Regioselective synthesis of α-methyl 2-methyleneglutarate via a novel lactonization-elimination rearrangement

Article abstract of DOI:10.1021/jo051854a

A facile route to the α-methyl ester of 2-methyleneglutarate via a three-step sequence from 3-hydroxymethylcyclopentene is described. Regioselective formation of the monoacid from a diester precursor proceeds via a novel fluoride-mediated, tandem deprotection/rearrangement of O-silyl 2-(hydroxymethyl)dimethylglutarate.

Full text of DOI:10.1021/jo051854a

SCHEME 1
Regioselective Synthesis of r-Methyl
2-Methyleneglutarate via a Novel
Lactonization-Elimination Rearrangement
David M. Bartley and James K. Coward*
Departments of Medicinal Chemistry and Chemistry, UniVersity
of Michigan, Ann Arbor, Michigan 48109-1055
jkcoward@umich.edu
ReceiVed September 2, 2005
A facile route to the R-methyl ester of 2-methyleneglutarate
via a three-step sequence from 3-hydroxymethylcyclopentene
is described. Regioselective formation of the monoacid from
a diester precursor proceeds via a novel fluoride-mediated,
tandem deprotection/rearrangement of O-silyl 2-(hydroxy-
methyl)dimethylglutarate.
carbinol, 4, as a glutarate surrogate leading to (2R)-2-(hydroxy-
methyl)glutaric acid, 3, was investigated
Racemic 4 (rac-4) and its sulfonate esters have been
investigated as precursors of delocalized carbonium ions, leading
to rearranged products on solvolysis.11 These authors reported
a multistep, low-yielding synthesis of rac-4, which has been
used by at least one other group but with no yields given.12 To
synthesize pseudopeptide 1 with the desired stereochemistry
(2S,2′S), a stereospecific synthesis of 3 was required which, in
turn, required a substituted cyclopentene precursor, e.g., 4, of
high stereochemical purity. The enantiomer of 4, (3R)-3-
(hydroxymethyl)cyclopentene (ent-4), has been described by
Maeda and Inouye.13 Thus, ent-4 was obtained from ethyl (2-
oxo)cyclopentane carboxylate via an enzyme-catalyzed dynamic
kinetic resolution to yield the (2R)-2-hydroxy ester, followed
by xanthate formation, pyrolytic elimination to form the cyclic
olefin, and finally reduction of the carboxylic acid ester to yield
ent-4. This compound is readily synthesized in high yield and
in large quantities if desired (see the Supporting Information
for details). To investigate the synthetic method outlined in
Scheme 1, ent-4, which is much more readily accessible than
4,9 was used in the research described in this paper.
Acrylic acids and acrylate esters substituted at C-2 are
synthetically useful intermediates, particularly in the synthesis
of natural products,1-3 pseudopeptides,4-6 and polymers.7 Our
interest in the design of phosphorus-containing pseudopeptides
as inhibitors of ATP-dependent ligases8,9 and Zn proteases10
has led us to develop new routes to both the R- and γ-monoesters
of 2-methyleneglutaric acid. As shown in Scheme 1, retrosyn-
thetic analysis suggested that the desired pseudopeptide, 1, could
possibly be obtained by either of two routes. These included
the stereoselective conjugate addition of a nucleophilic orga-
nophosphorus synthon to the differentially protected R-meth-
yleneglutarate, 2, bearing a chiral auxiliary (e.g., Evans’
oxazolidinone).5 In our hands, the diastereoselectivity of this
reaction was modest,9 so the possible use of ∆2-cyclopentenyl-
Protection of the alcohol as the O-silyl ether followed by
oxidative ring opening and concomitant methyl esterification
with the method of Marshall and Garafalo14 provided a mixture
of mono- and diesters. Following treatment with TMSCHN2,
diester 7 was obtained in 70% yield (Scheme 2). At this point,
the strategy was to remove the silyl ether (7 f 3) in order to
incorporate various phosphorus functionalities, which would be
converted to a nucleophilic reagent (PIII species, phosphorus
anion, phosphorus radical) for construction of the second P-C
bond required in the synthesis of 1. To our surprise, treatment
of 7 with TBAF resulted in a novel deprotection-rearrangement
reaction to give 5 in 84% yield.
* Address correspondence to this author. Phone: 734-936-2843. Fax: 734-
647-4865.
(1) Wolinsky, J.; Novak, R.; Vasileff, R. J. Org. Chem. 1964, 29, 3596-
3598.
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(12) Colombini, M.; Crotti, P.; Di Bussolo, V.; Favero, L.; Gardelli, C.;
Macchia, F.; Pineschi, M. Tetrahedron 1995, 51, 8089-8112.
(13) Maeda, K.; Inouye, Y. Bull. Chem. Soc. Jpn. 1994, 67, 2880.
(14) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675-
3680.
(8) Valiaeva, N.; Bartley, D.; Konno, T.; Coward, J. K. J. Org. Chem.
2001, 66, 5146-5154.
(9) Bartley, D. M.; Coward, J. K. J. Org. Chem. 2005, 70, 6757-6774.
(10) Tsukamoto, T.; Flannery, J.; Rojas, C.; Slusher, B. S.; Valiaeva,
N.; Coward, J. K. Bioorg. Med. Chem. Lett. 2002, 12, 2189-2192.
10.1021/jo051854a CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/25/2005
372
J. Org. Chem. 2006, 71, 372-374

SCHEME 2
SCHEME 3
Formation of 5 can be rationalized by the mechanism shown
in Scheme 3. Deprotection of the silyl protecting group results
in formation of alkoxide 8, which attacks the γ-methyl ester to
form lactone 9 and generate 1 equiv of methoxide anion. The
methoxide anion then abstracts the acidic lactone methine
proton, generating compound 10, which upon workup provides
5 in excellent yield. To our knowledge this is the first time that
this type of rearrangement has been described in the literature.
While synthetic routes to both 2-methylene glutaric acid and
the corresponding diesters are readily available,4,15-21 selective
esterification of one of the two acids has been reported only
rarely. 2-Methyleneglutaric acid 1-methyl ester, 5, has been
reported in a mechanistic study on the photooxygenation of
2-methoxy-3-methyl-2-cyclopenen-1-one;22 however, the iso-
lated yield was not reported and NMR analysis of the crude
reaction indicates yields of less than 50% for the formation of
5. The corresponding R-ethyl ester has been reported in the
patent literature via a lipase-catalyzed de-esterification of diethyl
2-methyleneglutarate.23 The regioisomeric ester, 2-methylene-
glutaric acid 5-methyl ester, has been prepared electrochemically
by the addition of CO2 to pent-4-ynoic acid methyl ester in 38%
yield; however, the free acid was not isolated. Instead, the
product was converted to the dimethyl ester for isolation and
purification.24 As reported in the patent literature, this regioi-
somer has also been synthesized via an iodine-mediated selective
esterification of the nonconjugated carboxylic acid of 2-meth-
yleneglutaric acid.25 We recently described an efficient synthesis
of 2-methylene glutaric acid 5-tert-butyl ester through Michael
addition of protected malonates to tert-butyl acrylate followed
by a tandem Mannich reaction and in situ decarboxylation.9
The efficient synthesis of 5 described herein uses an enan-
tiomerically pure 3-substituted cyclopentene, ent-4, for the
reasons described above. However, since the chirality at the
stereogenic center is lost during the rearrangement to form 5,
possible use of a racemic precursor, rac-4, that may be more
readily available was investigated. In addition to the syntheses
of rac-4 noted above, a low-yielding multistep synthesis of
racemic rac-4 has been reported26 via LAH reduction of the
corresponding carboxylic acid which, in turn, was generated
from the addition of CO2 to the Grignard reagent of 3-chloro-
cyclopentene. In our hands, the yield of this Grignard reaction
was extremely low. A higher yielding preparation of racemic
rac-4 using Rieke magnesium has been reported,27 but the use
of highly flammable Rieke magnesium for the large-scale
preparation of rac-4 is of concern. Since a search of the literature
and our own experience did not produce an efficient synthesis
of rac-4, the use of ent-4 as described (Scheme 2) is recom-
mended.
In summary, a concise 3-step synthesis of an R-protected
methyleneglutarate 5 from easily prepared starting materials has
been developed. This compound is a useful precursor for the
synthesis of peptidomimetic compounds and may be useful as
intermediates for synthesizing partially or fully reduced func-
tionalities, i.e., aldehyde or alcohol, at the γ-position of
2-methyleneglutarate.
(15) Shabtai, J.; Hey-Igner, E. J. Org. Chem. 1978, 43, 4186-4090.
(16) Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron Lett. 1989, 30,
7381-7382.
Experimental Section
(17) Drewes, S. E.; Emslie, N. D.; Karodia, N. Synth. Commun. 1990,
20, 1915-1921.
General Experimental Procedures. See the Supporting Infor-
mation.
(18) Jackson, P. F.; Cole, D. C.; Slusher, B. S.; Stetz, S. L.; Ross, L. E.;
Donzanti, B. A.; Trainor, D. A. J. Med. Chem. 1996, 39, 619-622.
(19) Brase, S.; Waigell, B.; de Meijere, A. Synthesis 1998, 2, 148-152.
(20) Yi, C. S.; Liu, N. J. Organomet. Chem. 1998, 553, 157-161.
(21) Jenner, G. Tetrahedron Lett. 2000, 41, 3091-3094.
(22) Kwon, B.-M.; Foote, C. S. J. Org. Chem. 1989, 54, 3878-3882.
(23) Yamauchi, Y. Japanese Patent 06228053, 1994.
(R)-1- tert-Butyldimethylsilyloxymethylcyclopent-2-ene, 6. To
a solution of ent-413 (0.9 g, 9.2 mmol) and TBDMSCl (2.8 g, 18.4
(26) Coe, D. M.; Parry, D. M.; Roberts, S. M.; Storer, R. J. Chem. Soc.,
Perkins Trans. 1 1991, 10, 2373-2377.
(27) Chapman, O. L.; Mattes, K. C.; Sheridan, R. S.; Klun, J. A. J. Am.
Chem. Soc. 1978, 100, 4878-4884.
(24) Dunach, E.; Perichon, J. Synlett 1990, 3, 143-145.
(25) Mitusbishi Petrochemical Co. Ltd. Japanese Patent 59152347, 1984.
J. Org. Chem, Vol. 71, No. 1, 2006 373

mmol) in anhydrous DMF (10 mL) at room temperature under Ar
was added imidazole (3.1 g, 46 mmol) in one portion. The reaction
was stirred at room temperature for 24 h. The reaction was
concentrated under reduced pressure (2 mmHg, 40 °C) and the crude
oil was partitioned between hexanes/Et2O (1:1, 100 mL) and
saturated aqueous NaHCO3 (50 mL). The aqueous layer was
extracted with hexanes/Et2O (1:1, 50 mL) and the combined organic
layers were washed with H2O (50 mL). The organic layer was dried
over MgSO4, filtered, and concentrated. The crude product was
purified by silica gel chromatography (4:1 hexanes/EtOAc) to give
1.8 g of 6 as a clear oil (92%). 1H NMR (CDCl3) δ 5.77 (m, 1H),
5.69 (m, 1H), 3.48 (m, 2H), 2.86 (m, 1H), 2.30 (m, 2H), 1.96 (m,
1H), 1.52 (m, 1H), 0.89 (s, 9H), 0.07 (s, 6H). 13C NMR (CDCl3)
δ 132.5, 132.0, 67.4, 48.9, 32.0, 26.3, 26.1, 18.5, -5.1. MS (ESI)
m/z 212.2 ([M + H]+, 100). HRMS (ESI) calcd for C12H24OSi
212.1596 [M + H]+, found 212.1593.
(R)-2-(tert-Butyldimethylsilyloxymethyl)pentanedioic Acid Di-
methyl Ester, 7. Ozone was bubbled through a solution of 6 (1.0
g, 4.7 mmol) in 2.5 M NaOH in MeOH (10 mL) and CH2Cl2 (40
mL) at -78 °C until a persistent blue color of excess ozone was
observed. O2 was bubbled through the solution for 20 min to purge
the excess ozone. The reaction was allowed to warm to room
temperature and was partitioned between diethyl ether (25 mL) and
H2O (25 mL). The aqueous layer was extracted with diethyl ether
(3 × 25 mL). The organic layer was concentrated and the crude
oil was taken up in EtOAc (25 mL), dried over Na2SO4, filtered,
and concentrated. The resulting clear oil was dissolved in MeOH
(10 mL), cooled to 0 °C, and treated with TMSCHN2 until a
persistent yellow color was observed. The ice bath was removed
and the reaction was stirred at room temperature for 15 min, then
quenched with AcOH and concentrated. The crude product was
purified by silica gel chromatography (4:1 hexanes/EtOAc) to give
0.98 g of 7 as a clear oil (70%). 1H NMR (CDCl3) δ 3.77 (m, 2H),
3.68 (s, 3H), 3.67 (s, 3H), 2.61 (m, 1H), 2.36 (m, 2H), 1.90 (m,
2H), 0.89 (s, 9H), 0.07 (s, 6H). 13C NMR (CDCl3) δ 174.4, 173.6,
64.0, 51.75, 51.72, 47.7, 31.8, 25.9, 23.7, 18.3, -5.4. MS (ESI)
m/z 304.2 ([M + H]+, 100). HRMS (ESI) calcd for C14H28O5Si
304.1706 [M + H]+, found 304.1704.
2-Methylenepentanedioic Acid 1-Methyl Ester (R-Methyl
2-Methyleneglutarate), 5. To a solution of 7 (0.75 g, 2.5 mmol)
in anhydrous THF (10 mL) at 0 °C was added TBAF (3.8 mL, 3.8
mmol). The reaction was allowed to warm to room temperature
and stirred for 2 h. The reaction was concentrated and the crude
oil was portioned between EtOAc (50 mL) and 1% aq HCl (10
mL). The organic layer was dried over Na2SO4, filtered, and
concentrated. The crude product was purified by silica gel chro-
matography (1:1 hexanes/EtOAc then 100% EtOAc) to give 0.33
1
g of 5 as a clear oil (84%). H NMR (CDCl3) δ 9.41 (br s, 1H),
6.21 (d, 1H, J ) 1.1 Hz), 5.62 (d, 1H, J ) 1.1 Hz), 3.75 (s, 3H),
2.63 to 2.53 (overlapping m, 4H). 13C NMR (CDCl3) δ 178.8, 167.2,
138.6, 126.3, 52.1, 33.0, 27.1. MS (CI/NH3) m/z 159.1 ([M + H]+,
100). HRMS (CI/NH3) calcd for C7H11O4159.1623 [M + H]+, found
159.0656.
Acknowledgment. This research was supported by a grant
from the National Cancer Institute (CA28097). D.M.B. is a
trainee in the Pharmacological Sciences Training Program
supported by a grant from the National Institutes of General
Medical Sciences (GM07767). We thank Matthew Alexander
for helpful discussions concerning the reactions depicted in
Scheme 3 and Debatosh Majumdar for providing a sample of
an ester precursor of ent-4. The authors also thank Craig A.
Townsend and The Johns Hopkins University for providing the
use of their facilities to complete this research.
Supporting Information Available: 1H and 13C NMR spectral
data for compounds 5-7 and experimental procedures for the large-
scale synthesis of ent-4. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO051854A
374 J. Org. Chem., Vol. 71, No. 1, 2006