Complementary α-alkylation approaches for a sterically hindered spiro[pyrazolopyranpiperidine]ketone

Article abstract of DOI:10.1016/j.tetlet.2012.03.030

Complementary α-alkylation methods are used to derivatize a sterically hindered spiro[pyrazolopyranpiperidine]ketone. More specifically, enolate alkylations in the presence of DMPU and aldol condensations are employed to deliver these compounds.

Full text of DOI:10.1016/j.tetlet.2012.03.030

Tetrahedron Letters 53 (2012) 2543–2547
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Complementary
a-alkylation approaches for a sterically
hindered spiro[pyrazolopyranpiperidine]ketone
⇑
Chris Limberakis , Jianke Li, Gayatri Balan, David A. Griffith, Daniel W. Kung, Colin Rose, Derek Vrieze
CVMED Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Complementary a-alkylation methods are used to derivatize a sterically hindered spiro[pyrazolopyranpi-
peridine]ketone. More specifically, enolate alkylations in the presence of DMPU and aldol condensations
are employed to deliver these compounds.
Received 18 February 2012
Revised 6 March 2012
Accepted 8 March 2012
Available online 15 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spiro[pyrazolopyranpiperidine]ketone
Enolate alkylation
DMPU
Aldol condensation
1,4-Addition
According to the World Health Organization (WHO), 346 million
people globally have diabetes with numbers projected to steadily
increase over the coming decades.1 Of these diabetics, 90% suffer
from type II diabetes (T2DB) where patients do not effectively use
insulin. In recent years, acetyl CoA carboxylase (ACC) inhibitors
have emerged as novel targets for the treatment of type II diabetes
mellitus (T2DM) since ACC is a key metabolic switch which regu-
lates lipogenesis and fatty acid oxidation.2 To this end, our research
program has identified a series of ACC inhibitors including the novel
spiro[pyrazolopyranpiperidine]ketone 13 which was synthesized
using intermediate 23a,c,4 (Fig. 1). We were interested in exploring
the impact of substitution adjacent to the ketone on ACC inhibition
experiments were performed to test the viability of the enolate
alkylation method. In a typical experiment, ketone 2 was treated
with either LDA or LiHMDS at ꢀ78 °C to afford the enolate, then a
variety of alkylating agents and aldehydes were added. To our disap-
pointment, none of the desired products were isolated. Instead, the
major product was the a,b-unsaturated ketone (7) which arose from
a b-elimination pathway (Scheme 1).
Given these ungratifying results, we sought to enhance the rate
of alkylation relative to b-elimination by focusing our efforts on
increasing the enolate nucleophilicity and/or stabilizing the eno-
late. Like other organolithium species,6 lithium enolates have com-
plex aggregation states and exist in dimeric, trimeric, and other
and metabolic clearance, so we embarked to synthesize
a-mono and
a,a-disubstituted derivatives of 2 to deliver building blocks 3 and 4.
During our synthetic efforts, we discovered that direct
a-alkylation
O
O
of the ketone was challenging due to the sterically congested envi-
ronment of the keto -center and the propensity for b-elimination
N
N
N
H
N
N
a
N
N
O
N
under basic conditions. Hence, a multi-strategy approach was de-
vised which involved enolate alkylations and aldol condensations.
It is well established that the related 4-chromanones can be di-
O
N
N
O
O
O
1
O
O
2
rectly a
-alkylated with electrophiles via their respective enolates,5
O
O
but there are examples where the resulting enolates also undergo
preferentialb-eliminationto affordchalcones.5b,d Based on thisliter-
ature precedent, we recognized that our spiro[pyrazolopyranpiperi-
dine]ketone could suffer the same fate. Nonetheless, the necessary
R1
R1
N
H
R2
N
O
O
N
O
N
O
4
3
⇑
Corresponding author. Tel.: +1 860 686 9168.
E-mail address: chris.limberakis@pfizer.com (C. Limberakis).
Figure 1. Key compounds.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.030

2544
C. Limberakis et al. / Tetrahedron Letters 53 (2012) 2543–2547
O
O
O
O
O
OH
1. LDA or LiHMDS
N
R
N
N
R
N
or
N
N
X
O
2. RX or RCHO
N
N
N
2
BOC
5
6
BOC
BOC
O
BOC =
O
Li+
BOC
O-
O
O
N
N
N
β-elimination
N
N
OH
N
7
2a
BOC
Scheme 1. Initial alkylation experiments and b-elimination.
O
O
N
N
1. LiHMDS, THF/DMPU (5:1), -70 °C
N
N
O
O
2. MeI, -70 °C to rt
65%
N
N
BOC
BOC
2
8
BOC
O
N
N
N
O
8a
Scheme 2. Alkylation with methyl iodide in the presence of DMPU.
BOC
O
O
N
R
1. LiHMDS, THF/PhMe/DMPU (5:2:1), -70 °C
2.electrophile, -70 °C to rt
N
N
2
N
N
+
O
O
R
N
BOC
10a: R = allyl
10b: R = Et
10c: R = Bn
9a: R = allyl
9b: R = Et
9c: R = Bn
spiroketone
β-elimination product
10a (19%)
R-X
EtI
I
9a (39%)
9b (0%)
10b (58%)
10c (63%)
-
-
9c (0%)
Ph
Br
Scheme 3. Expanding alkylation with other electrophiles.
oligomeric forms depending on the solvent.6,7 In addition, mixed
aggregates may also form between the enolate and the base (i.e.,
LDA, LiHMDS, LiTMP, etc).7 It is well known that polar aprotic
solvents such as hexamethylphosphoramide (HMPA)8 and 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)9 en-
hance the basicity and nucleophilicity of reagents by forming
cation–ligand complexes and thus alter the aggregation state and
possibly lead to increased reactivity. Unlike its carcinogenic coun-
terpart HMPA, DMPU has no apparent mutagenic properties, but
exhibits similar solvent effects to HMPA.9 Moreover, Seebach and
coworkers demonstrated that DMPU can ‘stabilize’ enolates which
are prone to b-elimination.9,10 These DMPU effects are well docu-
mented and demonstrated with a wide variety of reactions.11
Our preliminary experiments were run in the binary mixture of
THF/DMPU (5:1). In the event, ketone 2 was treated with LiHMDS
in THF at ꢀ70 °C. After 30 min, DMPU was added, and stirring was
continued at this temperature for an additional 10 min. Methyl
iodide (5 equiv) was added, and the reaction mixture was then
slowly warmed to room temperature over 3 h. To our delight,
a-methylketone 8 was afforded in 65% yield with less than 10% yield
of 8a (Scheme 2).12 Although we examined higher ratios of THF/
DMPU (i.e., 10:1 and 20:1), the yield of 8 was significantly decreased
to 30–35%. We also discovered that the alkylation worked equally as
well in the ternary mixture of THF:toluene:DMPU (5:2:1).13
Armed with these results, the reaction conditions were applied
to other electrophiles. Unfortunately, the results were mixed as
shown in Scheme 3. Of the three additional electrophiles exam-
ined, only allyl iodide gave the corresponding
a-alkylated ketone
9a; however, the b-elimination product 10a was also isolated
(Scheme 3). Treatment of the enolate with ethyl iodide or benzyl
bromide afforded only b-elimination products.14
Undaunted by the limited range of viable electrophiles using
the enolate alkylation chemistry to make
a-monosubstituted
ketones, we studied the reaction of methylketone 8 to prepare

C. Limberakis et al. / Tetrahedron Letters 53 (2012) 2543–2547
2545
O
O
O
N
N
R
1. LiHMDS, THF/DMPU (5:1), -70 °C
N
N
O
2.electrophile, -70 °C to rt
N
N
BOC
BOC
8
11a: R = Me
11b: R = F
11c: R =OH
electrophile
MeI
spiroketone
11a (60%)
SelectFluorTM
O
11b (88%)
11c (80%)
N
O
S
O
Davis' oxaziridine
Scheme 4. Alkylations with DMPU to deliver
a,
a-disubstituted spiroketones.
O
O
R
R
N
N
D
H
conditions
N
N
O
O
N
N
BOC
BOC
12
: R = H
2
: R = H
13: R = Me
8: R = Me
Deuterium incorporation at the α-center1
Conditions
2
12
8
13
17%
55%
a. LiHMDS, THF/PhMe (2.5:1), -70 °C, 30 min
b. CD3COOD
88%
a. LiHMDS, THF/PhMe (2.5:1), -70 °C, 30 min
>95%
b. DMPU, -70 C, 10 min2
c. CD3COOD
1based on 1H NMR integration of the α-H
2THF/PhMe/DMPU (5:2:1)
Scheme 5. Deuterium experiments and the role of DMPU.
a
-methyl-a-substituted ketones. Like the enolate of spiroketone 2,
O
O
R
the enolate of spiroketone 8 also underwent b-elimination in the
absence of DMPU. However, upon applying the identical DMPU
conditions, methyl ketone 8 was converted to gem-dimethylketone
11a in 60% yield. It is notable that a quaternary center was formed
in the process resulting in two adjacent quaternary centers in the
molecule (Scheme 4). Seeking to expand the scope of electrophiles,
we treated the enolate with SelectFluor™ and Davis’ oxaziridine15
1. MesCl
2. DBU
(c-hexyl)2BCl, RCHO
N
OH
N
2
N
BOC
14
15
: R = Me (56%)
: R = Et (21%)
O
O
R
O
O
R
N
N
N
Pd(OH)2/C
to afford racemic
-hydroxy spiroketone 11c in high yield.
After these gratifying results, there was a desire to examine the
a-methyl-a-fluoro ketone 11b and a-methyl-
N
a
N
N
BOC
BOC
9a
18
reason for DMPU’s effectiveness with some of the examples. While
DMPU likely created a more reactive enolate, did it affect the
deprotonation of the ketone to form the enolate? To probe this
question, deuterium experiments were conducted with and with-
out DMPU in the formation of the enolates derived from 2 and 8.
First, the enolate of 2 was generated with LiHMDS at ꢀ70 °C, and
then quenched with acetic acid-d4 to give 88% deuterium incorpo-
ration based on 1H NMR (Scheme 5). In the presence of DMPU, deu-
terium incorporation increased to greater than 95%. In both
instances, the enolate of 2 did not undergo b-elimination at
: R = Me (100%)
: R = Et (100%)
16
17
: R = Me (100%)
: R = Et (100%)
Scheme 6. Aldol approach.
sterically hindered
a-methylketone 8 (Scheme 5). Interestingly,
formation of the enolate from this substrate was greatly affected
by DMPU’s presence. Without DMPU, deuterium incorporation
was only 17%; however, with DMPU, deuterium incorporation
more than tripled to 55%. Once again, only a-D and a-H products
ꢀ70 °C since the only products observed were
a
-D and
a
-H. Hence,
were observed by 1H NMR, so the enolate remained stable at
ꢀ70 °C. Since alkylation products were only seen in the presence
of the additive, DMPU also increased the enolate reactivity. So, in
the case of the enolate of 8, DMPU played a dual purpose: enhance-
ment of enolate formation and enolate reactivity.
it is logical to conclude that b-elimination occurred upon warming
the enolate and that DMPU did not play a dominant role in the
enolate formation. Since the desired
a-alkylated products were
isolated using methyl iodide and allyl iodide, DMPU did enhance
the reactivity of the enolate. The identical deuterium experiments
were then conducted with the enolate derived from the more
Although some success was achieved in the direct alkylation
approach to make
a-substituted ketones, we required a more

2546
C. Limberakis et al. / Tetrahedron Letters 53 (2012) 2543–2547
O
O
O
N
, NaOH
N
N
H
H
N
O
N
O
H2O, 45 °C
65%
BOC
N
BOC
2
19
O
O
H2, Pd(OH)2/C
EtOAc, 40 °C
N
N
quantitative
N
BOC
BOC
8
O
(Me)2CuLi, TMSCl
THF, -78 °C
N
N
97%
O
9b
N
19
, Rh(nbd)2BF4
B(OH)2
O
N
N
N
N
quantitative
O
9c
N
N
BOC
BOC
+
O
Me3S(O)I-, NaH
THF, DMSO
66%
O
20
Scheme 7. Derivatives using a,b-unsaturated ketone 19.
diverse set of derivatives to explore SAR, so our attention then
turned to an aldol condensation. After surveying various aldol con-
ditions, we were pleased to discover that treatment of the
dicyclohexylboron enolate of ketone 2, generated using dicyclohex-
ylboron chloride,16 with acetaldehyde afforded aldol product 14 in
56% yield (Scheme 6). The alcohol was then converted to the mesy-
in quantitative yield using a Rh-catalyzed 1,4-addition with bis-
(norbornadiene)rhodium(I) tetrafluoroborate and phenylboronic
acid.19 Finally, cyclopropyl derivative 20 was afforded in 66% yield
via a Corey–Chaykovsky cyclopropanation using trimethylsulfoxo-
nium ylide which was generated with trimethylsulfoxonium io-
dide and NaH in DMSO.20
late and treatment of the mesylate with DBU delivered
rated ketone 16 in quantitative yield. Finally, hydrogenation using
Pearlman’s catalyst gave the previously elusive -ethylketone in
56% yield over four steps. Extension of this methodology proved dif-
ficult. With propionaldehyde, the desired alcohol was isolated in
only 21% yield. The more sterically demanding isobutyraldehyde,
benzaldehyde, and 2-phenylacetaldehyde gave no desired products.
a
,b-unsatu-
In conclusion, we accessed a number of a-substituted and a,a-
disubstituted spiro[pyrazolopyranpiperidine]ketones using two
complementary approaches: enolate alkylations and aldol conden-
sations. Although the enolate alkylations were not a panacea, we
demonstrated that the additive DMPU was critical in delivering
some of the alkylated products in a direct fashion. Finally, the aldol
condensations produced useful intermediates to afford products
unattainable with the former route.
a
We reasoned that the scope of a-functionalization was limited
by steric hinderance from the adjacent quaternary center. A two-
step approach was thus considered to introduce a wider range of
Acknowledgments
alkyl groups utilizing a,b-unsaturated ketone 19. Despite the limi-
We are grateful for the NMR support and mass spectroscopy
assistance provided by Dennis P. Anderson, Kathleen A. Farley
and Jason Ramsay. We would also like to thank David Edmonds,
David Piotrowski, and Aaron Smith for their insightful discussions.
tations of the aldol approach, we discovered after some experimen-
tation that treatment of ketone 2 with formaldehyde in the
presence of sodium hydroxide gave an intermediate aldol product
which readily dehydrated to
a,b-unsaturated ketone 19 in 65%
yield.17 With this versatile intermediate in hand, we envisaged a
scenario where a diverse set of derivatives were accessible by tak-
ing advantage of this conjugated system (Scheme 7). To this end,
Supplementary data
Supplementary data (characterization data for compounds 7,
8a, 9a–c, 10a–c, 11a–c, 16, 19, and 20 and a detailed experimental
procedure for the synthesis of 19) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.03.030.
a
,b-unsaturated ketone 19 was quantitatively hydrogenated in
the presence of Pearlman’s catalyst to yield 8. Also, we were
pleased to obtain -ethyl ketone 9b in 97% yield with a conjugate
addition reaction using dimethylcuprate/TMSCl.18 Moreover, the
previously unattainable -benzyl ketone 9c was smoothly formed
a
a

C. Limberakis et al. / Tetrahedron Letters 53 (2012) 2543–2547
2547
12. Representative procedure using DMPU as an additive: tert-Butyl-2-tert-butyl-
60methyl-70-oxo-60,70-dihydro-20H-spiro[piperidine-4,50-pyrano[3,2-c]pyrazole]-
1-carboxylate (8). Ketone 2 (50 mg, 0.14 mmol) in THF (0.5 mL) was cooled to
ꢀ70 °C, then treated with LiHMDS (1 M in toluene, 0.207 mL, 0.207 mmol) over
10 min. The resulting yellow solution was stirred at ꢀ70 °C for 30 min, then
DMPU (0.1 mL) was added and stirring continued at this temperature for an
additional 10 min. Methyl iodide (0.043 mL, 0.690 mmol) was added, and the
reaction mixture was stirred at ꢀ70 °C for 10 min, then allowed to warm to
room temperature over 3 h. The reaction mixture was quenched with saturated
aqueous sodium bicarbonate (0.5 mL) and partitioned between EtOAc (10 mL)
and water (2 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (5 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The resulting crude product
was purified using medium pressure flash chromatography (silica gel, 12 g)
eluting with a gradient of heptanes:EtOAc (90:10 to 60:40) to deliver 34 mg
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-methylketone 8. 1H NMR (400 MHz, CDCl3) d 7.21 (s, 1H), 3.94–3.81
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9H), 1.59–1.50 (m, 2H), 1.46 (s, 9H), 1.22 (d, J = 7.3 Hz, 3H); 13C NMR (CDCl3,
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H
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O
O
N
O
O
N
N
N
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δ
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17. The
a
,b-unsaturated ketone 19 was also obtained using the Eschenmoser
methylenation: ketone
2
(1 equiv), N,N,N,N0-tetramethylmethylenediamine
(4 equiv), AcOH (8 equiv), THF, reflux, 55%.
18. Martin, S. F.; Dodge, J. A.; Burgess, L. E.; Limberakis, C.; Hartmann, M.
Tetrahedron 1996, 52, 3229–3246.
19. (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844; (b) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169–196.
20. Saito, N.; Masuda, M.; Saito, H.; Takenouchi, K.; Ishizuka, S.; Namekawa, J.-I.;
Takimoto-Kamimura, M.; Kittaka, A. Synthesis 2005, 2533–2543.