Bis-sulfonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3 + 2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1021/ja804021m

Enantioenriched 3-pyrrolines have been synthesized by highly enantioselective Fesulphos-Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl ethylene, followed by reductive sulfonyl elimination. High levels of reactivity, exoselectivity, and enantioselectivity have been accomplished for a variety of substituted azomethine ylides. This cycloaddition-desulfonylation strategy has been applied as a key step in the enantioselective synthesis of a biologically active C-azanucleoside. Copyright

Full text of DOI:10.1021/ja804021m

Published on Web 07/10/2008
Bis-Sulfonyl Ethylene as Masked Acetylene Equivalent in Catalytic
Asymmetric [3 + 2] Cycloaddition of Azomethine Ylides
Ana Lo´pez-Pe´rez, Javier Adrio, and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de Madrid,
Cantoblanco 28049 Madrid, Spain
Received June 4, 2008; E-mail: juancarlos.carretero@uam.es
Table 1. Reaction Conditions for the Model Reaction
The metal-catalyzed asymmetric 1,3-dipolar cycloaddition of
azomethine ylides derived from R-iminoesters with alkenes is a
very practical and atom-economical method for the enantioselective
synthesis of highly substituted pyrrolidines.1 In recent years, an
outstanding progress has been achieved in this field, with a variety
of efficient protocols involving Zn,2 Ag,3 Cu,4 and Ni5 chiral
complexes of bidentate chiral ligands having been developed. One
of the intrinsic scope limitations of this approach is that it is only
applicable to low LUMO dipolarophiles, mainly electron-deficient
conjugated alkenes such as R,ꢀ-unsaturated esters, imides, nitriles,
sulfones, and nitro compounds, restricting severely the substitution
pattern at the pyrrolidine ring. For instance, acetylene and simple
alkynes are unreactive dipolarophiles in this reaction, which
hampers the catalytic asymmetric preparation of 3-pyrrolines.6
However, this heterocyclic unsaturated ring system is a very
appealing and widely used intermediate in the preparation of
substituted pyrrolidines,7 especially hydroxylated pyrrolidines which
present outstanding biological activities.8 To overcome this limita-
tion, an indirect strategy for the catalytic asymmetric synthesis of
3-pyrrolines could be the use of an electron-deficient alkene acting
as a masked acetylene equivalent.
entry
x
solvent
yield (%)a
ee (%)b
1
2
3
4
5
10
10
10
3
CH2Cl2
toluene
THF
THF
THF
85
83
90
93
96
98
90 (88)c
65
98 (94)c
90
1
a Isolated yield after column chromatography. b By HPLC. c Reaction
from N-benzylidenglycine ethyl ester.
Table 2. Scope of the Asymmetric Fesulphos-Cu-Catalyzed
Cycloaddition of Azomethine Ylides with Sulfonylethylene 2
We describe herein that commercially available trans-1,2-
bisphenylsulfonyl ethylene can efficiently play this role by means
of a highly enantioselective CuI-Fesulphos-catalyzed 1,3-dipolar
cycloaddition with azomethine ylides, followed by reductive
elimination of both sulfonyl groups9 (Figure 1).
entry
R1
R2
R3
product
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
(p-OMe)C6H4
(m-Me)C6H4
(m-F)C6H4
(o-Me)C6H4
(p-N-(Boc)2)C6H4
2-naphtyl
2-furyl
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
79
93
90
83
82
91
74
77
78
65
81
90
65
0
92
94
97
95
85
95
96
H
H
H
H
H
H
H
H
H
H
H
H
Ph
CH)CH-Ph
85 (99)c
30
26
98
96
97
9
Cy
t-Bu
Ph
10
11
12
13
14
15
Figure 1. Strategy for the enantioselective synthesis of 3-pyrrolines and
substituted pyrrolidines.
(p-OMe)C6H4
CHdCH-Ph
Ph
On the basis of our recent results on the asymmetric 1,3-dipolar
cycloaddition of azomethine ylides with typical electron-deficient
alkenes catalyzed by CuI/Fesulphos,4b,g we chose this catalyst
system for the study of the model reaction of N-benzylidenglycine
methyl ester 1a with trans-1,2-bisphenylsulfonyl ethylene 2.10
Gratifyingly, in the first experiment carried out with 10 mol % of
Cu(MeCN)4PF6 and ligand Fesulphos (R)-3 in the presence of Et3N
(20 mol %) as base, the disulfonylated pyrrolidine 4a was obtained
in good yield (85%), complete exoselectivity, and high enantiose-
lectivity (Table 1, entry 1, 93% ee). Its configurational and
stereochemical assignment was unequivocally established by X-ray
diffraction.11 A brief study of solvents showed a significant
improvement of the asymmetric induction when the reaction was
performed in THF (Table 1, entry 3, 98% ee). The catalyst loading
could be reduced to 3 mol % with very similar reactivity and
enantioselectivity (Table 1, entry 4, 98% ee). However, a further
-
-
Ph
H
Me 4p
0
a Isolated yield after column chromatography. b By HPLC. c Enan-
tiomeric excess after recrystallization.
reduction in the catalyst loading to 1 mol % (Table 1, entry 5)
resulted in a lower chemical yield and enantioselectivity.
With these optimal reaction conditions in hand, Table 2 shows
the scope of the 1,3-dipolar cycloaddition with regard to the
substitution at the azomethine ylide. Except in the case of the
ketimine dipole precursors (entries 14 and 15), which proved to be
unreactive, in all cases, a single diastereomer was detected and
isolated (65-93% yield). All aryl- and heteroaryl-substituted glycine
derivatives (R2 ) H) provided an excellent enantiocontrol regardless
of the electronic nature of the substituent (85-95% ee, entries 1-7).
The procedure can also be applied to R,ꢀ-unsaturated imines (entry
9
10084 J. AM. CHEM. SOC. 2008, 130, 10084–10085
10.1021/ja804021m CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Enantioselective Synthesis of 3-Pyrrolines and
In summary, we have described a practical approach to the
catalytic asymmetric synthesis of 3-pyrrolines. This method is based
on the highly enantioselective Fesulphos-Cu-mediated 1,3-dipolar
cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl
ethylene, followed by reductive desulfonylation. The application
of this protocol to the enantioselective synthesis of a biologically
active trihydroxylated pyrrolidine is also described.
Hydroxymethyl Pyrrolidinesa
Acknowledgment. This work was supported by the Ministerio
de Educacio´n y Ciencia (Project CTQ2006-01121) and UAM-
Consejer´ıa de Educacio´n de la Comunidad Auto´noma de Madrid
(Project CCG07-UAM/PPQ-1670). J.A. thanks the MEC for a
Ramo´n y Cajal contract. A.L. thanks the CAM for a predoctoral
fellowship. We are also very grateful to Prof. Correia for sending
us the NMR spectra of compound 11.
a Conditions: (a) Na(Hg), Na2HPO4, MeOH/THF, rt; (b) LiAlH4, THF,
0 °C; (c) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (d) CbzCl, K2CO3, CH3CN;
(e) O3, CH2Cl2, then NaBH4, 0 °C.
Supporting Information Available: Experimental procedures,
characterization data of new compounds, copies of NMR spectra, and
X-ray crystallography data of exo-4a. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 2. Synthesis of Schramm’s C-Azanucleosidea
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a Conditions: (a) Cu(MeCN)4PF6 (3 mol %), (R)-9 (3 mol %), Et3N (20
mol %), CH2Cl2, 48 h, -78 °C; 94% ee; (b) LiAlH4, THF, 0 °C; (c)
TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (d) Na(Hg), Na2HPO4, MeOH/THF;
(e) OsO4, TMEDA, CH2Cl2, -78 °C; (f) HCl/MeOH, rt.
8) and alanine base dipoles (R2 ) Me, entries 11-13) with similar
enantioselectivities. In contrast, the reaction of alkyl imines was
much less enantioselective (entries 9 and 10).
The straightforward application of this [3 + 2] cycloaddition
methodology to the asymmetric synthesis of 3-pyrrolines and
hydroxymethyl pyrrolidines is shown in Scheme 1. Direct reductive
elimination of the vicinal sulfonyl groups of pyrrolidines 4l and
4n by treatment with Na(Hg)12 gave rise to 3-pyrrolines 5 and 6 in
85 and 77% yields, respectively, without any observable epimer-
ization. Similarly, the ester reduction of pyrrolidine 4i with LiAlH4,
protection of the hydroxyl group as TIPS ether, and desulfonylation
afforded the 3-pyrroline 7 in 49% overall yield.13 On the other
hand, ozonolysis of the Cbz derivative of 4i, followed by reductive
treatment (NaBH4), afforded the bishydroxymethyl pyrrolidine 8
in 57% overall yield.
Applying these chemical transformations, Schramm’s C-aza-
nucleoside14 (11), a promising trypanosomal nucleoside hydrolase
inhibitor, was readily prepared in six steps15 (Scheme 2). The Cu-
catalyzed 1,3-dipolar cycloaddition between the azomethine ylide
precursor 1f and dipolarophile 2 in the presence of (R)-3 afforded
the pyrrolidine 4f in 82% yield and 85% ee (Table 1, entry 5). A
similar yield but higher enantioselectivity (94% ee) was achieved
by performing the reaction at -78 °C in the presence of the bulkier
Fesulphos ligand (R)-9. Further reduction of the ester moiety
(LiAlH4), protection of the alcohol as TIPS, and reductive elimina-
tion of the sulfonyl groups afforded the 3-pyrroline 10 (46% overall
yield). Finally, the completely stereoselective dihydroxylation of
10 with OsO4/TMEDA at -78 °C, followed by acid cleavage of
the protecting groups, provided 11 in 60% yield.
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Angew. Chem., Int. Ed. 2007, 46, 9261–9264.
(10) Unlike the very high stereoselectivity with the trans-bis-sulfone 2, the 1,3-
dipolar cycloaddition of the cis-1,2-bis-p-tolylsulfonyl ethene with 1a
occurred with formation of endo + exo adducts.
(11) Exo refers to the pyrrolidine with trans-stereochemistry at C4-C5. See
Supporting Information for details of the X-ray structure of exo-4a.
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Yus, M. Tetrahedron 1999, 55, 10547–10658.
(13) The direct treatment of pyrrolidine 4i with Na(Hg) led mainly to the
aromatic pyrrole product instead of the 3-pyrroline.
(14) Miles, R.; Tyler, P. C.; Evams, G. B.; Furneaux, R. H.; Parkin, D. W.;
Schramm, V. L. Biochemistry 1999, 38, 13147–13154.
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Garc´ıa, A. L. L.; Correia, C. R. D. Org. Lett. 2003, 5, 305–308. (b)
Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm, V. L. Tetrahedron
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J. AM. CHEM. SOC. VOL. 130, NO. 31, 2008 10085