On the basis of our solution-phase study, we set out to develop a
solid-phase version of our chiral acetylating agent with a benzyl-
type anchorage. Polymer-supported reagent (1S,2S)-4 (Fig. 1) was
thus prepared in four steps as shown in Scheme 1; each step being
monitored using IR spectroscopy (recorded using a Perkin-Elmer
2000 FT-IR directly on the resin beads). The solid-phase synthesis
was initiated by treating commercially available Merrifield resin
(chloromethylated polystyrene, 1% cross-linked divinylbenzene,
1.58 mmol g21) with 4-hydroxybenzaldehyde and sodium hydro-
xide in DMSO (90 uC),16 to afford the benzaldehyde resin 5
(nCLO 5 1695 cm21) in excellent yield (.95% determined by
elemental analysis; loading 5 1.39 mmol g21). Resin 5 was then
treated with 1,3,5-triisopropylbenzene sulfonyl hydrazine at room
temperature leading to the supported hydrazone 6 which was
subsequently treated with potassium hydroxide in a MeOH/THF
mixture (90 uC). The resulting supported benzyl diazonium salt 7
reacted at room temperature with (1S,2S)-N-acetyl-1,2-bis-trifluor-
omethanesulfonamidocyclohexane (1S,2S)-1 leading to the desired
supported chiral reagent 4 (nCLO 5 1732 cm21). The loading of
resin 4 was determined as 0.58 mmol g21 by treating it with an
excess of (¡)-1-phenylethylamine and quantifying the recovered
acetylated product. This value, also confirmed by fluorine
elemental analysis, represents a 65% overall yield from readily
available Merrifield resin.
Table 2 Influence of the solvent on the selectivity using 4
Entry
Chiral reagent
Solvent
eea (%)
1
2
3
4
5
6
7
a
DMF
4 (Rb)
32 (R)
40 (R)
46 (R)
48 (R)
Cyclohexane
CH2Cl2
THF
Dioxane
CHCl3
Benzene
62 (R)
82 (R) 82 (Rc)
Enantiomeric excess determined by HPLC analysis using a chiral
b
phase column. Absolute configuration of the acetylated enantiomer
c
assigned by comparison with an authentic standard. Enantiomeric
excess after 4 consecutive cycles.
respectively led to 62 and 82% ee (entries 6–7) while they
respectively led to 50 and 54% when using (1S,2S)-3. Benzene
was found to be the solvent of choice for the KR of (¡)-1-
phenylethylamine as, in this solvent system, the product was
obtained in 82% ee at room temperature (s 5 12.3; entry 7).17
Moreover, these results appeared to compare favourably with
those described in the literature by Fu8 and Murakami.6
This phenomenon where the cross-linked polymer-supported
version of a chiral auxiliary gives higher ee values than its solution-
phase counterpart is not unique.18 However at this stage, it is
difficult to say how much of this is due to conformational
constraints imposed by the cross-link environment, how much
arises from other effects of the microenvironment such as
modification in solvation in the polymer interior, or how much
is due to the ratio between the racemic amine and the supported
chiral reagent. However, we can probably rule out the latter as
only 4% variation of the selectivity was previously observed when
using 2 equivalents of amines instead of 3 (amine/reagent ratio of
2 vs 3 led to 86 vs 90% ee).9
With chiral-4 in hand, we investigated its efficiency in the KR of
(¡)-1-phenylethylamine. The reactions were performed at room
temperature in various solvents using 0.2 equivalents of supported
reagent under otherwise identical conditions.{ The results are
collected in Table 2.
The first experiment in DMF was consistent with our
expectation as no reversal of stereoselectivity was observed along
with a very low level of selectivity (4% ee, Table 2, entry 1). In all
other solvents however, the selectivities were moderate to good. In
addition, except in dioxane (entry 5) where supported-(1S,2S)-4 led
to a level of selectivity comparable to the one observed when using
(1S,2S)-3, the ee’s were higher. Hence, CHCl3 and benzene
Under these reaction conditions, we could achieve the stereo-
selective acylation of a family of racemic amines with moderate to
good enantioselection. Thus, the KR of (¡)-a-ethylbenzylamine
(Table 3, entry 2), (¡)-1-naphthylethyl amine (entry 3) and
(¡)-phenylalanine methylester (entry 4) were obtained with
respectively 69, 78 and 70% ee.
Fig. 1 (1S,2S)-4.
In order to investigate how many times (1S,2S)-4 could be
reused, we carried out multiple acetylation–regeneration sequences.
Thus, it was observed that chiral-4 could be reused repeatedly at
least up to 4 times without any noticeable loss of selectivity (entry
7; Table 2).
In summary, we have developed the first, fully recyclable solid-
supported reagent for the non-enzymatic KR of amines. The best
selectivity was observed in benzene, in which (1S,2S)-4 led to the
KR of (¡)-1-phenylethylamine with 82% ee using 0.2 equivalents
of solid-supported chiral reagent (s 5 12.3). This is a remarkable
result given the fact it is obtained at room temperature. In
addition, this work demonstrates that cross-linked polymer-
supported chiral reagents can lead to higher ee values then their
solution-phase counterparts. Ongoing efforts are focused on both
enlarging the scope of (1S,2S)-4 and developing a rational for its
stereoselectivity.
Scheme 1 Synthesis of (1S,2S)-4.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3310–3312 | 3311