Scheme 3a
a Reagents and conditions: (a) 6, c-Hex2BCl, Et3N, Et2O, -20 °C; 5, -78 to -30 °C. (b) SmI2, EtCHO, THF, -20 °C. (c) TESOTf,
lutidine, CH2Cl2, -78 °C. (d) DIBAL, CH2Cl2, -78 °C. (e) Me3OBF4, proton sponge, CH2Cl2, 0 °C. (f) DDQ, CH2Cl2, pH 7 buffer, reflux.
(g) Dess-Martin periodinane, CH2Cl2. (h) BF3‚Et2O, CH2Cl2, -100 °C. (i) PPTS, (MeO)3CH, MeOH. (j) TBSOTf, lutidine, CH2Cl2, -78
°C. (k) TBAF, THF; (l) Ba(OH)2‚8H2O, MeOH. (m) 2,4,6-Cl3(C6H2)COCl, Et3N; DMAP, PhMe, 80 °C.
was used here in place of the standard 4-methoxybenzyl
(PMB) variant. Aldol coupling of the (E)-enolate generated
from 6 with aldehyde 5 gave adduct 11 in 99% yield and
20:1 dr, where the remote silyloxy-bearing stereocenter at
C13 had minimal influence on the stereoinduction. An
Evans-Tishchenko 1,3-anti reduction16 of â-hydroxy ketone
11 and formation of the TES ether from the resulting C7
hydroxyl group (obtained with 98:2 dr) was followed by
reductive cleavage of the C9 ester and O-methylation to
afford 12 in 79% overall yield.
Our choice of the DMB protecting group was precipitated
by concerns over unwanted oxidation of the allylic TBS ether
at C13 in 12 under the agency of DDQ. Indeed, this increased
electron density led to enhanced chemoselectivity in com-
parison with the PMB group.4 Treating DMB ether 12 with
a slight excess of DDQ in moist CH2Cl2 for 15 min provided
the alcohol 13 in 67% yield (96% based on recovered 12),
with none of the C13 ketone observed. Dess-Martin
oxidation then gave the aldehyde 14 (84%) in readiness for
a Mukaiyama-type aldol reaction. Addition of the 1,3-bis-
(silyloxy)diene 717 to the aldehyde 14, in the presence of
BF3‚OEt2 at -100 °C, provided the Felkin-Anh product 15
in 85% yield and 95:5 dr. Cleavage of the TES ether and
concomitant methyl acetal formation (PPTS, (MeO)3CH,
MeOH) then gave 16. Formation of the TBS ether at C5,
followed by selective deprotection of the allylic TBS ether
at C13 with TBAF and saponification with Ba(OH)2, then
provided the corresponding seco-acid (90%), which under-
went the crucial Yamaguchi macrolactonization reaction18
to give macrocycle 2 in 64% yield.
At this stage, it still remained to build out the chloro-
cyclopropyl-containing side chain and glycosylate the C5
alcohol with an appropriate sugar derivative (Scheme 4).
First, the fully elaborated side chain was introduced by a
Sonogashira-type19 sp2-sp cross-coupling between the vinyl
iodide 2 and the (20S,21R)-alkyne 3,4 obtained on treatment
of an Et2O solution of dibromoalkene 17 with n-BuLi. Under
optimized coupling conditions (PdCl2(PPh3)2, CuI, i-Pr2NH,
EtOAc), this provided the protected aglycon 18 cleanly in
83% yield. Deprotection of the TBS ether and concomitant
hydrolysis to the methyl acetal with TFA in aqueous THF
then gave the callipeltoside aglycon 19 (98%). Final comple-
tion of the total synthesis of callipeltoside A relied on
coupling of this aglycon with the activated sugar 4 (obtained
from L-rhamnose by adaptation of the sequence reported by
Guiliano and co-workers6) via a Schmidt-type glycosylation.2a,20
Treatment of a mixture of the C5 alcohol 19 and the
trichloroacetimidate 4 with a catalytic amount of TMSOTf
in CH2Cl2 at -30 °C, followed by desilylation with TBAF/
AcOH, then gave (-)-callipeltoside A (1) in 76% yield. The
1H and 13C NMR data and, importantly, the specific rotation
value,21 [R]20D ) -17.0 (c 0.34, MeOH) cf. [R]23D ) -17.6
(13) Ethyl ketone 6 was prepared in 60% yield from methyl (R)-3-
hydroxy-2-methylpropionate in an analogous manner to that reported
previously for the PMB ether: (i) DMBO(CCl3)CdNH, PPTS, CH2Cl2;
(ii) MeONHMe‚HCl, i-PrMgCl, THF, -20 °C; (iii) EtMgCl, THF, 0 °C.
(a) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185. (b) Paterson,
I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.
2001, 123, 9535.
(14) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287.
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(15) Oikawa, Y.; Tanaka, T.; Horita, K.; Yoshioka, T.; Yonemitsu, O.
Tetrahedron Lett. 1984, 25, 5393.
(16) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
(17) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J. Can. J.
Chem. 1983, 61, 688.
(19) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (b) Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc.
1997, 119, 12159.
(20) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19,
731.
Org. Lett., Vol. 5, No. 23, 2003
4479