Concise synthesis of (±)-rhazinilam

Article abstract of DOI:10.1016/S0040-4020(01)00859-6

2-Piperidone has been converted into (±)-rhazinilam in nine steps in 8% overall yield. The key transformation involves the conversion of the lactam 5 into the annulated pyrrole derivative 3 via the thiophenyl imine 8.

Full text of DOI:10.1016/S0040-4020(01)00859-6

TETRAHEDRON
Pergamon
Tetrahedron 57 2001) 8647±8651
Concise synthesis of ꢀ^)-rhazinilam
Philip Magnusp and Trevor Rainey
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 16 August 2001; accepted 27 August 2001
AbstractÐ2-Piperidone has been converted into ^)-rhazinilam in nine steps in 8% overall yield. The key transformation involves
the conversion of the lactam 5 into the annulated pyrrole derivative 3 via the thiophenyl imine 8. q 2001 Published by Elsevier
Science Ltd.
2)-Rhazinilam 1 has been isolated from a number of plant
sources such as Rhazya stricta Decaisne,1 Melodinus
australis2 and Kopsia singapurensis., Scheme 1.3 Since
the original elucidation of structure4,5 and synthesis6 of 1
there has been increasing interest in this alkaloidal structural
type because of its ability to mimic the cellular effects of
paclitaxel.7 Much synthetic work has been devoted to
structural analogs of 1,8 although recently Sames reported
a new synthesis of ^)-19 that involves the use of a stoichio-
metric platinum complex dehydrogenation reaction to
functionalize a gem-diethyl group. The synthesis of ^)-
rhazinal 2 has also been recently described.10
sponding piperidone. N-Alkylation of 5 with 6 leads to 4
which is in the correct oxidation state to be directly
converted into 3. Conversion of the terminal alkene of 3
into a carboxyl group, followed by reduction of the nitro
group to an amine and lactamization provides rhazinilam.
While the synthesis of 5 described here is that of the
racemate, reported adaptations of chiral oxazolidinone tech-
nology11 could be used to synthesize 5 in an enantioenriched
form.12
The gem-dialkyl piperidone 5 was synthesized by stepwise
alkylation of 2-piperidone, Scheme 2. Treatment of 2-piper-
idone with n-BuLi 2.01 equiv., to form the dianion),
followed by excess ethyl iodide gave 7 90%).13 It was
found that this same protocol did not work satisfactorily
for the allylation, and in situ protection of the amide was
needed. Treatment of 7 with n-BuLi/Me3SiCl, followed by
The strategy depicted in Scheme 1 has the gem-alkyl
groups on the piperidine ring differentiated early in the
synthesis as 5, and introduced by alkylation of the corre-
i
LiNPr2 and a large excess of allyl bromide gave 5 61%) in
reasonable reproducible yields.
The next step requires annulation of a pyrrole ring onto an
amide. While the Grigg methodology14 is applicable to this
problem see Ref. 9), it would involve reduction of the
amide to an imine. Consequently, we examined the direct
conversion of the lactam 5 into the pyrrole 3 without
changing the oxidation state of 5. After unsuccessfully
experimenting with various iminoethers derived from 5, it
was found that treatment of the thiophenyl imino ether 8
with 2-nitrocinnamyl bromide, followed by 1,8-diaza-
bicyclo[5.4.0]undec-7-ene DBU) gave 3 71%) as a yellow
crystalline solid. This sequence of transformations provided
3 in four steps in an overall yield of 32%.
To complete the synthesis, 3 was converted into the
alcohol 9 using standard hydroboration reaction conditions
followed by oxidative work-up. Oxidation of 9 to the
aldehyde 10 was accomplished with pyridine/sulfur
trioxide/dimethylsulfoxide.15 Attempts to oxidize 10 to the
acid 11 using sodium chlorite also caused oxidation of the
Scheme 1.
Keywords: rhazinilam; alkylation; thiophenylimine; pyrrole.
Corresponding author. Tel.: 11-512-471-3966; fax: 11-512-471-7839;
e-mail: p.magnus@mail.utexas.edu
p
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020 01)00859-6

8648
P. Magnus, T. Rainey / Tetrahedron 57 ,2001) 8647±8651
Scheme 2.
Scheme 3.
pyrrole ring,16 whereas silver nitrate under alkaline condi-
tions Fehling's solution) converted 10 into 11 without any
complications. Finally, Raney nickel reduction of the nitro
group in 11 and treatment of the crude amino acid with 2-
chloro-1-methylpyridinium iodide/NEt3/PhMe Mukaiyama
conditions)17 gave ^)-rhazinilam 1 in 51% yield from 11
Scheme 3).
indicated solvent and are reported in ppm relative to tetra-
methylsilane and referenced internally to the residually
protonated solvent. 13C NMR spectra were recorded on a
General Electric QE-300 spectrometer at 75 MHz in the
solvent indicated and are reported in ppm relative to tetra-
methylsilane and referenced internally to the residually
protonated solvent. Mass spectra were obtained on a VG
ZAB2E or a Finnigan TSQ70. Routine monitoring of
reactions was performed using Merck 60 F254 silica gel,
aluminum-backed TLC plates. PLC was performed using
Merck 60 F254 silica gel, glass supported plates. Flash
column chromatography was performed with the indicated
eluents on Merck 60H F254 silica gel.
The synthesis of 1 proceeds through nine steps in 8% overall
yield.
1. Experimental
1.1. General
Solvents and commercial reagents were puri®ed in accor-
dance with Perrin and Armarego or used without further
puri®cation.
Melting points were taken on a Thomas±Hoover capillary
tube apparatus and are uncorrected. Infrared spectra were
recorded on a Nicolet FT-IR spectrophotometer neat unless
1.1.1. ꢀ^)-3-Ethyl-2-piperidone 7. A solution of n-butyl
lithium 2.14 M in hexanes, 21.4 mL, 45.7 mmol) was
added to a degassed solution of freshly distilled 2-piperidone
1
otherwise indicated. H NMR spectra were recorded on a
General Electric QE-300 spectrometer at 300 MHz in the

P. Magnus, T. Rainey / Tetrahedron 57 ,2001) 8647±8651
8649
2.25 g, 22.7 mmol) in anhydrous THF 50 mL) at 2788C
under an atmosphere of argon. The resulting pale yellow
solution was warmed to 08C and stirred for 1 h, and ethyl
iodide 2.73 mL, 34.1 mmol) was added dropwise. After
stirring the solution for a further 45 min. at 08C the mixture
was quenched with saturated aqueous ammonium chloride
10 mL), and extracted with CHCl3 3£20 mL). The
combined extracts were washed with saturated aqueous
NaCl 15 mL), dried Na2SO4), and evaporated in vacuo
to give a yellow oil. The crude oil was puri®ed by ¯ash
column chromatography SiO2, 100% EtOAc) to yield a
pale yellow crystalline solid. Rf 0.3 100% EtOAc). Bulb
to bulb distillation 1258C, 0.5 mmHg) afforded 7 as a white
crystalline solid 2.60 g, 90%.). Mp 62±638C hexanes). IR
evaporated in vacuo. The resulting residue was dissolved
in anhydrous THF 3.5 mL), to which was subsequently
added distilled triethylamine 2.44 mL, 17.5 mmol) and
distilled thiophenol 1.8 mL, 18 mmol.). After stirring the
mixture for 2.5 h. at room temperature the solution was
cooled to 08C, saturated aqueous NaHCO3 5 mL) was
added, and the mixture extracted with EtOAc 3£15 mL).
The combined extracts were washed with 1.25 M aqueous
NaOH 4£10 mL), water 15 mL), and saturated aqueous
NaCl 15 mL.), and dried Na2SO4). Evaporation of the
extracts in vacuo gave a green oil, which was puri®ed by
¯ash column chromatography SiO2, 5% EtOAc in hexanes)
to give 8 as a pale yellow oil 0.733 g, 81%). Rf 0.63 25%
EtOAc in hexanes). IR neat) 2964, 2934, 2855, 1627 cm21
.
thin ®lm) 3287, 3203, 3074, 2957, 2873, 1672 cm21. H
1H NMR 300 MHz, CDCl3) d 7.51±7.48 2H, m),
7.41±7.34 3H, m), 5.97±5.85 1H, m), 5.23±5.15 2H,
m), 3.53±3.48 2H, m), 2.67 1H, dd, Jˆ14.0, 6.3 Hz),
2.32 1H, dd, Jˆ14.0, 8.3 Hz), 1.96±1.86 1H, m), 1.75±
1.56 5H, m), 1.04 3H, t, Jˆ7.4 Hz.). 13C NMR 75 MHz,
CDCl3) d 171.7, 135.3, 134.2, 130.6, 128.6, 128.0, 118.0,
51.2, 45.2, 44.7, 32.5, 29.1, 20.0, 8.7 ppm. HRMS calcd for
C16H22NS MH1) 260.1473. Found 260.1478.
1
NMR 300 MHz, CDCl3) d 6.93 1H, br s), 3.28±3.21 2H,
m), 2.20±2.11 1H, m), 1.95±1.41 6H, m), 0.90 3H, t,
Jˆ7.5 Hz). 13C NMR 75 MHz, CDCl3) d 175.2, 42.2,
25.4, 24.3, 21.2, 11.2 ppm. HRMS calcd for C7H14NO
MH1) 128.1075. Found 128.1076.
1.1.2. ꢀ^)-3-Ethyl-3-allyl-2-piperidone 5. A solution of
n-butyl lithium 1.41 M in hexanes, 14.6 mL, 20.6 mmol)
was added to a degassed solution of 7 2.60 g, 20.4 mmol) in
anhydrous THF 60 mL) at 2788C under an atmosphere of
argon. The resulting canary yellow solution was warmed to
08C and stirred for 1.25 h, and freshly distilled trimethylsilyl
chloride 3.77 mL, 22.5 mmol) was added in one portion.
After stirring the mixture for a further 1.75 h at 08C a solu-
tion of lithium diisopropylamide [prepared by the addition
of a solution of n-butyl lithium in hexanes 1.41 M,
21.6 mL, 30.4 mmol) to a solution of distilled diisopropyl-
amine 4.29 mL, 30.6 mmol) in THF 15 mL) at 2788C,
followed by stirring at 08C for 20 min] was added in one
portion, and the resulting solution stirred at 08C for 45 min.
After cooling the mixture to 2788C, freshly distilled allyl
bromide 21 mL, 250 mmol) was added dropwise. The
mixture was warmed to 08C and stirred for a further
1.25 h. The mixture was quenched with saturated aqueous
NH4Cl 20 mL), extracted with CHCl3 3£150 mL), and the
combined extracts washed with 1 M aqueous HCl
2£15 mL), water 20 mL), and saturated aqueous NaCl
20 mL), and dried Na2SO4). Evaporation of the extracts
in vacuo gave a yellow oil. Puri®cation of the oil by ¯ash
column chromatography SiO2, 50% EtOAc in hexanes)
gave 5 as a pale yellow oil 2.09 g, 61%). Rf 0.2 50%
EtOAc in hexanes.). IR neat) 3204, 3071, 2939, 2869,
1.1.4. 2-Nitrocinnamyl bromide. Triphenylphosphine
5.53 g, 21.1 mmol) and carbon tetrabromide 7.00 g,
21.1 mmol) were added sequentially to a solution of 2-nitro-
cinnamyl alcohol 2.52 g, 14.0 mmol) in anhydrous CH2Cl2
50 mL) at 08C. The dark brown solution was stirred for one
hour at 08C, at which time it was concentrated in vacuo, and
adsorbed onto SiO2 for puri®cation. Flash column
chromatography SiO2, 5% EtOAc in hexanes) gave 2-nitro-
cinnamyl bromide 3.06 g, 90%) as a pale green oil which
solidi®ed upon cooling. Rf 0.51 25% EtOAc in hexanes).
Mp 34±358C. IR thin ®lm) 2960, 2920, 2850, 1521 cm21
.
1H NMR 300 MHz, CDCl3) d 7.96 1H, d, Jˆ8.3 Hz),
7.62±7.56 2H, m), 7.46±7.40 1H, m), 7.14 1H, d,
Jˆ15.4 Hz), 6.41±6.31 1H, m), 4.18±4.14 2H, m). 13C
NMR 75 MHz, CDCl3) d 147.8, 133.2, 131.5, 130.3,
129.3, 128.8, 128.7, 124.7, 32.0 ppm. HRMS calcd for
C9H9NO2Br MH1) 241.9817. Found 241.9819.
1.1.5. ꢀ^)-8-Ethyl-8-allyl-1-ꢀ2-nitrophenyl)-5,6,7,8-tetra-
hydroindolizine 3. A mixture of 8 0.743 g, 2.87 mmol)
and 2-nitrocinnamyl bromide 1.32 g, 5.46 mmol) in dry
toluene was azeotroped in vacuo three times 3£1 mL),
and the mixture was heated at 1008C under an atmosphere
of argon for 15 min. The dark brown colored mixture was
subsequently cooled to room temperature, dissolved in
anhydrous THF 10 mL), and cooled further to 08C.
Distilled 1,8-diazabicyclo[5.4.0]undec-7-ene 2.14 mL,
14.3 mmol) was added dropwise to the mixture, and the
solution allowed to warm to room temperature. The mixture
was poured into 5% aqueous NaHCO3 30 mL) and
extracted with EtOAc 3£15 mL). The combined extracts
were washed with saturated aqueous NaCl 15 mL), dried
Na2SO4), ®ltered, and the solvent evaporated in vacuo. The
residue was passed through a plug of SiO2 5% EtOAc in
hexanes), and the crude product was puri®ed by recrystalli-
zation from hexanes to give 3 0.631 g, 71%) as yellow
crystalline solid. Mp 105±1078C. Rf 0.6 25% EtOAc in
1
1650 cm21. H NMR 300 MHz, CDCl3) d 6.48 1H, br
s), 5.82±5.69 1H, m), 5.06±5.00 2H, m), 3.24±3.20 2H,
m), 2.45 1H, dd, Jˆ13.7, 8.1 Hz), 2.15 1H, dd, Jˆ13.7,
6.6 Hz), 1.79±1.63 5H, m), 1.52±1.40 1H, m), 0.86 3H, t,
Jˆ7.6 Hz.). 13C NMR 75 MHz, CDCl3) d 176.7, 134.6,
117.8, 44.8, 42.8, 42.7, 31.0, 28.6, 19.7, 8.6 ppm. HRMS
calcd for C10H18NO MH1) 168.1388. Found 168.1397.
1.1.3. ꢀ^)-3-Ethyl-3-allyl-2-thiophenyl-2-piperideine 8.
Phosphorous pentachloride 0.743 g, 3.57 mmol) was
added to a solution of 5 0.587 g, 3.51 mmol) in anhydrous
toluene 3.5 mL) under an atmosphere of argon. The result-
ing pale yellow solution was heated at re¯ux for 3 h, after
which time it was cooled to room temperature and concen-
trated in vacuo. The dark yellow colored residue was
redissolved in anhydrous toluene 5 mL) and solution
1
hexanes). IR thin ®lm) 2961, 2875, 1527 cm21. H NMR
300 MHz, CDCl3) d 7.80±7.78 1H, m), 7.52±7.38 3H,
m), 6.55 1H, d, Jˆ2.7 Hz), 6.06 1H, d, Jˆ2.7 Hz), 5.68±

8650
P. Magnus, T. Rainey / Tetrahedron 57 ,2001) 8647±8651
5.56 1H, m), 4.99±4.92 2H, m), 3.90 2H, t, Jˆ5.4 Hz),
2.33±2.27 1H, m), 2.05±1.72 3H, m), 1.69±1.66 2H, m),
1.50±1.32 2H, m), 0.75 3H, t, Jˆ7.0 Hz). 13C NMR
75 MHz, CDCl3) d 150.7, 135.7, 133.8, 133.7, 131.2,
130.9, 127.5, 123.5, 118.5, 117.0, 114.1, 110.6, 46.3, 46.1,
39.4, 33.8, 29.9, 20.8, 9.1 ppm. HRMS calcd for
C19H23N2O2 MH1) 311.1760. Found 311.1763.
aqueous solution of potassium hydroxide 1.0 M, 6.1 mL,
6.1 mmol). After stirring the mixture for 30 min the solution
was ®ltered through Celitew, washing the ®lter cake with
EtOAc 50 mL) and water 20 mL). The EtOAc layer of the
®ltrate was extracted with 1.5 MNaOH 4£10 mL) and the
combined aqueous extracts subsequently acidi®ed pH 3)
with the slow addition of a 2 M solution of H2SO4. The
solution was extracted with CHCl3 3£10 mL) and the
combined extracts washed with water 15 mL), followed
by saturated aqueous NaCl 10 mL), and dried Na2SO4).
The extract was evaporated in vacuo to give 11 0.329 g,
94%) as a yellow crystalline solid, which was used without
further puri®cation. Rf 0.45 50% EtOAc in hexanes). Mp
174±1758C. IR thin ®lm) 2951, 2876, 1706, 1526 cm21. 1H
NMR 300 MHz, CDCl3) d 9.50 1H, br s), 7.78 1H, dd,
Jˆ1.0, 8.0 Hz), 7.61±7.37 3H, m), 6.54 1H, d, Jˆ2.6 Hz),
6.02 1H, d, Jˆ2.6 Hz), 3.93±3.88 2H, m), 2.27 2H, t,
Jˆ8.1 Hz), 1.97±1.82 2H, m), 1.75±1.38 6H, m), 0.77
3H, m). 13C NMR 75 MHz, CH3OD) d 177.7, 152.2,
134.8, 134.5, 132.2, 131.4, 128.8, 124.5, 120.0, 115.7,
111.5, 47.1, 40.5, 37.8, 36.3, 31.5, 31.0, 22.7, 9.5 ppm.
HRMS calcd for C19H23N2O4 MH1) 343.1658. Found
343.1649.
1.1.6.
ꢀ^)-8-Ethyl-8-ꢀ3-hydroxypropyl)-1-ꢀ2-nitro-
phenyl)-5,6,7,8-tetrahydroindolizine 9. Borane±THF
complex 1.0 M in THF, 4.0 mL, 6.0 mmol) was added in
one portion to a solution of 3 0.622, 2.00 mmol) in
anhydrous THF 13.5 mL) at 08C under an atmosphere of
argon. After stirring the mixture at 08C for 1 h, NaOH
3.0 M aqueous, 6.0 mL, 18 mmol) was added dropwise,
resulting in the vigorous evolution of gas. Hydrogen
peroxide 30% aqueous, 2.1 mL, 18 mmol) was added to
the mixture, and the resulting solution stirred for a further
30 min. The mixture was warmed to room temperature,
poured into water 50 mL), and extracted with EtOAc
4£20 mL). The combined extracts were dried Na2SO4),
®ltered, and concentrated in vacuo. The residue was puri®ed
by ¯ash column chromatography 25±50% EtOAc in
hexanes) to give 9 as a yellow oil 0.513 g, 78%). Rf 0.10
25% EtOAc in hexanes). IR neat) 3378, 2940, 2873,
1.1.9. ꢀ^)-Rhazinilam 1. Raney nickel ca. 0.5 g, washed
with methanol) was added to a solution of 11 0.329 g,
0.961 mmol) in anhydrous methanol 15 mL), followed by
hydrogenation at 20 psi H2 pressure in a Parr shaker until
complete by TLC ca. 1.5 h). The mixture was ®ltered
through Celitew and concentrated in vacuo to give the
crude amino acid as a yellow foam 0.295 g, 98%). A solu-
tion of the crude amino acid in a mixture of toluene
28.5 mL), THF 19 mL), and triethylamine 1.7 mL,
12 mmol) was added via syringe pump to a solution of
triethylamine 2.5 mL, 18 mmol) and 2-chloro-1-methyl-
pyridinium iodide 2.549 g, 9.98 mmol) in anhydrous
toluene 47 mL) over a period of 5 h. After stirring the
mixture for a further 2 h at room temperature, the solution
was ®ltered and the ®ltrate concentrated in vacuo. Puri®ca-
tion of the residue by ¯ash column chromatography SiO2,
50% EtOAc in hexanes) gave 1 0.145 g, 51%) as a white
crystalline solid. Mp 215.5±216.58C. Rf 0.18 50% EtOAc
in hexanes). IR thin ®lm) 3169, 3047, 2957, 2920,
1
1522 cm21. H NMR 300 MHz, CDCl3) d 7.75 1H, d,
Jˆ7.3 Hz), 7.51±7.36 3H, m), 6.53 1H, d, Jˆ2.6 Hz),
6.05 1H, d, Jˆ2.6 Hz), 3.89 2H, t, Jˆ5.9 Hz), 3.42±3.41
2H, m), 1.95±1.87 2H, m), 1.76±1.61 2H, m), 1.51±1.25
7H, m), 0.75 3H, t, Jˆ7.1 Hz). 13C NMR 75 MHz,
CDCl3) d 150.7, 133.7, 133.6, 131.4, 130.9, 127.4, 123.4,
118.5, 113.8, 110.7, 63.4, 46.1, 39.3, 37.6, 34.7, 30.1, 28.1,
21.2, 9.1 ppm. HRMS calcd for C19H25N2O3 MH1)
329.1865. Found 329.1868.
1.1.7.
ꢀ^)-3-[1-ꢀ2-Nitrophenyl)-8-ethyl-5,6,7,8-tetra-
hydroindolizin-8-yl]-propionaldehyde 10. Pyridine±
sulfur trioxide complex 0.765 g, 4.80 mmol) was added
in one portion to a solution of 9 0.513 g, 1.61 mmol) in a
mixture of DMSO 10 mL), THF 1.6 mL), and triethyl-
amine 1.6 mL) under an atmosphere of argon. After stirring
the mixture for 45 min the solution was poured into water
30 mL) and extracted with CHCl3 4£15 mL). The
combined extracts were dried Na2SO4), ®ltered, and the
solvent evaporated in vacuo. Puri®cation by ¯ash column
chromatography 10±25±50% EtOAc in hexanes) gave 10
as a crystalline yellow solid 0.334 g, 66%). Mp 102±
1038C. Rf 0.52 50% EtOAc in hexanes). IR thin ®lm)
1
1670 cm21. H NMR 300 MHz, CDCl3) d 7.42 1H, dd,
Jˆ2.1, 6.8 Hz), 7.36±7.28 2H, m), 7.19 1H, dd, Jˆ1.3,
7.0 Hz), 6.83 1H, s), 6.49 1H, d, Jˆ2.6 Hz), 5.74 1H, d,
Jˆ2.6 Hz), 4.01 1H, dd, Jˆ5.1, 11.9 Hz), 3.78 1H, dt,
Jˆ4.7, 11.9 Hz), 2.49±2.32 2H, m), 2.27±2.20 1H, m),
1.98±1.82 2H, m), 1.71 1H, dt, Jˆ3.0, 13.3 Hz), 1.56±
1.40 3H, m), 1.30±1.21 2H, m), 0.71 3H, t; Jˆ7.3 Hz).
13C NMR 75 MHz, CDCl3) d 177.3, 140.3, 138.1, 131.3,
130.5, 127.9, 127.1, 126.7, 119.0, 117.3, 109.5, 46.0, 38.8,
36.5, 33.0, 30.1, 28.1, 19.4, 8.1 ppm. HRMS calcd for
C19H23N2O MH1) 295.1810. Found 295.1814. Identical
mp, IR, 1H NMR, 13C NMR , HRMS, tlc) with a synthetic
sample. The spectral data are in good agreement with litera-
ture data for the natural product.
1
2960, 2876, 2721, 1721, 1526 cm21. H NMR 300 MHz,
CDCl3) d 9.58 1H, s), 7.73 1H, d, Jˆ7.7 Hz), 7.51±7.36
3H, m), 6.54 1H, d, Jˆ2.7 Hz), 6.01 1H, d, Jˆ2.7 Hz),
3.90 2H, t, Jˆ5.6 Hz), 2.36±2.31 2H, m), 1.98±1.80 2H,
m), 1.78±1.38 6H, m), 0.79 3H, t, Jˆ6.5 Hz). 13C NMR
75 MHz, CDCl3) d 202.3, 150.5, 133.3, 131.0, 130.3,
127.6, 123.4, 118.9, 114.2, 110.5, 45.9, 39.9, 39.0, 35.0,
32.6, 30.0, 21.0 9.0 ppm. HRMS calcd for C19H23N2O3
MH1) 327.1709. Found 327.1704.
1.1.8.
ꢀ^)-3-[1-ꢀ2-Nitrophenyl)-8-ethyl-5,6,7,8-tetra-
hydroindolizin-8-yl]-propionic acid 11. A solution of
silver nitrate 0.282 g, 1.66 mmol) in water 1 mL) was
added to a solution 10 0.334 g, 1.02 mmol) in absolute
ethanol 10 mL), followed by the dropwise addition of an
Acknowledgements
The National Institutes of Health GM 32718), The Robert
A. Welch Foundation, Merck Research Laboratories and

P. Magnus, T. Rainey / Tetrahedron 57 ,2001) 8647±8651
8651
10. Banwell, M.; Edwards, A.; Smith, J.; Hamel, E.; Verdier-
Pinard, P. J. Chem. Soc., Perkin Trans. 1 2000, 1497.
11. Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979,
101, 6120. Evans, D. A.; Dow, R. L. Tetrahedron Lett. 1986,
27, 1007.
Novartis are thanked for their support of this research.
Professor Dalibor Sames is thanked for a sample and spectra
of synthetic ^)-rhazinilam.
12. Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.;
Koo, B.-A.; Kim, H.-S. Angew. Chem., Int. Ed. Engl. 1999, 38,
3545. Mavunkel, B. J.; Lu, Z.; Kyle, D. J. Tetrahedron Lett.
1993, 34, 2255.
References
1. Banerji, A.; Majumder, P. L.; Chatterjee, A. G. Phytochemistry
1970, 9, 1491.
2. Linde, H. H. A. Helv. Chim. Acta 1965, 48, 1822.
13. Padwa, A.; Harring, S. R.; Semones, M. A. J. Org. Chem.
1998, 63, 44.
Â
Â
3. Thoison, O.; Guenard, D.; Sevenet, T.; Kan-Fan, C.; Quirion,
J.-C.; Husson, H.-P.; Deverre, J.-R.; Chan, K. C.; Potier, P.
C. R. Acad. Sci. Paris II 1987, 304, 157.
14. Grigg, R.; Myers, P.; Somasunderam, A.; Sridharan, V.
Tetrahedron 1992, 48, 9735.
15. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505.
4. De Silva, K. T.; Ratcliffe, A. H.; Smith, G. F.; Smith, G. N.
Tetrahedron Lett. 1972, 913.
16. The sodium chlorite procedure caused oxidation of the pyrrole
ring to give 11a, which readily lactonized to give 11b.
5. Abraham, D. J.; Rosenstein, R. D.; Lyon, R. L.; Fong, H. H. S.
Tetrahedron Lett. 1972, 909.
6. Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett.
1973, 5179.
Â
Â
7. Alazard, J.-P.; Millet-Paillusson, C.; Boye, O.; Guenard, D.;
Chiaroni, A.; Riche, C.; Thal, C. Bioorg. Med. Chem. Lett.
1991, 1, 725.
Â
Â
8. Dupont, C.; Guenard, D.; Thal, C.; Thoret, S.; Gueritte, F.
Tetrahedron Lett. 2000, 41, 5853. Ghosez, L.; Cuisinier, C.;
Denonne, F.; Franc, C. Tetrahedron Lett. 1999, 40, 4555.
Â
Pascal, C.; Dubois, J.; Guenard, D.; Tchertanov, L.; Thoret,
Â
S.; Gueritte, F. Tetrahedron 1998, 54, 14737. Dupont, C.;
 Â
Guenard, D.; Tchertanov, L.; Thoret, S.; Gueritte, F. Bioorg.
Â
Med. Chem. 1999, 7, 2961. David, B.; Sevenet, T.; Thoison,
Â
O.; Awang, K.; Paõs, M.; Wright, M.; Guenard, D. Bioorg.
È
Med. Chem. Lett. 1997, 7, 2155. Pasquinet, E.; Rocca, P.;
 Â
Richalot, S.; Gueritte, F.; Guenard, D.; Godard, A.; Marsais,
Â
F.; Queguiner, G. J. Org. Chem. 2001, 66, 2654.
9. Sames, D.; Johnson, J. A. J. Am. Chem. Soc. 2000, 122, 6321.
17. Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163.