Expedient synthesis, on large scale, of aliphatic chaetomellic anhydrides from N-allyl-2,2-dichlorocarboxyamides

Article abstract of DOI:10.1080/00397910903029974

Chaetomellic anhydride A and an analog (with two additional carbons) were obtained, on a preparative scale, starting from amides derived from the acylation of 2-(2-propenylamino)pyridine with 2,2-dichloropalmitic or 2,2-dichlorostearic acid. An alternative approach, in which the methyl substituent of the target anhydride is introduced by the carboxylic acid reactant and the long aliphatic chain is added through the allylamino moiety, proved unviable.

Full text of DOI:10.1080/00397910903029974

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Expedient Synthesis, on Large Scale, of
Aliphatic Chaetomellic Anhydrides from
N-Allyl-2,2-dichlorocarboxyamides
Franco Ghelfi a , Mariella Pattarozzi a , Fabrizio Roncaglia a , Valerio
Giangiordano a & Andrew F. Parsons b
a Department of Chemistry, University of the Studies of Modena and
Reggio Emilia, Modena, Italy
b Department of Chemistry, University of York, Heslington, York,
United Kingdom
Published online: 04 Mar 2010.
To cite this article: Franco Ghelfi , Mariella Pattarozzi , Fabrizio Roncaglia , Valerio Giangiordano
& Andrew F. Parsons (2010) Expedient Synthesis, on Large Scale, of Aliphatic Chaetomellic
Anhydrides from N-Allyl-2,2-dichlorocarboxyamides, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:7, 1040-1051, DOI:
10.1080/00397910903029974
To link to this article: http://dx.doi.org/10.1080/00397910903029974
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Synthetic Communications1, 40: 1040–1051, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903029974
EXPEDIENT SYNTHESIS, ON LARGE SCALE, OF
ALIPHATIC CHAETOMELLIC ANHYDRIDES FROM
N-ALLYL-2,2-DICHLOROCARBOXYAMIDES
Franco Ghelfi,1 Mariella Pattarozzi,1 Fabrizio Roncaglia,1
Valerio Giangiordano,1 and Andrew F. Parsons2
1Department of Chemistry, University of the Studies of Modena and Reggio
Emilia, Modena, Italy
2Department of Chemistry, University of York, Heslington, York,
United Kingdom
Chaetomellic anhydride A and an analog (with two additional carbons) were obtained, on a
preparative scale, starting from amides derived from the acylation of 2-(2-propenylamino)
pyridine with 2,2-dichloropalmitic or 2,2-dichlorostearic acid. An alternative approach, in
which the methyl substituent of the target anhydride is introduced by the carboxylic acid
reactant and the long aliphatic chain is added through the allylamino moiety, proved
unviable.
Keywords: Chaetomellic anhydride; halocompounds; lactams; radical reactions
INTRODUCTION
Chaetomellic acid A 1a, a natural compound isolated in 1993 from the
coelomycete Chaetomella acutiseta,[1] has aroused the interest of a number of
scientists because of its capacity of inhibiting recombinant human farnesyl-protein
transferase (FPTase) at low dosage (IC50 ¼ 55 nM).[1,2] Because 1a has a high predis-
position to cyclize, it was indeed isolated as chaetomellic anhydride A (CCA) 3.[1]
The cyclic form, however, under mildly basic conditions (pH 7.5), such as those
encountered in biological fluids, can be readily hydrolyzed to give the dicarboxylate
anion 2a, which is the actual biologically active structure (Scheme 1).[1,2]
Recently it was discovered that 2a, by selectively blocking the activation of
Ha-Ras through the inhibition of FPTase, worked powerfully against the damages
following renal or cerebral ischemic phenomena, accomplishing an effective organo-
protective action in vivo;[3,4] 2a thus emerged as an excellent lead structure for develop-
ing anti-ischemic drugs.
From its isolation, chaetomellic acid A 1a has continuously attracted the inter-
est of synthetic chemists, and a number of different solutions have been devised for
Received April 20, 2009.
Address correspondence to Franco Ghelfi, Dipartimento di Chimica, Universita degli Studi di
`
Modena e Reggio Emilia, via Campi 183, I-41100 Modena, Italy. E-mail: franco.ghelfi@unimore.it
1040

ALIPHATIC CHAETOMELLIC ANHYDRIDES
1041
Scheme 1. pH-dependent switch between chaetomellic anhydrides 3 and the corresponding open forms.
its preparation.[2,5–7] Almost exclusively, the proposed routes have been addressed to
the synthesis of the anhydride 3a, a structure more easy to manipulate than the cor-
responding diacid 1a. The strategies to build the heterocycle 3a can be grouped into
two general categories: (i) alkylation of maleic precursors and (ii) construction of the
pivotal 1,4-dicarbonyl assembly.
A few year ago, we devised an interesting way to prepare CAA, where the
anhydride nucleus was constructed through the ATRC (atom-transfer radical cycli-
zation) of N-(benzyl)-N-(3-chloro-2-propenylamino)-2,2-dichlorohexadecanamide
5 and the functional rearrangement of the intermediate trichloro c-lactam 6
(Scheme 2, path I).[6] The route was streamlined by replacing the benzyl substituent,
attached to the amide nitrogen, with the 2-pyridyl group. In this way, the direct con-
version of the adduct from the functional rearrangement (FR) of 9, to give 3a under
acid hydrolytic conditions, was achieved (Scheme 2, path II).[7]
However, the use of 1,3-dichloropropene limits the scope of these methods
because it is the only commercially available c-chloroallyl chloride and the prep-
aration of higher homologs is not straightforward.[8]
Scheme 2. (a) CuCl-TMEDA, CH3CN, argon, 60 ꢀC, 20 h; (b) (1) Na0, MeOH=ether, 25 ꢀC, 20 h; (2) Hþ=
H2O; (c) (1) KOH, MeOH=THF, reflux, 2 h; (2) Hþ=H2O; (d) (1) Na0, MeOH=ether, 25 ꢀC, 20 h; and (2)
H2SO4 4 N, 110 ꢀC, 2 h.

1042
F. GHELFI ET AL.
Scheme 3. (a) CuCl-TMEDA, toluene, argon, 60 ꢀC, 24 h; (b) Na0, toluene=MeOH, 25 ꢀC, 24 h; (c)
H2SO4=H2O, 110 ꢀC, 3 h; (d) one-pot procedure: (1) Na0, toluene=MeOH, 25 ꢀC, 24 h; (2) H2SO4=H2O,
110 ꢀC, 3 h; (e) MnO2, CH2Cl2, 25 ꢀC, 20 h; and (f) H2SO4=H2O, 110 ꢀC, 4 h.
To solve these problems, we recently developed a new process for the prep-
aration of 2,3-disubstituted maleic anhydrides starting from the much more easy
obtainable 2-allylamino-pyridine.[9] The preparation of secondary c-nonhalogenated
allylamines is in fact more advantageous, because a substantial number of commer-
cially available starting materials and synthetic strategies can be employed.
Now, as a part of a project aimed at identifying novel biological active maleic
acid (to tackle acute ischemic renal or cerebral insults), we report the application of
the new procedure (Scheme 3) to the syntheses of CAA 3a and its analog 3b on a
preparative scale.
RESULTS AND DISCUSSION
First, the ATRC of amide 10a was examined. To secure a high cis=trans ratio,
the transformation was run at 60 ꢀC. A number of different ligands [N,N,N0,N0-
tetramethylethylenediamine (TMEDA), N,N,N0,N00,N000-pentamethyldiethylenetria-
mine (PMDETA), or 2,20-bipyridyl (BP)]=solvents (toluene, acetonitrile, or CH2Cl2)
were tested. The best results were obtained using TMEDA=toluene or TMEDA=
acetonitrile—in both cases the lactam 11a was isolated in excellent yield (95–97%)
with a cis=trans ratio of 9:1. The next step, the FR of the dichloro-c-lactam 11a
to the 5-methoxy-1,5-dihydro-2H-pyrrol-2-one 12a, gave the greatest yield (84%)
when using a mixture of toluene=CH3OH=CH3ONa.
Subsequent hydrolysis of 12a to obtain the more easy oxidizable 5-hydroxy-
1,5-dihydro-2H-pyrrol-2-one 13a was achieved using H2SO4=H2O (yield 81%). In
contrast to the conditions reported in Scheme 3, the reaction was undertaken at

ALIPHATIC CHAETOMELLIC ANHYDRIDES
1043
110 ꢀC under a stream of argon to remove the methanol released in the reaction
mixture. The oxidation of 13a with MnO2, as expected, gave the maleimide 14a in
good yield (80%). This reagent is particularly attractive from an industrial point
of view because of a number of helpful properties: low toxicity, low cost, easy hand-
ling, commercial availability, and recyclability.[10] The synthetic path was finally
completed by the hydrolysis of 14a with H2SO4=H2O at 110 ꢀC, which secured
CCA 3a in an overall yield of 45% from 10a.
Our attention was then turned to the preparation of 3b, an analog of 3a with a
C16 aliphatic chain. The ATRC of amide 10b proceeded smoothly to give the
dichloro-c-lactam 11b (yield 96%), under the same conditions as those described
for the reaction of 10a. Then, to shorten the reaction path, we considered the appeal-
ing opportunity to integrate the FR of 11b and the subsequent hydrolysis step to
give 13b in a one-pot process (see Experimental). The intermediate 5-hydroxy-1,5-
dihydro-2H-pyrrol-2-one 13b was thus isolated, with our satisfaction, in 70% yield.
The oxidation of 13b, with MnO2 (yield 82%), and the following hydrolysis of 14b,
with H2SO4=H2O, afforded 3b was in a respectable overall yield of 48% from 10b.
Finally, we tested the viability of a complementary strategy in which the methyl
substituent of 3 is introduced by the acid reactant and the long aliphatic chain is
added through the allylamino moiety.
To examine this, the model substrate N-benzyl-N-[(E)-2-hexenyl)]-2,2-dichloro-
propanamide 15 was prepared and subjected to ATRC (Scheme 4). However, the
reaction proceeded with unsatisfactory stereoselectivity, affording the dichloro-c-
lactam 16 as a 66=34 cis=trans mixture of four diastereomers [cis-16 (74 þ 26) and
trans-16 (83 þ 17)]. It was not possible to improve the cis=trans ratio; evidently,
a large substituent at C4 experiences a similar steric interaction with the Cl or
the CH3 group at position C3. Because the 5-methoxy-1,5-dihydro-2H-pyrrol-2-
ones 17 can only derive from the FR of the cis-dichloro-c-lactams 16,[9,11] it is
Scheme 4. (a) CuCl-TMEDA, CH3CN, argon, 60 ꢀC, 24 h; (b) Na0, toluene=MeOH, 25 ꢀC, 24 h.

1044
F. GHELFI ET AL.
clear that the synthesis of 3 along this way will suffer a fatal efficiency loss, thus
losing any appeal.
CONCLUSION
In summary, CAA 3a and its larger analog 3b were obtained from amides 10a,b
[produced from the reactions of 2,2-dichloropalmitic and 2,2-dichlorostearic acids
with 2-(2-propenylamino)pyridine] in a reasonable global yield of 45–50%, a value
certainly improvable because no effort was made to optimize the individual steps.
As the starting materials and all the intermediates were obtained using simple, econ-
omic, and high-yielding procedures, this new method is well suited for large-scale
preparations. The alternative approach, in which the methyl substituent of the target
anhydride is introduced by the carboxylic acid reactant and the long aliphatic chain
is added through the allylamino moiety, proved unviable.
EXPERIMENTAL
General Information
Reagents and solvents were standard-grade commercial products, purchased
from Aldrich, Acros, Fluka, or RdH and used without further purification. The
silica gel used for flash chromatography was silica gel 60 (Merck, 0.040–0.063 mm).
2,2-Dichloropalmitic acid, 2,2-dichlorostearic acid, and 2,2-dichloropropanoyl chlo-
ride acids were prepared according to given protocols.[6,7,11] (2-Propenylamino)pyri-
dine was prepared by amino-de-chlorination of 2-chloropyridine with allylamine,[9]
whereas (E)-N-benzylhex-2-en-1-amine was obtained by N-alkylation of benzylamine
with (E)-1-chlorohex-2-ene, following the procedure of Ince et al.[12] The acylations of
2-(2-propenylamino)pyridine with 2,2-dichloropalmitic acid or 2,2-dichlorostearic
acid, and of (E)-N-benzylhex-2-en-1-amine with 2,2-dichloropropanoyl choride, were
carried out by adapting earlier methods.[7] 1H NMR, infrared (IR), and mass spectra
(MS) were recorded on Bruker DPX 200 and Bruker Avance 400, Perkin Elmer 1600
Series Fourier transform (FT)–IR, and HP 5890 GC-HP 5989A MS instruments,
respectively. The structural assignment, were determined for compounds 11, 12, 16,
17, and 18 by heteronuclear H,C inverse-detection NMR correlation techniques
and for 11, 16, and 18 also by homonuclear nuclear Overhauser enhancement.
N-(2-Pyridyl)-3-chloro-4-chloromethyl-3-tetradecyl-2-pyrrolidinone
(11a)
CuCl (0.45 g, 4.5 mmol) and the 2,2-dichloroamide 10a (39.74 g, 90 mmol) were
weighed in a Schlenk tube fitted with a pierceable septum (blocked by a screw cap)
and a magnetic stirrer bar. Toluene (60 mL) and TMEDA (1351 mL, 9 mmol) were
then added under argon. The mixture was stirred at 60 ꢀC and after 24 h diluted with
H2O (60 mL), then extracted with CH2Cl2 (3 ꢁ 30 mL). The combined organic layers
were concentrated, and the crude product was purified by flash chromatography on
silica gel, eluting with petroleum ether (bp 40–60 ꢀC)=diethyl ether gradient (from

ALIPHATIC CHAETOMELLIC ANHYDRIDES
1045
10=0 to 8=2). This gave 38.55 g (97%) of 11a as an 89=11 (1H NMR spectrum)
mixture of cis=trans-diastereomers; white powder.
1H NMR (400 MHz, CDCl3): (cis) d ¼ 0.88 (t, J ¼ 6.9 Hz, 3 H, CH3), 1.22–1.40
[m, 23 H, C3-CH2CH(CH2)11], 1.52 (m, 1H, C3-CH2CH), 2.22 (m, 2H, C3-CH2),
2.85 (m, 1 H, C4-H), 3.70 (dd, J ¼ 11.4, 9.3 Hz, 1 H, C5-H), 3.77 (dd, J ¼ 11.3,
8.9 Hz, 1 H, CHCl), 3.90 (dd, J ¼ 11.3, 5.2 Hz, 1 H, CHCl), 4.52 (dd, J ¼ 11.4,
7.3 Hz, 1 H, C5-H), 7.10 (dd, J ¼ 7.1, 5.3 Hz, 1 H, H5py), 7.73 (td, J ¼ 7.9, 1.8 Hz,
1 H, H4py), 8.39 (m, 2 H, H3,6py); (trans) d ¼ 0.88 (t, J ¼ 6.9 Hz, 3 H, CH3),
1.22–1.40 [m, 22 H, (CH2)11], 1.50 (m, 1 H, C3-CH2CH), 1.75 (m, 1 H, C3-CH2CH),
1.77 (m, 1 H, C3-CH), 2.13 (m, 1 H, C3-CH), 3.03 (m, 1 H, C4-H), 3.51 (dd, J ¼ 11.2,
10.0 Hz, 1 H, CHCl), 3.78 (dd, J ¼ 11.2, 4.0 Hz, 1 H, CHCl), 4.12 (dd, J ¼ 11.7,
4.5 Hz, 1 H, C5-H), 4.35 (dd, J ¼ 11.7, 6.6 Hz, 1 H, C5-H), 7.10 (dd, J ¼ 7.1,
5.3 Hz, 1 H, H5py), 7.73 (td, J ¼ 7.9, 1.8 Hz, 1 H, H4py), 8.39 (m, 2 H, H3,6py).
13C NMR (100 MHz, CDCl3): (cis) d ¼ 14.1, 22.7, 25.2, 29.29, 29.33, 29.5, 29.57,
29.61, 29.63, 29.64, 29.7, 31.9, 37.5, 42.47, 42.53, 47.8, 74.1, 115.0, 120.4, 137.9,
147.6, 151.0, 170.0; (trans) d ¼ 14.1, 22.7, 24.1, 29.29, 29.33, 29.47, 29.52, 29.57,
29.61, 29.63, 29.64, 29.7, 31.9, 33.7, 42.1, 46.9, 47.5, 73.4, 115.0, 120.4, 138.0,
147.6, 151.0, 170.0. IR (KBr): 1711 (C O) cmꢂ1. MS (EI, 70 eV): m=z (%) ¼ 440
=
(3) [M]þ, 439 (5), 405 (66), 369 (9), 355 (15), 244 (94), 223 (21), 195 (100). Anal. calcd.
for C24H38Cl2N2O: C, 65.29; H, 8.68; N, 6.35. Found: C, 65.31; H, 8.70; N, 6.35.
N-(2-Pyridyl)-3-chloro-4-chloromethyl-3-hexadecyl-2-pyrrolidinone
(11b)
Following the procedure for the preparation of 11a, after flash chromato-
graphy of the crude product on silica gel using a petroleum ether (bp 40–60 ꢀC)=
diethyl ether gradient (from 10=0 to 8=2) as eluant, the 2,2-dichloroamide 10b
(39.91 g, 85 mmol) gave 38.31 g of 11b (96%), as a 92=8 (1H NMR spectrum) mixture
of cis=trans-diastereomers; white powder.
1H NMR (400 MHz, CDCl3): (cis) d ¼ 0.87 (t, J ¼ 6.8 Hz, 3 H, CH3), 1.00–1.40
[m, 27 H, C3-CH2CH(CH2)13], 1.42–1.60 (m, 1 H, C3-CH2CH), 2.05–2.30 (m, 2 H,
C3-CH2), 2.85 (m, 1 H, C4-H), 3.69 (dd, J ¼ 11.3, 9.6 Hz, 1 H, C5-H), 3.76
(dd, J ¼ 11.2, 8.8 Hz, 1 H, CHCl), 3.90 (dd, J ¼ 11.2, 5.2 Hz, 1 H, CHCl), 4.51
(dd, J ¼ 11.3, 7.4 Hz, 1 H, C5-H), 7.09 (ddd, J ¼ 7.3, 4.9, 1.1 Hz, 1 H, H5py), 7.72
(ddd, J ¼ 8.3, 7.3, 2.1 Hz, 1 H, H4py), 8.35–8.43 (m, 2 H, H3,6py); (trans) d ¼ 0.87 (t,
J ¼ 6.8 Hz, 3 H, CH3), 1.00–1.40 [m, 26 H, (CH2)13], 1.42–1.60 (m, 1 H, C3-CH2CH),
1.70–1.85 (m, 2 H, C3-CHCH), 2.00–2.20 (m, 1 H, C3-CH), 3.02 (m, 1 H, C4-H), 3.50
(dd, J ¼ 11.6, 9.2 Hz, 1 H, CHCl), 3.70–3.80 (m, 1 H, CHCl), 4.12 (dd, J ¼ 11.6, 4.4 Hz,
1 H, C5-H), 4.35 (dd, J ¼ 11.6, 6.4 Hz, 1 H, C5-H), 7.09 (ddd, J ¼ 7.3, 4.9, 1.1 Hz, 1 H,
H5py), 7.72 (ddd, J ¼ 8.3, 7.3, 2.1 Hz, 1 H, H4py), 8.35–8.43 (m, 2 H, H3,6py). 13C
NMR (100 MHz, CDCl3): (cis) d ¼ 14.1, 22.6, 25.2, 29.26, 29.31, 29.45, 29.54, 29.58,
29.62, 29.64, 31.9, 37.5, 42.4, 42.5, 47.7, 74.0, 114.9, 120.3, 138.0, 147.5, 150.9,
169.9; (trans) d ¼ 14.1, 22.6, 24.0, 29.26, 29.31, 29.45, 29.54, 29.58, 29.62, 29.64,
31.9, 33.6, 42.1, 46.8, 47.5, 73.3, 114.9, 120.3, 138.1, 147.4, 150.9, 169.9. IR (KBr):
1711 (C O) cmꢂ1. MS (EI, 70 eV): m=z (%) ¼ 468 (2) [M]þ, 467 (2), 453 (12), 439
=
(19), 433 (59), 383 (13), 244 (94), 195 (100). Anal. calcd. for C26H42Cl2N2O: C,
66.51; H, 9,02; N, 5,97. Found: C, 66.30; H, 8.99; N, 5.98.

1046
F. GHELFI ET AL.
5-Methoxy-4-methyl-1-(2-pyridyl)-3-tetradecyl-1,5-dihydro-2H-
pyrrol-2-one (12a)
Toluene=CH3OH 1=1 (140 mL) and 11a (30.91 g, 70 mmol) were added to a
Schlenk tube fitted with a pierceable septum blocked by a screw cap. The solution
was thermostated at 25 ꢀC. Apart, in a second Schlenk tube, Na0 (4.83 g, 210 mmol)
was carefully dissolved in CH3OH (70 mL), and when the effervescence ceased, the
alkaline solution was thermostated at 25 ꢀC, after which it was cannulated into the
first Schlenk tube. The reaction mixture was stirred for 24 h. Then it was diluted with
water (100 mL) and extracted with CH2Cl2 (3 ꢁ 30 mL). The combined organic layers
were collected and concentrated. Flash chromatography of the crude product on sil-
ica gel using a petroleum ether (bp 40–60 ꢀC)=diethyl ether gradient (from 10=0 to
7=3) as eluant afforded 23.56 g of 12a (84%); colorless oil.
1H NMR (400 MHz, CDCl3): d ¼ 0.88 (t, J ¼ 6.9 Hz, 3 H, CH3), 1.22–1.37 [m,
22 H, (CH2)11], 1.52 (qn, J ¼ 7.0 Hz, 2 H, C3-CH2CH2), 2.01 (s, 3 H, C4-CH3), 2.32
(m, 2 H, C3-CH2), 3.10 (s, 3 H, OCH3), 6.28 (s, 1 H, C5-H), 7.03 (ddd, J ¼ 7.4, 5.0,
1.0 Hz, 1 H, H5py), 7.72 (ddd, J ¼ 8.4, 7.4, 1.9 Hz, 1 H, H4py), 8.17 (dt, J ¼ 8.4,
1.0 Hz, 1 H, H3py), 8.42 (ddd, J ¼ 5.0, 1.9, 1.0 Hz, 1 H, H6py). 13C NMR
(100 MHz, CDCl3): d ¼ 11.6, 14.1, 22.6, 23.4, 28.3, 29.3, 29.4, 29.50, 29.53, 29.60,
29.63, 31.9, 50.4, 87.3, 114.9, 119.3, 135.2, 138.0, 147.7, 147.9, 150.2, 169.9. IR (film):
1713 (C O) cmꢂ1. MS (EI, 70 eV): m=z (%) ¼ 385 (46) [M-15]þ, 370 (59), 227 (3), 213
=
(19), 187 (100). Anal. calcd. for C25H40N2O2: C, 74.95; H, 10.06; N, 6.99. Found: C,
74.89; H, 10.03; N, 7.10.
5-Hydroxy-4-methyl-1-(2-pyridyl)-3-tetradecyl-1,5-dihydro-2H-
pyrrol-2-one (13a)
5-Methoxy-1,5-dihydro-2H-pyrrol-2-one 12a (20.83 g, 52 mmol), H2SO4 2 M
(26 mL), and H2O (26 mL) were added to a double-necked, round-bottomed flask
(100 mL) fitted with a Liebig condenser bearing a needle valve and a rubber septum
adapter. The vigorously stirred mixture was heated to 110 ꢀC for 3 h under a slight
stream of argon to remove the methanol released by 12a, after which time it was
neutralized with NaOHaq 1 M and extracted with CH2Cl2 (3 ꢁ 30 mL). The com-
bined organic layers were concentrated under vacuum. Flash chromatography of
the crude product on silica gel, using a petroleum ether (bp 40–60 ꢀC)=diethyl ether
gradient (from 10=0 to 7=3) as eluant, gave 16.28 g of 13a (81%); white powder. Mp
43–45 ꢀC.
1H NMR (400 MHz, CDCl3): d ¼ 0.87 (t, J ¼ 6.9 Hz, 3 H, CH3), 1.21–1.38
[m, 22 H, C3-CH2CH2(CH2)11], 1.51 (qn, J ¼ 7.0 Hz, 2 H, C3-CH2CH2), 2.06 (s,
3 H, C4-CH3), 2.30 (m, 2 H, C3-CH2), 5.71 (broad s, 1 H, OH), 6.00 (s, 1 H,
C5-H), 7.00 (ddd, J ¼ 7.5, 5.0, 1.0 Hz, 1 H, H5py), 7.72 (ddd, J ¼ 8.5, 7.5,
1.9 Hz, 1 H, H4py), 8.25 (ddd, J ¼ 5.0, 1.9, 1.0 Hz, 1 H, H6py), 8.38 (dt, J ¼ 8.5,
1.0 Hz, 1 H, H3py). 13C NMR (100 MHz, CDCl3): d ¼ 11.4, 14.1, 22.6, 23.3,
28.2, 29.3, 29.4, 29.51, 29.53, 29.6, 29.7, 31.9, 83.5, 113.1, 118.6, 134.3, 138.8,
146.7, 149.4, 151.5, 169.4. IR (KBr): 3438 (OH), 1715 (C O) cmꢂ1. MS (EI,
=
70 eV): m=z (%) ¼ 386 (10) [M]þ, 385 (16), 368 (9), 229 (9), 215 (29), 203 (100),
189 (72). Anal. calcd. for C24H38N2O2: C, 74.57; H, 9.91; N, 7.25. Found: C,
74.48; H, 9.92; N, 7.27.

ALIPHATIC CHAETOMELLIC ANHYDRIDES
1047
3-Hexadecyl-5-Hydroxy-4-methyl-1-(2-pyridyl)-1,5-dihydro-2H-
pyrrol-2-one (13b)
Toluene=CH3OH 1=1 (160 mL) and 11b (37.56 g, 80 mmol) were added to a
double-necked, round-bottomed flask (250 mL) fitted with a Liebig condenser bear-
ing a needle valve connected to a CaCl2 tube and a rubber septum adapter. The
solution was thermostated at 25 ꢀC. Apart, in a Schlenk tube, Na0 (5.52 g,
240 mmol) was carefully dissolved in CH3OH (70 mL), and when the effervescence
ceased, the alkaline solution was thermostated at 25 ꢀC, after which it was cannu-
lated into the round-bottomed flask. The reaction mixture was stirred for 24 h.
Then the CaCl2 tube was dismantled, and the solvent was evacuated (under
reduced pressure) and replaced by H2SO4 2 M (85 mL). The vigorously stirred mix-
ture was heated to 110 ꢀC for 3 h under a slight stream of argon to remove the
methanol released in the reaction mixture by 12b, after which time it was neutra-
lized with NaOHaq 1 M and extracted with CH2Cl2 (3 ꢁ 30 mL). The combined
organic layers were concentrated under vacuum. Flash chromatography of the
crude product on silica gel, using a petroleum ether (bp 40–60 ꢀC)=diethyl ether
gradient (from 10=0 to 8=2) as eluant, gave 23.22 g of 13b (70%); white powder.
Mp 58–59 ꢀC.
1H NMR (200 MHz, CDCl3): d ¼ 0.88 (t, J ¼ 6.4 Hz, 3 H, CH3), 1.15–1.40 [m,
26 H, (CH2)13], 1.52 (qn, J ¼ 7.3 Hz, 2 H, C3-CH2CH2), 2.07 (s, 3 H, C4-CH3), 2.31
(t, J ¼ 7.4 Hz, 2 H, C3-CH2), 5.64 (broad s, 1 H, OH), 5.97 (s, 1 H, C5-H), 7.00 (ddd,
J ¼ 7.4, 5.0, 0.9 Hz, 1 H, H4py), 7.71 (ddd, J ¼ 8.5, 7.4, 1.9 Hz, 1 H, H5py), 8.26 (ddd,
J ¼ 5.0, 1.9, 0.9 Hz, 1 H, H6py), 8.38 (dt, J ¼ 8.5, 0.9 Hz, 1 H, H3py). 13C NMR
(50 MHz, CDCl3): d ¼ 11.4, 14.1, 22.7, 23.3, 28.2, 29.3, 29.4, 29.52, 29.54, 29.6,
29.7, 31.9, 83.5, 113.1, 118.6, 134.3, 138.6, 146.9, 149.4, 151.7, 169.4. IR (KBr):
3406 (OH), 1717 (C O) cmꢂ1. MS (EI, 70 eV): m=z (%) ¼ 414 (17) [M]þ, 413 (20),
=
396 (16), 213 (11), 203 (100), 189 (76). Anal. calcd. for C26H42N2O2: C, 75.32; H,
10.21; N, 6.76. Found: C, 75.41; H, 10.20; N, 6.77.
N-(2-Pyridyl)-3-methyl-4-tetradecylmaleimide (14a)
In a 25-mL round-bottomed flask, 5-hydroxy-3-pyrrolin-2-one 13a (15.46 g,
40 mmol), MnO2 (80 g), and CH2Cl2 (50 mL) were added in sequence. The reaction
mixture was vigorously stirred at room temperature and monitored by gas chroma-
tography. After 20 h the mixture was filtered, and the filtrate was evaporated under
reduced pressure. Flash chromatography of the crude product on silica gel using a
petroleum ether (bp 40–60 ꢀC)=diethyl ether gradient (from 10=0 to 1=1) as eluant
afforded 12.31 g (80%) of the N-(2-pyridyl)-3-methyl-4-tetradecylmaleimide (14a);
white powder. Mp 66–68 ꢀC.
1H NMR (200 MHz, CDCl3): d ¼ 0.88 (t, J ¼ 6.9 Hz, 3 H, CH3), 1.20–1.41 [m,
22 H, C3-CH2CH2(CH2)11], 1.59 (qn, J ¼ 7.1 Hz, 2 H, C3-CH2CH2), 2.06 (s, 3 H,
C4-CH3), 2.47 (t, J ¼ 7.5 Hz, 2 H, C3-CH2), 7.28 (ddd, J ¼ 7.5, 4.9, 1.0 Hz, 1H,
H5py), 7.34 (dt, J ¼ 8.1, 1.0 Hz, 1 H, H3py), 7.81 (ddd, J ¼ 8.1, 7.6, 1.9 Hz, 1 H,
H4py), 8.61 (ddd, J ¼ 4.9, 1.9, 1.0 Hz, 1 H, H6py). 13C NMR (50 MHz, CDCl3):
d ¼ 8.7, 14.0, 22.6, 23.8, 28.1, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 121.1, 122.7, 137.6,
138.0, 141.7, 146.3, 149.3, 169.9, 170.2. IR (film): 1709 (C O) cmꢂ1. MS (EI,
=

1048
F. GHELFI ET AL.
70 eV): m=z (%) ¼ 384 (16) [M]þ, 369 (6), 229 (23), 215 (84), 202 (100). Anal. calcd.
for C24H36N2O2: C, 74.96; H, 9.44; N, 7.28. Found: C, 74.95; H, 9.44; N, 7.30.
N-(2-Pyridyl)-4-hexadecyl-3-methyl-maleimide (14b)
Following the procedure for the preparation of 14a, after flash chromato-
graphy of the crude product on silica gel using a petroleum ether (bp 40–60 ꢀC)=
diethyl ether gradient (from 10=0 to 1=1) as eluant, the 5-hydroxy-1,5-dihydro-2H-
pyrrol-2-one 13b (22.39 g, 54 mmol) gave 18.27 g of 14b (82%); pale yellow powder.
Mp 88–89 ꢀC.
1H NMR (200 MHz, CDCl3): d ¼ 0.88 (t, J ¼ 6.4 Hz, 3 H, CH3), 1.15–1.40 [m,
26 H, (CH2)13], 1.60 (qn, J ¼ 7.6 Hz, 2 H, C3-CH2CH2), 2.06 (s, 3 H, C4-CH3), 2.47
(t, J ¼ 7.5 Hz, 2 H, C3-CH2), 7.20–7.40 (m, 2 H, H3,4py), 7.82 (dt, J ¼ 7.8, 1.9 Hz, 1
H, H5py), 8.62 (broad dd, J ¼ 4.9, 1.9 Hz, 1 H, H6py). 13C NMR (50 MHz, CDCl3):
d ¼ 8.8, 14.0, 22.6, 23.8, 28.1, 29.25, 29.30, 29.4, 29.5, 29.60, 29.64, 31.9, 121.1, 122.7,
137.6, 138.1, 141.8, 146.3, 149.2, 169.9, 170.2. IR (KBr): 1708 (C O) cmꢂ1. MS (EI,
=
70 eV): m=z (%) ¼ 412 (40) [M]þ, 229 (24), 215 (79), 202 (100), 189 (21). Anal. calcd.
for C26H40N2O2: C, 75.68; H, 9.77; N, 6.79. Found: C, 75.95; H, 9.81; N, 6.80.
Chaetomellic Anhydride A (3a)
N-(2-Pyridyl)-3-methyl-4-tetradecylmaleimide 14a (11.54 g 30 mmol), H2SO4
2 M (20 mL), and H2O (20 mL) were added to a Schlenk tube. Under vigorous stir-
ring, the mixture was heated to 110 ꢀC for 4 h, after which time it was extracted with
CH2Cl2 (3 ꢁ 30 mL). The combined organic layers were concentrated under vacuum.
Flash chromatography of the crude product on silica gel, using a petroleum ether (bp
40–60 ꢀC)=diethyl ether gradient (from 10=0 to 1=1) as eluant, gave 7.87 g of CAA 3a
(85%) as a pale yellow oil and 1.38 g of starting 14a (12%). The spectroscopic features
of the isolated 3a were in agreement with the values reported in the literature.[9]
3-Hexadecyl-4-methylmaleicanhydride (3b)
Following the procedure for the preparation of 3a, after flash chromatography
of the crude product on silica gel using a petroleum ether (bp 40–60 ꢀC)=diethyl ether
gradient (from 10=0 to 1=1) as eluant, the maleimide 14b (17.74 g, 43 mmol) gave
12.59 g of 3b (87%); white powder. Mp 40–41 ꢀC.
1H NMR (200 MHz, CDCl3): d ¼ 0.88 (t, J ¼ 6.5 Hz, 3 H, CH3), 1.15–1.40 [m,
28 H, C3-CH2CH2(CH2)13], 1.58 (qn, J ¼ 7.1 Hz, 2 H, C3-CH2), 2.06 (t, J ¼ 1.7 Hz,
3 H, C4-CH3), 2.45 [t, J ¼ 6.7 Hz, 2 H, C(3)CH2]. 13C NMR (50 MHz, CDCl3):
d ¼ 9.4, 14.0, 22.6, 24.4, 27.5, 29.2, 29.3, 29.4, 29.5, 29.57, 29.61, 29.64, 31.9,
140.4, 144.7, 165.8, 166.2. IR (KBr): 1766 (C O) cmꢂ1. MS (EI, 70 eV): m=z
=
(%) ¼ 336 (11) [M]þ, 150 (25), 126 (100). Anal. calcd. for C21H36O3: C, 74.95; H,
10.78. Found: C, 74.89; H, 10.81.
N-(Benzyl)-3-chloro-4-(1-chlorobutyl)-3-methyl-2-pyrrolidinone (16)
Following the procedure for the preparation of 11a, after flash chromatogra-
phy of the crude product on silica gel using a petroleum ether (bp 40–60 ꢀC)=diethyl

ALIPHATIC CHAETOMELLIC ANHYDRIDES
1049
ether gradient (from 10=0 to 7=3) as eluant, the 2,2-dichloroamide 15 (10.06 g,
32 mmol) gave 8.75 g of 16 (87%) as a 66=34 (1H NMR spectrum) mixture of two
cis (74=26) and two trans (83=17) diastereomers; pale yellow oil.
1H NMR (400 MHz, CDCl3): (cis major) d ¼ 0.96 (t, J ¼ 7.3 Hz, 3 H,
CH2CH3), 1.51 (m, 1 H, CHCH3), 1.64 (m, 1 H, CHCH3), 1.71 (m, 1 H,
CHCH2CH3), 1.86 (s, 3 H, C3-CH3), 2.03 (m, 1 H, CHCH2CH3), 2.45 (m, 1 H,
C4-H), 3.11 (dd, J ¼ 10.5, 9.0 Hz, 1 H, C5-H), 3.43 (dd, J ¼ 10.5, 7.1 Hz, 1 H,
C5-H), 4.20 (m, 1 H, CHCl), 4.37 (d, J ¼ 14.7 Hz, 1 H, CHPh), 4.64 (d, J ¼ 14.7 Hz,
1 H, CHPh), 7.20–7.40 (m, 5 H, 5 CHAr); (cis minor) d ¼ 0.90 (t, J ¼ 7.3 Hz, 3 H,
CH2CH3), 1.46 (m, 1 H, CHCH3), 1.54 (m, 1 H, CHCH2CH3), 1.62 (m, 1 H,
CHCH3), 1.63 (m, 1 H, CHCH2CH3), 1.99 (s, 3 H, C3-CH3), 2.48 (m, 1 H,
C4-H), 2.94 (t, J ¼ 9.8 Hz, 1 H, C5-H), 3.16 (dd, J ¼ 9.8, 7.3 Hz, 1 H, C5-H), 4.23
(m, 1 H, CHCl), 4.34 (d, J ¼ 14.7 Hz, 1 H, CHPh), 4.67 (d, J ¼ 14.7 Hz, 1 H, CHPh),
7.20–7.40 (m, 5 H, 5 CHAr); (trans major) d ¼ 0.94 (t, J ¼ 7.4 Hz, 3 H, CH2CH3), 1.44
(m, 1 H, CHCH3), 1.64 (m, 1 H, CHCH3), 1.71 (s, 3 H, C3-CH3), 1.75 (m, 1 H,
CHCH2CH3), 1.89 (m, 1 H, CHCH2CH3), 2.86 (m, 1 H, C4-H), 3.05 (dd,
J ¼ 10.4, 6.3 Hz, 1 H, C5-H), 3.49 (dd, J ¼ 10.4, 7.7 Hz, 1 H, C5-H), 4.04 (m, 1 H,
CHCl), 4.41 (d, J ¼ 14.7 Hz, 1 H, CHPh), 4.59 (d, J ¼ 14.7 Hz, 1 H, CHPh),
7.20–7.40 (m, 5 H, 5 CHAr); (trans minor) d ¼ 0.85 (t, J ¼ 7.3 Hz, 3 H, CH2CH3),
1.31 (m, 1 H, CHCH2CH3), 1.34 (m, 1 H, CHCH3), 1.38 (m, 1 H, CHCH2CH3),
1.58 (m, 1 H, CHCH3), 1.74 (s, 3 H, C3-CH3), 2.99 (m, 1 H, C4-H), 3.06 (dd,
J ¼ 10.2, 4.9 Hz, 1 H, C5-H), 3.44 (dd, J ¼ 10.2, 7.2 Hz, 1 H, C5-H), 3.98 (m, 1 H,
CHCl), 4.47 (d, J ¼ 14.5 Hz, 1 H, CHPh), 4.51 (d, J ¼ 14.5 Hz, 1 H, CHPh),
7.20–7.40 (m, 5 H, 5 CHAr). 13C NMR (100 MHz, CDCl3): (cis major) d ¼ 13.2,
19.0, 26.8, 37.9, 47.1, 48.9, 51.1, 63.4, 68.3, 127.9, 128.1, 128.9, 135.4, 171.2; (cis
minor) d ¼ 13.4, 18.9, 26.4, 37.4, 46.8, 47.0, 51.7, 60.5, 70.2, 127.9, 128.1, 128.9,
135.4, 171.6; (trans major) d ¼ 13.3, 19.4, 21.3, 38.6, 46.6, 47.3, 51.5, 61.3, 68.7,
127.9, 128.1, 128.9, 135.4, 171.6; (trans minor) d ¼ 13.1, 19.6, 21.2, 35.8, 45.8, 47.3,
52.2, 60.6, 68.5, 127.9, 128.1, 128.9, 135.4, 171.6. IR (film): 1713 (C O) cmꢂ1. MS
=
(EI, 70 eV): m=z (%) ¼ 313 (3) [M]þ, 278 (67), 242 (7), 186 (51), 91 (100). Anal. calcd.
for C16H21Cl2NO: C, 61.15; H, 6,74; N, 4.46. Found: C, 61.32; H, 6.75; N, 4.46.
1-Benzyl-4-butyl-5-methoxy-3-methyl-1,5-dihydro-2H-pyrrol-2-one
(17)
Following the procedure for the rearrangement of 11a, after flash chromato-
graphy of the crude product on silica gel eluting with a petroleum ether (bp
40–60 ꢀC)=diethyl ether gradient (from 10=0 to 4=6), 16 (66=34 mixture of cis=trans
isomers, 2.51 g, 8 mmol) gave 1.01 g (46%) of 17 as pale yellow oil.
1H NMR (200 MHz, CDCl3): d ¼ 0.85 (t, J ¼ 6.9 Hz, 3 H, CH2CH3), 1.10–1.55
(m, 4 H, CH2CH2), 1.82 (s, 3 H, C3-CH3), 2.00–2.20 (m, 1 H, C4-CH), 2.20–2.40 (m,
1 H, C4-CH), 2.87 (s, 3 H, OCH3), 4.06 (d, J ¼ 14.7 Hz, 1 H, CHPh), 4.87 (d,
J ¼ 14.7 Hz, 1 H, CHPh), 5.03 (s, 1 H, C5-H), 7.10–7.30 (m, 5 H, 5 CHAr). 13C
NMR (50 MHz, CDCl3): d ¼ 8.6, 13.7, 22.7, 25.7, 30.1, 43.4, 49.2, 86.5, 127.4,
128.4, 128.6, 131.4, 137.4, 149.4, 171.1. IR (film): 1703 (C O) cmꢂ1. MS (EI,
=
70 eV): m=z (%) ¼ 273 (28) [M]þ, 242 (27), 201 (17), 180 (6), 91 (100). Anal. calcd.
for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.43; H, 8.50; N, 5.13.

1050
F. GHELFI ET AL.
N-(Benzyl)-4-butyliden-3-methoxy-3-methyl-2-pyrrolidinone (18), as pale
yellow oil, was also recovered (0.35 g, 16%).
1H NMR (200 MHz, CDCl3): d ¼ 0.83 (t, J ¼ 7.0 Hz, 3 H, CH2CH3), 1.10–1.70
(m, 4 H, CH2CH2), 1.84 (s, 3 H, C3-CH3), 3.12 (s, 3 H, OCH3), 3.63 (s, 2 H, C5-H2),
C
4.07 (t, J ¼ 6.5 Hz, 1 H, ¼CH), 4.52 (s, 2 H, CH2Ph), 7.10–7.30 (m, 5 H, 5 CHAr). 13
NMR (50 MHz, CDCl3): d ¼ 8.6, 13.7, 22.7, 25.7, 30.1, 43.4, 49.2, 86.5, 127.4, 128.4,
128.6, 131.4, 137.4, 149.9, 171.1. IR (film): 1685 (C O) cmꢂ1. MS (EI, 70 eV): m=z
=
(%) ¼ 273 (79) [M]þ, 242 (11), 230 (71), 186 (23), 91 (100). Anal. calcd. for
C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.85; H, 8.47; N, 5.13.
ACKNOWLEDGMENT
`
We thank the Ministero della Istruzione, Universita e Ricerca (MIUR), for
financial assistance.
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