Organocatalytic Michael addition of indanone carboxylates to vinyl selenone for the asymmetric synthesis of polycyclic pyrrolidines

Article abstract of DOI:10.1016/j.tet.2012.08.077

A Michael addition of racemic indanone carboxylates to vinyl selenone catalyzed by C6′hydroxyl cinchona derivatives is the key step of a synthetic sequence for a practical access to highly enantioenriched (up to 98% ee) polycyclic pyrrolidines bearing contiguous tertiary and quaternary stereocenters.

Full text of DOI:10.1016/j.tet.2012.08.077

Tetrahedron 68 (2012) 10536e10541
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic Michael addition of indanone carboxylates to vinyl selenone for
the asymmetric synthesis of polycyclic pyrrolidines
*
Silvia Sternativo, Ola Walczak, Benedetta Battistelli, Lorenzo Testaferri, Francesca Marini
ꢀ
Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, 06123 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
A Michael addition of racemic indanone carboxylates to vinyl selenone catalyzed by C60hydroxyl cin-
chona derivatives is the key step of a synthetic sequence for a practical access to highly enantioenriched
(up to 98% ee) polycyclic pyrrolidines bearing contiguous tertiary and quaternary stereocenters.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 29 June 2012
Received in revised form 16 August 2012
Accepted 25 August 2012
Available online 4 September 2012
Dedicated to the memory of Professor
Marcello Tiecco
Keywords:
Selenium
Organocatalysis
Asymmetric synthesis
Pyrrolidines
Aminoesters
1. Introduction
cinchona derivatives, which has been successfully employed for the
enantioselective synthesis of spirolactones (Scheme 1).4a This
Organoselenium compounds are nowadays considered versatile
reagents for many synthetic transformations, which take advantage
of the ease with which these compounds effect functional group
interconversions. In the last years, they found many interesting
applications in the stereoselective preparation of chiral molecules
under mild and operationally simple reaction conditions.1 Despite
the explosion of organocatalysis, which has recently emerged as
a robust and powerful strategy for the asymmetric construction of
valuable building blocks and molecules of pharmaceutical interest,
very few organocatalytic processes involving selenium reagents
have been explored.2 In this field, we have recently developed new
enantioselective methods for the preparation of important classes
practical one-pot sequence is based on the peculiar properties of
the selenonyl moiety, which acts both as an electron-withdrawing
group during the addition step and as a leaving group during the
following cyclization. We now report that the same Michael ad-
ducts 3 are useful intermediates in the diastereo- and enantiose-
lective synthesis of polycyclic pyrrolidines bearing a b-aminoester
motif. These structures contain synthetically challenging contigu-
ous tertiary and quaternary stereocenters.
O
O
R1
R2
R1
R2
CO2tBu
*
O
of selenium compounds, such as
a
-selenocarbonyl derivatives.3
SiO
O
2
R1
R2
SeO2Ph
CO2tBu
O
2
cat*
Moreover, the ease of handling and the unique reactivity of vinyl
selenones have been exploited in new organocatalytic strategies for
the practical asymmetric construction of densely functionalized
cyclic compounds from simple precursors.4 An example is the Mi-
chael addition/cyclization sequence with the easily accessible cyclic
*
+
20 mol%
H
N
*
3
R1
R2
SeO2Ph
1
*
CO2tBu
this work
b
-ketoesters 2 and the vinyl selenone 1 catalyzed by C60hydroxyl
Scheme 1.
In the last years novel strategies for the synthesis of compounds
that incorporate a pyrrolidine ring have received considerable
* Corresponding author. Tel.: þ39 075 585 5105; fax: þ39 075 585 5116; e-mail
address: marini@unipg.it (F. Marini).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.077

S. Sternativo et al. / Tetrahedron 68 (2012) 10536e10541
10537
attention.5e9 Properly substituted indenopyrrolidines A have been
studied as hypoglycemic agents6 or as antagonists of NMDA re-
ceptor (Fig. 1).7 Proline derivatives B and conformationally re-
transfer are well documented, but most examples are restricted to
nonhindered derivatives.13 Although 1H NMR analysis of the crude
reaction mixture showed the complete conversion of the starting
imine and the presence of rac-6a as the sole reaction product, it was
recovered after column chromatography in acceptable 50% yield.
The cis stereochemistry at the ring junction was assigned by
a NOESY experiment. A diagnostic dipolar interaction between the
ring junction hydrogen and the tert-butyl group was observed.
Encouraged by these results, we focused on the asymmetric variant
of the process (Table 1). In the previous report concerning the
synthesis of spirolactones,4a we demonstrated that quinidine C60-
OH 9-O-(90-phenanthryl) ether C60OH-QD exhibits a high catalytic
activity and an excellent enantiocontrol over the formation of ad-
dition product 3a, which is also the key intermediate in the con-
struction of the indeno pyrrolidine 6a. Thus, the same bifunctional
catalyst was used for the new cyclization sequence affording 5a
with an excellent enantiomeric excess (98% ee by chiral HPLC).
Interestingly, decreasing of the catalyst loading from 20 mol % to
5 mol % do not affect the chemical and optical yields.14 As expected,
the reduction gave 6a as a single diastereoisomer without loss of
enantiomeric purity. The cyclization sequence and the following
reduction were applied to some indanone derivatives bearing
electron-withdrawing or electron-donating groups on the aromatic
ring. Reaction conditions, chemical yields and enantiomeric ex-
cesses of the final products are reported in Table 1. The inden-
opyrrolidines were prepared with complete diastereoselectivity
and high enantiomeric excesses. Both enantiomers are readily ac-
cessible. In fact replacement of catalyst C60OH-QD with its pseu-
doenantiomer C60OH-Q led to the formation of ent-6a and ent-6b in
comparable yields and enantiomeric excesses (Table 1, entries 1
and 2). The method was extended to the trans Michael donor rac-2e
containing an additional stereocenter and the compound 6e was
obtained as a single diastereoisomer in 95% ee. Under the usual
conditions, the chiral catalyst not only controls the absolute con-
figuration at the quaternary stereocenter formed during the addi-
tion but also reacts almost exclusively with one of the enantiomers
of rac-2e.
stricted rivastigmine analogues
C have been evaluated as
angiotensin converting enzyme inhibitor analogues8 or acetylcho-
linesterase inhibitors, respectively.9 Moreover, in the last decade
the asymmetric synthesis of b-aminoacids and derivatives has re-
ceived great attention10 and the development of new catalytic
methodologies is particularly appreciated. Our method, which
employs the easy to handle vinyl selenone for the key addition step,
nicely complements procedures based on the catalytic 1,4-addition
of cyclic
b-ketoesters to nitroethylene followed by reduction and
cyclization.11
O
R3
N
H3C
H
H
N
R4(H)
R1
H
CO2H
RHN
O
N
H
R1
H
R2(H)
H
R2
X
B
A
C
Fig. 1. General structures of biologically active polycyclic pyrrolidines.
2. Results and discussion
For preliminary studies we chose the reaction of tert-butyl
indanone carboxylate rac-2a (2 equiv) and the vinyl selenone 1.
When these compounds were treated in toluene with a catalytic
amount of anhydrous Na2CO3 (Scheme 2) the Michael adduct rac-
3a was formed quantitatively. We hypothesized that the conversion
of 3a into the corresponding alkyl azide could give access to
indenopyrrolidines via a Staudinger/aza-Wittig sequence.12 Due to
the good leaving group properties of the phenylselenonyl unit, the
nucleophilic substitution was complete after 1 h and rac-4a was
isolated after column chromatography in 80% yield. The cyclization
by treatment with triphenylphosphine in toluene gave rac-5a in
78% yield in 1 h. The formation of the iminophosphorane in-
termediate was not observed because it rapidly reacts chemo-
selectively with the carbonyl group. In order to save time and
resources, minimize the generation of chemical waste and reduce
manual operations, the multi-reaction sequence was carried out
excluding unnecessary purification processes. Thus, the crude rac-
3a was used for the nucleophilic substitution after toluene evapo-
ration and only an aqueous work-up was employed for the next
DMF removal. Under these conditions rac-5a was isolated in 80%
overall yield. Finally, the reduction was carried out with an excess of
sodium borohydride in MeOH. Reductions of imines by hydride
Finally we try to adapt the strategy to the synthesis of ben-
zoindoles (Table 1, entry 6), but compounds 5f an 6f were obtained
in very poor stereoselectivities. A slow rate of reduction and a poor
diastereoselectivity have been already observed in these ring
systems.13b
3. Conclusions
In conclusion a practical synthetic sequence for the asymmetric
construction of indeno[1,2-b]pyrrolidines starting from easily
available starting materials has been described. The reactions
proceed with good chemical yields and generate compounds with
O
CO2tBu
O
O
N3
SeO2Ph
Na2CO3 (20 mol%)
NaN3
PPh3
rac-2a
toluene, rt
+
DMF, 80 °C
toluene,
50 °C
CO2tBu
rac-4a
CO2tBu
SeO2Ph
1
rac-3a
H
N
N
H
O
N
PPh3
NaBH4
MeOH, rt
CO2tBu
CO2tBu
rac-6a
CO2tBu
Ph3PO
rac-5a
Scheme 2.

10538
S. Sternativo et al. / Tetrahedron 68 (2012) 10536e10541
Table 1
Asymmetric synthesis of polycyclic pyrrolidines
1) cat* (5 mol%), toluene, rt, 24 h
then evaporation
O
R1
[H]
6a-f
5a-f
CO2tBu
SeO2Ph
+
R2
2) NaN3, DMF, 80 °C then aqueous work-up
3) Ph3P, toluene, 50 °C then evaporation
and SiO2 column
1
R3
2a-e (2 equiv.)
or
O
OH
N
OH
N
CO2tBu
H
H
N
N
C6'OH-QD
C6'OH-Q
2f (2 equiv.)
O
O
or
Entry
1
Cyclic iminoester
Yieldaec
%
Cyclic aminoester
Yieldb,c
%
ee %d
H
N
N
H
5a
65
65
6a
55
56
98
98
ent-5ae
ent-6ae
CO2tBu
CO2tBu
H
N
N
H
H
Cl
Cl
2
5b
85
65
6b
57
72
94
93
ent-5be
ent-6be
CO2tBu
CO2tBu
H
N
N
O
O
3
4
5
5c
74
6c
50
96
96
CO2tBu
O
CO2tBu
O
H
N
N
H
H3CO
H3CO
5d
df
6d
44g
H3CO
H3CO
CO2tBu
CO2tBu
H
N
N
H
5e
5f
60
53
6e
6f
45 (70)h
95
CO2tBu
CO2tBu
CO2tBu
CO2tBu
Ph
Ph
N
HN
6
40 (67)h
dr 56:44
20i
a
Unless otherwise specified, addition reactions were performed on a 0.4 mmol scale at room temperature with C60OH-QD as the catalyst. 3aef and 4aef were not isolated.
Yield of the isolated product.
The absolute configurations at the quaternary stereocenter were assigned according to Ref. 4a. The remaining stereogenic centres were assigned considering the relative
b
c
configuration established for 6a and 6e by NOESY correlations.
d
ee values of the aminoesters were determined after Boc-protection by HPLC analysis on a chiral stationary phase.
e
Obtained by using the catalyst C60OH-Q.
f
Not determined because the isolated product was impure of Ph3PO.
Overall yield calculated on the starting vinyl selenone 1.
Yield in brackets is based on recovered starting material.
The ee was determined on the imine 5f.
g
h
i
adjacent tertiary and quaternary stereocenters with an excellent
diastereo and enantiocontrol. Further studies to expand the syn-
thetic applications of the present sequence are currently underway.
Avance DR 200, respectively. Chemical shifts (d) are reported in
parts per million relative to residual solvent signals (CHCl3,
7.26 ppm for 1H NMR, CDCl3, 77.0 ppm for 13C NMR). Coupling
constants are given in hertz. The following abbreviations are used
to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad signal. GCeMS analyses were car-
ried out with an HP 6890 gas chromatograph (HP-5MS capillary
4. Experimental section
4.1. General
column, 30 m, I.D. 0.25 mm, film 0.25 mm) equipped with an HP
5973 Mass Selective Detector at an ionizing voltage of 70 eV. IR
spectra were recorded with a Jasco model 410 spectrometer
1H and 13C NMR were recorded in CDCl3 at 400 and 100 MHz or
at 200 and 50.3 MHz on a Bruker Avance-DRX 400 or a Bruker

S. Sternativo et al. / Tetrahedron 68 (2012) 10536e10541
10539
equipped with a diffuse reflectance accessory. High resolution mass
spectra (HRMS) were recorded on Agilent 6540-UHD Accurate Mass
Q-TOF LC/MS instrument. Optical rotations were measured with
a Jasco DIP-1000 digital polarimeter, the concentrations (c) are
reported in gram per 100 mL. Chiral HPLC analyses were performed
on an HP 1100 series instrument equipped with Chiralcel OD-H
(250ꢀ4.6 mm), Lux amylose-2 (250ꢀ4.6 mm) or Lux cellulose-2
(250ꢀ4.6 mm) columns and an UV detector. Thin layer chroma-
tography (TLC) was performed on silica gel 60 F254 (Merck) on al-
uminium sheets. Reaction products were purified by column
chromatography performed on Merck silica gel 60 (70e230 mesh).
Deactivated silica gel was prepared by washing the silica gel with
a 5% suspension of NaHCO3 in MeOH. After removal of the solvent,
the silica gel was oven-dried at 150 ꢁC.
201 (87), 184 (19), 157 (44), 156 (100), 129 (37), 128 (46), 127 (25),
116 (12), 57 (79). FT-IR (KBr):
1716.8 (C]O), 1652.7 (C]N) cmꢂ1
n
.
4.5. tert-Butyl (3aR)-7-chloro-2,4-dihydroindeno[1,2-b]pyr-
role-3a(3H)-carboxylate (5b)
This compound was isolated as an oil by column chromatogra-
phy (elution: light petroleum/ethyl acetate 85:15) in 85% yield.
28
1
[
d
a
]
¼ꢂ18.9 (c 0.98, CHCl3); H NMR (200 MHz, CDCl3, 25 ꢁC):
D
¼7.77e7.66 (m, 1H, CH), 7.40e7.20 (m, 2H, CH), 4.41 (dd, 2H; J¼3.1,
9.1 Hz, CH2N), 3.51 (d, 1H; J¼15.6 Hz, CH2), 2.65 (d, 1H; J¼15.6 Hz,
CH2), 2.59 (td, 1H; J¼3.1, 12.5 Hz, CH2CH2N), 1.99 (td, 1H; J¼9.1,
12.5 Hz, CH2CH2N), 1.33 (s, 9H, CH3); 13C NMR (50.3 MHz, CDCl3,
25 ꢁC):
d
¼181.1, 170.7, 149.8, 134.2, 133.3, 131.3, 126.9, 123.2, 81.8,
68.4, 67.3, 38.2, 37.0, 27.7 (3C). MS (70 eV, EI): m/z (%): 293 (2)
[Mþþ2], 291 (7) [Mþ], 237 (41), 236 (21), 235 (88), 218 (16), 192
(51), 191 (41), 190 (100), 156 (22), 155 (35), 154 (32), 128 (31), 127
4.2. Starting material
(35), 57 (100). FT-IR (KBr):
n .
1717 (C]O), 1661 (C]N) cmꢂ1
Commercial grade solvents and reagents were used without
further purification. Starting vinyl selenone 1 was prepared from
the corresponding selenide by oxidation with an excess of m-
chloroperbenzoic acid (m-CPBA) in dichloromethane.15 Racemic
4.6. tert-Butyl (7aR)-6,8-dihydro[1,3]dioxolo[5,6]indeno[1,2-
b]pyrrole-7a(7H)-carboxylate (5c)
tert-butyl b-ketoesters 2aef were prepared from the corresponding
ketones (Aldrich Inc.) by deprotonation with NaH in THF, followed
by treatment with tert-butyl 1H-pyrrole-1-carboxylate.16 The cat-
alysts were prepared according to literature procedures.17
This compound was isolated as an oil by column chromatogra-
phy (elution: light petroleum/ethyl acetate 85:15) in 74% yield.
28
1
[a
]
¼ꢂ37.3 (c 1.75, CHCl3); H NMR (400 MHz, CDCl3, 25 ꢁC):
D
d
¼7.14 (s, 1H, CH), 6.78 (s, 1H, CH), 6.04e6.0 (m, 2H, CH2O),
4.3. One-pot synthesis of cyclic imines 5: general procedure
4.39e4.34 (m, 2H, CH2N), 3.43 (d, 1H; J¼15.3 Hz, CH2), 2.60 (d, 1H;
J¼15.3 Hz, CH2), 2.53 (ddd, 1H; J¼2.2, 3.8, 12.4 Hz, CH2CH2N), 1.97
(td, 1H; J¼9.1, 12.4 Hz, CH2CH2N), 1.35 (s, 9H, CH3); 13C NMR
Vinyl selenone
(0.02 mmol, 5 mol %) were dissolved in toluene (1.6 mL). The
1
(0.4 mmol) and C60OH-QD or C60OH-Q
b
-
(50.3 MHz, CDCl3, 25 ꢁC):
d
¼181.5, 171.2, 150.9, 147.6, 147.4, 126.1,
ketoester rac-2aef (0.8 mmol, 2 equiv) was added at room tem-
perature and the resulting solution was stirred for 24 h. Toluene
was removed under reduced pressure, then DMF (1.6 mL) and NaN3
(0.8 mmol, 2 equiv) were added and the reaction was warmed at
80 ꢁC. The progress of the reaction was monitored by TLC analysis.
The reaction was stirred until 3aef was completely consumed
(1e2 h). The reaction mixture was cooled to room temperature,
poured into water (15 mL) and extracted with Et2O (3ꢀ15 mL). The
ethereal layers were washed with brine, dried over Na2SO4 and
evaporated under reduced pressure. The crude mixture was dis-
solved in toluene, then Ph3P (0.52 mmol, 1.3 equiv) was added at
room temperature. When nitrogen evolution had ceased, the
mixture was warmed to 50 ꢁC. The progress of the reaction was
monitored by TLC. After 1e2 h the solvent was evaporated and the
residue was purified by column chromatography. Physical and
spectral data of compounds 5aef are reported below. Racemic
compounds for HPLC analyses were prepared with the same pro-
cedure using Na2CO3 (0.08 mmol, 20 mol %) as catalyst in the first
step. The intermediate azide rac-4a was isolated and characterized
by 1H and 13C.
106.0, 102.8, 101.7, 81.5, 68.5, 66.8, 38.5, 36.8, 27.7 (3C). MS (70 eV,
EI): m/z (%): 301 (30) [Mþ], 245 (68), 244 (28), 201 (47), 200 (100),
199 (20),173 (30),142 (17),115 (30), 57 (44). FT-IR (KBr):
n 1718 (C]
O), 1653 (C]N) cmꢂ1
.
4.7. tert-Butyl (3aR)-6,7-dimethoxy-2,4-dihydroindeno[1,2-b]
pyrrole-3a(3H)-carboxylate (5d)
This compound after column chromatography (elution: light
petroleum/ethyl acetate 90:10) was impure of Ph3P]O. 1H NMR
(400 MHz, CDCl3, 25 ꢁC):
d
¼7.20 (s, 1H, CH), 6.80 (s, 1H, CH),
4.44e4.32 (m, 2H, CH2N), 3.92 (s, 3H OCH3), 3.90 (s, 3H OCH3), 3.49
(d, 1H; J¼15.2 Hz, CH2), 2.64 (d, 1H; J¼15.2 Hz, CH2), 2.54 (ddd, 1H;
J¼1.5, 4.4, 12.5 Hz, CH2CH2N), 1.97 (ddd, 1H; J¼8.4, 9.7, 12.5 Hz,
13
CH2CH2N), 1.33 (s, 9H, CH3); C NMR (100 MHz, CDCl3, 25 ꢁC):
d
¼182.2, 171.4, 152.2, 149.0, 145.4, 124.6, 107.9, 104.9, 81.4, 68.3,
67.0, 56.0, 55.9, 38.4, 36.9, 27.8 (3C). MS (70 eV, EI): m/z (%): 317
(48) [Mþ], 262 (21), 261 (82), 260 (49), 217 (36), 216 (100), 200 (21),
189 (24), 185 (18), 172 (12), 57 (33). FT-IR (KBr):
n 1713 (C]O), 1653
(C]N) cmꢂ1
.
4.4. tert-Butyl (3aR)-2,4-dihydroindeno[1,2-b]pyrrole-3a(3H)
carboxylate (5a)
4.8. tert-Butyl (3aS,4S)-4-phenyl-2,4-dihydroindeno[1,2-b]
pyrrole-3a(3H)-carboxylate (5e)
This compound was isolated as an oil by column chromatogra-
phy (elution gradient: light petroleum/ethyl acetate 90:10 to 80:20)
in 65% yield and 98% ee as determined by HPLC analysis [Lux
This compound was obtained as a single diastereoisomer and
isolated as an oil by column chromatography (elution: light
21
cellulose-2, hexane/IPA 99:1, 1.0 mL/min,
l
230 nm, t (major
petroleum/ethyl acetate 70:30) in 60% yield. [
a
]
¼ꢂ127.0 (c 1.20,
D
enantiomer)¼19.9 min,
t
(minor
enantiomer)¼21.6 min].
CHCl3); 1H NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼7.95e7.75 (m, 1H, CH),
27
1
[
a]
¼ꢂ16.5 (c 0.68, CHCl3); H NMR (400 MHz, CDCl3, 25 ꢁC):
7.48e7.10 (m, 8H, CH), 4.37 (s, 1H, CHPh), 4.28 (dd, 1H; J¼7.5,
15.0 Hz, CH2N), 4.0 (ddd, 1H; J¼5.0, 11.0, 15.0 Hz, CH2N), 2.84 (dd,
1H; J¼5.0, 12.0 Hz, CH2CH2N), 2.05 (ddd, 1H; J¼7.5, 11.0, 12.0 Hz,
D
d
¼7.76e7.74 (m, 1H, CH), 7.42e7.27 (m, 3H, CH), 4.41 (dd, 2H; J¼3.1,
9.1 Hz, CH2N), 3.55 (d, 1H; J¼15.6 Hz, CH2N), 2.71 (d, 1H; J¼15.6 Hz,
CH2), 2.59 (td, 1H; J¼3.1, 12.5 Hz, CH2CH2N), 2.1 (td, 1H; J¼9.1,
12.5 Hz, CH2CH2N), 1.32 (s, 9H, CH3); 13C NMR (50.3 MHz, CDCl3,
13
CH2CH2N), 0.95 (s, 9H, CH3); C NMR (50.3 MHz, CDCl3, 25 ꢁC):
d
¼182.4, 168.2, 152.1, 137.9, 135.0, 131.0, 129.2 (2C), 128.3 (2C), 127.9,
25 ꢁC):
d
¼182.5, 171.0, 151.7, 132.6, 131.4, 127.3, 125.8, 123.1, 81.4,
127.3, 126.3, 122.8, 81.4, 74.3, 65.4, 57.0, 37.2, 27.5 (3C). MS (70 eV,
68.0, 67.2, 38.7, 37.0, 27.7 (3C). MS (70 eV, EI): m/z (%): 257 (9) [Mþ],
EI): m/z (%): 333 (19) [Mþ], 277 (100), 276 (52), 260 (13), 233 (46),

10540
S. Sternativo et al. / Tetrahedron 68 (2012) 10536e10541
232 (72), 200 (56), 156 (28), 154 (18), 57 (34). FT-IR (KBr):
(C]O), 1657 (C]N) cmꢂ1
n
1724
25 ꢁC):
d
¼7.45e7.38 (m, 1H, CH), 7.29e7.22 (m, 2H, CH), 7.21e7.16
.
(m, 1H, CH), 5.03 (s, 1H, CHN), 3.65 (d, 1H; J¼16.9 Hz, CH2), 3.16
(ddd, 1H; J¼4.6, 7.6, 11.8 Hz, CH2N), 3.05 (d, 1H; J¼16.9 Hz, CH2),
2.76 (td, 1H; J¼7.6, 11.8 Hz, CH2N), 2.75 (br s, 1H, NH), 2.42 (td,
1H; J¼7.6, 13.0 Hz, CH2CH2N), 1.84 (ddd, 1H; J¼4.6, 7.6, 13.0 Hz,
4.9. tert-Butyl (3aR)-2,3,4,5-tetrahydro-3aH-benzo[g]indole-
3a-carboxylate (5f)
13
CH2CH2N), 1.45 (s, 9H, CH3); C NMR (100 MHz, CDCl3, 25 ꢁC):
This compound was isolated as an oil by column chromatog-
raphy (elution gradient: light petroleum/diethyl ether 80:20 to
50:50) in 53% yield and 20% ee as determined by HPLC analysis
d
¼176.0, 141.9, 141.5, 128.2, 128.0, 125.2, 124.5, 80.9, 74.0, 60.3,
47.1, 41.8, 40.7, 28.0 (3C). FT-IR (KBr):
n 3205 (NH), 1722 (C]O)
cmꢂ1. HRMS (ESI): m/z calcd for C16H21NO2 (MþH)þ 260.16451,
26
[Lux cellulose-2, hexane/IPA 90:10, 1 mL/min,
l
230 nm, t (minor
found: 260.16473. ent-6a: 56% yield, 98% ee, [
a
]
¼þ56.6 (c 1.85,
D
enantiomer)¼4.8 min,
t
(major
enantiomer)¼5.6 min].
CHCl3).
27
1
[
a
]
¼þ15.21 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3, 25 ꢁC):
D
d
¼8.08 (dd, 1H; J¼1.4, 7.5 Hz, CH), 7.3 (dt, 1H; J¼1.4, 7.5 Hz, CH),
4.13. tert-Butyl (3aR,8bS)-7-chloro-2,3,4,8b-tetrahydroindeno
[1,2-b]pyrrole-3a(1H)-carboxylate (6b)
7.26 (t, 1H; J¼7.5 Hz, CH), 7.2 (d, 1H; J¼7.5 Hz, CH), 4.18 (ddd, 1H,
J¼1.0, 7.9, 15.6 Hz, CH2N), 3.86 (ddd, 1H, J¼6.8, 10.4, 15.6 Hz,
CH2N), 3.08 (ddd, 1H, J¼5.1, 13.1, 17.7 Hz, CH2), 2.86 (ddd, 1H, J¼1.9,
5.2, 17.7 Hz, CH2), 2.67 (ddd, 1H, J¼1.9, 5.1, 13.1 Hz, CH2), 2.47 (ddd,
1H; J¼1.0, 6.8, 13.0 Hz, CH2CH2N), 1.94 (ddd, 1H; J¼7.9, 10.4,
This compound was obtained as a single diastereoisomer and
isolated as an oil by column chromatography (elution gradient:
hexane/ethyl acetate 90:10 to 70:30) in 57% yield and 94% ee as
determined by HPLC analysis of the corresponding Boc-protected
13.0 Hz, CH2CH2N), 1.80 (dt, 1H; J¼5.2, 13.1 Hz, CH2), 1.34 (s, 9H,
13
CH3); C NMR (100 MHz, CDCl3, 25 ꢁC):
d
¼172.1, 171.4, 139.6,
derivative [Chiralcel OD-H, hexane/IPA 98:2, 0.8 mL/min, l
130.5, 130.0, 128.6, 126.4, 126.0, 81.4, 59.9, 58.8, 37.6, 32.8, 27.8,
230 nm, t (major enantiomer)¼6.4 min, t (minor enantiomer)¼
28
27.5 (3C). MS (70 eV, EI): m/z (%): 271 (7) [Mþ], 215 (60), 171 (23),
7.3 min]. [
25 ꢁC):
a]
¼ꢂ58.5 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3,
D
170 (100), 128 (13), 115 (11), 57 (53). FT-IR (KBr):
n
1722 (C]O),
d
¼7.32 (s, 1H, CH), 7.20 (d, 1H, J¼8.1 Hz, CH), 7.09 (d, 1H,
1626 (C]N) cmꢂ1
.
J¼8.1 Hz, CH), 4.98 (s, 1H, CHN), 3.58 (d, 1H; J¼16.9 Hz, CH2), 3.13
(ddd, 1H; J¼4.2, 7.8, 11.6 Hz, CH2N), 2.98 (d, 1H; J¼16.9 Hz, CH2),
2.68 (td, 1H; J¼7.8, 11.6 Hz, CH2N), 2.36 (td, 1H; J¼7.8, 12.9 Hz,
CH2CH2N), 2.3 (br s, 1H, NH), 1.81 (ddd, 1H; J¼4.2, 7.8, 12.9 Hz,
4.10. tert-Butyl 2-(2-azidoethyl)-1-oxo-2-indanecarboxylate
(rac-4a)
13
CH2CH2N), 1.45 (s, 9H, CH3); C NMR (100 MHz, CDCl3, 25 ꢁC):
This compound was isolated as an oil by column chromatogra-
phy (elution: light petroleum/ethyl acetate 95:5) in 80% yield. 1H
d
¼175.8, 144.8, 139.8, 132.8, 128.2, 125.5, 125.3, 80.9, 74.0, 60.8,
47.3, 41.1, 41.0, 28.0 (3C). FT-IR (KBr):
n 3251 (NH), 1718 (C]O)
NMR (200 MHz, CDCl3, 25 ꢁC):
d¼7.78 (m, 1H, CH), 7.70e7.35 (m,
cmꢂ1. HRMS (ESI): m/z calcd for C16H20ClNO2 (MþH)þ 294.12553,
22
3H, CH), 3.65 (d, 1H; J¼17.2 Hz, CH2), 3.50e3.26 (m, 2H, CH2N), 3.12
(d,1H; J¼17.2 Hz, CH2), 2.32 (ddd, 1H; J¼6.0, 8.0,14.1 Hz, CH2CH2N),
2.13 (ddd, 1H; J¼6.7, 8.5, 14.1 Hz, CH2CH2N), 1.39 (s, 9H, CH3); 13C
found: 294.12522. ent-6b: 72% yield, 93% ee, [
a]
¼þ60.9 (c 1.25,
D
CHCl3).
NMR (50 MHz, CDCl3, 25 ꢁC):
127.7, 126.3, 124.7, 82.3, 59.7, 47.5, 37.1, 33.3, 27.7 (3C).
d
¼201.9, 169.4, 152.7, 136.4, 135.3,
4.14. tert-Butyl (4bS,7aR)-4b,6,7,8-tetrahydro[1,3]dioxolo [5,6]
indeno[1,2-b]pyrrole-7a(5H)-carboxylate (6c)
4.11. Synthesis of the cyclic -amino esters 6aef
b
This compound was obtained as a single diastereoisomer and
isolated as an oil by column chromatography (elution: dichloro-
methane/methanol 95:5) in 50% yield and 96% ee as determined by
HPLC analysis of the corresponding Boc-protected derivative
Compounds 5aef were dissolved in MeOH and the reaction
mixture was cooled to 0 ꢁC with an ice bath. Then NaBH4
(10 equiv) was carefully added in three portions during 1/2 h.
After 1 h, the ice bath was removed and the reaction mixture was
stirred overnight. Next 3 equiv of NaBH4 were added and the re-
action was stirred for additional 3 h. MeOH was partially removed
under reduced pressure and the reaction was quenched with a 5%
aqueous solution of NaOH. The mixture was transferred into
a separatory funnel and extracted with CH2Cl2 (3ꢀ10 mL). The
organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure. Compounds 6aef were purified by col-
umn chromatography on deactivated silica gel. The enantiomeric
[Chiralcel OD-H, hexane/IPA 98:2, 0.8 mL/min,
enantiomer)¼7.8 min, t (minor enantiomer)¼9.1 min]. [
(c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3, 25 ꢁC):
l 230 nm, t (major
29
a
]
¼ꢂ61.9
D
d
¼6.75 (s,1H, CH),
6.57 (s, 1H, CH), 5.93e5.89 (m, 2H, CH2O), 4.82 (s, 1H, CHN), 3.51 (d,
1H; J¼16.6 Hz, CH2), 3.08 (ddd, 1H; J¼4.0, 7.5, 11.6 Hz, CH2N), 2.88
(d, 1H; J¼16.6 Hz, CH2), 2.68 (td, 1H; J¼7.5, 11.6 Hz, CH2N), 2.32 (td,
1H; J¼7.5, 12.8 Hz, CH2CH2N), 2.15 (br s, 1H, NH), 1.79 (ddd, 1H;
J¼4.0, 7.5, 12.8 Hz, CH2CH2N), 1.45 (s, 9H, CH3); 13C NMR (100 MHz,
CDCl3, 25 ꢁC):
d
¼176.1, 148.0, 147.3, 135.3, 134.2, 105.0, 104.4, 101.0,
80.6, 74.1, 61.0, 47.1, 41.5, 41.4, 28.0 (3C). FT-IR (KBr):
n 3314 (NH),
excesses of the final
b
-amino esters were determined by HPLC
1718 (C]O) cmꢂ1. HRMS (ESI): m/z calcd for C17H21NO4 (MþH)þ
analyses with chiral columns after Boc-protection of the amine
group with di-tert-butyl dicarbonate. Racemic samples were pre-
pared for HPLC analyses.
304.15433, found: 304.15354.
4.15. tert-Butyl (3aR,8bS)-6,7-dimethoxy-2,3,4,8b-tetrahy-
droindeno[1,2-b]pyrrole-3a(1H)-carboxylate (6d)
4.12. tert-Butyl (3aR,8bS)-2,3,4,8b-tetrahydroindeno[1,2-b]
pyrrole-3a(1H)-carboxylate (6a)
This compound was obtained as a single diastereoisomer and
isolated as an oil by column chromatography (elution:
dichloromethane/methanol 95:5) in 44% yield calculated on the
starting vinyl selenone 1 and 96% ee as determined by HPLC
analysis of the corresponding Boc-protected derivative [Lux
This compound was obtained as a single diastereoisomer and
isolated as an oil by column chromatography (elution gradient:
hexane/ethyl acetate 90:10 to 60:40) in 55% yield and 98% ee as
determined by HPLC analysis of the corresponding Boc-protected
amylose-2, hexane/IPA 95:5, 1.0 mL/min,
l 230 nm, t (minor
derivative [Lux cellulose-2, hexane/IPA 99:1, 0.8 mL/min,
l
enantiomer)¼28.1 min,
t
(major
enantiomer)¼31.1 min].
34
1
230 nm, t (minor enantiomer)¼10.2 min, t (major enantiomer)¼
[
a
]
¼ꢂ33.6 (c 0.91, CHCl3); H NMR (400 MHz, CDCl3, 25 ꢁC):
D
27
10.6 min]. [
a
]
¼ꢂ58.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3,
d
¼6.84 (s, 1H, CH), 6.65 (s, 1H, CH), 4.90 (s, 1H, CHN), 3.87 (s, 3H,
D

S. Sternativo et al. / Tetrahedron 68 (2012) 10536e10541
10541
OMe), 3.85 (s, 3H, OMe), 3.57 (d, 1H; J¼16.5 Hz, CH2), 3.10 (ddd,
1H; J¼3.9, 8.0, 11.6 Hz, CH2N), 2.93 (d, 1H; J¼16.5 Hz, CH2), 2.69
(ddd, 1H; J¼7.0, 8.0, 11.6 Hz, CH2N), 2.32 (td, 1H; J¼8.0, 12.8 Hz,
CH2CH2N), 2.18 (br s, 1H, NH), 1.80 (ddd, 1H; J¼3.9, 7.0, 12.8 Hz,
(3C). HRMS (ESI): m/z calcd for C17H23NO2 (MþH)þ 274.18015,
found: 274.18026.
Acknowledgements
13
CH2CH2N), 1.47 (s, 9H, CH3); C NMR (100 MHz, CDCl3, 25 ꢁC):
d
¼176.2, 149.4, 148.8, 133.9, 133.0, 107.3, 106.9, 80.6, 74.7, 61.0,
Financial support from MIUR (PRIN, Progetto Nazionale Ster-
eoselezione in Sintesi Organica: Metodologie ed Applicazioni),
University of Perugia, Consorzio CINMPIS and Fondazione Cassa di
Risparmio, Perugia is gratefully acknowledged.
55.9, 55.8, 47.3, 41.6, 41.5, 28.0 (3C). FT-IR (KBr):
n 3314 (NH),
1718 (C]O) cmꢂ1. HRMS (ESI): m/z calcd for C18H25NO4 (MþH)þ
320.18563, found: 320.18542.
References and notes
4.16. tert-Butyl (3aS,4S,8bS)-4-phenyl-2,3,4,8b-tetrahy-
droindeno[1,2-b]pyrrole-3a(1H)-carboxylate (6e)
1. (a) Organoselenium Chemistry: Synthesis and Reactions; Wirth, T., Ed.; Wiley-
VCH GmbH & KGaA: Weinheim, 2012; (b) Organoselenium Chemistryda Prac-
tical Approach; Back, T. G., Ed.; Oxford University: Oxford, 1999; (c) Godoi, M.;
Paixao, M. W.; Braga, A. L. Dalton Trans. 2011, 40, 11347e11355; (d) Freudendahl,
D. M.; Santoro, S.; Shahzad, S. A.; Santi, C.; Wirth, T. Angew. Chem., Int. Ed. 2009,
48, 8409e8411; (e) Braga, A. L.; Ludtke, D. S.; Vargas, F.; Braga, R. C. Synlett
2006, 1453e1466; (f) Zhu, C.; Huang, Y. Curr. Org. Chem. 2006, 10, 1905e1920;
(g) Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 3740e3749.
2. For catalytic selenoetherification reactions of alkenes see: (a) Denmark, S. E.;
Kalyani, D.; Collins, W. R. J. Am. Chem. Soc. 2010, 132, 15752e15765; (b) Guan,
H.; Wang, H.; Huang, D.; Shi, Y. Tetrahedron 2012, 68, 2728e2735.
3. (a) Tiecco, M.; Carlone, A.; Sternativo, S.; Marini, F.; Bartoli, G.; Melchiorre, P.
Angew. Chem., Int. Ed. 2007, 46, 6882e6885; (b) Marcos, V.; Aleman, J.; Garcia
Ruano, J. L.; Marini, F.; Tiecco, M. Org. Lett. 2011, 13, 3052e3055.
4. (a) Sternativo, S.; Calandriello, A.; Costantino, F.; Testaferri, L.; Tiecco, M.;
Marini, F. Angew. Chem., Int. Ed. 2011, 50, 9382e9385; (b) Marini, F.; Sternativo,
S.; Del Verme, F.; Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2009, 351,
1801e1806; (c) Marini, F.; Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco, M.
Adv. Synth. Catal. 2009, 351, 103e106.
5. For some recent synthesis of indenopyrrolidines see: (a) Biggs-Houck, J. E.;
Davis, R. L.; Wei, J.; Mercado, B. Q.; Olmstead, M. M.; Tantillo, D. J.; Shaw, J. T. J.
Org. Chem. 2012, 77, 160e172; (b) Zheng, D.; Li, S.; Luo, Y.; Wu, J. Org. Lett. 2011,
13, 6402e6405; (c) Wu, K. J.; Li, G. Q.; Li, Y.; Dai, L. X.; You, S. L. Chem. Commun.
2011, 493e495; (d) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49,
This compound was obtained as a single diastereoisomer and
isolated as an oil by column chromatography (elution:
dichloromethane/methanol 97:3) in 70% yield based on re-
covered starting material (35% of 5e was recovered) and 95% ee
as determined by HPLC analysis of the corresponding Boc-
protected derivative [Lux cellulose-2, hexane/IPA 99:1, 1.0 mL/
min,
enantiomer)¼13.9 min]. [
(400 MHz, CDCl3, 25 ꢁC):
l
230 nm,
t
(major enantiomer)¼9.8 min,
t (minor
21
a
]
¼þ97.0 (c 0.85, CHCl3); 1H NMR
D
d
¼7.38e7.32 (m, 1H, CH), 7.25e7.03 (m,
5H, CH), 6.97e6.86 (m, 3H, CH), 5.35 (s, 1H, CHN), 4.62 (s, 1H,
CHPh), 2.96 (ddd, 1H; J¼5.8, 7.4, 11.2 Hz, CH2N), 2.66 (dt, 1H;
J¼7.4, 11.2 Hz, CH2N), 2.37 (dt, 1H; J¼7.4, 13.3 Hz, CH2CH2N), 2.10
(br s, 1H, NH), 1.94 (ddd, 1H; J¼5.8, 7.4, 13.3 Hz, CH2CH2N), 0.97
13
(s, 9H, CH3); C NMR (100 MHz, CDCl3, 25 ꢁC):
d
¼173.6, 144.6,
143.4, 143.1, 128.8 (2C), 128.3, 128.2 (2C), 127.9, 126.5, 125.4, 125.1,
80.3, 70.2, 67.2, 59.9, 45.8, 41.1, 27.3 (3C). FT-IR (KBr): n 3309, 1711
(C]O). HRMS (ESI): m/z calcd for C22H25NO2 (MþH)þ 336.19581,
~
8181e8184; (e) El Kaïm, L.; Gamez-Montano, R.; Grimaud, L.; Ibarra-Rivera, T.
Chem. Commun. 2008, 1350e1352.
6. De, A. U.; Saha, B. P. J. Pharm. Sci. 1973, 62, 1363e1372.
found: 336.19541.
7. (a) Carroll, F. I.; Blough, B. E.; Mascarella, S. W.; Xu, H.; Goodman, C. B.;
Rothman, R. B. Med. Chem. Res. 1993, 3, 178e182; (b) Hayashibe, S.; Yamasaki, S.;
Shiraishi, N.; Hoshii, H.; Tobe, T. PCT Int. Appl., WO 2009069610, 2009.
8. Hanessian, S.; Papeo, G.; Angiolini, M.; Fettis, K.; Beretta, M.; Munro, A. J. Org.
Chem. 2003, 68, 7204e7218.
4.17. tert-Butyl (3aR)-1,2,3,4,5,9b-hexahydro-3aH-benzo[g]in-
dole-3a-carboxylate (6f)
9. Bolognesi, M. L.; Bartolini, M.; Cavalli, A.; Andrisano, V.; Rosini, M.; Minarini, A.;
This compound was obtained as a mixture of diastereoisomers
(A:B¼44:56) in 67% yield based on recovered starting material (40%
of 5f was recovered) and isolated by column chromatography
(elution gradient: dichloromethane/methanol 98:2 to 95:5). 1H
Melchiorre, C. J. Med. Chem. 2004, 47, 5945e5952.
10. For recent reviews see: (a) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard,
A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656e1691; (b) Miller, J. A.; Nguyen,
S. T. Mini-Rev. Org. Chem. 2005, 2, 39e45; (c) Kuhl, A.; Hahn, M. G.; Dumic, M.;
Mittendorf, J. Amino Acids 2005, 29, 89e100; (d) Ma, J. Amino Acids 2003, 42,
4290e4299; (e) Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794e5795; (f) Liu,
M.; Sibi, M. P. Tetrahedron 2002, 58, 7991e8035.
NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼7.47e7.43 (m, 1H, CH isomer A),
7.35e7.29 (m,1H, CH isomer B), 7.20e7.08 (m, 6H, CH isomers A and
B), 4.46 (s, 1H, CHN isomer A), 3.84 (s, 1H, CHN isomer B), 3.41e3.23
(m, 2H, CH2N isomer B), 3.17e2.86 (m, 6H, CH2N isomer A, CH2
isomer B, NH isomers A and B), 2.77e2.70 (m, 2H, CH2 isomer A),
2.65 (ddd, 1H, J¼2.3, 8.7, 13.1 Hz, CH2 isomer B), 2.33 (ddd, 1H;
J¼5.3, 8.5, 13.4 Hz, CH2 isomer A), 2.22 (ddd, 1H; J¼4.0, 8.6, 12.8 Hz,
CH2 isomer B), 2.18 (td, 1H; J¼4.8, 13.4 Hz, CH2 isomer A), 1.88 (td,
1H; J¼7.5, 15.3 Hz, CH2 isomer A), 1.1.84e1.66 (m, 3H, CH2 isomer A,
CH2 isomer B); 1.42 (s, 9H, isomer A), 1.11 (s, 9H, isomer b); 13C NMR
11. Mitsunuma, H.; Matsunaga, S. Chem. Commun. 2011, 469e471.
12. For recent reviews on applications of intramolecular aza-Wittig reactions for
the synthesis of heterocyclic compounds see: (a) Palacios, F.; Alonso, C.;
Aparicio, D.; Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63, 523e575; (b)
Eguchi, S. Arkivoc 2005, 2, 98e119.
13. For reductions of imines containing a quaternary stereocenter see: (a) Almahli,
ꢀ
H.; Hendra, F.; Troufflard, C.; Cave, C.; Joseph, D.; Delarue-Cochin, S. Chirality
2011, 23, 265e271; (b) Bhattacharya, S.; Mandal, A. N.; Chaudhuri, S. R. R.;
Chatterjee, A. J. Chem. Soc., Perkin Trans. 1 1984, 5e13.
14. The addition step reached completion in a reasonable reaction time (24 h).
15. Sternativo, S.; Marini, F.; Del Verme, F.; Calandriello, A.; Testaferri, L.; Tiecco, M.
Tetrahedron 2010, 66, 6851e6857.
16. Moss, T. A.; Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130,
10076e10077.
(100 MHz, CDCl3, 25 ꢁC):
d¼174.3, 165.6, 137.0, 136.6, 136.2, 130.0,
128.3, 128.1, 127.0, 126.5, 126.2, 125.6, 123.2, 80.7, 70.5, 68.4, 62.3,
58.8, 54.2, 46.6, 45.3, 38.8, 36.9, 29.8, 29.5, 27.9, 27.5, 27.3 (3C), 27.0
17. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906e9907.