Synthesis of methyl 2-oxo-5-vinyl-2,5-tetrahydrofuran-3-carboxylate

Article abstract of DOI:10.1016/j.tetlet.2005.12.114

A synthesis of methyl 2-oxo-5-vinyl-tetrahydrofuran-3-carboxylate involving five synthetic steps from commercially available 3,4-dihydroxybutene is reported.

Full text of DOI:10.1016/j.tetlet.2005.12.114

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1625–1626
Synthesis of methyl 2-oxo-5-vinyl-2,5-tetrahydrofuran-3-
carboxylate
Maximilian A. Silvestri,a Chang He,a Anita Khoramb and Salvatore D. Leporea,*
aDepartment of Chemistry, Florida Atlantic University, Boca Raton, FL 33431, USA
bCustom Synthesis Inc., Delray Beach, FL 33445, USA
Received 15 November 2005; revised 19 December 2005; accepted 21 December 2005
Available online 19 January 2006
Abstract—A synthesis of methyl 2-oxo-5-vinyl-tetrahydrofuran-3-carboxylate involving five synthetic steps from commercially
available 3,4-dihydroxybutene is reported.
Ó 2006 Elsevier Ltd. All rights reserved.
As part of an ongoing total synthesis project, we
required a reliable and scaleable procedure for the prepa-
ration of methyl 2-oxo-5-vinyl-tetrahydrofuran-3-car-
boxylate (1a).1 Initial attempts to prepare 1a centered
on a reported one-step procedure for the synthesis of
ethyl ester analog 1b involving the condensation of
diethyl malonate with butadiene monoxide.2 However,
repeated attempts to condense malonate ester with buta-
diene monoxide following the reported protocol led to
the formation of undesired regioisomers 2 as the major
products (Scheme 1).3 These data suggest that the struc-
ture of the lactone product described in earlier reports
were incorrectly assigned.4 In this letter, we describe
our attempts to develop an alternative approach to the
synthesis of 1a.
quent methoxycarbonylation would be expected to yield
1a (Scheme 2).6 Although the addition of Grignard
reagents to 3 has been previously described,5a we were
not able to obtain the desired lactone in reasonable
yields even after extensive optimization.
We next attempted a three-step synthesis of 1a starting
from 3,4-dihydroxybutene, which is commercially
available as the racemate and non-racemic forms.
Mono-tosylation of 3,4-dihydroxybutene7 to give 5
was followed by the formation of malonate ester 6.8
The addition of sodium hydride to 6 failed to give intra-
molecular C–C bond formation leading to 1a. Instead,
malonic esters 8 and 9 were isolated as a mixture (1:1)
after aqueous workup of the reaction. We hypothesize
that these two regioisomers arise from ketene acetal
intermediate 7 formed by O-alkylation, which is rapidly
hydrolyzed to afford observed products 8 and 9 (Scheme
3). Alternatively, intermediate 7 may be hydrolyzed
under workup conditions to afford either product 8 or
9, which are subsequently equilibrated to the observed
1:1 mixture via an acyl migration mechanism. In an
attempt to increase the likelihood of C-alkylation, the
tosylate leaving group of malonate 6 was converted to
the softer iodide in intermediate 10.9 However, attempts
We initially envisioned a two-step approach for the
preparation of 1a beginning with the addition of vinyl
Grignard to commercially available aldehyde ester 3 to
give lactone 4 following a related procedure.5 Subse-
O
O
O
O
O
O
ROH, Na, 50 o
OR
O
C
O
O
OR
RO
RO
R = Me or Et
1a (R = Me), 4%
1b (R = Et), 2%
2a, 26%
2b, 26%
O
O
CO(OMe)2
NaH, DME
50 oC
13%
MgBr
THF
Scheme 1. Condensation of butadiene monoxide with dimethyl and
diethyl malonate.
1a
MeO
O
O
-78 to 25 o
C
30%
4
3
*
Corresponding author. Tel.: +1 561 297 0330; fax: +1 561 297
2759; e-mail: slepore@fau.edu
Scheme 2. Two-step synthesis of 1a.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.114

1626
M. A. Silvestri et al. / Tetrahedron Letters 47 (2006) 1625–1626
O
O
Acknowledgements
O
O
OH
O
OMe
Cl
OMe
We thank the Florida Center of Excellence in Marine
Biotechnology for financial support. This work was also
supported by a grant from the National Institute of
General Medical Science (GM067635-01) and the Na-
tional Science Foundation Division of Undergraduate
Education (NSF-0311369) for the 400 MHz NMR used
in this study.
OTs
X
6
(X = OTs)
NaI
64%
CH2Cl2, TEA
90%
5
10 (X = I)
O
O
O
O
OMe
H
NaH
THF
ratio
(1:1)
OH
OMe
8
6
or
10
0
oC
57 - 78%
OH
O
O
O
OMe
7
9
O
O
Supplementary data
Scheme 3. Attempted intramolecular synthesis of 1a from 3,4-
dihydroxybutene.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2005.
12.114.
CH2(CO2Me)2
TBSCl,
TEA
OTBS
OTs
OTBS
NaI
NaH, DMF
References and notes
5
I
50 oC
76%
acetone
81%
CH2Cl2
76%
11
12
1. Morizawa, Y.; Hiyama, T.; Nozaki, H. Tetrahedron Lett.
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2. (a) Van Zyl, G.; Van Tamelen, E. E. J. Am. Chem. Soc.
1950, 72, 1357; (b) Russell, R. R.; Vander Werf, C. A. J.
Am. Chem. Soc. 1947, 69, 11.
3. The observed preference for malonate ion attack at the
vinyl substituted position of the oxirane has been
explained in terms of charge delocalization by the vinyl
p-orbitals in the transition state. Carrion, F.; Dewar, M. J.
S. J. Am. Chem. Soc. 1984, 106, 3531. The preference for
1,2-attack by soft nucleophiles is likely due to metal ion
coordination to the epoxide oxygen. Jamie, C.; Ortuno,
R. M.; Font, J. J. Org. Chem. 1988, 53, 139.
TBSO
OMe
TBAF
1a
THF
70%
MeO
O
O
13
Scheme 4. Intermolecular synthesis of 1a.
to cyclize iodide 10 under basic conditions also led to the
exclusive formation of 8 and 9 (1:1) in similar yields.
4. 1H NMR (including COSY) and 13C NMR spectra of the
major product formed in this reaction clearly support the
assignment of structure 2b. Specifically, the methyne
malonate proton appears as a doublet whereas in structure
1b it should appear as a doublet of doublets. Also the
chemical shift of methylene protons of 2b indicates
bonding of the methylene carbon to the lactone oxygen.
5. (a) Clive, D. L. J.; Wang, J. Tetrahedron Lett. 2003, 44,
7731; (b) Janowitz, A.; Kunz, T.; Handke, G.; Reissig,
H. U. Synlett 1989, 24.
6. Quesada, M. L.; Schlessinger, R. H. J. Org. Chem. 1978,
43, 346.
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Eur. J. Org. Chem. 1999, 1671; (b) Kabalka, G. W.;
Varma, M.; Varma, R. S.; Srivastava, P. C.; Knapp, F. F.,
Jr. J. Org. Chem. 1986, 51, 2386.
To accomplish an intermolecular malonate addition to 5
the secondary hydroxyl group of 5 was protected using
TBSCl to give ether 11 using standard conditions
(Scheme 4).10 An attempt to condense the tosylate 11
with dimethylmalonate using sodium hydride as a base
in DMF at 90 °C failed to yield the desired condensation
product. Further alkylation attempts involving the use
of a variety of solvents and added crown ether catalysts
also failed to yield the desired alkylation product. How-
ever, conversion to iodide 12 followed by condensation
with dimethyl malonate (9 equiv) using sodium hydride
as a base in DMF successfully yielded coupling product
13 in 76% yield.11 This intermediate was then converted
to the desired lactone 1a as a 1:1 mixture of diastereo-
mers in 70% yield in the presence of TBAF.12
8. Hudlicky, T.; Govindan, S. V.; Frazier, J. O. J. Org.
Chem. 1985, 50, 4166.
9. Ali, S.; Bittman, R. J. Org. Chem. 1988, 53, 5547–5549.
10. Drury, W. J.; Zimmermann, N.; Keenan, M.; Hayashi,
M.; Kaiser, H. S.; Goddard, R.; Pfaltz, A. Angew. Chem.,
Int. Ed. 2004, 43, 70.
11. (a) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 493; (b)
Lorca, M.; Kuroso, M. Tetrahedron Lett. 2001, 42, 2431.
12. Experimental procedures are provided in Supplementary
Data for compounds 5, 6, 8–10, 11–13, and 1a. Copies of
NMR spectra for compounds 1a (1H and 13C), 2b (1H,
1H–1H COSY, and 13C), 5, 6, and 8–13 (1H) are also
provided.
In conclusion, we have explored alternative synthetic ap-
proaches and identified a reliable synthesis of 1a starting
from 3,4-dihydroxybutene. Given the accessibility of
non-racemic 1,2-diols through highly selective catalytic
asymmetric dihydroxylation, we anticipate that the opti-
mized procedure described in this letter can be used to
obtain a variety of c-butyrolactones containing p-conju-
gating substituents at the c-position. Finally, the present
work provides a correction to earlier reports involving
malonate additions to vinyl oxirane.