Enantioselective synthesis of β,β-dialkyl α-hydroxy γ-butyrolactones

Article abstract of DOI:10.1016/S0040-4039(01)01979-7

An ephedrine-derived morpholine dione is employed in the synthesis of chiral alkylidene morpholinones that are efficiently converted to β-substituted α,γ-dihydroxy butyramides, precursors of the corresponding butyrolactones. Enantioselective synthesis of a spiro analog of pantolactone as well as a naturally occurring pantolactone homolog is achieved with this protocol.

Full text of DOI:10.1016/S0040-4039(01)01979-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9265–9267
Enantioselective synthesis of b,b-dialkyl a-hydroxy
g-butyrolactones
Sunil V. Pansare* and Annyt Bhattacharyya
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 11 September 2001; revised 12 October 2001; accepted 19 October 2001
Abstract—An ephedrine-derived morpholine dione is employed in the synthesis of chiral alkylidene morpholinones that are
efficiently converted to b-substituted a,g-dihydroxy butyramides, precursors of the corresponding butyrolactones. Enantioselective
synthesis of a spiro analog of pantolactone as well as a naturally occurring pantolactone homolog is achieved with this protocol.
© 2001 Elsevier Science Ltd. All rights reserved.
The enantioselective synthesis of a-hydroxy g-
butyrolactones1 has been the subject of several recent
investigations. A number of these lactones are natural
products and this has spurred interest in their total
synthesis.2 b,b-Dialkyl a-hydroxy g-butyrolactones
have recently been employed as components of inter-
leukin inhibitors.3 This particular class of butyrolac-
tones and the parent hydroxy acids are also of interest
due to their structural similarity to pantolactone4 and
the potential for application as pantothenic acid
analogs in biologically relevant molecules.5 Herein, we
describe the application of an ephedrine-derived mor-
pholine-dione in a general, stereoselective synthesis of
b,b-disubstituted a-hydroxy butyramides and the corre-
sponding butyrolactones.
stereochemistry of 3b and 3c is based on the downfield
shift of the methylene hydrogens in 3b (l 2.6–2.8) as
compared to 3c (l 2.2–2.4).7 Olefins 3b and 3c are
separable by chromatography and further reactions
were conducted on isomerically homogeneous material.
We next investigated the synthesis of a spiro analog of
pantolactone. The Prins reaction8 ((CH2O)n, acetic acid,
cat. H2SO4, 85°C) of the cyclohexylidene morpholinone
3a efficiently generates the spiro bis-acetal 4a (90%,
Scheme 2) as a single diastereomer. This remarkably
rapid reaction is complete within 2 min. Prolonged
heating results in decomposition of 4a. The alkylidene
morpholinones 3b and 3c are converted to the spiro
bis-acetals 4b and 4c in an analogous manner. The
stereochemistry at the spiro acetal stereocenter in 4a–c
The reaction of ephedrine and oxalyl chloride at ambi-
ent temperature generates the morpholine-dione 1 in
63% yield. Dione 1 reacts readily with a variety of
Grignard and organolithium reagents6 at the lactone
carbonyl to generate the corresponding hemiacetals 2
(Scheme 1). Thus, treatment of 1 with cyclohexyl mag-
nesium bromide generates 2a (80%, ds=2.5/1) and
reaction with sec-butyl magnesium chloride gives a
mixture of diastereomers 2b–e (84%, dr=3/3/1/1). The
stereochemistry at the hemiacetal carbon and the sec-
butyl carbon for 2b–e has not been established. Dehy-
dration of the hemiacetals is best achieved by treatment
with BF3 etherate at ambient temperature and the
cyclohexylidene morpholinone 3a is obtained in 82%
from 2a. Dehydration of the 2b–e mixture gives 3b/3c
(90%, 1/1 mixture of E/Z isomers, Scheme 1). The
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01979-7

9266
S. V. Pansare, A. Bhattacharyya / Tetrahedron Letters 42 (2001) 9265–9267
is assigned by analogy to other reactions of the oxocar-
benium ion intermediate in the ephedrine-derived tem-
plate.9 At this stage, the stereochemistry at the quater-
nary carbon (bearing the methyl and ethyl groups) in 4b
and 4c was tentatively assigned as shown (Scheme 2).
The assignment was later confirmed by synthesis of the
derived lactones and by correlation.
lute configuration of which has been unambiguously
established as 3S,4S by synthesis from
-glucose.13
D
A
synthesis from (S)-malic acid has also been reported
recently.14 The specific rotation and spectroscopic data
of 7b (97% e.e.) obtained from our study are in agree-
ment with those of the natural product15 and 7b there-
fore has the 3S,4S configuration. Since the
stereochemistry of the a-hydroxy bearing carbon has
been established as ‘S’ in the present as well as other
related systems,4b and 7b and 7c are diastereomers, it
follows that 7c (97% e.e.) has the 3S,4R configuration.
The Prins reaction of the alkylidene morpholinones 3 is
therefore stereospecific and proceeds with retention of
the olefin geometry. Thus, the E-isomer 3b generates 4b
whereas the Z-isomer 3c generates 4c.
Morpholinones 4 incorporate all the required carbons
for the target a-hydroxy butyrates and possess a spiro
acetal stereocenter that is subject to stereoselective
reduction with silanes. Accordingly, treatment of 4a–c
with excess TiCl4/triethylsilane efficiently generates the
morpholinones 5a–c as single diastereomers resulting
from axial reduction of the intermediate oxocarbenium
ion under stereoelectronic control (Scheme 3). Mor-
pholinones 5a–c are protected versions of the requisite
a,g-dihydroxy butyric acid precursors of the target lac-
tones. Dissolving metal reduction of 5a–c generates the
a-hydroxy g-methoxy butyramides 6a–c (50–52%).
Conversion of 6 to the lactones 7 was readily achieved
by a one-pot reaction sequence. Liberation of the pri-
mary hydroxyl group in 6 by demethylation (BBr3) and
subsequent acid catalyzed lactonization (H2SO4/H2O,
−15°C to rt) generates the lactones 7a–c in good yield
(70–86%, Scheme 3).10
In conclusion, the ephedrine derived morpholine dione
1 is a convenient precursor for chiral alkylidene mor-
pholinones that are key substrates in a highly stereose-
lective Prins reaction/acetal reduction protocol. A
general, enantioselective route to b,b-disubstituted a-
hydroxy butyrolactones has been established. Current
efforts focus on other applications of the dione 1 in the
enantioselective synthesis of a-hydroxy acids and
derivatives.
Acknowledgements
This constitutes the first asymmetric synthesis of the
spiro lactone (S)-7a (98% e.e. by chiral GC analysis).11
One of the pantolactone homologs 7 is a natural
product isolated from Marshallia tenuifolia,12 the abso-
Financial assistance (in part) from the Department of
Science and Technology (Grant SP/S1/G-11/96) is
gratefully acknowledged. We thank Mr. D. Mandal for
assistance in determining the enantiomeric excess of the
lactones.
References
1. (a) Peterson, M.; Kalbermatten, G. PCT Int. Appl. WO
2001018231 A2, 2001; (b) Nakano, T.; Oh-Hashi, N.;
Ino, Y.; Nagai, Y. Main Group Met. Chem. 2000, 23, 259;
(c) Eliel, E. L.; Bai, X.; Ohwa, M. J. Chin. Chem. Soc.
2000, 47, 63; (d) Blandin, V.; Carpentier, J.-F.;
Mortreaux, A. Eur. J. Org. Chem. 1999, 1787.
2. (a) Sefkow, M. J. Org. Chem. 2001, 66, 2343; (b) Ueki,
T.; Ichinari, D.; Yoshihara, K.; Morimoto, Y.;
Kinoshita, T. Tetrahedron Lett. 1998, 39, 667; (c) Ichi-
nari, D.; Ueki, T.; Yoshihara, K.; Kinoshita, T. Chem.
Commun. 1997, 1743.
Scheme 2.
3. Lacrampe, J. F.; Armand, F.; Eddy, E. J.; Deroose, D.
F.; Fortin, J. M. C.; Coesemans, E. PCT Int. Appl. WO
0,110,866 A1 20010215, 2001.
4. For studies on the resolution and enantioselective synthe-
sis of pantolactone, see: (a) Kesseler, M.; Hauer, B.;
Friedrich, T.; Mattes, R. PCT Int. Appl. WO 2001032890
A1, 2001; (b) Pansare, S. V.; Jain, R. P. Org. Lett. 2000,
2, 175; (c) Haughton, L.; Williams, J. M.; Zimmerman, J.
A. Tetrahedron: Asymmetry 2000, 11, 1697; (d) Paetow,
M.; Ahrens, D.; Hoppe, D. Tetrahedron Lett. 1992, 33,
5323 and references cited therein.
5. (a) Fissekis, J. D.; Skinner, C. G.; Shive, W. J. Am.
Chem. Soc. 1960, 82, 1654; (b) Klar, U.; Schwede, W.;
Skuballa, W.; Buchmann, B.; Schriner, M. Ger. Offen.
DE 19735574 A1 19990211, 1999 (CAN 130: 168162).
Scheme 3.

S. V. Pansare, A. Bhattacharyya / Tetrahedron Letters 42 (2001) 9265–9267
9267
6. Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.-I.; Mura-
hashi, S.-I. Bull. Chem. Soc. Jpn. 1996, 69, 2079.
7. The stereochemical assignment is based on the reported
trend in chemical shifts for the olefinic methine protons
in E- and Z-benzylidene camphor derivatives. See: Kos-
sanyi, J.; Furth, B.; Morizur, J. P. Tetrahedron 1970, 26,
395.
8. For reviews on the Prins reaction, see: (a) Adams, D. R.;
Bhatnagar, S. P. Synthesis 1977, 661; (b) Snider, B. B.
Compr. Org. Synth. 1991, 2, 527.
(CH2), 25.3 (CH2), 22.9 (CH2), 21.8 (CH2); IR (CHCl3):
3425, 2931, 2857, 1779, 1455, 1166, 1144, 1009, 1005
cm−1
; HRMS calcd for C9H14O3: 170.0943, found:
170.0942; [h]2D5=+13.9 (c 0.55, CHCl3).
11. The enantiomeric excess of the lactones was determined
by GC analysis with a HP Chiral (20% permethylated
b-cyclodextrin) column (30 m×0.320 mm×0.25 mm).
12. Herz, W.; Bruno, M. Phytochemistry 1987, 26, 1175.
13. Tadano, K.; Kanazawa, S.; Ogawa, S. J. Org. Chem.
1988, 53, 3868.
14. Ueki, T.; Ichinari, D.; Yoshibara, K.; Morimoto, Y.;
9. Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem.
Kinoshita, T. Tetrahedron Lett. 1998, 39, 667.
1998, 63, 4120.
15. 1H NMR (200 MHz, CDCl3): l 4.2 (d, 1H, J=9.3,
CH2O), 4.16 (s, 1H, CHOH), 3.87 (d, 1H, J=9.3,
CH2O), 3.0 (br, 1H, OH), 1.61–1.39 (m, 2H, CH2CH3),
1.19 (s, 3H, CH3), 0.92 (t, 3H, J=7.3, CH2CH3); 13C
NMR (50 MHz, CDCl3): l 177.6 (CꢀO), 76.0 (CHOH),
73.7 (CH2O), 43.6 (Cquat.), 24.2 (CH2CH3), 21.0 (CH3),
8.2 (CH2CH3); [h]2D5=+4.5 (c 0.25, CHCl3) for 7b and
[h]2D0=+4.7 (c 0.26, CHCl3) for the natural product.
10. All new compounds were characterized by 1H and 13C
NMR, IR and elemental analysis/HRMS. Data for 4S-4-
hydroxy-2-oxa-spiro[4,5]decan-3-one (7a): mp 92–93°C;
1H NMR (200 MHz, CDCl3): l 4.38 (d, 1H, J=9.3,
OCH2), 4.12 (bs, 1H, CHOH), 3.91 (dd, 1H, J=9.3, 1.4,
OCH2), 3.46 (bs, 1H, OH), 1.84–1.1 (m, 10H, cyclo-
hexyl); 13C NMR (50 MHz, CDCl3): l 178 (CꢀO), 75.7
(CHOH), 73.7 (OCH2), 44.1 (Cquat.), 33.7 (CH2), 25.8