Synthesis of Chiral Azabicycles from Pyroglutaminols

Article abstract of DOI:10.1021/acs.orglett.6b03024

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery.

Full text of DOI:10.1021/acs.orglett.6b03024

Letter
pubs.acs.org/OrgLett
Synthesis of Chiral Azabicycles from Pyroglutaminols
,†
†
†
†
‡
Chulho Choi,* Philippe Nuhant, James J. Mousseau, Xiaojing Yang, Brian S. Gerstenberger,
§
†
Jessica M. Williams, and Stephen W. Wright
†
Medicinal Chemistry, Medicine Design, Pfizer WorldWide R&D, 445 Eastern Point Road, Groton, Connecticut 06340, United States
Medicinal Chemistry, Medicine Design, Pfizer WorldWide R&D, 610 Main Street, Cambridge, Massachusetts 02139, United States
Kutztown University of Pennsylvania, 15200 Kutztown Road, Kutztown, Pennsylvania 19530, United States
‡
§
*
S Supporting Information
ABSTRACT: The stereocontrolled synthesis of a range of substituted bicyclic
morpholine and piperazine derivatives is reported from substituted pyroglutaminols
via an intramolecular S 2 cyclization as the key step. This enantiospecific approach
N
toward chiral bicyclic morpholines and piperazines offers new opportunities to access
these challenging ring systems, which are becoming increasingly common motifs in
drug discovery.
tructurally constrained bicyclic morpholine and piperazine
S
cores are key structural components of natural products
1
such as loline and also found in medicinally relevant motifs
2
(
Figure 1). These strained ring systems have been
Figure 2. Stereocontrolled synthesis of morpholinones and piper-
azinones from enantiopure pyroglutaminols prepared by stereo-
controlled cuprate conjugate addition.
SN2 cyclization reaction (Table 1). The cyclized intermediate
was trapped in situ with benzyl chloride in order to facilitate
both reaction monitoring and the isolation of the morpholi-
Figure 1. Selected compounds containing stereodefined bicyclic
piperazines and morpholines.
Table 1. Screening of Conditions for S 2 Cyclization
N
incorporated, for example, as critical structural vectors for
pharmacological activity in structure-guided drug discovery
strategies. Despite their desirability, current synthetic routes to
3
access these structural motifs are generally lengthy and lack
stereocontrol, requiring the separation and structure elucidation
4
of multiple stereoisomers. A stereocontrolled synthesis of
these bicyclic structures would be a worthwhile addition to the
synthetic chemist’s toolbox.
As part of a recent medicinal chemistry program, we were
interested in the stereocontrolled synthesis of chiral morpho-
linones such as 2a−f. We noted the lack of literature precedent
and envisioned a synthesis from pyroglutamic acid derivatives.
Recently, we disclosed a methodology to access chiral
5
pyroglutaminols via a stereospecific conjugate addition
6
strategy. We reasoned that a suitably halogenated pyrogluta-
minol could be the key precursor in the synthesis of the target
morpholinones (Figure 2) by an intramolecular S 2 cyclization
N
7
of the primary alcohol to the alkyl halide of 1a−f. Such a
stereocontrolled transformation would allow access to the
bicyclic systems of interest in an efficient manner.
To probe this synthetic hypothesis, we selected the α-
chloropyroglutaminol 1a as a candidate for the intramolecular
Received: October 7, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03024
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Letter
none product 2a. Initial screening of reaction conditions
revealed that both NaH and KHMDS in ethereal solvents were
ineffective (entries 1−3). Precipitates were observed in these
ethereal solvents that presumably resulted in poor reactivity.
Screening in DMF revealed that NaHMDS gave a moderate
yield (42%, entry 4), and KHMDS (entry 5) or t-BuOK (entry
Table 3. Tandem Synthesis and in Situ Derivitization of
Substituted Bicyclic Morpholinones
6) gave the best results (87% and 91%, respectively). The
intermediate alkoxide was significantly more soluble in DMF, as
no precipitate formation was observed when DMF was used as
solvent. Interestingly, fluoride was also found to be an excellent
leaving group. Starting from the α-fluoropyroglutamic lactam
1
b, KHMDS (entry 7) or t-BuOK (entry 8) in DMF gave
similar yields (85% and 87%, respectively). The structure of 2a
was confirmed through small-molecule X-ray crystallography
(see the Supporting Information).
Having identified productive conditions for the cyclization,
we next investigated the influence of size and configuration of
the lactam β-substituent during the cyclization (Table 2, entries
pyroglutaminol precursor 1a to typical palladium-mediated N-
arylation conditions with 3-bromopyridine resulted in con-
comitant cyclization and N-arylation to afford the same product
1
2
Table 2. Effect of the Lactam β-Substituents R and R on
the S 2 Cyclization Reaction
N
10
3b (65%, entry 3). These results demonstrate the usefulness
of these intermediates for derivatization without need for
isolation.
Further elaboration of these versatile bicyclic morpholinones
could be accomplished by reduction to bicyclic morpholines.
Bicyclic morpholinones 2b and 2c were readily reduced with
borane−THF to provide the corresponding bicyclic PMB-
protected morpholines (4a and 4b), which were carried
forward without purification in a one-pot hydrogenation/Boc
protection sequence to afford the Boc morpholines 4c and 4d
in 32% and 51% overall yields from 2b and 2c, respectively
(
Scheme 1).
Scheme 1. Preparation of Bicyclic Morpholines by
Reduction and Protecting Group Exchange
1
−6). In substrates lacking a substituent (e.g., 1c), the reaction
performed well to afford 2b (entry 1, 91%). Interestingly a 1:1
mixture of the syn and anti α-F epimers of 1c led to the
cyclization of only one epimer, presumably 1c, in which8
fluorine is trans relative to the alcohol (entry 1, 35%).
Substrates with a β-methyl substituent cyclized in very good
yield (entry 2 and 3, 90% and 88% respectively). Steric effects
were observed with a β-alkyl group larger than a methyl group.
A change from a syn β-methyl group (1a) to a syn β-ethyl group
With the stereocontrolled synthesis of substituted bicyclic
morpholines established, we next turned our attention to the
stereocontrolled synthesis of substituted bicyclic piperazines by
replacing the primary alcohol group in the pyroglutaminol
starting material with a primary amine. Efforts to install a
primary amine via reductive amination techniques resulted in
disappointingly low isolated yields (<20%). We developed a
successful stepwise process in which the masked amine could
be installed via an azide displacement of a primary O-
(
4
1e) led to a decrease in yield from 87% (Table 1, entry 7) to
5% (Table 2, entry 4), presumably as a result of steric
crowding of the transition state by the ethyl group. As expected,
the anti β-ethyl substrate 1f was more easily cyclized under the
same conditions (69%, entry 5). Enantiomers could also be
easily accessed (88%, entry 6).
With successful cyclization outcomes in hand for a variety of
pyroglutaminol substrates, we were next interested in trapping
the cyclized intermediate with a panel of electrophiles (Table
11
tosylpyroglutaminol 5 with TBAN3. Staudinger reduction of
the azide 6 with PPh3 led to the desired amine, which
spontaneously underwent cyclization in the presence of base to
afford the bicyclic piperazinone 7 (Scheme 2). Subsequent
protection of the amine with CbzCl, reduction of the lactam
with BH −THF, and protection with Boc O yielded the
3
). Pleasingly, allyl bromide performed well under the reaction
conditions (66%, entry 1). S Ar trapping reactions of the
N
cyclized morpholinone intermediate with heterocyclic halide
such as ethyl 2-chloropyrimidine-5-carboxylate proceeded in
moderate yields (33%, entry 4). Likewise, an in situ copper-
mediated Chan−Lam coupling of the cyclized morpholinone
intermediate could be effected to afford the 3-aminopyridine
3
2
differentially protected bicyclic piperazine 9 as a single
stereoisomer.
Previous work had shown that halogenation of the protected
pyroglutaminols I and II gave mixtures of halogen diaster-
eomers which could often be separated by column chromatog-
9
derivative 3b (79%, entry 2). Interestingly, exposure of the
B
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Scheme 2. Preparation of a Differentially Protected Bicyclic
Piperazine from Pyroglutaminol 1a
Scheme 3. In Situ Epimerization/Cyclization Sequence of
syn-Halopyroglutaminols to Bicyclic Morpholinones
1
2
1
raphy (Figure 3). Depending on the R substituent and the
Scheme 4. Conversion of syn-Halopyroglutaminols to
Bicyclic Piperazinones
specific halogenation reaction conditions, the diastereoselectiv-
1
Figure 3. Influence of R relative stereochemistry on the halogenation
reaction.
would be exchanged to the anti iodo lactam 13, which should
cyclize under the reaction conditions. Given the high reactivity
ities varied from 2:1 to 10:1 in favor of the diastereomer in
which the halogen is anti to the R substituent. The major
13
1
of MgI for this purpose, we applied this reagent in a
2
Finkelstein reaction. Gratifyingly, the desired bicyclic piper-
azinone 14 was obtained in 81% yield. This substance was
subsequently derivatized by reductive amination to afford 15 in
excellent yield.
In conclusion, we have demonstrated that novel bicyclic
morpholine and piperazine derivatives can be synthesized with
full stereocontrol from halogenated pyroglutaminols by means
product of the halogenation of lactam I is the diastereomer Iα
1
in which the halogen is placed anti to both the R substituent
and the latent CH OH group. This diastereomer undergoes the
2
cyclization reaction readily (eq 1). On the other hand,
halogenation of lactam II affords primarily diastereomer IIβ,
1
in which the halogen is anti to the R substituent as expected
but is unfortunately syn to the latent CH OH group. This
2
of an intramolecular S 2 cyclization reaction. The products are
diastereomer is resistant to cyclization as may be expected, and
we viewed this as a potential limitation of the utility of this
chemistry.
N
readily functionalized by subsequent alkylation, S Ar reaction,
N
Chan−Lam coupling, and palladium-mediated arylation.
Further, we have demonstrated that syn-halogenated pyroglu-
taminols could also be productively used in this chemistry via
epimerization under the reaction conditions or by a double-
displacement strategy.
In order to overcome this limitation, we reasoned that it
should be possible to epimerize the halogenated stereocenter
during the course of the cyclization reaction. Such an
epimerization would lead to the formation of the anti halogen
isomer and subsequent cyclization. Initially, when the α-fluoro
pyroglutaminol 1g was used, epimerization did not occur.
Presumably, deprotonation of the secondary lactam makes
epimerization difficult by the establishment of a negative charge
adjacent to the carbon atom of interest. Accordingly, the PMB-
protected lactam 1i was prepared. This was readily epimerized
in situ under the cyclization reaction conditions, leading to the
desired bicyclic morpholinone 2b. In the same manner,
pyroglutaminol 1j was similarly epimerized and converted to
morpholinone 2e (Scheme 3).
We applied a similar sequence of reactions to the preparation
of bicyclic piperazinones from syn halo intermediates. Thus, the
primary amine 12 was prepared in four steps from the
pyroglutaminol 1h (Scheme 4). Surprisingly, base-mediated
epimerization and cyclization did not proceed under the same
conditions employed previously, despite N-protection of the
lactam with a benzyl group. As an alternative, we considered a
double-inversion strategy in which the syn fluoro lactam 12
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03024.
Experimental procedures and characterization data for all
new compounds; ORTEP drawing and crystallographic
data for 2a, 3b, and 4c (PDF)
NMR spectra for all new compounds (PDF)
Crystallgraphic data for 2a (CIF)
Crystallgraphic data for 3b (CIF)
Crystallgraphic data for 4c (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chulho.choi@pfizer.com.
C
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Letter
Notes
(12) Anderson, D. R.; Bunnage, M. E.; Curran, K. J.; Dehnhardt, C.
M.; Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hepworth, D.; Huang, H.-
C.; Lee, A.; Lee, K. L.; Lovering, F. E.; Lowe, M. D.; Mathias, J. P.;
Papaioannou, N.; Patny, A.; Pierce, B. S.; Saiah, E.; Strohbach, J. W.;
Trzupek, J. D.; Vargas, R.; Wang, X.; Wright, S. W.; Zapf, C. W.
Bicyclic-fused heteroaryl or aryl compounds as IRAK4 inhibitors and
their preparation. WO2015150995A1, 8 Oct 2015.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Pfizer Worldwide R&D for a summer internship for
J.M.W. We also thank Brian Samas (Pfizer) and Ivan
Samardjiev (Pfizer) for determination of X-ray crystal
structures, Katherine Lee (Pfizer) for useful discussions and
suggestions, as well as Mark Bunnage, David Hepworth, and
Yvette Fobian (Pfizer) for their support.
(
13) YbI3 was reported to be superior to MgI2 for C−F bond
dissociation. Traff, A. M.; Janjetovic, M.; Ta, L.; Hilmersson, G. Angew.
Chem., Int. Ed. 2013, 52, 12073.
̈
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