(Z)-2,2-Dimethyl-5-carboxymethylene-1,3-dioxolan-4-one: a new synthon for the synthesis of α,γ-diketoacid derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.04.032

The synthesis and reactivity of (Z)-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one, a new and versatile synthon useful for the synthesis of selectively protected α,γ-diketoacid derivatives, are described. This new, protected form of hydroxyl fumaric a

Full text of DOI:10.1016/j.tetlet.2010.04.032

Tetrahedron Letters 51 (2010) 3170–3173
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
(Z)-2,2-Dimethyl-5-carboxymethylene-1,3-dioxolan-4-one: a new synthon
for the synthesis of a,c-diketoacid derivatives
*
Jacques Banville , Gilles Bouthillier, Serge Plamondon, Roger Remillard, Nicholas A. Meanwell, Alain Martel,
*
Michael A. Walker
Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 February 2010
Revised 7 April 2010
Accepted 8 April 2010
Available online 21 April 2010
The synthesis and reactivity of (Z)-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one, a new and
versatile synthon useful for the synthesis of selectively protected
a,c-diketoacid derivatives, are
described. This new, protected form of hydroxyl fumaric acid along with its acid chloride was used to pre-
pare ester, amide, and aryl derivatives. The dioxolane moiety was found to be a convenient functionality
that facilitated ready unmasking by straightforward hydrolysis to reveal
derivatization to yield ester, amide, and 2,3-pyrrolidinedione derivatives.
a,c-diketoacid derivatives or
Ó 2010 Elsevier Ltd. All rights reserved.
HIV integrase is one of three essential enzymes in the replica-
tion cycle of the human immunodeficiency virus (HIV) and has
emerged as an important target for the development of HIV thera-
approach. In this Letter, we describe the initial synthetic approach
developed to prepare (Z)-2,2-dimethyl-5-carboxymethylene-1,3-
dioxolan-4-one (10) and its acid chloride 12.8
Two approaches to highly functionalized keto-esters related to
3 are described in the literature. An approach first described by
Ramage et al.9 employed a Wittig reaction between t-butyl glyoxy-
late and a phosphorane–dioxolanone moiety to provide 4 (Fig. 2),
peutics.1 The 4-aryl-
a,c
-diketoacid derivatives 1 and 2 were
among the first compounds to be validated as authentic inhibitors
of HIV integrase in cell culture.2 Compounds bearing this pharma-
cophore were also found to demonstrate inhibitory activity toward
hepatitis C virus RNA-dependent RNA polymerase, hepatitis B virus
polymerase and HIV RT,3 as well as flap endonuclease 1.4 Given the
wherein the
a-enol and adjacent carboxylic acid moieties are
potential broad utility of the a,c-diketoacid acid moiety in medic-
F
O
OH
O
OH
inal chemistry, we were interested in developing synthetic ap-
proaches that would allow preparation and functionalization
along diverse pathways.
O
OH
OH
N
O
O
1
2
O
The synthesis of a,c-diketoacid derivatives 1 and 2 is generally
accomplished through a base-promoted Claisen condensation be-
tween a methyl ketone and a dialkyl oxalate followed by alkaline
or acid hydrolysis of the intermediate ester (Fig. 1, method A).5
Alternatively, the addition of the dianion of the dimethylhydrazone
of pyruvic acid to aryl esters has been reported to yield diketoacids
after acidic hydrolysis of the hydrazone.6 We proposed that a suit-
ably functionalized hydroxyl fumaric acid derivative based on the
dioxolanone 3 in Figure 1, which employs a single protecting group
for both the enol and one of the carboxylic acid groups, would pro-
vide a new and versatile synthon for this class of compound that
would extend existing methodology by allowing the facile prepara-
tion of esters, amides, and other derivatives.7 Compound 3 is a pro-
tected derivative of the naturally occurring oxaloacetic acid;
however, attempts to selectively protect this material were unsuc-
cessful, thus requiring development of an alternative synthetic
O
N
A: literature methods
O
O
R
O
N
+
+
R
O
R
OH
R
R
O
R
O
O
B
OH
O
OH
R
A
O
OP
O
Z
OP
+
X
B: new method
3
O
Figure 1. Comparison of method A and method B.
O
O
O
O
O
O
O
O
O
O
4
5
* Corresponding authors. Tel.: +1 203 677 6686.
E-mail address: michael.a.walker@bms.com (M.A. Walker).
Figure 2. Compounds previously reported in the literature.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.032

J. Banville et al. / Tetrahedron Letters 51 (2010) 3170–3173
3171
acid 3 could be obtained by saponification of the terminal ester
in 5 in the presence of the highly reactive lactone carbonyl, a mod-
ification of this route was required in order to provide easy access
to the carboxylic acid. A silyl ester was anticipated to be a suitable
protecting group for this purpose since it can readily be removed
under acidic conditions or by exposure to fluoride.
O
O
O
O
O
O
a
b
O
R
O
O
R
O
HO
O
Br
O
O
O
6
7a, R = TBDPS
8a, R = TBDPS
8b, R = TBDMS
7b, R = TBDMS
Toward this end, both the tert-butyldiphenylsilyl and the
tert-butyldimethylsilyl esters were explored, as summarized in
Scheme 1. Reaction of (S)-(+)-2,2-dimethyl-5-oxo-dioxolane-4-
acetic acid (6) with tert-butlyldiphenylsilyl chloride gave 7a in
quantitative yield after chromatography on silica gel, while
tert-butyldimethylsilyl chloride provided 7b in 96% yield after dis-
tillation. The reaction of 7a and 7b with N-bromosuccinimide12 in
CCl4 in the presence of 2,2-azobisisobutyronitrile at reflux resulted
in a mild exothermic reaction and clean formation of the bromides
8a and 8b. These bromides were immediately treated with 1,8-
diazabicyclo[5,4,0]undec-7-ene to give the unsaturated esters 9a
and 9b, respectively. Attempts to purify 9a by chromatography
on silica gel gave variable yields, probably due to partial hydrolysis
of the silyl group during the purification process. In contrast, crude
9a could be treated with tetrabutylammonium fluoride and acetic
acid to give crystalline 10 in 70% overall yield from 7a. The crude
silyl ester 9b is also easily hydrolyzed with acetic acid and dilute
HCl to provide the acid 10 in 82% yield by what is, essentially, a
one-pot reaction from the silyl ester 7b. 1H NMR analysis (CDCl3)
of the acid obtained using this method indicated that in addition
to the expected (Z)-isomer 10, in which the vinyl proton resonates
at d = 5.89, a trace amount (<5%) of the (E)-isomer 11 was also
formed, detected by the presence of the vinyl proton resonating
at d = 6.03. The identity of the products was confirmed by analysis
of the proton gate-decoupled 13C NMR spectrum, an experiment
performed in DMSO-d6. The ring carbonyl carbon of 10 resonates
as a doublet, J = 3.8 Hz, at d 95.63, consistent with a cis relationship
between the exocyclic proton (d 5.55) and the ring carbon.13 In
O
O
O
O
O
O
d
O
c
O
R
+
HO
O
O
O
O
HO
O
9a, R = TBDPS
9b, R = TBDMS
10
11
e
O
O
O
Cl
O
12
Scheme 1. Synthesis of compounds 10 and 12. Reagents and conditions: (a)
TBDPSCl, imidazole, DMF, 99% for 7a; TBDMSCl, imidazole, DMF, 96% for 7b; (b)
NBS, AIBN, CCl4, reflux; (c) DBU, THF; (d) TBAF, AcOH or AcOH, 1 N HCl, 82%; (e)
oxalyl chloride, CH2Cl2, quantitative.
included in a cyclohexanone ketal. This ketal is quite stable to
aqueous acid but the carbonyl group of the five-membered ring
in 4 was found to be quite sensitive to nucleophilic attack. An alter-
native synthetic method was subsequently described by both
Kneer et al.10 and Schwenker and Stiefvater11 in which unsaturated
dioxolanone esters 5 (Fig. 2) were obtained from saturated dioxola-
none esters similar to 7 (R = Et and Me), in turn derived from malic
acid, by using a synthetic sequence similar to that depicted in
Scheme 1. This approach appeared to be suitable for the purpose
at hand; however, since it was deemed unlikely that the desired
Table 1
Ester and amides derived from 10 and 12
OH
O
O
O
1. NaOH
2. HCl
OH
O
R
R
10 or 12
O
O
13a-19a
13b-19b
Entry
1
R
Methoda
A
Compd
% Yieldb
Compd
% Yield
55
∗
O
13a
14a
15a
78
73
88
13b
F
∗
O
2
3
A
A
14b
15b
90
91
F
F
F
F
∗
N
H
∗
N
4
5
B
B
16a
17a
81
90
16b
17b
100
95
∗
N
O
F
F
6
7
∗
A
A
18a
19a
95
93
18b
19b
85
89
N
H
∗
N
a
Method A: Acid chloride 12/alcohol or amine/pyridine/CH2Cl2. Method B: Acid 10/amine/BOP/Et3N/CH3CN.
Yields are for recrystallized material except for 16b which was obtained as a syrup.
b

3172
J. Banville et al. / Tetrahedron Letters 51 (2010) 3170–3173
Table 2
Diketoacid derivatives
Stannane
(CH3CN)2PdCl2
O
OH
O
O
O
O
1. NaOH
2. HCl
O
O
OH
R
R
Cl
or
O
O
O
Friedel-Crafts
20b-23b
20a-23a
12
Entry
1
Reactant
R
Compd
% Yield
71
Compd
% Yield
48
Sn(Me)3
∗
20a
20b
Sn(Bu)3
∗
2
3
21a
22a
75
69
21b
22b
65
95
O
Sn(Bu)3
O
∗
∗
4
23a
61
23b
88
Me
Me
contrast, the carbonyl carbon of the minor isomer 11 resonates as a
doublet centered at d 102.45 that couples to the vinyl proton res-
onating at d 5.99 with J = 10.0 Hz. A simple recrystallization of
the crude acid from ethyl acetate gave the pure (Z)-isomer 10 with
high recovery.
As an illustration of the acid stability of the unsaturated diox-
olanone moiety, the acid chloride 12 was easily prepared using
oxalyl chloride and obtained as a stable, crystalline solid. Acid chlo-
ride 12 reacted smoothly and selectively with 4-fluorobenzyl alco-
hol and 4,40-difluorobenzhydrol to afford the corresponding esters
13a and 14a in 78% and 73% yield, respectively. The acid chloride
12, or the acid 10 combined with standard peptide coupling re-
agents like BOP, reacts with a variety of amines to provide amides
in high yield, as summarized in Table 1. Both the ester and amide
derivatives were found to be stable compounds readily purified by
chromatography on silica gel.
toacids 15b–19b in excellent yield using 2 equiv of 1 N NaOH solu-
tion (Table 1, entries 3–7).
To complement the formation of ester and amide derivatives,
the preparation of C-linked, a,c-diketoacid derivatives was also ex-
plored with the palladium-catalyzed coupling of the acid chloride
12 with unsymmetrical organotin reagents14 examined first. Reac-
tion of 12 with trimethyl(phenyl)tin and (E)-b-styryltributyltin15
catalyzed by bis(acetonitrile)dichloropalladium (II) produced diox-
olanones 20a and 21a in 71% and 75% yield, respectively (Table 2,
entries 1 and 2). Also, 2-(Tri-n-butylstannyl)benzofuran16 gave the
dioxolanone 22a in 69% yield.
We were also pleased to find that the acid chloride 12 was suf-
ficiently stable to react with nucleophiles under Friedel–Crafts
conditions. For example, the reaction of 12 with toluene in the
presence of AlCl3 gave the dioxolanone 23a in 61% yield (Table 2,
entry 4). This is another good example that demonstrates the sta-
bility of this ketal under acidic conditions. Similar to the case of the
amides described above, these aryl dioxolanones were easily
The final step to release the a,c-diketoacid required the hydro-
lysis of the dioxolanone moiety to give the ester and amide keto-
acid derivatives. In the case of the esters 13a and 14a, the
dioxolanone ring could be selectively cleaved at low temperature
(ice bath) with 1 N NaOH followed by acidification to give the acids
13b and 14b in good yield (Table 1, entries 1 and 2). The amides
15a–19a were also rapidly hydrolyzed at 25 °C to provide the dike-
hydrolyzed to the known
-diketoacid derivatives 20b,17 21b,18
and 23b19 and the new
a,c-diketoacid 22b.
a,c
Taking advantage of the reactivity of the dioxolane ring toward
nucleophiles, the protected carboxylic acid moiety was also found
to be a convenient functionality for direct derivatization. When
Table 3
Reactions at the dioxolane moiety
Entry
1
Dioxolane
Method
A
Compd
Structure
% Yield*
88
F
O
OH
19a
24
OMe
O
N
O
O
O
N
O
Ph
N
H
2
3
4
15a
15a
21a
B
C
C
25
26
27
69
33
40
O
F
F
OH
N
H
N
O
OH
O
N
Method A: 0.03 equiv of NaOMe/22 °C/4 h/THF, MeOH. Method B: 2.0 equiv of N-benzyl-N-methylamine/50 °C/4 h/THF. Method C: 2.0 equiv of paraformaldehyde and
methylamine/50 °C/1 h/MeOH.
*
Yields are for recrystallized material except for 25 which was obtained as an oil.

J. Banville et al. / Tetrahedron Letters 51 (2010) 3170–3173
3173
11. Schwenker, G.; Stiefvater, K. Arch. Pharm. 1991, 324, 307.
12. Mattay, J.; Mertes, J.; Maas, G. Chem. Ber. 1989, 122, 327.
13. (a) Prokof’ev, E. P.; Karpeiskaya, E. I. Tetrahedron Lett. 1979, 20, 737; (b)
Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding, D. L.; Wright, J. J. K. J. Org.
Chem. 1991, 56, 6897.
14. Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634.
15. Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129.
16. Liebeskind, L. S.; Wang, J. J. Org. Chem. 1993, 58, 3550.
17. (a) Pais, G. C. G.; Zhang, X.; Marchand, C.; Neamati, N.; Cowansage, K.;
Svarovskaia, E.; Pathak, V. K.; Tang, Y.; Nicklaus, M.; Pommier, Y.; Burke, T. R.,
Jr. J. Med. Chem. 2002, 45, 3184; (b) Andreichikov, Y. S.; Maslivets, A. N.;
Smirnova, L. I.; Krasnykh, O. P.; Kozlov, A. P.; Perevozchikov, L. A. Zh. Org. Chem.
1987, 23, 1534.
18. Williams, H. W. R.; Eichler, E.; Randall, W. C.; Rooney, C. S.; Cragoe, E. J., Jr.;
Streeter, K. B.; Schwam, H.; Michelson, S. R.; Patchett, A. A.; Taub, D. J. Med.
Chem. 1983, 26, 1196.
19. Sof’ina, O. A.; Igidov, N. M.; Koz’minykh, E. N.; Trapeznikova, N. N.; Kasatkina,
Y. S.; Koz’minykh, V. O. Russ. J. Org. Chem. 2001, 37, 1017.
20. (a) Walker, M. A.; Ma, Z.; Naidu, B. N.; Sorenson, M. E.; Pendri, A.; Banville, J.;
Plamondon, S.; Remillard, R. U.S. Patent 7,109,186, 2006; (b) Pace, P.; Spieser, S.
A. H.; Summa, V. Bioorg. Med. Chem. Lett. 2008, 18, 3865.
21. (a) Southwick, P. L.; Seivard, L. L. J. Am. Chem. Soc. 1949, 71, 2532; (b) Merchant,
J. R.; Srivinasan, V. Recl. Trav. Chim. Pays-Bas 1962, 81, 144; (c) Andreichikov, Y.
S.; Gein, V. L. Chem. Heterocycl. Compd. (Engl. Transl.) 1990, 26, 627.
22. Procedures for key compounds:
treated with an alcohol and a trace of base, the dioxolanone ring
was readily cleaved to provide the corresponding ketoester deriv-
ative. For example, reaction of the dioxolanone 19a with MeOH
and a catalytic amount of NaOMe gave the ketoester 24 in high
yield (Table 3, entry 1). The dioxolane ring in 15a could also be
opened by a secondary amine, exemplified by the reaction with
N-benzyl-N-methylamine which gave 25 in 69% yield (Table 3, en-
try 2). Interestingly, while the
a,c-diketoacids and their ester
derivatives exist mainly in the enol form, the amide derivative
25 exists predominantly in the keto form in solution in CHCl3.
2,3-Pyrrolidinediones are highly functionalized heterocycles
which, like the a-ketoacids, have been found to possess HIV integr-
ase inhibitory activity.20 It has been demonstrated that 2,3-pyrro-
lidinediones can be obtained via the Mannich reaction of
a,c-diketoester derivatives with an imine generated in situ from
an aldehyde and a primary amine.21 The dioxolanone scaffold is a
useful substrate for the synthesis of 2,3-pyrrolidinediones. Thus,
reaction of the dioxolanones 15a and 21a with paraformaldehyde
and methylamine in MeOH gave the pyrrolidinenones 26 and 27
in 33% and 40% yield, respectively, after crystallization. Methanol
was found to be essential for the reaction to proceed, which prob-
(S)-(+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl
ester (7b):
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic
acid (6) (13.20 g, 75.8 mmol) in DMF (25 mL) was treated at 22 °C with
imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride
(12.0 g, 79.6 mmol) and the resulting mixture was stirred for 18 h. The mixture
was diluted with toluene (500 mL), washed with H2O, saturated NaHCO3, brine,
and dried (MgSO4). The solvent was evaporated under reduced pressure and
the residual oil was distilled under vacuum to give 20.9 g (96% yield) of 7b as a
clear oil, bp 80–90 °C/0.1 torr (bulb–bulb distillation). 1H NMR (C6D6) d 0.33 (s,
3H), 0.36 (s, 3H), 1.0 (s, 9H), 1.11 (s, 3H), 1.37 (s, 3H), 2.72 (AB part of ABX
ably implies the formation of an intermediate
ester prior to pyrrolidinedione formation.
a,c-diketo methyl
In conclusion, we have demonstrated a convenient method for
the synthesis of a selectively protected derivative of oxalacetic acid
that is a useful synthetic precursor to a wide range of products.22 It
can readily be appreciated by the examples described that the
chemistry used to derivatize this starting material is readily ame-
nable to high throughput synthetic methods, an aspect that will
be described in due course. One additional feature of this chemis-
try that is worthy of note is that we have found that the dioxolane
protecting group confers stability to the diketoacid moiety, often
an unstable functional group. For example, when incorporated into
the dioxolane ring, diketoacids such as those described are much
more resistant to decomposition upon storage when compared to
the corresponding free keto-acids.
system, J(AX) = 6.1 Hz, J(BX) = 4.1 Hz, J(AB) = 17.0 Hz,
J(AX) = 6.1 Hz, J(BX) = 4.1 Hz, 1H).
Dm = 41.5 Hz, 2H), 4.35 (dd,
4-Bromo-2,2-dimethyl-5-oxo-1,3–dioxolane-4-acetic acid, tert-butyldimethylsilyl
ester (8b): solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic
A
acid, tert-butyldimethylsilyl ester 7b (20.9 g, 72.4 mmol) in CCl4 (200 mL)
was treated with freshly recrystallized N-bromosuccinimide (14.18 g,
79.6 mmol) and 2,20-azobisisobutyronitrile (0.30 g) and the resulting mixture
was heated under reflux while irradiating with a 500 W lamp. After 5 min, a
mild exothermic reaction was observed and the mixture was heated for an
additional 5 min (at this point most of the succinimide was floating on the
solvent). The mixture was cooled in an ice bath and the succinimide was
filtered and washed with
a small amount of CCl4. The filtrate was used
immediately without further purification for the next step. 1H NMR (CCl4–
CDCl3) d 0.27 and 0.28 (2s, 2 ꢀ 3H), 0.94 (s, 9H), 1.66 (s, 3H), 1.84 (s, 3H), 3.62
(AB system, J(AB) = 21.2 Hz,
Dm = 11.8 Hz, 2H).
Acknowledgment
(Z)-2,2-Dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-
4-one (9b): Under vigorous mechanical stirring, the solution of crude ester 8b
(72.4 mmol) in CCl4 (ꢁ220 mL) was cooled to 0–5 °C and treated, dropwise
over 10 min, with a solution of 1,8-diazabicyclo [5,4,0] undec-7-ene (12.1 g,
79.6 mmol) in dry THF (125 mL). A heavy precipitate formed that was difficult
to stir but which gradually became a granular solid. After 1 h, the solid was
filtered and washed with a small amount of THF. The filtrate was concentrated
under reduced pressure to give the crude silyl ester 9b as a light orange oil
which was used as such for the next step. 1H NMR (CDCl3) d 0.33 (s, 6H), 0.97 (s,
9H), 1.75 (s, 6H), 5.85 (s, 1H).
The authors wish to acknowledge Stella Huang for carrying out
the 13C NMR experiments on compound 10.
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203–204 °C (dec.). IR (KBr) m ;
max (1805, 1707 and 1662 cmꢂ1 1H NMR (CDCl3) d
1.78 (s, 6H), 5.89 (s, 1H). Anal. Calcd for C7H8O5: C, 48.84; H, 4.68. Found: C,
48.84; H, 4.65.
(E)-2,2-Dimethyl-5-carboxymethylene-1,3-dioxolan-4-one (11): 1H NMR (CDCl3)
d 1.80 (s, 6H), 6.03 (s, 1H).
(Z)-2,2-Dimethyl-5-chlorocarbonylmethylene-1,3-dioxolan-4-one (12): A mixture
of (Z)-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one (0.50 g, 2.9 mmol)
in dry CH2Cl2 (10 mL) was treated at 22 °C with oxalyl chloride (0.5 mL,
5.8 mmol) followed by a trace (capillary) of DMF. After 1 h at 22 °C, the clear
solution was concentrated in vacuo to give 0.55 g (quantitative yield) of the title
acid chloride 12 as a white crystalline solid. 1H NMR (CDCl3) d 1.80 (s, 6H), 6.19
(s, 1H).