Enantioselective hydroesterificative cyclization of 1,6-enynes to chiral γ-lactams bearing a quaternary carbon stereocenter

Article abstract of DOI:10.1021/acs.orglett.1c00952

A palladium-catalyzed asymmetric hydroesterification-cyclization of 1,6-enynes with CO and alcohol was developed to efficiently prepare a variety of enantioenriched γ-lactams bearing a chiral quaternary carbon center and a carboxylic ester group. The approach featured good to high chemo-, region-, and enantioselectivities, high atom economy, and mild reaction conditions as well as broad substrate scope. The correlation between the multiple selectivities of such process and the N-substitutes of the amide linker in the 1,6-enyne substrate has been depicted by the crystallographic evidence and control experiments.

Full text of DOI:10.1021/acs.orglett.1c00952

pubs.acs.org/OrgLett
Letter
Enantioselective Hydroesterificative Cyclization of 1,6-Enynes to
Chiral γ‑Lactams Bearing a Quaternary Carbon Stereocenter
Xinyi Ren,# Lin Tang,# Chaoren Shen, Huimin Li, Peng Wang, and Kaiwu Dong*
Cite This: Org. Lett. 2021, 23, 3561−3566
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A palladium-catalyzed asymmetric hydroesterification-cyclization of 1,6-enynes with CO and alcohol was developed
to efficiently prepare a variety of enantioenriched γ-lactams bearing a chiral quaternary carbon center and a carboxylic ester group.
The approach featured good to high chemo-, region-, and enantioselectivities, high atom economy, and mild reaction conditions as
well as broad substrate scope. The correlation between the multiple selectivities of such process and the N-substitutes of the amide
linker in the 1,6-enyne substrate has been depicted by the crystallographic evidence and control experiments.
hiral γ-lactams play a significant role in a variety of
bioactive compounds and are also regarded as a
corresponding asymmetric variant is rather sluggish, probably
due to the difficulty of simultaneously controlling the chemo-,
regio-, and enantioselectivities under a nonbeneficial reaction
temperature and high CO pressure.14 Following our interest in
catalytic asymmetric carbonylation15 and cyclization16 reac-
tions, we envisioned integrating the challenging but rewarding
alkoxycarbonylation with enyne cyclization reaction would
offer a novel entry to chiral heterocyclic compounds containing
both a carboxylic ester group and a quaternary carbon center
with high efficiency of carbon−carbon/heteroatom bond
formation.
Herein, we described the first palladium-catalyzed asym-
metric hydroesterificative cyclization of 1,6-enynes (Scheme
1). The type of amide-tethered 1,6-enyne substrate, containing
an internal alkyne and a terminal gem-disubstituted alkene, was
investigated recently for the palladium-catalyzed nonasym-
metric hydrohalogenation-cyclization to δ-lactams by Pobla-
dor-Bahamonde and Lautens17 as well as the cobalt-catalyzed
enantioselective hydroboration-cyclization to chiral γ-lactams
from the group of Ge.8a Generally, these hydrofunctionalizative
cyclization processes start with the formation of metal hydride
followed by the alkyne group addition and subsequent
intramolecular insertion of the alkene unit into the formed
metal−alkenyl intermediates to generate a metal−alkyl
complex. In the previous studies, such species were trapped
C
serviceable synthesis precursor of N-heterocyclic molecules
due to the versatile transformation of the amide functional
group.1 Thus, a variety of catalytic asymmetric methods has
been established toward preparing optically active γ-lactams.2
The intrinsic effect of all-carbon quaternary stereocenter on
biological characteristics, i.e., activity, metabolism, solubility,
and hydrophobicity, endows its construction method with
long-lasting research interest.3 Owing to the congested
circumstances, catalytic enantioselective creation of such a
quaternary carbon center via a forming carbon−carbon bond is
an imperative but quite challenging task.4 In this context,
despite significant progress in the enantioselective synthesis of
chiral γ-lactams, only a few protocols could construct such a
skeleton bearing an all-carbon quaternary stereocenter.5
Transition-metal-catalyzed stereoselective cycloisomeriza-
tion,6 reductive cyclization,7 and hydrofunctionalizative cycli-
zation8−10 of 1,6-enynes provide an efficient and convenient
access to five-membered (hetero)cycles. Especially, merging
the hydrofunctionalization of unsaturated bond with the
cyclization reaction manifests high bond-forming efficiency,
rapid construction of complex molecules, and/or high atomic
economy. Apart from the established asymmetric hydro-
boration-,8 hydrosilylation-,9 and hydrovinylation-cyclization,11
to our knowledge, neither the nonasymmetric nor enantiose-
lective hydrocarbonylation-cyclization process of dienes/
enynes has yet to be exploited.12 Palladium-catalyzed hydro-
esterification reaction constitutes one of the ideal routes to
prepare carboxylic acid derivatives from readily available
feedstocks of unsaturated hydrocarbons, CO, and alcohols.13
Compared with the well-established industrial application of
nonasymmetric alkoxycarbonylation, the development of
Received: March 22, 2021
Published: April 28, 2021
https://doi.org/10.1021/acs.orglett.1c00952
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3561−3566
3561

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Asymmetric Hydroesterification-Cyclization of
Scheme 2. Effect of the N-Substituent of the Substrate
Amide-Tethered 1,6-Enynes
by the reactive H-X (X = halide or -Bpin) substrate and
converted into the corresponding lactams along with the active
catalyst regeneration. In our protocol, CO was introduced to
insert the palladium−alkyl complex, and the alcohol
nucleophile was utilized to alcoholize the resulting palla-
dium−acyl species (Scheme 1). A series of chiral carboxylic
esters containing a γ-lactam skeleton and a quaternary carbon
stereocenter were delivered. This approach proceeded under
ambient reaction temperature and exhibited high bond
construction efficiency and good functional group compati-
bility. By changing the N-substitutes of amide linker in the 1,6-
enynes substrate to adjust the stable spatially conformation
around the active metal center, the chemo-, regio-, and
enantioselectivities of this unprecedented process were
controlled.
At the beginning of our studies, the palladium-catalyzed
asymmetric hydroesterificative cyclization of p-toluenesulfo-
nate (Ts-) protected 1,6-enynes 1a with CO and MeOH was
chosen as the model reaction. After the optimization of the
reaction conditions, the combination of Pd(OAc)2, (S)-MeO-
BIPHEP, and TsOH·H2O was used as the catalyst system, and
this tandem process was conducted with 4 equiv of alcohol
under 20 bar pressure of CO in a mixed solvent of toluene/
DCE (9/1) at room temperature (Scheme 2). The desired
chiral γ-lactam 2a was isolated in excellent ee value and good
yield, along with the presence of uncyclized alkyne carbon-
ylation compound 3a (2a/3a = 74/36). Besides 3a, no other
uncyclized isomer was detected. On the basis of the reaction
pathway (Scheme 1), this result indicated the irreversible
regioselective hydropalladation step of the alkyne unit in 1a
with the active palladium-hydride catalyst determined the ratio
of 2a/3a. The subsequent cyclization step via adding the PdII−
C(sp2) bond of PdII−alkenyl intermediate onto the CC
bond of the alkene moiety is crucial to both chemoselectivity
and enatioselectivity. In principle, such an insertion step could
be adjusted by the relative spatial position between PdII−
alkenyl and alkene moieties, which probably could be affected
by the N-substitutes of the amide linker in the substrate.
Therefore, a series of substitutes on the N-atom as well as
other type of the linker were investigated. Both electron-
donating and electron-withdrawing substituents on the phenyl
ring of the sulphonyl group in the enyne exhibited an
unnoticeable effect on the enantioselectivity but considerable
influence on the distribution of the cyclization/uncyclization
a
(a) Reactions were run on 0.1 mmol scale. Yield and ratio of 2a/3a
were determined by GC-FID using n-decane as an internal standard.
Ee values were determined by HPLC analysis. Isolated yield. (b)
ORTEP diagrams with thermal ellipsoids at the 50% probability level.
products (2a−2f). Replacing the sulphonyl group in the
substrate by methyl (2g), phenyl (2h), hydrogen (2i), or aroyl
(2j) group resulted in significantly low yield or trace amounts
of wanted γ-lactams. When the tether was changed from the
amide group to the corresponding protected amine unit (1k),
the yield of cyclized product dropped significantly. These
results suggested both the sulphonyl and carbonyl groups are
essential to this carbonylation-cyclization reaction.
Because the configuration flipping of the amide linker
between Z and E forms via C−N bond rotation in the enyne
substrates is rather sluggish at such low reaction temperature,17
the spatial conformation of these reactants might affect the
ratio of 2/3 and the reaction stereoselectivity. To validate such
a relationship, single crystals of the substrates (1a, 1h, and 1i−
1k) were cultivated and suitable for the X-ray diffraction
characterization (Scheme 2). Seemingly, the close distance
between the alkyne and the alkene moieties in the 1,6-enynes
was beneficial to the chemoselectivity toward cyclized
products.
After exploring the effect of the N-substitute of the enyne
substrate on the multiple selectivities for the tandem
methoxycarbonylation-cyclization, we therefore began the
evaluation of reaction conditions. The standard reaction was
carried out with 1a, CO (20 bar), and MeOH (4.0 equiv)
using 2.5 mol % Pd(OAc)2, 3 mol % L1, and 24 mol % PTSA·
3562
https://doi.org/10.1021/acs.orglett.1c00952
Org. Lett. 2021, 23, 3561−3566

Organic Letters
pubs.acs.org/OrgLett
Letter
H2O as the catalyst at room temperature (for details see
Supporting Information (SI), Table S1). With the optimized
reaction conditions in hand, the substrate scope and functional
group compatibility for this catalytic asymmetric hydro-
esterfication-cyclization of 1,6-enynes were studied. First, the
substituents on the alkyne moiety of 1 were varied and the
desired chiral γ- lactams (2l-2aa) were afforded in reasonable
to good yields with high enantioselectivity using the suitable
chiral bidentate phosphine ligand and Pd(OAc)2 as the catalyst
system (Table 1). The aryl group attached to the triple bond of
the substrate bearing both electron-rich (2l−2o) and electron-
deficient substituents (2r−2w) at the para-, ortho-, or meta-
position was suitable for this conversion, giving slightly lower
yields with the same level of ee value. A variety of functional
groups, such as methoxy (2m), halide (2r−2t), nitrile (2u),
ester (2v), trifluoromethyl (2w), and piperonyl (2x), were
well-tolerated with up to 95% ee without significantly
compromising the yield under slightly modificated reaction
conditions. Besides aryl and 2-naphthyl (2q) units, hetero-
aromatic rings, including 2-thienyl and 2-furyl groups (2y, 2z),
were also compatible and high ee value with reasonable to
moderate yields was obtained. In addition, the enyne substrate
with aliphatic methyl substitute at the terminus of the alkyne
(2aa) was also smoothly transformed into the wanted γ-lactam
in 50% yield with 82% ee using chiral phosphine ligand L3
instead of L1. When the enyne (1ab) bearing tertiary butyl
substituent at the terminus of the alkyne was used as the
substrate, no substrate conversion was obtained.
We next turned our attention to investigating the influence
of the substituted alkene moiety of the enyne on this tandem
cyclized alkoxycarbonylation (Table 2). Replacing the methyl
Table 1. Scope of 1,6-Enynes with Various Substituted
Alkynes
a
Table 2. Scope of 1,6-Enynes with Different Substituted
Alkenes
a
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2/L1/PTSA•H2O
(2.5/3/24 mol %), CO (20 bar), R′OH (0.8 mmol, 4 equiv),
b
c
toluene/DME (1.8/0.2 mL), rt, 12 h. L4 instead of L1. Pd(OAc)2
(5 mol %), L2 (6 mol %).
group by ethyl, n-butyl, or ether-containing aliphatics was able
to deliver the corresponding lactams 2ac−2ad or 2af−2ag in
moderate yields with high ee value. Besides normal aliphatic
one, phenyl-, and benzyl-substituted substrates were also
compatible to furnish the products 2ae and 2ah−2aj with
excellent enantioselectivity and reasonable to good yields. Both
electron-acceptor (2ai) and electron-donor (2aj) groups on
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2/L1/PTSA•H2O
(2.5/3/24 mol %), CO (20 bar), MeOH (0.8 mmol, 4 equiv),
toluene/DME (1.8/0.2 mL), rt, 12 h. Pd(OAc)2 (5 mol %), L2 (6
b
c
d
mol %). Pd(OAc)2 (5 mol %), L1 (6 mol %). L4 instead of L1.
e
ORTEP diagram with thermal ellipsoids at the 50% probability level.
f
Pd(OAc)2 (5 mol %), L3 (6 mol %), and reaction temperature was
10 °C.
3563
https://doi.org/10.1021/acs.orglett.1c00952
Org. Lett. 2021, 23, 3561−3566

Organic Letters
pubs.acs.org/OrgLett
Letter
the benzyl ring tethered to the alkene exhibited no effect on
this reaction. Inspired by these results, the nucleophile sources
for such transformation were examined, and the alcohol EtOH
carbonylation products of 7 and 8 with the ratio of 1:1 in high
yield. The decreased regioselectivity with 6 as the substrate
may be caused by the loss of the coordination of the alkene
moiety in the enyne substrate to the palladium catalyst.8a With
dienyne 9 as the substrate, cyclization/uncyclization products
10/11 with a ratio of 3/1 were afforded in high yield, wherein
very low ee value of the lactam 10 was observed. These results
suggested the alkene group of the enyne substrate plays a
function to affect the site selectivity in the initial hydro-
palladation step, and the -Ts group is essential to the
enantioselectivity.
In conclusion, the first palladium-catalyzed enantioselective
hydroesterification-cyclization of amide-tethered 1,6-enynes
was developed. Various chiral γ-lactams bearing all-carbon
quaternary stereocenters with high ee value were synthesized
efficiently under milder conditions. Changing the substituent
on the amide tether of the enyne substrate could alter the
relative spatial position between the alkyne and the alkene
moieties, which was demonstrated to be critical to adjust the
multiple selectivities of this reaction process.
n
and BuOH were also amenable to generate target products
2ak and 2al with 92% ee and slightly diminished yield. The
substrate 1am (R = H) without methyl substituent on the
alkene was also investigated in the enantioselective methox-
ycarbonylative cyclization, which gave the desired product 2am
in 50% isolated yield with 69% ee value. Other types of
nucleophiles, such as amine and thiol, were demonstrated to be
not suitable in this hydrocarbonylation-cyclization reaction
(2an and 2ao). Substrates (1ap and 1aq) including O- and C-
tethered 1,6-enynes failed to undergo such asymmetric
hydroesterificative cyclization reaction.
After exploring the substrate scope of the hydroesterifica-
tion-cyclization of the enynes, gram-scale synthesis was carried
out, and the γ-lactam 2a was obtained in good yield and
excellent enantioselectivity (Scheme 3A). The protecting
a
Scheme 3. Derivatization and Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00952.
Experimental details, X-ray data, characterization data,
and NMR spectra (PDF)
Accession Codes
CCDC 2009853, 2010126, 2061495−2061498, and 2061500
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.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
■
Kaiwu Dong − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P.R. China;
orcid.org/0000-0001-6250-2629; Email: kwdong@
chem.ecnu.edu.cn
a
Reaction conditions: (a) 2a (0.1 mmol), SmI2 (1.0 mL, 0.1 M in
THF), THF (4 mL), rt, 10 min; (b) 2a (0.1 mmol), RuCl3·xH2O (2
mol %), NaIO4 (3 equiv), CH2Cl2/CH3CN/H2O (0.5/0.5/1.0 mL),
rt, 1 h. The ratio of 7/8 was determined by GC-FID. The ratio of 10/
1
11 was determined by H NMR.
Authors
Xinyi Ren − Chang-Kung Chuang Institute, and Shanghai Key
Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P.R. China
Lin Tang − Chang-Kung Chuang Institute, and Shanghai Key
Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P.R. China
group -Ts in 2a was easily removed by SmI2 to give the
corresponding chiral γ-lactam 4 in good yield and 92% ee. The
chiral 2,3-pyrrolidinedione 5 could be readily obtained by
oxidation of 2a without diminishing enantiomeric excess,
which could be further converted regioselectively to the β-
amino acid derived N-carboxyanhydride according the
reported reference.18
To probe the mechanism and disclose the role of the double
bond in the enyne substrate on the reaction stereoselectivity
for the palladium-catalyzed asymmetric hydroesterification-
cyclization, control experiments using alkyne 6 and dienyne 9,
bearing isobutyl or two isobutenyl groups, were carried out
under identical reaction conditions (Scheme 3B). Replacing
the isobutenyl group of 1a by an isobutyl group led to the
Chaoren Shen − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P.R. China;
orcid.org/0000-0002-2849-7990
Huimin Li − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
3564
https://doi.org/10.1021/acs.orglett.1c00952
Org. Lett. 2021, 23, 3561−3566

Organic Letters
pubs.acs.org/OrgLett
Letter
12564−12580. (d) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.;
Zhou, J. Catalytic Enantioselective Desymmetrization Reactions to
All-Carbon Quaternary Stereocenters. Chem. Rev. 2016, 116, 7330−
7396. (e) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective
Synthesis of Quaternary Carbon Stereocentres. Nature 2014, 516,
181−191.
(5) (a) Seki, T.; Tanaka, S.; Kitamura, M. Enantioselective Synthesis
of Pyrrolidine-, Piperidine-, and Azepane-Type N-Heterocycles with
α-Alkenyl Substitution: The CpRu-Catalyzed Dehydrative Intra-
molecular N-Allylation Approach. Org. Lett. 2012, 14, 608−611.
(b) Song, T.; Arseniyadis, S.; Cossy, J. Org. Lett. 2019, 21, 603−607.
(c) Jette, C. I.; Geibel, I.; Bachman, S.; Hayashi, M.; Sakurai, S.;
Shimizu, H.; Morgan, J. B.; Stoltz, B. M. Palladium-Catalyzed
Construction of Quaternary Stereocenters by Enantioselective
Arylation of γ-Lactams with Aryl Chlorides and Bromides. Angew.
Chem., Int. Ed. 2019, 58, 4297−4301.
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P.R. China
Peng Wang − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P.R. China;
orcid.org/0000-0003-1217-4801
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00952
Author Contributions
#X. Ren and L. Tang contributed equally to this work.
Notes
The authors declare no competing financial interest.
(6) (a) Deng, Xu.; Shi, L.-Y.; Lan, J.; Guan, Y.-Q.; Zhang, X.; Lv, H.;
Chung, L.; Zhang, X. Enantioselective Rhodium-Catalyzed Cyclo-
isomerization of 1,6-Allenynes to access 5/6-Fused Bicycle[4.3.0]-
nonadienes. Nat. Commun. 2019, 10, 949. (b) Nishimura, T.; Maeda,
Y.; Hayashi, T. Chiral Diene-Phosphine Tridentate Ligands for
Rhodium-Catalyzed Asymmetric Cycloisomerization of 1,6-Enynes.
Org. Lett. 2011, 13, 3674−3677. (c) Masutomi, K.; Noguchi, K.;
Tanaka, K. Enantioselective Cycloisomerization of 1,6-Enynes to
Bicyclo[3.1.0]hexanes Catalyzed by Rhodium and Benzoic Acid. J.
Am. Chem. Soc. 2014, 136, 7627−7630. (d) Nicolaou, K. C.; Li, A.;
Ellery, S. P.; Edmonds, D. J. Rhodium-Catalyzed Asymmetric Enyne
Cycloisomerization of Terminal Alkynes and Formal Total Synthesis
of (−)-Platensimycin. Angew. Chem., Int. Ed. 2009, 48, 6293−6295.
(e) Trost, B. M.; Ryan, M. C.; Rao, M.; Markovic, T. Z. Construction
of Enantioenriched [3.1.0] Bicycles via a Ruthenium-Catalyzed
Asymmetric Redox Bicycloisomerization Reaction. J. Am. Chem. Soc.
2014, 136, 17422−17425. (f) Dieckmann, M.; Jang, Y.-S.; Cramer, N.
Chiral Cyclopentadienyl Iridium(III) Complexes Promote Enantio-
selective Cycloisomerizations Giving Fused Cyclopropanes. Angew.
Chem., Int. Ed. 2015, 54, 12149−12152. (g) Liang, R.-X.; Song, L.-J.;
Lu, J.-B.; Xu, W.-Y.; Ding, C.; Jia, Y.-X. Palladium-Catalyzed
Enantioselective Heteroarenyne Cycloisomerization Reaction.
Angew. Chem., Int. Ed. 2021, 60, 7412−7417.
(7) (a) Park, J. H.; Kim, S. M.; Chung, Y. K. Rh-Catalyzed Reductive
Cyclization of Enynes using Ethanol as a Source of Hydrogen. Chem. -
Eur. J. 2011, 17, 10852−10856. (b) Jang, H.-Y.; Hughes, F. W.; Gong,
H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. Enantioselective Reductive
Cyclization of 1,6-Enynes via Rhodium-Catalyzed Asymmetric
Hydrogenation: C-C Bond Formation Precedes Hydrogen Activa-
tion. J. Am. Chem. Soc. 2005, 127, 6174−6175.
(8) (a) Wang, C.; Ge, S. Versatile Cobalt-Catalyzed Enantioselective
Entry to BorylFunctionalized All-Carbon Quaternary Stereogenic
Centers. J. Am. Chem. Soc. 2018, 140, 10687−10690. (b) Yu, S.; Wu,
C.; Ge, S. Cobalt-Catalyzed Asymmetric Hydroboration/Cyclization
of 1,6-Enynes with Pinacolborane. J. Am. Chem. Soc. 2017, 139,
6526−6529.
ACKNOWLEDGMENTS
National Natural Science Foundation of China and ECNU are
gratefully acknowledged for their financial support.
■
REFERENCES
■
(1) For selected reviews, see: (a) Ye, L.-W.; Shu, C.; Gagosz, F.
Recent Progress towards Transition Metal-Catalyzed Synthesis of γ-
lactams. Org. Biomol. Chem. 2014, 12, 1833−1845. (b) Caruano, J.;
Muccioli, G. G.; Robiette, R. Biologically Active γ-lactams: Synthesis
and Natural Sources. Org. Biomol. Chem. 2016, 14, 10134−10156.
(c) Rivas, F.; Ling, T. Advances toward the Synthesis of Function-
alized γ-Lactams. Org. Prep. Proced. Int. 2016, 48, 254−295.
(2) (a) Rhee, J. U.; Krische, M. J. Highly Enantioselective Reductive
Cyclization of Acetylenic Aldehydes via Rhodium Catalyzed
Asymmetric Hydrogenation. J. Am. Chem. Soc. 2006, 128, 10674−
10675. (b) Shao, C.; Yu, H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng,
C.-G.; Lin, G.-Q. Asymmetric Synthesis of β-Substituted γ-Lactams
via Rhodium/Diene-Catalyzed 1,4-Additions: Application to the
Synthesis of (R)-Baclofen and (R)-Rolipram. Org. Lett. 2011, 13,
788−791. (c) Kanbayashi, N.; Takenaka, K.; Okamura, T.-a.;
Onitsuka, K. Asymmetric Auto-Tandem Catalysis with a Planar-
Chiral Ruthenium Complex: Sequential Allylic Amidation and Atom-
Transfer Radical Cyclization. Angew. Chem., Int. Ed. 2013, 52, 4897−
4901. (d) Lang, Q.; Gu, G.; Cheng, Y.; Yin, Q.; Zhang, X. Highly
Enantioselective Synthesis of Chiral γ-Lactams by Rh-Catalyzed
Asymmetric Hydrogenation. ACS Catal. 2018, 8, 4824−4828.
(e) Park, Y.; Chang, S. Asymmetric Formation of γ-lactams via C-H
Amidation Enabled by Chiral Hydrogen-bond-donor Catalysts. Nat.
Catal. 2019, 2, 219−227. (f) Wu, X.; Qu, J.; Chen, Y. Quinim: A New
Ligand Scaffold Enables Nickel-Catalyzed Enantioselective Synthesis
of α-Alkylated γ-Lactam. J. Am. Chem. Soc. 2020, 142, 15654−15660.
(g) Panger, J.; Denmark, S. Enantioselective Synthesis of γ-Lactams
by Lewis Base Catalyzed Sulfenoamidation of Alkenes. Org. Lett.
2020, 22, 2501−2505.
(9) (a) Chakrapani, H.; Liu, C.; Widenhoefer, R. A. Enantioselective
Cyclization/Hydrosilylation of 1,6-Enynes Catalyzed by a Cationic
Rhodium Bis(phosphine) Complex. Org. Lett. 2003, 5, 157−159.
(b) Fan, B.-M.; Xie, J.-H.; Li, S.; Wang, L.-X.; Zhou, Q.-L. Highly
Enantioselective Hydrosilylation/Cyclization of 1,6-Enynes Catalyzed
by Rhodium(I) Complexes of Spiro Diphosphines. Angew. Chem., Int.
Ed. 2007, 46, 1275−1277.
(10) (a) Whyte, A.; Torelli, A.; Mirabi, B.; Prieto, L.; Rodríguez, J.
F.; Lautens, M. Cobalt-Catalyzed Enantioselective Hydroarylation of
1,6-Enynes. J. Am. Chem. Soc. 2020, 142, 9510−9517. (b) Whyte, A.;
Bajohr, J.; Torelli, A.; Lautens, M. Enantioselective Cobalt-Catalyzed
Intermolecular Hydroacylation of 1,6-Enynes. Angew. Chem., Int. Ed.
2020, 59, 16409−16413.
(3) (a) Christoffers, J.; Baro, A., Eds. Quaternary Stereocenters
Challenges and Solutions for Organic Synthesis; Wiley-VCH, 2005.
(b) Ling, T.; Rivas, F. All-Carbon Quaternary Centers in Natural
Products and Medicinal Chemistry: Recent Advances. Tetrahedron
2016, 72, 6729−6777. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M.
Catalytic Enantioselective Construction of Quaternary Stereocenters:
Assembly of Key Building Blocks for the Synthesis of Biologically
Active Molecules. Acc. Chem. Res. 2015, 48, 740−751.
(4) For selected reviews, see: (a) Eppe, G.; Didier, D.; Marek, I.
Stereocontrolled Formation of Several Carbon-Carbon Bonds in
Acyclic Systems. Chem. Rev. 2015, 115, 9175−9206. (b) Marek, I.;
Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.; Das, J. P.
All-Carbon Quaternary Stereogenic Centers in Acyclic Systems
through the Creation of Several C-C Bonds per Chemical Step. J.
Am. Chem. Soc. 2014, 136, 2682−2694. (c) Feng, J.; Holmes, M.;
Krische, M. J. Acyclic Quaternary Carbon Stereocenters via
Enantioselective Transition Metal Catalysis. Chem. Rev. 2017, 117,
(11) (a) Li, Ke.; Li, M.-L.; Zhang, Q.; Zhu, S.-F.; Zhou, Q.-L. Highly
Enantioselective Nickel-Catalyzed Intramolecular Hydroalkenylation
of N- and O-Tethered 1,6-Dienes to Form Six-Membered Hetero-
cycles. J. Am. Chem. Soc. 2018, 140, 7458−7461. (b) Pagar, V. V.;
3565
https://doi.org/10.1021/acs.orglett.1c00952
Org. Lett. 2021, 23, 3561−3566

Organic Letters
pubs.acs.org/OrgLett
Letter
RajanBabu, T. V. Tandem Catalysis for Asymmetric Coupling of
Ethylene and Enynes to Functionalized Cyclobutanes. Science 2018,
361, 68−72.
(12) For selected examples for asymmetric heck/carbonylation, see:
(a) Yuan, Z.; Zeng, Y.; Feng, Z.; Guan, Z.; Lin, A.; Yao, H.
Constructing Chiral Bicyclo[3.2.1]octanes via Palladium-Catalyzed
Asymmetric Tandem Heck/Carbonylation Desymmetrization of
Cyclopentenes. Nat. Commun. 2020, 11, 2544. (b) Chen, M.;
Wang, X.; Yang, P.; Kou, X.; Ren, Z.-H.; Guan, Z.-H. Palladium-
Catalyzed Enantioselective Heck Carbonylation with a Monodentate
Phosphoramidite Ligand: Asymmetric Synthesis of (+)-Physostig-
mine, (+)-Physovenine, and (+)-Folicanthine. Angew. Chem., Int. Ed.
2020, 59, 12199−12205. (c) Carmona, R. C.; Köster, O. D.; Correia,
C. R. D. Chiral N,N Ligands Enabling Palladium-Catalyzed
Enantioselective Intramolecular Heck-Matsuda Carbonylation Reac-
tions by Sequential Migratory and CO Insertions. Angew. Chem., Int.
Ed. 2018, 57, 12067−12070. (d) Cheng, C.; Wan, B.; Zhou, B.; Gu,
Y.; Zhang, Y. Enantioselective Synthesis of Quaternary 3,4-
dihydroisoquinolinones via Heck Carbonylation Reactions: Develop-
ment and Application to the Synthesis of Minalrestat analogues.
Chem. Sci. 2019, 10, 9853−9858. (e) Hu, H.; Teng, F.; Liu, J.; Hu,
W.; Luo, S.; Zhu, Q. Enantioselective Synthesis of 2-Oxindole
Spirofused Lactones and Lactams by Heck/Carbonylative Cylization
Sequences: Method Development and Applications. Angew. Chem.,
Int. Ed. 2019, 58, 9225−9229.
(13) (a) Kollär, L. Modern Carbonylation Methods; Wiley-VCH:
Weinheim, 2008. (b) Peng, J.-B.; Geng, H.-Q.; Wu, X.-F. The
Chemistry of CO: Carbonylation. Chem. 2019, 5, 526−552. (c) Kiss,
G. Palladium-Catalyzed Reppe Carbonylation. Chem. Rev. 2001, 101,
3435−3456. (d) Yang, J.; Liu, J.; Neumann, H.; Franke, R.; Jackstell,
R.; Beller, M. Direct Synthesis of Adipic Acid Esters via Palladium-
Catalyzed Carbonylation of 1,3-dienes. Science 2019, 366, 1514−
̈
1517. (e) Brennfuhrer, A.; Neumann, H.; Beller, M. Palladium-
Catalyzed Carbonylation Reactions of Alkenes and Alkynes.
ChemCatChem 2009, 1, 28−41.
(14) (a) Godard, C.; Munoz, B. K.; Ruiz, A.; Claver, C. Pd-
Catalysed Asymmetric Mono- and Bis-alkoxycarbonylation of Vinyl-
arenes. Dalton Trans 2008, 853−860. (b) Alper, H.; Hamel, N.
Asymmetric Synthesis of Acids by the Palladium-Catalyzed Hydro-
carboxylation of Olefins in the Presence of (R)-(−)- or (S)-(+)-1,1’-
binaphthyl-2,2’-diyl Hydrogen Phosphate. J. Am. Chem. Soc. 1990,
112, 2803−2804. (c) Konrad, T. M.; Fuentes, J. A.; Slawin, A. M. Z.;
Clarke, M. L. Highly Enantioselective Hydroxycarbonylation and
Alkoxycarbonylation of Alkenes using Dipalladium Complexes as
Precatalysts. Angew. Chem., Int. Ed. 2010, 49, 9197−9200. (d) Wang,
X.; Wang, B.; Yin, X.; Yu, W.; Liao, Y.; Ye, J.; Wang, M.; Hu, L.; Liao,
J. Palladium-Catalyzed Enantioselective Thiocarbonylation of Styr-
enes. Angew. Chem., Int. Ed. 2019, 58, 12264−12270. (e) Yao, Y.-H.;
Yang, H.-Y.; Chen, M.; Wu, F.; Xu, X.-X.; Guan, Z.-H. Asymmetric
Markovnikov Hydroaminocarbonylation of Alkenes Enabled by
Palladium-Monodentate Phosphoramidite Catalysis. J. Am. Chem.
Soc. 2021, 143, 85−91.
(15) Xu, Z.; Shen, C.; Zhang, H.; Wang, P.; Dong, K. Constructing
chiral aza-quaternary carbon centers by enantioselective carbonylative
Heck reaction of o-iodoanilines with allenes. Org. Chem. Front.2021,
81163.
(16) Xu, Z.; Tang, Y.; Shen, C.; Zhang, H.; Gan, Y.; Ji, X.; Tian, X.;
Dong, K. Nickel-Catalyzed Regio- and Diastereoselective Hydro-
arylative and Hydroalkenylative Cyclization of 1,6-dienes. Chem.
Commun. 2020, 56, 7741−7744.
(17) Petrone, D. A.; Franzoni, I.; Ye, J.; Rodríguez, J. F.; Poblador-
Bahamonde, A. I.; Lautens, M. Palladium-Catalyzed Hydrohalogena-
tion of 1,6-Enynes: Hydrogen Halide Salts and Alkyl Halides as
Convenient HX Surrogates. J. Am. Chem. Soc. 2017, 139, 3546−3557.
(18) Badiola, E.; Olaizola, I.; Vazquez, A.; Vera, S.; Mielgo, A.;
Palomo, C. β2, 2-Amino Acid N-Carboxyanhydrides Relying on
Sequential Enantioselective C(4)-Functionalization of Pyrrolidin-
2,3-diones and Regioselective Baeyer-Villiger Oxidation. Chem. -
Eur. J. 2017, 23, 8185−8195.
3566
https://doi.org/10.1021/acs.orglett.1c00952
Org. Lett. 2021, 23, 3561−3566