Facile enantioselective synthesis of multi-substituted norbornanes/norbornenes using a latent synthon strategy

Abstract

The development of a new catalytic asymmetric synthetic methodology has been following virtually the same pattern in the past decades. Herein, we present a latent synthon strategy within this well-established research domain. By employing substrates containing latent groups, specifically "ON-alkene" in this investigation, a single optimization exercise yields the Diels-Alder adduct with excellent enantiomeric purity. This adduct serves as a universal intermediate, undergoing late-stage diversifications via robust and easily performed synthetic transformations. Consequently, a broad array of structurally diverse chiral norbornanes (NBAs) and norbornenes (NBEs) are obtained with consistent and high enantiomeric purities. Furthermore, our methodology allows for facile asymmetric preparation of chiral NBE ligands as well as the concise synthesis of (+)-gemmacin, ( + )-gemmacin B, and their structural analogs.

Fig. 1. Background.

a Conventional methodology development: an illustration. b Our proposal: the latent synthon strategy. Cat., catalyst.

Fig. 2. The latent synthon strategy for asymmetric Diels–Alder reaction, a straightforward and unifying synthesis of chiral norbornanes and norbornenes.

a Chiral norbornanes (NBAs)/norbornenes (NBEs). b Synthesis of NBEs via Diels–Alder reaction. c Diels–Alder synthesis of NBEs using the latent synthon strategy. d Facile synthesis of the key alkene latent synthon, ON-alkene. THF, tetrahydrofuran; aq., aqueous solution; NHPI, N-hydroxyphthalimide; DIC, N,N’-diisopropylcarbodiimide; DMAP, 4-dimethylaminopyridine.

Fig. 3. Reaction development.

a Optimizing the reaction conditions. b Gram-scale preparation of Diels–Alder adduct 1 and its derivatization to advanced intermediates for further diversifications. c Late-stage diversifications of Diels–Alder products through sequential couplings of the latent groups. 1,2-DCE, 1,2-dichloroethane; BOX, bisoxazoline; Ph, phenyl; tBu, tert-butyl; NMO, N-methylmorpholine N-oxide; THF, tetrahydrofuran; PPTS, pyridinium p-toluenesulfonate.

Fig. 4. The scope of reaction: stage-1 diversification of Diels–Alder products via decarboxylative coupling reactions.

Reaction conditions: either 2 or 3 (0.10 mmol) was used. ^aStandard conditions for arylation: Ni(glyme)Cl₂ (20 mol%), dtbbpy (40 mol%), ArZnCl·LiCl (0.30 mmol), DMF (0.50 mL), THF (0.70 mL). ^bReaction performed at 50 °C. ^cStandard conditions for photo-induced iodination: LiI (0.20 mmol), PPh₃ (10 mol%), acetone (1.0 mL), 30 W Blue LEDs irradiation. ^dNaI is used as the iodine source, then DBU (0.20 mmol). See General Procedures G–J in the Supplementary Information for detailed conditions. Yields refer to isolated yields. The dr ratios were determined by ¹H NMR analysis of the crude mixture. The ee values were determined by HPLC analysis on a chiral stationary phase. tBu, tert-butyl; Bn, benzyl; Ph, phenyl.

Fig. 5. The scope of reaction: stage-2 diversification of Diels–Alder products via decarboxylative coupling reactions.

Reaction conditions: 6a to 6e (0.050 mmol) (derived from 4 or 5) were used. ^aStandard conditions for photo-induced borylation: B₂cat₂ (0.15 mmol), DMAc (0.50 mL) under 30 W Blue LEDs irradiation, then pinacol (0.20 mmol) and Et₃N (0.20 mL). ^bDerivatized from the corresponding boronates 6g, 6h. See General Procedures K–N in the Supplementary Information for detailed conditions. Yields refer to isolated yields. The dr ratios were determined by ¹H NMR analysis of the crude mixture. The ee values were by HPLC analysis on a chiral stationary phase. NHPI, N-hydroxyphthalimide; DIC, N,N’-diisopropylcarbodiimide; DMAP, 4-dimethylaminopyridine.

Fig. 6. Synthesis and applications of chiral NBE-type ligands.

a Facile synthesis of chiral NBE-ligands. b The applications of NBE-ligands in the construction of atropisomers. Ph, phenyl; iPr, isopropyl.

Fig. 7. Applications to total synthesis of natural products and their structural analogs.

a Asymmetric synthesis of (+)-gemmacin and (+)-gemmacin B. b Preparation of close structural analogs of (+)-gemmacin and (+)-gemmacin B. dtbbpy, 4,4’-di-tert-butyl-2,2’-dipyridyl; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; TsOH, p-toluenesulfonic acid; TFA, trifluoroacetic acid; 1,2-DCE, 1,2-dichloroethane.