DABCO-promoted reaction sequence of β-nitro alcohols and α-oxoaldehydes: construction of diverse tetrahydrofurans and total synthesis of (+)-bruguierol B

Abstract

A DABCO-promoted highly efficient reaction sequence has been developed. Under mild conditions, β-nitro alcohols (chiral/achiral or cyclic/acyclic) reacted smoothly with α-oxoaldehydes through a sequential Henry reaction, HNO₂ elimination, and intramolecular hemiketalization to form the functionalized hemiketal intermediates. These intermediates serve as oxocarbenium ion precursors, reacting with external or internal nucleophiles diastereoselectively to afford diverse tetrahydrofuran derivatives, including dihydrofuran-3-one, benzoxa[3.2.1]octane, furo[3,2-b]furan, and hexahydrobenzofuranol scaffolds. Notably, this strategy enabled the first total synthesis of (+)-bruguierol B.

---

Introduction

Tetrahydrofuran scaffolds are important structural units found in a variety of natural products and bioactive unnatural molecules.¹ Consequently, the development of novel synthetic strategies for efficient construction of these oxacyclic systems has garnered significant attention.² Structurally, tetrahydrofuran-2-ol derivatives containing cyclic hemiketal moieties should be versatile precursors for the preparation of tetrahydrofuran compounds (Scheme 1a). Upon treatment with an acid (H⁺), tetrahydrofuran-2-ol can undergo hydroxyl group elimination to form an oxocarbenium ion intermediate, which readily reacts with various nucleophiles (Nu) to afford functionalized tetrahydrofuran derivatives.³ Therefore, establishing general synthetic protocols for tetrahydrofuran-2-ol derivatives is highly desirable.

Scheme 1 Synthesis of tetrahydrofuran derivatives and our design.

Under basic conditions, β-nitrocarbonyl compounds undergo HNO₂ elimination to form electron deficient alkenes.⁴ For synthesizing these β-nitrocarbonyl precursors, existing synthetic methods typically involve Michael additions between simple nitroalkanes and β-carbonyl alkenes (Scheme 1b; EWG = electron withdrawing group).⁵ In 2015, Palmieri et al. reported a notable Henry reaction/HNO₂ elimination sequence, where α-oxoaldehydes reacted with simple nitroalkanes to afford 1,2-diketone products after tautomerization (Scheme 1c).⁶ However, despite its synthetic potential, this method remains underdeveloped in the literature. Building on this work, our group recently extended the reaction scope to include nitroalkanes with diverse remote functionalities (Scheme 1d),⁷ thereby facilitating access to various heterocyclic architectures.

Surprisingly, a literature survey revealed that β-nitro alcohols, easily accessible through Henry reactions between nitroalkanes and carbonyl compounds, have been remarkably underutilized in this addition/elimination sequence. To the best of our knowledge, only one single report exists describing the application of β-nitro alcohols in this synthetic strategy, which afforded functionalized silyl enol ethers.⁸

Based on our previous work about hemiketal chemistry⁹ and HNO₂ elimination,¹⁰ we hypothesized that integrating β-nitro alcohols and α-oxoaldehydes in an addition/elimination/cyclization/substitution cascade could offer a robust route to highly functionalized tetrahydrofuran scaffolds, which are challenging to synthesize conventionally. As outlined in Scheme 1e, several steps are involved in our design: (1) the Henry reaction of β-nitro alcohol and α-oxoaldehyde leads to the required nitro diol; (2) the base-promoted elimination of HNO₂ affords the enol intermediate, which tautomerizes to give the corresponding 1,2-diketone; and (3) the intramolecular cyclization between the hydroxyl group and the keto carbonyl furnished the desired tetrahydrofuran-2-ol intermediate, which could serve as versatile precursor for oxocarbenium ion to work with either external or internal nucleophiles, affording various biologically important tetrahydrofuran scaffolds, such as dihydrofuran-3-one (A),¹¹ benzoxa[3.2.1]octane (B),¹² furo[3,2-b]furan (C),¹³ and hexahydrobenzofuranol (D).¹⁴ Herein, we report such a concise addition/elimination/cyclization sequence to construct the key tetrahydrofuran-2-ol intermediates. A variety of chiral/achiral or cyclic/acyclic β-nitro alcohols were employed to access functionalized tetrahydrofuran derivatives via reaction with α-oxoaldehydes. Notably, this reaction sequence enabled us to successfully accomplish the total synthesis of (+)-bruguierol B for the first time.¹⁵

Results and discussion

As shown in Table 1, we started our investigation by reacting cyclopentanone derived β-nitro alcohol 1a with α-oxoaldehyde 2a in the presence of triethylamine (TEA) in CH₂Cl₂ solvent at 25 °C (entry 1). To our delight, the reaction sequence proceeded smoothly to afford the key cyclic hemiketal intermediate 3a, as an equilibrium mixture with its corresponding ring opened form 3a′. It should be noted that the hemiketal 3a was obtained just by simple aqueous acid workup and used directly in the next transformation without further purification. Subsequently, treatment of hemiketal 3a with indole in the presence of Sc(OTf)₃ (10 mol%) provided the desired dihydrofuran-3-one 4a bearing a quaternary stereocenter in 58% yield (over two steps) after 15 min at 25 °C. Several other kinds of solvents were tested for this two-step sequence and it was found that the isolated yield of 4a could not be improved (entries 2–6). Next, various organic bases were examined (entries 7–10) and DABCO proved to be a better choice, while DIPEA and DBU gave no products. Further experiments showed that decreasing the loading of DABCO gave lower yields (entries 11 and 12).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Base (x equiv.)	Yield^b (%)
a Unless otherwise specified, all reactions were carried out using 1a (0.2 mmol) and 2a (0.3 mmol) in solvent (0.4 mL) with base (0.4 mmol) at 25 °C for 48 h; followed by Sc(OTf)3 (0.02 mmol) and indole (0.3 mmol) in CH2Cl2 (0.4 mL) at 25 °C for 15 min. See the SI for more details. b Isolated yield of 4a over two steps. DMAP = 4-dimethylaminopyridine. DABCO = 1,4-diazabicyclo[2.2.2]octane. DIPEA = N,N-diisopropylethylamine. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
1	CH2Cl2	TEA (2.0)	58
2	CHCl3	TEA (2.0)	37
3	CH3CN	TEA (2.0)	43
4	Ethyl acetate	TEA (2.0)	34
5	Toluene	TEA (2.0)	45
6	Acetone	TEA (2.0)	46
7	CH2Cl2	DMAP (2.0)	66
8	CH2Cl2	DABCO (2.0)	73
9	CH2Cl2	DIPEA (2.0)	—
10	CH2Cl2	DBU (2.0)	—
11	CH2Cl2	DABCO (1.5)	59
12	CH2Cl2	DABCO (1.2)	57

---

With the optimized reaction conditions in hand (Table 1, entry 8), we investigated the substrate scope between β-nitro alcohols 1 and α-oxoaldehydes 2 for this two-step sequence to prepare dihydrofuran-3-ones 4. As shown in Scheme 2, β-nitro alcohols bearing aliphatic cycles with different ring size or heterocycles were all applicable to this synthetic protocol, leading to spiro products 4a–4e in moderate to good yields. It is noteworthy that the designed reaction sequence proceeded with an excellent level of diastereocontrol, since product (±)-4f was obtained bearing three stereogenic centers (two of them are oxygenated quarternary centers) as a single diastereoisomer. Then, the impact of the substituents at the phenyl moiety of α-oxoaldehyde 2 on the reaction was investigated. Different substituents on the phenyl ring of α-oxoaldehydes, regardless of their electronic nature and position, were tolerated (4g–4m). Except substituted benzene ring, α-oxoaldehydes containing a 2-thienyl (4n) and even an aliphatic group (4o) could also be transformed into the corresponding products in good yields. Next, the scope of nucleophiles was also investigated. A series of indoles with different substituents at the N-, C2-, C3-, C4-, C5-, C6- and C7-positions were tested in the reaction sequence, and the desired products 4aa–4ai were obtained in good yields. Substituted furans were also applicable as nucleophiles to this reaction, providing the corresponding products 4aj and 4ak with moderate yields. Moreover, allyl and methallyl trimethylsilanes, and trimethylsilyl cyanide were tolerated in this process and produced products 4al–4an in serviceable yields.

Scheme 2 Substrate scope.

Somewhat surprisingly, messy products were observed when simple β-nitro alcohol 5a was applied to the reaction. While, by protecting the OH group with tert-butyldimethylsilyl (TBS), the addition/elimination sequence underwent smoothly to deliver the hemiketal intermediate after deprotection of the OH group with AcOH, which was converted to 2,2-disubstituted dihydrofuran-3-one 6 in 42% yield (over three steps). Under the present conditions, no elimination of HNO₂ occurred with α-substituted β-nitro alcohol 5c, and the reductive dehydroxylation of the corresponding Henry/cyclization hemiketal product proceeded efficiently in the presence of Et₃SiH and BF₃·Et₂O, followed by TMS-protection to furnish highly substituted tetrahydrofuran (±)-7 in 74% yield (over three steps).

Building on our success in synthesizing functionalized dihydrofuran-3-ones using external nucleophiles, we subsequently explored the construction of more complex architectures through intramolecular trapping of the oxocarbenium ion intermediate by internal nucleophiles (Scheme 3). In the presence of DABCO, the reaction of β-nitro alcohols 8a and 8b with α-oxoaldehyde 2a occurred smoothly, followed by BF₃·Et₂O-catalyzed cyclization to afford 5,6-bridged benzoxa[3.2.1]octane derivatives (±)-9a and (±)-9b, respectively, with excellent diastereoselectivities (dr >20 : 1). Under analogous conditions, the reaction sequence of nitroalcohol 1a with α-oxoaldehyde 10a and 10b, respectively, could be realized, leading to spirocyclic products 11a and 11b in good yields.

Scheme 3 Formation of dihydrofuran-3-one scaffolds with internal nucleophiles.

To demonstrate the synthetic utility of this methodology, a series of transformations were performed to construct structurally diverse tetrahydrofuran analogues (Scheme 4). Upon reduction of the ketone group in 4ai, an isolable diastereomeric mixture of alcohols (±)-12a and (±)-12b was obtained. Interestingly, the subsequent base-catalyzed reaction sequence of (±)-12a with CH₂Br₂ proceeded along a regiodivergent pathway, leading to C-alkylation product (±)-13avia intramolecular S_N2 substitution at the C3 position of indole moiety and N-alkylation product (±)-13bvia intramolecular N,O-acetal formation. The structure of (±)-13a was unambiguously confirmed by X-ray single-crystal diffraction analysis (CCDC 2466831; see SI for details). Treatment of 4al with allylmagnesium chloride afforded alcohol (±)-14, featuring two adjacent quaternary stereocenters with complete diastereocontrol. The subsequent olefin ring-closing metathesis provided hexahydrobenzofuranol (±)-15 under mild conditions. The BF₃·Et₂O-catalyzed intramolecular etherification of compound (±)-14 yielded bicyclic furo[3,2-b]furan (±)-16 as a single diastereomer, containing three stereogenic centers (including two oxygenated quaternary centers). Next, the terminal alkene in 4al was transformed to aldehyde 17via oxidative cleavage. Reduction of 4al gave the corresponding dihydrofuran-3-one 18, which underwent Baeyer–Villiger oxidation with m-chloroperbenzoic acid (m-CPBA) smoothly to afford ketal-lactone 19 in 62% yield. The reductive dehydroxylation of hemiketal 3a with hantzsch ester (HE) resulted in dihydrofuran-3-one 20, which served as a Michael donor to work with acrylonitrile, yielding dihydrofuran-3-one 21 in 45% yield (over two steps). Additionally, hemiketal 3g, prepared from 1a and 2-(2-bromophenyl)-2-oxoacetaldehyde, was converted to allylic intermediate 22via Sc(OTf)₃-mediated allylation, followed by intramolecular Heck reaction to form spirocycle 23 with an exocyclic alkene.

Scheme 4 Useful transformations.

As delineated in Scheme 5, not only ketone-derived but also aldehyde-derived chiral β-nitro alcohol 24 (94% ee) could be used in this two-step sequence to give the corresponding 5,6-bridged products 25a and 25b, respectively, with maintained enantioselectivity as a single diastereoisomer (dr >20 : 1). Most notably, this oxo-bridged bicyclic scaffold is the key structure of natural product bruguierols A–C with antimicrobial activities.^15a In 2007, Ramana et al. reported the first total synthesis of (−)-bruguierol A by employing a cross alkyne cyclotrimerisation reaction.^15b In the same year, Jennings et al. reported the first total synthesis of (+)-bruguierol C via an intramolecular Friedel–Crafts alkylation.^15c However, to the best of our knowledge, there is no specific report on the synthesis of optically pure bruguierol B. We then focused on the development of a complementary strategy by using the obtained oxo-bridged bicyclic compounds as the key precursors to prepare bruguierol B and various related bruguierol derivatives. Conversion of the ketone group in 25a to the dithiane followed by desulfuration with RANEY® Ni provided oxo-bridged bicycle 26 in 42% yield (over two steps). Treatment of 26 with lead tetraacetate and subsequent hydrolysis with aqueous HCl gave (+)-bruguierol B 27 in 26% yield (over two steps) with 91% ee. It should be noted that (+)-bruguierol B has been synthesized for the first time. Under the same conditions, the methylene acetal moiety of compounds 25a and 25b can be easily removed, yielding bruguierol B derivatives 28a and 28b, respectively. The NaBH₄ reduction of 25a and 25b resulted in alcohol 29a and 29b, respectively, in a highly diastereocontrolled manner. Finally, 25b was treated with allylmagnesium chloride to afford alcohol 30 bearing two adjacent oxygenated quaternary centers with excellent stereoselectivity.

Scheme 5 Total synthesis of (+)-bruguierol B and related derivatives.

Conclusions

In conclusion, we found that either chiral/achiral or cyclic/acyclic β-nitro alcohols could be used in a DABCO-mediated highly efficient reaction sequence to react with various α-oxoaldehydes under mild conditions, leading to the key hemiketal intermediates. Subsequently, the hemiketal intermediates have been applied as the precursor of oxocarbenium ions to work with either external or internal nucleophiles to afford various functionalized tetrahydrofuran derivatives in a diastereoselective manner. Investigations in our laboratory toward leveraging this synthetic protocol for the preparation of more complex heterocyclic compounds are currently underway.

Author contributions

Y.-K. Liu conceived the project. Y.-X. Lu and X.-J. Lv performed the experiments. Y.-X. Lu wrote the initial manuscript draft. Y.-K. Liu and X.-J. Lv finalized the manuscript draft. All authors contributed to discussions.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information (SI): all experimental procedures, mechanistic investigations, characterisation data, spectroscopic data, NMR spectra. See DOI: https://doi.org/10.1039/d5qo01330e.

CCDC 2466831 contains the supplementary crystallographic data for this paper.¹⁶

Acknowledgements

This work was supported by the National Nature Science Foundation of China (22171250), and the Natural Science Foundation of Shandong Province (ZR201911080241).

References

1. (a) A. Bermejo, B. Figadère, M.-C. Zafra-Polo, I. Barrachina, E. Estornell and D. Cortes, Acetogenins from annonaceae: recent progress in isolation, synthesis and mechanisms of action, Nat. Prod. Rep., 2005, 22, 269–303; (b) Y. Chen, J.-W. Chen and X. Li, Cytotoxic bistetrahydrofuran annonaceous acetogenins from the seeds of annona squamosa, J. Nat. Prod., 2011, 74, 2477–2481; (c) A. Lorente, J. Lamariano-Merketegi, F. Albericio and M. Álvarez, Tetrahydrofuran-containing macrolides: a fascinating gift from the deep sea, Chem. Rev., 2013, 113, 4567–4610; (d) L. Fernández-Peña, C. Díez-Poza, P. González-Andrés and A. Barbero, The tetrahydrofuran motif in polyketide, Mar. Drugs, 2022, 20, 120.
2. (a) J. P. Wolfe and M. B. Hay, Recent advances in the stereoselective synthesis of tetrahydrofurans, Tetrahedron, 2007, 63, 261–290; (b) D. J. Mack and J. T. Njardarson, Recent advances in the metal-catalyzed ring expansions of three- and four-membered rings, ACS Catal., 2013, 3, 272–286; (c) J. Cornil, L. Gonnard, C. Bensoussan, A. Serra-Muns, C. Gnamm, C. Commandeur, M. Commandeur, S. Reymond, A. Guérinot and J. Cossy, Iron- and Indium-catalyzed reactions toward nitrogen- and oxygen-containing saturated heterocycles, Acc. Chem. Res., 2015, 48, 761–773; (d) A. de la Torre, C. Cuyamendous, V. Bultel-Poncé, T. Durand, J.-M. Galano and C. Oger, Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis, Tetrahedron, 2016, 72, 5003–5025.
3. (a) T. Siu, D. Qin and S. J. Danishefsky, The total synthesis of heliquinomycinone, Angew. Chem., Int. Ed., 2001, 40, 4713–4716; (b) P. Magnus and M. A. H. Stent, Stereospecific synthesis of (±)-1,2-anhydro methyl rocaglate, Org. Lett., 2005, 7, 3853–3855; (c) R. Fan, Y. Sun and Y. Ye, Iodine(III)-mediated tandem acetoxylation−cyclization of o-acyl phenols for the facile construction of α-acetoxy benzofuranones, Org. Lett., 2009, 11, 5174–5177; (d) J.-F. Parent, X. Bertrand, G. Deslongchamps and P. Deslongchamps, Applying the bent bond/antiperiplanar hypothesis to the stereoselective glycosylation of bicyclic furanosides, J. Org. Chem., 2020, 85, 758–773.
4. N. Ono, The nitro group in organic synthesis, Wiley-VCH, New York, 2001.
5. (a) A. P. Kozikowski and J.-P. Wu, A general approach to the pseudopterosins and their C-11 and C-13 stereoisomers. construction of the tricyclic skeleton of the pseudopterosins, Synlett, 1991, 465–468; (b) J. C. Anderson, A. S. Kalogirou and G. J. Tizzard, Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes, Tetrahedron, 2014, 70, 9337–9351; (c) S. Gabrielli, L. Ciabattoni, S. Sampaolesi, R. Ballini and A. Palmieri, A new fully heterogeneous synthesis of pyrrole-2-acetic acid derivatives, RSC Adv., 2016, 6, 44341–44344; (d) S. Gabrielli, A. Giardinieri, S. Sampaolesi, R. Ballini and A. Palmieri, A new one-pot synthesis of quinoline-2-carboxylates under heterogeneous conditions, Molecules, 2016, 21, 776; (e) Y. Li, L. Ibsen and K. A. Jørgensen, Formal asymmetric α-alkenylation of aldehydes and the synthetic application toward forming α-exo-methylene-γ-butyrolactones and skipped dienes, Org. Lett., 2017, 19, 1200–1203.
6. A. Palmieri, S. Gabrielli, S. Sampaolesi and R. Ballini, Nitroaldol (Henry) reaction of 2-oxoaldehydes with nitroalkanes as a strategic step for a useful, one-pot synthesis of 1,2-diketones, RSC Adv., 2015, 5, 36652–36655.
7. Y.-X. Lu, X.-J. Lv, C. Liu and Y.-K. Liu, Triethylamine-promoted henry reaction/elimination of HNO₂/cyclization sequence of functionalized nitroalkanes and 2-oxoaldehydes: diversity-oriented synthesis of oxacycles, Org. Lett., 2023, 25, 4033–4037.
8. C. Zhu, M.-Y. Han, X.-X. Liang, B. Guan, P. Li and L. Wang, Hydrogen-bond-assisted sequential reaction of silyl glyoxylates: stereoselective synthesis of silyl enol ethers, Org. Lett., 2021, 23, 54–59.
9. (a) L. Qiao, Z.-W. Duan, X.-N. Wu, D.-H. Li, Q.-Q. Gu and Y.-K. Liu, Organocatalytic diversity-oriented asymmetric synthesis of structurally and stereochemically complex heterocycles, Org. Lett., 2018, 20, 1630–1633; (b) X.-N. Wu, Z.-H. You and Y.-K. Liu, Different hybridized oxygen atoms controlled chemoselective formation of oxocarbenium ions: synthesis of chiral heterocyclic compounds, Org. Biomol. Chem., 2018, 16, 6507–6520; (c) X.-J. Lv, W.-W. Zhao, Y.-H. Chen, S.-B. Wan and Y.-K. Liu, Organocatalytic asymmetric synthesis of both cis- and trans-configured pyrano[2,3-b]chromenes via different dehydration pathways, Org. Chem. Front., 2019, 6, 1972–1976; (d) C. Wang, Y.-H. Chen, H.-C. Wu, C. Wang and Y.-K. Liu, The quinary catalyst–substrate complex induced construction of spiro-bridged or cagelike polyheterocyclic compounds via a substrate-controlled cascade process, Org. Lett., 2019, 21, 6750–6755; (e) J.-H. Liu, X.-J. Lv and Y.-K. Liu, Asymmetric retro-Claisen reaction catalyzed by chiral aza-bisoxazoline–Zn(II) complex: enantioselective synthesis of α-arylated ketones, Org. Lett., 2023, 25, 1706–1710.
10. (a) J.-P. Pei, Y.-H. Chen and Y.-K. Liu, Asymmetric organocatalytic sequential reaction of structurally complex cyclic hemiacetals and functionalized nitro-olefins to synthesize diverse heterocycles, Org. Lett., 2018, 20, 3609–3612; (b) C.-J. Peng, J.-P. Pei, Y.-H. Chen, Z.-Y. Wu, M. Liu and Y.-K. Liu, Enantioselective organocatalytic sequential Michael-cyclization of functionalized nitroalkanes to 2-hydroxycinnamaldehydes: synthesis of benzofused dioxa[3.3.1] and oxa[4.3.1] methylene-bridged compounds, Org. Chem. Front., 2021, 8, 4217–4223.
11. (a) B. Jiang, J.-F. Liu and S.-Y. Zhao, Enantioselective total syntheses of slagenins A−C and their antipodes, J. Org. Chem., 2003, 68, 2376–2384; (b) S.-W. Yang, T.-M. Chan, J. Terracciano, E. Boehm, R. Patel, G. Chen, D. Loebenberg, M. Patel, V. Gullo, B. Pramanik and M. Chu, Caryophyllenes from a fungal culture of chrysosporium pilosum, J. Nat. Prod., 2009, 72, 484–487; (c) A. Husain, S. A. Khan, F. Iram, M. A. Iqbal and M. Asif, Insights into the chemistry and therapeutic potential of furanones: a versatile pharmacophore, Eur. J. Med. Chem., 2019, 171, 66–92; (d) J. Huang, Y. Chen, Y. Guo, M. Bao, K. Hong, Y. Zhang, W. Hu, J. Lei, Y. Liu and X. Xu, Synthesis of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid molecules and biological evaluation against colon cancer cells as selective Akt kinase inhibitors, Mol. Divers., 2023, 27, 845–855.
12. (a) F. J. Fañanás, A. Fernández, D. Çevic and F. Rodríguez, An expeditious synthesis of bruguierol A, J. Org. Chem., 2009, 74, 932–934; (b) Z.-W. Jiao, Y.-Q. Tu, Q. Zhang, W.-X. Liu, S.-Y. Zhang, S.-H. Wang, F.-M. Zhang and S. Jiang, Tandem C–H oxidation/cyclization/rearrangement and its application to asymmetric syntheses of (−)-brussonol and (−)-przewalskine E, Nat. Commun., 2015, 6, 7332.
13. (a) D. J. Saxon, M. Nasiri, M. Mandal, S. Maduskar, P. J. Dauenhauer, C. J. Cramer, A. M. LaPointe and T. M. Reineke, Architectural control of isosorbide-based polyethers via ring-opening polymerization, J. Am. Chem. Soc., 2019, 141, 5107–5111; (b) K. C. Nicolaou, S. Pan, Y. Shelke, Q. Ye, D. Das and S. Rigol, A highly convergent total synthesis of norhalichondrin B, J. Am. Chem. Soc., 2021, 143, 20970–20979.
14. (a) H. M. C. Ferraz and L. S. Longo, Bicyclic β-hydroxytetrahydrofurans as precursors of medium ring keto-lactones, J. Org. Chem., 2007, 72, 2945–2950; (b) T. A. Wenderski, S. Huang and T. R. R. Pettus, Enantioselective total synthesis of all of the known chiral cleroindicins (C−F): clarification among optical rotations and assignments, J. Org. Chem., 2009, 74, 4104–4109; (c) D. Moock, T. Wagener, T. Hu, T. Gallagher and F. Glorius, Enantio- and diastereoselective, complete hydrogenation of benzofurans by cascade catalysis, Angew. Chem., Int. Ed., 2021, 60, 13677–13681.
15. (a) L. Han, X. Huang, I. Sattler, U. Moellmann, H. Fu, W. Lin and S. Grabley, New aromatic compounds from the marine mangrove bruguiera gymnorrhiza, Planta Med., 2005, 71, 160–164; (b) C. V. Ramana, S. R. Salian and R. G. Gonnade, An expeditious assembly of 3,4-benzannulated 8-oxabicyclo[3.2.1]octane systems by [2+2+2] alkyne cyclotrimerisation: total synthesis of (–)-bruguierol A, Eur. J. Org. Chem., 2007, 5483–5486; (c) D. M. Solorio and M. P. Jennings, Total synthesis and absolute configuration determination of (+)-bruguierol C, J. Org. Chem., 2007, 72, 6621–6623.
16. CCDC 2466831: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2nsy6m.

---