Asymmetrization of 2-methylpropane-1,3-diol by Mucor miehei lipase-catalyzed benzoylation in organic solvent

Article abstract of DOI:10.1016/j.tetasy.2004.09.005

Asymmetrization of prochiral 2-methylpropane-1,3-diol by Mucor miehei lipase (MML)-catalyzed acylation with vinyl benzoate affords the corresponding (S)-monobenzoate (65% ee), that can be obtained enantiomerically pure in 40% yield by a sequential benzoyl

Full text of DOI:10.1016/j.tetasy.2004.09.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3177–3179
Asymmetrization of 2-methylpropane-1,3-diol by Mucor miehei
lipase-catalyzed benzoylation in organic solvent
*
Enzo Santaniello, Silvana Casati, Pierangela Ciuffreda and Luca Gamberoni
Dipartimento di Scienze Precliniche LITA Vialba-Universit a` degli Studi di Milano,Via G.B. Grassi,74-20157 Milano,Italy
Received 19 July 2004; accepted 6 September 2004
Available online 2October 20 04
Abstract—Asymmetrization of prochiral 2-methylpropane-1,3-diol by Mucor miehei lipase (MML)-catalyzed acylation with vinyl
benzoate affords the corresponding (S)-monobenzoate (65% ee), which can be obtained enantiomerically pure in 40% yield from
a sequential benzoylation procedure at 58% conversion of the diol to the corresponding dibenzoate.
ꢀ
2004 Elsevier Ltd. All rights reserved.
2-Methylpropane-1,3-diol 1a is the simplest meso-1,3-
diol and its enantiomerically pure derivatives, such as
monobenzyl ether 1b, constitute an important series
of synthetically useful chiral building blocks (Fig. 1).
by PCL-catalyzed hydrolysis of the prochiral diacetate
6
3a (Scheme 1).
,7
1
The enantiomerically enriched monoacetate 2a has been
used as an intermediate in the preparation of the deriv-
atives of 2-methylpropane-1,3-diol such as benzyl ether
1
8
1
b or the silyl derivative 1c. However, chemical mani-
pulation of a monoacetate such as 2a may be compli-
cated by the attitude of the acyl moiety to migrate
towards the vicinal hydroxy group, an unfavourable side
RO
OH
ROCO
OH ROCO
OCOR
1
2
3
a. R=H
b. R=CH Ph
c. R=Si(CH ) tBu
a. R=Me
b. R=Ph
9
reaction encountered mainly in 1,2-diols and observed
1
also in the enzymatic preparation of monoacetate 2a,
2
0
3
2
with the consequence that the final enantiomeric excess
of the product can be considerably lowered. The above
isomerization also occurs in the preparation of benzyl
ether 1b from the optically active acetate 2a and so the
experimental conditions for avoiding the side reaction
Figure 1.
The enantiotopic differentiation of the two primary hydr-
oxy groups of the diol 1a is one of the most fascinating
challenges in asymmetric organic synthesis that has been
1
had to be carefully studied.
2,3
only recently been achieved by chemical methods. The
4
enzymatic asymmetrization of prochiral substrates,
when applied to the diol 1a, allow the formation of
Differently from reactive esters such as acetyls, where
partial isomerization may occur even during work-up,
for a moderately reactive monoester such as benzoyl,
(
(
S)-monoacetate 2a by the Pseudomonas cepacia lipase
5
PCL)-catalyzed acetylation in chloroform, whereas
,6
9
the same equilibration is considerably slower. Since a
benzoate moiety is also more resistant than an aliphatic
the opposite enantiomer (R)-acetate 2a can be obtained
VA
PCL
H O
PCL
HO
OH
AcO
OH
AcO
OAc
2
HO
OAc
1
a
(S)-2a
3a
(R)-2a
Scheme 1.
*
0
Corresponding author. Tel.: +39 0250319691; fax: +39 0250319631; e-mail: enzo.santaniello@unimi.it
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.005

3178
E. Santaniello et al. / Tetrahedron: Asymmetry 15 (2004) 3177–3179
1
1
16–18
ester to several synthetic transformations, we decided
to investigate the enzymatic asymmetrization of diol
1
According to described procedures,
the preparation
of the enantiomerically pure compound (S)-1c from (R)-
ester 4 was realized via the (R)-ester 5 and reduction of
this intermediate with DIBAL. From the enantiomeri-
cally pure compound (S)-1c, after benzoylation/desilyl-
ation steps, an enantiomerically pure (>98% ee, as
established by NMR of the MTPA ester) sample of
(R)-(À)-2b could be prepared. The specific rotation re-
a in order to achieve the preparation of enantiomeri-
cally pure monobenzoate 2b.
We recently reported that the selective enzymatic ben-
zoylation of a primary group in 1,2-diols can be
achieved using Mucor miehei lipase (MML) as the most
suitable biocatalyst in an organic solvent and vinyl ben-
zoate (VB) as acyl transfer. The fastest reaction and
the highest enantioselectivity were observed for pro-
pane-1,2-diol. This result showed that the size of the
substrate might constitute a limiting factor for the activ-
ity of the enzyme.
corded for this sample [a] = À8.0, (c 1, MeOH) was
D
1
2
8
considerably higher than the reported value and the
enantiomeric excess of the product confirms that the
benzoate group is stable during the protection/deprotec-
tion, work-up and purification steps of the above syn-
thetic route.
On the basis of the above results, we thought that the
simplest prochiral 1,3-diol 1a could be a good substrate
for the MML-catalyzed benzoylation and an enantio-
topic asymmetrization could be expected. The benzoyl-
ation was carried out in the presence of MML and VB
in t-butylmethyl ether, stopping the reaction before the
formation of the dibenzoate 3b. In 30min we observed
However, the enantiomeric purity of the (S)-benzoate 2b
formed by the MML-catalyzed asymmetrization of 1,3-
diol 1a was not satisfactory and we reinvestigated the
enzymatic reaction in the presence of other lipases. Only
the lipase from Candida antarctica (CAL) furnished sim-
ilar result, but the reaction was much slower that the one
1
9
catalyzed by MML. We decided to study the sequen-
tial benzoylation of diol 1a, that, according to similar re-
1
3
8
ration was established as (S) by comparison of its spe-
4% conversion to monobenzoate 2b, whose configu-
2
0
ports on the enzymatic acetylation of 1,2-diols, could
furnish an enantiomerically pure monoester 2b, should
the esterification proceed to a >50% formation of
8
cific rotation with that reported for (R)-2b. A 65%
enantiomeric excess (ee) was established by H NMR
analysis of the ester obtained by reaction of enzymati-
1
2
1
diester.
1
4
cally prepared (S)-2b with (S)-MTPACl. However,
the published specific rotation for (R)-(À)-2b obtained
from 98% ee silyl derivative 1c was considerably lower
than the recorded value for the sample of (S)-(+)-2b ob-
Considering also that the MML-catalyzed dibenzoyl-
ation of propane-1,2-diol was feasible and it enhanced
the enantioselectivity of the monobenzoylation in rais-
1
5
22
tained by MML-catalyzed asymmetrization of diol 1a
Scheme 2).
ing the E value from 5.3 to 9.2, we decided to study
(
the sequential benzoylation of the diol 1a. It was inter-
esting to observe that in 1.5h, the enzymatic dibenzoyl-
ation proceeded to 58% conversion with complete
reaction of diol 1a, so that enantiomerically pure (S)-
2b was obtained in 40% yield after purification by flash
This discrepancy could be due to either low purity of the
sample used to record the reported values or to migra-
tion of the benzoyl moiety that might have occurred at
the stage of protection/deprotection required for the
2
3
chromatography (Scheme 4).
8
transformation of (S)-(À)-1c into (R)-(À)-2b. The sec-
ond point is especially important, in view of the assumed
stability of the benzoate with respect to acyl migration
towards vicinal hydroxy groups and, therefore, deserved
a careful investigation. For this purpose, we prepared a
sample of (R)-benzoate 2b starting from methyl (2R)-3-
hydroxy-2-methylpropionate (R)-4 (Scheme 3).
In conclusion, 2-methylpropane-1,3-diol 1a can be
asymmetrized by means of MML-catalyzed benzoyl-
ation with VB in t-butylmethyl ether to afford the (S)-
monobenzoate 2b with moderate enantioselectivity
(65%). A sequential benzoylation of diol 1a at 58% con-
version to the dibenzoate 3b, allowed the isolation of the
VB
MML
HO
OH
PhOCO
OH
(S)-(+)-2b
SiO
(S)-(-)-1c
OH
HO
OCOPh
(R)-(-)-2b
1
a
Scheme 2.
HO
O
TBMSCl
Py
SiO
O
DIBAL
CH Cl
SiO
OH
2
2
O
O
(
R)-4
(R)-5
(S)-1c
BzCl
Py
LiBF
CN/CH
4
HO
OCOPh
CH
Cl
(R)-(-)-2b
3
2
2
Scheme 3.

E. Santaniello et al. / Tetrahedron: Asymmetry 15 (2004) 3177–3179
3179
HO
OH
PhOCO
OH
+
PhOCO
OCOPh
1a
(S)-2b
3b
Scheme 4.
enantiomerically pure (S)-monobenzoate 2b. A final re-
mark should concern the usefulness of the benzoate as a
protecting group in diol systems, where a monobenzoate
is less prone to a migration side reaction that may lower
the chemical or enantiomeric purity of the final product.
(S)-MTPACl and by comparison with a sample of (RS)-
monobenzoate 2b prepared by partial benzoylation of 1a.
Significant signals corresponding to the Mosher derivative
of the major enantiomer, (S)-1-benzoyloxy-2-methylpro-
pan-3-ol (S)-2b: (500MHz, CDCl ) d: 4.41 (1H, dd, J = 5.6
3
and 11.2Hz, CHHO), 4.30 (1H, dd, J = 5.6 and 11.2Hz,
CHHO), 4.23–4.16 (2H, m, part AB of ABX system,
CH
.04 (3H, d, J = 7.0Hz, CH
sponding to the Mosher derivative of the minor (R)-
enantiomer (R)-2b: (CDCl ) d: 4.38 (1H, dd, J = 5.6 and
1.2Hz, CHHO), 4.32(1H, dd, J = 5.6 and 11.2Hz,
CHHO), 4.24 (1H, dd, J = 5.6 and 11.2Hz, CHHO), 4.15
1H, dd, J = 5.6 and 11.2Hz, CHHO), 3.52(3H, s, OC H3),
2.41–2.34 (1H, m, CHCH ), 1.07 (3H, d, J = 7.0Hz, CH ).
2
O), 3.52(3H, s, OC H
3
), 2.41–2.34 (1H, m, CHCH
3
),
Acknowledgements
1
3
). Significant signals corre-
This work has been financially supported by Universita`
degli Studi di Milano (Fondi FIRST).
3
1
(
References
3
3
1
5. In Ref. 8 it has been reported that the specific rotation of
(S)-(+)-2b prepared by enzymatic resolution of (RS)-2b
was +2.1 (c 1, MeOH, 84% ee), whereas for a sample of
(R)-(À)-2b it was assumed to be 98% enantiomerically
with a specific rotation of À2.5 (c 1, MeOH).
1
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ꢁ
zym 435 , acrylic resin supported lipase, 11.4U/mg solid)
was purchased from Novo Nordisk Bioindustrial Group.
Lipase from Mucor miehei (Chirazyme L-9, cf. C2, lyo,
ꢁ
carrier-fixed lipase, 8U/mg solid) was purchased from
Roche Diagnostics GmbH. The enzymatic benzoylation
with CAL was carried out as for MML; the reaction
reached 68% conversion in 24h with formation of 4%
dibenzoate 3b. After flash chromatography (hexane/ethyl
acetate, 80:20; v/v) pure (S)-2b was obtained as a
1
1
1
1
0. Liu, K.-C. K.; Nozaki, K.; Wong, C.-H. Biocatalysis 1990,
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3
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
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colourless oil (48% yield; 55% ee) [a] = +4.3 (c 1, MeOH).
The reactions with PCL (20%, 72h) and CCL (10%, 72h)
were too slow to be further examined.
D
20. Lemke, K.; Theil, F.; Kunath, A.; Schick, H. Tetrahedron:
Asymmetry 1996, 7, 971–974, and references therein.
21. We have applied the sequential acetylation procedure to
3. In a typical procedure for MML-mediated benzoylation of
1
a, lipase (100mg) was added to a solution of 1a
1.0mmol) and VB (1.2mmol) in t-butylmethyl ether
6
(
(
diol 1a and obtained enantiomerically pure (S)-2a.
10mL). The mixture was allowed to react at room
22. The enzymatic dibenzoylation of propane-1,2-diol
occurred in 40h affording 62% of dibenzoate and 40% of
unreacted monobenzoate. For other diols, the same
temperature under magnetic stirring with the progress of
the reaction monitored by TLC (hexane/ethyl acetate,
1
2
8
0:20; v/v). GLC analyses were carried out on an HP-5
procedure was very slow and enantioselectivity lower.
Hewlett Packard column (30m · 0.32mm; 0.25mm ID,
film thickness 0.25lm). After 0.5h, the reaction had
reached 84% conversion and the enzyme filtered off and
washed with methanol. The solvents were distilled under
vacuum and flash chromatography (hexane/ethyl acetate,
23. The sequential benzoylation was carried out by adding
MML (100mg) to a solution of 1a (1.0mmol) and VB
(2.4mmol) in t-butylmethyl ether (10mL). The mixture
was allowed to react at room temperature under magnetic
stirring and the progress of the reaction monitored by
TLC and GLC. After 1.5h the starting diol 1a disappeared
and 58% of dibenzoate 3b was formed. After the usual
work-up, pure compound (S)-2b was obtained after flash
8
0:20; v/v) afforded pure compound 2b as a colourless oil
(
58% yield; 65% ee) [a] = +4.9 (c 1, MeOH).
D
1
4. The ee of the monobenzoate 2b could not be established
by HPLC analysis, using a Merck (R,R) Whelk-O1
D
chromatography (40% yield); [a] = +7.9 (c 1, MeOH). A
>98% ee was established by the NMR spectrum of MTPA
derivative that showed no signal corresponding to (R)-2b.
1
column (4mm · 25cm). Ee was established by H NMR
analysis of the ester obtained by reaction of (S)-2b with