Synthesis of (+)-Ipalbidine Based on 6-exo-trig Radical Cyclization of a β-Amino Radical

Article abstract of DOI:10.1021/acs.joc.5b01890

N-Boc (S)-proline was converted into (2S)-2-[(phenylselanyl)methyl]pyrrolidine, which was alkylated on nitrogen with 2-bromo-1-(4-methoxyphenyl)ethan-1-one. Reaction with vinyllithium, 6-exo-trig radical cyclization (Bu₃SnH, AIBN, PhMe, 110 °C), dehydration (P₂O₅, H₃PO₄), and demethylation (BBr₃) gave (+)-ipalbidine with ee >99%.

Full text of DOI:10.1021/acs.joc.5b01890

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Article
Synthesis of (+)-ipalbidine based on 6-exo-
trig radical cyclization of a beta-amino radical
JongMyoung Chea, and Derrick L. J. Clive
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01890 • Publication Date (Web): 24 Sep 2015
Downloaded from http://pubs.acs.org on September 29, 2015
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Synthesis of (+)-ipalbidine based on 6-exo-trig radical cyclization of a β-amino
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radical
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JongMyoung Chea and Derrick L. J. Clive*
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Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.clive@ualberta.ca
ABSTRACT:
NꢀBoc (S)ꢀproline was converted into (2S)ꢀ2ꢀ[(phenylselanyl)methyl]pyrrolidine which was
alkylated on nitrogen with 2ꢀbromoꢀ1ꢀ(4ꢀmethoxyphenyl)ethanꢀ1ꢀone.
Reaction with
vinyllithium, 6ꢀexoꢀtrigonal radical cyclization (Bu3SnH, AIBN, PhMe, 110 °C), dehydration
(P2O5, H3PO4) and demethylation (BBr3) gave (+)ꢀipalbidine with ee >99%.
INTRODUCTION
The hexahydroindolizine alkaloid ipalbine (1) and its aglycone (2) were each isolated
many years ago from seeds of Ipomoea alba L.1,2 and, subsequently, the aglycone was obtained
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from Ipomoea hardwickii Hemsl. and Ipomoea muricata
.
Compound 2 is reported to be a nonꢀ
addictive analgesic,5 it has antiꢀinflammatory properties,6 exerts an inhibitory effect on the
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respiratory burst of leucocytes, and also scavenges oxygen free radicals.7 It is likely that ipalbine
ꢀglycosides of racemic ipalbidine.8,9
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from some sources is a mixture of βꢀ
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Numerous syntheses (including formal syntheses) of racemic ipalbidine have been
described8,10 and in one case8 the material was resolved by Oꢀacetylation and formation of
diastereoisomeric salts with (+)ꢀ and with (ꢀ)ꢀdiꢀOꢀpꢀtoluoyl tartaric acid. The isomers of
ipalbidine were crystallized from a mixture of benzene and cyclohexane, but the crystals
tenaciously retain some of these solvents. However, solventꢀfree (–)ꢀipalbidine was obtained as
a glass by distillation (150 °C, 0.1 Torr) and it then had [α]25 –237 (c 1, CHCl3) and [α]25
–
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190.5 (c 1, MeOH).8
Five syntheses of (+)ꢀipalbidine have been reported,11 but some of the observed optical
rotations [[α]D +158.6 (c 0.8, MeOH);11b [α]D +189.4 (c 1, CHCl3);11b [α]D +202 (c 1, CHCl3);11c
[α]23 +199 (c 1.00, CHCl3);11d [α]20 +213.1 (c 1, CHCl3)11e] differ significantly12 from the
D
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above numerical value measured8 on distilled material. However, mechanistic considerations
support the conclusion that the ee values of the products from these syntheses were very high.
Only in two cases11c,d have the synthetic compounds been evaluated by chiral HPLC, indicating
for (+)ꢀipalbidine with [α]D +202 (c 1, CHCl3) an ee of 96%11c and for (+)ꢀipalbidine with [α]23
D
+199 (c 1.00, CHCl3) an ee of 94%.11d
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RESULTS AND DISCUSSION
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We report a synthesis of (+)ꢀipalbidine based on 6ꢀexoꢀtrig radical cyclization (3→4) as a
key step (Scheme 1). Cyclization of alkyl radicals by a 6ꢀexoꢀtrig pathway has been applied in
synthesis less frequently than the corresponding 5ꢀexo process, part of the reason being that, in
the general case, allylic hydrogen abstraction (see arrow a in 5) can compete13 with ring closure
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SCHEME 1. The synthetic plan.
(arrow b) unless the distal terminus14 of the double bond carries an electronꢀwithdrawing or
radicalꢀstabilizing group. With structures of type 3 however, such allylic hydrogen abstraction
cannot intervene and the geminal substitution (ThorpeꢀIngold effect15) and presence of the
heteroatom16 may facilitate ring closure.
Radical 3 is a βꢀamino radical and it has been established that such radicals can undergo
reversible ring opening and ring closure.17,18 In particular, the rate constants at 80 °C for opening
of radical 6 and closing of the resulting aminyl radical 7 have been determined17 to be 14.6 × 104
sꢀ1 and 5 × 104 sꢀ1, respectively (Scheme 2). While βꢀamino radicals have indeed been used to
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SCHEME 2. Reversible ring opening of βꢀamino radicals.
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construct rings,16,19 we have been unable to locate any reports of their application in situations
where reversible ring opening would degrade the optical purity of the starting radical.
Consequently, our approach to ipalbidine would test the relative rates of the desired 6ꢀexo
closure and the undesired ring opening and closing pathways under the normally obligatory
cyclization conditions of low stannane concentration—a circumstance that would probably favor
the incursion of ring opening. In contrast to the situation for amines, cyclization of radicals β to
nitrogen to generate optically active products have been reported using substrates in which the
nitrogen is part of a lactam.20,21
Our starting point was commercial NꢀBocꢀproline (8) which was reduced (98%) with
BH3.SMe2 by a literature procedure22 to the corresponding alcohol (Scheme 3). This was then
converted (93%) to its tosylate 10.22 When the tosylate was treated with the phenylselenide
anion, generated in situ from PhSeSePh and NaBH4 in DMF, the selenide 1123 was formed in
high yield (87%). The NꢀBoc group was then removed in the standard way (11→12) and the
resulting amine was alkylated with 4ꢀmethoxyphenacyl bromide (MeCN, K2CO3).24
SCHEME 3. Construction of ketone 14.
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The next step required conversion of ketone 14 into a vinyl alcohol. This was best
achieved (89%) by the action of freshlyꢀprepared vinyllithium (from tetravinyltin and MeLi)25 in
Et2O, rather than with vinylmagnesium bromide, so as to obtain the expected mixture of
diastereoisomeric alcohols 15 (Scheme 4). Radical cyclization by slow addition of a PhMe
SCHEME 4. Elaboration of ketone 14 to (+)ꢀipalbidine.
a
Footnote to Table: Corrected for recovered starting material.
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solution of Bu3SnH and AIBN to a refluxing solution of 15 in the same solvent afforded the
required cyclization product as a mixture of stereoisomers. One isomer could be isolated in pure
form by preparative layer chromatography and fully characterized. Dehydration of the combined
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isomers by heating with a mixture of P2O5 and 85% H3PO4 gave Oꢀmethyl ipalbidine (17),
which contained an impurity that could not be removed by chromatography. However,
demethylation (86%) with BBr3 in CH2Cl2 at ꢀ78 °C to room temperature released pure
ipalbidine (2) and a distilled sample had [α]20 +252.45 (c 1.213, CHCl3). HPLC analysis
D
showed the material to have an ee of 99.3%.
One interpretation of our results is that ring opening of the intermediate βꢀamino radical
(cf. Scheme 2) does not occur to any significant extent, if at all, and so the optical purity of our
starting material was not degraded. However, our experiments do not rule out the possibility that
some ring opening occurs and that the resulting radical follows pathways other than ring closure.
In either event, it is clear that radical cyclization of βꢀamino radicals can indeed be used to
synthesize compounds of extremely high ee. The present case represents a demanding test
because a 6ꢀexoꢀtrigonal closure of radicals is significantly slower (at 25 °C a 0.023ꢀfold
reduction in the case of hexenyl radicals27) than the more usual 5ꢀexo mode. The rate constant
for cyclization of 3ꢀazahexꢀ6ꢀenyl radicals has not been reported.
During the course of this work we looked at the possibility of shortening the route along
the lines summarized in Scheme 5. The required allenyl bromide 22 was easily prepared, by
analogy with literature procedures for related compounds,28,29 as shown in the Scheme.
SCHEME 5. Attempted radical cyclization onto an allene.
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Although the Nꢀalkylation step 22→23 worked satisfactorily (70%), our attempts to
effect radical ring closure (23→17) by the use of Bu3SnH invariably led to complex mixtures,
notwithstanding the fact that several ring closures of alkyl radicals onto allenes have been
reported.30 Radical cyclizations onto allenes is not a highly developed subject and we did not
establish the reasons for the observed outcome with compound 23.
CONCLUSION
The radical cyclization route we have used gives (+)ꢀipalbidine with an ee >99%, and the
method establishes that reversible opening of the intermediate βꢀamino radical does not, in
practice, interfere with the process, even though the key ring closure is of the relatively slow 6ꢀ
exo type.
EXPERIMENTAL SECTION
General Procedures. Solvents used for chromatography were distilled before use. Commercial
thin layer chromatography plates (silica gel, Merck 60Fꢀ254) were used. Silica gel for flash
chromatography was Merck type 60 (230–400 mesh). Dry solvents were prepared under an inert
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atmosphere and transferred by syringe or cannula. The symbols s, d, t and q used for C NMR
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spectra indicate zero, one, two, or three attached hydrogens, respectively, the assignments being
made from APT spectra. Solutions were evaporated under water pump vacuum and the residue
was then kept under oil pump vacuum. High resolution electrospray mass spectrometric analyses
were done with an orthogonal time of flight analyzer and electron ionization mass spectra were
measured with a doubleꢀfocusing sector mass spectrometer.
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tert-Butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9).22
BH3.SMe2 (2 M in THF, 6 mL, 12 mmol) was added dropwise to a stirred and cooled (0
°C) solution of NꢀBocꢀLꢀproline (2.0 g, 9.2 mmol) in dry THF (20 mL). When gas evolution
ceased the ice bath was removed and stirring was continued overnight. The solution was cooled
to 0 °C and MeOH (0.3 mL) was added dropwise. The mixture was extracted with EtOAc,
washed with brine, dried (MgSO4) and evaporated to afford 9 (1.83 g, 98%) as a colorless oil that
was used directly in the next step. The material had: FTIR (CH2Cl2 cast) 3430, 2974, 2932,
2878, 1695, 1672, 1406, 1171 cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9 H), 1.76–1.84 (m,
2 H), 1.97–2.04 (m, 1 H), 3.28–3.33 (m, 1 H), 3.42–3.44 (m, 1 H), 3.56–3.67 (m, 2 H), 3.80–4.02
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(br, 2 H), 4.70–4.72 (br s, 1 H); C NMR (CDCl3, 125 MHz) δ 24.1 (t), 28.5 (q), 28.8 (s), 47.6
(t), 60.2 (d), 67.8 (t), 80.2 (t), 157.2 (s); exact mass (electrospray) m/z calcd for C10H19NNaO3 (M
+ Na) 224.1257, found 224.1253.
tert-Butyl (2S)-2-{[(4-methylbenzenesulfonyl)oxy]methyl)pyrrolidine-1-carboxylate
(10).22 TsCl (0.84 g, 4.0 mmol) was added as a solid to a stirred solution of NꢀBocꢀ
Lꢀprolinol (9)
(0.81 g, 4.0 mmol) in dry pyridine (0.8 mL). The mixture was stirred overnight at room
temperature, diluted with EtOAc and washed with iceꢀcold hydrochloric acid (1 N, 27 mL). The
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organic extract was washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and
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evaporated. Flash chromatography of the residue over silica gel (3 × 20 cm), using 3:7 EtOAcꢀ
hexane, gave 10 (1.32 g, 93%) as a colorless oil: [α]20 –37.65 (c 1.07600, CHCl3); FTIR
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(CH2Cl2 cast) 2976, 2932, 1694, 1177 cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.38–1.42 (m, 9 H),
1.80–2.00 (m, 4 H), 2.50 (s, 3 H), 3.29–3.35 (m, 2 H), 3.90–4.00 (m, 2 H), 4.10–4.12 (m, 1 H),
7.40 (br s, 2 H), 7.79 (d, J = 7.9 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 21.6 (q), 22.9 (t), 23.8
(t), 27.7 (t), 28.4 (q), 28.5 (t), 46.5 (t), 46.9 (t), 55.6 (d), 70.0 (s), 79.6 (t), 79.9 (t), 127.9 (d),
129.9 (d), 133.0 (s), 144.7 (s), 144.8 (s), 154.0 (s), 154.4 (s); exact mass (electrospray) m/z calcd
for C17H25NNaO5S (M + Na) 378.1346, found 378.1342.
tert-Butyl (2S)-2-[(phenylselanyl)methyl]pyrrolidine-1-carboxylate (11).31 NaBH4
(0.20 g, 5.6 mmol) was added to a stirred and warmed (40 °C) solution of PhSeSePh (0.87 g, 2.8
mmol) in dry DMF (8 mL). After 30 min a solution of 10 (1.54 g, 4.3 mmol) in DMF (8 mL)
was added and stirring at 40 °C was continued overnight. The mixture was cooled, poured into
water and extracted with Et2O. The combined organic extracts were washed with water and
brine, dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel (3 ×
20 cm), using increasing amounts of EtOAc in hexane from 5% EtOAc to 30% EtOAc in hexane,
gave 11 (1.3 g, 88%) as a yellow oil: [α]20 –17.79 (c 1.07200, CHCl3); FTIR (CH Cl cast)
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3070, 2973, 2929, 1693, 1392 cm−1; H NMR (CDCl3, 500 MHz) (rotamers) δ 1.30–1.40 (m, 9
H), 1.70–2.10 (m, 4 H), 2.92–2.96 (m, 1 H), 3.22–3.52 (m, 3 H), 3.97–4.11 (m, 1 H), 7.25–7.28
(m, 3 H), 7.55–7.56 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 22.8 (t), 23.7 (t), 28.6 (q), 30.4 (t),
30.9 (t), 31.1 (s), 31.9 (s), 46.7 (t), 47.2 (t), 57.1 (d), 79.2 (t), 79.6 (t), 126.5 (d), 127.0 (d), 129.1
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(d), 129.9 (s), 130.5 (s), 131.8 (d), 132.9 (d), 154.3 (s), 154.4 (s); exact mass (electron impact)
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m/z calcd for C16H23N80SeO2 341.0894, found 341.0896.
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(2S)-2-[(Phenylselanyl)methyl]pyrrolidine (12).23 CF3CO2H (5.7 mL was added
dropwise over 1 h to a stirred and cooled (0 °C) solution of 11 (0.57 g, 1.6 mmol) in CH2Cl2 (5.7
mL). After the addition stirring at 0 °C was continued for 4 h and then saturated aqueous
NaHCO3 was added dropwise until the pH of the solution was 8–9 (indicator paper). The
organic phase was dried (MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (3 × 20 cm), using 1:19 MeOHꢀCH2Cl2, gave material that was partitioned between
Et2O and 10%w/v aqueous NaOH. The organic extract was dried and evaporated to give 12
(0.36 g, 87%) as an amber oil: [α]20D +24.94 (c 1.496, CHCl3); FTIR (CH2Cl2 cast) 3052, 2960,
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2869, 1679, 1478, 1437, 1400, 737 cm−1; H NMR (CDCl3, 400 MHz) δ 1.45–1.52 (m, 1 H),
1.75–1.91 (m, 2 H), 1.94–2.01 (m, 1 H), 2.92–2.96 (m, 2 H), 3.02–3.10 (m, 3 H), 3.35 (quintet, J
= 6.9 Hz, 1 H), 7.23–7.29 (m, 3 H), 7.52–7.54 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 25.3 (t),
31.7 (t), 34.0 (t), 46.3 (t), 58.5 (d), 127.0 (d), 129.1 (d), 130.1 (s), 132.7 (d); exact mass
(electrospray) m/z calcd for C11H16N80Se 242.0442 [M + H], found 240.0442.
2-Bromo-1-(4-methoxyphenyl)ethan-1-one (13).24 A solution of Br2 (0.3 mL, 6.5
mmol) in CHCl3 (10 mL) was added slowly to a stirred solution of pꢀmethoxyacetophenone (1.0
g, 6.79 mmol) in CHCl3 (10 mL). The mixture was then stirred overnight, diluted with Et2O (10
mL) and washed with water. The organic phase was washed with brine, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (3 × 20 cm), using increasing
amounts of EtOAc in hexane from 0% to 5% EtOAc in hexane, gave 13 (1.14 g, 73%) as a white
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solid: mp 69–70 °C; FTIR (CH2Cl2 cast) 3078, 3061, 3011, 2943, 2844, 1685, 1602, 1206 cm−1;
1H NMR (CDCl3, 400 MHz) δ 3.90 (s, 3 H), 4.41 (s, 2 H), 6.96–7.02 (m, 2 H), 7.97–8.04 (m, 2
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H); C NMR (CDCl3, 125 MHz) δ 30.7 (t), 55.6 (q), 114.1 (d), 127.0 (s), 131.4 (d), 164.2 (d),
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190.0 (d); exact mass (electrospray) m/z calcd for C9H9 BrNaO2 (M + Na) 250.9678, found
250.9678.
1-(4-Methoxyphenyl)-2-[(2S)-2-[(phenylselanyl)methyl]pyrrolidin-1-yl]ethan-1-one
(14). K2CO3 (5.5 g, 4.0 mmol) was added to a stirred solution of amine 12 (580 mg, 2.40 mmol)
in dry MeCN (17 mL), followed by bromide 13 (450 mg, 2.0 mmol) (N2 atmosphere). Stirring at
room temperature was continued for 3 h and then water was added. The organic phase was
washed with brine, dried (MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (3 × 20 cm), using 1:1 EtOAcꢀhexane, gave 14 (710 mg, 76%) as a tanꢀcolored oil
containing minor impurities (1H NMR and 13C NMR) [We obtained a pure sample of the
corresponding racemic material; see Supporting Information for copies of the NMR spectra].
The compound is unstable and should be used within a day: [α]20 –18.66 (c 1.0200, CHCl3);
D
FTIR (CH2Cl2 cast) 3055, 2925, 2853, 1712, 1601, 1256 cm−1; H NMR (CDCl3, 400 MHz) δ
1
1.70–1.90 (m, 3 H), 2.04–2.10 (m, 1 H), 2.43 (q, J = 9.1 Hz, 1 H), 2.90–2.97 (m, 1 H), 3.00–3.09
(m, 1 H), 3.13–3.18 (m, 1 H), 3.21–3.25 (m, 1 H), 3.87 (s, 3 H), 3.97 (AB q, J = 15.9, ꢀνAB
=
235.7 Hz, 2 H), 6.91–6.95 (m, 2 H), 7.22–7.28 (m, 3 H), 7.47–7.51 (m, 2 H), 8.00–8.04 (m, 2 H);
13C NMR (CDCl3, 125 MHz) δ 22.9 (t), 31.2 (t), 32.9 (t), 54.6 (t), 55.5 (d), 60.3 (t), 63.8 (q),
113.7 (d), 126.7 (d), 129.1 (s), 129.2 (d), 130.6 (d), 130.9 (s), 132.3 (d), 163.6 (s), 196.0 (s);
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exact mass (electrospray) m/z calcd for C20H24NO2 Se (M + H) 390.0968, found 390.0961.
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2-(4-Methoxyphenyl)-1-[(2S)-2-[(phenylselanyl)methyl]pyrrolidin-1-yl]but-3-en-2-ol
(15). MeLi (1.6 M in Et2O, 5.2 mL, 8.2 mmol) was added dropwise to a stirred and cooled (0
°C) solution of tetravinyltin (0.37 mL, 2.04 mmol) in Et2O (40 mL).25 Stirring was continued for
1 h and the solution was then cooled to ꢀ78 °C. A solution of ketone 14 (200 mg, 0.51 mmol) in
Et2O (10 mL) was added dropwise at ꢀ78 °C, the cold bath was left in place, but not recharged,
and stirring was continued overnight. The mixture was cooled to 0 °C, quenched with water, and
extracted with Et2O. The combined organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (2 × 16 cm), using 1:1 EtOAcꢀhexane, gave 15
[190 mg, 89%, or 96% corrected for recovered 14 (15 mg)] as a pale yellow oil which was a
mixture of isomers: FTIR (CH2Cl2 cast) 3418, 3070, 3056, 2953, 2834, 1610, 1510, 1248, 1199
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cm−1; H NMR (CDCl3, 400 MHz) δ 1.55–1.85 (m, 4 H), 1.92–2.03 (m, 1 H), 2.35–2.40 (m, 1
H), 2.87–3.00 (m, 3 H), 3.05–3.08 (m, 0.5 H), 3.14–3.18 (m, 0.5 H), 3.30–3.42 (m, 1 H), 3.81–
3.82 (two s, 3 H), 4.34–4.48 (two br s, 1 H), 5.11 (ddd, J = 1.4, 10.4, 20.4 Hz, 1 H), 5.26 (dd, J =
1.4, 16.9 Hz, 0.5 H), 5.48 (dd, J = 1.4, 17.1 Hz, 0.5 H), 6.10 (dd, J = 16.9, 10.4 Hz, 0.5 H), 6.24
(dd, J = 10.4, 16.9 Hz, 0.5 H), 6.86–6.89 (m, 2 H), 7.22–7.30 (m, 3 H), 7.38–7.42 (m, 2 H),
7.48–7.55 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 23.7 (t), 23.8 (t), 30.2 (t), 30.5 (t), 33.81 (t),
33.89 (t), 55.2 (q), 56.0 (t), 56.9 (t), 65.0 (d), 65.3 (d), 65.7 (t), 66.6 (t), 74.0 (t), 112.9 (s), 113.2
(s), 113.4 (d), 113.6 (d), 126.2 (d), 126.7 (d), 126.8 (d), 126.9 (d), 129.0 (d), 129.1 (d), 130.4 (s),
132.67 (d), 132.70 (d), 132.74 (d), 137.62 (s), 137.68 (s), 143.5 (d), 144.5 (d), 158.3 (s), 158.4
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(s); exact mass (electrospray) m/z calcd for C22H27NO2 Se (M + H) 418.1280, found 418.1279.
(8aS)-6-(4-Methoxyphenyl)-7-methyloctahydroindolizin-6-ol (16). A solution of
Bu3SnH (0.2 mL, 0.76 mmol) and AIBN (6 mg, 0.03 mmol) in PhMe (2 mL) was added via
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syringe pump over 8 h to a stirred and heated (110 °C) solution of 15 (mixture of isomers) (160
mg, 0.38 mmol). Stirring at 110 °C was continued for 2 h after the addition, and the solvent was
then evaporated at room temp (waterpump vacuum). Flash chromatography of the residue over
10% KF on silica gel32 (2 × 16 cm) using 1:19 MeOHꢀEtOAc) gave 16 [75 mg, 75% or 85.9%
corrected for recovered 15 (20 mg)] as a lightꢀbrown oil which appeared to be a mixture of at
least two isomers. Preparative tlc (20 x 20 x 0.215 mm), using 1:4 iꢀPrOHꢀCH2Cl2, allowed
isolation of one isomer, which had: FTIR (CH2Cl2 cast) 3483, 2962, 2930, 2799, 1512, 1247
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cm−1; 1H NMR (CDCl3, 400 MHz) δ 0.69 (d, J = 6.4 Hz, 3 H), 1.23–1.32 (m, 1 H), 1.42–1.50 (m,
1 H), 1.68–1.94 (m, 6 H), 1.95–2.06 (m, 1 H), 2.21 (q, J = 8.8 Hz, 1 H), 2.57 (AB q, J = 11.2,
ꢀν = 223.8 Hz, 2 H), 2.96 (dt, J = 2.3, 8.5 Hz, 1 H), 3.47 (s, 1 H), 3.82 (s, 3 H), 6.87–6.91 (m,
AB
2 H), 7.38–7.42 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 15.0 (q), 21.5 (t), 30.6 (t), 35.9 (t), 39.0
(d), 53.3 (t), 55.2 (q), 64.1 (d), 65.5 (t), 73.6 (s), 113.4 (d), 126.1 (d), 136.7 (s), 158.2 (s); exact
mass (electrospray) m/z calcd for C16H24NO2 (M + H) 262.1802, found 262.1804.
(8aS)-6-(4-Methoxyphenyl)-7-methyl-1,2,3,5,8,8a-hexahydroindolizine (17).
P2O5
(8.4 mg, 0.06 mmol) was added to a solution of 16 (42 mg, 0.16 mmol) in 85% H3PO4 (12.6
mL)26 and the mixture was heated at 120 °C for 2 h, cooled, poured onto ice and basified to pH
12 with powdered KOH. The resulting mixture was extracted with CH2Cl2 and the combined
organic extracts were washed with brine, dried (MgSO4) and evaporated. Flash chromatography
of the residue over silica gel (1.1 × 15 cm), using 1:19 MeOHꢀEtOAc, gave 17 (20 mg, 50%) as
a colorless oil containing trace impurities (1H NMR): [α]20 +133.76 (c 0.676, CHCl3); FTIR
D
(CH2Cl2 cast) 3033, 2956, 2930, 1511 cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.49–1.57 (m, 1 H),
1.61 (s, 3 H), 1.76–2.35 (m, 7 H), 2.91–2.95 (m, 1 H), 3.24 (dt, J = 8.3, 2.0 Hz, 1 H), 3.64 (d, J =
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15.4 Hz, 1 H), 3.81 (s, 3 H), 6.86–6.89 (m, 2 H), 7.09–7.13 (m, 2 H); C NMR (CDCl3, 125
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MHz) δ 20.1 (q), 21.4 (t), 30.8 (t), 38.4 (t), 54.1 (t), 55.2 (q), 57.8 (t), 60.2 (d), 113.5 (d), 128.0
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(s), 129.8 (d), 130.3 (s), 133.7 (s), 158.2 (s); exact mass (electrospray) m/z calcd for C16H22NO
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(M + H) 244.1696, found 244.1696.
4-[(8aS)-7-Methyl-1,2,3,5,8,8a-hexahydroindolizin-6-yl]phenol [(+)-ipalbidine] (2).
BBr3 (1 M in CH2Cl2, 0.24 mL) was added to a stirred and cooled (ꢀ78 °C) solution of 17 (20
mg, 0.08 mmol) in dry CH2Cl2 (1.0 mL).11c,d The cold bath was left in place but not recharged
and stirring was continued overnight. The mixture was cooled to 0 °C and quenched by addition
of water. The mixture was stirred and saturated aqueous NaHCO3 was added until all the dark
gummy material dissolved. The mixture was extracted with CH2Cl2 and the combined organic
extracts were washed with brine, dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel (1.1 × 15 cm), using 1:19 MeOHꢀCH2Cl2, gave 2 (16 mg, 86%) as a semiꢀ
solid: FTIR (CH2Cl2 cast) 3030, 2966, 2914, 2878, 2829, 2791, 1609, 1585, 1513, 1445, 1267
1
cm−1; H NMR (CDCl3, 400 MHz) δ 1.62 (s, 3 H), 1.64–1.68 (m, 1 H), 1.81–1.86 (m, 1 H),
1.98–2.11 (m, 2 H), 2.20–2.33 (m, 3 H), 2.40–2.49 (m, 1 H), 3.10 (d, J = 15.4 Hz, 1 H), 3.30 (dt,
13
J = 1.5, 9.0 Hz, 1 H), 3.53 (d, J = 15.5 Hz), 6.79–6.82 (m, 2 H), 7.00–7.04 (m, 2 H); C NMR
(CDCl3, 125 MHz) δ 20.1 (q), 21.2 (t), 30.2 (t), 37.6 (t), 54.1 (t), 57.7 (t), 60.7 (d), 115.5 (d),
128.3 (s), 129.7 (d), 129.8 (s), 132.1 (s), 155.7 (s); exact mass (electrospray) m/z calcd for
C15H19NO (M + H) 230.1539, found 230.1542. Kugelrohr distillation of a sample (140 °C, 0.005
mmHg) gave (+)ꢀipalbidine as a glass: [α]20D +252.45 (c 1.21300, CHCl3) [Lit.8 [α]25D +233.5 (c
1, CHCl3)]. Chiral HPLC analysis [RegisPack CLAꢀ1, 250 x 4.6 cm, hexane/ethanol (90/10) +
0.1% Et2NH, 1 mL per min, wavelength 254 nm] established the ee as 99.3%. For comparison
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purposes racemic ipalbidine was made the same way as the optically active compound, starting
with racemic proline.
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2-(4-Methoxyphenyl)buta-2,3-dien-1-ol (21).29 Formaldehyde (37% aqueous solution,
0.32 mL, 3.2 mmol) was added to a vigorously stirred solution of 1ꢀ(3ꢀbromopropꢀ1ꢀyl)ꢀ4ꢀ
methoxybenzene28 (20) (0.82 g, 3.6 mmol) in 1:1 THFꢀwater (16.4 mL). Indium powder (0.62 g,
5.4 mmol) was added quickly and vigorous stirring was continued for 12 h. The mixture was
extracted with CH2Cl2 and the combined organic extracts were washed with brine, dried
(MgSO4) and evaporated. Flash chromatography of the residue over silica gel (1.8 × 16 cm),
using a gradient of hexane to 5% CH2Cl2 in hexane, gave 21 (0.52 g, 82%) as a white solid: mp
65–67 °C; FTIR (CH2Cl2 cast) 3367, 3039, 2935, 1940 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.62
(t, J = 6.0, 1 H), 3.83 (s, 3 H), 4.55–4.57 (m, 2 H), 5.24 (t, J = 2.5, 2 H), 6.89–6.92 (m, 2 H),
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7.35–7.39 (m, 2 H); C NMR (CDCl3, 125 MHz) δ 55.3 (q), 61.7 (t), 80.3 (s), 105.6 (t), 114.2
(d), 126.0 (s), 127.3 (s), 158.9 (s), 207.2 (s); exact mass (electron impact) m/z calcd for C11H12O2
176.0837, found 176.0837.
1-(1-Bromobuta-2,3-dien-2-yl)-4-methoxybenzene (22).28 CBr4 (2.74 g, 0.0081 mol)
was added to a stirred solution of 21 (1.2 g, 0.0068 mol) and Ph3P (2.14 g, 0.0081 mol) in
CH2Cl2 (25 ml) and stirring was continued at room temperature for 6 h. Evaporation of solvent
and flash chromatography of the residue over silica gel (2 × 16 cm), using 1:20 EtOAcꢀhexane,
gave 22 (1.2 g, 73.8%) as a yellow solid: mp 41–45 °C: FTIR (CH2Cl2 cast) 3038, 2956, 1934,
1512, 1250 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.85 (s, 3 H), 4.43 (s, 2 H), 5.20 (s, 2 H), 6.92–
13
6.94 (m, 2 H), 7.40–7.42 (m, 2 H); C NMR (CDCl3, 125 MHz) δ 32.0 (t), 55.3 (q), 79.3 (t),
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103.0 (s), 114.1 (s), 125.1 (d), 127.4 (d), 159.1 (s), 209.2 (s); exact mass (electron impact) m/z
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calcd for C11H11O79Br 237.9993, found 237.9995.
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(2S)-1-[2-(4-Methoxyphenyl)buta-2,3-dien-1-yl]-2-[(phenylselanyl)methyl]pyrro-
lidine (23). K2CO3 (2.76 g, 20.0 mmol) was added to a stirred solution of amine 12 (300 mg, 1.2
mmol) in dry MeCN (8.6 mL) followed by bromide 22 (230 mg, 1.0 mmol) (N2 atmosphere).
Stirring at room temperature was continued for 3 h and then water was added. The organic phase
was washed with brine, dried (MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (3 × 20 cm), using 3:7 EtOAcꢀhexane, gave 23 (280 mg, 70%) as a yellow oil:
1
FTIR (CH2Cl2 cast) 3056, 2963, 2832, 1940, 1510, 1248 cm−1; H NMR (CDCl3, 400 MHz) δ
1.66–1.76 (m, 3 H), 1.98–2.03 (m, 1 H), 2.30–2.37 (m, 1 H), 2.79–2.83 (m, 1 H), 2.99–3.04 (m,
1 H), 3.06–3.15 (m, 1 H), 3.15–3.19 (m, 1 H), 3.21–3.25 (br d, 1 H), 3.80 (s, 3 H), 3.82–3.86 (m,
1 H), 4.96–5.03 (m, 2 H), 6.85–6.88 (m, 2 H), 7.22–7.27 (m, 3 H), 7.46–7.51 (m, 4 H); 13C NMR
(CDCl3, 125 MHz) δ 22.6 (t), 31.3 (t), 33.3 (t), 54.4 (t), 55.3 (q), 55.6 (t), 63.7 (d), 102.5 (t),
113.8 (d), 126.5 (d), 127.68 (s), 127.71 (d), 129.0 (d), 131.2 (s), 132.4 (d), 158.6 (s), 209.7 (s);
exact mass (electrospray) m/z calcd for C22H26NO80Se (M + H) 400.1174, found 400.1171.
ACKNOWLEDGEMENTS
We thank the Natural Sciences and Engineering Research Council of Canada for financial
support, H. Fu for the Chiral HPLC measurement, Ted Szczerba (Regis Technologies, Inc) for
first establishing chiral HPLC conditions, and Dr. R. Sunasee for assistance in the preparation of
12.
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Supporting Information
Copies of NMR spectra of all compounds, copies of chiral HPLC and a complete list of
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references to the synthesis of racemic ipalbidine. This material is available free of charge via the
Internet at http://pubs.acs.org.
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(1) (a) Gourley, J. M.; Heacock, R. A.; McInnes, A. G.; Nikolin, B.; Smith, D. G. Chem.
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Poupat, C.; Potier, P. J. Nat. Prod. 1987, 50, 152–156.
(2) Absolute configuration of (+)ꢀipalbidine: (a) Fan, Z.; Lu, R.ꢀR.; Lao, X.; Liu, Z.ꢀJ.
Youji Huaxue 1985, 3, 249–254; Chem. Abstr. 104, 149208. (b) Liu, Z.ꢀJ.; Lu, R.ꢀR.; Chen, Q.;
Hong, H. Huaxue Xuebao 1986, 44, 729–733; Chem. Abstr. 106, 120114.
(3) Lu, RꢀR. Faming Zhuanli Shenqing Gongkai Shuomingshu 1987, CN 86100561 A
19871104; Chem. Abstr. 111, 84072.
(4) (a) Dawidar, A. M.; Winternitz, F.; Johns, S. R. Tetrahedron 1977, 33, 1733–1734 . (b)
Wang, Y.ꢀM.; Li, X.ꢀJ.; Wang, Y.ꢀW.; Gu, J.ꢀK.; Zhou, H. Chin. Trad. Herbal Drugs
(Zhongcaoyao) 2002, 33, 111–113; Chem. Abstr. 138, 86507.
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111; Chem. Abstr. 108, 179965.
(6) Chen, X.; Chu, Y.; Han, G. Zhongguo Yaolixue Tongbao 1998, 14, 167–169; Chem.
Abstr. 129, 339545.
(7) Chen, X.; Chu, Y. Zhongguo Yaolixue Tongbao 1988, 14, 243–244; Chem. Abstr. 130,
60742.
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(8) Wick, A. E.; Bartlett, P. A.; Dolphin, D. Helv. Chim. Acta 1971, 54, 513–522.
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(9) Quoted in reference 11a.
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(10) The three most recent syntheses of racemic ipalbidine: (a) Sheehan, S. M.; Padwa,
A. J. Org. Chem. 1997, 62, 438–439. (b) Ikeda, M.; Shikaura, J.; Mackawa, N.; Daibuzono, K.;
Teranishi, H.; Teraoka, Y.; Oda, N.; Ishibashi, H. Heterocycles 1999, 50, 31–34. (c) Padwa, A.;
Sheehan, S. H.; Straub, C. S. J. Org. Chem. 1999, 64, 8648–8659.
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(11) Syntheses of (+)ꢀipalbidine: (a) Liu, Z.ꢀJ.; Lu, R.ꢀR.; Chen, Q.; Hong, H. Acta
Chimica Sinica 1985, 3, 262−265. (b) Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H.
ARKIVOC 2003, viii, 188–198; preliminary communication: Honda, T.; Namiki, H.; Nagase,
H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035–3038. (c) Niphakis, M. J.; Georg, G. I. J.
Org. Chem. 2010, 75, 6019–6022. (d) Pansare, S. V.; Lingampally, R.; Dyapa, R. Eur. J. Org.
Chem. 2011, 2235−2238. (e) Hanessian, S.; Chattopadhyay, A. K. Org. Lett. 2014, 16, 232–235.
(12) In one case (reference 11a) the optical rotation is given only for the hydrobromide, for
which no comparison values are available.
(13) Examples illustrating both 6ꢀexo trig cyclization and reduction, possibly via allylic
hydrogen abstraction: (a) Ward, J.; Johnson, A. B.; Clark, G. R. Caprio, V. Synthesis 2009,
3411–3418. (b) Pedrosa, R.; Andrés, C.; DuqueꢀSoladana, J. P.; Rosón, C. D. Tetrahedron:
Asymmetry 2000, 11, 2809–2821.
(14) E.g. (a) Stork, G.; Mook, Jr., R.; Biller, S. A.; Rychnovsky, S. D. J. Am. Chem. Soc.
1983, 105, 3741–3742. (b) Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. L. Can. J. Chem. 1987,
65, 1859–1866. (c) Evans, P.A.; Roseman, J. D. Tetrahedron Lett. 1995, 36, 31–34.
(15) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735–1766.
(16) Della, E. W.; Knill, A. M. Aust. J. Chem. 1995, 48, 2047–2051.
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(17) Newcomb, M.; Musa, O. M.; Martinez, F. N.; Horner, J. H. J. Am. Chem. Soc. 1997,
119, 4569–4577.
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(18) (a) Roubaud, V.; Moigne, F. L.; Mercier, A.; Tordo, P. Synth. Commun. 1996, 26,
1507–1516. (b) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50, 1275–
1294.
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