Total syntheses of heliotridane and pseudoheliotridane through nitrodiene–acrylate 6π-electrocyclization/[3+2] cycloaddition

Article abstract of DOI:10.1016/j.tet.2016.12.056

The total syntheses of the pyrrolizidine alkaloids heliotridane and pseudoheliotridane have been accomplished in six steps (overall yields: 24 and 7%, respectively) using, for the first time, the tandem 6π-electrocyclization/[3+2] dipolar cycloaddition of

Full text of DOI:10.1016/j.tet.2016.12.056

Accepted Manuscript
Total syntheses of heliotridane and pseudoheliotridane through nitrodiene–acrylate
6π-electrocyclization/[3+2] cycloaddition
Esra Koc, Ohyun Kwon
PII:
S0040-4020(16)31353-9
10.1016/j.tet.2016.12.056
TET 28348
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 July 2016
Revised Date: 30 November 2016
Accepted Date: 22 December 2016
Please cite this article as: Koc E, Kwon O, Total syntheses of heliotridane and pseudoheliotridane
through nitrodiene–acrylate 6π-electrocyclization/[3+2] cycloaddition, Tetrahedron (2017), doi: 10.1016/
j.tet.2016.12.056.
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ACCEPTED MANUSCRIPT
Koc and Kwon
Total Syntheses of Heliotridane and Pseudoheliotridane
Through Nitrodiene–Acrylate 6π-Electrocyclization/[3+2] Cycloaddition
Esra Koc†‡ and Ohyun Kwon*‡
† Current Address: Department of Chemistry, Faculty of Arts and Sciences, University of
Gaziosmanpasa, Tokat, 60250, Turkey.
‡ Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E.
Young Dr. East, Los Angeles, California 90095-1569.
Keywords
nitrodiene, 6π-electrocyclization/[3+2] cycloaddition, total synthesis, pyrrolizidine alkaloids,
heliotridane, pseudoheliotridane
* Corresponding author E-mail address: ohyun@chem.ucla.edu
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Graphical Abstract
Abstract
The total syntheses of the pyrrolizidine alkaloids heliotridane and pseudoheliotridane have been
accomplished in six steps (overall yields: 24 and 7%, respectively) using, for the first time, the tandem
6π-electrocyclization/[3+2] dipolar cycloaddition of an acyclic nitrodiene, 1-nitro-2-methyl-1,3-
butadiene.
Introduction
Pyrrolizidine alkaloids are widespread in Nature and possess a diverse array of biological activities,
including hepatotoxicity, pneumotoxicity, and nucleotoxicity (mutagenesis, carcinogenesis, and
antimitotic effects).1 These biological activities, in conjunction with often novel structures, have made
the pyrrolizidine alkaloids popular synthetic targets for showcasing new synthetic methods and
strategies.2 With few exceptions,3 the syntheses of pyrrolizidine alkaloids described to date have mainly
relied on chiral pool materials as starting materials.4 The tandem [4+2]/[3+2] cycloaddition process
developed by Denmark has been applied successfully to the syntheses of a variety of pyrrolizidine
alkaloids, including platynecine, rosmarinecine, crotanecine, australine, and 3-epiaustraline.5 We
recently developed6 a new, general strategy, based on tandem 6π-electrocyclization of nitrodienes and
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[3+2] cycloaddition of the resulting nitronates, to form nitroso acetals with well-defined
stereochemistry. In this one-pot domino process, two rings are formed and one quaternary center is
generated, with the products obtained predominantly as single diastereoisomers in good yields.
Hydrogenolysis of the resulting nitroso acetals provides functionalized, synthetically useful, five-
membered azacyclic ring systems with well-defined stereochemistry, suitable for the formation of
pyrrolizidine alkaloids.
N
H
N
H
CH3
CH3
Pseudoheliotridane
Heliotridane
2
1
Figure 1. Heliotridane and pseudoheliotridane
The pyrrolizidine alkaloids heliotridane (1) and pseudoheliotridane (2) are natural products that
have been isolated from various plant sources. Heliotridane has been obtained as a degradation product
of a large number of alkaloids found in the Senecio, Heliotrofiiuna, Crotalaria, Erechtites, and
Trichodesma genera. Pseudoheliotridane, a diastereoisomer of heliotridane, has been obtained from the
alkaloids in Trachelanthus korolkovi.7
This paper describes the total syntheses of the pyrrolizidine alkaloids heliotridane and
pseudoheliotridane using, for the first time, the tandem 6π-electrocyclization/[3+2] cycloaddition
reaction developed for cyclic nitrodienes but, instead, applying an acyclic nitrodiene, 1-nitro-2-methyl-
1,3-butadiene.
Results and Discussion
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Scheme 1 illustrates the synthetic blueprint for heliotridane. We expected the tandem isomerization/6π-
electrocyclization/[3+2] cycloaddition of 1-nitro-2-methyl-1,3-butadiene (3) with methyl acrylate to
result in the nitroso acetal 4b. According to our previous observations, we anticipated that treatment of
this nitroso acetal with Raney nickel and H2, and subsequent heating under reflux in toluene, would
provide the bicyclic lactam 5.6 Sequential deoxygenation and reduction of 5 would then give the
pyrrolizidine alkaloids heliotridane and pseudoheliotridane.
Scheme 1. Synthetic Plan for Heliotridane and Pseudoheliotridane
First, we synthesized 1-nitro-2-methyl-1,3-butadiene (3) from isoprene (6) in four steps through
modification of known patent procedures.8,9 Nitroacetylation of isoprene with HNO3 and Ac2O gave 3-
methyl-4-nitrobut-2-en-1-yl acetate (7) in 34% yield. 3-Methyl-4-nitrobut-2-en-1-ol (8) was obtained
after hydrolysis of 7 with p-TsOH in MeOH in 89% yield. Bromination of 8 provided 4-bromo-2-
methyl-1-nitrobut-2-ene (9) in 97% yield. Treatment of 9 with Et3N furnished 3 in 98% yield as a 1:3.4
mixture of E/Z-isomers (Scheme 2).
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Scheme 2. Synthesis of 1-Nitro-2-methyl-1,3-diene (3)
Nitroso acetals were obtained upon heating 1-nitro-2-methyl-1,3-butadiene (3) with various alkyl
acrylates6 in the presence of hydroquinone monomethyl ether (MeHQ) and NaHCO3. The nitroso acetal
pairs 10a/10b, 11a/11b, and 4a/4b were synthesized from ethyl acrylate in 71% yield, isopropyl
acrylate in 74% yield, and methyl acrylate in 81% yield, respectively (Table 1). Because similar
endo/exo diastereoselectivity (1:11 dr) was identified in each case, we preferred to use methyl acrylate
as the reaction partner because it provided a greater yield and the product isomers could be separated.
The 81% isolated yield of the nitroso acetal 4 exceeds the maximum theoretical yield if only the
nitrodiene Z-3 had reacted, implying that the nitrodiene 3 underwent E-to-Z isomerization during the
period of the cycloaddition. The stereochemistry of the isomers 4a and 4b was established through
NOESY experiments.
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Table 1. Reactions of 1-nitro-2-methyl-1,3-butadiene with dienophiles
Dienophile
Methyl acrylate
Ethyl acrylate
Isomers (endo/exo)
4a/4b
Yield (endo:exo dr)
81% (1:11 dr)
10a/10b
71% (1:11 dr)
11a/11b
74% (1:11 dr)
Isopropyl acrylate
Hydrogenation of the nitroso acetal 4b was tested through treatment with Raney nickel in the
presence of H2.6 Regardless of the H2 pressure applied in this reaction, we obtained two isomers of the
lactam alcohol 12 instead of the desired pyrrolizidinone 5 (Table 2). Because both ring opening and
hydrogenation of the double bond occurred in this reaction, the desired pyrrolizidinone 5 or 13 was not
obtained, even after heating under reflux in toluene as in our previous study.6 The hydrogenation of the
olefinic bond removed the allylic hydroxyl group and, thereby, prevented the ring closure from
occurring while heating in toluene. We obtained the best isomeric ratio of 12a to 12b (1:3) under a H2
pressure of 200 psi (Table 2); these isomers could not be separated.
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Scheme 3. Synthesis of Heliotridane and Pseudoheliotridane
Table 2. Hydrogenolysis of 4b
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H2
Pressure
15 psi (1 atm)
50 psi
12a:12b
Isomer ratio
No reaction
1:1.8
Product
Yield (%)
0
72
78
80
83
79
1:2
100 psi
160 psi
1:1
1:3
200 psi
1:1.5
450 psi
The pyrrolizidinones 13a and 13b were obtained in 90% yield through a Mitsunobu reaction of
the lactam alcohols 12 in the presence of 1,1´-(azodicarbonyl)dipiperidine (ADDP) and tri-n-
butylphosphine.10 Again, these pyrrolizidinones 13a and 13b could not be separated.
Treatment of the mixture of compounds 13a and 13b with phenyl chlorothionocarbonate in the
presence of 4-dimethylaminopyridine (DMAP) afforded the separable thionocarbonates 14a (60% yield)
and 14b (19% yield). Deprotection of 14a and 14b, performed in the presence of more than 4 equiv of
KOH under reflux in aqueous EtOH (1:4, v/v) for 1 h, provided pure samples of the pyrrolizidinones
13a (70% yield) and 13b (71% yield), respectively (Scheme 4). The stereochemistry of the isomers 13a
and 13b was established through NOESY experiments. For the pyrrolizidinone 13a, a strong cross peak
appeared between the signals for protons Ha and Hb; for 13b, no cross peak appeared between the
signals of the corresponding protons.
Radical deoxygenations were accomplished by treating the thionocarbonates 14a and 14b with
2,2´-azobis(isobutyronitrile) (AIBN) and tributyltin hydride,10 providing the lactams 15a and 15b,
respectively, in yields of 83 and 80%, respectively (Scheme 3). Heliotridane was obtained in 90% yield
after treatment of the lactam 15a with LAH; the overall yield of heliotridane from the known nitrodiene
7 was 24%. Similarly, pseudoheliotridane was obtained in 85% yield upon treatment of the lactam 15b
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1
13
with LAH; its overall yield from 3 was 7%. The experimental data (melting points; H and C NMR
spectra) of heliotridane and pseudoheliotridane were consistent with those reported in the literature.11
Scheme 4. Syntheses of 13a and 13b
In summary, the pyrrolizidine alkaloids heliotridane and pseudoheliotridane have been
synthesized in six steps, starting with the key step of 6π-electrocyclization/[3+2] dipolar cycloaddition
of 1-nitro-2-methyl-1,3-butadiene with methyl acrylate, in overall yields of 24 and 7%, respectively.
Experimental
General Information
All reactions were performed under Ar atmosphere with dry solvents in flame-dried reaction vessels
containing stirrer bars. CH2Cl2 and 1,2-dichloroethane were distilled afresh from CaH2; MeOH was
distilled afresh from Mg(0); THF and diethyl ether were distilled from Na with benzophenone indicator.
All reagents were obtained commercially and used without further purification. Thin layer
chromatography (TLC) was performed on 0.25-mm Silicycle Glass-Backed Extra-Hard-Layer, 60-Å
silica gel plates (TLG-R10011B-323) and visualized under UV light or through permanganate and
anisaldehyde staining. Flash column chromatography was performed using Silicycle SilicaFlash® P60
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(230–400 mesh, R12030B) and compressed air. Melting points (mp) were recorded using an
Electrothermal capillary melting point apparatus; they are uncorrected. IR spectra were recorded using a
Thermo Nicolet Avatar 370 FT-IR spectrometer. NMR spectra were recorded using Bruker ARX-400
1
and AV-300 instruments calibrated to CH(D)Cl3 as an internal reference (7.26 and 77.00 ppm for H
and 13C NMR spectra, respectively). Data for 1H NMR spectra are reported as follows: chemical shift (δ,
ppm), multiplicity, coupling constant (Hz), and integration. Data for 13C NMR spectra are reported in
terms of chemical shift (δ, ppm). The following abbreviations are used to denote the multiplicities: s =
singlet; d = doublet; t = triplet; m = multiplet. Mass spectra were recorded using a Waters LCT Premier
XE Time-of-Flight instrument controlled by MassLynx 4.1 software. Samples were infused using direct
loop injection from a Waters Acquity UPLC into the Multi Mode Ionization source. The lock mass
standard for accurate mass determination was leucine enkephalin (Sigma L9133).
3-Methyl-4-nitro-2-buten-1-yl acetate (7). HNO3 (48 mL, 0.48 mol, 1.6 equiv) was added dropwise
over 45 min to Ac2O (206 mL, 2.2 mol, 7.2 equiv) with cooling in an ice bath and stirring at 23–25 °C.
Isoprene (20 g, 0.30 mol, 1.0 equiv) was added slowly over 1 h at 23–25 °C. After an additional 60 min
at this temperature, the reaction was quenched through the addition of ice. The aqueous phase was
extracted with CH2Cl2 and the combined extracts washed with water. The solvent and some of the
excess Ac2O were removed in vacuo (max. bath temperature: 50 °C). The crude product was purified
through flash column chromatography (EtOAc/hexanes, 1:9) to provide a colorless oil (34%). IR (ѵ,
cm–1): 2924, 1735, 1551, 1431, 1368, 1227, 1025, 963, 607, 546; 1H NMR (400 MHz, CDCl3, δ, ppm):
5.76 (t, J = 6.4 Hz, 1H), 4.86 (s, 2H), 4.65 (d, J = 6.4 Hz, 2H), 2.05 (s, 3H), 1.84 (s, 3H); 13C NMR (100
MHz, CDCl3, δ, ppm): 170.8, 130.2, 129.9, 83.2, 60.4, 20.8, 15.2.
4-Nitro-3-methyl-2-butenol (8). p-TsOH (0.50 g, 0.0030 mol, 5.0% equiv) was added to a solution of
3-methyl-4-nitro-2-buten-1-yl acetate (10 g, 0.060 mol, 1.0 equiv) in MeOH at room temperature under
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an Ar atmosphere and then the resulting solution was stirred overnight. The solvent was evaporated
under reduced pressure and the residue purified through flash column chromatography (EtOAc/hexanes,
1:4) to produce a colorless oil (89%). IR (ѵ, cm–1): 3355, 2919, 1546, 1374, 1312, 1198, 1006, 694, 629,
1
573; H NMR (400 MHz, CDCl3, δ, ppm): 5.82 (t, J = 6.4 Hz, 1H), 4.86 (s, 2H), 4.26 (d, J = 6.4 Hz,
2H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm): 135.0, 127.8, 83.5, 59.0, 15.0.
1-Bromo-3-methyl-4-nitro-2-butene (9). Ph3P (30.3 g, 0.12 mol, 1.5 equiv) was added in small
portions to a stirred solution of the alcohol 8 (10 g, 0.077 mol, 1.0 equiv) and CBr4 (31.5 g, 0.095 mol,
1.25 equiv) in dry CH2Cl2 (10 mL) at 0 °C. After the mixture had stirred for 15 min, half of the solvent
was evaporated under reduced pressure and the remaining solution treated with Et2O (20 mL) and
filtered. The filtrate was concentrated under reduced pressure and the crude product purified through
flash column chromatography (EtOAc/hexanes, 1:39) to give a colorless oil (97%). IR (ѵ, cm–1): 2988,
1
2870, 1558, 1541, 1394, 1376, 1141, 1066, 669, 649; H NMR (400 MHz, CDCl3, δ, ppm): 5.89 (t, J =
8.4 Hz, 1H), 4.82 (s, 2H), 3.92 (d, J = 8.4 Hz, 2H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm):
131.2, 131.0, 83.1, 26.0, 14.7.
1-Nitro-2-methyl-1,3-butadiene (3). Et3N (9.0 mL, 0.06 mol, 1.2 equiv) was added dropwise to a
solution of 1-bromo-3-methyl-4-nitro-2-butene (9) (10 g, 0.050 mol, 1.0 equiv) in Et2O at 0 °C. The
ammonium salt was filtered off and filtrate washed with dilute HCl and water. The solution was
concentrated under reduced pressure to give a yellow oil (98%) that was not subjected to further
purification; IR (ѵ, cm–1): 2988, 1588, 1557, 1509, 1339, 1146, 991, 822, 765, 669; (Z-isomer) 1H NMR
(400 MHz, CDCl3, δ, ppm): 7.64 (dd, J = 17.6, 10.8 Hz, 1H), 6.90 (s, 1H), 5.80 (d, J = 17.6 Hz, 1H),
5.68 (d, J = 10.8 Hz, 1H), 2.0 (s, 3H); 13C NMR (CDCl3, 100 MHz, δ, ppm): 143.39, 134.78, 130.94,
125.41, 17.41; (E-isomer) 1H NMR (CDCl3, 400 MHz, δ, ppm): 7.6 (s, 1H), 6.34 (dd, J = 17.2, 10.8 Hz,
1H), 5.86 (d, J = 17.2 Hz, 1H), 5.63 (d, J = 10.8 Hz, 1H), 2.31 (s, 3H); 13C NMR (CDCl3, 100 MHz, δ,
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ppm): 143.4, 134.8, 130.9, 125.4, 17.4; HRMS (ESI) calcd for C5H7NO2 [M + H]+: m/z 114.0590, found
114.0660.
Nitroso Acetals 4a and 4b. 1-Nitro-2-methyl-1,3-butadiene (3), (2.0 g, 0.018 mol, 1.0 equiv) was
added via syringe in one portion to a mixture of NaHCO3 (1.81 g, 0.020 mol, 1.2 equiv), MeHQ (0.90 g,
7.0 mmol, 0.40 equiv), distilled dichloroethane, and methyl acrylate (5 mL, 0.05 mol, 3 equiv) and then
the reaction vessel was submerged in an oil bath (90 °C) and stirred for 18 h. The solvent was
evaporated in vacuo. The residue was loaded directly onto a silica gel column and purified through flash
column chromatography (EtOAc/hexanes, 1:9). 4b: 74% yield; slightly yellow oil; IR (ѵ, cm–1): 2974,
1
2879, 1741, 1540, 1508, 1436, 1348, 1290, 1208, 1181, 1070, 1053, 929, 815, 669, 649; H NMR (400
MHz, CDCl3, δ, ppm): 5.51–5.49 (m, 1H), 5.09 (dd, J = 10.0, 3.6 Hz, 1H), 4.56–4.49 (m, 1H), 4.16–
4.10 (m, 1H), 3.77 (s, 3H), 3.71 (t, J = 9.2, Hz, 1H), 2.60–2.54 (m, 1H), 2.49–2.41 (m, 1H), 1.76 (s,
3H); 13C NMR (100 MHz, CDCl3, δ, ppm): 171.0, 130.30, 119.75, 81.06, 70.28, 67.04, 52.53, 34.56,
20.42; HRMS (ESI) calcd for C9H13NO4 [M + H]+: m/z 200.0923, found 200.0939. 4a: 7% yield;
slightly yellow oil; IR (ѵ, cm–1): 2921, 2844, 1748, 1543, 1521, 1417, 1321, 1295, 1214, 1191, 1088,
1053, 931, 812, 671, 649; 1H NMR (400 MHz, CDCl3, δ, ppm): 5.50–5.49 (m, 1H), 4.91–4.87 (m, 1H),
4.54–4.49 (m, 1H), 4.16–4.11 (m, 1H), 3.79 (s, 3H), 3.63 (t, J = 9.2, Hz, 1H), 2.76–2.68 (m, 1H), 2.55–
2.48 (m, 1H), 1.77 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm): 171.4, 130.2, 119.7, 81.6, 71.0, 67.2,
52.6, 33.4, 20.4; HRMS (ESI) calcd for C9H13NO4 [M + H]+: m/z 200.0923, found 200.0933.
Lactam Alcohol 12. A catalytic amount of MeOH-washed Raney Nickel 2800 (slurry in H2O; 3 drops)
was added to a solution of the nitroso acetal 4b (1.0 g, 5.0 mmol) in MeOH.8 The suspension was stirred
under H2 (200 psi) at room temperature for 18 h. The catalyst was filtered off and washed with MeOH.
The filtrate was concentrated in vacuo and the residue purified through silica gel column
chromatography (MeOH/EtOAc, 1:9) to afford a white solid (83%). IR (ѵ, cm–1): 3265, 2987, 2901,
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1
1669, 1405, 1394, 1382, 1250, 1115, 1103, 1065, 1016, 738, 669, 649; H NMR (400 MHz, d-DMSO,
δ, ppm): 7.76 (s, 1H, OH), 7.75 (s, 1H, OH) 5.30 (d, J = 5.6, Hz, 2H), 4.38–4.32 (m, 2H), 4.01–3.96 (m,
2H), 3.53–3.32 (m, 4H), 3.21–3.16 (m, 2H), 2.30–2.17 (m, 2H), 1.64–1.45 (m, 4H), 1.36–1.29 (m, 2H),
1.17–1.06 (m, 2H), 0.79 (d, J = 6.4, Hz, 3H), 0.74 (d, J = 6.4, Hz, 3H); 13C NMR (100 MHz, d-DMSO,
δ, ppm): 177.1, 176.9, 69.3 (2C), 59.1, 59.1, 54.6, 54.1, 35.8, 35.4, 34.8, 34.3, 33.7, 33.6, 15.6, 14.5;
HRMS (ESI) calcd for C8H15NO3 [M + H]+: m/z 174.1130, found 174.1127.
O-(7-Methyl-3-oxohexahydro-1H-pyrrolizin-2-yl) O-Phenyl Carbonothioates 14a and 14b. Tri-n-
butylphosphine (2.0 mL, 8.0 mmol, 1.5 equiv) and ADDP (2.0 g, 8.0 mmol, 1.5 equiv) were added to a
solution of the alcohol 12 (1.0 g, 5.0 mmol) in dry THF (5 mL) at 0 °C under an argon atmosphere. The
resulting mixture was stirred at 0 °C for 1 h and then at room temperature for 24 h. The solvent was
evaporated in vacuo and the residue purified through column chromatography (EtOAc/hexanes, 1:1) to
give an inseparable mixture of 13a and 13b (90%). DMAP (0.60 g, 0.80 mmol, 0.80 equiv) and phenyl
chlorothionoformate (0.70 g, 0.80 mmol, 0.80 equiv) were added to a solution of the alcohols 13a and
13b (0.90 g, 5.0 mmol, 1.0 equiv) in MeCN. The resulting yellow solution was stirred at room
temperature in a foil-covered round-bottom flask for 2.5 h, then additional charges of DMAP (0.60 g,
0.80 mmol, 0.80 equiv) and phenyl chlorothionoformate (0.70 g, 0.80 mmol, 0.80 equiv) were added.
The solution was stirred for an additional 2.5 h and then it was concentrated to afford a yellow oil. The
residue was purified through silica gel column chromatography (EtOAc/hexanes, 2:3), with
recrystallization (EtOAc/hexanes, 3:7) providing 14a and 14b as white solids. 14a: 60% yield; mp 118–
120 °C; IR (ѵ, cm–1): 2973, 2958, 2926, 2900, 1714, 1653, 1488, 1455, 1424, 1286, 1257, 1215, 1076,
1
771, 758, 687; H NMR (400 MHz, CDCl3, δ, ppm): 7.47–7.43 (m, 2H), 7.35–7.31 (m, 1H), 7.19–7.17
(m, 2H), 6.11 (t, J = 9.0, Hz, 1H), 3.71–3.64 (m, 1H), 3.40–3.28 (m, 2H), 3.18–3.11 (m, 1H), 2.34–2.31
(m, 1H), 1.92–1.72 (m, 3H), 1.13 (d, J = 5.6, Hz, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm): 194.6,
167.6, 153.6, 129.6 (2C), 126.7, 121.9 (2C), 82.1, 63.1, 41.6, 41.2, 34.7, 33.9, 15.3; HRMS (ESI) calcd
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for C15H17NO3S [M + H]+: m/z 292.1007, found 292.0999. 14b: 19% yield; mp 80–82 °C; IR (ѵ, cm–1):
2972, 2958, 2926, 2900, 1713, 1653, 1286, 1257, 1215, 1185, 1077, 771, 758, 687; 1H NMR (400 MHz,
CDCl3, δ, ppm): 5.79–7.55 (m, 2H), 7.46–7.43 (m, 1H), 7.32–7.29 (m, 2H), 6. 23 (t, J = 9.0, Hz, 1H),
4.07–4.02 (m, 1H), 3.79–3.74 (m, 1H), 3.33–3.28 (m, 1H), 3.00–2.94 (m, 1H), 2.48–2.36 (m, 2H), 2.12–
2.06 (m, 1H), 2.04–1.91 (m, 1H), 1.06 (d, J = 7.2, Hz, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm):
194.7, 167.8, 153.6, 129.6 (2C), 126.7, 121.9 (2C), 82.2, 59.4, 39.9, 33.8, 32.8, 29.9, 13.9; HRMS (ESI)
calcd for C15H17NO3S [M + H]+: m/z 292.1007, found 292.1002.
Pyrrolizidinones 13a and 13b. The carbonothioate 14a (1.0 g, 3.0 mmol, 1.0 equiv) was added to a
solution of KOH (0.20 g, 4.0 mmol, 1.2 equiv) in EtOH/water (4:1, 5 mL) and then the mixture was
heated under reflux for 1 h. The EtOH was evaporated off under reduced pressure and the remaining
aqueous solution was acidified with 6 M HCl and then extracted with EtOAc. The combined organic
extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified
through flash column chromatography (EtOAc/hexanes, 1:1) to provide 13a as a colorless oil (70%); IR
1
(ѵ, cm–1): 3237, 2970, 2900, 1671, 1457, 1438, 1406, 1394, 1312, 1288, 1251, 1228, 755, 731, 669; H
NMR (400 MHz, CDCl3, δ, ppm): 4.56–4.51 (m, 1H), 3.64 (bs, 1H, OH), 3.48–3.43 (m, 1H), 3.21–3.11
(m, 2H), 2.71–2.65 (m, 1H), 2.19–2.15 (m, 1H), 1.66–1.53 (m, 3H), 0.99 (d, J = 6.0, Hz, 3H); 13C NMR
(100 MHz, CDCl3, δ, ppm): 174.1, 73.4, 63.4, 41.2, 41.0, 36.8, 34.8, 15.4; HRMS (ESI) calcd for
C8H13NO2 [M + H]+: m/z 156.1024, found 156.1030. The pyrrolizidinone 13b was prepared in a similar
manner from 14b: 71% yield; colorless oil; IR (ѵ, cm–1): 3229, 2969, 2900, 1671, 1458, 1438, 1312,
1
1288, 1251, 1228, 1105, 1065, 1050, 755, 669, 647; H NMR (400 MHz, CDCl3, δ, ppm): 4.60–4.55
(m, 1H), 3.84–3.79 (m, 1H), 3.57–3.52 (m, 1H), 3.10–3.05 (m, 2H), 2.49–2.42 (m, 1H), 2.28–2.26 (m,
13
1H), 2.20–2.15 (m, 1H), 1.76–1.68 (m, 2H), 0.88 (d, J = 7.2, Hz, 3H); C NMR (100 MHz, CDCl3, δ,
ppm): 129.1, 73.3, 59.5, 39.8, 34.0, 32.8, 32.7, 13.9; HRMS (ESI) calcd for C8H13NO2 [M + H]+: m/z
156.1024, found 156.1030.
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7-Methyltetrahydro-1H-pyrrolizin-3(2H)-one (15a). A solution of tributyltin hydride (1.3 g, 4.4
mmol, 1.3 equiv) and AIBN (0.90 g, 0.50 mmol, 0.16 equiv) in benzene (10 mL) was added dropwise
over 50 min to a solution of the thionocarbonate 14a (1.0 g, 1.0 mmol, 1.0 equiv) under reflux in
benzene (25 mL). The resulting solution was heated under reflux for an additional 2.5 h and then it was
concentrated in vacuo. The residue was purified through column chromatography (silica gel with a plug
of potassium fluoride at the top of the column; EtOAc/hexane, 1:1, 2:1, 1:0) to give 15a as a colorless
1
oil (83%); IR (ѵ, cm–1): 2969, 2891, 1670, 1457, 1438, 1312, 1288, 1106, 755; H NMR (400 MHz,
CDCl3, δ, ppm): 3.47–3.38 (m, 2H), 3.12–3.08 (m, 1H), 2.69–2.65 (m, 1H), 2.42–2.35 (m, 1H), 2.25–
2.18 (m, 2H), 1.70–1.56 (m, 3H), 0.99 (d, J = 6.0, Hz, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm):
174.69, 68.21, 40.95, 40.63, 35.57, 34.92, 25.22, 15.33; HRMS (ESI) calcd for C8H13NO [M + H]+: m/z
149.1075, found 140.1065. 7-Methyltetrahydro-1H-pyrrolizin-3(2H)-one (15b) was prepared in a
similar manner from 14b: 80% yield; colorless oil; IR (ѵ, cm–1): 2968, 2891, 1671, 1458, 1438, 1312,
1
1288, 1106, 755, 669; H NMR (400 MHz, CDCl3, δ, ppm): 3.93–3.90 (m, 1H), 3.44–3.38 (m, 1H),
3.00–2.94 (m, 1H), 2.65–2.58 (m, 1H), 2.39–2.32 (m, 1H), 2.13–2.08 (m, 2H), 1.96–1.91 (m, 1H), 1.81–
1.74 (m, 1H), 1.70–1.65 (m, 1H), 0.76 (d, J = 7.2, Hz, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm):
175.0, 64.6, 39.4, 35.0, 34.7, 33.0, 20.9, 13.5; HRMS (ESI) calcd for C8H13NO [M + H]+: m/z 149.1075,
found 140.1078.
Heliotridane (picrate) and Pseudoheliotridane (picrate). LAH (0.54 g, 14.5 mmol, 0.40 equiv) was
added directly to a solution of the lactam 15a (0.50 g, 3.5 mmol, 0.10 equiv) in Et2O (4.0 mL) in a
sealed tube at 0 °C. After stirring at 65 °C for 6.5 h, the mixture was cooled to RT and then
Na2SO4·10H2O (0.40 mmol) was added slowly. The resulting solution was stirred at RT overnight. The
solid material in the vial was filtered off and washed with Et2O. The solvent was evaporated from the
filtrate under a steady stream of N2. The residue was treated with picric acid and recrystallized (MeOH)
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to give heliotridane as its picrate salt (90%); mp 232–234 °C (decomp); IR (ѵ, cm–1): 2987, 2900, 1633,
1558, 1518, 1490, 1474, 1456, 1394, 1263, 1161, 1075, 1011, 961, 909, 742, 707; 1H NMR (400 MHz,
CDCl3, δ, ppm): 11.36 (bs, 1H, OH), 8.76 (s, 2H), 3.94–3.87 (m, 1H), 3.82–3.71 (m, 1H), 3.62–3.54 (m,
1H), 3.00–2.94 (m, 1H), 2.79–2.71 (m, 1H), 2.19–2.06 (m, 3H), 2.02–1.74 (m, 4H), 1.10 (d, J = 6.4, Hz,
3H); 13C NMR (100 MHz, CDCl3, δ, ppm): 162.4, 141.7, 128.2, 126.6 (3C), 74.0, 55.6, 55.4, 40.0, 33.9,
29.3, 24.8, 16.7; HRMS (ESI) calcd for C8H15N [M + H]+: m/z 126.1283, found 126.1290.
Pseudoheliotridane (picrate) was prepared in a similar manner from 15b: 90% yield; mp 238–240 °C
(decomp); IR (ѵ, cm–1): 2988, 2910, 2744, 1633, 1558, 1507, 1474, 1456, 1434, 1364, 1312, 1075, 909,
1
707; H NMR (400 MHz, CDCl3, δ, ppm): 11.42 (bs, 1H), 8.88 (s, 2H), 4.34–4.26 (m, 1H), 4.09–4.04
(m, 1H), 3.75–3.66 (m, 1H), 3.16–3.09 (m, 1H), 2.86–2.78 (m, 1H), 2.71–2.59 (m, 1H), 2.22–2.06 (m,
4H), 1.82–1.71 (m, 2H), 1.16 (d, J = 6.8, Hz, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm): 162.4, 141.7,
128.2, 126.6 (2C), 118.1, 71.1, 57.0, 54.8, 34.8, 30.7, 26.0, 25.9, 13.5; HRMS (ESI) calcd for C8H15N
[M + H]+: m/z 126.1283, found 126.1287.
Author Information
Corresponding Author
ohyun@chem.ucla.edu
Notes
The authors declare no competing financial interests.
Acknowledgment
We thank the NSF (CHE7096481) for financial support. E. K. thanks Gaziosmanpasa University and the
Scientific and Technical Research Council of Turkey (TUBITAK-BIDEP) for support.
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