Cohen and Chamberlin
(m, 1H), 3.72 (dd, J ) 9.8, 5.2, 1H), 3.69-3.63 (m, 2H), 2.58 (dd,
J ) 15.1, 8.2, 1H), 2.42 (dd, J ) 15.1, 2.8, 1H), 2.19 (td, J )
13.6, 4.0, 1H), 1.90 (td, J ) 13.7, 4.0, 1H), 1.86-1.77 (m, 1H),
1.64-1.56 (m, 1H), 1.06 (s, 9H), 0.88 (s, 9H), 0.05 (d, J ) 1.2,
6H); 13C NMR (125 MHz, CDCl3) δ 175.4, 136.0, 135.9, 135.4,
133.4, 133.3, 130.3, 128.3, 128.3, 65.9, 62.9, 62.1, 53.7, 39.2, 37.6,
29.5, 27.3, 26.4, 19.7, 18.7, -4.9; IR (thin film) 3215, 3071, 2948,
1714, 1466, 1255, 1102 cm-1; HRMS (CI/methanol) m/z calcd for
circumvented by exposure of the crude reaction mixture to
TMSCHN2, affording methyl ester 31 in 76% yield over two
steps. Acidic hydrolysis of 31 and purification of crude 3 by
ion exchange chromatrography were accomplished following
the method of Yoshifuji and Kaname to furnish lycoperdic acid
as a white solid.10a Recrystallization of solid 3 from water
provided thin crystals that were suitable to obtain a single-crystal
X-ray structure of synthetic 3.20 The spectral data of synthetic
3 (1H NMR, 13C NMR, [R]D, HRMS) were in accord with the
reported values for natural lycoperdic acid.10
C30H46BrNO3Si2 (M + Na)+ 626.2097, found 626.2125; [R]24
D
+26.7 (c 0.28, CHCl3).
Glutamate Appended Oxolane (21). To a cooled (0 °C) solution
of 1421 (0.055 g, 0.088 mmol) in anhydrous MeOH (6 mL) was
added NaOMe (0.006 g, 0.106 mmol). The slightly cloudy reaction
mixture was slowly warmed to room temperature. After 22 h,
saturated aqueous NH4Cl (1.5 mL) was added, and the cloudy white
reaction mixture was diluted with EtOAc (4 mL) and H2O (4 mL).
The aqueous layer was extracted with EtOAc (3 × 5 mL), and the
combined organic layers were washed with brine (8 mL), dried
(MgSO4), and concentrated in vacuo. Purification of the crude oil
by flash chromatography (25:75 EtOAc/hexanes) furnished the title
compound as a clear oil (0.043 g, 89%): 1H NMR (500 MHz,
DMSO-d6, 368 K) δ 7.66-7.62 (m, 4H), 7.45-7.39 (m, 6H), 5.95
(br s, 1H), 3.82 (dd, J ) 15.1, 6.2, 1H), 3.79-3.71 (m, 2H), 3.61
(s, 3H), 3.59-3.55 (m, 2H), 2.23-2.18 (m, 1H), 2.06 (dd, J )
Conclusion
The successful stereocontrolled total syntheses of lycoperdic
acid (3) and deoxylycoperdic acid (26) demonstrate that the
pyroglutamate ring annulation sequence is an efficient method
for the stereocontrolled annulation of an oxolane ring onto the
γ-position of glutamic acid. The key transformation in the
synthetic route was a high yielding diastereoselective annulation
of an oxolane ring onto a pyroglutamate scaffold to construct
the carbon framework of 3 and 26. The reaction sequence also
featured an improved method for the halogenation of pyro-
glutamate derivatives in high yield with enhanced stereoselec-
tion. Furthermore, the syntheses of lycoperdic acid and deox-
ylycoperdic acid reported herein provided ample material for
biological evaluation, and preliminary testing for iGluR activity
is currently underway.
14.4, 4.5, 1H), 1.94-1.78 (m, 4H), 1.38 (s, 9H), 1.04 (s, 9H); 13
C
NMR (125 MHz, DMSO-d6) δ 175.0, 155.8, 136.0, 135.9, 133.9,
133.6, 130.6, 130.2, 128.7, 128.6, 85.4, 78.3, 69.0, 66.9, 52.6, 49.5,
38.8, 34.7, 29.1, 27.4, 25.8, 19.7; IR (thin film) 3406, 2941, 2866,
1717, 1500, 1361, 1068 cm-1; HRMS (CI/methanol) m/z calcd for
C30H43NO6Si (M + Na)+ 564.2758, found 564.2758; [R]24D -17.9
(c 0.33, CHCl3).
Experimental Section
Spirolactone (29). To a cooled (0 °C) solution of bromide 19a
(0.997 g, 1.65 mmol) in acetone (15 mL) was added Jones reagent
(1.3 mL, 3.63 mmol, 2.7 M CrO3 in 4 M H2SO4). The clear red
solution was slowly warmed to room temperature over 1 h, and a
brown precipitate formed. After being stirred for 2 h at room
temperature, the brown reaction mixture was cooled to 0 °C and
2-propanol (2 mL) was added. The resulting green reaction mixture
was warmed to room temperature and stirred for 30 min. The
mixture was filtered through Celite, the Celite pad was washed with
EtOAc (3 × 10 mL), and the filtrate was concentrated in vacuo to
a green residue. The crude residue was dissolved in acetone (10
mL), and K2CO3 (1.14 g, 8.25 mmol) was added. The green
suspension was stirred vigorously for 40 min at room temperature.
The reaction mixture was diluted with EtOAc (12 mL) and H2O (8
mL), and 1 M HCl was added until the solution was acidic. The
aqueous layer was removed and extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (20
mL), dried (MgSO4), and concentrated in vacuo to give a white
foam. The crude foam was purified by flash chromatography (50:
50 EtOAc/hexanes-60:40 EtOAc/hexanes) to afford the title
Bromide (19). A cooled (0 °C) solution of 1521 (3.14 g, 5.02
mmol) in CH2Cl2 (25 mL) was treated with Et3N (2.20 mL, 16.1
mmol) followed by TMSOTf (2.01 mL, 11.0 mmol). The clear,
colorless solution was stirred at 0 °C for 1 h. A solution of
N-bromosuccinimide (1.07 g, 6.02 mmol) in CH2Cl2 (20 mL) was
added dropwise via cannula over 10 min. The resultant brown
solution was allowed to warm to room temperature and stirred for
2 h. The reaction was quenched by the addition of saturated aqueous
NaHCO3 (15 mL), and the mixture was further diluted with water
(20 mL). The aqueous layer was extracted with CH2Cl2 (3 × 25
mL). The combined organic layers were washed with 1.0 M HCl
(20 mL) and brine (50 mL), dried (MgSO4), and concentrated in
vacuo to provide a crude orange oil. 1H NMR analysis of the crude
reaction mixture revealed that two diastereomeric bromides (19a/
19b) were formed in a ratio of 6.3:1, respectively. Purification of
the crude orange oil by flash chromatography (10:90 EtOAc/Hex-
15:85 EtOAc/hexanes) afforded bromides 19a (2.46 g) and 19b
(0.418 g) as white foams (2.88 g, 95%).
19a: 1H NMR (500 MHz, CDCl3) δ 7.66-7.64 (m, 4H), 7.47-
7.39 (m, 6H), 6.67 (s, 1H), 3.92 (m, 1H), 3.74 (dd, J ) 10.5, 3.7,
1H), 3.66 (m, 2H), 3.56 (dd, J ) 10.5, 7.2, 1H), 2.44 (dd, J )
14.2, 5.4 1H), 2.25 (m, 1H), 1.92-1.78 (m, 3H), 1.08 (s, 9H), 0.88
(s, 9H), 0.06 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 174.8, 136.0,
135.9, 133.3, 133.1, 130.5, 130.4, 128.4, 128.3, 66.1, 65.4, 62.9,
53.6, 40.5, 36.1, 29.6, 27.2, 26.4, 19.6, 18.7, -4.9; IR (thin film)
1
compound as a white foam (0.552 g, 79%): mp ) 45-49 °C; H
NMR (500 MHz, CDCl3) δ 7.65-7.60 (m, 4H), 7.46-7.38 (m,
6H), 6.78 (s, 1H), 3.76-3.71 (m, 1H), 3.69-3.65 (dd, J ) 10.3,
4.5, 1H), 3.65-3.59 (dd, J ) 10.2, 8.1, 1H), 2.97-2.89 (m, 1H),
2.56-2.49 (m, 2H), 2.26 (dd, J ) 14.1, 7.3, 1H), 2.20 (dd, J )
14.1, 5.1, 1H), 2.16-2.08 (m, 1H), 1.06 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 176.2, 174.2, 136.0, 135.9, 133.3, 133.1, 130.5,
130.4, 128.4, 128.3, 84.7, 67.4, 52.6, 35.7, 31.4, 29.0, 27.2, 19.6;
IR (KBr) 2955, 2853, 1785, 1714, 1425, 1109 cm-1; HRMS (CI/
methanol) m/z calcd for C24H29NO4Si (M + Na)+ 446.1764, found
3194, 3071, 2948, 2860, 1714, 1476, 1425, 1384, 1249, 1106 cm-1
;
HRMS (CI/methanol) m/z calcd for C30H46BrNO3Si2 (M + Na)+
626.2097, found 626.2076; [R]24 +18.4 (c 1.37, CHCl3).
D
19b: 1H NMR (500 MHz, CDCl3) δ 7.67-7.64 (m, 4H), 7.46-
446.1752; [R]24 -20.9 (c 0.31, CHCl3).
D
7.38 (m, 6H), 6.64 (s, 1H), 3.90 (dd, J ) 9.7, 8.4, 1H), 3.82-3.77
(S)-(+)-Lycoperdic Acid (3). A suspension of methyl ester 3121
(0.064 g, 0.206 mmol) in 6 M HCl (4 mL) was heated at reflux for
9 h. The resulting clear, colorless solution was cooled to room
temperature and concentrated in vacuo to give a white residue. The
residue was applied to an ion-exchange column (AG 1 × 8, 200-
400 mesh, acetate form) and eluded with 2 N AcOH (150 mL).
The collected fractions were lyophilized to furnish the title
(20) Crystallographic data (excluding structure factors) for structure 3
in this article have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 299403 and are
presented in the Supporting Information.
(21) The experimental procedure is provided in the Supporting Informa-
tion.
9246 J. Org. Chem., Vol. 72, No. 24, 2007