Asymmetric Synthesis of a Potent CXCR7 Modulator Featuring a Hindered Tertiary β-Amino Amide Stereocenter

Article abstract of DOI:10.1021/acs.orglett.8b02261

A practical and asymmetric synthesis of a small-molecule CXCR7 modulator featuring a highly functionalized and hindered tertiary β-amino amide framework is reported. The cornerstone of this strategy relied on the intermediacy of a reactive aziridinium species, which, following regioselective ring opening with cyanide, furnished the desired chiral β-tertiary amino nitrile for further elaboration. As a means of further highlighting this synthetic strategy, an expanded scope of hindered β-amino amide synthesis is also presented.

Full text of DOI:10.1021/acs.orglett.8b02261

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of a Potent CXCR7 Modulator Featuring a
Hindered Tertiary β‑Amino Amide Stereocenter
Daniel P. Canterbury,† Francois Godin,‡ Samuel Desjardins,‡ Malken Bayrakdarian,‡ Jeffrey S. Albert,‡
David A. Perry,† and Kevin D. Hesp*,†
†Pfizer, Medicine Design, 558 Eastern Point Road, Groton, Connecticut 06340, United States
‡IntelliSyn Pharma, 7171 Frederick-Banting Road, Montreal, Quebec H4S 1Z9, Canada
S
* Supporting Information
ABSTRACT: A practical and asymmetric synthesis of a small-molecule
CXCR7 modulator featuring a highly functionalized and hindered tertiary β-
amino amide framework is reported. The cornerstone of this strategy relied on
the intermediacy of a reactive aziridinium species, which, following
regioselective ring opening with cyanide, furnished the desired chiral β-tertiary
amino nitrile for further elaboration. As a means of further highlighting this
synthetic strategy, an expanded scope of hindered β-amino amide synthesis is
also presented.
tromal-cell-derived factor 1α (SDF-1α) is the natural
ligand of the G-protein-coupled receptor CXCR7, which,
studies, which necessitated investigation to find a more refined
asymmetric synthesis.
S
in conjunction with CXCR4, has been reported to play a
protective role following a cardiac event to improve both
function and cardiac injury repair processes.1 We postulated
that a potent small-molecule CXCR7 modulator could interact
with the target receptor to prevent binding, internalization, and
degradation of SDF-1α.2 By increasing the bioavailability SDF-
1α, we sought its prolonged interaction with CXCR4 and thus
enhanced cardioprotection in the event of heart failure. As a
result of a rigorous medicinal chemistry campaign targeting
upregulation of the systemic circulation of SDF-1α,3 the
sterically hindered tertiary β-amino amide 1 was identified as a
promising candidate for further in vivo efficacy evaluations on
the basis of its potent and selective binding of CXCR7 as well
as its desirable physicochemical properties (Figure 1).
The original synthesis of 1 suffered from several low-yielding
and poorly scalable synthetic steps as well as a requisite chiral
separation of an advanced racemic intermediate midway
through the synthetic sequence (Scheme 1).3 Indeed, the
key step featured a Lewis acid-mediated three-component
Mannich reaction using amine 5, aldehyde 6, and silyl ketene
Scheme 1. Original Synthesis of 13
Figure 1. Potent CXCR7 inhibitor 1 and its physicochemical
properties.
The medicinal chemistry strategy employed en route to the
identification of 1 relied heavily on the use of advanced
versatile synthetic intermediates to rapidly drive our under-
standing of the structure−activity relationships for this
program via highly enabled parallel chemical synthesis. After
optimizing this series for potency against CXCR7 as well as
desirable physicochemical properties,3 we required more
significant quantities of 1 for compound-demanding efficacy
Received: July 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02261
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acetal 7 that furnished the racemic ester 8,4 which necessitated
a laborious chiral separation to achieve the requisite
enantiomeric excess. Following deprotection of the piperidine,
a HATU-mediated amide bond formation with the known
chiral bicyclic carboxylic acid 105 was executed in good yield.
The resulting pendent ester was hydrolyzed to the correspond-
ing carboxylic acid with KOTMS, followed by a low-yielding
HATU-mediated amidation with NH4Cl to generate the target
tertiary β-amino amide 1 after arduous chromatography.
Notably, the yields of this ester-to-amide sequence were highly
variable during larger-scale campaigns.
Scheme 2. Asymmetric Synthesis of Nitrile 14
Taking into account the observed limitations of the current
synthesis, several alternative disconnections were considered
when approaching an improved and scalable asymmetric
synthesis of 1 (Figure 2). Whereas strategies centered on
aziridinium ring to prepare hindered tertiary β-amino nitrile 14
with excellent enantiomeric excess.11a Although this approach
has been employed to access less-hindered systems, we believe
that this tactic represents a general and powerful way to access
systems featuring strongly sterically encumbered substituents,
as represented by the synthesis of 14 (Scheme 2).
Having established a robust and scalable synthesis of chiral
nitrile 14, we next focused our efforts on the nitrile hydrolysis
to access the requisite carboxamide 15. At the outset of this
effort, we surmised that the hindered nature of the nitrile,
coupled with the potential for unproductive β-amino
elimination of the nitrile (or amide), could present challenges
for efficiently achieving this hydrolysis. Initially, our attempts
to hydrolyze 14 under acidic or metal-mediated conditions led
to either no reaction or decomposition of the starting
material,13 which prompted us to explore alternative basic
conditions (Table 1). Whereas the use of aqueous NaOH or
Figure 2. Retrosynthetic options for the asymmetric synthesis of 1.
asymmetric reductions of suitably substituted β-keto esters6 or
dehydro amino acid derivatives7 were considered heavily, the
risks associated with enone formation or the uncertainty of de
novo homopiperazine synthesis prevented further investiga-
tion. Additionally, the scant precedent for enantioselective aza-
Michael additions8 with hindered secondary amines, such as
homopiperazine, or enantioselective Mannich reactions of
enolate equivalents with imines9 presented significant pause for
investing into reaction identification and optimization. A
consistent theme identified while assessing the synthesis of
chiral β-amino acids was that the current state of the literature
significantly catered to amines that lacked the requisite steric
profile of the tertiary β-amino amide in 1.10 With the objective
of preparing 1 with exquisite enantiomeric excess and being
able to translate the asymmetric route to bulk synthesis, we
elected to focus our efforts on maximizing the route efficiency
while minimizing low-risk procedures. As such, we prioritized
our efforts around robust and scalable chiral epoxide ring-
opening strategies for accessing the requisite enantiomeric
excess of 1.
Table 1. Optimization of the Hydrolysis of Nitrile 14 to
Amide 15
a
a
entry
conditions
15 (%)
15′ (%)
1
2
3
4
5
6
LiOH (1 equiv), H2O2 (1 equiv)
LiOH (2 equiv), H2O2 (2 equiv)
LiOH (5 equiv), H2O2 (5 equiv)
LiOH (1 equiv), H2O2 (10 equiv)
NaOH (2 equiv), H2O2 (2 equiv)
35
45
45
40
50
5
10
45
60
25
<1
b
NaOH (1 equiv), H2O2 (1.5 equiv),
65 (63 )
DMSO (1.2 equiv)
a
b
Yields determined by LC−MS analysis. Isolated yield.
The cornerstone of our strategy relied on the intermediacy
of a reactive aziridinium species,11 which, following ring
opening with cyanide, would furnish the desired chiral tertiary
β-amino nitrile for further elaboration (Scheme 2). As a
starting point for asymmetric route development, the known
epoxide 12 was prepared using a two-step epoxidation/Co-
catalyzed kinetic resolution sequence initiated from benzyl 4-
formylpiperidine-1-carboxylate.12 Aminolysis of chiral epoxide
12 with advanced homopiperazine intermediate 5 was readily
achieved in refluxing EtOH solvent to access chiral β-amino
alcohol 13 in excellent yield with complete regioselectivity.12
Subsequent treatment of 13 with methanesulfonic anhydride
and triethylamine in acetonitrile generated aziridinium
intermediate 13′,11 which was then subjected to an aqueous
solution of sodium cyanide in one pot to selectively open the
LiOH solutions in methanol proved to be unreactive toward
14, employing basic hydrogen peroxide reaction conditions
began to provide partial conversion to the desired amide 15,
albeit with concomitant formation of the α,β-unsaturated side
product 15′ (Table 1, entry 1). Attempts to favor nitrile
hydrolysis relative to the unproductive oxidative β-amino
elimination pathway by increasing the amounts of base and
oxidant resulted in modest yield gains but were accompanied
by increased side-product formation (Table 1, entries 2−4).
Using previously documented conditions for the hydrolysis of
challenging nitrile substrates,14 we successfully executed the
hydrolysis of 14 using a mixture of NaOH and H2O2 in
conjunction with DMSO as an additive to prepare 15 in 63%
isolated yield with only trace amounts of 15′ (Table 1, entry
B
DOI: 10.1021/acs.orglett.8b02261
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
6). Of importance, these conditions were seamlessly translated
to the decagram synthesis of advanced intermediate 15 without
any loss in yield or purity profile.
Given the lack of synthetic strategies for the robust
asymmetric synthesis of hindered β-tertiary amino amides,
we elected to explore this sequence on a representative set of
hindered epoxide and amine reaction partners (Scheme 3). A
HATU coupling procedure in the original synthesis of 1
(Scheme 1),3 the persistence of trace fluoride-containing
impurities derived from the coupling reagent in the final
compound led us to evaluate alternative strategies. Following a
screen of conditions to identify a suitable HATU replacement,
we found that reaction of the in situ-generated acyl chloride of
10 with the piperidine provided a clean and reproducible route
to the target 1. Of importance, no erosion of the enantiomeric
excess of the chiral bicyclic moiety derived from 10 was
observed by NMR or chiral analysis.13
Scheme 3. Scope of the Three-Step Sequence To Generate
β-Amino Amides from Epoxides13
In response to the demand for bulk quantities of the CXCR7
modulator 1 to support critical in vivo efficacy studies, we have
developed a robust and scalable asymmetric synthesis that has
been executed on a decagram scale. In contrast to the first-
generation synthesis, the strategy reported herein capitalizes on
the ready access of enantiopure starting materials via well-
established chiral epoxide synthesis. Following regioselective
ring opening of the epoxide with a homopiperazine derivative,
the cornerstone of the synthesis features the transient
preparation of a reactive aziridinium species that, when treated
with cyanide, furnished the requisite tertiary β-amino nitrile.
Subsequent hydrolysis of the hindered nitrile to the primary
amide provided access to the sterically congested framework
featured in compound 1. Given the limited strategies available
for the asymmetric preparation of hindered β-amino amides,
we anticipate this tactic to be of interest to the broader
synthetic community in the context of drug discovery and
other complex molecule synthesis.
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.8b02261.
series of racemic epoxides with varied steric profiles were
prepared and subjected to the three-step sequence with a set of
hindered cyclic amines to generate the corresponding β-amino
amides. Epoxides featuring both cyclic and acyclic α-secondary
as well as α-tertiary branched substitution patterns were readily
accessible in comparable yields at each step of the exemplified
sequence. In regard to the individual reactions of this three-
step sequence, the epoxide ring opening and nitrile hydrolysis
reactions proceeded in consistently good yields, whereas the
aziridinium formation/cyanide addition sequence represented
the more challenging reaction.13 When combined with the
minor deviations in yield observed for each representative
amine tested, the reported synthetic strategy offers a robust
approach for the preparation of hindered β-amino amides.
Completion of the asymmetric synthesis of CXCR7
modulator 1 required deprotection of the piperidine moiety
followed by formation of the final amide bond connection to
the chiral bicyclic carboxylic acid 10 (Scheme 4). Treatment of
an acidic solution of 15 in methanol with palladium on carbon
under a hydrogen atmosphere cleanly provided the hydro-
chloride salt of the unprotected piperidine. Whereas the final
amide bond formation was previously established using a
Experimental procedures and characterization data of all
synthesized compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kevin.hesp@pfizer.com.
ORCID
Francois Godin: 0000-0001-9264-5807
Kevin D. Hesp: 0000-0002-3917-0547
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Pfizer coauthors thank Dr. Vincent Mascitti (Pfizer) and
Dr. Elnaz Menhaji-Klotz (Pfizer) for supporting this research
and for their insightful suggestions and feedback over the
course of the study.
Scheme 4. Completed Asymmetric Synthesis of 1
REFERENCES
■
(1) Rajagopal, S.; Kim, J.; Ahn, S.; Craig, S.; Lam, C. M.; Gerard, N.
P.; Gerard, C.; Lefkowitz, R. J. Proc. Natl. Acad. Sci. U. S. A. 2010, 107,
628−632.
(2) For a selection of reported small-molecule CXCR7 modulators,
see: (a) Wijtmans, M.; Maussang, D.; Sirci, F.; Scholten, D. J.; Canals,
M.; Mujic-Delic, A.; Chong, M.; Chatalic, K. L.; Custers, H.; Janssen,
E.; de Graaf, C.; Smit, M. J.; de Esch, I. J.; Leurs, R. Eur. J. Med. Chem.
2012, 51, 184−192. (b) Uto-Konomi, A.; McKibben, B.; Wirtz, J.;
C
DOI: 10.1021/acs.orglett.8b02261
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Sato, Y.; Takano, A.; Nanki, T.; Suzuki, S. Biochem. Biophys. Res.
Commun. 2013, 431, 772−776. (c) Yoshikawa, Y.; Oishi, S.; Kubo, T.;
Tanahara, N.; Fujii, N.; Furuya, T. J. Med. Chem. 2013, 56, 4236−
4251. (d) Chen, X.; Fan, P.; Gleason, M. M.; Jaen, J. C.; Li, L.;
McMahon, J. P.; Powers, J.; Zeng, Y.; Zhang, P. Diazepane derivatives
as CXCR7 modulators and their preparation, pharmaceutical
compositions and use in the treatment of diseases.
WO2010054006A1, 2010. (e) Fretz, H.; Gude, M.; Guerry, P.;
Kimmerlin, T.; Lehembre, F.; Pfeifer, T.; Valdenaire, A. 1-[m-
Carboxamido(hetero)aryl-methyl]piperidine-4-carboxamide deriva-
tives as CXCR7 modulators and their preparation.
US20130345199A1, 2013. (f) Fretz, H.; Guerry, P.; Kimmerlin, T.;
Lehembre, F.; Pothier, J.; Siendt, H.; Valdenaire, A. Preparation of
isoquinolinylalkanamides as CXCR7 receptor modulators.
WO2014191929A1, 2014. (g) Fan, J.; Krasinski, A.; Lange, C. W.;
Lui, R. M.; McMahon, J. P.; Powers, J. P.; Zeng, Y.; Zhang, P.
Prepararion of pyrrolidinylazolopyrazine derivatives as CXCR7
antagonists. WO2014085490A1, 2014.
Miskowski, T. A.; Sehon, C. A.; Viet, A. Q.; Wang, G. Z.; Zhang, J.
Preparation of spiro-indoline derivatives as chemokine receptor
modulators. WO2008157741A1, 2008.
(13) See the Supporting Information for additional details
(14) (a) McIsaac, J. E.; Ball, R. E.; Behrman, E. J. J. Org. Chem. 1971,
36, 3048−3050. (b) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis
1989, 1989, 949−950.
(3) Menhaji-Klotz, E.; Hesp, K. D.; Londregan, A. T.; Kalgutkar, A.
S.; Piotrowski, D. W.; Boehm, M.; Song, K.; Ryder, T.; Beaumont, K.;
Jones, R.; Atkinson, K.; Brown, J.; Litchfield, J.; Xiao, J.; Canterbury,
D. P.; Burford, K.; Thuma, B. A.; Limberakis, C.; Jiao, W.; Bagley, S.
W.; Agarwal, S.; Crowell, D.; Pazdziorko, S.; Ward, J.; Price, D. A.;
Clerin, V. J. Med. Chem. 2018, 61, 3685−3696.
(4) Tanaka, Y.; Hidaka, K.; Hasui, T.; Suginome, M. Eur. J. Org.
Chem. 2009, 2009, 1148−1151.
(5) Wirz, B.; Spurr, P.; Pfleger, C. Tetrahedron: Asymmetry 2010, 21,
159−161.
(6) Erion, M. D.; Reddy, K. R.; MacCoss, M.; Olsen, D. B.
Preparation of 2′-C-Me nucleoside 5′-monophosphate and 4′-C-Me
nucleoside 5′-monophosphate prodrugs for the treatment of hepatitis
C viral infection. WO2007022073A2, 2007.
(7) (a) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Natl. Acad. Sci.
U. S. A. 2004, 101, 5821−5823. (b) Yang, P.; Xu, H.; Zhou, J. Angew.
Chem., Int. Ed. 2014, 53, 12210−12213. (c) Hsiao, Y.; Rivera, N. R.;
Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J.
D.; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am.
Chem. Soc. 2004, 126, 9918−9919.
(8) Enders, D.; Wang, C.; Liebich, J. X. Chem. - Eur. J. 2009, 15,
11058−11076.
(9) (a) Notte, G. T.; Baxter Vu, J. M.; Leighton, J. L. Org. Lett. 2011,
13, 816−818. (b) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57,
3221−3242. (c) He, H.-X.; Du, D.-M. Tetrahedron: Asymmetry 2014,
25, 637−643.
(10) (a) Enantioselective Synthesis of β-Amino Acids, 2nd ed.; Juaristi,
E., Soloshonok, V. A., Eds.; John Wiley & Sons: Hoboken, NJ, 2005.
́
(b) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656−1691.
(11) For selected examples of the use of aziridinium ions, see:
(a) Chen, Y.; Sun, X.; Wu, N.; Li, J.; Jin, S.; Zhong, Y.; Liu, Z.;
Rogachev, A.; Chong, H.-S. Org. Biomol. Chem. 2016, 14, 920−939.
(b) Sun, X.; Chen, Y.; Wu, N.; Kang, C. S.; Song, H. A.; Jin, S.; Fu, Y.;
Bryant, H., Jr.; Frank, J. A.; Chong, H.-S. RSC Adv. 2015, 5, 94571−
94581. (c) Chong, H.-S. Synthesis of therapeutic and diagnostic drugs
centered on regioselective and stereoselective ring opening of
aziridinium ions. US9446995B2, 2016. (d) Frizzle, M. J.; Caille, S.;
Marshall, T. L.; McRae, K.; Nadeau, K.; Guo, G.; Wu, S.; Martinelli,
M. J.; Moniz, G. A. Org. Process Res. Dev. 2007, 11, 215−222.
(e) Oxenford, S. J.; Moore, S. P.; Carbone, G.; Barker, G.; O’Brien, P.;
Shipton, M. R.; Gilday, J.; Campos, K. R. Tetrahedron: Asymmetry
2010, 21, 1563−1568. (f) Mujahid, M.; Mujumdar, P.; Sasikumar, M.;
Deshmukh, S. P.; Muthukrishnan, M. Tetrahedron: Asymmetry 2017,
28, 983−986. (g) Coulton, S.; Gilpin, M.; Porter, R. A. Compounds
which inhibit the glycine transporter and uses thereof.
WO2007113309A2, 2007. (h) Feigelson, G.; Zeldis, J.; Jirkovsky, I.
Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl-
(2-pyridyl)amino]-2-propane substitution. US6713626B2, 2004.
(12) Budzik, B. W.; Eidam, H. S.; Fox, R. M.; Goodman, K. B.;
Gotchev, D. B.; Haile, P. A.; Hughes, T. V.; Liu, R.; Miller, N. A.;
D
DOI: 10.1021/acs.orglett.8b02261
Org. Lett. XXXX, XXX, XXX−XXX