Lipase-catalyzed 1,6-acylation of D-mannitol

Article abstract of DOI:10.1071/CH04040

The selective synthesis of 1,6-diacyl D-mannitols from 2,2,2-trifluoroethyl esters using transesterification, catalyzed by lipases, has been investigated, and the results have been compared with those obtained from a typical acid chloride procedure and a

Full text of DOI:10.1071/CH04040

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 741–745
Lipase-Catalyzed 1,6-Acylation of d-Mannitol
Peter J. Duggan,A,D David G. Humphrey, and Victoria McCarl
B
C
A
School of Chemistry, Monash University, Clayton VIC 3800, Australia.
CSIRO Forestry and Forest Products, Private Bag 10, Clayton South VIC 3169, Australia.
Centre for Green Chemistry, School of Chemistry, Monash University, Clayton VIC 3800, Australia.
Author to whom correspondence should be addressed (e-mail: peter.duggan@sci.monash.edu.au).
B
C
D
The selective synthesis of 1,6-diacyl d-mannitols from 2,2,2-trifluoroethyl esters using transesterification, catalyzed
by lipases, has been investigated, and the results have been compared with those obtained from a typical acid
chloride procedure and a phenylboronic acid-assisted approach. Three commercially available lipases and five
2
,2,2-trifluoroethyl esters were examined. In most cases, the yields obtained from the lipase reactions were superior
to those produced from either of the other two methods.
Manuscript received: 17 February 2004.
Final version: 8 April 2004.
Introduction
,6-Diacyl hexitols have several applications, including
as components of industrial emulsifiers and non-ionic
surfactants, as precursors to chiral glycerides, and as
starting materials for chiral ligands for use in organometal-
[
2,7,8]
with triaroylation occurring
can be routinely achieved,
1
[
9]
to only a relatively low extent. The steric hindrance around
the secondary hydroxyls of the hexitols apparently limits fur-
ther reactions with the less reactive aroylating agents, but
does not prevent the formation of poly-alkanoates during
alkanoylation.
The contamination of poly-alkanoyl hexitols in industrial
emulsifiers and surfactants is not generally seen as a major
problem, except where they are used as food additives.
When the 1,6-dialkanoates are required for biological testing
or as intermediates in pharmaceutical production, however,
much higher purity and reaction selectivities are required. In
our investigation of the detailed structure–activity relation-
ships of wood preservatives derived from acylated mannitols,
we also required high-purity 1,6-diacyl mannitol derivatives.
To illustrate how such compounds have been previously pre-
pared, it is instructive to examine the work of Schollkopf
and coworkers. In their preparation of A-32390A 1 and
its analogues, a multi-step approach was used to introduce
esters at the 1- and 6-positions of d-mannitol, with a key
step involving the displacement of mesylate groups from the
dimesyl dibenzylidene 2 by a carboxylate salt 3 derived from
N-formyldehydrovaline (Scheme 2).
Koster and coworkers showed that selective protection
of d-galactitol with triethylborane can lead to the pro-
duction of 1,6-diesters in high yield.
investigated a similar strategy, in which phenylboronic acid
PBA) was used in the selective derivatization of d-mannitol
(Scheme 3). Using this approach, we found that pure
d-mannitol diesters such as the 1,6-dioctanoate 7 can be
prepared by a single-pot method in moderate yields without
the need for chromatography or recrystallization. The simple
[1]
[2]
[
3]
lic catalysis.
importance; the d-mannitol derivative and fungal metabo-
1,6-Diacyl hexitols also have medicinal
[
4]
lite A-32390A 1 (Scheme 1) has antimicrobial activity,
d-sorbityl salicylate is currently under investigation for
[1]
[5]
the treatment of dermatological disorders, and a naph-
thylpropanoate derived from d-mannitol has been used as
intermediate in an enantioselective synthesis of (S)-(+)-
[6]
Naproxen. Our interest in the clean and facile synthesis
of 1,6-diacyl mannitols relates to our investigation of their
use in the formulation of organic-soluble borate esters as
preventative agents for fungal and termite attack in wood.
The presence of six hydroxy groups in hexitols like
d-mannitol makes selective acylation to give pure hexitol
esters challenging. The lack of organic solubility of these
polyols means that standard reactions that employ acylating
agents dissolved in organic solvents often produce complex
[7]
mixtures, presumably because the low concentration of
hexitols dissolved in the organic medium readily become
over-acylated. The exception is the selective 1,6-aroylation
of these compounds, which, although relatively low yielding,
[
10]
[
11]
We have recently
NC
HO HO
O
O
O
(
[
7]
O
HO
HO
NC
A-32390A 1
Scheme 1.
©
CSIRO 2004
10.1071/CH04040
0004-9425/04/080741

7
42
P. J. Duggan, D. G. Humphrey and V. McCarl
hydrolysis of the intermediate diboronate ester 5 with aque-
ous hydroxide allowed the recovery of the PBA. Lower yields
of the 1,6-dibenzoate 8 were obtained with this method, and
to hydrolysis, so that oxidative conditions, which preclude
the recycling of the boronic acid, were required to liber-
ate 8. Selective 1,6-dibenzylation and disilylation
d-mannitol has also been achieved in a similar way.
[
7]
[13]
of
[12]
the intermediate diboronate 6
was much more resistant
The use of enzymes in synthetic chemistry is now well
[
14]
established.
With the growing concern about the fate of
Ph
chemicals in the laboratory and industry, the use of bio-
logical catalysts is an attractive alternative to traditional
methods of synthesis. This is because enzymes usually cat-
alyze specific reactions with particular functional groups
without affecting other groups present in the substrate. They
also act under mild conditions, can often be re-used, and are
biodegradable. Lipases are particularlyuseful enzymes in this
regard. Since many lipases are active in organic solvents, they
can be used to catalyze esterification and transesterification
reactions. We describe here the results of a comparison of
such lipase-catalyzed acylation reactions of d-mannitol with
those obtained with a more traditional method, as well as our
recently reported boronate-assisted approach.
O
O
HO2C
NHCHO
MsO
OMs
ꢀ
O
O
Ph
2
3
Et3N, HMPA
00–110ºC
1
[
15]
Ph
O
O
O
OHCHN
CO2
O C
NHCHO
2
Results and Discussion
O
The insolubility of polyols in organic media presents an
apparent problem for their lipase-catalyzed acylation reac-
tions. Ikeda and Klibanov, however, reported in 1993 that
specific sugar and alditol acrylates could be produced in
t-butanol in high yields from their more organic-soluble
phenylboronate esters, by transesterification from vinyl acry-
Ph
1
[16]
late in the presence of Pseudomonas sp. lipoprotein lipase.
Scheme 2.
Scheme 4 shows how 6-O-acryloyl-d-glucose 10 can be pro-
duced in this way from the diphenylboronate ester of glucose
Ph
B
9.We thus initially set out to investigate similar reactions with
PBA, PhH,
ꢂ, -H2O
HO HO
the phenylboronate esters of d-mannitol (e.g. 4). Unfortu-
nately, all of the lipase-catalyzed reactions that we performed
in the presence of PBA or its esters gave no acylated prod-
uct. This might be because boronic acids have an inhibitory
O
O
HO
pyridine
HO
OH
OH
HO HO
O
O
B
[
17]
D-mannitol
Ph
effect on lipases,
which could explain why Ikeda and
Klibanov had to employ an enzyme-to-boronate ester mass
ratio of approximately 3 : 1 in their lipase-promoted acylation
reactions.
4
RCOCI
O
More recently, Otero and coworkers have shown that
d-sorbitol can be quantitatively converted into the corre-
sponding 1,6-diesters by treatment with fatty acids in dry
acetone containing immobilized Candida antartica lipase
Ph
B
O
HO HO
HO HO
boronate
cleavage
RCO2
RCO2
OCOR
[1]
OCOR
B (Novozym 435). Precipitation of the products at lower
O
O
B
temperature was thought to prevent over-acylation and a
two-stage temperature regime resulted in a reduction of the
reaction times to three days. Maugard et al. have used the
same enzyme to prepare mono- and di-salicyl esters of d-
sorbitol in relatively low yields by transesterification with
Ph
7
8
R ꢁ n -C7H15-, 48%
R ꢁ Ph-, 10%
5 R ꢁ n -C7H15-
6 R ꢁ Ph-
Scheme 3.
[
5]
methyl salicylate in tert-amyl alcohol. A serine protease
from Bacillus licheniformis (Optimase M-440) has also been
used to prepare amino acid–d-sorbitol conjugates in pyri-
dine by transesterification from 2,2,2-trifluorethyl esters of
OH
1
. lipase/vinyl acrylate
Bu OH, RT, 4 days
O
O
B
O
O
t
O
O
OH
Ph
O
O
OH
OH
2. H O, 30ºC, 2hr.
2
HO
[18]
B
N-protected amino acid.
77%
Ph
Activated esters, such as 2,2,2-trifluoroethyl esters, are
often used as substrates for enzyme-catalyzed transesterifi-
9
10
[19]
cation reactions because the weakly electron-withdrawing
Scheme 4.

Lipase-Catalyzed 1,6-Acylation of d-Mannitol
743
trifluoroethyl group activates the acyl group towards nucle-
ophilic attack. The presence of the fluorines is also thought
to shift the equilibrium of the reaction in favour of the prod-
uct by destabilization of the starting ester relative to the alkyl
ester product and reducing the nucleophilicity of the alco-
hol by-product. We thus set out to examine the acylation
of d-mannitol by transesterification with a range of 2,2,2-
trifluoroethyl esters, promoted by commercially available
lipases. Five acyl sources, 2,2,2-trifluoroethyl octanoate 11,
isovalerate 12, decanoate 13, phenylacetate 14, and benzoate
marginal solubility of d-mannitol in that solvent. These reac-
tions employed a simple workup procedure and 7 was the
only product obtained from the reactions that used t-butanol,
pyridine, and THF as the solvent (entries 2–4). Of all the sol-
vents used, DMF solublizes d-mannitol the most effectively,
but no acylated product was obtained from the reaction that
used DMF (entry 1). This is consistent with the findings of
[
20]
Bergbreiter,Wong, and coworkers who also found DMF to
be a poor solvent for lipase-catalyzed reactions. Such reac-
tions tend to work better in more non-polar solvents, with
highly polar solvents thought to deactivate the enzyme.
Having established the best solvent and enzyme combina-
tion, we next set out to determine the generality of the reaction
through variation of the acyl source. It was thus found that
the only product from the transesterification reactions with
11–14 was the 1,6-acyl mannitol, with a low-to-moderate
yield being obtained in these cases (Table 1, entries 4–7).
The reaction with 2,2,2-trifluoroethyl benzoate produced no
d-mannitol dibenzoate 8 (entry 8). The production of aryl
esters through lipase-catalyzed transesterification reactions
1
5, were chosen. Three lipases, porcine pancreatic lipase,
a lipase from Pseudomonas, and the immobilized Candidia
enzyme Novozym 435, were considered.
In order to establish the appropriateness of the chosen
enzymes for the planned transesterification reactions, a solu-
tion of 2,2,2-trifluoroethyl octanoate 11 and heptan-1-ol (4 : 1
◦
molar ratio) in THF was stirred for 72 min at 30 C in the
presence of each of the lipases. Gas chromatography was
used to measure the extent of reaction. With Novozym 435
and the Pseudomonas enzyme, the reaction was found to go
to completion, whereas with the porcine enzyme, only 25%
of the heptanol was consumed. Given that Novozym 435
was more readily available than the Pseudomonas enzyme,
all subsequent enzymatic reactions were performed with the
immobilized enzyme (Novozym 435).
Nextwe performedexperiments to determine the optimum
solvent for the lipase-catalyzed acylation of d-mannitol.
Dimethylformamide, t-butanol, pyridine, andTHF were used
in reactions that contained 2,2,2-trifluoroethyl octanoate 11
and Novozyme 435 (Scheme 5). As Table 1 shows, the best
result was obtained with THF (entry 4), with a 38% yield
of d-mannitol 1,6-dioctanoate 7 being produced, despite the
[
21]
so the latter
has previously been found to be low yielding,
result is not unexpected.
The results of the lipase-catalyzed acylation of d-mannitol
were then compared with two alternative methods of prepar-
ing 1,6-diacyl mannitols, the conventional reaction using an
acid chloride in hot pyridine, and our previously reported
[
7]
PBA-assisted method. The results of these reactions are
[7]
shown in Table 2. It had already been established that
the conventional acid chloride method for the acylation of
d-mannitol is low yielding and the results shown in Table 2
support this assessment. With the exception of the prepara-
tionof the 1,6-dioctanoate 7, the PBA-assisted reactions were
HO HO
RCO2
Novozym 435
OCOR
ꢀ
CF3CH2OH
D-mannitol
ꢀ
RCO2CH2CF3
HO
HO
1
1
1
1
1
1 R ꢁ n -C H15-
7 R ꢁ n-C H15-
7
7
2 R ꢁ (CH ) CHCH -
16 R ꢁ (CH ) CHCH -
3
2
2
3 2 2
3 R ꢁ n -C H
-
17 R ꢁ n-C H
19
-
9
19
9
4 R ꢁ PhCH -
18 R ꢁ PhCH -
2
2
5 R ꢁ Ph-
8 R ꢁ Ph-
Scheme 5.
Table 1. Yields of d-mannitol esters from lipase-catalyzed reactionsA
Entry
2,2,2-TFE ester
Solvent
DMF
Bu OH
Pyridine
THF
THF
THF
THF
THF
Product
Yield [%]B
1
2
3
4
5
6
7
8
Octanoate 11
Octanoate 11
Octanoate 11
Octanoate 11
Isovalerate 12
Decanoate 13
Phenylacetate 14
Benzoate 15
–
0
18
14
38
11
40
26
0
t
1,6-Dioctanoate 7
1,6-Dioctanoate 7
1,6-Dioctanoate 7
1,6-Diisovalerate 16
1,6-Didecanoate 17
1,6-Diphenylacetate 18
–
C
A
◦
Reaction mixtures were stirred at 50 C for 4 days. Lipase used was Novozym 435. Ratio of 2,2,2-TFE ester to
d-mannitol was 4 : 1.
B
Isolated yields based on d-mannitol.
A 43% yield was obtained when ratio of 2,2,2-TFE ester to d-mannitol was 7.3 : 1.0.
C

7
44
P. J. Duggan, D. G. Humphrey and V. McCarl
Table 2. Yields of 1,6-d-mannitol esters from acid chloride/
Samples were analyzed as thin films (neat) or Nujol mulls mounted
1
13
pyridine and PBA-assisted reactions
on NaCl plates. H and C NMR spectra were recorded on a Varian
00 MHz spectrometer, referenced to tetramethylsilane (δ 0.00) when
3
Entry
Product
Conventional
method [%]
PBA
method [%]A
CDCl3 was used as the solvent and to the residual protonated solvent
peak (δ 2.62) when (CD3)2SO was the solvent. Low-resolution mass
spectra of methanol solutions were recorded with a Micromass Platform
IIAPIQMSelectrospraymassspectrometeroperatinginthepositive-ion
mode.The lipase from Pseudomonas and porcine pancreatic lipase were
both obtained as lipophilized powders from Sigma Aldrich. Novozym
A
16B
48B
1
2
3
4
7
17
18
8
9
0
7
0
B
B
22
10
4
35 (Candidia antarctica lipase immobilized on Accyrek EP-100) was
A
a gift from Novo Nordisk A/S, Denmark. Gas chromatography was per-
formed on aVarian gas chromatograph 3700 using a 20% SE-30, DMCS
Chromosorb-W, 80/100 column, with dimensions of 1.8 m by 6 mm
Isolated yields based on d-mannitol.
Results from reference 7.
B
(
O.D.).
also found to be low yielding. Thus, apart from the prepara-
tion of the 1,6-dibenzoate 8, the lipase method reported here
is superior to the two previously reported methods for the pro-
duction of 1,6-diacyl mannitols, including the PBA-assisted
method of preparing the dioctanoate 7, which, although pro-
viding a higher yield of the acylated product (48% cf. 38%
from the lipase method), suffers from the need to preform the
di-PBA ester 4 and to recover the PBA after use.
General Procedure for the Preparation of 2,2,2-Trifluoroethyl Esters
A solution of 2,2,2-trifluoroethanol (730 µL, 10 mmol) and pyridine
◦
(
3.2 mL, 40 mmol) in dry diethyl ether (4 mL) was cooled to 0 C and
the acid chloride (12 mmol) was added dropwise, resulting in a yellow
suspension.The mixture was then allowed to warm to room temperature,
stirred for 5 h, then quenched with ice water, extracted with diethyl ether,
the ether extracts were washed with 1 M HCl and brine, and dried over
MgSO4. Filtration and removal of the solvent under vacuum gave a
crude oil that was distilled to afford a colourless oil.
Conclusions
2
,2,2-Trifluoroethyl Octanoate 11
◦
[22]
◦
84 C/18 mmHg).
We have found that lipases can be used to prepare pure 1,6-
acylated d-mannitols by transesterification from a range of
Yield 0.46 g (38%), bp 130 C/10 mmHg (lit.
−
1
vmax/cm (neat) 978, 1115, 1170, 1283, 1378, 1412, 1458, 1762, 2859,
959. δH (CDCl3) 0.88 (3H, t, J 6.6, CH2CH3), 1.31 (8H, m, CH2), 1.64
(2H, m, COCH2CH2), 2.43 (2H, d, J 7.5, OCOCH2), 4.49 (2H, q, J 8.5,
CF3CH2). δC (CDCl3) 14.5, 23.0, 25.1, 29.3, 32.0, 34.1, 60.5 (q, J 37),
2
2
,2,2-trifluoroethyl alkanoates in organic solvents following
[21]
a simple procedure. In line with previous findings,
this
method was unsuccessful for the preparation of benzoate
1
23.3 (q, J 277), 172.3.
esters. In contrast to results described for the acylation of d-
[16]
glucose,
however, the solubilization of d-mannitol in the
2,2,2-Trifluoroethyl 3-Methylbutanoate 12
◦
−1
organic solvent through the preformation of phenylboronate
esters resulted in no acylated product; this suggests that inhi-
bition of the enzyme-promoted transesterification reaction
had occurred.
Yield 0.48 g (24.6%), bp 85–90 C. vmax/cm (neat) 982, 1051, 1188,
1276, 1391, 1410, 1489, 1748, 2876, 2966. δH (CDCl3) 0.98 (6H, d, J
.6, CH(CH3)2), 2.14(1H, m, CH(CH3)2), 2.28(2H, d, J7.0, OCOCH2),
.45 (2H, q, J 8.5, CF3CH2).
6
4
The maximum yields of the most successful lipase-
catalyzed transesterification reactions were approximately
2
,2,2-Trifluoroethyl Decanoate 13
◦
[22]
◦
139 C/18 mmHg).
Yield 1.36 g (50%), bp 180 C/10 mmHg (lit.
vmax/cm (neat) 978, 1115, 1170, 1285, 1378, 1412, 1458, 1762, 2856,
2929. δH (CDCl ) 0.88 (3H, t, J 6.6, CH CH ), 1.31 (12H, m, CH ),
4
0%, which might reflect the position of the equilibrium
−1
between acylated mannitol and trifluoroethyl ester starting
material. Otero and coworkers have previously shown that
the removal of the by-product from similar lipase-catalyzed
reactions of d-sorbitol, in that case water, through the use of
molecular sieves, as well as the precipitation of the acylated
3
2
3
2
1.66 (2H, m, COCH2CH2), 2.42 (2H, d, J 7.5, OCOCH2), 4.49 (2H, q, J
8.5, CF3CH2). δC (CDCl3) 14.4, 15.3, 23.0, 29.3, 29.5, 29.5, 32.1, 34.0,
61.3 (q, J 35), 124.5 (q, J 278), 172.6.
2
,2,2-Trifluoroethyl Phenylacetate 14
[
1]
product, resulted in quantitative conversion of d-sorbitol.
◦
[22]
◦
98 C/18 mmHg).
Yield 1.06 g (49%), bp 130 C/10 mmHg (lit.
vmax/cm
3091. δH (CDCl3) 3.74 (2H, s, OCOCH2Ph), 4.53 (2H, q, J 8.5,
CF3CH2), 7.40 (5H, m ArH). δC (CDCl3) 40.9, 60.9 (q, J 37), 123.2
Similar approaches might improve the yield of the lipase-
catalyzed reactions of d-mannitol. Despite the moderate
yields of d-mannitol 1,6-alkanoates obtained here, though,
the results obtained are still superior to those obtained from
the traditional acid chloride/pyridine method and all but one
PBA-assisted acylation reaction.
The wood preservation properties of borate esters derived
from 1,6-diacyl mannitols will be described in a subsequent
publication.
−1
(neat) 1051, 1411, 1455, 1497, 1604, 1758, 2974, 3034,
(
q, J 276), 127.7, 128.9, 129.4, 133.1, 170.1.
2
,2,2-Trifluoroethyl Benzoate 15
◦
[22]
◦
120 C/35 mmHg).
Yield 0.83 g (41%), bp 122 C/18 mmHg (lit.
vmax/cm
3091. δH (CDCl ) 4.53 (2H, q, J 8.5, CF CH ), 7.40 (5H, m ArH). δ
C
(CDCl3) 60.8 (q, J 38), 123.2 (q, J 278), 129.2, 129.4, 129.9, 133, 170.1.
−1
(neat) 1051, 1411, 1455, 1497, 1604, 1758, 2974, 3034,
3
3
2
General Procedure for Lipase-Catalyzed Acylation of D-Mannitol
Experimental
d-Mannitol (27 mg, 0.15 mmol), the 2,2,2-trifluoroethyl ester
General Methods
(
0.60 mmol), and Novozym 435 (20 mg) were added to the solvent
◦
Distillations were performed in a Buchi GRK 50 Kugelrohr apparatus.
Quoted boiling points are approximate. Melting points were recorded
with a Stuart Scientific SMP3 melting point apparatus. Infrared spectra
were recorded on a Perkin–Elmer 1600 Fourier-transform instrument.
(2 mL) and the resulting reaction mixture was stirred for 4 days at 50 C.
The enzyme was then removed by vacuum filtration and the solvent
evaporated under vacuum. The residue was taken up in ethyl acetate,
then washed with saturated NaHCO3 (replaced with 1 M HCl in the

Lipase-Catalyzed 1,6-Acylation of d-Mannitol
745
and
case of the pyridine reaction), water, and brine. The organic layer was
then dried over MgSO4, filtered, and the solvent removed under reduced
pressure. The solid that remained was triturated with hexane.
Acylation of D-Mannitol Assisted by PBA
[7]
These reactions followed a previously reported procedure,
employed d-mannitol (1.0 g, 5.5 mmol), PBA (1.33 g, 11.0 mmol), pyri-
dine(40 mL), benzene(50 mL), andacidchloride(12 mmol). Inthisway,
d-mannitol 1,6-didecanoate 17 (0.19 g, 7%) was obtained; the yield of
d-mannitol 1,6-di(phenyl)acetate 18 obtained, however, was 0%.
D-Mannitol 1,6-Dioctanoate 7
◦
This was obtained as a fine white powder (25 mg, 38%), mp 135–137 C
[23]
◦
(
lit.
132–136 C). δH [(CD3)2SO/D2O] 0.91 (6H, t, J 6.9, 2 CH3),
1
.28 (16H, br s, 2 (CH2)4CH3), 1.58 (4H, m, 2 CO2CH2CH2), 2.35 (4H,
Acknowledgments
t, J 7.3, 2 CO2CH2CH2), 3.42 (2H, d, J 8.9, 2 CH2CH(OH)CH(OH)),
.58 (2 H, ddd, J 2.4, 6.4, and 8.9, 2 CH2CH(OH)CH(OH)), 3.89 (2 H,
3
This worked was funded by the Australian Research
Council and Monash University. V.M. is a recipient of an
AustralianPostgraduateAward. NovoNordiskA/S, Denmark,
is acknowledged for its generous donation of Novozym
435, and Jessica Unthank is thanked for performing the
transesterification with 12 on a larger scale.
a
b
dd, J 6.0 and 11.9, 2 OCH H CH(OH)), 4.71 (2H, dd, J 2.1 and 11.4,
2
those previously reported.
a
b
OCH H CH(OH)). Other spectroscopic properties were identical to
[
7]
D-Mannitol 1,6-Di(3-methyl)butanoate 16
This was obtained as a fine white powder (6 mg, 11%) [repeated
with 1.5 mmol d-mannitol and 10.9 mmol 12 to give a yield of
◦
−1
2
2
23 mg (43%)], mp 149–151 C. vmax/cm (Nujol) 1093, 1302, 1716,
923, 3372. δH [(CD3)2SO/D2O] 0.95 (6H, d, J 6.9, 2 CH3), 2.04
References
(
(
2H, m, 2 CO2CH2CH), 2.23 (4H, d, J 7.3, 2 CO2CH2CH), 3.65
2H, d, J 8.9, 2 CH2CH(OH)CH(OH)), 4.02 (2H, ddd, J 2.4, 6.4,
[1] J. A. Arcos, M. Bernabe, C. Otero, Biotechnol. Bioeng.
1998, 60, 53. doi:10.1002/(SICI)1097-0290(19981005)60:1<
53::AID-BIT6>3.3.CO;2-W
[2] C. Morpain, M. Tisserand, J. Chem. Soc., Perkin Trans. 1 1979,
1379. doi:10.1039/P19790001379
and 8.9, 2 CH2CH(OH)CH(OH)), 4.37 (2H, dd, J 6.0 and 11.9, 2
OCH H CH(OH)), 4.85 (2H, dd, J 2.1 and 11.4, 2 OCH H CH(OH)).
δC [(CD3)2SO] 23.2, 26.1, 43.7, 67.8, 69.2, 70.1, 172.5. m/z 373.2
a
b
a
b
+
[
M + Na] .
[3] J. M. Brown, F. M. Dayrit, J. Chem. Soc., Perkin Trans. 2
1
987, 91.
D-Mannitol 1,6-Didecanoate 17
[4] (a) L. D. Boeck, M. M. Hoehn, T. H. Sands, R. W. Wetzel,
J. Antibiot. 1978, 31, 19.
◦
This was obtained as a fine white powder (28 mg, 40%), mp 102–106 C.
−1
(b) G. G. Marconi, B. B. Molloy, R. Nagarajan, J. W. Martin,
J. B. Deeter, J. L. Occolowitz, J. Antibiot. 1978, 31, 27.
vmax/cm (Nujol) 1078, 1172, 1292, 1747, 3327. δH [(CD3)2SO] 0.91
6H, t, J 6.9, 2 CH3), 1.28 (24H, br s, 2 (CH2)6CH3), 1.50–1.52 (4H,
m, 2 CO2CH2CH2), 2.35 (4H, t, J 8.5, 2 CO2CH2CH2), 3.55–3.65
4H, m, 4 CH2CH(OH)CH(OH)), 4.02 (2H, dd, J 2.0 and 11.4, 2
(
(
c) J. R. Turner, T. F. Butler, R. S. Gordee, A. L. Thakkar,
J. Antibiot. 1978, 31, 33.
(
a
b
a
b
[5] T. Maugard, M. Boulonne, B. Rejasse, M. D. Legoy, Biotechnol.
Lett. 2001, 23, 989. doi:10.1023/A:1010575309233
OCH H CH(OH)), 4.30 (2H, dd, J 2.0 and 9.0, 2 OCH H CH(OH)),
.38 (2H, d, J 7.9, 2 CH2CH(OH)CH(OH)), 4.85 (2H, d, J 6.1, 2
CH(OH)CH(OH)). δH [(CD3)2SO/D2O] 0.82 (6H, t, J 6.9, 2 CH3), 1.21
24H, m, 2 (CH2)6CH3), 1.48 (4H, m, 2 CO2CH2CH2), 2.26 (4H, t, J 7, 2
4
[
6] B. Wang, H.-Z. Ma, Q.-Z. Shi, Synth. Commun. 2002, 32, 1697.
doi:10.1081/SCC-120004263
[7] V. Bhaskar, P. J. Duggan, D. G. Humphrey, G. Y. Krippner,
(
a
b
CO2CH2CH2), 3.92 (2H, dd, J 11.4, 7.0, OCH H CH(OH)), 4.22 (2H,
a
b
V. McCarl, D. A. Offermann, J. Chem. Soc., Perkin Trans. 1
br d, J 11.0, 2 OCH H CH(OH)); signals for CH2CH(OH)CH(OH) and
CH2CH(OH)CH(OH) obscured by HOD/H2O. δC [(CD3)2SO] 14.9,
2
001, 1098. doi:10.1039/B009450L
[
8] P. Brigl, H. Gruner, Ber. Dtsch. Chem. Ges. 1932, 65, 641.
2
2.9, 29.0, 29.1, 29.2, 29.3, 32.1, 34.4, 68.9, 69.8, 173.7. m/z 513.4
+
[9] J. M. Carr, S. P. Draffin, P. J. Duggan, G. D. Fallon,
D. G. Humphrey, Acta Crystallogr. 2001, E57, o1118.
[
M + Na] .
[
10] H.-H. Wust, J. Bardenhagen, U. Schollkopf, Liebigs Ann. Chem.
D-Mannitol 1,6-Di(phenyl)acetate 18
1
985, 1825.
◦
This was obtained as a fine white powder (16 mg, 26%), mp 151–153 C.
[
[
11] W. V. Dahlhoff, R. Koster, J. Org. Chem. 1976, 41, 2316.
12] P. J. Duggan, D. G. Humphrey, D. J. Price, E. M. Tyndall, Acta
Crystallogr. 2003, E59, o372.
−1
vmax/cm (Nujol) 696.4, 723.6, 842, 980, 1052, 1169, 1282, 1604.1,
1
9
4
759. δH [(CD3)2SO/D2O] 3.71 (4H, s, 2 PhCH2CO2), 3.79 (2H, d, J
.2, 2 CH2CH(OH)CH(OH)), 4.07 (2H, m, 2 CH2CH(OH)CH(OH)),
[
13] V. Bhaskar, A. D’Elia, P. J. Duggan, D. G. Humphrey,
G. Y. Krippner, T. T. Nhan, E. M. Tyndall, J. Carbohydr.
Chem. 2003, 22, 867. doi:10.1081/CAR-120026598
a
b
.38 (2H, dd, J 1.4 and 11.0, 2 OCH H CH(OH)), 4.45 (2H, dd, J 6.0
a
b
and 11.0, 2 OCH H CH(OH)), 7.39 (4H, dd, J 1.5 and 8.5, 2ArH), 7.48
(
4H, m, 2 ArH), 7.62 (2H, m, 2 ArH). δC [(CD3)2SO] 41.9, 68.7, 71.08,
[
14] Biotransformations in Organic Chemistry, 2nd edn (Ed. K. Faber)
+
7
1.13, 127.7, 129.3, 130.4, 139.3, 172.0. m/z 441.2 [M + Na] .
2
001 (Springer: Berlin).
[
[
15] A. M. Klibanov, Acc. Chem. Res. 1990, 23, 114.
16] I. Ikeda, A. M. Klibanov, Biotechnol. Bioeng. 1993, 42, 788.
General Procedure for the Conventional Acid Chloride Method
d-Mannitol (1.0 g, 5.5 mmol) was heated in pyridine (8 mL) under an
inert atmosphere at 100 C for 15 min, after which time only about half of
[17] G. Youssef, S. Ransac, R. Verger, Biochim. Biophys. Acta 1997,
1334, 6.
◦
the d-mannitol was observed to dissolve. The acid chloride (11.0 mmol)
was then added dropwise, with the reaction mixture becoming homo-
geneous once approximately half of the acid chloride had been added.
The reaction mixture was then stirred and heated at reflux for 5 h, and
then allowed to cool slowly to room temperature. The resulting reaction
mixture was added to H2SO4 (10%, 50 mL) and further H2SO4 was
added until a pH of 2 was attained. The reaction mixture was then left
to stand overnight, resulting in the precipitation of a fine white solid.
The precipitate was collected by vacuum filtration and then recrystal-
lized from ethanol to yield a white powder. In this way, d-mannitol
[18] G.-Y. Jeon, O.-J. Park, B.-K. Hur, J.-W. Yang, Biotechnol. Lett.
2001, 23, 929. doi:10.1023/A:1010598031929
[19] G. Kirchner, M. P. Scollar, A. M. Klibanov, J. Am. Chem. Soc.
1985, 107, 7072.
[20] Y.-F. Wang, J. J. Lalonde, M. Momongan, D. E. Bergbreiter,
C.-H. Wong, J. Am. Chem. Soc. 1988, 110, 7200.
[21] K. Takashi, T. Yoshimoto, A. Ajima, Y. Tamaura, Y. Inada,
Enzyme 1984, 32, 235.
[22] G. Carrea, S. Riva, F. Secundo, J. Chem. Soc., Perkin Trans. 1
1989, 1057. doi:10.1039/P19890001057
1
1
,6-didecanoate 17 (0.25 g, 9%) was obtained; the yield of d-mannitol
,6-di(phenyl)acetate 18 obtained, however, was 0%.
[23] E. Reinefeld, G. Klauenberg, Tenside 1968, 5, 266 [Chem. Abstr.
1969, 70, 11 929f].