Synthesis of the 'southern' tripeptide of Cyclomarins A and C having novel anti-tuberculocidal mode of action

Article abstract of DOI:10.1016/j.tetasy.2011.08.026

The synthesis of the 'southern' tripeptide of Cyclomarins A and C has been described which includes two unusual amino acids. The unusual amino acids have been synthesized and coupled with l-alanine to obtain the tripeptide.

Full text of DOI:10.1016/j.tetasy.2011.08.026

Tetrahedron: Asymmetry 22 (2011) 1568–1573
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of the ‘southern’ tripeptide of Cyclomarins A and C having novel
anti-tuberculocidal mode of action
⇑
Kurapati Sathish, Gangireddy Pavan Kumar Reddy, Prathama S. Mainkar, Srivari Chandrasekhar
Organic Chemistry Division-I, 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:
The synthesis of the ‘southern’ tripeptide of Cyclomarins A and C has been described which includes two
Received 27 July 2011
Accepted 25 August 2011
Available online 1 October 2011
unusual amino acids. The unusual amino acids have been synthesized and coupled with
obtain the tripeptide.
L-alanine to
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Cyclomarins are cyclic heptapeptides isolated from the marine
bacterium Streptomyces sp. strain CNB-982 (Fig. 1). The yield of
Cyclomarins by fermentation of 11 1 L flasks was A—57 mg, B—
1 mg and C—1 mg. The crude extract displayed moderate cytotox-
icity activity against HCT-116, a human colon cancer cell line.
Cyclomarine A is cytotoxic in vitro towards cancer cells (mean
R1
N
O
H
N
"Northern tetrapeptide"
N
H
HO
O
N
O
N
O
O
IC50 against a panel of human cancer cell lines in 2.6 lM). Cyclom-
R2
arin A is more interesting for its significant in vitro and in vivo anti-
inflammatory properties. It also shows antiviral and
antimycobacterial activity and is currently being explored for ther-
HN
H
N
N
H
O
apeutic applications.1
A recent publication highlighted that
"Southern tripeptide"
O
Cyclomarin has Mycobacterium tuberculosis bacteriocidal proper-
ties.2 The activity of cyclomarin is expected through an allosteric
site by interfering with the protein Clpc1 in multi-drug resistant
Mycobacteria as well, without affecting any Gram positive or neg-
ative bacteria. Structurally, Cyclomarins show a remarkable resem-
blance to each other. Cyclomarins A and C both contain three
common amino acids (Ala, Val and N-MeLeu), two less common
ones (b-methoxyphenylalanine, N-methylleucine) and one novel
non-coded amino acid (2-amino-3,5-dimethylhex-4-enoic acid).
The only difference between A and C is in the unusual tryptophan
derivative, with N0-prenyltryptophan being in cyclomarin C and N0-
(1,1-dimethyl-2,3-epoxypropyl)-b-tryptophan in Cyclomarin A.
This marine natural product has attracted considerable attention
from synthetic chemists and to date two total3 and a few partial
syntheses of Cyclomarins have been documented.4
MeO
R1=
R1=
R1=
R2=OH
Cyclomarin A
O
O
R2=H
Cyclomarin B
Cyclomarin C
R2=OH
Figure 1. Structures of Cyclomarins.
The ‘southern tripeptide’ comprises of two uncommon amino acids
connected through natural proteinogenic amino acid
synthesis of which we herein report (Scheme 1).
L-alanine, the
Our continued interest in the synthesis of marine natural prod-
ucts in general5 and cyclic peptides in particular6 directed us to
take up the synthesis of Cyclomarins. We envisaged the Cycloma-
rin molecule to be composed of ‘northern’ and ‘southern’ peptides.
2. Results and discussion
Initially, a large scale synthetic strategy for the preparation of
amino acids 2 and 4 was desired. Thus, the synthesis of 2 was
achieved from lactone 5. The amino lactone 5 (synthesized from
(R)-Garner aldehyde following the protocol of Nevalaine et al.7)
⇑
Corresponding author.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.026

K. Sathish et al. / Tetrahedron: Asymmetry 22 (2011) 1568–1573
1569
OH
BocN
O
COOH
NHBoc
COOH
CH2Cl2
EDCI,HOBt,
H
N
COOEt
BzO
OMe
Ph
N
H
0 °C-rt, 24 h, 75%
NH2
O
3
4
OMe
1 (Southern tripeptide)
OH
COOEt
COOEt
Ph
Ph
Ag2O, MeI, THF
45 °C,48 h,92%
HN
HN
COOEt
OH
Boc
NHBoc
11
NHBoc
N
Boc
HN
O
O
O
H2N
HO
OH
OMe
OH
10
O
COOEt
Ph
2
3
TFA
HN
NH2.TFA
4
O
Scheme 1. Retrosynthetic analysis of ‘southern’ tripeptide.
12
Scheme 3. Synthesis of dipeptide 12.
was reduced with LiAlH4; the polar amino diol was protected as
the N,O-isopropylidene derivative 6 with 2,2-DMP, CSA in CH2Cl2
in 67% yield for two steps. Silylation of the primary alcohol group
in 6 was achieved with TBDPSCl and imidazole in quantitative
yields to provide 7. Hydrolysis of the isopropylidene group in 7
was accomplished with p-TSA in methanol at 0 °C to give 8 in
81% yield. Oxidation of the primary alcohol to acid 9 and N-meth-
ylation with NaH/CH3I gave 2 (Scheme 2).
The other unusual amino acid fragment 4 was synthesized fol-
lowing a known protocol.8 Then, coupling of ester 4 with N-Boc
alanine 3 was carried out using EDCI/HOBt in CH2Cl2, which gave
10 in 75% yield. Compound 10 was reacted with silver oxide and
methyl iodide in THF at 45 °C to give 11 in 92% yield, which is re-
ported in the literature.3b Methyl ether 11 was reacted with TFA to
give the free amine 12, which was used as such for the next reac-
tion (Scheme 3).
The next step in the synthesis of tripeptide 1 was to carry out
the coupling of dipeptide 12 with amino acid 2. Thus, the TFA salt
of the amino compound 12 was reacted with 2 under standard
peptide bond formation reaction conditions of EDCI–HOBt–DIPEA
to give tripeptide 13 in 76% yield. Hydrolysis of 13 using LiOH gave
free acid 14 in 87% yield. In order to compare spectral data with the
literature, 14 was converted to methyl ester 15 in 81% yield using
NMU, KOH. Compound 15 was subjected to deprotection of TBDPS
group with tetrabutylammonium fluoride followed by conversion
of the free hydroxyl into benzoate ester, which resulted in 1 in
68% yield over two steps. The tripeptide 1 so obtained constitutes
the synthesis of the ‘southern tripeptide’ of Cyclomarins which had
identical spectroscopic data in all respects to the literature, which
O
CHO
Ref. 7
O
O
1). LiAlH4, THF
NBoc
2). 2,2,- DMP, CSA,
CH2Cl2, 67%, 2 steps
NHBoc
(R)-Garner's
aldehyde
5
OH
OTBDPS
O
O
TBDPS-Cl
NBoc
NBoc
Imidazole, CH2Cl2
0 °C, 0.5 h
quantitative
7
6
BAIB,TEMPO
OTBDPS
HO
p-TSA, MeOH
CH3CN:H2O (7:3),
rt, 4h, 71%
BocHN
8
0 °C-rt, 3h, 81%
O
O
HO
BocHN
OTBDPS
HO
OTBDPS
NaH, MeI, THF
NBoc
0 °C-rt, 48 h
85%
9
2
Scheme 2. Synthesis of amino acid 2.

1570
K. Sathish et al. / Tetrahedron: Asymmetry 22 (2011) 1568–1573
OMe
O
COOEt
Ph
EDCI, HOBt, DIPEA
CH2Cl2, 18 h, rt.
76%
HO
OTBDPS
HN
NH2
NBoc
O
2
12
BocN
O
COOEt
OMe
LiOH,THF:H2O (7:3)
0 °C, 3 h, 87%
H
N
TBDPSO
N
H
O
Ph
13
NMU, KOH
(Et)2O, 0 °C, 20 min
81%
BocN
BocN
O
COOH
Ph
H
N
TBDPSO
TBDPSO
OMe
N
H
O
O
14
1. TBAF, THF, 0 0C
2. Bz-Cl, TEA
O
COOCH3
OMe
H
N
CH2Cl2, 1h, 0 °C.68%
N
H
Ph
15
BocN
O
COOCH3
OMe
H
N
BzO
N
H
O
Ph
1
Scheme 4. Synthesis of ‘southern’ tripeptide 1.
was successfully utilized in the total synthesis of Cyclomarin C3b
(Scheme 4).
under an atmosphere of nitrogen in flame-dried or oven-dried
glassware with magnetic stirring.
4.1.1. (S)-tert-Butyl 4-((R)-3-hydroxy-2-methylpropyl)-2,2-
dimethyl oxazolidine-3-carboxylate 6
3. Conclusion
In a dried two neck round bottom flask, LiAlH4 (1.6 g, 3.7 mmol)
was added followed by dry THF (20 mL) at 0 °C under a nitrogen
atmosphere. To this, lactone 5 (2.0 g, 8.73 mmol) dissolved in dry
THF (20 mL), was added slowly at the same temperature. The mix-
ture was stirred at 0 °C for 1.5 h. After completion of the reaction
(monitored by TLC), the mixture was quenched slowly with a sat-
urated Na2SO4 solution at 0 °C and was filtered using a Celite pad.
The solids were washed thoroughly with EtOAc (4 ꢀ 20 mL). The
filtrate was evaporated on a rotary evaporator to afford the crude
amino diol (1.5 g) as a yellowish liquid. This crude compound
was used for the next reaction without further purification.
The above crude amino diol (1.5 g, 7.85 mmol) was dissolved in
dry CH2Cl2 (15 mL) under a nitrogen atmosphere. 2,2-Dimethoxy-
propane (1.2 mL, 11.7 mmol) and dry pTSA (0.165 g, 0.89 mmol)
were added to it at room temperature and the mixture was stirred
for 2 h. After completion of the reaction (by TLC), the mixture was
quenched with a saturated NaHCO3 solution (10 mL). 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 (30% EtOAc/
petroleum ether) to afford alcohol 6 (1.4 g, 67%) as a light yellow
In conclusion, we have successfully carried out the synthesis of
the ‘southern tripeptide’ unit of Cyclomarins A and C with the
syntheses of two unusual amino acids and their coupling with
L-alanine.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 on a 300, 500 or
75 MHz spectrometer at ambient temperature. The chemical shifts
(d) are reported in ppm on a scale downfield from TMS, as the
internal standard and signal patterns indicated as follows: s, sin-
glet; d, doublet; dd, doublet of doublet; td, triplet of doublet; t,
triplet; m, multiplet; br s, broad singlet. Coupling constants J are
in Hertz. 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 the reagents and solvents were
reagent grade and used without further purification unless speci-
fied otherwise. Technical grade ethyl acetate and petroleum ether
used for column chromatography were distilled prior to use. Col-
umn chromatography was carried out using silica gel (60–
120 mesh) packed in glass columns. All reactions were performed
liquid. ½a 2D3
ꢁ
¼ þ20:6 (c 1.0, CHCl3); 1H NMR showed a mixture of
rotamers (60:40 ratio). 1H NMR (300 MHz, CDCl3): d 4.17–4.06
(m, 1H), 3.95–3.83 (qt, J = 8.3, 13.5 Hz, 2H), 3.73–3.61 (m, H),

K. Sathish et al. / Tetrahedron: Asymmetry 22 (2011) 1568–1573
1571
3.51 (m, 2H), 3.14–3.0 (br s, 1H), 1.58–1.42 (m, 17H), 0.98–0.84 (d,
J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 152.5, 151.5, 93.5, 93.1,
80.3, 79.5, 68.2, 68.0, 67.6, 66.9, 55.6, 55.17, 37.2, 37.0, 33.5, 32.9,
28.4, 28.3, 27.6, 26.8, 24.4, 23.2, 16.4, 15.9; IR (neat): mmax 3456,
2978, 2935, 2875, 1697, 1391, 1257, 1174, 1090, 851 cmꢂ1; MS
(ESI): m/z 296 [M+Na]+; HRMS (ESI): calcd for C14H27NO4Na
296.1837, found: 296.1848 [M+Na]+.
7.33 (m, 6H), 5.24–5.15 (br s, 1H), 3.62–3.54 (m, 1H), 3.52–3.45
(m, 2H), 2.07–1.99 (m, 1H), 1.89–1.80 (m, 1H), 1.64–1.54 (m,
1H), 1.43 (s, 9H), 1.07 (s, 9H), 0.99–0.94 (d, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 177.8, 155.6, 135.5, 133.5, 129.6, 127.6,
80.0, 67.8, 51.8, 35.6, 32.4, 28.2, 26.8, 19.2, 17.1; IR (neat): mmax
3322, 2925, 1715, 1590, 1367, 1251, 1112, 938, 702 cmꢂ1; MS
(ESI): m/z 486 [M+H]+; HRMS (ESI): calcd for C27H40NO5Si
486.2675, found: 486.2679 [M+H]+.
4.1.2. (S)-tert-Butyl 4-((R)-3-(tert-butyldiphenylsilyloxy)-2-
methyl propyl)-2,2-dimethyl oxazolidine-3-carboxylate 7
To a stirred solution of compound 6 (500 mg, 1.83 mmol) in dry
CH2Cl2 (20 mL), were added imidazole (250 mg, 3.66 mmol) and
TBDPS–Cl (500 mg, 1.83 mmol) at 0 °C under a nitrogen atmo-
sphere. The reaction was stirred at the same temperature for
30 min. (completion of reaction was monitored by the TLC). The
reaction was diluted with CH2Cl2 (10 mL) and quenched with
water (15 mL). The organic layer was separated, washed with brine
(10 mL) and dried over anhydrous Na2SO4. The solvent was evapo-
rated in vacuo and the residue was purified by column chromatog-
raphy (7% EtOAc/petroleum ether) to afford 7 (0.90 g, 94%) as a
4.1.5. (6R,8S)-2,2,6,9,12,12-Hexamethyl-10-oxo-3,3-diphenyl-
4,11-dioxa-9-aza-3-silatridecane-8-carboxylic acid 2
In
a dried two neck round bottom flask, NaH (100 mg,
0.206 mmol) was added followed by dry THF (10 mL) at 0 °C under
a nitrogen atmosphere. To this was added amino acid 9 (100 mg,
0.206 mmol) slowly at the same temperature. The mixture was
stirred for 15 min after which methyl iodide (366 mg, 2.60 mmol)
was added. The reaction was then stirred at room temperature
for 48 h. After completion of the reaction (monitored by TLC), it
was quenched with ice at 0 °C. The compound was extracted in
EtOAc (2 ꢀ 10 mL). The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. The solvent was removed
in vacuo. The crude was purified using column chromatography
(55% EtOAc/petroleum ether) to give 2 (80 mg, 78%) as a colourless
light yellow liquid.
½
a 2D8
ꢁ
¼ þ18:5 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.62 (dd, J = 1.5, 6.7 Hz, 4H), 7.42–7.30 (m,
6H), 3.96–3.72 (m, 2H), 3.68–3.57 (m, 1H), 3.44 (d, J = 6.0 Hz,
2H), 1.60–1.48 (m, 8H), 1.44 (s, 9H), 1.05 (s, 9H), 0.99–0.91 (qt,
J = 6.7, 8.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 151.5, 135.5,
133.7, 129.5, 127.5, 93.4, 92.9, 79.3, 79.7, 69.0, 66.8, 66.5, 55.6,
33.9, 33.5, 28.4, 26.8, 24.6, 23.2, 19.2, 15.9; IR (neat): mmax 3458,
2960, 2932, 2859, 1698, 1389, 1258, 1030, 702 cmꢂ1; MS (ESI):
m/z 512 [M+H]+; HRMS (ESI): calcd for C30H46NO4Si 512.3196,
found: 512.3195 [M+H]+.
liquid. ½a 2D3
ꢁ
¼ ꢂ12:0 (c 0.5, CHCl3); 50:50 (rotamers), 1H NMR
(300 MHz, CDCl3): d 7.65 (d, J = 6.8 Hz, 4H), 7.42–7.32 (m, 6H),
4.83–4.69 (m, 0.5H), 4.50–4.39 (m, 0.5H), 3.55 (d, J = 4.5 Hz, 2H),
2.80 (s, 3H), 2.24–2.12 (m, 1H), 1.78–1.52 (m, 2H), 1.39 (s, 9H),
1.06 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
177.6, 155.5, 135.6, 133.7, 132.2, 129.6, 127.6, 80.4, 67.5, 67.0,
57.5, 56.8, 32.75, 32.51, 32.3, 31.9, 31.3, 28.3, 28.2, 26.9, 19.3,
17.7, 17.4; IR (neat): mmax 3503, 2951, 2931, 1694, 1428, 1367,
1255, 1112, 822, 703 cmꢂ1; (ESI): m/z 521.8 [M+Na]+; HRMS
(ESI): calcd for C28H41NO5Na 522.2651 found 522.2633 [M+Na]+.
4.1.3. tert-Butyl (2S,4R)-5-(tert-butyldiphenylsilyloxy)-1-
hydroxy-4-methylpentan-2-yl carbamate 8
Compound 7 (500 mg 0.956 mmol) was dissolved in methanol
(20 mL). Next, pTSA (18 mg, 0.095 mmol) was added at 0 °C and
the mixture was stirred for 2 h at same temperature. After comple-
tion of the reaction (by TLC), the mixture was quenched with aq
saturated NaHCO3 (10 mL) and methanol (20 mL) was evaporated
in vacuo. The residue was extracted with ethyl acetate (20 mL).
The organic layer was washed with brine (10 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuo and the
crude was purified by column chromatography (25% EtOAc/petro-
4.1.6. (2S,3R) Ethyl 2-((S)-2-(tert-butoxycarbonylamino) propan
amido)-3-hydroxy-3-phenyl propanoate 10
At first, N-Boc alanine 3 (409 mg, 2.39 mmol) was dissolved in
dry CH2Cl2 (15 mL). HOBt (625 mg, 4.7 mmol) was added to it at
0 °C and mixture was stirred for 10 min. Then to the mixture, EDCI
(900 mg, 4.78 mmol) was added, followed by DIPEA (0.8 mL,
7.17 mmol). The mixture was stirred for 20 min, then amine 4
(500 mg, 2.39 mmol) dissolved in dry CH2Cl2 (15 mL) was added
to it. The resulting mixture was stirred for 24 h at room tempera-
ture. The progress of the reaction was monitored by TLC. After
completion of the reaction, it was diluted with CH2Cl2 (10 mL).
The organic layer was washed with H2O (10 mL), 1 M HCl (8 mL),
saturated NaHCO3 (8 mL) and dried over anhydrous Na2SO4. The
solvent was reduced in vacuo and the crude was chromatographed
over silica gel (30% EtOAc/petroleum ether) to give pure 10
leum ether) to afford 5 (400 mg, 81%). ½a D28
¼ ꢂ11:0 (c 1.0, CHCl3);
ꢁ
1H NMR (300 MHz, CDCl3): d 7.62 (dd, J = 1.7, 7.3 Hz, 4H), 7.41–
7.31 (m, 6H), 4.82–4.72 (d, J = 4.9 Hz, 1H), 3.75–3.40 (m, 5H),
2.56–2.36 (br s, 1H), 1.89–1.57 (m, 2H), 1.42 (s, 9H), 1.35–1.24
(m, 1H), 1.05 (s, 9H), 0.94 (d, J = 6.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d 156.5, 135.5, 133.6, 129.6, 127.6, 79.6, 68.2, 66.1, 50.9,
34.6, 32.6, 28.3, 26.8, 19.2, 17.2; IR (neat): mmax 3448, 2959, 2930,
2857, 1686, 1366, 1250, 1172, 702 cmꢂ1; MS (ESI): m/z 472
[M+Na]+; HRMS (ESI): calcd for C27H41NO4NaSi 494.2707, found:
494.2707 [M+Na]+.
(700 mg, 77%) as a colourless liquid. ½a D23
¼ ꢂ21:5 (c 1.0 CHCl3);
ꢁ
1H NMR (300 MHz, CDCl3):
d 7.36–7.26 (m, 5H), 7.10 (d,
J = 8.9 Hz, 1H), 6.09 (d, J = 5.1 Hz, 1H), 5.44 (br s, 1H), 4.99 (qt,
J = 6.0, 9.1 Hz, 1H), 4.29–4.0 (m, 3H), 1.46 (d, J = 4.1 Hz, 9H), 1.33
(d, J = 7.2 Hz, 3H), 1.14–1.16 (m, 3H); 13C NMR (75 MHz, CDCl3):
d 173.3, 169.5, 155.2, 136.5, 130.6, 128.4, 128.0, 127.8, 126.54,
4.1.4. (6R,8S)-2,2,6,12,12-Pentamethyl-10-oxo-3,3-diphenyl-
4,11-dioxa-9-aza-3-silatridecane-8-carboxylic acid 9
To a solution of compound 8 (200 mg, 0.424 mmol) in acetoni-
trile and water 1:1 (20 mL), were added BAIB (327 mg, 1.27 mmol)
and TEMPO (13 mg, 0.084 mmol) at room temperature. The reac-
tion was stirred at the same temperature for 3 h. Completion of
the reaction was monitored by the TLC. The reaction was quenched
with a saturated hypo solution (15 mL) and was extracted with
EtOAc (2 ꢀ 20 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
82.2, 79.4, 60.9, 49.5, 40.9, 27.9, 18.2,13.7; IR (KBr): mmax, 3321,
2980, 2934, 1745, 1667, 1522, 1367, 1249, 1027, 861 cmꢂ1; MS
(ESI): m/z 403 [M+Na]+; HRMS (ESI): calcd. for C19H28N2O6Na
403.1831 found 403.1845 [M+Na]+.
4.1.7. (2S,3R)-Ethyl 2-((S)-2-(tert-butoxycarbonylamino)propan
amido)-3-methoxy-3-phenyl propanoate 11
To a stirred solution of alcohol 10 (200 mg, 0.52 mmol) in dry
THF (20 mL) was added slowly Ag2O (243 mg, 1.05 mmol) and
methyl iodide (141 mg, 1.05 mmol) in the dark. The mixture was
stirred at 45 °C, for 48 h. After completion of the reaction
residue was purified by column chromatography to give
9
(165 mg, 81%) as a pale yellow liquid. ½a D30
¼ þ4:5 (c 0.64, CHCl3);
ꢁ
1H NMR (500 MHz, CDCl3): d 7.66–7.61 (d, J = 6.3 Hz, 4H), 7.42–

1572
K. Sathish et al. / Tetrahedron: Asymmetry 22 (2011) 1568–1573
(monitored by TLC), the mixture was filtered through a bed of Cel-
ite. The filtrate was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude was purified by chromatogra-
NMR (300 MHz, CDCl3): d 7.58 (d, J = 6.0 Hz, 5H), 7.38–7.21 (m,
10H), 6.68–6.62 (br s, 1H), 4.81 (s, 1H), 4.72–4.63 (br s, 1H),
4.45–4.28 (br s, 1H), 3.54 (dd, J = 4.5, 9.0 Hz, 2H), 3.45–3.34 (m,
2H), 3.20 (s, 3H), 2.65 (s, 3H), 1.69–1.50 (m, 2H), 1.45–1.25 (m,
1H), 1.19 (s, 3H), 0.98 (s, 9H), 0.94 (d, J = 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 171.9, 157.5, 135.5, 133.7, 129.5, 128.4, 127.5,
126.6, 85.8, 81.9, 57.5, 48.6, 32.3, 29.6, 28.2, 26.8, 19.2, 17.3,
17.4; IR (KBr): mmax 3306, 2930, 2857, 1668, 1513, 1390, 1257,
1111, 702 cmꢂ1; MS (ESI): m/z 769.6 [M+Na]+; HRMS (ESI): calcd
for C41H58N3O8Si 748.3988, found 748.4022 [M+H]+.
phy to give 11 as a colourless liquid (180 mg, 86%). ½a D28
¼ ꢂ45 (c
ꢁ
1.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.35–7.22 (m, 5H),
6.58 (d, J = 9.1 Hz, 1H), 4.77 (d, J = 3.0 Hz, 1H), 4.73–4.66 (dd,
J = 2.8 Hz, 1H), 4.28–4.03 (m, 3H), 3.28 (s, 3H), 1.46 (s, 9H), 1.45–
1.41 (d, J = 2.6 Hz, 3H), 1.29–1.24 (m, 3H); 13C NMR (75 MHz,
CDCl3): d 172.3, 169.6, 155.0, 136.7, 128.2, 128.0, 126.0, 82.3,
79.7, 67.0, 61.4, 57.4, 49.6, 28.1, 18.2, 13.9; IR (neat): mmax 3315,
2958, 2924, 2853, 1715, 1499, 1250, 1168, 1051, 701 cmꢂ1; MS
(ESI): m/z 394 [M+Na]+; HRMS (ESI): calcd for C20H30N2O6Na
417.2001 found: 417.1989 [M+Na]+.
4.1.10. (6R,8S,11R,14S)-Methyl 8-(tert-butoxycarbonyl (methyl)
amino)-14-((R)-methoxy(phenyl)methyl)-2,2,6,11-tetramethyl-
9,12-dioxo-3,3-diphenyl-4-oxa-10,13-diaza-3-sila pentadecan-
15-oate 15
4.1.8. (6R,8S,11S,14S)-Ethyl 8-(tert-butoxycarbonyl(methyl)
amino)-14-((R)-methoxy(phenyl)methyl)-2,2,6,11-tetramethyl-
9,12-dioxo-3,3-diphenyl-4-oxa-10,13-diaza-3-silapenta decan-
15-oate 12
N-Boc protected dipeptide 11 (100 mg, 0.25 mmol) was dis-
solved in dry CH2Cl2 (1 mL), after which TFA (0.9 mL 0.73 mmol)
was added to it at 0 °C. The resultant mixture was stirred at room
temperature for 2 h. The progress of the reaction was monitored by
TLC. After completion of the reaction, CH2Cl2 and TFA were evapo-
rated in vacuo to afford a pale yellow coloured crude amine 12
(75.0 mg) which was used for the coupling reaction without any
further purification.
To a stirred solution of acid 14 (20 mg, 0.026 mmol) in diethyl-
ether (5 mL), was added diazomethane in diethylether, prepared
from N-nitrosomethyl urea (40 mg) and 40% KOH (10 mL) at 0 °C
in diethylether. The reaction was stirred at the same temperature
for 20 min. After completion of reaction (monitored by the TLC),
the mixture was quenched with a saturated NH4Cl solution
(6 mL) and extracted with diethyl ether (2 ꢀ 5 mL). The combined
organic layers were dried over anhydrous Na2SO4 and solvent re-
moved under reduced pressure. The crude was purified by column
chromatography, which yielded 15 (17 mg, 81%) as a gummy li-
quid. ½a 2D3
ꢁ
¼ ꢂ1:85 (c 0.27, CHCl3); 1H NMR (300 MHz, CDCl3): d
N-Methyl protected acid 2 (126 mg, 0.253 mmol) was dissolved
in dry CH2Cl2 (10 mL). Next, HOBt (66.0 mg, 0.506 mmol) was
added to it at 0 °C. The mixture was allowed to stir for 10 min, then
EDCI (96 mg, 0.506 mmol), followed by DIPEA (0.9 mL, 0.73 mmol)
were added to it. The resulting mixture was stirred for 20 min, then
amine 12 (75.0 mg, 0.253 mmol) dissolved in dry CH2Cl2 (3 mL)
was added and the whole mixture was stirred for 24 h at room
temperature. The reaction was monitored by TLC. After comple-
tion, the mixture was diluted with CH2Cl2 (10 mL). The organic
layer was washed with H2O (10 mL), 1 M HCl (5 mL), saturated
NaHCO3 (6 mL) 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 pure 13 (148 mg,
7.64 (d, J = 7.5 Hz, 4H), 7.42–7.16 (m, 11H), 6.81–6.41 (br s, 1H),
4.79 (d, J = 2.2 Hz, 1H), 4.73 (dd, J = 3.0, 9.0 Hz, 1H), 4.50–4.35 (m,
1H), 4.11 (q, J = 6.8, 14.3 Hz, 1H), 3.73 (s, 3H), 3.61 (q, J = 4.5,
9.8 Hz, 1H), 3.47 (qt, J = 6.0, 9.8 Hz, 1H), 3.28–3.21 (m, 3H), 2.71
(s, 3H), 2.09–1.98 (m, 1H), 1.74 (br s, 1H), 1.49–1.33 (m, 9H),
1.28–1.20 (m, 3H), 1.05 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 171.6, 170.1, 169.8, 159.7, 136.7, 135.5, 133.7,
129.4, 128.3, 126.8, 126.5, 83.2, 82.1, 60.6, 57.7, 57.4, 52.5, 48.5,
32.3, 31.0, 30.1, 28.2, 26.8, 20.9, 19.2, 14.1; IR (KBr): mmax 3330,
3071, 2927, 2855, 1745, 1682, 1525, 1455, 1212, 1154, 822,
701 cmꢂ1; MS (ESI): m/z 784 [M+Na]+; HRMS (ESI): calcd for
C
42H59N3O8NaSi 784.3969, found 784.3948 [M+Na]+.
76%) as a colourless liquid. ½a D30
ꢁ
¼ ꢂ32:0 (c 0.025, CHCl3); 1H
4.1.11. (6S,9R,12S)-Methyl 6-((R)-3-(benzoyloxy)-2-
NMR (300 MHz, CDCl3): d 7.66–7.58 (d, J = 7.2 Hz, 4H), 7.40–7.13
(m, 11H), 6.74–6.42 (br s, 1H), 4.75 (br s, 1H), 4.67 (dd, J = 3.2,
8.8 Hz, 1H), 4.37 (t, J = 6.6, 13.5 Hz, 1H), 4.25–4.11 (m, 2H), 3.60
(dd, J = 4.2, 9.6 Hz, 1H), 3.51–3.41 (m, 1H), 3.25 (s, 3H), 2.10–1.95
(m, 1H), 1.82–1.55 (m, 1H), 1.53–1.16 (m, 13H), 1.05 (s, 9H), 0.92
(qt, J = 7.3, 15.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 171.5,
169.6, 136.7, 135.5, 133.7, 130.8, 129.4, 128.7, 128.3, 128.2,
127.5, 126.5, 82.2, 80.5, 68.0, 61.5, 57.8, 57.5, 48.4, 38.6, 32.2,
30.9, 30.1, 29.6, 28.2, 26.8, 23.6, 22.9, 19.3, 14.0; IR (KBr): mmax
3306, 2936, 2857, 1735, 1689, 1502, 1259, 1110, 704 cmꢂ1; MS
(ESI): m/z 798 [M+Na]+; HRMS (ESI): calcd for C43H61N3O8NaSi
798.4115, found 798.4125 [M+Na]+.
methylpropyl)-12-((R)-methoxy(phenyl)methyl)-2,2,5,9-
tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate
1
To a stirred solution of ester 15 (17 mg, 0.022 mmol) in THF
(4 mL) was added TBAF (23 mg, 0.088 mmol) at 0 °C, The reaction
was stirred at the same temperature for 1 h. After completion of
the reaction (monitored by the TLC), the mixture was quenched
with ice and extracted with EtOAc (2 ꢀ 20 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and removed un-
der reduced pressure. The crude (22 mg) was used for the next
step without further purification.
To the stirred crude alcohol derivative in dry CH2Cl2 (10 mL)
was added triethylamine (7 mg, 0.071 mmol) and benzoyl chloride
(6 mg 0.0325 mmol) at 0 °C, the reaction was stirred at same tem-
perature for 1 h. After completion of the reaction (monitored by
the TLC), the mixture was quenched with NaHCO3 (10 mL) and ex-
tracted with CH2Cl2 (2 ꢀ 10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and removed under reduced pres-
sure. The crude was purified by column chromatography which
4.1.9. (6R,8S,11S,14S)-8-(tert-Butoxycarbonyl(methyl)amino)-
14-((R)-methoxy(phenyl)methyl)-2,2,6,11-tetramethyl-9,12-
dioxo-3,3-diphenyl-4-oxa-10,13-diaza-3-silapentadecan-15-oic
acid 14
To a stirred solution of ester 13 (20 mg, 0.054 mmol) in THF/
H2O (7:1) (20 mL), was added LiOH (4.0 mg, 0.15 mmol) at 0 °C.
The reaction was stirred at the same temperature for 2 h. After
completion, (monitored by the TLC), the reaction was quenched
yielded 1 (11 mg, 78%) as a gummy liquid. ½a D23
¼ ꢂ56:9 (c 0.65,
ꢁ
CHCl3); 1H NMR (300 MHz, CDCl3): d 8.08 (dd, J = 7.6, 18.8 Hz,
2H), 7.62–7.52 (m, 1H), 7.50–7.40 (m, 2H), 7.38–7.20 (m, 5H),
6.93–6.81 (m, 1H), 6.82–6.44 (m, 1H), 4.85–4.70 (m, 2H), 4.60–
4.40 (m, 2H), 4.30–4.20 (m, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 2.78
(m, 3H), 2.21–2.00 (m, 1H), 2.01–1.83 (m, 1H), 1.71–1.52 (m,
1H), 1.47 (s, 9H), 1.34–1.22 (m, 3H), 1.1 (d, J = 6.8 Hz, 3H); 13C
with
a saturated KHSO4 solution and extracted with EtOAc
(2 ꢀ 20 mL). The combined organic layers were dried over anhy-
drous Na2SO4 and removed under reduced pressure, the crude
was purified by column chromatography which yielded 14
(12 mg, 78%) as a gummy liquid. ½a D23
ꢁ
¼ ꢂ16:2 (c 0.30, CHCl3); 1H

K. Sathish et al. / Tetrahedron: Asymmetry 22 (2011) 1568–1573
1573
4. (a) Dellasala, G.; Izzo, I.; Spinella, A. Synlett 2006, 1319–1322; (b) Wen, S.-J.;
Zhang, H.-W.; Yao, Z.-J. Tetrahedron Lett. 2002, 43, 5291–5294; (c) Sugiyama, H.;
Shioiri, T.; Yokokawa, F. Tetrahedron Lett. 2002, 43, 3489–3492; (d) Tarver, J. E.,
Jr.; Terranova, K. M.; Joullie, M. M. Tetrahedron 2004, 60, 10277–10284; (e)
Hansen, D. B.; Starr, M.-L.; Tolstoy, N.; Joullie, M. M. Tetrahedron: Asymmetry
2005, 16, 3623–3627; (f) Hansen, D. B.; Joullie, M. M. Tetrahedron: Asymmetry
2005, 16, 3963–3969; (g) Hansen, D. B.; Lewis, A. S.; Gavalas, S. J.; Joullie, M. M.
Tetrahedron: Asymmetry 2006, 17, 15–16; (h) Sugiyama, H.; Yokokawa, F.;
Aoyama, T.; Shioiri, T. Tetrahedron Lett. 2001, 42, 7277–7280.
NMR (75 MHz, CDCl3): d 171.7, 170.4, 170.1, 166.6, 155.9, 136.6,
133.3, 132.8, 130.8, 129.5, 128.4, 128.3, 126.5, 120.3, 115.3, 83.2,
82.1, 68.8, 57.7, 57.5, 52.5, 48.6, 31.4, 30.1, 29.7, 28.2, 18.4, 17.8;
IR (KBr): mmax 3331, 3065, 2975, 1686, 1519, 1451, 1314, 1273,
1155, 1072, 713 cmꢂ1; MS (ESI): m/z 649.7 [M+Na]+; HRMS (ESI):
calcd for C33H45N3O9Na 650.3048, found 650.3057 [M+Na]+.
5. (a) Chandrasekhar, S.; Sudhakar, A. Org. Lett. 2010, 12, 236–238; (b)
Chandrasekhar, S.; Rambabu, Ch.; Reddy, A. S. Org. Lett. 2008, 10, 4355–4357;
(c) Chandrasekhar, S.; Yaragorla, S. R.; Sreelaksmi, L.; Reddy, Ch. R. Tetrahedron
2008, 64, 5174–5183; (d) Chandrasekhar, S.; Rambabu, Ch.; Shyamsundar, T.
Tetrahedron Lett. 2007, 48, 4683–4685; (e) Chandrasekhar, S.; Shyamsundar, T.;
Jayaprakash, S.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, 47, 47–49.
6. (a) Chandrasekhar, S.; Lohitha Rao, Ch.; Seenaiah, M.; Naresh, P.; Jagadeesh, B.;
Manjeera, D.; Sarkar, A.; Bhadra, M. P. J. Org. Chem. 2009, 74, 401–404; (b)
Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009, 74, 9531–9534;
(c) Chandrasekhar, S.; Reddy, G. P. K.; Sathish, K. Tetrahedron Lett. 2009, 50,
6851–6854.
Acknowledgments
K.S. and G.P.K. thank Council of Scientific and Industrial Re-
search (CSIR), New Delhi for research fellowship. The authors are
thankful to DST, New Delhi for funding the research grant.
References
1. Renner, M. K.; Shen, Y. C.; Cheng, X. C.; Jensen, P. R.; Frankmolle, W.; Kauffman,
C. A.; Fenical, W.; Lobkovsky, E.; Clardy, J. J. J. Am. Chem. Soc. 1999, 121, 11273–
11276.
2. Schmitt, E. K.; Riwanto, M.; Sambandamurthy, V.; Roggo, S.; Miault, C.;
Zwingelstein, C.; Krastel, P.; Nobel, C.; Beer, D.; Rao, P. S. S.; Au, M.;
Niyomrattanakit, P.; Lim, V.; Zheng, J.; Jeffery, D.; Pethe, K.; Camacho, L. R.
Angew. Chem., Int. Ed. 2011, 50, 5889–5891.
7. (a) Nevalainen, M.; Koskinen, A. M. P. Synlett 2001, 640–642; (b) Tarver, J. E.;
Joullie, M. M., Jr. J. Org. Chem. 2004, 69, 815–820.
8. (a) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185–7194; (b) Lee,
S.-H.; Song, I.-W. Bull. Korean Chem. Soc. 2005, 26, 223–224; (c) Lee, K.-D.; Suh, J.-
M.; Park, J.-H.; Ha, H.-J.; Choi, H. G.; Park, C. S.; Chang, J. W.; Lee, W. K.; Dong, Y.;
Yun, H. Tetrahedron 2001, 57, 8267–8276; (d) Loncaric, C.; Wulff, W. D. Org. Lett.
2001, 3, 3675–3678; (e) Manaka, T.; Nagayama, S.-I.; Desadee, W.; Yajima, N.;
Kumamoto, T.; Watanabe, T.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K. Helv.
Chim. Acta 2007, 90, 128–141.
3. (a) Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721–2724; (b) Wen, S.-J.; Hu, T.-S.;
Yao, Z.-J. Tetrahedron 2005, 61, 4931–4938.