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Synlett 2007(15): 2379-2382  
DOI: 10.1055/s-2007-986633
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Stereocontrolled Entry to 3-Functionalized cis-3a-Methyloctahydroindoles: Building Blocks for Daphniphyllum Alkaloid Synthesis

Alejandro Cordero-Vargas, Xavier Urbaneja, Josep Bonjoch*
Laboratorio de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: +34(93)4024539; e-Mail: josep.bonjoch@ub.edu;
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Publication History

Received 15 May 2007
Publication Date:
28 August 2007 (online)

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Abstract

A synthetic entry to cis-3a-methyl-3-methyleneoctahydroindol-5-ones employing ozonolysis, chemoselective methylenation, and double reductive amination of 2-(1-formylvinyl)-2-methyl-1,4-cyclohexanedione monoethylene acetal is described. The same process using a 2-methoxycarbonyl derivative gave a trans-diastereoselectivity in the formation of the azabicyclic compound. Diastereoselective hydroboration of the exocyclic methylene of cis-octahydroindole derivative gives a valuable synthetic intermediate for Daphniphyllum alkaloid synthesis.

Key words

alkenation - aminations - fused-ring systems - ring closure - stereoselectivity

    References and Notes

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14

This was higher than the 30% yield obtained when the intermediate aldehyde was submitted to methylenation with the Eschenmoser reagent.

15

2-[(1-Methylene)formylmethyl]-2-methylcyclohexane-1,4-dione Monoethylene Acetal (2)
A stirred solution of ketone 1 (1.1 g, 5.23 mmol) in CH2Cl2 (105 mL) at -78 °C was treated with a constant stream of ozone. When the solution turned a characteristic pale blue, it was purged with oxygen. To this solution (at -78 °C) was added a mixture of CH2Br2 (1.84 mL, 4.54 g, 26.15 mmol) and Et2NH (8.15 mL, 5.74 g, 78.47 mmol; preheated to 55 °C for 1.5 h and then cooled to r.t.) and the resulting yellow solution was stirred at r.t. for 2.5 h. The reaction mixture was concentrated, Et2O was added (most of the ammonium salts precipitated), and the mixture was filtered and washed with Et2O. The residue was purified by flash column chromatography (silica gel, hexane-EtOAc, 2:1 to 1:1) to give aldehyde 2 (42% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 3 H, CH3), 1.62 (dd, J = 13.9, 2.9 Hz, 1 H, H-3), 2.00 (dm, J = 12.8 Hz, 1 H, H-5eq), 2.32 (td, 1 H, J = 12.8, 5.1 Hz, H-5ax), 2.42 (d, J = 13.9 Hz, 1 H, H-3), 2.59 (dt, J = 16.5, 4.8 Hz, 1 H, H-6eq), 2.75 (ddd, J = 16.6, 12.4, 5.7 Hz, 1 H, H-6ax), 4.05-3.91 (m, 4 H, OCH2), 6.16 (s, 1 H, =CH), 6.35 (s, 1 H, =CH), 9.46 (s, 1 H, CHO). 13C NMR (75 MHz, CDCl3): δ = 23.5 (Me), 32.8 (C-5), 35.9 (C-6), 43.7 (C-3), 49.5 (C-2), 64.2 and 64.6 (OCH2), 107.4 (C-4), 134.8 (=CH2), 140.3 (=C), 193.3 (CHO), 211.1 (C-1). IR (NaCl, neat): 2969, 2888, 1711, 1688, 1282, 1114, 1072, 1036 cm-1.

16

cis -1-Benzyl-3a-methyl-3-methyleneoctahydroindol-5-one Ethylene Acetal (3)
To a solution of aldehyde 2 (0.4 g, 1.78 mmol) in MeOH (9 mL) were added first benzylamine hydrochloride (1.13 g, 7.85 mmol) and then NaBH3CN (0.09 g, 1.43 mmol). After stirring for 30 min, an additional portion of NaBH3CN (0.09 g, 1.43 mmol) was added and stirring was continued for 1 h. A third portion of NaBH3CN (0.25 g, 3.92 mmol) was then added, and stirring was continued overnight. After removing the MeOH, CH2Cl2 was added and the resulting organic solution was washed with sat. aq NaHCO3 solution, dried and concentrated. The resulting mixture was purified by column chromatography (silica gel, hexane-EtOAc, 4:1 to 2:1) to give amine 3 (60% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3, gCOSY): δ = 1.21 (s, 3 H, H-9), 1.35 (dd, J = 13.7, 2.5 Hz, 1 H, H-4), 1.46 (ddd, J = 12.5, 6.0, 2.9 Hz, 1 H, H-7), 1.77-2.10 (m, 4 H, H-4, H-6, and H-7), 2.23 (t, J = 2.7 Hz, 1 H, H-7a), 2.79 (dt, J = 13.7, 2.5 Hz, 1 H, H-2), 3.02 (d, J = 13.2 Hz, 1 H, CH2Ph), 3.64 (dt, J = 14.5, 1.8 Hz, 1 H, H-2), 3.88-4.01 (m, 4 H, OCH2), 4.10 (d, J = 13.2 Hz, 1 H, CH2Ph), 4.66 (t, J = 2.1 Hz, 1 H, =CH), 4.69 (t, J = 2.6 Hz, 1 H, =CH), 7.21-7.35 (m, 5 H, ArH). 13C NMR (75 MHz, CDCl3): δ = 21.4 (C-7), 21.8 (CH3), 28.6 (C-6), 42.3 (C-4), 45.5 (C-3a), 57.5 (NCH2Ar), 57.9 (C-2), 63.6 and 64.3 (OCH2), 67.8 (C-7a), 101.5 (=CH2), 102.1 (C-5), 123.7 (ArH), 128.3 (ArH), 128.4 (ArH), 139.7 (Ar), 157.4 (C-3).

18

(3 RS ,3a RS ,7a RS )-1-Benzyl-3-hydroxymethyl-3a-methyloctahydroindol-5-one Ethylene Acetal (4)
To a solution of 3 (0.9 g, 3.0 mmol) in anhyd THF (30 mL) at r.t. was added dropwise BH3·THF complex (15 mL, 15.0 mmol; 1 M solution in THF). When the starting material was completely consumed, the reaction was cooled to 0 °C and 3 N NaOH (6 mL) and H2O2 (3 mL of an 30% aq solution) were carefully added to the solution. After stirring for an hour, brine was added to the reaction and extracted with EtOAc. The organic layers were dried, filtered, and concentrated. The residue was purified by column chromatography (SiO2, CH2Cl2-EtOAc, 98:2 to 95:5) to afford alcohol 4 (705 mg, 76%) as a yellow oil: 1H NMR (300 MHz, CDCl3, gCOSY): δ = 1.21 (s, 3 H, CH3), 1.28 (dd, J = 13.1, 2.2 Hz, 1 H, H-4), 1.45 (ddd, J = 12.4, 5.9, 3.2 Hz, 1 H, H-7), 1.87-1.76 (m, 2 H, H-4 and H-6), 1.91-2.11 (m, 2 H, H-6 and H-7), 2.38 (t, J = 2.6 Hz, 1 H, H-7a), 2.52 (t, J = 10.1 Hz, 1 H, H-2), 2.74 (dd, J = 10.1, 8.2 Hz, 1 H, H-2), 3.19 (d, J = 13.4 Hz, 1 H, CH2Ph), 3.47 (dd, J = 10.4, 8.4 Hz, 1 H, CH2OH), 3.69 (dd, J = 10.4, 5.9 Hz, 1 H, CH2OH), 3.87-3.99 (m, 4 H, OCH2), 4.02 (d, J = 13.5 Hz, 1 H, CH2Ph), 7.20-7.32 (m, 5 H, ArH). 13C NMR (300 MHz, CDCl3, gHSQC): δ = 21.5 (C-6), 21.9 (Me), 28.6 (C-7), 36.5 (C-4), 43.0 (C-3a), 51.0 (C-3), 55.1 (C-2), 57.9 (NCH2Ar), 62.6 (CH2OH), 63.5 and 64.4 (OCH2), 68.5 (C-7a), 109.6 (C-5), 126.6 (ArH), 128.1 (ArH), 128.3 (ArH), 140.2 (Ar). IR (NaCl, neat): 3440, 2926, 2877, 2788, 1359, 1091 cm-1.

19

trans -1-Benzyl-3a-hydroxymethyl-3-methylene-octahydroindol-5-one Ethylene Acetal (8)
1H NMR (300 MHz, CDCl3, NOESY): δ = 1.57-1.60 (m, 2 H, H-4 and H-7), 1.74-1.89 (m, 2 H, H-4 and H-6), 1.89-2.01 (m, 2 H, H-6 and H-7), 2.40 (dd, J = 11.9, 3.4 Hz, 1 H, H-7a), 2.82 (td, J = 14.4, 2.4 Hz, 1 H, H-2), 3.12 (d, J = 12.9 Hz, 1 H, NCH2Ar), 3.44 (d, J = 11.0 Hz, 1 H, CH2OH), 3.69 (d, J = 14.4 Hz, 1 H, H-2), 3.86-4.00 (m, 4 H, OCH2), 4.04 (d, J = 13 Hz, 1 H, NCH2Ar), 4.40 (d, J = 11.0 Hz, 1 H, CH2OH), 4.80 (t, J = 2.5 Hz, 1 H, =CH2), 4.88 (t, J = 2.0 Hz, 1 H, =CH2), 7.26-7.30 (m, 5 H, ArH). 13C NMR (75 MHz, CDCl3, gHSQC): δ = 21.1 (C-7), 34.5 (C-6), 40.3 (C-4), 49.5 (C-3a), 58.0 (CH2Ph), 59.9 (C-2), 63.9 and 64.7 (OCH2), 66.3 (CH2OH), 72.3 (C-7a), 103.7 (=CH2), 109.0 (C-5), 127.1 (ArH), 128.3 (ArH), 128.5 (ArH), 138.0 (Ar), 152,1 (C-3). IR (NaCl, neat): 3410, 3300, 2947, 2881, 2804, 1452, 1359, 1252, 1206, 1142, 1110, 1059, 1011 cm-1.

20

trans -1-Benzyl-3a-methyl-3-methyleneoctahydroindol-5-one Ethylene Acetal (10)
1H NMR (300 MHz, CDCl3, gCOSY): δ = 1.18 (s, 3 H, CH3), 1.56-1.62 (m, 3 H, H-4 and H-7), 1.72-1.75 (m, 1 H, H-7), 1.91-1.96 (m, 2 H, H-6), 1.97 (dd, J = 13.2, 2.4 Hz, 1 H, H-7), 2.04-2.12 (m, 1 H, H-7a), 2.73 (dt, J = 14.8, 2.1 Hz, 1 H, H-2), 3.18 (d, J = 13.5 Hz, 1 H, CH2Ph), 3.70 (dt, J = 15.2, 1.9 Hz 1 H, H-2), 3.86-4.07 (m, 5 H, OCH2 and CH2Ph), 4.58 (t, J = 2.3 Hz 1 H, =CH2), 7.22-7.37 (m, 5 H, ArH). 13C NMR (75 MHz, CDCl3): δ = 20.3 (CH3), 21.5 (C-7), 34.6 (C-6), 42.6 (C-4), 45.4 (C-3a), 58.1 (NCH2Ar), 58.6 (C-2), 63.6 and 63.6 (OCH2), 71.8 (C-7a), 100.0 (=CH2), 109.8 (C-5), 126.7 (ArH), 128.1 (ArH), 128.3 (ArH), 139.8 (Ar), 156.7 (C-3).

22

Both precursors 2 and 6 seem to have the same preferred conformation, according to their NMR data. For methyl derivative 2, see ref. 15. For 6: 1H NMR (300 MHz, CDCl3): δ = 2.00 (ddd, J = 13.1, 6.5, 3.3 Hz, 1 H, H-5), 2.26 (dt, J = 13.5, 5.2 Hz, 1 H, H-5), 2.51 (d, J = 13.0 Hz, 1 H, H-3), 2.56 (d, J = 13.7 Hz, 1 H, H-3), 2.63 (ddd, J = 15.9, 5.2, 3.0 Hz, 1 H, H-6), 3.04 (ddd, J = 15.9, 13.7, 6.5 Hz, 1 H, H-6), 3.79 (s, 3 H, OMe), 3.91-4.04 (m, 4 H, OCH2), 6.23 and 6.28 (2 s, 1 H each, =CH2), 9.47 (s, 1 H, CHO). 13C NMR (75 MHz, CDCl3): δ = 33.9 (C-5), 37.6 (C-6), 39.7 (C-3), 53.0 (OMe), 61.4 (C-2), 64.3 and 64.8 (OCH2), 106.4 (C-4), 135.9 (=CH2), 147.5 (=C), 170.4 (CO2Me), 192.0 (CHO), 203.1 (C-1). IR (NaCl, neat): 2956, 2894, 1740, 1710, 1695, 1434, 1279, 12361121, 1089, 1040 cm-1.