Catalytic asymmetric [3+2] cycloaddition of azomethine ylides. Development of a versatile stepwise, three-component reaction for diversity-oriented synthesis

Article abstract of DOI:10.1021/ja036558z

We report a new catalyst system that should enhance the use of enantioselective 1,3-dipolar cycloadditions of azomethine ylides with electronic-deficient olefins in the divergent pathways of diversity-oriented synthesis (DOS). The underlying reaction is o

Full text of DOI:10.1021/ja036558z

Published on Web 08/05/2003
Catalytic Asymmetric [3+2] Cycloaddition of Azomethine Ylides. Development
of a Versatile Stepwise, Three-Component Reaction for Diversity-Oriented
Synthesis
Chuo Chen, Xiaodong Li, and Stuart L. Schreiber*
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute (HHMI), Institute of Chemistry
and Cell Biology (ICCB), HarVard UniVersity, 12 Oxford Street, Cambridge, Massachusetts 02138
Received June 7, 2003; E-mail: sls@slsiris.harvard.edu
We report a procedure that should enhance the use of enantio-
selective 1,3-dipolar cycloadditions of azomethine ylides1 with
electronic-deficient olefins in the divergent pathways of diversity-
oriented synthesis (DOS).2 The underlying reaction is of consider-
able interest in DOS because its stereospecificity enables stereo-
chemical diversification of up to four tetrahedral centers on
pyrrolidine rings.
The biological importance of pyrrolidines has inspired the
development of diastereoselective [3+2] azomethine ylide cycload-
ditions using chiral auxiliaries3 and, recently by Zhang and co-
Figure 1. Chiral phosphine ligands screened for the azomethine ylide
workers4 and Jørgensen and co-workers,5 of enantioselective
cycloadditions.
variants using chiral catalysts.6 Both Zhang’s silver(I)/xylyl-FAP
and Jørgensen’s zinc(II)/t-BuBOX systems give moderate to
excellent levels of stereoselectivity with imines derived from methyl
glycinate.7 We describe a new catalyst system that extends the scope
and selectivity of the azomethine ylide cycloaddition and is
compatible with reagents used in a one-bead/one-stock solution
Figure 2. Silver(I)/(S)-QUINAP-catalyzed azomethine ylide cycloaddition.
technology platform for DOS.8
Table 1. Exploration of the Reactivity of the Aromatic Moietya
Focusing on the silver(I)-catalyzed enantioselective cycloaddition
developed by Zhang and co-workers, we aimed to identify a
commercially available and general catalyst system capable of
maximizing the number and directionality of pyrrolidine append-
ages. Six different chiral phosphines, each available in both
enantiomeric forms, were examined in combination with silver(I)
c
acetate (Figure 1). The reaction was initially explored by reacting
methyl N-benzylideneglycinate (7), derived from benzaldehyde and
methyl glycinate, with 1.5 equiv of tert-butyl acrylate (8) with 3
mol % catalyst loading. While the Trost ligands (1 and 2) gave
low conversion at 4 °C, the other four ligands (3-6) showed
excellent reactivity. With the exception of ligand 3, the diastereo-
selectivity was in general high. Strikingly, the P,N-ligand QUINAP
(4) showed excellent levels of both diastereo- and enantioselectivity,
comparable to that reported by Zhang and co-workers.4,9 The
catalyst loading can be reduced to 1 mol % without deleterious
effect. Pyrrolidine 9, in this case the enantiomer of that available
by the Zhang catalyst, was obtained in 84% yield and 91% ee after
reacting at -45 °C for 40 h (Figure 2).
To explore the scope of the silver(I) acetate/QUINAP-catalyzed
[3+2] azomethine ylide cycloaddition, we investigated R-imino-
esters (10-14) derived from aromatic aldehydes with a variety of
steric and electronic properties (Table 1). Under these conditions,
the reaction showed excellent levels of diastereoselectivity (>20:
1) and enantioselectivity (94-96% ee) regardless of the electronic
property of the aromatic ring (entry 1-4), although the sterically
hindered iminoester 14 resulted in slightly lower enantioselectivity
(89% ee, entry 5).
entry
Ar
pyrrolidine
yieldb
ee
1
2
3
4
5
4-methoxyphenyl (10)
4-bromophenyl (11)
4-cyanophenyl (12)
2-naphthyl (13)
15
16
17
18
19
93%
89%
92%
89%
95%
95%
95%
96%
94%
89%
2-tolyl (14)
a Catalyst loading: 3 mol %. b Isolated yield. c Determined by HPLC.
23 was obtained only in 60% ee (entry 1).10 In this case, reactions
proceeding in toluene provided higher enantioselectivity than those
in THF. In contrast, tert-butyl crotonate (21) showed lower
reactivity, and pyrrolidine 24 was obtained in 97% yield with 84%
ee after reacting at -20 °C for 85 h with 10 mol % catalyst loading
(entry 2). This represents the first example of incorporating an alkyl
group at the 3-position of pyrrolidine using catalytic asymmetric
azomethine ylide cycloadditions. On the other hand, tert-butyl
cinnamate (22) showed poor diastereoselectivity (2:1), and the major
endo product pyrrolidine 25a was obtained in 81% ee while the
minor exo product 25b was obtained in 50% ee with a combined
yield of 62% (entry 3).
We also probed the silver(I) acetate/QUINAP-catalyzed [3+2]
azomethine cycloaddition with iminoesters derived from amino
esters other than glycinate. The tested substrates generate pyrroli-
dines with a quaternary center at the 2-position (Table 3).
Pyrrolidine 30 was isolated in 98% yield and 80% ee after reacting
We next examined the silver(I) acetate/QUINAP catalyst system
with different dipolarophiles (Table 2). Dimethyl maleate (20)
reacted with iminoester 7 even at -60 °C. However, pyrrolidine
9
10174
J. AM. CHEM. SOC. 2003, 125, 10174-10175
10.1021/ja036558z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Exploration of the Reactivity of Dipolarophiles
stereogenic centers in the [3+2] azomethine ylide cycloaddition,
including a previously unreported quaternary center on the pyrroli-
dine ring with good to excellent levels of selectivity. Its application
in a divergent DOS pathway leading to stereochemically diverse
alkaloids is underway.
Acknowledgment. We thank the NIGMS for support of this
research. Harvard ICCB is supported by Merck & Co., Merck
KGaA, the Keck Foundation, and NCI. C.C. is a postdoctoral
fellow, and S.L.S is an Investigator with the Howard Hughes
Medical Institute at the Department of Chemistry and Chemical
Biology, Harvard University. We thank Dr. Michael M.-C. Lo for
helpful discussions.
c
entry
1a dimethyl
maleate (20)
2b tert-butyl
crotonate (21)
3b tert-butyl
cinnamate (22)
dipolarophile
temp
time
yield
endo:exod
eee
60%
-60 °C 48 h 88% (23)
>20:1
-20 °C 85 h 97%f (24)
>20:1
-20 °C 85 h 62%g (25a, 25b) 81%,
2:1
50%h
84%
a Catalyst loading: 3 mol %, solvent: toluene. b Catalyst loading: 10
Supporting Information Available: General experimental proce-
dures, characterization data, and X-ray crystallographic file (PDF and
CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
1
mol %. c Isolated yield. d Determined by crude H NMR spectra. e Deter-
mined by HPLC. f ca. 95% purity. g Combined yield of endo and exo
products. h Enantioselectivity of the exo product 25b.
Table 3. Extending the Scope of the Silver(I)/QUINAP-Catalyzed
[3+2] Azomethine Ylide Cycloadditiona
References
(1) For reviews, see: (a) Kanemasa, S. Synlett 2002, 1371-1387. (b) Grigg,
R. Chem. Soc. ReV. 1987, 16, 89-121. (c) Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry toward Heterocycles and Natural
Products; Padwa, A., Pearson, W., Eds; Wiley-VCH: Weinheim, 2002;
pp 169-252.
(2) Schreiber, S. L. Science 2000, 287, 1964-1969.
(3) Only azomethine ylides derived from aldehydes and R-aminoesters are
reviewed here. (a) Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.
Urushido, K. Bull. Chem. Soc. Jpn. 1990, 63, 2857-2865. (b) Kanemasa,
S.; Hayashi, T.; Tanaka, J.; Yamamoto, H.; Sakurai, T. J. Org. Chem.
1991, 56, 4473-4481. (c) Annunziata, R.; Cinquini, M.; Cozzi, F.;
Raimondi, L.; Pilati, T. Tetrahedron: Asymmetry 1991, 2, 1329-1342.
(d) Grigg, R.; Montgomery, J.; Somasunderam, A. Tetrahedron 1992, 48,
10431-10442. (e) Waldmann, H.; Blaeser, E.; Jansen, M.; Letschert, H.-
P. Chem.-Eur. J. 1995, 1, 150-154. (f) Pyne, S. G.; Safaei-G., J.; Koller,
F. Tetrahedron Lett. 1995, 36, 2511-2514. (g) Barr, D. A.; Dorrity, M.
J.; Grigg, R.; Hargreaves, S.; Malone, J. F.; Montgomery, J.; Redpath, J.;
Stevenson, P.; Thornton-Pett, M. Tetrahedron 1995, 51, 273-294. (h)
Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P.; Redpath, J.
Tetrahedron 1995, 51, 7791-7808. (i) Galley, G.; Liebscher, J.; Pa¨tzel,
M. J. Org. Chem. 1995, 60, 5005-5010. (j) Schnell, B.; Bernardinelli,
G.; Ku¨ndig, E. P. Synlett 1999, 348-350. (k) Roussi, F.; Chauveau, A.;
Bonin, M.; Micouin, L.; Husson, H.-P. Synthesis 2000, 1170-1179. (l)
Garner, P.; Dogan, O¨ .; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.;
Zaniewski, R. Tetrahedron 2001, 57, 71-85. (m) Dogan, O¨ .; O¨ ner, I.;
U¨ lku¨, D.; Arici, C. Tetrahedron: Asymmetry 2002, 13, 2099-2104. (n)
See also ref 6b.
c
entry
R
time
yieldb
pyrrolidine
ee
1
2
3
4
methyl (26)
iso-butyl (27)
benzyl (28)
24 h
48 h
48 h
96 h
98%
77%d
93%
47%e
30
31
32
33
80%
80%
77%
81%
3-indolylmethyl (29)
a Catalyst loading: 10 mol %. b Isolated yield. c Determined by HPLC.
d 85% conversion. e 50% conversion.
(4) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
13400-13401.
(5) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 4236-4238.
(6) For the early development of catalytic asymmetric [3+2] azomethine ylide
cycloaddition, see: (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32,
5817-5820. (b) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-2486.
(7) While the silver(I) system gives better selectivity and has a broader scope
than the zinc(II) system, the xylyl-FAP ligand requires an eight-step
synthesis. The zinc(II) system resulted in low conversions on the solid
phase (500 µm polystyrene beads). The (R,R)-t-BuBOX is not com-
mercially available.
Figure 3. Silver(I)-catalyzed azomethine cycloaddition on macrobeads.
iminoester 2611 derived from benzaldehyde and alanine at -20 °C
for 24 h with 10 mol % catalyst loading (entry 1). We also examined
the iminoesters derived from leucine (27, entry 2), phenylalanine
(28, entry 3), and tryptophan (29, entry 4). Good enantioselectivity
(77-81%) was observed in all cases, although iminoesters 27 and
29 reacted sluggishly. To the best of our knowledge, this is the
first general catalytic asymmetric [3+2] cycloaddition reaction to
generate quaternary centers at the 2-position of pyrrolidines.12
To show the applicability of this reaction on 500-600 µm
polystyrene “macrobeads”,8 we loaded 4-hydroxybenzaldehyde onto
alkylsilyl-derivatized macrobeads and condensed the resulting
phenolic ether 34 with methyl glycinate. Reacting the macrobead-
bound iminoester with tert-butyl acrylate (8) using 10 mol % silver-
(I) acetate/(S)-QUINAP at -45 °C for 40 h, followed by cleavage
with HF-py and TMSOEt quench, provided the pyrrolidine 35 in
79% yield and 90% ee over three steps (Figure 3).
(8) (a) Blackwell, H. E.; Pe´rez, L.; Stavenger, R. A.; Tallarico, J. A.; Cope
Eatough, E.; Foley, M. A.; Schreiber, S. L. Chem. Biol. 2001, 8, 1167-
1182. (b) Clemons, P. A.; Koehler, A. N.; Wagner, B. K.; Sprigings, T.
G.; Spring, D. R.; King, R. W.; Schreiber, S. L.; Foley, M. A. Chem.
Biol. 2001, 8, 1183-1195.
(9) In this case, the QUINAP ligand (4) showed superior reactivity as it took
48 h at 0 °C for 3 mol % of silver(I) acetate/xylyl-FAP to complete the
reaction. For details, see Supporting Information.
(10) The silver(I)/xylyl-FAP catalyst system was reported to give 87% yield
and 87% ee after reacting at 0 °C for 7 h (ref 4).
(11) It was reported that condensing aldehydes with R-amino acids or esters
provided racemic iminoacids or iminoesters. Grigg, R.; Gunaratne, H. Q.
N. Tetrahedron Lett. 1983, 24, 4457-4460.
(12) Only three scattered examples of catalytic asymmetric [3+2] azomethine
cycloaddition reactions using iminoesters derived from amino acid other
than glycine were reported. (a) Reference 6b: Iminoester generated from
naphthaldehyde and alanine, reacting with methyl vinyl ketone (83% yield,
70% ee) or phenyl vinyl sulfone (64% yield, 70% ee). (b) Longimire, J.
M. Ph. D. Dissertation, Penn State University, 2000; iminoester 26 reacting
with dimethyl maleate: 70% yield, 65% ee.
Both enantiomers of the new catalyst system are easily prepared
from commercially available reagents. They enable the enantio-
and diastereoselective introduction of up to four consecutive
JA036558Z
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J. AM. CHEM. SOC. VOL. 125, NO. 34, 2003 10175