Regio- and Enantioselective Synthesis of Trifluoromethyl-Substituted Homoallylic α-Tertiary NH2-Amines by Reactions Facilitated by a Threonine-Based Boron-Containing Catalyst

Article abstract of DOI:10.1002/anie.202001184

A method for catalytic regio- and enantioselective synthesis of trifluoromethyl-substituted and aryl-, heteroaryl-, alkenyl-, and alkynyl-substituted homoallylic α-tertiary NH₂-amines is introduced. Easy-to-synthesize and robust N-silyl ketimin

Full text of DOI:10.1002/anie.202001184

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Angewandte
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International Edition
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Accepted Article
Title: Regio- and Enantioselective Synthesis of Trifluoromethyl-
Substituted Homoallylic a -Tertiary NH2-Amines by Reactions
Facilitated by a Threonine-Based Boron-Containing Catalyst
Authors: Amir H. Hoveyda, Diana C. Fager, and Ryan J. Morrison
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001184
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http://dx.doi.org/10.1002/ange.202001184

10.1002/anie.202001184
Angewandte Chemie International Edition
Regio- and Enantioselective Synthesis of Trifluoromethyl-Substituted Homoallylic
a
-Tertiary NH2-Amines by Reactions Facilitated by a Threonine-Based Boron-
Containing Catalyst
Diana C. Fager,+ Ryan J. Morrison,+ and Amir H. Hoveyda*
Prof. A. H. Hoveyda, D. C. Fager, R. J. Morrison
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
Prof. A. H. Hoveyda
Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, 67000 Strasbourg (France)
E-mail: ahoveyda@unistra.fr
[+] These authors contributed equally to this work.
Dedicated to Professor Jean-Marie Lehn
Abstract: A method for catalytic regio- and enantioselective synthesis of trifluoromethyl-substituted and
aryl-, heteroaryl-, alkenyl-, and alkynyl-substituted homoallylic a-tertiary NH2-amines is introduced. Easy-
to-synthesize and robust N-silyl ketimines are converted to NH-ketimines in situ, which then react with a
Z-allyl boronate. Transformations are promoted by a readily accessible L-threonine-derived aminophenol-
based boryl catalyst, affording the desired products in up to 91% yield, >98:2 a:g selectivity, >98:2 Z:E
selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl
boronates, which may contain an alkyl-, a chloro-, or a bromo-substituted Z-alkene, can either be
purchased or prepared by catalytic stereoretentive cross-metathesis. What is more, Z-trisubstituted allyl
boronates may be used. Various chemo-, regio-, and diastereoselective transformations of the a-tertiary
homoallylic NH2-amine products highlight the utility of the approach; this includes diastereo- and
regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.
Introduction
Catalytic enantioselective transformations that furnish a-tertiary amines,[1,2] fragments
found in many bioactive molecules (Scheme 1a), are small in number, rendering their
development a compelling research objective. Strategies for preparation of a-tertiary
homoallylic NH2-amines with a trifluoromethyl and an aryl substituent are especially desirable,
as the resulting products can be converted to a variety of organofluorine compounds that cannot
be easily prepared otherwise in high diastereo- and enantioselectivity. Among the available
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10.1002/anie.202001184
Angewandte Chemie International Edition
Fager & Morrison, et al.; Page 2
approaches, there are reactions of an enantiomerically pure N-tert-butylsulfinyl ketimine with an
allylzinc or a costly allyl–In compound (Scheme 1b).[ 3 , 4 ] Two other strategies are catalytic
enantioselective processes involving in situ generated allyl species and N-benzyl substrates
(Scheme 1c).[5,6] Products either bear an alkene with an internal carboxylic ester unit[5] or an
a. Representative bioactive compounds bearing a F3C- and aryl-substituted !-tertiary amine moiety:
Br
Me
N
HN
F
O
OMe
O
O
O
CF3
CF3
N
N
H
N
H
CF3
NH2
O
BACE-1 inhibitor
(anti-Alzheimer)
Lead competitive inhibitor
of MGAT2
b. Previous work involving enantiomerically pure ketimines:
2013 & 2017 (Lin & Grellepois, et al.; Ref. 3):
tBu
O
S
O
S
O
with Zn:
67% yield, 96:4 d.r.
with In:
2.5 equiv. Zn (0),
S
or 3.0 equiv. In (0)
CF3
HN
tBu
N
tBu
HN
Ph
or
Br
Ph
CF3
OEt
Ph
CF3
63% yield, 96:4 d.r.
dmf, –20 °C,
or thf, reflux
c. Previous work involving enantioselective catalysis:
2016 (Zhang, et al.; Ref. 5a):
1. 10 mol %
NCH2Ar
phosphine catalyst
CF3
H2N
Ph
CO2tBu
Ph
CF3
BocO
CO2tBu
2. 1 M HCl/thf, room temp.
Ar =
4-NO2C6H4
78% overall yield,
99:1 e.r.
2019 (Wang and Zhang/Niu et al.; Ref. 6):
1. 3.0–5.0 mol %
Ir-based complex;
CF3
H2N
Ar
R
BocO
R
N
acid workup
R = mostly aryl
or heteroaryl
up to 90% yield,
and >99:1 e.r.
Ar
CF3
d. This work:
Direct access to NH2-amines
CF3
CF3
H2N
Ar
H2N
Ar
readily accessible
catalyst;
NSiMe3
CF3
!
!
in situ deprotection
alkyl
Cl/Br/OR
Ar
G2
Me
CF3
H2N
Ar
readily accessible (g scale),
stable & easy to use,
NH-ketimine
(pin)B
!
!
G1
alkyl
readily generated in situ
accessible by catalytic
cross-metathesis
Efficiency? ! Selectivity?
Z:E? Enantioselectivity?
Scheme 1. Bioactive compounds that contain a F3C- and aryl-substituted a-tertiary amine moiety and methods that may be used
to prepare them. Abbreviations = BACE-1: b-secretase-1; MGAT: monoacylglycerol acyltransferase.
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10.1002/anie.202001184
Angewandte Chemie International Edition
Fager & Morrison, et al.; Page 3
(E)-b-substituent.[6,7] These are significant advances no doubt, but the following issues remain
unaddressed: 1) Direct formation of unprotected a-tertiary homoallylic amines would obviate
the need for subsequent release of the NH2-amine by acid treatment, which can be detrimental
to the structural integrity of a sensitive benzylic C–N bond.[8] 2) Availability of catalysts that can
be readily modified/optimized and do not require a costly and/or precious metal. 3) Regio- and
diastereoselective product modification, a characteristic more easily accommodated with Z-
homoallylic amine (vs. an E- or a monosubstituted olefin).[9]
A problem with directly accessing NH2-amines is that F3C-substituted NH-ketimines are
unstable (moisture-sensitive).[10] We surmised that one might utilize N-protected ketimines that
are readily available, robust, and can be converted to NH-ketimines in situ. We thus chose to
investigate N-trimethylsilyl ketimines, stable entities accessible in multigram quantities by
[ 11 ]
reactions between ketones and lithium bis(trimethylsilyl)amide (1.5 h, 50–95% yield)
in
sufficiently high purity for N-trimethylsilyl ketimines to be directly usable (no purification).
Whether in situ NH-ketimine formation would occur readily or the minimally electrophilic NH-
ketimines would react efficiently and enantioselectively, we did not know. As catalysts, we opted
for aminophenol-based boryl systems, easily to prepare and modifiable entities that at the time
had been used for enantioselective additions to aldimines,[12] ketones, [13] and aldehydes,[14] but
not the far less reactive NH-ketimines.
Results and Discussion
We began by probing the possibility of synthesizing 2a (Scheme 2a) by reaction of silyl
ketimine 1a and allyl–B(pin) (pin = pinacolato) with 5.0 mol % ap-1a under the standard
conditions (e.g., 5.0 mol % Zn(OMe)2, 1.5–2.5 equiv. alcohol, tol., 0–22 °C), but none of 2a was
formed (<2%). We then examined the influence of different fluorides for in situ NH-ketimine
generation,[15] establishing that with 5.0 mol % tetra-n-butylammonium difluorotriphenylsilicate
(tbat, (nBu)4N(Ph3SiF2)), 2a can be generated in 94% yield and 91:9 enantiomeric ratio (e.r.). This
was despite the fact there was 35% conversion to rac-2a without an aminophenol. By monitoring
the transformation spectroscopically (19F NMR; see data in Scheme 2a), we found that the NH-
ketimine (1a’) is formed rapidly, indicating that silyl removal occurs in the course of the reaction
(i.e., the addition does not directly involve silyl-ketimine 2a). Investigation of other aminophenol
ligands and/or silyl ketimines, did not result in any significant improvement in e.r.[15]
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 4
We found it intriguing that the e.r. values in Scheme 2a are lower than those for allyl
additions to F3C-substituted ketones (92.5:7.5–96:4 e.r.).[13b, 16] For a ketone (I, Scheme 2b),
electrostatic attraction involving the ammonium unit diminishes electron–electron repulsion
between the carbonyl oxygen and a C–F bond.[13a] With a ketimine, on the other hand, reaction
via II or III can lead to the major enantiomer, but in the former (II), electrostatic attraction (see I
a. Initial observations:
iPr
5.0 mol %
SiMe3
CF3
N
N
N
H
OH
Ph
O
H
1a
19F NMR:
ap-1a
tBu
N
CF3
H2N
Ph
–69.1 ppm
Ph
CF3
5.0 mol % Zn(OMe)2, 5.0 mol % tbat,
2.5 equiv. iPrOH,
1a’
2a
(pin)B
(1.5 equiv.)
19F NMR:
94% yield,
91:9 e.r.
tol. (0.5 M), 4 °C, 14 h
–69.6, –68.3 ppm
Key points:
1. <2% conv. without tbat.
2. Significant addition without aminophenol (e.g., 35% conv. to rac-2a without ap-1a).
CF3
CF3
CF3
CF3
H2N
H2N
H2N
H2N
OMe
F
F
F3C
2b
2c
2d
2e
67% yield,
68% yield,
91:9 e.r.
67% yield,
86:14 e.r.
32% yield,
89:11 e.r.
91.5:8.5 e.r.
b. Additions to NH-ketimines present new challenges (other than lower reactivity):
tBu
–
L3B–OMe
O
B
Ketones: Electrostatic attraction
more dominant
H
+
F
N
O
R2N
F
H
F
I
O
steric
strain
tBu
tBu
tBu
–
–
–
L3B–OMe
L3B–OMe
L3B–OMe
O
O
O
B
H
CF3
H
H
H
+
+
+
B
B
N
F
N
N
N
N
H
N
H
R2N
R2N
R2N
F
H
H
H
F
F
F
O
O
O
F
major enantiomer
II
III
IV minor enantiomer
NH-Ketimines: Electrostatic attraction less dominant
iPr
iPr
N
N
N
H
OH
N
H
OH
2a
2a
O
O
89% yield,
72:28 e.r.
57% yield,
ap-1b
ap-1c
SiPh3
CF3
52:48 e.r.
Scheme 2. Initial studies involving allyl–B(pin) and new challenges regarding reaction with NH-ketimines. See the Supporting
Information for details. Abbreviation: tbat = (nBu)4N(Ph3SiF2).
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 5
and III) is not feasible because of the NH proton; steric factors in II thus become central and
transformation via IV more competitive. In line with this scenario, when Ph3Si-substituted ap-1b
(Scheme 2b) was used, 2a was formed in 72:28 e.r. (89% yield).
a. Addition with a catalyst bearing a single stereogenic center:
NSiMe3
Ph
CF3
CF3
!
5.0 mol % ap-1a
H2N
Ph
1a
(pin)B
10 mol % Zn(OMe)2, 5.0 mol % tbat,
3.5 equiv. MeOH,
Me
4a
Me
(Z)-3
82:18 !:",
tol. (0.2 M), 22 °C, 3 h
(1.3 equiv.; >98:2 Z:E,
73% yield (pure !),
98:2 Z:E, 96:4 e.r.
12% conv. (>98:2 ":!) without ap-1a
(comm. avail.)
tBu
tBu
net
–
L3B–OMe
–
L3B–OMe
Zn(OMe)2
!-addn
O
O
B
H
H
H
+
+
H
B
N
N
H
N
Ph
R2N
Me
R2N
!
Me
H
F
F
O
O
F
V
VI
electrostatic attraction
"-addn
(cf. III)
product
tBu
tBu
–
L3B–OMe
–
L3B–OMe
O
B
O
B
Ph
F
H
+
H
+
N
N
N
H
R2N
R2N
O
F
"
Me
H
H
F
O
Me
VIII
VII
b. Addition with threonine-derived and related catalysts:
Me
OMe
N
MeO
Me
Me
Et
N
N
N
H
OH
N
H
OH
N
H
OH
O
O
O
tBu
tBu
tBu
ap-2a
ap-2b
ap-3
81:19 !:",
97:3 !:",
91:9 !:",
80% yield (pure !),
74% yield (pure !),
98:2 Z:E, 89:11 e.r.
62% yield (pure !),
98:2 Z:E, 97.5:2.5 e.r.
>98:2 Z:E, 94.5:5.5 e.r.
tBu
tBu
–
steric strain
L3B–OMe
–
(syn-pentane)
L3B–OMe
#*C–O←#C–N
O
B
O
Me
+
H
+
H
H
B
MeO
MeO
N
N
Me
H
R2N
R2N
Me
Me
H
H
O
O
X
IX
Scheme 3. Catalytic reactions with Z-crotyl–B(pin) are highly a- and enantioselective as a result of several favorable steric and
electronic factors originating from O-methyl threonine-derived catalyst. See the Supporting Information for details.
The above findings insinuated that it might be possible to exploit steric factors to improve
e.r. We recently showed that additions of Z-disubstituted allyl boronates to ketones or aldehydes
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 6
are more enantioselective probably because the substituent at the stereogenic carbon center of
the chiral allyl boronate (e.g., Me unit in VI, Scheme 3a) prefers to be oriented pseudo-axially,
away from the catalyst framework.[13d,14] Accordingly, we investigated the reaction with Z-crotyl–
B(pin) ((Z)-3). Control experiments indicated that the non-catalytic pathway, while completely g-
selective, is inefficient (12% conv.; Scheme 3a), and, indeed, with 5.0 mol % ap-1a there was
>98% conversion to 4a, which was formed in 96:4 e.r. (vs. 91:9 e.r. for 2a). Consistent with the
proposed model, and similar to previous cases,[13c] reaction with (E)-3 was inefficient (<10% conv.
under otherwise identical conditions). Nevertheless, a:g selectivity was moderate (82:18; 73%
yield of the a isomer), implying that conversion of V to lower energy VII by borotropic shift and
addition via VIII (Scheme 3a) to generate the g isomer competes with reaction via VI to give 4a.
We reasoned that one way to improve the a:g selectivity might be to enhance the Lewis
acidity of a chiral catalyst’s B center. Our hope was that by enhancing ketimine activation, C–C
bond formation could be accelerated to a greater extent than the alternative borotropic shift
(V®VII). Somewhat surprisingly, however, a smaller (expected to lower steric repulsion in II) and
electron-withdrawing CF3 unit in ap-1c (Scheme 2b)[13e] adversely impacted the e.r. We therefore
chose to investigate a threonine-based catalyst based on the logic that the C–O bond neighboring
the C–N bond might increase Lewis acidity of the boron center and the ammonium unit to
enhance electrostatic attraction (III, Scheme 2b) and facilitate catalyst-ketimine association (pre-
empting borotropic shift).
With O-methyl-L-threonine derived ap-2a (Scheme 3b), 4a was generated in 97:3 a:g
selectivity (vs. 82:18, ap-1a) without any diminution in Z:E ratio or e.r. Equally important, with
diastereomeric ap-2b, derived from O-methyl-D-threonine, 4a was formed in lower a- and
enantioselectivity (91:9 and 89:11, respectively). A rationale for the improvement in a selectivity
in the reaction with ap-2a is that, as depicted in IX, proper alignment of the C–OMe and C–N
bonds allows for effective sC–N®s*C–O hyperconjugation, leads to diminished electron density at
nitrogen. This is consistent with the reduced a:g selectivity when ap-2b was used, as the requisite
conformation would exacerbate steric pressure (X). The much lower a selectivity with ap-3
(Scheme 3b) underscores the positive impact of the additional C–O bond.
Various aryl- and F3C-substituted silyl ketimines may be converted to a-tertiary
homoallylic NH2-amines (4b-m, Table 1). In only four instances the pure a-addition isomer was
not obtained (entries 1–2, 4, and 11). Reactions of hindered o-Cl and o-tolyl ketimines afforded
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 7
4c and 4e in 79% and 52% yield, respectively (entries 2 and 4). In such instances or with strongly
electron-rich aryl ketimines (e.g., 1m), to maximize efficiency, in situ silyl removal was performed
prior to charging the mixture with ap-2a and (Z)-3.[15] With ketimines that are less reactive due
to steric (e.g., entries 2–4) or electronic factors (e.g., entries 4 and 12), borotropic shift became
more competitive and a:g selectivity suffered.
Heterocyclic a-tertiary amines were prepared in high Z:E ratios and enantioselectivities,
as indicated by 4n-p (Scheme 4). However, these processes presented additional challenges. Low
stability of the silyl ketimine (hydrolysis to ketone) was one problem, and thus 4n, bearing a more
electron donating 2-furyl substituent, was isolated in 32% yield (vs. benzofuryl- and 2-thienyl-
substituted 4o-p in 77% and 84% yield, respectively). We could not obtain an indole-substituted
silyl ketimine in sufficiently high purity, and attempts to promote addition to the 2- or 3-pyridyl
variants were thwarted due solubility issues and/or rapid formation of the derived hemiaminal
(reaction with MeOH). Efforts to carry out reactions with alkyl-substituted substrates led to the
formation of hydrolyzed products (ketones), enamines, or hemiaminals (<5% desired product).
Table 1: Catalytic enantioselective additions to aryl-substituted ketimines.[a]
CF3
!
NSiMe3
H2N
Ar
5.0 mol % ap-2a
(pin)B
Ar
CF3
Me
10 mol % Zn(OMe)2, 5.0 mol % tbat,
3.5 equiv. MeOH,
Me
(Z)-3
1
4
(comm. avail.,
1.3 equiv.)
tol. (0.2 M), 22 °C, 3 h
e.r.[d]
[b]
Entry
Ar
Conv. [%][a]
!:"
Yield (pure
[%][c]
!
)
Z:E[b]
89[f]
79[f]
70
1
oFC6H4; b[d]
oClC6H4; c[e]
oMeOC6H4; d
oMeC6H4; e[e]
mClC6H4; f
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
96
96:4
74:26
96:4
45:55
>98:2
98:2
93:7
95:5
96:4
98:2
94:6
87:13
98:2
98:2
98:2
98:2
97:3
98:2
98:2
95:5
97:3
96:4
98:2
98:2
98.5:1.5
96.5:3.5
>99:1
2
3
52[f]
90
4
95.5:4.5
96.5:3.5
98:2
5
82
6
mF3CC6H4; g
pFC6H4; h
68
7
97:3
87
8
pClC6H4; i
96:4
67
9
pBrC6H4; j
98:2
61
10
11
12
pF3CC6H4; k
pMeOC6H4; l
pMe2NC6H4; m[e,g]
97.5:2.5
98:2
78[f]
50
98
96.5:3.5
[a] All reactions performed under N2 atm. [b] Conv., d.r., and a:g ratios determined by analysis of 19F NMR spectra of unpurified mixtures; conv. (±2%)
refers to disappearance of the silyl ketimine starting material. [c] Yield of isolated and purified material (±5%). [d] Enantioselectivity determined by HPLC
analysis (±1%); the derived acetate was used in entry 1. [e] NH-Ketimine generated first. [f] Yield is for mixture of a- and g-addition products. [g] Reaction
time = 8 h. See the Supporting Information for details.
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Fager & Morrison, et al.; Page 8
Allylic and propargylic a-tertiary amines 5 and 6 were isolated in 64% and 81% yield (a+g
isomers), respectively, and in high Z selectivity and e.r. The lower a:g ratio (80:20) for 6 probably
arises from increased stability of the hemiaminal derivative (~20% detected[15]), owing to a more
diminutive alkynyl group, which lowers the barrier to borotropic shift (see Scheme 3a).
CF3
CF3
CF3
H2N
H2N
H2N
O
Me
O
Me
S
Me
4n
4o
4p
89:11 !:",
87:13 !:",
98:2 !:",
32% yield (!+"),
98:2 Z:E, 97:3 e.r.
77% yield (!+"),
84% yield (!+"),
97:3 Z:E, 93:7 e.r.
>98:2 Z:E, 97.5:2.5 e.r.
CF3
CF3
H2N
H2N
Ph
Me
Me
Ph
Me
5
6
91:9 !:",
64% yield (!+"),
96:4 Z:E, 98.5:1.5 e.r.
80:20 !:",
81% yield (!+"),
96:4 Z:E, 96.5:3.5 e.r.
Scheme 4. Heterocyclic, alkenyl-, and alkynyl-substituted ketimines may be used. Same conditions as in Table 1 were used, except
for 4o the NH-ketimine was generated first in situ. Yield of isolated and purified material (±5%); enantioselectivity determined by
HPLC analysis (±1%). See the Supporting Information for further details.
Other Z-allyl boronates, accessible by catalytic cross-metathesis,[ 17 ] may be used,
providing access to products with different alkenyl moieties (Scheme 5). We prepared a-tertiary
CF3
CF3
H2N
H2N
nHept
Cl
7
8
98:2 !:"
,
97:3 !:"
,
86% yield (pure
!
),
91% yield (pure ),
!
98:2 Z:E, 97:3 e.r.
>98:2 Z:E, 88:12 e.r.
CF3
H2N
CF3
H2N
Br
Br
Cl
F3C
9a
9b
84:16 !:"
,
93:7 !:"
,
74% yield (pure ),
!
76% yield (pure ),
!
>98:2 Z:E, 89.5:10.5 e.r.
>98:2 Z:E, 93:7 e.r.
Me
CF3
H2N
nBu
10
98:2 !:"
88% yield (pure
,
!
),
98:2 Z:E, 88.5:11.5 e.r.
Scheme 5. The enantioselective approach is applicable to different allyl boronates, accessible by stereoretentive catalytic cross-
metathesis. Same conditions as in Table 1 used, except that 14 h was needed for 8a-b and 10. For 8a-b and 9a-b, the silyl group
was removed first. Yield of isolated and purified material (±5%); enantioselectivity determined by HPLC analysis (±1%). See the
Supporting Information for further details. Abbreviation = MEM: methoxyethoxymethyl.
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 9
amines bearing an n-heptyl (7), a chloro (8), or a bromo (9a-b) substituent. Yields (56-91% for
pure a isomers), regioselectivities (84:16–98:2 a:g), and Z:E selectivities (³98%) were generally
high; enantioselectivity ranged from 88.5:11.5 to 97:3 e.r. Trisubstituted olefin 10 was obtained
in 88% yield (pure a), >98:2 Z:E selectivity, and 88.5:11.5 e.r.
Another feature of the new strategy is that aminophenols can be easily prepared in
multigram quantities from inexpensive starting materials,[18] and are commercially available. By
using O-benzyl-L-threonine derived ap-4, which recently became commercially available, we
were able to prepare 4a in 69% yield (pure a), [97:3 Z:E and 92:8 e.r. vs. 80% yield (pure a,
Scheme 6a), 98:2 Z:E, 97:3 e.r. with ap-2a]. The feasibility of synthesizing a-tertiary NH2-amines
with a halogen-substituted Z-alkene means that additional derivatives can be conveniently
prepared by cross-coupling reactions, stereoretentive catalytic processes that do not require
amine protection. A representative case is the two-step transformation of ketimine 1j to 11 in
71% overall yield, >98:2 Z:E selectivity, and 92.5:7.5 e.r. (Scheme 6b). Another example is a cross-
a. Reaction with a commercially available aminophenol:
c. Diastereoselective directed epoxidation/regioselective cleavage and net dihydroxyl addition:
Me
OBn
NMe2
5.0 mol %
4.0 equiv. CCl3CO2H,
10 equiv.
K2CO3
NSiMe3
OH
CF3
CF3
H2N
Ph
H2N
Ph
1.5 equiv. m-cpba
OCOCCl3
N
H
OH
Ph
CF3
O
1a
ap-4
(comm. avail.)
MeOH,
CH2Cl2, 22 °C, 18 h
Me
Me
14
(>98:2 r.r.)
CF3
H2N
Ph
4a
22 °C, 6 h
t-Bu
(pin)B
Me
10 mol % Zn(OMe)2, 5.0 mol % tbat,
3.5 equiv. MeOH,
Me
4a
(Z)-3
91:9 !:"
,
(1.3 equiv.)
tol. (0.2 M), 22 °C, 3 h
69% yield (pure
!
),
97:3 Z:E, 92:8 e.r.
1. 4.0 equiv. Cl3CCO2H,
5.0 equiv. (MeO)2CMe2
2.0 mol % H2SO4,
Cl
b. Catalytic chemoselective cross-coupling:
CF3
H2N
Me
O
NSiMe3
Me
1. Catalytic Enantioselective Addn
OH
CF3
O
CF3
H2N
CH2Cl2, 22 °C, 12 h
HN
Ph
CF3
OH
O
Cl
Ph
2. 5.0 mol % Pd(dppf)Cl2•CH2Cl2,
4.0 equiv allyl–B(pin), 3.0 equiv CsF,
thf/H2O (10/1), 14 h, 60 °C
2. 1.2 equiv. ClCOCH2Cl,
tol., reflux, 4 h
Br
11
Me
Me
1j
71% yield (2 steps),
>98:2 Z:E, 92.5:7.5 e.r.
15
16
54% overall yield
57% overall yield,
93:7 d.r.
X-ray of 16
CF3
H2N
CF3
H2N
10 mol % ruphos–Pd-G3
10 mol % ruphos
4.0 equiv. CCl3CO2H,
CF3 Me
Me
CF3
OH
H2N
Ph
H2N
Ph
1.5 equiv. m-cpba
Br
OCOCCl3
F3C
9b
F3C
3.0 equiv. K3PO4
thf/H2O (10/1), 14 h,
55 °C (dark)
nBu
nBu
CH2Cl2, 22 °C, 18 h
nHex
(pin)B
10
13
17
72% yield,
>98:2 r.r., 91:9 d.r.
nHex
98:2 !:", 88% yield (pure
98:2 Z:E, 88.5:11.5 e.r.
!
),
54% yield, >98:2 Z/E:E/E
12
(1.3 equiv.)
d. Formal enantioselective synthesis of BACE-1 inhibitor:
F
NSiMe3
CF3
Cl
O
5.0 mol % ap-2a,
O
O
10 mol % Zn(OMe)2, 5.0 mol % tbat,
3.5 equiv MeOH, tol., 22 °C, 3 h
1. O3, NaHCO3,
CF3
HN
HN
F3C
1b
CH2Cl2/MeOH; NaBH4
BACE-1 inhibitor
(anti-Alzheimer)
(pin)B
Me
F
2. 2.0 equiv. KOtBu,
thf/tBuOH, reflux, 1 h
remove MeOH; 1.2 equiv. ClCOCH2Cl,
tol., reflux, 4 h
F
Me
18
19
(Z)-3
1.86 g;
1.21 g;
76% yield (2 steps)
(1.3 equiv.)
X-ray of
69% yield, 98.5:1.5 e.r.
18
Scheme 6. The practical nature and utility of the new catalytic enantioselective method. Yield of isolated and purified material
(±5%); enantioselectivity determined by HPLC analysis (±1%). See the Supporting Information for further details.
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 10
coupling involving homoallylic a-tertiary NH2-amine 9b and alkenyl–B(pin) 12, leading to the
formation of 1,3-diene 13 in 54% yield (>98:2 Z/E:E/E).[15]
Thus, the possibility of generating products that contain a Z-alkenyl chloride, not only
makes it possible to access a much wider range of other a-tertiary NH2-amines, it can be done so
with high chemoselectivity.
As noted earlier, a central attribute of the present method is that the products contain a
Z alkene, transformations of which are considerably more diastereoselective than the
corresponding E isomers or monosubstituted olefins.[9, 19 ] The following data highlight the
importance of this feature. Directed epoxide formation/regioselective cleavage with m-
chloroperbenzoic acid and trichloroacetic acid (Scheme 6c), according to a procedure introduced
for reactions involving cyclic allylic tertiary alkylamines and g-tertiary alkylamino a,b-unsaturated
esters,[20] afforded 14 in >98:2 regiosiomeric ratio (r.r.); mild hydrolysis converted 14 to diol 15
in 57% overall yield and 93:7 diastereomeric ratio (d.r.). The X-ray structure of amide/acetonide
derivative 16 confirmed the identity of the major stereoisomer. Similarly, 10 was converted to
trichloroacetate 17 in 72% yield, >98:2 r.r., and 91:9 d.r.
The gram-scale synthesis of cyclic amide 19 (1.21 g) via 18 (Scheme 6d), previously
converted to BACE-1 inhibitor (Scheme 1a), further highlights the utility of the approach. A
homoallylic amine with a monosubstituted alkene can also be used in the same way for this last
sequence. Nevertheless, the fact that precious metal salts are not needed, the aminophenol can
be prepared in significant amounts at relatively low cost, and multigram quantities of Z-crotyl–
B(pin) may be accessed by simple procedures and with inexpensive starting materials,[18] point
to the truly practical nature of the approach.
Conclusion
We have described a method for enantioselective preparation of readily modifiable F3C-
and aryl-, heteroaryl-, alkynyl, or alkenyl-substituted a-tertiary Z-homoallylic NH2-amines.
Reactions involve an easy-to-handle N-silyl ketimine and a Z-allyl boronate, which might either
be purchased or accessed in high stereoisomeric purity by catalytic cross-metathesis, and are
promoted by a catalyst generated in situ from a readily accessible aminophenol. High a:g
selectivities arise from attractive electrostatic forces and the steric and stereoelectronic
attributes of the catalyst’s L-threonine residue. Development of additional catalytic protocols for
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10.1002/anie.202001184
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Fager & Morrison, et al.; Page 11
enantioselective synthesis of a broader range of a-tertiary NH2-amines (e.g., F3C-/alkyl-
substituted) are in progress.
Acknowledgements
This work was made possible by financial support by the NIH (GM-130395). We are grateful to Y.
Mu and T. Koengeter for advice and helpful discussions.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: catalysis, enantioselective synthesis, homoallylic amines, NH2-amines, NH-ketimines
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