Younai et al.
JOCNote
syn-Methyl 2-(4-Isopropoxy-3-methoxyphenyl)-1-(4-isopropoxy-
phenethyl)-5-oxo-3-(phenylthio)pyrrolidine-3-carboxylate (13).
A solution of 8 (530.9 mg, 2.74 mmol), 12 (490.7 mg, 2.74 mmol),
maleic anhydride (268.0 mg, 2.74 mmol), and thiophenol (0.28 mL,
2.74 mmol) in toluene (41 mL, 0.07 M) was stirred at reflux
with a Dean-Stark trap for 24 h. After being cooled to room
temperature, the mixture was concentrated in vacuo. The res-
idue was then dissolved in acetone (55 mL, 0.05 M), to this
mixture were added K2CO3 (1.511 g, 10.92 mmol) and CH3I
(0.68 mL, 10.92 mmol), and the resulting mixture was stirred at
room temperature overnight. The solution was concentrated in
vacuo, diluted in water (20 mL), and extracted with ethyl acetate
(3 ꢀ 20 mL). The combined organic layers were then washed
with brine (60 mL) and dried over MgSO4. Concentration in
vacuo and purification by flash chromatography (0:100-50:50
EtOAc/hexanes) afforded an orange oil (990.7 mg, 76%, 86:14
dr). A small sample of the major diastereomer was purified by
HPLC for characterization: 1H NMR (600 MHz, CDCl3) δ
7.35-7.31 (m, 1H), 7.25 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.22
(d, J = 1.2 Hz, 1H), 7.21 (t, J = 1.7 Hz, 1H), 6.99 (s, 1H), 6.97
(s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.78-6.74 (m, 3H), 6.71 (s, 1H),
5.02 (s, 1H), 4.58 (sep, J = 6.1 Hz, 1H), 4.48 (sep, J = 6.1 Hz,
1H), 4.02-3.95 (m, 1H), 3.87 (s, 3H), 3.55 (s, 3H), 3.17 (d, J =
17.1 Hz, 1H), 2.86 (d, J = 17.0 Hz, 1H), 2.82 (dd, J = 7.1, 13.7
Hz, 1H), 2.74-2.69 (m, 1H), 2.67-2.61 (m, 1H), 1.405 (d,
J = 6.1 Hz, 3H), 1.400 (d, J = 6.1 Hz, 3H), 1.30 (d, J = 6.1
Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 172.2, 172.1, 156.7,
150.3, 148.3, 136.3, 136.2, 130.4, 130.3, 130.0, 129.9, 129.8,
129.5, 129.1, 126.6, 116.1, 114.7, 71.4, 70.1, 68.3, 59.1, 56.4,
53.2, 42.6, 41.1, 32.7, 22.33, 22.30, 22.29, 22.25; IR (neat) 1695,
1728 cm-1; HRMS (ESI) m/z calcd for C33H40NO6S (M þ H)þ
578.2576, found 578.2587.
FIGURE 1. Chemical shift correlation and NOESY assignments
for the alkene configuration of heliotropamide. The 1H NMR
spectra were recorded in CD3OD (1) or CDCl3 (19-21) at room
temperature.
respectively. Although chemical shift overlap prevents accu-
rate NOESY correlation of heliotropamide, model com-
pound 21 exhibited NOESY correlation and a chemical
shift of the arylidene proton consistent with the assignment
of E geometry about the trisubstituted alkene.
In summary, we have demonstrated the utility of our
recently discovered 4CR in the efficient synthesis of helio-
tropamide in an overall yield of 41% over 11 steps. In so
doing, we have confirmed the identity of this structurally
distinct natural product. We are currently applying similar
strategies to related natural products, the syntheses of which
will be reported in due course.
syn-Methyl 2-(4-Isopropoxy-3-methoxyphenyl)-1-(4-isopropoxy-
phenethyl)-5-oxopyrrolidine-3-carboxylate (14). A solution of 13
(50 mg, 0.09 mmol), AIBN (10 mg, 0.06 mmol), and tributyl tin
hydride (0.10 mL, 0.49 mmol) in toluene (3.4 mL, 0.02 M) was
stirred at 90 °C for 8 h. The reaction was cooled and concen-
trated in vacuo, and purification by flash chromatography
(60:40 to 100:0 EtOAc/hexanes) afforded a colorless oil (38 mg,
91%, 81:19 dr).
Experimental Section
tert-Butyl 4-Isopropoxyphenethylcarbamate (11). To a solu-
tion of 10 (847 mg, 3.57 mmol) and sodium hydride (257 mg,
10.71 mmol) in DMF (35.7 mL, 0.1 M) was added isopropyl
iodide (1.21 mL, 10.71 mmol), and the solution was stirred at
80 °C overnight. The solution was diluted in water (10 mL),
extracted with CHCl3 (3 ꢀ 10 mL), and dried over MgSO4.
Concentration in vacuo and purification by flash chromatogra-
phy (33:67 EtOAc/hexanes) afforded a pale yellow solid (871
mg, 87%): mp 42-45 °C; 1H NMR (300 MHz, CDCl3) δ 7.08
(d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 4.54-4.46 (m, 2H),
3.33 (d, J = 6.3 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H), 1.43 (s, 9H),
1.32 (d, J = 6.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 156.7,
156.1, 131.0, 130.0, 116.2, 79.4, 70.1, 42.2, 35.5, 28.6, 22.3; IR
(neat) 1691, 3376 cm-1; HRMS (ESI) m/z calcd for C16H26NO3
(M þ H)þ 280.1913, found 280.1914.
14: Alternate Procedure for Larger Scale Reactions. A solu-
tionof 13 (622.1 mg, 1.08 mmol), tris(trimethylsilyl)silane(freshly
distilled, 1.16 mL, 3.77 mmol), and AIBN (63.2 mg, 0.38 mmol)
in toluene (43.0 mL, 0.025 M) was stirred at 90 °C for 24 h. The
reaction was cooled, concentrated in vacuo, and purified by
flash chromatography (50:50 EtOAc/hexanes) to afford a color-
less oil (433.4 mg, 86%, 93:7 dr). Major diastereomer: 1H NMR
(600 MHz, CDCl3) δ 6.95 (d, J = 8.1 Hz, 2H), 6.73 (m, 3H), 6.48
(d, J = 7.4 Hz, 1H), 6.41 (s, 1H), 4.48 (d, J = 9.1 Hz, 1H),
4.45-4.39 (m, 2H), 3.89-3.83 (m, 1H), 3.71 (s, 3H), 3.38 (q, J =
9.3 Hz, 1H), 3.19 (d, J = 0.8 Hz, 3H), 2.97 (dd, J = 9.9, 17.2 Hz,
1H), 2.74-2.68 (m, 2H), 2.63-2.57 (m, 1H), 2.41 (dd, J = 9.3,
17.2 Hz, 1H), 1.26 (d, J = 6.0 Hz, 6H), 1.242 (d, J = 6.1 Hz, 3H),
1.240 (d, J = 6.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 172.8,
170.2, 156.2, 150.1, 147.2, 130.3, 129.3, 128.37, 119.5, 115.8,
115.2, 110.7, 71.0, 69.5, 63.2, 55.7, 51.3, 42.9, 42.3, 32.5, 31.5,
21.8, 21.73, 21.72, 21.71. Visible peaks for minor diastereomer:
1H NMR (600 MHz, CDCl3) δ 6.89 (d, J = 8.1 Hz, 2H), 6.77
(d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 8.2 Hz,
1H), 6.54 (s, 1H), 4.47 (d, J = 6.0 Hz, 1H), 3.74 (s, 3H), 3.60
(s, 3H), 1.28 (d, J = 6.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ
2-(4-Isopropoxyphenyl)ethanamine (12). To a solution of 11
(4.203 g, 15.04 mmol) in dioxane (50.0 mL, 0.3 M) was added
concentrated hydrochloric acid (25.0 mL), and the solution was
stirred at room temperature for 2 h. The mixture was basified
with 10% NaOH, extracted with CH2Cl2, and dried over
MgSO4. Concentration in vacuo afforded a yellow oil (2.669 g,
1
100%) which was used without further purification: H NMR
172.2, 171.9, 129.4, 45.8, 33.4; IR (neat) 1689, 1740 cm-1
;
(300 MHz, CDCl3) δ 7.02 (d, J = 8.5 Hz, 2H), 6.76 (d, J =
8.6 Hz, 2H), 4.43 (sep, J = 6.1 Hz, 1H), 2.85 (t, J = 6.9 Hz, 2H),
2.61 (t, J = 6.9 Hz, 2H), 1.48 (s, 2H), 1.25 (d, J = 6.1 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 156.5, 131.8, 129.9, 116.1, 70.0,
43.8, 39.2, 22.3; IR (neat) 3357 cm-1; HRMS (ESI) m/z calcd for
C11H18NO (M þ H)þ 180.1388, found 180.1390.
HRMS (ESI) m/z calcd for C27H36NO6 (M þ H)þ 470.2543,
found 470.2546.
anti-2-(4-Isopropoxy-3-methoxyphenyl)-1-(4-isopropoxyphe-
nethyl)-5-oxopyrrolidine-3-carboxylic Acid (15). To a solution of
14 (2.771 g, 5.90 mmol) in methanol (60.0 mL, 0.1 M) was added
sodium methoxide (3.188 g, 59.00 mmol) and the mixture stirred
J. Org. Chem. Vol. 75, No. 23, 2010 8335