Quinim: A New Ligand Scaffold Enables Nickel-Catalyzed Enantioselective Synthesis of α-Alkylated ?-Lactam

Article abstract of DOI:10.1021/jacs.0c07126

Herein, we report a nickel-catalyzed reductive cross-coupling reaction of easily accessible 3-butenyl carbamoyl chloride with primary alkyl iodide to access the chiral α-alkylated pyrrolidinone with broad substrate scope and high enantiomeric excess. The current art of synthesis still remains challenging on the enantioselective α-monoalkylation of pyrrolidinones. The newly designed chiral 8-quinoline imidazoline ligand (Quinim) is crucial for maintaining the reactivity and enantioselectivity to ensure the reductive cyclization of monosubstituted alkenes for unprecedented synthesis of chiral non-aromatic heterocycles.

Full text of DOI:10.1021/jacs.0c07126

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Communication
Quinim: a New Ligand Scaffold Enabled Nickel-Catalyzed
Enantioselective Synthesis of #-Alkylated #-Lactam
Xianqing Wu, Jingping Qu, and Yifeng Chen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07126 • Publication Date (Web): 26 Aug 2020
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Journal of the American Chemical Society
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Quinim: a New Ligand Scaffold Enabled Nickel-Catalyzed Enantiose-
lective Synthesis of α-Alkylated γ-Lactam
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Xianqing Wu, Jingping Qu,* Yifeng Chen*
Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular
Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic
Chemistry, School of Chemistry and Molecular Engineering, East China University of Science & Technology, 130 Meilong
Road, Shanghai, 200237, China.
ABSTRACT: Herein, we report a nickel-catalyzed reductive cross-coupling reaction of easily accessible 3-butenyl carbamoyl chlo-
ride with primary alkyl iodide to access the chiral -alkylated pyrrolidinone with broad substrate scope and high ee. The current art
of synthesis still remains challenging on the enantioselective -monoalkylation of pyrrolidinones. The newly designed chiral 8-quin-
oline imidazoline ligand (Quinim) is crucial for maintaining the reactivity and enantioselectivity to ensure the reductive cyclization
of mono-substituted alkenes for unprecedented synthesis of chiral nonaromatic heterocycles.
The-Lactam represents one of the most significant and
ubiquitous structural motifs in the framework of numerous bio-
logically active natural products and pharmaceuticals.1 Thus,
tremendous efforts have been devoted to the efficient construc-
tion of chiral -lactam in organic and enzymatic synthesis.2,3
Particularly, chiral -alkylated pyrrolidinone is a vital class of
scaffold that exhibits biological reactivity (Figure 1).4 However,
The enantioselective -monoalkylation of easily accessible -
lactam still remains challenge due to the potential overalkyla-
tion side reaction as well as epimerization under basic condition,
even stoichiometric chiral base could only lead to low enanti-
oselectivity and yield (Scheme 1).5 The major approach in me-
dicinal chemistry for the chiral -alkylated pyrrolidinone syn-
thesis still mainly relies on the introduction the chirality via the
-alkylation of Evan’s auxiliary, followed by multiple synthetic
manipulations to form pyrrolidinone ring.4a-4c Only recently,
few asymmetric catalytic methodologies have been employed
for the synthesis of -alkylated pyrrolidinone, including the
asymmetric hydrogenation of cyclic aryl substituted enamides
developed by Zhang and Ding groups independently to synthe-
size the chiral -benzyl pyrrolidinone,6 and asymmetric hydro-
carbamoylation of alkene-tethered formamides with the
Scheme 1. Approaches for Asymmetric Synthesis of -Al-
kylated Pyrrolidinones
incorporation of a methyl group adjacent to the lactam group
developed by Cramer and co-workers.7 Despite the advances, it
is still highly desirable to achieve the chiral -alkylated pyrrol-
idinone synthesis in asymmetric catalysis, introducing the sim-
ple and unactivated alkyl group with broad functional group tol-
erance.
Transition metal-catalyzed enantioselective difunctionaliza-
tion of alkene has emerged as a useful synthetic tool for the sim-
ultaneous introduction of two functionalities across the double
bond, alongside increasing molecular complexity.8,9 Ni-cata-
lyzed asymmetric reductive difunctionalization of alkenes is es-
pecially of great research interest, as it circumvents the use of
preformed organometallic nucleophiles.10-14 Most two-compo-
nent enantioselective reductive cross-coupling protocols are in-
itiated from the intramolecular cyclization of aryl (pseudo)hal-
ide tethered 1,1-disubsituted alkenes to generate a chiral quater-
nary center with the formation of benzo-fused ring system.10
However, synthesis of simple chiral non-aromatic heterocycles,
such as pyrrolidinones, using asymmetric reductive cross-cou-
Figure 1. Examples of pharmaceuticals and biologically active
compounds bearing chiral -alkylated pyrrolidinone.
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pling, still remains elusive likely due to the difficulty on the ste-
Table 1. Optimization of the Reaction Conditionsa
reoselective radical migratory insertion.11a, 11b Based on our con-
tinuous research interest on Ni-catalyzed carbonylations,15 we
are intrigued that homoallylic carbamoyl chloride would be an
appropriate precursor to access the chiral pyrrolidinone synthe-
sis. Carbamoyl chloride could be synthesized from easily avail-
able secondary amine and is well recognized as a versatile
building block for the nitrogen-containing heterocycles synthe-
sis.16 Since the seminal work by Grigg17 and Takemoto,18 tran-
sition-metal catalyzed the cyclization of 1,1-disubstituted al-
kene-tethered carbamoyl chloride has offered a straightforward
route to construct oxindole scaffolds.19 More recently, the qua-
ternary stereogenic center incorporated in oxindole derivatives
have been realized independently by Lautens20 and Wang
group.10i, 10j To the best of our knowledge, the enantioselective
cyclization of mono-substituted alkene-tethered carbamoyl
chloride for the formation of non-aromatic heterocycles has not
been achieved. Herein, we have disclosed a newly developed 8-
Quinoimidazoline ligand (Quinim) enabled Ni-catalyzed enan-
tioselective reductive cross-coupling of monosubstituted alkene
tethered carbamoyl chloride with unactivated primary alkyl io-
dide to access the non-aromatic heterocycle, -monoalkylated
pyrrolidinone, and the non-basic condition allows the tertiary
chiral center without the erosion of ee.
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At the outset of our investigation, we selected carbamoyl
chloride 1a as the model substrate with primary alkyl iodide 2a
as the coupling component. The chiral ligand screening was
o
performed in NMP at 30 C with Ni(ClO4)2•6H2O as catalyst
and Mn as reducing reagent. Employing the common chiral lig-
and utilized in Ni-catalyzed reductive cross-coupling received
limited success (Table 1, entries 1-3).21 After many trials, we
are gratified to realize that the 8-Quinox L4 originally devel-
oped by Zhou and coworkers decades ago,22 elevated both reac-
tion yield and e.r., whereas the efficiency dramatically dropped
down with L5, which indicated the importance of tert-butyl
group in oxazoline (entries 4-5). This less-common six-mem-
bered chelation model of the chiral ligand with nickel catalyst
encouraged us to investigate the ligand effect. The ligand L6,
which resulted from removing the benzene ring from L4, com-
pletely failed to afford the desired product, demonstrating that
the configuration of 8-Quinox is crucial for this reductive cross
coupling (entry 6). To our delight, when the oxazoline moiety
was changed with the more electronic rich chiral imidazoline
backbone at the 8-position of quinoline, the Quinim L8 would
provide the desired product 3a in 92:8 e.r., albeit with low yield
(entry 8).23 Both yield and e.r. increased when the reaction was
performed at 0 oC (entry 9). Next, we evaluated the substitution
effect on the nitrogen atom in the imidazoline group to alter
both electronic and steric effect (entries 10-16). It was found
that the electronically neutral aromatic ring of aniline provided
the best results (entries 10-11), while both electronically rich 4-
methoxyl group (L11) and electronic deficient 4-trifluorome-
thyl group (L12), 3,5-ditrifluoromethyl group (L13) on the
arenes lowered the e.r. Either the introduction of the methyl
groups at the ortho-position on the aromatic ring (L14) or the
use of cyclohexyl group (L15) is detrimental to the reaction.
Next, replacing NMP to DMF improved overall reaction effi-
ciency, regarding both yield and enantioselectivity (entry 17).
Finally, we could further enhance the yield employing the
Ni(cod)2 as catalyst, the desired -lactam 3a was obtained in 86%
isolated yield with 97:3 e.r. (entry 18). The current protocol was
not suitable for primary alkyl bromide, the starting material
completely decomposed (entry 19). The reaction efficiency
aReaction conditions: 1a (0.2 mmol), 2a (3.0 equiv., 0.6 mmol), [Ni]
(15 mol%, 0.03 mmol), ligand (22 mol%, 0.044 mmol), Mn (4.0
equiv., 0.8 mmol), LiBr (1.0 equiv., 0.2 mmol), solvent (1 mL) un-
der the indicated temperature for 48 h. bCorrected GC yield. cDeter-
mined by HPLC-analysis. dNi(cod)2 (15 mol%, 0.03 mmol); L8 (18
mol%, 0.036 mmol), 48 h, isolated yield in parentheses. enC7H15Br
f
(3.0 equiv.) was used instead of 2a. Zn (4.0 equiv.) was used in-
stead of Mn.
dramatically dropped down when zinc powder was employed
as the reductant (entry 20).
With the optimized conditions in hand, we investigated the
substrate scope of this Ni-catalyzed reductive coupling of
homoallylic carbamoyl chloride with alkyl iodide (Scheme 2).
It was found that a variety of simple primary alkyl iodides were
tolerated, ethyl iodide was also compatible with this protocol
(3b). It should be noted that yield and enantioselectivity
dropped down with the introduction of the steric group nearby
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Scheme 2. Substrate Scope of Ni-catalyzed Enantioselective Carbamoyl-Alkylation of Unactivated Alkenesa
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aReaction conditions: 1 (1.0 equiv.), 2 (3.0 equiv.), Ni(cod)2 (15 mol%), L8 (18 mol%), Mn (4.0 equiv.), LiBr (1.0 equiv.), DMF (0.2 M), 0
oC for 35-107 h. b5 oC
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the bond forming center. The isobutyl group could be incorpo-
to the relative slow migratory insertion of electronic deficient
carbamoyl nickel intermediate.
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rated into the reaction in 41% isolated yield and 90.5:9.5 e.r.
(3c), while the product (3d) was obtained in 85% isolated yield
and 94.5:5.5 e.r. when isopentyl iodide was employed as the
coupling component. Next, we examined the functional group
tolerance of alkyl electrophiles. Gratefully, alkyl iodides bear-
ing chloride (3f), protected ether (-OTBS for 3g, -OAc for 3h),
internal alkene (3k) were obtained with high e.r. Trifluoride and
perfluoride substituted alkyl electrophiles were also compatible,
albeit with lower e.r. (3i, 3j). Additionally, various carbonyl
functional group, including amide (3l), ester (3m), aldehyde
(3n), nitrile (3o) were all tolerated under this reductive condi-
tion with good e.r. The Ni/L8 catalyst would selectively react
with the alkyl iodide in the presence of the aryl chloride and
heteroaryl bromide, the desired products 3p and 3r would pro-
vide the feasibility for further transformation. The success of
the BPin functionality highlighted the high selectivity of this
reductive condition, and the product 3q could be further deri-
vatized via C–B bond transformations. Finally, the phthalimide
containing pyrrolidinone 3s was obtained in 90% isolated yield
with high e.r., and the absolute configuration was assigned as S
configuration, unambiguously confirmed by X-ray diffraction.
To our delight, aryl substituted homoallylic carbamoyl chloride
were tolerated under the standard condition, providing expedi-
ent access to N-arylated pyrrolidinones (3t-3x). The enantiose-
lectivity was high when the electron-donating group was em-
ployed (3u), while the yield declined when the chloride group
was employed in the reaction (3x). We next turned our attention
to probe the substitution effect on the homoallylic carbamoyl
chloride, it was found that various substituted benzylic group
on the nitrogen atom were compatible, providing a wide scope
of functionalized pyrrolidinone (3y-3ae). Noteworthy was the
tolerance of the ortho-bromide benzylic N-substituted product
(3ae), allowing further potential derivatization. The presence of
heterocyclic rings including furan (3af) and indole (3al) toler-
ated the standard condition with high yield and e.r. Moreover,
the simple alkyl-substituted carbamoyl chlorides all proceeded
well with high e.r. (3ag-3ai), even including complex natural
product derivative (3am). Notably, both -amino ester and -
amino ester derivatives can be applied in the current protocol
(3aj, 3ak). It should be noted that the -lactam 3aj was prepared
by Bristol-Myers Squibb via six synthetic steps.24 When active
MeI (3an), secondary iPrI (3ao) and aryl iodide (3ap) were em-
ployed as the coupling component, the desired product was ob-
tained in low yield. The tosylate protected carbamoyl chloride
(3aq) didn’t work with this Ni/Quinim catalyst presumably due
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To further demonstrate the potential synthetic utility of this
asymmetric protocol in valuable skeletons construction, we per-
form diverse transformations with the chiral γ-lactam products
(Scheme 3). The thioamide 4 could be obtained in 98% yield
with treatment with Lawesson's reagent. The cleavage of PMB
group from 3y by treatment with ceric ammonium nitrate (CAN)
provides 5 in high yield and excellent e.r. retention. Hydrolysis
of 5 affords non-natural γ-amino acid derivative with maintain-
ing the enantiopurity.
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We performed the preliminary mechanistic studies to shed
light on the reaction mechanism (Scheme 4): stoichiometric ex-
periment was carried out in the absence of alkyl iodide. When
1.0 equivalent of Ni(ClO4)2•6H2O and 1.0 equivalent of Mn
powder was employed in the reaction, the 2-methyl pyrroli-
dinone 8 was obtained in 41% isolated yield with 97.5:2.5 e.r.,
which indicates that the enantioselectivity-determining step
(EDS) is the intramolecular migratory insertion of the car-
bamoyl nickel intermediate into the alkene (Scheme 4a). When
6-iodohex-1-ene was employed as the coupling component, the
Scheme 4. Plausible mechanism
Scheme 3. Derivatization of -lactama
aConditions: i) 0.5 equiv. Lawesson's reagent, 3a, toluene, 80 oC, 6
h; ii) 5.0 equiv. CAN, 3y, MeCN/H2O (5/1), 0 oC, 1 h; iii) 6 N HCl,
100 oC for 12 h; iv) 3.0 equiv. K2CO3, 1.3 equiv. PhCOCl, MeCN,
45 oC, 12 h.
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Lactams: Synthesis and Natural Sources. Org. Biomol. Chem.
-lactam was obtained as a mixture of 9 and 10 (Scheme 4b).
The formation of 10 revealed that the cyclized alkyl radical spe-
cies might be formed by the single electron transfer (SET) path-
way of 6-iodohex-1-ene with the nickel intermediate, followed
by intramolecular radical cyclization, then underwent the sub-
sequent coupling to form the cyclized product.10j,25 The addition
of TEMPO (1.0 equiv.) completely inhibited the reductive cross-
couplings.26 Therefore, we propose the tentative mechanism in
Scheme 4c:10j the low-valent nickel undergoes oxidative addi-
tion with homoallylic carbamoyl chloride, followed by intramo-
lecular migratory insertion to furnish the alkyl-nickel interme-
diate C, which proceeds with Mn reduction to generate the in-
termediate D. The alkyl iodide reacts with D via a single elec-
tron transfer (SET) pathway to form the intermediate F, which
subsequently furnishes the desired products 3 following reduc-
tive elimination.
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In conclusion, we have developed a Ni-catalyzed cycliza-
tion of carbamoyl chloride with unactivated alkyl iodide to af-
ford the tertiary -alkylated pyrrolidinone with broad substrate
scope in high ee. This protocol represents an unprecedented,
chiral non-aromatic heterocycles synthesis via enantioselective
Ni-catalyzed reductive cross-coupling strategy. The newly syn-
thesized nitrogen-containing, bidentate 8-Quinline-imazaloline
ligand is the key feature for this transformation, enabling both
high reactivity and enantioselectivity. The investigation of de-
tailed mechanism via theoretical studies and further application
of 8-Quinoimidazoline ligand in other asymmetric syntheses is
currently underway.
ASSOCIATED CONTENT
Experimental procedures, spectroscopic data for all new com-
pounds including 1H- and 13C-NMR spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*qujp@dlut.edu.cn
*yifengchen@ecust.edu.cn
(3) (a) Biegasiewicz, K. F.; Copper, S. J.; Gao, X.; Oblinsky, D. G.;
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G. D.; Hyster, T. K. Photoexcitation of Flavoenzymes Enables a
Stereoselectiveradical Cyclization. Science 2019, 364, 1166. (b)
Ren, X.; Chandgude, A. L.; Fasan, R. Highly Stereoselective
Synthesis of Fused Cyclopropane-γ-Lactams via Biocatalytic
Iron-Catalyzed Intramolecular Cyclopropanation. ACS Catal.
2020, 10, 2308.
Notes
The authors declare no competing financial interest.
(4) For selected examples, see: (a) Dragovich, P. S.; Prins, T. J.; Zhou,
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K.; Matthews, D. A.; Lee, C. A.; Ford, C. E.; Burke, B. J.; Rejto,
P. A.; Hendrickson, T. F.; Tuntland, T.; Brown, E. L.; Meador III,
J. W.; Ferre, R. A.; Harr, J. E.; Kosa, M. B.; Worland, S. T. S.
Structure-Based Design, Synthesis, and Biological Evaluation of
Irreversible Human Rhinovirus 3C Protease Inhibitors. 4. Incor-
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Med. Chem. 1999, 42, 1213. (b) Boy, K. M.; Guernon, J. M.; Shi,
J.; Toyn, J. H.; Meredith, J. E.; Barten, D. M.; Burton, C. R.;
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Muckelbauer, J. K.; Camac, D. M.; Lentz, K. A.; Bronson, J. J.;
Olson, R. E.; Macor, J. E.; Thompsoon III, L. A. Monosubstituted
-Lactam and Conformationally Constrained 1,3-Diaminopropan-
2-ol Transition-state Isostere Inhibitors of -Secretase (BACE).
Bioorg. Med. Chem. Lett. 2011, 21, 6916. (c) Meissner, R. S.;
Perkins, J. J.; Duong, L. T.; Hartman, G. D.; Hoffman, W. F.; Huff,
J. R.; Ihle, N. C.; Leu, Ch.-T.; Nagy, R. M.; Naylor-Olsen, A.;
Rodan, G. A.; Rodan, S. B.; Whitman, D. B.; Wesolowski, G. A.;
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Glycyl Amides Derived from the RGD Tripeptide. Bioorg. Med.
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ACKNOWLEDGMENT
This work is dedicated to the 70th anniversary of the Shanghai In-
stitute of Organic Chemistry (SIOC), Chinese Academy of Sci-
ences. This work was supported by NSFC/China (21421004,
21702060), Shanghai Rising-Star Program, Shanghai Municipal
Science
and
Technology
Major
Project
(Grant
No.2018SHZDZX03) and the Program of Introducing Talents of
Discipline to Universities (B16017), and the Fundamental Re-
search Funds for the Central Universities. Y.C. thanks Prof.
Zhipeng Zhang (ECUST) for sharing the instruments. Y.C. thanks
Prof. Timothy Newhouse (Yale University) for helpful discussion.
The authors thank Research Center of Analysis and Test of East
China University of Science and Technology for the help on NMR
analysis.
REFERENCES
(1) For selected reviews on -lactam, see: (a) Ye, L.-W.; Shu, C.;
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