Enantioselective synthesis of pantolactone analogues from an ephedrine-derived morpholine-dione

Article abstract of DOI:10.1016/S0040-4020(03)00408-3

An efficient enantioselective synthesis of β,β-dialkyl α-hydroxy γ-butyrolactones, analogues of pantolactone, has been developed employing a stereoselective Prins reaction of chiral alkylidene morpholinones, as the key step. Enantioselective synthesis of a naturally occurring pantolactone homologue and a spiro analogue of pantolactone was achieved with this protocol.

Full text of DOI:10.1016/S0040-4020(03)00408-3

Tetrahedron 59 (2003) 3275–3282
Enantioselective synthesis of pantolactone analogues from an
ephedrine-derived morpholine-dione
*
Sunil V. Pansare and Annyt Bhattacharyya
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 27 November 2002; revised 18 February 2003; accepted 14 March 2003
Abstract—An efficient enantioselective synthesis of b,b-dialkyl a-hydroxy g-butyrolactones, analogues of pantolactone, has been
developed employing a stereoselective Prins reaction of chiral alkylidene morpholinones, as the key step. Enantioselective synthesis of a
naturally occurring pantolactone homologue and a spiro analogue of pantolactone was achieved with this protocol. q 2003 Elsevier Science
Ltd. All rights reserved.
The enantioselective synthesis of a-hydroxy g-butyro-
lactones has been the subject of several recent investi-
gations.1 The synthesis of such lactones has attracted
attention since they comprise crucial components in several
naturally occurring chiral molecules.2 A number of these
lactones are natural products and this has spurred interest in
their total synthesis.3 b,b-Dialkyl a-hydroxy g-butyro-
lactones have recently been employed as components of
interleukin inhibitors.4 This particular class of butyro-
lactones and the parent hydroxy acids are also of interest
due to their structural similarity to pantolactone5 and the
potential for application as pantothenic acid analogues in
biologically relevant molecules.6 Herein, we describe the
application of an ephedrine-derived morpholine-dione in a
general, stereoselective synthesis of b,b-disubstituted
a-hydroxy butyramides and the corresponding
butyrolactones.
BF3·OEt2 at ambient temperature and the cyclohexylidene
morpholinone 3a is obtained from 2a in 82% yield under
these conditions. Dehydration of the 2b–e mixture gives
3b/c (90%, 1/1 mixture of E/Z isomers, Scheme 1). The
stereochemistry of 3b and 3c is based on the downfield shift
of the methylene hydrogens in 3b (d 2.6–2.8) as compared
to 3c (d 2.2–2.4).8 Olefins 3b and 3c are separable by
chromatography and further reactions were conducted on
the pure E and Z isomers.
The synthesis of a spiro analogue of pantolactone was
examined with 3a as the starting material. The Prins
reaction9 [(CH2O)n, acetic acid, cat. H2SO4, 858C] of 3a
efficiently generates the spiro bis-acetal 4a (90%, Scheme 2)
as a single diastereomer. This reaction is remarkably rapid
and all of 3a is consumed within 2 min. Prolonged heating
of the reaction mixture results in decomposition of the
desired product 4a. The alkylidene morpholinones 3b and
3c are also converted into the spiro bis-acetals 4b and 4c in
an analogous manner. The stereochemistry at the spiro
acetal stereocenter in 4a–c is assigned by analogy to other
reactions of the oxocarbenium ion intermediate in the
ephedrine-derived template.10 At this stage, the stereo-
chemistry at the quaternary 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.
The reaction of ephedrine and oxalyl chloride at ambient
temperature generates the morpholine-dione 1 in 63%
yield.1e Dione 1 reacts readily with a variety of Grignard
and organolithium reagents7 at the lactone carbonyl to
generate the corresponding hemiacetals 2 (Scheme 1). Thus,
treatment of 1 with cyclohexyl magnesium bromide
generates 2a (80%, ds¼2.5/1) and reaction with sec-butyl
magnesium chloride gives a mixture of diastereomers 2b–e
(84%, dr¼3/3/1/1, stereochemistry at the hemiacetal carbon
and the sec-butyl carbon for 2b–e has not been established).
Although the dehydration of these hemiacetals can be
achieved by treatment with trifluoroacetic acid in dichloro-
methane, the procedure of choice is treatment with
Morpholinones 4 incorporate all the required carbons for the
target a-hydroxy butyrates and possess a spiro acetal
stereocenter that can be reduced stereoselectively with a
combination of Lewis acid and silanes. Accordingly,
treatment of 4a–c with excess TiCl4/triethylsilane
efficiently generates the morpholinones 5a–c as single
diastereomers. The reaction probably proceeds by
preferential cleavage of the anomeric carbon–oxygen
Keywords: asymmetric synthesis; lactones; Prins reaction; dehydration;
reduction.
*
Corresponding author. Tel./fax: þ91-205893153;
e-mail: pansare@ems.ncl.res.in
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00408-3

3276
S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
Scheme 1.
Scheme 2.
bond (C–O(1), Fig. 1) in 4a–c to generate the endocyclic
oxocarbenium ion which is reduced under stereoelectronic
control.11 Further reduction of the resulting methylenedioxy
functionality generates 5a–c. The stereochemistry of the
newly generated stereocenter was assigned as S from
previous observations in a related system.5b
is essential for the conversion of 4a–c into 5a–c. Use of
lesser equivalents of triethylsilane results in the retro-Prins
reaction of the intermediate oxocarbenium ion and
variable amounts of the olefin 3a (from 4a) and mixtures
of 3b and 3c (from 4b and 4c) are obtained as side products
(Fig. 2).
It should be noted that an excess of triethylsilane (20 equiv.)
Morpholinones 5a–c are protected versions of the a,g-
dihydroxy butyric acid precursors of the target lactones.
Dissolving metal reduction of 5a–c generates the
a-hydroxy g-methoxy butyramides 6a–c (50–52%). Con-
version of 6 into the lactones 7 is readily achieved by a one-
pot reaction sequence. Liberation of the primary hydroxyl
group in 6 by demethylation (BBr3) and subsequent acid
catalyzed lactonization (H2SO4/H2O, 2158C to rt)
generates the lactones 7a–c in good yield (70–86%
Scheme 3).
Thus, the spiro analogue of pantolactone (S)-7a is obtained
in 86% yield (98% e.e. by chiral GC analysis). One of the
pantolactone homologues 7 is a natural product isolated
from Marshallia tenuifolia, the absolute configuration of
which has been unambiguously established as 3S,4S by
synthesis from D-glucose.12 A synthesis from (S)-malic acid
has also been reported recently.13 The specific rotation
([a]D25¼þ4.45 (c¼0.25, CHCl3); lit.14 [a]2D0¼þ4.7 (c¼0.26,
CHCl3)) and spectroscopic data of 7b (97% e.e.) obtained
from our study are in agreement with those of the natural
product14 and 7b therefore has the 3S,4S configuration.
Figure 1.

S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
3277
Figure 2.
Scheme 3.
Since the stereochemistry of the a-hydroxy bearing carbon
has been established as S in the present as well as other
related systems5b and 7b and 7c are diastereomers, it
follows that 7c 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 (Fig. 3).
chiral alkylidene morpholinones that are key substrates in a
highly stereoselective Prins reaction/acetal reduction
protocol. A general, enantioselective route to b,b-
disubstituted a-hydroxy butyrolactones has been
established. The above procedure should provide access to
a variety of enantiomerically enriched b,b-disubstituted
a-hydroxy g-butyrolactones in either enantiomeric form,
since both enantiomers of ephedrine are commercially
available. Current efforts focus on other applications of the
dione 1 in the enantioselective synthesis of a-hydroxy acids
and derivatives.
In conclusion, we have demonstrated that the ephedrine
derived morpholine dione 1 is a convenient precursor for
Figure 3.

3278
S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
1. Experimental
1H NMR (200 MHz, CDCl3): d 7.53–7.24 (m, 5H, ArH),
5.49 (d, 1H, J¼3.0 Hz, PhCH), 3.46 (dq, 1H, J¼3.0, 6.3 Hz,
CH3CH), 3.03 (s, 3H, NCH3), 2.23–1.11 (m, 11H,
cyclohexyl CH2, CH), 0.95 (d, 3H, J¼6.3 Hz, CHCH3).
Visible peaks of the minor diastereomer: d 5.49 (d, 1H,
J¼3.0 Hz, PhCH), 3.55 (dq, 1H, J¼3.0, 6.3 Hz, CH3CH),
0.98 (d, 3H, J¼6.3 Hz, CHCH3). 13C NMR (50 MHz,
CDCl3): d 169.0 (CvO), 137.6 (ArCipso), 128.1 (ArCH),
127.3 (ArCH), 125.5 (ArCH), 98.8 (OCOquat), 70.8 (PhCH),
59.0 (NCH), 45.4 (CH, cyclohexyl), 33.4 (NCH3), 28.2
(CH2, cyclohexyl), 26.4 (CH2, cyclohexyl), 26.0 (CH2,
cyclohexyl), 24.4 (CH2, cyclohexyl), 12.5 (CH3CH). IR
(CHCl3): 3353, 2931, 2854, 1643, 1452, 1380, 1215, 1145,
1020, 756, 700 cm21. MS (EI, 70 eV): m/z 58 (14), 91 (11),
118 (100), 146 (20), 197 (10), 220 (26), 275 (3). Analysis for
C18H25NO3: calcd: C, 71.25; H, 8.23; N, 4.61, found: C,
71.28; H, 8.34; N, 4.38.
1.1. General
All reactions requiring anhydrous conditions were per-
formed under a positive pressure of argon using oven-dried
glassware (1208C). THF was distilled from sodium and
benzophenone. Dichloromethane, triethylamine were dis-
tilled from calcium hydride. Solvents for chromatography
were distilled at their respective constant boiling point.
Petroleum ether refers to the fraction in the 60–808C range.
Commercially available TiCl4 was distilled and used.
Grignard reagents were freshly prepared. Triethylsilane
and boron tribromide were obtained from Aldrich Chemical
Company. Reactions were monitored by TLC on com-
mercial precoated silica (Merck 60F-254) by staining in
phosphomolybdic acid (10% solution in ethanol) followed
by charring at 2008C. Silica gel for column chromatography
was 230–400 mesh. 1H and 13C NMR spectra were recorded
on Bruker MSL-300 or Ac-200 instruments. IR spectra was
recorded on FTIR-8400 Fourier Transform, (Shimadzu)
instrument. Optical rotations were measured at the sodium
D line on a JASCO P-1020 polarimeter. Mass spectra (EI)
were recorded on a Finnigan-Mat 1020C mass spectrometer
at ionization potential of 70 eV. High resolution mass
spectra were recorded on a Jeol JMS-SX-102 spectrometer.
All melting points are uncorrected. The enantiomeric excess
of the lactones 7a–c was determined by gas chromato-
graphy (Agilent 6890 series GC system) using a flame
ionization detector and a Supelco b-DEX 120 (20%
permethylated b-cyclodextrin) capillary column
(30 m£0.32 mm£0.25 mm). Temperature gradient: 408C
(5 min); 58C/min to 2408C (10 min); carrier gas: nitrogen;
flow rate: 2 mL/min. Elemental analyses were performed by
the microanalysis facility at NCL, Pune.
1.1.4. (5S,6R)-2-sec-Butyl-2-hydroxy-4,5-dimethyl-6-
phenylmorpholin-3-one (2b–e). Reaction of 1 (1.01 g,
4.63 mmol) and sec-butylmagnesium chloride (6.95 mL,
1 M solution in ether) in anhydrous THF (10 mL) furnished
a 3:3:1:1 mixture of diastereomers 2b–e as a gum (1.08 g,
84%) which was used further without purification. An
analytical sample was obtained by flash column chroma-
tography (1/1 ethyl acetate/pet. ether).
1H NMR (200 MHz, CDCl3). Major diastereomers: d 7.49–
7.24 (m, 5H, ArH), 5.5 (br, 1H, PhCH), 3.62–3.41 (m, 2H,
CHCH3, CHOH), 3.03 (s, 3H, NCH3), 2.26–2.07 (m, 1H,
CHCH2), 2.02–1.80 (m, 1H, CH2), 1.50–1.19 (m, 1H,
CH2), 1.14–0.91 (m, 9H, 2£CHCH3, CH2CH3). Visible
peaks for the minor diastereomers: d 5.72 (d, 1H, J¼2.5 Hz,
PhCH), 5.61 (d, 1H, J¼3.0 Hz, PhCH), 3.12 (s, 3H, NCH3),
3.05 (s, 3H, NCH3), 1.15 (d, 3H, CHCH3). 13C NMR
(50 MHz, CDCl3): d 169.3 (CvO), 137.9 (ArCipso), 128.4
(ArCH), 127.6 (ArCH), 125.8 (ArCH), 99.8 (COH), 99.5
(COH, diastereomer), 71.0 (PhCH), 59.3 (NCH), 42.8
(CHCH2), 42.5 (CHCH2, diastereomer), 33.7 (NCH3),
25.2 (CH2CH3), 21.4 (CH2CH3, diastereomer), 14.8
(CHCH3), 12.7 (CH2CHCH3), 12.4 (CH2CHCH3, dia-
stereomer), 10.8 (CH2CH3). IR (CHCl3): 3332, 2969,
1738, 1632, 1452, 1147, 700 cm21. MS (EI, 70 eV): m/z
58 (53), 91 (14), 118 (100), 160 (14), 220 (13), 277 (Mþ, 1).
HRMS for C16H23NO3: calcd: 277.1678, found: 277.1673.
1.1.1. 5S,6R-4,5-Dimethyl-6-phenyl-morpholin-2,3-dione
(1). This was prepared from ephedrine hydrochloride and
oxalyl chloride according to the reported procedure.1e Mp:
1828C; [a]2D5¼2184.0 (c¼0.8, CHCl3); lit.1e [a]2D5¼2184.3
(c¼0.82, CHCl3). Spectroscopic data consistent with that
reported in the literature.1e
1.1.2. Synthesis of hemiacetals 2. General procedure for
the reaction of 1 with Grignard reagents. To a solution of
1 (n mmol) at an ambient temperature in anhydrous THF
was added the Grignard reagent (n£1.5 mmol) over a period
of 30 min and the reaction mixture was stirred for 1 h.
Saturated aqueous NH4Cl solution was added and the
precipitated solids were dissolved by adding sufficient
water. The mixture was extracted with dichloromethane and
the combined extracts were dried over anhydrous Na2SO4
and concentrated to furnish the crude product. This was used
further without purification.
1.2. General procedure for dehydration of hemiacetals
2a–e
To a solution of hemiacetal in anhydrous dichloromethane,
at 08C, was added BF3·Et2O at 08C and the mixture was
warmed to ambient temperature. After stirring for 6 h, cold
water was added and the organic layer was separated. The
aqueous layer was extracted with dichloromethane and the
combined organic layers were dried (Na2SO4) and concen-
trated under reduced pressure to give the crude product
which was purified by flash column chromatography on
silica gel to furnish olefins 3a–c.
1.1.3. (5S,6R-2-Cyclohexyl-2-hydroxy-4,5-dimethyl-6-
phenyl-morpholin-3-one 2a. Reaction of 1 (1 mmol,
219 mg) and cyclohexyl magnesium bromide (1.5 mL,
1.5 mmol, 1 M solution in THF) in anhydrous THF
(5 mL) afforded 2a as a mixture of diastereomers
(242 mg, 80%). This was used without purification. An
analytical sample was obtained by flash column chroma-
tography (2/3 ethyl acetate/pet. ether).
1.2.1. 5S,6R-2-Cyclohexylidene-4,5-dimethyl-6-phenyl-
morpholin-3-one (3a). Reaction of 2a (1.108 g,
3.65 mmol) with BF3·Et2O (4.62 mL, 36.5 mmol) in
anhydrous dichloromethane (20 mL), gave after purification

S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
3279
by flash column chromatography (1/4 ethyl acetate/pet.
ether) 1.04 g (89%) of 3a as colourless liquid which
solidified upon refrigeration.
for C16H21NO2: calcd: C, 74.08; H, 8.16; N, 5.40, found: C,
73.70; H, 7.85; N, 5.10.
1.4. General procedure for the Prins reaction of olefins
3a–c
Mp 184–1858C. 1H NMR (200 MHz, CDCl3): d 7.42–7.32
(m, 5H, ArH), 5.12 (d, 1H, J¼2.2 Hz, PhCH), 3.55 (dq, 1H,
J¼2.2, 6.7 Hz, CH3CH), 3.22–2.84 (m, 1H, CH2, cyclo-
hexyl), 3.06 (s, 3H, NCH3), 2.96–2.88 (m, 1H, CH2,
cyclohexyl), 2.53–2.34 (m, 2H, CH2, cyclohexyl), 1.73–
1.51 (m, 6H, CH2, cyclohexyl) 0.98 (d, 3H, J¼6.7 Hz,
CHCH3). 13C NMR (50 MHz, CDCl3): d 160.7 (CvO),
137.3 (ArCipso), 135.7 (OCvC), 134.0 (OCvC), 128.0
(ArCH), 127.3 (ArCH), 125.1 (ArCH), 76.7 (PhCH), 58.4
(NCH), 33.1 (NCH3) 28.3 (CH2CvC), 28.0 (CH2CvC),
27.7 (CH2, cyclohexyl), 27.4 (CH2, cyclohexyl), 26.1 (CH2,
cyclohexyl), 11.5 (CH3CH). IR (CHCl3): 2948, 2850, 1649,
1622, 1448, 1292, 1016, 756, 707 cm21. MS (EI, 70 eV):
m/z 67 (11), 77 (16), 91 (20), 118 (100), 168 (4), 205 (14),
285 (Mþ, 8). Analysis for C18H23NO2: calcd: C, 75.75; H,
8.05, N, 4.90, found: C, 76.08; H, 8.03; N, 4.77.
[a]2D5¼2148.3 (c¼2.1, CHCl3).
To a solution of the olefin 3 and paraformaldehyde in glacial
acetic acid was added conc. H2SO4 (two drops) and the
mixture was heated rapidly for 90 s in a preheated oil-bath
set at 858C. After cooling reaction mixture it was
neutralized with saturated aqueous sodium bicarbonate
solution. The mixture was extracted with ether and the
combined extracts were washed with water, brine, dried
(Na2SO4) and concentrated. Removal of ether under
reduced pressure gave crude product which was purified
by flash column chromatography.
1.4.1. 2R,3S,6R-3,4-Dimethyl-2-phenyl-1,14,16-trioxa-4-
aza-dispiro[5.0.5.4]hexadecane-5-one (4a). Reaction of 3a
(830 mg, 2.9 mmol) with paraformaldehyde (437 mg,
14.6 mmol) in glacial acetic acid (10 mL) gave after
purification by flash column chromatography (1/4 ethyl
acetate/pet. ether) on silica gel 939 mg (93%) 4a as a white
solid.
1.3. Olefins 3b and 3c
Reaction of 2b–e (1.08 g, 3.9 mmol) with BF3·Et2O
(4.95 mL, 39 mmol) in anhydrous dichloromethane
(30 mL) gave crude 3 a mixture of diastereomers. Careful
chromatography (crude mixture loaded on 1/19 ethyl
acetate/pet. ether and eluted with 3/17 ethyl acetate/pet.
ether) gave 450 mg (45%) of 3b as a white solid and 450 mg
(45%) of 3c as a gum.
1
Mp 748C. H NMR (200 MHz, CDCl3): d 7.45–7.29 (m,
5H, ArH), 5.42 (d, 1H, J¼3.0 Hz, PhCH), 5.12 (d, 1H,
J¼5.4 Hz, OCH2O), 5.09 (d, 1H, J¼5.4 Hz, OCH2O), 4.39
(d, 1H, J¼11.0 Hz, OCH2C), 4.13 (d, 1H, J¼11.0 Hz,
OCH2C), 3.47 (dq, 1H, J¼3.0, 6.4 Hz, CH3CH), 3.02 (s, 3H,
NCH3), 2.09–1.19 (m, 10H, cyclohexyl), 1.00 (d, 3H,
J¼6.4 Hz, CH3CH). 13C NMR (50 MHz, CDCl3): d 164.7
(CvO), 137.1 (ArCH), 128.2 (ArCH), 127.4 (ArCH), 125.2
(ArCH), 99.5 (OCOquat, cyclohexyl), 88.0 (OCH2O), 70.4
(PhCH), 66.7 (CCH2O), 58.6 (NCH), 40.6 (Cquat), 33.4
(NCH3), 27.7 (CH2, cyclohexyl), 27.3 (CH2, cyclohexyl),
25.7 (CH2, cyclohexyl), 20.9 (CH2, cyclohexyl), 12.2
(CH3CH). IR (CHCl3): 4214, 3631, 3450, 3018, 2931,
1.3.1. (2,10)E,5S,6R-4,5-Dimethyl-2-(1-methylpropyl-
1
idene)-6-phenylmorpholin-3-one (3b). Mp 80–818C. H
NMR (200 MHz, CDCl3): d 7.41–7.35 (m, 5H, ArH), 5.14
(d, 1H, J¼2.9 Hz, ArCH), 3.56 (dq, 1H, J¼2.9, 6.8 Hz,
CH3CH), 3.07 (s, 3H, NCH3), 2.81–2.65 (m, 2H, CH2CH3),
1.90 (s, 3H, CCH3), 1.14 (t, 3H, J¼7.3 Hz, CH2CH3), 0.98
(d, 3H, J¼6.8 Hz, CHCH3). 13C NMR (50 MHz, CDCl3):
160.3 (CvO), 138.0 (ArCipso), 137.6 (OCO), 132.5
(CCH2CH3), 128.2 (ArCH), 127.6 (ArCH), 125.3 (ArCH),
76.7 (PhCH), 58.6 (NCH), 33.2 (NCH3), 26.3 (CH2CH3),
17.4 (CH2CH3), 12.9 (CCH3), 11.7 (CHCH3). IR (CHCl3):
3031, 2957, 2872, 1657, 1498, 1378, 1286, 1172, 1069,
1018, 706 cm21. MS (EI, 70 eV): m/z 69 (22), 98 (31), 118
(100), 126 (8), 142 (4), 186 (5), 259 (Mþ, 12). Analysis for
C16H21NO2: calcd: C, 74.08; H, 8.16; N, 5.40, found: C,
73.71; H, 8.48; N, 5.62. [a]2D5¼2180.0 (c¼0.5, CHCl3).
2866, 2401, 1654, 1454, 1215, 985, 765, 669, 451 cm21
.
MS (EI, 70 eV): 81 (17), 91 (23), 118 (100), 130 (4), 146
(5), 192 (5), 220 (21), 345 (Mþ, 4). HRMS for C20H27NO4:
calcd: 345.1941, found: 345.1941. [a]2D5¼281.1 (c¼1.4,
CHCl3).
1.4.2. (5S,8R,9S)-5-Ethyl-5,9,10-trimethyl-8-phenyl-
1,3,7-trioxa-10-azaspiro[5.5]undecan-11-one (4b). Reac-
tion of 3b (382 mg, 1.5 mmol) with paraformaldehyde
(221 mg, 7.4 mmol) in glacial acetic acid (9 mL) gave after
purification by flash column chromatography (3/17 ethyl
acetate/pet. ether) 352 mg (75%) of 4b as white solid.
1.3.2. (2,10)Z,5S,6R-4,5-Dimethyl-2-(1-methylpropyl-
idene)-6-phenylmorpholin-3-one
(3c).
1H
NMR
1
(200 MHz, CDCl3): d 7.40–7.30 (m, 5H, ArH), 5.13 (d,
1H, J¼3.0 Hz, ArCH), 3.60 (dq, 1H, J¼2.9 Hz, 6.8,
CH3CH), 3.07 (s, 3H, NCH3), 2.41–2.28 (m, 2H,
CH2CH3), 2.25 (s, 3H, CCH3), 1.09 (t, 3H, J¼7.4 Hz,
CH2CH3), 0.97 (d, 3H, J¼6.8 Hz, CHCH3). 13C NMR
(50 MHz, CDCl3): 160.4 (CvO), 137.6 (ArCipso), 137.2
(OCO), 131.7 (CCH2CH3), 127.9 (ArCH), 127.2 (ArCH),
124.9 (ArCH), 76.3 (PhCH), 58.3 (NCH), 32.9 (NCH3),
26.4 (CH2CH3), 17.4 (CH2CH3), 11.5 (CCH3), 11.3
(CHCH3). IR (CHCl3): 2972, 2874, 1657, 1498, 1378,
1260, 1171, 1067, 1020, 707 cm21. MS (EI, 70 eV): 69 (15),
91 (19), 118 (100), 142 (5), 205 (1), 259 (Mþ, 19). Analysis
Mp 1108C. H NMR (200 MHz, CDCl3): d 7.45–7.31 (m,
5H, ArH), 5.48 (d, 1H, J¼3.0 Hz, PhCH), 5.24 (d, 1H,
J¼5.4 Hz, OCH2O), 5.03 (d, 1H, J¼5.4 Hz, OCH2O), 4.26
(d, 1H, J¼11.0 Hz, OCH2C), 3.83 (d, 1H, J¼11.0 Hz,
OCH2C), 3.50 (dq, 1H, J¼3.0, 6.4 Hz, CH3CH), 3.01 (s, 3H,
NCH3), 1.79 (m, 2H,CCH2CH3), 1.16 (s, 3H, CCH3), 0.99
(d, 3H, J¼6.4 Hz, CHCH3), 0.89 (t, 3H, J¼7.4 Hz,
CH2CH3). 13C NMR (50 MHz, CDCl3): d 164.8 (CvO),
137.0 (ArCipso), 128.1 (ArCH), 127.4 (ArCH), 125.1
(ArCH), 99.1 (OCOquat), 88.5 (OCH2O), 70.6 (OCH2C),
70.6 (PhCH), 58.5 (NCH), 40.6 (CCH2CH3), 33.2 (NCH3),
25.3 (CCH2CH3), 17.2 (CCH3), 12.2 (CH3CH), 7.5

3280
S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
(CH2CH3). IR (CHCl3): 3018, 2979, 2885, 1650, 1497,
1215, 1095, 975, 757 cm21. MS (EI, 70 eV): m/z 69 (23),
103 (19), 118 (100), 146 (4), 220 (6), 319 (Mþ, 1). Analysis
for C18H25NO4: calcd: C, 67.67; H, 7.89; N, 4.38, found: C,
67.29; H, 8.22; N, 4.13. [a]2D5¼2136.0 (c¼0.5, CHCl3).
(NCH3), 29.6 (CH2, cyclohexyl), 29.4 (CH2, cyclohexyl),
25.8 (CH2, cyclohexyl), 21.4 (CH2, cyclohexyl), 21.3 (CH2,
cyclohexyl), 12.4(CH3CH). IR (CHCl3): 3452, 3005, 2929,
2865, 1642, 1453, 1379, 1249, 1188, 1105, 1061, 702,
666 cm21. MS (EI, 70 eV): 58 (26), 67 (15), 91 (20), 105
(17), 148 (10), 205 (99), 267 (7), 331 (Mþ, 2). HRMS for
C20H29NO3: calcd: 331.2147, found: 331.2128.
[a]2D5¼2123.2 (c¼3.4, CHCl3).
1.4.3. (5R,8R,9S)-5-Ethyl-5,9,10-trimethyl-8-phenyl-
1,3,7-trioxa-10-azaspiro[5.5]undecan-11-one (4c). Reac-
tion of 3c (342 mg, 1.3 mmol) with paraformaldehyde
(198 mg, 6.6 mmol) in glacial acetic acid (8 mL) gave after
purification by flash column chromatography (3/17 ethyl
acetate/pet. ether) 328 mg (78%) of 4c as a colourless liquid.
1.5.2. (2S,5S,6R)-2-[(1S)-1-(Methoxymethyl)-1-methyl-
propyl]-4,5-dimethyl-6-phenylmorpholin-3-one
(5b).
Reduction of 4b (334 mg, 1 mmol) with titanium tetra-
chloride (3.3 mL, 30 mmol) and triethylsilane (3.3 mL,
21 mmol) in anhydrous dichloromethane (15 mL) gave after
purification by flash column chromatography (1/4 ethyl
acetate / pet. ether) 747 mg (93%) of 5b as colourless oil.
1
Mp 858C. H NMR (200 MHz, CDCl3): d 7.40–7.31 (m,
5H, ArH), 5.42 (d, 1H, J¼2.9 Hz, PhCH), 4.99 (AB system,
J¼7.0 Hz, 2H, OCH2O), 4.05 (d, 1H, J¼11.0 Hz, OCH2C),
3.76 (d, 1H, J¼11.0 Hz, OCH2C), 3.53 (dq, 1H, J¼2.9,
6.3 Hz, CH3CH), 3.00 (s, 3H, NCH3), 1.63–1.48 (m, 2H,
CH2CH3), 1.41 (s, 3H, CH3), 0.99 (d, 3H, J¼6.3 Hz,
CH3CH), 0.90 (t, 3H, J¼7.3 Hz, CH2CH3). 13C NMR
(50 MHz, CDCl3): d 164.6 (CvO), 136.9 (ArCipso), 128.3
(ArCH), 127.6 (ArCH), 125.2 (ArCH), 99.5 (OCOquat), 87.3
(OCH2O), 72.1 (OCH2C), 70.3 (PhCH), 58.8 (NCH), 40.7
(CCH2CH3), 33.6 (NCH3), 25.7 (CCH2CH3), 18.4 (CCH3),
12.2 (CH3CH), 7.4 (CH2CH3). IR (CHCl3): 3018, 2883,
1658, 1461, 1400, 1215, 1095, 977, 756 cm21. MS (EI,
70 eV): m/z 73 (81), 103 (100), 118 (73), 133 (10), 220 (3),
319 (Mþ, 3). Analysis for C18H25NO4: calcd: C, 67.67; H,
7.89; N, 4.38, found: C, 67.77; H, 8.05; N, 4.49.
[a]2D5¼293.1 (c¼0.58, CHCl3).
1H NMR (200 MHz, CDCl3): d 7.45–7.24 (m, 5H, ArH),
4.93 (d, 1H, J¼3.0 Hz, PhCH), 4.26 (s, 1H, CHO), 3.64 (d,
1H, J¼8.8 Hz, OCH2), 3.51 (dq, 1H, J¼3.0, 6.4 Hz,
CH3CH), 3.43 (d, 1H, J¼8.8 Hz, OCH2), 3.33 (s, 3H,
OCH3), 3.00 (s, 1H, NCH3), 1.95–1.47 (m, 2H, CCH2CH3),
1.13 (s, 3H, CCH3), 0.97 (d, 3H, J¼6.4 Hz, CHCH3), 0.89
(t, 3H, J¼7.4 Hz, CH2CH3). 13C NMR (50 MHz, CDCl3): d
168.9 (CvO), 138.2 (ArCipso), 128.1 (ArCH), 127.2
(ArCH), 125.2 (ArCH), 80.7 (CHO), 76.8 (OCH2), 76.3
(PhCH), 58.8 (OCH3), 58.6 (CH3CH), 42.6 (Cquat), 33.3
(NCH3), 26.9 (CH2CH3), 19.1 (CCH3), 12.8 (CHCH3), 7.9
(CH2CH3). IR (CHCl3): 4214, 3016, 2935, 2881, 1641,
1461, 1380, 1215, 756 cm21. MS (EI, 70 eV): m/z 58 (9), 97
(21), 105 (7), 118 (100), 148 (6), 205 (37), 260 (2), 290 (4),
305 (Mþ, 7). HRMS for C18H27NO3: calcd: 305.1991,
found: 305.1978. [a]2D5¼2166.8 (c¼1.7, CHCl3).
1.5. General procedure for reductive cleavage of
spirobisacetals 4
To a solution of the Prins product 4 in anhydrous
dichloromethane was added at 2788C titanium tetrachloride
followed by triethylsilane. The reaction mixture was
warmed to ambient temperature and stirred for 24 h. It
was then cooled to 258C and saturated aqueous ammonium
chloride was added and warmed to ambient temperature.
Water was added to dissolve the precipitated solids and the
solution was extracted with dichloromethane. The dichloro-
methane layer was dried (Na2SO4), and concentrated to
obtain crude product which on purification by flash column
chromatography rendered 5a–c as colourless oils.
1.5.3. (2S,5S,6R)-2-[(1R)-1-(Methoxymethyl)-1-methyl-
propyl]-4,5-dimethyl-6-phenylmorpholin-3-one
(5c).
Reduction of 4c (238 mg, 0.75 mmol) with titanium
tetrachloride (1.40 mL, 12.75 mmol) and triethylsilane
(3.0 mL, 18.75 mmol) in anhydrous dichloromethane
(13 mL) for 12 h gave after purification by flash column
chromatography (1/5 ethyl acetate/pet. ether) 212 mg (93%)
of 5c as a colourless liquid.
1H NMR (200 MHz, CDCl3): d 7.45–7.20 (m, 5H, ArH),
4.93 (d, 1H, J¼2.4 Hz, PhCH), 4.25 (s, 1H, CHO), 3.65–
3.41 (m, 3H, OCH2, CH3CH), 3.34 (s, 3H, OCH3), 3.00 (s,
3H, NCH3), 1.74 (q, 2H, J¼7.3 Hz, CCH2CH3), 1.07 (s, 3H,
CH3), 0.99–0.85 (m, 6H, CHCH3, CH2CH3). 13C NMR
(50 MHz, CDCl3): d 168.7 (CvO), 137.9 (ArCipso), 127.9
(ArCH), 127.0 (ArCH), 124.9 (ArCH), 80.0 (CHO), 76.0
(OCH2), 75.9 (PhCH), 58.6 (OCH3), 58.2 (CH3CH), 42.3
(Cquat), 33.1 (NCH3), 26.6 (CH2CH3), 18.6 (CCH3), 12.6
(CHCH3), 7.7 (CH2CH3). IR (CHCl3): 3475, 2972, 2877,
1649, 1452, 1251, 1108, 1064, 702 cm21. MS (EI, 70 eV):
58 (9), 97 (13), 117 (27), 148 (7), 205 (50), 290 (10), 305
(Mþ, 6). HRMS for C18H27NO3: calcd: 305.1991, found:
305.1983. [a]2D5¼2177.6 (c¼1.2, CHCl3).
1.5.1. 2S,5S,6R-2-((1-Methoxymethyl)cyclohexyl)-4,5-
dimethyl-6-phenyl-morpholin-3-one (5a). Reduction of
4a (840 mg, 2.4 mmol) with titanium tetrachloride (4.6 mL,
42 mmol) and triethylsilane (7.8 mL, 48.6 mmol) in
anhydrous dichloromethane (28 mL) gave after purification
by flash column chromatography (1/4 ethyl acetate/pet.
ether) 747 mg (93%) of 5a as colourless oil.
1H NMR (500 MHz, CDCl3): d 7.38–7.39 (m, 5H, ArH),
4.92 (d, 1H, J¼3.0 Hz, PhCH), 4.32 (s, 1H, CHO), 3.73 (d,
1H, J¼9.1 Hz, CH2), 3.52 (d, 1H, J¼9.1 Hz, CH2), 3.51 (dq,
1H, J¼3.0, 6.3 Hz, CH3CH), 3.30 (s, 3H, OCH3), 2.99 (s,
3H, NCH3), 2.00–1.35 (m, 10H, cyclohexyl), 0.96 (d, 3H,
J¼6.3 Hz, CH3CH). 13C NMR (50 MHz, CDCl3): d 169.0
(CvO), 138.1 (ArCH), 127.9 (ArCH), 127.1 (ArCH), 125.1
(ArCH), 79.5 (CHO), 76.1 (PhCH), 74.2 (CH2O), 58.6
(OCH3), 58.4 (CH3CH), 42.6 (Cquat, cyclohexyl), 33.2
1.6. General procedure for dissolving metal reduction of
morpholinones 5
To anhydrous liquid ammonia (distilled over sodium), was
added sodium metal at 2788C and the mixture was stirred

S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
3281
for 15 min. To the resulting blue solution was added a
solution of 6a–c dissolved in anhydrous THF. The mixture
was stirred at 2788C for three and a half minutes, methanol
was added and the mixture was stirred at room temperature
till the ammonia was completely removed. The methanol
was removed under reduced pressure and the residue was
partitioned in ethyl acetate and water. The ethyl acetate
layer was separated and the aqueous layer was extracted
several times with ethyl acetate. The combined extracts
were dried (Na2SO4) and concentrated to obtain crude
product which on purification by flash column chromato-
graphy gave 6 as colourless oils.
1H, CCH2CH3), 1.38–1.17 (m, 1H, CCH2CH3) 0.90 (s, 3H,
CCH3), 0.84 (t, 3H, J¼7.4 Hz, CH2CH3). 13C NMR
(50 MHz, CDCl3): d 172.8 (CvO), 79.1 (OCH2), 78.3
(CHOH), 59.0 (OCH3), 40.9 (Cquat), 25.4 (NCH3), 24.9
(CH2CH3), 18.0 (CCH3), 7.6 (CH2CH3). IR (CHCl3): 3382,
2968, 1650, 1537, 1107, 1031 cm21. MS (EI, 70 eV): 58
(43), 71 (28), 81 (7), 89 (100), 113 (13), 131 (10), 189 ((Mþ,
2). ESMS for C9H19NO3Na: calcd: 212.1263, found:
212.1263. [a]2D5¼233.86 (c¼0.9, CHCl3).
1.7. General procedure for lactonization of 6a–c to 7a–c
To a stirred solution of 6 in anhydrous dichloromethane was
added at 2788C boron tribomide in anhydrous dichloro-
methane and the resulting reaction mixture was gradually
warmed to 2158C with continuous stirring for 4 h. Water
was then added over a period a 5 min, the mixture was
stirred for 15 min and 6 M H2SO4 was added. The mixture
was then stirred overnight (approximately 12 h) during
which time it warmed to ambient temperature. The mixture
was then cooled in an ice bath and neutralized with saturated
sodium bicarbonate solution. It was then extracted with
dichloromethane and the combined dichloromethane
extracts were dried (Na2SO4) and concentrated to obtain
the crude lactone which was purified by flash column
chromatography.
1.6.1. 2S-2-Hydroxy-2-((1-methoxymethyl)cyclohexyl)-
N-methyl acetamide (6a). Prepared from 5a (293 mg,
0.9 mmol) in THF (2 mL) and Na (116 mg, 4.8 mmol) in
ammonia (10 mL). Purification by flash column chroma-
tography (3/2 ethyl acetate/pet. ether) furnished 95 mg
(50%) of 6a as a colourless oil.
1H NMR (200 MHz, CDCl3): d 6.79 (br s, 1H, NH), 4.28 (d,
1H, J¼6.0 Hz, OH), 4.04 (d, 1H, J¼6.0 Hz, CH), 3.61 (d,
1H, J¼9.3 Hz, OCH2), 3.35 (s, 3H, OCH3), 3.33 (d, 1H,
J¼9.3 Hz, OCH2), 2.86 (d, 3H, J¼5.3 Hz, NCH3), 2.09–
1.37 (m, 10H, cyclohexyl). 13C NMR (50 MHz, CDCl3): d
173.1 (CvO), 78.2 (CHOH), 77.4 (OCH2), 59.4 (OCH3),
40.8 (Cquat), 30.0 (CH2, cyclohexyl), 28.9 (CH2, cyclo-
hexyl), 26.0 (CH2, cyclohexyl), 25.7 (NCH3), 21.5 (CH2,
cyclohexyl), 21.4 (CH2, cyclohexyl). IR (CHCl3): 3306,
2920, 1650, 1531, 1409, 1203, 1094, 799 cm21. MS (EI,
70 eV): 58 (8), 81 (15), 89 (100), 95 (23), 139 (14), 183 (5),
215 (Mþ, 3). HRMS: calcd: 215.1521, found: 215.1525.
[a]2D5¼241.6 (c¼3.2, CHCl3).
1.7.1. 4S-4-Hydroxy-2-oxa-spiro[4,5]decan-3-one: (7a).
Demethylation of 6a (70 mg 0.32 mmol) in anhydrous
dichloromethane (4 mL) with boron tribromide (0.26 mL,
2.8 mmol diluted in 1 mL anhydrous dichloromethane)
followed by addition of water (1 mL) and 6 M H2SO4
(1.5 mL), gave after purification by flash column chroma-
tography (1/4 ethyl acetate/pet. ether) 53 mg (86%) of 7a as
a white crystalline solid.
1.6.2. (2S,3S)-2-Hydroxy-3-(methoxymethyl)-N,3-
dimethylpentanamide (6b). Prepared from 5b (86 mg,
0.28 mmol) in THF (0.5 mL) and Na (34 mg, 1.4 mmol) in
ammonia (4 mL). Purification by flash column chromato-
graphy (3/2 ethyl acetate/pet. ether) gave 27 mg (50%) of 6b
as a gum.
1
Mp 92–938C. H NMR (200 MHz, CDCl3): d 4.38 (d, 1H,
J¼9.3 Hz, CH2), 4.12 (s, 1H, CHOH), 3.91 (d, 1H,
J¼9.3 Hz, CH2), 3.46 (br, s, 1H, OH), 1.84–1.1 (m, 10H,
cyclohexyl). 13C NMR (50 MHz, CDCl3): 177.9 (CvO),
75.6 (CHOH), 73.6 (OCH2), 44.0 (Cquat), 33.7 (CH2,
cyclohexyl), 25.8 (CH2, cyclohexyl), 25.3 (CH2, cyclo-
hexyl), 22.9 (CH2, cyclohexyl), 21.7 (CH2, cyclohexyl). IR
(CHCl3): 3425, 2931, 2857, 1778, 1455, 1166, 1005,
731 cm21. MS (EI, 70 eV): m/z 55 (97), 67 (100), 79 (51),
83 (59), 95 (77), 108 (14), 170 (Mþ, 7). HRMS: calcd:
170.0943, found: 170.0942. [a]2D5¼þ13.9 (c¼0.55, CHCl3).
1H NMR (200 MHz, CDCl3): d 6.84 (br s, 1H, NH), 4.39 (br
s, 1H, OH), 4.05 (s, 1H, CH), 3.35 (s, 5H, CH2OCH3), 2.85
(d, 3H, J¼4.9 Hz, NCH3), 1.74–1.39 (m, 2H, CCH2CH3),
0.97 (s, 3H, CCH3), 0.92 (t, 3H, J¼7.4 Hz, CH2CH3). 13C
NMR (50 MHz, CDCl3): d 173.3 (CvO), 79.6 (OCH2),
77.6 (CHOH), 59.2 (OCH3), 40.9 (Cquat), 27.6 (CH2CH3),
25.6 (NCH3), 17.8 (CCH3), 7.6 (CH2CH3). IR (CHCl3):
3380, 2968, 2881, 2812, 1658, 1411, 1286, 1108, 732 cm21
.
1.7.2. (3S,4S)-4-Ethyl-3-hydroxy-4-methyldihydrofuran-
2(3H)-one (7b).14 Demethylation of 6b (17 mg, 0.09 mmol)
in anhydrous dichloromethane (4 mL) with boron tri-
bromide (0.08 mL, 0.79 mmol) diluted in anhydrous
dichloromethane (0.5 mL), followed by addition of water
(0.4 mL) and 6 M H2SO4 (0.3 mL) gave after purification by
flash column chromatography (3/7 ethyl acetate/pet. ether)
gave 9 mg (70%) of 7b as a syrup.
MS (EI, 70 eV): 58 (60), 71 (37), 89 (100), 113 (13), 189
(Mþ, 4). ESMS for C9H19NO3Na: calcd: 212.1263, found:
212.1264. [a]2D5¼234.75 (c¼0.28, CHCl3).
1.6.3. (2S,3R)-2-Hydroxy-3-(methoxymethyl)-N,3-
dimethylpentanamide (6c). Prepared from 5c (199 mg,
0.65 mmol) in THF (1 mL) and Na (78 mg, 3.26 mmol) in
ammonia (7 mL). Purification by flash column chromato-
graphy (3/2 ethyl acetate/pet. ether) gave 62 mg (50%) of 6c
as a gum.
1H NMR (200 MHz, CDCl3): d 4.23 (d, 1H, J¼9.3 Hz,
CH2), 4.16 (s, 1H, CHOH), 3.89 (d, 1H, J¼9.3 Hz, CH2),
3.0 (br s, 1H, OH), 1.50 (m, 2H, CH2CH3), 1.19 (s, 3H,
CH3), 0.96 (t, 3H, J¼7.3 Hz, CH2CH3). 13C NMR (50 MHz,
CDCl3): 177.5 (CvO), 75.9 (CHOH), 73.7 (CH2), 43.5
(Cquat), 24.2 (CH2CH3), 20.9 (CH3), 8.2 (CH2CH3).
1H NMR (200 MHz, CDCl3): d 6.81 (br, s, 1H, NH), 4.46
(br s, 1H, OH), 3.99 (s, 1H, CH), 3.43–3.19 (m, 5H,
CH2OCH3), 2.79 (d, 3H, J¼4.9 Hz, NCH3), 1.70–1.50 (m,

3282
S. V. Pansare, A. Bhattacharyya / Tetrahedron 59 (2003) 3275–3282
[a]D25¼þ4.45 (c¼0.25, CHCl3) (lit.14 [a]2D0¼þ4.7 (c¼0.26,
Perkin Trans. 1 1991, 490. (b) Kabeya, M.; Hamada, Y.;
Shioiri, T. Tetrahedron 1997, 53, 9769. (c) Okabe, M.; Sun,
R.-C.; Zenchoff, G. B. J. Org. Chem. 1991, 56, 4392.
3. (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) Ichinari, D.; Ueki, T.;
Yoshihara, K.; Kinoshita, T. Chem. Commun. 1997, 1743.
4. Lacrampe, J. F.; Armand, F.; Eddy, E. J.; Deroose, D. F.;
Fortin, J. M. C.; Coesemans, E. PCT Int. Appl. WO 0110866
A1 20010215, 2001.
CHCl3)).
1.7.3. (3S,4R)-4-Ethyl-3-hydroxy-4-methyldihydro-
furan-2(3H)-one (7c). Demethylation of 6c (45 mg,
0.24 mmol) in anhydrous dichloromethane (5 mL), with
boron tribromide (0.20 mL, 2.1 mmol) diluted in anhydrous
dichloromethane (1 mL) followed by addition of water
(1 mL) and 6 M H2SO4 (0.6 mL) gave after purification by
flash column chromatography (3/7 ethyl acetate/pet. ether)
26 mg (76%) of 7c as colourless oil.
5. For studies on the resolution and enantioselective synthesis 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.
1H NMR (200 MHz, CDCl3): d 4.21 (s, 1H, CHOH), 4.05–
3.95 (AB system, J¼10.8 Hz, 2H, CH2), 3.45 (br s, 1H,
OH), 1.60 (m, 2H, CH2CH3), 1.08 (s, 3H, CH3), 1.01 (t, 3H,
J¼7.4 Hz, CH2CH3). 13C NMR (50 MHz, CDCl3): 177.8
(CvO), 75.6 (CHOH), 75.0 (CH2), 44.1 (Cquat), 30.1
(CH2CH3), 15.9 (CH3), 8.5 (CH2CH3). IR (CHCl3): 3444,
2968, 1776, 1460, 1112, 999, 715 cm21. ESMS for
C7H12O3Na: calcd: 167.0684, found: 167.0687.
[a]2D5¼þ25.65 (c¼0.35, CHCl3).
6. (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).
7. Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.-I.; Murahashi,
S.-I. Bull. Chem. Soc. Jpn 1996, 69, 2079.
Acknowledgements
8. The stereochemical assignment is based on the reported trend
in chemical shifts for the olefinic methine protons in E and Z
benzylidene camphor derivatives: Kossanyi, J.; Furth, B.;
Morizur, J. P. Tetrahedron 1970, 26, 395.
Financial assistance (in part) from the Department of
Science and Technology (Grant SP/S1/G-11/96) is grate-
fully acknowledged. We thank Mr D. Mandal for assistance
in determining the enantiomeric excess of the lactones.
9. 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.
References
10. Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem. 1998, 63,
4120.
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. (e) Pansare, S. V.; Shinkre, B. A.;
Bhattacharyya, A. Tetrahedron 2002, 58, 8985.
11. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1989; Chapter 2.
12. Tadano, K.; Kanazawa, S.; Ogawa, S. J. Org. Chem. 1988, 53,
3868.
13. Ueki, T.; Ichinari, D.; Yoshihara, K.; Morimoto, Y.; Kinoshita,
T. Tetrahedron Lett. 1998, 39, 667.
14. Herz, W.; Bruno, M. Phytochemistry 1987, 26, 1175.
2. (a) Ballini, R.; Marcantoni, E.; Petrini, M. J. Chem. Soc.,