Stereoselective approach to hydroxyindolizidines: Protection/deprotection of the nitrone functionality via cycloaddition/retrocycloaddition

Article abstract of DOI:10.1021/ol006125q

(equation presented) The enantiomerically pure indolizidine (-)-21 has been synthesized starting from L-malic acid. The key intermediate 20 has been assembled through an intramolecular 1,3-dipolar cycloaddition of a nitrone generated in situ by retrocyclo

Full text of DOI:10.1021/ol006125q

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2475-2477
Stereoselective Approach to
Hydroxyindolizidines: Protection/
Deprotection of the Nitrone Functionality
via Cycloaddition/Retrocycloaddition
Franca M. Cordero,* Martina Gensini, Andrea Goti, and Alberto Brandi*
Dipartimento di Chimica Organica “U. Schiff”, Centro di Studio sulla Chimica e la
Struttura dei Composti Eterociclici e loro Applicazioni - C.N.R., UniVersita` di Firenze,
Via G. Capponi 9, I-50121 Firenze, Italy
cordero@chimorg.unifi.it
Received May 30, 2000
ABSTRACT
The enantiomerically pure indolizidine (−)-21 has been synthesized starting from L-malic acid. The key intermediate 20 has been assembled
through an intramolecular 1,3-dipolar cycloaddition of a nitrone generated in situ by retrocycloaddition from isoxazolidine 17 or 18. The
configuration of the new three stereocenters was set up with complete control in the cycloaddition step. The presented synthetic route
provides a general and highly selective methodology toward indolizidines having the [1,8a]-cis configuration.
A large number of indolizidine alkaloids are present in
nature.1 These compounds show unique biological activities
depending on the substitution pattern of the bicyclic ring
system. Polyhydroxylated indolizidines,1,2 like lentiginosine,
swainsonine and castanospermine (Figure 1), are structural
glycosidases in several biological processes3 has prompted
the search of new general and selective synthetic approaches
to these substances.
The 1,3-dipolar cycloaddition of hydroxypyrroline N-
oxides4 followed by a suitable elaboration of the primary
cycloadducts5 has proved to be a practical strategy for the
synthesis of lentiginosine6 and of several hydroxyindolizine
analogues.4d,4g,6c The trans reationship between C(1)-H and
C(8a)-H of lentiginosine was achieved in the cycloaddition
(1) (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological PerspectiVes Pelletier, S. W., Ed.; Wiley-VCH: New York, 1987;
Vol. 5, Chapter 1. (b) Howard, A. S.; Michael, J. P. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1986; Vol. 28, Chapter 3.
(2) (a) Elbein, A. D. Annu. ReV. Biochem. 1987, 56, 497-534. (b) Vogel,
P. Chimica Oggi 1992, 10, 9-15. (c) Winchester, B.; Fleet, G. W. J.
Glycobiology 1992, 2, 199-210. (d) Legler, G. AdV. Carbohydr. Chem.
Biochem. 1990, 48. 319-384. (e) Cossy, J.; Vogel, P. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science Publisher B.
V., 1993; Vol. 12, pp 275-363.
Figure 1.
analogues of carbohydrates and can competitively interact
with glycosidases. The nature of the interaction between a
particular enzyme and an iminosugar is determined by the
number and the spatial position of hydroxy groups. The
demand for new sugar analogues to study the key role of
(3) (a) Stu¨tz, A. E. Iminosugars as glycosidase inhibitors: nojirimycin
and beyond; Wiley-VHC: Weinheim, 1999. (b) Heightman, T. D.; Vasella,
A. Angew Chem., Int. Ed. Engl. 1999, 121, 2621-2622.
10.1021/ol006125q CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/12/2000

step as a result of the preferential attack of the dipolarophile
anti to the C(3)-alkoxy substituent on the nitrone (A, Scheme
1).
at the C(3)-alkoxy substituent.4f,g To benefit from an easily
removable group we synthesized the new THP protected
pyrroline nitrone 7 in 44% overall yield through the well-
established method4f,g starting from l-malic acid diethyl ester
(5) (Scheme 3). The regioisomeric 5-pyrroline N-oxide 8
Scheme 1
Scheme 3a
a Key: (i) 2H-dihydropyran, Amberlyst 15, pentane, rt; (ii)
LiAlH4, diethyl ether, reflux temperature; (iii) MsCl, TEA, CH2Cl2,
0 °C; (b) (i) NH2OH HCl, TEA, reflux temperature; (ii) HgO,
CH2Cl2, 0 °C f rt.
The opposite facial selectivity could be selectively induced
only by connecting the dipolarophile with the nitrone C(3)-
substituent by an appropriate tether (B, Scheme 1). In a
preliminary example, indeed, the intramolecular cycloaddi-
tion of 3-(allyloxy)-1-pyrrolin-N-oxide (B, X ) R3 ) R4 )
H, Scheme 1) gave exclusively the expected endo-syn
adduct.4f The resulting C(1)-H, C(8a)-H cis relative config-
uration would allow an entry to swainsonine and castano-
spermine analogues, if the linkage could be easily cleaved.
An alkoxycarbonyl linker (B, X ) O, Scheme 1) was then
envisaged as a proper candidate. Therefore, the intramolecu-
lar version of the cycloaddition of 3-hydroxy-1-pyrroline
N-oxide with 5-hydroxypent-2-enoate was studied and the
results are reported in this communication.
formed in 4% overall yield was easily separated by silica
gel chromatography.
The pyrroline N-oxide 9, disappointingly, lost enantiomeric
purity in the deprotection step. Albeit the THP protecting
group could be removed in very mild conditions, the best
being Amberlyst 15 in methanol, the nitrone 9 (Scheme 3)
was obtained always in low yield accompanied by partial or
total racemization as indicated by variation of specific
rotation. Purification by silica gel chromatography or re-
crystallization also caused racemization of 9.9
The lack of configurational stability of 9 can tentatively
be explained with the occurrence of a fast, not detectable
by NMR, nitrone-hydroxyenamine tautomerism11 (Scheme
4).
The dipolarophile moiety, 5-(p-MeO-benzyloxy)-2-pen-
tenoic acid (4) was obtained in good yield starting from 1,3-
propanediol (1) (Scheme 2).
Scheme 4a
Scheme 2a
a:10 Amberlyst 15, CH3OH, 40 °C
a Key:7 (a) (i) p-anisaldehyde, p-TsOH cat., toluene, 110 °C; (ii)
DIBAL, toluene 0°; (b) (i) (COCl)2, DMSO, TEA, CH2Cl2 (Swern
oxidation8); (ii) Trimethyl phosphonoacetate, K2CO3, H2O; (c)
NaOH 1 M, THF.
To overcome the problem of partial racemization, it
appeared opportune to seek a protection of the nitrone
(5) (a) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. In
Current Trends in Organic Synthesis; Scolastico, C., Nicotra, F., Eds.;,
Kluwer Academic/Plenum Publishers: New York, 1999; pp 213-220. (b)
Goti, A.; Cicchi, S.; Cordero, F. M.; Fedi, V.; Brandi, A. Molecules 1999,
4, 1-12.
(6) (a) Cordero, F. M.; Cicchi, A.; Goti, A.; Brandi, A. Tetrahedron Lett.
1994, 35, 949-952. (b) Brandi, A.; Cicchi, A.; Cordero, F. M.; Frignoli,
R.; Goti, A.; Picasso, S.; Vogel P. J. Org. Chem. 1995, 60, 6806-6812.
(c) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761-763. (d) Cardona,
F.; Goti, A.; Picasso, S.; Vogel P.; Brandi, A. J. Carbohydr. Chem. 2000,
in press.
(7) Martinelli, M. J. J. Org. Chem. 1990, 55, 5068-5073.
(8) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(9) In previous reports (see ref 3f,g) the deprotection of a TIPS or
TBDMS protected 3-hydroxy-1-pyrroline N-oxide was erroneously reported
as giving enantiopure 9.
To connect the dipolarophile 4 to the nitrone moiety we
considered to introduce 4 on a preformed nitrone deprotected
(4) (a) Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57,
1316-1318. (b) Cicchi, S.; Ho¨ld, I.; Brandi, A. J. Org. Chem. 1993, 58,
5274-5275. (c) Brandi, A.; Cicchi, S.; Goti, A.; Koprowski, A.; Pi-
etrusiewicz, K. M. J. Org. Chem. 1994, 59, 1315-1318. (d) Goti, A.;
Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahedron: Asymmetry
1996, 7, 1659-1674. (e) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem.
1995, 60, 4743-4748. (f) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi,
A. J. Org. Chem. 1997, 62, 3119-3125. (g) Goti, A.; Cacciarini, M.;
Cardona, F.; Brandi, A. Tetrahedron Lett. 1999, 40, 2853-2856
2476
Org. Lett., Vol. 2, No. 16, 2000

functionality which would allow the safe introduction of the
dipolarophile moiety. To our knowledge, only two methods
have been proposed to protect a nitrone functionality: an
addition of HCN12 or a reversible cycloaddition reaction.13
However, only occasional examples of the latter procedure
have been reported in synthetic sequences.14
Mitsunobu reaction15 of the free acid 4. The inversion of
configuration afforded the more valuable final products with
the configuration deriving from D-malic acid.16
Isoxazolidines 17 and 18 were then heated in a high boiling
solvent in order to induce retrocycloaddition-intramolecular
cycloaddition (Scheme 5). Phenyl substituted isoxazolidines
17 required a higher temperature (190 °C) than the ethoxy-
carbonyl ones 18 (150 °C). In both cases the intermediate
nitrone 19 was not observed and the isoxazolidine 20 was
the only product recovered in good yields (Scheme 5). Of
course, compound 20 was the same product deriving from
the two different isoxazolidine mixtures 17 and 18, and
showed the same specific rotation ([R]1D9 ) -17.9 (c )
0.547, CHCl3)), which is a further confirmation of the high
stereoselectivity of the process.
Styrene (11) and ethyl acrylate (12) were used as masking
dipolarophiles (Scheme 5). The corresponding cycloadducts
Scheme 5
Preliminary studies have already demonstrated the utility
of cycloadduct 20 as precursor of hydroxyindolizidines. In
fact, deprotection of the methoxybenzyl ether in 20 followed
by mesylation and hydrogenolysis17 afforded indolizidine 21
(Scheme 5). It is worth underlining the versatility of this
approach. A simple esterification, instead of a Mitsunobu
reaction, would lead, at the end, to the enantiomer of
indolizidine 21.
Optimization of the whole process, as well as the applica-
tion of the same strategy to the synthesis of other related
compounds, including natural products, is now in progress
in our laboratories.
Acknowledgment. We thank MURST (Ministry of
University and Scientific Research-Italy) for financial support
(Cofin 1998-2000).
a Key: R ) Ph: toluene, 80 °C, 10 h, 79%; R ) CO2Et: CH2Cl2,
rt, 70%; (b) Amberlyst 15, CH3OH, 40 °C, 15: 90% yield (77%
conversion); 16: 53%; (c) R ) Ph: 4, PPh3 (polystyrene supported),
DEAD, CH2Cl2, 59%; R ) CO2Et: 4, PPh3, DEAD, THF, 82%
(50% conversion); (d) R ) Ph: o-dichlorobenzene, 190 °C, 64 h,
62%; R ) CO2Et: o-dichlorobenzene, 150 °C, 3 h, 74%; (e) (i)
TFA, CH2Cl2, rt; (ii) MsCl, TEA, CH2Cl2, 0 °C; H2, Pd-C, CH3OH.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL006125Q
13 and 14 from nitrone 7 were obtained in high yields as
mixtures of diastereoisomers. No separation of diastereomeric
pairs was necessary at this step, as both diastereoisomers
could undergo deprotection followed by introduction of the
dipolarophile. Deprotection with Amberlyst 15 gave isox-
azolidines 15 and 16 without epimerization at C-4. The
introduction of the dipolarophile was achieved through a
(13) Bianchi, G.; Gandolfi, R. in 1, 3.Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley-Interscience: New York, 1984; Vol. 2, Chapter 14,
pp 451-543.
(14) (a) Williams, G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.
J. Am. Chem. Soc. 1999, 121, 4900-4901. (b) De Sarlo, F.; Brandi, A. J.
Chem. Res., Synop. 1980, 122-123. (c) Tufariello, J. J.; Mullen, G. B.;
Tegeler, J. J.; Trybulski, E. J.; Chun Wong, S.; Asrof Ali, Sk. J. Am. Chem.
Soc. 1979, 10, 1, 2435-2442. (d) Delpierre, G. R.; Lamchen, M J. Chem.
Soc. 1963 4693-4701.
(10) Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. Synthesis 1979,
618-620.
(15) (a) Hughes, D. L. Org. React. 1992, 42, 335-395. (b) Mitsunobu,
O. Synthesis 1981, 1-28.
(11) Breuer, E. in Nitrones, Nitronates, and Nitroxides; Patai, S.,
Rappoport, Z., Ed.; Wiley-Interscience: New York, 1989; Chapter 2, pp
139-244.
(16) Goti, a., Fedi, V.; Nannelli, L.; De Sarlo, F.; Brandi, A. Synlett
1997, 577-579.
(17) Cordero, F. M.; Machetti, F.; De Sarlo, F.; Brandi, A. Gazz. Chim.
Ital. 1997, 127, 25-29.
(12) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 6469-6472.
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