A two-step Kinugasa/Conia-ene-type sequential reaction for the asymmetric synthesis of 8-methylene-2,6-diazaspiro[3.4]octane-1,5-diones

Abstract

2,6-Diazaspiro[3.4]octane-1,3-dione, integrating β-lactam and γ-lactam into one structure, is an important skeleton found in many bioactive molecules. This article describes a simple and practical synthesis of 8-methylene-2,6-diazaspiro[3.4]octane-1,5-diones from N-(prop-2-yn-1-yl)propiolamides and nitrones. The method proceeds via a two-step sequential process: a Kinugasa reaction, followed by a Conia-ene-type cyclization. The transformation afforded 8-methylene-2,6-diazaspiro[3.4]octane-1,5-diones in satisfactory yields and high diastereo- and enantioselectivity.

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Introduction

β-Lactam and γ-lactam are privileged heterocyclic skeletons that widely exist in many bioactive molecules.^1,2 2,6-Diaza-spiro[3.4]octane 1,5-diones and analogues, which integrate the two distinctive units of β-lactam and γ-lactam, have drawn tremendous attention in the field of synthetic chemistry and medicinal chemistry (Fig. 1).³ However, the methods for constructing such rigid structures have rarely been reported and multiple-step transformations are generally required.⁴ Simple and practical protocols toward 2,6-diazaspiro[3.4]octane 1,5-diones are highly desirable.

Fig. 1 Selected examples of 2,6-diazaspiro[3.4]octane-containing bioactive molecules.

Among existing protocols,⁵ copper catalyzed 1,3-dipolar cycloaddition of terminal alkynes and nitrones is one of the most straightforward and practical methods for the formation of functionalized β-lactams. This type of cycloaddition, known as the Kinugasa reaction, was initially developed by Kinugasa and Hashimoto in 1972,⁶ and in 1995 Miura et al. reported the first example of asymmetric transformation for the construction of chiral β-lactams.⁷ Since then, significant progress has been witnessed with remarkable efforts from Fu, Tang, Feng, and Sawamura et al.^8–10

According to the proposed mechanism,¹¹ an enolate copper(I) intermediate was in situ generated in the Kinugasa reaction. Considerable efforts have been devoted to the development of cascade or one-pot transformations by trapping this Kinugasa enolate copper(I) with additional electrophiles (Scheme 1a).¹² Elegant asymmetric cascade reactions have been realized by Fu,¹³ Enders,¹⁴ Xu¹⁵ and Lautens.¹⁶ However, the Kinugasa enolate copper(I) intermediate is extremely reactive with a strong tendency for protonation rather than competitive trapping by electrophiles. Thus, only highly electrophilic reagents or functional groups may be suitable for the trapping, greatly limiting the development of interrupted Kinugasa reactions.

Scheme 1 Copper(I)-catalyzed asymmetric Kinugasa and related reactions.

Recently, by taking propiolamides as the terminal alkyne substrates, we have developed a series of novel cascade reactions by interrupting the Kinugasa reaction with additional electrophiles. In these cascade reactions, the α-amide enolate copper(I) intermediates were trapped by intramolecular electrophilic functional groups such as aryl iodide,^17a ketone^17b or α,β-unsaturated ester groups^17c to afford different spiro β-lactam products (Scheme 1b). The electron-withdrawing effect of the α-amide group made the intermediates more stable and a protonation–deprotonation equilibrium process under basic conditions is conducive to the following transformations. The use of propiolamides as the terminal alkyne substrates made the Kinugasa reaction and following transformations more controllable, and thus further expanded the reaction scope. In continuation of our interest in the Kinugasa reaction, an asymmetric two-step sequential reaction of N-(prop-2-yn-1-yl)propiolamides with nitrones was studied. The process is through a copper-catalyzed Kinugasa reaction, followed by a Conia-ene-type cyclization reaction,¹⁸ which provided a simple and practical access to chiral 8-methylene-2,6-diazaspiro[3.4]-octane-1,5-diones (Scheme 1c). Herein we'd like to report the details.

Results and discussion

Our exploration was initiated with a two-step reaction using N-benzyl-N-(prop-2-yn-1-yl)propiolamide 1a and nitrone 2a as the model substrates. As shown in Table 1, although a single solvent like MeCN can be used for both the steps,¹⁹ the desired product 3aa was afforded in only 31% yield and with a moderate enantiomeric ratio (78 : 22, Table 1, entry 1). Thus, the two step reactions were optimized in two different solvents. Generally, low temperature is good for the Kinugasa reaction since nitrones are not stable at high temperatures, whereas high temperature is beneficial for the second spirocyclization step. Thus, the first Kinugasa reaction was performed at −10 °C in one solvent for 6 hours, then another solvent was added to the mixture and the reaction temperature was elevated to 60 °C for the second spirocyclization step. Screening of solvents (Table 1, entries 1–8) revealed that PhCF₃ is the optimal solvent for the Kinugasa reaction step and the polar solvent DMSO will facilitate the challenging spirocyclization process to afford the desired product 3aa in 49% yield (Table 1, entry 8) with good enantioselectivity (90.5 : 9.5 er) and diastereomeric ratio (3aa/3aa′ = 7 : 1). Different chiral bisoxazoline ligands L2–L8 were further screened (Table 1, entries 9–15), and it was found that L5 is the optimal ligand for this cascade reaction and the enantioselectivity of 3aa was increased to 94 : 6 (dr = 7 : 1, Table 1, entry 12). Next, different bases, such as ^tBuOLi, K₂CO₃ and Et₃N, were examined and all performed poorly (Table 1, entries 16–18).²⁰

Table 1 Optimization of the reaction conditions^a

Entry	L*	Base	Solvent 1/solvent 2	Yield^b (%)	er^c (3aa)	3aa/3aa′ ^d
a Reagents and reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Cu(MeCN)4PF6 (10 mol%), ligand (12 mol%), base (0.6 mmol), solvent 1 (2 mL), −10 °C for 6 h, then in solvent 2 (2 mL), 60 °C for 6 h. b Isolated yields. c Determined by HPLC analysis. d Determined by ^1H NMR analysis of the crude reaction mixture.
1	L1	Cs2CO3	MeCN/MeCN	31	78 : 22	9 : 1
2	L1	Cs2CO3	MeCN/DMSO	48	78.5 : 21.5	9 : 1
3	L1	Cs2CO3	Tol/DMSO	39	86.5 : 13.5	7 : 1
4	L1	Cs2CO3	DCM/DMSO	34	80 : 20	7 : 1
5	L1	Cs2CO3	DMF/DMSO	Trace	—	—
6	L1	Cs2CO3	MTBE/DMSO	47	77.5 : 22.5	7 : 1
7	L1	Cs2CO3	THF/DMSO	40	88 : 12	6 : 1
8	L1	Cs2CO3	PhCF3/DMSO	49	90.5 : 9.5	7 : 1
9	L2	Cs2CO3	PhCF3/DMSO	42	75 : 25	6.5 : 1
10	L3	Cs2CO3	PhCF3/DMSO	41	78 : 22	6 : 1
11	L4	Cs2CO3	PhCF3/DMSO	49	90.5 : 9.5	7 : 1
12	L5	Cs2CO3	PhCF3/DMSO	53	94 : 6	7 : 1
13	L6	Cs2CO3	PhCF3/DMSO	57	88.5 : 11.5	5 : 1
14	L7	Cs2CO3	PhCF3/DMSO	55	87 : 13	7 : 1
15	L8	Cs2CO3	PhCF3/DMSO	52	91 : 9	5 : 1
16	L5	tBuOLi	PhCF3/DMSO	Trace	—	—
17	L5	K2CO3	PhCF3/DMSO	Trace	—	—
18	L5	Et3N	PhCF3/DMSO	Trace	—	—

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Under the optimized conditions (Table 1, entry 12), we then explored the reaction scope with a variety of N-(prop-2-yn-1-yl)propiolamides and nitrones. As shown in Scheme 2, the N-(prop-2-yn-1-yl)propiolamide substrates 1b and 1c with different protecting groups on the amide nitrogen were first examined.

Scheme 2 Substrate scope.

The PMB group displayed good performance and the expected spiro product 3ba was achieved in 49% yield with 95.5 : 4.5 er and 6.5 : 1 dr whereas the enantioselectivity for the N-ⁿbutyl substrate 1c is inferior and the corresponding product 3ca was obtained in 42% yield, with 88 : 12 er and 6.5 : 1 dr. We next examined the scope of the nitrones by reacting with 1b. Different substituents on the C-aryl ring of nitrones, including alkyl, methoxy, halogen, ester and trifluoromethyl, showed good tolerance to the reaction system and the corresponding 3bb–3bj were delivered in moderate yields with high enantio- and diastereoselectivities. The steric factor did not affect the reaction efficiency, as shown by the formation of product 3bk with good stereoselectivity. Disubstituted phenyl, naphthyl and furyl-containing substrates were also applicable to the reaction system and the corresponding spiro products 3bl–3bo were furnished in 52–59% yields with good er and dr. Further substrate scope exploration suggested that both electron-donating groups and electron-withdrawing groups on the N-aryl ring of nitrones were also compatible with the reaction, and the corresponding products 3bp–3bv were furnished in acceptable yields and high enantio- and diastereoselectivities. When N-o-tolyl nitrone was exploited, an inferior yield was obtained, as observed in the case of 3bw. An N-pyridinyl nitrone was also explored and the desired product 3bx was afforded in satisfactory yield and high er and dr. The absolute configurations of 3aa and 3aa′ were unambiguously determined through X-ray single-crystal diffraction experiments.²¹

As shown in Scheme 3, a gram-scale synthesis of 3ba was performed to demonstrate the potential synthetic application of the method. The desired product 3ba was obtained in 48% yield and with 95.5 : 4.5 enantiomeric ratio under the standard conditions. Reduction of 3ba with LiAlH₄/AlCl₃ led to the formation of 2,6-diazaspiro[3.4]octane 4 in 50% yield without any loss of enantiomeric purity. Removal of the PMB group with CAN, followed by hydrogenation afforded product 6 with three contiguous stereogenic centres.

Scheme 3 Gram-scale reaction and synthetic transformations of 3ba.

For a better understanding of the reaction process, the control experiments were performed as shown in Scheme 4. The reaction of 1a and 2a was carried out in PhCF₃ at −10 °C for 6 hours, and the Kinugasa reaction product 7 was isolated in 55% yield with 94 : 6 er. Complete conversion of compound 7 was observed with 1.0 equivalent of Cs₂CO₃ in DMSO at 60 °C under copper- and ligand-free conditions. Similar base-promoted cyclization has been recognized as the variant of classic thermal Conia-ene reaction by Trauner and co-workers.^18b In our case, the Cs₂CO₃-promoted transformation delivered the desired spirobilactam 3aa in 99% yield, with 94 : 6 er and 7 : 1 dr. The production of the minor diastereomer may be due to the high temperature in the second step. These results indicated that the Cu(MeCN)₄PF₆/L5 catalyst was required only for the first Kinugasa step and was not necessary for the second spirocyclization process. Based on the experimental observations and literature reports,^11,18 our protocol proposed that the reaction is a two-step process as shown in Fig. 2. The first step is a copper-catalyzed asymmetric Kinugasa reaction and the enantioselectivity was controlled by the chiral ligand. The second step is possibly through a copper-promoted Conia-ene-type transformation of intermediate III or a base-promoted Conia-ene-type reaction of Kinugasa product 7,¹⁸ both leading to the formation of the spiro product.

Scheme 4 Control experiments.

Fig. 2 Proposed reaction process.

In summary, a mild copper-catalyzed asymmetric Kinugasa/Conia-ene sequential process of propargyl-tethered propiolamides with nitrones was developed. The reaction provided an efficient way for the assembly of a set of structurally novel chiral 8-methylene-2,6-diazaspiro[3.4]octane-1,5-dione in satisfactory yields and with good enantio- and diastereoselectivities. Further research on the applications of the method is ongoing in our laboratory.

Data availability

Experimental procedures, characterisation data, crystallographic data, NMR spectra and HPLC spectra for this article can be found in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors are grateful to the Zhejiang Normal University and the National Natural Science Foundation of China (22001093 and 21971087) for financial support.

Notes and references

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19. Other single solvents such as THF and 1,4-dioxane delivered a trace amount of desired product 3aa.
20. For more details about condition screening, see the ESI.†.
21. CCDC 2371699 (3aa) and 2371702 (3aa′) contain the supplementary crystallographic data for this paper.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2371699 and 2371702. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01388c

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