Synthetic approach to pentacyclic quassinoids from communic acids, via ambracetal derivatives

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1 Tetrahedron 61 (2005) Synthetic approach to pentacyclic quassinoids from communic acids, via ambracetal derivatives E. J. Alvarez-Manzaneda, a, * J. L. Romera, a A. F. Barrero, a R. Alvarez-Manzaneda, b R. Chahboun, a R. Meneses a and M. Aparicio b a Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, Granada, Spain b Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Almería, Almería, Spain Received 26 June 2004; revised 12 November 2004; accepted 15 November 2004 Available online 30 November 2004 Abstract Methyl (8R,13S)-8a,13:13,17-diepoxy-14,15-dinorlabdane-19-oate, easily prepared from communic acids, is a suitable intermediate for synthesizing pentacyclic quassinoids, because it enables the elaboration of the A ring and the further construction of the B C D ring system of these terpenoids. The cetal group is stable under the reaction conditions utilized during the elimination of the ester group and the introduction of the hydroxyl group on C-3. At the same time, it enables the regeneration of the methylketone and exocyclic double bond presented by methyl 13-oxo-14,15-dinorlabd-8(17)en-19-oate. The latter compound was previously used to construct the B C D-ring of these quassinoids. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction In a previous paper we reported the efficient preparation of the tetracyclic derivative 3, a possible intermediate in the synthesis of pentacyclic quassinoids from communic acids (1a c) via methylketone 2 (Scheme 1). 1 3 presents the B, C and D rings suitably functionalized to construct the B C D E framework of such quassinoids, but the elaboration of the A ring of quassinoids from this intermediate is likely to be difficult. Thus we have investigated how to functionalize the A ring during the early steps of the synthetic sequence, before creating the B C D E system. We believed that cetal 4, the preparation of which, from 1a c in a 3-step sequence, we have reported elsewhere, 1,2 could well be suitable for this purpose. Cetal 4, bearing the methylketone and exocyclic double-bond groups as masked functions, would allow us to functionalize the A ring according to the method we have described previously. 3 Thus, the functionalized cetal A would be prepared and then the regeneration of methylketone and the exocyclic double bond would lead to B, which, following the previously developed synthetic sequence utilized to convert 2 into 3, 1 would provide the tetracyclic intermediate C. The whole ring of this compound is suitably functionalized, and thus Keywords: Quassinoids; Labdane diterpenes; Acetal cleavage; Wolff Kishner elimination. * Corresponding author. Tel./fax: C ; eamr@ugr.es pentacyclic quassinoids, as bruceantin, may be obtained (Scheme 1). In this paper we report a procedure to create the methylketone and exocyclic double bond groups from the cetal function in 4, in addition to two methods to functionalize the A ring of Results and discussion We began by investigating methods to create methylketone and exocyclic double-bond groups from cetal 4, the preparation of which from 1a c via the reduction derivatives 5a b, has now been considerably improved. 5a b was converted into 4 in one-pot reaction, without isolating the intermediate methylketone 2. Our previous studies revealed that the TiCl 4 -catalysed nucleophilic cleavage of cetal could be used to this end. 4 We assayed the reaction of 4 with TiCl 4 in the presence of Et 3 SiH as the nucleophile under various conditions. 5 The most significant results are shown in Table 1 (Scheme 2). As can be seen, good yields of oxane derivatives 6a b were always obtained. Formate 7 showed similar reactivity, affording a 1:1 mixture of oxanes 8a b when treated at K78 8C. The epimeric mixture 6a b was used as the starting material to prepare methylketone 2. The key step in the sequence was the C O cleavage of the a-alkoxyaldehydes 9a b under /$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi: /j.tet

2 838 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) Scheme 1. Table 1. Treatment of 4 with TiCl 4 Et 3 SiH in CH 2 Cl 2 Entry Reaction time (h) Temperature 6a 6b (% conversion) 1 1 K78 8C 1:1 (95%) 2 2 rt 1:6 (96%) 3 14 rt 0:1 (70%) Wolff Kishner reduction conditions (Scheme 3). 6 The treatment of 6a b with PCC in CH 2 Cl 2 at room temperature afforded aldehydes 9a b, which, by treating with KOH and H 2 NNH 2 in triethylene glycol at 160 8C for 2 h, yielded a mixture of alcohols 10a b, after esterification with diazomethane. These were transformed into methylketone 2 by Jones reagent. In a similar way 8a b was transformed into methylketone 13. After the procedure to transform cetals 4 and 7 into the corresponding methylketones 2 and 13 had been established, we undertook the functionalization of the A rings of 4 and 7. Two synthetic sequences were developed to achieve our objective, the key step of both being the Baeyer Villiger rearrangement of aldehyde 15 to give the formate 7. 3 The refluxing of a solution of 15 in CH 2 Cl 2 in the presence of MCPBA afforded formate 7, which underwent the regioselective elimination of formic acid by heating with collidine, thus yielding 16. The treatment of 16 with SeO 2 tbuooh in CH 2 Cl 2 gave alcohol 17 which was converted into ketone 18 after oxidation with PCC, reduction with Raney nickel 7 and epimerization with MeONa in MeOH (Scheme 4). We also assayed an alternative route to 18 from 7, involving saponification, dehydration and oxidation. By treating 7 with KOH in methanol we obtained nor-alcohol 19. The dehydration of 19 with MsCl and pyridine at room temperature yielded a 1:4 mixture of regiosomers 16 and 20. By treating this under reflux with Na 2 CrO 4 in the presence of NaAcO, Ac 2 O and AcOH we obtained b-enone 21, the exocyclic alkene 16 being recovered unaltered. The b-enone 21 was transformed under Birch reduction conditions into ketone 18, which, after reduction with sodium borohydride, was transformed into 22, which bears the characteristic A-ring functionalization pattern of the postulated intermediates in the synthesis of pentacyclic quassinoids, 8 with the appropriate configuration on C-3 and C-4 (Scheme 5). Scheme 2. Reagents and conditions: (i) OsO 4 0.2%, tbuoh H 2 O, rt, 15 min; NaIO4, 90 8C, 16 h; Jones, acetone, rt, 3 h (80%).

3 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) In summary, cetal 4 is a key intermediate for synthesizing pentacyclic quassinoids from communic acids (1a c). This cetal is efficiently converted into the functionalized A-ring compound 22 via a 7-step sequence at a 10% overall yield. 4 is also transformed into methylketone 2, a precursor of the B C D E ring system of quassinoids, via a 4-step sequence at a 65% overall yield. The successive development of both synthetic sequences will enable to convert 4 into the intermediate B, which will then be transformed, following our described procedure, 1 into C, a very advanced precursor of quassinoids General 3. Experimental Scheme 3. Reagents and conditions: (i) PCC, CH 2 Cl 2, rt, 1 h. (ii) H 2 NNH 2, KOH, triethylene glycol, 160 8C, 2 h; CH 2 N 2, OEt 2 (95%). (iii) H 2 NNH 2, KOH, triethylene glycol, 160 8C, 2 h (95%). (iv) Jones reagent, acetone, 0 8C, 1 h (89%). (v) PCC, CH 2 Cl 2, rt, 45 min (90%). Melting points were determined with a Kofler hot stage melting point apparatus and are uncorrected. IR spectra were obtained on Perkin Elmer Models 782 and 983G spectrometers with samples between sodium chloride plates or as potassium bromide pellets. Proton nuclear magnetic Scheme 4. Reagents and conditions: (i) Ref. 2, 4. (ii) PCC, CH 2 Cl 2 rt, 30 min (85%). (iii) MCPBA, CH 2 Cl 2, reflux, 16 h (70%). (iv) Collidine, reflux, 12 h (90%). (v) SeO 2, tbuooh, CH 2 Cl 2, rt, 12 h (55%). (vi) PCC, CH 2 Cl 2 ; Raney-Ni, THF; MeONa, MeOH, reflux (58%) (yield of 3 steps). Scheme 5. Reagents and conditions: (i) KOH, MeOH, reflux, 1 h (95%). (ii) MsCl, pyridine, rt, 16 h (90%). (iii) Na 2 CrO 4, NaAcO, AcOH, Ac 2 O, reflux, 2.5 h (70%). (iv) THF, tbuoh, Li, NH 3, K78 8C (85%). (v) NaBH 4, EtOH, rt, 1 h (92%).

4 840 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) resonance spectra were taken on a Bruker AMX 300 (300 MHz), Bruker ARX 400 (400 MHz) and Bruker AMX 500 (500 MHz) spectrometers using CDCl 3, and CD 3 - COCD 3 as solvent and TMS or residual protic solvent CHCl 3 (d H Z7.25 ppm) as internal reference, and the multiplicity of a signal is a singlet unless otherwise stated, when the following abbreviations are used: s, singlet; bs, broad singlet; d, doublet; bd, broad doublet; dd, double doublet; t, triplet; m, multiplet. 13 C NMR spectra were run at 75 MHz on Bruker AMX 300, ARX 400 and AMX 500 instruments. Chemical shifts are in ppm (d scale) and the coupling constants are in Hertz. Carbon substitution degrees were established by DEPT pulse sequence. MS were recorded on a Hewlett Packard 5988A spectrometer using an ionizing voltage of 70 ev. HRMS were obtained on a trisector WG AutoSpecQ spectrometer. For analytical TLC Merck silica gel 60G in 0.25 mm thick layers was used. Chromatographic separations were carried out by conventional column on Merck silica gel 60 ( mesh) and by flash column on Merck silica gel 60 ( mesh) using hexane MeO t Bu (H E) mixtures of increasing polarity. Routinely, dry organic solvents were stored under argon, over freshly activated molecular sieves. Ether, benzene, and THF, were dried over sodium-benzophenone ketyl, HMPA from Na, dichloromethane over calcium hydride, and methanol from magnesium methoxide. Where necessary reactions were carried out under a nitrogen or argon atmosphere Methyl (8R,13S)-8a,13:13,17-diepoxy-14,15-dinorlabdane-19-oate (4). A 0.2% aq OsO 4 solution (47 ml) was added to a solution of 5a b (17 g, 53.5 mmol (17.0 g, 53.6 mmol) in t-buoh (195 ml) and H 2 O (82 ml), and the mixture was stirred for 15 min. Then NaIO 4 (60 g, 283 mmol) was added and the mixture was further stirred at 90 8C for 16 h. After filtration, the solvent was evaporated and the residue was fractionated into t-buome (150 ml) H 2 O (40 ml). The organic phase was successively washed with 10% aq K 2 CO 3 (2!50 ml) and brine (2!50 ml), dried over anhydrous Na 2 SO 4 and evaporated to give a crude (16.26 g). A 2 M solution of Jones reagent (8 ml) was added slowly to a stirred solution of the above crude (16.26 g) in acetone (75 ml) until orange colour permanence, and the mixture was further stirred at room temperature for 3 h. Then it was poured into H 2 O-ice (150 ml) and extracted with Et 2 O(4! 50 ml). The organic phase was successively washed with satd aq Na 2 CO 3 solution (3!50 ml) and brine (2!50 ml), dried over anhydrous Na 2 SO 4 and evaporated to give 4 as a colourless oil (13.8 g, 80%). Compound 4 had identical spectroscopic properties to those reported in the literature Methyl (8R,13S)-8a,13-epoxy-17-hydroxy-14,15- dinorlabdan-19-oate (6a) and methyl (8R,13R)-8a,13- epoxy-17-hydroxy-14,15-dinorlabdan-19-oate (6b). Procedure A: Et 3 SiH (0.76 ml, 4.8 mmol) was added to a solution of 4 (0.23 g, 0.75 mmol) in CH 2 Cl 2 (10 ml) under an argon atmosphere at K78 8C and the mixture was stirred at this temperature for 10 min. Then a 1.0 M TiCl 4 solution (1.45 ml, 1.45 mmol) was added and the reaction was stirred for 1 h. A satd NaHCO 3 solution (2 ml) was slowly added and the mixture was stirred for an additional 2 h. The mixture was extracted with ether (3!10 ml) and washed with water (3!10 ml) and brine (3!10 ml). The organic phase was dried over anhydrous Na 2 SO 4, filtered and evaporated to give a crude residue which after chromatography (hexane ether, 3:2) yielded 96 mg (42%) of 6a, 95 mg (41%) of 6b and 30 mg (13%) of starting material. 6a:[a] D ZC (c 5.45, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3451, 2948, 2873, 2852, 1725, 1466, 1449, 1378, 1315, 1233, 1207, 1190, 1154, 1044, 1001, 984, 958, 851, 834, 774, 735, H NMR (CDCl 3, 400 MHz) d: 0.51 (3H, s, Me-20), (3H, m), 1.12 (3H, d, JZ6.1 Hz, Me-16), 1.16 (3H, s, Me-18), (11H, m), (3H, m), 3.59 (1H, dd, JZ11.1, 1.68 Hz, H-17), 3.61 (3H, s, COOMe) 3.67 (1H, dc, JZ6.1, 2.6 Hz, H-13), 3.91 (1H, d, JZ11.0 Hz, H-17). 13 C NMR (CDCl 3, 100 MHz) d: 177,6 (COOMe), 76.7 (C-8), 66.1 (C-13), 58.2 (C-17), 56.7* (C-9), 56.3* (C-5), 51.1 (COOMe), 43.8 (C-4), 39.4 (C-1), 38.1 (C-3), 37.2 (C-10), 35.9 (C-12), 34.8 (C-6), 28.5 (C-18), 22.4 (C-16), 21.2 (C-7), 19.2 (C-2), 18.3 (C-11), 13.5 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 3 Na (M C C Na) , found b: [a] D ZC (c 5.1, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3439, 2948, 2874, 1725, 1467, 1447, 1381, 1326, 1234, 1210, 1151, 1101, 1063, 1037, 956, H NMR (CDCl 3, 400 MHz) d: 0.61 (3H, s, Me-20), (3H, m), 1.17 (3H, d, JZ6.1 Hz, Me-16), 1.20 (3H, s, Me-18), (12H, m), (2H, m), 3.45 (1H, dd, JZ10.5, 1.2 Hz, H-17), 3.62 (1H, d, JZ 10.7 Hz, H-17), 3.64 (3H, s, COOMe), 4.02 (1H, dc, JZ6.1, 2.8 Hz, H-13). 13 C NMR (CDCl 3, 100 MHz) d: 177,7 (COOMe), 76.1 (C-8), 66.3 (C-13), 63.8 (C-17), 56.9* (C-9), 50.2* (C-5), 51.3 (COOMe), 43.8 (C-4), 39.3 (C-1), 38.1 (C-3), 37.8 (C-10), 37.2 (C-12), 29.6 (C-6), 28.7 (C-18), 22.8 (C-16), 21.4 (C-7), 19.2 (C-2), 16.0 (C-11), 12.9 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 3 Na (M C C Na) , found Procedure B: Et 3 SiH (3.93 ml, 24.8 mmol) was added to a solution of 4 (1 g, 3.1 mmol) in CH 2 Cl 2 (60 ml) under an argon atmosphere at room temperature, and the mixture was stirred at this temperature for 10 min. Then a 1.0 M TiCl 4 solution (7.44 ml, 7.44 mmol) was added, and the reaction was stirred for 2 h. A satd NaHCO 3 solution (5 ml) was slowly added and the mixture was stirred for an additional 2 h. The mixture was extracted with ether (3!50 ml) and washed with water (3!30 ml) and brine (3!30 ml). The ethereal phase was dried over anhydrous Na 2 SO 4, filtered and evaporated to give a crude residue which after chromatography (hexane ether, 3:2) yielded 100 mg of 6a, 545 mg of 6b and 330 mg of starting material (8R,13S)-8a,13-Epoxy-17-hydroxy-14,15.19-trinorlabdan-4b-yl formate (8a) and (8R,13R)-8a,13- Epoxy-17-hydroxy-14,15.19-trinorlabdan-4b-yl formate (8b). Et 3 SiH (1.23 ml, 8 equiv) was added to a solution of 7 (0.3 g, 0.97 mmol) in CH 2 Cl 2 (15 ml) under an argon atmosphere at K78 8C and the mixture was stirred at this temperature for 10 min. Then a 1.0 M TiCl 4 solution (2.33 ml, 2.4 mmol) was added, and the reaction was stirred for 1 h. A satd NaHCO 3 solution (2 ml) was slowly added and the mixture was stirred for an additional 2 h. Following the same work-up used for 4 and after chromatography (hexane ether, 1:1) 143 mg of 8a and 140 mg of 8b were obtained (95%). 8a: [a] D ZC (c

5 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) , CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3494, 2931, 2870, 1721, 1650, 1466, 1448, 1203, 1164, 1062, 1043, H NMR (CDCl 3, 400 MHz) d: 0.87 (3H, s, Me-20), (4H, m), 1.16 (3H, d, JZ6.1 Hz, Me-16), 1.30 (1H, dt, JZ14.4, 4.7 Hz), 1.54 (3H, s, Me-18), 2.24 (1H, dt, JZ12.9, 3.3 Hz), 2.69 (1H, dt, JZ12.5, 1.6 Hz), 2.85 (1H, bs), 3.48 (1H, dd, JZ10.4, 2.7 Hz, H-17), 3.60 (1H, d, JZ10.4 Hz, H-17), 3.99 (1H, m, H-13), 8.05 (1H, s, OCHO). 13 C NMR (CDCl 3, 100 MHz) d: (OCHO), 83.9 (C-4), 75.9 (C-7), 66.4 (C-13), 64.1 (C-17), 56.5* (C-9), 50.2* (C-5), 38.2 (C-12), 36.9 (C-10), 36.9 (C-3), 35.8 (C-1), (C-7), 26.2 (C-18), 22.7 (C-16), 19.2 (C-2), 17.6 (C-11), 15.8 (C-6), 14.7 (C-20). FAB HRMS m/z calcd for C 18 H 30 O 4 Na (M C C Na) , found b: [a] D ZC (c 2.2, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3458, 2932, 2871, 1720, 1449, 13.77, 1203, 1174, 1055, 1038, 958, 875, H NMR (CDCl 3, 400 MHz) d: 0.82 (3H, s, Me-20), (15H, m), 1.17 (3H, d, JZ5.8 Hz, Me-16), 1.54 (3H, s, Me-18), 2.22 (1H, dt, JZ12.7, 3.3 Hz), 2.70 (1H, bd, JZ 14.7 Hz), 3.65 (1H, d, JZ11.1 Hz, H-17), 3.70 (1H, dc, JZ 5.8, 2.6 Hz, H-13), 3.99 (1H, dd, JZ11.1, 2.1 Hz, H-17), 8.05 (1H, s, OCHO). 13 C NMR (CDCl 3, 100 MHz) d: (OCHO), 84.1 (C-4), 76.7 (C-8), 66.4 (C-13), 58.7 (C-17), 56.6* (C-9), 56.6* (C-5), 38.4 (C-12), 37.0 (C-10), 35.9 (C-3), 35.7 (C-1), 34.7 (C-7), 26.2 (C-18), 22.5 (C-16), 19.2 (C-2), 18.2 (C-11), 17.8 (C-6), 15.7 (C-20). FAB HRMS m/z calcd for C 18 H 30 O 4 Na (M C C Na) , found Methyl (8R,13R)-8a,13-epoxy-17-oxo-14,15-dinorlabdan-19-oate (9b). PCC (167 mg, 1.2 equiv) was added to a solution of 6b (0.2 g, 0.64 mmol) in CH 2 Cl 2 (7 ml) under argon atmosphere, and the mixture was stirred at room temperature for 1 h. Then it was filtered through a short silica gel column (eluted with ether) and the solvent was evaporated under reduced pressure, affording 179 mg (90%) of the aldehyde 9b. [a] D ZC (c 1.2, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3428, 2948, 2874, 2851, 1725, 1675, 1465, 1449, 1377, 1329, 1232, 1153, 1093, 1032, 984, 942, 820, H NMR (CDCl 3, 400 MHz) d: 0.63 (3H, s, Me-20), (2H, m), 1.14 (3H, d, JZ6.2 Hz, Me-16), 1.18 (3H, s, Me-18), (11H, m), (3H, m), 3.60 (3H,s, COOMe), 4.06 (1H, dc, JZ6.3, 3.0 Hz, H-13), 9.70 (1H, s, H-17). 13 C NMR (CDCl 3, 100 MHz) d: (C-17), 177,5 (COOMe), 78.6 (C-8), 66.8 (C-13), 56.4* (C-9), 51.3 (COO CH 3 ), 50.1* (C-5), 43.8 (C-4), 39.2 (C-1), 38.3 (C-10), 38.1 (C-3), 35.2 (C-12), 30.4 (C-6), 28.6 (C-18), 22.7 (C-16), 21.1 (C-7), 19.1 (C-2), 15.7 (C-11), 13.1 (Me-10). FAB HRMS m/z calcd for C 19 H 30 O 4 Na (M C CNa) , found Methyl (13R)-13-Hydroxy-14,15-dinor-8(17)-labden-19-oate (10b). Hydrazine hydrate (0.1 ml) and KOH (104 mg, 6 equiv) was added to a solution of 9b (100 mg, 0.31 mmol) in triethyleneglycol (5 ml) and the mixture was heated at 160 8C for 2 h. Then the reaction mixture was diluted with water (5 ml) and extracted with tbuome (3! 10 ml). The combined organic phases were washed with HCl 1 N (2!10 ml) and brine (3!10 ml), and dried over anhydrous Na 2 SO 4, filtered, and evaporated. The residue was treated with a solution of diazomethane in ether to give 91 mg (95%) of 10b. [a] D ZC (c 3.5, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3441, 3080, 2931, 2851, 1725, 1644, 1465, 1451, 1383, 1332, 1316, 1228, 1187, 1154, 1137, 1091, 1031, 988, 889, 808, 775, H NMR (CDCl 3, 300 MHz) d: 0.53 (3H, s, Me-20), (2H, m), 1.19 (3H, d, JZ6.2 Hz, Me-16), 1.20 (3H, s, Me-18), (11H, m), 2.19 (1H,dc, JZ12.0, 1.5 Hz), (1H, m), 3.63 (3H, s, COOMe), 3.79 (1H, m, H-13), 4.56 (1H, s, H-17), 4.87 (1H, s, H-17). 13 C NMR (CDCl 3,75MHz)d: (C-19), (C-8), (C-17), 68.5 (C-13), 56.5 (C-9), 56.2 (C-5), 51.2 (COOMe), 44.4 (C-4), 40.4 (C-10), 39.4 (C-1), 38.9 (C-3), 38.5 (C-12), 38.4 (C-7), 28.9 (C-18), 26.4 (C-6), 23.8 (C-16), 20.1 (C-2), 19.8 (C11), 12.6 (C-20). FAB HRMS m/z calcd for C 19 H 32 O 3 Na (M C CNa) , found Methyl 13-oxo-14,15-dinor-8(17)-labden-19-oate (2). A 2 M solution of Jones reagent (8 ml) was added slowly to a stirred solution of 10b (0.2 g, 0.75 mmol) in acetone (10 ml) at 0 8C, until orange colour permanence, and the mixture was further stirred at room temperature for 1 h. Then it was poured into H 2 O-ice (5 ml) and extracted with Et 2 O(3!10 ml). The organic phase was successively washed with satd NaHCO 3 (2!10 ml) and brine (2! 10 ml), dried over anhydrous Na 2 SO 4 and evaporated to give a crude which after treating with a diazomethane solution in tbuome afforded 2 as a colourless oil (186 mg, 89%) (13R)-8a,13-Epoxy-17-oxo-14,15.19-trinorlabdan- 4b-yl formate (11b). PCC (250 mg) was added to a solution of 8b (0.3 g, 0.96 mmol) in CH 2 Cl 2 (10 ml) under argon atmosphere and the mixture was stirred at room temperature for 1 h. Following the same work-up used for 15, 268 mg of formate 11b was obtained (90%). [a] D ZK3.368 (c 0.95, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 2931, 2871, 1722, 1644, 1448, 1378, 1254, 1203, 1175, 1114, 1062, 1020, 865, H NMR (CDCl 3, 400 MHz) d: 0.89 (3H, s, Me-20), (3H, m), 1.16 (3H, d, JZ6.1 Hz, Me-16), 1.31 (1H, bt, JZ13.7 Hz), 1.55 (3H, s, Me-18), (8H, m), 2.37 (1H, dt, JZ12.9, 3.2 Hz), 2.73 (1H, bd, JZ15.0 Hz), 4.08 (1H, m, H-13), 8.00 (1H, s, OCHO), 9.75 (1H, s, H-17). 13 C NMR (CDCl 3, 100 MHz) d: (C-17), (OCHO), 83.8 (C-4), 78.4 (C-8), 66.4 (C-13), 55.9* (C-9), 49.6* (C-5), 37.9 (C-12), 37.7 (C-10), 35.6 (C-3), 34.2 (C-1), (C-7), 26.2 (C-18), 22.7 (C-16), 19.2 (C-2), 17.5 (C-11), 15.4 (C-6), 14.8 (Me-10). FAB HRMS m/z calcd for C 18 H 28 O 4 Na (M C CNa) , found (13R)-14,15,19-Trinor-8(17)-labden-4b,13-diol (12b). Hydrazine hydrate (0.1 ml) and KOH (104 mg, 6 equiv) was added to a solution of 11b (100 mg, 0.31 mmol) in triethyleneglycol (5 ml) and the mixture was heated at 160 8C for 2 h. Following the same work-up used for 9a b, and after chromatography (hexane ether 3:7) 82 mg of 12b was obtained (95%). [a] D ZC (c 0.35, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3408, 2931, 2847, 1643, 1454, 1374, 1263, 1186, 1125, 1089, 1021, 938, 888, 803, H NMR (CDCl 3, 400 MHz) d: 0.86 (3H, s, Me-20), 1.09 (1H, dt, JZ14.7, 5.5 Hz), 1.20 (3H, s, Me-18), 1.21 (3H, d, JZ6.2 Hz, Me-16), (15H, m), 2.03 (1H, dc, JZ12.9, 5.1 Hz), 2.47 (1H, dc, JZ12.9, 2.3 Hz), 3.80 (1H, m, H-13), 4.55 (1H, s, H-17), 4.90 (1H, d, JZ1.3 Hz, H-17). 13 C NMR (CDCl 3,75MHz)d: (C-8), (C-17), 72.4 (C-4), 69.0 (C-13), 56.2 (C-9), 53.8 (C-5), 41.0

6 842 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) (C-12), 39.7 (C-10), 38.7 (C-1), 38.7 (C-3), 37.9 (C-7), 31.1 (C-18), 23.4 (C-11), 23.6 (C-16), 19.9 (C-2), 18.6 (C-6), 14.1 (C-20). FAB HRMS m/z calcd for C 17 H 30 O 2 Na (M C C Na) , found b-Hydroxy-14,15,19-trinor-8(17)-labden-13-one (13). PCC (48 mg, 1.2 equiv) was added to a solution of 12b (50 mg, 0.19 mmol) in CH 2 Cl 2 (5 ml) under argon atmosphere, and the mixture was stirred at room temperature for 45 min. Following the same work-up used for 6a b, 45 mg of 13 was obtained (90%). [a] D ZC (c 0.25, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3499, 3078, 2930, 2849, 1713, 1643, 1453, 1374, 1261, 1185, 1162, 1096, 1022, 940, 884, H NMR (CDCl 3, 400 MHz) d: 0.87 (3H, s, Me- 20), (3H, m), 1.19 (3H, s, Me-18), (10H, m), 2.00 (1H, dt, JZ13.1, 5.0 Hz), 2.13 (3H, s, H-16), (1H, m), 2.45 (1H, bd, JZ11.5 Hz), 2.60 (1H, ddd, JZ9.7, 5.8, 3.9 Hz), 4.49 (1H, s, H-17), 4.89 (1H, s, H-17). 13 C NMR (CDCl 3, 75 MHz) d: (C-13), (C-8), (C-17), 72.3 (C-4), 55.4 (C-9), 53.7 (C-5), 43.0 (C-12), 39.7 (C-10), 41.0 (C-3), 38.5 (C-1), 37.8 (C-7), 31.1 (C-18), 30.1 (C-16), 23.3 (C-11), 18.6 (C-2), 17.5 (C-6), 14.0 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 2 Na (M C C Na) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15-dinorlabdan-19-al (15). PCC (1.76 g, 1.2 equiv) was added to a solution of 14 (2.0 g, 6.79 mmol) in CH 2 Cl 2 (35 ml) under argon atmosphere, and the mixture was stirred at room temperature for 30 min. Then it was filtered through a short silica gel column (eluted with ether) and solvent was evaporated under reduced pressure affording 1.68 g of the aldehyde 15 (85%). [a] D ZC (c 0.4, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 2943, 2870, 1717, 1447, 1393, 1269, 1215, 1194, 1159, 1107, 1067, 1029, 979, 921, 865, 818, H NMR (CDCl 3, 400 MHz) d: 0.76 (3H, s, Me-20), 1.05 (3H, s, CH 3 K18), (7H, m), 1.43 (3H, s, Me- 16), (8H, m), (2H, m), 2.17 (1H, bd, JZ14.2 Hz), 3.42 (1H, d, JZ7.1 Hz, H-17), 4.29 (1H, d, JZ7.1, H-17), 9.72 (1H, s, H-19). 13 C NMR (CDCl 3, 100 MHz) d: (C-19), (C-13), 82.2 (C-8), 73.4 (C-17), 56.0 (C-9), 52.3 (C-5), 48.3 (C-4), 37.7 (C-10), 38.3 (C-12), (C-3), 36.0 (C-1), 34.3 (C-7), 24.4 (C-18), 24.2 (C-16), 19.8 (C-2), 18.2 (C-6), 17.9 (C-11), 13.8 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 3 Na (M C CNa) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinorlabdan-4b-yl formate (7). A solution of MCPBA (2.5 g, 2.5 equiv) in CH 2 Cl 2 (20 ml) was added to a solution of the aldehyde 15 (1.1 g, 3.76 mmol) in CH 2 Cl 2 (20 ml) and the mixture was stirred under reflux for 16 h. The solvent was evaporated under reduced pressure to give a crude which was dissolved in tbuome (100 ml) and washed with satd NaHCO 3 (5!30 ml), and brine (3!30 ml). The organic phase was dried (Na 2 SO 4 ) and concentrated to give a crude, which after chromatography on silica gel (25% ether hexane) afforded 0.81 g of 7 (70%). [a] D ZC (c 0.75, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 2985, 2935, 2872, 1721, 1449, 1386, 1266, 1204, 1161, 1111, 1027, 866, H NMR (CDCl 3, 400 MHz) d: (3H, m), 0.99 (3H, s, Me-20), 1.33 (1H, dt, JZ14.3, 4.4 Hz), 1.42 (3H, s, Me-16), (3H, m), 1.56 (3H, s, Me-18), (8H, m), 2.68 (1H, bd, JZ14.7 Hz), 3.40 (1H, d, JZ7.1 Hz, H-17), 4.37 (1H, d, JZ7.1 Hz, H-17), 8.02 (1H, s, OCHO). 13 C NMR (CDCl 3, 100 MHz) d: (OCHO), (C-13), 83.9 (C-4), 82.3 (C-8), 73.5 (C-17), 55.7 (C-9), 52.9 (C-5), 37.3 (C-10), 38.0 (C-12), 35.9 (C-1), 35.9 (C-3), 35.7 (C-7), 27.2 (C-18), 24.2 (C-16), 19.4 (C-2), 17.4 (C-6), 17.3 (C-11), 14.5 (C-20). FAB HRMS m/z calcd for C 18 H 28 O 4 Na (M C CNa) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinor- 4(18)-labdene (16). A solution of formate 7 (0.5 g, 1.66 mmol) in collidine (6 ml) was stirred under reflux for 12 h. The mixture was cooled to room temperature, diluted with tbuome (20 ml) and washed with 2 N HCl (5!10 ml) and brine (3!20 ml). The organic layer was dried and concentrated under reduced pressure to afford 373 mg (90%) of the nor-olefin 16. [a] D ZC498 (c 3.0, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3079, 2931, 2869, 1789, 1738, 1646, 1451, 1385, 1238, 1206, 1157, 1111, 1069, 1030, 979, 916, 890, 867, H NMR (CDCl 3, 400 MHz) d: 0.70 (3H, s, Me-20), (1H, m), 1.16 (1H, dt, JZ 12.8, 4.9 Hz), 1.42 (3H, s, Me-16), (12H, m), 1.95 (1H, dt, JZ11.1, 3.2 Hz), 2.29 (1H, bd, JZ10.7 Hz), 3.41 (1H, d, JZ7.0 Hz, H-17), 4.32 (1H, d, JZ7.1 Hz, H-17), 4.42 (1H, s, H-18), 4.72 (1H, s, H-18). 13 C NMR (CDCl 3, 100 MHz) d: (C-4), (C-13), (C-18), 82.6 (C-8), 73.6 (C-17), 51.5 (C-9), 51.5 (C-5), 38.6 (C-3), 36.4 (C-12), 36.3 (C-1), 35.1 (C-7), 29.8 (C-10), 24.3 (C-16), 22.7 (C-6), 22.5 (C-2), 18.4 (C-11), 12.6 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 2 Na (M C CNa) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinor- 4(18)-labden-3a-ol (17). A mixture of 16 (250 mg, 0.89 mmol) and SeO 2 (74 mg, 0.75 equiv) in EtOH (10 ml) was added at 0 8C to a 5.5 M solution of t-buooh in undecane (0.162 ml, 1 equiv). The mixture was stirred at room temperature for 12 h, the solvent evaporated and the residue was fractionated into t-buome (30 ml) and water (10 ml). The organic extract was washed with water (3!30 ml) and brine (3!30 ml) and dried (Na 2 SO 4 ), filtered and evaporated to give a crude which after chromatography (hexane ether, 3:7) gave 136 mg (55%) of 17 as a colourless oil. [a] D ZC (c 2.0, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3442, 3076, 2982, 2937, 2871, 1788, 1712, 1650, 1448, 1386, 1268, 1236, 1199, 1166, 1148, 1113, 1099, 1068, 1028, 984, 967, 940, 894, 865, 817, 736, 701, 680, H NMR (CDCl 3, 400 MHz) d: 0.67 (3H, s, Me-20), (2H, m), 1.42 (3H, s, Me- 16), (10H, m), (2H, m), 2.42 (1H, bdd, JZ12.0, 1.6 Hz), 3.41 (1H, d, JZ7.0 Hz, H-17), 4.27 (1H, t, JZ2.8 Hz, H-3), 4.31 (1H, d, JZ7.1 Hz, H-17), 4.57 (1H, bs, H-18), 4.96 (1H, bs, H-18). 13 C NMR (CDCl 3, 100 MHz) d: (C-4), (C-18), (C-13), 82.5 (C-8), 73.6 (C-17), 72.9 (C-3), 51.2 (C-9), 45.0 (C-5), 39.2 (C-10), 36.2 (C-12), 34.9 (C-1), 32.6 (C-7), 29.1 (C-2), 24.3 (C-16), 22.0 (C-6), 18.4 (C-11), 11.8 (C-20). FAB HRMS m/z calcd for C 16 H 26 O 3 Na (M C CNa) , found (4S,8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinorlabdan-3-one (18). PCC (126 mg, 1.2 equiv) was added to a stirred solution of 17 (136 mg, 0.49 mmol) in

7 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) CH 2 Cl 2 (35 ml) under argon atmosphere, and the mixture was stirred at room temperature for 45 min. Then it was filtered through a short silica gel column (eluted with ether) and the solvent was evaporated under reduced pressure affording a crude which was dissolved in THF (30 ml) and then Raney nickel (1.5 g) (Fluka, cat no ) was added. The mixture was stirred at room temperature for 30 min and filtered through a silica gel bed, affording a crude which was dissolved in a solution of MeONa (40 mg, 1.5 equiv) in MeOH (10 ml). The mixture was stirred at reflux for 1 h and the solvent was evaporated at vacuum, the crude was dissolved in ether (30 ml) and washed with water (3! 30 ml) and brine (3!30 ml) and the ethereal phase was dried over anhydrous Na 2 SO 4, filtered and evaporated to give a crude which after chromatography (hexane ether, 7:3) yielded 79 mg (58%) of 18. [a] D ZC25.28 (c 0.6, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 2980, 2949, 2939, 2867, 1708, 1448, 1392, 1367, 1352, 1332, 1305, 1269, 1234, 1199, 1179, 1163, 1134, 1112, 1089, 1066, 1021, 977, 941, 922, 894, 866, 817, H NMR (CDCl 3, 300 MHz) d: 1.00 (3H, d, JZ6.6 Hz, Me-18), 1.07 (3H, s, Me-20), (2H, m), 1.41 (3H, s, Me-16), (2H, m), (7H, m), 1.99 (1H, ddd, JZ13.3, 6.7, 2.4 Hz), 2.26 (1H, dda, JZ12.7, 5.9 Hz), 2.36 (1H, dd, JZ5.6, 2.5 Hz), 2.42 (1H, ddd, JZ13.3, 6.7, 0.8 Hz), 3.43 (1H, d, JZ 7.0 Hz, H-17), 4.35 (1H, d, JZ7.0 Hz, H-17). 13 C NMR (CDCl 3, 75 MHz) d: (C-3), (C-13), 82.1 (C-8), 73.5 (C-17), 52.8 (C-9), 51.2 (C-5), 44.7 (C-4), 38.4 (C-12), 37.1 (C-2), 36.9 (C-10), 36.1 (C-1), 35.1 (C-7), 24.2 (C-16), 23.6 (C-6), 18.3 (C-11), 12.5 (C-20), 11.8 (C-18). FAB HRMS m/z calcd for C 17 H 26 O 3 Na (M C CNa) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinorlabdan-4b-ol (19). To a solution of formate 7 (0.7 g, 2.27 mmol) in MeOH (15 ml) a 2 N solution of KOH in MeOH (7 ml) was added and the mixture was refluxed for 1 h. The solvent was evaporated and the crude was diluted with ether (50 ml) and washed with water (3!30 ml) and brine (3!30 ml). The organic layer was dried and concentrated under reduced pressure to afford 0.64 g (95%) of the nor-alcohol 19. [a] D ZC (c 0.5, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3485, 2935, 2872, 1713, 1453, 1385, 1304, 1267, 1189, 1164, 1098, 1066, 1027, 976, 937, 922, 865, 815, 786, 744, H NMR (CDCl 3, 400 MHz) d: 0.94 (2H, dt, JZ13.2, 3.8 Hz), 1.03 (3H, s, Me-20), 1.07 (1H, dd, JZ12.5, 2.1 Hz), 1.21 (3H, s, Me-18), (2H, m), 1.42 (3H, s, Me-16), (2H, m), (10H, m), 3.39 (1H, d, JZ7.1 Hz, H-17), 4.37 (1H, d, JZ7.1 Hz, H-17). 13 C NMR (CDCl 3, 100 MHz) d: (C-13), 82.5 (C-8), 73.7 (C-17), 71.9 (C-4), 53.9 (C-9), 52.8 (C-5), 37.2 (C-10), 41.0 (C-3), 38.4 (C-12), 36.1 (C-1), 35.8 (C-7), (C-18), 24.3 (C-16), (C-6), 17.6 (C-2), 17.5 (C-11), 14.4 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 3 Na (M C CNa) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinor-4- labdene (20). MsCl (0.25 ml, 1.5 equiv) was added to a solution of alcohol 19 (0.6 g, 2.14 mmol) in pyridine The Raney nickel was weighed as an aqueous slurry after removing four fifty of water. (10 ml) at 0 8C and the mixture was stirred at room temperature for 16 h. Then the mixture was poured into ice and diluted with ether (50 ml). The organic layer was washed with 2 N HCl (3!20 ml), water (3!15 ml), saturated NaHCO 3 (3!15 ml) and brine (3!10 ml). Then it was dried (anh. Na 2 SO 4 ) and concentrated under reduced pressure to give a crude which was after chromatography on silica gel (hexane ether 85:15) afforded 0.51 g (90%) of a 4:1 mixture of nor-olefins 20 and : [a] D ZC73.98 (c 2.5, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 2934, 2869, 1799, 1728, 1575, 1449, 1386, 1268, 1239, 1206, 1166, 1130, 1097, 1029, 891, 865, 819, H NMR (CDCl 3, 300 MHz) d: 0.99 (3H, s, Me-20), (2H, m), 1.41 (3H, s, Me-16), 1.61 (3H, s, Me-18), (14H, m), 2.59 (1H, bdd, JZ10.5, 3.3 Hz), 3.48 (1H, dd, JZ7.0, 1.2 Hz, H-17), 4.40 (1H, d, JZ7.0 Hz, H-17). 13 C NMR (CDCl 3, 75 MHz) d: (C-5), (C-4), (C-13), 82.7 (C-8), 73.3 (C-17), 52.0 (C-9), 38.1 (C-12), 37.7 (C-10), 36.2 (C-3), 35.7 (C-1), 32.7 (C-7), 24.3 (C-16), 23.3 (C-6), 20.1 (C-20), 19.6 (C-18), 18.7 (C-2), 18.6 (C-11). FAB HRMS m/z calcd for C 17 H 24 O 3 Na (M C CNa) , found (8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinor-4- labden-3-one (21). To a solution of the mixture of 20 and 16 (250 mg, 1 mmol) in benzene (15 ml), sodium chromate (216 mg, 1.4 equiv), sodium acetate (390 mg, 5 equiv), acetic anhydride (1.5 ml), and glacial acetic acid (1.2 ml) were added, and the mixture was stirred under reflux for 2.5 h. The reaction mixture was poured into ice and extracted with ether (3!50 ml). The combined organic phases were washed with satd NaHCO 3 (3!30 ml) and brine (2!30 ml). The ethereal phase was dried over anhydrous Na 2 SO 4, filtered and evaporated to give a crude residue which after chromatography (hexane ether, 45:55) yielded 185 mg (70%) of 21. [a] D ZC (c 3.25, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 2946, 2874, 1709, 1667, 1614, 1449, 1386, 1359, 1316, 1267, 1239, 1202, 1166, 1139, 1090, 1029, 990, 972, 920, 898, 863, 821, 751, 699, H NMR (CDCl 3, 300 MHz) d: (1H, m), 1.18 (3H, s, Me-20), 1.44 (3H, s, Me-16), (8H, m), 1.80 (3H, s, Me-18), 1.98 (1H, dt, JZ13.2, 3.0 Hz), 2.41 (1H, dd, JZ5.4, 3.3 Hz), 2.46 (1H, d, JZ5.1 Hz), 2.81 (1H, m), 3.57 (1H, d, JZ6.6 Hz, H-17), 4.43 (1H, d, JZ6.2 Hz, H-17). 13 C NMR (CDCl 3,75MHz)d: (C-3), (C-5), (C-4), (C-13), 81.6 (C-8), 72.9 (C-17), 51.4 (C-9), 39.1 (C-10), 36.0 (C-12), 35.5 (C-2), 33.1 (C-1), 34.0 (C-7), 25.6 (C-6), 24.2 (C-16), 18.1 (C-20), 18.1 (C-11), 11.2 (C-18). FAB HRMS m/z calcd for C 17 H 24 O 3 Na (M C CNa) , found (4S,8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinorlabdan-3-one (18). To a solution of ketone 21 (250 mg, 0.9 mmol) in 20 ml of liquid NH 3 was added under an argon atmosphere 10 ml of THF, 1 ml of tbuoh and Li (63 mg, 10 equiv) at K78 8C. The mixture was stirred at K45 8C for 3 h. Then the cooling bath was removed to allow the solution to warm to room temperature. The mixture was diluted with ether (50 ml) and washed with water (3!25 ml) and brine (3!25 ml) and the ethereal phase was dried over anhydrous Na 2 SO 4, filtered and evaporated to give a crude residue which after

8 844 E. J. Alvarez-Manzaneda et al. / Tetrahedron 61 (2005) chromatography (hexane ether, 7:3) yielded 200 mg (85%) of (4S,8R,13S)-8a,13:13,17-Diepoxy-14,15,19-trinorlabdan-3b-ol (22). Sodium borohydride (16 mg, 4 equiv) was added to a solution of ketone 18 (120 mg, 0.43 mmol) in EtOH (5 ml) and the mixture was stirred at room temperature for 1 h. Then 20 ml of ether was added and the organic phase was washed with water (5!10 ml) and brine (3!10 ml), and the ethereal phase was dried over anhydrous Na 2 SO 4, filtered and evaporated to give 111 mg (92%) of 22. [a] D ZC (c 0.25, CH 2 Cl 2 ). IR (film, cm K1 ) n max : 3446, 2933, 2870, 1727, 1453, 1386, 1267, 1237, 1206, 1164, 1139, 1106, 1081, 1027, 973, 915, 894, 864, 819, H NMR (CDCl 3, 300 MHz) d: 0.87 (3H, s, Me-20), 1.00 (3H, d, JZ6.4 Hz, Me-18), (1H, m), (2H, m), 1.43 (3H, s, Me-16), (14H, m), 3.14 (1H, ddd, JZ11.1, 9.8, 5.1 Hz, H-3), 3.41 (1H, d, JZ7.0, 2.1 Hz, H-17), 4.33 (1H, d, JZ7.0 Hz, H-17). 13 C NMR (CDCl 3,75MHz)d: (C-13), 82.6 (C-8), 76.4 (C-3), 73.7 (C-17), 51.6 (C-9), 50.8 (C-5), 38.5 (C-4), 36.7 (C-10), 36.3 (C-12), 36.2 (C-1), 30.3 (C-2), 35.5 (C-7), 22.3 (C-16), 22.3 (C-6), 17.9 (C-11), 15.3 (C-18), 12.9 (C-20). FAB HRMS m/z calcd for C 17 H 28 O 3 Na (M C CNa) , found Acknowledgements The authors thank the Spanish Ministry of Science and Technology for its financial support (Project PPQ ). References and notes 1. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda, R.; Chahboun, R.; Meneses, R.; Cuerva, J. M.; Aparicio, M.; Romera, J. L. Org. Lett. 2001, 3, Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S. Tetrahedron 1993, 49, Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda, R.; Chahboun, R.; Meneses, R.; Aparicio, M. Synlett 1999, Barrero, A. F.; Alvarez-Manzaneda, E. J.; Romera Santiago, J. L.; Chahboun, R. Synlett 2003, (a) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. Chem. Lett. 1988, (b) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989, 54, (c) Kotsuki, H. Synlett 1992, (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, (e) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990, 46, (f) Kim, Y.; Mundy, B. P. J. Org. Chem. 1982, 47, (g) Masaki, Y.; Serizawa, Y.; Nagata, K.; Kaji, K. Chem. Lett. 1983, (h) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, (i) Fotsch, C. H.; Chamberlin, A. R. J. Org. Chem. 1991, 56, Szmant, H. H. Angew. Chem. Int. Ed. 1968, 7, Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Meneses, R. Synlett 1999, Chiu, C. K.-F.; Govindan, S. V.; Fuchs, P. L. J. Org. Chem. 1994, 59,