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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2010 August 7.
Published in final edited form as:
PMCID: PMC2736316
NIHMSID: NIHMS132562

A Divergent Synthesis of the Δ13-9-Isofurans

Abstract

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A stereodivergent total synthesis of the Δ13-9-isofurans has been developed. The four core substituted tetrahydrofurans were prepared by the Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation followed by cascade cyclization. The relative configuration at C-8 was inverted by oxidation followed by immediate L-selectride reduction. The relative configuration of the C-15 diastereomers were assigned by (S)-Binol/LAH/EtOH reduction of the corresponding enone. This synthesis of the Δ13-9-isofurans will provide sufficient material for further investigation of their biological activity.

Introduction

The isofurans (Fig. 1), represented by SC-Δ13-9-IsoF 1aaa, are produced by human metabolism of arachidonic acid.1,2 Previously,3 we prepared the two diastereomeric isofurans that we judged were the closest in structure to the enzymatically produced human hormone PGF. One of the diastereomers was found to have significant bioactivity. On re-preparation, however, no bioactivity was observed. Suspecting that the initially observed bioactivity might have been due to a minor contaminating diastereomer, we have developed a general strategy for the preparation of each of the 32 of the enantiomerically-pure diastereomers of the Δ13-9-isofurans. As the previous route to the isofurans had suffered from poor regioselectivity in the dihydroxylation step, we have devised an improved and much more robust route to the isofurans.

Fig. 1
There are 32 ep diastereoisomers of SC–Δ13 -9-IsoF.

Results and Discussion

Our interest was to develop a stereodivergent route to the Δ13-9-isofurans, such that each of the enantiomerically-pure (ep) diastereomers could be prepared by branching from advanced intermediates. The eight substituted tetrahydrofurans 2a–2h (Scheme 1) would each lead to four of the final thirty-two (ep) diastereomers. The four intermediates 2a–2d were to be prepared from the previously unknown monotrityl ether 3 by Sharpless asymmetric epoxidation (SAE)4 followed by Sharpless asymmetric dihydroxylation (SAD).3,5 We planned to prepare the tetrahydrofurans 2e–2h from the intermediates 2a–2d by Mitsunobu esterification3,6 followed by hydrolysis.

For this approach to the isofurans to be successful, there were three central issues to be addressed (Eq. 1):

  1. Would the asymmetric dihydroxylation of the epoxy sulfonate derived from 3 show matched vs unmatched diastereoselectivity?
  2. Could the stereocenters at C-8 and C-11 be inverted without elimination?
  3. Could the anticipated C-15 allylic alcohol diastereomers be separated?
equation image
(1)

Preparation of the monotrityl ether 3

We prepared 3 (Scheme 2) from methyl 4-bromocrotonate 5. Reduction by LiAlH4/AlCl37 afforded the allylic alcohol 6. This alcohol was coupled8 with propargyl alcohol to give a mixture (2:1) of the linear product 7a and the branched product 7b, that were not easily separable. The mixture was submitted to LiAlH4 reduction to give the diols 8a and 8b. After protection with TrCl, the monoether 3 was readily purified.

Preparation of the Four Core Tetrahydrofurans

The monoether 3 was first carried on (Scheme 3, Table 1) to the epoxy alcohol 9a by Sharpless asymmetric epoxidation with the adjunct D-diethyl tartrate (D-DET) (Scheme 3). The derived benzenesulfonate 10a was subjected to the Sharpless asymmetric dihydroxylation with AD-mix followed by direct treatment with K2CO3 in MeOH3,9 to give the cyclized product. Using L-DET in the Sharpless asymmetric epoxidation, when AD-mix α was employed (entry 1), it gave a 3:1 mixture of diastereomers, that were not ready separable by silica gel chromatography. We were pleased to observe that the two diastereomers were readily separable after silylation of the secondary hydroxyl group, leading to 2a and 2b. The structure of 2a was confirmed by X-ray analysis of the crystalline free alcohol (11a, Scheme 4). Alternatively, when AD-mix β was used (entry 2), primarily, (>9:1) the single diastereomer 2b was found. Similarly, using L-DET in the Sharpless asymmetric epoxidation and AD-mix α in the dihydroxylation (entry 4) delivered primarily (>9:1) the diastereomer 2d, whereas L-DET followed by AD-mix β (entry 3) gave a 2:1 mixture of diastereomers of 2c and 2d. Note that the major diastereomers prepared this way showed >99% ee (chiral HPLC), while the minor diastereomers (entry 1, entry 3) were about 67% ee and 53% ee, respectively (chiral HPLC). Only the high ee diastereomers were carried on in the synthesis.

Table 1
Tetrahydrofurans by sequential SAE and SAD

Inversion of the C-11 Stereochemistry

To achieve stereodivergence, it was necessary to invert the alcohols at C-11 (isofuran numbering, Scheme 4). Deprotection of the silyl group of 2a with TBAF gave the free alcohol 11a. The secondary alcohol at C-11 participated efficiently in Mitsunobu esterification6 to give, after methanolysis, the inverted alcohol 11e. Protection of 11e with TBS gave the tetrahydrofuran diastereomer 2e. Similarly, 2b2d were converted to 2f2h.

Construction of the Upper Side Chain

Lewis-acid BF3·OEt2 assisted10 opening (Scheme 5) of the epoxide 2a with the lithium anion derived from the commercially available 4-pentynenitrile at low temperature gave efficient conversion to the alkyne 12a. Partial hydrogenation using P-2 Ni catalyst11 afforded the cis-alkene 13aa. Protection of 13aa with TBS resulted in the trityl ether 4aa.

Inversion of the C-8 Stereochemistry

When Mitsunobu inversion was attempted with alcohol 13aa (Scheme 6), predominantly dehydration was observed. Fortunately, oxidation12 followed by immediate L-Selectride reduction of the alcohol 13aa gave predominantly the inverted alcohol 13ab. Protection of 13ab with TBS gave the diastereomer 4ab.

Construction of the Lower Side Chain

The next step in the synthesis was the removal of the trityl group from 4aa (Scheme 7). Formic acid13 worked well with 4aa, but destroyed 4ab. Deprotection of 4aa with 3 eq of Et2AlCl at −50 °C14 gave the desired alcohol 14aa accompanied by some unidentified impurities. Fortunately, deprotection of 4aa and related compounds with 5 eq of Et2AlCl at −78 °C for 10 min gave clean conversion to the primary alcohol. Dess-Martin oxidation12 of the alcohol 14aa afforded the aldehyde. Horner-Emmons condensation of the aldehyde with commercial dimethyl 2-oxo-heptylphosphonate 15 gave the enone 16aa. Luche reduction15 of the enone gave the allylic alcohols 17aaa and 17aab in a ratio of about 1:1. We were pleased to observe that these two diastereomers were readily separable by silica gel chromatography.

Assignment of the C-15 Absolute Configuration

The enone 16aa (Scheme 7) was also reduced with LiAlH4/(S)-Binol/EtOH at −100 °C, that was expected16 to give predominantly 17aaa. The major diastereomer from the reduction was contaminated with the (S)-Binol. However, this material was found to be congruent with the upper TLC spot from the Luche reduction by 13C NMR (δ 72.4 vs 72.4, lower spot δ 72.6). This allowed us to assign the absolute configurations at C-15 of the two diastereomeric alcohols 17aaa (S) and 17aab (R).

Synthesis of the Isofurans

Desilylation of 17aaa with TBAF gave the free alcohol (Scheme 8). The nitrile group was hydrolyzed17 with 15% aqueous NaOH in EtOH at 85 °C, and the desired carboxylic acid 1aaa was isolated in excellent yield. Isofuran 1aab was prepared in the same way. The 13C NMR of the two free acids appeared to be complicated, so the 1aab was converted to its methyl ester 18aab. Both 1aaa and 1aab and the methyl ester 18aab were found to be congruent (1H, 13C NMR, [α]D) to the substances that we had previously3a prepared.

Using this approach, we have prepared all thirty-two of the enantiomerically pure diastereomers of Δ13-9-IsoF. The full experimental details for the preparation of a representative six more of those diastereomers are included in the supporting information, along with physical characteristics and spectroscopic data for each of the other 31 enantiomerically-pure diastereomers of the Δ13-9-isofurans.

Conclusion

We have developed a general route to the enantiomerically-pure diastereomers of Δ13-9-IsoF. The four key intermediates 2a–2d were obtained by Sharpless asymmetric epoxidation and Sharpless dihydroxylation, followed by cascade cyclization. Mitsunobu inversion of each of these four key intermediates (2a–2b) gave the other four diastereomers (2e–2h). This approach has made each of the thirty-two ep diastereomers of Δ13-9-IsoF, previously known only in microgram quantities as mixtures, available in sufficient quantity to assess the individual physiological activity of each. We believe that the robust synthetic approach outlined here will allow ready access both to the other regioisomeric isofurans and to the neurofurans.18,19

Experimental Section

((2R, 3R)-3-((E)-4-trityloxybut-2-enyl) oxiran-2-yl) methanol 9a

To a stirred solution of diethyl D-tartrate (680 mg, 3.3 mmol) in CH2Cl2 (150 mL) was added Ti(OiPr)4 (924 mg, 3.3 mmol) at − 30 to − 20 °C. The reaction mixture was stirred for 30 min at this temperature, then a solution of 3 (1.11 g, 3.0 mmol) in CH2Cl2 (18 mL) was added over a period of 15 min. After an additional 30 mins at − 30 to −20 °C, tBuOOH (4.7 M in CH2Cl2, 1.7 mL, 8.0 mmol) was added dropwise over a period of 5 min. The reaction mixture was stirred for 3 h at − 30 to −20°C. Aqueous L-(+) tartaric acid (10%, 6 mL) was added, then the reaction mixture was stirred at −20 °C for 25 min, allowed to warm to rt, and stirred for 40 min. Aqueous NaOH (1 N, 18 mL) was added at 0°C, and the resulting reaction mixture was stirred for 1.5 h,. The reaction mixture was then partitioned between CH2Cl2 and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford the epoxide 9a as a colorless oil (879 mg, 76% yield from monotrityl ether 3), TLC Rf (MTBE/petroleum ether = 3/7) = 0.28; [α]D +13.8 (c 1.0, CH2Cl2); 1H NMR δ 7.44–7.46 (m, 6 H), 7.20–7.30 (m, 9 H), 5.67–5.75 (m, 2 H), 3.87–3.91 (m, 1 H), 3.58–3.63 (m, 3 H), 3.02–3.05 (m, 1 H), 2.93–2.95 (m, 1 H), 2.34–2.37 (m, 2 H), 2.03 (t, 1 H, J = 6.0 Hz); 13C NMR δ u20: 144.2, 86.9, 64.6, 61.6, 34.4 d: 130.1, 128.7, 127.9, 127.0, 126.0, 58.1, 55.0; IR (film) 3415, 2862, 1447, 1049, 751 cm−1; HRMS: calcd. C26H26O3Na 409.1774, found 409.1775.

((2R, 3R)-3-((E)-4-trityloxybut-2-enyl)oxiran-2-yl) methyl benzenesulfonate 10a

To a stirring solution of 9a (879 mg, 2.28 mmol) in CH2Cl2 (20 mL) was added DMAP (20 mg, cat) and Et3N (806 mg, 7.98 mmol) at 0°C. Then a solution of benzensulfonyl chloride (1.01g, 5.70 mmol) in CH2Cl2 (4 mL) was added. The reaction mixture was stirred for 30 min at 0°C, then partitioned between CH2Cl2 and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to give the desired epoxide 10a (1.14 g, 95% yield from epoxide 9a), TLC Rf (MTBE/petroleum ether = 2/8) = 0.28; [α]D +14.7 (c 1.6, CH2Cl2); 1H NMR δ 7.90–7.93 (m, 2 H), 7.62–7.64 (m, 1 H), 7.52–7.58 (m, 2 H), 7.42–7.45 (m, 6 H), 7.21–7.32 (m, 9 H), 5.66–5.68 (m, 2 H), 4.24 (dd, 1 H, J = 11.2 Hz and 3.6 Hz), 4.01 (dd, 1 H, J = 11.2 Hz and 6.0 Hz), 3.57 (d, 2 H, J = 3.6 Hz), 2.92–2.99 (m, 1 H), 2.87–2.88 (m, 1H), 2.32–2.33 (m, 2H); 13C NMR δ u: 144.1, 135.8, 86.9, 70.1, 64.5, 34.0 d: 134.0, 130.5, 129.3, 128.6, 127.9, 127.8, 127.0, 125.2, 55.7, 54.0; IR (film) 3058, 1447, 1185, 863,753 cm−1; HRMS: calcd. C32H30O5SNa 549.1731, found 549.1713.

((2S,3S,5S)-tetrahydro-5-((S)-oxiran-2-yl)-2-(trityloxymethyl)furan-3-yloxy)(tert-butyl) dimethylsilane 2a

To a stirred solution of 10a (770 mg, 1.46 mmol) in a mixed tBuOH and H2O solution (v/v 1:1, 3 mL) was added AD-mix-α (2.13 g). After 10 min at room temperature, methanesulfonamide (141 mg, 1.48 mmol) was added. The reaction mixture was stirred for 60 h. NaHSO3 (2.18 g, 21.0 mmol) was added and the mixture was stirred for 60 min. The reaction mixture was partitioned between EtOAc and water. The organic extract was dried (Na2SO4) and concentrated to afford the diol crude (871 mg).

To a stirred solution of the crude diol (499 mg) in MeOH (7.5 mL) at 0 °C was added powdered K2CO3 (307 mg, 2.23 mmol). After an additional 2.5 h at 0°C, the reaction mixture was partitioned between EtOAc and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford the mixture of alcohol 11a and 11b (244 mg, two steps, 72% yield from 10a).

To a stirred solution of the mixture of alcohols (360 mg, 0.90 mmol) in CH2Cl2 (7 mL) was added TBSCl (405 mg, 2.69 mmol), imidazole (350 mg, 5.15 mmol) and DMAP (6 mg, cat) at room temperature. After an additional 40 min, the reaction mixture was partitioned between CH2Cl2 and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford 2b (110 mg, 24% yield from mixture of 11a and 11b, 17% yield for three steps from 10a), TLC Rf (MTBE/petroleum ether = 1/9) = 0.46; [α]D −23.8 (c 1.0, CH2Cl2). Further elution gave 2a as a colorless oil (316 mg, 68% yield from the mixture of 11a and 11b, 49% yield for three steps from 10a), TLC Rf (MTBE/petroleum ether = 1/9) = 0.31; [α]D +42.2 (c 1.0, CH2Cl2);1H NMR δ7.46–7.49 (m, 6 H), 7.19–7.29 (m, 9 H), 4.29–4.31 (m, 1 H), 4.05–4.09 (m, 1 H), 3.79–3.83 (m, 1 H), 3.43 (dd, 1 H, J = 6.8 Hz and 10.0 Hz), 3.13 (dd, 1H, J = 4.0 Hz and 10.0 Hz), 3.04–3.10 (m, 1 H), 2.78 (dd, 1 H, J = 4.0 Hz and 5.2 Hz), 2.70 (dd, 1 H, J = 2.4 Hz and 5.2 Hz), 2.23–.30 (m, 1 H), 1.95 (ddd, 1H, J = 2.0 Hz, 3.6 Hz and 14.6 Hz), 0.70 (s, 9 H), −0.03 (s, 3 H), −0.18 (s, 3 H); 13C NMR δ u: 144.1, 86.9, 64.2, 46.9, 38.9, 17.8 d: 128.8, 127.7, 126.9, 83.2, 78.6, 72.5, 54.0, 25.7, −4.8, −5.4; IR (film) 2930, 2857, 1254, 1074, 835 cm−1; HRMS: calcd. C32H40O4SiNa 539.2594, found 539.2572.

(2S,3S,5S)-2-((trityloxy)methyl)-tetrahydro-5-((S)-oxiran-2-yl)furan-3-ol 11a

To a stirred solution of 2a (1.57 g, 3.3 mmol) in THF (20 mL) at room temperature was added a Bu4NF solution in THF (1M, 6.6 mL, 6.6 mmol) at 0°C. After an additional 5 h, the mixture was partitioned between CH2Cl2 and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford 11a as a solid (1.15 g, 96% yield from 2a), A 50 mg portion was crystallized from 1.0 mL of 1:5 CH2Cl2/hexanes, m.p. = 142 °C; TLC Rf (MTBE/petroleum ether = 3/7) = 0.33; [α]D +13.3 (c 0.60, CH2Cl2); 1H NMR δ 7.44–7.48 (m, 6 H), 7.19–7.30 (m, 9 H), 4.32 (d, 1 H, J = 5.2 Hz), 4.06–4.08 (m, 1 H), 3.94 (dd, 1 H, J = 2.0 Hz and 5.2 Hz), 3.45 (dd, 1 H, J = 5.6 Hz and 9.6 Hz), 3.38 (dd, 1 H, J = 5.6 Hz and 9.6 Hz), 3.17–3.20 (m, 1 H), 2.77–2.82 (m, 2 H), 2.60 (dd, 1 H, J = 2.8 Hz and 4.8 Hz), 2.18–2.26 (m, 1 H), 1.75–1.79 (m, 1 H); 13C NMR δ u: 143.8, 87.1, 62.8, 45.7, 36.0 d: 128.8, 128.0, 127.2, 82.3, 77.8, 72.1, 53.7; IR (film) 3458, 1265, 1072, 756 cm−1; HRMS: calcd. C26H26O4Na 425.1729, found 425.1733.

Alkyne 12a

To a stirred solution of 5-hexynenitrile (1.07 g, 11.44 mmol) in THF (10 mL) was added dropwise n-BuLi (2.28 M in hexane, 4.1 mL, 9.36 mmol) at −78 °C over a period of 5 min. After an additional 40 min at −78 °C, a solution of 2a (1.00 g, 1.94 mmol) in THF (15 mL) was added, followed by the addition of a solution of BF3·OEt2 (986 mg, 6.95 mmol) in THF (3 ml) over a period of 3 min. The reaction mixture was stirred for 40 min at −78 °C. The reaction mixture was quenched with saturated aqueous NH4Cl. The mixture was partitioned between CH2Cl2 and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford 12a (1.08 g, 91% yield from 2a), TLC Rf (MTBE/petroleum ether = 3/7) = 0.30; [α]D +27.0 (c 1.0, CH2Cl2); 1H NMR δ 7.45–7.48 (m, 6 H), 7.20–7.30 (m, 9 H), 4.26–4.27 (m, 1 H), 4.19–4.21 (m, 1 H), 3.97–4.01 (m, 1 H), 3.87–3.93 (m, 1 H), 3.42 (dd, 1 H, J = 6.8 Hz and 10.0 Hz), 3.12 (dd, 1 H, J = 4.0 Hz and 10.0 Hz), 2.73 (d, 1 H, J = 2.8 Hz), 2.43–2.49 (m, 3 H), 2.33–2.37 (m, 3 H), 2.12–2.17 (m, 1 H), 1.93 (ddd, 1H, J = 0.8 Hz, 4.4 Hz and 14.6 Hz), 1.81–1.88 (m, 2 H), 0.71 (bs, 9H), −0.03 (s, 3 H), −0.19 (s, 3 H); 13C NMR δ u: 144.1, 119.3, 86.9, 79.5, 78.3, 64.0, 35.1, 24.8, 24.0, 18.0, 17.9, 16.2 d: 128.8, 127.8, 127.0, 82.6, 80.0, 72.6, 71.1, 25.7, −4.9, −5.4; IR (film) 3454, 2932, 2048, 1256, 1072, 705 cm−1; HRMS: calcd. C38H47NO4SiNa 632.3172, found 632.3177.

Alkene 13aa

To a stirred solution of Ni(OAc)4·4H2O (259 mg, 1.04 mmol) in EtOH (8 mL) was added NaBH4 solution in EtOH (1 M, 1.0 mL, 1.0 mmol). The black mixture was evacuated and backfilled with H2 three times. Ethylenediamine (70 uL, 0.95 mmol) was added, followed by alkyne 12aa (317 mg, 0.52 mmol) in EtOH (5 mL). The reaction mixture was stirred for 2.5 h at rt under H2. The reaction mixture was diluted in MTBE and filtered through a pad of silical gel. The filtrate was concentrated and the residue was chromatographed to afford the desired alkene 13aa as a colorless oil (301 mg, 95% yield from the alkyne 12aa), TLC Rf (MTBE/petroleum ether = 3/7) = 0.37; [α]D +24.2 (c 1.0, CH2Cl2); 1H NMR δ 7.64–7.66 (m, 6 H), 7.38–7.48 (m, 9 H), 5.75–5.81 (m, 1 H), 5.61–5.65 (m, 1 H), 4.43–4.46 (m, 1 H), 4.22–4.26 (m, 1 H), 4.12–4.14 (m, 1 H), 4.04–4.08 (m, 1 H), 3.61 (dd, 1 H, J = 6.4 Hz and 10,0 Hz), 3.32 (dd, 1 H, J = 4.0 Hz and 10.0 Hz), 2.83 (s, 1 H), 2.50 (t, 2 H, J = 7.2 Hz), 2.29–2.41 (m, 1 H), 2.11–2.15 (m, 1 H), 1.89–1.93 (m, 2 H), 0.90 (s, 9 H), 0.16 (s, 3 H), 0.00(s, 3 H); 13C NMR δ u: 144.1, 119.7, 86.9, 63.9, 34.7, 31.8, 26.1, 25.3, 17.9, 16.5 d: 130.0, 128.8, 127.9, 127.8, 127.0, 82.4, 80.6, 72.6, 71.8, 25.7, −4.9, −5.5; IR (film) 3440, 2933, 2245, 2048. 1448, 1072, 774, 704 cm−1; HRMS: calcd. C38H49NO4SiNa 634.3329, found 634.3329.

Alkene 4aa

To a stirred solution of 13aa (348.3 mg, 0.57 mmol) in CH2Cl2 (8 mL) was added TBSCl (430 mg, 2.85 mmol), imidazole (371 mg, 5.70 mmol) and DMAP (5 mg, cat) at room temperature. After an additional 17 h, the reaction mixture was partitioned between CH2Cl2 and water. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford 4aa (349 mg, 84% yield from 13aa), TLC Rf (MTBE/petroleum ether = 1/9) = 0.50; [α]D +14.2 (c 1.0, CH2Cl2); 1H NMR δ 7.70–7.72 (m, 6 H), 7.43–7.53 (m, 9 H), 5.87–5.91 (m, 1 H), 5.65–5.68 (m, 1 H), 4.45–4.48 (m, 1 H), 4.13–4.17 (m, 1 H), 4.03–4.06 (m, 1 H), 3.89–3.94 (m, 1 H), 3.57–3.60 (m, 1 H), 3.29 (dd, 1 H, J = 2.4 Hz and 10.0 Hz), 2.78–2.85 (m, 1 H), 2.42–2.50 (m, 6 H), 1.92–1.97 (m, 3 H), 1.10 (s, 9 H), 0.92 (s, 9 H), 0.31 (s, 3 H), 0.27 (s, 3 H), 0.14 (s, 3 H), 0.00 (s, 3 H); 13C NMR δ u: 144.3, 119.9, 86.6, 64.7, 38.8, 32.3, 26.4, 25.5, 18.1, 17.9, 16.4 d: 128.9, 128.9, 127.7, 126.9, 82.5, 79.6, 74.4, 73.0, 25.9, 25.8, −4.0, −4.3, −4.8, −5.4; IR (film) 3432, 2932, 2264, 1253, 1078, 834 cm−1; HRMS: calcd. C44H63NO4Si2Na 748.4193, found 748.4192.

Alcohol 14aa

To a stirred solution of 4aa (20 mg, 0.0275 mmol) in CH2Cl2 (4 mL) was added diethyl aluminum chloride (1N in hexane, 0.15 mL, 0.15 mmol) at −78 °C. After an additional 10 min, the reaction mixture was quenched with water and filtered through a pad of silica gel, washing with methanol. The filtrate was concentrated and the residue was chromatographed to give the desired alcohol 14aa (11.2 mg, 84% yield from the ether 4aa), TLC Rf (MTBE/petroleum ether = 3/7) = 0.32; [α]D −5.2 (c 1.0, CH2Cl2); 1H NMR δ5.58–5.61 (m, 1 H), 5.38–5.41 (m, 1 H), 4.50 (dd, 1 H, J = 6.0 Hz and 13.2 Hz), 3.79–3.83 (m, 2 H), 3.72–3.75 (m, 2 H), 3.63–3.68 (m, 1 H), 2.32–2.40 (m, 4 H), 2.17–2.25 (m, 4 H), 1.78–1.83 (m, 1 H), 1.70–1.76 (m, 2 H), 0.88 (s, 18 H), 0.07 (s, 12 H); 13C NMR δ u: 119.7, 62.7, 38.1, 32.5, 26.5, 25.3, 18.1, 18.0, 16.5 d: 128.8, 127.7, 81.1, 79.4, 73.8(2), 25.9, 25.8, −4.2, −4.4, −4.6, −5.2; IR (film) 2932, 2256, 1254, 1079, 835 cm−1; HRMS: calcd. C25H49NO4Si2Na 506.3098, found 506.3097.

Enone 16aa

To a stirred solution of 14aa (64 mg, 0.13 mmol) in CH2Cl2 (1.5 mL) was added Dess-Martin periodinane (111 mg, 0.26 mmol). After an additional 40 min at rt, the reaction mixture was directly poured on the silica gel and chromatographed to afforded the crude aldehyde (53 mg).

To a stirred suspension of NaH (26 mg, 0.66 mmol) in THF (5 mL) was added dimethyl 2-oxoheptylphosphonate 15 (244 mg, 1.10 mmol) at 0°C. After an additional 1 hr at 0 °C, a solution of the crude aldehyde (53 mg) in THF (1 ml) was added. After an additional 40 min at 0°C, the mixture was partitioned between CH2Cl2 and saturated aqueous NH4Cl. The organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to afford 16aa (64 mg, 84% yield from 14aa), TLC Rf (MTBE/petroleum ether = 3/7) = 0.73; [α]D +5.9 (c 1.0, CH2Cl2); 1H NMR δ 6.79 (dd, 1 H, J = 4.2 Hz and 16.0 Hz), 6.26 (dd, 1 H, J = 1.6 Hz and 16.0 Hz), 5.595.64 (m, 1 H), 5.39–5.45 (m, 1 H), 4.42–4.46 (m, 1 H), 4.28 (dt, 1 H, J = 1.6 Hz and 5.6 Hz), 3.86 (q, 1 H, J = 5.2 Hz), 3.74 (q, 1 H, J = 7.2 Hz), 2.54–2.58 (m, 2 H), 2.43–2.50 (m, 1 H), 2.19–2.35 (m, 6 H), 1.82–1.89 (m, 1 H), 1.70–1.77 (m, 2 H), 1.59–1.66 (m, 2 H), 1.25–1.37 (m, 4 H), 0.86–0.90 (m, 21 H), 0.09 (s, 6 H), 0.05 (s, 3 H), 0.02 (s, 3 H); 13C NMR δ u: 200.5, 119.7, 39.9, 38.3, 32.4, 31.5, 26.3, 25.3, 23.8, 22.5, 18.1, 18.0, 16.5 d: 142.7, 130.8, 128.9, 127.6, 82.3, 80.1, 74.3, 73.8, 25.9, 25.8, 13.9, −4.1, −4.3, −4.7, −5.0; IR (film) 3442, 2929, 2250, 1641, 833, 775 cm−1; HRMS: calcd. C32H59NO4Si2Na 600.3880, found 600.3876.

Alcohol 17aaa and 17aab

To a stirred solution of 16aa (118 mg, 0.20 mmol) in MeOH (6 ml) was added CeCl3·7H2O (74 mg, 0.20 mmol). After 5 min, NaBH4 (12 mg) was added. The mixture was stirred for an additional 30 min at rt, then the reaction mixture was filtered through a pad of silica gel, washing with MTBE, the filtrate was concentrated and the residue was chromatographed to give the desired alcohol 17aaa (45 mg, 38% yield from the enone 16aa), TLC Rf (Et2O/CH2Cl2/petroleum ether = 1/3/6) = 0.23; [α]D +4.5 (c 1.0, CH2Cl2); 1H NMR δ 5.75–5.82 (m, 2 H), 5.58–5.62 (m, 1 H), 5.36–5.43 (m, 1 H), 4.28–4.31 (m, 1 H), 4.06–4.15 (m, 2 H), 3.84 (q, 1 H, J = 4.8 Hz), 3.66 (q, 1 H, J = 7.2 Hz), 2.65 (d, 1 H, J = 9.6 Hz), 2.39–2.47 (m, 1 H), 2.30–2.34 (m, 2 H), 2.17–2.27 (m, 4 H), 1.83–1.87 (m, 1 H), 1.68–1.76 (m, 2 H), 1.50–1.56 (m, 4 H), 1.26–1.43 (m, 4 H), 0.87–0.90 (m, 21 H), 0.03–0.08 (m, 12 H); 13C NMR δ u: 119.8, 38.3, 37.1, 32.3, 31.8, 26.4, 25.3, 25.2, 22.6, 18.2, 18.1, 16.5 d: 136.3, 128.7, 127.9, 127.6, 83.5, 79.7, 74.3, 74.0, 72.4, 25.9 (3), 25.9 (3), 14.1, −4.1, −4.3, −4.6, −4.9; IR (film) 2931, 2250, 1464, 1252, 1073, 834 cm−1; HRMS: calcd. C32H61NO4Si2Na 602.4033, found 602.4025. Further elution gave 17aab (41 mg, 35% yield from the enone 16aa), TLC Rf (Et2O/CH2Cl2/petroleum ether = 1/3/6) = 0.33; [α]D +6.9 (c 1.0, CH2Cl2); 1H NMR δ 5.68–5.81 (m, 2 H), 5.58–5.64 (m, 1 H), 5.37–5.42 (m, 1 H), 4.25–4.29 (m, 1 H), 4.03–4.13 (m, 2 H), 3.82–3.86 (m, 1 H), 3.64–3.70 (m, 1 H), 2.65 (d, 1 H, J = 9.6 Hz), 2.42–2.48 (m,1 H), 2.31–2.35 (m, 2 H), 2.18–2.25 (m, 4 H), 1.81–1.86 (m, 1 H), 1.60–1.75 (m, 4 H), 1.49–1.55 (m, 2 H), 1.37–1.44 (m, 1 H), 1.26–1.36 (m, 3 H), 0.88–0.90 (m, 21 H), 0.01–0.09 (m, 12 H); 13C NMR δ u: 119.9, 38.6, 37.1, 32.2, 31.8, 26.4, 25.3, 25.2, 22.6, 18.2, 18.1, 16.5 d: 136.8, 128.7, 128.0, 127.8, 83.9, 79.7, 74.1, 74.0, 72.6, 25.90 (3), 25.87 (3), 14.1, −4.1, −4.3, −4.6, −4.9; IR (film) 3449, 2932, 2250, 1254, 1074, 835 cm−1; HRMS: calcd. C32H61NO4Si2Na 602.4037, found 602.4023.

Isofuran 1aaa

To a stirred solution of 17aaa (45 mg, 0.078 mmol) in THF (0.8 ml) was added a 1M solution of Bu4NF (1.0 M in THF, 1.0 mL). After an additional 1.5 hr at rt, the reaction mixture was partitioned between CH2Cl2 and H2O. The organic extract was concentrated to afford the crude triol. The crude triol was dissolved in EtOH (1.0 mL), then 15% aqueous NaOH (2.0 mL) was added. After an additional 16 h at 85 °C, the reaction mixture was cooled to rt and acidified with NaH2PO4 (0.5 M, 3 mL) and AcOH(3 mL). The mixture was partitioned beween CH2Cl2 and water. The organic extract was concentrated and the residue was chromatographed to give 1aaa (26 mg, 89% yield from 17aaa), TLC Rf (Et2O/0.5 M aqueous NaH2PO4/HOAc = 90/9/1) = 0.35; [α]D +25.0 (c 0.5, CH2Cl2) [α]D +35.4 (c 0.58, CH3OH); 1H NMR δ 5.98 (s, 3 H), 5.81–5.82 (m, 2 H), 5.44–5.49 (m, 2 H), 4.08–4.16 (m,4 H), 3.86–3.87 (m, 1 H), 2.35 (s, 1 H), 2.02–2.27 (m, 7 H), 1.70 (s, 2 H), 1.22–1.53 (m, 9 H), 0.86–0.91 (m, 3 H); 13C NMR δ u: 36.7, 34.1, 31.8, 26.4, 25.2, 24.4, 22.6 d: 137.5, 131.6, 126.0, 125.9, 84.0, 80.4, 73.1, 72.0, 71.8, 30.3, 14.1; the carbonyl carbon was not observed; IR (film) 3334, 2925, 1708, 1018 cm−1; HRMS: calcd C20H34O6Na 393.2253, found 393.2246.

Isofuran 1aab

The reaction was performed with the alcohol 17aab (36 mg, 0.062 mmol) in the same manner as described for the preparation of isofuran 1aaa to give isofuran 1aab (24 mg, 92% yield from 17aab), TLC Rf (Et2O/0.5 M aqueous NaH2PO4/HOAc = 90/9/1) = 0.38; [α]D +15.6 (c 0.48, CH2Cl2) [α]D +23.1 (c 0.50, CH3OH); 1H NMR δ 5.71–5.88 (m, 3 H), 5.43–5.48 (m, 3 H), 4.05–4.20 (m, 4 H), 3.89 (s, 1 H), 2.36 (s, 2 H), 2.04–2.27 (m, 6 H), 1.70–1.73 (m, 2 H), 1.43–1.57 (m, 3 H), 1.25–1.36 (m, 7 H), 0.86–0.89 (m, 3 H); 13C NMR δ u: 178.1, 36.5, 34.2, 32.0, 31.8, 26.4, 25.2, 24.4, 22.6 d: 136.5, 131.3, 126.2, 126.2, 83.1, 80.3, 72.7, 72.3, 71.8, 30.3, 14.1; the carbonyl carbon was not initially observed, but when 1aab was prepared by saponification of the ester 18aab, the carbonyl was evident; IR (film) 3447, 3034, 2926, 1708, 1240, 1018 cm−1; HRMS: calcd. C20H34O6Na 393.2253, found 393.2246.

Ester 18aab

To a stirred solution of isofuran 1aab (8 mg, 0.021 mmol) in MeOH/benzene (1:4, 0.5 mL) was added trimethylsilyl diazomethane (2.0 M in Et2O, 50 uL). The mixture was stirred at room temperature for 20 min. The mixture was concentrated and the residue was chromatographed to afford the ester 18aab (8 mg, 96% yield from the isofuran 1aab), TLC Rf (acetone/CH2Cl2 = 4/1) = 0.38; [α]D +23.8 (c 0.38, CH2Cl2) [α]D +23.1 (c 0.55, CH3OH; 1H NMR δ 5.81–5.87 (m, 1 H), 5.73 (dd, J = 15.6 Hz and 5.2 Hz, 1 H), 5.44–5.51 (m, 2 H), 4.88 (s, 1 H), 4.79 (s, 1 H), 4.18–4.20 (m, 1 H), 4.11–4.16 (m, 2 H), 4.02–4.08 (m, 1 H), 3.85–3.90 (m, 1 H), 3.70–3.85 (m, 1 H), 3.67 (s, 3 H), 2.32 (t, 2 H, J = 7.2 Hz), 2.03–2.29 (m, 5 H), 1.66–1.74 (m, 3 H), 1.41–1.60 (m, 2 H), 1.21–1.38 (m, 6 H), 0.87 (t, 3 H, J = 6.4 Hz); 13C NMR δu: 174.0, 36.5, 34.0, 33.4, 32.2, 31.7, 26.7, 25.3, 24.7, 22.6 d: 136.4, 131.2, 126.5, 126.2, 83.1, 80.2, 72.8, 72.2, 71.8, 51.5, 14.1. HRMS: calcd. C21H36O6Na 407.2404, found 407.2410.

Supplementary Material

1_si_001

2_si_002

Acknowledgments

We thank the National Institutes of Health (GM42056) for support of this work. We thank Dr. John Dykins for mass spectrometric measurements, supported by the NSF (0541775), and Dr. Glenn Yap for X-ray analysis.

Footnotes

Supporting Information Available. General experimental procedures, experimental procedures and spectra for all new compounds, and details of the x-ray structural analysis of 11a. This material is available free of charge via the Internet at http://pubs.acs.org.

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