Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Synthesis of (-)-Septicine and (-)-Tylophorine

Article abstract of DOI:10.1021/jo9711495

A concise asymmetric synthesis of (-)-septicine (1) and (-)-tylophorine (2) was accomplished with a high degree of stereocontrol in eight and nine steps, respectively. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 3, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of (-)-trans-2-(α-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 7. Oxidative cleavage of 7 and subsequent reduction provided alcohol 6 in 81% yield. Conversion of 6 to the chloride followed by treatment with sodium methoxide gave indolizidinone 9 in high yield. Bromination and conjugate reduction of 9 with L-Selectride, and trapping the intermediate enolate with N-(5-chloro-2-pyridyl)triflimide, provided bromovinyl triflate 11. Palladium-catalyzed cross-coupling of excess (3,4-dimethoxyphenyl)zinc bromide and 11 gave (-)-septicine (1). On the basis of this synthesis, (-)-1 was assigned the R configuration. Reaction of 1 with vanadium(V) trifluoride oxide in TFA/CH₂Cl₂ effected oxidative coupling to give a 68% yield of (-)-tylophorine (2).

Full text of DOI:10.1021/jo9711495

J . Org. Chem. 1997, 62, 7435-7438
7435
En a n tiop u r e N-Acyld ih yd r op yr id on es a s Syn th etic In ter m ed ia tes:
Asym m etr ic Syn th esis of (-)-Sep ticin e a n d (-)-Tylop h or in e
Daniel L. Comins,* Xinghai Chen, and Lawrence A. Morgan
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
Received J une 24, 1997X
A concise asymmetric synthesis of (-)-septicine (1) and (-)-tylophorine (2) was accomplished with
a high degree of stereocontrol in eight and nine steps, respectively. Addition of 4-(1-butenyl)mag-
nesium bromide to 1-acylpyridinium salt 3, prepared in situ from 4-methoxy-3-(triisopropylsilyl)py-
ridine and the chloroformate of (-)-trans-2-(R-cumyl)cyclohexanol, gave a 91% yield of diastereo-
merically pure dihydropyridone 7. Oxidative cleavage of 7 and subsequent reduction provided
alcohol 6 in 81% yield. Conversion of 6 to the chloride followed by treatment with sodium methoxide
gave indolizidinone 9 in high yield. Bromination and conjugate reduction of 9 with L-Selectride,
and trapping the intermediate enolate with N-(5-chloro-2-pyridyl)triflimide, provided bromovinyl
triflate 11. Palladium-catalyzed cross-coupling of excess (3,4-dimethoxyphenyl)zinc bromide and
11 gave (-)-septicine (1). On the basis of this synthesis, (-)-1 was assigned the R configuration.
Reaction of 1 with vanadium(V) trifluoride oxide in TFA/CH2Cl2 effected oxidative coupling to give
a 68% yield of (-)-tylophorine (2).
The indolizidine alkaloid septicine (1) was isolated by
Russel1 from Ficus septica, a plant belonging to the
Moraceae family, and is considered to be a biogenetic
precursor to the phenanthroizidine alkaloid, tylophorine
(2). Tylophorine has also been found in various plants
of the Asclepiadarceae family.1 The configuration at
C-13a in naturally occurring (-)-tylophorine (2) was
originally assigned to be S on the basis of correlation to
degradation products.2 The stereochemistry at C-13a of
2 was latter revised to R since synthetic (S)-tylophorine
had a positive rotation and CD.3
us to prepare racemic septicine and tylophorine in five
and six steps, respectively.7f We now report a modifica-
tion of our racemic synthesis which incorporates our
recently developed enantioselective preparation of 2-alkyl-
2,3-dihydro-4-pyridones.10 This approach has allowed us
to prepare (-)-septicine and (-)-tylophorine in a concise
asymmetric fashion.
Our synthetic plan called for the preparation of enan-
tiopure dihydropyridone 6. Initially, we investigated the
addition of Grignard reagent 4 to chiral 1-acylpyridinium
salt 3, which was prepared in situ from 4-methoxy-3-
(triisopropylsilyl)pyridine11 and the chloroformate of (-)-
trans-2-(R-cumyl)cyclohexanol (TCC)12 (Scheme 1). The
crude dihydropyridone product 5 was reduced to give a
Septicine isolated from F. septica and from Tylophora
crebriflora has been reported to have a negative rotation;
however, (+)-septicine has been found in extracts of T.
asthmatica.4 The only enantioselective synthesis of
septicine was reported in 1969 by Russel and Hunziker.5
Their synthesis used L-prolinol as a building block and
(7) Syntheses of (()-septicine: (a) Govindachari, T. R.; Viswanethan,
N. Tetrahedron 1970, 26, 715. (b) Stevens, R. V.; Luh, Y. Tetrehedron
Lett. 1977, 979. (c) Iwashita, T.; Suzuki, M.; Kusumi, T.; Kakisawa,
H. Chem. Lett. 1980, 383. (d) Cragg, J . E.; Herbert, R. B.; J ackson, F.
B.; Moody, C. J .; Nicolson, I. T. J . Chem. Soc., Perkin Trans. 1 1982,
2477. (e) Iida, H.; Watanabe, Y.; Tanaka, M.; Kibayashi, C. J . Org.
Chem. 1984, 49, 2412. (f) Comins, D. L.; Morgan, L. A., Tetrahedron
Lett. 1991, 32, 5919. (g) Verxa, B. R.; Yang, K.; Moore, H. W.
Tetrahedron 1994, 50, 6173. (h) Ciufolini, M. A.; Roschangar, F. J . Am.
Chem. Soc. 1996, 118, 12082.
(8) Syntheses of (()-tylophorine: (a) Govindachari, T. R.; Laksmi-
kantham, M. V.; Rajadurai, S. Tetrahedron 1961, 14, 284-287. (b)
Herbert, R. B.; Moody, C. J . J . Chem. Soc. D 1970, 2, 121. (c) Chauncy,
B.; Gellert, E. Aust. J . Chem. 1970, 23, 2503. (d) Liepa, A. J .; Summons,
R. E. J . Chem. Soc., Chem. Commun. 1977, 826. (e) Weinreb, S. M.;
Khatri, N. A.; Shringarpure, J . J . Am. Chem. Soc. 1979, 101, 5073. (f)
Mangla, V. K.; Bhakuni, D. S. Tetrahedron 1980, 36, 2489. (g) Khatri,
N. A.; Schmitthenner, H. F.; Shringarpure, J .; Weinreb, S. M. J . Am.
Chem. Soc. 1981, 103, 6387. (h) Cragg, J . E.; Herbert, R. B.; J ackson,
F. B.; Moody, C. J .; Nicholson, I. T. J . Chem. Soc., Perkin Trans. 1
1982, 2477. (i) Iida, H.; Tanaka, M.; Kibayashi, C. J . Chem. Soc., Chem.
Commun. 1983, 271. (j) Iida, H.; Watanabe, Y.; Tanaka, M.; Kibayashi,
C. J . Org. Chem. 1984, 49, 2412. (k) Ihara, M.; Tsuruta, M.; Fukumoto,
K.; Kametani, T. J . Chem. Soc., Chem. Commun. 1985, 1159. (l)
Comins, D. L.; Morgan, L. A. Tetrahedron Lett. 1991, 32, 5919. (m)
Pearson, W. H.; Walavalkar, R. Tetrahedron Lett. 1994, 50, 12293. (n)
Reference 7h.
produced (-)-septicine ([R]22 -16.2), which apparently
D
assigned the stereochemistry of (-)-1 as S.
The phenanthoindolizidine alkaloids, i.e., 2, exhibit a
wide range of biological properties including antitumor
activity.1,6 A considerable amount of synthetic work has
produced a variety of racemic syntheses of both septicine
and tylophorine.7,8 In contrast, only one preparation of
(-)-septicine,5 two syntheses of unnatural (+)-tylopho-
rine,3 and one asymmetric synthesis of (-)-tylophorine
have been reported.9 Our approach to alkaloid synthesis
using N-acyldihydropyridones as building blocks allowed
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) Reviews: (a) Gellert, E. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; J ohn Wiley & Sons: New York, 1987;
Vol. 5, p 55. (b) Suffness, M.; Cordell, G. A. In The Alkaloids; Brossi,
A., Ed.; Academic Press: Orlando, FL, 1985; Vol. 25, Chapter 1, pp
3-355.
(2) Giovindachari, T. R.; Rajagopalan, T. G. J .; Viswanathan, N. J .
J . Chem. Soc., Perkin Trans. 1 1974, 1161.
(3) (a) Buckley, T. F., III; Rapoport, H. J . Org. Chem. 1983, 48, 4222.
(b) Nordlander, J . E.; Njoroge, F. G. J . Org. Chem. 1987, 52, 1627. (c)
Abe, F.; Iwase, Y.; Yamauchi, T.; Honda, K.; Hayashi, N. Phytochem-
istry 1995, 39, 695.
(9) Ihara, M.; Takino, Y.; Tomotake, M.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1990, 2287.
(4) (a) Rao, K. V.; Wilson, R.; Cummings, B. J . Pharm. Sci. 1970,
59, 1501. (b) Govindachari, T. R.; Viswanathan, N.; Radhakrishnan,
J .; Pai, B. R.; Natarajan, S.; Subramaniam, P. S. Tetrahedron Lett.
1973, 29, 891.
(5) Russel, J . H.; Hunziker, H. Tetrahedron Lett. 1969, 25, 4035.
(6) Duan, J .; Yu, L. Zhongcaoyao 1991, 22, 316; Chem. Abstr. 1992,
116, 386u.
(10) (a) Comins, D. L.; J oseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J ., Ed.; J AI Press, Inc.: Greenwich, CT, 1996;
Vol. 2, pp 251-294. (b) Comins, D. L.; Zhang, Y. J . Am. Chem. Soc.
1996, 118, 12248 and references cited therein.
(11) (a) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem.
Soc. 1994, 116, 4719. (b) Comins, D. L.; Guerra-Weltzien, L. Tetrahe-
dron Lett. 1996, 37, 3807.
S0022-3263(97)01149-3 CCC: $14.00 © 1997 American Chemical Society

7436 J . Org. Chem., Vol. 62, No. 21, 1997
Comins et al.
Sch em e 1
Sch em e 2
57% overall yield of 6. Although this route was quite
convenient, the diastereoselectivity was only 65%. This
is low in contrast to similar reactions with most other
primary Grignard reagents where the de is usually in
the 90-95% range.11 The decreased degree of asym-
metric induction must be due to the presence of a
coordinating oxygen atom in the Grignard reagent.
Although we had previously been successful in using
similar functionalized Grignards, a less practical chiral
auxiliary was required in order to obtain a high de.13 An
alternative route to alcohol 6 was investigated as shown
in Scheme 2. The Grignard reagent prepared from
commercially available 4-bromo-1-butene was added to
chiral 1-acylpyridinium salt 3 using our standard condi-
tions.11 This time the desired crude product 7 was
obtained in 90% de. Recrystallization from methanol and
chromatography of the mother liquor gave a 91% yield
of diastereomerically pure 7. Oxidative cleavage and
subsequent reduction of the crude aldehyde with L-
Selectride provided alcohol 6 in 81% yield. Conversion
of 6 to chloride 8 was carried out in 96% yield using
triphenylphosphine and N-chlorosuccinimide.14 On treat-
ment of 8 with sodium methoxide in methanol, the chiral
auxiliary (TCC) was removed and concomitant cyclization
occurred to give indolizidinone 9 in 91% yield. In
addition, the chiral auxiliary, (-)-TCC, was recovered
(92%) during the purification step. Bromodesilylation of
9 using pyridinium bromide perbromide efficiently pro-
vided bromide 10. Conjugate reduction with L-Selectride
followed by addition of N-(5-chloro-2-pyridyl)triflimide15
gave a 71% yield of bromovinyl triflate 11. Palladium-
catalyzed cross-coupling of excess (3,4-dimethoxyphe-
nyl)zinc bromide and 11 provided (-)-septicine (1). The
Sch em e 3
value significantly higher than those reported for the
natural material ([R]D -16 to -42). In addition, our
synthesis allows us to assign the absolute configuration
of (-)-1 as R, not S as is suggested by previous synthetic
work.5 The stereochemical assignment was further
confirmed by conversion of (-)-1 to (R)-(-)-tylophorine
(2) as discussed below.
Reaction of our synthetic (-)-septicine with vana-
dium(V) trifluoride oxide in TFA/CH2Cl2 at room tem-
perature effected oxidative coupling to provide a 68%
yield of (-)-tylophorine (2) as a yellow solid (Scheme 3).
specific rotation of our synthetic 1 was [R]28 -172, a
D
The melting point, specific rotation ([R]30 -76), and
D
(12) (a) Comins, D. L.; Salvador, J . M. Tetrahedron Lett. 1993, 34,
801. (b) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656.
(13) Comins, D. L.; Hong, H. J . Am. Chem. Soc. 1991, 113, 6672.
(14) Comins, D. L.; Zeller, E. Tetrahedron Lett. 1991, 32, 5889 and
references cited therein.
(15) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299. (b) Comins, D. L.; Dehghani, A.; Foti, C. J .; J oseph, S. P. Org.
Synth. 1996, 74, 77.
NMR data were in agreement with literature values.
This synthetic work has again demonstrated the
versatility of enantiopure 2,3-dihydro-4-pyridones as
building blocks for the concise asymmetric synthesis of
alkaloids. The synthetic route is highly stereoselective
and efficient, allowing (-)-septicine and (-)-tylophorine

Synthesis of (-)-Septicine and (-)-Tylophorine
J . Org. Chem., Vol. 62, No. 21, 1997 7437
dropwise at 0 °C. The mixture was stirred for 20 min at room
temperature, 1 h at 0 °C, and 2 h at room temperature.
In a separate flask, to a solution of 4-methoxy-3-(triiso-
propylsilyl)pyridine11a (2.92 g, 11 mmol) in 20 mL of anhydrous
toluene was added a solution of the chloroformate of (-)-trans-
2-(R-cumyl)cyclohexanol (3.24 g, 11.55 mmol) in 20 mL of
anhydrous toluene at -42 °C. The reaction mixture was
stirred at -42 °C for 1.5 h and then cooled to -78 °C. The
previously prepared Grignard reagent was transferred drop-
wise via a double-tipped stainless steel needle to the flask
containing the newly formed chiral N-acylpyridinium salt
solution, and stirring was continued at -78 °C for 4 h.
Saturated aqueous oxalic acid (30 mL) was added. The
reaction mixture was warmed to rt and stirred overnight. The
aqueous layer was extracted with diethyl ether. The combined
organic extracts were washed with brine and dried over
anhydrous K2CO3. Filtration and concentration in vacuo gave
7.24 g (90% de) of the desired crude product. Crystallization
from 5% H2O/MeOH yielded 4.80 g (100% de) of desired (2R)-
2,3-dihydro-4-pyridone 7. The mother liquid was concentrated
and purified by radical PLC (silica gel, 2-5% EtOAc/hexanes)
to be prepared from readily available 4-methoxy-3-
(triisopropylsilyl)pyridine in eight and nine steps, re-
spectively. Our asymmetric synthesis of (-)-septicine has
established the absolute stereochemistry of this alkaloid
as R, and the specific rotation of the synthetic material
indicates that the natural septicine is isolated or present
in the plant in low enantiomeric purity.
Exp er im en ta l Section
2(R)-(3′-(Ben zyloxy)p r op yl)-1-[(((1R,2S)-2-(r-cu m yl)cy-
cloh exyl)oxy)ca r bon yl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-
4-p yr id on e (5). Magnesium turnings (340 mg, 14 mmol) were
mechanically stirred at rt overnight under argon, and then 2
mL of anhydrous THF was added to the flask. Benzyl
3-bromopropyl ether (0.71 mL, 4 mmol) was added dropwise
at 0 °C. The mixture was stirred 20 min at rt and then 4 h at
0 °C. In a separate flask, the chloroformate of (-)-trans-2-(R-
cumyl)cyclohexanol (TCC) (589 mg, 2.1 mmol) in 6 mL of
anhydrous toluene was added to a solution of 4-methoxy-3-
(triisopropylsilyl)pyridine11a (531 mg, 2 mmol) in 10 mL of
toluene at -42 °C. The reaction mixture was stirred at -42
°C for 1 h and then cooled to -78 °C. THF (4 mL) was added,
and the mixture was stirred for 1 h at -78 °C. The previously
prepared Grignard reagent was transferred dropwise via a
double-tipped stainless steel needle to the flask containing the
newly formed chiral N-acylpyridinium salt solution at -78 °C
over a period of 1 h, and the resulting solution was stirred for
1.5 h at -78 °C. Saturated aqueous oxalic acid (10 mL) was
added, the reaction mixture was warmed to room temperature,
and the mixture was stirred 0.5 h. The aqueous layer was
extracted with diethyl ether. The combined organic extracts
were washed with brine and dried over anhydrous K2CO3.
Filtration and concentration in vacuo gave 2.05 g of the crude
product. (This crude material was used directly in the next
step.) Purification by radial PLC (silica gel, 10% EtOAc/
to yield another 0.85 g (99.8% de) of 7: mp 117-8 °C; [R]25
D
-62.3 (c 0.975, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.71 (br
s, 1 H), 7.23-7.38 (m, 5 H), 7.11 (t, 1 H, J ) 6.6 Hz), 5.63 (m,
1 H), 5.05-4.80 (m, 3 H), 2.77 (br s, 1 H), 2.43-1.65 (series of
m, 8 H), 1.40-1.17 (m, 15 H), 1.05 and 1.01 (dd, 18 H, J ) 7.4
Hz); 13C (75 MHz, CDCl3) δ 196.7, 152.5, 152.2 (due to
rotamer), 147.4, 137.1, 128.1, 125.1, 115.2, 110.2, 78.1, 51.1,
40.1, 39.5, 33.5, 30.7, 30.0, 29.5, 26.8, 25.8, 24.6, 21.7, 18.84,
18.78, 11.1. Anal. Calcd for C34H53NO3Si: C, 74.00; H, 9.68;
N, 2.54. Found: C, 73.93; H, 9.68; N, 2.53.
2(R)-(3′-Hyd r oxyp r op yl)-1-[(((1R,2S)-2-(r-cu m yl)cyclo-
h exyl)oxy)ca r bon yl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-
p yr id on e (6) fr om 7. A stirred solution of 7 (1.04 g, 1.88
mmol) in 80 mL of H2O/THF (1:1) was treated with NaIO4 (3.66
g, 17.1 mmol) and OsO4 (0.12 mL, 0.0196 mmol, 4 wt % in
H2O), and stirring was continued for 19 h at room temperature.
The reaction mixture was filtered through Celite and extracted
with methylene chloride. The organic extracts were dried over
anhydrous K2CO3. Filtration and concentration in vacuo gave
a clear oil that was treated with L-Selectride (2.1 mL, 2.1
mmol, 1.0 M solution in THF) in 80 mL of anhydrous THF at
-78 °C. After 2 h of stirring, 5 mL of water and 1 g of sodium
perborate tetrahydrate (NaBO3‚4H2O) were added and stirring
was continued for 6 h as the reaction mixture warmed to room
temperature. The aqueous layer was extracted with ether. The
combined organic extracts were washed with brine and dried
over anhydrous K2CO3. Filtration, concentration, and purifi-
cation by radial PLC (silica gel, 30-50% EtOAc/hexane)
yielded 851 mg (81%) of the desired dihydropyridone 6.
2(R)-(3′-Ch lor op r op yl)-1-[(((1R,2S)-2-(r-cu m yl)cyclo-
h exyl)oxy)ca r bon yl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-
p yr id on e (8). To a stirred solution of dihydropyridone 6 (0.97
g, 1.75 mmol) in 20 mL of anhydrous dichloromethane at -23
°C was added triphenylphosphine (0.92 g, 3.43 mmol). N-
Chlorosuccinimide (0.47 g, 3.43 mmol) was added at -23 °C,
and the mixture was stirred for 1 h. After being warmed to
25 °C, the reaction mixture was stirred for another 2 h and
then quenched with methanol (0.2 mL). After removal of the
solvent, the residue was dissolved in ethyl ether. Filtration,
concentration, and purification by radial PLC (silica gel, 20%
EtOAc/hexane) yielded 0.96 g (96%) of the desired chloroalkyl-
hexanes) gave 5 as white needles: mp 73.6-74.5 °C; [R]24
D
-48.1 (c 0.585, CHCl3); IR (KBr) 2939, 2861, 1716, 1659 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.72 (br s, 1 H), 7.38-7.24 (m,
10 H), 7.11 (t, 1 H, J ) 6.8 Hz), 4.85 (br s, 1 H), 4.47 (s, 2 H),
3.34 (br s, 2 H), 2.71 (br s, 1 H), 2.45-2.33 (m, 1 H), 2.28-
2.16 (m, 1 H), 2.05-1.90 (m, 3 H), 1.82-1.66 (m, 2 H), 1.36-
1.17 (m, 16 H), 1.05 and 1.01 (dd due to rotamer, 18 H, J )
7.5 Hz); 13C (75 MHz, CDCl3) δ 196.8, 152.23, 152.18 (rotamer),
147.4, 147.3 (rotamer), 138.5, 128.3, 128.1, 127.7, 127.4, 125.1,
110.2, 78.1, 72.8, 69.7, 51.4, 51.0 (rotamer), 40.4, 39.4, 33.4,
30.9, 27.5, 26.8, 25.8, 24.6, 21.6, 18.9, 18.8, 11.1. Anal. Calcd
for C40H59NO4Si: C, 74.37; H, 9.21; N, 2.17. Found: C, 74.28;
H, 9.26; N, 2.18.
2(R)-(3′-Hyd r oxyp r op yl)-1-[(((1R,2S)-2-(r-cu m yl)cyclo-
h exyl)oxy)ca r bon yl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-
p yr id on e (6). A flask containing a solution of crude 5 (2.05
g) in 50 mL of absolute ethanol at rt was purged with argon.
To this solution was added 0.81 g (40% by weight) of palladium
hydroxide (Pearlman’s catalyst, 20% on carbon/31% H2O). The
mixture was stirred for 14 h under hydrogen at balloon
pressure. Filtration and concentration in vacuo gave the
desired crude product (63.5% de). Purification by radical PLC
(silica gel, 30-50% EtOAc/hexanes) yielded 633 mg (99.8% de)
of desired 6 as a white solid: mp 122-3 °C; [R]27 -98.1 (c
D
0.995, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.71 (s, 1 H),
7.34-7.14 (m, 5 H), 7.11 (t, 1 H, J ) 6.7 Hz), 4.86 (m, 1 H),
3.49 (d, 3 H, J ) 5.5 Hz), 2.65 (br s, 1 H), 2.40-1.63 (series of
m, 7 H), 1.46-1.09 (m, 16 H), 1.04 and 1.01 (dd, 18 H, J ) 7.5
Hz); 13C (75 MHz, CDCl3) δ 196.9, 152.7, 152.1 (due to
rotamer), 147.4, 128.0, 125.1, 110.2, 78.2, 62.2, 51.2, 50.9, 40.3,
39.4, 33.4, 30.9, 28.5, 26.9, 25.8, 24.6, 21.4, 18.81, 18.74, 11.1.
Anal. Calcd for C33H53NO4Si: C, 71.30; H, 9.61; N, 2.52.
Found: C, 71.36; H, 9.58; N, 2.48.
dihydopyridone 5 as a white solid: mp 117-118 °C; [R]25
D
-61.3 (c 0.955, CHCl3); IR (KBr) 2941, 2864, 1715, 1659 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.71 (br s, 1 H), 7.36-7.26 (m, 5
H), 7.11 (t, 1 H, J ) 6.6 Hz), 4.85 (br s, 1 H), 3.37 (br s, 2 H),
2.57 (br s, 1 H), 2.36-1.56 (series of m, 7 H), 1.36-1.24 (m, 16
H), 1.04 and 1.00 (dd due to rotamer, 18 H, J ) 7.5 Hz); 13C
NMR (CDCl3, 75 MHz) δ 196.6, 152.9, 152.1 (rotamer), 147.3,
128.1, 125.1, 124.9, 110.4, 78.4, 50.9, 50.7 (rotamer), 44.2, 40.4,
39.4, 33.4, 31.2, 28.5, 27.8, 26.8, 25.9, 24.7, 21.2, 18.9, 18.8,
11.1. Anal. Calcd for C33H52NO3SiCl: C, 68.56; H, 9.16; N,
2.60. Found: C, 69.01; H, 9.13; N, 2.44.
2(R)-(3′-Bu t en yl)-1-[(((1R,2S)-2-(r-cu m yl)cycloh exyl)-
oxy)ca r b on yl]-5-(t r iisop r op ylsilyl)-2,3-d ih yd r o-4-p yr i-
d on e (7). Magnesium turnings (1.60 g, 66 mmol) were
mechanically stirred at room temperature overnight under
argon, and then 16.5 mL of anhydrous THF was added to the
flask. Neat 4-bromo-1-butene (2.26 mL, 22 mmol) was added
(9R)-6-(Tr iisop r op ylsilyl)-5,6-d id eh yd r o-7-in d olizid i-
n on e (9). To a mixture of dihydropyridone 8 (0.94 g, 1.64
mmol) in 80 mL of anhydrous methanol was added sodium

7438 J . Org. Chem., Vol. 62, No. 21, 1997
Comins et al.
methoxide (2.39 mL, 10.45 mmol, 4.37 M in MeOH). After 6
h of reflux, the reaction mixture was cooled to rt and stirred
for 14 h. Acetic acid (0.60 mL, 10.45 mmol) was added, and
the mixture was stirred for 10 min. After removal of the
solvent, the residue was dissolved in dichloromethane and
dried over K2CO3. Filtration through Celite, concentration,
and purification by radial PLC (silica gel, 20% EtOAc/hexanes)
yielded 437 mg (91%) of the desired indolizidinone 9 as a white
refluxed for 2 d. The reaction was quenched with aqueous
saturated NaHCO3 (5 mL) and extracted with Et2O (20 mL).
After drying with anhydrous K2CO3, the solvent was evapo-
rated, and purification of the residue by radial PLC (silica gel,
10% EtOAc/hexanes/1% TEA) gave 91 mg of 1 as a white
1
solid: mp 137-8 °C; [R]28 -172 (c 0.755, MeOH); H NMR
D
(CDCl3, 300 MHz) δ 6.66 (t, 4 H, J ) 8.8 Hz), 6.52 (d, 2 H, J
) 4.7 Hz), 3.88 (d, 1 H, J ) 16.0 Hz), 3.81 (s, 6 H), 3.60 (s, 3
H), 3.58 (s, 3 H), 3.31 (t, 1 H, J ) 7.7 Hz), 3.10 (d, 1 H, J )
15.8 Hz), 2.73 (dd, 1 H, J ) 20.3, 9.0 Hz), 2.45-2.35 (m, 2 H),
2.26 (dd, 1 H, J ) 17.9, 8.9 Hz), 2.30-2.04 (m, 1 H), 2.04-
1.80 (m, 2 H), 1.62-1.52 (m, 1 H); 13C (75 MHz, CDCl3) δ 148.2,
148.1, 147.5, 147.3, 135.2, 133.7, 132.8, 132.7, 121.0, 120.7,
113.1, 112.9, 110.7, 60.4, 57.6, 55.7, 55.6, 54.2, 38.5, 30.8, 21.5;
IR (KBr) 1600, 1581, 1509, 1461, 1243, 1026 cm-1. These data
are in agreement with those reported.4,5,7
solid: [R]26 +501 (c 0.895, CHCl3).13
D
(9R)-6-Br om o-5,6-d id eh yd r o-7-in d olizid in on e (10). To
a mixture of indolizidinone 9 (67 mg, 0.228 mmol) in 3 mL of
anhydrous dichloromethane at -23 °C was added pyridinium
bromide perbromide (109 mg, 0.342 mmol). After 4.5 h of
stirring at -23 °C, the resulting yellow slurry was quenched
with 0.3 mL of saturated aqueous Na2S2O3, and the mixture
was warmed to rt. Dichloromethane (8 mL) and anhydrous
K2CO3 (0.5 g) were added. Filtration, concentration, and
purification by radial PLC (silica gel, 20-50% EtOAc/hexanes/
1% TEA) yielded 47 mg (95%) of the desired indolizidinone 10
(-)-Tylop h or in e (2). To a mixture of (-)-septicine (50 mg,
0.1264 mmol) in 1 mL of anhydrous dichloromethane at 0 °C
were added vanadium(V) oxytrifluoride (39 mg, 0.316 mmol)
and TFA (1 mL). After the red solution was stirred at 0 °C
for 1 h, it was warmed to room temperature and stirring was
continued for 1 h. Another portion of vanadium(V) oxytri-
fluoride (16 mg, 0.126 mmol) was added, and the reaction was
continued at 25 °C for 1 h. The reaction was quenched with
1 mL of saturated aqueous Na2S2O3, diluted with 10 mL of
dichloromethane, and neutralized with 10% NaOH. The
mixture was extracted with dichloromethane. The combined
organic extracts were washed with brine and dried over
anhydrous K2CO3. Filtration, concentration, and purification
by radial PLC (silica gel, 50% EtOAc/hexanes-10% EtOH/
EtOAc/1% TEA) yielded 34 mg (68%) of the desired (-)-
tylophorine (2) as a yellow solid: mp 273-275 °C; [R]30D -76.0
(c 0.10, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.85 (s, 2 H),
7.34 (s, 1 H), 7.19 (s, 1 H), 4.65 (d, 1 H, J ) 14.7 Hz), 4.13 (s,
6 H), 4.07 (s, 6 H), 3.70 (d, 1 H, J ) 14.5 Hz), 3.50 (t, 1 H, J
) 8.2 Hz), 3.40 (dd, 1 H, J ) 2.3, 16.0 Hz), 2.95 (t, 1 H, J )
14.9 Hz), 2.59-2.42 (m, 2 H), 2.34-2.20 (m, 1 H), 1.90-2.14
(m, 2 H), 1.72-1.88 (m, 1 H); 13C NMR (CDCl3, 75 MHz) δ
148.8, 148.6, 148.5, 126.3, 125.9, 124.4, 123.7, 123.5, 104.1,
103.6, 103.5, 103.3, 60.2, 56.1, 55.9, 55.1, 53.9, 33.7, 31.3, 21.6.
These data were in agreement with those reported.3b,9 The
ee was determined to be >98% by chiral column HPLC
analysis (Chiracel-OD, J . T. Baker, 10% 2-propanol/hexanes,
0.4 mL/min).
as a white solid: mp 96-97 °C; [R]25 +793 (c 1.53, CHCl3);
D
1
IR (KBr) 3033, 2977, 1632 cm-1; H (300 MHz, CDCl3) δ 7.58
(s, 1 H), 3.90-3.81 (m, 1 H), 3.66-3.51 (m, 2 H), 2.74-2.66
(m, 1 H), 2.45 (t, 1 H, J ) 16.3 Hz), 2.39-2.27 (m, 1 H), 2.20-
2.11 (m , 1 H), 2.03-1.92 (m, 1 H), 1.81-1.69 (m, 1 H); 13C (75
MHz, CDCl3) δ 183.7, 150.4, 88.3, 58.1, 49.8, 41.0, 32.3, 24.5;
MS (EI, m/ z) 217 (M + 2, 98), 216 (M + 1, 24), 214 (M+, 100),
136 (21), 108 (36); HRMS exact mass calcd for C8H10NOBr
214.9946, found 214.9953.
(9R)-6-Br om o-7-[((tr iflu r om eth yl)su lfon yl)oxy]-5,6-d i-
d eh yd r oin d olizid in e (11). To a solution of 10 (80 mg, 0.37
mmol) in 3.5 mL of anhydrous THF was added L-Selectride
(0.41 mL, 0.41 mmol, 1 M in THF) dropwise. After the reaction
was stirred at -23 °C for 3 h, 5-chloro-2-[N,N-bis((trifluro-
methyl)sulfonyl)amino]pyridine (174 mg, 0.44 mmol) was
added, and the mixture was stirred for 14 h at -23 °C. The
reaction was quenched with aqueous saturated NaHCO3 (0.5
mL) and CH2Cl2 (10 mL). Drying over anhydrous K2CO3,
filtration through Celite, concentration, and purification by
column chromatography (neutral alumina, 0-10% EtOAc/
hexanes) gave 92 mg (71%) of 11 as a colorless oil: [R]23D -62.3
(c 0.35, CHCl3); IR (neat) 2969, 2800, 1676 cm-1; 1H (300 MHz,
CDCl3) δ 3.78 (d, 1 H, J ) 16.1Hz), 3.23-3.15 (m, 2 H), 2.60-
2.41 (m, 3 H), 2.28 (dd, 1 H, J ) 8.9, 17.5 Hz), 2.10-1.82 (m,
3H), 1.65-1.50 (m, 1 H); 13C (75 MHz, CDCl3) δ 144.2, (124.7,
120.5, 116.2, 112.0) (Tf), 112.5, 60.0, 57.6, 52.9, 35.6, 30.2, 22.3;
MS (EI, m/ z) 351 (M + 2, 26), 350 (M + 1, 7), 349 (M+, 124),
218 (16), 216 (17), 69 (100); HRMS exact mass calcd for
C9H11NSO3F3Br 348.9595, found 348.9586.
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (Grant GM 34442) for
financial support of this research. The 300-MHz NMR
spectra and mass spectra were obtained at NCSU
instrumentation laboratories, which were established
by grants from the North Carolina Biotechnology Center
and the National Science Foundation (CHE-9121380).
(-)-Sep ticin e (1). A dry 10-mL round-bottomed flask
containing anhydrous ZnBr2 (0.401 g, 1.782 mmol) was heated
to 160 °C under vacuum for 14 h. While the flask was still
hot argon gas was introduced. The flask was then cooled to
25 °C, and anhydrous THF (4 mL) was added.
To a separate flask containing 5 mL of THF at -78 °C was
added tert-butyllithium (2.9 mL, 3.59 mmol, 1.23 M in THF),
and then the 4-bromovertrole (0.25 mL, 1.713 mmol) was
added dropwise. The mixture was stirred at -78 °C for 2 h,
and the solution of ZnBr2 in THF was transferred via a
cannula. The resulting zinc reagent was stirred at -78 °C
for 10 min, warmed to 25 °C, and cannulated to a stirred
mixture of vinyl triflate 11 (120 mg, 0.343 mmol) and tetraki-
s(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The
resulting yellow mixture was stirred at 25 °C for 2 h and then
Su p p or tin g In for m a tion Ava ila ble: Comparison tables
of spectroscopic data for synthetic 1 and 2 and 1H and 13C NMR
spectra of 1, 2, 10, and 11 (11 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O9711495