Total synthesis of (+)-blastmycinone and formal synthesis of (+)-antimycin A3b

Article abstract of DOI:10.1016/j.tetlet.2006.12.088

The formal synthesis of (+)-antimycin A_3b and the total synthesis of (+)-blastmycinone were achieved using, as a key step, a method developed by us for the synthesis of 2-methyl-1,3-diols via Ti(III)-mediated diastereo- and regioselective openi

Full text of DOI:10.1016/j.tetlet.2006.12.088

Tetrahedron Letters 48 (2007) 1139–1142
Total synthesis of (+)-blastmycinone and formal
I
synthesis of (+)-antimycin A3b
Tushar Kanti Chakraborty,* Amit Kumar Chattopadhyay and Subhash Ghosh
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 3 November 2006; revised 4 December 2006; accepted 13 December 2006
Available online 8 January 2007
Abstract—The formal synthesis of (+)-antimycin A3b and the total synthesis of (+)-blastmycinone were achieved using, as a key
step, a method developed by us for the synthesis of 2-methyl-1,3-diols via Ti(III)-mediated diastereo- and regioselective opening
of trisubstituted 2,3-epoxy alcohols, to carry out the stereoselective construction of the hydroxy-acid segment. An interesting intra-
molecular radical translocation took place during the epoxide opening process transforming its vicinal PMB-ether in situ, into an
‘1,2-O-(p-methoxy)benzylidene’ ring.
Ó 2006 Elsevier Ltd. All rights reserved.
Antimycins belong to a family of antifungal antibiotics,
sharing a common nine-membered dilactone ring-struc-
O
O
O
O
O
ture, isolated as secondary metabolites during the last 5–
6 decades from various strains of Streptomyces.1–12 The
pronounced biological activities of the antimycins rang-
ing from antifungal to antitumor properties13–15 make
them attractive targets to synthetic organic chemists.
Although many syntheses of these molecules have
already been reported, there is always scope for new
schemes that will give, not only access to various mem-
bers of this family, but also help to synthesize useful
analogs and other structurally similar compounds, like
UK-2A-D, UK-3A, etc.16 In this Letter, we describe
the formal synthesis of (+)-antimycin A3b17 and the total
synthesis of (+)-blastmycinone, a degradation product
of antimycins.18,19 The salient feature of our synthesis
is the successful application, as a key step, of a very effi-
cient method developed by us earlier for the synthesis of
2-methyl-1,3-diols via radical-mediated regioselective
ring opening of trisubstituted 2,3-epoxy alcohols at the
more substituted center using Cp2TiCl.20 The excellent
diastereoselectivities observed in these reactions
prompted us to employ it in our present study for the
stereoselective construction of the hydroxy-acid segment
of the molecule.
N
O
H
O
OH
O
O
O
HN
H
O
O
2
1
Scheme 1 outlines the details of the synthesis of 1. The
starting material 3 could easily be prepared in two steps
from (S)-lactic acid ethyl ester following a reported pro-
cedure21—PMB-protection with O-(p-methoxybenzyl)
trichloroacetimidate under acidic conditions,22 followed
by reduction of the ester with DIBAL-H. Horner–
Wadsworth–Emmons olefination of 3 with (EtO)2-
P(O)CH(n-Bu)CO2Et using Z-selective reagents DBU–
NaI23 furnished a mixture of Z- and E-alkenes, in a
7:3 ratio, which could be separated after the next step.
1H NOE difference spectroscopic study, which showed
the proximity of the alkenic and allylic protons of the
butyl group, confirmed the Z-configuration of the major
product 4. Irradiation of the alkenic doublet signal of
the major product at d 5.26 enhanced the peak of
allylic-CH2 triplet at d 2.12.
Reduction of the mixture of a,b-unsaturated esters with
DIBAL-H gave the allylic alcohols in quantitative yield,
which could be separated easily using standard silica gel
column chromatography. The pure Z-allylic alcohol 5
(70% overall yield from 3) was treated with m-CPBA
Keywords: Antimycin A3b; Blastmycinone; Epoxide opening; 2-Alkyl-
1,3-diol.
q IICT Communication No. 060924.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275/
27193108; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.088

1140
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 1139–1142
OPMB
OPMB
OPMB
OPMB
a
c
b
HO
EtO2C
HO
OH
O
OHC
4
3
5
6
PMP
H
e
OH
O
f
d
g
O
TBSO
HO
HO
OH
OPMB
OPMB
7
8
9
O
O
O
O
O
j
i
h
TBSO
TBSO
NHBoc
TBSO
OPMB
O
OPMB
10
11
12
OBn
O
O
O
O
O
O
O
O
l
k
ref. 17f
1
HO
NHBoc
HO
NHBoc
OBn
HO
NHBoc
O
O
O
O
OH
O
O
OBn
15
13
14
Scheme 1. Reagents and conditions: (a) (EtO)2P(O)CH(n-Bu)CO2Et, DBU, NaI, THF, 0 °C to rt, 1 h; (b) DIBAL-H, CH2Cl2, ꢀ78 to ꢀ10 °C, 0.5 h,
70% overall yield of 5 from 3; (c) m-CPBA, NaHCO3, CH2Cl2, 0 °C, 45 min, 72% yield of 6; (d) Cp2TiCl2, ZnCl2, Zn, THF, ꢀ20 °C to rt, 12 h, 90%;
˚
(e) Na(CN)BH3, TMSCl, CH3CN, 4 A MS, 0 °C, 10 min, 80% yield of 8; (f) TBSCl, Et3N, CH2Cl2, 0 °C to rt, 12 h, 95% (based on recovered starting
material); (g) (1) DMP, NaHCO3, CH2Cl2, 0 °C to rt, 1 h, quantitative; (2) Zn(BH4)2, ether, 0 °C, 10 min, 75% overall yield of 10 from 9; (h)
isovaleryl chloride, DMAP (cat), CH2Cl2/py (3:2), 0 °C to rt, 8 h, quantitative; (i) (1) DDQ, CH2Cl2, pH 7 buffer, 0 °C, 30 min, 96%; (2) DCC,
DMAP (cat), Boc–Thr(Bn)–OH, CH2Cl2, 0 °C, 8 h, quantitative; (j) CSA (cat), CH2Cl2/MeOH (1:1), 0 °C, 3 h, 95%; (k) (1) same as in l; (2) NaClO2,
NaH2PO4Æ2H2O, 2-methyl-2-butene/t-BuOH (1:2), rt, 30 min, 67% after two steps; (l) H2, Pd(OH)2–C, MeOH, 45 °C, 5 h, 78%.
to give the requisite epoxide 6 as the major product in
72% yield. The minor isomer was removed by column
chromatography. The stereochemistry of the major
product was confirmed after the next step by H NMR
analysis of the product 7.
gel column chromatography to give the acetal 7 in good
yield. To see whether such radical translocation reaction
occurs with other substrates, similar radical-mediated
reactions were carried out with two more epoxides, 17
and 19.
1
With the trisubstituted epoxy alcohol 6 in hand, the
stage was now set to carry out the crucial radical-medi-
ated epoxide opening reaction. Treatment of 6 with
Cp2TiCl, generated in situ from Cp2TiCl2 using Zn dust
and freshly fused anhydrous ZnCl2 following a reported
procedure,20 gave an intermediate ‘2-butyl-1,3-diol’ with
excellent diastereoselectivity, which underwent a sponta-
neous acetalization under the reaction conditions with
the adjacent O-PMB ether to furnish the p-methoxyben-
zylidene protected acetal 7 as a single product in 90%
yield. The usual work-up procedure followed in these
reactions involving quenching the reaction mixture with
dilute HCl20 was not used here. Instead, the reaction
mixture was quenched by adding saturated aqueous
NH4Cl solution, which were followed by extraction with
EtOAc. A small amount of Et3N (<1%) was added to
the combined organic extracts, which were filtered
through a sintered funnel and concentrated in vacuo.
The residue was purified by Et3N-impregnated silica
In these cases, in situ acetalization concomitant with the
epoxide-opening process was indeed observed, resulting
in the formation of benzylidene-protected products 18
and 20, respectively (Scheme 2).
PMP
OPMB
H
O
HO
O
Cp2TiCl
85%
O
HO
HO
17
18
PMP
H
O
HO
O
Cp2TiCl
62%
O
OPMB
19
20
Scheme 2.

T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 1139–1142
1141
2. Dunshee, B. R.; Leben, C.; Keitt, G. W.; Strong, F. M.
J. Am. Chem. Soc. 1949, 71, 2436–2437.
3. (a) Schneider, H. G.; Tener, G. M.; Strong, F. M. Arch.
Biochem. Biophys. 1952, 37, 147–157; (b) Lockwood, J. L.;
Leben, C.; Keitt, G. W. Phytopathology 1954, 44, 438–
446.
a
b
O
O
O
2
11
MeO
4. (a) Sakagami, Y.; Takeuchi, S.; Yonehara, H.; Sakai, H.;
Takashima, M. J. Antibiot. 1956, 9, 1–5; (b) Watanabe,
K.; Tanaka, T.; Fukuhara, K.; Miyairi, N.; Yonehara, H.;
Umezawa, H. J. Antibiot. Ser. A 1957, 10, 39–45; (c)
Yonehara, H.; Takeuchi, S. J. Antibiot. Ser. A 1958, 11,
254–263.
OPMB
16
Scheme 3. Reagents and conditions: (a) (1) CSA (cat), CH2Cl2/MeOH
(1:1), 0 °C, 3 h, 95%; (2) DMP, NaHCO3, CH2Cl2, 0 °C to rt, 1 h,
quantitative; (3) NaClO2, NaH2PO4Æ2H2O, 2-methyl-2-butene/
t-BuOH (1:2), rt, 30 min, 90%; (4) CH2N2, ether, 0 °C, 5 min,
quantitative; (b) (1) DDQ, CH2Cl2, pH 7 buffer, 0 °C, 30 min, 95%;
(2) CSA (cat), CH2Cl2/MeOH (1:1), 0 °C, 3 h, 95%.
5. Liu, W.-C.; Strong, F. M. J. Am. Chem. Soc. 1959, 81,
4387–4390.
6. (a) Van Tamelene, E. E.; Dickie, J. P.; Loomans, M. E.;
Dewey, R. S.; Strong, F. M. J. Am. Chem. Soc. 1961, 83,
1639–1646; (b) Birch, A. J.; Cameron, D. W.; Harada, Y.;
Rickards, R. W. J. Chem. Soc. 1961, 889–895.
7. Kinoshita, M.; Asuraki, S.; Umezawa, S. J. Antibiot. 1972,
25, 373–376.
The 3J coupling of 6.2 Hz of the vicinal protons,
CH(O)–CH(O), of the 1,3-dioxolane ring in 7 confirmed
the assigned stereochemistry of the major isomer 6 dur-
ing the epoxidation step.24 Reductive opening of the
benzylidene ring using Na(CN)BH3–TMSCl25 gave the
diol 826 in 80% yield after separating the minor product
chromatographically. Silylation of 8 with TBSCl selec-
tively protected the primary alcohol giving 9 in 95%
yield based on recovered starting material. Compound
9 was next subjected to inversion following a two-step
oxidation–reduction protocol—oxidation with Dess–
Martin periodinane (DMP),27 followed by reduction
using Zn(BH4)2—to furnish the requisite isomer 10 in
75% yield from 9. The minor isomer 9, ca. 20%, formed
during the reduction could be separated chromato-
graphically and recycled. Acylation of 10 with isovaleryl
chloride gave the ester 11 in quantitative yield. PMB-
deprotection of 11 was followed by reaction with Boc–
Thr(Bn)–OH using DCC–DMAP (cat.) to furnish 12
in 96% yield from 11. Desilylation of 12 gave 13 in
95% yield. Compound 13 was oxidized to acid 14 in
two steps—oxidation with DMP to aldehyde followed
by NaClO2 oxidation to the acid—in 67% yield. Debenz-
ylation of 14 by catalytic hydrogenation furnished the
hydroxy-acid 1528 in 78% yield. Conversion of 15 to
(+)-antimycin A3b 1 has already been reported.17f
8. Schilling, G.; Berti, D.; Kluepfel, D. J. Antibiot. 1970, 23,
81–90.
9. Barrow, C.; Oleynek, J.; Marinelli, V.; Sun, H. H.;
Kaplita, P.; Sedlock, D. M.; Gillum, A. M.; Chadwick,
C. C.; Cooper, R. J. Antibiot. 1997, 50, 729–733.
10. Shiomi, K.; Hatae, K.; Hatanho, H.; Matsumoto, A.;
Takahashi, Y.; Jiang, C.-L.; Tomoda, H.; Kobayashi, S.;
Tanaka, H.; Omura, S. J. Antibiot. 2005, 58, 74–78.
11. Hosotani, N.; Kumagai, K.; Nakagawa, H.; Shimatani,
T.; Saji, I. J. Antibiot. 2005, 58, 460–467.
12. Chen, G.; Lin, B.; Lin, Y.; Xie, F.; Lu, W.; Fong, W.-F. J.
Antibiot. 2005, 58, 519–522.
13. (a) Kido, G. S.; Spyhalski, E. Science 1950, 112, 172–173;
(b) Sakagami, Y.; Takeuchi, S.; Yonehara, H.; Sakai, H.;
Takashima, M. J. Antibiot. 1956, 9, 1–5; (c) Leben, C.;
Keitt, G. W. Phytopathology 1949, 39, 529–540; (d) Chen,
G.; Lin, B.; Lin, Y.; Xie, F.; Lu, W.; Fong, W.-F. J.
Antibiot. 2005, 58, 519–522; (e) Nakayama, K.; Okamoto,
F.; Harada, Y. J. Antibiot. 1956, 9, 63–66.
14. (a) Potter, V. R.; Reif, A. E. J. Biol. Chem. 1952, 194, 287–
297; (b) Barrow, C.; Oleynek, J.; Marinelli, V.; Sun, H. H.;
Kaplita, P.; Sedlock, D. M.; Gillum, A. M.; Chadwick, C.
C.; Cooper, R. J. Antibiot. 1997, 50, 729–733; (c) Thorn,
M. B. Biochem. J. 1956, 63, 420–436; (d) Reif, A. E.;
Potter, V. R. Cancer Res. 1953, 13, 49–57.
15. (a) King, M. A. Cytometry, Part A 2005, 63A, 69–76; (b)
Tzung, S.-P.; Kim, K. M.; Basanez, G.; Giedt, C. D.;
˜
Simon, J.; Zimmerberg, J.; Zhang, K. Y. J.; Hockenbery,
D. M. Nat. Cell Biol. 2001, 3, 183–191.
Intermediate 11 was next transformed into (+)-blast-
mycinone 2 as shown in Scheme 3. Desilylation of 11
was followed by two-step oxidation with subsequent
esterification using CH2N2 in ether to furnish the methyl
ester 16 in 85% yield. PMB-deprotection of 16 was fol-
lowed by lactonization using acid to furnish the desired
product 2 in 90% yield. The spectroscopic data, namely,
IR, NMR, mass spectra as well as the rotation of our
synthetic product 229 were in conformity with those
reported earlier.19a
16. For isolation and structure elucidation of UK-2A-D see:
(a) Ueki, M.; Abe, K.; Hanafi, M.; Shibata, K.; Tanaka,
T.; Taniguchi, M. J. Antibiot. 1996, 49, 639–643; (b)
Hanafi, M.; Shibata, K.; Ueki, M.; Taniguchi, M. J.
Antibiot. 1996, 49, 1226–1231; (c) Shibata, K.; Hanafi, M.;
Fujii, J.; Sakanaka, O.; Iinuma, M.; Ueki, M.; Taniguchi,
M. J. Antibiot. 1998, 51, 1113–1116; For UK-3A see: (d)
Ueki, M.; Kusumoto, A.; Hanafi, M.; Shibata, K.;
Tanaka, T.; Taniguchi, M. J. Antibiot. 1997, 50, 551–
555.
17. For earlier syntheses of antimycin A3b see: (a) Kinoshita,
M.; Wada, M.; Umezawa, S. J. Antibiot. 1969, 22, 580–582
(racemic synthesis); For enantioselective syntheses of
antimycin A3b see: (b) Kinoshita, M.; Wada, M.; Aburagi,
S.; Umezawa, S. J. Antibiot. 1971, 24, 724–726; (c)
Kinoshita, M.; Aburaki, S.; Wada, M.; Umezawa, S. Bull.
Chem. Soc. Jpn. 1973, 46, 1279–1287; (d) Tsunoda, T.;
Nishii, T.; Yoshizuka, M.; Yamasaki, C.; Suzuki, T.; Ito,
S. Tetrahedron Lett. 2000, 41, 7667–7671; (e) Nishii, T.;
Suzuki, S.; Yoshida, K.; Araki, K.; Tsunoda, T. Tetra-
Acknowledgment
The authors wish to thank CSIR, New Delhi, for a
research fellowship (A.K.C.).
References and notes
1. Leben, C.; Keitt, G. W. Phytopathology 1948, 38, 899–
906.

1142
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 1139–1142
hedron Lett. 2003, 44, 7829–7832; (f) Wu, Y.; Yang, Y.-Q. 24. Lorenz, K.; Lichtenthaler, F. W. Tetrahedron Lett. 1987,
J. Org. Chem. 2006, 71, 4296–4301; For formal syntheses
of antimycin A3b see: (g) Aburaki, S.; Kinoshita, M. Bull.
Chem. Soc. Jpn. 1979, 52, 198–203; (h) Nakata, T.; Fukui,
M.; Oishi, T. Tetrahedron Lett. 1983, 24, 2657–2660; (i)
Wasserman, H. H.; Gambale, R. J. J. Am. Chem. Soc.
1985, 107, 1423–1424; (j) Wasserman, H. H.; Gambale, R.
J. Tetrahedron 1992, 48, 7059–7070; (k) Inghart, T.; Frejd,
T. Tetrahedron 1991, 47, 6483–6492.
28, 6437–6440.
25. Johansson, R.; Samuelsson, B. J. Chem. Soc., Chem.
Commun. 1984, 201–202.
26. The stereochemistry of the newly generated chiral center
carrying the n-butyl group was established by transform-
ing 8 into an acetonide 21. The 3J couplings of the
acetonide ring protons of 21 confirmed the assigned S-
stereochemistry of the new chiral center.
2,2-dimethoxypropane,
O
Hb
O
CSA (cat), CH2Cl2, 0 oC to rt,
H
OPMB
O
n-Bu
8
O
H
R =
R
20 min, quantitative
OPMB
Ha
21
Ja,b = 10.4 Hz
18. (a) Tener, G. M.; van Tamelen, E. E.; Strong, F. M. J.
Am. Chem. Soc. 1953, 75, 3623–3625; (b) Yohehara, H.;
Takeuchi, S. J. Antibiot., Ser. A 1958, 11, 254.
19. For some earlier syntheses of blastmycinone see: (a)
Nishide, K.; Aramata, A.; Kamanaka, T.; Inoue, T.;
Node, M. Tetrahedron 1994, 50, 8337–8346; (b) de
Azevedo, M. B. M.; Greene, A. E. J. Org. Chem. 1995,
60, 4940–4942; (c) Sibi, M. P.; Lu, J.; Talbacka, C. L. J.
Org. Chem. 1996, 61, 7848–7855; (d) Berkenbusch, T.;
27. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
28. Data of the hydroxy-acid 15. Rf = 0.4 (silica, 80% ethyl
27
acetate in petroleum ether eluant); ½aꢁD ꢀ3.2 (c 2.2,
CHCl3); IR (KBr): 3443 (br), 1739, 1719, 1509, 1458, 1368,
1164, 1086, 760 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 5.41
(d, J = 9.1 Hz, 1H ), 5.34 (dd, J = 9.1, 3.8 Hz, 1H ), 5.12
(dq, J = 6.1, 6.8 Hz, 1H); 4.28 (q, J = 6.1 Hz, 1H); 4.20 (d,
J = 9.1 Hz, 1H), 2.93–3.61 (br s, 2H), 2.56 (td, J = 9.8,
3.8 Hz, 1H), 2.28 (d, J = 6.8 Hz, 2H), 2.05–2.21 (m, 1H),
1.48–1.70 (m, 2H), 1.45 (br s, 9H), 1.28 (d, J = 6.8 Hz,
3H), 1.22 (d, J = 6.1 Hz, 3H), 0.99 (d, J = 6.8, 6H), 0.87 (t,
J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 175.64,
173.12, 170.39, 156.45, 80.04, 73.61, 71.73, 67.14, 56.03,
51.14, 47.31, 43.40, 31.92, 29.69, 29.34, 28.98, 28.31, 25.64,
22.77, 22.68, 22.35, 19.54, 14.53, 14.09, 13.75; FAB-MS:
m/z 476 [M+H]+, 498 [M+Na]+.
Bruckner, R. Tetrahedron 1998, 54, 11461–11470; (e)
¨
Chen, M.-J.; Lo, C.-Y.; Chin, C.-C.; Liu, R.-S. J. Org.
Chem. 2000, 65, 6362–6367; (f) Peng, Z. H.; Woerpel, K.
A. Org. Lett. 2001, 3, 675–678; (g) Liu, B.; Chen, M.-J.;
Lo, C.-Y.; Liu, R.-S. Tetrahedron Lett. 2001, 42, 2533–
2535; (h) He, M.; Lei, A.; Zhang, X. Tetrahedron Lett.
2005, 46, 1823–1826; (i) Seitz, M.; Reiser, O. Curr. Opin.
Chem. Biol. 2005, 9, 285–292, and references cited therein.
20. (a) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2002,
43, 2313–2315; (b) Chakraborty, T. K.; Dutta, S. J. Chem.
Soc., Perkin Trans. 1 1997, 1257–1259.
21. Shimano, M.; Shibata, T.; Kamei, N. Tetrahedron Lett.
1998, 39, 4363–4366.
22. (a) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247–2250; (b) Nakajima, N.;
Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139–4142.
29. Data of 2. Rf = 0.4 (silica, 80% ethyl acetate in petroleum
27
25
ether eluant); ½aꢁD +9.1 (c 0.17, CHCl3) [reported, ½aꢁD
+11.2 (c 0.85, CHCl3), Ref. 19a]; IR (KBr): 3463 (br),
1784, 1742, 1176, 1116, 1036, 760 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 4.91 (dd, J = 5.9, 4.7 Hz, 1H), 4.32
(dq, J = 6.6, 4.7 Hz, 1H), 2.64 (dt, J = 5.9, 8.1 Hz, 1H),
2.2 (d, J = 7.4 Hz, 2H), 2.11 (m, 1H), 1.80–1.92 (m, 1H),
1.56–1.70 (m, 1H), 1.47 (d, J = 6.6 Hz, 3H), 1.30–1.44 (m,
4H), 0.98 (d, J = 6.6 Hz, 6H), 0.93 (t, J = 7.0 Hz, 3H); MS
(LCMS): m/z 257 [M+H]+, 279 [M+Na]+.
23. Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J.
Org. Chem. 2000, 65, 4745–4749.