A new synthesis of 3-carboxy-2,5-disubstituted furans and their conversion to 5-vinyl derivatives

Article abstract of DOI:10.1016/S0040-4039(99)02290-X

A new route to the title compounds is described. The key transformation involves treatment of a 2-(4-keto-2-alkynyl)-3-ketobutanoate with silica gel or Et₃N to effect ring closure and subsequent double bond isomerization. (C) 2000 Elsevier Scie

Full text of DOI:10.1016/S0040-4039(99)02290-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1347–1350
A new synthesis of 3-carboxy-2,5-disubstituted furans and their
conversion to 5-vinyl derivatives
James A. Marshall ∗ and Dong Zou
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA
Received 8 November 1999; accepted 29 November 1999
Abstract
A new route to the title compounds is described. The key transformation involves treatment of a 2-(4-keto-2-
alkynyl)-3-ketobutanoate with silica gel or Et3N to effect ring closure and subsequent double bond isomerization.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cyclization; furans; diones; isomerization.
Cembranes are a large group of macrocyclic diterpenes isolated from diverse sources including pine
trees, soft coral, and ants.1 A subgroup of these compounds contains a furan ring and a butenolide
embedded within a 12- or 14-membered carbocycle. Some of the more structurally and biologically
interesting members of this subgroup feature a 3-carboxy-2,5-furan system (Fig. 1).2a
Fig. 1. Representative furanocembrane and pseudopterolide natural products
A number of synthetic routes to 3-methyl-2,5-dialkyl and 3-methyl-2-alkyl-5-vinyl substituted furans
have been reported.2a–c However, general routes to the 3-carboxy 5-vinyl analogues are less common.3,4
A recent method utilizes the Pd(0) or base-catalyzed ring closure of an α-propargylic β-keto ester to
prepare prototype 2-isopropyl-3-carboxy-5-vinyl furans (Eq. (1)).5
∗
Corresponding author. Tel: +00 804-924-7997; fax: +00 804-924-7993; e-mail: jam5x@virginia.edu (J. A. Marshall)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02290-X
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(1)
We have developed a mild and potentially versatile synthesis of 3-carboxy furans and effected
the transformation of these intermediates to 5-vinylfurans with structural features required for the
construction of furanocembrane (14-membered) and pseudopterane (12-membered) natural products
(Fig. 1).2a The essence of our approach is detailed in Eq. (2). Accordingly, a β-keto ester such as I
was expected to undergo acid- or base-catalyzed enolization and ensuing intramolecular 1,4-addition
to the alkynone to afford a vinylic ketone III. Subsequent double bond isomerization would afford the
furan IV. The carbonyl substituent of this intermediate could then be further transformed to a vinylic
substituent with the desired substitution pattern.
(2)
Our initial studies were conducted with β-keto ester 2 obtained by alkylation of methyl acetoacetate
with mesylate 1 (Scheme 1).6 Deprotection and Dess–Martin oxidation7 afforded diketone 4 in high
overall yield. Upon brief exposure to silica gel in hexane, diketone 4 was converted to furan 5 in
near quantitative yield. This cyclization could also be effected, in quantitative yield, by exposure of
diketone 4 to Et3N in hexanes. Methylation was achieved via the enol triflate 78 through treatment with
Me2Zn in the presence of Pd(PPh3)4. The stereochemistry of the vinylfuran 8 was confirmed through
NOE measurements. None of the (Z)-isomer could be detected. The direct sp2–sp3 coupling leading to
vinylfuran 8 is noteworthy for its efficiency.9
Scheme 1. (a) TBS=t-BuMe2Si, NaHMDS=NaN(TMS)2
A second application of the new methodology is outlined in Scheme 2. This sequence starts from the β-
keto ester 910 and proceeds via diketone 11 along the lines described in Scheme 1. As before, cyclization
to the keto furan 12 proceeds in high yield by treatment with silica gel or Et3N.

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Scheme 2. (a) DPS=t-BuPh2Si, PPTS=pyridinium p-toluenesulfonate; (b) (i) LiN(TMS)2, THF–HMPA; (ii) 2-(C5H4N)NTf2
(6), (90%); (iii) Pd(PPh3)4, Me2Zn (95%)
The foregoing route to 3-carboxyfurans should be well suited to the synthesis of furanocembranes such
as pukalide. In fact, preliminary findings on a ‘furan last’2 approach show great promise.11 These studies
are currently in progress and will be reported in due course.
1. Representative procedures
1.1. 2-Methyl-3-carbomethoxy-5-(2-ketoheptyl)furan (5)
Silica gel procedure: To a stirred solution of 100 mg of ketone 4 in 10 mL of hexanes was added
1 g of silica gel. The mixture was stirred at room temperature overnight and filtered. The filtrate was
concentrated and the residue was purified by flash column chromatography with 10% EtOAc-hexanes as
eluent to afford 95 mg (95%) of furano ketone 5. 1H NMR (300 MHz, CDCl3): δ 6.42 (s, 1H), 3.80 (s,
3H), 3.63 (s, 2H), 2.53 (s, 2H), 2.44 (t, 2H), 2.53 (m, 2H), 1.26 (m, 5H), 0.86 (t, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 250.8, 164.3, 158.9, 146.3, 114.1, 108.9, 51.2, 41.9, 41.8, 31.2, 23.2, 22.4, 13.8, 13.7.
Anal. calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.43; H, 8.00.
Et3N procedure: To a solution of 90 mg of ketone 4 in 10 mL of hexanes was added 0.05 mL of Et3N
at room temperature. The mixture was stirred at room temperature for 5 min and quenched with brine.
The mixture was extracted with ether twice and the combined ether extracts were dried over MgSO4 and
filtered through silica gel. The filtrate was concentrated to afford 89 mg (99%) of furano ketone 5.
1.2. 2-Methyl-3-carbomethoxy 5-[(E)-2-methyl-1-heptenyl]furan (8)
To a solution of 30 mg (0.12 mmol) of furano ketone 5 in 1.2 mL of anhydrous THF at −78°C was
added 0.3 mL of HMPA and 0.13 mL (0.13 mmol) of 1.0 M LHMDS in hexanes. The mixture was stirred
for 15 min and a solution of 71 mg (0.24 mmol) of Commin’s reagent 67 in THF was added. The cooling
bath was removed and, after 1 h, water and ether were added. The mixture was extracted with ether three
times and the combined extracts were washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by flash column chromatography with 10% EtOAc-hexanes
as eluent to afford 44 mg (95%) of triflate 7. 1H NMR (CDCl3): δ 6.77 (s, 1H), 5.98 (s, 1H), 3.82 (s, 3H),
2.60 (s, 3H), 2.46 (t, 2H), 1.59 (m, 2H), 1.35 (m, 4H), 0.93 (m, 3H) ppm.
To a stirred solution of 35 mg of triflate 7 in 1 mL of THF at 0°C was added 4 mg of Pd(PPh3)4.
The mixture was stirred for 15 min and 0.27 mL of Me2Zn (1.0 M solution in heptane) was added. The
mixture was allowed to warm to rt slowly and stirred for 24 h. The reaction was quenched with water and
the mixture was extracted with ether twice. The combined ether layers were dried over MgSO4, filtered
and concentrated. The residue was purified by flash column chromatography with 5% EtOAc-hexanes as
eluent to afford 22 mg (99%) of furan 8. 1H NMR (300 MHz, CDCl3): δ 6.39 (s, 1H), 5.99 (s, 1H), 3.82

1350
(s, 3H), 2.56 (s, 3H), 2.14 (t, 2H), 1.94 (s, 3H), 1.49 (m, 2H), 1.40–1.20 (m, 4H), 0.89 (t, 3H) ppm. Anal.
calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.85; H, 8.99.
Acknowledgements
Financial support was provided by research grant GM29475 from the National Institutes of General
Medical Sciences.
References
1. Weinheimer, A. J.; Chang, C. W. J.; Matson, J. A.; Progress in the Chemistry of Organic Natural Products 1979, 36, 286.
2. (a) Marshall, J. A. Recent Res. Devel. in Organic Chem. 1997, 1. (b) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60,
5966. (c) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687.
3. Access to these compounds has typically involved the synthesis of a 5-formyl derivative and subsequent Wittig-type
condensation4a or Pd(0)-catalyzed coupling of a 5-furanylzinc halide or tributylstannane with a vinylic halide4b to install the
vinyl substituent.
4. (a) Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J. Am. Chem. Soc. 1992, 114, 3910. Marshall, J. A.; Bartley, G. S.;
Wallace, E. M. J. Org. Chem. 1996, 61, 5729. (b) Paterson, I.; Gardner, M.; Banks, B. J. Tetrahedron 1989, 45, 5283. (c)
Paterson, I.; Brown, R. E.; Urch, C. J. Tetrahedron Lett. 1999, 40, 5807.
5. Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63, 7132.
6. This mesylate was prepared from 1-octyn-3-ol (Aldrich 12,728-0) by the sequence (1) silylation; TBSCl, imidazole (99%)
(2) formylation; BuLi (CH2O)n (89%) (3) mesylation; MsCl, Et3N (94%).
7. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
8. Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org. Synth. 1997, 74, 77.
9. Hu, T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229. Smith III, A. B.; Kaufman, M. D.; Beauchamp, T. J.;
LaMarche, M. J.; Arimoto, H. Organic Lett. 1999, 1, in press.
10. The β-keto ester was prepared from 1,3-propanediol by the sequence (1) silylation; t-BuPh2SiCl (DPSCl), imidazole (64%)
(2) Swern oxidation; (COCl)2, DMSO, Et3N, CH2Cl2 (84%) (3) acetylide addition; LiC^CCH2OPMB, THF (96%) (4)
silylation; TBSCl, imidazole (95%) (5) PMB cleavage; DDQ, CH2Cl2, H2O (81%) (6) mesylation; MsCl, Et3N (95%) (7)
alkylation; MeCOCH2CO2Me, NaHMDS, Bu4NI, THF (62%).
11. The following example (Zou, D.; VanDevender, E. A., unpublished) is illustrative: