Scheme 4
Table 4 Alkylation of lactones 2d,f–h to the symmetrically and un-
symmetrically substituted lignan analogues 1
Scheme 3
Entry Lactone Bromide Residue (RA)
Lignan Yield (%)a
selectivity decreased with higher contents of the oxidation
reagent (entries 4–6).
1
2
3
4
5
2d
2f
2f
2g
2h
8d
8f
8h
8g
8h
H
1d
1f
30
43
25
18
35
2,4,6-Trimethyl
Lactones 6 and 7 were inseparable by flash chromatography
and were therefore used as a mixture for the Stille coupling.
This reaction was performed with benzyl bromides 8a–h as
described previously.9 The a,b-unsaturated lactones 9a–h were
isolated as isomerically pure compounds (Scheme 2). Sweeney
et al. described recently, that the reaction rates for the Stille
coupling of lactones 6 and 7 with aryl halides are different.15 In
analogy, only lactone 6 reacted with benzyl bromides 8a–h to
the coupling products 9a–h (Table 2).
3,4-Methylendioxy 1fb
3-Methoxy 1g
3,4-Methylendioxy 1h
a Reaction conditions not optimized.
metal catalysed reactions. Alkylation of these compounds
produced lignan analogues 1 with cytotoxic activities. An
enantioselective route to this class of lignans is in progress.
This research was supported by the Deutsche Forschungsge-
meinschaft (DFG) (INK A26/1-1 and B26/1-1). MS acknowl-
edges a habilitation grant from the DFG (Se875/1-1).
Table 2 Benzyl bromides 8a–h employed for the Stille coupling and yields
of the reaction products 9a–h
Entry
Residue (R)
Bromide
Lactone
Yield (%)
1
2
3
4
5
6
7
8
4-Mesyl-3-methoxy
3,4,5-Trimethoxy
4-Methyl
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
80
56
76
70
24
77
59
45
Notes and references
1 D. C. Ayres and J. D. Loike, Lignans: Chemical, Biological and Clinical
Properties, Cambridge University Press, Cambridge, 1990; R. S. Ward,
Nat. Prod. Rep., 1999, 16, 75.
2 Recent reviews: J. L. Charlton, J. Nat. Prod., 1998, 61, 1447; E. Eich,
ACS Symp. Ser., 1998, 691, 83; A. J. Vlietinck, T. De Bruyne, S. Apers
and L. A. Pieters, Planta Med., 1998, 64, 97.
H
4-Nitro
2,4,6-Trimethyl
3-Methoxy
8g
8h
9g
9h
3,4-Methylendioxy
3 Recent reviews: S. E. Rickard and L. U. Thompson, ACS Symp. Ser.,
1997, 662, 273; D. M. Tham, C. D. Gardner and W. L. Haskell, J. Clin.
Endocrinol. Metab., 1998, 83, 2223; C. D. N. Humfrey, Nat. Toxins,
1998, 6, 51; J. M. Cline and C. L. Hughes, Jr., Cancer Treat. Res., 1998,
94, 107; W. Mazur and H. Adlercreutz, Pure Appl. Chem., 1998, 70,
1759; S. Bingham, Pure Appl. Chem., 1998, 70, 1777.
4 S. R. Stitch, J. K. Toumba, M. B. Groen, C. W. Funke, J. Leemhuis, J.
Vink and G. F. Woods, Nature, 1980, 287, 738; K. D. R. Setchell, A. M.
Lawson, F. L. Mitchell, H. Adlercreutz, D. N. Kirk and M. Axelson,
Nature, 1980, 287, 740; M. Axelson, J. Sjövall, B. E. Gustafsson and
K. D. R. Setchell, Nature, 1982, 298, 659; L. U. Thompson, P. Robb, M.
Serraino and F. Cheung, Nutr. Cancer, 1991, 16, 43.
5 R. S. Ward, Chem. Soc. Rev., 1982, 11, 75; R. S. Ward, Tetrahedron,
1990, 46, 5029.
6 N. J. Cartwright and R. D. Haworth, J. Chem. Soc., 1944, 535; K.
Weinges and R. Spänig, in Oxidative Coupling of Phenols, ed. W. I.
Taylor and A. R. Battersby, Marcel Dekker, New York, 1967; D. E.
Bogucki and J. L. Charlton, 1997, 75, 1793.
7 J. M. de L. Vanderlei, F. Coelho and W. P. Almeida, Synth. Commun.,
1998, 28, 3047.
Hydrogenation of lactones 9a–h to lactones 2a–h were
achieved by means of 10% Pd on charcoal or Ra-Ni T4 (Table
3). The former catalyst, however, gave irreproducible results or
no conversion. Additionally, high pressure (100 bar) and long
reaction times ( > 24 h) were required. With Ra-Ni T4 as
catalyst, complete conversion was found in all cases within 2 h
at 0.1 bar positive pressure.
Table 3 Hydrogenation of the unsaturated lactones 9a–h using different
catalysts
Unsat.
Yield
(%)
Entry
lactone
Product Catalyst
p/bar
t/h
1
2
3
4
5
6
7
8
9
9a
9a
9b
9b
9c
9d
9e
9f
2a
2a
2b
2b
2c
2d
2e
2f
Pd/C
Ra-Ni T4
Pd/C
Ra-Ni T4
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Ra-Ni T4
Pd/C
0.1
0.1
0.1
0.1
0.1
50
0.1
0.1
100
0.1
100
100
0.1
14
2
14
2
24
48
14
14
72
2
14
16
2
93
98
0
70
98
97
0
8 J. K. Stille, Angew. Chem., 1986, 98, 504; V. Farina, V. Krishnamurthy
and W. J. Scott, Org. React., 1997, 50, 512.
9 S. Kamlage, M. Sefkow and M. G. Peter, J. Org. Chem., 1999, 64,
2938.
10 H. X. Zhang, F. Guibe and G. Balavoine, J. Org. Chem., 1990, 55,
1857.
11 A. G. M. Barrett, T. E. Barta and J. A. Flygare, J. Org. Chem., 1989, 54,
4246.
0
9f
2f
88
98
92
0
10
11
12
13
9f
2f
9g
9h
9h
2g
2h
2h
Pd(OH)2
Ra-Ni T4
12 G. J. Hollingworth, G. Perkins and J. Sweeney, J. Chem. Soc., Perkin
Trans. 1, 1996, 1913.
70
13 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis, 1994,
639–666.
14 R. Bloch and C. Brillet, Synlett, 1991, 829.
15 R. Mabon, A. M. E. Richecœur and J. B. Sweeney, J. Org. Chem., 1999,
64, 328.
16 R. Chênevert, G. Mohammadi-Zirani, D. Caron and M. Dasser, Can. J.
Chem., 1999, 77, 223.
17 T. Mukhopadhyay and D. Seebach, Helv. Chim. Acta, 1982, 65, 385.
18 T. W. Becker, M. G. Peter and B. L. Pool-Zobel, in Proceedings of the
Food and Cancer Prevention III Meeting, Norwich, UK, 1999, ed. I. T.
Johnson and G. R. Fenwick, Special Publication No 255, Royal Society
of Chemistry, Cambridge, UK, p. 151.
Alkylation of lactones 2 with benzyl halides using LDA as
base and HMPA as cosolvent provides lactone lignans 1.1,7,16
We found that alkylation using LHMDS as base and DMPU17 as
non-carcinogenic substitute for HMPA afforded lactones 1 in
moderate yields (Scheme 4 and Table 4).
Bioassay of the synthetic lignan analogues using colon-tumor
lines HT29 revealed that compound 1f possesses high cytotoxic
activity (IC50 = 40 mM).18
We have shown that b-benzyl-g-butyrolactones 2 were
effectively synthesised from butynediol 4 in four transition
332
Chem. Commun., 2001, 331–332