Access to 1-hydroxymethylpyrrolizidines utilizing malate enolate-imine condensation and ring-closing methathesis: Synthesis of (-)-croalbinecine

Full text of DOI:10.1021/jo0012187

J . Org. Chem. 2000, 65, 9249-9251
9249
Sch em e 1a
Access to 1-Hyd r oxym eth ylp yr r olizid in es
Utilizin g Ma la te En ola te-Im in e
Con d en sa tion a n d Rin g-Closin g
Meth a th esis: Syn th esis of
(-)-Cr oa lbin ecin e
J ung-Bok Ahn, Chang-Soo Yun, Kyoung Hoon Kim, and
Deok-Chan Ha*
Department of Chemistry, Korea University,
5-1-2 Anam-dong, Seoul 136-701, Korea
dechha@korea.ac.kr
Received August 9, 2000
Pyrrolizidine alkaloids are nitrogen-fused bicyclo[3.3.0]-
octanes and have long attracted synthetic interest due
to their relatively simple structural features and wide
range of pharmacologic activity.1 Diverse and elegant
synthetic methods have been developed for the construc-
tion of this core structure, especially for the 1-hydroxy-
methylpyrrolizidines, also called necine bases.2 Many
synthetic methods for these alkaloids rely on an efficient
approach to functionalized 2-pyrrolidinones.3
In our previous paper, we developed a new approach
to highly functionalized 2-pyrrolidinones using the con-
densation between the enolate dianion of malate and
nonenolizable imines.4 Though the yield and diastereo-
selectivity of this condensation were less than optimal,
this method provides an expedient approach to 2-pyrro-
lidinones appropriate for the synthesis of necines. In this
paper, the synthesis of (-)-croalbinecine (2), an enanti-
omer of the polyhydroxylated pyrrolizidine, is discussed
utilizing ester-imine condensation and ring-closing me-
tathesis.5
a
Reagents: (a) 2NaN(TMS)2, Ph-CtC-CHdN-PMP (4); (b)
LiBH4, diglyme; (c) NaH, BnBr, DMF; (d) H2, Lindlar cat.; (e)
(NH4)2Ce(NO3)6, H2O-CH3CN; (f) CH2dCHCH2Br, NaH; (g)
(Cy3P)2Cl2RudCHPh (11, 3 mol %), PhH; (h) H2, Pd(OH)2, CH3OH;
(i) LiAlH4, THF.
(trimethylsilyl)amide was reacted with phenylpropar-
gylidene p-anisidine (4)6 at -78 °C in THF to give 5a
(47%) and its C(5)-epimer 5b (11%) (Scheme 1). Selective
reduction of the ester moiety of pyrrolidinone 5a with
LiBH4 followed by the protection of the resulting diol 6
provided 7. We proposed in our earlier study the stere-
ochemistry of 5a on the basis of the NOE results and
further confirmed it in this study by X-ray crystal-
lographic analysis of 7.7 Partial reduction of the triple
bond of 7 followed by oxidative removal of the p-
methoxyphenyl group on nitrogen provided 9, which was
N-allylated for the second ring formation. Ring-closing
olefin metathesis of 10 to 12 with Grubbs catalyst 11 was
successful despite the possible deactivation of the inter-
mediate by the neighboring amide carbonyl.8 Addition of
0.3 equiv of Ti(O-iPr)4 together with Grubbs catalyst gave
essentially the same results.9 The neighboring benzyloxy
group may play a steric effect to inhibit the chelation
between the amide oxygen and the ruthenium intermedi-
ate. Catalytic hydrogenation of 12 smoothly produced 13,
which was reduced with LAH to give the dihydroxylated
pyrrolizidine 14, C(1)-epimer of (+)-petasinecine.10
Selective introduction of the hydroxy group at the C(7)
position of 12 was accomplished by epoxidation followed
by ring opening with LAH. Epoxidation of 12 with
m-CPBA gave a chromatographically separable mixture
of the epoxides 15 (61%) and 16 (10%) (Scheme 2).
Simultaneous epoxide opening and amide reduction with
LAH produced 17 in 65% yield together with the regio-
isomer 18 (9%). Hydrogenolysis of the benzyl groups from
17 with cat. Pd(OH)2 in methanol produced (-)-croalbi-
The enolate dianion generated from diethyl (S)-malate
(3) by treating with two equivalents of sodium bis-
* To whom correspondence should be addressed. Phone: 82-2-3290-
3131. Fax: 82-2-3290-3121.
(1) Liddell, J . R. Nat. Prod. Rep. 1999, 16, 499-507. Michael, J . P.
Nat. Prod. Rep. 1997, 14, 619-636. Robins, D. J . Nat. Prod. Rep. 1995,
12, 413-418. Dai, W.-M.; Nagao, Y.; Fujita, E. Heterocycles 1990, 30,
1231-1261.
(2) Kim, S.-H.; Kim, S.-I.; Lai, S.; Cha, J . K. J . Org. Chem. 1999,
64, 6771-6775. Bertrand, S.; Hoffmann, N.; Pete, J .-P. Tetrahedron
Lett. 1999, 40, 3173-3174. Denmark, S. E.; Thorarensen, A. J . Am.
Chem. Soc. 1997, 119, 125-137. Ito, H.; Ikeuchi, Y.; Taguchi, T.;
Hanzawa, Y. J . Am. Chem. Soc. 1994, 116, 5469-5470. Mulzer, J .;
Shanyoor, M. Tetrahedron Lett. 1993, 34, 6545-6548.
(3) Himstra, H.; Speckamp. W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: London, 1991; Vol. 2, p 1047.
Hart, D. J . In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1988; Vol. 6, p 227.
(4) Ha, D.-C.; Yun, K.-S.; Park, H.-S.; Choung, W.-K.; Kwon, Y.-E.
Tetrahedron Lett. 1995, 36, 8445-8448. For the synthesis of 2-azeti-
dinones using ester enolate-imine condensation, see: Hart, D. J .; Ha,
D.-C. Chem. Rev. 1988, 89, 1447-1465.
(6) Matsui, S.; Hashimoto, Y.; Saigo, K. Synthesis 1998, 1161-1165.
Layer, R. W. Chem. Rev. 1963, 63, 489-510.
(7) Details are described in the Supporting Information.
(8) White, J . D.; Hrnciar, P.; Yokoshi, A. F. T. J . Am. Chem. Soc.
1998, 120, 7359-7360. Martin, S. F.; Liao, Y.; Chen, H.-J .; Pa¨tzel, M.;
Ramser, M. N. Tetrahedron Lett. 1994, 35, 6005-6008.
(9) Fu¨rstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119,
9130-9136.
(5) White, J . D.; Hrnciar, P.; Yokoshi, A. F. T. J . Am. Chem. Soc.
1998, 120, 7359-7360. Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2036-2056. Grubbs, R. H.; Miller, S. J .; Fu, G. C.
Acc. Chem. Res. 1995, 28, 446-452. Fu, G. C.; Nguyen, S. T.; Grubbs,
R. H. J . Am. Chem. Soc. 1993, 115, 9856-9857.
(10) Aasen, A. J .; Culvenor, C. C. J . J . Org. Chem. 1969, 34, 4143-
4147.
10.1021/jo0012187 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/30/2000

9250 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
(relative intensity) 379 (M+, 91), 128 (100). Anal. Calcd for
C22H21NO5: C, 69.64; H, 5.58; N, 3.69. Found: C, 69.73; H, 5.66;
N, 3.58.
Sch em e 2
(3S,4S,5S)-3-H yd r oxy-4-h yd r oxym et h yl-1-(4-m et h oxy-
p h en yl)-5-p h en yleth yn yl-2-p yr r olid in on e (6). To a slurry of
NaBH4 (689 mg, 18.2 mmol) in 80 mL of diglyme was added
LiCl (850 mg, 20.2 mmol) followed by stirring for 30 min at
ambient temperature. A solution of 5a (1.72 g, 4.6 mmol) in 30
mL of diglyme was added slowly for 10 min to the above solution
at 0 °C and the resulting mixture was stirred for 24 h at ambient
temperature. The mixture was quenched with 200 mL of
saturated NH4Cl solution and extracted three times with 200-
mL portions of CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Purification
of the residue by chromatography on silica gel (2:1, EtOAc/
hexanes) gave 6 (1.40 g, 91%) as a white solid: Rf ) 0.13 (2:1,
EtOAc/hexanes); mp 133-134 °C; [R]20 -91.9 (c 2.13, EtOH);
D
IR (KBr, cm-1) 3342, 1687, 1249; H NMR (CDCl3, 300 MHz) δ
1
7.37 (d, 2H, J ) 9 Hz), 7.25 (s, 5H), 6.90 (d, 2H, J ) 9 Hz), 5.04
(s, 1H), 4.93 (d, 1H, J ) 9 Hz), 4.62 (d, 1H, J ) 9 Hz), 4.13 (d,
1H, J ) 11 Hz), 3.99 (d, 1H, J ) 11 Hz), 3.77 (s, 3H), 3.23 (s,
1H), 2.63 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 173.6, 157.9,
131.6, 129.3, 128.7, 128.2, 125.5, 121.8, 114.0, 86.6, 84.8, 69.3,
57.8, 55.4, 51.8, 49.6; MS (EI) m/e (relative intensity) 337 (M+,
100). Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15.
Found: C, 71.47; H, 5.73; N, 4.01.
necine (2) in 61% yield. Spectroscopic and physical data
of 2 except for the sign of the optical rotation were
identical to those of natural and synthetic materials.11,12
In summary, we have shown that the condensation
between the enolate dianion of diethyl malate and imine
combined with ring-closing olefin metathesis provides an
expedient approach to 1-hydroxymethylpyrrolizidines,
necine bases. The synthesis of pyrrolizidine alkaloid, (-)-
croalbinecine, from diethyl (S)-malate in 10 steps dem-
onstrates the synthetic utility of this approach for diverse
pyrrolizidine alkaloids and their analogues.
(3S,4S,5S)-3-Ben zyloxy-4-b en zyloxym et h yl-1-(4-m et h -
oxyp h en yl)-5-p h en yeth yn yl-2-p yr r olid in on e (7). To a slurry
of 60% NaH (85 mg, 3.54 mmol) in 5 mL of DMF was added a
solution of 6 (398 mg, 1.18 mmol) in 7 mL of DMF. The mixture
was stirred for 30 min, and benzyl bromide (0.42 mL, 3.54 mmol)
was added followed by stirring at ambient temperature for 1 h.
The mixture was quenched with 50 mL of saturated NH4Cl
solution, and the aqueous layer was extracted twice with 100-
mL portions of CH2Cl2. The combined organic layers was dried
(MgSO4) and concentrated under reduced pressure. Purification
of the residue by chromatography on silica gel (1:6, EtOAc/
hexanes) gave 7 (527 mg, 86%) as a light yellow solid: Rf ) 0.25
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents obtained from commercial
sources were used as received, and solvents were dried prior to
use. All reactions, unless otherwise noted, were performed in
flame-dried glassware under an atmosphere of dry argon.
Column chromatography was performed on silica gel. Melting
points are uncorrected. 1H NMR spectra were recorded at 300
MHz and 13C NMR at 75 MHz. Infrared spectra were recorded
in the FT mode. Data for high-resolution mass spectra and
elemental analyses were obtained from Organic Chemistry
Research Center, Sogang University at Seoul, Korea.
(1:4, EtOAc/hexanes); mp 104-105 °C; [R]20 -63.6 (c 0.55,
D
CHCl3); IR (KBr, cm-1) 2889, 1709, 1248; 1H NMR (CDCl3, 300
MHz) δ 7.44-6.90 (m, 19H) 5.15 (d, 1H, J ) 12 Hz), 4.89 (d,
1H, J ) 8 Hz), 4.84 (d, 1H, J ) 12 Hz), 4.50 (d, 1H, J ) 12 Hz),
4.43 (d, 1H, J ) 12 Hz), 4.34 (d, 1H, J ) 8 Hz), 3.79 (s, 3H),
3.82-3.76 (m, 1H), 3.68-3.64 (m, 1H), 2.73(m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 171.4, 157.6, 137.8, 137.7, 131.6, 129.9, 128.6,
128.4, 128.3, 128.1, 127.8, 127.7, 127.6, 125.2, 122.0, 113.0, 86.1,
85.6, 75.2, 73.2, 72.7, 65.6, 55.4, 49.9, 48.2; MS (EI) m/e (relative
intensity) 517 (M+, 3), 91 (100). Anal. Calcd for C34H31NO4: C,
78.89; H, 6.04; N, 2.71. Found: C, 79.02; H, 6.19; N, 2.47.
(3S,4S,5R)-3-Ben zyloxy-4-b en zyloxym et h yl-1-(4-m et h -
oxyp h en yl)-5-[(Z)-2-p h en yleth en yl]-2-p yr r olid in on e (8). A
mixture of 7 (704 mg, 1.36 mmol) and Lindlar catalyst (49 mg,
7% w/w) in 10 mL of benzene was reacted under 40 psi hydrogen
pressure using Parr hydrogenator for 40 min. The mixture was
filtered over Celite, and the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography
on silica gel (1:7, EtOAc/hexanes) to give 8 (597 mg, 85%) as a
(3S,4R,5S)-4-E t h oxyca r b on yl-3-h yd r oxy-1-(4-m et h oxy-
p h en yl)-5-p h en ylp r op a r gyl-2-p yr r olid in on e (5a ). To a solu-
tion of hexamethyldisilazane (7.5 mL, 35.5 mmol) and n-BuLi
(1.6M in hexane, 22.2 mL) in 50 mL of THF stirred for 1 h at
-78 °C was added a solution of diethyl malate (3, 3.0 mL, 17.6
mmol) in 20 mL of THF slowly over a 5-min period. The solution
was stirred for 30 min at -78 °C, and a solution of phenlprop-
argylidene p-anisidine (4, 3.0 g, 12.7 mmol) in 60 mL of THF
was added slowly for 1.5 h. The mixture was slowly warmed to
0 °C over 1.5 h, quenched with 300 mL of saturated NH4Cl
solution, and extracted three times with 200-mL portions of
EtOAc. The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. Purification of the residue
by chromatography on silica gel (1:1, EtOAc/hexanes) gave 5a
(2.28 g, 47%) as a white solid and its C(5)-epimer 5b (0.53 g,
11%) as a light yellow solid. 5a : Rf ) 0.20 (1:1, EtOAc/hexanes);
light yellow oil: Rf ) 0.32 (1:3, EtOAc/hexanes); [R]20 -26.7 (c
D
8.87, CHCl3); IR (CHCl3, cm-1) 1704; 1H NMR (CDCl3, 300 MHz)
δ 7.43-7.18 (m, 15H) 7.04 (d, 2H, J ) 9 Hz), 6.77 (d, 2H, J ) 9
Hz), 6.61 (d, 1H, J ) 11 Hz), 5.37(t, 1H, J ) 11 Hz), 5.16-5.07
(m, 2H), 4.86 (d, 1H, J ) 11 Hz), 4.40-4.27 (3H, m), 3.76 (s,
3H), 3.65-3.57 (m, 2H), 2.34 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ 171.9, 157.2, 137.9, 137.6, 135.8, 134.5, 130.4, 129.9, 128.4,
128.3, 127.8, 127.7, 127.6, 127.5, 125.1, 113.6, 75.5, 73.2, 72.7,
65.4, 55.3, 54.3, 47.5; MS (EI) m/e (relative intensity) 519 (M+,
1), 91(100). Anal. Calcd for C34H33NO4: C, 78.59; H, 6.40; N,
2.70. Found: C, 78.61; H, 6.46; N, 2.66.
mp 129-130 °C; [R]25 -57.7 (c 0.75, CHCl3); IR (KBr, cm-1
)
D
3389, 1724, 1683; 1H NMR (CDCl3, 300 MHz) δ 7.39 (d, 2H, J )
7 Hz), 7.28 (m, 5H), 6.92 (d, 2H, J ) 7 Hz), 5.16 (d, 1H, J ) 9
Hz), 4.68 (d, 1H, J ) 9 Hz), 4.34-4.29 (m, 3H), 3.79 (s, 3H),
3.45 (t, J ) 9 Hz), 1.35 (t, 1H, J ) 7 Hz); 13C NMR (CDCl3, 75
MHz) δ 171.2, 170.5, 158.2, 131.6, 128.9, 128.2, 125.7, 121.5,
114.1, 87.3, 84.1, 72.1, 62.1, 55.4, 53.7, 50.9, 14.2; MS (EI) m/e
(3S,4S,5R)-3-Ben zyloxy-4-b en zyloxym et h yl-5-(2-p h en -
yleth en yl)-2-p yr r olid in on e (9). To a solution of 8 (87 mg, 0.17
mmol) in 16 mL of acetonitrile cooled at 0 °C was added a
solution of ceric ammonium nitrate (275 mg, 0.50 mmol) in 4
mL of water over a 5-min period. The mixture was stirred for 1
h at 0 °C, warmed to 10 °C, and diluted with 60 mL of water.
The aqueous layer was extracted three times with 100-mL
portions of EtOAc. The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Purification
(11) Ru¨eger, H.; Benn, M. Heterocycles 1983, 20, 1331-1334. Mo-
hanraj, S.; Kulanthaivel, P.; Subramanian, P. S.; Herz, W. Phytochem-
istry 1981, 20, 1991-1995. Sawhney, R. S.; Atal, C. K.; Culvenor, C.
C. J .; Smith, L. W. Aust. J . Chem. 1974, 27, 1805-1808.
(12) Conversion of 17 to C(7)-epimer of (-)-croalbinecine through
Mitsunobu reaction was studied. Experimental details and 1H NMR
data for this study are in the Supporting Information.

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9251
of the residue by chromatography on silica gel (1:2, EtOAc/
chromatography on silica gel (1:1, EtOAc/hexanes) to give 15
(63 mg, 61%) and 16 (10 mg, 10%) as a colorless oil. 15: Rf )
0.23 (1:1, EtOAc/Hexane); [R]27D -103 (c 0.6, CHCl3); IR (CHCl3,
hexanes) gave 9 (53 mg, 77%) as a white solid: Rf ) 0.13 (1:2,
EtOAc/hexanes); mp 106-107 °C; [R]22 -95.9 (c 1.4, CHCl3);
D
IR (KBr, cm-1) 3330, 1724; 1H NMR (CDCl3, 300 MHz) δ 7.37-
7.07 (m, 15H), 6.67 (d, 1H, J ) 12 Hz), 6.26 (s, 1H), 5.50 (dd,
1H, J ) 11, 10 Hz), 5.07 (d, 1H, J ) 12 Hz), 4.75 (d, 1H, J ) 12
Hz), 4.61 (t, 1H, J ) 9 Hz), 4.25 (m, 2H), 4.16 (d, 1H, J ) 8.7
Hz), 3.46 (m, 2H), 2.27(m, 1H); 13C NMR (CDCl3, 75 MHz) δ
175.3, 137.9, 137.7, 135.7, 133.9, 130.6, 128.5, 128.4, 128.2, 127.7,
127.5, 127.4, 75.2, 73.0, 72.6, 65.6, 50.0. 49.0; MS (EI) m/e
(relative intensity) 414 (M+, 0.04), 91 (100). Anal. Calcd for
C27H27NO3: C, 78.42; H, 6.58; N, 3.39. Found: C, 78.65; H, 6.76;
N, 3.16.
cm-1) 1709; H NMR (CDCl3, 300 MHz) δ 7.37-7.25 (m, 10H),
1
5.02 (d, 1H, J ) 12 Hz), 4.67 (d, 1H, J ) 12 Hz), 4.44 (m, 2H),
4.27 (d, 1H, J ) 10 Hz), 4.03 (d, 1H, J ) 13 Hz), 3.68-3.56 (m,
4H), 3.50 (dd, 1H, J ) 10, 7 Hz), 2.95 (d, 1H, J ) 13 Hz), 2.64
(1H, m); 13C NMR (CDCl3, 75 MHz) δ 174.8, 137.7, 128.3, 128.2,
128.0, 127.6, 127.4, 78.6, 73.0, 72.1, 67.9, 59.0, 55.7, 55.3, 44.6,
43.9; MS(EI) m/e (relative intensity) 366 (M + 1, 0.08), 91 (100).
Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found:
C, 72.34; H, 6.42; N, 3.52.
(1S ,2S ,7S ,7a S )-2-Be n zyloxy-1-b e n zyloxym e t h yl-7-h y-
d r oxy-7a -p yr r olizid in e (17). To a slurry of LiAlH4 (46 mg, 1.23
mmol) in 5 mL of THF at 0 °C was added slowly a solution of 15
(75 mg, 0.21 mmol) in 5 mL of THF. The resulting mixture was
stirred for 2 h at 0 °C and 12 h at ambient temperature. The
mixture was cooled to room temperature and a few drops of
water were added slowly until no more hydrogen gas evolved.
The resulting mixture was filtered over Celite, and the filtrate
was concentrate under reduced pressure. The residue was
purified by chromatography on silica gel (CH3OH) followed by
dissolving into CH2Cl2 to remove the silica gel eluted. Removal
of the solvent under reduced pressure gave 17 (47 mg, 65%) and
(3S,4S,5R)-1-Allyl-3-ben zyloxy-4-ben zyloxym eth yl-5-(2-
p h en yleth en yl)-2-p yr r olid in on e (10). To a mixture of 9 (193
mg, 0.47 mmol) and NaH (22 mg, 0.93 mmol) in 8 mL of THF
were added allyl bromide (0.081 mL, 0,93 mmol) and tetra-n-
butylammonium iodide (17 mg, 0,04 mmol). The mixture was
stirred for 1 h at ambient temperature and quenched with 50
mL of saturated NH4Cl solution. The aqueous layer was
extracted three times with 50-mL portions of EtOAc. The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. Purification of the residue by chroma-
tography on silica gel (1:4, EtOAc/hexanes) gave 10 (201 mg,
95%) as a white solid: Rf ) 0.20 (1:4, EtOAc/hexanes); mp 72
°C; [R]24D -115 (c 1.08, CHCl3); IR (CHCl3, cm-1) 1698; 1H NMR
(CDCl3, 300 MHz) δ 7.39-7.12 (m, 15H), 6.76 (d, 1H, J ) 11
Hz), 5.57 (m, 1H), 5.45 (t, 1H, J ) 11 Hz), 5.09 (d, 1H, J ) 11
Hz), 4.94 (m, 2H), 4.78 (d, 1H, J ) 11 Hz), 4.62 (dd, 1H, J ) 11,
7 Hz), 4.26 (m, 2H), 4.16 (m, 2H), 3.46 (m, 3H), 2.21 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ 172.4, 138.0, 137.7, 135.7, 134.6,
132.1, 130.3, 128.4, 128.3, 128.2, 127.7, 127.6, 127.5, 127.3, 117.9,
75.9, 73.1, 72.5, 66.0, 53.2, 47.5, 43.4; MS (EI) m/e (relative
intensity) 454 (M+, 0.04), 91(100). Anal. Calcd for C30H31NO3:
C, 79.44; H, 6.89; N, 3.09. Found: C, 79.67; H, 7.17; N, 2.81.
(1S,2S,7a R)-2-Ben zyloxy-1-b en zyloxym et h yl-2,5,7a -t r i-
h yd r op yr r olizin -3-on e (12). A mixture of 10 (185 mg, 0.41
mmol) and Grubbs catalyst 11 (10 mg, 0.012 mmol) in 30 mL of
benzene was heated at reflux for 12 h, and quenched by exposure
to air for 4 h. The mixture was filtered over Celite, and the
filtrate was concentrate under reduced pressure. The residue
was purified by chromatography on silica gel (1:3, EtOAc/
hexanes) to give 12 (129 mg, 90%) as a colorless oil: Rf ) 0.21
18 (7 mg, 9%) as a colorless oil. 17: Rf ) 0.21 (CH3OH); [R]24
D
-40.7 (c 0.55, CHCl3); IR (CHCl3, cm-1) 3406; 1H NMR (CDCl3,
300 MHz) δ 7.30 (m, 10H), 4.50 (s, 4H), 4.19 (m, 1H), 4.00 (q,
1H, J ) 5 Hz), 3.57 (dd, 1H, J ) 9, 7 Hz), 3.37 (m, 2H), 3.23 (dd,
1H, J ) 11, 5 Hz), 3.12 (m, 1H), 2.80 (m, 3H), 1.93 (m, 2H); 13
C
NMR (CDCl3, 75 MHz) δ 137.8, 137.4, 128.4, 128.3, 127.7, 127.6,
127.4, 83.1, 73.1, 72.1, 71.8, 71.6, 71.1, 58.1, 53.2, 43.8, 36.1;
MS (EI) m/e (relative intensity) 353 (M+, 2), 202 (5), 188 (28),
141 (31), 112 (46), 100 (37), 91 (100).
(1S,2S,7S,7a S)-2, 7-Dih yd r oxy-1-h yd r oxym eth yl-7a -p yr -
r olizid in e [2, (-)-Cr oa lbin ecin e]. A mixture of 17 (30 mg,
0.085 mmol) and 20% Pd(OH)2 (30 mg, 100% w/w) in 3 mL of
ethanol was shaken for 10 days under 45-psi hydrogen pressure
using Parr hydrogenator. The mixture was filtered over Celite,
and the filtrate was concentrate under reduced pressure. The
residue was purified by chromatography on silica gel (20:1, CH3-
OH/NH4OH) to give 2 (9 mg, 61%) as a colorless oil. 2: Rf )
0.21 (20:1, CH3OH/NH4OH); [R]24 ) -35 (c 0.17, EtOH); IR
D
(CHCl3, cm-1) 3326, 2918, 1409, 1090; 1H NMR (D2O, 300 MHz)
δ 4.28 (m, 1H), 4.18 (m, 1H), 3.74 (dd, 1H, J ) 11, 5 Hz), 3.63
(dd, 1H, J ) 11, 7 Hz), 3.27 (m, 2H), 3.13 (m, 1H), 2.75 (m, 1H),
2.55 (t, 1H, J ) 9 Hz), 2.34 (quint, 1H, J ) 7 Hz), 2.02 (m, 1H);
13C NMR (CD3OD, 75 MHz) δ 75.4, 72.4, 71.8, 62.8, 62.5, 53.8,
48.0, 37.2; MS (EI) m/e (relative intensity) 173 (M+, 7)
(1:3, EtOAc/hexanes); [R]24 -108 (c 2.0, CHCl3); IR (CHCl3,
D
cm-1) 3031, 1708; H NMR (CDCl3, 300 MHz) δ 7.29 (m, 10H),
1
5.92 (m, 1H), 5.85 (m, 1H), 5.09 (d, 1H, J ) 12 Hz), 4.70 (d, 1H,
J ) 12 Hz), 4.51-4.39 (m, 3H), 4.28 (m, 2H), 3.66 (m, 2H), 3.52
(dd, 1H, J ) 10, 7 Hz), 2.37 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ 175.5, 137.8, 137.7, 128.2, 128.1, 128.0, 127.6, 127.5, 127.3,
77.9, 73.0, 72.4, 68.2, 65.5, 51.7, 50.0; MS (EI) m/e (relative
intensity) 349 (M+, 0.02), 91(100). Anal. Calcd for C22H23NO3:
C, 75.62; H, 6.63; N, 4.01. Found: C, 75.65; H, 6.38; N, 4.03.
(1a S,5S,6S,6a S,6bR)-5-Ben zyloxy-6-(ben zyloxym eth yl)-
p er h yd r oxir en o[2,3-a ]p yr r olizin -4-on e (15). A mixture of 12
(98 mg, 0.28 mmol), NaHCO3 (25 mg, 1.12 mmol), and m-CPBA
(193 mg, 1.12 mmol) in 10 mL of benzene was stirred for 36 h
at ambient temperature. The mixture was diluted with 100 mL
of EtOAc and sequentially washed with 100 mL of saturated
Na2CO3 and 100 mL of saturated NaHCO3 solutions. Each
aqueous layer was extracted with 50 mL of EtOAc. The aqueous
layer was extracted three times with 50-mL portions of EtOAc.
The combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure. Purification of the residue by
Ack n ow led gm en t. This work was financially sup-
ported by the Korea Science and Engineering Founda-
tion (98-0501-04-01-3) and the Center for Molecular
Design and Synthesis (CMDS) at KAIST.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data for 5b, 13, 14,
16, and 18 and X-ray crystallographic data for 7. Experimental
1
details and H NMR data for the conversion of 17 to the C(7)-
epimer of (-)-croalbinecine. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0012187