Studies toward the synthesis of potent anti-inflammatory peptides solomonamides A and B: Synthesis of a macrocyclic skeleton and key fragment 4-amino-6-(2′-amino-4′-hydroxyphenyl)-3-hydroxy-2-methyl-6- oxohexanoic acid (AHMOA)

Article abstract of DOI:10.1021/ol303149k

A first synthetic effort toward total synthesis of highly potent solomonamides is disclosed. An efficient strategy to synthesize this class of compounds, along with the synthesis of a core macrocycle (shown in red) and the key fragment AHMOA, is described.

Full text of DOI:10.1021/ol303149k

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6222–6225
Studies toward the Synthesis of
Potent Anti-inflammatory Peptides
Solomonamides A and B: Synthesis of a
Macrocyclic Skeleton and Key Fragment
4‑Amino-6-(20-amino-40-hydroxyphenyl)-3-
hydroxy-2-methyl-6-oxohexanoic
Acid (AHMOA)
K. Kashinath, N. Vasudevan, and D. Srinivasa Reddy*
CSIR-National Chemical Laboratory, Division of Organic Chemistry, Dr. Homi Bhabha
Road, Pune, 411008, India
ds.reddy@ncl.res.in
Received October 29, 2012
ABSTRACT
A first synthetic effort toward total synthesis of highly potent solomonamides is disclosed. An efficient strategy to synthesize this class of
compounds, along with the synthesis of a core macrocycle (shown in red) and the key fragment AHMOA, is described.
In early 2011, two cyclic peptides solomonamide A (1)
and solomonamide B (2) with an unprecedented chemo-
type were isolated from the marine sponge Theonella
swinhoei by Zampella’s group from Italy.1 The gross
structures of these cyclic peptides were established on the
basis of detailed NMR analysis and HRMS. The Marfey
method,2 QM J based analysis, and DFT J/13C calcula-
tions were used in combination to determine the absolute
configuration of the molecules. Solomonamide A (1) showed
significant reduction (∼60%) of inflammation in the carra-
geenan induced paw edema model.1
Interestingly, this compound 1 exhibits its anti-inflam-
matory potential at a very low concentration of 100 μg/kg
in animal models. The scarcity of the material has ham-
pered further profiling of these compounds. Because of
potent in vivo biological activity, novel chemotype, and
scarcity of the material, it is expected that many synthetic
and medicinal chemists across the globe are in a race to
synthesize this target.3 We have initiated a program to
access these important class of molecules by means of
chemical synthesis in sufficient quantities for further biolo-
gical evaluation. We have plans to perform systematic SAR
(1) Festa, C.; De Marino, S.; Sepe, V.; D’Auria, M. V.; Bifulco, G.;
Debitus, C.; Bucci, M.; Vellecco, V.; Zampella, A. Org. Lett. 2011, 13,
1532.
(3) Solomonamides A and B were highlighted as part of a “Hot off
the press” natural products review published May, 2011. See: Hill,
R. A.; Sutherland, A. Nat. Prod. Rep. 2011, 28, 1031.
(2) Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.
r
10.1021/ol303149k
Published on Web 12/05/2012
2012 American Chemical Society

monitoring around this scaffold (including the simplifica-
tion of structural complexity)4 to come up with optimized
lead(s) which may potentially bring forth a novel com-
pound to be developed as an anti-inflammatory agent.5
Herein, we report an efficient strategy to synthesize this
class of compounds, the synthesis of a macrocyclic core,
and the synthesis of a key fragment AHMOA (3).
The key disconnections toward the total synthesis of the
target compounds are shown in Figure 1. The macrolacta-
mization was chosen as a final step to assemble cyclic
peptides. The fragment AHMOA (3) could be prepared
starting from known compound B in which diastereose-
lective crotylation and Photo-Fries rearrangement/palla-
dium catalyzed CꢀH activation would be the key steps.
Other building blocks A and C could be used for assem-
bling the southern part of the target molecules. Rubottom
oxidation6 could be used for the stereoselective installation
of R-hydroxylation of ketone in the final stages of synthesis
to obtain solomonamide A.
commenced with the key CꢀH activation step starting
from known N-acyl-m-anisidine 47 and aldehyde 5.8 After
a few attempts, we were successful in obtaining com-
pound 6 by employing the recently reported Li and
Kwong method (Pd(TFA)2 catalyst, TBHP in toluene)
in 65% yield.9 Deacetylation was carried out by acidic
hydrolysis to release free amine 7 in 92% yield.10 As
anticipated the peptide coupling was not smooth because
of the weak nucleophilicity of the aryl-NH2 which was in
an extended conjugation with the carbonyl group (such as
vinylogous amide).11 As we were not successful in the
coupling of dipeptide Boc-Gly-Ala-OH despite several
attempts, Fmoc-protected alanine was coupled through
the corresponding acid chloride, Fmoc-D-Ala-Cl,12 to
provide compound 8 in good yield. Next, deprotection
of the Fmoc group in 8 was carried out using standard con-
ditions (piperidine). However, we could not isolate the
desired compound 90; instead benzodiazepinone 9 was
isolated in 93% yield. It is interesting to note that compound
9 and its derivatives can be explored further, as this skeleton
is a privileged structure in medicinal chemistry.13,14
To circumvent the problem of benzodiazepinone forma-
tion, the ketone present in 6 was protected with propane-
dithiol inthepresenceofBF3 Et2O togivedithioketal10in
3
89% yield. At this stage, coupling of dipeptide Boc-Gly-
Ala-OH was attempted considering that the protection of
ketone removed the vinylogous amide functionality. How-
ever, the coupling of dipeptide was not successful. Hence,
the compound 10 was transformed to compound 11 in a
two-step sequence (deacetylation followed by N-acylation
with Fmoc-D-Ala-Cl). Fmoc deprotection (piperidine) gave
the desired free amine 12, which was coupled with Boc-Gly-
OH to produce 13 which on further hydrolysis furnished the
acyclic precursor 14 in good yields. The crude acyclic amino
acid resulting from Boc deprotection was subjected to key
macrolactamization15 using HATU followed by thioketal
deprotection under standard conditions resulted in the for-
mation of key macrocyclic core 1516 of solomonamides.
(7) Belov, V. N.; Bossi, M. L.; Folling, J.; Boyarskiy, V. P; Hell, S.
Chem.;Eur. J. 2009, 15, 10762.
(8) Rogers, L. R.; Konstantinou, Z.; Reddy, M.; Organ, M. G. Eur. J.
Figure 1. Key disconnections and building blocks.
Org. Chem. 2011, 5374.
(9) Wu, Y.; Li, B.; Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13,
3258.
Beforeembarkingonthesynthesisofanactualmolecule,
we wanted to explore the model synthesis to test the de-
signed strategy, in particular, oxidative coupling of aldehyde
to N-acyl-m-anisidine through CꢀH activation, less reactive
aniline peptide coupling, and key macrocyclization. Accord-
ingly, the model synthesis of a macrocycle was achieved and
the results are compiled in Scheme 1. The model synthesis
(10) Varying amounts of ester hydrolysis product was also observed
during this reaction. The mixture of products was subjected to ester-
ification. See details in the Supporting Information.
(11) (a) Elassar, A-Z. A.; El-Khai, A. A. Tetrahedron 2003, 59, 8463.
(b) The Chemistry of Enamines Part 1; Rappoport, Z., Ed.; John Wiley and
Sons: Chichester, New York, Brisbane, Toronto, Singapore, 1994.
(12) Tantry, S. J.; Venkataramanarao, R.; Chennakrishnareddy, G.;
Sureshbabu, V. V. J. Org. Chem. 2007, 72, 9360.
(13) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
(4) Inspired by the concept of diverted total synthesis of bioactive
natural products: (a) Danishefsky, S. Nat. Prod. Rep. 2010, 27, 1114.
(b) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329.
(5) Selected reviews on the role of natural products in drug discovery:
(a) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311. (b) Molinski,
T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nat. Rev. Drug Discovery
2009, 1, 69. (c) Kingston, G. I. J. Nat. Prod. 2011, 74, 496. (d) Harvey, A. L.
Drug Discovery Today 2008, 13, 894. (e) Zhonghong, G.; Reddy, P. T.;
Quevillion, S.; Couve-Bonnaire, S.; Ayra, P. A. Angew. Chem., Int. Ed.
2005, 44, 1366.
(14) Selected references related to synthesis of benzodiazepinones:
(a) Ferrini, S.; Ponticelli, F.; Taddei, M. J. Org. Chem. 2006, 71, 9217.
(b) Im, I.; Webb, T. R.; Gong, Y.-D.; Kim, J.-I.; Kim, Y.-C. J. Comb.
Chem. 2004, 6, 207. (c) Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P.
C.-H. J. Am. Chem. Soc. 2003, 125, 11482.
(15) Selected reviews for macrocyclization of peptides: (a) A. Parenty,
A.; Moreau, X.; Niel, G.; Campagne, J.-M. Chem. Rev. 2012, ASAP
article, dx.doi.org/10.1021/cr300129n. (b) White, J. C.; Yudin, A. K. Nat.
Chem. 2011, 3, 509. (c) Kopp, F.; Marahiel, M. A. Nat. Prod. Rep. 2007,
24, 735. (d) Davies, J. S. J. Peptide Sci. 2003, 9, 471 and references cited
therein.
(6) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319.
Org. Lett., Vol. 14, No. 24, 2012
6223

Scheme 1. Synthesis of Macrocyclic Skeleton of Solomonamides
After the successful synthesis of the macrocyclic core, we
turned our attention toward the synthesis of key fragment
AHMOA (3). The known aldehyde 1617 was subjected to a
key crotylation reaction to introduce the new chiral centers
present in the target molecule. Freshly activated CrCl2
gave a 1:2 ratio of diastereomers 17a and 17b in which the
desired 17b was the major compound.18 The stereochem-
istry of more deshielded chiral protons was established by
comparing their proton coupling constants in the corre-
sponding cyclic carbamates 18a and 18b.18a It is worth
mentioning that undesired isomer 17a can be converted to
17b via an inversion reaction.19 The complete stereostructure
of 18b as drawn was further confirmed by the single X-ray
crystal structure (Scheme 2). The carboxylic acid 19 pre-
pared from cyclic carbamate 18b (TBS deprotection fol-
lowed by Jones oxidation) was coupled with TIPS pro-
tected m-amino-phenol 2020 to provide compound 21.
Attempts to form sp2ꢀsp2 CꢀC bond formation through
CꢀH activation in a similar way to that of the model
substrate resulted in very poor yields of the desired pro-
duct. Photolysis of the amide 21 using a Hg lamp (254 nm)
under dilute conditions in acetonitrile furnished the photo-
Fries rearranged product 22 in a highly regioselective
manner.21,22 This reaction needs further optimization to
improve the yield. Oxidative cleavage of olefin in 22 fol-
lowed by further oxidation furnished carboxylic acid 23 in
good yield. Thus, we have prepared the key fragment
AHMOA in a protected form which will be carried for-
ward to the total synthesis of natural solomonamides.
(16) All the spectral data are in agreement with the assigned struc-
ture. See details in the Supporting Information.
(17) Compound 16 was prepared by following modified and econom-
ical procedures starting from D-methionine. Aleiwi, B. A.; Schneider,
C. M.; Kurosu, M. J. Org. Chem. 2012, 77, 3859.
(18) (a) Ciapetti, P.; Falorni, M.; Taddei, M. Tetrahedron 1996, 52,
7379. (b) Ciapetti, P.; Falorni, M.; Taddei, M.; Ulivi, P. Tetrahedron
Lett. 1994, 35, 3183. (c) Furstner, A.; Shi, N. J. Am. Chem. Soc. 1996,
118, 12349. (d) Furstner, A. Chem. Rev. 1999, 99, 991. (e) Cintas, P.
Synthesis 1991, 248.
(19) 17a was transformed to 17b via a Mitsunobu reaction followed
by ester hydrolysis in modest yield. This inversion reaction needs further
optimization which is ongoing experimentation in the lab.
(20) Choy, J.; Figueroa, S.; Jiang, L.; Wagner, P. Synth. Commun.
2008, 38, 3840.
(21) (a) Guerrini, G.; Ponticelli, F.; Taddei, M. J. Org. Chem. 2011,
76, 7597. (b) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9, 69.
(22) Photo-Fries rearrangement of the m-methoxy aniline derivative
resulted in a mixture of regioisomers. Introduction of bulky TIPS
protection solved the problem. Details will be reported in a full paper.
6224
Org. Lett., Vol. 14, No. 24, 2012

Scheme 2. Synthesis of 4-Amino-6-(20-amino-40-hydroxyphenyl)-3-hydroxy-2-methyl-6-oxohexanoic Acid Residue (AHMOA)
In short, we have designed a feasible strategy and
executed key steps toward the total synthesis of highly
attractive and potent anti-inflammatory cyclic peptides.
Synthesis of the macrocyclic core and a key fragment in an
orthogonally protected form are the highlights of the
present work. Having tested the feasibility of key reactions
and established a synthetically viable route, the total syn-
thesis, synthesis of analogues, and their biological evalua-
tion will constitute our future publications.
MLP022126) for financial support; Dr. Nithyanandhan,
NCL for helpful discussions on photolysis reactions; Mr.
Santoshkumar S. Dange, NCL for his help in scale up of
intermediates; and Mr. Bishnu Biswal, NCL for helping
in X-ray analysis. K.K. and N.V. thank CSIR and UGC
for the award of research fellowships, respectively.
Supporting Information Available. Characterization
data, NMR spectra, detailed experimental procedures, and
CIF file of X-ray crystal structure. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank DST, New Delhi
(SR/S1/OC-17/2011) and NCL, Pune (Start-up grant
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
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