Stereoselective Construction of γ-Lactams via Copper-Catalyzed Borylacylation

Article abstract of DOI:10.1021/acs.orglett.0c02837

A versatile and highly stereoselective borylative cyclization to generate polyfunctionalized γ-lactams has been developed. The stereoselective synthesis of these key ring systems is crucial due to their ubiquity in natural products. We report the diastero- and enantioselective construction of di- and trisubstituted γ-lactam cores, with examples containing an enantioenriched quaternary carbon.

Full text of DOI:10.1021/acs.orglett.0c02837

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Letter
Stereoselective Construction of γ‑Lactams via Copper-Catalyzed
Borylacylation
Alexa Torelli, Andrew Whyte, Iuliia Polishchuk, Jonathan Bajohr, and Mark Lautens*
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ABSTRACT: A versatile and highly stereoselective borylative
cyclization to generate polyfunctionalized γ-lactams has been
developed. The stereoselective synthesis of these key ring systems
is crucial due to their ubiquity in natural products. We report the
diastero- and enantioselective construction of di- and trisubstituted
γ-lactam cores, with examples containing an enantioenriched
quaternary carbon.
yclic amides sit among the privileged motifs in synthetic
chemistry. In particular, polyfunctionalized γ-lactams are
found in an array of bioactive natural products (Figure 1) and
Scheme 1. Examples of Prior Work in Copper-Catalyzed
Borylacylation and the Current Work
C
Figure 1. Examples of the γ-lactam core found in natural products.
serve as valuable scaffolds with pharmaceutical applications.1
Efficient methods to construct these heterocycles is an area of
ongoing interest. Despite transition-metal catalysis proving to
be a versatile synthetic tool for the construction of chiral γ-
lactams, the majority of these methods rely on precious metals
and some have limited selectivity and scope.2,3 Herein, we
report a mild, copper-catalyzed intramolecular borylacylation
process to access a broad array of differentially substituted γ-
lactams. This versatile route enables the utilization of base-
metal catalysis to furnish modular variants of γ-lactams.
Borylcupration has emerged as a powerful strategy to
difunctionalize π-systems, yielding boronate-containing prod-
ucts capable of undergoing subsequent transformations.4
These reactions proceed through an initial borylcupration,
generating a nucleophilic organocopper species, which can
then be intercepted with a variety of electrophiles. Early efforts
of Ito5 and Hoveyda6 utilized 1,2- and 1,1-disubstitued alkenes
in borylation strategies. More recently, Brown7 and Meng8
built on these studies and developed methods using acyl
electrophiles to intercept the organocopper intermediate.9
There are limited examples of borylacylation strategies to
access highly sought-after amide-containing molecules.10−14 In
2018, we disclosed the use of carbamoyl chlorides as acylating
electrophiles in the copper-catalyzed borylacylation of styrenes
to generate chiral oxindoles (Scheme 1a).10 More recently, the
Mazet13 and Tao14 groups concomitantly reported using
exogenous isocyanides to generate secondary amides (Scheme
1b). Notably, utilizing internal alkenes has yet to be fully
realized yet represents a potentially valuable pathway toward
creating amides with two contiguous stereocenters.
Building on our recent interest in copper-catalyzed
cyclization strategies to generate heterocycles,10,11,15−17 we
sought to develop a general route to construct chiral borylated
Received: August 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02837
© XXXX American Chemical Society
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Letter
γ-lactams. Utilizing either 1,2- or 1,1-disubstituted alkenes in
an intramolecular borylacylation with a tethered carbamoyl
chloride would enable the construction of γ-lactams in a
stereocontrolled manner (Scheme 1c). Furthermore, the
incorporation of a carbon−boron handle would facilitate
downstream functionalization adding to the synthetic value of
these scaffolds.
Scheme 2. Diastereoselective Borylacylation of 1,2-
Disubstituted Alkenes
a
Substrate 1a was the starting point for the investigation,
using reaction conditions similar to our previous report.10 The
optimal conditions involve dppe (L1) as the ligand and THF
as the solvent (Table 1, entry 1). At room temperature, the
Table 1. Optimization of Reaction Conditions
a
b
entry
variation of standard condition
yield (%)
dr
1
2
3
4
5
6
7
8
9
none
L2 instead of L1
L3 instead of L1
L4 instead of L1
KOtBu instead of NaOtBu
LiOtBu instead of NaOtBu
toluene instead of THF
MTBE instead of THF
1,4-dioxane instead of THF
99 (97)
86
71
65
80
94
60
84
87
>20:1
6:1
3:1
>20:1
5:1
11:1
>20:1
>20:1
>20:1
a
Reactions performed on a 0.2 mmol scale. All reported yields are
1
after isolation; dr determined by H NMR spectroscopic analysis of
the crude reaction mixture. PMP = p-methoxyphenyl. Reaction
performed on a 2.0 mmol scale. Reaction run at 50 °C for 24 h using
MTBE instead of THF.
b
a
NMR yield determined by using 1,3,5-trimethoxybenzene as a
c
b
standard (isolated yield in parentheses). dr determined by 1H NMR
spectroscopic analysis of the crude reaction mixture.
of starting material. Both electron-donating (2g) and electron-
withdrawing substituents (2h) at the meta position generated
products in excellent yield. Similarly, 2i was obtained in nearly
quantitative yield, while the bromo substrate (2j) proved to be
less reactive. An ortho-methoxy substituent delivered product
2k in only 23% yield. Substituting a functionalized phenyl ring
by a furyl group or thienyl group was successful and generated
the respective products 2l and 2m in excellent yield.
Modification of the aryl substituent at nitrogen had minor
effects on the reaction, with the phenyl (2n) and para-tolyl
(2o) groups generating products in 85% and 76% yield,
respectively. Beyond N-aryl-derived products, a substrate
bearing a benzylic substituent on the nitrogen participated in
the reaction, delivering 2p in excellent yield. Attempts to
prepare a 3,4,5-trisubstituted γ-lactam revealed that the
cyclization was more sluggish, requiring elevated temperature
and prolonged reaction time. Following optimization, the all-
syn trisubstituted product 2q was formed in 69% yield while
maintaining high diastereoselectivity (see the Supporting
Information for details). Preliminary investigations of an
enantioselective variant revealed the highest asymmetric
induction with the Josiphos ligand L5, which generated 3n
in 83.5:16.5 er (Scheme 3). Further optimization is needed.
We applied similar conditions to 1,1-disubstituted alkene-
tethered carbamoyl chloride (3a) to provide the 3,3-
3,4-disubstituted γ-lactam (2a) was isolated in 97% yield as a
single diastereomer with syn configuration (Scheme 2). Other
bidentate ligands eroded either selectivity (Table 1, entries 2
and 3) or yield (Table 1, entry 4). Of the commonly employed
alkoxide bases, we found that NaOtBu gave the highest
diastereoselectivity (Table 1, entries 5 and 6). Toluene
delivered the product in slightly lower yield (Table 1, entry
7). Other ethereal solvents such as MTBE or dioxane were
suitable; however, improved solubility of the substrate was
observed in THF (Table 1, entries 8 and 9). Notably, side-
products resulting from direct attack of the borylcopper or
alkoxide to the carbamoyl chloride group were not observed.
Furthermore, the reaction was amenable to scale-up, as the
product could be formed in near identical yield and dr at 2.0
mmol (Scheme 2).
The ability to access diverse 3,4-disubstituted γ-lactams was
investigated by examining variation of the styrenyl substituent
(Scheme 2). An electron-donating group in the para position
(2b) gave the product in somewhat lower yield. In contrast,
electron-withdrawing groups such as trifluoromethyl (2c) and
fluoro (2d) gave the desired product in high yields. A chloro
group in the para position furnished product 2e in 83% yield;
however, the analogous bromo substrate was less reactive and
gave 2f in significantly lower yield, with incomplete conversion
B
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found that changing the solvent from THF to Et2O improved
enantioselectivity and delivered 4f in 93:7 er and 65% yield.
On the basis of our results and previous literature,18,19 we
propose that a syn migratory insertion and stereoretentive
cyclization leads to the observed syn stereoisomer of the 3,4-
disubstituted γ-lactams (Scheme 5a). To investigate the origin
Scheme 3. Enantioselective 3,4-Disubstituted γ-Lactam
Synthesis
a
Scheme 5. Proposed Diastereo- and Enantioselectivity
Models
a
1
Reactions performed on a 0.2 mmol scale; dr determined by H
NMR spectroscopic analysis of the crude. Isolated yields reported; er
determined by chiral HPLC.
disubstituted γ-lactam (4a) (Scheme 4). More importantly, the
chiral bisphosphine ligand L6 gave 4a in 95% yield and 97:3 er.
Scheme 4. Asymmetric Borylacylation of 1,1-Disubstituted
a
Alkenes
of enantioinduction of the 3,3-disusbtituted products, we
generated a quadrant diagram to predict the enantiomer of the
migratory insertion step (Scheme 5b). In our analysis, we
propose the enantioselective borylcupration of styrene 3a
generates the benzylcopper intermediate 3aint with an S-
configuration.16 The subsequent cyclization of the benzylic
copper species proceeds with stereoinversion to generate
product 4a, aligning with previous reports16,18,20
With the ability to increase the scale of the reaction, while
maintaining yield and selectivity, we carried out the reaction of
1a on a 2 g scale under reduced catalyst loading and increased
concentration (Scheme 6a). The product was isolated in >20:1
dr and 75% yield. We then briefly examined reactions of the
carbon−boron bond, including oxidation, to obtain product 5a
in 90% yield, with no deterioration of the diastereoselectivity
(Scheme 6b). The boronate was also converted to a new
carbon−carbon bond through a vinylation procedure, which
delivered 5b in 49% yield and >20:1 dr. In addition, a
heterocycle could be installed at the β-carbon through a
stereoretentive arylation procedure21 to furnish product 5c in
synthetically useful yields while maintaining high diastereose-
lectivity.
In conclusion, we have developed a general and mild
method to synthesize polyfunctionalized γ-lactams in a highly
stereoselective manner. This strategy utilizes simple 1,2-
disubstituted olefins in a facile intramolecular borylacylation
to generate chiral 3,4-disubsituted γ-lactams in excellent
diasteroselectivity. Furthermore, 1,1-disubstituted olefins can
be employed to generate 3,3-disubstituted γ-lactams in
excellent enantioselectivity. We demonstrated scalability of
this methodology and reactivity of the boronate handle
a
Reactions performed on a 0.2 mmol scale. All reported yields are
b
after isolation; er determined by chiral HPLC. Reaction run using
MTBE instead of THF.
Single crystal X-ray diffraction of 4a was used to determine the
absolute stereochemistry, and the stereochemistry of all other
products was assumed by analogy. We surveyed the effect of
aryl substituents on the styrenyl moiety. A bulky methoxy
substituent at the ortho position of 3b appeared to compromise
the cyclization and delivered the product 4b in moderate yield
and enantioselectivity (64% yield, 89.5:10.5 er) In contrast, a
substituent at the meta position gave 4c in 82% yield and 98:2
er. A naphthyl substituent delivered product 4d in excellent
enantioselectivity (96.5:3.5 er) and good yield (74%).
Likewise, an electron-rich substituent at the para position
was tolerated, furnishing 4e in 85% yield and 97:3 er. An
electron-withdrawing group at this position resulted in an
erosion in the enantioselectivity, as seen in product 4f. We
C
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Letter
a
Andrew Whyte − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto, Ontario M5S
3H6, Canada; orcid.org/0000-0001-7261-4309
Iuliia Polishchuk − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada
Scheme 6. Gram-Scale and Derivatizations
Jonathan Bajohr − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02837
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Toronto, the Natural Science and
Engineering Research Council (NSERC), and Kennarshore
Inc. for financial support. A.T. thanks NSERC for a
postgraduate scholarship (PGS-D). A.W. thanks the Walter
C. Sumner Memorial Fellowship and the Province of Ontario
(QEII) for funding. I.P. thanks Professor M. Rueping and
RWTH Aachen University for financial support. J.B. thanks the
Province of Ontario (OGS) for funding. We thank Alan Lough
(University of Toronto) for X-ray crystallography of 2a and 4a.
We thank E. M. Larin (University of Toronto) and B. Mirabi
(University of Toronto) for insightful discussions and
proofreading.
a
1
All reported yields are after isolation. dr determined by H NMR
spectroscopic analysis of the crude. PMP = para-methoxyphenyl. See
the Supporting Information for details.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02837.
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Experimental procedures, characterization data, crystal-
lographic data for 2a and 4a, NMR spectra, and HPLC
spectra for new compounds (PDF)
Accession Codes
CCDC 2023481−2023482 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mark Lautens − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto, Ontario M5S
3H6, Canada; orcid.org/0000-0002-0179-2914;
Email: mark.lautens@utoronto.ca
Authors
Alexa Torelli − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto, Ontario M5S
3H6, Canada; orcid.org/0000-0002-6800-7706
D
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