Short and efficient chiral pool and RCM approach towards the synthesis of the macrocyclic core of the salicylihalamides

Article abstract of DOI:10.1039/b008842k

The macrolactone core structure of the salicylihalamides was prepared from diacetone-D-Glucose and via a ring-closing metathesis reaction.

Full text of DOI:10.1039/b008842k

Short and efficient chiral pool and RCM approach towards the synthesis of the
macrocyclic core of the salicylihalamides
Gunda I. Georg,* Yu Mi Ahn, Burchelle Blackman, Faryar Farokhi, Patrick T. Flaherty, Craig J. Mossman,
Subho Roy and KyoungLang Yang
Department of Medicinal Chemistry, Center for Cancer Experimental Therapeutics, and Drug Discovery Program,
Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66045, USA. E-mail: georg@ku.edu
Received (in Corvallis, OR, USA) 1st November 2000, Accepted 20th December 2000
First published as an Advance Article on the web 23rd January 2001
The macrolactone core structure of the salicylihalamides
was prepared from diacetone-
closing metathesis reaction.
D-glucose and via a ring-
Salicylihalamides A and B (1 and 2) are naturally occurring
cytotoxic macrolides isolated from an Australian sponge
Haliclona sp. in 1997.1 They were the first examples of a novel
class of macrolides that have in common the salicylic acid
moiety and an unsaturated enamide side chain.2–6
This class of compounds possesses diverse biological
activities, including inhibition of tumor cell proliferation.1–6
Salicylihalamide A displayed a striking pattern of differential
cytotoxicity in the NCI’s 60-cancer cell line human tumor
screen.1 COMPARE pattern-recognition analyses7 of the mean-
graph profiles of salicylihalamide A suggest that the salicylihal-
amides may act by a novel mechanism of action. Despite their
promise as potential anticancer agents, further studies of this
new class of compounds are hampered by limited availability
from natural sources. The unique structural features of the
salicylihalamides coupled with promising biological activity
prompted us to develop a flexible approach toward the synthesis
of these molecules and related analogues.
Scheme 1 Retrosynthesis for the salicylihalamide macrolide.
We initially focused on the synthesis of intermediate 3
(Scheme 1), the macrocyclic core structure of the salicylihala-
mides containing the three chiralacnedntehres
D
9,10 E-alkene.
The masked aldehyde functionality in 3 provides an opportunity
for side chain attachment at C16 and subsequent completion of
the total synthesis.
Our synthetic strategy for the preparation of building block 3
features the use of readily available diacetone- -glucose as the
D
source for the three chiral centers of the molecule (chiral pool
approach). The regioselective formation of the E-double bond at
C9 was accomplished through a ring-closing metathesis (RCM)
reaction employing intermediate 4. Although the RCM strategy
has been used before to form the 12-membered macrolactone
ring of unsubstituted or side chain truncated salicylihala-
mides,8,9 we herein report the use of the same protocol with a
fully-substituted salicylihalamide macrocyclic core. Intermedi-
ate 4 can be obtained from lactone 6 via Mitsunobu esterifica-
tion with 6-allylsalicylic acid (5). 6-Allylsalicylic acid (5) can
be prepared from O-methylsalicylic acid10 and diacetone-
D-
glucose 7 is the precursor for lactone 6.11,12
The macrolide synthesis started with known alcohol 8, which
Scheme 2 Reagents and conditions: (a) Tf2O, 2,6-dimethylpyridine, 0 °C,
1.5 h; (b) (CH2NCHCH2)2Cu)CN)Li2, THF, 278 °C, 2 h, 78%; (c) 70% aq.
acetic acid, 70 °C, 6 h, 98%; (d) Ag2CO3–Celite, 80 °C, 1 h, 85%.
was prepared in five straightforward steps from diacetone- -
D
glucose (Scheme 2).11–13 The secondary hydroxy group in 8
DOI: 10.1039/b008842k
Chem. Commun., 2001, 255–256
This journal is © The Royal Society of Chemistry 2001
255

was found to be the major reaction product (E+Z ratio 15+85;
60% yield). When the phenolic hydroxy of 12 was protected as
its TBDPS ether 13 (85% yield) and lactone 13 was reduced to
lactol 4 (80% yield), RCM of intermediate 4 furnished the two
stereoisomeric lactols 15 and 16 in a 70+30 E+Z ratio and in
60% yield. The introduction of the sterically demanding
TBDPS protecting group apparently promotes a conformational
change in the transition state of the RCM reaction that favors the
formation of the E-alkene. After deprotection of the silyl ethers
15 and 16, the stereoisomers 3 and 17 (85% yield) were
separated by column chromatography furnishing the desired E-
isomer 3 in 60% yield.
Scheme 3 Reagents and conditions: (a) sec-BuLi, TMEDA, THF, allyl
bromide, 290 °C to rt, 0.5 h, 46% (based on recovered starting material); (b)
BCl3, (n-Bu)4NI, DCM, 278 °C, 2 h, 80%.
was converted to its corresponding triflate 9, which was reacted
immediately and without purification with a higher order
allylcyanocuprate to provide 10 with inversion of configuration
in 78% yield† (Scheme 2). Deprotection of the acetonide group
was carried out with 70% acetic acid to yield alcohol 11.
Selective oxidation of the anomeric hydroxy group with
Ag2CO3–Celite afforded lactone 6 in excellent yield. The
synthesis of 5 was carried out in a two-step sequence as outlined
in Scheme 3. Ortho-lithiation of O-methylsalicylic acid with
sec-BuLi–TMEDA and quenching the carbanion with allyl
bromide,10 followed by deprotection of the methyl ether using
BCl3–(n-Bu)4NI,14 afforded 5 in moderate overall yield.
Esterification of carbohydrate building block 6 with 5 under
Mitsunobu conditions (Scheme 4) afforded intermediate 12 in
good yield.
Having completed the synthesis of the macrolactone with
correct stereo- and regiochemistry,15 studies directed at in-
troducing the enamide side chain are in progress.
This work was financially supported by the National Cancer
Institute (N01-CM-67259 and RO1 CA84173), and the Drug
Discovery Program of the Higuchi Biosciences Center at the
University of Kansas. B. B. gratefully acknowledges financial
support from predoctoral NIH training grant GM-07775 and the
American Foundation for Pharmaceutical Education (AFPE)
for a predoctoral fellowship. F. F. is grateful for an AAPS-
AFPE ‘Gateway’ Research Scholarship for undergraduate
students.
Note added in proof. For a revision of the absolute
configuration of salicylihalamide A through total synthesis, see:
Y. Wu, L. Esser and J. K. Brabander, Angew. Chem., Int. Ed.,
2000, 39, 4308.
After the three stereogenic centers had been installed, the
9,10
next step was the RCM reaction to form the D
alkene.
Surprisingly, RCM employing lactone 12 failed to give any of
the desired product. Therefore the lactone functionality of 12
was reduced to lactol 14 (88+12, a+b; 80% yield) using
DIBAL-H at 278 °C. RCM reaction with this substrate
provided the desired reaction product. However, the Z isomer
Notes and references
† All new compounds exhibited satisfactory spectral data in accordance
with their structures. Yields refer to chromatographically pure com-
pounds.
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Scheme 4 Reagents and conditions: (a) Ph3P, DEAD, THF, 220 °C to 0 °C,
1 h, 85%; (b) TBDPSCl, imidazole, DMF, rt, 1 h, 85%; (c) DIBAL-H, ether,
278 °C, 2 h, 80%; (d) RuCl2NCHPh)(PCy3)2, DCM, reflux, 3 h, 60%; (e)
TBAF, THF, rt, 1 h, 85%.
256
Chem. Commun., 2001, 255–256