C
A. de la Torre et al.
Letter
Synlett
transesterification of the ethyl ester by methanol as a by-
product. When one hydroxyl function is more sterically
hindered than the other, such as in the case of a tertiary al-
cohol vs. a secondary one (Table 1, entry 6) or in the case of
a secondary alcohol vs. a primary one (Table 1, entry 7), the
benzoyl shift does not take place and the protecting group
stays on the less substituted alcohol. Finally, in the case of a
substrate containing two ester moieties, low yields are ob-
tained, probably due to undesired side reactions such as
lactonization (Table 1, entry 8).
The regioselectivity of the benzoyl shift can be ex-
plained by the superior leaving-group ability of the α-hy-
doxyl group in comparison to the β-hydroxyl. To assess this
hypothesis, pKa calculations were made on the various sub-
strates studied in the scope of the reaction (Table 2).12 In-
deed, the results show a high correlation between the rela-
tive pKa of the two hydroxyl functions and the regioisomer-
ic ratio of the benzoyl-substituted compounds. Remarkably,
the reverse regioselectivity in the case of an ester with a CF3
substituent in the β-position matches with the pKa calcula-
tion that shows the β-hydroxyl group is more acidic (Table
2, entry 5). This acidity-controlled shift is limited by steric
hindrance (Table 2, entries 6 and 7), or when side reactions
can occur (Table 2, entry 8).
BzCl
Et3N
DMAP
CH2Cl2
OBz
OH
OH
NaHCO3
MeOH/H2O
OEt
OEt
OEt
OH
O
OH
O
OBz O
Scheme 2 Proposed strategy for the β-protection of α,β-dihydroxy esters
The plan was to perform a monoacylation of vic-diols
using a cheap and straightforward procedure without con-
cern for the selectivity of the protection followed by basic
workup to initiate the benzoyl shift. The initial protection
was achieved using a standard procedure; that is, benzoyl
chloride and triethylamine in dichloromethane, catalyzed
by DMAP at 0 °C to room temperature over three hours.4
However, under these conditions, the subsequent one-flask
basic workup (10 equiv solid NaHCO3) needed to perform
the benzoyl shift led to unreproducible results in the migra-
tion. After experimentation, it was found that an acidic
workup was necessary to avoid reproducibility issues, elim-
inating the possibility to perform a one-flask transforma-
tion. Therefore the second step for that latter stage was per-
formed with solid NaHCO3 (5 equiv) in MeOH–H2O (9:1,
v/v).9 The use of different bases (KHCO3, Na2CO3) did not
improve the migration. Thanks to this procedure, syn-ethyl-
2,3-dihydroxybutanoate was regioselectively monoprotect-
ed on the β-position with a 6.8:1.2 ratio and 69% yield of
the desired isomer (Table 1, entry 1),10 while the initial ben-
zoylation gave a 1.8:10.2 ratio in favour of the α position.
Interestingly, the procedure by Oikawa et al. gave a similar
yield and ratio, even if in our case we also observed bispro-
tection inherent in our straightforward initial protection
conditions. However, benzoylation at lower temperature
(–78 °C) can minimize the bisprotection ratio if the diol
substrate is valuable. No epimerization was observed
during the reaction.
A number of other vic-diols was tested under these con-
ditions. Ethyl syn-2,3-dihydroxy-3-phenylpropanoate could
also be protected on the β-position, although with lower re-
gioselectivity (Table 1, entry 2). It appears that α,β-dihy-
droxy nitriles can also be regioselectively protected on the
β position (Table 1, entries 3 and 4).11 The presence of a ni-
trile function instead of the ester improves the regioselec-
tivity of the reaction. Again, substantially better regioselec-
tivity was observed with a methyl rather than a phenyl sub-
stituent in the β-position. Interestingly, when a highly
electron-withdrawing group was present in the β-position,
no migration was observed. Thus, in the case of ethyl 4,4,4-
trifluoro-2,3-dihydroxybutanoate, the major product has
the benzoyl moiety on the α position (Table 1, entry 5).
Comparative NMR analysis before and after the basic work-
up showed the same ratio, meaning that the first step is re-
gioselective for the α-position and that no benzoyl shift oc-
curs in this specific case. Moreover, with this substantially
more electrophilic substrate, we also observed traces of
Table 2 Relative pKa of the Hydroxyl Functions
A
OH
R2
R1
R3
OH
B
6
Entry
Ratio 7/8/9
pKa (A)a
pKa (B)a
1
2
3
4
5
6
7
8
6.8:1.2:1
5:2.3:1
13.2:1.3:1
3:0.3:1
0.6:4.7:1
0:1:0
14.75b
13.83b
14.22b
13.34b
11.24b
14.82c
15.55b
13.36b
12.87b
12.33b
11.04b
10.63b
12.46b
12.94b
14.43b
12b
0.8:7:1
3.4:6:1
a pKa calculated using ACDLabs 12.0.
b ± 0.20.
c ± 0.29.
In conclusion, we have described a simple and conve-
nient method for the regioselective monoprotection of acti-
vated vic-diols, using only inexpensive and readily available
reagents. This method is a complementary approach to the
one described by Oikawa et al. because it gives similar ra-
tios but can be performed faster and cheaper. The regiose-
lectivity of the reaction is guided by the relative acidity of
the hydroxyl functions, when both are equally hindered.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D
De La Torre, Aurélien
