A straightforward approach towards cyclic peptides via ring-closing metathesis - Scope and limitations

Article abstract of DOI:10.1039/b411228h

N- and C-terminal diallylated peptides are obtained by several approaches, such as peptide Claisen rearrangement, N- and O- allylation, and the Ugi reaction of allyl-protected components. These diallylated peptides are suitable substrates for ring-closing metathesis and the success of this cyclisation was investigated with respect to the ring size, the position of the allyl moieties and the reaction parameters. In general, excellent yields are obtained for cyclisation of allyl glycine subunits and N-allylated amides, while allyl esters and allyl carbamates often presented serious problems. However, yields of up to 73% were obtained under optimised conditions, and the new generated double bond is formed with excellent trans-selectivity.

Full text of DOI:10.1039/b411228h

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A R T I C L E
A straightforward approach towards cyclic peptides via ring-closing
metathesis—scope and limitations†‡
Uli Kazmaier,* Christina Hebach, Anja Watzke, Sabine Maier, Heike Mues and Volker Huch
Institut fu¨r Organische Chemie, Universita¨t des Saarlandes, Saarbru¨cken, D-66123, Germany.
E-mail: u.kazmaier@mx.uni-saarland.de; Fax: +49 681 302 2409; Tel: +49 681 302 3409
Received 26th July 2004, Accepted 19th October 2004
First published as an Advance Article on the web 26th November 2004
N- and C-terminal diallylated peptides are obtained by several approaches, such as peptide Claisen rearrangement,
N- and O- allylation, and the Ugi reaction of allyl-protected components. These diallylated peptides are suitable
substrates for ring-closing metathesis and the success of this cyclisation was investigated with respect to the ring size,
the position of the allyl moieties and the reaction parameters. In general, excellent yields are obtained for cyclisation
of allyl glycine subunits and N-allylated amides, while allyl esters and allyl carbamates often presented serious
problems. However, yields of up to 73% were obtained under optimised conditions, and the new generated double
bond is formed with excellent trans-selectivity.
Introduction
Cyclic peptides are found in a wide variety of marine or-
ganisms and fungi.1 Many of these peptides show significant
biological activity,2 and are therefore highly interesting from
a pharmaceutical point of view.3 In higher organisms, cyclic
structures can be formed by the oxidation of two cysteine
subunits, a process which is generally used to stabilise the sec-
ondary and tertiary structure of peptides. Cysteine-containing
peptides are preferentially found in peptide hormones and
a number of redox active proteins, such as glutaredoxin 1.4
Here, the disulfide bridge locks a tetrapeptide fragment of the
protein chain into a b-turn type structure.5 Frequently, loops
and turns in peptides and proteins are responsible for their
biological activity, making these structures are highly interesting
from both a pharmaceutical point of view and as targets for
peptidomimetics.6 In general, cyclisation of peptides results in an
increased stability towards proteases. Since in cysteine peptides
the disulfide bonds are sensitive to reduction, the metabolic
stability of these compounds can be dramatically increased by
replacing the sensitive disulfide bond by a non-cleavable C–C
bond.7 Therefore, a lot of investigation has been carried out
on the synthesis of carba analogues of cysteine, such as 2,7-
diaminosuberic acid.8 Very recently, Williams et al. and Grubbs
et al. described syntheses based on the dimerisation of tethered
allyl glycines via ring-closing metathesis.9–11 As shown by Grubbs
et al. this ring-closing approach can be directly used for the
synthesis of cyclic peptides, such as 2, a carba analogue of
the glutaredoxin active site 1 (Fig. 1).12 This is an extremely
straightforward approach towards b-turn mimetics, and since
the publication of this pioneering work, several examples of the
synthesis of smaller and larger ring systems were reported, many
of which featured interesting pharmaceutical properties.13–15
Ring-closing metathesis was not only used for the cyclisation
of simple peptides to form cyclic peptidomimetics, but also for
the fixation of helix structures and the interconnection of cyclic
peptides.16–17
Fig. 1 Natural and artificial peptide loops.
cyclisation step depend on the ring size as well as on the
distance between the double bonds and other functionalities.
Liskamp et al. investigated the ring-closing metathesis of a
wide range of peptides bearing the unsaturation on the amide
functionality.22 In this case, the introduced loops connect two
amide nitrogens, leaving the amino acid sequence unaffected.
Importantly, these macrocycles may be formed by connecting
any two amide nitrogens, as long as the length of the alkene
substituents is adjusted appropriately. It was established that the
ring-closing metathesis can be conducted using N-alkylamides
for a loop bridging two amides, N-pentenylamides for a loop
spanning three amides and N-homoallylamides when four or
more amides are involved in the ring. Libraries of cyclic peptides
were obtained by this approach.
For quite some time we have been investigating syntheses
of c,d-unsaturated amino acids.23 Besides Pd-catalysed allylic
alkylations of chelated amino acid ester enolates,24 especially
the Claisen rearrangement, proceeding via those chelated amino
acid ester enolates is suitable for this purpose.25 If esters of chiral
allylic alcohols are used, the corresponding enantiomerically
pure amino acids are obtained.26 This protocol is not limited
to the rearrangement of amino acid esters, but can also be
applied to peptides.27 In particular, allylic esters of tosylated
peptides are suitable substrates for the Claisen rearrangement,
yielding the products in a highly diastereoselective fashion, while
the configuration of the newly formed stereogenic centre is
controlled by the peptide chain.28 Tosyl-protected amino acids
are also appropriate substrates for palladium-catalysed allylic
alkylations, giving rise to N-allylated derivatives under very mild
conditions.29 Therefore, these protocols open up an easy access
to fully functionalised diallylic peptides, suitable precursors for
ring-closing metathesis.30
Peptides containing allyl glycines are very often used as
precursors,18 thus leading to surrogates for cysteine, as illustrated
in Fig. 1. However, other unsaturated substrates can be cyclised,
such as allylic ethers, esters or amides.19–21 The yields in the
† Electronic supplementary information (ESI) available: Preparation
and analytical/spectroscopic data of linear tetrapeptides, X-ray data
of cyclopeptides 27–29. See http://www.rsc.org/suppdata/ob/b4/
b411228h/
Results and discussion
We started our investigations with the rearrangement of peptide
ester 3 (Scheme 1). In the presence of tin chloride, used for
‡ Dedicated to the memory of Professor U. Schmidt, a pioneer in
cyclopeptide chemistry.
1 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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chelation, the rearranged product 4 was obtained with excellent
yield and in a highly stereoselective manner. An induced
diastereoselectivity of 84% was remarkable, especially with
respect to the fact that the only chiral centre in the peptide 3
was 7 atoms away from the newly formed chiral centre. The (R)-
configured amino acid was formed preferentially with high syn
selectivity (>95%). Peptide 4 was subsequently subjected to a
palladium-catalysed N-allylation, giving rise to the product 5
without any racemisation. Unfortunately, all attempts to cyclise
this diallylated substrate 5 under different reaction conditions
and various amounts of Grubbs’ catalyst were unsuccessful.31
Scheme 2 Peptide Claisen rearrangement and subsequent ring-closing
metathesis; (a) 5.0 equiv LHMDS, 2.0 equiv SnCl2, THF, −78 ◦C → rt,
16 h; (b) CH2N2, ether, 10 min; (c) 1 mol% (allyl PdCl)2, 4.5 mol% PPh3,
=
allyl carbonate, THF, rt, 16 h; (d) 10 mol% RuCl2(PCy3)2( CHPh),
CH2Cl2, reflux, 14 h.
Scheme 1 Peptide Claisen rearrangement of crotyl ester 3; (a) 5.0 equiv
LHMDS, 2.0 equiv SnCl2, THF, −78 ◦C → rt, 16 h; (b) CH2N2, ether,
10 min; (c) 1 mol% (allyl PdCl)2, 4.5 mol% PPh3, allyl carbonate, THF,
rt, 16 h; (d) 10–15 mol% RuCl2(PCy3)2( CHPh), toluene, rt → 90 ◦C,
=
8 h.
Several factors influence the tendency of ring-closure metathe-
sis, but we focused mainly on the following three parameters:
(i) the unsaturated amino acid, (ii) the ring size and (iii) the
amino acid sequence. In ring-closing metatheses described in
the literature so far, unbranched allylglycines (or related amino
acids) were generally used as substrates. Therefore, one might
reason that the more steric demanding methyl group in a-
position to the terminal olefin could inhibit the ring-closure.
Unfortunately, exchanging this amino acid with allylglycine
was just as fruitless as reducing the ring size by replacing the
b-amino acid by an a-amino acid such as leucine. Obviously
12- and 13-membered peptide rings were difficult to obtain
by this strategy. Most likely, the problems with these medium
sized rings result from an unsuitable conformation of the linear
peptide chain in solution, with trans amide bonds inhibiting the
allyl termini from coming within close proximity. Therefore we
decided to enlarge the ring size and to introduce one proline,
which is able to form cis amide bonds and turn structures.32
Rearrangement of the tetrapeptide ester 6 gave the desired
allylated tetrapeptide 7 in excellent yield (Scheme 2).33 N-
allylation provided the substrate 8 for the subsequent ring-
closing metathesis, which now resulted in the formation of the
desired cyclic peptide 9 (15-membered ring) in high yield.34 This
was in good agreement with the results described by Grubbs et al.
for comparable peptides such as 2 (14-membered ring).12 The
double bond was obtained as an inseparable cis/trans-mixture.
To determine if the proline plays a significant role in the
cyclisation, we came back to our allylated tripeptides such as 10,
which could not by cyclised previously after N-allylation. Cleav-
age of the N-protecting group and coupling with allylated amino
acids provided the elongated peptides 11 and 12. Subsequent
ring-closing metathesis yielded the corresponding 16-membered
cyclic peptides 13 and 14 in even higher yields in comparison
to the smaller proline peptide (Scheme 3). Obviously ring size
played a major role for the success of this reaction; the amino
Scheme 3 Cyclisation of 16-membered rings; (a) HCl, dioxane, 0 ◦C,
30 min; (b) 1 equiv N-tosyl-N-allyl-b-Ala, 1.1 equiv TBTU,35 5 equiv,
NEt3, CH2Cl2, 10 h; (c) 1 equiv Boc-Ser(OAll), 1.1 equiv TBTU, 5 equiv,
NEt3, CH2Cl2, 8 h; (d) 10 mol% RuCl2(PCy3)2( CHPh), CH2Cl2, reflux,
15 h.
=
acid sequence and conformational issues were less important, at
least for peptides with more than 14 ring members.
We further enlarged the ring size by replacing the allylglycine
by an O-allylserine (Scheme 4, 15). For comparison, the proline-
containing peptide 17 was also prepared by conventional peptide
synthesis. Both peptides 15 and 17 gave the expected 18-
membered cyclisation products 16 and 18 in excellent yield,
comparable to the 16-membered analogues. Product 18 was
obtained as a separable 1 : 1 mixture of the cis/trans-isomers,
while in the case of 16 the isomers could not be separated.
An interesting observation was made after the C-terminal O-
allylserine unit was replaced by the serine allyl ester 19. In this
case, the yield of the ring-closing metathesis dropped to 21%,
although the ring size was the same as in 16 and 18.
Ring strain should not be the problem, and therefore one
might not expect higher yields at higher temperatures. Indeed,
when the cyclisation is carried out in toluene at 60 ◦C,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5
1 3 7

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Scheme 5 Multi component reactions and ring-closing metathesis;
=
(a) 10 mol% RuCl2(PCy3)2( CHPh), CH2Cl2, reflux, 15 h.
diastereomeric mixture in acceptable yield. In the presence of
(R)-p-methoxy-1-phenylethylamine the corresponding peptide
22 could be obtained in a 3 : 1 diastereomeric ratio at rt. The
selectivity could be ◦increased to nearly 9 : 1 if the reaction was
carried out at −30 C. In this case the diastereomers could be
separated by flash chromatography. The substrates were then
subjected to ring-closing metathesis. No reaction was observed
using depsipeptide 21 even with 10% catalyst, while the major
diastereomer of 22 gave cyclisation product 23 in only 13% yield
(Table 1, Entry 1).
Interestingly, only the trans-configured product was obtained
(>95%) as determined by HPLC. The olefin geometry as well as
the configuration of the newly formed stereogenic centre could
be determined by X-ray structure analysis.41§All amide and ester
bonds showed trans configuration, even the N-alkylated amide
bond. Therefore it is not obvious, why depsipeptide 21 did not
undergo cyclisation.
Since the Ugi reaction turned out to be a valuable approach
to the required substrates, we investigated the influence of
several parameters on the outcome of the ring-closing metathesis
(Scheme 6). One might expect an influence from the peptide
sequence, especially if loop inducing amino acids such as prolines
or N-alkylated amino acids are incorporated. Therefore we
also varied the N-terminal amino acid using Alloc-protected
alanine, proline and sterically demanding N-methyl valine as
carbocyclic acids. With (S)-m-methoxy-1-phenylethylamine all
peptides were obtained in high yield and especially with Alloc-
alanine (24) in excellent diastereoselectivity. Unfortunately for
the peptides 25 and 26 the diastereomeric ratio could not
be determined because of the occurrence of several rotamers.
Therefore the diastereomeric mixture was subjected to ring-
closing metathesis and the yields are given in Table 1. None
of the reactions ran to completion and in all cases the starting
material was recovered. In agreement with the cyclisation of 22
only the all-(S)-substrates underwent cyclisation, while the other
diastereomer was the major component of the recovered starting
material. In all examples only the trans configured double bond
(>95 trans) was obtained, as determined by X-ray structure
analysis of 28 and comparison of the NMR spectra of the other
cyclic peptides.†
Scheme 4 Cyclisation of 18-membered rings; (a) 10 mol% RuCl2-
=
(PCy3)2( CHPh), CH2Cl2, reflux, 15 h.
only unreacted starting material 19 was recovered. Obviously,
allylic esters are much less suited for ring-closing metathesis in
comparison to allylic ethers or amides. This might be explained
by a coordination of the carbonyl group to the ruthenium carbon
complex formed in the first step of the metathesis, giving rise
to a stable 6-membered chelate ring, which does not undergo
further reactions.36 This chelate formation can, in principle, be
suppressed by addition of Ti(OiPr)4, which coordinates more
strongly to the carbonyl group.37 Unfortunately, the addition of
5 equiv. of Ti(OiPr)4 had no effect on the cyclisation. Another
reason for the low yield might result from an interaction of the
free hydroxy group on the C-terminal serine with the catalyst.
We therefore protected this functionality by benzoylation, but
the cyclisation yield was lower than with the free hydroxy group.
Because of our ongoing interest in stereoselective modi-
fications of peptides we wanted to use cyclic peptides as
templates for the stereoselective introduction of side chains,
since stereoselective modifications of linear peptides are not a
trivial issue.38 The advantage of cyclisation via an allylic ester is
that the latter can easily be cleaved after the modification under
palladium catalysis. Most interesting from this point of view
should be a fixation of peptide conformation by metathesis of
two allylic protecting groups; an allyl ester on the C-terminus
and an allyloxycarbonyl (Alloc)-protecting group on the N-
terminus of the peptide. Sequential palladium-catalysed cleavage
of both protecting groups in one step should provide fully
unprotected modified peptides. We intensively investigated a
ring-closure approach with these two allylic protecting groups.
As substrates we chose N-allyl protected tripeptide allylic esters,
since they lead to 16-membered rings, which has previously
been reported to be a suitable size. To get rapid access to our
substrates with a high potency of variation, the Passerini and
Ugi multi-component reactions have been used, providing the
required substrates in one step (Scheme 5).39–40 With Alloc-
protected valine as the acid component and the allylic ester
of isocyanoacetic acid the depsipeptide, 21 was obtained as
§ CCDC reference numbers 197619, 245782, 245783. See http://
www.rsc.org/suppdata/ob/b4/b411228h/ for crystallographic data in
.cif format.
1 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5

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Table 1 Ring-closing metathesis of peptides 22 and 24–26
Entry
Peptide
Product
Catalyst
Reaction conditions
Yield/%
Comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
22
25
26
22
22
25
25
24
24
24
22
22
22
22
22
23
28
29
23
23
28
28
27
27
27
23
23
23
23
23
10% A
5% A
10% A
10% B
5% C
10% B
5% C
10% A
10% A
10% A
10% A
10% A
10% A
10% B
10% A
CH2Cl2, rt
CH2Cl2, rt
13
37
33
—
—
—
5
15
16
27
34
26
—
—
< 5
Only trans double bond
21% starting material recovered
Toluene, 60 ◦
CH2Cl2, rt
Toluene, rt
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
Toluene, 30 ◦
C
34% starting material recovered
Polymerisation
Polymerisation
Polymerisation
Polymerisation
21% starting material recovered
—
—
C
Toluene, 90 ◦C or N2 stream
CH2Cl2, rt, 0.3 eq. Ti(OiPr)4
—
—
—
CH2Cl2, rt, 1 eq. Ti(OiPr)4
CH2Cl2, rt, 4 eq. Ti(OiPr)4
CH2Cl2, rt, 0.3 eq. Ti(OiPr)4
Polymerisation
—
Catalyst added in 30 min to a 0.05 M solution of 25
in CH2Cl2 at rt
16
17
18
19
20
21
25
22
25
22
25
25
28
23
28
23
28
26
5% A
10% A
5% A
Catalyst added in 30 min to a 0.05 M solution of 28
in CH2Cl2 at rt
Catalyst added in 2 h to a 0.05 M solution of 25 in
CH2Cl2 at rt
Catalyst added in 30 min to a 0.05 M solution
(CH2Cl2) of 28 under N2 stream at rt
Catalyst added in 30 min to a 0.05 M solution
(CH2Cl2) of 28 under reflux–N2 stream
Peptide (0.01 M solution) added to catalyst in
CH2Cl2 under reflux–N2 stream
Peptide (0.01 M solution) added to catalyst in
CH2Cl2 under reflux–N2 stream
< 5
23
34
38
51
73
—
—
—
5% A
—
10% A
10% A
Only trans double bond
Only trans double bond
With this substrate harsher reaction conditions were nec-
essary. In comparison to 24 and 25 the reaction was rather
slow at rt, but could be accelerated significantly by heating the
reaction mixture to 60 ◦C. Since the pioneering work of Grubbs
et al. using the 1st generation ruthenium catalyst A, several new
catalysts have been developed such as the more reactive 2nd
generation catalyst B, or the “boomerang catalyst” C, which
allows regeneration of the metal complex (Fig. 2).42–44
Fig. 2 Metathesis catalysts investigated.
We chose catalyst A for our investigations, because it is
commercially available at a reasonable price and shows high
tolerance towards functional groups. With respect to higher
yields for cyclisations of our critical substrates, we also investi-
gated the other catalysts, albeit without the desired effect. Both
catalysts failed in the cyclisation of peptide 25 and 26. Mainly,
polymerisation was observed with catalyst B, while with catalyst
C only traces of product (ca. 5%) were obtained in the reaction
of 26, and 50–60% of starting material could be recovered.
Therefore, catalyst A was used for the further investigation of
the influence of reaction conditions.
As illustrated with peptide 26, higher temperatures are some-
times necessary for satisfying results. The combined influence
of the reaction temperature and solvent was also investigated
(entries 8–10). Inthe cyclisation of 24 theyield could beincreased
by switching from CH2Cl2 to toluene at higher temperatures
(entry 10), while changing the solvent alone had no influence.
An increase of yield was also observed if nitrogen was bubbled
through the solution, to remove the ethylene that was formed.
Peptide 22 was used to investigate the influence of Lewis
acids, such as Ti(OiPr)4, on the outcome of the reaction. As
Scheme 6 Ugi reactions and ring-closing metathesis.
As expected, the best results were obtained with the proline
peptide 25. The isolated yield was better than 26, for which more
starting material was recovered.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5
1 3 9

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illustrated in entries 11–14, subequimolar ratios of Lewis acids
can indeed increase the yield, while in higher ratios the reaction
can be suppressed completely. Lewis acids only accelerated the
metathesis reaction with catalyst A, but with the more reactive
B, only homodimerisation and polymerisation occurred. The
best results were obtained in a 0.01 M solution of substrate 22,
but the yield could not be increased to more than 35% under all
conditions investigated so far; we thus presume that deactivation
of the catalyst by the substrate occurs during the reaction.
Therefore, the mode of addition was thoroughly investigated
with peptides 22 and 25 (entries 15–21). In both cases the yield
of cyclisation product was below 5% if a solution of the catalyst
was added over 30 min to a solution of the peptide in CH2Cl2 at
rt (entries 15,16). If the catalyst solution was added more slowly,
over 2 h via a syringe pump, a significant increase in the yield was
observed (entry 17). The same results were obtained when the
reaction mixture was degassed with N2 to remove the ethylene
liberated in the ring-closing step (entries 18–19). But by far the
best results were obtained if the peptide solution was added to
the catalyst solution in refluxing CH2Cl2 under an N2 stream.
Under these conditions the yield could be increased to 51 and
73%, respectively (entries 20 and 21). In both cases, only the
product with the trans-configured double bond was obtained,
no cis product could be determined by HPLC and NMR.
and 6.0), 4.54 (2H, d, J 6.7), 5.54 (1H, dtq, J 15.2 and 6.7, 1.6),
5.62 (1H, d, J 8.5), 5.78 (1H, dq, J 15.2 and 6.6), 6.64 (1H, t, J
5.5), 7.18 (1H, t, J 6.0), 7.23 (2H, d, J 8.9), 7.66 (2H, d, J 8.3).
13C NMR (75 MHz, CDCl3): d 17.54, 17.74, 19.06, 21.50, 31.05,
36.04, 36.13, 41.48, 62.45, 66.36, 124.34, 127.36, 129.55, 132.38,
136.38, 143.74, 170.46, 171.06, 172.45. C21H31N3O6S (453.56)
calcd.: C 55.61 H 6.89 N 9.26 S 7.07; found: C 55.52 H 6.87 N
9.22 S 7.18.
N-(4-Toluolsulfonyl)-(S)-valinyl-b-alaninyl-(R)-c,d-dehydro-allo-
isoleucine methylester (4)
Peptide 3 (227 mg, 0.5 mmol) and tin chloride (190 mg,
1.0 mmol) were placed in a Schlenk flask under argon. Abs.
THF (10 ml) was added and the clear solution was cooled
to −78 ◦C. A freshly prepared solution of LHMDS (from
3.13 mmol HMDS and 2.50 mmol BuLi) in THF (3 ml) was
slowly added. The reaction mixture was warmed to rt overnight,
diluted with Et2O (20 ml) and hydrolysed with 1 N HCl (20 ml).
Stirring was continued to destroy the peptide–metal complex.
The layers were separated, the organic layer was washed again
with 1 N HCl, dried (Na2SO4) and evaporated in vacuo. The
crude product was esterified with diazomethane and purified by
flash chromatography (hexane–EtOAc–EtOH 6 : 4 : 1) giving
rise to 4 (190 mg, 0.44 mmol, 89%) as a colourless solid, mp
215–216 ◦C. Diastereomeric ratio: 16 : 84. HPLC (Daicel OD–H,
Conclusion
hexane–isopropanol 90 : 10, 0.5 ml min−1): tR1 = 28.17 min, tR2
=
35.35 min. 1H NMR (300 MHz, CD3OD): d 0.81 (3H, d,
J 6.4), 0.86 (3H, d, J 6.5), 1.03 (3H, bs), 1.84 (1H, m), 2.27 (2H,
m), 2.40 (3H, s), 2.62 (1H, m), 3.15 (2H, m), 3.37 (1H, bs), 3.67
(3H, s), 4.42 (1H, bs), 5.03–5.09 (2H, m), 5.73 (1H, m), 7.33
(2H, d, J 8.4), 7.69 (2H, d, J 7.6). 13C NMR (75 MHz, CD3OD):
d 16.11, 18.56, 19.56, 21.45, 32.46, 35.92, 36.69, 41.33, 52.38,
58.17, 63.81, 116.14, 128.40, 130.53, 138.95, 140.36, 144.77,
173.17, 173.52. C22H33N3O6S (467.58) calcd.: C 56.51 H 7.11
N 8.99; found: C 56.24 H 7.08 N 8.72.
In conclusion, we have shown that not only the length and
sequence of a peptide chain is responsible for the success of a
ring-closing metathesis but also the synthetic protocol. While
peptides containing amino acids with allylic side chains or
with allylether side chains can be cyclised under “standard
conditions”, allylic esters and carbamates require optimised
reaction conditions.
Experimental
All reactions were carried out in oven-dried glassware (100 ◦C)
under argon. All solvents were dried before use. THF was
distilled from sodium benzophenone, dichloromethane and
diisopropylamine from calcium hydride. LHMDS solutions
were prepared from freshly distilled hexamethyldisilazane and
commercially available n-butyllithium solution (15% in hexane)
in THF at −20 ◦C directly before use. The starting materials
and the products were purified by flash chromatography on
silica gel (32–63 lm). 1H and 13C NMR: Bruker AC 300,
Bruker Advance 300, Bruker 400 MHz or Bruker DRX-500
spectrometer, respectively.
Diastereomeric ratios were determined by analytical HPLC
using a Shimadzu workstation with an SPD-M10A diodearray
detector and a Lichrosorb silicagel column (250 × 4 mm,
5 lm) or a Daicel “Chiralcel OD–H” column (250 × 4 mm,
5 lm). Optical rotations were measured using a Perkin-Elmer
241 polarimeter.
[N-Allyl-N-(4-toluolsulfonyl)]-(S)-valinyl-b-alaninyl-(R)-c,
d-dehydro-allo-isoleucin methylester (5)
A solution of allylpalladium chloride dimer (1.3 mg, 3.4 lmol,
1 mol%), triphenylphosphine (4 mg, 15.2 mmol, 4.5 mol%) and
allyl ethyl carbonate (91 mg, 0.7 mmol) in abs. THF (2 ml)
was added to a solution of 4 (165 mg, 0.35 mmol) in THF (5
ml). The reaction mixture was stirred overnight and the solvent
was evaporated in vacuo. The crude product was purified by flash
chromatography on silica (hexane–EtOAc 1 : 1) giving 5 (132 mg,
0.26 mmol, 73%) as a colourless oil. 1H NMR (300 MHz,
CDCl3): d 0.62 (3H, d, J 6.6), 0.81 (3H, d, J 6.5), 1.04 (3H, d,
J 7.0), 2.15 (1H, m), 2.34–2.47 (2H, m), 2.38 (3H, s), 2.65 (1H,
m), 3.33 (1H, m), 3.45 (1H, m), 3.64 (1H, d, J 10.8), 3.71 (3H, s),
3.86 (1H, dd, J 16.2 and 6.0), 4.13 (1H, dd, J 16.3 and 7.0), 4.60
(1H, dd, J 8.6 and 5.2), 5.01–5.18 (4H, m), 5.62–5.84 (2H, m),
6.03 (1H, d, J 8.2), 6.63 (1H, bs), 7.23 (2H, d, J 8.1), 7.67 (2H, d,
J 8.2). 13C NMR (75 MHz, CDCl3): d 15.54, 19.03, 19.45, 21.26,
27.00, 35.12, 35.26, 40.26, 47.08, 51.92, 55.79, 66.04, 116.23,
117.31, 127.23, 129.25, 134.86, 137.43, 138.21, 143.16, 169.49,
170.72, 171.51. C25H37N3O6S (507.65) calcd.: C 59.15 H 7.35 N
8.28 S 6.32; found: C 59.11 H 7.44 N 8.13 S 6.54.
N-(4-Toluolsulfonyl)-(S)-valinyl-b-alaninyl-glycine crotylester (3)
To a solution of Tos-Val-b-Ala-OH (1.03 g, 3.0 mmol) in THF
(15 ml) carbonyldiimidazole (0.49 g, 3.0 mmol) was added at
rt. After evolution of CO2 the reaction mixture was stirred for
10 min, before Gly-OAll·HCl (0.50 g, 3.0 mmol) was added as
solid. After stirring for 10 h, the reaction mixture was diluted
with Et2O and washed with sat. NaHCO3 and 1 N HCl. The
aqueous layer was extracted with Et2O. The combined organic
layers were dried (Na2SO4) and evaporated in vacuo giving rise to
a pale yellow solid. Crystallisation from MeOH–EtOAc–Et2O
gave 1.01 g (2.3 mmol, 75%) of 3 as colourless crystals, mp 171–
172 ◦C. 1H NMR (300 MHz, CDCl3): d 0.73 (3H, d, J 6.8), 0.76
(3H, d, J 6.8), 1.67 (3H, dd, J 6.5 and 1.0), 1.94 (1H, m), 2.32
(2H, dt, J 6.7 and 4.9), 2.40 (3H, s), 3.37 (1H, dd, J 8.3 and 5.9),
3.43 (2H, m), 3.84 (1H, dd, J 18.0 and 5.5), 4.03 (1H, dd, J 18.0
N-(4-Toluolsulfonyl)-(S)-valinyl-(S)-prolinyl-(S)-leucinyl-
glycine allylester (6)
Tetrapeptide 6 was obtained by standard peptide coupling
reactions in a 4 mmol scale. Crystallisation from EtOAc–Et2O–
hexane gave colourless needles, mp 158–159 ◦C. 1H NMR
(300 MHz, CDCl3): d 0.82 (3H, d, J 6.1), 0.84 (3H, d, J 6.0),
0.86 (3H, d, J 6.6), 0.91 (3H, d, J 6.8), 1.47–2.14 (8H, m), 2.39
(3H, s), 3.13 (1H, m), 3.38 (1H, m), 3.60 (1H, dd, J 9.9 and
6.5), 3.94 (1H, dd, J 18.2 and 5.4), 4.02 (1H, dd, J 18.2 and
5.3), 4.13 (1H, dd, J 8.4 and 2.6), 4.33 (1H, m), 4.58 (2H, dt,
1 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5

View Article Online
J 6.2 and 1.3), 5.22 (1H, dt, J 10.4 and 1.3), 5.28 (1H, dt, J
17.2 and 1.4), 5.86 (1H, ddt, J 17.1, 10.4 and 6.3), 6.39 (1H,
d, J 9.9), 6.76 (1H, t, J 5.4), 7.17 (1H, d, J 7.8), 7.26 (2H,
d, J 8.1), 7.69 (2H, d, J 8.3). 13C NMR (75 MHz, CDCl3):
d 17.68, 19.07, 21.47, 21.77, 22.88, 24.57, 24.90, 27.14, 31.68,
40.60, 41.18, 47.24, 51.90, 59.34, 59.67, 65.87, 118.82, 127.41,
129.43, 131.48, 136.01, 143.59, 169.31, 170.92, 171.14, 172.06.
C28H42N4O7S (578.73) calcd.: C 58.11 H 7.32 N 9.68 S 5.54;
found: C 57.94 H 7.29 N 9.53 S 5.68.
d 19.11, 20.73, 21.50, 23.17, 24.34, 25.72, 27.68, 28.36, 28.63,
40.66, 40.81, 47.25, 52.36, 52.41, 54.79, 56.94, 61.52, 127.80,
128.56, 128.62, 129.52, 136.97, 143.73, 167.61, 171.35, 171.99,
172.71. HMRS: calcd. for C30H45N4O7S ([M+H]+), 605.2993;
found, 605.3029. HMRS: calcd. for C30H44N4O7SNa ([M+Na]+),
627.2812; found, 627.2820.
Cyclopeptide 13
According to the preparation of 9, peptide 13 was obtained
from 11 (61 mg, 0.10 mmol) as a pale yellow oil. Yield: 46 mg
(0.08 mmol, 80%). 1H NMR (500 MHz, d7-DMF): d 0.86 (3H,
d, J 6.3), 0.88 (3H, d, J 6.4), 0.99 (3H, d, J 7.0), 1.00 (3H, d, J
7.0), 1.62–1.70 (2H, m), 1.76 (1H, m), 2.11 (1H, m), 2.43 (3H,
s), 2.44–2.52 (3H, m), 2.69 (1H, m), 3.26 (1H, m), 3.51 (1H,
m), 3.64 (3H, s), 3.75 (1H, dd, J 14.7 and 6.3), 3.81 (1H, dd, J
14.8 and 7.1), 3.97 (1H, dd, J 6.0 and 5.7), 4.43 (1H, m), 4.59
(1H, m), 5.43 (1H, dt, J 15.4, 6.7), 5.64 (1H, dt, J 15.4, 7.0),
7.47 (2H, d, J 8.0), 7.62 (1H, d, J 8.0), 7.71 (1H, d, J 8.3), 7.75
(2H, d, J 8.0), 8.15 (1H, d, J 6.1). 13C NMR (125 MHz, d7-
DMF): d 18.67, 19.50, 21.23, 21.35, 23.38, 25.13, 30.43, 33.88,
40.62, 43.28, 50.18, 51.94, 52.27, 52.39, 61.86, 127.81, 128.84,
130.42, 131.29, 137.32, 144.18, 171.89, 171.98, 172.50, 172.76.
C28H42N4O7S (578.73) calcd.: C 58.11 H 7.32 N 9.68; found: C
58.15 H 7.38 N 9.27.
N-(4-Toluolsulfonyl)-(S)-valinyl-(S)-prolinyl-(S)-leucinyl-
allylglycine methylester (7)
According to the preparation of 4, rearrangement product 7
was obtained from 6 (289 mg, 0.50 mmol) as a colourless
foam in a diastereomeric ratio of 40 : 60. Yield: 275 mg
(0.46 mmol, 93%). HPLC (Daicel OD–H, hexane–isopropanol
90 : 10, 0.5 ml min−1): tR1 = 24.67 min, tR2 = 30.83 min. 1H NMR
(300 MHz, CDCl3): d 0.82 (3H, d, J 6.1), 0.86 (3H, d, J 6.2), 0.89
(3H, d, J 6.8), 0.94 (3H, d, J 6.7), 1.46–2.09 (8H, m), 2.39 (3H, s),
2.47 (2H, m), 3.12 (1H, m), 3.37 (1H, m), 3.64 (1H, dd, J 10.1 and
6.3), 3.69 (3H, s), 4.04 (1H, dd, J 8.4 and 2.7), 4.30 (1H, m), 4.56
(1H, m), 5.04 (1H, d, J 15.4), 5.05 (1H, d, J 11.6), 5.65 (1H, m),
6.06 (1H, d, J 10.0), 6.59 (1H, d, J 7.7), 7.00 (1H, d, J 7.7), 7.27
(2H, d, J 8.2), 7.69 (2H, d, J 8.3). 13C NMR (75 MHz, CDCl3):
d 17.28, 18.99, 21.27, 21.66, 22.66, 24.42, 25.12, 26.85, 31.40,
36.04, 40.57, 46.99, 51.44, 51.66, 52.07, 59.13, 59.47, 118.79,
127.25, 129.18, 132.03, 136.61, 143.36, 170.47, 170.85, 171.17,
171.60. HMRS: calcd. for C29H45N4O7S ([M+H]+), 593.2993;
found, 593.3022. HMRS: calcd. for C29H44N4O7SNa ([M+Na]+),
615.2812; found, 615.2847.
Cyclopeptide 14
According to the preparation of 9, peptide 14 was obtained
from 12 (80 mg, 0.14 mmol) as a colourless solid, mp 178–
◦
1
179 C. Yield: 69 mg (0.13 mmol, 91%). H NMR (300 MHz,
CD3OD): d 0.92 (3H, d, J 6.2), 0.94 (3H, d, J 6.9), 0.96 (3H,
d, J 6.0), 0.97 (3H, d, J 6.2), 1.42 (9H, s), 1.63 (2H, m),
1.69 (1H, m), 2.10 (1H, m), 2.35 (1H, m), 2.60 (1H, m), 1.57
(2H, m), 3.71 (3H, s), 3.84 (1H, d, J 11.8), 3.93 (1H, d, J
11.5), 4.26 (1H, m), 4.28 (1H, d, J 6.9), 4.37 (1H, m), 4.66
(1H, dd, J 9.8 and 3.3), 5.58 (2H, m). 13C NMR (75 MHz,
CD3OD): d 18.44, 19.75, 22.56, 22.97, 25.99, 28.65, 32.29, 34.88,
41.74, 52.80, 52.85, 53.70, 55.40, 62.07, 70.77, 72.19, 80.76,
128.18, 130.34, 157.42, 172.79, 173.04, 173.29, 173,69. HMRS:
calcd. for C26H45N4O8 ([M+H]+), 541.3222; found, 541.3256.
HMRS: calcd. for C26H44N4O8Na ([M+Na]+), 563.3041; found:
563.3052.
[N-(4-Toluolsulfonyl)-N-allyl]-(S)-valinyl-(S)-prolinyl-(S)-
leucinyl-allylglycine methylester (8)
According to the preparation of 5, N-allylated product 8 was
obtained from 7 (260 mg, 0.440 mmol) as a pale yellow oil.
Yield: 210 mg (0.33 mmol, 75%). 1H NMR (300 MHz, CDCl3):
d 0.83 (3H, d, J 6.1), 0.85 (3H, d, J 7.2), 0.88 (3H, d, J 6.7),
0.89 (3H, d, J 6.6), 1.39–1.49 (1H, m), 1.53–1.89 (2H, m), 1.89
(1H, m), 1.98–2.20 (4H, m), 2.38 (3H, s), 2.49 (2H, m), 3.52
(1H, m), 3.65–3.76 (1H, m), 3.69 (3H, s), 3.96 (1H, dd, J 16.6
and 5.3), 4.22–4.32 (3H, m), 4.39 (1H, dd, J 16.5 and 7.7), 4.56
(1H, m), 4.99–5.15 (4H, m), 5.63 (1H, m), 5.87 (1H, m), 6.70
(1H, d, J 7.7), 6.86 (1H, d, J 7.9), 7.23 (2H, d, J 7.9), 7.58
(2H, d, J 8.3). 13C NMR (75 MHz, CDCl3): d 8.59, 19.75,
21.25, 21.78, 22.57, 24.50, 24.66, 27.32, 28.93, 36.06, 40.49,
47.31, 51.43, 51.70, 51.91, 52.07, 59.89, 62.16, 116.64, 118.78,
127.04, 129.18, 132.05, 135.71, 137.09, 143.30, 170.73, 170.84,
171.19, 171.61. C32H48N4O7S (632.82) calcd.: C 60.74 H 7.64
N 8.85 S 5.07; found: C 60.94 H 7.59 N 8.79 S 5.08. HMRS:
calcd. for C32H49N4O7S ([M+H]+), 633.3305; found, 633.3329.
HMRS: calcd. for C32H48N4O7SNa ([M+Na]+), 655.3124; found,
655.3154.
Cyclopeptide 16
According to the preparation of 9, peptide 16 was obtained from
15 (80 mg, 0.134 mmol) using 5% catalyst (6 mg, 0.067 mmol).
Purification of the crude product by flash chromatography
(hexane–EtOAc 6 : 4 → 1 : 1) gave 16 as a colourless solid,
mp 184–185 ◦C. Yield: 65 mg (0.144 mmol, 85%). The cis/trans
1
ratio could not be determined. [a]2D0 = −3.5 (c 1, CHCl3). H
NMR (300 MHz, CDCl3): d 0.89–0.97 (12H, m), 1.43 (9H,
s), 1.50–1.57 (3H, m), 2.20 (1H, m), 3.60–3.63 (2H, m), 3.75
(3H, s), 3.78–3.81 (2H, m), 4.10–4.15 (4H, m), 4.20–4.25 (2H,
m), 4.44 (1H, m), 4.65 (1H, m), 5.30–5.43 (2H, m), 5.86 (1H,
m), 6.06 (1H, dbr), 7.25 (1H, dbr), 7.35 (1H, dbr). 13C NMR
(75 MHz, CDCl3): d 16.47, 19.49, 21.84, 22.81, 24.83, 28.23,
31.05, 39.05, 52.46, 52.59, 52.75, 57.95, 69.63, 70.32, 71.29,
80.27, 127.81, 129.44, 155.73, 170.25, 170.95, 171.16, 171.32.
C27H46O9N4 (570.684) calcd.: C 56.83 H 8.12 N 9.82; found: C
55.69 H 8.07 N 8.91. HMRS: calcd. for C27H47N4O9 ([M+H]+),
571.3343; found, 571.3359. HMRS: calcd. for C27H46N4O9Na
([M+Na]+), 593.3163; found, 593.3127.
Cyclopeptide 9
Tetrapeptide 8 (85 mg, 0.134 mmol) was dissolved in CH2Cl2
(10 ml) in a Schlenk tube under argon. A solution of Grubbs’
catalyst A (12 mg, 13.4 lmol, 10 mol%) in CH2Cl2 (15 ml) was
added slowly to the peptide solution via a syringe. The mixture
was refluxed for 2 h and allowed to stir overnight at rt. The
solvent was evaporated in vacuo and the dark brown residue was
purified by flash chromatography (hexane–EtOAc 6 : 4) giving
1
rise to 9 (67 mg, 0.103 mmol, 77%) as a pale yellow oil. H
Cyclopeptide 18
NMR (300 MHz, CDCl3): d 0.53 (3H, d, J 6.1), 0.83 (3H, d,
J 6.4), 0.89 (3H, d, J 6.6), 0.94 (3H, d, J 6.6), 1.48–2.33 (8H,
m), 2.40 (3H, s), 2.82 (2H, m), 3.67 (3H, s), 3.64–3.70 (3H, m),
3.82 (1H, dd, J 16.5 and 10.5), 3.96 (1H, m), 4.09 (1H, m),
4.23 (1H, d, J 10.5), 4.74 (1H, m), 5.19 (1H, t, J 10.5), 5.47
(1H, d, J 8.4), 5.55 (1H, t, J 10.9), 7.27 (2H, d, J 8.3), 7.70
(2H, d, J 8.3), 8.61 (1H, d, J 8.3). 13C NMR (75 MHz, CDCl3):
According to the preparation of 9, peptide 18 was obtained
from 17 (134 mg, 0.23 mmol) using 5% catalyst A (9 mg, 0.01
mmol). To remove traces of the catalyst, the products were
dissolved in methanol and stirred vigorously after addition of
3% H2O2 solution. The mixture was diluted with CH2Cl2 and the
phases were separated. The organic layer was nearly colourless.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5
1 4 1

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In this case the cis/trans isomers could be separated by flash
chromatography (hexane–EtOAc 2 : 8 → EtOAc) giving 66 mg
(0.12 mmol, 52%) trans-21 and 52 mg (0.09 mmol, 41%) cis-21.
Overall yield: 118 mg (0.21 mmol, 93%). HPLC (Daicel OD-
Allyloxycarbonyl-(S)-valyl-N-[(R)-1-methyl-p-methoxy-benzyl]-
(R,S)-valyl-glycine allylester ((S,R,R/S)-22)
Isobutyraldehyde (360 mg, 5.0 mmol) was added to a solution
of (R)-1-methyl-p-methoxy-benzylamine (755 mg, 5.0 mmol) in
trifluoroethanol (5 ml). The solution was stirred for 15 min
and subsequently cooled to −30 ◦C before (S)-Aloc-ValOH
(1120 mg, 5.5 mmol) in trifluoroethanol (5 ml) was added.
After a further 15 min, isocyanoacetic acid allylester (750 mg,
5.0 mmol) was added via a syringe over 20 min. The solution
was kept at −30 ◦C for three days before the solvent was
evaporated in vacuo. Workup was carried out as described for 21.
The diastereomers could be separated by flash chromatography
(hexane–EtOAc 7 : 3 → 6 : 4) giving rise to (S,R,R)-22 (196 mg,
0.4 mmol) and (S,R,S)-22 (1589 mg, 3.1 mmol) as viscous
aromatic oils. Overall yield: 1.785 g (3.6 mmol, 71%). The
diastereomeric ratio was determined to 11 : 89 by HPLC (silica,
hexane–EtOAc 73 : 27, 2 ml min−1): tR(S,R,R-22) = 7.40 min;
H, hexane–isopropanol 85 : 15, 0.5 ml min−1): trans-18: tR1
=
28.14 min, cis-18: tR2 = 31.17 min. trans-18: [a]2D2 = +11.7◦ (c 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3): d 0.70 (3H, d, J 6.8), 0.94
(3H, d, J 6.8), 1.40 (9H, s), 1.86–1.99 (2H, m), 2.06–2.13 (2H,
m), 2.38 (1H, m), 3.46–3.65 (5H, m), 3.71 (3H, s), 3.72 (1H, m),
3.80 (1H, m), 3.96 (1H, m), 4.13–4.20 (2H, m), 4.29 (1H, sbr),
4.52 (1H, m), 4.59–4.66 (2H, m), 5.49 (1H, d, J 4.8), 5.90 (1H,
d, J 15.5), 6.09 (1H, d, J 15.5), 7.81 (1H, d, J 7.9), 7.87 (1H,
d, J 8.5). 13C NMR (75 MHz, CDCl3): d 15.81, 20.16, 25.79,
26.31, 28.33, 30.15, 47.51, 52.31, 52.52, 52.91, 55.97, 60.31,
70.04, 70.46, 70.67, 71.42, 79.82, 127.10, 128.67, 154.94, 170.52,
170.70, 170.98, 171.15. cis-18: [a]2D2 = −44.4◦ (c = 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): d 0.84 (3H, d, J 6.7), 0.96 (3H,
d, J 6.7), 1.43 (9H, s), 1.79 (1H, m), 1.94 (1H, m), 2.00 (1H, m),
2.11 (1H, m), 2.39 (1H, m), 3.51 (1H, m), 3.56–3.58 (2H, m),
3.63–3.69 (3H, m), 3.72 (3H, s), 3.90 (1H, m), 3.94–3.96 (2H,
m), 3.99 (1H, m), 4.22 (1H, m), 4.49 (1H, d, J 7.7), 4.54 (1H,
m), 4.76 (1H, dd, J 9.2 and 4.2), 5.53 (1H, d, J 5.7), 5.67 (1H,
m), 5.75 (1H, m), 7.16 (1H, d, J 9.2), 7.70 (1H, d, J 7.4). 13C
NMR (75 MHz, CDCl3): d 16.45, 19.59, 24.61, 27.20, 28.04,
31.30, 47.06, 52.28, 52.67, 54.78, 59.91, 67.52, 69.51, 69.84,
70.69, 80.12, 126.85, 129.39, 154.94, 170.20, 170.51, 170.55,
170.85. HMRS: calcd. for C26H43N4O9 ([M+H]+), 555.3030;
found, 555.3036. HMRS: calcd. for C26H42N4O9Na ([M+Na]+),
577.2849; found, 577.2839.
tR(S,R,S-22) = 10.71 min. (S,R,R)-22: [a]22 = +44.5◦ (c 1,
D
1
CHCl3, >99% de). H NMR (300 MHz, HH-COSY): d 0.21
(3H, d, J 6.6), 0.70 (3H, d, J 6.6), 1.00 (3H, d, J 6.8,) 1.08
(3H, d, J 6.6), 1.54 (3H, d, J 7.0), 2.28 (1H, m), 2.81 (1H,
m), 3.15 (1H, d, J 10.8), 3.75–3.85 (4H, m), 4.20 (1H, dd,
J 18.0 and 7.0), 4.52–4.55 (4H, m), 4.80 (1H, m), 5.14–5.38
(5H, m), 5.58 (1H, d, J 9.6), 5.81–5.96 (2H, m), 6.88 (2H, d,
J 8.5), 7.28 (2H, d, J 8.8), 8.50 (1H, m). 13C NMR (75 MHz,
HMBC): d 17.0, 17.8, 19.6, 20.2, 20.8, 27.1, 27.1, 31.4, 41.0,
55.3, 57.2, 57.4, 65.8, 68.8, 113.8, 117.5, 118.8, 126.6, 132.8,
130.0, 130.2, 131.7, 156.2, 159.5, 169.6, 173.4, 173.6. HMRS:
calcd. for C28H41N3O7 ([M]+), 531.2944; found, 531.2951; calcd.
for C28H42N3O7 ([M+H]+), 532.3022; found, 532.2994. (S,R,S)-
22, [a]2D2 = −54.5◦ (c 1, CHCl3, >98% de). 1H NMR (300 MHz,
HH-COSY): d 0.79 (3H, d, J 6.3), 0.83 (3H, d, J 6.3), 1.04 (3H,
d, J 7.0), 1.06 (3H, d, J 7.7), 1.64 (3H, d, J 6.8), 2.19 (1H,
m), 2.80–2.94 (2H, m), 3.67 (1H, dd, J 18.2 and 4.7), 3.76 (3H,
s), 3.93 (1H, dd, J 18.2 and 6.5), 4.54–4.61 (5H, m), 5.17–5.33
(5H, m), 5.45 (1H, d, J 9.4), 5.83–5.93 (2H, m), 6.78 (2H, d,
J 8.8), 7.20 (2H, d, J 8.8), 8.38 (1H, bs). 13C NMR (75 MHz,
HMBC): d17.2, 17.9, 19.9, 20.0, 20.4, 26.5, 31.6, 40.8, 55.2,
55.8, 57.2, 65.6, 65.9, 69.9, 113.9, 117.6, 118.6, 128.9, 129.9,
131.7, 132.6, 156.2, 159.3, 169.5, 171.4, 174.1. HMRS: calcd.
for C28H41N3O7 ([M]+), 531.2944; found, 531.2953; calcd. for
C28H42N3O7 ([M+H]+), 532.3022; found, 532.3036.
Cyclopeptide 20
According to the preparation of 9, peptide 20 was obtained from
19 (88 mg, 0.15 mmol) using 5% catalyst A (7 mg, 0.008 mmol).
1
Yield: 18 mg (32.4 lmol, 21%) of a grey–brown oil. H NMR
(300 MHz, CDCl3): d 0.88–0.94 (12H, m), 1.44 (9H, s), 1.50–
1.60 (3H, m), 1.88 (1H, m), 3.74 (2H, m), 3.91–4.00 (2H, m),
4.09 (1H, m), 4.60–4.65 (7H, m), 5.57 (1H, dbr), 5.68–5.75
(2H, m), 6.75 (1H, dbr), 6.90 (1H, dbr), 7.05 (1H, dbr). 13C
NMR (75 MHz, CDCl3): d 18.41, 19.28, 20.89, 23.19, 24.83,
28.26, 30.51, 40.05, 51.57, 54.98, 63.41, 63.95, 69.95, 80.30,
127.74, 128.45, 155.71, 169.77, 171.21, 171.60, 172.34. HMRS:
calcd. for C26H45N4O9 ([M+H]+), 557.3187; found, 557.3173.
HMRS: calcd. for C26H44N4O9Na ([M+Na]+), 579.3006; found,
579.2990.
Cyclopeptide 26
In a 100 ml Schlenk flask peptide, (S,R,S)-22 (531 mg,
1.00 mmol) was dissolved in CH2Cl2 (80 ml) under reflux and
a constant stream of N2 was bubbled through the solution. A
solution of Grubbs’ catalyst (81 mg, 0.10 mmol, 10 mol%) in
CH2Cl2 (10 ml) was added slowly over a period of 2 h via a
syringe. After 4 h when nearly all starting material was consumed
(TLC), the solvent was removed in vacuo and the crude product
was purified by flash chromatography (hexane–EtOAc 6 : 4 →
1 : 1→ 3 : 7) giving rise to 23 (367 mg, 0.73 mmol, 73%) as a
colourless solid, mp 170–172 ◦C. In addition a small amount of
22 (80 mg, 0.15 mmol, 15%) was recovered. The trans-isomer
was obtained with 95% selectivity as determined by HPLC. 1H
NMR (500 MHz, CDCl3, HH-COSY): d 0.28 (3H, d, J 6.6), 0.65
(3H, d, J 6.6), 0.99 (3H, d, J 7.0), 1.13 (3H, d, J 6.6), 1.63 (3H,
d, J 6.9), 2.29 (1H, m), 2.74 (1H, m), 3.13 (1H, d, J 11.0), 3.60
(1H, dd, 1H, J 17.8 and 2.5), 3.78 (3H, s), 4.16 (1H, m), 4.47
(1H, dd, J 17.3 and 7.7), 4.51 (1H, dd, J 12.1 and 7.0), 4.68 (1H,
dd, J 12.1 and 3.5), 4.80 (1H, dd, J 9.9 and 3.7), 4.95 (1H, dd, J
13.0 and 4.8), 5.31 (1H, q, J 6.6), 5.40 (1H, d, J 9.0,) 5.78–5.96
(2H, m), 6.90 (2H, d, J 8.8), 7.30 (2H, d, J 8.8), 8.42 (1H, d, J
5.9). 13C NMR (75 MHz, HMBC): d 16.5, 18.7, 19.8, 20.6, 27.0,
31.0, 42.1, 55.3, 56.8, 57.8, 63.2, 64.6, 68.4, 113.9, 127.3, 130.9,
129.8, 130.2, 156.7, 159.6, 168.7, 173.3, 174.7. HMRS: calcd.
for C26H38N3O7 ([M+H]+), 504.2621; found, 504.2655; calcd. for
C26H37N3O7Na ([M+Na]+), 526.2532; found, 526.2482.
Depsipeptide 21
A solution of (S)-Aloc-ValOH (1.94 g, 5.00 mmol) in triflu-
oroethanol (5 ml) was added to a solution of pivalaldehyde
(0.54 ml, 5.00 mmol) in the same solvent (5 ml) at 0 ◦C. Iso-
cyanoacetic acid allylester (625 mg, 5.00 mmol) was added via
a syringe over 20 min and the mixture was allowed to warm
to rt overnight. Stirring at rt was continued for 24 h, before
the solvent was removed in vacuo. The residue was dissolved in
EtOAc (30 ml) and the organic layer was washed twice with sat.
NaHCO3 (30 ml) and 1 N KHSO4 (30 ml). After drying (Na2SO4)
and evaporation of the solvent the crude product was purified by
flash chromatography (hexane–EtOAc 7 : 3 → 6 : 4). Subsequent
crystallisation from ether gave 21 (1.10 g, 2.55 mmol, 53%) as a
single diastereomer, mp 173–174 ◦C. The absolute configuration
of the newly formed stereogenic centre was not determined. 1H
NMR (500 MHz, CDCl3, HH-COSY): d 0.88–0.98 (15H, m),
2.12 (1H, m), 3.82 (1H, dd, J 18.0 and 4.4), 4.11 (1H, m), 4.19
(1H, dd, J 18.0 and 5.8), 4.48–4.62 (5H, m), 5.15–5.32 (4H, m),
5.71 (1H, d, J 8.5), 5.84–5.88 (2H, m), 6.73 (1H, d, J 8.5). 13C
NMR (125 MHz, CDCl3, HMBC, DEPT): d 16.4, 18.4, 25.5,
25.6, 30.5, 33.7, 40.1, 59.1, 59.2, 64.7, 65.0, 116.8, 117.9, 130.5,
131.1, 156.8, 168.5, 169.7, 170.4. C20H32N2O7 (412.48) calcd.: C
58.24 H 7.82 N 6.79; found: C 58.17 H 7.75 N 6.83.
1 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5

View Article Online
Allyloxycarbonyl-(S)-alanyl-N-[(S)-1-methyl-m-methoxy-
benzyl]-(R,S)-valyl-glycine allylester ((S,S,R/S)-24)
hyde (0.46 ml, 5.00 mmol) and isocyanoacetic acid allyl ester
(625 mg, 5.00 mmol) in 12 h at 4 ◦C. Flash chromatography
(hexane–EtOAc 7 : 3 → 6 : 4) provided 26 (1.96 g, 3.53 mmol,
72%) as viscous colourless oil as a mixture of diastereomers
and rotamers. The diastereomers could in part be separated by
a second flash chromatography. (S,S,R)-26: [a]2D0 = −137.4◦ (c
1.1, CHCl3). 1H NMR (500 MHz, CDCl3, HH-COSY, mixture
of rotamers): d 0.16–0.18 (2.1H, d, J 6.5), 0.87 (2.1H, d, J 6.5),
0.82–0.97 (7.8H, m), 1.59 (3H, d, J 7.1), 2.43 (1H, m), 2.79–
3.18 (5H, m), 3.63 (3H, s), 4.31–4.63 (2H, m), 4.59–4.63 (4H,
m), 4.94 (0.7H, d, J 10.5), 5.06 (0.3H, d, J 10.5), 5.20–5.27
(4H, m), 5.31 (0.3H, q, J 6.9), 5.42 (0.7H, q, J 7.2), 5.56–5.98
(2H, m), 6.79–6.89 (2H, m), 7.19–7.26 (2H, m), 8.32 (0.3H, bs),
8.40 (0.7H, bs). Coalescence was observed for the signals of the
rotamers at 398 K in d6-DMSO. 13C NMR (125 MHz, CDCl3,
HMBC, DEPT): d 17.1, 17.3, 17.9, 18.1, 19.4, 19.7, 19.8, 19.9,
20.1, 20.9, 25.8, 27.4, 28.5, 28.7, 29.2, 29.7, 40.8, 40.9, 53.2,
54.7, 55.0, 55.2, 60.6, 62.5, 63.2, 65.4, 65.6, 66.6, 68.5, 111.1,
111.9, 113.3, 113.6, 117.3, 117.7, 118.3, 118.6, 118.9, 120.0,
128.5, 129.5, 131.4, 131.8, 132.1, 132.5, 139.7, 144.7, 156.7,
159.3, 168.7, 171.2, 171.4. (S,S,S)-26: [a]2D0 = −111.0◦ (c = 1,
According to the preparation of 22, peptide 24 was obtained
from (S)-Aloc-AlaOH (952 mg, 5.50 mmol), (S)-1-methyl-m-
methoxy-benzyl amine (830 mg, 5.00 mmol), isobutyraldehyde
(0.45 ml, 5.00 mmol) and isocyanoacetic acid allyl ester (625 mg,
5.00 mmol) in 91% yield. Flash chromatography (hexane–EtOAc
8 : 2 → 7 : 3→ 6 : 4) allowed the separation of the diastereomers
giving rise to (S,S,R)-24 (1.50 g, 2.98 mmol, 60%) and (S,S,S)-24
(0.65 g, 1.29 mmol, 28%) as viscous oils. HPLC (silica, hexane–
EtOAc 75 : 25, 2 ml min−1): tR(S,S,R-27) = 12.05 min; tR(S,S,S-
24) = 14.94 min. (S,S,R)-24: [a]2D2 = −52.9◦ (c 0.8, CHCl3). 1H
NMR (500 MHz, CDCl3, HH-COSY): d 0.16 (3H, d, J 6.4),
0.71 (3H, d, J 6.6), 1.42 (3H, d, J 6.7), 1.65 (3H, d, J 7.0), 2.78
(1H, m), 3.10 (1H, m), 3.75–3.80 (4H, m), 4.21 (1H, dd, J 18.1
and 7.0), 4.56–4.60 (4H, m), 5.11 (1H, t, J 7.3), 5.16–5.32 (5H,
m), 5.58 (1H, d, J 8.3), 5.83–5.93 (2H, m), 6.84 (1H, dd, J 8.4
and 2.2), 7.05 (1H, d, J 8.6), 7.07 (1H, s), 7.26 (1H, t, J 8.0),
8.39 (1H, bs). 13C NMR (75 MHz, CDCl3): d 17.0, 18.8, 19.6,
19.8, 27.5, 40.8, 48.4, 55.4, 56.5, 65.7, 68.2, 114.2, 114.4, 117.7,
118.8, 120.6, 129.4, 131.7, 132.6, 139.4, 155.7, 159.9, 169.4,
173.7, 174.5. HMRS: calcd. for C26H37N3O7 ([M]+), 503.2632;
1
CHCl3). H NMR (500 MHz, CDCl3, HH-COSY, mixture of
rotamers): d 0.84–1.04 (11.1H, m), 1.11 (0.9H, d, J 6.7), 1.56
(0.9H, d, J 7.1), 1.59 (2.1H, d, J 7.1), 2.59 (1H, m), 2.96–2.97
(2H, m), 3.07 (3H, s), 3.67–3.73 (3.7H, m), 3.80 (0.7H, dd, J
18.4 and 6.6), 3.82 (0.3H, dd, J 18.5 and 5.7), 3.95 (0.3H, dd, J
18.5 and 5.7), 4.46–4.75 (5H, m), 5.07 (0.3H, dd, J 10.3 and 1.0),
5.15 (0.7H, ddd, J 10.5, 1.2 and 1.0), 5.22–5.51 (3H, m), 5.42
(0.3H, q, J 6.8), 5.53 (0.7H, q, J 6.8), 5.74 (0.3H, m), 5.79–5.96
(1.7H, m), 6.59 (1H, m), 6.64 (0.3H, m), 6.65–6.81 (2H, m), 7.07
(0.3H, t, J 8.2), 7.20 (0.7H, t, J 9.0), 8.40 (0.3H, bs), 8.46 (0.7H,
bs). 13C NMR (125 MHz, CDCl3, HMBC, DEPT): d 17.2, 17.3,
17.9, 18.0, 19.4, 19.7, 19.8, 19.9, 20.1, 20.9, 25.9, 27.3, 28.5, 28.8,
29.2, 29.6, 40.85, 40.9, 53.4, 54.9, 55.0, 55.1, 60.7, 62.4, 63.0, 65.5,
65.8, 66.6, 70.2, 111.0, 111.7, 113.3, 113.8, 117.2, 117.5, 118.2,
118.6, 118.9, 119.9, 128.5, 129.3, 131.5, 131.7, 132.1, 132.6,
139.7, 144.6, 156.6, 159.6, 168.9, 171.2, 171.5. HMRS: calcd. for
C29H43N3O7 ([M]+), 545.3101; found, 545.3072. HMRS: calcd.
for C29H44N3O7 ([M+H]+), 546.3179; found, 546.3177.
found, 503.2632. (S,S,S)-24: [a]2D2 = −6.9◦ (c 1.1, CHCl3). H
1
NMR (500 MHz, CDCl3, HH-Cosy): d 0.85 (3H, d, J 6.7), 0.89
(3H, d, J 6.4), 1.35 (3H, d, J 6.7), 1.65 (3H, d, J 7.0), 2.85
(1H, m), 3.20 (1H, m), 3.68–3.79 (5H, m), 4.55–4.60 (4H, m),
4.83 (1H, m), 5.19 (1H, dd, J 10.4 and 1.2), 5.21 (1H, dd, J
10.6 and 1.2), 5.25–5.32 (3H, m), 5.67 (1H, d, J 6.7), 5.83–5.93
(2H, m), 6.78 (1H, dd, J 8.2 and 2.4), 6.83 (1H, s), 6.85 (1H, d,
J 7.6), 7.19 (1H, t, J 7.9), 8.05 (1H, bs). 13C NMR (75 MHz,
CDCl3): d 17.4, 19.2, 19.9, 20.4, 26.8, 40.9, 48.3, 55.2, 59.5,
65.7, 65.7, 68.2, 113.2, 114.0, 117.7, 118.7, 119.5, 129.5, 131.7,
132.7, 139.6, 155.6, 159.7, 169.4, 171.1, 174.7. HMRS: calcd. for
C26H37N3O7 ([M]+), 503.2632; found, 503.2635. HMRS: calcd.
for C26H38N3O7 ([M+H]+), 504.2709; found, 504.2713.
Allyloxycarbonyl-(S)-prolinyl-N-[(S)-1-methyl-m-methoxy-
benzyl]-(R,S)-valyl-glycine allylester ((S,S,R/S)-25)
According to the preparation of 22, peptide 25 was obtained
from (S)-Aloc-ProOH (995 mg, 5.00 mmol), (S)-1-methyl-m-
methoxy-benzyl amine (830 mg, 5.50 mmol), isobutyraldehyde
(0.45 ml, 5.00 mmol) and isocyanoacetic acid allyl ester (625 mg,
5.00 mmol) in 12 h at 4 ◦C. Flash chromatography (hexane–
EtOAc 7 : 3 → 6 : 4) provided 25 (2.27 g, 4.38 mmol, 89%)
as viscous colourless oil as a mixture of diastereomers and
rotamers. 1H NMR (500 MHz, CDCl3, HH-COSY): d 0.21
(1.8H, d, J 6.6), 0.37 (1.8H, d, J 6.6), 1.66 (1.8H, d, J 5.4),
1.93–2.33 (4H, m), 2.82–2.87 (1H, m), 3.04 (1H, m), 3.57–3.87
(6H, m), 4.33 (1H, dd, J 17.9 and 7.9), 4.30–4.78 (4H, m), 5.11–
5.35 (6H, m), 6.84 (2H, m), 6.86 (1H, m), 7.15 (0.6H, d, J 7.7),
7.20 (0.6H, s), 7.30 (1H, m), 8.55 (1H, m). Selected signals of
the minor isomer: d = 0.71 (1.2H, d, J 6.3), 0.73 (1.2H, d,
J 6.0), 1.70 (1.2H, d, J 5.6), 7.00 (0.4H, s), 7.06 (0.4H, d, J
7.5). 13C NMR (125 MHz, CDCl3, HMBC, DEPT): d 16.8, 18.8,
18.8, 23.3, 27.8, 29.5, 30.6, 40.7, 46.8, 55.4, 55.9, 58.6, 65.7, 65.9,
69.8, 115.2, 117.2, 118.7, 120.6, 121.0, 129.8, 131.7, 133.0, 139.9,
154.8, 159.8, 169.6, 173.6, 174.2. Selected signals of the minor
isomer: d = 16.6, 24.3, 27.4, 30.6, 47.4, 55.2, 56.0, 58.9, 66.4,
69.3, 112.7, 114.2, 118.3, 121.0, 154.2, 174.3. HMRS: calcd. for
C28H40N3O7 ([M+H]+), 530.2801; found, 530.2861.
Cyclopeptide 27
In a 250 ml Schlenk flask, peptide 24 (505 mg, 1.00 mmol) was
dissolved in toluene (100 ml) at rt and a constant stream of
N2 was bubbled through the solution. A solution of Grubbs’
catalyst (82 mg, 0.10 mmol, 10 mol%) in toluene (8 ml) was
added slowly over a period of 2 h via a syringe. After stirring
for 16 h, no starting material could be detected and the
solution was concentrated to 20 ml. A 1% aqueous solution
of H2O2 (to destroy the catalyst) was added and the mixture
was stirred vigorously for 1 h, before charcoal was added. After
15 min the mixture was filtered through celite. The solvent was
removed in vacuo and the crude product was purified by flash
chromatography (hexane–EtOAc 6 : 4 → 3 : 7 → EtOAc) giving
rise to 27 (129 mg, 0.27 mmol, 27%) as a colourless solid,
mp 164–167 ◦C. Crystallisation from CH2Cl2–toluene–EtOAc
provided crystals suitable for X-ray structure analysis.† 1H NMR
(500 MHz, CDCl3, HH-COSY): d 0.81 (3H, d, J 6.3), 0.83 (3H,
d, J 6.3), 1.44 (3H, d, J 7.3), 1.60 (3H, d, J 7.3), 2.76 (1H,
m), 2.94 (1H, d, J 11.2), 3.50 (1H, dd, J 17.6 and 2.4), 3.70
(3H, s), 3.85 (1H, dd, J 17.6 and 6.4), 4.19 (1H, d, J 13.7),
4.53 (1H, m), 4.66 (1H, m), 4.93–5.01 (2H, m), 5.41 (1H, d, J
8.8), 5.54 (1H, q, J 6.9), 5.90–5.92 (2H, m), 6.79 (1H, dd, J
8.2 and 2.4), 6.92 (1H, d, J 7.8), 6.98 (1H, s), 7.20 (1H, dd, J
8.3 and 7.8), 8.20 (1H, d, J 5.4). 13C NMR (125 MHz, CDCl3,
HMBC): d 16.7, 18.9, 19.8, 20.6, 26.2, 42.3, 48.2, 55.2, 55.8, 63.2,
64.7, 70.0, 113.7, 114.5, 119.5, 126.2, 131.2, 129.2, 139.4, 156.1,
159.7, 168.2, 170.3, 175.9. HMRS: calcd. for C24H33N3O7Na
([M+Na]+), 498.2216; found, 498.2226.
Allyloxycarbonyl-(S)-N-methyl-valyl-N-[(S)-1-methyl-m-
methoxy-benzyl]-(R,S)-valyl-glycine allylester ((S,S,R/S)-26)
According to the preparation of 22, peptide 26 was obtained
from N-Aloc-N-Me-ValOH (1.07 g, 5.00 mmol), (S)-1-methyl-
m-methoxy-benzyl amine (830 mg, 5.50 mmol), isobutyralde-
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5
1 4 3

View Article Online
Cyclopeptide 28
5 J. Rizo and L. M. Gierasch, Annu. Rev. Biochem., 1992, 61, 387–418.
6 Reviews: (a) Tetrahedron, 1993, 49, 3433–3690; (b) A. Giannis and
T. Kolter, Angew. Chem., 1993, 105, 1303–1326; A. Giannis and T.
Kolter, Angew. Chem., Int. Ed. Engl., 1993, 32, 1244–1267.
7 R. F. Nutt, D. F. Veber and R. Saperstein, J. Am. Chem. Soc., 1980,
102, 6539–6545.
8 (a) R. F. Nutt, R. G. Strachan, D. F. Veber and F. W. Holly, J. Org.
Chem., 1980, 45, 3078–3080; (b) R. M. Williams and C. Yuan, J. Org.
Chem., 1992, 57, 6519–6527; (c) G. Bold, T. Allmendinger, P. Herold,
L. Moesch, H. P. Scha¨r and R. O. Duthaler, Helv. Chim. Acta, 1992,
75, 865–882; (d) M. Lange and P. M. Fischer, Helv. Chim. Acta, 1998,
81, 2053–2061.
In a 250 ml Schlenk flask, peptide 25 (257 mg, 0.50 mmol) was
dissolved in CH2Cl2 (50 ml) at rt and a constant stream of N2 was
bubbled through the solution. A solution of Grubbs’ catalyst
(20 mg, 0.025 mmol, 5 mol%) in CH2Cl2 (2.5 ml) was added
slowly over a period of 90 min via a syringe. After all starting
material was consumed, workup was carried out as described
for 27. The solvent was removed in vacuo and the crude product
was purified by flash chromatography (hexane–EtOAc 6 : 4 →
1 : 1→ 3 : 7) giving rise to 28 (90 mg, 0.19 mmol, 38%) as a
colourless solid. Crystallisation from EtOAc–heptane provided
crystals suitable for X-ray structure analysis.† If the reaction was
carried out in the presence of 10% Grubbs’ catalyst under reflux
according to the preparation of 23, the yield could be increased
to 51%. 1H NMR (500 MHz, CDCl3, HH-COSY): d 0.85 (3H,
d, J 6.7), 0.87 (3H, d, J 6.6), 1.60 (3H, d, J 7.1), 2.02 (2H, m,),
2.25 (2H, m,), 2.80 (1H, m), 2.91 (1H, d, J 11.0), 3.56–3.62 (2H,
m), 3.76–3.79 (4H, m), 3.84 (1H, dd, J 17.8 and 6.1), 4.31 (1H,
d, J 14.2), 4.43 (1H, dd, J 11.1 and 3.8), 4.88 (1H, dd, J 11.2
and 6.8), 4.92 (1H, dd, J 14.2 and 3.8), 5.03 (1H, dd, J 7.7 and
4.0), 5.63 (1H, q, J 6.9), 5.88–5.90 (2H, m), 6.82 (1H, dd, J 8.2
and 2.2), 6.98 (1H, d, J 7.6), 7.16 (1H, s), 7.24 (1H, t, J 8.0), 8.48
(1H, d, J 4.1). 13C NMR (125 MHz, CDCl3, HMQC, HMBC): d
16.9, 19.7, 20.7, 24.7, 26.2, 30.6, 42.8, 46.5, 55.2, 55.9, 58.0,63.7,
64.7, 70.4, 114.0, 114.4, 119.5, 125.7, 131.7, 129.2, 138.6, 154.2,
159.8, 168.0, 170.4, 175.6. C26H35N3O7 (501.58) calcd.: C 62.26
H 7.03 N 8.38; found: C 62.07 H 6.82 N 8.29. HMRS: calcd. for
C26H35N3O7 ([M]+), 501.2481; found, 501.2478.
9 R. M. Williams and J. Liu, J. Org. Chem., 1998, 63, 2130–2132.
10 D. J. O’Leary, S. J. Miller and R. H. Grubbs, Tetrahedron Lett., 1998,
39, 1689–1690.
11 Reviews: (a) R. H. Grubbs, S. J. Miller and G. C. Fu, Acc. Chem. Res.,
1995, 28, 446–452; (b) U. Koert, Nachr. Chem. Tech. Lab., 1995, 43,
809; (c) M. Schuster and S. Blechert, Angew. Chem., 1997, 109, 2124–
2144; M. Schuster and S. Blechert, Angew. Chem., Int. Ed. Engl., 1997,
36, 2036–2055; (d) S. K. Armstrong, J. Chem. Soc., Perkin Trans. 1,
1998, 371–388; (e) R. H. Grubbs and S. Chang, Tetrahedron, 1998,
54, 4413–4450; (f) A. Fu¨rstner, Angew. Chem., 2000, 112, 3140–3172;
A. Fu¨rstner, Angew. Chem., Int. Ed., 2000, 39, 3012–3043.
12 S. J. Miller, H. E. Blackwell and R. H. Grubbs, J. Am. Chem. Soc.,
1996, 118, 9606–9614.
13 (a) S. J. Miller and R. H. Grubbs, J. Am. Chem. Soc., 1995, 117, 5855–
5856; (b) T. D. Clark and M. R. Ghadiri, J. Am. Chem. Soc., 1995, 117,
12364–12365; (c) B. E. Fink, P. R. Kym and J. A. Katzenellenbogen,
J. Am. Chem. Soc., 1998, 120, 4334–4344; (d) P. W. Harris, M. A.
Brimble and P. D. Gluckman, Org. Lett., 2003, 5, 1847–1850; (e) L.
Banfi, A. Basso, G. Guanti and R. Riva, Tetrahedron Lett., 2003, 44,
7655–7658.
14 (a) E. R. Jarvo, G. T. Copeland, N. Papaioannou, P. J. Bonitatebus
and S. J. Miller, J. Am. Chem. Soc., 1999, 121, 11638–11643; (b) S.
Hanessian and M. Angiolini, Chem. Eur. J., 2002, 8, 111–117; (c) N.
Schmiedeberg and H. Kessler, Org. Lett., 2002, 4, 59–62.
15 (a) A. S. Ripka, R. S. Bohacek and D. H. Rich, Bioorg. Med. Chem.
Lett., 1998, 8, 357–360; (b) L. M. M. Cabrejas, S. Rohrbach, D.
Wagner, J. Kallen, G. Zenke and J. Wagner, Angew. Chem., 1999,
111, 2595–2599; L. M. M. Cabrejas, S. Rohrbach, D. Wagner, J.
Kallen, G. Zenke and J. Wagner, Angew. Chem., Int. Ed., 1999, 38,
2443–2446; (c) C.-Q. Wei, Y. Gao, K. Lee, R. Guo, B. Li, M. Zhang,
D. Yang and T. R. Burke, Jr., J. Med. Chem., 2003, 46, 244–254;
(d) S. M. Miles, R. J. Leatherbarrow, S. P. Marsden and W. J. Coates,
Org. Biomol. Chem., 2004, 2, 281–283.
16 (a) H. E. Blackwell and R. H. Grubbs, Angew. Chem., 1998,
110, 3469–3472; (b) C. H. Schafmeister, J. Po and G. L. Verdine,
J. Am. Chem. Soc., 2000, 122, 5891–5892; (c) H. E. Blackwell, J. D.
Sadowsky, R. J. Howard, J. N. Sampson, J. A. Chao, W. E. Steinmetz,
D. J. O’Leary and R. H. Grubbs, J. Org. Chem., 2001, 66, 5291–
5302.
Cyclopeptide 29
In a 100 ml Schlenk flask, peptide 26 (272 mg, 0.50 mmol) was
dissolved in toluene (20 ml) at rt and a solution of Grubbs’
catalyst (41 mg, 0.05 mmol, 10 mol%) in toluene was added
◦
slowly via a syringe. The solution was heated to 60 C and the
workup was carried out as described for 30. The solvent was
removed in vacuo and the crude product was purified by flash
chromatography (hexane–EtOAc 6 : 4 → 1 : 1 → 3 : 7) giving rise
to 29 (85 mg, 0.17 mmol, 33%) as a colourless solid and recovered
1
26 (93 mg, 0.18 mmol, 34%). H NMR (500 MHz, CDCl3): d
0.79 (3H, d, J 6.6), 0.94 (3H, d, J 6.4), 1.01 (3H, d, J 6.6), 1.08
(3H, d, J 6.9), 1.59 (3H, d, J 7.1), 2.41 (1H, m), 2.83 (1H, m),
3.02 (1H, d, J 10.1), 3.20 (3H, s), 3.32 (1H, dd, J 16.7 and 3.0),
3.72 (3H, s), 4.25–4.31 (2H, m), 4.41 (1H, m), 4.48 (1H, d, J
10.3), 4.93 (1H, m), 5.09 (1H, dd, J 14.4 and 4.9), 5.89 (1H, m),
6.06 (1H, d, J 15.7), 6.16 (1H, q, J 7.1), 6.65–6.90 (3H, m), 7.13
(1H, t, J 8.2), 8.11 (1H, d, J 6.9). 13C NMR (125 MHz, CDCl3,
DEPT, HSQC): d 18.2, 19.7, 19.8, 20.1, 22.2, 25.5, 28.9, 30.5,
41.1, 55.1, 55.9, 61.1, 63.2, 64.8, 71.0, 111.3, 117.0, 121.1, 126.6,
128.9, 132.0, 139.5, 157.0, 159.5, 169.3, 170.3, 174.4. HMRS:
calcd. for C27H40N3O7 ([M+H]+), 518.2865; found, 518.2866.
17 T. D. Clark, K. Kobayashi and M. R. Ghadiri, Chem. Eur. J., 1999,
5, 782–792.
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Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
We also thank the Degussa-Hu¨ls AG for generous gifts of amino
acids.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 – 1 4 5
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