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(CHN), 113.0, 159.5, 165.0 (isoxazole-C), 168.6, 173.2 (CO). HRMS (ESI):
MNa+ 273.1211; C13H18N2O3 requires MNa+ 273.1210.
§ Crystal data for 11c: C13H16N2O3, M = 248.28, orthorhombic, P212121,
a = 6.9698(12), b = 9.5108(16), c = 19.233(3) Å, V = 1274.9(4) Å3, Z = 4,
m(Mo-Ka) = 0.71073 Å, 11 350 reflections measured at 150 K on a Bruker
APEX 2 CCD diffractometer, 2618 unique data, Rint = 0.034, R[for 2390
data with F2 > 2s(F2)] = 0.032, wR2 (all data) = 0.078, 227 parameters.
H atoms were freely refined. Absolute structure {x = 0.0(6)} could not be
determined reliably. CCDC 959645.
1 For example: World Health Organisation, Fact Sheet no. 194, May 2013,
2013. U. Theuretzbacher and J. H. Toney, Curr. Opin. Invest. Drugs, 2006,
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2 A. Holtzel, M. G. Ganzle, G. J. Nicholson, W. P. Hammes and
G. Jung, Angew. Chem., Int. Ed., 2000, 39, 2766–2768.
Fig. 1 X-ray crystal structure of N-acyl pyrroloisoxazole 11c.
3 B. J. L. Royles, Chem. Rev., 1995, 95, 1981–2001; R. Schobert and
A. Schlenk, Bioorg. Med. Chem., 2008, 16, 4203–4221; Y.-C. Jeong and
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5 G. F. Kaufmann, R. Sartorio, S.-H. Lee, C. J. Rogers, M. M. Meijler,
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Antimicrob. Agents Chemother., 2010, 54, 683.
Scheme 4 Formation of N-acyltetramides 12 from pyrroloisoxazoles 11.
either returned unchanged enaminoketone (e.g. H2O at 20 1C
or 2 M aq. HCl at reflux; NaNO2, 3 M aq. H2SO4) or led to
N-deacylation (aq. NaOH, 2 M at reflux or 0.1 M at 20 1C).
In conclusion, we have developed a synthetic route, based
on a nitrone 1,3-dipolar cycloaddition, from amino acids to
N-acylpyrrolo[3,4-c]isoxazoles 11 as reutericyclin analogues, and
presented a diverse selection of 12 novel compounds. Further-
more, we have demonstrated the conversion of these hetero-
bicycles into N-acyltetramides 12. All of these new compounds
are currently undergoing biological evaluation.
6 R. Yendapally, J. G. Hurdle, E. I. Carson, R. B. Lee and R. E. Lee,
¨
J. Med. Chem., 2008, 51, 1487–1491; M. G. Ganzle and R. F. Vogel,
¨
Appl. Environ. Microbiol., 2003, 69, 1305–1307; M. G. Ganzle, Appl.
Microbiol. Biotechnol., 2004, 64, 326–332.
7 C. Ueda, K. Tateda, M. Horikawa, S. Kimura, Y. Ishii, K. Nomura,
K. Yamada, T. Suematsu, Y. Inoue, M. Ishiguro, S. Miyairi and
K. Yamaguchi, Antimicrob. Agents Chemother., 2010, 54, 683–688; J. G.
Hurdle, A. E. Heathcott, L. Yang, B. Yan and R. E. Lee, J. Antimicrob.
Chemother., 2011, 6, 1773–1776.
8 For leading references to our early pre-isoxazole work: R. C. F. Jones and
M. Tankard, J. Chem. Soc., Perkin Trans. 1, 1991, 250–251; R. C. F. Jones,
G. Bhalay, J. M. Patience and P. Patel, J. Chem. Res., 1999, 250–251.
9 For our related work on the 3-acyl-4-hydroxypyridin-2-one series:
R. C. F. Jones, A. K. Choudhury, J. N. Iley, M. E. Light, G. Loizou and
T. A. Pillainayagam, Beilstein J. Org. Chem., 2012, 8, 308–312, and
refs. therein.
The authors acknowledge Loughborough University for the
award of studentships (C. C. M. L and J. P. B.) and Novartis for
financial support (C. C. M. L.).
10 For our 2nd generation approach: (a) R. C. F. Jones, C. E. Dawson
and M. J. O’Mahony, Synlett, 1999, 873–876; (b) R. C. F. Jones and
T. A. Pillainayagam, Synlett, 2004, 2815–2817; (c) R. C. F. Jones,
C. C. M. Law and M. R. J. Elsegood, ARKIVOC, 2013, (iii), 81–97.
Notes and references
‡ Typical procedure for N-acylpyrrolo[3,4-c]isoxazole formation: 11 For our 1st generation approach: R. C. F. Jones, G. Bhalay,
(S)-5-butyryl-6-isopropyl-3-methyl-5,6-dihydro-4H-pyrrolo[3,4-c]isoxazol-
4-one 11a. (S)-6-(1-Methylethyl)-3-methyl-5,6-dihydro-4H-pyrrolo[3,4-c]-
P. A. Carter, K. A. M. Duller and S. H. Dunn, J. Chem. Soc., Perkin
Trans. 1, 1999, 765–776, and refs. therein.
isoxazol-4-one 10a (50.0 mg, 0.277 mmol) was suspended in dry THF 12 Cf. L. M. Halo, J. M. Marshall, A. A. Yakasai, Z. Song, C. P. Butts,
(20 mL) stirred at ꢀ78 1C under a nitrogen atmosphere. n-Butyl-lithium
(0.201 mL, 1.41 M in hexanes, 0.283 mmol) was added and the reaction
stirred for 15 min at this temperature, during which time the solution
turned yellow. Butanoyl chloride (29.6 mg, 27.0 mL, 0.283 mmol) was
then added in two portions over 10 min and the mixture stirred at
M. P. Crump, M. Heneghan, A. M. Bailey, T. J. Simpson, C. M.
Lazarus and R. J. Cox, ChemBioChem, 2008, 9, 585–594; L. M. Halo,
M. N. Heneghan, A. A. Yakasai, Z. Song, K. Williams, A. M. Bailey,
R. J. Cox, C. M. Lazarus and T. J. Simpson, J. Am. Chem. Soc., 2008,
130, 17988–17996.
ꢀ78 1C for a further 3 h before quenching by addition of satd. NH4Cl 13 For an enantiospecific synthesis of reutericyclin via the Dieckmann
¨
solution. The mixture was tested for pH to ensure neutrality had been
achieved and then separated between water (20 mL) and EtOAc (25 mL).
strategy: R. Bohme, G. Jung and E. Breitmaier, Helv. Chim. Acta,
2005, 88, 2837–2841.
The organic layer was dried over MgSO4, filtered and concentrated 14 For a survey of coupling reagents: P. D. Bailey, in Comprehensive
under reduced pressure to produce the title compound 11a as a yellow oil
Functional Group Transformations, ed. A. R. Katritzky and R. J. K.
Taylor, Elsevier, Oxford, 2005, vol. 5, pp. 221–225.
(62 mg, 89%); [a]D20 +36.0 (c 5.00 ꢂ 10ꢀ3, CHCl3); nmax (CHCl3)/cmꢀ1
´
3025, 1725 (CQO), 1689 (CQO), 1650, 1389, 1250, 1131; dH (400 MHz; 15 A. L. L. Garcıa, Synlett, 2007, 1328–1329; H. Wissman and H.-J.
CDCl3) 0.50 (3H, d, J = 6.8, CH(CH3)2) 0.92 (3H, t, J = 7.2, CH2CH3), 1.17
Kleiner, Angew. Chem., Int. Ed. Engl., 1980, 133–134.
(3H, d, J = 6.8, CH(CH3)2), 1.55–1.61 (2H, m, CH2CH3), 2.61 (3H, s, 3-CH3), 16 There was no evidence of racemisation during the sequence to form
2.68–2.72 (1H, m, CH(CH3)2), 2.81, 2.92 (each 1H, dt, J = 7.6, 14.8,
CH2CO), 5.13 (1H, d, J = 4, CHN); dC (100 MHz; CDCl3) 11.8, 12.8, 13.1
pyrroloisoxazoles 10a–c; for further discussion of the stereochemical
integrity of intermediates in the sequence, see ref. 10a and b.
(CH3), 17.0 (CH2CH3), 17.9 (CH3), 27.0 (CH(CH3)2), 38.2 (CH2CO), 59.9 17 M. Nitta and T. Kobayashi, J. Chem. Soc., Perkin Trans. 1, 1985, 1401–1406.
1590 | Chem. Commun., 2014, 50, 1588--1590
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