Direct catalytic enantioselective mannich reactions: Synthesis of protected anti-α,β-diamino acids

Article abstract of DOI:10.1021/ja073473f

Anti-configured protected α,β-diamino acids are prepared with up to 99% ee using a direct catalytic enantioselective Mannich reaction. A catalyst system incorporating a chiral bis(oxazoline) ligand, Mg(ClO₄)₂ and Huenigs base, promot

Full text of DOI:10.1021/ja073473f

Published on Web 08/11/2007
Direct Catalytic Enantioselective Mannich Reactions: Synthesis of Protected
anti-r,â-Diamino Acids
Gary A. Cutting,† Nikki E. Stainforth,‡ Matthew P. John,§ Gabriele Kociok-Ko¨hn,† and
Michael C. Willis*,‡
Department of Chemistry, UniVersity of Bath, Bath BA2 7AY, U.K., Department of Chemistry, UniVersity of Oxford,
Chemical Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K., and Chemical DeVelopment DiVision,
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SteVenage SG1 2NY, U.K.
Received May 16, 2007; E-mail: michael.willis@chem.ox.ac.uk
Table 1. Catalyst Evaluation for the Direct Addition of Imide 1 to
R,â-Diamino acids are important structural motifs present in
Imine 2a
many natural products and medicinal agents, and are implicated in
a variety of biological functions.1 1,2-Diamines derived from these
amino acids have also found wide application as chiral auxilaries
and as ligands for asymmetric synthesis.2 Although a number of
methods for their preparation exist, catalytic enantioselective
variants remain rare.1 A direct, catalytic, enantioselective Mannich
entry
ligand
yield (%)b
syn:antic
ee (%)d
reaction between a glycine equivalent and an imine, involving the
creation of a C-C bond and two stereogenic centers in a single
operation, represents an attractive and atom-efficient route to these
compounds (eq 1). Although a handful of syntheses corresponding
to this approach has been described, all lead to the selective
formation of syn-configured products.3 In this communication
we detail a new synthesis of protected R,â-diamino acids, which
delivers anti-configured products in good yields and with excellent
enantioselectivities.
1
2
3
4
5
6
7
8e
9
3
5
6
7
8
9
10
10
-
99
99
99
99
97
83
94
87
80
36:64
30:70
20:80
14:86
34:66
40:60
12:88
25:75
15:85
45
8
43
70
39
4
96
37
-
a Conditions: imide (1.0 equiv), imine (2.0 equiv), Mg(ClO4)2 (10 mol
%), ligand (11 mol %), DIPEA (20 mol %), CH2Cl2, -78 °C, 24 h. b Isolated
yields. c Determined by 1H NMR spectroscopy of crude reaction mixtures.
d Determined by chiral HPLC using Chiracel OD column. e 5 mol %
Mg(ClO4)2, 6 mol % ligand.
ligands, we speculated that the DBFox12 ligand 10 might also
generate a selective catalyst. Pleasingly, a reaction incorporating
ligand 10 delivered the required adduct in 94% yield as an 88:12
mixture of anti:syn diastereomers in 96% ee (entry 7). Reactions
employing lower catalyst loadings resulted in significantly reduced
enantioselectivites; for example, 5 mol % catalyst delivered material
of only 37% ee (entry 8). A reaction employing the magnesium
salt and base, in the absence of any chiral ligand was used as a
control to establish the inherent diastereoselectivity of the process;
the adduct was obtained in 80% yield with the anti-isomer again
dominating (entry 9).
Enantioselective Mannich reactions employing enolate sur-
rogates,4 or carbonyl compounds directly,5 have been used to
prepare a variety of amine-containing systems, although anti-
selective reactions are generally limited to unfunctionalized nu-
cleophiles.6,7 Direct enantioselective Mannich reactions employing
nucleophiles at the carboxylic acid oxidation level are also rare.8
At the outset of our study our goals were to develop a highly
selective synthesis of R,â-diamino acids that would allow an acid
derivative to be employed directly as the nucleophilic component
and that both enolizable and non-enolizable imines could be used
as electrophiles.
On the basis of our successful synthesis of R-amino-â-hydroxy
acids,9 we selected isothiocyanate-substituted oxazolidinone 1 as
an ideal nucleophilic partner,10 and chose to study the union of 1
and the N-Ts-imine derived from benzaldehyde 2 as a test reaction.
The starting point for catalyst selection was based on those
developed for enantioselective aldol reactions employing oxazoli-
dinone 1; the use of a catalyst composed of Mg(ClO4)2, Ph-PyBox
ligand 3, and Hu¨nigs base, delivered the Mannich adduct 4 in 99%
yield but only 45% ee (Table 1, entry 1). A variety of alternative
i
PyBox ligands11 were investigated, and the Pr-substituted variant
We next explored the scope of the imine component (Table 2).
The three regioisomeric imines generated from tolualdehyde all
provided the Mannich adducts with similarly high levels of yield
and selectivity to the parent system (entries 1-4). In general,
functionalized aryl imines are excellent substrates for the reaction,
with examples of electron-donating and -withdrawing groups, and
a number of halo-substituted examples all performing well (entries
5-11). The successful use of 2-thiophenyl-, 3-furyl-, and 2-(N-
delivered the Mannich adduct with the highest selectivity of 70%
ee (entries 2-4). Two bis(oxazoline) ligands were also evaluated;
however, their performance offered no advantages (entries 5 and
6). Given the higher selectivities achieved with the tridentate PyBox
† University of Bath.
‡ University of Oxford.
§ GlaxoSmithKline.
9
10632
J. AM. CHEM. SOC. 2007, 129, 10632-10633
10.1021/ja073473f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 anti to syn Epimerization
Table 2. Enantioselective Addition of Imide 1 to N-Ts-iminesa
Acknowledgment. This work was supported by the EPSRC and
GlaxoSmithKline. The EPSRC Mass Spectrometry Service at the
University of Wales Swansea is also thanked for their assistance.
Supporting Information Available: Experimental procedures and
full characterization for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
entry
R
yield (%)b
syn:antic
ee (%)d
1
2
3
4
5
6
7
8
Ph
94
96
91
94
96
86
86
98
98
85
94
95
94
99
97
98
96
63
12:88
12:88
14:86
14:86
18:82
24:76
16:84
20:80
24:76
32:68
7:93
13:87
14:86
10:90
22:78
32:68
28:72
32:68
96e
99f
99
99
99
97f
98
95
93
99f
98
90f
91g
99
97
99e
85
84
References
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-tBu-C6H4
4-MeO-C6H4
4-Br-C6H4
4-Cl-C6H4
4-F-C6H4
4-CN-C6H4
2-Np
(1) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.; Flores, A. Chem. ReV.
2005, 105, 3167.
(2) For a review on the chemistry of vicinal diamines, see; Lucet, D.; Le
Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(3) (a) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2006, 8, 2839. (b) Okada, A.; Shibuguchi, T.;
Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4564. (c) Ooi, T.; Kameda, M.; Fujii, J.-i; Maruoka, K.
Org. Lett. 2004, 6, 2397. (d) Benardi, L.; Gothelf, A. S.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
(4) Selected examples: (a) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 500. (b) Saruhasi, K.; Kobayahi, S. J. Am. Chem. Soc.
2006, 128, 11232. (c) Ihori, Y.; Yamashita, Y.; Ishitani, H.; Kobayahi, S.
J. Am. Chem. Soc. 2005, 127, 15528. (d) Kobayashi, S.; Matsubara, R.;
Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125,
2507. (e) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. AdV. Synth.
Catal. 2005, 347, 1523. (f) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Ind. Ed. 2004, 43, 1566. (g) Josephsohn, N. S.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734. (h) Wenzel,
A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (i) Ferraris,
D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.;
Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67.
(5) Selected examples: (a) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu,
Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 3790. (b) Cheong, P. H.-
Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C.
F., III. Org. Lett. 2006, 8, 811. (c) Yamaguchi, A.; Matsunaga, S.;
Shibasaki, M. Tetrahedron Lett. 2006, 47, 3985. (d) Sugita, M.; Yamagu-
chi, A.; Yamigiwa, N.; Handa, S.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2005, 7, 5339. (e) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006,
8, 2003. (f) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem.
Soc. 2005, 127, 11256. (g) Hayashi, Y.; Urushima, T.; Shoji, M.;
Uchimaru, T.; Shiina, I. AdV. Synth. Catal. 2005, 347, 1595. (h) Cobb,
A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84. (i) Hamashima, Y.; Sasamoto, N.; Hotta, D.;
Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005,
44, 1525. (j) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2004, 43, 4476. (k) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 1367. (l) Trost, B. M.; Terrell, L. R. J. Am.
Chem. Soc. 2003, 125, 338.
(6) (a) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 9630. (b) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.;
Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc., 2006,
128, 1040. (c) Ibrahem, I.; Co´rdova, A. Chem. Commun. 2006, 1760.
(7) For examples of anti-selective Mannich reactions employing hydroxyl-
substituted ketones, see: (a) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul,
V. J. Am. Chem. Soc. 2006, 128, 2778. (b) Matsunaga, S.; Kumagai, N.;
Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712.
(8) (a) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4365. (b) Also see ref 3d.
9
10
11
12
13
14
15
16
17
18
2-thiophenyl
3-furyl
2-N-Ts-indolyl
(E)-cinnamyl
cyclohexyl
cyclopropyl
C5H11
a Conditions; imide 1 (1.0 equiv), imine (2.0 equiv), Mg(ClO4)2 (10 mol
%), 10 (11 mol %), DIPEA (20 mol %), CH2Cl2, -78 °C, 24 h. b Isolated
yields. c Determined by 1H NMR spectroscopy of crude reaction mixtures.
d Determined by chiral HPLC using Chiracel OD column, of anti-isomer.
e Absolute configuration established by X-ray diffraction study. All others
assigned by analogy. f ee measured on ethyl ester derivative. g ee measured
on isopropyl ester derivative.
Ts)-indolyl-derived imines demonstrates that heteroaromatic imines
can be successfully employed (entries 12-14). The indole-derived
imine provides a potentially useful â-amino-tryptophan derivative.13
The methodology is not limited to aromatic imines; addition of
imide 1 to the N-Ts imine generated from cinnamaldehyde
proceeded smoothly (entry 15). The cyclohexyl-derived imine
delivered the Mannich adduct in 98% yield with 99% ee, although
the smaller cyclopropyl- and hexyl-derived imines showed reduced
enantioselectivity (entries 16-18). In all cases the anti-diastereomer
was obtained as the major product. This selectivity is opposite that
observed in the additions of imide 1 to the corresponding aryl
aldehydes9 and presumably originates from the tosyl group of the
E-configured imines forcing coordination of the Lewis acid syn to
the imine substituent.14 Control experiments established that the
diasteromer ratios are constant throughout the reaction.
The in situ protection of the anti-diamines as the corresponding
cis-cyclic thioureas provided an opportunity to access the syn-
Mannich diastereomers. For example, conversion of imide 4 to ester
11 provides a substrate suitable for R-epimerization; treatment of
ester 11 with DBU results in the formation of the trans-substituted
thiourea 12, corresponding to the syn-Mannich adduct (Scheme 1).
In conclusion, we have developed a new enantioselective route
to anti-configured protected R,â-diamino acids using a direct
enantioselective Mannich reaction. A variety of aryl-, heteroaryl-,
alkenyl-, and alkyl-derived imines can all be employed. Conversion
(9) (a) Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John,
M. P. Angew. Chem., Int. Ed. 2005, 44, 1543. (b) Willis, M. C.; Piccio,
V. J.-D. Synlett 2002, 1625.
(10) For examples of the use of a chiral version of 1 in diastereoselective aldol
additions, see: (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986,
108, 6757. (b) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109,
7151. (c) Lago, M. A.; Samanen, J.; Elliot, J. D. J. Org. Chem. 1992, 57,
3493. (d) Boger, D. L.; Colletti, S. L.; Honda, T.; Menezes, R. F. J. Am.
Chem. Soc. 1994, 116, 5607.
(11) McManus, H. A.; Guiry, P. J. Chem. ReV. 2004, 104, 4151.
(12) (a) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.; Wada, E.;
Curran, D. P. J. Org. Chem. 1997, 62, 6454. (b) Iserloh, U.; Oderaotoshi,
Y.; Kanemasa, S.; Curran, D. P. Org. Synth. 2003, 80, 46.
(13) (a) Fueloep, F.; Martinek, T. A.; Toth, G. K. Chem. Soc. ReV. 2006, 35,
323. (b) Sewald, N. Angew. Chem. Int. Ed. 2003, 42, 5794.
(14) For a review of enantioselective additions to imines, see: Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069.
i
of the products to their Pr-ester derivatives allows epimerization
to the syn-diastereomers.
JA073473F
9
J. AM. CHEM. SOC. VOL. 129, NO. 35, 2007 10633