Synthesis of 2,2-Disubstituted Pentalenes and Indenes by a Useful Modification to Nakamura’s DMCP [3+2]-Cycloaddition Protocol

Abstract

A two-pot tactic is presented to reach the oxidized 2,2-dimethyl-substituted pentalene and indene ring systems.

Key words

illudin - trimethylenemethane - [3+2]-cycloaddition - 5,6-fused-ring systems - indene - pentalene - ketene acetal methylation

References and Notes

• Synthesis of (±)-illudin C:
• 1a Aungst RA. Chan C. Funk RL. Org. Lett.  2001,  3:  2611 
• Synthesis of (±)-illudin M:
• 1b Kinder FR. Bair KW. J. Org. Chem.  1994,  59:  6965 
• 1c Matsumoto T. Shirahama H. Ichihara A. Shin H. Kagawa S. Sakan F. Tetrahedron Lett.  1970,  1171 
• 1d Matsumoto T. Shirahama H. Ichihara A. Shin H. Kagawa S. Sakan F. Matsumoto S. Nishida S. J. Am. Chem. Soc.  1968,  90:  3280 
• Synthesis of (±)-illudin S:
• 1e Matsumoto T. Shirahama H. Ichihara A. Shin H. Kagawa S. Sakan F. Miyano K. Tetrahedron Lett.  1971,  2049 
• Approaches toward members in the family:
• 1f Padwa A. Curtis EA. Sandanayaka VP. J. Org. Chem.  1997,  62:  1317 
• 1g McMorris TC. Hu Y. Yu J. Kelner MJ. Chem. Commun.  1997,  315 
• 1h Kinder FR. Wang R.-M. Bauta WE. Bair KW. Bioorg. Med. Chem. Lett.  1996,  6:  1029 
• 2a Dufresne C. Young K. Pelaez F. Gonzalez Del Val A. Valentino D. Graham A. Platas G. Bernard A. Zink D. J. Nat. Prod.  1997,  60:  188 
• 2b Gonzalez Del Val A. Platas G. Arenal F. Orihuela JC. Garcia M. Hernandez P. Royo I. De Pedro N. Silver LL. Young K. Vicente MF. Pelaez F. Mycol. Res.  2003,  107:  1201 
• 3 Nakamura M. Wang XQ. Isaka M. Yamago S. Nakamura E. Org. Synth.  2003,  80:  144 
• 4 Nakamura E. Yamago S. Acc. Chem. Res.  2002,  35:  867 
• 5a Nakamura M. Toganoh M. Wang XQ. Isaka M. Yamago S. Nakamura E. Chem. Lett.  2000,  29:  664 
• 5b Yamago S. Nakamura M. Wang XQ. Yanagawa M. Tokumitsu S. Nakamura E. J. Org. Chem.  1998,  63:  1694 
• 5c Yamago S. Ejiri S. Nakamura E. Angew. Chem., Int. Ed. Engl.  1995,  34:  2154 
• 5d Yamago S. Ejiri S. Nakamura M. Nakamura E. J. Am. Chem. Soc.  1993,  115:  5344 
• 5e Ejiri S. Yamago S. Nakamura E. J. Am. Chem. Soc.  1992,  114:  8707 
• 5f Yamago S. Nakamura E. J. Am. Chem. Soc.  1989,  111:  7285 
• 6 Furukawa J. Kawabata N. Nishimura J. Tetrahedron Lett.  1966,  3353 

7

Preparation of 15; Representative Procedure for Ester 15c: Compounds 11c (0.123 g, 0.489 mmol) and 10 (0.038 g, 0.246 mmol) were dissolved in CD₃CN (0.500 mL) and heated in a sealed NMR tube at 80 ˚C for 0.5 h. Additional 10 (0.100 g, 0.648 mmol) was added to the reaction mixture and it was heated for 2 h. After cooling to r.t., MeI (0.150 mL, 2.41 mmol) was added and the reaction mixture was heated to 80 ˚C for 24 h. Afterwards, the mixture was concentrated in vacuo and purified by silica gel chroma-tography (75% CH₂Cl₂-hexanes) to afford 15c as a light yellow oil (0.074 g, 41% based on recovered starting material); R _f = 0.22 (75% CH₂Cl₂-hexanes). ^¹H NMR (500 MHz, CDCl₃): δ = 7.47 (d, J = 7.1 Hz, 2 H), 7.36 (d, J = 6.8 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 2 H), 3.84 (q, J = 10.5 Hz, 2 H), 3.12-3.17 (m, 3 H), 2.75 (m, 1 H), 2.13-2.28 (m, 3 H), 1.99 (m, 2 H), 1.86 (d, J = 14.4 Hz, 1 H), 1.64 (m, 3 H), 1.37 (s, 3 H), 1.05 (s, 6 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 205.7, 177.2, 136.8, 129.5, 129.3, 129.1, 71.3, 47.2, 47.1, 46.4, 40.7, 37.3, 34.7, 27.1, 24.8, 24.5, 24.4, 22.2, 19.3. IR (thin film): 3505, 2959, 2932, 2870, 1728, 1693, 1462, 1207, 1134, 741 cm^-¹. HRMS: m/z calcd for C₂₂H₂₉IO₃Se: 548.0327; found: 548.0340.
Selected data of ortho-ester 14d: R _f = 0.20 (5% EtOAc-hexanes). ^¹H NMR (500 MHz, CDCl₃): δ = 6.30 (t, J = 4.1 Hz, 1 H), 5.48 (t, J = 2.4 Hz, 1 H), 5.17 (t, J = 2.4 Hz, 1 H), 4.09 (d, J = 10.3 Hz, 1 H), 4.01 (d, J = 10.3 Hz, 1 H), 3.42 (m, 2 H), 3.14 (dt, J = 16.1, 2.7 Hz, 1 H), 2.53 (dt, J = 16.1, 1.9 Hz, 1 H), 2.15 (m, 1 H), 2.06 (m, 2 H), 1.90 (m, 1 H), 1.81 (m, 1 H), 1.63 (m, 1 H), 1.26 (s, 3 H), 0.78 (s, 3 H).
Selected data for exocyclic methylene adduct 13e: R _f = 0.28 (10% EtOAc-hexanes). ^¹H NMR (500 MHz, CDCl₃): δ = 5.50 (t, J = 2.4 Hz, 1 H), 5.25 (t, J = 2.1 Hz, 1 H), 3.66 (m, 1 H), 3.59 (m, 2 H), 3.40 (d, J = 11.3 Hz, 1 H), 2.87 (m, 2 H), 2.68 (m, 3 H), 2.27 (dd, J = 16.8, 2.7 Hz, 1 H), 1.98 (m, 1 H), 1.87 (m, 1 H), 1.75 (m, 1 H), 0.94 (s, 3 H), 0.93 (s, 3 H).
Preparation of 16 and 17; Representative Procedure from Bromide: Compound 12d (0.010 g, 0.021 mmol) was dissolved in THF (1.0 mL) and cooled to 0 ˚C. To the solution was added DBN (0.020 mL, 0.162 mmol) and the reaction was stirred at 0 ˚C to r.t. for 14 h. The reaction mixture was filtered through a pad of silica gel then concentrated in vacuo. The crude residue was purified by silica gel chromatography (15% EtOAc-hexanes) to afford 16 as a colorless oil (0.0060 g, 72% yield, 40% overall yield from 11d).
Data for compound 16: R _f = 0.10 (20% EtOAc-hexanes). ^¹H NMR (500 MHz, CDCl₃): δ = 3.95 (s, 2 H), 3.21 (d, J = 16.4 Hz, 1 H), 3.18 (s, 2 H), 2.93 (d, J = 16.2 Hz, 1 H), 2.74 (s, 2 H), 2.55 (s, 2 H), 2.45 (d, J = 18.8 Hz, 1 H), 2.36 (d,
J = 16.1 Hz, 1 H), 1.44 (s, 3 H), 1.09 (s, 6 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 203.7, 183.4, 176.6, 146.1, 71.6, 54.2, 43.9, 40.8, 37.2, 34.7, 26.7, 26.0, 24.3, 18.6. IR (thin film): 2962, 2928, 1732, 1697, 1643, 1377, 1215, 1169, 1111
cm^-¹. HRMS: m/z calcd for C₁₅H₂₁IO₃Na: 399.0433; found: 399.0430.
Procedure from Phenyl Selenide: Compound 15c (0.027 g, 0.049 mmol) was dissolved in CH₂Cl₂ (1.0 mL). To the solution was added H₂O (0.020 mL) followed by H₂O₂ (30% w/w in H₂O, 0.13 mL, 0.104 mmol). The reaction was then stirred for 1.5 h. The reaction was quenched with sat. aq NaHCO₃ and diluted with CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂ (3 ×) and the combined organics were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The crude residue was purified by silica gel chromatography (15% EtOAc-hexanes) to afford 17 as a colorless oil (0.014 g, 74% yield).
Data for compound 17: R _f = 0.14 (15% EtOAc-hexanes).
^¹H NMR (500 MHz, CDCl₃): δ = 3.93 (s, 2 H), 3.23 (dt, J = 2.3, 14.0 Hz, 1 H), 3.18 (s, 1 H), 3.04 (dt, J = 2.3, 14.0 Hz, 1 H), 2.54 (d, J = 13.9 Hz, 1 H), 2.45 (d, J = 14.0 Hz, 1 H), 2.41 (m, 2 H), 2.34 (m, 2 H), 2.06 (quint, J = 6.5 Hz, 2 H), 1.39 (s, 3 H), 1.09 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 197.6, 177.0, 162.6, 135.5, 71.4, 48.9, 47.1, 41.4, 37.7, 34.7, 26.6, 26.2, 24.3, 23.5, 18.7. IR (thin film): 2962, 2978, 2870, 1732, 1666, 1393, 1184 cm^-¹. HRMS: m/z calcd for C₁₆H₂₃IO₃Na: 413.0590; found: 413.0595.
Preparation of 18 and 19; Representative Procedure from Ester 17: To a cooled (-78 ˚C) solution of 17 (0.016 g, 0.041 mmol) in toluene (0.5 mL) was added DIBAL-H
(1 M in hexanes, 0.246 mL, 0.246 mmol). The resulting solution was stirred at -78 ˚C for 1 h. The reaction was quenched with 1 M aq Rochelle’s salt, diluted with EtOAc, and stirred vigorously for 1 h. The aqueous layer was extracted with EtOAc (4 ×). The combined organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to afford an inconsequential mixture (ca. 1:1) of allylic alcohols. The crude product was sufficiently pure for the subsequent reaction. However, the mixture of allylic alcohols could be separated by silica gel chromatography (40% EtOAc-hexanes → 75% EtOAc-hexanes) with R _f = 0.55 and 0.48 (75% EtOAc-hexanes) (combined mass of 0.0060 g, 86% yield).
The crude mixture of allylic alcohols (0.0060 g, 0.033 mmol) was dissolved in CH₂Cl₂ (1.0 mL). MnO₂ (0.069 g, 0.78 mmol) was added to the flask and the reaction was stirred at r.t. for 12 h. The mixture was filtered through Celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40% EtOAc-hexanes → 50% EtOAc-hexanes) to afford 19 as a colorless oil (0.0049 g, 83% yield).
Data for compound 19: R _f = 0.15 (40% EtOAc-hexanes). ^¹H NMR (500 MHz, CDCl₃): δ = 3.46 (s, 2 H), 2.67 (d, J = 18.4 Hz, 1 H), 2.49 (d, J = 15.6 Hz, 1 H), 2.38 (m, 2 H), 2.22-2.35 (m, 4 H), 2.04 (quint, J = 6.6 Hz, 2 H), 1.13 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 164.1, 136.3, 70.8, 47.7, 42.4, 39.5, 37.7, 26.9, 25.1, 23.6 (C=O carbon unresolved).
IR (thin film): 3413, 2924, 2854, 1651, 1393, 1045 cm^-¹. HRMS: m/z calcd for C₁₁H₁₆O₂: 180.1150; found: 180.1148.