Towards solomonamide A: Asymmetric synthesis of the unusual γ-amino acid part

Article abstract of DOI:10.1016/j.tetlet.2013.02.032

Fully functional and differentially protected synthesis of the unusual γ-amino acid part of the very powerful anti-inflammatory cyclic peptide solomonamide A has been achieved in a straight forward manner in good yields.

Full text of DOI:10.1016/j.tetlet.2013.02.032

Tetrahedron Letters 54 (2013) 2128–2130
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Towards solomonamide A: asymmetric synthesis of the unusual
acid part
c-amino
⇑
Nerella Kavitha, Vemula Praveen Kumar, Srivari Chandrasekhar
Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Fully functional and differentially protected synthesis of the unusual c-amino acid part of the very pow-
erful anti-inflammatory cyclic peptide solomonamide A has been achieved in a straight forward manner
in good yields.
Received 5 January 2013
Revised 4 February 2013
Accepted 8 February 2013
Available online 16 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Solomonamide A
Horner–Emmons olefination
Sharpless asymmetric dihydroxylation
Unusual amino acid
Novel bioactive metabolites are essential components in drug
discovery. Undoubtedly marine sponges are occupying the front
slot in providing interesting natural products and scaffolds with
very diverse biological profiles.1 Very recently, Zampella and co-
workers have reported the isolation of new octacyclopeptides per-
thamides C and D2 from Theonella Swinhoei. Further investigations
on Theoneela Swinhoei by the same group provided two minor pep-
tide derivatives solomonamide A (1) and B (2, Fig. 1).3 The solomo-
DIBAL-H reduction of ester 7 and homologation of the rather
unstable aldehyde (degradation observed within 1 h) under Horn-
er–Emmons conditions7 using KH as a base and 18-crown-6 as
phase transfer catalyst provided Z-olefinic ester 8 in 72% yield as
the major isomer (The minor E-isomer was separated by column
chromatography). Further, the compound 8 was reduced with DI-
BAL-H to generate the Z-allyl alcohol 9 which underwent a facile
epoxidation8 with m-CPBA in CH2Cl2 at ꢀ10 °C to provide epoxy
alcohol 10 with excellent diastereoselectivity (97:3).9 The epoxy
alcohol 10 after purification when exposed to NaN3 in the presence
of trimethyl borate allowed a smooth regioselective epoxide cleav-
age10 to yield the azido diol 11. The unwanted 1,2-diol (1,3-open-
ing) was destroyed by the addition of NaIO4 to the reaction
mixture. Disilylation of 10 with TBSOTf was rather easily
accomplished to furnish 12 in 84% yield. The azido group in 12
was reduced under Staudinger conditions11 and the resultant
namide A (1) has exhibited anti-inflammatory activity at 100 lg/kg
in animal models. The extensive degradation and spectral studies
have revealed that solomonamide A comprises of an unprece-
dented 4-amino(20-amino-40-hydroxy phenyl)-3,5-dihydroxy-2-
methyl-6-oxohexanoic acid (ADMOA) besides the proteinogenic
alanine and glycine as a 15-membered cyclic tripeptide.
While no synthetic efforts are reported in the literature to date
towards solomonamide A, the partial synthesis of solomonamide B
is recently published.4 Our group is engaged in the synthesis of
marine natural cyclic peptides as part of a programme towards
building repository of natural products.5 Herein, we describe the
first synthesis of fully functionalized and appropriately protected
unusual amino acid framework 4 with excellent stereo control
in a convergent fashion starting from commercially available
(R)-Roche ester via chiral epoxide 10 and amino aldehyde 6
(Scheme 1).
NH2
NH
NH2
NH
HO
HO
O
O
HO
O
O
OH NH
OH NH
O
O
With this strategy as the backdrop, we embarked upon the syn-
thesis of 4 wherein, the precursor compound 7 was synthesized
from (R)-Roche ester following the literature procedure.6 The
HO
NH HN
O
HO
NH HN
O
O
O
Solomonamide A (1)
Solomonamide B (2)
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Figure 1. Structures of 1 and 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.032

N. Kavitha et al. / Tetrahedron Letters 54 (2013) 2128–2130
2129
Solomonomaide A (1)
Cbz
O
HN
O
BocHN
TBSO
COOH
Cbz
H
N
+
+
COOH
OTBSOTBS
MeO
OH
NHBoc
O
MeO
NO2
3
4
5
NH
(R)-Roche ester
O
OPMB
PMBO
O
OTBS
10
6
Scheme 1. Retrosynthesis of solomonamide A.
PPh3+Br-
COOMe
Cbz
a
b
PMBO
OMe
NO2
HN
PMBO
PMBO
O2N
b
a
OPMB
Cbz
O
6
+
7
8, (cis: trans 9:1)
OTBS
15
MeO
OH
16
NO2
OMe
OH
c
d
PMBO
PMBO
Cbz
NO2 OH HN
O
O
HN
c
10, dr = 97:3
9
OPMB
OPMB
N3
N3
OH OTBS
OH OTBS
f
MeO
d
e
MeO
PMBO
g
OTBS
17
18
OH OH
NHCbz
OTBS
12
11
Cbz
NO2
O
HN
e
NHCbz
OH
OPMB
PMBO
h
OTBS
PMBO
OR OR
13
14
MeO
NO2
OTBS
OTBS
19, R = TBS
Cbz
6
Cbz
HN
O
HN
NO2
O
OH
f
Scheme 2. Reagents and conditions: (a) DIBAL-H, hexane, ꢀ78 °C, 10 min followed
by triphenylphosphonoacetate, KH, 18-crown-6, THF, ꢀ78 °C, 2 h, 72% (for two
steps); (b) DIBAL-H, CH2Cl2, 0 °C, 2 h, 78%; (c) m-CPBA, CH2Cl2, ꢀ10 °C, 6 h, 88%; (d)
NaN3, B(OMe)3, DMF, 50 °C, 15 h followed by NaIO4, THF/H2O (8:2), 1 h, 84%; (e)
TBSOTf, DIPEA, CH2Cl2, ꢀ78 °C, 3 h, 84%; (f) (i) triphenyl phosphine, benzene/H2O,
60 °C, 24 h; (ii) CbzCl, Et3N, CH2Cl2, rt, 12 h, 87% (for two steps); (g) pTSA, MeOH,
0 °C, 1 h, 80%; (h) Dess–Martin periodinane, CH2Cl2, rt, 1 h, 90%.
COOH
OR OR
MeO
OR OR
4, R = TBS
MeO
20, R = TBS
Scheme 3. Reagents and conditions: (a) NaH, CH2Cl2, rt, 12 h, 83%; (b) AD-mix-b,
MeSO2NH2, tBuOH/H2O (1:1), 0 °C, 48 h, 74%; (c) DMP, CH2Cl2, rt, 2 h, 83%; (d)
TBSOTf, DIPEA, CH2Cl2, 0 °C, 3 h, 76%; (e) DDQ, CH2Cl2/pH buffer (10:1), 0 °C, 4 h,
85%; (f) BAIB, TEMPO, CH3CN/pH buffer (1:1), rt, 4 h, 78%.
amine was quickly protected as benzyl carbamate 13 in 87% overall
yield for two steps. The selective primary desilylation in 13 with
pTSA in methanol furnished 14, which underwent oxidation to
aldehyde 6 using Dess–Martin periodinane conditions (Scheme 2).
After constructing the aliphatic chiral component, the next task
was to stitch the aryl group which was accomplished by a Wittig
protocol.12 Thus, the aldehyde 6 was exposed to the Wittig salt
1512 with NaH as a base to yield the styrene derivative 16 as a sep-
arable E/Z mixture (70:30).13 The major E-isomer 16 was obtained
by careful chromatography and was subjected to sharpless asym-
metric dihydroxylation14 using AD-mix-b to install the diol group.
The resultant diol 17 was subjected to controlled oxidation using
Dess–Martin periodinane in dichloromethane to yield compound
18 wherein the benzylic hydroxy group was selectively oxidized.
The free hydroxyl group in 18 was silylated to 19 and oxidative
cleavage of PMB ether using DDQ15 provided the primary alcohol
20. Following, Epp and Widlanski conditions16 (BAIB, TEMPO,
CH3CN) under buffer medium resulted in the fully functionalized
and appropriately protected unusual amino acid precursor 4 in
78% yield (Scheme 3). This compound is fully characterized by 1H
In conclusion, we have used robust and easily accessible
chemicals and reactions viz (R)-Roche ester, sharpless
asymmetric dihydroxylation and Wittig reaction as key compo-
nents in the synthesis of the unusual
c-amino acid fragment of
solomonamide A. Further work towards total synthesis is in
progress.
Acknowledgments
N.K. and V.P.K. thank CSIR, New Delhi for research fellowships.
S.C. is thankful to the Ministry of Earth Sciences, New Delhi for re-
search grant.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.032.
and 13C NMR, HRMS and other supporting spectral data17
.

2130
N. Kavitha et al. / Tetrahedron Letters 54 (2013) 2128–2130
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ꢂ
¼ þ82:4 (c = 0.94, CHCl3); IR (neat):
m
max 3440, 2934, 2858, 1715, 1535, 1251, 1125, 837, 694 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 7.68 (d, J = 8.4 Hz, 1H), 7.41–7.31 (m, 6H), 7.08–7.02 (dd, J = 2.4,
8.6 Hz, 1H), 5.12 (d, J = 9.8 Hz, 1H), 5.07 (s, 2H), 4.72 (d, J = 4.9 Hz, 1H), 4.27–
4.18 (m, 1H), 4.03 (t, J = 4.7 Hz, 1H), 3.89 (s, 3H), 2.75–2.65 (m, 1H), 1.13 (d,
J = 7.1 Hz, 3H), 0.87 (s, 9H), 0.84 (s, 9H), 0.11–0.02 (m, 12H); 13C NMR (CDCl3,
75 MHz): d 198.4, 177.8, 161.8, 155.9, 149.4, 136.4, 132.1, 128.4, 128.2, 128.1,
124.4, 118.0, 109.8, 72.2, 67.0, 60.3, 56.0, 55.1, 43.6, 29.6, 25.8, 25.7, 13.5, ꢀ4.0,
8. Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
ꢀ4.5, ꢀ4.6, ꢀ5.0; HRMS (ESI): m/z calcd for
C
34H52N2NaO10Si2: [M+Na]+
9. Using HPLC column: ZORBAX C3 (4.6 ꢁ 150 mm); Mobile phase: 45%
Acetonitrile in water at flow rate 1.0 mL/min, Rt major = 3.5 min and Rt
minor = 4.8 min.
727.3054, found 727.3052.