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Synlett 2002(4): 0593-0597
DOI: 10.1055/s-2002-22703
LETTER
© Georg Thieme Verlag Stuttgart · New York

Highly Diastereoselective Intramolecular α-Amidoalkylation Reactions of Hydroxylactams Derived from N-Phenethylimides. Enantioselective Synthesis of Dihydropyrrolo[2,1-a] isoquinolones

Inés González-Temprano, Nuria Sotomayor, Esther Lete*
Departamento de Química Orgánica II, Facultad de Ciencias, Universidad del País Vasco, Apdo. 644-48080 Bilbao, Spain
Fax: +34(94)4648500; e-Mail: qopleexe@lg.ehu.es;
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Publication History

Received 29 January 2002
Publication Date:
05 February 2007 (online)

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Abstract

α-Hydroxylactams, derived from organolithium addition to an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide with a 2-exo-hydroxy-10-bornylsulfinyl group as chiral auxiliary, undergo efficient and highly diastereoselective N-acyliminium ion cyclization. Subsequent removal of the auxiliary and retro-Diels-Alder reaction lead to the enantioselective synthesis of C-10b substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines.

Key words

asymmetric synthesis - chiral auxiliaries - organolithium addition - cyclization - N-acyliminium ion

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14

Nuclear Overhauser effect difference spectroscopy and 1H-1H decoupling experiments confirmed the stereochemistry of isoquinolines. For instance, isoindoloisoquinoline 2a (Figure [2] ) demonstrated an enhancement of the H-11, H-12 and H-6ax signals upon irradiation on C-12b methyl hydrogens and vice versa. This fact, together with the absence of NOE between C-12b methyl hydrogens and the protons H-12a and H-13, confirms an R configuration for C-12b. The rest of the NOE experiments carried out were fully consistent with the proposed stereochemistry in each case.

Figure 2

16

The enantiomeric excess of 11a,b and 1a,b was determined in each case by CSP HPLC (Chiralcel OD, 20% hexane-2-propanol, 0.4 mL/min) by comparison with the corresponding racemates. The racemates were prepared by an alternate procedure described in ref. [8b] . Representative procedures and characterization data for 1a, 2a, 10a, 11a: (8a R ,9 S ,12 R ,12a S ,12b R )-(+)-8a-[(1 S ,2 R ,4 R ,S S )-(2-Hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methylsulfinyl]-2,3-dimethoxy-12b-methyl-5,6,8a,9,12,12a-hexahydro-9,12-methaneisoindolin[2,3- a ]isoquinolin-8-one(2a). To a solution of the imide 3 (1.15 g, 2.2 mmol) in dry THF (45 mL), MeLi (7.6 mL of a 0.66 M solution in pentane, 5 mmol) was added at -78 °C. The resulting mixture was stirred at this temperature for 6 h, quenched by the addition of saturated NH4Cl (20 mL), and allowed to warm to room temperature. The organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford hydroxy lactam 9a (1.18 g, 99%), which was used without further purification.
To a solution of the so obtained hydroxy lactam 9a (203 mg, 0.4 mmol) in CH2Cl2 (10 mL), TFA (2.5 mL, 32.4 mmol) was added and the resulting solution was stirred at room temperature for 3 days. The reaction mixture was treated with saturated aqueous NaHCO3, the organic layer was decanted and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried (Na2SO4) and concentrated in vacuo. The resulting crude reaction mixture was purified by column flash chromatography (silica gel, 60% hexane-ethyl acetate), yielding two fractions.
2a (101 mg, 51%): [α ]D 23 +117.9 (0.5, CHCl3); mp (Et2O-pentane) 121-122 °C; IR (CHCl3): 3400, 2975, 1673, 1407 cm-1; 1H NMR (CDCl3) 0.60 (s, 3 H), 1.04 (s, 3 H), 1.23-1.25 (m, 2 H), 1.48 (s, 3 H), 1.60-1.72 (m, 6 H), 2.1 (d, J = 8.3 Hz, 1 H), 2.54 (dd, J = 16.2, 4.4 Hz, 1 H), 2.75 (d, J = 13.1 Hz, 1 H), 2.81-2.92 (m, 1 H), 3.07 (ddd, J = 13.1, 12.3, 4.8 Hz, 1 H), 3.21 (d, J = 13.1 Hz, 1 H), 3.32 (d, J = 3.6 Hz, 1 H), 3.37 (s, 1 H), 3.74-3.78 (m, 2 H), 3.81-3.89 (m, 1 H),* 3.82 (s, 3 H),* 3.89 (s, 3 H),* 4.18 (dd, J = 13.1, 6.3 Hz, 1 H), 6.33-6.37 (m, 1 H), 6.45-6.48 (m, 2 H), 6.60 (s, 1 H) (*: partially overlapped signals); 13C NMR (CDCl3) 19.9, 20.4, 26.5, 27.0, 27.6, 30.5, 35.4, 38.3, 48.7, 44.9, 45.8, 46.5, 48.1, 50.2, 51.0, 52.5, 55.7, 56.2, 60.6, 75.4, 76.8, 107.4, 112.0, 124.1, 135.3, 135.8, 139.2, 147.9, 148.0, 168.4; MS (EI)
m/z (rel. intensity) 526 (M+ + 1, 2), 525 (M+, 1), 373(47), 325(19), 324(23), 310(16), 308(25), 307(100), 292(21), 290(27), 258(26), 206(16), 164(8), 119(35), 91(26).
10a (38 mg, 16%): [α ]D 23 +95.7 (1, CHCl3); IR (CHCl3): 2950, 1780, 1673 cm-1; 1H NMR (CDCl3) 0.86 (s, 3 H), 1.04 (s, 3 H), 1.48 (s, 3 H), 1.23-1.25 (m, 2 H), 1.58-1.92 (m, 5 H), 2.1 (d, J = 8.3 Hz, 1 H), 2.47 (dd, J = 16.0, 3.8 Hz, 1 H), 2.79 (ddd, J = 16.0, 12.3, 6.5 Hz, 1 H), 3.03 (td, J = 12.6, 4.4 Hz, 1 H), 3.12-3.23 (m, 2 H), 3.28 (s, 1 H), 3.52 (d, J = 3.6 Hz, 1 H), 3.59 (s, 1 H), 3.82-3.88 (m, 1 H),* 3.82 (s, 3 H),* 3.89 (s, 3 H),* 4.10 (dd, J = 13.1, 6.1 Hz, 1 H), 5.05 (dd, J = 7.4, 2.8 Hz, 1 H), 6.31-6.34 (m, 1 H), 6.45-6.49 (m, 2 H), 6.60 (s, 1 H) (*: partially overlapped signals); 13C NMR (CDCl3) 19.6, 20.0, 26.3, 26.7, 27.6, 29.9, 35.7, 38.5, 46.7, 44.8, 45.3, 45.6, 49.2, 50.2, 50.4, 52.6, 55.7, 56.2, 60.7, 75.7, 82.0, 107.6, 111.7, 110.7, 124.0, 135.4, 136.2, 139.7, 147.8, 147.9, 155.6, 169.2; MS (EI) m/z (rel. intensity) 621 (M+, 6), 622 (M + 1, 3), 623 (M + 2, 1), 325(5), 324(100), 308(17), 307(18), 290(12), 258(15), 206(15), 164(13), 135(10), 119(52), 93(11), 91(20).
(8a S ,9 S ,12 R ,12a S ,12b R )-(+)-2,3-Dimethoxy-12b-methyl-5,6,8a,9,12,12a-hexahydro-9,12-methaneisoindolin[2,3- a ]isoquinolin-8-one(11a). To a solution of 2a (100 mg, 0.2 mmol) in dry THF (5 mL), SmI2 (20 mL of a 0.1 M solution in THF, 2 mmol), t-BuOH (0.2 mL, 2.1 mmol), and HMPA (2.5 mL, 15 mmol) were added sequentially at r.t. The resulting mixture was stirred at this temperature for 1.5 h, and quenched by the addition of cold HCl (15 mL of a 1 M solution). The organic layer was separated, and the aqueous phase was extracted with CHCl3 (3 × 10 mL). The combined organic extracts were washed with saturated Na2S2O3 (3 × 10 mL) and with brine (3 × 10 mL), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate) afforded isoindoloisoquinoline 11a (59 mg, 96%), whose spectroscopic data are coincidental to those previously reported for the racemate [8b] : [α]D 23 +202.8 (1.43, CHCl3); mp (Et2O) 183-184 °C [Lit. [8a] racemate (Et2O) 158-160 °C]; 1H NMR (CDCl3) 1.45 (s, 3 H),* 1.41-1.45 (m, 1 H),* 1.64 (d, J = 8.3 Hz, 1 H), 2.44 (d, J = 11.9 Hz, 1 H), 2.96-2.99 (m, 2 H), 3.09-3.11 (m, 2 H), 3.23-3.25 (m, 2 H), 3.82 (s, 3 H), 3.90 (s, 3 H), 4.10-4.14 (m, 1 H), 6.21-6.23 (m, 2 H), 6.48 (s, 1 H), 6.65 (s, 1 H) (*: partially overlapped signals). The enantiomeric excess was determined by CSP HPLC to be
> 99%, by comparison with the racemic mixture. Chiralcel OD, 20% hexane-2-propanol, 0.4 mL/min; tr (ent-11a) = 18.5 min (< 1%); tr(11a) = 21.2 min (> 99%).
(10b R )-(+)-(-8,9-Dimethoxy-10b-methyl-5,6-dihydropyrrolo[2,1- a ]isoquinolin-3(10b H )-one(1a). Isoindoloisoquinoline 11a (92 mg, 0.28 mmol) was heated at 560 °C under vacuum (1 mm Hg) for short periods of time (10 min). [18] The evolution of the reaction was monitored by 1H NMR, and the procedure was repeated until complete evolution of starting material was observed. The crude product was purified by column chromatography (silica gel, 80% hexane-EtOAc) (63 mg, 85%), whose spectroscopic data were coincidental to those previously reported for the racemate. [8b] [α]23 D +201.4 (0.35, CHCl3); 1H NMR (CDCl3) 1.59 (s, 3 H), 2.65 (dd, J = 15.8, 3.9 Hz, 1 H), 2.85-2.99 (m, 1 H), 3.22 (td, J = 12.0, 4.5 Hz, 1 H), 3.83 (s, 3 H), 3.90 (s, 3 H), 4.4 (dd, J = 13.5, 6.3 Hz, 1 H), 6.10 (d, J = 5.5 Hz, 1 H), 6.59 (s, 1 H), 6.68 (s, 1 H), 7.34 (d, J = 5.9 Hz, 1 H). The enantiomeric excess was determined by CSP HPLC to be
> 99%, by comparison with the racemic mixture. Chiralcel OD, 20% hexane-2-propanol, 0.4 mL/min; tr (ent-1a) = 14.5 min (< 1%); tr(1a) = 18.2 min (> 99%).

18

Continuous heating at 1 mm Hg for longer periods of time resulted in decomposition of starting material.