LETTER
Synthesis of C1–C11 Fragment of Macrolactin A
2429
cross-metathesis
in Scheme 5, was subjected to the Wittig olefination with
phosphorane 26. Compound 25 was obtained in 74% yield
and with 83:17 E/Z ratio. Considering that there were not
substantial improvements in the yield and selectivity in
the latter reaction, the shorter route to compound 3 re-
mained that reported in Scheme 7.
OP
11
7
TMS
CO2Me
Wittig
3
olefination
Still–Gennari
olefination
PPh3+Br–
OP
OTBS
OTBS
+
P'O
11
7
a
7
26
OTBS
27
TMS
OHC
OTBS
CO2Me
TMS
24
Still–Gennari
olefination
25
8E/8Z 83:17
1. desilylation of 1° alcohol
2. oxidation
3. Still–Gennari reaction
OTBS
PMBO
+
(CF3CH2O)2OP
28
CO2Me
7
OH
3
21
Scheme 8 Reagents and conditions: a) 26, n-BuLi, –78 °C to 0 °C,
3 h (74%).
Scheme 6 Second proposed route to the C1–C11 fragment.
starting from commercially available propargylic triphen-
ylphosphorane 26, phosphonate 28, and from alcohol 21
prepared, as described in Schemes 4 and 5, via the cross-
metathesis route.
In conclusion, after various attempts, an efficient prepara-
tion of a key C1–C11 intermediate toward the total syn-
thesis of macrolactin A (1) was described showing high
stereoselectivity in the introduction of the required three
double bonds.
Aldehyde 29 (Scheme 7), easily prepared from alcohol 21
via oxidation with Dess–Martin periodinane, was allowed
to react with phosphonate 28 affording (2Z,4E)-diene 27
with excellent stereoselectivity (Z,E/E,E, 95:5) in 70%
yield. Deprotection of 27 with DDQ afforded alcohol 30
in 73% yield, which was subsequently oxidized with
Dess–Martin periodinane to aldehyde 31 in 75% yield.
Preparation of the required compound 3 was finally
achieved by reacting the propargylic triphenylphos-
phorane 2613 with aldehyde 31 in the presence of n-BuLi
at –78 °C. This final Wittig reaction produced the target
C1–C11 fragment 314 of macrolactin A in 75% yield and
with a good level of stereoselectivity (E/Z, 79:21 ratio) at
the C8–C9 double bond.
Acknowledgment
Thanks are due to the University of Basilicata and the MIUR
(FIRB-Progettazione, preparazione e valutazione biologica e far-
macologica di nuove molecole organiche quali potenziali farmaci
innovativi) for financial support.
References and Notes
(1) Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc.
1989, 111, 7519.
(2) (a) Kim, H.-H.; Kim, W.-G.; Ryoo, I.-J.; Kim, C.-J.; Suk, J.-
E.; Han, K.-H.; Hwang, S.-Y.; Yoo, I.-D. J. Microbiol.
Biotechnol. 1997, 7, 429. (b) Jaruchoktaweechai, C.;
Suwanborirus, K.; Tanasupawatt, S.; Kittakoop, P.;
Menasveta, P. J. Nat. Prod. 2000, 63, 984. (c) Nagao, T.;
Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H. J. Antibiot.
2001, 54, 333. (d) Romero-Tabarez, M.; Jansen, R.; Sylla,
M.; Lünsdorf, H.; Häußler, S.; Santosa, D. A.; Timmis, K.
N.; Molinari, G. Antimicrob Agents Chemother. 2006, 50,
1701.
OTBS
OTBS
a
b
PMBO
PMBO
7
OH
7
O
21
29
OTBS
OTBS
e
c
PMBO
7
7
R
(3) For the total synthesis, see: (a) Smith, A. B. III.; Ott, G. R. J.
Am. Chem. Soc. 1996, 118, 13095. (b) Kim, Y.; Singer, R.
A.; Carreira, E. M. Angew. Chem. Int. Ed. 1998, 37, 1261.
(c) Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto,
J. V.; Tucci, F. C. J. Am. Chem. Soc. 2001, 124, 1664.
(4) For partial syntheses, see: (a) Benvegnu, T.; Schio, L.; Le
Floch, Y.; Grèe, R. Synlett 1994, 505. (b) Donaldson, W.
A.; Bell, P. T.; Wang, Z.; Bennett, D. W. Tetrahedron Lett.
1994, 35, 5829. (c) Boyce, R. J.; Pattenden, G. Tetrahedron
Lett. 1996, 37, 3501. (d) Benvegnu, T.; Toupet, L.; Greè, R.
Tetrahedron 1996, 52, 11811. (e) Benvegnu, T.; Greè, R.
Tetrahedron 1996, 52, 11821. (f) Prahlad, V.; Donaldson,
W. A. Tetrahedron Lett. 1996, 37, 9169. (g) Gonzàlez, A.;
Aiguadè, J.; Urp, F.; Villarasa, J. Tetrahedron Lett. 1996, 37,
8949. (h) Tanimori, S.; Morita, Y.; Tsubota, M.; Nakayama,
M. Synth. Commun. 1996, 26, 559. (i) Donaldason, W. A.;
Barmann, H.; Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.
Tetrahedron 2000, 56, 2283. (j) Li, S.; Xu, R.; Bai, D.
27
CO2Me
30: R = CH2OH
31: R = CHO
CO2Me
d
2Z,4E/2E,4E 95:5
OTBS
4
7
2
11
3
TMS
CO2Me
8E/8Z 79:21
Scheme 7 Reagents and conditions: a) Dess–Martin periodinane,
CH2Cl2, r.t., 3 h (78%); b) 28, KHMDS, 18-crown-6, THF, –78 °C,
4 h (70%); c) DDQ, buffer pH 7, CH2Cl2, r.t., 5 h, 73%; d) Dess–
Martin periodinane, CH2Cl2, r.t., 6 h (75%); e) 26, n-BuLi, –78 °C to
0 °C, 3 h (75%).
In order to improve the selectivity of the Wittig reaction
additional experiments were performed. The aldehyde 24
(Scheme 8), prepared according to the conditions reported
Synlett 2006, No. 15, 2427–2430 © Thieme Stuttgart · New York