Aromatic spiroketal bisphosphine ligands: Palladium-catalyzed asymmetric allylic amination of racemic Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1002/anie.201204925

Showing a backbone: The spiroketal backbone of the bis(phosphine) ligand 1 led to good regio- and enantioselectivity in the palladium-catalyzed asymmetric allylic amination of racemic Morita-Baylis-Hillman adducts with aromatic amines. The methodology provides a facile and efficient synthesis of precursors for optically active β-lactam derivatives, including the cholesterol drug Ezetimibe.

Full text of DOI:10.1002/anie.201204925

Angewandte
Chemie
DOI: 10.1002/anie.201204925
Asymmetric Catalysis
Aromatic Spiroketal Bisphosphine Ligands: Palladium-Catalyzed
Asymmetric Allylic Amination of Racemic Morita–Baylis–Hillman
Adducts**
Xiaoming Wang, Fanye Meng, Yan Wang, Zhaobin Han, Yong-Jun Chen, Li Liu,* Zheng Wang,*
and Kuiling Ding*
The design of chiral ligands plays a central role in the
development of chiral catalysts for asymmetric reactions, in
which the right combination of a sterically well-defined
scaffold with a chelating moiety can lead to excellent
enantioselective control in the catalysis.[1] From this point of
view, spirobackbones (Scheme 1) have been recognized as
one of the privileged structures for the construction of chiral
which have an interesting spiro-2,2’-bis(chroman) backbone
and their transition-metal complexes have been studied in
catalysis.[4] Despite the success of their rhodium(I) complexes
in the catalysis of methanol carbonylation,[4c] the application
of spiro-2,2ꢀ-bis(chroman)-based chiral ligands in asymmetric
catalysis still remains relatively unexplored.[4e,g,5]
Very recently, we developed a catalytic asymmetric syn-
thesis of aromatic spiroketals by the tandem hydrogenation
and spiroketalization of a,a’-bis(2-hydroxyarylidene)keto-
nes[6a] using Ir/SpinPHOX as the catalyst,[6] and it provides
a facile and practical synthesis of a new type of enantiopure
analogoue to SPANphos, namely SKP (1). In our ongoing
endeavor towards seeking new spirochiral ligands for asym-
metric catalysis, we communicate herein our preliminary
results on the synthesis of one type of chiral bisphospine
ligand having an aromatic spiroketal motif (1; SKP) and their
application in palladium-catalyzed enantioselective allylic
amination of racemic Morita–Baylis–Hillman (MBH)
adducts[7] with aromatic amines. The developed methodology
has provided a facile and efficient synthesis of optically active
b-lactam derivatives,[8] including the chiral drug Ezetimibe
which is used to treat high cholesterol.[9]
As shown in Scheme 2, synthesis of the enantiopure spiro-
2,2’-bis(chroman)-based bishosphine ligands (R,R,R)-1 is
quite simple and straightforward from readily available
a,a’-bis(2-hydroxy-3-bromophenylidene)ketone (2) by using
our previously published procedure.[6a] The key intermediate,
the 3-bromo-substituted aromatic spiroketal (R,R,R)-3 was
treated with nBuLi and the resulting lithium salt was reacted
with Ar2PCl in THF to afford the corresponding enantiopure
spiroketal-based bisphosphine ligands (R,R,R)-1a–f in mod-
erate to good yields (40–80%) on gram scale.
Optically active a-alkylidene-b-arylamino carbonyl com-
pounds represent one type of valuable building blocks with
wide applications in the synthesis of medicinally relevant
molecules and natural products,[10] but these building blocks
are not readily accessible using direct asymmetric aza-MBH
reactions because of the electron-rich nature of the corre-
sponding N-aromatic imines.[7,11] In contrast, the enantiose-
lective, metal-catalyzed allylic amination is a useful method
for the preparation of enantiomerically enriched allylic
amines.[12] Despite the success of palladium- or organocata-
lyzed asymmetric allylic aminations of esters of racemic MBH
adducts using cyclic imides, aliphatic amines, or benzophe-
none imines as nucleophiles,[10] the amination of racemic
acyclic MBH adducts using less-nucleophilic aromatic amines
to afford the corresponding optically active a-alkylidene-b-
Scheme 1. Spiro-backbone-based bisphosphine ligands.
ligands[2] ever since the pioneering work by Chan et al.
(SpirOP), Sasai and co-workers, and Zhou and co-workers
(SDP).[3] In contrast, van Leeuwen and co-workers reported
the development of the bisphosphine ligands SPANphos
[*] X. M. Wang, F. Y. Meng, Dr. Z. Han, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
E-mail: wzsioc@mail.sioc.ac.cn
kding@mail.sioc.ac.cn
Y. Wang, Prof. Dr. Y. J. Chen, Prof. Dr. L. Liu
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS
Key Laboratory for Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: lliu@iccas.ac.cn
[**] We thank the NSFC (grant nos. 21172237, 21121062, 21032007),
Major Basic Research Development Program of China (grant no.
2010CB833300), and the Chinese Academy of Sciences for financial
support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204925.
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Table 1: Catalytic asymmetric allylic amination of 4a with aniline 5a
catalyzed by palladium complexes of various enantiopure bisphosphine
ligands.[a]
Scheme 2. Synthesis of enantiopure the spiro-2,2’-bis(chroman)-based
bisphosphine ligands (R,R,R)-1a–f.
arylamino carbonyl compounds still remains underdevel-
oped.[13] With the spiro-bisphosphine ligands (R,R,R)-1a–f in
hand, we then investigated their application in palladium-
catalyzed asymmetric allylic amination of acyclic MBH
Entry
Ligand
6aa/7aa[c]
6aa
Yield [%][b]
ee [%][d]
adducts using aromatic amines as the nucleophiles.[14]
A
preliminary survey of the reaction conditions was conducted
for the amination of the methyl ester of a MBH adduct with
aniline (5a) as the nucleophile using the complexes generated
in situ from (R,R,R)-1a (2.5 mol%) and a variety of palla-
dium precursors ([Pd] = 2 mol%) as the catalysts. Many
reaction parameters were found to have impact on the
reactivity as well as the regio- and enantioselectivities. As
shown in Tables S1–S5 in the Supporting Information, the
reaction performed in CH2Cl2 by using [{Pd(h3-C3H5)Cl}2] as
the catalyst precursor at room temperature with aqueous
K2CO3 as the base and the ethyl ester of the MBH adduct (4a)
as the substrate turned out to be optimal, thus affording the
corresponding amination product in 90% yield with a 94:6
regioselectivity for 6aa/7aa and 93% enantioselectivity
(Table 1; entry 1). Under the optimized reaction conditions,
a variety of spiroketal-based bisphosphine ligands [(R,R,R)-
1b–f] with different aryl substituents at the P atom were then
evaluated to further improve the enantioselectivity of the
catalysis. As shown in Table 1, the steric hindrance of the aryl
groups on P has a significant impact on the asymmetric
induction in the catalysis (entries 1–4). The ligand (R,R,R)-1b
having 2-tolyl moieties on the P atoms obviously deteriorates
the catalytic activity and enantioselectivity (entry 2) in
comparison with the analogous variants (entry 2 versus
entries 3–5 and 1). The introduction of the electron-with-
drawing F group on the aryl rings appended to P slightly
decreases the enantioselectivity of the reaction (entry 6). The
ligand (R,R,R)-1c with 3,5-xylyl groups on P turned out to be
the best in terms of both reactivity and enantioselectivity, thus
affording the corresponding amination product (+)-6aa in
89% yield with a 92:8 regioselectivity and 96% ee (entry 3).
1
2
3
4
5
6
7
8
9
10
(R,R,R)-1a
(R,R,R)-1b
(R,R,R)-1c
(R,R,R)-1d
(R,R,R)-1e
(R,R,R)-1 f
(+)-SPANphos
(R)-binap
(R)-SDP
94:6
90:10
92:8
95:5
92:8
90
71
89
89
90
87
55
6
93
59
96
95
93
89
39
10
11
92:8
66:34
13:87
20:80
31:69
10
25
(R,R)-Trost ligand
À21
[a] Unless otherwise noted, the reactions were performed with 4a
(0.1 mmol) and 5a (0.3 mmol) in CH2Cl2 (1 mL) for 3 h. [b] Yield of the
isolated 6aa. [c] Determined by 1H NMR spectroscopy. [d] The ee value
of 6aa was determined by chiral HPLC with a chiral AD-H column.
The SPANphos developed by van Leeuwen was also resolved
and examined in the model reaction, and afforded (+)-6aa in
55% yield with moderate regio- and enantioselectivities
(entry 7). It is noteworthy that the application of some
privileged ligands,[1d] such as (R)-binap, (R)-SDP or (R,R)-
Trost ligand, in the catalysis only afforded poor catalytic
performance (entries 8–10), thus indicating the unique fea-
ture of the present spiroketal skeleton of the bisphosphine
ligand in this catalytic system. Although we are unable to
clarify the underlying reason for the outstanding catalytic
performance of the SKP-type ligands at the present stage,
a relatively large bite angle of chelating P atoms and the
unique geometry of the backbone in the ligand seems to be
critically important for the regio- and stereocontrol of the
catalysis.
With the optimized catalyst and reaction conditions in
hand, we then investigated the substrate scope of the catalysis.
2
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Table 2: Catalytic asymmetric allylic amination of MBH adducts 4 with various aromatic amines 5 catalyzed by Pd/(R,R,R)-1c.[a]
Entry
6
6/7[c]
8
Yield
[%][b]
ee
Yield
[%][b]
ee
[%][d]
[%][d]
1
2
3
4
5
6
7
6aa
6ab
6ac
6ad
6ae
6af
89
88
89
83
67
91
86
96
95
95
95
95
95
96
92:8
8aa
8ab
8ac
8ad
8ae
8af
85
94
79
73
72
81
74
96
95
95
95
95
97
97
91:9
92:8
90:10
75:25
93:7
95:5
6ag
8ag
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Table 2: (Continued)
Entry
6
6/7[c]
8
Yield
[%][b]
ee
Yield
[%][b]
ee
[%][d]
[%][d]
8
6ah
85
96
91:9
8ah
74
96
9
6ba
6ca
6da
6ea
6 fa
64
89
90
96
96
91
97
95
95
97
92:8
92:8
8ba
8ca
8da
8ea
8 fa
83
90
92
74
73
91
97
95
94
96
10
11
12
13
96:4
>98:2
97:3
14
6ga
6ha
6ia
6lc
85
90
83
87
97
96
98
94
91:9
93:7
90:10
92:8
8ga
8ha
8ia
8lc
80
93
82
75
97
94
96
94
15
16
17[e]
[a] Unless otherwise noted, the reactions were performed with 4 (0.5 mmol) and 5 (1.5 mmol) in CH2Cl2 (5 mL) for 3 h. [b] Yield of the isolated
product. [c] Determined by 1H NMR spectroscopy. [d] The ee value is determined by HPLC using a chiral column.
[e] 1.5 mol% [{Pd(h3-C3H5)Cl}2]/(R,R,R)-1c was used. TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
As shown in Table 2, the allylic amination of the racemic
MBH adduct with various aromatic amines using the Pd/
(R,R,R)-1c catalyst is quite general. The reaction proceeded
smoothly to afford the corresponding optically active amina-
tion products 6 in high yields (up to 96%) with excellent
regioselectivities (up to > 98:2) and enantioselectivities (up to
4
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98% ee). Neither the electronic property nor the steric
hindrance of the aromatic amine (R2) had an obvious
influence on the enantioselectivity (Table 2, entries 1–8), but
there was a slight negative effect, with regard to sterics, on the
reactivity and regioselectivity (entry 5). Substituents on the
aryl ring of the MBH adducts seem to have negligible effect
on the catalytic performance (entries 9–17). The optically
active allylic amination products 6 can be readily transformed
into their corresponding b-lactam derivatives 8 in good yields
without loss of enantioselectivity by reaction with Sn[N-
(TMS)2]2 in refluxing toluene.[15] It has been recognized that
1,4-diaryl-2-azetidinones (b-lactam) represents one type of
potentially useful scaffolds for the development of antitumor
agents that target tubulin.[8f] In particular, the molecules
containing a 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, or 4-
methoxy-3-hydroxyphenyl moiety displayed the most potent
antiproliferative activity in inhibiting tubulin polymerization
for human MCF-7 and MAD-MB-213 breast cancer cell lines
without significant cytotoxicity in normal murine breast
epithelial cells.[8f] Therefore, we further investigated the
reaction of the methoxy-substituted MBH adducts with
methoxy-substituted anilines using this catalyst system. As
shown in entries 18–21 of Table S6 in the Supporting Infor-
mation, all the examined reactions proceeded very well to
afford the corresponding allylic amination products 6 in
excellent yields (84–92%), regio- (91:9–98:2) and enantiose-
lectivities (93–98%). The resultant amination products were
converted into the corresponding b-lactam derivatives 8
without loss of enantioselectivity (95–98% ee). The reaction
of the substrates containing a fluorine atom (entries 22–23,
Table S6) afforded the corresponding optically active fluo-
rine-containing[16] amination products and the b-lactam
derivatives in good yields with excellent regio- and enanio-
selectivities. The absolute configuration of (+)-8ad was
established by X-ray crystal diffraction analysis (Figure 1) to
be S and the absolute configurations of the analogous b-
lactam products were deduced by comparison of their Cotton
effects with those of (S)-(+)-8ad as shown in the circular
dichroism (CD) spectra (see the Supporting Information).
To demonstrate the utility of the present methodology, the
optically active a-methylene b-lactam derivative (S)-8aa was
subjected to chemical transformations into several types of
biologically interesting b-lactam derivatives. As shown in
Scheme 3, the hydrogenation of (S)-8aa in the presence of
5 mol% of Pd/C gave (3R,4R)-9a as the major diastereomer
(97:3 d.r.) in 91% yield.[17a] The reaction of (S)-8aa with
Scheme 3. Transformation of (S)-8aa into a variety of biologically
interesting b-lactam derivatives (9a–e). NMO=N-meth-ylmorpholine
N-oxide.
CH2N2 in CH2Cl2 afforded the corresponding cyclopropane
derivative (S)-9b in 85% yield with the retention of
stereochemistry at the b position. Dihydroxylation of (S)-
8aa in the presence of OsO4 and NMO gave (3S,4R)-9c with
high diastereoselectivity (95:5 d.r.) in 96% yield. The [3+2]
cycloaddition of (S)-8aa with diphenylnitrone yielded the
corresponding spiroisoxacolidine adduct (3S,4S,7S)-9d in
92% yield with a 93:7 d.r. and 93% ee.[17b] Finally, the cross-
metathesis of (S)-8aa with 1-hexene in the presence of the
Grubbs II catalyst results in the formation of the butyl-
substituted a-methylene b-lactam derivative (S)-9e with a Z/
E ratio of 1.4:1. All these transformations clearly indicate the
synthetic advantages of a-methylene moiety in the optically
active b-lactam scaffold, thus providing a useful platform for
the synthesis of various biologically interesting b-lactam
derivatives.
Encouraged by the results mentioned above, we subse-
quently employed our methodology in the asymmetric syn-
thesis of the drug Ezetimibe,[9] a drug for treating high
cholesterol, using (R)-6lc as the starting material (Scheme 4).
(R)-6lc was obtained in 91% yield with 95% ee from the
reaction of 4l with 5c in the presence 1.5 mol% of [[Pd(h3-
C3H5)Cl}2]/(S,S,S)-1c. The reaction of (R)-6lc with the
nucleophile 10 under basic conditions afforded the corre-
sponding Michael addition product, which was then treated
with [Pd(PPh3)4] (5 mol%) without purification to remove
the allyloxycarbonyl group to give 11 in 71% total yield
(2 steps). Treatment of 11 with LiHMDS in THF at À208C
yielded the b-lactam (3R,4S)-12 as a single isomer in 77%
yield with 95% ee. The b-lactam(3R,4S)-12 can be readily
transformed into Ezetimibe in two steps using reported
methods.[18] Thus the present methodology has provided an
alternative process for the efficient synthesis of Ezetimibe by
using the catalytic asymmetric allylic amination as the key
step.
Figure 1. X-ray crystal structure (S)-8ad shown with thermal ellipsoids
at 30% probability.[19]
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Chiral Ligands and Catalysts (Ed. Q.-L. Zhou), Wiley-VCH,
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Scheme 4. Asymmetric synthesis of Ezetimibe using (R)-6lc as the key
intermediate. Bn=benzyl, DBU=1,8-diazabicyclo[5.4.0]undecene-7,
HMDS=hexamethyldisilazide, THF=tetrahydrofuran.
In summary, a new class of aromatic spiroketal-based
bisphosphine ligands (SKPs) has been developed by simple
transformation from readily available optically pure spiro-
2,2’-bis(chroman) derivatives. Their palladium complexes
were found to be highly efficient in the enantioselective
allylic amination of the esters of racemic MBH adducts with
aromatic amines, thus affording the corresponding optically
active b-arylamino acid esters in good yields with high regio-
and enantioselectivities. The resultant optically active b-
arylamino acid esters can be readily transformed into their
corresponding b-lactam derivatives without loss of enantio-
selectivity, thus providing a useful platform for the synthesis
of various biologically important molecules. The utility of this
method is demonstrated in the context of a facile synthesis of
the drug Ezetimibe. The excellent performance of this type of
ligand in the reaction will stimulate future explorations into
their applications in transition metal catalyzed asymmetric
reactions, and to further understand the underlying mecha-
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Received: June 23, 2012
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Published online: && &&, &&&&
Keywords: asymmetric catalysis · lactams · palladium ·
.
phosphane ligands · spiro compounds
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[14] For examples of the palladium-catalyzed asymmetric allylic
substitution of MBH adducts using oxygen nucleophiles, see:
[19] CCDC 880880 [(S)-8ad] contains the supplementary crystallo-
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charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Angew. Chem. Int. Ed. 2012, 51, 1 – 8
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www.angewandte.org
7
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.
Angewandte
Communications
Communications
Asymmetric Catalysis
X. M. Wang, F. Y. Meng, Y. Wang, Z. Han,
Y. J. Chen, L. Liu,* Z. Wang,*
K. Ding*
&&&& — &&&&
Aromatic Spiroketal Bisphosphine
Ligands: Palladium-Catalyzed
Asymmetric Allylic Amination of Racemic
Morita–Baylis–Hillman Adducts
Showing a backbone: The spiroketal
backbone of the bis(phosphine) ligand
1 led to good regio- and enantioselectivity
in the palladium-catalyzed asymmetric
allylic amination of racemic Morita–
Baylis-Hillman adducts with aromatic
amines. The methodology provides
a facile and efficient synthesis of precur-
sors for optically active b-lactam deriva-
tives, including the cholesterol drug Eze-
timibe.
8
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!