Doi:10.1016/j.tet.2003.09.076

Regioselective reduction of N-alkyl-3-sulfonyl glutarimides to d-lactams. Formal synthesis of (6)-paroxetine and (6)-tacamonineq Chung-Yi Chen,a Bo-Rui Chang,a Min-Ruei Tsai,a Meng-Yang Changb,* aDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC bDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, ROC Received 19 August 2003; accepted 19 September 2003 Abstract—A convenient method for the preparation of 4- or 5-substituted 3-sulfonyl-d-lactams via regioselective reduction of N-alkyl-3-sulfonyl glutarimides is described. Formal synthesis of (^)-paroxetine and (^)-tacamonine is also reported.
q 2003 Elsevier Ltd. All rights reserved.
the 3-sulfonyl and C-2 carbonyl. The sulfonyl group alsoincreased the electrophilicity of C-2 carbon. Regioselective Six-membered nitrogen-containing heterocycles are abun- reduction of the C-6 carbonyl of glutarimide 1 was dant in nature and exhibit diverse and important biological accomplished by protection of the C-2 carbonyl as an properties.Alkaloids that contain the piperidine ring continue to be the targets of extensive synthetic interest,partly because there are many biologically active naturalproducts of this Accordingly, the development of ageneral method for the preparation of piperidine derivativeshas been the subject of considerable synthetic efforts.d-Lactams have been generally regarded as the precursors ofthe corresponding piperidines. It is well documented thatone of the most widely used methods for the construction ofthe tetracyclic carbon skeleton of indole alkaloids is tosynthesize an appropriate d-lactam, which is then cyclizedto indole alkaloids via the Bischler – Napieralski reaction.
Herein, we report a convenient method for the preparationof 4- or 5-substituted 3-sulfonyl-d-lactams from N-alkyl-3-sulfonyl glutarimide 1.
Recently, we developed an efficient route to the unsym-metrical glutarimides with a sulfonyl group at C-3 positioThe feature of this approach is the utility of a sulfonyl groupto control subsequent regioselective functionalizations Scheme 1. Regioselective reduction of N-alkyl-3-sulfonyl glutarimide 1 to that lead to a variety of hydroxy d-lactams with diverse substituenRegioselective reduction of C-2 carbonyl ofglutarimide 1 was accomplished with NaBH attributed to the chelation of the reducing agent with both 2.1. Regioselective reduction of N-alkyl-3-sulfonylglutarimide 1 to d-lactam 5 with LiAlH4 q Supplementary data associated with this article can be found at doi: It was reported that reduction of glutarimides with NaBH4or LiAlH4 yielded hydroxy lactams or over-reduced product Keywords: glutarimide; d-lactam; regioselective reduction; paroxetine; hydroxy amides.However, reduction of glutarimides directly to d-lactams has never been achieved. We Corresponding authors. Tel.: þ886-7-5252000x3913; fax: þ886-7-5253913; e-mail: [email protected] discovered that treatment of glutarimide 1 with 1.2 equiv.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.076 C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387 Scheme 2. Regioselective reduction of N-alkyl-3-sulfonyl glutarimide 1 with LiAlH4.
Et3N at 258C for 30 min followed by addition of 5 equiv. of LiAlH4, the resulting mixture was further refluxed in THFsolution for 3 h, d-lactam 5 was obtained in good yields To demonstrate the synthetic utility of this methodology, the efficient formal synthesis of (^)-paroxetine (8), which ismarketed as the hydrochloride Paxil/Seroxat, a selective In order to examine the generality of this new method for the serotonin reuptake inhibitor, was reported. Reductive preparation of d-lactam 5, several examples were tested; the desulfonylation of 5e with sodium amalgam in methanol results are listed in The regioselective reduction of solution furnished 7 in good yield, which had been readily 1 and the formation of d-lactam 5 could be rationalized by converted into (^)-paroxetine (8) by Yu.The spectro- the formation of enolate 4, which prevented the C-2 scopic data for 7 were identical to those reported in the carbonyl group from LiAlH4 reduction. It is worth noting that when reduction of 1 proceeded at rt (258C), hydroxylactam 3 was obtained exclusively. Nevertheless, when thereaction mixture was heated to refluxing temperature inTHF solution, the corresponding d-lactam 5 was yielded asthe only product, presumably via B intermediate. Sincedianion intermediate C is more unstable compared with Aand B, the corresponding hydroxy amides (ring openingproducts) were not observed at elevated temperature.
Table 1. Synthesis of 5 via regioselective LiAlH4 reduction Scheme 3. Formal synthesis of (^)-paroxetine.
Tacamonine (11), one of the few indole alkaloids of the tacamane type, was isolated in 1984 from Tabernaemontana eglandulosa,which possess vasodilator and hypotensive activities. Lactam 10 has been converted to 11 in three All yields were based on glutarimide 1.
b The structure of 5d was confirmed by X-ray analysis (see Ref. steps via Bischler – Napieralski cyclizatAs shown in C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387 bath, and concentrated under reduced pressure. The residuewas diluted with water (5 mL) and extracted with ethylacetate (3£20 mL). The combined organic layers werewashed with brine, dried, filtered and evaporated. Purifi-cation on silica gel (hexane/ethyl acetate¼4/1 – 2/1) pro-duced products.
4.2.1. 3-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-5-(toluene-4-sulfonyl)piperidine-2,6-dione (1h). 82% Yield; mp 168 –1708C; 1H NMR (500 MHz, CDCl3) d 8.07 (brs, 0.7H), 8.04(brs, 0.3H), 7.87 (d, J¼8.5 Hz, 0.7H), 7.72 – 7.63 (m, 2.3H),7.36 (t, J¼8.0 Hz, 2.1H), 7.31 (t, J¼8.0 Hz, 0.9H), 7.18 –7.14 (m, 1H), 7.12 – 7.08 (m, 1H), 7.01 (d, J¼2.5 Hz, 0.7H),6.95 (d, J¼2.5 Hz, 0.3H), 4.15 – 3.96 (m, 3H), 3.13 – 3.07(m, 0.7H), 2.99 – 2.95 (m, 1.3H), 2.90 – 2.85 (m, 0.7H),2.78 – 2.74 (m, 0.7H), 2.61 – 2.56 (m, 0.3H), 2.44 (s, 3H),2.31 – 2.25 (m, 0.3H), 2.05 – 1.87 (m, 2H), 1.59 – 1.48 (m,1H), 0.93 (t, J¼8.0 Hz, 2.1H), 0.90 (t, J¼8.0 Hz, 0.9H); 13CNMR (125 MHz, CDCl3) d 173.15 (0.7C), 172.52 (0.3C),165.01 (0.3C), 164.66 (0.7C), 145.72 (0.7C), 145.34 (0.3C), Scheme 4. Formal synthesis of (^)-tacamonine.
136.07, 135.50 (0.3C), 135.01 (0.7C), 129.86, 129.57, 128.94, 127.52 (0.7C), 127.40 (0.3C), 122.35, 121.91, the key intermediate 10 was obtained in 3 119.34, 118.89, 112.34 (0.7C), 112.19 (0.3C), 111.06, 65.86 steps from 9 (61% overall yield). The spectroscopic data for (0.7C), 65.70 (0.3C), 41.94, 41.25, 39.21, 23.84, 23.39 10 matched those reported in the literature.The present (0.3C), 23.24 (0.7C), 22.59 (0.7C), 22.46 (0.3C), 21.71 work constitutes a formal synthesis of (^)-tacamonine (11).
(0.7C), 21.69 (0.3C), 10.61 (0.3C), 10.46 (0.7C); IR(CHCl3, cm21) 3025, 1667. Mass m/z (EI, 30 eV) 438(Mþ, 8.26%), 143 (100%), 130 (76.27%); HRMS calcd for C24H26O4N2S: 438.1613, found: 438.1617. Anal. calcd forC24H26O4N2S: C, 65.73; H, 5.98; O, 14.59; N, 7.31, found: In conclusion, we have developed a convenient method C, 65.79; H, 5.96; O, 14.55; N, 7.28.
for the preparation of substituted d-lactams in good yield.
We also successfully accomplished the formal synthesis of 4.3. Procedure of regioselective reduction of glutarimide (^)-paroxetine and (^)-tacamonine. Further application of this methodology in the synthesis of other alkaloids iscurrently underway in our laboratory.
A solution of glutarimides 1 (2.0 mmol) in THF (20 mL)was added to a stirred solution of triethylamine (2.4 mmol)in THF (10 mL). After the reaction mixture was stirred at rt for 30 min, lithium aluminum hydride (10.0 mmol) wasadded. The resulting mixture was refluxed for 3 h, quenched with NH4Cl (1 mL) in an ice bath, filtered and thenconcentrated under reduced pressure. The residue was Before use, THF was distilled from a deep blue solution diluted with water (5 mL) and extracted with ethyl acetate resulting from sodium and benzophenone under nitrogen.
(3£20 mL). The combined organic layers were washed with All reagents and solvents were obtained from commercial brine, dried, filtered and evaporated. Purification on silica sources and used without further purification. Thin layer gel (hexane/ethyl acetate¼3/1 – 1/1) produced products.
chromatography (TLC) analysis was performed with pre-coated silica gel (60 f254 plates) and column chroma- 4.3.1. 1-Benzyl-3-(toluene-4-sulfonyl)piperidin-2-one tography was carried out on silica (70 – 230 mesh). All (5a). 75% Yield; 1H NMR (500 MHz, CDCl3) d 7.82 (d, reactions were performed under an atmosphere of nitrogen J¼7.5 Hz, 2H), 7.31 – 7.22 (m, 7H), 4.74 (d, J¼14.5 Hz, in dried (except those concerned with aqueous solutions) 1H), 4.43 (d, J¼14.5 Hz, 1H), 4.03 (t, J¼7.0 Hz, 1H), 3.37 – spherical flasks and stirred with magnetic bars.
3.32 (m, 1H), 3.24 – 3.18 (m, 1H), 2.75 – 2.69 (m, 1H), 2.44(s, 3H), 2.31 – 2.17 (m, 2H), 1.81 – 1.75 (m, 1H); 13C NMR 4.2. Procedure of [313] cycloaddition to N-alkyl-3- (125 MHz, CDCl3) d 162.01, 144.67, 136.67, 136.23, 129.46 (2C), 129.10 (2C), 128.67 (2C), 127.77 (2C),127.50, 65.86, 50.56, 47.16, 22.08, 21.70, 20.39; IR A solution of N-substituted-2-(toluene-4-sulfonyl) aceta- (CHCl3, cm21) 3027, 1662. Mass m/z (EI, 30 eV) 349 mide (2.0 mmol) in THF (15 mL) was added to a rapidly (Mþþ1, 3.66%), 91 (100%); HRMS calcd for C19H21O3NS: stirred suspension of sodium hydride (4.4 mmol, 60%) in THF (10 mL). After the reaction mixture was stirred at rtfor 15 min, a solution of a,b-unsaturated ester (2.0 mmol) 4.3.2. 1-Benzyl-4-methyl-3-(toluene-4-sulfonyl)piperi- in THF (10 mL) was added. The resulting mixture was din-2-one (5b). 86% Yield; 1H NMR (500 MHz, CDCl3) d 7.78 (d, J¼8.5 Hz, 2H), 7.35 – 7.26 (m, 7H), 4.67 (d, C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387 J¼15.0 Hz, 1H), 4.52 (d, J¼15.0 Hz, 1H), 3.76 (d, J¼ CDCl3) d 7.80 (d, J¼8.5 Hz, 2H), 7.35 (d, J¼8.5 Hz, 2H), 4.0 Hz, 1H), 3.41 – 3.36 (m, 1H), 3.25 – 3.20 (m, 1H), 3.09 – 7.18 (D, J¼8.5 Hz, 2H) 6.86 (d, J¼8.5 Hz, 2H), 4.62 (d, J¼ 3.05 (m, 1H), 2.44 (s, 3H), 2.39 – 2.33 (m, 1H), 1.57 – 1.50 14.5 Hz, 1H), 4.51 (d, J¼3.0 Hz, 1H) 4.40 (d, J¼14.5 Hz, (m, 1H), 1.19 (d, J¼7.5 Hz, 3H); 13C NMR (125 MHz, 1H), 4.01 (d, J¼7.5 Hz, 1H), 3.80 (s, 3H), 3.39 – 3.33 (m, CDCl3) d 161.82, 144.73, 136.40, 136.33, 129.49 (2C), 2H), 3.21 – 3.17 (m, 1H), 3.00 – 2.91 (m, 2H), 2.90 – 2.73 (m, 128.99 (2C), 128.67 (2C), 127.81 (2C), 127.52, 72.52, 2H), 2.45 (s, 3H), 2.35 – 2.33 (m, 1H), 2.11 – 1.90 (m, 3H); 50.77, 44.27, 27.67, 27.57, 21.71, 20.22; IR (CHCl C NMR (125 MHz, CDCl3) d 161.46, 159.31, 145.10, 3025, 1668. Mass m/z (EI, 30 eV) 358 (Mþþ1, 1.36%), 202 136.46, 129.81 (2C), 129.50 (2C), 129.19 (2C), 128.42, (100%), 91 (86.07%); HRMS calcd for C20H23O3NS: 114.29 (2C), 68.93, 55.50, 50.30, 50.03, 44.00, 36.71, 29.34, 29.15, 25.57, 23.99, 21.98; IR (CHCl3, cm21) 3045, 1682.
Mass m/z (EI, 30 eV) 491 (Mþ, 1.28%), 336 (91.88%), 121 4.3.3. 1-Benzyl-4-phenyl-3-(toluene-4-sulfonyl)piperi- (100%); HRMS calcd for C24H29O4NS3: 491.1259, found: din-2-one (5c). 78% Yield; 1H NMR (500 MHz, CDCl3) d 7.77 (d, J¼8.0 Hz, 2H), 7.35 – 7.21 (m, 10H), 7.10 (d, J¼7.0 Hz, 2H), 4.73 (d, J¼15.0 Hz, 1H), 4.56 (d, J¼15.0 Hz, 4.3.7. 1-[2-(1H-Indol-3-yl)ethyl]-3-(toluene-4-sulfonyl)- 1H), 4.30 – 4.27 (m, 2H), 3.38 – 3.36 (m, 1H), 3.06 – 3.00 (m, piperidin-2-one (5g). 85% Yield; 1H NMR (500 MHz, 1H), 2.66 – 2.60 (m, 1H), 2.43 (s, 3H), 1.89 – 1.83 (m, 1H); CDCl3) d 8.35 (brs, 1H), 7.80 (d, J¼8.5 Hz, 2H), 7.58 (d, 13C NMR (125 MHz, CDCl3) d 162.05, 144.83, 141.36, J¼5.0 Hz, 1H), 7.33 – 7.30 (m, 3H), 7.16 (t, J¼7.5 Hz, 1H), 136.28, 136.06, 129.47 (2C), 128.99 (2C), 128.80 (2C), 7.09 (t, J¼2.5 Hz, 1H), 7.05 (s, 1H), 3.96 (t, J¼6.0 Hz, 1H), 128.59 (2C), 127.97 (2C), 127.54, 127.18, 126.95 (2C), 3.75 – 3.70 (m, 1H), 3.50 – 3.45 (m, 1H), 3.15 – 3.10 (m, 1H), 70.59, 50.85, 44.00, 37.75, 28.57, 21.66; IR (CHCl3, cm21) 3.04 – 2.98 (m, 4H), 2.59 – 2.54 (m, 1H), 2.40 (s, 3H), 2.09 – 3030, 1658. Mass m/z (EI, 30 eV) 420 (Mþþ1, 2.29%), 264 2.07 (m, 2H); 13C NMR (125 MHz, CDCl3) d 161.54, (95.59%), 91 (100%); HRMS calcd for C25H25O3NS: 144.62, 136.25, 129.43 (2C), 128.99 (2C), 127.21, 122.62, 121.80, 119.15, 118.45, 112.38, 111.30, 65.80, 51.09, 49.08,48.76, 22.85, 21.93, 21.62, 20.40; IR (CHCl3, cm21) 3052, 4.3.4. 1-Benzyl-4-dimethoxymethyl-3-(toluene-4-sulfo- 1688. Mass m/z (EI, 30 eV) 396 (Mþ, 1.35%), 143 (100%); nyl)piperidin-2-one (5d)7. 95% Yield; mp 96 – 988C; 1H HRMS calcd for C22H24O3N2S: 396.1507, found: 396.1510.
NMR (500 MHz, CDCl3) d 7.81 (d, J¼8.0 Hz, 2H), 7.40 (d,J¼8.0 Hz, 2H), 7.34 – 7.27 (m, 5H), 4.61 (dd, J¼15.0, 4.3.8. 5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-3-(toluene-4- 4.0 Hz, 2H), 4.35 (d, J¼5.6 Hz, 1H), 4.13 (d, J¼2.5 Hz, sulfonyl)piperidin-2-one (5h). 83% Yield; mp 173 – 1H), 3.38 (s, 1H), 3.37 (s, 1H), 3.35 (t, J¼4.5 Hz, 1H), 1758C; 1H NMR (500 MHz, CDCl3) d 8.14 (brs, 1H), 7.82 3.28 – 3.23 (m, 2H), 2.46 (s, 3H), 2.36 – 2.31 (m, 1H), 1.87 – (d, J¼8.5 Hz, 1H), 7.79 (d, J¼8.5 Hz, 1H), 7.61 (d, J¼ 1.83 (m, 1H); 13C NMR (125 MHz, CDCl3) d 161.75, 8.0 Hz, 0.5H), 7.57 (d, J¼8.0 Hz, 0.5H), 7.35 – 7.31 (m, 144.71, 136.27, 136.22, 129.45, 128.93, 128.51, 127.80, 3H), 7.18 (t, J¼7.5 Hz, 1H), 7.12 – 7.08 (m, 1H), 7.02 (d, 127.39, 104.88, 66.82, 54.96, 54.37, 50.75, 44.62, 34.83, J¼2.5 Hz, 1H), 4.05 (dd, J¼3.5, 7.5 Hz, 0.5H), 3.92 (dd, 21.65, 20.73; IR (CHCl3, cm21) 3030, 2928. Mass m/z (EI, J¼2.5, 4.5 Hz, 0.5H), 3.78 – 3.73 (m, 0.5H), 3.69 – 3.65 (m, 30 eV) 418 (Mþþ1, 1.32%), 262 (58.37%), 91 (100%); 0.5H), 3.55 – 3.44 (m, 1H), 3.15 – 3.12 (m, 0.5H), 3.04 – 3.01 HRMS calcd for C22H27O5NS: 417.1610, found: 417.1604.
(m, 0.5H), 3.03 – 2.85 (m, 2H), 2.75 (t, J¼10.5 Hz, 1H), Single-crystal X-ray diagram: crystal of 5d was grown by 2.44 – 2.39 (m, 0.5H), 2.42 (s, 3H), 2.27 – 2.24 (m, 0.5H), slow diffusion of ethyl acetate into a solution of 5d in 1.96 – 1.89 (m, 0.5H), 1.68 – 1.61 (m, 1H), 1.53 – 1.48 (m, dichloromethane to yield colorless prism. The compound 0.5H), 1.30 – 1.14 (m, 2H), 0.82 (t, J¼7.5 Hz, 1.5H), 0.77 (t, crystallizes in the primitive orthorhombic crystal system, J¼7.5 Hz, 1.5H); 13C NMR (125 MHz, CDCl3) d 161.86 (0.5C), 161.51 (0.5C), 144.63 (0.5C), 144.50 (0.5C), 136.84 (0.5C), 136.61 (0.5C), 136.24, 129.46 (0.5C), 129.35 F(000)¼888.00, 2u range 16(20.5 – 27.98).
(0.5C), 129.17, 128.98, 127.26, 122.55 (0.5C), 122.36(0.5C), 121.97 (0.5C), 121.93 (0.5C), 119.30 (0.5C), 119.28 4.3.5. 1-Benzyl-4-(4-fluorophenyl)-3-(toluene-4-sulfo- (0.5C), 118.54, 112.62, 111.22 (0.5C), 111.20 (0.5C), 65.71 (0.5C), 65.54 (0.5C), 53.99 (0.5C), 53.80 (0.5C), 49.12 (500 MHz, CDCl3) d 7.76 (d, J¼8.5 Hz, 2H), 7.34– 7.29 (0.5C), 49.01 (0.5C), 34.95, 31.58, 27.67 (0.5C), 27.42 (m, 7H), 7.09 – 7.06 (m, 2H), 6.97 – 6.93 (m, 2H), 4.68 (d, (0.5C), 26.01 (0.5C), 26.00 (0.5C), 22.87 (0.5C), 22.82 J¼14.5 Hz, 1H), 4.59 (d, J¼14.5 Hz, 1H), 4.26 – 4.23 (m, (0.5C), 21.67, 11.00 (0.5C), 10.94 (0.5C); IR (CHCl3, 1H), 4.21 (d, J¼2.5 Hz, 1H), 3.42 – 3.38 (m, 1H), 3.07 – 3.02 cm21) 3053, 1687. Mass m/z (EI, 30 eV) 424 (Mþ, 1.18%), (m, 1H), 2.62 – 2.56 (m, 1H), 2.44 (s, 3H), 1.86 – 1.81 (m, 143 (100%); HRMS calcd for C24H28O3N2S: 424.1821, 1H); 13C NMR (125 MHz, CDCl3) d 161.96, 160.81, found: 424.1817. Anal. calcd for C24H28O3N2S: C, 67.90; 145.00, 137.33, 136.16, 136.02, 129.55 (2C), 129.06 (2C), H, 6.65; O, 11.31; N, 6.60, found: C, 67.93; H, 6.61; O, 128.68 (2C), 128.66, 128.59, 128.08 (2C), 127.70, 115.81, 115.63, 71.00, 50.99, 44.11, 37.41, 28.91, 21.71; IR (CHCl3,cm21) 3021, 1616. Mass m/z (EI, 30 eV) 438 (Mþþ1, 4.4. Procedure of reductive desulfonylation of 3-sulfonyl 6.47%), 282 (23.70%), 91 (100%); HRMS calcd for C25H24O3NSF: 437.1461, found: 437.1464.
6% Sodium amalgam (Na/Hg, 3.0 g) and sodium phosphate 4.3.6. 1-Benzyl-4-[1,3]dithian-2-yl-3-(toluene-4-sulfo- (40 mg) were added to a stirred solution of 3-sulfonyl nyl)piperidin-2-one (5f). 88% Yield; 1H NMR (500 MHz, lactam 5 (2.0 mmol) in methanol (5 mL), and vigorously C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387 stirred for 2 h at rt. The residue was filtered and washed with New York, 1985; Vol. 26, p 89. (b) Oefner, C.; Binggeli, A.; methanol (2£10 mL). The combined organic layers were Breu, V.; Bur, D.; Clozel, J. P.; d’rcy, A.; Dorn, A.; Fischli, concentrated to obtain the crude product. Purification on W.; Gruninger, F.; Guller, R.; Hirth, G.; Marki, H.; Mathews, silica gel (hexane/ethyl acetate¼2/1 – 1/1) produced S.; Miller, M.; Ridley, R. G.; Stadler, H.; Viera, E.; Wilhelm, M.; Winklr, F.; Wostl, W. Chem. Biol. 1999, 6, 127. (c) Viera,E.; Binggeli, A.; Breu, V.; Bur, D.; Fischli, W.; Gu¨ller, R.; 1-Benzyl-4-(4-fluorophenyl)piperidin-2-one Hirth, G.; Ma¨rki, H. P.; Mu¨ller, M.; Oefner, C.; Stadler, H.; 90% Yield; 1H NMR (500 MHz, CDCl3) d 7.35 –7.32 (m, Wilhelm, M.; Wostl, W. Bioorg. Med. Chem. Lett. 1999, 9, 2H), 7.30 – 7.27 (m, 3H), 7.15 (dd, J¼5.0, 8.5 Hz 2H), 7.01 1397. (d) Gu¨ller, R.; Binggeli, A.; Breu, V.; Bur, D.; Fischli, (t, J¼8.5 Hz, 2H), 4.74 (d, J¼14.5 Hz, 1H), 4.55 (d, J¼ W.; Hirth, G.; Jenny, C.; Kansy, M.; Montavon, F.; Mu¨ller, 14.5 Hz, 1H), 3.33 – 3.24 (m, 2H), 3.12 – 3.06 (m, 1H), 2.80 M.; Oefner, C.; Stadler, H.; Vieira, E.; Wilhelm, M.; Wostl, (ddd, J¼2.0, 5.5, 17.0 Hz, 1H), 2.55 (dd, J¼11.0, 17.0 Hz, W.; Ma¨rki, P. Bioorg. Med. Chem. Lett. 1999, 9, 1403.
2H), 2.08 – 2.03 (m, 1H), 1.94 – 1.86 (m, 1H); 13C NMR 2. (a) Southon, I. W.; Buckingham, J. Dictionary of Alkaloids; (125 MHz, CDCl3) d 169.04, 162.57, 139.05, 136.98, Chapman & Hall: London, 1989. (b) Daly, J. W. J. Nat. Prod.
128.60 (2C), 128.14 (2C), 127.93, 127.87, 127.44, 115.57, 115.41, 49.98, 46.19, 39.57, 37.94, 30.26; IR (CHCl3, 3. (a) Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, cm21) 3027, 1618. Mass m/z (EI, 30 eV) 283 (Mþ, 2.48%), M. J. Org. Chem. 1988, 53, 3507. (b) Comins, D. L.; Killpack, 91 (100%); HRMS calcd for C18H18ONF: 283.1367, found: M. O. J. Am. Chem. Soc. 1992, 114, 10973. (c) Midland, M. M.; McLoughlin, J. I. Tetrahedron Lett. 1988, 29, 4653.
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(10). 90% Yield; mp 147 – 1498C; 1H NMR (500 MHz, Tetrahedron Lett. 1992, 33, 4103. (f) Castro, P.; Overman, CDCl3) d 8.22 (brs, 1H), 7.66 (d, J¼8.0 Hz, 1H), 7.35 (d, L. E.; Zhang, X.; Mariano, P. S. Tetrahedron Lett. 1993, 34, J¼8.0 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 7.11 (t, J¼7.5 Hz, 5243. (g) de Kimpe, N.; Boelens, M.; Piqueru, J.; Baele, J.
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(m, 1H), 2.38 – 2.31 (m, 1H), 1.85 – 1.81 (m, 1H), 1.58 – 1.54 (i) Francois, D.; Lallemand, M. C.; Selkti, M.; Tomas, A.; (m, 1H), 1.38 – 1.32 (m, 1H), 1.28 – 1.22 (m, 2H), 0.83 (t, Kunesch, N.; Husson, H. P. Angew. Chem., Int. Ed. Engl.
J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 169.94,136.25, 127.51, 121.94, 121.92, 119.26, 118.75, 113.20, 111.13, 53.82, 48.39, 35.52, 31.62, 26.87, 26.01, 22.93, 4. (a) Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C.
Tetrahedron Lett. 2000, 41, 10273. (b) Chang, M. Y.; Chen, 3, cm21) 3050, 1681. Mass m/z (EI, 30 eV) S. T.; Chang, N. C. Tetrahedron 2002, 58, 5075.
5. (a) Chang, M. Y.; Chen, S. T.; Chang, N. C. Tetrahedron 2002, 17H22ON2: 270.1732, found: 270.1729. Anal. calcd for 58, 3623. (b) Hsu, R. T.; Cheng, L. M.; Chang, N. C.; Tai, 17H22ON2: C, 75.52; H, 8.21; O, 5.92; N, 10.36, found: C, H. M. J. Org. Chem. 2002, 67, 5044. (c) Chang, B. R.; Chen,C. Y.; Chang, N. C. Tetrahedron Lett. 2002, 43, 3233.
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7. CCDC 219521 contains the supplementary crystallographic Experimental procedures and photocopies of spectral data data for this paper. This data can be obtained free of charge via CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:þ44-1223-336033; e-mail: 8. Yu, M. S.; Lantos, I.; Peng, Z. O.; Yu, J.; Cacchio, T.
Financial support from the National Science Council of the 9. van Beek, T. A.; Verpoorte, R.; Baerheim Svendsen, A.
Republic of China is gratefully acknowledged.
10. (a) Massiot, G.; Sousa Oliverira, F.; Le´vy, J. Bull. Soc. Chim.
Fr. II 1982, 185. (b) Danieli, B.; Lesma, G.; Macecchini, S.; Passarella, D.; Silvani, A. Tetrahedron: Asymmetry 1999, 10,4057.
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