4.37 (1 H, m, NHCH ), 2.28 (1 H,
d, J 2, –CH), 1.92 (1 H, m, CHMe2) and 0.98 (6 H, d, J 8,
CHMe2); δC see Table 4; m/z (EI) 231 (Mϩ, 3%), 188 (8), 144
(11), 108 (13), 91 (100) and 65 (6).
(E )-Ethyl 4-benzoxycarbonylamino-5-methylhexa-2,4-dien-
oate 32. Compound 32 was isolated as a yellow oil (18 mg, 11%)
(Found: Mϩ Ϫ PhCH2, 212.0931. C17H21NO4 requires M Ϫ
PhCH2, 212.0923); νmax/cmϪ1 3322, 2981, 1728, 1625, 1371,
Ethyl (4S,5S)-4-ethoxycarbonylamino-5-methylhept-2-ynoate 28
FVP of the ylide 16 (440 mg) gave the title compound (80 mg,
38%) as a yellow oil (Found: C, 61.3; H, 8.3; N, 5.7; M ϩ Hϩ,
256.1547. C13H21NO4 requires C, 61.2; H, 8.3; N, 5.5%; M ϩ H,
256.1549); [α]2D0 ϩ9.1 (c 0.52 in CH2Cl2); νmax/cmϪ1 3310, 2960,
2230, 1710, 1530, 1240, 1040 and 750; δH 5.34 and 5.06 (1 H, 2 ×
m, NHCH), 4.79 and 4.62 (1 H, 2 × m, NHCH ), 4.24 (2 H, m,
OCH2), 4.15 (2 H, m, OCH2), 1.76–1.58 (1 H, m, HCH), 1.27
(5 H, m, MeCHCH2), 1.00 (3 H, d, J 7, Me) and 0.94 (3 H, t,
J 7, Me); δC see Table 4; m/z (CI) 256 (M ϩ Hϩ, 67%), 228 (37),
210 (31) and 184 (11).
1279, 1176, 1029, 747 and 699; δ 7.80 (1 H, d, J 15, HC᎐), 7.38
᎐
H
(5 H, s, Ph), 5.88 (1 H, d, J 15, HC᎐), 5.68 (1 H, br s, NH), 5.16
᎐
(2 H, s, CH2Ph), 4.20 (2 H, q, J 7, OCH2Me), 2.03 (3 H, s, Me),
1.86 (3 H, s, Me) and 1.32 (3 H, t, J 7, OCH2Me); δC 167.3
(CO ), 154.3 (NHCO), 144.3 (NHC᎐), 138.8 (᎐CH), 136.2 (Ph
᎐
᎐
2
C-1), 128.6 (2 C), 128.2 (2 C), 127.6 (Ph C-4), 125.9 (᎐CMe ),
᎐
2
116.7 (᎐CH), 67.2 (OCH Ph), 60.4 (OCH Me), 21.5 (CHMe),
᎐
2
2
20.3 (CHMe) and 14.3 (Me); m/z (EI) 212 (Mϩ Ϫ PhCH2, 42%),
127 (10), 109 (16) and 91 (100).
Ethyl (4S)-4-(isobutoxycarbonylamino)pent-2-ynoate 29. FVP
of the ylide 17 (500 mg) gave the title compound (77 mg, 33%)
as a pale yellow oil (Found: M ϩ Hϩ, 242.1392. C12H19NO4
requires M ϩ H, 242.1401); [α]2D3 Ϫ9.1 (c 0.615 in CH2Cl2);
νmax/cmϪ1 3320, 2970, 2250, 1715, 1530, 1470, 1370, 1255, 1055,
1025, 780 and 755; δH 4.97 (1 H, m, NH), 4.69 (1 H, m, NCH),
4.23 (2 H, q, J 7, OCH2), 3.86 (2 H, d, J 6, CH2CH), 2.92 (1H,
m, CHMe2), 1.48 (3 H, d, J 7, CHMe), 1.31 (3 H, t, J 7,
CH2Me) and 0.93 (6 H, d, J 7, Me); δC see Table 4; m/z (CI) 242
(M ϩ Hϩ, 100%).
Ethyl (4S)-4-benzoxycarbonylamino-6-methylhept-2-ynoate
23. FVP of the ylide 11 (360 mg) gave the title compound
(68 mg, 30%) as a yellow oil (Found: M ϩ Hϩ, 318.1707.
C18H23NO4 requires M ϩ H, 318.1705); [α]2D2 Ϫ26.7 (c 0.49 in
CH2Cl2); νmax/cmϪ1 3320, 2960, 2240, 1710, 1530, 1245, 1030,
750 and 700; δH 7.35 (5 H, s, Ph), 5.12 (2 H, s, OCH2Ph), 4.93
(1 H, br s, NH), 4.68 (1 H, m, NHCH ), 4.22 (2 H, q, J 7,
OCH2), 1.78 (1 H, m, CH2CH ), 1.62 (2 H, m, CHCH2), 1.30
(3 H, t, J 7, Me) and 0.94 (6 H, d, J 7, CHMe2); δC see Table 4;
m/z (CI) 318 (M ϩ Hϩ, 26%), 274 (100), 246 (13) and 202 (10).
Ethyl (S)-3-(1-benzoxycarbonylpyrrolidin-2-yl)propynoate 33.
FVP of the ylide 18 (352 mg) gave the title compound (90 mg,
48%) as a pale yellow oil (Found: C, 68.0; H, 6.6; N, 4.6.
C17H19NO4 requires C, 67.8; H, 6.4; N, 4.7%); [α]2D2 Ϫ114.4
(c 1.01 in CH2Cl2); νmax/cmϪ1 3400, 2980, 2240, 1705, 1410,
1355, 1250, 1180, 1120, 1090, 750 and 700; δH 7.34 (5 H, m, Ph),
5.18 (2 H, m, OCH2Ph), 4.68 (1 H, m, CHN), 4.22 (2 H, q, J 7,
OCH2), 3.44 (2 H, m, CHCH2), 2.12 (4 H, m, CH2CH2) and
1.30 (3 H, t, J 7, Me); δC see Table 4; m/z (CI) 302 (M ϩ Hϩ,
61%), 272 (11), 258 (33), 168 (12), 147 (27), 111 (28), 97 (53),
86 (32), 71 (37) and 59 (100).
Ethyl 4-(ethoxycarbonylamino)but-2-ynoate 24. FVP of the
ylide 12 (200 mg) gave the title compound (33 mg, 39%) as a
yellow oil (Found: C, 54.0; H, 6.9; N, 7.0; M ϩ Hϩ, 200.0913.
C9H13NO4 requires C, 54.3; H, 6.5; N, 7.0%; M ϩ H, 200.0922);
νmax/cmϪ1 3340, 2980, 2240, 1705, 1520, 1360, 1240, 750 and
720; δH 4.25 (7 H, m, 3 × CH2 and NH), 1.28 (3 H, t, J 7, Me)
and 1.23 (3 H, t, J 7, Me); δC see Table 4; m/z (EI) 199 (Mϩ, 7%),
171 (6), 154 (45), 127 (100), 98 (83), 84 (82), 66 (47), 54 (68) and
49 (93).
Ethyl (4S)-4-(ethoxycarbonylamino)pent-2-ynoate 25. FVP of
the ylide 13 (475 mg) gave the title compound (78 mg, 32%) as a
yellow oil (Found: C, 56.6; H, 7.2; N, 6.6; M ϩ Hϩ, 214.1083.
C10H15NO4 requires C, 56.3; H, 7.1; N, 6.6%; M ϩ H,
214.1079); [α]2D0 Ϫ91.0 (c 0.695 in CH2Cl2); νmax/cmϪ1 3300, 2960,
2210, 1695, 1520, 1430, 1355, 1235, 1165, 1109 and 1044;
δH 4.99 (1 H, br s, NHCH), 4.69 (1 H, m, NHCH ), 4.23 (2 H,
q, J 7, OCH2), 4.14 (2 H, q, J 7, OCH2), 1.47 (3 H, d, J 7,
CHMe), 1.31 (3 H, t, J 7, CH2Me) and 1.25 (3 H, t, J 7,
CH2Me); δC see Table 4; m/z (CI) 214 (M ϩ Hϩ, 79%), 168 (100)
and 142 (16).
Ethyl (S)-3-(1-ethoxycarbonylpyrrolidin-2-yl)propynoate 34.
FVP of the ylide 19 (500 mg) gave the title compound (110 mg,
48%) as a yellow oil (Found: M ϩ Hϩ, 240.1226. C12H17NO4
requires M ϩ H, 240.1236); [α]2D0 Ϫ137.7 (c 0.535 in CH2Cl2);
νmax/cmϪ1 2960, 2220, 1700, 1410, 1330, 1250, 1120, 1090, 770
and 750; δH 4.68 (1 H, m, NCH), 4.59 (2 H, m, OCH2), 4.16
(2 H, m, OCH2), 3.44 (2 H, m, CH2), 2.13 (4 H, m, CH2CH2)
and 1.29 (6 H, t, J 7, 2 × Me); δC see Table 4; m/z (CI) 240 (M ϩ
Hϩ, 55%), 212 (98), 194 (70), 167 (100), 138 (77), 94 (33) and
70 (39).
J. Chem. Soc., Perkin Trans. 1, 2002, 533–541
539

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Ethyl 5-(ethoxycarbonylamino)pent-2-ynoate 35. FVP of the
ylide 20 (505 mg) gave the title compound (107 mg, 49%) as a
pale yellow oil (Found: C, 56.6; H, 7.3; N, 6.4. C10H15NO4
requires C, 56.3; H, 7.1; N, 6.6%); νmax/cmϪ1 3330, 2980, 2240,
1700, 1540, 1360, 1250, 1070, 1030 and 750; δH 5.16 (1 H, br s,
NH), 4.22 (2 H, q, J 7, OCH2), 4.12 (2 H, q, J 7, OCH2), 3.38
(2 H, q, J 7, NHCH2), 2.57 (2 H, t, J 7, CH2), 1.31 (3 H, t, J 7,
Me) and 1.24 (3 H, t, J 7, Me); δC see Table 4; m/z 213 (Mϩ,
15%), 185 (20), 168 (40), 141 (14), 122 (31), 102 (100), 84 (29)
and 66 (22).
Ethyl (4R)-4-amino-6-methylheptanoate 39. This was pre-
pared as above using ethyl (4S)-4-benzoxycarbonylamino-6-
methylhept-2-ynoate 23 (94 mg, 0.30 mmol) and Pd/C catalyst
(94 mg) to give the title compound (39 mg, 70%) as colourless
crystals, mp 124–125 ЊC (Found:
M ϩ
Hϩ, 188.1644.
C10H21NO2 requires M ϩ H, 188.1650); [α]2D5 ϩ6.9 (c 0.50 in
MeOH); νmax/cmϪ1 3390, 1730, 1600, 1510, 1275, 1190 and
1020; δH 8.93 (2 H, br s, NH2), 4.14 (2 H, q, J 7, OCH2), 3.37
(1 H, m, NCH), 2.59 (2 H, t, J 7, COCH2), 2.04 (2 H, m, CH2),
1.88 and 1.70 (2 H, 2 × m, CH2), 1.49 (1 H, m, CH), 1.25 (3 H, t,
J 7, OCH2Me) and 0.95 (6 H, d, J 7, CHMe2); δC 172.5 (CO2),
60.7 (OCH2), 50.2 (NCH), 42.1 (CHCH2), 30.1 (COCH2), 28.2
(CH2), 24.4 (CH), 22.4 (CHMe), 22.2 (CHMe) and 14.2
(OCH2Me); m/z (CI) 188 (M ϩ Hϩ, 100%).
Reactions of acetylenic amino acid esters
Hydrobromination. (E) and (Z)-Ethyl (4S)-2-bromo-4-
(ethoxycarbonylamino)pent-2-enoate 36. To a solution of ethyl
(4S)-4-(ethoxycarbonylamino)pent-2-ynoate 25 (0.12 g, 0.56
mmol) in dry CH2Cl2 (5 cm3) was added a solution of hydro-
bromic acid in acetic acid (45% w/v, 0.20 cm3, 1.1 mmol) and
the mixture stirred overnight at RT. The solvent was evaporated
under vacuum and the residue was chromatographed (SiO2,
ethyl acetate–hexane, 1 : 1) to give the product (0.13 g, 80%) as a
yellow oil (Found: 79Br Ϫ M ϩ Hϩ, 294.0347. C10H1679BrNO4
requires M ϩ H, 294.0340); νmax/cmϪ1 3320, 2980, 1710, 1625,
1520, 1445, 1330, 1300, 1250, 1170, 1090, 1050, 1030, 865 and
Ethyl (S)-3-(pyrrolidin-2-yl)propanoate 40. This was pre-
pared as above using ethyl (S)-3-(1-benzoxycarbonylpyrrolidin-
2-yl)propynoate 33 (90 mg, 0.30 mmol) and Pd/C catalyst
(90 mg) to give the title compound (40 mg, 78%) as a yellow oil
(Found: M ϩ Hϩ, 172.1339. C9H17NO2 requires M ϩ H,
172.1338); [α]2D5 Ϫ8.6 (c 1.0 in MeOH); νmax/cmϪ1 3440, 2960,
2750, 2500, 1730, 1630, 1450, 1420, 1375, 1280, 1190 and 1025;
δH 8.90 (1 H, br s, NH), 4.09 (2 H, q, J 7, OCH2), 3.61 (1 H, m,
NCH), 3.40 (2 H, m, CH2), 2.57 (2 H, t, J 8, COCH2), 2.05 (5 H,
m, 2 × CH2 and 1 H of CH2CH), 1.71 (1 H of CH2CH, m) and
1.26 (3 H, t, J 7, Me); δC 172.3 (CO2), 60.8 (OCH2), 59.8 (NCH),
44.6 (CH2), 31.5 (CH2), 30.3 (CH2), 27.1 (CH2), 23.4 (CH2)
and 14.2 (Me); m/z (CI) 172 (M ϩ Hϩ, 100%); m/z (EI) 170
(M Ϫ Hϩ, 6%), 126 (14), 84 (6) and 70 (100).
750; δ 6.57 and 6.36 (1 H, 2 × s, ᎐CH), 5.74 and 5.61 (1 H, 2 ×
᎐
H
s, NH), 5.73 and 4.49 (1 H, 2 × s, NHCH ), 4.14 and 4.10 (2 H,
m, OCH2), 4.041 and 4.042 (2 H, m, OCH2), 1.29 (3 H, d, J 7,
Me), 1.21 and 1.16 (3 H, t, J 7, Me) and 1.14 (3 H, t, J 7, Me);
δC 164.1 and 163.6 (CO2Et), 155.4 (2 × NHCO), 151.7 and
143.4 (᎐CBr), 123.5 and 119.6 (᎐CH), 61.2 and 61.0 (OCH ),
᎐
᎐
2
Preparation of Mosher amides
54.9 and 48.6 (NCH), 20.3 and 19.6 (CHMe), 14.6 (CH2Me)
and 14.2 (CH2Me); m/z 296/294 (81/79Br Ϫ M ϩ Hϩ, 94/94%),
146 (26), 116 (35), 99 (34), 90 (48), 73 (85), 59 (53) and 46 (5).
These derivatives were prepared by a modification of the method
by Mosher and co-workers14 as illustrated by the example
below. In the spectra * denotes the minor diastereomer.
Hydrogenation: preparation of GABA analogues. Ethyl (4S)-
4-aminopentanoate 37. To a solution of ethyl (4S)-4-(benz-
oxycarbonylamino)pent-2-ynoate 21 (80 mg, 0.29 mmol) in
methanol (10 cm3) was added Pd/C catalyst (80 mg) and the
mixture was stirred under a hydrogen atmosphere. After 12 h
the mixture was filtered through a Celite pad and the solvent
removed. Chromatography on silica (methanol–diethyl ether,
2 : 1) gave the pure product (31 mg, 74%) as a yellow oil (Found:
M ϩ Hϩ, 146.1179. C7H15NO2 requires Mϩ H, 146.1181); [α]2D5.5
Ϫ2.5 (c 0.50 in MeOH); νmax/cmϪ1 3400, 1730, 1600, 1505, 1275,
1188 and 1020; δH 7.52 (2 H, br s, NH2), 4.14 (2 H, q, J 7,
OCH2), 3.47 (1 H, m, CH), 2.51 (2 H, t, J 7, COCH2), 2.17 and
1.98 (1 H, 2 × m, CH2), 1.43 (3 H, d, J 5, CHMe) and 1.25
(3 H, t, J 7, OCH2Me); δC 172.7 (CO2), 60.8 (OCH2), 47.8 (CH),
30.4 (COCH2), 29.7 (CH2CH), 18.5 (CHMe) and 14.2 (Me);
m/z (CI) 146 (M ϩ Hϩ, 100%).
Derivative of ethyl (4S)-4-aminopentanoate 37. A solution of
(S)-α-methoxy-α-trifluoromethylphenylacetyl chloride (156 mg,
0.62 mmol) in dry toluene (2 cm3) under a nitrogen atmosphere
was cooled to 0 ЊC. DMAP (76 mg, 0.62 mmol) and 37 (30 mg,
0.21 mmol) in dry toluene (2 cm3) were then added and the
mixture stirred at RT for 2 h. The reaction mixture was recooled
to 0 ЊC and washed successively with 1 M HCl (1 cm3) and
saturated NaHCO3 (1 cm3). The organic phase was dried and
concentrated under vacuum to give the Mosher amide deriv-
ative which was analysed without further purification; δH 7.59
(2 H, m, Ph), 7.50 (3 H, m, Ph), 6.81 and 6.74* (1 H, 2 × d, J 8,
NH), 4.05 (3 H, m, NCH ϩ OCH2), 3.41 and 3.38* (3 H, 2 × q,
J 2, OMe), 2.28 (2 H, m, COCH2), 1.81 (2 H, m, CH2), 1.25
(3 H, t, J 7, OCH2Me) and 1.20 and 1.17* (3 H, 2 × d, J 6,
CHMe); δC 173.3 and 173.2 (CO), 165.83 and 165.78 (CO2),
132.8 and 132.6 (C-1 of Ph), 129.5 (C-4 of Ph), 128.59 and
128.54 (2 C, Ph), 127.72 and 127.65 (2 C, Ph), 124.0 (q, J 290,
CF3), 84.1 (q, J 26, CCF3), 60.6 (OCH2), 54.9 (OMe), 45.4
(NCH), 31.4 and 31.3 (CH2), 31.0 (CH2), 20.85 and 20.77
(CHMe) and 14.2 (OCH2Me); δF Ϫ70.46 and Ϫ70.51*; de =
76%.
( )-Ethyl 4-aminopentanoate. This was prepared as above
using ethyl ( )-4-(benzoxycarbonylamino)pent-2-ynoate, the
racemic analogue of 21 (100 mg, 0.36 mmol) and Pd/C catalyst
(100 mg) to give the title compound (38 mg, 72%) as an oil.
Spectroscopic properties were identical to the non-racemic
compound.
Ethyl (4R)-4-amino-5-methylhexanoate 38. This was pre-
pared as above using ethyl (4S)-4-benzoxycarbonylamino-5-
methylhex-2-ynoate 22 (88 mg, 0.29 mmol) and Pd/C catalyst
(88 mg) to give the title compound (40 mg, 72%) as colourless
crystals, mp 101–102 ЊC (Found: M ϩ Hϩ, 174.1498. C9H19NO2
requires M ϩ H, 174.1494); [α]2D5 ϩ7.2 (c 0.50 in MeOH);
νmax/cmϪ1 3340, 1725, 1640, 1540, 1260, 1180, 1100, 1040 and
800; δH 7.96 (2 H, br s, NH2), 4.13 (2 H, q, J 7, CH2), 3.14 (1 H,
m, NCH), 2.62 (2 H, t, J 7, COCH2), 2.02 (3 H, m, CH ϩ CH2),
1.25 (3 H, t, J 7, OCH2Me), 1.10 (3 H, d, J 5, CHMe) and 1.08
(3 H, d, J 5, CHMe); δC 172.5 (CO2), 60.7 (OCH2), 57.3 (NCH),
30.52 (CH), 30.48 (COCH2), 25.0 (CH2CH), 18.1 (CHMe),
18.0 (CHMe) and 14.2 (OCH2Me); m/z (CI) 174 (M ϩ Hϩ,
100%), 128 (8) and 102 (6).
Derivative of ethyl (4R)-4-amino-5-methylhexanoate 38. This
was prepared as above using 38 to give the Mosher amide
derivative as an oil; δH 7.56 (2 H, m, Ph), 7.40 (3 H, m, Ph), 6.69
and 6.56* (1 H, 2 × br d, J 8, NH), 4.06 (2 H, m, OCH2), 3.82
(1 H, m, CHN), 3.44 and 3.39* (3 H, 2 × q, J 2, OMe), 2.20
(2 H, m, COCH2), 1.84 (2 H, m, CH2), 1.63 (1 H, m, CH), 1.20
(3 H, t, J 7, Me), 0.94 (3 H, d, J 6, CHMe) and 0.92 (3 H, d, J 6,
CHMe); δC 173.6 (CO), 166.4 (CO2), 133.1 (d, J 17, C-1 of Ph),
129.6 (Ph), 128.7 (2 C, d, J 4, Ph), 127.7 (2 C, d, J 5, Ph), 124.0
(q, J 290, CF3), 84.2 (q, J 26, CCF3), 60.6 (OCH2), 55.2 (NCH),
54.2 (OMe), 39.5 (CH), 32.0 (CH2), 29.8 (CH2), 19.0 (CHMe),
17.8 (CHMe) and 14.2 (OCH2Me); δF Ϫ69.68 and Ϫ69.86*;
de = 85%.
540
J. Chem. Soc., Perkin Trans. 1, 2002, 533–541

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4 R. A. Aitken, H. R. Cooper and A. P. Mehrotra, J. Chem. Soc.,
Perkin Trans. 1, 1996, 475.
5 S. A. Abdulganeeva and K. B. Erzhanov, Russ. Chem. Rev., 1991, 60,
676.
Derivative of ethyl (4R)-4-amino-6-methylheptanoate 39. This
was prepared as above 39 to give the Mosher amide derivative
as an oil; δH 7.53 (2 H, m, Ph), 7.31 (3 H, m, Ph), 6.64 (1 H, br s,
NH), 4.07 (3 H, m, CHN and OCH2), 3.39 and 3.38* (3 H, 2 ×
q, J 2, OMe), 2.32 (1 H, m, COCH2), 1.89 (2 H, m, CH2), 1.64
(1 H, m, CH), 1.41 (2 H, m, CH2), 1.21 (3 H, t, J 7, OCH2Me),
0.94 (3 H, d, J 6, CHMe) and 0.92 (3 H, d, J 6, CHMe);
δC 173.99* and 173.86 (CO), 166.3 (CO2), 132.4 (C-1 of Ph),
129.4 (C-4 of Ph), 128.6* and 128.5 (2 C, Ph), 127.6* and 127.4
(2 C, Ph), 123.8* and 123.2 (2 × q, J 288, CF3), 84.1 (q, CCF3,
J 26), 60.8 (OCH2), 55.5 (OMe), 47.6 (NCH), 44.4 (CHCH2),
30.8 (CH2), 30.3 (CH2), 24.9 (CH), 23.0 (CHMe), 22.0 (CHMe)
and 14.1 (OCH2Me); δF Ϫ69.68 and Ϫ69.86*; de >85%.
6 C. Walsh, Tetrahedron, 1982, 38, 871.
7 P. M. Beart and G. A. R. Johnston, Aust. J. Chem., 1972, 25, 1359.
8 A. G. Doutheau, J. Gore and G. Quash, EP 133 407, 1985.
9 B. W. Metcalf, P. Bey, C. Danzin, M. J. Jung, P. Casara and J. P.
Vevert, J. Am. Chem. Soc., 1978, 100, 2551; P. Casara, C. Danzin,
B. W. Metcalf and M. J. Jung, J. Chem. Soc., Chem. Commun., 1982,
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Perkin Trans. 1, 1985, 2201.
10 B. W. Metcalf and P. Casara, Tetrahedron Lett., 1975, 3337; A. B.
Tabor, A. B. Holmes and R. Baker, J. Chem. Soc., Chem. Commun.,
1989, 1025; J. R. Burke and R. B. Silverman, J. Am. Chem. Soc.,
1991, 113, 9329.
11 Preliminary communication: R. A. Aitken and N. Karodia, Chem.
Commun., 1996, 2079.
12 H. H. Wasserman, D. S. Ennis, C. A. Blum and V. M. Rotello,
Tetrahedron Lett., 1992, 33, 6003; H. H. Wasserman, D. S. Ennis,
P. L. Power and M. J. Ross, J. Org. Chem., 1993, 58, 4785.
13 M. T. Reetz, T. J. Strack, J. Kanand and R. Goddard, Chem.
Commun., 1996, 733.
14 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969,
34, 2543; H. Niwa, T. Ogawa, O. Okamoto and K. Yamada,
Tetrahedron, 1992, 48, 10531.
15 M. Smrcina, P. Majer, E. Majerová, T. A. Guerassina and M. A.
Eissenstat, Tetrahedron, 1997, 53, 12867.
Derivative of ethyl (S)-3-(pyrrolidin-2-yl)propanoate 40. This
was prepared as above using 40 to give the Mosher amide
derivative as an oil; δH 7.54 (2 H, m, Ph), 7.34 (3 H, m, Ph), 4.18
(3 H, m, CHN and OCH2), 3.46 (1 H, m, CH), 3.42 (3 H, d,
J <2, OMe), 2.36 (4 H, m), 1.85 (2 H, m), 1.70 (2 H, m), 1.59
(2 H, m) and 1.26 (3 H, t, J 7, Me); δC 173.6 (CO), 164.6 (CO2),
132.3 (C-1 of Ph), 130.6 (Ph), 128.7 (2 C, d, J 4, Ph), 127.9 (2 C,
d, J 5, Ph), 124.1 (q, J 290, CF3), 84.3 (q, J 26, CCF3), 60.8
(OCH2), 58.4 (NCH), 55.4 (OMe), 46.1 (CHCH2), 31.5 (CH2),
28.5 (CH2), 27.5 (CH2), 24.4 (CH2) and 14.2 (Me); δF Ϫ71.96;
de >95%.
16 J.-N. Denis, S. Tchertchian, A. Tomassini and Y. Vallée, Tetrahedron
Lett., 1997, 38, 5503.
17 K. Yamada, M. Takeda and T. Iwakuma, J. Chem. Soc., Perkin
Trans. 1, 1983, 265.
18 M. Bergmann and L. Zervas, Ber. Dtsch. Chem. Ges., 1932, 65, 1192.
19 W. Grassmann and E. Wünsch, Chem. Ber., 1958, 91, 462.
20 A. Hantzsch and W. V. Metcalf, Ber. Dtsch. Chem. Ges., 1896, 29,
1680.
Acknowledgements
We thank EPSRC and GlaxoSmithKline for a CASE student-
ship (T. M.)
21 K. Freudenberg and M. Meister, Liebigs Ann. Chem., 1935, 518,
86.
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