Short synthesis of pulchellalactam

Article abstract of DOI:10.1080/00397910600639182

tert -Butyl 4-methyl-2-oxo-2,5-dihydro-1 H -pyrrole-1-carboxylate 4 was synthesized by a short two-step procedure: regioselective 1,3-dipolar diazomethane cycloaddition to N -Boc-pyrrolinone 2 and thermolysis of the adduct. The compound 4 could be converted in one step into pulchellalactam. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600639182

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Short Synthesis of Pulchellalactam
Jean‐Paul Hermet a , Virginie Caubert a & Nicole Langlois a
a Institute of Organic Chemistry , National Center of Scientific Research ,
Gif‐sur‐Yvette, France
Published online: 16 Feb 2007.
To cite this article: Jean‐Paul Hermet , Virginie Caubert & Nicole Langlois (2006) Short Synthesis of
Pulchellalactam, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:15, 2253-2257, DOI: 10.1080/00397910600639182
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Synthetic Communicationsw, 36: 2253–2257, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600639182
Short Synthesis of Pulchellalactam
Jean-Paul Hermet, Virginie Caubert, and Nicole Langlois
Institute of Organic Chemistry, National Center of Scientific Research,
Gif-sur-Yvette, France
Abstract: tert-Butyl 4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate 4 was
synthesized by a short two-step procedure: regioselective 1,3-dipolar diazomethane
cycloaddition to N-Boc-pyrrolinone 2 and thermolysis of the adduct. The compound
4 could be converted in one step into pulchellalactam.
Keywords: Diazomethane cycloaddition, marine metabolite, pyrazolines, unsaturated
g-lactams
Pulchellalactam 1 is a potent CD45 protein tyrosine phosphatase (PTP)
inhibitor, which was isolated in 1998 from the marine fungus Corollospora
pulchella, growing on driftwood from Peleliu.[1] PTP inhibitors are
promising biochemical agents, and CD45 is a therapeutic target for several
autoimmune and inflammatory diseases. Because of these biological activities
and the restricted availability of the natural pulchellalactam, four syntheses of
1 have been achieved today.[2–5] Three of them involve the unsaturated
g-lactam 4 as a synthetic precursor of 1.[2,4,5] The first synthesis of both
isomers E and Z allowed the assignment of Z configuration to the chain
double bond of pulchellalactam and described the conversion of 4 into 1 in
one step and high yield.
We describe here a new and straightforward route to this direct precursor
4, starting from N-Boc pyrrolinone 2.
We anticipated that regioselective 1,3-dipolar diazomethane cyclo-
addition to 2, followed by thermolysis of the adduct, would afford the
desired compound 4, as outlined in Scheme 1.
Received in the UK October 24, 2005
Address correspondence to Nicole Langlois, Institute of Organic Chemistry,
National Center of Scientific Research, 91198, Gif-sur-Yvette, France. E-mail:
nicole.langlois@icsn.cnrs-gif.fr
2253

2254
J.-P. Hermet, V. Caubert, and N. Langlois
Scheme 1.
Diazomethane cycloadditions to electron-deficient double bonds have
been known for a long time.[6] They occurred generally with high regioselec-
tivity, explained by the magnitude of the orbital coefficients for the dipole
HOMO and the dipolarophile LUMO.[7] Several types of a,b-unsaturated
carbonyls have been studied as dipolarophiles: ketones,[8] esters[6,9] or
lactones,[10] imides,[11] N-acyllactams,[12] and N-acylsultams.[13] To the best
of our knowledge, few examples of dipolar cycloaddition of diazomethane
to a,b-unsaturated lactams have been described today,[7] and acyclic unsatu-
rated amides have not been used as dipolarophiles. The thermolysis of the
resulting cycloadducts to prepare derivatives of b-methyl unsaturated
lactams have been reported only in rare cases,[12] probably due, in part, to
the possible isomerisation of initial D1 into D2-pyrazolines.
Accordingly, the N-Boc pyrrolinone 2 was prepared by oxidation of
pyrrole with hydrogen peroxide as described,[14] followed by protection of
the nitrogen as a tert-butylcarbamate,[15] a suitable and particularly inexpen-
sive method for our purpose.[16] The cycloaddition was performed at room
temperature by simple addition of a diazomethane solution in diethyl ether
to the N-Boc-pyrrolinone 2. The cycloaddition proceeded smoothly with
complete regioselectivity. Varying the reaction time, we observed the initial
formation of D1-pyrazoline 3 as a single isomer. After 14 h, this cycloadduct
was isolated in68% yield (c.a. 100% based onthe recoveredstarting material 2).
Thus, the reaction was stopped at this stage before completion to avoid
by-product formation.
For the following thermolysis step, a solution of 3 in dry toluene was
heated under reflux (oil bath at 1258C) for 8 h, giving rise to the target
methylated pyrrolinone 4 (71%), together with small amounts of the known
N-tert-butoxycarbonyl-3,4-methano-2-pyrrolidinone 5 (9%).[17] The com-
pound 4, by condensation of isobutyraldehyde in the presence of NaH with
concomitant Boc N-O migration and elimination, led to pulchellalactam 1
in 86% yield.[2]

Short Synthesis of Pulchellalactam
2255
In conclusion, we developed a very short route to the direct synthetic
precursor of natural pulchellalactam 1 by the regiospecific cycloaddition of
diazomethane to the easily available unsaturated g-lactam 2 and thermolysis
of the cycloadduct in 48% overall yield.
EXPERIMENTAL
General
Melting points were determined with a Bu¨chi B-540 apparatus and are
uncorrected. Optical rotations were measured on a Jasco P-1010 polarimeter
and concentrations are given in g/100 mL. IR spectra (film, CHCl3) were
1
recorded on a Perkin Elmer Spectrum BX (FT) instrument. H NMR spectra
were obtained (CDCl3, CHCl3 d ¼ 7.27 ppm) from a Bruker AM 300 spec-
trometer (s, d, t, dd, and m indicate singlet, doublet, triplet, doublet of
doublets, and multiplet, respectively). 13C NMR spectra were recorded also
with the AM 300 (75.0 MHz, CDCl3 centered at 77.0 ppm). Mass spectra
and high-resolution mass spectra were measured on a Navigator (ESI) or a
Micromass LC-TOF spectrometer. Chromatography was performed on silica
gel (SDS 230–400 mesh) and preparative thin-layer chromatography on
silica gel (Merck HF 254 þ 366).
tert-Butyl 6-oxo-3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-5(3H)-
carboxylate 3
An excess of diazomethane (prepared in Et2O from diazald just before the
use)[18] was added, in three portions, to tert-butyl 2-oxo-2,5-dihydro-1H-
pyrrole-1-carboxylate 2 (128 mg, 0.70 mmol), and the mixture was stirred
at room temperature for 14 h. The colorless reaction mixture was evapor-
ated to dryness under reduced pressure at rt. The residue was purified by
preparative TLC (eluent– heptane-EtOAc 3:7) to afford 3 as white crystals
(107 mg, 68%) and starting 2 (41 mg, 32%). Decomposition with release of
gas at 142–38C. IR: 2978, 2931, 1774, 1712, 1367 cm–1. MS (ESI,
MeOH): 248 (MNa+, 100%). HRMS: calcd. for C10H15N3O3Na:
248.1011, found: 248.1030. 1H NMR (300 MHz, CDCl3): 5.49 (ddd, 1H,
J ¼ 9, J0 ꢀ J00 ꢀ 2 Hz, H-6a), 4.83 (ddd, 1H, J ¼ 18.4, J0 ¼ 9, J00ꢀ
2 Hz, Ha-3), 4.72 (ddd, 1H, J ¼ 18.4, J0 ꢀ 3, J00 ꢀ 2 Hz, Hb-3), 3.97
(dd, 1H, J ¼ 11.7, J0 ¼ 9.2 Hz, Ha-4), 3.27 (dd, 1H, J ¼ 11.7,
J0 ¼ 4.3 Hz, Hb-4), 2.81 (m, 1H, H-3a), 1.51 (s, 9H, CH3, t-Bu) ppm.
13C NMR (75.0 MHz, CHCl3): 164.65 (CO), 149.53 (NCO2), 96.95 (C-
6a), 86.34 (C-3), 83.98 (qC, t-Bu), 51.05 (C-4), 27.92 (CH3, t-Bu),
25.38 (C-3a) ppm.

2256
J.-P. Hermet, V. Caubert, and N. Langlois
tert-Butyl 4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate 4
A solution of pyrazoline 3 (94.5 mg, 0.42 mmol) in toluene (5 mL) was heated
under reflux (oil bath thermostated at 1258C) for 8 h. After being cooled at
room temperature, the solvent was eliminated by evaporation under reduced
pressure to give the crude thermolysis product, which was purified by prepara-
tive TLC (eluent–heptane-Et2O 1:2) affording 4 as colorless needles after
crystallization in a Et2O–pentane mixture (58.6 mg, 71%) and cyclopropane
5 (7.5 mg, 9%). 4: mp: 72–738C (lit.: oil).[2,5] IR: 2989, 2976, 2930, 1774,
1702, 1698, 1636, 1455 cm21 (lit.: 1774, 1643, 1445 cm–1).[5] MS (ESI,
MeOH): 220 (MNaþ, 100%), HRMS: calcd. for C10H15NO3Na (MNaþ):
220.0950, found: 220.0952.1H (300 MHz, CDCl3): 5.82 (m, 1H, H-3), 4.18
(m, 1H, H2-5), 2.07 (m, 3H, CH3-4), 1.47 (s, 9H, CH3 t-Bu) ppm (lit. d:
5.82, 4.18, 2.06, 1.51 ppm).[5] 13C NMR (75.0 MHz, CHCl3): 169.57 (CO),
157.97 (NCO2), 149.46 (C-4), 122.90 (C-3), 82.64 (qC, t-Bu), 54.32 (C-5),
28.01 (CH3, t-Bu), 15.49 (CH3-4) ppm (lit. d: 169.7, 158.1, 149.4, 122.8,
82.6, 54.3, 28.0, 15.5 ppm).[5] Anal. calcd. for C10H15NO3: C, 60.89; H,
7.67; N, 7.10. Found: C, 60.69; H, 7.75; N, 7.06.
ACKNOWLEDGMENT
We are grateful to CNRS and Professor J. Y. Lallemand, director of ICSN, for
financial support (J.-P. H; V. C.).
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