Towards allopumiliotoxins: A concise synthesis of the indolizidine core

Article abstract of DOI:10.1002/ejoc.201101430

The common bicyclic indolizidine core present in several allopumiliotoxins was synthesized by the sequential use of a Crimmins' aldol reaction, an SOCl₂-mediated S_Ni displacement, and an intramolecular nucleophilic acyl substitution (INAS) as the key transformations. A concise synthesis of the indolizidine core of allopumiliotoxins is described by using an aldol reaction, an S_Ni displacement and an intramolecular nucleophilic acyl substitution as key steps. Copyright

Full text of DOI:10.1002/ejoc.201101430

FULL PAPER
DOI: 10.1002/ejoc.201101430
Towards Allopumiliotoxins: A Concise Synthesis of the Indolizidine Core
Bodduri V. D. Vijaykumar,[a] Pitchakuntla Mallesham,[a] and Srivari Chandrasekhar*[a]
Keywords: Alkaloids / Nitrogen heterocycles / Aldol reactions / SNi displacement reaction / Nucleophilic substitution
The common bicyclic indolizidine core present in several al-
lopumiliotoxins was synthesized by the sequential use of a
Crimmins’ aldol reaction, an SOCl2-mediated SNi displace-
ment, and an intramolecular nucleophilic acyl substitution
(INAS) as the key transformations.
Intrigued by their complexity and activity, several re-
search groups embarked on the synthesis of this class of
molecules.[3–5] Interestingly, most of the reported syntheses
began with l-proline or its analogs to stitch the second pip-
eridine skeleton leading to the indolizidine core.[3] However,
Tan and co-workers[4a,4b] utilized a cycloaddition approach
to build the indolizidine moiety. Comins et al.[4c] and Wang
et al.[4d] independently reported concise syntheses of
allopumiliotoxin 267A (1a) using an enantiopure di-
hydropyridone building block and a (β-aminoalkenyl)lith-
ium reagent, respectively.
Introduction
Dendrobates frogs are a rich source for new chemical sub-
stances, especially the poisonous materials found in the skin
secretions produced for self-defense. These and several
interesting compounds from the indolizidine class of natu-
ral products have been isolated and characterized.[1] Of
more than 40 identified alkaloids, some display potent
cardiotonic and myotonic activities.[2] Allopumiliotoxins
(i.e., 1a–d) belong to the indolizidine class of alkaloids iso-
lated from the Dendrobatidae family of frogs and are 7-hy-
droxy congeners of pumiliotoxins. The complexity involved
in this class of molecules includes a highly substituted 5,6-
fused azabicyclic core (indolizidine frame), an (E)-geomet-
ric exocyclic olefin, and a varied side chain as shown in
Figure 1.
Results and Discussion
Our group has been engaged in the total syntheses of
alkaloids with various frameworks such as piperidines, pyr-
rolidines, and indolizidines.[6] We conceived that exploi-
tation of asymmetric aldol reactions and an SNi reaction
would provide a flexible strategy for the synthesis of the
indolizidine core 2 as shown in the retrosynthetic analysis
(Scheme 1). Several allopumiliotoxins could be realized
from the indolizidine core 2, which in turn can be con-
structed from fragments 4 and 5 through 3. Fragment 4 can
be synthesized easily in a stereoselective fashion as a result
of an asymmetric aldol reaction through 6. Allylic chloride
5 can be obtained by a stereoselective SNi displacement (by
SOCl2) of the aldol adduct obtained by a Crimmins’ aldol
reaction between aldehyde 7 and propionyl auxiliary 8.
Thus, the synthesis of pyrrolidine 4 began with an asym-
metric aldol reaction[7] between benzyloxybutyraldehyde (9)
and Evans’ auxiliary-appended amide 10 by using Ti(OiPr)3-
Cl and ethyldiisopropylamine (DIPEA) to result in aldol
adduct 6 in 83% yield and approximately a dr of 95:5[8]
(Scheme 2).[9] This reaction allowed us to install the tertiary
asymmetric carbon atom with the required stereochemistry.
Methyl ester 11 was obtained in 92% yield by oxidative
cleavage of 6 followed by treatment with diazomethane. The
selective debenzylation of the primary ether group of 11 by
using Pd/C and H2 at atmospheric pressure in EtOAc pro-
Figure 1. Structure of representative allopumiliotoxin alkaloids.
[a] Division of Natural Products Chemistry, Indian Institute of
Chemical Technology,
Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: srivaric@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101430.
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Eur. J. Org. Chem. 2012, 988–994

Towards Allopumiliotoxins: A Concise Synthesis of the Indolizidine Core
A highly diastereoselective asymmetric Crimmins’ aldol
addition[10,11] of the titanium enolate derived from the aux-
iliary N-propionylthiazolidinethione 8 [TiCl4/DIPEA/NMP
[12]
(N-methylpyrrolidone)] to aldehyde 7
gave the Evans
syn-aldol product 14 as the major isolable diastereomer (dr
Ͼ 98:2)[13] in 78% yield. The newly formed chiral centers
in 14 were confirmed by converting it to a known derivative
20 via intermediate 19.[14,15] This aldol adduct 14 has a pe-
culiar iodoallylic alcohol moiety, and when treated with
SOCl2 in a mixture of Et2O/pentane, 14 underwent a dia-
stereoselective SNi displacement reaction to afford a mix-
ture of allyl chlorides 5 and 5a [(E)/(Z), respectively] in 69%
overall yield (Scheme 3).[16] This reaction facilitated the
short synthesis of chiral (E)-2-iodoallylic chloride 5 in good
selectivity and yield.
The solvent ratio (Et2O/pentane) and temperature played
a key role in the reactivity of SOCl2 with allylic alcohol 14
and in optimizing the product ratio (Table 1). The (E)/(Z)
ratio of allyl chlorides 5/5a was 7:1 by using a mixture of
Et2O/pentane (2:1) at 0 °C and then at room temp. and was
confirmed by 1H NMR spectroscopy and nOe studies (Fig-
ure 2).[17] Compound 5 showed an nOe correlation between
Scheme 1. Retrosynthetic analysis of (+)-allopumiliotoxins.
vided diol 12 in 85% yield. The mesylation of 12 to dimesyl- both the allylic protons (Ha and Hb, see Figure 2) confirm-
ate 13 was achieved in 96% yield, and upon treatment with ing the (E) configuration for the olefin, and compound 5a
BnNH2 in CH3CN at 70 °C, pyrrolidine 4 was provided in did not show any nOe correlation between the allylic pro-
95% yield.
tons confirming the (Z) configuration.
Scheme 2. Synthesis of pyrrolidine 4.
Scheme 3. Synthesis of (E)-2-iodoallylic chloride 5.
Eur. J. Org. Chem. 2012, 988–994
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989

B. V. D. Vijaykumar, P. Mallesham, S. Chandrasekhar
FULL PAPER
Table 1. Effect of solvents and temperature on the reactivity of atom than 1,3-diaxial-type interactions from the proton at
SOCl2 with allylic alcohol 14.
the third carbon atom, which can also be envisaged by
Sample Et2O/pentane Temperature and time (E)/(Z)[a] Yield of
5 and 5a
Newman projections 15Ј and 15aЈ. We assume that the
strain due to the hindrance between the large R and iodo
groups could be relieved by placing them at the maximum
possible distance from each other as shown in transition
state 15Ј, which results in the formation of (E)-allylic chlor-
ide 5 as the major isomer.
1
2
3
1:3
1:1
2:1
–78 °C to 0 °C, 4 h,
then room temp., 2 h
–78 °C to 0 °C, 4 h,
then room temp., 2 h
–78 °C to 0 °C, 4 h,
then room temp., 2 h
1.5:1
2.2:1
7:1
70%
64%
69%
Having both key fragments 4 and 5 in hand, we pro-
ceeded to the synthesis of indolizidine core 2 as shown in
Scheme 4. The hydrogenation of pyrrolidine 4 by using
standard conditions (H2, Pd/C) in MeOH at room temp.
afforded amino alcohol 16. The filtrate containing amino
alcohol 16 was concentrated and then directly subjected to
N-allylation by treatment with allylic chloride 5 in the pres-
ence of DIPEA and a catalytic amount of KI in DMF
(N,N-dimethylformamide) at room temp. for 4 h to afford
17 in 64% yield. After successful allylation of the amine,
compound 17 was treated with 1 equiv. of NaBH4 at 0 °C
to afford alcohol 3 as a viscous liquid in 79% yield with
negligible amounts of the over-reduced product of the
methyl ester. The primary alcohol in 3 was selectively con-
verted into silyl ether 18 in 91% isolated yield by using tert-
butyldimethylsilyl chloride (TBSCl) and imidazole in DMF
as the solvent at room temp. The deliberate intramolecular
nucleophilic acyl substitution (INAS) reaction was per-
formed on vinyl iodoester 18 by treatment with 2 equiv. of
nBuLi in tetrahydrofuran (THF) at –78 °C to afford enone
2 in 67% yield, which completes the concise synthesis for
the indolizidine core of (+)-allopumiliotoxins.[19]
1
[a] (E)/(Z) ratios were determined by H NMR spectroscopy.
Figure 2. nOe correlation between allylic protons in 5 and 5a.
On the basis of the above results, the selectivity of re-
arranged (E) isomer 5 over (Z) isomer 5a in the allylic chlor-
ination reaction can be explained by an SNi process[18]
through a hypothetical chair-like six-membered transition
state as shown in Figure 3. The large R group would induce
1,3-diaxial-type interactions in transition state 15, but not
in 15a. In contrast, the R group is likely to face more steric
hindrance from the bulky iodo group at the adjacent carbon
Conclusions
We have achieved a concise synthesis for the indolizidine
core 2 of allopumiliotoxins by using asymmetric aldol reac-
tions, an SOCl2-mediated stereoselective SNi displacement
reaction, and an INAS reaction as the key transformations.
Experimental Section
General Methods: FTIR spectra were recorded as KBr thin films
Figure 3. Plausible chlorination transition states for 15.
or neat. For low- (MS) and high-resolution mass spectrometry
Scheme 4. Synthesis of allopumiliotoxin core 2.
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Eur. J. Org. Chem. 2012, 988–994

Towards Allopumiliotoxins: A Concise Synthesis of the Indolizidine Core
(HRMS), m/z (mass/charge) ratios are reported as values in atomic
mass units. All the reagents and solvents were reagent grade and
used without further purification unless specified otherwise. Tech-
nical grade ethyl acetate and petroleum ether used for column
chromatography were distilled prior to use. Column chromatog-
raphy was carried out by using silica gel (60–120 mesh) packed in
glass columns. All the reactions were performed under nitrogen in
flame- or oven-dried glassware with magnetic stirring. The prod-
ucts were characterized by IR spectroscopy, 1H and 13C NMR
spectroscopy, and mass spectrometry.
(5 mL) and aqueous KOH (10 % aqueous solution, 2 mL,
3.5 mmol). The mixture was cooled to 0 °C, N-nitroso-N-meth-
ylurea (NMU·HCl; 313 mg, 3.05 mmol) was slowly added, and the
mixture was vigorously stirred. After 10–15 min, the diethyl ether
layer was separated, dried with anhydrous Na2SO4, and slowly
added to the carboxylic acid at 0 °C. After complete consumption
of the acid, the reaction mixture was concentrated. Purification by
flash column chromatography on silica gel (10% EtOAc in hexanes)
afforded methyl ester 11 (0.52 g, 92%) as clear, colorless oil. Rf =
0.29 (SiO , 30% EtOAc in petroleum ether). IR (neat): νmax = 3443,
˜
2
2926, 2857, 1734, 1453, 1373, 1262, 1125, 1118, 738 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.25 (m, 10 H), 4.56–4.44 (m, 2 H),
4.49 (s, 2 H), 3.80 (d, J = 10.0 Hz, 1 H), 3.76 (s, 3 H), 3.50 (t, J =
6.0 Hz, 2 H), 2.82 (br. s, 1 H), 1.92–1.78 (m, 1 H), 1.77–1.63 (m, 2
H), 1.52 (s, 3 H), 1.51–1.41 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 173.6, 138.3, 138.2, 128.3, 128.3, 127.6, 127.5, 127.5,
82.9, 75.7, 72.8, 70.0, 66.9, 52.0, 28.1, 26.6, 17.1 ppm. MS (ESI):
m/z (%) = 395 (100) [M + Na]+. [α]2D5 = +6.9 (c = 1.0, CH2Cl2).
(4R)-3-[(2R,3R)-2,6-Bis(benzyloxy)-3-hydroxy-2-methylhexanoyl]-
5,5-dimethyl-4-phenyloxazolidin-2-one (6): In a clean, dry 250 mL
round-bottomed flask, equipped with magnetic stir bar, under ni-
trogen, freshly distilled diisopropylamine (0.58 mL, 4.16 mmol) was
dissolved in dry THF (15 mL). The resulting clear, colorless solu-
tion was cooled to –78 °C in a dry ice/acetone bath. To it was added
nBuLi (2.5 m solution in hexane, 1.03 mL, 2.57 mmol) dropwise,
and the cold reaction mixture was stirred at –78 °C for 20 min.
(4R)-5,5-Dimethyl-4-phenyloxazolidin-2-one 10 (0.7 g, 1.98 mmol)
was dissolved in THF (5 mL), and the resulting solution was added
dropwise to the freshly prepared lithium diisopropylamide (LDA)
to afford a pale yellow solution that was stirred at –78 °C for
30 min. To it was added Ti(OiPr)3Cl (1 m solution in THF,
6.54 mL, 6.54 mmol) dropwise by syringe to give rise to a dark red/
brown solution that was stirred at –40 °C for 1 h. After cooling the
reaction mixture to –78 °C, 4-(benzyloxy)butanal (9; 1.06 g,
5.95 mmol) in THF (5 mL) was added dropwise to the reaction
mixture. The reaction mixture was stirred at –40 °C for 2 h. After
completion of the reaction, which was monitored by thin layer
chromatography, it was quenched under cold conditions by the ad-
dition of saturated NH4Cl (2 mL) and Celite. After warming to
room temp., the resulting suspension was filtered through a fritted
funnel, the filter cake was rinsed with ethyl acetate, and the filtrate
was concentrated in vacuo. The crude reaction mixture was purified
by flash column chromatography on silica gel (10% EtOAc in hex-
anes) to afford compound 6 (0.87 g, 83%) as a white solid. Rf =
0.35 (SiO2, 30% EtOAc in petroleum ether); m.p. 82–84 °C. IR
Methyl (2R,3R)-2-(Benzyloxy)-3,6-dihydroxy-2-methylhexanoate
(12): To a solution of compound 11 (0.465 g, 1.25 mmol) in EtOAc
(10 mL) was added Pd/C (10%, 15 mg, 0.13 mmol). The mixture
was stirred under hydrogen. After 2 h, the reaction mixture was
filtered through a short bed of Celite to remove the catalyst and
washed with EtOAc (2ϫ5 mL). The filtrate was concentrated in
vacuo. Purification of the crude compound by column chromatog-
raphy on silica gel (30% EtOAc in hexanes) afforded compound 12
(0.299 g, 85%) as a viscous liquid. Rf = 0.34 (SiO2, 40% EtOAc in
petroleum ether). IR (neat): ν
= 3390, 2943, 2872, 2360, 1731,
˜
max
1514, 1453, 1265, 1123, 742 cm–1. H NMR (300 MHz, CDCl3): δ
= 7.40–7.27 (m, 5 H), 4.56–4.45 (m, 2 H), 3.83–3.78 (m, 1 H), 3.78
(s, 3 H), 3.72–3.56 (m, 2 H), 2.76 (br. s, 2 H), 1.79–1.66 (m, 3 H),
1.53 (s, 3 H), 1.51–1.40 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 173.5, 138.1, 128.3, 127.6, 82.9, 75.9, 67.0, 62.6, 52.1, 29.7,
28.1, 17.1 ppm. HRMS (ESI): calcd. for C15H23O5 [M + H]+
283.1540; found 283.1513. [α]2D5 = +8.0 (c = 1.35, CHCl3).
1
Methyl (2R,3R)-2-(Benzyloxy)-2-methyl-3,6-bis(methylsulfonyloxy)-
hexanoate (13): Diol 12 (0.245 g, 0.86 mmol) was dissolved in dry
CH2Cl2 (5 mL), and pyridine (346 μL, 4.34 mmol) was added at
0 °C under nitrogen. To the mixture, MsCl (167 μL, 2.17 mmol)
was added slowly, and the reaction mixture was stirred at room
temp. After confirming the complete consumption of the starting
material by TLC, HCl (1 n, 4 mL) was added, and the mixture was
extracted with CH2Cl2 (2ϫ5 mL). The combined organic layers
were washed with saturated NaHCO3, separated, dried with
Na2SO4, and concentrated in vacuo. The crude product was puri-
fied by column chromatography on silica gel (20% EtOAc in hex-
anes) to afford dimesyl compound 13 (0.365 g, 96% yield) as an
oily liquid. Rf = 0.24 (SiO2, 30% EtOAc in petroleum ether). IR
(neat): νmax = 3445, 2930, 2861, 2360, 1778, 1696, 1508, 1456, 1370,
˜
1
1217, 1100, 740 cm–1. H NMR (300 MHz, CDCl3): δ = 7.37–7.24
(m, 13 H), 7.18–7.11 (m, 2 H), 5.14 (s, 1 H), 4.54–4.45 (m, 5 H),
3.51–3.45 (m, 2 H), 3.23 (br. s, 1 H), 1.92–1.78 (m, 1 H), 1.75–1.58
(m, 2 H), 1.69 (s, 3 H), 1.54–1.40 (m, 1 H), 1.49 (s, 3 H), 0.94 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.3, 151.7, 138.4,
138.2, 136.3, 128.7, 128.5, 128.3, 127.6, 127.4, 127.3, 127.3, 126.3,
85.9, 82.0, 73.5, 72.8, 70.1, 69.0, 66.6, 28.8, 28.5, 26.4, 23.6,
16.8 ppm. HRMS (ESI): calcd. for C32H38NO6 [M + H]+ 532.2694;
found 532.2665. [α]2D5 = –44.0 (c = 1.0, CH2Cl2).
Methyl (2R,3R)-2,6-Bis(benzyloxy)-3-hydroxy-2-methylhexanoate
(11): To a solution of compound 6 (0.81 g, 1.52 mmol) in MeOH
(10 mL) in a 25 mL round-bottomed flask were added LiOH (10%
aqueous solution, 0.73 mL, 3.05 mmol) and H2O2 (25% solution,
1.02 mL, 10.88 mmol) very slowly at 0 °C. After 15 min at the same
temperature, TLC was used to monitor for the completion of the
reaction, and the reaction was quenched by the addition of a satu-
rated solution of Na2SO3 (2 mL) followed by aqueous NaHCO3
(2 mL). The solvent, MeOH, was evaporated under reduced pres-
sure at low temperature. The aqueous layer was diluted with water
and acidified by the addition of HCl (1 n), and the carboxylic acid
was extracted with ethyl acetate (4ϫ10 mL). The combined or-
ganic layers were dried with Na2SO4, filtered, and concentrated.
The crude acid was dissolved in diethyl ether (5 mL), and the solu-
tion was cooled to 0 °C in an ice bath. To a separate 25 mL round-
bottomed flask equipped with stir bar were added diethyl ether
(neat): ν
= 3026, 2977, 1691, 1516, 1344, 1259, 1164, 1054,
˜
max
741 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H),
4.95–4.88 (m, 1 H), 4.5 (q, J = 10.3 Hz, 2 H), 4.35–4.20 (m, 2 H),
3.82 (s, 3 H), 2.97 (s, 3 H), 2.92 (s, 3 H), 2.08–1.82 (m, 4 H), 1.57
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.5, 137.3, 128.3,
127.9, 84.6, 82.1, 69.0, 67.1, 52.5, 38.8, 37.2, 25.9, 25.4, 17.1 ppm.
HRMS (ESI): calcd. for C17H30NO9S2 [M + NH4]+ 456.1356;
found 456.1318. [α]2D5 = +12.5 (c = 1.0, CHCl3).
Methyl (2R)-2-(Benzyloxy)-2-[(2S)-1-benzylpyrrolidin-2-yl]propano-
ate (4): In a 50 mL round-bottomed flask, compound 13 (0.316 g,
0.72 mmol) was dissolved in CH3CN (5 mL), and the solution was
stirred under nitrogen. Benzylamine (231 mg, 2.16 mmol) was
added, and the reaction mixture was heated to reflux until the start-
ing material was consumed (monitored by TLC). After 4 h,
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991

B. V. D. Vijaykumar, P. Mallesham, S. Chandrasekhar
FULL PAPER
CH3CN was removed under reduced pressure, and the reaction
mixture was diluted with water (10 mL). The compound was ex-
tracted with diethyl ether (2ϫ10 mL). The combined organic layers
were dried with Na2SO4 and concentrated in vacuo. The crude resi-
due was purified on silica gel by column chromatography (5%
ter completion in 15 min (monitored by TLC), the reaction was
quenched by the addition of saturated NH4Cl (1 mL), and MeOH
was evaporated under reduced pressure. The aqueous layer was di-
luted with water (4 mL), and the compound was extracted with
ethyl acetate (2ϫ5 mL). The combined organic layers were dried
EtOAc in hexanes) to afford pyrrolidine 4 (242 mg, 95%) as an oily, with Na2SO4 and concentrated in vacuo. Purification by flash
yellow liquid. Rf = 0.44 (SiO2, 10% EtOAc in petroleum ether). chromatography (15 % EtOAc in hexanes) afforded 1,3-diol 19
IR (neat): ν = 2950, 2867, 2361, 1734, 1454, 1378, 1259, 1113, (0.104 g, 96%) as a colorless liquid. IR (neat): ν = 2928, 2862,
˜
˜
max
max
737 cm–1. H NMR (300 MHz, CDCl3): δ = 7.41–7.16 (m, 10 H), 2355, 1444, 1160 cm–1. H NMR (300 MHz, CDCl3): δ = 6.48 (d,
1
1
4.55 (d, J = 11.3 Hz, 1 H), 4.46 (d, J = 13.5 Hz, 1 H), 4.35 (d, J = J = 2.0 Hz, 1 H), 5.96 (s, 1 H), 4.19 (d, J = 4.0 Hz, 1 H), 3.74–3.68
11.3 Hz, 1 H), 3.73 (s, 3 H), 3.38 (d, J = 13.5 Hz, 1 H), 3.21 (dd,
J = 8.8, 4.7 Hz, 1 H), 2.96–2.87 (m, 1 H), 2.28–2.19 (m, 1 H), 1.86–
1.73 (m, 1 H), 1.73–1.59 (m, 3 H), 1.56 (s, 3 H) ppm. 13C NMR
(m, 2 H), 2.23 (br. s, 1 H), 2.20–2.13 (m, 1 H), 0.95 (d, J = 7.0 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 125.4, 114.1, 79.2,
65.9, 37.5, 9.4 ppm. MS (ESI): m/z (%) = 243 (100) [M + H]+.
(75 MHz, CDCl3): δ = 174.0, 140.8, 138.7, 128.4, 128.1, 128.0, [α]2D0 = –1.94 (c = 0.72, CHCl3).
127.2, 126.4, 85.5, 69.1, 67.0, 61.1, 54.8, 51.8, 27.3, 23.8, 15.9 ppm.
(2S,3E)-1-[(3S)-4-Benzyl-2-thioxothiazolidin-3-yl]-5-chloro-4-iodo-
HRMS (ESI): calcd. for C22H27NO3 [M + H]+ 354.2064; found
2-methylpent-3-en-1-one (5): In a 25 mL round-bottomed flask
equipped with a stir bar, compound 14 (0.638 g, 1.42 mmol) was
dissolved in Et2O/pentane (2:1, 50 mL), and the solution was co-
oled to 0 °C. To this mixture was added SOCl2 in Et2O/pentane
(2:1, 20 mL) at 0 °C, and the reaction mixture was stirred at room
temp. for 5 h. The reaction mixture was cooled to –78 °C, and Et3N
(3.97 mL, 28.5 mmol) was added. The resulting mixture was stirred
for 30 min followed by the addition of saturated NaHCO3 (10 mL).
The compound was extracted with Et2O (2ϫ10 mL). The com-
bined organic layers were dried with Na2SO4 and concentrated
quickly in vacuo at room temp. The crude residue was purified by
flash column chromatography on silica gel (5% EtOAc in hexanes)
to afford (E)-2-iodoallyl chloride 5 (0.405 g, 61%) as viscous, yel-
low liquid. Rf = 0.48 (SiO2, 10% EtOAc in petroleum ether). IR
354.2055. [α]2D5 = +3.79 (c = 1.45, CHCl3).
2-Iodoacrylaldehyde (7): To a solution of acrylaldehyde (1.0 g,
17.8 mmol) dissolved in diethyl ether (25 mL) was added triethyl-
amine (1.24 mL, 8.9 mmol) at 0 °C. To the mixture was added io-
dine (1.29 g, 8.9 mmol) in portions at the same temperature. After
15 min, the reaction mixture was filtered through a bed of Celite,
and the filtrate was concentrated in vacuo at low temperature.
Bulb-to-bulb distillation (b.p. 64 °C/18 mm) of the crude residue
afforded 2-iodoacrylaldehyde (7; 40%) as a yellow liquid. Rf = 0.60
(SiO , 5 % EtOAc in petroleum ether). IR (neat): ν
= 3445,
˜
2
max
1634 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.60 (s, 1 H), 7.42 (d,
J = 1.5 Hz, 1 H), 7.27 (d, J = 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 186.8, 144.3, 113.0 ppm.
(neat): ν
= 2926, 2857, 2360, 1689, 1448, 1344, 1192, 869,
˜
max
742 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H),
6.49 (d, J = 10.0 Hz, 1 H), 4.89 (ddd, J = 10.3, 6.9, 3.7 Hz, 1 H),
4.67 (qd, J = 10.1, 6.7 Hz, 1 H), 4.48 (d, J = 12.4 Hz, 1 H), 4.25
(d, J = 12.4 Hz, 1 H), 3.37 (ddd, J = 11.3, 7.1, 0.7 Hz, 1 H), 3.13
(dd, J = 13.0, 3.5 Hz, 1 H), 2.95 (dd, J = 13.2, 10.3 Hz, 1 H), 2.92
(d, J = 11.5 Hz, 1 H), 1.32 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.6, 171.8, 144.1, 136.3, 129.3, 128.8,
127.2, 97.3, 59.9, 49.2, 40.8, 37.3, 28.6, 17.7 ppm. MS (EI): m/z =
449 [M – OH]+, 414 [449 – Cl]+, 322 [449 – I]+, 286 [322 – Cl]+.
[α]2D5 = +82.16 (c = 1.25, CHCl3).
(2S,3S)-1-[(4S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-hydroxy-4-iodo-
2-methylpent-4-en-1-one (14): A solution of the N-acylthiazolidine-
thione 8 (0.548 g, 2.06 mmol) in CH2Cl2 (20 mL) was cooled to
0 °C and stirred under nitrogen. TiCl4 (1.08 mL, 2.17 mmol) was
added, and the mixture was stirred for 5 min. DIPEA (0.39 mL,
2.27 mmol) was added slowly dropwise to observe a dark brown
solution. This solution was stirred at 0 °C for 40 min, and then 1-
methyl-2-pyrrolidinone (0.20 mL, 2.06 mmol) was added at the
same temperature. After 10 min, freshly distilled 2-iodoacrylal-
dehyde (7; 0.451 g, 2.48 mmol) was added, and the reaction mixture
was stirred at 0 °C for 1 h. The reaction was quenched by the ad-
dition of saturated NH4Cl, and the mixture was warmed to 25 °C.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2ϫ). The combined extracts were washed with brine,
dried with Na2SO4, filtered, and concentrated in vacuo. Purifica-
tion by flash chromatography (10% EtOAc in hexanes) afforded
aldol adduct 14 (0.72 g, 78% yield) as a yellow solid. Rf = 0.30
(SiO2, 20% EtOAc in petroleum ether); m.p. 103–105 °C. IR (neat):
Methyl (2R)-2-[(2S)-1-{(2E,4S)-5-[(4S)-4-Benzyl-2-thioxothiazol-
idin-3-yl]-2-iodo-4-methyl-5-oxopent-2-enyl}pyrrolidin-2-yl]-2-
hydroxypropanoate (17): To a stirred solution of pyrrolidine 4
(0.183 g, 0.51 mmol) in MeOH (4 mL) was added Pd/C (10 %,
0.006 g, 0.05 mmol), and then the mixture was stirred under hydro-
gen with the help of hydrogen balloons. After 4 h, the reaction mix-
ture was filtered through a short bed of Celite and washed with
MeOH (2ϫ4 mL). The filtrate was concentrated in vacuo. This
crude amino alcohol 16 (0.089 g, 99%) was used directly in the next
reaction without further purification; Rf = 0.21 (SiO2, 20% MeOH
in CH2Cl2). To a stirred solution of amino alcohol 16 (0.089 g,
0.51 mmol) in dry DMF (1 mL) were added DIPEA (133 μL,
0.77 mmol) and allyl chloride 5 (0.314 g, 0.67 mmol) in dry DMF
(1 mL) followed by a catalytic amount of KI (26 mg, 0.15 mmol).
The reaction mixture was stirred at room temp. for 4 h. After con-
sumption of the amine (monitored by TLC), water (5 mL) was
added to the reaction mixture, and the compound was extracted
with ethyl acetate (2ϫ5 mL). The combined organic layers were
dried with Na2SO4 and concentrated in vacuo. The crude residue
was purified by flash column chromatography on silica gel (10%
EtOAc in hexanes) to afford coupled compound 17 (0.199 g, 64%)
as viscous, yellow liquid. Rf = 0.34 (SiO2, 20% EtOAc in petroleum
ν
˜
= 2925, 2853, 2356, 1680, 1459, 1164 cm–1 1H NMR
.
max
(300 MHz, CDCl3): δ = 7.35–7.21 (m, 5 H), 6.48 (d, J = 1.5 Hz, 1
H), 5.90 (s, 1 H), 5.12 (ddd, J = 10.5, 6.7, 3.7 Hz, 1 H), 4.61 (quint,
J = 6.7 Hz, 1 H), 4.00 (t, J = 5.2 Hz, 1 H), 3.44 (dd, J = 11.3,
6.7 Hz, 1 H), 3.22 (dd, J = 13.5, 3.7 Hz, 1 H), 3.04 (dd, J = 12.8,
10.5 Hz, 1 H), 2.91 (d, J = 11.3 Hz, 1 H), 2.53 (d, J = 5.2 Hz, 1
H), 1.32 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 201.0, 176.4, 136.2, 129.4, 128.8, 127.9, 127.2, 113.1, 79.5, 68.8,
44.3, 36.6, 32.7, 12.0 ppm. HRMS (ESI): calcd. for C16H18INO2S2
[M + H]+ 447.9896; found 447.9931. [α]2D5 = +175.36 (c = 1.0,
CHCl3).
(2R,3S)-4-Iodo-2-methylpent-4-ene-1,3-diol (19): In a 25 mL round-
bottomed flask equipped with a stir bar, compound 14 (0.200 g,
0.44 mmol) was dissolved in MeOH (2 mL), and the solution was
cooled to 0 °C. NaBH4 (0.034 g, 0.89 mmol) was added slowly. Af-
ether). IR (neat): ν
= 2926, 2856, 1737, 1692, 1546, 1194,
˜
max
992
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 988–994

Towards Allopumiliotoxins: A Concise Synthesis of the Indolizidine Core
746 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.34–7.30 (m, 2 H), were washed with brine, dried with Na2SO4, and concentrated in
7.28–7.24 (m, 3 H), 6.39 (d, J = 9.7 Hz, 1 H), 4.86 (ddd, J = 10.6,
6.7, 3.8 Hz, 1 H), 4.73 (qd, J = 10.6, 6.7 Hz, 1 H), 3.74 (s, 3 H),
3.35 (dd, J = 11.6, 7.7 Hz, 1 H), 3.26 (dd, J = 7.7, 5.8 Hz, 1 H),
3.16 (d, J = 14.5 Hz, 1 H), 3.09 (dd, J = 12.6, 2.9 Hz, 1 H), 3.04–
2.88 (m, 4 H), 2.36–2.28 (m, 1 H), 2.23–2.14 (m, 1 H), 1.94–1.85
(m, 2 H), 1.79–1.59 (m, 2 H), 1.32 (s, 3 H), 1.24 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.0, 172.4, 172.3,
140.4, 136.3, 129.3, 128.8, 127.2, 106.9, 75.6, 68.7, 60.2, 59.7, 54.1,
52.4, 40.9, 37.2, 28.6, 26.6, 24.1, 22.6, 17.9 ppm. MS (ESI): m/z =
586 [M – OH]+. [α]2D5.6 = +46.33 (c = 1.1, CHCl3).
vacuo. The crude residue was purified on silica gel by column
chromatography (10 % EtOAc in hexanes) to afford enone 2
(0.036 g, 67%) as a colorless oil. Rf = 0.25 (SiO2, 20% EtOAc in
petroleum ether). IR (neat): ν
= 3392, 2926, 2856, 1622, 1460,
˜
max
1384, 1085, 839, 778 cm–1. H NMR (300 MHz, CDCl3): δ = 6.49
(d, J = 10.1 Hz, 1 H), 4.03 (d, J = 14.3 Hz, 1 H), 3.54–3.34 (m, 2
H), 3.26–3.14 (m, 1 H), 3.04 (dd, J = 14.1, 2.4 Hz, 1 H), 2.63–2.47
(m, 1 H), 2.46–2.25 (m, 1 H), 2.00–1.92 (m, 2 H), 1.90–1.76 (m, 2
H), 1.70–1.45 (m, 2 H), 1.26 (s, 3 H), 1.0 (d, J = 6.6 Hz, 3 H), 0.86
(s, 9 H), 0.02 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.0,
144.4, 131.3, 73.0, 69.2, 67.0, 55.1, 52.2, 35.9, 31.9, 25.8, 23.5, 22.7,
18.2, 17.8, –5.3, –5.4 ppm. HRMS (ESI): calcd for C19H36NO3Si
[M + H]+ 354.2459; found 354.2434. [α]3D0 = –10.65 (c = 1.0,
CHCl3).
1
Methyl (2R)-2-Hydroxy-2-{(2S)-1-[(2E,4S)-5-hydroxy-2-iodo-4-
methylpent-2-enyl]pyrrolidin-2-yl}propanoate (3): To a solution of
17 (0.188 g, 0.31 mmol) in MeOH (5 mL), NaBH4 (0.013 g,
0.34 mmol) was added at –20 °C under nitrogen, and the mixture
was stirred at 0 °C for 5 min. When still cold, the reaction was
quenched by the addition of saturated NH4Cl (3 mL), and the com-
pound was extracted with CH2Cl2 (2ϫ5 mL). The combined or-
ganic layers were dried with Na2SO4 and concentrated in vacuo.
The crude residue was purified on silica gel by column chromatog-
raphy (15% EtOAc in hexanes) to afford diol 3 (0.098 g, 79%) as
a colorless, oily liquid. Rf = 0.20 (SiO2, 30% EtOAc in petroleum
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new compounds.
Acknowledgments
B. V. D. V. and P. M. are grateful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for the research fellow-
ships.
ether). IR (neat): ν
= 3396, 2956, 2926, 1730, 1623, 1452, 1255,
˜
max
1117, 1039 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.15 (d, J =
10.0 Hz, 1 H), 3.78 (s, 3 H), 3.51 (dd, J = 10.3, 5.2 Hz, 1 H), 3.38–
3.18 (m, 4 H), 3.15–3.05 (m, 1 H), 2.84–2.68 (m, 1 H), 2.42 (dd, J
= 16.9, 7.5 Hz, 1 H), 1.94–1.85 (m, 2 H), 1.80–1.66 (m, 2 H), 1.34
(s, 3 H), 0.96 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 177.1, 146.8, 102.1, 75.7, 69.3, 66.5, 60.7, 54.1, 52.5,
39.2, 26.6, 24.0, 23.1, 16.4 ppm. HRMS (ESI): calcd for
C14H25INO4 [M + H]+ 398.0823; found 398.0809. [α]2D5.6 = –45.86
(c = 1.0, CHCl3).
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Methyl (2R)-2-{(2S)-1-[(2E,4S)-5-(tert-Butyldimethylsilyloxy)-2-
iodo-4-methylpent-2-enyl]pyrrolidin-2-yl}-2-hydroxypropanoate (18):
To a solution of diol 3 (0.076 g, 0.19 mmol) in DMF (1.5 mL) were
added imidazole (0.039 g, 0.57 mmol) and TBSCl (0.043 g,
0.28 mmol) at room temp. After 2 h, the reaction mixture was di-
luted with water (2 mL), and the compound was extracted with
Et2O (2ϫ3 mL). The combined organic layers were washed with
brine, dried with Na2SO4, and concentrated in vacuo. The crude
residue was purified on silica gel by column chromatography (5%
EtOAc in hexanes) to afford the silyl ether 18 (0.089 g, 91%) as a
colorless, oily liquid. Rf = 0.44 (SiO2, 10% EtOAc in petroleum
ether). IR (neat): ν
= 2924, 2855, 1738, 1461, 1106, 839,
˜
max
778 cm–1. H NMR (300 MHz, CDCl3): δ = 6.04 (d, J = 10.0 Hz,
1 H), 3.73 (s, 3 H), 3.42–3.29 (m, 2 H), 3.28–3.19 (m, 2 H), 3.04–
2.88 (m, 2 H), 2.79–2.68 (m, 1 H), 2.29–2.18 (m, 1 H), 1.92–1.81
(m, 2 H), 1.78–1.60 (m, 2 H), 1.30 (s, 3 H), 0.91 (d, J = 6.6 Hz, 3
H), 0.85 (s, 9 H), 0.01 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 177.0, 146.0, 103.9, 75.5, 68.6, 66.9, 59.8, 53.6, 52.3, 39.1, 26.8,
25.8, 24.1, 22.7, 18.2, 16.4, –5.2, –5.4 ppm. HRMS (ESI): calcd. for
C20H39INO4Si [M + H]+ 512.1688; found 512.1692. [α]2D5.6 = –25.40
(c = 1.0, CHCl3).
1
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propylidene]-8-hydroxy-8-methylhexahydroindolizin-7(1H)-one (2):
A solution of 18 (0.077 g, 0.15 mmol) in dry THF (5 mL) was co-
oled to –78 °C under nitrogen, and nBuLi (125 μL, 0.31 mmol) was
added. The reaction mixture was stirred at the same temperature
for 30 min and was monitored by TLC for the consumption of
starting material. The reaction was quenched by the addition of a
saturated solution of NH4Cl (4 mL), and the compound was ex-
tracted with ethyl acetate (2ϫ5 mL). The combined organic layers
Eur. J. Org. Chem. 2012, 988–994
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
993

B. V. D. Vijaykumar, P. Mallesham, S. Chandrasekhar
FULL PAPER
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water, 70:30; flow rate: 1.0 mL/min; retention time [min] =
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[13] HPLC analysis: Waters Atlantis dc18 column, 150ϫ4.6 mm,
5 μm; acetonitrile/water, 60:40; flow rate: 1.0 mL/min; retention
time [min]: 9.12 (major) and 10.44 (minor).
[14] Aldol adduct 14 was treated with NaBH4 in MeOH to afford
diol 19 (96% yield), which upon treatment with an excess
amount of nBuLi in THF gave known diol 20[15] (83% yield).
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[19] The stereoselective reduction of the carbonyl functionality in
analogs of enone 2 to (R)- as well as (S)-hydroxy groups has
been well established.[4c,4d,5] Thus, 2 can be utilized for ac-
cessing (+)-allopumiliotoxins.
Received: September 30, 2011
Published Online: December 16, 2011
994
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 988–994