Synthesis of a naturally occurring diene-containing amino acid and its glutamyl dipeptide via N-acyliminium ion chemistry

Article abstract of DOI:10.1002/ejoc.200701016

The syntheses of the naturally occurring unusual unsaturated amino acid (S)-2-amino-3-methylene-4-pentenoic acid and the corresponding γ-glutamyl dipeptide are described. Key steps are an N-acyliminium ion addition using allenylmethylsilane as nucleophile and an enzymatic resolution mediated by the L-aminopeptidase from Pseudomonas putida. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701016

FULL PAPER
DOI: 10.1002/ejoc.200701016
Synthesis of a Naturally Occurring Diene-Containing Amino Acid and Its
Glutamyl Dipeptide via N-Acyliminium Ion Chemistry
[
a]
[a]
[b]
[c]
[a]
Martin Berkheij, Jan Dijkink, Olivier R. P. David, Theo Sonke,
[d]
[d]
Denis R. IJzendoorn, Richard H. Blaauw, Jan H. van Maarseveen,
Hans E. Schoemaker,[ and Henk Hiemstra*
a,c]
[a]
Keywords: Natural products / Dienes / Enzymatic resolutions / Peptides / Allylsilanes
The syntheses of the naturally occurring unusual unsaturated
amino acid (S)-2-amino-3-methylene-4-pentenoic acid and
the corresponding γ-glutamyl dipeptide are described. Key
steps are an N-acyliminium ion addition using allenylmethyl-
silane as nucleophile and an enzymatic resolution mediated
by the -aminopeptidase from Pseudomonas putida.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
L
Introduction
The leaves of the ornamental shrub Philadelphus coro-
narius (Hydrangeaceae) contain a number of unusual amino
acids and glutamylpeptides.[ Among these natural prod-
ucts are the dienic α-amino acid 1a and its γ-glutamylpep-
tide 1b (Figure 1). The dipeptide 1b appeared quite unstable
during the isolation, while the amino acid 1a could not be
isolated at all. Nevertheless, the authors reported the har-
vest of 150 mg of 1b from 4400 g of leaves. The glutamyl
part of dipeptide 1b appeared to have the natural (S)-con-
figuration, but little further information about the proper-
ties of these interesting diene amino acids is available.
The α-amino acid 1a belongs to a fairly large group of
unusual unsaturated linear, branched and cyclic α-amino
1]
acids, which were isolated in recent decades from several
different biological sources.[
1–6]
A limited selection of these
interesting molecules is depicted in Figure 1. Some of these
amino acids also occur as their corresponding γ-glutamyl
dipeptides, like 1b and 4b. Although the exact biological Figure 1. Natural unsaturated α-amino acids.
relevance of these amino acids is unknown they are believed
to play a role in the defence against predators, either as
[7]
toxin or as an intermediary metabolite. For example, hy-
poglycin A and B (4a and 4b in Figure 1)[
3,4,6]
to cause Jamaican vomiting sickness and ultimately
death.
are known
[
7]
The salient feature of 1a,b is the 1,3-diene function which
is expected to make these molecules quite sensitive to acidic
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Nether- and basic conditions. The structural assignment of 1a and
[
a] Van’t Hoff Institute for Molecular Sciences, Faculty of Science,
University of Amsterdam,
lands
1
b is based on scarce spectroscopic data and on the amount
Fax: +31-20-5255670
of hydrogen taken up in a hydrogenation reaction.
Amino acid 1a can be regarded as a tetradehydro deriva-
tive of isoleucine (tdIle). The diene moiety offers a unique
E-mail: hiemstra@science.uva.nl
[
[
[
b] Institute Lavoisier de Versailles, UMR 8180, Université de Ver-
sailles,
Avenue des Etats-Unis, 78035 Versailles Cedex, France
c] DSM Pharmaceutical Products – Advanced Synthesis, Cataly- site for further derivatization, as was already described for
sis & Development,
[8,9]
the homologous diene amino acid.
For a synthesis of 1a
P. O. Box 18, 6160 MD Geleen, The Netherlands
d] Chiralix BV,
one cannot readily rely on the functionalization of glycine
anion equivalents. Instead, a synthesis proceeding via a cat-
P. O. Box 31070, 6503 CB Nijmegen, The Netherlands
914
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 914–924

Diene-Containing Amino Acid and Its Glutamyl Dipeptide
ionic intermediate, i.e. an N-acyliminium ion, seems a more
First, we investigated the racemic synthesis of α-amino
logical option. In view of our expertise in this area and our acid 1a. Protected α-hydroxyglycine 14 was obtained by
desire to investigate the synthesis and properties of diene condensation of methyl carbamate with methyl glyoxylate
[
15]
amino acids of type 1a we undertook this investigation methyl hemiacetal 10
under Dean–Stark conditions in
which is described herein. cyclohexane (Scheme 3). Under these conditions the prod-
N-Acyliminium ion chemistry is a powerful method for uct precipitated from the reaction mixture. Treatment of 14
the formation of C–C bonds,[10,11] and has been intensively with acidic methanol gave the more stable N-acyliminium
studied in our group for many years.[
12,13]
We envisioned ion precursor 15 in 63% yield over two steps (Scheme 3).
[
14,16]
that these tetradehydro-isoleucine (tdIle) derivatives could Coupling of allene 6
with 15 was performed in acetoni-
be prepared using a method developed earlier in our group, trile at 0 °C, using BF ·OEt as the Lewis acid providing
3
2
using allenylmethylsilane 6 as a nucleophile in a reaction the desired α-diene amino acid 16 in 87% yield.
[
14]
with a glycine derived N-acyliminium ion 5 (Scheme 1).
Next, the consecutive liberation of the acid and the
In this article we report the first total syntheses of 1a and 1b amine group was studied. Saponification of the methyl ester
employing this strategy. In addition we detail the enzymatic using LiOH in aqueous THF gave free acid 18 in 97% yield.
resolution of the diene amino acid 1a.
Gratifyingly, no double bond isomerization was observed
under these conditions. Curious to know which circum-
stances would lead to isomerization, we added a catalytic
amount (ca. 15%) of DBU to a solution of 16 in dichloro-
methane. In this way the expected conjugated diene amino
acids 19a and 19b were obtained as a 1:1 mixture in quanti-
tative yield. Removal of the methoxycarbonyl (Moc) group
in 16 by using trimethylsilyl iodide (TMSI) in acetonitrile
provided free amine 17, albeit in a disappointing 37% yield.
Possibly, simultaneous with the nitrogen liberation, the ester
[
17]
is also cleaved via a similar mechanism.
This trouble-
some Moc-removal prompted us to follow a different pro-
tective group strategy.
Scheme 1.
We therefore turned our focus to a Boc-protection strat-
egy, because this would allow an orthogonal deprotection
of the amine and the acid moieties. So we prepared Boc-α-
hydroxyglycine methyl ester 20 (79%, Scheme 4) using the
Results and Discussion
The retrosynthetic approach towards pseudodipeptide 1b same strategy as used for the synthesis of 14. However, con-
is illustrated in Scheme 2. We distinguished two options for version of 20 into its α-methoxy derivative using a catalytic
its synthesis, namely via an N-acyliminium ion reaction of amount of sulfuric acid in methanol resulted in partial loss
allenylmethylsilane 6 with γ-glutamyl dipeptide 8 (route A, of the Boc protective group.
Scheme 2) or by carrying out a peptide coupling between
Therefore, we decided to use the acetoxy group as an
the suitably protected glutamic acid 11 and diene 12 (route improved leaving group. The acetate was introduced by stir-
B). Dipeptide 8 was expected to arise from condensation of ring of 20 in acetic anhydride in the presence of a catalytic
suitably protected glutamine 9 with hemiacetal 10. Conden- amount of pyridine, providing 21 in 92% yield. Initial
sation of 10 with a simple carbamate or amide of choice attempts to couple 21 with allenylmethylsilane 6 under the
should lead to N,O-acetal 13, the precursor for the prepara- same conditions as used previously for the synthesis of 16,
tion of the protected diene amino acid 12.
led to a substantial BF ·OEt induced loss of the Boc group
3 2
Scheme 2.
Eur. J. Org. Chem. 2008, 914–924
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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915

H. Hiemstra et al.
FULL PAPER
Scheme 3.
Scheme 4.
from both 21 and 22. Therefore, the temperature was low- (Scheme 4). After saponification of the methyl ester using
ered to –78 °C and dichloromethane was used as the sol- LiOH (23, 95%) and subsequent Boc-removal (90%), race-
vent. At this low temperature no reaction was observed and mic 2-amino-3-methylene-4-pentenoic acid (1a) was iso-
the reaction mixture was warmed-up slowly while closely lated. Using this sequence, natural product 1a was obtained
monitoring the reaction by TLC. These reaction conditions as a racemic TFA-salt in 53% yield over 5 steps (Scheme 4).
1
provided the desired 22 in 86% yield as a crude product The H NMR spectrum and TLC-properties were in agree-
[
1]
containing some impurities as judged from TLC and NMR ment with those reported in the literature. With the race-
spectroscopy. Attempts to purify 22 by column chromatog- mic product in hand we focussed on the synthesis of the
raphy resulted in considerable loss of material, most proba- pure enantiomers.
bly due to polymerization.[
18]
In order to gain access to enantiopure 1a, we carried out
[
19]
®
Thus, crude 22, containing only minor amounts of impu- an enzymatic resolution on 16, using the lipase Alcalase
rities, was used without further purification in the next step (Novozymes Alcalase 2.5 L DX, Scheme 5).
[
20,21]
Prelimi-
Scheme 5.
16
9
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 914–924

Diene-Containing Amino Acid and Its Glutamyl Dipeptide
Scheme 6.
nary experiments showed that (S)-16 was selectively con-
verted into its free acid (S)-18 whereas the (R)-ester 16 re-
[
22]
mained untouched as monitored by chiral HPLC
(Scheme 5). When the reaction was stopped at 39% conver-
sion, (S)-18 could be isolated in 13% yield with Ͼ99% en-
antiomeric excess (ee). The (R)-enriched methyl ester 16 was
recovered in 30% yield and 31% ee. These small-scale ex-
periments also showed that after 45% conversion the ee of
acid 18 dropped, indicating that the enzyme is not com-
pletely enantioselective.
Therefore, we turned our attention to the -aminopeptid-
ase PepA from Pseudomonas putida, which is known to hy-
drolyze α-amino amides with high (S)-selectivity.[ As it
requires amino amides as substrates, acid 23 was converted
Figure 2. Resolution of 25 by P. putida -aminopeptidase.
23]
into its corresponding amide 24 via the mixed anhydride replaced by CHCl for solubility reasons. However, when
3
method (Scheme 6) using, successively, N-methylmorph- the N-acyliminium ion reaction was performed under the
oline/isobutyl chloroformate and ammonia[ in 76% yield. same conditions as used in the synthesis of amino acid 22,
Boc removal provided amino amide 25 (97%) as the sub- dipeptide 28 was isolated as a ca. 1:1 mixture of dia-
strate for the enzymatic resolution. In a small scale experi- stereomers in a disappointing 25% yield. The reaction
ment the -aminopeptidase from P. putida appeared to be showed slow conversion, but raising the temperature re-
completely selective, as even 15 h after reaching 50% con- sulted in partial Boc deprotection and the use of other
version, the ee of the product remained Ͼ99% (Figure 2). Lewis acids did not improve the yield either. Furthermore,
The actual aminopeptidase mediated resolution was per- 28 was quite unstable. Aiming at a diastereoselective syn-
formed using a known procedure,[ but separation of the thesis we then decided to synthesize 1b by using the dipep-
product and starting material via the Schiff base of benzal- tide coupling approach (route B, Scheme 2).
dehyde proved to be tedious. The (R)-amino amide (R)-25
24]
23]
(partly) racemized in the Schiff-base stage, but fortunately
(S)-amino acid 1a could be isolated in a satisfying 38%
yield (75% based on one enantiomer). Thus, the (S)-enantio-
mer of the naturally occurring 2-amino-3-methylene-4-
pentenoic acid (S)-1a has been synthesized in 17% yield
over 7 steps. With the enantiopure diene amino acid in
hand, we aimed for the synthesis of the natural glutamyl
dipeptide 1b.
Synthesis of the iminium ion precursor 27 (Scheme 7) to
allow for the N-acyliminium ion reaction in the dipeptide
(
route A, Scheme 2) was straightforward. Thus, condensa-
tion of methyl glyoxylate methyl hemiacetal 10 with N-Boc-
S)-glutamine methyl ester 9 (readily available from N-Boc-
(
glutamine by esterification with trimethylsilyldiazometh-
ane) gave suitably protected γ-glutamyl hydroxyglycine 26
(58%), which was readily converted into the acetoxy deriva-
tive 27 in 97% yield. For the condensation, cyclohexane was Scheme 7.
Eur. J. Org. Chem. 2008, 914–924
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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917

H. Hiemstra et al.
FULL PAPER
Synthesis of the dipeptide via a peptide coupling ap-
proach was first tested on racemic allylglycine (Scheme 8)
using the mixed anhydride method which was also used for
the synthesis of 24 (Scheme 6). Commercially available al-
lylglycine was first converted into its corresponding methyl
[25]
ester using SOCl in MeOH. An aqueous solution of al-
2
lylglycine methyl ester was added to the mixed anhydride of
IBC and Boc-Glu-OMe (11) to yield the desired dipeptide
29 in 46% yield and an expected 1:1 ratio of diastereomers
(Scheme 8). An EDC/HOBt mediated peptide coupling
gave 29 in 39% yield. After saponification of 29 by LiOH
to give di-acid 30 and TFA-mediated Boc removal (both Scheme 9.
84%) γ-glutamyl dipeptide 31 was obtained in 32% yield
over 5 steps.
tide. Di-ester 28 was readily saponified to 33 in 80% yield,
followed by Boc removal (93%) to give the desired natural
product 1b and its epimer as a 1:1 mixture of diastereomers
in an overall yield of 23% over 7 steps.
The same sequence was repeated for de synthesis
of (S,S)-γ-glutamyl-2-amino-3-methylene-4-pentenoic acid
(S,S)-1b. Therefore, (S)-32 was prepared via a protection/
deprotection strategy (Scheme 9). First, a Boc-group was
installed on the amine, followed by treatment of the re-
sulting acid (S)-23 with trimethylsilyldiazomethane to ar-
rive at methyl ester (S)-22 in 72% yield over two steps.
Amine liberation using TFA/CHCl (1:1) gave the desired
3
TFA salt (S)-32. Now, subjection of (S)-32 to the coupling
conditions as used for the coupling of rac-32 with 9
(
Scheme 10) gave (S,S)-28 in a satisfying 67% yield over
two steps.
Finally, both saponification and Boc-removal of (S,S)-28
Scheme 8.
Now the stage was set for the synthesis of the naturally proceeded smoothly, providing the desired dipeptide (S,S)-
1
occurring dipeptide 1b. As the derivatives of 1,3-butadiene- 1b in 98% yield over two steps. The H-NMR spectrum and
containing amino acids already proved to be more difficult TLC-properties were in agreement with those reported in
to handle than, e.g., allylglycine (most probably caused by literature, and therefore we could confirm the proposed
3
4
the C =C bond, Figure 1), we decided to synthesize 1b first structure of (S,S)-γ-glutamyl-2-amino-3-methylene-4-pen-
by using racemic tdIle. TFA-mediated N-Boc deprotection tenoic acid 1b. This naturally occurring 1,3-diene-contain-
of rac-22 delivered our diene-methyl ester TFA salt 32 in ing γ-glutamyl dipeptide was synthesized in a stereoselective
90% yield (Scheme 9). Subsequent coupling with Boc-Glu- manner in 7.9% overall yield in 13 steps, starting from tert-
OMe 11 via the mixed anhydride method using NaHCO3 butyl carbamate. Unfortunately, due to the limited availabil-
to liberate the amine of 32 gave the desired dipeptide 28 in ity of physical and spectroscopic data, and the absence of a
56% yield (Scheme 10). Other coupling conditions (NMM/ sample of the original isolate, we were not able to deduce
IBC/DIPEA, HATU/DIPEA, EDC/HOBt/DIPEA or the absolute configuration of both the amino acid and di-
PyBop/DIPEA) all resulted in a lower yield of the dipep- peptide natural products.
Scheme 10.
918
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 914–924

Diene-Containing Amino Acid and Its Glutamyl Dipeptide
Cl
TDM 6.2 g/AcOH 25 mL/H
50 mL. Solution C: ninhydrine 0.6 g/AcOH 20 mL/H
2
/TDM (for the visualisation of amides on TLC): Solution A:
O 125 mL. Solution B: KI 12.5 g/H
O 180 mL.
Conclusions
2
2
O
In summary, rac-2-amino-3-methylene-4-pentenoic acid
2
2
(
tdIle) has been synthesized in 53% yield (5 steps) starting TDM solution: A:B:C = 30:50:0.75. Cl2 source: Ca(OCl) . Use:
2
from tert-butyl carbamate using allenylmethylsilane as nu- Place TLC 1 min in jar filled with a 2-cm layer of Ca(OCl) . Re-
2
2
cleophile in the addition to a glycine-derived N-acylimi- move TLC from jar and blow off excess Cl with cold air. Then dip
TLC in TDM solution and warm gently. Brown/green spots should
appear on a slightly blue background. When plate is completely
blue without spots: blow off Cl longer or refresh TDM solution.
2
When plate is covered with black spots: remove free Si particles
from TDM solution via filtration.
nium ion. We were able to confirm the structure of the com-
pound containing an α-diene moiety as proposed by
Campos et al. Both enantiomers of the amino acid were
separated via an enzymatic kinetic resolution catalyzed by
the -aminopeptidase PepA from P. putida, and (S)-tdIle
was isolated in 38% yield (75% based on one enantiomer) Methyl 2-Hydroxy-2-(methoxycarbonylamino)acetate (14):
A
5
0
0
00 mL flask containing a suspension of methyl carbamate (55 g,
and Ͼ 99% ee. Separation and isolation of the (S)-amino
acid and (R)-amino amide proved to be difficult and needs
further optimalization. (S)-2-amino-3-methylene-4-pen-
tenoic acid has been synthesized in 17% overall yield (7
steps).
.732 mol) and methyl glyoxylate methyl hemiacetal (96.8 g, 80 mL,
.806 mol) in cyclohexane (300 mL, HPLC grade) was equipped
with a Dean Stark apparatus. The suspension was stirred vigor-
ously at reflux for 15 h, followed by refrigeration until completely
frozen. After the solvent had melted again it was decanted and the
viscous crude product was carefully dried under high vacuum while
heated in a water bath at 55 °C. After cooling down at room tem-
Further, (S,S)-γ-glutamyl-2-amino-3-methylene-4-pen-
tenoic acid was synthesized via a peptide coupling of (S)-2-
amino-3-methylene-4-pentenoic methyl ester and Boc glu- perature, the crude hydroxyglycine 14 was obtained as a white solid
tamic acid methyl ester in 7.9% (15.5% based on one en- and was used as such in the following step. (spectroscopic data
antiomer) over 13 steps (starting from tert-butyl carba- identical to those reported in the literature).[
26]
1
H
NMR
): δ = 5.88 (br. s, 1 H), 5.46 (br. d, J = 7.6 Hz, 1
H), 4.86 (br. d, J = 7.6 Hz, 1 H), 3.85 (s, 3 H), 3.73 (s, 3 H) ppm.
(
400 MHz, CDCl
3
mate). The diastereomeric dipeptide was prepared in 23%
over 7 steps (starting from tert-butyl carbamate). N-acylimi-
nium ion chemistry in the γ-glutamyl dipeptide is still
troublesome, and is currently under further investigation.
–
1
IR (neat): ν˜ = 3344, 2959, 1719, 1528, 1447, 1231, 1055 cm .
(EtOAc) = 0.38.
R
f
Methyl 2-Methoxy-2-(methoxycarbonylamino)acetate (15): Crude
4 was dissolved in methanol (200 mL) and the solution was cooled
to 0 °C. Trimethyl orthoformate (50 mL) was added followed by
neat H SO (0.2 mL). The mixture was warmed to room tempera-
ture and stirred for 15 h. Then a saturated aqueous NaHCO3 solu-
tion (10 mL) was added under vigorous stirring and left for 15 min
when solid NaHCO was added to “quench” the water. The mix-
3
ture was filtered through a pad of neutral alumina (2 cm), which
was washed with more methanol. The volatiles were removed in
1
Experimental Section
General Remarks: Unless stated otherwise, chemicals were pur-
chased from commercial suppliers and used as such. Methyl glyox-
ylate methyl hemiacetal was kindly donated by DSM, Linz, Aus-
tria. Dichloromethane and acetonitrile were freshly distilled from
calcium hydride. Tetrahydrofuran was freshly distilled from sodium
using benzophenone as indicator. All reactions were carried out
under an inert atmosphere of dry nitrogen, unless stated otherwise.
Column chromatography was performed using Biosolve silica gel
2
4
2
vacuo and while the viscous product was still warm, Et O (300 mL)
was added leading to a clear solution. The solution was cooled
to –18 °C and then left standing overnight, providing the impure
methoxyglycine as a white solid. The compound was filtered,
f
(230–460 mesh, 60 Å). R values were obtained by using Thin Layer
Chromatography (TLC) on silica gel coated alumina sheets (Merck
silica gel 60 F254) with indicated solvents. Compounds were visual-
ised by UV and/or exposure to KMnO
2 2
washed with diethyl ether and redissolved in CH Cl (200 mL) and
cooled to –18 °C for another night. The precipitate (14) was filtered
and the filtrate was concentrated in vacuo to give 15 (82 g, 0.463
mol, 63% over two steps) as an off-white oil which crystallized
4 2
, ninhydrine, or Cl /TDM
(see below). Infrared spectra were recorded on a Bruker IFS 28
or a Shimadzu FTIR-8400S spectrophotometer. Nuclear magnetic
resonance (NMR) data were obtained on a Bruker ARX 400,
Bruker Avance 400 or a Varian Inova-500. Spectra are reported in
units of ppm on the δ scale, relative to the solvent used. When a
diastereomeric mixture of products was obtained, all relevant
NMR signals for the mixture are given. Mass spectra were mea-
sured using a JEOL JMS SX/SX102A four-sector mass spectrome-
ter, coupled to a JEOL MS-MP7000 data system. Melting points
were determined on a Wagner & Munz Polytherm A and are uncor-
rected. Optical rotations were measured on a Perkin–Elmer 241
polarimeter.
1
upon standing as transparent needles. H NMR (400 MHz,
CDCl
H), 3.73 (s, 3 H), 3.46 (s, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 168.07, 156.38, 80.62, 55.98, 52.75, 52.54 ppm. IR
neat): ν˜ = 3356, 2956, 2835, 1736, 1524, 1441, 1342, 1220, 1057,
3
): δ = 5.90 (br. s, 1 H), 5.33 (br. d, J = 7.6 Hz, 1 H), 3.82 (s,
1
3
3
3
(
–
1
+
1
1
0
000, 901 cm . HRMS(FAB): calcd. for [C
6
H
11NO
5
+ H] :
78.0715, found: 178.0715; m.p. 33–35 °C, R
f
(PE/EtOAc, 1:1) =
.43.
Methyl 2-(Methoxycarbonylamino)-3-methylenepent-4-enoate (16):
To a stirred solution of 15 (1.50 g, 8.47 mmol) in acetonitrile
(45 mL) at 0 °C was added allenylmethyltrimethylsilane 6 (1.60 g,
Abbreviations: DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA
=
diisopropylethylamine, EDC = 1-[3-(dimethylamino)propyl]-
3 2
12.7 mmol), followed by the drop wise addition of BF ·OEt
3
-ethylcarbodiimide, HATU O-(7-azabenzotriazol-1-yl)-
=
(1.60 mL, 12.7 mmol). The reaction was stirred at 0 °C for 3 h after
N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate, HOBt = 1-
hydroxybenzotriazole, IBC = isobutyl chloroformate, NMM = N-
methylmorpholine, PyBop = (benzotriazol-1-yloxy)tripyrrolidino-
phosphonium hexafluorophosphate, TDM = 4,4Ј-methylenebis-
which period the yellow solution was poured on a saturated aque-
ous NaHCO
layer was washed with brine, dried with Na
3
solution and extracted with EtOAc (3ϫ). The organic
SO , filtered, and con-
2
4
centrated in vacuo to afford a yellow oil. Purification by column
(N,NЈ-dimethylaniline).
chromatography (PE/EtOAc, 3:1) afforded 16 (1.47 g, 7.37 mmol,
Eur. J. Org. Chem. 2008, 914–924
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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919

H. Hiemstra et al.
FULL PAPER
1
8
(
(
7%) as a colorless oil which solidified upon standing. H NMR
400 MHz, CDCl ): δ = 6.32 (dd, J = 17.7, J = 11.2 Hz, 1 H), 5.44
d, J = 17.7 Hz, 1 H), 5.41 (br. d, J = 8.8 Hz, 1 H), 5.30 (s, 1 H),
oic Acid [(S)-18]: To a stirred solution of 16 (0.109 g, 0.547 mmol)
in H
2
O/tBuOH (5 mL/0.3 mL) was added Alcalase® (Novozymes
3
2.5 l DX, PLN 04810; 50 µL). After stirring at room temperature
for 24 h, 1 mL of enzyme was added and the mixture was heated
at 37 °C for 6.5 h when aqueous HCl (10 mL, 1 ) was added. The
mixture was extracted with EtOAc (3ϫ) and the organic layer was
5
3
=
.23 (s, 1 H), 5.19 (d, J = 11.2 Hz, 1 H), 5.12 (d, J = 8.8 Hz, 1 H),
.75 (s, 3 H), 3.69 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl
): δ
171.23, 155.97, 141.69, 134.93, 118.69, 115.69, 54.89, 52.53, 52.25
3
–
1
ppm. IR (neat): ν˜ = 3333, 2954, 1719, 1523, 1206, 1060 cm .
2 4
washed with brine, dried with Na SO , filtered, and concentrated
+
HRMS(EI): calcd. for [C
(PE/EtOAc, 1:1) = 0.61.
9
H13NO
4
] : 199.0845, found: 199.0832; in vacuo. The crude brownish oil was purified by column
chromatography (PE/EtOAc/AcOH, 2:1:0.01) to yield (R)-16 in the
R
f
first fraction as a colorless oil (24 mg, 0.121 mmol) in 22%. In the
Methyl 2-Amino-3-methylenepent-4-enoate (17): In an oven dried
0 mL flask, 16 (0.253 g, 1.27 mmol) was dissolved in dry acetoni-
trile (25 mL). The solution was degassed (three vacuum-argon bal-
loon cycles) and kept under an argon atmosphere. Then at room
temperature, of iodotrimethylsilane (1 g, 725 µL, 5.09 mmol) was
added in one portion, and the solution was stirred for 1 h. The
second fraction, (S)-18 was isolated as a colorless oil (19 mg,
.103 mmol) in 19%.
5
0
Data for (R)-16: Identical to rac-16. [α]1 = –39.0 (c = 0.4, MeOH)
9
D
Data for (S)-18: Identical to rac-18; ee 99% (HPLC), [α]1
c = 0.3, MeOH).
9
= +58.7
D
(
mixture was poured on a 5% aqueous NaHSO
tracted CH Cl
(3ϫ) (be aware of emulsion formation). The aque- Methyl 2-(tert-Butoxycarbonylamino)-2-hydroxyacetate (20):
ous fase was basified until pH 9 with solid K CO and extracted
mixture of tert-butyl carbamate (13.54 g, 0.116 mol) and methyl
with CH Cl (5ϫ). The combined organic layer was dried with
Na SO filtered and concentrated in vacuo at room temperature
to prevent diketopiperazine formation) to afford 56 mg of the
crude amino-ester 17, which was used as such in the next reaction.
4
solution and ex-
A
2
2
2
3
glyoxylate methyl hemiacetal (15.27 g, 12.66 mL, 0.127 mol) in cy-
clohexane (150 mL) was refluxed in a Dean Stark apparatus for
15.5 h. After cooling to room temperature a yellow oil was formed
on the bottom of the flask, which solidified upon standing over-
2
2
2
4
(
1
H NMR (400 MHz, CDCl
3
): δ = 6.34 (dd, J = 17.7, 11.2 Hz, 1 night. The precipitate was collected by filtration and washed twice
H), 5.42 (d, J = 17.7 Hz, 1 H), 5.25 (s, 1 H), 5.21 (s, 1 H), 5.17 (d,
J = 11.2 Hz, 1 H), 4.33 (s, 1 H), 3.74 (s, 3 H), 2.31 (br. s, 2 H)
with cyclohexane yield 20 as a white solid (18.68 g, 91.0 mmol,
1
3
78.5%). H NMR (400 MHz, CDCl ): δ = 5.73 (br. s, 1 H), 5.44
ppm. 13C NMR (100 MHz, CDCl
): δ = 174.17, 145.07, 135.56, (br. s, 1 H), 3.84 (s, 3 H), 3.78 (br. s 1 H), 1.46 (s, 9 H) ppm. 13
C
3
1
1
16.79, 114.98, 55.89, 52.16 ppm. IR (neat): ν˜ = 3373, 2953, 1739, NMR (100 MHz, CDCl
3
): δ = 170.12, 155.02, 81.02, 73.23, 53.02,
–1
f
595, 1436, 1201, 993, 909 cm . R (EtOAc/MeOH, 2:1) = 0.17.
28.19 ppm. IR (neat): ν˜ = 3373, 2981, 1714, 1516, 1442, 1369, 1252,
–
1
1
159, 1056, 913, 856 cm . HRMS(FAB): calcd. for [C
8
H15NO
5
+
2
-(Methoxycarbonylamino)-3-methylenepent-4-enoic Acid (18): To a
+
H] : 206.1028, found: 206.1027; R
f
(PE/EtOAc, 1:1) = 0.31.
stirred solution of 16 (0.100 g, 0.502 mmol) in THF (3 mL) at 0 °C
was added drop wise a solution of LiOH (18 mg, 0.753 mmol) in
Methyl 2-Acetoxy-2-(tert-butoxycarbonylamino)acetate (21):
A
H
2
O (3 mL). The slight yellow mixture was stirred at 0 °C for 3 h
when it was poured on 5% KHSO and extracted with EtOAc
3ϫ). The organic layer was washed with brine, dried with Na SO
filtered, and concentrated in vacuo to yield 18 (91 mg, 0.491 mmol,
solution of 20 (25.55 g, 0.125 mol) and pyridine (0.30 mL,
3.71 mmol) in Ac O (150 mL) was stirred for 19 h. Volatiles were
co-evaporated with toluene (3ϫ) to give 21 as a yellow oil (30.89 g,
4
2
(
2
4
,
1
0.125 mmol, 99%). H NMR (400 MHz, CDCl
3
): δ = 6.22 (br. s, 1
1
98%) as a slight yellow oil. H NMR (400 MHz, MeOD): δ = 6.42
H), 5.92 (br. s, 1 H), 3.81 (s, 3 H), 2.11 (s 3 H), 1.46 (s, 9 H) ppm.
1
3
(
(
3
ddd, J = 0.4, 11.1, 17.6 Hz, 1 H), 5.44 (d, J = 17.7 Hz, 1 H), 5.34
s, 1 H), 5.28 (s, 1 H), 5.19 (d, J = 11.1 Hz, 1 H), 5.04 (s, 1 H),
3
C NMR (100 MHz, CDCl ): δ = 170.26, 167.09, 153.94, 81.25,
74.30, 53.11, 28.08, 20.63 ppm. IR (neat): ν˜ = 3358, 2980, 1730,
.67 (s, 3 H) ppm. 13C NMR (100 MHz, MeOD): δ = 172.62,
–1
1511, 1439, 1371, 1231, 1159, 1030, 859 cm . HRMS(FAB): calcd.
+
157.50, 142.40, 135.78, 117.64, 114.20, 54.73, 51.36 ppm. IR (neat):
for [C10
H17NO
6
+ H] : 248.1134, found: 248.1135; R
f
(PE/EtOAc,
–1
ν˜ = 3314, 2960, 2360, 1716, 1521, 1061, 913 cm . HRMS(FAB): 1:1) = 0.60.
+
calcd. for [C
EtOAc, 1:1) = 0.61.
8 4 f
H11NO + H] : 186.0766, found: 186.0762; R (PE/
Methyl
2-(tert-Butoxycarbonylamino)-3-methylenepent-4-enoate
(
22): To a stirred solution of 21 (1.50 g, 6.07 mmol) and allenyltri-
[14,16]
Methyl 2-(Methoxycarbonylamino)-3-methylpenta-2,4-dienoate (19):
To a solution of 16 (0.200 g, 1.00 mmol) in CH Cl was added
DBU (25 µL, 0.167 mmol) and the yellow mixture was stirred at
room temperature for 69 h when it was poured into 5% KHSO
and extracted with EtOAc (3ϫ). The organic layer was washed with
brine, dried with Na SO , filtered, and concentrated in vacuo to
yield 19 as a 1:1 mixture of (E,Z)-isomers in 99% yield (0.200 g,
methylsilane
(1.53 g, 1.21 mmol) in CH
2 2
Cl (30 mL) at –78 °C
was added slowly BF
3
·OEt (1.53 mL, 1.21 mmol). The resulting
2
2
2
yellow reaction mixture was warmed slowly to –20 °C, carefully
monitored by TLC (PE/EtOAc, 2:1). After 4 h the solution was
4
poured onto a saturated aqueous NaHCO
with EtOAc (3ϫ). The organic layer was washed with brine, dried
with Na SO , filtered, and concentrated in vacuo to give crude 22
.00 mmol). H NMR (400 MHz, MeOD): δ = 7.17 (dd, J = 11.0, in 1.26 g as a yellow oil. A small sample was purified by column
3
solution and extracted
2
4
2
4
1
1
1
1
0
2
1
7.3 Hz, 0.5 H), 6.84 (dd, J = 10.9, 17.3 Hz, 0.5 H), 5.63 (d, J =
chromatography (PE/EtOAc, 4:1) for analysis. H NMR (400 MHz,
): δ = 6.32 (dd, J = 11.3, 17.9 Hz, 1 H), 5.46 (d, J = 17.7 Hz,
7.4 Hz, 0.5 H), 5.54 (d, J = 17.3 Hz, 0.5 H), 5.43 (d, J = 10.9 Hz, CDCl
3
.5 H), 5.30 (d, J = 11.0 Hz, 0.5 H), 3.76 (s, 3 H), 3.70 (s, 3 H),
.10 (s, 1.5 H), 1.94 (s, 1.5 H) ppm. C NMR (100 MHz, MeOD):
1 H), 5.28 (s, 1 H), 5.24 (m, 2 H), 5.19 (d, J = 11.3 Hz, 1 H), 5.08
13
13
(d, J = 7.7 Hz, 1 H), 3.75 (s, 3 H), 1.44 (s, 9 H) ppm. C NMR
δ = 166.14, 165.43, 156.32, 155.95, 135.73, 134.86, 134.71, 133.36, (100 MHz, CDCl
3
): δ = 170.86, 157.64, 142.09, 135.27, 118.53,
1
1
25.60, 125.06, 123.96, 118.35, 116.78, 51.42, 50.91, 50.83, 12.37,
2.22 ppm. IR (neat): ν˜ = 2955, 1722, 1452, 1383, 1236, 1065, 921 1714, 1504, 1441, 1369, 1251, 1160, 1057, 916, 856 cm .
115.78, 80.03, 53.22, 53.04, 28.19 ppm. IR (neat): ν˜ = 3364, 2980,
–
1
–1
+
+
cm . HRMS(FAB): calcd. for [C
9
H13NO
4
+ H] : 200.0923, found:
HRMS(FAB): calcd. for [C12
4
H19NO + H] : 242.1392, found:
2
00.0926; R (PE/EtOAc, 1:1) = 0.50.
f
242.1405; R (PE/EtOAc, 2:1) = 0.70.
f
(
R)-Methyl 2-(Methoxycarbonylamino)-3-methylenepent-4-enoate
(S)-Methyl 2-(tert-Butoxycarbonylamino)-3-methylenepent-4-enoate
[(S)-22]: To a stirred solution of crude (S)-23 (63 mg) in MeOH/
[(R)-16] and (S)- 2-(Methoxycarbonylamino)-3-methylenepent-4-en-
920
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 914–924

Diene-Containing Amino Acid and Its Glutamyl Dipeptide
benzene (2 mL, 1:1) under an argon atmosphere was added drop
wise TMS-diazomethane (2  in hexanes, ca. 0.25 mL) until the
yellow color persisted. After stirring at room temperature for
tered, and concentrated in vacuo to give a yellowish solid which
was purified by column chromatography (PE/EtOAc, 1:2) to give
24 as a white powder (1.23 g, 5.46 mmol, 76%). H NMR
1
30 min, 5% AcOH/MeOH (1 drop) was added until the yellow
3
(400 MHz, CDCl ): δ = 6.37 (dd, J = 11.2, 17.8 Hz, 1 H), 5.91 (br.
color disappeared. Solid NaHCO was added and the reaction mix-
ture was concentrated in vacuo. The residue was purified by col-
umn chromatography (PE/EtOAc, 5:1, column rinsed with 2%
3
s, 1 H), 5.62 (br. s, 1 H), 5.57 (br. s, 1 H), 5.47 (d, J = 17.8 Hz, 1
H), 5.38 (m, 2 H), 5.24 (d, J = 11.2 Hz, 1 H), 4.97 (br. d, J =
4.9 Hz, 1 H), 1.46 (s, 9 H) ppm. C NMR (100 MHz, CDCl ): δ
3
1
3
Et
colorless oil. H NMR (400 MHz, CDCl
7.7 Hz, 1 H), 5.46 (d, J = 17.7 Hz, 1 H), 5.29 (s, 1 H), 5.26 (m, 1
H), 5.24 (s, 1 H), 5.20 (d, J = 11.1 Hz, 1 H), 5.09 (d, J = 8.0 Hz, 1
H), 3.76 (s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl
):
δ = 171.67, 154.96, 142.18, 135.28, 118.54, 115.81, 80.18, 54.73,
3
N) to give (S)-22 (26 mg, 0.11 mmol, 73% over 2 steps) as a
= 172.39, 155.29, 142.98, 135.39, 119.06, 115.94, 80.13, 55.92, 28.30
1
–1
3
): δ = 6.33 (dd, J = 11.1,
ppm. IR (neat): ν˜ = 3329, 2979, 1680, 1503, 1251, 1167, 914 cm .
+
1
HRMS(FAB): calcd. for [C11
227.1388; R (EtOAc) = 0.43.
H
18
N
2
O
3
+ H] : 227.1396, found:
f
3
2-Amino-3-methylenepent-4-enamide, TFA Salt (25): To a stirred
solution of 24 (2.68 g, 11.8 mmol) in CHCl (25 mL) was added
3
5
1
2.61, 28.29 ppm. IR (neat): ν˜ = 2978, 1749, 1706, 1491, 1368,
157 cm . HRMS(FAB): calcd. for [C12H19NO + H] : 242.1392,
4
–1
+
TFA (25 mL). The resulting yellow solution was stirred at room
temperature for 30 min when it was co-evaporated with toluene
found: 242.1396.
-(tert-Butoxycarbonylamino)-3-methylenepent-4-enoic Acid (23):
To a stirred solution of crude 21 (2.0 g, 8.29 mmol) in THF
100 mL) at 0 °C was added drop wise a solution of LiOH (0.596 g,
4.9 mmol) in H O (100 mL). The slight yellow mixture was stirred
at 0 °C for 4 h when it was poured on 5% KHSO and extracted
with EtOAc (3ϫ). The organic layer was washed with brine, dried
with Na SO , filtered, and concentrated in vacuo to yield 18 in
5% (1.78 g, 7.84 mmol) as a yellow oil. H NMR (400 MHz,
(
1
3ϫ) to afford 25 as an off-white solid in 97% yield (2.75 g,
2
1
1.4 mmol). H NMR (500 MHz, D
2
O): δ = 6.33 (dd, J = 11.2,
1
7.8 Hz, 1 H), 5.55 (s, 1 H), 5.41 (s, 1 H), 5.36 (d, J = 17.8 Hz, 1
(
13
H), 5.23 (d, J = 11.2 Hz, 1 H), 4.77 (s, 1 H) ppm. C NMR
100 MHz, D O): δ = 170.13, 163.09 (q), 138.08, 133.55, 122.79,
2
2
(
1
1
2
–
4
16.67, 53.37 ppm. CF
601, 1516, 1395, 1143, 930, 840 cm . HRMS(FAB): calcd. for
3
COO not observed. IR (neat): ν˜ = 1660,
–1
+
2
4
6 10 2
[C H N
O + H] : 127.0871, found: 127.0871.
1
9
(
S)-2-Amino-3-methylenepent-4-enoic Acid [(S)-1a]: To a suspension
3
CDCl ): δ = 9.42 (br. s, 1 H), 6.37 (dd, J = 11.2, 17.6 Hz, 1 H),
of racemic amide-TFA salt 25 (0.731 g, 3.04 mmol) in water (3 mL)
was added drop wise an aqueous KOH solution until pH 9. A
5
.50 (d, J = 17.6 Hz, 1 H), 5.33 (s, 2 H), 5.21 (m, 1 H), 5.12 (d, J
1
3
=
7.4 Hz, 1 H), 4.91 (d, J = 4.4 Hz, 1 H), 1.45 (s, 9 H) ppm.
): δ = 174.95, 154.95, 141.73, 135.05,
18.67, 115.80, 80.26, 54.55, 28.12 ppm. IR (neat): ν˜ = 3311, 2979,
C
4
80 mmol/L solution of MnSO (88 µL, 0.007 mmol) was added and
NMR (100 MHz, CDCl
1
1
3
the total volume of the solution was brought up to 7 mL. The solu-
tion was brought to 40 °C before adding the enzyme (a cell free
extract of a recombinant Escherichia coli strain overexpressing the
P. putida -aminopeptidase gene,[ 0.25 mL) and the mixture was
shaken at 40 °C for 16 h. After cooling to room temperature the
–1
723, 1504, 1394, 1369, 1250, 1162, 1056, 913 cm . HRMS(FAB):
+
calcd. for [C11
H17NO
4
+ H] : 228.1236, found: 228.1233;
19]
R
f
(EtOAc/MeOH/AcOH, 9:1:0.01) = 0.57.
(
2
H
0
S)-2-(tert-Butoxycarbonylamino)-3-methylenepent-4-enoic Acid [(S)-
3]: To a stirred solution of (S)-1a (19 mg, 0.15 mmol) in THF/
(2 mL, 1:1) were added subsequently Boc (65 mg,
.30 mmol) and NaHCO (32 mg, 0.38 mmol). The reaction mix-
2 4
pH was brought to pH 4 with H SO and the mixture was filtered
through Celite. The mixture was brought back to pH 9 with a KOH
solution when benzaldehyde (165 µL, 1.63 mmol) was added. The
mixture was stirred for 2 h at room temperature when it was ex-
tracted with dichloromethane (3 ϫ 20 mL) to extract the Schiff
base of the -amide. The combined organic phases were dried with
2
O
2
O
3
ture was stirred for 2 h at room temperature after which all volatiles
were removed in vacuo. The residue was acidified to pH 3–4 with
10% citric acid solution and extracted with EtOAc (4ϫ). The com-
2 4
Na SO and concentrated in vacuo. The -acid in the aqueous
bined organic layers were washed with brine, dried with MgSO
4
,
phase was purified via Ion Exchange Chromatography, using the
strong basic resin Amberlite IRA-410 to give the desired amino
filtered, and concentrated in vacuo to yield (S)-23 (63 mg) as a
colorless oil which was used as such in the next step.
1
acid (S)-1a (146 mg, 1.15 mmol 37.7%) as a white solid. H NMR
(
400 MHz, D
2
O): δ = 6.31 (dd, J = 11.2, 17.8 Hz, 1 H), 5.41 (s, 1
rac-2-Amino-3-methylenepent-4-enoic Acid TFA Salt (rac-1a): To a
stirred solution of 23 (0.225 g, 0.99 mmol) in CHCl (3 mL) was
3
added TFA (3 mL), After 45 min the brown mixture was concen-
trated in vacuo to yield a brown oil (0.216 g, 0.896 mmol, 90.4%).
H), 5.32 (m, 2 H), 5.17 (d, J = 11.2 Hz, 1 H), 4.41 (s, 1 H) ppm.
1
3
C NMR (125 MHz, D
2
O): δ = 139.90, 134.57, 121.85, 116.11,
–
5
5.35 ppm. COO not observed. HRMS(FAB): calcd. for
+
20
1
[C H NO + H] : 128.0712, found: 128.0712. [α]D = +102 (c =
0
H NMR (500 MHz, D
2
O): δ = 6.31 (dd, J = 11.2, 17.8 Hz, 1 H),
.46 (s, 1 H), 5.33 (d, J = 17.8 Hz, 1 H), 5.32 (s, 1 H), 5.18 (d, J =
1.2 Hz, 1 H), 4.64 (s, 1 H) ppm. 13C NMR (100 MHz, D
O): δ
170.51, 162.67 (q), 138.03, 134.05, 122.22, 116.66, 53.02 ppm.
6
9
2
.05, D
2
O); m.p. Ͼ 250 °C (dec.).
5
1
=
2
(
(
4
S)-Methyl 5-Amino-2-(tert-butoxycarbonylamino)-5-oxopentanoate
Boc-Glutamine Methyl Ester, 9): TMS-CHN (2.0  in hexanes,
0.6 mL, 81.2 mmol) was added slowly via a pressure equalising
CF
3
COO– not observed. IR (neat): ν˜ = 1737, 1657, 1515, 1434,
2
–1
1
145, 1040, 921 cm .
tert-Butyl N-(1-Amino-3-methylene-1-oxopent-4-en-2-yl)carbamate
24): To a stirred solution of crude 23 (1.63 g, 7.18 mmol) at –40 °C
in THF (15 mL) were added N-methylmorpholine (1.18 mL,
dropping funnel to a stirred solution of Boc-glutamine (8.00 g,
32.5 mmol) in MeOH/toluene (30 mL/75 mL). After 0.5 h acetic
(
acid was added to the yellow solution to quench excess TMS-CHN
and the colorless mixture was concentrated in vacuo. The crude
0.8 mmol) and isobutyl chloroformate (0.977 mL, 7.54 mmol). product was precipitated from TBME/pentane to afford 9 as a
2
1
1
The resulting brown-grey suspension was stirred at –20 °C for
white solid (7.41 g, 28.5 mmol, 87.5%). H NMR (500 MHz,
CDCl ): δ = 6.10 (br. s, 1 H), 5.39 (br. s, 1 H), 5.31 (br. d, J =
7.5 Hz, 1 H), 4.35 (br. s, 1 H), 3.77 (s, 3 H), 2.34 (m, 2 H), 2.21 (m
1 H), 1.94 (m, 1 H), 1.46 (s, 9 H) ppm. C NMR (100 MHz,
CDCl ): δ = 174.56, 172.75, 155.87, 80.18, 52.95, 52.46, 31.83,
28.82, 28.28 ppm. IR (neat): ν˜ = 3350, 2979, 1668, 1520, 1454,
10 min when NH
4
OH (25%, 3.35 mL, 21.5 mmol) was slowly
3
added. The reaction temperature was kept between –15 and –25 °C
for 4.5 h when the orange-brown solution was poured onto a satu-
1
3
rated aqueous NaHCO
The organic layer was washed with brine, dried with Na
3
solution and extracted with EtOAc (3ϫ).
SO , fil-
3
2
4
Eur. J. Org. Chem. 2008, 914–924
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
921

H. Hiemstra et al.
FULL PAPER
–1
1
367, 1167, 1054, 918 cm . HRMS(FAB): calcd. for
Methyl 2-[(S)-4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxopen-
tanamido]pent-4-enoate (29): To a stirred solution of Boc-Glu-OMe
+
[C
11
H
20
N
2
O
5
+H] : 261.1450, found: 261.1448.
(
(
1.00 g, 3.83 mmol) at –20 °C in THF (10 mL) were added NMM
0.644 mL, 5.74 mmol) and IBC (0.521 mL, 4.02 mmol). The mix-
(
2S)-Methyl
2-(tert-Butoxycarbonylamino)-5-(1-hydroxy-2-meth-
oxy-2-oxoethylamino)-5-oxopentanoate (26): A stirred solution of 9
(
(
reflux condenser was placed on a pressure equalising dropping fun-
nel filled with 4 Å mol. sieves. After cooling to room temperature
ture was stirred at –20 °C for 10 min when an aqueous solution
1 mL) of allylglycine methyl ester HCl salt (0.697 g, 4.21 mmol)
2.50 g, 9.61 mmol) and methyl glyoxylate methyl hemiacetal
1.91 mL, 19.2 mmol) was refluxed for 19 h in CHCl (90 mL). The
(
3
and DIPEA (0.800 mL, 4.59 mmol) was slowly added. The re-
sulting mixture was stirred at –20 °C for 2 h before it was warmed
to room temperature in 19h. The mixture was poured on 5%
the yellow solution was washed with a saturated aqueous NaHCO
solution and brine. The organic layer was dried with Na SO , fil-
3
KHSO
4
and extracted with EtOAc (3ϫ). The organic layer was
SO , filtered, and concentrated
2
4
washed with brine, dried with Na
in vacuo to afford a yellow oil. Purification by column chromatog-
raphy (PE/EtOAc, 1:1) afforded 29 in 46.5% (0.662 g, 1.78 mmol
1
6
5
3
1
2
4
tered, and concentrated in vacuo. The crude product was purified
by column chromatography (EtOAc) to afford 26 as thick yellow
oil in 58% yield (1.94 g, 5.58 mmol) in a 1:1 mixture of dia-
1
:1 mixture of diastereomers). H NMR (500 MHz, CDCl
3
): δ =
stereomers. 1H NMR (400 MHz, CDCl
6
0
): δ = 7.53 (br. d, J =
.6 Hz, 0.5 H), 7.45 (br. s, J = 6.6 Hz, 0.5 H), 5.63 (d, J = 7.4 Hz,
.5 H), 5.57 (d, J = 7.4 Hz, 0.5 H), 5.40 (br. s, 1 H), 4.61 (br. s, 1
3
.77 (br. s, 0.5 H), 6.46 (br. s, 0.5 H), 5.69 (m, 1 H), 5.33 (m, 1 H),
.13 (m, 2 H), 4.65 (m, 1 H), 4.39 (br. s, 0.5 H), 4.29 (br. s, 0.5 H),
.73 (s, 6 H), 2.57 (m, 1 H), 2.49 (m, 1 H), 2.30 (m, 2 H), 2.17 (m,
H), 4.34 (m, 1 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 2.36 (m, 2 H), 2.23
m, 1 H), 1.92 (m, 1 H), 1.45 (s, 9 H) ppm.[27] 13C NMR (100 MHz,
CDCl ): δ = 172.93, 172.63, 169.94, 169.87, 155.91, 80.52, 72.35,
2.22, 53.25, 53.20, 52.59, 32.16, 29.05, 28.81, 28.28 ppm. IR
13
H), 1.91 (m, 1 H), 1.42 (s, 9 H) ppm. C NMR (125 MHz,
(
CDCl
1
5
3
): δ = 173.01, 172.96, 172.45, 172.39, 172.07, 171.77, 156.09,
55.91, 132.59, 132.54, 119.33, 119.26, 80.31, 80.24, 53.12, 53.06,
2.63, 52.60, 52.53, 52.11, 51.98, 36.62, 36.47, 32.57, 32.47, 28.43
3
7
(
–
1
neat): ν˜ = 3332, 2980, 1746, 1694, 1531, 1443, 1166 cm .
–1
ppm. IR (neat): ν˜ = 3326, 2979, 1745, 1714, 1659, 1525, 1167 cm .
HRMS(FAB): calcd. for [C17H N O + H] : 373.1975, found:
28 2 7
3
+
HRMS(FAB): calcd. for [C14
49.1592; R (EtOAc) = 0.38.
H
24
N
2
O
8
+ H] : 349.1611, found:
+
3
f
f
73.1982; R (PE/EtOAc, 1:2) = 0.40.
(
2S)-Methyl 5-(1-Acetoxy-2-methoxy-2-oxoethylamino)-2-(tert-bu-
toxycarbonylamino)-5-oxopentanoate (27): A mixture of 26 (1.14 g,
.27 mmol) and pyridine (0.1 mL, 1.24 mmol) in Ac O (10 mL) was
2
-[(S)-4-(tert-Butoxycarbonylamino)-4-carboxybutanamido]pent-4-
enoic Acid (30): To a stirred solution of 29 (50 mg, 0.134 mmol) in
THF (1.5 mL) at 0 °C was added drop wise a pre-cooled aqueous
3
2
stirred for 20 h when the orange solution was concentrated in vacuo
and co-evaporated with toluene (3ϫ) to give 27 as a sticky yellow
oil in 97% (1.24 g, 3.18 mmol). H NMR (500 MHz, CDCl
6
(
1.5 mL) solution of LiOH (12.9 mg, 0.537 mmol). The resulting
mixture was stirred at 0 °C for 4.25 h when it was poured on 5%
KHSO and extracted with EtOAc (3ϫ). The organic layer was
washed with brine, dried with Na SO , filtered, and concentrated
in vacuo to afford 30 as a colorless oil in 84% (39 mg, 0.113 mmol,
1
3
): δ =
4
.41 (m, 1 H), 5.25 (br. s, 1 H), 4.35 (br. s, 1 H), 3.83 (s, 3 H), 3.77
2
4
(
s, 3 H), 2.36 (m, 2 H), 2.23 (m, 1 H), 2.14 (s, 3 H), 1.96 (m, 1 H),
.46 (s, 9 H) ppm. 1 C NMR (100 MHz, CDCl
3
): δ = 172.64,
1
1
5
1
3
1
1:1 mixture of diastereomers). H NMR (400 MHz, MeOD): δ =
5.81 (tdd, J = 7.0, 10.1, 17.2 Hz, 1 H), 5.16 (dd, J = 1.7, 17.1 Hz,
1 H), 5.11 (dd, J = 1.0, 10.2 Hz, 1 H), 4.48 (ddd, J = 2.8, 5.1,
7.9 Hz, 1 H), 4.13 (dt, J = 4.9, 8.6 Hz, 1 H), 2.62 (m, 1 H), 2.47
71.94, 170.34, 170.28, 167.19, 155.69, 80.19, 72.13, 53.25, 52.72,
2.48, 31.97, 28.26, 20.62 ppm. IR (neat): ν˜ = 3344, 2979, 1747,
–1
519, 1439, 1369, 1218, 1166, 1032, 917 cm . HRMS(FAB): calcd.
+
for [C16
1
26 2 9 f
H N O + H] : 391.1717, found: 391.1726; R (PE/EtOAc,
(
m, 1 H), 2.38 (t, J = 7.5 Hz, 2 H), 2.16 (m, 1 H), 1.92 (m, 1 H),
:2) = 0.38.
13
1.46 (s, 9 H) ppm. C NMR (100 MHz, MeOD): δ = 175.66,
175.61, 174.98, 174.90, 174.76, 174.74, 158.11, 134.54, 118.78,
118.77, 80.65, 54.53, 54.46, 53.44, 37.01, 36.99, 33.20, 33.09, 30.98,
28.93, 28.21 ppm. IR (neat): ν˜ = 3328, 2981, 2506, 1727, 1537,
1
Methyl 2-[(S)-4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxopen-
tanamido]-3-methylenepent-4-enoate [(S)-28]: To a stirred solution
of 27 (0.475 g, 1.22 mmol) and allenylmethyltrimethylsilane
–
1
394, 1369, 1246, 1163, 1056 cm . HRMS(FAB): calcd. for
(
0.307g, 2.43 mmol) in CH
wise BF ·OEt (0.461 g, 3.65 mmol). The resulting mixture was
warmed slowly following the reaction with TLC. After 5.5 h (T =
25 °C), the yellow solution was poured onto a saturated aqueous
NaHCO solution and extracted with EtOAc (3ϫ). The organic
layer was washed with brine, dried with Na SO , filtered, and con-
2 2
Cl (6 mL) at –78 °C, was added drop
+
[C
15
H
24
N
2
O
7
+ H] : 345.1662, found: 345.1660; R
f
(EtOAc/AcOH,
3
2
1
:0.02) = 0.05.
–
2
-[(S)-4-Amino-4-carboxybutanamido]pent-4-enoic Acid, TFA Salt
3
(
31): To a stirred solution of 30 (39 mg, 0.113 mmol) in CDCl
3
2
4
(
1 mL) was added TFA (1 mL). The resulting slight brown solution
centrated in vacuo to afford a yellow oil. Purification by column
chromatography (PE/EtOAc, 1:1) afforded (S)-28 in 26% (0.123 g,
0
6
J = 2.7, 11.1, 17.7 Hz, 1 H), 5.44 (d, J = 17.7 Hz, 1 H), 5.37 (dd,
J = 4.5, 7.8 Hz, 1 H), 5.33 (br. s, 1 H), 5.30 (d, J = 2.0 Hz, 1 H),
5
4
3
was stirred for 1h, when all volatiles were removed by co-evapora-
tion with toluene to give 31 as brown oil in 84% (34 mg,
0
D O): δ = 5.71 (tdd, J = 7.1, 10.1, 17.2 Hz, 1 H), 5.09 (m, 1 H),
2
4
1
D
1
3
1
.32 mmol) as a colorless oil. 1H NMR (500 MHz, CDCl
): δ =
.92 (d, J = 6.2 Hz, 0.5 H), 6.62 (d, J = 5.3 Hz, 0.5 H), 6.32 (ddd,
3
1
.949 mmol, 1:1 mixture of diastereomers). H NMR (400 MHz,
.36 (td, J = 5.2, 7.6 Hz, 1 H), 3.97 (t, J = 6.5 Hz, 1 H), 2.54 (m,
13
H), 2.44 (m, 3 H), 2.14 (m, 2 H) ppm. C NMR (125 MHz,
.25 (d, J = 8.6 Hz, 1 H), 5.18 (d, J = 11.1 Hz, 1 H), 4.42 (dt, J =
.4, 9.2 Hz, 0.5 H), 4.28 (dt, J = 4.5, 8.6 Hz, 0.5 H), 3.74 (s, 3 H),
.73 (s, 1.5 H), 3.72 (s, 1.5 H), 2.33 (m, 2 H), 2.18 (m, 1 H), 1.91
2
O): δ = 174.96, 174.06, 173.99, 171.47, 171.46, 162.72 (q),
32.48, 118.62, 52.40, 52.36, 52.20, 52.14, 34.68, 34.62, 30.64,
–
0.50, 25.42, 25.38 ppm. CF
728, 1642, 1536, 1148, 930 cm .
3
COO not observed. IR (neat): ν˜ =
13
(
m, 1 H), 1.43 + 1.42 (s, 9 H, rotamers) ppm. C NMR (100 MHz,
–1
CDCl ): δ = 173.06, 172.97, 171.92, 171.61, 171.53, 156.10, 155.91,
3
1
5
42.00, 135.53, 119.27, 119.18, 116.16, 116.14, 80.35, 80.31, 53.61, Methyl 2-Amino-3-methylenepent-4-enoate, TFA Salt (rac-32): To a
3.08, 53.00, 52.93, 52.89, 52.68, 32.56, 32.42, 29.49, 28.95, 28.50 solution of 22 (1.35 g, 5.57 mmol) in CHCl (5 mL) was added TFA
(10 mL). The mixture was stirred for 1.5 h when it was concentrated
3
ppm. IR (neat): ν˜ = 3327, 2979, 2955, 1746, 1713, 1519, 1367, 1208,
1
–1
+
168, 914 cm . HRMS(FAB): calcd. for [C18
H
28
N
2
O
7
+ H] : in vacuo and co-evaporated with toluene (3ϫ) to yield rac-32 as a
1
385.1975, found: 385.1981; R (PE/EtOAc, 1:1) = 0.28.
f
brown solid in 99% (1.42 g, 5.57 mmol). H NMR (400 MHz,
922
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 914–924

Diene-Containing Amino Acid and Its Glutamyl Dipeptide
D
2
O): δ = 6.37 (dd, J = 11.2, 17.8 Hz, 1 H), 5.57 (s, 1 H), 5.38 (d, filtered, and concentrated in vacuo to afford (S,S/R)-33 as a fluffy
J = 17.8 Hz, 1 H), 5.27 (d, J = 11.2 Hz, 1 H), 4.93 (s, 1 H), 3.77 white powder in 80% yield (0.288 g, 0.808 mmol, 1:1 mixture of
1
(
1
s, 3 H) ppm. 13C NMR (100 MHz, D
37.70, 133.99, 122.17, 116.82, 53.94, 52.91 ppm. CF
observed. IR (neat): ν˜ = 1737, 1655, 1540, 1433, 1178, 1129, 904
2
O): δ = 169.32, 162.79 (q),
3
diastereomers). H NMR (400 MHz, CDCl ): δ = 6.43 (dd, J =
–
3
COO not
11.1, 17.6 Hz, 1 H), 5.83 (br. s, 1 H), 5.43 (d, J = 17.6 Hz, 1 H),
5.36 (s, 1 H), 5.29 (m, 2 H), 5.18 (d, J = 11.1 Hz, 1 H), 2.38 (m, 2
H), 2.17 (m, 1 H), 1.90 (m, 1 H), 1.46 (s, 9 H) ppm. C NMR
–1
+
13
8
38 cm . HRMS(FAB): calcd. for [C
7
H11NO
2
+ H] : 142.0868,
found: 142.0870.
(100 MHz, CDCl
3
): δ = 174.30, 173.32, 173.27, 172.43, 172.40,
56.71, 142.24, 135.88, 135.74, 117.83, 114.24, 114.21, 79.16, 51.52,
8.45, 31.61, 31.52, 27.32 ppm. IR (neat): ν˜ = 3313, 2980, 1714,
1
4
1
(
S)-Methyl 2-Amino-3-methylenepent-4-enoate, TFA Salt [(S)-32]:
To a stirred solution of (S)-22 (28 mg, 0.12 mmol) in CHCl
0.4 mL) at 0 °C was added TFA (0.4 mL). The solution was stirred
3
–
1
694, 1519, 1249, 1165, 1055, 913 cm . HRMS(FAB): calcd. for
(
+
[C
16
H
24
N
2
O
7
+ H] : 357.1662, found: 357.1663; R
f
(EtOAc/AcOH,
at room temperature for 10 min, when it was concentrated in vacuo
and co-evaporated with toluene (3ϫ) to give (S)-32 as a colorless
oil which was used as such in the next step.
1:0.02) = 0.10.
(
S)-2-[(S)-4-(tert-Butoxycarbonylamino)-4-carboxybutanamido]-3-
methylenepent-4-enoic Acid [(S,S)-33]: To a stirred solution of (S,S)-
8 (25 mg, 0.065 mmol) in THF (0.6 mL) at 0 °C was added a pre-
cooled (0 °C) solution of LiOH (6.2 mg, 0.260 mmol) in H O. The
resulting yellow solution was stirred at 0 °C for 1.5 h when it was
poured on 5% KHSO and extracted with EtOAc (3ϫ). The or-
ganic layer was washed with brine, dried with Na SO , filtered, and
(S)-Methyl 2-[4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxopen-
tanamido]-3-methylenepent-4-enoate [(S,S/R)-28]: To a stirred solu-
tion of Boc-Glu-OMe (0.563 g, 2.16 mmol) at –20 °C in THF
2
2
(
(
5.6 mL) were added NMM (0.275 mL, 2.45 mmol) and IBC
0.294 mL, 2.26 mmol). The mixture was stirred at –20 °C for
4
10 min when an mixture of rac-32 (0.500 g, 1.96 mmol) and
2
4
NaHCO (0.206 mL, 2.45 mmol) in H O/THF (2 mL, 1:1) was
3
2
concentrated in vacuo to afford (S,S)-33 as a colorless oil in 99%
slowly added. The resulting mixture was warmed to room tempera-
ture in 18 h, when all volatiles were evaporated. The residue was
1
yield (23 mg, 0.0645 mmol). H NMR (500 MHz, MeOD): δ = 6.41
(
dd, J = 11.1, 17.6 Hz, 1 H), 5.41 (d, J = 17.6 Hz, 1 H), 5.34 (s, 1
H), 5.28 (m, 2 H), 5.17 (d, J = 11.1 Hz, 1 H), 4.09 (dd, J = 4.5,
.1 Hz, 1 H), 2.37 (t, J = 7.3 Hz, 2 H), 2.14 (m, 1 H), 1.89 (m, 1
taken up in EtOAc and washed with saturated NaHCO
dried with Na SO , filtered, and concentrated in vacuo to afford a
brown foam. Purification by column chromatography (PE/EtOAc,
:1) afforded (S,S/R)-28 in 56% (0.421 g, 1.10 mmol 1:1 mixture
3
, brine,
2
4
9
1
3
H), 1.44 (s, 9 H) ppm. C NMR (125 MHz, MeOD): δ = 174.46,
1
1
1
73.50, 172.55, 156.94, 142.41, 142.39, 136.07, 118.05, 118.00,
14.49, 79.39, 54.64, 53.26, 53.22, 31.73, 29.72, 27.54 ppm. IR
of diastereomers). Analytical data were identical to those reported
earlier in this paper.
(
1
3
neat): ν˜ = 3327, 2977, 2930, 1720, 1657, 1525, 1394, 1249, 1164,
(S)-Methyl 2-[(S)-4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxo-
–1
+
24 2 7
050, 914 cm . HRMS(FAB): calcd. for [C16H N O + H] :
pentanamido]-3-methylenepent-4-enoate [(S,S)-28]: To a stirred solu-
tion of Boc-Glu-OMe (63 mg, 0.24 mmol) in THF (1 mL) at –20 °C
under an argon atmosphere were added NMM (32 µL, 0.29 mmol)
and IBC (34 µL, 0.26 mmol). The suspension was stirred at –20 °C
for 20 min when a precooled solution (0 °C) of crude (S)-32
20
57.1662, found: 357.1660. [α]
D
= +45.9 (c = 1.15, MeOH),
R
f
(EtOAc/AcOH, 1:0.02) = 0.08.
(
S)-2-(4-Amino-4-carboxybutanamido)-3-methylenepent-4-enoic
Acid, TFA Salt [(S,S/R)-1b)]: To stirred solution of 33 (0.100 g,
.281 mmol) in CHCl (2 mL) was added TFA (2 mL). The re-
0
3
(
0
0.12 mmol) in THF (0.5 mL)/H
.15 mL) was added drop wise. The resulting mixture was warmed
to room temperature in 3 h, and stirred at room temperature for
0 h. THF was evaporated in vacuo and the residue was diluted
with a saturated aqueous NaHCO solution and extracted with
EtOAc (4ϫ). The combined organic layers were washed with brine,
dried with MgSO , filtered, and concentrated in vacuo. The crude
product (58 mg) was purified by column chromatography (PE/
EtOAc, 1:1, column rinsed with 2% Et N) to give (S,S)-28 (31 mg,
.081 mmol, 67% over 2 steps) as a white needles (Et O/pentane).
): δ = 6.61 (br. d, J = 6.8 Hz, 1 H),
.34 (dd, J = 11.1, 17.7 Hz, 1 H), 5.46 (d, J = 17.7 Hz, 1 H), 5.38
d, J = 7.7 Hz, 1 H), 5.31 (s, 1 H), 5.29 (br. s, 1 H), 5.27 (s, 1 H),
2
O
(0.5 mL)/NaHCO
3
(1 ,
sulting solution was stirred at room temperature for 45 min when
it was co-evaporated with toluene to yield (S,S/R)-1b as a yellow
1
oil (97 mg, 0.262 mmol, 93%, 1:1 mixture of diastereomers).
NMR (500 MHz, D
s, 1 H), 5.20 (d, J = 17.7 Hz, 1 H), 5.16 (s, 1 H), 5.09 (d, J =
H
2
2
O): δ = 6.28 (dd, J = 11.1, 17.7 Hz, 1 H), 5.29
3
(
6
2
1
1
.7 Hz, 1 H), 5.07 (s, 1 H) 3.91 (t, J = 6.5 Hz, 1 H), 2.40 (m, 2 H),
.07 (m, 2 H) ppm. C NMR (100 MHz, D O): δ = 174.00, 173.93,
2
73.86, 173.84, 171.35, 171.33, 162.79 (q), 140.46, 140.40, 135.22,
4
1
3
3
20.17, 120.09, 115.57, 53.88, 53.82, 52.10, 52.04, 30.69, 30.53,
0
2
–
1
25.40, 25.36 ppm. CF COO not observed. HRMS(FAB): calcd.
for [C13
H NMR (400 MHz, CDCl
3
3
+
H
17
F
3
N
2
O
7
+ H] : 371.1066, found: 371.1097.
6
(
(
S)-2-[(S)-4-Amino-4-carboxybutanamido]-3-methylenepent-4-enoic
Acid, TFA Salt [(S,S)-1b]: To stirred solution of (S,S)-33 (11 mg,
.031 mmol) in CHCl (0.2 mL) was added TFA (0.2 mL). The re-
5
3
.20 (d, J = 11.1 Hz, 1 H), 4.30 (dt, J = 4.5, 8.3 Hz, 1 H), 3.76 (s,
H), 3.74 (s, 3 H), 2.35 (t, J = 7.4 Hz, 2 H), 2.20 (m, 1 H), 1.93
0
3
(
(
td, J = 6.8, J = 14.6 Hz, 1 H), 1.45 (s, 9 H) ppm. 13C NMR
sulting solution was stirred at room temperature for 10 min when
100 MHz, CDCl
3
): δ = 172.73, 171.37, 171.30, 155.68, 141.77,
it was co-evaporated with toluene to yield (S,S)-1b as a yellow oil
1
2
3
35.29, 118.97, 115.94, 80.12, 53.39, 52.86, 52.69, 52.44, 32.21,
1
(
11 mg, 0.031 mmol, 99%). H NMR (400 MHz, D
2
O): δ = 6.33
+
8.76, 28.28 ppm. HRMS(FAB): calcd. for [C18
H
28
N
2
O
7
+ H] :
(dd, J = 11.1, 17.7 Hz, 1 H), 5.33 (s, 1 H), 5.24 (d, J = 17.8 Hz, 1
85.1975, found: 385.1981. [α]2
0
= +72.6 (c = 0.5, CHCl
); R (PE/
D
3
f
H), 5.20 (s, 1 H), 5.12 (m, 2 H), 3.90 (t, J = 6.6 Hz, 1 H), 2.43 (t,
EtOAc, 1:2) = 0.45; m.p. 108–112 °C.
1
3
J = 7.3 Hz, 2 H), 2.09 (m, 2 H) ppm. C NMR (125 MHz, D
2
O):
(
S)-2-[4-(tert-Butoxycarbonylamino)-4-carboxybutanamido]-3-meth-
δ = 174.311, 174.26, 172.16, 163.18 (q), 140.71, 140.69, 135.56,
–
ylenepent-4-enoic Acid [(S,S/R)-33]: To a stirred solution of (S,S/
R)-28 (0.390 g, 1.02 mmol) in THF (10 mL) at 0 °C was added drop
wise a precooled solution of LiOH (97 mg, 4.06 mmol) in H
120.33, 115.72, 54.21, 52.76, 30.99, 25.79 ppm. CF
served. IR (neat): ν˜ = 2924, 2854, 1724, 1639, 1517, 1161, 915 cm .
HRMS(FAB): calcd. for [C13
+ H]+ (TFA salt):
371.1066, found: 371.1097, HRMS(FAB): calcd. for [C11
3
COO not ob-
–
1
2
O
17 3 2 7
H F N O
(10 mL). The resulting yellowish mixture was stirred at 0 °C for 3
16 2 5
H N O
= +35.5 (c =
+ H]+ (free amine): 257.1137, found: 257.1128, [α]
20
h when it was poured on 5% KHSO
4
and extracted with EtOAc
SO
D
(3ϫ). The organic layer was washed with brine, dried with Na
2
4
,
0.55, D O).
2
Eur. J. Org. Chem. 2008, 914–924
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
923

H. Hiemstra et al.
FULL PAPER
[
[
[
[
[
14] G. Mentink, J. H. Van Maarseveen, H. Hiemstra, Org. Lett.
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The authors kindly acknowledge M. Boesten and I. Maes (DSM,
Geleen, The Netherlands) for their efforts on the HPLC analysis
of the amino acid resolutions. B. Dassen is thanked for his help
2001, 22, 1385–1389.
®
on the Alcalase -mediated resolution. This research was financially
17] From a short literature survey, TMSI-induced diene degrada-
tion can be excluded as another possible reason.
supported by the Council for Chemical Sciences of the Netherlands
Organization for Scientific Research (NWO-CW).
18] In another experiment we also have observed polymerization.
Solid products are relatively stable; when the product was iso-
lated as an oil, polymerization occurred overnight, even when
the compound was stored under nitrogen. When stored in solu-
tion, the compounds proved to be stable, even after prolonged
storage times.
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