A second-generation cycloaddition route to 5-substituted 3-acyltetramic acids

Article abstract of DOI:10.1055/s-1999-3091

The 1,3-dipolar cycloaddition of α-aminonitrile oxides, formed from α- amino-acids, to enamines of β-ketoesters affords 3-(1-aminoalkyl)isoxazole- 4-carboxylic esters that are convened via pyrrolo[3,4-c]isoxazol-4-ones into 5-substituted 3-acetyltetramic

Full text of DOI:10.1055/s-1999-3091

LETTER
873
A Second-Generation Cycloaddition Route to 5-Substituted 3-Acyltetramic
Acids
Raymond C. F. Jones,*,a Claire E. Dawson,a Mary J. O’Mahonyb
a Chemistry Department, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
Fax +44(1908)858327; E-mail: R.C.F.Jones@open.ac.uk
b AgrEvo UK Ltd, Chesterford Park, Saffron Walden, Essex CB10 1XL, UK
Received 25 January 1999
Dedicated to Professor Albert Eschenmoser
The path A approach is successful for 5-(1-aminomethyl)-
isoxazoles 4 (R1 = H) but we have so far been unable to ex-
tend it to more substituted examples, 4 (R1 ≠ H),4 and
thence to 5-substituted 3-acyltetramic acids. We report
now on a second-generation isoxazole strategy that over-
comes this difficulty.
Abstract: The 1,3-dipolar cycloaddition of a-aminonitrile oxides,
formed from a-amino-acids, to enamines of b-ketoesters affords 3-
(1-aminoalkyl)isoxazole-4-carboxylic esters that are converted via
pyrrolo[3,4-c]isoxazol-4-ones into 5-substituted 3-acetyltetramic
acids.
Key words: acyltetramic acid, isoxazole, nitrile oxide, dipole,
cycloaddition
N–O Bond cleavage and hydrolysis of isoxazoles, to re-
veal a 1,3-dicarbonyl functionality, renders the N–O re-
giochemistry irrelevant. Our new strategy is thus based on
3-(1-aminoalkyl)isoxazole-4-carboxylic esters 5, Scheme
1, path B. The 4-carboxyisoxazoles of path A are prepared
by 1,3-dipolar cycloaddition of nitrile oxides to enamines
of g-amino-b-ketoesters derived from a-amino-acids;
path B involves reversing the origins of dipole and dipo-
larophile components, i.e. a-aminonitrile oxides derived
from a-amino-acids, with enamines of b-ketoesters as di-
polarophiles.
During our synthetic studies towards the 3-acyltetramic
acids 1, a group of biologically active metabolites con-
taining the (enolised) tricarbonyl motif 21 and exemplified
by the structurally simplest example, tenuazonic acid 3,2
we have developed the strategy summarized in Scheme 1,
path A.3 This uses 5-(1-aminoalkyl)isoxazole-4-carboxyl-
ic esters 4 as latent tricarbonyl units, and the highly polar
enolic functionality is masked until late in the sequence.
Initially methyl esters of the N-benzyloxycarbonyl-(S)-a-
amino-acids alanine, isoleucine, leucine and phenylala-
nine were reduced (DIBAL-H, toluene, –78 °C) to the cor-
responding aldehydes, which were not stored but
converted directly (NH2OH·HCl, NaOAc, EtOH aq., 70
°C) to the corresponding stable, solid oximes 6a-d as syn/
anti mixtures, without epimerisation. Subsequently this
was repeated with the N-tert-butoxycarbonylamino-esters
to afford oximes 6e-h (Scheme 2, Table 1).5 Treatment of
the oximes 6 with N-chlorosuccinimide (CHCl3, reflux)
resulted in C-chlorination. When these crude hydroxi-
Scheme 1 (P = Protecting group)
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R. C. F. Jones et al.
LETTER
the mixed anhydrides 10a-d (EtOCOCl, Et3N, THF,
0Æ20 °C) was complete after 16 h, as judged by 1H NMR
spectroscopy. However, on brief treatment of these anhy-
drides with HBr-HOAc (33% w/v; 20 °C, 1 h), instead of
the cyclisation expected on the basis of our earlier report
on the path A strategy,3 the major products isolated were
the amino-acids 11a-d as their HBr salts (Table 2).9
We decided therefore to complete lactam closure to the
desired
5,6-dihydro-4H-pyrrolo[3,4-c]isoxazol-4-ones
from the amino acids 11. In addition to the results above,
amino-acids 11a (86%) and 11b (94%) were also obtained
by hydrolysis (1M NH3 aq., reflux, 3 h) of the amino-es-
ters 8a and 8b, respectively. The method of choice for
preparation of amino-acids 11 was, however, direct aci-
dolysis (TFA, 20 °C, 4 h) of the N-tert-butoxycarbonyl-
isoxazole tert-butyl esters 7e-h, to afford amino-acids
11a-d, respectively, isolated as their HCl salts (2M HCl,
20 °C, 0.5 h) (Table 2). After evaluating a number of C-
activation protocols, we opted for lactam formation using
the water-soluble carbodiimide 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride (EDCI), to per-
mit extractive removal of the urea by-product. Thus the
HCl salts of 11a-d in DMF were treated with N-hydro-
xysuccinimide and EDCI (0Æ20 °C, 12 h) to afford pyr-
roloisoxazolones 12a-d in good yield (Table 2).10 The
identity of lactams 12b and 12c was confirmed by X-ray
crystal structure determinations.11
Scheme 2
moyl chlorides were treated with Et3N in the presence of
an enamine formed from ethyl or tert-butyl acetoacetate
and pyrrolidine (toluene, reflux),6 the nitrile oxides
formed in situ underwent regiospecific cycloaddition with
spontaneous elimination of pyrrolidine7 to afford the ap-
propriate protected 3-(1-aminoalkyl)isoxazole-4-carbox-
ylates 7a-l in good yields (Table 1).8
The next stage was closure to a pyrroloisoxazolone. Treat-
ment of the 3-(N-benzyloxycarbonylalkyl)isoxazoles 7a-
c with HBr-AcOH (33% w/v; 20 °C, 16h) afforded, on
basification, amino-esters 8a-c (89, 79 and 96%, respec-
tively), which distilled unchanged and could not be cyc-
lised by a range of techniques. This is in accord with our
earlier findings for ethyl 5-aminomethyl-3-methylisox-
azole-4-carboxylate.3 In order to further activate the C-4
carboxy group, the N-benzyloxycarbonyl-4-carboxylic
acids 9a-d were prepared. Acids 9a (88%), 9b (62%) and
9c (66%) were obtained by saponification (NaOH aq., re-
flux, 4 h) of ethyl esters 7a-c, respectively; alternatively
and more efficiently, the acids 9a-d were prepared by ac-
idolysis (TFA, CH2Cl2, 0 °C, 3 h) of the tert-butyl esters
7i-l, respectively, in high yield (Table 2). Conversion into
Figure 1 X-ray crystal structure Figure 2 X-ray crystal structure
of pyrroloisoxazolone 12b
of pyrroloisoxolone 12c
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LETTER
A Cycloaddition Route to 5-Substituted 3-Acyltetramic Acids
875
ml), sodium hydroxide solution (5% w/v, 500 ml) and satura-
ted brine (500 ml), dried (MgSO4) and concentrated under
reduced pressure to yield a dark oil purified by chromato-
graphy on silica gel, eluting with hexane:ethyl acetate (8:1 v/
v) to yield the title compound (5.24 g, 52%) as a yellow oil
(Found: C, 61.73; H, 8.66; N, 7.85%; MH+, 369.2389.
C19H32N2O5 requires C, 61.93; H, 8.75; N, 7.60%; MH,
369.2389); [α]D20 –40 (c 1.8 in CHCl3); lmax(EtOH)/nm 217
Unmasking of the tricarbonyl functionality was accom-
plished via hydrogenolysis of the bicyclic lactams 12a-d
(1 atm. H2, 10% Pd-C, MeOH, 20 °C, 12 h) and hydrolysis
of the intermediate enamino-ketones (2M NaOH aq.,
90 °C, 16 h) to afford the 3-acetyltetramic acids 13b-d
(Table 2).12 5-(1-Methylpropyl)-3-acetyltetramic acid
13b has the structure of the antitumour13 fungal metabo-
lite tenuazonic acid, and examination by 1H NMR
spectroscopy14 revealed that this hydrolysis step had gen-
erated tenuazonic acid 3 and its C-5 epimer as a 1:2
mixture of diastereoisomers.15,16 When we employed
the minimum conditions found to give complete
hydrolysis (0.05M NaOH aq., 50 °C, 20 h), the mixture
was improved to 4:1 in favour of natural tenuazonic
acid 3.17
1
(ε/dm3 mol– cm–1 11,500); nmax(CHCl3)/cm–1 3448, 2978,
1709, 1600, 1505, 1442, 1370, 1314 1170, 1121 and 1018;
δH(400 MHz; CDCl3) 0.75 (3H, d, J 6.8, CH3CH), 0.80 (3H,
t, J 7.3, CH3CH2), 1.06 (1H, m, CH3CHH), 1.33 and 1.50
(each 9H, s, (CH3)3), 1.53 (1H, m, CH3CHH), 1.77 (1H, m,
CH3CH), 2.53 (3H, s, 5-CH3), 4.92 (1H, m, CHNH) and 5.73
(1H, br d, J 10.3, NH); δC(100 MHz; CDCl3) 11.1 (CH3), 13.3
(5-CH3), 15.8 (CH3), 24.0 (CH3CH2), 28.0 (C(CH3)3), 28.1
(C(CH3)3), 38.1 (CH3CH), 52.0 (CHNH), 78.9 (C(CH3)3),
82.3 (C(CH3)3), 108.7 (C-4), 155.2 (OCONH), 161.4 (C-3),
162.7 (C-5) and 175.2 (CO2 Bu); m/z(EI) 369 (MH+, 11%),
t
We have thus demonstrated that the isoxazole strategy for
preparation of 5-substituted 3-acyltetramic acids is suc-
cessful using 3-aminoalkylisoxazole-4-carboxylates; the
shortest route is 6Æ7 Æ11Æ12Æ13. Elaboration studies
on the pyrroloisoxazolones 12 as building blocks for more
complex 3-acyltetramic acids are underway.
311, 255, 239, 211, 155, 137 and 57 (100).
(9) A low yield (≤ 18%) of pyrroloisoxazolone 12b was obtained
in some attempts using mixed anhydride 10b.
(10) (6S)-3-Methyl-6-[(1S)-methylpropyl]-5,6-dihydro-4H-pyrro-
lo-[3,4-c]isoxazol-4-one 12b: To (S,S)-3-(1-amino-2-methyl-
butyl)-5-methylisoxazole-4-carboxylic acid 11b, as the HCl
salt (0.489 g, 1.98 mmol), and N-hydroxysuccinimide (0.251
g, 2.18 mmol) in dry DMF (30 ml) at 0 °C was added EDCI
(0.456 g, 2.38 mmol) in portions over 0.5 h and the mixture
left to stir at 20 °C for 12 h. Triethylamine (0.602 g, 5.95
mmol) was added dropwise over 3 h via syringe pump and the
mixture left to stir for a further 5 h at 20 °C before concentra-
tion under reduced pressure. The residue was dissolved in
ethyl acetate (25 ml), washed successively with water (25 ml),
hydrochloric acid (2M, 2 x 25 ml), saturated sodium hydrogen
carbonate solution (2 x 25 ml) and saturated brine (25 ml),
dried (MgSO4) and concentrated under reduced pressure to
afford the title compound (0.33 g, 86%) as an off-white solid;
a portion was recrystallised from hexane:ethyl acetate to yield
colourless crystals, m.p. 110 °C (Found: C, 61.70; H, 7.24; N,
14.31%; M+, 194.1055. C10H14N2O2 requires C, 61.84; H,
Acknowledgement
We thank EPSRC & AgrEvo UK for a CASE studentship (C. E. D.),
Dr D A Whiting (University of Nottingham) for helpful discussion,
and the EPSRC National Mass Spectrometry Service Centre and
EPSRC X-Ray Crystallography Service for measurements.
References and Notes
(1) For a recent review and leading references, see: Royles, B. J.
L. Chem. Rev. 1995, 95, 1981; Jones, R. C. F.; Begley, M. J.;
Peterson, G. E.; Sumaria, S. J. Chem. Soc. Perkin Trans. 1
1990, 1959.
(2) Stickings, C.E. Biochem. J. 1957, 67, 390.
7.26; N, 14.42%; M, 194.1055); [α]D26 +20 (c 1.9 in CHCl3);
(3) 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;
Jones, R. C. F.; Bhalay, G.; Carter, P. A.; Duller, K. A. M.;
Dunn, S. H. J. Chem. Soc., Perkin Trans. 1 1999, in press.
(4) We have to date been unable to form the required pyrrolidine
enamines of g-amino-b-ketoesters other than 4-amino-3-oxo-
butanoates.
(5) Cf. Chung, Y. J.; Ryu, E. J.; Keum G.; Kim, B. H. Bioorg.
Chem. 1996, 4, 209; Kim, B. H.; Chung, Y. J.; Ahn, H. J.; Ha,
T.-K. Bull. Korean Chem. Soc. 1996, 17, 401.
1
λ
max(EtOH)/nm 228 (ε/dm3 mol– cm–1 8,600); νmax(CHCl3)/
cm–1 3443, 3035, 2968, 1710, 1655, 1529, 1382, 1326 and
1126; δH(300 MHz; CDCl3) 0.92 (3H, d, J 6.7, CH3CH), 0.98
(3H, t, J 7.4, CH3CH2), 1.41 and 1.57 (each 1H, m, CH3CHH),
1.84 (1H, m, CH3CH), 2.61 (3H, s, 3-CH3), 4.55 (1H, d, J 5.7,
CHNH) and 6.74 (1H, br s, NH); δC(75 MHz; CDCl3) 11.4
(CH3CH2), 12.0 (3-CH3), 13.8 (CH3CH), 25.6 (CH3CH2),
37.8 (CH3CH), 57.6 (CHNH), 114.2 (C-3a), 163.7 (C-6a),
166.0 (C-3) and 171.3 (CONH); m/z(EI) 194 (M+, 8%), 179,
165, 151, 137 (100), 123, 110, 95, 70 and 57. The structure
was confirmed by an X-ray crystal structure determination, ref
11.
(6) The enamine geometry is undetermined; Scheme 2 shows the
E-isomer for convenience.
(7) Stork, G.; McMurry, J.E. J. Am. Chem. Soc. 1967, 89, 5461.
(8) (S,S)-3-(1-tert-Butyloxycarbonylamino-2-methylbutyl)-4-
tert-butyloxycarbonyl-5-methylisoxazole 7f: To (2S,3S)-2-
tert-butyloxycarbonylamino-3-methylpentanaldoxime 6f
(6.77 g, 27.63 mmol) in chloroform (600 ml) at 0 °C was ad-
ded
(11) Crystal data for 12b and 12c (m.p. 170-171 °C from hexane:
ethyl acetate) is deposited at the Cambridge Crystallographic
Database.
(12) UV spectroscopy indicated hydrolysis of the enaminoketone
derived from 12a was complete, but acyltetramic acid 13a
proved too polar to be extracted from aqueous solution.
(13) For leading references to the toxicity spectrum of tenuazonic
acid, see: Lebrun, M. H.; Nicolas, L.; Boutar, M.; Gaudemer,
F.; Ranomenjanahary, S.; Gaudemer, A. Phytochemistry
1988, 27, 77.
N-chlorosuccinimide (4.06 g, 30.40 mmol) in portions over 20
min and the mixture heated under reflux for 1.5 h, by which
time no oxime remained by tlc. tert-Butyl 3-pyrrolidino-2-bu-
tenoate (11.66 g, 55.26 mmol) was added in one portion
followed by triethylamine (3.07 g, 30.39 mmol) dropwise to
the refluxing mixture over a period of 3 h via syringe pump.
The mixture was heated under reflux for a further 2 h, cooled
and poured into deionised water (600 ml). The organic phase
was separated, washed with citric acid solution (2M, 2 x 600
(14) Cf. Poncet, J.; Jouin, P.; Castro, B.; Nicolas, L.; Boutar, M.;
Gaudemer, A. J. Chem. Soc., Perkin Trans. 1 1990, 611.
(15) Precursor 12b was found to be a single diastereoisomer.
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R. C. F. Jones et al.
LETTER
(16) Although the 3-acetyltetramic acids 13c,d are consistent with
samples reported to retain optical activity [13c: m.p. 110 °C
(lit. 114-114.5 °C; Yuki, H.; Tohira, Y.; Aoki, B.; Kano, T.;
Takama, S.; Yamazaki, T. Chem. Pharm. Bull. 1967, 15,
1107). 13d: m.p. 132-135 °C (lit. 133-134 °C; Schmidlin, T.;
Tamm, C. Helv. Chim. Acta 1980, 63, 121)], we assume epi-
merisation comparable to 13b, cf. ref. 13.
(17) Attempted acidic hydrolysis of the enaminoketone formed
from 12b was unsuccessful.
Article Identifier:
1437-2096,E;1999,0,S1,0873,0876,ftx,en;W02899ST.pdf
Synlett 1999, S1, 873–876 ISSN 0936-5214 © Thieme Stuttgart · New York