9
was confirmed by examining the spectral properties of
0% yield. The C25ꢀC27 stereochemistry of diol 22
27 with hydrogen sulfide in a solution of methanol/
triethylamine (2:1) provided the thioamide inter-
1
7
acetonide 25. The acetonide methyl groups (δ 23.6, 25.8)
mediate, which was then converted into 28 through a
two-step sequence including a second cyclodehydration of
the β-hydroxy thioamide with DAST to produce a thiazo-
line followed by further dehydrogenation by the use of
1
3
and ketal carbon (δ 100.2) of 25 exhibited C NMR
chemical shifts (CDCl , 125 MHz) characteristic of anti-
3
1
and distinct from those observed for syn-1,3-diol acet-
,3-diol acetonides (δ 23.6ꢀ25.6 and 100.2ꢀ101.0)
1
8
DBU and bromotrichloromethane. Saponification of the
methyl ester 28 followed by coupling with amine 12 in the
15
onides (δ 18.6ꢀ19.9/29.8ꢀ30.2 and 98.0ꢀ99.3). Further-
more, the correlation for H25ꢀH26 by NOESY experi-
ment confirmed the expected 25,26-syn, 26,27-anti
stereochemistry.
1
9
presence of a Mukaiyama reagent provided the corre-
sponding amide in 57% yield, which was then treated with
tetrabutylammonium flouride (TBAF) to afford hoiamide
C in 51% yield. The optical rotation of the synthetic
With the three key fragments in hand, the stage was now
set for their assembly and elaboration into hoiamide C
(Scheme 6). Our fragment assemblybegan with couplingof
fragments 3 and 4. Thus, the Boc and acetonide protecting
2
0
D
product, [a]
with the value reported in the literature for natural hoia-
þ12 (c 0.2, CHCl ), was in close agreement
3
2
3
1
mide C, [a]
MHz, pyridine-d ) and C NMR (125 MHz, pyridine-d )
þ16 (c 0.2, CHCl ). The H NMR (500
D
3
1
3
5
5
spectra for this compound exactly matched the data
reported for naturally derived hoiamide C. Thus, the
original assignment of the relative and absolute configura-
tion of hoiamide C had been corroborated via unambig-
uous total synthesis.
Scheme 6. Synthesis of Hoiamide C
In summary, we have accomplished the total synthesis of
hoiamide C from homoallylic alcohol 18 in 1.8% overall
yield with the longest linear sequence of 16 steps. This
synthesis confirmed the structure of hoiamide C. The
extension of this chemistry toward the total synthesis of
hoiamide A and novel hoiamide analogues for biological
evaluation is underway and will be reported in due course.
Acknowledgment. We acknowledge financial support
from the Hong Kong Research Grants Council (Project:
PolyU5638/07M, PolyU5040/10P) and from the Shenz-
hen Bureau of Science, Technology and Information
(
JC200903160367A, ZD200806180051A). Z.S.X. (PK-
USZ) is thankful for support from National Natural
Science Foundation of China (21072007), Guangdong
province Scientific Foundation (10151805704000005),
and the opening Fund by Key Laboratory of Organic
Chemistry, Jiangxi Science & Technology Normal Uni-
versity. L.W. (PKUSZ) would like to thank Mr. K. Qiao
for his helpful technical assistance.
Supporting Information Available. Full details for
experimental procedures for compounds 1ꢀ5, 5a, 8ꢀ12,
0
1
13
1
4a, 15a, 15ꢀ17, 19, 20a, 21ꢀ28, 27 , 28a and H and
C
groups of bisthiazoline 3 were removed under mild condi-
tions (TMSOTf, triethyl amine) to afford hydroxyl amine
NMR spectra for compounds 1ꢀ4, 5a, 8, 10ꢀ12, 14a,
0
15ꢀ17, 19, 20a, 21ꢀ25, 27 , 27, 28, and 28a. This material
2
6. Acid 4 was activated as a mixed anhydride first and
is available free of charge via the Internet at http://pubs.
acs.org.
then condensed with hydroxyl amine 26 to provide the
corresponding β-hydroxy amide, which was then con-
verted into the oxazoline 27 by the action of diethylami-
(
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