Stereoselective construction of a 5-aza-spiro[2,4]heptane motif via catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides and ethyl cyclopropylidene acetate

Article abstract of DOI:10.1039/c0cc04329j

A direct and facile synthesis of highly functional 5-aza-spiro[2,4] heptanes, a valuable structural motif for drug discovery, is developed via catalytic asymmetric 1,3-dipolar cycloaddition of cyclopropylidene acetate and azomethine ylides for the first t

Full text of DOI:10.1039/c0cc04329j

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Stereoselective construction of a 5-aza-spiro[2,4]heptane motif via
catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides
and ethyl cyclopropylidene acetatew
Tang-Lin Liu,a Zhao-Lin He,a Hai-Yan Tao,a Yue-Peng Caibc and Chun-Jiang Wang*ab
Received 10th October 2010, Accepted 21st December 2010
DOI: 10.1039/c0cc04329j
A direct and facile synthesis of highly functional 5-aza-
spiro[2,4]heptanes, valuable structural motif for drug
both gram-positive and gram-negative bacteria.3 In sharp
contrast to the well-documented approaches to access either
cyclopropane or pyrrolidine-containing compounds, an
effective and atom-economic construction of the challenging
5-aza-spiro-[2,4]heptane structural skeletons still remains
elusive.
a
discovery, is developed via catalytic asymmetric 1,3-dipolar
cycloaddition of cyclopropylidene acetate and azomethine
ylides for the first time.
Both cyclopropane moiety1 and pyrrolidine moiety2 are
commonly present in many bioactive natural products and
compounds of pharmaceutical interest, which has prompted
the development of methodologies for their synthesis in the
past decades. The 5-aza-spiro[2,4]heptane structure motif,3
that is, spiro[cyclopropan-3,30-pyrrolidine], containing the
two key units via a spiro carbon, plays a significant role in
structure–activity relationship of several antibacterial agents
as exemplified by those shown in Fig. 1. It has been revealed
that the unique 5-aza-spiro[2,4]heptane scaffold could
remarkably enhance the carbapenems analogues, substituted
oxazolidinones and quinolone antibiotics especially against
Recently, we reported that Cu(I) or Ag(I)/TF–BiphamPhos
complexes exhibited excellent results in asymmetric 1,3-dipolar
cycloaddition of azomethine ylides for the construction of
highly substituted pyrrolidines.4,5 Encouraged by these
achievements and stimulated by the biological significance of
the 5-aza-spiro[2,4]-heptane-containing compounds,3 we
envisioned that 5-aza-spiro[2,4]heptane derivatives could be
realized via 1,3-dipolar cycloaddition of azomethine ylides4,5
with highly strained but readily accessible cyclopropylidene
acetates6 (Scheme 1). Despite the large body of asymmetric 1,3-
dipolar cycloadditions in organic synthesis,5 alkylidene-
cyclopropanes are still underestimated as valuable partners in
these reactions.7 Most of the reactions involving highly
strained methylene-cyclopropanes (MCPs) are ring-opening
processes due to the potent thermodynamic driving force
rendered by the relief of 3-membered ring strain,8 and the
few reported ring-untouched asymmetric transformations are
limited to chiral-auxiliary-induced 1,3-dipolar cycloaddition
using chiral nitrone as dipole9 and Diels–Alder cycloaddition
using chiral cyclopropylidene imide10 or chiral acetate as
dienophiles.11 Herein, we reported the first asymmetric 1,3-
dipolar cycloaddition of various azomethine ylides with cyclo-
propylidene acetate catalyzed by Cu(I)/(S)-TF–BiphamPhos
complexes, providing the efficient and facile access to the
bioactive 5-aza-spiro[2,4]heptane derivatives with excellent
levels of diastereoselectivity and enantioselectivity.
Fig.
1
Representatives of bioactive 5-aza-spiro[2,4]heptane-
containing compounds.
a College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China. E-mail: cjwang@whu.edu.cn;
Fax: +86-27-68754067
b Shanghai Institute of Organic Chemistry, 354 Fenglin Road,
Shanghai 200032, China
c School of Chemistry and Environment, South China Normal
University, 510006, China
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 785673. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc04329j
Scheme 1 Proposed 1,3-dipolar cycloaddition of cyclopropylidene
acetate and azomethine ylide for the construction of
spiro[2,4]heptanes motif.
a 5-aza-
c
2616 Chem. Commun., 2011, 47, 2616–2618
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Initially, we began our investigation by using ethyl
2-cyclopropylidene acetate 1a as the dipolarophile and N-(4-
chlorobenzylidene)-glycine methyl ester 2a as the dipolar
precursor in the presence of AgOAc/(S)-TF–BiphamPhos
(L1) (3 mol%) and Et3N (15 mol%) in DCM at room
temperature. Gratifyingly, the 1,3-dipolar addition reaction
proceeded smoothly without ring-opening of the cyclopropane
to afford the adduct endo-3aa containing 5-aza-spiro[2,4]-
heptane moiety exclusively (dr > 98 : 2) with 83% yield and
71% ee in 3 h (Table 1, entry 1). Encouraged by this result,
different metal salts and chiral ligands were subsequently
examined to establish optimal reaction conditions, and the
representative results are summarized in Table 1. Combined
with TF–BiphamPhos, both Ag(I) and Cu(I/II) salts afforded
the desired adducts with excellent endo-selectivity, but the
latter gave better catalytic activity (Table 1, entries 1,2 vs.
3–7). Among the tested copper salts, Cu(CH3CN)4BF4 gave
the best result in terms of the reaction rate and
enantioselectivity. Further ligands survey revealed that ligand
L1 was the most promising, and provided endo-3aa as the sole
product in 85% yield and 96% ee (Table 1, entry 3). Reducing
the reaction temperature from rt to ꢀ20 1C led to a completed
reaction with excellent enantioselectivity of 98% ee (Table 1,
entry 8). In addition, the effect of the ester functional group
of 1 was also investigated for this transformation. Although
no obvious differentiation of enantioselectivity was observed
when the ester functional group of 1 switched from ethyl to
methyl, the bulky tert-butyl ester functional group has obviously
a detrimental effect on the reactivity and only trace amount of
product was detected even in extended reaction time probably
due to the unfavored steric hindrance (Table 1, entries 8–10).
With the optimal reaction conditions in hand, the scope
of 5-aza-spiro[2,4]heptane formation was demonstrated with
various imino esters derived from glycine ester. As summarized
in Table 2, a variety of imino esters 2 derived from aromatic
aldehydes reacted smoothly with ethyl 2-cyclopropylidene
acetate 1a to afford the sole endo-adducts in high yields and
excellent enantioselectivities. Imino esters bearing electron-
deficient (Table 2, entries 1–4), electron-neutral (Table 2,
entry 5), and electron-rich substitutents (Table 2, entries
6–10) on the aryl rings all work well, providing the
corresponding products in high yields (76–97%), excellent
diastereoselectivities (95 : 5 to >98 : 2 dr) and enantio-
selectivities (92–98% ee). The substitution pattern of the
arene had little effect on the selectivity of the reaction, and
ortho-substituted imino esters 2b and 2h underwent this
transformation leading to exclusive endo-adducts 3ab and
3ah with 97% ee and 96% ee, respectively (Table 2, entries 2
and 8). Similar results were also obtained for heteroaromatic
imino ester 2k (Table 2, entry 11). Additionally,
a,b-unsaturated imino ester 2l also proved to be a viable
substrate in this process, producing the desired endo-3al with
excellent diastereoselectivity and enantioselectivity (Table 2,
entry 12).12 The relative and absolute configuration of endo-
3aa achieved by Cu(CH3CN)4BF4/(S)-L1 was unequivocally
determined as (4R,6S,7R) (Fig. 2) by X-ray diffraction analysis
(see ESIw)z. Those of other adducts were tentatively proposed
on the basis of these results.
Table 1 Screening studies of asymmetric 1,3-dipolar cycloaddition of
imino ester 2a with 2-cyclopropylideneacetate 1a
Table 2 Asymmetric 1,3-dipolar cycloaddition of various imino ester
2 with 2-cyclopropylideneacetate 1aa
Yieldb eec
Entry
L
[M]
R
T/1C Time/h
3
(%)
(%)
1
2
3
4
5
6
7
8
9
10
L1 AgOAc
L2 AgOAc
L1 CuBF4
L2 CuBF4
L1 CuClO4
L1 CuOTf
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
rt
rt
rt
rt
rt
rt
rt
ꢀ20
3
3
0.5
0.5
1
1
1
1
1
3aa 83
3aa 73
3aa 85
3aa 87
3aa 89
3aa 58
3aa 90
3aa 90
3ba 87
3ca Trace
71
75
96
93
95
95
91
98
98d
—
Entry R (2)
endo-3 Yieldb (%) endo : exo eec (%)
1
p-Cl–Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
90
97
87
85
81
78
90
87
78
82
89
76
>98 : o2 98
2
3
4
5
o-Cl–Ph (2b)
p-Br–Ph (2c)
p-F–Ph (2d)
Ph (2e)
97 : 3
95 : 5
97 : 3
95 : 5
96 : 4
97
98
97
95
97
L1 Cu(OTf)2 Et (1a)
L1 CuBF4
L1 CuBF4
L1 CuBF4
Et (1a)
Me (1b) ꢀ20
6
7
8
p-Me–Ph (2f)
m-Me–Ph (2g)
o-Me–Ph (2h)
>98 : o2 98
>98 : o2 96
>98 : o2 98
>98 : o2 92
>98 : o2 94
>98 : o2 93
t-Bu (1c) ꢀ20
5
a
9
p-MeO–Ph (2i) 3ai
1-Naphthyl (2j) 3aj
2-Thienyl (2k)
Cinnamyl (2l)
All reactions were carried out with 0.20 mmol of 1 and 0.40 mmol of
mL DCM. CuOTf
CuOTfꢁ1/2C6H6, CuBF4
Cu(CH3CN)4BF4, CuClO4
10
11
12d
2a in
2
=
=
b
3ak
3al
=
Cu(CH3CN)4ClO4. Isolated
c
yield. ee was determined by chiral HPLC analysis, and >98 : 2 dr
was determined by HPLC analysis. Minor diastereomer was not
detected on the crude 1H NMR. dr = 86 : 14.
a
b
c
d
See Table 1. See Table 1. See Table 1. Reaction was carried out
at 0 1C in 1 h.
d
c
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Chem. Commun., 2011, 47, 2616–2618 2617

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all calculations. The final wR2 = 0.1506 (all data). Flack w = ꢀ0.11(7).
CCDC 785673 (3aa).
1 (a) J. Pietruszka, Chem. Rev., 2003, 103, 1051; (b) L. A.
Wessjohann, W. Brandt and T. Thiemann, Chem. Rev., 2003,
103, 1625; (c) J. E. Baldwin and D. W. Parker, Chem. Rev., 2003,
103, 11974.
2 Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products, ed. L. M. Harwood,
R. J. Vickers, A. Padwa and W. Pearson, Wiley & Sons, New York,
2002.
3 (a) S.-Y. Kim, H. B. Park, J.-H. Cho, K. H. Yoo and C.-H. Oh,
Bioorg. Med. Chem. Lett., 2009, 19, 2558; (b) H. B. Park, N. H. Jo,
J. H. Hong, J. H. Chei, J.-H. Cho, K. H. Yoo and C.-H. Oh, Arch.
Pharm. Chem. Life Sci., 2007, 340, 530; (c) G. Cianchetta,
R. Mannhold, G. Cruciani, M. Baroni and V. Cecchetti, J. Med.
Chem., 2004, 47, 3139; (d) N. Jiraskova, Curr. Opin. Invest. Drugs,
2000, 1, 31; (e) T. Yoshida, Y. Yamamoto, H. Orita, M. Kakiuchi
and H. Kato, Chem. Pharm. Bull., 1996, 44, 1376; (f) Y. Takahashi,
N. Masuda, M. Otsuki, M. Miki and T. Nishino, Antimicrob.
Agents Chemother., 1997, 41, 1326; (g) K. Youichi, A. Shohgo,
K. Katsuhiro, S. Kenichi and H. Isao, J. Med. Chem., 1994, 37,
3344.
Fig. 2 X-Ray structure of (4R,6S,7R)-3aa.
4 (a) C.-J. Wang, G. Liang, Z.-Y. Xue and F. Gao, J. Am. Chem.
Soc., 2008, 130, 17250; (b) C.-J. Wang, Z.-Y. Xue, G. Liang and
Z. Lu, Chem. Commun., 2009, 2905; (c) G. Liang, M.-C. Tong and
C.-J. Wang, Adv. Synth. Catal., 2009, 351, 3101; (d) Z.-Y. Xue,
T.-L. Liu, Z. Lu, H. Huang, H.-Y. Tao and C.-J. Wang, Chem.
Commun., 2010, 46, 1727.
5 For excellent reviews about 1,3-dipolar cycloaddition reactions of
azomethine ylides, see: (a) L. M. Stanley and M. P. Sibi, Chem.
Rev., 2008, 108, 2887; (b) G. Pandey, P. Banerjee and S. R. Gadre,
Chem. Rev., 2006, 106, 4484.
6 (a) J. Salaun and J. Marguerite, Org. Synth., Coll. Vol. 7, 131;
J. Salaun and J. Marguerite, Org. Synth., Coll. Vol. 63, 147;
(b) T. Thiemann, D. Ohira, Y. Q. Li, T. Sawada, S. Mataka,
K. Rauch, M. Noltemeyer and A. de Meijere, J. Chem. Soc., Perkin
Trans. 1, 2000, 2968.
7 For achiral examples on the ring-untouched 1,3-dipolar
cycloaddition of alkylidenecyclopropanes with nitrone dipoles,
see: (a) F. M. Cordero, I. Barile, F. D. Sarlo and A. Brandi,
Tetrahedron Lett., 1999, 40, 6657; (b) F. M. Cordero, M. Salvati,
F. Pisaneschi and A. Brandi, Eur. J. Org. Chem., 2004, 2205;
(c) J. Revuelta, S. Cicchi and A. Brandi, J. Org. Chem., 2005, 70,
5636; (d) F. M. Cordero, F. Pisaneschi, M. Salvati, V. Paschetta,
Fig. 3 The results of 1,3-dipolar cycloaddition of imino esters derived
from a-substituted amino acids with ethyl cyclopropylidene acetate 1a.
To further expand the synthetic utility of this reaction for
construction of 5-aza-spiro[2,4]heptanes bearing a unique nitrogen-
substituted quaternary stereogenic center,13 azomethine ylide
derived from various a-substituted amino acids has also been
examined. The results are summarized in Fig. 3. Pleasingly,
high yield and excellent diastereo-/enantioselectivity were
uniformly observed for those imino esters derived from
(ꢂ)-alanine, (ꢂ)-2-aminobutyric acid and (ꢂ)-leucine under
the optimal reaction conditions.
J. Ollivier, J. Salaun and A. Brandi, J. Org. Chem., 2003, 68, 3271;
¨
In conclusion, we have developed a general solution for the
direct and facile synthesis of various optically active 5-aza-
spiro[2,4]heptane derivatives in high yield and excellent
diastereo-/enantioselective (95 : 5 to >98 : 2 dr, 93–98% ee) via
the Cu(I)/(S)-TF–BiphamPhos-catalyzed asymmetric 1,3-dipolar
cycloaddition reaction for the first time. Notably, this
methodology presented herein could open up new prospects for
selectively constructing highly functional 5-aza-spiro[2,4]heptanes,
a valuable structural motif for drug discovery. Further studies on
the reaction scope and its application are ongoing.
For achiral examples on the ring-untouched 1,3-dipolar
cycloaddition of alkylidenecyclopropanes with diazoalkane
dipoles, see: (e) I. P. Klimenko, E. V. Shulishov, Y. V. Tomilov
and O. M. Nefedov, Russ. Chem. Bull., 2003, 52, 659;
(f) A. P. Molchanov, V. V. Diev, J. Magull, D. Vidovic,
S. I. Kozhushkov, A. de Meijere and R. R. Kostikov, Eur. J.
Org. Chem., 2005, 593.
8 For excellent reviews, see: (a) M. Shi, L.-X. Shao, J.-M. Lu, Y. Wei,
K. Mizuno and H. Maeda, Chem. Rev., 2010, 110, 5883;
(b) H. Pellisier, Tetrahedron, 2010, 66, 8341; (c) A. Galano,
J. Alvarez-Idaboy and A. Vivier-Bunge, Theor. Chem. Acc., 2007,
118, 597; (d) A. Brandi, S. Cicchi, F. M. Cordero and A. Goti,
Chem. Rev., 2003, 103, 1213.
9 F. Pisaneschi, M. Piacenti, F. M. Cordero and A. Brandi,
Tetrahedron: Asymmetry, 2006, 17, 292.
10 J. T. Kuethe, D. L. Zhao, G. R. Humphrey, M. Journet and
A. E. McKeown, J. Org. Chem., 2006, 71, 2192.
11 J. R. Henderson, M. Parvez and B. A. Keay, Org. Lett., 2007, 9,
5167.
12 No cycloaddition was observed when alkyl substituted imino ester
was tested under the same reaction conditions.
This work was supported by National Natural Science
Foundation of China (20702039, 20972117), 973
(2011CB808600), SRFDP (20090141110042), and the
Fundamental Research Funds for the Central Universities.
Notes and references
z Crystal data for (4R,6S,7R)-3aa: C17H20ClNO4, Mr = 337.79,
13 (a) Quaternary Stereocenters: Challenges and Solution for Organic
Synthesis, ed. J. Christoffers and A. Baro, Wiley-VCH, Weinheim,
2005; (b) B. M. Trost and C. Jiang, Synthesis, 2006, 369.
T
= 298 K, monoclinic, space group P2(1), a = 9.479(2),
b = 27.837(6), c = 13.143(4) A, V = 3467.8(13) A3, Z = 8, 11 687
reflections measured, 7093 unique (Rint = 0.0514) which were used in
c
2618 Chem. Commun., 2011, 47, 2616–2618
This journal is The Royal Society of Chemistry 2011