Catalytic asymmetric construction of spirocycles containing pyrrolidine motifs and spiro quaternary stereogenic centers via 1,3-dipolar cycloaddition of azomethine ylides with 2-alkylidene-cycloketones

Article abstract of DOI:10.1002/adsc.201100104

The first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with various sterically hindered α,α,β-trisubstituted 2-alkylidene-cycloketones has been developed successfully with silver acetate/TF-BiphamPhos complex for the construction of spiro heterocyclic compounds containing pyrrolidine motifs and a spiro quaternary stereogenic carbon center. The highly efficient catalytic system exhibited high reactivity, excellent diastereoselectivity, good enantioselectivity and broad substrate scope under mild conditions. Subsequent transformations led to the expedient preparation of synthetically useful spiro[pyrrolidine-tetrahydropyranone] and spiro[pyrrolidine-isochroman-1-one] without loss of the diastereo- and enantiomeric excesses. Copyright

Full text of DOI:10.1002/adsc.201100104

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DOI: 10.1002/adsc.201100104
Catalytic Asymmetric Construction of Spirocycles Containing
Pyrrolidine Motifs and Spiro Quaternary Stereogenic Centers
via 1,3-Dipolar Cycloaddition of Azomethine Ylides with
2-Alkylidene-Cycloketones
Tang-Lin Liu,a Zhao-Lin He,a Qing-Hua Li,a Hai-Yan Tao,a
and Chun-Jiang Wanga,b,*
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430071, Peopleꢀs Republic of China
Fax : (+86)-27-6875406; e-mail: cjwang@whu.edu.cn
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
b
Received: February 14, 2011; Revised: April 12, 2011; Published online: July 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100104.
Abstract: The first catalytic asymmetric 1,3-dipolar
cycloaddition of azomethine ylides with various
sterically hindered a,a,b-trisubstituted 2-alkylidene-
cycloketones has been developed successfully with
silver acetate/TF-BiphamPhos complex for the con-
struction of spiro heterocyclic compounds contain-
ing pyrrolidine motifs and a spiro quaternary ste-
reogenic carbon center. The highly efficient catalyt-
ic system exhibited high reactivity, excellent diaste-
reoselectivity, good enantioselectivity and broad
substrate scope under mild conditions. Subsequent
transformations led to the expedient preparation of
synthetically useful spiro[pyrrolidine-tetrahydropyr-
anone] and spiro[pyrrolidine-isochroman-1-one]
without loss of the diastereo- and enantiomeric ex-
cesses.
catalytic asymmetric version of the 1,3-dipolar cyclo-
addition of azomethine ylides. Since the pioneering
work of Grigg[3] employing stoichiometric amounts of
a chiral metal complex and the first catalytic asym-
metric version reported by Zhang[4] using Ag(I)/xylyl-
FAP system, various types of chiral metal catalysts[5–9]
and organocatalysts[10] have been successfully devel-
oped to afford moderate to high enantio-/diastereose-
lectivities for this reaction over the last few years. Al-
though most of the electron-deficient alkenes applied
in these reactions are the derivatives of conjugated
unsaturated esters, maleimides, vinyl sulfones, nitroal-
kenes and cyclopropylideneacetates,[3–10] a,b-disubsti-
tuted enones as dipolarophiles have also received at-
tention in the asymmetric 1,3-dipolar cycloaddition
due to their high electron-withdrawing carbonyl
group and synthetic potential (left side of Scheme 1).
Recently, Carretero has developed a general proce-
dure for the first asymmetric 1,3-dipolar cycloaddition
of azomethine ylides with a,b-disubstituted enones[11]
catalyzed by Cu(I)/Fesulphos affording high diaste-
reoselectivity and enantioselectivity. Chiral silver(I)
complex-catalyzed asymmetric 1,3-dipolar cycloaddi-
tions with cyclic and acyclic a,b-disubstituted enones
have been reported by Nꢁjera using chiral AgClO4/
Keywords: asymmetric catalysis; azomethine ylides;
diastereoselectivity; 1,3-dipolar cycloaddition; enan-
tioselectivity; a,a,b-trisubstituted 2-alkylidene-cy-
cloketones
The catalytic enantioselective 1,3-dipolar cycloaddi- phosphoramidite[5c] and Fukuzawa using AgOAc/Thi-
tion of azomethine ylides to electron-deficient alkenes oClickFerrophos[5d] with excellent performances, re-
is a powerful and atom-economical carbon-carbon spectively. More recently, Zheng and Huꢀs seminal
bond forming reaction that facilitates the synthesis of work[12] showed that the combinations of Cu(I) or
a range of structurally and stereochemically rich pyr- Ag(I) salts and newly-designed chiral ferrocenyl P,S-
rolidines.[1] Because the resulting highly substituted ligands also provided excellent enantioselectivities
pyrrolidines are prevalent in many natural alkaloids, and diastereoselectivities for the catalytic 1,3-dipolar
compounds of pharmaceutical significance, organoca- cycloaddition of azomethine ylides with various cyclic
talysts, and biologically important building blocks in and acyclic a,b-disubstituted enones, such as cyclo-
organic synthesis,[2] recent research has focused on the pent-2-enone, cyclohex-2-enone and chalcones. Never-
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Scheme 1. Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylide with a,b-disubstituted enones (previous work)
and a,a,b-trisubstituted enones for the construction of spirocyclic compounds (this work).
Table 1. Optimization of catalytic asymmetric 1,3-dipolar cy-
cloaddition of methyl N-(4-chlorobenzylidene)-glycinate 1a
with (E)-2-benzylidenecyclopentanone 2a.[a]
theless, in spite of recent advances on the application
of enones as dipolarophiles, notable shortcomings still
persist in this area, particularly in the context of effi-
cient construction of spiro quaternary stereogenic
carbon centers[13] using easily accessible but sterically
hindered a,a,b-trisubstituted 2-alkylidene-ketones as
dipolarophiles. In view of the simultaneous creation
of one unique spiro quaternary and three tertiary ste-
reogenic centers in the five-membered pyrrolidine
rings, it is a great challenge to control both high enan-
tioselectivity and diastereoselectivity in the asymmet-
ric 1,3-dipolar cycloaddition reaction involving a,a,b-
trisubstituted enones. Herein, we describe the first
catalytic asymmetric 1,3-dipolar cycloaddition reac-
tion of azomethine ylide with various a,a,b-trisubsti-
tuted 2-alkylidene-ketones for the synthesis of spiro
heterocyclic compounds containing pyrrolidine motifs
and spiro quaternary stereogenic carbon centers using
Ag(I)/TF-BiphamPhos complex[14] with excellent dia-
stereoselectivity and up to 92% enantioselectivity
(the right side of Scheme 1). In addition, subsequent
transformations allowed for facile access to otherwise
inaccessible enantioenriched spiro pyrrolidine-pyra-
nones and pyrrolidine-isochroman- 1-ones via direct
Baeyer–Villiger oxidation.
We began our investigations by examing the ability
of Cu(I) and Ag(I)/TF-BiphamPhos complexes, previ-
ously developed in our laboratories, to promote the
1,3-dipolar cycloaddition of N-(4-chlorobenzylidene)-
glycine methyl ester 1a with a,a,b-trisubstituted
enones. As the main objective of this research is 2-al-
kylidene-cycloketones, we chose (E)-2-benzylidenecy-
clopentanone 2a to serve as the model dipolarophile.
To our delight, the reaction was finished remarkably
[a]
All reactions were carried out with 0.40 mmol of 1a and
0.20 mmol of 2a in 2 mL solvent. CuBF4 =
CuACHTUNRTGNE(NUG CH3CN)4BF4.
Isolated yield.
in less than 3 h with CuACTHNUTRGNE(UNG CH3CN)4BF4/(S)-TF-Bipham-
[b]
[c]
Phos (L1) as the catalyst and Et3N as base in di-
chloromethane at room temperature, yielding the ex-
pected spiro[cyclopentanone-2,3’-pyrrolidine] 3aa
with exclusive diastereoselectivity and 50% ee
(Table 1, entry 1), which indicated that a,a,b-trisubsti-
tuted cyclic enones could be applied in our catalytic
system as dipolarophiles for the efficient construction
Enantioselectivity was determined by chiral HPLC analy-
sis, and a >99:1 diastereomeric ratio was determined by
HPLC analysis. Minor diastereomer was not detected in
1
the crudematerial by H NMR.
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Catalytic Asymmetric Construction of Spirocycles Containing Pyrrolidine Motifs
Table 2. Substrate scope of Ag(I)-catalyzed asymmetric 1,3-
of chiral spirocyclic compounds. Subsequent studies
showed that a silver(I) salt as the metal precursor
gave better results than copper(I) salts in terms of the
yield and enantioselectivity (Table 1, entry 2). Encour-
aged by these promising results, AgOAc was selected
as the metal source for further ligand, solvent and
base screening, and the representative results are pre-
sented in Table 1. (S)-TF-BiphamPhos (L2) bearing
two bromines at the 3,3’-positions of the TF-
BIPHAM backbone was the chiral ligand of choice
and provided 3aa as the sole product in high yield
and 84% ee (Table 1, entry 3). The other commercial-
ly available chiral phosphine ligands such as BINAP
and MonoPhos are either ineffective or provide rela-
tively poor enantiomeric excesses (Table 1, entries 6
and 7). Reducing the temperature to À208C in DCM
led to full conversion with exclusive diastereoselectiv-
ity and 91% ee within 5 h (Table 1, entry 5), but fur-
ther lowering the temperature could not improve the
enantioselectivity. Examination of various bases such
as DBU, TMG, DMAP, and K2CO3 disclosed that
Et3N was the optimal base. A study of reaction with
AgOAc/(S)-L2 in various solvents identified PhMe
and CHCl3 as suitable alternatives to CH2Cl2 (Table 1,
entries 5 and 8–12).
dipolar cycloaddition of imino esters 1 with various substi-
tuted a,a,b-trisubstituted 2-alkylidenecyclopentanones 2.[a]
In the presence of 3 mol% of AgOAc/(S)-TF-Bi-
phamPhos (L2), and 15 mol% Et3N in CH2Cl2, 1,3-di-
polar cycloadditions of different glycine imino esters
with various substituted a,a,b-trisubstituted 2-alkyli-
dene cyclopentanones were carried out to test the
generality of the reaction. As shown in Table 2, imino
esters bearing electron-rich (Table 2, entries 7 and 8),
electron-neutral (Table 2, entries 6, 9 and 10), and
electron-deficient groups (Table 2, entries 1–5) on the
aryl rings reacted with 2-benzylidenecyclopentanone
2a smoothly affording the corresponding spiro cyclo-
adducts (3aa–3ja) exclusively in good yields (72–90%)
and good enantioselectivities (87–92%) at À208C
within 3–7 h. The substitution pattern and electronic
property of the phenyl ring have little effect on the
[a]
All of the reaction was carried out with 0.20 mmol of 2
and 0.40 mmol of 1 in 2 mL of DCM.
Isolated yield.
Enantioselectivity was determined by chiral HPLC analy-
sis, and a >99:1 diastereomeric ratio was determined by
[b]
[c]
HPLC analysis. Minor diastereomer was not detected in
1
the crude matreial by H NMR.
enantioselectivity. It is noteworthy that comparable with good yields and 77–91% ee (Table 2, entries 17–
results were still achieved for the sterically hindered 20). However, no cycloaddition was observed when
ortho-bromo-, ortho-methyl- and 1-naphthyl-substitut- an alkyl-substituted imino ester was tested under the
ed imino esters 1d, 1h and 1i in terms of diastero/ same reaction conditions.
enantioselectivity and reactivity (Table 2, entries 4, 8
The asymmetric 1,3-dipolar cycloaddition of imino
and 9). Additionally, the heteroaryl substituted imino ester with other a,a,b-trisubstituted 2-benzylidene-cy-
ester 1k derived from 2-furylaldehyde also works in cloketones was also investigated. As shown in
this transformation leading to 80% yield and 78% ee Scheme 2, this catalytic system could also affect on
(Table 2, entry 11). The potential of this catalytic ap- the asymmetric cycloaddition of both six-membered
proach is further demonstrated by the reaction of cyclohexanone derived 2j and seven-membered cyclo-
other trisubstituted 2-arylidenecyclopentanones (2b– heptanone derived 2k. Although moderate enantiose-
2e) with imino esters to afford the desired spirocyclic lectivities were achieved with AgOAc/(S)-TF-
compounds in excellent diastereoselectivities and high BiphamPhos (L2) complex for the expected cycload-
enantioselectivities (88–92% ee) (Table 2, entries 12– ducts spiro[cyclohexanone-2,3’-pyrrolidine] 3aj and
16). Noticeably, alkylidenecyclopentanones with alkyl spiro[cyclohepetanone-2,3’-pyrrolidine] 3ak, the cor-
substitution (2f–2i) were also able to undergo the 1,3- responding enantioselectivities could be improved sig-
dipolar cycloaddition providing the desired products nificantly through switching the metal precursor
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Scheme 2. The results of catalytic asymmetric 1,3-dipolar cycloaddition of other a,a,b-trisubstituted 2-benzylidene-cycloke-
tones and bicyclic 2-benzylidene-cycloketones.
Scheme 4. The results of catalytic asymmetric 1,3-dipolar cy-
cloaddition of imino ester 1a with acyclic a,a,b-trisubstitut-
ed (E)-3-benzylidenebutanone 2n.
Scheme 3. Catalytic asymmetric 1,3-dipolar cycloaddition of
Prompted by these results for the a,a,b-trisubstitut-
methyl N-(4-chlorobenzylidene)-glycinate 1a with (Z)-2-
benzylidenecyclopentanone 2a’.
ed 2-alkylidene-cycloketones, we then investigated
acyclic butan-2-one derived trisubstituted (E)-3-ben-
zylidenebutanone 2n, from which a unique quaternary
stereogenic center was still generated in the corre-
sponding non-spiro cycloadduct. To our delight, the
AgOAc into Cu
ACHTUNGTRENNUNG
cycloketones 2l and 2m were also tested in this reac- or CuAHCTUNGTRENNUNG
tion, and 93% ee and 91% ee were achieved with lyst to give the highly diastereoselective cycloadduct
Ag(I)/TF-BiphamPhos and Cu(I)/TF-BiphamPhos 3an in 80% ee and 91% ee, respectively (Scheme 4).
complex, respectively, for the corresponding cycload-
The absolute configuration of the adduct 3al ach-
ducts spiro[indene-2,3’-pyrrolidin]-1(3H)-one 3al and ieved by AgOAc/(S)-L2 was unequivocally deter-
3,4-dihydro-1H-spiro[naphthalene-2,3’-pyrrolidin]-1-
mined as (2R,2’R,4’R,5’R) by X-ray crystallographic
one 3am. These results indicated that Ag(I)/TF- analysis of a single crystal (Figure 1).[16] Those of
BiphamPhos complex was more efficient for a,a,b-tri- other adducts were tentatively proposed on the basis
substituted 2-alkylidene-cycloketones derived from of these results.
five-membered cyclopentanone, and Cu(I)/TF-Bi-
The optically active cycloadducts containing one
phamPhos complex exhibited better asymmetric in- spiro quaternary and three tertiary stereogenic cen-
duction capacity for 2-alkylidene-cycloketones de- ters can be readily converted into synthetically useful
rived from six-membered cyclohexanone and seven- compounds. As shown in Scheme 5, direct Baeyer–
membered cycloheptanone.
Villiger oxidation[17] of the cycloadducts 3aa and 3al
The asymmetric 1,3-dipolar cycloaddition of methyl with m-CPBA in DCM at room temperature afforded
N-(4-chlorobenzylidene)-glycinate 1a with (Z)-2-ben- otherwise inaccessible spiro[pyrrolidine-tetrahydro-
zylidenecyclopentanone 2a’[15] using (S)-TF-Bipham- pyranone] and spiro[pyrrolidine-isochroman-1-one]
Phos L2 as chiral ligand was also investigated without loss of diastereo- and enantiomeric excesses,
(Scheme 3). Although the reactivity of the Z-2a’ was and the oxidative transformation selectively occurs on
lower than that of trans-substrate E-2a, the expected the carbon-carbon single bond between the spiro qua-
adduct 3aa’ was still obtained in moderate yield and ternary carbon and the carbon of carbonyl group in
93% ee when employing AgOAc or CuACHTNUGTRENNUNG
as the metal precursor.
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Catalytic Asymmetric Construction of Spirocycles Containing Pyrrolidine Motifs
Figure 1. X-ray crystal structure of (2R,2’R,4’R,5’R)-3al.
Experimental Section
General Procedure for Asymmetric 1,3-Dipolar
Cycloaddition of Azomethine Ylides with (E)-
Benzylidene Cyclopentanones Catalyzed by AgOAc/
(S)-TF-BiphamPhos Complex:
Under an argon atmosphere (S)-TF-BiphamPhos L2
(5.8 mg, 0.0072 mmol) and AgOAc (1.0 mg, 0.006 mmol)
were dissolved in 2 mL DCM, and stirred at room tempera-
ture for about 1 h. Then, the imine substrate (0.4 mmol),
Et3N (0.03 mmol) and (E)-benzylidenecyclopentanone
(0.2 mmol) were added sequentially. Once the starting mate-
rial had been consumed (monitored by TLC), the mixture
was filtered through celite and the filtrate was concentrated
to dryness. The product purified by column chromatography
to give the corresponding cycloaddition product, which was
then directly analyzed by chiral HPLC to determine the
enantiomeric excess.
Scheme 5. Synthetic transformations of the spiro heterocy-
clic compounds 3aa and 3al.
(1R,3R,4R,5R)-Methyl
1-(4-chlorophenyl)-6-oxo-4-
phenyl-2-azaspiro[4.4]nonane-3-carboxylate (3aa): The title
AHCTUNGTRENNUNG
In conclusion, we have successfully developed the
first catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine ylides with various sterically hindered
a,a,b-trisubstituted 2-alkylidene-cycloketones. This
catalytic system performances well over a broad
scope of substrates and provides the desired spirocy-
clic compounds containing pyrrolidine motifs and
spiro quaternary stereogenic carbon centers in excel-
lent diastereoselectivity and up to 92% ee, and subse-
quent transformations lead to the expedient prepara-
tion of synthetically useful spiro[pyrrolidine-tetrahy-
dropyranone] and spiro[pyrrolidine-isochroman-1-
one] without loss of diastereo- and enantiomeric ex-
cesses. Further investigations on the scope and syn-
thetic application of this methodology are ongoing,
and the results will be reported in due course.
compound was prepared according to the general procedure
as described above in; yield: 85%; [a]2D5: +46.5 (c 0.12,
CHCl3). 1H NMR (CDCl3, TMS, 300 MHz): d=7.35–7.22
(m, 9H), 4.32 (s, 1H), 4.23 (d, J=6.9 Hz, 1H), 3.82 (d, J=
6.3 Hz, 1H), 3.75 (s, 3H), 2.04–1.26 (m, 6H); 13C NMR
(CDCl3, TMS, 75 MHz): d=219.92, 173.04, 139.13, 136.93,
133.72, 129.09, 128.59, 128.43, 127.04, 72.82, 64.99, 55.82,
53.36, 52.09, 57.53,32.20, 18.38; IR (KBr): n=3681, 3621,
3021, 2977, 2899, 2428, 2400, 1735, 1521, 1476, 1424, 1215,
1047, 929, 878, 773, 669, 626 cmÀ1; HR-MS: m/z=384.1363,
calcd. for C22H22ClNO3: 384.1361. The product was analyzed
by HPLC to determine the enantiomeric excess: 91% ee
(Chiralcel AS-H, 2-propanol/hexane=10/90, flow rate
1.0 mLminÀ1, l=220 nm): tr =14.01 and 31.58 min.
Acknowledgements
This work is supported by the National Natural Science
Foundation of China (20702039, 20972117), the program for
new century excellent talents in university (NCET-10-0649),
the program for Chiangjung Scholars and Innovative Re-
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program
(2011CB808600), and the Fundamental Research Funds for
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