Solution- and solid-phase asymmetric synthesis of substituted N-hydroxypyrrolidine dicarboxylic acids

Article abstract of DOI:10.1016/S0040-4039(02)02288-8

Nitrone ylids prepared from α-amino aldehyde derivatives undergo 1,3-dipolar cyclocondensation reactions to give enantiopure C-4 branched N-hydroxy proline esters. The different functional groups can be manipulated to provide diversely substituted N-hydro

Full text of DOI:10.1016/S0040-4039(02)02288-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9441–9444
Solution- and solid-phase asymmetric synthesis of substituted
N-hydroxypyrrolidine dicarboxylic acids
Stephen Hanessian* and Malken Bayrakdarian
Department of Chemistry, Universite´ de Montre´al, C. P. 6128, Succ. Centre-Ville, Montre´al, P. Q., Canada H3C 3J7
Received 31 July 2002; revised 8 October 2002; accepted 10 October 2002
Abstract—Nitrone ylids prepared from a-amino aldehyde derivatives undergo 1,3-dipolar cyclocondensation reactions to give
enantiopure C-4 branched N-hydroxy proline esters. The different functional groups can be manipulated to provide diversely
substituted N-hydroxypyrrolidine dicarboxylic acids. The reaction can be adapted to solid-phase synthesis. © 2002 Elsevier
Science Ltd. All rights reserved.
The 1,3-dipolar cycloaddition reaction is one of the
most efficient methods for the synthesis of substituted
pyrrolidines and prolines.1 For example, the reaction of
azomethine ylids2 with alkenes generates substituted
pyrrolidines and related structures. Saturated nitrogen
heterocycles are common subunits of many natural
alkaloids.3 Many synthetic pyrrolidine and proline ana-
logues exhibit enzyme inhibitory activities,4 and agonist
or antagonist properties toward certain receptors.5
deficient alkenes.6 In this paper, we report the stereose-
lective synthesis of substituted N-hydroxypyrrolidine
dicarboxylic acids from the reaction of nitrone ylids
(prepared from a-amino aldehydes) with acrylates. The
products corresponding to the general expression A
(Fig. 1) represent prototypes of versatile N-containing
scaffolds for diversity-oriented synthesis projects. They
can also be considered as intermediates for the synthesis
of a novel class of neuraminidase inhibitors such as
A-192558 and A-315675 (Fig. 1).7,8
Recently, we reported the synthesis of polysubstituted
N-hydroxypyrrolidines from the cycloaddition of
nitrone ylids derived from glycinate esters with electron
Treatment of N,O-bis(tert-butoxycarbonyl)hydroxyl-
amine ethyl or benzyl glycinate 1 with TFA, followed
by condensation9 with aldehydes 3–5, easily prepared
from the corresponding amino acids,10 afforded the
intended nitrones 6–9 as single isomers based on NOE
studies (Scheme 1).
Cycloadditions of benzyl acrylate with nitrones 6–9
were carried out in THF at 0°C in the presence of
lithium bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) as catalyst,2 which afforded
a
single
diastereomer of the substituted N-hydroxypyrrolidines
11–14 (Scheme 2).11,12 The resulting cycloadducts can
be formed via an endo-like transition state as shown in
Fig. 2.13 The observed diastereoselectivity can be
explained by minimizing 1,3-allylic strain,14 in the tran-
sition state model where Ha is in the same plane as the
nitrone oxygen. Attack occurs from the less encum-
bered Re face of the nitrone. Under the reactions
conditions utilized, no formation of isoxazolidine was
observed.
Figure 1.
Keywords: cycloaddition; nitrone; amino acid; N-hydroxylactone.
* Corresponding author. Tel.: (514) 343-6738; fax: (514) 343-5728;
e-mail: stephen.hanessian@umontreal.ca
We chose to study a number of chemoselective trans-
formations that would differentiate the functional
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02288-8

9442
S. Hanessian, M. Bayrakdarian / Tetrahedron Letters 43 (2002) 9441–9444
Scheme 1.
Scheme 2.
Scheme 3.
was transformed into the N-Troc derivative 21 (Scheme
4).
Solid-phase synthesis has been established as a versatile
method for preparing potentially bioactive molecules in
high throughput screening assays.17 Highly substituted
pyrrolidine libraries have been achieved by several
research groups through solid-phase synthesis.18
The nitrone cycloaddition methodology described here
for generating polyfunctional N-hydroxypyrrolidine
dicarboxylic acid motifs was readily adapted to solid-
phase synthesis to produce core scaffolds with function-
ally diverse appendages (Scheme 5). The Wang acrylate
resin19 22 was treated with 7, LiBr, DBU in THF to
afford a resin-bound cycloadduct 23.20,21 Acidic cleav-
age of the N,O-acetal in 23 released the bicyclic lactone
16 from the resin in a clean and efficient manner
(overall yield of 40%from 7).
Figure 2.
appendages and offer opportunities for further modifi-
cation in the context of a program aimed at generating
diversity in a proline-type scaffold.6,15 Acid-catalyzed
acetal cleavage of 11 and 12 afforded bicyclic lactones
15 and 16, respectively. Hydrogenolysis of the benzyl
ester 11 and intramolecular transesterification afforded
the novel bicyclic lactone 17, whose configuration was
confirmed by an X-ray crystal structure (Scheme 3).
Diverse sets of functionalized N-hydroxypyrrolidine
dicarboxylic acids with orthogonal protective groups
can now be readily prepared in solution or on solid-
support based on this nitrone ylid cycloaddition
methodology. These motifs represent useful scaffolds
onto which a variety of functional groups can be
deployed as potential pharmacophores. In addition, the
methodology can find immediate application in the
synthesis of neuraminidase inhibitors related to those
shown in Fig. 1.
The unique internal N-hydroxy lactone6 offers several
possibilities for functional group diversification while
maintaining the original oxidation state at nitrogen.
Thus, selective opening of bicyclic lactone 17 with a
prototypical amine gave benzylamide 18, while a reduc-
tion afforded diol 19. Cleavage of the NꢀO bond using
molybdenum hexacarbonyl16 afforded amine 20, which

S. Hanessian, M. Bayrakdarian / Tetrahedron Letters 43 (2002) 9441–9444
9443
3. (a) Hamilton, G. S.; Steiner, J. P. Curr. Pharm. Des.
1997, 3, 405; (b) Yaron, A.; Naider, F. Curr. Rev.
Biochem. Mol. Biol. 1993, 28, 31; (c) Williams, R. M.;
Sebahar, P. R. J. Am. Chem. Soc. 2000, 122, 5666; (d)
Clark, R. B.; Pearson, W. H. Org. Lett. 1999, 1, 349; (e)
Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett.
1999, 40, 3339; (f) Heathcock, C. H.; Griffith, D. A.;
Denhart, D. J. J. Org. Chem. 1998, 63, 9616.
4. See for example: (a) Hanessian, S.; Reinhold, U.;
Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998,
8, 2123; (b) Bhagwat, S. S.; Gude, C.; Chan, K. Tetra-
hedron Lett. 1996, 37, 4627; (c) Murphy, M. M.; Schullek,
J. R.; Gordon, E.; Gallop, M. A. J. Am. Chem. Soc.
1995, 117, 7029; (d) Guo-Qiang, L.; Chum-Min, Z.;
Zhi-Cai, S. Heterocycles 1995, 41, 277.
5. (a) Hansen, J. J.; Krogsgaard-Larsen, P. Med. Res. Rev.
1990, 10, 55; (b) Cushman, D. W.; Ondetti, M. A. Prog.
Med. Chem. 1980, 17, 41.
6. Hanessian, S.; Bayrakdarian, M. Tetrahedron Lett. 2002,
43, 967.
Scheme 4.
7. (a) For A-192558, see: Wang, G. T.; Chen, Y.; Wang, S.;
Gentles, R.; Sowin, T.; Kati, W.; Muchmore, S.;
Giranda, V.; Stewart, K.; Sham, H.; Kempf, D. I.; Laver,
W. G. J. Med. Chem. 2001, 44, 1192; (b) For A-315675,
see: DeGoey, D. A.; Chen, H.-J.; Flosi, W. J.; Grampov-
nik, D. J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. J.
Org. Chem. 2002, 67, 5445.
8. Hanessian, S.; Bayrakdarian, M.; Luo, X. J. Am. Chem.
Soc. 2002, 124, 4716.
9. Dondoni, A.; Merino, P.; Franco, S.; Mercha´n, F.;
Tejero, T.; Junquera, F. Synth. Commun. 1994, 24, 2537.
10. For aldehyde 3, see: (a) Campbell, A. D.; Raynham, T.
M.; Taylor, R. J. K. Synthesis 1998, 1707. For aldehyde
4, see: (b) Garner, P.; Park, J.-M. J. Org. Chem. 1987, 52,
2361; (c) Garner, P.; Park, J.-M. Org. Synth. 1991, 70, 18.
For aldehyde 5, see: (c) Jayaraman, M.; Deshmukh, A.
R.; Bhawal, B. M. Tetrahedron 1996, 52, 8989.
Scheme 5.
11. With the less reactive benzyl crotonate and benzyl cinna-
mate, the cycloaddition reaction failed and decomposi-
tion of the nitrone was observed. Furthermore,
replacement of LiBr with other additives (AgOAc,
MgBr2, KBr, etc.) resulted in the recovery of the nitrone.
12. The cycloaddition reaction of nitrones, derived from
aldehydes B and C, did not generate the desired N-
hydroxypyrrolidines presumably due to b-elimination.
Acknowledgements
We thank NSERC for financial assistance through the
Medicinal Chemistry Chair Program. We also thank
Dr. Michel Simard for X-ray structure determinations.
References
1. (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863; (b) Frederickson, M. Tetrahedron 1997, 53, 403; (c)
Figade`re, B.; Pichon, M. Tetrahedron: Asymmetry 1996,
7, 927; (d) Padwa, A. In Comprehensive Organic Synthe-
sis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 4, p. 1069; (e) Wade, P. A. In Compre-
hensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 4, p. 1111.
2. (a) Grigg, R.; Montgomery, J.; Somasunderam, A. Tetra-
hedron 1992, 48, 10431; (b) Tsuge, O.; Kanemasa, S.;
Yoshioka, M. J. Org. Chem. 1988, 53, 1384; (c) Ayerbe,
M.; Arrieta, A.; Coss´ıo, F. P. J. Org. Chem. 1998, 63,
1795; (d) Annuziata, R.; Benaglia, M.; Cinquini, M.;
Raimondi, L. Tetrahedron 1993, 49, 8629; (e) Pyne, S. G.;
Safaei, G. J.; Koller, F. Tetrahedron Lett. 1995, 36, 2511.
13. The reaction may proceed in a concerted asynchronous
manner. Although we did not observe single addition
products, we cannot exclude a stepwise mechanism of
cycloaddition formation. The stereochemistry of the
adducts can be rationalized based on an anti-oriented
nitrone ylide/enolate, and s-cis conformation of the endo-
placed acrylate ester. The stereochemical outcome of the
cycloadducts 13 and 14 was assigned by analogy to 11.
14. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
15. Hanessian, S.; Bayrakdarian, M. Bioorg. Med. Chem.
Lett. 2000, 10, 427.
16. (a) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo,
F. Tetrahedron Lett. 1990, 31, 3351; (b) Hanessian, S.;
Yang, R.-Y. Tetrahedron Lett. 1996, 37, 5273.

9444
S. Hanessian, M. Bayrakdarian / Tetrahedron Letters 43 (2002) 9441–9444
17. (a) Peng, G.; Sohn, A.; Gallop, M. A. J. Org. Chem.
1999, 64, 8342; (b) Tan, D. S.; Foley, M. A.; Shair, M.
D.; Schreiber, S. L. J. Am. Chem. Soc. 1998, 120, 8565;
(c) Vojkovsky´, T.; Weichsel, A.; Pa´tek, M. J. Org.
Chem. 1998, 63, 3162; (d) Bicknell, A. J.; Hird, N. W.;
Readshaw, S. A. Tetrahedron Lett. 1998, 39, 5869.
18. (a) Steger, M.; Hubschwerlen, C.; Schmid, G. Bioorg.
Med. Chem. Lett. 2001, 11, 2537; (b) Karoyan, P.; Tri-
olo, A.; Nannicini, R.; Gionnotti, D.; Altamura, M.;
Chassaing, G.; Perrotta, E. Tetrahedron Lett. 1999, 40,
71; (c) Murphy, M. M.; Schulleck, J. R.; Gordon, E.
M.; Gallop, M. A. J. Am. Chem. Soc. 1995, 117, 7029;
(d) Hollingshead, S. P. Tetrahedron Lett. 1996, 37, 9157.
19. Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron
Lett. 1996, 37, 3209.
anthan, S. Tetrahedron Lett. 2000, 41, 967.
21. To a solution of nitrone 7 (235 mg, 0.60 mmol) in THF
(5 mL), was added Wang acrylate resin 22 (100 mg, 0.06
mmol) followed by LiBr (16 mg, 0.18 mmol) and DBU
(18 mL, 18 mg, 0.12 mmol) at rt. The suspension was
shaken for 24 h at rt, filtered, washed with THF (2×3
mL) and MeOH (2×3 mL), and dried to give resin
bound cycloadduct 23. To a solution of 23 in a mixture
dioxane/H2O (4 mL, 10:1), was added pTsOH (11 mg,
0.06 mmol) at rt. The suspension was shaken for 24 h at
rt, filtered and washed with EtOAc (3×5 mL). The
filtrate was washed with
a saturated solution of
NaHCO3 (4 mL), dried (Na2SO4), filtered and evapo-
rated to dryness. The resulting residue was purified by
flash chromatography (EtOAc/hexanes, 1:1) to give the
desired bicyclic N-hydroxypyrrolidine lactone as a color-
less oil.
20. Dondas, H. A.; Grigg, R.; MacLachlan, W. S.;
MacPherson, D. T.; Markandu, J.; Sridharan, V.; Sug-