Highly Enantioselective Arylation of N,N-Dimethylsulfamoyl-Protected Aldimines Using Simple Sulfur-Olefin Ligands: Access to Solifenacin and (S)-(+)-Cryptostyline II

Article abstract of DOI:10.1021/acs.orglett.7b00776

With the use of a simple sulfur-olefin ligand, a highly enantioselective rhodium-catalyzed addition of arylboroxines to N,N-dimethylsulfamoyl-protected aldimines has been achieved, allowing access to a broad range of chiral diarylmethylamines in high yields (up to 98%) with uniformly excellent enantioselectivities (up to 99% ee). This catalyst system is also applicable to the arylation of N-tosyl arylimines. By utilizing this method, some biologically active molecules possessing a chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline core such as Solifenacin and (S)-(+)-Cryptostyline II are facilely constructed.

Full text of DOI:10.1021/acs.orglett.7b00776

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Arylation of N,N‑Dimethylsulfamoyl-
Protected Aldimines Using Simple Sulfur−Olefin Ligands: Access to
Solifenacin and (S)‑(+)-Cryptostyline II
Tao Jiang,†,‡ Wen-Wen Chen,† and Ming-Hua Xu*,†
†State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: With the use of a simple sulfur−olefin ligand, a highly enantioselective rhodium-catalyzed addition of
arylboroxines to N,N-dimethylsulfamoyl-protected aldimines has been achieved, allowing access to a broad range of chiral
diarylmethylamines in high yields (up to 98%) with uniformly excellent enantioselectivities (up to 99% ee). This catalyst system
is also applicable to the arylation of N-tosyl arylimines. By utilizing this method, some biologically active molecules possessing a
chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline core such as Solifenacin and (S)-(+)-Cryptostyline II are facilely constructed.
Scheme 1. Rh-Catalyzed Asymmetric Arylation of N,N-
Dimethylsulfamoyl Imines
pticallyactivediarylmethylaminesareembodiedinavariety
O
of biologically significant compounds.1 Due to their
pharmaceutical importance, great attention has been drawn to
the development of their synthesis.2 Since the first report by
Tomioka in 2004,3a rhodium-catalyzed asymmetric addition of
arylboron reagents to aldimines has been recognized as a
particularly attractive and powerful strategy for efficient
enantioselective assembly of the skeleton.3 Although some
major achievements have been made; however, most methods
rely on the use of N-tosyl or nosyl activated/protected imines,
which suffers from the disadvantage of protecting group removal
under relatively harsh or environmentally unfriendly conditions.
To address this issue, N,N-dimethylsulfamoyl was developed as
an inexpensive, low-molecular-weight, and easily removable
protecting group for this transformation. In 2006, de Vries,
Feringa, and Minnaard4 reported the first development of a
monodentate, para-methoxyaniline-derived phosphoramidite as
the chiral ligand for Rh-catalyzed asymmetric arylation of N,N-
dimethylsulfamoyl imines. Later, Du5 applied binaphthyl-based
chiral diene ligands in the same reaction, providing the
diarylmethylamine products with up to 84% ee (Scheme 1).
Despite this remarkable progress, the substrate generality is likely
influencedbytheelectronicandstericsubstitutionpatternofboth
reaction partners and the enantioselectivities require further
improvement. Quite recently, Kim6 disclosed the use of a chiral
bicyclic bridgehead phosphoramidite ligand and found that the
reactions with phenyl, p-methoxyphenyl, p-tolyl, and m-tolyl
boronic acids could occur with high stereocontrol (87−96% ee).
However, the yield dropped dramatically with m-tolyl boronic
acid and no product was attained with more sterically hindered o-
tolyl boronic acid. To date, there are no other known reports of
enantioselective arylation of N,N-dimethylsulfamoyl imines,
presumably due to the diminished reactivity of these substrates
relative to N-tosyl and nosyl imines as well as the difficulty in
controlling the diaryl stereodifferentiation. Therefore, the
development of a new, benign, and effective catalyst system that
Received: March 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
would successfully lead to a broad range of desired diarylmethyl-
amineswithgreatenantioselectivitiesstillrepresentsachallenging
task and is highly desirable.
and stereochemical control (L5, 86% yield, 95% ee) (entry 5).
Similar enantioselectivity was obtained with the use of weak base
K2CO3 (entry 6). In addition, varying the solvent did not furnish
better results (entries 7 and 8). Notably, only a trace amount of
product was detected inwater-miscible solvent dioxane duetothe
drastic hydrolysis of substrate under the basic conditions (entry
7). In contrast to SOLs, C2-symmetric chiral diene ligands L6 and
L7 exhibited much lower reactivity (19−20% yields) in spite of
comparable enantiocontrol performance (entries 9and 10), while
bisphosphine ligand BINAP could hardly catalyze the reaction
(entry 11).
Inthepastfewyears, chiralsulfur-basedolefinshaveemergedas
a new promising class of hybrid ligands for asymmetric catalysis.7
Our group has demonstrated that simple and readily available
chiral sulfinamide-olefins could display great catalytic activities
and enantioselectivities in a series of Rh-catalyzed asymmetric
additions to carbonyl compounds and cyclic N-sulfonyl imines.8
Encouraged by these results, we sought to further explore this
chemistry in the enantioselective arylation of acyclic imines.
Herein, we describe our development of an elegant catalyst
system for the highly enantioselective arylation of N,N-
dimethylsulfamoyl aryl imines, enabling access to chiral diary-
lmethylamines with excellent ee in high yields (Scheme 1).
Using our previously developed sulfur−olefin ligands (SOLs)
L1−L3 as chiral ligands, we initially performed the reaction
between N,N-dimethylsulfamoyl imine 1a and p-methylphenyl-
boroxine 2a in the presence of 1.5 mol % of [Rh(COE)2Cl]2
under aqueous KOH (1.5 M)/toluene at 60 °C (Table 1, entries
Having established the optimal ligand and reaction parameters,
we then investigated the substrate scope of this Rh-catalyzed
asymmetric arylation (Scheme 2). We were pleased to find that a
Scheme 2. Rh-Catalyzed Asymmetric Arylation of N,N-
a d
−
Dimethylsulfamoyl Imines
Table 1. Ligand Screening and Optimization of Reaction
a
Conditions
b
c
entry
ligand
base(aq)
solvent
yield (%)
ee (%)
1
L1
L2
L3
L4
L5
L5
L5
L5
L6
L7
L8
KOH
KOH
KOH
KOH
KOH
K2CO3
KOH
KOH
KOH
KOH
KOH
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DCE
60
−81
81
80
84
95
94
−
93
96
91
−
2
83
3
79
4
66
5
86
6
80
7
trace
75
8
9
toluene
toluene
toluene
20
10
11
19
trace
a
Conditions: 1a (0.20 mmol), 2a (boroxine, 1.0 equiv), [Rh-
a
Conditions: 1 (0.20 mmol), 2 (1.0 equiv), [Rh(COE)2Cl]2 (1.5 mol
%), L5 (3.3 mol %), and KOH (1.5 M, 3.0 equiv) in 1.0 mL of toluene
(COE)2Cl]2 (1.5 mol %), ligand (3.3 mol %), and base (1.5 M, 3.0
b
equiv) in 1.0 mL of solvent at 60 °C for 6 h. Isolated yield.
b
c
d
c
at 60 °C for 6 h. Isolated yield. Determined by chiral HPLC. The
Determined by chiral HPLC analysis.
absolute stereochemistry was determined by comparing the [α]D with
known data.4 Reaction at a 1 mmol scale.
e
1−3). As expected, these Rh(I)/SOLs were found to be able to
catalyze the reaction smoothly. Compared with the linear ligand
L1, the branched SOL L2 and L3 exhibited higher catalytic
activity while maintaining the same level of enantioselectivity
(80−81% ee) (entries 1−3). These results inspired us to evaluate
other branched SOLs with different substituents. Changing the
phenyl group in L3 to the bulkier 1-naphthyl group resulted in a
slight increase in enantiocontrol (L4, 84% ee, entry 4).
Gratifyingly, the incorporation of a sterically hindered t-Bu
group was found to be clearly beneficial for both catalyst activity
variety of arylboroxines bearing substituents with diverse
electronic and steric properties all smoothly reacted with N,N-
dimethylsulfamoyl imine 1a to provide the desired products in
good yields with excellent enantioselectivities (90−99% ee) (3a−
i). Extremely high enantiomeric excesses (98−99% ee) were
attained with electron-deficient or sterically encumbered
arylboroxines (3c−f and 3h). Furthermore, a broad range of
electronically and sterically different aryl imines was tested.
B
DOI: 10.1021/acs.orglett.7b00776
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Organic Letters
Letter
Regardless of the substitution pattern on the phenyl ring, all these
imines reacted well with arylboroxines to provide the
corresponding diarylmethylamines in good yields with excellent
levels of enantioselectivity (90−99% ee) (3j−m, 3o, 3a′−c′, and
3h′). Interestingly, significant enantiocontrol was observed with
electron-rich imines; this trend is opposite to what is observed
with arylboroxines. Thus, insome cases such as for 3a′ and 3b′, by
simply reversing the corresponding Ar1 and Ar2 groups of the two
substrates, the ee of the product can be readily enhanced (3a vs
3a′, 3b vs 3b′, and also 3c′ vs 3c). These results indicate that even
minor disadvantages of using electron-deficient imines or
electron-rich arylboroxines could be overcome to furnish the
desired highly enantioenriched product by easily switching the
aryl acceptor/donor and changing the ligand configuration.
Moreover, the heteroaromatic imine substrate containing a furan
ring also proved competent in the arylation, affording 3n with
excellent ee (98%), albeit in a decreased yield (52%). Another
fascinating feature is that the reaction exhibits a truly remarkable
ortho-substitution tolerance. In all cases with sterically encum-
bered substrates, as exemplified by 3f, 3h, 3m, 3n, and 3h′, nearly
perfect enantiomeric excesses (97−99% ee) could be achieved.
Under the optimal reaction conditions, we further explored the
scope of N,N-dimethylsulfamoyl imine substrates using aldimine
4 containing an ortho-ester functionality as a more challenging
reactant. To our delight, the expected chiral 3-substituted
phthalimidine product 5 was afforded through the diarylmethyl-
amine formation followed by in situ lactamization in good yield
(84%) with satisfactory enantioselectivity (97% ee) when the
reaction was performed under the same catalysis at slightly higher
temperature (Scheme 3).
Scheme 5. Rhodium-Catalyzed Asymmetric Arylation of N-
Tosylphenylimine with Arylboroxines
On the basis of the stereochemical outcome of the reaction, a
plausible enantio-determiningtransition-state modelisproposed.
As shown in Figure 1, the arylrhodium species has a favored
Figure 1. Proposed transition state models for enantioselectivity.
conformation with the aryl group positioned trans to the olefin
moietyofligandandthetert-butylgroupisstaggered. Toavoidthe
steric congestion, the imine substrate coordinates to rhodium
preferentially from its si face, inwhich the N,N-dimethylsulfamoyl
(or tosyl) group orients away from the bulky R substituent on the
double bond of the ligand, and consequently the carborhodation
takes place to afford the observed major enantiomer.
To demonstrate the practical synthetic utility of this method,
we carried out the asymmetric synthesis of two biologically
important molecules. Solifenacin10,11 is a urinary antispasmodic
prescription drug used for the treatment of an overactive bladder.
Chiral resolution,11 asymmetric hydrogenation,12 and deracem-
ization13 of 1-phenyl-1,2,3,4-tetrahydroisoquinoline are the main
strategies to access its chiral tetrahydroisoquinoline core. By
taking advantage of the extraordinary ortho-substitution compat-
ibility of our protocol, asymmetric synthesis of enatiomerically
pure diarylmethylamine 3p (99% ee) was accomplished with ease
in 82% yield. Removal of the N,N-dimethylsulfamoyl group
followed by ethoxycarbonylation and TBS-deprotection fur-
nished the intermediate 9. Subsequently, the intramolecular
Mitsunobu reaction of 9 with DIAD/PPh3 gave (S)-1-phenyl-
1,2,3,4-tetrahydroisoquinoline derivative 10, which could be
easily transformed into (+)-Solifenacin by means of trans-
esterification with (R)-3-quinuclidinol following the known
procedure11 (Scheme 6a). In a similar fashion, arylation product
3q was accessed in high yield (96%) as a single enantiomer (99%
ee) using the same catalyst system. N-Deprotection of 3q under
microwave irradiation, followed byreprotection with Boc, yielded
the intermediate 11 with complete preservation of the optical
purity. Treatment of N-Boc amine 11 with LAH in refluxing THF
gave the corresponding N-methyl amino alcohol, which was
smoothly cyclized under Mitsunobu conditions to give (S)-
(+)-Cryptostyline IIin88%yieldovertwosteps. Thetotalyieldof
this method is 79%, which compares very favorably with the
previous synthesis14 (19%,14a 27%,14b and 37%14c). Notably, (S)-
Cryptostylines I (R1 = H; R2, R3 = O−CH2−O), II (R1 = H; R2, R3
= OCH3), and III (R1, R2, R3 = OCH3) are natural products
isolated from the plant Cryptostylis fulva15a,b and reported as
probes for dopamine receptor D115c (Scheme 6b). With the same
strategy, it is believed that (S)-(+)-Cryptostylines I and III could
also be readily prepared with appropriate arylboroxines.
Scheme 3. Synthesis of Chiral 3-Substituted Phthalimidine 5
Subsequently, the removal of the N,N-dimethylsulfamoyl
group was conducted.4 As exemplified by 3c, cleavage of the
N−S bond proceeded readily within 30 min in 1,3-diaminopro-
pane under microwave-assisted heating conditions, giving the N-
free diarylmethylamine 6 in almost quantitative yield without loss
of optical purity9 (Scheme 4).
Scheme 4. Removal of the N,N-Dimethylsulfamoyl Group
To further extend the substrate generality of this catalyst
system, we examined the reaction of N-tosylarylimines with
arylboroxines. AsshowninScheme5,asimilartrendasthatforthe
arylation of N,N-dimethylsulfamoyl arylimines was observed,
with uniformly high enantioselectivities (91−99% ee) being
achieved in the Rh/L5-catalyzed asymmetric arylation of N-
tosylphenylimine 7; the reaction also works optimally with
electron-deficientorsterically encumberedarylboroxines (8band
8d, 98−99% ee).
In summary, a rather simple but highly effective rhodium/
sulfur−olefin catalyst system for asymmetric addition of
C
DOI: 10.1021/acs.orglett.7b00776
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Organic Letters
Letter
Municipal Committee of Science and Technology
(14xd1404400) is greatly acknowledged.
Scheme 6. Facile Asymmetric Synthesis of Solifenacin and (S)-
(+)-Cryptostyline II
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xumh@simm.ac.cn.
ORCID
Ming-Hua Xu: 0000-0002-1692-2718
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation
of China (21325209, 21472205, 81521005) and the Shanghai
■
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DOI: 10.1021/acs.orglett.7b00776
Org. Lett. XXXX, XXX, XXX−XXX