Total synthesis of hirsutellide A

Article abstract of DOI:10.1016/j.tetlet.2005.04.087

The total synthesis of hirsutellide A 1 was described. The linear hexadepsipeptide precursor 2 was synthesized in 45% yield from N-Boc-Me-Gly by three coupling reactions with DCC, HATU and BOP-Cl, respectively. Macrocyclization was successfully performed on the fully deprotected amino acid 14 with BOP-Cl in 15% yield and with FDDP in 22% yield.

Full text of DOI:10.1016/j.tetlet.2005.04.087

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4377–4379
Total synthesis of hirsutellide A
Yanjie Xu,a,b Ligong Chen,a,b Xuemin Duan,a,b Yi Meng,b Liqin Jiang,a,b Meiling Li,a,b
Guangle Zhaoa,b and Yang Lia,*
aCollege of Pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072, China
bShenzhen Graduate School of Peking University, Shenzhen University Town, Shenzhen 518055, China
Received 15 November 2004; revised 19 April 2005; accepted 20 April 2005
Available online 11 May 2005
Abstract—The total synthesis of hirsutellide A 1 was described. The linear hexadepsipeptide precursor 2 was synthesized in 45%
yield from N-Boc-Me-Gly by three coupling reactions with DCC, HATU and BOP–Cl, respectively. Macrocyclization was success-
fully performed on the fully deprotected amino acid 14 with BOP–Cl in 15% yield and with FDDP in 22% yield.
Ó 2005 Elsevier Ltd. All rights reserved.
Hirsutellide A 1, an 18-membered cyclic depsipeptide
isolated from the cell extracts of Hirsutella kobayasii
BCC 1660, exhibits antimycobacterial activity with a
MIC (minimum inhibitory concentration) of 6–12 lg/mL
with no cytotoxic effect towards Vero cells at 50
lg/mL and weak in vitro antimalarial activity with an
IC50 value of 2.8 lg/mL.1 The retrosynthetic analysis
of hirsutellide A 1 is shown in Figure 1.
Ring closure can be achieved by either amide bond or
ester bond formation. In this letter, the macrocyclization
of linear precursor 2 through the formation of the amide
bond from the amino function of the isoleucine residue
and the carboxylic acid function of the 2-hydroxy-3-phen-
ylpropanoic acid residue was chosen. Firstly, the forma-
tion of an amide bond is more rapidly and the formation
does not require a high level of activation of the
O
OBn
O
O
O
N
O
H
NHBoc
N
O
O
N
O
N
O
O
N
O
Me
O
Me
OBn
Me
Me
O
O
O
N
H
H
N
N
O
O
O
O
O
NHBoc
3
1
2
O
NHBoc
OH
OH
BocN
OBn
+
+
Me
O
OH
O
4
5
6
Figure 1. Retrosynthetic analysis of hirsutellide A (1).
Keywords: Hirsutellide A; Cyclohexadepsipeptide; Coupled reagent; Diazotization hydrolysis; Boc protection.
*
Corresponding author. Tel.: +86 22 27891034; fax: +86 22 27406314; e-mail: liyang777@tju.edu.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.087

4378
Y. Xu et al. / Tetrahedron Letters 46 (2005) 4377–4379
O
O
O
a
b
OH
OH
OBn
OH
7
NH2
-Phenylalanine
OH
4
D
Scheme 1. Reagents and conditions: (a) NaNO2, H2SO4, 36 h, 98%; (b) BnOH, TsOH, reflux, 4 h, toluene, 60%.
carboxyl group. Secondly, if the other amide bond was
chosen, the reaction of the N-methyl glycine with the
carboxylic acid of the isoleucine would be blocked.
Now sub target molecule 2 was divided into two tridep-
sipeptides units 3. Further divisions led to three sub-
units, 2-hydroxy-3-phenylpropanoic acid benzyl ester
added in 24 h to push the reaction to completion. Unit
6 was the N-Boc-protected isoleucine.
The synthetic sequence of compound 2 was shown in
Scheme 3. Esterification of
4 (1.0 equiv) and 5
(1.0 equiv) using DCC (1.1 equiv) and HOBt (1.1 equiv)
as catalyst yielded the fully protected didepsipeptide 9.5
Removal of the Boc protecting group by treatment with
TFA (6.5 equiv) afforded compound 10. Then the amine
TFA salt 10 (1.0 equiv) was coupled with unit 6
(1.1 equiv) by using triethylamine (10.0 equiv) as base,
DMAP (0.1 equiv) as catalyst and three coupling re-
agents, respectively. The corresponding protected tri-
depsipeptide 36 was obtained by using HATU-promoted
reagent (1.2 equiv) in 81% yield, compared with Py-
BOP-promoted (1.2 equiv) in 60% yield and DCC
(1.2 equiv) in 51.2% yield. Cleavage of the benzyl ester
or the Boc group gave two deprotected precursors 11
or 12, respectively. Subsequently the coupling reaction
of the amine TFA salt 12 (1.0 equiv) and free acid resi-
due 11 (1.0 equiv) were performed to synthesize the lin-
ear hexadepsipeptide 2 by using HATU (1.1 equiv),
PyBOP (1.1 equiv) or BOP–Cl (1.1 equiv), with diiso-
propyl ethylamine (DIPEA) (10.0 equiv) as base and
HOBt (1.1 equiv) as catalyst. Only the reaction with
BOP–Cl reagent worked in 77% yield to provide the
product 2.7
4, (tert-butoxycarbonyl-methyl-amino)-acetic acid
5
and 2-tert-butoxycarbonyl amino-3-methyl-pentanoic
acid 6.
Compound 44 was obtained from D-phenylalanine
through the diazotization hydrolysis2 and esterification3
by benzyl alcohol (Scheme 1). In the first step compound
7 was obtained as a white solid with mp 125–127
20
D
°C (lit.,2a 123–124 °C) and ½aꢀ +38.6 (c 1.00, DMF)
25
[lit.,2a ½aꢀ +26.7 (c 3.80, acetone)].
D
Subunit 5 was obtained from glycine by a N-Boc-protec-
tion and N-methylation with CH3I (Scheme 2). CH3I
was added in two portions. After the addition of first
part of CH3I (4.0 equiv) and NaH (2.5 equiv), second
part of CH3I (2.0 equiv) and NaH (1.0 equiv) were
OH
OH
OH
a
b
H2N
BocHN
BocN
Me
O
O
O
Glycine
8
5
Subsequent reductive removal of the benzyl group and
cleavage of the Boc group gave the carboxylic acid
amine TFA salt 14 (Scheme 4).
Scheme 2. Reagents and conditions: (a) Boc2O, NaOH, THF, 0 °C to
rt, 24 h; HCl, 90%; (b) CH3I, NaH, THF, 0 °C to rt, 2 d; HCl, 92%.
O
O
O
OH
a
Boc-Ile 6
OR1
BocN
OBn
NR
OBn
c
+
O
Me
O
OH
O
N
O
O
5
4
O
9: R=Boc
10: R=H
b
NHR2
3: R1=Bn, R2=Boc
11: R1=H, R2=Boc
12: R1=Bn, R2=H
d
e
O
O
N
H
N
O
O
O
N
f
11
+
12
Me
Me
O
O
Boc
O
HN
OBn
2
Scheme 3. Reagents and conditions: (a) DCC, HOBt, DCM, 0 °C to rt, 24 h, 72%; (b) TFA, DCM, 0 °C to rt, 5 h, used directly in the next step; (c)
HATU, Et3N, DMAP, DCM, 81%; (d) 5% Pd–C, H2, AcOEt, rt, 24 h; (e) TFA, DCM, 0 °C to rt, 5 h, used directly in coupling; (f) BOP–Cl, DIPEA,
HOBt, DCM, 0 °C to rt, 24 h, 77%.

Y. Xu et al. / Tetrahedron Letters 46 (2005) 4377–4379
4379
O
O
O
O
N
H
N
H
N
O
O
O
N
N
O
O
O
N
Me
Me
a
c
b
1
2
Me
O
Me
O
O
Boc
O
O
HN
O
H2N
TFA
OH
OH
14
13
Scheme 4. Reagents and conditions: (a) 5% Pd–C, H2, AcOEt, rt, 24 h, 86%; (b) TFA, DCM, 0 °C to rt, 5 h, used directly in cyclization; (c) BOP–Cl,
DIPEA, DMF, 0 °C to rt, 3 d, 15%.
1179, 1160, 1070, 746, 703 cmꢁ1 1H NMR (400 MHz,
;
The macrocyclization proceeded with BOP–Cl
(4.5 equiv), DIPEA (10.0 equiv) in DMF under highly
dilute conditions (1.0 L solvent/1.0 mmol reactant) in
15% yield for hirsutellide A 1. And the yield was 22%
when the coupling reagent FDDP (4.5 equiv) was used
instead of BOP–Cl. The structure was determined by
mass spectrometry and NMR spectroscopy.8 The rota-
tion value is consistent with the value of natural
product.1
CDCl3) d (rotamer): 7.14–7.32 (m, 10H), 5.30–5.32 (m, 1H),
5.08–5.15 (m, 2H), 3.91–4.05 (m, 2H), 3.10–3.18 (m, 2H),
2.79, 2.78 (s, 3H, rotamer), 1.26–1.46 (m, 9H); 13C NMR
(100 MHz, CDCl3) d (rotamer): 169.05, 168.64, 155.60,
154.95, 135.20, 135.13, 134.84, 129.16, 129.06, 128.31,
128.28, 128.26, 128.19, 128.09, 128.05, 126.81, 79.83,
79.77, 73.09, 73.01, 66.86, 50.39, 49.68, 36.98, 34.93,
28.06, 27.87.
20
6. Analytical data of compound 3: ½aꢀD +6.3 (c 1.0, CHCl3);
IR (KBr) mmax: 3409, 3316, 2969, 1753, 1708, 1652, 1497,
1402, 1377, 1246, 1176, 1075, 1031, 745, 703 cmꢁ1 1H
;
In conclusion, the antimycobacterial cyclohexadepsipep-
tide hirsutellide A 1 has been prepared in nine steps
starting from 2- hydroxy-3-phenylpropanoic acid benzyl
ester 4, (tert-butoxycarbonyl-methyl-amino)-acetic acid
5 and 2-tert-butoxycarbonyl amino-3-methyl-pentanoic
acid 6. The linear hexadepsipeptide precursor 2 was syn-
thesized in 45% yield based on compound 5 using three
coupling reactions with DCC, HATU and BOP–Cl,
respectively. The macrocyclization was successfully per-
formed on the fully deprotected amino acid 14 with
BOP–Cl in 15% yield and with FDDP in 22% yield.
NMR (400 MHz, CDCl3) d (rotamer): 7.10–7.34 (m, 10H),
5.31 (dd, 1H, J1 = 5.2 Hz, J2 = 7.6 Hz), 5.04–5.17 (m, 3H),
4.51 (br, NH), 4.53 (d, 1H, J = 17.6 Hz), 3.80 (d, 1H,
J = 17.6 Hz), 3.16 (dd, 1H, J1 = 5.2 Hz, J2 = 14.4 Hz), 3.10
(dd, 1H, J1 = 7.6 Hz, J2 = 14.4 Hz), 3.00 (s, 3H), 1.66–1.71
(m, 1H), 1.40 (s, 9H), 0.88–0.96 (m, 8H); 13C NMR
(100 MHz, CDCl3) d (rotamer): 173.12, 168.95, 168.38,
155.83, 135.23, 134.97, 129.33, 128.56, 128.52, 128.49,
128.42, 128.36, 127.13, 79.48, 73.43, 67.23, 54.22, 49.16,
38.03, 37.15, 36.36, 28.32, 23.91, 15.55, 11.29.
20
7. Analytical data of compound 2: ½aꢀD +1.06 (c 3.16, CHCl3);
IR (KBr) mmax: 3309, 2963, 2931, 1753, 1705, 1645, 1501,
1465, 1406, 1376, 1250, 1176, 1071, 745, 707 cmꢁ1 13C
;
References and notes
NMR (100 MHz, CDCl3) d: 174.24, 172.53, 168.84, 168.67,
168.19, 167.47, 156.06, 136.29, 135.28, 134.90, 130.83,
129.32, 129.29, 129.25, 128.56, 128.53, 128.48, 128.45,
128.40, 128.39, 128.35, 128.28, 127.07, 126.90, 126.79,
79.19, 74.79, 73.42, 67.21, 65.47, 54.00, 52.38, 49.06, 38.00,
37.27, 36.83, 36.28, 30.51, 29.61, 28.40–28.38 (3C), 24.27,
24.24, 15.37, 15.20, 10.84, 10.57. MS: m/z = 895.5 (M+Na)+.
1. Vongvanich, N.; Kittakoop, P.; Iaska, M.; Trakulnaleam-
sai, S.; Vimuttipong, S.; Tanticharoen, M.; Thebtaranonth,
Y. J. Nat. Prod. 2002, 65, 1346–1348.
2. (a) Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U.
J. Chem. Soc., Perkin Trans. 1 1993, 11–14; (b) Honda, Y.;
Ori, A.; Tsuchihashi, G. Bull. Chem. Soc. Jpn. 1987, 60,
1027–1036.
20
8. Analytical data of compound 1: ½aꢀD ꢁ13.8 (c 0.22, CHCl3)
28
[lit.,1 ½aꢀD ꢁ13.6 (c 0.25, CHCl3)]; IR (film) mmax: 3283.69,
3018.56, 2962.65, 2927.93, 1753.57, 1661.38, 1630.27,
1529.52, 1482.58, 1060.54 cmꢁ1
3. Furuta, K.; Gao, Q.; Yamamoto, H. Org. Synth., Coll. Vol.
9, 722–728.
;
1H NMR (400 MHz,
20
CDCl3) d: 7.54 (d, 2NH, J = 10.0 Hz), 7.29–7.14 (m,
10H), 5.61 (dd, 2H, J1 = 2.8 Hz, J2 = 11.6 Hz), 4.91 (t,
2H, J = 10.2 Hz), 4.44 (d, 2H, J = 17.2 Hz), 3.66 (dd, 2H,
J1 = 2.8 Hz, J2 = 14.0 Hz), 3.25 (s, 6H), 3.17 (d, 2H,
J = 17.2 Hz), 2.73 (dd, 2H, J1 = 11.6 Hz, J2 = 14.0 Hz),
2.27–2.20 (m, 2H), 1.57–1.51 (m, 2H), 1.27–1.14 (m, 2H),
0.90 (t, 6H, J = 7.4 Hz), 0.85 (d, 6H, J = 6.8 Hz); 13C NMR
(100 MHz, CDCl3) d: 174.08, 168.77, 166.82, 136.16,
129.11, 128.58, 127.11, 74.07, 52.33, 51.75, 38.73, 37.90,
35.86, 24.27, 15.38, 10.17. HR-MS (FAB) m/z calcd for
C36H49N4O8 (M+1) 665.3550, found 665.3545.
4. Analytical data of compound 4: ½aꢀD +54.9 (c 1.5, DCM)
25
[lit.,2a ½aꢀD +55.2 (c 1.88, DCM)]; IR (KBr) mmax: 3484,
3034, 2928, 1737, 1495, 1450, 1380, 1264, 1189, 1094, 745,
698 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 7.18–7.41 (m,
;
10H), 5.20 (s, 2H), 4.51 (dd, 1H, J1 = 4.8 Hz, J2 = 6.4 Hz),
3.15 (dd, 1H, J1 = 4.8 Hz, J2 = 13.6 Hz), 3.01 (dd, 1H,
J1 = 6.4 Hz, J2 = 13.6 Hz), 2.92 (br, OH); 13C NMR
(100 MHz, CDCl3) d: 173.85, 136.09, 134.94, 129.40,
128.50, 128.44, 128.23, 126.67, 71.17, 67.18, 40.34.
20
5. Analytical data of compound 9: ½aꢀD +16.3 (c 1.0, CHCl3);
IR (KBr) mmax: 2970, 2932, 1754, 1703, 1453, 1381, 1243,