Continuous flow biocatalytic resolutions of methyl sulfinylacetates

Article abstract of DOI:10.1016/j.tetlet.2011.09.024

Product inhibition was encountered for some substrates in the resolution of methyl sulfinylacetates mediated by lipase Amano AK, so an apparatus to continually extract the carboxylate product was devised. This was applied to resolve some sulfoxides with h

Full text of DOI:10.1016/j.tetlet.2011.09.024

Tetrahedron Letters 52 (2011) 6325–6327
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Continuous flow biocatalytic resolutions of methyl sulfinylacetates
Zhanxiang Liu a,b, Kevin Burgess b,
⇑
a Department of Chemistry, Zhejiang University, Campus Xixi, Hangzhou 310028, PR China
b Department of Chemistry, Texas A&M University, Box 31002, College Station,, TX 77842, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Product inhibition was encountered for some substrates in the resolution of methyl sulfinylacetates med-
iated by lipase Amano AK, so an apparatus to continually extract the carboxylate product was devised.
This was applied to resolve some sulfoxides with high enantiodifferentiation.
Ó 2011 Published by Elsevier Ltd.
Received 4 August 2011
Revised 29 August 2011
Accepted 6 September 2011
Available online 10 September 2011
Keywords:
Biocatalytic resolution
Sulfoxide
Lipase
Enantiomerically pure sulfinyl acetates 1 have the potential to
be used as chiral reagents.1 The best known among the proven
applications are reactions that combine Knoevenagel condensa-
tions, double-bond migrations, and [2+3] allylic sulfoxide rear-
rangements to give allylic alcohols.2 For instance, this reaction
has been used in the syntheses of statin analogs,3 (+)-brefeldin
A,4,5 and an amphidinol fragment.6 The sulfoxide in those synthe-
ses was derived from a lipase-mediated hydrolysis reaction devel-
oped in our group.7–9 Recently we had cause to expand the range of
sulfoxides accessible by this kinetic resolution reaction; however, a
problem was encountered that motivated us to develop the im-
proved procedure reported here.
Scheme 1 illustrates the problem with our original methods. At-
tempted resolution of the 3,5-di(trifluoromethyl) substituted-sys-
tem 1a was followed by HPLC to monitor the conversion and
enantiomeric excess of the starting material (the product could
not be observed simultaneously). After about 60 h, the reaction slo-
wed down to an insignificant rate. The addition of more enzyme or
adjusting the pH level had little effect hence the conversion and
enantiomeric excess of the recovered ester (R)-1a peaked at the
values shown.
Scheme 1. Resolution of methyl 2-((3,5-bis(trifluoromethyl) phenyl)sulfinyl)ace-
tate 1.
tuent, and was least for the substrate where that aryl group is
4-ClC6H4–.
Product inhibition can be avoided if the product is removed from
the enzyme and substrate as the transformation progresses. This
can be convenient in the highlighted resolution since the sulfinyl
carboxylate products 2 can have appreciable water-solubilities.
Consequently, a simple experimental set-up was devised to extract
products 2 as the reaction proceeds (Fig. 2). To implement this, it
was first necessary to find an organic co-solvent that could be used
for the resolution process, and that was also denser than water.
Chlorobenzene was found to be suitable in this regard.
Suspecting product inhibition, we tested the consequences of
pulsing the reaction with a sample of the acid (S)-2a after the reac-
tion had been in progress for 16 h (Fig. 1). Introduction of the prod-
uct had
a significant suppression effect on the rate of the
subsequent reaction, providing strong evidence that product inhi-
bition was involved. Other experiments, not shown, implied that
the degree of product inhibition was dependent on the aryl substi-
Resolution of sulfinyl acetates 1 was achieved by first suspend-
ing the lipase (Pseudomonas sp. AK) in a chlorobenzene solution of
the substrate. A volume of pH 7.5, 0.05 M phosphate buffer, equal
to the volume of chlorobenzene, was added and the mixture was
⇑
Corresponding author. Tel.: +1 979 845 4345; fax: +1 979 845 8839.
E-mail address: Burgess@tamu.edu (K. Burgess).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.09.024

6326
Z. Liu, K. Burgess / Tetrahedron Letters 52 (2011) 6325–6327
Table 1
no acid
t =16h, added 0.5 eq. sulfinylacetic acid
Resolution of sulfinyl acetates 1
100
80
60
40
20
0
sulfinylacetic
acid added
1
a
R
Time (h)
Ester
Acid
Yield (%)
% eea
100
Yield (%)
% eeb
98
96
45
35
0
20
40
60
80
100
120
time (h)
b
c
24
60
72
46
43
46
100
100
100
38
36
35
99
91
98
Figure 1. Product inhibition in the resolution of 1a.
d
e
f
72
72
47
42
100
99
39
36
97
91
buffer
a
Enantiomeric excess determined via HPLC on OB chiral column.
The crude acid was esterified with TMSCH2N2, ee was obtained from the cor-
1 M 1 in C6H5Cl
b
responding ester.
Figure 2. Resolution of the sulfinyl esters 1 with continuous extraction of the
product.
stirred gently. An important feature of the reaction vessel was that
the combined volumes of chlorobenzene and buffer were such that
the reaction mixture filled the flask right up to the side arm that
acted as an overflow.
As the reaction progressed, buffer was added via a syringe
pump through a needle that was immersed in the chlorobenzene
layer. Predominantly buffer, with dissolved sulfinyl carboxylate,
was displaced via the overflow, having the effect of continuous
extraction. Typically, the total volume of buffer added was ca.
30–40 times the volume of chlorobenzene, over a period of
24–96 h. These volumes and times were adjusted according to
the substrate as the project evolved.
The data for biocatalytic resolutions of substrates 1a–f are
shown in Table 1. In the case of the 4-ClC6H4-substituted system
1b, continuous extraction offered no significant advantage. How-
ever, continuous extraction improved the conversion and, there-
fore, the enantiomeric purities of the recovered starting esters for
the substrates 1a and 1c–f. For comparison, experimental data
for typical conventional resolutions of the methyl sulfinyl acetates
are included in the supporting material. Throughout, the E-values10
measured were >100, indicative of highly effective resolutions.
Methyl sulfinate 1e had poor solubility in water, and in acetoni-
trile. This is unfortunate because acetonitrile is the preferred sol-
vent for the condensation/alkene isomerization/rearrangement
process alluded to the above. However, the pyrimidine halides
can be displaced via SNAr reactions providing a gateway to deriva-
Scheme 2. Modification of the methyl sulfinate 1e via the SNAr reaction.
tives with more favorable solubility characteristics. Scheme 2 gives
an example of this.
In conclusion, we report a simple modification to the lipase-
mediated hydrolyses of sulfinyl esters, which significantly expands
the scope of this reaction.
Experimental section
General Methods
NMR spectra were recorded on a VXR-300 spectrometer in
CDCl3. Flash chromatography was performed using silica gel
(230–600 mesh). Thin layer chromatography was performed using
glass plates coated with silica gel 60 F254. All substrates were pre-
pared under an atmosphere of nitrogen in oven-dried glassware
with magnetic stirring. Air sensitive reagents and solutions were
transferred via syringe and were introduced to the apparatus

Z. Liu, K. Burgess / Tetrahedron Letters 52 (2011) 6325–6327
6327
through rubber septa. 0.05 M, pH 7.5 buffer was made from NaH2-
Acknowledgments
PO4/Na2HPO4. The enzyme Pseudomonas sp. AK (Amano) is pur-
chased from Amano International Enzyme Co. Inc. (Japan). The
methyl sulfinylacetates were prepared according to the reference
(Supplementary data). The absolute configurations were assigned
according to the reference for compound 1b.7
Financial support for this work was provided by The National
Science Foundation (CHE-0939825) and The Robert A. Welch Foun-
dation. Dr. Z. Liu is grateful to the National Natural Science Foun-
dation of China (No. 20802068).
Conventional resolution of the methyl sulfinylacetates 1. A solution
of 10 mmol racemic sulfinyl ester in 10 mL toluene was mixed with
80 mL pH 7.5, 0.05 M phosphate buffer and Enzyme AK (20 wt %of
ester). This mixture was stirred at 25 °C for 48 h. The mixture was
filtered to remove the enzyme and extracted with CH2Cl2
(3 Â 30 mL). The combined organic fractions were dried over
Na2SO4, filtered and removal of the solvent from the organic layer
gave the crude (R) —ester. Glacial acetic acid (20 mL) was added to
the aqueous solution and extracted with CH2Cl2 (4 Â 20 mL).
The collected organic fractions were dried over Na2SO4, filtered,
and evaporation of the solvent gave the crude (S)-sulfinylacetic
acid.
Supplementary data
Supplementary data (1H and 13C NMR spectra for 1a–g, general
experimental details of preparation of these compounds) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.09.024.
References and notes
1. Pellissier, H. Tetrahedron 2006, 62, 5559–5601.
2. Kosugi, H.; Kitaoka, M.; Takahashi, A.; Uda, H. J. Chem. Soc., Chem. Commun.
1986, 1268–1270.
Continuous flow resolution of the methyl sulfinylacetates 1. A solu-
tion of 10 mmol racemic sulfinyl ester in 10 mL chlorobenzene was
mixed with Enzyme AK (20 wt % of ester) and 10 mL, pH 7.5, of
0.05 M phosphate buffer in a 25 mL flask with a branch pipe. The
buffer was added to the organic layer of the mixture using a syr-
inge pump very slowly to keep the pH at 7.2 and the sulfinyl salt
was separated continuously from the branch pipe to the beaker.
The resolution was checked by HPLC on DAICEL chiral OB column
(see the Supplementary data). After reaction the workup is similar
to the general method.
3. Burgess, K.; Cassidy, J.; Henderson, I. J. Org. Chem. 1991, 56, 2050–2058.
4. Corey, E. J.; Carpino, P. Tetrahedron Lett. 1990, 31, 7555.
5. Nokami, J.; Ohkura, M.; Dan-Oh, Y.; Sakamoto, Y. Tetrahedron Lett. 1991, 32,
2409–2412.
6. de Vicente, J.; Huckins, J. R.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2006, 45,
7258–7262.
7. Burgess, K.; Henderson, I. Tetrahedron Lett. 1989, 30, 3633–3636.
8. Burgess, K.; Henderson, I.; Ho, K.-K. J. Org. Chem. 1992, 57, 1290–1295.
9. Mikolajczyk, M.; Kielbasinski, P.; Zurawinski, R.; Wieczorek, M. W.; Blaszczyk, J.
Synlett 1994, 127–129.
10. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.