Regio- and diastereoselective tandem addition-carbocyclization promoted by sulfanyl radicals on chiral perhydro-1,3-benzoxazines

Article abstract of DOI:10.1016/j.tetasy.2003.06.003

Radical addition-carbocyclization of 2-allyl-3-acyloyl-substituted perhydro-1,3-benzoxazines readily provides 3,4-disubstituted pyrrolidinone derivatives with total regioselectivity and good diastereoselectivity. The key step of the reaction is a tandem addition-5-exo-cyclization promoted by a sulfanyl radical.

Full text of DOI:10.1016/j.tetasy.2003.06.003

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2985–2990
Regio- and diastereoselective tandem addition–carbocyclization
promoted by sulfanyl radicals on chiral
perhydro-1,3-benzoxazines
Rafael Pedrosa,* Celia Andre´s,* Juan P. Duque-Soladana, Alicia Maestro and Javier Nieto
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n,
47011 Valladolid, Spain
Received 6 May 2003; accepted 8 July 2003
Abstract—Radical addition–carbocyclization of 2-allyl-3-acyloyl-substituted perhydro-1,3-benzoxazines readily provides 3,4-disub-
stituted pyrrolidinone derivatives with total regioselectivity and good diastereoselectivity. The key step of the reaction is a tandem
addition–5-exo-cyclization promoted by a sulfanyl radical.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
This strategy has been used previously in the prepara-
tion of cyclopentanes8 and pyrrolidines,9 and more
recently, in the synthesis of substituted tetra-
hydrofurans,10 g-lactones,11 lactams12 or 2,3-disubsti-
tuted pyrrolidines.13 Recently, we have studied this
addition–cyclization process directed at the preparation
of enantiopure stannanes and 3-methylstannyl-4-substi-
tuted pyrrolidines14 starting from 3-acryloyl-2-vinyl per-
hydro-1,3-benzoxazines derived from (−)-8-amino
menthol, and now we report the diastereoselective addi-
Diastereoselective free-radical addition to olefinic
bonds is one of the most attractive ways to form
carbonꢀcarbon bonds.1 Excellent diastereoselectivities
have been described for intermolecular additions to
a,b-unsaturated amides attached to different chiral
auxiliaries2 including chiral oxazolidinones.3 Although
the intramolecular version of this reaction has been less
studied, it has been successfully used in the synthesis of
lactams4 and macrocyclic derivatives.5 Recently, we
have described the synthesis of enantiopure substituted
pyrrolidines6 and piperidines7 by diastereoselective
intramolecular addition of radicals generated from chi-
ral 2,3-disubstituted perhydrobenzoxazines. Both enan-
tiomers of the substituted heterocycles can be obtained
from regioisomeric perhydrobenzoxazines which differ
in the substituents at C-2 and the nitrogen atom.
tion–cyclization reaction promoted by
radical.
a sulfanyl
First, we explored the reaction of N-allyl-2-cinnamyl
perhydro-1,3-benzoxazine 1, which was prepared in two
steps by condensation of (−)-8-amino menthol with
cinnamaldehyde followed by alkylation with allyl bro-
mide and potassium carbonate in refluxing acetonitrile.
The addition compound 2 was formed in 80%, as an
equimolar mixture of epimers, when a 0.02 M solution
of 1, thiophenol (1.2 equiv.) and AIBN (0.2 equiv.) was
refluxed in benzene for 4 h, and no cyclization products
were detected (Scheme 1).
The synthesis of 3,4-disubstituted pyrrolidines could
also be achieved by addition–cyclization of a preformed
heteroatom-centered radical to chiral perhydrobenzox-
azines with two double bonds. The advantages of this
approach are: (i) the starting compounds are inexpen-
sive and easily obtained; (ii) the functionality of the
final compounds can be changed by the choice of the
radical that promotes the reaction, and (iii) it is possible
to create two contiguous stereocenters in a single
process.
The failure of the cyclization step led us to consider
changing the allyl group at the nitrogen atom to a
better acceptor acryloyl substituent. In this way, perhy-
drobenzoxazines 4a–e were prepared in excellent yields
in two steps (Scheme 2). Condensation of (−)-8-amino
menthol with the corresponding a,b-unsaturated alde-
hyde in benzene at 25°C yielded 2-vinyl substituted
perhydrobenzoxazines 3a–e, which were then acylated
* Corresponding authors. E-mail: pedrosa@qo.uva.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.06.003

2986
R. Pedrosa et al. / Tetrahedron: Asymmetry 14 (2003) 2985–2990
Scheme 1. Reagents and conditions: (i) cinnamaldehyde, ben-
zene, reflux, 6 h (86%); (ii) CH2ꢁCHCH2Br, K2CO3, acetoni-
trile, reflux (80%); (iii) PhSH (1.2 equiv.), AIBN (0.2 equiv.),
benzene, reflux, 4 h (80%).
Scheme 3. Reagents and conditions: PhSH, AIBN (20% mol),
benzene, reflux.
of the major diastereoisomer was established as 5b by
NOE experiments. The cross signals showed a cis rela-
tionship between the hydrogen atoms at C-3 and C-5,
and a trans disposition of the substituents at C-3 and
C-4 of the pyrrolidinone ring. The photochemically
induced reaction of 4b also leads to a mixture (53:30:17)
of three diastereoisomers, but with lower stereoselection
than the thermally induced process.
The behavior of allylphenylsulphide derivative 4c is
noteworthy because only a single diastereomer 5c (90%)
was obtained on refluxing in toluene a solution (0.06
M) of 4c, as a mixture of Z and E isomers, thiophenol
(1 equiv.) and AIBN (0.2 equiv.). But more interest-
ingly, 5c was obtained in the same yield when the
reaction of 4c was carried out in refluxing toluene for
24 h with only 0.3 equiv. of thiophenol. This fact must
be interpreted taking into account that the cyclization
reaction is followed by elimination of a phenylsulfanyl
radical which reinitiates the process and, in this way,
the reaction can then be consider as a catalytic process
Scheme 2.
by reaction with the corresponding acyl chloride in
methylene chloride at 0°C in the presence of triethyl-
amine. All these compounds were obtained as pure
diastereomers except 4c, which was prepared as a mix-
ture of Z and E isomers.
The transformation of 4a–e into the pyrrolidinone 5a–e
and 6a–e was carried out by refluxing a 0.02 M solution
of 4a–e, thiophenol (1.1 equiv.) and AIBN (0.2 equiv.)
in dry degassed benzene (Scheme 3). Under these condi-
tions, compound 4a was transformed into an insepara-
ble mixture (61:25:7:7) of four diastereoisomers. In an
attempt to improve the diastereoselection, the reaction
was carried out under photochemical conditions by
irradiation of the reaction mixture with a high-pressure
mercury lamp at 25°C, but a very complex mixture of
products was formed.
Much better results were obtained in the reaction of
perhydro-1,3-benzoxazine 4b. This compound was
regioselectively transformed into a mixture (80:8:9:3) of
four diastereomers when reacted under the described
thermal conditions. Once isolated, the stereochemistry
Scheme 4.

R. Pedrosa et al. / Tetrahedron: Asymmetry 14 (2003) 2985–2990
2987
chloride. The treatment of 7c with PCC oxidized the
sulfide group to the sulfone derivative.
(Scheme 4). After isolation, the stereochemistry of 5c
was determined by NOE experiments, and is coincident
with that described for 5b.
In summary, the described protocol allowed the
diastereoselective formation of 2,3-disubstituted pyrro-
lidine derivatives in good yields and total regioselectiv-
ity and moderate diastereoselectivity.
The described results open the possibility to create
quaternary stereocenters at C-3 or C-4 in the cyclized
pyrrolidinone ring. To this end, we tested the cycliza-
tion of two different perhydrobenzoxazines 4d, with a
methyl group at C-a in the vinyl substituent at C-2 in
the starting perhydrobenzoxazine (R1=Me) and 4e,
with a methyl substituent at C-a in the a,b-unsaturated
amide group (R4=Me).
2. Experimental
All solvents were distilled prior to use. TLC was per-
formed on silica gel 60 F254 plates. Flash chromatogra-
phy was conducted using 240–300 mesh silica gel. All
commercially available products were used without
purification. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter with a sodium lamp.
Proton and carbon magnetic resonance spectra were
recorded on a Bruker AC-300 or Bruker ARX-300 (300
MHz for proton, 75.2 MHz for carbon) using CDCl3 as
solvent; chemical shifts (l) are given in ppm related to
TMS as internal standard (l=0 for TMS). Mass spec-
tra were obtained on a Hewlett-Packard 5988A spec-
trometer by chemical ionization. Infrared spectra were
registered on a Philips PU9706 apparatus as neat films.
The reaction of 4d with thiophenol (1 equiv.) and
AIBN (0.2 equiv.) in boiling benzene for 1 h was totally
regioselective, but not diastereoselective leading to an
equimolar mixture of three diastereomeric pyrrolidi-
nones. On the contrary, the reaction of 4e was highly
regio- and diastereoselective. Methacryloyl derivative 4e
gave a mixture of 5e (70%) and 6e (30%) by reaction
with thiophenol in the same experimental conditions
(Scheme 3).
Once isolated, diastereoisomers 5b, 5c, 5e, and 6e were
transformed into the pyrrolidinyl menthols 7b, 7c, 7e,
and 8e, respectively, by reductive ring opening with
alane in THF at 0°C (Scheme 5). Compound 7c was
oxidized with excess PCC to the 8-pyrrolidinyl men-
thone derivative, which exert (+)-pulegone and enan-
tiopure pyrrolidine derivative 9 by sequential treatment
with a solution of KOH in THF/H2O/MeOH, and tosyl
2.1. Synthesis of perhydro-1,3-benzoxazines 3a–e. Gen-
eral procedure
Compounds 3a–e were prepared, as previously
described for related compounds,6c by condensation of
(−)-8-amino menthol with the corresponding a,b-unsat-
urated aldehyde in CH2Cl2 at rt. Compound 3a has
been previously described.15
2.2. 4,4,7a-Trimethyl-2a-prenyl-trans-octahydro-1,3-
benzoxazine 3b
1
Yellow oil. [h]D25=−4.9 (c 1.2, CH2Cl2). H NMR, l:
0.91 (d, 3H, J=6.5 Hz); 0.94–1.08 (m, 3H); 1.09 (s,
3H); 1.13 (s, 3H); 1.41–1.55 (m, 1H); 1.65–1.74 (m, 3H);
1.71 (s, 3H); 1.73 (s, 3H); 1.91–1.96 (m, 1H); 3.47 (dt,
1H, J1=3.5 Hz, J2=10.5 Hz); 5.02 (d, 1H, J=7.4 Hz);
5.12 (d, 1H, J=7.4 Hz). 13C NMR, l: 18.6; 19.6; 22.2;
25.5; 25.6; 29.8; 31.3; 34.9; 41.6; 51.2; 51.3; 74.7; 79.6;
124.0; 137.3. IR (film): 3300, 1450, 1380, 830. CIMS,
m/z (%): 238 (M+1, 100). Anal. calcd for C15H27N: C,
75.90%; H, 11.46%; N, 5.90%. Found: C, 75.76%; H,
11.61%; N, 5.76%.
2.3. 2a-(2%-Butenyl)-4,4,7a-trimethyl-trans-octahydro-
1,3-benzoxazine 3d
Colorless oil. [h]D25=−46.4 (c 1.0, CH2Cl2). 1H NMR, l:
0.92 (d, 3H, J=6.3 Hz); 1.10 (s, 3H); 1.12 (s, 3H); 1.61
(d, 3H, J=6.2 Hz); 1.68 (d, 3H, J=1 Hz); 3.47 (dt, 1H,
J1=4.2 Hz, J2=10.2 Hz); 4.66 (s, 1H); 5.67 (dd, 1H,
J1=1.0 Hz, J2=6.2 Hz). 13C NMR, l: 11.4, 12.8, 19.4,
22.1, 25.4, 29.8, 31.2, 34.8, 41.5, 51.1, 51.5, 74.7, 86.4,
121.9, 134.2. IR (film): 3200, 2900, 1650, 970, 750, 690.
Anal. calcd for C15H27NO: C, 75.90%; H, 11.46%; N,
5.90%. Found: C, 76.02%; H, 11.63%; N, 5.99%.
Scheme 5.

2988
R. Pedrosa et al. / Tetrahedron: Asymmetry 14 (2003) 2985–2990
2.4. Synthesis of N-allyl-2a-cinnamyl-4,4,7a-trimethyl-
trans-octahydro-1,3-benzoxazine 1
Hz); 5.74 (d, 1H, J=5.3 Hz); 6.13 (dd, 1H, J1=2.2 Hz,
J2=16.8 Hz); 6.27 (dd, 1H, J1=10.4 Hz, J2=16.8 Hz).
13C NMR, l: 18.5, 18.7, 21.9, 24.6, 25.2, 25.5, 31.5,
34.5, 43.0, 46.7, 57.7, 73.0, 79.6, 126.0, 127.1, 131.2,
137.2, 137.8, 165.9. IR (film): 2910, 1645, 1610, 1450,
1360, 980, 960, 810. Anal. calcd for C18H29NO2: C,
74.18%; H, 10.03%; N, 4.81%. Found: C, 74.31%; H,
10.14%; N, 4.97%.
A mixture of perhydrobenzoxazine 3a (5.0 mmol),
potassium carbonate (0.69 g, 7 mmol) and allyl bro-
mide (7.5 mmol), in acetonitrile (8 mL) was refluxed
with stirring for 24 h. The solid was separated by
filtration, the solid was washed with hot EtOAc (25
mL), and the solvents were evaporated. Colorless oil.
1
[h]2D5=−46.4 (c 1.0, CH2Cl2). H NMR, l: 0.86–1.06
2.8. N-Acryloyl-2a-(2%-butenyl)-4,4,7a-trimethyl-trans-
octahydro-1,3-benzoxazine 4d
(m, 2H); 0.93 (d, 3H, J=6.5 Hz); 1.03–1.23 (m, 1H);
1.17 (s, 3H); 1.18 (s, 3H); 1.40–1.60 (m, 2H); 1.62–1.72
(m, 2H); 1.95–1.99 (m, 1H); 3.16, dd, 1H, J1=5.6 Hz,
J2=17.2 Hz); 3.44 (dd, 1H, J1=5.3 Hz, J2=17.2 Hz);
3.54 (dt, 1H, J1=4.0 Hz, J2=10.6 Hz); 4.95 (dd, 1H,
J1=1.6 Hz, J2=10.1 Hz); 5.07 (dd, 1H, J1=1.6 Hz,
J2=17.1 Hz); 5.15 (d, 1H, J=4.9 Hz); 5.81–5.93 (m,
1H); 6.16 (dd, 1H, J1=4.9 Hz, J2=16.1 Hz); 6.66 (d,
1H, J=16.1 Hz); 7.18–7.37 (m, 5H). 13C NMR, l: 18.7,
22.2, 25.1, 26.8, 31.3, 35.0, 41.4, 46.5, 47.0, 56.8, 75.6,
87.5, 114.1, 126.5 (2C), 127.5, 128.4 (2C) 129.3, 131.9,
136.8, 140.5. IR (film): 2922, 1684, 1638, 972, 746, 690.
Anal. calcd for C22H31NO: C, 81.18%; H, 9.60%; N,
4.30%. Found: C, 81.01%; H, 9.49%; N, 4.49%.
Colorless oil. [h]D25=+36.4 (c 1.0, CH2Cl2). 1H NMR, l:
0.76 (d, 3H, J=6.2 Hz); 1.36 (s, 3H); 1.46 (s, 3H); 1.52
(d, 3H, J=6.9 Hz); 1.55 (s, 3H); 3.48 (dt, 1H, J1=3.7
Hz, J2=11.5 Hz); 5.21 (z, 1H); 5.36 (dd, 1H, J1=3.3
Hz, J2=9.0 Hz); 5.51 (d, 1H, J=6.6 Hz); 5.92–6.02 (m,
2H). 13C NMR, l: 13.2, 13.4, 18.8, 21.7, 23.5, 24.9,
31.4, 34.3, 42.7, 45.1, 57.5, 73.9, 85.7, 122.1, 126.6,
130.9, 137.3, 166.6. IR (film): 3040, 2900, 2830, 1650,
1600, 970, 750, 690. Anal. calcd for C18H29NO2: C,
74.18%; H, 10.03%; N, 4.81%. Found: C, 74.26%; H,
9.92%; N, 4.91%.
2.9. N-Methacryloyl-2a-prenyl-4,4,7a-trimethyl-trans-
octahydro-1,3-benzoxazine 4e
2.5. Synthesis of perhydrobenzoxazines 4a–e
To a solution of perhydrobenzoxazines 3a–e (4.2 mmol)
and triethylamine (4.8 mmol, 0.39 mL) in dry CH2Cl2
(30 mL) under argon, at 0°C was slowly added the
corresponding acyl chloride (4.6 mmol). The mixture
was stirred for additional 30 min at rt and then was
diluted with hexane (75 mL). The solid was collected by
filtration, and the solvents were evaporated under vac-
uum. The residue was chromatographed on silica gel
using CH2Cl2 as eluent.
Colorless oil. [h]D25=+53.1 (c 1.1, CH2Cl2). 1H NMR, l:
0.84–1.18 (m, 2H); 0.92 (d, 3H, J=6.5 Hz); 1.35–1.60
(m, 2H); 1.48 (s, 3H); 1.62 (s, 3H); 1.65 (s, 3H);
1.69–1.87 (m, 2H); 1.73 (s, 3H); 1.89–2.02 (m, 2H); 1.90
(s, 3H); 3.62 (dt, 1H, J1=4.0 Hz, J2=11.3 Hz); 4.98 (s,
1H); 5.05 (s, 1H); 5.40 (d, 1H, J=5.6 Hz); 5.72 (d, 1H,
J=5.6 Hz). 13C NMR, l: 18.3; 18.5; 20.0; 21.9; 25.1;
25.4; 25.6; 31.5; 34.6; 43.1; 47.2; 57.9; 73.4; 80.4; 114.9;
127.4; 136.3; 142.6; 172.2. IR (film): 2910, 1645, 1610,
1450, 1360, 940, 840, 810. CIMS, m/z (%): 306 (M+1,
100). Anal. calcd for C19H31NO2: C, 74.71%; H,
10.23%; N, 4.59%. Found: C, 74.59%; H, 10.40%; N,
4.66%.
2.6. N-Acryloyl-2a-cinnamyl-4,4,7a-trimethyl-trans-
octahydro-1,3-benzoxazine 4a
Colorless solid, mp 86–87°C. [h]2D5=−32.6 (c 1.1,
1
CHCl3). H NMR, l: 0.93 (d, 3H, J=6.5 Hz); 1.56 (s,
2.10. Cyclization of acrylamides 4a–e. General
procedure
3H); 1.68 (s, 3H); 3.72 (dt, 1H, J1=3.9 Hz, J2=11.4
Hz); 5.59 (dd, 1H, J1=2.2 Hz, J2=10.2 Hz); 5.91 (t,
1H, J=2.2 Hz); 6.24 (dd, 1H, J1=2.2 Hz, J2=16.8 Hz);
6.38 (dd, 1H, J1=10.2 Hz, J2=16.8 Hz); 6.46 (dd, 1H,
J1=2.6 Hz, J2=16.2 Hz); 6.57 dd, 1H, J1=1.9 Hz,
J2=16.2 Hz); 7.27–7.40 (m, 5H). 13C NMR, l: 18.9,
21.9, 24.5, 25.2, 31.5, 34.3, 43.7, 46.1, 58.0, 73.5, 81.9,
126.7, 127.2, 128.2, 128.7, 130.8, 131.5, 132.0, 135.8,
166.5. IR (film): 3040, 2900, 2840, 1650, 1600, 980, 960,
750, 690. CIMS, m/z (%): 340 (M+1, 100); 236 (24); 208
(46); 186 (64). Anal. calcd for C22H29NO2: C, 77.84%;
H, 8.61%; N, 4.13%. Found: C, 77.69%; H, 8.78%; N,
3.99%.
A 0.02 M of the corresponding amide 4a–e thiophenol
(1.1 equiv.) and AIBN (0.2 equiv.) in benzene was
refluxed, while stirring, under an argon atmosphere
until the starting compound have disappeared (TLC).
When the reaction was finished, the solvent was
removed under vacuum, and the residue was chro-
matographed on silica gel using EtOAc/hexanes or
dichloromethane as eluents.
1
Lactam 5b. Yellow oil. [h]2D5=−41.2 (c 1.2, CH2Cl2). H
NMR, l: 0.87 (d, 3H, J=6.7 Hz); 0.89 (d, 3H, J=6.6
Hz); 0.93 (d, 3H, J=6.6 Hz); 1.17 (s, 3H); 1.67 (s, 3H);
1.79–1.86 (m, 1H); 1.93–1.99 (m, 2H); 2.31–2.37 (m,
1H); 3.15 (dd, 1H, J1=7.6 Hz, J2=13.0 Hz); 3.40 (dt,
1H, J1=4.2 Hz, J2=10.9 Hz); 3.42 (dd, 1H, J1=4.3 Hz,
J2=13.0 Hz); 4.65 (d, 1H, J=4.4 Hz); 7.11–7.33 (m,
5H). 13C NMR, l: 19.2, 19.3, 20.0, 22.0, 24.0, 25.3,
29.7, 31.2, 34.4, 36.2, 41.4, 44.7, 47.8, 49.8, 52.3, 57.4,
76.3, 87.0, 125.9, 128.8, 129.2, 136.2, 172.7. IR (film):
2.7. N-Acryloyl-2a-prenyl-4,4,7a-trimethyl-trans-
octahydro-1,3-benzoxazine 4b
Colorless oil. [h]D25=+37.7 (c 1.0, CH2Cl2). 1H NMR, l:
0.92 (d, 2H, J=6.5 Hz); 1.49 (s, 3H); 1.62 (s, 3H); 1.73
(s, 3H); 1.76 (s, 3H); 3.60 (dt, 1H, J1=3.7 Hz, J2=11.4
Hz); 5.41 (m, 1H); 5.54 (dd, 1H, J1=2.0 Hz, J2=10.4

R. Pedrosa et al. / Tetrahedron: Asymmetry 14 (2003) 2985–2990
2989
2.12. (3%R,4%R)-8-(3%-Phenylsulfinylmethyl-4%-iso-
propenylpyrrolidinyl) menthol 7c
3050, 2970, 2870, 1710, 1590, 1450, 740, 690. Anal.
calcd for C24H35NO2S: C, 71.78%; H, 8.78%; N, 3.49%.
Found: C, 71.65%; H, 8.90%; N, 3.60%.
1
Yellow oil. [h]2D5=+19.3 (c 1.2, CH2Cl2). H NMR, l:
0.89 (s, 3H); 1.11 (s, 3H); 1.63 (s, 3H); 1.85–1.91 (m,
1H); 2.38 (q, 1H); 2.64–2.72 (m, 2H); 2.94–2.98 (m,
2H); 3.07–3.11 (m, 2H); 3.58 (dt, 1H, J1=3.86 Hz,
J2=10.3 Hz); 4.71 (d, 1H, J=1.2 Hz); 4.76 (d, 1H,
J=1.2 Hz); 7.10–7.30 (m, 5H). 13C NMR, l: 21.6, 22.1,
25.5, 30.9, 34.9, 44.2, 48.3, 51.4, 59.4, 72.8, 112.4, 126.0,
128.8, 129.2. IR (film): 3100, 2940, 1650, 1600, 1500,
1450, 750. CIMS, m/z (%): 388 (M+1, 100); 389 (M+2,
26); 386 (19); 274 (32). Anal. calcd for C24H37NOS: C,
74.37%; H, 9.62%; N, 3.61%. Found: C, 74.40%; H,
9.79%; N, 3.77%.
1
Lactam 5c. Yellow oil. [h]2D5=−45.5 (c 1.0, CH2Cl2). H
NMR, l: 0.95 (d, 3H, J=6.5 Hz); 1.19 (s, 3H); 1.72 (s,
3H); 1.74 (s, 3H); 2.55–2.61 (m, 1H); 2.66 (dt, 1H,
J1=6.2 Hz, J2=9.5 Hz); 3.15 (dd, 1H, J1=4.3 Hz,
J2=11.1 Hz); 4.66 (d, 1H, J=6.2 Hz); 4.85 (d, 1H,
J=1.2 Hz); 4.92 (d, 1H, J=1.2 Hz). 13C NMR, l: 18.5,
20.9, 22.0, 23.9, 25.5, 31.1, 34.3, 34.4, 40.9, 45.0, 49.5,
50.7, 57.2, 76.2, 87.1, 113.8, 125.8, 128.8, 129.1, 136.4,
141.7, 171.8. IR (film): 3060, 2920, 2840, 1670, 1570,
1450, 730, 680. CIMS, m/z (%): 400 (M+1, 100); 401
(M+2, 39; 246 (11). Anal. calcd for C24H33NO2S: C,
72.14%; H, 8.32%; N, 3.51%. Found: C, 72.26%; H,
8.45%; N, 3.60%.
2.13. (3%R,4%R)-8-(3%-Methyl-3%-phenylsulfinylmethyl-4%-
isopropylpyrrolidinyl) menthol 7e
Lactam 5e. Yellow solid. [h]2D5=−17.7 (c 1.0, CH2Cl2).
1H NMR, l: 0.92 (d, 3H, J=6.6 Hz); 0.95 (d, 3H,
J=6.5 Hz); 1.00 (d, 3H, J=6.7 Hz); 1.14 (s, 3H); 1.66
(s, 3H); 1.90–2.00 (m, 1H); 2.11 (dd, 1H, J1=6.9 Hz,
J2=9.0 Hz); 2.98 (d, 1H, J=12.6 Hz); 3.35 (dt, 1H,
J1=4.2 Hz, J2=10.6 Hz); 3.44 (d, 1H, J=12.6 Hz);
4.58 (d, 1H, J=6.8 Hz); 7.12–7.44 (m, 5H). 13C NMR,
l: 18.3, 19.6, 21.2, 22.0, 22.3, 23.9, 25.6, 27.4, 31.2,
34.4, 41.1, 42.5, 48.0, 48.8, 49.3, 56.8, 76.0, 87.0, 126.0,
128.6, 130.4, 137.0, 174.9. IR (film): 3060, 2940, 2860,
1690, 1590, 1450, 750, 695. CIMS, m/z (%): 416 (M+1,
100); 417 (M+2, 27); 348 (39). Anal. calcd for
C25H37NO2S: C, 72.24%; H, 8.97%; N, 3.37%. Found:
C, 72.12%; H, 9.08%; N, 3.46%.
1
Yellow oil. [h]2D5=−16.6 (c 1.6, CH2Cl2). H NMR, l:
0.89 (d, 3H, J=6.6 Hz); 0.91 (d, 3H, J=6.5 Hz); 0.96
(d, 3H, J=6.0 Hz); 1.10 (s, 3H); 1.12 (s, 3H); 1.54 (s,
3H); 1.58–1.68 (m, 1H); 1.90–1.94 (m, 1H); 2.64–2.97
(m, 4H); 3.02 (d, 1H, J=12.1 Hz); 3.21 (d, 1H, J=12.1
Hz); 3.61 (dt, 1H, J1=3.9 Hz, J2=10.3 Hz); 7.14–7.33
(m, 5H); 8.79 (broad s, 1H). 13C NMR, l: 16.7, 21.6,
22.1, 25.5, 30.9, 34.9, 44.2, 48.3, 51.4, 59.4, 72.8, 112.4,
126.0, 128.8, 129.2. IR (film): 3040, 2960, 2820, 1680,
1580, 1450, 730, 680. CIMS, m/z (%): 404 (M+1, 100);
405 (M+2, 27). Anal. calcd for C25H41NOS: C, 74.39%;
H, 10.24%; N, 3.47%. Found: C, 74.52%; H, 10.35%;
N, 3.36%.
2.14. (3%S,4%R)-8-(3%-Methyl-3%-phenylsulfinylmethyl-4%-
1
Lactam 6e. Yellow oil. [h]2D5=−51.1 (c 1.3, CH2Cl2). H
isopropylpyrrolidinyl) menthol 8e
NMR, l: 0.94 (d, 3H, J=6.5 Hz); 0.95 (d, 3H, J=6.5
Hz); 1.23 (s, 3H); 1.33 (s, 3H); 1.71 (s, 3H); 1.92–1.96
(m, 1H); 2.06 (dd, 1H, J1=6.5 Hz, J2=10.7 Hz); 3.10
(d, 1H, J=12.8 Hz); 3.23 (d, 1H, J=12.8 Hz); 3.38 (dt,
1H, J1=4.2 Hz, J2=12.7 Hz); 4.93 (d, 1H, J=7.1 Hz);
7.25–7.41 (m, 5H). 13C NMR, l: 18.9, 21.6, 22.0, 23.3,
24.0, 25.7, 27.2, 27.5, 31.2, 34.5, 40.5, 41.2, 48.2, 49.6,
54.5, 57.6, 76.0, 87.6, 126.0, 128.8, 129.1, 137.0, 175.4.
IR (film): 3060, 2940, 2860, 1690, 1590, 1450, 750, 695.
CIMS, m/z (%): 416 (M+1, 100); 417 (M+2, 27); 348
(39). Anal. calcd for C25H37NO2S: C, 72.24%; H,
8.97%; N, 3.37%. Found: C, 72.38%; H, 8.86%; N,
3.36%.
1
Yellow oil. [h]2D5=+10.2 (c 0.9, CH2Cl2). H NMR, l:
0.93 (d, 3H, J=6.5 Hz); 0.97 (d, 3H, J=6.4 Hz); 1.05
(d, 3H, J=6.4 Hz); 1.17 (s, 3H); 1.28 (s, 3H); 1.89–1.95
(m, 1H); 2.57–2.79 (m, 2H); 3.03–3.10 (m, 4H); 3.66 (dt,
1H, J1=4.2 Hz, J2=12.7 Hz); 7.19–7.45 (m, 5H); 8.40
(broad s, 1H). 13C NMR, l: 19.1, 21.2, 22.1, 22.8, 25.4,
29.6, 30.9, 35.0, 43.6, 44.1, 45.1, 48.6, 50.5, 52.2, 58.9,
72.8, 125.9, 128.8, 129.3, 137.7. IR (film): 3110, 2940,
1640, 1600, 1500, 1450, 740. calcd for C25H41NOS: C,
74.39%; H, 10.24%; N, 3.47%. Found: C, 74.28%; H,
10.34%; N, 3.59%.
2.15. Elimination of the menthol appendage. Synthesis
of tosylate of (3R,4R)-3-methylsulfonyl phenyl-4-isopro-
pyl pyrrolidine 9
2.11. Reductive cleavage of lactams 5b,c,e and 6e. Gen-
eral procedure
The elimination of the chiral appendage was carried out
as previously described.6c In this case the sulfide group
was also oxidized to sulfone, and the pyrrolidine
derivative was isolated as tosylate. Yellow oil. [h]2D5=
To a mixture of LiAlH4 (0.5 g, 13.1 mmol) and AlCl3
(713 mg, 5.34 mmol) in anhydrous THF (30 mL) at 0°C
was slowly added to a solution of the corresponding
lactams (2.7.mmol) in the same solvent. The solution
was stirred for 10 min at that temperature and then
carefully quenched with water (40 mL) and extracted
with chloroform (3×50 mL). The organic layer was
washed with brine, dried over anhydrous Na2SO4, and
the solvent was evaporated under vacuum to give pure
pyrrolidinyl menthols.
1
+21.4 (c 1.2, CH2Cl2). H NMR, l: 0.66 (d, 3H, J=6.7
Hz); 0.77 (d, 3H, J=6.7 Hz); 1.48 (m, 1H, J=6.7 Hz);
1.65 (m, 1H, J=7.5 Hz); 2.24–2.29 (m, 1H); 2.43 (s,
3H); 2.77 (dd, 1H, J1=9.0 Hz, J2=9.0 Hz); 2.95 (dd,
1H, J1=10.4 Hz, J2=14.1 Hz); 3.10 (dd, 1H, J1=7.6
Hz; J2=10.4 Hz); 3.12 (dd, 1H, J1=7.6 Hz, J2=10.4
Hz); 3.30 (dd, 1H, J1=9.0 Hz, J2=9.0 Hz); 3.46 (dd,

2990
R. Pedrosa et al. / Tetrahedron: Asymmetry 14 (2003) 2985–2990
1H, J1=7.6 Hz, J2=10.4 Hz); 7.27–7.87 (m, 9H). 13C
NMR, l: 18.3; 20.9; 21.5; 29.1; 35.5; 49.1; 50.0; 53.0;
59.5; 127.7; 127.8; 129.4; 129.7; 132.4; 134.0; 138.9;
143.6. CIMS, m/z (%): 422 (M+1, 100); 423 (23). Anal.
calcd: C21H25NO4S2: C, 60.12%; H, 6.01%; N, 3.34%.
Found: C, 60.01%; H, 5.89%; N, 3.47%.
Am. Chem. Soc. 1996, 118, 9200; (c) Sibi, M. P.; Ji, J.
J. Org. Chem. 1997, 62, 3800.
4. Colombo, L.; Di Giacomo, M.; Scolastico, C.; Man-
zoni, L.; Belvisi, L.; Molteni, V. Tetrahedron Lett.
1995, 36, 625.
5. (a) Porter, N. A.; Lacher, B.; Chang, V. H.-T.; Mag-
nin, D. R. J. Am. Chem. Soc. 1989, 111, 8309; (b)
Blake, A. J.; Hollingworth, G. J.; Pattenden, G. Synlett
1996, 643.
Acknowledgements
6. (a) Pedrosa, R.; Andre´s, C.; Duque-Soladana, J. P.;
Mendiguch´ıa, P. Eur. J. Org. Chem. 2000, 3727; (b)
Andre´s, C.; Duque-Soladana, J. P.; Pedrosa, R. J. Org.
Chem. 1999, 64, 4282; (c) Andre´s, C.; Duque-Soladana,
J. P.; Pedrosa, R. J. Org. Chem. 1999, 64, 4273; (d)
Andre´s, C.; Duque-Soladana, J. P.; Iglesias, J. M.;
Pedrosa, R. Tetrahedron Lett. 1996, 37, 9085.
7. (a) Pedrosa, R.; Andre´s, C.; Duque-Soladana, J. P.;
Roso´n, C. Tetrahedron: Asymmetry 2000, 11, 2809; (b)
Andre´s, C.; Duque-Soladana, J. P.; Iglesias, J. M.;
Pedrosa, R. Tetrahedron Lett. 1999, 40, 2421.
8. Kuehne, M. E.; Damon, R. E. J. Org. Chem. 1977, 42,
1825.
9. Padwa, A.; Nimmersgern, H.; Wong, G. S. K. J. Org.
Chem. 1985, 50, 5620.
10. Bertrand, M. P.; De Riggi, I.; Lesueur, C.; Gastaldi, S.;
Nouguir, R.; Jaime, C.; Virgili, A. J. Org. Chem. 1995,
60, 6040.
11. Miyata, O.; Nishiguchi, A.; Nimomiya, I.; Naito, T.
Tetrahedron Lett. 1996, 37, 229.
12. De Riggi, I.; Gastaldi, S.; Surzur, J. M.; Bertrand, M.
P. J. Org. Chem. 1992, 57, 6118.
We thank the financial support provided by the Spanish
Ministerio de Ciencia y Tecnolog´ıa (Project BQU2002-
1046) and Junta de Castilla y Leo´n (Project VA042/03).
References
1. See for instance: (a) Curran, D. P.; Porter, N. A.;
Giese, B. In Stereochemistry of Radical Reactions;
VCH: Weinheim, 1996; (b) Radicals in Organic Synthe-
sis, Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH: Wein-
heim, 2001; Vols. 1 and 2.
2. (a) Porter, N. A.; Scott, D. M.; Lacher, B.; Giese, B.;
Zeitz, H.-G.; Lindner, H. J. J. Am. Chem. Soc. 1989,
111, 8311; (b) Curran, D. P.; Shen, W.; Zhang, J.;
Heffner, T. A. J. Am. Chem. Soc. 1990, 112, 6738; (c)
Porter, N. A.; Swann, E.; Nally, J.; McPhail, A. T. J.
Am. Chem. Soc. 1990, 112, 6740; (d) Giese, B.; Zehn-
der, M.; Roth, M.; Zeitz, H. G. J. Am. Chem. Soc.
1990, 112, 6741; (e) Porter, N. A.; Rosenstein, I. J.;
Breyer, R. A.; Bruhnke, J. D.; Wu, W.-X.; McPhail, A.
T. J. Am. Chem. Soc. 1992, 114, 7664; (f) Sibi, M. P.;
Jasperse, C. P.; Ji, J. J. Am. Chem. Soc. 1995, 117,
10779; (g) Tararov, V. I.; Kuznetzov, N. Y.; Bakhmu-
tov, V. I.; Ikonnikov, N. S.; Bubnov, Y. N.;
Khrustalev, V. N.; Saveleva, T. F.; Belokon, Y. N. J.
Chem. Soc., Perkin Trans. 1 1997, 3101.
13. (a) Bertrand, M. P.; Gastaldi, S.; Nouguier, R. Tetra-
hedron Lett. 1996, 37, 1229; (b) Miyata, O.; Muroya,
K.; Koide, J.; Naito, T. Synlett 1998, 271.
14. Andre´s, C.; Duque-Soladana, J. P.; Pedrosa, R. Chem.
Commun. 1999, 31.
15. Pedrosa, R.; Andre´s, C.; Iglesias, J.; Pe´rez-Encabo, A.
J. Am. Chem. Soc. 2001, 123, 1817.
3. (a) Wu, J. H.; Radinov, R.; Porter, N. A. J. Am.
Chem. Soc. 1995, 117, 11029; (b) Sibi, M. P.; Ji, J. J.