Synthesis of (±)-γ-Lycorane by Using an Intramolecular Friedel-Crafts Reaction

Article abstract of DOI:10.1055/s-0036-1589067

A total synthesis of γ-lycorane has been achieved by employing N -tosylpyrrole as a key building block. The synthesis employs both an intermolecular and an intramolecular Friedel-Crafts reaction, as well as a completely diastereoselective hydrogenation of

Full text of DOI:10.1055/s-0036-1589067

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
B. N. Doan et al.
Paper
Synthesis
Synthesis of (±)-γ-Lycorane by Using an Intramolecular Friedel–Crafts
Reaction
Bao Nguyen Do Doan
NTs
Xin Yi Tan
Chin May Ang
O
O
O
O
SO3H
OH
Roderick W. Bates*
N
Ts
Division of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
University, 21 Nanyang Link, 637371, Singapore
roderick@ntu.edu.sg
Received: 29.04.2017
Accepted after revision: 26.05.2017
Published online: 20.07.2017
tivity. Indeed, Angle and Boyce had to employ an uncom-
mon Lewis acid, Sn(OTf)2, for the second pyrrole bond
forming reaction. In contrast, N-tosyl pyrrole 4a is relatively
acid stable and the ability of the N-tosyl group to direct
Friedel–Crafts acylation to the β-position has been well
documented.4 Substitution at the β-position represents the
thermodynamic pathway; α-substitution is possible under
kinetic control. N-Tosyl pyrrole 4a is also readily available
and cheaply prepared.5
DOI: 10.1055/s-0036-1589067; Art ID: ss-2017-t0284-op
Abstract A total synthesis of γ-lycorane has been achieved by employ-
ing N-tosylpyrrole as a key building block. The synthesis employs both
an intermolecular and an intramolecular Friedel–Crafts reaction, as well
as a completely diastereoselective hydrogenation of a late-stage pyrrole
intermediate.
Key words heterocycle, pyrrole, Friedel–Crafts, hydrogenation
H
H
N
O
O
Numerous syntheses of γ-lycorane 1 have been reported
despite, as various authors have pointed out, its apparent
lack of useful pharmacological properties.1 Nevertheless, it
is one of the prototypical N-heterocycles of its group and
syntheses of this compound serve to demonstrate the suit-
ability or otherwise of synthetic methodology.
O
O
H
H
H
H
HN
1
2
β
O
α
N
HN
O
Ts
γ-Lycorane 1 may be viewed as a substituted pyrroli-
dine. One strategy for the synthesis of pyrrolidine natural
products is by reduction of the corresponding pyrrole. This
strategy has seen some use by organic chemists, but infre-
quently.2 An advantage of taking pyrrole as a starting mate-
rial is that electrophilic substitution can be directed to ei-
ther the α- or β-positions, depending, principally, on the
substitution pattern, especially the identity of the N-sub-
stituent.3 This ability recommends pyrrole as a starting ma-
terial for γ-lycorane, as both α- and β-substitution are re-
quired. It is known that γ-lycorane can be formed by the
Pictet–Spengler reaction of pyrrolidine 2,1b which, in turn,
might be formed by hydrogenation of pyrrole 3 (Scheme 1).
The α- and β-positioned bonds on the pyrrole could then be
formed by electrophilic chemistry, with the α-bond put in
place by an intramolecular Friedel–Crafts reaction. Indeed,
Angle and Boyce have reported such a method.1s They used
the N-TIPS substituent to direct electrophilic substitution to
the β-position, then switched to an N-Boc group for later
chemistry. A disadvantage of using pyrrole is its acid sensi-
3
4
Scheme 1 γ-Lycorane retrosynthesis
Our plan was to prepare alcohol 8 as the substrate for
the α-bond forming intramolecular Friedel–Crafts reaction.
In our first approach (Scheme 2), N-tosyl pyrrole 4a was
converted into the corresponding 3-vinyl derivative 5 in
three steps by the method of Kakushima.4c Alcohol 7 was
prepared in excellent yield from piperonal 6 by Luche’s
modification6 of the Barbier reaction. Cross metathesis be-
tween pyrrole 5 and alcohol 7 using the second-generation
Grubbs catalyst in toluene gave the desired product 8 in
modest yield (Table 1), but exclusively as the trans isomer.
This is, to our knowledge, the first example of the cross me-
tathesis of a vinyl pyrrole. Much higher yields were ob-
tained when the reaction was carried out in hexafluoroben-
zene,7 although higher dilution was helpful. Alkene 8 could
be easily hydrogenated, giving alcohol 9 without any com-
plications arising from the presence of the benzylic alcohol.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
B. N. Doan et al.
Paper
Synthesis
1. Ac2O, AlCl3
2. NaBH4
3. DMSO, Δ
OH
N
N
N
Ts
Ts
73%
5
O
O
Ts
4a
Ts
Grubbs II
OH
Br
8
H2, Pd/C, EtOH
83%
CHO
O
O
O
O
Zn, NH4Cl
98%
7
6
OH
N
O
O
9
Scheme 2 The cross-metathesis approach
Table 1 Cross-Metathesis Reactions between Alkenes 7 and 5
Entry
Ratio of 7/5
Solvent
Concn of 5 (M)
T (°C)
t (h)
Yield (%)
1
2
3
4
5
6
1:1
1:1
3:1
3:1
3:1
3:1
toluene
toluene
C6F6
0.2
70–80
70–80
reflux
reflux
reflux
reflux
overnight
6.5
0
37
80
79
52
69
0.05
0.05
0.1a
0.1b
0.15
6.5
C6F6
8.5
C6F6
8.5
C6F6
6.5
a Using 1 mmol of pyrrole 5.
b Using 2 mmol of pyrrole 5.
Seeking an alternative approach due to the cost of C6F6,
the need for excess of one metathesis partner, and the diffi-
culties in scale-up, N-tosyl pyrrole 4a was subjected to
Friedel–Crafts acylation with succinic anhydride (Scheme
3). The keto group of acid 10 was then deleted by Clem-
mensen reduction. This reaction sequence dates back to Ha-
worth,8 who employed zinc amalgam for the reduction.
Wishing to avoid the use of mercury for environmental and
safety reasons,9 we found that the same reaction could be
accomplished by using a large excess of zinc powder in the
presence of HCl, provided that dioxane was employed as the
organic co-solvent. The use of toluene was ineffective,
while tetrahydrofuran (THF) underwent ring opening un-
der these conditions. When ethanol was used, partial ester-
ification was observed. The resulting acid 11 was then con-
verted into the corresponding Weinreb amide 12, which
was coupled with the lithium derivative 13.10 In this trans-
formation, it was found to be essential to maintain the tem-
perature below –50 °C, otherwise partial detosylation of
14a to the corresponding N-unsubstituted pyrrole 14b
would also be observed. Pyrroles 14a and 14b were chro-
matographically inseparable. Reduction of the ketone with
sodium borohydride gave alcohol 9, which was identical to
the material prepared before.
found that scandium triflate11 was an effective catalyst for
this cyclization, but gave a very poor yield (18%). As the N-
tosyl group had now served its purpose, attempts were
made to remove it. With pyrroles, this is typically done by
heating with sodium hydroxide.12 However, no reaction was
observed when dioxane or methanol were used as the sol-
vent. We have previously observed that sodium hydroxide
is much more reactive in dimethyl sulfoxide (DMSO).2b This
proved to be so, but, in this case, the result was elimination
of tosic acid to give 16. We attribute this unexpected reac-
tivity to the degree of steric hindrance around the tosyl
group of 15. Reasoning that a stronger nucleophile but a
weaker base was required, we employed sodium ethanethi-
olate and were delighted to find clean detosylation upon
heating in DMSO. With the N-unsubstituted pyrrole 3 in
hand, we turned to hydrogenation1b,1s to convert it into the
pyrrolidine. Hydrogenation over Rh/C, Rh/Al2O3, or Pd/C
proved fruitless,13 but the method of Kray and Reinecke,14–16
using platinum oxide in acetic acid and hydrogen under
modest pressure, gave pyrrolidine 2 as a single stereoiso-
mer. The presumption that this was the desired isomer was
vindicated by the eventual conversion into the natural
product. While experimenting with the reduction reaction,
we also investigated a modified Knorr–Rabe reduction.17
Treatment of pyrrole 15 with sodium cyanoborohydride
and trifluoroacetic acid gave dihydropyrrole 17 as a ca. 5:1
mixture of stereoisomers. The major isomer was found by
X-ray crystallography to possess the desired stereochemis-
try.18 As this pathway offered no advantages (and lower ste-
Treatment of alcohol 9 with amberlyst-15 smoothly
provided the Friedel–Crafts product 15 in 82% average yield,
by formation of the new carbon–carbon bond at the α-posi-
tion. The reaction proceeded much more rapidly in acetoni-
trile than in either dichloromethane or chloroform. We also
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
B. N. Doan et al.
Paper
Synthesis
O
Zn (25 equiv), HCl,
aq dioxane, ↑↓
HO2C
XOC
MeOMeNH2Cl
EDCI, DMAP
Et3N, CH2Cl2
72–86%
AlCl3
11 X = OH
O
O
O
N
N
N
90%
82%
12 X = NMeOMe
Ts
Ts
Ts
4a
10
O
OH
Li
13
N
R
N
Ts
O
O
O
O
O
NaBH4, MeOH
85%
THF, –78°C
O
14a R = Ts
14b R = H
9
74%
O
NaOH, DMSO
58%
N
H
H
O
O
O
O
Amberlyst-15
MeCN
16
H
N
HN
O
72–98%
Ts
O
O
15
NaBH3CN
2
EtSNa , DMSO
70 °C
(CH2O)n, CF3CO2H
CHCl3, 4 Å MS
62%
H2, PtO2, AcOH
85%
99%
HN
CF3CO2H, CH2Cl2
99%
3
H
H
O
O
O
O
H
H
H
N
N
Ts
17
1
Scheme 3 The second approach and completion of the synthesis
reoselectivity) over the eventual hydrogenation route, it
was not continued. The synthesis was completed by treat-
ment of pyrrolidine 2 with paraformaldehyde under acidic
conditions in a Pictet–Spengler process to deliver γ-lycor-
ane 1. The NMR spectroscopic data for our synthetic mate-
rial were in excellent agreement with those reported previ-
ously.1h
In conclusion, a diastereoselective synthesis of (±)-γ-ly-
corane 1 has been completed relying on the robust N-tosyl
group to control regioselectivity in pyrrole functionaliza-
tion. Two routes have been developed to access the key
Friedel–Crafts precursor: both routes to (±)-γ-lycorane total
nine steps.
tered through Celite™ and extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were washed with brine (20 mL) and dried over
Na2SO4. The solution was concentrated to give 7.
Yield: 3.13 g (98%); orange oil.
1H NMR (400 MHz, CDCl3): δ = 6.87 (app dd, J = 0.4, 1.6 Hz, 1 H), 6.80
(dd, J = 1.6, 8.0 Hz, 1 H), 6.77 (dd, J = 0.4, 8.0 Hz, 1 H), 5.95 (s, 2 H),
5.85–5.73 (m, 1 H), 5.18–5.11 (m, 2 H), 4.65 (t, J = 6.5 Hz), 2.47 (m,
2 H), 2.02 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.7, 146.9, 138.0, 134.4, 119.2,
118.4, 108.0, 106.4, 101.0, 73.2, 43.8.
Alcohol 8
A solution of alcohol 7 (1.50 mmol, 288 mg, 3 equiv) and pyrrole 5
(0.50 mmol, 124 mg, 1 equiv) in C6F6 (10 mL) was thoroughly de-
gassed for 15 minutes and then heated at reflux under a continuous
nitrogen flow. A solution of Grubbs II catalyst (25 μmol, 23 mg, 5
mol%) in C6F6 (5 mL) was added portionwise (1 mL per hour). After
adding the last portion, the mixture was further stirred for 2.5 h. The
solution was concentrated, and the crude material was purified by
flash chromatography, (EtOAc/hexane, gradient 20–40%) to give 8.
When appropriate, reactions were run under a nitrogen atmosphere
in oven-dried glassware. THF was distilled from sodium/benzophe-
none, toluene was distilled from sodium, dichloromethane was dis-
tilled from calcium hydride, and chloroform was passed through ac-
tive alumina. Other solvents and reagents were used as received. Col-
umn chromatography was carried out on silica gel 230–400 mesh,
and analytical TLC on glass plates (silica gel 60, F254). NMR spectra
were recorded in CDCl3 solutions at 400 MHz (1H) or 100 MHz (13C).
Chemical shifts are given in ppm and coupling constants are given in
Hz.
Yield: 164 mg (80%); light-brown oil.
FTIR (KBr): 3416, 3134, 3053, 3147, 2778, 2538, 1919, 1850, 1721,
1654, 1595, 1487, 1367, 1171, 1099, 1061, 1038, 1018, 966, 868, 812,
702, 603 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.09–7.02 (m, 2 H), 6.79–6.74 (m, 3 H), 6.37–6.25 (m,
2 H), 5.95–5.84 (m, 1 H), 5.93 (s, 2 H), 4.64 (t, J = 6.4 Hz, 1 H), 2.52
(app t, J = 6.4 Hz, 2 H), 2.39 (s, 3 H), 2.08 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.7, 146.9, 145.0, 138.0, 135.9,
128.0, 127.3, 126.8, 125.6, 124.7, 121.6, 119.1, 117.8, 111.1, 108.0,
106.3, 101.0, 73.5, 42.9, 21.6.
Alcohol 719
Activated zinc (33.4 mmol, 2.18 g, 2 equiv) was added to a solution of
piperonal 6 (16.7 mmol, 2.50 g, 1 equiv) in THF (4 mL), followed by
saturated NH4Cl solution (20 mL). The mixture was cooled to 0 °C and
distilled allyl bromide (33.4 mmol, 2.90 mL, 2 equiv) was added drop-
wise. The reaction was stirred overnight. The mixture was then fil-
MS (ESI): m/z (%) = 412 [M + H]+, 394 (100), 380 (62).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H22NO5S: 412.1219; found:
412.1218.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
B. N. Doan et al.
Paper
Synthesis
Alcohol 9 (by Hydrogenation)
13C NMR (100 MHz, CDCl3): δ = 179.7, 144.8, 136.1, 129.9, 128.3,
126.7, 121.1, 117.5, 114.4, 33.2, 25.9, 24.8, 21.5.
Pd/C (15 mg, 10% w/w) was added to a solution of alkene 8 (0.367
mmol, 151 mg) in EtOH (5 mL). The system was then flushed with ni-
trogen, followed by hydrogen. The mixture was stirred under hydro-
gen (balloon pressure) for 4 h. The solution was filtered through
Celite™ and concentrated to give alcohol 9.
Amide 12
Triethylamine (15.0 mmol, 2.10 mL, 2 equiv) was added dropwise to a
solution of acid 11 (7.47 mmol, 2.30 g, 1 equiv) and N,O-dimethylhy-
droxylamine hydrochloride (11.2 mmol, 1.09 g, 1.5 equiv) in anhy-
drous CH2Cl2 (40 mL) at 0 °C. EDCI·HCl (11.2 mmol, 2.15 g, 1.5 equiv)
and DMAP (1.49 mmol, 183 mg, 0.2 equiv) were added as solids to the
solution, and the mixture was allowed to warm to r.t. The mixture
was stirred overnight, then the solution was washed with 2 M aq. HCl
(2 × 30 mL), saturated NaHCO3 solution (30 mL) and brine. The organ-
ic layer was dried over Na2SO4 and concentrated. The residue was pu-
rified by flash chromatography (EtOAc/hexane, 40–50%) to give amide
12.
Yield: 125 mg (83%); pale-yellow solid; mp 90–92 °C.
FTIR (KBr): 3485, 3148, 2725, 2673, 2353, 2309, 2043, 1923, 1857,
1834, 1304, 1250, 1169, 1101, 928, 891, 870, 844, 812, 773, 723, 667,
644 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.0 Hz, 2 H), 7.26 (d, J =
8.0 Hz, 2 H), 7.05 (dd, J = 2.2, 3.2 Hz, 1 H), 6.87–6.85 (m, 1 H), 6.81 (m,
1 H), 6.77–6.72 (m, 2 H), 6.11 (dd, J = 1.6, 3.2 Hz, 1 H), 5.95 (s, 2 H),
4.55 (m, 1 H), 2.39 (t, J = 6.4 Hz, 2 H), 2.39 (s, 3 H), 1.75 (br. d, J = 4 Hz,
1 H), 1.76–1.72 (m, 2 H), 1.65–1.58 (m, 2 H), 1.52–1.44 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 147.8, 146.9, 144.7, 138.7, 136.3,
129.9, 129.4, 126.7, 120.9, 119.3, 117.3, 114.6, 108.0, 106.3, 101.0,
74.3, 38.4, 26.5, 26.1, 21.6.
Yield: 2.24 g (86%); pale-yellow oil.
FTIR (KBr): 3134, 2927, 2870, 2822, 2587, 2532, 1921, 1790, 1732,
1634, 1595, 1360, 1308, 1292, 1258, 1173, 1101, 1061, 995, 957, 916,
870, 814, 779, 704 cm–1
.
MS (ESI): m/z (%) = 436 [M + Na]+, 396 (100).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H23NO5SNa: 436.1195;
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.07 (dd, J = 2.4, 3.2 Hz, 1 H), 6.91 (dd, J = 1.6, 2.4, 1 H),
6.15 (dd, J = 1.6, 3.2 Hz, 1 H), 3.61 (s, 3 H), 3.16 (s, 3 H), 2.44 (t, J =
7.0 Hz, 2 H), 2.39 (s, 3 H), 2.39 (t, J = 7.0 Hz, 2 H), 1.85 (quint, J =
7.4 Hz, 2 H).
found: 436.1183.
Ketone 1020
13C NMR (100 MHz, CDCl3): δ = 174.2, 144.7, 136.2, 129.9, 129.0,
126.7, 120.9, 117.4, 114.5, 61.1, 32.1, 31.1, 26.2, 24.7, 21.6.
MS (ESI): m/z (%) = 351 [M + H]+, 290 (9).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H23N2O4S: 351.1379;
Succinic anhydride (11.0 mmol, 1.10 g, 1.1 equiv) was added to a sus-
pension of anhydrous AlCl3 (22.0 mmol, 2.93 g, 2.2 equiv) in CH2Cl2
(40 mL). The mixture was stirred for 15 minutes until a clear solution
was obtained. A solution of N-tosyl pyrrole 4 (10.0 mmol, 2.21 g, 1
equiv) in CH2Cl2 (5 mL) was added slowly to the mixture, which was
stirred at r.t. for 3 h until TLC showed completion. The reaction was
quenched with ice water and the organic layer was separated. The re-
maining aqueous layer was further extracted with CH2Cl2 (2 × 30 mL).
The combined organic layers were washed with brine (20 mL), dried
over MgSO4, and concentrated to give ketone 10.
found: 351.1377.
Ketone 14a
n-BuLi (1.6 M in hexane, 5.6 mL, 2.2 equiv) was added slowly to a
solution of 5-bromo-1,3-benzodioxole (7.29 mmol, 1.47 g, 1.80 equiv)
in anhydrous THF (60 mL) at –78 °C. The resulting solution was
stirred at –78 °C for 1 h. A solution of amide 12 (4.05 mmol, 1.42 g, 1
equiv) in anhydrous THF (15 mL) was added dropwise while the tem-
perature was maintained between –78 °C and –55 °C. After addition,
the mixture was stirred at –78 °C for 1 h, until TLC showed comple-
tion. The reaction was quenched at –78 °C with saturated NaHCO3
solution (50 mL), and the mixture was allowed to warm to r.t. The
mixture was then extracted with EtOAc (3 × 30 mL) and the combined
organic layers were washed with brine, dried over Na2SO4 , and con-
centrated. The residue was purified by flash chromatography
(EtOAc/hexane, gradient 10–20%) to give 14a.
Yield: 2.88 g (90%); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 2 H), 7.77 (app t, J =
2.0 Hz, 1 H) 7.34 (d, J = 8.0 Hz, 2 H), 7.14 (dd, J = 2.0, 3.2 Hz, 1 H),
6.69–6.67 (dd, J = 2.0, 3.2 Hz, 1 H), 3.07 (t, J = 6.6 Hz, 2 H), 2.74 (t, J =
6.6 Hz, 2 H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 192.8, 177.8, 146.0, 135.0, 130.4,
128.2, 127.3, 124.3, 121.6, 112.2, 34.0, 27.6, 21.7.
Carboxylic Acid 1120
Activated zinc (213 mmol, 13.5 g, 25 equiv), followed by concentrated
aqueous hydrochloric acid (5 mL) were added to a refluxing solution
of ketone 10 (8.50 mmol, 2.72 g, 1 equiv) in aqueous dioxane (diox-
ane–water, 9:1, 100 mL). The mixture was maintained at gentle re-
flux, and concentrated aqueous hydrochloric acid was further added
dropwise (1 mL per 10 minutes) until TLC showed completion (ca.
4 h). All excess zinc was quenched with concentrated aqueous hydro-
chloric acid. The mixture was then diluted with brine and saturated
with NaCl. The mixture was extracted with ether (3 × 30 mL) and the
combined organic layers were washed with brine, dried over MgSO4
and concentrated. The residue was purified by flash chromatography
(MeOH/CH2Cl2, 3%) to give acid 11.
Yield: 1.23 g (74%); pale-purple solid; mp 93–96 °C.
FTIR (KBr): 2723, 2669, 2357, 2340, 1667, 1304, 1242, 1169, 1103,
1034, 928, 891, 768, 721 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.49 (d, J =
8.0 Hz, 1 H), 7.38 (app s, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.08 (t, J = 2.4 Hz,
1 H), 6.91 (m, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.16 (m, 1 H), 6.04 (s, 2 H),
2.84 (t, J = 7.0 Hz, 2 H), 2.47 (t, J = 7.0 Hz, 2 H), 2.38 (s, 3 H), 1.94
(quint, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 198.1, 151.6, 148.1, 144.7, 136.2,
131.8, 129.9, 128.9, 126.7, 124.1, 121.1, 117.5, 114.5, 107.8, 101.8,
37.4, 26.2, 24.6, 21.6.
Yield: 2.14 g (82%); colorless solid.
MS (ESI): m/z = 412 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H22NO5S: 412.1219; found:
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.07 (dd, J = 2.4, 3.2 Hz, 1 H), 6.91 (dd, J = 1.6, 2.4 Hz,
1 H), 6.14 (dd, J = 1.6, 3.2 Hz, 1 H), 2.44 (t, J = 7.5 Hz, 2 H), 2.39 (s, 3 H),
2.32 (t, J = 7.5 Hz, 2 H), 1.84 (quint, J = 7.5 Hz, 2 H).
412.1214.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
B. N. Doan et al.
Paper
Synthesis
Alcohol 9 (by Ketone Reduction)
Pyrrole 3
NaBH4 (9.39 mmol, 355 mg, 3 equiv) was added portionwise to a solu-
tion of ketone 12 (3.13 mmol, 1.29 g, 1 equiv) in MeOH (60 mL) at
0 °C. The mixture was stirred at 0 °C for 30 min until TLC showed
completion. The mixture was diluted cautiously with water (50 mL).
All of the volatiles were then removed, and the remaining aqueous
layer was extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with brine, dried over Na2SO4 and concentrated.
The residue was purified by flash chromatography (EtOAc/hexane,
30%) to give alcohol 9.
Pyrrole 15 (138 mg, 1 equiv, 0.349 mmol) was added to a solution of
EtSH (4 mL) and NaOH (5.24 mmol, 210 mg, 15 equiv) in DMSO (20
mL). The solution was then warmed to 60–70 °C and stirred under ni-
trogen overnight. After TLC showed completion, the solution was al-
lowed to cool to r.t. and diluted with water (200 mL). The mixture was
extracted with Et2O (8 × 15 mL) and the combined organic layers
were shaken vigorously with 5% aqueous H2O2 (20 mL) for 10 seconds.
The aqueous layer was separated; the remaining organic layer was
washed with saturated Na2SO3 solution (20 mL), dried over Na2SO4,
and concentrated. The residue was purified by flash chromatography
(EtOAc/hexane, 5%) to give pyrrole 3.
Yield: 1.11 g (85%); colorless crystalline solid; identical to the materi-
al prepared earlier.
Yield: 83 mg (99%); pink oil.
Pyrrole 15
FTIR (KBr): 3418, 2928, 2851, 2778, 2683, 2538, 2307, 2041, 1919,
1850, 1674, 1607, 1504, 1485, 1435, 1368, 1186, 1117, 1038, 931,
Amberlyst-15 (222 mg, 20% w/w) was added to a solution of alcohol 9
(2.68 mmol, 1.11 g, 1 equiv) in acetonitrile (60 mL). The solution was
stirred at r.t. for 2 h until TLC showed completion. The solution was
filtered and concentrated to give pyrrole 15, which was used directly
in the next reaction without further purification.
858, 812 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50 (br s, 1 H), 6.73 (app dd, J = 1.0,
7.0 Hz, 1 H), 6.64–6.59 (m, 3 H), 6.01 (app t, J = 2.4 Hz, 1 H), 5.92 (m,
2 H), 3.91 (app t, J = 6 Hz, 1 H), 2.62–2.59 (m, 2 H), 2.16–2.10 (m, 1 H),
1.90–1.87 (m, 1 H), 1.76–1.67 (m, 2 H).
Yield: 1.04 g (98%); colorless solid; mp 181–183 °C.
13C NMR (100 MHz, CDCl3): δ = 147.8, 146.1, 139.1, 128.8, 121.1,
118.2, 116.4, 108.4, 108.1, 107.1, 100.9, 40.9, 34.3, 23.0, 22.6.
MS (ESI) m/z = 242 [M + H]+.
FTIR (KBr): 3169, 2723, 2669, 2407, 1902, 1850, 1736, 1634, 1597,
1313, 1288, 1238, 1169, 1122, 1094, 1059, 1040, 993, 937, 926, 902,
858, 808, 781, 721, 671 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 3.4 Hz, 1 H), 7.20 (d, J =
8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.49 (d, J = 8.0 Hz, 1 H), 6.30 (dd,
J = 1.6, 8 Hz, 1 H), 6.15 (d, J = 3.4 Hz, 1 H), 6.13 (d, J = 1.6 Hz, 1 H), 5.84
(m, 2 H), 4.50–4.49 (m, 1 H), 2.57–2.42 (m, 2 H), 2.33 (s, 3 H), 2.03–
1.94 (m, 1 H), 1.76–1.72 (m, 1 H), 1.55–1.50 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 146.9, 145.5, 143.6, 138.7, 135.9,
129.9, 129.1, 126.7, 124.9, 121.9, 121.4, 111.6, 108.8, 107.7, 100.6,
37.8, 32.7, 22.9, 21.5, 16.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H16NO2: 242.1181; found:
242.1179.
Pyrrolidine 21h
PtO2 (11 mg, 30% w/w) was added to a solution of pyrrole 3 (0.133
mmol, 32 mg, 1 equiv) in glacial acetic acid (3 mL) in a Fisher–Porter
tube. The solution was then placed under H2 atmosphere (100 psi)
and stirred overnight. The reaction was quenched with 2 M NaOH
solution (20 mL), and the mixture was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by flash chroma-
tography (10% MeOH/1% Et3N/CHCl3) to give pyrrolidine 2.
MS (ESI) m/z = 396 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H22NO4S: 396.1270; found:
396.1262.
Yield: 28 mg (85%); yellow oil.
Alkylidene Pyrrole 16
1H NMR (400 MHz, CDCl3): δ = 6.78 (s, 1 H), 6.76–6.72 (m, 2 H), 5.91
(s, 2 H), 3.19–3.17 (m, 1 H), 3.07–2.98 (m, 1 H), 2.85–2.76 (m, 1 H),
2.07–1.21 (m, 9 H).
Solid sodium hydroxide (6.06 mmol, 242 mg, 20 equiv) was added to
a solution of pyrrole 15 (0.303 mmol, 120 mg, 1 equiv) in DMSO (5
mL). The mixture was stirred at r.t. overnight until TLC showed com-
pletion. The solution was diluted with water (50 mL) and the mixture
was then extracted with Et2O (6 × 10 mL). The combined organic lay-
ers were washed with brine (20 mL), dried over Na2SO4, and concen-
trated. The residue was purified by flash chromatography (EtOAc/
hexane, 40%) to give 16.
γ-Lycorane 11h
Paraformaldehyde (0.675 mmol, 21 mg, 5 equiv) was added to a solu-
tion of pyrrolidine 2 (0.135 mmol, 33 mg, 1 equiv) in anhydrous CHCl3
(5 mL). The mixture was stirred at r.t. for 5 min. Trifluoroacetic acid
(2.70 mmol, 210 μL, 20 equiv), followed by 4Å molecular sieves (300
mg), were added. The solution was heated at gentle reflux overnight.
The reaction was quenched by addition of 2 M NaOH (10 mL). The or-
ganic layer was collected, and the remaining aqueous layer was fur-
ther extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated. The
residue was purified by flash chromatography (MeOH/CHCl3, 5%) to
give γ-lycorane 1.
Yield: 43 mg (58%); pale-yellow solid; mp 185–187 °C.
FTIR (KBr): 3167, 2723, 2669, 2407, 1921, 1651, 1304, 1284, 1248,
1227, 1153, 1101, 1036, 961, 928, 903, 874, 814, 723 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33 (br s, 1 H), 6.89–6.83 (m, 3 H),
6.00 (s, 2 H), 5.80 (app s, 1 H), 2.68 (app t, J = 7.0 Hz, 2 H), 2.60 (t, J =
7.0 Hz, 2 H), 1.96 (quint, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 149.5, 148.3, 147.6, 133.7,
132.2, 123.2, 121.4, 115.6, 108.7, 107.6, 101.4, 29.3, 24.2, 23.6.
MS (ESI): m/z (%) = 256 (100) [M + OH]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H14NO2: 240.1025; found:
240.1020.
Yield: 21 mg (62%); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 6.62 (s, 1 H), 6.50 (s, 1 H), 5.90–5.88
(m, 2 H), 4.03 (d, J = 14.0 Hz, 1 H), 3.45–3.33 (m, 1 H), 3.23 (d, J =
14.0 Hz, 1 H), 2.82–2.70 (m, 1 H), 2.46–2.33 (m, 1 H), 2.27–2.10 (m,
2 H), 2.07–1.98 (m, 1 H), 1.80–1.25 (m, 7 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
B. N. Doan et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 145.7, 145.1, 133.2, 127.4, 108.3,
106.2, 100.7, 63.0, 57.1, 53.7, 39.4, 37.3, 31.7, 30.4, 29.3, 25.2.
1925. (p) Cossy, J.; Tresnard, L.; Pardo, D. G. Tetrahedron Lett.
1999, 40, 1125. (q) Ikeda, M.; Ohtani, S.; Sato, T.; Ishibashi, H.
Synthesis 1998, 1803. (r) Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui,
S.; Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016.
(s) Angle, S. R.; Boyce, J. P. Tetrahedron Lett. 1995, 36, 6185.
(t) Banwell, M. G.; Wu, A. W. J. Chem. Soc., Perkin Trans. 1 1994,
2671. (u) Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
(v) For a review of the synthesis of amaryllidaceae alkaloids,
see: Ghave, M.; Froese, J.; Pour, M.; Hudlicky, T. Angew. Chem.
Int. Ed. 2016, 55, 5642.
Dihydropyrrole 17
Trifluoroacetic acid (2 mL) was added to a solution of 15 (0.126 mmol,
50 mg, 1 equiv) in CH2Cl2 (4 mL). The mixture was cooled to 0 °C in an
ice bath and NaBH3CN (0.378 mmol, 24 mg, 3 equiv) was added in one
portion. The reaction was then warmed to r.t. and stirred for 1 h until
TLC showed completion. Saturated Na2CO3 solution (15 mL) was add-
ed to quench the reaction, then the organic layer was separated and
the remaining aqueous layer was further extracted with CH2Cl2
(2 × 10 mL). The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by
flash chromatography (EtOAc/hexane, 10%) to give dihydropyrrole 17.
A crystal that was suitable for X-ray analysis was grown from a CHCl3/
hexane mixture.
(2) For a review, see: (a) Jefford, C. W. Curr. Org. Chem. 2000, 4, 205.
(b) For an example from this laboratory, see: Bates, R. W.;
Sridhar, S. J. Org. Chem. 2011, 76, 5026.
(3) For a review of achieving β-substitution in pyrroles, see:
Anderson, H. J.; Loader, C. E. Synthesis 1985, 353.
(4) (a) Xu, R. X.; Anderson, H. J.; Gogan, N. J.; Loader, C. E.;
McDonald, R. Tetrahedron Lett. 1981, 22, 4899. (b) Rokach, J.;
Hamel, P.; Kakushima, M. Tetrahedron Lett. 1981, 22, 4901.
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(5) From 2,5-dimethoxytetrahydrofuran by the Clausson-Kaas
method: Elming, N.; Clausson-Kaas, N. Acta Chem. Scand. 1952,
6, 867.
Yield: 49 mg (99%); reddish solid; d.r. ca. 5:1 (inseparable).
1H NMR (major isomer, 400 MHz, CDCl3): δ = 7.51 (d, J = 8.2 Hz, 2 H),
7.19 (d, J = 8.2 Hz, 2 H), 6.79–6.69 (m, 3 H), 5.90 (s, 2 H), 4.53 (m, 1 H),
4.10–4.07 (m, 1 H), 3.89–3.88 (m, 1 H), 3.62–3.61 (m, 1 H), 2.61–2.57
(m, 1 H), 2.38 (s, 3 H), 2.08–2.04 (m, 2 H), 1.91–1.81 (m, 2 H), 1.69–
1.50 (m, 2 H).
(6) Pétrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910.
(7) Samojłowitz, C.; Niebiek, M.; Pazio, A.; Makal, A.; Woźniak, K.;
Poater, A.; Cavallo, L.; Wójcik, J.; Zdanowski, K.; Grela, K. Chem.
Eur. J. 2011, 17, 12981.
Funding Information
We thank the Agency for Science Technology and Research (A-Star)
for financial support of this work (PSF grant number 1321202095).
(8) Haworth, R. D. J. Chem. Soc. 1932, 1125.
(9) (a) Practical Synthetic Organic Chemistry; Caron, S., Ed.; J. Wiley
& Sons: New York, 2009. (b) Yamamura, S.; Toda, M.; Hirata, Y.
Org. Synth. 1973, 53, 86. (c) Yamamura, S.; Toda, M.; Hirata, Y.
Chem. Commun. 1968, 1494.
B.N.D.D. thanks the URECA programme of NTU for support.
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Supporting Information
(10) Hamze, A.; Giraud, A.; Messaoudi, S.; Provot, O.; Peyrat, J.-F.;
Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.;
Brion, J.-D.; Alami, M. ChemMedChem 2009, 4, 1912.
(11) Kobayashi, S. Eur. J. Org. Chem. 1999, 15.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589067.
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(12) Jolicoeur, B.; Chapman, E. E.; Thompson, A.; Lubell, W. D. Tetra-
hedron 2006, 62, 11531.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F