Asymmetric Synthesis of Oxa-spirocyclic Indanones with Structural Com­plexity via an Organocatalytic Michael–Henry–Acetalization Cascade

Abstract

The highly enantioselective preparation of drug-like oxa-spirocyclic indanone derivatives employing a multicomponent cascade reaction is described. This approach utilizes an organocatalytic Michael reaction followed by a Henry–acetalization sequence that yields the desired chiral spirocyclic backbone, bearing four contiguous stereogenic centers and multiple functional groups, in good yields and high stereoselectivities (up to 99% ee and 95:5 dr).

Key words

organocatalysis - chiral indanone - oxa-spirocycles - tandem reactions - asymmetric synthesis

• References and Notes

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• 14 Compounds 7a–m; General Procedure The reaction was carried out with aldehyde 1 (0.4 mmol) and nitroolefin 2 (0.3 mmol) in the presence of catalyst 3a (0.04 mmol) and AcOH (0.04 mmol) in toluene (2.0 mL) at r.t. for 3 h to afford the Michael adduct 4. When the reaction was complete, a solution of ninhydrin (5) (0.2 mmol) and DBU (0.6 mmol) in toluene (2.0 mL) was added. The mixture was stirred at r.t. for the requisite amount of time until the reaction was complete (monitored by TLC). The mixture was concentrated and the residue purified by flash chromatography on silica gel (PE–EtOAc, 10:1) to give hemiacetal 6. To a solution of 6 in CH₂Cl₂ (2 mL) was added PCC (0.5 mmol) and the mixture stirred for 2 h at 50 °C. The solid was removed by filtration through Celite. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography (PE–EtOAc, 20:1) to give spiroindanone δ-lactone 7. Oxa-spirocyclic indanone 7a was obtained as a white solid in 70% yield over the two steps after flash chromatography. The enantiomeric excess was determined to be 93% by HPLC on a Chiralpak OD-H column (i-PrOH–n-hexane, 3:7, 1 mL/min); UV (254 nm), t _minor = 11.05 min, t _major = 12.11 min; mp 167–168 °C; [α]_D ²⁰ –129.4 (c 0.12, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.12–8.05 (m, 2 H), 8.01–7.94 (m, 2 H), 7.40–7.34 (m, 3 H), 7.27–7.26 (m, 2 H), 5.64 (d, J = 12.4 Hz, 1 H), 4.16 (t, J = 12.0 Hz, 1 H), 3.10–3.02 (m, 1 H), 1.39 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 192.31, 190.03, 169.62, 141.15, 140.18, 138.00, 137.48, 135.43, 129.51, 129.05, 127.77, 124.99, 124.72, 87.28, 46.58, 41.42, 14.74. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₅NO₆Na: 388.0797; found: 388.0795.
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The hexahydrofuro[2,3-b]pyran derivatives are synthetically useful building blocks. For selected examples, see:
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