Preparation of pyrrolidine-based PDE4 inhibitors via enantioselective conjugate addition of α-substituted malonates to aromatic nitroalkenes

Article abstract of DOI:10.1021/ol060398p

The enantioselective conjugate addition of α-substituted malonates to aromatic nitroalkenes generates a stereocenter at the carbon bearing the aromatic group and an adjacent prochiral center from the α-substituted malonate. Nitro reduction followed by dia

Full text of DOI:10.1021/ol060398p

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1495-1498
Preparation of Pyrrolidine-Based PDE4
Inhibitors via Enantioselective Conjugate
Addition of
Aromatic Nitroalkenes
r-Substituted Malonates to
Paul J. Nichols,* John A. DeMattei, Bradley R. Barnett, Nicole A. LeFur,
Tsung-Hsun Chuang, Anthony D. Piscopio,† and Kevin Koch
Department of Process Chemistry Research, Array BioPharma, 3200 Walnut Street,
Boulder, Colorado 80301
pnichols@arraybiopharma.com
Received February 15, 2006
ABSTRACT
The enantioselective conjugate addition of
r-substituted malonates to aromatic nitroalkenes generates a stereocenter at the carbon bearing
the aromatic group and an adjacent prochiral center from the
r-substituted malonate. Nitro reduction followed by diastereoselective cyclization
provides pyrrolidinones with two contiguous stereocenters, one of which is quaternary. This sequence was used for the preparation of the
PDE4 inhibitor IC86518. Additional examples of the enantioselective Michael addition illustrate the scope of the reaction.
In recent years, phosphodiesterase type 4 (PDE4), a cyclic
adensosine monophosphate (cAMP)-specific enzyme, has
become an important medicinal target.1 Inhibition of PDE4
has been shown to lower the inflammatory response in a
variety of pro-inflammatory cells.2 Unfortunately, early
clinical candidates suffered from undesired side effects,
including nausea and emesis.1 Over the course of a medicinal
chemistry program targeting PDE4, a number of highly
potent, nonemetic, selective PDE4 inhibitors were devel-
oped.3 The pyrrolidine IC86518 (Figure 1) is a potent
inhibitor of PDE4 (IC50 ) 14 nm), and only the stereoisomer
shown significantly reduced undesired emetic side effects
in animal models. IC86518 was one of a number of
N-substituted pyrrolidines that were prepared from the
common intermediate 1 (Figure 1).
† Present Address: Chemizon, Inc., P.O. Box 1437, Longmont, CO
80502.
(1) For a review of PDE4 inhibitors and related patents, see: Housley,
M. D.; Schafer, P.; Zhang, K. Y. J. Drug DiscoVery Today 2005, 10, 1503-
1519. (b) Odingo, J. Expert Opin. Ther. Pat. 2005, 15, 773-787. (c) Smith,
V. B.; Spina, D. Curr. Opin. InVestig. Drugs 2005, 6, 1136-1141. (d)
Norman, P Expert Opin. Ther. Pat. 2002, 12, 93-111. (e) Martin, T. J.
IDrugs 2001, 4, 312-338.
(2) (a) Burnouf, C.; Pruniaux, M.-P. Curr. Pharm. Des. 2002, 8, 1255-
1296. (b) Manganiello, V. Br. J. Pharmacol. 2002, 136, 339-340. (c)
Torphy, T. J.; Compton, C. H.; Marks, M. J.; Sturton, G Prog. Respir. Res.
2001, 31, 321-325. (d) Donnelly, L. E.; Rogers, D. F. Drugs 2003, 63,
1973-1998.
Figure 1. PDE4 inhibitor IC86518 and desired intermediate.
10.1021/ol060398p CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/04/2006

Compound 1 is a challenging synthetic target containing
three contiguous stereocenters, one of which is a quaternary
carbon bearing four carbon-based substituents. The prepara-
tion of quaternary carbon stereocenters continues to be a
significant challenge for synthetic chemists and is an active
area of research.4 Initially, a 3 + 2 cycloaddition approach
was used to access compound 1 (Scheme 1). While the
metal-6 and organocatalysis.7 In the work of Ji and co-
workers,6a the known bis(oxazoline) ligand 38 was used in
the presence of Mg(OTf)2 and N-methylmorpholine (NMM)
to provide enantiomerically enriched addition products in
high yields. In this report and in the process patent that
followed, there was no discussion of the application of this
method to R-substituted malonates.9 Subsequently, a full
paper describing this method reported four examples of
R-substituted malonates, three of which gave low enantio-
selectivities, including the methyl-substituted malonate re-
quired for the synthesis of intermediate 1.10 In this paper,
we describe the synthesis of 1 and its conversion to IC86518
via the Michael addition of R-substituted malonates to
aromatic nitroalkenes in high yields and enantiomeric excess.
The current synthesis of the common intermediate 1 is
illustrated in Scheme 2. The enantioselective Michael addi-
Scheme 1. Initial Synthesis of the Common Intermediate Core
Scheme 2. Synthesis of Common Intermediate 1
preparation of the quaternary center was stereoselective, the
generation of the requisite secondary alcohol, either via the
addition of MeMgI to the intermediate aldehyde, or by
reduction of the correseponding methyl ketone, was not.
Faced with multiple selectivity issues and the potential
requirement of chromatography on scale, an alternative
synthetic strategy based on the preparation of lactam 6 was
investigated.
The asymmetric conjugate addition5 of 1,3-dicarbonyl
compounds to nitroalkenes has been reported using both
tion between nitrostyrene 2 and dimethyl methylmalonate
gave crude compound 4 in 86% ee. Recrystallization
provided pure material in 87% yield with 87% ee on a 4 kg
(3) (a) Odingo, J. O.; Oliver, A. R.; Kesicki, E. A.; Burgess, L. E.;
Gaudino, J. J.; Jones, Z. S.; Newhouse, B. J.; Schlachter, S. T.; Wang, S.;
Hertel, C.; Stephan, T. E.; Martins, T. J.; Fowler, K. W. Abstracts of Papers,
226th American Chemical Society National Meeting, New York, 2003;
American Chemical Society: Washington, DC, 2003. (b) Martins, T. J.;
Fowler, K. W.; Odingo, J.; Kesicki, E. A.; Oliver, A.; Burgess, L. E.;
Gaudino, J. J.; Jones, Z. S.; Newhouse, B. J.; Schlachter, S. T. U.S. Patent
US 6,458, 87, 2002; U.S. Patent US 6,423,710, 2002; U.S. Patent US
6,258,833, 2001.
(6) (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenburger, S. J.;
Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215-10216. (b) Evans, D.
A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958-9959.
(7) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672-12673. (b) Okino T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119-125.
(4) For reviews in this area, see: (a) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. Engl. 1998, 37, 389-401. (b) Fuji, K. Chem. ReV.
1993, 93, 2037-2066. (c) Martin, S. F. Tetrahedron 1980, 36, 419-460.
(5) (a) For a review on asymmetric Michael additions. see: Berner, O.
M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-1894. (b)
For a review of catalytic enantioselective Michael additions, see: Krause,
N.; Hoffmann-Ro¨der, A. Synthesis 2001, 2, 171-196.
(8) Davies, I. W.; Gerena, L.; Castonguay, L.; Seneneyake, C. H.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J. Chem. Commun. 1996, 1753-1754.
(9) Ji, J.; Barnes, D. M.; King, S. A.: Plagge, F. A.; Wittenberger, S. J.;
Zhang, J. PCT Int. Appl. WO 00 15,599, 2000.
(10) Barnes, M. A.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.;
Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S.
J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097-13105.
1496
Org. Lett., Vol. 8, No. 7, 2006

scale. A zinc-mediated nitro reduction of compound 4
followed by addition of a NaHCO3 solution at 0 °C promoted
cyclization and gave pyrrolidinone 5 with a 4:1 preference
for the desired diastereomer. Fortuitously, recrystallization
of the mixture from tert-butyl methyl ether provided the
desired diastereomer in 44% yield and 91% ee. While the
low yield can be attributed to the modest selectivity of the
cyclization and difficulties in isolation, subsequent research
showed that cyclization on the corresponding diethyl methyl-
malonate substrate provided diastereoselectivities greater than
10:1.11 Conversion of methyl ester 5 to methyl ketone 6 was
accomplished via a two-step procedure in which the enolate
of tert-butyl acetate was condensed with the methyl ester
followed by acid-catalyzed decarboxylation. Following an
extractive workup and a solvent switch from toluene to THF,
ketone 6 was selectively reduced (10:1 dr) with lithium tri-
tert-butoxyaluminum hydride at -40 °C. The sense of
asymmetric induction observed for the reduction is consistent
with chelation control. Upon completion of the ketone
reduction, lithium aluminum hydride (LAH) was added in
situ and the mixture was heated to 60 °C for 15 h to provide
common intermediate 1. Subsequent recrystallization from
isopropyl acetate gave a single diastereomer in 64% yield
from 6.12 Over 1 kg of compound 1 was prepared by this
route. The relative and absolute stereochemistry of 1 was
confirmed by NMR and X-ray crystallography.
Due to the high efficiency and selectivity observed in the
synthesis of compound 1, we began to examine the scope
of the R-substituted malonate addition. In the disclosure that
reports the use of R-substituted malonates, morpholine was
used as the base with a 5 mol % catalyst loading. In this
report, the authors claim the reaction was sluggish and gave
low ee’s in all but one case.10 In contrast, we found this
reaction to be selective over a variety of R-substituted
malonates (Table 1). For entries 1-4 (Table 1) (substrates
Table 1. Scope of the Malonate Michael Addition
entry
R1
R2
Me
NHBoc
time (h) adduct yield (%) ee (%)
1
2
3
4
5
6
7
8
OEt
OEt
OMe OMe
OEt
OEt
OEt
OEt
OEt
16
19
24
17
45
18
64
48
8a
8b
8c
8d
8e
8f
99
90
88
75
72
84
85
NR
93
65
90
44
82
99
94
NR
NHAc
Allyl
Cl
F
Ph
8g
8h
Intermediate 1 was readily converted to IC86518 in three
steps (Scheme 3). Carbamate formation with methyl chloro-
previously reported), we observed higher yields and selec-
tivities in all cases. In particular, the 93% ee shown in entry
1 is substantially higher than the 46% ee previously disclosed
for this substrate.10 Our results suggest that this reaction can
tolerate a number of different substituents on the malonate
including amines, ethers, halogens, and allyl groups (Table
1). While the reaction seems to be limited to aromatic
nitroalkenes, functionally substituted aromatic groups are
well tolerated (Table 2). Aromatic nitroalkenes containing
ortho substitution were extremely selective in the cases
Scheme 3. Synthesis of IC86518 from Common Intermediate
1
Table 2. Scope of the Malonate Michael Addition
formate followed by benzyl deprotection (H2, Pd/C) gave
the crude phenol 7. Alkylation with cyclopentyl bromide
provided IC86518 in 74% overall yield for the three steps.
entry
R1
2-furyl
2-thiophenyl
4-BrPh
2-NO2Ph
4-OCF3Ph
3-CF3Ph
2-CF3Ph
time (h) adduct yield (%) ee (%)
1
2
3
4
5
6
7
18
21
21
19
20
45
67
9a
9b
9c
9d
9e
9f
92
99
96
92
66
86
77
92
92
94
99
93
90
98
(11) Investigations regarding the scope and limitations of the reduction/
diastereotopic group selective cyclization step are ongoing and will be
disclosed in due course.
(12) The final ee of compound 1 was found to be >99% following chiral
derivatization and comparison to authentic, racemic samples which were
derivatized and separated independently.
9g
Org. Lett., Vol. 8, No. 7, 2006
1497

examined (entries 4 and 7, Table 2). We have found that
toluene may be used as solvent in these reactions without
loss of ee. For the reaction shown in Table 1, entry 1,
substitution of toluene for chloroform gave 96% ee in 74%
yield. Increasing the catalyst loading to 5 mol % was
observed to decrease reaction time from 16 to 3 h for the
substrate shown in Table 1, entry 1.13
In conclusion, we have demonstrated an enantioselective
Michael addition of R-substituted malonates to nitrostyrenes.
Addition products can be reduced and then cyclized selec-
tively to give substituted pyrrolidinones containing contigu-
ous stereocenters, one of which is quaternary. Yields and
selectivities range from moderate to excellent. The method
has been demonstrated to be applicable to a variety of
substituted malonates and has been executed on kilogram
scale in the synthesis of the PDE4 inhibitor IC86518.
Acknowledgment. We thank John Gaudino and Stephen
Schlachter for helpful discussions, Lingyang Zhu for NMR
elucidations, Dawn Cherico, Rachael Jacob, and Andrew
Allen for chiral chromatography, and the ICOS Corp. for
funding a portion of this research and assisting with this
publication.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) In our hands, using the conditions reported by the Barnes, Ji, and
co-workers10 for entry 1 of Table 1 provided 8a in 39% yield and 90% ee
in 6 h, which was in contrast to the published report (71% yield, 46% ee,
44 h). We found that using morpholine as a base gave significantly lower
yields over catalyst loadings ranging from 1 to 5% as compared with NMM.
OL060398P
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Org. Lett., Vol. 8, No. 7, 2006