Use of the Claisen/metathesis reaction sequence for the synthesis of enantiomerically pure 1-aminocycloalkene-1-carboxylic acids

Article abstract of DOI:10.1016/j.tet.2010.05.008

An effective method for the preparation of enantiomerically pure 1-aminocycloalkene-1-carboxylic acids is reported using a chelate Claisen rearrangement-metathesis sequence. Enantioselectivity is achieved through substrate control and a highly ordered transition state, without the use of a chiral auxiliary. A synthesis of 1-aminocyclopent-3-ene-1-carboxylic acid 1 in five steps and 47% overall yield is also described.

Full text of DOI:10.1016/j.tet.2010.05.008

Tetrahedron 66 (2010) 5030e5035
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Use of the Claisen/metathesis reaction sequence for the synthesis of
enantiomerically pure 1-aminocycloalkene-1-carboxylic acids
*
Karen Plé , Arnaud Haudrechy, Nicolas P. Probst
Institut de Chimie Moléculaire de Reims, CNRS 6229, UFR Sciences, Bât 18, BP 1039, 51687 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective method for the preparation of enantiomerically pure 1-aminocycloalkene-1-carboxylic acids
is reported using a chelate Claisen rearrangementemetathesis sequence. Enantioselectivity is achieved
through substrate control and a highly ordered transition state, without the use of a chiral auxiliary. A
synthesis of 1-aminocyclopent-3-ene-1-carboxylic acid 1 in five steps and 47% overall yield is also
described.
Received 5 January 2010
Received in revised form 3 May 2010
Accepted 4 May 2010
Available online 11 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Rearrangement
Asymmetric Synthesis
Amino acids
Synthetic methods
1. Introduction
aminocycloalkane-1-carboxylic acids (Acnc, n¼ring size, Scheme 1)
are one of the simplest cyclic derivatives which, when introduced
The incorporation of
a
-quaternary amino acids into peptides has
in a peptide sequence, significantly modify its secondary structure.
1-Aminocycloalkene-1-carboxylic acids have proven to be syn-
thetically useful intermediates for the preparation of Acnc acids and
their derivatives. Appropriate functionalization of the double bond
could also lead to analogues which, when incorporated into pep-
tides, could further modify their elementary structure or biological
activity.
been extensively used to modify secondary as well as tertiary
peptide structures.1e3 These modified peptides are useful tools that
can be used to probe the molecular structure of receptors or even
enhance the biological activity of the parent peptide by imposing
a pre-determined spatial conformation. The introduction of con-
strained cyclic a-quaternary amino acids can further rigidify the
system and give analogues with well defined backbone confor-
In the case of 1-aminocyclopent-3-ene-1-carboxylic acid 1, the
configuration of the amino acid is irrelevant because of the existing
C2 symmetry plane in the molecule. In larger unsymmetrical ring
mations. As a result, much effort has been devoted to the synthesis
of different cyclic a
-quaternary amino acids.4,5 Among these, the 1-
1. n-BuLi, THF
H2N
H2N
N
N
OCH3
COOH
COOH
Br
N
N
OCH3
m
n
H3CO
m
2. n-BuLi, THF
H2N COOH
Acnc
H3CO
Ac5c
1
Br
n
3
4
H2N COOH
H2N COOH
RCM
m = 1-3
n = 1-3
N
N
OCH3
n
Ac6c
2
COOMe
n
hydrolysis
H2N
Scheme 1.
H3CO
m
m
6
5
* Corresponding author. Tel.: þ33 3 26 91 33 07; fax: þ33 3 26 91 31 66; e-mail
Scheme 2.
address: karen.ple@univ-reims.fr (K. Plé).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.008

K. Plé et al. / Tetrahedron 66 (2010) 5030e5035
5031
systems however, few methods exist, which give specific control of
2. Results and discussion
this chiral center. The enantioselective synthesis of 1-amino-
cycloalkene-1-carboxylic acids has been reported using the
The commercially available (R) or (S)-but-3-yn-2-ol (98% ee)
served as the starting point for the synthesis of the desired esters.
Esterification was performed using standard DCC coupling tech-
niques, and Lindlar reduction of the triple bond led to the protected
amino esters in good to excellent yields (Table 1).
Schollkopf methodology.6,7 Stereoselective alkylation of the
€
bislactim 3 followed by RCM and hydrolysis gave the desired 1-
aminocycloalkene-1-carboxylic acid methyl esters 6 (Acnc, n¼5e7)
in overall yields ranging from 16 to 42% (Scheme 2).8,9
This sequence proved to be highly substrate dependent with
difficulties occurring in the RCM step (n¼5) and in the sluggish
hydrolysis of the chiral auxiliary (3e8 days). More recently, this
methodology has been applied to the synthesis of spiro-2,5-dike-
topiperazines, where improvements were made using microwave
irradiation.10
In the particular case of the cyclohexene amino acid derivative 2,
an enantioselective DielseAlder reaction was described with
a dehydroalanine derivative and butadiene.11 Esterification of the
starting dehydroalanine with a chiral auxiliary in the presence of
trimethyl aluminum followed by Lewis acid catalyzed cycloaddition
gave the desired cyclic quaternary amino acid in varying yields and
selectivity. The best results were observed with (ꢀ)-8-phenyl-
menthol after 6 days in the presence of TiCl4 (Scheme 3).
Table 1
Ester synthesis
1.
(S)
OH
DCC, DMAP
CH2Cl2
NHR
OH
NHR
O
n
n
O
O
2. H2, 5% Pd/CaCO3,
(Lindlar)
R = Boc, Ac
n =1,2
quinoline, EtOAc
Alcohol
Acid
Ester
Yield (%)
63
NHBoc
O
(S)
n¼1, R¼Boc (7)
(S)
(R)
OH
O
10
11
AcHN COR*
NHBoc
(R)
O
O
n¼1, R¼Boc (7)
n¼1, R¼Ac (8)
69
57
O
OH
TiCl4, 25 °C
O
6 days
NHAc
O
NHAc
91 % (S)/(R) 99:1
(S)
(S)
Scheme 3.
OH
O
12
NHBoc
O
We have recently shown that the chelate Claisen/metathesis
reaction sequence can be applied to the diastereoselective syn-
thesis of quaternary hydroxy and amino acid carbocycles.12 The
excellent diastereoselectivity observed is a result of the highly or-
dered six-member chairlike transition state and the use of a chiral
(S)
n¼2, R¼Boc (9)
59
(S)
OH
O
13
The resulting products (10e13) were then treated with LDA in
the presence of zinc(II) chloride to give, after esterification with
diazomethane, the rearranged esters (Table 2).
allylic alcohol in the starting ester. The a-heteroatom stabilizes the
enolate through a five-member chelate ring, resulting in almost
exclusive formation of a (Z)-enolate (Scheme 4).13 An extremely
efficient chirality transfer occurs from the carbinol center to the
newly formed stereocenters at C2 and C3 of the acid product.
Table 2
Chelate Claisen rearrangement
1. LDA, ZnCl2
NHR
R3
THF, -78 °C
2. CH2N2
RHN COOMe
n
O
XR
COOH
O
R1
O
base
XR
R3
n
R1
R2 R3
O
O
R1R2
XR
R2
O
M
X = O, N
O
Scheme 4.
N
O
R
Zn
This methodology has been described for the enantioselective
synthesis of tertiary amino acids as part of the synthesis of Chla-
mydocin14 or cylindrospermopsin alkaloids,15 as well as simple
tertiary and quaternary amino acids.16
In order to further demonstrate the efficiency of the chelate
Claisen/metathesis reaction sequence, the enantioselective syn-
thesis of several 1-aminocycloalkene-1-carboxylic esters based on
a highly effective 1,4-chirality transfer is presented. The enantio-
selectivity of the reaction is controlled by the stereogenic center of
the simple chiral allylic alcohol precursor, and either enantiomer
can be obtained based on the configuration of the starting alcohol.
An alternative route for the preparation of 1-aminocyclopent-3-
ene-1-carboxylic acid (1)17e28 is also described.
Ester
Quaternary amido ester
Yield (%)
BocHN
BocHN
COOMe
COOMe
10, n¼1, R¼Boc
11, n¼1, R¼Boc
63
68
14
15
AcHN
COOMe
12, n¼1, R¼Ac
13, n¼2, R¼Boc
84
71
16
BocHN COOMe
17

5032
K. Plé et al. / Tetrahedron 66 (2010) 5030e5035
In order to evaluate the enantioselectivity of the reaction, the
clearly reflected the excellent enantioselectivity of the chelate
Claisen rearrangement (Fig. 1). The exact ratio of the two com-
pounds was difficult to determine by NMR as peak overlaps made
integration unreliable. Chemical shift differences were seen in two
areas: the vinyl alkene hydrogens (5.5 ppm) and the terminal
methyl group of the trans double bond (1.62 ppm).
crude chiral acids 140 and 150 were coupled to both (R) and (S)-
methylbenzyl amine (ꢁ99% ee) (Table 3). These amides were then
compared with those formed using the racemic acid 18.
Table 3
Chiral amide formation
The rearranged derivatives then underwent a ring closing me-
tathesis reaction in the presence of Grubbs first generation catalyst
to give the desired carbocycles in good yield (Table 4).
In order to better quantify reaction enantioselectivity, the cyclic
derivatives 23e26 were subjected to chiral column analysis using
a Chiralcel IC or OD-H column. An excellent enantioselectivity was
observed (eeꢁ96%) for all substrates. The absolute configuration of
the obtained products was assigned based on the use of chiral
auxiliaries and 1H NMR published in our previous paper.12
(S)
Ph
H2N Ph
(S)
O
DEPBT[a]
NH
BocHN COOH
(S)
BocHN
C
(S)
i-Pr2EtN
THF
14'
19
Acid
Amine
Amide
Table 4
Ring closing metathesis
(R)
Ph
BocHN COOH
(S)
O
RHN COOMe
NH
BocHN
C
RHN COOMe
n
Grubbs I
H2N Ph
(R)
(S)
14’
n
20
(S)
Ph
Amido-ester
Carbocycle
Yield (%)
ee (%)
O
NH
BocHN COOMe
BocHN COOMe
AcHN COOMe
BocHN
C
H2N Ph
(S)
14
95
90
83
ꢁ97
(R)
BocHN COOH
(R)
23
24
21
(R)
Ph
15’
15
16
ꢁ97
ꢁ98
O
NH
BocHN
C
H2N Ph
(R)
(R)
22
(S)
Ph
25
O
NH
COOMe
BocHN
C
BocHN
H2N Ph
(S)
17
72
ꢁ96
BocHN
COOH
19/21
26
(R)
18
Ph
In order to prepare 1-aminocyclopent-3-ene-1-carboxylic acid
1, coupling of the Boc protected allyl glycine derivative 27 with allyl
alcohol gave ester 28 (Scheme 5). Claisen rearrangement in the
presence of zinc(II) chloride, treatment with diazomethane and
O
NH
BocHN
C
H2N Ph
(R)
20/22
[a] DEPBT¼3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one.
O
O
OH
NMR spectral analysis (500 MHz) of the chiral amides (19e22)
showed the presence of one major diastereoisomer with only mi-
nor amounts of the other in each case. Comparison of compounds
19 and 21 with amide 19/21 (prepared from the racemic acid 18)
OH
O
DCC, DMAP
NHBoc
NHBoc
27
28
CH2Cl2
94%
1. LDA, ZnCl2
THF
(S)
2. CH2N2
Ph
NH
O
19
65%
BocHN
C
(S)
Grubbs I
BocHN COOCH3
BocHN COOCH3
29
(S)
Ph
NH
CH2Cl2
40 °C, 86%
O
21
30
BocHN
C
(R)
4M HCl
rt, 90 %
(S)
Ph
NH
O
19
BocHN
C
HCl.NH2 COOH
19/21
1
Scheme 5.
Figure 1. Comparative NMR spectra.

K. Plé et al. / Tetrahedron 66 (2010) 5030e5035
5033
RCM gave the desired cyclopentene derivative 30 in good yield.
Final deprotection with aqueous HCl then gave the desired com-
pound 1 as a hydrochloride salt.
NMR (mixture of rotamers) (250 MHz, CDCl3):
d
¼1.45 (s, 9H), 1.78
(m, 1H), 1.96 (m, 1H), 2.17 (m, 2H), 4.14 (m, 0.35H, CHNHBoc), 4.36
(m, 0.65H, CHNHBoc), 5.07 (m, 2H), 5.14 (br s, 0.65H, NHBoc), 5.80
(m, 1H), 6.49 (s, 0.35H, NHBoc), 10.78 (br s, 1H). 13C NMR (62.5 MHz,
3. Conclusions and summary
CDCl3):
d
¼28.2, 29.4, 31.6, 52.9, 80.15, 115.8, 136.8, 155.5, 177.3.
We have described the enantioselective preparation of several
1-aminocycloalkene-1-carboxylic acids. The obtained selectivity
was based on the configuration of the starting allylic alcohol and is
an example of a highly stereoselective 1,4-chirality transfer from
a simple chiral alcohol precursor. One of the advantages of this
method is the preparation of unsymmetrical unsaturated carbo-
cycles, which are not easily available by controlled alkylation of
a glycine equivalent. A straightforward synthesis of 1-amino-
cyclopent-3-ene-1-carboxylic acid 1 was also described.
4.3. 2-tert-Butoxycarbonylamino-hept-6-enoic acid (9)
This acid was prepared using the same procedure as for com-
pound 729 using diethylacetamidomalonate and 5-bromo-1-pen-
tene. 1H NMR (mixture of rotamers) (250 MHz, CDCl3):
d¼1.45 (s,
11H), 1.70 (m, 1H), 1.85 (m, 1H), 2.09 (m, 2H), 4.11 (m, 0.35H,
CHNHBoc), 4.33 (m, 0.65H, CHNHBoc), 5.00 (m, 2H), 5.22 (d,
J¼8.1 Hz, 0.65H, NHBoc), 5.78 (m, 1H), 6.60 (d, J¼6.4 Hz, 0.35H,
NHBoc), 10.89 (br s, 1H). 13C NMR (62.5 MHz, CDCl3):
d
¼24.4, 28.2,
31.4, 31.8, 33.0, 53.1, 54.4, 80.0, 81.6, 115.0, 137.8, 155.5, 156.9, 177.1.
4. Experimental section
4.1. General
ESI-MS: m/z¼266 [MþNa]þ, 509 [2MþNa]þ.
4.4. Two-step general procedure for esterification
and alkyne reduction
All reactions were performed under argon with magnetic stir-
ring unless otherwise specified. Moisture or air-sensitive reactions
were conducted under an argon atmosphere in oven-dried glass-
ware. Tetrahydrofuran (THF) was freshly distilled from sodium/
benzophenone under argon prior to use. Dichloromethane was
distilled from calcium hydride under argon. Diisopropylamine,
triethylamine, and diisopropylethylamine were dried with potas-
sium hydroxide and freshly distilled before use. Commercial an-
hydrous zinc(II) chloride was used without further purification. All
other reagents were used as supplied. Flash chromatography was
performed on an Armen SpotFlash with silica gel 60 (particle size
(a) Esterification
The carboxylic acid (1.1 equiv) was dissolved in dry methylene
chloride (10 mL) and cooled to 0 ꢂC. The chiral alcohol [(R) or (S)-
but-3-yn-2-ol (both 98% ee)] (1 equiv) was then added followed by
a
catalytic amount of DMAP (0.1 equiv). A solution of DCC
(1.2 equiv) in CH2Cl2 was slowly added dropwise. The mixture was
allowed to warm to rt and was stirred overnight. The solvent was
evaporated, a minimal amount of EtOAc was added, and the re-
action mixture was filtered on Celite to remove most of the pre-
cipitated urea. The crude product was used without further
purification in the next step.
15e40
m
m). Optical rotations were recorded at 20 ꢂC. Mass spectra
(MS and HRMS) were acquired using ESI techniques. NMR spectra
were obtained using a 500 or a 250 MHz spectrometer. Chemical
shifts were measured in
(solvent peak reference:
d
(ppm) and coupling constants J in hertz
(b) Alkyne reduction
d
¼7.27 for 1H, 77.0 for 13C). Multiplicities
are indicated by s (singlet), d (doublet), t (triplet), q (quartet), qui
(quintuplet), m (multiplet) or br (broad). Elemental analyses were
performed on a Flash EA 1112 apparatus. Enantiomeric excess was
determined by chiral HPLC analysis using a Chiralcel IC column
(n-hexane/isopropanol 92:8 with a flow rate of 0.7 mL/min for
compounds 23 and 24; n-hexane/isopropanol 80:20 with a flow
rate of 0.8 mL/min for compound 25) or a Chiralcel OD-H column (n-
hexane/isopropanol 99:1 with a flow rate of 1.0 mL/min for com-
pound 26). Peak detection was done at 220 nm.
Lindlar’s catalyst (palladium (5%) on calcium carbonate, poi-
soned with lead,10 wt %) was added to a solution of freshly distilled
quinoline (0.25 equiv) and the chiral ester in EtOAc at rt. The re-
action flask was then evacuated and flushed with hydrogen gas
three times, and the reaction mixture was left to stir under a balloon
of hydrogen gas. After 15e30 min, the mixture was filtered through
a pad of Celite and evaporated under reduced pressure. After 1H and
13C NMR analysis of the crude reaction mixture to verify the absence
of the starting alkyne as well as the fully saturated alkane, it was
purified by column chromatography to give the desired ester.
1H and 13C spectra are described only once for each pair of
enantiomers.
4.4.1. 2-tert-Butoxycarbonylamino-hex-5-enoic acid (S)-1-methyl-
allyl ester (10). Yield 63% (two steps, colorless oil, mixture of di-
astereoisomers). Rf¼0.38 (petroleum ether/EtOAc 95:5). 1H NMR
4.2. 2-tert-Butoxycarbonylamino-hex-5-enoic acid (7)
This acid was prepared from diethylacetamidomalonate and 4-
bromo-1-pentene using a slightly modified procedure to obtain
compound 7 in the last step.29 2-Acetylamino-hex-5-enoic acid (8)
was an intermediate in this reaction sequence.
(250 MHz, CDCl3):
d
¼1.34/1.35 (2ꢃd, J¼2.7 Hz, 3H), 1.45 (s, 9H), 1.73
(m, 1H), 1.90 (m, 1H), 2.11 (m, 2H), 4.30 (m, 1H), 5.04 (m, 2H), 5.16
(dd, J¼10.5, 1.1 Hz, 1H), 5.26 (dd, J¼17.3, 1.2 Hz, 1H), 5.39 (m, 1H),
5.82 (m, 2H). 13C NMR (62.5 MHz, CDCl3):
32.0, 53.1, 72.0, 72.1, 79.7, 115.6, 116.2, 116.3, 137.0, 155.3, 171.9. ESI-
MS: m/z¼329.3 [Mþ2Na]þ. C15H25NO4 (283.36): calcd C 63.58, H
8.89, N 4.94; found C 63.26, H 8.91, N 4.84.
d
¼19.8, 19.9, 28.3, 29.4,
2-Amino-hex-5-enoic acid hydrochloride (2.48 g, 15 mmol) was
suspended in a 1:1 1,4-dioxane/water mixture (50 mL) at rt. To this
mixture was added di-tert-butyldicarbonate (3.92 g, 17.9 mmol
1.2 equiv) followed by diisopropylethylamine (5.8 g, 45 mmol,
7.8 mL, 3 equiv). The reaction mixture was allowed to stir overnight
before removing the dioxane under reduced pressure. The aqueous
layer was then extracted with diethyl ether (2ꢃ30 mL) and acidi-
fied with aqueous 4 N HCl. The acidified aqueous layer was then
extracted with EtOAc (3ꢃ50 mL). The combined organic layers
were washed with brine, dried with MgSO4, filtered, and evapo-
rated under reduced pressure to give a colorless oil (3.2 g, 94%). The
acid was used without further purification in the coupling steps. 1H
4.4.2. 2-tert-Butoxycarbonylamino-hex-5-enoic acid (R)-1-methyl-
allyl ester (11). Yield 69% (two steps, colorless oil, mixture of di-
astereoisomers). ESI-MS: m/z¼329.3 [Mþ2Na]þ. C15H25NO4
(283.36): calcd C 63.58, H 8.89, N 4.94; found C 63.24, H 8.93, N 4.86.
4.4.3. 2-Acetylamino-hex-5-enoic acid (S)-1-methyl-allyl ester (12).
Yield 57% (two steps, colorless oil, mixture of diastereoisomers).
Rf¼0.23 (petroleum ether/EtOAc 70:30). 1H NMR (500 MHz, CDCl3):

5034
K. Plé et al. / Tetrahedron 66 (2010) 5030e5035
d
¼1.34/1.35 (2ꢃd, J¼2.7 Hz, 3H), 1.77 (m, 1H), 1.96 (m, 1H), 2.03 (s,
J¼17.1, 1.3 Hz,1H), 5.21 (m,1H), 5.51 (m, 1H), 5.75 (m, 1H), 6.39 (br s,
1H). 13C NMR (125 MHz, CDCl3):
64.7, 115.0, 124.5, 129.5, 137.4, 169.0, 174.2. ESI-MS: m/z¼240.2
[MþH]þ. C13H21NO3 (239.31): calcd C 65.25, H 8.84, N 5.85; found C
64.91, H 8.84, N 5.88.
3H), 2.09 (m, 2H), 4.63 (dt, J¼7.7, 5.4 Hz, 1H), 5.02 (m, 2H), 5.17 (d,
J¼10.5 Hz, 1H), 5.27 (dd, J¼17.3, 1.2 Hz, 1H), 5.39 (m, 1H), 5.81 (m,
d
¼18.0, 24.0, 28.6, 33.7, 38.2, 52.6,
2H), 6.21 (br s, 1H). 13C NMR (125 MHz, CDCl3):
d¼19.8, 19.9, 23.1,
29.3, 29.4, 31.7, 31.7, 51.9, 72.3, 72.4, 115.6, 116.4, 116.6, 136.9, 137.0,
169.8, 171.8. ESI-MS: m/z¼226.2 [MþH]þ. C12H19NO3 (225.28):
calcd C 63.98, H 8.50, N 6.22; found C 63.93, H 8.62, N 6.19.
4.5.4. (E)-(S)-2-But-2-enyl-2-tert-butoxycarbonylamino-hept-6-
enoic acid methyl ester (17). Yield 71% (colorless oil). Rf¼0.58 (pe-
20
4.4.4. 2-tert-Butoxycarbonylamino-hept-6-enoic acid (S)-1-methyl-
troleum ether/EtOAc 95:5). [
a]
þ15.9 (c 0.48, CHCl3). 1H NMR
D
allyl ester (13). Yield 59% (two steps, colorless oil, mixture of di-
(250 MHz, CDCl3):
d
¼1.13 (m, 1H), 1.44 (br s, 10H), 1.63 (d, J¼6.1 Hz,
astereoisomers). 1H NMR (250 MHz, CDCl3):
d
¼1.33/1.35 (2ꢃd,
3H), 1.75 (m, 1H), 2.02 (q, J¼7.1 Hz, 2H), 2.23 (m, 1H), 2.40 (dd,
J¼13.9, 7.0 Hz, 1H), 2.93 (m, 1H), 3.74 (s, 3H), 4.97 (m, 2H), 5.22 (m,
1H), 5.47 (m, 2H), 5.75 (tdd, J¼16.8, 10.1, 6.6 Hz, 1H). 13C NMR
J¼3.9 Hz, 3H), 1.44 (br s, 11H), 1.65 (m, 1H), 1.80 (m, 1H), 2.07 (m,
2H), 4.29 (m, 1H), 4.91e5.32 (m, 4H), 5.39 (m, 1H), 5.80 (m, 2H). 13C
NMR (62.5 MHz, CDCl3):
d
¼19.7, 19.8, 24.3, 28.2, 32.0, 33.0, 53.3,
(62.5 MHz, CDCl3):
d
¼18.0, 23.2, 28.3, 33.3, 34.6, 38.5, 52.4, 63.7,
71.8, 79.5, 114.9, 116.1, 116.2, 137.0, 137.1, 137.8, 155.2, 171.9. ESI-MS:
m/z¼320.3 [MþNa]þ. C16H27NO4 (297.39): calcd C 64.62, H 9.15, N
4.71; found C 64.47, H 9.20, N 4.58.
78.9, 114.7, 124.7, 129.4, 138.2, 153.8, 174.1. ESI-MS: m/z¼312.4
[MþH]þ. C17H29NO4 (311.41): calcd C 65.57, H 9.39, N 4.50; found C
65.90, H 9.49, N 4.48.
4.5. General procedure for the Claisen rearrangement
4.5.5. [(E)-(S)-1-But-3-enyl-1-((S)-1-phenyl-ethylcarbamoyl)-pent-3-
enyl]-carbamic acid tert-butyl ester (19). To a solution of the crude
acid 140 (0.073 g, 0.26 mmol) in dry THF (2 mL) was added (S)-
methylbenzylamine (0.94 g, 0.77 mmol, 0.100 mL, 3 equiv), diiso-
propylethylamine (0.067 g, 0.51 mmol, 0.90 mL, 2 equiv), and 3-
(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (DEPBT)30
(0.154 g, 0.51 mmol, 2 equiv) at rt. After stirring overnight, a satu-
rated aqueous NaCl solution was added (2 mL), and the amide
extracted with EtOAc (3ꢃ2 mL). The combined organic layers were
washed with aqueous 1 N HCl, water, aqueous 5% Na2CO3, brine, and
dried over MgSO4. The solvent was removed under reduced pressure
and the crude reaction purified by flash column chromatography to
give 0.059 g of the amide 19 as a white amorphous powder. Yield
Zinc(II) chloride (1.5 equiv) was melted under vacuum with
a heat gun and then cooled. In a separate flask, n-BuLi (2.7 equiv,
2.3 M solution in hexanes) was added to diisopropylamine
(3.4 equiv) in anhydrous THF at 0 ꢂC. After 15 min, the solution was
cooled to ꢀ78 ꢂC. THF (1 mL) was then added to the melted ZnCl2,
and the solution was stirred at rt to dissolve all of the white solid.
The starting ester (1 equiv) suspended in a minimum amount of
THF was added to the ZnCl2 solution and this mixture was cooled to
0 ꢂC. This solution was then slowly added by cannula to the LDA
flask at ꢀ78 ꢂC. The mixture was allowed to stir for a further 5 min
before being placed at ꢀ5 ꢂC for 4e6 h. After addition of an aqueous
1 M KHSO4 solution, the phases were separated, and the aqueous
layer was extracted with diethyl ether. The combined organic layers
were dried with MgSO4, filtered, and the solvent evaporated in
vacuo. The crude reaction mixture was treated with diazomethane
to generate the corresponding methyl ester and purified by flash
chromatography (petroleum ether/EtOAc, 95:5 (Boc derivative) or
70:30 (Ac derivative)). Alternatively, in the presence of unreacted
starting material, the acid was purified by flash chromatography
(petroleum ether/EtOAc, 90:10 to 50:50). The clean acid was then
treated with a solution of diazomethane in ether to give the cor-
responding methyl ester.
59%. [
a
]
20 ꢀ36.7 (c 0.22, CHCl3).1H NMR (500 MHz, CDCl3):
d¼1.42 (s,
D
9H, C(CH3)3), 1.49 (d, J¼6.9 Hz, 3H, CH3CHPh), 1.61 (d, J¼6.1 Hz, 3H,
CH3CH]CHe), 1.79 (m, 1H, CH2), 1.91 (m, 1H, CH2), 2.01 (m, 1H, CH2),
2.19 (br s, 1H, CH2), 2.50 (dd, J¼14.2, 6.7 Hz, 1H, CH2), 2.67 (br s, 1H,
CH2), 4.93 (d, J¼10.1 Hz, 1H, CH2]CHe), 4.98 (dd, J¼17.1, 1.4 Hz, 1H,
CH2]CHe), 5.11 (qui, J¼7.0 Hz, 1H, CH3CHPh), 5.25 (m, 1H, eCH]
CHCH3), 5.45 (td, J¼13.0, 6.1 Hz, 1H, eCH]CHCH3), 5.76 (tdd, J¼16.8,
10.1, 6.5 Hz, 1H, CH2]CHe), 6.49 (br s, 1H, NH), 7.26 (m, 1H, Ph), 7.32
(m, 4H, Ph). 13C NMR (125 MHz, CDCl3):
d
¼18.1, 21.5, 28.1, 28.3, 34.9,
38.7, 48.9, 62.2, 114.9, 124.7, 126.2, 127.3, 128.6, 130.2, 137.7, 143.0,
154.5, 171.9. ESI HRMS: m/z calcd for C23H34N2O3 (MþNa)þ 409.2467,
found 409.2459. C23H34N2O3 (386.50): calcd C 71.47, H 8.87, N 7.25;
found C 71.39, H 8.88, N 7.09.
4.5.1. (E)-(S)-2-But-3-enyl-2-tert-butoxycarbonylamino-hex-4-enoic
acid methyl ester (14). Yield 63% (colorless oil). Rf¼0.60 (petroleum
20
ether/EtOAc 95:5). [
a
]
þ19.8 (c 0.55, CHCl3). 1H NMR (500 MHz,
4.5.6. [(E)-(S)-1-But-3-enyl-1-((R)-1-phenyl-ethylcarbamoyl)-pent-
3-enyl]-carbamic acid tert-butyl ester (20). This compound was
prepared using the same procedure as for 19.
D
CDCl3):
d
¼1.44 (s, 9H), 1.63 (d, J¼5.8 Hz, 3H), 1.84 (m, 2H), 2.06 (m,
1H), 2.35 (m, 1H), 2.40 (dd, J¼13.8, 7.1 Hz, 1H), 2.96 (br s, 1H), 3.74
(s, 3H), 4.93 (d, J¼10.1 Hz, 1H), 4.99 (dd, J¼17.1, 1.2 Hz, 1H), 5.22 (m,
1H), 5.48 (m, 2H), 5.75 (ddt, J¼16.6, 10.2, 6.5 Hz, 1H). 13C NMR
Yield 55%. [
a]
20 þ3.2 (c 0.29, CHCl3). 1H NMR (500 MHz, CDCl3):
D
d
¼1.41 (s, 9H, C(CH3)3), 1.49 (d, J¼6.9 Hz, 3H, CH3CHPh), 1.65 (d,
(125 MHz, CDCl3):
d¼18.1, 28.3, 28.5, 34.3, 38.7, 52.5, 63.5, 79.1,
J¼6.0 Hz, 3H, CH3CH]CHe), 1.81 (m, 2H, CH2), 2.02 (m, 1H, CH2),
2.21 (br s, 1H, CH2), 2.53 (m, 1H CH2), 2.71 (br s, 1H, CH2), 4.95 (m,
2H, CH2]CH), 5.12 (m, 1H, CH3CHPh), 5.30 (m, 1H, eCH]CHCH3),
5.52 (dt, J¼12.6, 6.0 Hz, 1H, eCH]CHCH3), 5.74 (tdd, J¼12.8, 9.9,
6.4 Hz, 1H, CH2]CHe), 6.49 (br s, 1H, NH), 7.27 (m, 1H, Ph), 7.32 (m,
114.9, 124.6, 129.6, 137.6, 153.8, 174.0. ESI-MS: m/z¼298.2 [MþNa]þ.
C16H27NO4 (297.39): calcd C 64.62, H 9.15, N 4.71; found C 64.49, H
9.11, N 4.86.
4.5.2. (E)-(R)-2-But-3-enyl-2-tert-butoxycarbonylamino-hex-4-
4H, Ph). 13C NMR (125 MHz, CDCl3):
d
¼18.1, 21.6, 28.1, 28.2, 35.0,
enoic acid methyl ester (15). Yield 68% (colorless oil). [
a
]
20 ꢀ18.2 (c
38.8, 48.8, 62.2, 114.9, 124.8, 126.1, 127.3, 128.6, 130.1, 137.6, 143.0,
154.4, 171.9. ESI HRMS: m/z calcd for C23H34N2O3 (MþNa)þ
409.2467, found 409.2465. C23H34N2O3 (386.50): calcd C 71.47, H
8.87, N 7.25; found C 71.73, H 8.93, N 7.17.
D
0.53, CHCl3). ESI-MS: m/z¼343.3 [Mþ2Na]þ. C16H27NO4 (297.39):
calcd C 64.62, H 9.15, N 4.71; found C 64.27, H 9.12, N 4.68.
4.5.3. (E)-(S)-2-Acetylamino-2-but-3-enyl-hex-4-enoic acid methyl
ester (16). Yield 84% (colorless oil). Rf¼0.32 (petroleum ether/
4.6. General procedure for ring closing metathesis
20
EtOAc 70:30). [
a]
þ34.9 (c 0.97, CHCl3). 1H NMR (500 MHz,
D
CDCl3):
d¼1.64 (d, J¼5.8 Hz, 3H), 1.80 (m, 1H), 1.86 (m, 1H), 2.02 (s,
The methyl ester (1 equiv) was dissolved in CH2Cl2 (0.2 M so-
lution). First generation Grubbs catalyst (0.1 equiv) was added and
the reaction mixture heated to 40 ꢂC until disappearance of the
3H), 2.05 (br s, 1H), 2.42 (dd, J¼13.8, 7.3 Hz, 1H), 2.57 (m, 1H), 3.14
(dd, J¼13.8, 7.4 Hz, 1H), 3.77 (s, 3H), 4.95 (d, J¼9.6 Hz, 1H), 5.00 (dd,

K. Plé et al. / Tetrahedron 66 (2010) 5030e5035
5035
starting material as indicated by TLC (1e3 h). At the end of the
reaction, the catalyst was effectively removed by filtering the crude
mixture through a pad of silica gel. The filtered solution was then
treated with activated charcoal overnight,31 filtered, and purified
by flash chromatography.
procedure for ring closing metathesis. Yield 86% (white amorphous
solid). Rf¼0.28 (petroleum ether/EtOAc 90:10). 1H NMR (250 MHz,
CDCl3):
d
¼1.43 (s, 9H), 2.62 (br d, J¼16.5 Hz, 2H), 3.06 (br d,
J¼15.9 Hz, 2H), 3.75 (s, 3H), 5.15 (br s, 1H), 5.66 (s, 2H). 13C NMR
(62.5 MHz, CDCl3):
d
¼28.2, 44.9, 52.5, 64.2, 79.9, 127.6, 154.9, 174.7.
ESI HRMS: m/z calcd for C12H19NO4 (MþNa)þ 264.1212, found
264.1212. C12H19NO4 (241.28): calcd C 59.73, H 7.94, N 5.81; found C
59.77, H 7.99, N 5.79.
4.6.1. (S)-1-tert-Butoxycarbonylamino-cyclohex-3-enecarboxylic
acid methyl ester (23). Yield 95% (white amorphous powder).
20
Rf¼0.28 (petroleum ether/EtOAc 90:10). [
a
]
þ53.0 (c 0.91,
D
CHCl3). 1H NMR (500 MHz, CDCl3):
d
¼1.43 (s, 9H), 1.92 (m, 1H), 2.11
4.6.8. 1-Aminocyclopent-3-ene-1-carboxylic acid hydrochloride (1).
Compound 30 (0.21 g, 0.87 mmol) was stirred with HCl (4 M,
20 mL) at rt for 14 h. The reaction mixture was filtered and con-
centrated under vacuum to give 0.128 g (90%) of the hydrochloride
salt of carboxylic acid 1. 1H and 13C NMR were performed in D2O
and were in agreement with published data.28
(m, 2H), 2.24 (m, 2H), 2.57 (br d, J¼17.7 Hz, 1H), 3.74 (s, 3H), 4.83
(br s, 1H), 5.59 (m, 1H), 5.74 (m, 1H). 13C NMR (125 MHz, CDCl3):
d
¼21.7, 27.5, 28.3, 34.1, 52.3, 56.9, 79.8, 122.4, 127.1, 154.9, 174.7. ESI
HRMS m/z calcd for C13H21NO4 (MþNa)þ 278.1368, found
278.1361. C13H21NO4 (255.31): calcd C 61.16, H 8.29, N 5.49; found
C 61.29, H 8.31, N 5.40.
4.6.2. (R)-1-tert-Butoxycarbonylamino-cyclohex-3-enecarboxylic
Acknowledgements
20
acid methyl ester (24). Yield 90% (amorphous white powder). [a]
D
ꢀ51.5 (c 0.84, CHCl3). ESI HRMS: m/z calcd for C13H21NO4 (MþNa)þ
278.1368, found 278.1360. C13H21NO4 (255.31): calcd C 61.16, H
8.29, N 5.49; found C 61.10, H 8.25, N 5.43.
We would like to thank the University of Champagne Ardennes
and the Centre National de Recherche Scientifique (CNRS) for their
financial support, as well as AstraZeneca for the PhD scholarship
awarded to N.P. Special thanks are due to Mme Sylvie Lanthony for
performing the chiral HPLC analyses.
4.6.3. (S)-1-Acetylamino-cyclohex-3-enecarboxylic acid methyl ester
(25). Yield 83% (white amorphous powder). Rf¼0.13 (petroleum
20
ether/EtOAc 50:50). [
a
]
þ85.8 (c 0.51, CHCl3). 1H NMR (500 MHz,
D
CDCl3):
d
¼1.92 (m,1H),1.99 (s, 3H), 2.04 (br m,1H), 2.14 (m,1H), 2.24
Supplementary data
(br d, 2.25, J¼17.3 Hz, 1H), 2.36 (m, 1H), 2.57 (d, J¼17.9 Hz, 1H), 3.73
(s, 3H), 5.60 (m,1H), 5.77 (m, 2H). 13C NMR (125 MHz, CDCl3):
d¼21.7,
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.008.
23.1, 26.8, 33.9, 52.4, 56.8, 122.3, 127.3, 169.8, 174.1. ESI HRMS: m/z
calcd for C10H15NO3 (MþH)þ 198.1130, found 198.1140. C10H15NO3
(197.23): calcd C 60.90, H 7.67, N 7.10; found C 60.98, H 7.70, N 7.10.
References and notes
4.6.4. (S)-1-tert-Butoxycarbonylamino-cyclohept-3-enecarboxylic
1. Toniolo, C.; Formaggio, F.; Kaptein, B.; Broxterman, Q. B. Synlett 2006,1295e1310.
2. Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001,101, 3131e3152.
3. Kaptein, B.; Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Veerman, J. J.
N.; Kamphuis, J.; Peggion, C.; Formaggio, F.; Toniolo, C. Tetrahedron 2001, 57,
6567e6577.
acid methyl ester (26). Yield 72% (white amorphous powder).
Rf¼0.35 (petroleum ether/EtOAc 90:10). [
a
]
20 ꢀ57.4 (c 0.73, CHCl3).
D
1H NMR (500 MHz, CDCl3):
d
¼1.43 (s, 10H), 1.67 (m, 1H), 2.05 (m,
1H), 2.13 (m, 1H), 2.24 (m, 1H), 2.39 (br d, J¼10.7 Hz, 1H), 2.62 (m,
4. Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645e732.
5. Cativiela, C.; Ordóñez, M. Tetrahedron: Asymmetry 2009, 20, 1e63.
2H), 3.73 (s, 3H), 4.80 (br s, 1H), 5.58 (m, 1H), 6.02 (m, 1H). 13C NMR
(125 MHz, CDCl3):
d
¼20.9, 28.3, 28.6, 35.1, 37.7, 52.3, 59.0, 124.7,
€
6. Schollkopf, U.; Groth, U.; Deng, C. Angew. Chem. 1981, 93, 793e795.
136.0, 154.5, 175.1. ESI-MS: m/z¼292.3 [MþNa]þ. C14H23NO4
€
7. Schollkopf, U.;Hinrichs, R.;Lonsky, R. Angew. Chem., Int. Ed. Engl.1987, 26,143e145.
8. Hammer, K.; Undheim, K. Tetrahedron 1997, 53, 2309e2322.
9. Undheim, K. Amino Acids 2008, 34, 357e402.
(269.34): calcd C 62.43, H 8.61, N 5.20; found C 62.11, H 8.60, N 5.13.
10. Jam, F.; Tullberg, M.; Luthman, K.; Grøtli, M. Tetrahedron 2007, 63, 9881e9889.
11. Avenoza, A.; Cativiela, C.; Fernández-Recio, M. A.; Peregrina, J. M. Tetrahedron:
Asymmetry 1996, 7, 721e728.
4.6.5. 2-tert-Butoxycarbonylamino-pent-4-enoic acid allyl ester
(28). This compound was prepared as described in the general
esterification protocol with 2-tert-butoxycarbonylamino-pent-4-
enoic acid3 and an excess (3 equiv) of allyl alcohol. Yield 94% (col-
orless oil). Rf¼0.24 (petroleum ether/EtOAc 95:5). 1H NMR
12. Probst, N. P.; Haudrechy, A.; Plé, K. J. Org. Chem. 2008, 73, 4338e4341.
13. Kazmaier, U. In The Claisen Rearrangement; Hiersemann, M., Nubbemeyer, U.,
Eds.; Wiley-VCH GmbH KgaA: Weinheim, 2007; pp 233e299.
14. Quirin, C.; Kazmaier, U. Eur. J. Org. Chem. 2009, 2009, 371e377.
15. Looper, R. E.; Runnegar, M. T. C.; Williams, R. M. Tetrahedron2006, 62, 4549e4562.
16. Kazmaier, U.; Schneider, C. Synthesis 1998, 1321e1326.
17. Deprés, J. P.; Greene, A. E. J. Org. Chem. 1984, 49, 928e931.
18. Doller, D.; Chackalamannil, S.; Stamford, A.; McKittrick, B.; Czarniecki, M. Bio-
org. Med. Chem. Lett. 1997, 7, 1381e1386.
19. Hodgson, D. M.; Thompson, A. J.; Wadman, S. Tetrahedron Lett. 1998, 39,
3357e3358.
20. Hodgson, D. M.; Thompson, A. J.; Wadman, S.; Keats, C. J. Tetrahedron 1999, 55,
10815e10834.
(500 MHz, CDCl3):
d
¼1.44 (s, 9H), 2.53 (m, 2H), 4.40 (m, 1H), 4.63
(m, 1H), 5.05 (d, J¼7.3 Hz, 1H), 5.13 (m, 2H), 5.25 (d, J¼10.4 Hz, 1H),
5.34 (dd, J¼17.2, 1.1 Hz, 1H), 5.69 (m, 1H), 5.90 (m, 1H). 13C NMR
(125 MHz, CDCl3):
d
¼28.3, 36.7, 52.9, 65.9, 79.9, 118.8, 119.2, 131.6,
132.2, 155.2, 171.8. ESI-MS: m/z¼278.2 [MþNa]þ. C13H21NO4
(255.31): calcd C 61.16, H 8.29, N 5.49; found C 61.11, H 8.18, N 5.57.
21. Park, K.-H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 6579e6585.
22. Park, K.-H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 113e117.
23. Park, K.-H.; Kurth, T. M.; Olmstead, M. M.; Kurth, M. J. Tetrahedron Lett. 2001, 42,
991e992.
24. Amori, L.; Costantino, G.; Marinozzi, M.; Pellicciari, R.; Gasparini, F.; Flor, P. J.;
Kuhn, R.; Vranesic, I. Bioorg. Med. Chem. Lett. 2000, 10, 1447e1450.
25. Larionov, O. V.; Kozhushkov, S. I.; de Meijere, A. Synthesis 2005, 158e160.
26. Kotha, S.; Sreenivasachary, N. Bioorg. Med. Chem. Lett. 1998, 8, 257e260.
27. Kotha, S.; Sreenivasachary, N.; Mohanraja, K.; Durani, S. Bioorg. Med. Chem. Lett.
2001, 11, 1421e1423.
28. Casabona, D.; Cativiela, C. Synthesis 2006, 2440e2443.
29. Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc., Perkin Trans. 1 1998,
2485e2500.
30. Ye, Y.-h.; Li, H.; Jiang, X. Pept. Sci. 2005, 80, 172e178.
31. Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531e533.
4.6.6. 2-Allyl-2-tert-butoxycarbonylamino-pent-4-enoic acid methyl
ester (29). This compound was prepared using the general pro-
cedure for the Claisen rearrangement. Yield 63% (colorless oil).
Rf¼0.39 (petroleum ether/EtOAc 95:5). 1H NMR (250 MHz, CDCl3):
d
¼1.43 (s, 9H), 2.53 (dd, J¼13.8, 7.3 Hz, 2H), 3.0 (m, 2H), 3.75 (s, 3H),
5.09 (m, 4H), 5.40 (br s, 1H), 5.64 (m, 2H). 13C NMR (62.5 MHz,
CDCl3):
d
¼28.4, 39.6, 52.6, 63.4, 79.4, 119.1, 132.4, 154.0, 173.5. ESI
HRMS: m/z calcd for C14H23NO4 (MþH)þ 270.1705, found 270.1699.
4.6.7. 1-tert-Butoxycarbonylamino-cyclopent-3-enecarboxylic acid
methyl ester (30). This compound was prepared using the general