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Stereoselective synthesis of contiguous THF–THF and THF–THP units via PdII-catalyzed tandem reaction with 1,3-chirality transfer
Tetrahedron 69 (2013) 11017e11024
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Stereoselective synthesis of contiguous THFeTHF and THFeTHP units via PdII-catalyzed tandem reaction with 1,3-chirality transfer Nobuyuki Kawai *, Yuhei Fujikura, Jun Takita, Jun’ichi Uenishi Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 August 2013 Received in revised form 18 September 2013 Accepted 21 September 2013 Available online 2 October 2013
The PdII-catalyzed tandem cyclization of chiral allylic alcohols possessing an internal epoxide and a terminal alcohol provided a contiguous THFeTHP and THFeTHP ring units stereospecifically. The cyclizations take place via a 5-exo-tet-5-exo-trig mode, however, the cyclization of methyl substituted epoxy diols proceeded via 6-endo-tet-6-exo-trig fashion in a part to construct the oxygen-fused THPeTHP ring. The different reaction rates of precursors, which are different stereochemistry at allylic alcohol have been elucidated. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Contiguous THFeTHF and THFeTHP Pd(II)-catalyst Tandem reaction 1,3-Chirality transfer Oxygen-fused THPeTHP rings
1. Introduction The synthesis of contiguous THFeTHF and THFeTHP ring units remains a topic of considerable interest due to the existence of these structures in natural products and biologically active compounds. Annonaceous acetogenins have important biological activities, such as anticancer and immunosuppressive activities, and include a contiguous THFeTHF and THFeTHP ring unit with stereoisomers.1,2 A represent examples of acetogenins, Muconin,2 and Chamuvarinin3 possess contiguous THFeTHF and THFeTHP ring unit. The stereochemistry of contiguous THFeTHF core has been considered to affects their inhibitory effect on mitochondrial NADHeubiquinone oxidoreductase (complex I).4 Therefore, a stereocontrolled construction of these units is an important task. Construction of these compounds has received much attention, especially with regard to efforts directed at asymmetric synthesis.5 For example, a cascade reaction via epoxide-opening reaction has been utilized on the basis of biosynthetic pathway. Although these cascade reactions were promoted by acid6 or base,7 very few transition metal catalyzed promotions have been reported.8
* Corresponding author. Tel.: þ81 75 595 4666; fax: þ81 75 595 4763; e-mail address: [email protected] (N. Kawai). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.09.067
We have developed a PdII-catalyzed intramolecular oxypalladation reaction for the formation of 2-alkenyl substituted oxoheterocycles.9 Recently, we have reported some PdII-catalyst triggered tandem cyclization of chiral allylic alcohols 1a and 1b possessing an internal epoxide and a terminal alcohol provided a contiguous THFeTHF ring unit stereospecifically (Scheme 1).10 The cyclization takes place in a 5-exo-tet-5-exo-trig fashion with high chirality transfer through a syn-SN20 like process for the formation of the internal THF ring. However, as the mechanistic proposal was made on the basis of a limited number of substrates, we have now expanded this study to additional substrates. Herein we describe a detailed study of the PdII-catalyzed cyclization reactions of epoxy allylic alcohols, especially on the difference of the reactivity of the diastereomeric epoxy allylic alcohols.
Scheme 1. Pd(II)-catalyzed cyclization of 1a and 1b.
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2. Results and discussion Four optically pure epoxy diols, 3a, 3b that are homologated between alkene and epoxide from 1a and 1b, and 4a, 4b that possess a methyl substituted epoxide, were chosen as precursors for the cyclization. When these diols cyclized, two kinds of stereoisomeric contiguous THFeTHP and THFeTHF compounds, 5a, 5b, 6a, and 6b, will be formed. These structures are shown in Fig. 1.
Fig. 1. Cyclization precursors and contiguous THFeTHP, THFeTHF compounds.
The synthesis of 3a and 3b is shown in Scheme 2. Wittig reaction of the chiral epoxide 710 with (3-benzoyloxypropyl)-triphenylphosphonium bromide,11 followed by diimide reduction of the resulting alkene with 2-nitrobenzenesulfonyl hydrazine,12 in situ prepared, gave 9 in 65% yield in two steps. Deprotection of benzoate with K2CO3 in MeOH gave alcohol 10 in 96% yield. Swern oxidation of 10 gave epoxy aldehyde 11 in 98% yield, which was homologated to afford 12 in 85% yield. The cross-metathesis of 12 with chiral segments 1310 (97% ee) and 14b10 (97% ee) in the presence of Grubbs’ second-generation catalyst gave 15a in 88% yield and 15b in 92% yield, respectively. Removal of the two TBS groups for 15a with TBAF in THF gave 3a in 88% yield.13 Deprotection of benzoyl group of 15b with K2CO3 in THFeMeOH gave 16b in 95% yield, followed by desilylation with TBAF to afford 3b in 90% yield.13
unsaturated ester 19 in 93% yield in two steps. Diimide reduction of 19 with 2-nitrobenzenesulfonyl hydrazine gave saturated ester 20 in 91% yield. Reduction of ester 20 with LiBH4 in MeOH to afford alcohol 21 in 83% yield, oxidation with IBX to the aldehyde followed by homologation via Wittig reaction gave 22 in 86% yield in two steps. The cross-metathesis of 22 with chiral segments 11a and 11b in the presence of Grubbs’ second-generation catalyst gave 23a in 81% yield and 23b in 72% yield, respectively. Deprotection of 17a and 17b by the same two steps sequence as that of 12b afforded 4a and 4b in 62% and 80% yield, respectively.13 PdII-catalyzed cyclization was examined for diols 3a and 3b (Scheme 4). When diol 3a was subjected to a PdII-catalyzed reaction with 10 mol % of PdCl2(CH3CN)2 in THF at 0 C for 25 min, the THF2,6-cis-THP ring product 5a was selectively obtained with a 92:8 ratio in 92% yield. The structure of 5a was identified by NOE experiment. On the other hand, the reaction of 3b required 2.5 h at room temperature to reach completion to give THF-2,6-trans-THP ring product 5b preferentially with a 93:7 ratio in 92% yield. The ring structures of 5a and 5b were determined NOE experiments. Stereochemistry of the reactions is quite similar to those of our previous result.9 In comparison, PdII-catalyzed cyclization of the diol 4a in THF at 0 C for 25 min, the THF-2,5-cis-THF ring product 6a (82% de; 6a:6b¼91:9) and the fused THP-2,6-trans-THP 25a (84% de; 25a:25b¼92:8) were obtained with a 1.2:1 ratio in 86% yield (Scheme 5). After separation of 6a and 25a by silica-gel column chromatography, the structures of products were identified by NOE experiments. Also, the cyclization of 4b at 0 C for 1 h gave bis THFeTHF compound 6b (92% de; 6a:6b¼4:96) and the fused THPeTHP compound 25b (90% de; 25a:25b¼5:95) with a 1.3:1 ratio in 79% yield. With respect to the reaction process, we considered that PdIIcatalyst triggered reaction in a tandem pathway based on several experiments reported in previous communication (Scheme 6).7 Initially, the Pd p-complex is formed by a coordination of PdCl2 with the olefinic bond on the syn-face side to the hydroxyl group of allylic alcohol preferentially. Then, a ligand exchange of the hy-
Scheme 2. Synthesis of 3a and 3b.
The syntheses of 4a and 4b began with Sharpless epoxidation of 1714 to afford 1814 in 88% yield in 97% ee (Scheme 3). Swern oxidation of 18 followed by Wittig reaction of the resulting aldehyde with methyl (triphenylphosphoranylidene)acetate gave
droxyl group with epoxy function generates an intermediate I. Successively, I prompts the tandem cyclization along with epoxide opening by a nucleophilic attack of the terminal alcohol to give a contiguous THFeTHF or THFeTHP compounds, 2a or 5a. On the
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Scheme 3. Synthesis of 4a and 4b.
Scheme 4. Cyclization of 3a and 3b.
Scheme 6. Proposed reaction pathway.
Scheme 5. Cyclization of 4a and 4b.
cyclization of methyl substituted 4a, a tandem reaction from the intermediate II proceeds not only via 5-exo-tet-5-exo-trig to afford 6a in which was same mode as those of 1a and 3a. At the same time, another tandem reaction takes place via 6-endo-tet-6-exo-trig mode to afford 25a. This formation would be explained by the endo cyclization onto the C-5 carbon of which cation is stabilized by the methyl group. Similar epoxide ring opening processes were known well in literature.14 It is quite interesting that electronically favored 6-endo-tet mode of epoxide-opening competes with 5-exo-tet mode favored by Baldwin rules.
The different rates of reactions for 3a and 3b may be attributed to the stability of the precursor I for the cyclization (Scheme 7). For the arrangement of the Pd complex in the reaction of 3a and 3b, the Pd p-complexes A from 3a, B/C from 3b, are available and could react. Although the Pd p-complexes B/C possess an unfavorable steric repulsion in their conformations, the Pd p-complex A does not. Therefore, the cyclization of 3a proceeds more smoothly than that of 3b. 3. Conclusion In summary, a PdII-catalyzed tandem cyclization of chiral nonracemic allylic alcohols possessing an internal epoxide and a terminal alcohol resulted in the stereospecific formation of chiral nonracemic contiguous THFeTHF and THFeTHP ring units with high 1,3-chirality transfer. The cyclizations take place via a 5-exotet-5-exo-trig mode, however, the cyclization of methyl substituted epoxy diols proceeded via 6-endo-tet-6-exo-trig mode in a part to
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J¼8.4, 7.6 Hz), 5.77 (1H, dtd, J¼10.8, 7.6, 0.8 Hz), 5.22 (1H, ddt, J¼10.8, 8.8, 1.6 Hz), 4.39 (2H, t, J¼6.8 Hz), 3.69e3.59 (2H, m), 3.38 (1H, ddd, J¼8.8, 2.4, 1.2 Hz), 2.87 (1H, dt, J¼4.4, 2.4 Hz), 2.71 (2H, dtdd, J¼7.6, 6.8, 1.6, 1.2 Hz), 1.70e1.54 (4H, m), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 166.5, 133.0, 130.9, 130.2, 130.1, 129.6, 128.4, 63.9, 62.6, 59.9, 54.1, 29.1, 28.5, 27.4, 25.9, 18.3, 5.3; IR (neat, cm1) 3019, 2955, 2858, 1716, 1603, 1452, 1386, 1315, 1278, 1216, 1177, 1113, 1027; MS (FAB) m/z 391 (MþHþ). HRMS calcd for C22H35O4Si: 391.2305: found; m/z 391.2311.
Scheme 7. Proposed intermediates: A from 3a and B/C from 3b.
construct the oxygen-fused THPeTHP ring units. The chirality transfer can be considered as the initial formation of a hydroxydirected p-face recognition of the PdII-catalyst and the subsequent tandem cyclization process through the intermediates. The different reaction rates of cyclization precursors that are different stereochemistry at allylic alcohol have been elucidated. 4. Experimental section 4.1. General methods Ether and THF were dried over sodium benzophenone ketide and toluene was dried over CaH2. They were used freshly after distillation. CH2Cl2 was distilled from P2O5. All other reagents were used without further purification. Unless otherwise stated, all reactions were run under an atmosphere of nitrogen. 1H and 13C NMR spectra were obtained at 25 C with a JEOL JNM-AL-500 (500 MHz and 125 MHz), JEOL JNM-AL-300 (300 MHz and 75 MHz) JEOL JNMAL-600 (600 MHz and 150 MHz), and Varian Inova Unity XL-400 (400 MHz, 100 MHz) spectrometers. Proton chemical shifts were internally referenced to the residual proton resonance in CDCl3 (d 7.26) and C6D6 (d 7.16). Carbon chemical shifts were internally referenced to the deuterated solvent signals in CDCl3 (d 77.00) and C6D6 (d 128.06). Mass spectra were recorded on JEOL JMC-GC MATE and JEOL JMS-SX 102A QQ. IR spectra were recorded on a JASCO FT/ IR-410 and optical rotations were recorded on a JASCO P-2200. Chiral HPLC analyses were performed on a SHIMADZU SPD-6A. A TLC was run on Merck silica gel 60F254 plates. Flash column chromatography was performed with Merck silica gel 60 (40e63 mm). Chromatorex NH-SGgrade NH DM1020SG (amino silica gel) purchased from Fuji Silysia Chemical was used for the chromatography for acid sensitive materials. 4.2. Experimental procedure and characterization data for compounds 4.2.1. (Z)-(5S,6S)-1-Benzoyloxy-9-(tert-butyldimethylsiloxy)-5,6-epoxy-non-3-ene (8). To a suspension of 3-(benzoyloxy)propyltriphenylphosphoium bromide (677 mg, 1.32 mmol) in THF (20 mL) were added K2CO3 (608 mg, 4.40 mmol) and 18-crown-6-ether (20 mg, 0.075 mmol) and the mixture was refluxed for 1 h. To this solution, a solution of the aldehyde 7 (215 mg, 0.88 mmol) in THF (10 mL) was added. The reaction mixture was refluxed for 1.5 h before quenching with satd NH4Cl aq The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 8 (290 mg) in 84% yield. Colorless oil, Rf¼0.61 (20% 1 EtOAc in hexane); ½a20 D 15.5 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 8.06e8.03 (2H, m), 7.56 (1H, tt, J¼7.6, 1.6 Hz), 7.44 (2H, dd,
4.2.2. (5S,6S)-1-Benzoyloxy-9-(tert-butyldimethylsiloxy)-5,6epoxynonane (9). To a solution of 8 (103 mg, 0.26 mmol) in CH2Cl2 (2 mL) was added o-nitrobenzensulfonylchloride (232 mg, 1.05 mmol). To this solution, hydrazine monohydrate (0.10 mL, 2.10 mmol) and Et3N (0.29 mL, 2.10 mmol) were added dropwise at 0 C. The reaction mixture was stirred for two days before quenching with satd NH4Cl aq. The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 9 (80.8 mg) in 78% yield. Colorless oil, Rf¼0.71 (20% 1 EtOAc in hexane); ½a20 D 15.9 (c 1.08, CHCl3); H NMR (400 MHz, CDCl3) d 8.05e8.02 (2H, m), 7.55 (1H, tt, J¼7.6, 1.6 Hz), 7.43 (2H, t, J¼7.6 Hz), 4.33 (2H, t, J¼6.8 Hz), 3.66e3.61 (2H, m), 2.73e2.69 (2H, m), 1.83 (2H, quin, J¼6.8 Hz), 1.68e1.54 (8H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 166.6, 132.9, 130.4, 129.5, 128.3, 64.7, 62.6, 58.54, 58.51, 31.7, 29.2, 28.6, 28.5, 25.9, 22.7, 18.3, 5.3; IR (neat, cm1) 3683, 3019, 2955, 2400, 1715, 1472, 1278, 1216, 1112, 1046; MS (FAB) m/z 393 (MþHþ). HRMS calcd for C22H37O4Si: 393.2461: found; m/z 393.2466. 4.2.3. (5S,6S)-9-(tert-Butyldimethylsiloxy)-5,6-epoxynonan-1-ol (10). To a mixed solution of 8 (87.4 mg, 0.22 mmol) in MeOH (5 mL) and THF (5 mL) was added K2CO3 (92.6 mg, 0.67 mmol) at room temperature. The reaction mixture was stirred for 4.5 h before quenching with satd NH4Cl aq. The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 10 (62.1 mg) in 96% yield. Colorless oil, Rf¼0.14 (20% 1 EtOAc in hexane); ½a20 D 21.4 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 3.68e3.60 (4H, m), 2.72e2.66 (2H, m), 1.71e1.46 (10H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 62.6, 62.6, 58.7, 58.6, 32.4, 31.7, 29.2, 28.6, 25.9, 22.3, 18.3, 5.3; IR (neat, cm1) 3431, 2931, 2859, 2738, 1741, 1472, 1389, 1361, 1254, 1099, 1007; MS (FAB) m/z 289 (MþHþ). HRMS calcd for C15H33O3Si: 289.2199: found; m/z 289.2206. 4.2.4. (5S,6S)-9-(tert-Butyldimethylsiloxy)-5,6-epoxynonanal (11). To a solution of oxalyl chloride (0.08 mL, 0.96 mmol) in CH2Cl2 (7 mL) was added DMSO (0.10 mL, 1.44 mmol) at 78 C and the mixture stirred for 20 min. To the mixture was added a solution of 10 (62.1 mg, 0.22 mmol) in CH2Cl2 (3 mL) and the mixture was stirred for 40 min before addition of Et3N (0.40 mL, 2.88 mmol). The resulting mixture was warmed to room temperature. H2O was added to the mixture and the mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 11 (135 mg) in 98% yield. Yellow oil, Rf¼0.38 (20% EtOAc in hexane); 1 ½a20 D 20.0 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 9.77 (1H, t, J¼1.6 Hz), 3.68e3.58 (2H, m), 2.71e2.65 (2H, m), 2.51 (2H, td, J¼7.2, 1.6 Hz), 1.84 (2H, m), 1.70e1.59 (4H, m), 1.57e1.42 (2H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 202.0, 62.6, 58.3, 58.2, 43.4, 31.3, 29.1, 28.5, 25.9, 18.6, 18.3, 5.4; IR (neat, cm1) 2930, 2857, 2718, 1727, 1471, 1389, 1362, 1254, 1097, 1048, 1007; MS (FAB)
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m/z 287 (MþHþ). HRMS calcd for C15H31O3Si: 287.2042: found; m/z 287.2049. 4.2.5. (6S,7S)-10-(tert-Butyldimethylsiloxy)-6,7-epoxydec-1-ene (12). To the mixture of methyltriphenylphosphonium bromide (514.4 mg, 1.44 mmol) in THF (10 mL) was added a solution of sodium bis(trimethylsilyl)amide (1.34 mmol, 1.9 M in THF, 0.71 mL) at 0 C and the mixture was stirred for 1 h at room temperature. After cooling to 0 C, the solution of 11 (137.5 mg, 0.48 mmol) in THF (3 mL) was slowly dropped and the reaction mixture was stirred for 5 min at the same temperature. The mixture was quenched with satd NH4Cl aq and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 10% EtOAc in hexane gave 12 (115.5 mg) in 85% yield. Colorless oil, Rf¼0.67 (10% EtOAc in hexane); ½a20 D 24.2 (c 1.50, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.79 (1H, ddt, J¼17.2, 10.4, 6.4 Hz), 5.01 (1H, dq, J¼17.2, 1.6 Hz), 4.96 (1H, ddt, J¼10.4, 1.6, 1.2 Hz), 3.69e3.59 (2H, m), 2.71e2.68 (2H, m), 2.15e2.09 (2H, m), 1.68e1.53 (8H, m), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 138.3, 114.8, 62.7, 58.7, 58.6, 33.4, 31.5, 29.2, 28.6, 25.9, 25.3, 18.3, 5.3; IR (neat, cm1) 3078, 2930, 2858, 1641, 1471, 1388, 1361, 1254, 1100, 1006; MS (FAB) m/z 285 (MþH þ). HRMS calcd for C16H32O2Si: 285.2250: found; m/z 285.2255; Anal. Calcd for C16H31O2Si: C, 67.54; H, 11.34. Found: C, 67.69; H, 11.30. 4.2.6. Alkene metathesis reaction of 12 with 13 and 14b. A mixture of 9 (142 mg, 0.5 mmol) and 13 (280 mg, 1.5 mmol) or 14b (264 mg, 1.5 mmol) in CH2Cl2 (10 mL) and Grubbs’ second-generation catalyst (21 mg, 0.025 mmol) was refluxed for 3 h under an Ar atmosphere. Concentration and purification of the residue by column chromatography on silica gel eluted with 5% Et2O in hexane gave 15a (195 mg) in 88% yield or 15b (199 mg) in 92% yield. 4.2.7. (E)-(2S,8S,9S)-2,12-Bis-(tert-butyldimethylsiloxy)-8,9epoxydodec-3-ene (15a). Colorless oil, Rf¼0.25 (10% CHCl3 in hex1 ane); ½a20 D 13.5 (c 1.07, CHCl3); H NMR (500 MHz, CDCl3) d 5.55e5.49 (1H, m), 5.45 (1H, dd, J¼16.0, 16.0 Hz), 4.24 (1H, quin, J¼6.0 Hz), 3.68e3.60 (2H, m), 2.68e2.67 (2H, m), 2.06e2.03 (2H, m), 1.67e1.48 (8H, m), 1.18 (3H, d, J¼6.0 Hz), 0.89 (18H, s), 0.04 (12H, s); 13C NMR (125 MHz, CDCl3) d 135.3, 128.3, 69.3, 62.7, 58.7, 58.6, 31.8, 31.5, 29.2, 28.6, 25.93, 25.91, 25.7, 24.6, 18.3, 18.3, 4.4, 4.7, 5.3; IR (neat, cm1) 2929, 285, 2738, 2710, 1733, 1671, 1472, 1389, 1362, 1254, 1148, 1096, 1004; MS (FAB) m/z 465 (MþNaþ). HRMS calcd for C24H50O3Si2Na: 465.3196: found; m/z 465.3203. 4.2.8. (E)-(2R,8S,9S)-2-Benzoyloxy-12-(tert-butyldimethylsiloxy)8,9-epoxydodec-3-ene (15b). Colorless oil, Rf¼0.19 (50% CHCl3 in 1 hexane); ½a20 D 25.8 (c 0.82, CHCl3); H NMR (500 MHz, CDCl3) d 8.04 (2H, d, J¼8.0 Hz), 7.54 (1H, t, J¼8.0 Hz), 7.43 (2H, t, J¼8.0 Hz), 5.77 (1H, dt, J¼14.0, 7.0 Hz), 5.63e5.50 (2H, m), 3.71e3.59 (2H, m), 2.75e2.61 (2H, m), 2.17e2.04 (2H, m), 1.70e1.48 (8H, m), 1.42 (3H, d, J¼6.5 Hz), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 165.8, 132.7, 132.6, 130.8, 130.1, 129.5, 128.3, 71.6, 62.7, 58.59, 58.58, 31.9, 31.5, 29.2, 28.6, 25.9, 25.3, 20.5, 18.3, 5.3; IR (neat, cm1) 2930, 2858, 1718, 1603, 1584, 1471, 1374, 1361, 1315, 1272, 1217, 1176, 1100, 1043, 1005; MS (FAB) m/z 455 (MþNaþ). HRMS calcd for C25H40O4SiNa: 455.2594: found; m/z 455.2599. 4.2.9. (E)-(2R,8S,9S)-12-(tert-Butyldimethylsiloxy)-8,9-epoxydodec3-ene-2-ol (16b). A solution of 15b (47.6 mg, 0.11 mmol) in a mixture of MeOH (2 mL) and THF (2 mL) was stirred at room temperature overnight in the presence of K2CO3 (43.7 mg, 0.32 mmol). The reaction was quenched with satd NH4Cl aq and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The purification of the residue by column
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chromatography on silica gel eluted with 20% EtOAc in hexane gave 16b (34.3 mg) in 95% yield. Colorless oil, Rf¼0.20 (20% EtOAc in 1 hexane); ½a20 D 14.9 (c 0.32, CHCl3); H NMR (500 MHz, CDCl3) d 5.62 (1H, dt, J¼15.5, 6.5 Hz), 5.53 (1H, dd, J¼15.5, 6.5 Hz), 4.26 (1H, dq, J¼6.5, 6.0 Hz), 3.70e3.60 (2H, m), 2.69e2.67 (2H, m), 2.09e2.05 (2H, m), 1.66e1.50 (8H, m), 1.25 (3H, d, J¼6.5 Hz), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 134.7, 130.3, 68.8, 62.7, 58.64, 58.60, 31.8, 31.5, 29.2, 28.6, 25.9, 25.5, 23.4, 18.3, 5.3; IR (neat, cm1) 3433, 2929, 2850, 1638, 1462, 1254, 1099; MS (FAB) m/z 351 (MþNaþ). HRMS calcd for C18H36O3SiNa: 351.2331: found; m/z 351.2328. 4.2.10. Desilylation of 15a and 16b. To the solution of the silyl ether (0.1 mmol) in THF (3 mL) was added a solution of TBAF in THF (1.0 M 0.13 mL, 0.13 mmol for 16b, or 0.25 mL, 0.25 mmol for 15a) at room temperature and the reaction mixture was stirred for 30 min. Evaporation of solvent and purification of the residue by column chromatography on amino silica gel eluted with 70% EtOAc in hexane gave 3a (17.4 mg; 81%) or 3b (19.3 mg; 90%). 4 . 2 .11. ( E ) - ( 2 S , 8 S , 9 S ) - 8 , 9 - E p o x y d o d e c - 3 - e n e - 2 ,12 - d i o l (3a). Colorless oil, Rf¼0.14 (60% EtOAc in hexane); ½a20 D 21.6 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.62 (1H, dt, J¼15.6, 6.4 Hz), 5.53 (1H, dt, J¼15.6, 6.4 Hz), 4.26 (1H, quin, J¼6.4 Hz), 3.69 (2H, t, J¼6.4 Hz), 2.72 (2H, d like, J¼4.0 Hz), 2.07 (2H, d like, J¼4.0 Hz), 1.81e1.68 (4H, m), 1.63 (2H, br s), 1.56e1.48 (4H, m), 1.25 (3H, d, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3) d 134.8, 130.2, 68.8, 62.4, 58.8, 58.6, 31.7, 31.4, 29.1, 28.7, 25.5, 23.4; IR (neat, cm1) 3366, 2928, 2861, 1722, 1624, 1454, 1367, 1283, 1062; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/z 237.1472. 4 . 2 .12 . ( E ) - ( 2 R , 8 S , 9 S ) - 8 , 9 - E p o x y d o d e c - 3 - e n e - 2 ,12 - d i o l (3b). Colorless oil, Rf¼0.14 (60% EtOAc in hexane); ½a20 D 19.4 (c 0.55, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.62 (1H, dt, J¼15.6, 6.4 Hz), 5.53 (1H, ddt, J¼15.6, 6.4, 1.2 Hz), 4.26 (1H, quin, J¼6.4 Hz), 3.69 (2H, td, J¼6.4, 1.2 Hz), 2.73e2.70 (2H, m), 2.07 (2H, qd, J¼6.4, 1.2 Hz), 1.82e1.68 (4H, m), 1.65 (2H, br s), 1.59e1.49 (4H, m), 1.25 (3H, d, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3) d 134.8, 130.1, 68.8, 62.3, 58.8, 58.6, 31.7, 31.4, 29.1, 28.6, 25.5, 23.4; IR (neat, cm1) 3435, 3019, 2935, 2395, 1628, 1516, 1445, 1374, 1216, 1047; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/ z 237.1459. 4.2.13. (2R,3S)-6-(tert-Butyldimethyl silox y)-2 ,3-epoxy-2 methylhexanal (18). Sharpless epoxidation of 17 with (þ)-diethyl tartrate in the reported procedure using ()-diethyl tartrate,15 was conducted and yielded 18 (88%, 97% ee) as a colorless oil. 4.2.14. Methyl (E)-(4S,5S)-8-(tert-butyldimethylsilyl)oxy-4,5-epoxy4-methyloct-2-enoate (19). Following a similar procedure that was described for the synthesis of 11 from 10, oxidation of 18 (416 mg, 1.6 mmol) yielded the aldehyde as a colorless oil, which was used for the next step without further purification. To a solution of the aldehyde in benzene (18 mL) was added methyl (triphenylphosphoranylidene)acetate (646 mg, 1.92 mmol) at room temperature. The reaction mixture was stirred for 5 min and condensed. The purification of the residue by column chromatography on silica gel eluted with 10% EtOAc in hexane gave 19 (468 mg) in 93% yield. Colorless oil, Rf¼0.40 (10% EtOAc in hexane); ½a20 D þ7.42 (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) d 6.76 (1H, d, J¼15.9 Hz), 6.01 (1H, d, J¼15.9 Hz), 3.74 (3H, s), 3.68e3.62 (2H, m), 2.86 (1H, t, J¼6.1 Hz), 1.68e1.62 (4H, m), 1.42 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13 C NMR (125 MHz, CDCl3) d 166.2, 150.2, 120.9, 65.7, 62.4, 58.5, 51.6, 29.4, 25.9, 25.1, 18.2, 15.1, 5.4; IR (neat, cm1) 2953, 2857, 1728, 1655, 1463, 1436, 1388, 1362, 1310, 1256, 1170, 1098, 1010; MS
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(FAB) m/z 315 (MþHþ). HRMS calcd for C16H31O4Si: 315.1992: found; m/z 315.1996. 4.2.15. Methyl (4S,5S)-8-(tert-butyldimethylsiloxy)-4,5-epoxy-4methyloctanoate (20). Following a similar procedure that was described for the synthesis of 9 from 8, diimide reduction of 19 gave 20 in 91% yield. Colorless oil, Rf¼0.20 (10% EtOAc in hexane); ½a20 D 8.01 (c 0.59, CHCl3); 1H NMR (500 MHz, CDCl3) d 3.67 (3H, s), 3.65e3.60 (2H, m), 2.75 (1H, t, J¼6.1 Hz), 2.40 (2H, td, J¼7.0, 2.0 Hz), 1.92e1.82 (2H, m), 1.70e1.55 (4H, m), 1.25 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 173.5, 63.1, 62.6, 59.8, 51.7, 33.4, 29.62, 29.61, 25.9, 25.1, 18.3, 16.5, 5.3; IR (neat, cm1) 3018, 2954, 2930, 2858, 1738, 1463, 1438, 1387, 1362, 1255, 1216, 1169, 1098, 1007; MS (FAB) m/z 317 (MþHþ). HRMS calcd for C16H33O4Si: 317.2148: found; m/z 317.2151. 4.2.16. (4S ,5S)-8-( tert-Butyl dimethylsilo xy) -4, 5 -epox y-4 methyloctan-1-ol (21). To the solution of ester 20 (50.3 mg, 0.16 mmol) in ether (5 mL) was added LiBH4 (3.5 mg, 0.16 mmol) and MeOH (6.5 mL, 0.16 mmol) at room temperature and the reaction mixture was stirred for 30 min. After quenching with satd NH4Cl aq, the mixture was extracted with ether (three times) and combined organic extracts were washed with brine and dried over MgSO4. Evaporation of the solvent and purification of the residue by column chromatography on amino silica gel eluted with 30% EtOAc in hexane gave 21 (38.1 mg) in 83% yield. Colorless oil, Rf¼0.19 (30% EtOAc in hexane); ½a20 D 6.73 (c 0.59, CHCl3); 1H NMR (500 MHz, CDCl3) d 3.67e3.63 (4H, m), 2.79 (1H, t, J¼6.0 Hz), 1.87 (1H, br s), 1.72e1.57 (8H, m), 1.27 (3H, s), 0.89 (9H, s), 0.05 (6H, s); 13C NMR (125 MHz, CDCl3) d 63.7, 62.6, 62.5, 60.7, 35.0, 29.6, 17.9, 15.9, 25.2, 18.3, 16.3, 5.3; IR (neat, cm1) 3430, 2930, 2858, 1740, 1471, 1387, 1362, 1254, 1098; MS (FAB) m/z 289 (MþHþ). HRMS calcd for C15H33O3Si: 289.2199: found; m/z 289.2195. 4.2.17. (5S,6S)-9-(tert-Butyldimethylsiloxy)-5,6-epoxy-5-methylnon1-ene (22). To the solution of 21 (38.1 mg, 0.13 mmol) in acetone (4 mL) was added IBX (111 mg, 6.9 mmol) at room temperature and the reaction mixture was refluxed for 3 h. The reaction mixture was filtered off and the filtrate was condensed. The residue was passed through short silica gel pad to give almost pure aldehyde, which was used for the next step without further purification. To a suspension of methyltriphenylphosphonium bromide (70.7 mg, 0.20 mmol) in THF (3 mL) was added a solution of sodium bis(trimethylsilyl)amide in toluene (0.6 M, 0.3 mL, 0.18 mmol) at 0 C and the mixture was stirred for 1 h at room temperature. To this solution, a solution of the crude aldehyde (38.1 mg) in THF (1 mL) was slowly added at 20 C. The reaction mixture was stirred for 5 min at 20 C before quenching with satd NH4Cl aq. The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 10% EtOAc in hexane gave 22 (32.1 mg) in 86% yield. Colorless oil, 1 Rf¼0.83 (20% EtOAc in hexane); ½a20 D 1.36 (c 1.16, CHCl3); H NMR (500 MHz, CDCl3) d 5.80 (1H, ddt, J¼17.1, 10.4, 6.7 Hz), 5.02 (1H, ddt, J¼17.1, 1.8, 1.5 Hz), 4.96 (1H, dd, J¼10.4, 1.8 Hz), 3.69e3.60 (2H, m), 2.74 (1H, t, J¼6.0 Hz), 2.21e2.09 (2H, m), 1.74e1.47 (6H, m), 1.26 (3H, s), 0.89 (9H, s), 0.05 (6H, s); 13C NMR (125 MHz, CDCl3) d 138.0, 114.8, 63.4, 62.7, 60.5, 38.0, 29.7, 29.5, 25.9, 25.2, 18.3, 16.4, 5.3; IR (neat, cm1) 2929, 2858, 1642, 1472, 1386, 1254, 1099; MS (FAB) m/z 285 (MþHþ). HRMS calcd for C16H33O2Si: 285.2250: found; m/z 285.2252. 4.2.18. (E)-(2S,7S,8S)-2-Benzoyloxy-11-(tert-butyldimethylsiloxy)7,8-epoxy-7-methylundec-3-ene (23a). Following a similar procedure that was described for the synthesis of 15b from 12, alkene
metathesis of 22 with 14a gave 23a in 81% yield. Colorless oil, 1 Rf¼0.14 (10% EtOAc in hexane); ½a20 D þ6.59 (c 0.45, CHCl3); H NMR (500 MHz, CDCl3) d 8.04 (2H, d, J¼7.5 Hz), 7.54 (1H, t, J¼7.5 Hz), 7.43 (2H, t, J¼7.5 Hz), 5.77 (1H, dt, J¼15.0, 6.5 Hz), 5.62e5.55 (2H, m), 3.64e3.57 (2H, m), 2.73 (1H, t, J¼5.5 Hz), 2.19e2.13 (2H, m), 1.73e1.47 (6H, m), 1.42 (3H, d, J¼6.0 Hz), 1.24 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 165.8, 132.8, 132.3, 130.7, 130.0, 129.5, 128.3, 71.5, 63.4, 62.6, 60.4, 38.1, 29.7, 27.9, 25.9, 25.2, 20.5, 18.3, 16.5, 5.3; IR (neat, cm1) 2930, 2857, 1719, 1451, 1271, 1109; MS (FAB) m/z 455 (MþNaþ). HRMS calcd for C25H40O4SiNa: 455.2594: found; m/z 455.2597. 4.2.19. (E)-(2R,7S,8S)-2-Benzoyloxy-11-(tert-butyldimethylsiloxy)7,8-epoxy-7-methylundec-3-ene (23b). Following a similar procedure that was described for the synthesis of 15b from 12, alkene metathesis of 22 with 14b gave 23b in 72% yield. Colorless oil, 1 Rf¼0.14 (10% EtOAc in hexane); ½a20 D 12.5 (c 0.49, CHCl3); H NMR (400 MHz, CDCl3) d 8.05e8.02 (2H, m), 7.54 (1H, tt, J¼7.6, 1.2 Hz), 7.42 (2H, tt, J¼7.6, 1.2 Hz), 5.77 (1H, dt, J¼14.4, 5.6 Hz), 5.62e5.51 (2H, m), 3.68e3.58 (2H, m), 2.72 (1H, t, J¼6.0 Hz), 2.22e2.04 (2H, m), 1.74e1.48 (6H, m), 1.41 (3H, d, J¼6.4 Hz), 1.24 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 165.8, 132.7, 132.3, 130.7, 130.0, 129.5, 128.2, 71.5, 63.3, 62.6, 60.4, 38.0, 29.7, 27.9, 25.9, 25.2, 20.4, 18.3, 16.5, 5.3; IR (neat, cm1) 2929, 2857, 1718, 1451, 1271, 1109; MS (FAB) m/z 455 (MþNaþ). HRMS calcd for C25H40O4SiNa: 455.2594: found; m/z 455.2590. 4.2.20. (E)-(2S,7S,8S)-11-(tert-Butyldimethylsiloxy)-7,8-epoxy-7methylundec-3-ene-2-ol (24a), (E)-(2R,7S,8S)-11-(tert-butyldimethylsiloxy)-7,8-epoxy-7-methylundec-3-ene-2-ol (24b). Following a similar procedure that was described for the synthesis of 16 from 15b, a deprotection of benzoates of 23a and 23b gave 24a (87% yield) and 24b (81% yield), respectively. Compound 24a: colorless oil, Rf¼0.19 (20% EtOAc in hexane); 1 ½a20 D 10.1 (c 0.64, CHCl3); H NMR (500 MHz, CDCl3) d 5.61 (1H, dt, J¼15.5, 7.5 Hz), 5.53 (1H, dd, J¼15.5, 6.0 Hz), 4.25 (1H, quin, J¼6.0 Hz), 3.68e3.60 (2H, m), 2.73 (1H, t, J¼6.5 Hz), 2.21e2.09 (2H, m), 1.67e1.52 (6H, m), 1.25e1.23 (6H, m), 0.89 (9H, s), 0.05 (6H, s); 13 C NMR (125 MHz, CDCl3) d 134.7, 129.8, 68.7, 63.3, 62.7, 60.5, 38.2, 29.6, 27.9, 25.9, 25.2, 23.4, 18.3, 16.4, 5.3; IR (neat, cm1) 3437, 2958, 2930, 2858, 1463, 1386, 1254, 1099; MS (FAB) m/z 351 (MþNaþ). HRMS calcd for C18H36O3SiNa: 351.2331: found; m/z 351.2328. Compound 24b: colorless oil, Rf¼0.19 (20% EtOAc in hexane); 1 ½a20 D þ0.15 (c 0.77, CHCl3); H NMR (500 MHz, CDCl3) d 5.62 (1H, dtd, J¼16.0, 7.0, 1.0 Hz), 5.53 (1H, ddt, J¼16.0, 6.5, 1.0 Hz), 4.25 (1H, quin, J¼6.5 Hz), 3.69e3.60 (2H, m), 2.73 (1H, t, J¼6.0 Hz), 2.20e2.07 (2H, m), 1.71e1.48 (6H, m), 1.25 (3H, s), 1.24 (3H, d, J¼6.5 Hz), 0.89 (9H, s), 0.05 (6H, s); 13C NMR (125 MHz, CDCl3) d 134.6, 129.9, 68.7, 63.4, 62.7, 60.5, 38.2, 29.7, 27.9, 25.9, 25.2, 23.4, 18.3, 16.4, 5.3; IR (neat, cm1) 3433, 2955, 2929, 2858, 1471, 1463, 1386, 1254, 1099; MS (FAB) m/z 351 (MþNaþ). HRMS calcd for C18H36O3SiNa: 351.2331: found; m/z 351.2327. 4.2.21. (E)-(2S,7S,8S)-7,8-Epoxy-7-methylundec-3-ene-2,11-diol (4a), (E)-(2R,7S,8S)-7,8-epoxy-7-methylundec-3-ene-2,11-diol (4b). Following a similar procedure that was described for the synthesis of 3b from 16b, desilylation of 24a and 24b gave 4a (72% yield) and 4b (99% yield), respectively. Compound 4a: colorless oil, Rf¼0.14 (70% EtOAc in hexane); ½a20 D þ0.97 (c 0.47, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.59 (1H, dt, J¼15.0, 6.0 Hz), 5.52 (1H, dd, J¼15.0, 6.0 Hz), 4.29 (1H, quin, J¼6.0 Hz), 3.69e3.67 (2H, m), 2.75 (1H, t, J¼5.5 Hz), 2.18e2.03 (2H, m), 1.75e1.63 (4H, m), 1.60e1.46 (2H, m), 1.26e1.23 (6H, m); 13C NMR (125 MHz, CDCl3) d 134.8, 129.6, 68.7, 63.4, 62.2, 60.9, 38.1, 29.5, 27.9, 25.1, 23.5, 16.4; IR (neat, cm1) 3419, 2973, 2933, 2871,
N. Kawai et al. / Tetrahedron 69 (2013) 11017e11024
1739, 1448, 1374, 1244, 1048; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/z 237.1464. Compound 4b: colorless oil, Rf¼0.14 (70% EtOAc in hexane); ½a20 D 0.62 (c 0.40, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.61 (1H, dt, J¼16.0, 6.0 Hz), 5.53 (1H, dd, J¼16.0, 6.0 Hz), 4.25 (1H, quin, J¼6.0 Hz), 3.71e3.68 (2H, m), 2.76 (1H, m), 2.23e2.05 (2H, m), 1.76e1.65 (4H, m), 1.60e1.48 (2H, m), 1.26e1.24 (6H, m); 13C NMR (125 MHz, CDCl3) d 134.7, 129.7, 68.6, 63.4, 62.3, 60.9, 38.1, 29.5, 27.8, 25.2, 23.3, 16.5; IR (neat, cm1) 3400, 2960, 2930, 2878, 1739, 1454, 1373, 1244, 1060; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/z 237.1462. 4.3. General procedure of PdII-catalyzed reaction To the solution of the precursor (0.1 mmol) in THF (2.5 mL) was added PdCl2(MeCN)2 (2.2 mg, 10 mmol) at 0 C or room temperature and the reaction mixture was stirred for 10e90 min. The mixture was quenched with aq NaHCO3 and extracted with EtOAc. The extract was washed with brine and dried over MgSO4. Solvent was removed and the residue was purified by column chromatography on silica gel eluted with 10% EtOAc in hexane to give the cyclized product. Reactions of 3a, 3b, 4a, and 4b. Compounds 5a from 3a (reaction time and temperature: 1 h, 23 C; yield: 92%; 5a:5b¼92:8). Compounds 5b from 3b (reaction time and temperature: 2.5 min, 23 C; yield: 86%; 5a:5b¼7:93). Compounds 6a and 25a from 4a (reaction time and temperature: 25 min, 0 C; yield: 86%; 6a (6a:6b¼91:9): 25a (25a:25b¼92:8)¼1.2:1). Compounds 6b and 25b from 4b (reaction time and temperature: 1 h, 0 C; yield: 79%; 6b (6a:6b¼4:96): 25b (25a:25b¼5:95)¼ 1.3:1). 4.3.1. (E)-(2R,20 R,6S)-2-(Prop-1-enyl)-6-(tetrahydrofuran-20 -yl)tetrahydropyran (5a). Colorless oil, Rf¼0.64 (20% EtOAc in hexane); 1 ½a20 D þ8.65 (c 0.67, CHCl3); H NMR (400 MHz, CDCl3) d 5.66 (1H, dqd, J¼15.6, 6.4, 1.2 Hz), 5.50 (1H, ddq, J¼15.6, 6.4, 1.2 Hz), 3.87e3.70 (4H, m), 3.27 (1H, ddd, J¼11.2, 6.4, 2.4 Hz), 1.98e1.19 (10H, m), 1.68 (3H, dt, J¼6.4, 1.2 Hz); 13C NMR (100 MHz, CDCl3) d 132.6, 126.0, 81.6, 79.7, 78.1, 68.4, 31.8, 27.8, 27.7, 25.7, 23.2, 17.8; IR (neat, cm1) 3155, 2939, 2253, 1793, 1469, 1381, 1262, 1094; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1457. 4.3.2. (E)-(2S,20 R,6S)-2-(Prop-1-enyl)-6-(tetrahydrofuran-20 -yl)tetrahydropyran (5b). Colorless oil, Rf¼0.55 (20% EtOAc in hexane); 1 ½a20 D þ12.5 (c 0.31, CHCl3); H NMR (500 MHz, CDCl3) d 5.64 (1H, dq, J¼15.5, 6.0 Hz), 5.58 (1H, dd, J¼15.5, 5.0 Hz), 4.29 (1H, q, J¼5.0 Hz), 3.87 (1H, t, J¼7.0 Hz), 3.83 (1H, t, J¼7.0 Hz), 3.73 (1H, q, J¼7.0 Hz), 3.53 (1H, ddd, J¼10.0, 7.0, 3.0 Hz), 2.00e1.41 (10H, m), 1.71 (3H, d, J¼6.0 Hz); 13C NMR (125 MHz, CDCl3) d 131.2, 127.4, 80.2, 73.0, 72.6, 68.3, 29.4, 28.1, 27.4, 25.6, 18.4, 18.0; IR (neat, cm1) 2925, 2854, 1736, 1665, 1458, 1374, 1260, 1031; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1460. 4.3.3. (E)-(2R,20 R,5S)-5-Methyl-2-(prop-1-enyl)-5-(tetrahydrofuran20 -yl)tetrahydrofuran (6a). Colorless oil, Rf¼0.26 (5% EtOAc in 1 benzene); ½a20 D þ3.95 (c 0.28, CHCl3); H NMR (400 MHz, CDCl3) d 5.69 (1H, dqd, J¼15.2, 6.4, 0.8 Hz), 5.48 (1H, ddq, J¼15.2, 7.2, 1.6 Hz), 4.33 (1H, q, J¼7.2 Hz), 3.86 (1H, m), 3.81e3.74 (2H, m), 2.04e1.98 (2H, m), 1.93e1.83 (3H, m), 1.75e1.58 (3H, m), 1.68 (3H, dd, J¼6.4, 1.6 Hz), 1.18 (3H, s); 13C NMR (100 MHz, CDCl3) d 132.2, 127.6, 84.4, 84.3, 79.7, 68.6, 35.0, 32.8, 27.1, 26.2, 22.5, 17.7; IR (neat, cm1) 2966, 2928, 2857, 1454, 1370, 1071; MS (EIþ) m/z
11023
196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1469. 4.3.4. (E)-(2R,4aR,8aS)-4a-Methyl-2-propenyloctahydropyrano[3,2b]pyran (25a). Colorless oil, Rf¼0.41 (5% EtOAc in benzene); ½a20 D 138.9 (c 0.15, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.69e5.67 (2H, m), 4.37 (1H, d, J¼6.0 Hz), 3.71 (1H, td, J¼12.4, 3.2 Hz), 3.60 (1H, ddt, J¼12.4, 5.6, 1.2 Hz), 3.45 (1H, dd, J¼11.6, 4.4 Hz), 2.10 (1H, m), 1.78e1.48 (10H, m), 1.27 (3H, s); 13C NMR (100 MHz, CDCl3) d 130.4, 128.1, 73.3, 73.1, 73.0, 60.5, 33.9, 26.4, 26.2, 24.6, 18.0, 13.5; IR (neat, cm1) 2929, 2856, 1455, 1377, 1261, 1075; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1469. 4.3.5. (E)-(2S,20 R,5S)-5-Methyl-2-(prop-1-enyl)-5-(tetrahydrofur an-20 -yl)tetrahydrofuran (6b). Colorless oil, Rf¼0.26 (5% EtOAc in 1 benzene); ½a20 D þ0.46 (c 0.54, CHCl3); H NMR (400 MHz, CDCl3) d 5.67 (1H, dqd, J¼15.2, 6.4, 0.8 Hz), 5.45 (1H, ddq, J¼15.2, 7.6, 1.6 Hz), 4.35 (1H, q, J¼7.6 Hz), 3.90e3.75 (3H, m), 2.06e1.97 (2H, m), 1.95e1.83 (3H, m), 1.75e1.59 (3H, m), 1.67 (3H, dd, J¼6.4, 1.6 Hz), 1.18 (3H, s); 13C NMR (100 MHz, CDCl3) d 132.8, 127.9, 84.9, 84.4, 81.3, 68.6, 33.9, 32.8, 27.5, 26.2, 24.1, 17.7; IR (neat, cm1) 2961, 2927, 2856, 1457, 1373, 1072; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1471. 4.3.6. (E)-(2S,4aR,8aS)-4a-Methyl-2-propenyloctahydropyrano[3,2b]pyran (25b). Colorless oil, Rf¼0.41 (5% EtOAc in benzene); ½a20 D 34.9 (c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.71 (1H, qqd, J¼15.2, 6.8, 0.8 Hz), 5.50 (1H, qqd, J¼15.2, 6.8, 1.6 Hz), 3.90 (1H, q, J¼6.8 Hz), 3.70 (1H, td, J¼12.0, 3.2 Hz), 3.61 (1H, ddt, J¼12.0, 5.6, 0.8 Hz), 3.19 (1H, dd, J¼12.0, 4.0 Hz), 1.78e1.56 (8H, m), 1.69 (3H, ddd, J¼6.4, 1.6, 0.8 Hz), 1.24 (3H, s); 13C NMR (100 MHz, CDCl3) d 131.7, 127.9, 80.6, 79.4, 72.2, 60.5, 37.8, 30.6, 26.2, 24.7, 17.8, 13.9; IR (neat, cm1) 2939, 2862, 1456, 1375, 1277, 1089; MS (CIþ) m/z 197. HRMS calcd for C12H21O2 (MþHþ): 197.1541: found; m/z 196.1546. Acknowledgements This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.09.067. References and notes 1. For recent review on Annonaceous acetogenin, (a) Liaw, C.-C.; Wu, T.-Y.; Chang, F.-R.; Wu, Y.-C. Plant. Med. 2010, 76, 1390e1404; (b) Spurr, I. B.; Brown, R. C. D. Molecules 2010, 15, 460e501; (c) Kojima, N.; Tanaka, T. Molecules 2009, 14, 3621e3661; (d) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; re, B.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275e306; (e) Bermejo, A.; Figade Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269e303. 2. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; Mac-Dougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988e7989. 3. (a) Fall, D.; Duval, R. A.; Gleye, C.; Laurens, A.; Hocquemiller, R. J. Nat. Prod. 2004, 67, 1041e1043; (b) Derbre, S.; Poupon, E.; Gleye, C.; Hocquemiller, R. J. Nat. Prod. 2004, 70, 300e303 For other acetogenin as having a THP ring, see the following; (c) Jimenezine: Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61, 419e421; (d) Pyranicin and pyragonicin: Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron 1998, 54, 5833e5844. 4. Ichimaru, N.; Yoshinaga, N.; Nishioka, T.; Miyoshi, H. Tetrahedron 2007, 63, 1127e1139. 5. (a) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993e1998; (b) Florence, G. J.; Morris, J. C.; Murray, R. G.; Osler, J. D.; Reddy, V. R.; Smith, T. K. Org. Lett. 2011, 13, 514e517; (c) Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1980, 102, 1155e1157; (d) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025e2028.
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6. (a) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691e1694; (b) Hoye, T. R.; Jenkins, S. A. J. Am. Chem. Soc. 1987, 109, 6196e6198. 7. Kumar, V. S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2002, 4, 2489e2492. 8. An Aueallene complex promoted intramolecular epoxide opening reaction was reported with medium stereoselectivity; see: Tarselli, M. A.; Zuccarello, J. L.; , M. R. Org. Lett. 2009, 11, 3490e3492. Lee, S. J.; Gagne 9. (a) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem.dAsian J. 2008, 3, 473e484; (b) Kawai, N.; Lagrange, J.-M.; Uenishi, J. Eur. J. Org. Chem. 2007, 2808e2814; (c) Kawai, N.; Lagrange, J. M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71, 4530e4537; (d) Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron: Asymmetry 2005, 16, 1299e1303. 10. Uenishi, J.; Fujikura, Y.; Kawai, N. Org. Lett. 2011, 13, 2350e2353.
11. Ohtsuka, Y.; Niitsuma, S.; Tadokoro, H.; Hayashi, T.; Oishi, T. J. Org. Chem. Soc. 1984, 49, 2326e2332. 12. Marsh, B. J.; Carbery, D. R. J. Org. Chem. 2009, 74, 3186e3188. 13. NH-silica gel was used for the purification of the cyclization precursors due to their acid sensitive property. 14. Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5331e5334. 15. (a) Clark, J. S.; Berger, R.; Hayes, S. T.; Senn, H. M.; Farrugia, L. J.; Thomas, L. H.; Morrison, A. J.; Gobbi, L. J. Org. Chem. 2013, 78, 673e696; (b) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321e5330.
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Stereoselective synthesis of contiguous THFeTHF and THFeTHP units via PdII-catalyzed tandem reaction with 1,3-chirality transfer Nobuyuki Kawai *, Yuhei Fujikura, Jun Takita, Jun’ichi Uenishi Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 August 2013 Received in revised form 18 September 2013 Accepted 21 September 2013 Available online 2 October 2013
The PdII-catalyzed tandem cyclization of chiral allylic alcohols possessing an internal epoxide and a terminal alcohol provided a contiguous THFeTHP and THFeTHP ring units stereospecifically. The cyclizations take place via a 5-exo-tet-5-exo-trig mode, however, the cyclization of methyl substituted epoxy diols proceeded via 6-endo-tet-6-exo-trig fashion in a part to construct the oxygen-fused THPeTHP ring. The different reaction rates of precursors, which are different stereochemistry at allylic alcohol have been elucidated. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Contiguous THFeTHF and THFeTHP Pd(II)-catalyst Tandem reaction 1,3-Chirality transfer Oxygen-fused THPeTHP rings
1. Introduction The synthesis of contiguous THFeTHF and THFeTHP ring units remains a topic of considerable interest due to the existence of these structures in natural products and biologically active compounds. Annonaceous acetogenins have important biological activities, such as anticancer and immunosuppressive activities, and include a contiguous THFeTHF and THFeTHP ring unit with stereoisomers.1,2 A represent examples of acetogenins, Muconin,2 and Chamuvarinin3 possess contiguous THFeTHF and THFeTHP ring unit. The stereochemistry of contiguous THFeTHF core has been considered to affects their inhibitory effect on mitochondrial NADHeubiquinone oxidoreductase (complex I).4 Therefore, a stereocontrolled construction of these units is an important task. Construction of these compounds has received much attention, especially with regard to efforts directed at asymmetric synthesis.5 For example, a cascade reaction via epoxide-opening reaction has been utilized on the basis of biosynthetic pathway. Although these cascade reactions were promoted by acid6 or base,7 very few transition metal catalyzed promotions have been reported.8
* Corresponding author. Tel.: þ81 75 595 4666; fax: þ81 75 595 4763; e-mail address: [email protected] (N. Kawai). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.09.067
We have developed a PdII-catalyzed intramolecular oxypalladation reaction for the formation of 2-alkenyl substituted oxoheterocycles.9 Recently, we have reported some PdII-catalyst triggered tandem cyclization of chiral allylic alcohols 1a and 1b possessing an internal epoxide and a terminal alcohol provided a contiguous THFeTHF ring unit stereospecifically (Scheme 1).10 The cyclization takes place in a 5-exo-tet-5-exo-trig fashion with high chirality transfer through a syn-SN20 like process for the formation of the internal THF ring. However, as the mechanistic proposal was made on the basis of a limited number of substrates, we have now expanded this study to additional substrates. Herein we describe a detailed study of the PdII-catalyzed cyclization reactions of epoxy allylic alcohols, especially on the difference of the reactivity of the diastereomeric epoxy allylic alcohols.
Scheme 1. Pd(II)-catalyzed cyclization of 1a and 1b.
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2. Results and discussion Four optically pure epoxy diols, 3a, 3b that are homologated between alkene and epoxide from 1a and 1b, and 4a, 4b that possess a methyl substituted epoxide, were chosen as precursors for the cyclization. When these diols cyclized, two kinds of stereoisomeric contiguous THFeTHP and THFeTHF compounds, 5a, 5b, 6a, and 6b, will be formed. These structures are shown in Fig. 1.
Fig. 1. Cyclization precursors and contiguous THFeTHP, THFeTHF compounds.
The synthesis of 3a and 3b is shown in Scheme 2. Wittig reaction of the chiral epoxide 710 with (3-benzoyloxypropyl)-triphenylphosphonium bromide,11 followed by diimide reduction of the resulting alkene with 2-nitrobenzenesulfonyl hydrazine,12 in situ prepared, gave 9 in 65% yield in two steps. Deprotection of benzoate with K2CO3 in MeOH gave alcohol 10 in 96% yield. Swern oxidation of 10 gave epoxy aldehyde 11 in 98% yield, which was homologated to afford 12 in 85% yield. The cross-metathesis of 12 with chiral segments 1310 (97% ee) and 14b10 (97% ee) in the presence of Grubbs’ second-generation catalyst gave 15a in 88% yield and 15b in 92% yield, respectively. Removal of the two TBS groups for 15a with TBAF in THF gave 3a in 88% yield.13 Deprotection of benzoyl group of 15b with K2CO3 in THFeMeOH gave 16b in 95% yield, followed by desilylation with TBAF to afford 3b in 90% yield.13
unsaturated ester 19 in 93% yield in two steps. Diimide reduction of 19 with 2-nitrobenzenesulfonyl hydrazine gave saturated ester 20 in 91% yield. Reduction of ester 20 with LiBH4 in MeOH to afford alcohol 21 in 83% yield, oxidation with IBX to the aldehyde followed by homologation via Wittig reaction gave 22 in 86% yield in two steps. The cross-metathesis of 22 with chiral segments 11a and 11b in the presence of Grubbs’ second-generation catalyst gave 23a in 81% yield and 23b in 72% yield, respectively. Deprotection of 17a and 17b by the same two steps sequence as that of 12b afforded 4a and 4b in 62% and 80% yield, respectively.13 PdII-catalyzed cyclization was examined for diols 3a and 3b (Scheme 4). When diol 3a was subjected to a PdII-catalyzed reaction with 10 mol % of PdCl2(CH3CN)2 in THF at 0 C for 25 min, the THF2,6-cis-THP ring product 5a was selectively obtained with a 92:8 ratio in 92% yield. The structure of 5a was identified by NOE experiment. On the other hand, the reaction of 3b required 2.5 h at room temperature to reach completion to give THF-2,6-trans-THP ring product 5b preferentially with a 93:7 ratio in 92% yield. The ring structures of 5a and 5b were determined NOE experiments. Stereochemistry of the reactions is quite similar to those of our previous result.9 In comparison, PdII-catalyzed cyclization of the diol 4a in THF at 0 C for 25 min, the THF-2,5-cis-THF ring product 6a (82% de; 6a:6b¼91:9) and the fused THP-2,6-trans-THP 25a (84% de; 25a:25b¼92:8) were obtained with a 1.2:1 ratio in 86% yield (Scheme 5). After separation of 6a and 25a by silica-gel column chromatography, the structures of products were identified by NOE experiments. Also, the cyclization of 4b at 0 C for 1 h gave bis THFeTHF compound 6b (92% de; 6a:6b¼4:96) and the fused THPeTHP compound 25b (90% de; 25a:25b¼5:95) with a 1.3:1 ratio in 79% yield. With respect to the reaction process, we considered that PdIIcatalyst triggered reaction in a tandem pathway based on several experiments reported in previous communication (Scheme 6).7 Initially, the Pd p-complex is formed by a coordination of PdCl2 with the olefinic bond on the syn-face side to the hydroxyl group of allylic alcohol preferentially. Then, a ligand exchange of the hy-
Scheme 2. Synthesis of 3a and 3b.
The syntheses of 4a and 4b began with Sharpless epoxidation of 1714 to afford 1814 in 88% yield in 97% ee (Scheme 3). Swern oxidation of 18 followed by Wittig reaction of the resulting aldehyde with methyl (triphenylphosphoranylidene)acetate gave
droxyl group with epoxy function generates an intermediate I. Successively, I prompts the tandem cyclization along with epoxide opening by a nucleophilic attack of the terminal alcohol to give a contiguous THFeTHF or THFeTHP compounds, 2a or 5a. On the
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Scheme 3. Synthesis of 4a and 4b.
Scheme 4. Cyclization of 3a and 3b.
Scheme 6. Proposed reaction pathway.
Scheme 5. Cyclization of 4a and 4b.
cyclization of methyl substituted 4a, a tandem reaction from the intermediate II proceeds not only via 5-exo-tet-5-exo-trig to afford 6a in which was same mode as those of 1a and 3a. At the same time, another tandem reaction takes place via 6-endo-tet-6-exo-trig mode to afford 25a. This formation would be explained by the endo cyclization onto the C-5 carbon of which cation is stabilized by the methyl group. Similar epoxide ring opening processes were known well in literature.14 It is quite interesting that electronically favored 6-endo-tet mode of epoxide-opening competes with 5-exo-tet mode favored by Baldwin rules.
The different rates of reactions for 3a and 3b may be attributed to the stability of the precursor I for the cyclization (Scheme 7). For the arrangement of the Pd complex in the reaction of 3a and 3b, the Pd p-complexes A from 3a, B/C from 3b, are available and could react. Although the Pd p-complexes B/C possess an unfavorable steric repulsion in their conformations, the Pd p-complex A does not. Therefore, the cyclization of 3a proceeds more smoothly than that of 3b. 3. Conclusion In summary, a PdII-catalyzed tandem cyclization of chiral nonracemic allylic alcohols possessing an internal epoxide and a terminal alcohol resulted in the stereospecific formation of chiral nonracemic contiguous THFeTHF and THFeTHP ring units with high 1,3-chirality transfer. The cyclizations take place via a 5-exotet-5-exo-trig mode, however, the cyclization of methyl substituted epoxy diols proceeded via 6-endo-tet-6-exo-trig mode in a part to
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J¼8.4, 7.6 Hz), 5.77 (1H, dtd, J¼10.8, 7.6, 0.8 Hz), 5.22 (1H, ddt, J¼10.8, 8.8, 1.6 Hz), 4.39 (2H, t, J¼6.8 Hz), 3.69e3.59 (2H, m), 3.38 (1H, ddd, J¼8.8, 2.4, 1.2 Hz), 2.87 (1H, dt, J¼4.4, 2.4 Hz), 2.71 (2H, dtdd, J¼7.6, 6.8, 1.6, 1.2 Hz), 1.70e1.54 (4H, m), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 166.5, 133.0, 130.9, 130.2, 130.1, 129.6, 128.4, 63.9, 62.6, 59.9, 54.1, 29.1, 28.5, 27.4, 25.9, 18.3, 5.3; IR (neat, cm1) 3019, 2955, 2858, 1716, 1603, 1452, 1386, 1315, 1278, 1216, 1177, 1113, 1027; MS (FAB) m/z 391 (MþHþ). HRMS calcd for C22H35O4Si: 391.2305: found; m/z 391.2311.
Scheme 7. Proposed intermediates: A from 3a and B/C from 3b.
construct the oxygen-fused THPeTHP ring units. The chirality transfer can be considered as the initial formation of a hydroxydirected p-face recognition of the PdII-catalyst and the subsequent tandem cyclization process through the intermediates. The different reaction rates of cyclization precursors that are different stereochemistry at allylic alcohol have been elucidated. 4. Experimental section 4.1. General methods Ether and THF were dried over sodium benzophenone ketide and toluene was dried over CaH2. They were used freshly after distillation. CH2Cl2 was distilled from P2O5. All other reagents were used without further purification. Unless otherwise stated, all reactions were run under an atmosphere of nitrogen. 1H and 13C NMR spectra were obtained at 25 C with a JEOL JNM-AL-500 (500 MHz and 125 MHz), JEOL JNM-AL-300 (300 MHz and 75 MHz) JEOL JNMAL-600 (600 MHz and 150 MHz), and Varian Inova Unity XL-400 (400 MHz, 100 MHz) spectrometers. Proton chemical shifts were internally referenced to the residual proton resonance in CDCl3 (d 7.26) and C6D6 (d 7.16). Carbon chemical shifts were internally referenced to the deuterated solvent signals in CDCl3 (d 77.00) and C6D6 (d 128.06). Mass spectra were recorded on JEOL JMC-GC MATE and JEOL JMS-SX 102A QQ. IR spectra were recorded on a JASCO FT/ IR-410 and optical rotations were recorded on a JASCO P-2200. Chiral HPLC analyses were performed on a SHIMADZU SPD-6A. A TLC was run on Merck silica gel 60F254 plates. Flash column chromatography was performed with Merck silica gel 60 (40e63 mm). Chromatorex NH-SGgrade NH DM1020SG (amino silica gel) purchased from Fuji Silysia Chemical was used for the chromatography for acid sensitive materials. 4.2. Experimental procedure and characterization data for compounds 4.2.1. (Z)-(5S,6S)-1-Benzoyloxy-9-(tert-butyldimethylsiloxy)-5,6-epoxy-non-3-ene (8). To a suspension of 3-(benzoyloxy)propyltriphenylphosphoium bromide (677 mg, 1.32 mmol) in THF (20 mL) were added K2CO3 (608 mg, 4.40 mmol) and 18-crown-6-ether (20 mg, 0.075 mmol) and the mixture was refluxed for 1 h. To this solution, a solution of the aldehyde 7 (215 mg, 0.88 mmol) in THF (10 mL) was added. The reaction mixture was refluxed for 1.5 h before quenching with satd NH4Cl aq The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 8 (290 mg) in 84% yield. Colorless oil, Rf¼0.61 (20% 1 EtOAc in hexane); ½a20 D 15.5 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 8.06e8.03 (2H, m), 7.56 (1H, tt, J¼7.6, 1.6 Hz), 7.44 (2H, dd,
4.2.2. (5S,6S)-1-Benzoyloxy-9-(tert-butyldimethylsiloxy)-5,6epoxynonane (9). To a solution of 8 (103 mg, 0.26 mmol) in CH2Cl2 (2 mL) was added o-nitrobenzensulfonylchloride (232 mg, 1.05 mmol). To this solution, hydrazine monohydrate (0.10 mL, 2.10 mmol) and Et3N (0.29 mL, 2.10 mmol) were added dropwise at 0 C. The reaction mixture was stirred for two days before quenching with satd NH4Cl aq. The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 9 (80.8 mg) in 78% yield. Colorless oil, Rf¼0.71 (20% 1 EtOAc in hexane); ½a20 D 15.9 (c 1.08, CHCl3); H NMR (400 MHz, CDCl3) d 8.05e8.02 (2H, m), 7.55 (1H, tt, J¼7.6, 1.6 Hz), 7.43 (2H, t, J¼7.6 Hz), 4.33 (2H, t, J¼6.8 Hz), 3.66e3.61 (2H, m), 2.73e2.69 (2H, m), 1.83 (2H, quin, J¼6.8 Hz), 1.68e1.54 (8H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 166.6, 132.9, 130.4, 129.5, 128.3, 64.7, 62.6, 58.54, 58.51, 31.7, 29.2, 28.6, 28.5, 25.9, 22.7, 18.3, 5.3; IR (neat, cm1) 3683, 3019, 2955, 2400, 1715, 1472, 1278, 1216, 1112, 1046; MS (FAB) m/z 393 (MþHþ). HRMS calcd for C22H37O4Si: 393.2461: found; m/z 393.2466. 4.2.3. (5S,6S)-9-(tert-Butyldimethylsiloxy)-5,6-epoxynonan-1-ol (10). To a mixed solution of 8 (87.4 mg, 0.22 mmol) in MeOH (5 mL) and THF (5 mL) was added K2CO3 (92.6 mg, 0.67 mmol) at room temperature. The reaction mixture was stirred for 4.5 h before quenching with satd NH4Cl aq. The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 10 (62.1 mg) in 96% yield. Colorless oil, Rf¼0.14 (20% 1 EtOAc in hexane); ½a20 D 21.4 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 3.68e3.60 (4H, m), 2.72e2.66 (2H, m), 1.71e1.46 (10H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 62.6, 62.6, 58.7, 58.6, 32.4, 31.7, 29.2, 28.6, 25.9, 22.3, 18.3, 5.3; IR (neat, cm1) 3431, 2931, 2859, 2738, 1741, 1472, 1389, 1361, 1254, 1099, 1007; MS (FAB) m/z 289 (MþHþ). HRMS calcd for C15H33O3Si: 289.2199: found; m/z 289.2206. 4.2.4. (5S,6S)-9-(tert-Butyldimethylsiloxy)-5,6-epoxynonanal (11). To a solution of oxalyl chloride (0.08 mL, 0.96 mmol) in CH2Cl2 (7 mL) was added DMSO (0.10 mL, 1.44 mmol) at 78 C and the mixture stirred for 20 min. To the mixture was added a solution of 10 (62.1 mg, 0.22 mmol) in CH2Cl2 (3 mL) and the mixture was stirred for 40 min before addition of Et3N (0.40 mL, 2.88 mmol). The resulting mixture was warmed to room temperature. H2O was added to the mixture and the mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 5% EtOAc in hexane gave 11 (135 mg) in 98% yield. Yellow oil, Rf¼0.38 (20% EtOAc in hexane); 1 ½a20 D 20.0 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 9.77 (1H, t, J¼1.6 Hz), 3.68e3.58 (2H, m), 2.71e2.65 (2H, m), 2.51 (2H, td, J¼7.2, 1.6 Hz), 1.84 (2H, m), 1.70e1.59 (4H, m), 1.57e1.42 (2H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 202.0, 62.6, 58.3, 58.2, 43.4, 31.3, 29.1, 28.5, 25.9, 18.6, 18.3, 5.4; IR (neat, cm1) 2930, 2857, 2718, 1727, 1471, 1389, 1362, 1254, 1097, 1048, 1007; MS (FAB)
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m/z 287 (MþHþ). HRMS calcd for C15H31O3Si: 287.2042: found; m/z 287.2049. 4.2.5. (6S,7S)-10-(tert-Butyldimethylsiloxy)-6,7-epoxydec-1-ene (12). To the mixture of methyltriphenylphosphonium bromide (514.4 mg, 1.44 mmol) in THF (10 mL) was added a solution of sodium bis(trimethylsilyl)amide (1.34 mmol, 1.9 M in THF, 0.71 mL) at 0 C and the mixture was stirred for 1 h at room temperature. After cooling to 0 C, the solution of 11 (137.5 mg, 0.48 mmol) in THF (3 mL) was slowly dropped and the reaction mixture was stirred for 5 min at the same temperature. The mixture was quenched with satd NH4Cl aq and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 10% EtOAc in hexane gave 12 (115.5 mg) in 85% yield. Colorless oil, Rf¼0.67 (10% EtOAc in hexane); ½a20 D 24.2 (c 1.50, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.79 (1H, ddt, J¼17.2, 10.4, 6.4 Hz), 5.01 (1H, dq, J¼17.2, 1.6 Hz), 4.96 (1H, ddt, J¼10.4, 1.6, 1.2 Hz), 3.69e3.59 (2H, m), 2.71e2.68 (2H, m), 2.15e2.09 (2H, m), 1.68e1.53 (8H, m), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) d 138.3, 114.8, 62.7, 58.7, 58.6, 33.4, 31.5, 29.2, 28.6, 25.9, 25.3, 18.3, 5.3; IR (neat, cm1) 3078, 2930, 2858, 1641, 1471, 1388, 1361, 1254, 1100, 1006; MS (FAB) m/z 285 (MþH þ). HRMS calcd for C16H32O2Si: 285.2250: found; m/z 285.2255; Anal. Calcd for C16H31O2Si: C, 67.54; H, 11.34. Found: C, 67.69; H, 11.30. 4.2.6. Alkene metathesis reaction of 12 with 13 and 14b. A mixture of 9 (142 mg, 0.5 mmol) and 13 (280 mg, 1.5 mmol) or 14b (264 mg, 1.5 mmol) in CH2Cl2 (10 mL) and Grubbs’ second-generation catalyst (21 mg, 0.025 mmol) was refluxed for 3 h under an Ar atmosphere. Concentration and purification of the residue by column chromatography on silica gel eluted with 5% Et2O in hexane gave 15a (195 mg) in 88% yield or 15b (199 mg) in 92% yield. 4.2.7. (E)-(2S,8S,9S)-2,12-Bis-(tert-butyldimethylsiloxy)-8,9epoxydodec-3-ene (15a). Colorless oil, Rf¼0.25 (10% CHCl3 in hex1 ane); ½a20 D 13.5 (c 1.07, CHCl3); H NMR (500 MHz, CDCl3) d 5.55e5.49 (1H, m), 5.45 (1H, dd, J¼16.0, 16.0 Hz), 4.24 (1H, quin, J¼6.0 Hz), 3.68e3.60 (2H, m), 2.68e2.67 (2H, m), 2.06e2.03 (2H, m), 1.67e1.48 (8H, m), 1.18 (3H, d, J¼6.0 Hz), 0.89 (18H, s), 0.04 (12H, s); 13C NMR (125 MHz, CDCl3) d 135.3, 128.3, 69.3, 62.7, 58.7, 58.6, 31.8, 31.5, 29.2, 28.6, 25.93, 25.91, 25.7, 24.6, 18.3, 18.3, 4.4, 4.7, 5.3; IR (neat, cm1) 2929, 285, 2738, 2710, 1733, 1671, 1472, 1389, 1362, 1254, 1148, 1096, 1004; MS (FAB) m/z 465 (MþNaþ). HRMS calcd for C24H50O3Si2Na: 465.3196: found; m/z 465.3203. 4.2.8. (E)-(2R,8S,9S)-2-Benzoyloxy-12-(tert-butyldimethylsiloxy)8,9-epoxydodec-3-ene (15b). Colorless oil, Rf¼0.19 (50% CHCl3 in 1 hexane); ½a20 D 25.8 (c 0.82, CHCl3); H NMR (500 MHz, CDCl3) d 8.04 (2H, d, J¼8.0 Hz), 7.54 (1H, t, J¼8.0 Hz), 7.43 (2H, t, J¼8.0 Hz), 5.77 (1H, dt, J¼14.0, 7.0 Hz), 5.63e5.50 (2H, m), 3.71e3.59 (2H, m), 2.75e2.61 (2H, m), 2.17e2.04 (2H, m), 1.70e1.48 (8H, m), 1.42 (3H, d, J¼6.5 Hz), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 165.8, 132.7, 132.6, 130.8, 130.1, 129.5, 128.3, 71.6, 62.7, 58.59, 58.58, 31.9, 31.5, 29.2, 28.6, 25.9, 25.3, 20.5, 18.3, 5.3; IR (neat, cm1) 2930, 2858, 1718, 1603, 1584, 1471, 1374, 1361, 1315, 1272, 1217, 1176, 1100, 1043, 1005; MS (FAB) m/z 455 (MþNaþ). HRMS calcd for C25H40O4SiNa: 455.2594: found; m/z 455.2599. 4.2.9. (E)-(2R,8S,9S)-12-(tert-Butyldimethylsiloxy)-8,9-epoxydodec3-ene-2-ol (16b). A solution of 15b (47.6 mg, 0.11 mmol) in a mixture of MeOH (2 mL) and THF (2 mL) was stirred at room temperature overnight in the presence of K2CO3 (43.7 mg, 0.32 mmol). The reaction was quenched with satd NH4Cl aq and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The purification of the residue by column
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chromatography on silica gel eluted with 20% EtOAc in hexane gave 16b (34.3 mg) in 95% yield. Colorless oil, Rf¼0.20 (20% EtOAc in 1 hexane); ½a20 D 14.9 (c 0.32, CHCl3); H NMR (500 MHz, CDCl3) d 5.62 (1H, dt, J¼15.5, 6.5 Hz), 5.53 (1H, dd, J¼15.5, 6.5 Hz), 4.26 (1H, dq, J¼6.5, 6.0 Hz), 3.70e3.60 (2H, m), 2.69e2.67 (2H, m), 2.09e2.05 (2H, m), 1.66e1.50 (8H, m), 1.25 (3H, d, J¼6.5 Hz), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 134.7, 130.3, 68.8, 62.7, 58.64, 58.60, 31.8, 31.5, 29.2, 28.6, 25.9, 25.5, 23.4, 18.3, 5.3; IR (neat, cm1) 3433, 2929, 2850, 1638, 1462, 1254, 1099; MS (FAB) m/z 351 (MþNaþ). HRMS calcd for C18H36O3SiNa: 351.2331: found; m/z 351.2328. 4.2.10. Desilylation of 15a and 16b. To the solution of the silyl ether (0.1 mmol) in THF (3 mL) was added a solution of TBAF in THF (1.0 M 0.13 mL, 0.13 mmol for 16b, or 0.25 mL, 0.25 mmol for 15a) at room temperature and the reaction mixture was stirred for 30 min. Evaporation of solvent and purification of the residue by column chromatography on amino silica gel eluted with 70% EtOAc in hexane gave 3a (17.4 mg; 81%) or 3b (19.3 mg; 90%). 4 . 2 .11. ( E ) - ( 2 S , 8 S , 9 S ) - 8 , 9 - E p o x y d o d e c - 3 - e n e - 2 ,12 - d i o l (3a). Colorless oil, Rf¼0.14 (60% EtOAc in hexane); ½a20 D 21.6 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.62 (1H, dt, J¼15.6, 6.4 Hz), 5.53 (1H, dt, J¼15.6, 6.4 Hz), 4.26 (1H, quin, J¼6.4 Hz), 3.69 (2H, t, J¼6.4 Hz), 2.72 (2H, d like, J¼4.0 Hz), 2.07 (2H, d like, J¼4.0 Hz), 1.81e1.68 (4H, m), 1.63 (2H, br s), 1.56e1.48 (4H, m), 1.25 (3H, d, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3) d 134.8, 130.2, 68.8, 62.4, 58.8, 58.6, 31.7, 31.4, 29.1, 28.7, 25.5, 23.4; IR (neat, cm1) 3366, 2928, 2861, 1722, 1624, 1454, 1367, 1283, 1062; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/z 237.1472. 4 . 2 .12 . ( E ) - ( 2 R , 8 S , 9 S ) - 8 , 9 - E p o x y d o d e c - 3 - e n e - 2 ,12 - d i o l (3b). Colorless oil, Rf¼0.14 (60% EtOAc in hexane); ½a20 D 19.4 (c 0.55, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.62 (1H, dt, J¼15.6, 6.4 Hz), 5.53 (1H, ddt, J¼15.6, 6.4, 1.2 Hz), 4.26 (1H, quin, J¼6.4 Hz), 3.69 (2H, td, J¼6.4, 1.2 Hz), 2.73e2.70 (2H, m), 2.07 (2H, qd, J¼6.4, 1.2 Hz), 1.82e1.68 (4H, m), 1.65 (2H, br s), 1.59e1.49 (4H, m), 1.25 (3H, d, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3) d 134.8, 130.1, 68.8, 62.3, 58.8, 58.6, 31.7, 31.4, 29.1, 28.6, 25.5, 23.4; IR (neat, cm1) 3435, 3019, 2935, 2395, 1628, 1516, 1445, 1374, 1216, 1047; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/ z 237.1459. 4.2.13. (2R,3S)-6-(tert-Butyldimethyl silox y)-2 ,3-epoxy-2 methylhexanal (18). Sharpless epoxidation of 17 with (þ)-diethyl tartrate in the reported procedure using ()-diethyl tartrate,15 was conducted and yielded 18 (88%, 97% ee) as a colorless oil. 4.2.14. Methyl (E)-(4S,5S)-8-(tert-butyldimethylsilyl)oxy-4,5-epoxy4-methyloct-2-enoate (19). Following a similar procedure that was described for the synthesis of 11 from 10, oxidation of 18 (416 mg, 1.6 mmol) yielded the aldehyde as a colorless oil, which was used for the next step without further purification. To a solution of the aldehyde in benzene (18 mL) was added methyl (triphenylphosphoranylidene)acetate (646 mg, 1.92 mmol) at room temperature. The reaction mixture was stirred for 5 min and condensed. The purification of the residue by column chromatography on silica gel eluted with 10% EtOAc in hexane gave 19 (468 mg) in 93% yield. Colorless oil, Rf¼0.40 (10% EtOAc in hexane); ½a20 D þ7.42 (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) d 6.76 (1H, d, J¼15.9 Hz), 6.01 (1H, d, J¼15.9 Hz), 3.74 (3H, s), 3.68e3.62 (2H, m), 2.86 (1H, t, J¼6.1 Hz), 1.68e1.62 (4H, m), 1.42 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13 C NMR (125 MHz, CDCl3) d 166.2, 150.2, 120.9, 65.7, 62.4, 58.5, 51.6, 29.4, 25.9, 25.1, 18.2, 15.1, 5.4; IR (neat, cm1) 2953, 2857, 1728, 1655, 1463, 1436, 1388, 1362, 1310, 1256, 1170, 1098, 1010; MS
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(FAB) m/z 315 (MþHþ). HRMS calcd for C16H31O4Si: 315.1992: found; m/z 315.1996. 4.2.15. Methyl (4S,5S)-8-(tert-butyldimethylsiloxy)-4,5-epoxy-4methyloctanoate (20). Following a similar procedure that was described for the synthesis of 9 from 8, diimide reduction of 19 gave 20 in 91% yield. Colorless oil, Rf¼0.20 (10% EtOAc in hexane); ½a20 D 8.01 (c 0.59, CHCl3); 1H NMR (500 MHz, CDCl3) d 3.67 (3H, s), 3.65e3.60 (2H, m), 2.75 (1H, t, J¼6.1 Hz), 2.40 (2H, td, J¼7.0, 2.0 Hz), 1.92e1.82 (2H, m), 1.70e1.55 (4H, m), 1.25 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 173.5, 63.1, 62.6, 59.8, 51.7, 33.4, 29.62, 29.61, 25.9, 25.1, 18.3, 16.5, 5.3; IR (neat, cm1) 3018, 2954, 2930, 2858, 1738, 1463, 1438, 1387, 1362, 1255, 1216, 1169, 1098, 1007; MS (FAB) m/z 317 (MþHþ). HRMS calcd for C16H33O4Si: 317.2148: found; m/z 317.2151. 4.2.16. (4S ,5S)-8-( tert-Butyl dimethylsilo xy) -4, 5 -epox y-4 methyloctan-1-ol (21). To the solution of ester 20 (50.3 mg, 0.16 mmol) in ether (5 mL) was added LiBH4 (3.5 mg, 0.16 mmol) and MeOH (6.5 mL, 0.16 mmol) at room temperature and the reaction mixture was stirred for 30 min. After quenching with satd NH4Cl aq, the mixture was extracted with ether (three times) and combined organic extracts were washed with brine and dried over MgSO4. Evaporation of the solvent and purification of the residue by column chromatography on amino silica gel eluted with 30% EtOAc in hexane gave 21 (38.1 mg) in 83% yield. Colorless oil, Rf¼0.19 (30% EtOAc in hexane); ½a20 D 6.73 (c 0.59, CHCl3); 1H NMR (500 MHz, CDCl3) d 3.67e3.63 (4H, m), 2.79 (1H, t, J¼6.0 Hz), 1.87 (1H, br s), 1.72e1.57 (8H, m), 1.27 (3H, s), 0.89 (9H, s), 0.05 (6H, s); 13C NMR (125 MHz, CDCl3) d 63.7, 62.6, 62.5, 60.7, 35.0, 29.6, 17.9, 15.9, 25.2, 18.3, 16.3, 5.3; IR (neat, cm1) 3430, 2930, 2858, 1740, 1471, 1387, 1362, 1254, 1098; MS (FAB) m/z 289 (MþHþ). HRMS calcd for C15H33O3Si: 289.2199: found; m/z 289.2195. 4.2.17. (5S,6S)-9-(tert-Butyldimethylsiloxy)-5,6-epoxy-5-methylnon1-ene (22). To the solution of 21 (38.1 mg, 0.13 mmol) in acetone (4 mL) was added IBX (111 mg, 6.9 mmol) at room temperature and the reaction mixture was refluxed for 3 h. The reaction mixture was filtered off and the filtrate was condensed. The residue was passed through short silica gel pad to give almost pure aldehyde, which was used for the next step without further purification. To a suspension of methyltriphenylphosphonium bromide (70.7 mg, 0.20 mmol) in THF (3 mL) was added a solution of sodium bis(trimethylsilyl)amide in toluene (0.6 M, 0.3 mL, 0.18 mmol) at 0 C and the mixture was stirred for 1 h at room temperature. To this solution, a solution of the crude aldehyde (38.1 mg) in THF (1 mL) was slowly added at 20 C. The reaction mixture was stirred for 5 min at 20 C before quenching with satd NH4Cl aq. The mixture was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluted with 10% EtOAc in hexane gave 22 (32.1 mg) in 86% yield. Colorless oil, 1 Rf¼0.83 (20% EtOAc in hexane); ½a20 D 1.36 (c 1.16, CHCl3); H NMR (500 MHz, CDCl3) d 5.80 (1H, ddt, J¼17.1, 10.4, 6.7 Hz), 5.02 (1H, ddt, J¼17.1, 1.8, 1.5 Hz), 4.96 (1H, dd, J¼10.4, 1.8 Hz), 3.69e3.60 (2H, m), 2.74 (1H, t, J¼6.0 Hz), 2.21e2.09 (2H, m), 1.74e1.47 (6H, m), 1.26 (3H, s), 0.89 (9H, s), 0.05 (6H, s); 13C NMR (125 MHz, CDCl3) d 138.0, 114.8, 63.4, 62.7, 60.5, 38.0, 29.7, 29.5, 25.9, 25.2, 18.3, 16.4, 5.3; IR (neat, cm1) 2929, 2858, 1642, 1472, 1386, 1254, 1099; MS (FAB) m/z 285 (MþHþ). HRMS calcd for C16H33O2Si: 285.2250: found; m/z 285.2252. 4.2.18. (E)-(2S,7S,8S)-2-Benzoyloxy-11-(tert-butyldimethylsiloxy)7,8-epoxy-7-methylundec-3-ene (23a). Following a similar procedure that was described for the synthesis of 15b from 12, alkene
metathesis of 22 with 14a gave 23a in 81% yield. Colorless oil, 1 Rf¼0.14 (10% EtOAc in hexane); ½a20 D þ6.59 (c 0.45, CHCl3); H NMR (500 MHz, CDCl3) d 8.04 (2H, d, J¼7.5 Hz), 7.54 (1H, t, J¼7.5 Hz), 7.43 (2H, t, J¼7.5 Hz), 5.77 (1H, dt, J¼15.0, 6.5 Hz), 5.62e5.55 (2H, m), 3.64e3.57 (2H, m), 2.73 (1H, t, J¼5.5 Hz), 2.19e2.13 (2H, m), 1.73e1.47 (6H, m), 1.42 (3H, d, J¼6.0 Hz), 1.24 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 165.8, 132.8, 132.3, 130.7, 130.0, 129.5, 128.3, 71.5, 63.4, 62.6, 60.4, 38.1, 29.7, 27.9, 25.9, 25.2, 20.5, 18.3, 16.5, 5.3; IR (neat, cm1) 2930, 2857, 1719, 1451, 1271, 1109; MS (FAB) m/z 455 (MþNaþ). HRMS calcd for C25H40O4SiNa: 455.2594: found; m/z 455.2597. 4.2.19. (E)-(2R,7S,8S)-2-Benzoyloxy-11-(tert-butyldimethylsiloxy)7,8-epoxy-7-methylundec-3-ene (23b). Following a similar procedure that was described for the synthesis of 15b from 12, alkene metathesis of 22 with 14b gave 23b in 72% yield. Colorless oil, 1 Rf¼0.14 (10% EtOAc in hexane); ½a20 D 12.5 (c 0.49, CHCl3); H NMR (400 MHz, CDCl3) d 8.05e8.02 (2H, m), 7.54 (1H, tt, J¼7.6, 1.2 Hz), 7.42 (2H, tt, J¼7.6, 1.2 Hz), 5.77 (1H, dt, J¼14.4, 5.6 Hz), 5.62e5.51 (2H, m), 3.68e3.58 (2H, m), 2.72 (1H, t, J¼6.0 Hz), 2.22e2.04 (2H, m), 1.74e1.48 (6H, m), 1.41 (3H, d, J¼6.4 Hz), 1.24 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) d 165.8, 132.7, 132.3, 130.7, 130.0, 129.5, 128.2, 71.5, 63.3, 62.6, 60.4, 38.0, 29.7, 27.9, 25.9, 25.2, 20.4, 18.3, 16.5, 5.3; IR (neat, cm1) 2929, 2857, 1718, 1451, 1271, 1109; MS (FAB) m/z 455 (MþNaþ). HRMS calcd for C25H40O4SiNa: 455.2594: found; m/z 455.2590. 4.2.20. (E)-(2S,7S,8S)-11-(tert-Butyldimethylsiloxy)-7,8-epoxy-7methylundec-3-ene-2-ol (24a), (E)-(2R,7S,8S)-11-(tert-butyldimethylsiloxy)-7,8-epoxy-7-methylundec-3-ene-2-ol (24b). Following a similar procedure that was described for the synthesis of 16 from 15b, a deprotection of benzoates of 23a and 23b gave 24a (87% yield) and 24b (81% yield), respectively. Compound 24a: colorless oil, Rf¼0.19 (20% EtOAc in hexane); 1 ½a20 D 10.1 (c 0.64, CHCl3); H NMR (500 MHz, CDCl3) d 5.61 (1H, dt, J¼15.5, 7.5 Hz), 5.53 (1H, dd, J¼15.5, 6.0 Hz), 4.25 (1H, quin, J¼6.0 Hz), 3.68e3.60 (2H, m), 2.73 (1H, t, J¼6.5 Hz), 2.21e2.09 (2H, m), 1.67e1.52 (6H, m), 1.25e1.23 (6H, m), 0.89 (9H, s), 0.05 (6H, s); 13 C NMR (125 MHz, CDCl3) d 134.7, 129.8, 68.7, 63.3, 62.7, 60.5, 38.2, 29.6, 27.9, 25.9, 25.2, 23.4, 18.3, 16.4, 5.3; IR (neat, cm1) 3437, 2958, 2930, 2858, 1463, 1386, 1254, 1099; MS (FAB) m/z 351 (MþNaþ). HRMS calcd for C18H36O3SiNa: 351.2331: found; m/z 351.2328. Compound 24b: colorless oil, Rf¼0.19 (20% EtOAc in hexane); 1 ½a20 D þ0.15 (c 0.77, CHCl3); H NMR (500 MHz, CDCl3) d 5.62 (1H, dtd, J¼16.0, 7.0, 1.0 Hz), 5.53 (1H, ddt, J¼16.0, 6.5, 1.0 Hz), 4.25 (1H, quin, J¼6.5 Hz), 3.69e3.60 (2H, m), 2.73 (1H, t, J¼6.0 Hz), 2.20e2.07 (2H, m), 1.71e1.48 (6H, m), 1.25 (3H, s), 1.24 (3H, d, J¼6.5 Hz), 0.89 (9H, s), 0.05 (6H, s); 13C NMR (125 MHz, CDCl3) d 134.6, 129.9, 68.7, 63.4, 62.7, 60.5, 38.2, 29.7, 27.9, 25.9, 25.2, 23.4, 18.3, 16.4, 5.3; IR (neat, cm1) 3433, 2955, 2929, 2858, 1471, 1463, 1386, 1254, 1099; MS (FAB) m/z 351 (MþNaþ). HRMS calcd for C18H36O3SiNa: 351.2331: found; m/z 351.2327. 4.2.21. (E)-(2S,7S,8S)-7,8-Epoxy-7-methylundec-3-ene-2,11-diol (4a), (E)-(2R,7S,8S)-7,8-epoxy-7-methylundec-3-ene-2,11-diol (4b). Following a similar procedure that was described for the synthesis of 3b from 16b, desilylation of 24a and 24b gave 4a (72% yield) and 4b (99% yield), respectively. Compound 4a: colorless oil, Rf¼0.14 (70% EtOAc in hexane); ½a20 D þ0.97 (c 0.47, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.59 (1H, dt, J¼15.0, 6.0 Hz), 5.52 (1H, dd, J¼15.0, 6.0 Hz), 4.29 (1H, quin, J¼6.0 Hz), 3.69e3.67 (2H, m), 2.75 (1H, t, J¼5.5 Hz), 2.18e2.03 (2H, m), 1.75e1.63 (4H, m), 1.60e1.46 (2H, m), 1.26e1.23 (6H, m); 13C NMR (125 MHz, CDCl3) d 134.8, 129.6, 68.7, 63.4, 62.2, 60.9, 38.1, 29.5, 27.9, 25.1, 23.5, 16.4; IR (neat, cm1) 3419, 2973, 2933, 2871,
N. Kawai et al. / Tetrahedron 69 (2013) 11017e11024
1739, 1448, 1374, 1244, 1048; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/z 237.1464. Compound 4b: colorless oil, Rf¼0.14 (70% EtOAc in hexane); ½a20 D 0.62 (c 0.40, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.61 (1H, dt, J¼16.0, 6.0 Hz), 5.53 (1H, dd, J¼16.0, 6.0 Hz), 4.25 (1H, quin, J¼6.0 Hz), 3.71e3.68 (2H, m), 2.76 (1H, m), 2.23e2.05 (2H, m), 1.76e1.65 (4H, m), 1.60e1.48 (2H, m), 1.26e1.24 (6H, m); 13C NMR (125 MHz, CDCl3) d 134.7, 129.7, 68.6, 63.4, 62.3, 60.9, 38.1, 29.5, 27.8, 25.2, 23.3, 16.5; IR (neat, cm1) 3400, 2960, 2930, 2878, 1739, 1454, 1373, 1244, 1060; MS (FAB) m/z 237 (MþNaþ). HRMS calcd for C12H22O3Na: 237.1467: found; m/z 237.1462. 4.3. General procedure of PdII-catalyzed reaction To the solution of the precursor (0.1 mmol) in THF (2.5 mL) was added PdCl2(MeCN)2 (2.2 mg, 10 mmol) at 0 C or room temperature and the reaction mixture was stirred for 10e90 min. The mixture was quenched with aq NaHCO3 and extracted with EtOAc. The extract was washed with brine and dried over MgSO4. Solvent was removed and the residue was purified by column chromatography on silica gel eluted with 10% EtOAc in hexane to give the cyclized product. Reactions of 3a, 3b, 4a, and 4b. Compounds 5a from 3a (reaction time and temperature: 1 h, 23 C; yield: 92%; 5a:5b¼92:8). Compounds 5b from 3b (reaction time and temperature: 2.5 min, 23 C; yield: 86%; 5a:5b¼7:93). Compounds 6a and 25a from 4a (reaction time and temperature: 25 min, 0 C; yield: 86%; 6a (6a:6b¼91:9): 25a (25a:25b¼92:8)¼1.2:1). Compounds 6b and 25b from 4b (reaction time and temperature: 1 h, 0 C; yield: 79%; 6b (6a:6b¼4:96): 25b (25a:25b¼5:95)¼ 1.3:1). 4.3.1. (E)-(2R,20 R,6S)-2-(Prop-1-enyl)-6-(tetrahydrofuran-20 -yl)tetrahydropyran (5a). Colorless oil, Rf¼0.64 (20% EtOAc in hexane); 1 ½a20 D þ8.65 (c 0.67, CHCl3); H NMR (400 MHz, CDCl3) d 5.66 (1H, dqd, J¼15.6, 6.4, 1.2 Hz), 5.50 (1H, ddq, J¼15.6, 6.4, 1.2 Hz), 3.87e3.70 (4H, m), 3.27 (1H, ddd, J¼11.2, 6.4, 2.4 Hz), 1.98e1.19 (10H, m), 1.68 (3H, dt, J¼6.4, 1.2 Hz); 13C NMR (100 MHz, CDCl3) d 132.6, 126.0, 81.6, 79.7, 78.1, 68.4, 31.8, 27.8, 27.7, 25.7, 23.2, 17.8; IR (neat, cm1) 3155, 2939, 2253, 1793, 1469, 1381, 1262, 1094; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1457. 4.3.2. (E)-(2S,20 R,6S)-2-(Prop-1-enyl)-6-(tetrahydrofuran-20 -yl)tetrahydropyran (5b). Colorless oil, Rf¼0.55 (20% EtOAc in hexane); 1 ½a20 D þ12.5 (c 0.31, CHCl3); H NMR (500 MHz, CDCl3) d 5.64 (1H, dq, J¼15.5, 6.0 Hz), 5.58 (1H, dd, J¼15.5, 5.0 Hz), 4.29 (1H, q, J¼5.0 Hz), 3.87 (1H, t, J¼7.0 Hz), 3.83 (1H, t, J¼7.0 Hz), 3.73 (1H, q, J¼7.0 Hz), 3.53 (1H, ddd, J¼10.0, 7.0, 3.0 Hz), 2.00e1.41 (10H, m), 1.71 (3H, d, J¼6.0 Hz); 13C NMR (125 MHz, CDCl3) d 131.2, 127.4, 80.2, 73.0, 72.6, 68.3, 29.4, 28.1, 27.4, 25.6, 18.4, 18.0; IR (neat, cm1) 2925, 2854, 1736, 1665, 1458, 1374, 1260, 1031; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1460. 4.3.3. (E)-(2R,20 R,5S)-5-Methyl-2-(prop-1-enyl)-5-(tetrahydrofuran20 -yl)tetrahydrofuran (6a). Colorless oil, Rf¼0.26 (5% EtOAc in 1 benzene); ½a20 D þ3.95 (c 0.28, CHCl3); H NMR (400 MHz, CDCl3) d 5.69 (1H, dqd, J¼15.2, 6.4, 0.8 Hz), 5.48 (1H, ddq, J¼15.2, 7.2, 1.6 Hz), 4.33 (1H, q, J¼7.2 Hz), 3.86 (1H, m), 3.81e3.74 (2H, m), 2.04e1.98 (2H, m), 1.93e1.83 (3H, m), 1.75e1.58 (3H, m), 1.68 (3H, dd, J¼6.4, 1.6 Hz), 1.18 (3H, s); 13C NMR (100 MHz, CDCl3) d 132.2, 127.6, 84.4, 84.3, 79.7, 68.6, 35.0, 32.8, 27.1, 26.2, 22.5, 17.7; IR (neat, cm1) 2966, 2928, 2857, 1454, 1370, 1071; MS (EIþ) m/z
11023
196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1469. 4.3.4. (E)-(2R,4aR,8aS)-4a-Methyl-2-propenyloctahydropyrano[3,2b]pyran (25a). Colorless oil, Rf¼0.41 (5% EtOAc in benzene); ½a20 D 138.9 (c 0.15, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.69e5.67 (2H, m), 4.37 (1H, d, J¼6.0 Hz), 3.71 (1H, td, J¼12.4, 3.2 Hz), 3.60 (1H, ddt, J¼12.4, 5.6, 1.2 Hz), 3.45 (1H, dd, J¼11.6, 4.4 Hz), 2.10 (1H, m), 1.78e1.48 (10H, m), 1.27 (3H, s); 13C NMR (100 MHz, CDCl3) d 130.4, 128.1, 73.3, 73.1, 73.0, 60.5, 33.9, 26.4, 26.2, 24.6, 18.0, 13.5; IR (neat, cm1) 2929, 2856, 1455, 1377, 1261, 1075; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1469. 4.3.5. (E)-(2S,20 R,5S)-5-Methyl-2-(prop-1-enyl)-5-(tetrahydrofur an-20 -yl)tetrahydrofuran (6b). Colorless oil, Rf¼0.26 (5% EtOAc in 1 benzene); ½a20 D þ0.46 (c 0.54, CHCl3); H NMR (400 MHz, CDCl3) d 5.67 (1H, dqd, J¼15.2, 6.4, 0.8 Hz), 5.45 (1H, ddq, J¼15.2, 7.6, 1.6 Hz), 4.35 (1H, q, J¼7.6 Hz), 3.90e3.75 (3H, m), 2.06e1.97 (2H, m), 1.95e1.83 (3H, m), 1.75e1.59 (3H, m), 1.67 (3H, dd, J¼6.4, 1.6 Hz), 1.18 (3H, s); 13C NMR (100 MHz, CDCl3) d 132.8, 127.9, 84.9, 84.4, 81.3, 68.6, 33.9, 32.8, 27.5, 26.2, 24.1, 17.7; IR (neat, cm1) 2961, 2927, 2856, 1457, 1373, 1072; MS (EIþ) m/z 196. HRMS calcd for C12H20O2 (Mþ): 196.1463: found; m/z 196.1471. 4.3.6. (E)-(2S,4aR,8aS)-4a-Methyl-2-propenyloctahydropyrano[3,2b]pyran (25b). Colorless oil, Rf¼0.41 (5% EtOAc in benzene); ½a20 D 34.9 (c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.71 (1H, qqd, J¼15.2, 6.8, 0.8 Hz), 5.50 (1H, qqd, J¼15.2, 6.8, 1.6 Hz), 3.90 (1H, q, J¼6.8 Hz), 3.70 (1H, td, J¼12.0, 3.2 Hz), 3.61 (1H, ddt, J¼12.0, 5.6, 0.8 Hz), 3.19 (1H, dd, J¼12.0, 4.0 Hz), 1.78e1.56 (8H, m), 1.69 (3H, ddd, J¼6.4, 1.6, 0.8 Hz), 1.24 (3H, s); 13C NMR (100 MHz, CDCl3) d 131.7, 127.9, 80.6, 79.4, 72.2, 60.5, 37.8, 30.6, 26.2, 24.7, 17.8, 13.9; IR (neat, cm1) 2939, 2862, 1456, 1375, 1277, 1089; MS (CIþ) m/z 197. HRMS calcd for C12H21O2 (MþHþ): 197.1541: found; m/z 196.1546. Acknowledgements This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.09.067. References and notes 1. For recent review on Annonaceous acetogenin, (a) Liaw, C.-C.; Wu, T.-Y.; Chang, F.-R.; Wu, Y.-C. Plant. Med. 2010, 76, 1390e1404; (b) Spurr, I. B.; Brown, R. C. D. Molecules 2010, 15, 460e501; (c) Kojima, N.; Tanaka, T. Molecules 2009, 14, 3621e3661; (d) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; re, B.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275e306; (e) Bermejo, A.; Figade Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269e303. 2. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; Mac-Dougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988e7989. 3. (a) Fall, D.; Duval, R. A.; Gleye, C.; Laurens, A.; Hocquemiller, R. J. Nat. Prod. 2004, 67, 1041e1043; (b) Derbre, S.; Poupon, E.; Gleye, C.; Hocquemiller, R. J. Nat. Prod. 2004, 70, 300e303 For other acetogenin as having a THP ring, see the following; (c) Jimenezine: Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61, 419e421; (d) Pyranicin and pyragonicin: Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron 1998, 54, 5833e5844. 4. Ichimaru, N.; Yoshinaga, N.; Nishioka, T.; Miyoshi, H. Tetrahedron 2007, 63, 1127e1139. 5. (a) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993e1998; (b) Florence, G. J.; Morris, J. C.; Murray, R. G.; Osler, J. D.; Reddy, V. R.; Smith, T. K. Org. Lett. 2011, 13, 514e517; (c) Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1980, 102, 1155e1157; (d) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025e2028.
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