1,2-additions did so (with conformational control over the sense
of stereoinduction also possible), while catalysts characterised
by a greater distance between the acidic and basic functionality
proved inactive. This order of catalytic efficacy was completely
reversed in a 1,4-addition process. The study resulted in the
catalysis of highly enantioselective DKR processes, including
the catalytic enantioselective preparation of an orthogonally
protected extraterrestrial amino acid for the first time.
Financial support from Science Foundation Ireland and
The Irish Research Council for Science Engineering and
Technology is gratefully acknowledged.
Scheme 1 DKR catalysed by 16: investigation of substrate scope.
Notes and references
1 Selected general recent reviews: (a) T. Marcelli and H. Hiemstra,
Synthesis, 2010, 1229; (b) Cinchona Alkaloids in Synthesis and
Catalysis: Ligands Immobilization and Organocatalysis, ed.
C. E. Song, Wiley-Vch, Weinheim, 2009; (c) S. J. Connon, Synlett,
2009, 354; (d) X. Yu and W. Wang, Chem.–Asian J., 2008, 3, 516;
(e) S. J. Connon, Chem. Commun., 2008, 2499; (f) Y. Chen, Synlett,
2008, 1919; (g) G. Bartoli and P. Melchiorre, Synlett, 2008, 1759.
2 Representative seminal references (a) B. J. Li, L. Jiang, M. Liu,
Y. C. Chen, L. S. Ding and Y. Wu, Synlett, 2005, 603;
(b) B. Vakulya, S. Varga, A. Csampai and T. Soos, Org. Lett.,
2005, 7, 1967; (c) S. H. McCooey and S. J. Connon, Angew. Chem.,
Int. Ed., 2005, 44, 6367; (d) J. Ye, D. J. Dixon and P. S. Hynes,
Chem. Commun., 2005, 4481.
3 Seminal work on related non-alkaloid-based (thio)urea catalysts:
H. Miyabe and Y. Takemoto, Bull. Chem. Soc. Jpn., 2008, 81, 785.
4 (a) S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. You, J. Chin
and C. E. Song, Angew. Chem., Int. Ed., 2008, 47, 7872;
(b) A. Peschiulli, B. Procuranti, C. J. O’ Connor and
S. J. Connon, Nat. Chem., 2010, 2, 380; (c) S. E. Park,
E. H. Nam, H. B. Jang, J. S. Oh, S. Some, Y. S. Lee and
C. E. Song, Adv. Synth. Catal., 2010, 352, 2211.
5 Representative references: (a) J. P. Malerich, K. Hagihara and
V. H. Rawal, J. Am. Chem. Soc., 2008, 130, 14416; (b) J. W. Lee,
T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang and C. E. Song, Chem.
Commun., 2009, 7224; (c) Y. Zhu, J. P. Malerich and V. H. Rawal,
Angew. Chem. Int. Ed., 2010, 49, 153; (d) L. Dai, S. X. Wang,
F. E. Chen, Wang and F. E. Chen, Adv. Synth. Catal., 2010,
352, 2137; (e) H. Konishi, T. Y. Lam, J. P. Malerich and
V. H. Rawal, Org. Lett., 2010, 12, 2028.
6 Representative recent references: (a) F. Wu, H. Li, R. Hong and
L. Deng, Angew. Chem., Int. Ed., 2006, 45, 947; (b) J. Wang. H. Li,
L. Zu and W. Wang, Org. Lett., 2006, 8, 1391; (c) Y. Wang, X. Liu
and L. Deng, J. Am. Chem. Soc., 2006, 128, 3928; (d) T. Marcelli,
R. N. S. van der Haas, J. H. van Maarseveen and H. Hiemstra,
Angew. Chem., Int. Ed., 2006, 45, 929; (e) M. Bandini, R. Sinisi and
A. Umani-Ronchi, Chem. Commun., 2008, 4360.
develop a novel class of DKR reaction whereby a commercially
available 1 : 1 mixture (48a) of the inexpensive L-isoleucine and
the highly expensive D-allo-isoleucine (48b – also present in
the Murchison meteorite,12 Scheme 1), after N-acylation and
dehydrative cyclisation, could be converted to 48 (an
orthogonally protected variant of the rare and expensive
D-allo-isoleucine) with good diastereoselectivity.
Finally, we were also naturally interested in whether
catalysts characterised by the location of the hydroxy group
at a further remove from the amine base would preferentially
promote
a conjugate addition. In a preliminary study
2-methylindole (49) was reacted with nitroalkene 50 (Table 3).
We were pleased to find that both the monofunctional catalyst
9 and analogues bearing o-hydroxy substituents at the C-9 aryl
ring (i.e. 10 and 16) proved barely capable of promoting the
Michael addition faster than the uncatalysed reaction (entries
1–4). However the 2,7-substituted naphthol-based 18 — which
is inactive in the 1,2-addition process — was capable of
significantly more efficient catalysis than any other member
of the library (entry 5). This superiority was further underlined
at 20 mol% loading (entries 6–7). Unfortunately, the enantio-
selectivity of these reactions was unsatisfactory (o 5% ee). It
is clear that the further development of catalysts such as 17–18
with the goal of improving upon their activity and selectivity
profiles is the next challenge.
To conclude, we have prepared a small library of novel
cinchona alkaloid-derived materials with the aim of rationally
designing a library of catalysts in which the relative proximity
and orientation of the catalytically relevant components can
be rapidly and systematically modified. In these preliminary
studies it was found that catalysts designed to favour
7 C-5 substituted cinchona alkaloid-based catalysts are known, see:
(a) S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard and
K. A. Jørgensen, Chem.–Eur. J., 2006, 12, 6039; (b) X. Liu, B. Sun
and L. Deng, Synlett, 2009, 1685; (c) C. Palacio and S. J. Connon,
Org. Lett., 2011, 13, 1298.
8 (a) P. J. Boratynski, I. Turowska-Tyrk and J. Skarzewski, Org.
˙
Lett., 2008, 10, 385; (b) P. J. Boratynski, I. Turowska-Tyrk and
Table 3 Catalyst evaluation in a 1,4-addition process
J. Skarzewski, J. Org. Chem., 2008, 73, 7357; (c) P. J. Boratynski
˙
˙
and J. Skarzewski, Synthesis, 2009, 3113.
9 Recent review: H. Pellissier, Tetrahedron, 2008, 64, 1563.
10 Representative examples: (a) J. Liang, J. C. Ruble and G. C. Fu,
J. Org. Chem., 1998, 63, 3154; (b) L. Xie, W. Hua, A. S. C. Chan
and Y. C. Leung, Tetrahedron: Asymmetry, 1999, 10, 4715;
(c) A. Berkessel, F. Cleeman, S. Mukherjee, T. N. Muller and
J. Lex, Angew. Chem., Int. Ed., 2005, 44, 807; (d) A. Berkessel,
S. Mukherjee, F. Cleemann, T. N. Muller and J. Lex, Chem.
Commun., 2005, 1898; (e) A. Peschiulli, C. Quigley, S. Tallon,
Y. K. Gun’ko and S. J. Connon, J. Org. Chem., 2008, 73, 6409;
(f) X. Yang, G. Lium and V. B. Birman, Org. Lett., 2010, 12, 892;
(g) L. Guojian and V. B. Birman, Org. Lett., 2011, 13, 356.
11 CHCl3 is also a suitable reaction solvent.
Entry
Catalyst
Loading (mol%)
t (d)
Yield (%)
1
2
3
4
5
6
7
—
9
—
10
10
10
10
20
20
3
3
3
3
3
7
7
7
8
10
16
18
10
18
10
12
30
35
61
12 J. R. Cronin and S. Pizzarello, Adv. Space Res., 1983, 3, 5.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1443–1445 1445