Radical carboxyarylation approach to lignans. Total synthesis of (-)-arctigenin, (-)-matairesinol, and related natural products

Article abstract of DOI:10.1021/ol049878b

Total syntheses of seven biologically important lignan natural products, including (-)-arctigenin, (-)-matairesinol, and (-)α-conidendrin, by way of a highly stereoselective domino radical sequence is presented. The reported stereochemistry of the natural product 7-hydroxyarctigenin is shown to be erroneous; a diastereoisomeric structure is assigned to the natural product.

Full text of DOI:10.1021/ol049878b

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1345-1348
Radical Carboxyarylation Approach to
Lignans. Total Synthesis of
(−)-Arctigenin, (−)-Matairesinol, and
Related Natural Products
,‡
Joshua Fischer,† Aaron J. Reynolds,† Lisa A. Sharp,‡ and Michael S. Sherburn*
Research School of Chemistry, Australian National UniVersity, Canberra ACT 0200, Australia,
and School of Chemistry, UniVersity of Sydney, Sydney NSW 2006, Australia
sherburn@rsc.anu.edu.au
Received January 20, 2004
ABSTRACT
Total syntheses of seven biologically important lignan natural products, including (−)-arctigenin, (−)-matairesinol, and (−)-r-conidendrin, by
way of a highly stereoselective domino radical sequence is presented. The reported stereochemistry of the natural product 7-hydroxyarctigenin
is shown to be erroneous; a diastereoisomeric structure is assigned to the natural product.
Matairesinol (1) and arctigenin (5) (Figure 1) are naturally
occurring dibenzylbutyrolactone lignans isolated from several
plant sources.1,2 Both compounds are potent cytostatic agents
against human leukemic HL-60 cells, with IC50 values of
less than 100 ng/mL.3 Arctigenin and analogues have also
been shown to be potent inhibitors of HIV Type-1 Integrase.4
In addition to antitumor and antiviral activities, these
compounds display phytoestrogenic,5 immunoregulatory,6and
neuroprotective7 properties. Despite their modest size and
structural complexity, surprisingly few synthetic studies have
been reported on these compounds.8-10
Three C7-oxygenated analogues of matairesinol11 and one
of arctigenin have been reported as natural products: (-)-
7(S)-hydroxymatairesinol 2,12 (-)-7(R)-hydroxymatairesinol
3,12 (+)-7-oxomatairesinol 4,12 and (+)-7(S)-hydroxyarcti-
(6) Cho, J. Y.; Kim, A. R.; Yoo, E. S.; Baik, K. U.; Park, M. H. J.
Pharm. Pharmacol. 1999, 51, 1267-1273.
(7) (a) Jang, Y. P.; Kim, S. R.; Kim, Y. C. Planta Med. 2001, 67, 470-
472. (b) Jang, Y. P.; Kim, S. R.; Choi, Y. H.; Kim, J.; Kim, S. G.;
Markelonis, G. J.; Oh, T. H.; Kim, Y. C. J. Neurosci. Res. 2002, 68, 233-
240.
† University of Sydney.
‡ Australian National University.
(1) (a) Shinoda, J. Yakugaku Zasshi 1929, 49, 1165-1169; Chem. Abstr.
1930, 24, 12404. (b) Haworth, R. D.; Kelly, W. J. Chem. Soc. 1936, 998-
1003.
(2) Esterfield, T. H.; Bee, J. J. Chem. Soc. 1910, 97, 1028-1032.
(3) (a) Hirano, T.; Gotoh, M.; Oka, K. Life Sci. 1994, 55, 1061-1069.
(b) Takasaki, M.; Konoshima, T.; Komatsu, K.; Tokuda, H.; Nishino, H.
Cancer Lett. 2000, 158, 53-59.
(4) (a) Eich, E.; Pertz, H.; Kaloga, M.; Schulz, J.; Fesen, M. R.;
Mazumder, A.; Pommier, Y. J. Med. Chem. 1996, 39, 86-95. (b) Yang,
L.-M.; Lin, S.-J.; Yang, T.-H.; Lee, K.-H. Bioorg. Med. Chem. Lett. 1996,
6, 941-944.
(5) Meagher, L. P.; Beecher, G. R.; Flanagan, V. P.; Li, B. W. J. Agric.
Food Chem. 1999, 47, 3173-3180.
(8) Asymmetric syntheses of arctigenin: (a) Brown, E.; Daugan, A.
Tetrahedron 1989, 45, 141-154. (b) Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.;
Chen, J. J. Org. Chem. 2002, 67, 1738-1745.
(9) Asymmetric synthesis of matairesinol: Daugan, A.; Brown, E. J. Nat.
Prod. 1991, 54, 110-118.
(10) Recent reviews on lignan synthesis: (a) Ward, R. S. In Recent
AdVances in the Chemistry of Lignans; Atta-ur-Rahman, Ed.; Studies in
Natural Products Chemistry, Vol. 24: Bioactive Natural Products, Part E;
Elsevier: Amsterdam, 2000; pp 739-798. (b) Ward, R. S. Nat. Prod. Rep.
1999, 16, 75-96 and references therein.
10.1021/ol049878b CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/24/2004

Scheme 1. Intramolecular Alkene Carboxyarylation Approach
to Dibenzyl butyrolactone Lignans
Figure 1. Dibenzyl butyrolactone lignan natural products and
congeners under scrutiny.
genin 6.13 The identity of the natural product isolated from
the aerial parts of Centaurea calcitrapa was assigned
structure 6 since the spectroscopic data for this compound
matched that of a compound previously synthesized from
arctigenin. The stereochemistry of the semisynthetic sample
was assigned by comparing its 13C chemical shifts with those
of the two known 7-hydroxy matairesinol diastereomers.14
The 7(R)-hydroxy and 7-oxo derivatives of arctigenin 7 and
8 have not been reported in the literature. Herein we disclose
short asymmetric syntheses of the eight compounds depicted
in Figure 1.
This work represents the first asymmetric total synthesis
of the four naturally occurring C7-oxygenated lignans.15
Lignan natural products of this type lend themselves to
disconnection (Scheme 1) involving an intramolecular alkene
1,2-carboxyarylation reaction (10 f 9)16 and an Evans
asymmetric crotonate aldol reaction.17 The proposed radical
sequence forms two C-C bonds, incorporating the lactone
ring and an aromatic ring through a sequence involving
an addition, two 5-exo cyclizations, and two elimination
steps.18 The trans-disubstituted lactone was expected to
be the dominant product on the basis of Beckwith’s models
for stereoselectivity in radical cyclizations (cf. 13 f
14).19
Syntheses of 7(S)-hydroxymatairesinol 2 and 7(S)-hy-
droxyarctigenin 6 via this strategy are depicted in Scheme
2. Thus, an aldol reaction between the requisite aromatic
aldehyde 17a/b and the dibutylboron dienolate derived
from crotonyl oxazolidinone 18 gave the Evans syn-adduct
19 in >95% diastereoselectivity. These aldol adducts
proved to be unstable toward chromatography, so they
were immediately protected as the corresponding silyl
ethers 20. Reductive removal of the phenylalanine-derived
oxazolidinone auxiliary gave homoallylic alcohol 21,
which was united with aryl chlorothionoformate 23 in high
yield.
(11) 7-Hydroxymatairesinol has recently been shown to be a useful
starting material: (a) Eklund, P. C.; Sjoholm, R. E. Tetrahedron 2003, 59,
4515-4523. (b) Eklund, P.; Lindholm, A.; Mikkola, J.-P.; Smeds, A.;
Lehtilae, R.; Sjoeholm, R. Org. Lett. 2003, 5, 491-493. (c) Eklund, P. C.;
Riska, A. I.; Sjoeholm, R. E. J. Org. Chem. 2002, 67, 7544-7546. (d)
Eklund, P.; Sillanpaeae, R.; Sjoeholm, R. J. Chem. Soc., Perkin Trans. 1
2002, 1906-1910.
(12) Originally isolated from Picea mariana (black spruce): Freudenberg,
K.; Knof, L. Chem. Ber. 1957, 90, 2857-2869.
(13) Marco, J. A.; Sanz, J. F.; Sancenon, F.; Susanna, A.; Rustaiyan,
A.; Saberi, M. Phytochemistry 1992, 31, 3527-3530.
(14) Nishibe, S.; Chiba, M.; Sakushima, A.; Hisada, S.; Yamanouchi,
S.; Takido, M.; Sankawa, U.; Sakakibara, A. Chem. Pharm. Bull. 1980,
28, 850-860.
(15) Synthesis of racemic 7-oxygenated matairesinols: Makela, T.
H.; Kaltia, S. A.; Wahala, K. T.; Hase, T. A. Steroids 2001, 66, 777-
784.
(16) Reynolds, A. J.; Scott, A. J.; Turner, C. I.; Sherburn, M. S. J. Am.
Chem. Soc. 2003, 125, 12108-12109.
(17) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957-4960.
Thionocarbonates 24a and 24b underwent the desired
domino radical reaction in acceptable yields and very high
(18) (a) Mander, L. N.; Sherburn, M. S. Tetrahedron Lett. 1996, 37,
4255-4258. (b) Bachi, M. D.; Bosch, M.; Denenmark, D.; Girsh, D. J.
Org. Chem. 1992, 57, 6803-6810.
(19) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941.
1346
Org. Lett., Vol. 6, No. 9, 2004

Scheme 2. Total Syntheses of 7(S)-Hydroxymatairesinol 2 and 7(S)-Hydroxyarctigenin 6a
a Key: (a) 18 (1.8 equiv), n-Bu2BOTf (2 equiv), NEt3 (2.6 equiv), CH2Cl2, then 17 (1 equiv), -78 to 0 °C, 1 h, then H2O2, pH 7.2 buffer,
Et2O, 25 °C, 48 h; (b) TBSOTf (1.2 equiv), 2,6-lutidine (1.8 equiv), CH2Cl2, 25 °C, 0.5 h, overall yields from 17: 20a, 83%; 20b, 92%;
(c) NaBH4 (10 equiv), THF-H2O, 25 °C, 16 h, 21a, 77%; 21b, 85%; (d) m-CPBA (1.5 equiv), CH2Cl2, 40 °C, 2 h, 98%; (e) K2CO3 (1
equiv), MeOH, 25 °C, 10 min, 90%; (f) DBU (1.6 equiv), CH2Cl2, 25 °C, 0.5 h, then CSCl2 (4.3 equiv), CH2Cl2, 0 °C, 20 min, 100%; (g)
21 (1 equiv), pyridine (2 equiv), 23 (1.2 equiv), CH2Cl2, 2 h, 24a, 81%; 24b, 88%; (h) (Me3Si)3SiH (1.1 equiv), AIBN (0.4 equiv added
over 6 h), PhH, 80 °C, 25a, 44%; 25b, 44%; (i) n-Bu4NF (15 equiv), AcOH (15 equiv), THF, 25 °C, 96 h, 2, 90%; 6, 86%.
(>95%) trans-diastereoselectivity with (Me3Si)3SiH as re-
agent. Removal of the silyl protecting groups furnished the
7(S)-hydroxy lignans. Spectroscopic and physical data for
synthetic 7(S)-hydroxymatairesinol 2 were in good agreement
with data reported for this compound.20 In contrast, charac-
terization data collected on synthetic 7(S)-hydroxyarctigenin
6 were not in accord with literature13,14 figures. We suspected
that the stereochemistry of this natural product had been
incorrectly assigned in these previous investigations. To
clarify this issue, we pursued the preparation of 7, the 7(R)-
diastereoisomer of 6. The results of this and related chemistry
is depicted in Scheme 3. Inversion of the C7-hydroxy group
of 6 was achieved under modified Mitsunobu conditions.21
Spectroscopic and physical data for synthetic 7(R)-hydroxy-
arctigenin 7 was in good agreement with literature data for
natural 7-hydroxyarctigenin.13,14 We therefore conclude that
the stereochemistry of the natural product has been incor-
rectly assigned.22
be carried out in the presence of a free C4′ phenol (6 f 7
and 6 f 8, respectively), a free phenolic residue at C4 caused
these reactions to fail. Thus, access to oxygenated mataires-
inol natural products 3 and 4 was by way of the silyl-
protected compound 30. Spectroscopic and physical data for
synthetic 7(R)-hydroxymatairesinol 3 and 7-oxomatairesinol
4 were in good agreement with literature data.12,20 Hydro-
genolytic deoxygenation of the benzylic alcohol group23 (2
f 1; 6 f 5) afforded samples of (-)-matairesinol and (-)-
arctigenin.24
The synthetic potential of these compounds was further
exemplified by their ready conversion into aryl tetrahy-
dronaphthalene (2 f 28; 6 f 29)25 and dibenzocyclooctane
(5 f 27)26 lignan skeletons. Once again, characterization
data for (-)-R-conidendrin 28 (and the corresponding
monomethyl ether 29) prepared by this route matched those
reported in the literature for the natural product.27
Interestingly, whereas both Mitsunobu inversion and
Parikh-Doering oxidation of the C7-hydroxyl group could
(23) Enders, D.; Lausberg, V.; Del Signore, G.; Berner, O. M. Synthesis
2002, 515-522.
(24) Spectroscopic and physical data were in excellent agreement with
literature data for (-)-arctigenin and (-)-matairesinol: Rahman, M. M.;
Dewick, P. M.; Jackson, D. E.; Lucas, J. A. Phytochemistry 1990, 29, 1971-
1980. See also refs 4a and 12.
(25) Nishibe, S.; Tsukamoto, H.; Hisada, S.; Yamanouchi, S.; Takido,
M. Chem. Parm. Bull. 1981, 29, 2082-2085. See also ref 12.
(26) Hughes, D. D.; Ward, R. S. Tetrahedron 2001, 57, 4015-4022.
(20) Mattinen, J.; Sjo¨holm, R.; Ekman, R. ACH Models Chem. 1998,
135, 583-590. The authors of this paper incorrectly assigned the configura-
tions of the two 7-hydroxymatairesinol diastereoisomers. This error was
recently corrected following X-ray analysis. See ref 11d.
(21) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020.
(22) See the Supporting Information for full details.
Org. Lett., Vol. 6, No. 9, 2004
1347

Scheme 3. Transformations of 7(S)-Hydroxy Lignans 2 and 6a
a Key: (a) H2 (4 atm), 10% Pd/C (0.1 equiv), HClO4 (0.1 equiv), EtOH, 48 h, 25 °C, 2 f 1, 78%; 6 f 5, 80%; (b) RuO2‚2H2O (2
equiv), CF3CO2H (54 equiv), (CF3CO)2O (15 equiv), BF3‚Et2O (7 equiv), CH2Cl2, 16 h, 25 °C, 1 f 26, 0%; 5 f 27, 80%; (c) PPh3 (3
equiv), p-NO2C6H4CO2H (3 equiv), DEAD (3 equiv), PhH, 25 °C, 48 h, then K2CO3 (2.5 equiv), KHCO3 (0.7 equiv), MeOH-H2O, 25 °C,
1 h, overall yields: 6 f 7, 47%; 30 f 31, 83%; (d) CF3CO2H (3.3 equiv), CH2Cl2, 25 °C, 1 h, 2 f 28, 100%; 6 f 29, 100%; (e) i-Pr2NEt
(6 equiv), SO3‚pyr (3 equiv), DMSO, 25 °C, 1 h, 6 f 8, 84%; (f) TBSCl (2.1 equiv). imidazole (2.1 equiv), DMF, 2 h, 25 °C, 2 f 30,
77%; (g) PCC, CH2Cl2, 1 h, 25 °C, 30 f 32, 77%; (h) TBAF (4 equiv), AcOH (4 eq) THF, 16 h, 25 °C, 31 f 3, 72%; 32 f 4, 84%.
In summary, a conceptually novel route to lignans has been
developed. Many new analogues of biologically important
compounds are now accessible due to the short and conver-
gent nature of this approach. Optimization studies and further
applications of the radical carboxyarylation reaction are under
way.
Acknowledgment. We thank the Australian Research
Council for funding.
Supporting Information Available: Experimental pro-
cedures, product characterization data, and 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) Dhal, R.; Nabi, Y.; Brown, E. Tetrahedron 1986, 42, 2005-2016.
See also refs 12 and 25.
OL049878B
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Org. Lett., Vol. 6, No. 9, 2004