Total syntheses of arylindolizidine alkaloids (+)-ipalbidine and (+)-antofine

Article abstract of DOI:10.1021/jo101051w

This paper presents the first application of two recently developed reactions to natural product synthesis. The first method involves a 6-endo-trig cyclization to prepare a versatile chiral enaminone building block. The second is a direct C-H arylation reaction. As a showcase for the utility of these methods, (+)-antofine and (+)-ipalbidine were synthesized in only 8 steps and 24-26% overall yields.

Full text of DOI:10.1021/jo101051w

pubs.acs.org/joc
Our interest in indolizidine alkaloids led us to prepare
Total Syntheses of Arylindolizidine Alkaloids
(þ)-Ipalbidine and (þ)-Antofine
(þ)-ipalbidine and (þ)-antofine. These natural products
were chosen not only by virtue of their prototypical struc-
tures but also by their remarkable biological profiles.
(þ)-Ipalbidine is a nonaddictive analgesic, an oxygen-free
radical scavenger, and has demonstrated inhibitory effects
on the respiratory burst of leukocytes.4 (-)-Antofine, on the
other hand, exhibits low nanomolar antiproliferative activity
(GI50) in drug-sensitive and multidrug resistant cancer cell
lines5 and antiviral activity.6 This phenanthroindolizidine is
the only member in its class to have established DNA and
RNA binding affinities,7 which may shed light on the elusive
mechanism of action of these planar natural products. We
chose to synthesize the unnatural enantiomer, (þ)-antofine,
considering that both natural products could be synthesized
in a divergent fashion from a late-stage intermediate derived
from the Boc-L-proline. Although these natural products
have been synthesized before,5b,6-8 this route gives access to
these molecules in a remarkably concise and high-yielding
fashion that will contribute to the ongoing search for their
cellular target(s).
Micah J. Niphakis† and Gunda I. Georg*,‡
†Department of Medicinal Chemistry, University of Kansas,
1251 Wescoe Hall Drive, Lawrence, Kansas 66045, and
‡Department of Medicinal Chemistry and the Institute for
Therapeutics Discovery and Development, University of
Minnesota, 717 Delaware Street SE, Minneapolis,
Minnesota 55414
georg@umn.edu
Received May 30, 2010
To begin our syntheses, diazoketone 1 was prepared from
Boc-L-proline and was then treated with catalytic CF3CO2Ag
in the presence of freshly distilled N,O-dimethylhydroxylamine
(Scheme 1).9 The resulting Weinreb amide 2 was converted to
ynone 3 upon addition of excess ethynylmagnesium bromide.
(4) (a) Chen, X.; Chu, Y.; Han, G. Zhongguo Yaolixue Tongbao 1998, 14,
167–169. (b) Chen, X.; Chu, Y. Zhongguo Yaolixue Tongbao 1998, 14, 243–
244. (c) Wang, L.; Chu, Y. Yaoxue Xuebao 1996, 31, 806–811.
This paper presents the first application of two recently
developed reactions to natural product synthesis. The first
method involves a 6-endo-trig cyclization to prepare a versa-
tile chiral enaminone building block. The second is a direct
C-H arylation reaction. As a showcase for the utility of these
methods, (þ)-antofine and (þ)-ipalbidine were synthesized
in only 8 steps and 24-26% overall yields.
€
(5) (a) Gao, W.; Chen, A. P. C.; Leung, C. H.; Gullen, E. A.; Furstner, A.;
Shi, Q.; Wei, L.; Lee, K. H.; Cheng, Y. C. Bioorg. Med. Chem. Lett. 2008, 18,
704–709. (b) Fu, Y.; Lee Sang, K.; Min, H. Y.; Lee, T.; Lee, J.; Cheng, M.;
Kim, S. Bioorg. Med. Chem. Lett. 2007, 17, 97–100. (c) Lee, S. K.; Nam,
K.-A.; Heo, Y.-H. Planta Med. 2003, 69, 21–25.
(6) Wang, K.; Su, B.; Wang, Z.; Wu, M.; Li, Z.; Hu, Y.; Fan, Z.; Mi, N.;
Wang, Q. J. Agric. Food Chem. 2009, 58, 2703–2709.
(7) (a) Xi, Z.; Zhang, R.; Yu, Z.; Ouyang, D.; Huang, R. Bioorg. Med.
Chem. Lett. 2005, 15, 2673–2677. (b) Xi, Z.; Zhang, R.; Yu, Z.; Ouyang, D.
Bioorg. Med. Chem. Lett. 2006, 16, 4300–4304.
(8) For recent syntheses of antofine, see: (a) Yang, X.; Shi, Q.; Bastow,
K. F.; Lee, K. H. Org. Lett. 2010, 12, 1416–1419. (b) Ambrosini, L. M.;
Cernak, T. A.; Lambert, T. H. Tetrahedron 2010, 66, 4882–4887. (c) Wang,
Z.; Li, Z.; Wang, K.; Wang, Q. Eur. J. Org. Chem. 2010, 292–299. (d)
Yamashita, S.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K. Eur. J. Org.
Chem. 2009, 1173–1180. (e) Su, C. R.; Damu, A. G.; Chiang, P. C.; Bastow,
K. F.; Morris-Natschke, S. L.; Lee, K. H.; Wu, T. S. Bioorg. Med. Chem.
2008, 16, 6233–6241. (f) Wang, K. L.; Lue, M. Y.; Wang, Q. M.; Huang,
R. Q. Tetrahedron 2008, 64, 7504–7510. (g) Kim, S.; Lee, Y. M.; Lee, J.; Lee,
T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org. Chem. 2007, 72, 4886–4891. (h)
Camacho-Davila, A.; Herndon, J. W. J. Org. Chem. 2006, 71, 6682–6685. (i)
The indolizidine alkaloids are extraordinarily prevalent in
nature and are endowed with a host of biological properties that
are being harnessed to treat numerous diseases.1 For this reason,
methods to prepare the indolizidine core, particularly in enan-
tiomeric form, are valuable. We have recently developed a chiral
pool approach to generate mono- and bicyclic enaminones,
which has enabled the synthesis of a versatile indolizidine
building block from Boc-L-proline.2 The multifaceted reactivity
of the enaminone scaffold lends itself to many chemoselective
transformations. Having established a practical route to these
molecules, we next demonstrated that cyclic enaminones were
viable C-H donors in a Pd(II)-catalyzed cross-coupling reaction
with aryltrifluoroborates.3 Until now, these methods have not
been applied to the synthesis of more complex molecules. Herein,
we show for the first time that these two methods enable an
efficient synthesis of aryl indolizidine alkaloids.
€
Furstner, A.; Kennedy, J. W. J. Chem.;Eur. J. 2006, 12, 7398–7410. (j) Kim,
S.; Lee, T.; Lee, E.; Lee, J.; Fan, G. J.; Lee, S. K.; Kim, D. J. Org. Chem. 2004,
69, 3144–3149. (k) Fan, G. J.; Lee, S. K.; Kim, D. J. Org. Chem. 2004, 69 (9),
3144–3149. For select syntheses of ipalbidine, see: (l) Honda, T.; Namiki, H.;
Nagase, H.; Mizutani, H. Arkivoc 2003, 188–198. (m) Honda, T.; Namiki, H.;
Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035–3038. (n) Ikeda,
M.; Shikaura, J.; Maekawa, N.; Daibuzono, K.; Teranishi, H.; Teraoka, Y.;
Oda, N.; Ishibashi, H. Heterocycles 1999, 50, 31–34. (o) Sheehan, S. M.;
Padwa, A. J. Org. Chem. 1997, 62, 438–439. (p) Danishefsky, S. J.; Vogel, C.
J. Org. Chem. 1986, 51, 3915–3916. (q) Jefford, C. W.; Kubota, T.; Zaslona,
A. Helv. Chim. Acta 1986, 69, 2048–2061. (r) Liu, Z.; Lu, R.; Chen, Q.; Hong,
H. Huaxue Xuebao 1985, 43, 992–995. (s) Stevens, R. V.; Luh, Y. Tetrahedron
Lett. 1977, 979–982. (t) Wick, A. E.; Bartlett, P. A.; Dolphin, D. Helv. Chim.
Acta 1971, 54, 513–522. (u) Govindachari, T. R.; Sidhaye, A. R.; Viswa-
nathan, N. Tetrahedron 1970, 26, 3829–3831.
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.
(2) (a) Turunen, B. J.; Georg, G. I. J. Am. Chem. Soc. 2006, 128, 8702–
8703. (b) Niphakis, M. J.; Turunen, B. J.; Georg, G. I. J. Org. Chem. In press.
(3) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130,
3708–3709.
(9) We attempted to generate HN(OMe)Me in situ from commercially
available HN(OMe)Me HCl using excess Et3N, but the yields were con-
siderably lower.
3
DOI: 10.1021/jo101051w
r
Published on Web 08/12/2010
J. Org. Chem. 2010, 75, 6019–6022 6019
2010 American Chemical Society

Niphakis and Georg
JOCNote
SCHEME 1. Synthesis of Indolizidine Scaffolda
SCHEME 3. Synthesis of (þ)-Ipalbidinea
aReagents and conditions: (a) Et3N, ClCO2Et, THF; then CH2N2; (b)
CF3CO2Ag (20 mol %), HN(OMe)Me, Et3N, THF; (c) ethynylmagnesium
bromide (5 equiv), THF, 0 °C; then NaHSO4 (aq); (d) NaI, HCO2H.
(e) K2CO3, MeOH.
SCHEME 2. Methods for Arylation of Indolizidine Enaminonea
aReagents and conditions: (a) Pd(OAc)2 (30 mol %), Cu(OAc)2 (3equiv),
PMP-BF3K, K2CO3, t-BuOH/AcOH/DMSO (20:5:1), 60 °C; (b) L-Selec-
tride, THF, -78 to 0 °C; (c) MeLi, THF, -78 °C; (d) SOCl2, pyridine,
THF, -30 to -10 °C; (e) L-Selectride, THF, -78 to 0 °C; then Comins’
reagent, -78 to 0 °C; (f) Pd(PPh3)4 (10 mol %), MeZnBr, THF, 60 °C;
(g) BBr3, CH2Cl2, -78 °C to rt. PMP = p-methoxyphenyl.
the enaminone has the distinct advantage of being less suscep-
tible to degradative processes such as hydrolysis. In this regard,
we exploited this reactivity to install the aryl moiety.
In our initial studies, enaminone 5 was treated with iodine
and DMAP which furnished iodoenaminone 6 (Scheme 2).
The p-methoxylphenyl (PMP) substituent was then installed
by way of Buchwald’s modified Suzuki-Miyaura protocol.13
Although the yields of this reaction were comparable to our
previously reported microwave-assisted cross-coupling reac-
tion,14 the Buchwald method was used because the product
could be obtained in higher purity. Despite the success of this
iodination/cross-coupling sequence, we pursued a more direct
route involving a C-H arylation reaction. We reasoned that
the nucleophilicity of the unsubstituted enaminone could
be harnessed to access a palladated intermediate that could
then be intercepted with an appropriate coupling partner
(PMP-X). This reasoning led us to the discovery of a Pd(II)-
catalyzed C-H-arylation reaction where organotrifluorobo-
rates proved to be viable aryl donors.3 This direct-arylation
was used to prepare arylindolizidine 7 (Scheme 3), from which
both (þ)-antofine and (þ)-ipalbidine could be synthesized.
Two separate routes were developed to install the indolizi-
dine methyl substituent for (þ)-ipalbidine (Scheme 3). The first
approach, which takes cues from Liu’s endgame sequence,8r
involved 1,4-reduction of enaminone 7 with L-Selectride. To the
resulting ketone was added MeLi, which furnished 75% of the
desired tertiary alcohol 8. Although the stereochemistry of the
newly formed chiral centers was not critical to this sequence, it
is worth mentioning that both reactions proceeded with high
diastereoselectivity (>95%).
aReagents and conditions: (a) I2, DMAP, CH2Cl2; (b) Pd(OAc)2
(1.0 mol %), S-Phos (2.0 mol %), PMP-BF3K, K2CO3, MeOH, 50 °C,
5 h. PMP =p-methoxyphenyl.
Quenching the reaction with NaHSO4 minimized addition of
the released amine into the ynone product.10 To prepare the
enaminone, a modification of our one-flask, two-step proce-
dure was used in which the Boc-protecting group was removed
with formic acid. The NaI served to simultaneously activate the
ynone through the formation of vinyl iodide intermediate 4,
which is poised for a 6-endo-trig cyclization. This mild depro-
tection protocol was designed as an alternative to the previously
reported1 deprotection conditions with 4 N HCl/dioxane in
order to mitigate racemization at the β-stereocenter.2 Racemi-
zation of this type most likely proceeds through a retro-
Michael/Michael process, which has been shown to be pro-
moted by both acidic and basic conditions and is particularly
problematic for β-homoproline derivatives.11 Fortunately,
these deprotection/activation conditions were sufficient to
suppress this undesired side reaction, and enaminone 5 could
be obtained with an er of 98:212 following treatment of vinyl
iodide 4 with methanolic K2CO3.
One unique characteristic of cyclic enaminones of this type is
their exceptional nucleophilicity at the C3-position. Although
its reactivity is attenuated in comparison to a naked enamine,
In the penultimate step, the endo-olefin was obtained
upon dehydration of alcohol 8. A number of dehydrating
conditions were investigated,15 but the highest yields were
(10) Pirc, S.; Bevk, D.; Golobic, A.; Stanovnik, B.; Svete, J. Helv. Chim.
Acta 2006, 89, 30–44.
(11) Kimball, F. S.; Turunen, B. J.; Ellis, K. C.; Himes, R. H.; Georg, G. I.
Biorg. Med. Chem. 2008, 16, 4367–4377.
(12) The enantiomeric ratio of enaminone 5 was determined by chiral
HPLC following arylation to indolizidine 7.
(13) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649–2652.
(14) Wang, X.; Turunen, B. J.; Leighty, M. W.; Georg, G. I. Tetrahedron
Lett. 2007, 48, 8811–8814.
(15) See the Supporting Information.
6020 J. Org. Chem. Vol. 75, No. 17, 2010

Niphakis and Georg
JOCNote
SCHEME 4. Synthesis of (þ)-Antofinea
then dissolved in MeOH (100 mL). A separate flask was charged
with 700 mL of MeOH and K2CO3 (10.9 g, 79.0 mmol, 5.0 equiv).
To this flask was added the solution of deprotected ynone over
15 min. The reaction was stirred for 1 h and the solvent was
evaporated. At this time CH2Cl2 was added to redissolve the
product (but not the inorganic salts), the slurry was suction
filtered, and the filtrate was concentrated. To the solid residue
was added more CH2Cl2 and the precipitates were once again
filtered away. This residue after removal of solvent was purified
via SiO2 flash chromatography to provide the title compound as
an off-white solid (2.05 g, 96% yield) after SiO2 flash chroma-
tography (100% acetone): Spectral data of the title compound
were identical with those reported in the literature2 with the
exception of optical rotation. [R]D -727 (c 1.00, CHCl3).
aReagents and conditions: (a) Pd(PPh3)4 (10 mol %), 3,4-dimethoxy-
phenylzinc bromide, THF, 60 °C; (b) PhI(O2CCF3)2, BF3 Et2O, CH2Cl2.
3
(S)-6-(4-Methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-
one (7). Freshly purified enaminone 5 (750 mg, 5.5 mmol, 1.0
equiv), Pd(OAc)2 (370 mg, 1.7 mmol, 0.30 equiv), anhydrous
Cu(OAc)2 powder (3.0 g, 17 mmol, 3.0 equiv), and granular
K2CO3 (1.5 g, 11 mmol, 2.0 equiv) were combined in a 20:5:1
mixture of degassed t-BuOH/AcOH/DMSO (55 mL) under N2
and stirred for 5 min. (Note: Solvents were used without
purification.) The reaction mixture was heated to 60 °C and
the p-methoxyphenyl trifluoroborate (3.5 g, 17 mmol, 3.0 equiv)
was added incrementally over 5 h as a solid. Approximately 0.20
equiv of trifluoroborate was added every 30 min. The reaction
was stirred for an additional hour and was monitored by TLC
with 100% EtOAc as the mobile phase. The reaction mixture
was diluted with EtOAc and added to a separatory funnel
containing brine. The product was extracted with EtOAc
(3ꢀ). The combined organic layers were washed with brine
(2ꢀ) and sat. NaHCO3 (aq) (2ꢀ), dried over Na2SO4, and
concentrated in vacuo. The title compound was obtained as a
pale yellow solid (930 mg, 70% yield) after SiO2 flash chroma-
tography (80% EtOAc/hexanes). The spectral data were iden-
tical with those reported in the literature.3 [R]D -97.5 (c 1.00,
CHCl3). Enantiomeric ratio was determined to be 98:2 via chiral
HPLC, using a Chiralcel OJ column. Conditions: i-PrOH 70%
in hexanes, 30 min, 1.0 mL/min, 30 °C. (-)-Enantiomer: Rt=
20.9 min; (þ)-enantiomer: Rt = 11.1 min.
obtained with use of SOCl2 and pyridine, which provided
a single isomer of indolizidine 9. Upon BBr3 deprotection,
(þ)-ipalbidine was obtained in 80% yield.
An alternative route to (þ)-ipalbidine was devised in order
to shorten this synthetic sequence and improve yields. In this
second approach, enaminone 7 was again reduced with
L-Selectride only the resulting enolate was trapped in situ
with 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloro-
pyridine (Comins’ reagent).16 The methyl group was then
installed by subjecting this triflate to Negishi cross-coupling
conditions17 to furnish common intermediate 9 in 69% yield
over two steps. As before, upon methyl deprotection, the natural
product was obtained. The er of synthesized (þ)-ipalbidine
was 98:2, showing that the stereochemical integrity had been
retained over the previous three steps.
Witha rising medicinal interestin the phenanthropiperidine
and phenanthroquinolizidine alkaloids, we were inspired to
apply our methodologies to the construction of these natural
products as well. Thus, (þ)-antofine was synthesized in two
steps from triflate 10 (Scheme 4), whose synthesis has already
been discussed. First, antofine’s seco-analogue was prepared
with Negishi cross-coupling conditions17 to install the 3,4-di-
methoxyphenyl group in 95% yield. In the final step, the
phenanthrene system was established with a PhI(O2CCF3)2-
mediated biaryl coupling to furnish (þ)-antofine in 70% yield.
The optical rotation for the natural product was in agreement
with data reported in the literature.8a-k
In summary, the syntheses of (þ)-antofine and (þ)-ipalbi-
dine has been accomplished with the aid of two methodol-
ogies: a deprotection/6-endo-trig cyclization reaction of a
Boc-L-proline-derived ynone and a direct Pd(II)-catalyzed
C-H arylation of enaminones with an organotrifluorobo-
rate. This is the first time that these methods have been
applied to natural product synthesis. Their utility is exem-
plified by the fact that these natural products were prepared
in only 8 steps, with overall yields of 24-26% and in up to
96% ee.
(S)-6-(4-Methoxyphenyl)-1,2,3,5,8,8a-hexahydroindolizin-7-yl
Trifluoromethanesulfonate (10). Enaminone 7 (590 mg, 2.4 mmol,
1.0 equiv) was dissolved in anhydrous THF (30 mL) under a N2
atmosphere. The solution was cooled to -78 °C at which point L-
Selectride (0.23 mL, 0.23 mmol, 1.0 equiv, 1.0 M in THF) was
added over 15 min. After stirring for 1 h, the reaction was slowly
warmed to 0 °C over 2 h. The reaction mixture was once again
cooled to -78 °C and 2-[N,N-bis(trifluoromethanesulfonyl)-
amino]-5-chloropyridine (1.1 g, 2.7 mmol, 1.1 equiv) was added
all at once. The mixture was stirred for another hour at -78 °C
and then slowly warmed to 0 °C over 2 h. The reaction was
quenched with a saturated solution of NaHCO3 (aq) and added
to a separatory funnel. The product was extracted with EtOAc
(3ꢀ). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The title compound was obtained as a
colorless oil (690 mg, 76%yield) after SiO2 flash chromatography
(10% EtOAc/hexanes (1%Et3N):1H NMR(500 MHz, CDCl3) δ
1.49-1.57 (m, 1H), 1.76-1.84 (m, 1H), 1.87-1.96 (m, 1H), 2.00-
2.07 (m, 1H), 2.22 (dd, J = 18.1, 9.2 Hz, 1H), 2.47-2.62 (m, 3H),
3.06 (d, J = 15.8 Hz, 1H), 3.18 (dt, J = 4.4, 2.1 Hz, 1H), 3.72-
3.75 (m, 1H), 3.74 (s, 3H), 6.83 (d, J = 8.8 Hz, 2H), 7.14 (d, J =
8.8 Hz, 2H); 13C NMR(125 MHz, CDCl3) δ 22.2, 30.5, 35.2, 53.4,
55.3, 55.6, 60.5, 113.9, 118.1 (q, JCF = 320 Hz), 126.6, 129.2,
129.5, 142.0, 159.5; IR (neat) 2959, 1610, 1512, 1416, 1209, 1146
cm-1; HRMS (ESIþ) m/e calcd for [M þ H]þ C16H19F3NO4S
378.0987, found 378.0974; [R]D þ66.3 (c 1.00, CHCl3).
Experimental Section
(S)-2,3,8,8a-Tetrahydroindolizin-7(1H)-one (5). Ynone 3 (3.74
g, 15.8 mmol, 1.0 equiv) was dissolved in formic acid (50 mL)
solution under a N2 atmosphere and NaI (7.09 g, 47.3 mmol, 3.0
equiv) was added. The reaction was left stirring for 6 h at rt. The
solvent was removed by passing N2 over the reaction mixture.
The remaining residue was placed under vacuum for 15 min and
(S)-6-(4-Methoxyphenyl)-7-methyl-1,2,3,5,8,8a-hexahydroin-
dolizine (9): Preparation of Organo Zinc Reagent. A flame-dried
round-bottomed flask under N2 was charged with anhydrous
(16) Comins, D. L.; Deghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
(17) Comins, D. L.; Chen, X.; Morgan, L. A. J. Org. Chem. 1997, 62,
7435–7438.
J. Org. Chem. Vol. 75, No. 17, 2010 6021

Niphakis and Georg
JOCNote
THF (10.0 mL) and cooled to -78 °C. Methyl lithium (1.6 mL,
2.5 mmol, 5.0 equiv, 1.6 M in Et2O) was added and the solution
was allowed to sit. A separate round-bottomed flask was
charged with anhydrous ZnBr2 (590 mg, 2.6 mmol, 5.2 equiv).
The ZnBr2 was dried by heating the round-bottomed flask under
a vacuum with a heat gun for 5 min. When the ZnBr2 had cooled
to rt it was dissolved in anhydrous THF (6.0 mL) under N2. This
ZnBr2 solution was slowly cannulated into the MeLi solution
and the resulting mixture was stirred at -78 °C for 5 min and
then allowed to warm to rt.
(dd, J = 15.6, 2.2 Hz, 1H), 3.26 (ddd, J = 9.1, 9.1, 2.1 Hz, 1H),
3.69 (d, J = 15.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 7.00 (d, J =
8.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 20.0, 21.1, 30.2,
37.6, 54.1, 57.7, 60.6, 115.5, 128.3, 129.7, 129.9, 132.0, 155.9;
HRMS (ESIþ) m/e calcd for [M þ H]þ C15H20NO 230.1545,
found 230.1531; [a]D þ202 (c 1.00, CHCl3) [lit.18 S-enantiomer:
[R]D þ233.5 (c 1, CHCl3); R-enantiomer: [R]D -237 (c 1, CHCl3),
-190.5 (c 1, MeOH)].
(þ)-Antofine. Secoantofine (48 mg, 0.13 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (2.0 mL) and cooled to -78 °C. To this
solution was sequentially added PhI(O2CCF3)2 (62 mg, 0.14
Triflate 10 (190 mg, 0.50 mmol, 1.0 equiv), dissolved in a
minimal amount of THF, and Pd(PPh3)4 (29 mg, 0.025 mmol,
5.0 mol %) were added sequentially to the zinc reagent. If the
reaction had not gone to completion after 1 h at rt, the reaction
mixture was heated to 50 °C. Upon consumption of the triflate
starting material (as judged by TLC) SiO2 was added to the
reaction mixture and the solvent was evaporated to leave a
free-flowing powder. Following flash chromatography (20%
EtOAc/hexanes (1% Et3N)) 110 mg (91%) of the title com-
mmol, 1.1 equiv) and BF3 Et2O (16 mg, 0.14 mmol, 1.1 equiv).
3
The solution was stirred for 4 h while being monitored by TLC.
A solution of PhI(O2CCF3)2 (62 mg in 2.0 mL of CH2Cl2) was
added dropwise to the reaction mixture until the reaction had
gone to completion. Upon consumption of starting material the
reaction was quenched with 10% NaOH (aq) and the mixture
was vigorously stirred for 1 h. The product was extracted from
the aqueous layer with CH2Cl2 (3ꢀ). The combined organic
layers were dried with Na2SO4, concentrated, and purified via
flash chromatography [70% EtOAc/hexane (1% Et3N)] to
provide 34 mg (70%) of (þ)-antofine as a white crystalline solid:
1
pound was obtained as a colorless oil: H NMR (400 MHz,
CDCl3) δ 1.46-1.54 (m, 1H), 1.60 (s, 3H), 1.73-1.81 (m, 1H),
1.85-1.94 (m, 1H), 2.00-2.32 (m, 5H), 2.91 (d, J = 15.4 Hz,
1H), 3.22 (dd, J = 3.2, 3.2 Hz, 1H), 3.62 (d, J = 15.4 Hz, 1H),
3.82 (s, 3H), 6.86 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 20.0, 21.4, 30.8, 38.5, 54.2, 55.2,
57.8, 60.2, 113.5, 127.9, 130.0, 130.3, 133.8, 158.1; IR (neat)
2907, 1609, 1510, 1244, 1175, 831 cm-1; HRMS (ESIþ) m/e
calcd for [M þ H]þ C16H22NO 244.1701, found 244.1688;
[R]D þ142 (c 1.00, CHCl3).
1
mp 226-227 °C dec; H NMR (400 MHz, CDCl3) 1.65-1.75
(m, 1H), 1.80-2.02 (m, 2H), 2.13-2.22 (m, 1H), 2.35-2.46 (m,
2H), 2.79-2.86 (m, 1H), 3.28 (ddd, J = 15.8, 3.7, 1.5 Hz, 1H),
3.38 (dt, J = 4.3, 2.1 Hz, 1H), 3.63 (d, J = 14.9 Hz, 1H), 3.95 (s,
3H), 3.99 (s, 3H), 4.04 (s, 3H), 4.63 (d, J = 14.9 Hz, 1H), 7.13
(dd, J = 9.0, 2.5 Hz, 1H), 7.25 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H),
7.83 (d, J= 2.5 Hz, 1H), 7.85 (s, 1H); 13C NMR (100 MHz, CDCl3)
21.6, 31.3, 33.7, 53.8, 55.0, 55.5, 55.9, 56.0, 60.3, 104.0, 104.7, 114.9,
123.5, 124.1, 124.2, 125.5, 126.7, 127.0, 130.2, 148.4, 149.4, 157.5;
HRMS (ESIþ) m/e calcd for [M þ H]þ C23H26NO3 364.1913,
found 364.1909; [R]D þ111 (c 1.00, CHCl3) [lit. R-enantiomer:
-113.4 (c 1.23, CHCl3),8c -125.2 (c 1.27, CHCl3),8d -108.2 (c 0.71,
CHCl3)19].
(þ)-Secoantofine. With 3,4-dimethoxyphenyllithium instead
of MeLi, the above procedure was used for the preparation of
the title compound. Following flash chromatography [40%
EtOAc/hexanes (1% Et3N)] 380 mg (96%) of the (þ)-secoanto-
fine was obtained as a yellow oil: 1H NMR (400 MHz, CDCl3) δ
1.51-1.63 (m, 1H), 1.78-2.01 (m, 2H), 2.06-2.14 (m, 1H), 2.25
(dd, J = 9.0, 9.0 Hz, 1H), 2.36-2.45 (m, 2H), 2.69-2.77 (m, 1H),
3.07 (dt, J = 16.0, 3.1 Hz, 1H), 3.29 (dt, J = 4.3, 2.0 Hz, 1H), 3.54
(s, 3H), 3.72 (s, 3H), 3.81 (s, 3H), 3.86 (d, J= 15.8 Hz, 1H), 6.47 (d,
Acknowledgment. This work was supported by National
Institutes of Health Grants CA90602, GM069663, GM076302,
and GM081267, the Kansas Masonic Cancer Research Insti-
tute, the University of Minnesota through the Vince and
McKnight Endowed Chairs and an ACS Division of Medicinal
Chemistry Predoctoral Fellowship (to M.J.N). We thank Xin
Wang for some initial efforts on the synthesis of (þ)-ipalbidine.
J = 1.1 Hz, 1H), 6.66-6.69 (m, 4H), 6.97 (d, J = 8.8 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ 21.5, 30.8, 38.6, 54.3, 55.1, 55.5, 55.7,
57.9, 60.4, 110.4, 113.1, 113.4, 120.7, 130.2, 132.6, 132.7, 133.6,
135.1, 147.1, 147.9, 158.0; IR (neat) 2955, 1607, 1511, 1245, 1030,
755 cm-1; HRMS (ESIþ) m/e calcd for [M þ H]þ C23H28NO3
366.2064, found 366.2068; [R]D þ169 (c 1.00, CHCl3).
(þ)-Ipalbidine. Indolizidine 9 (56 mg, 0.23 mmol, 1.0 equiv)
was dissolved in CH2Cl2 (1.0 mL) and cooled to -78 °C under
N2. To this solution was added BBr3 (0.23 mL, 0.23 mmol, 1.0 M
in CH2Cl2). The reaction was allowed to warm to rt overnight.
The reaction was quenched with water (1.0 mL) and then 5.0 mL
of a saturated solution of NaHCO3 (aq). The product was
extracted from the aqueous layer with CH2Cl2 (3ꢀ). The
combined organic layers were dried with Na2SO4, concentrated,
and purified via flash chromatography [80% EtOAc/hexane
(1% Et3N)] to provide 42 mg (80%) of (þ)-ipalbidine as a white
crystalline solid (mp 122.2-124.6 °C): 1H NMR (400 MHz,
CDCl3) δ 1.59 (s, 3H), 1.55-1.68 (m, 1H), 1.74-1.88 (m, 1H),
1.91-2.11 (m, 2H), 2.14-2.32 (m, 3H), 2.35-2.45 (m, 1H), 3.00
Note Added after ASAP Publication. Scheme 1 footnote
contained an error in the version published ASAP August 12;
the corrected version reposted August 27, 2010.
Supporting Information Available: Full experimental details
and copies of NMR spectral data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(18) Wick, A. E.; Bartlett, P. A.; Dolphin, D. Helv. Chim. Acta 1971, 54,
513–22.
(19) Kim, S.; Lee, J.; Lee, T.; Park, H.-g.; Kim, D. Org. Lett. 2003, 5,
2703–2706.
6022 J. Org. Chem. Vol. 75, No. 17, 2010