Silver-catalyzed enantioselective desymmetrization: Facile access to spirolactone-pyrrolidines containing a spiro quaternary stereogenic center

Article abstract of DOI:10.1021/ol400821q

An unprecedented Ag(I)-catalyzed asymmetric desymmetrization of spiro cyclohexadienone lactones has been developed successfully, which performs well over a broad scope of substrates and provides a facile access to optically active spirolactone-pyrrolidines in high yields with excellent levels of diastereo-/enantioselectivities.

Full text of DOI:10.1021/ol400821q

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2250–2253
Silver-Catalyzed Enantioselective
Desymmetrization: Facile Access to
Spirolactone-Pyrrolidines Containing a
Spiro Quaternary Stereogenic Center
Kang Liu,†,§ Huai-Long Teng,†,§ Lu Yao,† Hai-Yan Tao,† and Chun-Jiang Wang*,†,‡
College of Chemistry and Molecular Sciences, Wuhan University, 430072, China, and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Shanghai, China 230012
cjwang@whu.edu.cn
Received March 26, 2013
ABSTRACT
An unprecedented Ag(I)-catalyzed asymmetric desymmetrization of spiro cyclohexadienone lactones has been developed successfully, which
performs well over a broad scope of substrates and provides a facile access to optically active spirolactone-pyrrolidines in high yields with
excellent levels of diastereo-/enantioselectivities.
The application of chirotechnology in fine-chemicals
and materials sciences has achieved the goal of efficiently
constructing versatile building blocks in enantioenriched
forms within recent decades.1 Spiro heterocycles with
multiple contiguous stereogenic centers are prevalent scaf-
folds in bioactive molecules and natural products and
have always been a great challenge for synthetic organic
chemists.2 Elegant and creative strategies toward the con-
struction of spiro quaternary stereogenic centers with
excellent stereoselective control are still quite limited due
to the intrinsic steric congestion.3,4 Asymmetric de-
symmetrization5 is a versatile and economical protocol
for generating enantioenriched products with complex
structures and multiple stereogenic centers,6,7 which is
effected by differentiation of two enantiotopic groups on
the readily available symmetric or prochiral molecules.
Highly functionalized spirolactones such as spiro
γ-butyrolactone and butenolide constitute the core structure
(6) For very recent examples of catalytic asymmetric desymmetriza-
tion, see: (a) Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.; Feng, X.
J. Am. Chem. Soc. 2012, 134, 17023. (b) Xu, S.; Wang, Z.; Zhang, X.;
Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, 2840. (c) Aikawa,
K.; Okamoto, T.; Mikami, K. J. Am. Chem. Soc. 2012, 134, 10329. (d)
Hayashi, M.; Shiomi, N.; Funahashi, Y.; Nakamura, S. J. Am. Chem.
Soc. 2012, 134, 19366. (e) Sun, X.; Worthy, A. D.; Tan, K. L. Angew.
Chem., Int. Ed. 2011, 50, 8167. (f) Ren, L.; Lei, T.; Gong, L.-Z. Chem.
† Wuhan University.
‡ State Key Laboratory of Organometallic Chemistry.
§ These authors contributed equally.
(1) New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M.,
Eds.; Wiley: Hoboken, NJ, 2007.
(2) (a) The Alkaloids, Vol. 14; Bindra, J. S., Manske, R. H. F., Eds.;
Academic Press: New York, 1973. (b) Galliford, C. V.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 8748.
(3) For a very recent review, see: Hong, L.; Wang, R. Adv. Synth.
Catal. 2013, 355, doi: 10.1002/adsc.201200808.
(4) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A.; Eds.; Wiley-VCH: Weinheim, 2005.
(5) For reviews: (a) Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003,
€
Commun. 2011, 47, 11683. (g) Muller, S.; Webber, M. J.; List, B. J. Am.
Chem. Soc. 2011, 133, 18534. (h) Wasa, M.; Engle, K. M.; Lin, D. W.;
Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598.
(7) For selected recent example of asymmetric desymmetrization of
cyclohexadienones, see: (a) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.-L.
J. Am. Chem. Soc. 2010, 132, 4056. (b) Gu, Q.; You, S.-L. Chem. Sci.
2011, 2, 1519. (c) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.
(d) Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T.
J. Am. Chem. Soc. 2012, 134, 13554. (e) Takizawa, S.; Nguyen, T. M.-N.;
Grossmann, A.; Enders, D.; Sasai, H. Angew. Chem., Int. Ed. 2012, 51,
5423.
103, 2965. (b) Garcıa-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev.
´
2005, 105, 313.
r
10.1021/ol400821q
Published on Web 04/23/2013
2013 American Chemical Society

in a number of biologically interesting natural and syn-
thetic products.8 Furthermore, they also serve as versatile
building blocks for organic synthesis.9 Five-membered
nitrogen heterocycles, especially highly substituted pyrro-
lidines, areobservedwidelyinpharmaceuticalsand natural
alkaloids.10 Therefore, a combination of the above two
key units may introduce some unprecedented benefits
and is expected to find valuable applications in medicinal
chemistry. We envisioned that the efficient stereochemical
control attained recently in azomethine ylide involved 1,3-
dipolar cycloaddition reactions11 for pyrrolidine synthesis
renders them highly suitable in the implementation of
the desymmetrization strategy, thereby fulfilling the asym-
metric assembly of a structurally diverse spirolactone
and pyrrolidine moiety from a readily available cyclohex-
adienone spirolactone and simultaneous generation of
a unique spiro quaternary stereogenic center. Herein,
we reported the first asymmetric construction of spiro-
lactone-pyrrolidines through Ag-catalyzed desymmetriza-
tion of a prochiral spirolactone via asymmetric 1,3-dipolar
cycloaddition. The advantage of this method is that var-
ious complicated but structurally diverse spiro-lactone-
pyrrolidine derivatives containing one spiro quaternary
and up to five contiguous stereogenic centers could be
efficiently constructed by a single process.
Guided by these considerations and the application of a
desymmetrization strategy,5,7 we began our initial investi-
gation by testing the reaction of prochiral spiro cyclo-
hexadienone butyrolactone 2a and imino ester 3a with the
Cu(I)/rac-TF-BiphamPhos12 (1a) as the catalyst and Et3N
as the base. Gratifyingly, the reaction reached completion
in less than 8 h at room temperature and delivered a single
isomer 4a in 85% yield with excellent diastereoselectivity
(>20:1 dr)13 (Table 1, entry 1). Spirocyclic 4a is stable, and
no further reaction occurred with the remaining CdC
double bond. Encouraged by the initial desymmetriza-
tion results exerted by the Cu(I)/rac-1a complex, we then
conducted the asymmetric variant of this reaction
to evaluate the enantioselectivity with a chiral ligand.
Empolying the Cu(I)/(S)-1a complex as the catalyst, the
adduct 4a was exclusively obtained in good yield with
Table 1. Screening Studies of the Catalytic Asymmetric
Desymmetrization of Spiro Cyclohexadienone Butyrolactone 2aa
entry
L
[M]
solvent t (°C) yield (%)b ee (%)c
1
rac-1a CuBF4 CH2Cl2
(S)-1a CuBF4 CH2Cl2
(S)-1a AgOAc CH2Cl2
(S)-1b AgOAc CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
85
83
85
81
68
74
50
80
82
84
84
88
ꢀ
2
66
94
88
65
67
69
82
88
84
67
97
3
4
5
(S)-1c
(S)-1d AgOAc CH2Cl2
(S)-1e AgOAc CH2Cl2
AgOAc CH2Cl2
6
7
8
(S)-1a AgOAc THF
(S)-1a AgOAc Et2O
(S)-1a AgOAc PhMe
(S)-1a AgOAc MeCN
(S)-1a AgOAc CH2Cl2
9
10
11
12d
a All reactions were carried out with 0.30 mmol of 2a and 0.40 mmol
of 3 in 2 mL of solvent. CuBF4 = Cu(CH3CN)4BF4. b Isolated yield.
c >20:1 dr was determined by crude 1H NMR, and ee was determined by
HPLC analysis. d In 10 h.
excellent diastereoselectivity albeit moderate enantio-
selectivity (66% ee) (entry 2). To our delight, significant
enhancement of the enantioselectivity (94% ee) was
achieved while maintaining high diastereoselectivity by
switching the metal precursor from Cu(CH3CN)4BF4
into AgOAc (entry 3). Then, using AgOAc as the metal
precursor, we then carried out the reaction with other
(S)-TF-BiphamPhos ligands (1bꢀ1e). When the phenyl
group on the phosphorus atom of ligand 1a was replaced
by a bulky xylyl, 3,5-bis(trifluoromethyl)phenyl, or cyclo-
hexyl group, the enantioselectivity of the desymmetriza-
tion product dropped from 94% to 88%, 65%, and
67%, respectively (entries 4ꢀ6). Sterically hindered chiral
ligand 1e afforded almost the same stereoselectivity as the
simple ligand 1a but with much lower reactivity (entry 7).
A subsequent survey of the solvent effect indicated that
CH2Cl2 was the best solvent of choice (entries 8ꢀ11). After
further optimization of the reaction temperature with
ligand 1a, spirolactone-pyrrolidine 4a was isolated in
88% yield, with >20:1 dr and 97% ee after 10 h at 0 °C
(entry 12).
(8) (a) Carney, J. R.; Pham, A. T.; Yoshida, W. Y.; Scheuer, P. J.
Tetrahedron Lett. 1992, 33, 7115. (b) Koike, K.; Suzuki, Y.; Ohmoto, T.
Phytochemistry 1994, 35, 701. (c) Su, J.-Y.; Zhong, Y.-L.; Zeng, L.-M.
J. Nat. Prod. 1993, 56, 288. (d) Murakami, T.; Morikawa, Y.; Hashimoto,
M.; Okuno, T.; Harada, Y. Org. Lett. 2004, 6, 157.
(9) (a) Lehmann, J.; Marquart, N. Synthesis 1987, 1064. (b) Reid,
A. M.; Steel, P. G. J. Chem. Soc., Perkin Trans. 1 1998, 2795. (c) Takagi,
R.; Miyanaga, W.; Tojo, K.; Tsuyumine, S.; Ohkata, K. J. Org. Chem.
2007, 72, 4117.
(10) Harwood, L. M.; Vickers, R. J. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W., Eds.; Wiley & Sons: New York, 2002.
(11) For recent reviews about 1,3-dipolar cycloaddition reactions of
azomethine ylides, see: (a) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008,
ꢀ
108, 2887. (b) Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005,
44, 6272. (c) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784.
(12) (a) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem.
Soc. 2008, 130, 17250. (b) Xue, Z.-Y.; Li, Q.-H.; Tao, H.-Y.; Wang, C.-J.
J. Am. Chem. Soc. 2011, 133, 11757. (c) He, Z.-L.; Teng, H.-L.; Wang,
C.-J. Angew. Chem., Int. Ed. 2013, 52, 2934.
(13) When PPh3 was employed as the ligand, the desymmetrical
cycloadduct was separated in 75% yield along with around 10% of
the uncyclized imine adduct via a Michael addition reaction.
Having observed that Ag-catalyzed desymmetrization
of a prochiral spiro butyrolactone under the above opti-
mized reaction conditions can be realized with highly
Org. Lett., Vol. 15, No. 9, 2013
2251

Table 2. Substrate Scope for Ag-Catalyzed Desymmetrization
of Spiro Cyclohexadienone Butyrolactone 2aa
Table 3. Use of a Variety of R-Substituted Imino Esters for
Ag-Catalyzed Desymmetrization of Spiro Cyclohexadienone
Butyrolactone 2aa
entry
R
4
yield (%)b
ee (%)c
1
p-Cl-C6H4 (3a)
o-Cl-C6H4 (3b)
m-Cl-C6H4 (3C)
p-CF3-C6H4 (3d)
p-CO2Me-C6H4 (3e)
p-NO2-C6H4 (3f)
Ph (3g)
4a
4b
4c
4d
4e
4f
88
80
84
87
89
82
85
81
88
82
88
83
73
78
97
95
95
95
95
98
98
99
96
95
96
93
98
99
2
3
4
5
6
7
4g
4h
4i
8
p-Me-C6H4 (3h)
o-Me-C6H4 (3i)
2-naphthyl (3j)
2-furyl (3k)
9
10
11
12
13d
14d
4j
4k
4l
2-thienyl (31)
Cy (3m)
iBu (3n)
4m
4n
a All reactions were carried out with 0.30 mmol of 2a and 0.40 mmol
of 3 in 2 mL of CH2Cl2. b Isolated yield. c >20:1 dr was determined by
crude 1H NMR, and ee value was determined by HPLC analysis.
d Inorganic base Cs2CO3 was used.
a All reactions were carried out with 0.30 mmol of 2a and 0.40 mmol
of 5 in 2 mL of CH2Cl2. b Isolated yield. c >20:1 dr was determined by
crude 1H NMR and ee value was determined by HPLC analysis.
stereoselective control, we then decided to investigate the
substrate scope of this process. We were pleased to find
that a wide array of imino esters 3 derived from aromatic
aldehydes bearing electron-deficient(Table 2, entries 1ꢀ6),
electron-neutral (entry 7), and electron-rich substituents
(entries 8 and 9) on the aryl rings reacted smoothly with
spirolactone 2a, affording the corresponding spiro hetero-
cyclic products in good to high yields (81ꢀ89%), with
excellent diastereoselectivities (>20:1 dr) and high enan-
tioselectivities (95ꢀ99% ee). The substitution pattern of
the arene had little effect on the selectivity of the reaction,
and ortho-substituted imino ester 3b and 3i were readily
applicable in this desymmetrization leading exclusively to
the desiredspirolactone-pyrrolidines4band 4iwith95% ee
and 96% ee, respectively (entries 2 and 9). Additionally,
heteroaromatic derived imino ester 3k and 3l underwent
this transformation as 2-naphthylaldehyde derived imino
ester 3j, affording the corresponding adducts in good
yields with excellent diastereo-/enantioselectivity (entries
10ꢀ12). It is noteworthy that less reactive alkyl imino
esters11 3m and 3n were also readily applicable in this
desymmetrization process with Cs2CO3 as the base, deli-
vering the desired adducts ingood yield with98%and 99%
ee, respectively (entries 13 and 14).
the corresponding spirolactone-pyrrolidines. The results
are summarized in Table 3. Gratifyingly, (()-alanine de-
rived imino esters have proved to be excellent substrates
affording the desired spiro adducts in good yields with
excellent diastereo-/enantioselectivities, regardless of the
position and electronic property of the substituents on
the aromatic ring (Table 3, entries 1ꢀ6). Noticeably, up
to 98% ee was still obtained for heteroaromatic 2-furyl
derived imino ester 5g (entry 7). Furthermore, imino esters
derived from other R-substituted amino acids have also
been examined for this transformation. Under the opti-
mized reaction conditions, a satisfactory yield and an
excellent stereoselectivity were uniformly observed for the
imino esters derived from (()-2-aminobutyric acid, (()-2-
aminopentanoic acid, (()-leucine, and (()-phenylalanine
(entries8ꢀ11). Additionally, (()-homoserinederivedcyclic
imino ester 5l worked well in this reaction (98% ee), giving
the desired highly functionalized spirocyclic 6l containing
two spiro γ-butyrolactone moieties (entry 12).
Finally, in order to investigate more deeply the scope
and generality of this desymmetrization reaction, other
prochiral spirolactones were also examined under the
optimized reaction conditions. As shown in Table 4, spiro
cyclohexadienone-butenolide 7a and 7b bearing different
substituents on the lactone ring proved to be excellent
substrates for this tranformation affording good yields
and excellent diastereo-/enantioselectivities (Table 4,
Encouraged by the desymmetrization results for less
sterically hindered imino esters from glycinate, we then
investigated this reaction with the challenging imino ester
derived from various R-substituted amino acids, from
which a nitrogen-substitutedquaternary stereogenic center
was generated along with one spiro stereogenic center in
2252
Org. Lett., Vol. 15, No. 9, 2013

Table 4. Enantioselective Desymmetrization of Spiro
Cyclohexadienone Butenolides and Spiro Cyclohexadienone
Pentylolactonea
Scheme 1. Synthetic Transformations
according to crystal X-ray analysis of 10. Remarkably, the
desymmetrization and subsequent sulfa-Michael addition
reaction could be carried out via a one-pot protocol in
higher yield without loss of diastereomeric and enantio-
meric excess.
In summary, we have developed the first catalytic
asymmetric synthesis of highly functional spirolactone-
pyrrolidine derivatives bearing five contiguous stereocenters
and one unique spiro quaternary stereocenter through
enantioselective desymmetrization of a prochiral spirodie-
none-lactone via silver-catalyzed asymmetric 1,3-dipolar
cycloaddition. This catalytic system exhibited excellent
diastereoselectivity, enantioselectivity, and a broad sub-
strate scope. Notably, this methodology presented herein
could reveal new prospects in the stereoselective construc-
tion of spirolactone-pyrrolidine derivatives, a valuable
structural motif for drug discovery. Efforts are currently
underway to elucidate the mechanistic details as well as
scope and limitations of this reaction.
a All reactions were carried out with 0.30 mmol of 7 and 0.40 mmol of
3 in 2 mL of CH2Cl2. b Isolated yield. c >20:1 dr was determined by
crude 1H NMR and ee value was determined by HPLC analysis.
entries 1 and 2). Spiro cyclohexadienone phthalanone 7c
was tested as a prochiral partner in this reaction, and 96%
ee was achieved for the desired adduct 8c (entry 3). More-
over, desymmetrization of spiro cyclohexadienone penty-
lolactone 7d was also tolerated in this catalytic system.
The relative and absolute configuration of product 8b
catalyzed by Ag(I)/(S)-1a was unequivocally determined
as (10S,2S,30R,3a0S,7a0R) by X-ray diffraction analysis.
The optically active spirolactone-pyrrolidines can serve
as precursors for other stereochemically rich structures
(Scheme 1). Chemoselective reduction of the CdC bond of
4a with Rh/Al2O3 and Adams’ catalyst afforded 9 in 85%
yield. Upon treatment of 4a with thiophenol in the pre-
sence of a catalytic amount of Et3N, the highly functiona-
lized sulfa-Michael adduct 10 was obtained in an excellent
diastereoselective manner, and the generated sixth stereo-
genic center was determined to possess an R configuration
Acknowledgment. This work is supported by the 973
Program (2011CB808600), the National Natural Science
Foundation of China (20972117, 21172176), NCET-10-
0649, IRT1030, the Fundamental Research Funds for the
Central Universities, and Large-scale Instrument And
Equipment Sharing Foundation of Wuhan University.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
2253