Application of the intramolecular PIFA-mediated amidation of alkynes to the synthesis of substituted indolizidinones

Article abstract of DOI:10.1016/j.tet.2012.03.033

The construction of the title compounds has been achieved from properly substituted linear alkynylamides through the suitable combination of two key cyclization steps. First, an intramolecular PIFA-mediated alkyne amidation protocol leads to the creation

Full text of DOI:10.1016/j.tet.2012.03.033

Tetrahedron 68 (2012) 3692e3700
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Application of the intramolecular PIFA-mediated amidation of alkynes to the
synthesis of substituted indolizidinones
*
*
Leticia M. Pardo, Imanol Tellitu , Esther Domínguez
ꢀ
Departamento de Química Organica II, Facultad de Ciencia y Tecnología (ZTF/FCT), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), PO Box 644,
48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The construction of the title compounds has been achieved from properly substituted linear alkynyla-
mides through the suitable combination of two key cyclization steps. First, an intramolecular PIFA-
mediated alkyne amidation protocol leads to the creation of the pyrrolidinone nucleus, which under
proper manipulation of the generated ketoecarbonyl group permits the assembling of the indolizidinone
skeleton by the introduction of a subsequent ring closing olefin metathesis step. Finally, its trans-
formation into a series of substituted mono- and trihydroxylated indolizidinone derivatives is achieved
by manipulation of the remaining unsaturated fragment under hydrogenation and dihydroxylation
conditions.
Received 3 February 2012
Received in revised form 8 March 2012
Accepted 9 March 2012
Available online 15 March 2012
Keywords:
Hypervalent iodine
Alkynylamides
PIFA
Ó 2012 Elsevier Ltd. All rights reserved.
Olefin metathesis
Indolizidinones
1. Introduction
selection of different groups (X and R in II) would represent a new
starting point for the synthesis of a number of nitrogen containing
Some years ago, our group demonstrated that the intramolecular
amidation of properly substituted alkynes (I) can be performed in
the presence of the hypervalent iodine reagent PIFA [bis(tri-
fluoroacetoxy)phenyliodane] to render a series of 5-aroyl- and 5-
alkenoyl-2-pyrrolidinones of type II (see Fig. 1).1 As a constituent
of the framework of a number of important heterocycles, we con-
sidered the construction of highly functionalized pyrrolidinone
skeletons as a main object of our research. In this context, the subtle
heterocycles and, in fact, we have recently confirmed the value of
this approach in the preparation of pyrrolodiazepinone and pyrro-
lobenzodiazepinone derivatives from N-(3-aminopropyl)-, N-(2-
aminomethylphenyl)-, and N-(20-nitrobenzyl)-substituted pyrroli-
dinones,2 and also in the synthesis of pyrroloepyrazinones from
N-(20-aminoethyl)pyrrolidinones3 by the inclusion, in both cases, of
an additional reductive amination step.
With the aim of expanding the applicability of the proposed
synthetic strategy, we show in this paper our efforts to prepare
differently substituted indolizidinones of type III starting from 5-
aryl- and 5-alkenyl-N-allylpentynamides V.4 According to the ret-
rosynthetic analysis shown Fig. 2, the success of our plan will rely
on two key cyclization steps: (i) the PIFA-mediated alkyne amida-
tion to render IV, in which the presence of the hydroxy group will
be developed by the insertion of an additional reductive step or,
alternatively, with the addition of an organometallic vinylic reagent
to the previously generated ketoecarbonyl group, and (ii) a ring
closing metathesis step performed on the N-allyl group and the
remaining olefin fragment. Manipulation of the resultant unsatur-
ationdacross C(6) and C(7) positionsdunder reductive and oxi-
dative conditions will be also attempted as a source for higher
structural diversity in the final mono- and trihydroxylated indoli-
zidinones that will be eventually prepared, our final challenge.
Polyhydroxylated indolizidines have been the target of a myriad
of well-established and novel synthetic approaches as a result of
Fig. 1. PIFA-mediated construction of substituted pyrrolidinones.
* Corresponding authors. Tel.: þ34 94 601 5438; fax: þ34 94 601 2748; e-mail
address: imanol.tellitu@ehu.es (I. Tellitu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.033

L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
3693
Fig. 2. Key retrosynthetic disconnections for the construction of the indolizidinone
skeleton.
the relevant biological activity that these naturally occurring or
synthetically-derived heterocycles display.5 For this purpose, the
selection of a number of carbohydrates, mainly
D-mannitol, D-ri-
bose, -glucose or -sorbose, among others, from the chiral pool has
D
L
been a recurrent option to create the indolizidine skeleton.6 These
strategies benefit from the well defined stereochemistry that will
be induced in the final compounds but, contrarily, they are occa-
sionally limited by their lack of stereochemical flexibility and, in
some cases, are usually longer than desired mainly because of the
introduction of unavoidable protection and deprotection steps.
Therefore, we show in this paper our efforts to design a new
protecting-free non-sugar based route to the synthesis of racemic
8-hydroxyindolizidinones.7
Scheme 1. Preparation of pyrrolidinones 4 and 5aed.
The survey to perform the diastereoselective reduction of 4 was
carried out by combining a number of different reducing agents,
solvents, and coordinating metal sources (see Scheme 2). In partic-
ular, when a sterically demanding reducing agent, such as L-Selec-
tride was tested in THF at ꢀ78 ꢁC, we were rewarded with
a completely diastereoselective transformation leading to (syn)-6.11
In contrast, we met only limited success in the preparation of (anti)-
6. In fact, under the best circumstances, the use of NaBH4 in com-
bination with ZnCl2, which was introduced with the aim to induce
a chelation-controlled addition, produced a chromatographically
separable mixture of both diastereoisomers. On the other hand, the
selection of the adequate conditions to conduct the diaster-
eodivergent addition of vinylmagnesium bromide to pyrrolidinones
5aed was also examined (see Scheme 2). Thus, it was found that
2. Results and discussion
Looking for a high structural diversity in the final compounds,
our synthetic design was conceived to incorporate a number of aryl
and alkenyl groups at the terminal position of the starting N-allyl-
5-pentynamide (1) in the first stage of the synthesis, as shown in
Scheme 1. For that purpose, the required Sonogashira coupling
process had to be optimized with respect to the nature of the halide
component of the reaction.8 Thus, the experimental conditions
employed to obtain amides 3aed, which required a series of aryl
iodides and the catalytic use of CuI and Pd(PPh3)2Cl2 in triethyl-
amine as solvent at room temperature, had to be modified with the
additional participation of PPh3 and working at solvent reflux
temperature to prepare amide 2 from 1 and (E)-b
-bromostyrene.9
When all parts of substrates 2 and 3aed were assembled, they
were submitted to the PIFA-mediated cyclization conditions. Thus,
treatment of these alkynylamides 2 and 3 with a slight excess
(1.5 equiv) of the hypervalent iodine reagent in trifluoroethanol
(TFE) as solvent at room temperature, followed by a basic aqueous
work up (aq K2CO3), rendered the corresponding 5-styryl- and 5-
aroyl-2-pyrrolidinones 4 and 5aed in acceptable yields.
Prior to the planned ring closing metathesis step, we found that
both types of pyrrolidinones 4 and 5 had to be manipulated. Con-
sidering that, in the case of pyrrolidinone 4, all attempts to perform
the projected cyclization didn’t afford the expected results under
a number of Ru-catalyzed conditions, a reductive step to generate
the corresponding hydroxy group was introduced. Complementary,
and with the same purpose, 5-aroylpyrrolidinones 5aed were
submitted to the action of vinylmagnesium bromide in order to fix
the olefin fragment and, at the same time, to develop the hydroxy
group that eventually will be located at the C(8) position of the
indolizidinone skeleton. In any case, both processes, the reduction
of the keto group and the addition of the Grignard reagent, were
studied with the aim to obtain pure samples of both possible syn/
anti diastereoisomers, as it will be now disclosed.10
Scheme 2. Preparation of hydroxylated pyrrolidinones 6 and 7a.

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L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
when the reaction was performed under chelation-controlled con-
ditions, a series of pyrrolidinones (syn)-7aed was obtained with
complete diastereocontrol in good to excellent yields. Particularly,
the behavior of ZnCl2 resulted to be superior over other additives
that were also studied, such as Mg(ClO4)2, 18-crown-6, CeCl3, or
CuI.12 Contrarily, none of the experimental conditions that were
tested with the aim to prepare pyrrolidinones (anti)-7aed led to
good levels of diastereocontrol (up to 66/34 for 7a).13
With these materials in hand, we moved to our next synthetic
step. In order to overcome a number of difficulties associated to the
lack of reactivity and partial olefin isomerization14 that were
detected in our preliminary assays, a combination of several ex-
perimental parameters including the use of Grubbs I or Grubbs II
catalysts (see Fig. 3), the use of different solvents (CH2Cl2 and tol-
uene), and different temperatures (rt and solvent reflux) had to be
optimized to perform the ring closing metathesis reaction on de-
rivatives 6 and 7.15
order to extend the structural diversity of the series of indolizidi-
none derivatives that can be prepared. Firstly, (see Table 2) it
was found that treatment of separated samples of both di-
astereoisomers 8 under an atmosphere of H2 (70 psi) using Pd (C) as
catalyst in MeOH rendered indolizidinones (syn)-10 and (anti)-10
in a moderate 46 and 43% yields, respectively. Similarly, when
indolizidines 9 were submitted to the same reaction conditions,
a series of indolizidinones 11aed was prepared in moderate to
good yields.
Table 2
Preparation of a series of indolizidinones 10 and 11a,b
Entry
Ar
Substrate (syn/anti)
Product (syn/anti)
Yield (%)
1
2
3
4
5
6
7
8
9
d
8 (100/0)
8 (0/100)
10 (100/0)
10 (0/100)
11a (33/67)
11a (100/0)
11b (53/47)
11b (100/0)
11c (41/59)
11c (100/0)
11d (38/62)
11d (100/0)
46
43
69
60
67
63
65
53
68
56
d
Ph
Ph
PMP
PMP
p-ClC6H4
p-ClC6H4
2-Thyenyl
2-Thyenyl
9a (33/67)
9a (100/0)
9b (53/47)
9b (100/0)
9c (41/59)
9c (100/0)
9d (38/62)
9d (100/0)
Fig. 3. First (GI) and second (GII) generation Grubbs’ catalysts.
Such optimization process led to the conclusion (see Table 1)
that whereas the transformation of either (syn)-6 or (anti)-6 into
the corresponding indolizidinones 8 had to be performed under the
assistance of GII catalyst in refluxing toluene (71 and 86% yield,
respectively), the preparation of indolizidinones 9aed required the
use of CH2Cl2 as solvent at room temperature with the aid of
Grubbs’ GII catalyst as well (58e66 yield).16 The 1H NMR-based
stereochemical analysis of the crude samples revealed that the
projected cyclization resulted to be successful in the absence of OH
protection and with no detectable epimerization in none of the
cases under study.17
10
a
All reactions were performed under an atmosphere of H2 in MeOH as solvent at
room temperature, and in the presence of 10% Pd (C).
b
The diastereomeric composition was determined from the crude 1H NMR.
Finally, we found that the projected dihydroxylation step, that
would render the desired trihydroxylated indolizidinone skeleton,
resulted to be much more problematic.18 In fact, although indoli-
zidinone (syn)-8 behaved as expected to render the 6,7,8-
trihydroxyindolizidinone (syn)-12 in an excellent 93% yield under
modified Upjohn conditions,19 for which the stereochemical out-
come is the result of a stereoelectronic repulsion with the existing
C(8)-hydroxy group,20 indolizidinone (anti)-8 resulted to be in-
explicably unreactive under all different conditions that were
tested. Similarly, none of all syn or anti indolizidinones 9 produced
the desired trihydroxylated derivatives when submitted to an array
of different dihydroxylation conditions, except for (anti)-9a. Thus,
Table 1
Preparation of a series of indolizidinones 8 and 9a,b
when
a syn/anti mixture of (syn/anti)-9a was treated with
K2OsO4$2H2O under Upjohn conditions, pure (anti)-13a was
obtained in 57% yield (86% based on consumed starting material)
together with unreacted (syn)-9a (Scheme 3).
Entry
Ar
Substrate (syn/anti)
Product (syn/anti)
Yield (%)
1
2
3
4
5
6
7
8
9
10
d
6 (100/0)
6 (0/100)
8 (100/0)
8 (0/100)
71
86
66
65
60
65
65
58
65
58
Although the explanation for the dramatic difference in the
observed reactivity with respect to the nature of the aryl ring in the
series of indolizidinones 9aed is out of our knowledge, din fact,
only 9a appears to be reactive enoughd, we can suggest (see Fig. 4)
a possible explanation for the higher reactivity of (anti)-9a over its
diastereoisomer (syn)-9a. If we assume that substrate 9a is stabi-
lized in a half-chair conformation, the allylic substituents at C(8)
will occupy pseudoaxial and pseudoequatorial positions. Now, in
the case of the syn-stereoisomer, the oxidative reagent will find
opposition for its approach to both faces of the double bond, due to
electronic repulsion with the hydroxy group located in the pseu-
doaxial position in combination with the nitrogen lone pair, in one
case, and to the steric hindrance that the bulky phenyl group exerts
in the opposite face. But, although the latter repulsion also exists for
the phenyl group in the anti-stereoisomer, the electronic repulsion
that the hydroxy group induces is diminished since it lies far from
d
Ph
Ph
PMP
PMP
p-ClC6H4
p-ClC6H4
2-Thienyl
2-Thienyl
7a (33/67)
7a (100/0)
7b (53/47)
7b (100/0)
7c (41/59)
7c (100/0)
7d (38/62)
7d (100/0)
9a (33/67)
9a (100/0)
9b (53/47)
9b (100/0)
9c (41/59)
9c (100/0)
9d (38/62)
9d (100/0)
a
GII catalyst was employed in refluxing toluene for the transformation of com-
pound 6, and in CH2Cl2 at room temperature for the transformation of compounds
7aed.
b
The diastereomeric composition was determined from the crude 1H NMR.
To conclude our projected research, the resultant unsaturation
generated on indolizidinones 8 and 9 was submitted to new ma-
nipulations, both under reductive and oxidative conditions, in

L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
3695
shifts (
d
) were measured in ppm relative to chloroform (
d
¼7.26 for
1H or 77.0 for 13C) as internal standard. Coupling constants, J, are
reported in hertz. DEPT and several bidimensional NMR experi-
ments (COSY, HSQC, NOESY) were used to assist with the assigna-
tion of the signals and structural and stereochemical
determinations. Mass spectra were recorded under electron impact
(EI, 70 eV) or chemical ionization conditions (CI).
4.2. Synthesis of N-allyl-4-pentynamide (1)
A solution of 4-pentynoic acid (640 mg, 6.5 mmol) in 5 mL of
DCM was added to a magnetically stirred solution of EDC$HCl (1.9 g,
9.9 mmol) and HOBt (1.35 g, 9.9 mmol) in 30 mL of the same solvent
followed by the addition of allylamine (0.75 mL, 9.9 mmol) dis-
solved in 10 mL of DCM. The mixture was cooled to 0 ꢁC and Et3N
(1.4 mL, 9.9 mmol) was added dropwise and was left to react at rt
overnight. Then, the reaction was diluted with DCM and water
(30 mL), the mixture decanted, and the aqueous phase extracted
with DCM (3ꢂ15 mL). The combined organic layers were dried over
Na2SO4, filtered, and the solvent was removed under vacuum. The
resultant chromatographically pure colorless oil was triturated
with cold Et2O to afford amide 1 as a while solid (82%): mp
Scheme 3. Preparation of hydroxylated pyrrolidinones (syn)-12 and (anti)-13a.
46e48 ꢁC (Et2O); 1H NMR (CDCl3)
d (ppm) 5.90e5.77 (m, 2H),
5.23e5.11 (m, 2H), 3.91e3.88 (m, 2H), 2.57e2.51 (m, 2H), 2.44e2.39
(m, 2H), 2.00 (t, J¼2.0, 1H); 13C NMR (CDCl3)
d (ppm) 170.7, 134.0,
116.4, 82.9, 69.3, 41.9, 35.3, 14.9; IR y
(cmꢀ1) 3295, 1648; MS [CI] m/
z: 138 (100), 136 (8); HRMS calcd for C8H11NO$Hþ138.0919, found
Fig. 4. Possible explanation for the different reactivity of (syn)- and (anti)-9 toward
the dihydroxylation reagent.
138.0925.
4.3. Synthesis of (E)-N-allyl-5-(b-styryl)-4-pentynamide (2)
the double bond because of its pseudoequatorial location. Conse-
quently, this situation is also in agreement with the all-syn re-
lationships that the three hydroxy groups display in indolizidinone
(anti)-13a.
A
solution of (E)- -bromostyrene (500 mg, 3
b
mmol),
PdCl2(PPh3)2 (21 mg, 0.03 mmol), PPh3 (23 mg, 0.09 mmol), and
amide 1 (615 mg, 4.5 mmol) in Et3N (20 mL) was stirred at 40 ꢁC for
15 min. Then, CuI (17 mg, 0.09 mmol) was added and the stirring
was continued at 80 ꢁC until total consumption of the starting
material (TLC, 6 h). Then, after cooling, the solvent was evaporated
under vacuum and the residue purified by column chromatography
(EtOAc) to afford amide 2 as a yellowish solid that was crystallized
3. Conclusions
In summary, the design of a new, short, and efficient strategy for
the preparation of
a series of unsaturated, saturated, and
from Et2O (54%): mp 68e70 ꢁC (Et2O); 1H NMR (CDCl3)
d (ppm)
substituted indolizidinones has been achieveddin racemic fash-
iondfrom highly and properly functionalized linear alkynylamides.
The combination of two key cyclization steps (PIFA-mediated al-
kyne amidation and a RCM step) allowed the creation of the re-
quired unsaturated bicyclic skeletons, on which the final
hydrogenation and dihydroxylation processes were performed. It
must be highlighted that all four continuous stereogenic centers in
the final compounds are produced in a complete diastereoselective
fashion and with no need of undesirable protection steps in any of
the stages of the synthesis.
7.37e7.29 (m, 5H), 6.87 (d, J¼16.2, 1H), 6.11 (d, J¼16.2, 1H),
5.91e5.80 (m, 1H), 5.74 (br s, 1H), 5.26e5.13 (m, 2H), 3.73 (t, J¼5.6,
11.2, 2H), 2.73 (t, J¼5.8, 12.7, 2H), 2.46 (t, J¼7.1, 14.3, 2H); 13C NMR
(CDCl3)
d (ppm) 170.9, 140.8, 134.1, 128.7, 128.5, 126.1, 116.4, 108.2,
90.8, 80.8, 42.0, 35.7, 16.2; IR
y
(cmꢀ1) 3295, 1638; MS [CI] m/z: 240
(100), 198 (32), 155 (23), 141 (25); HRMS calcd for
C16H17NO$Hþ240.1388, found 240.1392.
4.4. Typical procedure for the Sonogashira coupling reaction
4.4.1. Synthesis of N-allyl-5-phenyl-4-pentynamide (3a). A solution
of iodobenzene (0.5 mL, 4.05 mmol), PdCl2(PPh3)2 (28 mg,
0.04 mmol), CuI (15 mg, 0.08 mmol), and amide 1 (555 mg,
4.05 mmol) in Et3N (20 mL) was stirred at room temperature until
total consumption of the starting material (TLC, 72 h). Then, water
(30 mL) was added, the mixture was extracted with EtOAc
(3ꢂ25 mL), and the combined organic extracts were dried over
Na2SO4 (anh). Once the solvent was evaporated under vacuum, the
whole crude was purified by column chromatography (hexanes/
EtOAc, 1/1) to afford amide 3a as a white solid that was crystallized
4. Experimental section
4.1. General procedures
All reagents were purchased and used as received. All solvents
used in reactions were dried and purified according to standard
procedures. All air- or moisture-sensitive reactions were performed
under argon. The glassware was oven dried (140 ꢁC) overnight and
purged with argon prior to use. Melting points were measured
using open glass capillaries and are uncorrected. Infrared spectra
were recorded as thin films and peaks are reported in cmꢀ1. Only
representative absorptions are given. Flash chromatography was
carried out on SiO2 (silica gel 60, 230e400 mesh ASTM). NMR
spectra were recorded on a 300 instrument (300 MHz for 1H and
75.4 MHz for 13C) at 20e25 ꢁC unless otherwise stated. Chemical
from Et2O (94%): mp 72e73 ꢁC (Et2O); 1H NMR (CDCl3)
d (ppm)
7.37e7.32 (m, 2H), 7.25e7.23 (m, 3H), 6.30 (br s, 1H), 5.89e5.74 (m,
1H), 5.22e5.06 (m, 2H), 3.90e3.86 (m, 2H), 2.76e2.70 (m, 2H),
2.51e2.45 (m, 2H); 13C NMR (CDCl3)
d
(ppm) 171.1, 133.9, 131.4,
128.1, 127.7, 123.3, 116.1, 88.4, 81.4, 41.8, 35.4, 15.8; IR
(cmꢀ1) 3301,
1631; MS [EI] m/z: 213 (15), 212 (41), 185 (45), 184 (98), 172 (100),
y

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L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
170 (31), 128 (67); HRMS calcd for C14H15NO 213.1154, found
213.1149.
(m, 1H), 3.39 (dd, J¼15.0, 7.9, 1H), 2.42e2.39 (m, 3H), 2.01e1.96 (m,
1H); 13C NMR (CDCl3)
(ppm) 196.8, 175.0, 134.0, 133.9, 132.3128.9,
128.2, 118.6, 60.6, 44.2, 29.4, 23.0; IR
(cmꢀ1) 1690; MS [M] m/z:
d
y
4.4.2. N-Allyl-5-(4-methoxyphenyl)-4-pentynamide (3b). According
to the typical procedure, amide 3b was prepared from amide 1 and
4-iodoanisole in 57% yield as a yellowish solid. It was purified by
column chromatography (hexanes/EtOAc, 2/8) followed by crys-
229 (1), 124 (100), 105 (23); HRMS calcd for C14H15NO2: 229.1103,
found 229.1111.
4.5.3. (ꢃ)-N-allyl-5-(4-methoxyphenyl)-2-pyrrolidinone
(5b). According to the typical procedure, pyrrolidinone 5b was
prepared from amide 3b in 40% yield as a yellowish solid. It was
purified by column chromatography (EtOAc) followed by crystalli-
tallization from Et2O: mp 82e83 ꢁC (Et2O); 1H NMR (CDCl3)
d (ppm)
7.28 (d, J¼8.7, 2H), 6.77 (d, J¼8.7, 2H), 6.10 (br s, 1H), 5.88e5.75 (m,
1H), 5.21e5.07 (m, 2H), 3.88 (t, J¼5.6, 2H), 3.76 (s, 3H), 2.71 (t, J¼7.2,
2H), 2.47 (t, J¼7.2, 2H); 13C NMR (CDCl3)
d
(ppm) 171.2, 159.3, 134.4,
zation from Et2O: mp 72e73 ꢁC (Et2O); 1H NMR (CDCl3)
d (ppm)
132.9, 115.5, 113.8, 116.2, 86.8, 81.4, 55.2, 41.9, 35.8, 15.9; IR
y
(cmꢀ1
)
7.86 (d, J¼8.9, 2H), 6.91 (d, J¼8.9, 2H), 5.72e5.59 (m, 1H), 5.10e4.99
3310, 1633; MS [CI] m/z: 244 (100), 243 (44), 202 (50), 145 (10);
(m, 3H), 4.45e4.38 (m, 1H), 3.82 (s, 3H), 3.37e3.30 (m, 1H),
HRMS calcd for C15H17NO2$Hþ244.1337, found 244.1345.
2.44e2.33 (m, 3H), 1.96e1.90 (m, 1H); 13C NMR (CDCl3)
d
(ppm)
195.4, 175.2, 164.2, 132.5, 130.6128.9, 118.5, 114.2, 60.4, 55.6, 44.3,
4.4.3. N-Allyl-5-(4-chlorophenyl)-4-pentynamide (3c). According to
the typical procedure, amide 3c was prepared from amide 1 and 4-
chlorophenyl iodide in 54% yield as a white solid. It was purified by
column chromatography (hexanes/EtOAc, 2/8) followed by crys-
tallization from Et2O: mp 196e197 ꢁC (Et2O); 1H NMR (CDCl3)
29.6, 23.4; IR y
(cmꢀ1) 1690; MS [CI] m/z: 260 (100), 124 (40); HRMS
calcd for C15H17NO3$Hþ260.1287, found 270.1277.
4.5.4. (ꢃ)-N-allyl-5-(4-chlorophenyl)-2-pyrrolidinone
(5c). According to the typical procedure, pyrrolidinone 5c was
prepared from amide 3c in 54% yield as a yellowish oil. It was pu-
d
(ppm) 7.30e7.22 (m, 4H), 5.88e5.77 (m, 2H), 5.23e5.09 (m, 2H),
3.91 (t, J¼5.7, 2H), 2.75 (t, J¼7.2, 2H), 2.48 (t, J¼7.2, 2H); 13C NMR
rified by column chromatography (EtOAc): 1H NMR (CDCl3)
d (ppm)
(CDCl3)
d
(ppm) 170.9, 134.1, 133.8, 132.8, 128.5, 121.9, 116.4, 89.5,
7.81 (d, J¼8.6, 2H), 7.40 (d, J¼8.6, 2H), 5.66e5.56 (m, 1H), 5.08e4.97
80.5, 42.0, 35.5, 15.9; IR (film)
248 (100), 247 (25), 206 (42), 149 (10); HRMS calculated for
C14
y
(cmꢀ1) 3305, 1631; MS (CI) m/z (%)
(m, 3H), 4.41e4.35 (m, 1H), 3.37e3.29 (m, 1H), 2.44e2.32 (m, 3H),
1.93e1.87 (m, 1H); 13C NMR (CDCl3)
d
(ppm) 195.8, 175.0, 140.5,
132.5, 132.4, 129.7129.3, 118.7, 60.7, 44.3, 29.4, 23.1; IR
(cmꢀ1
1697; MS [CI] m/z: 266 (34), 264 (100), 124 (47); HRMS calcd for
35
H
ClNO$Hþ248.0842, found 248.0839.
y
)
14
35
4.4.4. N-Allyl-5-(2-thyenyl)-4-pentynamide (3d). According to the
typical procedure, amide 3d was prepared from amide 1 and 2-
iodothiophene in 44% yield as a brown solid. It was purified by
column chromatography (hexanes/EtOAc, 1/1) followed by crys-
C14H
ClNO2$Hþ264.5791, found 264.0785.
14
4.5.5. (ꢃ)-N-allyl-5-(2-thyenyl)-2-pyrrolidinone (5d). According to
the typical procedure, pyrrolidinone 5d was prepared from amide
3d in 64% yield as a yellowish oil. It was purified by column chro-
tallization from Et2O: mp 68e69 ꢁC (Et2O); 1H NMR (CDCl3)
d (ppm)
7.18e7.10 (m, 2H), 6.93e6.91 (m, 1H), 5.97 (br s, 1H), 5.90e5.77 (m,
1H), 5.23e5.09 (m, 2H), 3.91 (t, J¼5.5, 2H), 2.77 (t, J¼7.3, 2H), 2.48 (t,
matography (EtOAc): 1H NMR (CDCl3)
d (ppm) 7.71e7.67 (m, 2H),
7.13e7.10 (m, 1H), 5.65e5.56 (m, 1H), 5.06e4.90 (m, 3H), 4.39e4.32
(m, 1H), 3.37e3.29 (m, 1H), 2.46e2.31 (m, 3H), 2.03e1.93 (m, 1H);
J¼7.3, 2H); 13C NMR (CDCl3)
d (ppm) 170.9, 134.0, 131.4, 126.3, 123.5,
116.4, 92.5, 74.8, 42.0, 35.4, 16.2; IR
y
(cmꢀ1) 3305, 1633; MS [CI] m/
13C NMR (CDCl3)
d (ppm) 190.5, 175.1, 140.9, 135.1, 132.6132.2, 128.6,
z: 220 (100), 179 (47), 178 (96), 135 (10); HRMS calcd for
118.8, 61.7, 44.3, 29.5, 23.7; IR y
(cmꢀ1) 1690; MS [CI] m/z: 237 (12),
C12H13NOS$Hþ220.0796, found 220.0790.
236 (100), 124 (48); HRMS calcd for C12H13NO2S$Hþ236.0745,
found 236.0734.
4.5. Typical procedure for the PIFA-mediated
heterocyclization
4.6. ( )-(5R,10R)-N-allyl-5-(1-hydroxy-3-phenylallyl)-
pyrrolidin-2-one (syn-6)
4.5.1. (ꢃ)-N-allyl-5-cinnamoyl-2-pyrrolidinone (4). A solution of
alkynylamide 2 (348 mg, 1.4 mmol) in CF3CH2OH (20 mL) was
stirred at 0 ꢁC and a solution of PIFA (940 mg, 2.2 mmol) in 12 mL of
the same solvent was added dropwise. The reaction mixture was
stirred at that temperature until total consumption of the starting
material (TLC, 2 h). For the work up, aqueous Na2CO3 (20%) was
added (30 mL) and the mixture extracted with CH2Cl2 (3ꢂ20 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, and the solvent evaporated. Purification of the crude by
flash chromatography (EtOAc) gave pyrrolidinone 4 as a chro-
A solution of L-SelectrideÒ (1.8 mL, 1.0 M in THF) was added
dropwise to a cold (ꢀ78 ꢁC) solution of pyrrolidinone 4 (230 mg,
0.9 mmol) in 4.5 mL of the same solvent. After 30 min, temperature
was raised to room temperature and 2 mL of an aqueous solution of
NaOH (10%) was added. The whole mixture was extracted with
CH2Cl2 (3ꢂ10 mL), the combined organic layers were dried over
Na2SO4, and the solvent evaporated. Purification of the crude by
flash chromatography (EtOAc) gave pyrrolidinone (syn)-6 as
a chromatographically pure yellowish oil (70%): 1H NMR (CDCl3)
matographically pure yellowish oil (74%): 1H NMR (CDCl3)
d
(ppm)
d
(ppm) 7.30e7.17 (m, 5H), 6.59 (d, J¼15.9, 1H), 6.10 (dd, J¼15.9,
7.70 (d, J¼15.8, 1H), 7.54e7.39 (m, 5H), 6.76 (d, J¼15.8, 1H),
5.75e5.62 (m, 1H), 5.15e5.08 (m, 2H), 4.53e4.41 (m, 2H),
3.46e3.38 (m, 1H), 2.48e2.33 (m, 3H), 2.00e1.93 (m, 1H); 13C NMR
6.00, 1H), 5.72e5.65 (m, 1H), 5.14 (d, J¼4.5, 1H), 5.10 (s, 1H),
4.39e4.25 (m, 2H), 3.76e3.64 (m, 2H), 2.88 (br s, 1H), 2.36e1.98 (m,
4H); 13C NMR (CDCl3)
d (ppm) 175.9, 136.2, 132.8,132.3,128.7, 128.0,
(CDCl3)
d
(ppm) 197.2, 175.2, 145.2, 133.9, 132.1, 131.2, 129.1, 128.6,
127.5, 126.5, 117.8, 73.4, 61.6, 44.7, 30.2, 20.5; IR y
(cmꢀ1) 3374,1670;
121.4, 118.8, 63.7, 44.5, 29.6, 21.4; IR 1692, 1609; MS [CI] m/z: 256
(89), 124 (100); HRMS calcd for C16H17NO2$Hþ256.1338, found
256.1335.
HRMS calculated for C16H19NO2$Hþ258.1494, found 258.1507.
4.7. ( )-(5R,10S)-N-allyl-5-(1-hydroxy-3-phenylallyl)-
pyrrolidin-2-one (anti-6)
4.5.2. (ꢃ)-N-allyl-5-benzoyl-2-pyrrolidinone (5a). According to the
typical procedure, pyrrolidinone 5a was prepared from amide 3a in
66% yield as a yellowish oil. It was purified by column chroma-
Solid NaBH4 (68 mg, 1.8 mmol) was added in one portion to
a cold (-78 ꢁC) solution of pyrrolidinone 4 (230 mg, 0.9 mmol) in
MeOH (5 mL). After 30 min, H2O (2 mL) was added and temperature
was raised to rt. The whole mixture was extracted with CH2Cl2
tography (EtOAc): 1H NMR (CDCl3)
d
(ppm) 7.91 (d, J¼7.1, 2H),
7.63e7.45 (m, 3H), 5.78e5.55 (m, 1H), 5.15e5.02 (m, 3H), 4.51e4.45

L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
3697
(3ꢂ10 mL). The combined organic layers were dried over Na2SO4,
and the solvent evaporated. Purification of the crude by flash
chromatography (MeCN) rendered, independently, pyrrolidinones
(syn)-6 and (anti)-6 as chromatographically pure yellowish oils in
a 68:32 ratio (46% combined yield). Only the data for (anti)-6 is
purified by column chromatography (EtOAc) as a brownish oil: 1H
NMR (CDCl3) (ppm) 7.28e7.26 (m, 1H), 6.99e6.95 (m, 2H),
d
6.29e6.20 (m, 1H), 5.76e5.63 (m, 1H), 5.54 (d, J¼17.2, 1H), 5.37 (d,
J¼10.6, 1H), 5.16 (d, J¼10.2, 1H), 5.04 (br s, 1H), 4.36 (d, J¼17.2, 1H),
4.04e3.97 (m, 1H), 3.53e3.41 (m, 1H), 2.92 (s, 1H), 2.22e1.91 (m,
now reported: 1H NMR (CDCl3)
d
(ppm) 7.40e7.25 (m, 5H), 6.73 (d,
4H); 13C NMR (CDCl3)
d
(ppm) 176.7, 148.0, 138.6, 132.8, 127.1, 125.4,
124.5, 117.6, 116.8, 79.0, 65.6, 45.0, 29.9, 21.4; IR (film)
(cmꢀ1
3339, 1670; MS [EI] m/z (%) 246 (20), 124 (93); HRMS calculated for
J¼16.0, 1H), 6.14 (dd, J¼16.0, 5.5, 1H), 5.87e5.74 (m, 1H), 5.27 (d,
J¼9.2, 1H), 5.23 (s, 1H), 4.63 (s, 1H), 4.36 (dd, J¼15.5, 4.8, 1H), 3.72
(dd, J¼16.2, 6.9, 2H), 2.92 (br s, 1H), 2.59e2.47 (m, 1H), 2.32e2.26
y
)
32
C14
H SNO2 263.0980, found 263.0957.
17
(m, 1H), 2.14e1.87 (m, 2H); 13C NMR (CDCl3)
d (ppm) 176.1, 136.4,
132.8, 132.1, 128.7, 127.3, 126.5, 118.2, 70.7, 61.9, 43.6, 30.6, 18.2;
4.9. Typical procedure for the nucleophilic addition of
vinylmagnesium bromide to pyrrolidinones 5 (method B)
HRMS calculated for C16H19NO2$Hþ258.1494, found 258.1500.
4.8. Typical procedure for the nucleophilic addition of
vinylmagnesium bromide to pyrrolidinones 5 (method A)
4.9.1. Synthesis of (ꢃ)-(5R,1’R)-N-allyl-5-(1-hydroxy-1-phenylallyl)-
pyrrolidin-2-one (anti-7a). A vinylmagnesium bromide solution
(0.35 mL, 1.0 M in THF) was added to a solution of pyrrolidinone 5a
(50 mg, 0.2 mmol) in THF (2 mL) and the temperature was raised to
40 ꢁC. After 5 h, 4 mL of a saturated solution of NH4Cl were added
and the whole mixture was extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic layers were dried over Na2SO4, and the solvent
evaporated. Purification of the crude by flash chromatography
(EtOAc) gave pyrrolidinone (anti)-7a and (syn)-7a in an in-
separable 67/33 ratio (86% combined yield). Only the data for the
4.8.1. Synthesis of (ꢃ)-(5R,10S)-N-allyl-5-(1-hydroxy-1-phenylallyl)-
pyrrolidin-2-one (syn-7a). ZnCl2 (30 mg, 0.22 mmol) was added to
a solution of pyrrolidinone 5a (50 mg, 0.2 mmol) in THF (2 mL).
After 30 min, the mixture was cold to -20 ꢁC and vinylmagnesium
bromide (0.8 mL, 1.0 M in THF) was added. After 5 h, 4 mL of
a saturated solution of NH4Cl were added, and the whole mixture
was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers
were dried over Na2SO4, and the solvent evaporated. Purification of
the crude by flash chromatography (EtOAc) gave pyrrolidinone
(syn)-7a as a chromatographically pure yellowish oil (90%): 1H
(anti)-7a isomer is now reported: 1H NMR (CDCl3)
d (ppm)
7.46e7.26 (m, 5H), 6.49e6.40 (m, 1H), 5.60e5.44 (m, 1H), 5.47 (d,
J¼17.2, 1H), 5.23 (d, J¼10.8, 1H), 5.18 (d, J¼10.2, 1H), 5.07 (d, J¼17.1,
1H), 4.50e4.45 (m, 1H), 4.12e4.06 (m, 1H), 3.58e3.50 (m, 1H),
NMR (CDCl3)
d (ppm) 7.26e7.13 (m, 5H), 6.29e6.20 (m, 1H),
5.57e5.51 (m, 1H), 5.45 (d, J¼17.2, 1H), 5.27 (d, J¼10.8, 1H), 5.08 (d,
J¼10.2, 1H), 4.90 (d, J¼17.1, 1H), 4.26e4.19 (m, 1H), 4.09e4.05 (m,
1H), 2.98e3.90 (m, 1H), 2.28e1.86 (m, 4H); 13C NMR (CDCl3)
2.28e1.80 (m, 4H); 13C NMR (CDCl3)
d (ppm) 177.2, 143.7, 141.9,
132.8, 128.5, 127.3125.7, 117.9, 114.1, 78.9, 64.4, 45.1, 30.0, 21.4; GC-
HRMS calculated for C16H19NO2$Hþ258.1494, found 258.1599.
d
(ppm) 176.9, 143.4, 140.0, 132.6, 128.5127.6, 125.7, 117.5,
115.5, 79.3, 64.5, 44.5, 30.0, 21.3; IR
m/z: 258 (100), 240 (23), 124 (54); HRMS calculated for
C16H19NO2$Hþ258.1494, found 258.1501.
y
(cmꢀ1) 3368, 1670; MS [CI]
4.9.2. Synthesis of (ꢃ)-(5R,10R)-N-allyl-5-[1-hydroxy-1-(4-
methoxyphenyl)allyl]-pyrrolidin-2-one (anti-7b). According to the
typical procedure pyrrolidinones (anti)-7b and (syn)-7b were
obtained from 5b in an inseparable 47/53 ratio (80% combined
yield) as yellowish oils after purification by column chromatogra-
phy (EtOAc). Only the data for the (anti)-7b isomer is now repor-
4.8.2. Synthesis of (ꢃ)-(5R,10S)-N-allyl-5-[1-hydroxy-1-(4-
methoxyphenyl)allyl]-pyrrolidin-2-one (syn-7b). According to the
typical procedure pyrrolidinone (syn)-7b was obtained from 5b in
86% yield. It was purified by column chromatography (EtOAc) as
ted: 1H NMR (CDCl3)
d
(ppm) 7.34 (d, J¼8.8, 2H), 6.88 (d, J¼8.8, 2H),
6.49e6.36 (m, 1H), 5.94e5.80 (m, 1H), 5.45 (d, J¼17.1, 1H), 5.31 (d,
J¼10.8, 1H), 5.19e5-15 (m, 1H), 4.99 (d, J¼17.1, 1H), 4.46e4.41 (m,
1H), 4.15e4.10 (m, 1H), 3.79 (s, 3H), 3.56e3.48 (m, 1H), 2.32e1.68
a yellowish oil: 1H NMR (CDCl3)
d
(ppm) 7.34 (d, J¼8.8, 2H), 6.88 (d,
J¼8.8, 2H), 6.30e6.21 (m, 1H), 5.67e5.54 (m, 1H), 5.45 (d, J¼17.1,
1H), 5.31 (d, J¼10.8, 1H), 5.12 (d, J¼10.2, 1H), 4.99 (d, J¼17.1, 1H),
4.31e4.27 (m, 1H), 4.05e4.02 (m, 1H), 3.80 (s, 3H), 3.20e3.12 (m,
(m, 4H); 13C NMR (CDCl3)
d (ppm) 177.2, 159.1, 139.9, 132.7, 126.8,
117.9, 115.7, 113.4, 78.9, 64.6, 55.3, 44.5, 30.1, 21.3; GC-HRMS cal-
1H), 2.32e1.68 (m, 4H); 13C NMR (CDCl3)
d
(ppm) 176.9, 159.1, 139.3,
culated for C17H21NO3$Hþ288.1599, found 288.1600.
135.0, 132.7, 127.0, 117.5, 115.7, 113.9, 79.3, 64.7, 55.3, 44.7, 30.1, 21.3;
IR (film)
y
(cmꢀ1) 3394, 1668; MS (CI) m/z (%) 288 (100), 272 (13),
4.9.3. Synthesis of (ꢃ)-(5R,10R)-N-allyl-5-[1-(4-chlorophenyl)-1-
hydroxyallyl]-pyrrolidin-2-one (anti-7c). According to the typical
procedure pyrrolidinones (anti)-7c and (syn)-7c were obtained
from 5c in an inseparable 59/41 ratio (73% combined yield) as
yellowish oils after purification by column chromatography
(EtOAc). Only the data for the (anti)-7c isomer is now reported: 1H
270 (23), 163 (17); HRMS calculated for C17H21NO3$Hþ288.1599,
found 288.1605.
4.8.3. Synthesis of (ꢃ)-(5R,10S)-N-allyl-5-[1-(4-chlorophenyl)-1-
hydroxyallyl]-pyrrolidin-2-one (syn-7c). According to the typical
procedure pyrrolidinone (syn)-7c was obtained from 5c in 81%
yield. It was purified by column chromatography (EtOAc) as a yel-
NMR (MeOD)
d (ppm) 7.51e7.35 (m, 4H), 6.53e6.45 (m, 1H),
5.88e5.72 (m, 1H), 5.47 (d, J¼17.2, 1H), 5.31 (d, J¼10.5, 1H), 5.19 (d,
lowish oil: 1H NMR (MeOD)
d
(ppm) 7.50 (d, J¼8.7, 2H), 7.35 (d,
J¼10.5, 1H), 4.96 (d, J¼17.2, 1H), 4.21 (br s, 1H), 4.40e4.35 (m, 2H),
J¼8.7, 2H), 6.41e6.31 (m, 1H), 5.65e5.52 (m, 1H), 5.46 (d, J¼17.2,
1H), 5.31 (d, J¼10.5, 1H), 5.09 (d, J¼10.5, 1H), 4.96 (d, J¼17.2, 1H),
4.21 (br s, 1H), 4.15e4.11 (m, 2H), 3.14e3.04 (m, 1H), 2.10e1.96 (m,
3.14e3.04 (m, 1H), 2.10e1.96 (m, 4H); 13C NMR (MeOD)
d (ppm)
179.4, 142.6, 142.1, 134.3, 134.0, 129.3, 129.1, 117.4, 116.0, 80.0, 65.3,
35
45.1, 30.8, 23.4; GC-HRMS calculated for C16
found 292.1107.
H
ClNO2$Hþ292.1104,
18
4H); 13C NMR (MeOD)
d (ppm) 179.4, 144.2, 134.3, 141.8, 133.4,
129.3, 129.1, 117.8, 116.0, 80.0, 66.5, 45.8, 30.9, 22.3; IR (film)
y
(cmꢀ1) 3354, 1668; MS (Mþ1, CI) m/z (%) 292 (100), 276 (15), 234
4.9.4. Synthesis of (ꢃ)-(5R,10R)-N-allyl-5-[1-hydroxy-1-(2-thyenyl)
allyl]-pyrrolidin-2-one (anti-7d). According to the typical pro-
cedure pyrrolidinones (anti)-7d and (syn)-7d were obtained from
5d in an inseparable 38/62 ratio (83% combined yield) as yellowish
oils after purification by column chromatography (EtOAc). Only the
data for the (anti)-7d isomer is now reported: 1H NMR (CDCl3)
35
(10),167 (12); HRMS calculated for C16
292.1107.
H
ClNO2$Hþ292.1104, found
18
4.8.4. Synthesis of (ꢃ)-(5R,10S)-N-allyl-5-[1-hydroxy-1-(2-thyenyl)
allyl]-pyrrolidin-2-one (syn-7d). According to the typical procedure
pyrrolidinone (syn)-7d was obtained from 5d in 61% yield. It was
d
(ppm) 7.28e7.26 (m, 1H), 6.99e6.95 (m, 2H), 6.44e6.35 (m, 1H),

3698
L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
5.80e5.62 (m, 1H), 5.58 (d, J¼17.2, 1H), 5.34 (d, J¼10.6, 1H), 5.16 (d,
J¼10.2, 1H), 5.04 (br s, 1H), 4.46 (d, J¼17.2, 1H), 4.04e3.97 (m, 1H),
3.53e3.41 (m, 1H), 2.95 (s, 1H), 2.22e1.91 (m, 4H); 13C NMR (CDCl3)
an inseparable diastereomeric mixture. Only the data for the (anti)-
9a isomer is now reported: 1H NMR (CDCl3)
(ppm) 7.43e7.30 (m,
5H), 6.01 (s, 2H), 3.79 (d, J¼7.7, 1H), 3.73e3.69 (dd, J¼3.7, 2H), 3.42
(br s, 1H), 2.58e2.14 (m, 4H); 13C NMR (CDCl3)
(ppm) 175.5, 142.8,
d
d
(ppm) 176.7, 148.0, 140.0, 135.8, 126.9, 125.6, 124.7, 117.4, 116.9,
d
32
68.2, 65.6, 45.2, 29.8, 21.4; GC-HRMS calculated for C14
263.0980, found 263.0966.
H
17
SNO2
132.6, 128.0127.6, 126.6, 123.3, 71.6, 64.0, 40.1, 30.3, 17.3; GC-HRMS
calculated for C14H15NO2$Hþ230.1181, found 230.1191.
4.10. Typical procedure for the olefin metathesis reaction on
pyrrolidinones 7
4.10.6. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-8-(4-methoxyphenyl)-
1,2,8,8a-tetrahydroindolizin-3(5H)-one (anti)-9b. According to the
typical procedure indolizidinone (anti)-9b and (syn)-9b were
obtained from a syn/anti (53/47) mixture of 7b in 60% combined
yield. It was purified by column chromatography (EtOAc) as
a brown oil to give an inseparable diastereomeric mixture. Only the
data for the (anti)-9b isomer is now reported: 1H NMR (CDCl3)
4.10.1. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-8-phenyl-1,2,8,8a-tetra-
hydroindolizin-3(5H)-one (syn)-9a. Grubbs II catalyst (5 mg, 10%
wt) was added in one portion onto a solution of pyrrolidinone
(syn)-7a (50 mg, 0.2 mmol) in CH2Cl2 (10 mL) at rt. After 12 h, the
solvent was eliminated under vacuum and the resulting residue
was column chromatographed (EtOAc) to afford indolizidinone
(syn)-9a as a white solid that was triturated in Et2O (65%): mp
d
(ppm) 7.23 (d, J¼8.7, 2H), 6.85 (d, J¼8.7, 2H), 5.98 (s, 2H), 4.46 (d,
J¼18.9, 1H), 3.80 (br s, 4H), 3.61 (d, J¼18.9, 1H), 2.57 (br s, 1H),
1.97e1.77 (m, 4H); 13C NMR (CDCl3)
(ppm) 175.4, 158.8, 134.9,
d
162e165 ꢁC (Et2O); 1H NMR (CDCl3)
d
(ppm) 7.41e7.26 (m, 5H), 5.97
133.7, 132.9, 126.8, 126.5, 71.5, 63.9, 55.3, 40.0, 30.3, 17.4; GC-HRMS
(d, J¼10.3, 1H), 5.82 (d, J¼10.3, 1H), 4.48 (d, J¼18.8, 1H), 3.79 (d,
calculated for C15H17NO3$Hþ260.1286, found 260.1280.
J¼7.7, 1H), 3.63 (d, J¼18.8, 1H), 2.79 (br s, 1H), 2.02e1.75 (m, 3H),
1.41e1.27 (m, 1H); 13C NMR (CDCl3)
d
(ppm) 174.9, 139.0, 133.5,
4.10.7. Synthesis of (ꢃ)-(8R,8aR)-8-(4-chlorophenyl)-8-hydroxy-
1,2,8,8a-tetrahydroindolizin-3(5H)-one (anti)-9c. According to the
typical procedure indolizidinone (anti)-9c and (syn)-9c were
obtained from a syn/anti (41/49) mixture of 7c in 65% combined
yield. It was purified by column chromatography (EtOAc) as a brown
oil to give an inseparable diastereomeric mixture. Only the data for
128.2127.8,126.5,123.7, 73.9, 63.0, 40.0, 29.2,18.8; IR (film) y )
(cmꢀ1
3359, 1670; MS (CI) m/z (%) 230 (100), 212 (83), 211 (53), 146 (34);
HRMS calculated for C14H15NO2$Hþ230.1181, found 230.1191.
4.10.2. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-8-(4-methoxyphenyl)-
1,2,8,8a-tetrahydroindolizin-3(5H)-one (syn)-9b. According to the
typical procedure indolizidinone (syn)-9b was obtained from (syn)-
7b in 65% yield. It was purified by column chromatography (EtOAc)
the (anti)-9c isomer is now reported: 1H NMR (CDCl3)
d (ppm)
7.36e7.27 (m, 4H), 6.09 (s, 2H), 4.51 (d, J¼19.2, 1H), 3.78 (d, J¼8.3,
1H), 3.63 (d, J¼19.2, 1H), 2.33 (br s, 1H), 1.98e1.54 (m, 4H); 13C
as a brown oil: 1H NMR (CDCl3)
d
(ppm) 7.23 (d, J¼8.7, 2H), 6.85 (d,
NMR (CDCl3) d (ppm) 175.4, 159.6, 134.9, 133.6, 132.9, 129.1,
J¼8.7, 2H), 5.94 (d, J¼10.2, 1H), 5.79 (d, J¼10.2, 1H), 4.46 (d, J¼18.9,
128.3, 123.2, 63.9, 40.0, 30.2, 18.7; GC-HRMS calculated for
35
1H), 3.77 (br s, 4H), 3.61 (d, J¼18.9,1H), 2.57 (br s,1H),1.97e1.77 (m,
C14
H
ClNO2$Hþ264.0791, found 264.0800.
14
4H); 13C NMR (CDCl3)
d (ppm) 174.8, 159.3, 133.7, 133.5, 131.4, 127.7,
123.5, 73.6, 63.0, 55.2, 39.9, 29.2, 18.8; IR (film)
y
(cmꢀ1) 3389, 1670;
4.10.8. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-8-thyenyl-1,2,8,8a-tet-
rahydroindolizin-3(5H)-one (anti)-9d. According to the typical
procedure indolizidinone (anti)-9d and (syn)-9d were obtained
from a syn/anti (38/62) mixture of 7c in 69% combined yield. It was
purified bycolumn chromatography (EtOAc) as a brown oil to give an
inseparable diastereomeric mixture. Only the data for the (anti)-9d
MS (CI) m/z (%) 260 (100), 242 (99), 241 (77), 240 (41), 223 (11), 176
(53); HRMS calculated for C15H17NO3$Hþ260.1286, found 260.1285.
4.10.3. Synthesis of (ꢃ)-(8S,8aR)-8-(4-chlorophenyl)-8-hydroxy-
1,2,8,8a-tetrahydroindolizin-3(5H)-one (syn)-9c. According to the
typical procedure indolizidinone (syn)-9c was obtained from (syn)-
7c in 58% yield. It was purified by column chromatography (EtOAc) as
isomer is now reported: 1H NMR (CDCl3)
d (ppm) 7.31e7.25 (m, 1H),
7.00e6.93 (m, 1H), 6.81e6.77 (m, 1H) 6.92 (s, 2H), 4.45 (d, J¼19.3,
a brown oil: 1H NMR (CDCl3)
d (ppm) 7.36e7.27 (m, 4H), 6.00 (d,
1H), 3.87e3.82 (m,1H), 3.61 (d, J¼19.3,1H), 3.12 (br s,1H), 2.11e2.00
J¼10.6, 1H), 5.80 (d, J¼10.6, 1H), 4.51 (d, J¼19.2, 1H), 3.78 (d, J¼8.3,
(m, 3H), 1.41e1.31 (m, 1H); 13C NMR (CDCl3)
d (ppm) 175.4,
1H), 3.63 (d, J¼19.2, 1H), 2.33 (br s, 1H), 1.98e1.54 (m, 4H); 13C NMR
147.4132.71, 127.1, 126.8, 125.1, 123.4, 71.3, 63.7, 40.0, 29.5, 18.0; GC-
(CDCl3)
29.1,18.7; IR (film)
(36), 246 (40); HRMS calculated for C14
d
(ppm) 174.6,159.3,133.1,131.4,128.3,128.0,124.3, 63.0, 40.0,
HRMS calculated for C12H13NO2S$Hþ236.0745, found 236.0746.
y
(cmꢀ1) 3387,1670; MS (CI) m/z (%) 264 (100), 248
35
H
14
ClNO2$Hþ264.0791, found
4.11. Typical procedure for the olefin metathesis reaction on
264.0804.
pyrrolidinones 6
4.10.4. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-8-thyenyl-1,2,8,8a-tet-
rahydroindolizin-3(5H)-one (syn)-9d. According to the typical pro-
cedure indolizidinone (syn)-9d was obtained from (syn)-7d in 60%
yield. It was purified by column chromatography (EtOAc) as a brown
4.11.1. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-1,2,8,8a-tetrahydroin-
dolizin-3(5H)-one (syn)-8. Grubbs II catalyst (3 mg, 10% wt) was
added in one portion onto a solution of pyrrolidinone (syn)-6
(90 mg, 0.35 mmol) in toluene (10 mL) and temperature was raised
to reflux. After 4 h, the mixture was cooled to rt and solvent was
eliminated under vacuum. The resulting residue was column chro-
matographed (EtOAc) to afford indolizidinone (syn)-8 as a white
solid that was triturated in hexanes (71%): mp 111e113 ꢁC (hexanes);
oil: 1H NMR (CDCl3)
d (ppm) 7.31e7.25 (m, 1H), 7.00e6.93 (m, 1H),
6.81e6.77 (m,1H) 6.04e5.88 (m, 2H), 4.45 (d, J¼19.3,1H), 3.87e3.82
(m, 1H), 3.61 (d, J¼19.3, 1H), 3.12 (br s, 1H), 2.11e2.00 (m, 3H),
1.41e1.31 (m,1H); 13C NMR (CDCl3)
d (ppm) 175.0,144.8,133.7,127.3,
126.2,125.4,123.6, 73.3, 62.6, 39.9, 29.0,19.0; IR (film)
y
(cmꢀ1) 3330,
1H NMR (CDCl3)
d
(ppm) 6.83 (d, J¼7.0,1H), 4.96 (dd, J¼11.9, 5.9,1H),
1670; MS (CI) m/z (%) 236 (100), 218 (89), 217 (64), 152 (60); HRMS
3.98 (s, 1H), 3.76 (dd, J¼16.1, 8.0, 1H), 2.51e1.95 (m, 7H); 13C NMR
calculated for C12H13NO2S$Hþ236.0745, found 236.0741.
(CDCl3)
d (ppm) 172.7, 121.8, 105.0, 63.4, 58.9, 31.6, 30.7, 20.1; IR y
(cmꢀ1) 3359, 1670; MS [CI] m/z (%) 154 (100), 153 (37), 136 (12);
HRMS calculated for C8H11NO2$Hþ154.0868, found 154.0866.
4.10.5. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-8-phenyl-1,2,8,8a-tet-
rahydroindolizin-3(5H)-one (anti)-9a. According to the typical
procedure indolizidinone (anti)-9a and (syn)-9a were obtained
from a syn/anti (33/67) mixture of 7a in 66% combined yield. It was
purified by column chromatography (EtOAc) as a brown oil to give
4.11.2. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-1,2,8,8a-tetrahydroin-
dolizin-3(5H)-one (anti)-8. According to the typical procedure
indolizidinone (anti)-8 was obtained from (anti)-6 in 86%

L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
3699
combined yield. It was purified by column chromatography (EtOAc)
as a brown oil: 1H NMR (CDCl3)
56% yield. It was purified as a yellowish oil by column chroma-
tography (EtOAc): 1H NMR (CDCl3)
(ppm) 7.26e7.18 (m, 1H),
6.95e6.87 (m, 1H), 4.17e4.13 (m, 1H), 3.61e3.56 (m, 1H), 3.75e2.67
(m, 1H), 2.28e1.66 (m, 9H); 13C NMR (CDCl3)
(ppm) 174.8, 146.3,
d
(ppm) 6.72 (d, J¼7.5, 1H),
d
5.05e5.00 (m, 1H), 3.68e3.60 (m, 1H), 3.54e3.45 (m, 1H), 2.97 (br s,
1H), 2.45e1.39 (m, 4H), 2.20e2.11 (m, 1H), 1.83e1.76 (m, 1H); 13C
d
NMR (CDCl3)
d
(ppm) 171.9, 121.2, 107.2, 70.4, 60.4, 32.5, 31.1, 24.3;
126.8, 124.3, 123.7, 73.9, 66.0, 39.4, 39.1, 30.1, 21.0, 18.1; IR (film) y
HRMS calculated for C8H11NO2$Hþ154.0868, found 154.0863.
(cmꢀ1) 3334, 1660; MS (CI) m/z (%) 238 (100), 222 (14), 220 (48),
32
219 (23); HRMS calculated for C12
238.0913.
H
SNO$Hþ238.0902, found
15
4.12. Typical procedure for the hydrogenation reaction
4.12.1. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-hexahydroindolizin-
3(5H)-one (syn)-10. A solution of indolizidine (syn)-8 (37 mg,
0.24 mmol) in MeOH (5 mL) was hydrogenated (70 psi) in the
presence of Pd/C (4 mg, 10% weight) until total consumption of the
starting material (TLC, 8 h). Then, the mixture was filtered through
Celite, the solvent evaporated, and the resulting residue was column
chromatographed (EtOAc) to yield indolizidinone (syn)-10 as a col-
4.12.7. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-8-phenyl-hexahydroin-
dolizin-3(5H)-one (anti)-11a. According to the typical procedure
indolizidinone 11a was obtained as a diastereomeric mixture from
(33/67) (syn/anti)-9a in 69% combined yield. It was purified as
a yellowish oil by column chromatography (EtOAc). Data for the
anti isomer is now reported: 1H NMR (CDCl3)
d
(ppm) 7.47 (d, J¼7.4,
2H), 7.33e7.25 (m, 3H), 4.21 (d, J¼13.1, 1H), 3.70 (t, J¼8.3, 1H),
orless oil (46%): 1H NMR (MeOD)
1H), 3.53 (t, J¼12.6, 6.3, 1H), 2.65 (t, J¼22.9, 10.2, 1H), 2.40e1.24 (m,
9H); 13C NMR (MeOD)
(ppm) 174.7, 66.5, 60.9, 39.9, 30.8, 30.4,19.3,
d
(ppm) 4.11 (d, J¼12.6,1H), 3.81 (s,
2.86e2.76, 2.74 (s, 2H), 2.41e2.04 (m, 4H), 1.90e1.63 (m, 4H); 13C
NMR (MeOD)
d (ppm) 184.4, 143.7, 128.1, 127.9, 126.8, 73.6, 67.5,
d
40.9, 40.3, 31.3, 21.4, 19.8.
17.7; IR
y
(cmꢀ1) 3379, 1660; MS [CI] m/z: 156 (100), 155 (17), 138
(13); HRMS calculated for C8H13NO2$Hþ156.1025, found 156.1024.
4.12.8. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-8-(4-methoxyphenyl)-
hexahydroindolizin-3(5H)-one (anti)-11b. According to the typical
procedure indolizidinone 11b was obtained as a diastereomeric
mixture from (53/47) (syn/anti)-9b in 67% combined yield. It was
purified as a yellowish oil by column chromatography (EtOAc). Data
4.12.2. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-hexahydroindolizin-
3(5H)-one (anti)-10. According to the typical procedure indolizidi-
none (anti)-11a was obtained from (anti)-9a in 43% yield. It was
identified on the basis of the disappearance of the olefinic protons in
the crude NMR spectrum. However, all efforts to isolate it by column
chromatography resulted in a complete decomposition of the material.
for the anti isomer is now reported: 1H NMR (MeOD)
d (ppm) 7.36
(d, J¼8.9, 2H), 6.89 (d, J¼8.9, 2H), 4.11 (d, J¼13.2, 1H), 3.75e3.71 (m,
4H), 2.91e2.83 (m, 1H), 2.38e1.65 (m, 8H); 13C NMR (MeOD)
d
(ppm) 176.5, 160.0, 135.6, 128.8, 114.3, 73.6, 67.5, 56.7, 40.9, 40.5,
4.12.3. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-8-phenyl-hexahydroin-
dolizin-3(5H)-one (syn)-11a. According to the typical procedure
indolizidinone (syn)-11a was obtained from (syn)-9a in 60% yield. It
was purified as a white solid by column chromatography (MeOH)
followed by crystallization from Et2O: mp 144e148 ꢁC (Et2O): 1H
32.1, 21.6, 19.7.
4.12.9. Synthesis of (ꢃ)-(8S,8aR)-8-(4-chlorophenyl)-8-hydroxy-
hexahydroindolizin-3(5H)-one (anti)-11c. According to the typical
procedure indolizidinone 11c was obtained as a diastereomeric
mixture from (41/59) (syn/anti)-9c in 65% combined yield. It was
purified as a yellowish oil by column chromatography (EtOAc). Data
NMR (CDCl3)
J¼13.1, 1H), 3.71 (t, J¼8.3, 1H), 2.85e2.77 (m, 1H), 2.74 (s, 1H),
2.41e2.04 (m, 4H), 1.92e1.64 (m, 4H); 13C NMR (MeOD)
(ppm)
184.5, 143.7, 128.0, 127.9, 126.3, 73.6, 67.4, 40.8, 40.4, 31.1, 21.4, 19.8;
d
(ppm) 7.47 (d, J¼7.4, 2H), 7.35e7.26 (m, 3H), 4.22 (d,
d
for the anti isomer is now reported: 1H NMR (MeOD)
d (ppm) 7.44
(d, J¼8.7, 2H), 7.33 (d, J¼8.7, 2H), 4.14e4.10 (m, 1H), 3.80e3.73 (m,
IR (film) y
(cmꢀ1) 3379,1663; MS (CI) m/z (%) 232 (100), 214 (47), 213
1H), 2.90e2.83 (m, 1H), 2.39e1.69 (m, 8H); 13C NMR (MeOD)
(28); HRMS calculated for C14H17NO2$Hþ232.1337, found 232.1343.
d (ppm) 176.7, 143.7, 134.0, 129.3, 128.1, 73.8, 67.5, 40.9, 40.4, 31.1,
21.4, 19.8.
4.12.4. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-8-(4-methoxyphenyl)-
hexahydroindolizin-3(5H)-one (syn)-11b. According to the typical
procedure indolizidinone (syn)-11b was obtained from (syn)-9b in
63% yield. It was purified as a yellowish oil by column chroma-
4.12.10. Synthesis of (ꢃ)-(8S,8aR)-8-hydroxy-8-(2-thyenyl)-hexahy-
droindolizin-3(5H)-one (anti)-11d. According to the typical pro-
cedure indolizidinone 11d was obtained as a diastereomeric
mixture from (38/62) (syn/anti)-9d in 68% combined yield. It was
purified as a yellowish oil by column chromatography (EtOAc). Data
tography (EtOAc): 1H NMR (MeOD)
d
(ppm) 7.37 (d, J¼8.9, 2H), 6.88
(d, J¼8.9, 2H), 4.10 (d, J¼13.2, 1H), 3.77e3.71 (m, 4H), 2.91e2.81 (m,
1H), 2.40e1.69 (m, 8H); 13C NMR (MeOD)
(ppm) 176.6, 160.0,
136.6, 128.8, 114.4, 73.7, 67.7, 56.7, 41.0, 40.5, 31.1, 21.6, 19.7; IR (film)
d
for the anti isomer is now reported: 1H NMR (CDCl3)
d (ppm)
7.40e7.37 (m, 1H), 6.93e6.90 (m, 1H), 6.87e6.83 (m, 1H), 3.85e3.80
y
(cmꢀ1) 3379, 1660; MS (CI) m/z (%) 262 (67), 244 (100), 243 (49);
(m, 1H), 3.39e3.23 (m, 2H), 2.23e1.43 (m, 9H); 13C NMR (CDCl3)
HRMS calculated for C15H19NO3$Hþ262.1443, found 262.1455.
d (ppm) 174.8, 146.2, 126.6, 124.3, 123.7, 74.0, 66.1, 39.3, 39.2, 30.1,
21.0, 18.1.
4.12.5. Synthesis of (ꢃ)-(8R,8aR)-8-(4-chlorophenyl)-8-hydroxy-
hexahydroindolizin-3(5H)-one (syn)-11c. According to the typical
procedure indolizidinone (syn)-11c was obtained from (syn)-9c in
53% yield. It was purified as a brownish oil by column chroma-
4.13. Typical procedure for the dihydroxylation reaction
4.13.1. Synthesis of (ꢃ)-(6S,7S,8R,8aR)-6,7,8-trihydroxy-hexahy-
droindolizidin-3-one (syn-12). K2OsO4$2H2O (7 mg, 0.015 mmol)
and N-methylmorpholine-N-oxide (70 mg, 0.6 mmol) were se-
quentially added to 2 mL of an acetone/water (1/1) solution of
indolizidinone (syn)-8 (50 mg, 0.3 mmol). The mixture was stirred
at room temperature for 18 h, and then filtered through Celite. The
volatiles were eliminated and the residue was column chromato-
graphed (EtOAc) to render trihydroxyindolizidinone (syn)-12 as
tography (EtOAc): 1H NMR (MeOD)
d
(ppm) 7.44 (d, J¼8.7, 2H), 7.33
(d, J¼8.7, 2H), 4.14e4.10 (m, 1H), 3.80e3.73 (m, 1H), 2.90e2.83 (m,
1H), 2.39e1.69 (m, 8H); 13C NMR (MeOD)
(ppm) 176.7, 144.8,
d
134.0, 129.4, 129.1, 73.6, 67.4, 40.8, 40.5, 31.1, 21.4, 19.8; IR (film)
y
(cmꢀ1) 3379, 1660; MS (CI) m/z (%) 266 (100), 250 (10), 248 (19);
35
HRMS calculated for C14
H
ClNO2$Hþ266.0948, found 266.0948.
16
4.12.6. Synthesis of (ꢃ)-(8R,8aR)-8-hydroxy-8-(2-thyenyl)-hexahy-
droindolizin-3(5H)-one (syn)-11d. According to the typical pro-
cedure indolizidinone (syn)-11d was obtained from (syn)-11d in
a colorless oil (93%): 1H NMR (MeOD)
3.94e3.64 (m, 3H), 2.49e2.29 (m, 2H), 2.11e1.87 (m, 4H); 13C NMR
(MeOD) (ppm) 177.5, 74.5, 68.2, 65.0, 57.2, 35.2, 32.5, 19.6; IR
d
(ppm) 5.48 (d, J¼3.7, 1H),
d
y

3700
L.M. Pardo et al. / Tetrahedron 68 (2012) 3692e3700
(cmꢀ1) 3408, 1660; HRMS calculated for C8H13NO4$Hþ: 188.0923,
found: 188.0915.
6. For some recent representative examples, including references therein, see: (a)
Kamal, A.; Vangala, S. R. Tetrahedron 2011, 67, 1341e1347; (b) Hu, X.-G.; Bar-
tholomew, B.; Nash, R. J.; Wilson, F. X.; Fleet, G. W. J.; Nakagawa, S.; Kato, A.; Jia,
Y.-M.; van Well, R.; Yu, C.-Y. Org. Lett. 2010, 12, 2562e2565; (c) Izquierdo, I.;
Tamayo, J. A.; Rodríguez, M.; Franco, F.; Lo Re, D. Tetrahedron 2008, 64,
7910e7913; (d) Karanjule, N. S.; Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J.
Org. Chem. 2006, 71, 4667e4670.
4.13.2. Synthesis of (ꢃ)-(6R,7S,8S,8aR)-6,7,8-trihydroxy-8-phenyl-
hexahydroindolizidin-3-one (anti-13a). According to the typical
procedure, indolizidine (anti)-13a was obtained from a 0.5/1.0 di-
astereomeric mixture of (syn/anti)-9a in 57% yield. It was purified
by column chromatography (EtOAc) followed by crystallization
7. For selected non-sugar based strategies for the construction of the skeleton of
polyhydroxylated indolizidines, see: (a) Zambrano, V.; Rassu, G.; Roggio, A.;
Pinna, L.; Zanardi, F.; Curti, C.; Casiraghi, G.; Battistini, L. Org. Biomol. Chem.
2010, 8, 1725e1730; (b) Tian, Y.-S.; Joo, J.-E.; Kong, B.-S.; Pham, V.-T.; Lee, K.-Y.;
Ham, W.-H. J. Org. Chem. 2009, 74, 3962e3965; (c) Alam, M. A.; Kumar, A.;
Vankar, Y. D. Eur. J. Org. Chem. 2008, 4972e4980; (d) Shi, G.-F.; Li, J.-Q.; Jiang, X.-
P.; Cheng, Y. Tetrahedron 2008, 64, 5005e5012; (e) Abrams, J. N.; Babu, R. S.;
Guo, H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem. 2008, 73,
1935e1940; (f) Guo, H.; O’Doherty, G. A. Tetrahedron 2008, 64, 304e313; (g) Bi,
J.; Aggarwal, V. K. Chem. Commun. 2008, 120e122; (h) Ceccon, J.; Greene, A. E.;
Poisson, J.-F. Org. Lett. 2006, 8, 4739e4742; (i) Michael, J. P. Nat. Prod. Rep. 2008,
25, 139e165.
from Et2O: mp 183e184 ꢁC (Et2O); 1H NMR (MeOD)
d (ppm)
7.50e7.47 (m, 2H), 7.37e7.27 (m, 3H), 4.21e4.17 (m, 1H), 4.04e3.98
(m, 1H), 3.89e3.83 (m, 1H), 3.71 (s, 1H), 3.06e2.99 (m, 1H),
2.55e2.09 (m, 3H), 1.87e1.75 (m, 1H); 13C NMR (MeOD)
d
(ppm)
176.6, 142.7, 129.2, 128.5, 128.3, 78.0, 76.3, 65.4, 60.8, 40.9, 31.7,18.6;
IR (film)
(cmꢀ1) 3408, 1658; MS (CI) m/z (%) 264 (100), 246 (33),
y
230 (33), 228 (61), 212 (26), 210 (17), 190 (12), 140 (17), 115 (13), 84
ꢀ
8. For useful reviews on the Sonogashira reaction, see: (a) Chinchilla, R.; Najera, C.
(11); HRMS calculated for C14H17NO4$Hþ264.1236, found 264.1244.
ꢀ
Chem. Soc. Rev. 2011, 40 5084e5121; (b) Chinchilla, R.; Najera, C. Chem. Rev.
2007, 107, 874e922 and references therein.
9. (E)-b-bromostyrene was prepared as a single isomer from cinnamic acid by
a modified catalytic Hunsdiecker reaction Chowdhury, S.; Roy, S. J. Org. Chem.
1997, 62, 199e200.
Acknowledgements
10. Here, the terms syn and anti refers to the stereochemical relationship that the
OH and the nitrogen atom will show in the indolizidine skeletons.
11. This result that can be explained by considering a FelkineAhn model for the
nucleophilic addition to the carbonyl group.
12. For some examples on the use of organoceric and organocuprate reagents in
the addition reaction to carbonyls, see: (a) Liu, H.-J.; Shia, K.-S.; Shang, X.; Zhu,
B.-Y. Tetrahedron 1999, 55, 3803e3830; (b) Imamoto, T.; Hatajima, T.; Ogata, K.
Tetrahedron Lett. 1991, 32, 2787e2790; (c) Lopez, F.; Harutyunyan, S. R.; Min-
naard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2004, 126, 12784e12785; (d)
Kiyotsuka, Y.; Katayama, Y.; Acharya, H. P.; Hyodo, T.; Kobayashi, y. J. Org. Chem.
2009, 74, 1939e1951.
Financial support from the University of the Basque Country
(UPV 41.310e13656 and a fellowship granted to L.M.P.), the Basque
Government (GIU 06/87 and SAIOTEK S-PE11UN006), and the
Spanish Ministry of Science and Innovation (CTQ2007-64501/BQU
and CTQ2010-20703) is gratefully acknowledged. The authors
gratefully acknowledge PETRONOR, S.A. (Muskiz, Bizkaia) for the
generous gift of hexanes.
Supplementary data
13. Compounds 6e13 are obviously obtained in racemic form. Stereochemical
representations refer to relative relationships.
14. For some reports on Ru-catalyzed olefin isomerization, see: (a) Hong, S. H.; Day,
M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414e7415; (b) Arisawa, M.;
Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2002, 41,
4732e4734.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.033.
15. See, for instance, the following selected reviews and the references cited
therein. (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110,
1746e1787; (b) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim,
Germany, 2003; (c) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243e251;
(d) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45e52; (e) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490e4527; (f)
Grubbs, R. H. Tetrahedron 2004, 60, 7117e7140; (g) Furstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3013e3043; (h) This approach has been also applied in the
synthesis of indolizidine skeleton. See Ben-Othman, R.; Othman, M.; Ciamala,
K.; Knorr, M.; Strohmann, C.; Decroix, B. Tetrahedron 2009, 65, 4846e4854.
16. The reason for the lower temperature required to transform 7, with respect to
6, is probably due to the terminal nature of both olefinic fragments that are
involved in the cyclization reaction.
17. A combination of NOESY, selective COSY, and HMBC experiments were carried
out to establish the stereochemical relationships in compounds 8e10. From
these results, the relative stereochemistry in both diastereoisomers of pyrroli-
dinones 6 and 7 was inferred.
18. For a description of the combined use of several dihydroxylation methods, see:
Reddy, J. S.; Rao, B. V. J. Org. Chem. 2007, 72, 2224e2227.
References and notes
1. (a) Tellitu, I.; Serna, S.; Herrero, M. T.; Moreno, I.; Domínguez, E.; SanMartin, R. J.
Org. Chem. 2007, 72, 1526e1529; (b) Serna, S.; Tellitu, I.; Domínguez, E.; Mor-
eno, I.; SanMartin, R. Org. Lett. 2005, 7, 3073e3076.
2. Pardo, L. M.; Tellitu, I.; Domínguez, E. Tetrahedron 2010, 66, 5811e5818.
3. Pardo, L. M.; Tellitu, I.; Domínguez, E. Synthesis 2010, 971e978.
4. For a preliminary communication, see: Pardo, L. M.; Tellitu, I.; Domínguez, E.,
Synlett, in press.
5. These derivatives are highly considered for their strong glycosidase inhibitory
activity. See, for example: (a) Díaz, L.; Bujons, J.; Casas, J.; Llebaria, A.; Delgado,
A. J. Med. Chem. 2010, 53, 5248e5255; (b) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645e1680; (c) Sinnott, M. L.
Chem. Rev. 1990, 90, 1171e1202 Some other biological activities have been also
reported as chemotherapeutic agents against diabetes, cancer, and HIV. For
some selected contributions on availability, synthesis and biological evaluation
of polyhydroxylated indolizidines, see: (d) Platt, F. M.; Neises, G. R.; Re-
inkensmeier, G.; Townsend, M. J.; Perry, V. H.; Proia, R. L.; Winchester, B.;
Dwek, R. A.; Butters, T. D. Science 1997, 276, 428e431; (e) Gupta, P.; Pal, A. P. J.;
Reddy, Y. S.; Vankar, Y. D. Eur. J. Org. Chem. 2011, 1166e1175; (f) El Nemr, A. E.
Tetrahedron 2000, 56, 8579e8629; (g) Burgess, K.; Henderson, I. Tetrahedron
1992, 48, 4045e4066; (h) De Clercq, E. Med. Res. Rev. 2000, 20, 323e349; (i)
Wikler, D. A.; Holan, G. J. Med. Chem. 1989, 32, 2084e2089; (j) Pili, R.; Chang, J.;
Partis, R. A.; Mueller, R. A.; Chrest, F. J.; Passaniti, A. Cancer Res. 1995, 55,
2920e2926.
19. VanRheenen, V.; Kelly, C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973e1976.
20. The fact that the dihydroxylation of cyclic allylic alcohols takes place from the
face of the alkene, that is, opposite to the hydroxyl group was first reported by
Kishi. For the original seminal works, see: (a) Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron Lett. 1983, 24, 3943e3946; (b) Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron Lett. 1983, 24, 3947e3950; (c) Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron 1984, 40, 2247e2255.