Desymmetrization of bicyclo[3. n.1]-3-one derivatives by palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/ol4016207

Desymmetrization of carbon nucleophiles by palladium-catalyzed asymmetric allylic alkylation has been realized for the first time. Products with three chiral centers were obtained in good yield and with high diastereo- and enantioselectivity. The method o

Full text of DOI:10.1021/ol4016207

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3880–3883
Desymmetrization of Bicyclo[3.n.1]-3-one
Derivatives by Palladium-Catalyzed
Asymmetric Allylic Alkylation
Yang Yu,† Xiao-Fei Yang,† Chao-Fan Xu,† Chang-Hua Ding,*,† and Xue-Long Hou*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai-Hong Kong Joint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
dingch@sioc.ac.cn; xlhou@sioc.ac.cn
Received June 9, 2013
ABSTRACT
Desymmetrization of carbon nucleophiles by palladium-catalyzed asymmetric allylic alkylation has been realized for the first time. Products with
three chiral centers were obtained in good yield and with high diastereo- and enantioselectivity. The method offers an efficient access to optically
active tropane derivatives.
The tropane (8-azabicyclo[3.2.1]octane) ring system is
present in a variety of valuable biologically active natural
alkaloids such as atropine, scopolamine, and cocaine.1 The
synthesis of functionalized tropanes has attracted the
attention of synthetic chemists due to their important
role in accessing tropane alkaloids and their analogues.2
Existing methods for the enantioselective synthesis of
tropane derivatives rely heavily on the use of chiral build-
ing blocks, auxiliaries, and reagents.2 The development of
a catalytic asymmetric route would be highly desirable.
Enantioselective desymmetrization of a prochiral or
meso substrate is a powerful synthetic tool for the synthesis
of a range of optically active molecules.3 Although many
impressive advances have been realized, the reactions
available for catalytic asymmetric desymmetrization are still
limited. Palladium-catalyzed asymmetric allylic alkylations
(2) For a review, see: (a) Pollini, G. P.; Benetti, S.; De Risi, C.;
Zanirato, V. Chem. Rev. 2006, 106, 2434. For some examples, see:
(b) Zhang, Y.; Liebeskind, L. S. J. Am. Chem. Soc. 2006, 128, 465.
(c) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312.
(d) Garnier, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 7449.
(e) Sienkiewicz, M.; Wilkaniec, U.; Lazny, R. Tetrahedron Lett. 2009, 50,
7196. (f) Shing, T. K. M.; So, K. H. Org. Lett. 2011, 13, 2916. (g) Schultz,
D. M.; Wolfe, J. P. Org. Lett. 2011, 13, 2962. (h) Cheng, G.; Wang, X.;
Zhu, R.; Shao, C.; Xu, X.; Hu, Y. J. Org. Chem. 2011, 76, 2694. (i) Brock,
E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett.
ꢀ
2012, 14, 4278. (j) Cordova, A.; Lin, S.; Tseggaia, A. Adv. Synth. Catal.
2012, 354, 1363. (k) Hodgson, D. M.; Charlton, A.; Paton, R. S.;
Thompson, A. L. J. Org. Chem. 2013, 78, 1508. (l) Ischay, M. A.;
Takase, M. K.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013,
135, 2478.
† State Key Laboratory of Organometallic Chemistry.
‡ Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai
Institute of Organic Chemistry.
(1) (a) Lounasmaa, M.; Tamminen, T. In The Tropane Alkaloids in
Alkaloids; Academic Press: New York, 1993; p 1. (b) Fodor, G.;
Dharanipragada, R. Nat. Prod. Rep. 1994, 11, 443. (c) O’Hagan, D.
Nat. Prod. Rep. 2000, 17, 435.
(3) Reviews: (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999,
´
1765. (b) Garcıa-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005,
105, 313. (c) Rovis, T. In New Frontiers in Asymmetric Catalysis; Mikami,
K., Lautens, M., Eds.; Wiley: 2007; p 275.
r
10.1021/ol4016207
Published on Web 07/19/2013
2013 American Chemical Society

(AAA) have proven to be some of the most important
methods for the asymmetric formation of CÀC and CÀX
bonds.4 These reactions have been demonstrated success-
fully in the desymmetrization of meso-allylic substrates.5
In sharp contrast, examples of the desymmetrization of
nucleophiles are very scarce and only isolated cases have
been reported using O- or N-nucleophiles.6 Recently, the
desymmetrization of meso-carbon nucleophiles through
dual palladium- and proline-catalyzed allylic alkylation
We commenced our studies using 8-allyl-nortropan-3-
one (1a) as a model substrate. Initially, the nortropan-3-one
1a was subjected to a reaction with allyl reagent 2a under
the effect of the catalyst derived from [Pd(η3-C3H5)Cl]2
and (Rphos,Ra)-L1 in the presence of LiHMDS (entry 1,
Table 1). Allylation product 3a was afforded in 43%
yield and with 71% ee and excellent diastereoselectivity.
Encouraged by these results, the impact of the chiral
ferrocene-based SIOCPhox ligands on the reaction was
investigated (Figure 1). Ligand (Sphos,Ra)-L2 gave much
lower ee compared with (Rphos,Ra)-L1 (entry 2 vs 1,
Table 1), which indicated that the chiralities in the ligand
L1 were matched. Further investigation of different com-
binations of chiral elements in the ferrocene-based ligands
SIOCPhox uncovered that the chiralities in the ligand
(Sc,Sphos,Sa)-L6 were matched (entries 3À6, Table 1).
Then the influence of substituents on the oxazoline ring
of SIOCPhox was examined (entries 6À8, Table 1) and the
(Sc,Sphos,Sa)-L6 with isopropyl as the substituent proved
to be the best ligand, affording the allylated product 3a in
74% ee andin 44%yield. Theuseof (Sc,Sphos,Sa)-L7 ledto
a higher yield but an inferior enantiomeric ratio compared to
(Sc,Sphos,Sa)-L6 (entry 6 vs 7, Table 1). With (Sc,Sphos,Sa)-
L6 as the ligand, the allyl reagents 2 were evaluated
(entries 9À11, Table 1). It was found that the acetate 2b
was superior in terms of the enantioselectivity (entry 9,
Table 1). The yield decreased to 19% when the allyl 2c was
employed while 80% ee was obtained (entry 10, Table 1).
ꢀ
was reported with moderate diastereoselectivity by Cordova
and Breit respectively, but enantioselective control was not
realized.7 On the basis of our recent work on Pd-AAA using
enolates as nucleophiles,8 we envisioned that desymmetriza-
tion of 8-azabicyclo[3.2.1]-3-one by Pd-AAA might provide
a possible method for the synthesis of optically active
tropane derivatives bearing three chiral centers. In this
communication, we disclose our preliminary results on this
study.
Table 1. Influence of Ligand and Allyl Substrates on the Pd-
Catalyzed Desymmetrization of 8-Allyl-nortropan-3-one (1a)a
Figure 1. Ferrocene-based ligands SIOCPhox.
(4) (a) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catal-
ysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Vol. 2, p 833. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003,
103, 2921. (c) Lu, Z.; Ma, S. M. Angew. Chem., Int. Ed. 2008, 47, 258.
(5) Review: (a) Trost, B. M. Isr. J. Chem. 1997, 37, 109. For some
recent examples, see: (b) Stragies, R.; Blechert, S. J. Am. Chem. Soc.
2000, 122, 9584. (c) Trost, B. M.; Dirat, O.; Dudash, J., Jr.; Hembre, E. J.
Angew. Chem., Int. Ed. 2001, 40, 3658. (d) Piarulli, U.; Daubos, P.;
Claverie, C.; Roux, M.; Gennari, C. Angew. Chem., Int. Ed. 2003, 42,
234. (e) Piarulli, U.; Claverie, C.; Daubos, P.; Gennari, C.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2003, 5, 4493. (f) Trost, B. M.; Aponick,
A. J. Am. Chem. Soc. 2006, 128, 3931. (g) Chapsal, B. D.; Ojima, I. Org.
Lett. 2006, 8, 1395. (h) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006,
128, 6054.
yield
(%)b
ee
entry
2
ligand
drc
(%)c
1
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2b
(Rphos,Ra)-L1
43
41
43
36
48
44
66
40
43
19
45
35
99/1
67
32
32
7
2
(Sphos,Ra)-L2
99/1
3
(Sc,Rphos,Ra)-L3
(Sc,Sphos,Ra)-L4
(Sc,Rphos,Sa)-L5
(Sc,Sphos,Sa)-L6
(Sc,Sphos,Sa)-L7
(Sc,Sphos,Sa)-L8
(Sc,Sphos,Sa)-L6
(Sc,Sphos,Sa)-L6
(Sc,Sphos,Sa)-L6
(Sphos,Sa)-L9
99/1
4
63/1
(6) (a) Jiang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411. (b) Kitagawa,
O.; Yotsumoto, K.; Kohriyama, M.; Dobashi, Y.; Taguchi, T. Org. Lett.
2004, 6, 3605. (c) Kitagawa, O.; Matsuo, S.; Yotsumoto, K.; Taguchi, T.
J. Org. Chem. 2006, 71, 2524.
5
>99/1
>99/1
>99/1
>99/1
99/1
7
6
74
47
47
81
80
64
1/2
7
8
ꢀ
(7) (a) Ibrahern, I.; Cordova, A. Angew. Chem., Int. Ed. 2006, 45,
9
1952. (b) Usui, I.; Schmidt, S.; Breit, B. Org. Lett. 2009, 11, 1453.
(8) (a) Yan, X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.;
Dai, L.-X.; Hou, X.-L. Angew. Chem., Int. Ed. 2005, 44, 6544. (b) Zheng,
W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. J. Am. Chem. Soc. 2007,
129, 7718. (c) Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y.-D. Angew.
Chem., Int. Ed. 2008, 47, 1741. (d) Liu, W.; Chen, D.; Zhu, X.-Z.; Wan,
X.-L.; Hou, X.-L. J. Am. Chem. Soc. 2009, 131, 8734. (e) Lei, B.-L.;
Ding, C.-H.; Yang, X.-F.; Wan, X.-L.; Hou, X.-L. J. Am. Chem. Soc.
2009, 131, 18250. (f) Chen, J.-P.; Ding, C.-H.; Liu, W.; Hou, X.-L.; Dai,
L.-X. J. Am. Chem. Soc. 2010, 132, 15493.
10
11
12d
99/1
49/1
1/1.3
a Molar ratio of [Pd(η3-C3H5)Cl]2/L/1a/2/LiHMDS/LiCl = 2.5/5/
100/150/100/400. b Isolated yield. c Determined by chiral GC. d Com-
pound 1c was used as substrate.
Org. Lett., Vol. 15, No. 15, 2013
3881

The ee value decreased to 64% in the case of the carbonate
2d (entry 11, Table 1). The phenolic hydroxyl group of the
SIOCPhox ligand was important to achieve high selectiv-
ity because a SIOCPhox L9 bearing no ÀOH group gave
both low diastereoselectivity and low enantioselectivity
(entry 12, Table 1).
epimerization of the product 3a. Lowering the reaction
temperature increased the diastereo- and enantioselectivity
(entries 9 vs 8, Table 2). The results did not improve by
using 3 equiv of LiHMDS (entry 10, Table 2).
The scope of the reaction was examined, and the results
are compiled in Figure 2. A variety of 8-azabicyclo[3.n.1]-
3-one gave the corresponding allylation products in good
yield (3aÀ3g). Excellent diastereo- and enantioselectivities
werealsorealizedforN-methyltropinone, withthedrbeing
33:1, while the ee value was 91% (3b). The substituents on
the nitrogen atom of the nortropan-3-one 1 affected the
selectivity (3c and 3d). Employing N-benzyltropinone as
the substrate led to lower diastereo- and enantiomeric
excesses (3c). Replacing the methyl group with a phenyl
group in nortropan-3-one 1 gave a moderate diastereo-
meric excess, but the enantioselectivity remained excellent
(3d). The reaction also occurred with excellent diastereo-
and enantioselectivities for pseudopelletierine, with a 19:1
dr and 96% ee for product 3e. 10-Methyl-10-aza-bicyclo-
[4.3.1]decan-8-one was also a suitable substrate to give
product (3f); however, the diastereomeric ratio was 1:1 in
this case. Substituting t-BuOK for LiHMDS afforded the
product 3f with an improved diastereomeric ratio (15:1),
The additives played an important role in the Pd-
catalyzed AAA using enolates as nucleophiles.8aÀd,9 Here-
in, we found some salts had dramatic effects on the yield
and enantioselectivity of the reaction. The screening of
additives revealedthatboth the lithium cation and chloride
anion were crucial for the reaction. The absence of LiCl
resulted in a sharp decrease in yield and enantioselectivity
(entry 2 vs 1, Table 2). The use of other additives contain-
ing either a chloride anion or lithium cation gave inferior
results compared with the use of LiCl (entries 3À6 vs 1,
Table 2). We were delighted to observe the yield and
enantioselectivity increased dramatically by raising the
ratio of LiHMDS to the nortropan-3-one 1a (entries
7À9, Table 2). Allylated product 3a was produced in
68% yield and with 94% ee when 2 equiv of LiHMDS
were used (entry 9, Table 2). We have no clear explanation
for the phenomena at present. The presence of excess
LiHMDS resulted in a decrease of diastereoselectivity
(entry 8 vs 1, Table 2), which may be attributed to the
Table 2. Effect of Additive and Amount of LiHMDS on the Pd-
Catalyzed Desymmetrization of 8-Allyl-nortropan-3-one (1a)a
base
yield
(%)b
ee
(%)c
entry
(equiv)
additive
drc
1
1
LiCl
43
27
37
30
18
9
99/1
>99/1
99/1
32/1
25/1
26/1
31/1
20/1
32/1
28/1
81
56
46
15
73
46
89
89
94
93
2
1
À
3
1
nBu4NCl
ZnCl2
LiClO4
LiBr
LiCl
4
1
5
1
6
1
7
1.2
1.5
2
52
60
68
65
8
LiCl
9d
10d
LiCl
3
LiCl
a Molar ratio of [Pd(η3-C3H5)Cl]2/L6/1a/2b/LiHMDS/additive =
2.5/5/100/150/100À300/400. b Isolated yield. c Determined by chiral GC.
d Reaction run at 0 °C.
(9) For a review on additive effects in asymmetric catalysis, see:
€
Figure 2. Substrate scope for desymmetrization of bicyclo-
[3.n.1]-3-one by Pd-catalyzed AAA reaction. Molar ratio of
[Pd(η3-C3H5)Cl]2/L6/1/2/LiHMDS/LiCl = 2.5/5/100/150/200/
400. Reaction time: 24 h. Isolated yield; ee determined by chiral
GC or HPLC. at-BuOK used as base. bdr of the product 3f was
reduced to 2/1 after purification due to easy epimerization.
(a) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570. For some reports on the LiCl effect in the Pd-catalyzed
€
AAA reaction, see: (b) Sjogren, M. P. T.; Hansson, S.; Akermark, B.;
Vitagliano, A. Organometallics 1994, 13, 1963. (c) Burckhardt, U.;
Baumann, M.; Togni, A. Tetrahedron: Asymmetry 1997, 8, 155. (d)
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. (e) Cantat,
ꢀ
T.; Genin, E.; Giroud, C.; Meyer, G.; Jutand, A. J. Organomet. Chem.
2003, 687, 365.
3882
Org. Lett., Vol. 15, No. 15, 2013

Scheme 1. Conversion of Product 3a into Compound 5
Figure 3. ORTEP drawing of Compound 5.
In conclusion, desymmetrization of carbon nucleophiles
by palladium-catalyzed asymmetric allylic alkylation has
been realized for the first time. The resulting products with
three chiral centers were obtained in good yield and with
highdiastereo- and enantioselectivity. The ferrocene-based
SIOCPhox ligand proved to be highly effective. The
method provides efficient access to chiral tropane deriva-
tives, which may find application in the enantioselective
synthesis of tropane alkaloids. Further investigations into
the reaction scope and identifying possible applications of
the methodology in organic synthesis are underway.
excellent ee, and good yield. Unfortunately, the dr was
reduced to 2:1 during purification by column chromat-
graphy on silica gel due to the easy epimerization of the
product 3f. Cinnamyl acetate was subjected to the reaction
with 8-allyl-nortropan-3-one (1a) in the presence of
t-BuOK. The allylation product 3g was obtained with 9:1
dr and 98% ee; however, the yield was only 25%. The low
yield is attributable to a low conversion. Other types of
bicyclic ketones were also examined. It is interesting to
note that the reaction led to excellent diastereomeric and
enantiomeric ratios when bicyclo[3.2.1]octan-3-one was
used (3h). However, lower enantioselectivity was observed
from the reaction with bicyclo[3.3.1]nonane-3-one as the
substrate (3i). A 1,3-disubstituted allylic acetate, (E)-1,3-
diphenylallyl acetate, was reacted with 8-benzyl-8-azabicyclo-
[3.2.1]octan-3-one (1c) under optimized reaction conditions.
However, no allylic alkylation occurred and compound 1c
was recovered in 91% yield.
Acknowledgment. Financially supported by the Major
Basic Research Development Program (2010CB833300),
National Natural ScienceFoundation of China(21121062,
21002113, 21032007), the External Cooperation Program
of Chinese Academy of Sciences, the Technology Commis-
sion of Shanghai Municipality, and the Croucher Founda-
tion of Hong Kong.
Allylated product 3a was converted to ester 4 by
DIBAL-H reduction and esterfication. The reaction of 4
with hydrogen chloride provided 5 (Scheme 1). Its X-ray
diffraction analysis showed the absolute configuration of
product 5 to be (1R,2R,3S,5S) (Figure 3). Accordingly, the
allylated product 3a has the (1R,2R,5S) configuration.
Supporting Information Available. Experimental proce-
dure, spectral data of compounds 3À5. This material 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. 15, 2013
3883