A Regio- and Stereodivergent Synthesis of Homoallylic Amines by a One-Pot Cooperative-Catalysis-Based Allylic Alkylation/Hofmann Rearrangement Strategy

Article abstract of DOI:10.1002/anie.201905426

Herein, we report a modular synthetic route to linear and branched homoallylic amines that operates through a sequential one-pot Lewis base/transition-metal catalyzed allylic alkylation/Hofmann rearrangement strategy. This protocol is operationally trivial, proceeds from simple and easily prepared substrates and catalysts, and enables all aspects of regio- and stereoselectivity to be controlled through a conserved experimental protocol. Overall, the high levels of enantio-, regio-, and diastereoselectivity obtained, in concert with the ability to access orthogonally protected or free amines, render this a straightforward and effective approach for the preparation of useful enantioenriched homoallylic amines. We have also demonstrated the utility of the products in the context of pharmaceutical synthesis.

Full text of DOI:10.1002/anie.201905426

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A Regio- and Stereodivergent Synthesis of Homoallylic Amines
via a One-Pot Cooperative Catalysis-based Allylic Alkylation/
Hofmann Rearrangement Strategy
Authors: Colin Pearson, James Fyfe, and Thomas Neil Snaddon
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905426
Angew. Chem. 10.1002/ange.201905426
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10.1002/anie.201905426
Angewandte Chemie International Edition
RESEARCH ARTICLE
A Regio- and Stereodivergent Synthesis of Homoallylic Amines
via a One-Pot Cooperative Catalysis-based Allylic
Alkylation/Hofmann Rearrangement Strategy
Colin M. Pearson,+ James W. B. Fyfe+ and Thomas N. Snaddon*[a]
Dedicated to Professor Alois Fürstner
Abstract: Herein, we report a modular synthetic route to linear and
branched homoallylic amines that operates via a sequential one-pot
(a) Carbinamine stereocenters in bioactive natural products and pharmaceuticals
Lewis base/transition metal catalyzed allylic alkylation/Hofmann
F
F
F
Me
O
NH2
rearrangement strategy. This protocol is operationally trivial, proceeds
from simple and easily prepared substrates and catalysts, and
enables all aspects of regio- and stereoselectivity to be controlled via
a conserved experimental protocol. Overall, the high levels of enantio-,
regio- and diastereoselectivity obtained, in concert with the ability to
N
H
N
N
N
S
sitagliptin
N
rotigotine
OH
HO
F3C
CO2H
Me
N
O
O
Me
H
H
N
N
access orthogonally-protected or free amines, render this
a
H
Me
O
straightforward and effective approach for the preparation of useful
enantioenriched homoallylic amines. We have also demonstrated the
utility of the products in the context pharmaceutical synthesis.
H
lysergic
acid
O
O
morphine
H
OH
OH
HN
chelidonine
(b) Catalytic asymmetric approaches to homoallylic amine synthesis
homoallylic amines
Allyl Nucleophiles
Allyl Electrophiles
Introduction
NRR3
α-aza, α-imino,
α-nitro anions
nucleophiles
activated imines,
imines, hydrazones
electrophiles
Enantiomerically-enriched carbinamines are among the most
prevalent structural motifs in bioactive alkaloids and
pharmaceuticals (Figure 1a).[1] They also constitute a diversity of
essential chemical building blocks for applications in asymmetric
synthesis and catalysis, and methods for their synthesis have
been intensely pursued. Homoallylic amines, in particular, are
widely employed for the synthesis of unnatural amino acids and
bespoke heterocycles via elaboration of the embedded amine and
alkene functional groups.[2] Therefore, the development of
operationally straightforward, direct and modular synthetic routes
to homoallylic amines, which are capable of incorporating a
diversity of functionality whilst simultaneously controlling reaction
regio- and stereoselectivity, is of continuing importance.
R1
R2
R3
N
R3
R
branched, syn- or anti-
N
–
NRR3
R1
R1
H
R1
+
+
R2
M
LnM+
NRR3
R2
R2
R2
R1
allylmetal
nucleophiles
allylmetal
electrophiles
linear
M = B, Cu
M = Pd, Ir
(c) Design plan. One pot allylic alkylation/Hofmann rearrangement sequence
O
H
R3
The catalytic asymmetric synthesis of homoallylic amines
continues to be the subject of considerable effort. The catalyzed
addition of allylmetal nucleophiles to imine (and related)
electrophiles has attracted significant attention (Figure 1b, left).[3]
Transition metal and Brønsted acid catalyzed addition of
allylboron nucleophiles is especially effective and provides
branched products with high levels of enantio- and
diastereoselectivity.[4] More recently, allylcopper nucleophiles
O
NH2
N
O
O
R2
R2
R1
R1
R1
OPfp
(R2)
(R2)
linear or branched
homoallylic amines
acyclic
esters
intermediate
primary amides
+
–O
R1
NR3
O
linear
(Pd)
+NH3
+R3OH
N
LnM+
R2
R1
R2
Dr. C. M. Pearson,+ Dr. J. W. B. Fyfe,+ Prof. T. N. Snaddon
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, IN 47405 (USA)
E-mail: tsnaddon@indiana.edu
branched
(Ir)
R2
cooperative catalysis
Lewis base (NR3) / transition metal (MLn)
isocyanate intrermediates
control over N-substitution
regio-, enantio- and diastereoselectivity free amine or common carbamates
+ These authors contributed equally.
Figure 1. a) Examples of secondary amine-containing bioactive molecules. b)
Complementary polarity approaches to catalytic asymmetric homoallylic amine
synthesis. c) This work: A modular, one pot synthesis of homoallylic amines
featuring a cooperative Lewis base/transition metal catalysed regio- and
stereodivergent allylic alkylation/Hofmann rearrangement strategy.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201905426
Angewandte Chemie International Edition
RESEARCH ARTICLE
that can be conveniently prepared in situ, undergo
enantioselective reaction with aldimines and ketimines under the
action of both metal and non-metal catalysts.[4i-k] The
complementary polarity approach using p(allyl)metal electrophiles
(Figure 1b, right) has also been explored. Nitro-stabilized anions,
Oxidant Assessment and Optimization of a One-pot Protocol.
Our initial efforts focused on identifying an appropriate oxidant to
induce stereospecific Hofmann-type C®N rearrangement of
enantioenriched amides.[24,25] In the presence of methanol a
variety of oxidants effectively mediated the Hofmann
[5-7]
glycine-derived metalloenolates[8-10] and fluorenyl imine-
rearrangement of (R)-2-(4-methoxyphenyl)pent-4-enamide A
derived anions[11] have been most intensively studied and are
effective nucleophiles for a host of enantioselective Pd- and Ir-
catalyzed allylic alkylation reactions. While each of these methods
is effective and efficient they cannot be easily modified to
rationally prepare linear or branched homoallylic amines. Thus, a
general and flexible protocol for their preparation remains a
significant challenge.
giving the
Table 1. Optimization of oxidative Hofmann rearrangement and application to
full one-pot allylation–Hofmann rearrangement sequence.
O
+
O
(R)-BTM
XantphosPd G3
iPr2NEt, THF, r.t.
Ar
O
NH2
H
OPfp
N
OMe
see
Ar
Ar
Table
then
NH3 (g)
MsO
As part of a long-standing program directed toward catalyzed and
stereocontrolled carbon–carbon bond formation, we sought to
provide a straightforward, operationally trivial and modular
catalysis-based protocol for the regio- and stereodivergent[12]
synthesis of enantioenriched homoallylic amines.[13] Principal
among our concerns was catalyst control over all aspects of
selectivity during carbon–carbon bond formation, whilst also
working within a useful N-protecting group regime. Herein, we
describe such a protocol, which provides a straightforward and
modular preparation of these valuable building blocks.
amide
Ar = (4-methoxy)phenyl
Entry[a]
Oxidant
Base
Solvent
Temp.
[°C]
Yield
[%][b]
1
PIFA
PIDA
KOH
MeOH
MeOH
MeOH
MeOH
MeOH
rt
rt
90
80
2
KOH
3
PhI/oxone
Pb(OAc)4
NBS
-
rt
-
Reaction Design. We have invested considerable effort in the
development of Lewis base/transition metal cooperative catalysis
to control enantioselective C(sp3)–C(sp3) bond formation between
acyclic pentafluorophenyl esters (Pfp esters, hereafter) and allyl
electrophiles.[14,15] This versatile platform proceeds via the union
of C1-ammonium enolate nucleophiles[16,17] and p(allyl)Pd
electrophiles[18] and provides highly enantioenriched and
functionalized a-branched esters that can be readily diversified
without compromising optical purity.[19] Two crucial features of this
orthogonal regime are relevant to our proposed synthesis of
homoallylic amines (Figure 1c). Firstly, all aspects of enantio-,
regio- and diastereodivergent C(sp3)–C(sp3) formation could be
controlled by judicious choice of the Lewis base/transition metal
catalyst combination (see Figure 1c, cooperative catalysis).
Secondly, rapid in situ conversion of product Pfp esters (not
shown) to intermediate primary amides[14b,20] would permit
subsequent stereospecific Hofmann-type rearrangement[21,22] to
forge the necessary C(sp3)–N bond via isocyanates (see Figure
1c, isocyanate intermediates). These could be intercepted with an
appropriate alcohol (R1-OH) to give the corresponding
carbamate-protected or unprotected enantioenriched linear or
branched homoallylic amines. We also expected that the
projected efficiency of each constituent transformation in the
sequence would provide ample opportunity for a sequential single
pot process.
4
5
-
rt
89
DBU
rt
76
6
PIFA
KOH
THF/MeOH (25:1)
THF/MeOH (2:1)
THF/MeOH (2:1)
THF/MeOH (2:1)
THF/MeOH (2:1)
THF/MeOH (2:1)
rt
43
7
PIFA
KOH
rt
66
8
PIFA
-
-
-
-
rt
80
9
PIFA
60
60
60
99
10[c]
11[c,d]
PIFA
67
PIFA
74 (73)
[a] Reactions run on 0.1 mmol scale from isolated amide. [b]
1H NMR yield calculated using internal standard. [c] Full one-pot
procedure from starting Pfp ester (0.1 mmol scale). [d] 2.0
equivalents of PIFA were used.
corresponding methyl carbamate-protected homoallylic amine
(Table
1).[25a]
We
initially
identified
[bis(trifluoroacetoxy)iodo]benzene (PIFA, 1.5 equivalents) in
combination with potassium hydroxide (2.5 equivalents) in
methanol as an effective system, which gave the rearranged
product in 90% isolated yield and with complete stereotransfer
(96:4 er, Entry 1). Further optimization (Entries 6–9) resulted in a
mixed solvent system of THF/MeOH in 2:1 ratio at 60 °C from
which desired homoallylic methyl carbamate was isolated in
quantitative yield (Entry 9. For full solvent screening, see
Supporting Information). These conditions obviated the need for
potassium hydroxide, which not only simplified the protocol
Here, we report the successful realization of this design, which
provides a modular, operationally-trivial and convenient one-pot
enantioselective protocol for the regio- and stereodivergent
preparation homoallylic amines.[23]
Results and Discussion
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10.1002/anie.201905426
Angewandte Chemie International Edition
RESEARCH ARTICLE
O
A
B (X = S) ; C (X = O)
(R)-BTM (20 mol%)
A or B (5 mol%)
R3
H
Ph2P
O
OPfp
N
O
X
iPr2NEt, THF, r.t.; NH3 (g), 10 min
then
MsO
Me
+
O
X
PIFA, R3OH, 60 °C
Me
Pd
P
NH2
Pd
P
X
H
Ph2
OMs
N
acyclic
esters
(R)-BTM :
linear N-substituted
homoallylic amines
allylic
sulfonates/carbonates
3
N
S
Ph
Scope of Nucleophile: Aryl and vinyl acetic acid esters.
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
OMe NHCO2Me
F
NHCO2Me
MeO
MeO
Br
Ph
Cl
MeO
Me
6
7
8 (x-ray)
A: 76%, 93:7 er
5
1
2
3
4
A: 66%, 97:3 er
A: 70%, 89:11 er
A: 66%, 90:10 er
A: 76% 93:7 er
A: 73%, 92:8 er
A: 74%, 96:4 er
A: 73%, 97:3 er
Me
OMe
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
Me
NHCO2Me
NHCO2Me
Me
Me
Br
9
10
11
12
13
14
Me
MeO
A: 80%, 93:7 er
A: 58%, 92:8 er
A: 51%, 92:8 er
A: 80%, 94:6 er
A: 70%, 91:9 er
A: 50%, 91:9 er
Scope of N-Substitution: Common carbamate protecting groups and unprotected amine.
O
O
O
Me
Me
Me
O
H
SiMe3
H
H
H
H
H
N
O
N
N
O
N
O
N
O
MeO
MeO
MeO
MeO
MeO
18
15
16
17
19
Teoc-protected
A: 75%, 98:2 er
Boc-protected
A: 61%, 97:3 er
Alloc-protected
A: 63%, 98:2 er
Cbz-protected
A: 69%, 97:3 er
Unprotected amine
A: 42%, 97:3 er
Scope of Electrophile: Internal and terminal substitution.
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
MeO
Me
MeO
MeO
MeO
MeO
MeO
SiMe3
20
B: 72%, 96:4 er
21
22
23
A: 56%, 95:5 er
24
25
OMe
O
OMe
O
OtBu
O
N
B: 79%, 94:6 er
B: 30%, 95:5 er
A: 58%, 95:5 er
B: 62%, 95:5 er
Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
Pd2dba3 (2.5 mol%)
nBu4NF, H2O
THF, 0 °C to r.t.
MeO
MeO
MeO
MeO
SiMe2Ph
SiMe2Bn
26
27
28
29
I
O
NH
B: 37%, 92:8 er
A: 68%, >99:1 er
C: 66%, 90:10 er
C: 78%, 91:9 er
2 g scale
Me
CO2Me
Scope of Hiyama Cross Coupling: (Hetero)aryl and vinyl iodides
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
MeO
MeO
MeO
MeO
MeO
MeO
F
33
65%
90:10 er
34
67%
90:10 er
35
46%
90:10 er
30
73%
92:8 er
31
67%
90:10 er
32
67%
90:10 er
N
OMe
Br
O
OMe
N
O
Me
O
Me
Me
Application: toward sertraline
OPfp
Me
O
Me
Me
Me
Me
NHMe
Cl
Cl
I
(S)- BTM (20 mol%)
(R)-C (4 mol%)
iPr2NEt, THF, r.t.;
NH3 (g), 10 min
then
O
NH
O
NH
O
SiMe2Bn
+
MsO
PIFA
t-BuOH, 60 °C
Pd2dba3 (2.5 mol%)
nNBu4F, H2O
SiMe2Bn
36
53%, 91:9 er
37
70%
91:9 er
THF, 0 °C – rt
38
sertraline
Cl
Cl
Cl
Cl
Scheme 1. Preparation of enantioenriched linear homoallylic amines: evaluation of nucleophile scope, N-substitution (via preparation of common carbamate-
protected amines and free amine) and electrophile scope. A combination of these components in the synthesis of 37, a key intermediate en route to the synthesis
of sertraline 38.
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10.1002/anie.201905426
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RESEARCH ARTICLE
considerably but also raised the prospect of greater functional
group tolerance. These conditions were then applied to a
streamlined cooperative catalysis–rearrangement protocol.
Employing Birman’s benzotetramisole (BTM)[26] in combination
with Buchwald’s Xantphos-ligated 3rd generation Pd precatalyst
(XantphosPd G3),[27] allylation via enantioselective cooperative
catalysis was followed by instantaneous formation of the
corresponding primary amide by bubbling NH3 gas through the
reaction mixture. Thereafter, treatment of the reaction mixture
with PIFA and MeOH gave the methyl carbamate-protected
homoallylic amine in 67% yield (Entry 10). Increasing the
stoichiometry of PIFA to 2 equivalents gave the carbamate in an
preparation of an a,b-unsaturated ester-substituted homobenzylic
amine 27 was possible using a 2-naphthylic phenylphosphate
electrophile in combination with XantphosPd G3.[14d] Again,
preparation of 27 via common imine addition reactions would be
problematic. The major limitation of this protocol concerns the
poor compatibility of the styrenyl motif within the electrophile
scaffold, which leads to numerous unidentifiable products during
the oxidative rearrangement. To address this limitation,
benzyldimethylsilyl-substituted carbamate 29 could be directly
elaborated in diverse fashion via Pd-catalyzed Hiyama cross
coupling[31,32] with a range of (hetero)aryl- and alkenyl iodides
without erosion of enantioenrichment (Scheme 2, 30–35); ketone
(32), indole (33), pyridine (34) and dienoate (35) -containing
products are all accessible from a common intermediate (29). We
expect that late-stage diversification in this manner will prove
convenient for the preparation of varied homoallylic amine
structures of interest to therapeutic development. Finally, to
demonstrate the utility of this method to pharmaceutically-relevant
molecules we prepared Boc-protected homoallylic amine 36 using
the protocol described and elaborated this via Hiyama cross-
coupling to 37, which has been converted to selective serotonin
reuptake inhibitor sertraline 38 (Scheme 1).[11a,33]
enhanced
73%
isolated
yield
and
with
excellent
enantioenrichment (97:3 er, Entry 11).
Linear Homoallylic Amine Synthesis with Palladium. With
these optimized conditions in hand we examined the scope of
nucleophile (Scheme 1). A range of aryl and alkenyl acetic acid
esters successfully afforded the corresponding carbamate-
protected homoallylic amines in good isolated yields and with high
levels of enantioenrichment. Noteworthy is the tolerance of aryl
halides (5, 7–8, 10) electron-rich arenes (2–4, 6) and p-extended
arenes (9, 10) to this oxidative protocol. Finally, both conjugated
and non-conjugated alkene-substituted esters (11–14) were
effective; significant is the preparation of 14, which is chiral only
by virtue of the alkene position. As yet, we have been
unsuccessful in our attempts to engage either aliphatic esters or
terminal alkyl-substituted electrophiles in this chemistry; both are
the subject of ongoing study.
Branched Homoallylic Amine Synthesis with Iridium. Having
established a general and modular protocol for the synthesis of
carbamate-protected linear homoallylic amines we sought to
address the of branched regioisomers with control over
diastereoselectivity (Scheme 2). We expected this protocol would
translate to the corresponding branched-selective cooperative
BTM/Iridium-catalyzed process, where control over both
stereogenic centers should proceed under the independent
direction of Lewis base and Ir catalysts, respectively, and provide
stereodivergent access to any stereoisomer.[15b] Employing
Hartwig’s cyclometalated iridum(I)-phosphoramidite (S)-D [(S)-Ir]
in combination with (R)-BTM within the same experimental
protocol gave (1R,2S)-39 in 83% yield, 95:5 dr and as a single
enantiomer (for detailed optimization see the Supporting
Information). As previously described,[15b] judicious choice of
catalyst permutations during allylic alkylation provides
stereodivergent access to all possible stereoisomers of 39 with
similar efficiency. Thus, this protocol constitutes a formal catalytic
We then evaluated the scope of N-substitution (Scheme 1). In
many approaches to homoallylic amine synthesis nitrogen
substitution needs to be tailored to enhance reactivity and/or
provide a site for catalyst engagement. Here, simply changing the
identity of the alcohol used to trap the putative isocyanates
derived from oxidative Hofmann-type rearrangement provides
access to the most commonly encountered and synthetically
orthogonal carbamate protective groups;[28] tert-Butoxycarbonyl-
(Boc, 15), allyloxycarbonyl- (Alloc, 16), benzyloxycarbonyl- (Cbz,
17) and 2-(trimethylsilyl)-ethoxycarbonyl- (Teoc, 18) protected
amines are all obtained with high levels of enantioselectivity.
Furthermore, employing water as the nucleophile provides the
corresponding free amine 19 with similar enantioenrichment.
Here, the lower isolated yield (42%) is due to more difficult
chromatographic purification rather that compromised protocol
efficiency, as evidenced by spectroscopic analysis of the crude
material. Thereafter, we move to examine the scope of allyl
sulfonate electrophiles (Scheme 1). Employing Pd[P(2-thienyl)3]3
(B) as the catalyst[29] enabled 2-substituted allyl electrophiles to
react effectively giving functionalized homoallylic amines 20–
22,[14b] the latter containing a trimethylsilylacetylene substituent.
Using the same catalyst ester (23,24), Weinreb amide (25) and
secondary amide (26) -substituted allyl electrophiles were also
effective.[14f] Recourse to P(2-furyl)3 (C) as a supporting ligand
enabled the synthesis of silyl-substituted products 28 and 29.[14c]
Functionalized electrophiles 23–29 are particularly noteworthy as
their incorporation via allylmetal addition to imines would, beyond
challenges associated with enantio- and regioselectivity, be
precluded due to functional group compatibility issues and
concerns over a– vs g– nucleophile addition.[30] Finally, the
stereodivergent cinnamylation of imines and represents
a
completely catalyst-controlled evolution of Leighton’s branched
selective reagent-controlled synthesis of homoallylic amines.[34]
As the stereodivergent nature of the allylic alkylation has
previously been confirmed[15b] we assessed the branched-
selective synthesis of homoallylic amine via unbiased
nucleophile, electrophile and catalyst combinations. As expected,
in this protocol both aryl and alkenyl nucleophiles were effective
in combination with a range of electrophilic partners (40-50).
Furthermore, halides, nitroarene, indole, thiophene, pyridine, and
pinacol borane esters are all tolerated. More specifically, electron-
rich aryl (anti-40, syn-41), indole (syn-42) and thiophene (anti-43)-
substituted electrophiles all provided products with high levels of
diastereo- and enantioselectivity, thus demonstrating excellent
individual catalyst control. Interrogation of electron-deficient F-,
NO2-, and Cl-substituted aryl electrophiles (syn-44, anti-45, syn-
46) revealed an unexpected influence on
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10.1002/anie.201905426
Angewandte Chemie International Edition
RESEARCH ARTICLE
+
–BF4
(R)- or (S)- BTM (20 mol%)
(R)- or (S)-D (4 mol%)
iPr2NEt, THF, r.t.; NH3 (g), 10 min
then
O
OPfp
NHCO2Me
*
*
BocO
+
PIFA, MeOH, 60 °C
O
O
Ph
P
Ir
H
N
achiral
acyclic esters
(R)-BTM :
allylic
t-butyl carbonate
Me
N
N
S
Ph
(R)-D
branched homoallylic amines
Ph
Ph
Stereodivergent Homoallylic Amine Synthesis: All stereoisomers of 39
using: (R)-BTM / (S)-Ir
using: (R)-BTM / (R)-Ir
using: (S)-BTM / (R)-Ir
using: (S)-BTM / (S)-Ir
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
(S)
(R)
(R)
(S)
(R)
(R)
(S)
(S)
MeO
MeO
MeO
MeO
(1S,2S)-39
(1R,2S)-39
83% (x-ray)
(1R,2R)-39
78%
(1S,2R)-39
75%
83%
95:5 dr, >99:1 er
95:5 dr, >99:1 er
95:5 dr, >99:1 er
94:6 dr, 98:2 er
Scope of Branched Homoallylic Amine Synthesis: Assessment of electronic effects, functional group compatability and aryl/vinyl components.
Electron-rich Electrophiles
Electron-deficient Electrophiles
matched/mismatched
vinyl–vinyl combination
F
NHCO2Me
Me
NHCO2Me
NHCO2Me
NHCO2Me
Br
NHCO2Me
NHCO2Bn
Me
Me
Me
Me
MeO
OMe
syn-48
67%
80:20 dr, 99:1 er
Me
Me
syn-49
40%
85:15 dr
O
anti-40
75%
syn-41
66%
95:5 dr, >99:1 er
anti-44
83%
85:15 dr, >99:1 er
syn-45
63%
81:19 dr, 98:2 er
O
OMe
F
NO2
90:10 dr, >99:1 er
Boron-substituted
Me NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
NHCO2Me
Br
NHCO2Me
Cl
Ph
Cl
MeO
N
S
O
N
OMe
Me
Me
Me
B
Ts
syn-42
77%
Cl
O
anti-43
72%
90:10 dr, >99:1 er
syn-46
62%
syn-47
64%
88:12 dr, >99:1 er
anti-48
81%
77:23 dr, 99:1 er
anti-50
38%
94:6 dr, >99:1 er
Me
Me
93:7 dr, 97:3 er
80:20 dr, 99:1 er
Application: toward MDM2 inhibitor
Me
Me
O
O
CO2H
O
O
O
OPfp
(S)- BTM (20 mol%)
(R)-D (4 mol%)
iPr2NEt, THF, r.t.; NH3 (g), 10 min
Me3Si
Me
S
O
NH
N
Cl
BocO
Me
Me
then
PIFA
+
Cl
Cl
53, 68%
91:9 dr, >99:1 er
Cl
Me3SiCH2CH2OH, 60 °C
51
52
54
MDM2 inhibitor
Cl
Cl
Scheme 2. Preparation of enantioenriched branched homoallylic amines: The fully stereodivergent preparation of branched homoallylic amines 39 via different
catalyst enantiomer combinations. The unbaised evaluation of scope via nucleophile/electrophile combinations and application to the synthesis of MDM2-inhibitor
core scaffold 53.
diastereoselectivity (ca 80:20). In each case the major
diastereoisomer was produced in high enantiopurity. This was
also true when employing an electron-deficient pyridyl-substituted
heteroaromatic electrophile (syn-47). Similarly, alkene-
substituted electrophiles also exhibited more modest
diastereoselectivity, which does not arise due to matched–
mismatched interaction between catalysts (see syn-48 vs. anti-
48). Again, the exceptional enantioselectivity of the major
diastereoisomer is unaffected. Preparation of syn-49
demonstrated the tolerance of vinyl substituents on both reaction
components. Boronic ester substituted electrophiles (anti-50)
were also tolerated and provide another synthetic handle for
further functionalization. Finally, this procedure was used to
construct the core scaffold 53 of the MDM2 inhibitor 54[35] with
excellent control over both diastereo- and enantioselectivity.
Overall, when integrated with BTM/Ir-catalyzed allylic alkylation,
this one-pot protocol provides robust stereocontrolled access to
branched homoallyl amines with incorporation of diverse
functionality.[36]
Conclusion
By pairing cooperative Lewis base/transition metal catalysis with
stereospecific C–N bond formation we have developed a unified
and operationally simple experimental protocol for the catalytic
enantioselective synthesis of homoallylic amines. This protocol
exhibits broad functional group tolerance, and enantio-, regio- and
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10.1002/anie.201905426
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RESEARCH ARTICLE
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used can be readily accessed using robust methods. Overall, this
study demonstrates the potential of combining simultaneous
catalysis events with subsequent value-added transformations in
stereoselective chemical synthesis.
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Acknowledgements
We gratefully acknowledge Indiana University and the National
Institutes of Health (R01GM121573) for generous financial
support. We also thank Dr. Maren Pink (IU) for X-ray
crystallography.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: amine • ammonium enolate • alkylation • palladium •
rearrangement
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RESEARCH ARTICLE
C. M. Pearson, J. W. B. Fyfe, T. N.
Snaddon*
O
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OR
A Regio- and Stereodivergent
Synthesis of Homoallylic Amines via
a One-Pot Cooperative Catalysis-
based Allylic Alkylation/Hofmann
Rearrangement Strategy
Cooperation then Amination: A unified one-pot experimental protocol enables a
versatile regio- and stereodivergent synthesis of homoallylic amines. Critical to the
successful development of this method was the recognition that initial catalysed C-
C bond formation controls all aspects of reaction regio- and stereoselectivity.
Thereafter, in situ amination/Hofmann rearrangement results in stereospecific C–N
bond formation with attendant control over N-substitution.
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