2.3. Actividad Turística
2.6.6. Contaminación Cruzada
Despite the poor d.r. of the three component coupling, we proceeded with cleavage of the chiral auxiliary by treatment of the diastereomeric mixture with TsOH and (MeO)3CH in refluxing methanol. As predicted, the tertiary auxiliary underwent
facile cleavage to mixed methyl ketal 58 (mixture of syn and anti, 53% combined yield; compare to <10% yield with auxiliary 55d). The enantiopurity of the mixed methyl ketal was not tested, but should be ~63:37 e.r. based on the 1.7:1.0 ratio of diastereomers that
137
are believed to possess the desired relative stereochemistry between C3 and C4. Future work could involve the synthesis of more chiral tertiary silyl glyoxylates for testing in the three component coupling, since we have demonstrated their acid lability.
3.4 Conclusion
In summary, we have developed a three component coupling of enolates, silyl glyoxylates, and enones which demonstrates counterion-dependent regioselectivity. Additionally, we have developed a nitrile-oxide cycloaddition with enolsilane dipolarophiles for the synthesis of isoxazoles that are challenging to access by other means. These new reactions allowed the synthesis of trachyspic acid dimethyl ester in 10 linear steps from undecanal in 4% overall yield (average of >70% yield per step). The three component coupling step may be done asymmetrically by utilizing a chiral silyl glyoxylate. The aim of future work is to evaluate the scope of the tandem aldol/Michael reaction in the context of other alkyl citrate natural products.
3.5 Experimental
Materials and Methods: General. Infrared (IR) spectra were obtained using a Nicolet 560-E.S.P. infrared spectrometer. Proton and carbon nuclear magnetic resonance spectra (1H and 13C NMR) were recorded on either a Bruker model Avance 600 (1H NMR at 600 MHz and 13C NMR at 150 MHz), Bruker model Avance 500 (1H at 500 MHz and 13C NMR at 125 MHz), Bruker model Avance 400 (1H NMR at 400 MHz and 13C NMR at 100 MHz), or a Varian Gemini 300 (1H NMR at 300 MHz and 13C at 75 MHz) spectrometer with solvent resonance as the internal standard (1H NMR: CDCl3 at 7.26
ppm; C6D6 at 7.15 ppm and 13C NMR: CDCl3 at 77.0 ppm and C6D6 at 128.62 ppm). 1H
138
singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet), coupling constants (Hz), and integration. Analytical thin layer chromatography (TLC) was performed on Whatman 0.25 mm silica gel 60 plates. Visualization was accomplished with UV light and aqueous ceric ammonium molybdate solution followed by heating. Purification of the reaction products was carried out by flash chromatography using Sorbent Technologies silica gel 60 (32-63 µm). All reactions were carried out under an atmosphere of nitrogen in oven-dried glassware with magnetic stirring. Yield refers to isolated yield of analytically pure material. Yields are reported for a specific experiment and as a result may differ slightly from those found in the tables, which are averages of at least two experiments. Diethyl ether, methylene chloride, tetrahydrofuran, and toluene were dried by passage through a column of neutral alumina under nitrogen prior to use.21 Unless otherwise noted, reagents were obtained from commercial sources and used without further purification. Triethylamine, diisopropylamine, and pyridine were freshly distilled from CaH2 under Ar prior to use.
General Procedure A for Aldol/Michael Three Component Couplings: To a solution of LiCl (8.0 equiv, 1.9 M) in THF was added iPr2NH (2.1 equiv). The solution was
cooled to 0 °C and nBuLi (1.4 M in hexanes, 2.0 equiv) was added. The solution was stirred at 0 °C for 10 min, then stirred at room temperature for 10 min. The solution was cooled to -78 °C and a solution of tBuOAc (1.9 equiv) in THF (1.1 M) was added. The solution was stirred at -78 °C for 1 h. A solution of ,-unsaturated ketone (1.0 equiv, 0.2 M) and t-butyl t-butyldimethylsilyl glyoxylate23 (2.1 equiv) in THF was added. The solution was allowed to slowly warm to room temperature over 3 h and then stirred at room temperature for 14-24 h. The reaction was diluted with Et2O (15 mL) and quenched with saturated
139
NH4Cl (5 mL). The layers were separated and the aqueous layer was extracted with Et2O
(3 X 20 mL). The organic extracts were combined, washed with brine (15 mL), dried with MgSO4, and concentrated under reduced pressure. The resulting oil was purified as
indicated.
(E)-di-tert-butyl 2-(1,5-bis(4-methoxyphenyl)-3-oxopent-4-en-1-yl)-2-((tert- butyldimethylsilyl)oxy)succinate (35a). General procedure A was performed using dianisylideneacetone (59 mg, 0.200 mmol, 1.0 equiv). Purification by flash chromatography (95:5 to 85:15 petroleum ether:Et2O gradient) furnished 35a (52 mg,
0.0794 mmol, 40% yield) as a clear oil. Analytical data for 35a: IR (thin film, cm-1) 2930, 2854, 1740, 1658, 1602, 1513, 1463, 1422, 1393, 1107, 1036; 1H NMR (400 MHz, CDCl3) 7.43-7.37(m, 3H), 7.27-7.25 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 16.4 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.61 (dd, J = 2.4, 10.4 Hz, 1H), 3.20 (dd, J = 10.8, 16.8 Hz, 1H), 3.06 (dd, J = 2.8, 16.8 Hz, 1H), 2.65 (d, J = 17.2 Hz, 1H), 2.22 (d, J = 16.8 Hz, 1H), 1.43 (s, 9H), 1.39 (s, 9H), 0.93 (s, 9H), 0.37 (s, 3H), 0.16 (s, 0.16); 13C NMR (150 MHz, CDCl3) 198.3, 172.3, 169.0, 161.5, 158.5, 142.1, 131.8, 130.9, 130.0, 127.2, 124.3, 114.3, 113.4, 81.6, 80.6, 80.2, 55.4, 55.2, 48.8, 44.3, 42.6, 28.1, 27.8, 26.5, 19.2, -2.1, -2.6; LRMS (ESI) exact mass calculated for C37H54O8SiNa: 677.35. Found: 677.37.
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(E)-di-tert-butyl 2-(1,5-bis(3,5-dimethoxyphenyl)-3-oxopent-4-en-1-yl)-2-((tert- butyldimethylsilyl)oxy)succinate (35b). General procedure A was performed using (1E,4E)-1,5-bis(3,5-dimethoxyphenyl)-1,4-pentadien-3-one (60 mg, 0.169 mmol, 1.0 equiv). Purification by flash chromatography (85:15 petroleum ether:Et2O) furnished 35b (50 mg, 0.0699 mmol, 41% yield) as a clear oil. Analytical data for 35b: IR (thin film, cm-1) 2929, 2850, 1740, 1651, 1595, 1463, 1428, 1368, 1067; 1H NMR (400 MHz, CDCl3) 7.37-7.33 (m, 1H), 6.61-6.47 (m, 6H) 6.28 (d, J = 18.4 Hz, 1H), 3.80 (s, 3H),
3.75 (s, 3H), 3.48 (d, J = 7.2 Hz, 1H), 3.26-3.14 (m, 2H), 2.71 (d, J = 17.2 Hz, 1H), 2.35 (d, J = 17.2 Hz, 1H), 1.42 (s, 9H), 1.40 (s, 9H), 0.95 (s, 9H), 0.36 (s, 3H), 0.16 (s, 3H);
LRMS (ESI) exact mass calculated for C39H58O10SiNa: 737.37. Found: 737.39.
(E)-di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(1,5-di(furan-2-yl)-3-oxopent-4- en-1-yl)succinate (35c). General procedure A was performed using difurylideneacetone (31 mg, 0.145 mmol, 1.0 equiv). Purification by flash chromatography (97:3 hexanes:Et2O) furnished 35c (40 mg, 0.0695 mmol, 48% yield) as a clear oil. Analytical
data for 35c: IR (thin film, cm-1) 2855, 1739, 1614, 1555, 1473, 1369, 1150, 1107, 1017;
1
H NMR (300 MHz, CDCl3) 7.48 (s, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.21 (s, 1H), 6.62
(d, J = 3.3 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 6.46 (dd, J = 1.8, 3.6 Hz, 1H), 6.25 (dd, J
141
(m, 1H), 2.97 (dd, J = 2.4, 16.5 Hz, 1H), 2.89 (d, J = 16.8 Hz, 1H), 2.42 (d, J = 16.8 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H), 0.87 (s, 9H), 0.30 (s, 3H), 0.12 (s, 3H); 13C NMR (100 MHz, CDCl3) 197.3, 171.8, 168.9, 152.9, 151.1, 144.8, 141.4, 128.6, 123.2, 115.6,
112.5, 110.2, 108.6, 81.7, 80.3, 79.7, 43.6, 43.4, 40.5, 28.1, 28.0, 27.9, 27.8, 27.7, 26.2, 19.0, -2.5, -2.9; LRMS (ESI) exact mass calculated for C31H46O8SiNa: 597.29. Found:
597.30.
di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(3-oxo-3-phenyl-1-(4- (trifluoromethyl)phenyl)propyl)succinate (35d). General procedure A was performed using (E)-1-phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (40 mg, 0.145 mmol, 1.0 equiv). Purification by flash chromatography (97:3 hexanes:Et2O) furnished 35d (49
mg, 0.0769 mmol, 53% yield) as a clear oil. Analytical data for 35d: IR (thin film, cm-1) 2931, 2359, 1741, 1618, 1472, 1394, 1325, 1255, 1222, 1164, 1069, 1019; 1H NMR (600 MHz, CDCl3) 7.85 (d, J = 8.4 Hz, 2H), 7.53-7.50 (m, 5H), 7.44-7.40 (m, 2H), 3.88 (dd, J = 2.4, 10.2 Hz), 3.58 (t, J = 10.2 Hz, 1H), 3.51 (dd, J = 3, 18 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.22 (d, J = 17.4 Hz, 1H), 1.42 (s, 9H), 1.40 (s, 9H), 0.93 (s, 9H), 0.39 (s, 3H), 0.18 (s, 3H); 13C NMR (150 MHz, CDCl3) 197.5, 171.8, 168.6, 136.8, 133.1, 130.3, 128.6, 127.8, 124.9, 82.1, 80.6, 80.2, 48.6, 44.4, 40.6, 28.1, 27.7, 26.5, 19.2, -2.2, -2.6;
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di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(1-(furan-2-yl)-3-oxo-3- phenylpropyl)succinate (35e). General procedure A was performed using (E)-3-(furan- 2-yl)-1-phenylprop-2-en-1-one (29 mg, 0.145 mmol, 1.0 equiv). Purification by flash chromatography (97:3 hexanes:Et2O) furnished 35e (53 mg, 0.0948 mmol, 65% yield) as
a clear oil. Analytical data for 35e: IR (thin film, cm-1) 2930, 2855, 1741, 1692, 1598, 1472, 1393, 1368, 1251, 1149, 1106, 1012; 1H NMR (500 MHz, CDCl3) 7.90 (d, J = Hz, 2H), 7.53 (t, J = 7 Hz, 1H), 7.44-7.40 (m, 2H), 7.28 (s, 1H), 6.24 (d, J = 2 Hz, 1H), 6.14 (d, J = 3.5 Hz, 1H), 3.95 (dd, J = 2, 10.5 Hz, 1H), 3.66 (dd, J = 10.5, 17.5 Hz, 1H), 3.31 (dd, J = 2, 17 Hz, 1H), 2.92 (d, J = 16.5 Hz, 1H), 2.45 (d, J = 17 Hz, 1H), 1.43 (s, 9H), 1.39 (s, 9H), 0.87 (s, 9H), 0.33 (s, 3H), 0.14 (s, 3H); 13C NMR (100 MHz, CDCl3) 197.7, 171.9, 168.9, 153.1, 141.4, 137.0, 132.9, 128.5, 128.0, 110.2, 108.5, 81.7, 80.3, 79.8, 43.6, 43.3, 28.1, 27.7, 26.2, 19.0, -2.4, -2.9; LRMS (ESI) exact mass calculated for C31H46O7SiNa: 581.29. Found: 581.31.
di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(3-oxo-1,3-diphenylpropyl)succinate (35f). General procedure A was performed using trans-chalcone (42 mg, 0.200 mmol, 1.0 equiv). Purification by flash chromatography (97:3 petroleum ether:Et2O) furnished 35f (67 mg, 0.118 mmol, 59% yield) as a clear oil. Analytical data for 35f: IR (thin film, cm-1) 2929, 2855, 2360, 2124, 1739, 1691, 1607, 1578, 1495, 1017; 1H NMR (600 MHz, CDCl3) 7.86 (d, J = 6.6 Hz, 2H), 7.51-7.49 (m 1H), 7.49-7.36 (m, 4H), 7.25-7.19 (m,
143
3H), 3.79 (d, J = 10.2 Hz, 1H), 3.60 (dd, J = 10.2, 18.0 Hz, 1H), 3.47 (d, J = 18.0 Hz, 1H), 2.70 (d, J = 16.8 Hz, 1H), 2.24 (d, J = 17.4 Hz, 1H), 1.40 (s, 9H), 1.39 (s, 9H), 0.92 (s, 9H), 0.39 (s, 3H), 0.18 (s, 3H); 13C NMR (100 MHz, CDCl3) 198.0, 172.3, 169.0,
140.0, 137.2, 132.8, 130.2, 130.0, 128.5, 128.0, 127.9, 127.5, 126.9, 81.7, 80.5, 80.3, 49.1, 44.4, 40.6, 28.1 (2 peaks), 27.8, 26.5, 26.3, 19.2, -2.1, -2.6; LRMS (ESI) exact mass calculated for C15H26O3SiNa: 591.31. Found: 591.33.
di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-((1E,4E)-1,5-di(furan-2-yl)-3- hydroxypenta-1,4-dien-3-yl)succinate (36a). To the Reformatsky reagent of t-butyl bromoacetate11 (0.39 M in Et2O, 1.5 mL, 0.583 mmol, 2.5 equiv) was added 0.9 mL
Et2O. The solution was cooled to -30 °C and a solution of t-butyl t-butyldimethylsilyl
glyoxylate24 (142 mg, 0.583 mmol, 2.5 equiv) in Et2O (1.5 mL) was added. The solution was
slowly warmed to 0 °C over 30 min before a solution of Zn(OTf)2 (85 mg, 0.233 mmol, 1.0
equiv) and difurylideneacetone (50 mg, 0.233 mmol, 1.0 equiv) in Et2O (3.0 mL) was
added (Some Zn(OTf)2 would not dissolve and was not transferred into reaction). The
solution was slowly warmed to room temperature over 15 h and then saturated NH4Cl (5
mL) was added. The layers were separated and the aqueous layer was extracted with Et2O (3 X 20 mL). The organic extracts were combined, washed with brine (15 mL),
dried with MgSO4, and concentrated under reduced pressure. Purification by flash
chromatography (97:3 to 95:5 petroleum ether:EtOAc gradient) furnished 36a (56 mg, 0.0974 mmol, 42% yield) as a colorless oil. Analytical data for 36a: 1H NMR (400
144 MHz, CDCl3) 7.33 (s, 2H), 6.59-6.52 (m, 3H), 6.38-6.33 (m, 3H), 6.21 (t, J = 4.4 Hz, 2H), 3.83 (brs, 1H), 3.17 (d, J = 17.6 Hz, 1H), 2.64 (d, J = 17.6 Hz, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 0.93 (s, 9H), 0.25 (s, 3H), 0.16 (s, 3H); 13C NMR (150 MHz, CDCl3) 171.7, 169.7, 152.9, 142.0, 128.5, 127.6, 118.1, 117.5, 111.2, 108.0 (2 peaks), 83.1, 82.7, 80.6, 78.8, 41.4, 28.1, 27.9, 26.2, 19.0, -2.5, -2.8.
General Procedure B for Dipolar Cycloadditions: To a solution of enolsilane (2.0 to 8.0 equiv) and ethyl chlorooximidoacetate (1.0 equiv, 0.04 M in hexanes) was added a solution of Et3N (1.5 equiv, 0.1 M in hexanes) via syringe pump over 15 h. The solution
was stirred at room temperature for 4-72 h and then TsOH.H2O (4.0 equiv) was added.
The flask was fitted with a reflux condenser and the solution was heated to reflux for 4- 24 h. The reaction was cooled to room temperature and H2O was added. The solution
was extracted with EtOAc (3X) and the combined organic extracts were dried with MgSO4 and concentrated under reduced pressure. The resulting brown oil was purified
as indicated.
Ethyl 4-isopropylisoxazole-3-carboxylate (52a). General procedure B was performed using the trimethylsilyl enol ether of 3-methylbutyraldehyde (1.69 g, 10.6 mmol, 8.0 equiv), ethyl chlorooximidoacetate (200 mg, 1.32 mmol, 1.0 equiv), Et3N (0.276 mL,
1.98 mmol, 1.5 equiv), and TsOH.H2O (1.00 g, 5.28 mmol, 4.0 equiv). Purification by
flash chromatography (95:5 petroleum ether:Et2O) furnished 52a (87 mg, 0.475 mmol,
145
2936, 2874, 1731, 1587, 1468, 1338, 1270, 1163, 1016; 1H NMR (400 MHz, CDCl3)
8.29 (s, 1H), 4.46 (q, J = 6.8 Hz, 2H), 3.29-3.22 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.27 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) 160.5, 155.9, 153.3, 128.3, 61.8,
23.0, 14.1; TLC (10:90 EtOAc: petroleum ether) Rf 0.29; LRMS (ESI) exact mass
calculated for C9H13NO3Na: 206.08. Found: 206.10.
Ethyl 4-butylisoxazole-3-carboxylate (52b). General procedure B was performed using the trimethylsilyl enol ether of hexanal (230 mg, 1.32 mmol, 2.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N (0.138 mL, 0.990 mmol, 1.5
equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv). Purification by flash
chromatography (97:3 petroleum ether:Et2O) furnished 52b (29 mg, 0.147 mmol, 22%
yield) as a clear oil. Analytical data for 52b: IR (thin film, cm-1) 2960, 1732, 1457, 1236, 1119; 1H NMR (400 MHz, CDCl3) 8.29 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.67 (t, J =
7.2 Hz, 2H), 1.58 (m, 2H), 1.45-1.36 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) 160.5, 157.1, 153.8, 121.4, 61.8, 31.6, 22.3, 21.8, 14.1; TLC (10:90
EtOAc: petroleum ether) Rf 0.19; LRMS (ESI) exact mass calculated for C10H15NO3Na:
220.10. Found: 220.11.
Ethyl 4-octylisoxazole-3-carboxylate (52c). General procedure B was performed using the trimethylsilyl enol ether of decanal (300 mg, 1.32 mmol, 2.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N (0.138 mL, 0.990 mmol, 1.5
146
equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv). Purification by flash
chromatography (97:3 petroleum ether:Et2O) furnished 52c (49 mg, 0.194 mmol, 29%
yield) as a clear oil. Analytical data for 52c: IR (thin film, cm-1) 3115, 2927, 2856, 1732, 1592, 1461, 1390, 1291, 1236, 1173, 1122, 1018; 1H NMR (400 MHz, CDCl3) 8.29 (s,
1H), 4.45 (q, J = 6.8 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H), 1.34-1.27 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) 160.5, 157.0, 153.9,
121.4, 61.8, 31.8, 29.5, 29.3, 29.2, 22.6, 22.1, 14.1, 14.0; TLC (10:90 EtOAc: petroleum ether) Rf 0.33; LRMS (ESI) exact mass calculated for C14H23NO3Na: 276.16. Found:
276.17.
Ethyl 4-benzylisoxazole-3-carboxylate (52d). General procedure B was performed using the trimethylsilyl enol ether of hydrocinnamaldehyde (540 mg, 2.64 mmol, 4.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N (0.138 mL,
0.990 mmol, 1.5 equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv). Purification by
flash chromatography (97:3 petroleum ether:Et2O) furnished 52d (40 mg, 0.172 mmol,
26% yield) as a clear oil. Analytical data for 52d: IR (thin film, cm-1) 2360, 1732, 1456, 1237, 1105, 708; 1H NMR (400 MHz, CDCl3) 8.12 (s, 1H), 7.36-7.23 (m, 5H), 4.47 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
160.3, 158.3, 153.6, 138.4, 128.7, 128.6, 126.8, 121.0, 63.6, 62.0, 53.4, 28.5, 14.1;
TLC (10:90 EtOAc: petroleum ether) Rf 0.15; LRMS (ESI) exact mass calculated for
147
Ethyl 4-phenylisoxazole-3-carboxylate (52e). General procedure B was performed using the trimethylsilyl enol ether of phenylacetaldehyde (250 mg, 1.32 mmol, 2.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N (0.138 mL,
0.990 mmol, 1.5 equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv). Purification by
flash chromatography (95:5 petroleum ether:Et2O) furnished 52e (14 mg, 0.066 mmol,
10% yield) as a clear oil.
Ethyl 5,6-dihydro-4H-cyclopenta[d]isoxazole-3-carboxylate (52f). General procedure B was performed using the trimethylsilyl enol ether of cyclopentanone (413 mg, 2.64 mmol, 4.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N
(0.138 mL, 0.990 mmol, 1.5 equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv).
Purification by flash chromatography (95:5 petroleum ether:Et2O) furnished 52f (77 mg,
0.425 mmol, 64% yield) as a clear oil. Analytical data for 52f: IR (thin film, cm-1) 2981, 1747, 1618, 1434, 1389, 1307, 1239, 1134, 1040; 1H NMR (400 MHz, CDCl3) 4.42 (q, J = 7.2 Hz, 2H), 2.88-2.83 (m, 2H), 2.76-2.69 (m, 4H), 1.41 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) 181.7, 160.3, 151.8, 124.5, 61.9, 30.4, 24.6, 21.5, 14.1; TLC
(10:90 EtOAc: petroleum ether) Rf 0.17; LRMS (ESI) exact mass calculated for
148
Ethyl 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (52g). General procedure B was performed using the trimethylsilyl enol ether of tetralone (870 mg, 3.95 mmol, 6.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N (0.138 mL,
0.990 mmol, 1.5 equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv). Purification by
flash chromatography (95:5 petroleum ether:Et2O) furnished 52g (112 mg, 0.461 mmol,
70% yield) as a white solid. Analytical data for 52g: 1745, 1634, 1596, 1569, 1367, 1350, 1285, 1192, 1018; 1H NMR (600 MHz, CDCl3) 8.01 (d, J = 7.8 Hz, 1H), 7.46-
7.27 (m, 3H), 4.45 (q, J = 7.2 Hz, 2H), 3.05-3.00 (m, 4H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 167.6, 160.3, 153.2, 136.5, 130.1, 128.3, 126.9, 124.3, 121.8,
113.6, 61.7, 28.4, 18.4, 14.0; TLC (10:90 EtOAc: petroleum ether) Rf 0.21.
Ethyl 5,6,7,8-tetrahydro-4H-cyclohepta[d]isoxazole-3-carboxylate (52h). General procedure B was performed using the trimethylsilyl enol ether of cycloheptanone (487 mg, 2.64 mmol, 4.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.66 mmol, 1.0 equiv), Et3N (0.138 mL, 0.990 mmol, 1.5 equiv), and TsOH.H2O (0.50 g, 2.64 mmol, 4.0 equiv).
Purification by flash chromatography (97:3 petroleum ether:Et2O) furnished 52h (89 mg,
0.421 mmol, 64% yield) as a clear oil. Analytical data for 52h: IR (thin film, cm-1) 1730, 1619, 1452, 1389, 1369, 1348, 1120, 1094, 1074; 1H NMR (400 MHz, CDCl3) (q, J = 6.8 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 1.86-1.83 (m, 2H), 1.77-1.70 (m, 4H), 1.44 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) 173.4, 161.1,
149
154.3, 117.5, 61.6, 30.4, 27.8, 25.4, 22.1, 14.1; TLC (10:90 EtOAc: petroleum ether) Rf
0.19. LRMS (ESI) exact mass calculated for C11H15NO3Na: 232.10. Found: 232.11.
Ethyl 4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylate (52i). General procedure B was performed using the trimethylsilyl enol ether of cyclohexanone (900 mg, 5.28 mmol, 4.0 equiv), ethyl chlorooximidoacetate (200 mg, 1.32 mmol, 1.0 equiv), Et3N (0.280 mL,
1.98 mmol, 1.5 equiv), and TsOH.H2O (1.00 g, 5.28 mmol, 4.0 equiv). Purification by
flash chromatography (95:5 petroleum ether:Et2O) furnished 52i (64 mg, 0.330 mmol,
25% yield) as a clear oil. Analytical data for 52i: IR (thin film, cm-1) 1728, 1630, 1455, 1333, 1272, 1240, 1213, 1177, 1045; 1H NMR (400 MHz, CDCl3) 4.43 (q, J = 7.2 Hz,
2H), 2.75 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 4.4 Hz, 2H), 1.91-1.86 (m, 2H), 1.80-1.76 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 170.5, 160.8, 153.7, 113.9,
61.6, 22.7, 22.2, 21.9, 20.2, 14.1; TLC (10:90 EtOAc: petroleum ether) Rf 0.17; LRMS
(ESI) exact mass calculated for C10H13NO3Na: 218.08. Found: 218.09.
ethyl 5-ethyl-4-methylisoxazole-3-carboxylate (52j). General procedure B was performed using the trimethylsilyl enol ether of 3-pentanone (830 mg, 5.28 mmol, 4.0 equiv), ethyl chlorooximidoacetate (100 mg, 0.660 mmol, 1.0 equiv), Et3N (0.138 mL,
0.990 mmol, 1.5 equiv), and TsOH.H2O (0.502 g, 2.64 mmol, 4.0 equiv). Purification by
flash chromatography (95:5 petroleum ether:Et2O) furnished 52j (49 mg, 0.268 mmol,
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1454, 1389, 1365, 1328, 1293, 1270, 1201, 1165, 1085, 1019; 1H NMR (400 MHz, CDCl3) 4.42 (q, J = 6.8 Hz, 2H), 2.76 (q, J = 7.6 Hz, 2H), 2.14 (s, 3H), 1.41 (t, J = 7.2
Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) 172.1, 160.9, 154.7,
110.3, 61.6, 53.4, 18.8, 14.1, 11.8; TLC (10:90 EtOAc: petroleum ether) Rf 0.25; LRMS
(ESI) exact mass calculated for C9H13NO3Na: 206.08. Found: 206.09.
Trimethyl(undec-1-en-1-yloxy)silane (51d). To undecanal (20.0 g, 117 mmol, 1.0 equiv) in 35 mL DMF was added Et3N (37.6 mL, 270 mmol, 2.3 equiv) followed by
TMSCl (17.8 mL, 140 mmol, 1.2 equiv). The flask was fitted with a reflux condenser and stirred at reflux for 46 h and then cooled to room temperature. Water (200 mL) was added, and the solution was extracted with petroleum ether (400 mL). The organic phase was separated and washed with 1 M HCl (3 X 100 mL), followed by saturated aqueous NaHCO3 (3 X 100 mL), followed by brine (1 X 150 mL). The organic phase was dried with MgSO4 and concentrated under reduced pressure to give trimethyl(undec-1-en-1-
yloxy)silane (51d) (25.4 g, 105 mmol, 90% yield) as a pale orange liquid. The product was >95% pure by 1H NMR analysis, and was used in the following step without purification. Analytical data for 51d (~1:1 Z:E): IR (thin film, cm-1) 3029, 2958, 2925, 2854, 2359, 1730, 1659, 1465, 1401, 1253, 1162, 1093; 1H NMR (300 MHz, CDCl3)
6.21-6.13 (m, 2H), 5.00 (dd, J = 6.9, 11.7 Hz, 1H), 4.48 (d, J = 6, 13.2 Hz, 1H), 2.08- 2.04 (m, 2H), 1.90-1.85 (m, 2H), 1.26 (brs, 28H), 0.88 (t, J = 6.3 Hz, 6H); 13C NMR
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29.3, 29.1, 27.4, 23.6, 22.7, 14.1, -0.5, -0.6; LRMS (ESI) exact mass calculated for C14H30OSiH: 243.21. Found: 243.23.
Ethyl 4-nonylisoxazole-3-carboxylate(26). To ethyl chlorooximidoacetate (10.2 g, 67.2 mmol, 1.0 equiv) and 51d (48.9 g, 202 mmol, 3.0 equiv) in hexanes (2.0 L) at room temperature was added slowly a solution of Et3N (14.1 mL, 101 mmol, 1.5 equiv) and
hexanes (10 mL) via syringe pump over 15 h. The solution was stirred at room temperature for an additional 9 h, then TsOH (76.8 g, 404 mmol, 6.0 equiv) was added and the flask was fitted with a reflux condenser and stirred at reflux for 70 h. The reaction was cooled to room temperature and 500 mL of water was added. The solution was extracted with hexanes (3 X 700 mL). The organic extracts were combined, dried with MgSO4, and concentrated under reduced pressure. Purification by flash
chromatography (97:3 petroleum ether:EtOAc) furnished ethyl 4-nonylisoxazole-3- carboxylate (26) (8.26 g, 30.9 mmol, 46% yield) as a pale yellow liquid. Analytical data for 26: IR (thin film, cm-1) 3114, 2926, 2856, 1732, 1592, 1460, 1389, 1302, 1236, 1173, 1122, 1018; 1H NMR (400 MHz, CDCl3) 8.27 (s, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.64 (t, J = 8 Hz, 2H), 1.60-1.54 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.32-1.24 (m, 12H), 0.87 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 160.4, 157.0, 153.4, 121.3, 61.6, 31.8,
29.5, 29.4, 29.2, 22.5, 22.0, 14.0; LRMS (ESI) exact mass calculated for C15H25NO3Na:
152
Dimethyl (2-(4-nonylisoxazol-3-yl)-2-oxoethyl)phosphonate (54). To dimethyl methylphosphonate (163 L, 1.50 mmol, 2.0 equiv) in THF (3 mL) at -78 °C was added n
BuLi (1.5 M in hexanes, 1.00 mL, 1.50 mmol, 2.0 equiv) and the solution was
stirred at -78 °C for 1 h. A solution of ester 26 (201 mg, 0.752 mmol, 1.0 equiv)
in THF (6.7 mL) was added dropwise. The resulting solution was stirred at -78 °C
for 1 h, gradually turning dark red. The reaction mixture was quenched with
saturated NH4Cl (10 mL) and extracted with CH2Cl2 (3 X 40 mL). The organic
phase was washed with brine (40 mL), dried with MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography (50:50 petroleum ether:EtOAc) furnished dimethyl (2-(4-nonylisoxazol-3-yl)-2-oxoethyl)phosphonate (54) (224 mg, 0.649 mmol, 86% yield) as a clear liquid. Analytical data for 54: IR (thin film, cm-1) 2926, 2855, 1703, 1455, 1263, 1033; 1H NMR (300 MHz, CDCl3) 8.26 (s, 1H), 3.82-
3.75 (m, 8H), 2.65 (t, J = 7.8 Hz, 2H), 1.56-1.51 (m, 2H), 1.26 (brs, 12H), 0.88 (t, J = 6.9 Hz, 3H); TLC (50:50 EtOAc: petroleum ether) Rf 0.18; LRMS (ESI) exact mass
calculated for C16H28NO5PNa: 368.16. Found: 368.17.
(E)-3-(furan-2-yl)-1-(4-nonylisoxazol-3-yl)prop-2-en-1-one (25b). To 54 (2.22 g, 6.43 mmol, 1.0 equiv) and furfural (1.85 g, 19.3 mmol, 3.0 equiv) in H2O (20 mL) at room
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(175 mL). The solution was stirred at reflux for 4.5 h and then was cooled to room temperature. The reaction mixture was quenched with 1 M HCl (50 mL)
and extracted with Et2O (3 X 150 mL). The organic phase was washed with brine
(75 mL), dried with MgSO4, and concentrated under reduced pressure. Purification by
flash chromatography (95:5 petroleum ether:EtOAc) furnished (E)-3-(furan-2-yl)-1-(4- nonylisoxazol-3-yl)prop-2-en-1-one (25b) (1.76 g, 5.58 mmol, 87% yield) as a yellow solid. Analytical data for 25b: MP 39 °C; IR (thin film, cm-1) 2925, 2852, 1672, 1605, 1556, 1431, 1389, 1264, 1202, 1166, 1097, 1014; 1H NMR (400 MHz, CDCl3) (s,
1H), 7.64 (d, J = 15.6 Hz, 1H), 7.53 (d, J = 15.6 Hz, 2H), 6.78 (d, J = 3.2 Hz, 1H), 6.52 (dd, J = 2, 3.6 Hz, 1H), 2.71 (t, J = 8 Hz, 1H), 1.60-1.56 (m, 2H), 1.35-1.25 (m, 12H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) 183.9, 158.9, 156.6, 151.4,
145.5, 131.0, 121.1, 120.7, 116.9, 112.7, 31.8, 29.5, 29.4, 29.3, 29.2, 22.6, 22.2, 14.1;
TLC (10:90 EtOAc: petroleum ether) Rf 0.35; LRMS (ESI) exact mass calculated for
C19H25NO3Na: 338.17. Found: 338.17.
Di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(1-(furan-2-yl)-3-(4-nonylisoxazol-3- yl)-3-oxopropyl)succinate (56). To LiCl (3.97 g, 93.6 mmol, 8.0 equiv) in THF (110 mL) at room temperature was added iPr2NH (3.60 mL, 25.7 mmol, 2.2 equiv). The
solution was cooled to 0 °C and nBuLi (1.5 M in hexanes, 16.4 mL, 24.6 mmol,
2.1 equiv) was added. The solution was stirred at 0 °C for 10 min and then the ice
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then cooled to -78 °C. A solution of tBuOAc (3.15 mL, 23.5 mmol, 2.0 equiv) in
THF (110 mL) was added and the solution was stirred at -78 °C for 1 h. A
solution of t-butyl t-butyldimethylsilyl glyoxylate24 (5.74 g, 23.5 mmol, 2.0 equiv)
in THF (35 mL) was added and the solution was slowly warmed to 0 °C over 1.5
h. A solution of enone 25b (3.70 g, 11.7 mmol, 1.0 equiv) in THF (85 mL) was
added and the solution was slowly warmed to room temperature over 2 h. The reaction was stirred at room temperature for 21 h and then was quenched with
saturated NH4Cl (100 mL) and extracted with Et2O (3 X 300 mL). The combined
organic extracts were washed with brine (200 mL), dried with MgSO4, and
concentrated under reduced pressure. Purification by flash chromatography (97:3 petroleum ether:Et2O) furnished di-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(1-(furan-
2-yl)-3-(4-nonylisoxazol-3-yl)-3-oxopropyl)succinate (56) (4.85 g of shown diastereomer, 7.17 mmol; 1.80 g of undesired diastereomer, 2.66 mmol; 84% overall yield) as a clear liquid. Analytical data for 56: IR (thin film, cm-1) 3118, 2928, 2856, 1740, 1705, 1592, 1504, 1471, 1393; 1368; 1252; 1153; 1106; 1012 1H NMR (400 MHz, CDCl3) 8.18 (s, 1H), 7.29 (d, J = 1.2 Hz, 1H) 6.24 (t, J = 1.2 Hz, 1H), 6.14 (d, J = 3.2 Hz, 1H), 3.94 (dd, J = 2, 11.2 Hz, 1H), 3.78 (dd, J = 11.2 Hz, 17.6, 1H), 3.41 (dd, J = 2.4, 17.6 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H), 2.55-2.48 (m, 3H), 1.42 (s, 9H), 1.38 (s, 9H), 1.25 (brs, 14H), 0.88 (t, J = 6.6 Hz, 3H), 0.85 (s, 9H), 0.29 (s, 3H), 0.13 (s, 3H); 13C NMR (100 MHz, CDCl3) 193.7, 171.6, 168.8, 158.2, 156.6, 152.9, 141.4, 120.4, 110.1, 108.6, 81.6, 80.1, 79.7, 31.8, 29.4, 29.2, 29.2, 29.1, 28.1, 27.6, 26.1, 22.6, 21.9, 18.9, 14.0, -2.6, -3.0; TLC (10:90 EtOAc: petroleum ether) Rf 0.45; LRMS (ESI) exact mass
155
Methyl 3-(furan-2-yl)-5-methoxy-2-(2-methoxy-2-oxoethyl)-5-(4-nonylisoxazol-3- yl)tetrahydrofuran-2-carboxylate (58). To 56 (3.48 g, 5.15 mmol, 1.0 equiv) in MeOH (220 mL) at room temperature was added (MeO)3CH (5.64 mL, 51.5 mmol, 10
equiv) and TsOH.H2O (3.92 g, 20.6 mmol, 4.0 equiv). The solution was stirred at
reflux for 42 h and then was cooled to room temperature. The reaction mixture
was concentrated under reduced pressure and redissolved in CH2Cl2 (200 mL).
The solution was washed with saturated NaHCO3 (200 mL) and the aqueous phase
was extracted with CH2Cl2 (3 X 100 mL). The combined organic layers were
dried with Na2SO4 and concentrated under reduced pressure. Purification by flash
chromatography (80:20 petroleum ether:EtOAc) furnished a mixture of diastereomers of methyl methyl 3-(furan-2-yl)-5-methoxy-2-(2-methoxy-2-oxoethyl)-5-(4-nonylisoxazol- 3-yl)tetrahydrofuran-2-carboxylate (58) (2.23 g, 4.54 mmol, 88% yield) as a clear liquid. Analytical data for 58: IR (thin film, cm-1) 2926, 2855, 2359, 1745, 1436, 1359, 1205, 1042; 1H NMR (300 MHz, CDCl3) 8.16 (s, 1H), 7.33 (t, J = 0.6 Hz, 1H), 6.30 (dd, J =
1.8, 3 Hz, 1H), 6.17 (d, J = 3 Hz, 1H), 4.33 (dd, J = 7.5, 11.4 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H), 3.28 (s, 3H), 2.85-2.55 (m, 4H), 2.46 (t, J = 7.8 Hz, 2H), 1.60-1.54 (m, 2H), 1.25 (brs, 12H), 0.86 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) 172.4, 169.7, 160.3,
156.0, 150.5, 142.3, 118.9, 110.5, 108.9, 106.0, 86.6, 52.5, 51.5, 50.9, 43.3, 42.0, 40.0, 31.8, 29.5, 29.4, 29.2, 22.6, 22.3, 14.0; TLC (30:70 EtOAc: petroleum ether) Rf 0.50; LRMS (ESI) exact mass calculated for C26H37NO8Na: 514.24. Found: 514.18.
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Methyl 5-(1-amino-2-formylundec-1-en-1-yl)-3-(furan-2-yl)-5-methoxy-2-(2- methoxy-2-oxoethyl)tetrahydrofuran-2-carboxylate (59). To 58 (42 mg, 0.0854 mmol, 1.0 equiv) in MeCN (13 mL) at room temperature was added H2O (24 L) and
Mo(CO)6 (34 mg, 0.128 mmol, 1.5 equiv). The solution was stirred at reflux for 5
h and then was cooled to room temperature. The reaction mixture was diluted
with Et2O (50 mL). The solution was washed with NaHCO3 (25 mL) and the
aqueous phase was extracted with Et2O (3 X 30 mL). The combined organic
layers were dried with MgSO4 and concentrated under reduced pressure. Purification by
flash chromatography (70:30 petroleum ether:EtOAc) furnished a mixture of diastereomers of methyl 5-(1-amino-2-formylundec-1-en-1-yl)-3-(furan-2-yl)-5-methoxy- 2-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-carboxylate (59) (31 mg, 0.0628 mmol, 74% yield) as a clear oil. Analytical data for 59 (4 diastereomers): IR (thin film, cm-1) 3211, 1743, 1600, 1485, 1437, 1360, 1297, 1198, 1076, 1034; 1H NMR (400 MHz, CDCl3) 9.90 (s, 0.28H), 9.26 (s, 0.72H), 7.36 (s, 1H), 6.34 (s, 1H), 6.23-6.19 (m, 1H), 4.27-4.22 (m, 1H), 3.85 (s, 3H), 3.68-3.65 (m, 3H), 3.33 (s, 0.64H), 3.30 (s, 1.67H), 3.23 (s, 0.19H), 3.20 (s, 0.50H), 2.86-2.27 (m, 5H), 1.26 (brs, 14H), 0.86 (t, J = 5.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) 193.0, 192.6, 171.8, 170.2, 158.1, 157.4, 149.6, 149.2, 142.6, 110.6, 109.3, 109.1, 106.6, 104.0, 85.7, 52.8, 52.1, 51.9, 50.6, 44.2, 42.6, 39.9, 39.2, 33.1, 31.9, 29.8, 29.6, 29.4, 29.3, 27.3, 22.7, 22.6, 14.1; TLC (50:50 EtOAc: petroleum ether) Rf 0.53; LRMS (ESI) exact mass calculated for C26H39NO8Na: 516.26. Found: 516.24.
157
Methyl 3-(furan-2-yl)-7-hydroxy-2-(2-methoxy-2-oxoethyl)-8-nonyl-9-oxo-1,6- dioxaspiro[4.4]nonane-2-carboxylate (60). To 59 (1.17 g, 2.37 mmol, 1.0 equiv) in CH2Cl2 (275 mL) at room temperature was added a solution of TiCl4 (0.47 mL, 4.27
mmol, 1.8 equiv) in CH2Cl2 (20 mL). The solution was stirred at room
temperature for 1.5 h and then 1 M HCl (275 mL) was added. The solution was
stirred vigorously for 20 h and was extracted with CH2Cl2 (2 X 200 mL). The
combined organic layers were dried with MgSO4 and concentrated under reduced
pressure. Purification by flash chromatography (60:40 petroleum ether:EtOAc) furnished a mixture of diastereomers of methyl 3-(furan-2-yl)-7-hydroxy-2-(2-methoxy-2- oxoethyl)-8-nonyl-9-oxo-1,6-dioxaspiro[4.4]nonane-2-carboxylate (60) (1.07 g, 2.23 mmol, 94% yield) as a clear oil. Analytical data for 60 (8 diastereomers): 1H NMR (400 MHz, CDCl3) 7.39-7.37 (m, 1H), 6.35-6.26 (m, 2H), 5.78-5.36 (m, 1H), 4.12-4.07 (m,
1H), 3.86-3.79 (m, 3H), 3.64-3.56 (m, 3H), 2.90-2.15 (m, 5H), 1.62-1.39 (m, 2H), 1.26 (brs, 12 H), 0.88 (t, J = 6.8 Hz, 3H); LRMS (ESI) exact mass calculated for C25H36O9Na:
503.23. Found: 503.22.
Trachyspic acid dimethyl ester 9-hydrate (63). To NaIO4 (1.16 g, 5.43 mmol, 7.0
equiv) in H2O (18 mL) was added a solution of RuCl3.3H2O (10 mg, 0.0383 mmol, 0.05
158
then a solution of 60 (373 mg, 0.776 mmol, 1.0 equiv) in EtOAc (18 mL) was added. The solution was stirred at room temperature for 5.5 h. Brine (15 mL) was added, and the solution was extracted with EtOAc (3 X 120 mL). The combined organic layers were dried with MgSO4 and concentrated under reduced pressure. Purification by flash
chromatography (60:38:2 petroleum ether:EtOAc:HOAc) furnished a mixture of diastereomers of trachyspic acid dimethyl ester 9-hydrate (63) (242 mg, 0.528 mmol, 68% yield) as a clear oil. Analytical data for 63 (8 diastereomers): IR (thin film, cm-1) 3460, 2954, 2926, 2855, 1744, 1611, 1439, 1366, 1211, 1178, 1136, 1073; 1H NMR (400 MHz, CDCl3) 5.76-5.39 (m, 1H), 3.88-3.78 (m, 3H), 3.71-3.64 (m, 3H), 3.32-2.09 (m,
5H), 1.49-1.39 (m, 2H), 1.25 (brs, 12 H), 0.88 (t, J = 6 Hz, 3H); TLC (50:50 EtOAc: petroleum ether) Rf 0.16; LRMS (ESI) exact mass calculated for C13H22O2Na: 481.22.
Found: 481.21.
Trachyspic acid dimethyl ester (64). To 63 (467 mg, 1.02 mmol, 1.0 equiv) in pyridine (20 mL) at room temperature was added a solution of MsCl (0.120 mL, 1.53 mmol, 1.5 equiv) in pyridine (5 mL). The solution was stirred for 17 h and then was diluted with Et2O (100 mL). The solution was washed with 1 M HCl (3 X 50 mL), followed by
saturated CuSO4 (50 mL). The organic phase was dried with MgSO4 and concentrated
under reduced pressure. Purification by flash chromatography (70:28:2 petroleum ether:EtOAc:HOAc) furnished trachyspic acid dimethyl ester (64) (286 mg, 0.649 mmol, 64% yield overall; 5:1 mixture of separable spiroketal diastereomers) as a clear oil. Analytical data for 64: IR (thin film, cm-1) 2926, 2855, 2358, 1746, 1557, 1506, 1437,