Inversion of configuration of (S)-β-hydroxy-γ-butyrolactone with total retention of the enantiomeric purity

Article abstract of DOI:10.1002/(sici)1099-0690(199911)1999:11<2705::aid-ejoc2705>3.0.co;2-4

In this paper we report the inversion of configuration of (S)β-hydroxy- γ-butyrolactone [(S)-1] to its (R) enantiomer (R)-1, with total retention of the enantiomeric purity, by a four-step procedure. The (R)-β-hydroxy-γ- butyrolactone [(R)-1] was thus synthetized with an overall chemical yield of 47% and > 97% ee. This transformation opens an economic route to the production of (R)-GABOB and (R)-carnitine, among other biologically active compounds, from a D-hexose source, or, alternatively, from the industrial waste compound (S)carnitine. During the reaction sequence, the intermediate β-lactone 4 is also prepared, which is now under investigation as a chiral synthon for new synthetic applications.

Full text of DOI:10.1002/(sici)1099-0690(199911)1999:11<2705::aid-ejoc2705>3.0.co;2-4

SHORT COMMUNICATION
Inversion of Configuration of (S)-β-Hydroxy-γ-butyrolactone with Total
Retention of the Enantiomeric Purity
Francesco De Angelis,*[a] Enrico De Fusco,[b] Paola Desiderio,[c] Fabio Giannessi,*[b]
Fabrizio Piccirilli,[c] and Maria Ornella Tinti[b]
Keywords: Asymmetric synthesis / Chiral synthons / Configuration inversion / Hydroxy lactones / Lactones
In this paper we report the inversion of configuration of (S)-
β-hydroxy-γ-butyrolactone [(S)-1] to its (R) enantiomer (R)-1,
with total retention of the enantiomeric purity, by a four-step
procedure. The (R)-β-hydroxy-γ-butyrolactone [(R)-1] was
thus synthetized with an overall chemical yield of 47% and
> 97% ee. This transformation opens an economic route to
the production of (R)-GABOB and (R)-carnitine, among other
biologically active compounds, from a -hexose source, or,
alternatively, from the industrial waste compound (S)-
carnitine. During the reaction sequence, the intermediate β-
lactone 4 is also prepared, which is now under investigation
as a chiral synthon for new synthetic applications.
D
(S)-β-Hydroxy-γ-butyrolactone (S)-1 is a natural prod- termediate β-lactone 4 is also prepared, which is now under
uct[1a] and a known chiral synthon that can be obtained by investigation as a chiral synthon for new synthetic appli-
several synthetic methods.[1bϪ1e] Two of them, which make cations.
use of a -hexose source[1b] or (S)-carnitine,[1c] the waste
The transformation was realized as described in Scheme
product of the industrial production of (R)-carnitine, as 1. The key step is the formation of the (R)-β-lactone 4 with
starting materials, appear particularly economical and con- clean inversion of configuration at the stereogenic center,
venient for large scale syntheses. Moreover, (S)-1 has also starting from the (S)-β-hydroxy-γ-lactone derivative 2, via
been recently introduced to the market both in bulk and on intramolecular nucleophilic displacement of the activated
a laboratory scale. (R)-1 is also a valuable synthon which
has been used for the preparation of (R)-GABOB and (R)-
carnitine,[2] for the synthesis of β-lactam antibiotics,[3] and
also natural products like (Ϫ)-aplysistatin[4a] and (S)-(ϩ)-
ipsdienol.[4b] The absence from the literature of a con-
venient synthesis of (R)-1,[5] as compared with those re-
ported for the (S)-enantiomer, prompted us to investigate
the possibility of converting, with simple reactions, the (S)-
enantiomer into the (R)-enantiomer, in order to exploit the
same cheap sources. In addition, the inversion of configura-
tion of chiral, biologically active compounds or their syn-
thetic precursors is a chemical challenge of great import-
ance in the pharmaceutical business.[6] In this paper we re-
port the inversion of configuration of (S)-β-hydroxy-γ-bu-
tyrolactone {(S)-1} to its (R)-enantiomer {(R)-1}, with total
retention of the enantiomeric purity, according to a four-
step procedure (two steps are performed in sequence with
no need for isolation of the intermediate compound).[7] The
(R)-β-hydroxy-γ-butyrolactone {(R)-1} was thus synthe-
sized with an overall chemical yield of 47% and >97% ee.
The overall process is straightforward and does not employ
sophisticated reagents. Along the reaction sequence, the in-
[a]
`
Universita di LЈAquila, Dipartimento di Chimica, Ingegneria
Chimica e Materiali,
Coppito, I-67010 LЈAquila, Italy
E-mail: deangelis@axscaq.aquila.infn.it
Sigma-Tau, Dipartimento Ricerca Chimica,
Via Pontina Km 30.400, I-00040 Pomezia, Roma, Italy
Fax: (internat.) ϩ 39-06/91393638
E-mail: fabio.giannessi@sigma-tau.it
Sigma-Tau, Dipartimento Ricerca Analitica,
Via Pontina Km 30.400, I-00040 Pomezia, Roma, Italy
Fax: (internat.) ϩ 39-06/91393638
[b]
[c]
Scheme 1. Inversion of configuration of (S)-β-hydroxy-γ-butyrolac-
tone {(S)-1} to give the (R)-1 enantiomer
Eur. J. Org. Chem. 1999, 2705Ϫ2707
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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F. De Angelis, F. Giannessi, et al.
SHORT COMMUNICATION
hydroxyl group of compound 3 operated by the carboxylate
anion. Basic hydrolysis of 4, followed by acid catalyzed re-
cyclization, gave the desired product (R)-1 without racemiz-
ation, with the expected (R)-configuration at carbon 3. The
stereochemical course of the reaction allows the assigne-
Experimental Section
Melting points were determined by the capillary method on an elec-
trothermal apparatus and are uncorrected. H NMR spectra were
recorded at 200 MHz; chemical shifts are expressed in δ values
1
downfield from TMS. Chiral GC analyses were performed using a
ment of the R configuration for the β-lactone 4, which has 2,6-O-dimethyl-3-trifluroacetyl-β-cyclodextrin column supplied
from ASTEC {length ϭ 30 m; injector temperature ϭ 200°C; col-
umn temperature ϭ 100°C (5 min), 100 Ǟ 160°C (rate 10°C/min),
160°C (15 min), detector temperature (FID) ϭ 250°C}. Meth-
anesulfonyl chloride, Amberlite IR 120, dry pyridine and dry di-
chloromethane, sodium bicarbonate and dry sodium sulfate were
purchased from Aldrich. (S)-β-Hydroxy-γ-butyrolactone (S)-1 was
prepared as described in ref.[1c] from (S)-Carnitine (Biosint, Sigma-
tau group).
been previously described in the literature only as a race-
mate.[8]
We devised this synthetic strategy after the failure of
other inversion of configuration strategies; in particular the
Mitsunobu reaction led only to elimination products, owing
to the high tendency of the triphenylphosphonium inter-
mediate to convert into the stable 2-furanone, while treat-
ment with dicyclohexylcarbodiimide and carboxylic acids[9]
led only to degradation products.
Following the “β-lactone” strategy described in Scheme
1, (S)-β-hydroxy-γ-butyrolactone {(S)-1} was thus treated
with methanesulfonyl chloride to afford the (S)-β-methane-
sulfonyloxy-γ-butyrolactone 2 in 89% yield.[10] Compound
(S)-β-Methanesulfonyloxy-γ-butyrolactone (2): To a solution of (S)-
1 (8 g, 78.36 mmol) and dry pyridine (9.3 g, 117.54 mmol) in dry
CH2Cl2 (400 mL), refrigerated in an ice bath, was added meth-
anesulfonyl chloride (13.464 g, 117.54 mmol) dropwise under stir-
ring. The solution was stirred for an additional 5 h at room temp.,
washed with 5% aqueous HCl, H2O, a saturated solution of NaCl,
2 was then treated with Amberlite IR-120 to catalyze ring and dried over anhydrous Na2SO4. Diisopropyl ether was added to
hydrolysis, in a modification of a literature procedure.[11]
A
the residue; precipitation of the product occurred, and the mixture
1H NMR spectrum (D2O) of the reaction mixture showed
the presence of the intermediate (S)-γ-hydroxy-β-methane-
sulfonyloxy-butyric acid (3) which was not isolated due to
its high tendency, under acidic or neutral conditions, to un-
dergo back-cyclization to 2. Sodium hydrogencarbonate
was then added. After water evaporation and column chro-
matography (R)-β-hydroxymethyl-β-propiolactone (4) was
obtained as an oil, in 55% yield starting from 2. Compound
4 was then hydrolyzed with base; after acidification and sol-
vent evaporation the residue was taken up with EtOAc and
the insoluble material was filtered off to give pure (R)-β-
was left overnight at 4°C. Solvent was then decanted off and the
solid collected and dried under vacuum to give (2) in 89% yield
20
(12.6 g). Ϫ M.p. 81Ϫ82°C (decomp.). Ϫ [α]D ϭ Ϫ62 (c ϭ 0.6,
CHCl3). Ϫ Rf (TLC, silica gel) ϭ 0.69 (EtOAc). Ϫ 1H NMR
(200 MHz, CDCl3, 25°C, TMS): δ ϭ 5.45 (m, 1 H), 4.55 (dd, 2J ϭ
3
2
3
11.5 Hz, J ϭ 1.5 Hz, 1 H), 4.45 (dd, J ϭ 11.5 Hz, J ϭ 5.0 Hz, 1
2
3
H), 3.08 (s, 3 H), 2.90 (dd, J ϭ 17.5 Hz, J ϭ 6.0 Hz, 1 H), 2.80
(dd, J ϭ 17.5 Hz, J ϭ 3.5 Hz, 1 H). Ϫ C5H8O5S (180.18): calcd.
2
3
C 33.33, H 4.47, S 17.79; found C 33.32, H 4.48, S 17.53.
(R)-β-Hydroxymethyl-β-propiolactone (4): Amberlite IR 120 in
acidic form (230 mL) was added to a mixture of (2) (10.6 g,
58.83 mmol) in water (115 mL). After 24 h at room temp. under
flask shaking the resin was filtered off and washed with additional
20
hydroxy-γ-butyrolactone {(R)-1} {[α]D ϭ ϩ86, c ϭ 0.8 in
MeOH; [α]D20 ϭ ϩ88, c ϭ 0.8 in MeOH[1c]} with an optical water (550 mL). The 1H NMR spectrum of a sample evidenced the
presence of the intermediate (S)-γ-hydroxy-β-methanesulfonyloxy-
butyric acid (3) (1H NMR (200 MHz, D2O, 25°C): δ ϭ 5.12 (m, 1
H), 3.88 (dd, 2J ϭ 12.5 Hz, 3J ϭ 3.5 Hz, 1 H), 3.75 (dd, 2J ϭ
purity of ca. 98% (97.8% ee) checked by gas chromatogra-
phy on a chiral stationary phase [2,6-O-dimethyl-3-triflu-
roacetyl-β-cyclodextrin column].[12]
All attempts to perform the direct conversion of the β-
lactone 4 into (R)-1 under acidic conditions, i.e. hydrolysis
followed by cyclization, under different reaction conditions,
always ended up in the partial racemization. For example,
addition of 1 HCl to an aqueous solution of 4 down to
pH ϭ 1 and stirring for 1 h at 50°C, gave, after water evap-
3
3
12.5 Hz, J ϭ 5.5 Hz, 1 H), 3.20 (s, 3 H), 2.82 (d, J ϭ 6.0 Hz, 2
H)). NaHCO3 (3.953 g; 47.06 mmol, in order to avoid excess alka-
linity) was added, the solution heated at 50°C under stirring for
2 h and evaporated under vacuum. The residue was taken up with
EtOAc, the solid was filtered off and the solvent evaporated. Flash
chromatography (silica gel, n-hexane/EtOAc 6:4) of the residue gave
20
(4) (3.31 g, 55%) as a colorless oil. Ϫ [α]D ϭ Ϫ 29 (c ϭ 0.95,
oration, 5 in only 80% ee. Even more surprisingly, treatment CHCl3). Ϫ Rf (TLC, silica gel) ϭ 0.21 (n-hexane/EtOAc 6:4). Ϫ 1H
NMR (200 MHz, CDCl3, 25°C, TMS): δ ϭ 4.65 (m, 1 H), 4.10
of 4 with a stoichiometric amount of NaHCO3 in water
at room temp., led slowly (4 days) to the expected sodium
dihydroxybutyrate; after acidification and water evapor-
ation, an almost racemic mixture of the final hydroxy-γ-
butyrolactone was obtained.
2
3
2
(dd, J ϭ 13.5 Hz, J ϭ 2.5 Hz, 1 H), 3.80 (dd, J ϭ 13.5 Hz, 3J ϭ
3
4 Hz, 1 H), 3.45 (d, J ϭ 5 Hz, 2 H), 2.15 (br. s, 1 H). Ϫ C4H6O3
(102.09): calcd. C 47.06, H 5.92; found C 46.75, H, 5.97.
(R)-β-Hydroxy-γ-butyrolactone {(R)-1}: Compound
4
(3.5 g,
34.28 mmol) was dissolved in 3 NaOH (100 mL) and the solution
stirred at room temp. for 45 min. 3 HCl was added whilst cooling
the solution with an ice bath and the pH was adjusted to 2. Solvent
was then evaporated under vacuum and the residue taken up with
EtOAc. Solid NaCl was eliminated by filtration, the solution dried
over anhydrous Na2SO4, and the solvent evaporated under vacuum
to give {(R)-1} as a colorless oil (3.4 g, 97%). Ϫ [α]D20 ϭ ϩ 86 (c ϭ
In conclusion this simple and relatively high yielding
transformation opens an economic route to the production
of (R)-GABOB and (R)-carnitine,[2] among other biologi-
cally active compounds,[3,4] from a -hexose source or,
alternatively, from the industrial waste compound (S)-carni-
tine. We anticipate that the intermediate compound β-lac-
tone 4 could also be a versatile chiral synthon offering, for
example, new opportunities for the synthesis of chiral β-
functionalized-γ-hydroxybutyric acids.
1
0.8, MeOH). Ϫ Rf (TLC, silica gel) ϭ 0.63 (EtOAc). Ϫ H NMR
2
(200 MHz, CDCl3, 25°C,TMS): δ ϭ 4.62 (m, 1 H), 4.40 (dd, J ϭ
10.5 Hz, 3J ϭ 4.0 Hz, 1 H), 4.28 (dm, 2J ϭ 10.5 Hz, 1 H),
2706
Eur. J. Org. Chem. 1999, 2705Ϫ2707

Inversion of Configuration of (S)-β-Hydroxy-γ-butyrolactone
3.00Ϫ2.30 (br, 1 H), 2.73 (dd, 2J ϭ 18.5 Hz, 3J ϭ 6.0 Hz, 1 H),
2.45 (dm, J ϭ 18.5 Hz, 1 H). Ϫ C4H6O3 (102.09): calcd. C 47.06,
H, 5.92; found C 46.75, H 5.97.
SHORT COMMUNICATION
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Received May 19, 1999
[O99291]
Eur. J. Org. Chem. 1999, 2705Ϫ2707
2707