Enantioselective Copper-Catalyzed Borylative Cyclization with Cyclic Imides

Article abstract of DOI:10.1021/acs.orglett.9b03144

An enantioselective borylative cyclization cascade utilizing cyclic imides has been developed. We employ a highly enantioselective borylcupration process that includes a 1,2-addition to a cyclic imide. The products contain a valuable hemiaminal and boronate handle for further elaborations within a congested framework. This work demonstrates the utility of cyclic imides as simple precursors to unlock access to sought-after polycyclic indolines. Futhermore, this report highlights the capability to harness reactive catalytic intermediates to exploit otherwise unreactive functional groups.

Full text of DOI:10.1021/acs.orglett.9b03144

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Copper-Catalyzed Borylative Cyclization with Cyclic
Imides
Andrew Whyte, Alexa Torelli, Bijan Mirabi, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S
3H6, Canada
S
* Supporting Information
ABSTRACT: An enantioselective borylative cyclization cascade
utilizing cyclic imides has been developed. We employ a highly
enantioselective borylcupration process that includes a 1,2-addition to
a cyclic imide. The products contain a valuable hemiaminal and
boronate handle for further elaborations within a congested framework.
This work demonstrates the utility of cyclic imides as simple precursors to unlock access to sought-after polycyclic indolines.
Futhermore, this report highlights the capability to harness reactive catalytic intermediates to exploit otherwise unreactive
functional groups.
a
yclic imides have found limited use in asymmetric
catalysis despite their potential to access valuable
Scheme 1. Cyclization Strategies Employing Cyclic Imides
C
stereoenriched hemiaminals.1 This is likely attributable to
their relatively stable nature when compared to traditionally
employed acyl groups such as ketones and aldeyhydes. Chiral
hemiaminals and imides are ubiquitous in natural products and
are often embedded in polycyclic systems.2 As a result,
hemiaminal-containing heterocycles have become key targets
in organic synthesis. Although this framework appears readily
accessible via cyclization from the corresponding imide, no
enantioselective examples have been reported to date.3 Several
nonenantioselective cyclizations have been developed by
Hoye,4 Szostak,5 Cha,6 and others (Scheme 1);7 however,
these methods often employ stoichiometric Lewis or Brønsted
acids, or radical initiators, thereby hindering asymmetric
variants. To address this synthetic challenge, we envisioned
harnessing a chiral benzylic copper intermediate to react with a
tethered imide by employing an asymmetric borylcupration
process.
The asymmetric addition of boron to olefins is an
indispensable tool to readily introduce molecular complexity
and flexibility. Copper catalysis has played a central role in fully
realizing the potential of this concept, often via the 1,2-
bisfunctionalization of alkenes.8 Ito,9 Hoveyda,10 and Brown11
have illustrated this approach by employing various π-systems
and a plethora of external electrophiles. These methods initiate
through an enantioselective borylcupration across a π-system,
followed by electrophilic trapping of the organocopper
intermediate. Carbonyl-based reagents, including acid hal-
ides,12 esters,13 ketones,14 aldehydes,15 and carbamoyl
chlorides,16 have been investigated as electrophiles; however,
imides remain entirely unexplored.
a
Examples of imide cyclizations to access hemiaminals.
this strategy to access polycyclic heterocycles remains largely
underexplored. Polycyclic indolines have been widely studied
due to their prevalence in natural products and pharmaceuti-
cally relevant compounds.20 These frameworks are often found
in congested ring systems containing sensitive functionalities
and contiguous stereocenters. Although numerous asymmetric
strategies have been developed to assemble complex indolines,
We aimed to exploit the unrealized potential of cyclic imides
as terminal electrophiles to access polycyclic indolines in a
borylative cyclization.17 This cascade reaction has been studied
to assemble simple ring systems18 and bicyclic carbocycles19
while employing well-known electrophiles. The application of
Received: September 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
access to densely functionalized scaffolds remains a chal-
lenge.21
Scheme 2. Reaction Scope with Varied Aryl Backbone
We initiated our work by screening conditions based on our
previous report and found optimal conditions utilizing (S,S)-
Ph-BPE as a chiral ligand.16 The product was obtained in 80%
yield as a single diastereomer in 97% ee. Other chiral ligands
demonstrated significantly lower enantioselectivities (Table 1,
Table 1. Optimization of Reaction Conditions
conversion
a
b
entry variation of standard condition
[%]
yield [%]
ee
1
2
3
4
5
6
7
8
9
none
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
L7 instead of L1
THF instead of MTBE/THF
dioxane instead of MTBE/THF
full
full
full
full
full
74
>83 (80)
97
−19
68
−53
45
−17
9
89
81
95
81
84
74
81
20
53
39
63
67
77
a
Reaction scope with varied aryl backbone (0.2 mmol scale) for 4 h
full
full
76
unless otherwise indicated. All reported yields are after isolation; all
observed in >20:1 dr unless otherwise indicated; ee determined by
10
2 equiv of MeOH instead of
1 equiv
b
chiral HPLC. Run for 24 h.
11
12
iPrOH instead of MeOH
tert-amyl alcohol instead of
MeOH
full
full
72
79
95
95
1944263), and all products are assigned their stereochemistry
by analogy. A substrate bearing a chloride as well as an ortho-
fluoride on the pendant ring (2g) showed no decrease in ee;
however, it was obtained in only moderate yield. While
electron-rich substituents (2h, 2i) were tolerated in good
yields and enantioselectivities, product 2j, containing the
dimethoxy substituents, was obtained in lower yield and
enantioselectivity after 24 h. Electron-poor substituents such as
trifluoromethyl (2k) and fluoride (2l) yielded products in
excellent enantioselectivities. Consistent with our previous
report,16 product 2m containing a para-chloride was obtained
with very poor enantioselectivity. The analogous bromide
substrate yielded only trace product (see Supporting
Information (SI) for details). A fluoride substituent positioned
ortho to the succinimide furnished product 2n in high ee;
however, poor yield and a lower dr were observed.
Following this study, we surveyed substitution patterns on
the pendant aromatic ring (Scheme 3). We observed that
methoxy and ethyl substituents (4a and 4b) were tolerated
with excellent enantioselectivities at the meta position.
However, when examining electron-poor substituents (4c
and 4e), we observed lower enantioselectivities. Interestingly,
introducing a chloride in the backbone (4d) led to an increase
in enantioselectivity to 98% ee. Other meta substituents
a
NMR yield determined by using 1,3,5-trimethoxybenzene as
standard; isolated yield in parentheses. Determined by chiral
HPLC using OD-H column eluting with 25% IPA in hexanes.
b
entries 2−7). A solvent mixture of MTBE/THF (19:1) was
employed; while MTBE was an effective solvent for high
enantioselectivity, THF was required to improve the solubility
of the substrate. Other ethereal solvents such as THF or
dioxane delivered poorer results (Table 1, entries 8−9). It was
found that one equivalent of methanol provided the best
results, as bulkier alcohols showed lower enantioselectivities
(Table 1, entries 10−12). Throughout the optimization,
product 2a was only obtained as a single diastereomer.
Next, we examined the applicability of our methodology by
varying the substitution on the aryl backbone (Scheme 2).
Product 2b was obtained in lower yield likely due to the
increased steric bulk around the olefin; however, high
enantioselectivity was maintained. A methyl group (2c) and
various halogens (2d, 2e, 2f) were all tolerated with good
yields and excellent enantioselectivities when situated meta
relative to the alkene. The absolute stereochemistry was
determined for 2e by single crystal X-ray diffraction (CCDC
B
DOI: 10.1021/acs.orglett.9b03144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Reaction Scope with Varied Alkenyl
Substituents
Scheme 4. Scale-up and Derivatizations
a
a
Large scale reaction using 2 mmol of substrate (above).
Derivatizations of product (below). All reported yields are after
isolation; dr determined by 1H NMR analysis of crude; ee determined
b
by chiral HPLC. Batch of 2e used was 98% ee.
83% yield and 97% ee which was in good agreement with the
small-scale result. Next, we aimed to showcase the versatility of
the carbon−boron bond. We began with oxidation using
sodium perborate and obtained alcohol 5a, in 97% yield. The
resulting primary alcohol could be selectively acylated in 80%
yield (5c). Treatment of 5c with CSA furnished enamine 5e in
77% yield. Alternatively, the hemiaminal could be reduced with
triethylsilane in the presence of a Lewis acid to provide 5b, in
85% yield in 19:1 dr. We also successfully performed Matteson
homologation followed by oxidation to obtain product 5d in
78% yield, with minimal loss in enantiomeric purity.
a
Reaction scope with varied alkenyl substituents (0.2 mmol scale) for
4 h unless otherwise indicated. All reported yields are after isolation;
all observed in >20:1 dr unless otherwise indicated; ee determined by
chiral HPLC. Run for 24 h.
b
In summary, we have developed an enantioselective copper-
catalyzed borylation/1,2-imide addition cascade reaction to
assemble boron-containing indolines. Our reaction exploits
tethered imides as electrophiles to generate highly congested
molecular frameworks. The process was found to be highly
diastereo- and enantioselective and tolerated a variety of aryl
substituents. The highly functionalized indoline products
served as valuable platforms to access a diverse library of
new indolines. This work demonstrates the utility of copper
catalysis to assemble complex boron-containing heterocycles
and establishes a new method to access biologically relevant
indolines.
including chloride (4f) and a disubstituted aryl ring (4g) were
tolerated in moderate yields and good enantioselectivities.
Product 4h containing a para-methyl substituent was obtained
in 78% yield and 97% ee. In the case of a methoxy substituent
(4i), we observed a slower reaction that required 24 h;
however, the product was obtained in excellent enantiose-
lectivity. Electron-withdrawing substituents at the para
position (4j and 4k) gave excellent ee but led to a slight
decrease in yield. Analogous to 2m, product 4l was obtained in
lower yield and enantioselectivity. When aromatic rings were
replaced with 2-thienyl (4m) or 3-thienyl (4n) groups, the
products were obtained in lower enantioselectivities (82% and
78% ee respectively). However, introduction of a chloride to
the aryl backbone (4o) restored enantioselectivity to 90% ee.
Unfortunately, products bearing a methyl (4p) or no
substituent (4q) could not be obtained (see SI for details).
The analogous six-membered ring product could be obtained
in poor yields and stereoselectivity (see SI for details).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03144.
1
Experimental procedures, characterization data, H/13C
To demonstrate the scalability of this process we performed
the reaction using 2 mmol of 1e while reducing the catalyst
and ligand loadings (Scheme 4). Product 2e was obtained in
NMR spectra, X-ray structures of 2e, and HPLC spectra
for new compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b03144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
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CCDC 1944263 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mark.lautens@utoronto.ca.
ORCID
Andrew Whyte: 0000-0001-7261-4309
Mark Lautens: 0000-0002-0179-2914
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Toronto, the Natural Science and
Engineering Research Council (NSERC), Alphora/Eurofins,
and Kennarshore Inc. for financial support. A.W. thanks the
Walter C. Sumner Memorial Fellowship, Province of Ontario
(OGS), and CREATE ChemNET for funding. A.T. and B.M.
thank the Province of Ontario (OGS) for funding. We thank
Alan Lough (University of Toronto) for X-ray crystallography
of 2e. We thank Dr. Darcy Burns and Dr. Jack Sheng
(University of Toronto) for their assistance in NMR
́
experiments. We thank J. F. Rodriguez (University of Toronto)
for insightful discussions and proofreading.
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