Alternative Access to Functionalized 2,8-Ethanonoradamantane Derivatives

7a-(Methoxycarbonyl)-N-methyl-1,3a,5,6,7,7a-hexahydro-4H-1,4,6-(epiethane[1,1,2]triyl)indene-4,9-dicarboximide has been prepared through a modification of a previous synthetic sequence, in which the benzyloxymethyl hydroxyl protecting group has been replaced by methoxymethyl, to avoid the apparent formation of a benzyl ester derivative as a side product. The overall yield of the new synthetic sequence is comparable to the previous one. Two advantages of the new procedure are: (a) no benzyl ester was formed and (b) a stereoisomeric mixture of syn- and anti-alcohols at the beginning of the synthetic sequence could be separated and the rest of the synthesis could be carried out with the main syn-stereoisomer instead of the corresponding stereoisomeric mixture as it was the case in the previous process. Additionally, several functional 2,8-ethanonoradamantane derivatives have been prepared.


Introduction
Some time ago, the synthesis of the functionalized polycycle 13 as a new scaffold for the preparation of compounds with potential biological activity was described [1]. Later on, improvements of the synthesis of 13 were performed [2,3], the highly-optimized synthetic route to this compound is shown in Scheme 1. During purification of this compound, implying a sublimation process, the presence of a benzyl ester derivative, probably 14, in the non-sublimed residue was suggested by 1 H-NMR. To solve this problem, an alternative synthesis of polycycle 13 was planned in which the methoxymethyl hydroxyl-protecting group would be used instead of the benzyloxymethyl one (Scheme 2).

Results and Discussion
The reaction of anthrone with methoxymethyl chloride, using NaH as the base, and following a procedure similar to that used to prepare anthracene 2 [4,5], gave 9-methoxymethylanthracene 16. The reaction of N-methylmaleimide 1 with anthracene 16 gave the corresponding Diels-Alder adduct 17. The reaction of 17 with 3-chloro-2-chloromethyl-1-propene using lithium diisopropylamide as the base gave the methylenecyclopentane derivative 18 in 70% yield. Hydroboration of 18 with the borane-THF complex in THF followed by hydrogen peroxide oxidation of the intermediate boranes under strongly basic conditions gave a stereoisomeric mixture of alcohols 19 and 20 in a ratio 19/20 = 2.8:1 ( 1 H-NMR). Worthy of note, this mixture was separated by silica gel column chromatography and each stereoisomer could be fully characterized. In the previous synthetic sequence using the benzyloxymethyl hydroxyl protecting group, the stereoisomeric mixture of alcohols 5 could not be separated and, consequently, the next steps in that synthetic sequence were carried out with the corresponding stereoisomeric mixtures. In the present work, however, the synthetic sequence of Scheme 2 was carried out with the main stereoisomeric racemate syn-alcohol 19.
As previously observed for the main syn-stereoisomer of 5 [2], the 1 H-NMR data of the syn-alcohol 19 suggests that exists mainly in the shown envelope conformation, the 16-Hn (δ = 0.92 ppm) and 18-Hn (δ = 1.14 ppm) protons appearing quite shielded by the aromatic ring as triplets ( 2 J(HH) = 3 J(HH) = 12. 8 Hz) due to the similar value of the geminal and vicinal (dihedral angle close to 180°) coupling constants. The 16-Hx (δ = 2.16 ppm) and 18-Hx (δ = 2.28 ppm) protons of alcohol 19 are not so affected by the aromatic ring. In the case of the minor anti-stereoisomer 20, 17-H is the more shielded proton (δ = 1.09-1.20 ppm). In this case, the 16-Hn (δ = 1.71 ppm) and 18-Hn (δ = 2.12 ppm) protons are not significantly affected by the aromatic ring. However, the vicinal coupling constants of 16-Hx (δ = 1.83-1.89 ppm, 3 J(H,H) = 6. 8 Hz) and 18-Hx (δ = 1.79-1.85 ppm, 3 J(H,H) = 6. 8 Hz), suggest the contribution of other conformations apart from that shown in Scheme 3, for which a higher value of the above vicinal coupling constants would be expected. The mesylation of alcohol 19 under the usual conditions gave, after purification of the crude product by silica gel column chromatography, mesylate 21, in which the methoxymethyl-protecting group had been hydrolyzed. However, purification of the crude mesylate by basic aluminum oxide column chromatography gave the desired mesylate 22 in high yield. The reaction of mesylate 22 with powdered sodium iodide in refluxing acetone gave iodide 23 in good yield. In one occasion, the methoxymethyl group of compound 23 was hydrolyzed on standing ( 1 H-NMR), thus, it is recommended not to stock this compound. In the sequence of Scheme 1, in which the benzyloxymethyl was the hydroxyl-protecting group, no hydrolysis at the level of the corresponding mixtures of mesylates 6 or iodides 7 was ever observed. Reaction of iodide 23 with the sodium salt of methyl 2-oxocyclopentanecarboxylate in DMF gave an essentially 1:1 steroisomeric mixture of the substitution product 24 and the C1′ epimer 25 in 59% yield, after column chromatography. Some elimination product 18 was also isolated in 17% yield. After repeated crystallization of this mixture from EtOAc/hexane, stereoisomer 24 was obtained in pure form. The structure of 24 was established by X-ray diffraction analysis ( Figure 1). Although compounds 17 to 27 of this synthetic sequence are racemic, the unit cell of the crystal used for the X-ray analysis of 24 contained four molecules of the same enantiomer whose absolute configuration could not be established from the X-ray data [6]. Reaction of the stereoisomeric mixture of keto esters 24 and 25 with trimethylsilyl triflate gave the corresponding mixture of trimethylsilyl enol ethers that was oxidized without purification with The mesylation of alcohol 19 under the usual conditions gave, after purification of the crude product by silica gel column chromatography, mesylate 21, in which the methoxymethyl-protecting group had been hydrolyzed. However, purification of the crude mesylate by basic aluminum oxide column chromatography gave the desired mesylate 22 in high yield. The reaction of mesylate 22 with powdered sodium iodide in refluxing acetone gave iodide 23 in good yield. In one occasion, the methoxymethyl group of compound 23 was hydrolyzed on standing ( 1 H-NMR), thus, it is recommended not to stock this compound. In the sequence of Scheme 1, in which the benzyloxymethyl was the hydroxyl-protecting group, no hydrolysis at the level of the corresponding mixtures of mesylates 6 or iodides 7 was ever observed. Reaction of iodide 23 with the sodium salt of methyl 2-oxocyclopentanecarboxylate in DMF gave an essentially 1:1 steroisomeric mixture of the substitution product 24 and the C1 epimer 25 in 59% yield, after column chromatography. Some elimination product 18 was also isolated in 17% yield. After repeated crystallization of this mixture from EtOAc/hexane, stereoisomer 24 was obtained in pure form. The structure of 24 was established by X-ray diffraction analysis ( Figure 1). Although compounds 17 to 27 of this synthetic sequence are racemic, the unit cell of the crystal used for the X-ray analysis of 24 contained four molecules of the same enantiomer whose absolute configuration could not be established from the X-ray data [6].
Reaction of the stereoisomeric mixture of keto esters 24 and 25 with trimethylsilyl triflate gave the corresponding mixture of trimethylsilyl enol ethers that was oxidized without purification with Pd(OAc) 2 in DMSO [7] to give the stereoisomeric mixture of cyclopentenones 26 and 27, in 75% overall yield. For characterization purposes, the same transformation was carried out with pure stereoisomer 24, thus, obtaining pure stereoisomer 26. Pd(OAc)2 in DMSO [7] to give the stereoisomeric mixture of cyclopentenones 26 and 27, in 75% overall yield. For characterization purposes, the same transformation was carried out with pure stereoisomer 24, thus, obtaining pure stereoisomer 26. Transformation of the stereoisomeric mixture of 26 and 27 to polycycle 13 was carried out without isolating any of the intermediates, as was the case in the sequence of Scheme 1. Thus, reduction of the 26 and 27 mixture with NaBH4 in the presence of CeCl3·7H2O (Luche conditions) [8] gave the diastereomeric mixture of allylic alcohols 28 which on heating in refluxing benzene in the presence of a catalytic amount of p-toluenesulfonic acid was dehydrated with simultaneous deprotection of the methoxymethyl group to compound 29. The oxide anion accelerated retro Diels-Alder reaction of 29 leading to anthrone and maleimide 12 was carried out as usual by treatment with KH in THF [9]. Maleimide 12 experience an intramolecular Diels-Alder reaction producing imide 13 in 30% overall yield from the mixture of 24 and 25. The overall yield of the synthetic sequence of Scheme 2 (5.1%) is comparable to that of Scheme 1 (7.2%). As expected, no formation of 14 was observed in this case and, worthy of note, the sequence of Scheme 2 made possible the characterization of all of the intermediates as pure racemates. The lower stability of the methoxymethyl hydroxyl-protecting group compared with the benzyloxymethyl required using neutral aluminum oxide instead of silica gel during the column chromatography purification.
Additionally, the imide function of compound 13 has been transformed into the corresponding diacid (compound 32, Scheme 3), a transformation that is worth of mention. Thus, basic hydrolysis of 13 took place smoothly at room temperature leading cleanly to the amide acid 30. This result was surprising taking into account that both α-carbon atoms of the imide function are quaternary. In fact, only a closely-related example of this kind of hydrolysis has been previously described, although in this case the reaction was carried out at 50 °C [10]. Under these conditions the ester function, whose α-carbon atom is also quaternary, was not hydrolyzed. We consider that the easy hydrolysis of imide 13 might take place as follow: (i) intramolecular retro-Diels-Alder to revert to maleimide 12; (ii) fast basic hydrolysis of maleimide 12, in accord with our previous experience with related maleimides [2]; and (iii) intramolecular Diels-Alder reaction to give 30. Under more forcing basic conditions the ester function of 30 was fully hydrolyzed while only partial hydrolysis of the amide function was observed. However, amide acid 30 was transformed into anhydride 31 by the reaction with NaNO2 in a 1:1 mixture of AcOH and Ac2O at room temperature. It is known that N-alkyl-N-nitrosoamides decompose thermally to alkyl esters [11,12]. In the present case, the expected ester from the decomposition of the N-methyl-N-nitrosoamide, on reaction with the neighbor carboxylate under the reaction conditions would give anhydride 31. Alternatively, addition of the carboxylate group to the carbonyl of the neighbor N-nitrosoamide followed by elimination of the N-methyl-N-nitrosoamide anion would give Transformation of the stereoisomeric mixture of 26 and 27 to polycycle 13 was carried out without isolating any of the intermediates, as was the case in the sequence of Scheme 1. Thus, reduction of the 26 and 27 mixture with NaBH 4 in the presence of CeCl 3 ·7H 2 O (Luche conditions) [8] gave the diastereomeric mixture of allylic alcohols 28 which on heating in refluxing benzene in the presence of a catalytic amount of p-toluenesulfonic acid was dehydrated with simultaneous deprotection of the methoxymethyl group to compound 29. The oxide anion accelerated retro Diels-Alder reaction of 29 leading to anthrone and maleimide 12 was carried out as usual by treatment with KH in THF [9]. Maleimide 12 experience an intramolecular Diels-Alder reaction producing imide 13 in 30% overall yield from the mixture of 24 and 25. The overall yield of the synthetic sequence of Scheme 2 (5.1%) is comparable to that of Scheme 1 (7.2%). As expected, no formation of 14 was observed in this case and, worthy of note, the sequence of Scheme 2 made possible the characterization of all of the intermediates as pure racemates. The lower stability of the methoxymethyl hydroxyl-protecting group compared with the benzyloxymethyl required using neutral aluminum oxide instead of silica gel during the column chromatography purification.
Additionally, the imide function of compound 13 has been transformed into the corresponding diacid (compound 32, Scheme 3), a transformation that is worth of mention. Thus, basic hydrolysis of 13 took place smoothly at room temperature leading cleanly to the amide acid 30. This result was surprising taking into account that both α-carbon atoms of the imide function are quaternary. In fact, only a closely-related example of this kind of hydrolysis has been previously described, although in this case the reaction was carried out at 50 • C [10]. Under these conditions the ester function, whose α-carbon atom is also quaternary, was not hydrolyzed. We consider that the easy hydrolysis of imide 13 might take place as follow: (i) intramolecular retro-Diels-Alder to revert to maleimide 12; (ii) fast basic hydrolysis of maleimide 12, in accord with our previous experience with related maleimides [2]; and (iii) intramolecular Diels-Alder reaction to give 30. Under more forcing basic conditions the ester function of 30 was fully hydrolyzed while only partial hydrolysis of the amide function was observed. However, amide acid 30 was transformed into anhydride 31 by the reaction with NaNO 2 in a 1:1 mixture of AcOH and Ac 2 O at room temperature. It is known that N-alkyl-N-nitrosoamides decompose thermally to alkyl esters [11,12]. In the present case, the expected ester from the decomposition of the N-methyl-N-nitrosoamide, on reaction with the neighbor carboxylate under the reaction conditions would give anhydride 31. Alternatively, addition of the carboxylate group to the carbonyl of the neighbor N-nitrosoamide followed by elimination of the N-methyl-N-nitrosoamide anion would give anhydride 31. Following a related procedure [13], heating anhydride 31 in water under reflux, diacid 32 was obtained in high yield.

General
Melting points were determined in open capillary tubes with a MFB 595010M Gallenkamp melting point apparatus (Weiss Gallenkamp, Loughborough, UK). All new compounds were fully characterized by their analytical [melting point, elemental analysis and/or accurate mass measurement, spectroscopic data (IR, 1 H-NMR and 13 C-NMR, see supplementary)] and, in the case of compound 24, also X-ray diffraction analysis. Assignments given for the NMR spectra are based on DEPT, COSY, 1 H/ 13 C single quantum correlation (gHSQC sequence) and 1 H/ 13 C multiple bond correlation (gHMBC sequence) spectra and by comparison with previous assignments for the benzyloxymethyl series. 1 H-NMR and 13 C-NMR spectra were recorded on a Varian Mercury 400 (400 MHz for 1 H and 100.6 MHz for 13 C, Varian, Palo Alto, CA, USA) spectrometer. Unless otherwise stated, the NMR spectra have been performed in CDCl 3 . Chemical shifts (δ) are reported in parts per million related to internal TMS or CDCl 3 for 1 H-and 13 C-NMR, respectively. Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; or their combinations. IR spectra were registered on a FTIR Perkin-Elmer Spectrum RX1 spectrometer (Perkin-Elmer, Seer Green, UK) using the attenuated total reflectance (ATR) technique. Absorption values are given as wavenumbers (cm −1 ), the intensity of the absorptions are given as strong (s) . The compounds and reagents were purchased to the following companies: methyl 2-oxocyclopentanecarboxylate, methyl chloromethyl ether, silica gel, 60% NaH and 30% KH, both in mineral oil, and p-toluenesulfonic acid to Sigma-Aldrich; anthrone and Pd(OAc) 2 to Alfa Aesar; N-methylmaleimide and NaBH 4 to TCI; 3-chloro-2-chloromethyl-1-propene to Secant Chemicals, Inc., Winchendon, MA, USA; borane THF complex, n-BuLi in hexanes, neutral aluminum oxide Brockman I (50-200 µm), methanesulfonyl chloride, and NaI to ACROS Organics; diisopropylamine and 35% H 2 O 2 to Panreac; trimethylsilyl triflate, CeCl 3 ·7H 2 O, and NaNO 2 to Fluka. All of them were used without further purification.
9-(Methoxymethoxy)anthracene (16). NaH (60% in mineral oil, 3.09 g, 77 mmol) was added in portions to a cold (0 • C, ice-water bath) solution of anthrone 15 (10.0 g, 51.5 mmol) in anhydrous THF (600 mL) and the mixture was stirred for 45 min at this temperature. Methoxymethyl chloride (5.87 mL, 6.22 g, 77.3 mmol) were added at 0 • C and the mixture was stirred for 12 h at room temperature. Water (250 mL) and EtOAc (300 mL) were added, the organic phase was separated and the aqueous one was extracted with EtOAc (2 × 300 mL). The combined organic phases were washed with water (250 mL) and brine (250 mL), dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo to give 16 (11.6 g, 95% yield). An analytical sample of 16 (105 mg) was obtained as yellow solid by crystallization of a sample of the above product (300 mg) from a mixture of hexane (5 mL) and EtOAc (2 mL

4-[(Methoxy)methoxy)-2-methyl-17-methylene-4,9-dihydro-4,9[1 ,2 ]benzeno-3a,9a-propano-1H-benz[f]isoindole-1,3(2H)-dione (18).
A solution of n-BuLi in hexanes (2.75 mL, 2.5 M, 6.87 mmol) was added dropwise to a cold (−78 • C, acetone/solid CO 2 bath) and magnetically-stirred solution of diisopropylamine (0.97 mL, 6.9 mmol) in anhydrous THF (18 mL) under an Ar atmosphere. When n-BuLi addition was finished, the solution was allowed to warm to 0 • C for 1 h, it was cooled again to −78 • C, and a solution of 17 (1.00 g, 2.86 mmol) in anhydrous THF (18 mL) was added dropwise. Then, the solution was stirred a −78 • C for 15 min and allowed to warm to 0 • C for 1 h. The solution was again cooled to −78 • C and 3-chloro-2-(chloromethyl)-1-propene (0.48 mL 96% content, 498 mg, 3.98 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and it was stirred for three days at this temperature. The mixture was made acidic with aqueous 2 N HCl (8 mL) and was extracted with Et 2 O (3 × 40 mL). The combined organic extracts were dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo to give a brown waxy residue (1.29 g) that was subjected to column chromatography (silica gel 35-70 µm, 65 g, hexane/EtOAc mixtures) to give an elution with hexane/EtOAc 19:1 to 9:1, product 18 (801 mg, 70% yield) as yellow solid. m.p 150-152 • C (EtOAc/hexane); 1   . A solution of the BH 3 THF complex in anhydrous THF (26.5 mL, 1 M in THF, 26.5 mmol) was added dropwise to a cold (0 • C, ice-water bath) and magnetically-stirred solution of compound 18 (4.62 g, 11.5 mmol) in anhydrous THF (150 mL) under an Ar atmosphere, and the reaction mixture was stirred at 0 • C for 4 h. After addition of EtOH (12.7 mL), the mixture was allowed to warm to room temperature, and aqueous solutions of 35% H 2 O 2 (9.4 mL) and 3 M NaOH (14.8 mL) were simultaneously added dropwise in 15 min, occasionally cooling with a water bath, and the reaction mixture was stirred at room temperature for 15 min. Water (50 mL) and EtOAc (100 mL) were added, the organic phase was separated and the aqueous one was extracted with EtOAc (2 × 100 mL). The combined organic phases were dried (anhydrous Na 2 SO 4 ) and concentrated to dryness in vacuo to give a white solid (5.5 g) that was subjected to column chromatography (silica gel 35-70 µm, 165 g, hexane/EtOAc mixtures). Alcohol 19 (1.40 g), a 2:1 mixture of 19 and 20 (1.174 g) and alcohol 20 (330 mg) were successively eluted as white solids with hexane/EtOAc 3:2, 1:1, and 2:3, respectively (overall yield: 2.56 g, 72%, approximate ratio 19/20 = 2.8/1 ( 1 H-NMR). Syn-4-hydroxy-17-(methanesulfonyloxymethyl)-2-methyl-4,9-dihydro-4,9 [1 ,2 ]benzeno-3a,9a-propano-1Hbenz[f]isoindole-1,3(2H)-dione (21). MsCl (60 µL, 86 mg, 0.75 mmol) was added dropwise to a cold solution (0 • C, ice-water bath) of alcohol 19 (300 mg, 0.72 mmol) and anhydrous Et 3 N (0.23 mL, 166 mg, 1.65 mmol) in anhydrous CH 2 Cl 2 (14 mL) under an Ar atmosphere, and the mixture was stirred for 4 h at 0 • C. Saturated aqueous solution of NaHCO 3 (4 mL) and water (14 mL) were successively added to the reaction mixture. The organic phase was separated and the aqueous one was extracted with CH 2 Cl 2 (2 × 20 mL). The combined organic phases were successively washed with aqueous 1 N HCl (3 × 15 mL), water (20 mL) and brine (20 mL), dried (anhydrous Na 2 SO 4 ) and concentrated to dryness in vacuo to give a white solid (370 mg), that was subjected to column chromatography (silica gel 35-70 µm, 12 g, hexane/EtOAc mixtures) to give mesylate 21 (223 mg, 68% yield) as white solid, on elution with hexane/EtOAc 3:2 to 1:1. An analytical sample of 21 (65 mg) was obtained as white solid by crystallization of a sample of the above product (120 mg) from EtOAc (8 mL Syn-17-(methanesulfonyloxymethyl)-4-(metoxymethoxy)-2-methyl- 4,9-dihydro-4,9[1 ,2 ]benzeno-3a,9a-propano-1H-benz[f]isoindole-1,3(2H)-dione (22). MsCl (0.23 mL, 334 mg, 2.92 mmol) was added dropwise to a cold solution (0 • C, ice-water bath) of alcohol 19 (1.16 g, 2.77 mmol) and anhydrous Et 3 N (0.89 mL, 646 mg, 6.4 mmol) in anhydrous CH 2 Cl 2 (60 mL) under an Ar atmosphere and the mixture was stirred for 4 h at 0 • C. Saturated aqueous solution of NaHCO 3 (15 mL) and water (30 mL) were successively added to the reaction mixture. The organic phase was separated and the aqueous one was extracted with CH 2 Cl 2 (2 × 30 mL). The combined organic phases were successively washed with aqueous 1 N HCl (3 × 30 mL), water (30 mL) and brine (30 mL), dried (anhydrous Na 2 SO 4 ) and concentrated to dryness in vacuo to give a white solid (1.32 g), that was subjected to column chromatography ( and NaI (2.03 g, 99%, 13.4 mmol) in anhydrous acetone (40 mL) was heated at reflux for 16 h under an Ar atmosphere. The mixture was allowed to cool to room temperature, the precipitate was filtered through a pad of Celite ® , and the solid was washed with EtOAc (100 mL). The combined filtrate and washings were concentrated in vacuo, and the residue (860 mg) was subjected to column chromatography (30 g 50-200 µm silica gel, hexane/EtOAc mixtures). On elution with hexane/EtOAc 9:1, iodide 23 (617 mg, 87% yield) was obtained as yellow solid. An analytical sample of 23 (72 mg) was obtained as white solid by crystallization of a sample of the above product (100 mg) from EtOAc  Stereoisomeric mixture of 26 and its C1 epimer (27). Trimethylsilyl trifluoromethanesulfonate (310 µL, 98% content, 372 mg, 1.68 mmol) was added at once to a cold (0 • C, ice-water bath) solution of a stereoisomeric mixture of keto esters 24 and 25 (approximate ratio 24/25 = 1:1, 400 mg, 0.74 mmol) and anhydrous Et 3 N (0.51 mL, 370 mg, 3.7 mmol) in anhydrous CH 2 Cl 2 (3 mL) under an Ar atmosphere, and the mixture was stirred at room temperature for 30 min. The solution was cooled to 0 • C (ice-water bath), a saturated aqueous solution of NaHCO 3 (3 mL) was added, the organic phase was separated and the aqueous one was extracted with CH 2 Cl 2 (2 × 6 mL). The combined organic phases were dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo to give a brown oily residue, mixture of the corresponding trimethylsilyl enol ethers (412 mg), which was used as such in the next step. Accurate mass measurement: m/z calcd. for C 35 H 41 NO 7 Si + H + : 616.2725; found: 616.2731. Pd(OAc) 2 (169 mg, 98% content, 0.74 mmol) was added to a solution of the above stereoisomeric mixture of enol ethers (412 mg) in anhydrous DMSO (15 mL) and the mixture was stirred at room temperature for 16 h. The suspension was filtered through a pad of Celite ® , and the solid was washed with EtOAc (20 mL). The combined filtrate and washings were concentrated in vacuo, the residue was taken in EtOAc (20 mL) and was washed with water (20 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phase and extracts were washed with brine (2 × 25 mL), dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo to give a brown oily residue (390 mg), which was subjected to column chromatography (10 g, 50-200 µm basic Al 2 O 3 , hexane/EtOAc mixtures). On elution with hexane/EtOAc 3:2, a stereoisomeric mixture of enones 26 and 27 in an approximate ratio 26/27 = 1:1 (301 mg, 75% yield from 24 + 25) was obtained as white solid. m.p. 76-86 • C (EtOAc/hexane); accurate mass measurement: m/z calcd. for C 32   (a) NaBH 4 (67 mg, 1.72 mmol) was added portionwise to a cold (−40 • C) solution of a diastereomeric mixture of enones 26 and 27 (233 mg, 0.43 mmol) and CeCl 3 ·7H 2 O (417 mg, 1.12 mmol) in a mixture of THF (4.5 mL) and MeOH (5 mL) and the mixture was stirred at this temperature for 1 h. A saturated aqueous solution of NaHCO 3 (2 mL) and water (2 mL) were added and the mixture was extracted with CH 2 Cl 2 (3 × 15 mL). The combined organic phases were dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo to give a complex diastereoisomeric mixture of cyclopentenols 28 (172 mg) as white solid, that was used as such in the next step. (b) p-TsOH H 2 O (16.4 mg, 0.09 mmol) was added to a solution of the above cyclopentenols 28 (172 mg) in benzene (15 mL) and the solution was heated under reflux for 14 h with azeotropic elimination of water with a Dean-Stark equipment. Then, the solution was allowed to cool to room temperature and was treated with solid K 2 CO 3 (about 100 mg). The suspension was filtered and the filtrate was concentrated in vacuo to give cyclopentadiene alcohol 29 as light brown solid (180 mg) that was used as such in the next step. (c) A suspension of 30% KH in mineral oil (150 mg, about 1.1 mmol) was placed in a three-necked flask, provided with a low temperature thermometer and an Ar atmosphere. The mineral oil was removed by washing with anhydrous THF (5 × 5 mL) and after the last washing anhydrous THF (12 mL) was added. The mixture was cooled to 0 • C with an ice-water bath and a solution of the above product 29 (180 mg) in anhydrous THF (12 mL) was added dropwise with magnetic stirring and the mixture was stirred at room temperature for 1 h. The excess KH was destroyed by careful addition of 2 N HCl (1 mL) plus 5 N HCl (0.5 mL) under an Ar atmosphere. The solution