Useful dual Diels-Alder behavior of 2-azetidinone-tethered aryl imines as azadienophiles or azadienes: A β-lactam-based stereocontrolled access to optically pure highly functionalized indolizidine systems

Article abstract of DOI:10.1002/chem.200304712

Imines derived from 4-oxoazetidine-2-carbaldehydes have been found to be versatile Diels - Alder reagents in that they exhibit two reactivity patterns. 2-Azetidinone-tethered imines undergo diastereoselective reaction with Danishefsky's diene in the prese

Full text of DOI:10.1002/chem.200304712

FULL PAPER
Useful Dual Diels Alder Behavior of 2-Azetidinone-Tethered Aryl Imines as
Azadienophiles or Azadienes: A b-Lactam-Based Stereocontrolled Access to
Optically Pure Highly Functionalized Indolizidine Systems
Benito Alcaide,*[a] Pedro Almendros,*[b] Jose M. Alonso,[a] and Moustafa F. Aly[a, c]
Abstract: Imines derived from 4-oxoa-
zetidine-2-carbaldehydes have been
found to be versatile Diels Alder re-
agents in that they exhibit two reactivity
patterns. 2-Azetidinone-tethered imines
undergo diastereoselective reaction with
Danishefsky×s diene in the presence of
different Lewis acids. The effect of the
amount of catalyst on the conversion
rate as well as on the product ratio has
been studied. Under standard reaction
conditions, indium(iii) chloride and zin-
c(ii) iodide provided the best yields, and
indium(iii) triflate the highest diastereo-
selectivity in the Lewis acid promoted
aza-Diels Alder cycloaddition. Treat-
ment of the aforementioned imines with
cyclopentadiene, 2,3-dimethyl-1,3-buta-
diene or 3,4-dihydro-2H-pyran led to
cycloadducts arising from inverse elec-
tron-demand condensation involving
the b-lactam-tethered aryl imine as the
heterodiene component. In addition, the
first methodology for preparing indoli-
zidines from b-lactams has been devel-
oped. This process involves amide bond
cleavage of the b-lactam ring in the aza-
Diels Alder cycloadducts with con-
comitant cyclization. Full chirality trans-
fer occurs when the reaction is per-
formed with an enantiomerically pure
substrate.
Keywords: asymmetric synthesis
¥
cyclization ¥ cycloaddition ¥ lactams
¥ small ring systems
selective synthetic methods.[3] In addition, functionalized
bicyclic lactams structurally related to indolizidine have been
found to act as conformationally restricted peptide mimet-
ics,[4] and they have been utilized in asymmetric synthesis
leading to natural products.[5] On the other hand, the
importance of 2-azetidinones as synthetic intermediates has
been widely recognized in organic synthesis.[6] [8] Despite the
versatility of the 2-azetidinone ring,[9] there is no information
available on the use of b-lactams as chiral synthons for the
synthesis of indolizidine alkaloids.[10] Our interest in the use of
carbonyl b-lactams as starting substrates for the preparation
of potentially bioactive products[11] prompted us to evaluate
the combination of the aza-Diels Alder reaction of 2-azeti-
dinone-tethered imines with rearrangement reactions on the
2-azetidinone ring as a route to complex indolizidine alkaloids
(Scheme 1). We report herein full details of the asymmetric
synthesis of different kinds of highly functionalized bi-, tri-,
and tetracyclic indolizidine systems using b-lactams as chiral
building blocks.
Introduction
Hetero Diels Alder reactions involving imino-dienes or
imino-dienophiles are widely used for the construction of
nitrogen-containing compounds.[1] Indolizidine alkaloids have
recently attracted a lot of attention due to their widespread
occurrence and their utility as research tools in pharmacology.
Their structural and stereochemical complexity, coupled with
their diverse and potent biological activities,[2] makes indoli-
zidine alkaloids as well as related non-natural compounds
very attractive synthetic targets in the search for efficient and
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. J. M. Alonso, Dr. M. F. Aly
¬
Departamento de QuÌmica Organica I
Facultad de QuÌmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax : (‡34)91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
¬
Instituto de QuÌmica Organica General
Consejo Superior de Investigaciones CientÌficas
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (‡34)91-5644853
E-mail: iqoa392@iqog.csic.es
[c] Dr. M. F. Aly
Permanent address: Department of Chemistry, Faculty of Science at
Qena, South Valley University, Qena (Egypt)
Supporting information for this article is available on the www under
http://www.chemeurj.org/ or from the author.
Scheme 1. Retrosynthetic analysis of indolizidine-type systems from
4-oxoazetidine-2-carbaldehydes.
Chem. Eur. J. 2003, 9, 3415 3426
DOI: 10.1002/chem.200304712
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B. Alcaide, P. Almendros et al.
FULL PAPER
Because
1-methoxy-3-trimethylsilyloxy-1,3-butadiene
Results and Discussion
(Danishefsky×s diene) is among the best dienes traditionally
used in Diels Alder reactions, we decided to attempt the use
of 2-azetidinone-tethered imines 2 as dienophiles. First, we
studied the aza-Diels Alder reaction of aldimine (À)-2 f with
Danishefsky×s diene in the presence of various catalysts. The
cycloaddition tookplace at low temperature under Lewis acid
catalysis. Diastereoselectivities were generally reasonable, in
all cases giving rise to mixtures of cycloadducts (‡)-3 f and
(‡)-4 f, but the chemical yield of the process proved to be a
function of the nature of the Lewis acid (Scheme 3, Table 1).
Starting substrates, 4-oxoazetidine-2-carbaldehydes 1a g,
were prepared both in the racemic form and in optically pure
form by using standard methodology. Racemic compounds
1a c were obtained as single cis diastereoisomers, following
our one-pot method from N,N-di-(p-methoxyphenyl)glyoxal
diimine.[12] Enantiopure 2-azetidinones 1c g were obtained
as single cis enantiomers from imines of (R)-2,3-O-isopropy-
lideneglyceraldehyde, through Staudinger reaction with the
appropriate alkoxyacetyl chloride in the presence of Et3N,
followed by sequential acidic acetonide hydrolysis and
oxidative cleavage.[11b] Treatment of aldehydes 1 with p-
anisidine or benzylamine at room temperature in the presence
of magnesium sulfate provided the corresponding imines 2
(Scheme 2). Aldimines 2 were amenable to purification by
flash chromatography and were obtained in good yields.
Importantly, the b-lactam ring stereochemistry was unaffected
by this process.
Scheme 3. Lewis acid mediated Diels Alder cycloaddition between
2-azetidinone-tethered imines and Danishefsky×s diene. Reagents and
conditions: a) Lewis acid, acetonitrile, À208C.
These results show that under standard reaction conditions,
zinc(ii) iodide (Table 1, entries 1 and 2) and indium(iii)
chloride (Table 1, entries 3 and 4) provided the best yields,
and indium(iii) triflate (Table 1, entry 6) the highest diaster-
eoselectivity in the Lewis acid promoted aza-Diels Alder
cycloaddition. The use of boron trifluoride diethyl etherate or
tin(iv) chloride resulted in a sluggish reaction, leading mainly
to decomposition products (Table 1, entries 9 and 10). The
effect of the amount of catalyst on the conversion rate as well
as on the product ratio was studied, and it was found that the
efficiency of the process did not increase on increasing the
amount of catalyst. On the basis of these results, we chose to
use zinc(ii) iodide (20 mol%) in our study with different
substituted 2-azetidinone-tethered imines 2. The effect of
altering the reaction solvent (acetonitrile, tetrahydrofuran,
diethyl ether or dichloromethane) was then explored. No
significant solvent effect on the diastereoselectivity was
observed, but the reaction proceeded more quickly in polar
solvents. In terms of achieving good yields with a reasonable
rate of reaction, acetonitrile seemed to be the solvent of
choice for this reaction. Reaction of aldimines 2 with
Danishefsky×s diene in acetonitrile at À208C in the presence
of zinc(ii) iodide gave cycloadducts 3 and 4 with moderate to
good anti stereoselectivities (de 20 100%, by integration of
Scheme 2. Preparation of 2-azetidinone-tethered imines 2a i. Reagents
and conditions: a) R3NH2, MgSO4, dichloromethane, room temperature.
Abstract in Spanish: Se ha descubierto que las iminas
derivadas de 4-oxoazetidin-2-carbaldehidos son unos reactivos
¬
¬
muy versatiles en la reaccion de Diels Alder al presentar dos
modos diferentes de reactividad. Estas iminas, por tratamiento
¬
con el dieno de Danishefsky dan una reaccion aza-Diels Al-
¬
¬
der catalizada por acidos de Lewis. Se llevo a cabo un estudio
¬
exhaustivo sobre el efecto del catalizador acido de Lewis. Los
¬
mejores rendimientos en la reaccion de aza-Diels Alder se
obtuvieron utilizando cloruro de indio(iii) o yoduro de cinc(ii),
1
¬
well-resolved signals in the H NMR spectra of the crude
mientras que la mejor diastereoselectividad se logro con triflato
¬
reaction mixtures before purification) (Table 1). Fortunately,
in all cases, the diastereomeric tetrahydropyridin-4-ones 3 and
4 could be easily separated by gravity flow chromatography.
The vicinal coupling constants of the two protons (H4 in the
b-lactamic ring, hydrogen a to the nitrogen in the six-
membered ring) located at the single bond connecting the
two rings were diagnostic of the relative stereochemistry of
these stereocenters. The vicinal coupling constants for cyclo-
adducts 3 are approximately 10.0 Hz, which suggests a relative
anti stereochemistry for this connection, whereas these vicinal
coupling constants for the minor isomers 4 are approximately
de indio(iii). Cabe destacar, que las iminas b-lactamicas por
¬
reaccion con ciclopentadieno, 2,3-dimetil-1,3-butadieno o 3,4-
dihidro-2H-pirano experimentan una cicloadicion de deman-
da electronica inversa, comportandose ahora el componente
imÌnico como heterodieno. Ademas, se describe la primera
metodologÌa para la preparacion de indolizidinas a partir de b-
lactamas. Este proceso implica la ruptura del enlace amida en
el anillo de b-lactama y su ciclacion posterior. Cuando se
utilizaron sustratos enantiomericamente puros la transferencia
¬
¬
¬
¬
¬
¬
¬
¬
de quiralidad fue total, permitiendo una sÌntesis asimetrica.
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Highly Functionalized Indolizidine Systems
3415 3426
Table 1. Lewis acid mediated Diels Alder cycloaddition between 2-azetidinone-tethered imines and Danishefsky×s diene.[a]
Entry
Imine
R1
R2
R3
LA (mol%)
t [h]
3/4 Ratio[b]
Yield 3/4[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(Æ)-2a
(Æ)-2b
(Æ)-2c
(Æ)-2d
(‡)-2e
(‡)-2g
(‡)-2h
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Tol
PhO
PhO
PhO
PhO
PhO
PhO
PhO
PhO
PhO
PhO
Ph
Ph
Pht
BnO
BnO
MeO
MeO
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Bn
PMP
PMP
Bn
PMP
PMP
ZnI2 (100)
ZnI2 (20)
InCl3 (100)
InCl3 (20)
In(TfO)3 (100)
In(TfO)3 (20)
HfCl4 (100)
HfCl4 (20)
BF3 ¥ Et2O
SnCl4
ZnI2 (20)
ZnI2 (20)
ZnI2 (20)
ZnI2 (20)
ZnI2 (20)
ZnI2 (20)
ZnI2 (20)
6
6
2
2
2
(‡)-3 f/(‡)-4f 75:25
(‡)-3 f/(‡)-4f 72:28
(‡)-3 f/(‡)-4f 76:24
(‡)-3 f/(‡)-4f 78:22
(‡)-3 f/(‡)-4f 80:20
(‡)-3 f/(‡)-4f 82:18
(‡)-3 f/(‡)-4f 74:26
(‡)-3 f/(‡)-4f 75:25
65/22
61/24
62/20
63/18
33/8
33/7
49/17
49/16
2
3.5
3.5
16
14
6
6
6
6
6
(Æ)-3a/(Æ)-4a 71:29
(Æ)-3b/(Æ)-4b 100:0
(Æ)-3c/(Æ)-4c 70:30
(Æ)-3d/(Æ)-4d 60:40
(‡)-3e/(‡)-4e 70:30
(‡)-3g/(‡)-4g 70:30
(‡)-3h/(‡)-4h 75:25
60/25
64/0
34/14
45/30
56/24
57/25
43/14
6
6
[a] PMP ˆ 4-MeOC6H4. Pht ˆ phthalimido. Tol ˆ 4-MeC6H4. [b] The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of
the crude reaction mixtures before purification. [c] Yield (%) of pure, isolated product with correct analytical and spectral data.
3.0 Hz, and indicate a relative
syn stereochemistry. This config-
urational assignment was con-
firmed by means of an X-ray
diffraction analysis of the cyclo-
adduct (Æ)-4d,[13] which is the
minor product from the reaction
of imine (Æ)-2d with Danishef-
Scheme 4. Lewis acid-mediated Diels Alder cycloaddition between 2-azetidinone-tethered imines and 2,3-
dimethyl-1,3-butadiene. Reagents and conditions: a) Lewis acid, acetonitrile, room temperature.
sky×s diene. The stereochemical
course of the reaction can be
explained by assuming that the
Lewis acid catalyst coordinates to the imine nitrogen and that
the b-lactam moiety preferentially adopts an anti-Felkin
Anh conformation, in which the large substituent of the
four-membered ring (the amino group) is oriented perpen-
dicular to the imine group. The
properties.[15] The cycloaddition did not take place with
electron-poor dienophiles such as 2-cyclohexen-1-one or
methyl acrylate, confirming that an inverse electron-demand
Diels Alder reaction was involved. This azadiene behavior is
well known for aryl imines derived from aromatic or a,b-
unsaturated aldehydes,[16] but little is known about the use of
aliphatic aldehyde derived-imines as the 4p component,[17]
and even less on their optically active derivatives.[18] Further-
more, to the best of our knowledge, the dual behavior of
aliphatic aldehyde-derived imines as both azadienes and as
dienophiles is unprecedented.
silyloxydiene should then pref-
erentially attackfrom the Re-
side and give the observed ma-
jor product (Figure 1).[14] The
stereoselectivity of the aza-
Diels Alder reaction was
found to be dependent on the
bulkiness of the N substituents
on the imines. Thus, on fixing
both substituents at the b-lac-
Next, the effect of Lewis acid on the conversion rate and
diastereoselectivity was explored. No improvements in ster-
eoselectivity were obtained with indium(iii) chloride or
indium(iii) triflate (Table 2, entries 4 and 6), but the reactions
were faster. Of the Lewis acids surveyed at this point,
indium(iii) triflate gave good yields and good conversion
rates. Therefore, we focused on further exploration of the
indium(iii) triflate mediated reaction of 2,3-dimethyl-1,3-
butadiene with a variety of imines 2 (Table 2, entries 9 12).
The nature of the N substituent on the b-lactam nucleus
appeared to influence the stereoselectivity of the cycloaddi-
tion. While N-aryl-substituted b-lactams afforded moderate
selectivities (60:40 to 75:25), by far the best selectivity (100:0)
was observed when the N functionality at the four-membered
ring was an aliphatic moiety (Table 2, entry 12). Again,
cycloadducts 5 and 6 were easily separable by column
chromatography.
Figure 1. Model showing the
origin of the observed syn ster-
eochemistry.
tam ring (Table 1, entries 11 and 12), when less hindered N-
benzyl imine (Æ)-2b rather than the N-4-methoxyphenyl
imine (Æ)-2a was used for cycloadduct formation, fully
distereoselective conversion was obtained.
We next turned our attention to studying the reactivity of
aldimines 2 with less electron-rich dienes. Reaction of
2-azetidinone-tethered imine (À)-2 f with 2,3-dimethyl-1,3-
butadiene in acetonitrile at room temperature in the presence
of zinc(ii) iodide led to cycloadducts (‡)-5 f and (‡)-6 f as a
chromatographically separable mixture (60:40) of two dia-
stereomers (Scheme 4, Table 2) in good yield. Interestingly,
the dienophilic behavior of the imine in the Diels Alder
reaction was reversed such that it exhibited heterodienic
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B. Alcaide, P. Almendros et al.
FULL PAPER
Table 2. Lewis acid mediated Diels Alder cycloaddition between 2-azetidinone-tethered imines and 2,3-dimethyl-1,3-butadiene.[a]
Entry
Imine
R1
R2
LA (mol%)
t [h]
5/6 Ratio[b]
Yield 5/6[c]
1
2
3
4
5
6
7
8
9
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(À)-2f
(Æ)-2a
(‡)-2g
(‡)-2h
(‡)-2i
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Tol
PhO
PhO
PhO
PhO
PhO
PhO
PhO
PhO
Ph
ZnI2 (100)
ZnI2 (20)
216
216
16
16
3
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(‡)-5 f/(‡)-6f 60:40
(Æ)-5a/(Æ)-6a 75:25
(‡)-5g/(‡)-6g 65:35
(‡)-5h/(‡)-6h 65:35
(‡)-5i/(‡)-6i 100:0
47/31
51/34
49/32
49/32
51/34
52/35
35/24
36/24
62/21
56/30
58/31
67/0
InCl3 (100)
InCl3 (20)
In(TfO)3 (100)
In(TfO)3 (20)
HfCl4 (100)
HfCl4 (20)
In(TfO)3 (20)
In(TfO)3 (20)
In(TfO)3 (20)
In(TfO)3 (20)
3
16
16
1
1.5
1
1
10
11
12
MeO
MeO
MeO
Allyl
[a] PMP ˆ 4-MeOC6H4; Tol ˆ 4-MeC6H4. [b] The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction
mixtures before purification. [c] Yield (%) of pure, isolated product with correct analytical and spectral data.
Cyclic alkenes such as cyclo-
pentadiene and 3,4-dihydro-
2H-pyran (DHP) were tested
as well. The reactions proceed-
ed smoothly at ambient temper-
ature under trivalent indium
salt catalysis. Thus, indium tri-
chloride catalyzed (20 mol%)
reaction between the 2-azetidi-
none-tethered imine (‡)-2g
and cyclopentadiene afforded
the chromatographically sepa-
rable derivatives (‡)-7 and (‡)-
8 (1:1 mixture) in an excellent
98% yield (Scheme 5). Further
reactions of N-benzylidene-2-
azetidinones 2 with DHP in
the presence of catalytic
Scheme 5. Lewis acid mediated Diels Alder cycloaddition between 2-azetidinone-tethered imines and cyclic
amounts of indium(iii) triflate
resulted in the formation of
isomeric pyrano[3,2-c]quino-
line-b-lactams 9 and 10. These
alkenes. Reagents and conditions: a) indium(iii) chloride, acetonitrile, room temperature, 1 h. b) indium(iii)
triflate, acetonitrile, room temperature.
adducts, which could be separated by column chromatography
on silica gel, were obtained in good yields (70 95%) with
acceptable levels of stereoselectivity (60:40 to 100:0). Thus,
for example, adduct (‡)-9c was obtained as a single diaster-
eomer (Scheme 5). Detailed NMR studies have established
the structure and stereochemistry of compounds 7 10.
Both of the observed products from the [4‡2] cycloaddition
step, when using less electron-rich dienes, are derived from
endo cycloaddition of the dienophile to the azadiene. Stereo-
selectivity must be achieved by controlling the approach of
the dienophile to the azadiene from either the top or the
bottom face. Therefore, the approach of the dienophile from
the appropriate face when the N of the 2-azetidinone bears an
allyl group results in only a slight steric interaction.
by means of a sodium methoxide rearrangement reaction
(Scheme 6). Similarly, indolizidinones 13 16 were obtained
in good yields and in high purity after aqueous workup,
without the need for further purification (Scheme 7). The
A common and relevant feature of some indolizidines that
act as glycosidase inhibitors is the presence of a vicinal amino-
alcohol or -alkoxy functionality.[19] In this context, our aim was
to find an expedient transformation of our cycloadducts into
indolizidine systems bearing this substitution pattern. To our
delight, quantitative transformation of adducts (‡)-5 f and
(‡)-6 f into fused azatricycles 11 and 12 was directly effected
Scheme 6. Sodium methoxide promoted transformation of quinoline-b-
lactams into enantiopure fused tricyclic indolizidinones. Reagents and
conditions: a) MeONa, MeOH, room temperature, 16 h.
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Highly Functionalized Indolizidine Systems
3415 3426
at the six-membered ring is a
convenient way to obtain the
tetrahydropyridone (‡)-18. So-
dium borohydride reduction of
the ketone moiety on compound
(‡)-18 gave a 60:40 mixture of
epimeric alcohols (‡)-19 and
(‡)-20, which were separated
by flash chromatography. Pro-
tection of the hydroxyl group to
give the corresponding tert-bu-
tyldimethylsilyl ethers (‡)-21
and (‡)-22, followed by CAN-
promoted oxidative cleavage of
the N-4-methoxyphenyl substitu-
ent, provided the key intermedi-
ate
oxoazetidinyl-piperidines
(‡)-23 and (‡)-24 (Scheme 8).
Compounds 25 28 were ob-
tained in a similar way starting
from the minor cycloadduct (‡)-
4h (Scheme 9). Fortunately, the
Scheme 7. Sodium methoxide promoted transformation of quinoline-b-
lactams into enantiopure fused tetracyclic indolizidinones. Reagents and
conditions: a) MeONa, MeOH, room temperature, 16 h. b) PTSA, toluene,
reflux, 30 min.
reaction of compound (‡)-8 with sodium methoxide in
methanol overnight gave in quantitative yield as crude
product the compound (À)-17. Product (À)-17 has a fused
tricyclic tetrahydroquinoline structure, and it was found to
require heating for 30 min in toluene under PTSA catalysis
using a Dean Starkapparatus to give the expected indolizi-
dinone system (À)-14. Aza-polycyclic compounds 11 16
1
showed a single set of signals in their H NMR spectra, thus
proving that these transformations proceeded without detect-
able isomerization.
Alternatively, this transformation can be carried out by
dissolving the aza-Diels Alder adducts 5 10 in a saturated
solution of HCl(g) in 2-propanol. However, the 1H NMR
spectra of the crude reaction mixtures showed mainly 11 16
together with unquantifiable traces of other isomer, which
could arise from partial epimerization. Fused aza-polycycles
11 16 are pyrrolidinoisoquinolines, and the isomeric pyrro-
lidino[2,1-a]quinolines represent a structural fragment of
erytrinan alkaloids that exhibit significant pharmacological
activity.[20]
Cycloadducts 3 and 4 require further manipulation to
obtain the desired alkaloid system. Thus, the dihydropyridone
(‡)-3h underwent sequential reduction of the alkene and
carbonyl moieties. l-Selectride reduction of the alkene moiety
Scheme 8. Preparation of oxoazetidinyl-piperidines (‡)-23 and (‡)-24.
Reagents and conditions: a) l-Selectride, THF, À788C, 5 h. b) NaBH4,
MeOH, 08C. c) TBSCl, imidazole, DMF, room temperature. d) CAN,
CH3CN/H2O, À358C.
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B. Alcaide, P. Almendros et al.
FULL PAPER
lactams 33 35. Enantiopure indolizidinones (‡)-33, (‡)-34,
and (À)-35 were cleanly produced without byproducts in
quantitative yields (Scheme 11). This result demonstrates that
efficient asymmetric access to a plethora of stereochemically
different indolizidine moieties can be achieved through b-
lactam chemistry.
Scheme 9. Preparation of oxoazetidinyl-piperidine (À)-28. Reagents and
conditions: a) l-Selectride, THF, À788C, 1 h. b) NaBH4, MeOH, 08C.
c) TBSCl, imidazole, DMF, room temperature. d) CAN, CH3CN/H2O,
À358C.
Scheme 11. Sodium methoxide promoted transformation of piperidine-b-
lactams into enantiopure functionalized bicyclic indolizidinones. Reagents
and conditions: a) MeONa, MeOH, room temperature, 16 h.
reduction of ketone (‡)-25 was totally stereoselective, and
alcohol (‡)-26 was obtained as the sole product without any
sign of the diastereomeric isomer.
The configuration at the carbinolic chiral centers of the
above major alcohols (‡)-19 and (‡)-26 was established by
The transformation of piperidine-2-azetidinones 5 10, (‡)-
23, (‡)-24, and (À)-28 into indolizidine derivatives 11 16 and
33 35 involves amide bond cleavage of the b-lactam ring,
followed by cyclization of the resulting amino ester with
concomitant ring expansion. The polycyclic structures (by
DEPT, HETCOR, and COSY) and the stereochemistry (by
vicinal proton couplings and NOE experiments) of indolizi-
dinones 11 16 and 33 35 were established by one- and two-
dimensional NMR techniques.
1
comparison of the H NMR chemical shifts of their acetyl-
mandelates 29 32 (Scheme 10).[21]
Substrates (‡)-23, (‡)-24, and (À)-28 were submitted to
sodium methoxide treatment to afford bicyclic indolizidine
To further illustrate the use of this chemistry in alkaloid
synthesis, the conversion of indolizidinones to indolizidines
was easily accomplished by reduction of the amide group.
Thus, the fused-lactams (‡)-11, (‡)-15b, (‡)-34, and (À)-35,
on treatment with a suspension of powdered lithium alumi-
num hydride in tetrahydrofuran or diethyl ether, smoothly
afforded the cyclic amines 36 39 (Scheme 12).
Conclusion
In conclusion, imines derived from 4-oxoazetidine-2-carbal-
dehydes have been found to be versatile aza-Diels Alder
reagents in that two reactivity patterns have been observed.
These imines lead to cycloadducts arising from normal as well
as inverse electron-demand [4‡2] cycloaddition. Further-
more, we have presented the first methodology for the
preparation of indolizidines from b-lactams. This b-lactam-
Scheme 10. Synthesis of acetylmandelates 29 32. Reagents and condi-
tions: a) (R)-acetylmandelic acid, DCC, DMAP, dichloromethane, room
temperature. b) (S)-acetylmandelic acid, DCC, DMAP, dichloromethane,
room temperature.
3420
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 3415 3426

Highly Functionalized Indolizidine Systems
3415 3426
solid; m.p. 121 1228C (hexanes/ethyl acetate); [a]D ˆ ‡107.3 (c ˆ 1.0 in
CHCl3); 1H NMR (300 MHz, C6D6, 258C): d ˆ 7.62 (d, J ˆ 7.1 Hz, 1H), 6.89
and 7.40 (d, J ˆ 8.9 Hz, each 2H), 6.47 (m, 4H), 4.27 (dd, J ˆ 7.0, 5.1 Hz,
1H), 3.99 (d, J ˆ 5.1 Hz, 1H), 3.04 and 3.07 (s, each 3H), 2.96 ppm (s, 3H);
13C NMR (75 MHz, C6D6, 258C): d ˆ 163.3, 159.5, 158.8, 144.0, 132.2, 122.9,
118.4, 114.9, 114.7, 85.5, 61.3, 58.6, 55.0 ppm; IR (KBr): nÄ ˆ 1742, 1644 cmÀ1
;
‡
MS (EI): m/z (%): 340 (100) [M] ; elemental analysis calcd (%) for
C19H20N2O4 (340.4): C 67.05, H 5.92, N 8.23; found: C 67.12, H 5.90, N 8.25.
Imine (‡)-2h: Compound (‡)-2h (3.12 g; 75%) was obtained from the
aldehyde (‡)-1 f (3.0 g, 12.9 mmol), after column chromatography (elution
with ethyl acetate/hexanes (1:1; containing 1% triethylamine)); yellow
solid; m.p. 117 1188C (hexanes/ethyl acetate); [a]D ˆ ‡92.5 (c ˆ 0.8 in
CHCl3); 1H NMR (200 MHz, CDCl3, 258C): d ˆ 7.88 (m, 1H), 7.04 (m, 4H),
6.76 and 7.25 (m, each 2H), 4.78 (m, 2H), 3.48 and 3.74 (s, each 3H),
2.23 ppm (s, 3H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 163.7, 159.1, 158.9,
143.5, 135.2, 134.6, 129.9, 122.4, 117.1, 114.5, 85.2, 61.3, 59.3, 55.6, 21.1 ppm;
‡
IR (KBr): nÄ ˆ 1744, 1645 cmÀ1; MS (EI): m/z (%): 326 (7) [M‡H] , 325
‡
(100) [M] ; elemental analysis calcd (%) for C19H20N2O3 (324.4): C 70.35, H
6.21, N 8.64; found: C 70.43, H 6.23, N 8.60.
General procedure for the synthesis of cycloadducts 3 and 4: A solution of
the corresponding imine (1.0 mmol) in acetonitrile (5 mL) was added
dropwise to a stirred suspension of the appropriate Lewis acid (0.2 mmol)
in acetonitrile (13 mL) at À208C. The reaction mixture was stirred at
À208C for 15 min and then Danishefsky×s diene (1.20 mmol) was added.
After the imine had been consumed (TLC), saturated aqueous NaHCO3
(1 mL) was added, and the mixture was extracted with ethyl acetate (3 Â
20 mL). The combined organic extracts were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate/hexanes mixtures (containing 1%
triethylamine) gave analytically pure compounds 3 and 4. Spectroscopic
and analytical data for some representative pure forms of 3 and 4 are given
below.
Scheme 12. LAH-promoted transformation of indolizidinones into enan-
tiopure functionalized indolizidines. Reagents and conditions: a) LiAlH4,
THF, room temperature, 16 h. b) LiAlH4, Et2O, room temperature, 30 min.
c) LiAlH4, Et2O, room temperature, 45 min. d) LiAlH4, Et2O, room
temperature, 40 min.
Preparation of cycloadducts (‡)-3 f and (‡)-4 f: The less polar compound
(‡)-3 f (150 mg; 63%) and the more polar compound (‡)-4 f (42 mg; 18%)
were obtained from the imine (‡)-2 f (201 mg; 0.5 mmol), after column
chromatography (elution with ethyl acetate/hexanes (1:1 containing 1%
triethylamine)).
Cycloadduct (‡)-3 f: Colorless oil; [a]D ˆ ‡425.3 (c ˆ 0.9 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.08 (m, 7H), 6.65 (m, 7H), 5.39 (d,
J ˆ 5.9 Hz, 1H), 5.28 (d, J ˆ 7.3 Hz, 1H), 5.07 (dd, J ˆ 10.3, 5.9 Hz, 1H),
3.65 (s, 6H), 4.75 (m, 1H), 3.01 (dd, J ˆ 17.1, 5.9 Hz, 1H), 2.44 ppm (d, J ˆ
17.1 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 191.0, 164.2, 157.5,
157.1, 156.8, 148.3, 137.5, 129.9, 129.8, 123.2, 120.7, 119.8, 116.3, 114.7, 114.2,
based stereocontrolled route to bi- or polycyclic alkaloid
scaffolds is carried out asymmetrically, allowing efficient
access to a variety of optically pure highly functionalized
indolizidines.
102.2, 80.1, 58.1, 55.6, 55.5, 52.7, 38.1 ppm; IR (CHCl3): nÄ ˆ 1757, 1638 cmÀ1
;
‡
‡
MS (CI): m/z (%): 471 (100) [M‡H] , 470 (39) [M] ; elemental analysis
calcd (%) for C28H26N2O5 (470.5): C 71.47, H 5.57, N 5.95; found: C 71.58, H
5.54, N 5.92.
Experimental Section
Cycloadduct (‡)-4 f: Yellow solid; m.p. 186 1878C (hexanes/ethyl ace-
tate); [a]D ˆ ‡128.7 (c ˆ 0.7 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 7.01 (m, 14H), 5.24 (d, J ˆ 5.2 Hz, 1H), 4.86 (d, J ˆ 7.9 Hz, 1H), 4.71 (m,
2H), 3.72 and 3.74 (s, each 3H), 2.94 (dd, J ˆ 17.0, 7.3 Hz, 1H), 2.71 ppm
(dd, J ˆ 17.0, 5.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 190.0,
163.2, 157.9, 157.3, 151.2, 137.5, 129.8, 129.7, 124.1, 122.8, 120.5, 115.6, 115.3,
114.4, 101.2, 79.3, 58.5, 56.9, 55.7, 55.5, 37.3 ppm; IR (KBr): nÄ ˆ 1751,
General methods: 1H and 13C NMR spectra were recorded on a Bruker
Avance-300, Varian VRX-300S or Bruker AC-200 spectrometer. NMR
spectra were recorded in CDCl3 solutions, except where otherwise stated.
Chemical shifts are given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3
(13C, 76.9 ppm). Low- and high-resolution mass spectra were measured on a
HP5989A spectrometer, operating in chemical ionization (CI) mode unless
otherwise stated. Specific rotations [a]D are given in deg per dm at 208C,
and the concentration (c) is expressed in g/100 mL. All commercially
available compounds were used without further purification.
‡
‡
1711 cmÀ1; MS (CI): m/z (%): 471 (100) [M‡H] , 470 (27) [M] ; elemental
analysis calcd (%) for C28H26N2O5 (470.5): C 71.47, H 5.57, N 5.95; found: C
71.39, H 5.53, N 5.98.
General procedure for the preparation of imines 2: A solution of the
corresponding amine (1.50 mmol) in dichloromethane (4 mL) was added
dropwise to a stirred suspension of the appropriate 4-oxoazetidine-2-
carbaldehyde 1 (1.0 mmol) and magnesium sulfate (1.50 mmol) in dichloro-
methane (100 mL) at room temperature. After stirring for 16 h at room
temperature, the mixture was filtered and the solvent was removed under
reduced pressure. Chromatography of the residue eluting with ethyl
acetate/hexanes mixtures (containing 1% triethylamine) gave analytically
pure compounds 2. Spectroscopic and analytical data for some representa-
tive pure forms of 2 follow.[22]
Cycloadduct (Æ)-3b: Compound (Æ)-3b (305 mg; 64%) was obtained as a
colorless oil from the imine (Æ)-2b (400 mg, 1.08 mmol), after column
chromatography (elution with ethyl acetate/hexanes (2:1 containing 1%
triethylamine)); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.01 (m, 14H), 6.75
(d, J ˆ 7.4 Hz, 1H), 4.97 (d, J ˆ 7.4 Hz, 1H), 4.92 (dd, J ˆ 10.6, 5.9 Hz, 1H),
4.66 (d, J ˆ 5.9 Hz, 1H), 3.87 (d, J ˆ 15.0 Hz, 1H), 3.73 (s, 3H), 3.68 (d, J ˆ
14.8 Hz, 1H), 3.26 (m, 1H), 2.09 (dd, J ˆ 17.0, 6.9 Hz, 1H), 1.61 ppm (d, J ˆ
17.0 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 189.6, 165.9, 156.9,
153.2, 135.9, 130.9, 130.6, 129.8, 129.0, 128.9, 128.4, 128.3, 127.6, 119.9, 114.4,
97.7, 59.7, 57.4, 55.5, 55.4, 51.3, 36.6 ppm; IR (CHCl3): n ˆ 1753, 1703 cmÀ1
;
‡
‡
Imine (‡)-2g: Compound (‡)-2g (4.12 g; 95%) was obtained from the
aldehyde (‡)-1e (3.0 g, 12.7 mmol) after column chromatography (elution
with ethyl acetate/hexanes (1:1; containing 1% triethylamine)); yellow
MS (CI): m/z (%): 439 (100) [M‡H] , 438 (23) [M] ; elemental analysis
calcd (%) for C28H26N2O3 (438.5): C 76.99, H 5.98, N 6.39; found: C 76.90, H
5.95, N 6.43.
Chem. Eur. J. 2003, 9, 3415 3426
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3421

B. Alcaide, P. Almendros et al.
FULL PAPER
Preparation of cycloadducts (‡)-3e and (‡)-4e: The less polar compound
(‡)-3e (327 mg; 56%) and the more polar compound (‡)-4e (141 mg;
24%) were obtained from the imine (‡)-2e (599 mg, 1.25 mmol), after
column chromatography (elution with ethyl acetate/hexanes (2:1 contain-
ing 1% triethylamine)).
1H), 1.49 (m, 1H), 1.41 and 1.48 ppm (s, each 3H); 13C NMR (75 MHz,
CDCl3, 258C): d ˆ 163.9, 157.4, 157.0, 152.5, 150.8, 137.6, 130.4, 129.6, 128.7,
122.5, 120.7, 116.3, 115.7, 114.2, 113.2, 112.9, 111.9, 79.5, 61.4, 55.6, 55.4, 50.3,
42.4, 37.4, 29.4, 19.7 ppm; IR (KBr): nÄ ˆ 3420, 1757 cmÀ1; MS (CI): m/z (%):
‡
‡
485 (100) [M‡H] , 484 (37) [M] ; elemental analysis calcd (%) for
C30H32N2O4 (484.6): C 74.36, H 6.66, N 5.78; found: C 74.46, H 6.63, N 5.81.
Cycloadduct (‡)-3e: Colorless oil; [a]D ˆ ‡201.1 (c ˆ 0.5 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.28 (m, 12H), 6.80 (d, J ˆ 7.8 Hz,
1H), 6.79 (m, 2H), 5.02 (d, J ˆ 7.8 Hz, 1H), 4.86 (m, 2H), 4.75 (d, J ˆ
4.8 Hz, 1H), 4.66 (d, J ˆ 11.7 Hz, 1H), 3.92 (d, J ˆ 15.6 Hz, 1H), 3.89 (m,
1H), 3.73 (s, 3H), 3.68 (d, J ˆ 15.6 Hz, 1H), 2.72 (dd, J ˆ 17.1, 6.8 Hz, 1H),
2.24 ppm (d, J ˆ 17.1 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ
190.2, 165.5, 156.9, 152.9, 136.4, 130.3, 129.0, 128.6, 128.5, 128.3, 128.2,
128.0, 127.2, 119.3, 114.4, 98.0, 80.2, 73.5, 59.6, 55.9, 55.5, 52.5, 37.8 ppm; IR
Cycloadduct (‡)-6 f: Colorless oil; [a]D ˆ ‡22.1 (c ˆ 0.8 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.49 (m, 2H), 7.09 (m, 5H), 6.83
(m, 2H), 6.55 (dd, J ˆ 5.7, 3.9 Hz, 1H), 6.43 (d, J ˆ 2.9 Hz, 1H), 5.43 (d, J ˆ
5.3 Hz, 1H), 4.88 and 4.97 (s, each 1H), 4.33 (t, J ˆ 5.4 Hz, 1H), 4.01 (m,
1H), 3.62 and 3.73 (s, each 3H), 1.98 (m, 1H), 1.57 (m, 1H), 1.31 and
1.39 ppm (s, each 3H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 163.8, 157.5,
156.9, 152.9, 150.8, 137.8, 130.9, 129.9, 129.8, 129.6, 122.8, 120.3, 116.4, 115.9,
114.4, 113.4, 113.3, 112.2, 79.8, 62.4, 55.8, 55.6, 49.6, 42.5, 37.3, 29.7,
20.0 ppm; IR (CHCl3): nÄ ˆ 3421, 1755 cmÀ1; MS (CI): m/z (%): 485 (100)
‡
(CHCl3): nÄ ˆ 1749, 1705 cmÀ1; MS (CI): m/z (%): 469 (100) [M‡H] , 468
‡
(17) [M] ; elemental analysis calcd (%) for C29H28N2O4 (468.6): C 74.34, H
6.02, N 5.98; found: C 74.44, H 6.05, N 5.94.
‡
‡
[M‡H] , 484 (29) [M] ; elemental analysis calcd (%) for C30H32N2O4
Cycloadduct (‡)-4e: Colorless oil; [a]D ˆ ‡150.0 (c ˆ 0.7 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.27 (m, 10H), 7.01 (d, J ˆ 7.6 Hz,
1H), 6.90 (m, 2H), 6.78 (m, 2H), 4.94 (d, J ˆ 7.6 Hz, 1H), 4.78 (m, 5H), 4.21
(d, J ˆ 14.9 Hz, 1H), 3.94 (m, 1H), 3.68 (s, 3H), 2.47 (dd, J ˆ 17.4, 7.3 Hz,
1H), 2.15 ppm (d, J ˆ 17.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ
189.9, 165.6, 157.4, 153.1, 137.1, 136.5, 129.7, 129.1, 128.9, 128.8, 128.7, 128.3,
127.5, 120.8, 114.5, 99.7, 80.3, 73.5, 58.3, 56.6, 55.5, 54.5, 37.2 ppm; IR
(484.6): C 74.36, H 6.66, N 5.78; found: C 74.27, H 6.69, N 5.80.
Cycloadduct (‡)-5i: Compound (‡)-5i (518 mg; 67%) was obtained from
the imine (‡)-2i (200 mg, 0.73 mmol), after column chromatography
(elution with ethyl acetate/hexanes (1:1)); colorless oil; [a]D ˆ ‡41.8 (c ˆ
1
0.6 in CHCl3); H NMR (300 MHz, CDCl3, 258C): d ˆ 6.52 (m, 3H), 5.70
(m, 1H), 5.18 (m, 2H), 4.94 and 5.04 (s, each 1H), 4.47 (d, J ˆ 4.9 Hz, 1H),
3.95 (m, 2H), 3.61 (m, 2H), 3.55 and 3.60 (s, each 3H), 1.97 (m, 1H), 1.56
(m, 1H), 1.35 and 1.49 ppm (s, each 3H); 13C NMR (75 MHz, CDCl3,
258C): d ˆ 167.8, 152.5, 151.1, 138.3, 132.6, 128.6, 118.8, 116.4, 113.5, 113.2,
112.2, 83.9, 62.1, 59.8, 55.9, 48.1, 44.5, 42.8, 38.1, 29.5, 20.1 ppm; IR (CHCl3):
‡
(CHCl3): n ˆ 1756, 1711 cmÀ1; MS (CI): m/z (%): 469 (100) [M‡H] , 468
‡
(31) [M] ; elemental analysis calcd (%) for C29H28N2O4 (468.6): C 74.34, H
6.02, N 5.98; found: C 74.23, H 6.00, N 6.01.
nÄ ˆ 3429, 1751 cmÀ1; MS (CI): m/z (%): 357 (100) [M‡H] , 356 (25) [M] ;
elemental analysis calcd (%) for C21H28N2O3 (356.5): C 70.76, H 7.92, N
7.86; found: C 70.86, H 7.96, N 7.83.
Preparation of cycloadducts (‡)-3h and (‡)-4h: The less polar compound
(‡)-3h (518 mg; 43%) and the more polar compound (‡)-4h (169 mg;
14%) were obtained from the imine (‡)-2h (1.0 g, 3.09 mmol), after
column chromatography (elution with ethyl acetate/hexanes (1:1 contain-
ing 1% triethylamine)).
‡
‡
Procedure for the synthesis of cycloadducts (‡)-7 and (‡)-8: Indium(iii)
chloride (44 mg, 0.2 mmol) was added in portions to a solution of the imine
(‡)-2g (340 mg, 1.0 mmol) and cyclopentadiene (120 mg, 2.0 mmol) in
acetonitrile (7 mL) at À208C. The reaction mixture was stirred at room
temperature for 1 h, and then saturated aqueous NaHCO3 (1 mL) was
added and the mixture was extracted with ethyl acetate (3 Â 20 mL). The
combined organic extracts were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the residue
eluting with dichloromethane/ethyl acetate/hexanes (1:1:1 containing 1%
triethylamine) gave the less polar compound (‡)-8 (398 mg; 49%) and the
more polar compound (‡)-7 (398 mg; 49%).
Cycloadduct (‡)-3h: Yellow solid; m.p. 144 1458C (hexanes/ethyl ace-
tate); [a]D ˆ ‡58.0 (c ˆ 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 7.08 (d, J ˆ 7.6 Hz, 1H), 6.82 (m, 8H), 5.29 (d, J ˆ 7.6 Hz, 1H), 4.95 (dd,
J ˆ 10.1, 5.5 Hz, 1H), 4.63 (d, J ˆ 5.5 Hz, 1H), 4.54 (m, 1H), 3.59 and 3.66
(s, each 3H), 2.99 (d, J ˆ 17.1 Hz, 1H), 2.35 (dd, J ˆ 17.1, 6.2 Hz, 1H),
2.16 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 191.3, 165.8, 156.7,
148.5, 137.5, 134.7, 134.2, 129.3, 120.7, 118.0, 114.5, 101.8, 82.6, 59.9, 57.9,
55.5, 52.2, 38.0, 20.9 ppm; IR (KBr): n ˆ 1740, 1705 cmÀ1; MS (CI): m/z
‡
‡
(%): 393 (100) [M‡H] , 392 (22) [M] ; elemental analysis calcd (%) for
C23H24N2O4 (392.5): C 70.39, H 6.16, N 7.14; found: C 70.30, H 6.14, N 7.17.
Cycloadduct (‡)-7: Pale green oil; [a]D ˆ ‡243.2 (c ˆ 0.6 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d ˆ 6.80 and 7.20 (m, each 2H), 6.43 (m,
3H), 5.70 (m, 1H), 5.56 (m, 1H), 4.68 (d, J ˆ 5.3 Hz, 1H), 4.17 (dd, J ˆ 9.0,
5.3 Hz, 1H), 3.71 (m, 4H), 3.63 (m, 7H), 2.54 (m, 2H), 2.11 ppm (m, 1H);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 165.6, 157.7, 153.2, 138.4, 133.9,
130.1, 129.4, 127.1, 122.4, 117.3, 114.4, 113.9, 112.5, 83.2, 59.8, 59.3, 56.0, 55.7,
55.5, 46.1, 40.6, 31.4 ppm; IR (CHCl3): nÄ ˆ 3345, 1743 cmÀ1; MS (CI): m/z
Cycloadduct (‡)-4h: Yellow solid; m.p. 150 1518C (hexanes/ethyl ace-
tate); [a]D ˆ ‡114.2 (c ˆ 0.7 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 7.15 (m, 9H), 4.98 (d, J ˆ 7.8 Hz, 1H), 4.68 (m, 1H), 4.60 (dd, J ˆ 5.4,
2.9 Hz, 1H), 4.48 (d, J ˆ 5.4 Hz, 1H), 3.46 and 3.83 (s, each 3H), 2.93 (dd,
J ˆ 17.1, 7.5 Hz, 1H), 2.64 (dd, J ˆ 17.1, 6.3 Hz, 1H), 2.31 ppm (s, 3H);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 190.3, 165.1, 157.8, 151.5, 137.6,
134.9, 134.2, 129.5, 124.2, 118.6, 114.9, 101.1, 82.3, 59.4, 57.7, 56.7, 55.6, 37.4,
20.9 ppm; IR (KBr): nÄ ˆ 1743, 1706 cmÀ1; MS (CI): m/z (%): 393 (100)
‡
‡
(%): 407 (100) [M‡H] , 406 (47) [M] ; elemental analysis calcd (%) for
‡
‡
C24H26N2O4 (406.5): C 70.92, H 6.45, N 6.89; found: C 70.99, H 6.44, N 6.91.
[M‡H] , 392 (17) [M] ; elemental analysis calcd (%) for C23H24N2O4
(392.5): C 70.39, H 6.16, N 7.14; found: C 70.47, H 6.15, N 7.11.
Cycloadduct (‡)-8: Pale green solid; m.p. 166 1678C (hexanes/ethyl
acetate); [a]D ˆ ‡243.2 (c ˆ 0.8 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d ˆ 6.94 and 7.51 (m, each 2H), 6.57 (d, J ˆ 2.8 Hz, 1H), 6.46 (ddd,
J ˆ 8.6, 2.9, 0.5 Hz, 1H), 6.21 (d, J ˆ 8.6 Hz, 1H), 5.86 (m, 1H), 5.75 (m,
1H), 4.68 (d, J ˆ 5.5 Hz, 1H), 4.34 (dd, J ˆ 9.8, 5.5 Hz, 1H), 3.98 (m, 1H),
3.83 (m, 4H), 3.67 and 3.71 (s, each 3H), 3.06 (qd, J ˆ 10.8, 2.9 Hz, 1H), 2.81
(m, 1H), 2.38 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 166.0,
157.1, 153.3, 138.1, 134.3, 130.9, 130.1, 127.1, 120.2, 117.3, 114.6, 113.9, 112.3,
82.8, 60.5, 59.8, 59.7, 56.1, 55.7, 55.6, 46.2, 39.1, 31.6 ppm; IR (KBr): nÄ ˆ
General procedure for the synthesis of cycloadducts 5 and 6: Indium(iii)
triflate (0.2 mmol) was added in portions to a solution of the appropriate
imine 2 (1.0 mmol) and 2,3-dimethyl-1,3-butadiene (2.0 mmol) in acetoni-
trile (7 mL) at 08C. After the imine had been consumed (TLC), saturated
aqueous NaHCO3 (1 mL) was added, and the mixture was extracted with
ethyl acetate (3 Â 20 mL). The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue eluting with ethyl acetate/hexanes mixtures gave
analytically pure compounds 5 and 6. Spectroscopic and analytical data for
some representative pure forms of 5 and 6 are given below.
‡
‡
3342, 1744 cmÀ1; MS (CI): m/z (%): 407 (100) [M‡H] , 406 (36) [M] ;
elemental analysis calcd (%) for C24H26N2O4 (406.5): C 70.92, H 6.45, N
6.89; found: C 70.84, H 6.43, N 6.87.
Preparation of cycloadducts (‡)-5 f and (‡)-6 f: The less polar compound
(‡)-5 f (121 mg; 52%) and the more polar compound (‡)-6 f (82 mg; 35%)
were obtained from the imine (À)-2 f (200 mg, 0.498 mmol), after column
chromatography (elution with ethyl acetate/hexanes (1:6)).
General procedure for the synthesis of cycloadducts 9 and 10: Indium(iii)
triflate (0.2 mmol) was added in portions to a solution of the appropriate
imine 2 (1.0 mmol) and 3,4-dihydro-2H-pyran (1.2 mmol) in acetonitrile
(7 mL) at 08C. After the imine had been consumed (TLC), saturated
aqueous NaHCO3 (1 mL) was added, and the mixture was extracted with
ethyl acetate (3 Â 20 mL). The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue eluting with ethyl acetate/hexanes mixtures gave
Cycloadduct (‡)-5 f: Colorless solid; m.p. 158 1598C (hexanes/ethyl
acetate); [a]D ˆ ‡75.5 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d ˆ 7.44 (m, 2H), 7.05 (m, 5H), 6.74 (m, 2H), 6.46 (m, 2H), 6.28 (d,
J ˆ 9.4 Hz, 1H), 5.37 (d, J ˆ 5.2 Hz, 1H), 4.92 and 5.02 (s, each 1H), 4.38
(dd, J ˆ 6.8, 5.4 Hz, 1H), 3.94 (m, 1H), 3.61 and 3.74 (s, each 3H), 1.97 (m,
3422
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 3415 3426

Highly Functionalized Indolizidine Systems
3415 3426
analytically pure compounds 9 and 10. Spectroscopic and analytical data for
some representative pure forms of 9 and 10 are given below.
(75 MHz, CDCl3, 258C): d ˆ 167.4, 158.6, 156.2, 153.0, 149.8, 140.3, 134.0,
129.3, 128.4, 122.1, 120.8, 116.8, 115.9, 114.8, 113.3, 112.7, 112.1, 82.9, 61.8,
55.8, 55.6, 55.2, 43.0, 38.9, 29.1, 19.8 ppm; IR (CHCl3): nÄ ˆ 3305, 1690 cmÀ1
;
Preparation of cycloadducts (‡)-9a and (‡)-10a: The less polar compound
(‡)-9a (53 mg; 46%) and the more polar compound (‡)-10a (21 mg;
24%) were obtained from the imine (À)-2 f (95 mg, 0.236 mmol), after
column chromatography (elution with ethyl acetate/hexanes (1:6)).
‡
MS (EI): m/z (%): 485 (100) [M] ; elemental analysis calcd (%) for
C30H32N2O4 (484.6): C 74.36, H 6.66, N 5.78; found: C 74.25, H 6.68, N 5.77.
Fused indolizidinone (‡)-13: Compound (‡)-13 (83 mg; 90%) was
obtained from the cycloadduct (‡)-7 (93 mg, 0.229 mmol); pale brown
oil; [a]D ˆ ‡44.6 (c ˆ 0.9 in CHCl3); 1H NMR (300 MHz, C6D6, 258C): d ˆ
9.09 (d, J ˆ 9.0 Hz, 1H), 6.80 and 6.93 (m, each 2H), 6.73 (m, 2H), 5.67 (m,
1H), 5.42 (m, 1H), 3.84 (t, J ˆ 6.5 Hz, 1H), 3.79 (s, 3H), 3.68 (m, 2H), 3.39
and 3.49 (s, each 3H), 3.20 (m, 1H), 2.72 (qd, J ˆ 8.9, 3.4 Hz, 1H), 2.66 (m,
1H), 2.07 ppm (ddq, J ˆ 18.8, 16.2, 1.4 Hz, 1H); 13C NMR (75 MHz, C6D6,
258C): d ˆ 169.5, 156.8, 143.6, 141.3, 133.6, 131.4, 130.2, 129.1, 121.6, 115.8,
115.2, 114.3, 111.7, 85.0, 60.7, 59.1, 58.4, 55.2, 54.9, 46.2, 40.9, 31.8 ppm; IR
Cycloadduct (‡)-9a: Yellow oil; [a]D ˆ ‡66.0 (c ˆ 1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 7.48 (m, 2H), 7.25 (m, 2H), 6.97 (m, 3H), 6.74
(m, 3H), 6.56 (ddd, J ˆ 8.7, 2.9, 0.5 Hz, 1H), 6.18 (d, J ˆ 8.7 Hz, 1H), 5.00
and 5.37 (d, J ˆ 5.4 Hz, each 1H), 4.63 (dd, J ˆ 9.8, 5.4 Hz, 1H), 3.92 (m,
1H), 1.46 (m, 4H), 3.67 and 3.77 (s, each 3H), 3.51 (m, 2H), 2.40 ppm (m,
1H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 164.2, 157.5, 157.0, 153.2, 137.9,
130.4, 129.6, 122.6, 121.5, 120.1, 116.4, 115.8, 114.9, 114.3, 111.6, 79.5, 71.5,
60.9, 57.8, 56.6, 55.6, 55.4, 33.0, 24.9, 18.8 ppm; IR (CHCl3): nÄ ˆ 3418,
‡
(CHCl3): nÄ ˆ 3330, 1730 cmÀ1; MS (EI): m/z (%): 406 (100) [M] ; elemental
‡
‡
1751 cmÀ1; MS (CI): m/z (%): 487 (100) [M‡H] , 486 (46) [M] ; elemental
analysis calcd (%) for C29H30N2O5 (486.6): C 71.59, H 6.21, N 5.76; found: C
71.69, H 6.25, N 5.73.
analysis calcd (%) for C24H26N2O4 (406.5): C 70.92, H 6.45, N 6.89; found: C
70.99, H 6.47, N 6.86.
Cycloadduct (‡)-10a: Yellow oil; [a]D ˆ ‡35.7 (c ˆ 0.7 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 7.18 (m, 6H), 6.84 (m, 3H), 6.65 (dd, J ˆ 8.7,
2.9 Hz, 1H), 6.37 (d, J ˆ 8.7 Hz, 1H), 4.93 and 5.46 (d, J ˆ 5.2 Hz, each 1H),
4.51 (dd, J ˆ 9.4, 5.2 Hz, 1H), 4.07 (m, 1H), 3.68 and 3.77 (s, each 3H), 3.41
(m, 3H), 1.57 ppm (m, 4H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 163.6,
157.6, 157.0, 153.3, 137.9, 129.7, 129.6, 129.1, 122.8, 121.7, 116.3, 115.7, 115.1,
114.4, 111.4, 80.4, 71.7, 60.6, 57.2, 56.7, 55.6, 55.4, 33.7, 24.9, 18.6 ppm; IR
Fused indolizidinone (‡)-15b: Compound (‡)-15b (38 mg; 75%) was
obtained from the cycloadduct (‡)-9c (50 mg, 0.139 mmol); colorless oil;
[a]D ˆ ‡38.0 (c ˆ 0.7 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d ˆ
7.91 (d, J ˆ 8.9 Hz, 1H), 7.03 (d, J ˆ 2.9 Hz, 1H), 6.78 (dd, J ˆ 8.9, 2.9 Hz,
1H), 5.90 (m, 1H), 5.15 (m, 2H), 4.92 (d, J ˆ 5.6 Hz, 1H), 3.86 (m, 2H), 3.74
and 3.76 (s, each 3H), 3.51 (m, 2H), 3.29 (m, 2H), 3.19 (m, 1H), 2.29 (m,
1H), 1.69 ppm (m, 4H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 169.8,
157.4, 136.1, 129.4, 128.3, 122.5, 116.7, 113.9, 111.9, 83.4, 72.4, 61.1, 59.1, 58.8,
58.2, 55.5, 51.5, 33.3, 24.5, 20.3 ppm; IR (CHCl3): nÄ ˆ 3318, 1710 cmÀ1; MS
‡
(CHCl3): nÄ ˆ 3422, 1750 cmÀ1; MS (CI): m/z (%): 487 (100) [M‡H] , 486
‡
(33) [M] ; elemental analysis calcd (%) for C29H30N2O5 (486.6): C 71.59, H
‡
‡
‡
(ES): m/z (%): 381 (3) [M‡Na] , 359 (100) [M‡1] , 358 (3) [M] ;
elemental analysis calcd (%) for C20H26N2O4 (358.4): C 67.02, H 7.31, N 7.82;
found: C 67.10, H 7.34, N 7.79.
6.21, N 5.76; found: C 71.48, H 6.18, N 5.73.
Cycloadduct (‡)-9c: Compound (‡)-9c (620 mg; 95%) was obtained as a
colorless oil from the imine (‡)-2i (500 mg (1.825 mmol), after column
chromatography (elution with ethyl acetate/hexanes (1:1)); [a]D ˆ ‡43.5
(c ˆ 0.5 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 6.90 (d, J ˆ
2.9 Hz, 1H), 6.61 (dd, J ˆ 8.6, 2.9 Hz, 1H), 6.39 (d, J ˆ 8.6 Hz, 1H), 5.77 (m,
1H), 5.30 (m, 2H), 4.95 (d, J ˆ 5.6 Hz, 1H), 4.49 (d, J ˆ 5.1 Hz, 1H), 3.99
(m, 1H), 3.81 (m, 2H), 3.69 (s, 3H), 3.55 (m, 2H), 3.50 (s, 3H), 3.42 (m,
1H), 2.24 (m, 1H), 1.67 ppm (m, 4H); 13C NMR (75 MHz, CDCl3, 258C):
d ˆ 168.4, 153.3, 138.4, 133.4, 121.9, 118.5, 116.4, 115.1, 111.8, 83.4, 71.8, 60.9,
60.3, 59.4, 55.8, 54.6, 44.7, 33.5, 25.2, 19.1 ppm; IR (CHCl3): nÄ ˆ 3419,
General procedure for the synthesis of piperidones (‡)-18 and (‡)-25: A
cooled solution of l-Selectride (49 mg, 0.259 mmol) in tetrahydrofuran
(0.259 mL) was added dropwise to a stirred solution of the appropriate
cycloadduct (‡)-3h or (‡)-4h (0.236 mmol) in tetrahydrofuran (3.5 mL) at
À788C, and the mixture was stirred at À788C [5 h for (‡)-3h and 1 h for
(‡)-4h]. Saturated aqueous sodium hydrogen carbonate (0.5 mL) was then
added, and the mixture was allowed to warm to room temperature, before
being extracted with ethyl acetate. The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated under reduced
pressure. Chromatography of the residue eluting with ethyl acetate/
hexanes (1:1 containing 1% triethylamine) gave analytically pure com-
pounds (‡)-18 and (‡)-25.
‡
‡
1755 cmÀ1; MS (CI): m/z (%): 359 (100) [M‡H] , 358 (43) [M] ; elemental
analysis calcd (%) for C20H26N2O4 (358.4): C 67.02, H 7.31, N 7.82; found: C
67.11, H 7.28, N 7.86.
Sodium methoxide promoted reaction of tetrahydroquinolinyl-b-lactams:
general procedure for the preparation of polycyclic indolizidinones 11 16:
Sodium methoxide (108.3 mg, 2.0 mmol) was added in portions at 08C to a
solution of the appropriate tetrahydroquinolinyl-b-lactam (0.50 mmol) in
methanol (10 mL). The reaction mixture was stirred at room temperature
until the starting material had been completely consumed (TLC), and then
water (1 mL) was added. The methanol was evaporated under reduced
pressure, the aqueous residue was extracted with ethyl acetate (10 Â 3 mL),
and the combined organic extracts were dried over MgSO4 and then
concentrated under reduced pressure. Chromatography of the residue
eluting with ethyl acetate/hexanes mixtures gave analytically pure com-
pounds 11 16.
Piperidone (‡)-25: Compound (‡)-25 (152 mg; 80%) was obtained from
the cycloadduct (‡)-4h (188 mg, 0.479 mmol); yellow solid; m.p. 158
1
1598C (hexanes/ethyl acetate); [a]D ˆ ‡21.2 (c ˆ 1.0 in CHCl3); H NMR
(300 MHz, CDCl3, 258C): d ˆ 7.48 (m, 4H), 7.04 (m, 4H), 6.82 (m, 2H), 4.34
and 4.41 (d, J ˆ 5.6 Hz, each 1H), 4.00 (m, 1H), 3.54 and 3.74 (s, each 3H),
3.28 (m, 2H), 2.48 (m, 4H), 2.25 ppm (s, 3H); 13C NMR (75 MHz, CDCl3,
258C): d ˆ 207.2, 165.4, 154.3, 144.1, 135.4, 134.6, 129.7, 122.9, 118.4, 115.2,
82.5, 59.8, 59.1, 57.4, 55.7, 52.7, 41.9, 40.9, 21.1 ppm; IR (KBr): nÄ ˆ 1751,
‡
‡
1720 cmÀ1; MS (CI): m/z (%): 395 (100) [M‡1] , 394 (15) [M] ; elemental
analysis calcd (%) for C23H26N2O4 (394.5): C 70.03, H 6.64, N 7.10; found: C
69.92, H 6.61, N 7.13.
General procedure for the synthesis of hydroxypiperidines (‡)-19, (‡)-20,
and (‡)-26: Sodium borohydride (51 mg, 1.29 mmol) was added in portions
to a stirred solution of the appropriate piperidone (‡)-18 or (‡)-25
(0.645 mmol) in methanol (6.5 mL) at 08C, and the mixture was stirred at
08C until the starting material had been consumed (TLC). Saturated
aqueous ammonium chloride (1.0 mL) was added, and the mixture was
allowed to warm to room temperature, before being extracted with ethyl
acetate. The combined organic extracts were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate/hexanes mixtures gave analytically
pure compounds (‡)-19, (‡)-20, and (‡)-26.
Hydroxypiperidine (‡)-26: Compound (‡)-26 (230 mg; 90%) was ob-
tained from the piperidone (‡)-25 (254 mg, 0.645 mmol); yellow solid; m.p.
71 728C (hexanes/ethyl acetate); [a]D ˆ ‡22.2 (c ˆ 0.6 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.60 (m, 2H), 7.05 (m, 4H), 6.78
(m, 2H), 4.20 and 4.38 (d, J ˆ 4.0 Hz, each 1H), 3.81 (m, 4H), 3.64 (s, 3H),
3.46 (dd, J ˆ 7.6, 2.0 Hz, 1H), 3.22 (dt, J ˆ 7.8, 2.2 Hz, 1H), 2.66 (td, J ˆ 8.0,
1.6 Hz, 1H), 2.32 (s, 3H), 2.27 (dt, J ˆ 7.8, 2.0 Hz, 1H), 1.87 (m, 1H), 1.69
Fused indolizidinone (‡)-11: Compound (‡)-11 (70 mg; 100%) was
obtained from the cycloadduct (‡)-5 f (70 mg, 0.145 mmol); pale orange
1
oil; [a]D ˆ ‡140.3 (c ˆ 0.7 in CHCl3); H NMR (300 MHz, CDCl3, 258C):
d ˆ 8.38 (d, J ˆ 9.0 Hz, 1H), 7.21 (m, 2H), 7.02 (m, 3H), 6.63 (m, 6H), 4.95
and 5.05 (s, each 1H), 4.68 (d, J ˆ 3.5 Hz, 1H), 4.49 (m, 1H), 4.24 (m, 1H),
3.66 and 3.68 (s, each 3H), 1.49 and 2.09 (m, each 1H), 1.41 and 1.45 ppm (s,
each 3H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 167.4, 157.9, 156.5, 152.9,
150.2, 140.1, 134.8, 129.5, 128.9, 122.1, 121.4, 116.3, 115.1, 115.0, 113.4, 112.6,
112.0, 81.4, 55.6, 55.5, 55.3, 55.2, 43.4, 34.7, 29.2, 19.9 ppm; IR (CHCl3): nÄ ˆ
‡
3304, 1684 cmÀ1; MS (EI): m/z (%): 485 (100) [M] ; elemental analysis
calcd (%) for C30H32N2O4 (484.6): C 74.36, H 6.66, N 5.78; found: C 74.46, H
6.69, N 5.76.
Fused indolizidinone (‡)-12: Compound (‡)-12 (40 mg; 100%) was
obtained from the cycloadduct (‡)-6 f (40 mg, 0.083 mmol); pale orange
oil; [a]D ˆ ‡34.4 (c ˆ 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 8.50 (d, J ˆ 9.0 Hz, 1H), 7.14 (m, 4H), 6.82 (m, 7H), 4.97 and 5.05 (s,
each 1H), 4.80 (d, J ˆ 7.9 Hz, 1H), 3.97 (m, 2H), 3.66 and 3.67 (s, each 3H),
1.97 (m, 2H), 1.37 and 1.44 (s, each 3H), 1.18 ppm (s, 1H); 13C NMR
Chem. Eur. J. 2003, 9, 3415 3426
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3423

B. Alcaide, P. Almendros et al.
FULL PAPER
(m, 1H), 1.60 (m, 1H), 1.41 ppm (m, 1H); 13C NMR (75 MHz, CDCl3,
258C): d ˆ 165.1, 156.8, 144.5, 135.8, 133.7, 129.2, 125.9, 117.9, 114.7, 81.8,
68.7, 59.4, 58.9, 57.1, 55.4, 55.3, 36.6, 35.1, 20.8 ppm; IR (CHCl3): nÄ ˆ 3511,
133.3, 129.2, 129.1, 128.7, 127.4, 125.9, 117.9, 114.8, 81.8, 74.7, 72.8, 59.5, 58.9,
56.6, 55.5, 55.3, 32.1, 25.3, 20.8, 20.5 ppm; IR (CHCl3): nÄ ˆ 1744 cmÀ1; MS
‡
‡
(CI): m/z (%): 573 (100) [M‡1] , 572 (18) [M] ; elemental analysis calcd
(%) for C33H36N2O7 (572.7): C 69.21, H 6.34, N 4.89; found: C 69.28, H 6.37,
N 4.86.
‡
‡
1745 cmÀ1; MS (CI): m/z (%): 397 (100) [M‡1] , 396 (15) [M] ; elemental
analysis calcd (%) for C23H28N2O4 (396.5): C 69.67, H 7.12, N 7.07; found: C
69.57, H 7.15, N 7.03.
(S)-O-Acetylmandelate (‡)-32: Compound (‡)-32 (39 mg; 88%) was
obtained from the hydroxypiperidine (‡)-26 (31 mg, 0.078 mmol); yellow
oil; [a]D ˆ ‡25.1 (c ˆ 0.8 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 7.10 (m, 13H), 5.86 (s, 1H), 4.96 (m, 1H), 4.18 and 4.38 (d, J ˆ 5.8 Hz,
each 1H), 3.79 (s, 3H), 3.64 (s, 3H), 3.16 and 3.49 (m, each 1H), 2.67 (t, J ˆ
12.5 Hz, 1H), 2.33 (s, 3H), 2.16 (s, 3H), 1.57 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 170.2, 168.3, 165.4, 157.1, 144.3, 135.9, 133.9,
133.3, 129.4, 129.2, 128.8, 127.7, 126.1, 118.1, 114.9, 81.9, 74.6, 72.7, 59.7, 58.9,
56.7, 55.8, 55.5, 32.5, 31.4, 20.9, 20.7 ppm; IR (CHCl3): nÄ ˆ 1746 cmÀ1; MS
General procedure for the synthesis of tert-butyldimethylsilyl ethers (‡)-
21, (‡)-22, and (‡)-27: A solution of the appropriate hydroxypiperidine
(‡)-19, (‡)-20, or (‡)-26 (0.505 mmol) in dimethylformamide (1.0 mL) was
added dropwise to a stirred suspension of tert-butyldimethylsilyl chloride
(126 mg, 0.833 mmol) and imidazole at 08C, and the mixture was stirred at
room temperature until the starting material had been consumed (TLC).
Saturated aqueous ammonium chloride (1.0 mL) was added, and the
mixture was extracted with dichloromethane. The combined organic
extracts were washed with brine and water, dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the residue eluting with
ethyl acetate/hexanes mixtures gave analytically pure compounds (‡)-21,
(‡)-22, and (‡)-27.
‡
‡
(CI): m/z (%): 573 (100) [M‡1] , 572 (33) [M] ; elemental analysis calcd
(%) for C33H36N2O7 (572.7): C 69.21, H 6.34, N 4.89; found: C 69.43, H 6.38,
N 4.87.
Sodium methoxide promoted reaction of piperidinyl-b-lactams: general
procedure for the preparation of indolizidinones 33 35: Sodium meth-
oxide (0.6 mmol) was added in portions at 08C to a solution of the
appropriate piperidinyl-b-lactam (0.15 mmol) in methanol (3 mL). The
reaction mixture was stirred at room temperature until the starting material
had been completely consumed (TLC), and then water (0.5 mL) was added.
The methanol was evaporated under reduced pressure, the aqueous residue
was extracted with ethyl acetate (5 Â 3 mL), and the combined organic
layers were dried over MgSO4 and then concentrated under reduced
pressure. Chromatography of the residue eluting with ethyl acetate/
hexanes mixtures gave analytically pure compounds 33 35.
tert-Butyldimethylsilyl ether (‡)-27: Compound (‡)-27 (207 mg; 80%)
was obtained from the hydroxypiperidine (‡)-26 (200 mg, 0.505 mmol);
yellow oil; [a]D ˆ ‡68.1 (c ˆ 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d ˆ 7.62 (m, 2H), 7.05 (m, 4H), 6.77 (m, 2H), 4.17 and 4.38 (d, J ˆ
5.6 Hz, 1H), 3.64 and 3.79 (s, each 3H), 3.41 (m, 1H), 3.19 (dt, J ˆ 12.4,
3.4 Hz, 1H), 2.64 (td, J ˆ 11.9, 2.7 Hz, 1H), 2.32 (s, 3H), 2.15 (m, 1H), 1.53
(m, 3H), 0.87 (s, 9H), 0.05 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C):
d ˆ 165.5, 156.9, 145.0, 136.0, 133.9, 129.4, 126.2, 118.4, 114.9, 81.9, 70.1,
59.5, 59.2, 57.8, 56.1, 55.6, 36.9, 36.0, 26.0, 25.8, 21.0, 18.4 ppm; IR (CHCl3):
‡
‡
nÄ ˆ 1747 cmÀ1; MS (CI): m/z (%): 511 (100) [M‡1] , 510 (31) [M] ;
elemental analysis calcd (%) for C29H42N2O4Si (510.8): C 68.20, H 8.29, N
5.48; found: C 68.11, H 8.25, N 5.51.
Indolizidinone (‡)-33: Compound (‡)-33 (18 mg; 100%) was obtained
from the piperidinyl-b-lactam (‡)-23 (18 mg, 0.043 mmol); colorless oil;
[a]D ˆ ‡23.6 (c ˆ 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d ˆ
7.01 (m, 2H), 6.58 (m, 2H), 4.20 (ddd, J ˆ 13.7, 5.1, 1.5 Hz, 1H), 4.09 (t, J ˆ
6.8 Hz, 1H), 3.76 (m, 3H), 3.61 (s, 3H), 2.69 (td, J ˆ 13.7, 3.2 Hz, 1H), 2.25
(s, 3H), 1.84 (m, 2H), 1.27 (m, 2H), 0.83 (s, 9H), 0.02 (s, 3H), 0.00 ppm (s,
3H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 169.2, 144.3, 129.9, 127.9,
113.4, 82.6, 69.4, 58.5, 55.6, 55.3, 38.3, 36.2, 34.4, 25.7, 20.3, 17.9 ppm; IR
General procedure for the CAN-mediated N-deprotection: synthesis of
piperidines (‡)-23, (‡)-24, and (À)-28: A solution of CAN (171 mg,
0.313 mmol) in water (2 mL) was slowly added to a stirred solution of the
corresponding N-protected piperidine (‡)-21, (‡)-22, or (‡)-27
(0.136 mmol) in acetonitrile (2 mL) at À358C. The reaction mixture was
stirred at À358C for 30 min. Aqueous 10% sodium sulfite (1.0 mL) was
then added, and the mixture was extracted with ethyl acetate. The
combined organic extracts were washed with brine and water, dried
(MgSO4), and concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate/hexanes mixtures gave analytically
pure compounds (‡)-23, (‡)-24, and (À)-28.
‡
(CHCl3): nÄ ˆ 3432, 1710 cmÀ1; MS (CI): m/z (%): 405 (100) [M‡1] , 404
‡
(25) [M] ; elemental analysis calcd (%) for C22H36N2O3Si (404.6): C 65.30,
H 8.97, N 6.92; found: C 65.20, H 9.00, N 6.96.
Indolizidinone (‡)-34: Compound (‡)-34 (50 mg; 100%) was obtained
from the piperidinyl-b-lactam (‡)-24 (50 mg, 0.119 mmol); colorless oil;
[a]D ˆ ‡42.9 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d ˆ
6.99 (m, 2H), 6.55 (m, 2H), 4.26 (m, 1H), 4.20 (m, 1H), 4.05 (dd, J ˆ 6.9,
6.8 Hz, 1H), 3.97 (m, 1H), 3.82 (d, J ˆ 6.6 Hz, 1H), 3.61 (s, 3H), 3.13 (td,
J ˆ 12.5, 3.9 Hz, 1H), 2.23 (s, 3H), 1.49 (m, 4H), 0.86 (s, 9H), 0.05 (s, 3H),
0.00 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 168.9, 144.6,
129.9, 127.8, 113.4, 83.0, 64.9, 58.3, 55.4, 52.3, 35.5, 33.7, 32.3, 25.8, 20.4,
18.1 ppm; IR (CHCl3): nÄ ˆ 3426, 1712 cmÀ1; MS (CI): m/z (%): 405 (100)
Piperidine (À)-28: Compound (À)-28 (56 mg; (43%) was obtained from
the N-protected piperidine (‡)-27 (160 mg, 0.311 mmol); red oil; [a]D
ˆ
À32.5 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.31 (m,
2H), 7.10 (m, 2H), 6.99 (s, 1H), 4.60 (d, J ˆ 5.4 Hz, 1H), 4.16 (dd, J ˆ 5.9,
5.4 Hz, 1H), 3.65 (s, 3H), 3.56 (m, 1H), 3.16 (m, 2H), 2.55 (td, J ˆ 12.4,
2.2 Hz, 1H), 2.29 (s, 3H), 1.80 (m, 2H), 1.27 (m, 2H), 0.79 (s, 9H), 0.00 ppm
(s, 6H); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 165.2, 134.6, 134.3, 129.4,
118.4, 82.7, 69.7, 60.5, 59.3, 55.5, 44.5, 39.7, 36.1, 25.6, 20.7, 17.9 ppm; IR
‡
‡
[M‡1] , 404 (25) [M] ; elemental analysis calcd (%) for C22H36N2O3Si
‡
(CHCl3): nÄ ˆ 3438, 1743 cmÀ1; MS (CI): m/z (%): 405 (100) [M‡1] , 404
(404.6): C 65.30, H 8.97, N 6.92; found: C 65.42, H 9.01, N 6.88.
‡
(17) [M] ; elemental analysis calcd (%) for C22H36N2O3Si (404.6): C 65.30,
Indolizidinone (À)-35: Compound (À)-35 (45 mg; 100%) was obtained as a
colorless oil from the piperidinyl-b-lactam (À)-28 (45 mg, 0.107 mmol);
H 8.97, N 6.92; found: C 65.42, H 9.00, N 6.89.
1
General procedure for the preparation of O-acetylmandelates 29 32: (R)-
or (S)-O-Acetylmandelic acid (20 mg, 0.10 mmol) and 4-dimethylamino-
pyridine (DMAP) (cat.) were added to a solution of the corresponding
alcohol (0.09 mmol) in dichloromethane (1.0 mL), followed by a solution of
dicyclohexylcarbodiimide (DCC) (37 mg, 0.18 mmol) in dichloromethane
(500 mL) at 08C. The reaction mixture was allowed to warm to room
temperature and stirred for 16 h. The solvent was removed under reduced
pressure and diethyl ether was added. The resulting mixture was then
filtered and the filtrate was concentrated under reduced pressure.
Chromatography of the residue eluting with dichloromethane/ethyl acetate
mixtures gave analytically pure O-acetylmandelates 29 32.
[a]D ˆ À12.5 (c ˆ 0.9 in CHCl3); H NMR (300 MHz, CD3OD, 258C): d ˆ
6.95 (m, 2H), 6.66 (m, 2H), 4.06 (ddd, J ˆ 13.4, 5.1, 1.7 Hz, 1H), 3.83 (dd,
J ˆ 6.1, 1.2 Hz, 1H), 3.69 (dd, J ˆ 6.6, 6.1 Hz, 1H), 3.52 (s, 3H), 3.24 (m,
2H), 2.74 (td, J ˆ 13.2, 2.2 Hz, 1H), 2.19 (s, 3H), 1.88 and 2.14 (m, each
1H), 1.30 (m, 4H), 0.86 (s, 9H), 0.06 (s, 3H), 0.04 ppm (s, 3H); 13C NMR
(75 MHz, CD3OD, 258C): d ˆ 172.0, 146.7, 130.9, 128.6, 115.6, 85.7, 70.0,
62.8, 60.1, 59.6, 42.8, 38.7, 35.2, 26.4, 20.8, 19.0 ppm; IR (CHCl3): nÄ ˆ 3335,
‡
‡
1722 cmÀ1; MS (CI): m/z (%): 405 (100) [M‡1] , 404 (18) [M] ; elemental
analysis calcd (%) for C22H36N2O3Si (404.6): C 65.30, H 8.97, N 6.92; found:
C 65.19, H 8.93, N 6.89.
General procedure for the reduction of indolizidinones: Synthesis of
(R)-O-Acetylmandelate (‡)-31: Compound (‡)-31 (38 mg; 86%) was
obtained from the hydroxypiperidine (‡)-26 (31 mg, 0.078 mmol); yellow
oil; [a]D ˆ ‡47.1 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 7.42 (m, 13H), 5.77 (s, 1H), 4.88 (m, 1H), 4.16 and 4.34 (d, J ˆ 5.8 Hz,
each 1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.22 and 3.45 (m, each 1H), 2.69 (t, J ˆ
12.5 Hz, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 1.42 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 170.3, 168.4, 165.2, 156.9, 144.2, 135.8, 133.8,
indolizidines 36 39:
(0.10 mmol) in tetrahydrofuran or diethyl ether (1 mL) was added
dropwise to well-stirred suspension of lithium aluminum hydride
(0.80 mmol) in the same solvent (1 mL) at 08C, and the mixture was
stirred at room temperature until the starting material had been consumed
(TLC). Saturated aqueous ammonium chloride (1.0 mL) was added at 08C,
and the mixture was allowed to warm to room temperature, before being
A solution of the appropriate indolizidinone
a
3424
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 3415 3426

Highly Functionalized Indolizidine Systems
3415 3426
extracted with ethyl acetate. The combined organic extracts were washed
with brine, dried (MgSO4), and concentrated under reduced pressure.
Chromatography of the residue eluting with ethyl acetate/hexanes mixtures
gave analytically pure compounds 36 39.
M¸ller, G. Hessler, H. Y. Decornez, Angew. Chem. 2000, 112, 926;
Angew. Chem. Int. Ed. 2000, 39, 894; h) W. Li, C. E. Hanau, A.
d×Avignon, K. D. Moeller, J. Org. Chem. 1995, 60, 8155.
[5] For the total synthesis of (‡)-parotexine and (‡)-femoxetine, see:
¬
¬
a) M. Amat, J. Bosch, J. Hidalgo, M. Canto, M. Perez, N. Llor, E.
Molins, C. Miravitlles, M. Orozco, J. Luque, J. Org. Chem. 2000, 65,
3074. For the total synthesis of (À)-coniine, see: b) M. Amat, N. Llor,
J. Bosch, X. Solans, Tetrahedron 1997, 53, 719. For the synthesis of
isoquinoline alkaloids, see: c) S. M. Allin, D. G. Vaidya, S. L. James,
J. E. Allard, T. A. D. Smith, V. McKee, W. P. Martin, Tetrahedron Lett.
2002, 43, 3661.
Fused indolizidine (‡)-37: Compound (‡)-37 (18 mg; 72%) was obtained
from the indolizidinone (‡)-15b (26 mg, 0.073 mmol); colorless oil; [a]D
ˆ
1
‡71.0 (c ˆ 0.6 in CHCl3); H NMR (300 MHz, CDCl3, 258C): d ˆ 6.93 (d,
J ˆ 2.9 Hz, 1H), 6.67 (dd, J ˆ 8.7, 2.9 Hz, 1H), 6.35 (d, J ˆ 8.7 Hz, 1H), 5.87
(m, 1H), 5.01 (m, 2H), 4.97 (d, J ˆ 5.6 Hz, 1H), 3.69 (m, 7H), 3.32 (m, 7H),
3.12 (dd, J ˆ 9.4, 5.8 Hz, 1H), 1.64 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3, 258C): d ˆ 153.7, 140.8, 134.2, 127.9, 122.2, 114.4, 113.4, 112.7, 83.8,
72.8, 60.6, 60.4, 57.7, 55.9, 53.3, 51.5, 32.7, 29.2, 26.7, 22.1 ppm; IR (CHCl3):
[6] For reviews, see: a) I. Ojima, The Organic Chemistry of b-Lactams
(Ed.: G. I. Georg), VCH Publishers, New York, 1993, p. 197; b) I.
Ojima, Adv. Asymm. Synth. 1995, 1, 95; c) C. Palomo, J. M. Aizpurua,
I. Ganboa, M. Oiarbide, Amino Acids 1999, 16, 321; d) C. Palomo,
J. M. Aizpurua, I. Ganboa, M. Oiarbide, Synlett 2001, 1813.
‡
‡
nÄ ˆ 3320 cmÀ1; MS (CI): m/z (%): 345 (100) [M‡1] , 344 (25) [M] ;
elemental analysis calcd (%) for C20H28N2O3 (344.5): C 69.74, H 8.19, N
8.13; found: C 69.85, H 8.22, N 8.10.
Indolizidine (À)-38: Compound (À)-38 (30 mg; 79%) was obtained from
the indolizidinone (‡)-34 (40 mg, 0.098 mmol); colorless oil; [a]D ˆ À36.0
[7] For a review on the b-lactam synthon method, see: I. Ojima, F.
Delaloge, Chem. Soc. Rev. 1997, 26, 377.
1
(c ˆ 0.6 in CHCl3); H NMR (300 MHz, CDCl3, 258C): d ˆ 6.99 (m, 2H),
[8] For reviews on selective bond breakage and rearrangement reactions,
see: a) B. Alcaide, P. Almendros, Synlett 2002, 381; b) M. S. Manhas,
D. R. Wagle, J. Chiang, A. K. Bose, Heterocycles 1988, 27, 1755.
[9] For the application of 4-oxoazetidine-2-carbaldehydes as efficient
chiral synthons, see: a) B. Alcaide, P. Almendros, Chem. Soc. Rev.
2001, 30, 226. For a review on the chemistry of azetidine-2,3-diones,
see: b) B. Alcaide, P. Almendros, Org. Prep. Proced. Int. 2001, 33, 315.
[10] For a preliminary communication of a part of this work, see: a) B.
Alcaide, P. Almendros, J. M. Alonso, M. F. Aly, M. R. Torres, Synlett
2001, 1531. More recently, we have developed a different route to
fused tetracyclic indolizidines from b-lactams: b) B. Alcaide, C. Pardo,
6.58 (m, 2H), 4.11 (m, 1H), 3.89 (m, 1H), 3.65 (m, 2H), 3.39 (m, 1H), 3.31
(s, 3H), 2.82 (m, 2H), 2.47 (td, J ˆ 10.9, 4.5 Hz, 1H), 2.21 (s, 3H), 2.12 (dd,
J ˆ 9.9, 4.9 Hz, 1H), 1.61 (m, 3H), 0.86 (s, 9H), 0.01 ppm (s, 6H); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 144.9, 129.8, 126.4, 113.4, 85.0, 64.9, 60.3, 59.2,
57.1, 47.7, 33.7, 32.9, 29.8, 25.9, 20.4, 18.1 ppm; IR (CHCl3): nÄ ˆ 3431 cmÀ1
;
‡
‡
MS (CI): m/z (%): 391 (100) [M‡1] , 390 (19) [M] ; elemental analysis
calcd (%) for C22H38N2O2Si (390.6): C 67.64, H 9.80, N 7.17; found: C 67.75,
H 9.76, N 7.11.
¬
E. Saez, Synlett 2002, 85.
Acknowledgements
[11] See, for instance: a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem.
Eur. J. 2002, 8, 3646; b) B. Alcaide, P. Almendros, C. Aragoncillo,
Chem. Eur. J. 2002, 8, 1719; c) B. Alcaide, P. Almendros, J. M. Alonso,
Support of this workby the DGI-MCYT (Project BQU2000 0645) is
gratefully acknowledged. J. M. Alonso thanks the Universidad Complu-
tense de Madrid for a fellowship.
¬
M. F. Aly, C. Pardo, E. Saez, M. R. Torres, J. Org. Chem. 2002, 67,
7004; d) B. Alcaide, P. Almendros, R. RodrÌguez-Acebes, J. Org.
Chem. 2002, 67, 1925; e) B. Alcaide, P. Almendros, J. M. Alonso, M. F.
Aly, Org. Lett. 2001, 3, 3781.
¬
[12] a) B. Alcaide, Y. MartÌn-Cantalejo, J. Plumet, J. RodrÌguez-Lopez,
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¬
¬
¬
Monge, V. Perez-GarcÌa, J. Org. Chem. 1992, 57, 5921.
[13] X-ray data of (Æ)-4e: crystallized from ethyl acetate/n-hexane at
208C; C29H28N2O5 (Mr ˆ 484.53); monoclinic; space group ˆ P2(1)/c;
a ˆ 9.6518(9), b ˆ 10.2323(9), c ˆ 25.376(2) ä; b ˆ 97.816(2)8; Vˆ
2482.9(4) ä3; Z ˆ 4; 1calcd ˆ 1.296 mgmÀ3; m ˆ 0.089mmÀ1; F(000) ˆ
1024. A transparent crystal of dimensions 0.11 Â 0.25 Â 0.25 mm3 was
used; 6050 independent reflections were collected on a Bruker
Smart CCD diffractometer. The structure was solved by direct
methods and Fourier synthesis. It was refined by full-matrix least-
squares procedures on F 2 (SHELXTL version 5.1). The non-hydrogen
atoms were refined anisotropically. The hydrogen atoms were refined
only in terms of their coordinates. CCDC-163979 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.can.ac.uk/conts/retrie-
ving.html (or from the Cambridge Crystallographic Center, 12 Union
Road, Cambridge CB21EZ, UK; Fax: (‡44)1223-336033; or deposit
@ccdc.cam.ac.uk).
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Aznar, C. Valdes, Org. Lett. 2002, 4, 1971; b) N. Buschmann, A.
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[14] The observed facial selectivity is in agreement with a previous report
on the asymmetric reaction of (R)-2,3-di-O-benzylglyceraldehyde-
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¬
M. D. DÌaz-de-Villegas, J. A. Galvez, Tetrahedron 1999, 55, 7601.
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¬
¬
¬
¬
c) P. Gloanec, Y. Herbe, N. Bremand, J.-P. Lecouve, F. Breard, G.
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Chem. Eur. J. 2003, 9, 3415 3426
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3425

B. Alcaide, P. Almendros et al.
FULL PAPER
see: b) S. Hermitage, D. A. Jay, A. Whiting, Tetrahedron Lett. 2002, 43,
9633.
Chemistry and Pharmacology, Vol. 48 (Ed.: G. A. Cordell), Academic
Press, San Diego, 1996, Chap. 4, 249. For a selected reference, see: b) I.
¬
[17] There is one report involving formaldehyde-derived imines: a) S.
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¬
E. Quinƒoa, R. Riguera, J. Am. Chem. Soc. 1998, 120, 877; c) R. GarcÌa,
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67, 4579.
¬
¬
ƒ
[22] Full spectroscopic and analytical data for compounds not included in
this Experimental Section are described in the Supporting Informa-
tion.
[19] S. Cicchi, P. Ponzuoli, A. Goti, A. Brandi, Tetrahedron Lett. 2000, 41,
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[20] These compounds possess antidepressant, muscarinic agonist, and
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Received: January 3, 2003 [F4712]
3426
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 3415 3426