Ring closing metathesis of α- and β-amino acid derived dienes

Article abstract of DOI:10.1016/j.jorganchem.2006.09.061

Three new classes of conformationally constrained peptidomimetics, derived from modified α- and β-amino acids, have been prepared by ring closing metathesis (RCM). The first involves C_α-N′ cyclisation of the peptidic diene (23, 24, 26), the sec

Full text of DOI:10.1016/j.jorganchem.2006.09.061

Journal of Organometallic Chemistry 691 (2006) 5487–5496
www.elsevier.com/locate/jorganchem
Ring closing metathesis of a- and b-amino acid derived dienes
*
James Gardiner, Steven G. Aitken, Stephen B. McNabb, Shazia Zaman, Andrew D. Abell
Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
Received 7 August 2006; received in revised form 11 September 2006; accepted 12 September 2006
Available online 12 October 2006
Abstract
Three new classes of conformationally constrained peptidomimetics, derived from modified a- and b-amino acids, have been prepared
by ring closing metathesis (RCM). The first involves Ca–N0 cyclisation of the peptidic diene (23, 24, 26), the second Cb2–N0 cyclisation
(27, 28, 29), and the third N–Cb2 cyclisation (30). The key C-centred olefin of the dienes was introduced by stereoselective a-allylation of
either an a- or b-amino acid. The normal favourable influence of a tertiary amide linker in the diene towards RCM is negated by sig-
nificant steric congestion, and the combination of a secondary amide linker and a,a-disubstitution promotes ring contraction on RCM.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Cyclic peptidomimetics; b-Amino acids; Ring closing metathesis; Conformation; b-Turn
1. Introduction
functional group tolerance and resistance to oxygen and
moisture has also greatly facilitated progress in this area
[14,15].
The introduction of conformational restriction (e.g. a
ring) into a peptide can lead to increased binding, and
hence potency, towards its corresponding bio-receptor.
This is not a random process since the geometry and elec-
trostatics of the modified peptide must complement that of
the binding site in the receptor. Each system has its own
requirements and as such versatile and reliable synthetic
methods are needed that introduce rings into linear pep-
tides in a variety of ways, as shown in Fig. 1 for a- and
b-peptides. One method that has recently shown much
promise in this area is ring closing metathesis (RCM) [1–
11].
The advantage of RCM is that it allows the introduction
of rings of varying size, and hence conformation, into a
modified peptide. However, one must first construct a suit-
able diene substrate by introducing olefinic groups into a
precursor acyclic peptide. This is now possible in a number
of ways as evidenced in this paper and discussed elsewhere
[2,3,9,12,13]. The commercial availability of well-defined
metathesis catalysts with high activity, thermal stability,
b-Strands and b-turns are ideal targets for work in this
area since these geometries are central to a number of
important biological interactions and hence effects. For
example, proteases are known to bind their substrates in
an extended b-strand geometry, a fact that has been put
to good effect in inhibitor design [16]. RCM has been used
to prepare potent inhibitors (1) of the Hepatitis C Virus
NS3 protease by linking the side chains of the first and
third residues of an acyclic precursor (Ca–Ca, Fig. 1) to
give a b-strand constraint [17]. A good example of the
use of turn motifs can be found in the area of peptide-acti-
vated G protein-coupled receptors. Here agonists and
antagonists are designed to adopt turn motifs that mimic
the intramolecular hydrogen bond between the carbonyl
of residue i and the NH of either the third, fourth or fifth
residue of the natural peptide backbone [18]. The antago-
nist 2, prepared by RCM, functions as a turn mimetic in
binding to the Grb2 SH2 domain protein [19] (see Fig. 2).
We have had an interest for some time in developing
general RCM-based methods for the preparation of a vari-
ety of constrained peptides, e.g. cyclic b-amino acids (Cb3–
Cb2) [2,20], proline peptidomimetics (N–Ca) [3,21] and
*
Corresponding author. Tel.: +64 3 3642818; fax: +64 3 3642110.
E-mail address: andrew.abell@canterbury.ac.nz (A.D. Abell).
0022-328X/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.09.061

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J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
Fig. 1. Possible sites for the inclusion of ring constraints into (a) a-
peptides, and (b) b-peptides.
cyclic dipeptides (Ca–Ca) [22]. We now extend this work to
prepare new conformationally constrained peptidomimet-
ics 23, 24, and 26 (Ca–N0 cyclisation), 27, 28, 29, (Cb2–N0
cyclisation) and 30 (N–Cb2 cyclisation), that literature
[9,23], and some preliminary modeling, suggested would
adopt turn geometries. Our work also provides some
insights into the factors that influence RCM in peptide-like
structures. In addition, we demonstrate some approaches
for introducing olefins into amino acids and peptides to
give the diene substrates for RCM. With these factors in
mind the dienes 4, 9, 13, 17, 20, 21, and 22 were prepared,
and subjected to RCM to give previously unknown 6- and
7-membered peptidomimetics (Table 1). Some work is also
presented on determining the ability of the cyclic peptidom-
imetics to form turns: the lactams 26, 27, 28 and 30 were
modeled in-silico to determine their ability to stabilize b-
turn conformations in penta-residue peptides, and the aze-
pine unit of 30 was incorporated into a calpain inhibitor.
Fig. 2. Conformationally constrained peptidomimetics.
components of dienes, particularly those giving rise to
small and medium sized rings. With these points in mind
dienes with secondary amides (4, 9, 17 and 20) and tertiary
amides (13 and 21) where prepared to gain some insight
into the effect of ring size and substitution on the outcome
of RCM. Phenylalanine-containing systems were targeted
due to ease of synthesis, but the methods presented are
amenable to introducing a variety of amino acids into
structures of this type.
The requisite diene 4 (92%) was prepared by coupling
( )-N-Boc-allyl glycine with allylamine under standard
N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide hydro-
chloride (EDCI) and 1-hydroxybenzotriazole hydrate
(HOBt) conditions, see Scheme 1. Dienes 9 and 13 required
the introduction an allyl substituent at the a-carbon of (S)-
phenylalanine with control of stereochemistry and this was
2. Results and discussion
It has been reported that dienes in which a secondary
amide links the component double bonds do not readily
undergo RCM [24]. By contrast a tertiary amide linker
facilitates RCM by increasing the population of the amide
rotamer in which the alkenes are cis [25,26]. In fact, the
introduction of a further and removable substituent onto
nitrogen of an amide, has been used to promote RCM
[24]. Increased substitution of a diene, as provided by a ter-
tiary amide, would also be expected to enhance the rate of
cyclisation via the Gem-Dimethyl effect [27,28]. Examples
of the use of secondary amides in RCM are known and
these generally give rise to larger-ring lactams, such as 9-
[29], 10- [24,30], and 18-membered systems [31]. However,
little is known about the effect on the RCM of introducing
substituents into the a- and particularly b-amino acids
Scheme 1. Allylamine, EDCI, HOBt, DIPEA, DCM, rt.

J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
5489
achieved using Seebach oxazolidinone chemistry (Scheme
2). In particular, the anti-oxazolidinone 7 [32], obtained
from the sodium salt of 6 on treatment with benzaldahyde
followed by benzoyl chloride, was allylated to give a,a-
disubstituted 8 as the single stereoisomer shown [33]. Treat-
ment of this with the lithium salt of allylamine in THF gave
the desired diene 9 in 91% after purification by chromatog-
raphy. The diene 13 was similarly prepared (Scheme 2), but
using N-carbobenzyloxy (Cbz) protection to provide prod-
ucts after RCM that were suitably protected for incorpora-
tion into peptide synthesis. It is interesting to note that this
change in protecting group gives rise to compounds with
the opposite absolute configuration in the allylation step,
but this was not considered of significance. Preparation
of the tertiary amide 13 required hydrolysis of the oxazolin-
inone 11 [34] followed by coupling with N-allyl-glycine
ethyl ester in the presence of the peptide coupling agent,
(7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumm
hexafluorophosphate (PyAOP). This gave a modest 18%
yield of 13.
The b-amino acid based dienes 17, 20, 21 and 22 were
prepared as shown in Scheme 3. Arndt-Eistert homologa-
tion [35,36] of N-Cbz-(S)-phenylalanine 10, followed by
Scheme 3. (i) Et3N, ClCO2Et, THF, ꢀ20 ꢁC; (ii) CH2N2; (iii) PhCO2Ag,
Et3N, MeOH ꢀ20 ꢁC to rt; (iv) MeI, LDA, LiCl, THF ꢀ78 ꢁC; (v) allyl
bromide, LDA, LiCl, THF ꢀ78 ꢁC; (vi) NaOH, MeOH, reflux; (vii) allyl
amine, EDCI, HOBt, DIPEA, DCM; (viii) allyl bromide, LDA, LICl,
THF ꢀ78 ꢁC; (ix) PyAOP, N-allylglycine ethyl ester, DIPEA, DMF; (x)
allyl bromide, P4-phosphazene, THF.
stereocontrolled allylation or methylation, gave 18 and
14, respectively [37,38]. The disubstituted b-amino acid 14
was then allylated to give a,a-disubstituted 15. The methyl
esters of 18 and 15 were hydrolyzed, on treatment with
NaOH, and the resulting free acids 19 and 16 (respectively)
were coupled with allylamine, in the presence of EDCI and
HOBt, to give 20 (74%) and 17 (71%). Here again the more
active peptide coupling agent PyAOP was required to cou-
ple N-allyl-glycine ethyl ester with 19, to give 21, in 29%
after purification by chromatography. Diene 22 required
an alternative allylation on nitrogen and this was achieved
on treatment of 18 with allyl bromide and 1-tert-butyl-
4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phos-
phoranylidenamino]-25,45-catenadi(phosphazene)
(P4-
Scheme 2. (i) NaOH(aq); (ii) PhCHO, DCM, reflux; (iii) PhCOCl, DCM,
phosphazene) (Scheme 3). From our experience this is the
preferred base for the allylation of an amide [11] or carba-
mate nitrogen, and reaction does not proceed with more
conventional bases such as sodium hydride.
0 ꢁC; (iv) LiHMDS, allyl bromide, THF, ꢀ78 ꢁC; (v) n-BuLi, allylamine,
˚
THF, ꢀ78 ꢁC to rt; (vi) benzaldehyde dimethylacetyl, BF3 Æ OEt2, 4 A
sieves, ether; (vii) NaOH, THF, H2O, MeOH; (viii) N-allylglycine ethyl
ester, PyAOP, DIPEA, DMF.

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J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
Table 1
Each of the dienes was then subjected to Grubbs sec-
RCM of amino acid based dienes
ond-generation ruthenium catalyst [Cl2(PCy3)(IMes)-
Ru(:CHPh)] under conditions A (refluxing benzene), or
B (refluxing dichloromethane) and the results obtained
are presented in Table 1. Treatment of diene 4, under con-
ditions B, gave returned starting material only. However,
reaction in refluxing benzene (conditions A) for 4 h, gave
a 1:1 mixture of the expected 7-membered lactam 23 and
the ring contracted 6-membered lactam 24. Purification of
this sample by silica chromatography gave 23 and 24 in
45% and 46%, respectively. Ring contraction presumably
results from isomerization of the N-allyl group prior to
RCM, rather than from any subsequent reaction of 23
[31,39,40]. This is supported by the fact that (i) a sample
of 23 was shown to be stable to conditions A and that (ii)
alkenes are known to isomerize in the presence of ruthe-
nium catalysts due to the action of ruthenium hydride
complexes formed under the reaction reactions [41]. It
has also been suggested that coordination of the ruthe-
nium catalyst to the least sterically crowded olefin (N-allyl
group in this case), followed by deprotonation at the
allylic position gives a p-allyl complex that leads to dou-
ble bond isomerism [40]. By contrast the analogue 5,
which contains a tertiary amide linker known to favour
RCM, is reported to cyclise efficiently in refluxing chloro-
form to give only a 7-membered lactam (25) [11]. It is
interesting to note that we observed the formation of 23
and ring contracted 24 on refluxing 4 in chloroform with
Grubbs second generation catalyst.
The a,a-disubstituted diene 9 was similarly difficult to
cyclise, and treatment for 2 h in refluxing benzene (condi-
tions A) gave consumption of starting material with forma-
tion of the 6-membered lactam 26 as the sole product,
which was isolated in 32% after chromatography. The 7-
membered lactam was not isolated, nor was it evident in
the crude product by NMR. The absence of 7-membered
product in this case is likely due to increased steric conges-
tion in 9 (relative to 4) retarding RCM to allow competing
isomerization, and hence ring contraction, under the
extended reaction conditions [39,42]. In support of this
we found that diene 13, which contains still further steric
congestion, did not undergo RCM, or double bond isomer-
ization, under conditions C (2 h) or A (4 h). Here, both the
direct formation of the 7-membered product and also
isomerism to allow formation of the 6-membered lactam
are disfavoured. Thus only starting material was recovered
from these reactions. As discussed earlier, a tertiary amide
(as in 13) normally favours RCM but this effect would
appear to be negated by significant steric congestion in this
case. It is interesting that reaction of the a,a-disubstituted
b-amino acid based diene 17, in refluxing benzene, also
gave rise to ring contracted amide as the sole product, with
27 being isolated in 71%. Dienes 9 and 17 are similar in that
they both contain a secondary amide linker and a,a-disub-
stitution. A secondary amide of this type has been reported
to favour isomerism of an allyl group on nitrogen [31] and
thus facilitate ring contraction. The secondary amide in 4
Diene
Conditionsa Product (yield)
A 4 h
NH
NH
4
BocHN
BocHN
NH
BocHN
O
23 (46%)
24 (45%)
O
O
C 4 h
5
N
CO2Me
BocHN
N
CO2Me
BocHN
O
25b (52%)
O
A 2 h
Ph
Ph
9
NH
NH
PhCOHN
PhCOHN
O
26 (32%)
O
A 4 h
13
Ph
13
N
O
CO2Et
CbzHN
O
A 4 h
Ph
Ph
O
O
CbzHN
NH
CbzHN
NH
27 (71%)
17
B 2 h
B 2 h
B 2 h
Ph
Ph
O
CbzHN
NH
CbzHN
NH
20
28 (89%)
Ph
Ph
O
O
CbzHN
N
CO2Et
CbzHN
N
CO2Et
21
29 (88%)
Ph
Ph
22
CO2Me
CO2Me
30 (82%)
CbzN
CbzN
a
Grubbs 2nd generation catalyst [Cl2(PCy3)(IMes)Ru(:CHPh)] under a
nitrogen atmosphere. A, reflux in benzene; B, reflux in DCM; C, CHCl3,
50 ꢁC.
b
Reaction details from [11].

J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
5491
also appears to promote ring contraction, but to a lesser
extent.
The less congested b-amino acid derived dienes 20 and
21 gave the 7-membered lactams 28 (89%) and 29 (88%),
without evidence of ring contraction under the relatively
mild conditions C. These results compare favourably to
those obtained for 5 [11], and to a lesser extent 4, which
both possess monosubstitution at the a-carbon. The sec-
ondary amide linker in 4 does, however, necessitate the
use of harsher reaction conditions to allow some competing
isomerism and ring contraction. Ring contraction was also
apparent on the introduction of a further substituent at the
a-carbon as in 9 (a-amino acid) and 17 (b-amino acid). In
the final example, RCM of diene 22 under conditions C
gave the b-phenylalanine derived azepine 30 in 82% yield
after purification by chromatography.
In general, it appears that a secondary amide linker (as
in 4, 9, and 17) and a,a-disubstitution both necessitate the
use of harsher RCM conditions. As a result competing
isomerism of the allyl group on nitrogen is favoured, with
subsequent RCM giving ring-contracted product. In fact
ring contraction is the sole pathway when both factors
are present (see 9 and 17). On the other hand, a tertiary
amide linker is well documented to favour RCM (e.g. see
5) by encouraging the formation of the requisite rotamer
for cyclisation. However, the favourable influence of this
group can be negated with the introduction of significant
and further steric congestion as in 13.
Fig. 3. Global minima b-turn adopted by the model peptide containing 30
(a truncated carbon peptide backbone is shown for clarity).
8-membered hydrogen-bonded ring between C@Oi+1 and
HNi+3. This hydrogen bonding pattern existed in 87% of
the structures found within a range up to 12 kJ/mol above
the global minimum energy. The absence of hydrogen
bonding between C@Oi and HNi+3 indicates a non-classical
b-turn. However, the high proportion of structures in the
ensemble with the two before mentioned hydrogen bonds,
Next, the representative lactams 26, 27, 28, and 30 were
modeled in-silico as components of a penta-peptide (Ac-
Ala-Ala-Xaa-Gly-Ala-NHMe) using MacroModel [43] to
gain some insight into their ability to stabilize b-turn con-
formations. In each case a Monte Carlo investigation was
carried out and the ensembles of generated structures,
within a 12 kJ/mol window of the global minima, were fur-
ther analyzed on the basis of hydrogen bonding between
C@Oi and HNi+3, the Cai–Cai+3 distance, and the pseudo-
dihedral angle defined by Cai–Cb2–Cai+2–Cai+3. The result
of this analysis indicates that the model peptides containing
26 and 28 do not adopt turn like structures. This was appar-
ent by the lack of a hydrogen bond between C@Oi and
HNi+3 and a wide distribution of values for the Cai–Cai+3
distance and pseudo-dihedral angle across the ensembles
of generated structures. By contrast 30 gave a global mini-
mum structure (E ꢀ523.3 kJ/mol) with an 11-membered
ring hydrogen bond between C@Oi and HNi+3 which is
characteristic of a b-turn (Fig. 3). This hydrogen bond
existed in 62% of the structures found within the range up
to 12 kJ/mol above the global minimum energy. The aver-
˚
coupled with an average Cai–Cai+3 distance value of 5.9 A
and an average pseudo-dihedral angle of ꢀ54ꢁ, is consistent
with a turn like structure.
Finally, the b-turn mimic 30 was elaborated into a pep-
tidic aldehyde 33 (Scheme 4) and this was assayed against a
˚
age Cai–Cai+3 distance in these structures was 5.8 A, which
is slightly longer than the optimal for an a-amino acid b-
turn [44] The observed average pseudo-dihedral angle of
ꢀ31ꢁ is also consistent with a b-turn like geometry, where
the ideal value lies between 50ꢁ and ꢀ50ꢁ [44]. The model
penta-peptide containing 27 gave a global minimum
structure (E ꢀ554.4 kJ/mol) with a 12-membered hydro-
gen-bonded ring between HNi+1 and C@Oi+3 and an
Scheme 4. (i) NaOH, THF, H2O, MeOH; (ii) (S)-leucinol, EDC, HOAT,
DIPEA, DMF; (iii) SO3 Æ Pyr, DIPEA, DMSO, DCM.

5492
J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
protease (calpain 1) [45] to give an IC50 of 4.23 lM. This
compares to a value of 0.23 lM [46] for the acyclic dipep-
tide aldehyde N-Cbz-Phe-LeuH 34, which is able to adopt a
b-strand geometry known to favour binding. The 20-fold
decrease in potency of 33 reflects the inability of 30 to
adopt the requisite b-strand binding geometry as predicted
by the modeling.
The following compounds were prepared as described:
N-allylglycine ethyl ester [47], 7 [32], 8 [33], 11 [34], 12
[34], 14 [37], 15 [37], 18 [38]. Compounds 31–34 were pre-
pared by standard methods.
4.2. Synthesis of dienes
4.2.1. Preparation of (1-allycarbamoylbut-3-enyl)carbamic
acid tert-butyl ester ( )-4
3. Conclusions
A mixture of EDCI (459 mg, 2.24 mmol), HOBt
(378 mg, 2.58 mmol), allylamine (145 mL, 2.58 mmol) and
N-Boc ( )-allylglycine (370 mg, 1.72 mmol) were dissolved
in CH2Cl2 (15 mL). Diisopropylethylamine (205 mL,
0.95 mmol) was added and the mixture was stirred at rt
for 16 h. The reaction mixture was then diluted with
EtOAc and partitioned with 1 M HCl(aq). The organic
phase was washed with saturated NaHCO3(aq), brine and
dried over MgSO4, filtered and concentrated in vacuo.
Purification by radial chromatography (EA/PE 1:3) gave
Three new classes of conformationally constrained pepti-
domimetics, derived from modified a- and b-amino acids,
have been prepared by RCM. The first involves Ca–N0 cyc-
lisation (see Fig. 1 and 23, 24, 26), the second Cb2–N0 cycli-
sation (see Fig. 1 and 27, 28, 29) and the third N–Cb2
cyclisation (see Fig. 1 and 30). The olefins of the precursor
dienes were introduced by either (i) a-allylation of a- and b-
amino acids with control of absolute configuration or (ii) N-
allylation using P4-phosphazene as the base (see Schemes 2
and 3). It appears that a secondary amide linker (as in 4, 9,
and 17), and a,a-disubstitution, both necessitate the use of
harsher conditions for RCM. This then favours isomerism
of an allyl group on nitrogen and hence RCM to give the
ring-contracted product. Ring contraction would appear
to be the sole pathway when both a,a-disubstitution and
a secondary amide linker are present (see 9 and 17). The
normal favourable influence of a tertiary amide linker on
RCM is negated with the introduction of significant steric
congestion as in 13. Peptidomimetics 22 and 26 have been
shown to promote turn like structures in model peptides.
1
4 (404 mg, 92%) as a colourless solid. H NMR dH 6.53
(H, br s, NHCH2), 5.68–5.85 (2H, m, 2 · CH@CH2)
5.05–5.20 (5H, m, 2 · CH@CH2 and NHCH), 4.18 (H, br
s, NHCHC@O), 3.80–3.93 (2H, m, NHCH2CH@CH2),
2.40–2.55 (2H, m, CHCH2CH@CH2), 1.42 (9H, s,
CCH3). 13C NMR dC 171.3, 155.6, 133.8, 133.1, 118.8,
116.2, 80.1, 53.8, 41.7, 36.9, 28.2. FTIR (KBr) 3261,
2980, 1697, 1661, 1547 cmꢀ1
. HRMS (ES+) found
(MNa) m/z 277.1517, calculated for C13H22N2NaO3
requires m/z 277.1528.
4. Experimental
4.2.2. Preparation of (1R)-N-(1-allylcarbamoyl-1-
benzylbut-3-enyl)benzamide 9
4.1. General methods
Allylamine (11.5 lL, 0.15 mmol) was dissolved in dry
THF (2 mL) and cooled to ꢀ78 ꢁC. n-Butyl lithium
(95 lL, 0.15 mmol) was added and the mixture stirred at
ꢀ78 ꢁC for 5 min. A solution of 8 [33] (20 mg, 0.05 mmol)
in dry THF (1 mL) was added and allowed to warm to rt
overnight. The reaction mixture was quenched with satu-
rated NH4Cl(aq) and successively washed with saturated
NaHCO3(aq) (5 mL), NaCl(aq) (5 mL) and dried over
MgSO4, filtered and concentrated in vacuo. Purification
by radial chromatography (EA/PE 1:3) gave 9 (16 mg,
All synthetic manipulations were carried out under a
nitrogen atmosphere and CH2Cl2, benzene and THF were
dried by distillation over the appropriate drying agents
prior to use. Dry degassed solvents were obtained by means
of multiple freeze–pump–thaw cycles. Allylamine, (S)-
phenylalanine, N-Cbz-(S)-phenylalanine, n-butyl lithium,
Grubbs’ 2nd generation catalyst were all used as received.
Proton NMR spectra were recorded on
a Varian
1
500 MHz NMR spectrometer, unless otherwise stated.
Carbon NMR spectra were recorded on a Varian
300 MHz NMR spectrometer operating at 75 MHz, unless
otherwise stated. Spectra were recorded in deuterochloro-
form using TMS as the internal reference, unless stated
otherwise. Melting points were measured on a Gallenkamp
electrothermal melting point apparatus. Infrared spectra
were obtained using a Shimadzu 8201PC series FTIR inter-
faced with an Intel 486 PC operating Shimadzu’s HyperIR
software. Mass spectrometry data were detected on Kratos
MS80 RFA and Micromass LCT TOF mass spectrometers.
Radial chromatography was carried out using a Chromato-
tron (Harrison Research Inc.) using glass plates coated
with Merck type 60 PF254 silica gel.
91%) as a colourless solid. H NMR dH 7.64–7.70 (2H,
m, ArH), 7.49 (H, m, ArH), 7.38–7.43 (2H, m, ArH),
7.20–7.25 (3H, m, ArH), 7.10–7.16 (3H, m, ArH and
PhCONH), 6.51 (H, br t, J = 4.5 Hz, NH), 5.80–5.90 (H,
m, NHCH2CH@CH2), 5.68–5.78 (H, m, CCH2CH@CH2),
5.12–5.26 (4H, m, 2 · CH@CH2), 3.88–4.02 (2H, m,
NHCH2), 3.67 (H, d, J = 13.9 Hz, PhCHH), 3.37 (H, d,
J = 13.9 Hz, PhCHH), 3.25 (H, dd, J = 14.3 and 8.1 Hz,
CCHHCH@), 2.77 (H, dd, J = 14.3 and 6.4 Hz,
CCHHCH@). 13C NMR dC 171.91, 167.29, 135.68,
135.03, 133.62, 132.33, 131.61, 130.10, 128.61, 128.31,
127.08, 126.83, 119.82, 117.14, 64.43, 42.48, 40.87, 40.00.
HRMS (EI+) found (M+) m/z 348.1829, calculated for
C22H24N2O2 requires m/z 348.1838.

J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
5493
4.2.3. Synthesis of [N-allyl((S)-2-benzoylamino-2-
benzylpent-4-enoyl)amino]acetic acid ethyl ester 13
6.09 (H, d, J = 10.3 Hz, NHCH), 5.79–5.87 (2H, m,
NHCH2 and NHCH2CH@CH2), 5.68–5.74 (H, m,
CCH2CH@CH2), 5.06–5.22 (4H, m, 2 · CH@CH2), 4.94
(H, d, J = 12.7 Hz, PhCHHO), 4.86 (H, d, J = 12.7 Hz,
PhCHHO), 3.85–3.90 (3H, m, NHCH and NHCH2), 2.98
(H, dd, J = 13.6 and 3.4 Hz, PhCHHCH), 2.58 (H, dd,
J = 13.5 and 6.5 Hz, CHHCH@CH2), 2.48 (H, dd,
J = 13.6 and 10.7 Hz, PhCHHCH), 2.27 (H, dd, J = 13.5
and 7.8 Hz, CHHCH@CH2), 1.28 (3H, s, CCH3). 13C
NMR dC 175.4, 156.2, 138.2, 136.9, 133.3, 129.3, 128.3,
128.2, 127.7, 127.6, 126.3, 119.1, 116.8, 66.1, 59.0, 48.8,
42.0, 41.9, 37.8, 19.9. FTIR (KBr) 3279, 1709, 1634,
1547 cmꢀ1. HRMS (ES+) found (MH+) m/z 407.2334, cal-
culated for C25H31N2O3 requires m/z 407.2335. Microanal-
ysis calculated for C25H30N2O3: C, 73.86; H, 7.44; N, 6.89.
Found: C, 73.56; H, 7.54; N, 6.98%.
Carboxylic acid 12 [34] (302 mg, 0.89 mmol), N-allylgly-
cine ethyl ester (191 mg, 1.34 mmol) and PyAOP (600 mg,
1.16 mmol) were dissolved in anhydrous DMF (20 mL).
DIPEA (360 lL, 2.05 mmol) was added and the reaction
mixture stirred at rt for 18 h. This was partitioned between
EtOAc and 1 M HCl(aq). The organic phase was then
washed sequentially with 1 M HCl(aq), brine and dried over
MgSO4, filtered and concentrated in vacuo. The crude
material was purified by flash chromatography on silica
using a gradient of EtOAc and petroleum ether (50/70)
to give a mixture of rotamers 13 (146 mg, 35%) as a colour-
less oil. Data for the mixture: 1H NMR dH 7.15–7.40 (11H,
m, ArH and NH), 5.54–5.65 (H, m, NCH2CH@CH2), 5.51
(H, br d, NH), 5.01–5.18 (6H, m, 2 · CH@CH2 and
OCH2Ph),
4.87–4.93
and
4.64–4.70
(H,
m,
CCH2CH@CH2), 3.68–4.22 (7H, m), 2.92–3.14 (2H, m),
1.27 and 1.24 (3H, t, J = 7.2 Hz, CO2CH2CH3). 13C
NMR dC 172.0, 171.9, 168.9, 168.7, 155.6, 155.5, 136.2,
135.9, 132.0, 129.5, 129.3, 128.3, 127.9, 127.8, 127.7,
126.9, 126.8, 118.5, 118.3, 66.7, 61.6, 61.1, 52.2, 51.8,
51.1, 49.5, 48.1, 47.1, 39.4, 14.0, 13.9. HRMS (ES+) found
(MNa) m/z 487.2201, calculated for C27H32N2NaO5
requires m/z 487.2209.
4.2.5. Preparation of (1S,2S)-(2-allylcarbamoyl-1-
benzylpent-4-enyl)carbamic acid benzyl ester 20
Aqueous sodium hydroxide (1 M 1.74 mL, 1.74 mmol)
was added to a solution of 18 [38] (320 mg, 0.87 mmol) dis-
solved in MeOH (15 mL), and the solution was refluxed for
4 h. The MeOH was removed in vacuo and 20 mL of water
was added. The solution was acidified to pH 2 with 10%
HCl(aq) and extracted with EtOAc (3 · 10 mL). The com-
bined EtOAc extracts were dried over MgSO4, filtered
and concentrated in vacuo to give 19 (305 mg, 99%) as a
4.2.4. Preparation of (1S,2S)-(2-allylcarbamoyl-1-benzyl-2-
methylpent-4-enyl)carbamic acid benzyl ester 17
1
yellow oil. This was used without further purification. H
Sodium hydroxide (1 M aq 2.36 mL, 2.36 mmol) was
added to a solution of 15 [37] (450 mg, 1.18 mmol) dis-
solved in MeOH (20 mL), and refluxed for 4 h. The MeOH
was removed in vacuo and 20 mL of water was added. The
solution was acidified to pH 2 with 10% HCl(aq) and
extracted with EtOAc (3 · 10 mL). The combined EtOAc
extracts were dried over MgSO4, filtered and concentrated
in vacuo to give 16 (420 mg, 97%) as a yellow oil. This was
NMR dH 7.14–7.37 (10H, m, ArH), 5.71 (H, d,
J = 9.8 Hz, PhCONH), 5.68 (H, m, CH@CHH), 5.00–
5.15 (4H, m, PhCH2 and CH@CHH), 4.24 (H, m, NHCH),
2.95 (H, dd, J = 13.9 and 6.6 Hz, CHHPh), 2.77 (H, dd,
J = 13.7 and 8.8 Hz, CHHPh), 2.64 (H, m, CHCO2H),
2.46 (H, m, CHHCH@CH2), 2.34 (H, m, CHHCH@CH2).
A mixture of EDC (232 mg, 1.12 mmol), HOBt (190 mg,
1.3 mmol), allylamine (73 lL, 1.3 mmol) and 19 (305 mg,
0.86 mmol) were dissolved in CH2Cl2 (10 mL). Diisopro-
pylethylamine (0.205 mL, 0.95 mmol) was added and the
mixture was stirred at rt for 16 h. The reaction mixture
was then diluted with EtOAc and partitioned with 1 M
HCl(aq). The organic phase was washed with saturated
NaHCO3(aq), brine and dried over MgSO4, filtered and
concentrated in vacuo. Purification by radial chromatogra-
phy (EA/PE 1:4) gave 20 (261 mg, 74%) as colourless crys-
tals. mp 168–169 ꢁC. 1H NMR dH 7.16–7.36 (10H, m,
ArH), 6.50 (H, d, J = 8.8 Hz, NHCH), 5.80–5.90 (H, m,
NHCH2CH@CH2), 5.58–5.68 (H, m, CHCH2CH@CH2),
5.47 (H, br s, NHCH2), 5.15–5.26 (2H, m, CH@CH2),
5.09 (H, d, J = 12.7 Hz, PhCHHO), 5.07 (H, d,
J = 12.7 Hz, PhCHHO), 4.94–5.04 (2H, m, CH@CH2),
4.00–4.10 (H, m, NHCH), 3.82–3.94 (2H, m,
NHCH2CH@CH2), 3.05 (H, dd, J = 13.8 and 6.1 Hz,
CHCHHPh), 2.62 (H, dd, J = 13.8 and 9.2 Hz,
CHCHHPh), 2.38–2.47 (2H, m, CHCHHCH@CH2),
2.22–2.30 (H, m, CHCHHCH@CH2), 2.10–2.16 (H, m,
CHCH2CH@CH2).13C NMR dC 173.6, 156.2, 138.1,
136.8, 134.7, 133.7, 129.0, 128.6, 128.4, 127.9, 127.8,
1
used without further purification. H NMR dH 7.17–7.39
(10H, m, ArH), 5.78 (H, m, CH@CH2), 5.12 (2H, m,
CH@CH2), 4.87 (2H, dd, J = 74.9 and 12.2 Hz, PhCH2O),
4.11 (H, td, J = 11.1 and 3.4 Hz, NHCH), 3.07 (H, dd,
J = 13.9 and 3.4 Hz, CHCHHPh), 2.62 (H, dd, J = 13.7
and 7.3 Hz, CHHCH@CH2), 2.51 (H, dd, J = 13.9 and
11.5 Hz, CHCHHPh), 2.36 (H, dd, J = 13.7 and 7.8 Hz,
CHHCH@CH2), 1.44 (3H, s, CCH3). HRMS (ES+) found
(MH+) m/z 368.1864, calculated for C22H26NO4 requires
m/z 368.1862.
A mixture of EDC (118 mg, 0.57 mmol), HOBt (97 mg,
0.66 mmol), allylamine (37 mL, 0.66 mmol) and 16
(160 mg, 0.44 mmol) were dissolved in CH2Cl2 (5 mL).
Diisopropylethylamine (0.104 mL, 0.48 mmol) was added
and the mixture was stirred at rt for 16 h. The residue
was partitioned between EtOAc and 1 M HCl(aq). The
organic phase was washed sequentially with 1 M HCl(aq)
and brine before being dried over MgSO4, filtered and con-
centrated in vacuo. Purification by radial chromatography
(EA/PE 1:3) gave 17 (128 mg, 71%) as colourless crystals.
mp 99–101 ꢁC. 1H NMR dH 7.16–7.37 (10H, m, ArH),

5494
J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
126.6, 117.7, 117.1, 66.3, 53.8, 47.2, 41.8, 40.4, 34.9. FTIR
(KBr) 3433, 1693, 1643, 1551, 1265 cmꢀ1. HRMS (EI+)
found (MH+) m/z 393.2176, calculated for C24H29N2O3
requires m/z 393.2178.
136.9, 136.4, 134.4, 134.2, 134.1, 129.4, 129.3, 128.4,
128.3, 128.2, 127.8, 127.7, 126.4, 126.3, 117.3, 117.2,
116.8, 116.4, 67.3, 66.5, 53.3, 51.5, 51.3, 49.2, 48.2, 36.5,
35.3, 34.5, 34.4. LRMS (ES+) found (MH+) m/z 408.2, cal-
culated for C25H30NO4 requires m/z 408.2.
4.2.6. Preparation of (1S,2S)-{N-allyl-[2-
(1-benzyloxycarbonylamino-2-phenylethyl)pent-4-
enoyl]amino}acetic acid ethyl ester 21
4.3. RCM reactions
Carboxylic acid 19 (64 mg, 0.18 mmol), N-allylglycine
ethyl ester (44 mg, 0.31 mmol) and PyAOP (123 mg,
0.24 mmol) were dissolved in anhydrous DMF. DIPEA
(85 lL, 0.49 mmol) was added and the reaction mixture
stirred at room temperature for 18 h. This was parti-
tioned between EtOAc and 1 M HCl(aq). The organic
4.3.1. General procedure A
The diene was dissolved in the appropriate amount of
distilled benzene and to this Grubbs 2nd generation cata-
lyst was added. This was heated at reflux for 4 h, cooled
and concentrated in vacuo. Purification of the residue
was carried out by radial silica chromatography.
phase was then washed sequentially with 1 M HCl(aq)
,
brine and dried over MgSO4, filtered and concentrated
in vacuo. Purification by radial chromatography (EA/
PE 1:4) gave 21 (25 mg, 29%) as a colourless oil. 1H
NMR dH 7.12–7.38 (10H, m, ArH), 6.67 (H, d,
4.3.2. General procedure B
The diene was dissolved in the appropriate amount of
distilled dichloromethane and to this Grubbs 2nd genera-
tion catalyst was added. This was heated at reflux for
2 h, cooled and concentrated in vacuo. Purification of the
residue was carried out by silica chromatography.
J = 9.5 Hz,
NHCH),
5.60–5.80
(2H,
m,
2 · CH2CH@CH2), 5.08–5.22 (2H, m, CH@CH2), 4.98–
5.08 (4H, m, CH@CH2 and PhCH2O), 4.22 (2H, q,
J = 7.1 Hz, OCH2CH3), 4.14–4.19 (H, m, NHCHCH),
4.13 (H, d, J = 17.6 Hz, CHHCO2CH2CH3), 3.90 (H, d,
J = 17.1 Hz, CHHCO2CH2CH3), 3.79 (2H, br d,
J = 5.6 Hz, NHCH2CH@CH2), 2.97 (H, dd, J = 13.6
and 6.74 Hz, PhCHH), 2.76–2.82 (H, m, CHCHCO),
2.71 (H, dd, J = 13.6 and 9.1 Hz, PhCHH), 2.28–2.42
(2H, m, CHCH2CH@CH2), 1.29 (3H, t, J = 7.1 Hz,
OCH2CH3). 13C NMR dC 175.3, 169.0, 156.2, 138.2,
136.8, 134.5, 132.4, 129.1, 128.4, 128.3, 127.8, 127.7,
126.4, 118.5, 117.7, 66.2, 61.2, 53.3, 51.9, 47.0, 41.36,
40.0, 34.4, 14.1. FTIR (KBr) 3402, 2945, 1747, 1717,
1635 cmꢀ1. HRMS (ES+) found (MH+) m/z 479.2542,
calculated for C28H35N2O5 requires m/z 479.2546.
4.3.3. Preparation of (2-oxo-2,3,4,7-tetrahydro-1H-
azepin-3-yl)carbamic acid tert-butyl ester ( )-23 and
(2-oxo-1,2,3,4-tetrahydropyridin-3-yl)carbamic acid tert-
butyl ester ( )-24
The diene 4 (60 mg, 0.24 mmol) and Grubbs 2nd gener-
ation catalyst (9 mg, 0.01 mmol) in dry degassed benzene
(10 mL) were reacted according to general procedure A
giving 23 (23 mg, 46%) as a colourless solid and 24
(24 mg, 45%) as a colourless solid.
1
Data for ( )-23: H NMR dH 6.34 (H, br s, NHCH2),
5.65–5.80 (2H, m, CH@CHCH2 and NHCH2), 4.78–4.87
(H, m, CH@CHCH2), 4.15 (H, br d,J = 7.1 Hz,
NHCHCH2), 3.40–3.50 (H, m, NHCHH), 2.60–2.70 (H,
m, NHCHH), 2.20–2.34 (2H, m, CHCH2CH@CH), 1.44
(9H, s, C(CH3)3). 13C NMR (CDCl3)dC 174.7, 155.1,
142.5, 129.0, 124.6, 79.6, 49.8, 39.5, 32.6, 28.3. HRMS
(ES+) found (MNa) m/z 249.1220, calculated for
C11H18N2NaO3 requires m/z 249.1215.
4.2.7. Synthesis of (1S,2S)-2-[1-(allylbenzyloxycarbonyl-
amino)-2-phenylethyl]pent-4-enoic acid methyl ester 22
A solution of 18 [38] (960 mg, 2.61 mmol) was dissolved
in anhydrous THF (25 mL). This was cooled to ꢀ78 ꢁC
and P4-phosphazene (5.22 mL, 5.22 mmol) was added,
and stirred at ꢀ78 ꢁC for 1 h and then allyl bromide
(454 mL, 5.22 mmol) was added. This was stirred at
ꢀ78 ꢁC for a further 2 h and then at rt for 18 h before being
concentrated in vacuo. The residue was partitioned
between EtOAc and 1 M HCl(aq). The organic phase was
washed sequentially with 1 M HCl(aq) and brine before
being dried over MgSO4, filtered and concentrated in
vacuo. The crude material was purified by flash chromatog-
raphy on silica using a gradient of EtOAc and petroleum
ether (50/70) to give as a mixture of rotamers 22 (0.926 g,
Data for ( )-24: 1H NMR dH 7.67 (H, br s,
CH@CHNH), 6.02–6.10 (H, m, CH@CHNH), 5.49 (H,
br s, NHCHCH2), 5.16 (H, t, J = 7.1 Hz, CH@CHNH),
4.23–4.32 (H, m, NHCHCH2), 2.78–2.88 (H, m,
CHHCH@), 2.15–2.25 (H, m, CHHCH@CH), 1.44 (9H,
s, C(CH3)3). 13C NMR dC 170.1, 155.6, 124.7, 105.5,
79.8, 50.0, 28.3, 27.2. HRMS (ES+) found (MNa) m/z
235.1051 (M++Na), calculated for C10H16N2O3Na
requires m/z 235.1059.
4.3.4. Preparation of (R)-N-(3-benzyl-2-oxo-1,2,3,4-
tetrahydropyridin-3-yl)benzamide 26
1
87%) as a colourless oil. H NMR ((CD3)2SO, 300 MHz,
80 ꢁC) dH 7.20–7.49 (10H, m, ArH), 5.77–5.92 (H, m,
CH2CH@CH2), 5.25–5.50 (H, m, CH2CH@CH2), 4.85–
5.24 (6H, m, OCH2Ph and CH2CH@CH2), 4.05–4.25 (H,
m), 3.50–3.70 (5H, m), 3.00–3.30 (3H, m), 2.35–2.65 (2H,
m). 13C NMR dC 174.1, 173.6, 156.0, 155.2, 138.3, 137.9,
The diene 9 (48 mg, 0.14 mmol) and Grubbs 2nd gener-
ation catalyst (117 mg, 0.014 mmol) in benzene (10 mL)
were reacted according to general procedure A giving 26
(14 mg, 32%) as a colourless oil. H NMR dH 7.68–7.74
(2H, m, Ar-H), 7.38–7.52 (3H, m, Ar-H), 7.32 (H, br s,
1

J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
5495
NH), 7.18–7.22 (3H, m, Ar-H), 7.04–7.10 (2H, m, Ar-H),
6.93 (H, br s, NH), 6.14–6.18 (H, m, CH@CHNH), 5.28–
5.34 (H, m, CH2CH@CH), 3.67 (H, dd, J = 17.7 and
6.7 Hz, NHCH@CHCHH), 3.66 (H, d, J = 13.8 Hz,
CHHPh), 3.42–3.50 (H, m, NHCH@CHCHH), 3.26 (H,
d, J = 13.8 Hz, CHHPh), 2.70–2.80 (H, m, CHHPh).
LRMS (ES+) found (MH+) m/z 307.1, calculated for
C19H19N2O2 m/z requires 307.1.
were reacted according to general procedure B. Resid-
ual ruthenium was removed according to the literature
[48] to give 29 (20.3 mg, 88%) as a colourless oil. 1H
NMR dH 7.16–7.38 (10H, m, ArH), 6.62 (H, d,
J = 9.9 Hz, NHCH), 5.68–5.74 (H, m, CH2CH@CH),
5.58–5.64 (H, m, NCH2CH@CH), 5.10 (H, d,
J = 12.3 Hz, PhCHHO), 5.07 (H, d, J = 12.3 Hz,
PhCHHO), 4.52 (H, d, J = 17.1 Hz, CHHCO2Me), 4.24
(2H, q, J = 7.1 Hz, OCH2CH3), 4.18–4.28 (H, m,
NCHHCH@CH), 3.95 (H, dddd, 10.1, 8.7, 5.9, 2.8 Hz,
NHCHCH), 3.86 (H, d, J = 17.1 Hz, CHHCO2Me),
3.23 (H, dd, J = 17.4 and 5.9 Hz, NCHHCH@CH),
3.09 (H, dt, J = 13.1 and 2.8 Hz, CHCHCO), 3.03 (H,
dd, J = 13.1 and 5.5 Hz, PhCHH), 2.92 (H, dd,
J = 13.1 and 9.9 Hz, PhCHH), 2.42–2.52 (H, m,
CHCHHCH@CH), 2.10–2.20 (H, m, CHCHHCH@CH),
1.30 (3H, t, J = 7.1 Hz, OCH2CH3). 13C NMR dC
175.4, 169.1, 156.6, 138.7, 136.8, 131.2, 129.3, 128.6,
128.4, 127.8, 127.7, 126.4, 123.3, 66.4, 61.3, 55.9, 49.8,
47.3, 40.6, 39.9, 30.0, 14.2. FTIR (KBr) 3410, 2981,
1744, 1717, 1647 cmꢀ1. HRMS (ES+) found (MH+) m/
z 451.2252, calculated for C26H31N2O5 requires m/z
451.2233.
4.3.5. Preparation of (1S,3S)-[1-(3-methyl-2-oxo-1,2,3,4-
tetrahydropyridin-3-yl)-2-phenylethyl]carbamic acid
benzyl ester 27
The diene 17 (75 mg, 0.19 mmol) and Grubbs 2nd gener-
ation catalyst (8 mg, 0.009 mmol) in benzene (3.5 mL) were
reacted according to general procedure A giving 27 (59 mg,
88%) as a colourless solid. 1H NMR dH 7.11–7.32 (10H, m,
ArH), 6.96–7.02 (H, m, NH), 5.95–6.00 (H, m,
NHCH@CH), 5.00–5.10 (2H, m, CCH2CH@CH and
NH), 4.93 (H, d, J = 12.7 Hz, PhCHHO), 4.80 (H, d,
J = 12.7 Hz, PhCHHO), 4.07–4.13 (H, m, NHCH), 3.14
(H, dd, J = 13.7 and 3.4 Hz, PhCHHCH), 2.97–3.04 (H,
m, PhCHHCH), 2.62 (H, br d, J = 17.1 Hz,
CHHCH@CH), 2.03 (H, dd, J = 17.1 and 5.6 Hz,
CHHCH@CH), 1.31 (3H, s, CCH3). 13C NMR dC 174.7,
156.6, 138.9, 136.6, 129.2, 128.4, 128.2, 127.8, 127.7,
126.2, 123.7, 103.9, 66.3, 57.5, 45.1, 37.7, 31.1, 20.3. HRMS
(ES+) found (MH+) m/z 365.1866, calculated for
C22H25N2O3 requires m/z 365.1865.
4.3.8. Synthesis of (2S,3S)-2-benzyl-2,3,4,7-
tetrahydroazepine-1,3-dicarboxylic acid 1-benzyl ester
3-methyl ester 30
The diene 22 (930 mg, 2.28 mmol) and Grubbs 2nd
generation catalyst (193 mg, 0.228 mmol) in DCM
(200 mL) were reacted according to general procedure B
giving as a mixture of rotamers 30 (710 mg, 82%) as a
brown solid. Data for the mixture: 1H NMR dH 7.13–
7.33 (10H, m, ArH), 5.71–5.80 (2H, m, NCH2CH@CH
and CH@CHCH2), 5.25–5.33 and 5.15–5.20 (H, m,
CHCH2Ph), 5.05–5.13 (2H, m, OCH2Ph), 4.45–4.51 and
4.25–4.32 (2H, m, NCH2CH@CH), 3.71–3.77 (H, m,
CHCO2CH3), 3.64 (3H, s, CO2CH3), 3.01–3.04 (H, m,
CHCHHPh), 2.89–2.95 (H, m, CHCHHPh), 2.50–2.70
(2H, m, CHCH2CH@CH). LRMS (ES+) found (MH+)
m/z 380.1, calculated for C23H26NO4 requires m/z
380.2.
4.3.6. Preparation of (1S,3S)-[1-(2-oxo-2,3,4,7-tetrahydro-
1H-azepin-3-yl)-2-phenylethyl]carbamic acid benzyl ester
28
The diene 20 (70 mg, 0.18 mmol) and Grubbs 2nd gener-
ation catalyst (8 mg, 0.009) in benzene (3.5 mL) were
reacted according to general procedure B giving 28
(58 mg, 89%) as a colourless solid.1H NMR dH 7.20–7.37
(10H, m, ArH), 6.58 (H, d, J = 9.8 Hz, NHCH), 6.16 (H,
br s, NHCH2), 5.65–5.70 (H, m, CHCH2CH@CH2),
5.56–5.61 (H, m, NHCH2CH@CH2), 5.10 (H, d,
J = 12.5 Hz, PhCHHO), 5.06 (H, d, J = 12.5 Hz,
PhCHHO), 3.96–4.02 (H, m, NHCH), 3.81 (H, br d,
J = 7.6 Hz, NHCHHCH@CH), 3.25–3.32 (H, m,
NHCHHCH@CH), 3.06 (H, dd, J = 13.2 and 6.3 Hz
PhCHH), 2.91–2.99 (2H, m, CHCH2CH@CH and
PhCHH), 2.44–2.51 (H, m, CHCHHCH@CH), 2.15 (H,
br d, J = 9.0 Hz, CHCHHCH@CH). 13C NMR dC 177.5,
156.5, 138.6, 136.7, 130.5, 129.1, 128.6, 128.4, 127.9,
127.8, 126.4, 124.3, 66.4, 55.5, 40.6, 39.9, 39.2, 29.5. FTIR
(KBr) 3275, 2924, 1699, 1651 cmꢀ1. HRMS (ES+) found
(MH+) m/z 365.1862, calculated for C22H25N2O3 requires
m/z 365.1865.
4.4. Computational methods
Molecular mechanics calculations were carried out on a
SGI IRIX 6.5 workstation, with use of MacroModel (v6.5)
molecular modelling software, OPLS_01 force field and the
implicit H2O/chloroform GB/SA solvation system. Monte
Carlo conformational searches were carried out without
imposition of any constraint and with inclusion of amide
bonds in the rotatable bonds. Ring-closure was defined
for the 6- and 7-membered rings of our peptidomimetics.
5000 structures were generated and minimized until the
4.3.7. Preparation of (1S,3S)-[3-(1-benzyloxycarbonyl-
amino-2-phenylethyl)-2-oxo-2,3,4,7-tetrahydro-azepin-
1-yl]acetic acid ethyl ester 29
The diene 21 (25 mg, 0.05 mmol) and Grubbs 2nd gen-
eration catalyst (4.4 mg, 0.005 mmol) in DCM (5 mL)
˚
gradient was less than 0.05 kJ/A mol by the TNCG gradi-
ent implemented in MacroModel. All conformers with
energy 12 kcal/mol above the global minimum conformer
were discarded.

5496
J. Gardiner et al. / Journal of Organometallic Chemistry 691 (2006) 5487–5496
[22] A.D. Abell, K.M. Brown, J.M. Coxon, M.A. Jones, S.
Acknowledgments
Miyamoto, A.T. Neffe, J.M. Nikkel, B.G. Stuart, Peptides 26
(2005) 251.
Financial support from the Royal Society of New Zea-
land Marsden Fund, Foundation for Research Science
and Technology (postdoctoral fellowship, S.B.M), and
the University of Canterbury (postgraduate scholarship,
S.G.A.) are gratefully acknowledged. The Calpain assay
was conducted by Janna Nikkel, Matthew Jones and Mat-
thew Muir and is gratefully acknowledged.
[23] T. Yamanaka, M. Ohkubo, M. Kato, Y. Kawamura, A. Nishi, T.
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