A New Alkoxyallene-Based [3+2] Approach to the Synthesis of Highly Substituted Cyclopentenones

Abstract

Lithiated methoxyallene 1 and aldehydes 2 provided after base- or gold-catalyzed cyclization dihydrofurans 3 which were oxidatively cleaved giving α,β-unsaturated γ-ketoaldehydes 4 as key intermediates. These smoothly underwent intramolecular aldol addition to furnish highly substituted cyclopentene derivatives 5 in good yields. Due to their dense pattern of functional groups compounds 5 are versatile intermediates, suitable for subsequent elaborations. This was demonstrated by transformation of 5e into enol phosphate 8 and of 5c into tetracyclic nitrone cycloadduct 13.

Key words

allenes - gold catalysis - aldol reactions - cyclopentenones - cycloadditions

References and Notes

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• Related ketoaldehydes have recently been utilized for the total synthesis of the cyclopentenone core of Litseaverticillols:
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• 20a

  We also tried [2+1] and [4+2] cycloadditions of cyclopentenone 5c or its tert-butyldimethylsilyl ether with methyl diazoacetate and α-trifluoromethyl-α-nitrosoalkene, respectively, but in all cases no cycloadducts were formed.

• 20b For a recent study on 1,3-dipolar cycloadditions of captodative olefins see: Herrera R. Mendoza JA. Morales MA. Méndez F. Jiménez-Vázquez HA. Delgado F. Tamariz J. Eur. J. Org. Chem.  2007,  2352 
• 21a Gothelf KV. Kanemasa S. Jørgensen KA. In Cycloaddition Reactions in Organic Synthesis   Kobayashi S. Jørgensen KA. Wiley-VCH; Weinheim: 2001.  p.211-326  
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• 22 Tamura O. Yamaguchi T. Noe K. Sakamoto M. Tetrahedron Lett.  1993,  34:  4009 
• 24 For an interesting alternative approach to cyclopentene derivatives employing lithiated allenyl MOM ethers, see: Huang X. Zhang L. J. Am. Chem. Soc.  2007,  129:  6398 

13

Typical Procedure for the Intramolecular Aldol Reaction: Preparation of Compound 5c
The mixture of ketoaldehyde 4c (1.61 g, 8.20 mmol) and MeONa (44 mg, 0.82 mmol) in dry MeOH (15 mL) was stirred at r.t. overnight. The reaction was quenched with sat. aq NH₄Cl solution, extracted with Et₂O, and dried (Na₂SO₄). After evaporation of solvents the resulting crude product was purified by flash chromatography [silica gel, EtOAc-hexane (1:2)] yielding 1.23 g (76%) of a brownish syrup.
¹H NMR (500 MHz, CDCl₃): δ = 1.32-1.80 (m, 10 H, 5 × CH₂), 1.90 (s_br, 1 H, OH), 3.76 (s, 3 H, OCH₃), 4.60 (d_br, J = 3.2 Hz, 1 H, 4-H), 6.22 (d, J = 3.2 Hz, 1 H, 3-H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 22.1, 22.7, 25.0, 27.7, 34.1 (5 t, 5 × CH₂), 50.6 (s, C-5), 57.1 (q, OCH₃), 74.1 (d, C-4), 123.6 (d, C-3), 156.5 (s, C-2), 205.1 (s, C-1) ppm. IR (film): ν = 3430 (OH), 3010-2855 (=CH, CH), 1710 (C=O), 1635 (C=C) cm^-1. MS (EI, 80 eV): m/z (%) = 196 (64) [M⁺], 179 (7) [M⁺ - OH], 71 (100) [C₅H₁₁ ⁺]. HRMS (ESI-TOF): m/z calcd for C₁₁H₁₇O₃ ⁺ [M + H]⁺ 197.1178; found: 197.1157.

14

The organocatalytic approach using l-proline as catalyst for aldol reaction resulted only in moderate yields (12-34%) of cyclopentenones 5a. Moreover, in most cases a significant amount of starting ketoaldehyde 4a was recovered: Dugovič, B.; Reissig, H.-U. unpublished results.

15

Typical Procedure for the One-Pot Transformation: Preparation of Compound 4c
Methoxyallene (6.90 mL, 5.80 g, 82.6 mmol) was dissolved in Et₂O (150 mL) at -40 °C under an atmosphere of Ar. n-BuLi (30.4 mL, 2.5 M in hexane, 75.9 mmol) was added, the mixture was stirred for 1 h and then cooled to -78 °C. A solution of cyclohexanecarbaldehyde (2c, 4.00 mL, 3.70 g, 33.0 mmol) in Et₂O (50 mL) was slowly added and the mixture was stirred at -78 °C for 1.5 h. Then, H₂O (50 mL) was added and the mixture was warmed up to r.t. The layers were separated and the aqueous layer was extracted with Et₂O. The combined organic layers were dried (Na₂SO₄), filtered, and after evaporation the allenyl alcohol was obtained as a yellow oil (6.13 g, quant.). The crude product was dissolved in dry CH₂Cl₂ (300 mL). Pyridine (0.40 mL, 0.39 g, 4.95 mmol) and AuCl (0.38 g, 1.65 mmol) were added with vigorous stirring under an atmosphere of Ar at r.t. After 1 h TLC showed complete consumption of allenyl alcohol. Water (15.0 mL) and DDQ (15.0 g, 66.0 mmol) were added and stirring was continued for 1 h. The mixture was poured into sat. aq NaHCO₃ solution, and the aqueous phase was extracted with CH₂Cl₂. The combined organic phases were washed with brine and dried (Na₂SO₄) and the solvent was removed to provide 6.75 g of crude ketoaldehyde 4c. Purification by flash chromatography on silica gel (CH₂Cl₂) provided 5.51 g (85%) of pure 4c.
Mp 41-45 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.19-1.27, 1.28-1.40, 1.68-1.71, 1.78-1.87 (4 m, 10 H, 5 × CH₂), 2.90-2.95 (m, 1 H, 1′-H), 3.79 (s, 3 H, OCH₃), 5.53 (d, J = 7.3 Hz, 1 H, 2-H), 9.76 (d, J = 7.3 Hz, 1 H, 1-H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 25.4, 25.7, 27.7 (3 t, 3 × CH₂), 46.7 (d, C-1′), 56.4 (q, OCH₃), 108.4 (d, C-2), 169.5 (s, C-3), 191.0 (d, C-1), 201.3 (s, C-4) ppm. IR (KBr): ν = 3070-2850 (=CH, CH), 1705, 1660 (C=O), 1595 (C=C) cm^-1. MS (EI, 80 eV): m/z (%) = 196 (35) [M⁺], 83 (72) [C₆H₁₁ ⁺], 55 (100) [C₃H₃O⁺]. Anal. calcd for C₁₁H₁₆O₃ (196.2): C, 67.32; H, 8.22. Found: C, 67.22; H, 8.11.

17

Preparation of Compound 8
The solution of 6 (329 mg, 0.91 mmol) in MeCN (12 mL) and H₂O (1 mL) was treated with NBS (161 mg, 0.91 mmol) at r.t. for 18 h. Water was added and the mixture was extracted with hexane, the combined extracts were dried (Na₂SO₄), and after evaporation the crude product was filtered through silica gel and washed with 2.5% i-PrOH in hexane to yield 292 mg (75%) of compound 7. A solution of 7 (68 mg, 0.16 mmol) and P(OMe)₃ (56 µL, 59 mg, 0.48 mmol) in CH₂Cl₂ (1.5 mL) was stirred at r.t. for 2 d. The volatile components were removed in vacuo and the residue was purified by chromatography (silica gel, 1:3 EtOAc-hexane) to yield 31 mg (42%) of 8 as colorless oil.
¹H NMR (500 MHz, CDCl₃): δ = 0.06, 0.10 [2 s, 2 × 3 H, Si(CH₃)₂], 0.88 [s, 9 H, C(CH₃)₃], 2.41-2.43 (m, 1 H, 5-H), 3.71 (dd, J = 9.4, 3.5 Hz, 1 H, CH₂O), 3.83 (d, J _HP = 11.9 Hz, 3 H, OCH₃), 3.85 (t, J = 9.4 Hz, 1 H, CH₂O), 3.88 (d, J _HP = 11.4 Hz, 3 H, OCH₃), 4.44, 4.52 (2 d, J = 12.0 Hz, 2 × 1 H, CH₂Ph), 4.96 (s_br, 1 H, 4-H), 7.06 (dt, J = 2.5, 1.2 Hz, 1 H, 3-H), 7.27-7.36 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = -4.7 [q, Si(CH₃)₂], 17.9 [s, C(CH₃)₃], 25.7 [q, C(CH₃)₃], 55.1 (d, C-5), 55.3 (2 qd, J _CP = 6.3 Hz, OCH₃), 65.9 (t, CH₂O), 68.9 (d, C-4), 73.3 (t, CH₂Ph), 127.7, 127.8, 128.3, 137.7 (3 d, s, Ph), 141.2 (dd, J _CP = 3.3 Hz, C-3), 148.3 (s, C-2), 197.5 (s, C-1) ppm. IR (film): ν = 2955-2855 (=CH, CH), 1735 (C=O), 1630 (C=C) cm^-1. HRMS (ESI-TOF): m/z calcd for C₂₁H₃₃O₇NaPSi⁺ [M + Na]⁺: 479.1631; found: 479.1631.

18

Preparation of Compound 9
Under an atmosphere of Ar a solution of 7 (200 mg, 0.47 mmol) in Et₂O (5 mL) was successively treated at -78 °C with n-BuLi (2.5 M in hexane, 0.19 mL, 0.47 mmol) and Tf₂O (0.10 mL, 0.17 g, 0.62 mmol). After 1 h, the reaction was quenched by addition of sat. aq NaHCO₃ solution, H₂O was added and the mixture was extracted with Et₂O, the combined extracts were dried (Na₂SO₄), and the solvent was evaporated. The crude product was purified by chromatography on silica gel (3% EtOAc in hexane) to yield 100 mg (38%) of 9 as colorless oil.
¹H NMR (500 MHz, CDCl₃): δ = 0.06, 0.19 [2 s, 2 × 3 H, Si(CH₃)₂], 0.89 [s, 9 H, C(CH₃)₃], 2.64 (td, J = 3.3, 2.0 Hz, 1 H, 5-H), 3.69, 3.89 (2 dd, J = 9.6, 3.3 Hz, 2 × 1 H, CH₂O), 4.43, 4.54 (2 d, J = 12.1 Hz, 2 × 1 H, CH₂Ph), 4.96 (d, J = 2.0 Hz, 1 H, 4-H), 7.25-7.36 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = -4.6, -4.5 [2 q, Si(CH₃)₂], 18.0 [s, C(CH₃)₃], 25.6 [q, C(CH₃)₃], 56.4 (d, C-5), 65.2 (t, CH₂O), 72.4 (d, C-4), 73.5 (t, CH₂Ph), 127.9, 128.0, 128.5, 137.2 (3 d, s, Ph), 147.2, 150.9 (2 s, C-2, C-3), 191.3 (s, C-1) ppm, signal of CF₃ not detectable. IR (film): ν = 3090-2860 (=CH, CH), 1740 (C=O), 1635 (C=C) cm^-1. HRMS (ESI-TOF): m/z calcd for C₂₀H₂₇BrF₃O₆SSi⁺ [M + H]⁺: 559.0433; found: 559.0438.

23

Preparation of Compound 13
The reaction was carried out under an argon atmosphere. To a stirred solution of cyclopentenone 5c (0.46 g, 2.35 mmol) and nitrone 12 (0.96 g, 4.63 mmol) in CH₂Cl₂ (10 mL) was added Ti(Oi-Pr)₄ (0.70 mL, 0.87 g, 2.35 mmol) at r.t., and stirring was continued at the same temperature until cyclopentenone 5c disappeared (monitored by TLC, 2 d). The reaction mixture was poured onto silica gel, which was then washed with EtOAc-hexane (1:3). After removal of solvents the crude product was recrystallized (EtOAc-hexane, 1:3) to provide 0.62 g (75%) of 13 as colorless solid.
Mp 148-152 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.36-1.54, 1.61-1.66, 1.73-1.81 (3 m, 4 H, 2 × 3 H, CH₂), 3.49 (s, 3 H, OCH₃), 4.00 (s_br, 1 H, 4-H), 4.25 (d, J = 13.3 Hz, 1 H, CH₂Ph), 4.30 (d, J = 7.7 Hz, 1 H, 3-H), 4.48 (d_br, J = 13.3 Hz, 1 H, CH₂Ph), 4.84 [d, J = 6.9 Hz, 1 H, CHOC(O)], 7.29 (d, J = 7.2 Hz, 1 H, Ph), 7.34 (t, J = 7.2 Hz, 2 H, Ph), 7.44 (d, J = 7.2 Hz, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.0, 21.5, 25.0, 26.5, 30.9 (5 × t, CH₂), 52.8 (q, OCH₃), 54.1 (d, C-4), 57.4 [s, C(CH₂)₂], 67.3 (d_br, C-3), 79.7 [d, CHOC(O)] 127.7, 128.5, 128.8, 135.9 (3 × d, s, Ph), 172.4 [s_br, OC(O)], 206.2 (s, C=O) ppm; signals of C-5 and NCH₂Ph are not visible, according to HMBC C-5, δ ca. 110.2, NCH₂Ph, δ ca. 67.3 ppm. IR (KBr): ν = 3110-2840 (=CH, CH), 1790, 1750 (C=O) cm^-1. HRMS (ESI-TOF): m/z calcd for C₂₀H₂₄NO₅ ⁺ [M + H]⁺: 358.1655; found: 358.1687. Anal. calcd for C₈H₁₂O₃ (357.4): C, 67.21, H, 6.49; N, 3.92. Found: C, 67.03; H, 6.46; N, 3.95.