Stereoselective synthesis of 3-alkylsulfinylmethylisoxazolines and their use as chiral nucleophiles in the chain elongation of 2,3-O-isopropylidene-D-glyceraldehyde

Article abstract of DOI:10.1016/S0957-4166(00)00453-5

The reaction of racemic 3-methylisoxazolines and enantiomerically pure (R_S)- and (S_S)-methanesulfinates and (R_S)- and (S_S)-ethanesulfinates of 1,2:5,6-di-O-isopropylidene-D-glucofuranose allows enantiomerically pure 3-alkylsulfinylmethylisoxazolines with both absolute configurations at sulfur to be obtained. One of these has been used as a chiral nucleophile in the four carbon homologation of 2,3-O-isopropylidene-D-glyceraldehyde 17.

Full text of DOI:10.1016/S0957-4166(00)00453-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4791–4803
Stereoselective synthesis of 3-alkylsulfinylmethylisoxazolines
and their use as chiral nucleophiles in the chain elongation
of 2,3-O-isopropylidene- -glyceraldehyde
D
J. A. Lo´pez-Sastre,a J. D. Mart´ın-Ramos,b J. F. Rodr´ıguez-Amo,a,* M. Santos-Garc´ıaa and
M. A. Sanz-Tejedora,*
aDepartamento de Qu´ımica Orga´nica (E.T.S.I.I.), Paseo del Cauce s/n, 47011 Valladolid, Spain
bDepartamento de Mineralog´ıa y Petrolog´ıa, Facultad de Ciencias, C/Fuentenueva s/n, 18002 Granada, Spain
Received 31 October 2000; accepted 14 November 2000
Abstract
The reaction of racemic 3-methylisoxazolines and enantiomerically pure (RS)- and (SS)-methanesulf-
inates and (RS)- and (SS)-ethanesulfinates of 1,2:5,6-di-O-isopropylidene-D-glucofuranose allows enan-
tiomerically pure 3-alkylsulfinylmethylisoxazolines with both absolute configurations at sulfur to be
obtained. One of these has been used as a chiral nucleophile in the four carbon homologation of
2,3-O-isopropylidene- -glyceraldehyde 17. © 2001 Elsevier Science Ltd. All rights reserved.
D
1. Introduction
The rational construction of substances with multiple stereogenic centres is a leading subject
in the modern organic synthesis panorama. Among the various techniques with which a densely
functionalized homochiral compound can be constructed,1 one of the more viable methodologies
exploits, as a key operation, carbonꢀcarbon bond forming homologation of readily available
sugar derived templates (incorporating suitable stereogenic centres) by means of n-carbon
synthons.2 Towards this end, versatile five-membered heterocycles as functional elongation
reagents have been frequently used in reactions with enantiopure aldehydo or imino sugars. For
example, Casiraghi et al. have shown the utility of 2-siloxy-furan, pyrrole and thiophene
derivatives as four-carbon building blocks for the construction of complex molecules bearing
multiple contiguous stereogenic centres.3 Likewise, several 2-substituted thiazoles have been
exploited by Dondoni et al. in n-carbon chain extension of aldehydes and aldonitrones4 and,
recently, 4-substituted isoxazoles have also been used.5
* Corresponding author.
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00453-5

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J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
For this purpose, the isoxazoline ring is another especially valuable heterocycle. As distin-
guished from other heterocycles that have been used to date, they can bear two stereogenic
centres (C4 and C5) in their structure and, moreover, they are versatile intermediates in organic
synthesis.6 Isoxazoline ring reductive cleavage can be controlled to give either g-amino alcohols
or b-hydroxyketones.7 The latter transformation stands as a very interesting alternative to the
aldol reaction.
In connection with our research devoted to asymmetric synthesis using the sulfinyl group as
a chiral auxiliary,8 and to the iterative chain elongation of 2,3-O-isopropylidene-
-glyceralde-
D
hyde 17 using ethyl ethylthiomethyl sulfoxide9 and (RS)-methyl p-tolyl sulfoxide10 as formyl
anion equivalents, we thought to study the chain elongation of aldehyde 17 in four-carbon
atoms, in one synthetic step, by using enantiomerically pure 3-alkylsulfinylmethylisoxazolines as
chiral nucleophiles. The sulfinyl group in alkylsulfinylmethylisoxazolines offers the advantage of
providing a handle for the resolution and increasing the acidity of the hydrogens a to this
sulfinyl group; in this way, these intermediates can be exploited for further synthetic transforma-
tions, before unmasking the functionalities latent in the heterocyclic ring.
Herein we provide a simple approach to enantiomerically pure 3-alkylsulfinylmethylisoxaz-
olines, and the synthesis of b,g,d-trihydroxymethylisoxazolines according to a four-carbon
homologative protocol exploiting the aforementioned sulfinylisoxazolines as functional elonga-
tion reagents.
2. Results and discussion
Preparation of 3-alkylsulfinylmethylisoxazolines, compounds 9a,b–15a,b (Table 1), has been
carried out using the methodology developed by Cinquini et al.,11 that consists of the exo-metal-
lation of racemic 3-methylisoxazolines and subsequent reaction with a chiral non-racemic
sulfinic ester.
The starting racemic 3-methylisoxazolines (compounds 1–4) were synthesized by 1,3-dipolar
cycloaddition between ethanonitrile oxide12 and different monosubstituted and symmetric
1,2-disubstituted alkenes. The sulfinic esters employed in this study are (RS)- and (SS)-
methanesulfinates13 and (RS)- and (SS)-ethanesulfinates14 of 1,2:5,6-di-O-isopropylidene-
-gluco-
D
furanose (compounds 5, 6, 7 and 8, respectively). They have been synthesized according to
Llera’s procedure15 by addition of the corresponding methyl or ethylsulfinylchloride to 1,2:5,6-
di-O-isopropylidene- -glucofuranose (DAG) in the presence of a suitable base (pyridine for the
D
i
(RS) epimer or Pr2EtN for the (SS) epimer).
3-Alkylsulfinylmethylisoxazolines (compounds 9a,b–15a,b, Table 1) were easily prepared by
exo-deprotonation of isoxazolines 1–4 with the appropriate lithium amide16 and subsequent
Andersen reaction with enantiomerically and diastereomerically pure methane or ethanesulfi-
nates of DAG (compounds 5–8). As is shown in Table 1, the base employed for metallation of
4,5-disubstituted isoxazolines, compounds 1 and 2, was lithium diisopropylamide (LDA) (entries
1–6). When metallation was carried out on 4-unsubstituted isoxazolines, compounds 3 and 4,
which might be deprotonated at unsubstituted C4 position, a more hindered base such as
lithium tetramethylpiperidide (LTMP) was used in order to minimize the endo-deprotonation. In
the case of isoxazoline 3 (entry 7) the endo-metallation reaction is not overridden completely,
yielding 20% of the corresponding endo-metallated product (16).

J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
4793
Table 1
Synthesis of 3-sulfinylmethylisoxazolines 9a,b–15a,b
Entry
Isoxazoline
Base
Sulfinate
Product (% yield)a
d.r./a:b
1
2
4
5
6
7
8
1a,b
1a,b
2a,b
2a,b
2a,b
3a,b
4a,b
LDA
LDA
LDA
LDA
LDA
LTMP
LTMP
6
8
5
6
7
6
6
9a,b (70)
48:52
48:52
53:47
50:50
48:52
55:45
52:48
10a,b (65)
11a,b (65)
12a,b (55)
13a,b (56)
14a,b (47)b
15a,b (32)
a Isolated yield.
b A 20% yield of 3-methyl-4-methylsulfinyl-5-n-pentyl-isoxazoline (16) was also obtained.
In each reaction, mixtures of two diastereoisomeric sulfinylmethylisoxazolines (a,b) in almost
equal proportions, were generated because the diastereoselection in the process, as expected, was
low. However, in every case, column chromatography or, in one instance (entry 1, compounds
9a,b), fractional crystallization allowed a clean separation of the diastereoisomeric mixtures into
diastereomerically and enantiomerically pure derivatives (Table 1). Compounds 11a and 11b are
enantiomers of compounds 12a and 12b, respectively, as confirmed by their having the same
spectroscopic data and only differing in the sign of their optical rotation. This result is in
agreement with both the suggested concerted mechanism for 1,3-dipolar cycloadditions17,18
(synthesis of isoxazolines 1–4) and with the inversion of sulfur atom configuration that occurs
in these Andersen reactions, employed to obtain compounds 9a,b–15a,b.
Next, we studied the four carbon chain elongation of aldehyde 17 using enantiomerically pure
3-methylsulfinylmethylisoxazoline 12a as the homologating reactant (Scheme 1). Metallation of
compound 12a with LDA (at −90°C) gave rise to the corresponding exo-azaenolate, whose
aldol-type reaction with compound 17 afforded hydroxysulfoxides 18, 19 and 20 in high yield,
and in a high level of diastereoselectivity (12:4:84, 18:19:20, ratio). These compounds were
isolated as pure diastereoisomers by flash chromatography.
The absolute configuration of major compound 20 was unequivocally assigned by X-ray
analysis as (4R,5R,1%S,2%R) (Fig. 1).

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J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
Scheme 1.
Figure 1. X-Ray structure of compound 20
The observed (2R) stereochemistry at the HO-bearing carbon in compound 20, which is the
predominant isomer obtained from reaction of compounds 12a and 17, is in accord with a
non-chelation controlled addition (Felkin–Anh–Houk model).19 To account for the stereochem-
istry at C1% in the major product 20, we propose that this aldol reaction derives from the
transition state shown in Fig. 2, in which the chelation of the lithium cation by the azaenolate
and the oxygen of the sulfinyl group causes the chiral azaenolate to have a distinct facial bias,
with the ‘si’ face shielded by the phenyl group at C4 and the methyl group at sulfur. So, as can
be seen in Fig. 2, the aldehyde approaches the azaenolate from the less hindered face (‘re’ face).
This is in agreement with previous results obtained in related systems.11b,20

J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
4795
Figure 2.
On the basis of the structural assignment of compound 20,21 we can establish the same
absolute configuration at sulfur, C4 and C5 for the other products (compounds 18 and 19)
obtained in the same process, and for the starting isoxazoline 12a. Furthermore, compound 12b
has the same absolute configuration at sulfur but the opposite at the centres in the ring to
compound 12a. In the same way, the absolute configurations of compounds 11a and 11b could
be established as (RS,4S,5S) and (RS,4R,5R), respectively, because they are enantiomers of 12a
and 12b.
In summary, several enantiomerically pure 3-alkylsulfinylmethylisoxazolines with both abso-
lute configurations at sulfur have been prepared. Although the present synthesis employs a
conventional diastereoisomeric separation, it can provide an efficient and short route to all
possible enantiomers of 3-alkylsulfinylmethylisoxazolines. Furthermore, the wide range of
substituents available in the dipolarophile should allow the synthesis of a considerable number
of isoxazoline derivatives capable of being exploited as chiral homologous reactants.
The reaction of isoxazoline 12a with 2,3-O-isopropylidene- -glyceraldehyde 17 takes place
D
with high diastereoselectivity and allows access to complex molecules bearing multiple contigu-
ous stereogenic centres capable of different transformations due to the isoxazoline ring versatil-
ity. The study of the reductive ring cleavage that is able to provide optically pure
b-hydroxyketones, g-aminoalcohols or a,b-unsaturated ketones is currently in progress.
3. Experimental
3.1. General methods
Dry solvents and liquid reagents were distilled under argon just prior to use: THF and diethyl
ether were distilled from sodium and benzophenone ketyl, benzene over sodium, and triethyl-
amine and diisopropylamine over calcium hydride. Alkenes, nitroethane and phenylisocyanate
were commercially available from Aldrich Chemical Co. and used without further purification.
All reaction vessels, after being flame-dried, were kept under argon. Organic solutions were
dried over anhydrous sodium or magnesium sulfate, and the solvent was evaporated at reduced
pressure below 40°C.
TLC was performed on glass plates coated with silica gel G (Merck) or SI-F-254 (Scharlau),
spots being developed either with sulfuric acid in ethanol (10%) or with phosphomolybdic acid
in ethanol. Column chromatographic separations were performed by using silica gel Merck 60
(70–230 mesh, ASTM, for gravity chromatography) or 230–400 mesh (for flash
chromatography).

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J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
Optical rotations were measured with a 141 Perkin–Elmer polarimeter. [h]D values are given
in units of 10−1 deg cm2 g−1.
1H NMR (300 MHz, CDCl3) and 13C NMR (80 MHz, CDCl3) spectra were performed with
a Bruker AC-300 spectrometer. Chemical shifts were measured in ppm (l), relative to SiMe4 as
the internal reference; signal multiplicities are quoted as s, singlet; d, doublet; dd, double
doublet; ddd, doubled double doublet; dq, double quartet; t, triplet; q, quartet, and m, multiplet.
J values are given in Hz. Diastereoisomeric ratios were determined by integration of well
1
separated signals at H NMR spectra. IR spectra were measured on a Nicolet FTIR-20-SX
spectrometer. Mass spectra were recorded by the direct insertion technique by electronic impact
(ei) or chemical ionization (ci), using a HP-588-A spectrometer at 70 eV with a temperature
source of 200°C. Elemental analyses were performed in a Carlo Erba Elemental Analyzer 1106.
2,3-O-Isopropylidene-
D
-glyceraldehyde 17 was synthesized from 1,2:5,6-di-O-isopropylidene- -
D
mannitol by oxidation with sodium periodate.22
3.2. Synthesis of 3-alkylsulfinylmethylisoxazolines. General procedure
To a stirred solution of the base (LDA23 or LTMP24) (15 mmol) in THF (10 ml) cooled at
−95°C, 3-methylisoxazoline (10 mmol) in THF (20 ml) was added over 10 min. The mixture was
stirred for an additional 4 hour period at −80°C or at −95°C (depending on the 3-methylisoxaz-
oline), and the sulfinate (5 mmol) in THF (20 ml) was then added. After being stirred for 30
minutes, the reaction mixture was quenched with a saturated aqueous ammonium chloride
solution. The organic layer was separated and the aqueous phase extracted twice with
dichloromethane. The combined organic layers were dried, concentrated under reduced pressure
and the residue was purified by column chromatography.
3.2.1. 3-(Methylsulfinyl)methyl-4,5-trimethyleneisoxazoline 9a,b
3-Methyl-4,5-trimethyleneisoxazoline 1a,b, (4.25 g, 34 mmol) was treated with (S)-methylsulfi-
nate of DAG, 6 (7.35 g, 25 mmol) and LDA (41 mmol) at −80°C, following the general
procedure. The work-up led to a mixture containing compounds 9a and 9b in a 48:52 ratio
1
(estimated by integration of the signals corresponding to CH3SO in the H NMR spectrum of
the crude reaction). Column chromatography using diethyl ether:hexane (2:1) as the eluent
afforded a mixture of diastereoisomers 9a and 9b (3.25 g, 17.4 mmol, 70%). Separation of both
diastereoisomers by crystallization (diethyl ether:hexane 10:1) afforded pure 9a as a yellow syrup
and pure 9b as a white solid (mp 98–99°C).
3.2.1.1. 3-(Methylsulfinyl)methyl-4,5-trimethyleneisoxazoline 9a. Rf=0.17 (isopropanol:diethyl
ether, 1:10); [h]2D0=+377.2 (c 1.00, CHCl3); H NMR l 1.36–1.46 (m, 1H, -CH2-cyclopent.),
1
1.64–1.81 (m, 3H, -CH2-cyclopent.), 1.88–1.97 (m, 1H, -CH2-cyclopent.), 2.08–2.15 (m, 1H,
-CH2-cyclopent.), 2.67 (s, 3H, CH3-SO-), 3.52 (d, 1H, Jgem 13.9, SO-CH2-CCN), 3.84 (d, 1H,
Jgem 13.9, SO-CH2-CCN), 3.83 (m, 1H, H-C4), 5.16 (dd, 1H, J5,4 8.9, Jvic 5.0, H-C5); 13C NMR
l 23.2, 30.1 and 35.7 (-CH2-cyclopent.), 37.9 (CH3-SO-), 49.0 (SOCH2CCN), 54.7 (C4), 87.3
(C5) and 151.9 (C3). IR (KBr, liquid film): 2975, 2890, 1610, 1455, 1440, 1415, 1405, 1345, 1320,
1050, 1025, 920 and 760 cm−1; MS (m/e) (ei): 187 (M+, 11), 172 (3), 124 (100), 107 (4), 94 (37),
79 (87), 67 (26), 41 (18). Anal. calcd for C8H13NO2S: C, 51.31; H, 7.00; N, 7.48. Found: C,
51.21; H, 7.02; N, 7.51.

J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
4797
3.2.1.2. 3-(Methylsulfinyl)methyl-4,5-trimethyleneisoxazoline 9b. Rf=0.12 (isopropanol:diethyl
ether, 1:10); [h]2D0=−158.3 (c 0.67, CHCl3); H NMR l 1.38–1.48 (m, 1H, -CH2-cyclopent.),
1
1.65–1.81 (m, 3H, -CH2-cyclopent.), 1.91–2.00 (m, 1H, -CH2-cyclopent.), 2.09–2.18 (m, 1H,
-CH2-cyclopent.), 2.72 (s, 3H, CH3-SO-), 3.65 (d, 1H, Jgem 13.3, SO-CH2-CCN), 3.73 (dd, 1H,
Jvic 8.5, J4,5 8.9, H-C4), 3.80 (d, 1H, Jgem 13.3, SO-CH2-CCN), 5.13 (dd, 1H, J5,4 0.9, Jvic 5.0,
H-C5); 13C NMR l 23.3, 30.3 and 35.8 (-CH2-cyclopent.), 39.6 (CH3-SO-), 52.0 (SOCH2CCN),
54.1 (C4), 87.5 (C5) and 152.6 (C3); IR (KBr, liquid film): 2975, 2890, 1615, 1460, 1450, 1415,
1405, 1345, 1320, 1040, 970, 915 and 760 cm−1; MS (m/e) (ei): 187 (M+, 6), 172 (2), 124 (100),
107 (5), 94 (44), 79 (98), 63 (40), 41 (34). Anal. calcd for C8H13NO2S: C, 51.31; H, 7.00; N, 7.48.
Found: C, 51.47; H, 7.03; N, 7.46.
3.2.2. 3-(Ethylsulfinyl)methyl-4,5-trimethyleneisoxazoline 10a,b
3-Methyl-4,5-trimethyleneisoxazoline 1a,b (2.82 g, 22.6 mmol) was treated with (S)-ethylsulfi-
nate of DAG, 8 (3.79 g, 11.3 mmol) and LDA (31.64 mmol) at −80°C, as described in the
general procedure. The work-up led to a mixture containing compounds 10a and 10b in a 48:52
1
ratio (estimated by integration of the signals corresponding to SO-CH2-CCN in the H NMR
spectrum of the crude reaction).9c
3.2.3. 4,5-Diphenyl-3-(methylsulfinyl)methylisoxazoline 11a,b
4,5-Diphenyl-3-methylisoxazoline 2a,b (4.94 g, 36 mmol) was treated with (R)-methylsulfinate
of DAG, 5 (5.80 g, 18 mmol) and LDA (44 mmol) at −80°C, according to the general procedure.
The work-up led to a mixture containing compounds 11a and 11b in a 53:47 ratio (estimated by
1
integration of the signals corresponding to HC-4 in the H NMR spectrum of the crude
reaction). Column chromatography using diethyl ether:hexane (2:1) as the eluent afforded a
mixture of diastereoisomers 11a and 11b (3.50 g, 11.7 mmol, 65%), which were separated by
successive chromatographies (diethyl ether:hexane, 4:1) to yield pure 11a and pure 11b as yellow
syrups.
3.2.3.1. 4,5-Diphenyl-3(methylsulfinyl)methylisoxazoline 11a. Rf=0.08 (diethyl ether:hexane, 4:1);
1
[h]2D0=+222.9 (c 1.02, CHCl3); H NMR l 2.60 (s, 3H, CH3-SO-), 3.42 (d, 1H, Jgem 13.9,
SO-CH2-CCN), 3.64 (d, 1H, Jgem 13.5, SO-CH2-CCN), 4.64 (d, 1H, Jtrans 7.1, H-C4), 5.60 (d, 1H,
Jtrans 7.1, H-C5) and 7.24–7.41 (m, 10H, H-arom.); 13C NMR l 37.7 (CH3-SO-), 47.7 (SO-CH2-
CCN), 64.8 (C4), 91.0 (C5), 125.5, 128.0, 128.2, 128.4, 128.8 and 129.4 (CH-arom.), 137.1
(C4-C-arom.), 139.6 (C5-C-arom.) and 152.6 (C3); IR (KBr, liquid film): 3075, 3050, 2975, 2925,
1605, 1495, 1460, 1425, 1410, 1315, 1310, 1055, 910, 760 and 700 cm−1; MS (m/e) (ci): 340
(M++41, 4), 328 (M++29, 12), 300 (M++1, 100), 284 (2), 265 (5), 237 (13), 222 (4), 197 (14), 160
(2), 132 (7), 107 (51). Anal. calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68. Found: C, 68.19;
H, 5.70; N, 4.70.
3.2.3.2. 4,5-Diphenyl-3-(methylsulfinyl)methylisoxazoline 11b. Rf=0.05 (diethyl ether:hexane,
4:1); [h]2D0=−221.4 (c 1.04, CHCl3); H NMR l 2.64 (s, 3H, CH3-SO-), 3.51 (d, 1H, Jgem 13.1,
1
SO-CH2-CCN), 3.71 (d, 1H, Jgem 13.1, SO-CH2-CCN), 4.40 (d, 1H, Jtrans 7.1, H-C4), 5.57 (d, 1H,
Jtrans 7.1, H-C5) and 7.22–7.43 (m, 10H, H-arom.); 13C NMR l 39.5 (CH3-SO-), 51.3 (SO-CH2-
CCN), 64.5 (C4), 91.0 (C5), 125.3, 127.9, 128.5, 128.9 and 129.6 (CH-arom.), 136.8 (C4-C-
arom.), 139.6 (C5-C-arom.) and 153.0 (C3); IR (KBr, liquid film): 3075, 3050, 2975, 2925, 1605,
1495, 1460, 1425, 1410, 1315, 1050, 915, 760 and 700 cm−1; MS (m/e) (ci): 340 (M++41, 5), 328

4798
J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
(M++29, 16), 300 (M++1, 100), 284 (2), 265 (8), 237 (12), 222 (4), 197 (8), 132 (3), 130 (4), 107
(17). Anal. calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68. Found: C, 68.31; H, 5.70; N, 4.66.
3.2.4. 4,5-Diphenyl-3-(methylsulfinyl)methylisoxazoline 12a,b
4,5-Diphenyl-3-methylisoxazoline 2a,b (4.94 g, 36 mmol) was treated with (S)-methylsulfinate
of DAG, 6 (5.80 g, 18 mmol) and LDA (40 mmol) at −80°C, as in previous experiments. The
work-up led to a mixture containing compounds 12a and 12b in an equimolar ratio (estimated
1
by integration of the signals corresponding to H-C4 in the H NMR spectrum of the crude
reaction). Column chromatography using diethyl ether:hexane (2:1) as the eluent afforded a
mixture of diastereoisomers 12a and 12b (2.88 g, 9.6 mmol, 55%), which were separated by
successive chromatographies (diethyl ether:hexane, 10:1) to yield pure 12a and pure 12b as
yellow syrups.
3.2.4.1. 4,5-Diphenyl-3-(methylsulfinyl)methylisoxazoline 12a. Rf=0.12 (diethyl ether:hexane,
10:1); [h]2D0=−221.7 (c 1.05, CHCl3); H NMR l 2.60 (s, 3H, CH3-SO-), 3.42 (d, 1H, Jgem 13.5,
1
SO-CH2-CCN), 3.64 (d, 1H, Jgem 13.5, SO-CH2-CCN), 4.64 (d, 1H, Jtrans 7.1, H-C4), 5.60 (d, 1H,
Jtrans 7.1, H-C5) and 7.24–7.41 (m, 10H, H-arom.); 13C NMR l 37.8 (CH3-SO-), 47.8 (SO-CH2-
CCN), 64.9 (C4), 91.1 (C5), 125.6, 128.1, 128.3, 128.5, 128.9 and 129.5 (CH-arom.), 137.2
(C4-C-arom.), 139.7 (C5-C-arom.) and 152.6 (C3); IR (KBr, liquid film): 3075, 3050, 2975, 2925,
1605, 1500, 1460, 1425, 1410, 1315, 1310, 1055, 910, 760 and 700 cm−1. MS (m/e) (ci): 340
(M++41, 6), 328 (M++29, 14), 300 (M++1, 100), 284 (2), 265 (4), 237 (14), 230 (3), 222 (4), 197
(13), 160 (2), 132 (6), 107 (47). Anal. calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68. Found:
C, 68.19; H, 5.75; N, 4.66.
3.2.4.2. 4,5-Diphenyl-3-(methylsulfinyl)methylisoxazoline 12b. Rf=0.06 (diethyl ether:hexane,
1
10:1); [h]2D0=+227.3 (c 1.00, CHCl3); H NMR l 2.64 (s, 3H, CH3-SO-), 3.51 (d, 1H, Jgem 13.1,
SO-CH2-CCN), 3.71 (d, 1H, Jgem 13.1, SO-CH2-CCN), 4.40 (d, 1H, Jtrans 7.1, H-C4), 5.57 (d, 1H,
Jtrans 7.1, H-C5) and 7.22–7.43 (m, 10H, H-arom.); 13C NMR l 39.5 (CH3-SO-), 51.3 (SO-CH2-
CCN), 64.5 (C4), 91.0 (C5), 125.3, 127.9, 128.5, 128.9 and 129.6 (CH-arom.), 136.8 (C4-C-
arom.), 139.6 (C5-C-arom.) and 153.0 (C3); IR (KBr, liquid film): 3075, 3050, 2975, 2925, 1605,
1495, 1460, 1425, 1410, 1315, 1055, 915, 760 and 700 cm−1; MS (m/e) (ci): 340 (M++41, 6), 328
(M++29, 10), 300 (M++1, 100), 284 (2), 265 (6), 237 (12), 230 (3), 222 (4), 197 (12), 160 (2), 132
(5), 107 (39). Anal. calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68. Found: C, 68.27; H, 5.71;
N, 4.69.
3.2.5. 4,5-Diphenyl-3-(ethylsulfinyl)methylisoxazoline 13a,b
4,5-Diphenyl-3-methylisoxazoline 2a,b (2.08 g, 15.2 mmol) was treated with (R)-ethylsulfinate
of DAG, 7 (2.57 g, 7.6 mmol) and LDA (22.8 mmol) at −80°C, as in the previous experiments.
The work-up led to a mixture containing compounds 13a and 13b in a 48:52 ratio (estimated by
1
integration of the signals corresponding to H-C4 in the H NMR spectrum of the crude
reaction).9c
3.2.6. 3-(Methylsulfinyl)methyl-5-n-pentylisoxazoline 14a,b
3-Methyl-4-n-pentylisoxazoline 3a,b (2.17 g, 14 mmol) was treated with (S)-methylsulfinate of
DAG, 6 (2.25 g, 7 mmol) and LTMP (21 mmol) at −95°C, as in previous preparations. The
work-up led to a mixture containing compounds 14a and 14b in a 55:45 ratio (estimated by

J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
4799
1
integration of the signals corresponding to H-C4 in the H NMR spectrum of the crude
reaction). Column chromatography using diethyl ether:hexane (1:1) as the eluent afforded a
mixture of diastereoisomers 14a and 14b (715 mg, 3.30 mmol, 47%) and pure 3-methyl-4-
methylsulfinyl-5-n-pentylisoxazoline, 16 (304 mg, 1.40 mmol, 20%). The mixture of compounds
14a and 14b was successively chromatographed (diethyl ether:hexane 2:1) to produce pure 14a
as a white solid from diethyl ether–hexane (mp 43–45°C) and pure 14b as a white solid from
diethyl ether–hexane (mp 63–64°C).
3.2.6.1. 3-(Methylsulfinyl)methyl-5-n-pentylisoxazoline 14a. Rf=0.20 (isopropanol:diethyl ether,
1:10); [h]2D0=−91.2 (c 0.60, CHCl3); H NMR l 0.89 (t, 3H, Jvic 6.6, CH3-alk), 1.25–1.39 (m, 6H,
1
-CH2-), 1.41–1.63 (m, 1H, C5-CH2-), 1.69–1.79 (m, 1H, C5-CH2-), 2.67 (s, 3H, CH3-SO-), 2.86
(dd, 1H, Jtrans 8.5, Jgem 17.4, H-C4), 3.14 (dd, 1H, Jcis 10.4, Jgem 17.4, H-C4), 3.57 (d, 1H, Jgem
13.5, SO-CH2-CCN), 3.88 (d, 1H, Jgem 13.5, SO-CH2-CCN) and 4.60–4.71 (m, 1H, H-C5); 13C
NMR l 13.9 (CH3-alk), 22.5 (C4%), 25.1 (C3%), 31.5 (C2%), 34.8 (C1%), 38.3 (CH3-SO-), 42.8 (C4),
50.9 (SO-CH2-CCN), 81.9 (C5) and 150.8 (C3); IR (KBr, liquid film): 2975, 2925, 2875, 1615,
1470, 1425, 1415, 1400, 1350, 1340, 1040, 1030, 915, 815 and 730 cm−1; MS (m/e) (ei): 217 (M+,
16), 200 (2), 154 (15), 146 (100), 122 (4), 98 (24), 83 (58), 67 (32), 41 (52). Anal. calcd for
C10H19NO2S: C, 55.28; H, 8.81; N, 6.44: Found: C, 55.65; H, 8.92; N, 6.25.
3.2.6.2. 3-(Methylsulfinyl)methyl-5-n-pentylisoxazoline 14b. Rf=0.15 (isopropanol:diethyl ether,
1
1:10); [h]2D0=+108.2 (c 0.60, CHCl3); H NMR l 0.89 (t, 3H, Jvic 6.6, CH3-alk), 1.31–1.43 (m,
6H, -CH2-), 1.51–1.62 (m, 1H, C5-CH2-), 1.67–1.76 (m, 1H, C5-CH2-), 2.67 (s, 3H, CH3-SO-),
2.71 (dd, 1H, Jtrans 8.7, Jgem 17.4, H-C4), 3.25 (dd, 1H, Jcis 10.4, Jgem 17.4, H-C4), 3.58 (d, 1H,
Jgem 13.5, SO-CH2-CCN), 3.87 (d, 1H, Jgem 13.5, SO-CH2-CCN) and 4.62–4.71 (m, 1H, H-C5);
13C NMR l 13.9 (CH3-alk), 22.5 (C4%), 25.0 (C3%), 31.5 (C2%), 34.9 (C1%), 38.3 (CH3-SO-), 42.7
(C4), 51.0 (SO-CH2-CCN), 81.9 (C5) and 150.8 (C3); IR (KBr, liquid film): 2975, 2925, 2875,
1615, 1480, 1435, 1420, 1405, 1355, 1340, 1040, 1030, 915, 730 and 690 cm−1; MS (m/e) (ei): 217
(M+, 13), 154 (12), 146 (78), 112 (26), 98 (33), 83 (46), 63 (58), 41 (100). Anal. calcd for
C10H19NO2S: C, 55.28; H, 8.81; N, 6.44. Found: C, 55.65; H, 8.92; N, 6.25.
3.2.6.3. 3-Methyl-4-methylsulfinyl-5-n-pentylisoxazoline 16. Rf=0.22 (diethyl ether:hexane,
1
10:1); H NMR l 0.90 (t, 3H, Jvic 6.5, CH3-C4H8-); 1.30–1.72 (m, 8H, -(CH2)4-); 2.12 (s, 3H,
CH3-CNC); 2.48 (s, 3H, CH3-SO-); 3.98 (d, 1H, J4,5 4.2, H-C4) and 4.35 (m, 1H, H-C5).
3.2.7. 5-Phenyl-3-(methylsulfinyl)methylisoxazoline 15a,b
5-Phenyl-3-methylisoxazoline 4a,b (1.51 g, 9.4 mmol) was treated with (S)-methylsulfinate of
DAG, 6 (1.50 g, 4.7 mmol) and LTMP (14 mmol) at −95°C, as in previous experiments. The
work-up led to a mixture containing compounds 15a and 15b in a 52:48 ratio (estimated by
1
integration of the signals corresponding to H-C4 in the H NMR spectrum of the crude
reaction). Column chromatography using diethyl ether:hexane (4:1) as the eluent afforded a
mixture of diastereoisomers 15a and 15b (335 mg, 1.50 mmol, 32%), which were separated by
successive chromatographies (diethyl ether:hexane, 1:1) to yield pure 15a and pure 15b as yellow
syrups.
3.2.7.1. 5-Phenyl-3-(methylsulfinyl)methylisoxazoline 15a. Rf=0.32 (isopropanol:diethyl ether,
1:3); [h]2D0=−227.8 (c 1.00, CHCl3); H NMR l 2.66 (s, 3H, CH3-SO-), 3.26 (dd, 1H, Jtrans 8.6,
1

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J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
Jgem 17.8, H-C4), 3.53 (dd, 1H, Jcis 11.1, Jgem 17.8, H-C4), 3.63 (d, 1H, Jgem 13.5, SO-CH2-CCN),
3.92 (d, 1H, Jgem 13.5, SO-CH2-CCN), 5.68 (dd, 1H, Jtrans 8.6, Jcis 11.1, H-C5) and 7.32–7.40 (m,
5H, H-arom.); 13C NMR l 38.4 (CH3-SO-), 45.4 (C4), 50.8 (SO-CH2-CCN), 82.8 (C5), 125.8,
128.4 and 128.8 (CH-arom.), 140.0 (C-arom.) and 150.7 (C3); IR (KBr, liquid film): 3050, 3025,
2975, 2950, 1610, 1475, 1460, 1430, 1410, 1335, 1305, 1210, 1030, 910, 760 and 700 cm−1; MS
(m/e) (ei): 223 (M+, 23), 206 (4), 175 (2), 160 (78), 142 (16), 129 (72), 115 (100), 91 (24), 77 (38)
and 51 (23). Anal. calcd for C11H13NO2S: C, 59.17; H, 5.87; N, 6.27. Found: C, 59.52; H, 6.06;
N, 6.31.
3.2.7.2. 5-Phenyl-3-(methylsulfinyl)methylisoxazoline 15b. Rf=0.27 (isopropanol:diethyl ether,
1:3); [h]2D0=+229.0 (c 1.00, CHCl3); H NMR l 2.68 (s, 3H, CH3-SO-), 3.07 (dd, 1H, Jtrans 8.4,
1
Jgem 17.4, H-C4), 3.63 (d, 1H, Jgem 13.5, SO-CH2-CCN), 3.66 (dd, 1H, Jcis 11.0, Jgem 17.4, H-C4),
3.91 (d, 1H, Jgem 13.5, SO-CH2-CCN), 5.68 (dd, 1H, Jtrans 8.4, Jcis 11.0, H-C5) and 7.27–7.41 (m,
5H, H-arom.); 13C NMR l 38.2 (CH3-SO-), 45.6 (C4), 50.4 (SO-CH2-CCN), 82.8 (C5), 125.7,
128.4 and 128.8 (CH-arom.), 140.0 (C-arom.) and 150.6 (C3); IR (KBr, liquid film): 3050, 3025,
2975, 2925, 1610, 1475, 1460, 1430, 1415, 1340, 1305, 1210, 1115, 1080, 1030, 905, 760, 735 and
700 cm−1; MS (m/e) (ei): 223 (M+, 18), 160 (57), 142 (16), 129 (72), 115 (160), 91 (26), 77 (40)
and 51 (33). Anal. calcd for C11H13NO2S: C, 59.17; H, 5.87; N, 6.27. Found: C, 59.52; H, 6.06;
N, 6.23.
3.3. Addition of 4,5-diphenyl-3-(methylsulfinyl)methylisoxazoline 12a to 2,3-O-isopropylidene-
D
-glyceraldehyde 17
To a stirred solution of compound 12a (1 g, 3.34 mmol) in THF (70 ml) cooled at −90°C,
LDA (5 mmol) as a solution in THF was added dropwise. After two hours at −90°C, freshly
distilled aldehyde 17 (1.3 g, 10.03 mmol) was added at once and the reaction mixture was stirred
for an additional hour, then quenched by addition of a saturated aqueous ammonium chloride
solution and warmed to room temperature. The organic layer was separated and the aqueous
phase extracted twice with dichloromethane; the combined organic layers were dried and
concentrated under reduced pressure. The work-up led to a mixture containing compounds 18,
19 and 20 in a 12:4:84 ratio (estimated by integration of the signals corresponding to H-C5 in
the 1H NMR spectrum of the crude reaction). Column chromatography using diethyl
ether:hexane (1:1) as the eluent afforded a fraction (145 mg, 20% yield) containing a mixture of
compounds 18 and 19, and pure 20 (664 mg, 48% yield) as a white solid. After subsequent flash
chromatography (diethyl ether:hexane, 1:2) pure 18 and pure 19 were obtained as clear syrups.
3.3.1. (4R,5R)-Diphenyl-3-(2%-hydroxy-(3%R)-4%-isopropylidendioxy-1%-(SS)-methylsulfinyl)-
butylisoxazoline 18
Rf=0.20 (diethyl ether:hexane, 10:1); [h]2D0=−301.3 (c 0.31, CHCl3); H NMR l 1.10 and 1.24
1
(2s, each 3H, C(CH3)2), 2.63 (s, 3H, CH3-SO-), 3.30 (d, 1H, J2%,OH 2.1, HO-C2%, exchanges with
D2O), 3.67 (dd, 1H, Jgem 8.6, J4%,3% 5.7, H-C4%), 3.81 (dd, 1H, Jgem 8.6, J4%,3% 3.7, H%-C4%), 4.01–4.07
(m, 3H, H-C1%, H-C2% and H-C3%), 4.76 (d, 1H, J4,5 6.4, H-C4), 5.66 (d, 1H, J5,4 6.4, H-C5) and
7.29–7.45 (m, 10H, H-arom.); 13C NMR l 24.9 and 26.6 (C(CH3)2), 36.2 (CH3-SO-), 58.8 (C2%),
65.7 (C4), 66.0 (C4%), 71.8 (C3%), 75.1 (C1%), 90.3 (C5), 109.7 (C(CH3)2), 125.7, 128.2, 128.4,

J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
4801
128.6, 129.0 and 129.6 (CH-arom.), 137.4 (Carom-C4), 139.6 (Carom-C5) and 156.6 (C3); IR
(KBr, liquid film): 3250, 3010, 2950, 2900, 1610, 1495, 1460, 1380, 1375, 1245, 1220, 1070,
1020, 905 and 705 cm−1; MS (m/z) (ei) (relative intensity): 431 (1, M++2), 430 (3, M++1), 429
(12, M+), 414 (3, M+−15), 366 (11, M+−CH3SO), 351 (9, M+−(CH3SO+CH3)), 266 (100,
C17H16NO+2), 101 (84, C5H9O2+), 43 (77, C2H3O+). Anal. calcd for C23H27O5NS: C, 64.32; H,
6.34, N, 3.26. Found: C, 64.25; H, 6.33; N, 3.31.
3.3.2. (4R,5R)-Diphenyl-3-(2%-hydroxy-(3%R),4%-isopropylidendioxy-1%-(SS)-methylsulfinyl)-
butylisoxazoline 19
Rf=0.12 (diethyl ether:hexane, 10:1); [h]2D0=+164.0 (c 0.45, CHCl3); H NMR l 1.19 and
1
1.32 (2s, each 3H, C(CH3)2), 2.83 (s, 3H, CH3-SO-), 3.54 (d, 1H, J1%,2% 8.4, H-C1%), 3.89–3.94
(m, 1H, H-C3%), 3.94 (dd, 1H, Jgem 7.9, J4%,3% 2.5, H-C4%), 4.04 (dd, 1H, Jgem 7.9, J4%,3% 2.8,
H-C4%), 4.22 (ddd, 1H, J2%,1% 8.4, J2%OH 2.9, J2%,3% 6.8, H-C2%, collapses to dd on exchange with
D2O, J2%,1% 8.4, J2%,3% 6.8), 4.46 (d, 1H, J2%,OH 2.9, HO-C2%, exchanges with D2O), 4.74 (d, 1H,
J4,5 7.5, H-C4), 5.60 (d, 1H, J5,4 7.5, H-C5) and 7.28–7.49 (m, 10H, H-arom.); 13C NMR l
25.3 and 26.4 (C(CH3)2), 35.3 (CH3-SO-), 57.9 (C2%), 64.6 (C4), 66.1 (C4%), 72.4 (C3%), 77.2
(C1%), 91.0 (C5), 110.0 (C(CH3)2), 125.5, 128.2, 128.4, 128.8 and 129.8 (CH-arom.), 137.2
(Carom.-C4), 139.6 (Carom.-C5) and 153.7 (C3); IR (KBr, liquid film): 3300, 3010, 2950,
2900, 1605, 1495, 1460, 1385, 1375, 1260, 1220, 1070, 1030 and 705 cm−1; MS (m/z) (ei)
(relative intensity): 430 (1, M++1), 429 (3, M+), 414 (2, M+−15), 366 (7, M+−CH3SO), 351 (4,
M+−(CH3SO+CH3)), 299 (11, C17H17NO2S+), 266 (90, C17H16NO+2), 101 (100, C5H9O+2), 43
(76, C2H3O+). Anal. calcd for C23H27O5NS: C, 64.32; H, 6.34, N, 3.26. Found: C, 64.37; H,
6.40; N, 3.29.
3.3.3. (4R,5R)-Diphenyl-3-(2%R)-hydroxy-(3%R),4%-isopropylidendioxy-(1%S)-methyl-(SS)-
sulfinyl)butylisoxazoline 20
A white solid was recrystallized from isopropanol–diethyl ether to give crystals and its
structure was determined by X-ray diffraction: mp 137.5–138.5°C. Rf=0.31 (ethyl ace-
1
tate:diethyl ether, 1:1.5); [h]2D0=−228.3 (c 1.00, CHCl3); H NMR l 1.20 and 1.32 (2s, each
3H, C(CH3)2), 2.62 (s, 3H, CH3-SO-), 3.62 (d, 1H, J2%,OH 8.7, HO-C2%, exchanges with D2O),
3.80 (d, 1H, J1%,2% 2.3, H-C1%), 3.75–3.82 (m, 1H, H-C3%), 3.93 (dd, 1H, Jgem 8.7, J4%,3% 5.1,
H-C4%), 4.06 (dd, 1H, Jgem 8.7, J4%,3% 6.2, H-C4%), 4.40 (ddd, 1H, J2%,1% 2.3, J2%OH 8.7, J2%,3% 8.8,
H-C2%, collapses to dd on exchange with D2O, J2%,1% 2.3, J2%,3% 8.8), 4.36 (d, 1H, J4,5 6.2,
H-C4), 5.64 (d, 1H, J5,4 6.2, H-C5) and 7.24–7.46 (m, 10H, H-arom.); 13C NMR l 25.0 and
26.7 (C(CH3)2)), 35.5 (CH3-SO-), 57.4 (C2%), 66.2 (C4), 67.6 (C4%), 69.0 (C3%), 76.1 (C1%), 89.6
(C5), 109.9 (C(CH3)2), 125.2, 128.0, 128.5, 128.8, 128.9 and 129.5 (CH-arom.), 136.3
(Carom.-C4), 139.8 (Carom.-C5) and 154.4 (C3); IR (KBr, liquid film): 3150, 3050, 3010,
2950, 2900, 1605, 1495, 1460, 1385, 1370, 1295, 1215, 1060, 1025, 915, 860 and 705 cm−1; MS
(m/z) (ci) (relative intensity): 328 (2), 300 (12), 197 (5), 180 (6), 147 (2), 131 (66) 107 (100).
Anal. calcd for C23H27NO5S: C, 64.32; H, 6.34, N, 3.26. Found: C, 64.02; H, 6.31; N, 3.13.
Acknowledgements
We thank JCYL (VA07/00B) for financial support.

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J. A. Lo´pez-Sastre et al. / Tetrahedron: Asymmetry 11 (2000) 4791–4803
4803
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Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp. 1–176.
18. (a) Coss´ıo, F. P.; Morao, I.; Jiao, H.; Schleyer, P. v. R. J. Am. Chem. Soc. 1999, 121, 6737–6746; (b) Morao, I.;
Coss´ıo, P. J. Org. Chem. 1999, 64, 1868–1874.
19. (a) Chere´st, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199; (b) Anh, N. T.; Eisenstein, O. Tetrahedron
Lett. 1976, 155.
20. Curran, D. P.; Chao, J.-Ch. Tetrahedron 1990, 46, 1325–1339.
21. Crystal structure analysis of 20 (C23H27NO5S): monoclinic, space group P2; a=16.803(1), b=9.847(1), c=
3
13.570(1) A; V=2233.5(7) A ; Z=4, formula weight 429.52; zcalcd=1.277 Mg m−3. Crystal size: 0.25×0.09×0.3
,
,
3
,
mm . Theta range: 3 to 60°. v(Mo Ka)=0.71073 A. T=293 K. Reflections collected: 3958. Independent
reflections: 3848 (Rint=0.0341). Refinement method full-matrix least-squares on F2. Goodness-of-fit on F2=1.32.
Final R indices [I>2|(I)]: R1=0.0481, wR2=0.0569. R indices (all data) R1=0.0960, wR2=0.0719. Largest
−3
,
difference peak and hole: 0.78 and −0.45 e A
.
22. Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.;
Vianco, C. S. J. Org. Chem. 1991, 56, 4056.
23. Tre`court, F.; Mallet, M.; Marsais, G.; Que´guiner, G. J. Org. Chem. 1988, 53, 1370.
24. Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron 1986, 42, 2129–2134.
.