Accepted Article
01/2020
Accepted Article
Title:
Strategies for the Development of Asymmetric and Non-Directed
Petasis Reactions
Authors:
Kevin J. Gonzalez, Chloe Cerione, and Brian Stoltz
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). The VoR will be published online
in Early View as soon as possible and may be different to this Accepted
Article as a result of editing. Readers should obtain the VoR from the
journal website shown below when it is published to ensure accuracy of
information. The authors are responsible for the content of this Accepted
Article.
To be cited as:
Chem. Eur. J.
2024
, e202401936
Link to VoR:
https://doi.org/10.1002/chem.202401936
CONCEPT
1
Strategies for the Development of Asymmetric and Non
-
Directed
Petasis Reactions
Kevin J. Gonzalez
,
+
Chloe Cerione,
+
and
Brian M. Stoltz
*
[a]
[a]
Mr. K. J. Gonzalez, Ms. C. Cerione, Prof. Dr. B. M.
Stoltz
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd., MC 101
-
20, Pasadena, CA 91125 (USA)
E
-
mail:
stoltz@caltech.edu
Abstract:
The Petasis reaction is a multicomponent reaction of
aldehydes, amines and organoboron reagents and is a useful method
for the construction of substituted amines. Despite the significant
advancement of the Petasis re
a
ction since its
invention
in 1993,
strategies for asymmetric and non
-
directed Petasis reactions remain
limited. To date, there are very few catalytic asymmetric Petasis
reactions and almost all asymmetric reports employ a chiral auxiliary.
Likewise, the aldehyde component often re
quir
es a directing group,
ultimately limiting the reaction’s scope. In this concept, key methods
for asymmetric and non
-
directed Petasis reactions are discussed,
focusing on how these conceptual advances can be applied to solve
long
-
standing
gaps in the Petasis literature.
1.
Introduction
Amine
-
containing
molecules
represent
a broad class of
compounds that includes
countless biologically active
natural
products and pharmaceuticals.
[1]
A central method for the
synthesis of functionalized amines is
the addition of nucleophiles
into imines (and their derivatives).
[
2
]
In particular, methods that
utilize organoboron reagents as nucleophiles have grown in
prominence
due
to these reagents’ availability, low toxicity, wide
functional group tolerance, and stability to air and water.
The Petasis reaction
, first reported in 1993,
is the three
-
component coupling of an aldehyde, amine, and organoboron
compound
which
pr
ovides
⍺
-
functionalized amines
(Figure 1a)
.
[
3
,
4
]
Th
is
efficient
reaction is operationally simple, not requiring
rigorously dry or degassed solvents
,
and
proceeds under mild
conditions that can tolerate many unprotected
moieties
.
Therefore
,
i
t
has seen extensive use for the preparation of
diverse amine
-
containing scaffolds
including
⍺
-
amino acids, heterocycles, and
natural pro
ducts
(Figure 1b)
.
[
5
]
Despite its utility, the
reaction
suffers from several
restrictions that have limited its scope
(Figure 1c)
:
1) T
o date, the
vast
majority of asymmetric Petasis reactions utilize chiral
auxiliary
-
based approaches
.
[
6
–
10
]
T
here are
relatively few
catalytic
asymmetric
methods
and most suffer from limited scopes and
modest levels of
e
nantio
selectivity
.
[
11
a
]
2) In
most Petasis
reactions,
a
directing group
is required
to
recruit
the
boronic acid,
generating the more reactive “ate complex”
(
1
)
,
and enabling an
intramolecular attack on the iminium ion to furnish product.
In this
C
oncept
paper
, a brief review of methods that have
guided the development of asymmetric and non
-
directed Petasis
reactions (or variants) is provided with a focus on how they
could
be further utilized to develop solutions to long
-
standing limitations.
There have been many
outstanding
reviews written on the Petasis
reaction that should be referred to if the reader desires a more
comprehensive overview of the history
of this reaction
.
[
4
,
11
]
Petasis
-
type reactions, a subclass of this chemistry based on
utilizing preformed i
mine substrates (or a suitable iminium ion
precursor) in a two
-
component coupling, are discussed.
[
12
]
Metal
-
catalyzed variants are
outlined
as well; while they present their
own challenges (such as air sensitivity/requiring expensive
catalysts), these reactions represent an orthogonal reaction
manifold that can circumvent many of the traditional limitations of
the Petasis reaction. Finally, o
ne area not covered by this
Concept is the allylation of imines via allyl
-
organoboron
compounds. For a detailed discu
ssion of these processes,
we
refer
the reader
to the following references.
[
13
]
Figure 1.
The Petasis reaction
and its
applications
and limitations.
a) The Petasis Reaction
B
OH
OH
N
H
H
O
OH
+
N
OH
+
Mild reaction conditions
Three-component coupling
Structurally diverse products
b) Synthetic Applications
N
N
Me
H
N
H
N
H
Me
H
non-natural
⍺
-amino acids
heterocycles
natural products
Br
HN
OH
O
Ph
Ph
N
H
HO
H
OH
H
n
-Bu
c) Limitations
H
O
N
B
HO
OH
directing heteroatom
generally required to
enable reactivity
1
Chiral
Catalyst
Few catalytic asymmetric reports
Limited scope and modest ee’s
N
OH
H
N
OH
achiral
enantioenriched
10.1002/chem.202401936
Accepted
Manuscript
Chemistry - A European Journal
This
article
is protected
by
copyright.
All
rights
reserved.
15213765, ja, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202401936 by California Inst of Technology, Wiley Online Library on [25/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CONCEPT
2
Kevin J. Gonzalez graduated from Rice
University in 2020 with a B.S. in Chemistry.
He is currently conducting his Ph.D. studies
in chemistry in the Stoltz Lab at the
California Institute of
Technology. His
research focuses on the total synthesis of
complex, biologically
-
active natural products
with an interest in developing novel reaction
methodologies to enable efficient syntheses.
Chloe Cerione earned her B.A. in Chemistry
and Chemical Biology from Cornell
University in 2022. She is currently a
second
-
year Ph.D. student at Caltech under
the supervision of Prof. Brian Stoltz, where
she is studying asymmetric transition
-
metal
catalysi
s and methodology development.
Prof. Brian Stoltz completed his doctoral
studies at Yale University under the direction
of Prof. John L. Wood focused on total
synthesis. He then pursued a NIH post
-
doctoral fellowship in the group of Prof. E. J.
Corey at Harvard University
where he
synthesized the nicandrenone natural
products
. In 2000, he started his
independent career at Caltech and is now
the
Victor and Elizabeth Atkins Professor of
Chemistry and a Heritage Medical Research Institute Investigator. His
research group is focused on the d
evelopment of new strategies
and
tactics
for the preparation of structurally complex molecules.
2. Asymmetric Petasis Reactions
2.1 Chiral Thiourea
C
atalysts
C
atalytic processes
employing small
-
organic molecules
are
attractive due to their cost
-
effective and environmentally friendly
nature.
[
14
]
Chiral thiourea
catalysts have been successful in
enabling asymmetric Petasis reactions. In 2007, Takemoto and
coworkers reported the use of a chiral thiourea catalyst in the first
catalytic asymmetric Petasis
-
type transformation.
[
15
]
The group
employed
Cat. A
,
in combination with water and NaHCO
3
, in the
reaction of quinolines with vinylboronic acids and phenyl
chlorofo
rmate (Scheme 1,
2
–
5
). It was proposed that the thiourea
moiety activates the
N
-
acylated quinolinium salt through
hydrogen
-
bonding, while the 1,2
-
amino alcohol functionality of the
catalyst activates the boronic acid and directs the stereochemical
outcome (Scheme 1,
6
).
Subsequently, Takemoto and coworkers expanded their
method to prepare
N
-
aryl amino acid derivatives by employing a
thiourea catalyst with a Lewis basic ether moiety (
Cat. B
).
[
16
]
In
the two step, one pot reaction sequence, an aniline derivative (
8
)
and
N
-
ethyl
-
2
-
oxo
-
acetanilide (
7
) first form the imino
-
amide
intermediate (not shown), which is then reacted with the thiourea
-
hydroxy catalyst and a vinyl boronate (Scheme 1). The reaction
demonstrated a wide scope with respect to the vinyl boronate and
aniline reaction components. Nota
bly, the enantioselectivity
remained high when an aliphatic
-
substituted vinyl boronic acid (
9
)
was employed.
Scheme 1.
Examples of thiourea
-
based
catalysts in asymmetric Petasis
reactions.
In 2012, Yuan and coworkers reported a novel thiourea
-
BINOL
-
catalyst (
Cat. C
) in an asymmetric Petasis reaction
between salicylaldehyde derivatives, cyclic secondary amines
and aryl
-
, heteroaryl
-
or vinylboronic acids (Scheme 1).
[
17
]
The
o
-
hydroxy substituent on the benzaldehyde was necessary for
reactivity; it was speculated that thiourea moiety forms critical
hydrogen bonds with the phenoxide anion. In general, the
reported thiourea
-
catalyzed asymmetric Petasis reactions are
restricted by
the requirement
for an anchoring group on the
Takemoto, 2011:
Cy
B(OH)
2
+
then, Cat. B (10 mol%)
7
9
8
Thiourea-catalyzed Petasis Reactions:
N
O
Et
Ph
N
H
N
H
S
O
Cat. B
H
N
N
O
Ph
Et
H
Cy
MeO
OMe
Yuan, 2012:
B(OH)
2
+
Cat. C (20 mol%)
MTBE, 5 °C
91% yield
95% ee
11
13
12
OH
MeO
O
N
H
OMe
OH
OH
N
H
HN
S
HN
Ar
Ar = 3,5-(CF
3
)
2
C
6
H
3
Cat. C
OH
MeO
N
OMe
Takemoto, 2007:
Ph
B(OH)
2
+
Cat. A (10 mol%)
NaHCO
3
(2 equiv)
CH
2
Cl
2
/H
2
O (10:1)
70% yield
96% ee
2
4
H
Ph
O
Cl
O
N
Me
3
N
Me
HO
NH
NH
S
Ar
Ar = 3,5-(CF
3
)
2
C
6
H
3
Cat. A
N
Me
CO
2
Ph
Ph
53% yield
80% ee
5
10
14
NH
2
MeO
OMe
OH
Ar
Ar = 3,5-(CF
3
)
2
C
6
H
3
H
O
+
N
O
OR
H
H
N
N
S
Ar
N
O
B
HO
Ph
activation of
nucleophile
activation of
electrophile
6
Mechanistic Proposal:
Me
Author Portrait
((
P
assport
-
style
photographs of the
correspond
ing
authors
should be submitted
;
3.2x4.5 cm (width
x height)
.
)
)
Author Portrait
((
P
assport
-
style
photographs of the
correspond
ing
authors
should be submitted
;
3.2x4.5 cm (width
x height)
.
)
)
Author Portrait
((
P
assport
-
style
photographs of the
correspond
ing
authors
should be submitted
;
3.2x4.5 cm (width
x height)
.
)
)
10.1002/chem.202401936
Accepted
Manuscript
Chemistry - A European Journal
This
article
is protected
by
copyright.
All
rights
reserved.
15213765, ja, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202401936 by California Inst of Technology, Wiley Online Library on [25/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CONCEPT
3
generated iminium ion to enable sufficient interaction with the
catalyst (
i.e., carbonyl in
6
).
Scheme 2.
Examples of
b
iphenol
-
based
catalysts in asymmetric Petasis
reactions.
2.2 Chiral Diol
C
atalysts
Chiral diol
catalysts have been extensively explored in
asymmetric Petasis reactions due to their ability to coordinate with
the organoboron and iminium ion species.
[
4
]
In 2008, Schaus and
coworkers were the first to employ a chiral biphenol
-
derived
catalyst in an asymmetric Petasis reaction which coupled
vinylboronic esters, secondary amines and glyoxylates to
construct chiral
α
-
amino acids (Scheme 2).
[
18
]
The
(S)
-
VAPOL
catalyzed reaction was tolerant of a variety of vinylboronic esters,
including dialkyl
-
substituted
1
7
, and is compatible with benzylic
and allylic secondary amines. Subsequently, Shi and coworkers
reported a BINOL
-
catalyzed asymmetric Petasis reaction of
salicylaldehydes, dibutyl vinylboronic esters, and secondary
amines, including a secondary
acyclic
alkyl amine
20
,
in the
presence of 4Å MS.
[19]
1
H and
11
B
NMR studies led to a proposed
cyclic BINOL
-
boronate intermediate
28
, which is formed with
phenol
19
and directs vinyl group migration with stereocontrol.
The authors found that
benzaldehyde
did not
react
under the
reaction conditions, confirming the necessity of salicylaldehyde’s
ortho
-
phenolic group.
Traceless Petasis reactions have been reported to construct
allenes, which are important synthetic building blocks.
[
20
]
Schaus
and co
-
workers developed a BINOL
-
catalyzed approach for the
asymmetric addition of substituted
-
boronates to sulfonyl
hydrazones to access enantioenriched allenes.
[
21
]
In the
highlighted approach, an alkynylboronic ester
(
25
) is reacted with
a sulfonylhydraz
o
ne to generate a propargylic hydrazide (
26
),
which then undergoes a fragmentation to lose sulfinic acid,
followed by a retro
-
e
ne reaction to release dinitrogen
and form the
corresponding allene (
27
) with complete chirality transfer
(Scheme 2). In the highlighted method, the hydroxy group within
the hydrazone is required for the transformation to proceed.
Chiral diol
-
based catalysts are among the most extensively
explored for catalytic asymmetric Petasis reactions.
[
22
]
Despite the
highlighted advances, BINOL
-
catalyzed asymmetric Petasis
reactions generally only achieve moderate enantioselectivities
and yields. Furthermore, these transformations tend to be limited
in both the amine and boronate scope.
2.3
Asymmetric
Metal
-
Catalyzed Petasis
-
type Reactions
Reports of three
-
component asymmetric transition metal
-
catalyzed Petasis processes are scarce in the literature. On the
other hand, two
-
component Rh
-
catalyzed processes have been
extensively investigated.
[
23
]
Tomioka and coworkers achieved the
first asymmetric rhodium
-
catalyzed arylation of imines in 2004.
[
24
]
They employed an
L
-
valine aminomonophosphane (
(S
,
S
)
-
L1
) as
a chiral ligand for the rhodium
-
catalyzed arylation of various
N
-
tosylimines
(
29
)
with arylboroxines
(
30
)
to access diarylamines
(
31
)
with good enantioselectivities (Scheme 3).
Despite the widespread success of Rh
-
catalyzed additions
of arylboron reagents to imines, the corresponding addition of
alkenylboron reagents
remains less developed. To this end, in
2012, Lam and coworkers employed alkenylboron reagents (i.e.,
33
) in the first enantioselective Rh
-
catalyzed addition of
potassium alkenyltrifluoroborates to cyclic imines.
[
25
]
A variety of
substituted benzoxathiazine
-
2,2
-
dioxides (i.e.,
32
) were reacted
with alkyl or aryl substituted alkenyltrifluoroborates in good yields
and e
nantioselectivities (Scheme 3). Despite being limited to
cyclic imines, this method
is attractive as aryl sulfamates are
effective in a range of nickel
-
catalyzed cross
-
coupling
reactions.
[
26
]
Furthermore, we were intrigued by a 2016 report on
the asymmetric Rh
-
catalyzed dearomative arylation/alkenylation
of quinolinium salts by Wang and coworkers (Scheme 3).
[
2
7]
This
reaction offers access to enantioenriched dihydroquinolines
containing tetrasubstituted centers (i.e.,
37
). The enantioselective
addition of boronic acids to quinolinium salts was achieved
despite the lack of an accessible coordination site on the
quinolinium ion. It was proposed that the
π
-
electron system of the
quinoline ring may enhance its coordination abilities to the
rhodium
-
complex. Notably, the three methods highlighted are
also examples of non
-
directed Petasis
-
type reactions,
demonstrating th
e ability of transition
-
metal
-
catalyzed processes
to overcome limitations traditionally faced by the Petasis reaction.
Biphenol-catalyzed Petasis Reactions:
(S)-
VAPOL (15 mol%)
3Å MS, PhCH
3
, –15 °C
71% yield
86% ee
17
16
Schaus, 2008:
18
B(OEt)
2
Me
n
-Bu
Bn
2
NH
+
H
CO
2
Et
O
15
Me
CO
2
Et
n
-Bu
NBn
2
+
(S)-
Me
2
-BINOL (20 mol%)
4Å MS, PhCH
3
, 23°C
43% yield
80% ee
19
21
Shi, 2013:
22
20
BuO
B
OBu
H
O
OH
N
H
Me
Me
OH
N
Me
Me
+
Schaus, 2017:
3 Å MS
(S)
-CF
3
-BINOL
(10 mol%)
62% yield
90% ee
24
23
mesitylene
O
O
OH
OH
23 °C
1.
2.
PhCH
3
, 0 °C
27
26
TBS
OH
NH
HN
S
O
O
Ar
–HSO
2
Ar
–N
2
•
H
OH
H
TBS
Ph
OH
Ph
OH
(S)-
VAPOL
OH
OH
R
2
R
2
(S)
-Me
2
-BINOL: R
1
= H, R
2
= Me
R
1
R
1
(S)
-(CF
3
)
4
-BINOL: R
1
= R
2
= CF
3
Ar
S
NH
NH
2
O
O
+
+
Ar = 2,5-(Br)
2
C
6
H
3
25
TBS
B
OEt
OEt
Mechanistic Proposal:
O
NHR
2
B
O
R’
O
28
*
10.1002/chem.202401936
Accepted
Manuscript
Chemistry - A European Journal
This
article
is protected
by
copyright.
All
rights
reserved.
15213765, ja, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202401936 by California Inst of Technology, Wiley Online Library on [25/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License