Total Synthesis of (-)-horsfiline via asymmetric nitroolefination

Full text of DOI:10.1021/jo981577q

J . Org. Chem. 1999, 64, 1699-1704
1699
Sch em e 1a
Tota l Syn th esis of (-)-Hor sfilin e via
Asym m etr ic Nitr oolefin a tion
Gingipalli Lakshmaiah, Takeo Kawabata,
Muhong Shang, and Kaoru Fuji*
Institute for Chemical Research, Kyoto University,
Uji, Kyoto 611-0011, J apan
Received August 4, 1998
In tr od u ction
(-)-Horsfiline (1) is an oxindole alkaloid isolated by
Bodo and co-workers in 1991 from the Malaysian me-
dicinal plant Horsfildea superba.1 Several synthetic ap-
proaches are available in the literature for the synthesis
of both racemic and enantiomeric horsfiline. In 1992
J ones et al. reported the synthesis of racemic 1 via radical
cyclization.2 Later, two strategies for the synthesis of
racemic 1 were reported, both involving oxidative rear-
rangement of a tetrahydrocarboline derivative and spi-
rocyclization of 2-oxo-5-methoxytryptamine with form-
aldehyde.3 Recently, two groups disclosed new synthetic
routes for the synthesis of enantiomeric 1 via rearrange-
ment of a tetrahydrocarboline derivative and 1,3-dipolar
cycloaddition of thermally generated N-azomethine ylide,
respectively.4 Herein, we report a highly enantioselective
total synthesis of (-)-horsfiline via asymmetric nitroole-
fination using chiral nitroenamine 2.
a
(a) KOH, (CH3)2SO4, 73%; (b) n-BuLi/THF, BrCH2CHdC(CH3)2,
79%; (c) 2,6-lutidine, TBDMSOTf, CH2Cl2, 95%; (d) n-BuLi/toluene:
ether (4:1), 2, 84%; (e) 1 M HCl/MeOH, 95%.
suited to the synthesis of 1.
Resu lts a n d Discu ssion
The oxindole 6 was prepared starting from 3, which
was readily available from p-anisidine through steps
described in the literature.7 Selective O-methylation of
3 was achieved by using dimethyl sulfate in the presence
of potassium hydroxide to afford 4 in 73% yield. A prenyl
group was introduced into 4 by treating it with 1-bromo-
3-methyl-2-butene to furnish 5. After the amide nitrogen
was protected with TBDMS, the oxindole 6 was treated
with n-BuLi/THF followed by chiral nitroenamine 2 at
-78 °C to give 7 in 38% ee. Then we began screening
solvents such as ether, toluene, and a toluene-ether
mixture. Among these, the toluene-ether (4:1) mixture
gave the highest enantioselectivity (97% ee) and a good
yield (84%). The enhanced enantioselectivity could be
rationalized by the tight coordination of the lithium
enolate of 6 with 2 at the cyclic transition state5b in the
less coordinating solvents such as toluene-ether. The
TBDMS group of 7 was removed by treating 7 with HCl
to give 8.
With compound 8 of high enantiomeric excess in hand,
we started to construct the spiropyrrolidine ring system
(Scheme 2). The nitroolefin was reduced with NaBH4 to
give 9 in high yield. Attempted conversion of the nitro
group of 9 into a carboxyl group using DMSO/NaNO2/
CH3COOH conditions8 instead resulted in several byprod-
ucts. It was suspected that the free amide hydrogen
might be causing trouble. Therefore, the amide was
protected with a benzyl group in 42% yield and recovery
of 9. Further extending the reaction time resulted in
benzylation R to the nitro group. Conversion of nitroal-
We have developed a methodology for the creation of
chiral quaternary carbon centers via an addition-
elimination process,5b and the resulting optically active
nitroalkenes have been used as precursors for the syn-
thesis of natural products such as aspidosperma and
huntarian alkaloids.5a,c More recently, we reported an
efficient asymmetric nitroolefination of oxindole deriva-
tives using chiral nitroenamine 2 and its application to
the synthesis of (-)-pseudophrynaminol and (-)-eser-
methole.6 A similar strategy involving asymmetric ni-
troolefination of 6 (Scheme 1) was expected to be well
(1) J ossang, A.; J ossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J .
Org. Chem. 1991, 56, 6527.
(2) J ones, K.; Wilkinson, J . J . Chem. Soc., Chem. Commun. 1992,
1767.
(3) Bascop, S.-I.; Sapi, J .; Laronze, J .-Y.; Levy, J . Heterocycles 1994,
38, 725.
(4) (a) Pelligrine, C.; Strassler, C.; Weber, M.; Borschberg, H.-J .
Tetrahedron: Asymmetry 1994, 5, 1979. (b) Palmisano, G.; Annunziata,
R.; Papeo, G.; Sisti, M. Tetrahedron: Asymmetry 1996, 7, 1.
(5) (a) Node, M.; Nagasawa, Fuji, K. J . Am. Chem. Soc. 1987, 109,
7901. (b) Fuji, K.; Node, M.; Nagasawa, H.; Naniwa, Y.; Taga, T.;
Machida, K.; Snatzke, G. J . Am. Chem. Soc. 1989, 111, 7921. (c) Node,
M.; Nagasawa, H.; Fuji, K. J . Org. Chem. 1990, 55, 517
(6) (a) Fuji, K.; Kawabata, T.; Ohmori, T.; Node, M. Synlett 1995,
367. (b) Fuji, K.; Kawabata, T.; Ohmori, T.; Shang, M.; Node, M.
Heterocycles 1998, 47, 951.
(7) Giovannini, E.; Portmann, P. Helv. Chim. Acta 1948, 31 (5), 1381.
(8) Matt, C.; Wagner, A.; Mioskowski, C. J . Org. Chem. 1997, 62,
234.
10.1021/jo981577q CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/13/1999

1700 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
Sch em e 2a
a
(a) NaBH4, dioxane/MeOH, 97%; (b) NaH, DMF, PhCH2Cl, 42%; (c) NaNO2, CH3COOH, DMSO, 80%; (d) (for 12a ) Et3N/DPPA, EtOH
71%; (for 12b) Et3N/DPPA, toluene/PhCH2OH, 81%; (e) (i) O3, ethanol, -78 °C, Me2S, (ii) NaBH4, MeOH, 13a (89%), 13b (81%); (f) (i)
Et3N/MsCl, CH2Cl2, (ii) NaH, THF, 14a (85%), 14b (94%); (g) from 14a (i) KOH, NH2NH2, HOCH2CH2OH, (ii) HCOOH/HCHO 87%; from
14b (i) Pd/C, H2, MeOH, (ii) HCHO, NaCNBH3, AcOH, 85%; (h) Li/NH3, 83%.
kane 10 into the carboxylic acid was successful, affording
11 in 80% yield. Thermal Curtius rearrangement of 11
in ethanol furnished the corresponding ethoxy carbamate
12a in 71% yield. Ozonolysis of 12a followed by reduction
of the resulting aldehyde with NaBH4 produced alcohol
13a in 89% yield. The hydroxy group of 13a was mesyl-
ated, and the crude residue was directly treated with
NaH/THF at room temperature to afford spiropyrrolidine
14a in high yield. Carbamate 14a was deprotected under
basic conditions (KOH, hydrazine, ethylene glycol, 100
°C) to give a free amine, which was N-methylated under
Eschweiler-Clarke conditions (HCOOH/HCHO, reflux)
to produce 15. Unfortunately, 15 did not show any
rotation.9 Compound 15 on debenzylation gave racemic
horsfiline, which was identical with the authentic sample,
mp 152-154 °C (lit.1 mp 156-157 °C).
Next, we investigated another route to 1, which
involved hydroxylation of the indole ring at the final step,
since the expected starting material, isatin, is readily
available and very cheap. Oxindole 16 was prepared from
isatin by the known method.11 The hydroxylation of the
indole ring system at the 5-position is well-known in
biological or chemical synthesis of various indole alka-
loids.10 We suspected that spiropyrrolidine 24 (Scheme
3) is quite suitable for the hydroxylation at the 5-position,
since it does not have any other carbon centers prone to
oxidation. Introduction of a prenyl group into 16, followed
by asymmetric nitroolefination using chiral nitroenamine
2, afforded 18 in 65% yield with >99% ee (Scheme 3).
Compound 18 was converted into Cbz-protected amine
21 by methods similar to those described above. Ozo-
nolysis of 21 followed by reduction with NaBH4 afforded
primary alcohol 22 and cyclic secondary alcohol 23 in 70%
and 14% yields, respectively. Mesylation of 22 followed
by base treatment afforded spiropyrrolidine 24, while
reduction of 23 with Et3SiH in the presence of BF3‚OEt2
gave 24. Regioselective oxidation of 24 at the 5-position
was achieved by treatment with Pb(CF3CO2)4 in TFA12
to give a crude phenolic compound which, upon O-
methylation, gave 14b in 61% yield. The product thus
obtained was identical with 14b obtained previously
It was suspected that acidic conditions for methylation
and/or strongly basic conditions for deprotection of car-
bamate might cause racemization.9 Therefore, an alter-
native route was chosen, which involved protection of
amine with a Cbz group. Carbamate 12b was readily
obtained in 81% yield under Curtius rearrangement of
11 using benzyl alcohol. Spiropyrrolidine 14b was ob-
tained from 12b by the same procedure as that for the
conversion of 12a to 14a . To confirm that no racemization
occurred until this stage, the ee of 14b was determined
by HPLC analysis to be 97% ee (Chiralpak AD, 2-pro-
panol-hexane ) 10:90). Then the Cbz group was depro-
tected under neutral conditions (Pd-C, H2, MeOH) at
room temperature to yield the free amine. Without
purification, it was methylated using formaldehyde and
NaCNBH3 at room temperature to furnish 15, which
1
(Scheme 2) in its H NMR and optical rotation.
In conclusion, we have developed two synthetic routes
to (-)-horsfiline using asymmetric nitroolefination as the
key step.
Exp er im en ta l Section
showed an optical rotation of [R]20 -2.7 (c 1.3, CHCl3).
D
TLC analyses and preparative TLC were performed on
commercial glass plates bearing a 0.25-mm layer and a 0.5-mm
layer of Merck Kieselgel 60 F254, respectively. Silica gel column
chromatography was carried out with Wakogel C-200, Fuji
Silysia BW-1277H, or Nacalai tesque silica gel 60 (150-325
mesh). Tetrahydrofuran (THF), ether, and toluene were distilled
Finally, debenzylation was achieved by using Li/NH3 to
give 1 whose optical rotation and melting point were
identical with those of natural (R)-(-)-horsfiline.1
(9) The possible mechanism of racemization of the quaternary
carbon center involves the bond fission-cyclization process as shown
in Scheme 4. For racemization in the related system, see: Wenkert,
E.; Udelhofen, J . H.; Bhattacharyya, N. K. J . Am. Chem. Soc. 1959,
81, 3763. For a review, see: Bindra, J . S. Oxindole Alkaloids in The
Alkaloids-Chemistry and Physiology; Manske, R. H. F., Ed.; Academic
Press: New York, 1973; Vol. XIV, pp 83-121.
(10) Taniguchi, M.; Anjiki, T.; Nakagawa, M.; Hino, T. Chem.
Pharm. Bull. 1984, 32, 2544 and references therein.
(11) Hirose, S.; Sohda, S.; Toyoshima, S. Yakugaku Zasshi 1971,
1323.
(12) Partch, R. E. J . Am. Chem. Soc. 1967, 89, 3662.

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1701
Sch em e 3a
a
(a) n-BuLi, THF, BrCH2CHdC(CH3)2, 60%; (b) n-BuLi, ether, 2, 65%; (c) NaBH4, dioxane/MeOH, 97%; (d) NaNO2, CH3COOH/DMSO,
87%; (e) Et3N, DPPA, toluene, BnOH, 83%; (f) (i) O3/EtOH, -78 °C, Me2S, (ii) NaBH4, MeOH, 22 (70%), 23 (14%); (g) (i) MsCl, Et3N,
CH2Cl2, (ii) NaH, THF, 96%; (h) Et3SiH, BF3‚Et2O, CH2Cl2, 86%; (i) (i) Pb(CF3CO2)4, CF3CO2H, (ii) NaH, THF, MeI, 61%.
3420, 3010, 1710, 1605 cm-1; MS m/z (rel intensity) 231 (M+,
29), 163 (100). Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N,
6.06. Found: C, 72.42; H, 7.32; N, 5. 98.
Sch em e 4
1-ter t-Bu tyld im eth ylsilyl-3-(3-m eth ylbu t-2-en yl)-5-m eth -
oxy-2-oxin d ole (6). A solution of 5 (1.50 g, 6.50 mmol) in
dichloromethane was treated with 2,6-lutidine (6.80 mL, 58.5
mmol) and TBDMS triflate (8.96 mL, 39.0 mmol) at 0 °C. The
resulting solution was stirred for 2 h at room tempertaure and
poured into a saturated NaHCO3 (100 mL) solution. The aqueous
layer was extracted with ether (3 × 100 mL). The organic layer
over benzophenone ketyl before each use. Dichloromethane was
was dried over Na2SO4, filtered, and concentrated in vacuo. The
distilled from calcium hydride.
crude material was purified by flash column chromatography
5-Meth oxy-2-oxin d ole (4). Dimethyl sulfate (2.1 mL, 22.1
(silica gel, hexane-acetone ) 9:1) to give 6 as a yellow oil (2.12
mmol) was added to an aqueous KOH solution (22.1 mL, 1.00
g, 95%): 1H NMR (CDCl3, 200 MHz) δ 0.49 (d, J ) 6.8 Hz, 6H),
M, 22.1 mmol) of 5-hydroxy-2-oxindole (3) (3.00 g, 20.1 mmol)
0.97 (s, 9H), 1.57 (s, 3H), 1.62 (s, 3H), 2.62 (t, J ) 6.8 Hz, 2H),
at 0 °C. The resulting solution was stirred for 2 h, diluted with
3.41 (t, J ) 5.8 Hz, 1H), 3.78 (s, 3H), 4.95-5.06 (m, 1H), 6.70
water, and extracted with EtOAc (3 × 50 mL). The organic phase
(dd, J ) 8.8, 2.5 Hz, 1H), 6.83 (d, J ) 2.5 Hz, 1H), 6.87 (d, J )
was washed with saturated NaCl, dried over Na2SO4, and
8.8 Hz, 1H); IR (CHCl3) 1700, 1590 cm-1; MS m/z (rel intensity)
concentrated in vacuo. The residue was purified by silica gel
345 (M+, 100); exact MS calcd for C20H31O2NSi M+ 345.2125,
flash chromatograpy (ethyl acetate-hexane ) 5:5) to give
found m/z 345.2111.
colorless needles 4 (2.40 g, 73%): mp 148-151 °C (actone-
hexane); 1H NMR (CDCl3, 200 MHz) δ 3.53 (s, 2H), 3.77 (s, 3H),
(S)-1-ter t-Bu t yld im et h ylsilyl-3-(3-m et h ylb u t -2-en yl)-5-
m eth oxy-3-(2-n itr ovin yl)-2-oxin d ole (7) a n d (S)-3-(3-Me-
6.76-6.85 (m, 3H), 8.47 (s, br 1H, NH); IR (CHCl3) 3420, 3200,
1750, 1710, 1490 cm-1; MS m/z (rel intensity) 163 (M+, 70), 58
(100). Anal. Calcd for C9H9NO2: C, 66.26; H, 5.52; N, 8.58.
Found: C, 66.21; H, 5.52; N, 8.54.
th ylbu t-2-en yl)-5-m eth oxy-3-(2-n itr ovin yl)-2-oxin d ole (8).
A solution of 6 (2.50 g, 7.10 mmol) in toluene-ether (4:1, 60 mL)
was treated with n-BuLi (1.59 M in hexane, 4.68 mL, 7.10 mmol)
at -78 °C. The reaction mixture was warmed to 0 °C and stirred
for 30 min. The resulting enolate solution was transferred to a
suspension of chiral nitroenamine 2 (600 mg, 1.80 mmol) in
toluene (12 mL) at -78 °C. The reaction mixture was warmed
immediately to -30 °C and then slowly warmed to -10 °C, and
the stirring was continued for an additional 3 h. The mixture
was poured into ice-cooled aqueous HCl (2.5 M, 40 mL) and
stirred for 10 min. The aqueous layer was extracted with EtOAc
(3 × 100 mL). The combined organic extracts were washed with
saturated NaHCO3 and saturated NaCl, dried over Na2SO4, and
concentrated in vacuo. The crude material was purified by flash
chromatography (silica gel, hexane-acetone ) 9:1) to afford 7
5-Meth oxy-3-(3-m eth ylbu t-2-en yl)-2-oxin d ole (5). A solu-
tion of 4 (2.52 g, 15.4 mmol) in THF (60 mL) was treated with
n-BuLi (1.42 M in hexane, 21.9 mL, 30.8 mmol) at -78 °C under
argon for 1 h followed by 1-bromo-3-methyl-2-butene (2.30 mL,
19.3 mmol). The reaction mixture was slowly warmed to -30
°C during a period of 2 h and then quenched with saturated NH4-
Cl. The mixture was extracted with EtOAc (3 × 90 mL). The
combined organic extracts were washed with saturated NaCl,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, ethyl
acetate-hexane ) 5:5) to afford compound 5 (2.80 g, 79%) as
pale yellow crystals: mp 96-98 °C (hexanes-ethyl acetate); 1H
NMR (CDCl3, 200 MHz) δ 1.59 (s, 3H), 1.68 (s, 3H), 2.50-2.80
(m, 2H), 3.44 (dd, J ) 7.7, 4.8 Hz, 1H), 3.77 (s, 3H), 5.13 (t, J )
6.6 Hz, 1H), 6.71-6.87 (m, 3H), 8.28 (s, br, 1H, NH); IR (CHCl3)
(617 mg, 84%) as
a pale yellow viscous oil. The ee was
determined to be 97% ee after conversion of 7 into 8 (95% yield)
by treatment with methanolic HCl. HPLC conditions: Daicel

1702 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
Chiralpak AD, 2-propanol-hexane ) 3:97, flow 1 mL/min, tR
)
TLC (silica gel, ethyl acetate-hexane ) 2:8) to afford 12a (91
36.9 min (R) and 50.3 min (S). (S)-7: [R]20 -15.4 (c 0.80,
mg, 71%) as a viscous oil: [R]20 +44.8 (c 1.1, CHCl3); 1H NMR
D
D
1
CHCl3); H NMR (CDCl3, 200 MHz) δ 0.51 (d, J ) 2.7 Hz, 6H),
(CDCl3, 200 MHz) δ 1.16 (t, J ) 7.2 Hz, 3H), 1.52 (s, 3H), 1.56
(s, 3H), 2.45-2.80 (m, 2H), 3.30-3.40 (m, 1H), 3.76 (s, 3H), 3.80-
3.90 (m, 1H), 4.09 (q, J ) 7.2 Hz, 2H), 4.68, 5.08 (ABq, J ) 15.8
Hz, 2H), 4.78 (t, J ) 8.0 Hz, 1H), 5.25 (s, br, 1H, NH), 6.55 (d,
J ) 8.4 Hz, 1H), 6.68 (dd, J ) 8.5, 2.3 Hz, 1H), 6.87 (br s, 1H),
7.16-7.36 (m, 5H); IR (CHCl3) 3420, 1710, 1520, 1495 cm-1; MS
m/z (rel intensity) 422 (M+, 36), 91 (100); exact MS calcd for
C25H30N2O4 M+ 422.2206, found m/z 422.2186.
(R)-1-Ben zyl-3-(3-m eth ylbu t-2-en yl)-3-(ben zyloxyca r bo-
n yla m in om eth yl)-5-m eth oxy-2-oxin d ole (12b). To a solution
of 11 (300 mg, 0.79 mmol) in toluene (15 mL) were added
triethylamine (183 µL, 1.60 mmol) and DPPA (220 µL, 1.60
mmol) at room temperature under argon. The resulting mixture
was refluxed for 2 h, and benzyl alcohol (0.30 mL, 2.80 mmol)
was added. After refluxing for another 12 h, solvent was removed
in vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, ethyl acetate-hexane ) 2:8) to afford 12b in
81% yield (310 mg) as a viscous oil: [R]20D +44.5 (c 0.28, CHCl3);
1H NMR (CDCl3, 200 MHz) δ 1.50 (s, 3H), 1.65 (s, 3H), 2.41-
2.79 (m, 2H), 3.39 (dd, J ) 13.6, 4.4 Hz, 1H), 3.76 (s, 3H), 3.78-
3.91 (m, 1H), 4.65 (d, J ) 16.1 Hz, 1H), 4.73-4.8 (m, 1H), 4.99-
5.12 (m, 3H), 5.34 (m, 1H), 6.55 (d, J ) 8.5 Hz, 1H), 6.68 (dd, J
) 8.5, 2.3 Hz, 1H), 6.89 (br s, 1H), 7.15-7.40 (m, 10 H); IR
(CHCl3) 3420, 1710, 1605, 1515, 1495 cm-1; MS m/z (rel intesity)
484 (M+, 20), 91 (100). Anal. Calcd for C30H32N2O4: C, 74.38; H,
6.61; N, 5.78. Found: C, 74.08; H, 6.63; N, 5.74.
(R)-1-Ben zyl-3-(2-h yd r oxyeth yl)-3-(eth oxyca r bon yla m i-
n om eth yl)-5-m eth oxy-2-oxin d ole (13a ). A solution of 12a (60
mg, 0.14 mmol) in ethanol (12 mL) was cooled to -78 °C and
treated with ozone until the starting material disappeared.
Excess ozone was removed by bubbling nitrogen, and dimethyl
sulfide (0.30 mL) was added. The resulting mixture was allowed
to warm to room temperature, and stirring was continued
overnight. After removal of the solvent under vacuo, the crude
product was dissolved in methanol (2.5 mL) and treated with
NaBH4 (30 mg, 0.70 mmol) at 0 °C. After stirring for 1 h, the
reaction mixture was quenched with saturated NH4Cl. After
removing methanol under vacuo, the mixture was extracted with
EtOAc (3 × 40 mL). The combined organic extracts were washed
with saturated NaCl, dried over Na2SO4, and concentrated in
vacuo. The crude material was purified by preparative TLC
0.97 (s, 9H), 1.53 (s, 3H), 1.56 (s, 3H), 2.51-2.84 (m, 2H), 3.81
(s, 3H), 4.75 (t, J ) 7.5 Hz, 1H), 6.75-6.96 (m, 3H), 7.02, 7.36
(ABq, J ) 13.6 Hz, 2H); IR (CHCl3) 1710, 1530 cm-1; MS m/z
(rel intensity) 416 (M+, 67), 301 (100); exact MS calcd for
C22H32N2O4Si M+ 416.2132, found m/z 416.2108. (S)-8: a pale
yellow oil; [R]20D -24.1 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz)
δ 1.54 (s, 3H), 1.64 (s, 3H), 2.70 (d, J ) 7.5 Hz, 2H), 3.81 (s,
3H), 4.91 (t, J ) 7.5 Hz, 1H), 6.80-6.92 (m, 3H), 7.03, 7.39 (ABq,
J ) 13.6 Hz, 2H), 8.50 (s, br, 1H, NH); IR (CHCl3) 3200, 1710,
1610, 1530 cm-1; MS m/z (rel intensity) 302 (M+, 5), 58 (100).
Anal. Calcd for C16H20N2O4: C, 63.58; H, 5.96; N, 9.27. Found:
C, 63.34; H, 5.99; N, 9.14.
(S)-3-(3-Meth ylbu t-2-en yl)-5-m eth oxy-3-(2-n itr oeth yl)-2-
oxin d ole (9). NaBH4 (347 mg, 9.20 mmol) was added portion-
wise to a solution of 8 (1.90 g, 6.12 mmol) in dioxane-methanol
(3:1, 100 mL) at 0 °C. After stirring for 1 h, the reaction mixture
was quenched with saturated NH4Cl (10 mL) and extracted with
ether (3 × 100 mL). The organic phase was washed with
saturated NaCl, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash chromatoghaphy (silica gel, ethyl
acetate-hexane ) 7:3) to give 9 (1.80 g, 97%) as a pale yellow
oil: [R]20 +41.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz) δ
D
1.53 (s, 3H), 1.61 (s, 3H), 2.45-2.64 (m, 4H), 3.80 (s, 3H), 3.95-
4.10 (m, 1H), 4.15-4.30 (m, 1H), 4.88 (t, J ) 7.5 Hz, 1H) 6.75-
6.87 (m, 3H), 8.25 (s, br, 1H, NH); IR (CHCl3) 3420, 3200, 1710,
1560, 1490 cm-1; MS m/z (rel intensity) 304 (M+, 28), 175 (100).
Anal. Calcd for C16H22N2O4: C, 63.16; H, 6.57; N, 9.21. Found:
C, 62.89; H, 6.68; N, 9.07.
(S)-1-Ben zyl-3-(3-m et h ylb u t -2-en yl)-5-m et h oxy-3-(2-n i-
tr oeth yl)-2-oxin d ole (10). A suspension of NaH (473 mg, 60%
in oil, 11.8 mmol) in DMF (4 mL) was treated with 9 (3.00 g,
9.90 mmol) in DMF (6 mL) at 0 °C. The resulting reaction
mixture was stirred at room temperature for 30 min and treated
with benzyl chloride (1.20 mL, 9.90 mmol) at 0 °C. After being
stirred at the same temperature for 5 h, the mixture was
quenched with saturated NH4Cl and extracted with EtOAc (3
× 100 mL). The combined organic extracts were washed with
saturated NaCl, dried (Na2SO4), filtered, and concentrated in
vacuo. The crude material was purified by flash chromatography
(silica gel, ethyl acetate-hexane ) 3:7) to give 10 (1.62 g, 42%)
as a colorless oil. The remaining starting material 9 was
recovered quantitatively. 10:[R]20D +79.8 (c 1.0, CHCl3); 1H NMR
(CDCl3, 200 MHz) δ 1.54 (s, 3H), 1.57 (s, 3H), 2.45-2.74 (m,
4H), 3.76 (s, 3H), 3.92-4.10 (m, 1H), 4.12-4.29 (m, 1H), 4.63
and 5.13 (ABq J ) 15.8 Hz, 2H), 4.78 (t, J ) 6.9 Hz, 1H), 6.62
(dd, J ) 8.5, 1.0 Hz, 1H), 6.70 (d, J ) 8.5 Hz, 1H), 6.81 (d, J )
2.4 Hz, 1H), 7.20-7.35 (m, 5H); IR (CHCl3) 1710, 1555, 1490
cm-1; MS m/z (rel intensity) 394 (M+, 50), 91 (100). Anal. Calcd
for C23H26N2O4: C, 70.05; H, 6.59; N, 7.10. Found: C, 70.01; H,
6.71; N, 6.97.
(silica gel, ethyl acetate-hexane ) 7:3) to give 13a (50 mg, 89%)
1
as a colorless oil: [R]20 -6.02 (c 0.3, CHCl3); H NMR (CDCl3,
D
200 MHz) δ 1.19 (t, J ) 7.0 Hz, 3H), 2.03-2.41 (m, 2H), 3.29-
3.65 (m, 3H), 3.76 (s, 3H), 3.70-3.90 (m, 1H), 4.08 (q, J ) 7.0
Hz, 2H), 4.88 (s, 2H), 5.25 (br, 1H), 6.63 (d, J ) 8.4 Hz, 1H),
6.72 (dd, J ) 8.4, 2.2 Hz, 1H), 6.88 (s, 1H), 7.20-7.40 (m, 5H);
IR (CHCl3) 3450, 1700, 1520, 1495 cm-1; MS m/z (rel intensity)
398 (M+, 23), 297 (100); exact MS calcd for C22H26N2O5 M+
398.1843, found m/z 398.1864.
(R)-1-Ben zyl-3-(2-h yd r oxyeth yl)-3-(ben zyloxyca r bon yl-
a m in om eth yl)-5-m eth oxy-2-oxin d ole (13b). 13b was ob-
tained from 12b in 81% yield through a procedure similar to
that for the conversion of 12a into 13a . 13b: [R]20D -14.6 (c 0.25,
CHCl3); 1H NMR (CDCl3, 200 MHz) δ 2.00-2.05 (m, 1H), 2.25-
2.40 (m, 1H), 3.32-3.60 (m, 3H), 3.74 (s, 3H), 3.80-3.90 (m, 1H),
4.86 (s, 2H), 5.01, 5.10 (ABq, J ) 12.1 Hz, 2H), 5.30 (s, br, 1H),
6.60 (d, J ) 8.5 Hz, 1H), 6.69 (dd, J ) 8.5, 2.4 Hz, 1H), 6.88 (d,
J ) 2.3 Hz, 1H), 7.20-7.40 (m, 10H); IR (CHCl3) 3450, 1710,
1600, 1515, 1490 cm-1; MS m/z (rel intensity) 460 (M+, 10), 91
(100); exact MS calcd for C27H28N2O5 M+ 460.1984, found m/z
460.1999.
(S)-3-[1-Ben zyl-3-(3-m et h ylb u t -2-en yl)-5-m et h oxy-2-ox-
in d olyl]a cetic Acid (11). A solution containing 10 (190 mg,
0.48 mmol), sodium nitrite (100 mg, 1.50 mmol), and acetic acid
(0.28 mL, 4.82 mmol) in DMSO (1.0 mL) was stirred for 8 h at
37 °C. The reaction mixture was diluted with water (20 mL),
acidified with 10% aqueous HCl, and extracted with ether (5 ×
120 mL). The organic phase was dried (Na2SO4) and concen-
trated in vacuo. The residue was purified by flash column
chromatography (silica gel, ethyl acetate-hexane ) 4:5) to yield
pure 11 (146 mg, 80%) as a yellow amorphous solid: [R]20D +34.8
1
(c 1.0, CHCl3); H NMR (CDCl3, 200 MHz) δ 1.49 (s, 3H), 1.57
(s, 3H), 2.44-2.63 (m, 2H), 2.86 & 3.06 (ABq, J ) 16.8 Hz, 2H),
3.73 (s, 3H), 4.73, 5.00 (ABq, J ) 15.8 Hz, 2H), 4.80 (t, J ) 7.2
Hz, 1H), 6.52 (d, J ) 8.6 Hz, 1H), 6.66 (dd, J ) 8.6, 1.8 Hz, 1H),
6.78 (d, J ) 1.8 Hz, 1H), 7.26 (s, 5H); IR (CHCl3) 1710, 1605,
1495 cm-1; MS m/z (rel intensity) 379 (M+, 40), 91 (100); exact
MS calcd for C23H25NO4 M+ 379.1784, found m/z 379.1810.
(R)-1-Ben zyl-3-(3-m eth ylbu t-2-en yl)-3-(eth oxyca r bon yl-
a m in om eth yl)-5-m eth oxy-2-oxin d ole (12a ). A solution of 11
(115 mg, 0.30 mmol) in ethanol (8.0 mL) was treated with
triethylamine (84 µL, 0.61 mmol) and diphenylphosphoryl azide
(DPPA) (131 µL, 0.61 mmol) at room temperature under argon.
The resulting mixture was refluxed for 48 h. After removal of
the solvent in vacuo, the residue was purified by preparative
(R)-1-Ben zyl-1′-et h oxyca r b on yl-5-m et h oxy-2-oxosp ir o-
(3H-in d ole-3,3′-p yr r olid in e) (14a ). A solution of 13a (40 mg,
0.10 mmol) in CH2Cl2 (4 mL) was treated with Et3N (20 µL, 0.14
mmol) and methane sulfonyl chloride (9.3 µL, 0.12 mmol) at 0
°C. The mixture was stirred for 1 h at 0 °C, quenched with water
(2 mL), and extracted with CH2Cl2 (2 × 20 mL). The combined
organic extracts were washed with saturated NaCl, dried over
Na2SO4, filtered, and concentrated under vacuo. The crude
product was used for the next step without purification. The
residue was dissolved in THF (2 mL) and treated with an NaH
(10 mg, 60% in oil, 0.19 mmol) suspension in THF (0.5 mL) at 0
°C. The reaction mixture was stirred for 10 h at room temper-
ature, quenched with saturated NH4Cl, and extracted with

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1703
EtOAc (3 × 25 mL). The combined oganic extracts were washed
with saturated NaCl, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by preparative TLC (silica gel,
ethyl acetate-hexane, 4:6) to give amorphous 14a (32 mg,
1-Ben zyl-3-(3-m eth ylbu t-2-en yl)-2-oxin d ole (17). 17 was
obtained from 16 in 60% yield by a procedure similiar to that
for the conversion of 4 into 5: a yellow oil; 1H NMR (CDCl3, 200
MHz) δ 1.60 (s, 3H), 1.59 (s, 3H), 2.74 (br t, J ) 6.6, Hz, 2H),
3.57 (t, J ) 6.6 Hz, 1H), 4.73, 5.10 (ABq, J ) 15.7 Hz, 2H), 5.03-
5.10 (m, 1H), 6.68 (d, J ) 7.7 Hz, 1H), 7.00 (t, J ) 7.7, 7.4 Hz,
1H), 7.11-7.36 (m, 7H); IR (neat) 1713, 1613, 1488 cm-1; MS
m/z (rel intensity) 291 (M+, 22), 223 (100); exact MS calcd for
85%): [R]20 -28.4 (c 0.46, CHCl3); 1H NMR (CDCl3, 200 MHz)
D
δ 1.20-1.38 (m, 3H), 2.02-2.66 (m, 2H), 3.50-3.70 (m, 2H), 3.76
(s, 3H), 3.78-3.88 (m, 2H), 4.10-4.26 (m, 2H), 4.90 (s, 2H), 6.60-
6.72 (m, 2H), 6.80 (m, 1H), 7.20-7.32 (m, 5H); IR (CHCl3) 1700,
1495 cm-1; MS m/ z (rel intensity) 380 (M+, 60), 265 (100); exact
MS calcd for C22H24N2O4 M+ 380.1736, found m/z 380.1737.
(R)-1-Ben zyl-1′-ben zyloxycar bon yl-5-m eth oxy-2-oxospir o-
(3H-in d ole-3,3′-p yr r olid in e) (14b). 14b was obtained from 13b
in 94% yield by a procedure similar to that for the conversion of
13a into 14a . 14b: [R]20D -36.8 (c 0.5, CHCl3); 1H NMR (CDCl3,
200 MHz) δ 2.02-2.20 (m, 1H), 2.40-2.60 (m, 1H), 3.61-3.70
(m, 1H), 3.73 (s, 3H), 3.80-4.0 (m, 3H), 4.89 (s, 2H), 5.21, 5.17
(two s, ratio ) 3:4, 2H), 6.62 (d, J ) 8.4 Hz, 1H), 6.70 (dd, J )
8.4, 2.4 Hz, 1H), 6.80 (t, J ) 2.8 Hz, 1H), 7.20-7.45 (m, 10 H);
IR (CHCl3) 1705, 1600, 1490 cm-1; MS m/z (rel intensity) 442
(M+, 25), 91 (100). Anal. Calcd for C27H26N2O4: C, 73.30; H, 6.11;
N, 6.33. Found: C, 73.05; H, 5.94; N, 6.15.
(R)-1-Ben zyl-1′-m eth yl-5-m eth oxy-2-oxosp ir o(3H-in d ole-
3,3′-p yr r olid in e) (15). (A) F r om 14a . A solution of 14a (24
mg, 0.06 mmol), KOH (53 mg, 0.94 mmol), and NH2NH2 (10 µL,
0.32 mmol) in ethylene glycol (1 mL) was heated at 100 °C for
10 h. The reaction mixture was diluted with water (10 mL) and
extracted with EtOAc (3 × 50 mL). The organic phase was
washed with saturated NaCl, dried over Na2SO4, and concen-
trated in vacuo. The crude free amine was refluxed in HCO2H
(1 mL) and HCHO (47 µL, 0.58 mmol, 37% in water) for 1 h.
The reaction mixture was cooled to room temperature, diluted
with water, basified with saturated NaHCO3, and extracted with
EtOAc (3 × 30 mL). The combined organic extracts were washed
with saturated NaCl, dried over Na2SO4, and concentrated in
vacuo. The crude material was purified by preparative TLC
(methanol-dichloromethane ) 1:9) to give 15 (18 mg, 87%) as
a colorless oil: 1H NMR (CDCl3, 200 MHz) δ 2.05-2.22 (m, 1H),
2.31-2.47 (m, 1H), 2.50 (s, 3H), 2.81 (t, J ) 8.2, Hz 1H), 2.90
(d, J ) 9.5 Hz, 1H), 3.01 (d, J ) 9.5 Hz, 1H), 3.15 (ddd, J )
11.5, 8.2, 3.9 Hz, 1H), 3.77 (s, 3H), 4.88 (s, 2H), 6.57 (d, J ) 8.5
Hz, 1H), 6.65 (dd, J ) 8.5, 2.4 Hz, 1H), 7.10 (d, J ) 2.4 Hz, 1H),
7.24-7.35 (m, 5H); IR (CHCl3) 1705, 1490 cm-1; MS m/z (rel
intensity) 322 (M+, 29), 265 (100); exact MS calcd for C20H22N2O2
M+ 322.1681, found m/z 322.1700.
C
20H21NO M+ 291.1624, found m/z 291.1598.
(S)-1-Ben zyl-3-(3-m et h ylb u t -2-en yl)-3-(2-n it r ovin yl)-2-
oxin d ole (18). A solution of 17 (10.1 g, 34.6 mmol) in dry ether
(90 mL) was treated with n-BuLi (1.59 M solution in hexane,
21.8 mL, 34.6 mmol) at -78 °C under argon. The reaction
mixture was warmed to 0 °C and stirred for 30 min. The
resulting enolate solution was transferred to a suspension of 2
(3.9 g, 11.5 mmol) in ether (30 mL) at -78 °C via cannula. The
mixture was warmed rapidly to -50 °C and then slowly allowed
to warm to 0 °C, and stirring was continued for 3 h. The reaction
mixture was poured into an HCl solution (2.50 M, 150 mL) and
stirred for 30 min. The mixture was extracted with EtOAc (3 ×
100 mL). The combined organic extracts were washed with
saturated NaHCO3 and saturated NaCl, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, ethyl acetate-
hexane ) 1: 9) to afford 18 (2.7 g, 65%) as pale yellow crystals,
mp 122-124 °C (ethyl acetate-hexane). The ee was determined
to be >99% by HPLC with CHIRALPAK AS (5% 2-propanol-
hexane, flow 1.0 mL/min, tR )21.8 min (S) and 26.0 min (R).
18: [R]20 +13.6 (c 1.4, CHCl3); 1H NMR (CDCl3, 200 MHz) δ
D
1.55 (s, 3H), 1.59 (s, 3H), 2.68-2.92 (m, 2H), 4.69, 5.15 (ABq, J
) 15.9 Hz, 2H), 4.81 (t, J ) 7.7 Hz, 1H), 6.75 (d, J ) 7.7 Hz,
1H), 7.06, 7.46 (ABq, J ) 13.6 Hz, 2H), 7.07-7.36 (m, 8H); IR
(KBr) 1717, 1612, 1512 cm-1; MS m/z (rel intensity) 362 (M+,
25), 247 (100). Anal. Calcd for C22H22N2O3: C, 72.91; H, 6.05;
N, 7.73. Found: C, 72.65; H, 6.14; N, 7.48.
(S)-1-Ben zyl-3-(3-m et h ylb u t -2-en yl)-3-(2-n it r oet h yl)-2-
oxin d ole (19). 19 was obtained from 18 in 97% yield by a
procedure similar to that for the conversion of 8 into 9. 19:
colorless crystals (benzene-heptane), mp 99-100 °C; [R]20
D
+55.7 (c 1.8, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 1.53 (s, 3H),
1.57 (s, 3H), 2.49-2.79 (m, 4H), 3.93-4.28 (m, 2H), 4.67, 5.16
(ABq, J ) 15.7 Hz, 2H), 4.77 (t, J )6.7 Hz, 1H), 6.73 (d, J ) 7.6
Hz, 1H), 7.02-7.36 (m, 8H); IR (KBr) 1717, 1610, 1550 cm-1
;
MS m/z (rel intensity) 364 (M+, 18), (100); exact MS calcd for
C22H24N2O3 M+ 364.1788, found m/z 364.1782.
(B) F r om 14b. A solution of 14b (50 mg, 0.11 mmol) and Pd/C
(10 mg) in methanol (5 mL) was stirred under atmospheric
hydrogen at room temperature for 8 h. The catalyst was filtered
and washed with methanol. The combined filtrate was concen-
trated under reduced pressure to give crude free amine. The
crude amine was dissolved in CH3CN (1.5 mL) and treated with
HCHO (49 µL, 0.60 mmol, 37% in water) and NaCNBH3 (12.8
mg, 0.20 mmol) at room temperature. The mixture was stirred
for 15 min and neutralized with acetic acid. After stirring was
continued for a further 1 h, the mixture was basified with
ammonia solution. Solvent was removed in vacuo, and the
residue was extracted with ethyl acetate (3 × 30 mL). The
combined organic extracts were washed with saturated NaCl,
dried over Na2SO4, and concentrated under vacuo. The crude
product was purified by preparative TLC (silica gel, methanol-
dichloromethane ) 1:9) to give 15 (31 mg, 85%) as a colorless
(S)-3-[1-Ben zyl-3-(3-m eth ylbu t-2-en yl)-2-oxin d olyl)]a ce-
tic Acid (20). 20 was obtained from 19 in 87% yield by a
procedure similar to that for the conversion of 10 into 11. 20: a
yellow oil; [R]20D +1.9 (c 2.2, CHCl3); 1H NMR (CDCl3, 200 MHz)
δ 1.49 (s, 3H), 1.57 (s, 3H), 2.56 (d, J ) 8.1 Hz, 2H), 2.92, 3.13
(ABq, J ) 16.7 Hz, 2H), 4.77, 5.08 (ABq, J ) 15.9 Hz, 2H), 6.67
(d, J ) 8.1 Hz, 1H), 6.98-7.29 (m, 8H); IR (neat) 1714, 1613,
1489 cm-1; MS m/z (rel intensity) 349 (M+, 26), 235 (100); exact
MS calcd for C22H23NO3 M+ 349.1679, found m/z 349.1669.
(S)-1-Ben zyl-3-(3-m eth ylbu t-2-en yl)-3-(ben zyloxyca r bo-
n yla m in om eth yl)-2-oxin d ole (21). 21 was obtained from 20
in 83% yield as a yellow oil by a procedure similar to that for
the conversion of 11 into 12b. 21: [R]20 -33.6 (c 1.3, CHCl3);
D
1H NMR (CDCl3, 200 MHz) δ 1.50 (s, 3H), 1.55 (s, 3H), 2.45-
2.57 (m, 1H), 2.67-2.78 (m, 1H), 3.40-3.51 (m, 1H), 3.78-3.89
(m, 1H), 4.63-4.81 (m, 2H), 4.98-5.14 (m, 2H), 5.24-5.30 (m,
1H), 6.67 (d, J ) 7.8 Hz, 1H), 7.0-7.40 (m, 13 H); IR (KBr) 3326,
1712, 1612, 1488 cm-1; MS m/z (rel intensity) 454 (M+, 12),
91(100); exact MS calcd for C29H30N2O3 M+ 454.2258, found m/z
454.2224.
oil: [R]20 -2.7 (c 1.3, CHCl3); 1H NMR and mass spectra were
D
identical with those of 15 obtained from 14a .
(-)-Hor sfilin e (1). A solution 15 (obtained from 14b, 15 mg,
0.05 mmol) in THF-t-BuOH (1.1 mL, 10:1) was added dropwise
to a dark blue solution of lithium (5.0 mg) in liquid ammonia
(ca 5 mL) at -78 °C. The resulting solution was stirred for 6
min and then quenched with 35 mg of NH4Cl. Ammonia was
allowed to evaporate, and the remaining solvent was removed
under vaccum. The crude material was treated with water (2.0
mL) and extracted with EtOAC (3 × 35 mL). The organic phase
was washed with saturated NaCl, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by preparative TLC
(silica gel, methanol-dichloromethane ) 1:9) to give 1 (9.2 mg,
(R)-1-Ben zyl-3-(h ydr oxym eth yl)-3-(3-ben zyloxycar bon yl-
a m in om eth yl)-2-oxin d ole (22) a n d (3R)-1-Ben zyl-1′-ben zyl-
oxycarbonyl-2′-hydroxy-2-oxospiro(3H-indole-3,4′-pyrrolidine)
(23). A solution of 21 (347 mg, 0.76 mmol) in ethanol (30 mL)
was treated with ozone at -78 °C until starting material was
disappeared. Excess ozone was removed by bubbling nitrogen,
and dimethyl sulfide (1.0 mL) was added. The reaction mixture
was allowed to warm to room temperature, and stirring was
continued for 24 h. After removal of solvent under reduced
pressure, the crude aldehyde was dissolved in methanol (10 mL)
and treated with NaBH4 (144 mg, 3.82 mmol) at 0 °C. After
stirring for 1 h, the reaction mixture was quenched with
83%) as colorless crystals: [R]20D -7.0 (c 0.32, MeOH) {lit.1 [R]20
D
-7.2 (c 1.0, MeOH)}, mp 120-122 °C (acetone) {lit.1 mp 124-
126 °C (acetone)}. The spectral data (1H NMR, mass, C13 NMR,
and HRMS) were identical with those reported.1

1704 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
saturated NH4Cl. Methanol was removed under reduced pres-
sure, and the residue was extracted with EtOAc (3 × 50 mL).
The combined organic extracts were washed with saturated
NaCl, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by preparative TLC (silica gel, ethyl acetate-
hexane ) 4:6) to afford 22 (230 mg, 70%) as a colorless oil and
23 (2:1 diastereomeric mixture, 47 mg, 14%) as a colorless oil.
1.4, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 2.04-2.20 (m, 1H),
2.40-2.60 (m, 1H), 3.65-4.0 (m, 4H), 4.92 (s, 2H), 5.21, 5.17
(two s, ratio ) 2:3, 2H), 6.47 (d, J ) 4.0 Hz, 1H), 7.02 (t, J ) 9.2
Hz, 1H), 7.49-7.41 (m, 12H); IR (neat) 1713, 1613, 1487 cm-1
;
MS m/z (rel intensity) 412 (M+, 33), 91 (100); exact MS calcd for
C
26H24N2O3 M+ 412.1788, found m/z 412.1773.
(B) F r om 22. 24 was obtained from 22 in 96% yield by a
22: [R]20 +8.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz) δ
D
procedure similar to that for the conversion of 13b into 14b.
The spectral data and the optical rotation of 24 thus obtained
were identical with those of 24 obtained from 23.
(2.07-2.16 (m, 1H), 2.26-2.50 (m, 1H), 3.39-360 (m, 3H), 3.80-
3.91 (m, 1H), 4.90 (s, 2H), 5.01, 5.09 (ABq, J ) 12.3, Hz, 2H),
5.17-5.28 (m, 1H), 6.74 (d, J ) 7.6 Hz, 1H), 7.0-7.37 (m, 13 H);
IR (KBr) 3331, 1694, 1612, 1488 cm-1; MS m/z (rel intensity)
430 (M+, 2), 91 (100); exact MS calcd for C26H26N2O4 M+
P r ep a r a tion of 14b fr om 24. To a solution of lead tetrakis-
(trifluoroacetate) (736 mg, 1.12 mmol) in trifluoroacetic acid (4
mL) was added a solution of 24 (92 mg, 0.22 mmol) in trifluo-
roacetic acid (4 mL) at 0 °C. The mixture was stirred for 1 h at
room temperature and then quenched with saturated aqueous
K2CO3, and stirring was continued for 30 min. The mixture was
extracted with ether (3 × 40 mL). The organic phase was washed
with saturated NaCl, dried over Na2SO4, and concentrated in
vacuo. The crude material was dissolved in THF (2.0 mL) and
added to a NaH (53 mg, 1.32 mmol, 60% in oil) suspension in
THF (1.0 mL) at 0 °C. The mixture was stirred for 10 min at 0
°C and treated with MeI (0.5 mL), and stirring was continued
for 30 min at room temperature. The reaction mixture was
quenched with saturated NH4Cl and extracted with EtOAc (3
× 40 mL). The combined organic extracts were washed with
saturated NaCl, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by preparative TLC (ethyl acetate-hexane
) 4:6) to afford 14b (60 mg, 61%) as a colorless oil. Spectral
data (1H NMR, mass, IR, and optical rotaion) were identical with
those of 14b obtained from 13b.
430.1894, found m/z 430.1915. 23: [R]20 -13.4 (c 2.4, CHCl3);
D
1H NMR (CDCl3, 200 MHz) δ 2.15-2.37 (m, 1H), 2.48-2.80 (m,
1H), 3.65-4.05 (m, 2H), 4.91 (s, 2H), 5.15-5.40 (m, 2H), 5.69-
6.10 (m, 1H), 6.73, 6.78 (two d, J ) 8.6, 8.6 Hz, ratio ) 2:1, 1H),
7.00-7.74 (m, 13H); IR (neat) 3404, 1612, 1488 cm-1, MS m/z
(rel intensity) 428 (M+, 3), 91 (100); exact MS calcd for
C26H24N2O4 M+ 428.1737, found 428.1764.
(R)-1-Ben zyl-1′-ben zyloxycar bon yl-2-oxospir o(3H-in dole-
3,3′-p yr r olid in e) (24). (A) F r om 23. A solution of 23 (47 mg,
0.11 mmol) in CH2Cl2 (2 mL) was treated with triethylsilane
(18 µL, 0.11 mmol) and boron trifluoride etherate (14 µL, 0.11
mmol) at -78 °C. After 30 min, additional triethylsilane (18 µL,
0.11 mmol) and boron trifluoride etherate (14 µL, 0.11 mmol)
were added and stirring was continued for another 3 h at -78
°C. The reaction mixture was quenched with saturated NaCl
and extracted with EtOAc (3 × 20 mL). The combined organic
extracts were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by preparative TLC (ethyl acetate-hexane
) 3:7) to afford 24 (39 mg, 86%) as a colorless oil: [R]20D -18.7(c
J O981577Q