To supply sufficient quantities of the target material for
pharmacological study, highly efficient syntheses of these
complex molecules are required. Our careful analysis of the
targets has led to a synthetic strategy that is characterized
by the following important features: (1) convergency, (2)
brevity, and (3) flexibility. Our retrosynthetic analysis of
daurichromenic acid (1) is outlined in Scheme 2. Sequential
Table 1. Various Conditions for the Formation of
2H-Benzopyran, the Core Structure of Daurichromenic Acid
entry
1
conditions
yield
15%
5 (1.2 equiv), Ca(OH)2 (0.83 equiv),
MeOH, reflux, 4 days
2
3
4
5 (1.2 equiv), Ca(OH)2 (0.83 equiv),
MeOH, sealed tube, 90 °C, 1 day
5 (1.2 equiv), Ca(OH)2 (0.83 equiv),
MeOH, microwave irradiation, 3 × 1 min
5 (1.2 equiv), CaCl2‚2H2O (0.83 equiv),
NEt3 (3.32 equiv), EtOH, microwave
irradiation, 20 × 1 min
32%
23%
50%
Scheme 2
5
6
5 (1.2 equiv), CaCl2‚2H2O (0.83 equiv),
NEt3 (3.32 equiv), EtOH, reflux, 2 days
(i) 5 (2.0 equiv), CaCl2‚2H2O (0.83 equiv),
NEt3 (3.32 equiv), EtOH, microwave
irradiation, 20 × 1 min;
<5%
70%
(ii) 5 (1.0 equiv), microwave irradiation,
20 × 1 min
7
5 (2.0 equiv), pyridine, microwave irradiation,
25 min
<5%
known that microwave irradiation can accelerate many
reactions.7 Thus, we decided to investigate the possibility
of applying microwave irradiation to accelerate our tandem
condensation and intramolecular SN2′-type cyclization.
As expected, a much faster reaction was indeed observed
when the reaction was irradiated in a microwave oven.8 After
only 3 min of irradiation, compound 7 was isolated in 23%
yield (entry 3).9 However, we were not able to improve the
yield with longer irradiation time or with the addition of more
aldehyde 5. After screening a few different reaction condi-
tions, we found that the reaction between 5 and 6 in the
presence of CaCl2‚2H2O, NEt3, and EtOH provided 50%
yield of the desired product 7 and required only 20 min of
microwave irradiation (entry 4). Without microwave irradia-
tion, the yield of compound 7 was only 5% (entry 5). The
optimized conditions were listed in entry 6 in which the
mixture of compound 5 (2.0 equiv) and compound 6 (1.0
equiv) was irradiated for 20 min. Then, an additional 1.0
equiv of compound 5 was added and the mixture was
irradiated again for 20 min. Using these optimized conditions
allowed compound 7 to be isolated in 70% yield. It should
be noted that in the absence of CaCl2‚2H2O, NEt3, and EtOH,
only a trace amount of compound 7 was isolated when the
reaction was run in pyridine (entry 7).10
disconnection at O1-C2 and C4-C9 reveal fragments 5 and
6 as two starting materials, with tandem condensation and
intramolecular SN2′-type cyclization playing crucial roles in
the synthetic strategy.
Synthesis of 2H-benzopyrans (chrom-3-enes) has been the
subject of many investigations.4 The reaction developed by
Shigemasa appeared to be quite promising for the synthesis
of this class of natural products.5 Unfortunately, we found
that the reaction between 6 and 56 was extremely slow under
Shigemasa’s conditions. The mixture gave only 15% yield
of the desired product 7 after being heated at reflux for 4
days (Table 1, entry 1). The yield was improved to 32%
when the mixture was heated at 90 °C in a sealed tube for
1 day (entry 2). However, the reaction stopped, and the yield
could not be improved even with the addition of excess
aldehyde 5 and longer heating time.
Because the intramolecular SN2′-type cyclization is a fast
reaction, the overall slow reaction is presumably due to the
high activation energy in the condensation reaction. It is
(3) For the synthesis of rhododaurichromanic acids A and B and methyl
daurichromenic ester, see: Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.;
Wang, J. Org. Lett. 2003, 5, 3935.
Unfortunately, the hydrolysis of the ester functionality of
compound 7 to daurichromenic acid (1) proved to be
extremely difficult. After examining many procedures,11 we
(4) (a) Dotz, K. H. Pure Appl. Chem. 1983, 55, 1689 and references
therein. (b) Henry, G. E.; Jacobs, H. Tetrahedron 2001, 57, 5335. (c) Chang,
S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864. (d) Saimoto, H.; Yoshida,
K.; Murakami, T.; Morimoto, M.; Sashiwa, H.; Shigemasa, Y. J. Org. Chem.
1996, 61, 6768. (e) North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.;
Real, S. D.; Chen, H. Y. J. Org. Chem. 1995, 60, 3397. (f) Gabbutt, C. D.;
Hartley, D. J.; Hepworth, J. D.; Heron, B. M.; Kanjia, M.; Rahman, M. M.
Tetrahedron 1994, 50, 2507. (g) Cruz-Almanza, R.; Perez-Flores, F.; Lemini,
C. Heterocycles 1994, 37, 759. (h) Rao, U.; Balasubramanian, K. K.
Tetrahedron Lett. 1983, 24, 5023. (i) Sartori, G.; Casiraghi, G.; Bolzoni,
L.; Casnati, G. J. Org. Chem. 1979, 44, 803.
(7) For a recent review on microwave-assisted reactions, see: (a)
Caddick, S. Tetrahedron 1995, 51, 10403. (b) Galema, S. A. Chem. Soc.
ReV. 1997, 26, 233.
(8) We simply use a commerical household microwave to run the
reaction. It is a Panasonic model NNS740 (1200 W).
(9) Reaction was carried out in a sealed 60 mL Teflon pressure vessel
(purchased from Savillex Corp) filled with Argon.
(10) Subburaj, K.; Trivedi, G. K. Bull. Chem. Soc. Jpn. 1999, 72, 259.
(11) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley: New York, 1999.
(5) Saimoto, H.; Yoshida, K.; Murakami, T.; Morimoto, M.; Sashiwa,
H.; Shigemasa, Y. J. Org. Chem. 1996, 61, 6768.
(6) Compound 5 was readily prepared via MnO2-mediated oxidation of
trans,trans-Farnesol (70%).
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Org. Lett., Vol. 5, No. 23, 2003