A novel chiral pentamine ligand for enantioselective α-alkylation of acyclic lithium amide enolates. Optimization of chiral ligands for asymmetric reactions using solid-phase organic synthesis

Article abstract of DOI:10.1021/ol990624d

(equation presented) A novel pentamine ligand has been developed for enantioselective α-alkylation of simple acyclic lithium amide enolates. It has been demonstrated that solid-phase organic synthesis provides a powerful and rapid method for finding effic

Full text of DOI:10.1021/ol990624d

ORGANIC
LETTERS
1999
Vol. 1, No. 2
345-347
A Novel Chiral Pentamine Ligand for
Enantioselective r-Alkylation of Acyclic
Lithium Amide Enolates. Optimization of
Chiral Ligands for Asymmetric
Reactions Using Solid-Phase Organic
Synthesis
Jun-ichi Matsuo, Kazunori Odashima, and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received April 30, 1999
ABSTRACT
A novel pentamine ligand has been developed for enantioselective r-alkylation of simple acyclic lithium amide enolates. It has been demonstrated
that solid-phase organic synthesis provides a powerful and rapid method for finding efficient chiral ligands.
Development of asymmetric R-alkylation reactions of car-
bonyl and related compounds is one of the most important
tasks in modern organic synthesis.1 Although many diaste-
reoselective alkylation reactions have been developed,1,2 only
limited examples of enantioselective reactions are reported.3-5
Among them, alkylation using lithium enolates is the most
promising, and enantioselective R-alkylation of cyclic ke-
tones, lactones, and lactams has been performed using a
chiral amine ligand.5 However, there is no successful
example, to the best of our knowledge, of the enantioselective
R-alkylation of simple acyclic carbonyl compounds. This is
probably because two geometrical isomers of enolates form
from acyclic compounds in most cases, and the stereocontrol
(1) For reviews see: (a) Evans, D. A. In Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic Press: New York, 1983-1984; Vol 3, pp 1-110. (b)
Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol 3, pp 1-63. (c) Seyden-Penne,
J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; John Wiley &
Sons: New York, 1995.
(2) (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233-
4236. (b) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre,
D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109-1127. (c) Evans, D.
A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737-1739.
(d) Evans, D. A. Aldrichim. Acta 1982, 15, 23-32. (e) Oppolzer, W.;
Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603-5606.
(3) Phase transfer catalyzed alkylation: Corey, E. J.; Bo, Y.; Busch-
Petersen, J. J. Am. Chem. Soc. 1998, 120, 13000-13001 and references
therein.
(4) Palladium-catalyzed reaction: (a) Hayashi, T.; Kanehira, K.; Hagi-
hara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113-120. (b) Genet, J. P.;
Ferroud, D.; Juge, F. S.; Montes, J. R. Tetrahedron Lett. 1986, 27, 4573-
4576. (c) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem.
Soc. 1992, 114, 2586-2592. (d) Trost, B. M.; Radinov, R.; Grenzer, E. M.
J. Am. Chem. Soc. 1997, 119, 7879-7880. (e) Åhman, J.; Wolfe, J. P.;
Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 1918-1919.
10.1021/ol990624d CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

of both enolates is difficult. Accordingly, we undertook the
task, and in this paper we report a novel chiral pentamine
ligand for the enantioselective alkylation of acyclic lithium
amide enolates.
Scheme 2. Solid-Phase Synthesis of 5-25
We chose an acyclic amide as a substrate, because it was
reported that a (Z)-lithium enolate was selectively formed
by lithium amide deprotonation,1a and that the amide group
could be readily converted to other useful functional groups.
We first used pyrrolidinepropionamide (1a, eq 1 in Scheme
1) for a model acyclic amide, and benzylation was performed
Scheme 1
amine was used for solid-phase peptide synthesis. After
coupling with three amino acids, N,N-dialkylglycine was
added. Cleavage from the solid support was performed at
this stage and terminal secondary amine was methylated.
Finally, reduction using BH3‚THF gave chiral pentamines.
The chiral ligands synthesized were tested in the benz-
ylation reaction of 1a (Table 1). First, three ligands having
a chiral pyrrolidine structure derived from L-proline were
investigated (entries 2-4). Among them, chiral amine 8, in
which L-proline was introduced as the third amino acid
(AA3), was found to be the most effective (36% ee). Thus,
L-proline was fixed as the third amine part (AA3), and then
the first and second amino acids (AA1 and AA2) and the
N,N-dialkyl groups of glycine were screened. It was revealed
that chiral ligand 22, which was prepared from L-leucine
(AA1), L-phenylalanine (AA2), L-proline (AA3), and N,N-
dimethylglycine, gave the best selectivitiy at this stage (47%
ee, entry 18). While the second amino acid (AA2), or the
N,N-dialkyl groups of glycine had little effect on the
enantioselectivity, the first amino acid (AA1) was shown to
play an important role in the selectivity.
using the chiral induction system consisting of chiral
tetradentate amine 3, LiBr, and a lithium enolate in toluene
(nonpolar solvent).5 While the first trial gave low chemical
yield and enantioselectivity (4% yield, 18% ee), both
chemical yield and ee were improved (30% yield, 25% ee)
when a pentadentate chiral amine (4) was used. From these
results, it was assumed that pentadentate chiral ligands would
be better in this alkylation reaction. To perform more efficient
and rapid ligand searching, we decided to use solid-phase
synthesis.6 The ligand syntheses using the solid-phase
protocols were performed as shown in Scheme 2. Piperazine
was connected to trityl-type resin and this polymer-supported
Although moderate selectivity was obtained at this stage,
it was not yet satisfactory. To optimize the chiral ligand
structure, we then modified the N-methylpiperazine moiety
of 22. When the N-methylpiperazine structure was replaced
by a piperidine group (26), the enantioselectivity was
improved to 62% ee (Table 2). Moreover, the ligand
complexation conditions of the lithium enolate were found
to influence the enantiofacial selectivity dramatically.7 When
(5) (a) Review: Koga, K.; Shindo, M. J. Synth. Org. Chem. Jpn. 1995,
53, 1021-1032. (b) Murakata, M.; Nakajima, M.; Koga, K. J. Chem. Soc.,
Chem. Commun. 1990, 1657-1658. (c) Hasegawa, Y.; Kawasaki, H.; Koga,
K. Tetrahedron Lett. 1993, 34, 1963-1966. (d) Yasukata, T.; Koga, K.
Tetrahedron: Asymmetry 1993, 4, 35-38. (e) Imai, M.; Hagihara, A.;
Kawasaki, H.; Manabe, K.; Koga, K. J. Am. Chem. Soc. 1994, 116, 8829-
8830. (f) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996, 37,
6343-6346. (g) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997,
38, 3531-3534. (h) Riviere, P.; Koga, K. Tetrahedron Lett. 1997, 38, 7579-
7592. (i) Murakata, M.; Yasukata, T.; Aoki, T.; Nakajima, M.; Koga, K.
Tetrahedron 1998, 54, 2449-2458. (j) Matsuo, J.; Kobayashi, S.; Koga,
K. Tetrahedron Lett. 1998, 39, 9723-9726. (k) Yamashita, Y.; Odashima,
K.; Koga, K. Tetrahedron Lett. 1999, 40, 2803-2806.
(7) (a) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271-1290. (b) Matsuo, J.;
Koga, K. Chem. Pharm. Bull. 1997, 45, 2122-2124.
24
(8) The absolute configuration of 2a (46% ee; [R]D +31.8 (c 1.0,
CHCl3)) was determined by acidic hydrolysis to (S)-R-benzylpropionic acid
(Helmchen, G.; Nill, G.; Flockerzi, D.; Youssef, M. S. K. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 63-65).
(6) (a) Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712-7713. (b)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902.
(c) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704-
1707 and references therein.
(9) Typical Experimental Procedure. Under Ar atmosphere, to the
solution of 27 (129 mg, 0.30 mmol) in toluene (2.7 mL) was added dropwise
n-buthyllithium in hexane (1.57 N, 0.36 mL, 0.57 mmol) at -20 °C. After
the solution was stirred 30 min, 1b (38 mg, 0.27 mmol) in toluene (1.5
346
Org. Lett., Vol. 1, No. 2, 1999

Table 1. Effect of Chiral Ligands in Benzylation of 1aa,b
Table 2. Effect of Chiral Ligands in Benzylationa
Furthermore, the enantiomeric excess was improved to 84%
when piperidinepropionamide (1b) was used.9 The same high
selectivity was obtained when using 1c, 1d, 1e, and 1f.
In conclusion, we have developed pentamine ligand 27
which is effective in enantioselective alkylation of acyclic
lithium amide enolates. It has been also demonstrated that
solid-phase organic synthesis provides a powerful and rapid
method for finding efficient ligands. While the effective
chiral ligand was found in this work, the precise structure
of the lithium enolate-chiral ligand complex and the transition
state of the enantioselective alkylation are still unclear.
Further studies to clarify them as well as to show synthetic
utility including the scope and limitation of this alkylation
are now in progress.
27 and 2 equiv of BuLi were supplied to the lithium amide,
the same level of ee was obtained (65%). It is noted that the
enantiofacial selectivity was reversed using the new system.
mL) was added and the solution was stirred 30 min. Benzyl bromide (0.04
mL, 0.34 mmol) of toluene (1.0 mL) solution was then added at -78 °C,
and the solution was stirred 10 min. The reaction was quenched with 0.1 N
aqueous citric acid (5.0 mL), and extracted with AcOEt (10 mL × 3). The
combined organic extracts were washed with saturated aqueous NaHCO3
and brine, and dried with Na2SO4. After filtration, the filtrate was
concentrated in vacuo to give a pale yellow oil. This crude product was
purified by preparative TLC (hexane/AcOEt) to give 2b (25 mg, 40% yield).
Enantiomeric excess of this product was determined by HPLC under the
following conditions: Chiralcel OD-H (hexane/2-propanol ) 30/1, 0.5 mL/
Acknowledgment. The authors thank Mr. Takayuki
Furuta for his contribution to the development of the new
polymer-supported amine. This work was partially supported
by CREST, Japan Science and Technology Corporation
(JST), and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture, Japan.
min, 254 nm) 23.5 min (minor), 28.9 min (major); 84% ee; [R]23 -39.4
Supporting Information Available: Experimental pro-
cedures and physical data of the products and ligands. This
material is available free of charge via the Internet at
http://pubs.acs.org.
D
1
(c 0.54, CHCl3); H NMR (400 MHz/CDCl3) δ 1.14 (3H, d, J ) 6.3 Hz),
1.3-1.6 (6H, m), 2.6-2.7 (1H, m), 2.9-3.0 (2H, m), 3.26 (2H, brs), 3.41
(2H, brs), 3.60 (1H, brs), 7.1-7.3 (5H, m); 13C NMR (100 MHz/CDCl3) δ
17.86, 24.57, 25.60, 26.38, 37.43, 40.57, 42.86, 46.56, 126.11, 128.28,
129.10, 140.31, 174.09; IR (neat, cm-1) 1637, 1443, 1227, 1010, 701.
HRMS Calcd for C15H21NO: 231.1623. Found: 231.1605.
OL990624D
Org. Lett., Vol. 1, No. 2, 1999
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