Formal chemoselective synthesis of leucascandrolide A

Article abstract of DOI:10.1021/ol070670a

A chemoselective synthesis of ths macrocyclic cors of leucascandrolide A has been achieved, utilizing highly enantioselective allylmetalations, an enantioselective Noyori reduction of a propargylic ketone and olefin metatheses as the key steps.

Full text of DOI:10.1021/ol070670a

ORGANIC
LETTERS
2
007
Vol. 9, No. 13
461-2464
Formal Chemoselective Synthesis of
Leucascandrolide A
2
Laurent Ferri e´ , S e´ bastien Reymond, Patrice Capdevielle, and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 Rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received March 19, 2007
ABSTRACT
A chemoselective synthesis of the macrocyclic core of leucascandrolide A has been achieved, utilizing highly enantioselective allylmetalations,
an enantioselective Noyori reduction of a propargylic ketone and olefin metatheses as the key steps.
Leucascandrolide A is a structurally unique macrolide
isolated in 1996 from the sponge Leucascandra caVeolata,
extracted from the northeastern coast of New Caledonia in
For our part, we would like to report here the synthesis of
the macrocyclic core of leucascandrolide A. Macrolide 1
would be obtained by the macrolactonization of A, and the
cis-tetrahydropyran moiety present in 1 would be obtained
by an intramolecular 1,4-addition of the hydroxy group at
C7 on the R,â-unsaturated ester present in A. Ester A would
be synthesized by using an olefin cross-metathesis between
methyl acrylate and B. In compound B, the stereogenic
centers at C5, C7, and C9 would be controlled by using
highly stereoselective allylmetalations of aldehydes. The
1
the Coral Sea. The relative stereochemistry of the substi-
tuents in macrolide 1 was determined by NMR analysis, and
the absolute configuration of the stereogenic centers was
assigned through correlation of the C5 stereocenter by
transforming the C5 hydroxy group to a Mosher ester. The
natural product has been shown to possess anticancer activity
against human KB and P388 tumor cell lines displaying IC50
values of 0.05 and 0.26 µg/mL, respectively. Furthermore,
leucascandrolide A also exhibits potent antifungal activity
against Candida albicans, a yeast that attacks AIDS patients.
Recent reports indicate that leucascandrolide A is no longer
available from its original natural source due to the fact that
this compound is actually not a secondary metabolite of
(3) (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 12894. (b) Wang, Y.; Janjic, J.; Kozmin, S. A. J. Am. Chem.
Soc. 2002, 124, 13670. (c) Fettes, A.; Carreira, E. M. Angew. Chem., Int.
Ed. 2002, 41, 4098. (d) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68,
9274. (e) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343. (f)
Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833. (g) Wang, Y.; Jelena,
J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77, 1161. (h) Su, Q.; Paneck, J.
S. Angew. Chem., Int. Ed. 2005, 44, 1223. (i) Su, Q.; Dakin, L. A.; Paneck,
J. S. J. Org. Chem. 2007, 72, 2.
2
Leucascandra caVeolata but that of opportunistic bacteria.
Because of its structural complexity and its interesting
(4) For syntheses of the macrolide core of leucascandrolide A, see: (a)
Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123, 8420. (b)
Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066. (c) Williams, D. R.;
Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed. 2003, 42, 3934. (d)
Williams, D. R.; Patnaik, S.; Plummer, S. V. Org. Lett. 2003, 5, 4641. (e)
Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641.
biological properties, leucascandrolide A has solicited con-
3
siderable interest among organic chemists, and five total
4
and four formal syntheses as well as the preparation of
5
several fragments have been reported.
(
5) For syntheses of other fragments of leucascandrolide A, see: (a)
Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2, 579. (b)
Kozmin, S. A. Org. Lett. 2001, 3, 755. (c) Wipf, P.; Graham, T. H. J. Org.
Chem. 2001, 66, 3242. (d) Dakin, L. A.; Langille, N. F.; Paneck, J. S. J.
Org. Chem. 2002, 67, 6812. (e) Dakin, L. A.; Paneck, J. S. Org. Lett. 2003,
5, 3995.
(
1) D’Ambrosio, M.; Guerriero, M.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51.
2) D’Ambrosio, M.; Tato, M.; Debitus, C.; Pietra, F. HelV. Chim. Acta
999, 82, 347.
(
1
1
0.1021/ol070670a CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/31/2007

stereogenic centers at C11 and C12 would be controlled by
applying an enantioselective crotylmetalation to an aldehyde,
and the C17 stereogenic center would be controlled by
utilizing a ruthenium-catalyzed Noyori reduction of a pro-
pargylic ketone. The addition of enol ether 7 to an oxonium
species derived from C would control the stereogenic center
at C15. To access tetrahydropyran C, a ring-closing meta-
thesis of diene D which would be synthesized from but-3-
en-1-ol was envisaged (Scheme 1).
second one-pot reaction was the transfomation of 5 to 6
in 98% yield by reduction of lactone 5 with DIBAL-H
(-78 °C, CH
aluminum intermediate (Ac
2 2
Cl ) followed by acylation of the alkoxy
1
1
2
O, Py, DMAP). On the other
hand, silyl enol ether 7 was prepared in two steps from the
commercially available 4-methyl pent-1-yne. The starting
alkyne was acylated via an organozinc intermediate (n-BuLi,
2
THF, -78 °C, then ZnBr and AcCl) providing the propar-
gylic ketone (76% yield). This ketone was treated with
LiHMDS to furnish the corresponding lithium enolate, which
was trapped with TMSCl to give the silyl enol ether 7 (86%
3
b
yield) (Scheme 2).
Scheme 1. Retrosynthesis of Macrolide 1
Scheme 2. Construction of Synthetic Intermediates 6 and 7
The synthesis of fragment C9-C15 started with the
transformation of but-3-en-1-ol to aldehyde 2 which was
obtained in 76% yield after protection of the alcohol
(
TBDMSCl, imidazole) and ozonolysis (O
3
, -78 °C, then
6
Et
complex Ti(R,R)-I to aldehyde 2 (Et
3
N). The addition of the highly face selective titanium
Fragment C16-C22 7 was then coupled with the
C9-C15 fragment 6 by using a Mukaiyama-type reaction.
An oxonium intermediate which was generated from 6 by
7
2
O, -78 °C) allowed
us to control the stereogenic centers at C11 and C12,
producing the desired homoallylic alcohol 3 in 86% yield
(
treatment with ZnCl at -78 °C was quenched with enol
2
dr > 95/5 and de > 95/5).8,9 After transformation of 3 to
ether 7 to afford tetrahydropyran 8 (trans/cis ) 13/1, 89%
1
2
3 2 2
the unsaturated ester 4 (acryloyl chloride, Et N, CH Cl , 92%
yield). After reduction of ketone 8 by using Noyori cata-
yield), two one-pot sequences were successfully applied to
produce the desired acetoxy acetal 6. The first one-pot
reaction involved a tandem RCM/hydrogenation1 (Ru-I, 3
lyst Ru(R,R)-II under phase transfer conditions (HCO Na,
2
13,14
n-Bu NCl, H O/CH Cl ),
4
2
2
2
the desired propargylic alcohol
0
9 was isolated in 76% yield accompanied by ketone 9′
1
5
mol %, then H
2
, Pd/C) forming lactone 5 in 70% yield. The
(18%). The propargyl alcohol 9 was reduced with RedAl
(
6) Hon, Y. S.; Lin, S. W.; Lu, L.; Chen, Y. J. Tetrahedron 1995, 51,
019.
7) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rhote-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(11) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(12) Trans/cis ratio determined by GC/MS and GC analysis.
(13) Matsumura, K.; Hashigushi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
(14) When the formic acid/Et3N system was used for the reduction,
cleavage of the TBS ether in compound 8 was observed, and when i-PrOH
was used as the hydride source with the 16-electron Noyori catalyst, high
catalytic loading was required to achieve the reduction of 8.
(15) A single diastereoisomer was observed by GC and NMR.
5
(
1
(8) dr based on the H NMR spectra of the crude reaction mixture.
(
9) Titanium complex Ti(R,R)-I or Ti(R,R)-II allows the delivery of the
nucleophile on the Si face of an aldehyde.
10) Bargiggia, F. C.; Bouzbouz, S.; Cossy, J. Tetrahedron Lett. 2002,
3, 6715.
(
4
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Org. Lett., Vol. 9, No. 13, 2007

Scheme 3. Synthesis of Diol 17
to the (E)-allylic alcohol, but a partial deprotection of the
furnish the desired aldehyde. This aldehyde was directly
subjected to a stereoselective allylation using Ti(R,R)-II to
produce homoallylic alcohol 15 (78% from diol 14). At this
stage, the stereodirected introduction of the C5 stereogenic
center was envisaged by using a stereoselective allylstan-
primary alcohol at C9 was observed. Due to the formation
of this by-product, the crude material was directly treated with
TBSOTf (92% yield over two steps) to give compound 10.
The primary alcohol was chemoselectively deprotected
16
18
(
NH
4
F, MeOH) to afford alcohol 11 (80% yield) along with
nylation. To realize this transformation, alcohol 15 was
diol 11′ (13%). Despite the formation of by-product 11′, this
compound could be easily recycled to 10 and transformed
to 11. Once primary alcohol 11 was obtained, it was oxidized
to an aldehyde (Dess-Martin periodinane) which was
directly treated with the highly face-selective titanium
transformed to an aldehyde using the same chemoselective
two-step oxidative cleavage as before. At first, triol 16 was
4
obtained by dihydroxylation (OsO cat, NMO, 66% yield,
1
7
17% recovered starting material), and its subsequent
oxidative cleavage with NaIO generated the corresponding
4
7
complex Ti(R,R)-II, to produce homoallylic alcohol 12 (80%
aldehyde. The obtained hydroxy-aldehyde was then directly
treated with a premixed solution of allyltrimethylsilane and
yield from 11, dr > 95:5).8 The hydroxy group at C9, in
,9
1
6
compound 12, was then transformed to a methyl ether,
SnCl at -78 °C, producing syn-1,3-diol 17 (74% yield,
4
leading to compound 13 (Ag
2
O, MeI, 96% yield). To
two steps from 16) (Scheme 3).
introduce the stereogenic centers at C7 by allylation,
compound 13 had to be converted to an aldehyde by
oxidative cleavage of the terminal double bond. However,
it was necessary to perform the oxidative cleavage of the
terminal double bond selectively over the internal C18-C19
double bond. As the internal double bond was protected by
the use of the bulky TBS protecting group at C17, the
At this point of the synthesis, seven of the eight stereogenic
centers of leucascandrolide A were installed. To complete
the synthesis of macrolactone 1 and to introduce the last C3
stereogenic center, an intramolecular 1,4-addition of the
hydroxy group at C7 to an R,â-unsaturated ester was
envisaged. Compound 17 was treated with methyl acrylate
4
dihydroxylation of 13 [OsO cat, NMO (1.1 equiv)] led
(17) After 24 h, no evolution of the conversion was observed and the
chemoselectively to diol 14 (61% yield, 32% unreacted
starting material), which was then treated with NaIO to
4
conditions were not forced to preserve the chemoselectivity of the
dihydroxylation.
1
7
(18) (a) Allais, F.; Cossy, J. Org. Lett. 2006, 8, 3655. (b) Allais, F.;
Louvel, M.-C.; Cossy, J. Synlett 2007, 451. (c) Allais, F.; Roche, C.;
Bouzbouz, S.; Cossy, J., unpublished results.
(16) Crich, D.; Herman, F. Tetrahedron Lett. 1993, 34, 3385.
Org. Lett., Vol. 9, No. 13, 2007
2463

but fortunately, they were separated in the next step by
column chromatography on silica gel. After treatment with
TBAF in THF, diol cis-20 was isolated as a single diaste-
Scheme 4. Completion of the Synthesis of Macrolide 1
2
2
reoisomer (38% over the two steps).
Finally, macrolactone 1 was obtained by applying two
3
,4
reported procedures. At first, a mild saponification of the
2
3
2
methyl ester with TMSOK in Et O afforded the hydroxy
acid, the cyclization of which provided selectively the
macrocyclic core of leucascandrolide A 1 under the Yone-
2
4
mitsu-modified Yamaguchi protocol (75% yield from
cis-20). Macrolide 1 was identical in all respects with the
spectral data and the specific rotation reported previously
3
,4
(Scheme 4).
Macrolide 1 was synthesized in 25 steps and 1.2% overall
yield from but-3-en-1-ol. Synthetic highlights include highly
stereoselective allylmetalations to control the stereogenic
centers at C5, C7, C9, C11, and C12, an enantioselective
Noyori reduction of a propargylic ketone to control the
stereogenic center at C5, a cross-metathesis followed by an
intramolecular 1,4-addition to build up the cis-tetrahydro-
pyran, and a ring-closing metathesis Mukaiyama reaction to
build up the trans-tetrahydropyran. Furthermore, by using
chemoselective reactions such as selective cleavage of TBS
ethers, dihydroxylation and cross-metatheses, this synthesis
appears to be one of the shortest syntheses of the macrolide
core of leucascandrolide A, considering the total number of
steps.
Acknowledgment. L.F. thanks the MRES for a grant.
Supporting Information Available: Experimental pro-
1
13
cedure and H and C NMR spectra for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
in the presence of Hoveyda-Grubbs catalyst Ru-III19
(
1
1
15 mol %) to provide chemoselectively the unsaturated ester
OL070670A
8 (84% yield).2 The elaboration of cis-tetrahydropyran
0
9 was realized under basic conditions by using a cata-
(
(
20) Bouzbouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465.
21) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
21
lytic amount of t-BuOK (20 mol %) which afforded two
diastereoisomers in a modest ratio (cis-19/trans-19 ) 3/1).
These two epimers were difficult to separate at this stage,
(22) The major isomer cis-20 showed the same spectral data as those
described by Crimmins: see ref 4e.
(23) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(
24) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
(
19) Kingbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Sakura ¨ı , Y.; Horita,
K.; Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.
A. H. J. Am. Chem. Soc. 2000, 122, 8168.
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