Palladium-Catalyzed Enantioselective Synthesis of Cyclic Sulfamidates and Application to a Synthesis of Verubecestat

Article abstract of DOI:10.1021/acs.orglett.7b03639

An enantioselective arylation reaction catalyzed by palladium complexed with substituted phosphinooxazoline (PHOX) ligands is described. Aza-quaternary stereocenters are readily accessible through the arylation reaction between cyclic iminosulfates and a wide variety of arylboronic acids, including electron-poor and ortho-substituted arylboronic acids. This reaction was applied to the preparation of verubecestat, which is currently undergoing clinical evaluation for the treatment of Alzheimer's disease.

Full text of DOI:10.1021/acs.orglett.7b03639

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Enantioselective Synthesis of Cyclic
Sulfamidates and Application to a Synthesis of Verubecestat
Wenyong Chen,* Dongfang Meng, Blaise N’Zemba, and William J. Morris
Process Research & Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: An enantioselective arylation reaction catalyzed
by palladium complexed with substituted phosphinooxazoline
(PHOX) ligands is described. Aza-quaternary stereocenters are
readily accessible through the arylation reaction between cyclic
iminosulfates and a wide variety of arylboronic acids, including
electron-poor and ortho-substituted arylboronic acids. This
reaction was applied to the preparation of verubecestat, which
is currently undergoing clinical evaluation for the treatment of Alzheimer’s disease.
erubecestat (MK-8931) is a β-secretase inhibitor currently
in phase III clinical trials for the treatment of Alzheimer’s
catalyzed by palladium complexed with substituted phosphi-
nooxazoline (PHOX) ligands, provides access to aza-quaternary
stereocenters from readily available arylboronic acids and cyclic
iminosulfates.
V
disease.1 The current synthesis of verubecestat involves a
diastereoselective addition of the necessary alkyllithium reagent
to the appropriate Ellman ketimine to afford the aza-quaternary
stereocenter.2,3 This approach is in line with current literature
for the state of the art in the formation of this chiral motif.
Existing catalytic methods in the literature are effective for
synthesizing aza-tertiary stereocenters, but the construction of
aza-quaternary stereocenters remains a significant challenge.4
While the synthesis employing Ellman’s auxiliary is robust
and high-yielding, we sought to identify a catalytic approach
that would obviate the need for this stoichiometric auxiliary to
access verubecestat. We envisioned that a more efficient and
elegant strategy to prepare verubecestat would instead involve
direct asymmetric catalytic addition of an arylmetal reagent to a
cyclic iminosulfate (Figure 1).5 Several challenges exist in the
Our initial efforts to develop a general arylation reaction
focused on identifying a catalyst system that addressed this
limited nucleophile scope. The reaction between arylboronic
acid 1a and cyclic iminosulfate 2a was investigated to access the
stereocenter in verubecestat in the presence of various metals
and ligands (Table 1). Rh and Pd were first examined with
various chiral ligands (entries 1−4). A rhodium−Josiphos
catalyst and a palladium−PHOX catalyst were identified from
this initial screen (entries 1 and 3). Ni and Co6 were further
investigated to identify a low-cost alternative metal catalyst, but
the screen turned out to be fruitless (entries 5 and 6). The Pd−
PHOX catalyst was selected for further development because it
provided the product with superior enantioselectivity. Interest-
ingly, this initial screen also revealed that a silver salt is a critical
component of the reaction, presumably because the non-
coordinative anion facilitates the addition of the arylpalladium
intermediate into the CN bond (entries 2, 3, and 7).7
Further reaction optimization, including ligand and solvent
effects and the impact of additives, is summarized in Table 2.8
Reactions that provided the desired product in low yield
suffered from significant consumption of 1a by protodebor-
ylation. Additional screening of commercial PHOX ligands
revealed that the substituent on the oxazoline had a significant
effect on the extent of protodeborylation (entries 1−5). Among
commercially available PHOX ligands, tBu-PHOX was found to
be superior to its less sterically hindered counterparts, and its
palladium complex provided the arylation product in 30% yield
(entry 1). Further exploring this trend, employment of
adamantyl-PHOX led to an additional improvement in the
yield of 3a (entry 5). 1,2-Dichlorobenzene (DCB) proved to be
Figure 1. Proposed strategy for the synthesis of verubecestat.
construction of aza-quaternary stereocenters from arylmetal
reagents and ketimines. In particular, the ketimine electrophile
typically requires activation by incorporation of adjacent
electron-withdrawing groups, such as carbonyl groups or a
trifluoromethyl group.5n,o Furthermore, the scope of competent
nucleophiles for metal-catalyzed arylation of ketimines has been
limited to electron-rich arylboronic acids, as electron-deficient
arylboronic acids and ortho-substituted arylboronic acids
perform poorly or are even unreactive under previously
described reaction conditions. Herein we report a general,
enantioselective arylation reaction and its application to the
synthesis of verubecestat. This enantioselective reaction,
Received: November 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03639
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
protodeborylation pathway. MgO and CaO were found to be
particularly effective in this respect, leading to the arylation
product in 94% yield with 99% ee (entries 8 and 9).9 Under the
optimized conditions, cyclic iminosulfate 2a reacted with 2.0
equiv of boronic acid 1a to deliver the arylation product 3a in
92% yield with 99% ee (entries 10 and 11).
Table 1. Metal, Ligand, and Additive Screen for
Enantioselective Arylation of Cyclic Iminosulfate 2a
a
We explored the substrate scope of this reaction by
evaluating a series of arylboronic acids with imine 2a under
the optimized conditions (Table 3). Arylboronic acids
Table 3. Scope of the Arylboronic Acid Component in the
Pd-Catalyzed Enantioselective Arylation of Cyclic
a
Iminosulfate 2a
b
c
entry
metal
ligand
additive
yield/%
ee/%
d
1
Rh
Pd
Pd
Pd
Ni
Co
Pd
L1
L2
L2
L3
L2
L4
L2
K3PO4
none
12
0
77
−
99
e
2
e
3
AgBF4
none
6
f
4
0
−
−
−
99
e
5
AgBF4
none
0
e
6
0
b
c
e
entry
R
product
yield/%
ee/%
96
7
AgSbF6
12
a
1
2
3
4
5
4-Me
4-F
3b
3c
3d
3e
3f
95
97
83
94
78
98
93
95
77
94
94
3.0 equiv of 1a and 1.0 equiv of 2a were used in screening. See the
98
99
99
99
Supporting Information (SI) for experimental details. The absolute
4-Cl
configuration of the arylation product was determined by chemical
b
correlation. Determined by HPLC analysis with mesitylene as an
4-Br
c
internal standard. Determined by chiral HPLC analysis of the reaction
4-I
d
e
d
e
mixtures. Dioxane was used as the solvent. 1,2-Dichloroethane was
6
4-OPh
4-CF3
3-acetyl
3-Cl
3g
3h
3i
98 (0 )
98
f
used as the solvent. 1,1,1-Trifluoroethanol was used as the solvent.
7
8
99
Table 2. Evaluation of Ligands, Additives, and Solvents in
the Pd-Catalyzed Enantioselective Arylation of Cyclic
9
3j
97
10
2-F
3k
3l
98
a
Iminosulfate 2a
d
e
11
2-MeO
99 (2 )
a
2.0 equiv of 1b−l and 1.0 equiv of 2a were used in the reactions. See
the SI for experimental details. The absolute configurations of the
b
arylation products were assigned by analogy. Isolated yields.
c
d
Determined by chiral HPLC analysis of the isolated products. The
e
reaction was run in the presence of 5 mol % DTBMP. The value in
parentheses is the ee value of the product in the absence of DTBMP.
b
c
d
entry
R
additive
solvent
yield/%
ee/%
containing either methyl or halo substitution reacted with 2a
to provide the corresponding products in good to excellent
yields with 97−99% ee (entries 1−5). Unexpectedly, 4-
phenoxyphenylboronic acid reacted with 2a to yield racemic
3g. We hypothesized that this product might racemize through
an intramolecular SN1 process due to the presence of an
electron-donating group on the aryl rings. To test this
hypothesis, we evaluated a series of tertiary amines to suppress
the racemization. Gratifyingly, we found that 5 mol % 2,6-di-
tert-butyl-4-methylpyridine (DTBMP) successfully suppressed
the racemization and provided the product in 98% yield with
98% ee.10 The reaction with electron-poor 4-trifluoromethyl-
phenylboronic acid likewise provided the arylation product 3h
in 93% yield with 97% ee. It is worth noting that electron-poor
arylboronic acids have rarely functioned as competent
nucleophiles under previously disclosed conditions for
transition-metal-catalyzed arylation of cyclic iminosulfates.
Arylboronic acids containing electron-withdrawing substituents
at the meta position also reacted with 2a to form the
corresponding arylation products in high yields with high
enantioselectivities (entries 8 and 9). Although ortho-
substituted arylboronic acids were problematic in previous
reports, our reaction conditions provided these arylation
1
2
3
4
5
6
7
8
9
i-Pr
Bn
none
none
none
none
none
none
DCE
DCE
DCE
DCE
DCE
DCB
DCB
DCB
DCB
DCB
DCB
11
0
97
−
−
Ph
0
t-Bu
30
45
72
16
94
94
82
92
99
99
99
99
99
99
99
99
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
K2CO3
MgO
CaO
e
10
MgO
MgO
f
11
a
3.0 equiv of 1a and 1.0 equiv of 2a were used in the reactions. See the
SI for experimental details. 1.0 equiv of additive. Determined by
HPLC analysis with mesitylene as an internal standard. Determined
by chiral HPLC analysis of the isolated products. 1.2 equiv of 1a, 3
mol % Pd−adamantyl-PHOX catalyst, 6 mol % AgSbF6. 2.0 equiv of
1a, 3 mol % Pd−adamantyl-PHOX catalyst, 6 mol % AgSbF6.
b
c
d
e
f
the optimal solvent for this reaction, providing the arylation
product in 72% yield (entry 6). In order to reduce the amount
of 1a required in the reaction, various additives were
investigated in the reaction to further suppress the undesired
B
DOI: 10.1021/acs.orglett.7b03639
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
products in 94% yield with 99% ee (entries 10 and 11). The
current catalyst system is the first reported in which both
electron-poor and ortho-substituted arylboronic acids are
competent partners in this reaction motif.
Scheme 1. Proposed Mechanism of Pd-Catalyzed
Asymmetric Arylation
The scope of the cyclic iminosulfate electrophile under our
optimized conditions is shown in Table 4. 4-Bromophenylbor-
a
Table 4. Scope of Cyclic Iminosulfates
b
c
entry
R
product
yield/%
93
ee/%
d
1
Et
3m
3n
3o
3p
3q
3r
99
99
98
96
95
95
d
2
PhCH2CH2
i-Pr
96
e
f
3
89 (42 )
e
4
c-hexyl
c-pentyl
i-Bu
90
90
83
e
5
e
6
a
2.0 equiv of 1e and 1.0 equiv of 2b−g were used in the reactions. See
the SI for experimental details. The absolute configurations of the
b
arylation products were assigned by analogy. Isolated yields.
c
a
Determined by chiral HPLC analysis of the isolated products.
Scheme 2. Utility of the Cyclic Sulfamidate Products
d
e
f
Adamantyl-PHOX was used. t-Bu-PHOX was used. The value in
parentheses is the yield of the product with adamantyl-PHOX as the
ligand.
onic acid (1e) reacted smoothly with ethyl- and phenethyl-
substituted cyclic iminosulfates (2b and 2c) under the reaction
conditions and furnished the products in high yields with
excellent enantioselectivities (entries 1 and 2). Iminosulfates
containing bulky alkyl groups provided the corresponding
products in modest yields with high enantioselectivities under
our optimized conditions: for example, the product from
isopropyl-substituted substrate 2d was isolated in only 42%
yield. We hypothesized that the bulky adamantyl group in the
ligand clashed with the i-Pr group and lowered the rate of the
arylation process. Consistent with this hypothesis, when t-Bu-
PHOX was employed as the ligand instead, the product was
generated in 89% yield while maintaining the same 99% ee
(entry 3). Cyclic iminosulfates containing other bulky groups,
such as c-hexyl, c-pentyl, and i-Bu, all underwent the arylation
smoothly when t-BuPHOX was employed as the ligand (entries
4−6).
a
See the SI for experimental details.
formed through intramolecular nucleophilic substitution of the
carbonyl oxygen in the Cbz group followed by desulfonylation.
This observation inspired the synthetic strategy to forge the C−
S bond found in verubecestat (Scheme 3). After acylation of 3a
Scheme 3. Synthesis of Verubecestat from 3a
A proposed mechanism is shown in Scheme 1. The Pd−
PHOX complex is converted to the cationic palladium complex
A in the presence of AgSbF6 and water. The hydroxide group in
A assists the transmetalation of ArB(OH)2 to form Ar−Pd
complex B. Coordination of cyclic iminosulfates with B leads to
intermediate C, which allows insertion of the CN bond into
the Pd−C bond to form D. Protonation releases the arylation
product and turns over the palladium catalyst to complex A. In
the catalytic cycle, protonation of intermediate B leads to the
undesired protodeborylation product ArH.
with O-phenyl chlorothionoformate, the thiocarbamate under-
went rearrangement−desulfonylation to yield dihydrothiazole
6. Exposure to NCS in HCl led directly to the formation of an
intermediate sulfonyl chloride, which was quenched with p-
methoxybenzylmethylamine. After addition of TBAF, amine 7
was isolated in 64% yield from 6. Copper-catalyzed amidation11
with 5-fluoropicolinamide followed by PMB deprotection and
guanidinylation provided verubecestat in 41% overall yield from
iminosulfate 2a. The catalytic route provided enantiopure
verubecestat in yield and efficiency comparable to those of the
The utility of the arylation products is shown in Scheme 2.
Cyclic sulfamidate 3a was protected with CbzCl to form 4,
which underwent rearrangement in DMF at 60 °C to form
cyclic carbamate 5. We speculated that cyclic carbamate 5 was
C
DOI: 10.1021/acs.orglett.7b03639
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
For a comprehensive review of the synthesis of chiral amines, see:
(b) Chiral Amine Synthesis: Methods, Developments and Applications;
Nugent, T. C., Ed.; Wiley-VCH: Weinheim, Germany, 2010.
(5) For Rh-catalyzed arylation, see: (a) Jiang, T.; Wang, Z.; Xu, M.-
H. Org. Lett. 2015, 17, 528. (b) Chen, Y.-J.; Chen, Y.-H.; Feng, C.-G.;
Lin, G.-Q. Org. Lett. 2014, 16, 3400. (c) Wang, H.; Li, Y.; Xu, M.-H.
Org. Lett. 2014, 16, 3962. (d) Wang, H.; Jiang, T.; Xu, M.-H. J. Am.
Chem. Soc. 2013, 135, 971. (e) Wang, H.; Xu, M.-H. Synthesis 2013,
45, 2125. (f) Nishimura, T.; Ebe, Y.; Fujimoto, H.; Hayashi, T. Chem.
Commun. 2013, 49, 5504. (g) Nishimura, T.; Noishiki, A.; Tsui, G. C.;
Hayashi, T. J. Am. Chem. Soc. 2012, 134, 5056. (h) Kong, J.;
Mclaughlin, M.; Belyk, K.; Mondschein, R. Org. Lett. 2015, 17, 5520.
For Pd-catalyzed arylation, see: (i) Jiang, C.; Lu, Y.; Hayashi, T. Angew.
Chem., Int. Ed. 2014, 53, 9936. (j) Yang, G.; Zhang, W. Angew. Chem.,
Int. Ed. 2013, 52, 7540. For Cu-catalyzed arylation, see: (k) Nunez, M.
G.; Farley, A. J. M.; Dixon, D. J. J. Am. Chem. Soc. 2013, 135, 16348.
(l) Hayashi, M.; Iwanaga, M.; Shiomi, N.; Nakane, D.; Masuda, H.;
Nakamura, S. Angew. Chem., Int. Ed. 2014, 53, 8411. (m) Yin, L.;
Takada, H.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2013,
52, 7310. (n) Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2008, 130, 5530. (o) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8,
2743.
(6) Karthikeyan, J.; Jeganmohan, M.; Cheng, C.-H. Chem. - Eur. J.
2010, 16, 8989.
(7) Jautze, S.; Peters, R. Angew. Chem., Int. Ed. 2008, 47, 9284.
(8) Preformed Pd−PHOX complex was used in further development
because of improved reproducibility.
(9) The protodeborylation appeared to occur through the Ar−Pd
intermediate because 1a was stable under the conditions without metal
catalyst. MgO/CaO suppressed the protodeborylation, presumably by
tuning the pH of the system and the water concentration.
(10) Isolated 3l (99% ee) underwent complete racemization after
stirring with 5 mol % Pd−Phox complex and AgSbF6 in the presence
of MgO at 70 °C for 4 h.
recently developed commercial process, which produced
verubecestat in 61% overall yield by employing a chiral Ellman
sulfinyl ketimine as the starting material and a recrystallization
to upgrade the enantiopurity.3b
In summary, we have described a general Pd-catalyzed
enantioselective arylation reaction between cyclic iminosulfates
and a wide variety of arylboronic acids. The reaction tolerates
electron-rich, electron-poor, and ortho-substituted arylboronic
acids and provides cyclic sulfamidates in high yields with
excellent enantioselectivities. This palladium catalyst system
significantly expands the scope for the asymmetric arylation of
ketimines. The cyclic sulfamidates formed in the reaction can
be funtionalized to generate the corresponding amino alcohols
and cyclic carbamates. A novel desulfonyl rearrangement of
thiocarbamate led to the formation of the desired C−S bond
found in verubecestat. A sequential oxidation−amination
reaction followed by C−N coupling, PMB deprotection, and
guanidine formation led to verubecestat in six total steps from
cyclic iminosulfate 2a (41% overall yield).
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.7b03639.
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wenyong.chen@merck.com.
ORCID
(11) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
Wenyong Chen: 0000-0002-7337-0876
William J. Morris: 0000-0003-4322-4509
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Xiaodong Bu, Li Zhang, Daniel Zewge, Joe Gouker,
Alexey Makorov, Huaming Sheng, and Wilfredo Pinto for
analytical chemistry support and Steven P. Miller, David A.
Thaisrivongs, Rebecca T. Ruck, Louis-Charles Campeau, Paul
N. Devine, and Ian Davies for helpful discussions. All are
members of Process Research and Development, Merck
Research Laboratories.
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D
DOI: 10.1021/acs.orglett.7b03639
Org. Lett. XXXX, XXX, XXX−XXX