Enantioselective Rh(I)-Catalyzed Addition of Arylboronic Acids to Cyclic Ketimines

Article abstract of DOI:10.1021/acs.orglett.5b02032

A method for the enantioselective synthesis of chiral α-tertiary amines via Rh-catalyzed 1,2-addition of arylboronic acids to cyclic ketimines is described. The products are efficiently accessed in good yields and excellent enantioselectivities using a co

Full text of DOI:10.1021/acs.orglett.5b02032

Letter
pubs.acs.org/OrgLett
Enantioselective Rh(I)-Catalyzed Addition of Arylboronic Acids to
Cyclic Ketimines
Jongrock Kong,* Mark McLaughlin,* Kevin Belyk, and Ryan Mondschein
Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: A method for the enantioselective synthesis of chiral α-tertiary amines via Rh-catalyzed 1,2-addition of arylboronic
acids to cyclic ketimines is described. The products are efficiently accessed in good yields and excellent enantioselectivities using
a commercially available chiral ligand. The reaction scope includes vinyl, aryl, and heteroarylboronic acids with yields ranging
from 40% to 99% and enantiomeric excesses from 88% to 99%. Conversion of an addition product into an α,α-diaryl-substituted
amino acid is also demonstrated.
asymmetric addition of arylboronic acids to generate the
corresponding chiral cyclic sulfamates containing a fully
substituted carbon stereocenter.7,8 More importantly, given
the importance of chiral α-tertiary amines in medicinal
chemistry programs, a general, reliable, and user-friendly
method for the synthesis of chiral α-tertiary amines has been
identified as a significant utility within the pharmaceutical
industry.
Our initial studies focused on a racemic addition of 4-
methoxyphenylboronic acid to 3,4-difluorophenyl substrate 1a
in the presence of a Rh(acac)(ethylene)2 and DPPBenzene in
2-Me-THF (Scheme 1).2c Gratifyingly, the reaction resulted in
clean conversion to the desired tertiary substituted cyclic
sulfamate product 2a in 93% isolated yield.
acile synthetic access to chiral α-tertiary amines is an active
1
Farea of research in the organic chemistry community.
Chiral amines are of particular interest to the pharmaceutical
industry because this functionality is ubiquitous in pharmaco-
logically active compounds. Although traditional methods for
preparing enantioenriched chiral amines, such as chiral acid
resolutions and chiral auxiliary-based techniques, continue to be
useful,2 effective catalytic asymmetric processes have the
advantages of both synthetic efficiency and atom economy.3
Transition-metal-catalyzed processes for the preparation of
chiral amines are well established and one example is the Rh-
catalyzed asymmetric addition of arylboronic acids to
aldimines.4 In contrast, the catalytic enantioselective addition
of organometallic reagents to ketimines is significantly less
developed.5 An ongoing interest in our laboratories is the use of
cyclic sulfamates as useful synthons for the construction of
chiral heterocycles that are typically found in pharmaceuticals.
In the course of developing a practical approach to a target
piperazinone derivative, we utilized a Pd-catalyzed asymmetric
hydrogenation to convert a prochiral cyclic ketimine into a
chiral cyclic sulfamate (Figure 1).6
To explore the feasibility of an enantioselective variant of this
reaction, additions of 4-methoxyphenylboronic acid to 3,4-
difluorophenyl substrate 1a and phenyl substrate 1b were
performed in the presence of chiral phosphine ligands. With the
Scheme 1. Initial Racemic Arylation Reaction
As part of this work we also defined a general and robust
procedure for the synthesis of these prochiral cyclic ketimine
substrates. Based on this earlier research, we were intrigued by
the possibility of engaging these intermediates in a Rh-catalyzed
Received: July 15, 2015
Figure 1. Related prior work and proposed study.
© XXXX American Chemical Society
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Letter
goal of a practical catalytic system in mind, our ligand screening
work focused on typical commercially available chiral
phosphines.9 Although reasonable conversions were observed
in almost all cases,10 most of the chiral phosphines in our
screen afforded low to moderate enantiocontrol. An exception
to this general pattern was SL-W001-1 (Walphos), which
provided excellent levels of enantiocontrol for the cyclic
ketimine−arylboronic acid combination used for the screen
(Table 1).
Table 2. Reactions of 1a with Different Arylboronic Acids
Table 1. Chiral Ligand Evaluation
a
b
Used commercially available phosphine ligands only. Determined by
SFC.
a
b
c
Isolated yield. Determined by SFC. 3 equiv of arylboronic acid
were used.
acceptable conversions. For example, 4-chloro- and 4-
carbethoxy-substituted substrates work well with various
arylboronic acids. In contrast, electron-rich cyclic ketimines
exhibit lower reactivity and typically require up to 3 equiv of
arylboronic acid to reach high conversions. Regardless of
substrate electronics and reactivity considerations, however,
high levels of enantiocontrol were generally observed, with
product enantiomeric excesses typically >95%. Of particular
note is the observation that aliphatic substrates are viable and
provide α,α-alkyl-aryl-substituted products (2t−2v) in good
yields with excellent enantioselectivities.
The absolute configuration of 2b was determined to be (S)
by X-ray crystallographic analysis (Figure 2).
Having established a strong proof-of-concept for the desired
asymmetric process, we investigated application of the
developed conditions to a range of arylboronic acids and cyclic
ketimine substrates. First we studied the reaction of the 3,5-
difluorophenylketimine with different arylboronic acids (Table
2). In general, conversion of the imine substrate was good to
excellent when 2 equiv of arylboronic acid were employed.11
Moreover, high levels of enantiocontrol were observed in all
cases. Of particular note is the ability to use heteroarylboronic
acids such as 2-furylboronic acid (2f) and 3-thienylboronic acid
(2h). In addition, a vinylboronic acid (2j) was shown to
participate effectively in the developed process albeit with
slightly lower enantioselection (88% ee).
Next we studied the scope of cyclic ketimine substrates
against several arylboronic acids. The results observed across a
variety of cyclic ketimines are shown in Table 3.
In general, electron-deficient cyclic ketimines displayed
greater reactivity toward the desired addition process, which
allowed for a reduced excess of arylboronic acid to achieve
To further demonstrate the synthetic utility of the derived
chiral cyclic sulfamate products, we elaborated arylation
product 2a into an α,α-diaryl-substituted amino acid (Scheme
2). Reduction of cyclic sulfamate 2a using Red-Al followed by
acidic hydrolysis during workup affords the expected amino
alcohol in good yield. After N-Boc protection of the amine,
one-pot oxidation of the alcohol to the carboxylic acid using the
Dess-Martin reagent followed by direct treatment under
standard Pinnick-type conditions gave the α,α-diaryl-substi-
tuted amino acid 3a in 70% overall yield (Scheme 2).12
In summary, we have developed a novel catalytic system for
the asymmetric 1,2-addition of arylboronic acids to a class of
cyclic ketimine substrates. Specifically, reaction development
within the Merck catalysis facility identified the readily available
chiral phosphine ligand Walphos as an excellent ligand for the
process. Extremely high levels of enantiocontrol were generally
observed, with measured product enantiomeric excesses in
most cases >98%. The utility of the derived products was
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Table 3. Reaction of Different Cyclic Ketimines with
Arylboronic Acids
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.5b02032.
Experimental details, characterization data, and NMR
spectra (PDF)
Crystallographic data for (S)-2b (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jongrock_kong@merck.com.
*E-mail: mark_mclaughlin@merck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank Bob Reamer (Merck) and Mikhail
Reibarkh (Merck) for assistance with NMR interpretation, Lin
Wang (Merck) for acquisition of HRMS data, Richard Ball and
Andrew Brunskill (Merck) for X-ray crystallography support,
Wes Schafer and Heather Wang (Merck) for chiral
chromatography support, and Cheng-yi Chen (Johnson and
Johnson) for helpful discussions during the early stages of this
work.
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■
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for asymmetric Rh(I)-catalyzed addition of arylboronic acids to cyclic
ketimines has not been successful due to poor enantioselectivity (see
ref 7).
(10) The reaction conversion is sensitive to oxygen or peroxide
impurities in the solvent, so it is recommended to employ 2-Me-THF
containing BHT inhibitor.
(11) For certain more easily deborylated substrates such as 2-
furylboronic acid, it was necessary to use 3 equiv to achieve acceptable
conversion.
(12) The enantiomeric excess of the amino acid 3a was determined
via chiral LC and found to be 97%, indicating no erosion occurred
during the chemical transformations from 2a.
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DOI: 10.1021/acs.orglett.5b02032
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