Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

Article abstract of DOI:10.3762/bjoc.8.33

A core 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-one scaffold is elaborated at C-3(Me) by base-mediated aldol condensation to give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natur

Full text of DOI:10.3762/bjoc.8.33

Aldol elaboration of 4,5,6,7-tetrahydro-
isoxazolo[4,3-c]pyridin-4-ones,
masked precursors to acylpyridones
Raymond C. F. Jones*1, Abdul K. Choudhury1, James N. Iley2,
Mark E. Light3, Georgia Loizou2 and Terence A. Pillainayagam1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 308–312.
1Department of Chemistry, Loughborough University, Loughborough,
Leics. LE11 3TU, United Kingdom, 2Department of Chemistry &
Analytical Sciences, The Open University, Walton Hall, Milton Keynes
MK7 6AA, United Kingdom and 3EPSRC National Crystallography
Service, School of Chemistry, University of Southampton, Highfield,
Southampton, SO17 1BJ, United Kingdom
doi:10.3762/bjoc.8.33
Received: 02 December 2011
Accepted: 10 February 2012
Published: 27 February 2012
Associate Editor: M. S. Sherburn
Email:
Raymond C. F. Jones* - r.c.f.jones@lboro.ac.uk
© 2012 Jones et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aldol reaction; fused-ring systems; heterocycles; isoxazole;
metalation; pyridone
Abstract
A core 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-one scaffold is elaborated at C-3(Me) by base-mediated aldol condensation to
give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural
products.
Introduction
The 3-acyl-4-hydroxypyridin-2-one moiety 1 (Figure 1) is the medicine to strengthen the immune system and improve
common structural unit of a family of natural products with a cognitive function. Farinosone A (2d) from Paecilomyces
range of interesting biological activities [1]. Examples are the farinosus, for example, induces and enhances neurite outgrowth
pigments tenellin (2a) and bassianin (2b) from insect patho- in the PC-12 cell line, although it is not clear whether the
genic fungus Beauveria bassiana [2,3], pyridovericin (2c) [4] (a pyridones in general display neuritogenic properties [6]. The
tyrosine kinase inhibitor) and the elfamycin antibiotics [5]. biosynthesis of tenellin and bassianin in Beauveria bassiana has
Interest has also been stimulated in these metabolites by the use recently been studied in detail by using genetic techniques, and
of the entomopathogenic fungi such as Cordyceps sp., many of been shown to involve conversion from an acyltetramic acid by
which contain pyridone metabolites, in traditional Chinese oxidative ring expansion [7,8].
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Beilstein J. Org. Chem. 2012, 8, 308–312.
Figure 1: The 3-acyl-4-hydroxypyridin-2-one motif, example natural products and the isoxazolopyridone scaffolds.
During a programme of synthesis towards metabolites starting material 6 (17%). 1H NMR studies indicated the newly
containing the enolised heterocyclic tricarbonyl motif 3 [9-16], formed alkene bond to have the expected E-configuration, with
we have reported nitrile oxide dipolar-cycloaddition strategies 3JCH=CH = 16.5 Hz. The structure of the 3-alkenyl compound
to access the isoxazolo[4,3-c]pyridin-4-one 4 as 2nd-generation 8a was confirmed by an X-ray crystallographic analysis
masked nonpolar scaffolds for the 3-acyl-4-hydroxypyridin-2- (Figure 2, Supporting Information File 1 for crystal data) [19].
one nucleus [12]; our 1st-generation approach had employed the
[4,5-c] isomer 5 [13-15]. We have recently reported on elabora-
tion of isoxazolopyridone 4 at C-3(Me) and C-7 towards natural
products and analogues [16]. An intermediate en route to scaf-
fold 4 is the 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-one 6
[12,16], and the availability of this compound, combined with
an interest in the biological potential of the acylpyridones and
their dihydro derivatives (which are also ring homologues of
bioactive 3-acyltetramic acid metabolites), led us to explore
elaboration of this 6,7-dihydro-scaffold at C-3(Me) to produce
masked forms of the acyldihydropyridones. We report here on
these findings.
Results and Discussion
Scheme 1: Aldol reactions of tetrahydroisoxazolopyridone 6.
Reagents: (i) LDA–TMEDA, RCHO, THF, −20 °C; (ii) toluene, reflux,
PTSA.
Our approach to the elaboration of the tetrahydroisoxazo-
lopyridone 6 was to use the direct deprotonation strategy
employed with the corresponding dehydro derivative 4 [16]. It
is well-precedented that 3,5-disubstituted isoxazoles undergo
lateral deprotonation–metalation preferentially at the C-5
substituent [17,18] (isoxazole numbering), which corresponds
to the C-3 substituent in isoxazolopyridine 6. We planned to
undertake aldol-type reactions to lead to 3-alkenylisoxazo-
lopyridones as masked forms of the corresponding acyl-
pyridones, in which 3-alkenoyl substituents feature promin-
ently, see Figure 1. Thus the 3-methyl compound 6 was treated
with LDA–TMEDA (2.1 mol equiv of each; THF, −20 °C
ice–salt bath) before addition of benzaldehyde (3.5 mol equiv;
Figure 2: X-ray crystal structure of 3-(2-phenylethenyl)-4,5,6,7-tetrahy-
droisoxazolo[4,3-c]pyridin-4-one (8a) [19].
THF, −20 °C). After 1 hour at −20 °C the mixture was allowed
to warm to 20 °C and stirred for 4 days. After this time, we
were pleased to be able to isolate the condensation product,
3-(2-phenylethenyl)tetrahydroisoxazolopyridone 8a (53%) By using the same protocol, the reaction was repeated with
rather than the presumed intermediate 3-(2-hydroxy-2- 4-nitrobenzaldehyde to afford 8b (52%). 4-Bromobenzalde-
phenylethyl) compound 7a (Scheme 1), along with unchanged hyde gave condensation product 8c (15%) with hydroxy-adduct
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Beilstein J. Org. Chem. 2012, 8, 308–312.
7c as the major product (35%); 2,4-dichlorobenzaldehyde simil-
arly afforded 8d (22%) and 7d (51%), and the nonenolisable
2,2-dimethylpropanal led to 8e in low yield (4%) along with
adduct 7e (55%). 3-Phenylpropenal gave condensation product
8f but in a poor yield (12%) along with recovered starting ma-
terial 6 (14%). These results are summarized in Table 1. In all
cases the new alkene bonds have E-configuration (3JCH=CH =
16.5–16.8 Hz). The less electrophilic 2,4-dimethoxy- and
4-dimethylaminobenzaldehydes did not react with the C-3(Me)
anion. The hydroxy adducts 7c–e could be made to undergo
elimination under Dean–Stark conditions of water removal
(toluene, reflux, PTSA in 2 portions; for quantities see
Supporting Information File 1) to deliver more of the conden-
sation products 8c–e (41, 38, 44%, respectively, Table 1, see
Supporting Information File 1 for full experimental and spectro-
scopic data).
Figure 3: Ilicicolin H as an example of a 3-decalinoyl-4-hydroxypyridin-
2-one metabolite.
As an alternative to the LDA protocol described above, the
tetrahydroisoxazolopyridone 6 was deprotonated, by using BuLi
(2.3 mol equiv; THF–hexanes, −78 °C), followed by addition of
benzaldehyde (1.5 mol equiv) to afford the hydroxy adduct 7a
(70%). Dehydration was accomplished under Dean–Stark
Scheme 2: Retrosynthetic analysis of a model 3-decalinyl-4,5,6,7-
tetrahydroisoxazolopyridone 10.
conditions (toluene, reflux, PTSA, 1.3 mol equiv) to give the The aldehyde 12 required for the 3-alkenyl side chain of triene
3-alkenyl compound 8a (63%). This revised protocol has not 11 was prepared in four steps by the route shown in Scheme 3,
yet been extended to the reaction of pyridone 6 with other alde- involving palladium-catalysed decarboxylative ring opening of
hydes, but has been routinely employed for elaboration of the cyclic carbonates [23]. Thus the enolate of α-tetralone was
dehydro version 4 [16].
added to propenal in an aldol addition (LDA, THF, −78 °C;
86%). The second step involved the reduction of the intermedi-
The acylpyridone antifungal natural product ilicicolin H (9) ate β-hydroxyketone 13, (LiAlH4, THF) to give the 1,3-diol 14
(Figure 3) [20,21] along with fischerin, apiosporamide and in 75% yield. This was followed by synthesis of the cyclic
YM-215343, displays a 3-decalinoyl-4-hydroxypyridin-2-one carbonate 15 by treating the 1,3-diol 14 with methyl chloro-
skeleton wherein the decalin unit may arise biosynthetically formate (Et3N, CH2Cl2; 74%). In the final step, carbonate 15
from a Diels–Alder reaction within the polyketide-derived side was treated with palladium dibenzylideneacetone in dry MeCN
chain [1,22]. As a further demonstration of the aldol methodo- at room temperature to afford the desired aldehyde 12 in 65%
logy, we proposed to construct the precursor triene 11, which yield. Reaction of this aldehyde (10 mol equiv) with tetrahy-
would facilitate a biomimetic cycloaddition approach to a droisoxazolopyridone 6 by using BuLi as a base (4.8 mol equiv;
benzo-fused decalin-substituted isoxazolopyridone, such as 10 THF–hexanes, −78 °C) led to the aldol-type adduct 16 in 53%
(Scheme 2).
yield with some of the dehydrated condensation product also
Table 1: Preparation of 3-alkenylisoxazolopyridones 8, hydroxy adducts 7, and dehydration of adducts 7.
R
Aldol reaction products 7 and 8a
3-Alkenyl compounds 8 (yield %)
Dehydration of adducts 7b
Hydroxy adducts 7 (yield %)
3-Alkenyl compounds 8 (yield %)
Ph
8a (53%)
8b (52%)
8c (15%)
8d (22%)
8e (4%)
7a (–)
–
4-O2NC6H4
4-BrC6H4
2,4-Cl2C6H3
CMe3
7b (–)
–
7c (35%)
7d (51%)
7e (55%)
7f (–)
8c (41%)
8d (38%)
8e (44%)
–
CH=CHPh
8f (12%)
aReagents: LDA–TMEDA, RCHO, THF, −20 °C; bReagents: toluene, reflux, PTSA.
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Beilstein J. Org. Chem. 2012, 8, 308–312.
Scheme 3: Synthesis of triene 11. Reagents: (i), LDA, propenal, THF, −78 °C; (ii), LiAlH4, THF, 20 °C (75%); (iii), MeOCOCl, Et3N, CH2Cl2 (74%);
(iv), Pd2(dba)3·CHCl3, MeCN, 20 °C (65%); (v), BuLi, isoxazolopyridone 6, THF–hexanes, −78 °C (53%); (vi), toluene reflux, PTSA (78%).
isolated as a minor product. This dehydration product, discussions, and the EPSRC Mass Spectrometry Service Centre
3-alkenylisoxazolopyridone 11, was prepared from the hydroxy (Swansea) for some high-resolution MS data.
adduct 16 by heating under a Dean–Stark water separator
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