A Method for the Catalytic Enantioselective Synthesis of Chiral α-Azido and α-Amino Ketones from Racemic α-Bromo Ketones, and Its Generalization to the Formation of Bonds to C, O, and S

Article abstract of DOI:10.1021/jacs.9b12315

A new and practical method has been developed for the transformation of racemic α-bromo ketones to chiral α-azido and α-amino ketones with high enantioselectivity using phase transfer, ion-pair mediated reactions with a recoverable chiral quaternary salt (10 mol %) as catalyst in fluorobenzene-water. The process has been generalized to a variety of other attachments including of C, O, S, and NHR.

Full text of DOI:10.1021/jacs.9b12315

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Communication
A Method for the Catalytic Enantioselective Synthesis of Chiral
-Azido and #-Amino Ketones from Racemic #-Bromo Ketones,
#
and Its Generalization to the Formation of Bonds to C, O, and S
Roberto da Silva Gomes, and Elias J. Corey
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12315 • Publication Date (Web): 10 Dec 2019
Downloaded from pubs.acs.org on December 10, 2019
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A Method for the Catalytic Enantioselective Synthesis of Chiral -
a
a a
Azido and -Amino Ketones from Racemic -Bromo Ketones, and
Its Generalization to the Formation of Bonds to C, O, and S
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Roberto da Silva Gomes and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Supporting Information Placeholder
ABSTRACT: A new and practical method has been developed for the transformation of racemic a-bromo ketones to chiral a-azido
and a-amino ketones with high enantioselectivity using phase transfer, ion-pair mediated reactions with a recoverable chiral quater-
nary salt (10 mol %) as catalyst in fluorobenzene-water. The process has been generalized to a variety of other attachments including
of C, O, S and NHR.
The serendipitous discovery that the long-used gen-
eral anesthetic ketamine (A) can also act at lower doses as a
rapid-onset antidepressant in a subset (20-30%) of patients, in-
cluding many who were unresponsive to mainline antidepres-
sants, has opened the possibility of significant advances in this
There has been considerable research activity recently
in the area of enantiocontrolled a-amination of ketone deriva-
8
-12
tives by the use of azodicarboxilic esters
and of nitroso-
1
3
arenes as electrophiles.
1-4
area of high medical need.
We describe herein a novel method for the enantiose-
lective synthesis of chiral a-amino ketones starting from the
corresponding racemic a-bromo ketones. The synthetic ra-
S-Ketamine was recently (2019) approved for the
treatment of depression and introduced commercially by John-
son and Johnson (in the form of an intranasal spray). However,
it is far from an ideal antidepressant because of dissociative and
addictive side effects.
14
tionale upon which our approach depended on the identification
of a highly preferred geometry for a contact ion-pair between
the designed cinchona alkaloid, chiral quaternary ion B and an
anionic reactant or transition state. That preferred arrangement
was apparent from X-ray crystallographic studies, for example
between B and p-nitrophenoxide ion which was determined to
O
CH3
NH
15
16
be C. The use of structure C as a model for ion-pair geometry
proved to be a reliable guide to the discovery of a wide variety
of useful applications of catalyst B to enantioselective synthesis
including synthesis of acyclic, cyclic and functionalized amino
Cl
A
1
7
18
acids, enantioselective epoxidation of a,b-enones, Michael
1
9-21
22
addition to a,b-enones
and nitroaldol reactions. We have
used these mechanistic insights to develop the enantioselective
ketone a-amination process set forth below. A key feature of
Figure 1. (±) Ketamine.
+
the structure B is that only one of the tetrahedral faces of N is
open to close approach of an anionic subunit.
More recently a rational explanation has been ad-
vanced for how ketamine, an N-methyl-D-aspartic acid receptor
(
NMDA-r) antagonist which blocks neurotransmission, can re-
H
store normal function of brain circuitry. Specifically, it has been
found that ketamine can block burst firing in the lateral
habenula, a region of the brain which triggers the kind of patho-
logical aversive signalling that has been associated with depres-
Br-
N
NO2
RO
H
N
H
-
+
H
5
O
sive illness. These developments have sparked our interest in
H
N
this area including the development of new enantioselective
routes to compounds related to ketamine that might exhibit
more selective and potent activity in blocking neuronal firing in
the lateral habenula. We have recently reported two useful new
methods for the enantioselective synthesis of chiral a-amino ke-
O
N
R = -CH -CH=CH
2
2
B
C
6
tones, one from olefins and the other from silyl enol ethers by
7
direct catalytic a-amination. We describe herein a totally dif-
Figure 2. Chiral quaternary ammonium salt (B) and its ion pair
with 4-nitrophenoxide (C).
ferent approach for the enantiocontrolled synthesis of a-amino
ketones using catalysis by a chiral quaternary ammonium salt.
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The application of chiral phase transfer catalysis to en-
antioselective synthesis has expanded enormously in the past
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1
1
1
1
1
1
1
1
1
1
2
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2
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2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cl
N3
2
3,24
N3
N3
N3
two decades, as is evident from recent reviews,
discussion of fine details.
as well as a
O
O
O
O
2
5
5
6
7
8
Our approach to chiral a-amino ketones, as exempli-
fied in Scheme 1 for the specific case of 2-bromo-2-phenylcy-
clohexanone 1, involves conversion to the corresponding oxime
8
0% yield
0% ee
79% yield
89% ee
90% yield
>99% ee
80% yield
90% ee
9
2
and treatment with the chiral quaternary ammonium salt B
O
O
O
N3
1
5
(derived from cinchonidine, 15 mol%), NaN
3
and tetramethyl-
N3
N3
o
guanidine (TMG) in H O-fluorobenzene at -10 C to give the
2
0
1
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5
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2
3
4
5
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8
9
0
chiral a-azido ketone 3 in good yield and with 97.5:2.5 enanti-
oselectivity. The absolute configuration of 3 was confirmed by
9
11
1
0
83% yield
91% ee
8
9% yield
90% ee
8
2% yield
91% ee
6a
comparison with the known compound. Hydrolysis of the in-
termediate azido oxime occurs in situ under the reaction condi-
tions.
Figure 3. Chiral a-azido ketones from (±) a-bromo ketones.
Scheme 1. Conversion of a (±) a-bromo ketone to a chiral a-
azido ketone.
The enantioselective conversion of racemic non-cy-
clic a-bromoketones to the corresponding chiral a-azido ke-
tones can also be accomplished efficiently as demonstrated by
2
7
the three examples shown in Figure 4.
+
-
Br
Triflic acid
2
NH
NaOAc
2
OH.HCl
Q Br (15%)
NaN /H O
3
2
Br
Br
O
EtOH, rt
NOH
O
O
O
TMG
2 2
CH Cl , rt
fluorobenzene
O
o
-
10
C
9
5% yield
1
87% yield
2
N
3
1
a
N3
O
N
3
Cl
H
12
13
14
Br-
P(Me)
3
H
2
N
N
3
8
0% yield
90% ee
79% yield
92% ee
80% yield
91% ee
H
O
N
+
O
CH Cl
2
2
+
-
0 C, rt
o
Q Br =
H
O
4
3
N
Figure 4. Chiral acyclic a-azido ketones from (±) a-bromo
9
0% yield
5% ee
85% yield
95% ee
ketones.
9
1
5-22
On the basis of our previous studies
we expected
Reduction of 3 as shown produces the corresponding
a-amino ketone 4 which can be isolated as the hydrochloride in
0% yield from 3 (using HCl gas in ether). We discovered by
that the azidation of racemic a-bromoketone 2 under phase-
transfer catalysis by the quaternary ammonium salt B would
produce the R-enantiomer of the aminoketone 4, as was in fact
the case. This highly enantioselective (97.5:2.5) process can be
understood as a Michael addition of the azide anion to the com-
plex between cation B and an a,b-unsaturated nitroso interme-
diate as depicted in Figure 5, in which the addition of the azide
anion occurs to the si (i.e. front) face of the complex D because
the rear face is obstructed by the proximate quinoline subunit.
Electrostatic attraction at the one accessible tetrahedral face of
the positively charged nitrogen center provides stabilization of
the transition state for the Michael addition of N
ation of the reaction. The geometry of Complex D is also fa-
voured by attractive van der Waals interactions between the
quinoline ring and phenyl subunit of the vinyl nitroso interme-
diate.
9
experimentation that the use of fluorobenzene as the organic
phase results in considerably better enantioselectivity than ob-
served with benzene or toluene. Equally good results were ob-
tained using the conditions outlined in Scheme 1 with several
other cyclic a-bromoketones, specifically 5-11, as summarized
ꢂꢃ
in Figure 3. The absolute configuration of 7 [ꢀ]ꢁ = +70.1 was
6
a
confirmed as R by comparison with an authentic sample. The
absolute configuration of the other a-azido ketones in Figure 3
are based in analogy with 3 and 7 as well as the rational mech-
anistic model (see below). It is important to note that the cata-
lytic chiral quaternary ammonium salt can readily be recovered
–
3
, and acceler-
2
6
for reuse.
N
RO
H
δ-
H
N
-
N
3
O
N
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Figure 5. Preferred ion pair between B and a nitroso-ene sub-
strate. R = CH -CH=CH
These results are summarized in Scheme 3 for the
bromo oxime 2 as substrate with 15 mol% of quaternary ammo-
nium salt B as catalyst in fluorobenzene/H O at -20 C or 0 C
2
1
2
3
4
5
6
7
8
9
2
.
2
o
o
as noted and with the reagents indicated.
We have also demonstrated that the chiral a-azido ke-
tones produced by the above-described method can be trans-
formed into various N-protected a-amino ketones. For example,
the a-azido ketones 5 and 8 were converted to the N-t-
butoxycarbonyl amides 15 and 16 (Figure 6) via the correspond-
ing amine hydrochlorides by the reaction with BOC anhydride
Scheme 3. Enantioselective replacement of bromine of the (±)-
a-bromo ketone 2 by a variety of other groups; products and
reagents.
o
and potassium carbonate in toluene at 80 C for 12 h in 80-85%
yield.
NO
O
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
E
O
O
2
0
21
22
NHBoc
NHBoc
O
80% yield
1% ee
InBr
62% yield
85% ee
(GeranylInBr
73% yield
O
8
28
87% ee
o
, 0 oC)28
3 2
(CH NO
, TMG, -20 oC)
2
, 0
C
2
1
5
16
O
O
Figure 6. Some N-protected chiral a-amino ketones.
CN
O
OOtBu
O
O
O
The results described above may be extended in many
other useful directions, most obviously involving various other
nucleophilic partners. One example of the numerous possibili-
ties is shown in Scheme 2. The nucleophile in this process,
which is outlined in Scheme 2, 4-nitrophenoxide ion, converts
the (±) a-bromo oxime 17 to the S-4-nitrophenoxy ether 18 with
better than 9:1 enantioselectivity. Reaction of 18 with t-butyla-
2
3
24
25
6
9% yield
68% yield
80% ee
69% yield
7
9% ee
89% ee
(NaCN, TMG, -20 oC)
, TMG, -20 oC)
(tBuOOH, TMG, -20 oC)
(CH
3
COCH
2
COOCH
3
OCOPh
O
SCOPh
O
2
NHCH Ph
o
mine occurs very rapidly even at -40 C to form the important
O
antidepressant R-bupropion 19 which was isolated as the crys-
talline hydrochloride in >99% ee. Bupropion, sold as the race-
mate and one of the fifty most prescribed medicines in the
United States, can now be produced efficiently as either enanti-
omer by the process summarized in Scheme 2. The enantiose-
lective synthesis of R-19 is also stereochemically consistent
with the mechanistic model exemplified in Figure 5.
26
27
28
77% yield
80% ee
(PhCOONa, TMG, -20 oC)
80% yield
1% ee
(PhCOSNa, TMG, -20
73% yield
86% ee
(PhCH NH , TMG, -20 C)
8
o
o
C)
2
2
Detailed experimental procedures for these enantiose-
lective reactions leading to products 20 to 28 can be found in
the Supporting Information. The synthesis of 22 is exemplified
in Scheme 4.
Scheme 2. Enantioselective route to R-bupropion.
+
-
NOH
Br
Q Br (0.15 eq)
O
O
t-BuNH
-40 C, 4 h
2
, CH
2
Cl ,
2
4
-nitrophenol (2.0 eq)
o
Scheme 4. Enantioselective synthesis exemplified with the
nitro compound 22.
CH
3
CH
3
CH
H
3
TMG (1.1 eq)
H
O
HCl/Et
2
O
HN
fluorobenzene
4
h
Cl
o
Cl
Cl
- 10 C
1
7
19
1
8
NO
2
+
-
8
0% yield
81% yield
>99% ee
Q Br (15%)
2
CH NO /H O
H C NO2
2
81% ee
Br
3
2
NOH
O
TMG
fluorobenzene
o
- 10
3 h
C
t-Bu
2
22
HO NH
t-Bu
CH
3
73% yield
HO
N
H
87% ee
H
O
CH
3
Cl
We emphasize several advantages of the methodology
described herein: (1) easy recoverability of the catalyst; (2) ease
of experimental execution; (3) freedom from expensive transi-
tion metals or complex ligands; (4) mechanistically predictable
pathway and (5) versatility. Widespread application of this ap-
proach can be expected in areas such as multi-step synthesis of
complex molecules and the synthesis of medicinal candidates.
Cl
NO
2
We believe that there are a very large number of other
applications of the new enantioselective approach described
herein to the synthesis of chiral a-substituted ketones. The con-
version of 17 to 19 represents just one example of extension
to other nucleophiles, in this case oxygen. In fact, the
strategy outlined above can also be applied to carbon, oxygen,
sulfur and even neutral nucleophiles.
-
from N
3
The enantioselective reactions described above fall
into a class of phase-transfer catalysed process that can be
thought of as charge-accelerated reactions of neutral substrates
with nucleophiles catalysed by chiral quaternary ammonium
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Page 4 of 5
salts having only one accessible tetrahedral face; for early ex-
amples see ref. 18-20. This type of (Class II) enantioselective
phase-transfer reaction can be distinguished mechanistically
from the earlier-discovered processes which can be described
as tight-ion pair formation between a chiral quaternary ammo-
nium salt and an enolate-type substrate followed by attack of an
uncharged electrophile at the most exposed face of the enolate
complex (Class I type reactions). We expect that for Class II
type processes fluorobenzene will prove to be superior to ben-
zene or toluene because of its lower affinity for the catalytic
quaternary ammonium cation.
(2) Elia, N.; Tramer, M. R. Ketamine and postoperative pain - a
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1
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1
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2
2
2
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2
2
2
2
2
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
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7
(
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A. M.; Gönczi, R. T.; Schlingloff, D.; Török, B.; Sipos, E.; Major, A.;
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0
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0
1
2
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4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
The strategy of using racemic a-bromo ketones via
their oximes as precursors of reactive a,b-unsaturated nitroso
intermediates has remained a neglected area of considerable po-
tential, especially for enantiocontrol. It allows easy access to
many otherwise not easily available chiral compounds. In con-
trast to existing methodology involving substitution alpha to
carbonyl using electrophilic reagents, the new approach in-
volves nucleophilic species.
(
7) Han, Y.; Corey, E. J. Method for the direct enantioselective syn-
ASSOCIATED CONTENT
thesis of chiral primary α-amino ketones by catalytic α-amination. Org.
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(
8) (a) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevid, A.;
Jørgensen, K. A. Direct l-proline-catalyzed asymmetric α-amination
of ketones. J. Am. Chem. Soc. 2002, 124, 6254-6255. (b) Takeda, T.;
Terada, M. Development of a chiral bis(guanidino)iminophosphorane
as an uncharged organosuperbase for the enantioselective amination of
ketones. J. Am. Chem. Soc. 2013, 135, 15306-15309.
(9) Trost, B. M.; Tracy, J. S.; Saget, T. Direct catalytic enantioselec-
tive amination of ketones for the formation of tri- and tetrasubstituted
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Supporting Information
Experimental procedures and characterization data for novel reac-
1
13
tions and products including copies of H- and C-NMR spectra
and chiral HPLC traces. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: corey@chemistry.harvard.edu
(
12) Takeda, T.; Terada, M. Development of a chiral bis(guani-
ORCID
dino)iminophosphorane as an uncharged organosuperbase for the en-
antioselective amination of ketones. J. Am. Chem. Soc. 2013, 135,
15306−15309.
Roberto da Silva Gomes: 0000-0002-8075-9716
E. J. Corey: 0000-0002-1196-7896
(
13) Maji, B.; Yamamoto, H. Use of in situ generated nitrosocar-
bonyl compounds in catalytic asymmetric α-hydroxylation and α-
amination reactions Bull. Chem. Soc. Jpn. 2015, 88, 753-762.
(
14) The a-bromoketones used in this work were generally made by
reaction of the parent ketone at room temperature in CH Cl containing
a catalytic amount of triflic acid (to initiate the reaction via enolization)
with 1 equiv. of Br
15) Corey, E. J.; Xu, F.; Noe, M. C. A rational approach to catalytic
Notes
2
2
The authors declare no competing financial interests.
2
.
(
enantioselective enolate alkylation using a structurally rigidified and
defined chiral quaternary ammonium salt under phase transfer condi-
tions. J. Am. Chem. Soc. 1997, 50, 12414-12415.
ACKNOWLEDGMENT
(
16) Only one of the tetrahedral faces of the positive nitrogen in B
We are very grateful to Pfizer Inc. and Bristol-Myers Squibb for
research grants.
can be approached closely by the anionic oxygen of p-nitrophenoxide
since the other three faces are obstructed by the bunchy subunits in the
structure, including both the cinchona and a-anthracenylmethyl
groups. As a result, the favorable arrangement for tight ion pairing in
charge-accelerated phase-transfer reaction involves approach to that
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(
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For Table of Contents Only
Graphical Abstract:
O
O
CH3
Chiral
Br
H
NH t-Bu
2
Catalyst
Cl
R-bupropion hydrochloride
99% ee
Cl
>
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