Phosphine-promoted intramolecular Rauhut–Currier/Wittig reaction cascade to access (hetero)arene-fused diquinanes

Abstract

We describe the first phosphine-promoted intramolecular Rauhut–Currier reaction that triggers an intramolecular Wittig process assembling new classes of diquinanes. The one-pot strategy provides ready access to simple diquinanes and various (hetero)arene-fused diquinanes incorporated with up to two contiguous all-carbon quaternary centers under metal-free and neutral conditions. We showcased the generality of the method on a broad range of substrates and demonstrated its synthetic utility in accessing various advanced intermediates relevant to natural product synthesis and material science.

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Benzannulated diquinanes (cyclopenta[a]indenes) are the key structural elements of many bioactive natural products and medicinally important molecules (Fig. 1).¹ Therefore, several synthetic protocols have been developed to synthesize cyclopenta[a]indene derivatives.² While most of them are metal-promoted strategies, the only metal-free approach to our knowledge is Ghorai's work on constructing benzannulated diquinanes employing a tandem iminium and enamine catalysis.³ Here, we report the first organophosphine-promoted Rauhut–Currier/Wittig reaction sequence to synthesize complex diquinane analogues.

Fig. 1 Representative bioactive natural products possessing cyclopenta[a]indene core.

The Rauhut–Currier (RC) reaction is a versatile carbon–carbon bond-forming reaction between two electron-deficient olefins promoted by an organic nucleophilic base.⁴ Since the RC reaction is atom-economic and organocatalytic, it has extensive applications in accessing diverse classes of highly functionalized molecules.⁵ Recently, several Lewis base-promoted intramolecular cascade transformations triggered by the RC reaction have been developed to create various cyclic structures.^4,6 However, to our knowledge, the RC reaction is yet to be explored in assembling an valuable diquinane scaffold. This manuscript describes an efficient approach to simple diquinanes and (hetero)arene-fused diquinanes and demonstrates its utility in preparing some advanced intermediates relevant to natural product synthesis.

To assemble cyclopenta[a]indenes by incorporating the mechanistic features of the RC reaction, the tethered bis-enone A was designed in such a way that the phospha-Michael addition preferentially occurs to the β-unsubstituted enone leading to the formation of the zwitterionic intermediate B, Scheme 1. The role of R¹ is to discourage a cross-RC reaction since activated α- and β-unsubstituted olefins tend to dimerize or oligomerize under the RC conditions. The enolate-mediated displacement of phosphine could generate dihydroindeno[2,1-c]pyran-9-one C. On the other hand, we expected that a proton transfer event might generate the phosphorous ylide D, which is poised to undergo an intramolecular Wittig reaction to deliver the benzo-fused diquinane E. At this stage, we do not rule out the phospha-Michael addition to the β-substituted enone generating the zwitterionic species F, a subsequent 1,3-proton transfer and an enolate-induced elimination of phosphine providing benzo-fused cycloheptenone G.

Scheme 1 Substrate design for cyclopenta[a]indenes and the possible mechanistic scenarios with a phosphine.

Although the substrate design (A) allows different mechanistic pathways leading to C, E or G, we prepared the bis-enone 7a to ascertain the preferred product under experimental conditions, Table 1. Since no reaction was observed under catalytic conditions, we exposed 7a to stoichiometric amounts of PPh₃ and PPh₂Et, but the starting material remained as such (entries 1 and 2). Interestingly, a more nucleophilic trialkylphosphine such as PCy₃ gave 8a over the other expected products, although in poor yields (entries 3–5). However, better results were achieved with PBu₃ as the Lewis base. An initial reaction of 7a with PBu₃ in DMF at room temperature delivered 8a in a good yield (entry 6). During the solvent screening, we realized that the yield of 8a improved in tert-butanol medium (entries 7–9). A few variations in the temperature with PBu₃ as the Lewis base and tert-butanol as the solvent gave 8a in an excellent yield (entries 10–12). We were delighted that we could establish the first synthesis of benzo-fused diquinanes, such as 8a, under the RC set up.

Table 1 Optimization of reaction parameters^a,b

Entry	PR3 (1.2 equiv.)	Solvent	Temperature (°C)	Time (h)/yield^c (%)
a See the ESI† for a detailed procedure. b The reactions were performed on a 0.1 mmol scale. c Isolated yields after column chromatography.
1	PPh3	DMF	30	48/—
2	PPh2Et	DMF	30	48/—
3	PCy3	DMF	30	2/28
4	PCy3	Toluene	30	2/14
5	PCy3	MeCN	30	2/32
6	PBu3	DMF	30	1/64
7	PBu3	MeCN	30	2/56
8	PBu3	DMSO	30	1/62
9	PBu3	t-BuOH	30	2/73
10	PBu3	t-BuOH	50	2/78
11	PBu3	t-BuOH	70	1/87
12	PBu3	t-BuOH	80	1/81

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Encouraged by the result, we evaluated the generality of the method under optimized conditions, Scheme 2. An array of benzannulated diquinanes (8b–8aa) and a heteroarene-fused diquinane (8ab) were assembled in good yields. The reaction fared well across a wide range of substrates irrespective of the electronic or steric nature of R¹, R² or R³. Different types of alkyl groups can be accommodated at R¹ (8b–8g, 8k, 8l, 8y, 8z and 8aa), and various kinds of electron-donating (methyl, and mono-, di- and trimethoxy) and marginally electron-withdrawing (fluoro) substituents were well-tolerated at R². Apart from the phenyl backbone, substrates with naphthyl (8l, 8n and 8o) and a benzothiophene backbone (8ab) were prepared in moderate to good yields. We could conveniently prepare a diverse range of cyclopenta[a]indenes possessing non-aryl (8p and 8q), aryl groups (8i, 8o, 8r–8v, 8y–8aa), and heteroaryl substituents (8w and 8x) at R³. The structure of a representative example (8m) was confirmed by the single crystal X-ray diffraction analysis (CCDC 2325678†). The poor yields in case of 8p and 8ab are attributed to the partial decomposition of the respective starting compounds leading to unidentifiable products.

Scheme 2 Substrate scope. See the ESI† for a detailed procedure. The reactions were performed on 0.1–0.2 mmol scale and the yields reported are after isolation by column chromatography ^aNot detected.

It is worth highlighting that the method can also be extended to synthesizing functionalized diquinanes such as 8ac and 8ad in moderate yields, Scheme 2. The intramolecular RC adduct 9ad was isolated, but 9ac was not observed. Accessing a fully alkyl-substituted diquinane 8ac significantly enhances the scope of the work. Further, these structures are amenable to further synthetic manipulations and the prevalence of numerous di- and triquinane-based bioactive natural products make it an attractive strategy.⁷

This method was also extended to synthesizing cyclopenta[a]indenes with two contiguous quaternary carbons, Scheme 3. The substituents at R¹ and R² in 10 would eventually translate to the quaternary carbons in 11. Accordingly, the required bis-enones 10 were prepared. By subjecting 10a–10d to the optimized conditions, we accessed 11a–11d in good to excellent yields. All the examples accommodated alkyl groups at R¹ and R², and aryl (11a and 11b), alkyl (11c) and heteroaryl (11d) groups at R³. Notably, a cyclopenta[a]indene derivative with all-alkyl substituents (11c) at R¹, R² and R³ can also be synthesized.

Scheme 3 Synthesis of cyclopenta[a]indenes with two contiguous quaternary carbons.

Next, we focused on establishing the synthetic utility of the benzannulated diquinanes accessed herein. We transformed 8g to 12gvia PMB deprotection followed by dehydration of the primary alcohol, Scheme 4. To undertake an oxy-Cope rearrangement, we converted 12g to the allyl vinyl carbinol 13g by the addition of the vinyl Grignard reagent, which, upon exposure to potassium hydride, prompted a cascade oxy-Cope rearrangement and intramolecular ene-type cyclization⁸ to generate an unexpected octahydrobenzo[e]-as-indacene 14g in 54% yield. Further, 14g was converted to the tetrahydrobenzo[e]-as-indacene 15g under acidic conditions. Indacenes such as 15 can exhibit interesting medicinal and photophysical properties.⁹

Scheme 4 Elaboration of 8g to 15gvia oxy-Cope and an ene-type cyclization sequence. Reagents and conditions: (a) (i) DDQ (1.5 equiv.), DCM : water (9 : 1), RT, 2 h. (ii) 2-Nitrophenyl selenocyanate (3 equiv.), PBu₃ (3 equiv.), anh. THF, RT, 4 h, then H₂O₂, 2 h, 65% (over two steps). (b) CH₂=CHMgBr (3 equiv.), anh. THF, 0 °C, 2 h, 95%. (c) KH (1.2 equiv.), 18-C-6 (1.1 equiv.), anh. THF, 0 °C-RT, 30 min, 54%. (d) p-TSA (0.1 equiv.), toluene, RT, 5 h, 72%.

The cyclopenta[a]indenes were also extended to synthesizing natural product-like polycyclic cyclopentanoids. For example, the benzo-fused diquinane 8a was converted to the diol 16a under OsO₄-catalyzed dihydroxylation conditions, Scheme 5. Transforming the diol 16a to the cyclic carbonate 17a represents the construction of the tetracyclic framework of clavulyne^1c and jejucarboside family of natural products.¹⁰

Scheme 5 Elaboration of 8a to the tetracyclic framework of clavulyne and jejucarboside family of natural products. Reagents and conditions: (a) OsO₄ (10 mol%), NMO (2.5 equiv.), THF : water (5 : 1), RT, 24 h, 90%. (b) CDI (2 equiv.), Et₃N (2 equiv.), dry DCM, RT, 6 h, 86%.

We also planned to extend cyclopenta[a]indenes 8 to other polycyclic structures, Scheme 6. Accordingly, we converted 8a to 19gvia PMB deprotection, IBX oxidation of the primary alcohol, and a methylene Wittig reaction of the resulting aldehyde. Next, 19g was treated with the vinyl Grignard reagent to achieve the respective allyl vinyl carbinol, which was subjected to ring-closing metathesis reaction using the Grubbs’ 2^nd generation catalyst and isolated the dicyclopenta[a,b]indene 20g. Similarly, we accessed cyclopenta[k]fluorene 21g and benzo[a]cyclopenta[c]azulene 22g, which are part structures of several pharmaceutically relevant molecules and materials.^1d,11

Scheme 6 Elaboration of 8g to various tetracyclic structures. Reagents and conditions: (a) (i) DDQ (1.5 equiv.), DCM : water (9 : 1), RT, 2 h, 79%. (ii) IBX (1.2 equiv.), DMSO, RT, 1 h, 81%. (iii) CH₂=PPh₃ (1.5 equiv.), anh. THF, 0 °C, 2 h, 89%. (b) (i) CH₂=CHMgBr (3 equiv.), anh. THF, 0 °C, 2 h. (ii) Grubbs’ 2^nd generation catalyst (G-II, 5 mol%), dry DCM, reflux, 1 h, 88% (over two steps). (c) (i) CH₂=CHCH₂MgCl (3 equiv.), anh. THF, 0 °C, 2 h, dr = 5 : 1. (ii) G-II (5 mol%), dry DCM, reflux, 1 h, 85% (over two steps), dr = 5 : 1. (d) (i) CH₂=CHCH₂CH₂MgBr (3 equiv.), anh. THF, 0 °C, 2 h. (ii) G-II (5 mol%), dry DCM, reflux, 1 h, 82% (over two steps).

Sativamide A 4 possesses a unique 6-5-5-5 tetracyclic rearranged nor-lignan carbon skeleton and exhibits potential neuroprotective activity on several cell models, Scheme 7.^1d To assemble the core structure of 4, we prepared the bis-enone 7ae, subjected it to the optimized conditions described in Scheme 3, and obtained the respective cyclopenta[a]indene 8ae in 46% yield. Then, we transformed 8ae to 20ae in five steps following the synthetic protocol described for 20g. With the presence of 6-5-5-5 core and the required functionalities in place, 20ae represents an advanced precursor for synthesizing sativamides.

Scheme 7 Synthesis of an advanced intermediate 20ae to synthesize sativamide A. Reagents and conditions: (a) PBu₃ (1.2 equiv.), ^tBuOH, 70 °C, 1 h, 46%. (b) (i) DDQ (1.5 equiv.), DCM : water (9 : 1), RT, 2 h. (ii) IBX (1.2 equiv.), DMSO, RT, 1 h. (iii) CH₂=PPh₃ (1.5 equiv.), anh. THF, 0 °C, 2 h, 55% over three steps. (c) (i) CH₂=CHMgBr (3 equiv.), anh. THF, 0 °C, 2 h. (ii) Grubbs’ 2^nd generation catalyst (G-II, 5 mol%), dry DCM, reflux, 1 h, 81% over two steps.

In summary, we developed a phosphine-promoted Rauhut–Currier/Wittig reaction cascade¹² to assemble diquinanes and a wide range of arene- and heteroarene-fused diquinanes. The scope and generality of the method were quite broad. The utility of the concept was thoroughly exemplified by synthesizing several complex cyclopentanoids and various advanced intermediates for natural product synthesis and materials chemistry. A few other merits of this strategy are (i) neutral and metal-free conditions, (ii) easily accessible starting compounds, and (iii) the occurrence of numerous bioactive molecules with the kind of molecular architectures accessed herein. We are applying this method to synthesize complex bioactive natural products, and the results will be communicated in due course.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

The authors thank IISER Mohali for the central and departmental NMR and X-ray facilities, and the mass spectrometry facility. S. S. V. R. thanks SERB for the Swarnajayanti fellowship (DST/SJF/CSA-01/2017-18), Elsevier's Reaxys grant and IISER Mohali for funding. J. P. M. thanks IISER Mohali and S. S. S. thanks CSIR for research fellowships.

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterisation data for new compounds. CCDC 2325678 [for 8m] and 2327817 [for 17a]. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4ob00984c

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