
==== Front
Org Lett
Org Lett
ol
orlef7
Organic Letters
1523-7060
1523-7052
American Chemical Society

39226135
10.1021/acs.orglett.4c02551
Letter
Formation of All-Carbon Quaternary Centers via Enantioselective Pd-Catalyzed α-Vinylation of γ-Lactams
Moghadam Farbod A. ‡
https://orcid.org/0000-0003-2787-4923
Barbor Jay P. ‡
https://orcid.org/0000-0002-2495-0110
Chan Melinda ‡
Jette Carina
Sakurai Shunya
https://orcid.org/0000-0001-9837-1528
Stoltz Brian M. *
The Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, California 91125, United States
* Email: stoltz@caltech.edu.
03 09 2024
13 09 2024
26 36 75517554
11 07 2024
27 08 2024
20 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Herein, we report an enantioselective vinylation of α-substituted γ-lactams that forges quaternary centers in up to 59% yield with 94% ee. The use of canonically inactive vinyl chloride electrophiles afforded the highest yields and levels of stereoselectivity, and a range of trisubstituted vinyl chlorides were found to be proficient in promoting this transformation. These stereogenic products could be further elaborated to functionally rich scaffolds, thereby highlighting the synthetic utility of this process.

National Institute of General Medical Sciences 10.13039/100000057 R01GM080269 Heritage Medical Research Institute 10.13039/100014221 NA California Institute of Technology 10.13039/100006961 NA National Institute of General Medical Sciences 10.13039/100000057 R35GM145239 document-id-old-9ol4c02551
document-id-new-14ol4c02551
ccc-price
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pmcγ-Lactams are ubiquitous heterocyclic motifs found in pharmaceuticals and natural products alike (Figure 1).1 Despite this, the direct vinylation of these and other2 scaffolds largely remains an unsolved problem in organic synthesis, which limits the feasibility of convenient disconnections in the synthesis of complex scaffolds with potential biological applications. Our group previously disclosed a novel, Pd-catalyzed strategy toward the α-arylation of PMP (para-methoxy phenyl)-protected γ-lactams containing substitution at the α-position.3 As such, we successfully achieved the first asymmetric α-arylation of γ-lactams to form enantioenriched all-carbon quaternary centers. We were next interested in translating this reaction to the unprecedented vinylation of these nucleophiles.

Figure 1 (A) Pd-catalyzed α-arylation of γ-lactams. (B) Selected examples of γ-lactams in pharmaceuticals and natural products.

Our investigation commenced by utilizing the same catalytic conditions disclosed in our prior report. Initial efforts illustrated the superiority of vinyl chloride electrophiles and lithium bases (Table 1). We observed a dramatic counterion effect, as the use of NaHMDS or KHMDS afforded no desired product, whereas LiHMDS afforded a 46% yield of 3a with an excellent 90% ee. Exploration of similar lithium bases, like LiTMP, garnered diminished yields. Similarly, vinyl chlorides were found to be essential for both yield and enantioselectivity, as the use of the corresponding vinyl bromide 2b afforded 3a in a low 27% yield and 77% ee. Use of the more sterically encumbered ligand L2 did not improve the reaction further. Although we initially found that CPME (cyclopentyl methyl ether) resulted in a slight improvement of the ee to 92%, we found that 1,4-dioxane was ultimately the optimal solvent for this transformation. Additionally, the dilution of the reaction to 0.05 M allowed for an improved 58% yield and 94% ee (entry 10).

Table 1 Reaction Optimizationa

entry	ligand	X	base	solvent	yield (%)	ee (%)	
1	L1	CI	NaHMDS	dioxane	0	 	
2	L1	CI	KHMDS	dioxane	0	 	
3	L1	CI	LiHMDS	dioxane	46	90	
4	L1	CI	LiTMP	dioxane	29	ND	
5	L1	Br	LiHMDS	dioxane	27	77	
6	L2	CI	LiHMDS	dioxane	43	88	
7b	L1	CI	LiHMDS	THF	19	ND	
8b	L1	CI	LiHMDS	CPME	43	92	
9c	L1	CI	LiHMDS	CPME	38	ND	
10c	L1	CI	LiHMDS	dioxane	58	93	

a Reactions performed at 0.1 mmol scale and 0.1 M. Yields determined by 1H NMR with CH2Br2 internal standard.

b Reaction performed at 70 °C for 48 h.

c Reaction performed at 0.05 M concentration.

With optimized conditions in hand, we sought to investigate the range of compatible substitution patterns on the vinyl halide coupling partner (Scheme 1). Vinyl electrophiles featuring cyclopentyl, cyclohexyl, and cycloheptyl substitution at the 2,2-position of the vinyl chloride afforded products 3b–3d with high enantioselectivity, although formation of product 3d was observed in diminished yields likely due to increased steric hindrance. Additionally, saturated heterocyclic moieties, such as a pyran and thiopyran, were well tolerated (3e and 3f). Although acyclic substrate 3h could also be obtained in comparable yield and ee, 3i was isolated in decreased yield. Substitution at the α-position was limited to methyl, but we were pleased to find that pre-existing substitution at the γ-position of the lactam resulted in a predictable match/mismatch situation. Enhancement of dr and higher reaction efficiency was observed for product 4, whereas lower yield and diastereoselectivity was observed for its epimer 5.4 We were also able to implement our method at a 3 mmol scale, thereby obtaining over 450 mg of 3a in a similar yield and enantioselectivity (59% yield, 94% ee).

Scheme 1 Substrate Scope

Reactions performed at 0.1 mmol scale.

Reaction performed at 3 mmol scale.

Yields determined by 1H NMR with CH2Br2 internal standard.

While exploring the scope of this transformation, we found that use of 1,1-disubstituted or trans-1,2-disubstituted electrophiles resulted in either a diminished yield or enantioselectivity, respectively (Figure 2). Hypothesizing that reductive elimination is both inner-sphere and enantiodetermining,5,6 we posit that the diminished yield of the 1,1-disubstituted electrophiles originates from steric congestion at the metal center, which may deter transmetalation of the lithium enolate to palladium. Conversely, we propose that the greatly minimized interactions between the ligand and trans-1,2-disubstituted electrophiles result in high conversion but with poor enantiocontrol.

Figure 2 Reaction with 1,1- and 1,2-disubstituted electrophiles.

These enantioenriched heterocycles, adorned with highly substituted quaternary centers, exhibit significant potential for pharmaceutical and total synthetic applications.7 As a result, we embarked on a series of derivatizations of product 3a to generate differentially substituted pyrrolidinone derivatives (Scheme 2). Our initial strategy involved the hydrogenation of product 3a to yield α-quaternary lactam 6. Given the inherent challenges associated with enantioselective α-alkylation of lactams using conventional methods, we postulate that this alternative approach offers great synthetic value.

Scheme 2 Product Derivatization

Conditions: (a) H2, Pd/C (10 mol %), MeOH, 12 h, 74% yield. (b) Lithium aluminium hydride (LAH) (5 equiv), Et2O, 0–18 °C, 21 h, 84% yield. (c) p-Toluenesulfonic acid (PTSA), AcOH, 70 °C, 12 h, 59% yield. (d) SeO2, 1,4-dioxane, reflux, 15 min, 49% yield. (e) Ceric ammonium nitrate (CAN), H2O, 60 °C, 32 h, 40% yield. (f) O3, PPh3 CH2Cl2, 15 min, 89% yield. (g) KOt-Bu, methyltriphenylphosphonium bromide, THF, 0 °C to reflux, 12 h, 84% yield.

Reduction of the lactam with lithium aluminum hydride yielded β-quaternary pyrrolidine 7. This derivative contains a heterocycle of significant pharmaceutical importance,8 as pyrrolidines are ubiquitous in various existing drug molecules and natural products.9 Hydration of the newly introduced vinyl group with p-TsOH produces the tertiary alcohol 8.10 Allylic oxidation with SeO2 results in the formation of aldehyde 9. Additionally, the deprotection of the PMP group with ceric ammonium nitrate (CAN) reveals unprotected lactam 10. Finally, 3a can undergo oxidative cleavage to yield the corresponding aldehyde 11 through ozonolysis. From 11, a Wittig reaction can be conducted to generate vinylated lactam 12 with no substitution at the terminal position.11

In conclusion, our study showcases an enantioselective vinylation method for γ-lactams yielding α-quaternary centers in up to 58% yield and 94% ee. Notably, the reaction exhibits distinct preferences among different classes of electrophiles. Particularly, we observed that trisubstituted vinyl chlorides outperformed other vinyl halides under these conditions in terms of both yield and ee. Moreover, these highly substituted γ-lactams hold significant synthetic potential, offering diverse functional handles for the synthesis of complex drug molecules or natural products.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c02551.Experimental procedures, spectroscopic data (1H NMR, 13C NMR, IR, HRMS), and SFC and HPLC data (PDF)

Supplementary Material

ol4c02551_si_001.pdf

Author Contributions

‡ F.A.M., J.P.B., and M.C. contributed equally to this research.

The NIH-NIGMS (R01GM080269 and R35GM145239), Heritage Medical Research Investigators Program, and Caltech are thanked for their support of our research program.

The authors declare no competing financial interest.

Acknowledgments

The authors would like to thank Dr. Mona Shagholi (Caltech) for mass spectrometry assistance and Dr. Scott Virgil (Caltech) for assistance with instrumentation.
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Synthesis of product 12 from vinyl chloride directly would be prohibitive as this would require a toxic gas as the electrophile and would be unlikely to exhibit asymmetric induction in a Pd-catalyzed system.
