Enantioselective synthesis of α-hydroxy γ-butyrolactones from an ephedrine-derived morpholine-dione

Article abstract of DOI:10.1016/S0040-4020(02)01151-1

An ephedrine-derived morpholine dione is employed in the enantioselective synthesis of (S)-α-hydroxy γ,γ-dimethyl-γ-butyrolactone and (S)-α-hydroxy γ-butyrolactone. A one-pot alkylation/allylation protocol for the stereoselective conversion of the dione to 2-alkyl-2-allyl morpholinones, key intermediates for α-alkyl-α-hydroxy-γ-butyrolactones, is described.

Full text of DOI:10.1016/S0040-4020(02)01151-1

Tetrahedron 58 (2002) 8985–8991
Enantioselective synthesis of a-hydroxy g-butyrolactones from an
ephedrine-derived morpholine-dione
*
Sunil V. Pansare, Bidhan A. Shinkre and Annyt Bhattacharyya
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 27 June 2002; revised 23 August 2002; accepted 12 September 2002
Abstract—An ephedrine-derived morpholine dione is employed in the enantioselective synthesis of (S)-a-hydroxy g,g-dimethyl-g-
butyrolactone and (S)-a-hydroxy g-butyrolactone. A one-pot alkylation/allylation protocol for the stereoselective conversion of the dione to
2-alkyl-2-allyl morpholinones, key intermediates for a-alkyl-a-hydroxy-g-butyrolactones, is described. q 2002 Elsevier Science Ltd. All
rights reserved.
The enantioselective synthesis of a-hydroxy acids and
esters1 and their derivatives such as a-hydroxy g-butyro-
lactones2 has been the subject of several recent investi-
gations. A number of these lactones are natural products,
which has spurred interest in their total synthesis.3 Herein,
we describe the application of an ephedrine-derived
morpholine-dione in the stereoselective synthesis of
a-hydroxy butyramides and the corresponding
butyrolactones.
The reaction of ephedrine with oxalyl chloride generates the
morpholine-dione 1 in 65% yield.4 Initially, we investigated
chemoselective reactions of 1 with nucleophilic reagents.
Treatment of 1 with (carbethoxymethylene) triphenyl-
phosphorane in dichloromethane at ambient temperature
Scheme 1.
generates the alkylidene morpholinone 2 (80%, Z/E¼20/1,
Scheme 1). The stereochemical assignment is based on the
chemical shift of the olefinic methine proton (d 6.22 in Z-2)
as compared to the upfield shift5 in the E-isomer (d 5.83).
reduction of the amide carbonyl and reduction at ambient
temperature is capricious, often giving poor yield of the
alcohol. Although hydrolysis of 3 followed by reduction of
the acid with BH3 in THF is also inefficient, reduction of the
Hydrogenation of the alkylidene ester 2 (H2, Pd/C, 1 atm)
provides 3 as a single diastereomer in quantitative yield
(Scheme 1). The stereochemistry of reduction is based on
the observed diastereoselectivity for allylation and
reduction on the ephedrine-derived template.6,7 It is
noteworthy that 3 is a fully protected and chemically
differentiated malic acid derivative that is a valuable
precursor to a-hydroxy butyrolactones. To this effect,
chemoselective transformations at the ester carbonyl in 3
were investigated. Selective ester reduction in 3 to give
alcohol 4 (Scheme 2) proved to be unexpectedly difficult.
Heating 3 with excess LAH results in concomitant partial
8
acid chloride with a combination of TiCl4/NaBH4 in
dioxane is the procedure of choice and provides the alcohol
4 in 70% yield. Subsequent protection with ethylvinyl ether
followed by removal of the ephedrine portion with
dissolving metal reduction (Na/NH3, 2788C) generates
the partially unmasked butyramide 5 (65% yield over two
steps, Scheme 2).
The ester group in 3 also serves as a useful tool for further
functionalization of the embedded a-alkoxy succinate
moiety. The potential of 3 as a common precursor to the
a-hydroxy butyrolactone scaffold was demonstrated with
the synthesis of (S)-g,g-dimethyl-a-hydroxy-g-butyro-
lactone. The (R) enantiomer of this lactone, which is a
valuable intermediate in the synthesis of bark beetle
Keywords: asymmetric synthesis; lactones; Wittig reaction; allylation;
diastereoselectivity.
*
Corresponding author; e-mail: pansare@ems.ncl.res.in
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01151-1

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S. V. Pansare et al. / Tetrahedron 58 (2002) 8985–8991
Scheme 2.
pheromones,9 should also be readily available by the present
methodology since 1S,2R ephedrine is commercially
available as well. Related g,g-dialkyl a-hydroxy butyro-
lactones have been employed as components of chiral
dopants in liquid crystals.10
hemiacetal 10 (R0¼MgX) with allyl trimethylsilane/TiCl4
(Scheme 4).
Thus, reaction of 1 with an alkyl Grignard reagent in ether at
2788C followed by allylation (278 to 2208C for 6 h, or
gradual warming to ambient temperature overnight)
furnished morpholinones 116 (Scheme 4) as single dia-
stereomers (1H NMR) in 50–60% yield.
Treatment of 3 with excess MeMgI yields the tertiary
alcohol 6 in 75% yield. The conversion of 6 to the hydroxy
amide 7 is achieved as described for the primary alcohol 4.
Protection of 6 as the ethoxyethyl ether followed by
reductive cleavage generates the substituted dihydroxy
butyramide 7 (55% yield over two steps (Scheme 2)).
Allyl morpholinones 11 are important intermediates in the
synthesis of a-hydroxy acids6 and more notably, they are
readily converted a-hydroxy a-alkyl-g-butyrolactones
(Scheme 4).12 The above one-pot procedure has a significant
advantage over the earlier, a-keto acid based method for
synthesis of the hemiacetals from ephedrine. The present
method does not require a-keto acids and it should now be
possible to prepare any hemiacetal by reaction of 1 and the
appropriate organometallic reagent. In addition, isolation
and purification of the hemiacetal is not required. A
selection of hemiacetals and allyl morpholinones prepared
by the one-pot protocol is shown in Fig. 1.
The deprotection of 5 and 7 with aqueous acid proceeds with
concomitant lactonization to generate a-hydroxy g-butyro-
lactones 8 (70%, 96% ee)11a and 9 (82%, 98% ee)11b
respectively. This facile lactonization probably proceeds via
an acyl group transfer from nitrogen to oxygen under acidic
conditions (Scheme 3). The synthesis of 5, 7, 8 and 9
highlights the utility of the dione 1 as a general precursor for
various a-hydroxy butyrates.
Morpholine-dione 1 also reacts chemoselectively with a
variety of alkyl metal reagents to generate the hemiacetals
106 (Scheme 4). In particular, the reaction of 1 with
Grignard reagents in ether at 2208C provides hemiacetals 10
in excellent yield and good diastereoselectivity6 (ds$10/1
by 1H NMR). We have previously demonstrated the
synthesis of these hemiacetals from ephedrine and a-keto
acids and also the stereoselective allylation of these
hemiacetals in a separate, subsequent step.6 In the present
study, a one-pot reaction protocol that combines the
hemiacetal synthesis and the allylation step was developed.
The procedure involves addition of the alkyl metal reagent
to the dione followed by allylation of the resulting salt of the
In conclusion, we have developed a novel, stereoselective
route to a-hydroxy g-butyrolactones by functionalization of
a readily available ephedrine derivative. The morpholinone
3 holds great potential as a common intermediate for a
Scheme 3.
Scheme 4.

S. V. Pansare et al. / Tetrahedron 58 (2002) 8985–8991
8987
layer was washed with water (70 mL), dried (Na2SO4) and
concentrated. The residue was purified by column chroma-
tography on silica gel (1/3 petroleum ether/ethyl acetate) to
furnish 1.42 g (65%) of 1 as a white solid.
Mp: 1828C; 1H NMR (200 MHz, CDCl3): d 7.50–7.28 (m,
5H, ArH), 5.90 (d, 1H, J¼2.9 Hz, CHPh), 3.77–3.66 (dq,
1H, J¼2.9, 6.8 Hz, CHCH3), 3.19 (s, 3H, NCH3), 1.12 (d,
3H, J¼6.8 Hz, CH3); 13C NMR (50 MHz, CDCl3): d 156.4
(OCvO), 153.0 (NCvO), 133.8 (ArCipso), 128.6 (ArC),
128.0 (ArC), 125.3 (ArC), 79.3 (PhCH), 58.1 (CH3CH),
33.2 (NCH3), 11.8 (CH3); IR (CHCl3): 3018, 1771, 1693,
1406, 1292, 1215, 1186, 1009 cm21; MS (EI, 70 eV): m/z 57
(90), 77 (45), 91 (35), 105 (25), 117 (100), 147 (3), 176 (3),
219 (Mþ, 12); Analysis for C12H13NO3: calcd: C, 65.74; H,
5.97; N, 6.38; Found: C, 65.35; H, 6.09, N, 6.36;
[a]2D5¼2184.3 (c¼0.8, CHCl3).
Figure 1. Hemiacetals 10 and allyl morpholinones 11 prepared from 1.
1.1.2. (Z)-5S,6R-2-Carbethoxymethylidene-4,5-
dimethyl-6-phenyl-morpholin-3-one (2). To a solution of
1 (219 mg, 1 mmol) in dichloromethane (3 mL) at room
temperature was added carbethoxymethylene triphenyl-
phosphorane (418 mg, 1.2 mmol) and the mixture was
stirred at ambient temperature for 48 h. The solvent was
removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (6/4
petroleum ether/ethyl acetate) to furnish 231 mg (80%) of
2 as a white solid.
variety of functionalized a-hydroxy acids and a-hydroxy
g-butyrolactones. The one-pot alkylation/allylation protocol
with morpholine-dione 1 significantly improves the scope of
the hemiacetal approach to a-hydroxy g-butyrolactones and
other a-hydroxy acid derivatives. Current efforts focus on
other reactions of 1.
1. Experimental
1.1. General
Mp: 161–1628C; 1H NMR (300 MHz, CDCl3): d 7.55–7.3
(m, 5H, ArH), 6.22 (s, 1H, vinylic), 5.47 (d, 1H, J¼2.9 Hz,
PhCH), 4.27–4.18 (m, 2H, OCH2C), 3.73–3.62 (dq, 1H,
J¼2.9, 6.6 Hz, CH3CH), 3.15 (s, 3H, NCH3), 1.32 (t, 3H,
J¼7.3 Hz, CH3CH2), 1.02 (d, 3H, J¼6.6 Hz, CH3CH); 13C
NMR: (50 MHz, CDCl3): d 164.6 (OCvO), 157.7
(NCvO), 153.5 (CvCH), 135.5 (ArCipso), 128.4 (ArC),
128 (ArC), 125.2 (ArC), 101 (CvCH), 77.9 (PhCH), 59.7
(OCH2), 57.9 (NCH), 33.6 (NCH3), 14.0 (CH2CH3), 11.4
(CH3CH); IR (CHCl3): 3018, 2983, 1701, 1668, 1637, 1338,
1285, 1258, 1215, 1194, 1034, 908 cm21; MS (EI, 70 eV):
m/z 69 (32), 77 (19), 91 (44), 107 (53), 117 (75), 135 (100),
147 (89), 154 (32), 174 (28), 244 (38), 289 (Mþ, 62);
Analysis for C16H19NO4: calcd: C, 66.42; H, 6.62; N, 4.84;
Found: C, 66.11; H, 6.75, N, 4.73; [a]2D5¼2238.1 (c¼0.6,
CHCl3).
All reactions requiring anhydrous conditions were per-
formed under a positive pressure of argon using oven-dried
(1208C) glassware. Ether, THF and dioxane were distilled
from sodium and benzophenone. Dichloromethane and
triethylamine were distilled from calcium hydride. Solvents
for chromatography were distilled at their respective
constant boiling points. Petroleum ether refers to the
fraction in the 60–808C range. Commercially available
TiCl4 was distilled and used. Grignard reagents were freshly
prepared. Commercially available oxalyl chloride and
NaBH4 were used. 1H and 13C NMR spectra were recorded
on Bruker MSL-300 or AC-200 instruments. IR spectra
were recorded on a Shimadzu FTIR-8400 instrument.
Optical rotations were measured at the sodium D line on
JASCO P-1020 polarimeter. Mass spectra (EI) were
recorded on a Finnigan-Mat 1020C mass spectrometer at
an ionization potential of 70 eV. High resolution mass
spectra were recorded on a Jeol JMS-SX-102 spectrometer.
All melting points are uncorrected. Elemental analyses were
performed by the microanalysis facility at NCL, Pune.
1.1.3. 2S,5S,6R-2-Carbethoxymethyl-4,5-dimethyl-6-
phenyl-morpholin-3-one (3). To a solution of 2 (289 mg,
1 mmol) in ethyl acetate (10 mL) was added Pd/C (5%,
25 mg) and the mixture was stirred under an atmosphere of
hydrogen (1 atm) for 12 h. The mixture was filtered through
a pad of Celitew and the filtrate was concentrated under
reduced pressure to give 291 mg (100%) of 3 as a clear
colorless gum.
1.1.1. 5S,6R-4,5-Dimethyl-6-phenyl-morpholin-2,3-dione
(1). To a stirred suspension of ephedrine hydrochloride (2 g,
9.9 mmol) and DMAP (60 mg, 0.49 mmol) in dichloro-
methane (200 mL) at 08C was added triethylamine (5.5 mL,
39.6 mmol). The mixture was stirred for 10 min and a
solution of oxalyl chloride (1.3 mL, 14.9 mmol) in dichloro-
methane (100 mL) was added dropwise over a period of 4 h
at 08C. The mixture was further stirred at 08C for 1 h and ice
was added. The mixture was warmed to ambient tempera-
ture and the biphase was separated. The dichloromethane
1H NMR (200 MHz, CDCl3): d 7.46–7.22 (m, 5H, ArH),
5.06 (d, 1H, J¼2.9 Hz, PhCH), 4.66 (t, 1H, J¼5.4 Hz,
CHCH2), 4.3–4.12 (q, 2H, J¼6.8 Hz, OCH2), 3.61–3.44
(dq, 1H, J¼2.9, 6.4 Hz, CH3CH), 3.15–2.88 (m, 2H,
CH2CO2Et), 3.04 (s, 3H, NCH3), 1.29 (t, 3H, J¼6.8 Hz,
CH3CH2), 0.99 (d, 3H, J¼6.4 Hz, CH3CH); 13C NMR
(50 MHz, CDCl3): d 170.0 (OCvO), 167.5 (NCvO), 137
(ArCipso), 128 (ArC), 127.3 (ArC), 125.1 (ArC), 76.4

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S. V. Pansare et al. / Tetrahedron 58 (2002) 8985–8991
(PhCH), 74.6 (CHCO), 60.2 (OCH2), 58.4 (N–CH), 37.3
(CH2CO2Et), 33.1 (NCH3), 13.9 (CH2CH3), 12.3 (CH3CH);
IR (CHCl3): 2982, 2937, 1738, 1653, 1497, 1489, 1456,
1400, 1378, 1270, 1182, 1148, 1109, 1027 cm21. HRMS for
C16H21NO4: calcd: 291.1471; Found: 291.1474;
[a]2D5¼2114.0 (c¼1.1, CHCl3).
trated to give the ethoxyethyl derivative of 4 that was used
further without purification.
The above derivative was dissolved in anhydrous THF
(2 mL) and added to a mixture of anhydrous liquid ammonia
(7 mL, distilled over sodium) and sodium (154 mg,
6.7 mmol) at 2788C. The mixture was stirred at 2788C
for 3 min and methanol (6 mL) was added. The mixture was
warmed to ambient temperature to remove ammonia and the
methanol was removed under reduced pressure. The residue
was taken up in water and the mixture was saturated with
sodium chloride. The aqueous phase was extracted with
ethyl acetate and the combined extracts were concentrated.
The residue was purified by rapid filtration through a short
silica gel column (ethyl acetate) to furnish 90 mg (65%) of 5
which was immediately used further.
1.1.4. 2S,5S,6R-2-(2-Hydroxyethyl)-4,5-dimethyl-6-
phenyl-morpholin-3-one (4). To the solution of
3
(580 mg, 2 mmol) in THF (8 mL) was added aqueous
NaOH (1 M, 8 mL) and the mixture was stirred at ambient
temperature for 6–7 h. The aqueous layer was acidified with
conc. HCl and extracted with ethyl acetate (3£20 mL). The
combined organic layers were washed with saturated
aqueous NaHCO3 (25 mL). The bicarbonate extract was
acidified with conc. HCl and the solution was extracted with
ethyl acetate (3£20 mL). The combined ethyl acetate
extracts were dried (Na2SO4) and concentrated to give
502 mg (96%) of the carboxylic acid.
1H NMR (200 MHz, CDCl3): Major diastereomer: d 6.95
(br s, 1H, NH), 4.7–4.6 (m, 1H, OCHO), 4.25 (br dd, 1H,
2.9, 8.3, CHOH), 3.9–3.36 (m, 4H, 2£OCH2), 2.81 (d, 3H,
J¼5.0 Hz, NCH3), 2.25 (br t, 1H, 7.0, CH2), 1.86 (br t, 1H,
J¼7.3 Hz, CH2), 1.28 (d, 3H, J¼5.3 Hz, CHCH3), 1.17 (t,
3H, J¼7.0 Hz, CH2CH3). Minor diastereomer: d 6.0 (br s,
NH), 4.7–4.6 (m, 1H, OCHO), 4.25 (br dd, 1H, CHOH),
3.9–3.36 (m, 4H, 2£OCH2), 2.76 (d, 3H, J¼5.0 Hz, NCH3),
2.19–2.08 (m, 1H, CH2), 1.98–1.79 (m, 1H, CH2), 1.25 (d,
3H, J¼5.4 Hz, CHCH3), 1.16 (t, 3H, J¼7.0 Hz, CH2CH3);
IR (neat): 3355, 2976, 2933, 2882, 1658, 1547, 1410, 1381,
To a solution of the carboxylic acid (502 mg, 1.91 mmol) in
dichloromethane (6 mL) was added oxalyl chloride
(0.83 mL, 9.54 mmol) dropwise and the mixture was stirred
at ambient temperature for 2 h. The solvent and excess
oxalyl chloride were removed under reduced pressure and
the residue was dissolved in dioxane (6 mL). The dioxane
solution was added to a stirred suspension of sodium
borohydride (722 mg, 19.1 mmol) in dioxane (6 mL)
followed by addition of TiCl4 (1.05 mL, 9.55 mmol). The
resulting mixture was heated to 908C for 8 h and then cooled
to 08C. Saturated aqueous bicarbonate was added and the
resulting mixture was extracted with ethyl acetate
(3£20 mL). The combined extracts were dried (Na2SO4)
and concentrated. The residue was purified by flash
chromatography on silica gel (ethyl acetate) to furnish
332 mg of alcohol 4 (70%) as a white solid.
1131, 1099, 1058 cm21
.
The dihydroxy amide obtained by deprotection of 5 was
1
characterized. H NMR (200 MHz, CDCl3): d 7.03 (b, 1H,
NH), 4.58 (b, 1H, OH), 4.38–4.25 (dd, 1H, J¼3.5, 7.9 Hz,
CHOH), 3.95–3.84 (m, 2H, CH2OH), 2.85 (d, 3H,
J¼5.4 Hz, NHCH3), 2.23–2.0 (m, 1H, CH2CHOH), 1.98–
1.73 (m, 1H, CH2CHOH); HRMS for C5H11NO3: calcd:
133.0925; Found: 133.0921; [a]2D5¼231.8 (c¼0.4, CHCl3).
Mp: 135–1368C; 1H NMR (200 MHz, CDCl3): d 7.55–7.2
(m, 5H, ArH), 5.03 (d, 1H, J¼2.9 Hz, PhCH), 4.47 (t, 1H,
J¼6.3 Hz, CHCO), 3.89 (t, 2H, J¼6.4 Hz, CH2OH),
3.58–3.43 (dq, 1H, J¼2.9, 6.3 Hz, CHCH3), 3.05 (s, 3H,
NCH3), 2.42–2.10 (m, 2H, CH2CH), 1.00 (d, 3H, J¼6.3 Hz,
CH3CH); 13C NMR (50 MHz, CDCl3): d 169.9 (NCvO),
137.1 (ArCipso), 127.7 (ArC), 126.9 (ArC), 124.8 (ArC),
75.8 (PhCH), 75.4 (CHCO), 58.4 (CH2OH), 57.9 (NCH), 35
(CH2CH2OH), 32.9 (NCH3), 12.2 (CH3CH); IR (CHCl3):
3404, 3013, 2980, 2928, 2860, 1641, 1634, 1497, 1452,
1404, 1381, 1250, 1215, 1148, 1109, 1065 cm21; MS
(EI, 70 eV): m/z 58 (100), 69 (7), 77 (20), 84 (24), 105
(14), 115 (39), 143 (27), 205 (15), 249 (Mþ, 5);
Analysis for C14H19NO3: calcd: C, 67.45; H, 7.68; N,
5.62; Found: C, 67.50; H, 7.83; N, 5.24; [a]2D5¼2177.7
(c¼0.5, CHCl3).
1.1.6. 2S,5S,6R-2-(2-Hydroxy-2-methyl-propyl)-4,5-
dimethyl-6-phenyl-morpholin-3-one (6). To a solution of
3 (160 mg, 0.55 mmol) in benzene (3 mL) was added
MeMgI in ether (5.5 mmol) at 10–158C and the mixture was
stirred for 2 h at ambient temperature. Saturated aqueous
NH4Cl was added and the mixture was extracted with ethyl
acetate (3£15 mL). The combined extracts were dried
(Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(4/6 petroleum ether/ethyl acetate) to furnish 115 mg (75%)
of 6 as a white solid.
Mp: 104–1058C; 1H NMR (200 MHz, CDCl3): d 7.45–7.17
(m, 5H, ArH), 5.04 (d, 1H, J¼2.5 Hz, PhCH), 4.66–4.5 (dd,
1H, J¼4.9, 7.8 Hz, CHCO), 4.25–4.05 (b, 1H, OH), 3.58–
3.4 (dq, 1H, J¼2.5, 6.3 Hz, CHCH3), 3.04 (s, 3H, NCH3),
2.39–2.15 (dd, 1H, J¼4.9, 14.6 Hz, CH2CHO), 2.14–1.9
(dd, 1H, J¼7.8, 14.6 Hz, CH2CHO), 1.33 (s, 6H, (CH3)2C),
1.0 (d, 3H, J¼6.3 Hz, CH3CH); 13C NMR (50 MHz,
CDCl3): d 169.6 (NCvO), 137.2 (ArCipso), 128.4 (ArC),
127.8 (ArC), 125.4 (ArC), 77.2 (PhCH), 76.4 (CHCO), 69.4
(C–OH), 58.7 (NCH), 45.13 (CH2CH), 33.7 (NCH3), 29.7
((CH3)2C), 29.5 ((CH3)2), 13 (CH3CH); IR (film): 3417,
2972, 2932, 1633, 1497, 1452, 1402, 1379, 1210, 1149,
1104 cm21; MS (EI, 70 eV): m/z 58 (100), 77 (10), 91 (12),
1.1.5. 2S-2-Hydroxy-4-ethoxyethyl-butanoic acid N-
methyl amide (5). To the solution of 4 (168 mg,
0.67 mmol) in chloroform (3 mL) was added ethyl vinyl
ether (0.52 mL, 5.4 mmol) and trichloroacetic acid (a few
crystals). The resulting mixture was stirred at ambient
temperature for 12 h. Saturated aqueous NaHCO3 was
added and the organic layer was separated. The bicarbonate
layer was extracted with chloroform (3£5 mL) and all the
CHCl3 layers were combined, dried (Na2SO4) and concen-

S. V. Pansare et al. / Tetrahedron 58 (2002) 8985–8991
8989
112 (48), 148 (8), 171 (12), 265 (25), 277 (Mþ, 2); HRMS
for C16H23NO3: calcd: 277.1679; Found: 277.1680;
[a]2D5¼2163.2 (c¼0.6, CHCl3).
NaHCO3. The organic layer was separated, dried
(Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(4/6 petroleum ether/ethyl acetate followed by ethyl acetate)
to furnish 98 mg (70%) of 8 as a clear, colorless gum.
1.1.7. 2S-2-Hydroxy-4-ethoxyethyl-4-methyl-pentanoic
acid N-methyl amide (7). To the solution of 6 (327 mg,
1.18 mmol) in chloroform (3 mL) was added ethyl vinyl
ether (0.9 mL, 9.40 mmol) and trichloroacetic acid (a few
crystals). The resulting mixture was stirred at ambient
temperature for 18–20 h. Solid sodium bicarbonate was
added and the chloroform was removed under reduced
pressure. Attempted isolation of the product by conventional
partitioning techniques results in decomposition to the
starting material and the crude ethoxyethyl ether was
therefore used further without any treatment or purification.
1H NMR (200 MHz, CDCl3): d 4.62–4.37 (m, 2H, CH2O),
4.25 (ddd, 1H, J¼6.0, 9.0, 10.0 Hz, CHOH), 3.58 (bs, 1H,
OH), 2.72–2.52 (m, 1H, CH2CH2O), 2.43–2.16 (m, 1H,
CH2CH2O); 13C NMR (50 MHz, CDCl3): d 177.7 (OCvO),
67.44 (CHOH), 65.09 (CH2O), 30.91 (CH2CH2O); IR
(CHCl3): 3441, 3020, 2920, 1776, 1626, 1454, 1375,
1323, 1217, 1178, 1126, 1087, 1018 cm21; [a]D25¼266
(c¼1, CHCl3).
1.1.9. S-3-Hydroxy-5,5-dimethyl-dihydro-2-(3H)-fura-
none (9). This was prepared from 7 (72 mg, 0.31 mmol)
in THF (1.5 mL) as described for 8 at ambient temperature
for 12–15 h. Purification by flash chromatography on silica
gel (7/3 petroleum ether/ethyl acetate) furnished 33 mg
(82%) of 9 as a clear, colorless gum that solidifies below
58C.
The crude ethoxyethyl ether was dissolved in THF (2 mL)
and the solution was added to the mixture of anhydrous
liquid ammonia (10 mL, distilled over sodium) and sodium
(270 mg, 11.8 mmol) at 2788C. The reaction mixture was
stirred at 2788C for 3 min, methanol was added and the
mixture was warmed to ambient temperature to remove
ammonia. The methanol was removed under reduced
pressure and the residue was taken up in water. The mixture
was saturated with solid NaCl and extracted with ethyl
acetate (3£15 mL). The combined organic layers were dried
(Na2SO4) and concentrated. The residue was purified by
rapid filtration through a short silica gel column (ethyl
acetate) to furnish 151 mg (55%) of 7 which was
immediately used further.
1H NMR (200 MHz, CDCl3): d 4.78–4.58 (dd, 1H, J¼8.3,
9.7 Hz, CHOH), 3.69 (b, 1H, OH), 2.63–2.45 (dd, 1H,
J¼8.3, 12.7 Hz, CH2CH), 2.18–1.94 (dd, 1H, J¼9.7,
12.7 Hz, CH2CH), 1.52 (s, 3H, CH3), 1.42 (s, 3H, CH3);
13C NMR (50 MHz, CDCl3): d 177.1 (CvO), 82.3
(C(CH3)2), 68.8 (CHOH), 42.9 (CH2), 29.1 (CH3), 27.7
(CH3); IR (CHCl3): 3431, 2980, 2937, 1770, 1456, 1391,
1377, 1306, 1197, 1154, 1105, 1033, 997 cm21; HRMS for
C6H10O3: calcd: 130.0630; Found: 130.0635; [a]2D5¼222.2
(c¼0.7, CH3OH).
1H NMR (200 MHz, CDCl3): Major diastereomer: d 7.04
(br s, 1H, NH), 5.04 (br s, 1H, OH), 5.0–4.8 (m, 1H,
OCHO), 4.46–4.28 (br t, 1H, J¼10.7 Hz, CHOH),
3.77–3.37 (m, 2H, OCH2), 2.84 (d, 3H, J¼4.9 Hz,
NCH3), 2.14–1.70 (m, 2H, CH2CH), 1.5–1.05 (m, 12H,
(CH3)2C, CH3CH, CH3CH2). Minor diastereomer: d 6.12
(br s, 1H, NH), 5.7 (br s, 1H, OH), 5.0–4.8 (m, 1H, OCHO),
4.46–4.28 (t, 1H, J¼10.7 Hz, CHOH), 3.77–3.37 (m, 2H,
OCH2), 2.79 (d, 3H, J¼4.8 Hz, NCH3), 2.6–2.25 (m, 2H,
CH2CH), 1.5–1.05 (m, 12H, (CH3)2C, CH3CH, CH3CH2);
IR (neat): 3360, 2972, 2937, 1659, 1651, 1549, 1470, 1452,
1.2. General procedure for the preparation of hemi-
acetals 10 from 1
To a suspension of 1 (1 equiv.) in anhydrous ether at 2208C
was added the Grignard reagent (5 equiv.) and the mixture
was stirred at 2208C for 1 h. Saturated aqueous NH4Cl was
added and the reaction mixture was warmed up to ambient
temperature. The precipitated solids were dissolved in water
and the solution was extracted in ether. The combined ether
extracts were dried (Na2SO4) and concentrated to give crude
10 which can be used further without purification. An
analytical sample is obtained by column chromatography.
1412, 1385, 1371, 1167, 1109, 1070, 966, 906 cm21
.
The dihydroxy amide obtained by deprotection of 7 was
1
characterized. H NMR (200 MHz, CDCl3): d 7.0 (b, 1H,
NH), 5.15 (b, 1H, OH), 4.46–4.28 (dd, 1H, J¼2.9, 10.3 Hz,
CHOH), 2.81 (d, 3H, J¼4.9 Hz, CH3NH), 2.1–1.93 (dd,
1H, J¼2.9, 14.7 Hz, CH2CH), 1.84–1.62 (dd, 1H, J¼10.3,
14.7 Hz, CH2CH), 1.34 (s, 3H, CH3C), 1.28 (s, 3H, CH3C);
13C NMR (50 MHz, CDCl3): d 174.9 (NCvO), 72.1
(CHOH), 70.5 ((CH3)2C), 44.8 (CH2CH), 31.4 (NHCH3),
27.6 (CH3), 25.7 (CH3); IR (CHCl3): 3348, 2967, 2953,
;
HRMS for C7H15NO3: calcd: 161.1052; Found: 161.1051;
[a]2D5¼225.9 (c¼1.5, CHCl3).
1.1.8. S-3-Hydroxy-dihydro-2-(3H)-furanone (8).10 To a
stirred solution of 5 (280 mg, 1.40 mmol) in THF (1.5 mL)
at 08C was added H2SO4 (3 M, 0.5 mL) dropwise over a
period of 3 min. The resulting solution was warmed to
ambient temperature stirred for 48 h. The mixture was then
diluted with ether and neutralized with excess solid
1.2.1. 2S,5S,6R-2,4,5-Trimethyl-2-hydroxy-6-phenyl
morpholin-3-one(10a). The reaction of
1 mmol) with MeMgI (5 mL of ,1 M solution in ether,
5 mmol) in anhydrous ether (3 mL) gave after purification
by column chromatography (petroleum ether/ethyl acetate,
3/7) 228 mg (97%) of 10a as a solid.
1 (219 mg,
2913, 1651, 1556, 1478, 1417, 1371, 1325, 1153 cm21
1
Mp: 79–808C; H NMR (200 MHz, CDCl3): d 7.36–7.23
(m, 5H, ArH), 5.47 (d, 1H, J¼2.9 Hz, PhCH), 4.58 (br s, 1H,
OH), 3.43 (dq, 1H, J¼2.9, 6.5 Hz, CHCH3), 2.99 (s, 3H,
NCH3), 1.71 (s, 3H, CH3COH), 0.93 (d, 3H, J¼6.5 Hz,
CHCH3). Visible peak of minor diastereomer: d 5.16 (d,
J¼2.9 Hz, PhCH); 13C NMR (50 MHz, CDCl3): d 168.7
(CvO), 137.4 (ArCipso), 128.1 (ArC), 127.4 (ArC), 125.6
(ArC), 95.9 (ArC), 71.2 (PHCH), 59.2 (NCH), 33.5 (NCH3),
26.3 (CH3O), 11.9 (CH3CH); IR (CHCl3): 3340, 2940,

8990
S. V. Pansare et al. / Tetrahedron 58 (2002) 8985–8991
1635, 1490, 1450, 1380, 1220, 1130, 1010, 940, 890,
750 cm21; MS (EI, 70 eV): m/z 58 (100), 77 (12), 91 (8),
100 (28), 105 (71), 118 (32), 146 (2), 235 (Mþ, ,1);
Analysis for C13H17NO3: calcd: C, 66.36; H, 7.28; N, 5.05;
Found: C, 66.38; H, 7.43, N, 5.97; [a]2D5¼2107.4 (c¼1.1,
CHCl3).
concentrated. The crude product was purified by flash
chromatography on silica gel.
1.3.1. 2R,5S,6R-2,4,5-Trimethyl-2-(1-propenyl)-6-phenyl
morpholin-3-one (11a). The reaction of 1 (219 mg,
1 mmol) in anhydrous dichloromethane (2 mL) and
MeMgI (1.3 mL of ,1 M solution in ether, 1.3 mmol) at
2788C for 1 h followed by TiCl4 (0.60 mL, 5.35 mmol) and
allyltrimethysilane (1.7 mL, 10.7 mmol), gradual warming
to 2208C for 8 h gave after purification by flash
chromatography on silica gel (7/3 petroleum ether/ethyl
acetate) 145 mg (56%) of 11a as colorless gum.
1.2.2. 2S,5S,6R-2-Ethyl-4,5-dimethyl-2-hydroxy-6-
phenyl morpholin-3-one (10b). The reaction of
1
(110 mg, 0.5 mmol) with EtMgI (2.5 mL of ,1 M solution
in ether, 2.5 mmol) in anhydrous ether (2 mL) gave after
purification by column chromatography (petroleum ether/
ethyl acetate, 2/3) 114 mg (92%) of 10b as a solid.
1H NMR (200 MHz, CDCl3): d 7.45–7.20 (m, 5H, ArH),
5.98–5.75 (m, 1H, CH2vCH), 5.20 (d, 1H, J¼2.7 Hz,
PhCH), 5.18–5.03 (m, 2H, CH2vCH), 3.5 (dq, 1H, J¼6.5,
2.7 Hz, CH3CH), 3.04 (s, 3H, NCH3), 2.83 (dd, 1H, J¼14.4,
5.9 Hz, CHCH2), 2.53 (dd, 1H, J¼14.4, 8.7 Hz, CHCH2),
1.50 (s, 3H, CCH3), 0.98 (d, 3H, J¼6.5 Hz, CH3CH); 13C
NMR (75 MHz, CDCl3): d 171.4 (CvO), 137.7 (ArCipso),
132.6 ((ArC), 127.8 (ArC), 127.0 (ArC), 125.1 (CHvCH2),
117.6 (CHvCH2), 78.8 (CCH3), 71.7 (PhCH), 58.7
(CH3CH), 40.2 (CH2), 33.2 (NCH3), 24.8 (CCH3), 12.1
1
Mp: 88–898C; H NMR (200 MHz, CDCl3): d 7.45–7.20
(m, 5H, ArH), 5.52 (d, 1H, J¼3.0 Hz, PhCH), 3.70 (br s, 1H,
OH), 3.46 (dq, 1H, J¼6.5, 3.0 Hz, CH3CH), 3.03 (s, 3H,
NCH3), 2.26–2.08 (m, 1H, CH3CH2), 2.02–1.84 (m, 1H,
CH3CH2), 1.06 (t, 3H, J¼7.0 Hz, CH3CH2), 0.97 (d, 3H,
J¼6.5 Hz, CHCH3). Visible peaks of minor diastereomer:
5.17 (d, J¼2.9 Hz, PhCH), 4.05 (br s, 1H, OH); 13C NMR
(50 MHz, CDCl3): d 168.2 (CvO), 137.5 (ArCipso), 127.9
(ArC), 127.1 (ArC), 125.3 (ArC), 97.9 (COH), 70.4 (PhCH),
58.8 (CH3CH), 33.2 (NCH3), 32.0 (CH2), 12.2 (CHCH3),
7.9 (CH2CH3); IR (CHCl3): 3340, 3120, 1640, 1450, 1452,
1220, 1214, 1140, 1021, 749 cm21; MS (EI, 70 eV): m/z 57
(43), 77 (15), 86 (35), 91 (15), 105 (8), 118 (100), 143 (7),
174 (2), 232 (2); Analysis for C14H19NO3: calcd: C, 67.45;
H, 7.68; N, 5.62; Found: C, 67.21; H, 7.75, N, 5.54;
[a]2D5¼2110.0 (c¼2.3, CHCl3).
(CHCH3); IR (CHCl3): 3000, 1630, 1430, 1210, 750 cm21
;
MS (EI, 70 eV) m/z 58 (53), 67 (22), 77 (19), 91 (27), 105
(18), 117 (40), 148 (100), 174 (6), 190 (27), 218 (69), 259
(8, Mþ, 3); HRMS (FABþ) for C16H22NO2 calcd:
260.1651; Found: 260.1645; [a]2D5¼267.1 (c¼2.1, CHCl3).
1.3.2. 2R,5S,6R-2-Ethyl-2-(1-propenyl)-4,5-dimethyl-6-
phenylmorpholin-3-one (11b). The reaction of
1
1.2.3. 2S,5S,6R-2-tert-Butyl-2-hydroxy-4,5-dimethyl-6-
phenyl morpholin-3-one (10c). The reaction of
(226 mg, 1.04 mmol) with t-BuMgCl (5.2 mL of ,1 M
solution in ether, 5 mmol) in anhydrous ether (3 mL) gave
after purification by column chromatography (petroleum
ether/ethyl acetate, 1/1) 257 mg (90%) of 10c as a solid.
(219 mg, 1 mmol) in anhydrous dichloromethane (2 mL)
and EtMgI (1.3 mL of ,1 M solution in ether, 1.3 mmol) at
2788C for 1 h followed by TiCl4 (0.55 mL, 5 mmol) and
allyltrimethysilane (1.27 mL, 8 mmol), gradual warming to
2208C and stirring for 6 h, gave after purification by flash
chromatography on silica gel (7/3 petroleum ether/ethyl-
acetate) 170 mg (62%) of 11b as colorless gum.
1
1
Mp: 85–868C; H NMR (200 MHz, CDCl3): d 7.42–7.24
(m, 5H, ArH), 5.41 (d, 1H, J¼2.9 Hz, PhCH), 3.54–3.41
(m, 2H, OH, CH3CH), 3.00 (s, 3H, NCH3), 1.18 (s, 9H,
C(CH3)3), 0.99 (d, 3H, J¼6.4 Hz, CH3CH); 13C NMR
(50 MHz, CDCl3): d 168.9 (CvO), 137.7 (ArCipso), 128.1
(ArC), 127.4 (ArC), 125.5 (ArC), 100.3 (COH), 71.0
(PhCH), 59.3 (CHCH3), 39.7 (Cquat(CH3)3), 33.5 (NCH3),
25.2 (C(CH3)3), 12.2 (CH3); IR (CHCl3): 3382, 2979, 2960,
2933, 1643, 1379, 1078, 757 cm21; MS (EI, 70 eV): m/z 57
(20), 71 (7), 91 (14), 105 (7), 118 (100), 262 (22); Analysis
for C16H23NO3: calcd: C, 69.29; H, 8.36; N, 5.05; Found: C,
69.42; H, 8.12, N, 5.28; [a]2D5¼2139.0 (c¼1.6, CHCl3).
1H NMR (200 MHz, CDCl3): d 1H NMR (200 MHz,
CDCl3): d 7.45–7.20 (m, 5H, ArH), 5.95–5.74 (m, 1H,
CHvCH2), 5.25 (d, 1H, J¼3.0 Hz, PhCH), 5.15–5.02 (m,
2H, CH2vCH), 3.54 (dq, 1H, J¼6.5, 3.0 Hz, CH3CH), 3.05
(s, 3H, NCH3), 2.85 (tdd, 1H, J¼16.1, 5.8, 1.3 Hz, CHCH2),
2.55 (dd, 1H, J¼14.6, 8.5 Hz, CHCH2), 2.08–1.75 (m, 2H,
CH3CH2), 1.02 (t, 3H, J¼6.6 Hz, CH3CH2), 0.98 (d, 3H,
J¼7.8 Hz, CH3CH); 13C NMR (75 MHz, CDCl3): d 171.2
(CvO), 138.1 (ArCipso), 133.0 (ArC), 128.1 (ArC), 127.3
(ArC), 125.5 (CHvCH2), 117.9 (CHvCH2), 82.3 (CCH3),
71.4 (PhCH), 59.1 (CH3CH), 40.1 (CH2vCHCH2), 33.5
(NCH3), 30.9 (CH3CH2), 12.9 (CH3), 8.7 (CH3); IR
1.3. General procedure for the one-pot alkylation/
allylation of dione 1
(CHCl3): 3010, 1625, 1440, 1215, 1140, 1030, 750 cm21
;
MS (EI, 70 eV): m/z 58 (100), 67 (23), 77 (21), 91 (31), 105
(12), 117 (39), 148 (90), 204 (35), 232 (78), 245 (1), 273 (6,
Mþ); HRMS (FABþ) for C17H24NO2 [M·H]þ: calcd:
274.1808; Found: 274.1812.
To a suspension of the dione 1 (1 equiv.) in dichloro
methane at 2788C was added the Grignard reagent (5
8 equiv.) and the mixture was stirred for 1 h at 2788C. TiCl4
(5 equiv.) was added followed by allyltrimethylsilane
(5–8 equiv.) and the mixture was stirred at 2608C or
allowed to warm up to ambient temperature. Saturated aq.
NH4Cl was added and the precipitated solids were dissolved
in water, the solution was extracted with dichloromethane
and the combined extracts were dried (Na2SO4) and
1.3.3. 2S,5S,6R-2-(tert-Butyl)-2-(1-propenyl) 4,5-
dimethyl-6-phenyl morpholin-3-one (11c). The reaction
of 1 (110 mg, 0.5 mmol) in anhydrous dichloromethane
(1 mL) and t-BuMgCl (1.5 mL of ,1 M solution in THF,
1.5 mmol) at 2788C for 1 h followed by TiCl4 (0.55 mL,
5 mmol) and allyltrimethysilane (0.8 mL, 5 mmol), gradual

S. V. Pansare et al. / Tetrahedron 58 (2002) 8985–8991
8991
K.; Morimoto, Y.; Kinoshita, T. Tetrahedron Lett. 1998, 39,
667. (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.
warming to ambient temperature and stirring overnight,
gave after purification by flash chromatography on silica gel
(5/1 petroleum ether/ethylacetate) 76 mg (50%) of 11c.
1H NMR (200 MHz, CDCl3): d 7.43–7.23 (m, 5H, ArH),
6.09–5.81 (m, 1H, CH2vCH), 5.4 (d, 1H, J¼3.4 Hz,
PhCH), 5.16–4.88 (m, 2H, CH2vCH), 3.5 (dq, 1H, J¼3.4,
6.8 Hz, CH3CH), 3.01 (s, 3H, NCH3), 2.95–2.90 (m, 1H,
CHCH2), 2.71 (dd, 1H, J¼8.8, 14.6 Hz, CHCH2), 1.18 (s,
9H, C(CH3)3), 0.98 (d, 3H, J¼6.8 Hz, CH3CH); 13C NMR
(75 MHz, CDCl3): d 171.2 (CvO), 138.6 (ArCipso), 135.5
(CHvCH2), 128.2 (ArC), 127.3 (ArC), 125.6 (ArC), 116.7
(CHvCH2), 85.5 (OCquat), 72.0 (PhCH), 59.2 (CH3CH),
39.7 (C(CH3)3), 38.1 (CH2CHvCH2), 33.7 (NCH3), 26.9
(C(CH3)3), 12.8 (CHCH3); IR (CHCl3): 3269, 2959, 1643,
1452, 1392, 1379, 1363, 1284, 1217, 1145, 1120, 1097,
1033, 914 cm21; MS (EI, 70 eV): m/z 57 (100), 77 (87), 91
(12), 105 (6), 118 (24), 148 (9), 260 (17), 301 (Mþ, 3);
HRMS for C19H27NO2: calcd: 301.2042; Found: 301.2036;
[a]2D5¼2110.2 (c¼3.4, CHCl3).
3. (a) Sefkow, M. J. Org. Chem. 2001, 66, 2343. (b) Ichinari, D.;
Ueki, T.; Yoshihara, K.; Kinoshita, T. Chem. Commun. 1997,
1743.
4. Dione 1 has been prepared earlier as a proof for the reactivity
of an activated oxalic acid derivative, see: Rudchenko, V. F.;
Shtamburg, V. G.; Pleshkova, A. P.; Kostyanovskii, R. G.
Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1981,
30, 825. For a preparation of racemic 1 see: Drefahl, G.;
Hartmann, M.; Skurk, A. Chem. Ber. 1963, 96, 1011. Synthetic
applications of 1 were not described.
5. The stereochemical assignment is based on the reported trend
in chemical shift for the olefinic methine protons in (E) and (Z)
benzylidenecamphor derivatives, see: Kossanyi, J.; Furth, B.;
Morizur, J. P. Tetrahedron 1970, 26, 395.
6. The stereochemistry at the hemiacetal centre has been
confirmed in an earlier study by X-ray crystallography, see:
Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem. 1998, 63,
4120.
Acknowledgements
7. For the application of other aminoalcohol based morpholi-
nones in the asymmetric synthesis of amino acids, see: (a) Cox,
G. G.; Harwood, L. M. Tetrahedron: Asymmetry 1994, 9,
1669. (b) Sinclair, P. J.; Zhai, D.; Reibenspies, J.; Williams,
R. M. J. Am. Chem. Soc. 1986, 108, 1103.
Financial assistance from the Council of Scientific and
Industrial Research (fellowship to B. A. S.) is gratefully
acknowledged. We thank Mr D. Mandal for assistance in
determining the enantiomeric excess of the lactones. Initial
experiments with 1 were conducted by Mr R. P. Jain.
8. Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S. Synthesis 1980, 9,
695.
9. Takigawa, T.; Mori, K.; Matsuo, T. Tetrahedron 1979, 35,
933.
References
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