Diastereochemical diversity of imidazoline scaffolds via substrate controlled TMSCI mediated cycloaddition of azlactones

Article abstract of DOI:10.1021/ol052118w

(Chemical Equation Presented) We report herein a trimethylsilyl chloride mediated substrate controlled 1,3-dipolar cycloaddition for the diastereoselective synthesis of either syn- or anti-imidazolines. This method provides scaffolds with four points of diversity and control over two stereocenters.

Full text of DOI:10.1021/ol052118w

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5091-5094
Diastereochemical Diversity of
Imidazoline Scaffolds via Substrate
Controlled TMSCl Mediated
Cycloaddition of Azlactones
Vasudha Sharma and Jetze J. Tepe*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48823
tepe@chemistry.msu.edu
Received September 2, 2005
ABSTRACT
We report herein a trimethylsilyl chloride mediated substrate controlled 1,3-dipolar cycloaddition for the diastereoselective synthesis of either
syn- or anti-imidazolines. This method provides scaffolds with four points of diversity and control over two stereocenters.
Small-molecule scaffolds offer a handle to dissect biological
pathways, identify targets, and modulate their functions for
potential therapeutic use.1 Diversity-oriented synthesis is a
strategy for the construction of libraries with stereochemical,
skeletal, and functional group diversity with the aim to create
a broad distribution of compounds in chemical space.2
Control over stereochemical diversity in particular increases
the number of relative orientations of potential macromolecule-
interacting elements in small molecules.
ical information generated in the cycloaddition reaction is
lost. Efficient stereoselective syntheses of imidazolines have
been very limited with respect to control of diastereochemical
diversity and has primarily provided the anti products.4 As
part of our program focused on generating structurally and
stereochemically diverse heterocyclic scaffolds, we have
reported the use of a Lewis acid mediated generation of
mu¨nchnones as a mild and stereoselective process to access
highly substituted dihydroheterocyclic scaffolds.5-7
The stereochemical diversity of these small dihydrohet-
erocyclic scaffolds presents novel territory in terms of both
structure and biological activity examplified by the unique
1,3-Dipolar cycloadditions of N-alkylated azlactones
(mu¨nchnones) with various dipolarophiles provide a general
method for the synthesis of aromatic heterocycles such as
pyrroles, imidazoles, oxazoles, etc.3 However, due to the ease
of aromatization under standard conditions, the stereochem-
(4) (a) Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Smyth,
M. P. J. Org. Chem. 2002, 67, 3919-3922. (b) Dhawan, R.; Dghaym, R.
D.; Arndtsen, B. A. J. Am. Chem. Soc. 2003, 125, 1474-1475. (c) Dghaym,
R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2001, 40, 3228-
3230. (d) Pei, W.; Wei, H. X.; Chen, D.; Headley, A. D.; Li, G. J. Org.
Chem. 2003, 68, 8404-8408. (e) Bon, R. S.; van Vliet, B.; Sprenkels, N.
E.; Schmitz, R. F.; de Kanter, F. J.; Stevens, C. V.; Swart, M.; Bickelhaupt,
F. M.; Groen, M. B.; Orru, R. V. J. Org. Chem. 2005, 70, 3542-3553. (f)
Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de Kanter, F. J.; Lutz,
M.; Spek, A. L.; Orru, R. V. Org. Lett. 2003, 5, 3759-3762. (g) Timmons,
C.; Chen, D.; Xu, X.; Li, G. Eur. J. Org. Chem. 2003, 3850-3854.
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3535.
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10.1021/ol052118w CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/27/2005

anticancer properties of syn-imidazolines (nutlins)8 and anti-
imidazolines (SP-4-84).9 The syn-imidazolines were found
to be inhibitors of MDM2, a protein that negatively regulates
the activity of the pro-apoptotic transcription factor p53
(Figure 1).8 The anti-imidazoline SP-4-84, on the other hand,
prevent steric interaction between the bulky silyl group of
the azlactone and R3 group of imine, the endo approach of
the imine was favored resulting in the anti isomer as the
major or sole product (Scheme 1, path a).6
However, by reducing the resonance stabilization of the
carbocation in the dipole by changing the electronic nature
of the R1 substituent, a significant change in diastereoselec-
tivity was observed (entries 1-4, Table 1). Replacement of
Table 1. Influence of R1 Group on Diastereoselectivity
Figure 1. Structure of nutlin (syn-imidazoline), SP-4-84, and anti-
imidazoline (4).
entry
R1
R2
R3
R4
yield
syn:anti
1
2
3
4
Ph
Bn
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
75
76
12a
72
>5:95
33:67
50:50
90:10
was found to be a drastic enhancer of the chemotherapeutic
efficacy of anticancer agents and modulator of the anti-
apoptotic NF-κB signaling pathway.9 In addition to their
diverse biological activities,10 imidazolines have been utilized
as building blocks for biologically interesting scaffolds11 and
recently attracted considerable interest as ligands for asym-
metric catalysis.12
We previously reported the preparation of anti-imidazo-
lines using a trimethylsilyl chloride mediated 1,3-dipolar
cycloaddition on the azlactone template in good yields and
high diastereoselectivity (Scheme 1).5,6 In view of a potential
a The azlactone for entry 2 is volatile resulting in low isolated yields
the phenyl group by a benzyl or a methyl moiety significantly
eroded the stereoselectivity (entries 1-3, Table 1). Further,
switching the Ph and Me groups at R1 and R2 positions
favored the formation of syn-imidazoline (with respect to
R2 and R3) as the major product in 90:10 ratio (compare
entries 1 and 4, Table 1).
Intrigued by the clear reversal of diastereoselectivity, we
investigated the role of the R1 and R2 substituents on the
azlactone template. The azlactones were prepared from the
N-acetyl amino acids via an EDCI mediated dehydration
process as previously reported.6,13 The N-acyl p-methoxy
phenylglycine (amino acids for entries 10 and 11, Table 2)
was synthesized by employing a modified procedure of
Wasserman et al. (see the Supporting Information).14
Scheme 1. Proposed Transition States for Diastereoselective
Synthesis of anti-Imidazolines
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diverse biological response resulting from the stereochemical
diversity of these imidazoline scaffolds, we report herein a
trimethylsilyl chloride mediated substrate controlled 1,3-
dipolar cycloaddition for the diastereoselective formation of
syn- or anti-imidazolines.
In the case of 2-phenylimidazolines, high diastereoselec-
tivity was attributed to A (1,3) strain, in the azlactone dipole,
which prevents coplanarity of Ph, TMS, and R2 groups. To
(12) (a) Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Muller-
Bunz, H.; Wilkes, P. Org. Biomol. Chem. 2004, 2, 1995-2002. (b) Casey,
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M. C.; Harris, R. E.; Jones, P. J.; Kim, J. Y.; Lorenz, J. C.; McKellop, K.
B.; O’Brien, E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So, R. C.; Spinelli,
E. M.; Vitous, J.; Zavattaro, C. J. Org. Chem. 2004, 69, 5187-5195. (e)
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Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.;
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Chem. 1981, 46, 2999.
5092
Org. Lett., Vol. 7, No. 22, 2005

The cycloaddition reactions were conducted under mild
reflux conditions in dichloromethane or THF in the presence
of 1.3 equiv of TMSCl. The imidazoline products were
isolated by precipitation. syn-Imidazolines were reprecipitated
from the mixture in modest to good yields and the syn
configuration (relative to R2 and R3) was confirmed unam-
biguously by X-ray crystallography (see Figure 2).
Table 3. Variation of R3 and R4
entry R1 R2
R3
R4
yield syn:anti
0a
12
13
14
15
16
17
18
19
20
21
22
23
24
Me Ph iPr
Ph Me 4-methoxyphenyl Bn
Me Ph 4-methoxyphenyl Bn
Ph Me 4-nitrophenyl
Me Ph 4-nitrophenyl
Ph Me -COOEt
Me Ph -COOEt
Ph Me Ph
Me Ph Ph
Ph Me Ph
Me Ph Ph
Ph Me Ph
Bn
78
60
51
71
65
32
70
44
>5:95
60:40
Bn
Bn
Bn
Bn
>9:95
>95:5
>5:95
>95:5
>5:95
>95:5
>5:95
>95:5
-CH2COOMe
-CH2COOMe
4-fluorophenyl 74
4-fluorophenyl 20
n-Bu
n-Bu
5a >95:5
43 >5:95
Me Ph Ph
a Main product is â-lactam
withdrawing groups enhanced syn-diastereoselectivity (entry
16, Table 3).
Not surprisingly, when R1 is phenyl, the nature of R2, R3,
or R4 did not compromise the anti-diastereoselectivity (entries
6, 8, 9, and 11, Table 2; entries 13, 15, 17, 19, and 21, Table
3). A bulky group such as isopropyl at the R3 position did
not afford any imidazoline and only yielded â-lactam,
presumably via a traditional [2+2] cycloaddition reaction
(entry 12, Table 3). Both aryl as well as substituted alkyl
groups are tolerated at the R4 position (entry 4, Table 1;
entries 20 and 22, Table 3).
Figure 2. X-ray crystal structure of compound 4.
To understand the role of the R2 group in the diastere-
ochemical outcome of the reaction, the R2 group was varied
while R1 was maintained as methyl or phenyl.
The anti diastereomer was obtained with R1 as a phenyl
group and R2 an alkyl or aryl group (entries 6, 8, and 9,
Table 2). However, when R1 is methyl and R2 is methyl,
benzyl, or isopropyl (entry 3, Table 1; entries 5 and 7, Table
2) a mixture of diastereomers was obtained. syn-Imidazolines
were obtained as the major or sole products with the R2
substituent as an aryl group (entry 4, Table 1; entry 10, Table
2). These results suggest a possible role of π-stacking
interactions between neighboring π-donor R2 and π-acceptor
R3 (the centroid-centroid distance between R2 and R3 in 4
was found to be 3.98 Å, corresponding to a van der Waals
contact) (Scheme 2).15
Scheme 2. Proposed Rationale for the Reversal in
Diastereoselectivity
Table 2. Influence of R2 Favoring syn-Imidazolines
entry
R1
R2
R3
R4
yield
syn:anti
The above observations indicate that R1 controls the branch
point of the stereochemical diversity. When R1 is aryl, the
anti diastereomer is exclusively formed via the endo ap-
proach. However, when R1 is alkyl, R2 needs to be aryl to
obtain syn-imidazolines with high diastereoselectivity. A
possible explanation for this switch in diastereoselectivity
5
6
7
8
10
11
Me
Ph
Me
Ph
Me
Ph
Bn
Bn
iPr
iPr
p-OMePh
p-OMePh
Ph
Ph
Ph
Ph
p-NO2Ph
p-NO2Ph
Bn
Bn
Bn
Bn
Bn
Bn
55
45
79
71
66
53
75:25
>5:95
50:50
>5:95
>95:5
>5:95
(15) (a) Blondeau, P.; van der Lee, A.; Barboiu, M. Inorg. Chem. 2005,
44, 5649-5653. (b) Shan, S.; Hu, W. X.; Xu, D. J. Acta Crystallogr., Sect.
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E. B.; Grubbs, R. H. J. Am. Chem. Soc. 1998, 120, 3641-3649. (e) Corey,
E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319-329.
Some control on the diastereoselectivity was observed
based on the electronic nature of the incoming dipolarophile.
Electron-donating groups at R3 resulted in reduced syn-
diastereoselectivity (entry 14, Table 3), while electron-
Org. Lett., Vol. 7, No. 22, 2005
5093

is the stabilization of the exo approach due to favorable
π-stacking interactions between R2 and R3 (Scheme 2). In
conclusion, we have identified an efficient branch point for
enhancing the stereochemical diversity of imidazoline scaf-
folds by manipulation of the substituents on the general
azlactone template. The previously reported high anti dias-
tereoselectivity could be completely reversed favoring the
syn-imidazolines in synthetically useful yields. The potential
biological applications of this class of compounds are
currently under investigation and will be reported in the near
future.
Acknowledgment. The authors greatly acknowledge Dr.
Rui Huang for carrying out the X-ray crystallography. We
would like to thank Dr. S. Peddibhotla for helpful discus-
sions. The authors gratefully acknowledge funds from
American Cancer Society (RSG CDD-106972)
Supporting Information Available: The experimental
procedures and 1H and 13C data for all new compounds and
X-ray structures for 4, 5, and 18. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052118W
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Org. Lett., Vol. 7, No. 22, 2005