Synthesis of the core structure of salicylihalamide A by intramolecular Suzuki reaction.

Article abstract of DOI:10.1021/ol026040k

[reaction: see text] An intramolecular Suzuki coupling was used to establish the core structure of the benzolactone enamide salicylihalamide A. This strategy combines a diastereoselective hydroboration with a subsequent cross-coupling.

Full text of DOI:10.1021/ol026040k

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2205-2208
Synthesis of the Core Structure of
Salicylihalamide A by Intramolecular
Suzuki Reaction
Matthias Bauer and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen,
Auf der Morgenstelle 18, D-72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received April 18, 2002
ABSTRACT
An intramolecular Suzuki coupling was used to establish the core structure of the benzolactone enamide salicylihalamide A. This strategy
combines a diastereoselective hydroboration with a subsequent cross-coupling.
Molecules that selectively interact with a cellular protein,
RNA, or DNA are important biological tools, particularly
in the context of chemical genetics.1 In addition, such
compounds are indispensable for the treatment of human
dysfunctions and diseases. While the number of natural
products might be insufficient for targeting each gene
product, they still help to find new targets and provide new
structural leads. Fascinating examples in this regard are the
benzolactone enamides, natural products that turned out to
be selective inhibitors of mammalian vacuolar (H+)-ATPase.2
This mode of action, resulting in high cytoxicity with a GI50
in the low nanomolar range, was discovered by comparing
the activity profile against the profile database of the NCI.
Figure 1. Two representative benzolactone enamides.
Prominent members from the benzolactone enamides include
the salicylihalamides,3 isolated from the sponge Haliclona
the oximidines,6 YM-75518,7 and the fungal metabolites CJ-
12,9508 and CJ-13,357. Structurally, these compounds have
in common a salicylic acid substructure, a macrolactone, and
an enamide side chain. The enamide side chain, which seems
sp., and the apicularens,4 produced by myxobacteria (Figure
1). Further members of this class include the lobatamides,5
(1) (a) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127-1152. (b)
Tan, D.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.; Schreiber, S. L. J.
Am. Chem. Soc. 1999, 121, 9073-9087. (c) King, R. W. Chem. Biol. 1999,
6, R327-R333. (d) Bishop, A.; Kung, C.-y.; Shah, K.; Witucki, L.; Shokat,
K. M.; Liu, Y. J. Am. Chem. Soc. 1999, 121, 627-631.
(2) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.;
Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E.
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(3) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II.; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188-8192.
(4) (a) Kunze, B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075-1080. (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913-919.
(5) McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J. H., II;
Laakso, J.; Ireland, C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. J. Org.
Chem. 1998, 63, 7805-7810.
(6) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J.
Org. Chem. 1999, 64, 153-155.
10.1021/ol026040k CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/01/2002

to be important for conferring biological activity, is also
found in some other natural products, including the chon-
driamides, zampanolide, and the proteasome inhibitors TMC-
95.9
alternative would be the formation of the C10-C11 bond
by a cross-coupling reaction. In this paper we show that
indeed a sequence of a diastereoselective hydroboration
followed by Suzuki coupling16,17 allows for the formation
of the salicylihalamide core structure.
Initial studies focused on the Suzuki coupling on a model
system. First, the benzoic acid 6 with a iodopropenyl side
chain was prepared from the known acid 3.11e Esterification
of 3 with dimethylformamide-di-tert-butyl acetal18 (Scheme
1) followed by ozonolysis gave the aldehyde 4. A subsequent
From a synthetic point of view the benzolactone enamides
represent challenging targets. In the meantime, total syntheses
of apicularen A10 and salicylihalamide11 were reported. In
addition, synthetic approaches to the core structure of these
natural products12,13 and studies aimed at the enamide side
chains14 have been published. The macrolactone portion of
salicylihalamide is unique in that it features a double bond
in an allylic position to the aromatic ring. A classical
macrolactonization approach is difficult as a result of steric
hindrance of the carboxylic group and participation of the
double bond. However, if the double bond is of a styrene
type, the macrolactonization works in acceptable yields.15
So far all successful approaches to salicylihalamide are based
on an intramolecular ring-closing metathesis reaction. We
asked ourselves how one would synthesize this molecule if
the ring-closing metathesis were not known. According to
the retrosynthetic analysis (Figure 2) we opted for formation
Scheme 1. Synthesis of Acid 6 and Propenol 9
Takai reaction19 of 4 gave the vinyl iodide 5 (E/Z ) 4:1).
The acid 6 was obtained by treatment of the ester 5 with
trifluoroacetic acid. It was important to employ the tert-butyl
ester 5 because a basic hydrolysis of the ester group (on the
corresponding methyl ester) is not survived by the vinyl
iodide. The pentenol derivative 9 was prepared in racemic
Figure 2. Retrosynthetic analysis for salicylihalamide A based on
a Suzuki coupling to form the C10-C11 bond.
(12) Salicylihalamide studies: (a) Fu¨rstner, A.; Seidel, G.; Kindler, N.
Tetrahedron 1999, 55, 8215-8230. (b) Fu¨rstner, A.; Thiel, O. R.; Blanda,
G. Org. Lett. 2000, 2, 3731-3734. (c) Feutrill, J. T.; Holloway, G. A.;
Hilli, F.; Hu¨gel, H. M.; Rizzacasa, M. A. Tetrahedron Lett. 2000, 41, 8569-
8572. (d) Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi, F.; Flaherty, P.
T.; Mossman, C. J.; Roy, S.; Yang, K. J. Chem. Soc., Chem. Commun.
2001, 255-256.
(13) (a) Bhattacharjee, A.; De Brabander, J. K. Tetrahedron Lett. 2000,
41, 8069-8073. (b) Ku¨hnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643-
646.
of a vinylic C-C bond, either in an inter- or intramolecular
fashion. The ester bond would be formed by a Mitsunobu
reaction. The creation of the C8-C9 bond has been described
in the literature but suffers from moderate yield.11f Another
(7) Suzumura, K.-i.; Takahashi, I.; Matsumoto, H.; Nagai, K.; Setiawan,
B.; Rantiatmodjo, R. M.; Suzuki, K.-i.; Nagano, N. Tetrahedron Lett. 1997,
38, 7573-7576.
(14) (a) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397-
399. (b) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407-408. (c) Shen, R.;
Porco, J. A., Jr. Org. Lett. 2000, 2, 1333-1336. (d) Stefanuti, I.; Smith, S.
A.; Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 3737-3738. (e) Fu¨rstner,
A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3, 3955-3957.
(15) We prepared the macrocyclic core of salicylihalamide with the
double bond in vinylic position using a macrolactonization strategy. Bauer,
M. Unpublished results.
(16) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457-2483. (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem. 2001, 113, 4676-4701; Angew. Chem., Int. Ed. 2001, 40, 4544-
4568.
(8) Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara, T.;
Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J. Antibiot. 1998,
51, 14-20.
(9) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu,
R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990-995.
(10) (a) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron
Lett. 2001, 42, 1217-1220. (b) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith,
S. A.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 5549-5552.
(11) (a) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem. 2000,
112, 4478-4480. (b) Labrecque, D.; Charron, S.; Rej, R.; Blais, C.;
Lamothe, S. Tetrahedron Lett. 2001, 42, 2645-2648. (c) Snider, B. B.;
Song, F. Org. Lett. 2001, 3, 1817-1820. (d) Fu¨rstner, A.; Dierkes, T.; Thiel,
O.; Blanda, G. Chem. Eur. J. 2001, 7, 5286-5298. (e) Smith, A. B., III;
Zheng, J. Synlett 2001, 1019-1023. (f) Wu, Y.; Liao, X.; Wang, R.; Xie,
X.-S.; De Brabander, J. K. J. Am. Chem. Soc. 2002, 124, 3245-3253.
(17) For recent examples, see: (a) Kallan, N. C.; Halcomb, R. L. Org.
Lett. 2000, 2, 2687-2690. (b) Chemler, S. R.; Danishefsky, S. J. Org. Lett.
2000, 2, 2695-2698.
(18) Widmer, U. Synthesis 1983, 135-136.
(19) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
2206
Org. Lett., Vol. 4, No. 13, 2002

form by an aldol reaction of tert-butyl acetate with acrolein
to give the hydroxy ester 8. This was followed by MOM
protection of the secondary hydroxyl group and reduction
of the ester function to produce alcohol 9.
Scheme 3. Synthesis of Alkene 18 via Evans
Aldol-Reduction-Elimination Sequence
With the substrates 6 and 9 in hand, the intramolecular
Suzuki reaction was investigated. Thus, by esterification of
the acid 6 with the alcohol 9 under Mitsunobu conditions,
the cyclization substrate 10 was prepared (Scheme 2).
Scheme 2. Synthesis of Macrolactone 11 by Intramolecular
Suzuki Coupling
After protecting the secondary alcohol of 14 as MOM ether,
a reductive removal of the chiral auxiliary with NaBH4 in a
THF/H2O mixture26 provided the primary alcohol 16. Next,
the corresponding tosylate was prepared. The elimination to
give the alkene 17 could be smoothly accomplished by
heating the tosylate in glyme in the presence of NaI (2.5
equiv) and DBU (5.0 equiv). Treatment of 17 with tetrabut-
ylammonium fluoride (TBAF) furnished the alcohol 18.
Esterification of the acid 6 with the alcohol 18 under
Mitsunobu conditions27,28 generated the cyclization substrate
19 (Scheme 4). For the intramolecular Suzuki reaction the
Preliminary studies on the methyl ester analogue of 5 had
shown that the vinyl iodide gives high yields in inter-
molecular Suzuki coupling reactions using the conditions of
Trost [(dppf)PdCl2 (5 mol %), Ph3As (5 mol %), Cs2CO3
(1.3 equiv), THF, 23 °C, 4 h].20 In contrast, the Suzuki
cyclization of 10 required some experimentation. First,
hydroboration of 10 turned out to be relatively slow, requiring
stirring overnight with up to 5 equiv of 9-BBN. The progress
of the hydroboration reaction could be followed by 1H NMR
spectroscopy. While the “Trost” conditions did not give the
cyclization product, the original Suzuki conditions21 brought
about the desired cyclization. This was achieved by adding
the intermediate borane via syringe pump to a heated mixture
(80 °C) of benzene, 3 N NaOH, and the palladium catalyst.
Because of the high dilution, a larger amount of the catalyst
(dppf)PdCl2 (20 mol %) was used. The steric hindrance at
the ester group probably retards cleavage of the lactone. This
way, a 62% yield of the macrocycle 11 was obtained.
The next phase of the project focused on a substrate with
a 1,1-disubstituted double bond and the issue of the diaste-
reoselective hydroboration prior to the cyclization. Accord-
ingly, the alkene part 18 lacking the side chain was prepared
in optically pure form as illustrated in Scheme 3. An Evans
aldol reaction22,23 of the chiral propionate 12 with aldehyde
1324 using TiCl4 (1.05 equiv) in the presence of sparteine25
(2.5 equiv) gave a high yield of the syn-aldol product 14.
Scheme 4. Intramolecular Suzuki Coupling to Give
Macrolactone 20
same conditions as before were employed. After workup, a
53% yield of the macrolactone 20 was obtained. The
stereochemistry of the hydroboration29 was assumed to follow
the Houk model.30,31
(20) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818-6819.
(21) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321.
(22) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83-91.
(23) For a review, see: Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-
947.
(24) Hamdouchi, C.; Sanchez-Martinez, C. Synthesis 2001, 833-840.
(25) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883-7884. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894-902.
(26) Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.; Har, D.; Repic, O.;
Blacklock, T. J.; Giannousis, P. J. Org. Chem. 1999, 64, 1750-1753.
(27) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem.
2000, 65, 7990-7995.
(28) For a review, see: Hughes, D. L. Org. React. 1992, 42, 335-656.
Org. Lett., Vol. 4, No. 13, 2002
2207

The Suzuki cyclization was also extended to a system
containing a side chain at C-15. By applying a Duthaler aldol
reaction32 between the aldehyde 2133 and tert-butyl acetate,
the 3-hydroxy ester 22 was prepared in 83% ee (Scheme 5).
the Duthaler aldol reaction, the stereochemistry at C-15
(salicylihalamide numbering) had to be inverted. This was
accomplished on the alcohol 28 by a Mitsunobu reaction34
using p-nitrobenzoic acid. Basic hydrolysis provided the syn-
configured diol derivative 29.
Next, the acid 6 was esterified with the alcohol 29 under
Mitsunobu conditions, providing the cyclization substrate 30
in 81% yield (Scheme 6). The macrocyclization was per-
Scheme 5. Synthesis of Alcohol 29
Scheme 6. Intramolecular Suzuki Coupling to Give
Salicylihalamide Core Structure 31
formed as described before. This gave a 48% yield of the
1
macrolactone 31. The H NMR spectrum of 31 shows 2
methyl doubletts (δ ) 0.91 major, 1.02 minor) that are due
to the major product and the cis-double bond isomer. From
this, it can be followed that the hydroboration is highly
diastereoselective. Separation of the isomers by preparative
HPLC gave pure 31.
In summary, we developed a synthesis of the core system
of salicylihalamide A by employing an intramolecular Suzuki
coupling as a key step. This exemplifies a novel strategic
retrosynthetic cut for reaching the macrocyclic ring. The
Suzuki cyclization is preceded by a diastereoselective hy-
droboration. In essence, the aldol-elimination-hydrobora-
tion sequence inverts the stereochemistry at C-12. Our efforts
concentrate now on the synthesis of isomerically pure vinyl
iodide 6 and streamlining the route to the alkenol 29 in order
to complete the total synthesis of salicylihalamide A.
Protection of the secondary hydroxy group with triisoprop-
ylsilyl chloride followed by DIBAL reduction furnished the
aldehyde 23. Again, an Evans aldol reaction was used to
extend the carbon chain, yielding compound 24. After
reductive removal of the chiral auxiliary, tosylation of the
primary alcohol and elimination in the presence of NaI
provided the 1,1-disubstituted alkene 27 in excellent yield.
Since di-O-isopropylidene-D-glucofuranose was employed in
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft (grant Ma 1012/10-1) and the Fonds
der Chemischen Industrie is gratefully acknowledged.
(29) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487-
2489.
(30) Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J. T.; Paddon-Row,
M. N. Tetrahedron 1984, 40, 2257-2274.
(31) To determine the stereochemistry of the hydroboration, 19 was
subjected to hydroboration and a subsequent oxidative workup. After basic
hydrolysis (LiOH, THF/H2O, 100 °C) an alcohol was obtained that was
different from the same alcohol prepared by Evans-aldol reaction (obtained
by TBAF treatment of 16).
(32) Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker,
M. Angew. Chem. 1989, 101, 490-491; Angew. Chem., Int. Ed. Engl. 1989,
28, 495-496.
(33) Ishikawa, T.; Ikeda, S.; Ibe, M.; Saito, S. Tetrahedron 1998, 54,
5869-5882.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026040K
(34) (a) Martin, S. P.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-
3020. (b) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 3899-
3902.
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Org. Lett., Vol. 4, No. 13, 2002