Asymmetric synthesis of the (S)-1,1-dioxido-isothiazolidin-3-one phosphotyrosine mimetic via reduction of a homochiral (R)-oxido-isothiazolidin- 3-one

Article abstract of DOI:10.1021/ol0701262

Figure presented The first asymmetric synthesis of the (S)-1,1-dioxido- isothiazolidin-3-one ((S)-IZD) pTyr mimetic, which has been incorporated into the recently reported potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, is presented herein. The

Full text of DOI:10.1021/ol0701262

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1279-1282
Asymmetric Synthesis of the
(S)-1,1-Dioxido-isothiazolidin-3-one
Phosphotyrosine Mimetic via Reduction
of a Homochiral
(R)-Oxido-isothiazolidin-3-one
Andrew P. Combs,* Brian Glass, Laurine G. Galya, and Mei Li
DiscoVery Chemistry, Experimental Station, Incyte Corporation, Route 141 and
Henry Clay Road, Wilmington, Delaware 19880
acombs@incyte.com
Received January 17, 2007
ABSTRACT
The first asymmetric synthesis of the (S)-1,1-dioxido-isothiazolidin-3-one ((S)-IZD) pTyr mimetic, which has been incorporated into the recently
reported potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, is presented herein. The key reaction is the reduction of the (R)-oxido-
isothiazolidin-3-one heterocycle with excellent regiochemical and stereochemical control (>98% ee; 82% yield).
The discovery of potent cell-permeable phosphatase inhibi-
tors has been a significant unmet medicinal chemistry
challenge for over a decade. The search for protein tyrosine
phosphatase 1B (PTP1B) is a particularly attractive drug
target due to the extensive in vitro and in vivo biological
data to support their use for the treatment of diabetes and
obesity.1-3 The deep active site of PTP1B that binds the
phosphotyrosine (pTyr) portion of the peptide substrates has
been the focus of most inhibitor design efforts to date.
Several excellent pTyr mimetics have been identified, though
nearly all contain a highly charged moiety, such as a
carboxylic acid or phosphonate, that does not allow for
adequate cell permeability.4-7
We recently reported the structure-based design of potent
PTP1B inhibitors that incorporate a novel diffusely anionic
1,1-dioxido-isothiazolidin-3-one (IZD) pTyr mimetic (Table
1).8-12 Of the two possible heterocyclic diastereomers, only
the compounds, such as 2, bearing the (S)-IZD isomer were
(4) Bialy, L.; Waldmann, H. Angew. Chem., Int. Ed. 2005, 44, 3814-
3839.
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Biol. 2000, 20, 5479-5489.
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Clampit, J. E.; Waring, J. F.; Xie, N.; Wilcox, D.; Jacobson, P.; Frost, L.;
Kroeger, P. E.; Reilly, R. M.; Koterski, S.; Opgenorth, T. J.; Ulrich, R. G.;
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11362.
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(7) Moller, N. P. H.; Andersen, H. S.; Jeppesen, C. B.; Iversen, L. F.
Handb. Exp. Pharmacol. 2005, 167, 215-262.
(8) Combs, A. P.; Yue, E. W.; 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.; Gonneville, L.; Reid, B. G.;
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, 48, 6544-
6548.
10.1021/ol0701262 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/06/2007

We also considered the use of a chiral nitrogen protecting
group on the (S)-IZD heterocycle, but reasoned this remote
substituent may not afford suitable chiral induction. Also,
recycling of the chiral auxiliary would not be possible and
thus less economical than other routes.
Table 1. (S)-IZD pTyr Mimetics Are Potent PTP1B Inhibitors
Utilization of the homochiral heterocyclic sulfoxide 6 to
control the stereochemistry of the desired (S)-IZD heterocycle
was chosen for further investigation for two key reasons.
Foremost, Ellman has demonstrated that chiral N-tert-
butanesulfinyl imines are substrates for a variety of nucleo-
philes, providing excellent stereochemical control for these
reactions.13-15 We inferred that similar stereochemical control
of the hydride delivery to the sulfamide heterocycle 6 could
be expected due to the close proximity of olefin to the chiral
sulfinamide center. Last, the resulting chiral sulfinamide can
easily be converted to the biologically active IZD heterocycle
4 via an oxidation.
A retrosynthetic analysis identified the chiral chloro
heterocycle 8 as the key source of chirality in this synthetic
design. Coupling of 8 to an arylboronic acid would provide
the unsaturated arylsulfinamide heterocycle 6. The key
transformation would rely on the stereocontrolled reduction
of 6 induced by the adjacent chiral sulfinamide. The synthesis
of the desired (S)-IZD 4 would be completed by oxidation
of the sulfinide 5 and deprotection (Scheme 1).
potent PTP1B inhibitors. Further studies demonstrated that
the (S)-IZD is the most potent pTyr mimetic known to date
and when incorporated in non-peptidic inhibitors can be
caco-2 permeable and cellularly active.
We report herein a general approach to the stereoselective
synthesis of the (S)-IZD pTyr mimetic via Suzuki coupling
of the chiral chlorosulfinamide heterocycle 8 followed by a
highly chemoselective (>99%) and stereoselective (>98%
ee) reduction of the heterocyclic olefin. Oxidation to the
heterocyclic sulfonamide 9 and deprotection afforded the
desired (S)-IZD-containing compound 15 in good yields. A
proposed mechanism is provided for this regioselective and
stereoselective reduction consistent with our X-ray analyses
and NMR studies.
Scheme 1. Retrosynthetic Analysis for (S)-IZD
An asymmetric synthesis of the (S)-IZD was envisioned
by several different synthetic processes. We initially at-
tempted the catalytic asymmetric hydrogenation of unsatur-
ated IZD-containing compounds, such as 1, with various
chiral ligands and metal catalysts. Although hydrogenation
with Pd/C gave high yields of the desired products in our
original research, none of the rhodium asymmetric reaction
conditions attempted gave acceptable yields and/or selectivi-
ties to be synthetically useful.
The racemate of the chloro-sulfinamide heterocycle 8 is
available in good yields and large quantities as previously
described.8 Initial studies demonstrated that the chlorosul-
finamide heterocycle 8 was an excellent Suzuki coupling
partner, affording the desired aryl heterocycle 9 in 90% yield
under standard conditions (K2CO3, THF, 100 °C, 8 h) with
phenylboronic acid 7.
A variety of reduction conditions were attempted with
racemic 9 (Table 2). Although hydrogenation conditions were
again unsuccessful, hydride sources proved to be effective.
(9) Yue, E. W.; Wayland, B.; Douty, B.; Crawley, M. L.; McLaughlin,
E.; Takvorian, A.; Wasserman, Z.; Bower, M. J.; Wei, M.; Li, Y.; Ala, P.
J.; Gonneville, L.; Wynn, R.; Burn, T. C.; Liu, P. C. C.; Combs, A. P.
Bioorg. Med. Chem. 2006, 14, 5833-5849.
(10) Ala, P. J.; Gonneville, L.; Hillman, M. C.; Becker-Pasha, M.; Wei,
M.; Reid, B. G.; Klabe, R.; Yue, E. W.; Wayland, B.; Douty, B.; Polam,
P.; Wasserman, Z.; Bower, M.; Combs, A. P.; Burn, T. C.; Hollis, G. F.;
Wynn, R. J. Biol. Chem. 2006, 281, 32784-32795.
(11) Combs, A. P.; Zhu, W.; Crawley, M. L.; Glass, B.; Polam, P.;
Sparks, R. B.; Modi, D.; Takvorian, A.; McLaughlin, E.; Yue, E. W.;
Wasserman, Z.; Bower, M.; Wei, M.; Rupar, M.; Ala, P. J.; Reid, B. M.;
Ellis, D.; Gonneville, L.; Emm, T.; Taylor, N.; Yeleswaram, S.; Li, Y.;
Wynn, R.; Burn, T. C.; Hollis, G.; Liu, P. C. C.; Metcalf, B. J. Med. Chem.
2006, 49, 3774-3789.
(12) Ala, P. J.; Gonneville, L.; Hillman, M.; Becker-Pasha, M.; Yue, E.
W.; Douty, B.; Wayland, B.; Polam, P.; Crawley, M. L.; McLaughlin, E.;
Sparks, R. B.; Glass, B.; Takvorian, A.; Combs, A. P.; Burn, T. C.; Hollis,
G. F.; Wynn, R. J. Biol. Chem. 2006, 281, 38013-38021.
(13) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709-6712.
(14) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995.
(15) Kochi, T.; Mukade, T.; Ellman, J. A. Yuki Gosei Kagaku Kyokaishi
2004, 62, 128-139.
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Org. Lett., Vol. 9, No. 7, 2007

An X-ray crystal structure of a single enantiomer of 13
(Chiral HPLC peak 1) provided the relative and absolute
configuration of each stereocenter as as S- for C3 and R-
for the sulfur atom. The enantiomeric setting was based upon
the refined flack parameter of 0.02(4) and an absolute
configuration analysis (teXsan), which compares differences
in Bijvoet pairs of reflection (see Supporting Information
for details). The ORTEP presentation of 13 clearly shows
the hydrogen on the C3 carbon is on the opposite face of
the heterocycle compared to that of the oxygen of the
sulfinamide (Figure 1).
Table 2. Optimization of Reduction Conditionsa
reducing
agent
temp
(°C)
yieldb
(%)
dec
(%)
entry
solvent
MeOH
1
2
3
4
5
6
7
H2/Pd/C
NaBH4
NaBH4
NaBH4
NaBH4
LiBH4
25
0
0
35
82
63
67
80
76
n.d.
n.d.
>98
>98
>98
>98
>98
THF
0
MeOH
0
25
0
1:1 THF/MeOH
1:1 THF/MeOH
1:1 THF/MeOH
1:1 THF/MeOH
LiBH4
25
a Conditions: 1.0 equiv of reducing agent was added to a solution of
the substrate at specified temperature. b Purified yields after chromatography.
c Diastereomeric purity (% de) determined by chiral HPLC analysis with
monitoring at 220 nm; n.d. ) determined.
Reduction of 9 with either NaBH4 or LiBH4 at 0 °C in MeOH
or a 1:1 MeOH/THF solution gave optimal yields of only
1
one pair of enantiomers by H NMR and HPLC, providing
evidence that a high degree of stereochemical control was
achieved.
To further establish the diastereoselectivity induced by the
chiral sulfinamide, we required the individual enantiomers
of 9. Separation of the racemate of sulfinamide heterocycle
8 by preparative chiral HPLC proved to be facile and
furnished multigram quantities of both enantiomers of 8 in
>98% ee. Suzuki coupling of each individual enantiomer
of sulfinamide heterocycle 8 to phenylboronic acid provided
the desired enantiomerically pure R- and S-arylsulfinamides
9 (>98% ee). Reduction of each enantiomer of 9 provided
only one unique diastereomer 13 for each, demonstrating
unequivocally that the chiral induction from the sulfinamide
was absolute (>98% de). We did not observe any of the
other diastereomer by chiral HPLC or NMR.
Figure 1. ORTEP presentation of 13.
The proposed mechanism for the stereoselective reduction
is depicted in Scheme 3, where the hydride attacks the
Scheme 3. Proposed Mechanism of Stereoselective Reduction
The regioselectivity of the reduction was probed to deduce
whether the hydride addition occurred R to the sulfinamide
or R to the carbonyl of the unsaturated IZD heterocycle.
Reduction of racemic 9 with NaBD4 and NMR analysis of
the reduced product 11 confirmed that the hydride addition
occurs only R to the sulfinamide or the most substituted
carbon (Scheme 2). The high degree of stereochemical
control in the hydride delivery can thus be rationalized by
the close proximity of the chiral sulfinamide to the newly
formed chiral center.
olefinic carbon adjacent to the sulfinamide from the opposite
face of the heterocycle that bears the oxygen of the
sulfinamide. This result is consistent with the hydride
delivery from the less sterically and electronically disfavored
face that bears only the lone pair of the sulfinamide. The
absolute configuration obtained for 13 is S for the C3 carbon
and R for the sulfur atom of the sulfinamide. Thus, the (R)-
chlorosulfinamide heterocycle 8 is the key chiral intermediate
required for the synthesis of the desired biologically active
(S)-IZD heterocycle containing inhibitors.
Scheme 2. Regioselective and Stereoselective Reduction
Org. Lett., Vol. 9, No. 7, 2007
1281

In summary, a highly stereoselective asymmetric synthesis
of the potent pTyr mimetic (S)-IZD has been established in
an atom-efficient method. The key transformation is a
regioselective and stereoselective additon of hydride to a (R)-
sulfinamide heterocycle 9 in high yield and absolute stere-
ochemical control (>98% de). The proposed mechanism for
the stereocontrolled addition of the hydride to the heterocycle
is consistent with the delivery of the hydride to C3 of the
heterocycle from the face opposite to that of the sulfinamide
oxygen as determined for the X-ray crystal structure of 13.
The use of this new methodology in the asymmetric synthesis
of novel inhibitors of phosphatases, such as PTP1B, will be
reported elsewhere.
Scheme 4. Sulfinamide Oxidation and Deprotection
a Percent ee inferred from derivatives 14 and 16.
Acknowledgment. The authors thank James Doughty of
Incyte for chiral purity analysis. We also thank Will J.
Marshall of the DuPont X-ray facility for solving the crystal
structure of compound 13.
The asymmetric synthesis of the (S)-IZD 15 (Scheme 4)
was completed in good yield by mCPBA oxidation of 13 to
afford sulfonamide 14, followed by cleavage of the N-tert-
butyl protecting group from the (S)-IZD heterocycle using
TFA and microwave irradiation for 60 seconds. Chiral HPLC
analysis of 14 and its Sem-protected derivative 16, since the
acid 15 could not be completely resolved by chiral HPLC,
confirmed there was no loss in stereochemical integrity
during the final oxidation and deprotection steps.
Supporting Information Available: General experimen-
tal and analytical data for 4-16 and X-ray crystal structure
data for 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
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