Total synthesis of apicularen a through transannular pyran formation

Article abstract of DOI:10.1002/anie.200460760

A macrocyclization-transannulation strategy is the crux of an efficient total synthesis of the benzolactone enamide apicularen A (see scheme; Bn = benzyl). Key steps include a four-component coupling, a Stille cross-coupling to introduce the aromatic moiety, and the formation of the enamide from a hemiaminal. The size-selective macrolactonization of the ethoxyvinyl ester shown was followed by transannular etherification in excellent yield.

Full text of DOI:10.1002/anie.200460760

Angewandte
Chemie
Natural Products Synthesis
Total Synthesis of Apicularen A through
Transannular Pyran Formation**
Andreas F. Petri, Alexander Bayer, and
Martin E. Maier*
Natural products that show cytotoxic effects are important in
cancer treatment. As resistance can occur, and not all tumor
cells are equally sensitive to a certain drug, there is a need for
compounds that have novel modes of action. Such compounds
include the benzolactone enamides,[1] for example, apicular-
en A (1) and salicylihalamide A (2). Salicylihalamide A was
isolated from the sponge Haliclona sp.,[2] whereas apicular-
en A has been found in various myxobacteria strains.[3] Both
compounds were shown to be selective inhibitors of mamma-
lian V-ATPases, which are important as proton pumps for
regulating intracellular pH.[4] Depending on the cell type
studied, other downstream effects were observed, such as the
phosphorylation of mitogen-activated protein kinases, which
results in apoptosis.[5,6] The structure of apicularen A is
characterized by the salicylic acid portion, a trans tetrahy-
dropyran embedded in a macrolactone, and an enamide side
chain. Several total syntheses of apicularen A,[7] formal total
syntheses,[8] and synthetic studies[9,10] have been reported.
Some time ago we proposed that the pyran ring of
apicularen A is probably formed by a transannular reaction of
a macrolactone precursor through the opening of an epoxide
or addition to an enone.[10a] Herein we describe the applica-
tion of the transannular etherification strategy for the total
synthesis of apicularen A (1).
As described previously,[10b] the dithiane 3, the epoxides 4
and 5, and trimethylsilylacetylene (6) were combined in a
four-component coupling[11,12] to give the alkyne
7
[*] A. F. Petri, A. Bayer, Prof. Dr. M. E. Maier
Institut für Organische Chemie
Universität Tübingen
Auf der Morgenstelle 18, 72076 Tübingen (Germany)
Fax: (+49)7071-295-137
E-mail: martin.e.maier@uni-tübingen.de
[**] Financial support by the Deutsche Forschungsgemeinschaft (grant
Ma 1012/10-1) and the Fonds der Chemischen Industrie is grate-
fully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 5821 –5823
DOI: 10.1002/anie.200460760
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Communications
(Scheme 1). Hydrolysis of the dithiane and desilylation
yielded a b-hydroxyketone, which was converted by syn
reduction and acetalization into the alkyne 8.
Scheme 1. Synthesis of the alkyne 8 by a four-component coupling
strategy. Bn=benzyl, TBDMS=tert-butyldimethylsilyl.
The conversion of the alkyne 8 into a suitable vinyl metal
species for cross-coupling turned out to be quite challenging
(Scheme 2). For example, the palladium-catalyzed hydro-
Scheme 3. Cross-coupling, size-selective macrolactonization, and
transannular etherification to yield the building block trans-18:
a) P(furyl)3, [Pd2(dba)3], LiCl, NMP, 608C, 48 h (93% from 8); b) 80%
AcOH, 238C, 80 min (99%); c) LiOH, MeOH/H2O, 608C, 72 h (99%);
d) [{RuCl2(p-cymene)}2], ethoxyacetylene, toluene, 08C; e) CSA, tolu-
ene, 808C (63% from 14); f) Hg(O2CCF3)2, CH2Cl2, 238C, 30 min, then
NaCl, 238C; g) Et3B, LiBH4, THF, ꢀ788C, 1 h (89% from 16). CSA=
camphorsulfonic acid, NMP=1-methyl-2-pyrrolidinone, Tf=trifluoro-
methanesulfonyl.
yield). In contrast to the results of our previous model
study,[10a] the treatment of the macrolactone 16 with N-
(phenylseleno)phthalimide left the starting material
unchanged.[18] Eventually, it was found that treatment with
mercuric trifluoroacetate in dichloromethane gave the
cyclized organomercurial intermediate within minutes. To
suppress the undesired retrocyclization[19] of the mercurial
intermediate during the reductive demercuration, it was
necessary to change the solvent from CH2Cl2 to THF and to
perform the reduction with LiBH4 in the presence of Et3B.[20]
The origin of the high selectivity in the transannular ether-
ification has not yet been clearly ascertained. However, on the
basis of previous work, we believe that the transition state of
the kinetically controlled reaction is productlike, thus leading
to the less strained product.[8d,10a]
The synthesis continued with the cleavage of all ether
protecting groups with 9-iodoborabicyclononane (9-I-9-BBN;
Scheme 4).[21] A sequence of complete silylation and selective
desilylation generated the primary alcohol 20, which was
oxidized to the aldehyde 21[7c] with tetra-n-propylammonium
perruthenate (TPAP).[22] The stage was set for the attachment
of the enamide side chain.[23] The addition of the aluminum
carboximidoate derived from the amide 22[23b] and diisobutyl-
aluminum hydride[24] to the aldehyde 21 provided the hemi-
aminal 23 in 86% yield (1:1 mixture of diastereomers). When
a solution of the hemiaminal 23 in THF was heated at reflux
in the presence of acetic anhydride and pyridine, the enamide
24 was obtained as a separable E/Z mixture (E/Z = 75:25).
The removal of the silicon protecting groups from (E)-24 with
Scheme 2. Synthesis of the vinylstannane 11 via an intermediate vinyl
borane: a) nBu3SnH, AIBN (cat.), toluene, reflux (56%);
b) (C6H11)2BH, THF, 08C, 1 h; c) NaOH, [Cu(acac)2] (cat.), nBu3SnCl,
ꢀ15!238C (>93%).
stannylation[13] of 8 gave an inseparable mixture of the
internal and terminal stannane. The hydrostannylation under
radical conditions led to the tetrahydrofuran 9 through an
atom-transfer and cyclization process. This difficulty was
overcome by generation of the vinyl borane 10[14] followed by
transmetalation to the stannane 11.[15] In this way the vinyl
stannane was obtained exclusively as the E isomer in excel-
lent yield.
The subsequent cross-coupling reaction of the triflate
12[10a] with the stannane 11 proceeded smoothly to furnish the
salicylate 13 in excellent yield (Scheme 3). Hydrolysis of the
acetal and ester functionalities then gave the dihydroxy acid
14. As we had observed in this and related cases,[10] the size-
selective macrolactonization under Yamaguchi conditions[16]
gave selectively the larger of the two macrolactones, but the
chemical yield was only in the range of 50%. Therefore, the
method of Trost and Chisholm was investigated.[17] In this
case, an ethoxyvinyl ester, prepared by the ruthenium-
catalyzed addition of the carboxylic acid 14 to ethoxyacety-
lene, serves as the precursor. The best results for the
macrolactonization were obtained at 808C (5 mm, 63%
5822
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Chemie
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Scheme 4. Synthesis of apicularen A via the hemiaminal 23: a) 9-I-9-
BBN, CH2Cl2, 238C, 90 s, MeOH; b) TBDMSCl, imidazole, DMAP
(cat.), DMF, 238C, 48 h (72% from 18); c) CSA (cat.), CH2Cl2/MeOH,
08C, 3 h (85%); d) TPAP, NMO, 08C, 1 h (98%); e) 22, DIBAL, THF,
08C, 30 min, add 21, 08C, 18 h (86%); f) THF, pyridine, Ac2O, reflux,
48 h ((E)-24: 46%, (Z)-24: 15%); g) TASF, DMF, 238C, 21 h (75%).
DIBAL=diisobutylaluminum hydride, DMF= N,N-dimethylform-
amide, NMO=4-methylmorpholine N-oxide, TASF=tris(dimethyl-
amino)sulfonium difluorotrimethylsilicate.
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conversion of an aldehyde into the corresponding enamide
via a bisamide derivative through a base-induced elimina-
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In summary, we have developed a concise total synthesis
of apicularen A, featuring a number of key transformations:
a) a four-component coupling that combines a 1,3-dithiane, a
terminal epoxide, an acetylide, and epichlorohydrin, b) a
Stille cross-coupling reaction with the vinylstannane gener-
ated from a vinylborane, c) a size-selective macrolactoniza-
tion of an ethoxyvinyl ester, d) a transannular etherification,
and e) formation of the enamide from a hemiaminal. This
successful strategy underscores the close relationship between
salicylihalamide and apicularen.
Received: May 24, 2004
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Keywords: cross-coupling · enamides · macrolactonization ·
.
total synthesis · transannulation
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