Syntheses of new chiral bicyclic sultams and their use as auxiliaries in asymmetric conjugate addition of Grignard reagents

Article abstract of DOI:10.1016/S0957-4166(02)00465-2

Starting from L-aminoacids, 5-N-unsubstituted isothiazolo[4,5-c]isoxazole 4,4-dioxides have been synthesized and used as chiral auxiliaries in asymmetric conjugated additions of Grignard reagents to α,β-unsaturated carboxylic acids.

Full text of DOI:10.1016/S0957-4166(02)00465-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1915–1921
Syntheses of new chiral bicyclic sultams and their use as
auxiliaries in asymmetric conjugate addition of Grignard
reagents
Ugo Chiacchio,a,* Antonino Corsaro,a Giovanni Gambera,a Antonio Rescifina,a Anna Piperno,b
Roberto Romeob and Giovanni Romeob,*
aDipartimento di Scienze Chimiche, Universita` di Catania, Viale Andrea Doria 6, Catania 95125, Italy
bDipartimento Farmaco-Chimico, Universita` di Messina, Viale SS. Annunziata, Messina 98168, Italy
Received 24 July 2002; accepted 6 August 2002
Abstract—Starting from L-aminoacids, 5-N-unsubstituted isothiazolo[4,5-c]isoxazole 4,4-dioxides have been synthesized and used
as chiral auxiliaries in asymmetric conjugated additions of Grignard reagents to a,b-unsaturated carboxylic acids. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Recently,6 we reported syntheses of enantiomerically
pure functionalized isothiazolo[4,5-c]isoxazole 4,4-diox-
ides 2 by intramolecular 1,3-dipolar cycloadditions of
suitably substituted a- and b-sulfonamidonitrones
The induction of chirality through the use of chiral
auxiliaries is a useful synthetic tool for the asymmetric
synthesis of a wide variety of organic compounds.1 The
development of new chiral agents continues to repre-
sent a challenging topic which interests many research
groups.2 Intensive investigations in this area have cul-
minated in the evolution of several versatile chiral
auxiliaries of wide applicability. Representative exam-
ples are Oppolzer’s N-enoyl sultams, accessible from
(+)- and (−)-camphorsulfonic acids, and Evans’ a,b-
unsaturated N-acyl oxazolidinones.3 These compounds
have been successfully exploited for asymmetric Diels–
Alder reactions, alkylations, acylations, aldolizations,
and 1,3-dipolar cycloaddition reactions.4
obtained from -aminoacids 1 (Scheme 1).
L
Herein, we report the use of sultams 2 as chiral auxil-
iaries. Thus, we have prepared compounds 8a and 8b
and have studied their use in asymmetric conjugate
Grignard additions.
2. Results and discussion
The synthetic approach was achieved in four simple
steps as shown in Scheme 2: the reaction of L-alanine
3a and -phenylalanine 3b with LiAlH4 afforded amino
L
Minor variations in the structure of an auxiliary may
exert great influence on the effectiveness of the asym-
alcohols 4a and 4b, respectively, which have been
metric induction in
a
chemical transformation.5
Although natural products are convenient sources of
chiral auxiliaries, their effectiveness is relatively difficult
to optimize via systematic structural modifications. In
contrast, chiral auxiliaries based on rational chemical
design provide greater flexibility for improvement
through structural variations.
Scheme 1. Synthesis of functionalized isothiazolo[4,5-c]-
* Corresponding author. Tel.: +39 095 738 50 14; fax: +39 095 58 01
38; e-mail: uchiacchio@dipchi.unict.it
isoxazole 4,4-dioxides.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00465-2

1916
U. Chiacchio et al. / Tetrahedron: Asymmetry 13 (2002) 1915–1921
reacted with trans 2-phenylethenesulfonyl chloride to
give N-(1-alkyl-2-hydroxyethylene)sulfonamides 5a and
5b. Dess–Martin oxidation7 and treatment of the result-
ing aldehydes 6a,b with N-substituted hydroxylamines
furnished the nitrones 7a,b, which spontaneously
underwent intramolecular cycloaddition to give the
stereoisomeric bicyclo compounds 8a, 9a and 8b, 9b,
respectively (overall yields 57–63%; ratios 8a/9a 18:1
confirmed by coupling constants and NOE measure-
ments. Thus the coupling constant for the ring junction
protons (J3a,6a) is 7.6 and 7.9 Hz, respectively, indicative
of a nearly eclipsed dihedral angle between them. Fur-
thermore, irradiation of H3a gives rise to a positive
NOE effect for H6a (9.4%), for aromatic protons at C3
(3.5%) and for methyl or benzylic protons at C6, thus
indicating a cis relationship between these protons. By
considering that the C6 configuration is S, the data are
1
and 8b/9b 10:1) (Scheme 2), as determined by H NMR
analysis of the crude reaction mixtures. The major
compounds 8a,b were isolated enantiomerically pure
after flash chromatography.
only compatible with
chemistry.
a
(3S,3aR,6S,6aS) stereo-
The efficiency of sultams 8a,b as chiral auxiliaries was
assessed in an asymmetric conjugated addition of a
Grignard reagent. Stereoselective 1,4-additions of
organometallic nucleophiles to conjugate carbonyl
derivatives are among the most reliable approaches to
enantiomerically pure b-substituted carbonyl com-
pounds.
N-Acylation of 8a,b by successive treatment with
sodium hydride and the corresponding acyl chlorides
gave N-crotonyl- 10A,C and N-cinnamoyl sultams
10B,D in 83–88% yields, respectively. Conjugate addi-
tions of ethyl magnesium chloride proceeded smoothly
at −80°C to give with a very high stereoselectivity, after
quenching with aqueous ammonium chloride, imides 11
in good yields (81–95%) (Scheme 3, Table 1). Only
1
traces of 12 were detected in the H NMR spectra of
the crude reaction mixtures. With methyl magnesium
chloride only products originated from 1,2-addition
reaction were observed.
Scheme 2. Reagents and conditions: (1) LiAlH4; (2) (E)-2-
phenylethylenesulfonyl chloride, Et3N, CH2Cl2, 0–25°C, 16 h;
(3) Dess–Martin periodinane, CH2Cl2, 0.5 h; (4) N-methylhy-
droxylamine hydrochloride, Et3N, EtOH, reflux, 24 h.
The investigated 1,3-dipolar cycloadditions showed a
high regioselectivity; in agreement with similar
intramolecular processes, no bridged adducts were
detected in the crude reaction mixture.8
The reaction was also found to proceed with a good
level of diastereofacial selectivity. The stereogenic cen-
ter of compounds 6 provides a satisfactory asymmetric
induction and controls the formation of new three
contiguous stereocenters: one of the six possible
stereoisomers is formed nearly exclusively.
1
The H NMR spectra of compounds 8 recorded in the
Scheme 3. Reagents and conditions: (1) NaH, acyl chloride,
toluene, 20 h; (2) EtMgCl, THF, −80°C, 2.5 h; (3) 5%
NaOH/H2O, 50°C, 16 h.
presence of increasing amounts of the chiral shift
reagent [Eu(tfc)3], do not show any splitting of reso-
nances in agreement of the assumption that chiral
integrity is maintained throughout the sequence of syn-
thetic steps.
The extent of diastereofacial differentiation was deter-
mined by 1H NMR analyses of the crude reaction
mixtures (Table 1).
The stereochemistry of the cycloadducts 8 was eluci-
dated by 1H NMR. The stereochemical information
present in the dipolarophile moiety is completely
retained in the cycloadducts and the relative stereo-
chemistry at C3 and C3a in the formed isoxazolidine
ring is predetermined by the alkene geometry. The ring
junction between the two fused ring is always cis, as
Compounds 11 were purified by flash chromatography
and fully characterized.
Hydrolysis with NaOH (2.5% in THF/H2O), followed
by acidification, afforded the enantiomerically pure

U. Chiacchio et al. / Tetrahedron: Asymmetry 13 (2002) 1915–1921
1917
Table 1. Grignard reaction and hydrolysis for compounds 10 versus Oppolzer’s sultam crotonyl derivative
Enoyl sultam
Yield (%)a
11:12 relative ratiob
Yield of 13 (%)c
Overall yield of 13 (%)
Oppolzerd
10A
10B
10C
10D
80d
81
80
95
82
94.5:5.5d
92:8
91:9
99:1
98:2
56d
85
83
82
88
44.8d
68.8
66.4
77.9
72.1
a Referred to Grignard reaction and relative to compounds 11.
b Measured by integration of the corresponding signals in the 1H NMR spectra.
c Referred to hydrolysis of compounds 11.
d See Ref. 9.
(3R)-3-methylvaleric and (3R)-3-phenylvaleric acids 13:
their absolute configuration was unambiguously deter-
mined to be R by comparison of the specific rotations
with those reported in the literature.10 Chiral auxiliaries
8 were recovered in 85–88% yield.
4. Experimental
Melting points are uncorrected. NMR spectra were
recorded at 500 MHz (1H) and at 125 MHz (13C) and
are reported in ppm downfield from TMS. The NOE
difference spectra were obtained by subtracting alterna-
tively right-off-resonance-free induction decays (FIDS)
from right-on-resonance-induced FIDS. All reactions
involving air-sensitive agents were conducted under
nitrogen atmosphere. All reagents were purchased from
commercial suppliers and were used without further
purification. The solvents for chromatography were
distilled at atmospheric pressure prior to use and were
dried using standard procedures. The HPLC purifica-
tions were made with a semipreparative column (Par-
tisil-10 Magnum 9, 9.4×250 mm). The purity of all
homochiral compounds was tested with a Nucleosil
Chiral-2, 4×250 mm column with mixtures of n-hex-
ane–2-propanol as an eluent.
The obtained results appear to be somewhat different
from Oppolzer’s systems.9 The control of diastereose-
lectivity, observed with these auxiliaries, is improved on
going from compounds 11A,B to compounds 11C,D,
where the diastereoselectivity is nearly complete. With
respect to analogous reactions performed with the
Oppolzer’s sultam as chiral auxiliary, which use 2.5 mol
equiv. of alkylmagnesium chloride, in our case the
reaction proceeds with only 1 equiv. of Grignard, as
experimentally
ascertained,
showing
a
better
diastereoselectivity and clearly better overall yields.
The facial stereoselectivity in the formation of 11 can
be explained by the transition state topology, presented
in Fig. 1, with anti-disposed SO2/CꢀO groups, and
CꢀO/CaꢀCb in s-cis conformation. This topology, in
accord with data reported in literature for similar sys-
tems,11 is also supported by ab initio calculations. In
this conformation, complexation of the carbonyl group
with the Grignard reagent brings the alkyl group close
to the double bond and favors attack from the bottom
face (Si face) opposite to the alkyl substituent at C6,
leading to the (R)-isomer via a six-membered cyclic
transition state.
The alternative coordination between the carbonyl
group and the Grignard reagent occurring from the top
face (Re face), and leading to (S)-isomer, is clearly
unfavored by the steric interaction with the substituent
at C6, which also accounts for the improved
diastereoselectivity observed on going from 11A,B to
11C,D.
3. Conclusions
In summary, we have developed a new class of highly
efficient chiral auxiliaries. A mechanism of their action
has been suggested. Applications to enantioselective
Diels–Alder and 1,3-dipolar cycloaddition reactions are
under investigation.
Figure 1. Transition state for Grignard addition to com-
pound 11A.

1918
U. Chiacchio et al. / Tetrahedron: Asymmetry 13 (2002) 1915–1921
2-Aminopropan-1-ol12 and 2-amino-3-phenylpropan-1-
ol13 were prepared by LiAlH4 reduction of the corre-
sponding amino acid, according to literature reports.
the organic layer was washed with H2O and brine. The
combined organic layers were dried (Na2SO4) and the
solvent removed under reduced pressure. The residue
was then subjected to silica-gel flash chromatography
(1% methanol/chloroform).
4.1. General procedure for synthesis of sulfonamido-
alcohols 5
4.2.1.
(E)-(+)-N-[(1S)-1-Methyl-2-oxoethyl]-2-phenyl-
A solution of (E)-2-phenylethylenesulfonyl chloride
(11.14 g, 55 mmol) in anhydrous dichloromethane (50
mL) was added dropwise, at 0°C, to a stirred solution
containing compounds 4 (50 mmol) and triethylamine
(5.44 g, 7.5 mL, 53.8 mmol). The reaction mixture was
stirred at 0°C for 30 min and then at 25°C for 16 h. At
the end of this time, the mixture was extracted with
dichloromethane, washed with 10% aqueous NaHCO3
and dried (Na2SO4). The solvent was removed and the
crude residue was purified by silica-gel flash chromatog-
raphy (40% ethyl acetate/cyclohexane).
ethylenesulfonamide 6a. Yield: 3.82 g, 85%; yellow oil;
[h]2D5=+15.3 (c 0.71, CHCl3); 1H NMR (CDCl3, 500
MHz): l 1.34 (d, J=7.5 Hz, 3H, CH3), 3.93 (dq, J=6.5
and 7.5 Hz, 1H, N-CH), 5.46 (d, J=6.5 Hz, 1H, NH),
6.72 (d, J=15.5 Hz, 1H, CHꢀ), 7.29–7.45 (m, 6H,
aromatic protons and CHꢀ), 9.48 (s, 1H, CHO); 13C
NMR (CDCl3, 125 MHz): l 13.7, 61.3, 115.7, 126.2,
127.7, 128.5, 134.5, 136.9, 200.8. Anal. calcd for
C11H13NO3S: C, 55.21; H, 5.48; N, 5.85; S, 13.40.
Found: C, 55.37; H, 5.46; N, 5.83; S, 13.44%. HRMS
calcd for C11H13NO3S: 239.0616. Found: 239.0614.
4.1.1.
(E)-(−)-N-[(1S)-2-Hydroxy-1-methylethyl]-2-
phenylethylenesulfonamide 5a. Yield: 10.98 g, 91%; light
yellow oil; [h]D25=−2.7 (c 0.74, CHCl3); 1H NMR
(CDCl3, 500 MHz): l 1.13 (d, J=6.5 Hz, 3H, CH3),
3.43 (m, 3H, CH6 2OH and OH), 3.61 (m, 1H), 5.18 (bs,
4.2.2.
(E)-(−)-N-[(1S)-1-Benzyl-2-oxoethyl]-2-phenyl-
ethylenesulfonamide 6b. Yield: 5.21 g, 88%; yellow oil;
[h]2D5=−19.7 (c 0.92, CHCl3); 1H NMR (CDCl3, 500
MHz): l 2.92 (dd, J=7.9 and 14.2 Hz, 1H, CHPh),
3.13 (dd, J=6.0 and 14.2 Hz, 1H, CHPh), 4.11 (ddd,
J=6.0, 7.1 and 7.9 Hz, 1H, N-CH), 5.32 (d, J=7.1 Hz,
1H, NH), 6.29 (d, J=15.4 Hz, 1H, CHꢀ), 7.06–7.35 (m,
10H, aromatic protons), 7.30 (d, J=15.4 Hz, 1H,
CHꢀ), 9.60 (s, 1H, CHO); 13C NMR (CDCl3, 125
MHz): l 36.1, 62.9, 124.6, 127.4, 128.4, 128.8, 128.9,
129.4, 130.9, 132.2, 134.9, 141.8, 198.9. Anal. calcd for
C17H17NO3S: C, 64.74; H, 5.43; N, 4.44; S, 10.17.
Found: C, 64.56; H, 5.45; N, 4.43; S, 10.15%. HRMS
calcd for C17H17NO3S: 315.0929. Found: 315.0927.
1H, NH), 6.78 (d, J=15.5 Hz, 1H, CHꢀ), 7.19–7.41 (m,
5H), 7.42 (d, J=15.5 Hz, 1H, CHꢀ); 13C NMR (CDCl3,
125 MHz): l 18.1, 51.5, 66.2, 125.7, 128.2, 129.0, 130.7,
132.5, 141.2. Anal. calcd for C11H15NO3S: C, 54.75; H,
6.27; N, 5.80; S, 13.29. Found: C, 54.88; H, 6.25; N,
5.83; S, 13.24%. HRMS calcd for C11H15NO3S:
241.0773. Found: 241.0771.
4.1.2.
(E)-(+)-N-[(1S)-1-Benzyl-2-hydroxyethyl]-2-
phenylethylenesulfonamide 5b. Yield: 14.76 g, 93%;
white solid; mp 68–70°C; [h]2D5=+4.1 (c 0.98, CHCl3);
1H NMR (CDCl3, 500 MHz): l 2.57 (bs, 1H, OH), 2.77
(dd, J=8.5 and 13.6 Hz, 1H, CHPh), 2.92 (dd, J=5.9
and 13.6 Hz, 1H, CHPh), 3.56 (ddddd, J=4.0, 5.0, 5.9,
7.7 and 8.5 Hz, 1H, N-CH), 3.64 (dd, J=5.0 and 11.0
4.3. General procedure for synthesis of sultams 8
A mixture containing compound 6 (50 mmol), triethyl-
amine (5.56 g, 7.66 mL, 55 mmol) and N-methylhy-
droxylamine hydrochloride (55 mmol) in absolute etha-
nol (50 mL) was refluxed for 24 h. At the end of this
time the solvent was removed and the residue extracted
with dichloromethane, washed with water and dried
(Na2SO4). The residue was then subjected to silica-gel
flash chromatography (25% ethyl acetate/cyclohexane)
to give pure 8.
Hz, 1H, CH
6 OH), 3.79 (dd, J=4.0 and 11.0 Hz, 1H,
CHOH), 5.00 (d, J=7.7 Hz, 1H, NH), 6.12 (d, J=15.3
6
Hz, 1H, CHꢀ), 7.12–7.44 (m, 11H, aromatic protons
and CHꢀ); 13C NMR (CDCl3, 125 MHz): l 38.1, 57.3,
65.0, 124.8, 126.9, 128.4, 128.6, 128.8, 129.4, 130.7,
132.4, 137.1, 141.2. Anal. calcd for C17H19NO3S: C,
64.33; H, 6.03; N, 4.41; S, 10.10. Found: C, 64.11; H,
6.01; N, 4.42; S, 10.13%. HRMS calcd for C17H19NO3S:
317.1086. Found: 317.1087.
4.2. General procedure for synthesis of sulfonamido-
aldehydes 6
4.3.1. (+)-(3S,3aR,6S,6aS)-1,6-Dimethyl-3-phenylhexa-
hydroisothiazolo[4,5-c]isoxazole 4,4-dioxide 8a. Yield:
10.46 g, 78%; white solid; mp 142–144°C; [h]2D5=+12.4
1
Wet CH2Cl2 (20 mL; 20 mL H2O in 20 mL CH2Cl2) was
added slowly to a vigorously stirred solution of sulfon-
amido alcohol 5 (18.8 mmol) and DMP7 (12.00 g, 28.3
mmol) in CH2Cl2 (230 mL) and allowed to stir for 30
min. The mixture was then diluted with ether, and
concentrated into a few mL of solvent by rotary evapo-
ration. The residue was taken up in ether (400 mL) and
then washed with a 1:1 solution of 10% aqueous
Na2S2O3 in saturated aqueous NaHCO3 (200 mL), fol-
lowed by H2O (80 mL) and brine (80 mL). The aqueous
washings were back-extracted with ether (160 mL), and
(c 0.81, CHCl3); H NMR (CDCl3, 500 MHz): l 1.37
(d, J=7.3 Hz, 3H, CH3), 2.74 (s, 3H, N-CH3), 3.38 (dq,
J=6.5 and 7.3 Hz, 1H, H6), 3.45 (d, J=7.6 Hz, 1H,
H6a), 3.92 (dd, J=6.9 and 7.6 Hz, 1H, H3a), 5.15 (d,
J=6.5 Hz, 1H, NH), 5.34 (d, J=6.9 Hz, 1H, H3),
7.25–7.36 (m, 5H, aromatic protons); 13C NMR
(CDCl3, 125 MHz): l 19.3, 43.1, 52.2, 71.9, 81.3, 82.3,
126.4, 128.8, 128.8, 136.6. Anal. calcd for
C12H16N2O3S: C, 53.71; H, 6.01; N, 10.44; S, 11.95.
Found: C, 53.95; H, 6.02; N, 10.47; S, 11.97%. HRMS
calcd for C12H16N2O3S: 268.0881. Found: 268.0876.

U. Chiacchio et al. / Tetrahedron: Asymmetry 13 (2002) 1915–1921
1919
4.3.2. (+)-(3S,3aR,6S,6aS)-6-Benzyl-1-methyl-3-phenyl-
hexahydroisothiazolo[4,5-c]isoxazole 4,4-dioxide 8b.
Yield: 13.95 g, 81%; white solid; mp 171–174°C; [h]2D5=
N, 7.03; S, 8.05. Found: C, 63.41; H, 5.54; N, 7.01; S,
8.07%. HRMS calcd for C21H22N2O4S: 398.1300.
Found: 398.1305.
1
+25.9 (c 0.81, CHCl3); H NMR (CDCl3, 500 MHz): l
2.46 (s, 3H, N-CH3), 2.80 (dd, J=7.9 and 13.8 Hz, 1H,
H6%a), 3.05 (dd, J=8.4 and 13.8 Hz, 1H, H6%b), 3.37
(ddd, J=5.8, 7.9 and 8.4 Hz, 1H, H6), 3.49 (d, J=7.9
Hz, 1H, H6a), 3.94 (dd, J=7.0 and 7.9 Hz, 1H, H3a),
5.31 (d, J=7.0 Hz, 1H, H3), 5.50 (d, J=5.8 Hz, 1H,
NH), 7.10–7.40 (m, 10H, aromatic protons); 13C NMR
(CDCl3, 125 MHz): l 39.1, 42.6, 58.1, 71.5, 79.0, 81.3,
126.4, 126.5, 127.1, 128.7, 128.8, 129.4, 136.4, 136.8.
Anal. calcd for C18H20N2O3S: C, 62.77; H, 5.85; N,
8.13; S, 9.31. Found: C, 62.88; H, 5.83; N, 8.12; S,
9.29%. HRMS calcd for C18H20N2O3S: 344.1195.
Found: 344.1191.
4.4.3.
(+)-(3S,3aR,6S,6aS)-6-Benzyl-5-[(2E)-but-2-
enoyl] - 1 - methyl - 3 - phenylhexahydroisothiazolo[4,5 - c]-
isoxazole 4,4-dioxide 10C. Yield: 1.27 g, 83%; white
1
solid; mp 137–142°C; [h]2D5=+17.7 (c 0.56, CHCl3); H
NMR (CDCl3, 500 MHz): l 1.99 (dd, J=1.5 and 6.8
Hz, 3H, CH3), 2.38 (s, 3H, N-CH3), 2.84 (dd, J=11.4
and 13.5 Hz, 1H, H6%a), 3.33 (dd, J=4.2 and 13.5 Hz,
1H, H6%b), 3.37 (d, J=8.4 Hz, 1H, H6a), 4.19 (dd, J=6.4
and 8.4 Hz, 1H, H3a), 4.58 (dd, J=4.4 and 11.2 Hz, 1H,
H6), 5.51 (d, J=6.4 Hz, 1H, H3), 6.74 (dq, J=1.5 and
14.9 Hz, 1H, CHꢀ), 7.18 (dq, J=6.8 and 14.9 Hz, 1H,
CHꢀ), 7.28–7.42 (m, 10H, aromatic protons); 13C NMR
(CDCl3, 125 MHz): l 18.5, 38.0, 41.8, 57.7, 70.2, 73.7,
81.2, 121.9, 126.5, 127.4, 128.9, 129.1, 129.1, 129.4,
135.8, 135.9, 147.1, 162.9. Anal. calcd for
C22H24N2O4S: C, 64.06; H, 5.86; N, 6.79; S, 7.77.
Found: C, 64.15; H, 5.87; N, 6.78; S, 7.75%. HRMS
calcd for C22H24N2O4S: 412.1457. Found: 412.1459.
4.4. General procedure for synthesis of sulfonamides 10
To a vigorously stirred suspension of 95% sodium
hydride (141 mg, 5.59 mmol) in anhydrous toluene (35
mL), a suspension of sultam 8 (3.72 mmol) in anhy-
drous toluene (35 mL) was added. After 2 h, a solution
of acyl chloride (4.47 mmol) in anhydrous toluene (35
mL) was added dropwise and the reaction mixture was
further stirred for 18 h. Then the reaction mixture was
quenched with water (30 mL); the separated organic
phase was extracted twice with water (30 mL), NaCl
saturated solution (25 mL), dried (Na2SO4) and the
residue was subjected to silica-gel flash chromatography
(20% ethyl acetate/cyclohexane).
4.4.4. (−)-(3S,3aR,6S,6aS)-6-Benzyl-1-methyl-3-phenyl-
5-[(2E)-3-phenylprop-2-enoyl]hexahydroisothiazolo[4,5-c]-
isoxazole 4,4-dioxide 10D. Yield: 1.50 g, 85%; white
1
solid; mp 167–170°C; [h]2D5=−33.5 (c 0.87, CHCl3); H
NMR (CDCl3, 200 MHz): l 2.39 (s, 3H, N-CH3), 2.88
(dd, J=11.2 and 13.3 Hz, 1H, H6%a), 3.38 (dd, J=4.4
and 13.3 Hz, 1H, H6%b), 3.42 (d, J=8.3 Hz, 1H, H6a),
4.24 (dd, J=6.5 and 8.3 Hz, 1H, H3a), 4.66 (dd, J=4.4
and 11.2 Hz, 1H, H6), 5.54 (d, J=6.5 Hz, 1H, H3),
7.22–7.63 (m, 16H, aromatic protons and CHꢀ), 7.87
(d, J=15.4 Hz, 1H, CHꢀ); 13C NMR (CHCl3, 50
MHz): l 37.9, 41.8, 57.9, 70.2, 73.5, 81.2, 116.8, 126.4,
127.4, 128.5, 128.9, 129.0, 129.3, 130.7, 134.1, 135.8,
146.3, 163.1. Anal. calcd for C27H26N2O4S: C, 68.33; H,
5.52; N, 5.90; S, 6.76. Found: C, 68.27; H, 5.54; N,
5.91; S, 6.74%. HRMS calcd for C27H26N2O4S:
474.1613. Found: 474.1610.
4.4.1.
(−)-(3S,3aR,6S,6aS)-5-[(2E)-But-2-enoyl]-1,6-
dimethyl - 3 - phenylhexahydroisothiazolo[4,5 - c]isoxazole
4,4-dioxide 10A. Yield: 1.10 g, 88%; white solid; mp
147–151°C; [h]D25=−23.2 (c 0.73, CHCl3); 1H NMR
(CDCl3, 500 MHz): l 1.46 (d, J=6.9 Hz, 3H, CH3),
1.94 (dd, J=1.7 and 7.0 Hz, 3H, CH3), 2.83 (s, 3H,
N-CH3), 3.30 (d, J=8.0 Hz, 1H, H6a), 4.18 (dd, J=6.0
and 8.0 Hz, 1H, H3a), 4.52 (q, J=6.9 Hz, 1H, H6), 5.55
(d, J=6.0 Hz, 1H, H3), 6.70 (dq, J=1.7 and 14.8 Hz,
1H, CHꢀ), 7.14 (dq, J=7.0 and 14.8 Hz, 1H, CHꢀ),
7.33–7.42 (m, 5H, aromatic protons); 13C NMR
(CDCl3, 125 MHz): l 18.43, 18.54, 42.76, 52.19, 73.93,
73.94, 81.06, 121.86, 126.46, 128.96, 129.08, 136.20,
146.89, 162.87. Anal. calcd for C16H20N2O4S: C, 57.12;
H, 5.99; N, 8.33; S, 9.53. Found: C, 57.25; H, 5.98; N,
8.32; S, 9.50%. HRMS calcd for C16H20N2O4S:
336.1144. Found: 336.1140.
4.5. General procedure for Grignard addition to sulfon-
amides 10
To a vigorously stirred solution of compound 10 (0.86
mmol) in dry THF (13 mL) at −80°C, 2N EtMgCl (445
mL, 0.86 mmol, in Et2O) was added dropwise. After 2.5
h the temperature was raised to −60°C and the reaction
mixture was quenched with NH4Cl saturated solution
(8.6 mL), and evaporated at reduced pressure. The
residue was extracted with dichloromethane (3×10 mL),
dried (Na2SO4) evaporated and subjected to silica-gel
flash chromatography (10% ethyl acetate/cyclohexane).
4.4.2.
(−)-(3S,3aR,6S,6aS)-1,6-Dimethyl-3-phenyl-5-
[(2E) - 3 - phenylprop - 2 - enoyl]hexahydroisothiazolo[4,5-
c]isoxazole 4,4-dioxide 10B. Yield: 1.26 g, 85%; white
1
solid; mp 153–155°C; [h]2D5=−37.8 (c 0.78, CHCl3); H
NMR (CDCl3, 200 MHz): l 1.35 (d, J=7.1 Hz, CH3),
2.77 (s, 3H, N-CH3), 3.26 (d, J=8.1 Hz, 1H, H6a), 4.15
(dd, J=5.8 and 8.1 Hz, 1H, H3a), 4.52 (q, J=7.1 Hz,
1H, H6), 5.51 (d, J=5.8 Hz, 1H, H3), 7.25 (d, J=15.4
Hz, 1H, CHꢀ), 7.27–7.53 (m, 10H, aromatic protons),
7.76 (d, J=15.4 Hz, 1H, CHꢀ); 13C NMR (CDCl3, 50
MHz): l 18.5, 42.7, 52.3, 73.8, 73.9, 81.1, 116.9, 126.4,
128.5, 128.8, 128.9, 129.0, 130.7, 134.1, 136.1, 146.2,
163.0. Anal. calcd for C21H22N2O4S: C, 63.30; H, 5.56;
4.5.1.
(−)-(3S,3aR,6S,6aS)-1,6-Dimethyl-5-[(3R)-3-
methylpentanoyl] - 3 - phenylhexahydroisothiazolo[4,5 - c]-
isoxazole 4,4-dioxide 11A. Yield: 255 mg, 81%; colorless
oil; [h]2D5=−11.5 (c 0.91, CHCl3); 1H NMR (CDCl3, 500
MHz): l 0.91 (t, J=7.3 Hz, 3H, CH3), 0.96 (d, J=6.7
Hz, 3H, CH3), 1.37 (m, 2H), 1.43 (d, J=6.9 Hz, 3H,
CH3), 2.05 (m, 1H), 2.75 (m, 2H), 2.82 (s, 3H, N-CH3),
3.28 (d, J=8.2 Hz, 1H, H6a), 4.18 (dd, J=5.8 and 8.2
Hz, 1H, H3a), 4.48 (q, J=6.9 Hz, 1H, H6), 5.55 (d,

1920
U. Chiacchio et al. / Tetrahedron: Asymmetry 13 (2002) 1915–1921
J=5.9 Hz, 1H, H3), 7.33–7.44 (m, 5H, aromatic pro-
tons); 13C NMR (CDCl3, 125 MHz): l 11.2, 18.3, 19.1,
29.2, 31.1, 42.3, 42.6, 52.1, 73.7, 81.0, 126.3, 128.8,
129.0, 136.1, 170.2. Anal. calcd for C18H26N2O4S: C,
58.99; H, 7.15; N, 7.64; S, 8.75. Found: C, 59.14; H,
7.16; N, 7.62; S, 8.73%. HRMS calcd for C18H26N2O4S:
366.1613. Found: 366.1611.
Found: C, 69.13; H, 6.38; N, 5.57; S, 6.33%. HRMS
calcd for C29H32N2O4S: 504.2083. Found: 504.2080.
4.6. General procedure for hydrolysis of adducts 11
A 5% aqueous solution of NaOH (4 mL, 5.00 mmol)
was added to 11 (0.43 mmol) in THF (5 mL), and the
mixture was vigorously stirred at 50°C for 16 h. The
two layers were separated and from the organic layer
washed with water (2×2 mL) and brine (1×2 mL), and
dried (Na2SO4), was recovered, after evaporation, the
sultam 8 (85–88%). Evaporation of the combined
aqueous layers, trituration of the residue with CH2Cl2,
and evaporation of the dried extracts (Na2SO4) gave 13
as sodium salt. Acidification of the CH2Cl2-insoluble
residue with 2N aqueous HCl, saturation with NaCl,
extraction with CH2Cl2, and evaporation of the dried
(Na2SO4) extracts gave the crude acid which was
purified by HPLC.
4.5.2.
(−)-(3S,3aR,6S,6aS)-1,6-Dimethyl-3-phenyl-5-
[(3R) - 3 - phenylpentanoyl]hexahydroisothiazolo[4,5 - c]-
isoxazole 4,4-dioxide 11B. Yield: 295 mg, 80%; colorless
1
oil; [h]2D5=−2.0 (c 1.26, CHCl3); H NMR (CDCl3, 500
MHz): l 0.80 (t, J=7.3 Hz, 3H, CH3), 1.41 (d, J=6.5
Hz, 3H, CH3), 1.65 (ddq, J=7.2, 7.4 and 13.2 Hz, 1H,
CH2
CH2CH3), 2.79 (s, 3H, N-CH3), 3.09 (dd, J=8.0 and
17.8 Hz, 1H, CH2CO), 3.15 (dd, J=7.5 and 17.8 Hz,
1H, CH2CO), 3.17 (dddd, J=5.3, 7.4, 7.5 and 8.0 Hz,
1H, CHPh), 3.26 (d, J=8.1 Hz, 1H, H6a), 4.15 (dd,
6 CH3), 1.75 (ddq, J=5.3, 7.2 and 13.2 Hz, 1H,
6
6
6
6
J=6.3 and 8.1 Hz, 1H, H3a), 4.40 (q, J=6.5 Hz, 1H,
H6), 5.48 (d, J=6.3 Hz, 1H, H3), 7.18–7.40 (m, 10H,
aromatic protons); 13C NMR (CDCl3, 125 MHz): l
12.0, 18.4, 29.7, 42.4, 42.8, 43.0, 52.3, 73.7, 73.9, 81.1,
126.4, 126.8, 127.7, 128.4, 128.5, 129.0, 129.1, 169.4.
Anal. calcd for C23H28N2O4S: C, 64.46; H, 6.59; N,
6.54; S, 7.48. Found: C, 64.28; H, 6.61; N, 6.57; S,
7.49%. HRMS calcd for C23H28N2O4S: 428.1770.
Found: 428.1772.
4.6.1. From 11A: (−)-(3R)-3-methylvaleric acid 13A.
Yield: 40.2 mg, 85%. Colorless oil; [h]2D5=−7.87 (c 0.25,
CHCl3).11a
4.6.2. From 11B: (−)-(3R)-3-phenylvaleric acid 13B.
Yield: 63.9 mg, 83%. Colorless oil; [h]2D5=−43.61 (c
0.31, CHCl3).11b
4.6.3. From 11C: (−)-(3R)-3-methylvaleric acid 13A.
Yield: 38.8 mg, 82%. Colorless oil; [h]2D5=−7.89 (c 0.25,
CHCl3).11a
4.5.3. (+)-(3S,3aR,6S,6aS)-6-Benzyl-1-methyl-5-[(3R)-3-
methylpentanoyl] - 3 - phenylhexahydroisothiazolo[4,5 - c]-
isoxazole 4,4-dioxide 11C. Yield: 362 mg, 95%; colorless
oil; [h]2D5=+41.1 (c 0.56, CHCl3); 1H NMR (CDCl3, 500
MHz): l 0.92 (t, J=7.4 Hz, 3H, CH3), 0.99 (d, J=6.7
Hz, 3H, CH3), 1.27 (m, 2H), 1.42 (m, 1H), 2.06 (m,
1H), 2.38 (s, 3H, N-CH3), 2.69 (dd, J=8.0 and 16.0 Hz,
1H, H5¦a), 2.78 (dd, J=6.0 and 16.0 Hz, 1H, H5¦b), 2.83
(dd, J=11.1 and 13.5 Hz, 1H, H6%a), 3.28 (dd, J=4.5
and 13.5 Hz, 1H, H6%b), 3.35 (d, J=8.6 Hz, 1H, H6a),
4.17 (dd, J=6.4 and 8.6 Hz, 1H, H3a), 4.55 (dd, J=4.5
and 11.1 Hz, 1H, H6), 5.49 (d, J=6.4 Hz, 1H, H3),
7.29–7.40 (m, 10H, aromatic protons); 13C NMR
(CDCl3, 125 MHz): l 11.3, 19.2, 29.32, 31.2, 37.9, 41.8,
42.5, 57.6, 70.2, 73.5, 81.2, 126.4, 127.4, 128.9, 128.9,
129.1, 129.3, 135.8, 135.9, 170.4. Anal. calcd for
C24H30N2O4S: C, 65.13; H, 6.83; N, 6.33; S, 7.25.
Found: C, 64.95; H, 6.81; N, 6.32; S, 7.26%. HRMS
calcd for C24H30N2O4S: 442.1926. Found: 442.1923.
4.6.4. From 11D: (−)-(3R)-3-phenylvaleric acid 13B.
Yield: 67.8 mg, 88%. Colorless oil; [h]2D5=−43.64 (c
0.35, CHCl3).11b
Acknowledgements
We thank MIUR and CNR for their financial support.
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