Br?nsted acid-mediated annulations of pyrroles featuring N-tethered α,β-unsaturated ketones and esters: Total syntheses of (±)-tashiromine and (±)-indolizidine 209I

Article abstract of DOI:10.1016/j.tet.2018.04.067

This study provides the first report of the construction of tetrahydroindolizines and tetrahydropyrrolo[1,2-a]azepines via Br?nsted acid-mediated annulation of pyrroles featuring N-tethered α,β-unsaturated esters. In addition, the Br?nsted acid-catalyzed cyclization of pyrroles featuring pendant α,β-unsaturated ketones was applied to complete total syntheses of the indolizidine alkaloids (±)-tashiromine and (±)-indolizidine 209I.

Full text of DOI:10.1016/j.tet.2018.04.067

Accepted Manuscript
Brønsted acid-mediated annulations of pyrroles featuring N-tethered α,β-unsaturated
ketones and esters: Total syntheses of (±)-tashiromine and (±)-indolizidine 209I
Wesley J. Olivier, Michael G. Gardiner, Alex C. Bissember, Jason A. Smith
PII:
S0040-4020(18)30471-X
10.1016/j.tet.2018.04.067
TET 29482
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 April 2018
Revised Date: 19 April 2018
Accepted Date: 20 April 2018
Please cite this article as: Olivier WJ, Gardiner MG, Bissember AC, Smith JA, Brønsted acid-mediated
annulations of pyrroles featuring N-tethered α,β-unsaturated ketones and esters: Total syntheses of (±)-
tashiromine and (±)-indolizidine 209I, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.067.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Brønsted acid-mediated annulations of pyrroles
featuring N-tethered α,β-unsaturated ketones and
esters: total syntheses of (±)-tashiromine and (±)-
indolizidine 209I
Leave this area blank for abstract info.
Wesley J. Olivier, Michael G. Gardiner, Alex C. Bissember,* Jason. A. Smith*

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Brønsted acid-mediated annulations of pyrroles featuring N-tethered α,β-unsaturated
ketones and esters: total syntheses of (±)-tashiromine and (±)-indolizidine 209I
Wesley J. Olivier, Michael G. Gardiner, Alex C. Bissember,* Jason A. Smith*
School of Natural Sciences – Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
Dedicated to the memory of Sir Derek H.R. Barton whose ongoing influence on chemistry and those he trained endures.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This study provides the first report of the construction of tetrahydroindolizines and
tetrahydropyrrolo[1,2-a]azepines via Brønsted acid-mediated annulation of pyrroles featuring N-
tethered α,β-unsaturated esters. In addition, the Brønsted acid-catalyzed cyclization of pyrroles
featuring pendant α,β-unsaturated ketones was applied to complete total syntheses of the
indolizidine alkaloids (±)-tashiromine and (±)-indolizidine 209I.
Available online
Keywords:
pyrrole
Brønsted acid
intramolecular Michael addition
total synthesis
indolizidine
tashiromine
products (83%), extended reactions times (24 h) were required.12
Stronger Lewis acids such as SnCl4 and TiCl4 mediate the
1. Introduction
cyclization reaction in low to moderate yields (38–59% yields).12
To date, two reports of Brønsted acid-promoted intramolecular
conjugate additions of pyrroles featuring N-tethered α,β-
unsaturated aldehyde13 or α,β-unsaturated ketones14 have been
published (Scheme 1).
Natural products featuring 5-membered N-heterocycles are
plentiful in nature.1 For example, indolizidine2 and pyrrolizidine
alkaloids,3 in addition to Stemona alkaloids,4 rhazinilam5 (and
related molecules) and lamellarin-type natural products6 all
feature this core motif. In each case, at least one 5-, 6- or 7-
membered ring is fused to the 5-membered N-heterocyclic core.
Barton utilized radical decarboxylation chemistry en route to
constructing the carbon skeleton of indolizidine alkaloids.7 A
common approach to the synthesis of the above-mentioned
natural products and other biologically active compounds (e.g.,
the pharmaceutical drug ketorolac) has exploited cyclizations of
pyrroles featuring N- or C-tethers, this includes intramolecular
conjugate addition strategies.8
Angle and co-workers were the first to report the
intramolecular 1,6-addition of a pyrrole in 1989.9 This approach
employed ZnCl2. Later, Banwell and Smith illustrated the
viability of intramolecular 1,4-addition of a pyrrole featuring an
N-tethered α,β-unsaturated ester mediated by AlCl3.10
Subsequent studies by these researchers demonstrated that the
transformation could be achieved enantioselectively.11 Research
concerning the annulation of esters has predominantly focused on
employing Lewis acids to promote the reaction.10,11,12 Despite
this, there are some limitations associated with employing Lewis
acids to effect these processes.
Scheme 1. All of the previously reported Brønsted acid-promoted
intramolecular conjugate additions of pyrroles featuring N-tethered
α,β-unsaturated carbonyl moieties in which the product remains in
the pyrrole (and not the pyrroline or pyrrolidine) oxidation state.
Although it has been shown that AlCl3-mediated
intramolecular cyclizations of α,β-unsaturated esters proceed
efficiently (90–95% yield; 2–4 h reaction time), these reactions
require particularly high dilution (3.8 mM; ~0.77 mg/mL).12
Although the use of BF3•OEt2 provides high yields of cyclization
We postulated that Brønsted (rather than Lewis) acid
catalysis may represent a more efficient strategy for the
annulation of pyrroles featuring pendant α,β-unsaturated esters/
ketones. Herein, we report the first study exploring Brønsted

2
Tetrahedron
ACCEPTED MANUSCRIPT
although the latter reaction proceeded at considerably slower rate
acid-catalyzed annulations of pyrroles featuring N-tethered α,β-
than the former. Moderate to excellent yields were achieved for
the cyclization of esters 3 and 4 with both of these acids. The
polarity of the solvent appeared to influence the rate of reaction.
Experiments performed in diethyl ether, the most polar solvent,
required much longer reaction times (19–26 h) and yields were
consistently low (0–26%). However, the stronger acid, TfOH,
was effective for the formation of product 5 under these
conditions (96% yield). We identified dichloromethane to be the
optimal solvent and reactions were completed relatively
efficiently and quickly (0.5–4.5 h) for both substrates 3 and 4
when MsOH or TfOH was employed. We determined that MsOH
was superior to TfOH, as it consistently provided both cyclized
products 5 and 6 in good yields and its ease of handling (due to
its greater stability to air and moisture).
unsaturated esters. This is consistent with our longstanding
interests in developing novel methods for the synthesis and
functionalization of pyrroles.10,11,15 We also exploited this
strategy to complete total syntheses of the indolizidine alkaloids
(±)-tashiromine (1) and (±)-indolizidine 209I (2).16
2. Results and discussion
We screened three Brønsted acids (TFA, MsOH, TfOH) for
their capacity to promote the respective cyclizations of acrylates
3 and 4 to form tetrahydroindolizine 5 and tetrahydropyrrolo[1,2-
a]-azepine 6 in three different solvents (Scheme 2). The reactions
were performed at a concentration of 14 mM (~3 mg/mL).
Having devised methodology for the annulation of pyrroles
with N-tethered α,β-unsaturated esters with Brønsted acids we
were interested in employing this type of chemistry to effect total
syntheses of indolizidine alkaloids (±)-tashiromine (1) and (±)-
indolizidine 209I (2). We anticipated, that ketone 9 (Scheme 3),
rather than ester 5, would serve as a better precursor to (±)-
tashiromine (1), as the ensuing cyclized product could be more
efficiently elaborated into tashiromine, utilizing a Baeyer–
Villiger reaction as the key step. Furthermore, α,β-unsaturated
ketone 9 is a stronger Michael acceptor than ester 5 and, thus,
was expected to be more reactive.
Scheme 2. Brønsted acid-promoted intramolecular conjugate
additions of pyrroles featuring N-tethered α,β-unsaturated esters 3
and 4. Values in brackets indicate the yield (%) of unreacted
substrate. a Yield estimated by 1H NMR spectroscopy. bReaction was
allowed to slowly warm to room temperature.
Initially, we attempted the cyclization of ester 3 using two
equivalents of TFA but found the reaction was rather slow, with
yields ranging between 30–40% after 3 h in CH2Cl2 at 0 °C. This
did not significantly improve with extended reaction times (16–
24 h), due to the apparent decomposition of product 5. However,
we determined that heterocycle 5 could be efficiently and rapidly
formed (79–100%; 20–30 min) employing 10% v/v TFA in
dichloromethane or toluene. Unfortunately, these conditions
failed to initiate cyclization of substrate 4.
Next, we investigated whether stoichiometric quantities of
stronger Brønsted acids (MsOH and TfOH) could facilitate the
cyclization of 3. In practice, both MsOH and TfOH were
effective in promoting cyclization of both acrylates 3 and 4,
Scheme 3. Synthesis of (±)-tashiromine (1)
Our synthesis of (±)-tashiromine (1) commenced from known
N-alkyl pyrrole 7 (Scheme 3) which was synthesized in 96%
yield from pyrrole. Cross-metathesis of olefin 7 with methyl
vinyl ketone provided α,β-unsaturated ketone 9. Upon exposure
to silica gel, pyrrole 9 cyclized to tetrahydroindolizine 10 via an
intramolecular Michael addition. This is consistent with
observations made by Bates and Sridhar in related studies
employing an α,β-unsaturated aldehyde (Scheme 1A).13 Given
this exceptional reactivity, we were not surprised to discover that
ketone 9 could be cyclized to tetrahydroindolizine 10 through

3
exposure to catalytic quantities (5–20%) of Brønsted acids, with
small time frames required for complete conversion (5–60 min).
Monitoring of the reaction by H NMR spectroscopy in CDCl3
substituent controlled facial selectivity in the hydrogenation
ACCEPTED MANUSCRIPT
(Figure 1). Similar observations have been reported previously.19
Ketone 18 was reduced to alcohol 19, followed by mesylation
and reduction with LiAlH4. In this way, (±)-indolizidine 209I (2)
was prepared in 8% overall yield from ester 14.
1
revealed that 20 mol% TFA was sufficient to catalyze the
reaction to completion in under 5 minutes. A 1 h reaction time
was necessary when 5 mol% TFA was employed.17 In practice,
pyrrole 10 was isolated in highest yield (78%), by loading the
crude residue from the synthesis of 9 on to a plug of silica gel
and eluting with EtOAc/hexanes.
Hydrogenation of tetrahydroindolizine 10 with Rh/Al2O3
furnished chromatographically separable diastereomers 11 and 12
(Scheme 3). Attempts at conducting a Baeyer–Villiger oxidation
on 12 with mCPBA were unsuccessful. However, the reaction
proceeded when the stronger oxidant trifluoroperacetic acid
(generated in situ), was employed, furnishing (±)-O-acetyl
tashiromine 13 in 61% yield in addition to (±)-tashiromine (1) in
10% yield. Compound 13 was efficiently converted to target 1,
completing the total synthesis in 21% overall yield.
An analogous strategy provided (±)-indolizidine 209I (2). This
approached began with known ester 14 which was prepared in
79% yield over three steps from DL-norvaline methyl ester
hydrochloride in accordance with literature methods (Scheme
4).15g Reduction of substrate 14 with DIBAL-H and subsequent
Wittig olefination provided terminal olefin 15 in 71% yield.
Alkene 15 was subjected to cross-metathesis with methyl vinyl
ketone. However, the anticipated cross-metathesis product was
not observed. Instead, the chromatographically inseparable
tetrahydroindolizines 16 were isolated (60% combined yield)
after chromatographic purification.18
C4
C2
C1
C3
C5
N1
C8
C13
O1
C6
C7
C12
C9
C14
C10
C11
Figure 1. Structure of the HCl salt of compound 17. Thermal
ellipsoids are shown at the 50% probability level. All methyl and
methylene hydrogen atoms are omitted for clarity, as is the chloride
counter anion (closely associated only with the N–H, N–H
0.909(17), H…Cl 2.194(18) Å, N–H…Cl 166.7 °).
3. Conclusion
We have developed a simple method for the efficient and high
yielding annulation of pyrrolic N-tethered α,β-unsaturated esters
with Brønsted acids. Pyrrole 9, which features a pendant α,β-
unsaturated methyl ketone, is exceptionally reactive toward
intramolecular Michael addition reactions. This transformation
has been exploited in a 4-step total synthesis of (±)-tashiromine
(1) from pyrrole 7 in 21% overall yield. In addition, we
accomplished a straightforward synthesis of (±)-indolizidine 209I
in 8% overall yield from known substrate 14. In future, we will
investigate the applications of this strategy to the development of
enantioselective Brønsted acid-catalyzed intramolecular Michael
additions to form annulated pyrroles.
4. Experimental
General experimental procedures
Unless otherwise specified, reactions were performed under
an atmosphere of air. Solvents were analytical grade and purified
by standard laboratory procedures. Reagents were purchased
from Sigma-Aldrich, AK Scientific, Combi-Blocks, and
Oakwood and were used without purification.
Infrared spectrometry was performed on a Shimadzu FTIR
8400s spectrometer. A thin film of material was deposited onto
NaCl plates following evaporation of CH2Cl2 and/or CHCl3.
NMR experiments were performed either on a Bruker Avance III
NMR spectrometer operating at 400 MHz (1H) or 100 MHz (13C)
or on a Bruker Avance III NMR spectrometer operating at 600
MHz (1H) or 150 MHz (13C). The deuterated solvents used were
either CDCl3, acetone-d6 or CD3OD as specified. Chemical shifts
were recorded in ppm. Spectra were calibrated by assignment of
the residual solvent peak to δH 7.26 and δC 77.16 for CDCl3, δH
2.09 and δC 29.84 for acetone-d6 and δH 3.31 and δC 49.0 for
CD3OD. Coupling constants (J) were recorded in Hz. HRESIMS
analyses were conducted on a Thermo-Scientific LTQ-Orbitrap
using a syringe pump operated at 3 ꢀL/min, and full scan data
acquired in positive ionization mode using an electrospray
voltage of 5 kV. X-ray crystallographic data for the structure
determination of the HCl salt of compound 17 was recorded at 120
K on a Bruker AXS D8 Quest diffractometer (Cu Kα radiation).
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
Scheme 4. Synthesis of (±)-indolizidine 209I {(±)-2}
Hydrogenation of diastereomeric mixture 16 with Rh/Al2O3
proceeded with complete diastereocontrol to yield the
chromatographically separable epimers 17 and 18 (18% and 29%
yield respectively; in addition to 32% yield of unreacted substrate
16). The relative stereochemistry assigned to indolizidine 17 was
supported through single crystal X-ray crystallography of the
corresponding HCl salt, which indicated that the C5-propyl

4
Tetrahedron
ACCEPTED MANUSCRIPT
CCDC 1832698. Copies of the data can be obtained, free of
heated at reflux. After 23 h, the solution was cooled and ethyl
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
vinyl ether (300 µL) was added. The ensuing mixture was eluted
through a plug of silica gel (10→35% EtOAc/hexanes elution) to
provide tetrahydroindolizine 10 as a colorless oil (356 mg, 2.01
mmol, 78% yield). [Found (M+Na)+, 200.1048. C11H15NO,
TLC was performed using Merck silica gel 60-F254 plates.
Developed chromatograms were visualized by UV absorbance
(254 nm) or through application of heat to a plate stained with
cerium molybdate {Ce(NH4)2(NO3)6, (NH4)6Mo7O24·4H2O,
H2SO4, H2O} or potassium permanganate (KMnO4, K2CO3,
H2O). Flash column chromatography was performed with flash
grade silica gel (60 ꢀm) and the indicated eluent in accordance
with standard techniques.20
requires (M+Na)+, 200.1046]. H NMR (600 MHz, acetone-d6) δ
1
6.46 (m, 1H), 5.94 (m, 1H), 5.72 (m, 1H), 3.95 (m, 1H), 3.81 (td,
J = 10.6, 4.1 Hz, 1H), 3.25 (sep, J = 4.6 Hz, 1H), 2.91 (dd, J =
17.0, 5.2 Hz, 1H), 2.59 (dd, J = 17.0, 8.2 Hz, 1H), 2.13 (s, 3H),
2.03–1.96 (m, 2H), 1.84 (m, 1H), 1.35 (m, 1H) ppm; 13C NMR
(150 MHz, acetone-d6) δ 207.3, 132.9, 119.5, 108.1, 104.2, 50.0,
45.8, 30.9, 30.4, 28.6, 23.4 ppm; IR (NaCl) 2941, 1713, 1361,
706 cm–1.
General procedure for the synthesis of compounds 5 and 6:
The α,β-unsaturated ester (20 mg) was placed under N2,
dissolved in the specified solvent (6.7 mL) and cooled to 0 °C.
The Brønsted acid was added and the solution was stirred at this
temperature for a given time, then the reaction was quenched
with NaHCO3 (5 mL of a saturated aqueous solution). The
aqueous phase was successively extracted with CH2Cl2 (2x 5 mL)
and EtOAc (5 mL). The combined organic extracts were dried
(MgSO4) and passed through a plug of silica gel (40%
EtOAc/hexanes elution) to provide compound 5 or 6. 5: [Found
(M+Na)+, 230.1154. C12H17NO2, requires (M+Na)+, 230.1152].
1H NMR (600 MHz, acetone-d6) δ 6.48 (m, 1H), 5.95 (t, J = 3.1
Hz, 1H), 5.79 (m, 1H), 4.13 (m, 2H), 3.96 (m, 1H), 2.83 (m, 1H),
3.21 (sep, J = 4.5 Hz, 1H), 2.74 (dd, J = 15.5, 5.82 Hz, 1H), 2.39
(dd, J = 15.5, 8.4 Hz, 1H), 2.02 (m, 2H; overlapping with
residual solvent signal), 1.87 (m, 1H), 1.45 (m, 1H), 1.23 (t, J =
7.1 Hz, 3H) ppm; 13C NMR (150 MHz, acetone-d6) δ 172.5,
132.2, 119.7, 108.2, 104.4, 60.6, 45.8, 41.1, 32.2, 28.5, 23.3, 14.6
ppm; IR (NaCl) 2940, 1732, 1179, 1156, 705 cm–1. 6: [Found
(M+Na)+, 244.1312. C13H19NO2, requires (M+Na)+, 244.1308].
1H NMR (600 MHz, acetone-d6) δ 6.52 (t, J = 2.2 Hz, 1H), 5.80
(m, 1H), 5.75 (m, 1H), 4.15–4.04 (m, 3H), 3.90 (m, 1H), 3.17
(m, 1H), 2.77 (m, 1H), 2.54 (dd, J = 15.5, 8.3 Hz, 1H), 1.97 (m,
1H), 1.89 (m, 1H), 1.69 (m, 1H), 1.42 (m, 1H), 1.33–1.26 (m,
2H),1.22 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (150 MHz, acetone-
d6) δ 172.7, 122.2, 106.2, 60.6, 50.2, 39.5, 35.8, 30.5, 30.2
(overlapping with residual solvent signal), 14.6 ppm; IR (NaCl)
2925, 1729, 1175, 705 cm–1.
Indolizidines 11 and 12. 2% AcOH/EtOH (30 mL) was added
to tetrahydroindolizidine 10 (1.128 g, 6.36 mmol) and 5%
Rh/Al2O3 (220 mg, 0.11 mmol, 1.7 mol%). The magnetically
stirred mixture was placed under a H2 atmosphere (balloon).
After 21 h, the mixture was filtered through a plug of Celite® and
eluted with MeOH. Na2CO3 (40 mL of saturated aqueous
solution) was then added to the ensuing solution. The aqueous
phase was extracted with EtOAc (4x 40 mL) and the combined
organic extracts were dried (Na2SO4), filtered and concentrated
under reduced pressure. The ensuing crude residue (1.01 g) was
subjected to flash column chromatography {1:9 (1.7%
NH3/MeOH)/CH2Cl2 elution; silica gel} to provide compound 11
(206 mg, 1.14 mmol, 18% yield) and compound 12 (465 mg,
2.57 mmol, 40% yield). 11: [Found (M+H)+, 182.1542.
C11H19NO, requires (M+H)+, 182.1539]. 1H NMR (600 MHz,
CDCl3) δ 3.04 (m, 1H), 2.99 (t, J = 8.6 Hz, 1H), 2.66 (dd, J =
16.7, 3.9 Hz, 1H), 2.49–2.41 (m, 2H), 2.13 (s, 3H), 2.03–1.98 (m,
2H), 1.92 (m, 1H), 1.70–1.58 (m, 4H), 1.49–1.40 (m, 2H), 1.28
(m, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 209.0, 66.8, 54.9,
53.9, 41.8, 30.6, 30.4, 29.6, 26.9, 21.4, 20.8 ppm. IR (NaCl)
2932, 2781, 1715, 1384, 1355, 1157 cm–1. 12: [Found (M+H)+,
182.1542. C11H19NO, requires (M+H)+, 182.1539]. 1H NMR (600
MHz, CDCl3) δ 3.07–3.04 (m, 2H), 2.47 (dd, J = 15.6, 4.2 Hz,
1H), 2.16 (dd, J = 15.6, 8.9 Hz, 1H), 2.11–2.06 (m, 4H), 1.92 (m,
1H), 1.86–1.73 (m, 4H), 1.66–1.58 (m, 3H), 1.52 (m, 1H), 1.40
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 208.2, 69.0, 54.6, 52.7,
48.1, 38.3, 31.0, 30.4, 29.2, 25.4, 20.5. IR (NaCl) 2931, 2780,
1718, 1359, 1331, 1165, 1155 cm–1.
1-(pent-4-en-1-yl)-1H-pyrrole (7). Pyrrole (930 µL, 13.4
mmol) was added dropwise to a magnetically stirred mixture of
NaH (2.53 g of 25% dispersion in mineral oil, 26.4 mmol) in
DMF (50 mL) maintained at 0 °C under N2. After 0.25 h, 5-
bromo-pent-1-ene (2.4 mL, 20.1 mmol) was added dropwise and
the ensuing mixture was allowed to slowly warm to room
temperature and was stirred. After 21.5 h, the mixture was cooled
to 0 °C and H2O (30 mL) was added. The aqueous phase was
extracted then with Et2O (3x 25 mL) and the combined organic
extracts were successively washed with water (3x 20 mL) and
brine (20 mL), dried (MgSO4), filtered, silica gel was then added,
and the mixture was concentrated under reduced pressure. The
ensuing residue was subjected to flash column chromatography
(3% Et2O/pentane elution; silica gel) to provide pyrrole 7 as a
colorless oil (1.73 g, 12.8 mmol, 96% yield).21 1H NMR (400
MHz, CDCl3) δ 6.65 (m, 2H), 6.12 (m, 2H), 5.79 (m, 1H), 5.08–
5.00 (m, 2H), 3.89 (t, J = 7.1 Hz, 2H), 2.06 (m, 2H), 1.88 (quin, J
= 7.2 Hz, 2H).
(±)-(Octahydroindolizin-8-yl)methyl acetate (13) and (±)-
tashiromine (1). Sodium percarbonate (815 mg, 5.19 mmol) was
added (over 0.67 h) to a magnetically stirred solution of ketone
12 (93 mg, 0.51 mmol) in TFA (6 mL) maintained at 0 °C and
the ensuing mixture was allowed to slowly warm to r.t. After 24
h, H2O (5 mL) and Na2CO3 (~70 mL of a saturated aqueous
solution) were added. The aqueous phase was extracted with
EtOAc (4x 50 mL) and the combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
ensuing residue (200 mg) was subjected to flash column
chromatography {1:9 (1.7% NH3/MeOH)/CH2Cl2) elution; silica
gel} to provide compound 13 (61 mg, 0.31 mmol, 61% yield) as
a colorless oil and (±)-tashiromine (1) (8 mg, 0.052 mmol, 10%)
as a colorless oil.22 13: [Found (M+H)+, 198.1491. C11H19NO2,
1
requires (M+H)+, 198.1489]. H NMR (600 MHz, CD3OD) δ
4.08 (m, 2H), 3.57–3.52 (m, 2H), 2.92 (q, J = 9.8 Hz, 1H), 2.85–
2.76 (m, 2H), 2.33 (m, 1H), 2.10–1.92 (m, 8H), 1.81–1.70 (m,
2H), 1.39 (dd, J = 13.0, 3.2 Hz, 1H) ppm; 13C NMR (150 MHz,
CD3OD) δ 172.4, 68.9, 66.3, 53.9, 52.4, 40.7, 28.4, 26.9, 24.1,
20.6, 20.5 ppm; IR (NaCl) 1742, 1733, 1239, 1200, 1176, 1128,
1-(5,6,7,8-Tetrahydroindolizin-8-yl)propan-2-one
(10).
Grubbs’ second-generation catalyst (110 mg, 0.13 mmol) was
added to a magnetically stirred solution of pyrrole 7 (350 mg,
2.59 mmol) and methyl vinyl ketone (260 µL, 3.12 mmol) in
CH2Cl2 (5 mL) maintained under N2 and the solution was then
1
719 cm–1; 1: H NMR (600 MHz, CDCl3) δ 3.61 (dd, J = 10.9,
4.7 Hz, 1H), 3.52 (dd, J = 10.9, 5.9 Hz), 3.31–3.26 (m, 2H), 2.29

5
(m, 1H), 2.16 (m, 1H), 2.10–1.99 (m, 2H), 1.92–1.86 (m, 2H),
(m, 12H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
ACCEPTED MANUSCRIPT
1.80–1.62 (m, 5H), 1.17 (m, 1H) ppm; 13C NMR (150 MHz,
CDCl3) δ 209.0, 67.2, 64.6, 52.1, 41.4, 36.9, 30.5, 30.1, 29.8,
27.2, 26.2, 20.4, 18.8, 14.5; IR (NaCl) 2957, 2934, 2872, 2781,
1715, 1383, 1355 cm–1. 18: [Found (M+H)+, 224.2011.
C14H25NO, requires (M+H)+, 224.2009]. 1H NMR (600 MHz,
CDCl3) δ 3.40 (t, J = 8.2 Hz, 1H), 2.49 (dd, J = 15.5, 3.7 Hz,
1H), 2.21–2.07 (m, 6H), 2.01–1.93 (m, 2H), 1.92–1.74 (m, 4H),
1.73–1.61(m, 3H), 1.56 (m, 1H), 1.43–1.34 (m, 3H), 1.22 (m,
1H), 1.03 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (150
MHz, CDCl3) δ 208.1, 69.5, 63.4, 51.2, 47.8, 37.0, 36.0, 30.7,
30.4, 29.9, 28.6, 20.1, 19.2, 14.4 ppm; IR (NaCl) 2956, 2934,
2872, 2779, 1717, 1356, 1156 cm–1.
CDCl3) δ 67.1, 65.0, 53.7, 52.4, 43.2, 28.4, 26.9, 24.2, 20.5 ppm.
(±)-Tashiromine (1). K2CO3 (120 mg, 0.87 mmol) was added
to a magnetically stirred solution of acetate 13 (40 mg, 0.20
mmol) in methanol (5 mL). After 2 h, the ensuing mixture was
filtered through a plug of Celite® and concentrated under reduced
pressure (202 mg). The ensuing residue was subjected to flash
column chromatography {1.5:8.5 (1.7% NH3/MeOH)/CH2Cl2
elution; silica gel} to provide (±)-tashiromine (1) as a colorless
oil (30 mg, 0.19 mmol, 95% yield).
(±)-1-(Oct-7-en-4-yl)-1H-pyrrole (15). n-BuLi (23 mL of 1.3
M solution in hexanes, 29.9 mmol) was added to a magnetically
stirred solution of methyltriphenylphosphonium iodide (12.1 g,
29.8 mmol) in THF (100 mL) maintained at –78 °C (mixture A).
The ensuing mixture was allowed to warm to r.t. over 1 h. In
parallel, DIBAL-H (15.8 mL of a 0.95 M solution, 15.01 mmol)
was added over 10 min to a solution of ester 14 (3.34 g, 15.1
mmol) in CH2Cl2 (50 ml) maintained at –78 °C under N2 (mixture
B). After 1 h, mixture A was cooled to –78 °C and added to
mixture B. After 0.25 h, the ensuing mixture was slowly warmed
to r.t. After 3 h, water was added (150 mL) and the aqueous
phase was extracted with CH2Cl2 (3x 100 mL). The combined
organic extracts were dried (MgSO4), filtered, and concentrated
under reduced pressure to a volume of ~50 mL. Silica gel was
then added and the remaining solvent was removed under
reduced pressure. The ensuing mixture was subjected to flash
column chromatography (10% CH2Cl2/pentane elution; silica gel)
to provide the olefin 15 (1.90 g, 10.7 mmol, 71% yield) as a
colorless oil. [Found (M+H)+, 178.1592. C12H29N, requires
(±)-Indolizidine 209I {(±)-2}. Step i. NaBH4 (35 mg, 0.92
mmol) was added to a magnetically stirred solution of ketone 18
(123 mg, 0.55 mmol) in EtOH (3 mL) maintained at 0 °C. After 1
h, the H2O (10 mL) was added and the aqueous phase was
extracted with EtOAc (3x 10 mL). The organic extracts were
combined, dried (Na2SO4), filtered and concentrated under
reduced pressure to provide alcohol 19 (121 mg, 0.54 mmol, 98%
yield) as a colorless oil, which was immediately subjected to the
next step. Step ii. MsCl (75 µL, 0.97 mmol) was added to a
magnetically stirred solution of alcohol 19 (113 mg, 0.50 mmol),
NEt3 (140 µL, 1.00 mmol) in CH2Cl2 (3 mL) maintained at 0 °C
under N2. The ensuing solution was slowly warmed to r.t. After
0.5 h, NEt3 (70 µL, 0.50 mmol) and MsCl (35 µL, 0.48 mmol)
were added. After 0.5 h, Na2CO3 (10 mL of saturated aqueous
solution) was added and the phases separated. The aqueous phase
was further extracted with EtOAc (3x 10 mL). The combined
organic extracts were then dried (Na2SO4) and concentrated
under reduced pressure to provide a light-yellow oil (170 mg).
Step iii. The ensuing oil was dissolved in THF (5 mL) and
LiAlH4 (58 mg, 1.52 mmol) was added. The ensuing mixture was
heated at reflux under N2. After 15 h, the mixture was cooled to
r.t. and H2O (20 mL) was added. The aqueous phase was
extracted with Et2O (3x 20 mL), the combined organic extracts
were dried (Na2SO4) and concentrated under reduced pressure to
provide a light-yellow oil (91 mg). The ensuing residue was
subjected to flash column chromatography {1:19 (1.7%
NH3/MeOH)/CH2Cl2 elution; silica gel} to provide (±)-
indolizidine 209I {(±)-2} as a colorless oil (67 mg, 0.32 mmol,
64% over two steps).23 1H NMR (600 MHz, CDCl3) δ 3.26 (t, J =
8.2 Hz, 1H), 1.97–1.89 (m, 2H), 1.87–1.82 (m, 2H), 1.78–1.70
(m, 2H), 1.66–1.53 (m, 3H), 1.46–1.33 (m, 4H), 1.32–1.15 (m,
5H), 1.03 (m, 1H), 0.91–0.83 (m, 7H) ppm; 13C NMR (150 MHz,
CDCl3) δ 70.4, 63.6, 52.0, 41.4, 37.1, 35.8, 31.3, 30.6, 29.3, 20.6,
19.8, 19.2, 14.7, 14.6 ppm.
1
(M+H)+, 178.1590]. H NMR (600 MHz, CDCl3) δ 6.65 (t, J =
2.0 Hz, 2H), 6.14 (t, J = 1.9 Hz, 2H), 5.74 (m, 1H), 4.97 (m, 2H),
3.81 (sep, J = 4.8 Hz, 1H), 1.90–1.64 (m, 6H), 1.24–1.08 (m,
2H), 0.87 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ 137.9, 119.0, 115.3, 107.5, 59.5, 39.0, 35.9, 30.5, 19.6, 13.9
ppm; IR (NaCl) 2958, 2936, 1490, 1086, 913, 720 cm–1.
Indolizidines 17 and 18. Step i. Grubbs’ second-generation
catalyst (285 mg, 0.34 mmol, 5 mol%) was added to a
magnetically stirred solution of olefin 15 (1.153 g, 6.50 mmol)
and methyl vinyl ketone (820 µL, 9.84 mmol) in CH2Cl2 (20 mL)
maintained under N2 and the ensuing solution was heated at
reflux. After 18 h, the solution was cooled to r.t., ethyl vinyl
ether (400 µL) was added and the solution was concentrated to
dryness under reduced pressure. The ensuing residue was passed
through a plug of silica gel (CH2Cl2 elution) to provide a mixture
of diastereomers 16 (843 mg, 3.84 mmol, 60% yield) as a
colorless oil. Step ii. 2% AcOH/EtOH (20 mL) was added to
diastereomers 16 (800 mg, 3.65 mmol) and Rh/Al2O3 (119 mg,
0.058 mmol, 1.6 mol%). The magnetically stirred mixture was
placed under a H2 atmosphere (balloon). After 16 h, the mixture
was filtered through a plug of Celite® and concentrated under
reduced pressure. The ensuing residue was subjected to flash
column chromatography {1:19 (1.7% NH3/MeOH)/CH2Cl2
elution; silica gel} to provide starting material 16 (260 mg, 1.19
mmol, 32% yield), product 17 (154 mg, 0.69 mmol, 18%) and
product 18 (251 mg, 1.12 mmol, 29% yield). A sample of
indolizidine 17 spontaneously crystallized following evaporation
of CDCl3 and was recrystallized as its HCl salt via slow
evaporation from CH2Cl2 to yield colorless needles suitable for
analysis by single crystal X-ray crystallography. 17: [Found
Acknowledgments
The authors gratefully acknowledge the School of Natural
Sciences – Chemistry for financial support, the Central Science
Laboratory at University of Tasmania for access to NMR
spectroscopy services, and Materia Inc. for the generous
provision of Grubbs’ second-generation catalyst. W.J.O. thanks
the Australian Government for a Research Training Program
Scholarship.
References and notes
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2.33 (m, 2H), 2.11–2.02 (m, 4H), 1.87–1.77 (m, 2H), 1.60–1.16

6
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Supplementary Material
1H and 13C NMR spectral data and single crystal X-ray
crystallographic data for the HCl salt of compound 17 and
experimental details for the synthesis of compounds 3, 4 and 14
are provided in the Supporting Information.