A novel diastereoselective 1,3-dipolar cycloaddition approach to cis-fused bispyrrolidines

Article abstract of DOI:10.1016/j.tetasy.2008.09.007

The intramolecular cycloaddition reactions of non-stabilized azomethine ylides generated by the condensation of N-aryl glycines and an enantiopure N-allyl-tethered alkenyl aldehyde derived from (S)-phenyl alanine were investigated. The stereoselective reactions led to the formation of novel cis-fused enantiomerically pure octahydropyrrolo[3,4-b]pyrroles, and the strategy was expanded to the synthesis of enantiopure novel heterotricyclic skeletons, perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles.

Full text of DOI:10.1016/j.tetasy.2008.09.007

Tetrahedron: Asymmetry 19 (2008) 2177–2183
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel diastereoselective 1,3-dipolar cycloaddition approach
to cis-fused bispyrrolidines
*
Mahalingam Poornachandran, Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular cycloaddition reactions of non-stabilized azomethine ylides generated by the conden-
sation of N-aryl glycines and an enantiopure N-allyl-tethered alkenyl aldehyde derived from (S)-phenyl
alanine were investigated. The stereoselective reactions led to the formation of novel cis-fused enantio-
merically pure octahydropyrrolo[3,4-b]pyrroles, and the strategy was expanded to the synthesis of enan-
tiopure novel heterotricyclic skeletons, perhydrothiazolo[30,40-2,3]pyrrolo[4,5-c]pyrroles.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 30 July 2008
Accepted 4 September 2008
Available online 9 October 2008
1. Introduction
natural and unnatural compounds with the pyrrolidine skeleton
have been synthesized stereoselectively.15 Catalytic enantioselec-
The pyrrolidine motif occurs in many families of biologically
active molecules. Owing to the ease of substitution and modifica-
tions at several positions, many derivatives of pyrrolidines and
pyrroles with varying properties have been synthesized.1
Pyrrolidines and their fused derivatives, such as pyrrolizidines,
indazolidines, and pyranoquinolines, have shown a wide spectrum
of biological activities.2 It has also been reported that the fused
bispyrrolidines are the basic units of adenosine kinase inhibiting
scaffolds for controlling neurodegeneration seizures, ischemia,
inflammation, and pain.3 Apart from this, pyrrolo[3,4-b]pyrrole
derivatives are found to serve as useful intermediates in the syn-
thesis of uracil-based antibacterials.4 Moreover, these heterocycles
have also been reported as h5-HT1D receptor agonists.5 In view of
the above-mentioned medicinal values of these heterocycles, we
reported the synthesis of a series of pyrrolo[3,4-b]pyrroles.6
Of all the available synthetic tools for the construction of pyrrol-
idine-based heterocycles, an azomethine ylide cycloaddition meth-
odology is the best suited for the synthesis of such heterocycles,
and since these reactions follow a concerted pathway, it always
results in retention of the geometries of the parent molecules.7
Among the intra- and intermolecular versions of this cycloaddition
protocol, the intramolecular variant has been used as a key step for
the elegant synthesis of stereochemically defined heterocycles.8–11
For instance, several polycyclic-fused pyrrolidine ring systems are
synthesized by intramolecular cycloadditions of cyclic azomethine
ylides with tethered dipolarophiles.12 In many targeted syntheses,
intramolecular 1,3-dipolar cycloaddition reactions have been used
as the key step.13 Moreover, this powerful tool has also been exten-
sively employed for the synthesis of chiral heterocycles.14 Many
tive variants of 1,3-dipolar cycloaddition reactions have also been
reported.16
2. Results and discussion
As the octahydropyrrolo[3,4-b]pyrrole scaffolds promise
potential bioactivities, the synthesis of a series of optically active
pyrrolo[3,4-b]pyrrole derivatives was envisaged. Of the available
methods for the induction of chirality in a molecule, subjecting a
chiral molecule to some chemical transformations to obtain a
target chiral product is one of the well-defined and best-suited
methods. Thus, starting from a chiral substrate (S)-phenyl alanine
1, a strategically positioned chiral alkenyl aldehyde 6 was synthe-
sized. Azomethine ylides, generated by decarboxylative route,17,18
were formed by the condensation of aldehyde 6 with various
N-aryl glycines and 2-thiazolidine carboxylic acids, and were
trapped by the tethered dipolarophile to yield a variety of enantio-
merically pure octahydropyrrolo[3,4-b]pyrroles and perhydro-
thiazolo[30,40-2,3]pyrrolo[4,5-c]pyrroles, respectively.
2.1. Synthesis of enantiomerically pure N-alkenyl aldehyde
It is mandatory to have a strategically positioned aldehyde
carbonyl component tethered to a dipolarophile for an effective
intramolecular cycloaddition reaction. Hence for the construction
of title enantiopure molecules, an allyl-tethered aldehyde built
on chiral backbone is necessary. Aminoacids are the potential
candidates on which wide ranges of modifications could be carried
out, since they possess both basic and acidic functionalities. Hence,
(S)-phenyl alanine 1 was chosen as the basic substrate and was
subjected to
a sequence of transformations as outlined in
* Corresponding author. Tel.: +91 44 22202811; fax: +91 44 22352494.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
Schemes 1 and 2. Accordingly, 1 was converted to its ethyl ester
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.007

2178
M. Poornachandran, R. Raghunathan / Tetrahedron: Asymmetry 19 (2008) 2177–2183
hydrochloride 2 by treatment with an excess of thionyl chloride in
dry ethanol. The hydrochloride salt of the ester was then reduced
by sodium borohydride in aqueous ethanolic solution to obtain
the amino alcohol 3 in good yield {½a D26
ꢀ
¼ ꢁ24:1 (c 1, EtOH)}19
(Scheme 1).
O
H
O
H
H
(ii)
(i)
Ph
OH
Ph
O
Ph
OH
NH2.HCl
NH2
NH2
3
2
Figure 1. The molecular structure of compound 4, showing 30% probability
displacement ellipsoids.
1
Scheme 1. Reagents and conditions: (i) SOCl2, ethanol, 0 °C–rt–reflux, 5 h; (ii)
NaBH4, ethanol–water (1:1), reflux.
Finally, attempts were made to oxidize alcohol 5 into aldehyde
6 with various oxidizing agents, such as PCC, PDC, and active MnO2,
under different reaction conditions. Successful oxidation was
achieved by IBX. Thus, the alkenyl alcohol was oxidized quantita-
tively into the alkenyl aldehyde, (S)-2-(N-allyl-N-tosylamino)-3-
phenylpropanal by stirring the suspension of IBX in DMSO with
the alcohol for 4 h21 (Scheme 2). The structure of alkenyl aldehyde
6 was confirmed on the basis of spectroscopic data. The specific
rotation of the aldehyde was found to be ꢁ0.2 (c 1, CHCl3).
With the requisite amino alcohol 3 in hand, the protection of
the amino group using p-toluenesulfonyl chloride was performed.
As described earlier,6b the N-sulfonylation reaction was carried out
under phase transfer catalysis condition to afford compound 4 in
good yield (Scheme 2).
Ph
OH
Ph
(i)
H
(ii)
Ts
H
Ts
N
N
Ph
H2N
2.2. Synthesis of enantiopure octahydropyrrolo[3,4-b]pyrroles
H
(iii)
H
HO
HO
Having synthesized the enantiomerically pure, strategically
positioned alkenyl aldehyde 6 in good yield, an intramolecular azo-
methine ylide cycloaddition reaction was performed for the syn-
thesis of enantiomerically pure cycloadducts. Thus, refluxing an
equimolar mixture of the alkenyl aldehyde 6 and N-phenyl glycine
7e in toluene under Dean–Stark conditions gave cycloadduct,
(3aR,6S,6aR)-cis-1-(4-bromophenyl)-5-tosyl-6-benzyl- octahydro-
pyrrolo[3,4-b]pyrrole, 8e in 68% yield. The same reaction was
extended to various substituted N-phenyl glycines 5a–f for the
synthesis of other cycloadducts 6a–f (Scheme 3, Table 1, entries
1–6).
5
3
4
H
CHO
Ph
N
Ts
6
Scheme 2. Reagents and conditions: (i) TBAB, 10% NaOH/benzene, tosyl chloride,
0 °C–rt, 8 h, 90%; (ii) allyl bromide, K2CO3/acetone, 5 h; (iii) iodoxybenzoic acid,
DMSO, 4 h, 94%.
Compound 4 was characterized by spectroscopic data. The spe-
cific rotation of the compound was found to be ꢁ21.4 (c 1, CHCl3).
Furthermore, the structure of the N-sulfonylated amino alcohol 4
was unambiguously corroborated by single crystal X-ray analysis20
(Fig. 1).
The N-sulfonylated chiral alcohol 4 was then subjected to N-
allylation using allylbromide with anhydrous potassium carbonate
in dry acetone solvent to obtain the N-allylated alcohol 5 in good
yield. The structure of chiral N-allyl-N-tosyl alcohol 5 was estab-
lished on the basis of its spectroscopic data. The specific rotation
of the compound 5 was found to be ꢁ1.2 (c 1, CHCl3).
The structures of the cycloadducts were confirmed by spectro-
scopic data. All the cycloadducts were obtained as a single diaste-
reomer and the specific rotation values were constant after
repeated crystallizations. The cycloadduct 8e as a typical example
of the series with a specific rotation of +29.8 (c 1, CHCl3) exhibits a
signal in the range d 3.97–4.00 as a doublet of doublet (J = 2.9 and
10.4 Hz), which is characteristic of N-methine proton at the ring
junction. The large coupling constant value suggests a cis fusion
at the ring junctions in analogy to the cycloadducts obtained in
our earlier work.6b The formation of the cycloadducts 8e was
further confirmed by the mass spectrum showing a molecular
R
R
NHCH2COOH
H
CHO
Ph
toluene
reflux
Ph
Ph
Ts
H
H
N
Ts
N
N
Ts
N
N
R
7a-f
6
a
b
c
d
e
f
Ph
Ts
R =
H
Me OMe Cl Br
F
H
Ar
N
H
H
N
8a-f
Scheme 3.

M. Poornachandran, R. Raghunathan / Tetrahedron: Asymmetry 19 (2008) 2177–2183
2179
Table 1
Intramolecular azomethine ylide cycloadditions of compound
amino acids 7a–f and 9a–f
6
with secondary
Yield (%)
Entry
Amino acid
Time (h)
Product
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
9a
9b
9c
9d
9e
9f
3
4
3
2.5
2
3.5
3
4.5
5
3.5
3
3
8a
8b
8c
8d
8e
70
69
68
72
68
71
68
67
65
70
69
66
8f
10a
10b
10c
10d
10e
10f
10
11
12
Figure 3. ORTEP diagram of 8e.
2.3. Synthesis of enantiopure perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrroles
It is well documented in the literature that the thiazolidine ring
has potential bioactivities such as anti-oxidizing, anti-amoebic,
anti-diabetic and anti-inflammatory.24 In order to extend the scope
of this reaction for the synthesis of optically active heterotricycles
with a pyrrolo[3,4-b]pyrrole moiety, the chiral alkenyl aldehyde 6
was reacted with 2-aryl-L-thiazolidine-4-carboxylic acids 9a–f in
refluxing toluene under Dean–Stark reaction conditions. The
reaction afforded a series of optically active cis-2-aryl-4-benzyl-
5-tosyl-perhydrothiazolo[30,40-2,3]pyrrolo[4,5-c]pyrroles 10a–f in
good yields (Scheme 4, Table 1, entries 7–12).
Figure 2. ORTEP diagram of 8d.
The specific rotation values of the cycloadducts were constant,
even after several recrystallizations. The stereochemistry of the
ion peak at m/z, 513.16 (M+). Moreover, the structure and
stereochemistry of the cycloadducts 8d and 8e were established
by the single crystal X-ray diffraction analysis22,23 (Figs. 2 and 3).
heterotricycles,
(2S,3aR,4S,6aR,7aR)-2(aryl)-4-benzyl-5-tosyl-
perhydrothiazolo[30,40-2,3]pyrrolo[4,5-c]pyrroles, 10a–f were
R
R
S
H
CHO
toluene
reflux
H
S
Ph
Ph
Ts
H
S
COOH
Ph
Ts
N
Ts
N
H
H
H
H
R
N
N
N
9a-f
N
6
a
b
c
d
e
f
F
R =
H
Me OMe Cl Br F
Ph
H
H
H
H
S
Ts
N
N
10a-f
Scheme 4.

2180
M. Poornachandran, R. Raghunathan / Tetrahedron: Asymmetry 19 (2008) 2177–2183
determined on the basis of NMR experiments. The hydrogens at the
ring junctions were cis to each other as the reaction between the
cyclic a-amino acids and carbonyl compound results in an anti-di-
photometer. Elemental analyses were carried out by Perkin–Elmer
CHNS 2400 instrument. Single crystal X-ray diffraction analyses
were performed by Bruker SMART APEX CCD area-detector
diffractometer and Bruker SMART APEXII CCD area-detector
diffractometer.
Column chromatography was performed on silica gel (ACME,
100–200 mesh). Routine monitoring of the reaction was done
using thin layer chromatogram developed on glass plates coated
with silica gel-G (ACME) of 25 mm thickness and visualized with
iodine.
pole; the cycloaddition to the dipolarophile is highly stereoselec-
tive yielding only the cis-adducts.25
In the 1H NMR spectrum of the representative cycloadduct 10e,
the benzylic proton on the thiazolidine ring resonated as a singlet
at d 4.53. The NCH proton at the ring junction appeared as a dou-
blet of doublet in the range d 3.75–3.78 (J = 2.9 and 9.8 Hz), con-
firming
a cis-fused cycloaddition. It was observed from the
NOESY experiments that the angular hydrogen atom next to the
nitrogen is in a trans-position to those hydrogens present at the
ring fusion. The high stereoselection of the cycloaddition reaction
could be attributed to the selective addition of the anti-dipole to
the tethered alkene through an exo-approach.26
4.2. Preparation of (S)-2-amino-3-phenylpropan-1-ol, 3
(S)-2-Amino-3-phenylpropan-1-ol was prepared in two stages
starting from (S)-phenyl alanine.18
In the 13C NMR spectrum, the methylene carbon displayed a sig-
nal at d 34.07 and the benzylic carbon in the thiozolidine ring
exhibited a signal at d 74.72. Furthermore, the structure of the
cycloadduct 10e was confirmed by the mass spectrum exhibiting
a molecular ion peak at m/z 570.08 (M+). The specific rotation of
the cycloadduct 10e was found to be ꢁ13.8 (c 1, CHCl3). The abso-
lute stereochemistry of the tricyclic compound was established by
single crystal X-ray diffraction analysis27 (Fig. 4).
4.2.1. Stage 1: preparation of (S)-phenylalanine ethyl ester
hydrochloride, 2
To a stirred, ice-cold suspension of (S)-phenylalanine (30 g,
0.182 mol) in absolute ethanol (800 mL), thionyl chloride (32.5 g,
0.273 mol) was added dropwise, and the reaction mixture was
heated at reflux for 3.5 h. The pale yellow solution was allowed
to stand overnight at room temperature, and the ethanol was evap-
orated in vacuo to obtain a colorless solid. The vacuum-dried (S)-
phenylalanine ethyl ester hydrochloride was washed with dry
diethyl ether, filtered, and dried in vacuo. The solid thus obtained
was used as such in the next step.
4.2.2. Stage 2: preparation of (S)-phenylalaninol from
(S)-phenylalanine ethyl ester hydrochloride, 3
To a solution of sodium borohydride (28 g, 0.736 mol) in 50%
aqueous ethanol (400 mL) was added dropwise a solution of (S)-
phenylalanine ethyl ester hydrochloride (40 g, 0.176 mol) in 50%
aqueous ethanol (400 mL), and the resulting mixture was refluxed
for 4.5 h. Ethanol was evaporated in vacuum. The aqueous solution
thus obtained was then extracted with ethyl acetate. The extract
was washed with saturated brine solution and dried over anhy-
drous sodium hydroxide. Evaporation of the ethyl acetate under re-
duced pressure afforded (S)-phenyl alaninol 3 as a pale yellow
solid. Pale yellow solid, 72% (19.16 g); ½a D26
ꢀ
¼ ꢁ24:1 (c 1, EtOH);
Mp: 85–87 °C; IR (KBr): 2990 and 3452 cmꢁ1
.
4.3. Synthesis of (S)-3-phenyl-2-(tosylamino)propan-1-ol, 4
Figure 4. ORTEP diagram of 10e.
To a solution of 15.10 g (0.1 mol) of (S)-2-amino-3-phenylpro-
pan-1-ol in 100 mL benzene at 0 °C was added half a portion of
19.06 g (0.1 mol) p-toluenesulfonyl chloride. The reaction mixture
was stirred vigorously, and after 10 min, 30 mL of benzene was
added followed by the remaining portion of p-toluenesulfonyl
chloride followed by a catalytic amount (500 mg) of the phase
transfer catalyst, tetrabutylammonium bromide (TBAB). To this
stirred mixture, a 25% solution of sodium hydroxide (0.1 mol)
was added dropwise using an additional funnel, resulting in a thick
flocculation. The temperature of the reaction mixture was raised to
room temperature once the addition of sodium hydroxide was
complete. After 8–10 h, the reaction mixture was diluted with
100 mL of water. It was then extracted with 100 mL of benzene
and washed with brine solution. The organic layer was then dried
over anhydrous sodium sulfate and concentrated in vacuum to
yield crude N-sulfonylated-(S)-phenyl alaninol. The pure 4 was ob-
tained by column chromatography using a 9:1 mixture of hexane–
3. Conclusion
In conclusion, the synthesis of enantiomerically pure
N-tethered alkenyl aldehyde was accomplished in good yield from
(S)-phenyl alanine. The enantiomerically pure alkenyl aldehyde
was then successfully subjected to intramolecular cycloaddition
reaction with N-aryl glycines and 2-aryl-L-thiazolidine-4-carbox-
ylic acids to obtain a series of enantiopure octahydropyrrolo[3,4-
b]pyrroles and perhydrothiazolo[30,40-2,3]pyrrolo[4,5-c]pyrroles,
respectively. The cycloaddition reactions were found to be stereo-
selective and gave cis-fused cycloadducts.
4. Experimental
4.1. General
All melting points are uncorrected. IR spectra were recorded on
a SHIMADZU IR-8300 series FT-IR spectrophotometer. 1H NMR
and 13C NMR spectra were recorded on JEOL 400 MHz and JEOL
500 MHz instruments in CDCl3 solvent with TMS as standard.
Mass spectra were recorded by JEOL-DX303 HF mass spectro-
ethyl acetate. Colorless solid, 89% (27.18 g); ½a D29
¼ ꢁ21:4 (c 1,
ꢀ
CHCl3); Mp: 75–77 °C; IR (KBr): 1338, 1167, 1600, 3100 and
3452 cmꢁ1 1H NMR (CDCl3, 400 MHz): d 2.01 (s, 1H, OH), 2.33 (s,
;
3H, Ar-CH3), 2.64–2.65 (dd, 1H, J1 = 6.8 Hz, J2 = 13.0 Hz), 2.73–
2.74 (dd, 1H, J1 = 6.8 Hz, J2 = 13.0 Hz), 3.48–3.58 (m, 3H), 5.85 (br

M. Poornachandran, R. Raghunathan / Tetrahedron: Asymmetry 19 (2008) 2177–2183
2181
s, NH, 1H), 6.96–7.60 (m, 9H, Ar-H); 13C NMR (CDCl3, 100 MHz): d
21.41, 37.61, 56.95, 63.73, 126.35, 126.89, 128.41, 128.53, 129.20,
129.59, 137.26, 137.29 and 143.12; Mass spectrum (EI, 70 eV):
m/z, 305.40 (M+). Anal. Calcd for C16H19NO3S: C, 62.93, H, 6.27, N,
4.59. Found: C, 62.81, H, 6.20, N, 4.48.
was refluxed under Dean–Stark conditions until the completion of
the reaction (3.5–5 h). The reaction mixture was then concentrated
under reduced pressure. The residue was extracted with dichloro-
methane (2 ꢂ 20 mL) and water (2 ꢂ 20 mL). The organic layer was
washed with brine solution (2 ꢂ 20 mL), dried over anhydrous
sodium sulfate and concentrated in vacuum. The residue was then
subjected to column chromatography (silica gel, 100–200 mesh)
with hexane–ethyl acetate (8:2) to obtain the cycloadducts 8a–f,
(3aR,6S,6aR)-1-(aryl)-5-tosyl-6-benzyl-octahydropyrrolo [3,4-b]-
pyrroles.
4.4. Synthesis of (S)-2-(N-allyl-N-tosylamino)-3-phenyl-
propan-1-ol, 5
To a solution of 20 mmol of (S)-3-phenyl-2-(tosylamino)pro-
pan-1-ol in 100 mL of dry acetone under a nitrogen atmosphere
was added 60 mmol of potassium carbonate. To this stirred solu-
tion, 20 mmol of allyl bromide in 50 mL of dry acetone was added.
The stirring was continued for 8–10 h. After completion of the
reaction, the solid was filtered off. The residue was washed several
times with acetone and the filtrate was concentrated in vacuum
and extracted with dichloromethane (100 mL) and water
(100 mL). The organic extract was washed with brine solution
and concentrated under reduced pressure. The crude product was
subjected to column chromatography with hexane–ethyl acetate
mixture (9:1) to obtain pure N-allylated (S)-3-phenyl-2-(tosylami-
4.6.1. (3aR,6S,6aR)-cis-1-Phenyl-5-tosyl-6-benzyl-
octahydropyrrolo[3,4-b]pyrrole, 8a
Colorless solid, 70% (0.302 g); ½a D28
ꢀ
¼ þ6:6 (c 1, CHCl3); Mp:
142–145 °C; IR (KBr): 1339 and 1169 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.55–1.80 (m, 2H, CH2), 2.32 (s, 3H, Ar-CH3), 2.57–
2.92 (m, 3H), 3.22–3.26 (dd, 1H, J = 2.6, 10.1 Hz), 3.66–3.68 (m,
2H), 3.97-4.10 (dd, 1H, J = 2.8, 10.2 Hz), 5.47 (d, 2H, J = 8.0 Hz),
6.58–7.40 (m, 14H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 21.47,
27.61, 30.92, 41.54, 42.41, 46.73, 51.94, 65.10, 65.80, 112.73,
116.25, 126.92, 127.06, 128.58, 129.37, 130.16, 133.95, 137.67,
142.91, and 145.44; Mass spectrum (EI, 70 eV): m/z, 432.19 (M+).
Anal. Calcd for C26H28N2O2S: C, 72.19, H, 6.52, N, 6.48. Found: C,
72.08, H, 6.61, N, 6.40.
no)propan-1-ol, 5. Colorless oil, 80% (5.52 g); ½a D29
ꢀ
¼ ꢁ1:2 (c 1,
CHCl3); IR (KBr): 1330, 1169, 1600, and 3546 cmꢁ1
;
1H NMR
(CDCl3, 400 MHz): d 2.01 (br s, 1H, OH), 2.39 (s, 3H, Ar-CH3),
2.65–2.67 (dd, 1H, J1 = 6.8 Hz, J2 = 13.0 Hz), 2.74–2.79 (dd, 1H,
J1 = 6.8 Hz, J2 = 13.0 Hz), 3.58–3.66 (m, 2H), 3.85–4.07 (m, 3H),
5.15–5.29 (dd, 2H, J1 = 9.8 Hz, J2 = 17.0 Hz), 5.88–5.89 (m, 1H),
7.02–7.63 (m, 9H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 21.49,
36.32, 47.38, 61.91, 62.43, 117.89, 126.59, 127.27, 128.59, 129.00,
129.64, 135.82, 137.73, and 143.33; Mass spectrum (EI, 70 eV):
m/z, 345.46 (M+). Anal. Calcd for C19H23NO3S: C, 66.06, H, 6.71, N,
4.05. Found: C, 66.25, H, 6.60, N, 4.15.
4.6.2. (3aR,6S,6aR)-cis-1-(4-Methyl)-phenyl-5-tosyl-6-benzyl-
octahydropyrrolo[3,4-b]pyrrole, 8b
Colorless solid, 69% (0.307 g); ½a D29
ꢀ
¼ 27:5 (c 1, CHCl3); Mp:
140–142 °C; IR (KBr): 1337 and 1169 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.63–1.72 (m, 2H, CH2), 2.34 (s, 3H, Ar-CH3), 2.41 (s,
3H, Ar-CH3), 2.54–2.89 (m, 3H), 3.25–3.27 (dd, 1H, J = 2.8,
10.2 Hz), 3.75–3.77 (m, 2H), 3.98–4.02 (dd, 1H, J = 2.7, 10.4 Hz),
5.48 (d, 2H, J = 8.0 Hz), 6.80–7.43 (m, 13H, Ar-H); 13C NMR (CDCl3,
100 MHz): d 21.44, 21.84, 27.50, 30.87, 41.51, 42.53, 46.87, 51.06,
64.19, 65.02, 113.34, 121.09, 127.23, 128.87, 128.27, 129.33,
130.00, 133.07, 137.29, 143.03, and 143.85; Mass spectrum (EI,
70 eV): m/z, 446.20 (M+). Anal. Calcd for C27H30N2O2S: C, 72.61,
H, 6.77, N, 6.27. Found: C, 72.50, H, 6.69, N, 6.36.
4.5. Synthesis of (S)-2-(N-allyl-N-tosylamino)-3-
phenylpropanal, 6
To
a stirred solution of 2-iodobenzoic acid, IBX (2.94 g,
0.010 mmol), dissolved in dimethyl sulfoxide, DMSO (10 mL), was
added 2.07 g (0.006 mmol) of (S)-2-(N-allyl-N-tosylamino)-3-phen-
ylpropan-1-ol, 5. After 2 h of vigorous stirring, the reaction
mixture was diluted with water and the precipitate formed was
filtered and washed with ethyl acetate (20 mL). The filtrate was
then extracted with ethyl acetate (2 ꢂ 20 mL). The organic layer
was dried over anhydrous sodium sulfate and the solvent was
distilled off at reduced pressure to obtain a brown colored crude
aldehyde in quantitative yield. It was subjected to column
chromatography (silica gel, 100–200 mesh) using hexane–ethyl
acetate mixture (9:1) to obtain pure (S)-2-(N-allyl-N-tosylamino)-
4.6.3. (3aR,6S,6aR)-cis-1-(4-Methoxy)-phenyl-5-tosyl-6-benzyl-
octahydropyrrolo[3,4-b]pyrrole, 8c
Colorless solid, 68% (0.314 g); ½a D29
ꢀ
¼ þ24:6 (c 1, CHCl3); Mp:
145–147 °C; IR (KBr): 1337 and 1169 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.65–1.72 (m, 2H, CH2), 2.39 (s, 3H, Ar-CH3), 2.59–
2.88 (m, 3H, NCH2), 3.25–3.28 (dd, 1H, J = 2.8, 10.3 Hz), 3.74–3.77
(m, 2H), 3.78 (s, 3H, Ar-OCH3), 3.97–4.00 (dd, 1H, J = 2.7,
10.4 Hz), 5.47 (d, 2H, J = 8.1 Hz), 6.83–7.45 (m, 13H, Ar-H); 13C
NMR (CDCl3, 100 MHz): d 21.94, 27.09, 30.87, 37.34, 41.87, 42.59,
46.12, 51.77, 64.18, 65.72, 113.55, 121.83, 127.89, 128.07, 128.87,
129.53, 130.70, 133.67, 137.22, 143.03, and 143.58; Mass spectrum
(EI, 70 eV): m/z, 462.52 (M+). Anal. Calcd for C27H30N2O3S: C, 70.10,
H, 6.54, N, 6.06. Found: C, 69.92, H, 6.63, N, 6.17.
3-phenylpropanal, 6. Yellow oil, 90% (1.86 g); ½a D29
ꢀ
¼ ꢁ0:2 (c 1,
CHCl3); IR (KBr): 1335, 1161, and 1735 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 2.40 (s, 3H, Ar-CH3), 2.73–2.79 (dd, 1H, J1 = 8.3 Hz,
J2 = 15.0 Hz), 3.36–3.41 (dd, 1H, J1 = 5.8 Hz, J2 = 15.0 Hz), 3.65–
3.71 (dd, 1H, J1 = 6.8 Hz, J2 = 6.8 Hz), 3.78–3.84 (dd, 1H, J1 = 6.3 Hz,
J2 = 6.3 Hz), 4.42–4.46 (dd, 1H, J1 = 6.3 Hz, J2 = 8.5 Hz), 5.10–5.18
(dd, CH2, 2H, J1 = 10 Hz, J2 = 17.5 Hz), 5.66–5.72 (m, 1H, CH), 7.04–
7.54 (m, 9H, Ar-H), 9.68 (s, 1H, CHO); 13C NMR (CDCl3, 100 MHz):
d 21.50, 33.30, 49.19, 67.41, 120.33, 126.68, 127.33, 128.62,
129.02, 129.75, 133.31, 137.03, 137.17, 143.71 and 198.89; Mass
spectrum (EI, 70 eV): m/z, 343.12 (M+). Anal. Calcd for C19H21NO3S:
C, 66.45, H, 6.16, N, 4.08. Found: C, 66.52, H, 6.01, N, 3.97.
4.6.4. (3aR,6S,6aR)-cis-1-(4-Chloro)-phenyl-5-tosyl-6-benzyl-
octahydropyrrolo[3,4-b]pyrrole, 8d
Colorless solid, 72% (0.336 g); ½a D28
ꢀ
¼ þ27:0 (c 1, CHCl3); Mp:
147–149 °C; IR (KBr): 1337 and 1166 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.62–1.74 (m, 2H, CH2), 2.35 (s, 3H, Ar-CH3), 2.59–
2.88 (m, 3H), 3.25–3.28 (dd, 1H, J = 2.8, 10.3 Hz), 3.70–3.74 (m,
2H), 3.99–4.00 (dd, 1H, J = 2.8, 10.4 Hz), 5.49 (d, 2H, J = 8.0 Hz),
6.84–7.43 (m, 13H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 21.47,
27.59, 30.90, 41.53, 42.50, 46.91, 51.86, 64.93, 65.75, 113.73,
121.05, 127.03, 128.23, 128.67, 129.38, 130.05, 133.95, 137.59,
143.03, and 143.95; Mass spectrum (EI, 70 eV): m/z, 466.80 (M+).
Anal. Calcd for C26H27ClN2O2S: C, 66.87, H, 5.83, N, 6.00. Found:
C, 66.70, H, 5.97, N, 5.89.
4.6. Synthesis of enantiopure cis-1-aryl-5-tosyl-6-benzyl
octahydropyrrolo[3,4-b]pyrroles, 8a–f
A mixture of (S)-2-(N-allyl-N-tosylamino)-3-phenylpropanal 6
(1.0 mmol), and N-aryl glycine (1.5 mmol) in 30 mL of dry toluene

2182
M. Poornachandran, R. Raghunathan / Tetrahedron: Asymmetry 19 (2008) 2177–2183
4.6.5. (3aR,6S,6aR)-cis-1-(4-Bromo)-phenyl-5-tosyl-6-benzyl-
octahydropyrrolo[3,4-b]pyrrole, 8e
2.45 (s, 3H), 2.65–2.79 (m, 3H), 3.05–3.08 (m, 1H), 3.25–3.31 (m,
2H), 3.46–3.49 (m, 1H), 3.66–3.73 (m, 1H), 3.74–3.78 (dd, 2H,
J = 2.9, 9.8 Hz), 4.52 (s, 1H), 6.97–7.74 (m, 13H, Ar-H); 13C NMR
(CDCl3, 100 MHz): d 21.57, 21.89, 27.79, 41.85, 42.37, 46.47,
51.37, 64.04, 65.19, 108.12, 114.98, 126.12, 127.15, 128.46,
129.89, 129.65, 130.86, 133.11, 137.76, 141.87, 143.43, and
144.76; Mass spectrum (EI, 70 eV): m/z, 504.71 (M+). Anal. Calcd
for C29H32N2O2S2: C, 69.01, H, 6.39, N, 5.55. Found: C, 69.07, H,
6.29, N, 5.50.
Colorless solid, 68% (0.348 g); ½a D29
ꢀ
¼ þ29:8 (c 1, CHCl3); Mp:
145–147 °C; IR (KBr): 1337 and 1166 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.60–1.75 (m, 2H, CH2), 2.33 (s, 3H, Ar-CH3), 2.53–
2.85 (m, 3H), 3.24–3.28 (dd, 1H, J = 2.9, 10.0 Hz), 3.66–3.73 (m,
2H), 3.97–4.00 (dd, 1H, J = 2.9, 10.4 Hz), 5.43 (d, 2H, J = 8.7 Hz),
6.96–7.43 (m, 13H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 21.46,
27.56, 41.49, 42.47, 46.84, 51.83, 64.84, 65.69, 108.18, 114.26,
126.82, 127.95, 128.20, 128.44, 129.65, 130.02, 131.07, 133.10,
137.56, 141.65, 143.04, and 144.30; Mass spectrum (EI, 70 eV):
m/z, 513.16 (M+). Anal. Calcd for C26H27BrN2O2S: C, 61.05, H,
5.32, N, 5.48. Found: C, 61.14, H, 5.24, N, 5.57.
4.7.3. (2S,3aR,4S,6aR,7aR)-cis-2-(p-Methoxy)-phenyl-4-benzyl-
5-N-(p-methyl)-benzenesulfonyl perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrrole, 10c
Brownish viscous liquid, 65% (0.338 g); ½a D29
ꢀ
¼ ꢁ15:8 (c 1,
4.6.6. (3aR,6S,6aR)-cis-1-(4-Fluoro)-phenyl-5-tosyl-6-benzyl-
octahydropyrrolo[3,4-b]pyrrole, 8f
CHCl3); IR (KBr): 1336 and 1168 cmꢁ1 1H NMR (CDCl3,
;
400 MHz): d 1.68–1.73 (m, 1H), 1.80–1.85 (m, 1H), 2.46 (s, 3H),
2.65–2.77 (m, 3H), 3.04–3.07 (m, 1H), 3.20–3.30 (m, 2H), 3.45–
3.49 (m, 1H), 3.67–3.71 (m, 1H), 3.74–3.77 (dd, 2H, J = 2.9,
9.8 Hz), 3.79 (s, 3H, Ar-OMe), 4.54 (s, 1H), 6.98–7.80 (m, 13H, Ar-
H); 13C NMR (CDCl3, 100 MHz): d 21.67, 27.89, 37.67, 41.23,
42.65, 46.38, 51.73, 64.76, 65.91, 108.43, 114.59, 126.41, 127.01,
128.09, 129.98, 129.33, 130.09, 133.52, 137.34, 141.09, 143.09,
and 144.98; Mass spectrum (EI, 70 eV): m/z, 520.77 (M+). Anal.
Calcd for C29H32N2O3S2: C, 66.89, H, 6.19, N, 5.38. Found: C,
66.75, H, 6.27, N, 5.30.
Colorless solid, 71% (0.320 g); ½a D27
ꢀ
¼ þ2:5 (c 1, CHCl3); Mp:
148–150 °C; IR (KBr): 1337 and 1168 cmꢁ1
;
1H NMR (CDCl3, 400
MHz): d 1.64–1.75 (m, 2H, CH2), 2.34 (s, 3H, Ar-CH3), 2.59–2.86
(m, 3H), 3.25–3.28 (dd, 1H, J = 2.6, 10.4 Hz), 3.69–3.73 (m, 2H),
3.99–4.02 (dd, 1H, J = 2.8, 10.4 Hz), 5.51 (d, 2H, J = 8.0 Hz), 6.63–
7.44 (m, 13H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 21.46, 27.55,
30.92, 41.59, 42.48, 47.29, 51.92, 65.05, 65.93, 113.14, 113.22,
114.76, 114.98, 127.07, 128.64, 129.34, 130.08, 133.95, 137.68,
142.01, 142.94, 153.84, and 156.17; Mass spectrum (EI, 70 eV):
m/z, 450.59 (M+). Anal. Calcd for C26H27FN2O2S: C, 69.31, H, 6.04,
N, 6.22. Found: C, 69.43, H, 6.10, N, 6.10.
4.7.4. (2S,3aR,4S,6aR,7aR)-cis-2-(p-Chloro)-4-benzyl-5-N-
(p-methyl)-benzenesulfonyl perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrrole, 10d
4.7. Synthesis of enantiopure perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrroles, 10a–f
Brownish viscous liquid, 70% (0.366 g); ½a D29
ꢀ
¼ ꢁ12:8 (c 1,
CHCl3); IR (KBr): 1338 and 1170 cmꢁ1
;
1H NMR (CDCl3,
A mixture of (S)-2-(N-allyl-N-tosylamino)-3-phenylpropanal 6
(1.0 mmol) and 2-aryl-thiazolidine-4-carboxylic acids 9a–f
(1.5 mmol) in 30 mL of dry toluene was refluxed under Dean–Stark
conditions until the completion of the reaction (2.5–4 h). The reac-
tion mixture was then concentrated under reduced pressure. The
concentrate was extracted with dichloromethane (2 ꢂ 20 mL) and
water (2 ꢂ 20 mL). The organic layer was washed with brine solu-
tion (2 ꢂ 20 mL), dried over anhydrous sodium sulfate, and con-
centrated in vacuum. The residue was then subjected to column
chromatography (silica gel, 100–200 mesh) with hexane–ethyl
acetate (8:2) to obtain the cycloadducts 10a–f, (2R,3aR,4S,6aR,7-
aR)-cis-2-aryl-4-benzyl-5-N-(p-methyl)-benzenesulfonyl-perhy-
drothiazolo[30,40-2,3]pyrrolo[4,5-c]pyrroles.
400 MHz): d 1.68–1.72 (m, 1H), 1.81–1.85 (m, 1H), 2.47 (s, 3H),
2.66–2.78 (m, 3H), 3.05–3.08 (m, 1H), 3.24–3.31 (m, 2H), 3.46–
3.49 (m, 1H), 3.66–3.70 (m, 1H), 3.75–3.79 (dd, 2H, J = 2.9,
9.8 Hz), 4.50 (s, 1H), 6.87–7.79 (m, 13H, Ar-H); 13C NMR (CDCl3,
100 MHz): d 21.89, 27.89, 41.43, 42.49, 46.38, 51.83, 64.23, 65.90,
108.43, 114.44, 126.11, 127.91, 128.09, 129.43, 129.66, 130.09,
133.80, 137.54, 141.69, 143.24, and 144.70; Mass spectrum (EI,
70 eV): m/z, 524.14 (M+). Anal. Calcd for C28H29ClN2O2S2: C,
64.04, H, 5.57, N, 5.33. Found: C, 64.12, H, 5.50, N, 5.41.
4.7.5. (2R,3aR,4S,6aR,7aR)-cis-2-(p-Bromo)-phenyl-4-benzyl-5-
N-(p-methyl)-benzenesulfonyl perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrrole, 10e
Colorless solid, 69% (0.393 g); ½a D29
ꢀ
¼ ꢁ13:8 (c 1, CHCl3); Mp:
4.7.1. (2S,3aR,4S,6aR,7aR)-cis-2-Phenyl-4-benzyl-5-N-
(p-methyl)-benzenesulfonyl perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrrole, 10a
162–164 °C; IR (KBr): 1339 and 1166 cmꢁ1 1H NMR (CDCl3,
;
400 MHz): d 1.69–1.72 (m, 1H), 1.80–1.85 (m, 1H), 2.45 (s, 3H),
2.64–2.79 (m, 3H), 3.06–3.08 (m, 1H), 3.24–3.30 (m, 2H), 3.47–
3.49 (m, 1H), 3.66–3.71 (m, 1H), 3.75–3.78 (dd, 2H, J = 2.9,
9.8 Hz), 4.53 (s, 1H), 6.66–7.74 (m, 13H, Ar-H); 13C NMR (CDCl3,
100 MHz): d 21.69, 34.07, 39.23, 40.36, 41.48, 54.23, 67.71, 68.70,
72.73, 74.72, 120.55, 126.71, 127.74, 128.12, 128.62, 129.62,
130.81, 134.42, 137.81, 141.92, and 143.22; Mass spectrum (EI,
70 eV): m/z, 570.08 (M+). Anal. Calcd for C28H29BrN2O2S2: C,
59.04, H, 5.13, N, 4.92. Found: C, 59.12, H, 5.05, N, 5.00.
Brownish viscous liquid, 68% (0.333 g); ½a D29
¼ ꢁ10:6 (c 1,
ꢀ
CHCl3); IR (KBr): 1335 and 1165 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.68–1.70 (m, 1H), 1.87–1.85 (m, 1H), 2.43 (s, 3H),
2.66–2.76 (m, 3H), 3.07–3.10 (m, 1H), 3.25–3.30 (m, 2H), 3.47–
3.49 (m, 1H), 3.69–3.72 (m, 1H), 3.74–3.78 (dd, 2H, J = 2.9,
9.8 Hz), 4.54 (s, 1H), 6.74–7.73 (m, 14H, Ar-H); 13C NMR (CDCl3,
100 MHz): d 21.89, 27.37, 41.77, 42.07, 46.14, 51.93, 64.81, 65.09,
108.68, 114.08, 126.02, 127.05, 128.67, 129.53, 129.08, 130.02,
133.19, 137.06, 141.25, 143.54, and 144.16; Mass spectrum (EI,
70 eV): m/z, 490.54 (M+). Anal. Calcd for C28H30N2O2S2: C, 68.54,
H, 6.16, N, 5.71. Found: C, 68.47, H, 6.08, N, 5.77.
4.7.6. (2S,3aR,4S,6aR,7aR)-cis-2-(p-Fluoro)phenyl-4-benzyl-5-N-
(p-methyl)-benzenesulfonyl perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrrole, 10f
Brownish viscous liquid, 66% (0.335 g); ½a D29
ꢀ
¼ ꢁ15:6 (c 1,
4.7.2. (2S,3aR,4S,6aR,7aR)-cis-2-(p-Methyl)-phenyl-4-benzyl-5-
N-(p-methyl)-benzenesulfonyl perhydrothiazolo[30,40-2,3]-
pyrrolo[4,5-c]pyrrole, 10b
CHCl3); IR (KBr): 1338 and 1170 cmꢁ1 1H NMR (CDCl3,
;
400 MHz): d 1.68–1.72 (m, 1H), 1.79–1.85 (m, 1H), 2.46 (s, 3H),
2.63–2.78 (m, 3H), 3.07–3.09 (m, 1H), 3.23–3.32 (m, 2H), 3.47–
3.55 (m, 1H), 3.66–3.71 (m, 1H), 3.74–3.79 (dd, 2H, J = 2.9,
9.8 Hz), 4.55 (s, 1H), 6.64–7.68 (m, 13H, Ar-H); 13C NMR (CDCl3,
100 MHz): d 21.37, 27.16, 41.88, 42.54, 46.98, 51.87, 64.00, 65.21,
Brownish viscous liquid, 67% (0.338 g); ½a D29
ꢀ
¼ ꢁ14:8 (c 1,
CHCl3); IR (KBr): 1335 and 1170 cmꢁ1
;
1H NMR (CDCl3,
400 MHz): d 1.69–1.73 (m, 1H), 1.79–1.84 (m, 1H), 2.43 (s, 3H),

M. Poornachandran, R. Raghunathan / Tetrahedron: Asymmetry 19 (2008) 2177–2183
2183
11. Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809.
108.06, 114.78, 126.21, 127.70, 128.00, 129.20, 129.76, 130.02,
133.09, 137.45, 141.98, 143.09, and 159.07; Mass spectrum (EI,
70 eV): m/z, 508.17 (M+). Anal. Calcd for C28H29FN2O2S2: C, 66.11,
H, 5.75, N, 5.51. Found: C, 66.20, H, 5.64, N, 5.59.
12. See, for example: (a) Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000, 2,
2299; (b) Marx, M. A.; Grillot, A.-L.; Louer, C. T.; Beaver, K. A.; Bartlett, P. A. J.
Am. Chem. Soc. 1997, 119, 6153; (c) Westling, M.; Smith, R.; Livingouse, T. J. Org.
Chem. 1986, 51, 1159.
13. Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–12275.
14. (a) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J. Chem. Soc., Perkin Trans. 1
2001, 452–456 and references cited therein; (b) Pedrosa, R.; Andrés, C.; Heras,
L.; Nieto, J. Org. Lett. 2002, 4, 2513–2516 and references cited therein.
15. (a) Chu, D. T. W.; Li, Q.; Claiborne, A.; Raye-Passarelli, K.; Cooper, C.; Fung, A.;
Lee, C.; Tanaka, S. K.; Shen, L.; Donner, P.; Armiger, Y. L.; Plattner, J. J. 34th
ICCAC Abstract, 1994, Abstract F41; (b) Flamm, R. K.; Vojtko, C.; Chu, D. T.; Li,
Q.; Beyer, J.; Hensey, D.; Ramer, N.; Clement, J. J.; Tanaka, S. K. Antimicrob.
Agents Chemother. 1995, 39, 964–970; (c) Ma, Z.; Chu, D. T.; Cooper, C. S.; Li, Q.;
Fung, A. K. L.; Wang, S.; Shen, L. L.; Flamm, R. K.; Nilius, A. M.; Alder, J. D.;
Meulbroek, J. A.; Or, Y. S. J. Med. Chem. 1999, 42, 4202.
Acknowledgments
The authors thank Department of Science and Technology
(DST), New Delhi, India, for financial support. One of the authors
Poornachandran thanks CSIR, New Delhi, for the award of Senior
Research Fellowship (SRF).
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