Lanthanum aryloxide/pybox-catalyzed direct asymmetric mannich-type reactions using a trichloromethyl ketone as a propionate equivalent donor

Article abstract of DOI:10.1021/ja073285p

Direct catalytic asymmetric Mannich-type reaction of a trichloromethyl ketone as a propionate equivalent donor is described. A new lanthanum aryloxide-iPr-pybox + lithium aryloxide combined catalyst was the most effective, promoting the reaction of N-2-th

Full text of DOI:10.1021/ja073285p

Published on Web 07/14/2007
Lanthanum Aryloxide/Pybox-Catalyzed Direct Asymmetric Mannich-Type
Reactions Using a Trichloromethyl Ketone as a Propionate Equivalent Donor
Hiroyuki Morimoto, Gang Lu, Naohiro Aoyama, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 9, 2007; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Enantioselective Mannich reactions are useful for providing
â-amino carbonyl compounds. Direct catalytic asymmetric
Mannich-type reactions using unmodified aldehydes and ketones
as donors have been intensively investigated over the past decade.1,2
On the other hand, the use of carboxylic acid derivatives as donors,
a straightforward method to synthesize â-amino acid derivatives,
requires further development. In contrast to recent reports on direct
catalytic asymmetric aldol reactions using propionate equivalent
donors,3 the corresponding Mannich-type reactions are limited to
donors with an R-OH-substituent4 and active methylene units.5
There are only two known racemic reactions using R-alkyl-
substituted ester equivalent donors.6,7 We previously reported the
usefulness of trichloromethyl ketones 1 (Figure 1) as a propionate
equivalent donor in a racemic reaction. Trichloromethyl ketone units
in Mannich adducts were transformed not only into esters, but also
into various building blocks such as dithianes, trichloromethyl
carbinols, and azetidine carboxylates.6,8 Herein, we report a direct
catalytic enantio- and diastereoselective variant using 1. A new
lanthanum aryloxide-iPr-pybox + lithium aryloxide combined
catalyst (Figure 1) was the most effective, giving syn-Mannich
adducts in high yield, dr, and enantioselectivity (up to 98% ee).
Transformations of the Mannich adduct are also described.
To develop an enantioselective variant, we screened libraries of
our Lewis acid-Brønsted base bifunctional metal-BINOLate
complexes;9 however, all of them resulted in poor enantioselectivity
(<10% ee). Therefore, we screened various Lewis acid-chiral
ligand-Brønsted base combinations to activate both 1 and imine.
La(OTf)3-pybox + LiOAr (Ar ) 4-MeO-C6H4-) gave promising
results: 10 mol % of La(OTf)3-iPr-pybox and 15 mol % of LiOAr
promoted the reaction of 2-pyridinesulfonyl imine 2a10 with 1a at
0 °C, giving Mannich adduct 3a in 78% ee and syn/anti of >30:1,
albeit in poor yield (26%; Table 1, entry 1). No reaction proceeded
at -40 °C in entry 1. With La(OTf)3-pybox alone, no reaction
proceeded at 0 °C (entry 2). A lanthanum metal counteranion had
crucial effects on reactivity, and aryloxide was the best. With
La(OAr)3 (Ar ) 4-MeO-C6H4-), the reaction proceeded at -40 °C,
and 3a was obtained in 99% yield and 90% ee (entry 3). Mixing
La/Li in a 1:0.5 ratio improved ee but decreased the reactivity (entry
4, 61%, 94% ee). Screening of imines revealed that 2-thiophene-
sulfonyl imine 2b10 had the best reactivity, and 3b was obtained in
97% yield, while maintaining a good dr and ee (entry 5). Further
optimization of the concentration and solvent improved the reaction
rate, and 3b was obtained in 96% after 9 h (entry 7, syn/anti )
21:1, 96% ee). The reaction proceeded with La(OAr)3-iPr-pybox
alone without LiOAr, albeit with a lower reaction rate (entry 8, 21
h). In entries 7 and 8, similar diastereoselectivity and enantio-
selectivity were observed. In contrast, the reaction completed within
2 h using LiOAr and iPr-pybox, but with low selectivity (entry 9,
syn/anti ) 5:1, 5% ee). Results in entries 7-9 suggested that a
La(OAr)3-iPr-pybox complex is important for high selectivity. No
reaction proceeded with the La(OTf)3-iPr-pybox complex in the
absence of LiOAr (entry 10), suggesting that the La-OAr moiety
Figure 1. Trichloromethyl ketones 1 and postulated structures of La(OAr)3-
(S,S)-iPr-pybox complex + LiOAr (Ar ) 4-MeO-C6H4-).
Table 1. Optimization of Reaction Conditions
LiOAr
concn
(y M)
time
(h)
yielda
(%)
dra
(syn/anti)
ee (%)
(syn)
entry
imine
LaX3
(
×
mol %)
1b
2b
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
La(OTf)3
La(OTf)3
La(OAr)3
La(OAr)3
La(OAr)3
La(OAr)3
La(OAr)3
La(OAr)3
none
15
0
15
5
5
5
5
0
5
0
0.5c
0.5c
0.5c
0.5c
0.5c
1.0c
1.0d
30
48
21
30
30
19
9
26
0
>30:1
78
99
61
97
99
96e
99
98
0
>30:1
>30:1
20:1
20:1
21:1
18:1
5:1
90
94
95
95
96
95
5
1.0d 21
1.0d
1.0d 24
2
10
La(OTf)3
a Determined by 1H NMR analysis. b Reaction was run at 0 °C, no
reaction proceeded at -40 °C. c THF/CH2Cl2 ) 1:1 was used. d THF/toluene
) 1:1 was used. e Isolated yield after purification.
in the La(OAr)3-iPr-pybox complex functions as a Brønsted base
to form La-enolate in entry 8.11 High ee in entry 7 as well as the
difference in the reaction rate between entries 7 and 9 implied that
the racemic pathway with LiOAr alone was negligible in entry 7.
Because similar selectivity was obtained in entries 7 and 8, we
assumed that the reaction proceeded via similar La-enolate species
in both entries. We speculate that LiOAr in entry 7 would accelerate
the reaction by enhancing the La-enolate-forming step.12
The substrate scope is summarized in Table 2. Various non-
enolizable aryl, heteroaryl, and alkenyl imines afforded products
in good yield and selectivity (entries 1-9). Product 3b was obtained
in good yield even with reduced amounts of 1a (entry 2-3). It is
noteworthy that isomerizable alkyl imines were also applicable
(entries 10-12). In the case of alkyl imines 2j and 2k, the use of
La(OAr)3 alone was better to avoid undesired isomerization of the
imines to enamines. Catalyst loading was successfully reduced to
5-2.5 mol % under concentrated conditions (entries 13-15, 2.0
M). Preliminary investigations using trichloromethyl ketone 1b as
a butanoate equivalent donor gave products in 83-87% ee (entries
16-17). Further optimizations studies are ongoing.
9
9588
J. AM. CHEM. SOC. 2007, 129, 9588-9589
10.1021/ja073285p CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Catalytic Asymmetric Mannich-Type Reaction of
Aryl, Heteroaryl, Alkenyl, and Alkyl Imines with Trichloromethyl
Ketonesa
Acknowledgment. This work was supported by Grand-in-Aid
for Specially Promoted Research, Grant-in-Aid for Encouragements
for Young Scientists (B), and the Sumitomo Foundation. H.M.
thanks JSPS predoctoral fellowship. We thank Prof. J. C. Carretero
and Dr. R. Go´mez Arraya´s for their helpful advice on imines
synthesis.
Supporting Information Available: Experimental procedures and
characterization data, determination of relative and absolute configu-
ration of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
La/pybox
mol %)
time yieldb
drc
ee (%)
(syn)
entry
imine:
R
(
×
1
(h)
(%)
(syn/anti)
1
Ph
2b
2b
2b
2c
2d
2e
2f
10
10
10
10
10
10
10
10
10
10
10
10
5
1a
9
96
21:1
18:1
17:1
20:1
25:1
22:1
8:1
96
95
94
96
96
95
96
95
96
96
98
97
95
92
96
83
87
References
2d Ph
1a 24
1a 36
1a 20
1a 20 >99
1a 21
1a
1a 19
1a 19
1a 22
1a 25
1a 23
1a 14
1a 29
1a 16
1b 32
1b 29
96
90
97
3e Ph
(1) Reviews: (a) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102. (b) Marques,
M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348. (c) Shibasaki, M.;
Matsunaga, S. J. Organomet. Chem. 2006, 691, 2089.
4
5
6
7
8
9
p-Cl-C6H4-
p-Me-C6H4-
p-MeO-C6H4-
2-furyl
2-thienyl
(E)-PhCHdCH- 2h
(2) Selected recent direct Mannich-type reactions of ketones and aldehydes:
(a) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc.
2006, 128, 2778. (b) Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777. (c) Ramasastry, S.
S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007,
129, 288. (d) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed.
2007, 46, 609. (e) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J.
Am. Chem. Soc. 2005, 127, 16408. For other examples, see reviews in
ref 1.
(3) Direct aldol reactions using ester equivalent donors: (a) Evans, D. A.;
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706. (b)
Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair,
M. D. J. Am. Chem. Soc. 2005, 127, 7284. (c) Suto, Y.; Tsuji, R.; Kanai,
M.; Shibasaki, M. Org. Lett. 2005, 7, 3757. (d) Saito, S.; Kobayashi, S.
J. Am. Chem. Soc. 2006, 128, 8704 and references therein.
96
98
98
75
4
2g
20:1
21:1
10 cyclohexyl
2i
2j
85 >30:1
72 30:1
74 >30:1
96
93
98
87
76
11f iBu
12f iPr
2k
2b
2g
2b
2b
2c
13g Ph
30:1
17:1
18:1
15:1
8:1
14g 2-thienyl
15g Ph
5
2.5
10
10
16 Ph
17 p-Cl-C6H4-
(4) (R-Hydroxyacetyl)pyrrole as a donor: Harada, S.; Handa, S.; Matsunaga,
a Reaction was run using 2.0 equiv of 1, x mol % of La(OAr)3/iPr-pybox
(x ) 2.5-10), and 0.5x mol % of LiOAr in THF/toluene ) 1:1 (1.0 M) at
-40 °C, unless otherwise noted. b Isolated yield after column chromatog-
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365.
(5) For selected examples with malonates and ketoesters: (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) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem.
Soc. 2006, 128, 14010. (d) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E.
J. Am. Chem. Soc. 2005, 127, 11256. (e) Song, J.; Wang, Y.; Deng, L. J.
Am. Chem. Soc. 2006, 128, 6048. With glycine Schiff base: (f) Bernardi,
L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003,
68, 2583. (g) Ooi, T.; Kameda, M.; Fujii, J.-i.; Maruoka, K. Org. Lett.
2004, 6, 2397. (h) Salter, M. M.; Kobayashi, J.; Shimizu, Y.; Kobayashi,
S. Org. Lett. 2006, 8, 3533. (i) Shibuguchi, T.; Mihara, H.; Kuramochi,
A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794.
1
raphy. c Determined by H NMR analysis. d Reaction run using 1.2 equiv
of 1. e Reaction run using 1.0 equiv of 1. f Reaction was run in the absence
of LiOAr. g Reaction was run in THF/toluene ) 1:1 (2.0 M).
Scheme 1. Transformation of the Mannich Adducta
(6) Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen, Z.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 3146.
(7) Saito, S.; Tsubogo, T.; Kobayashi, S. Chem. Commun. 2007, 1236.
(8) Utility of trichloromethyl ketones and trichloromethyl carbinols as building
blocks: (a) Corey, E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906.
(b) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 3431. See also
ref 6 and references therein.
(9) Reviews: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(b) Shibasaki, M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35, 269.
a
Reagents and conditions: (a) NaOMe, MeOH, 0 °C, 20 min, quant;
(10) N-Heteroarenesulfonyl imines showed better enantioselectivity than other
imines such as N-Ts imines and N-diphenylphosphinoyl imines. For
selected recent examples of N-heteroarenesulfonyl imines in asymmetric
synthesis: (a) Gonza´lez, A. S.; Go´mez Arraya´s, R.; Carretero, J. C. Org.
Lett. 2006, 8, 2977 and references therein. (b) Esquivias, J.; Go´mez,
Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480. (c)
Nakamura, S.; Nakashima, H.; Sugimoto, H.; Shibata, N.; Toru, T.
Tetrahedron Lett. 2006, 47, 7599 and references therein.
(11) For utility of rare earth metal (RE) triflate and/or halide-pybox complexes
as chiral Lewis acids, see a review: (a) Desimoni, G.; Faita, G.; Quadrelli,
P. Chem. ReV. 2003, 103, 3119. See also: (b) Evans, D. A.; Fandrick, K.
R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942 and references therein.
For exceptional examples using RE-Cl3/pybox complex as a bifunctional
catalyst to generate nucleophilic RE-cyanide species, see: (c) Schaus, S.
E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001. (d) Keith, J. M.; Jacobsen,
E. N. Org. Lett. 2004, 6, 153.
(12) Preliminary kinetic studies on the concentration of trichloromethyl ketone
1 suggested that the enolate formation is the rate-determining step in the
absence of LiOAr. There are two possibilities for the role of LiOAr: (a)
Complexation with La(OAr)3/pybox to form more basic ate complex or
(b) LiOAr deprotonates 1 to form Li-enolate, followed by rapid trans-
metallation to generate La-enolate. Further mechanistic studies to clarify
the role of LiOAr are ongoing.
(13) Preliminary investigation using trichloromethyl ketone 1c with a larger
substituent (R ) CH2Ph in Figure 1) gave Mannich adduct from imine
1b in 94% yield, syn/anti ) 7.4:1, and 78% ee after 20 h. Further
optimization studies using 1b and 1c are ongoing.
(b) i) Boc2O, DMAP, CH3CN, rt, 98%; ii) Mg, MeOH, rt, 95%; (c) EtSH,
BuLi, THF, 0 °C, 30 min, 79%; (d) DIBAL, CH2Cl2, -78 °C to -40 °C,
7.5 h, quant, 7/8 ) >30:1; (e) DIBAL/Ph3P(O) (1:2), THF, -78 °C to
-40 °C, 2 h, 99%, 8/7 ) >30:1.
The utility of the trichloromethyl ketone template was demon-
strated by transformations in Scheme 1, in which 3b was converted
into ester and dithiane in good yield. The 2-thiophenesulfonyl group
was removed after protection with Boc, followed by treatment with
Mg.10 Either syn- or anti-trichloromethyl carbinol, a unique building
block,6,8 was selectively obtained using either DIBAL (syn-7) or
DIBAL/Ph3P(O) ) 1:2 mixture (anti-8).
In summary, we developed a direct catalytic asymmetric
Mannich-type reaction of a trichloromethyl ketone 1a as a propi-
onate equivalent donor. The new La(OAr)3-iPr-pybox + LiOAr
system gave products in >99-72% yield, >30:1-8:1 dr, and 98-
92% ee (from 1a). The La-OAr moiety in the La(OAr)3-iPr-pybox
had a key role in promoting the reaction. La(OAr)3-iPr-pybox had
different reactivity from La(OTf)3-iPr-pybox. Further applications
of the catalyst13 as well as investigation of the reaction mechanism
are ongoing.
JA073285P
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J. AM. CHEM. SOC. VOL. 129, NO. 31, 2007 9589