A Simple and efficient route to chaetomellic anhydride A: A potent natural ras farnesyl-protein transferase inhibitor

Article abstract of DOI:10.1055/s-2004-829116

A new and efficient approach to chaetomellic anhydride A has been devised starting from 2,2-dichloropalmitic acid. This involves the atom transfer radical cyclization of an N-alkyl-N-(3-chloro-2-propenyl)amide followed by rearrangement of the resulting trichloro-pyrrolidin-2-one.

Full text of DOI:10.1055/s-2004-829116

1680
PAPER
A Simple and Efficient Route to Chaetomellic Anhydride A: A Potent Natural
Ras Farnesyl-Protein Transferase Inhibitor
S
imple andEffi
a
cient Route
u
to
C
haetom
r
ellic
A
nh
e
ydride
A
nt De Buyck,*a Rita Cagnoli,b Franco Ghelfi,*b Giulia Merighi,b Adele Mucci,b Ugo M. Pagnoni,b
Andrew F. Parsonsc
a
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, University of Gent, Coupure Links 653,
9000 Gent, Belgium
b
Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Fax +39(59)373543; E-mail: ghelfi.franco@unimo.it
c
Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom
Received 1 March 2004; revised 19 April 2004
sources. So far, nine routes have been devised for the
Abstract: A new and efficient approach to chaetomellic anhydride
preparation of this interesting product.3 In general, the
synthesis of anhydride 2a has been targeted since this
A has been devised starting from 2,2-dichloropalmitic acid. This in-
volves the atom transfer radical cyclization of an N-alkyl-N-(3-
compound is more easy to manipulate/isolate than diacid
1a. Anhydride 2a can also be easily hydrolysed to the bi-
ologically active dianion 3a using aqueous base [i.e., pH
> 7 (Scheme 1)].1a Recently, the dianion of chaetomellic
acid A (3a) has found application in characterizing the
FPP (farnesyl diphosphate) binding site in rubber trans-
ferase.4 The synthetic strategies investigated can be
grouped into two general categories: i) alkylation of ma-
leic precursors5a,5c–g and ii) assembly of the pivotal 1,4-di-
carbonyl group.5b,h,i In spite of the variety of methods
employed, all of the reported procedures suffer from one
or more of the following disadvantages: i) low yields, ii)
costly reagents, iii) unstable precursors and/or reactants,
iv) harmful solvents, and v) unwieldy protocols. As a re-
sult, these procedures are not well-suited for large scale
production, as evidenced by the high price of 1a, which is
sold by ICN or Calbio Chem at ca. 18000 /g.
chloro-2-propenyl)amide followed by rearrangement of the result-
ing trichloro-pyrrolidin-2-one.
Key words: amides, cyclisations, halogenation, pyrrolidinones,
radical reactions
Chaetomellic acid A (1a) is a natural substance which was
isolated in 1993 by the Singh’s research group, in the form
of anhydride 2a, from the fermentation extracts of the
coelomycete Chaetomella acutiseta (Scheme 1).1 The po-
tent and specific inhibition of ras farnesyl-protein
transferase (FPTase) by the dianion form 3a has attracted
the attention of laboratories involved in the development
of novel anticancer therapeutics.2
R
HOOC
COOH
R = CH2(CH2)12CH3
R
Owing to the appealing properties and uses of 1a–3a, the
design of more robust and facile synthetic approaches to
these molecules is of current interest. In this paper we re-
port a novel radical route to chaetomellic anhydride A
(2a). This involves the formation of the carbon-carbon
bond between the C(3) and C(4) positions of the furan-
2,5-dione ring.6
1a
R
OOC
COO
O
O
O
3a
2a
Scheme 1
The oncogene product Ras, which is synthesized in vivo,
is a protein that requires post-translational modification in
order to become biologically active and capable of trans-
forming mammalian cells. Since farnesylation has ap-
peared to be a critical modification in the Ras activation
process, inhibitors of the FPTase enzyme that catalyzes
this reaction might thus block ras-dependent tumorigene-
sis.3
Scheme 2
During our recent studies on the synthesis and reaction of
4-methyl-pyrrolidin-2-ones A chlorinated at the C(3) and
C(6) positions, we serendipitously discovered that when
treated with a solution of alkaline methoxide (in MeOH
under mild conditions), these compounds are transformed
into the N-substituted 5-methoxy or 5,5-dimethoxy-4-
methyl-3-pyrrolin-2-ones B (Scheme 2).7
Studies of structure-activity relationships and pharmaco-
logical tests have stimulated the development of chemical
syntheses for the production of larger quantities of chae-
tomellic acid A (1a) than that available from natural
SYNTHESIS 2004, No. 10, pp 1680–1686
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Advanced online publication: 23.06.2004
DOI: 10.1055/s-2004-829116; Art ID: Z04104SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Simple and Efficient Route to Chaetomellic Anhydride A
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The transformation involves a series of eliminations/sub- 3-chloro-2-propenylamine (4) as starting materials in a
stitutions that give rise to a remarkable functional rear- highly convergent approach.
rangement (FR), on considering that the starting oxidation
Attractive features of this strategy are the use of a radical
state of the molecule is preserved and the functionalities
cyclization to efficiently construct the substituted 5-mem-
repositioned. In practice two or three of the C–Cl groups
bered ring, the elegant functional rearrangement of the re-
at the C(3) and C(6) positions of A are replaced by an alk-
sulting pyrrolidinone and the handling of all of the
ene at C(3)–C(4) and one or two methoxy groups at C(5).
functionalities in line with the ‘rule of maximum simplic-
This approach is particularly attractive because the start- ity’.10 Furthermore, the starting material 7a can be secured
ing polyhalogenated 2-pyrrolidinones A can be efficiently by a straightforward transformation of the corresponding
prepared from N-allyl a-perchloro amides C by an atom and inexpensive fatty alcohol 1-hexadecanol.11
transfer radical cyclization (ATRC) (Scheme 3). The
Having in stock a large amount of 2,2-dichlorooctanoic
transformation can be accomplished using redox
acid (7b),11 we chose to experiment the viability of the ret-
catalysts8 such as the complex formed on reaction of CuCl
rosynthetic plan by preparing the more simple target mol-
and N,N,N¢,N¢-tetramethylethylenediamine (TMEDA).9
ecule, 3-hexyl-4-methylmaleic anhydride (2b). This
natural product is a component of essential oils from
R'
N
Cl R'
N
Agropyrum repens,12a almond hulls and raisins.12b Owing
to the reduced size of 2b, the aliphatic side-chain at C(3)
is roughly half the size of that of 2a, it was believed that
the feasibility of the approach would be easier to monitor
analytically. In addition, the alkyl chain was believed to
be long enough to establish any problems associated with
the synthetic route to 2a.
Cl Cl
R
R
C
D
O
O
CuCl
CuCl2
Cl
R
Cl
R
Cl
O
O
N
N
R'
A
E
R'
Bn
N
Cl Cl
R
Scheme 3
Cl Cl
CO2H
a-b
Cl
Cl
R
R
Cl CHCl2
c
7b
8b (89%)
O
The ring closure is initiated by abstraction of an a-halogen
atom from C by CuCl/TMEDA and this is followed by a
5-exo-trig cyclization of the resulting electrophilic a-N-
allyl-carbamoyl radical D. This forms nucleophilic radical
E, which reacts to afford A on abstraction of a chlorine
atom from CuCl2/TMEDA. This last step results in the re-
generation of the copper(I) catalyst, which can initiate a
new reaction cycle (Scheme 3). There are a number of ad-
vantages of this type of radical cyclization: i) low cost of
the catalyst, ii) ease of work-up and iii) preservation of all
of the carbon-halogen groups in the cyclic product.
O
N
Bn
d
R
Cl
R
OCH3
OCH3
9b (97%)
(cis/trans = 72/28)
O
O
e
N
Bn
N
Bn
(E)-12b (17%)
10b (73%)
R
R
f,g
O
O
O
O
O
2b (67%)
N
R = CH2(CH2)4CH3
Bn
11b (99%)
(overall 42%)
Scheme 5 (a) (COCl)2, CH2Cl2, DMF, 23 °C, 2 h; (b) 4, pyridine,
23 °C, 1 h; (c) CuCl/TMEDA, MeCN, 25 °C, 20 h; (d) Na, MeOH, 25
°C, 20 h; (e) H+/H2O; (f) KOH, MeOH–THF, reflux, 2 h; (g) H+/H2O.
The synthetic path from dichloride 7b to anhydride 2b is
outlined in Scheme 5. At first, 2,2-dichlorooctanoic acid
(7b) was activated with oxalyl chloride and the resulting
acyl chloride treated with N-benzyl-3-chloro-2-propenyl-
amine (4) to afford amide 8b in good yield (89%).9e Then
8b was smoothly cyclized using CuCl/TMEDA in MeCN
to provide the trihalogenated pyrrolidin-2-one 9b (97%).
This was isolated as an inseparable mixture of cis-/trans-
isomers, in a ratio of 72:28 as indicated by the 1H NMR
spectrum.
Scheme 4
The ensuing functional rearrangement of 9b was accom-
plished using Na in MeOH (at 25 °C) following the liter-
ature procedure.7 However, along with the desired acetal
10b, isolated in a respectable yield of 73%, we also recov-
ered a moderate amount (17%) of the exo-dehydrohaloge-
nated pyrrolidin-2-one (E)-12b. This product was
believed to be an intermediate in the transformation of 9b
A retrosynthetic analysis of the anhydride of chaetomellic
acid 2a, which incorporates the FR and ATRC reactions,
is shown in Scheme 4. This involves the disconnection of
2a to give 2,2-dichloro-palmitic acid (7a) and N-benzyl-
Synthesis 2004, No. 10, 1680–1686 © Thieme Stuttgart · New York

1682
L. De Buyck et al.
PAPER
to 10b and so we subjected 12b to the FR reaction condi- the functional rearrangement so as to shorten the synthetic
tions but, surprisingly, only unreacted 12b was isolated. path and directly form the maleimide intermediate 11a:
Even at 80 °C no rearrangement was observed, however, this was recovered in excellent yield (89%). As observed
at this higher temperature some degradation of (E)-12b for the reaction of 9b, a small amount (9%) of (E)-12a was
occurred. Evidently this compound cannot be regarded as isolated, which arose from a parasitic exo-dehydro-halo-
an intermediate in the FR reaction of 9b to 10b. Acetal genation. The synthesis of chaetomellic anhydride A (2a)
10b was then quantitatively converted into N-benzyl-3- was completed by hydrolysis of 11a, using conditions re-
hexyl-4-methyl-maleimide (11b) by reaction with ported in the literature, which gave 2a in a respectable
CH3SO3H/H2O at 100 °C. Finally, on hydrolysis of 11b, yield of 70%.5e The overall yield of chaetomellic anhy-
using the procedure devised by Argade,5e we isolated the dride A (2a) using this 4-step approach was 55%
desired anhydride 2b. Overall, a good yield of 42% was (Scheme 7). Similar results were also obtained when the
achieved over the 5 steps from 7b.
N-benzyl group of allyl amine 4 was changed to the small-
er-sized N-propyl group.
Encouraged by the success of the strategy to prepare 3-
hexyl-4-methylmaleic anhydride 2b, we concentrated our
efforts on preparing chaetomellic anhydride A (2a). The
required starting material, 2,2-dichloropalmitic acid (7a),
was easily prepared on a large scale from 1-hexadecanol
(5a), following a two-step protocol.11a While the initial
oxidation-chlorination of alcohol 5a to give 2,2-dichloro-
hexadecanal (6a) was efficiently achieved using the clas-
sical system of Cl2/DMF·HCl (84%),11a for the ensuing
oxidation of the intermediate aldehyde 6a we devised a
novel and more practical method: this involved treatment
of 6a with Br2/NaOH to give 2,2-dichloropalmitic acid
(7a) in quantitative yield (Scheme 6).13
Bn
N
Cl Cl
R
Cl Cl
CO2H
a-b
Cl
R
R
Cl CHCl2
c
7a
8a (89%)
O
O
N
Bn
R
Cl
Cl
R
d-e
9a (99%)
(cis/trans = 89/11
O
O
O
N
Bn
N
Bn
11a (89%)
R
f-g
(E)-12a (9%)
O
O
O
2a (70%)
(overall 55%)
R = CH2(CH2)12CH3
H H
CH2OH
Cl Cl
CHO
6a (84%)
Cl Cl
CO2H
7a (99%)
(overall 83%)
a
b
Scheme 7 (a) (COCl)2, CH2Cl2, DMF, 23 °C, 2 h; (b) 4, pyridine,
23 °C, 1 h; (c) CuCl/TMEDA, MeCN–CH2Cl2, 60 °C, 20 h; (d) Na,
MeOH–Et2O, 25 °C, 20 h; (e) H+/H2O; (f) KOH, MeOH–THF, reflux,
2 h; (g) H+/H2O.
R
R
R
5a
R = CH2(CH2)12CH3
Scheme 6 (a) Cl2, DMF·HCl, CHCl3, 70 °C, 3 h; (b) Br2, NaOH,
In summary, a short, simple, convergent and efficient syn-
thesis of chaetomellic anhydride A (2a) has been devel-
oped from inexpensive precursors. This represents the
first application of the FR reaction (using CH3ONa/
MeOH) of polychlorinated g-lactams [generated by the
ATRC of N-(3-chloro-2-propenyl)-a-perchloroamides] to
a furan-2,5-dione target molecule. This novel synthetic
approach is well suited to the preparation of structural an-
alogues of 2a with various alkyl side-chains at the C(3)
position. Moreover, this methodology could be applied to
the synthesis of related natural products, with interesting
biological properties, including tyromicine A14 and roc-
cellic acid.15 Our studies on the synthesis of these and sim-
ilar molecules are well underway and will be reported in
due course.
CH2Cl2–H2O, 1.5 h.
The acid 7a was then converted into the corresponding
acyl chloride using oxalyl chloride and then immediately
treated with allyl amine 4 to furnish the amide 8a in high
yield (84%). For the subsequent cyclization, since 8a is
insoluble in MeCN (because of its lipophilicity), some
CH2Cl2 was added to MeCN to increase the solubility of
the substrate. In spite of the adjustment, the ATRC (medi-
ated by CuCl/TMEDA) worked well and afforded the ex-
pected g-lactam 9a in 99% yield as an inseparable pair of
cis/trans isomers in a ratio of 89:11. It should be noted
that the selectivity for the cis-isomer of 9a was much
higher than that observed in the cyclization of 8b to give
9b (72:28). This is due to the different reaction tempera-
tures (namely 60 °C and 25 °C) under which the ring clo-
sure of 8a and 8b were accomplished. Since the C(3)
stereocenter of lactams of type A is configurationally un-
stable under the reaction conditions, the higher the reac-
tion temperature the greater the equilibration between the
cis- (more stable) and trans-isomers (less stable).9d,e
Reagents and solvents were standard grade commercial products,
purchased from Aldrich, Acros, Fluka or RdH, and used without
further purification, except for MeCN and CH2Cl2 that were dried
over three batches of 3 Å sieves (5% w/v, 12 h). Chlorine (99.8%)
was supplied by Praxair. N-Benzyl-3-chloro-2-propenylamine (as a
58:42 mixture of E/Z isomers) was prepared by N-alkylation of ben-
zylamine with 1,3-dichloro-2-propene, following the procedure of
Shipman.16 2,2-Dichlorooctanoic acid was prepared according to a
literature procedure.11a 1H NMR, IR and MS spectra were recorded
on Bruker DPX 200 and Bruker AMX 400 (both used for NMR),
Perkin Elmer 1600 Series FTIR, and HP 5890 GC–HP 5989A MS
instruments, respectively. The structural assignment of compounds
Substrate solubility was also a problem when 9a was
treated with CH3ONa/MeOH in the following FR step. As
before, the problem was circumvented by the addition of
a less polar co-solvent, in this case Et2O, to the reaction
mixture. An acidic work-up was also adopted following
Synthesis 2004, No. 10, 1680–1686 © Thieme Stuttgart · New York

PAPER
Simple and Efficient Route to Chaetomellic Anhydride A
1683
9a, 9b, 12a and 12b was determined by homonuclear Nuclear Over-
hauser Enhancement and heteronuclear H,C inverse-detection
NMR correlation techniques. The direct and long-range H,C corre-
lations on 12a and 12b allowed us to unambiguously establish their
regiochemistry, whereas NOESY experiments enabled the configu-
ration of the double bond in 12a and 12b, and the relative stereo-
chemistry at the C(3) and C(4) carbons in 9a and 9b to be
determined.
J = 6.9, 10.6 Hz, 1 H), 4.35 (d, J = 14.7 Hz, 1 H), 4.69 (d, J = 14.7
Hz, 1 H), 5.90 (d, J = 4.2 Hz, 1 H), 7.33 (m, 5 H).
13C NMR [100 MHz, CDCl3, cis-diastereoisomer (72%)]: d = 14.00,
22.52, 25.02, 29.05, 31.40, 37.17, 47.05, 47.15, 49.40, 71.75, 71.91,
128.08, 128.11, 128.97, 135.21, 169.97.
13C NMR [100 MHz, CDCl3, trans-diastereoisomer (28%)]: d =
14.03, 22.52, 24.63, 29.07, 31.42, 33.14, 45.39, 47.13, 54.56, 70.59,
71.33, 128.06, 128.39, 128.85, 135.18, 169.99.
MS (EI) m/z = 340 (29) [M+ – 35], 293 (20), 291 (21), 256 (12), 208
(83), 91 (100).
Preparation of N-Benzyl-N-(3-chloro-2-propenyl)-2,2-dichloro-
octanamide (8b); Typical Procedure
2,2-Dichlorooctanoic acid (7b, 6.42 g, 30.1 mmol) was weighed in
a Schlenk tube fitted with a perforable septum (blocked by a screw
cap) and a CaCl2 tube on the side arm. Next, anhyd CH2Cl2 (16.5
mL) was added under Ar. The solution was thermostated at 23 °C,
and under stirring, DMF (50 mL) and (COCl)2 (5.23 mL, 60 mmol)
were injected using a syringe. The side arm stopcock was opened to
vent out any gases (CO, CO2 and HCl) produced during the reac-
tion. After 2 h, solvent and excess oxalyl chloride were removed un-
der reduced pressure. The crude acyl chloride was diluted with
anhyd CH2Cl2 (40 mL), then the solution, thermostated at 23 °C,
was treated with a solution of pyridine (3.64 mL, 45 mmol) and
amine 4 (8.08 g, 45 mmol) in CH2Cl2 (10 mL). The reaction mixture
was stirred for 1 h and then washed with HCl (2.5% w/v, 2 × 45
mL). Flash chromatography of the crude product on silica gel, using
petroleum ether (bp 40–60 °C)–Et2O (9.8:0.2) as eluant, gave amide
8b (10.07 g, 89%) as a mixture of E/Z stereoisomers.
Anal. Calcd for C18H24Cl3NO: C, 57.38; H, 6.42; N, 3.72. Found: C,
57.44; H, 6.53; N, 3.59.
Rearrangement of 2-Pyrrolidinone 9b; Typical Procedure
In a Schlenk tube fitted with a perforable septum (blocked by a
screw cap), MeOH (30 mL) and Na (1.84 g, 80 mmol) were added.
When the effervescence ceased, the solution was thermostated at 25
°C and 9b (7.54 g, 20 mmol) in MeOH (30 mL) was added by sy-
ringe. The reaction mixture was stirred for 20 h, then diluted with
water (10 mL), extracted with CH2Cl2 (2 × 80 mL) and the com-
bined organic layers concentrated. Flash chromatography of the
crude product on silica gel, using a petroleum ether (bp 40–60 °C)–
Et2O gradient (from 10:0–8.5:1.5), gave acetal 10b (4.84 g, 73%)
and the dehydrohalogenated g-lactam 12b (1.16 g, 17%).
N-Benzyl-3-hexyl-4-methyl-5,5-dimethoxy-3-pyrrolin-2-one
(10b)
Orange oil.
IR (film): 1711 (C=O) cm–1.
N-Benzyl-N-(3-chloro-2-propenyl)-2,2-dichlorooctanamide
(8b)
Colourless oil.
1H NMR (200 MHz, CDCl3): d = 0.85 (m, 3 H), 1.28 (br m, 6 H),
1.49 (m, 2 H), 1.74 (s, 3 H), 2.30 (t, J = 6.1 Hz, 2 H), 2.75 (s, 6 H),
4.33 (s, 2 H), 7.22 (m, 3 H), 5.45 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 9.02, 13.82, 22.38, 23.22, 28.35,
29.01, 31.34, 41.37, 50.42, 112.60, 127.10, 128.06, 129.40, 137.19,
137.54, 143.75, 169.71.
IR (film): 1660 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.93 (m, 3 H), 1.38 (m, 6 H), 1.76
(m, 2 H), 2.53 (m, 2 H), 3.7–5.2 (m br s, 4 H), 5.7–6.3 (br s, 2 H),
7.33 (m, 5 H).
MS (EI): m/z = 375 (1) [M+], 340 (29), 300 (32), 180 (23), 132 (13),
91 (100).
MS (EI): m/z = 331 (33) [M+], 316 (4), 300 (41), 284 (16), 272 (15),
261 (14), 226 (8), 211 (24), 91 (100).
Anal. Calcd for C18H24Cl3NO: C, 57.38; H, 6.42; N, 3.72. Found: C,
57.26; H, 6.51; N, 3.67.
Anal. Calcd for C20H29NO3: C, 72.47; H, 8.82; N, 4.23. Found: C,
72.37; H, 8.80; N, 4.37.
Cyclization of N-Benzyl-N-(3-chloro-2-propenyl)-2,2-dichloro-
octanamide (8b); Typical Procedure
(E)-N-Benzyl-3-chloro-4-chloromethylen-3-hexyl-2-pyrrolidi-
none (12b)
Colourless liquid.
IR (film): 1713 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 6.6 Hz, 3 H), 1.24 (br
m, 8 H), 2.09 (ddd, J = 5.5, 10.9, 13.6 Hz, 1 H), 2.33 (ddd, J = 4.8,
11.3, 13.6 Hz, 1 H), 3.83 (dd, J = 2.2, 15.5 Hz, 1 H), 3.96 (dd, J =
2.5, 15.5 Hz, 1 H), 4.52 (d, J = 14.4 Hz, 1 H), 4.60 (d, J = 14.4 Hz,
1 H), 6.46 (t, J = 2.4 Hz, 1 H), 7.34 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.98, 22.42, 24.96, 28.97, 31.41,
39.86, 46.95, 47.62, 67.40, 119.31, 128.08, 128.21, 128.94, 135.05,
136.78, 170.03.
CuCl (0.99 g, 1.0 mmol) and dichloride 8b (3.77 g, 10 mmol) were
weighed in a Schlenk tube fitted with a perforable septum (blocked
by a screw cap). Anhydrous MeCN (15 mL) and TMEDA (302 mL,
2 mmol) were then added under Ar. The mixture was stirred at 25
°C and after 20 h diluted with HCl (5% w/v, 20 mL) and extracted
with CH2Cl2 (2 × 30 mL). The combined organic layers were con-
centrated and the crude product was purified using flash chromatog-
raphy on silica gel, eluting with petroleum ether (bp 40–60 °C)–
Et2O (8.5:1.5). This gave 2-pyrrolidinone 9b (3.67 g, 97%) as a
72:28 mixture of inseparable cis- and trans-diastereoisomers as in-
dicated by the 1H NMR spectrum.
N-Benzyl-3-chloro-4-dichloromethyl-3-hexyl-2-pyrrolidinone
(9b)
Yellow-orange oil.
IR (film): 1708 (C=O) cm–1.
1H NMR [400 MHz, CDCl3, cis-diastereoisomer (72%)]: d = 0.90
(m, 3 H), 1.33 (br m, 8 H), 2.37 (m, 2 H), 3.0–3.4 (m, 3 H), 4.42 (d,
J = 14.7 Hz, 1 H), 4.61 (d, J = 14.7 Hz, 1 H), 5.99 (m, 1 H), 7.33 (m,
5 H)
1H NMR [400 MHz, CDCl3, trans-diastereoisomer (28%)]: d = 0.90
(m, 3 H), 1.33 (br m, 8 H), 2.37 (m, 2 H), 3.0–3.4 (m, 2 H), 3.61 (dd,
MS (EI): m/z = 340 (1) [M+ + 1], 304 (40), 268 (9), 255 (57), 91
(100).
Anal. Calcd for C18H23Cl2NO: C, 63.53; H, 6.81; N, 4.12. Found: C,
63.39; H, 6.93; N, 4.22.
Hydrolysis of Acetal 10b; Typical Procedure
In a Schlenk tube, were added acetal 10b (0.33 g, 1 mmol), H2O (1
mL) and two drops of methanesulfonic acid. The mixture, under
vigorous stirring, was heated to 100 °C for 6 h, after which time it
was neutralized with NaHCO3 (5% w/v) and then extracted with
Synthesis 2004, No. 10, 1680–1686 © Thieme Stuttgart · New York

1684
L. De Buyck et al.
PAPER
CH2Cl2 (2 × 3 mL). The organic phases were collected and concen-
trated. Following flash chromatography of the crude product on sil-
ica gel, using petroleum ether (bp 40–60 °C)–Et2O (9.5:0.5) as
eluent, the desired maleimide 11b (0.28 g, 98%) was recovered.
lowed by the dropwise addition of a solution of NaOH (42.0 g, 1050
mmol) in H2O (300 mL), over a period of 40–80 min. The mixture
soon became difficult to stir magnetically and homogenization was
then effected by manual shaking. Towards the end of the dropwise
addition, the inner temperature of the reaction mixture reached 32–
33 °C. About 30 min after the addition of the aqueous hydroxide
some NaHSO3 was added (to remove any unreacted bromine) fol-
lowed by an excess of concd HCl (37.5%, 200–250 mL). The dried
(MgSO4) organic layer was distilled to recover most of the CH2Cl2
and this was followed by evaporation under reduced pressure (at
60–65 °C). The residue was then recrystallised from petroleum
ether (bp 40–60 °C, 120–140 mL) by leaving overnight at near 4 °C.
The first crop of crystals was isolated on vacuum filtration and sub-
sequent concentration and cooling of the mother liquor gave further
acid 7a (112.7 g, 99%) as a white solid; mp 33–35 °C (petroleum
ether).11a
N-Benzyl-3-hexyl-4-methylmaleimide (11b)
Colourless oil.
IR (film): 1693 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.2 Hz, 3 H), 1.32 (br
m, 6 H), 1.52 (m, 2 H), 1.95 (s, 3 H), 2.36 (t, J = 7.3 Hz, 2 H), 4.63
(s, 2 H), 7.24 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 8.48, 13.85, 22.36, 23.59, 27.96,
29.05, 31.31, 41.34, 127.46, 128.22, 128.43, 136.67, 136.89,
141.16, 171.48, 171.73.
MS (EI): m/z = 285 (66) [M+], 97 (83), 137 (100), 91 (89).
Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C,
75.62; H, 8.02; N, 4.85.
Preparation of N-Benzyl-N-(3-chloro-2-propenyl)-2,2-dichloro-
hexadecanamide (8a)
Following the procedure for the preparation of 8b, 2,2-dichloro-
hexadecanoic acid (7a, 9.76 g, 30 mmol) gave amide 8a (13.06 g,
89%) as a mixture of two diastereoisomers.
Hydrolysis of N-Benzylmaleimide 11b
According to Argade’s protocol,5e maleimide 11b (0.57 g, 2 mmol)
was hydrolysed to anhydride 2b (0.26 g, 67%).
N-Benzyl-N-(3-chloro-2-propenyl)-2,2-dichlorohexadecana-
mide (8a)
3-Hexyl-4-methylmaleic Anhydride (2b)12a
Colourless liquid.
Colourless oil.
IR (film): 1706 (C=O) cm–1.
IR (film): 1660 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.90 (t, J = 6.2 Hz, 3 H), 1.30 (br
m, 6 H), 1.58 (m, 2 H), 2.08 (s, 3 H), 2.46 (t, J = 7.1 Hz 2 H).
MS (EI): m/z = 196 (3) [M+], 168 (6), 140 (13), 139 (9), 127 (9), 126
1H NMR (200 MHz, CDCl3): d = 0.91 (t, J = 6.2 Hz, 3 H), 1.29 (m,
22 H), 1.75 (m, 2 H), 2.51 (m, 2 H), 3.7–5.2 (m, br s, 4 H), 5.7–6.3
(br s, 2 H), 7.31 (m, 5 H).
MS (EI): m/z = 487 (2) [M+], 452 (32), 412 (52), 180 (33), 91 (100).
(100), 43 (50).
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.44; H,
8.08.
Anal. Calcd for C26H40Cl3NO: C, 63.87; H, 8.25; N, 2.86. Found: C,
64.03; H, 8.08; N, 2.94.
Preparation of 2,2-Dichlorohexadecanal (6a); Typical Proce-
dure
Cyclization of N-Benzyl-N-(3-chloro-2-propenyl)-2,2-dichloro-
hexadecanamide (8a); Typical Procedure
1-Hexadecanol (5a) (290.4 g, 1198 mmol) was dissolved in DMF
(386 g), CHCl3 (420 mL) and CH2Cl2 (120 mL), and the mixture
was kept at 30–35 °C to prevent crystallization. In a three-necked
flask (2 L), protected against light and equipped with an internal
electronic thermometer, reflux condenser and chlorine inlet, was
added a magnetic stirring bar followed by DMF·HCl (60 g), DMF
(20 g) and CHCl3 (80 mL). The mixture was preheated to 50–60 °C,
then the flow of Cl2 was started. After 1 min, the solution containing
1-hexadecanol (5a) was added through a dropping funnel, whereby
the temperature increased to an optimum value of 67–69 °C. The
addition of 1-hexadecanol (5a) was carried out over 100–150 min
and a slight excess of chlorine was maintained over this period. The
stream of Cl2 was stopped 2–10 min after adding the alcohol (and
also rinsing the dropping funnel with 25 mL of CH2Cl2) and 30–50
min later, evacuation of Cl2–CH2Cl2–CHCl3 was started by means
of a membrane pump. When three quarters of the volume of the sol-
vent (CH2Cl2–CHCl3) was collected, the residue (Important: No
chlorine must remain in solution) was extracted with petroleum
ether (bp 45–50 °C, 500 mL) and the bottom layer (containing
DMF·HCl) was washed again with petroleum ether (250 mL).
DMF·HCl can subsequently be recovered by distillation (bp 60 °C/
12 mmHg). The petroleum ether layers were then combined,
washed with HCl (5 N, 2 × 100 mL) and dried over MgSO4. The
crude product was distilled to give dichloride 6a (311.3 g, 84%) as
a colourless liquid (bp 131–135 °C/0.05 mmHg).11a
CuCl (0.99 g, 1.0 mmol) and 8a (4.89 g, 10 mmol) were weighed in
a Schlenk tube fitted with a perforable septum (blocked by a screw
cap). Anhydrous MeCN (8 mL), anhyd CH2Cl2 (5 mL) and TMEDA
(302 mL, 2 mmol) were then added under Ar. The mixture was
stirred at 60 °C and after 20 h the mixture was diluted with HCl (5%
w/v, 20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined
organic layers were concentrated and purification by flash chroma-
tography on silica gel, eluting with petroleum ether (bp 40–60 °C)–
Et2O (8.5:1.5), gave the 2-pyrrolidinone 9a (4.84 g, 99%), as an
89:11 mixture of inseparable cis- and trans-diastereoisomers.
N-Benzyl-3-chloro-4-dichloromethyl-3-tetradecyl-2-pyrrolidi-
none (9a)
White powder.
IR (KBr): 1701 (C=O) cm–1.
1H NMR [400 MHz, CDCl3, cis-diastereoisomer (89%)]: d = 0.89
(t, J = 6.1 Hz, 3 H), 1.27 (br m, 24 H), 2.39 (m, 2 H), 3.0–3.5 (m, 3
H), 4.41 (d, J = 14.7 Hz, 1 H), 4.62 (d, J = 14.7 Hz, 1 H), 6.00 (m,
1 H), 7.30 (m, 5 H).
1H NMR [400 MHz, CDCl3, trans-diastereoisomer (11%)]: d = 0.89
(t, J = 6.1 Hz, 3 H), 1.27 (br m, 24 H), 2.39 (m, 2 H), 3.0–3.5 (m, 2
H), 3.61 (dd, J = 6.9, 10.6 Hz, 1 H), 4.32 (d, J = 14.7 Hz, 1 H), 4.71
(d, J = 14.7 Hz, 1 H), 5.89 (d, J = 4.2 Hz, 1 H), 7.30 (m, 5 H).
13C NMR [100 MHz, CDCl3, cis-diastereoisomer (89%)]: d = 14.14,
22.72, 25.62, 29.29, 29.38, 29.50, 29.62, 29.69, 31.95, 37.18, 47.08,
47.13, 49.42, 71.70, 71.94, 128.08, 128.98, 135.20, 169.99.
13C NMR [100 MHz, CDCl3, trans-diastereoisomer (11%)]: d =
14.14, 22.72, 24.66, 29.29, 29.38, 29.50, 29.62, 29.69, 31.95, 33.16,
Oxidation of 2,2-Dichlorohexadecanal (6a); Typical Procedure
2,2-Dichlorohexadecanal (6a) (108.3 g, 350 mmol) was stirred with
CH2Cl2 (250 mL) and H2O (250 mL) on a water bath at around 13–
15 °C. Then Br2 (21 mL, 410 mmol) was added in one portion fol-
Synthesis 2004, No. 10, 1680–1686 © Thieme Stuttgart · New York

PAPER
Simple and Efficient Route to Chaetomellic Anhydride A
1685
45.37, 47.12, 54.58, 70.55, 71.35, 128.08, 128.34, 128.87, 135.20,
170.02.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H), 1.25 (br
s, 22 H), 1.57 (m, 2 H), 2.07 (s, 3 H), 2.45 (t, J = 7.6 Hz, 2 H).
MS (EI): m/z = 488 (11) [M+ + 1], 452 (32), 382 (7), 368 (14), 293
MS (EI): m/z = 308 (5) [M+], 290 (15), 280 (4), 263 (7), 235 (8), 150
(36), 291 (48), 208 (66), 91 (100).
(33), 126 (100), 43 (45).
Anal. Calcd for C26H40Cl3NO: C, 63.87; H, 8.25; N, 2.86. Found: C,
63.92; H, 8.16; N, 2.94.
Anal. Calcd for C19H32O3: C, 73.98; H, 10.46. Found: C, 73.86; H,
10.52.
Rearrangement of N-Benzyl-3-chloro-4-dichloro-methyl-3-tet-
radecyl-2-pyrrolidinone (9a); Typical Procedure
Acknowledgment
In a Schlenk tube fitted with a perforable septum (blocked by a
screw cap) were added MeOH (30 mL) and Na (1.84 g, 80 mmol).
When the effervescence ceased, the solution was thermostated at 25
°C and a solution of 9a (9.78 g, 20 mmol) in Et2O (30 mL) was add-
ed by syringe. The reaction mixture was then stirred for 20 h, after
which time it was acidified with HCl (5% w/v) and left stirring at 25
°C for a further 20 h. Subsequently, the mixture was extracted with
CH2Cl2 (2 × 80 mL) and the combined organic layers concentrated
under reduced pressure. Flash chromatography of the crude product
on silica gel, using a petroleum ether (bp 40–60 °C)– Et2O gradient
(from 10:0–8.5:1.5), gave maleimide 11a (7.07 g, 89%) and the de-
hydrohalogenated g-lactam 12a (0.80 g, 9%).
We thank the Ministero della Università e della Ricerca Scientifica
e Tecnologica (MURST) and the Belgian N. F. W. O. and I. W. T.
for financial assistance.
References
(1) (a) Singh, S. B.; Zink, D. L.; Liesch, J. M.; Goetz, M. A.;
Jenkins, R. G.; Nallin-Omstead, M.; Silverman, K. C.; Bills,
G. F.; Mosley, R. T.; Gibbs, J. B.; Albers-Schonberg, G.;
Lingham, R. B. Tetrahedron 1993, 49, 5917. (b) Amirta,
R.; Fujimori, K.; Shirai, N.; Honda, Y.; Watanabe, T. Chem.
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(2) (a) Gibbs, J. B.; Oliff, A.; Kohl, N. E. Cell 1994, 77, 175.
(b) Gibbs, J. B.; Pompliano, D. L.; Mosser, S. D.; Rands, E.;
Lingham, R. B.; Singh, S. B.; Scolnick, E. M.; Kohl, N. E.;
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(b) Leonard, D. M. J. Med. Chem. 1997, 62, 4862.
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Vederas, J. C.; Cornish, K. Eur. J. Biochem. 2003, 270,
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61, 4164. (i) Argade, N. P.; Naik, R. H. Bioorg. Med. Chem.
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Lett. 1994, 35, 4071. (k) Singh, S. B. Tetrahedron Lett.
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(6) These results were the subject of preliminary
communication: De Buyck, L.; Bellesia, F.; Ghelfi, F.;
Merighi, G.; Mucci, A.; Pagnoni, U. M.; Pinetti, A.; Parsons,
A. F. Atti del XXI Congresso Nazionale della Società
Chimica Italiana, Vol. 2; Società Chimica Italiana: Torino,
2003, OR–CP-053.
(7) Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenem, E.;
Rogge, T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagnoni, U. M.; Schenetti, L. Tetrahedron
2003, 59, 1147.
N-Benzyl-4-methyl-3-tetradecylmaleimide (11a).
Colourless oil.
IR (film): 1710 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.3 Hz, 3 H), 1.27 (br
m, 22 H), 1.53 (m, 2 H), 1.97 (s, 3 H), 2.38 (t, J = 7.3 Hz, 2 H), 4.64
(s, 2 H), 7.30 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 8.67, 14.09, 22.66, 23.70, 28.15,
29.25, 29.33, 29.46, 29.53, 29.57, 29.60, 29.66, 31.89, 41.42,
127.59, 128.20, 128.36, 128.55, 136.70, 136.99, 171.64, 171.93.
MS (EI): m/z = 397 (63) [M+], 215 (100), 204 (28), 137 (61), 91
(53).
Anal. Calcd for C26H39NO2: C, 78.54; H, 9.89; N, 3.52. Found: C,
78.63; H, 9.91; N, 3.64.
(E)-N-Benzyl-3-chloro-4-chloromethylen-3-tetradecy-l-2-pyr-
rolidinone (12a)
Brownish oil.
IR (film): 1720 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 6.8 Hz, 3 H), 1.26 (br
m, 24 H), 2.07 (ddd, J = 5.5, 11.0, 13.5 Hz, 1 H), 2.33 (ddd, J = 5.1,
11.2, 13.5 Hz, 1 H), 3.83 (dd, J = 2.5, 15.1 Hz, 1 H), 3.98 (dd, J =
2.5, 15.1, 1 H), 4.55 (d, J = 14.7 Hz, 1 H), 4.62 (d, J = 14.7 Hz, 1
H), 6.46 (t, J = 2.5 Hz, 1 H), 7.32 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.09, 22.67, 25.02, 29.26, 29.34,
29.42, 29.56, 20.61, 29.64, 29.67, 31.91, 39.86, 46.96, 47.61, 67.36,
119.28, 128.07, 128.20, 128.94, 135.03, 136.79, 170.04.
MS (EI): m/z = 451 (11) [M+], 416 (65), 380 (12), 368 (8), 255 (78),
234 (16), 91 (100).
Anal. Calcd for C26H39Cl2NO: C, 69.01; H, 8.69; N, 3.10. Found: C,
69.14; H, 8.65; N, 3.23.
(8) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
(9) (a) Cagnoli, R.; Ghelfi, F.; Pagnoni, U. M.; Parsons, A. F.;
Schenetti, L. Tetrahedron 2003, 59, 9951. (b) Ghelfi, F.;
Parsons, A. F.; Tommasini, D.; Mucci, A. Eur. J. Org.
Chem. 2001, 1845. (c) Ghelfi, F.; Parsons, A. F. J. Org.
Chem. 2000, 65, 6249. (d) Ghelfi, F.; Bellesia, F.; Forti, L.;
Ghirardini, L.; Grandi, R.; Libertini, E.; Montemaggi, M. C.;
Pagnoni, U. M.; Pinetti, A.; De Buyck, L.; Parsons, A. F.
Tetrahedron 1999, 55, 5839. (e) Benedetti, M.; Forti, L.;
Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R. Tetrahedron 1997,
53, 14031.
Hydrolysis of N-Benzyl-3-tetradecyl-4-methylmaleimide (11a)
According to Argade’s protocol,5e maleimide 11a (0.795 g, 2 mmol)
was hydrolysed to anhydride 2a (0.432 g, 70%).
3-Tetradecyl-4-methylmaleic Anhydride (Chaetomellic Anhy-
dride A) (2a)1a
Pale yellow oil.
IR (film): 1766 (C=O) cm–1.
Synthesis 2004, No. 10, 1680–1686 © Thieme Stuttgart · New York

1686
L. De Buyck et al.
PAPER
(10) Serratosa, F.; Xicart, J. Organic Chemistry in Action: The
Design of Organic Synthesis; Elsevier: Amsterdam, 1996,
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(13) For other oxidative procedures see: Bellesia, F.; De Buyck,
L.; Ghelfi, F.; Pagnoni, U. M.; Strazzolini, P. Synth.
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(11) (a) De Buyck, L.; Casaert, F.; De Lepeleire, C.; Schamp, N.
Bull. Soc. Chim. Belg. 1988, 97, 525. (b) For a discussion
about the role of the Cl– anion in the oxidation-chlorination
see: Bellesia, F.; De Buyck, L.; Ghelfi, F.; Pagnoni, U. M.;
Parsons, A. F.; Pinetti, A. Synthesis 2003, 2173.
(12) (a) Buttery, R. G.; Seifert, R. M.; Haddon, W. F.; Lundin, R.
E. J. Agric. Food Chem. 1980, 28, 1336. (b) Boesel, R.;
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(16) Ince, J.; Ross, T. M.; Shipman, M.; Slawin, A. M. Z.
Tetrahedron 1996, 52, 7037.
Synthesis 2004, No. 10, 1680–1686 © Thieme Stuttgart · New York