Dual behavior of 2-azetidinone-tethered arylimines as azadienophiles or azadienes. Application to the asymmetric synthesis of indolizidine-type systems

Article abstract of DOI:10.1055/s-2001-17453

The first methodology to prepare indolizidine systems directly from β-lactams has been developed. This process involves the amide bond cleavage of the β-lactam ring in the aza Diels-Alder cycloadducts with concomitant cyclization. Indolizidinone precursor

Full text of DOI:10.1055/s-2001-17453

LETTER
1531
Dual Behavior of 2-Azetidinone-Tethered Arylimines as Azadienophiles or
Azadienes. Application to the Asymmetric Synthesis of Indolizidine-Type
Systems
D
ual Behavior of
e
2-Azetidin
n
one-Tethered
i
A
ryli
t
mines o Alcaide,*a Pedro Almendros,a Jose M. Alonso,a Moustafa F. Aly,c M. Rosario Torresb
a
b
c
Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040-Madrid, Spain
Laboratorio de Difracción de Rayos X, Facultad de QuímicaUniversidad Complutense, 28040-Madrid, Spain
Department of Chemistry, Faculty of Science at Qena, South Valley University, Qena, Egypt
Fax +34(91)3944103; E-mail: alcaideb@eucmax.sim.ucm.es
Received 12 June 2001
tion, functionalized bicyclic lactams structurally related to
indolizidine have been discovered as conformationally re-
stricted peptide mimetics.4 On the other hand, the impor-
tance of 2-azetidinones as synthetic intermediates has
Abstract: The first methodology to prepare indolizidine systems
directly from -lactams has been developed. This process involves
the amide bond cleavage of the -lactam ring in the aza Diels–Alder
cycloadducts with concomitant cyclization. Indolizidinone precur-
sors arise from normal, as well as inverse electron-demand conden- been widely recognized in organic synthesis.5 Despite the
versatility of the 2-azetidinone ring,6 there is no informa-
sation involving the C=N moiety of 2-azetidinone-tethered imines
as the dienophile or the heterodiene contributor.
tion available on the use of -lactams as chiral synthons
Key words: lactams, aza Diels–Alder cycloaddition, rearrange-
ment, indolizidines, asymmetric synthesis
for the synthesis of indolizidine alkaloids. Our interest in
the use of 4-oxoazetidine-2-carbaldehydes as substrates
for addition reactions and cyclization processes,7 prompt-
ed us to evaluate the combination of the aza-Diels–Alder
The hetero Diels–Alder reaction involving imino-dienes reaction of 2-azetidinone-tethered imines with rearrange-
or imino-dienophiles is widely used for the construction ment reactions on the 2-azetidinone ring as a route to com-
of nitrogen containing compounds, particularly for the plex indolizidine alkaloids. We report herein our
preparation of piperidine and tetrahydroquinolidine deriv- preliminary results for the synthesis of different kinds of
atives.1 Indolizidine alkaloids have recently attracted a lot highly functionalized bi- and tetracyclic indolizidine sys-
of synthetic attention2 due to their widespread occurrence tems using -lactams as chiral building blocks.
and their diverse and potent biological activities.3In addi-
Figure
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1531,1534,ftx,en;G11801st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1532
B. Alcaide et al.
LETTER
Table Zinc Iodide-Mediated Diels–Alder Cycloaddition between 2-Azetidinone-Tethered Imines and Danishefsky's Diene
Aldehyde
1a
R1
R2
Imine
2a
Yield (%)a
Cycloadducts
3a/4a
Ratio 3:4b
66:34
Yield 3:4 (%)a
PMP
PMP
PMP
Tol
Ph
95
90
95
75
49/25
45/30
36/16
43/14
1b
BnO
PhO
MeO
2b
3b/4b
60:40
(+)-1c
(+)-1d
(+)-2c
(+)-2d
(+)-3c/(+)-4c
(+)-3d/(+)-4d
69:31
75:25
a Yield of pure, isolated product with correct analytical and spectral data. PMP = 4-MeOC6H4. Tol = 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.
The starting 4-oxoazetidine-2-carbaldehydes 1 were pre-
pared using our methodology reported previously.7 The
requisite cycloadduct precursors, 2-azetidinone-tethered
imines 2, were smoothly prepared by condensation of al-
dehydes 1 with p-anisidine in dichloromethane at r.t. in
the presence of magnesium sulfate. Imines 2 were purified
by chromatography and obtained in good yields. Impor-
tantly, the -lactam ring stereochemistry was unaffected
by this process.
We then used 2-azetidinone-tethered imines 2 as dieno-
philes by reacting them with 1-methoxy-3-trimethylsily-
loxy-1,3-butadiene (Danishefsky’s diene). Cycloaddition
took place at low temperature under Lewis acid catalysis
(zinc iodide, 20 mol%) and gave rise to mixtures of cy-
cloadducts 3 and 4 with modest diastereoselectivity (Ta-
ble). Fortunately, in all cases the diastereomeric
cycloadducts 3 and 4 were easily separated by gravity
flow chromatography. Other tested Lewis acids, such as
Scheme 1
boron trifluoride diethyl etherate and hafnium chloride
were less effective to activate the imine.
The structure of the minor product from the reaction with
imine 2b was confirmed by X-ray diffraction. The Figure
(+)-5 and (+)-6 (1:1 mixture) in an excellent 98% yield
shows a projection of the minor product 4b as determined
(Scheme 1). Again, cycloadducts (+)-5 and (+)-6 were
by X-ray crystallography.8
easily separable by chromatography. Interestingly, the di-
enophilic behavior of the imine in the Diels–Alder reac-
tion was reversed to exhibit heterodienic properties.10 The
cycloaddition did not take place with electron poor dieno-
philes such as 2-cyclohexen-1-one or methyl acrylate, but
it proceeded with 2,3-dimethyl-1,3-butadiene and 3,4-di-
hydro-2H-pyran. This confirmed that an inverse electron-
demand Diels–Alder reaction was involved. This imino-
diene behavior is known for arylimines derived from aro-
matic or , -unsaturated aldehydes,10,11 but the use of
chiral imines as the 4 component in which the chiral ma-
trix is an aliphatic aldehyde is unrecorded.12 Furthermore,
Our next aim was to study the reactivity of 2 with less
electron rich dienes. Zinc iodide promoted the reaction
between imine (+)-2e and cyclopentadiene to give poor
yield, of an isomeric mixture of cycloadducts (+)-5 and
(+)-6. Indium-mediated reactions have emerged as an use-
ful tool in organic synthesis.9 In particular, it was found
that trivalent organoindium reagents can be useful in imi-
no Diels–Alder reactions.10 Thus, indium trichloride-ca-
talysed (20 mol%) reaction between the 2-azetidinone-
tethered imine (+)-2e and cyclopentadiene proceeded
smoothly at room temperature, to afford the derivatives
Synlett 2001, No. 10, 1531–1534 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Dual Behavior of 2-Azetidinone-Tethered Arylimines
1533
to the best of our knowledge, the dual behavior of aliphat- In conclusion, we have developed the first synthesis of in-
ic aldehyde-derived imines both as imino-diene as well as dolizidines directly from -lactams. 2-Azetidinone-teth-
dienophile is unprecedented.
ered arylimines function both as heterodienes and
dienophiles in the [4+2] imino Diels–Alder reaction to af-
ford different types of cycloadducts, which after rear-
rangement serve as valuable chiral intermediates for
different indolizidinones. The scope and limitations of the
present work are underway and will be reported in due
course.
A common and relevant feature of some indolizidines,
which act as glycosidase inhibitors, is the presence of a
vicinal amino-alcohol or -alkoxy functionality.13 In this
context, transformation of adduct (+)-5 into fused tetracy-
cle (+)-7 was directly effected via a sodium methoxide re-
arrangement reaction. After aqeous work-up (+)-7 was
obtained in high yield (90%) in high purity without fur-
ther purification (Scheme 2).14
Acknowledgement
Support for this work by the DGI-MCYT (Project BQU2000–0645)
is gratefully acknowledged. J. M. A. thanks the UCM for a predoc-
toral grant.
References and Notes
(1) For reviews, see: (a) Jørgensen, K. A. Angew. Chem. Int. Ed.
2000, 39, 3558. (b) Behforouz, M.; Ahmmadian, M.
Tetrahedron 2000, 56, 5259. (c) Kobayashi, S.; Ishitani, H.
Chem. Rev. 1999, 99, 1069. (d) Weinreb, S. M. Top. Curr.
Chem. 1997, 190, 131. (e) Tietze, L. F.; Kettschau, G. Top.
Curr. Chem. 1997, 190, 1. (f) Waldmann, H. Synlett 1995,
133.
Scheme 2
(2) For very recent selected examples, see: (a) Groaning, M.
D.; Meyers, A. I. Chem. Commun. 2000, 1027.
Cycloadducts (+)-3 and (+)-4 require further manipula-
tion to obtain the desired alkaloid system. Thus, the dihy-
dropyridone (+)-4d underwent sequential reduction of the
alkene and carbonyl moieties to give the corresponding al-
cohol as a single isomer, whose configuration of at C-4
was established by comparison of the 1H NMR chemical
shifts of its acetyl mandelates. Protection of the hydroxyl
group followed by oxidative cleavage of the N-4-methox-
yphenyl substituent provided the key intermediate pipe-
ridinyl- -lactam (–)-8. When substrate (–)-8 was
submitted to sodium methoxide treatment, bicyclic in-
dolizidine lactam (+)-9 was cleanly obtained without
byproducts in quantitative yield (Scheme 3).14
(b) Pourashraf, M.; Delair, P.; Rasmusen, M. O.; Greene, A.
E. J. Org. Chem. 2000, 65, 6966.
(3) Their interesting biological activities include antiviral,
antitumor, and glucosidase inhibitions. For selected reviews,
see: (a) Vlietinck, A. J.; De Bruyne, T.; Apers, S.; Pieters, L.
A. Planta Med. 1998, 64, 97. (b) Michael, J. P. J. Nat. Prod.
Rep. 1997, 14, 619. (c) Lidell, J. R. J. Nat. Prod. Rep. 1996,
13, 187. (d) Robin, D. J. J. Nat. Prod. Rep. 1995, 12, 413.
(e) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles 1988, 27,
1465.
(4) See among others: (a) Tong, Y.; Fobian, Y. M.; Wu, M.;
Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65, 2484.
(b) Sudau, A.; Münch, W.; Nubbemeyer, U. J. Org. Chem.
2000, 65, 1710. (c) Müller, G.; Hessler, G.; Decornez, H. Y.
Angew. Chem. Int. Ed. 2000, 39, 894. (d) Li, W.; Hanau, C.
E.; d’Avignon, A.; Moeller, K. D. J. Org. Chem. 1995, 60,
8155.
The transformation of piperidinyl-2-azetidinones into in-
dolizidine derivatives involves the amide bond cleavage
of the -lactam ring, followed by cyclization of the result-
ing 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 indolizidinones (+)-7, and (–)-9
were established by NMR one- and two-dimensional tech-
niques.
(5) For reviews, see: (a) Ojima, I. Adv. Asym. Synth. 1995, 1,
95. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Amino-acids 1999, 16, 321. (c) Ojima, I.; Delaloge, F.
Chem. Soc. Rev. 1997, 26, 377. (d) Manhas, M. S.; Wagle,
D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988, 27, 1755.
Scheme 3
Synlett 2001, No. 10, 1531–1534 ISSN 0936-5214 © Thieme Stuttgart · New York

1534
B. Alcaide et al.
LETTER
(6) For the applications of 4-oxoazetidine-2-carbaldehydes as
efficient chiral synthons, see: (a) Alcaide, B.; Almendros, P.
Chem. Soc. Rev. 2001, in press. (b) For a review on the
chemistry of azetidine-2,3-diones, see: Alcaide, B.;
Almendros, P. Org. Prep. Proced. Int. 2001, 33, 315.
(7) See, for instance: (a) Alcaide, B.; Almendros, P.;
Aragoncillo, C. J. Org. Chem. 2001, 66, 1612. (b) Alcaide,
B.; Almendros, P.; Alonso, J. M.; Aly, M. F. J. Org. Chem.
2001, 66, 1351. (c) Alcaide, B.; Almendros, P.; Alonso, J.
M.; Aly, M. F.; Redondo, M. C. Synlett 2001, 773.
(d) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett.
2000, 2, 1411. (e) Alcaide, B.; Almendros, P.; Aragoncillo,
C. Chem. Commun. 2000, 757.
(13) Cicchi, S.; Ponzuoli, P.; Goti, A.; Brandi, A. Tetrahedron
Lett. 2000, 41, 1583; and references cited therein.
(14) Compounds (+)-7 and (–)-9 showed a single set of signals in
their 1H NMR spectra, thus proving that these
transformations proceeded without detectable racemization.
All new compounds were fully characterized by
spectroscopic methods and microanalysis and/or HRMS.
General Procedure for the Rearrangement Reaction.
Sodium methoxide (108.3 mg, 2.0 mmol) was added in
portions at r.t. to a solution of the appropriate piperidinyl- -
lactam (0.50 mmol) in methanol (10 mL). The reaction was
stirred for 16 h and then water was added (1 mL). The
solution was concentrated under reduced pressure, the
(8) X-ray data of 4b: crystallized from ethyl acetate/n-hexane at
20 °C; C29H28N2O5 (Mr = 484.53); monoclinic; space
group = P2(1)/c; a = 9.6518(9)Å, b = 10.2323(9)Å;
c = 25.376(2)Å; = 97.816(2)°; V = 2482.9(4)Å3; Z = 4;
aqueous residue was extracted with ethyl acetate (10
3
mL), and the organic layer was dried over MgSO4. Then, the
solvent was removed under reduced pressure to give
analytically pure indolizidine derivatives. Selected data:
Fused Indolizidinone (+)-7. From 93 mg (0.229 mmol)of
the cycloadduct (+)-5, 83 mg (90%) of compound (+)-7 was
obtained as a pale brown oil. [ ]D = +44.6 (c 0.9, CHCl3). 1H
NMR (300 MHz, C6D6): 2.07 (ddq, 1 H, J = 18.8, 16.2, 1.4
Hz), 2.66 (m, 1 H), 2.72 (qd, 1 H, J = 8.9, 3.4 Hz), 3.20 (m,
1 H), 3.39 and 3.49 (s, each 3 H), 3.68 (m, 2 H), 3.79 (s, 3
H), 3.84 (t, 1 H, J = 6.5 Hz), 5.42 (m, 1 H), 5.67 (m, 1 H),
6.73 (m, 2 H), 6.80 and 6.93 (m, each 2 H), 9.09 (d, 1 H,
J = 9.0 Hz). 13C NMR (75 MHz, C6D6): 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. IR (CHCl3, cm–1): 3330, 1730. MS (EI), m/z: 406
(M+, 100). (Anal. calcd. for C24H26N2O4: C, 70.92; H, 6.45;
N, 6.89. Found: C, 70.99; H, 6.47; N, 6.86).
Indolizidinone (–)-9. From 45 mg (0.107 mmol)of the
piperidinyl- -lactam (–)-8, 45 mg (100%) of compound (–)-
9 was obtained as a pale brown oil. [ ]D = –12.5 (c 0.9,
CHCl3). 1H NMR (300 MHz, CD3OD): 0.04 and 0.06 (s,
each 3 H), 0.86 (s, 9 H), 1.30 (m, 4 H), 1.88 and 2.14 (m,
each 1 H), 2.19 (s, 3 H), 2.74 (td, 1 H, J = 13.2, 2.2 Hz), 3.24
(m, 2 H), 3.52 (s, 3 H), 3.69 (dd, 1 H, J = 6.6, 6.1 Hz), 3.83
(dd, 1 H, J = 6.1, 1.2 Hz), 4.06 (ddd, 1 H, J = 13.4, 5.1, 1.7
Hz), 6.66 and 6.95 (m, each 2 H). 13C NMR (75 MHz,
CD3OD): 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. IR
(CHCl3, cm–1): 3335, 1734. MS (CI), m/z: 377 (M+ +1, 100),
376 (M+, 44). (Anal. calcd. for C22H36N2O3: C, 70.18; H,
9.64; N, 7.44. Found: C, 70.24; H, 9.63; N, 7.40).
= 1.296 mg m–3; = 0.089 mm–1; F(000) = 1024. A
calcd
transparent crystal of 0.11 0.25 0.25 mm3 was used. 6050
independent reflections were collected on a Bruker Smart
CCD difractomer. The structure was solved by direct
methods and Fourier synthesis. The refinement was done by
full matrix least-squares procedures on F2 (SHELXTL
version 5.1). The non-hydrogen atoms were refined
anisotropically. The hydrogen atoms were refined the
coordinates only. Further crystallographic details for the
structure reported in this paper may be obtained from the
Cambridge Crystallographic Data Centre, on quoting the
depository number CCDC-163979.
(9) For recent selected reviews, see: (a) Ranu, B. C. Eur. J. Org.
Chem. 2000, 2347. (b) Chauhan, K. C.; Frost, C. G. J. Chem.
Soc., Perkin Trans. 1 2000, 3015. (c) Li, C. J.; Chan, T. H.
Tetrahedron 1999, 55, 11149.
(10) (a) Yadav, J. S.; Subba Reddy, B. V.; Madhuri, C. R.;
Sabitha, G. Synthesis 2001, 1065. (b) Babu, G.; Nagarajan,
R.; Nataraja, R.; Perumal, P. T. Synthesis 2000, 661.
(c) Gadhwal, S.; Sandhu, J. S. J. Chem. Soc., Perkin Trans.
1 2000, 2827.
(11) For a dual behavior of simple arylimines in the aza Diels–
Alder reaction using bismuth(III) chloride, see: Laurent-
Robert, H.; Garrigues, B.; Dubac, J. Synlett 2000, 1160.
(12) There is one report involving formaldehyde-derived imines:
Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995,
1195.
Synlett 2001, No. 10, 1531–1534 ISSN 0936-5214 © Thieme Stuttgart · New York