Application of desymmetrization protocol for the formal total synthesis of emericellamide B

Article abstract of DOI:10.1016/j.tetlet.2010.04.015

A highly convergent formal total synthesis of emericellamide B, a 19-membered antibacterial depsipeptide is described. The key feature of the strategy is the generation of four stereogenic centers from a bicyclic precursor via desymmetrization technique a

Full text of DOI:10.1016/j.tetlet.2010.04.015

Tetrahedron Letters 51 (2010) 3079–3082
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of desymmetrization protocol for the formal total synthesis
of emericellamide B
*
*
Debendra K. Mohapatra , Sk. Samad Hossain, Santu Dhara, J. S. Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), 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 25 February 2010
Revised 1 April 2010
Accepted 6 April 2010
Available online 10 April 2010
A highly convergent formal total synthesis of emericellamide B, a 19-membered antibacterial depsipep-
tide is described. The key feature of the strategy is the generation of four stereogenic centers from a bicy-
clic precursor via desymmetrization technique and utilization for emericellamide B and related natural
product synthesis.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Emericellamide B
Cytotoxicity
Desymmetrization
Barton-McCombie reaction
Wittig homologation
Cyclic peptides and depsipeptides are a rich source of biologi-
cally active compounds produced in nature by plants, bacteria, fun-
gi, and lower sea animals.1,2 In comparison with linear peptides,
cyclic peptides are more stable against proteolytic degradation
due to their lack of free N- or C-terminus and reduced conforma-
tional freedom. The entropic advantages associated with the in-
creased rigidity also makes cyclic peptides tighter binding and
potentially more specific ligands of macromolecular receptors.
We have been interested in marine cyclopeptides and cyclodepsi-
peptides from vantage of structure confirmation, modification,
and biological activity verification.3 Emericellamides A (1) and B
(2), two novel cyclic depsipeptides, were isolated from marine-de-
rived fungus Emericella sp. with the proposed structures as shown
in Figure 1.4 The planar structures of these two new cyclic
depsipeptides contain two main features: a pentapeptide and 3-
hydroxy-2,4-dimethyldecanoic acid or 3-hydroxy-2,4,6-trim-
ethyldodecanoic acid. The absolute configurations of the
stereogenic centers on the polyketide side chain were established
by application of the Marfey’s method5 combined with modified
Mosher’s method.6 Emericellamide A (1) displayed antimicrobial
activity against methicillin-resistant Staphylococcus aureus (MIC:
against HCT-116 of 40 lM. Encouraged by the interesting struc-
tural feature combined with prominent biological activities and
to demonstrate the application of our developed desymmetrization
protocol,7 we embarked on a formal total synthesis of emericella-
mide B (2).
The retrosynthetic analysis (Scheme 1) has shown the desired
cyclization at the lactone junction. As it is already reported in the
literature about the failure of the lactonization step in the case of
H
H
N
N
O
O
O
O
O
O
NH
H
N
N
H
O
Emericellamide A (1)
H
H
N
N
3.8
carcinoma cell line (IC50 23
icellamide B (2) were slightly weaker than those of 1, showing an
MIC value of 6.0 M against methicillin-resistant S. aureus and IC50
lM). It also showed cytotoxicity against HCT-116 human colon
O
O
O
O
O
l
M). The biological activities of emer-
O
NH
H
N
N
H
l
O
Emericellamide B (2)
* Corresponding authors. Tel.: +91 40 27193128; fax: +91 40 27160512 (D.K.M.).
E-mail addresses: mohapatra@iict.res.in, dkm_77@yahoo.com (D.K. Mohapatra).
Figure 1. Structures of emericellamides A (1) and B (2).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.015

3080
D. K. Mohapatra et al. / Tetrahedron Letters 51 (2010) 3079–3082
H
N
H
N
O
a
H
N
O
O
O
O
OH
OtBu
O
CbzHN
CbzHN
O
NH
H
N
O
O
N
H
8
9
O
b, c
Emericellamide B (2)
O
O
H
N
CbzHN
H
H
N
H
OtBu
N
N
O
O
O
O
O
10
O
NH
d, e, f
BocHN
COOtBu
H
N
O
O
H
N
H
O
3
N
H2N
N
H
OtBu
O
O
H
N
NH2
4
HO
+
O
Scheme 2. Reagents and conditions: (a) H-Ala-OtBu, EDCI, HOBt, CH2Cl2, 12 h, 80%;
(b) Pd/C (10%), H2, EtOAc, 2 h; (c) Cbz-Val-OH, EDCI, HOBT, CH2Cl2, 14 h, 76%; (d) Pd/
C (10%), H2, EtOAc, 2 h; (e) Cbz-Gly-OH, EDCI, HOBT, CH2Cl2, 18 h; (f) Pd/C (10%), H2,
MeOH, 3 h, 64% over three steps.
O
O
O
O
O
NH
O
H
N
OtBu
BocHN
O
5
4
O
O
gave 18 in 92% yield. The secondary hydroxyl group was con-
verted to its xanthate derivative 19 and subsequent treatment
with Bu3SnH in the presence of catalytic amount of AIBN under
Barton-McCombie11 conditions to afford 2012 (78% yield over
two steps). The desilylation of 20 with TBAF in THF provided
alcohol 21 in 94% yield. The primary hydroxyl group was oxi-
dized with IBX13 in DMSO and THF to furnish aldehyde, which
on Wittig homologation yielded olefin 22 (74% yield over two
steps). Treatment of 22 with catalytic amount of Pd–C (10%)
and 6 N HCl in ethyl acetate provided diol 23 (81% yield over
two steps). The primary hydroxyl was silylated with TBDMSCl
and imidazole to obtain the TBS-ether, esterification of the sec-
ondary hydroxyl group with Boc-ala-OH using EDCI and DMAP
followed by desilylation with CSA afforded 2414 in 56% yield over
three steps. The primary hydroxyl group was converted to acid
following TEMPO15-mediated oxidation to furnish 5 in 78% yield.
The acid 5 was activated with EDCI in the presence of HOBt and
the amine 4 was coupled to provide our desired final product 316
in 76% yield. The spectral and analytical data of 3 were in good
agreement with the previously reported data by Ye et al.17
In conclusion, we have achieved the formal total synthesis
of emericellamide B from a bicyclic precursor in 15 longest
linear steps with 10% overall yield in a convergent fashion
which reconfirmed the absolute stereochemistry of emericella-
mide B.
CHO
O
O
7
6
OBn
Scheme 1. Retrosynthetic analysis of 2.
emericellamide A8 (1), we decided to carry out macrolactamization
as the final step of the synthesis. Disconnection of the emericella-
mide B (2) at the two alanine residues would give an advanced
intermediate 3 which on further fragmentations would provide
tetrapeptide 4 and a polyketide 5. The tetrapeptide 4 could be ob-
tained following a standard peptide-coupling protocol starting
from commercially available protected amino acids. The polyketide
fragment 5 could be envisaged following desymmetrization proto-
col to afford four chiral centers starting from a known bicyclic lac-
tone 7.7,9
Tetrapeptide 4 was synthesized from the commercially avail-
able protected amino acids. The coupling of Cbz-leu-OH (8) with
H-ala-OtBu ester using EDCI (N-(3-dimethylaminopropyl)-N0-eth-
ylcarbodiimide hydrochloride and HOBt afforded the dipeptide 9
in 80% yield. Deprotection of the Cbz-group with Pd–C (10%) in
ethyl acetate under hydrogen atmosphere followed by coupling
with Cbz-val-OH furnished the tripeptide 10 in 76% yield over
two steps. Following the same sequence of reactions, 4 was ob-
tained in 64% yield over three steps (Scheme 2).
Acknowledgments
The synthesis of 5 was initiated (Scheme 3) from a bicyclic
intermediate 7, which was prepared from 12 following desym-
metrization with chiral (+)-Ipc2BH, PCC mediated oxidation,
Bayer–Villiger oxidation, and diastereoselective alkylation of the
lactone 14. Reduction of the bicyclic lactone 7 with LAH in THF
furnished mono-protected tetrol 15 in 89% yield. The 1,3-diol
moiety was converted to the acetonide followed by protection
of the primary hydroxyl group as its TBS-ether using TBDMSCl
and imidazole in CH2Cl2 to afford 1710 in 94% yield. Deprotection
of the benzyl-ether with Pd/C (10%) under hydrogen atmosphere
S.H. and S.D. thank Council of Scientific & Industrial research
(CSIR), New Delhi, for the financial assistance in the form of re-
search fellowships. D.K.M. thanks CSIR for a research grant (INSA
Young Scientist Award).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.015.

D. K. Mohapatra et al. / Tetrahedron Letters 51 (2010) 3079–3082
3081
O
O
O
Br
Br
HO
c
a
b
O
+
O
11
13
O
OBn
OBn
12
O
O
O
O
g
e
i
f
d
O
O
OR1 OR2 OR4 OR3
R1 = R2 = R3 = H
15
R
7
14
OBn
4 = Bn
OBn
k
O
j
O
OR4 OR3
4 = H
O
O
OR4 OR3
O
l
O
OR3
3 = H
16
20 R3 = TBDMS
R
R
R
18
19
h
4 = xanthate
17 R3 = TBDMS
21
R
3 = H
o,p
m,n
O
O
OH OH
22
23
HO
HO
q,r
s
O
O
O
O
O
5
24
BocHN
BocHN
H
H
N
N
O
O
O
ref 17
t
O
Emericellamide B (2)
O
NH
H
N
BocHN
CO2tBu
O
3
Scheme 3. Reagents and conditions: (a) Zn–Cu couple, DME, ꢁ10 °C, 6 h, 82%; (b) (1) DIBAL-H, CH2Cl2, ꢁ10 °C, 1 h, 74% (required product); (2) NaH, BnBr, THF, 50 °C, 94%; (c)
(+)-(Ipc)2BH, THF, ꢁ20 °C, five days, 92%; (d) (1) PCC, CH2Cl2, rt, 3 h, 90%; (2) m-CPBA, NaHCO3, CH2Cl2, rt, 90%; (e) LDA, MeI, THF, ꢁ78 °C, 1 h, 94%; (f) LAH, THF, 0 °C to rt, 12 h,
89%; (g) 2,2-DMP, p-TSA, CH2Cl2, 12 h, 91%; (h) TBDMSCl, imidazole, CH2Cl2, 1 h, 94%; (i) Pd/C, H2, dry hexane, 12 h, rt, 92%; (j) NaHMDS, CS2, MeI, THF, ꢁ78 °C, 1 h; (k)
Bu3SnH, AIBN, PhH, 80 °C, 3 h, 78% over two steps; (l) TBAF, THF, 3.5 h, 94%; (m) IBX, DMSO, THF, 3 h; (n) Ph3PC5H11Br, NaHMDS, THF, 1 h, 74% over two steps; (o) Pd/C (10%),
H2, EtOAc, 2 h; (p) 6 N HCl, 81% over two steps; (q) TBDMSCl, imidazole, CH2Cl2, 1 h, 93%; (r) (i) Boc-Ala-OH, EDCI, DMAP, 0 °C to rt, 12 h, 70%; (ii) CSA, CH2Cl2/MeOH (1:1),
0 °C, 1 h, 86%; (s) BAIB, TEMPO, CH3CN/H2O (1:1), 78% over two steps; (t) H-Gly-Val-Leu-Ala-OtBu, EDCI, HOBt, DIPEA, CH2Cl2, 12 h, 76%.
9. Yadav, J. S.; Srinivas, R.; Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603–1606.
References and notes
10. Spectral and analytical data of 17: ½a D27
ꢀ
+27.9 (c 1.2, CHCl3); IR (neat): mmax 2957,
2858, 1462, 1381 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.34–7.26 (m, 5H), 4.59
;
(ABq, J = 21.1, 12.1 Hz, 2H), 3.84 (dd, J = 9.8, 0.75 Hz, 1H), 3.77 (dd, J = 9.8, 6.0,
1H), 3.63 (dd, J = 11.3, 5.3 Hz, 1H), 3.49–3.39 (m, 2H), 3.37 (dd, J = 9.8, 1.5 Hz,
1H), 2.09–1.90 (m, 2H), 1.89–1.76 (m, 1H), 1.33 (s, 3H), 1.32 (s, 3H), 1.04 (d,
J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.88 (d, J = 6.0 Hz, 3H), 0.70 (d, J = 6.0 Hz, 3H), 0.04
(s, 6H); 13C NMR (75 MHz, CDCl3) d 139.44, 128.20, 127.11, 126.85, 97.94,
82.76, 74.61, 73.47, 66.32, 64.16, 38.24, 36.84, 30.30, 29.86, 25.94, 19.48, 15.95,
12.44, 9.91, ꢁ5.36; ESIMS: [M+H]+ 451.
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ꢀ
+16.4 (c 2.1, CHCl3); IR (neat): mmax 2955,
2857, 1463, 1380, 1225 cmꢁ1 1H NMR (300 MHz, CDCl3) d 3.69 (dd, J = 11.3,
;
4.9 Hz, 1H), 3.53–3.30 (m, 4H), 1.92–1.73 (m, 2H), 1.73–1.57 (m, 2H), 1.55–1.23
(m, 1H), 1.39 (s, 3H), 1.35 (s, 3H), 0.90 (s, 9H), 0.88 (d, J = 6.8 Hz, 3H), 0.87 (d,
J = 6.6 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) d
97.94, 75.97, 68.53, 66.41, 37.05, 32.89, 30.76, 30.17, 29.64, 25.92, 19.01, 18.34,
17.10, 13.39, 12.32, ꢁ5.37; ESIMS: [M+H]+ 345.
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4092–4096.
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14. Spectral and analytical data of 24: ½a D27
ꢀ
ꢁ2.4 (c 1.0, CHCl3); IR (neat):
mmax 3439,
3363, 1708, 1512, 1458, 1371 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 5.07–4.98 (m,
1H), 4.38 (dd, J = 11.3, 5.2 Hz, 1H), 4.26 (dd, J = 14.3, 6.7 Hz, 1H), 4.21–4.11 (m,
1H), 3.30–3.17 (m, 1H), 2.14–1.80 (m, 2H), 1.79–1.60 (m, 1H), 1.44 (s, 9H), 1.39
(d, J = 6.7 Hz, 3H), 1.36–1.16 (m, 10H), 1.11–1.01 (m, 2H), 0.92 (d, J = 6.7 Hz,
3H), 0.91 (t, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H); 13C
7. (a) Yadav, J. S.; Srinivas Rao, C.; Chandrasekhar, S.; Rama Rao, A. V. Tetrahedron
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3082
D. K. Mohapatra et al. / Tetrahedron Letters 51 (2010) 3079–3082
NMR (75 MHz, CDCl3) d 173.82, 155.14, 74.40, 68.24, 64.03, 49.27, 41.74, 36.92,
36.33, 31.87, 31.24, 29.77, 29.64, 28.25, 26.87, 22.61, 19.99, 18.52, 14.04, 13.84,
12.39; ESIMS: [M+Na]+ 438.
2.14–1.98 (m, 1H), 1.93–1.82 (m, 1H), 1.74–1.58 (m, 3H), 1.52 (m, 2H), 1.46 (s,
9H), 1.41 (s, 9H), 1.32 (d, J = 7.8 Hz, 3H), 1.30 (d, J = 7.8 Hz, 3H), 1.24 (br s, 11H),
1.12 (d, J = 6.8 Hz, 3H), 1.04–0.97 (m, 1H), 0.95–0.85 (m, 18H), 0.81 (d,
J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 174.22, 172.28, 171.67, 170.90,
169.25, 155.31, 81.48, 79.61, 77.67, 60.32, 58.67, 51.39, 49.42, 48.64, 43.10,
41.15, 36.59, 31.85, 31.49, 31.44, 29.58, 29.41, 28.35, 27.89, 26.67, 24.60, 22.80,
22.60, 22.10, 19.98, 19.13, 18.47, 18.09, 17.92, 14.45, 14.04, 13.52; HRMS calcd
for C43H79O10 [M+Na]+ 848.5724; found 848.5710.
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16. Spectral and analytical data of 3: ½a D27
ꢁ33.1 (c 0.4, CH2Cl2); mp 117 °C; IR
ꢀ
(neat): mmax 3281, 2962, 2928, 1733, 1688, 1635, 1538, 1455, 1369, 1220,
1158 cmꢁ1 1H NMR (500 MHz, CDCl3) d 7.84 (br s, 1H), 7.65 (br s, 1H), 7.16 (br
;
s, 1H), 5.55 (d, J = 7.6 Hz, 1H), 5.06 (d, J = 8.0 Hz, 1H), 4.71–4.57 (m, 1H), 4.50–
4.38 (m, 2H), 4.29–4.13 (m, 2H), 3.91 (d, J = 14.6 Hz, 1H), 2.79–2.68 (m, 1H),
17. Li, S.; Liang, S.; Tan, W.; Xu, Z.; Ye, T. Tetrahedron 2009, 65, 2695–2702.