Stereodivergent direct catalytic asymmetric mannich-type reactions of α-isothiocyanato ester with ketimines

Article abstract of DOI:10.1002/anie.201101034

Now accessible: Sterically hindered vicinal tetrasubstituted carbon stereocenters, which are not accessible by asymmetric hydrogenation, were constructed by a catalytic asymmetric C-C bond formation (see scheme; Dpp=diphenylphosphinoyl). By changing the Group 2 metal center, stereodivergent access to α,β-tetrasubstituted α,β-diamino esters was realized. Copyright

Full text of DOI:10.1002/anie.201101034

Communications
DOI: 10.1002/anie.201101034
Asymmetric Synthesis
Stereodivergent Direct Catalytic Asymmetric Mannich-Type Reactions
of a-Isothiocyanato Ester with Ketimines**
Gang Lu, Tatsuhiko Yoshino, Hiroyuki Morimoto, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
Chiral a,b-diamino acids are key structural motifs in many
biologically active compounds.[1] Catalytic asymmetric direct
Mannich-type reactions of aldimines and nucleophiles, which
contain an a-amino equivalent unit, provide straightforward
access to chiral a,b-diamino acids.[2] Unnatural amino acids
that contain tetrasubstituted carbon centers are useful chiral
building blocks for the synthesis of pharmaceuticals, and
artificial peptides with distinctive chemical and biological
properties.[3] Several research groups including ours, have
Figure 1. Structures of Schiff bases 1a and 1b and a-methyl-a-isothio-
reported Mannich-type reactions of aldimines with a-substi-
cyanato ester 2.
tuted donors, such as an alanine methyl ester Schiff base,[4] a-
substituted nitroacetates,[5] and a-substituted oxazolones,[6]
for the synthesis of a,b-diamino acid surrogates bearing an
a-tetrasubstituted carbon center.[7] In contrast, there are no
reports of the catalytic asymmetric synthesis of b-tetrasub-
stituted chiral a,b-diamino acids, which require the reaction
of much less reactive ketimines. Thus, there is a high demand
for the development of a new method for the synthesis of a,b-
tetrasubstituted a,b-diamino acid surrogates. To address this
issue, we herein report the utility of group 2 metal/Schiff base
1 complexes (Figure 1). The Sr/1 and Mg/1 catalysts promoted
a direct Mannich-type reaction of a-methyl-a-isothiocyanato
ester 2 with ketimines 3 (see Table 1), thus providing stereo-
divergent access to a,b-diamino esters with vicinal tetrasub-
stituted carbon stereocenters.
Among the ketimines screened, diphenylphosphinoyl (Dpp)
imine 3a gave promising results in terms of reactivity and
selectivity. Optimization studies using 3a are summarized in
Table 1. A 1:1 ratio of Bu2Mg/1a (10 mol%) promoted the
Table 1: Optimization studies.
Entry Metal
source
(R)- Solvent t [h] Yield[a] d.r.
ee [%][b]
(syn)
We have previously reported the direct asymmetric aldol
reaction of a-methyl-a-isothiocyanato ester 2 with ketones,
catalyzed by Bu2Mg/Schiff base 1a.[8] Therefore, we initially
utilized Bu2Mg/1a for the reaction of 2 with ketimines.[9]
1
syn/
anti
1
2
3
Bu2Mg
Bu2Mg
Bu2Mg
Bu2Mg
Ca(O-iPr)2
Sr(O-iPr)2
Ba(O-iPr)2
1a
THF
47
28
>95 68:32 44
>95 71:29 67
>95 86:14 80
1b THF
1b
1b
1b
1b
1b
CHCl3 20
CHCl3 48
CHCl3 48 trace
CHCl3 48
CHCl3 48 trace
4[c]
5
87[d] 91:9
n.d.
84
n.d.
[*] Dr. G. Lu, T. Yoshino, Dr. H. Morimoto, Dr. S. Matsunaga
Graduate School of Pharmaceutical Sciences
The University of Tokyo
6
7
86[d] 6:94 92[e]
n.d.
n.d.
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021 (Japan)
Fax: (+81)3-3447-7779
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Determined by HPLC analysis on a chiral stationary phase. [c] Reac-
tion was run at À108C. [d] Yield of the isolated product after purification
by column chromatography on silica gel. [e] Enantiomeric excess of anti-
4a. n.d.=not determined, THF=tetrahydrofuran.
E-mail: mshibasa@bikaken.or.jp
addition of 2 to 3a in THF at room temperature, to give 4a in
a greater than 95% yield, as determined by NMR spectros-
copy, albeit with modest diastereo- and enantioselectivity
(Table 1, entry 1). By using the Schiff base 1b, which has
additional methoxy substituents relative to 1a, improved the
enantioselectivity to 67% ee (Table 1, entry 2). Among the
solvents screened, CHCl3 gave the best selectivity, and 4a was
obtained with 86:14 (syn/anti) diastereoselectivity and 80% ee
at room temperature (Table 1, entry 3). The best syn selec-
[**] This work was supported by JSPS (Young Scientists A), the Takeda
Science Foundation (S.M.), and the Inoue Science Foundation
(S.M.). G.L. and H.M. thank JSPS for fellowships. We thank Prof.
Ohwada and Dr. Otani at the University of Tokyo for their generous
technical support, and helpful discussions. T.Y. and S.M. thank Prof.
Kanai at the University of Tokyo for his generous support, fruitful
discussions, and unrestricted access to the analytical facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101034.
4382
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4382 –4385

tivity (syn/anti = 91:9) and enantioselectivity (84% ee) were
obtained at À108C (Table 1, entry 4). In entries 5–7, other
group 2 metals were utilized.[10,11] Although Ca(O-iPr)2 and
Ba(O-iPr)2 gave poor results, Sr(O-iPr)2 gave 4a in an 86%
yield (Table 1, entry 6). In addition, the use of Sr(O-iPr)2/
Schiff base 1b led to an unexpected reversal of the
diastereoselectivity, and the anti adduct was obtained in
high diastereoselectivity (syn/anti = 6:94) and enantioselec-
tivity (92% ee, anti-4a) at ambient temperature.
The substrate scope of the strontium- and magnesium-
catalyzed reactions is summarized in Table 2. The reaction
temperature and solvent were optimized for each ketimine,
and the best results are reported. Absolute and relative
configurations of the products were unequivocally deter-
mined by X-ray crystallographic analysis (see the Supporting
Information).[12] The enantiofacial selectivity of the reaction
of the ketimines (3) catalyzed by Sr/1b was opposite to that of
the reaction catalyzed by Mg/1b. The results of the strontium-
catalyzed anti-selective reaction are shown in Table 2,
entries 1–12. Aryl ketimines 3a–3i gave products with high
anti selectivity and high enantioselectivity at either room
temperature or À58C (Table 2, entries 1–9). Good yields were
achieved even with ketimines bearing an electron-donating
group at the para position, such as 4-methyl imine 3e (Table 2,
entry 5) and 4-methoxy imine 3g (entry 7). However, a
strongly electron-donating 4-dimethylamine group had
adverse effects on the yield, but high anti selectivity and
enantioselectivity were maintained (Table 2, entry 8).
Heteroaryl ketimines 3j–3l were also applicable, and the
products were obtained in good to high enantioselectivity
(Table 2, entries 10–12), although slightly lower anti selectiv-
ity was observed (entries 10–12). The results of the magne-
sium-catalyzed syn-selective reaction are shown in entries 13–
20. Although the enantioselectivity was slightly lower than
with the strontium catalyst, except for ketimine 3m (Table 2,
entry 18), high syn selectivity was achieved in all cases
(Table 2, entries 13–20). Unfortunately, the present Sr/1b
and Mg/1b systems were not applicable to other ketimines,
such as aryl ethyl ketimines and aliphatic ketimines, because
of the lower reactivity of these ketimines. The a-ethyl-a-
isothiocyanato ester also showed
much lower reactivity and stereose-
Table 2: Stereodivergent direct catalytic asymmetric Mannich-type reaction of a-methyl-a-isothiocya-
nato ester 2 to ketimines 3.[a]
lectivity than the a-methyl-a-iso-
thiocyanato ester 2; this result is
possibly due to the severe steric
hindrance in the construction of
vicinal tetrasubstituted carbon ste-
reocenters.[13] Further optimization
studies, such as ligand modifications
to overcome the severe steric hin-
drance, and expansion of the scope
of the ketimines as well as a-iso-
thiocyanato esters, are ongoing.
Entry
Cat.
R
3
T
[8C]
t
[h]
Yield[e]
[%]
d.r.[f]
syn/anti
4
ee[g]
[%]
1[b]
2[b]
3[b]
4[b]
5[c]
6[c]
7[c]
8[c]
Sr
Sr
Sr
Sr
Sr
Sr
Sr
Sr
4-BrC6H4
4-ClC6H4
4-FC6H4
4-CF3C6H4
4-MeC6H4
3-MeC6H4
4-MeOC6H4
4-Me2NC6H4
3a
3b
3c
3d
3e
3 f
RT
RT
RT
RT
RT
RT
RT
RT
48
48
48
48
20
24
24
69
86
82
71
85
97
99
91
45
6:94
10:90
6:94
11:89
6:94
8:92
4:96
4:96
anti-4a
anti-4b
anti-4c
anti-4d
anti-4e
anti-4 f
anti-4g
anti-4h
92
87
90
92
95
93
97
97
Investigations to obtain a pre-
liminary insight into the structural
differences of the two catalysts by
1
using H NMR spectroscopy failed.
The 1H NMR spectra of the Bu2Mg/
1b (1:1) complex and the Sr(O-
iPr)2/1b (1:1) complex were com-
plicated, which is possibly due to
the oligomeric structures of the
catalysts.[14] Circular dichroism
(CD) spectra of the Bu2Mg/1b
(1:1) complex and the Sr(O-iPr)2/
1b (1:1) complex provided an
insight into the differences between
the aggregates of the two catalysts
(Figure 2).[15] The CD spectrum of
Schiff base 1b was clearly different
from those of Mg/1b and Sr/1b,
thus suggesting that a chiroptically
different aggregate was formed in
each metal/1b solution. In addition,
clear differences between Mg/1b
and Sr/1b in the 210–250 nm
region can be ascribed to the differ-
ence in the dihedral angle of the
binaphthyl unit in Mg/1b and Sr/
3g
3h
9[c]
Sr
3i
À5
47
76
6:94
anti-4i
95
10[c]
11[c]
12[c]
13[b]
14[b]
15[b]
16[d]
Sr
Sr
Sr
Mg
Mg
Mg
Mg
2-thienyl
3-thienyl
2-furyl
4-BrC6H4
4-ClC6H4
4-FC6H4
3-MeC6H4
3j
3k
3l
3a
3b
3c
3 f
0
À5
48
48
48
48
48
44
48
70
74
84
87
90
96
99
13:87
12:88
17:83
91:9
92:8
93:7
anti-4j
anti-4k
anti-4l
syn-4a
syn-4b
syn-4c
syn-4 f
90
92
84
84
85
84
82
À10
À10
À10
0
À25
90:10
17[d]
Mg
3i
À5
17
96
92:8
syn-4i
81
18[b]
19[d]
20[b]
Mg
Mg
Mg
2-naphthyl
3-thienyl
2-furyl
3m
3k
3l
0
À25
À5
48
48
48
99
80
70
93:7
93:7
93:7
syn-4m
syn-4k
syn-4l
95
81
80
[a] Reaction conditions: ketimine 3 (1.0 mmol), 2 (2.0 equiv), Sr(O-iPr)2 (10 mol%; entries 1–12) or
Bu2Mg (10 mol%; entries 13–20), (R)-Schiff base 1b (10 mol%), molecular sieves (5 ꢀ; 200 mg). [b] The
reaction was run in CHCl3 (0.2m). [c] The reaction was run in CHCl3/THF (2:1; 0.17m). [d] The reaction
was run in THF (0.2m). [e] The yield of 4 after isolation and purification by column chromatography on
silica gel. The yield of (syn-4 + anti-4) is shown. [f] Determined by 1H NMR analysis of the crude
mixture. [g] Determined by HPLC analysis on a chiral stationary phase. The enantiomeric excess of anti-4
is shown in entries 1–12 and that of syn-4 is shown in entries 13–20.
Angew. Chem. Int. Ed. 2011, 50, 4382 –4385
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4383

Communications
phenyl-imidazoline 7e, which contains vicinal tetrasubsti-
tuted carbon stereocenters, in a 71% yield.
In summary, we developed a stereodivergent direct
catalytic asymmetric Mannich-type reaction of the a-
methyl-a-isothiocyanato ester 2 with aryl or heteroaryl
methyl ketimines, in which access to both diastereomers is
achieved by a switch in the metal source. Sr(O-iPr)2/1b gave
anti adducts in 84–97% ee and 17:83–4:96 d.r. (syn/anti), and
the Bu2Mg/1b gave syn adducts in 80–95% ee and 90:10–
93:7 d.r. (syn/anti). Further studies to expand the range of
ketimines and a-isothiocyanato esters are ongoing.
Received: February 10, 2011
Published online: April 11, 2011
Figure 2. CD spectra of a) Schiff base 1b (black line), b) Bu2Mg/1b
(1:1; blue line), and c) Sr(O-iPr)2/1b (1:1 in THF without stabilizer;
red line).
Keywords: alkaline earth metals · asymmetric synthesis ·
homogeneous catalysis · Mannich reaction
.
1b.[16] Because the dihedral angle of the binaphthyl unit often
plays a key role in the stereodiscriminating step of asymmet-
ric reactions,[17] we believe that the difference in the dihedral
angles would cause the observed switch in diastereoselectiv-
ity.[18] Further studies to elucidate the precise structures of the
Mg/1b and Sr/1b catalysts are ongoing.
To demonstrate the synthetic utility of the protected a,b-
diamino esters 4, transformations that utilize the unique cyclic
thiourea unit were investigated. Treatment of anti-4e with
Raney Ni in MeOH gave the desulfurated adduct 5e in an
85% yield (Scheme 1). Because the 2-aryl-substituted imid-
azolines are useful in the field of medicinal chemistry for the
design of Nutlin analogues as potent antitumor agents,[19] the
direct desulfurative cross-coupling reaction of a cyclic thio-
urea to 2-aryl imidazoline was also investigated. After
removal of the diphenylphosphinoyl group in 4e using
[Cp2Zr(H)Cl] (96% yield), a palladium-catalyzed cross-
coupling reaction of 6e with PhB(OH)2 proceeded in the
presence of excess copper(thiophen-2-carboxylate) in DMF
under microwave irradiation (1308C, 1 h)[20] to give the 2-
[1] For a general review on synthesis and biological significance of
a,b-diamino acids, see: A. Viso, R. Fernꢀndez de la Pradilla, A.
Garcꢁa, A. Flores, Chem. Rev. 2005, 105, 3167.
[2] For a review on Mannich-type reactions for the synthesis of a,b-
diamino acids, see: a) R. Gꢂmez Arrayꢀs, J. C. Carretero, Chem.
Soc. Rev. 2009, 38, 1940; for a general review on the catalytic
asymmetric synthesis of b-amino acids, see: b) B. Weiner, W.
Szymanski, D. B. Janssen, A. J. Minnaard, B. L. Feringa, Chem.
Soc. Rev. 2010, 39, 1656.
[3] For reviews, see: a) C. Cativiela, M. D. Dꢁaz-de-Villegas, Tetra-
hedron: Asymmetry 1998, 9, 3517; b) Y. Ohfune, T. Shinada,
Bull. Chem. Soc. Jpn. 2003, 76, 1115.
[4] J. Hernꢀndez-Toribio, R. Gꢂmez Arrayꢀs, J. C. Carretero, J. Am.
Chem. Soc. 2008, 130, 16150.
[5] a) A. Singh, J. N. Johnston, J. Am. Chem. Soc. 2008, 130, 5866;
b) Z. Chen, H. Morimoto, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2008, 130, 2170; c) D. Uraguchi, K. Koshimoto, T.
Ooi, J. Am. Chem. Soc. 2008, 130, 10878; d) B. Han, Q.-P. Liu, R.
Li, X. Tian, X.-F. Xiong, J.-G. Deng, Y.-C. Chen, Chem. Eur. J.
2008, 14, 8094; e) A. Puglisi, L. Raimondi, M. Benaglia, M.
Bonsignore, S. Rossi, Tetrahedron Lett. 2009, 50, 4340; f) D.
Uraguchi, K. Koshimoto, C. Sanada, T. Ooi, Tetrahedron:
Asymmetry 2010, 21, 1189; for the reaction with an a-imino
ester, see: g) K. R. Knudsen, K. A. Jørgensen, Org. Biomol.
Chem. 2005, 3, 1362.
[6] a) D. Uraguchi, Y. Ueki, T. Ooi, J. Am. Chem. Soc. 2008, 130,
14088; b) X. Liu, L. Deng, X. Jiang, W. Yan, C. Liu, R. Wang,
Org. Lett. 2010, 12, 876; for related work, see: c) D. Uraguchi, K.
Koshimoto, T. Ooi, Chem. Commun. 2010, 46, 300.
[7] For other related works on catalytic asymmetric Mannich-type
reactions towards the synthesis of a,b-diamino acids bearing
vicinal trisubstituted carbon centers, see the review in Ref. [2a]
and references therein.
[8] T. Yoshino, H. Morimoto, G. Lu, S. Matsunaga, M. Shibasaki, J.
Am. Chem. Soc. 2009, 131, 17082.
[9] For related reports on the Mannich-type reaction of aldimines
with a-isothiocyanato imides for the synthesis of a,b-diamino
acids bearing vicinal trisubstituted carbon centers, see: a) G. A.
Cutting, N. E. Stainforth, M. P. John, G. Kociok-Kꢃhn, M. C.
Willis, J. Am. Chem. Soc. 2007, 129, 10632; b) L. Li, M. Ganesh,
D. Seidel, J. Am. Chem. Soc. 2009, 131, 11648; c) Z. Shi, P. Yu,
P. J. Chua, G. Zhong, Adv. Synth. Catal. 2009, 351, 2797; d) X.
Chen, S. Dong, Z. Qiao, Y. Zhu, M. Xie, L. Lin, X. Liu, X. Feng,
Chem. Eur. J. 2011, 17, 2583.
Scheme 1. Transformation of the Mannich adduct into imidazolines:
a) Raney Ni, MeOH, H2 (1 atm), 608C, 22 h, 85% yield;
b) [Cp2Zr(H)Cl], toluene, RT, 4 h, 96% yield; c) PhB(OH)2, CuTC
(3 equiv), [Pd(PPh3)4] (10 mol%), DMF, microwave, 1308C, 1 h, 71%
yield. Cp=cyclopentadienyl, DMF=N,N’-dimethylformamide,
TC=thiophen-2-carboxylate.
[10] Magnesium alkoxides resulted in much lower reactivity than
Bu2Mg, possibly because of their poor solubility.
4384
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4382 –4385

[11] For the use of Sr(OiPr)2 in other catalytic asymmetric reactions,
see: a) M. Agostinho, S. Kobayashi, J. Am. Chem. Soc. 2008, 130,
2430; b) H. Van Nguyen, R. Matsubara, S. Kobayashi, Angew.
Chem. 2009, 121, 6041; Angew. Chem. Int. Ed. 2009, 48, 5927;
c) Y. Tanaka, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2010,
132, 8862.
[12] CCDC 812101 (syn-6b) and 812102 (anti-4h) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[17] For selected examples of asymmetric reactions catalyzed by
metal/biaryl ligand complexes, see: a) K. Mikami, Y. Motoyama,
M. Terada, Inorg. Chim. Acta 1994, 222, 71; b) T. Harada, M.
Takeuchi, M. Hatsuda, S. Ueda, A. Oku, Tetrahedron: Asym-
metry 1996, 7, 2479; c) Z. Zhang, H. Qian, J. Longmire, X.
Zhang, J. Org. Chem. 2000, 65, 6223; d) T. T.-L. Au-Yeung, S.-S.
Chan, A. S. C. Chan, Adv. Synth. Catal. 2003, 345, 537; e) Y. Xu,
G. Lu, S. Matsunaga, M. Shibasaki, Angew. Chem. 2009, 121,
3403; Angew. Chem. Int. Ed. 2009, 48, 3353.
[18] For a related example of metal dependent diastereo-switching
[13] The reaction of ketimines 3e with a-ethyl-a-isothiocyanato ester
using the Sr/1b catalyst (10 mol%) gave the product in 33%
yield, 15:85 (syn/anti), and 57% ee after 24 h at RT.
using the same chiral ligand and based on a change in
aggregation, see: A. Nojiri, N. Kumagai, M. Shibasaki, J. Am.
Chem. Soc. 2009, 131, 3779.
[14] ESI-MS analysis also failed to provide useful information on the
oligomeric structures of Mg/1b and Sr/1b.
[19] For a review, see: a) L. Rꢃmer, C. Klein, A. Dehner, H. Kessler,
J. Buchner, Angew. Chem. 2006, 118, 6590; Angew. Chem. Int.
Ed. 2006, 45, 6440; see also: b) L. T. Vassilev, B. T. Vu, B. Graves,
D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, C.
Lukacs, C. Klein, N. Fotouhi, E. A. Liu, Science 2004, 303, 844;
c) C. Tovar, J. Rosinski, Z. Filipovic, B. Higgins, K. Kolinsky, H.
Hilton, X. Zhao, B. T. Vu, W. Qing, K. Packman, O. Myklebost,
D. C. Heimbrook, L. T. Vassilev, Proc. Natl. Acad. Sci. USA
2006, 103, 1888.
[20] a) R. S. Bon, N. E. Sprenkels, M. M. Koningstein, R. F. Schmitz,
F. J. J. de Kanter, A. Dꢃmling, M. B. Groen, R. V. A. Orru, Org.
Biomol. Chem. 2008, 6, 130; b) C. L. Kusturin, L. S. Liebeskind,
W. L. Neumann, Org. Lett. 2002, 4, 983; c) A. Lengar, C. O.
Kappe, Org. Lett. 2004, 6, 771.
[15] Because Schiff base 1b in the absence of a metal source was
relatively unstable in CHCl3 and gradually decomposed, THF
(without stabilizer) was used for the CD analysis. THF was also
used as the solvent, and showed similar diastereoselectivity.
[16] For detailed conformational studies of binaphthyl compounds
and the assessment of the dihedral angle in the solution phase
using CD analysis, see: a) C. Rosini, S. Superchi, H. W. I.
Peerlings, E. W. Meijer, Eur. J. Org. Chem. 2000, 61; b) L.
Di Bari, G. Pescitelli, P. Salvadori, J. Am. Chem. Soc. 1999, 121,
7998; c) S. F. Mason, R. H. Seal, D. R. Roberts, Tetrahedron
1974, 30, 1671; for the CD analysis of oligonaphthalenes, see:
d) K. Takaishi, M. Kawamoto, K. Tsubaki, Org. Lett. 2010, 12,
1832, and references therein.
Angew. Chem. Int. Ed. 2011, 50, 4382 –4385
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4385