Highly Efficient Asymmetric Access to 1-Azaspiro[4.4]nonane Skeleton

Abstract

Vinylogous Mukaiyama aldol type reaction of chiral non-racemic silyloxypyrroles followed by acidic treatment affords an efficient asymmetric access to 1-azaspiro[4.4]nonanes in high diastereoisomeric excess (up to 79%).

spiro compounds - asymmetric synthesis - ring expansion - rearrangement - pyrroles

References

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5

Typical Procedure for Silyloxypyrroles 5.
To a solution of 2,5-dimethoxy-2,5-dihydrofuran (1 equiv) and chiral amine 4a,c-e (1 equiv) in water (0.25 M) was added a concd solution of HCl (1.5 equiv). The mixture was stirred at r.t. for 3 h then neutralized with solid NaHCO₃ and extract with CH₂Cl₂. The combined organic layers were dried over MgSO₄ and the solvent distilled off. A red oil, mixture of the α,β and β,γ unsaturated lactams was then obtained. tert-Butyldimethylsilyl triflate (1 equiv) was slowly added to a solution of either the crude product or the purified lactams (1 equiv) and NEt₃ (2 equiv) in CH₂Cl₂ (0.1 M) and the mixture was stirred at r.t. for 1 h. The solvent was evaporated under vacuum and the residue purified by filtration on a pad of alumina with a mixture of heptane and EtOAc. (Nota: silyloxypyrroles are used to be kept under argon at -20 °C). Analyses for 5d: [α]_D ²⁵ +11.7 (c 0.69, CH₂Cl₂). Mp = 97 °C (heptane-EtOAc). IR (KBr): ν = 2929, 2858, 1560, 1492, 1438 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = -0.05 (s, 3 H), 0.23 (s, 3 H), 0.80 (s, 9 H), 1.89 (d, J = 7.0 Hz, 3 H), 5.31 (dd, J = 2.0, 3.6 Hz, 1 H), 6.01 (t, J = 3.5 Hz, 1 H), 6.16 (q, J = 7.0 Hz, 1 H), 6.35 (dd, J = 1.9, 3.4 Hz, 1 H), 7.10 (d, J = 7.2 Hz, 1 H), 7.42 (t, J = 7.9 Hz,
1 H), 7.50-7.55 (m, 2 H), 7.77 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 7.4 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H). ¹³C NMR
(75 MHz, CDCl₃): δ = -5.0, -4.6, 18.2, 21.4, 25.7, 49.5, 87.7, 105.2, 109.8, 123.2, 125.8, 126.5, 128.1, 129.1, 131.0, 134.1, 139.7, 142.2. HRMS (CI, NH₃): m/z calcd for C₂₂H₃₀NOSi (MH⁺): 352.2097. Found: 352.2101. Typical Procedure for Cyclobutanols 6. To a solution of silyloxypyrrole 5a-e (1 equiv) in anhyd CH₂Cl₂ (0.15 M) with 3Å MS, under argon, was added cyclobutanone (or cyclopentanone) (1.6 equiv). After 15 min at r.t., the solution was cooled at -78 °C and BF₃·OEt₂ (1.5 equiv) was added in the course of 15 min. The solution was stirred at -78 °C for 2 h and allowed to warm to 0 °C. The reaction was quenched by addition of H₂O, the aq phase was separated and extracted with CH₂Cl₂. The organic phases were combined, dried over Na₂SO₄ and the solvent was removed under vacuum. The resulting oil was purified by flash chromatography.
Analyses for 6d: Minor diastereoisomer: [α]_D ²⁵ -264.1 (c 0.52, CHCl₃). Mp = 245 °C (CH₂Cl₂). IR (KBr): ν = 3388, 2976, 2937, 1660 cm^-1. MS (CI, NH₃): m/z = 308 (MH⁺), 238 (MH⁺ - C₄H₆O). ¹H NMR (300 MHz, CDCl₃): δ = 0.35-0.5 (m, 1 H), 1.01 (s, 1 H, D₂O exch.), 1.35-1.55 (m, 2 H), 1.55-1.70 (m, 2 H), 1.78 (d, J = 7.1 Hz, 3 H), 1.85-2.00 (m,
1 H), 4.25 (t, J = 1.6 Hz, 1 H), 6.30 (m, 2 H), 6.94 (dd, J = 7.0, 6.0 Hz, 1 H), 7.40-7.60 (m, 4 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1 H). ¹³C NMR (75 MHz, DMSO): δ = 17.7, 24.4, 36.2, 40.6, 55.1, 74.8, 81.3, 128.5, 130.3, 130.8, 131.7, 132.9, 134.3, 134.5, 136.1, 139.0, 143.5, 151.3, 177.6. Major diastereoisomer: [α]_D ²⁵ -13.8 (c 0.97, CHCl₃). Mp = 196-198 °C (Et₂O). IR (KBr): ν = 3382, 2977, 2934, 1658, 1394 cm^-1. MS (CI, NH₃): m/z = 308 (MH⁺), 238 (MH⁺ - C₄H₆O). ¹H NMR (300 MHz, CDCl₃): δ = 1.36 (m, 1 H), 1.80-2.10 (m, 5 H), 1.75 (s, 1 H), 1.86 (d, J = 7.0 Hz, 3 H), 3.51 (t, J = 1.5 Hz, 1 H), 6.07 (q, J = 7.0 Hz, 1 H), 6.28 (dd, J = 1.6, 6.0 Hz, 1 H), 6.81 (dd, J = 1.8, 6.0 Hz, 1 H), 7.47 (m, 3 H), 7.63 (m, 2 H), 7.84 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 13.6, 19.1, 31.9, 36.2, 49.0, 69.6, 75.9, 123.2, 125.2, 125.8, 126.1, 127.3, 128.5, 129.1, 129.2, 132.0, 134.0, 136.2, 145.7, 173.3. Anal. Calcd for C₂₀H₂₁NO₂: C, 78.15; H, 6.89; N, 4.56. Found: C, 78.03; H, 7.06; N, 4.60.

6

The crystal structure has been deposited at the Cambridge Crystallographic Data Centre; deposition number CCDC 180815.

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8

Typical Procedure for Spiro Compounds 7.
To a solution of cyclobutanol 6a-e (1 equiv) in CH₂Cl₂ (0.05 M) was added concd aq HCl (1.5 equiv). After 9 h at 0 °C, the solvent was removed under vacuum. The crude product was redissolved twice in CH₂Cl₂ and reevaporated to eliminate trace amount of acid.
Analyses for 7d (cristallyzed from Et₂O): [α]_D ²⁵ -48.4
(c 1.04, CHCl₃). Mp = 140 °C (Et₂O). IR (KBr): ν = 2968, 1750, 1679, 1380, 1347, 780 cm^-1. MS (CI, NH₃): m/z = 308 (MH⁺). ¹H NMR (400 MHz, CDCl₃): δ = 1.07-1.17 (m, 2 H), 1.34-1.55 (m, 2 H), 1.62 (ddd, J = 6.5, 8.5, 12.3 Hz,
1 H), 1.67 (d, J = 7.0 Hz, 3 H), 1.87 (ddd, J = 9.5, 11.6, 18.9 Hz, 1 H), 1.93 (ddd, J = 6.8, 8.9, 12.3 Hz, 1 H), 2.23 (dd, J = 6.1, 18.9 Hz, 1 H), 2.43 (dd, J = 6.8, 8.5, 16.8 Hz, 1 H), 2.53 (ddd, J = 6.5, 8.9, 16.8 Hz, 1 H), 6.25 (q, J = 7.1 Hz,
1 H), 7.30-7.60 (m, 4 H), 7.83 (d, J = 9.7 Hz, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 7.8, 18.9, 29.0, 31.7, 32.3, 35.7, 47.5, 72.3, 124.0, 125.1, 125.9, 126.3, 127.2, 129.1, 129.3, 132.7, 133.9, 136.1, 175.7, 217.0. Anal. Calcd for C₂₀H₂₁NO₂: C, 78.15; H, 6.89; N, 4.56. Found: C, 77.96; H, 7.15; N, 4.41.

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