Total synthesis of the (+)-antimycin A3 family: Structure elucidation of (+)-antimycin A3a

Article abstract of DOI:10.1016/j.tetlet.2003.08.046

(+)-Antimycin A_3a (AA_3a), one component of the natural antibiotic antimycin A₃, was synthesized using an asymmetric aza-Claisen rearrangement. The stereochemistry at the 2′ position on the acyloxy side chain of AA_3a

Full text of DOI:10.1016/j.tetlet.2003.08.046

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7829–7832
Total synthesis of the (+)-antimycin A3 family: structure
elucidation of (+)-antimycin A3a
Takeshi Nishii, Shiho Suzuki, Katsuyoshi Yoshida, Kozue Arakaki and Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Received 16 July 2003; revised 4 August 2003; accepted 11 August 2003
Abstract—(+)-Antimycin A3a (AA3a), one component of the natural antibiotic antimycin A3, was synthesized using an asymmetric
aza-Claisen rearrangement. The stereochemistry at the 2% position on the acyloxy side chain of AA3a was established as
S-configuration by comparison of the synthetic AA3a and the natural AA3a.
© 2003 Elsevier Ltd. All rights reserved.
Antimycin A (AA) complex was isolated from Strepto-
myces sp. as antibiotics possessing antifungal activity.1
Among the components of AA complex, AA3, available
from Sigma Co., is one of most active agents and has
been widely used in biological and biochemical studies2
because of its unique inhibitory activity against
ubiquinol-cytochrome c oxidoreductase.3
thesis of (−)-AA3b taking development of a practical
synthetic route into consideration and having an inter-
est in biological activities.4 As part of our continuing
efforts toward antimycin chemistry, we synthesized the
two possible isomers of (+)-AA3a, which were (S)- and
(R)-2-methylbutanoates, named (+)-AA3a(S) and (+)-
AA3a(R), respectively in this paper. The synthesis eluci-
dated the stereochemistry of the acyloxy side chain at
the 8-position of the nine-membered dilactone ring in
natural AA3a. The results are reported herein.
Recently, we disclosed that this enchanting agent pur-
chased from Sigma Co. was a 6:4 mixture of AA3a and
AA3b,4 whose separation was possible only with enor-
mous effort.5 For precise biological and biochemical
investigations, the supply of each pure component
seems to be very important. Although AA3b has been
synthesized by several groups,6 further effort to a prac-
tical synthesis is still needed to supply sufficient amount
of pure AA3b. Furthermore, AA3a has not been synthe-
sized and the stereochemistry at the 2% position on the
acyloxy side chain of AA3a has not yet been
determined.
Starting from (S)-(−)-phenethylamine (1), a diastereo-
meric mixture of seco acids (7R,8R)-isomer 8a and
(7S,8S)-isomer 8b was obtained following the previous
route4 outlined in Scheme 1. In the previous synthesis
of AA3b, the mixture of 8a,b was converted to the
dilactones 10a,b via the formation of the 2-pyridinethiol
esters 9a,b which were treated with AgClO4 in benzene
under reflux conditions. Although the lactonization
proceeded in satisfactory yield (82%), we decided to
abandon the use of explosive AgClO4.8 We tested the
conditions for the cyclization of thiol esters with differ-
ent metal salts. The best results were obtained when a
We have developed an asymmetric aza-Claisen rear-
rangement,7 and applied the methodology to the syn-
Keywords: asymmetric synthesis; antimycin A3a; antibiotics; structure determination.
* Corresponding author. Fax: +81-88-655-3051; e-mail: tsunoda@ph.bunri-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.046

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T. Nishii et al. / Tetrahedron Letters 44 (2003) 7829–7832
Scheme 1. Reagents and conditions: (a)ꢀ(i) Ref. 4; (j) 2,2%-dipyridyl disulfide, PPh3, PhH, rt, 3 h, 99%; (k) Cu(OTf)2·PhH, PhH,
80°C, 3 h, 88%.
solution of 9a,b in benzene was added slowly over 2 h
to a refluxing benzene solution of one equivalent of
Cu(OTf)2·PhH complex under high dilution condi-
tions.9 The yield was improved to 88% and the resulting
dilactones 10a and 10b were separated by SiO2 column
chromatography.
(Scheme 2). Compound 11 was esterified with (S)- or
(R)-2-methylbutanoic acid11 in the presence of water-
soluble carbodiimide (WSC) and 4-(N,N-dimethy-
lamino)pyridine (DMAP) in CH2Cl2 to provide the
ester 12 or 13 in an unoptimized 60ꢀ72% yield. Fol-
lowing the previous procedure (hydrogenolysis of the
Cbz group, acylation, and hydrogenolysis of the benzyl
ether), the ester 12 or 13 was transformed into (+)-
AA3a(S) (72% yield from 12) or (+)-AA3a(R) (an unop-
timized 47% yield from 13).12
The TIPS group of the lactone 10a was removed
smoothly using HF·Py at 0°C to provide the alcohol 11
without epimerization at the C7 position10 (95% yield)
Scheme 2. Reagents and conditions: (l) HF·Py, THF, 32 h, 95%; (m) C2H5C*H(CH3)COOH, WSC, DMAP, CH2Cl2; (n) H2, Pd/C,
AcOEt; (o) (i) 14, WSC, HOBt, NMM, DMF; (ii) H2, Pd/C, AcOEt.

T. Nishii et al. / Tetrahedron Letters 44 (2003) 7829–7832
7831
1
Figure 1. 600 MHz H NMR spectra of AA3b, sigma AA3, AA3a(S) and AA3a(R)
.
In order to elucidate the stereochemistry of the 2-
P.; Sedlock, D. M.; Gillum, A. M.; Chadwick, C. C.;
Cooper, R. J. Antibiotics 1997, 50, 729–733; (d) Kim, H.;
Esser, L.; Hossain, M. B.; Xia, D.; Yu, C. A.; Rizo, J.;
van der Helm, D.; Deisenhofer, J. J. Am. Chem. Soc.
1999, 121, 4902–4903 and references cited therein.
3. Wikstrom, M. K. F.; Berden, J. A. Biochim. Biophys.
Acta 1972, 283, 403–420.
methylbutanoate moiety in the natural (+)-AA3a, we
1
carefully compared the 600 MHz H NMR spectra of
synthetic AA3b, AA3a(S), AA3a(R) and AA3 from
Sigma Co. The spectra (from 1.34 to 1.16 ppm) are
depicted in Figure 1.
4. Tsunoda, T.; Nishii, T.; Yoshizuka, M.; Yamasaki, C.;
Suzuki, T.; Itoˆ, S. Tetrahedron Lett. 2000, 41, 7667–7671.
5. (a) Abidi, S. L. J. Chromatography 1988, 447, 65–79; (b)
Abidi, S. L. J. Chromatography 1989, 464, 453–458.
6. The total synthesis of (+)-antimycin A3b: (a) Kinoshita,
M.; Wada, M.; Aburaki, S.; Umezawa, S. J. Antibiotics
1971, 24, 724–726; (b) Kinoshita, M.; Aburaki, S.; Wada,
M.; Umezawa, S. Bill. Chem. Soc. Jpn. 1973, 46, 1279–
1287: the total synthesis of (−)-antimycin A3b: (c) Kondo,
H.; Oritani, T.; Kiyota, H. Heterocyclic Communications
2000, 6, 211–214: the fomal synthesis: (d) Aburaki, S.;
Kinoshita, M. Bull. Chem. Soc. Jpn. 1979, 52, 198–203;
(e) Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett.
1983, 24, 2657–2660; (f) Wasserman, H. H.; Gambale, R.
J. J. Am. Chem. Soc. 1985, 107, 1423–1424; (g) Wasser-
man, H. H.; Gambale, R. J. Tetrahedron 1992, 48, 7059–
7070; (h) Inghart, T.; Frejd, T. Tetrahedron 1991, 47,
6483–6492.
The signal at 1.190 ppm (3H, d) in the spectrum of
sigmas AA3 is identical with the signal of AA3a(S),
which is assigned to the 2-methyl group on the 2-
methylbutanoate moiety. On the contrary, the signal
for the methyl group of AA3a(R) appears at 1.197 ppm
(3H, d). The signals of the methyl groups on the
nine-membered dilactone ring of sigmas AA3 are
observed from 1.33 to 1.28 ppm. This signal pattern can
be recognized as a superposition of the signal of AA3b
and AA3a(S). Consequently, the stereochemistry at the
2% position on the acyloxy side chain of AA3a was
established as S-configuration.
Thus, we succeeded in synthesizing of AA3a and deter-
mined the stereochemistry at the 2% position on the
acyloxy side chain of AA3a. Further synthetic studies of
AA3 analogs and the investigation of their biological
activities are now in progress.
7. Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo, Y.
Tetrahedron Lett. 1992, 33, 1651–1653.
8. Lanter, J. C. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1995; pp. 4469–4471.
9. For the macrolactonization of thioesters, the use of cop-
per salts has been reported. See, Masamune, S.; Hayase,
Y.; Schilling, W.; Chan, W. K.; Bates, G. S. J. Am.
Chem. Soc. 1977, 99, 6756–6758.
10. TBAF was used previously for the deprotection of the
TIPS group. This treatment was not reproducible, and
the C7 epimer was often obtained as a by-product to
some extent.
References
1. Dunshee, B. R.; Leben, C.; Keitt, G. W.; Strong, F. M. J.
Am. Chem. Soc. 1949, 71, 2436–2437.
2. (a) Tzung, S. P.; Kim, K. M.; Basanez, G.; Giedt, C. D.;
Simon, J.; Zimmerberg, J.; Zhang, K. Y. J.; Hockenbery,
D. M. Nature Cell Biology 2001, 3, 183–191; (b) Miyoshi,
H.; Tokutake, N.; Imaeda, Y.; Akagi, T.; Iwamura, H.
Biochim. Biophys. Acta 1995, 1229, 149–154; (c) Barrow,
C. J.; Oleynek, J. J.; Marinelli, V.; Sun, H. H.; Kaplita,

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T. Nishii et al. / Tetrahedron Letters 44 (2003) 7829–7832
11. (R)-2-Methylbutanoic acid was prepared following the
procedure in the literature. See, (a) Spino, C.; Beaulieu,
C. J. Am. Chem. Soc. 1998, 120, 11832–11833; (b) Spino,
C.; Beaulieu, C.; Lafreniere, J. J. Org. Chem. 2000, 65,
7091–7097.
1604, 1537 cm−1; MS (FAB) m/z 521 (M++1), 419, 329,
278, 236, 91 (bp); HRMS m/z 521.2463 (521.2499 calcd
for C26H37O9N2).
(+)-AA3a(R): colorless needles (rotamer mixture): mp
156.5ꢀ157.0°C (ether/pet. ether); [h]2D0 +74.4 (c 0.36,
1
CHCl3): H NMR (600 MHz, CDCl3) l 12.63 and 12.47
12. The physical properties were as follows:
(total integr. 1H, s and s), 8.79 and 8.51 (total integr. 1H,
d, J=12 Hz and d, J=1.8 Hz), 8.56 and 7.38 (total
integr. 1H, dd, J=7.8, 1.2 Hz and br.d, J=7.8 Hz), 7.95
and 7.76 (total integr. 1H, br.s and br.d, J=11.4 Hz),
7.29 and 7.25 (total integr. 1H, br.d, J=7.2 Hz and dd,
J=7.8, 1.2 Hz), 7.08 and 7.06 (total integr. 1H, br.d,
J=7.2 Hz and br.d, J=7.2 Hz), 6.93 and 6.90 (total
integr. 1H, t, J=7.8 Hz and t, J=7.8 Hz), 5.74 (1H, dq,
J=7.8, 6.6 Hz), 5.30 and 5.29 (total integr. 1H, t, J=7.8
Hz and t, J=7.8 Hz), 5.10 and 5.09 (total integr. 1H, t,
J=9.6 Hz and t, J=10.2 Hz), 5.00 (1H, dq, J=9.6, 6.6
Hz), 2.54 (1H, ddd, J=12.0, 10.8, 3.0 Hz), 2.43 (1H, ddq,
J=7.8, 7.2, 7.2 Hz), 1.75ꢀ1.67 (1H, m), 1.74 (1H, ddq,
J=15.0, 7.8, 7.8 Hz), 1.49 (1H, ddq, 15.0, 7.2, 7.8 Hz),
1.39ꢀ1.23 (4H, m), 1.32 (3H, d, J=6.6 Hz), 1.30 (3H, d,
J=6.6 Hz), 1.21ꢀ1.11 (1H, m), 1.20 (3H, d, J=7.2 Hz),
0.94 (3H, dd, J=7.8, 7.2 Hz), 0.87 (3H, t, J=7.2 Hz); IR
(neat) 3370, 2963, 2935, 2875, 1747, 1688, 1643, 1610,
1534 cm−1; MS (FAB) m/z 521 (M++1), 265, 237, 164,
136 (bp); HRMS m/z 521.2527 (521.2499 calcd for
C26H37O9N2).
(+)AA3a(S): colorless needles (rotamer mixture): mp
173.1ꢀ174.0°C (ether/pet. ether); [h]2D1 +91.6 (c 0.32,
1
CHCl3): H NMR (600 MHz, CDCl3) l 12.63 and 12.47
(total integr. 1H, s and s), 8.79 and 8.51 (total integr. 1H,
d, J=11.4 Hz and d, J=1.2 Hz), 8.55 and 7.38 (total
integr. 1H, dd, J=7.8, 1.2 Hz and br.d, J=7.2 Hz), 7.98
and 7.78 (total integr. 1H, br.s and br.d, J=11.4 Hz),
7.30 and 7.25 (total integr. 1H, br.d, J=7.2 Hz and dd,
J=7.8, 1.2 Hz), 7.09 and 7.07 (total integr. 1H, br.d,
J=7.2 Hz and br.d, J=7.2 Hz), 6.92 and 6.90 (total
integr. 1H, t, J=7.8 Hz and t, J=7.8 Hz), 5.75 (1H, dq,
J=7.8, 6.6 Hz), 5.31 and 5.29 (total integr. 1H, t, J=7.8
Hz and t, J=7.2 Hz), 5.11 and 5.09 (total integr. 1H, t,
J=10.2 Hz and t, J=10.2 Hz), 5.00 (1H, dq, J=9.6, 6.6
Hz), 2.53 (1H, ddd, J=12, 10.2, 3.6 Hz), 2.43 (1H, ddq,
J=7.8, 7.2, 6.6 Hz), 1.75ꢀ1.67 (1H, m), 1.74 (1H, ddq,
J=14.4, 7.2, 7.8 Hz), 1.50 (1H, ddq, J=14.4, 7.8, 7.2
Hz), 1.39ꢀ1.23 (4H, m), 1.32 (3H, d, J=6.6 Hz), 1.29
(3H, d, J=6.6 Hz), 1.21ꢀ1.11 (1H, m), 1.19 (3H, d,
J=6.6 Hz), 0.95 (3H, dd, J=7.8, 7.2 Hz), 0.87 (3H, t,
J=7.2 Hz); IR (neat) 3370, 2963, 2875, 1747, 1684, 1644,