New zinc(II)-based catalyst for asymmetric azomethine ylide cycloaddition reactions

Article abstract of DOI:10.1021/ol061521f

(Chemical Equation Presented) A new chiral aziridino alcohol ligand for zinc(II)-catalyzed azomethine ylide cycloadditions is described. In the presence of this catalyst, N-arylidene glycine methyl esters react with a variety of dipolarophiles to give sub

Full text of DOI:10.1021/ol061521f

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4687-4690
New Zinc(II)-Based Catalyst for
Asymmetric Azomethine Ylide
Cycloaddition Reactions
O2
zdemir Dogan,*,† Hasan Koyuncu,† Philip Garner,*,‡ Adnan Bulut,§
|
|
Wiley J. Youngs, and Matthew Panzner
Department of Chemistry, Middle East Technical UniVersity, 06531 Ankara, Turkey,
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland,
Ohio 44106-7078, Department of Chemistry, Kirikkale UniVersity, 71450 Kirikkale,
Turkey, and Department of Chemistry, UniVersity of Akron, Akron, Ohio 44325
dogano@metu.edu.tr; ppg@case.edu
Received June 21, 2006
ABSTRACT
A new chiral aziridino alcohol ligand for zinc(II)-catalyzed azomethine ylide cycloadditions is described. In the presence of this catalyst,
N-arylidene glycine methyl esters react with a variety of dipolarophiles to give substituted pyrrolidines in very good to excellent chemical
yields and up to 95% ee. The absolute sense of asymmetric induction appears to be dipolarophile-dependent.
Azomethine ylides1 and related species2 are important
reactive intermediates that have considerable synthetic
potential because they undergo [3+2] cycloadditions with
alkenes to give substituted pyrrolidines. Because the pyrro-
lidine ring system is found in many bioactive substances,
the development of more effective procedures for the
asymmetric syntheses of substituted pyrrolidines is of great
importance. The seminal discovery that N-metalated azo-
methine ylides undergo facile [3+2] cycloadditions3 has led
to the development of catalytic asymmetric versions of this
important reaction (Scheme 1). This possibility could be
divined from Grigg’s seminal work using stoichiometric
quantities of metal salts and chiral ligands.4 A number of
Scheme 1. Catalytic Asymmetric Azomethine Ylide
Cycloaddition
† Middle East Technical University.
‡ Case Western Reserve University.
§ Kirikkale University.
| University of Akron.
(1) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; Vol. 1, Chapter 1.
(2) Pearson, W. H.; Stoy, P. Synlett 2003, 903.
(3) (a) Grigg, R.; Sridharan, V. In AdVances in Cycloaddition; Curran,
D. P., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 3, p 161. (b) Kanemasa,
S. Synlett 2002, 9, 1371.
10.1021/ol061521f CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/09/2006

laboratories have now reported catalytic asymmetric [3+2]
azomethine ylide cycloadditions employing a variety of chiral
ligand-metal combinations (Figure 1).5,6 Despite these
the catalytic asymmetric azomethine ylide cycloadditions
reported to date, only Jørgensen’s original study (see ref 6a)
employed a zinc-based catalyst system. In that work, only
two types of dipolarophiles were examined (acrylates and
dimethyl fumarate).
Our chiral ligand design was based on the known attributes
of ferrocene-derived ligands7 and an improved route to
acryloylferrocene (4).8 We were also cognizant that aziridinyl
alcohols serve as effective chiral ligands for dialkylzinc
additions to aldehydes.9 These considerations prompted us
to survey a series of chiral aziridino alcohols that could be
prepared from 4 and led to the crystalline aziridinyl alcohol
7 as the most promising chiral ligand candidate.10 The
synthesis of 7 commenced with Gabriel-Cromwell aziridi-
nation11,12 of enone 4 using (R)-methylbenzylamine (Scheme
2). This reaction gave a mixture of diastereomeric aziridinyl
Scheme 2. Synthesis of Chiral Ligand 7
Figure 1. Known chiral ligand-metal combinations for catalytic
asymmetric azomethine ylide cycloadditions.
impressive advances, there remains a need for new catalysts
that are easily prepared and can tolerate variation of both
the dipole and the dipolarophile components.
ketones 5 (54%) and 6 (42%) that were easily separated by
flash chromatography on silica gel.13 Stereocontrolled reduc-
tion of aziridinyl ketones 5 with NaBH4 + ZnCl2 (chelation
control)14 according to Lee and co-workers afforded the syn-
aziridinyl alcohol 7 in high yield. Compound 7 is a stable
yellow crystalline solid (mp 83-85 °C) that is soluble in
typical organic solvents. Its (R,R,R)-configuration was
confirmed by X-ray crystallography (Figure 2).15
We now report a novel zinc(II) catalyst for the [3+2]
cycloaddition between three glycine methyl ester aldimine-
derived azomethine ylides and a representative set of
dipolarophile types (acrylate, fumarate, maleate, and male-
imide). This procedure utilizes a novel ferrocenyl-substituted
aziridino alcohol as the chiral ligand. The ease of ligand
preparation is a particularly attractive feature of this new
catalyst system. Under optimized reaction conditions, sub-
stituted pyrrolidine products are formed in generally high
yields and with ee’s ranging from 68 to 95%. Interestingly,
the absolute sense of asymmetric induction is found to be
consistently reversed in the case of dimethyl maleate. Of
(4) (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817. (b) Grigg,
R. Tetrahedron: Asymmetry 1995, 6, 2475.
(5) Reviews: (a) Husinec, S.; Savic, V. Tetrahedron: Asymmetry 2005,
16, 2047. (b) Na´jera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44,
6272.
(6) (a) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236. (b) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (c) Chen, C.; Li, X.;
Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174. (d) Oderaotoshi, Y.;
Cheng, W.; Fujitomi, S.; Kasano, Y. Minakata, S.; Komatsu, M. Org. Lett.
2003, 5, 5043. (e) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe,
T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (f) Stohler, R.;
Wahl, F.; Pfaltz, A. Synthesis 2005, 1431. (g) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241. (h) Zeng, W.; Zhou, Y.-G. Org.
Lett. 2005, 7, 5055. (i) Cabrera, S.; Arraya´s, R. G.; Carretero, J. C. J. Am.
Chem. Soc. 2005, 127 16394. (j) Alemparte, C.; Blay, G.; Jørgensen, K. A.
Org. Lett. 2005, 7, 4569. (k) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.;
Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979.
Figure 2. ORTEP diagram from the X-ray crystallographic analysis
of ligand 7.
The combination of ligand 7 with Zn(OTf)2 produced a
very effective catalyst for the asymmetric cascade imine f
azomethine ylide f [3+2] cycloaddition reaction (Table 1).
Three known aldimines, ArCHdNCH2CO2Me (Ar ) phenyl,
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Org. Lett., Vol. 8, No. 21, 2006

Table 1. Catalytic Asymmetric Azomethine Ylide Cycloadditions with Ligand 7a
a Procedure: (Rigorously dry conditions were employed; see Supporting Information for details.) To Zn(OTf)2 (10.0 or 5.0 mol %) was added ligand 7
(11.5 or 5.8 mol %) in DCM (1.8 mL per mmol of imine) under Ar at room temperature. The homogeneous mixture was stirred at this temperature for about
1 h and then cooled to -20 °C when the imine (1 equiv), Et3N (10.0 mol %, distilled and stored over NaOH), and the dipolarophile (1.1 equiv) were added
sequentially. The reaction was stirred at -20 °C until judged complete by TLC (∼6 h for the higher and 14 h for the lower catalyst loadings), at which point
the solvent was removed under reduced pressure and the product was isolated by flash column chromatography on silica gel.
2-naphthyl, and 4-methoxyphenyl; prepared as described in
ref 6a), were employed as azomethine ylide precursors.
Cycloadditions with a standard set of electron-deficient
dipolarophiles (dimethyl maleate, dimethyl fumarate, methyl
acrylate, tert-butyl acrylate, and N-methylmaleimide) were
investigated, and the products’ enantiomeric excesses (ee’s)
were determined by chiral HPLC analysis. In each case, a
very clean cycloaddition occurred in DCM solution at -20
(10) All four possible stereoisomeric aziridinyl alcohols were synthesized
and tested. The crystalline chiral ligand 7 was clearly superior to the other
three oily aziridinyl alcohol diastereomers. (See Supporting Information
for details.)
(11) Cromwell, N. H.; Babson, R. D.; Harris, C. E. J. Am. Chem. Soc.
1943, 65, 312.
(12) Dogan, O¨ .; Zeytinci, S.; Bulut, A. Synth. Commun. 2005, 35, 1067.
(13) Because the ferrocene group imparts a red color to these compounds,
the purification of 5 and 6 could be conveniently monitored visually.
(14) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K. J. Org. Chem.
2003, 68, 7675.
(7) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem.
Res. 2003, 36, 659.
(8) Dogan, O¨ .; Senol, V.; Zeytinci, S.; Koyuncu, H.; Bulut, A. J.
Organomet. Chem. 2005, 690, 430.
(9) (a) Tanner, D.; Kornø, H. T.; Guijarro, D.; Andersson, P. G.
Tetrahedron 1998, 54, 14213. (b) Lawrence, C. F.; Nayak, S. K.; Thijs, L.;
Zwannenburg, B. Synlett 1999, 1571. (c) Wang, M.-C.; Liu, L.-T.; Zhang,
J.-S.; Shi, Y.-Y.; Wang, D.-K. Tetrahedron: Asymmetry 2004, 15, 3853.
Org. Lett., Vol. 8, No. 21, 2006
4689

°C,16 providing pyrrolidines in high yield after flash chro-
matography. Qualitatively similar results in terms of yield
and enantiomeric excess were obtained with 10 and 5 mol
% catalyst loadings, though the latter reactions were slower.
The relative stereochemistry of the cycloadducts was con-
sistent with endo addition of the dipolarophile to an (E,E)-
configured metalated azomethine ylide. When acrylate
dipolarophiles were employed, the cycloaddition reaction was
regioselective for the 2,4,5-trisubstituted pyrrolidine.
The observed ee’s with ligand 7 at 10 mol % catalyst
loading ranged from 90 to 95% with dimethyl maleate
(entries 1a and 8a) and from 78 to 88% with tert-butyl
acrylate (entries 4a, 7a, and 9a) and were 68% for dimethyl
fumarate and 70% for N-methylmaleimide (entries 2 and 5).
Cycloadditions with methyl acrylate gave the lowest ee’s
(entries 3 and 6a). Except for the reactions with dimethyl
maleate, all of the ZnII-catalyzed [3+2] cycloadditions using
ligand 7 gave (2R)-configured pyrrolidines preferentially. The
absolute configurations shown for the cycloadducts 8-16
derive from comparison of their optical rotation and chiral
HPLC data with values reported in the literature (see
Supporting Information). In the case of cycloadduct 8, the
absolute configuration was unambiguously confirmed by
chemical correlation with a compound that had been previ-
ously characterized by X-ray crystallography.17 Literature
assignments for all cycloadducts except 12 were based on
analogy with structurally related compounds that had been
characterized by X-ray crystallography.
Figure 3. Proposed endo-re pre-TS leading to cycloadducts 9-14
and 16.
coordinate and the stereocenter at C2 of the aziridine
determines the chirality of the complex. The (E,E)-dipole is
oriented such that the phenyl group is positioned on the
convex face of the bicyclic ring system formed by zinc(II)
chelation to aziridino alcohol. In such a complex, the
N-substituent of ligand 7 effectively blocks the dipolarophile
approach from the bottom (si) face of the ylide, resulting in
re attack. Although the observed endo selectivity can be
ascribed to a stereoelectronic effect, a five-coordinate ZnII
complex with the ester dipolarophiles acting as ligands is
also possible (see ref 6a). Such an ensemble may be preferred
over si-favoring alternatives with a bulky tert-butyl ester.
At present, we do not have an adequate explanation for the
endo-si selectivity that is observed with dimethyl maleate.
In summary, a novel chiral ligand for ZnII-catalyzed [3+2]
cycloadditions of azomethine ylides is described. A key
feature of this ligand system is its ease of preparation, which
is facilitated by the judicious incorporation of a ferrocenyl
group into its structure. This catalytic asymmetric 1,3-dipolar
cycloaddition procedure is applicable to a variety of standard
dipolarophiles, providing substituted pyrrolidines in high
yields and up to 95% ee. These preliminary results warrant
further development of ferrocenyl-substituted aziridino al-
cohols as chiral ligands for catalytic asymmetric transforma-
tions.
The experimentally observed re facial selectivity with
acrylate, fumarate, and maleimide dipolarophiles can be
rationalized by the pre-transition state (TS) shown in Figure
3. According to this working model, the ZnII atom is four
(15) CCDC-619170 (chiral ligand 7) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
datarequest/cif.
(16) We initially employed Jørgensen’s original reaction conditions (ref
6a). However, the use of THF gave inferior results in our case, presumably
due to the heterogeneous nature of the reaction in this solvent.
(17) The previously prepared pyrrolidine acylsultam 17 (Garner, P.;
Dogan, O¨ .; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.; Zaniewski,
R. Tetrahedron 2001, 57, 71) was saponified and then Fisher-esterified to
give the leVorotary C2-epimerized pyrrolidine triester 18. On the other hand,
treatment of cycloadduct 8 with methoxide gave the dextrorotary C2-
epimerized pyrrolidine triester ent-18.
Acknowledgment. The authors thank the National Sci-
ence Foundation (INT-0242964) and TUBITAK (TBAG-U/
57) for support of this collaborative research project and the
NSF for funds used to purchase the X-ray diffractometer
(CHE-0116041). Special thanks to H. U¨ mit Kaniskan
(CWRU) for his technical assistance.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061521F
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Org. Lett., Vol. 8, No. 21, 2006