Alkynylation/dearomatizative cyclization to construct spiro[5.5]undecanes

Abstract

A new access to spiro[5.5]undecane frameworks was reported through the ZnMe₂-promoted alkynylation of salicylaldehyde and HCO₂H-mediated dearomatizative cyclization which can be used to construct an all-carbon quaternary spirocenter. This method can be applied to the rapid synthesis towards a series of useful motifs of natural products, such as the core of elatol and aphidicolin.

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Spirocycles¹ are a common structural pattern found at the core of numerous natural products with broad structural diversities and important bioactivities (Fig. 1).² For example, elatol displays activity against bacteria (including human pathogenic bacteria)^3a,b and demonstrates cytotoxicity against HeLa and Hep-2 human carcinoma cell lines.^3c Aphidicolin also exhibits significant antiviral and antitumor activity.^4a,b

Fig. 1 Selected natural products containing spiro[5.5]undecane cores.

One commonly exploited mechanistic approach to construct spirocycle skeleton is the dearomatizative spirocyclization of functionalized phenols and naphthols. For example, chiral hypervalent iodine catalyst using m-CPBA as terminal oxidant was developed for intramolecular spirolactonization.^5,6 Palladium- or iridium-catalyzed intramolecular allylic dearomatization of phenols was also described.⁷ Feringa et al. developed one-pot spirocyclization involving asymmetric conjugate addition and subsequent oxidative dearomatization of 2-naphthols.⁸ Katsuki et al. reported iron-catalyzed asymmetric tandem spirocyclization from 1-methyl-2-naphthols and phenols.⁹ Luan et al. and You et al. described Ru or Rh-catalyzed vinylative dearomatization of naphthols or phenols via a C(sp²)–H bond activation approach.¹⁰ Gulías et al. and Lam et al. independently reported Rh-catalyzed spiroannulation of ortho-vinylphenols triggered by terminal C–H functionalization of the alkenyl moiety.¹¹ Luan et al. developed a Pd-catalyzed [2 + 2 + 1] annulative dearomatization between β-naphthols and two alkyne units,¹² and Pd-catalyzed alkyne insertion/β-naphthol dearomatization cascade to construct spirocycles.¹³ Other methods were also described by various groups.^14–18 However, the reported approaches are either transition-metal catalysis or their substrates are mostly limited to structurally similar cyclic lactones or lactams. Thus, new strategies for intermolecular spirocyclization using different classes of starting materials in one-pot process are highly desirable but challenging.

In 2015, we reported an approach to synthesize 2,4-difunctionalized benzopyrans in one-pot process (Scheme 1, top).¹⁹ As a continuation of our focus on this research program, the present paper describes a new access to spiro[5.5]undecane frameworks through the ZnMe₂-promoted alkynylation of salicylaldehyde and HCO₂H-mediated dearomatizative cyclization that can be applied to construct an all-carbon quaternary spirocenter (Scheme 1, bottom).

Scheme 1 Alkynylation/cyclization in one-pot process.

The present investigation began by reacting different diene substrate (3a) with 5-methoxysalicylaldehyde (1a) and 3-methoxyprop-1-yne (2a) under standard reaction conditions, which were developed in our previous research.¹⁹ We unexpectedly obtained a spirocycle product (4a) in 7% yield instead of benzopyran compound (Table 1, entry 2). The structure of 4a was identified by X-ray crystallography (Fig. 2).

Table 1 Optimization of reaction conditions^a

Entry^b	Acid	Solvent	Temp (°C)	Yield^c (%)
a Unless otherwise specified, all reactions were performed using Cu(OTf)2 (8 mol%), ZnMe2 (5 equiv.), 1a (1 equiv.), 2a (4 equiv.), 3a (5 equiv.), and acid (1.5 equiv.).b For all entries, dr is >20 : 1, which was determined by ^1H NMR spectroscopy. In our experimental results, if diastereoisomers could not be detected in ^1H NMR spectra, we identified the dr as >20 : 1.c Yield of isolated product.d (R)-(−)-1,1′-Binaphthyl-2,2′-diyl hydrogenphosphate.e 2a (4 equiv.), and ZnMe2 (4 equiv.).f 2a (5 equiv.), and ZnMe2 (4 equiv.).
1	BiCl3	Toluene	40	Trace
2	ZnCl2·Et2O	Toluene	40	7
3	CF3CO2H	Toluene	40	Trace
4	MSA	Toluene	40	7
5	(R)-(−)-BPA^d	Toluene	40	11
6	p-TsOH	Toluene	40	18
7	CSA	Toluene	40	32
8	CH3CO2H	Toluene	40	41
9	HCO2H	Toluene	40	43
10^e	HCO2H	Toluene	40	39
11^f	HCO2H	Toluene	40	32
12	HCO2H	THF	40	Trace
13	HCO2H	Hexane	40	30
14	HCO2H	CH2Cl2	40	25
15	HCO2H	CH2Cl2	r.t.	46

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Fig. 2 The X-ray structure of 4a.

On the basis of this initial observation, we used 5-methoxysalicylaldehyde (1a), 3-methoxyprop-1-yne (2a), and 6,6-dimethyl-1-vinylcyclohex-1-ene (3a) as model substrates for further optimization (Table 1). Various acids were initially evaluated in toluene at 40 °C (entries 1–9). The experimental results indicated that HCO₂H is a beneficial acid. By using the ideal acid, we discovered that the stoichiometric ratio of 2a and ZnMe₂ in alkynylation sequence effectively facilitated the desired transformation (entries 9–11). We then screened several organic solvents, including THF, hexane and CH₂Cl₂ (entries 12–15). As a result, CH₂Cl₂ was found to be the best choice at room temperature, and the anticipated spirocycle containing product 4a can be produced in 46% yield. We also performed a stepwise investigation under the optimal conditions but leading to a lower yield (22%, for details see ESI†). So we proposed that the existence of ZnMe₂ may play a very significant role in the one-pot process.

Having identified optimal reaction conditions (Table 1, entry 15), we first examined the substrate scope of this transformation with respect to the substituted salicylaldehydes partner. Table 2 shows that the electronic effect of the substrates is very significant. Electron-donating groups, such as dimethoxy (4g), methoxy (4a, h), and methyl (4b) are more favorable for the envisioned spirocycle products than the electron-withdrawing groups, such as bromo (4d), chloro (4e), and ester (4f). The reaction is also restricted to the terminal alkyne (4a, 4h–k). The steric effect of these electron-rich alkynes exerts a great impact on the yields (23–46%). Functionalized 1,3-butadienes were also investigated. We obtained both spirocycle products (4l-1, 4m-1, 4n-1) and benzopyran compounds (4l-2, 4m-2, 4n-2) when the reaction was treated with isoprene or 2,3-dimethyl-1,3-butadiene. Benzopyran compounds were not observed when using 6,6-dimethyl-1-vinylcyclohex-1-ene (3a) as diene (Table 2, 4a–k). We then speculated that the benzopyran products corresponding to 3a are unstable under acidic conditions.

Table 2 Substrate scope of alkynylation/dearomatizative cyclization toward spirocycle compounds^a

a For all compounds, dr was determined by ¹H NMR spectroscopy, if diastereoisomers could not be detected in ¹H NMR spectra, we identified the dr as >20 : 1. 4g and 4i were also analysed by HPLC (see ESI).

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Based on these results and our previous findings, a plausible reaction mechanism for this spirocyclization is illustrated in Scheme 2. The reaction of ZnMe₂ with terminal alkyne (2) generated an active alkynylzinc,²⁰ which attacked the substituted salicylaldehyde (1) to form alcohol (5). Under acidic conditions, 5 was converted into carbocation TS-A, which was difunctionally stabilized by a phenyl group and an acetylenyl group through conjugation effects. The formed carbocation TS-A underwent electrophilic addition with diene 3 to deliver the resonance hybrids TS-B and TS-C. TS-C followed by enol–keto tautomerization of the phenol ring to produce spirocycle 4-1 (path a). At the same time, TS-B underwent intramolecular nucleophilic addition to form the benzopyran compound 4-2 through path b.

Scheme 2 Plausible reaction mechanism.

Conclusions

We developed an approach to construct spiro[5.5]undecanes. The ZnMe₂-promoted alkynylation of salicylaldehyde and HCO₂H-mediated dearomatizative cyclization occurred in sequence in a one-pot process, which not only involves readily available starting materials but also demonstrates high diastereoselectivities. Utilizing multicomponent synthesis and one-pot process as the core strategies, a number of spirocycles were prepared smoothly.

Acknowledgements

The authors acknowledge the financial support provided by the National Natural Science Foundation of China (21202069, 21272099, and 21472078). We thank Dr Yuan Zhang and Prof. Zhi-Xiang Xie (Lanzhou University) for helpful discussion.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1447716. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra02463g

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