A facile Diels-Alder route to dihydronaphthofuranones

Article abstract of DOI:10.1016/S0040-4039(00)00585-2

An efficient, multigram-scale synthesis of dihydronaphthofuranone 1 using a novel aryl intramolecular Diels-Alder reaction of propargyl trans- cinnamate 8 is described. Catalytic reduction of 1 gave the cis-fused tetrahydronaphthofuranone derivative 2. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00585-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4043–4047
A facile Diels–Alder route to dihydronaphthofuranones
Samuel Chackalamannil,a,∗ Darío Doller,a Martin Clasby,a Yan Xia,a Keith Eagen,a Yan Lin,a
Hsing-An Tsai a and Andrew T. McPhail b
aSchering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bP. M. Gross Chemistry Laboratory, Duke University, Durham, NC 27708-0346, USA
Received 11 February 2000; accepted 30 March 2000
Abstract
An efficient, multigram-scale synthesis of dihydronaphthofuranone 1 using a novel aryl intramolecular
Diels–Alder reaction of propargyl trans-cinnamate 8 is described. Catalytic reduction of 1 gave the cis-fused
tetrahydronaphthofuranone derivative 2. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: dihydronaphthofuranone; tetrahydronaphthofuranone; perhydronaphthofuranone; intramolecular Diels–Alder
reaction; aryl intramolecular Diels–Alder reaction.
The naphthofuranone ring system is found in a number of biologically important natural products such
as podophyllotoxin (3), conidendrin (4), and himbacine (5) (Fig. 1).1–4 The stereoselective construction
of tetrahydro- and perhydronaphthofuranone skeletons often requires lengthy protocols.5,6 In connec-
tion with the total synthesis of himbacine, we have reported an efficient intramolecular Diels–Alder
(IMDA) reaction (Eq. (1)) that leads to the stereoselective construction of perhydronaphthofuranone
ring system.6a,7,8 Herein we wish to report the extension of this methodology to the construction of
functionalized tetrahydronaphthofuranones using a novel aryl intramolecular Diels–Alder reaction as
represented in Eq. (2).
Fig. 1.
∗
Corresponding author. E-mail: samuel.chackalamannil@spcorp.com (S. Chackalamannil)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00585-2
tetl 16864

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(1)
(2)
Klemm has reported the intramolecular Diels–Alder cyclization of cinnamamide derivatives 9 (Eq.
(3)).9 However, these examples are limited to phenyl propargyl cinnamamides (9). Attempted cyclization
of the corresponding ester 11 has been reportedly unsuccessful.9a Our own attempts to cyclize cinnamate
derivatives 12 and 14 resulted only in the recovery of unreacted starting material. However, we have
found that the cinnamic acid ester 8, which contains an activated propargylic moiety as the dienophile,
undergoes efficient cyclization at 195°C to give the tricyclic dihydronaphthofuranone intermediate 1 (Eq.
(2)).
(3)
(4)
(5)
The general synthetic approach is presented in Scheme 1. Esterification of commercially available
cinnamoyl chloride (18) with the propiolate 17, prepared in two steps from commercially available
protected propargylic alcohol 16, yielded the IMDA precursor 8a. The cyclization was effected by heating
a solution of 8a in o-xylene for 24 h to give the tricyclic derivative 1a. A small quantity (10–15%) of
naphthofuranone 19 was isolated as the side product. Rigorous exclusion of oxygen and a shorter reaction
time minimized the relative amount of this side product, which presumably arises from the air oxidation
of 1a. A single diastereomer of the product, with exclusive presence of the double bond at the C9–C9a
position, was isolated in all cases.

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Scheme 1.
As shown in Table 1, the reaction is general for a variety of substrates and can be readily performed on
a 100 g scale. The unoptimized yields generally range between 45 and 65%. The versatility of this process
is further underscored by the ease with which the Diels–Alder precursor is synthesized from commer-
cially available cinnamoyl chlorides (Scheme 1). Catalytic hydrogenation of dihydronaphthofuranone 1a
Table 1

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yielded the cis-fused10,11 tetrahydronaphthofuranone carboxylic acid 2a (Fig. 2) which is potentially a
versatile intermediate for the synthetic exploration of some of the natural products mentioned above and
the structure–activity relationship (SAR) studies of their analogs.
Fig. 2. X-Ray crystallographic structure of 2a (hydrogen atoms shown only at C9a, C3a, and C4)
In summary, we have discovered a concise synthesis of functionalized dihydronaphthofuranone
derivatives in three steps using a novel aryl intramolecular Diels–Alder reaction of cinnamic acid esters.
Further application of this methodology in the synthesis of biologically active compounds and the
mechanistic aspects of this aryl intramolecular Diels–Alder reaction will be reported in the future.
Acknowledgements
The authors would like to thank Drs. Ashit K. Ganguly, Michael Czarniecki, James Kaminski, and
William J. Greenlee for helpful discussions and Dr. Pradip Das for mass spectral data.
References
1. Ward, R. S. Nat. Prod. Rep. 1999, 16, 75, and references cited therein.
2. (a) Middel, O. Expert. Opin. Ther. Pat. 1996, 6, 547. (b) McRae, W. D.; Towers. G.H. N. Phytochemistry 1984, 1207. (c)
Charleton, J. A. J. Nat. Prod. 1998, 61, 1447.
3. Ritchie, E.; Taylor, W. C. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. 9, p. 529.
4. (a) Miller, J. H.; Aagaard, P. J.; Gibson, V. A.; McKinney, M. J. Pharmacol. Exp. Ther. 1992, 263, 663.
5. (a) Ward, R. S. Tetrahedron 1990, 46, 5029. (b) Arimoto, M.; Yamaguchi, H.; Nishebe, S. In Studies in Natural Products
Chemistry; Rahman, A., Ed.; Elsvier: Amsterdam, 1996; Vol. 18, p. 551. (c) Ward, R. S. Nat. Prod. Rep. 1997, 14, 43.
6. (a) Chackalamannil, S.; Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D.; McPhail, A. T. J. Org.
Chem. 1999, 64, 1932. (b) Hart, D. J.; Li, J.; Wu, W.-L.; Kozikowski, A. P. J. Org. Chem. 1997, 62, 5023. (c) Baldwin, J.
E.; Chesworth, R.; Parker, J. S.; Russell, A. T. Tetrahedron Lett. 1995, 36, 9551. (d) Hofman, S.; De Baecke, G.; Kenda,
B.; De Clercq, P. J. Synthesis 1998, 479.
7. Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.; Leone, D. J. Am. Chem. Soc. 1996, 118, 9812.
8. Carbonyl activation of dienophile in the precursor 6 gives an excellent outcome of the intramolecular Diels–Alder reaction,
although this result has not been reported in Ref. 6a and 7.
9. (a) Klemm, L. H.; McGuire, T. M.; Gopinath, K. W. J. Org. Chem. 1976, 41, 2571. See their Table II, 4th entry, which
indicates that the corresponding cinnamic acid ester did not cyclize. (b) Revesz, L.; Meigel, H. Helv. Chim. Acta 1988, 71,
1697. (c) Glinski, M. B.; Durst, T. Can. J. Chem. 1983, 61, 573.
10. The relative stereochemistry of cyclization product 1a, initially established using NMR methods, was corroborated by
X-ray crystallographic analysis of the crystalline carboxylic acid 2a (Fig. 2).
11. Representative physical data: Compound 8a: 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 5.22 (s, 2H), 6.51 (d, J=16.0 Hz,
1H), 7.41–7.50 (m, 8H), 7.59–7.61 (m, 2H), 7.81 (d, J=16.0 Hz, 1H); IR (neat) 1716, 1635 cm−1. Compound 1a: 1H NMR
(400 MHz, CDCl3) δ 3.58–3.68 (m, 1H), 3.86 (d, J=15.0 Hz, 1H), 4.04 (t, J=9.0 Hz, 1H), 4.64 (t, J=9.0 Hz, 1H), 5.31 (d,
J=12.0 Hz, 1H), 5.38 (d, J=12.0 Hz, 1H), 7.16–7.21 (m, 2H), 7.29–7.45 (m, 8H); IR (neat) 1785, 1735 cm−1; MS (ESI)
m/e 321 (M+H)+. Compound 8c: 1H NMR (CDCl3) δ 3.84 (s, 3H), 4.91 (s, 2H), 5.21 (s, 2H), 6.30 (d, J=15.6 Hz, 1H), 6.91
(d, J=6.8 Hz, 2H), 7.38 (m, 5H), 7.48 (d, J=7.2 Hz, 2H), 7.70 (d, J=16 Hz, 1H); MS (ESI) m/e 351 (M+H)+. Compound
1c: 1H NMR (CDCl3) δ 3.59 (m, 1H), 3.65 (s, 3H), 3.82 (d, J=11 Hz, 1H), 4.02 (t, J=8.8 Hz, 1H), 4.64 (t, J=8.95 Hz, 1H),
5.27 and 5.40 (dd, J=12.0 Hz, 2H), 6.73 (s, 1H), 6.83 (d, J=1.6 Hz, 1H), 7.29 (d, J=4.8 Hz, 1H), 7.49 (m, 6H); MS (ESI)
m/e 351 (M+H)+. Compound 8d: 1H NMR (400 MHz, CDCl3): δ 4.93 (s, 2H), 5.22 (s, 2H), 6.55 (d, J=16.0 Hz, 1H), 7.11

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(t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.35–7.40 (m, 6H), 7.53 (td, J=8.0 Hz, 2.0 Hz, 1H), 7.87 (d, J=16.0 Hz, 1H); MS
(FAB) m/e 339 (M+H)+; anal. calcd for C20H15FO4: C, 71.00; H, 4.47. Found: C, 70.66; H, 4.51. Compound 1d: 1H NMR
(400 MHz, CDCl3): δ 3.58–3.65 (m, 1H), 3.84 (d, J=15.0 Hz, 1H), 4.05 (t, J=9.0 Hz, 1H), 4.65 (t, J=9.0 Hz, 1H), 5.31 (d,
J=12.0 Hz, 1H), 5.37 (d, J=12.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.24–7.31 (m, 1H), 7.35–7.42
(m, 5H), 7.72 (d, J=3.0 Hz, 1H); MS (FAB) m/e 339 (M+H)+; anal. calcd for C20H15FO4·0.78CH2Cl2: C, 61.69; H, 4.13.
Found: C, 61.62; H, 4.43. Compound 8l: 1H NMR (400 MHz, CDCl3): δ 4.92 (s, 2H), 5.22 (s, 2H), 6.36 (d, J=16.0 Hz,
1H), 7.10 (t, J=9.0 Hz, 2H), 7.36–7.39 (m, 5H), 7.50–7.54 (m, 2H), 7.70 (d, J=16.0 Hz, 1H); IR (neat) 1713 cm−1; MS
(FAB) m/e 339 (M+H)+; anal. calcd for C20H15FO4: C, 71.00; H, 4.47. Found: C, 70.60; H, 4.46. Compound 1l: 1H NMR
(400 MHz, CDCl3): δ 3.58–3.65 (m, 1H), 3.84 (d, J=15.0 Hz, 1H,), 4.04 (t, J=9.0 Hz, 1H), 4.65 (t, J=9.0 Hz, 1H), 5.32
(d, J=12.0 Hz, 1H), 5.38 (d, J=12.0 Hz, 1H), 6.95–7.04 (m, 2H), 7.33–7.43 (m, 7H); IR (neat) 1756, 1739, 1727 cm−1. MS
(ESI) m/e 339 (M+H)+; anal. calcd for C20H15FO4: C, 71.00; H, 4.50. Found: C. 70.70; H, 4.50.