Pyrroloisoxazoles as a building block for 3-enoyltetramic acids

Article abstract of DOI:10.1055/s-2004-835640

3-Methylpyrrolo[3,4-c]isoxazoles prepared by nitrile oxide cycloaddition, are deprotonated and condensed with aromatic aldehydes; N-O bond cleavage with Mo(CO)₆ affords 3-enoyltetramic acids whilst with H ₂-catalyst further reduction to 3-acyltetramic acids is observed.

Full text of DOI:10.1055/s-2004-835640

LETTER
2815
Pyrroloisoxazoles as a Building Block for 3-Enoyltetramic Acids
P
R
yrroloisoxazole
a
as
a
B
uild
y
ing Bloc
k
fo
m
r
3-Enoyltetramic
A
o
cids nd C. F. Jones,* Terence A. Pillainayagam
Department of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UK
Fax +44(1908)223926; E-mail: r.c.f.jones@lboro.ac.uk
Received 17 August 2004
crystalline oximes 6a–c (NH OH·HCl, NaOAc, EtOH aq,
2
Abstract: 3-Methylpyrrolo[3,4-c]isoxazoles prepared by nitrile
oxide cycloaddition, are deprotonated and condensed with aromatic
7
0 °C) in good yield (89%, 97% and 99%). In a one-pot
process, the oximes were subjected to C-chlorination (N-
aldehydes; N–O bond cleavage with Mo(CO) affords 3-enoyltetra-
6
chlorosuccinimide, CHCl , reflux) and then treated with
mic acids whilst with H -catalyst further reduction to 3-acyltetramic
3
2
acids is observed.
Et N and the enamine tert-butyl 3-pyrrolidinobut-2-
enoate (the latter prepared by reaction of tert-butyl ace-
3
5
Key words: acyltetramic acid, isoxazole, cycloaddition, condensa-
tion, heterocycle
toacetate with pyrrolidine in toluene at reflux under
Dean–Stark conditions). The nitrile oxide generated in
situ underwent dipolar cycloaddition to afford the protect-
ed 3-(1-aminoalkyl)-4-alkoxycarbonylisoxazoles 7a–c
As part of our ongoing programme of synthesis of the
6
(
54%, 52% and 48%) as a single regioisomer. Deprotec-
cyclic tricarbonyl moiety 1 found in a number of natural
1
tion (TFA, 20 °C) and conversion to the hydrochloride
salts (2 M HCl) for ease of handling afforded amino acid
hydrochlorides 8a–c (93%, 92% and 83%) that were cyc-
lised with 1-(3-dimethylaminopropyl)-3-ethylcarbodiim-
products, we have reported approaches to the 3-acyltetra-
mic acid nucleus 2 via 3-methyl-6-alkylpyrrolo[3,4-d]
1
b,2
and [3,4-c]isoxazoles, 3 (‘first generation’) and 4 (‘sec-
3
ond generation’), respectively (Figure 1). These fused
ide hydrochloride (EDCI) (N-hydroxysuccinimide, Et N,
isoxazoles, assembled via a nitrile oxide 1,3-dipolar cy-
cloaddition, were designed to act as non-polar scaffolds
for the elaboration of acyltetramic acids. We report herein
the realisation of this objective for C(3)-substituents by a
condensation reaction at the C(3)-methyl group of the
3
DMF, 0 → 20 °C) to pyrroloisoxazoles 4a–c (22%, 55%
and 60%). The lower recovered yield of alanine derivative
4
a is attributed to isolation problems (water solubility)
and awaits optimisation.
‘
second generation’ pyrroloisoxazole 4. 3-(Poly)enoyl Preliminary indications of acidity and potential nucleo-
derivatives feature prominently amongst the naturally philic reactivity at C(3)-Me were obtained on treatment of
occurring acyltetramic acids.
1
,4
bicycle 4c with base and an alkylating agent (2.2 equiv
BuLi, THF–hexanes, –78 °C, 5 equiv MeI) from which
the 3-ethylpyrroloisoxazole 9 was isolated (33%,
7
Scheme 2). However, the occurrence of (poly)enoyl 3-
substituents in many naturally occurring 3-acyltetramic
acids1 led us to focus on aldehyde electrophiles. The ki-
netic deprotonation of 4a or 4b (2.2 equiv LDA, THF–
hexanes, –78 °C) did afford the condensation products
,4
1
0a and 10d with benzaldehyde although in disappointing
8
yields (23%, 24%). On the other hand, thermodynamic
Figure 1
The set of pyrroloisoxazoles 4a–c was prepared according
to Scheme 1. The amino-acids (S)-alanine, (S)-valine
and (S)-leucine were converted into the N-protected esters
5
a–c (MeOH, AcCl, reflux; Boc O, Et N, CH Cl ) which
2 3 2 2
were reduced to the corresponding aldehydes (DIBALH,
toluene, –78 °C) and transformed directly into the stable
1
Scheme 1 R : a = Me, b = CHMe , c = CH CMe . Reagents:
2
2
2
SYNLETT 2004, No. 15, pp 2815–2817
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835640; Art ID: D10204ST
0
7
.1
2
.2
0
0
4
i, DIBALH, toluene, –78 °C; ii, NH OH·HCl, NaOAc, aq EtOH,
2
7
2
0 °C; iii, N-chlorosuccinimide, CHCl , reflux; iv, Et N; v, TFA,
0 °C; 2 M HCl; vi, EDCI, N-hydroxysuccinimide, DMF, 0 → 20 °C.
3
3
©
Georg Thieme Verlag Stuttgart · New York

2
816
R. C. F. Jones, T. A. Pillainayagam
LETTER
conditions (1.2 equiv NaOMe, MeOH, reflux, 3 h)
afforded 10a in acceptable yield (48%) from 4a. Only the
dehydrated product of condensation was observed, and
the new alkene bond was formed exclusively as the E-iso-
3
mer ( J = CH approx. 16 Hz). As anticipated, reaction
HC
with the more electrophilic 4-nitrobenzaldehyde proceed-
9
ed more efficiently to give 10b (66%) while 4-methoxy-
benzaldehyde gave 10c in only 17%. The same was found
with pyrroloisoxazoles 4b and 4c, affording 3-(2-
arylethenyl) derivatives 10d–j (Scheme 2, Table 1).
Figure 2 X-Ray crystal structure of condensation product 10d.
isolated crystals of 10d were non-racemic whereas 10g
crystallised in a centrosymmetric space group.11 The 3-
alkenylpyrroloisoxazoles 10 and the simpler 3-methyl de-
rivatives 4 crystallize as hydrogen-bonded dimers.
To validate this synthetic approach, the 3-elaborated
materials must be unmasked to the corresponding acyltet-
ramic acids. Under our standard conditions1b for hydro-
genolytic N–O cleavage (1 atm H , Pd/C, MeOH) and
2
hydrolysis of the resultant enaminone (2 M aq NaOH,
THF, reflux), the condensation products 10a,c,d,f,g,i
afforded the corresponding 3-(3-arylpropanoyl)tetramic
1
2
acids 11a,c,d,f,g,i (Scheme 2, Table 1). Thus as expect-
Scheme 2 R = Me, CHMe , CH CMe . Ar = Ph, 4-O NC H , 4- ed, N–O cleavage is accompanied by alkene reduction; no
1
2
2
2
2
6
4
MeOC H (see Table 1 for details). Reagents: i, 2.2 equiv BuLi, THF–
hexanes, –78 °C, excess MeI; ii, ArCHO, NaOMe, MeOH, reflux, 3
h; iii, H , Pd/C, MeOH; iv, aq NaOH; v, Mo(CO) , moist MeCN.
6
4
identifiable products were isolated from the nitro-substi-
tuted series. In contrast, the important carbon-carbon dou-
2
6
ble bond could be retained by N–O reduction using
molybdenum hexacarbonyl (moist MeCN).1
3,14
In this
X-Ray crystal structures of 10d (Figure 2) and 10g (not
shown) confirmed the structure and alkene geometry of
the condensation products. Under these conditions the
way, the desired 3-(3-arylpropenoyl)tetramic acids 12a–i
were efficiently prepared from 10a–i, respectively, in uni-
formly excellent yields (83–97%, Scheme 2, Table 1).
1
0
Table 1 Yields of Condensation Products 10, and of Liberated 3-Acyltetramic Acids 11 and 12
Pyrroloisoxazole 4
Ar
Product 10 (yield, %)
Acyltetramic acid 11
yield, %)
Enoyltetramic acid 12
(yield, %)
(
4
4
4
4
4
4
4
4
4
4
a
a
a
b
b
b
c
Ph
10a (48)
10b (66)
10c (17)
10d (44)
10e (61)
10f (18)
10g (39)
10h (57)
10i (12)
10j (63)
11a (57)
12a (92)
12b (83)
12c (86)
12d (97)
12e (96)
12f (96)
12g (86)
12h (95)
12i (87)
4-O NC H
4
2
6
4-MeOC H
11c (55)
11d (69)
6
4
4
4
Ph
4-O NC H
4
2
6
4-MeOC H
11f (59)
11g (58)
6
Ph
c
4-O NC H
4
2
6
c
4-MeOC H
11i (61)
6
b
2-MeC H
6
4
Synlett 2004, No. 15, 2815–2817 © Thieme Stuttgart · New York

LETTER
Pyrroloisoxazoles as a Building Block for 3-Enoyltetramic Acids
2817
We have thus demonstrated the value of pyrrolo[3,4-
c]isoxazoles as non-polar building blocks for elaboration
to novel acyltetramic acids, in particular 3-enoyl systems,
and are continuing to develop applications of this method-
ology.
(9) 6-Methyl-3-[2-(4-nitrophenyl)ethenyl]-5,6-dihydro-4H-
pyrrolo[3,4-c]isoxazol-4-one (10b): To 3,6-dimethyl-5,6-
dihydro-4H-pyrrolo[3,4-c]isoxazol-4-one (4a, 0.050 g,
0
(
.329 mmol) under nitrogen at 20 °C was added dry MeOH
5 mL) followed by 4-nitrobenzaldehyde (0.109 g, 0.723
mmol, 2.2 mol equiv), and sodium methoxide (0.021 g,
.395 mmol, 1.2 mol equiv) in dry MeOH (4 mL). The
0
reaction mixture was stirred for 1 min at 20 °C then heated
under reflux for 2 h and immediately cooled in an ice bath.
The resulting yellow crystals were filtered off and dried in
Acknowledgment
We acknowledge the financial support of Loughborough University
vacuo (0.062 g, 66%); (Anal. Calcd for C H N O : C,
(
studentship to T. A. P.), and Professor V. McKee, Dr M. R. J.
14 11
3
4
+
5
8.95; H, 3.89; N, 14.73%; [M ] 285.0750. Found: C, 59.09;
H, 3.80; N, 14.60%; [M ] 285.0747.). H NMR (250 MHz,
Elsegood for X-ray data.
+
1
CDCl ): d = 1.59 (3 H, d, J = 7 Hz, CH CH), 4.88 (1 H, q,
3
3
References
J = 7 Hz, CHCH ), 6.03 (1 H, br s, NH), 7.26 (1 H, d, J = 16
3
Hz, CH=CH), 7.76 (2 H, d, J = 9 Hz, ArH), 8.06 (1 H, d, J =
(
1) For a review and leading references, see: (a) Royles, B. J. L.
Chem. Rev. 1995, 95, 1981. (b) Jones, R. C. F.; Bhalay, G.;
Carter, P. A.; Duller, K. A. M.; Dunn, S. H. J. Chem. Soc.,
Perkin Trans. 1 1999, 765.
13
1
6 Hz, CH=CH), 8.28 (2 H, d, J = 9 Hz, ArH). C NMR
(
(
1
400 MHz, CDCl ): d = 20.4 (CH ), 48.9 (CHCH ), 112.1
3
3
3
C), 115.2 (CH=CH), 124.6 and 129.9 (ArCH), 134.8 (ArC),
41.5 (CH=CH), 148.8, 161.8 and 162.8 (C), 173.4 (C=O).
(
(
(
(
2) Jones, R. C. F.; Bhalay, G.; Carter, P. A.; Duller, K. A. M.;
Vulto, S. I. E. J. Chem. Soc., Perkin Trans. 1 1994, 2513.
3) Jones, R. C. F.; Dawson, C. E.; O’Mahony, M. J. Synlett
+
MS: m/z = 285 [M ], 270, 176, 164, 147, 102, 90, 55, 43.
10) Crystal data for 10d and 10g are deposited at the Cambridge
Crystallographic Centre Database.
(
(
1
999, 873.
4) Dixon, D. J.; Ley, S. V.; Longbottom, D. A. Org. Lett. 2000,
, 3611; and references cited therein.
11) Condensation products 10 in general displayed no optical
rotation. It is assumed loss of optical integrity occurred
under the basic conditions used, cf. ref. 3.
3
5) The enamine geometry was undetermined and is drawn as E
for convenience..
(
12) The acyltetramic acids are drawn as the exo-enol tautomer
that forms the major tautomer in CDCl solution, and the
3
(
(
(
6) Stork, G.; McMurry, J. E. J. Am. Chem. Soc. 1967, 89, 5461.
7) Similar treatment of 4b afforded the N-methyl derivative.
8) Under these conditions aliphatic ketones MeCO(CH2)2-6Me
as electrophiles also gave low yields (12–28%) but of the
hydroxy adducts.
tautomer observed in the solid state, see ref. 1.
(
(
13) Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun.
1982, 877.
14) See: Jones, R. C. F.; Bhalay, G.; Carter, P. A. J. Chem. Soc.,
Perkin Trans. 1 1993, 1715.
Synlett 2004, No. 15, 2815–2817 © Thieme Stuttgart · New York