A Modular Synthesis of Some Biologically Relevant Cyclic Peptides through Late-Stage Functionalization

Article abstract of DOI:10.1055/s-0035-1561561

A modular synthesis of some cyclic peptides related to a class of histone deacetylase inhibitors is reported. The synthesis utilizes a late-stage functionalization of a cyclic tetrapeptide scaffold to link the pendant alkyl chain through cross metathesis. It is observed that while the cross-metathesis reaction of a terminal olefin having a β-substituent is marginally successful with the scaffold, the corresponding reaction with an α,β-unsaturated ketone/ester is more promising. The utility of the protocol is demonstrated through the preparation of three cyclic tetrapeptides structurally related to the novel histone deacetylase inhibitors FR-225497 and trapoxin B.

Full text of DOI:10.1055/s-0035-1561561

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
J. P. Mukherjee et al.
Paper
Synthesis
A Modular Synthesis of Some Biologically Relevant Cyclic Peptides
through Late-Stage Functionalization
Jyoti Prasad Mukherjee
Suman Sil
O
O
R1
OR2
Amit K. Pahari
N
H
O
O
R
N
H
O
Shital K. Chattopadhyay*
N
H
N
O
HN
O
N
HN
H
N
N
O
HN
H
N
O
Department of Chemistry, University of Kalyani,
Kalyani-741235, West Bengal, India
skchatto@yahoo.com
H
N
O
O
various
conditions
up to 24%
G-II
O
CH2Cl2
1.5–2 h
77–82%
O
O
R2O
R
R1
Received: 26.11.2015
O
Accepted after revision: 11.01.2016
Published online: 02.02.2016
DOI: 10.1055/s-0035-1561561; Art ID: ss-2015-z0684-op
A
N
H
O
B
NH
HN
C
H
N
O
Abstract A modular synthesis of some cyclic peptides related to a class
of histone deacetylase inhibitors is reported. The synthesis utilizes a
late-stage functionalization of a cyclic tetrapeptide scaffold to link the
pendant alkyl chain through cross metathesis. It is observed that while
the cross-metathesis reaction of a terminal olefin having a β-substitu-
ent is marginally successful with the scaffold, the corresponding reac-
tion with an α,β-unsaturated ketone/ester is more promising. The utili-
ty of the protocol is demonstrated through the preparation of three
cyclic tetrapeptides structurally related to the novel histone deacetylase
inhibitors FR-225497 and trapoxin B.
O
R
O
I
O
O
N
H
N
O
O
H
N
N
HN
HN
H
N
H
N
Key words peptides, macrocycles, cross metathesis, modular synthe-
O
O
sis, catalysis
O
O
O
O
O
Several cyclic peptides, natural or synthetic modifica-
tions, thereof possess an interesting level of biological ac-
tivity mostly due to their well-known ability to pre-orga-
nize binding elements into a suitable conformation neces-
sary for interaction with biological receptors.1 For this, and
other reasons, the synthesis of biologically relevant cyclic
peptides has remained an active area of research over the
last few decades.2 For example, a class of cyclic tetrapep-
tides of the general structure I (Figure 1) consisting of three
common amino acids and an unusual fourth one having a
carbonyl group in a lipophilic alkyl chain, display biological
activities ranging from antiprotozoal to anticancer activi-
ties through metal binding by the terminal oxo group as a
requirement of their ability to inhibit histone deacetylase
enzymes.3 A few examples include compound 1 (trapoxin
B),4 FR-225497 (an analogue of 2),5 3 (apicidin A),6 and 4
(FR235222).7
1, trapoxin B
2, nor-FR-225497
O
O
O
N
H
N
H
O
N
HN
O
N
O
HN
H
H
N
N
O
N
H
OH
O
O
O
3, apicidin A
4, FR235222
Figure 1 Some biologically active naturally occurring cyclic tetrapep-
tide HDAC inhibitors
nature of the metal coordination site have remained as
popular choices for such kinds of activity.8 As a result, the
development of a synthetic stratagem that would allow in-
corporation of this two-fold diversity remains important.
The interesting levels of biological activity of these mol-
ecules have rendered these targets suitable for analogue
design, and a variation in the chain length/or the functional
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
J. P. Mukherjee et al.
Paper
Synthesis
Traditionally, synthesis of this class of natural products
involved individual preparation of the fourth amino acid,
and its incorporation into an acyclic tetrapeptide followed
by its macrocyclization. However, a scaffold-based ap-
proach for library design is of distinct advantage as demon-
strated recently by a radical-mediated process.9 While the
cross-metathesis (CM) reaction on a macrocyclic template
would constitute a direct approach to install the pendant
alkyl chain in these targets, grafting through cross metathe-
sis has occasionally proved to be problematic and therefore
seen as of limited utility in the synthesis/functionalization
of cyclic tetrapeptides due to low yields.10 Herein, we de-
scribe the utility of olefin cross metathesis on a cyclic tetra-
peptide scaffold as a possible general pathway to access
compounds related to 1–4.
Initially, we focused on the synthesis of the macrocyclic
template 13 (Scheme 1), which was obtained through elab-
oration of the acyclic tetrapeptide Boc-L-Hag-L-Phe-L-Phe-
D-Pro-OMe (11, Hag = homoallylglycine). The latter was ac-
cessed by solution phase peptide coupling between Z-L-
Phe-L-Phe-OH (6) (prepared by hydrolysis of the corre-
sponding commercially available ester 5) and D-Pro-
OMe·HCl (7) followed by elaboration of the resulting tripep-
tide 8 at its N-terminus involving sequential deprotection
and peptide coupling with the known11 Boc-L-Hag (10). The
doubly protected tetrapeptide 11 was obtained in an over-
all yield of 43% in a linear sequence of four steps from 5. The
two termini of 11 were then sequentially deprotected viz.
11 → 12, and then N-deprotection leading to a crude TFA
salt in readiness for a subsequent macrocyclization. Macro-
cyclization proceeded well under our developed condi-
tions12 to deliver the template 13 in an acceptable yield of
71% over two steps.
Cross-metathesis reaction of two type-I olefins has been
used13 for the synthesis of α-amino acids. This otherwise
difficult reaction is somewhat aided by the presence of a α-
or β-substituent in one of the olefinic partners. Encouraged
by our earlier success on cross metathesis of such a class of
olefins,14 we explored the viability of using the cross-
metathesis reaction on 13 with an appropriate partner to
access the desired oxygenation pattern as well as the chain
length of the pendant lipophilic part. We thus tried cross
metathesis of 13 with the olefins 14, 16, and 18 (Scheme 2).
Unfortunately, cross metathesis of 13 with 14 under a range
of conditions led to a disappointing yield of the correspond-
ing coupled product 15a. Prolonging the reaction time, the
use of elevated temperatures/more equivalents of one of
the olefins (14) and a catalyst loading of up to 25 mol% of
Grubbs’ 2nd-generation catalyst {benzylidene[1,3-bis(2,4,6-
trimethylphenyl)imidazolidin-2-ylidene]dichloro(tricyclo-
hexylphosphine)ruthenium, G-II} or Hoveyda–Grubbs 2nd-
generation catalyst {[1,3-bis(2,4,6-trimethylphenyl)imidaz-
olidin-2-ylidene]dichloro(2-isopropoxybenzylidene)ruthe-
nium, H-G-II} either singly or in combination with or with-
out microwave assistance did not alter the course of the re-
action to any significant extent, the recurring problem
being the dimerization of 13. Efforts to thermodynamically
equilibrate the dimer 15b with up to ten equivalents of 14
under some of the recommended conditions15 proved to be
equally frustrating in our hands as the dimer proved to be
robust. Changing the olefin partner to a somewhat more
crowded 16, or to a less crowded one 18, and employing all
the reaction conditions cited above for 14 was, unfortu-
nately, of not much help since the yield varied in the range
20–25%. The products 15a, 17, and 19 were each obtained
as a mixture of E/Z isomers.
O
O
ii
O
NHR
NHCbz
+
CO2Me
N
RO2C
N
H
N
H
H.HCl
N
MeO2C
7
8, R = Cbz
9, R = H
5, R = Me
6, R = H
i
iii
NHBoc
O
O
O
N
H
O
iv
v, vi
O
N
NH
9
N
N
HN
H
H
N
RO2C
O
O
13
11, R = Me
12, R = H
i
Scheme 1 Reagents and conditions: (i) LiOH, THF–H2O, r.t., 3 h, 88% (6), 89% (12); (ii) EDC·HCl, HOBt, NMM, CH2Cl2, DMF, 0 °C to r.t., 12 h, 79%; (iii) H2,
Pd-C, THF, r.t., 3 h, 81%; (iv) 10, EDC·HCl, HOBt, NMM, CH2Cl2, DMF, 0 °C to r.t., 12 h, 78%; (v) 50% TFA–CH2Cl2, 0 °C to r.t., 1.5 h; (vi) DPPA, DIEA, HOBt,
DMAP, CH2Cl2–DMF, r.t., 36 h, 71% over 2 steps.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
J. P. Mukherjee et al.
Paper
Synthesis
Ph
O
N
O
O
HN
NH
O
H
N
O
Ph
N
H
O
O
G-II (10 mol%)
CH2Cl2, reflux
13
+
N
HN
+
H
N
O
OBn
O
24 h
O
O
HN
Ph
14
NH
O
OBn
O
HN
N
15a (20%)
O
Ph
O
N
H
O
OTs
G-II (10 mol%)
TBSO
N
HN
+
15b (26%)
13
+
CH2Cl2, reflux
24 h
H
O
OBn
N
OTs
O
OTBS
16
OBn
17 (24%)
O
N
O
H
G-II (10 mol%)
N
HN
13
15b (27%)
+
+
H
N
OBn
18
CH2Cl2, reflux
24 h
O
O
OBn
19 (21%)
Scheme 2 Attempted cross metathesis of the macrocyclic template 13 with some class-I olefins
It is known that the cross metathesis between a class-I
olefin and an electron-poor olefin (class-II) proceeds better.
However, this has hardly been investigated with cyclic pep-
tides, possibly because of structural limitations. The pres-
ent opportunity led us to explore this alternative (Scheme
3). Pleasingly, cross-metathesis reaction of 13 with ethyl vi-
nyl ketone was nearly complete within couple of hours
leading to the desired 20 with no detectable formation of
15b. Under the optimized conditions, the yield of 20 was
raised to 82%. Hydrogenation of the latter smoothly pro-
duced 21, which is one carbon short of nor-FR-225497 (2).
In an effort to obtain analogues of 2 with different end
group, cross metathesis with methyl acrylate was studied.
The reaction proceeded well under the developed condi-
tions and the product 22 was obtained in comparable yield
and also as a single E isomer. The latter was then taken
through to the saturated compound 23.
We prepared the olefins 28 and 29 (Scheme 4) for possi-
ble incorporation of an additional oxygenation pattern in
the lipophilic amino acid segment because of the occur-
rence of such types of functionality in related natural prod-
ucts, e.g. 4. Thus, a straightforward oxidation–vinylation se-
quence on 3-(benzyloxy)propan-1-ol (24) gave quick access
to the allylic alcohol 2616 which was oxidized to the ketone
28.17 Similarly, an oxidation–vinylation–oxidation sequence
on the known18 alcohol 25 led to conjugated olefin 29
through the intermediate 27 in comparable yields. Cross
metathesis of the template 13 with the olefin 28 proceeded
rapidly under the developed conditions to provide the
product 30 in good yield. Saturation of the double bond in
the later with hydrogen also proceeded without event to
provide the terminally hydroxylated cyclic peptide 31. Sim-
ilarly, cross metathesis of 13 with the olefin 29 proceeded
well under the developed conditions to provide the macro-
cyclic product 32, which was taken through to 31 via two
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
J. P. Mukherjee et al.
Paper
Synthesis
O
O
N
H
N
H
O
O
ii
i
13
+
N
HN
N
HN
O
H
N
H
N
O
O
O
O
O
O
21
20
O
O
N
H
N
H
O
O
O
ii
i
13
+
N
HN
N
HN
O
H
N
H
N
O
O
O
O
O
O
O
O
22
23
Scheme 3 Reagents and conditions: (i) G-II (2.5 mol%), CH2Cl2, reflux, 2 h, 82% (20), 81% (22); (ii) H2, Pd-C, MeOH, r.t., 2 h, 83% (21), 78% (23).
conventional steps viz. saturation of the double bond lead-
ing to 33 followed by acid mediated deprotection of the
TBDPS group.
In conclusion, we have been able to demonstrate that
cross-metathesis reaction on a cyclic tetrapeptide template
proceeds better with α,β-unsaturated olefins compared to
olefins having a bulky β-substituent. The developed proto-
col provides scope for judicious manipulation of the spacer
region as well as the metal-binding domain attached to a
particular surface recognition part present in the class of
cyclic tetrapeptides. The developed protocol was utilized to
access three structural analogues of the important histone
ii
OR
OR
i
iii
HO
24, R = Bn
OR
OR
O
OH
26, R = Bn
O
28, R = Bn
25, R = TBDPS
27, R = TBDPS
29, R = TBDPS
O
O
O
N
H
O
N
H
O
N
O
OBn
O
v
H
N
HN
N
HN
iv
N
HN
H
N
H
N
O
H
N
O
O
O
O
O
O
O
OBn
OH
30
13
31
O
O
N
H
N
O
O
OTBDPS
O
v
H
vi
13
31
N
O
N
HN
HN
iv
H
N
H
N
O
O
O
O
O
OTBDPS
OTBDPS
32
33
Scheme 4 Reagents and conditions: (i) DMP, CH2Cl2, r.t. 2 h; (ii) vinylmagnesium bromide, THF, 0 °C to r.t., 6 h, 74% (26), 71% (27); (iii) IBX, DMSO, r.t.,
3 h, 79% (28), 77% (29); (iv) G-II (2.5 mol%), CH2Cl2, reflux, 2 h, 84% (30), 86% (32); (v) H2, Pd-C, MeOH, r.t., 2 h, 83% (31), 76% (33); (vi) HF-Py, THF, r.t.,
1.5 h, 79%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
J. P. Mukherjee et al.
Paper
Synthesis
deacetylase inhibitor FR-225497. The macrocyclic products
21, 23, and 31 have the same head group and spacer as nor-
FR-225497, but differ in the chain length or metal-binding
domain and therefore may serve as analogues. Moreover,
the opportunity to incorporate other functional groups
compatible with the cross-metathesis reaction appears
possible. The developed work may therefore prove to be
useful and it may thus complement the existing litera-
ture.19,20
ture was diluted with CH2Cl2 (50 mL). The organic extract was
washed successively with sat. aq NaHCO3 (30 mL), 1 M HCl (30 mL),
H2O (40 mL), and brine (40 mL), and then dried (anhyd MgSO4). It was
then filtered and the filtrate was concentrated in vacuo to leave the
crude product as a light yellow viscous solid that was purified by col-
umn chromatography (silica gel, PE–EtOAc, 7:3) to provide the cou-
pled product as a colorless solid; yield: 1.70 g (79%); mp 186–188 °C
(EtOAc–PE).
[α]D25 +26.7 (c 1.6, CHCl3).
IR (neat): 3360, 3228, 303, 1743, 1712, 1651, 1631, 1234 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.37–7.16 (m, 15 H), 6.71 (d, J = 7.6 Hz,
1 H), 5.26 (d, J = 7.6 Hz, 1 H), 5.08 (s, 2 H), 4.90 (dt, J = 5.2, 8.8 Hz, 1 H),
4.46 (q, J = 6.8 Hz, 1 H), 4.30 (dd, J = 4, 8 Hz, 1 H), 3.69 (s, 3 H), 3.47–
3.45 (m, 1 H), 3.11–3.08 (m, 1 H), 3.04–2.98 (m, 2 H), 2.93–2.88 (m, 1
H), 1.94–1.84 (m, 4 H), 1.55–1.52 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.1, 170.5, 169.7, 155.9, 136.9,
136.4, 136.2, 129.5, 129.3, 128.5, 128.5, 128.4, 128.1, 128.0, 127.1,
126.9, 66.8, 58.8, 55.8, 52.5, 52.2, 46.9, 39.6, 38.6, 29.0, 24.4.
Optical rotations were recorded in spectroscopic grade CHCl3 on a Ru-
dolph Autopol IV polarimeter, [α]D values are recorded in units of 10–1
deg cm2 g–1. IR spectra were recorded on a Perkin-Elmer Spectrum-1
spectrophotometer. 1H and 13C NMR spectra were recorded on a
Bruker Avance-400 spectrometer purchased through a DST-FIST
grant. Chemical shifts are recorded relative to residual solvent . Mass
spectra were recorded on a Waters Xevo QTOF instrument purchased
through DST-PURSE grant of Govt. of India. Petroleum ether (PE) re-
fers to the fraction boiling in the range 60–80 °C. Silica gel (230–400
mesh) for column chromatography was purchased from Spectrochem,
India.. Compounds 8 and 9 are known.21
HRMS: m/z [M
+
H]+ calcd for C32H36N3O6: 558.2604.; found:
558.2615.
Methyl (R)-1-{(S)-2-[(S)-2-Amino-3-phenylpropanamido]-3-phen-
ylpropanoyl}pyrrolidine-2-carboxylate (9)
(S)-2-[(S)-2-(Benzyloxycarbonylamino)-3-phenylpropanamido]-3-
phenylpropanoic Acid (6); Typical Procedure
Pd-C (60 mg) was added to a stirred solution of 8 (550 mg, 1.0 mmol)
in dry THF (10 mL) and the resulting heterogeneous mixture was then
vigorously stirred for 3 h at r.t. under a H2 atmosphere. The mixture
was then filtered through Celite, the filtercake was washed with
MeOH (10 mL) and the combined filtrates were concentrated in vac-
uo. The residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:1) to provide the product as a colorless gummy sol-
id; yield: 0.342 g (81%).
Solid LiOH·H2O (315 mg, 7.5 mmol) was added to a stirring solution of
the ester 5 (2.16 g, 5 mmol) in THF–H2O (4:1, 20 mL) and the mixture
was stirred for 3 h at r.t. The resulting mixture was then acidified to
pH 2 with 2 M HCl at 0 °C and the mixture was concentrated under
reduced pressure to leave a crude mass that was taken up in EtOAc
(80 mL). The organic extract was washed successively with H2O (60
mL) and brine (50 mL), and then dried (MgSO4). It was then filtered,
and the filtrate was concentrated in vacuo to leave the crude product
which was purified by column chromatography (silica gel, CHCl3–
MeOH, 19:1) to provide the product as a colorless solid; yield: 1.96 g,
(88%); mp 160–162 °C (CHCl3).
[α]D25 +4.89 (c 1.4, CHCl3).
IR (neat): 3363, 3062, 2953, 1743, 1644, 1497, 1451, 1197, 1174 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 8.8 Hz, 1 H), 7.32–7.16 (m,
10 H), 7.07 (d, J = 6.8 Hz, 1 H), 5.00 (dt, J = 6.4, 2.4 Hz, 1 H), 4.31 (q, J =
4 Hz, 1 H), 3.6 (s, 3 H), 3.61–3.57 (m, 3 H), 2.99–2.96 (m, 2 H), 2.61
(dd, J = 9.6, 14 Hz, 1 H), 1.94–1.79 (m, 4 H), 1.17 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.8, 172.3, 169.9, 137.8, 136.4,
129.5, 129.3, 128.6, 128.4, 127.0, 126.8, 58.7, 56.3, 52.3, 51.8, 46.9,
40.8, 39.5, 28.9, 24.4.
[α]D25 –38.06 (c 1.19, MeOH).
IR (neat): 3311, 2926, 1711, 1693, 1660, 1534, 1289, 1240 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.28 (d, J = 7.6 Hz, 1 H), 7.47 (d, J =
9.2 Hz, 1 H), 7.34–7.21 (m, 15 H), 4.92 (s, 2 H), 4.48–4.43 (m, 1 H),
4.30–4.24 (m, 1 H), 3.08 (dd, J = 5.2, 13.6 Hz, 1 H), 2.97–2.92 (m, 2 H),
2.71–2.65 (m, 1 H).
HRMS: m/z [M + H]+ calcd for C24H30N3O4: 424.2236; found: 424.2225.
13C NMR (100 MHz, DMSO-d6): δ = 173.2, 172.1, 156.2, 138.5, 137.8,
137.4, 129.6, 128.8, 128.7, 128.5, 128.1, 127.8, 127.2, 126.9, 126.7,
65.6, 56.4, 53.9, 37.8, 37.1.
HRMS: m/z [M + Na]+ calcd for C26H26N2NaO5: 469.1739; found:
469.1719.
Methyl (R)-1-[(S)-2-{(S)-2-[(S)-(2-(tert-Butoxycarbonylamino)hex-
5-enamido]-3-phenylpropanamido}-3-phenylpropanoyl]pyrroli-
dine-2-carboxylate (11)
Following the typical procedure for 8 using amine 9 (1.70 g, 4 mmol)
and acid 10 (0.915 g, 4 mmol) with chromatography (silica gel, CHCl3)
gave the product as a colorless solid; yield: 1.98 g (78%); mp 145–147
°C.
Methyl (R)-1-{(S)-2-[(S)-2-(Benzyloxycarbonylamino)-3-phenyl-
propanamido]-3-phenylpropanoyl}pyrrolidine-2-carboxylate (8);
Typical Procedure
[α]D25 +11.0 (c 1.8, CHCl3).
IR (neat): 3289, 2929, 1750, 1695, 1640, 1520, 1454, 1172 cm–1
.
NMM (900 μL, 8 mmol) was added dropwise to a stirred solution of D-
Pro-OMe·HCl (660 mg, 4 mmol) in anhyd CH2Cl2 (20 mL) at 0 °C under
a N2 atmosphere. A solution of the acid 6 (1.8 g, 4 mmol) in CH2Cl2–
DMF (1:1, 20 mL) was added dropwise over 10 min at the same tem-
perature. EDC·HCl (1.15 g, 6 mmol) followed by HOBt (540 mg, 4
mmol) were added sequentially at 0 °C under a N2 atmosphere while
the mixture was stirred for 15 min. The mixture was then allowed to
come up to r.t. and stirring was continued for a further 12 h; the mix-
1H NMR (400 MHz, CDCl3): δ = 7.28–7.16 (m, 10 H), 7.10–7.06 (m, 2
H), 6.79 (d, J = 7.6 Hz, 1 H), 5.77–5.75 (m, 1 H), 5.14 (s, 1 H), 5.04–4.69
(m, 2 H), 4.91 (dd, J = 5.6, 8.4 Hz, 1 H), 4.76–4.74 (m, 1 H), 4.33 (q, J =
4.0 Hz, 1 H), 3.69 (s, 3 H), 3.48 (br s, 1 H), 3.12–3.09 (m, 1 H), 3.03–
2.93 (m, 3 H), 2.67 (br s, 1 H), 2.08–2.04 (m, 2 H), 1.92–1.84 (m, 4 H),
1.70–1.65 (m, 1 H), 1.54–1.51 (m, 1 H), 1.45 (s, 9 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
J. P. Mukherjee et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 172.1, 171.7, 169.8, 169.4, 155.5,
137.2, 136.2, 136.1, 129.5, 129.2, 128.5, 128.4, 127.1, 126.9, 115.7,
80.0, 58.7, 54.0, 52.4, 52.2, 46.8, 39.6, 38.3, 31.7, 29.7, 29.0, 28.3, 24.4.
HRMS: m/z [M + Na]+ calcd for C29H34N4NaO4: 525.2478; found:
525.2476.
HRMS: m/z [M + Na]+ calcd for C35H46N4NaO7: 657.3264; found:
657.3262.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-{(S)-6-(benzyloxy)-6-[(S)-oxiran-2-
yl]hex-3-enyl}decahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclodo-
decine-1,4,7,10-tetraone (15a); Typical Procedure
Grubbs’ 2nd generation catalyst (G-II, 8 mg, 0.01 mmol, 10 mol%) was
added in 2 equal portions with an interval of 8 h to a stirred solution
of the cyclopeptide 13 (50 mg, 0.1 mmol) and compound 14 (61 mg,
0.3 mmol) in dry and degassed CH2Cl2 (2 mL) under an argon atmo-
sphere and the resulting mixture was heated to reflux for 24 h. The
mixture was allowed to cool to r.t. and then concentrated in vacuo to
leave a crude product that was purified by column chromatography
(silica gel, EtOAc–hexane, 4:6) to provide the coupled product as an
inseparable mixture of E- and Z-isomers as a colorless viscous liquid;
yield: 14 mg (20%).
(R)-1-[(S)-2-{(S)-2-[(S)-(2-(tert-Butoxycarbonylamino)hex-5-
enamido]-3-phenylpropanamido}-3-phenylpropanoyl]pyrroli-
dine-2-carboxylic Acid (12)
Following the typical procedure for 6 using ester 11 (1.27 g, 2.0
mmol) gave the product as a colorless solid; yield: 1.10 g (89%); mp
125–127 °C (EtOAc–PE).
[α]D25 –3.54 (c 1.5, CHCl3).
IR (neat): 3292, 2929, 1716, 1635, 1524, 1454, 1169 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.44 (br d, 1 H), 7.29–7.12 (m, 10 H),
6.99 (d, J = 7.2 Hz, 2 H), 6.93 (d, J = 7.2 Hz, 1 H), 5.77–5.75 (m, 1 H),
5.17–5.15 (m, 1 H), 5.05–4.99 (m, 2 H), 4.95 (d, J = 7.6 Hz, 1 H), 4.88–
4.86 (m, 1 H), 4.27–4.25 (m, 1 H), 3.65–3.63 (m, 1 H), 3.20–3.14 (m, 1
H), 3.13–3.07 (m, 2 H), 2.87–2.82 (m, 2 H), 2.07–2.04 (m, 3 H), 1.99–
1.85 (m, 3 H), 1.63–1.60 (m, 2 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 173.1, 172.3, 170.8, 170.0, 155.4,
137.1, 136.2, 135.5, 129.8, 129.5, 128.4, 128.2, 127.1, 126.7, 115.7,
80.0, 59.1, 54.1, 53.6, 52.2, 47.6, 39.5, 38.7, 32.2, 29.6, 28.8, 28.3, 24.7.
[α]D25 +21.7 (c 0.6, CHCl3).
IR (CHCl3): 3320, 2925, 1660, 1634, 1532, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.09 (m, 18 H), 5.49–5.44 (m, 2
H), 4.75 (d, J = 12 Hz, 1 H), 4.63–4.44 (m, 3 H), 4.25–4.12 (m, 2 H),
3.23–2.93 (m, 6 H), 2.74–2.67 (m, 2 H), 2.39–2.27 (m, 2 H), 2.02–1.96
(m, 4 H), 1.72–1.63 (m, 3 H), 1.34–1.26 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.5, 171.2, 170.8, 170.9, 140.9,
140.3, 138.5, 131.5, 129.3, 129.2, 129.0, 128.6, 128.5, 128.3, 127.7,
127.5, 127.3, 126.7, 80.1, 77.3, 71.5, 60.5, 54.6, 53.8, 53.5, 46.7, 43.4,
37.5, 36.6, 35.7, 30.4, 29.7, 28.9, 24.5.
HRMS: m/z [M + H]+ calcd for C34H45N4O7: 621.3288; found: 621.3269.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-(but-3-enyl)decahydropyrrolo[1,2-
a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetraone (13)
HRMS: m/z [M + Na]+ calcd for C40H46N4NaO6: 701.3315; found:
701.3311.
A solution of 17 (500 mg, 0.79 mmol) in CH2Cl2 (20 mL) was cooled to
0 °C under a N2 atmosphere and TFA (8.5 mL) was added dropwise.
The resulting solution was allowed to come to r.t. while being stirred
for 1.5 h and then concentrated in vacuo to leave the crude TFA salt as
a yellowish solid that was used directly in the next step. DPPA (260
μL, 1.20 mmol) followed by DIEA (290 μL, 1.70 mmol) were added se-
quentially to a solution of HOBt (160 mg, 1.18 mmol) and DMAP (48
mg, 0.39 mmol) in a mixture of anhyd CH2Cl2 (40 mL) and DMF (40
mL) at r.t. under a N2 atmosphere and the resulting mixture was
stirred for 15 min. A solution of the crude TFA salt in anhyd DMF (10
mL) was added dropwise to this solution at r.t. The resulting mixture
was stirred for 36 h at r.t. and then poured into 1 M aq HCl (60 mL) at
0 °C. The mixture was extracted with CH2Cl2 (2 × 50 mL) and the com-
bined extracts were washed successively with 3 M HCl (40 mL), sat. aq
NaHCO3 (70 mL), H2O (60 mL), and brine (70 mL), and dried (MgSO4)
and filtered. The filtrate was concentrated in vacuo to leave the crude
product as a yellowish solid which was purified by column chroma-
tography (silica gel, PE–EtOAc, 4:6) to afford the product as a colorless
solid; yield: 288 mg (71%, over 2 steps); mp 201–204 °C (EtOAc).
Elution with neat EtOAc provided compound 15b also as an insepara-
ble mixture of E- and Z-isomers as a colorless gum; yield: 34 mg
(36%).
[α]D25 +32.1 (c 1.2, CHCl3).
IR (CHCl3): 3318, 2931, 1658, 1639, 1533, 1490, 815 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.16 (m, 13 H), 5.74–5.69 (m, 1
H), 4.99–4.91 (m, 3 H), 4.71–4.61 (m, 2 H), 4.41–4.19 (m, 3 H), 3.28–
3.00 (m, 3 H), 2.7–2.49 (m, 2 H), 2.04–1.98 (m, 2 H), 1.87–1.45 (m, 3
H), 1.41–1.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 172.5, 171.8, 171.1, 137.4,
129.3, 129.2, 128.6, 128.5, 127.3, 126.7, 121.7, 61.0, 54.0, 53.8, 51.4,
47.0, 37.4, 36.5, 29.7, 28.9, 28.7, 28.2, 24.5.
HRMS: m/z [M + Na]+ calcd for C56H64N8NaO8: 999.4745; found:
999.4752.
(2R,3S)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)-8-
[(3S,6S,9S,14aR)-6,9-dibenzyl-1,4,7,10-tetraoxotetradecahydro-
pyrrolo[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl]oct-5-en-2-yl
4-Methylbenzenesulfonate (17)
[α]D25 +42.5 (c 1.15, CHCl3).
IR (neat): 3317, 3029, 2925, 1654, 1636, 1535, 1497, 1452 cm–1
.
Following the typical procedure for 15a using compound 16 (150 mg,
0.3 mmol) as the cross metathesis partner and 16 h reaction time
gave product 17 as a colorless viscous liquid; yield: 22 mg (24%).
[α]D25 –4.1 (c 1.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.74 (br s, 1 H), 7.31–7.16 (m, 11 H),
6.99 (br s, 1 H), 5.78–5.70 (m, 1 H), 5.02–4.94 (m, 2 H), 4.62–4.59 (m,
1 H), 4.37 (s, 1 H), 4.24–4.11 (m, 2 H), 3.26–2.96 (m, 5 H), 2.69–2.67
(m, 1 H), 2.04–1.97 (m, 4 H), 1.88–1.83 (m, 1 H), 1.73–1.64 (m, 2 H),
1.55–1.47 (m, 1 H).
IR (CHCl3): 3325, 2927, 1659, 1636, 1540, 1454, 1176 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 173.0, 172.4, 171.5, 170.9, 137.5,
137.1, 136.1, 129.3, 129.3, 128.6, 128.4, 127.2, 126.7, 115.7, 60.7, 56.9,
53.8, 46.8, 37.5, 36.6, 30.0, 29.7, 27.7, 24.4.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.0 Hz, 2 H), 7.32–7.17 (m,
19 H), 5.40–5.32 (m, 2 H), 4.60–4.49 (m, 5 H), 4.24–4.14 (m, 2 H),
3.88–3.74 (m, 3 H), 3.21–3.03 (m, 4 H), 2.70 (s, 1 H), 2.44–2.40 (m, 3
H), 2.18–2.17 (m, 3 H), 1.9 (br s, 3 H), 1.75–1.65 (m, 3 H), 1.51 (s, 2 H),
1.28 (t, J = 7.2 Hz, 1 H), 0.85–0.84 (m, 9 H), –0.01–0.03 (m, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
J. P. Mukherjee et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 172.7, 171.9, 171.7, 170.7, 144.5,
138.1, 137.4, 136.3, 134.1, 132.0, 131.8, 129.7, 129.3, 129.2, 128.9,
128.5, 128.4, 128.3, 127.9, 127.8, 127.6, 127.1, 126.6, 83.4, 77.2, 72.6,
61.1, 60.4, 53.7, 46.8, 37.6, 36.6, 33.8, 30.2, 29.7, 29.0, 28.3, 25.8, 24.5,
21.6, 18.2, 14.2, –5.5, –5.56.
HRMS: m/z [M + Na]+ calcd for C53H68N4NaO9SSi: 987.4374; found:
987.4361.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-(5-oxoheptyl)decahydropyrro-
lo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetraone (21);
Typical Procedure
Pd-C (40 mg) was added to a stirred solution of the olefin 20 (28 mg,
0.05 mmol) in dry MeOH (1 mL). The resulting mixture was vigorous-
ly stirred for 2 h at r.t. under a H2 atmosphere. The mixture was then
filtered through Celite, the filtercake was washed with MeOH (5 mL),
and the combined filtrate was concentrated in vacuo to leave a resi-
due that was purified by column chromatography (silica gel, EtOAc–
hexane, 1:1) to provide the hydrogenated product 21 as colorless
foam; yield: 22 mg (83%).
Compound 15b was also obtained; yield: 23 mg (26%).
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-[(E)-6-(benzyloxy)oct-3-enyl]deca-
hydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetr-
aone (19)
[α]D25 +86.6 (c 1.0, CHCl3).
IR (CHCl3): 3335, 2928, 1710, 1655, 1636, 1534, 1453, 744 cm–1
.
Following the typical procedure for 15a using 18 (57 mg, 0.3 mmol)
1H NMR (400 MHz, CDCl3): δ = 7.86 (br s, 1 H), 7.50 (br d, 1 H), 7.38–
7.23 (m, 10 H), 7.08 (d, J = 3.6 Hz, 1 H), 4.71 (quint, J = 4.8 Hz, 1 H),
4.50–4.42 (m, 1 H), 4.31 (q, J = 4 Hz, 1 H), 4.25–4.23 (m, 1 H), 3.39 (br
s, 1 H), 3.29–3.23 (m, 2 H), 3.17–3.15 (m, 1 H), 3.10 (dd, J = 5.2, 12.8
Hz, 1 H), 2.81 (d, J = 4.8 Hz, 1 H), 2.45–2.39 (m, 4 H), 2.09–2.07 (m, 2
H), 1.90–1.73 (m, 3 H), 1.60–1.50 (m, 3 H), 1.33–1.25 (m, 2 H), 1.08 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.9, 173.0, 172.2, 171.9, 170.7,
137.6, 136.2, 129.4, 129.3, 128.6, 128.5, 127.2, 126.7, 60.9, 56.7, 53.9,
53.8, 46.9, 41.9, 37.7, 36.6, 35.8, 30.1, 28.0, 25.3, 24.6, 23.0, 7.8.
gave the product as a colorless foam; yield: 14 mg (21%).
[α]D25 +17.3 (c 0.5, CHCl3).
IR (CHCl3): 3317, 3063, 2960, 2926, 2855, 1658, 1634, 1536, 1454 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 17 H), 5.54–5.40 (m, 2
H), 4.60–4.15 (m, 4 H), 4.31–4.11 (m, 2 H), 3.40–3.02 (m, 5 H), 2.66 (s,
1 H), 2.19 (d, J = 3.6 Hz, 2 H), 2.05–1.95 (m, 3 H), 1.72–1.62 (m, 4 H),
1.50–1.43 (m, 4 H), 0.98–0.81 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 172.2, 171.9, 171.7, 170.8, 139.0,
137.5, 136.1, 130.8, 129.3, 128.9, 128.6, 128.5, 128.3, 128.2, 127.7,
127.6, 127.4, 127.2, 126.7, 80.0, 70.7, 60.8, 56.2, 53.8, 53.6, 46.8, 37.6,
36.4, 29.7, 28.9, 26.3, 24.5, 14.1, 9.6.
.
HRMS: m/z [M + H]+ calcd for C32H41N4O5: 561.3077; found: 561.3083.
HRMS: m/z [M + Na]+ calcd for C40H48N4NaO5: 687.3522; found:
687.3511.
Methyl (E)-5-[(3S,6S,9S,14aR)-6,9-Dibenzyl-1,4,7,10-tetraoxotetra-
decahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl]pent-
2-enoate (22)
Compound 15b was also obtained; yield: 24 mg (27%).
Following the typical procedure for 20 using 13 (50 mg, 0.1 mmol)
and methyl acrylate (26 mg, 0.25 mmol) gave the product as colorless
foam; yield: 45 mg (81%).
[α]D25 +6.0 (c 2.0, CHCl3).
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-[(E)-5-oxohept-3-enyl]decahydro-
pyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetraone
(20); Typical Procedure
Grubbs’ 2nd generation catalyst (G-II, 2 mg, 0.0024 mmol, 2.5 mol%)
was added to a stirred solution of the cyclopeptide 13 (50 mg, 0.1
mmol) and ethyl vinyl ketone (21 mg, 25 μL, 0.25 mmol) in dry and
degassed CH2Cl2 (2 mL) and the resulting mixture was heated to re-
flux for 2 h. The mixture was allowed to cool to r.t. and then concen-
trated in vacuo. The residue was purified by chromatography (silica
gel, EtOAc–hexane, 1:1) to provide the coupled product as a colorless
viscous liquid; yield: 44 mg (82%).
IR (CHCl3): 3319, 3029, 2928, 1732, 1657, 1637, 1531, 1438 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (br s, 1 H), 7.48 (d, J = 7.2 Hz, 1 H),
7.33–7.16 (m, 10 H), 6.87 (td, J = 6.8, 15.6 Hz, 1 H), 5.80 (d, J = 15.6 Hz,
1 H), 4.61–4.59 (m, 1 H), 4.34–4.27 (m, 1 H), 4.20 (q, J = 3.6 Hz, 1 H),
4.12 (br s, 1 H), 3.66 (s, 3 H), 3.39 (br s, 1 H), 3.25–2.95 (m, 4 H), 2.75–
2.65 (m, 1 H), 2.13–2.06 (m, 2 H), 2.00–1.93 (m, 2 H), 1.82–1.82 (m, 3
H), 1.61–1.41 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 172.5, 171.8, 171.1, 166.9,
147.7, 137.4, 135.8, 129.3, 129.2, 128.6, 128.5, 127.3, 126.7, 121.7,
61.0, 54.0, 53.8, 51.4, 50.1, 47.0, 37.4, 36.5, 29.7, 28.7, 28.2, 24.5.
[α]D25 +69.5 (c 0.75, CHCl3).
IR (CHCl3): 3322, 2926, 1660, 1634, 1534, 1498, 1453 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (br s, 1 H), 7.48 (d, J = 7.2 Hz, 1 H),
7.31–7.11 (m, 10 H), 6.73 (td, J = 6.4, 16 Hz, 1 H), 6.05 (d, J = 16 Hz, 1
H), 4.59–4.57 (m, 1 H), 4.22–4.20 (m, 2 H), 4.11 (br s, 1 H), 3.42 (br m,
1 H), 3.26–3.20 (m, 1 H), 3.12 (dd, J = 5.2, 14 Hz, 1 H), 3.08–3.01 (m, 2
H), 2.70 (d, J = 7.6 Hz, 1 H), 2.46 (q, J = 7.2 Hz, 2 H), 2.20–2.12 (m, 2 H),
2.07–1.99 (m, 2 H), 1.86 (br s, 3 H), 1.62–1.53 (m, 1 H), 1.52–1.44 (m,
1 H), 1.03 (t, J = 7.2 Hz, 3 H).
HRMS: m/z [M + H]+ calcd for C31H37N4O6: 561.2713; found: 561.2722.
Methyl 5-[(3S,6S,9S,14aR)-6,9-Dibenzyl-1,4,7,10-tetraoxotetra-
decahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl)pen-
tanoate (23)
Following the typical procedure for 21 using 22 (28 mg, 0.05 mmol)
gave the product as colorless foam; yield: 21 mg (78%).
[α]D25 +4.7 (c 1.2, CHCl3).
IR (CHCl3): 3317, 3032, 2922, 1735, 1667, 1645, 1526, 1428 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.94–7.85 (br s, 1 H), 7.48 (d, J = 7.2 Hz,
1 H), 7.32–7.17 (m, 10 H), 6.95–7.00 (m, 1 H), 4.70–4.67 (m, 1 H),
4.44–4.42 (m, 1 H), 4.24–4.21 (m, 2 H), 3.65 (s, 3 H), 3.34 (br m, 1 H),
3.27–3.19 (m, 2 H), 3.16–3.14 (m, 1 H), 3.09–3.03 (m, 1 H), 2.78 (d, J =
7.2 Hz, 1 H), 2.26 (t. J = 7.2 Hz, 3 H), 2.08–2.01 (m, 2 H), 1.94–1.81 (m,
2 H), 1.77–1.63 (m, 2 H), 1.61–1.51 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 201.3, 172.7, 172.5, 171.8, 171.0,
145.2, 137.4, 135.8, 130.6, 129.3, 129.2, 128.6, 128.5, 127.3, 126.7,
60.9, 57.2, 53.9, 53.9, 47.0, 37.5, 36.5, 33.2, 29.7, 28.9, 28.3, 24.5, 8.0.
.
HRMS: m/z [M + H]+ calcd for C32H39N4O5: 559.2920; found: 559.2922.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
J. P. Mukherjee et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 174.1, 172.9, 172.5, 172.3, 170.7,
139.7, 136.3, 129.4, 129.3, 128.6, 128.5, 127.1, 126.7, 60.9, 56.9, 54.5,
53.8, 51.5, 46.8, 37.6, 36.9, 33.7, 30.0, 29.7, 25.3, 24.6, 24.2.
HRMS: m/z [M + Na]+ calcd for C31H38N4NaO6: 585.2689; found:
585.2695.
sat. aq Na2S2O3 and sat. aq NaHCO3 mixture (1:1, 50 mL). The aqueous
phase was extracted with CH2Cl2 (2 × 50 mL) and the combined or-
ganic layers were washed successively with H2O (2 × 50 mL) and brine
(50 mL), dried (anhyd MgSO4), and filtered. The filtrate was concen-
trated in vacuo to provide the crude product which was purified by
chromatography (silica gel, EtOAc–PE, 1:9) to give the α,β-unsaturat-
ed ketone as a colorless liquid; yield: 602 mg (79%).
5-(Benzyloxy)pent-1-en-3-ol (26); Typical Procedure
IR (CHCl3): 3371, 2854, 2925, 1740, 1718, 1366, 1164 cm–1
.
Dess–Martin periodinane (2.6 g, 6.0 mmol) was added portionwise to
a stirred solution of 3-(benzyloxy)propan-1-ol (24, 1 g, 6.0 mmol) in
anhyd CH2Cl2 (20 mL), at 0 °C under a N2 atmosphere and stirring was
continued for 2 h at r.t. The mixture was then diluted with CH2Cl2 (50
mL) and quenched with sat. aq Na2S2O3 and sat. aq NaHCO3 mixture
(1:1, 20 mL). The organic part was then successively washed with H2O
(50 mL) and brine (50 mL), and dried (anhyd MgSO4). It was then fil-
tered and the filtrate was concentrated in vacuo to leave the crude al-
dehyde (920 mg), which was used directly in the next step. The crude
aldehyde was dissolved in anhyd THF (15 mL) and cooled to 0 °C un-
der a N2 atmosphere. Vinylmagnesium bromide (2 M in THF, 4.0 mL, 8
mmol) was then added dropwise to the solution of the aldehyde and
the mixture was stirred for 30 min at 0 °C; it was then allowed to
come to r.t. and stirred for 5 h. The mixture was cooled to 0 °C and
then quenched by dropwise addition of sat. aq NH4Cl (5 mL). The vol-
atiles were removed under reduced pressure and the residue was di-
luted with CH2Cl2 (80 mL). The organic solution was washed succes-
sively with 10% aq NH4Cl solution (2 × 50 mL), H2O (100 mL), and
brine (100 mL), and then dried (anhyd MgSO4) and filtered. The fil-
trate was concentrated under reduced pressure to provide the crude
allylic alcohol which on column chromatography (silica gel, EtOAc–
PE, 1:9) provided the allylic alcohol as a colorless liquid; yield: 0.850 g
(74%).
1H NMR (400 MHz, CDCl3): δ = 7.27–7.16 (m, 5 H), 6.28 (dd, J = 10.4,
17.6 Hz, 1 H), 6.13 (d, J = 17.6 Hz, 1 H), 5.76 (d, J = 10.4 Hz, 1 H), 4.43
(s, 2 H), 3.71 (t, J = 6.4 Hz, 2 H), 2.81 (t, J = 6.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 198.9, 138.1, 136.7, 128.7, 128.4,
127.7, 127.6, 73.3, 65.3, 39.6.
HRMS: m/z [M + H]+ calcd for C12H15O2: 191.1072; found: 191.1051.
5-(tert-Butyldiphenylsilyloxy)pent-1-en-3-one (29)
Following the typical procedure for 28 using 27 (0.850 g, 2.5 mmol)
gave the product as a colorless liquid; yield: 0.651 g (77%).
IR (CHCl3): 3425, 3071, 2958, 2931, 2858, 1685, 1428, 1112 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65–7.57 (m, 5 H), 7.37–7.29 (m, 5 H),
6.29 (dd, J = 17.6, 10.8 Hz, 1 H), 6.12 (d, J = 17.6 Hz, 1 H), 5.77 (d, J =
10.8 Hz, 1 H), 3.91 (t, J = 6.4 Hz, 2 H), 2.75 (t, J = 6.4 Hz, 2 H), 0.95 (s, 9
H).
13C NMR (100 MHz, CDCl3): δ = 137.1, 135.6, 133.5, 129.8, 128.7,
127.8, 59.9, 42.2, 26.9, 19.2.
HRMS: m/z [M + Na]+ calcd for C21H26NaO2Si: 361.1600; found:
361.1619.
IR (CHCl3): 3428, 2936, 1642, 1450, 1103, 928 cm–1
.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-[(E)-7-(benzyloxy)-5-oxohept-3-
enyl]decahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-
1,4,7,10-tetraone (30)
1H NMR (400 MHz, CDCl3): δ = 7.31–7.14 (m, 5 H), 5.82–5.73 (m, 1 H),
5.17 (d, J = 17.2 Hz, 1 H), 5.01 (d, J = 10.4 Hz, 1 H), 4.42 (s, 2 H), 4.26–
4.22 (m, 1 H), 3.63–3.58 (m, 1 H), 3.55–3.51 (m, 1 H), 3.29 (br s, 1 H),
1.81–1.68 (m, 2 H).
Following the typical procedure for 20 using 13 (50 mg, 0.1 mmol)
and 28 (57 mg, 0.3 mmol) gave the product as a colorless liquid; yield:
55 mg (84%).
13C NMR (100 MHz, CDCl3): δ = 140.6, 138.0, 128.5, 127.8, 127.7,
[α]D +10.6 (c 1.5, CHCl3).
114.4, 73.3, 71.7, 68.3, 36.4.
IR (CHCl3): 3320, 2925, 2854, 1661, 1634, 1532, 1497, 1453 cm–1
.
HRMS: m/z [M + Na]+ calcd for C12H16NaO2: 215.1048; found:
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 7.2 Hz, 1 H), 7.34–7.11 (m,
15 H), 6.75 (td, J = 6.4, 16 Hz, 1 H), 6.78 (d, J = 16 Hz, 1 H), 4.56–4.50
(m, 1 H), 4.48 (s, 2 H), 4.21–4.20 (m, 2 H), 4.15–4.10 (m, 1 H), 3.72 (t, J
= 6.4 Hz, 2 H), 3.41 (br s, 1 H), 3.25–2.99 (m, 4 H), 2.77 (t, J = 6.4 Hz, 2
H), 2.71 (t, J = 6.0 Hz, 1 H), 2.16–2.11 (m, 2 H), 2.06–1.98 (m, 2 H), 1.88
(br m, 4 H), 1.62 (br m, 1 H), 1.52–1.50 (m, 1 H).
215.1029.
5-(tert-Butyldiphenylsilyloxy)pent-1-en-3-ol (27)
Following the typical procedure for 26 using 3-(tert-butyldiphenylsi-
lyloxy)propan-1-ol (25, 1.25 g, 4 mmol) gave the product as a color-
less liquid; yield: 0.965 g (71%).
13C NMR (100 MHz, CDCl3): δ = 198.5, 172.6, 172.5, 171.8, 171.1,
146.2, 138.2, 137.4, 135.7, 131.0, 129.3, 129.2, 128.7, 128.5, 128.4,
127.7, 127.6, 127.4, 126.8, 73.2, 65.3, 61.0, 57.6, 54.1, 53.9, 47.0, 40.0,
37.4, 29.7, 29.0, 28.3, 24.5, 22.7.
HRMS: m/z [M + Na]+ calcd for C39H44N4NaO6: 687.3159; found:
687.3145.
IR (CHCl3): 3421, 2957, 2932, 2858, 1473, 1428, 1112 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65–7.53 (m, 4 H), 7.36–7.25 (m, 6 H),
5.84–5.76 (m, 1 H), 5.22 (dd, J = 17.2, 1.2 Hz, 1 H), 5.02 (dd, J = 10.4,
1.2 Hz, 1 H), 4.36–4.33 (m, 1 H), 3.82–3.72 (m, 2 H), 3.16 (d, J = 3.6 Hz,
1 H), 1.72–1.68 (m, 2 H), 0.97 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 104.8, 135.6, 133.1, 129.9, 127.9,
114.4, 71.9, 62.5, 38.6, 26.9, 19.1.
HRMS: m/z [M + Na]+ calcd for C21H28NaO2Si: 363.1756; found:
363.1747.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-(7-hydroxy-5-oxoheptyl)decahy-
dropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetra-
one (31)
Following the typical procedure for 21 using 30 (33 mg, 0.05 mmol)
gave the product as a colorless viscous liquid; yield: 24 mg (83%).
5-(Benzyloxy)pent-1-en-3-one (28); Typical Procedure
IBX (1.5 g, 6 mmol) was added in one portion to a stirred solution of
the allylic alcohol 26 (770 mg, 4.0 mmol) in DMSO (8 mL) at r.t. and
stirring was continued for 3 h. The mixture was then poured into a
[α]D +10.9 (c 1.0, CHCl3).
IR (CHCl3): 3349, 3318, 2935, 2841, 1671, 1644, 1522, 1487, 1446 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
J. P. Mukherjee et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.98 (br s, 1 H), 7.45 (7.2 Hz, 1 H),
7.27–7.16 (m, 10 H), 4.58–4.55 (m, 2 H), 4.35 (br s, 2 H), 3.93 (br s, 1
H), 3.83–3.75 (m, 1 H), 3.20–3.12 (m, 4 H), 3.00–2.97 (m, 2 H), 2.68–
2.54 (m, 3 H), 2.45–2.37 (m, 2 H), 2.08–2.05 (m, 3 H), 1.85–1.51 (m, 6
H), 1.29–1.26 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 211.8, 172.9, 171.8, 171.3, 170.6,
137.1, 136.4, 129.4, 129.2, 128.6, 128.5, 127.1, 126.8, 60.2, 57.8, 55.9,
53.8, 53.2, 46.5, 44.7, 42.9, 37.3, 36.7, 30.5, 29.7, 25.1, 24.5, 21.9.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-(7-hydroxy-5-oxoheptyl)decahy-
dropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetra-
one (31) by Deprotection of the Silyl Ether 33
HF-Pyridine (0.3 mL) was added to a solution of the silyl ether 33 (19
mg, 0.024 mmol) in dry THF (1.5 mL) and pyridine (0.5 mL) at r.t. un-
der N2 and the resulting solution was stirred at r.t. for 1.5 h. The mix-
ture was diluted with EtOAc (10 mL) and quenched with sat. aq
NaHCO3 (5 mL). The aqueous layer was extracted with EtOAc (2 x 10
mL) and the combined organic extract was washed successively with
H2O (2 × 10 mL), sat. aq CuSO4 (2 × 5 mL), and brine (5 mL), then dried
(Na2SO4) and evaporated in vacuo. The residue was purified by chro-
matography (silica gel, EtOAc–PE, 1:1) to give the alcohol as a color-
less foam; yield: 11 mg (79%). The spectroscopic and optical proper-
ties of the compound thus obtained were found to be identical with
that described for 31.
HRMS: m/z [M + Na]+ calcd for C32H40N4NaO6: 599.2846; found:
599.2859.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-[(E)-7-(tert-butyldiphenylsilyl-
oxy)-5-oxohept-3-enyl]decahydropyrrolo[1,2-a][1,4,7,10]tetra-
azacyclododecine-1,4,7,10-tetraone (32)
Following the typical procedure for 20 using 13 (50 mg, 0.1 mmol)
and 29 (102 mg, 0.3 mmol) gave the product as a colorless foam;
yield: 69 mg (86%).
[α]D25 +19.8 (c 1.1, CHCl3).
Acknowledgement
We are thankful to DST, New Delhi, for funds (Grant No. SR/S1/OC-
92/2012), and CSIR, New Delhi, for funds (02/0164/13/EMR-II), and
fellowships to three of us (JPM, SS, AKP). Partial financial support
from the DST-PURSE programme and Teachers’ personal research
grant of the University of Kalyani is also gratefully acknowledged.
IR (CHCl3): 3322, 2957, 2925, 2854, 1661, 1636, 1535, 1429 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.54 (m, 5 H), 7.38–7.26 (m, 5 H),
7.22–7.13 (m, 5 H), 7.12–7.00 (m, 5 H), 6.60 (td, J = 6.4, 16.0 Hz, 1 H),
5.96 (d, J = 16.0 Hz, 1 H), 4.51–4.45 (m, 1 H), 4.13–4.11 (m, 2 H), 4.03–
3.99 (m, 1 H), 3.82 (t, J = 6.4 Hz, 2 H), 3.33 (br s, 1 H), 3.12–2.92 (m, 4
H), 2.60 (quint, J = 6.4 Hz, 3 H), 2.05–2.00 (m, 2 H), 1.97–1.89 (m, 4 H),
1.85–1.65 (m, 2 H), 1.19–1.12 (m, 3 H), 0.91 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 199.0, 172.6, 172.5, 171.8, 171.1,
145.9, 137.4, 135.6, 133.5, 131.2, 129.7, 129.3, 129.2, 128.7, 128.5,
127.7, 127.4, 126.8, 61.1, 59.7, 57.5, 54.2, 53.9, 47.1, 42.6, 37.4, 36.6,
29.7, 29.0, 28.3, 26.8, 24.5, 19.2.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561561.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
HRMS: m/z [M + Na]+ calcd for C48H56N4NaO6Si: 835.3867; found:
835.3851.
References
(1) For a recent review, see: Adamska, A.; Janecka, A. Curr. Med.
Chem. 2015, 22, 352.
(3S,6S,9S,14aR)-6,9-Dibenzyl-3-[7-(tert-butyldiphenylsilyloxy)-5-
oxoheptyl]decahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclodo-
decine-1,4,7,10-tetraone (33)
(2) For some reviews, see: (a) Hamada, Y.; Shioiri, T. Chem. Rev.
2005, 105, 4441. (b) Wipf, P. Chem. Rev. 1995, 95, 2115.
(c) Rama Rao, A. V.; Gurjar, M. K.; Laxma Reddy, K.; Srinivasa
Rao, A. Chem. Rev. 1995, 95, 2135. (d) Newkirk, T. L.; Bowers, A.
A.; Williams, R. M. Nat. Prod. Rep. 2009, 26, 1293.
(3) For a recent review, see: Zhang, J.; Zhong, Q. Cell. Mol. Life Sci.
2014, 71, 3885.
Following the typical procedure for 21 using 32 (40 mg, 0.05 mmol)
gave the product as a colorless foam; yield: 31 mg (76%).
[α]D +21.8 (c 0.25, CHCl3).
IR (CHCl3): 3324, 2935, 1710, 1646, 1545, 1461, 1171 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.55 (m, 4 H), 7.34–7.29 (m, 7 H),
7.24–7.17 (m, 8 H), 7.16–7.15 (m, 1 H), 7.09–7.08 (m, 1 H), 4.65–4.55
(m, 1 H), 4.38–4.31 (m, 1 H), 4.14–4.09 (m, 2 H), 3.81 (t, J = 6.0 Hz, 2
H), 3.26 (br s, 1 H), 3.13–3.04 (m, 3 H), 2.95 (dd, J = 4.8, 12.4 Hz, 1 H),
2.69 (br s, 1 H), 2.48 (t, J = 6.0 Hz, 2 H), 3.00 (t. J = 6.8 Hz, 2 H), 1.92–
1.89 (m, 1 H), 1.72–1.58 (m, 4 H), 1.40 (sext, J = 6.8 Hz, 3 H), 1.18 (s, 2
H), 1.12–1.06 (m, 2 H), 0.93 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 209.7, 172.9, 172.2, 171.9, 170.8,
137.6, 136.3, 135.5, 133.4, 129.7, 129.4, 129.3, 128.6, 128.5, 127.7,
127.2, 126.7, 60.9, 59.6, 56.9, 54.1, 53.8, 46.9, 45.3, 43.2, 37.6, 36.7,
29.7, 28.1, 26.8, 25.4, 24.6, 22.7, 19.1.
(4) Itazaki, H.; Nagashima, K.; Sugita, K.; Yoshida, H.; Kawamura, Y.;
Yasuda, Y.; Matsumoto, K.; Ishii, K.; Uotani, N.; Nakai, H.; Terui,
A.; Yoshimatsu, S.; Ikenishi, Y.; Nakawaga, Y. J. Antibiot. 1990,
63, 1524.
(5) Mori, H.; Mori, H.; Fumie, A.; Seiji, Y.; Shigehiro, T.; Motohiro, H.
WO 0008048, 2000.
(6) Singh, S.; Zink, D.; Polishook, J.; Dombrowski, A.; Darkin-Rat-
tray, S.; Schmatz, D.; Goetz, M. Tetrahedron Lett. 1996, 37, 8077.
(7) Xie, W.; Zou, B.; Pei, D.; Ma, D. Org. Lett. 2005, 7, 2775.
(8) Degenkolb, T.; Games, W.; Brückner, H. Chemistry & Biodiversity
2008, 5, 693.
(9) Traore, M.; Mietton, F.; Maubon, D.; Peuchmaur, M.; Hilario, F.
F.; de Freitas, R. P.; Bougdour, A.; Curt, A.; Maynadier, M.; Vial,
H.; Pelloux, H.; Hakimi, M.-A.; Wong, Y.-S. J. Org. Chem. 2013, 78,
3655.
HRMS: m/z [M + Na]+ calcd for C48H58N4NaO6Si: 837.4023; found:
837.4035.
(10) (a) Nasveschak, C.; Ungermannova, D.; Liu, X.; Philips, A. Org.
Lett. 2008, 10, 3595. (b) Souto, J. A.; Vaz, E.; Lepore, I.; Poppler,
A.-C.; Franci, G.; Alvarez, R.; Altucci, L.; de Lera, A. R. J. Med.
Chem. 2010, 53, 4654. (c) ElMarrouni, A.; Fukuda, A.; Heras, M.;
Arseniyadis, S.; Cossy, J. J. Org. Chem. 2010, 75, 8478.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
J. P. Mukherjee et al.
Paper
Synthesis
(11) Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc., Perkin
Trans. 1 1998, 2495.
(16) Yadav, J. S.; Anantha Lakhsmi, K.; Mallikarjun Reddy, N.; Prasad,
A. R.; Subba Reddy, B. V. Tetrahedron 2010, 66, 334.
(12) (a) Chattopadhyay, S. K.; Singha, S. K. Synlett 2010, 555.
(b) Chattopadhyay, S. K.; Biswas, S. Tetrahedron Lett. 2006, 47,
7897.
(17) Yamauchi, N.; Natsubori, Y.; Murae, T. Bull. Chem. Soc. Jpn. 2000,
73, 2513.
(18) Chaudhury, S. C.; Hernandez, O. Tetrahedron Lett. 1979, 20, 99.
(19) For some assorted recent reports on the synthesis of biologi-
cally relevant cyclic peptides see: (a) Adam, A.; Haberhauer, G.
Chem. Eur. J. 2015, 21, 4333. (b) Meyer, C.; Hoeger, B.;
Chatterjee, J.; Kohn, M. Bioorg. Med. Chem. 2015, 23, 2848.
(c) Oddo, A.; Münzker, L.; Hansen, P. R. Org. Lett. 2015, 17, 2502.
(d) Karmann, L.; Schultz, K.; Herrmann, J.; Muller, R.; Kazmaier,
U. Angew. Chem. Int. Ed. 2015, 54, 4502. (e) Pal, S.; Singh, G.;
Singh, S.; Tripathi, J. K.; Ghosh, J. K.; Sinha, S.; Ampapathi, R. S.;
Chakraborty, T. K. Org. Biomol. Chem. 2015, 13, 6789.
(f) Rensing, D. T.; Uppal, S.; Blumer, K. J.; Moeller, K. D. Org. Lett.
2015, 17, 2270. (g) Madsen, A. S.; Kristensen, H. M. E.; Lanz, G.;
Olsen, C. A. ChemMedChem 2014, 9, 537. (h) Vasudevan, N.;
Kashinath, K.; Srinivasa Reddy, D. Org. Lett. 2014, 16, 6148.
(i) Elduque, X.; Pedroso, E.; Grandas, A. Org. Lett. 2013, 15, 2038.
(j) Stolze, S. C.; Kaiser, M. Synthesis 2012, 44, 1755.
(k) Wakchaure, S.; Einsiedel, J.; Waiber, R.; Gmeiner, P. Synthesis
2012, 44, 2682. (l) Kiss, L.; Fülöp, F. Synlett 2010, 1302.
(m) Ammer, C.; Bach, T. Chem. Eur. J. 2010, 16, 14083.
(n) Bowers, A. A.; Greshock, T. J.; West, N.; Estiu, G.; Schreiber, S.
L.; Wiest, O.; Williams, R. M.; Bradner, J. E. J. Am.Chem. Soc.
2009, 131, 2900. (o) Quirin, C.; Kazmaier, U. Eur. J. Org. Chem.
2009, 371. (p) Grauer, A.; Konig, B. Eur. J. Org. Chem. 2009, 5099.
(q) Chatterjee, J.; Mierke, D.; Kessler, H. J. Am. Chem. Soc. 2006,
128, 15164. (r) Mukherjee, J. P.; Sil, S.; Chattopadhyay, S. K. Tet-
rahedron Lett. 2016, 57, 739.
(20) For a review on metathesis-mediated synthesis of cyclic pep-
tides, see ref. 19k. For some recent reports, see: (a) Grossmann,
T. N.; Glas, A. Synlett 2015, 26, 1. (b) Hoffman, J.; Kazmaier, U.
Synthesis 2015, 47, 411. (c) Aihara, K.; Komiya, C.; Shigenaga, A.;
Inokuma, T.; Takahasi, D.; Otaka, A. Org. Lett. 2015, 17, 696.
(d) Sundararaju, B.; Sridhar, T.; Achard, M. P. S. Eur. J. Org. Chem.
2012, 2414. (e) Khan, S. N.; Kim, A.; Grubbs, R. H.; Kwon, Y.-U.
Org. Lett. 2011, 13, 1582. (f) Pirrung, M. C.; Biswas, G.; Ibarra-
Rivera, T. R. Org. Lett. 2010, 12, 2402. (g) Illesinghe, J.; Guo, C. X.;
Garland, R.; Ahmed, A.; Van Lierop, B.; Elaridi, J.; Jackson, W. R.;
Robinson, A. J. Chem. Commun. 2009, 295.
(13) For some assorted recent examples of application of cross
metathesis in the synthesis of amino acids/peptides, see:
(a) Tsuruda, T.; Ebine, M.; Umeda, A.; Oishi, T. J. Org. Chem.
2015, 80, 859. (b) Zhang, Y.; Dlugosch, M.; Jübermann, M.;
Banwell, M. G.; Ward, J. S. J. Org. Chem. 2015, 80, 4828.
(c) Jayasinghe, S.; Venukadasula, P. K. M.; Hanson, P. R. Org. Lett.
2014, 16, 122. (d) Nair, R. N.; Bannister, T. D. J. Org. Chem. 2014,
79, 1467. (e) Siva Swaroop, S.; Tripathy, S.; Jachok, G.; Reddy, D.
S. Tetrahedron Lett. 2014, 55, 4777. (f) Reddy, C. R.; Jithender, E.;
Prasad, K. R. J. Org. Chem. 2013, 78, 4251. (g) Huang, W.; Ren, R.-
G.; Dong, H.-Q.; Wei, B.-G.; Lin, G.-Q. J. Org. Chem. 2013, 78,
10747. (h) Kotha, S.; Singh, K. Eur J. Org. Chem. 2007, 5909.
(i) Hoffman, T. J.; Rigby, J. H.; Arseniyadis, S.; Cossy, J. J. Org.
Chem. 2008, 73, 2400. (j) Ghosh, A.; Kulkarni, S. Org. Lett. 2008,
10, 3907.
(14) For some reports on metathesis-mediated synthesis of α-amino
acids from our laboratory, see: (a) Saha, N.; Chatterjee, B.;
Chattopadhyay, S. K. J. Org. Chem. 2015, 80, 1896. (b) Pahari, A.
K.; Mukherjee, J. P.; Chattopadhyay, S. K. Tetrahedron 2014, 70,
7185. (c) Chattopadhyay, S. K.; Mukherjee, J. P. Synthesis 2014,
46, 2481. (d) Kundu, I.; Maitra, R.; Jana, M.; Chattopadhyay, S. K.
Synthesis 2012, 44, 304. (e) Biswas, T.; Mukherjee, J. P.;
Chattopadhyay, S. K. Tetrahedron: Asymmetry 2012, 23, 1416.
(f) Chattopadhyay, S. K.; Roy, S. P.; Saha, T. Synthesis 2011, 43,
2664. (g) Bandyopadhyay, A.; Pahari, A. K.; Chattopadhyay, S. K.
Tetrahedron Lett. 2009, 50, 6036. (h) Sarkar, K.; Singha, S. K.;
Chattopadhyay, S. K. Tetrahedron: Asymmetry 2009, 20, 1719.
(i) Bandyopadhyay, A.; Pal, B. K.; Chattopadhyay, S. K. Tetrahe-
dron: Asymmetry 2008, 19, 1875. (j) Chattopadhyay, S. K.;
Sarkar, K.; Karmakar, S. Synlett 2005, 2083.
(15) For some reviews, see: (a) O’Leary, D. J.; O’Neil, G. W. Cross-
Metathesis, In Handbook of Metathesis; Grubbs, R. H.; Wenzel, A.
G.; O’Leary, D. J.; Khosravi, E., Eds.; Wiley-VCH: Weinheim,
2015, Chap. 16, 171-29. (b) Zukowska, K.; Grela, K. In Compre-
hensive Organic Synthesis, 2nd ed., Vol. 5; Knochel, P.; Molander,
G. A., Eds.; Elsevier: Amsterdam, 2014, 1257. (c) Connon, S.;
Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900. (d) Brik, A. Adv.
Synth. Catal. 2008, 350, 1161.
(21) Mukherjee, J. P.; Sil, S.; Chattopadhyay, S. K. Beilstein J. Org.
Chem. 2015, 11, 2487.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J