Synthesis of novel analogues of antimycin A3

Article abstract of DOI:10.1016/j.tetlet.2008.06.050

Four novel analogues of antimycin A₃, 1a-d, were synthesized in good overall yields.

Full text of DOI:10.1016/j.tetlet.2008.06.050

Tetrahedron Letters 49 (2008) 5192–5195
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel analogues of antimycin A3
*
Zilun Hu, Xiangjun Jiang, Wei Han
Discovery Chemistry, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Four novel analogues of antimycin A3, 1a–d, were synthesized in good overall yields.
Received 6 March 2008
Revised 9 June 2008
Accepted 10 June 2008
Available online 14 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Macrocyclization
Synthesis
Analogues
Antimycin
Antimycin A, a mixture of A1–A8, was isolated from streptomyces
species as antibiotics possessing antifungal activity.1 Among the
components of antimycin A complex, antimycin A3 is one of the
most active agents that specifically inhibits the electron transfer
activity of ubiquinol-cytochrome c oxidoreductase.2 Antimycin A3
also shows effects on mitochondrial function for the ability to
selectively kill cells with high versus low Bcl-XL expression in iso-
genic cell lines, which acted as selective apoptotic triggers in tumor
cells.3
As part of our drug discovery program in oncology, we were
interested in evaluating novel analogues of antimycin A3. Specifi-
cally, we were interested in analogues varying at R1, R2, and R3
groups as shown in Figure 1 (1a–d). Although the synthesis of anti-
mycin A3 is known in the literature,4 reports on analogues varying
at the dilactone core are limited. In this Letter, we wish to report
the synthesis of these four novel analogues of antimycin A3 (1a–d).
The retrosynthetic analysis of analogue 1a is outlined in Figure
2. As shown, 1a can be envisioned from connection of dilactone 3
with 3-formamido-2-methoxybenzoic acid (2) and isovaleryl chlo-
ride. The nine-membered dilactone 3 can be constructed from
H
O
OMe
HN
CO2H
H
O
9
O
Bu
O
2
HN
OMe
HN
O
O
O
8
2
O
3
7
4
Bu
6
O
O
O
O
8
BocHN
H
HN
1a
7
O
OTBS
R1
O
O
O
3
Bu
O
O
OR3
O
O
O
9
HN
Bu
BnO
HO
8
O
R2
OTBS
7
6
OH
antimycin A3: R1 = (R)-Me, R2 = Me, R3 = H
1a: R1 = (R)-Me, R2 = H, R3 = Me
1b: R1 = H, R2 = Me, R3= Me
1c: R1 = (S)-Me, R2 = H, R3 = Me
1d: R1 = H, R2 = H, R3 = Me
OH
O
Bu
5
O
O
8
BocHN
2
7
OTBS
OBn
OH
BOCHN
3
4
4
Figure 1.
O
6
* Corresponding author. Tel.: +1 609 818 5288.
E-mail address: Wei.hen1@BMC.com (W. Han).
Figure 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.050

Z. Hu et al. / Tetrahedron Letters 49 (2008) 5192–5195
5193
cyclization of hydroxy carboxylic acid 4, which could be built from
OH
OMe
alcohol 5 and threonine derivative 6.
a, b
O2N
CO2Bn
O2N
CO2H
Scheme 1 outlines the synthesis of aminodilactone 3. Starting
from ethyl hydroxy acetate (7), protection of hydroxy group fol-
lowed by reduction of ester provided aldehyde 8. The stereochem-
istry of C7 and C8 in 1a was then established via Evans aldol
condensation using aldehyde 8 and (R)-4-benzyl-3-hexanoyl-oxaz-
olidin-2-one (9), which was readily prepared from (R)-4-benzylox-
azolidin-2-one and hexanoyl chloride. Under these conditions,
alcohol 10 was obtained in 87% yield with high diastereoselectivity
(>98% de).5 Removal of chiral auxiliary under standard condition
followed by protection of the acid provided 11 in 90% yield. The
secondary hydroxy group in 11 was then protected as TBS ether,
and the primary hydroxy group was freed using DDQ to give alco-
hol 5. Coupling of 5 with threonine derivative 6 introduced C2–C4
fragment in 1a, and provided the corresponding benzyl ester in
84% yield. Reductive removal of benzyl groups freed both hydroxy
and carboxylic acid termini, and yielded hydroxy carboxylic acid 4.
Thus, intermediate 4 set up the stage for the nine-membered dilac-
tone formation.
Macrocyclization of 4 was conducted under Corey–Nicolaou’s
condition promoted by silver ion.6 To avoid dimerization, highly
diluted reaction solution (ꢀ0.001 M) was used. Thus pre-formed
thioester solution, obtained by refluxing 4 with triphenylphos-
phine and 2,20-dipyridyl disulfide in toluene, was added to a solu-
tion of silver perchlorate in toluene at reflux for over 2 h. After
stirring at reflux for an additional hour, dilactone 37 was formed
in 48% yield.
12
13
H
O
OMe
c, d
HN
CO2H
2
a: BnOH, H2SO4, toluene (>95%); b: MeI, K2CO3, DMF, rt, (>95%)
c: H2, Pd/C, EtOAc (>95%); d: MeC(O)-O-CHO, THF (90%)
;
O
Bu
a, b
O
O
O
BocHN
3
O
O
14
H
O
O
OMe
c, d
Bu
O
HN
O
O
HN
O
O
O
1a
a: HF.Pyr., THF, rt, 3 days (95%); b: isovaleryl chloride, CH2Cl2,
Pyr., 0 oC (88%); c: 50% TFA/CH2Cl2, rt (95%); d: 2, EDCI,
DMAP, CH2Cl2 (94%)
Scheme 2.
With the key intermediate 3 available, 1a was constructed by
installations of the two side chains as outlined in Scheme 2. First,
the aromatic side chain 3-formamido-2-methoxybenzoic acid
was prepared from commercially available material 2-hydroxy-3-
nitrobenzoic acid (12). Protection of the carboxylic acid followed
by conversion of the phenol to its methyl ether provided 13 in
excellent yields. Hydrogenation of 13 gave 3-amino-2-methoxy-
benzoic acid, which was converted to 3-formamido-2-methoxy-
benzoic acid (2) upon treatment with acetic formic anhydride.
Removal of TBS group in intermediate 3 with HF/pyridine fol-
lowed by treatment with isovaleryl chloride installed the isovaleryl
side chain. Finally, deprotection of BOC group followed by coupling
with 3-formamido-2-methoxybenzoic acid (2) completed the syn-
thesis of 1a7 in high yield.
A similar synthetic route was applied to the synthesis of 1b.
Starting from (S)-ethyl 2-hydroxypropanoate (15) and applying
the chemistry described in Scheme 1, steps a–g, C6–C8 chiral cen-
ters were established and alcohol 16 was obtained in 42% yield.
Coupling of alcohol 16 with Boc-Ser(OBn)-OH introduced C2–C4
fragment and thus provided, after deprotection, the hydroxy car-
boxylic acid intermediate 17 (Scheme 3). In this case, macrocycli-
O
OH
7
O
MPMO
8
H
O
N
OEt
c
MPMO
a, b
HO
Bu
O
O
O
Bn
10
7
8
OH
Bu
BnO
HO
9
6
a, b
8
O
OEt
OH
O
7
Bu
OTBS
f, g
h, i
BnO
HO
d, e
MPMO
O
OBn
16
15
OTBS
O
Bu
11
O
O
5
Bu
HO
Bu
2
OH
HO
c
O
O
BocHN
3
Bu
OH
2
4
O
Bu
O
OTBS
OTBS
BocHN
O
j
BOCHN
O
3
O
O
4
O
BocHN
18
OTBS
17
OTBS
O
O
O
H
3
4
O
O
O
Bu
d, e, f, g
HN
OMe
O
O
O
O
n-C5H11
N
HN
N
H
9
Bn
O
O
Scheme 1. Reagents and conditions: (a) MPM-Cl, NaH, DMF, Bu4NI, 0 °C to rt (88%);
(b) DiBALl, CH2Cl2, ꢁ78 °C (70%); (c) 9, Bu2BOTf, TEA, CH2Cl2 (87%); (d) LiOH, H2O2,
0 °C to rt; (e) BnOH, Ph3P, DIAD, THF, rt (90% for two steps); (f) TBSCl, Im., DMF, rt
(86%); (g) DDQ, CH2Cl2/H2O (>95%); (h) Boc-Thr(OBn)-OH (6), EDCI DMAP, CH2Cl2,
0 °C to rt (84%); (i) H2, Pd/C, EtOH, rt (>95%); (j) (1) (C5H4NS)2/Ph3P, tol., rt; (2)
AgClO4, tol., 120 °C (48%).
1b
Scheme 3. Reagents and conditions: (a) Boc-Ser(OBn)-OH, EDCI, DMAP, DMF (89%);
(b) H2, Pd/C, EtOH (>95%); (c) Ph3P, DIAD, CH2Cl2, (98%): (d) HFꢂPyr., THF, rt (95%);
(e) isovaleryl chloride, CH2Cl2, Pyr., 0 °C (82%); (f) 50% TFA/CH2Cl2, rt (95%); (g) 2,
EDCI, DMAP, CH2Cl2 (83%).

5194
Z. Hu et al. / Tetrahedron Letters 49 (2008) 5192–5195
zation of 17 proceeded smoothly under Mitsunobu conditions to
provide dilactone 187 in excellent yield. Again, installations of
the isovaleryl side chain and 3-formamido-2-methoxybenzoyl side
chain, which were used in the synthesis of 1a, completed the prep-
aration of 1b7 in good overall yield.
In summary, four novel analogues of antimycin A3 (1a–d) were
synthesized in good overall yields.
Supplementary data
The synthesis of analogues 1c and 1d adopted the intermediates
4 and 5, respectively, from Scheme 1. As outlined in Scheme 4, the
preparation of 1c started from hydroxy carboxylic acid 4. In this
case, cyclization of 4 under Mitsunobu conditions proceeded
smoothly with inversion of the stereo center at C2 to give dilactone
197 with desired stereochemistry in 91% yield. Again, coupling of
the two side chains as described previously finished the synthesis
of 1c7 in high yields.
The preparation of analogue 1d was from intermediate 5 as
shown in Scheme 5. Thus, coupling of alcohol 5 with Boc-
Ser(OBn)-OH in the presence of EDCI and DMAP introduced the
C2–C4 fragment and provided compound 20 in 91% yield. Then
deprotection of the two benzyl groups followed by cyclization un-
der Mitsunobu conditions yielded dilactone 21.7 Again, removal of
the TBS group with HF/pyridine followed by treatment with
isovaleryl chloride fixed the isovaleryl side chain, and deprotection
of BOC group followed by coupling with 3-formamido-2-meth-
oxybezoic acid completed the synthesis of analogue 1d.7
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.050.
References and notes
1. Duncshee, B. R.; Leben, C.; Keitt, G. W.; Strong, F. M. J. Am. Chem. Soc. 1949, 71,
2436–2437.
2. (a) Wilstrom, M. K. F. Biochim. Biophys. Acta 1972, 283, 403–420; (b) Anderson, K.
M.; Rubenstein, M.; Alfrefai, W. A.; Dudeja, P.; Tsui, P.; Harris, J. E. Anticancer Res.
2004, 24, 2601–2615; (c) Tzung, S. P.; Kim, K. M.; Basanez, G.; Giet, C. D.; Simon,
J.; Zimmerberg, J.; Zhang, K. Y. J.; Hockenbery, D. M. Nature Cell Biol. 2001, 3,
183–191; (d) Kim, K. M.; Giet, C. D.; Basanez, G.; O’Neill, J. W.; Hill, J. J.; Han, Y.
H.; Tzung, S. P.; Zimmerberg, J.; Hockenbery, D. M.; Zhang, K. Y. J. Biochem. 2001,
40, 4911–4922.
3. (a) Fujita, K.; Tani, K.; Usuki, Y.; Tanaka, T.; Taniguchi, M. J. Antibiot. 2004, 57,
511–517; (b) Fujita, K.; Kubo, I. J. Biosci. Eng. 2004, 98, 490–492; (c) Usuki, Y.;
Goto, K.; Kiso, T.; Tani, K.; Ping, X.; Fujita, K.; Lio, H.; Taniguchi, M. J. Antibiot.
2002, 55, 607–610.
4. (a) Nishii, T.; Suzuki, S.; Yoshida, K.; Arakaki, K.; Tsunoda, T. Tetrahedron Lett.
2003, 44, 7829–7832; (b) Kondo, H.; Oritani, T.; Kiyota, H. Heterocycl. Commun.
2000, 6, 211–214; (c) Shimano, M.; Kamei, N.; Shibata, T.; Inoguchi, K.; Itoh, N.;
Ikari, T.; Senda, H. Tetrahedron 1998, 54, 12745–12774; (d) Wasserman, H. H.;
Gambale, R. J. Tetrahedron 1992, 7059–7070; (e) Wasserman, H. H.; Gambale, R.
J. J. Am. Chem. Soc. 1985, 107, 1423–1424; (f) Nakata, T.; Fukui, M.; Oishi, T.
Tetrahedron Lett. 1983, 24, 2657–2660; (g) Aburaki, S.; Kinoshita, M. Bull. Chem.
Soc. Jpn. 1979, 52, 198–203; (h) Kinoshita, M.; Aburaki, S.; Wada, M.; Umezawa,
S. Bull. Chem. Soc. Jpn. 1973, 46, 1279–1287; (i) Kinoshita, M.; Wada, M.; Aburaki,
S.; Umezawa, S. J. Antibiot. 1971, 24, 724–726; (j) Kinoshita, M.; Wada, M.;
Umezawa, S. J. Antibiot. 1969, 22, 580–582.
O
O
OH
Bu
a
Bu
HO
O
5. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
6. (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614; (b) Nimitz, J. S.;
Wollenberg, R. H. Tetrahedron Lett. 1978, 19, 3523.
2
O
O
2
BocHN
BocHN
OTBS
O
OTBS
7. Experimental data for intermediates 3, 18, 19, 21; and compounds 1a, 1b, 1c,
and 1d.
O
O
19
Compound 3: 1H NMR(CDCl3) d ppm 5.51 (m, 1H), 5.26 (d, 1H), 4.94 (t, 1H), 4.50
(m, 1H), 3.96–3.88 (m, 2H), 2.26 (m, 1H), 1.78–1.55 (m, 2H), 1.45 (s, 9H), 1.29 (d,
2H), 1.25–1.00 (m, 4H), 0.89 (s, 9H), 0.88 (t, 3H), 0.04 (d, 6H).
4
H
O
Compound 18: 1H NMR(CDCl3) d ppm 5.2 (m, br, 2H), 4.6 (m, br, 2H), 3.5 (m, 2H),
2.2 (t, 1H), 1.6 (m, 1H), 1.3 (s, 9H), 1.2 (d, 3H), 1.2–1.0 (m, 5H), 0.8 (s, 9H), 0.76 (t,
3H), 0.03 (s, 3H), 0.00 (s, 3H). 13C NMR(CDCl3) d ppm 174.32, 170.62, 154.78,
80.39, 77.71, 77.42, 66.10, 53.05, 51.88, 29.40, 29.25, 28.23, 25.91, 22.44, 18.95,
18.15, 13.78, ꢁ3.11, ꢁ3.22. HRMS(ES+) calcd for C23H43NaSiNO7 (M+Na+):
496.2719, found 496.2713.
Bu
O
HN
OMe
HN
O
O
O
b, c, d, e
O
O
Compound 19: 1H NMR(CDCl3) d ppm 5.44 (d, 1H), 4.94 (br s, 1H), 4.56 (m, 1H),
4.20 (d, 1H), 3.95 (dt, 1H), 3.62 (t, 1H), 2.26 (m, 1H), 1.65 (m, 1H), 1.40 (d, 2H),
1.32 (s, 9H), 1.25–1.00 (m, 5H), 0.79 (s, 9H), 0.78 (t, 3H), 0.02 (d, 6H). 13C
NMR(CDCl3) d ppm 174.19, 168.57, 155.02, 80.26, 74.85, 69.85, 67.87, 60.87,
53.05, 28.92, 28.53, 28.25, 25.63, 22.32, 18.99, 17.88, 13.70, ꢁ4.46, ꢁ4.81.
MS(ES+) for (M+Na+): 496.2. HRMS(ES+) calcd for C23H44NO7Si (M+H+):
474.2887, found 474.2897.
1c
Scheme 4. Reagents and conditions: (a) DIAD, Ph3P, CH2Cl2, (91%); (b) HFꢂPyr., THF,
rt (90%); (c) isovaleryl chloride, Pyr. (89%); (d) TFA, CH2Cl2 (95%); (e) 2, EDCI, DMAP
(92%).
Compound 21: 1H NMR(CDCl3) d ppm 5.2 (m, 2H), 4.65 (m, 1H), 4.3 (b, 1H), 3.95
(b, 1H), 3.80 (dt, 1H), 3.60 (b, 1H), 2.24 (m, 1H), 1.65 (m, 1H), 1.48 (m, 1H), 1.38
(s, 9H), 1.25–1.00 (m, 4H), 0.80 (s, 9H), 0.76,(t, 3H), 0.03 (d, 6H). 13C NMR(CDCl3)
d ppm 173.85, 170.76, 154.80, 80.51, 72.19, 68.68, 65.59, 52.67, 52.60, 29.19,
28.45, 28.22, 25.62, 22.40, 17.89, 13.73, ꢁ4.50, ꢁ4.78. MS(ES+) for (M+Na+):
482.2. HRMS(ES+) calcd for C22H41NO7NaSi (M+Na+): 482.2532, found
482.2541.
O
OBn
O
2
Bu
Bu
a
BnO
BnO
HO
BocHN
O
4
O
Compound 1a: 1H NMR(CDCl3) d ppm 8.82–8.30 (m, 3H), 7.88–7.72 (m, 2H),
7.40–7.24 (m, 1H), 5.70 (m, 1H), 5.39 (m, 1H), 5.15 (dt, 1H), 4.64 (t, 1H), 4.15 (m,
1H), 3.89 (s, 3H), 2.54 (m, 1H), 2.22 (d, 2H), 2.12 (m, 1H), 1.73–1.45 (m, 2H), 1.34
(d, 3H), 1.35–1.20 (m, 4H), 0.97 (d, 6H), 0.88 (t, 3H). 13C NMR(CDCl3) d ppm
172.98, 171.69, 170.64, 164.31, 161.33, 158.77, 147.27, 130.88, 127.78, 126.66,
125.68, 125.52, 125.28, 125.08, 121.66, 72.04, 71.33, 65.12, 62.84, 54.21, 49.54,
43.17, 29.18, 28.06, 25.66, 22.44, 22.36, 22.29, 15.23, 13.75. MS(ES+) for (M+H+):
521.2 (M+Na+): 543.2. HRMS(ES+) calcd for C26H37N2O9 (M+H+): 521.2499,
OTBS
OTBS
O
20
5
Bu
O
O
b, c
2
4
BocHN
OTBS
O
found: 521.2513. [a] +46.2 (0.360 g/dL, MeOH).
D
O
Compound 1b: 1H NMR(DMSO-d6) d ppm 9.7 (s, 1H), 8.83 (d, 1H), 8.37 (s, 1H),
8.28 (d, 1H), 7.20 (d, 1H), 7.16 (t, 1H), 5.11 (t, 1H), 4.92 (q, 1H), 4.80 (m, 2H), 4.09
(t, 1H), 3.7 (s, 3H), 2.61 (t, 1H), 2.44 (m, 1H), 2.30 (d, 2H), 2.00 (m, 1H), 1.50 (m,
1H), 1.20 (d, 3H), 1.35–1.05 (m, 4H), 0.90 (d, 6H), 0.80 (t, 3H). 13C NMR(CDCl3) d
ppm 172.81, 171.61, 170.50, 161.20, 158.74, 147.21, 130.85, 126.61, 125.53,
125.26, 125.04, 121.80, 75.46, 74.89, 66.00, 62.71, 51.12, 50.19, 43.22, 29.69,
29.21, 28.28, 25.47, 22.40, 17.87, 13.73. MS(ES+) for (M+H+): 521.2. HRMS(ES+)
calcd for C26H37N2O9 (M+H+): 521.2499, found 521.2509.
21
H
O
Bu
O
HN
OMe
d, e, f, g
O
O
HN
O
O
O
1d
Compound 1c: 1H NMR(CDCl3) d ppm 8.82–8.50 (m, 2H), 7.87–7.75 (m, 2H),
7.42–7.22 (m, 1H), 5.25–5.21 (m, 2H), 4.94–4.85 (m, 2H), 3.92 (s, 3H), 3.90 (m,
1H), 2.67 (m, 1H), 2.20 (d, 2H), 2.11 (m, 1H), 1.70–1.50 (m, 2H), 1.59 (d, 3H),
1.35–1.18 (m, 4H), 0.96 (d, 6H), 0.89 (t, 3H). 13C NMR(CDCl3) d ppm 172.90,
Scheme 5. Reagents and conditions: (a) Boc-Ser(OBn)-OH, EDCI, DMAP (91%); (b)
H2, Pd/C, EtOH (95%); (c) DIAD, Ph3P, CH2Cl2 (92%); (d) HFꢂPyr., THF, rt (90%); (e)
isovaleryl chloride, Pyr. (87%); (f) TFA, CH2Cl2 (95%); (g) 2, EDCI, DMAP (95%).

Z. Hu et al. / Tetrahedron Letters 49 (2008) 5192–5195
5195
171.64, 167.68, 164.29, 158.75, 147.35, 130.86, 126.58, 125.36, 124.86, 121.28,
73.84, 70.93, 64.56, 62.84, 59.15, 49.84, 43.15, 29.09, 28.04, 25.62, 22.34, 22.28,
19.00, 13.72. MS(ES+) for (M+H+): 521.2. HRMS(ES+) calcd for C26H37N2O7
(s, 3H), 2.60 (m, 1H), 2.23 (d, 2H), 2.11 (m, 1H), 1.70–1.50 (m, 2H), 1.35–1.18 (m,
4H), 0.97 (d, 6H), 0.88 (t, 3H). 13C NMR(CDCl3) d ppm 172.80, 171.68, 164.32,
161.44, 158.85, 147.28, 130.88, 126.58, 125.48, 125.05, 121.58, 71.68, 65.59,
65.28, 62.70, 51.85, 49.57, 43.14, 29.15, 28.03, 25.64, 22.38, 22.35, 22.27, 13.73.
MS(ES+) for (M+H+): 507.2. HRMS(ES+) calcd for C25H35N2O9 (M+H+): 507.2356,
(M+H+): 521.2499, found: 521.2493. [
a] +43.0 (0.320 g/dL, CHCl3).
D
Compound 1d: 1H NMR(CDCl3) d ppm 8.82–8.39 (m, 3H), 7.87–7.75 (m, 2H),
7.25 (t, 1H), 5.28–5.14 (m, 3H), 4.68 (m, br, 1H), 4.34 (br, 1H), 4.05 (br, 1H), 3.89
found: 507.2349. [a] +55.9 (0.470 g/dL, CHCl3).
D