Synthesis of azaphilones and related molecules by employing cycloisomerization of o-alkynylbenzaldehydes

Article abstract of DOI:10.1002/anie.200353037

Right to the core: Gold(III)-catalyzed cycloisomerization of o-alkynylbenzaldehydes to 2-benzopyrylium salts and subsequent in situ oxidation have been employed to prepare the core structure of azaphilone natural products, such as the sphingosine kinase inhibitor S-15183 (see scheme, DCE = 1,2-dichloroethane, TFA = trifluoroacetic acid)), and several unnatural azaphilones.

Full text of DOI:10.1002/anie.200353037

Angewandte
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Natural Product Synthesis
(see 6).[2] A number of synthetic efforts concerning azaphi-
lones have been reported.[3] In general, pyronoquinones[3a]
and pyrylium salts[3b,c] have been employed as precursors.
Herein we report an approach to the synthesis of the
azaphilones involving cycloisomerization of o-alkynylbenzal-
dehydes to 2-benzopyrylium salts and subsequent oxidation
to the 6H-isochromene ring system.
Synthesis of Azaphilones and Related Molecules
by Employing Cycloisomerization of
o-Alkynylbenzaldehydes**
Jianglong Zhu, Andrew R. Germain, and John A. Porco,
Jr.*
Our retrosynthetic analysis for the azaphilones is shown in
Scheme 2. Core structure 7 may be prepared by acylation of
The azaphilones are a structurally diverse family of natural
products containing a highly oxygenated bicyclic core and a
quaternary center (see 1–6, Scheme 1).[1] These molecules
Scheme 2. Retrosynthetic analysis for the azaphilone core structure.
tertiary carbinol 8, which may be derived from oxidation of 2-
benzopyrylium salt 9.[3c,4] We planned to prepare 9 by
transition-metal-catalyzed cycloisomerization[5,6] of o-alky-
nylbenzaldehyde 10. This approach takes advantage of readily
available alkynes to construct azaphilones with diverse side
chains at C3. Alkynylbenzaldehyde 10 may be obtained by
Sonogashira coupling of 2-bromobenzaldehyde 11.
S-15183a (1), a sphingosine kinase inhibitor isolated from
Zopfiella inermis SANK 15183,[1e] was chosen as our initial
target and the basis for model experiments. Nitration of
commercially available 2,4-dimethoxy-3-methylbenzalde-
hyde (12) with Cu(NO3)2 in acetic anhydride afforded 13 in
which the aldehyde was protected in situ as the geminal
diacetate (85%).[7] Compound 13 was then reduced (Pd/C,
H2) and brominated to afford o-bromoaniline 14 (92%).
Deamination of 14 and in situ deprotection of the geminal
diacetate produced 6-bromo-2,4-dimethoxy-3-methylbenzal-
dehyde (15; 87%). Demethylation of 15 proceeded smoothly
with BBr3 to afford 2-bromobenzaldehyde 11 (95%). Sono-
gashira coupling of 11 with 1-nonyne afforded the desired o-
alkynylbenzaldehyde 16 (92%, Scheme 3).[8]
We next investigated cycloisomerization reactions of o-
alkynylbenzaldehyde 16. Recent reports have highlighted the
utility of Lewis acids for alkyne activation,[5,6,9,10] including
formal [4 + 2] benzannulations of o-alkynylbenzaldehydes
and alkynes/alkenes by employing gold(iii) catalysis.[5e–g,6] It
was envisaged that substrates such as 16 could be converted
directly into 2-benzopyrylium salts in the presence of a
catalytic amount of a carbophilic Lewis acid and stoichio-
metric amounts of a proton source. A number of Lewis acid
catalysts were investigated for the cycloisomerization
(Table 1). Among these Lewis acids, gold(iii) acetate
(Au(OAc)3)[11] was found to be optimal and led to formation
of 2-benzopyrylium salt 17 in 1 min at room temperature with
1,2-dichloroethane/trifluoroacetic acid (10:1) as the solvent
Scheme 1. Representative azaphilone natural products.
exhibit a wide range of biological activities, including gp120-
CD4,[1c] Grb2-SH2,[1d] and sphingosine kinase inhibition.[1e]
The potent biological activities of this class of compounds
may be related to reaction of the 4H-pyran nucleus with
amines to produce the corresponding vinylogous 4-pyridones
[*] J. Zhu, A. R. Germain, Prof. Dr. J. A. Porco, Jr.
Department of Chemistry
Center for Chemical Methodology and Library Development
Boston University, 590 Commonwealth Avenue
Boston, MA 02215 (USA)
Fax: (+1)617-353-6466
E-mail: porco@chem.bu.edu
[**] We thank Dr. Takafumi Kohama (Sankyo Co. LTD.) for providing 1H
and 13CNMR spectra of S-15183a and Dr. Emil Lobkovsky (Cornell
University) for X-ray crystal structure analysis. We thank CEM
Corporation (Matthews, NC) for providing the Explorer microwave
system, Bristol-Myers Squibb for an unrestricted Grant in Synthetic
Organic Chemistry (J.A.P, Jr.), and Novartis Pharma AG for research
support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Lewis acid catalyzed formation of 2-benzopyrylium salt 17.[a]
Entry
Catalyst (equiv)
t [min]
Conversion [%][b]
1[c]
2
3
4
5
None
AuCl3 (0.05)
AuBr3 (0.05)
Au(OAc)3 (0.05)
Cu(OTf)2 (0.05)
[CuOTf]2·toluene (0.025)
AgNO3 (0.05)
20
20
20
1
20
20
20
<1
75
48
100
41
74
6
7
Scheme 3. a) Cu(NO3)2·3H2O, Ac2O, RT, 85%; b) Pd/C, H2, THF, RT;
94
c) Br2, HOAc, RT, 92% for two steps; d) NaNO2, conc. HCl, THF/H2O,
[a] Reactions were conducted on a 0.1-mmol scale in ClCH2CH2Cl
(1.0 mL) and CF3COOH (0.1 mL). [b] Reactions were quenched with
CH3CN/H2O and conversion was determined by reversed-phase HPLC
analysis of the recovered starting material with benzophenone used as
an internal standard. See the Supporting Information for a detailed
procedure. [c] Less than 1% conversion was observed after 20 min at
408C.
ꢁ58C ; HPO2, 08C!408C, 87%; e) BBr3, C HCl2, ꢁ788C!RT, 95%;
3
2
f) [PdCl2(PPh3)2], 1-nonyne, CuI, Et3N, DMF, 608C, 92%. THF=tetra-
hydrofuran, DMF=N,N-dimethylformamide.
(entry 4).[12,13] In comparison, AuCl3
(entry 2) led to 75% conversion in 20
minutes (entry 2). In the absence of Lewis
acid catalyst, less than 1% conversion was
observed at 408C (entry 1). However, 2-
benzopyrylium salt 17 was formed com-
pletely in 2 h at 608C by using trifluoro-
acetic acid (TFA) as the solvent. The 2-
benzopyrylium salt 17 may thus be formed
by two possible pathways (Scheme 4).
Lewis acid activation of the triple bond of
o-alkynylbenzaldehyde 16 should provide
metal ate complex 18[5e] which may be
protonated to afford 17 (path A). In the
absence of a Lewis acid catalyst, the protic
acid may also activate the alkyne for attack
by the aldehyde carbonyl group to afford
17 directly (path B).[5b] Although Lewis
acid catalysis was not necessary for cyclo-
isomerization of 16 into 17, subsequent
experiments revealed that Lewis acid cat-
alysis is advantageous for cycloisomeriza-
tion of certain o-alkynylbenzaldehyde sub-
strates (see below). This methodology may
be a general approach for the preparation
of 2-benzopyrylium salts.[14]
Scheme 4. Proposed mechanism for cycloisomerization. M=metal, L=ligand.
Previous studies on the oxidation of 2-
benzopyrylium salts related to 17 to form
the azaphilone nucleus have typically
involved the use of lead tetraacetate.[3a–c]
However, after screening alternative oxi-
dants we found that o-iodoxybenzoic acid
(IBX)[15]
in
1,2-dichloroethane/TFA
cleanly afforded the desired azaphilone 21
in 84% yield after reductive workup
(Scheme 5). A key to this transformation
was the use of tetrabutylammonium iodide
as a phase-transfer catalyst and apparent
IBX activator.[16,17] Acylation of 21
afforded (ꢀ )-S-15183a (1; 61%) whose
Scheme 5. a) Au(OAc)3 (5 mol%), ClCH2CH2Cl/CF3COOH (10:1), RT; b) IBX, tetrabutylam-
monium iodide (5 mol%), RT, then sat. Na2S2O3, 84% (two steps); c) CH3(CH2)6COCl,
iPr2NEt, DMAP, CH2Cl2, RT, 61%; d) NCS, CH3CN, RT, 83%;[24] e) NBS, CH3CN, RT, 88%;
f) NIS, CH3CN, RT, 66%; g) Ac2O (4.0 equiv), Et3N (2.0 equiv), DMAP, CH2Cl2, RT, 73%;
h) Ac2O (4.0 equiv), Et3N (5.0 equiv), DMAP, RT, CH2Cl2, 42%; i) Ac2O (4.0 equiv), Et3N
(5.0 equiv), DMAP, CH2Cl2, RT, 47%. DMAP=4-dimethylaminopyridine, NCS=N-chlorosuc-
cinimide, NBS=N-bromosuccinimide, NIS=N-iodosuccinimide.
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1H NMR, 13C NMR, and mass spectra were found to be
identical to those of an authentic sample. Since a number of
azaphilone natural products contain chlorine or bromine at
the C5 position, we next investigated halogenation of 21. It
was found that chloroazaphilone 22a could be obtained in
83% yield when azaphilone 21 was treated with N-chloro-
succinimide in CH3CN. The structure of 22a was confirmed by
single-crystal X-ray structure analysis. Similarly, bromination
Scheme 7. Proposed mechanism for the formation of 25.
dehyde 11 with 1-ethynylcyclohexene and phenylacetylene
with PtBu3 employed as the ligand[20] cleanly afforded the
desired o-alkynylbenzaldehydes 29 and 30, respectively
(entries 1 and 2). In contrast, microwave conditions[21] were
required for efficient coupling with methyl propargyl ether
and propargyl cyclohexyl amide to prepare substrates 31 and
32, respectively (entries 3 and 4). Au(OAc)3-catalyzed cyclo-
Scheme 6. a) PIFA, RT, then sat. Na2S2O3, 46%; b) Pd(OAc)2,
(o-tolyl)3P, (E)-tributyl-1-propenylstannane, DMF, 808C , 81%.
or iodination of alcohol 21 with N-bromo-
Table 2: Synthesis of several unnatural azaphilones.
succinimide or N-iodosuccinimide, respec-
tively, afforded bromoazaphilone 22b[1c]
(88%) and iodoazaphilone 22c (66%).
These results reaffirm that halogenation of
the azaphilone nucleus may be performed
at a late stage.[18] Attempted acylation of
22a led to acetate 23 or angular azaphi-
lone 24, which is related to trichoflectin
(2)[1b] and 5-bromoochrephilone (3),[1c]
depending on the reaction conditions
employed.
Entry
1
Alkyne
o-Alkynylbenzaldehyde (yield[a])
Azaphilone (yield[a])
Interestingly, treatment of 2-benzo-
pyrylium salt 17 with the hypervalent
iodine reagent (bis(trifluoroacetoxy)-
iodo)benzene (PIFA) did not afford the
desired azaphilone but provided C-ary-
lated azaphilone 25 (46%; Scheme 6). A
proposed mechanism for this transforma-
tion is shown in Scheme 7. Reaction of 2-
benzopyrylium salt 17 with PIFA affords
intermediate 27, which may undergo
[3,3] sigmatropic rearrangement to dear-
omatized intermediate 28.[19] Rearomati-
zation and elimination of trifluoroacetic
acid affords C-arylated azaphilone 25.
Preliminary experiments showed that 25
may undergo further functionalization by
Pd-catalyzed cross-coupling to afford
novel styrenyl azaphilone 26 (81%;
Scheme 6).
29[b] (82%)
33 (65%)
2
30[b] (90%)
34 (82%)
35 (65%)
3
4
31[c] (68%)
The
cycloisomerization–oxidation
32[c] (65%)
36 (61%)
sequence was next applied to the synthesis
of several unnatural azaphilones (Table 2).
Sonogashira coupling of 2-bromobenzal-
[a] Yield of isolated product. [b] Method A: [PdCl2(PhCN)2], CuI, PtBu3·HBF4, iPr2NH, 1,4-dioxane, RT.
[c] Method B: [PdCl2(PPh3)2], CuI, Et3N, 1,2-dimethoxyethane, microwave (300 W, 1208C, 25 min).
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420; isochromophilone IX: f) A. P. Michael, E. J. Grace, M.
Kotiw, R. A. Barrow, Aust. J. Chem. 2003, 56, 13 – 15.
[2] M. Natsume, Y. Takahashi, S. Marumo, Agric. Biol. Chem. 1988,
52, 307 – 312.
isomerization of the resulting o-alkynylbenzaldehydes in 1,2-
dichloroethane/TFA (10:1) at room temperature produced
the corresponding 2-benzopyrylium salts.[22] Oxidation of the
2-benzopyrylium salts with IBX in the presence of tetrabu-
tylammonium iodide afforded the corresponding C3-func-
tionalized azaphilones 33–36 (61–82%).
As a prelude to the anticipated use of the azaphilones as
scaffolds in a chemical library synthesis, we conducted the
functionalization sequence shown in Scheme 8. Reaction of
[3] For representative synthetic efforts on azaphilones, see: a) R.
Chong, R. R. King, W. B. Whalley, J. Chem. Soc. C 1971, 3566 –
3571; b) R. Chong, R. R. King, W. B. Whalley, J. Chem. Soc. C
1971, 3571 – 3575; c) T. Suzuki, C. Okada, K. Arai, A. Awall, T.
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kawa, S. Kobayashi, Tetrahedron Lett. 2001, 42, 5249 – 5252.
[4] For reviews on the chemistry of 2-benzopyrylium salts, see: E.
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Chem. 1990, 50, 157 – 254.
[5] For recent examples of cycloisomerization of alkynyl substrates,
see: a) K. R. Roesch, R. C. Larock, Org. Lett. 1999, 1, 553 – 556;
b) J. D. Tovar, T. M. Swager, J. Org. Chem. 1999, 64, 6499 – 6504;
c) A. V. Kel'in, A. W. Sromek, V. Gevorgyan, J. Am. Chem. Soc.
2001, 123, 2074 – 2075; d) A. V. Kel'in, V. Gevorgyan, J. Org.
Chem. 2002, 67, 95 – 98; e) N. Asao, K. Takahashi, S. Lee, T.
Kasahara, Y. Yamamoto, J. Am. Chem. Soc. 2002, 124, 12650 –
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Soc. 2003, 125, 10921 – 10925; h) N. Asao, K. Sato, Y. Yama-
moto, Tetrahedron Lett. 2003, 44, 5675 – 5677.
Scheme 8. a) Benzylamine (1.2 equiv), CH3COOH (3.6 equiv), THF,
RT, 90%; b) benzoyl chloride (1.5 equiv), Et3N (1.0 equiv), DMAP
(0.5 equiv), CH2Cl2, RT, 86%.
[6] During the preparation of this manuscript,
a publication
appeared reporting the gold(iii)-catalyzed formation of isoben-
zopyrylium (2-benzopyrylium) cations and their cycloaddition
with olefins and electron-rich heteroarenes: G. Dyker, D.
Hildebrandt, J. Liu, K. Merz, Angew. Chem. 2003, 115, 4536 –
4538; Angew. Chem. Int. Ed. 2003, 42, 4399 – 4402.
azaphilone 21 with benzylamine in THF in the presence of
acetic acid[23] proceeded smoothly to afford the corresponding
vinylogous 4-pyridone 37, which underwent acylation with
benzoyl chloride to produce vinylogous 4-pyridone ester 38.
These experiments demonstrate access to three orthogonal
diversification points on the azaphilone core structure.
In conclusion, an approach to the synthesis of diverse
azaphilones has been developed by employing gold(iii)-
catalyzed cycloisomerization of o-alkynylbenzaldehydes into
2-benzopyrylium salts and subsequent oxidation to form the
azaphilone ring system by using IBX in conjunction with a
phase-transfer catalyst. Preliminary results suggest that the
azaphilones may be functionalized to afford highly function-
alized vinylogous 4-pyridones. Further studies including
asymmetric synthesis of select azaphilone targets and prep-
aration of azaphilone-based chemical libraries are in progress
and will be reported in due course.
[7] For use of a geminal diacetate (acylal) as a protecting group for
aldehydes, see: a) K. S. Kochhar, B. S. Bal, R. P. Deshpande,
S. N. Radadhyaksha, H. W. Pinnick, J. Org. Chem. 1983, 48,
1765 – 1767; b) A. Kawada, S. Takeda, K. Yamashita, H. Abe, T.
Harayama, Chem. Pharm. Bull. 2002, 50, 1060 – 1065.
[8] For Sonogashira coupling with 2,3-dibromobenzaldehyde as a
substrate, see: A. Fkyerat, G. Dubin, R. Tabacchi, Helv. Chim.
Acta 1999, 82, 1418 – 1422.
[9] For catalysis by gold species, see: a) G. Dyker, Angew. Chem.
2000, 112, 4407 – 4409; Angew. Chem. Int. Ed. 2000, 39, 4237 –
4239; b) two special issues on gold catalysis have appeared:
Catal. Today 2002, 72, 1 – 169.
[10] For gold(iii)-mediated activation of alkynes, see: a) R. O. C.
Norman, W. J. E. Parr, C. B. Thomas, J. Chem. Soc. Perkin Trans.
1 1976, 1983 – 1987; b) Y. Fukuda, K. Utimoto, J. Org. Chem.
1991, 56, 3729 – 3731; c) Y. Fukuda, K. Utimoto, Bull. Chem. Soc.
Jpn. 1991, 64, 2013 – 2015; d) Y. Fukuda, K. Utimoto, Synthesis
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Natile, G. Palmieri, L. Maresca, J. Am. Chem. Soc. 1993, 115,
4401 – 4402; f) J. H. Teles, S. Brode, M. Chabanas, Angew. Chem.
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4563 – 4565.
Received: October 8, 2003 [Z53037]
Keywords: alkynes · azaphilones · cycloisomerization · gold ·
.
Lewis acid catalysis
[11] Synthetic applications of Au(OAc)3 appear to be limited thus far
to sol–gel preparations for the reduction of NOx; see: E. Seker,
E. Gulari, Appl. Catal. A 2002, 232, 203 – 217.
[1] Daldinin: a) T. Hashimoto, S. Tahara, S. Takaoka, M. Tori, Y.
Asakawa, Chem. Pharm. Bull. 1994, 42, 2397 – 2399; trichoflec-
tin: b) E. Thines, H. Anke, O. Sterner, J. Nat. Prod. 1998, 61,
306 – 308; 5-bromoochrephilone: c) K. Natsuzaki, H. Tahara, J.
Inokoshi, H. Tanaka, J. Antibiot. 1998, 51, 1004 – 1011; 8-o-
methylsclerotiorinamine: d) J.-Y. Nam, H.-K. Kim, J.-Y. Kwon,
M. Y. Han, K.-H. Son, U. C. Lee, J.-D. Choi, B.-M. Kwon, J. Nat.
Prod. 2000, 63, 1303 – 1305; S-15183a: e) K. Kono, M. Tanaka, Y.
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[12] Formation of 2-benzopyrylium salt 17 was verified by 1H and
13C NMR spectroscopy (see the Supporting Information). For
previous NMR studies of 2-benzopyrylium salts, see ref. [3c].
[13] It is possible that gold(iii) acetate may undergo ligand exchange
with trifluoroacetic acid to form gold(iii) trifluoroacetate. For
preparation of gold(iii) triflate by exchange of AuBr3 with triflic
acid, see: N. E. Drysdale, R. E. Bockrath, WO 9409055, 1994.
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[14] 1H NMR analysis showed that cycloisomerization of o-alkynyl-
benzaldehyde 19 cleanly afforded 2-benzopyrylium salt 20. In
contrast to salt 17, deuterium incorporation at the C* position of
20 was approximately 87% as determined by 1H NMR analysis.
[15] For IBX oxidation of phenols to o-quinones, see: D. Magdziak,
A. A. Rodriguez, R. W. Van De Water, T. R. R. Pettus, Org.
Lett. 2002, 4, 285 – 288.
[16] For the use of phase-transfer catalysis for the oxidation of
sulfides with IBX, see: V. G. Shukla, P. D. Salgaonkar, K. G.
Akamanchi, J. Org. Chem. 2003, 68, 5422 – 5425.
[17] For further examples of ligand complexation/activation of IBX,
see: a) K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem.
2002, 114, 1035 – 1038; Angew. Chem. Int. Ed. 2002, 41, 993 – 996;
b) K. C. Nicolaou, D. L. F. Gray, T. Montagnon, S. T. Harrison,
Angew. Chem. 2002, 114, 1038 – 1042; Angew. Chem. Int. Ed.
2002, 41, 996 – 1000.
[18] For previous work on chlorination at the C5 position of
azaphilones (rotiorin), see: R. W. Gray, W. B. Whalley, J.
Chem. Soc. C 1971, 3575 – 3577.
[19] For [3,3] sigmatropic rearrangement of an allenyl (aryl) iodi-
ne(iii) intermediate (“iodonio Claisen” rearrangement), see:
a) M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, J. Am. Chem. Soc.
1991, 113, 1319 – 1323; b) M. Ochiai, M. Kida, T. Okuyama,
Tetrahedron Lett. 1998, 39, 6207 – 6210.
[20] For the use of PtBu3 in low-temperature Sonogashira couplings,
see: a) T. Hundertmark, A. F. Littke, S. L. Buchwald, G. C. Fu,
Org. Lett. 2000, 2, 1729 – 1731; b) M. R. Netherton, G. C. Fu,
Org. Lett. 2001, 3, 4295 – 4298.
[21] For microwave-promoted Sonogashira couplings, see: a) M.
ErdØlyi, A. Gogoll, J. Org. Chem. 2001, 66, 4165 – 4169; b) M.
ErdØlyi, A. Gogoll, J. Org. Chem. 2003, 68, 6431 – 6434.
[22] In contrast, formation of the 2-benzopyrylium salts from o-
alkynylbenzaldehydes 31 or 32 in CF3CO2D (608C) was
extremely slow and was accompanied by severe side reactions,
1
as observed by H NMR analysis.
[23] Control experiments revealed that acetic acid was required to
buffer the benzylamine and prevent decomposition of azaphi-
lone 21.
[24] CCDC 219685 (22a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
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