Synthesis of novel cyclopropylic sulfones and sulfonamides acting as glucokinase activators

Article abstract of DOI:10.1016/j.tetlet.2006.02.110

A synthetic route towards cyclopropylic compounds, which act as glucokinase activators is described herein. The present synthesis gives easy and rapid access to a wide variety of either sulfones or sulfonamides starting from readily available late-stage intermediates.

Full text of DOI:10.1016/j.tetlet.2006.02.110

Tetrahedron Letters 47 (2006) 2675–2678
Synthesis of novel cyclopropylic sulfones and sulfonamides
acting as glucokinase activators
Stefan Heuser,a,* David G. Barrett,a Martina Berg,a Benjamin Bonnier,b Astrid Kahl,a
Maria Luz De La Puente,c Niall Oram,d Rainer Riedl,a Ulrike Roettig,a Gema Sanz Gil,c
Erich Seger,a David J. Steggles,d Jutta Wannera, and Andreas G. Weicherta
aLilly Forschung GmbH, a Division of Eli Lilly Research Laboratories, Essener Bogen 7, 22419 Hamburg, Germany
bLilly CPR&D, MSG LC prep. lab., Parc Scientifique de Louvain-La-Neuve, Rue Granbonpre´ 11, 1348 Mont-Saint-Guibert, Belgium
cLilly, Avda. de la Industria, 30, 28108 Alcobendas, Madrid, Spain
dDCSG, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom
Received 22 December 2005; revised 14 February 2006; accepted 17 February 2006
Available online 3 March 2006
Abstract—A synthetic route towards cyclopropylic compounds, which act as glucokinase activators is described herein. The present
synthesis gives easy and rapid access to a wide variety of either sulfones or sulfonamides starting from readily available late-stage
intermediates.
Ó 2006 Elsevier Ltd. All rights reserved.
Glucokinase (GK), a unique member of the hexokinase
family, is predominantly expressed in liver and pancreas,
where it catalyses the phosphorylation of glucose.1 Un-
like other hexokinases, GK demonstrates a low affinity
for glucose and a sigmoidal response to glucose concen-
tration. These properties make GK an ideal glucose sen-
sor, the activity of GK being much higher at elevated
than at normal glucose levels. In the liver, the increased
GK activity at high glucose levels results in enhanced
glucose utilization, whereas in the pancreas, increased
GK activity results in enhanced insulin secretion.2
Therefore, it is proposed that activation of GK should
result in better control of blood glucose levels via both
hepatic and pancreatic effects, whereas the glucose-
dependency of GK activation may decrease the possibil-
ity of hypoglycaemia during treatment. In fact, several
groups including this one have described various
small-molecule GK activators (GKAs), which function
through binding to an allosteric site.3 By in-house efforts
we found that compound 1a (LY2121260) potently acti-
vates GK whereas its enantiomer ent-1a is much weaker
(Scheme 1).4
As part of our structure activity studies around 1a,5 we
were interested in phenyl sulfones and sulfonamides of
the general structure 1 and 2, and required a robust
and short synthetic route to such compounds.
Our initial synthesis (as exemplified in Scheme 2 for
Cyc = cyclopentyl) started from the cycloalkyl aldehyde.
Wadsworth–Horner–Emmons reaction gave the desired
E-olefin 4 in excellent yield. The following bromina-
tion–elimination sequence6 provided the a-brominated
a,b-unsaturated ethyl ester 5, which was readily reduced
to the bromoolefin 6 using DIBAH. 6 could then be
Cyc
Cyc
H
H
N
N
N
N
H
O
O
R
N
O
S
O
S
S
R
S
Keywords: Cyclopropanes; Sulfones; Sulfonamides; Glucokinase acti-
O
O
vators; Halogen–sulfur exchange.
1
2
1a : R = Me , Cyc = cHexyl
Cyc = chexyl, cpentyl
*
Corresponding author. Tel.: +49 40 5272 4409; fax: +49 40 5272
4601; e-mail: heuser_stefan@lilly.com
Present address: Roche Palo Alto LLC, 3431 Hillview Avenue
R6-123, Palo Alto, CA 94304, USA.
Scheme 1. Glucokinase activating sulfones 1 and sulfonamides 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.110

2676
S. Heuser et al. / Tetrahedron Letters 47 (2006) 2675–2678
transformed to the pinacol boronic acid ester 7 employ-
ing standard conditions published by Miyaura and
co-workers.7 This boron reagent was then successfully
used in Suzuki couplings with a variety of bromobenz-
enes in which the desired sulfone- or sulfonamide-linked
functionality had been incorporated. The resulting allylic
alcohols 8 could then be transformed easily into the cor-
responding racemic cyclopropyl methyl alcohols using
Simmons–Smith conditions.8 (Unfortunately, attempts9
to conduct the reaction in an enantioselective manner
failed to give even cyclopropane). The racemic cyclopro-
pyl methyl alcohol was then separated into its enantiomers
by chiral HPLC. Jones oxidation to the corresponding
carboxylic acid and O-benzotriazol-1-yl-N,N,N0,N0-
tetramethyluronium tetrafluoroborate (TBTU)-mediated
amide coupling with 2-aminothiazole finally provided
the desired target molecules 1 or 2 in good yield.
required per desired target compound, and in addition,
the route was not asymmetric. Because the interaction
with GK is enantiospecific, it was necessary to separate
the racemic products into their respective enantiomers
for advanced studies. This was accomplished by semi-
preparative chiral HPLC, but obviously lowered the
yield by 50% in a late step of the reaction sequence for
every final product. Therefore, the development of a
new synthetic route that circumvents these issues and
gives easy and rapid access to enantiopure compounds
with variations in the sulfone/sulfonamide-region was
highly desirable.
Being convinced that an enantiopure intermediate such
as 9 as depicted in Scheme 3 would be a suitable late-
stage intermediate, we first considered a protective
group strategy to mask the thiophenol throughout the
synthesis. Unfortunately, none of the protective groups
applied withstood the cyclopropanation conditions.
We then tried to synthesize 9 (Cyc = cyclopentyl) from
the corresponding diazo-compound 10, which was easily
accessible from 4-nitrobromobenzene and boronic acid
ester 7 via the known route, after reduction10 of the
nitro group and subsequent diazotization.11 However,
the reaction with potassium ethylxanthate12 did not fur-
nish the desired product.
The nature of our initial synthetic route posed several
problems in the exploration of the SAR. First, it was
necessary to incorporate the functional groups
appended via sulfone- or sulfonamide-linkages prior to
the Suzuki coupling; that is, at a fairly early stage of
the synthesis. Furthermore, four subsequent steps were
Cyc
b, c
a
Cyc
O
O
We therefore envisioned halogen–sulfur exchange as an-
other possibility to introduce sulfones or sulfonamides
at a very late stage of the synthesis. To test the hypo-
thesis we first performed a detailed study of a variety of
literature-precedented methods using 4-halogeno- meth-
ylbenzenes as test systems (Table 1). Many of the em-
ployed methodologies13 did not furnish the desired
sulfur-containing compounds. Only potassium triiso-
propylsilane-thiolate [KS(TIPS)] gave the triisopropyl-
silyl-(TIPS)-protected thiophenol in a Pd-catalyzed
coupling reaction14 with all test systems (entries 1, 4 and
5). Furthermore, 1-iodo-4-methylbenzene (13) under-
went the desired reaction with phenyl-methanethiol
using either a mixture of copper iodide and potassium
carbonate in ethyleneglycol15 (entry 2) or copper iodide,
sodium tert-butanolate and phenanthroline in toluene16
(entry 3). However, utilization of these reactions for our
purposes would have required a subsequent deprotec-
tion step prior to transformation of the free thiophenol
O
3
4
Cyc
Br
Cyc
Br
e
d
O
O
OH
5
6
Cyc
Cyc
f
OH
OH
O
B
O
R
O
S
O
7
8
Cyc
H
g-j
N
N
O
O
S
R
S
Cyc
O
H
N
N
1 or 2
Cyc = chexyl, cpentyl
O
S
HS
Scheme 2. Reagents and conditions (exemplified for Cyc = cyclopen-
tyl, R = –NH(CH2)2(2-pyridyl)): cyclopentane-carbaldehyde (3) was
prepared from cyclopentylmethanol using PCC, celite, rt, 16 h
(CH2Cl2), 78%; (a) (EtO)2POCH2CO2Et, NaH, 0 °C, 1 h (THF), then
3, ꢀ78 °C to rt, 1 h (THF), 100%; (b) bromine, ꢀ10 °C, 2 h (CH2Cl2),
not isolated; (c) NEt3, rt, overnight (CH2Cl2), 76%; (d) DIBAH,
ꢀ60 °C to rt, 1 h (THF/toluene), 79%; (e) bis-pinacolatodiboron,
KOAc, Pd(dppf)Cl2, dppf, 80 °C, 2 h (1,4-dioxane), 61%; (f) bromo-
arene, Pd(OAc)2, PPh3, Na2CO3, 80 °C, 16 h (iPrOH/water), 74%; (g)
ZnMe2, CH2I2, 60 °C, 2 h (CH2Cl2/toluene), 45%; (h) chiral HPLC-
separation; (i) CrO3, H2SO4, 0 °C to rt, 2 h (water/acetone), 89%; (j) 2-
aminothiazole, TBTU, NEt3, 40 °C, 24 h (THF), 40%.
9
Cyc
Cyc
H
H
N
N
N
N
BF4
+
N2
O
S
O
S
Br
10
11
Cyc = chexyl, cpentyl
Scheme 3. Possible late-stage intermediates.

S. Heuser et al. / Tetrahedron Letters 47 (2006) 2675–2678
Table 1. Halogen–sulfur exchange on test systems
2677
O
O
a
OEt
X
OEt
+
Conversiong
(%)
Cl
Entry
Nucleophile Product
Br
O
O
Br
18
19
20
Cyc
X =
S
1a
2b
Br 12
KS(TIPS)
(1 equiv)
100
100
Cyc
TIPS
Ar
Ar
15
g-h
OH
b-f
OH
Ph
Ph
S
I 13
BnSH
(1 equiv)
O
16
Br
Br
21
Cyc
22
Ar
3c
4d
5e
6f
I 13
BnSH
(1 equiv)
100
100
100
100
S
16
H
S
k, l
i, j
N
N
TIPS
TIPS
Ar
Ar
Ar
I 13
KS(TIPS)
(1 equiv)
Sulfones 1
15
O
S
HS
S
9
OTf 14
Br 12
KS(TIPS)
(1 equiv)
15
Cyc = chexyl, cpentyl
Late-Stage Intermediates
SH
Cyc
NaSMe
17
p, q
(8 equiv)
m-o
OMe
Sulfonamides 2
a Pd(PPh3)4, 20 h (benzene/THF), reflux.
O
b CuI, K2CO3, 16 h (ethyleneglycol/iPrOH), 80 °C.
c CuI, NaOtBu, phenanthroline, 20 h (toluene), 110 °C.
d Pd(PPh3)4, 15 min (benzene/THF), reflux.
e Pd(PPh3)4, 15 min (benzene/THF), reflux.
f (DMA), 150 °C.
Cl
O
S
O
23
R´ =
g As determined by GC–MS.
H
N
4
Et2N
Et2N
2
H
to sulfones or sulfonamides. In this respect, a third reac-
tion using a large excess of sodium thiomethylate in
DMA at high temperatures17 is highly remarkable as it
was possible under the reaction conditions to obtain
the free thiophenol directly (entry 6). Furthermore the
reaction does not require the more expensive iodo pre-
cursor and transition metal-catalysis is not necessary.
We therefore regarded this reaction to be well suited
for our actual synthesis of GK activators.
N
N
Et–, i Pr–, cpentyl–
O
R´
S
O
S
O
(n = 0 - 2)
n
Scheme 4. Reagents and conditions (exemplified for Cyc = cyclo-
hexyl): (a) AlCl3, ꢀ10 °C to rt, 4 h (DCM), 72%; (b) (cyc-
C6H11)CH2PPh3I, LiHMDS, 0 °C to rt, 16 h (THF), 80%; (c) NaOMe,
50 °C, 16 h (MeOH); (d) NaOH, 50 °C, 5 h (methanol/water), 75%
(two steps); (e) DIBAH, ꢀ70 °C to rt, 16 h (toluene), 86%; (f) ZnMe2,
CH2I2, 60 °C, 5 h (dichloroethane), 78%; (g) chiral HPLC-separation;
(h) CrO3, H2SO4, rt, 2 h (acetone/water), 90%; (i) 2-aminothiazole,
TBTU, NEt3, 0 °C to rt, 16 h (THF), 74%; (j) NaSMe, 150 °C, 16 h
(DMA), 94%; (k) R0–X, K2CO3, rt, 16 h (acetone), 60–70%; (l)
OxoneÒ, rt, 4 h (MeOH/water), >80% (two steps); (m) NaSMe,
150 °C, 16 h (DMA); (n) concd H2SO4, rt, 16 h (MeOH); (o) KNO3,
SO2Cl2, rt, 1 h (CHCl3), 76% (three steps); (p) R0 (=R00–NH2), NEt3,
rt, 16 h (CH2Cl2); (q) 2-aminothiazole, iPrMgCl, ꢀ20 °C to 60 °C, 16 h
(THF), >70% (two steps).
Initial plans to start from 4-bromoiodobenzene follow-
ing the known procedure shown in Scheme 2 proved
not to be viable as the Suzuki coupling with boronic acid
ester 7 provided a complex mixture of coupling prod-
ucts. We therefore envisioned an alternative route,
which is depicted in Scheme 4. Friedel–Crafts acylation
of bromobenzene (18) with 19 provided the a-keto phen-
ylacetic acid 20 in satisfactory yield.18 Subsequent Wit-
tig reaction19 furnished the expected olefin as an E/Z-
mixture. Interestingly, the equilibrium could be shifted
completely towards the E-isomer by treatment with so-
dium methoxide at 50 °C. In addition to causing trans-
esterification, the methoxide apparently catalyses the
E/Z equilibration via a Michael–retro-Michael addition
sequence. Subsequent addition of aqueous sodium
hydroxide to the reaction mixture resulted in saponifica-
tion of the ester to afford the E-carboxylic acid exclu-
sively.20 Reduction with DIBAL and standard
cyclopropanation gave racemic cyclopropylic alcohol
21. Its enantiomers could be separated in multigram
scale by prep. HPLC,21 enabling the rapid synthesis of
enantiomerically pure cyclopropyl carboxylic acid 22
after Jones oxidation.22 For the preparation of sulfones
1, 22 was converted to the desired amide prior to halo-
gen–sulfur exchange, alkylation and oxidation.23
Because the thiazole was not stable to the oxidative
chlorination conditions24 used in the synthesis of the sul-
fonamides, it was necessary to prepare the intermediate
methyl ester-containing sulfonyl chloride 23. This could
be transformed into the sulfonamides 2 by simple
reaction with an amine and subsequent amidation with
2-aminothiazole, activated by deprotonation with iso-
propyl magnesium chloride prior to addition to the
methylester. All target molecules were obtained in good
yields and high enantiomeric purity.25

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S. Heuser et al. / Tetrahedron Letters 47 (2006) 2675–2678
11. Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572–
1574.
In summary, we have developed a robust route to novel
enantiopure small molecule GK activators that provides
the desired sulfones and sulfonamides bearing a variety
of functional groups in only two steps from readily
available late-stage intermediates. By employing this
methodology we were able to increase the rate of com-
pound synthesis significantly and thereby accelerate
the SAR-exploration in this region of the molecule. A
summary of the results of this SAR study including a
detailed discussion of pharmacokinetic and pharmaco-
dynamic properties of the compounds will follow in
due course.
12. (a) Hanzlik, R. P.; Weller, P. E.; Desai, J.; Zheng, J.; Hall,
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