NaH and MeI in 93% overall yield. Finally, the product was
treated with glacial acetic acid and an acetic anhydride-
pyridine system to provide the diacetate 11 in 90% yield.15
Removal of two acetyl groups in the 3- and 4-position of 11
using NaOMe in MeOH and subsequent benzylation of two
hydroxy groups by NaH-BnBr allowed the synthesis of
dibenzyl ether 12. Selective hydrolysis of the acetal moiety
in 12 under acidic condition and activation of the resulting
free hydroxy group provided the activated sugar imidate 13
as a mixture of epimers (R/â ) 5:1) in 89% yield.
With two key intermediates 16 and 18 in our hands, total
synthesis of clavosolide B (2) was persued immediately
(Scheme 6). Alcohol 16 and carboxylic acid 18 were coupled
Scheme 6. Synthesis of (-)-Clavosolide B (2)
The synthesis of top half segment 16 was achieved
following the sequence summarized in Scheme 4. Transfor-
Scheme 4. Synthesis of Top Half Segment 16
with the aid of DIC and DMAP to provide the ester 19 in
54% yield over two steps from the glycosylation reaction of
17. Selective cleavage of the PMB protecting group by DDQ
in CH2Cl2-H2O and of the allyl ester protecting group with
Pd(PPh3)4 furnished the hydroxy acid. Macrolactonization
of the hydroxy acid using a protocol of Yamaguchi in slightly
modified conditions proceeded smoothly, and final depro-
tection of the benzyl group with Pd/C in MeOH provided
the target compound 2 as a white solid in 78% yield.
mation of methyl ketone 7 into the key intermediate 14 was
accomplished following the same procedure reported earlier
in the synthesis of (-)-clavosolide A (1).6a Schmidt-type
glycosylation16 of sec-alcohol 14 with an activated sugar
imidate 13 in the presence of TMSOTf and molecular sieves
produced a mixture of products with an R/â ) 1:1 ratio,
and the desired â-isomer 15 was separated by silica gel
column chromatography in 47% yield. Alcohol 16 was then
prepared in a three-step sequence from 15, via hydrolysis of
methyl ester, esterification of carboxylic acid with allyl
bromide and K2CO3, and deprotection of PMB ether.
Bottom half segment 18 was also synthesized in a similar
manner (Scheme 5). Schmidt-type glycosylation16 of 14 with
1
Comparison of the H NMR spectra of the isolated and
synthetic compounds turns out to be identical except for the
signals from the impurities contained in the isolated natural
product (Figure 2).17 This result leads to the revision of
relative stereochemistry of clavosolide B (2) around the
cyclopropyl system, which was already implied from the
enantioselective total synthesis of clavosolide A (1).6-9
Optical rotation of the synthetic compound was also mea-
sured to be [R]D -47.2 (c 0.4, CHCl3), which is similar to
the reported value of [R]D -41.0 (c 0.5, CHCl3) for the
natural compound, therefore establishing the absolute ster-
eochemistry of clavosolide B (2) as shown in Figure 1.
Scheme 5. Synthesis of Bottom Half Segment 18
(13) (a) Zhang, J.; Zhu, Y.; Kong, F. Carbohydr. Res. 2001, 336, 229-
235. (b) Mach, M.; Schlueter, U.; Mathew, F.; Reid, B. F.; Hazen, K. C.
Tetrahedron 2002, 58, 7345-7354. (c) Suhr, R.; Thiem, J. J. Carbohydr.
Chem. 2004, 23, 261-276.
(14) Czifra´k, K.; Hadady, Z.; Docsa, T.; Gergely, P.; Schmidt, J.;
Wessjohannd, L.; Somsa´k, L. Carbohydr. Res. 2006, 341, 947-956.
(15) Chu, J.; Guo, H.; Wang, S. Tianjin Daxue Xuebao 2004, 37, 434-
437.
activated sugar imidate 17, prepared following the literature
procedure by us,6a was accomplished in 47% isolated yield,
and subsequent hydrolysis produced another key intermediate
18, which was used without further purification in the next
step.
(16) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980,
19, 731-732. (b) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990,
694-696. (c) Furstner, A.; Albert, M.; Mlynarski, J.; Matheu, M.; Declercq,
E. J. Am. Chem. Soc. 2003, 125, 13132-13142.
(17) See Supporting Information for details.
Org. Lett., Vol. 9, No. 20, 2007
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