Synthesis of the core structure of apicularen a by transannular cyclization.

Article abstract of DOI:10.1021/ol017261d

[reaction: see text] An approach to the macrocyclic core of apicularen A is described. Thus, cross-coupling of the aryl triflate 7 with the vinylstannane 19 provided the styrene 20. Deprotection led to the dihydroxy acid 22. Through a size-selective macro

Full text of DOI:10.1021/ol017261d

ORGANIC
LETTERS
2002
Vol. 4, No. 4
643-646
Synthesis of the Core Structure of
Apicularen A by Transannular
Cyclization
Sven M. Ku1hnert 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 December 19, 2001
ABSTRACT
An approach to the macrocyclic core of apicularen A is described. Thus, cross-coupling of the aryl triflate 7 with the vinylstannane 19 provided
the styrene 20. Deprotection led to the dihydroxy acid 22. Through a size-selective macrolactonization, the 12-membered macrolactone 23 was
obtained. Treatment of 24 with N-phenyl selenophthalimide gave the desired trans-pyran 24. This approach might parallel the biosynthetic
pathway.
Recently a number of natural products were isolated that
contain a salicylic acid substructure, a macrolactone, and an
enamide side chain. This class of compounds comprises the
apicularens (1, 2),1 the salicylihalamides (3) (Figure 1),2 the
lobatamides, the oximidines, and CJ-12,950. All of these
compounds show potent antitumor activity. Of particular
interest was the fact that the screening profiles of these
compounds differed significantly from those of other known
antitumor compounds. In the meantime, it turned out that
the molecular targets of the benzolactone enamides are
mammalian vacuolar-type(H+)-ATPases.3 These membrane-
bound proton-translocating pumps are responsible for regula-
tion of pH in cellular spaces. A unique property of the
benzolactone enamides is their selectivity toward certain
V-ATPases.
As a result of their structural and biochemical features,
these compounds became prominent synthetic targets. Thus,
(1) (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.
(2) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188-8192.
(3) 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.
J. J. Pharmacol. Exp. Ther. 2001, 291, 114-120.
Figure 1. Structures of representative benzolactone enamides.
10.1021/ol017261d CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/24/2002

total synthesis of apicularen A4 and salicylihalamide5 were
reported. In addition, a range of analogues6,7 and studies
concerning the enamide side chains8 have appeared in the
literature.
Apicularen differs from the other benzolactone enamides
in that it contains a pyran ring, probably being formed
through a transannular cyclization. Figure 2 depicts some
Figure 3. Retrosynthetic analysis for apicularen A based on a
transannular etherification reaction
6 are usually prepared by monoetherification of a 2,6-
dihydroxy precursor10 or a mono cleavage of a dimethoxy
precursor.11 These steps are problematic and lead to mixtures.
The following route is based on a carboxylation reaction of
1-methoxy-3-tetrahydropyran-2-yloxybenzene 4 (Scheme 1).
Scheme 1. Facile Synthesis of the Ester 6
Figure 2. Potential biosynthetic precursors for apicularen A.
potential precursors. We reasoned that a similar strategy
might also work in a laboratory setting. In this paper we
demonstrate the feasibility of this approach.
The corresponding retrosynthetic analysis is shown in
Figure 3. According to this plan, the triflate 3.3 and a
vinylstannane, such as 3.4, appear as possible starting
materials. Initially we confined ourselves to the 11-deoxy
compound 3.1.
In related work9 we have used the triflate 3.3 (R1 ) Me),
which was prepared from commercially available 2-hydroxy-
6-methoxybenzoic acid 5. Because compounds of this type
are quite costly, we developed a new synthesis for this
benzoic acid. In the literature, the acid 5 or its methyl ester
As it is described in the literature,12 the O-THP protected
3-methoxyphenol can be deprotonated at the 2-position, the
common ortho-site. On this basis, we subjected 4 to a
metalation reaction with n-butyllithium in dry diethyl ether.
The resulting anion was quenched by adding solid carbon
dioxide. After acidification of the reaction mixture and
extractive workup the acid 5 was obtained directly in good
yield. A subsequent methylation of the carboxylic group
using 1,8-diazabicyclo[5.4.0] undec-7-en (DBU) and iodo-
methane13 gave the methyl ester 6. The latter could be
converted in the usual way (Tf2O, pyridine, 23 °C) to the
triflate 7.
(4) (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.
(5) (a) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem. 2000, 112,
4478-4480; Angew. Chem., Int. Ed. 2000, 39, 4308-4310. (b) Wu, Y.;
Seguil, O.; De Brabander, J. K. Org. Lett. 2000, 2, 4241-4244. (c)
Labrecque, D.; Charron, S.; Rej, R.; Blais, C.; Lamothe, S. Tetrahedron
Lett. 2001, 42, 2645-2648. (d) Smith, A. B., III; Zheng, J. Synlett 2001,
1019-1023. (e) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817-1820. (f)
Fu¨rstner, A.; Dierkes, T.; Thiel, O.; Blanda, G. Chem. Eur. J. 2001, 7,
5286-5298.
The other building block was constructed by connecting
two fragments via dithiane coupling (Scheme 2).14 The
synthesis of the epoxide began with the triol 8, which is
(6) Apicularen studies: Bhattacharjee, A.; De Brabander, J. K. Tetra-
hedron Lett. 2000, 41, 8069-8073.
(7) 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.
(10) Maugh, T., II; Bruice, T. C. J. Am. Chem. Soc. 1971, 93, 3237-
3248.
(11) Kung, H. F.; Kasliwal, R.; Pan, S.; Kung, M.-P.; Mach, R. H.; Guo,
Y.-Z. J. Med. Chem. 1988, 31, 1039-1043.
(12) Zacharie, B.; Attardo, G.; Barriault, N.; Penney, C. J. Chem. Soc.,
Perkin Trans. 1 1997, 2925-2929.
(13) Mal, D. Synth. Commun. 1986, 16, 331-335.
(14) (a) Smith, A. B., III; Condon, S. M.; McCauley, J. A. Acc. Chem.
Res. 1998, 31, 35-46. (b) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999,
1, 2001-2004.
(8) (a) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397-
399. (b) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333-1336. (c) Snider,
B. B.; Song, F. Org. Lett. 2000, 2, 407-408. (d) Stefanuti, I.; Smith, S. A.;
Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 3737-3738. (e) Raw, S. A.;
Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 10357-10361.
(9) Scheufler, F.; Maier, M. E. Synlett 2001, 1221-1224.
644
Org. Lett., Vol. 4, No. 4, 2002

Scheme 2. Synthesis of the Alkynediol 18 via Dithiane
Scheme 3. Coupling, Macrolactonization, and Transannular
Coupling
Etherification
be suitable.20 These conditions not only affected hydrolysis
of the dithiane but also cleavage of the triethylsilyl ether.
The resulting â-hydroxyketone 13 was then reduced to the
syn-1,3-diol 14.21 Again, acetal formation was used to protect
the neighboring hydroxyl groups. The primary alcohol 15
was extended to the alkyne 18 via the mesylate 16 and the
iodide 17. The direct substitution of the mesylate with lithium
acetylide was less efficient.
Before the cross-coupling, the alkyne 18 was converted
via a hydrostannylation to the vinyl stannane 19 in good yield
(Scheme 3). The merging of the fragments 7 and 19 was
realized by a palladium-catalyzed cross-coupling using Pd2-
dba3 as a catalyst and tri-(2-furyl)-phosphine as a ligand,
which formed the styrene derivative 20.22 After hydrolysis
of the isopropylidene group under acidic conditions, the ester
21 was cleaved with lithium hydroxide to provide the
dihydroxy acid 22. The macrolactonization under Yamaguchi
conditions allowed for a clear-cut differentiation of the two
available from d-glutamic acid.15 After differentiation of the
1,2-diol as the acetonide, benzylation16 of the primary
hydroxyl group gave compound 9. The isopropylidene
protecting group was then removed, and the resulting diol
was converted to the epoxide 10 with the Sharpless method.17
The other fragment, the dithiane 11, was prepared from
dihydrofuran in a two-step sequence.18 The crucial alkylation
of the 1,3-dithiane 11 with the epoxide 10 took place with
tert-butyllithium as base in the presence of tetramethyleth-
ylenediamine (TMEDA) to provide compound 12 in good
yield.19 The subsequent hydrolysis of the dithiane necessitated
some optimization studies in order to prevent elimination of
the hydroxyl group. The combination of mercury(II) per-
chlorate in the presence of diisopropylamine turned out to
(15) Brunner, H.; Lautenschlager, H.-H. Synthesis 1989, 706-709.
(16) Berninger, J.; Koert, U.; Eisenberg-Ho¨hl, C.; Knochel, P. Chem.
Ber. 1995, 128, 1021-1028.
(20) Smith, A. B., III; Lupo, A. T., Jr.; Ohba, M.; Chen, K. J. Am. Chem.
Soc. 1989, 111, 6648-6656.
(17) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530.
(18) Solladie´, G.; Fernandez, I.; Maestro, C. Tetrahedron: Asymmetry
1991, 2, 801-819.
(21) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158.
(22) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-
9595. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1-652.
(19) Steel, P. G.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1997,
371-380.
Org. Lett., Vol. 4, No. 4, 2002
645

secondary hydroxy groups.23 Essentially only the 12-
membered macrolactone 23 was formed under these condi-
tions. With the macrolactone 23 in hand, we were now in
the position to study the crucial transannular etherification.
Initial experiments using iodine (I2, CH2Cl2, 0 °C) only
caused oxidation of the alcohol to the corresponding ketone.
The same product was observed with trifluoroacetyl perrhe-
nate.24 Gratifyingly however, the pyran formation could be
realized with N-phenylselenophthalimide to give with com-
pound 24 as only one isomer.25 Reductive removal of the
phenylselenyl group with tributyltin hydride gave compound
25.
The relative stereochemistry of the pyran ring was
determined on the basis of NOE data. Thus, there was no
cross-peak between H-9 and H-13, which would be the case
for a cis stereochemistry. Instead, cross-peaks were observed
for H-13/H-15 and H-10/H-13. The calculated conformation,
which is in accordance with these NOE results, corresponds
to the right structure (model26trans) of Figure 4 (Macro-
Model 7.0,26 calculated energy 278.14 kJ mol-1). In this
compound the selenium atom was replaced with a sulfur atom
because of the lack of parameters. In addition, the side-chain
was truncated. This conformation corresponds to the one
found for apicularen A.1b The CdO bond is eclipsed to H-15
in this conformer. Further experiments and calculations will
be performed to elucidate the origin of the selectivity.
Figure 4. Low energy conformations of compound model26trans
calculated by conformational search using MacroModel 7.0.
In summary, we have described a synthesis of a model
system for the macrocyclic subunit of the apicularens. Key
reactions include the cross-coupling of the aryl triflate 7 with
the vinyl stannane 19, a size-selective macrolactonization,
and a final diastereoselective transetherification. This strategy
is also of interest, in that it might resemble the biochemical
pathway. Studies to include the 11-hydroxy group into this
scheme are underway in our laboratory.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Graeme
Nicholson for performing the FT-ICR measurements.
(23) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(24) (a) Kennedy, R. M.; Tang, S. Tetrahedron Lett. 1992, 33, 3729-
3732. (b) Towne, T. B.; McDonald, F. E. J. Am. Chem. Soc. 1997, 119,
6022-6028. (c) Sinha, S. C.; Keinan, E.; Sinha, S. C. J. Am. Chem. Soc.
1998, 120, 9076-9077.
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Chem. Soc. 1979, 101, 3884-3893. (b) Nicolaou, K. C.; Magolda, R. L.;
Sipio, W. J.; Barnette, W. E.; Lysenko, Z.; Joullie, M. M. J. Am. Chem.
Soc. 1980, 102, 3784-3793.
(26) (a) Saunders: M.; Houk, K. N.; Wu, Y.-D.; Still, W. C.; Lipton,
M.; Chang, G.; Guida, W. C. J. Am. Chem. Soc. 1990, 112, 1419-1427.
(b) Kolossva´ry, I.; Guida, W. C. J. Comput. Chem. 1993, 14, 691-698.
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.
OL017261D
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Org. Lett., Vol. 4, No. 4, 2002