Direct asymmetric amination of α-branched cyclic ketones catalyzed by a chiral phosphoric acid

Article abstract of DOI:10.1021/jacs.5b00229

Here we report the direct asymmetric amination of α-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N-containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantioenriched α-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical.

Full text of DOI:10.1021/jacs.5b00229

Communication
pubs.acs.org/JACS
Direct Asymmetric Amination of α‑Branched Cyclic Ketones
Catalyzed by a Chiral Phosphoric Acid
Xiaoyu Yang and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: Here we report the direct asymmetric
amination of α-substituted cyclic ketones catalyzed by a
chiral phosphoric acid, yielding products with a N-
containing quaternary stereocenter in high yields and
excellent enantioselectivities. Kinetic resolution of the
starting ketone was also found to occur on some of the
substrates under milder conditions, providing enantio-
enriched α-branched ketones, another important building
block in organic synthesis. The utility of this methodology
was demonstrated in the short synthesis of (S)-ketamine,
the more active enantiomer of this versatile pharmaceut-
ical.
α-Amino cyclic ketones with a N-containing quaternary
stereocenter are important building blocks in organic synthesis
and versatile precursors to physiologically active compounds
such as ketamine1 and tiletamine (Figure 1a).2 Additionally, β-
amino alcohols, which are derivatives of α-amino cyclic ketones,
are widely used as chiral ligands in asymmetric catalysis.3 The
past decade has witnessed the development of direct asymmetric
α-amination of carbonyl compounds as a useful method for the
preparation of chiral amine-containing structures.4 Despite these
advances, the majority of reported reactions rely on activated
carbonyl compounds, such as 1,3-dicarbonyls, 2-oxindoles, α-
cyanoacetates, and other reactive substrates.4,5 For carbonyl
compounds with lower reactivity, enamine catalysis has been
employed in the highly enantioselective amination of alde-
hydes6,7 and ketones8 without substitution at the α-position.9
Alternatively, chiral α-amino ketones have been accessed via
asymmetric amination of preactivated unsubstituted ketone
equivalents, such as silyl enol ethers,10 metal enolates,11 and
enamides.12 Terada’s chiral organosuperbase-catalyzed amina-
tion of 2-alkyl-substituted cyclic aromatic ketones (Figure 1c)13
and Yamamoto’s silver-catalyzed amination of the tin enolate of
2-phenylcyclohexanone (Figure 1b)11b stand as rare example of
enantioselective amination to produce N-containing quaternary
stereocenters.
Figure 1. Previous work on the catalytic asymmetric synthesis of 2-
aminocyclohexanone bearing a quaternary stereocenter.
We selected 2-phenylcyclohexanone as a model substrate and
di-tert-butyl azodicarboxylate as the nitrogen source, which is
widely used in asymmetric amination processes (Table 1).
Reaction of these two components, catalyzed by (S)-TRIP (10
mol%) in xylenes (0.1 M) at 45 °C for 60 h, produced a minor
amount of the desired product; substantial starting ketone
remained unreacted (entry 1). Other chiral phosphoric acids
(TCYP, H8-TCYP, and C8-TCYP) were also tested, and after
reaction for 60 h at 45 °C, the highest enantioselectivity (97% ee)
was generated with (R)-C8-TCYP as catalyst, albeit with low
conversion (38% yield, entry 4). In an attempt to improve the
conversion, the reaction mixture was heated at 60 °C for 60 h; a
higher yield of the product was isolated (57% yield), but with a
decrease in enantioselectivity (91% ee, entry 5). A less sterically
demanding electrophile, diethyl azodicarboxylate, was also
employed in this reaction, providing a higher yield (60%) but a
similar decrease in enantioselectivity (89% ee, entry 6). Utilizing
a higher concentration (0.4 M) at 45 °C improved the
conversion (52% yield) after 60 h with unchanged enantio-
selectivity (entry 7). Finally, we found that running the reaction
under “neat” conditions (via removal of the small amount of
DCM after all the reagents were dissolved) gave almost full
conversion after 60 h, and the desired product was obtained in
97% yield with 99% ee (entry 8).17 Surprisingly, the
Recently, our group reported the asymmetric fluorination of α-
branched cyclic ketones enabled by a combination of chiral anion
phase-transfer catalysis and enamine catalysis,14 a rare example of
asymmetric functionalization of α-branched cyclic ketones to
construct chiral quaternary stereocenters.15 Continuing our
interest in the asymmetric functionalization of α-branched cyclic
ketones, here we report the direct asymmetric amination of α-
branched cyclic ketones with azodicarboxylates catalyzed by a
chiral phosphoric acid.16
Received: January 8, 2015
Published: February 26, 2015
© 2015 American Chemical Society
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Table 1. Investigation of Asymmetric Amination of 2-
Phenylcyclohexanone Catalyzed by Chiral Phosphoric Acids
Table 2. Substrate Scope of the Asymmetric Amination of 2-
Aryl Cyclic Ketones
a
phosphoric temp
conc
(M)
conv
a
ee
(%)
b
entry
R
acid
(°C)
solvent
(%)
1
2
3
tBu (S)-TRIP
tBu (R)-TCYP
45
45
45
xylenes
xylenes
xylenes
0.1
0.1
0.1
18 (18)
31 (31)
26 (25)
−88
96
tBu (R)-H8-
97
TCYP
4
5
6
7
tBu (R)-C8-
45
60
45
45
45
xylenes
xylenes
xylenes
xylenes
_
0.1
0.1
39 (38)
70 (57)
68 (60)
53 (52)
97
97
91
89
97
99
TCYP
tBu (R)-C8-
TCYP
Et
(R)-C8-
TCYP
0.1
tBu (R)-C8-
0.4
TCYP
c
8
tBu (R)-C8-
neat
a
Reactions were carried out with ketone (0.3 mmol), BocNNBoc
TCYP
(0.39 mmol), (R)-C8-TCYP (0.03 mmol), and 5 Å MS (50 mg) in
DCM (0.3 mL). After removal of the solvent, the mixture was heated
at 45 °C for 40−60 h. Yields are isolated yields after chromatography.
Absolute configurations assigned by analogy with 2v (determined by
X-ray crystallography) and (S)-ketimine.
a
Conversions calculated based on isolated yield of recovered starting
material. Number in parentheses is isolated yields after chromatog-
b
raphy. Determined by chiral HPLC analysis of isolated products.
c
Reagents were dissolved in DCM; after removal of the solvent, the
mixture was heated at 45 °C for 60 h. In the absence of 5 Å MS, 2a
was formed in 87% yield and 99% ee.
Table 3. Substrate Scope of the Asymmetric Amination of 2-
Substituted Cyclic Ketones
a
regioselectivity of this reaction was excellent; no 6-amination or
2,6-diamination products were isolated.
With the optimized conditions in hand, we explored the
substrate scope of the reaction (Table 2). A range of substituted
aryl groups18 were tolerated at the α-position of cyclohexanone,
including electron-neutral, electron-donating, and electron-
withdrawing arenes (2b−2h). Surprisingly, substrates with
ortho substitution (2i, 2j), which were previously reported to
be unsuitable for enantioselective construction of quaternary
centers due to steric hindrance,14,15c also worked well.
Additionally, the cyclopentanone analogue (2k) gave the desired
amination product in high yield and with excellent enantio-
selectivity. Substrates bearing heteroatoms at the 4-position of
the cyclohexanone ring (2l, 2m) were also amenable to
enantioselective amination, extending this methodology to
potentially useful heterocyclic compounds.
Cyclic ketone substrates containing alkenyl substitution at the
α-position were also explored (Table 3).19 The reaction
proceeded well with several types of substrates, including trans-
1,2 (2n), cis-1,2 (2p, 2q), cyclic alkenyl (2r), and simple vinyl
substitution (2o). Substitution at the 4-positon of the cyclo-
hexanone ring also gave high yield and excellent enantio-
selectivity for products 2s and 2t. A cyclopentanone analogue
yielded product 2v, whose absolute (S)-configuration was
determined by X-ray crystallography. Seven-membered analogue
a
Conditions as indicated in Table 2, except 5 mol% (R)-C8-TCYP was
b
used. ee was determined after conversion to the benzamide derivative
(see Supporting Information). 10% catalyst was used.
c
2u formed slowly under the conditions and was obtained with
lower enantioselectivity (72% ee). α-Phenylethynyl-substituted
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Communication
1w gave the product with lower yield (33% yield, 93% ee) due to
some decomposition of substrate under the standard conditions.
Surprisingly, 2-methylcyclohexanone (1x) also exclusively
yielded the more substituted addition product, albeit with a
slightly diminished enantioselectivity (86% ee). Increasing the
size of the alkyl substituent (1y) furnished the adduct with high
enantioselectivity (99% ee).
Initially, we envisioned a mechanism in which the phosphoric
acid only mediated the enantioselective amination of the enol
form of the ketone. Given that the chiral center of the starting
ketone is destroyed in the keto/enol tautomerization, it seemed
likely that this reaction was a simple dynamic kinetic asymmetric
transformation; however, careful monitoring of the reaction
showed that, in some cases, the reaction rate slowed when the
conversion reached >50%. Therefore, milder reaction conditions
(e.g., room temperature and lower concentration of 0.1 or 1 M)
resulted in a good to excellent kinetic resolution of the starting
ketones (Table 4).20 For example, using ketone 1z, the desired
phosphoric acid catalysts, provided the rate of the electrophilic
addition (amination) step is faster than that of the enolization
process.
Derivatization of the enantioenriched amination products was
also investigated (Scheme 1). Deprotection of Boc groups with
Scheme 1. Further Transformations of the α-Amino Ketone
Products and Facile Synthesis of (S)-Ketamine
Table 4. Substrate Scope of Kinetic Resolution and
Asymmetric Amination of α-Branched Cyclic Ketones
TFA, followed by cleavage of the hydrazine bond using Raney Ni
and H2, afforded the β-amino alcohol, which was then protected
to afford benzamide 3a in 64% yield, preserving the enantio-
purity, over three steps. To further demonstrate the utility of this
method, a short synthetic route to (S)-ketamine was developed.
Ketamine, which is on the World Health Organization’s List of
Essential Medicines, is a drug with multiple applications,
including for general anesthesia, as a pain killer, and for
treatment of bronchospasm and bipolar depression.1 Normally
pharmaceutical preparations of ketamine are racemic, although
reports indicate that (S)-ketamine is 4 times more active than its
(R) isomer.25 Recently, commercial preparations obtain (S)-
ketamine via resolution of the tartaric acid salt, leaving the
undesired (R) isomer as the byproduct. To our knowledge, only
one asymmetric synthesis of (S)-ketamine, requiring nine steps,
has been reported.26 After deprotection of the Boc of 2j, cleavage
of the hydrazine bond with Zn/HOAc furnished norketamine
(4j) in 74% yield; monomethylation under reductive amination
conditions provided the (S)-ketamine in 52% yield with >99% ee.
In summary, we have developed a chiral phosphoric acid-
catalyzed asymmetric amination of α-substituted cyclic ketones
which generates a N-containing quaternary stereocenter. The
reaction tolerates a range of aryl, alkenyl, alkynyl, and alkyl
substitutions at the α-position, different ring sizes, and
modifications of the cyclohexanone ring. Kinetic resolution of
the starting ketone was observed for some substrates under
milder conditions, providing enantioenriched α-branched
ketones. A short synthetic route to enantioenriched (S)-
ketamine was developed starting with amination product 2j,
demonstrating the power of this methodology. More encourag-
ingly, using similar conditions, a highly enantioselective Mannich
reaction of α-branched cyclic ketone was also achieved, creating
an all-carbon quaternary center, which would broaden the
application of this strategy.27
a
Reactions were carried out with ketone (0.3 mmol), BocNNBoc
(0.39 mmol), (R)-C8-TCYP (0.03 mmol), and 5 Å MS (50 mg) in
DCM (0.3 mL) for 60 h at rt. Conditions as indicated as above
except 5 mol% (R)-C8-TCYP and DCM (3 mL) were used for 40 h at
rt. Absolute configurations of recovered ketones was assigned by
comparison of optical rotation of hydrogenated 1n with the literature
(see Supporting Information).
b
c
product was obtained in 55% yield with 93% ee, and the ketone
was recovered in 45% yield with 96% ee after 60 h stirring at rt (s-
factor of 32).21 trans-Styrene-substituted substrates 1n and 1t
also gave good to excellent kinetic resolution, affording the
recovered ketones with 99% ee and 97% ee, respectively. This
method provides an entry to chiral α-heteroaryl- and alkenyl-
substituted cyclic ketones, which are very useful building blocks
in organic synthesis but difficult to prepare enantiomerically
enriched.22
On the basis of these observations, we propose that, in
addition to mediating the enantioselective amination, the
phosphoric acid also catalyzes the enantioselective activation
(enolization) of chiral ketones.23 While phosphoric acid
protonation of carbonyl groups is a well-established mode of
activation toward nucleophilic addition,24 enolization has rarely
been considered. These observations suggest that it is possible to
achieve the kinetic resolution of the ketone substrates with
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and compound characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
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Communication
(12) (a) Chang, L.; Kuang, Y.; Qin, B.; Zhou, X.; Liu, X.; Lin, L.; Feng,
X. Org. Lett. 2010, 12, 2214. (b) Drouet, F.; Lalli, C.; Liu, H.; Masson,
G.; Zhu, J. Org. Lett. 2011, 13, 94.
AUTHOR INFORMATION
■
Corresponding Author
(13) Takeda, T.; Terada, M. J. Am. Chem. Soc. 2013, 135, 15306.
(14) Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136,
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(16) For chiral phosphoric acid-catalyzed asymmetric aminations, see:
(a) Zhang, Z.; Antilla, J. C. Angew. Chem., Int. Ed. 2012, 51, 11778.
(b) Wang, S.-G.; Yin, Q.; Zhuo, C.-X; You, S.-L. Angew. Chem., Int. Ed.
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(d) Felker, I.; Pupo, G.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2015, 54,
1960.
(17) A larger scale (2.0 mmol) asymmetric amination of 1a gave the
desired product in 96% yield and 99% ee, with recovery of 35% of the
catalyst (see Supporting Information).
(18) Several heteroarylketones were unstable to the reactions
conditions. For example, subjecting compound 1z to the standard
conditions led to partial decomposition of the starting material and
therefore low yield of the desired product. On the other hand, 1z showed
excellent kinetic resolution under milder conditions.
(19) Under the standard conditions, α-tetralone gave the amination
product in low yield and enantioselectivity (7% yield, 36% ee), and
acyclic ketones failed to give the desired product.
(20) For examples of kinetic resolution of α-substituted ketones, see:
(a) Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.; Feng, X. J. Am.
Chem. Soc. 2012, 134, 17023. (b) Reetz, M. T.; Wu, S. J. Am. Chem. Soc.
2009, 131, 15424. (c) Kim, H.; Kawasaki, H.; Nakajima, M.; Koga, K.
Tetrahedron Lett. 1989, 30, 6537.
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factor was calculated on the basis of the ee of the recovered starting
material.
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Z.; Lim, L. H.; Chen, Z.; Li, Y.; Zhou, F.; Su, H.; Zhou, J. Angew. Chem.,
Int. Ed. 2013, 52, 4906.
(23) The enantioselective enolization can be viewed as the microscopic
reverse of the catalytic enantioselective protonation: Cheon, C. H.;
Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246.
(24) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40,
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(25) Adams, H. A.; Werner, C. Anaesthesist 1997, 46, 1026.
(26) Yokoyama, R.; Matsumoto, S.; Nomura, S.; Higaki, T.; Yokoyama,
T.; Kiyooka, S. Tetrahedron 2009, 65, 5181.
*fdtoste@berkeley.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NIHGMS (R01 GM104534) for
financial support. X.Y. acknowledges SIOC, Zhejiang Medicine,
and Pharmaron for a fellowship. We thank William Wolf for
obtaining the X-ray crystallographic data for 2v using the College
of Chemistry CheXray (NIH Shared Instrumentation Grant S10-
RR027172).
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