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

Alejandro Cordero-Vargas; Xavier Urbaneja; Josep Bonjoch

doi:10.1055/s-2007-986633

LETTER

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;

Abstract

All articles of this category

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

Full Text

References

References and Notes

<A NAME="RD14807ST-1">1</A> Kobayashi J. Morita H. The Alkaloids 2003, 60: 165

<A NAME="RD14807ST-2">2</A> Morita H. Fujiwara M. Yoshida N. Kobayashi J. Tetrahedron 2000, 56: 5801

<A NAME="RD14807ST-3">3</A> Solé D. Urbaneja X. Bonjoch J. Org. Lett. 2005, 7: 5461

<A NAME="RD14807ST-4">4</A> Zhang H. Yang S.-P. Fan C.-Q. Ding J. Yue J.-M. J. Nat. Prod. 2006, 69: 533

<A NAME="RD14807ST-5">5</A> Morita H. Kobayashi J. Org. Lett. 2003, 5: 2895

<A NAME="RD14807ST-6A">6a</A> Saito S. Kubota T. Fukushi E. Kawabata J. Zhang H. Kobayashi J. Tetrahedron Lett. 2007, 48: 1587

<A NAME="RD14807ST-6B">6b</A> Li C. He H. Wang Y. Mu S. Li S. Gao Z. Gao Z. Hao X. Tetrahedron Lett. 2007, 48: 2737 ; and references therein

<A NAME="RD14807ST-7">7</A> By Zr-promoted reductive cyclization: Mori M. Uesaka N. Saitoh F. Shibasaki M. J. Org. Chem. 1994, 59: 5643

<A NAME="RD14807ST-8">8</A> By intramolecular reaction of enol ethers with alkynes catalyzed by Pt(II): Nevado C. Cárdenas DJ. Echavarren AM. Chem. Eur. J. 2003, 9: 2627

<A NAME="RD14807ST-9">9</A> By W(CO)₅(L)-catalyzed cyclization of ω-acetylenic silyl enol ethers: Grandmarre A. Kusama H. Iwasawa N. Chem. Lett. 2007, 36: 66

For the synthesis of 3a-unsubstituted cis-3-methylene-hydoindoles, see:

<A NAME="RD14807ST-10A">10a</A> Solé D. Cancho Y. Llebaría A. Moretó JM. Delgado A. J. Org. Chem. 1996, 61: 5895

<A NAME="RD14807ST-10B">10b</A> Lemaire-Audoire S. Savignac M. Dupuis C. Genêt J.-P. Tetrahedron Lett. 1996, 37: 2003

<A NAME="RD14807ST-10C">10c</A> Berteina S. De Mesmaeker A. Wendeborn S. Synlett 1999, 1121

<A NAME="RD14807ST-10D">10d</A> Gordon GJ. Luker T. Tuckett MW. Whitby RJ. Tetrahedron 2000, 56: 2113

<A NAME="RD14807ST-11">11</A> Carcache DA. Cho YS. Hua Z. Tian Y. Li Y.-M. Danishefsky SJ. J. Am. Chem. Soc. 2006, 128: 1016

For the enantioselective synthesis of 1, see:

<A NAME="RD14807ST-12A">12a</A> Behenna DC. Stoltz BM. J. Am. Chem. Soc. 2004, 126: 15044

<A NAME="RD14807ST-12B">12b</A> Mohr JT. Behenna DC. Harned AM. Stoltz BM. Angew. Chem. Int. Ed. 2005, 44: 6924

<A NAME="RD14807ST-13">13</A> Hon Y.-S. Chang F.-J. Liu L. Lin W.-C. Tetrahedron 1998, 54: 5233

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

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.

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).

<A NAME="RD14807ST-17">17</A> For the isolation of the 5-desoxo derivative, see: Mori M. Saitoh F. Uesaka N. Okamura K. Date T. J. Org. Chem. 1994, 59: 4993

(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.

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.

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).

<A NAME="RD14807ST-21">21</A> For the influence of the substituent at C-3a in the reduction of N-Boc-hexahydro-1H-indoles, see: Brodney MA. Cole ML. Freemont JA. Kyi S. Junk PC. Padwa A. Riches AG. Ryan JH. Tetrahedron Lett. 2007, 48: 1939

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.

<A NAME="RD14807ST-23A">23a</A> Ayala L. Lucero CG. Romero JAC. Tabacco SA. Woerpel KA. J. Am. Chem. Soc. 2003, 125: 15521

<A NAME="RD14807ST-23B">23b</A> Smith DM. Woerpel KA. Org. Lett. 2004, 6: 2063

<A NAME="RD14807ST-23C">23c</A> Smith DM. Woerpel KA. Org. Biomol. Chem. 2006, 4: 1195