HETEROCYCLES

Paper | Special issue | Vol. 77, No. 1, 2009, pp. 483-492
Received, 17th July, 2008, Accepted, 22nd August, 2008, Published online, 25th August, 2008.
DOI: 10.3987/COM-08-S(F)47

■ Total Synthesis of 2-Nor-macrosphelide A and B

Yuji Matsuya,* Takashi Matsushita, Keiji Sakamoto, and Hideo Nemoto*

Faculty of Pharmaceutical Sciences, Toyama University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan

Abstract

Total synthesis of 2-nor-macrosphelides, a 15-membered analogue of 16-membered natural macrosphelides, is described. The synthesis was accomplished starting from methyl L-(+)-lactate as a sole chiral source with a high efficiency.

INTRODUCTION
Macrosphelides are natural macrolides isolated from Microsphaeropsis sp. FO-5050 and Periconia byssoides, and characterized by a 16-membered tri-lactone framework.1 This novel class of macrolide compounds has been reported to exhibit potent inhibitory activity against adhesion of human leukemia HL-60 cells to human-umbilicalvein endothelial cells (HUVECs).2 Adhesion of tumor cells to the vessel wall endothelia of distant organs is a critical step in tumor metastasis, and it has been reported that macrosphelide B can suppress the metastasis of B16-BL6 mouse melanoma cells to the lung in vivo.3 In addition, macrosphelide B and relating compounds have been found to exert inhibitory activity against tumor cell growth (colon 26-L5 adenocarcinoma cells).4 We have recently first disclosed that several natural macrosphelides can induce apoptotic cell death of human lymphoma U937 cells,5 and that these compounds also have a notable property as an effective sensitizer of hyperthermia-induced apoptosis.6 These results have revealed that macrosphelides can be a potential lead compound for development of a new anticancer chemotherapeutic agent. We have been engaged in design, synthesis, and biological evaluation of macrosphelides and relating compounds,7,8 and recently reported that several artificial macrosphelides (hybridized compounds with epothilones) exhibit significantly improved apoptosis-inducing activity compared with natural macrosphelides.9 As a part of the structure-activity relationship studies of macrosphelides, we set about synthesizing novel 15-membered 2-nor-macrosphelides A and B (1 and 2, Scheme 1). Herein, we wish to report details of these synthetic studies.

RESULTS AND DISCUSSION
Because the macrocyclic core of macrosphelides is composed of three esters, protected hydroxy-acids possessing a suitable stereocenter are required as a synthetic block. For the synthesis of 2-nor-macrosphelides A and B (1 and 2), we chose the chiral blocks 3, 4, and 5 which are all derived from methyl L-(+)-lactate (Scheme 1). Ring-closing metathesis (RCM) is our choice for macrocyclization, as we have previously demonstrated its usefulness for macrosphelide syntheses.8

Preparation of the compounds 3, 4, and 5 from methyl L-(+)-lactate has already been reported in our previous studies.8 Initially, the alcohol 3a and the carboxylic acid 4 were connected using a Yamaguchi’s esterification protocol10 to give the ester 6a, which was then treated with TBAF to form desilylated alcohol 7a in satisfactory yields. The second esterification with the carboxylic acid 5 was carried out under the same condition. After desilylation of 8a, the third esterification of 9a was performed using acryloyl chloride to afford ω-diene compound 10a. Prior to the RCM, the PMB group needs to be removed, because steric congestion around the reaction site seriously interferes progress of the RCM reaction.8 After removal of the PMB group, RCM of the substrate 11 using Grubbs’ second-generation catalyst11 proceeded smoothly to provide the 15-membered macrocycle 12 in 85% yield. Finally, the
MEM group was eliminated by acid treatment to complete the synthesis of 2-nor-macrosphelide A (1).
Above synthesis seems to be very efficient and high yielding. In practice, however, there is a serious problem that bulk preparation of the starting chiral alcohol 3a is difficult, because p-methoxybenzylation of 4-(tert-butyldimethylsilyloxy)-1-penten-3-ol is a troublesome process as reported before.8 On the other hand, preparation of the chiral alcohol 3b, which appends a TBDPS group instead of the PMB group, was found to be much more convenient to realize large quantity synthesis. Thus, we decided to continue further synthetic study using 3b as a starting material. Following the above synthetic pathway (Scheme 2), successive esterification–deprotection sequence led to the same RCM substrate 11 after removal of the TBDPS group (Scheme 3). Selective desilylation of the TBS group could be achieved under AcOH–THF–H2O condition (8b→9b). The compound 12 obtained by RCM of 11 was subjected to PDC oxidation to give the corresponding ketone 13. The synthesis of 2-nor-macrosphelide B (2) was accomplished by TFA treatment of 13.

In this paper, we described total synthesis of 2-nor-macrosphelides A and B. All of the stereogenic centers bearing methyl group originate from an inexpensive chiral source, methyl L-(+)-lactate. These artificial macrosphelide analogues preserve the functional group arrangement, but may have different three-dimensional features from 16-membered natural macrosphelides. Bioactivities of these compounds are now under investigation, and will be reported in due course.

EXPERIMENTAL
All nonaqueous reactions were carried out under an Ar atmosphere. Reagents were purchased from commercial sources and used as received. Anhydrous solvents were prepared by distillation over CaH2, or purchased from commercial sources. 1H and 13C NMR spectra were obtained on a Varian Gemini 300 instrument, using chloroform peak as an internal reference. Mass spectra were measured on a JEOL D-200 or a JEOL AX 505 mass spectrometer, and the ionization method was electron impact (EI, 70 eV). IR spectra were recorded on a JASCO FT/IR-460Plus spectrometer. Column chromatography was carried out by employing Cica Silica Gel 60N (spherical, neutral, 40-50 µm or 63-210 µm). Preparative methods of the compounds 3, 4, and 5 have already been reported.8

(–)-3-(4-Methoxybenzyloxy)pent-1-en-4-yl 2-(tert-Butyldimethylsilyloxy)propanoate (6a)
To a solution of the carboxylic acid 4 (790 mg, 3.87 mmol) and Et3N (0.81 mL, 5.8 mmol) in toluene (35 mL) was added 2,4,6-trichlorobenzoyl chloride (0.6 mL, 3.87 mmol) at rt under Ar atmosphere, and the resulting mixture was stirred at rt for 1 h. The alcohol 3a (430 mg, 1.93 mmol) and DMAP (284 mg, 2.32 mmol) were added, and the reaction mixture was stirred for 1 h. After the reaction completed (by TLC), the mixture was diluted with benzene, and washed with sat. aq. NaHCO3 and brine, and dried over MgSO4. The solvent was evaporated off to leave a residue, which was chromatographed on silica gel to afford the ester 6a (648 mg, 82%) as a colorless oil. 1H-NMR (CDCl3): δ 7.14 (2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 8.4 Hz), 5.19 (1H, d, J = 16 Hz), 5.24 (2H, d, J = 6.8 Hz), 5.60 (1H, m), 4.94 (1H, q, J = 5.1 Hz), 4.44 (1H, d, J = 12 Hz), 4.20 (2H, dd, J = 12, 7.0 Hz), 3.70 (3H, s), 3.63 (1H, s), 0.80 (9H, s), –0.02 (6H, s); 13C-NMR (CDCl3): δ 173.34, 159.09, 134.92, 129.21, 119.64, 113.67, 81.63, 71.98, 70.04, 68.35, 68.32, 55.21, 25.71, 25.67, 25.44, 21.31, 21.22, 18.27, 15.16, –4.88, –5.02; IR (neat): 1752, 1613 cm-1; MS (EI): m/z 408 (M+); HRMS Calcd for C22H36O5Si: 408.2332 (M+), found: 408.2299; [α]D25 –29.96 (c 1.00, CHCl3).
(–)-3-(4-Methoxybenzyloxy)pent-1-en-4-yl 2-Hydroxypropanoate (7a)
A 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF (1.39 mL, 1.39 mmol) was added to a stirred solution of the TBS ether 6a (283 mg, 0.69 mmol) in THF (2 mL) at rt under Ar atmosphere, and the mixture was stirred for 0.5 h at rt. The solvent was evaporated off to leave a residue, which was dissolved in ether and the resulting organic layer was washed with water and brine, and dried over MgSO4. Evaporation of the solvent left a residue, which was chromatographed on silica gel to give the alcohol 7a (186 mg, 86%) as a colorless oil. 1H-NMR (CDCl3): δ 7.22 (2H, d, J = 8.4 Hz), 6.86 (2H, d, J = 8.4 Hz), 5.73 (1H, m), 5.32 (2H, m), 5.07 (1H, dt, J = 5.7, 4.9 Hz), 4.55 (1H, d, J = 12 Hz), 4.32 (1H, d, J = 12 Hz), 4.22 (1H, m), 3.80 (3H, s), 2.82 (1H, d, J = 5.4 Hz), 1.35 (3H, d, J = 6.9 Hz), 1.25 (3H, d, J = 6.3 Hz); 13C-NMR (CDCl3): δ 175.08, 159.17, 134.59, 130.12, 129.37, 129.27, 120.09, 113.80, 113.75, 81.47, 73.00, 70.02, 66.79, 55.25, 20.41, 15.61; IR (neat): 3470, 1737, 1613 cm-1; MS (EI): m/z 294 (M+); HRMS Calcd for C16H22O5: 294.1467 (M+), found: 294.1461; [α]D26 –38.22 (c 1.00, CHCl3).
(–)-1-[3-(4-Methoxybenzyloxy)pent-1-en-4-yloxycarbonyl]ethyl 5-(tert-Butyldimethylsilyloxy)-4-(methoxyethoxy)methoxyhex-2-enoate (8a)
According to the synthesis of 6a, the carboxylic acid 5 (321 mg, 0.92 mmol) and the alcohol 7a (135 mg, 0.46 mmol) gave the ester 8a (259 mg, 90%) as a colorless oil. 1H-NMR (CDCl3): δ 7.20 (2H, d, J = 8.4 Hz), 6.83 (2H, d, J = 8.4 Hz), 6.03 (1H, dd, J = 16, 1.1 Hz), 5.70 (1H, m), 5.28 (2H, t, J = 9.2 Hz), 5.06 (1H, d, J = 7.0 Hz), 5.00 (1H, m), 4.69 (2H, q, J = 3.8 Hz), 4.50 (1H, dd, J = 12 Hz), 4.29 (1H, d, J = 12 Hz), 4.06 (1H, dq, J = 3.8 Hz), 3.76 (3H, s), 3.71 (1H, dq, J = 7.3, 3.2 Hz), 3.63 (1H,m), 3.50 (2H, t, J = 4.6 Hz), 3.34 (3H, s), 1.42 (3H, d, J = 6.9 Hz), 1.22 (3H, d, J = 6.6 Hz), 1.12 (3H, d, J = 6.3 Hz), 0.84 (9H, s), 0.04 (6H, s); 13C-NMR (CDCl3): δ 170.02, 165.12, 159.12, 147.01, 146.97, 134.77, 130.24, 129.23, 122.23, 119.81, 113.71, 81.53, 79.87, 72.62, 71.65, 70.64, 70.05, 68.65, 67.23, 58.99, 55.22, 25.75, 19.75, 18.00, 16.93, 15.58, –4.66, –4.83; IR (neat): 1730, 1656 cm-1; MS (EI): m/z 624; HRMS Calcd for C32H52O10Si: 624.3330 (M+), found: 624.3307; [α]D24 –56.3 (c 1.00, CHCl3).
(–)-1-[3-(4-Methoxybenzyloxy)pent-1-en-4-yloxycarbonyl]ethyl 5-Hydroxy-4-(methoxyethoxy)methoxyhex-2-enoate (9a)
A 1 M solution of TBAF in THF (0.83 mL, 0.83 mmol) was added to a stirred solution of the TBS ether 8a (260 mg, 0.42 mmol) and acetic acid (47 µL, 0.83 mmol) in THF (3 mL) at rt under Ar atmosphere, and the mixture was stirred for 24 h at rt. The ethereal solution of the residue resulting from the evaporation of the solvent was washed with water, sat. aq. NaHCO3, and brine, and dried over MgSO4. Evaporation of the solvent left a residue, which was chromatographed on silica gel to give the alcohol 9a (190 mg, 90%) as a colorless oil. 1H-NMR (CDCl3): δ 7.21 (2H, d, J = 8.9 Hz), 6.85 (2H, d, J = 8.9 Hz), 6.10 (1H, dd, J = 16, 1.6 Hz), 5.70 (1H, m), 5.08 (1H, d, J = 7.0 Hz), 5.03 (1H, m), 4.76 (1H, d, J = 7.0 Hz), 4.68 (1H, d, J = 7.0 Hz), 4.51 (1H, d, J = 11 Hz), 4.31 (1H, d, J = 11 Hz), 4.22 (1H, q, J = 1.0 Hz), 3.91 (1H, m), 3.78 (3H, s), 3.54 (1H, d, J = 4.6 Hz), 3.37 (3H, s), 1.44 (3H, d, J = 6.9 Hz), 1.24 (3H, d, J = 6.3 Hz), 1.11 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3): δ 194.71, 181.72, 145.13, 134.75, 130.26, 129.27, 129.24, 122.83, 113.74, 94.60, 81.54, 72.73, 71.66, 70.08, 68.99, 68.82, 67.60, 60.73, 58.97, 55.26, 31.26, 27.07, 17.54, 16.94, 15.55, 15.24; IR (neat): 3650, 1728, 1613 cm-1; MS (EI): m/z 510 (M+); HRMS Calcd for C26H38O10: 510.2465 (M+), found: 510.2498; [α]D27 –47.76 (c 1.00, CHCl3).
(–)-1-[3-(4-Methoxybenzyloxy)pent-1-en-4-yloxycarbonyl]ethyl 5-Acryloyloxy-4-(methoxyethoxy)methoxyhex-2-enoate (10a)
Acryloyl chloride (76 µL, 0.94 mmol) was added dropwise to a stirred solution of the alcohol 9a (120 mg, 0.24 mmol) and N,N-diisopropylethylamine (200 µL, 1.18 mmol) in CH2Cl2 (3 mL) at 0 °C under Ar atmosphere. After continuous stirring for 1 h at rt, the reaction mixture was diluted with CH2Cl2, washed with water, 10% HCl, sat. aq. NaHCO3, and brine successively, and dried over MgSO4. Evaporation of the solvent afforded a residue, which was chromatographed on silica gel to give the ester 10a (124 mg, 93%), as a colorless oil. 1H-NMR (CDCl3): δ 7.22 (2H, d, J = 8.9Hz), 6.85 (2H, d, J = 8.9 Hz), 6.39 (1H, dd, J = 17, 1.4 Hz), 6.15 (1H, dd, J = 17, 1.4 Hz), 6.08 (1H, d, J = 10 Hz), 5.82 (1H, dd, J = 10, 1.4 Hz), 5.72 (1H, dq, J = 7.0 Hz), 5.33 (1H, d, J = 10 Hz), 5.21 (1H, s), 5.10 (2H, m), 4.73 (2H, q, J = 9.2 Hz), 4.53 (2H, d, J = 12 Hz), 4.40 (1H, m), 4.32 (2H, d, J = 12 Hz), 3.79 (3H, s), 3.75 (1H, d, J = 4.9 Hz), 3.66 (1H, m), 3.52 (2H, d, J = 4.6 Hz), 3.37 (3H, d, J = 2.4 Hz), 2.05 (1H, dq, J = 5.9, 1.6 Hz), 1.44 (3H, d, J = 6.9 Hz), 1.24 (3H, d, J = 6.3 Hz), 1.11 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3): δ 169.95, 165.32, 164.89, 159.11, 144.48, 134.70, 131.03, 130.19, 129.20, 128.37, 123.23, 119.86, 113.70, 93.87, 81.48, 72.68, 71.56, 71.36, 70.02, 69.84, 67.22, 58.96, 55.21, 16.89, 15.56, 14.88; IR (neat): 3781, 1727, 1659 cm-1; MS (EI): m/z 564; HRMS Calcd for C29H40O11: 564.2571 (M+), found: 564.2557; [α]D25 –43.18 (c 1.00, CHCl3).

(–)-1-(3-Hydroxypent-1-en-4-yloxycarbonyl)ethyl 5-Acryloyloxy-4-(methoxyethoxy)methoxyhex-2-enoate (11)
A mixture of the PMB ether 10a (57 mg, 0.1 mmol) and DDQ (34 mg, 0.15 mmol) in CH2Cl2/H2O (18 : 1, 1 mL) was stirred at rt for 1 h. The precipitate formed was removed by filtration, and the filtrate was concentrated to furnish a gummy mass, which was chromatographed on silica gel to give the alcohol 11 (42 mg, 93%) as a colorless oil. 1H-NMR (CDCl3): δ 6.94 (1H, dd, J = 16, 6.0 Hz), 6.40 (1H, dd, J = 17, 1.2 Hz), 6.17 (1H, dd, J = 16, 1.2 Hz), 6.09 (1H, d, J = 17 Hz), 5.84 (1H, d, J = 10 Hz), 5.78 (1H, m), 5.33 (1H, d, J = 17 Hz), 5.24 (1H, d, J = 10 Hz), 5.13 (1H, q, J = 3.6 Hz), 5.09 (1H, q, J = 7.2 Hz), 5.04 (1H, m), 4.74 (2H, q, J = 6.9 Hz), 4.43 (1H, q, J = 3.6 Hz), 4.19 (1H, m), 3.77 (1H, m), 3.67 (1H, m), 3.53 (2H, q, J = 4.8 Hz), 3.37 (3H, s), 1.89 (1H, br), 1.54 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J = 1.5 Hz), 1.23 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3): δ 170.28, 165.52, 165.40, 145.11, 135.41, 131.27, 128.42, 123.13, 117.79, 94.09, 77.39, 74.64, 71.76, 71.54, 69.47, 67.61, 67.48, 59.24, 17.22, 15.27, 14.80; IR (neat): 3481, 1727, 1660 cm-1; MS (EI): m/z 444 (M+); HRMS Calcd for C21H32O10: 444.1996 (M+), found: 444.2046; [α]D25 –28.80 (c 1.00, CHCl3).
RCM of the Compound 11 (Synthesis of the Compound 12)
Grubbs’ ruthenium catalyst (second generation) (7 mg, 7.9 µmol) was added to a solution of ω-diene compound 11 (35 mg, 0.079 mmol) in CH2Cl2 (80 mL) under Ar atmosphere. After continuous stirring for 24 h at rt, the solvent was evaporated to afford a residue, which was chromatographed on silica gel to give the compound 12 (28 mg, 85%) as a colorless oil. 1H-NMR (CDCl3): δ 6.75 (1H, dd, J = 16, 3.2 Hz), 6.69 (1H, dd, J = 16, 7.8 Hz), 5.98 (1H, dd, J = 16, 2.2 Hz), 5.95 (1H, d, J = 16 Hz), 4.98 (1H, dq, J = 7.3, 2.2 Hz), 5.05 (1H, q, J = 7.0 Hz), 4.69 (2H, td, J = 9.7, 3.0 Hz), 4.58 (1H, t, J = 4.2 Hz), 4.03 (2H, t, J = 8.9 Hz), 3.72 (1H, t, J = 5.1 Hz), 3.64 (1H, t, J = 4.3 Hz), 3.51 (2H, t, J = 4.3 Hz), 3.36 (3H, s), 1.38 (3H, d, J = 5.9 Hz), 1.47 (3H, d, J = 6.8 Hz), 1.41 (3H, d, J = 6.2 Hz); 13C-NMR (CDCl3): δ 198.60, 169.38, 165.05, 147.30, 146.07, 124.20, 120.60, 94.06, 80.49, 73.96, 71.49, 70.29, 69.55, 67.28, 58.96, 17.78, 17.17, 16.74, 2.36; IR (neat): 3447, 1737, 1661 cm-1; MS (EI): m/z 416; HRMS Calcd for C19H28O10: 416.1683 (M+), found: 416.1660; [α]D26 –131.11 (c 1.50, CHCl3).
2-Nor-Macrosphelide A (1)
Trifluoroacetic acid (TFA, 1 mL) was added to a solution of the MEM ether 12 (28 mg, 0.13 mmol) in CH2Cl2 (1 mL) at 0 °C under Ar atmosphere. After continuous stirring for 24 h at rt, the solvent was evaporated to afford a residue, which was chromatographed on silica gel to give 2-nor-macrosphelide A (1, 22 mg, 98%) as a colorless solid. Mp 135–137 °C; 1H-NMR (CDCl3): δ 6.85 (1H, dd, J = 16, 8.1 Hz), 6.82 (1H, dd, J = 16, 8.1 Hz), 6.75 (1H, dd, J = 16, 5.4 Hz), 5.95 (1H, dd, J = 16, 5.4 Hz), 5.07 (1H, q, J = 7.0 Hz), 4.96 (1H, m), 4.68 (1H, m), 4.08 (2H, t, J = 7.0 Hz), 2.20 (1H, br ), 4.03 (1H, t, J = 5.0 Hz), 1.50 (3H, d, J = 7.3 Hz), 1.46 (3H, d, J = 6.5 Hz), 1.38 (3H, d, J = 5.9 Hz); 13C-NMR (CDCl3): δ 169.50, 165.86, 164.91, 147.88, 146.29, 123.79, 122.24, 77.20, 74.55, 73.81, 73.44, 69.67, 17.74, 17.13, 16.78; IR (KBr): 3446, 1732, 1661 cm-1; MS (EI): m/z 328; HRMS Calcd for C15H20O9: 328.1158 (M+), found: 328.1139; [α]D28 +3.23 (c 1.00, CHCl3).
(–)-3-(tert-Butyldiphenylsilyloxy)pent-1-en-4-yl 2-(tert-Butyldimethylsilyloxy)propanoate (6b)
According to the synthesis of 6a, the carboxylic acid 4 (790 mg, 3.87 mmol) and the alcohol 3b (650 mg, 1.91 mmol) gave the ester 6b (915 mg, 91%) as a colorless oil. 1H-NMR (CDCl3): δ 7.65 (4H, m), 7.37 (6H, m), 5.77 (1H, ddd, J = 17, 10, 7.3 Hz), 5.01 (1H, d, J = 10 Hz), 4.95 (1H, m), 4.87 (1H, dd, J = 17, 1.0 Hz), 4.19 (1H, m), 4.08 (1H, m), 1.30 (3H, d, J = 6.6 Hz), 1.14 (3H, d, J = 6.3 Hz), 1.04 (9H, s), 0.89 (9H, s), 0.07 (6H, s); 13C-NMR (CDCl3): δ 173.45, 136.33, 136.05, 136.01, 133.76, 133.58, 129.69, 129.58, 127.49, 127.39, 117.74, 77.24, 73.61, 68.32, 26.94, 25.75, 21.29, 19.36, 18.32, 15.32, –4.83, –5.25; IR (neat): 1751, 1579 cm-1; MS (EI): m/z 469 (M+–57); HRMS Calcd for C26H37O4Si2: 469.2231 (M+–57), found: 469.2269; [α]D29 –9.24 (c 1.05, CHCl3).
(–)-3-( tert-Butyldiphenylsilyloxy)pent-1-en-4-yl 2-Hydroxypropanoate (7b)
A solution of the TBS ether 6b (980 mg, 1.86 mmol) in AcOH/THF/H2O (3 : 1 : 1, 15 mL) was stirred for 2 days at 50 °C. The reaction mixture was diluted with Et2O, washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel to afford the alcohol 7b (499 mg, 65%) as a colorless oil. 1H-NMR (CDCl3): δ 7.66 (4H, m), 7.37 (6H, m), 5.77 (1H, ddd, J = 17, 10, 7.3 Hz), 5.05 (1H, d, J = 10 Hz), 4.99 (1H, m), 4.91 (1H, d, J = 17 Hz), 4.16 (1H, m), 4.09 (1H, m), 2.68 (1H, br), 1.34 (3H, d, J = 7.0 Hz), 1.17 (3H, d, J = 6.6 Hz), 1.05 (9H, s); 13C-NMR (CDCl3): δ 175.11, 136.00, 135.94, 135.88, 133.47, 133.45, 129.77, 129.65, 127.52, 127.37, 117.97, 77.04, 74.70, 66.81, 26.89, 20.44, 19.30, 15.21; IR (neat): 3451, 1731, 1644 cm-1; MS (EI): m/z 413 (M++1); HRMS Calcd for C24H33O4Si: 413.2148 (M++1), found: 413.2169; [α]D27 –3.16 (c 1.150, CHCl3).
(–)-1-[3-(tert-Butyldiphenylsilyloxy)pent-1-en-4-yloxycarbonyl]ethyl 5-(tert-Butyldimethylsilyloxy)-4-(methoxyethoxy)methoxyhex-2-enoate (8b)
According to the synthesis of 6a, the carboxylic acid 5 (770 mg, 2.21 mmol) and the alcohol 7b (790 mg,
1.91 mmol) gave the ester 8b (1.16 g, 82%) as a colorless oil. 1H-NMR (CDCl3): δ 7.66 (2H, m), 7.61 (2H, m), 7.34 (6H, m), 6.92 (1H, dd, J = 16, 6.3 Hz), 6.05 (1H, dd, J = 16, 1.3 Hz), 5.73 (1H, ddd, J = 17, 10, 7.4 Hz), 5.02 (1H, m), 4.99 (1H, m), 4.96 (1H, m), 4.85 (1H, dd, J = 10, 1.1 Hz), 4.77 (1H, d, J = 6.9 Hz), 4.70 (1H, d, J = 6.9 Hz), 4.05 (2H, m), 3.82 (1H, m), 3.75 (1H, m), 3.64 (1H, m), 3.52 (2H, t, J = 4.6 Hz), 3.36 (3H, s), 1.40 (3H, d, J = 6.9 Hz), 1.15 (3H, d, J = 6.3 Hz), 1.14 ( 3H, d, J = 6.3 Hz), 1.03 (9H, s), 0.85 (9H, s), 0.02 (3H, s), 0.01 (3H, s); 13C-NMR (CDCl3): δ 170.10, 165.11, 146.93, 136.03, 136.00, 135.89, 133.65, 133.48, 129.72, 129.60, 127.21, 127.34, 122.32, 117.89, 94.11, 79.87, 77.15, 74.25, 71.66, 70.65, 68.68, 67.23, 59.01, 26.91, 25.76, 19.74, 19.31, 18.02, 16.97, 15.31, –4.64, –4.82; IR (neat): 1730, 1589 cm-1; MS (EI): m/z 742 (M+); HRMS Calcd for C40H62O9Si2: 742.3932 (M+), found: 742.3936; [α]D26 –5.920 (c 0.95, CHCl3).
(–)-1-[3-(tert-Butyldiphenylsilyloxy)pent-1-en-4-yloxycarbonyl]ethyl 5-Hydroxy-4-(methoxyethoxy)methoxyhex-2-enoate (9b)
According to the synthesis of 7b, the TBS ether 8b (1.10 g, 1.48 mmol) gave the alcohol 9b (850 mg, 91%) as a colorless oil. 1H-NMR (CDCl3): δ 7.65 (2H, m), 7.61 (2H, m), 7.34 (6H, m), 6.90 (1H, dd, J = 16, 5.7 Hz), 6.10 (1H, dd, J = 16, 1.3 Hz), 5.73 (1H, ddd, J = 17, 10, 7.3 Hz), 5.02 (1H, m), 4.99 (1H, m), 4.95 (1H, m), 4.85 (1H, dd, J = 17, 1.0 Hz), 4.77 (1H, d, J = 6.8 Hz), 4.70 (1H, d, J = 6.8 Hz), 4.24 (1H, m), 4.04 (1H, m), 3.92 (1H, m), 3.81 (1H, m), 3.67 (1H, m), 3.53 (2H, t, J = 4.6 Hz), 3.36 (3H, s), 1.89 (1H, br), 1.40 (3H, d, J = 6.9 Hz), 1.14 (3H, d, J = 6.6 Hz), 1.12 (3H, d, J = 6.6 Hz), 1.03 (9H, s); 13C-NMR (CDCl3): δ 170.14, 165.01, 145.07, 136.01, 135.98, 133.62, 133.47, 129.73, 129.60, 127.51, 122.86, 117.90, 94.57, 80.94, 77.12, 74.38, 71.64, 68.97, 68.83, 67.56, 58.94, 26.91, 19.30, 17.52, 16.97, 15.27; IR (neat): 3460, 1728, 1658 cm-1; MS (EI): m/z 571 (M+–57); HRMS Calcd for C30H39O9Si: 571.2363 (M+–57), found: 571.2342; [α]D25 –22.84 (c 1.55, CHCl3).
(–)-1-[3-(tert-Butyldiphenylsilyloxy)pent-1-en-4-yloxycarbonyl]ethyl 5-Acryloyloxy-4-(methoxyethoxy)methoxyhex-2-enoate (10b)
According to the synthesis of 10a, the alcohol 9b (150 mg, 0.23 mmol) gave the ester 10b (138 mg, 85%) as a colorless oil. 1H-NMR (CDCl3): δ 7.67 (2H, m), 7.63 (2H, m), 7.34 (6H, m), 6.90 (1H, dd, J = 16, 5.7 Hz), 6.40 (1H, dd, J = 17, 1.3 Hz), 6.16 (1H, dd, J = 17, 1.7 Hz), 6.10 (1H, m), 5.82 (1H, dd, J = 10, 1.3 Hz), 5.75 (1H, ddd, J = 17, 10, 7.3 Hz), 5.13 (1H, m), 5.04 (1H, m), 5.02 (1H, m), 4.99 (1H, m), 4.87 (1H, dd, J = 17, 1.3 Hz), 4.77 (1H, d, J = 6.9 Hz), 4.70 (1H, d, J = 6.9 Hz), 4.43 (1H, m), 4.05 (1H, m), 3.79 (1H, m), 3.65 (1H, m), 3.53 (2H, m), 3.37 (3H, s), 1.45 (3H, d, J = 6.8 Hz), 1.25 (3H, d, J = 6.8 Hz), 1.16 (3H, d, J = 6.4 Hz), 1.05 (9H, s); 13C-NMR (CDCl3): δ 170.02, 165.31, 164.86, 144.37, 135.95, 135.92, 133.50, 133.35, 131.06, 129.68, 129.56, 128.31, 127.46, 127.30, 123.25, 117.89, 93.79, 76.74, 76.46, 74.29, 71.51, 71.32, 68.84, 67.15, 58.94, 26.84, 19.24, 16.90, 15.26, 14.86; IR (neat): 3781, 1728, 1660 cm-1; MS (EI): m/z 625 (M+–57); HRMS Calcd for C33H41O10Si: 625.2469 (M+–57), found: 625.2450;
[α]D26 –12.858 (c 1.10, CHCl3).
Removal of the TBDPS group of the compound 10b
According to the synthesis of 9a, the TBDPS ether 10b (68 mg, 0.1 mmol) gave the alcohol 11 (261 mg, 59%) as a colorless oil. Spectral data of 11 have already been given.
PDC Oxidation of the Compound 12 (Synthesis of the Compound 13)
Pyridinium dichromate (PDC, 89 mg, 0.23 mmol) was added portionwise to a stirred solution of the alcohol 12 (22 mg, 0.053 mmol) and molecular sieves 4A (100 mg) in CH2Cl2 (5 mL) at 0 °C under Ar atmosphere. After continuous stirring for 3 h at rt, the reaction mixture was diluted with ether, and filtered through celite. The filtrate was evaporated to leave a residue, which was chromatographed on silica gel to give the ketone 13 (13 mg, 55%) as a colorless oil. 1H-NMR (CDCl3): δ 7.07 (1H, d, J = 16 Hz), 6.84 (1H, dd, J = 16, 8.9 Hz), 6.63 (1H, d, J = 16 Hz), 6.17 (1H, d, J = 16 Hz), 5.29 (1H, t, J = 7.3 Hz), 5.25 (1H, q, J = 6.9 Hz), 4.88 (1H, m), 4.74 (1H, d, J = 6.9 Hz), 4.67 (1H, d, J = 6.9 Hz), 4.17 (1H, t, J = 8.9 Hz), 3.74 (1H, m), 3.63 (1H, m), 3.51 (2H, t, J = 4.3 Hz), 3.35 (3H, s), 1.54 (3H, d, J = 6.9 Hz), 1.45 (3H, d, J = 6.3 Hz), 1.40 (3H, d, J = 6.9 Hz); 13C-NMR (CDCl3): δ 196.56, 168.99, 164.71, 164.25, 147.09, 133.75, 132.65, 124.40, 93.87, 79.72, 75.52, 72.21, 71.53, 69.01, 67.39, 59.00, 18.05, 16.94, 16.43; IR (neat): 1730, 1617 cm-1; MS (EI): m/z 414 (M+); HRMS Calcd for C19H26O10: 414.1525 (M+), found: 414.1537; [α]D29 –122.692 (c 1.30, CHCl3).
2-Nor-Macrosphelide B (2)
According to the synthesis of 1, the compound 13 (16 mg, 0.039 mmol) gave the 2-nor-macrosphelide B (2, 9 mg, 75%) as a colorless solid. Mp 100–102 °C; 1H-NMR (CDCl3): δ 7.16 (1H, d, J = 16 Hz), 6.99 (1H, dd, J = 16, 7.3 Hz), 6.64 (1H, d, J = 16 Hz), 6.13 (1H, dd, J = 16, 1.0 Hz), 5.28 (1H, q, J = 7.3 Hz), 5.25 (1H, m), 4.91 (1H, m), 4.25 (1H, t, J = 6.4 Hz), 1.56 (3H, d, J = 7.0 Hz), 1.51 (3H, d, J = 6.3 Hz), 1.43 (3H, d, J = 6.9 Hz); 13C-NMR (CDCl3): δ 196.67, 168.93, 164.94, 164.78, 147.82, 134.22, 132.31, 122.50, 75.99, 75.68, 74.68, 69.22, 17.88, 16.98, 16.60; IR (KBr): 3488, 1725, 1656 cm-1; MS (EI): m/z 326 (M+); HRMS Calcd for C15H18O8: 326.1002 (M+), found: 326.0987; [α]D25 –45.84 (c 0.60, CHCl3).

ACKNOWLEDGEMENTS
This work was supported by THE FUGAKU TRUST FOR MEDICINAL RESEARCH, and by Grant-in-Aid for Scientific Research (C) (No. 19590098) from Japan Society for the Promotion of Science (JSPS).

† Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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