Organic Letters
Letter
amino-squaramide 1125 gave comparable selectivity factors
(entries 5 and 6, respectively). Surprisingly, the pseudoenan-
tiomeric quinidine-derived amino-squaramide 1225 gave a
superior selectivity factor (entry 7).26 Other alcohols were
briefly explored with catalyst 12, but none proved superior to
benzhydrol (entries 8−10).
(cf. entries 14 and 15 in Table 4 vs entries 9 and 10 in Table
3). Alas, the tert-butyl substituent rendered the substrate
completely unreactive with benzhydrol and produced barely
detectable conversion with allyl alcohol (entries 16 and 17,
respectively). Surprisingly, replacing the Boc group with a Cbz
group also rendered the substrate unreactive toward
benzhydrol (entry 18). Once again, however, less sterically
demanding alcohols gave practically useful results (entries 19−
21). The reaction scale was easily increased 10-fold (cf. entry
22 vs entry 6). Finally, we confirmed that Takemoto’s catalyst
5 produces lower but still practically useful selectivity factors
with representative aryl- and alkyl-substituted substrates under
the same conditions (entries 23 and 24, respectively).
Having thus completed our optimization studies, we
proceeded to explore the substrate scope of the new
methodology (Table 4). In several cases, we encountered
a
Table 4. Substrate Scope
Various ester products obtained in the KR studies described
above underwent quantitative transesterification with methanol
under mild conditions (see, e.g., eq 1 in Figure 4), which
entry
1
R1
R2
ROH
% conversion
s
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
BnOH
allylOH
Ph2CHOH
allylOH
Ph2CHOH
MeOH
BnOH
45
45
37
41
31
44
45
29
42
48
50
40
24
35
37
N/A
<5%
N/A
54
361
487
344
301
127
107
430
171
334
352
80
b
2
b
3
4-ClC6H4
4-MeOC6H4
4-NO2Ph
2-ClC6H4
3-MeOC6H4
1-naphthyl
2-naphthyl
2-thienyl
styryl
isobutyl
isopropyl
isopropyl
isopropyl
tert-butyl
tert-butyl
Ph
b
4
c
5
6
7
d
8
d
9
10
11
12
13
14
15
16
17
18
19
20
21
67
151
144
92
N/A
N/A
N/A
27
40
50
80
118
21
c
Figure 4. Transformations of the products.
c
Ph
Ph
Ph
Bn
Bn
Bn
t-Bu
t-Bu
t-Bu
c
50
49
44
41
c
allylOH
e
proved to be useful for their HPLC analysis (see the
were stable and did not undergo spontaneous recyclization
upon storage or exposure to silica gel. One notable exception
was tert-butyl derivative 2m-Me: although its formation could
be observed on treating 1m with methanol, it reverted to the
starting isoxazolidinone even at room temperature (eq 2). This
thermodynamic instability explains the lack of success in its KR
(entries 16 and 17, Table 4). Other methyl esters could be
easily cyclized back to isoxazolidinones by heating in the
presence of catalytic dibutyltin oxide4,27 (see, e.g., eq 1). The
synthetic utility of resolved N-Boc-isoxazolidinones was
demonstrated by the quantitative hydrogenolysis of the N−O
bond giving rise to the N-protected β-amino acid (eq 3).2a
In conclusion, we have demonstrated that N-carbalkoxy-
isoxazolidin-5-ones are effectively activated toward enantiose-
lective alcoholysis by bifunctional organocatalysts. In fact,
some of the selectivity factors recorded in this study are among
the highest ever obtained in this type of transformation, thus
highlighting the potential of these underexplored acyl donors
in asymmetric catalysis. From a practical standpoint, the new
methodology is expected to offer a mechanistically different
alternative to existing asymmetric approaches to isoxazolidi-
nones and can be used to upgrade their level of enantiomeric
enrichment.
22
23
24
2-ClC6H4
2-naphthyl
isobutyl
Ph2CHOH
Ph2CHOH
Ph2CHOH
d
f
,f
27
a
General conditions: 0.10 mmol of substrate, 0.10 mmol of alcohol,
b
0.01 mmol of 12, 500 μL of tert-amyl alcohol. A 4:1 tert-amyl
alcohol/CHCl3 mixture was used as the solvent. CHCl3 was used as
the solvent. A 3:2 tert-amyl alcohol/CHCl3 mixture was used as the
solvent. Performed on 1.0 mmol of substrate. Catalyst 5 was used.
c
d
e
f
substrates that were poorly soluble in pure tert-amyl alcohol,
which would be detrimental to their KR. To remedy this
problem, we had to employ tert-amyl alcohol/chloroform
mixtures and occasionally pure chloroform. The addition of
chloroform did not have any negative effect on the selectivity
factor with substrate 1a (cf. entries 1 and 2). Substrates bearing
variously substituted aromatic and heteroaromatic groups were
resolved with excellent selectivity factors (entries 1−10).
Diminished but still useful levels of enantioselectivity were
observed with a styryl and alkyl group (entries 11−13).
However, branching at the α-position of the alkyl substituent
greatly diminished the reactivity, as one can see in the case of
the isopropyl group (entry 13). Fortunately, replacing
benzhydrol with benzyl or allyl alcohol improved the
conversion somewhat while producing enantioselectivities
higher than that obtained previously with the phenyl substrate
986
Org. Lett. 2021, 23, 984−988