Chemoselective carbon-carbon coupling of organocuprates with (bromomethyl)methylmaleic anhydride: Synthesis of chaetomellic acid A

Full text of DOI:10.1021/jo981114k

J . Org. Chem. 1998, 63, 9557-9558
9557
Sch em e 1a
Ch em oselective Ca r bon -Ca r bon Cou p lin g
of Or ga n ocu p r a tes w ith
(Br om om eth yl)m eth ylm a leic An h yd r id e:
Syn th esis of Ch a etom ellic Acid A†
Anil M. Deshpande, Arvind A. Natu, and
Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National
Chemical Laboratory, Pune 411 008, India
Received J une 10, 1998
Chaetomellic anhydrides A and B have been recently
isolated1 from Chaetomella acutiseta, and their dianionic
forms are potent and highly specific inhibitors of ras
farnesyl-protein transferase. The provision of facile
synthetic approaches to this bioactive natural product,
Chaetomellic acid A anhydride (tetradecylmethylmaleic
anhydride, 1e), is a task of current interest.2-9 Seven
alternate syntheses of 1e, including two from our group,6,7
have recently been accomplished using elegant strat-
egies.2-8 In recent years, a number of 2-alkyl-3-methyl-
substituted maleic anhydrides have been isolated as
natural products,10-15 and some of them exhibit a specific
biological activity.1,14 In an attempt to have easy access
to substituted maleic anhydrides of this type, we herein
report a simple two-step approach to n-alkylmethylmaleic
anhydrides 1a -e via copper(I) iodide (CuI) induced,
highly chemoselective, carbon-carbon coupling of Grig-
nard reagents with (bromomethyl)methylmaleic anhy-
dride (4) (Scheme 1).
a
Key: (i) NBS, Benzoyl peroxide, CCl4, reflux, 10 h. (ii) RMgX,
Et2O/THF, HMPA, CuI, -5 to 0 °C, 8 h.
literature. The unsymmetrical anhydride 4 has five
alternate sites available for nucleophilic reactions,21 viz
(i) two carbonyl carbons for 1,2-addition (with or without
ring opening), (ii) two sites for Michael addition, and (iii)
allylic halide for displacement reaction, and such chemo-
selective carbon-carbon coupling reaction of organo-
cuprates and 4 with preservation of the maleic anhydride
moiety has not been reported.22 Reaction of dimethyl-
maleic anhydride (3)23 with NBS/benzoyl peroxide in
carbon tetrachloride under reflux gave (bromomethyl)-
methylmaleic anhydride (4)24 (68%), accompanied by 2,3-
di(bromomethyl)maleic anhydride (2%) and starting ma-
terial (30%) (1H NMR). Vacuum distillation of this
mixture using a Kugelrohr apparatus yielded 60% of 4
with 98% purity (by 1H NMR). The reactions of (bro-
momethyl)methylmaleic anhydride (4) with excess (5
equiv) of freshly prepared Grignard reagents derived
from methyl iodide, n-pentyl iodide, n-octyl bromide,
n-dodecyl bromide, and n-tridecyl bromide, in the pres-
ence of catalytic amount of CuI in ether (or THF) and
HMPA as solvent system at -5 to 0 °C furnished
exclusively the corresponding anhydrides 1a -e in 55-
60% yields via chemoselective nucleophilic displacement
of allylic bromide. Optimization of the coupling reaction
was carried out by changing reaction temperature, mode
of addition, and molar amounts of Grignard reagents, CuI
and HMPA. The observed chemoselectivity could be
ascribed to the controlled reactivity of cuprates generated
from Grignard reagents and CuI in the presence of
Chemoselective Grignard reactions, with preservation
of substrate functional groups such as ester,5,17,18 car-
boxylic acid,19 nitrile,17 and epoxide20 are known in the
†NCL Communication no. 6444.
(1) Singh, S. B.; Zink, D. L.; Liesch, J . M.; Goetz, M. A.; J enkins, 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.
(2) Singh, S. B. Tetrahedron Lett. 1993, 34, 6521.
(3) Branchaud, B. P.; Slade, R. M. Tetrahedron Lett. 1994, 35, 4071.
(4) Kates, M. J .; Schauble, J . H. J . Org. Chem. 1996, 61, 4164.
(5) Ratemi, E. S.; Dolence, J . M.; Poulter, C. D.; Vederas, J . C. J .
Org. Chem. 1996, 61, 6296.
(6) Argade, N. P.; Naik, R. H. Bioorg. Med. Chem. 1996, 4, 881.
(7) Desai, S. B.; Argade, N. P. J . Org. Chem. 1997, 62, 4862.
(8) Poigny, S.; Guyot, M.; Samadi, M. J . Chem. Soc., Perkin Trans.
1 1997, 2175.
(9) For the synthesis of chaetomellic acid B, see refs 4 and 8.
(10) Wong, K. C.; Tan, G. L. Flavour Fragrance J . 1994, 9, 25.
(11) Poll, L.; Lewis, M. J . Lebensm-Wiss. Technol. 1986, 19, 258.
(12) Boesel, R.; Schilcher, H. Planta Med. 1989, 55, 399.
(13) Itoh, S.; Esaki, N.; Masaki, K.; Blank, W.; Soda, K. J . Ferment.
Bioeng. 1994, 77, 513.
(14) Nicolaou, K. C.; Marten, H. D. P.; Miller, N. D.; Yang, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2821 and references cited therein.
(15) The antifungal antibiotics tautomycin and tautomycetin also
contain a 2-substituted-3-methylmaleic anhydride segment.16
(16) Oikawa, H.; Yoneta, Y.; Uneo, T.; Oikawa, M.; Wakayama, T.;
Ichihara, A. Tetrahedron Lett. 1997, 38, 7897 and references cited
therein.
(17) Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J . Org. Chem.
1983, 48, 1912.
(18) Normant, J . F.; Villieras, J .; Scott, F. Tetrahedron Lett. 1977,
3263.
(19) (a) Dasgupta, S. K.; Rice, D. M.; Griffin, R. G. J . Lipid Res.
1982, 23, 197. (b) Baer, T. A.; Carney, R. L. Tetrahedron Lett. 1976,
4697.
(20) (a) Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahe-
dron Lett. 1984, 25, 2069. (b) Brevet, J .-L.; Mori, K. Synthesis 1992,
1007. (c) Mori, K.; Argade, N. P. Liebigs Ann. Chem. 1994, 695.
(21) Knight, D. W.; Pattenden, G. J . Chem. Soc., Perkin Trans. 1
1979, 62 and references cited therein.
(22) (a) Silverman, G. S.; Rakita. P. E. Handbook of Grignard
Reagents, 1st ed.; Marcel Dekker: New York, 1996. (b) Lipshutz, B.
H.; Sengupta, S. Organic Reactions. Vol-41, 1992, p-135.
(23) Baumann, M. E.; Bosshard, H. Helv. Chim. Acta. 1978, 61, 2751.
(24) Garman, A. J .; Kalindjian, S. B. Fed. Eur. Biochem. Soc. Lett.
1987, 223, 361.
10.1021/jo981114k CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

9558 J . Org. Chem., Vol. 63, No. 25, 1998
Notes
HMPA20a and will be useful for the tailor-made synthesis
of a wide range of alkylmethylmaleic anhydride deriva-
tives.
In summary, we have demonstrated for the first time
a simple chemoselective carbon-carbon coupling reaction
of 4 and organocuprates for the synthesis of 1a -e in 55-
60% yields with preservation of the dialkyl-substituted
maleic anhydride moiety.
The products obtained can also be purified by chemical
treatment. The crude products were basified with 5% aqueous
NaOH solution (10 mL) and then extracted with ether (10 mL
× 3). Subsequent acidification of the aqueous layer, followed
by ether extraction (15 mL × 3), washing of extract with water
(15 mL) and brine (15 mL), drying over Na2SO4, and concentra-
tion in vacuo furnished pure product with similar yield.
3-Eth yl-4-m eth yl-2,5-fu r a n d ion e (1a ):10,11 1H NMR (CDCl3,
200 MHz) δ 1.22 (t, J ) 8 Hz, 3H), 2.09 (s, 3H), 2.52 (q, J ) 8
Hz, 2H); IR (neat) νmax 1765, 1660 cm-1
. Anal. Calcd for
C7H8O3: C, 59.99; H, 5.75. Found: C, 59.76; H, 5.83.
Exp er im en ta l Section
3-Hexyl-4-m eth yl-2,5-fu r a n d ion e (1b):12 1H NMR (CDCl3,
200 MHz) δ 0.90 (m, 3H), 1.15-1.45 (m, 6H), 1.45-1.70 (m, 2H),
2.08 (s, 3H), 2.46 (t, J ) 7 Hz, 2H); MS (m/e) 196, 168, 139, 126,
98, 81, 70, 55; IR (neat) νmax 1765, 1655 cm-1. Anal. Calcd for
C11H16O3: C, 67.32; H, 8.22. Found: C, 67.57; H, 8.51.
3-Non yl-4-m eth yl-2,5-fu r a n d ion e (1c): 1H NMR (CDCl3,
200 MHz) δ 0.90 (t, J ) 6 Hz, 3H), 1.15-1.48 (bs, 12H), 1.48-
1.70 (m, 2H), 2.10 (s, 3H), 2.48 (t, J ) 8 Hz, 2H); MS (m/e) 238,
210, 193, 178, 153, 140, 126, 98, 81, 55; IR (neat) νmax 1765, 1670
cm-1. Anal. Calcd for C14H22O3: C, 70.56; H, 9.30. Found: C,
70.63; H, 9.39.
Column chromatographic separations were done on ACME
silica gel (60-120 mesh). Copper(I) iodide, HMPA, and the alkyl
halides were obtained from Aldrich Chemical Co.
3-(Br om om eth yl)-4-m eth yl-2,5-fu r a n d ion e (4). A mixture
of dimethylmaleic anhydride23 (3, 5.04 g, 50 mmol), NBS (14.24
g, 100 mmol), and a catalytic amount of benzoyl peroxide (200
mg, 0.83 mmol) in carbon tetrachloride (300 mL) was gently
refluxed for 5 h in a 500 mL round-bottom flask. The reaction
mixture was allowed to cool to room temperature, a second
portion of benzoyl peroxide (200 mg, 0.83 mmol) was added, and
again the refluxing was continued 5 h longer. The mixture was
left overnight at room temperature and then filtered. The
residue was washed with CCl4 (25 mL × 2); the combined organic
layer was washed with water (100 mL × 2) and brine (100 mL),
and then dried over Na2SO4 and concentrated in vacuo to furnish
thick yellow oil, which was purified by chromatography on a
silica gel column [elution with petroleum ether/ethyl acetate (8:
2)] to obtain a crude product (7.0 g) and then further purified
by distillation using Kugelrohr apparatus. The first fraction (2.5
g) was a mixture of 3 and 4 while the second fraction obtained
at 120-125 °C (2 mm) was the anhydride 4, 4.2 g, (60% yield,
3-Tr id ecyl-4-m eth yl-2,5-fu r a n d ion e (1d ): 1H NMR (CDCl3,
200 MHz) δ 0.88 (t, J ) 7 Hz, 3H), 1.10-1.45 (bs, 20H), 1.45-
1.70 (m, 2H), 2.08 (s, 3H), 2.46 (t, J ) 7 Hz, 2H); MS (m/e) 294,
276, 249, 221, 192, 163, 150, 140, 126, 98, 55; IR (neat) νmax
,
1770, 1675 cm-1. Anal. Calcd for C18H30O3: C, 73.43; H, 10.27.
Found: C, 73.11; H, 10.10.
3-Tetr adecyl-4-m eth yl-2,5-fu r an dion e (Ch aetom ellic Acid
A An h yd r id e, 1e):1 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J )
7 Hz, 3H), 1.15-1.45 (bs, 22H), 1.46-1.69 (m, 2H), 2.07 (s, 3H),
2.45 (t, J ) 7 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 9.6, 14.3,
22.9, 24.6, 27.7, 29.0-31.0 (9CH2), 32.1, 140.6, 144.9, 166.0,
166.4; MS (m/e) 308, 290, 191, 150, 126, 91, 81, 69; IR (neat)
νmax 1770, 1680 cm-1. Anal. Calcd for C19H32O3: C, 73.98; H,
10.46. Found: C, 73.73; H, 10.39.
1
98% purity by H NMR): 1H NMR (CDCl3, 200 MHz) δ 2.18 (s,
3H), 4.20 (s, 2H); 13C NMR (CDCl3, 50 MHz) δ 10.2, 16.2, 139.4,
144.0, 163.9, 165.2; MS (m/e) 206, 204, 125, 80, 53; IR (neat)
νmax 1775, 1675 cm-1. Anal. Calcd for C6H5BrO3: C, 35.15; H,
2.46. Found: C, 35.01; H, 2.49.
Gen er a l P r oced u r e for th e Syn th esis of Alk ylm eth yl-
m a leic An h yd r id es (1a -e). A freshly prepared solution of
Grignard reagent (10 mmol) in ether (15 mL) was added
dropwise to the solution of (bromomethyl)methylmaleic anhy-
dride (4, 410 mg, 2 mmol) and CuI (38 mg, 0.2 mmol) in ether
(10 mL) and HMPA (4 mL) under argon at -5 to 0 °C over 15 to
20 min under stirring. The reaction mixture was allowed to
reach rt and further stirred for 8 h. It was diluted with ether
(15 mL) and acidified with 4 N H2SO4 (10 mL), and the aqueous
layer was further extracted with ether (15 mL × 3). The
combined organic layer was washed with water (20 mL × 2),
brine (20 mL), and dried over Na2SO4. Concentration in vacuo
followed by silica gel column chromatographic purification of the
crude product using petroleum ether/ethyl acetate (19:1) as
eluent furnished pure alkylmethylmaleic anhydrides 1a -e in
55-60% yields. These reactions were also carried out under
identical conditions in THF without any loss of yield.
Ack n ow led gm en t. A.M.D. thanks CSIR, New Del-
hi, for the award of a research fellowship. N.P.A. thanks
D.S.T., New Delhi, for the financial support under the
Young-Scientist scheme. We thank Dr. K. N. Ganesh,
Head, Division of Organic Chemistry (Synthesis), for
constant encouragement.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and mass
spectra of 1b-e and 4, 13C NMR of 1e and 4 (14 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O981114K