Total synthesis of (+)-γ-lycorane from ethyl lactate using iterative Claisen and Overman rearrangement reactions

Article abstract of DOI:10.1016/j.tet.2020.131661

Total synthesis of (+)-γ-lycorane is accomplished from (S)-ethyl lactate. Key disconnections in the synthesis involve an iterative Claisen and Overman rearrangement reactions to install the chiral centers in the tetrahydroindole moiety while, Pictet-Speng

Full text of DOI:10.1016/j.tet.2020.131661

Journal Pre-proof
Total Synthesis of (+)-γ-Lycorane from Ethyl Lactate Using Iterative Claisen and
Overman Rearrangement Reactions
Manoj B. Uphade, Kavirayani R. Prasad
PII:
S0040-4020(20)30868-1
https://doi.org/10.1016/j.tet.2020.131661
TET 131661
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 August 2020
Revised Date: 1 September 2020
Accepted Date: 4 September 2020
Please cite this article as: Uphade MB, Prasad KR, Total Synthesis of (+)-γ-Lycorane from Ethyl Lactate
Using Iterative Claisen and Overman Rearrangement Reactions, Tetrahedron, https://doi.org/10.1016/
j.tet.2020.131661.
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Total Synthesis of (+)-γ-Lycorane from Ethyl Lactate Using Iterative Claisen
and Overman Rearrangement Reactions
Manoj B. Uphade and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, INDIA.
E-mail: prasad@iisc.ac.in, FAX: +91-80-23600529

Total Synthesis of (+)-γ-Lycorane from Ethyl Lactate Using Iterative Claisen
and Overman Rearrangement Reactions
Manoj B. Uphade and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, INDIA.
E-mail: prasad@iisc.ac.in, FAX: +91-80-23600529
Abstract: Total synthesis of (+)-γ-lycorane is accomplished from (S)-ethyl lactate. Key
disconnections in the synthesis involve an iterative Claisen and Overman rearrangement
reactions to install the chiral centers in the tetrahydroindole moiety while, Pictet-Spengler
reaction is used for the synthesis of the isoquinoline unit.
Key words: (+)-γ-lycorane, Sigmatropic rearrangement, (S)-lactic acid, Total synthesis,
Alkaloids.
Lycorane alkaloids belong to the subclass of Amaryllidaceae alkaloids exhibiting wide range
of biological activities.1 Lycorane alkaloids possess a tetracyclic framework comprising an
octahydroindole unit. Simple alkaloid in this series isγ- lycorane 1, while lycorine 2,
galanthine 3 and narcissidine 4 are alkaloids comprising hydroxy substitutions and
unsaturation at varied positions (Fig.1). A number of strategies were reported in the
literature for the asymmetric synthesis of lycorane alkaloids.2 Previous methods employed
for the installation of the chiral amine part in lycoranes include Curtius rearrangement,
reduction of oxazoloquinolones, reduction of the nitro group, Wittig rearrangement,
asymmetric bromo amination and Pd-catalyzed asymmetric allylic alkylation reactions.2 The
Overman rearrangement,3 a useful reaction for the synthesis of chiral amines involving a
[3,3]-sigmatropic rearrangement of allyl alcohol and has been widely utilized for the
synthesis of amine containing compounds. Herein, we report the synthesis of
using successive Claisen and Overman rearrangement reaction sequence.
γ-lycorane 1,
Fig. 1: Lycorane natural products
The approach for our synthesis of γ-lycorine is depicted in Scheme-1. We envisioned the
synthesis of 1 by a late stage formation of the isoquinoline using Pictet-Spengler reaction of
5. Synthesis of 5 is planned by Claisen rearrangement of the allyl alcohol in cyclohexenol 6
followed by lactamization. Formation of the required functionalized amino cyclohexenol 6 is
planned by ring closing metathesis (RCM) of the corresponding diene 7, the synthesis of
1

which is envisaged from the γ-amino ester 8. Construction of the γ-amino ester 8 is
envisioned by employing successive Claisen/ Overman rearrangements from the allyl
alcohol 9 derived from β-ketophosphonate obtained from lactic acid (Scheme-1).
Scheme-1: Retrosynthesis for γ-lycorane 1
Accordingly, the synthetic sequence commenced with the Horner-Wittig olefination of the
known phosphonate 104 derived from (S)-lactic acid with 3,4-methylenedioxy benzaldehyde
to afford the α, β-unsaturated ketone 11 in 72% yield. Reduction of the ketone 11 under
Luche condition5 furnished the alcohol 9 in 99% yield. Claisen rearrangement6 of the allyl
alcohol 9 using triethylorthoacetate under microwave irradiation afforded the ester 12 in
69% yield. Conversion of the ester 12 to the Weinreb amide 13 was accomplished in 85%
yield. Deprotection of the tert-butyldiphenysilyl ether in 13 with TBAF produced the free
alcohol 14 which on Overman rearrangement yielded the trichloroacetyl amide 15 in mere
27% yield. Our efforts to add vinylmagnesium bromide to the Weinreb amide 15 were
unsuccessful (Scheme-2).7
2

Scheme-2: Attempted synthesis of the functionalized diene 15a
Although we failed to obtain the product enone in the addition of vinylmagnesium bromide
to the Weinreb amide 15, the reaction of the Weinreb amide 13 with vinylmagnesium
bromide furnished the unsaturated ketone 16 in 77% yield. However, Luche reduction of the
ketone 16 resulted in a 1:1 diastereomeric mixture of alcohols 17 in almost quantitative
yield. Protection of the alcohol in 17 as the MOM ether followed by removal of the TBDPS
group afforded the allyl alcohol 19 in 99% yield. Overman rearrangement of the allyl alcohol
19 produced the corresponding trichloroacetamide 20 in 56% yield. RCM of the diene
containing the trichloroacetamide 20 yielded the functionalized cyclohexene 21 in 83%
yield. Deprotection of the MOM ether in 21 followed by oxidation of the resultant alcohol
22 gave the cyclohexenone 23 in excellent yield. Gratifyingly, stereoselective reduction of
8
the cyclohexenone under 1,2- reduction condition using NaBH4/CaCl2 resulted in the
cyclohexenol 24 as a single diastereomer. Claisen rearrangement of the allyl alcohol
furnished the ester 25 which on reaction with cesium carbonate afforded the known lactam
59 in 83% yield. Pictet-Spengler reaction10 of 5 with formaldehyde formed the isoquinoline
26 in 76% yield. Hydrogenation of the double bond in 26 followed by reduction of the
lactam 27 with LiAlH4 produced
γ-lycorane 1 in 79% yield (Scheme-3). The spectral and
physical data of the synthesized 3ycorine is identical with that reported in the literature.2g, 11
3

O
O
OMe
Me
N
CeCl3 ·7H2O, NaBH4
MeOH, rt to 0 °C, 1 h
98%
Me
MgBr
O
O
Me
O
O
THF, 0 °C, 30 min
77%
TBDPSO
TBDPSO
16
13
OMOM
OH
MOM-Cl, DIPEA
DMAP, CH2Cl2
∆, 2.5 h
TBAF, THF
0 °C to 50 °C, 4 h
99%
Me
Me
O
O
O
O
TBDPSO
18
TBDPSO
17
81%
OMOM
OMOM
i) Cl3CCN, DBU
CH2Cl2, 0 °C, 1 h
ii) xylene, MW
160 °C, 20 min
56% 2 steps
G-II (5 mol%)
CH2Cl2, ∆, 2.5 h,
83%
Me
CCl3
O
O
Me
O
O
HN
OH
19
20
O
OMOM
OH
DMP, NaHCO3, CH2Cl2
0 °C to rt, 1.5 h, 98%
PPTS
MeOH:H2O (9:1)
80 °C, 24 h, 86%
O
O
O
O
CCl3
HN
21
CCl3
HN
22
O
O
OH
O
CH3C(OEt)3
EtCO2H (8 mol%)
toluene, seal tube
NaBH4, CaCl2
MeOH, rt to 0 °C
30 min, 88%
O
O
O
O
150 °C, 24 h, 61%
CCl3
HN
24
CCl3
HN
O
23
O
(CH2O)n, TFA, DCE
rt, 30 h, 76%
O
O
CO2Et
CCl3
O
O
Cs2CO3, DMSO
100 °C, 5 h, 83%
HN
HN
O
5
25
O
H
O
H
H
H
H
H
H
O
O
O
H2, 10% Pd/C
O
O
LiAlH4, THF
MeOH, rt, 5 h
89%
N
∆, 20 h, 79%
N
O
N
O
1
27
26
Scheme-3: Total Synthesis of γ-lycorane
In conclusion, total synthesis of γ-lycorane is accomplished from (S)-lactic acid using
iterative Claisen-Overman rearrangement as the key reactions. Although, the present
sequence is longer than some of the reported approaches, it showcased the use of
sigmatropic rearrangements in construction of the required tricyclic unit. The synthesis of γ-
4

lycorane was accomplished in 2.4% overall yield in 19 linear steps from the phosphonate
derived from lactic acid.
General Procedures: Column chromatography was performed on silica gel, Acme grade 100-
200 mesh. TLC plates were visualized either with UV, in an iodine chamber, or with
phosphomolybdic acid spray, unless noted otherwise. All reagents were purchased from
commercial sources and used without additional purification. THF was freshly distilled over
Na-benzophenone ketyl. Melting points were uncorrected. Unless stated otherwise, 1H NMR
and 13C NMR spectra were recorded either on a 400 or on a 300 MHz machine in CDCl3 as
solvent with TMS as reference unless otherwise indicated. High-resolution mass spectra
(HRMS) were recorded on a Q-TOF micromass spectrometer using electron spray ionization
mode.
O
Me
O
TBDPSO
O
11
(S,E)-1-(benzo[d][1,3]dioxol-5-yl)-4-((tert-butyldiphenylsilyl)oxy)pent-1-en-3-one (11):
In a 50 ml two neck round bottom flask equipped with argon balloon was placed a solution
of 10 (1.75 g, 4.2 mmol) in iPrOH (12 mL). Cs2CO3 (2.72 g, 8.4 mmol) was introduced into the
flask all at once and was stirred for 45 min at room temperature. The reaction mixture was
then cooled to –15 °C and a solution of the 3,4-methylenedioxy benzaldehyde (0.69 g, 4.6
mmol) in iPrOH (8 mL) was added dropwise. The reaction mixture was slowly warmed up to
room temperature and stirred for 3 h at room temperature. After completion of the
reaction (TLC), the reaction mixture was cautiously quenched by addition of aqueous
solution of citric acid (10 mL), poured into water (15 mL) and extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over
anhydrous Na2SO4. Evaporation of solvent gave crude residue, which was purified on silica
gel column chromatography using petroleum ether/EtOAc (9:1) as eluent to furnish 11 (1.39
g, 72%) as a yellow oil. [α]D24−188.7 (c 1.45, CHCl3). IR (Neat):
νmax 2956, 1686, 1591, 1492,
1110 cm−1.
1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 6.8 Hz, 2H), 7.63 (d, J = 6.8 Hz, 2H), 7.56 (d, J = 16.0
Hz, 1H), 7.50-7.28 (m, 6H), 7.16 (d, J = 16.0 Hz, 1H), 7.02 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H),
6.00 (s, 2H), 4.36 (q, J = 6.8 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.13 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 201.3, 149.8, 148.3, 143.5, 135.74 (2 × C), 135.72 (2 × C), 133.5, 133.0, 129.88,
129.86, 129.3, 127.7 (2 × C), 127.67 (2 × C), 125.2, 118.6, 108.6, 106.6, 101.5, 75.2, 26.9 (3 ×
C), 21.2, 19.2.
HRMS (ESI) m/z: [M+Na]+ Calcd for C28H30O4Si+Na 481.1811; Found 481.1809.
OH
Me
O
TBDPSO
O
9
(3S,4S,E)-1-(benzo[d][1,3]dioxol-5-yl)-4-((tert-butyldiphenylsilyl)oxy)pent-1-en-3-ol (9): To
a stirred solution of 11 (1.38 g, 3.01 mmol) in MeOH (30 mL) was added CeCl3.7H2O (1.68 g,
4.5 mmol) and the reaction mixture was stirred for 30 min at room temperature. The
reaction mixture was cooled to −78 °C and NaBH4 (0.17 g, 4.5 mmol) was added portion
5

wise over a period of 5 min. The reaction mixture was slowly warmed up to 0 °C and stirred
at the same temperature for 45 min. After completion of the reaction (TLC), it was
quenched by addition of water (1 mL) and slowly warmed up to room temperature. Most of
the solvent was evaporated off and the crude residue was diluted with water (20 mL) and
extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (20
mL) and dried over anhydrous Na2SO4. Evaporation of the solvent gave the crude residue
which was purified by silica gel column chromatography using petroleum ether/EtOAc (9:1)
as eluent to furnish 9 (1.38 g, 99%) as a colorless oil. [α]D24−64.8 (c 1.6, CHCl3). IR (Neat):
ν
max 3332, 2926, 1643, 1587, 1219 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.6 Hz, 4H),
7.55-7.25 (m, 6H), 6.84 (s, 1H), 6.80-6.68 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 5.95 (dd, J = 16.0,
6.0 Hz, 1H), 5.93 (s, 2H), 4.06 (q, J = 5.6 Hz, 1H), 3.84 (quint, J = 6.0 Hz, 1H), 2.68 (d, J = 4.8
Hz, 1H, OH exchangeable with D2O), 1.10-1.00 (m, 12H). 13C NMR (100 MHz, CDCl3): δ 147.9,
147.2, 135.89 (2 × C), 135.86 (2 × C), 134.0, 133.3, 131.5, 131.3, 129.8, 129.7, 127.7 (2 × C),
127.5 (2 × C), 127.2, 121.1, 108.2, 105.7, 101.0, 77.1, 73.2, 27.0 (3 × C), 19.7, 19.3. HRMS
(ESI) m/z: [M+Na]+ Calcd for C28H32O4Si+Na 483.1968; Found: 483.1970.
O
OEt
Me
O
O
TBDPSO
12
ethyl (3R,6S,E)-3-(benzo[d][1,3]dioxol-5-yl)-6-((tert-butyldiphenylsilyl)oxy)hept-4-enoate
(12): To a solution of the allyl alcohol 9 (0.8 g, 1.74 mmol) in toluene (5 mL) were added
triethyl orthoacetate (1.7 mL, 8.7 mmol) and propionic acid (0.5 M in toluene, 0.28 mL, 0.14
mmol). The resulting solution was heated at 200 °C in microwave for 2 h. After completion
of the reaction (TLC), most of the solvent was evaporated off and the crude obtained which
was purified by silica gel column chromatography using petroleum ether/EtOAc (9.5:0.5) as
eluent to furnish 12 (0.64 g, 69%) as a colorless oil. [α]D24−50.9 (c 0.9, CHCl3). IR (Neat): νmax
1
2967, 2937, 2859, 1734, 1490, 1244 cm−1. H NMR (400 MHz, CDCl3): δ 7.75-7.56 (m, 4H),
7.44-7.28 (m, 6H), 6.69 (d, J = 8.0 Hz, 1H), 6.60-6.52 (m, 2H), 5.91 (s, 2H), 5.54 (dd, J = 15.6,
6.4 Hz, 1H), 5.47 (dd, J = 15.6, 5.2 Hz, 1H), 4.25 (quint, J = 6.0 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H),
3.68 (q, J = 7.6 Hz, 1H), 2.62-2.48 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H), 1.05
(s, 9H).
13C NMR (100 MHz, CDCl3): δ 171.7, 147.6, 146.0, 136.7, 135.86 (2 × C), 135.85 (2 × C),
134.44, 134.4, 134.2, 131.1, 129.5, 129.4, 127.5 (2 × C), 127.4 (2 × C), 120.5, 108.1, 108.0,
100.8, 70.0, 60.3, 43.7, 40.7, 26.9 (3 × C), 24.4, 19.2, 14.2. HRMS (ESI) m/z: [M+Na]+ Calcd
for C32H38O5Si+Na 553.2386; Found: 553.2387.
O
OMe
N
Me
Me
O
TBDPSO
O
13
(3R,6S,E)-3-(benzo[d][1,3]dioxol-5-yl)-6-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-
methylhept-4-enamide (13): In a two neck round bottom flask equipped with argon balloon
6

was placed a solution of 12 (0.26 g, 0.49 mmol) in THF (3 mL). N,O-Dimethylhydroxylamine
hydrochloride (0.1 g, 0.98 mmol) was introduced into the flask. The reaction mixture was
then cooled to –10 °C and a solution of iPrMgCl (1.2 M in THF, 1.6 mL, 1.96 mmol) was
added dropwise. The reaction mixture was stirred at the same temperature for 30 min.
After completion of the reaction (TLC), the reaction mixture was cautiously quenched by
addition of aqueous solution of NH4Cl (5 mL) and extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4.
Evaporation of solvent gave crude residue, which was purified on silica gel column
chromatography using petroleum ether/EtOAc (7.5:2.5) as eluent to furnish 13 (0.23 g, 85%)
as a colorless oil. [α]D24−47.1 (c 1.05, CHCl3). IR (Neat): νmax 2962, 2934, 1663, 1488, 1244
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.65 (t, J = 6.8 Hz, 4H), 7.45-7.25 (m, 6H), 6.68 (d, J = 8.0
Hz, 1H), 6.65-6.60 (m, 1H), 6.57 (d, J = 1.2 Hz, 1H), 5.87 (s, 2H), 5.60 (dd, J = 15.6, 6.8 Hz, 1H),
5.49 (dd, J = 15.6, 6.0 Hz, 1H), 4.27 (quint, J = 6.0 Hz, 1H), 3.82 (q, J = 7.2 Hz, 1H), 3.57 (s,
3H), 3.09 (s, 3H), 2.71 (d, J = 6.8 Hz, 2H), 1.14 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H). 13C NMR (100
MHz, CDCl3): δ 172.3, 147.4, 145.8, 137.2, 135.8 (2 × C), 135.7 (2 × C), 134.22, 134.2, 134.0,
131.6, 129.4, 129.3, 127.33 (2 × C), 127.3 (2 × C), 120.5, 108.1, 108.0, 100.6, 69.9, 61.1, 42.9,
37.6, 31.9, 26.8 (3 × C), 24.3, 19.1. HRMS (ESI) m/z: [M+Na]+ Calcd for C32H39NO5Si+Na
568.2495; Found: 568.2491.
O
OMe
N
Me
Me
O
OH
O
14
(3R,6S,E)-3-(benzo[d][1,3]dioxol-5-yl)-6-hydroxy-N-methoxy-N-methylhept-4-enamide
(14): To a solution of 13 (0.15 g, 0.28mmol) in THF (3 mL) was added a solution of TBAF
(0.67 mL of 1 M in THF, 0.67 mmol) at 0 °C and was allowed to stir at room temperature for
10 h. After the reaction was complete (TLC), it was diluted with cold water and extracted
with EtOAc (3×10 mL). The combined organic extract was washed with brine (5 mL) and
dried over anhydrous Na2SO4. Evaporation of the solvent followed by silica gel column
chromatography using petroleum ether/EtOAc (2:8) as eluent furnished the compound 14
(0.08 g, 92%) as colorless oil. [α]D24−22.0 (c 1.2, CHCl3). IR (Neat): νmax 3411, 2972, 2893,
1
1645, 1485, 1242, 1037 cm−1. H NMR (400 MHz, CDCl3): δ 6.78-6.58 (m, 3H), 5.88 (s, 2H),
5.76 (dd, J = 15.6, 7.2 Hz, 1H), 5.51 (dd, J = 15.6, 6.4 Hz, 1H), 4.23 (quint, J = 6.4 Hz, 1H), 3.83
(q, J = 7.2 Hz, 1H), 3.60 (s, 3H), 3.10 (s, 3H), 2.76 (d, J = 7.2 Hz, 2H), 2.42 (bs, 1H), 1.20 (d, J =
6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.4, 147.5, 145.9, 137.1, 134.4, 132.3, 120.4,
108.1, 107.9, 100.7, 68.2, 61.2, 43.2, 38.0, 32.0, 23.2. HRMS (ESI) m/z: [M+Na]+ Calcd for
C16H21NO5+Na 330.1317; Found: 330.1315.
O
OMe
N
Me
Me
O
HN
CCl3
O
O
15
7

(3S,4S,E)-3-(benzo[d][1,3]dioxol-5-yl)-N-methoxy-N-methyl-4-(2,2,2-
trichloroacetamido)hept-5-enamide (15): To a stirred solution of the allyl alcohol 14 (0.08
g, 0.24mmol) in CH2Cl2 (3 mL) were added Cl3CCN (0.06 mL, 0.53mmol) and DBU (0.01 mL,
0.05mmol) at 0 °C and was allowed to stir at same temperature for 1 h. After completion of
the reaction (TLC), most of the solvent was evaporated off and the crude obtained which
was purified by silica gel column chromatography (petroleum ether/EtOAc (6:4), 1% Et3N) as
eluent to furnish the imidate.
A solution of the imidate in xylene (5 mL) was heated at 160 °C in microwave for 20 min.
After completion of the reaction (TLC), most of the solvent was evaporated off and the
crude obtained which was purified by silica gel column chromatography using petroleum
ether/EtOAc (7:3) as eluent to furnish 15 (0.03 g, 27% for 2 steps) as a colorless oil.
[α]D24−7.1 (c 1.5, CHCl3). IR (Neat): νmax 3400, 2925, 1709, 1646, 1245, 1037 cm−1.1H NMR
(400 MHz, CDCl3): δ 7.47 (d, J = 8.4 Hz, 1H), 6.80-6.60 (m, 3H), 5.95 (s, 2H), 5.54 (sextet, J =
6.4 Hz, 1H), 5.24 (dd, J = 15.2, 6.4 Hz, 1H), 4.49 (q, J = 8.8 Hz, 1H), 3.62 (s, 3H), 3.42 (td, J =
8.8, 4.4 Hz, 1H), 3.15 (s, 3H), 2.87 (dd, J = 17.6, 8.4 Hz, 1H), 2.74 (dd, J = 17.6, 3.6 Hz, 1H),
1.60 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.9, 161.2, 147.8, 146.5, 135.0,
128.6, 127.7, 121.6, 108.4, 108.3, 101.0, 92.9, 61.2, 58.1, 44.2, 36.4, 32.2, 17.7. HRMS (ESI)
m/z: [M+Na]+ Calcd for C18H21Cl3N2O5+Na 473.0414; Found: 473.0416.
O
Me
O
O
TBDPSO
16
(5R,8S,E)-5-(benzo[d][1,3]dioxol-5-yl)-8-((tert-butyldiphenylsilyl)oxy)nona-1,6-dien-3-one
(16): To a solution of 13 (0.11 g, 0.2mmol) in THF (3 mL) was added a solution of
vinylmagnesium bromide (0.25 M in THF, 1.7 mL, 0.42 mmol) dropwise at 0 °C and was
allowed to stir at same temperature for 30 min. After the reaction was complete (TLC), it
was quenched by addition of saturated aqueous solution of NH4Cl (5 mL) and extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed with brine (5 mL) and dried
over anhydrous Na2SO4. Evaporation of solvent gave crude residue, which was purified by
silica gel column chromatography using petroleum ether/EtOAc (9:1) as eluent to furnish 16
(0.08 g, 77%) as a colorless oil. [α]D24−53.8 (c 1.25, CHCl3). IR (Neat):
νmax 2928, 1683, 1487,
1242 cm−1.
1H NMR (400 MHz, CDCl3): δ 7.64 (t, J = 8.0 Hz, 4H), 7.45-7.28 (m, 6H), 6.67 (d, J = 8.0 Hz,
1H), 6.57 (s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.27 (dd, J = 17.6, 10.4 Hz, 1H), 6.13 (d, J = 17.2 Hz,
1H), 5.88 (bs, 2H), 5.75 (d, J = 10.8 Hz, 1H), 5.52 (dd, J = 15.6, 6.4 Hz, 1H), 5.43 (dd, J = 15.6,
5.6 Hz, 1H), 4.26 (quint, J = 6.0 Hz, 1H), 3.79 (q, J = 6.8 Hz, 1H), 2.88-2.72 (m, 2H), 1.13 (d, J =
6.4 Hz, 3H), 1.04 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 198.6, 147.5, 145.9, 137.0, 136.6,
135.84 (2 × C), 135.80 (2 × C), 134.31, 134.3, 134.2, 131.5, 129.5, 129.4, 128.1, 127.4 (2 × C),
127.3 (2 × C), 120.5, 108.1, 108.0, 100.8, 70.0, 45.3, 42.6, 26.9 (3 × C), 24.3, 19.1. HRMS (ESI)
m/z: [M+Na]+ Calcd for C32H36O4Si+Na 535.2281; Found: 535.2279.
8

OH
Me
O
O
TBDPSO
17
(5R,8S,E)-5-(benzo[d][1,3]dioxol-5-yl)-8-((tert-butyldiphenylsilyl)oxy)nona-1,6-dien-3-ol
(17): To a stirred solution of 16 (0.57 g, 1.11 mmol) in MeOH (25 mL) was added CeCl3.7H2O
(0.62 g, 1.67 mmol) and the reaction mixture was stirred for 30 min at room temperature.
The reaction mixture was cooled to 0 °C and NaBH4 (0.064 g, 1.67 mmol) was added portion
wise over a period of 5 min. The reaction mixture stirred at the same temperature for 30
min. After completion of the reaction (TLC), it was quenched by addition of water (1 mL) and
slowly warmed up to room temperature. Most of the solvent was evaporated off and the
crude residue was diluted with water (15 mL) and extracted with EtOAc (2 × 25 mL). The
combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent gave the crude residue which was purified by silica gel column
chromatography using petroleum ether/EtOAc (8.5:1.5) as eluent to furnish 17 (0.56 g, 98%,
1:1 diastereomer) as a colorless oil. [α]D24−76.2 (c 0.85, CHCl3). IR (Neat): νmax 3376, 2931,
1
2859, 1487, 1242 cm−1. H NMR (400 MHz, CDCl3): δ 7.75-7.55 (m, 4H), 7.45-7.28 (m, 6H),
6.75-6.65 (m, 1H), 6.62-6.50 (m, 2H), 5.95-5.88 (m, 2H), 5.87-5.75 (m, 1H), 5.57-5.38 (m,
2H), 5.20-5.03 (m, 2H), 4.26 (sextet, J = 6.4 Hz, 1H), 3.95-3.80 (m, 1H), 3.42-3.22 (m, 1H),
1.82-1.72 (m, 1H), 1.71-1.62 (m, 1H), 1.14 (t, J = 6.8 Hz, 3H), 1.05 (bs, 9H). 13C NMR (100
MHz, CDCl3): δ 147.6 (4 × C), 145.8, 145.74 (2 × C), 141.2, 141.0 (2 × C), 138.2 (2 × C), 137.6,
135.9 (8 × C), 134.6, 134.4, 134.35, 134.3, 133.8, 132.8, 132.3, 129.6, 129.53, 129.5, 129.4,
127.43, 127.42, 127.4 (2 × C), 120.7, 120.3, 114.7, 114.5, 108.2 (2 × C), 108.0, 107.8, 100.8 (2
× C), 70.8, 70.6, 70.23, 70.2, 44.1, 43.9, 42.8, 42.7, 26.93 (3 × C), 26.9 (3 × C), 24.5, 24.4, 19.3
(2 × C). HRMS (ESI) m/z: [M+Na]+ Calcd for C32H38O4Si+Na 537.2437; Found: 537.2437.
OMOM
Me
O
TBDPSO
O
18
(7R,10S,E)-7-(benzo[d][1,3]dioxol-5-yl)-10,13,13-trimethyl-12,12-diphenyl-5-vinyl-2,4,11-
trioxa-12-silatetradec-8-ene (18): To a stirred solution of 17 (40 mg, 0.08 mmol) in CH2Cl2 (3
mL) were added diisopropylethylamine (0.16 mL, 0.96 mmol), MOMCl (0.04 mL, 0.48 mmol)
and DMAP (4 mg, 0.03 mmol) at 0 °C. The reaction mixture was heated to reflux for 2.5 h.
After completion of the reaction (TLC), it was allowed to cool to room temperature,
quenched by addition of saturated aqueous solution of NH4Cl (5 mL) and extracted with
diethyl ether (3 × 5 mL). The combined organic layers were washed with brine (5 mL) and
dried over anhydrous Na2SO4. Evaporation of the solvent gave the crude residue which was
purified by silica gel column chromatography using petroleum ether/EtOAc (9:1) as eluent
to furnish 18 (35 mg, 81%) as a colorless oil. [α]D24−63.7 (c 1.2, CHCl3). IR (Neat):
ν
max 2931,
2889, 1487, 1242, 1034 cm−1. H NMR (400 MHz, CDCl3): δ 7.70-7.55 (m, 4H), 7.45-7.35 (m,
2H), 7.35-7.25 (m, 4H), 6.70 (dd, J = 8.0, 4.4 Hz, 1H), 6.62-6.48 (m, 2H), 5.92 (s, 1H), 5.91 (s,
1H), 5.72-5.60 (m, 1H), 5.56-5.38 (m, 2H), 5.17 (dq, J = 10.4, 1.2 Hz, 1H), 5.12 (d, J = 17.2 Hz,
1H), 4.63 (dd, J = 6.4, 5.2 Hz, 1H), 4.48 (dd, J = 6.8, 5.2 Hz, 1H), 4.24 (q, J = 6.4 Hz, 1H), 3.92-
1
9

3.75 (m, 1H), 3.40-3.25 (m, 4H), 1.91 (quint, J = 8.0 Hz, 1H), 1.78-1.65 (m, 1H), 1.12 (dd, J =
6.4, 2.0 Hz, 3H), 1.09-1.00 (m, 9H). 13C NMR (100 MHz, CDCl3): δ 147.6 (2 × C), 145.8, 145.7,
138.5, 138.2, 138.1, 137.7, 135.9 (5 × C), 134.45 (2 × C), 134.42 (2 × C), 134.3, 134.29, 134.27
(2 × C), 133.8, 132.9, 132.4, 129.48, 129.47, 129.40, 129.39, 127.42 (4 × C), 127.4 (2 × C),
127.35 (2 × C), 120.8, 120.5, 117.7, 117.1, 108.2, 108.12, 108.07, 107.9, 100.7 (2 × C), 94.3,
93.9, 75.7, 75.5, 70.11, 70.10, 55.7, 55.4, 43.6, 43.5, 41.42, 41.40, 26.9 (6 × C), 24.4 (2 × C),
19.2 (2 × C). HRMS (ESI) m/z: [M+Na]+ Calcd for C34H42O5Si+Na 581.2699; Found: 581.2696.
OMOM
Me
O
OH
O
19
(2S,5R,E)-5-(benzo[d][1,3]dioxol-5-yl)-7-(methoxymethoxy)nona-3,8-dien-2-ol (19): To a
stirred solution of 18 (0.54 g, 0.97mmol) in THF (8 mL) was added a solution of TBAF (1 M in
THF, 2.9 mL, 2.91 mmol) at 0 °C. The reaction mixture was slowly warmed up to 50 °C and
stirred for 4 h. After the reaction was complete (TLC), it was allowed to cool to room
temperature, diluted with cold water (10 mL) and extracted with EtOAc (3×20 mL). The
combined organic extract was washed with brine (10 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent followed by silica gel column chromatography using petroleum
ether/EtOAc (1:1) as eluent furnished 19 (0.31 g, 99%) as colorless oil. [α]D24−31.5 (c 1.2,
CHCl3). IR (Neat): ν
max 3411, 2926, 1489, 1243, 1034 cm−1. 1H NMR (400 MHz, CDCl3): δ 6.74
(dd, J = 8.0, 4.0 Hz, 1H), 6.70-6.60 (m, 2H), 5.93 (s, 1H), 5.92 (s, 1H), 5.78-5.60 (m, 2H), 5.58-
5.46 (m, 1H), 5.25-5.10 (m, 2H), 4.65 (dd, J = 6.8, 4.8 Hz, 1H), 4.50 (dd, J = 6.8, 4.4 Hz, 1H),
4.26 (sextet, J = 6.8 Hz, 1H), 3.98-3.80 (m, 1H), 3.45-3.32 (m, 4H), 1.98 (quint, J = 7.2 Hz, 1H),
1.85-1.72 (m, 2H), 1.23 (dd, J = 6.4, 4.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 147.74, 147.73,
146.0, 145.9, 138.3, 138.1, 137.8, 137.4, 134.4, 133.91, 133.9, 133.3, 120.7, 120.4, 117.8,
117.3, 108.3, 108.2, 107.9, 107.8, 100.8 (2 × C), 94.1, 93.4, 75.6, 75.5, 68.6 (2 × C), 55.7,
55.6, 43.9, 43.8, 41.5, 41.4, 23.32, 23.3. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H24O5+Na
343.1521; Found: 343.1519.
OMOM
Me
CCl3
O
O
HN
20
O
N-((4S,5S,E)-5-(benzo[d][1,3]dioxol-5-yl)-7-(methoxymethoxy)nona-2,8-dien-4-yl)-2,2,2-
trichloroacetamide (20): To a solution of the allyl alcohol 19 (0.06 g, 0.19mmol) in CH2Cl2 (4
mL) were added Cl3CCN (0.04 mL, 0.42mmol) and DBU (0.01 mL, 0.04mmol) at 0 °C and was
allowed to stir at same temperature for 1 h. After completion of the reaction (TLC), most of
the solvent was evaporated off and the crude obtained which was purified by silica gel
column chromatography (petroleum ether/EtOAc (8.5:1.5), 1% Et3N) as eluent to furnish the
imidate.
A solution of the imidate in xylene (5 mL) was heated at 160 °C in microwave for 20 min.
After completion of the reaction (TLC), most of the solvent was evaporated off and the
crude obtained which was purified by silica gel column chromatography using petroleum
10

ether/EtOAc (8.5:1.5) as eluent to furnish 20 (0.05 g, 56% for 2 steps) as colorless oil.
[α]D24−1.4 (c 0.9, CHCl3). IR (Neat): max 3334, 2926, 1712, 1592, 1495, 1031 cm−1.
ν
1H NMR (400 MHz, CDCl3): δ 6.77 (dd, J = 8.0, 2.0 Hz, 2H), 6.75-6.55 (m, 5H), 6.51 (d, J = 8.8
Hz, 1H), 6.05-5.90 (m, 4H), 5.72-5.54 (m, 4H), 5.34-5.18 (m, 2H), 5.18-5.10 (m, 2H), 5.06 (dd,
J = 17.2, 0.8 Hz, 1H), 4.63 (dd, J = 6.8, 2.4 Hz, 2H), 4.58-4.40 (m, 4H), 3.90-3.78 (m, 2H), 3.32
(s, 3H), 3.31 (s, 3H), 3.15-3.05 (m, 1H), 2.90 (quint, J = 5.2 Hz, 1H), 2.10-2.00 (m, 1H), 1.98-
1.90 (m, 1H), 1.88-1.75 (m, 2H), 1.74-1.60 (m, 7H). 13C NMR (100 MHz, CDCl3): δ 160.6,
160.5, 148.0, 147.9, 146.8, 146.7, 138.1, 137.3, 133.0, 132.3, 130.1, 129.6, 126.2, 125.6,
122.5, 122.4, 118.9, 117.4, 108.68, 108.65, 108.2, 108.16, 101.1 (2 × C), 94.0, 93.6, 92.9,
92.8, 75.3, 75.2, 57.1, 56.9, 55.8, 55.3, 45.4, 44.8, 38.4, 37.4, 17.9, 17.8. HRMS (ESI) m/z:
[M+Na]+ Calcd for C20H24Cl3NO5+Na 486.0618; Found: 486.0615.
OMOM
O
CCl3
HN
21
O
O
N-((1S,6S)-6-(benzo[d][1,3]dioxol-5-yl)-4-(methoxymethoxy)cyclohex-2-en-1-yl)-2,2,2-
trichloroacetamide (21): A solution of 20 (0.20 g, 0.43mmol) and Grubbs’ 2nd generation
catalyst (19 mg, 0.022mmol) in CH2Cl2 (21 mL) was heated to refluxed for 2.5 h. After
completion of the reaction (TLC), most of the solvent was evaporated off and the crude
residue obtained was purified by silica gel column chromatography using petroleum
ether/EtOAc (7:3) as eluent to furnish 21 (0.15 g, 83%) as colorless oil. [α]D24+161.1 (c 0.8,
CHCl3). IR (Neat): ν
max 3332, 2890, 1707, 1504, 1443, 1034 cm−1. 1H NMR (400 MHz, CDCl3): δ
6.78-6.58 (m, 7H), 6.48 (dd, J = 13.6, 9.6 Hz, 2H), 6.11 (dd, J = 7.2, 4.4 Hz, 1H), 6.10-5.95 (m,
2H), 5.94-5.80 (m, 4H), 4.78-4.70 (m, 2H), 4.68-4.50 (m, 4H), 4.30 (t, J = 6.8 Hz, 1H), 4.23 (bs,
1H), 3.55-3.45 (m, 1H), 3.44-3.28 (m, 6H), 3.11 (dd, J = 14.0, 2.4 Hz, 1H), 2.35-2.20 (m, 1H),
2.15-1.93 (m, 2H), 1.88-1.70 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 160.8, 160.6, 147.6,
147.5, 146.4 (2 × C), 134.1, 133.8 (2 × C), 130.7, 129.0, 126.8, 120.7, 120.6, 108.2, 108.16,
108.08, 108.01, 100.8 (2 × C), 95.3, 95.2, 92.3 (2 × C), 72.7, 68.4, 55.3, 55.2, 49.3, 49.2, 40.9,
38.1, 29.8, 29.5. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H18Cl3NO5+Na 444.0148; Found:
444.0145.
OH
O
CCl3
HN
O
22
O
N-((1S,6S)-6-(benzo[d][1,3]dioxol-5-yl)-4-hydroxycyclohex-2-en-1-yl)-2,2,2-
trichloroacetamide (22): To a stirred solution of 21 (0.34 g, 0.81 mmol) in MeOH:H2O (9:1,
10 mL) was added PPTS (0.93 g, 3.70 mmol) at room temperature. The reaction mixture was
heated at 80 °C for 24 h. After completion of the reaction (TLC), it was allowed to cool to
room temperature, most of the solvent was evaporated off and the crude residue was
diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic
11

layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of
the solvent gave the crude residue which was purified by silica gel column chromatography
using petroleum ether/EtOAc (1:1) as eluent to furnish 22 (0.26 g, 86%) as a colorless oil.
ν
[α]D24+140.5, (c 1.2, CHCl3). IR (Neat): max 3599, 1703, 1506, 1442, 1037 cm−1. 1H NMR (400
MHz, CDCl3): δ 6.85-6.60 (m, 7H), 6.52 (d, J = 8.8 Hz, 1H), 6.08 (dd, J = 9.6, 4.4 Hz, 1H), 6.05-
5.90 (m, 2H), 5.89-5.72 (m, 5H), 4.70-4.50 (m, 2H), 4.49-4.30 (m, 2H), 3.60-3.40 (m, 1H),
3.20-3.00 (m, 1H), 3.00-2.68 (bs, 2H), 2.30-2.12 (m, 1H), 2.11-1.95 (m, 2H), 1.77 (q, J = 12.8
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 160.1, 160.9, 147.6, 147.5, 146.4, 146.3, 136.0, 133.9,
133.7, 132.4, 128.3, 126.0, 120.8, 120.6, 108.24, 108.22, 108.13, 108.1, 100.81, 100.8, 92.3
(2 × C), 67.3, 63.2, 49.3 (2 × C), 41.0, 37.8, 32.2, 32.1. HRMS (ESI) m/z: [M+Na]+ Calcd for
C15H14Cl3NO4+Na 399.9886; Found: 399.9890.
O
O
CCl3
HN
O
23
O
N-((1S,6S)-6-(benzo[d][1,3]dioxol-5-yl)-4-oxocyclohex-2-en-1-yl)-2,2,2-trichloroacetamide
(23): To a stirred solution of 22 (88 mg, 0.23 mmol) in CH2Cl2 (5 mL) were added NaHCO3 (58
mg, 0.69 mmol), DMP (0.15 g, 0.35 mmol) at 0 °C. The reaction mixture was stirred at same
temperature for 1.5 h. After completion of the reaction (TLC), it was quenched by addition
of aqueous solution of Na2S2O3 (5 mL) and extracted with EtOAc (2 × 25 mL). The combined
organic layers were washed with brine (25 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent gave the crude residue which was purified by silica gel column
chromatography using petroleum ether/EtOAc (7:3) as eluent to furnish 23 (86 mg, 98%) as
a colorless oil. [α]D24+145.9, (c 0.7, CHCl3). IR (Neat): νmax 3319, 2904, 1681, 1506, 1443,
1245 cm−1.
1H NMR (400 MHz, CDCl3): δ 6.96 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 10.4, 4.4 Hz, 1H), 6.72 (d, J
= 7.6 Hz, 1H), 6.68-6.55 (m, 2H), 6.17 (d, J = 10.0 Hz, 1H), 5.96-5.85 (m, 2H), 5.08-4.96 (m,
1H), 3.75-3.60 (m, 1H), 2.88 (dd, J = 16.8, 8.8 Hz, 1H), 2.75 (dd, J = 16.8, 4.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 197.4, 161.4, 148.0, 147.1, 145.6, 131.5, 131.2, 121.4, 108.38, 108.35,
101.1, 92.0, 49.7, 45.5, 39.9. HRMS (ESI) m/z: [M+Na]+ Calcd for C15H12Cl3NO4+Na 397.9730;
Found: 397.9732.
OH
O
CCl3
HN
24
O
O
N-((1S,4S,6S)-6-(benzo[d][1,3]dioxol-5-yl)-4-hydroxycyclohex-2-en-1-yl)-2,2,2-
trichloroacetamide (24): To a stirred solution of 23 (0.25 g, 0.67 mmol) in anhydrous MeOH
(25 mL) was added CaCl2 (fused) (0.15 g, 1.34 mmol) and the reaction mixture was stirred
for 30 min at room temperature. The reaction mixture was cooled to 0 °C and NaBH4 (0.038
g, 1.01 mmol) was added. The reaction mixture stirred at the same temperature for 30 min.
12

After completion of the reaction (TLC), it was quenched by addition of water (1 mL) and
slowly warmed up to room temperature. Most of the solvent was evaporated off and the
crude residue was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The
combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent gave the crude residue which was purified by silica gel column
chromatography using petroleum ether/EtOAc (1:1) as eluent to furnish 24 (0.22 g, 88%) as
1
a colorless oil. [α]D24+144.3, (c 0.7, CHCl3). IR (Neat): νmax 3415, 2884, 1702, 1504 cm−1. H
NMR (400 MHz, CDCl3): δ 6.84-6.64 (m, 3H), 6.59 (d, J = 8.8 Hz, 1H), 6.02 (d, J = 10.0 Hz, 1H),
5.98-5.80 (m, 3H), 4.68-4.50 (m, 1H), 4.49-4.35 (m, 1H), 3.22-3.05 (m, 1H), 2.44 (s, 1H), 2.32-
2.15 (m, 1H), 1.78 (q, J = 12.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 160.9, 147.6, 146.5,
135.9, 133.9, 126.3, 120.7, 108.2, 108.1, 100.9, 92.4, 67.5, 49.3, 41.0, 32.3. HRMS (ESI) m/z:
[M+Na]+ Calcd for C15H14Cl3NO4+Na 399.9886; Found: 399.9882.
CO2Et
CCl3
O
HN
O
25
O
Ethyl 2-((1S,5S,6S)-5-(benzo[d][1,3]dioxol-5-yl)-6-(2,2,2-trichloroacetamido)cyclohex-2-en-
1-yl)acetate (25): To a solution of the allyl alcohol 24 (0.18 g, 0.48 mmol) in toluene (5 mL)
were added triethyl orthoacetate (0.45 mL, 2.4 mmol) and propionic acid (0.08 mL, 0.04
mmol). The resulting solution was heated at 150 °C in seal tube for 24 h. After completion of
the reaction (TLC), most of the solvent was evaporated off and the crude obtained which
was purified by silica gel column chromatography using petroleum ether/EtOAc (9:1) as
eluent to furnish 25 (0.13 g, 61%) as a colorless oil. [α]D24+82.2 (c 1.05, CHCl3). IR (Neat):
1
νmax 3419, 2917, 1723, 1505, 1030 cm−1. H NMR (400 MHz, CDCl3): δ 6.80-6.60 (m, 4H),
6.02-5.85 (m, 3H), 5.55 (d, J = 9.6 Hz, 1H), 4.43 (d, J = 10.0 Hz, 1H), 4.22-4.05 (m, 2H), 3.30-
3.15 (m, 2H), 2.52-2.35 (m, 3H), 2.29 (dd, J = 16.0, 8.4 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 171.7, 161.5, 147.8, 146.5, 134.7, 127.5, 127.3, 120.2, 108.2,
107.7, 100.9, 92.9, 60.8, 52.8, 42.7, 38.0, 35.9, 26.2, 14.1. HRMS (ESI) m/z: [M+Na]+ Calcd for
C19H20Cl3NO5+Na 470.0305; Found: 470.0303.
O
HN
O
O
5
(3aS,7S,7aS)-7-(benzo[d][1,3]dioxol-5-yl)-1,3,3a,6,7,7a-hexahydro-2H-indol-2-one (5): To a
stirred solution of 25 (0.02 g, 0.05 mmol) in anhydrous DMSO (2 mL) was added Cs2CO3
(0.05 g, 0.15 mmol) at room temperature. The reaction mixture was heated at 100 °C for 5
h. After completion of the reaction (TLC), it was allowed to cool to room temperature,
cautiously quenched by addition water (5 mL) and extracted with diethyl ether (2 × 10 mL).
The combined organic layers were washed with brine (5 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent gave the crude residue which was purified by silica gel
column chromatography using petroleum ether/EtOAc (2:8) as eluent to furnish 5 (0.01 g,
83%) as a colorless oil. [α]D24+153.1, (c 0.9, CHCl3). IR (Neat): νmax 3409, 2918, 1685, 1203
1
cm−1. H NMR (400 MHz, CDCl3): δ 6.78 (d, J = 8.0 Hz, 1H), 6.73 (bs, 1H), 6.69 (d, J = 8.0 Hz,
13

1H), 5.94 (bs, 2H), 5.95-5.85 (m, 1H), 5.49 (d, J = 10.0 Hz, 1H), 5.32 (s, 1H), 4.05 (d, J = 4.4 Hz,
1H), 3.14 (bs, 1H), 2.95 (d, J = 10.8 Hz, 1H), 2.66 (dd, J = 16.8, 9.2 Hz, 1H), 2.48 (t, J = 14.8 Hz,
1H), 2.11 (d, J = 16.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 177.4, 148.2, 146.5, 135.9, 127.8,
126.7, 119.7, 108.6, 107.6, 101.1, 58.2, 41.1, 38.0, 35.4, 23.2. HRMS (ESI) m/z: [M+Na]+
Calcd for C15H15NO3+Na 280.0950; Found: 280.0948.
H
H
O
O
N
O
26
(3aS,3a1S,12bS)-3a,4,7,12b-tetrahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-
de]phenanthridin-5(3a1H)-one (26): To a stirred solution of 5 (56 mg, 0.22 mmol) in
dichloroethane (5 mL) were added paraformaldehyde (27 mg, 0.90 mmol) followed by TFA
(0.22 mL, 2.82 mmol) dropwise at room temperature. The reaction mixture was stirred at
same temperature for 30 h. After completion of the reaction (TLC), it was quenched by
addition of saturated aqueous solution of NaHCO3 (5 mL) and extracted with CH2Cl2 (2 × 25
mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent gave the crude residue which was purified by silica gel
column chromatography using petroleum ether/EtOAc (2:8) as eluent to furnish 26 (45 mg,
76%) as a viscous mass. [α]D24−12.2, (c 1.05, CHCl3). IR (KBr): νmax 2908, 1670, 1483, 1429,
1213, 1033 cm−1. 1H NMR (400 MHz, CDCl3): δ 6.61 (bs, 2H), 5.91 (d, J = 6.4 Hz, 2H), 5.76 (t, J
= 9.6 Hz, 1H), 5.65-5.50 (m, 1H), 4.61 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.6 Hz, 1H), 4.05-3.90
(m, 1H), 3.20-3.05 (bs, 1H), 2.88-2.70 (m, 2H), 2.19 (d, J = 17.2 Hz, 1H), 2.15-2.05 (m, 1H),
1.90-1.72 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 174.4, 146.8, 146.4, 132.0, 128.1, 125.6,
123.4, 108.3, 106.8, 101.0, 55.5, 42.9, 38.4, 37.3, 31.8, 28.1. HRMS (ESI) m/z: [M+H]+ Calcd
for C16H15NO3+H 270.1130; Found: 270.1126.
H
O
H
O
O
N
27
(3aR,3a1S,12bS)-2,3,3a,4,7,12b-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-
de]phenanthridin-5(3a1H)-one (27): A solution of 26 (45 mg, 0.17 mmol) and 10% Pd/C (5
mg) in MeOH (8 mL) was stirred under hydrogen atmosphere for 5 h at room temperature.
After completion of the reaction (TLC), most of the solvent was evaporated off and the
crude obtained which was purified by silica gel column chromatography using petroleum
ether/EtOAc (2:8) as eluent to furnish 27 (40 mg, 89%) as a white solid. Mp 145-150 °C
24
[α]D24+96.9 (c 0.9, CHCl3), Lit2f [α]D −96.0 (c 1.0, CHCl3) for the enantiomer. IR (KBr): νmax
1
2929, 1681, 1483, 1201, 1033 cm−1. H NMR (400 MHz, CDCl3): δ 6.57 (d, J = 11.2 Hz, 2H),
5.92-5.85 (m, 2H), 4.51 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.80-3.68 (m, 1H), 2.85-
2.68 (m, 1H), 2.55 (dd, J = 16.0, 6.8 Hz, 1H), 2.40 (sextet, J = 6.0 Hz, 1H), 2.06 (d, J = 16.0 Hz,
1H), 1.80-1.60 (m, 3H), 1.40-1.25 (m, 1H), 1.20-1.05 (m, 2H).13C NMR (100 MHz, CDCl3): δ
175.6, 146.6, 146.5, 131.5, 123.2, 108.4, 106.6, 100.9, 55.6, 42.6, 40.2, 39.8, 32.9, 30.2, 27.8,
23.5. HRMS (ESI) m/z: [M+H]+ Calcd for C16H17NO3+H 272.1287; Found: 272.1289.
14

H
H
H
O
O
N
1
γ-lycorane (1): To a stirred solution of 28 (36 mg, 0.13 mmol) in anhydrous THF (12 mL) was
added LiAlH4 (15 mg, 0.39 mmol) at 0 °C. The reaction mixture was heated to reflux for 20 h.
After completion of the reaction (TLC), it was cooled to room temperature, cautiously
quenched by addition of moist Na2SO4. Evaporation of the solvent gave the crude residue
which was purified by silica gel column chromatography using petroleum ether/EtOAc (6:4)
20
as eluent to furnish 1 (27 mg, 79%) as a colorless oil. [α]D20+17.0 (c 0.3, EtOH), Lit11 [α]D
+17.1 (c 0.25, EtOH). IR (Neat): ν
max 2924, 2854, 2778, 2626, 1481, 1233 cm−1. 1H NMR (400
MHz, CDCl3): δ 6.61 (s, 1H), 6.49 (s, 1H), 5.90-5.80 (m, 2H), 4.01 (d, J = 14.4 Hz, 1H), 3.37 (td,
J = 9.2, 4.0 Hz, 1H), 3.21 (d, J = 14.4 Hz, 1H), 2.80-2.68 (m, 1H), 2.37 (t, J = 4.8 Hz, 1H), 2.25-
2.10 (m, 2H), 2.08-1.95 (m, 1H), 1.80-1.68 (m, 2H), 1.67-1.57 (m, 1H), 1.54-1.35 (m, 2H),
1.32-1.20 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 146.0, 145.6, 133.1, 127.3, 108.3, 106.2,
100.6, 62.9, 57.1, 53.7, 39.4, 37.3, 31.7, 30.4, 29.3, 25.2. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H19NO2+H 258.1494; Found: 258.1492. The spectral data of the synthesized lycorane
were in complete agreement with that reported in the literature.2g
Acknowledgment
M. B. U. thanks Indian Institute of Science (IISc) Bangalore for a research fellowship.
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16

Total Synthesis of (+)-γ-Lycorane from Ethyl Lactate Using Iterative Claisen
and Overman Rearrangement Reactions
Highlights of the present work:
•
•
Total synthesis of (+)-γ-lycorane is accomplished from (S)-ethyl lactate.
Used iterative Claisen and Overman rearrangement reactions to install the chiral
centers in the tetrahydroindole moiety
•
Pictet-Spengler reaction is used for the synthesis of the isoquinoline unit.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: