Total syntheses of arenamides A, B and C

Article abstract of DOI:10.1016/j.tetasy.2014.01.004

Total syntheses of the three arenamides A-C, NFκB inhibitors, are described for the first time. The key steps involved in the synthesis are a Crimmin's aldol, Wittig olefination and a macrolactamization reaction.

Full text of DOI:10.1016/j.tetasy.2014.01.004

Tetrahedron: Asymmetry 25 (2014) 348–355
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total syntheses of arenamides A, B and C
⇑
⇑
Srivari Chandrasekhar , Kurapati Sathish, Gangireddy Pavan Kumar Reddy, Prathama S. Mainkar
Division of Natural Products 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:
Received 4 December 2013
Accepted 10 January 2014
Total syntheses of the three arenamides A–C, NF
steps involved in the synthesis are a Crimmin’s aldol, Wittig olefination and a macrolactamization
reaction.
j
B inhibitors, are described for the first time. The key
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
The synthesis and study of unusual peptides and their proper-
ties have been an area of interest for us.3 Our focus on the synthesis
New sources are constantly being explored to identify scaffolds
which can help in finding cures for diseases affecting human beings.
Marine organisms have provided some potent and complex com-
pounds which are being explored as leads for better healthcare.1
In 2009, Fenical et al. reported, from the extracts of Salinispora aren-
of complex and difficult to access natural products,4 in particular
cyclic peptides,5 attracted us towards the arenamides. Our efforts
have culminated in the first total synthesis of arenamide A6 which
also helped to reassure the stereochemical orientation of the side-
chain.7 Immediately after our publication, Ghosh et al.8 published a
synthesis of epi-arenamide A (di-epi, 28-epi and 29-epi) and the
absolute stereochemistry was confirmed to be (S) rather than (R).
Based on the data published by Fenical et al., arenamide B is more
potent than A and hence remained a molecule of interest for us. In
addition, we are interested in building a repository of marine cyclic
peptides as a part of a major drug discovery programme. Herein we
disclose the full details pertaining to the total synthesis of all three
arenamides A, B and C following a stereodivergent strategy.
Based on the structures, a retrosynthetic analysis was carried
out, as depicted in Scheme 1. The desired molecules could be ob-
tained from the key intermediates 2a/2b/2c which in turn could
be derived from 3a/3b/3c and 4 through a traditional peptide cou-
pling reaction. Compounds 3a/3b were envisioned to be constructed
by esterification of the corresponding amino acids with 5a/5b,
which were synthesized by a Wittig-olefination between the alde-
hyde 6 and ylides 11a/11b. Aldehyde 7 was in turn prepared from
1,3-propane diol.
icola strain CNT-088, the isolation, structural elucidation and NFjB
inhibition activities of three cyclic depsipeptides and named them
arenamides A–C.2 These natural cyclic depsipeptides are character-
ized by 19-membered macrocycles with six subunits:
L-Phe/L-Meth,
L
-Ala, -Val, Gly, -Leu and 3-hydroxy-4-methyldecanoic acid
L
L
(HMDA)/3-hydroxy-4-methyl octanoic acid (HMOA). The relative
configuration of HMDA (at C-28, C-29) has been assigned as ‘syn’
based on NOE studies while the absolute configuration was deter-
mined by Mosher ester data. For HMOA, the relative stereochemis-
try at C-29 was determined to be (S). The arenamides A and B
blocked TNF induced activation in a dose and time dependent man-
ner with IC50 values of 3.7 and 1.7
l
M, respectively (Fig. 1).
O
H
O
N
R1
NH
O
O
O
NH
2. Results and discussion
HN
R
N
Our synthesis began with Crimmin’s syn-aldol reaction9 be-
tween auxillary 8 and aldehyde 7 obtained from 1,3-propane diol,
using a titanium complex generated from TiCl4, DiPEA in CH2Cl2 to
furnish the chiral (S)-secondary alcohol 9 in 85% yield and with
95% diastereomeric excess (determined by HPLC). The secondary
hydroxyl group was protected using tert-butyldimethylsilyl
triflate, DiPEA in CH2Cl2 at ꢀ78 °C to give the silyl ether 10 in
82% yield. Reductive cleavage of the auxillary with DIBAL-H in
CH2Cl2 at ꢀ78 °C furnished aldehyde 6 in 78% yield (Scheme 2).
H
O
O
R = Ph, R1 = C5H11 arenamide A 1a
R = Ph, R1 = C3H7 arenamide B 1b
R = CH2SMe, R1 = C5H11 arenamide C 1c
Figure 1. Structures of arenamides.
⇑
Corresponding authors. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail addresses: srivaric@iict.res.in (S. Chandrasekhar), prathama@iict.res.in
(P.S. Mainkar).
0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2014.01.004

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
349
CbzHN
O
O
OPNB
NH
n
1a
1b
1c
O
O
NH
O
HN
N
H
R
O
O
R = Ph, n=5, 2a
R = Ph, n=3, 2b
R = CH2SMe, n=5, 2c
OPNB
O
O
n
H
N
H
N
O
O
NHCbz
N
H
HO
O
O
O
NH2TFA
R
4
R = Ph, n=5,3a
R = Ph, n=3, 3b
R = CH2SMe, n=5, 3c
OTBS
NO2
OBn
O
O
OBn
O
7
n
6
OH
O
n=5, 5a
n=3, 5b
Scheme 1. Retrosynthetic analysis of arenamides.
O
O
OH
S
S
TBS-OTf, DIPEA
7, TiCl4, DIPEA
N
N
OBn
S
S
CH2Cl2, 0 oC,
1 h, 82%
CH2Cl2, -78 oC,
3 h, 85%
9
8
Ph
N
Ph
OTBS
O
OTBS
OBn
S
DiBAL-H, CH2Cl2
-78 oC, 1h, 78%
O
OBn
S
6
10
Ph
Scheme 2. Synthesis of aldehyde fragment 6.
Aldehyde 6 was subjected to homologation with the respective
alkylphosphonium bromide salts 11a/11b in the presence of n-BuLi
to give olefins 12a/12b in 70% and 71% yields, respectively. How-
ever, no further characterization for the cis–trans isomer identifica-
tion was carried out since the olefin was saturated during
debenzylation carried out under catalytic hydrogenation using
10% Pd–C as catalyst to afford primary alcohols 13a/13b in 90%
and 91% yields, respectively. The primary alcohol was then sub-
jected to TEMPO mediated catalytic oxidation using BAIB, which
gave acids which were converted into p-nitrobenzyl esters using
p-nitrobenzyl alcohol, EDCI and DMAP in CH2Cl2 to afford 14a/
14b in 76% and 78% yields, respectively. Desilylation of 14a/14b
was carried out with HF-Py in dry THF to produce b-hydroxy esters
5a/5b in 80% and 82% yields, respectively (Scheme 3).
15a or N-Boc-L-metheonine 15b using EDCI, DMAP in dry CH2Cl2
which provided 16a/16b/16c in good yields. The N-Boc protected
depsidipeptides 16a/16b/16c were then reacted with TFA, in
CH2Cl2 to produce the TFA salt of amine 3a/3b/3c (Scheme 4).
Tetrapeptide 4 (Scheme 5) was synthesized from commercially
available
synthesis. Condensation of Boc-
ester 17 using EDCI and HOBt as coupling reagents gave dipeptide
(Boc- -Leu- -Ala-OMe) 19 in 82% yield. The Boc group of 19 was re-
moved using TFA in CH2Cl2 resulting in amine 20. The other dipep-
tide Cbz-Gly- -Val-OH 24 was prepared by the coupling of -valine
L-amino acids following a standard protocol for peptide
L
-Leu-OH 18 and -alanine methyl
L
L
L
L
L
methyl ester 21 with Cbz-protected glycine 22 followed by hydro-
lysis using lithium hydroxide. Dipeptides 20 and 24 were then
coupled using EDCI, HOBt and DIPEA in 58% yield to obtain 25.
Epimerization was not observed after the peptide coupling reac-
tion based on NMR data. The saponification of the ester group of
Esters 3a/3b/3c were synthesized from HMDA/HMOA frag-
ments 5a/5b by coupling with N-Boc protected L-phenyl alanine

350
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
OBn
6, nBuLi,THF,
PPh3Br
10% H2, Pd-C
ethanol, 12 h
n
n
0 oC-R.T, 3 h
OTBS
11a n=4
11b n=2
12a n=4, 71%
12b n=2, 70%
NO2
1. BAIB, TEMPO
O
CH3CH:H2O (1:1), rt, 3 h.
OH
n
n
TBSO
O
OTBS
2. p-nitrobenzyl alcohol
EDCI, DMAP, CH2Cl2, 3 h
14a n=4, 78%
14b n=2, 76%
13a n=4, 91%
13b n=2, 90%
NO2
O
n
HF-Py, THF
oC-rt, 24 h
OH
O
0
5a n=4, 80%
5b n=2, 82%
Scheme 3. Synthesis of HMDA and HMOA fragments 5a and 5b.
3. Conclusion
OPNB
n
In conclusion, we have successfully carried out the first total
syntheses of all three arenamides A, B and C involving Crimmin’s
aldol, Wittig olefination and macrolactamization reactions as the
key transformations.
O
5a or 5b,
O
O
EDCI, DMAP
OH
R
O
R
CH2Cl2, rt,
8 h, 60-78%
NHBoc
NHBoc
15a R=Ph
15b R=MeSCH2
16a R=Ph, n=5, 60%
16b R=Ph, n=3, 78%
16c R=MeSCH2, n=5, 67%
4. Experimental
4.1. General
OPNB
O
1H and 13C NMR spectra were recorded in CDCl3 solvent on 300,
500 or 75 MHz spectrometer at ambient temperature. The chemi-
cal shifts (d) are reported in ppm on scale downfield from TMS,
as the internal standard and signal patterns indicated as follows:
s, singlet; d, doublet; dd, doublet of doublet; td, triplet of doublet;
t, triplet; m, multiplet; br s, broad singlet. Coupling constants J are
in Hz. FTIR spectra were recorded as KBr thin films or neat. For low
(MS) and high (HRMS) resolution, m/z ratios are reported as values
in atomic mass units. All reagents and solvents were reagent grade
and used without further purification unless specified otherwise.
Technical grade ethyl acetate and petroleum ether used for column
chromatography were distilled prior to use. Column chromatogra-
phy was carried out using silica gel (60–120 mesh) packed in glass
columns. All reactions were performed under an atmosphere of
nitrogen in flame-dried or oven-dried glassware with magnetic
stirring.
n
O
TFA, CH2Cl2
oC-rt, 3 h
O
R
NH2TFA
0
3a R=Ph, n=5
3b R=Ph, n=3
3c R=MeSCH2, n=5
Scheme 4. Synthesis of depsi-dipeptide fragments 3a, 3b and 3c.
tetrapeptide 25 using lithium hydroxide in THF and water (3:1)
furnished tetrapeptide acid 4 in ꢁ70% yield which was used for
the next reaction without further purification.6 With all the
required intermediates in hand, we next carried out the synthesis
of the target molecules.
In order to prepare the linear depsipeptide of arenamides A, B
and C 2a/2b/2c, amines 3a/3b/3c were reacted with tetrapeptide
4 under standard coupling conditions using EDCI, HOBt and DIPEA
as coupling reagents, which resulted in 2a–2c in good yields. The
N-Cbz and p-nitrobenzyl groups were removed by catalytic hydro-
genation using 10% Pd–C as the catalyst in iso-propanol/THF (2.5:1)
for 24 h to afford the unprotected depsipeptides. Cyclization of the
depsipeptide was carried out using EDCI, HOBt in CH2Cl2 yielding
arenamides A–C 1a/1b/1c in good yields (Scheme 6). Analytical
data of the synthesized molecules were in accordance with the nat-
ural products. The specific rotation for arenamide A: observed:
4.1.1. (2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(ben-
zyloxy)-3-hydroxy-2-methylpentan-1-one 9
To a stirred solution of auxillary 87 (12.0 g, 45.7 mmol) in dry
CH2Cl2 (50 mL) cooled to ꢀ78 °C, was added 2 M TiCl4 in CH2Cl2
(16 mL, 30.12 mmol) at the same temperature under an N2 atmo-
sphere. The reaction mixture was stirred for 30 min. To this was
added DIPEA (5.2 mL, 30.12 mmol) and allowed to stir for 1 h at
the same temperature. Next, benzyl protected propanaldehyde 7
(5.0 g, 30.12 mmol) dissolved in CH2Cl2 (20 mL) was added to it
and the mixture was allowed to stir for 2 h at ꢀ78 °C. The reaction
was monitored by the TLC. After completion of the reaction, it was
quenched with 50% NH4Cl (10 mL) and extracted with CH2Cl2
(2 ꢃ 15 mL). The organic layer was washed with water, brine,
dried over anhydrous Na2SO4 and evaporated in vacuo. The crude
residue was chromatographed over silica gel (20% EtOAc/petro-
leum ether) to afford yellow coloured 9 (10.2 g, 85% yield, 95%
½
a 2D8
ꢂ
¼ ꢀ65:0 (c 0.07, CH3OH), reported: ½a D25
¼ ꢀ76:3 (c 0.08,
ꢂ
CH3OH);2 arenamide B: observed ½a 2D8
¼ ꢀ79 (c 0.08, CH3OH),
ꢂ
reported:2
½
a 25
ꢂ
¼ ꢀ96:3 (c 0.27, CH3OH) and arenamide C: ob-
served ½a 2D3
ꢂ
¼Dꢀ39:1 (c 0.30, CH3OH), reported: ½a 2D5
¼ ꢀ45 (c
ꢂ
0.09, CH3OH).2

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
351
O
O
NHBoc
EDCI, HOBt, DIPEA
CH2Cl2, 8h, 82%
NH2
HO
MeO
17
18
O
MeO
NHBoc
O
N
H
MeO
NH2TFA
O
N
H
TFA, CH2Cl2, 4h
O
19
20
O
O
EDCI, HOBt, DIPEA
CH2Cl2, 8h, 77%
NHCl
NHCbz
MeO
HO
22
21
O
LiOH,
THF:H2O (7:3),
4h
O
HO
NHCbz
MeO
NHCbz
N
N
H
H
O
O
O
24
23
O
O
H
N
H
N
EDCI, HOBt, DIPEA
CH2Cl2, 8h, 64%
MeO
N
H
NHCbz
24
20
O
25
O
O
H
H
LiOH, THF:H2O (7:3) 4h
70%
N
N
HO
N
H
NHCbz
O
O
4
Scheme 5. Synthesis of tetrapeptide 4.
R
O
O
O
PNBO
NH O
NH
3a
3b
3c
EDCI, HOBt, DIPEA
CH2Cl2, 0 oC-rt, 28 h
O
4
NH O
NH HN Cbz
O
n
2a R=Ph, n=5, 62% (over two steps from 16a)
2b R=Ph, n=3, 65% (over two steps from 16b)
2c R=MeSCH2, n=5, 67% (over two steps from 16c)
1. 10% Pd-C, H2
1a, 52% (over two steps)
1b, 61% (over two stps)
1c, 53% (over two steps)
iPr-OH:THF (2.5:1)
2. EDCI, HOBt, DIPEA,
CH2Cl2, 0 oC-rt, 48 h
Scheme 6. Syntheses of arenamides A, B and C.
de). ½a 2D0
ꢂ
¼ þ78:1 (c 0.44, CHCl3). 1H NMR (300 MHz, CDCl3): dH
4.1.2. (2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(ben-
zyloxy)-3-(tert-butyldimethylsilyloxy)-2-methylpentan-1-one
10
7.38–7.24 (m, 10H), 5.41–5.35 (m, 1H), 4.76–4.69 (m, 1H), 4.52
(s, 2H), 4.27 (d, J = 9.95 Hz, 1H), 3.73–3.59 (m, 2H), 3.35 (dd,
J = 7.24, 10.86 Hz, 1H), 3.22 (dd, J = 3.62, 12.67 Hz, 1H), 3.05–2.97
(m, 1H), 2.87 (d, J = 10.86 Hz, 1H), 1.92–1.81 (m, 1H), 1.78–1.70
(m, 1H), 1.53 (br s, 1H), 1.22 (d, J = 7.24 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dC = 201.3, 177.5, 138.0, 136.3, 129.3, 128.3,
127.65, 127.61, 127.1, 73.2, 69.9, 68.8, 68.3, 43.1, 36.9, 33.6,
To a stirred solution of compound 9 (5.0 g, 11.6 mmol) dissolved
in 20 mL of CH2Cl2 were added DIPEA (4.0 mL, 11.6 mmol) and TBS-
OTf (3.0 mL, 11.6 mmol) at 0 °C, the mixture was stirred at the same
temperature for 1 h. The reaction was monitored by TLC. After com-
pletion of the reaction, the mixture was diluted with water and the
aqueous layer was extracted in CH2Cl2 (2 ꢃ 20 mL). The organic
layer was washed with brine, dried over anhydrous Na2SO4 and con-
centrated in vacuo. The crude residue was purified by the column
31.7, 11.2. IR (neat) mmax
743 cmꢀ1; MS (ESI): m/z = 452.1 [M+H]+; HRMS (ESI): calcd for
23H27NO3S2Na: 452.1325; found: 452.1290 [M+Na]+.
: 3485, 2922, 2854, 1645, 1294,
C

352
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
chromatography (8% EtOAc/petroleum ether) to afford 10 (5.2 g,
82%) as a yellow coloured liquid, Rf = 0.3 (20% EtOAc in hexane).
(m, 2H), 1.02–0.85 (m, 15H), 0.08–0.02 (m, 6H). IR (neat) mmax
2956, 2930, 2857, 1459, 1253, 1095, 836 cmꢀ1
:
.
½
a 2D0
ꢂ
¼ þ19:5 (c 0.44, CHCl3). 1H NMR (300 MHz, CDCl3): dH 7.36–
7.21 (m, 10H), 5.34–5.26 (m, 1H), 4.75 (qn, J = 7.24, 14.48 Hz, 1H),
4.46 (qt, J = 11.76 Hz, 26.24 Hz, 3H), 4.25 (qt, J = 5.43, 10.86 Hz,
1H), 3.62–3.50 (m, 3H), 3.27 (dd, J = 7.24, 11.76 Hz, 1H), 3.15 (dd,
J = 3.62, 13.57 Hz, 1H), 2.87–2.77 (m, 2H), 2.01–1.84 (m, 3H), 1.21
(d, J = 7.24 Hz, 3H), 0.89 (s, 9H), 0.06 (d, J = 19.7 Hz, 6H). 13C NMR
(75 MHz, CDCl3): dC 200.9, 176.8, 138.4, 136.6, 129.4, 128.8, 128.2,
127.6, 127.4, 127.1, 73.0, 72.0, 69.3, 66.1, 44.4, 36.5, 34.84, 32.0,
4.1.6. (3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-methyloctan-1-ol
13a
Compound 12a (1.0 g, 2.5 mmol) was dissolved in ethanol
(8 mL) and to it was added 10% (w/w) Pd–C (26 mg, 0.25 mmol).
Hydrogenation was carried out at room temperature for 12 h. After
completion of the reaction (by TLC), the mixture was diluted with
chloroform (10 mL) and filtered through Celite. The filtrate was
concentrated under reduced pressure and the crude was chro-
matographed over silica gel (25% EtOAc/petroleum ether) to pro-
25.7, 17.9, 13.5, ꢀ4.4, ꢀ4.6. IR (neat)
mmax: 2930, 2855, 1694,
1361, 1256 cmꢀ1. MS (ESI) m/z: 540.8, [MꢀH]+. HRMS (ESI): calcd
for C29H41NO3SiNa: 566.2189; found: 566.2153.
vide syrupy primary alcohol 13a (0.7 g, 91%). ½a D28
¼ ꢀ17:6 (c
ꢂ
0.80, CHCl3). 1H NMR (300 MHz, CDCl3): dH 3.77–3.63 (m, 3H),
2.15 (br s, H), 1.66 (qt, J = 6.2 Hz, 2H), 1.54 (m, 1H), 1.42–0.94
(m, 10H), 0.91–0.85 (m, 12H), 0.82 (d, J = 7.1 Hz, 3H), 0.07 (s, 3H),
0.05 (s, 3H). 13C NMR (75 MHz, CDCl3): dC 75.2, 60.8, 38.5, 34.3,
1.8, 31.1, 29.6, 27.6, 25.8, 22.6, 18.0, 15.5, 14.0, ꢀ4.3, ꢀ4.5. IR
4.1.3. (2R,3S)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-2-
methyl pentanal 6
To a stirred solution of amide 10 (3.0 g, 5.52 mmol) in dry
CH2Cl2 (50 mL), cooled to ꢀ78 °C, was added 25% DiBAl-H in tolu-
ene (1.56 g, 11.04 mmol) at same temperature under an N2 atmo-
sphere. The mixture was stirred for 1 h. The reaction was
monitored by TLC and upon completion, it was quenched with
MeOH (1.0 mL), and diluted with CH2Cl2 (20 mL). Saturated sodium
potassium tartarate (10 mL) was added to it and the mixture was
stirred for 4 h at rt. The organic layer was separated, dried over
Na2SO4 and the solvent was evaporated under reduced pressure.
The crude residue was purified by column chromatography (15%
EtOAc/petroleum ether) to afford 6 (2.15 g, 78%) as a colourless
(KBr)
[M+H]+.
m
max: 3458, 2956, 2928, 2857 cmꢀ1. MS (ESI) m/z: 303.1
4.1.7. (3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-methyloctan-1-ol
13b
Compound 12b (1.0 g, 2.7 mmol) upon hydrogenation and
work-up gave 13b as a syrup (0.68 g, 90%). ½a D28
¼ ꢀ23:2 (c 0.62,
ꢂ
CHCl3). 1H NMR (300 MHz, CDCl3): dH 3.77–3.69 (m, 3H), 2.17 (s,
2H), 2.06–1.98 (br s, 1H), 1.68 (qt, J = 6.23, 12.46 Hz, 1H), 1.36–
1.22 (m, 5H), 0.93–0.87 (m, 12H), 0.84 (d, J = 6.79 Hz, 3H), 0.11–
0.05 (m, 6H). 13C NMR (75 MHz, CDCl3): dC 75.1, 60.7, 38.4, 34.3,
liquid. ½a 2D8
ꢂ
¼ ꢀ38:9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): dH
9.71 (s, 1H), 7.31–7.16 (m, 5H), 4.42 (dd, J = 12.0, 20.3 Hz, 2H),
4.31–4.22 (m, 1H), 3.52–3.37 (m, 2H), 2.48–2.34 (m, 1H), 1.85–
1.63 (m, 2H), 0.98 (d, J = 6.79 Hz, 3H), 0.79 (s, 9H), 0.01 (d,
J = 6.7 Hz, 6H). 13C NMR (75 MHz, CDCl3): dC 205.0, 138.2, 128.3,
127.6, 72.9, 69.2, 66.5, 51.5, 34.5, 25.7, 17.9, 7.85, ꢀ4.4, ꢀ4.6. IR
30.7, 29.8, 25.8, 22.9, 15.4, 14.0, ꢀ4.6, ꢀ4.3. IR (neat)
mmax: 3458,
2956, 2928, 2857, 1250, 1173 cmꢀ1. MS (ESI) m/z: 275 [M+H]+.
4.1.8. (3S,4S)-4-Nitrobenzyl 3-(tert-butyldimethylsilyloxy)-4-
methyl decanoate 14a
(KBr)
m
max: 2954, 2931, 1726, 1255, 1100, 1033, 873 cmꢀ1. MS
(ESI) m/z: 375 [M+K]+.
To a stirred solution of alcohol 12a (0.8 g, 2.6 mmol) in CH3CN
and H2O mixture (1:1, 20 mL), were added BAIB (1.7 g, 5.2 mmol)
and TEMPO (80 mg, 0.52 mmol) at room temperature. The reaction
was stirred at the same temperature for 3 h. The progress of the
reaction was monitored by the TLC. After completion of the reac-
tion, it was quenched with saturated sodium thiosulfate solution
(15 mL) and extracted with EtOAc (2 ꢃ 20 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and removed un-
der reduced pressure to give acid as a pale yellow liquid. To a
solution of crude acid (0.82 g, 2.60 mmol) dissolved in dry CH2Cl2
(15 mL) were added p-nitrobenzyl alcohol (0.4 g, 2.60 mmol), EDCI
(1.2 g, 6.5 mmol) and DMAP (150 mg, 1.3 mmol), at room temper-
ature, and stirred for 4 h. After completion of the reaction, it was
diluted with CH2Cl2 (10 mL) and quenched with water. The organic
layer was separated, washed with brine (10 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuo and the
residue was purified by column chromatography over silica gel
(15% EtOAc/petroleum ether) to provide fully protected ester 14a
4.1.4. ((3S,4S)-1-(Benzyloxy)-4-methyldec-5-en-3-yloxy)(tert-
butyl dimethylsilane) 12a
To pentyltriphenyl bromide Wittig salt 11a (1.82 g, 4.40 mmol)
was added dry THF (20 mL) at 0 °C under nitrogen atmosphere. To
this was added n-BuLi (2.0 mL, 4.40 mmol, 2.5 M) slowly at the
same temperature and the suspension was stirred for 15 min. Alde-
hyde 6 (1.0 g, 2.95 mmol) was then added at ꢀ20 °C and stirred for
1 h. The reaction was slowly quenched with saturated NH4Cl solu-
tion at 0 °C and extracted with EtOAc (3 ꢃ 20 mL). The combined
organic layers were washed with brine, dried over Na2SO4, concen-
trated and residue was purified by column chromatography over
silica (8% EtOAc/petroleum ether) to afford 12a (0.82 g, 71%) as a
pale yellow syrup. ½a D28
ꢂ
¼ þ9:3 (c 0.5, CHCl3). 1H NMR (300 MHz,
CDCl3): dH 7.31–7.14 (m, 5H), 5.37–5.12 (m, 2H), 4.42 (dd,
J = 12.08, 14.35 Hz, 1H), 3.65–3.55 (m, 1H), 3.52–3.39 (m, 2H),
2.55–2.41 (m, 1H), 2.03–1.90 (m, 2H), 1.83–1.62 (m, 2H), 1.36–
1.21 (m, 5H), 0.94–0.82 (m, 15H), 0.01 (d, J = 6.79 Hz, 6H). 13C
NMR (75 MHz, CDCl3): dC 138.6, 132.7, 129.4, 128.2, 127.5, 127.4,
73.5, 72.8, 66.9, 42.2, 37.3, 34.7, 31.9, 27.2, 25.9, 22.4, 16.8, 13.9,
(870 mg, 78%). ½a D28
ꢂ
¼ ꢀ20:8 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): dH 8.22 (d, J = 7.54 Hz, 2H), 7.51 (d, J = 7.5 Hz, 2H), 5.19
(s, 2H), 4.14–1.07 (m, 1H), 2.48 (d, J = 2.4 Hz, 1H), 2.47–2.45 (m,
1H), 1.56–1.07 (m, 2H), 1.08–0.95 (m, 1H), 0.92–0.78 (m, 12H),
0.04 (s, 3H), ꢀ0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): dC 171.9,
147.6, 143.1, 128.4, 123.7, 72.8, 64.6, 39.0, 38.8, 31.8, 31.6, 29.5,
ꢀ4.39, ꢀ4.6. IR (neat)
mmax: 2956, 2930, 2857, 1459, 1253, 1095,
836 cmꢀ1. MS (ESI) m/z: 413.3 [M+Na]+. HRMS (ESI) [M+Na]+: calcd
for C24H43O2Si: 391.3032; found: 391.3037.
27.5, 25.7, 22.6, 18.0, 14.7, 14.0, ꢀ4.5, ꢀ4.7. IR (KBr)
mmax: 2925,
4.1.5. ((3S,4S)-1-(Benzyloxy)-4-methyloct-5-en-3-yloxy)(tert-
butyl dimethylsilane) 12b
2855, 1743, 1526, 1463 cmꢀ1. MS (ESI) m/z: 452 [M+Na]+. HRMS
(ESI): calcd for C24H42NO5Si: 452.2827, found: 452.2833 [M+Na]+.
Propyltriphenyl bromide Wittig salt 11b (1.7 g, 4.40 mmol) and
aldehyde 6 (1.0 g, 2.95 mmol) afforded 12b (0.70 g, 70%). 1H NMR
(300 MHz, CDCl3): dH 7.37–7.26 (m, 5H), 5.32–5.12 (m, 2H), 4.42
(qt, J = 12.01, 20.02 Hz, 2H), 3.60 (qt, J = 5.0, 11.0 Hz, 2H), 3.50–
3.40 (m, 1H), 2.53–2.44 (m, 1H), 2.03–1.92 (m, 2H), 1.82–1.66
4.1.9. (3S,4S)-4-Nitrobenzyl 3-(tert-butyldimethylsilyloxy)-4-
methyl octanoate 14b
Alcohol 13b (0.8 g, 2.91 mmol) on TEMPO/BAIB oxidation and
reaction with p-nitrobenzyl alcohol (0.45 g, 2.90 mmol), EDCI

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
353
(1.4 g, 7.29 mmol) and DMAP (0.20 g, 1.45 mmol), at room temper-
ature gave, after workup, 14b (0.93 g, 76%) as a light yellow liquid.
1460 cmꢀ1. MS (ESI) m/z: 607 [M+Na]+. HRMS (ESI): calcd for
C28H44N2O8Na: 607.2990; found 607.3005 [M+Na]+.
½
a 2D3
ꢂ
¼ þ7:5 (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): dH 8.25–8.19
(m, 2H), 7.52 (d, J = 9.0 Hz, 2H), 5.19 (s, 2H), 4.18–4.04 (m, 1H), 2.49
(d, J = 3.0 Hz, 2H), 2.47 (s, 1H), 1.60–1.42 (m, 3H), 1.37–1.12 (m,
4H), 0.93–0.79 (m, 15H), 0.04 (s, 3H), 0.02 (t, J = 3.02 Hz, 3H). 13C
NMR (75 MHz, CDCl3): dC 171.8, 146, 143.1, 128.4, 123.7, 72.8,
64.6, 38.9, 38.8, 31.3, 29.8, 25.7, 22.8, 17.9, 14.6, 14.05, ꢀ4.6,
4.1.13. (3S,4S)-4-Nitrobenzyl 3-((R)-2-(tert-butoxycarbonyl-
amino)-3-phenylpropanoyloxy)-4-methyloctanoate 16b
A reaction of 5b (500 mg, 1.61 mmol) with N-Boc L-phenylala-
nine 15a (428 mg, 1.61 mmol) gave ester 16b (700 mg, 78%) as a
light yellow liquid.
½
a 2D8
ꢂ
¼ þ7:6 (c 0.75, CHCl3). 1H NMR
ꢀ4.7. IR (neat) mmax
:
2957, 2931, 2858, 1743, 1526, 1347,
(300 MHz, CDCl3): dH 8.27–8.16 (m, 2H), 7.56–7.46 (m, 2H), 7.35–
7.21 (m, 3H), 7.19–7.10 (m, 2H), 5.33–5.22 (m, 1H), 5.18 (d,
J = 3.7 Hz, 1H), 4.59–4.46 (m, 1H), 3.17–2.78 (m, 2H), 2.76–2.54
(m, 2H), 1.77–1.53 (m, 6H), 1.44–1.33 (m, 2H), 1.32–1.17 (m, 5H),
1.15–0.98 (m, 2H), 0.88 (t, J = 5.28 Hz, 6H). 13C NMR (75 MHz,
CDCl3): dC 171.4, 170.1, 154.9, 147.6, 142.7, 136.0, 135.9, 130.0,
129.2, 128.7 128.5, 128.4, 126.9, 126.8, 123.7, 79.7, 74.5, 65.0,
836 cmꢀ1. MS (ESI) m/z: 424 [M+H]+. HRMS (ESI) [M+H]+: calcd
for C22H38NO5Si: 424.2519; found: 424.2529.
4.1.10. (3S,4S)-4-Nitrobenzyl 3-hydroxy-4-methyldecanoate 5a
To a stirred solution of TBS protected alcohol 14a (500 mg,
1.10 mmol) in dry THF (20 mL), was added HF-Py (0.4 mL,
2.21 mmol) at 0 °C in a closed plastic vessel. The reaction was stir-
red at the same temperature for 18 h. The progress of the reaction
was monitored by TLC. The reaction was diluted with THF (10 mL),
slowly quenched with saturated NaHCO3, at 0 °C and extracted
with EtOAc. The organic layer was separated, washed with brine
(10 mL) and dried over anhydrous Na2SO4. It was evaporated in va-
cuo and the residue was purified by column chromatography, (25%
EtOAc/petroleum ether) to afford secondary alcohol 11 (300 mg,
54.2, 38.0, 36.5, 36.3, 32.0, 29.2, 28.1, 22.6, 14.2, 13.9. IR (neat) mmax
:
3390, 2961, 2930, 1739, 1605, 1456, 1165 cmꢀ1. MS (ESI) [M+Na]+
m/z: 579. HRMS (EI) [M+Na]+: calcd for C30H40N2O8Na: 579.2682,
found: 579.2706.
4.1.14. (3S,4S)-4-Nitrobenzyl 3-((R)-2-(tert-butoxycarbonyl-
amino)-4-(methylthio) butanoyloxy)-4-methyldecanoate 16c
Compound 5a and N-Boc
L-metheonine 15b (368 mg,
80%) as a light yellow liquid. ½a D30
ꢂ
¼ ꢀ19:5 (c 1, CHCl3). 1H NMR
1.48 mmol) gave 16c (657 mg, 67%) as a light yellow liquid.
(300 MHz, CDCl3): dH 8.22 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz,
2H), 5.25 (s, 2H), 3.99 (m, 1H), 2.58–2.49 (m, 3H), 1.59–1.19 (m,
10H), 1.18–1.07 (m, 1H), 0.91 (d, J = 6.7 Hz, 3H), 0.88 (t,
J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): dC 172.8, 147.6, 142.8,
128.3, 123.7, 71.2, 64.8, 38.8, 38.0, 32.6, 31.7, 29.4, 27.1, 22.6,
½
a 2D8
ꢂ
¼ ꢀ13:4 (c 0.75, CHCl3). 1H NMR (300 MHz, CDCl3): dH 8.26–
8.19 (m, 2H), 7.55–7.49 (m, 2H), 5.32–5.20 (m, 2H), 5.17 (s, 1H),
4.99 (m, 1H), 4.35–4.24 (m, 1H), 3.52 (d, J = 4.53 Hz, 1H), 2.70–
2.42 (m, 4H), 2.07 (s, 3H), 1.87–1.64 (m, 2H), 1.47–1.20 (m, 19H),
1.19–1.02 (m, 1H), 0.96–0.83 (m, 6H). 13C NMR (75 MHz, CDCl3):
dC 171.5, 169.9, 155.1, 147.6, 142.7, 128.5, 123.6, 79.7, 74.4, 65.0,
52.8, 36.5, 36.4, 32.5, 32.1, 31.6, 29.8, 29.2, 28.1, 26.9, 22.4, 15.3,
14.1, 14.0. IR (KBr) mmax
: 3424, 2923, 2852, 1638, 1523,
1346 cmꢀ1. MS (ESI) m/z: 360 [M+Na]+. HRMS (ESI) [M+Na]+: calcd
for C18H27NO5Na: 360.1781; found: 360.1788.
14.2, 13.9. IR (neat) mmax: 3736, 2929, 1744, 1532, 1165,
856 cmꢀ1. MS (ESI) m/z: 591 [M+Na]+. HRMS (ESI) [M+Na]+: calcd
4.1.11. (3S,4S)-4-Nitrobenzyl 3-hydroxy-4-methyloctanoate 5b
Desilylation of 14b (500 mg, 1.18 mmol) gave 5b (0.3 g, 82%) as
for C28H44N2O8Na: 591.2716; found: 591.2715.
a
light yellow liquid.
½
a 2D8
ꢂ
¼ þ12:0 (c 0.3, CHCl3). 1H NMR
4.1.15. ((S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-4-me-
thyl pentanamido)propanoate 19
(300 MHz, CDCl3): dH 8.23 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.8 Hz,
2H), 5.25 (s, 2H), 4.04–3.95 (m, 1H), 2.59–2.53 (m, 2H), 2.66–
2.42 (m, 3H), 1.56–1.06 (m, 6H), 0.97–0.83 (m, 6H). 13C NMR
(75 MHz, CDCl3): dC 172.7, 147.6, 142.9, 128.3, 123.7, 71.28, 64.8,
N-Boc-L-Leu-OH 18 (1.0 g, 4.30 mmol) was dissolved in dry
CH2Cl2 (15 mL) and to it was added HOBt (1.68 g, 12.9 mmol) at
0 °C. The solution was stirred for 10 min, then EDCI (2.46 g,
12.9 mmol), followed by DIPEA (2.0 mL, 12.9 mmol), and the HCl
salt of alanine methyl ester 17 (0.6 g, 4.30 mmol), which was dis-
solved in dry CH2Cl2 (12 mL), were added. The reaction mixture
was stirred for 24 h and monitored by TLC. After completion of
the reaction, it was diluted with CH2Cl2 (10 mL) and quenched
with H2O (10 mL). The separated organic layer was washed with
1 N HCl (10 mL), aqueous 5% NaHCO3 (10 mL) and brine and dried
over anhydrous Na2SO4. The solvent was reduced in vacuo and the
crude was chromatographed over silica gel (50% EtOAc/petroleum
ether) to give 19 as a white solid (1.2 g, 82%). Mp: 117–118 °C,
38.8, 38.0, 32.3, 22.8, 14.1, 14.0. IR (neat) mmax: 3505, 2958, 2929,
1735, 1523, 1347, 1163, 739 cmꢀ1. MS (ESI) m/z: 332 [M+Na]+.
4.1.12. (3S,4S)-4-Nitrobenzyl 3-((R)-2-(tert-butoxycarbonyl-
amino)-3-phenylpropanoyloxy)-4-methyldecanoate 16a
To a stirred solution of alcohol 5a (500 mg, 1.48 mmol) in dry
CH2Cl2 (10 mL) were added N-Boc L-phenylalanine 15a (393 mg,
1.48 mmol), EDCI (700 mg, 3.7 mmol) and DMAP (90 mg,
0.74 mmol) at room temperature. The mixture was stirred for 8 h
at the same temperature. After completion of the reaction (by
TLC), the mixture was diluted with CH2Cl2 (10 mL) and quenched
with water (10 mL). The organic layer was separated, washed with
brine and dried over anhydrous Na2SO4. The solvent was evapo-
rated in vacuo and the residue was purified by column chromatog-
raphy, 30% EtOAc/petroleum ether as eluent to afford ester 16a
½
a 2D8
ꢂ
¼ ꢀ32:4 (c 1.0, CHCl3), 1H NMR (300 MHz, CDCl3): dH 6.71
(d, J = 5.4 Hz, 1H), 4.95 (d, J = 8.1 Hz, 1H), 4.54 (qt, J = 7.3 Hz, 1H),
4.22–4.02 (m, 1H), 3.72 (s, 3H), 1.75–1.56 (m, 2H), 1.55–1.45 (m,
2H), 1.42 (s, 9H), 0.93 (d, J = 3.2 Hz, 3H), 0.91(d, J = 3.2 Hz, 3H).
13C NMR (75 MHz, CDCl3): dC 173.1, 172.1, 155.6, 80.0, 52.9, 52.3,
(0.62 g, 60%) as a light yellow liquid. ½a D28
ꢂ
¼ ꢀ6:9 (c 0.5, CHCl3).
47.9, 41.2, 28.2, 24.6, 22.8, 21.9, 18.2. IR (KBr) mmax: 3315, 3073,
1H NMR (300 MHz, CDCl3): dH 8.22 (d, J = 8.6 Hz, 2H), 7.51 (d,
J = 8.6 Hz, 2H), 7.32–7.18 (m, 3H), 7.17–7.10 (m, 2H), 5.27 (m,
1H), 5.18 (s, 2H), 4.88 (d, J = 8.1 Hz, 1H), 4.52 (m, 1H), 3.13 (dd,
J = 13.7, 6.4 Hz, 1H), 2.94 (dd, J = 13.7, 6.4 Hz, 1H), 2.75–2.53 (m,
2H), 1.76–1.62 (m, 1H), 1.37 (s, 9H), 1.33–1.16 (m, 9H), 1.11–
0.99 (m, 1H), 0.92–0.79 (m, 6H). 13C NMR (75 MHz, CDCl3): dC
171.5, 170.1, 154.9, 142.8, 135.9, 129.2, 128.5, 127.0, 123.8, 79.8,
74.7, 65.1, 54.4, 38.2, 36.6, 36.4, 32.4, 31.7, 29.3, 28.2, 27.1, 22.5,
2963, 1754, 1685, 1650, 1551 cmꢀ1. MS (ESI) m/z: 317, HRMS
(ESI) [M+Na]+; calcd for C15H29N2O5: 317.3075, found: 317.2071.
4.1.16. (S)-Methyl 2-(2-(benzyloxycarbonylamino)acetamido)-
3-methyl butanoate 23
The N-Cbz protected glycine 22 (1.0 g, 4.7 mmol) was dissolved
in CH2Cl2 (15 mL), after which HOBt (1.8 g, 14.1 mol) was added at
0 °C and stirred for 10 min. Next, EDCI (2.6 g, 14.1 m.mol), followed
14.3, 14.0. IR (neat) mmax
:
3438, 2923, 2852, 1743, 1523,
by DIPEA (2.3 mL, 14.1 mmol), and L-valine methyl ester hydro-

354
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
chloride 21 (0.8 g, 4.7 mmol) dissolved in dry CH2Cl2 (16 mL) were
added to it. The mixture was stirred for 18 h and monitored by TLC.
After completion of the reaction, work-up gave compound 23 as a
crude amine 3a, which was used for the next coupling reaction
without further purification.
To a stirred solution of 26 (175 mg, 0.34 mmol) in a mixture of
THF/H2O (7:1, 20 mL) was added LiOH (0.24 g, 1.02 mmol) at 0 °C.
The reaction was stirred at the same temperature for 3 h. After
completion of the reaction (monitored by the TLC), it was
quenched with saturated KHSO4 solution, the pH was adjusted to
2 and extracted with EtOAc (2 ꢃ 20 mL). The combined organic lay-
ers were dried over anhydrous Na2SO4 and removed under reduced
pressure to afford acid 4, which was used for the next coupling
reaction without any further purification.
white solid (1.18 g, 77%). Mp: 73–74 °C, ½a D30
¼ þ16:1 (c 1, CHCl3),
ꢂ
1H NMR (300 MHz, CDCl3): dH 7.50–7.27 (m, 5H), 6.77(d, J = 8.8 Hz,
1H), 5.69 (t, J = 5.6 Hz, 1H), 5.12 (s, 2H), 4.55 (dd, J = 8.8, 5.2 Hz,
1H), 3.92 (d, J = 5.6 Hz, 2H), 3.71 (s, 3H), 2.24–2.07 (m, 1H),
0.91(d, J = 3.2 Hz, 3H), 0.87 (d, J = 3.2 Hz, 3H), 13C NMR (75 MHz,
CDCl3): dC 172.2, 169.0, 156.5, 136.0, 128.4, 128.1, 127.9, 67.1,
57.0, 52.1, 44.4, 31.1, 18.8, 17.6.IR (KBr) mmax: 3291, 3159, 3070,
2955, 1734, 1657, 1548 cmꢀ1. MS (ESI): m/z [M+H]+: 323. HRMS
(ESI) [M+H]+: calcd for C16H23N2O5: 323.1601; found: 323.1601.
Tetrapeptide 4 (crude) was dissolved in dry CH2Cl2 (20 mL),
after which HOBt (134 mg, 1.02 mmol) was added at 0 °C and stir-
red for 10 min. Next, EDCI (194 mg, 1.02 mmol), followed by DIPEA
(0.2 mL, 1.02 mmol) were added and mixture was stirred for
20 min. Amine 3a (crude), which was dissolved in dry CH2Cl2
(2mL) was added to it and stirred for 28 h at room temperature.
The reaction was monitored by TLC; after completion, the reaction
was diluted with CH2Cl2 (10 mL) and H2O (10 mL). The organic lay-
ers were separated and washed with 1 M HCl, NaHCO3, brine and
dried over anhydrous Na2SO4. The solvent was reduced in vacuo
and crude was chromatographed over silica gel 2% MeOH/CHCl3
4.1.17. (8S,11S,14S)-Methyl 11-isobutyl-8-isopropyl-14-methyl-
3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-
15-oate 25
The N-Boc protected dipeptide ester 19 (1.0 g, 3.10 mmol) was
dissolved in dry CH2Cl2 (1.5 mL) and to it TFA (1.2 mL 9.3 mmol)
was added at 0 °C. The reaction was stirred at room temperature
for 2 h and monitored by TLC. After completion of the reaction,
CH2Cl2 and TFA were evaporated in vacuo to afford a pale yellow
crude amine 20. This crude compound was used for the next reac-
tion without any further purification.
as eluent to give 2a as a syrup (240 mg, 62%). ½a D28
¼ ꢀ28:2 (c
ꢂ
To
a
stirred solution of N-Cbz Gly-Val-OMe 23 (1.0 g,
0.7, CHCl3). 1H NMR (300 MHz, CDCl3): dH 8.19 (br s, 1H), 8.14 (d,
J = 8.7 Hz, 2H), 7.97 (br s, 1H), 7.49 (br s, 1H), 7.44 (d, J = 8.7 Hz,
2H), 7.37–7.04 (m, 10H), 6.35 (br s, 1H), 5.28–5.17 (m, 1H), 5.17–
5.02 (m, 6H), 5.01–4.72 (m, 2H), 4.24–3.81 (m, 2H), 3.19–2.83
(m, 2H), 2.74–2.43 (m, 2H), 2.14–1.88 (m, 1H), 1.84–1.50 (m,
6H), 1.29 (d, J = 5.8 Hz, 3H), 1.26–1.06 (m, 8H), 0.95–0.75 (m,
18H). 13C NMR (75 MHz, CDCl3): dC 172.3, 171.7, 171.1, 170.7,
170.0, 168.8, 156.6, 147.6, 142.8, 136.7, 135.9, 129.3, 129.1,
128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.7, 126.6, 123.7, 74.8,
66.6, 64.9, 57.9, 53.3, 51.2, 48.2, 44.4, 42.4, 37.9, 36.2, 36.1, 32.4,
3.10 mmol) in a mixture of THF: H2O (7:1, 20 mL,) was added LiOH
(0.22 g, 9.30 mmol) at 0 °C. The reaction was stirred at the same
temperature for 3 h. After completion of the reaction (monitored
by the TLC), it was quenched with a saturated KHSO4 solution,
the pH was adjusted to 2 and extracted with EtOAc (2 ꢃ 20 mL).
The combined organic layers were dried over anhydrous Na2SO4
and removed under reduced pressure to afford acid 24, which
was used for the next coupling reaction without any further
purification.
Dipeptide acid 24 (1.0 g, 3.10 mmol) was dissolved in dry
CH2Cl2 (10 mL), after which HOBt (1.21 g, 9.30 mmol) was added
at 0 °C, and stirred for 10 min. Next EDCI (1.77 g, 9.30 mmol), fol-
lowed by DIPEA (1.50 mL, 0.73 mmol), were added and stirred for
20 min. Amine 20 (crude), dissolved in dry CH2Cl2 (10 mL), was
then added and the mixture was stirred for 24 h at room temper-
ature. The reaction was monitored by TLC. After completion, the
reaction was diluted with (10 mL) CH2Cl2, H2O. The organic layer
was separated and washed with 1 M HCl, NaHCO3, brine and dried
over anhydrous Na2SO4. The solvent was reduced in vacuo and the
crude was chromatographed over silica gel (80% EtOAc/petroleum
ether) to give 26 as a white solid (1.0 g, 64%). Mp: 150–152 °C,
31.8, 29.3, 27.1, 26.9, 24.8, 22.7, 22.6, 18.9, 18.7, 14.0. IR (KBr) mmax:
3278, 3079, 2960, 2929, 1743, 1634, 1525 cmꢀ1. MS (ESI) m/z: 981
[M+H]+.
4.1.19. (8S,11S,14S,17S,20S)-17-Benzyl-20-((S)-hexan-2-yl)-11-
isobutyl-8-isopropyl-14-methyl-3,6,9,12,15,18-hexaoxo-1-phe-
nyl-2,19-dioxa-4,7,10,13,16-pentaazadocosan-22-oic 4-nitro-
benzoic anhydride 2b
Compound N-Boc-Phe-HMOA 16b (200 mg, 0.35 mmol) affor-
ded a pale yellow crude amine 3b, which was used for the next
reaction.
Tetrapeptide 26 (182 mg, 0.35 mmol) and amine 3b afforded 2b
½
a 3D0
ꢂ
¼ ꢀ55:6 (c 1, CHCl3), 1H NMR (300 MHz, CDCl3): dH 8.26 (d,
as a white solid (224 mg, 65% yield). Mp: 126–127 °C. ½a D28
¼ ꢀ4:5
ꢂ
J = 8.8 Hz, 1H), 8.14 (d, J = 7.3 Hz, 1H), 8.10 (d, J =7.7 Hz, 1H),
7.37–7.22 (m, 5H), 6.38 (d, J = 5.0 Hz, 1H), 5.08 (m, 2H), 4.81–
4.63 (m, 2H), 4.56 (qn, J = 14.6, 7.3 Hz, 1H), 4.13 (br s, 2H), 3.64
(s, 3H), 1.86 (m, 1H), 1.77–1.58 (m, 2H), 1.58–1.45 (m, 1H), 1.30
(d, J = 7.3 Hz, 3H), 0.94–0.80 (m, 12H). 13C NMR (75 MHz, CDCl3):
dC 173.1, 171.9, 171.3, 168.8, 156.4, 136.4, 128.3, 127.9, 127.8,
66.6, 57.9, 52.1, 47.8, 44.1, 44.4, 32.1, 31.5, 24.6, 22.5, 18.9, 18.6,
(c 1, CHCl3). 1H NMR (300 MHz, CDCl3): dH 8.34–8.11 (m, 2H), 7.47
(d, J = 8.30 Hz, 2H), 7.36–7.05 (m, 10H), 6.19–6.03 (m, 1H), 5.28–
5.17 (m, 2H), 5.12 (d, J = 6.79 Hz, 4H), 4.92–4.52 (m, 2H), 4.02–
3.82 (m, 2H), 3.24 (qt, J = 7.55, 15.1 Hz, 1H), 3.14–2.77 (m, 2H),
2.73–2.47 (m, 2H), 2.14–1.93 (m, 2H), 1.77–1.51(m, 9H), 1.37–
1.09 (m, 11H), 0.97–0.76 (m, 11H). 13C NMR (75 MHz, CDCl3): dC
172.2, 172.1, 171.7, 170.9, 170.6, 170.0, 168.9, 147.6, 142.7,
136.7, 136.5, 136.1, 135.9, 129.3, 129.2, 128.5, 128.3, 127.8,
127.6, 123.7, 74.7, 74.6, 66.8, 66.6, 64.9, 37.9, 37.8, 37.7, 36.1,
17.5.IR (KBr) mmax
: 3283, 3075, 2960, 1741, 1639, 1545,
1453 cmꢀ1
.
MS (ESI) m/z: 507 (100) [M+Na]+. HRMS (ESI)
[M+Na]+: calcd for C25H39N4O7 = 507.2813; found: 507.2821.
35.9, 32.0, 29.6, 29.1, 24.8, 22.8, 22.6, 19.1, 18.9. IR (KBr) mmax:
3279, 3077, 2929, 1740, 1632, 1526, 1223, 1164, 745 cmꢀ1. MS
4.1.18. (8S,11S,14S,17S,20S)-17-Benzyl-11-isobutyl-8-isopropyl-
14-methyl-20-((S)-octan-2-yl)-3,6,9,12,15,18-hexaoxo-1-phenyl-
2,19-dioxa-4,7,10,13,16-pentaazadocosan-22-oic 4-nitrobenzoic
anhydride 2a
At first, N-Boc-Phe-HMDA 16a (200 mg, 0.34 mmol) was dis-
solved in dry CH2Cl2 (1 mL), after which TFA (0.15 mL 1.02 mmol)
was added to it at 0 °C and stirred at room temperature for 2 h. The
reaction was monitored by TLC. After completion of the reaction,
CH2Cl2 and TFA were evaporated in vacuo, to afford a pale yellow
(ESI) m/z: 931 [M+H]+. HRMS (ESI) [M+H]+: calcd for
C49H66N6O12: 931.4811; found: 931.4751.
4.1.20. (8S,11S,14S,17S,20S)-11-Isobutyl-8-isopropyl-14-methyl-
17-(2-(methylthio)ethyl)-20-((S)-octan-2-yl)-3,6,9,12,15,18-
hexaoxo-1-phenyl-2,19-dioxa-4,7,10,13,16-pentaazadocosan-
22-oic 4-nitrobenzoic anhydride 2c
Compound N-Boc-Meth-HMDA 16c (250 mg, 0.44 mmol) gave
the TFA salt of amine 3c.

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 25 (2014) 348–355
355
Tetrapeptide acid 26 (222 mg, 0.44 mmol) and amine 3c
(0.44 mmol), upon coupling, gave 2c as a white solid (298 mg,
(d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): dC 172.3, 171.7,
171.1, 170.0, 168.8, 156.6, 147.6, 142.8, 136.7, 135.9, 129.3,
129.1, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.7, 126.6,
123.7, 74.8, 66.6, 64.9, 57.9, 53.3, 51.2, 48.2, 44.4, 42.4, 37.9,
36.2, 36.1, 32.4, 31.8, 29.3, 27.1, 26.9, 24.8, 22.7, 22.6, 18.9, 18.7,
67% yield). Mp: 225–227 °C, ½a D28
ꢂ
¼ ꢀ16:9 (c 2, CHCl3). 1H NMR
(400 MHz, CDCl3): dH 8.79–8.40 (m, 2H), 8.22–8.14 (m, 2H), 7.49–
7.42 (m, 2H), 7.37–7.22 (m, 6H), 6.62–6.31 (m, 1H), 5.32–5.21
(m, 1H), 5.20–4.9 (m, 5H), 4.95–4.56 (m, 2H), 4.33–4.03 (m, 2H),
4.00–3.73 (m, 2H), 2.74–2.62 (m, 1H), 2.62–2.52 (m, 1H), 2.51–
2.37 (m, 2H), 2.18–1.84 (m, 7H), 1.78–1.47 (m, 4H), 1.39–1.12
(m, 13H), 1.11–1.01 (m, 1H), 0.97–0.74 (m, 17H). 13C NMR
(75 MHz, CDCl3): dC 172.7, 172.0, 171.3, 170.7, 169.1, 156.6,
147.6, 142.9, 136.7, 129.5, 128.5, 128.4, 127.9, 127.7, 123.7, 74.6,
66.6, 65.0, 60.5, 56.2, 52.1, 51.7, 44.4, 36.5, 36.3, 32.6, 32.0, 31.7,
29.8, 29.4, 28.2, 27.1, 25.0, 24.8, 22.9, 22.7, 19.2, 15.3, 14.3, 14.1.
14.0. IR (neat) mmax: 3327, 2957, 1669, 1367, 1249, 1167, 1061,
700 cmꢀ1. (ESI): 666 [M+Na]+. HRMS (ESI): calcd for C34H53N5O7Na
666.3837; found: 666.3838 [M+Na]+.
4.1.20.3. Arenamide
C
1c.
Compound 2c (40.0 mg,
0.042 mmol) gave arenamide C 1c as a white solid (14.0 mg,
53%). Observed
½
a 2D3
ꢂ
¼ ꢀ39:1 (c 0.30, CH3OH), reported
½
a 2D5
ꢂ
¼ ꢀ45 (c 0.09 CH3OH).2 1H NMR (300 MHz, CDCl3): dH 5.08
IR (neat)
m
max: 3277, 2930, 1740, 1632, 1527, 771 cmꢀ1. MS (ESI)
(m, 1H), 4.38 (qt, J = 4.71, 8.5 Hz, 2H), 4.11 (d, J = 16.8 Hz, 1H),
4.06 (qt, J = 7.40, 14.13 Hz), 4.01 (dd, J = 4.03, 10.7 Hz, 1H), 3.95
(d, J = 7.4 Hz, 1H), 3.65 (d, J = 16.8 Hz, 2H), 2.55 (dd, J = 10.9,
14.8 Hz, 1H), 2.59 (dd, J = 4.7, 8.5 Hz, 1H), 2.41 (qn, J = 8.5, 13.4,
20.1 Hz, 2H), 2.33 (d, J = 14.1 Hz, 2H), 2.05 (s, 3H), 1.92–1.83 (m,
1H), 1.72–1.59 (m, 6H), 1.31 (d, J = 6.73 Hz, 6H), 1.02 (m, 1H), 0.9
(t, J = 6.6 Hz, 9H), 0.87 (d, J = 6.06 Hz, 6H), 0.82 (qn, 7.4, 15.4 Hz,
16H). 13C NMR (75 MHz, CDCl3): dC 174.0, 173.66, 173.6, 172.9,
171.7, 76.6, 62.1, 54.1, 53.4, 50.4, 43.6, 40.0, 38.9, 38.4, 33.6,
32.9, 31.5, 31.4, 31.0, 30.7, 30.6, 28.2, 26.1, 23.7, 21.2, 19.6, 19.1,
m/z: 965 [M+Na]+. HRMS (ESI) [M+H]+: calcd for C47H71N6O12SNa:
943.4845; found: 943.4867.
4.1.20.1. Arenamide A 1a.
To a stirred solution of hexadepsi-
peptide 2a (60 mg, 0.061 mmol) dissolved in a mixture of THF/IPA
(2.5:1, 20 mL) was added 10% (w/w) Pd–C (60 mg) at room temper-
ature. The reaction was kept under hydrogen pressure (atmo-
spheric) for 8 h. After completion of the reaction (by TLC), the
mixture was diluted with chloroform (10 mL). The reaction mix-
ture was filtered through a small pad of Celite and concentrated
under reduced pressure to provide a free amino acid as a white
solid.
17.5, 15.2, 14.4. IR (KBr)
mmax: 3376, 2930, 2857, 1667, 1514,
1364, 1257 cmꢀ1. HRMS (ESI) [M+Na]+: calcd for C32H57N5O7NaS:
678.38709; found: 678.38884.
To the crude amino acid dissolved in CH2Cl2 (100 mL,
0.5 ꢃ 10ꢀ3 M), were added HOBt (23.0 mg, 0.183 mmol), EDCI
(34 mg, 0.183 mmol), followed by DIPEA (0.4 mL, 0.183 mmol) at
0 °C under a nitrogen atmosphere. The reaction mixture was al-
lowed to reach room temperature and stirred for 48 h. The reaction
was monitored by TLC. It was then diluted with (10 mL) CH2Cl2 and
H2O. The separated organic layer was washed with 1 M HCl
(10 mL), H2O (10 mL), 5% aqueous NaHCO3 (10 mL), brine (10 mL)
and dried over anhydrous Na2SO4. The solvent was reduced in va-
cuo and the crude was chromatographed over silica gel (8% meth-
anol/chloroform) to give arenamide A 1a as a white solid (21 mg,
Acknowledgements
K.S. thanks Council of Scientific and Industrial Research (CSIR),
New Delhi and G.P.K. thanks UGC for research fellowships. The
authors are thankful to CSIR, New Delhi for funding under 12th
Five year Plan.
References
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Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311–315.
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Pezzuto, J. M. J. Nat. Prod. 2009, 72, 396–402.
52%). Mp: 228–220 °C. Observed ½a D28
¼ ꢀ65:0 (c 0.07, CH3OH), re-
ꢂ
ported ½a 2D5
ꢂ
¼ ꢀ76:3 (c 0.08 CH3OH).2 1H NMR (300 MHz, CDCl3):
dH 8.35 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.96 (d,
J = 8.3 Hz, 1H), 7.70 (t, J = 5.2, 4.1 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H),
7.28–7.18 (m, 5H), 4.93 (m, 1H), 4.29 (q, J = 13.6, 7.3 Hz, 1H),
4.27–4.09 (m, 3H), 3.92 (t, J = 8.3, 7.3 Hz, 1H), 3.69 (dd, J = 16.8,
4.1 Hz, 1H), 2.92 (dq, J = 22.0, 15.7, 8.3 Hz, 2H), 2.57 (dd, J = 14.6,
9.4 Hz, 1H), 2.18 (d, J = 14.6 Hz, 1H), 1.93 (m, 1H), 1.60–1.35 (m,
4H), 1.29–1.09 (m, 15H), 0.52 (d, J = 6.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dC 171.6, 171.2, 171.0, 170.8, 169.4, 169.1,
136.6, 129.1, 128.4, 126.8, 75.2, 60.3, 54.8, 51.5, 47.5, 42.5, 40.0,
37.2, 36.5, 35.9, 31.4, 31.3, 29.8, 29.0, 26.4, 24.4, 23.3, 22.2, 20.7,
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Jagadeesh, B. Chem. Commun. 2010, 6962–6964;; (c) Chandrasekhar, S.; Lohitha
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K.; Prakash, K. B.; Jagadeesh, B. J. Org. Chem. 2008, 73, 9443–9446; (d)
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Jagadeesh, B.; Prabhakar, A. Chem. Commun. 2006, 4847–4849; (e)
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Prabhakar, A.; Jagannadh, B. J. Am. Chem. Soc. 2005, 127, 9664–9665; (g)
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19.1, 19.0, 18.4, 14.5, 13.9. IR (neat)
2860, 1725, 1648, 1539 cmꢀ1. HRMS (ESI) [M+H]+: calcd for
36H58N5O7Na 672.4331; found: 672.4336.
mmax: 3329, 2958, 2928,
C
4.1.20.2. Arenamide B 1b.
Compound 2b (30.0 mg, 0.032
mmol) gave arenamide B 1b (12.0 mg, 61%) as a white solid. Mp:
221–223 °C. Observed
½
a 2D8
ꢂ
¼ ꢀ79 (c 0.08, CH3OH), reported
½
a 2D5
ꢂ
¼ ꢀ96:3 (c 0.27 CH3OH).2 1H NMR (300 MHz, CDCl3): dH 8.32
(d, J = 2.75 Hz, 1H), 8.18–8.03 (m, 2H), 7.93 (br s, 1H), 7.65 (br s,
1H), 7.32–7.15 (m, 5H), 4.94 (m, 1H), 4.35–4.24 (m, 1H), 4.23–
4.06 (m, 3H), 3.94 (t, J = 7.34, 15.6 Hz, 1H), 3.70 (dd, J = 2.75,
16.5 Hz, 1H), 2.94 (dq, J = 6.42, 12.85, 20.20 Hz, 2H), 2.58 (dd,
J = 9.18, 13.7 Hz, 1H), 2.19 (d, J = 13.7 Hz, 1H), 2.03–1.88 (m, 1H),
1.68–1.38 (m, 2H), 1.29–1.09 (m, 13H), 0.96–0.77 (m, 15H), 0.55