Asymmetric synthesis of α-alkyl-α-hydroxy-γ-butyrolactones

Article abstract of DOI:10.1016/S0957-4166(99)00343-2

A new enantioselective approach to α-alkyl-α-hydroxy-γ-butyrolactones employing (1R,2S)-ephedrine-derived chiral allyl morpholinones as starting materials is described.

Full text of DOI:10.1016/S0957-4166(99)00343-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3103–3106
Asymmetric synthesis of α-alkyl-α-hydroxy-γ-butyrolactones
Sunil V. Pansare,∗ Rajendra P. Jain and R. Gnana Ravi
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 13 July 1999; accepted 10 August 1999
Abstract
A new enantioselective approach to α-alkyl-α-hydroxy-γ-butyrolactones employing (1R,2S)-ephedrine-derived
chiral allyl morpholinones as starting materials is described. © 1999 Elsevier Science Ltd. All rights reserved.
The asymmetric synthesis of α-hydroxy-γ-butyrolactones, with or without alkyl substituents in the
ring,1–7 continues to be actively investigated due to their utility as chiral building blocks for the
synthesis of natural products and biologically active molecules such as (1S,2R)-(−)-frontalin and (R)-(−)-
mevalonolactone.8 Similarly, the synthesis of racemic α-alkyl-α-hydroxy-γ-butyrolactones has also been
examined and their application in the preparation of α,β-butenolides and furans has been demonstrated.9
As part of an ongoing program into the asymmetric functionalization of α-keto carboxylic acids using
(1R,2S)-ephedrine as a chiral controller,10,11 we decided to explore the possibility of functionalization
of ephedrine-based allyl morpholinones10 and their subsequent conversion to α-alkyl-α-hydroxy-γ-
butyrolactones. Herein we describe an enantioselective approach to α-alkyl-α,γ-dihydroxy butyramides
and their conversion to the corresponding butyrolactones. To the best of our knowledge, an asymmetric
approach to enantiomerically enriched α-alkyl-α-hydroxy-γ-butyrolactones involving stereoselective
functionalization of α-keto acids has not been examined.
Acylation of (1R,2S)-ephedrine hydrochloride with a variety of aliphatic α-keto acid chlorides gene-
rates the hemiacetals 1 in good yield (65–71%). Allylation of 1 with allyltrimethylsilane/TiCl4 proceeds
with excellent diastereoselectivity (>95/5) at −40°C, to generate the 2-alkyl-2-allyl-morpholinones 2 in
good yield (75–92%)10 (Scheme 1). These served as starting materials for this study.
Scheme 1.
∗
Corresponding author. E-mail: pansare@ems.ncl.res.in
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00343-2

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Oxidative cleavage of the allylic double bond in 2a–d with OsO4/NaIO4 in THF/water at ambient
temperature cleanly generates the aldehydes 3a–d (83–95% yield)† which are quantitatively converted
to the corresponding alcohols 4a–d by reduction with NaBH4 in ethanol. Treatment of 4a with Na in liq.
NH3 at −78°C resulted in a complex mixture, presumably due to the presence of the free hydroxyl group.
Conversion of 4 to the ethoxyethyl ether was beneficial and dissolving metal reduction of protected 4
proceeded smoothly at −78°C to generate the α-hydroxy amides 5a–d in 58–65% yield over two steps.
It is noteworthy that the crude alcohols 4 and the corresponding ethoxy ethyl ethers may be directly used
in the Na/liq. NH3 reduction. The overall transformation is shown in Scheme 2.
Scheme 2.
The conversion of the α-hydroxy amides 5 to the target lactones 6 was achieved under remarkably
mild conditions. Unmasking of the primary alcohol in 5 is readily achieved by treatment with 3 M
H2SO4/THF at ambient temperature and proceeds with concomitant lactonization, presumably due to
a very facile intramolecular acyl transfer from nitrogen to oxygen13 to generate the desired α-alkyl-α-
hydroxy-γ-butyrolactones 6a–d in 82–91% yield (Scheme 3).‡
†
Oxidative cleavage of 2d with OsO4/NaIO4: To the stirred solution of 2d (0.92 g, 3.2 mmol) in THF (12 mL) and H2O (4 mL)
at ambient temperature was added OsO4 (0.5 M in toluene, 0.07 mL, 0.04 mmol) at which point the colorless solution turned
dark brown. To this was added solid NaIO4 (1.64 g, 7.7 mmol) in portions over 20 min and the reaction mixture was stirred for
4 h. Brine (20 mL) was added followed by ethyl acetate (40 mL). The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 0.99 g of
crude 3d. Purification by flash chromatography on silica gel (ethyl acetate:petroleum ether, 40:60) furnished 774 mg (83%) of
3d. IR (CHCl3): 2972, 2877, 1715, 1636, 1452, 1401, 1383, 1338, 1316, 1289, 1206, 1180, 1143, 1098, 1070, 1038 cm−1; 1H
NMR (200 MHz, CDCl3) δ 9.85 (dd, 1H, J=2.5, 3.4, CHO), 7.5–7.1 (m, 5H, ArH), 5.15 (d, 1H, J=3.4, CHPh), 3.54 (dq, 1H,
J=3.4, 6.8, CH3CH), 3.05 (s, 3H, NCH3), 2.95 (dd, 1H, J=3.4, 15.1, CH2CHO), 2.80 (dd, 1H, J=2.5, 15.1, CH2CHO), 2.44
(sept, 1H, J=6.8, Me2CH), 1.16 (d, 3H, J=6.8, (CH3)2CH), 1.06 (d, 3H, J=6.8, (CH3)2CH), 0.98 (d, 3H, J=6.8, CHCH3); MS
(70 eV) m/z 58 (51), 69 (11), 77 (11), 91 (29), 97 (32), 105 (14), 118 (100), 125 (6), 133 (8), 148 (33), 156 (4), 184 (39), 218
(6), 246 (6), 260 (11), 289 (M+, 30).
‡
2-(1-Methylethyl)-2-hydroxy-γ-butyrolactone (6d): To the stirred solution of 5d (0.1 g, 0.4 mmol) in THF (2.5 mL) at 0°C
was added 3 M H2SO4 (2.5 mL) dropwise over 3 min. The resulting solution was warmed to and stirred at ambient temperature
for 12 h. It was then diluted with ether (20 mL) and neutralized with excess solid NaHCO3. The organic layer was separated and
the aqueous layer was extracted with ether (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated to
give 53 mg of crude 6d. Purification by flash chromatography on silica gel (ethyl acetate:petroleum ether, 30:70) furnished 48
mg (82%) of 6d as a clear colorless oil. [α]D25=+75.6 (c 3.2, CHCl3); IR (neat): 3445, 2968, 2924, 2880, 1759, 1472, 1373,
1300, 1136, 1107, 1013, 984, 961, 943 cm−1; 1H NMR (200 MHz, CDCl3) δ 4.5–4.3 (m, 1H, CH2O), 4.3–4.15 (m, 1H, CH2O),

S. V. Pansare et al. / Tetrahedron: Asymmetry 10 (1999) 3103–3106
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Scheme 3.
The absolute configuration and enantiomeric excesses of compounds 6 are based on those of the
precursors 2 since epimerization of the newly generated stereocenter in 2 during conversion of 2 to 3, 3
to 5 and 5 to 6 is unlikely. Thus, lactones 6a–c are assigned R configuration and 6d the S configuration.
The configurational assignment was further confirmed by conversion of 6a (R=CH3) to its benzoate
derivative (PhCOCl, Et3N, DMAP, CH2Cl2, 90%) and comparison of the sign of the optical rotation of
the benzoate with the literature value.8 The overall conversion of the allyl morpholinones 2 to the lactones
6 constitutes a new approach to these important intermediates that involves asymmetric functionalization
of readily available α-keto carboxylic acids as the key step. The results are summarized in Table 1.
Table 1
Conversion of allyl morpholinones 2 to aldehydes 3; 3 to hydroxy amides 5; and 5 to α-alkyl-
α-hydroxy-γ-butyrolactones 6
In conclusion, an asymmetric synthesis of α-alkyl-α-hydroxy-γ-butyrolactones has been achieved
from (1R,2S)-ephedrine-derived allyl morpholinones. The methodology developed has been successfully
applied for the synthesis of 2-methyl-2-hydroxy-γ-butyrolactone which serves as a key precursor in
the synthesis of (1S,2R)-(−)-frontalin and (R)-(−)-mevalonolactone.8 Since (1S,2R)-ephedrine is also
commercially available, the enantiomeric series of α-alkyl-α-hydroxy-γ-butyrolactones should also be
available by this methodology. Current efforts focus on other reactions of allyl morpholinones 2.
Acknowledgements
Financial assistance from the Department of Science and Technology (grant no. SP/S1/G-11/96) and
the Council of Scientific and Industrial Research (Senior Research Fellowship to R.P.J. and R.G.R.) is
gratefully acknowledged.
2.8–2.45 (b, 1H, OH), 2.45–2.10 (m, 2H, CH2), 2.05 (sept, 1H, J=6.8, Me2CH), 1.05 (d, 3H, J=6.8, CHCH3), 0.95 (d, 3H,
J=6.8, CHCH3); 13C NMR (75 MHz, CDCl3) δ 178.7 (C_O), 78.0 (C-OH), 65.4 (CH2-O), 33.8 (CH), 30.8 (CH2-C), 17.2
(CH3), 15.8 (CH3); MS (70 eV) m/z 57 (65), 67 (26), 71 (100), 85 (99), 102 (82), 126 (1), 144 (M+, 1).

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