Concise approach to novel isothiazolidinone phosphotyrosine mimetics: Microwave-assisted addition of bisulfite to activated olefins

Article abstract of DOI:10.1021/ol052076b

(Chemical Equation Presented) A novel and efficient synthesis of isothiazolidinone protein tyrosine phosphatase mimetics is presented. A practical, regiospecific microwave-assisted addition of bisulfite to activated olefins, including unprecedented reactions with styrene derivatives, is highlighted.

Full text of DOI:10.1021/ol052076b

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5067-5069
Concise Approach to Novel
Isothiazolidinone Phosphotyrosine
Mimetics: Microwave-Assisted Addition
of Bisulfite to Activated Olefins
Matthew L. Crawley,* Erin McLaughlin, Wenyu Zhu, and Andrew P. Combs
DiscoVery Chemistry, Experimental Station, Incyte Corporation, Route 141 and
Henry Clay Road, Wilmington, Delaware 19880
mcrawley@incyte.com
Received August 29, 2005
ABSTRACT
A novel and efficient synthesis of isothiazolidinone protein tyrosine phosphatase mimetics is presented. A practical, regiospecific microwave-
assisted addition of bisulfite to activated olefins, including unprecedented reactions with styrene derivatives, is highlighted.
The rising incidence of type 2 diabetes and obesity has
accelerated the search to find effective agents to treat these
diseases. Protein tyrosine phosphatase 1B (PTP1B) is highly
validated as a target for drug discovery. PTP1B knockout
studies have shown lowered blood glucose levels and
improved insulin responsiveness.1 Thus, the design and
synthesis of inhibitors of PTP1B has been a focus of the
pharmaceutical industry and academic research.2
Recently, we reported a structure-based design of potent
PTP1B inhibitor 1 (Scheme 1)3 that incorporated the novel
1,1-dioxidoisothiazolidin-3-one (IZD) protein tyrosine-phos-
phatase (pTyr) mimetic via a Suzuki coupling to a phenyl-
alanine boronic acid scaffold with a 5-chloroisothiazolone.
While this approach allowed for efficient synthesis of PTP1b
inhibitor 1, several important targets 2 with selected ortho
substituents (X) were not accessible utilizing this chemistry.
A novel route to the IZD 2 was envisioned utilizing a bisulfite
addition to readily available enoate 4 to form sulfonic acid
3, followed by cyclization (see Scheme 1). Reaction of
bisulfite with R,â-unsaturated ketones, esters, and amides
has been known for over a century.4 However, there are few
Scheme 1. Retrosynthetic Analysis of PTP1B Inhibitors
(1) (a) Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlisch, W.; Collins,
S.; Loy, A. L.; Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C.;
Ramachandran, C.; Gresser, M. J.; Tremblay, M. L.; Kennedy, B. P. Science
1999, 283, 1544.
(2) For recent comprehensive reviews, see: (a) Bialy, L.; Waldmann,
H. Angew. Chem., Int. Ed. 2005, 44, 3814. (b) Ross, S. A.; Gulve, E. A.;
Wang, M. Chem. ReV. 2004, 104, 1255. (c) Johnson, T. O.; Ermolieff, J.;
Jirousek, M. R. Nature ReV. 2002, 1, 696.
(3) Combs, A. P.; Yue, E, Bower, M.; Ala, P. J.; Wayland, B.; Douty,
B.; Takvorian, A.; Polam, P.; Wasserman, Z.; Zhu, W.; Crawley, M. L.;
Pruitt, J.; Sparks, R.; Glass, B.; Modi, D.; McLaughlin, E.; Bostrom, L.;
Li, M.; Galya, L.; Blom, K.; Hillman, M.; Gonnville, L.; Reid, B.; Wei,
M.; Becker-Pasha, M.; Klabe, R.; Huber, R.; Li, Y.; Hollis, G.; Burn, T.
C.; Wynn, R.; Liu, P.; Metcalf, B. J. Med. Chem. 2005, in press.
10.1021/ol052076b CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/28/2005

reported uses of it. Most examples are on highly activated
disubstituted enones or require long reaction times.5
We report herein a practical and general approach for
regiospecific addition of sodium bisulfite to activated olefins.
The sulfonic acid adducts’ utility is demonstrated by the rapid
assembly of the recently reported IZD class of pTyr
mimetics.
Table 2. Synthesis of Sulfonic Acids 6 via
Microwave-Assisted Additions of Sodium Bisulfite to Activated
Olefins 5
Ethyl cinnamate 5a was used as a model system to
optimize sodium bisulfite addition conditions that would
allow for exploration of a variety of substituted olefin
derivatives (Table 1). A solvent mixture of ethanol and water
Table 1. Optimization of Sodium Bisulfite Addition
Conditions
entry
heatingb
oil bath
oil bath
oil bath
microwave 165
microwave 180
T (ïC) pressure (bar) time (min) convc (%)
1
2
3
4
5
125
125
165
1
1
d
30
180
30
5
32
56
12
17
30
10
>95
>95
a Conditions: 1.0 equiv of ethyl cinnamate, 2.0 equiv of sodium bisulfite,
1:1 ) H2O/EtOH, 1.0 M concentration. b Heating at 165 and 180 °C was
done in 1.0 mL total solvent volume (1.0 mmol scale) in 10 mL sealed µW
tubes. c Determined by LCMS with monitoring UV at 220 nM. d Pressure
was not determined.
was selected to promote solubility of both the organic
reactant and the bisulfite salt. While reaction with sodium
bisulfite did proceed slowly at vigorous reflux (Table 1,
entries 1 and 2), clean conversion to product 6a was obtained
in a matter of minutes in the microwave at 165 and 180 °C
(Table 1, entries 4 and 5). While microwave tubes are
designed to withstand pressure up to 21 bar, we recommend
maintaining pressure under 15 bar.
Utilizing these optimized microwave-assisted conditions
a variety of â-aryl enoates were investigated as substrates
for sodium bisulfite additions (Table 2).
The expected products (6a-e) were initially isolated by
preparative HPLC/LCMS chromatography. However, on a
gram scale it was more convenient to isolate sulfonic acid
adducts via crystallization, which afforded comparable yields.
To explore the scope of the reaction, less reactive and more
hindered substrates were investigated. While in some cases
these examples required longer reaction times, cinnamide
5f, ethyl 3,3-dimethylacrylate 5g, and cyclic enoate 5h (Table
2) afforded moderate to high yields of adducts 6f-h utilizing
the optimized reaction conditions. In the case of enoate 5g,
the higher temperature and pressure in the microwave were
critical as the reaction did not proceed even after 24 h at
reflux in an oil bath.
Additional compounds with a methylene spacer between
the aryl ring and the IZD, substituted 4-but-2-enoic acid ethyl
esters, were examined as substrates. The first derivative 5i
afforded a high yield (87%) of product 6i. In attempts to
prepare further alkyl enoate derivatives, substituted styrene
5j was prepared with conjugation to the aryl ring instead of
(4) For early representative examples,, see: (a) Beilstein, F. K.; Wiegand,
H. Chem. Ber. 1885, 18, 482. (b) Dodge, F. D. J. Am. Chem. Soc. 1930,
52, 1724. (c) Thurston, J. T. U.S. Patent 2,402,512, 1944.
(5) For more recent representative examples, see: (a) Kellogg, R. M.;
Nieuwenhuijzen, J. W.; Pouwer, K.; Vries, T. R.; Broxterman, Q. B.;
Grimbergen, R. F. P.; Kaptein, B.; La Crois, R. M.; de Wever, E.; Zwaagstra,
K.; van der Laan, A. C. Synthesis 2003, 10, 1626. (b) Baczko, K.; Chasseray,
X.; Larpent, C. J. Chem. Soc., Perkin Trans. 2 2001, 2, 2179. (c) Hejchman,
E.; Haugwitz, R. D.; Cushman, M. J. Med. Chem. 1995, 38, 3407. (d)
Pfoertner, K. H. HelV. Chim. Acta 1980, 63, 664.
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Org. Lett., Vol. 7, No. 22, 2005

substituted derivatives (5k and 5l) were prepared and
subjected to the reaction conditions (Table 2). While the
reactions required additional time relative to the enoate
examples, clean conversions to 6k and 6l were achieved with
moderate isolated yields (62% and 71%, respectively). This
constitutes the first examples of sodium bisulfite adding to
monosubstituted derivatives to afford â-aryl sulfonic acids
as the major products.7
Table 3. Synthesis of Novel Isothiazolidinone 7
To obtain the desired IZDs 7, the appropriate sulfonic acids
6 were converted to sulfonamides via the acid chlorides and
subsequently cyclized (see Table 3).8 The conditions for both
steps afforded a minimal amount of elimation product
(enoates 5). In the case of sulfonic acid 6d, acyl protection
(6m) of the free alcohol was required before amination and
cyclization.
In summary, we have developed an efficient route to
access a novel class of phosphotyrosine (pTyr) mimetics
employing a practical and general microwave-assisted bisulfite
addition to activated olefins. The bisulfite chemistry devel-
oped herein utilizes readily accessible olefins with a variety
of substitution and is highly amenable to parallel synthesis.
Of note, the styrene derivatives 5j-l, were identified as
relatively unactivated substrates for this microwave-assisted
process. The utilization of this new methodology to synthe-
size novel PTP1B inhibitors containing IZD pTyr mimetics
will be reported elsewhere.9
a Isolated yields for two steps. b The hydroxyl group of 6e was acyl
protected to form 6m before attempting the amination/cyclization.
Supporting Information Available: General experimen-
tals and analytical data for 6a-l and 7a,c,d,i,j. This material
is available free of charge via the Internet at http://pubs.acs.org.
the ester.6 Unexpectedly, this derivative 5j afforded desired
adduct 6j under the optimized conditions. The result can be
rationalized by the high temperature and pressure isomerizing
the olefin into conjugation with the ester, allowing for the
desired Michael-type addition of bisulfite. However, it is
plausible that regiospecific addition to styrene 5j was in fact
the underlying process.
OL052076B
(7) There is a report of the reaction of styrene with sodium bisulfite to
give this type of adduct as the major product by: (a) Kharasch, M. S.;
May, E. M.; Mayo, F. R. J. Org. Chem. 1938, 3, 175. However, this was
later described by the authors in a subsequent publication identifying the
major product as 2-hydroxy-2-phenylethanesulfonic acid: (b) Kharasch, M.
S.; Schenck, R. T. E.; Mayo, F. R. J. Am. Chem. Soc. 1939, 61, 3092.
(8) Chen, Z.; Demuth, T. P.; Wireko, F. C. Biorg. Med. Chem. Lett.
2001, 11, 2111.
To test the hypothesis that activated styrenes could be
substrates for bisulfite addition, two electron-deficient mono-
(9) Combs, A. P.; Yue, E. W.; Bower, M. J.; Zhu, W.; Crawley, M. L.;
Sparks, R. B.; Pruitt, J.; Takvorian, A. Int. Patent WO 2005/035551 A2,
2005.
(6) The initially desired adduct in this preparation was the enoate.
Org. Lett., Vol. 7, No. 22, 2005
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