Synthesis of novel α,α′,β-trisubstituted β-lactones

Article abstract of DOI:10.1016/S0040-4039(02)02435-8

A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel lactones are easily obtained in five steps and will be dedicated to anionic ring opening polymerization.

Full text of DOI:10.1016/S0040-4039(02)02435-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9513–9515
Synthesis of novel a,a%,b-trisubstituted b-lactones
Christel Barbaud,* Mohamed Guerrouache and Philippe Gue´rin
Laboratoire de Recherche sur les Polyme`res, UMR C7581 CNRS-Universite´ Paris XII, Val de Marne, 2-8 Rue Henri Dunant,
F-94320 Thiais, France
Received 11 October 2002; revised 23 October 2002; accepted 29 October 2002
Abstract—A concise and efficient synthesis of a,a%,b-trisubstituted b-lactones is presented. These novel lactones are easily obtained
in five steps and will be dedicated to anionic ring opening polymerization. © 2002 Elsevier Science Ltd. All rights reserved.
A large family of b-substituted b-lactones, prepared
from racemic and optically active malic and alkylmalic
acids as precursors, has been used in the synthesis of
racemic and optically active polyesters.1,2 These poly-
meric materials are degradable, bioassimilable and bio-
compatible.3,4 They can be used in temporary
therapeutic applications such as drug delivery systems.
In this report, we are investigating the synthesis of
more intricate b-lactones such as a,a%,b-trisubstituted
b-lactones. These can be easily prepared in two steps
from diacids, synthesized from commercial diethyl oxal-
propionate in three stages (Scheme 1).
hydrogenolysis either on the lactone or on the
polyester, the carboxylic acid groups obtained will be
reacted with bioactive or targeting molecules. The allyl
group will be chemically modified after polymerization
and turned to epoxides, diols or even carboxylic acid.
The butyl group is used for its hydrophobic properties.
The presence of two methyl groups on the lactone will
increase the hydrophobicity of the polymer concerned.
The synthesis of these novel lactones is realized in five
steps from precursor diethyl oxalpropionate. We have
synthesized three different lactones. In the first step,
racemic diethyl oxalpropionate is alkylated in basic
conditions. To introduce the methyl substituent, we
have employed potassium t-butoxide in anhydrous tol-
uene in the presence of 18-crown-6 ether at room
temperature (Scheme 2).5 The alkylation is relatively
fast because of the acidity of the proton flanked by
ketone and ester groups. Diethyl 3,3-dimethyl-2-keto-
succinate 1 is obtained after purification by distillation
under reduced pressure with 85% yield. The alkylation
is followed by gas chromatography and the analysis of
compound 1 by 1H NMR has confirmed the presence of
the two methyl groups by the single peak at 1.39 ppm
integrating for six protons.
The R1 group can be benzyl, butyl or allyl. The benzyl
group is used for its protecting role. After catalytic
Scheme 1. Retrosynthetic pathway.
Scheme 2. Reagents and conditions: (a) tBuOK, crown ether, toluene, CH3–I, 85%; (b) NaBH4, EtOH, 70%.
Keywords: alkylation; dialkylmalic acids; lactonization; b-lactones.
* Corresponding author. E-mail: barbaud@glvt-cnrs.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02435-8

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C. Barbaud et al. / Tetrahedron Letters 43 (2002) 9513–9515
For the second step of our synthesis, the reduction of
keto-diesters with NaBH4 furnished racemic diethyl
3,3-dimethylmalate 2.6 This reaction is also followed by
gas chromatography. The GC analysis displayed one
peak corresponding to a racemic mixture of enan-
tiomers 2. The reduction of 1 resulted in the alcohol 2
with 70% yield.
(CH2-CH3), 1.57 ppm (CH2-CH2-CH3) and 4.13 ppm
(OCH2) for the monoester 6.
The lactonization is the last step of our synthesis.
Conceptually, b-lactones can be prepared by activation
of either the carboxyl or hydroxyl groups of
monoesters. Thus, a,a%,b-trisubstituted b-lactones were
synthesized by reaction with diisopropylazodicarboxyl-
ate (DIAD) and triphenylphosphine (TPP) according to
the Mitsunobu reaction (Scheme 4).10,11 In this reaction,
the lactones were obtained via hydroxyl group activa-
tion with inversion of configuration of asymmetric car-
bon atom according to the mechanism previously
described on the optically active lactones.1 Our three
monoesters 4, 5 and 6 were thus treated and the evolu-
tion of the reaction was controlled by thin layer chro-
matography. Each b-lactone was then purified by
chromatography over silica gel with a mixture of ethyl
The third step is concerned with the hydrolysis of ester
groups. The corresponding 3,3-dimethylmalic acid 3 is
obtained by basic treatment of diethyl 3,3-dimethyl-
1
malate 2 (Scheme 3).7 The H NMR spectra of diacid 3
confirmed the complete hydrolysis because of the disap-
pearance of peaks corresponding to ethyl ester groups.
The 3,3-dimethylmalic acid 3 is purified by recrystalliza-
tion in CHCl3/CH3CN with 60% yield.
After the hydrolysis of ester groups, the diacid is
treated by trifluoroacetic anhydride (TFAA) to provide
the non-isolated intermediate cyclic anhydride.8,9 The
solvolysis of this intermediate with a variety of alcohols
led to b-hydroxyacids having very good regioselectivity.
In our case, we have chosen three different alcohols:
benzyl, butyl and allyl alcohols. With the diacid 3, we
have successfully obtained the benzyl monoester 4 with
80% yield, the allyl monoester 5 with 83% yield and the
1
acetate/cyclohexane and analyzed by IR and H NMR.
b-Lactones
4-benzyloxycarbonyl-3,3-dimethyl-2-oxe-
tanone 7, 4-allyloxycarbonyl-3,3-dimethyl-2-oxetanone
8 and 4-butyloxycarbonyl-3,3-dimethyl-2-oxetanone 9
are obtained with 64, 65 and 53% of yield respectively.
The three structures are confirmed by IR; the presence
of a band at 1850 cm−1 characterized the carbonyl
1
function of the lactone. The H NMR spectra displayed
1
butyl monoester 6 with 90% yield (Scheme 3). The H
two singlets well separated corresponding to methyl
groups at about 1.00 ppm. One methyl group of each
lactone was downfield shifted by about 0.30 ppm due to
the rigidity of the cycle.12
NMR spectrum of 4 showed the presence of one singlet
at 5.00 ppm and one multiplet at 7.20 ppm correspond-
ing to CH2 and aromatic protons of benzyl group
respectively. For monoester 5, we have observed the
different protons of allyl group at 4.50 ppm (CH2-O),
5.08 and 5.22 ppm (CH2ꢀCH) and 5.82 ppm
(CH2ꢀCH). In the same way, we have observed the
protons of butyl group at 0.86 ppm (CH3), 1.32 ppm
The synthesis of these a,a%,b-trisubstituted b-lactones
will permit the study of anionic ring opening polymer-
ization. With these three different b-lactones, it will be
possible to have access to a large family of new homo-
Scheme 3. Reagents and conditions: (a) K2CO3, EtOH (reflux), 72 h, 60%; (b) TFAA; (c) PhCH2-OH or CH2ꢀCH-CH2-OH or
CH3-CH2-CH2-CH2-OH.
Scheme 4. Reagents: (a) DIAD, TPP, THF.

C. Barbaud et al. / Tetrahedron Letters 43 (2002) 9513–9515
9515
polymers or/and copolymers aimed at biomedical
studies.
CH2ꢀCH-), 5.82 (ddt, 1H, Jcis=10.5 Hz, Jtrans=17.5 Hz,
J=5.5 Hz, O-CH2-CHꢀCH2). 13C NMR (D2O, 50 MHz)
l 20, 22 (2×CH3), 47 (C), 67 (CH2O), 76 (CH), 120
(CH2ꢀCH), 132 (CH2ꢀCH), 174, 181 (2×C+O). Mp 67°C.
Anal. calcd for C9H14O5: C, 53.46; H, 6.98. Found: C,
53.30; H, 7.25%. Monoester 6: 1H NMR (CDCl3, 200
MHz) l 0.86 (t, 3H, J=7 Hz, CH3 butyl), 1.14 (s, 3H,
CH3), 1.23 (s, 3H, CH3), 1.32 (qt, 2H, J=7 Hz, CH2-
CH3), 1.57 (tt, 2H, J=7 Hz, CH2-CH2-CH3), 4.13 (t, 2H,
J=7 Hz, OCH2), 4.37 (s, 1H, CH), 8.00 (m, 1H, COOH).
13C NMR (CDCl3, 50 MHz) l 13 (CH3 butyl), 19 (CH2-
CH3), 20, 22 (2×CH3), 30 (CH2-CH2-CH3), 47 (C), 66
(OCH2), 75 (CH), 174, 183 (2×CꢀO). Mp 47°C. Anal.
calcd for C10H18O5: C, 55.03; H, 8.31. Found: C, 55.01;
References
1. (a) Gue´rin, Ph.; Vert, M.; Braud, C.; Lenz, R. W. Polym.
Bull. 1985, 14, 187–192; (b) Gue´rin, Ph.; Francillette, J.;
Braud, C.; Vert, M. Makromol. Chem. 1986, 6, 305–314;
(c) Gue´rin, Ph.; Vert, M. Polym. Commun. 1987, 28,
11–13; (d) Arnold, S. C.; Lenz, R. W. Makromol. Chem.,
Macromol. Symp. 1986, 6, 285–303.
2. Mabille, C.; Masure, M.; Hemery, P.; Gue´rin, Ph. Polym.
Bull. 1998, 40, 381–387.
3. Barbaud, C.; Cammas-Marion, S.; Gue´rin, Ph. Polym.
Bull. 1999, 43, 297–304.
4. Cammas-Marion, S.; Gue´rin, Ph. Macromol. Symp. 2000,
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hedron 1988, 44, 2137–2148.
6. Bhat, K. S.; Dixit, K. N.; Rao, A. S. Indian J. Chem.
1985, 24B, 509–512.
1
H, 8.47%. Lactone 7: H NMR (CD3COCD3, 200 MHz)
l 1.04 (s, 3H, CH3), 1.38 (s, 3H, CH3), 4.83 (s, 1H, CH
lactone), 5.17 (s, 2H, CH2Ph), 7.33 (m, 5H, Ph). 13C
NMR (CD3COCD3, 50 MHz) l 17, 21 (2×CH3), 58 (C
lactone), 67 (CH2), 77 (CH lactone), 128, 134 (Ph), 167,
172 (2×CꢀO). IR 1850 cm−1 (CꢀO lactone), 1750 cm−1
(CꢀO ester). MS (IE) m/z 234 (base peak), 178, 107, 91,
83, 72. Anal. calcd for C13H14O4: C, 66.66; H, 6.02.
Found: C, 66.64; H, 6.12%. Lactone 8: 1H NMR
(CD3COCD3, 200 MHz) l 1.10 (s, 3H, CH3), 1.40 (s, 3H,
CH3), 4.60 (d, 2H, J=6 Hz, CH-CH2-O), 4.80 (s, 1H, CH
lactone), 5.15 (dd, 1H, Jgem=1.5 Hz, Jcis=10.5 Hz,
CH2ꢀCH-), 5.28 (dd, 1H, Jgem=1.5 Hz, Jtrans=17 Hz,
CH2ꢀCH-), 5.88 (ddt, 1H, Jcis=10.5 Hz, Jtrans=17 Hz,
J=6 Hz, O-CH2-CHꢀCH2). 13C NMR (CD3COCD3, 50
MHz) l 17, 21 (2×CH3), 58 (C lactone), 66 (CH2O), 77
(CH lactone), 119 (CHꢀCH2), 132 (CHꢀCH2), 168, 174
(2×CꢀO). MS (IE) m/z 184 (base peak), 157, 111, 95, 83,
55. Anal. calcd for C9H12O4: C, 58.69; H, 6.57. Found: C,
7. Cammas, S. Ph.D. Thesis, University of Pierre et Marie
Curie (Paris VI), 1993.
8. Miller, M. J.; Balwa, J. S.; Mattingly, P. G.; Peterson, C.
J. Org. Chem. 1982, 47, 4928–4933.
9. Bajwa, J. S.; Miller, M. J. J. Org. Chem. 1983, 48,
1114–1116.
10. Mitsunobu, O. Synth. Rev. 1981, 1–28.
11. Mulzer, J.; Bruntrup, G.; Chucholowski, A. Angew.
Chem., Int. Ed. Engl. 1979, 18, 622–623.
12. Selected spectroscopic data for compounds are as fol-
1
lows. Monoester 4: H NMR (CD3COCD3, 200 MHz) l
1
58.36; H, 6.73%. Lactone 9: H NMR (CDCl3, 200 MHz)
1.06 (s, 3H, CH3), 1.12 (s, 3H, CH3), 4.30 (s, 1H, CH-
OH), 5.00 (s, 2H, CH2Ph), 7.20 (m, 5H, Ph). 13C NMR
(CD3COCD3, 50 MHz) l 20, 21 (2×CH3), 46 (C), 67
(CH2), 76 (CH-OH), 129, 136 (Ph), 173, 176 (2×CꢀO).
Mp 99°C. Anal. calcd for C13H16O5: C, 61.90; H, 6.39.
Found: C, 61.91; H, 6.51%. Monoester 5: 1H NMR
(CD3COCD3, 200 MHz) l 1.06 (s, 3H, CH3), 1.12 (s, 3H,
CH3), 4.30 (s, 1H, CH-OH), 4.50 (d, 2H, J=5.5 Hz,
CH-CH2-O), 5.08 (dd, 1H, Jgem=1.5 Hz, Jcis=10.5 Hz,
CH2ꢀCH-), 5.22 (dd, 1H, Jgem=1.5 Hz, Jtrans=17.5 Hz,
l 1.00 (t, 3H, J=7 Hz, CH3 butyl), 1.35 (s, 3H, CH3),
1.46 (qt, 2H, J=7 Hz, CH2-CH3), 1.61 (s, 3H, CH3), 1.74
(tt, 2H, J=7 Hz, CH2-CH2-CH3), 4.32 (t, 2H, J=7 Hz,
OCH2), 4.71 (s, 1H, CH). 13C NMR (CDCl3, 50 MHz) l
13 (CH3 butyl), 17 (CH3), 19 (CH2-CH3), 22 (CH3), 30
(CH2-CH2-CH3), 57 (C), 65 (OCH2), 77 (CH), 167, 172
(2×CꢀO). MS (IE) m/z 200 (base peak), 100, 82, 55. Anal.
calcd for C10H16O4: C, 59.98; H, 8.05. Found: C, 60.17;
H, 8.16%.