Asymmetric catalysis via dynamic substrate/ligand/rare earth metal conglomerate

Article abstract of DOI:10.1021/ja800326d

A highly enantio- and diastereoselective catalytic asymmetric Mannich-type reaction of α-cyanoketones and N-Boc imines promoted by an amide ligand/Sc(OⁱPr)₃ catalyst is described. The similar reaction outcome is obtained with/without

Full text of DOI:10.1021/ja800326d

Published on Web 04/05/2008
Asymmetric Catalysis via Dynamic Substrate/Ligand/Rare
Earth Metal Conglomerate
Akihiro Nojiri, Naoya Kumagai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
113-0033 Tokyo, Japan
Received January 15, 2008; E-mail: nkumagai@mol.f.u-tokyo.ac.jp; mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Catalytic Asymmetric Mannich-Type Reaction Promoted
by 1a/RE(OiPr)3 Complexa
Metalloenzymes constitute a particularly intriguing class of func-
tional biomolecules because of their plethora of vital roles in living
systems.1 Multiple cooperative noncovalent interactions are harnessed
to exhibit a highly integrated transition state architecture in an elegant
spatial arrangement, arising from a diverse set of peptide chains and
associated metal cations. We hypothesized that a simple amide ligand
associated with a rare earth metal (RE) would mimic a unitary
metalloenzyme to reproduce a highly ordered transition state.2,3 The
high coordination number (6 e CN e 12) and unpredictable
coordination mode may compensate for the simplicity of the ligand2
and allow for a variety of assembled structures to be obtained
depending on the ligand and reaction conditions. Our recent efforts in
this field identified a simple amide ligand that can construct a suitable
asymmetric environment upon complexation with an RE.4 Herein, we
expanded our strategy to construct a chiral quaternary stereocenter and
revealed a dynamic association of the substrate/ligand/metal mixture
to produce a defined transition state assembly, furnishing the desired
product in a highly stereoselective manner.
Catalytic asymmetric construction of a quaternary carbon center
has attracted increasing attention due to limited methodologies to
address the synthetic challenges.5 R-Cyanocarbanion, with its minimal
steric bias and its inherent nucleophilicity, is a suitable carbon
nucleophile for the formation of a chiral quaternary carbon center.6
We applied an amide ligand/RE catalytic system to an enantioselective
addition of R-cyanoketones to imines, a Mannich-type reaction,7,8
affording the densely functionalized product with a contiguous
quaternary carbon and trisubstituted stereocenter (eq 1). There are
several recent examples of the catalytic asymmetric Mannich-type
reaction of 1,3-dicarbonyl compounds producing syn-configured
ꢀ-amino ketones with an R-quaternary carbon center.8a–d None of these
examples, however, exhibits high anti diastereo- and enantioselectivity.
entry RE(OiPr)3
solvent
temp (°C) time (h) yieldb (%) anti/sync ee (anti) (%)
1
Sc
La
THF
THF
0
0
0
0
0
0
0
0
12
12
12
12
12
12
12
12
91
86
93
76
88
90
83
92
78
92
92
85
61
92/8
80
3
2
90/10
96/4
3
Nd THF
-1
1
4
Eu
Dy THF
Er THF
Yb THF
Sc
Sc
Sc
Sc
Sc
Sc
THF
84/16
87/13
15/85
59/41
88/12
94/6
5
2
6
5
7
6
8
toluene
85
92
94
93
92
14
9
CH2Cl2
-20 12
10
11
12
13
CH2Cl2
0
21
40
0
12
6
91/9
CH2Cl2
93/7
CH2Cl2
0.33
91/9
CH2Cl2-DMFd
12
55/45
a 1a and RE(OiPr)3 were mixed, and the resulting mixture was stirred
for 1 h at room temperature before addition of substrates. 2a: 0.2 mmol,
3a: 0.24 mmol, 0.2 M in 2a. b Determined by 1H NMR with DMF as
internal standard. c Determined by 1H NMR of crude mixture. d CH2Cl2/
DMF ) 1/1.
a highly ordered transition state architecture.9 The present reaction
afforded uniformly high ee within a broad range of reaction
temperatures (entries 9-12).10 The substantial decrease in both
reactivity and stereoselectivity with a CH2Cl2/DMF mixed solvent
system supports the involvement of hydrogen bonding (entry 13).11
The optimized conditions were applicable to various Boc imines
3 (Table 2).12,13 The reaction was completed with 2 mol % of
catalyst loading (entry 2). Six- and seven-membered cyclic cy-
anoketones also served as promising nucleophiles, providing the
products in a highly stereoselective manner (entries 3 and 4).
Nonpolar or noncoordinative substituents on the aromatic ring of
the imines only marginally impacted stereoselectivity, giving the
anti product with high diastereo- and enantioselectivity (entries
4-10). Stereoselectivity diminished in the reaction with imines
bearing coordinative substituents (MeO, furyl, thienyl), suggesting
that hydrogen bonding between the ligand and substrates is
manifested in the transition state (entries 11-14). The reaction also
proceeded using an aliphatic imine, albeit with lower stereoselec-
tivity (entry 15).
We began our study by evaluating an amide ligand/RE catalyst
prepared from ligand 1a and RE(OiPr)3 in a 2:1 ratio in a reaction
of 2-cyanocyclopentanone (2a) and N-Boc imine 3a (Table 1). 1a
and RE(OiPr)3 were mixed and stirred for 1 h at room temperature
prior to addition of the substrates. Among the initially screened
combinations of 1a with an RE, the 1a/Sc(OiPr)3 complex quickly
emerged as a nearly ideal catalyst, allowing for a smooth reaction
with 5 mol % of catalyst loading at 0 °C to give the Mannich
product 4aa in 91% yield with anti/syn ) 92/8 and 80% ee (entry
1). Except for the Er(OiPr)3/1a complex, which displayed syn
diastereoselectivity (entry 6), the present catalytic system prefer-
entially provided anti-4aa. Higher enantioselectivity was observed
when the reaction was run in the nonpolar solvents toluene (entry
8) or CH2Cl2 (entry 10), presumably because of the enhanced
hydrogen bond network between 1a and the substrates, leading to
Having developed a highly stereoselective Mannich-type reac-
tion, we aimed to better understand the precise nature of the present
1
catalysis. H NMR spectroscopy of the 1a/Sc solution produced
highly complicated spectra, suggesting that an oligo- or polymeric
1a/Sc conglomerate was formed without any order or regularity.14
No change in spectral complexity was observed after the addition
of 2a to the catalyst solution.14 We hypothesized that the reaction
components would be free to associate/dissociate in the reaction
mixture, and each reaction component orchestrates to form an
ordered transition state through Sc-O coordination and hydrogen
bonding during the reaction.15 The strong dependency of the
9
5630 J. AM. CHEM. SOC. 2008, 130, 5630–5631
10.1021/ja800326d CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
contributes to the high ee,14,18 suggesting that the well-organized
structural integration of the reaction components occurs in the
transition state.
Table 2. Catalytic Asymmetric Mannich-Type Reaction by 1a/Sc
Catalysta
In conclusion, we developed a catalytic asymmetric Mannich-
type reaction of R-cyanoketones and Boc imines with a 1a/Sc
catalyst, generating consecutive all-carbon quaternary and trisub-
stituted stereocenters in a highly stereoselective manner. Partic-
larly noteworthy is that the present catalysis proceeds through an
ordered association of substrates/1a/Sc from a conglomerate
mixture, eliminating the need for precomplexation of 1a/Sc. More
detailed mechanistic investigations are in progress.
cyanoketone imine
entry
x
n
R
product yieldb (%) anti/sync ee (anti) (%)
1d 5 1
2a
Ph
Ph
Ph
Ph
3a 4aa
3a 4aa
3a 4ba
3a 4ca
90
93
92
80
90
93
97
97
99
88
86
97
94
98
89
94/6
94
91
91
95
93
91
94
95
89
96
81
77
82
83
50
2
3
2 1
5 2
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
93/7
95/5
89/11
91/9
4e 5 3
5
6
7
8
9
5 1
5 1
5 1
5 1
5 1
2-MeC6H4 3b 4ab
4-MeC6H4 3c 4ac
2-naphthyl 3d 4ad
Acknowledgment. This work was financially supported by
91/9
90/10
88/12
91/9
Grant-in-Aid for Specially Promoted Research. N.K. thanks Grant-
in-Aid for Young Scientist (B). Dr. Motoo Shiro at Rigaku
Corporation is gratefully acknowledged for X-ray analysis of 4aa,
2-ClC6H4
4-ClC6H4
2-FC6H4
3e 4ae
3f 4af
3g 4ag
10 5 1
11 5 1
12 5 1
13 5 1
14 5 1
15 5 1
90/10
80/20
85/15
75/25
93/7
2-MeOC6H4 3h 4ah
4-MeOC6H4 3i 4ai
4ab, and 4ae.
2-furyl
3-thienyl
Ph(CH2)2
3j 4aj
3k 4ak
3l 4al
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
64/36
a 1a and RE(OiPr)3 were mixed, and the resulting mixture was stirred
for 1 h at room temperature before addition of substrates. 2a: 0.3 mmol,
3a: 0.36 mmol, 0.2 M in 2a. b Isolated yield. c Determined by 1H NMR
of crude mixture. d 1.0 mmol scale. Average of two runs. e Reaction
time was 48 h.
References
(1) For recent reviews, see: (a) McMaster, J. Annu. Rep. Prog. Chem. Sect. A
2006, 102, 564. (b) Sigel, R. K. O.; Pyle, A. M. Chem. ReV. 2007, 107,
97.
(2) For reviews, see: Bari, L. D.; Salvadori, P. Coord. Chem. ReV. 2005, 249, 2854
Table 3. Mannich-Type Reaction with One-Shot Additiona
and references cited therein.
(3) For recent reviews on small peptide-based asymmetric catalysis, see: (a)
Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun. 2004,
1779. (b) Blank, J. T.; Miller, S. J. Biopolymers 2006, 84, 38.
(4) (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki,
M. J. Am. Chem. Soc. 2007, 129, 11342. (b) Nitabaru, T.; Kumagai, N.;
Shibasaki, M. Tetrahedron Lett. 2008, 49, 272.
(5) For recent reviews, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363. (b) Trost, B. M.; Jiang, C. Synthesis 2006,
369.
entry substrates product phenolic additive mol % yieldb (%) anti/sync ee (anti) (%)
1
2a,3a 4aa
-
-
87
92
93
95
96
94
94/6
96/4
97/3
96/4
87/13
91/9
93
96
94
94
95
89
2a,3a 4aa p-tBu phenol
10
(6) For reviews, see: Fleming, F. F.; Iyer, P. S. Synthesis 2006, 893 and references
cited therein.
2
3
2a,3a 4aa Methyl salicylate 10
2a,3a 4aa Methyl salicylate 40
2c,3a 4ca
(7) For recent reviews on direct Mannich reactions using unmodified pronucleo-
philes, see: (a) Shibasaki, M.; Matsunaga, S. J. Organomet. Chem. 2006,
691, 2089. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797 and
references cited therein.
4
5d
6
2a, 3f 4af
a Sc(OiPr)3 was added to the CH2Cl2 solution of 1a, 2, 3, and phe-
(8) For selected examples of catalytic asymmetric Mannich reactions with 1,3-
dicarbonyl compounds generating quaternary carbon stereocenter, see: (a)
Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A.
Chem.—Eur. J. 2003, 9, 2359. (b) Hamashima, Y.; Sasamoto, N.; Hotta,
D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005,
44, 1525. (c) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003. (d)
Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. For
selected examples of catalytic asymmetric Mannich reactions with 1,3-
dicarbonyl compounds generating tertiary stereocenter, see: (e) Uraguchi,
D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (f) Lou, S.; Taoka,
B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256. (g)
Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (h)
Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc.
2006, 128, 14010.
nolic additive. b Determined by 1H NMR with DMF as internal standard.
c Determined by 1H NMR of crude mixture. d Reaction time was 48 h.
stereoselectivity on the nature of the solvent (Table 1) and the imine
substituent (Table 2) is consistent with this assumption. Further-
more, the use of 2a in concentrations higher than 0.2 M diminished
stereoselectivity,16 suggesting that concentration affects the orga-
nization process of the reaction components. If the spontaneous
assembly to attain an ordered transition state is operative, precom-
plexation of 1a/Sc is not required and the reaction can be run with
one-shot addition of all reaction components. On the basis of this
assumption, the Mannich-type reaction of 2a and 3a was conducted
with Sc(OiPr)3 added at the end of the procedure (Table 3). The
reaction proceeded smoothly to afford 4aa in 87% yield with anti/
syn ) 94/6 and 93% ee, which was comparable to the result
obtained with the premixed 1a/Sc catalyst (Table 2, entry 1, Table
3, entry 1). More importantly, eVen in the presence of 10-40 mol
% of p-tBu phenol or methyl salicylate, which has a pKa similar
to that of 1a and can disturb the preferential association of Sc and
1a, high stereoselectivity was attained (entries 2-4). Because of
the complicated NMR spectra of the 1a/Sc mixture and the simple
linear structure of 1a, the formation of a distinct 1a/Sc complex
upon the addition of Sc(OiPr)3 is less likely. In the reaction of 2a
and 3a, a salicyl ester analogue of 1a performed similarly, whereas
a catechol analogue resulted in poor stereoselectivity, likely due
to the lack of hydrogen bonding through aminophenol amide.17
Evaluation of the ee at several temperatures (Table 1) using a
differential Eyring equation indicated that the entropy term mainly
(9) The catalyst prepared from different 1a/Sc ratio gave inferior results. 1a/
Sc(OiPr)3 (5 mol %) ) 1/1: 77% yield, anti/syn ) 87/13, 78% ee (anti). 1a/
Sc(OiPr)3 (5 mol %) ) 1/2: 51% yield, anti/syn ) 77/23, 61% ee (anti).
(10) A recent example of a Sc catalyst which displays uniformly high ee at broad
range of temperatures: Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt,
K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029.
(11) The possibility that DMF dissociates ligand 1a from Sc cation cannot be
excluded.
(12) Relative and absolute configuration were determined by single crystal X-ray
crystallographic analysis. See Supporting Information for details.
(13) The reaction with an acyclic R-cyanoketone, 2-cyanopropiophenone (2d),
was performed (imine 3a, cat. 5 mol %, 0 °C, 18 h), giving the Mannich
product (4da) in 95% yield, anti/syn ) 8/92, 89% ee (syn).
(14) See Supporting Information for details.
(15) QFT-ESI MS analysis revealed the formation of 1a/Sc/2a ternary complex
upon addition of 2a to the 1a/Sc solution. See Supporting Information.
(16) Reaction of 2a and 3a with 2 mol % of catalyst at 0.8 M in 2a afforded
4aa in 91% yield with anti/syn ) 92/8 and 83% ee (anti).
(17) Salicyl ester analogue: 93% yield, anti/syn ) 89/11, 93% ee. Catechol
analogue: 78% yield, anti/syn ) 84/16, -24% ee. See Supporting
Information for details.
(18) (a) Leffler, J. E. J. Org. Chem. 1955, 20, 1202. (b) Inoue, Y.; Yokoyama,
T.; Yamasaki, N.; Tai, A. J. Am. Chem. Soc. 1989, 111, 6480. (c) Saito,
R.; Naruse, S.; Takano, K.; Fukuda, K.; Katoh, A.; Inoue, Y. Org. Lett.
2006, 8, 2067 and references cited therein.
JA800326D
9
J. AM. CHEM. SOC. VOL. 130, NO. 17, 2008 5631