Despite this exciting discovery, current and future research
related to 1 is impeded by its difficult synthesis. In particular,
the chiral pyrrolidine fragment 2 (Figure 1), which was
achieved by a seven-step procedure,3b,c suffered from major
disadvantages, e.g., expensive starting material, hard chro-
matographic purifications, and low overall yield (<2%).3b,c
Moreover, the utilization of racemic starting materials
requires extra chiral resolution step(s) using either HPLC or
chiral auxiliaries,3c which dramatically reduce the yield and
efficiency. Therefore, the development of an efficient route
to 2 is a bottleneck to future investigations of inhibitor 1.
Herein, we report the development of a concise stereospe-
cific synthesis of 2. Our initial plan was to use a disubstitution
reaction on dimesylate 3 with benzylamine (Scheme 1).5
protecting group was selected for two reasons. First, this
protecting group is known to be stable under a variety of
reaction conditions and can be easily removed under mild
conditions.8 Second, the electron-donating property of the
2,5-dimethylpyrrole group increases the chelating ability of
the pyridine nitrogen to the lithium ion, which favors
regioselective deprotonation of the 2-methyl group on the
pyridine ring.9 Compound 8 was treated with n-BuLi at 0
°C, and the resulting anion was quenched with chlorotrim-
ethylsilane (TMSCl) at the same temperature to generate 9
exclusively.8a Finally, 9 was allowed to react with 1,2-
dibromotetrafluoroethane in the presence of CsF to provide
6 in quantitative yields.10
Next, optimization of the conditions for the Frater-Seebach
alkylation was investigated (Table 1). When using lithium
Scheme 1. Retrosynthetic Analysis for 2
Table 1. Frater-Seebach Diastereoselective Alkylation
entry
R
base
LDA
6 (equiv)
yieldb (%)
trans/cisc
1
2
3
4
5
6
7
Me
i-Pr
Me
i-Pr
i-Pr
i-Pr
i-Pr
1.0
1.0
1.0
1.0
0.75
0.5
0.33
<2
<2
23
56
70
77
85
LDA
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
8:1
>15:1
>15:1
>15:1
>15:1
Dimesylated compound 3 could be derived from dialkyl
malate (4) using a sequential allylation-reduction procedure.
Stereospecific compound 4 could be achieved by the dias-
tereoselective alkylation protocol developed by Frater et al.6
and Seebach et al.7 using dialkyl (R)-(+)-malate (5) and
2-(bromomethyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-meth-
ylpyridine (6) as starting materials.
a General experimental conditions: 2 equiv of base was added to 1 equiv
of 5 at -78 °C, and then the reaction temperature was raised to 0 °C and
maintained for 20 min. The reaction was cooled to -78 °C and compound
c
6 was added. b Isolated yields. Determined by H NMR.
1
The synthesis of 6 began with 2-aminopyridine (7, Scheme
2). The amino functional group of 7 was protected using
diisopropylamide (LDA) as the base, we isolated only a trace
amount of product using either 5a or 5b as the starting
material (Table 1, entries 1 and 2). With lithium hexameth-
yldisilazide (LHMDS) as the base, however, we could isolate
products 4a and 4b in 23% and 56% yield, respectively, with
high diastereoselectivity (Table 1, entries 3 and 4). We then
improved the yield to 85% by changing the ratio between
5b and 6 (Table 1, entries 5-7).
Scheme 2. Synthesis of 6
Allylation of 4b via NaH and allylbromide yielded 10,
which was reduced using LiAlH4 to generate diol 11 in
excellent yields (Scheme 3). When 11 was submitted to a
variety of mesylation conditions, however, the only products
(8) (a) Hagmann, W. K.; Caldwell, C. G.; Chen, P.; Durette, P. L.; Esser,
C. K.; Lanza, T. J.; Kopka, I. E.; Guthikonda, R.; Shah, S. K.; MacCoss,
M.; Chabin, R. M.; Fletcher, D.; Grant, S. K.; Green, B. G.; Humes, J. L.;
Kelly, T. M.; Luell, S.; Meurer, R.; Moore, V.; Pacholok, S. G.; Pavia, T.;
Williams, H. R.; Wong, K. K. Bioorg. Med. Chem. Lett. 2000, 10, 1975.
(b) Xue, F.; Li, H.; Poulos, T. L.; Silverman, R. B. Unpublished results.
(9) Bowers, S. G.; Coe, D. M.; Boons, G.-J. J. Org. Chem. 1998, 63,
4570.
2,5-hexanedione in the presence of p-toluenesulfonic acid
(p-TsOH) to give 8 in high yields. The 2,5-dimethylpyrrole
(5) Kotian, P. L.; Chand, P. Tetrahedron Lett. 2005, 46, 3327.
(6) Frater, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269.
(7) Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1985, 63, 109.
(10) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63,
10048.
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