their derivatives can be reduced to alcohols by using a
combination of NaBH4 and Lewis acid (such as LiBr,
MgCl2, MgBr2, AlCl3, and CaCl2) by heating in diglyme
or THF/toluene, there have been many complex borohydrides
[such as NaBH4–MX (MX = LiCl, ZnCl2),2
NaBH4–CF3CO2H,3 NaBH4–H2SO4,4 NaBH4–I2,5
BH3Me2S,6 KBH4–MX (MX = ZnCl2, AlCl3)7]
reported for the similar reactions. To our surprise,
KBH4 combined with MgCl2 used as a reductant has
not been properly explored.
In continuation of our work7d to develop practical preparative
methods of pharmaceutical intermediate, (S)-
1,2-O-isopropylidene-1,2,4-butanetriol 1 from methyl
(S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate 2, we
developed a practical and efficient procedure for reduction
of carboxylic acids and their derivatives to the corresponding
reduced products with KBH4–MgCl2
combination (KBH4:MgCl2 = 1:1).
(S)-1,2-O-Isopropylidene-1,2,4-butanetriol 1 is an
important synthon, used as the chiral resources for the
total synthesis of many natural products.8 There are
two methods for its preparation based on starting
materials.
The first method used (S)-1,2,4-butanetriol 3 as the starting
material, which was selectively protected by acetone9
to give a mixture of 5-membered acetonide 1 and its corresponding
regioisomeric 6-membered acetonide 4 in the
ratio of 9:1. When cyclohexanone10 or 3,3-dimethoxypentane11
was used instead of acetone, the ratio of 5-
membered ketal to its isomeric 6-membered ketal was
19:1 and 45:1, respectively. Because of the similarity of
the physical and chemical characters, 1 and 4 cannot
be successfully separated by conventional techniques.
In order to remove 4, the mixture was converted into
the corresponding esters and purified by recrystallization9
or column chromatography,12 followed by hydrolyzation
to give pure 1 in a low yield of 34–66% (Scheme 1).
The second method used methyl (S)-3,4-O-isopropylidene-
3,4-dihydroxybutanoate 2 as the starting material
by reduction with LiAlH4
13 to give 1 in 72% yield or
with 6.0 mol equiv NaBH4 in methanol14 in 96.4% yield.
By these methods, the reducing agent became expensive
or was consumed in abundance.
In order to find a suitable reductive method, a series of
experiments were undertaken to use a combination of
KBH4 and several Lewis acids (LiCl, AlCl3, ZnCl2,
CaCl2, MgCl2) as reductant to prepare 1 from 2 (prepared
from lactose,15 and refined by fractional distillation;
GC purity >98%, bp = 70 _C/4 mmHg). It was
found that KBH4–MgCl2 system worked well to reduce
2 in THF to give a yield comparable with the above cited
reactions (Scheme 2).