A new approach for the synthesis of naturally occurring dihydrobenzo[b]furan-type neolignans of potential biological activity

Article abstract of DOI:10.1016/S0040-4039(00)00187-8

A new synthesis of racemic naturally occurring neolignan 1 possessing a PGI₂ inducing effect was achieved via the 2,3-dihydrobenzo[b]furan derivative 2, starting from the commercially available materials o-vanillin and acetovanillone. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00187-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2491–2494
A new approach for the synthesis of naturally occurring
dihydrobenzo[b]furan-type neolignans of potential biological
activity†
László Juhász,a Zoltán Dinya,a Sándor Antus a,∗ and Tamás E. Gunda b
aDepartment of Organic Chemistry, Lajos Kossuth University, PO Box 20, H-4010 Debrecen, Hungary
bResearch Group of Antibiotics of the Hungarian Academy of Sciences, Lajos Kossuth University, PO Box 70,
H-4010 Debrecen, Hungary
Received 9 December 1999; revised 12 January 2000; accepted 25 January 2000
Abstract
A new synthesis of racemic naturally occurring neolignan 1 possessing a PGI2 inducing effect was achieved
via the 2,3-dihydrobenzo[b]furan derivative 2, starting from the commercially available materials o-vanillin and
acetovanillone. © 2000 Elsevier Science Ltd. All rights reserved.
Neolignans possessing the 2,3-dihydrobenzo[b]furan skeleton are a class of naturally occurring hetero-
cyclic compounds with hepatoprotective,1 hormone blocking,2,3 antibacterial,4 antifungal,5 plant growth
regulator6 and antioxidant7 activity. The basic ring system of these compounds can be biosynthetically
deduced by dimerization of p-propenylphenols, such as isoeugenol, coniferyl or sinapyl alcohol. Until
now the practical synthetic routes to this structure were based on this biomimetic process involving a
neutral phenoxy radical8–10 or phenoxonium ion11 intermediate.
In continuation of our investigations of this type of biologically active natural neolignan10–13 we now
report a new simple approach for the synthesis of the neolignan 1 isolated from Zyziphus jujuba Mill14
which shows a significant PGI2 inducing effect. Although our previous approach12 based on the oxidative
coupling of methyl ferulate led to this natural product (1) in a straightforward fashion, it still appeared
reasonable to examine a new method permitting the synthesis of analogues differing in the side chain at
C-5.
∗
†
Corresponding author. Fax: (52) 453-836; e-mail: antuss@tigris.klte.hu (S. Antus)
This paper is dedicated with respect and admiration to Professor Hildebert Wagner on the occasion of his 70th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00187-8
tetl 16467

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The strategy of our synthesis was based on the well-documented15 synthetic availability of racemic
2 from the commercially available starting materials o-vanillin and acetovanillone. Thus, on the basis
of quantum chemical calculations [Mullikan charges16 (q) and superdelocalizations17 (sd) are given in
Table 1], we assumed that bromination of the acetyl derivative (3) of 2 would take place at C-5 and
this functional group offers opportunity to introduce various side chains to the 2,3-dihydrobenzo[b]furan
skeleton.
Table 1
Quantum chemical data of 3
Indeed, the 5-bromo-2,3-dihydrobenzo[b]furan derivative 4 could be obtained from 3 by a simple
bromination in acetic acid at room temperature in good yield (80%), although such a high selectivity in
this reaction could not be expected only on the basis of our quantum chemical calculations. The structure
of 4 was also independently proved by its synthesis from 5-bromo-2-benzyloxy-3-methoxybenzaldehyde
prepared from o-vanillin according to the literature18,19 by the same sequence as described for the
synthesis of 2.15
Starting from the 5-bromo-2,3-dihydrobenzo[b]furan derivative 4, the synthesis of neolignan 1 was
accomplished by two routes (Fig. 1). First, 4 was allowed to react with methyl acrylate under the
conditions of the Heck reaction20 to result in 5 in a moderate yield (30%). Saponification of 5 with
sodium methoxide in methanol at room temperature gave our target molecule (1).
In the other route, the acetyl protecting groups of 4 were exchanged for methoxymethyl ethers
(4→6→7), followed by replacement of the bromine substituent in 7 with an aldehyde group (7→8) using
n-butyllithium as the metallation reagent and DMF as the formyl source, in good overall yield (21%).
The E-olefinic side chain of 1 was stereoselectively introduced by a Wittig reaction of 8 with
carboxymethyltriphenylphosphorane in benzene at 60°C to give 9 in 44% yield. Then cleavage of the
methoxymethyl groups of 9 under mild acidic conditions also resulted in 1 in high yield (80%).21
In conclusion, we have achieved a simple synthesis of 2,3-dihydrobenzo[b]furan derivative 4, being
a suitable intermediate in the synthesis of neolignan 1. It is our belief that 4 will be a versatile
building block for the synthesis of a variety of natural products having the 2,3-dihydrobenzo[b]furan
skeleton.

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Fig. 1. (i) methylacrylate, Pd(OAc)2, PhP3/Et3N, 100°C (30%); (ii) and (iii) NaOMe/MeOH, rt (73% and 86%); (iv) MOMCl,
iPr2EtN/CH2Cl2, rt (62%); (v) BuLi, dry DHF/dry THF, −78°–25°C (41%); (vi) Ph3P_CHCOOCH3/dry benzene, 60°C (44%);
(vii) 5% HCl/MeOH, rt (71%)
References
1. Hikino, H.; Kiso, Y.; Wagner, H.; Fibig, H. Planta Med. 1984, 248–250.
2. Kemper, F. Arzneim.-Forsch. 1959, 9, 368–375.
3. Kemper, F.; Loser, A. Acta Endocrinol. 1958, 29, 525–530.
4. Hattori, H.; Hada, S.; Watahiki, A.; Ihara, H.; Shu, Y. Z.; Kakiuchi, N.; Mizuno, T.; Namba, T. Chem. Pharm. Bull. 1986,
34, 3885–3893.
5. Stoessl, A. Can. J. Chem. 1967, 45, 1745–1760.
6. Binns, A. N.; Chen, R. H.; Wood, H. N.; Lynn, D. G. Proc. Nat. Acad. Sci. USA 1987, 84, 980–984.
7. Fukuyama, Y.; Nakahara, M.; Minami, H.; Kodama, M. Chem. Pharm. Bull. 1996, 44, 1418–1420.
8. Freudenberg, K.; Hübner, H. H. Chem. Ber. 1952, 12, 1181–1191.
9. Leopold, B. Acta Chem. Scand. 1950, 4, 1523–1537.
10. Antus, S.; Bauer, R.; Gottsegen, Á.; Seligmann, O.; Wagner, H. Liebigs Ann. Chem. 1987, 357–360.
11. Juhász, L.; Kürti, L.; Antus, S. J. Nat. Prod., in press.
12. Antus, S.; Gottsegen, Á.; Kolonits, P.; Wagner, H. Liebigs Ann. Chem. 1989, 593–594.
13. Antus, S.; Baitz-Gács, E.; Gottsegen, Á.; Seligman, O.; Wagner, H. Liebigs Ann. Chem. 1990, 495–497.
14. Fukuyama, Y.; Mizuta, K.; Nagakawu, K.; Wenjuan, Q.; Xiue, W. Planta Med. 1986, 502–504.
15. Brunow, G.; Lundquist, K. Acta Chem. Scand. 1984, 38, 335–336.
16. The AM1 calculation were carried out using the MOPAC97 program embedded into Chem3D 5.0 (CambridgeSoft Corp.).
17. Schüürmann, G. Quant. Struct.-Act. Relat. 1990, 9, 326–331.
18. Natarajan, S.; Rajeswari, S.; Chandrasekaran, S.; Pai, B. R.; Shanmuganathan, Sp.; Rao, K. Indian J. Chem. Sect. B 1982,
21, 95–97.
19. Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004–1015.
20. Heck, R. F. Pure Appl. Chem. 1978, 50, 691–701.
21. Selected spectroscopic and physicochemical properties: rac-1, colorless needles of mp 174–176°C, identified with authentic
sample12 by mixed mp and spectroscopic methods. Compound 3, colorless oil, 1H NMR: δ 2.05 and 2.29 (6H, s, OAc); 3.78
(3H, s, OMe); 3.80 (1H, m, Hβ); 3.88 (3H, s, OMe); 4.30 (1H, dd, J=5.2, J=10.5, Hγ); 4.45 (1H, dd, J=5.2, J=10.5, Hγ‘);
1
5.52 (1H, d, J=6.71, Hα). Compound 4, colorless oil, H NMR: δ 2.07 and 2.32 (6H, s, OAc); 3.80 (3H, s, OMe); 3.80
(1H, m, Hβ); 3.89 (3H, s, OMe); 4.30 (1H, dd, J=5.21, J=10.5, Hγ); 4.41 (1H, dd, J=5.21, J=10.5, Hγ‘); 5.52 (1H, d,
J=6.72, Hα); 6.88–7.05 (5H, m, ArH); HRMS m/z 448.0518 (calcd for C21H21O6Br: 448.0518). Compound 5, colorless

2494
1
0
oil, H NMR: δ 3.82 (3H, s, COOMe); 6.32 (1H, d, J=15.9, Hβ ); 7.62 (1H, d, J=15.9, Hα); HRMS m/z 472.1730 (calcd
1
for C25H28O9: 472.1725). Compound 6, colorless oil, H NMR: δ 3.65 (1H, m, Hβ); 3.88 and 3.89 (6H, s, OMe); 3.92
(2H, m, Hγ); 5.55 (1H, d, J=6.71 Hα); 6.85–7.26 (5H, m, ArH); HRMS m/z 381.0337 (calcd for C17H18O5Br: 381.0342).
1
Compound 7, colorless oil, H NMR: δ 3.36, 3.50, 3.82 and 3.83 (12H, s, OMe); 4.68 and 5.22 (4H, s, OCH2O); HRMS
m/z 470.0944 (calcd for C21H27O7Br: 470.0932). Compound 8, colorless oil, 1H NMR: δ 9.85 (1H, s, CHO); 13C NMR: δ
178.93 (CHO); HRMS m/z 402.1673 (calcd for C22H26O7: 402.1678). Compound 9, colorless oil, 1H NMR: δ 3.85 (3H, s,
0
0
COOMe); 5.59 (1H, d, J=6.71, Hα); 6.30 (1H, d, J=15.1, Hβ ); 7.62 (1H, d, J=15.1, Hα ); HRMS m/z 476.2046 (calcd for
C25H32O9: 476.2037).