An olefin metathesis approach towards the solomonamides

Article abstract of DOI:10.1016/j.tetlet.2016.06.081

A new synthetic strategy directed towards the solomonamides, a novel class of cyclopeptides of marine origin, has been developed utilizing an olefin metathesis reaction to form the [15]-membered ring contained in these natural products. We demonstrated th

Full text of DOI:10.1016/j.tetlet.2016.06.081

Tetrahedron Letters 57 (2016) 3392–3395
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An olefin metathesis approach towards the solomonamides
y
⇑
Iván Cheng-Sánchez, Cristina García-Ruíz , Francisco Sarabia
Department of Organic Chemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic strategy directed towards the solomonamides, a novel class of cyclopeptides of marine
origin, has been developed utilizing an olefin metathesis reaction to form the [15]-membered ring con-
tained in these natural products. We demonstrated the efficiency and validity of this synthetic approach
for the construction of the macrocyclic core of the solomonamides in a minimally oxidized system. In fact,
the olefin metathesis cyclization proceeded in a stereoselective manner to provide exclusively the Z-iso-
mer in high yield. The described synthetic strategy for the solomonamides allows for access to the natural
products, as well as offering the opportunity for the generation of a diverse set of analogues in the sub-
sequent oxidation phase.
Received 9 May 2016
Revised 16 June 2016
Accepted 20 June 2016
Available online 21 June 2016
Keywords:
Solomonamides
Natural products
Ring closing metathesis
Antiinflammatory agents
Diversity-oriented synthesis
Ó 2016 Elsevier Ltd. All rights reserved.
The discovery of new natural products offers significant oppor-
tunities for the identification and development of new leads and
scaffolds in medicinal chemistry. In addition, natural products rep-
resent a great deal of fascination for organic chemists by virtue of
their structural diversity and challenging molecular frameworks
that many of them exhibit.1 Among the myriad of sources for nat-
ural products, particularly prolific is the marine sponge Theonella
swinhoei, which has proven to be an impressive source of sec-
ondary metabolites.2 In fact, this sponge provides at least nine dif-
ferent classes of natural products, including the very well-known
and important polyketide swinholide,3 together with a wide range
of bioactive peptidic-type natural products. Among the
peptidic-type natural products, it highlights acyclic peptides (poly-
theonamides and koshikamides), cyclic peptides (kombamide,
orbiculamide, barangamide, cupolamide, perthamides, etc.),
large-ring bicyclic peptides such as the theonellamides, depsipep-
tides (koshikamides, papuamides, nagahamide, or theopapuamide)
and glycopeptides.4 As further proof of the value of the genus
Theonella as an outstanding and bountiful source of new peptides,
Zampella and co-workers recently isolated two new cyclopeptides
termed the solomonamides A (1) and B (2) (Scheme 1), from a
Solomon islands collection. The cyclopeptides possessed unique
molecular structures and potent anti-inflammatory activities.5 An
exhaustive spectroscopic analysis of both compounds facilitated
the elucidation of their intricate cyclic structures, revealing the
presence of three conventional amino acids (D-Ala, Gly and L-Ser)
and an unprecedented 4-amino(20-amino-40-hydroxyphenyl)-3,5-
dihydroxy-2-methyl-6-oxohexanoic acid (ADMOA) and the corre-
sponding 5-deoxy derivative (AHMOA) for solomonamides A and
B, respectively. The absolute configurations were tentatively estab-
lished by a combination of spectroscopic and theoretical methods,
which must be confirmed, especially for the ADMOA and AHMOA
residues. Not surprisingly, these interesting and novel cyclopep-
tides were found to possess interesting biological properties. For
example, solomonamide A (1) displayed anti-inflammatory activ-
ity, causing a significant 60% reduction of inflammation of oedema
in an animal model at the dose of 100 lg/Kg. Unfortunately, the
extreme scarcity of the isolated solomonamides has hampered fur-
ther biological evaluations and, indeed, in the case of solomon-
amide B (2) it was not possible to evaluate its anti-inflammatory
activity. As a consequence, the solomonamides have been the sub-
ject of several synthetic efforts, notably by the Reddy group,6 who
recently reported a total synthesis of a deoxy analogue of solomon-
amide B7 together with an array of simple unfunctionalized
analogues.8
Intrigued by the enticing unique molecular structures of the
solomonamides, together with their promising biological proper-
ties, we initiated a programme directed towards the total synthesis
of this novel class of cyclopeptides. This synthetic programme pur-
sues the consecution of the following objectives: (1) Confirmation
of their proposed structures; (2) address the scarcity issue in order
to supply enough material for further biological evaluations; and
(3) establishment of a flexible synthetic strategy capable of gener-
ating analogues for structure–activity relationship studies. To this
⇑
Corresponding author. Tel.: +34 952 134 258; fax: +34 952 131 941.
E-mail address: frsarabia@uma.es (F. Sarabia).
y
´
Current address: School of Chemistry, University of Bristol, Cantocks Close, Bristol
aim, we designed
a retrosynthetic analysis of the targeted
BS8 1TS, UK.
http://dx.doi.org/10.1016/j.tetlet.2016.06.081
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

I. Cheng-Sánchez et al. / Tetrahedron Letters 57 (2016) 3392–3395
3393
NH2
Peptidic
Coupling
HO
Boc
RCM
NH Me
O
a) HATU, DIPEA
H
N
(This work)
Functional
Gr oup
O
R
NH Me
O
O
Heck Reaction
(Reddy´s wor k)
NHBoc
N
H
NH2
Me
H
N
O
1
5
6
Manipulations
6
OH NH
NH HN
Me
Me
O
NHBoc
HO
OH NH
8
O
Me
O
BnO
O
7
HO
NH HN
O
Me
O
c) TFA, CH2Cl2
b) TEMPO/BAIB
OH
Me
O
O
Me
10
d) HATU, DIPEA,
3
Solomonamide A, 1: R = OH
Solomonamide B, : R = H
OH
9
OH OH
10
2
Boc
Me
O
Me
Me
NH
O
O
O
OH NH
OH NH
e) RCM
OH NH
NH HN
Me
OH NH
NH HN
Me
NH HN
Me
O
NH HN
O Me
O
O
(See text for reaction
conditions)
BnO
O
O
O
O
5
4
11
5
Scheme 1. Molecular structures of the solomonamides and retrosynthetic analysis.
Scheme 2. RCM approach to the solomonamides: first generation. Reagents and
conditions: (a) 1.5 equiv HATU, 1.0 equiv DIPEA, DMF, 25 °C, 12 h, 78%; (b) 0.5 equiv
TEMPO, 5.0 equiv BAIB, CH3CN/H2O 1/1, 25 °C, 7 h, 65%; (c) 8% TFA in CH2Cl2,
0 °C ? 25 °C, 3 h; (d) 1.0 equiv 10, 1.0 equiv HATU, 3.0 equiv DIPEA, DMF,
molecules based on an olefin metathesis reaction as the key step
for the construction of the macrocycle,9 which could potentially
satisfy the established objectives. Thus, as depicted in Scheme 1,
our analysis began with a straightforward amide disconnection
25 °C, 12 h, 92% over
2 steps; (e) see text for different reaction conditions.
BAIB = (diacetoxyiodo)benzene, DIPEA = N,N-diisopropylethylamine, HATU = N-
[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methyl-
methanaminium hexafluorophosphate N-oxide, TEMPO = 2,2,6,6-tetramethyl-1-
piperidinyloxy free radical.
of the L-serine residue and functional group manipulations at the
C5 and C6 positions to generate the cyclic derivative 3, which rep-
resents a common precursor for both solomonamides. Cyclopep-
tide 3, in turn, could be obtained from the acyclic diolefin 4 via a
ring-closing metathesis (RCM) process. In order to demonstrate
the viability and efficiency of the planned olefin metathesis
approach to the synthesis of the solomonamides, we decided to
commence this synthetic study with a model system represented
by the diolefin 5 (Scheme 1).
its acyclic precursor, diene 14, given the favourable reactivity
effected by the hydroxyl group at the allylic position in facilitating
the ring closing metathesis reaction of olefins14 (Scheme 3). Thus,
we designed a synthetic plan to be executed in two phases, the first
initiated with a cyclization phase, via a ring closing metathesis, and
the second, an oxidation phase of the resulting macrocyclic pro-
duct to instal the functional groups in order to obtain the final
compound. It is noteworthy to point out the advantages of this
new synthetic strategy in that utilizes simple starting materials
and avoids the preparation of the complex ADMOA residue, which
would be constructed at the later stages of the synthesis. In addi-
tion, the relatively simple macrocyclic intermediate 13 may repre-
sent an interesting scaffold that could provide access to the
generation of analogues from late stage intermediates, allowing
the divergent entry to numerous scaffolds. Encouraged by these
appealing features, we initiated the synthetic route with the prepa-
ration of the readily accessible dipeptide 18 from the known
iodonitrobenzene derivative 1515 according to the synthetic
sequence depicted in Scheme 3. Thus, the introduction of the allylic
group in 15, via a Stille reaction, was followed by the reduction of
the nitro group to produce aniline 17. Coupling of 17 with dipep-
tide 7 was carried out under the same conditions as those
described before for 8 to obtain in good yield dipeptide 18. Prior
to the synthesis of the acyclic precursor 14, we decided to check
the olefin metathesis reaction by use of the model compound 20,
which was prepared by coupling of the amine derived from the
Boc derivative 18 with commercial acid 19. Thus, when 20 was
treated with 10 mol % of HG-II catalyst (A) in refluxing dichloro-
methane in the presence of p-benzoquinone,16 the macrocycle 21
was obtained as the sole product in an excellent 79% yield. To
For the synthesis of the model compound 5, we started from the
simple aniline 6,10 which was coupled with dipeptide 711 to obtain
derivative 8 in 78% yield. The coupling with the hydroxy acid 10,
obtained from the known diol 912 by selective oxidation with
TEMPO/BAIB,13 was achieved by conventional amide bond synthe-
sis to provide the model olefin metathesis precursor 5 in excellent
yield (92% over two steps). With the dialkene 5 in hand, we pro-
ceeded with the olefin metathesis reaction utilizing the
Hoveyda–Grubbs 2nd generation catalyst (HG-II, A) in refluxing
dichloromethane. However, after 24 h the reaction failed to afford
any macrocyclic product, leading instead to decomposition and/or
polymerization, together with the recovery of some starting mate-
rial (ꢀ12%). In an effort to obtain the ring-closing metathesis pro-
duct, more forcing conditions (toluene at 65 °C or 100 °C) and other
catalysts (Grubbs 1st and 2nd generations, Hoveyda–Grubbs, 1st
generation) were used, but the results were similarly unsuccessful
in all the cases, with no detection of the formation of the desired
macrocyclic product 11 (Scheme 2). Shortly after the execution of
these synthetic studies carried out by us in this direction, Reddy
et al. published a synthetic variant, based on an intramolecular
Heck reaction, that provided a synthetic precursor closely related
to compound 36c (see Scheme 1).
In reevaluating our approach to the solomonamides, we decided
to maintain the olefin metathesis reaction as a key step for the con-
struction of the macrocyclic structure. However, in this new ret-
rosynthetic scenario, we envisaged the C4AC5 bond of the
natural product for bond disconnection, which would require the
removal of functional groups present at these positions. This ret-
rosynthetic action would then lead to epoxy alcohol 12 as a poten-
tial precursor for solomonamide A (1), which, in turn, can be traced
back to the olefin 13. At this stage, the preparation of the macro-
cyclic olefin 13 was envisioned to proceed without difficulties from
our delight, the newly formed double bond (D
4,5) of 21 was present
exclusively as the Z-isomer, as demonstrated by the coupling con-
stant J = 12.9 Hz.
With the formation of the macrocyclic system demonstrated in
an efficient manner, we then proceeded to extend this reaction to
the desired system. To this aim, olefinic acid 29 was previously
prepared from the described epoxy alcohol 22,17 according to the
methodology reported in the literature for related compounds.18

3394
I. Cheng-Sánchez et al. / Tetrahedron Letters 57 (2016) 3392–3395
NH2
Me
Me
Oxidat ion Phase
HO
X
b) Zn, NaI, MeOH
c) TBAF
Peptidic
Coupling
Me
O
NH Me
O
O
TBDPSO
a) I2,
Ph3P,
imidazole
RO
24:
OH
R = TBDPS
R = H
O
HO
O
1
4
22: X = OH
23: X = I
d) PivCl ,
pyr
5
25:
OH NH
OH NH
1'
O
4'
BnO
NH HN
O
HO
NH HN
O
Me
g) DMP, CH2Cl2
h) NaClO2, NaH2PO4
Me
Me
f) DIBAL-H
HO
O
Me
O
Me
2-methyl-2-butene
1
12
Solomonamide A,
O
OTBS
29
HO
OTBS
28
PivO
26:
OR
R = H
R = TBS
e) TBS Cl , i mid.
27:
Cyclisation Phase
Me
Me
4
O
O
Scheme 4. Synthesis of the acid 29. Reagents and conditions: (a) 1.5 equiv I2,
1.5 equiv PPh3, 3.0 equiv imidazole, THF, 0 °C ? 25 °C, 20 min, 84%; (b) Zn dust,
1.5 equiv NaI, MeOH, reflux, 2 h, 88%; (c) 2.0 equiv TBAF, THF, 0 °C ? 25 °C, 3 h,
90%; (d) 1.3 equiv PivCl, 20.0 equiv pyridine, CH2Cl2, ꢂ30 °C; (e) 1.5 equiv TBSCl,
2.0 equiv imidazole, DMF, 25 °C, 12 h, quant. over 2 steps; (f) 2.0 equiv DIBAL-H,
CH2Cl2, ꢂ78 °C, 1 h; (g) 5.0 equiv DMP, CH2Cl2, 0 °C ? 25 °C, 12 h; (h) 7.0 equiv
NaClO2, 7.0 equiv NaH2PO4, 2.0 equiv 2-methyl-2-butene, t-BuOH/H2O (4:1), 25 °C,
12 h, 43% over 3 steps. DMP = Dess–Martin periodinane [1,1,1-tris(acetyloxy)-1,1-
dihydro-1,2-benziodoxol-3-(1H)-one, PivCl = pivaloyl chloride, TBSCl = tert-
butyldimethylsilyl chloride, TBAF = tetrabutylammonium fluoride.
5
OH NH
NH HN
Me
OH NH
BnO
O
BnO
NH HN
Me
O
O
O
14
13
I
a) Bu3SnCH2CH=CH2, Pd[PPh3]4
BnO
NO2
BnO
X
16:
X = NO2
15
b) Zn, AcOH
detected, only recovered starting material and some decomposi-
tion products were observed. Alternatively, when 30 was treated
with HFꢁpyr, to give allylic alcohol 14, followed by treatment with
the HG-II catalyst in dichloromethane at 40 °C in the presence of
p-benzoquinone, the expected macrocyclic olefin 13 was obtained
in 71% yield with the Z-olefin as the only isomer, as observed in the
1H NMR spectra of the resulting crude reaction mixture. With
macrocyclic derivative 13 in hand, we can now explore various
epoxidation methodologies directed towards the preparation of
epoxy alcohol 12 (Scheme 5).
17: X = NH2
O
H
N
c) HATU,
NHBoc
HO
DIPEA
Me
O
7
O
NHBoc
NH
d) TFA, CH2Cl2
e) HATU, DIPEA
O
BnO
NH HN
O
BnO
NH HN
O
O
Me
18
O
Me
19
OH
20
f) HG-II (A), 1,4-quinone,
CH2Cl2, 40 ºC
In conclusion, we have established the basis for a new synthetic
approach directed towards the solomonamides, a unique and
unprecedented class of cyclic peptides that represents a new scaf-
fold of biological and medicinal interest. This new synthetic strat-
egy features an olefin metathesis reaction, which allows for rapid
access into the macrocyclic core of the solomonamides in high-
yielding and stereoselective manners. In addition, the delineated
strategy was conceived to work with minimally oxidized deriva-
tives so as to allow introduction of the remaining functional groups
present in the natural products, in a subsequent oxidation phase,
as well as the possibility of introducing diverse structural modifi-
cations to rapidly and easily access analogues. Consequently, this
diversity-oriented synthetic approach to the solomonamides rep-
resents a novel and advantageous alternative to the synthetic
approaches reported thus far, and offers new opportunities for
the synthesis of solomonamide analogues as well as new cyclopep-
tide-type scaffolds based on their structures. The oxidation phase,
leading to the final products, is currently in progress and the
results will be reported in due course.
4
O
5
N
N
Mes
Mes
Cl
NH
Ru
Cl
BnO
NH HN
O
O
O
Me
A
21
Scheme 3. RCM approach to solomonamides: second generation. Reagents and
conditions: (a) 1.2 equiv allyl SnBu3, 0.15 equiv Pd[PPh3]4, DMF, 60 °C, 12 h, 73%; (b)
Zn dust, AcOH, 25 °C, 1 h, 65%; (c) 1.0 equiv 7, 1.5 equiv HATU, 1.0 equiv DIPEA,
CH2Cl2, 25 °C, 12 h, 81%; (d) 8% TFA in CH2Cl2, 0 °C ? 25 °C, 3 h; (e) 1.0 equiv 19,
1.0 equiv HATU, 3.0 equiv DIPEA, CH2Cl2, 25 °C, 12 h, 97% over 2 steps; (f) 0.10 equiv
Hoveyda–Grubbs 2nd generation (A), 0.10 equiv 1,4-benzoquinone, CH2Cl2, 40 °C,
12 h, 79%.
Thus, after the transformation of 22 into the iodide 23, a reductive
opening process was accomplished by treatment with Zn/NaI to
obtain allylic alcohol 24. After treatment of 24 with TBAF, all
attempts to directly oxidize the primary alcohol to the correspond-
ing acid of the resulting diol 25 met with no success. These disap-
pointing results forced us to manipulate the primary and
secondary hydroxyl groups of 25, via selective protection and
deprotection steps, to obtain alcohol 28 without difficulty. Olefinic
alcohol 28 was then oxidized in two steps, Dess–Martin periodi-
nane (DMP) oxidation19 followed by final treatment of the alde-
hyde with sodium chlorite under Pinnick conditions20 to furnish
acid 29 in good overall yield (Scheme 4).
The assembly of the key fragments, dipeptide 18 and acid 29,
was achieved in a similar manner as described before for 20, to
obtain 30 in 74% overall yield. In an initial attempt, 30 was sub-
jected to the action of the catalyst HG-II (A). Not surprisingly, the
reaction failed and no ring-closing metathesis product 31 was
Acknowledgments
This work was financially supported by the Ministerio de
Economía y Competitividad (MINECO) (CTQ2014-60223-R). I.C.-S.
thanks the Ministerio de Educación, Cultura y Deporte for a pre-
doctoral fellowship (FPU Programme). C.G.-R. thanks Ministerio
de Educación y Ciencia and Research Plan of the University of
Málaga for predoctoral and postdoctoral fellowships, respectively.
The authors thank Dr. J.I. Trujillo from Pfizer (Groton, CT) for assis-
tance in the preparation of this manuscript. The authors thank the
Unidad de Espectroscopía de Masas and the NMR facility of the
University of Málaga for exact mass and NMR spectroscopic
assistance.

I. Cheng-Sánchez et al. / Tetrahedron Letters 57 (2016) 3392–3395
Me
3395
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a) TFA, CH2Cl2
b) HATU, DIPEA
TBSO
NH
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H
N
Me
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TBSO
BnO
N
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BnO
CO2H
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Me
O
O
OH NH
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Me
TBSO
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NH
BnO
O
BnO
O
O
O
31
14
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O
O
OH NH
OH NH
NH HN
O Me
[O]
BnO
NH HN
Me
O
BnO
O
O
13
12
Scheme 5. Towards the total synthesis of solomonamides. Reagents and condi-
tions: (a) 15% TFA in CH2Cl2, 0 °C ? 25 °C, 3 h; (b) 1.0 equiv 29, 1.0 equiv HATU,
3.0 equiv DIPEA, CH2Cl2, 25 °C, 12 h, 74% over 2 steps; (c) 0.10 equiv Hoveyda–
Grubbs 2nd generation (A), 0.10 equiv 1,4-benzoquinone, CH2Cl2, 40 °C, 12 h, no
reaction; (d) 3.0 equiv HFꢁpyr, THF, 0 °C, 12 h, 83%; (e) 0.10 equiv Hoveyda–Grubbs
2nd generation (A), 0.10 equiv 1,4-benzoquinone, CH2Cl2, 40 °C, 12 h, 71%.
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Supplementary data
Supplementary data (experimental details, compound charac-
terization and copies of 1H and 13C NMR spectra) associated with
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2016.06.081.