Chiron approach to the total synthesis of Amaryllidaceae alkaloid (+)-lycoricidine

Article abstract of DOI:10.1016/j.tet.2017.10.033

A highly stereoselective total synthesis of Amaryllidaceae alkaloid starting from α-D-galactopyranoside has been described. The salient features of this total synthesis are Ferrier carbocyclization reaction for the synthesis of ring A and Suzuki Miyaura c

Full text of DOI:10.1016/j.tet.2017.10.033

Accepted Manuscript
Chiron approach to the total synthesis of Amaryllidaceae alkaloid (+)-lycoricidine
Puli Saidhareddy, Arun K. Shaw
PII:
S0040-4020(17)31061-X
10.1016/j.tet.2017.10.033
TET 29036
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 July 2017
Revised Date: 9 October 2017
Accepted Date: 12 October 2017
Please cite this article as: Saidhareddy P, Shaw AK, Chiron approach to the total synthesis of
Amaryllidaceae alkaloid (+)-lycoricidine, Tetrahedron (2017), doi: 10.1016/j.tet.2017.10.033.
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Chiron Approach to the Total Synthesis of Amaryllidaceae
Alkaloid (+)-Lycoricidine
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Puli Saidhareddy and Arun K. Shaw
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Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Sector-10,
Sitapur road, Janakipuram extension, Lucknow-226031.
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Tetrahedron
journal homepage: www.elsevier.com
Chiron Approach to the Total Synthesis of Amaryllidaceae Alkaloid (+)-
Lycoricidine
Puli Saidhareddy and Arun K. Shaw
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Sector-10, Sitapur road, Janakipuram extension, Lucknow-
226031.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly stereoselective total synthesis of Amaryllidaceae alkaloid starting from α-D-
galactopyranoside has been described. The salient features of this total synthesis are
Ferrier carbocyclization reaction for the synthesis of ring A and Suzuki Miyaura
coupling of chiral α-iodo enone fragment with aromatic boronic acid followed by
modified Bischler-Napieralski cyclization reaction to form the lactam ring.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Total synthesis
Lycoricidine
Amaryllidaceae
Chiron approach
Carbohydrates
utilizing monosaccharide derived chiral building blocks5,6
polyhydroxylated alkaloids, and iminosugars,7 motivated us to
take an attempt toward a chiron approach to total synthesis of
(+)-lycoricidine (1).
1. Introduction
The Amaryllidaceae alkaloids, which contains lycorine
type of structures such as (+)-lycoricidine 1, (+)-narciclasine
2, and (+)-pancratistatin 3 have been isolated from the plants
of the genus Amaryllidaceae including the bulbs of narcissi
and daffodils.1 The structural elucidation of these molecules
was done in 19702 showing highly oxygenated
benzophenanthridone-type of skeletons with four or six
contiguous stereogenic centers in the C-ring. The extensive
biological properties of these compounds, particularly their
anticancer and antiviral activities, have led them to being
considered as therapeutic agents.3 For instance, (+)-
pancratistatin and some of its analogues (fig. 1) have been the
subject of preclinical development studies as agents for the
treatment of certain cancers.2 Owing to their biological
importance and limited availability through the natural
resources, a significant body of work toward development of
synthetic routes to these class of molecules and various
analogues has been a challenging task to synthetic chemists.4
However, among the various synthetic routes reported so far
many of them have drawbacks such as harsh conditions, poor
stereoselectivity, long reaction series and incompetent
protecting group chemistry in the late stages resulting overall
low yield. In continuation of our passion in total synthesis of
natural products or biologically important molecules by
———
Figure 1: Structures of important Amaryllidaceae alkaloids.
The retrosynthetic strategy for the target molecule (+)-
lycoricidine 1 is depicted in Scheme 1. We envisaged that 1
could be elaborated from 4 by electrophilic ring cyclization
under modified conditions of Bischler–Napieralski reaction8
followed by debenzylation. The precursor 4 could be
synthesized either by Overmann rearrangement of 5 or
inversion of sterocenter C4 of the alcohol 6. The respective
precursors of 5 and 6 (7 and 8) could be anticipated by
Suzuki-Miyaura coupling of the substituted commercially
available phenyl boronic acid 9 and carbohydrate derived
iodine partners 10 and 11 which could be derived from
methyl-α-
D-mannopyranoside
14
and
methyl-α-D-
galactopyranoside 15 respectively.
Corresponding author. e-mail: akshaw55@yahoo.com
1

ACCEPTED MANUSCRIPT
Scheme 1: Retrosynthetic analysis of (+)-lycoricidine1
.
in the presence of catalytic amount of DMAP, but the yield
was comparatively low (75%).12
2. Results and Discussion
As per the above retrosynthetic analysis (Scheme 1), the
stereoselective total synthesis of the title molecule 1 was
Now, we switch on to palladium catalyzed Suzuki Miyaura
coupling between 9 and 10.14 First, we screened various
palladium catalysts under different conditions for the coupling
reaction. We realized that performing the reaction in presence
of palladium on carbon with sodium carbonate as a base and
DME and water as a solvent in 1:1 ratio at 50 °C was found to
be the most favorable condition for the coupling of 9 with 10
to obtain the coupled product 22 in 83% yield. The Luche’s
reduction of its α,β-unsaturated carbonyl group at 0 °C
produced the corresponding alcohol 7 with the required
stereochemical orientation of the OH functionality along with
its diastereomer in the ratio of 2.5:1 in 81% yield (HPLC).
However, the highly stereoselective reduction of 22 was
performed successfully with DIBAL-H at -78 °C to produce
the desired alcohol 7 almost exclusively in 79% yield (10:1,
commenced with methyl-α-D-mannopyranoside 14. Initially,
the pyranoside 14 was converted into the 6-deoxy-6-iodo-2,3-
di-O-benzyl-α,D-mannopyranoside 18 through sequential
four step reactions9 involving silyl protection of primary
alcohol followed by benzyl protection of remaining hydroxyl
groups to obtain a globally protected sugar 16. Its silyl
removal with TBAF at 0 °C and subsequent iodination
following regular protocol produced the iodide 18 with
overall 66% yield starting from 14. The compound 18 was
also prepared in 90% yield by following the modified
Pongdee et al protocol10 from mannopyranoside 14.
According to which, 14 was subjected to regioselective
iodination of C(6)-OH by using triphenylphosphine,
imidazole and I2 at 70 °C. The resulting iodide was purified
by filter column which on benzylation produced 6-iodo
derivative 18 (Scheme 2). It was subjected to
dehydrohalogenation with potassium tertiarybutoxide
(tBuOK) in THF to furnish exocyclic tetrahydro-2H-pyran 12
in 82% yield.11,12 The olefin 12 was subjected to the Ferrier’s
carbocyclization reaction12 in the presence of mercuric (II)
trifluoroacetate (Hg(OCOCF3)2) in acetone/water (1/1 V/V)
and subsequent dehydration of the resultant with mesyl
chloride and Et3N produced enone 20 in 76% yield over two
steps. Finally, α-iodo enone 10, a chiral fragment for the
synthesis of (+)-lycoricidine 1 was prepared by α-iodination
of 20 with iodine in the presence of K2CO3 and DMAP in
THF/H2O (1/1) in 89% yield.13 The formation of 10 from 20
was also possible by its treatment with iodine in pyridine/CCl4
HPLC).15 The allylic alcohol
7
was treated with
trichloroacetonitrile (CCl3CN) in the presence of base DBU at
0 °C to give the corresponding imidate 5 in 90% yield.
Overmann rearrangement16 of compound 5 with K2CO3 at 90
°C for 30 min in microwave conditions gave 23 in trace
amounts and the most of the starting material was found
untreated.16d Further changing the conditions like increasing
the temperature or reaction time was futile and the starting
material was decomposed. Therefore, we redesigned our
synthetic strategy based on retrosynthetic scheme 1.
According to it, we planned to carry out Mitsunobu reaction
of the alcohol 7 to introduce nitrogen functionality at C4.
However, before arrive to this stage, we need to move on to
galactose derived 15 in order to set the remaining sterocenters
of natural product 1 (scheme 3).
2

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Scheme 2: Synthesis of chiral fragment 10 and 11 from manno and galactopyranoside 14 and 15.
Reagents and conditions: (a) TBSCl, imidazole, DMF, RT, 6 h (b) NaH, BnBr, DMF, 0 °C -RT, 24 h (86% for 16 and 85% for 17 over 2
steps) (c) TBAF, THF, 0 °C-RT, 3 h (d) PPh3, imidazole, I2, toluene, 45 °C, 2 h (77% for 18 and 80% for 19 over 2 steps). (e) PPh3, imidazole,
t
I2, toluene, 70 °C, 2 h then NaH, BnBr, DMF, 0 °C -RT, 24 h (90% over 2 steps for both 18 and 19) (f) BuOK, dry THF, 0 °C –RT (82% for
12 and 85% for 13) (g) Hg(OCOCF3)2, acetone:water (2:1), RT, overnight then MsCl, Et3N, dry DCM, 0 °C -RT, 3 h (76% for 20 and 72% for
21 over two steps). (h) K2CO3, DMAP, I2, THF:H2O (1:1), 0 °C -RT, 12 h (89% for 10 and 91% for 11).
amount of its diastereomer (10:1 ratio). Its Mitsunobu reaction
to introduce nitrogen functionality at C4-position was realized
by treating it with diphenylphosphoryl azide (DPPA) and
diisopropyl azodicarboxyelate (DIAD) at -20 °C.6a
Unfortunately the reaction led to give the desired product 6 in
poor yield (30-40%). Therefore, we switched over to a
conventional method, in which the alcoholic group in 8 was
converted into its corresponding mesylate which on azidation
with sodium azide in DMF at room temperature produced the
desired azide 6 comparatively in very good yields (83%).4m
The stereochemistry of the newly created stereocenter was
established by its 2D-NMR spectroscopy (COSY and
NOESY). The azide 6 was reduced with PPh3 to an amine
whose subsequent protection with methyl chloroformate and
DMAP afforded the protected amine 4 in 78% yield over two
steps. It was then subjected to modified Bischler-Napieralski
Scheme 3: Attempt to synthesis of ent-lycoricidine through
cylization reaction (Tf2O, DMAP at 0 °C) to furnish the
Overmann rearrangement.
cyclized lactam 25 in 62% yield (scheme 4). Finally, its
Reagents and conditions: (a) Pd/C (10%), Na2CO3,
DME:H2O (1:1), RT, 50 °C, overnight, 83% (b) DIBAL-H,
THF, -78 °C, 3 h, 79% (c) CCl3CN, DBU, DCM, 0 °C, 90%
(d) K2CO3, 1,2-dichlorobenzene, microwave, 90 °C, 30 min
(in trace amount).
debenzylation with BCl3 at 0 °C, led to produce the final title
natural product 1 in 55% yield (Scheme 4). The spectral data
of 1 was exactly matched with the reported4c,f,n
3. Conclusion
In summary, we have developed a new route for the total
synthesis of Amaryllidaceae alkaloid (+)-lycoricidine 1 in 12
steps and with 7.8% overall yield and it is better approach
compared to the some previous reports in terms of yields and
number of steps.4 The synthesis involved Ferrier
carbocyclization reaction of the tetrahydro-2H-pyran 13 to
form chiral carbocyclic fragment 21, followed by Suzuki
Miyaura coupling of α-iodo enone 11 with aromatic boronic
acid 9 to form 24 and its Mitsunobu reaction to establish the
The α-iodo enone 11 (50% yield) was synthesized starting
from methyl α-D-galactopyranoside 15 by using similar
reaction sequences which were used in the case of mannose
derived chiral intermediate 10 (scheme 2). Its Suzuki-Miyaura
coupling reaction with boronic acid 9 in the presence of
palladium charcoal and Na2CO3 furnished enone 24 in 88%
yield (Scheme 4). Its ketone functionality was subjected to
DIBAL-H reduction at -78 °C to obtain the alcohol 8 with
required stereochemistry in 85% yield along with a trace
3

desired stereochemistry of title
carbamate (4) cyclization followed by global deprotection of
cyclic lactam 25 led to give the target alkaloid 1.
product. The
concentrations mentioned are in g/100 mL. For IR spectra
naturaAl CCEPTED MANUSCRIPT
were recorded on Perkin–Elmer 881 and FTIR-8210 PC
Shimadzu Spectrophotometers. Mass spectra were recorded
on a JEOL JMS-600H high resolution spectrometer using EI
mode at 70 eV. ESI-HRMS were recorded on a JEOL-
AccuTOF, JMS-T100LC spectrometer.
tert-butyldimethyl(((2R,3S,4S,5R)-3,4,5-tris(benzyloxy)-6-
methoxytetrahydro-2H-pyran-2-yl)methoxy)silane
(Compound 17): To
a
solution of methyl α-D-
galactopyranoside 15 (5.00 g, 0.026 mmol) and imidazole (3.5
g, 0.052 mmol) in DMF (50 mL) at room temperature was
added TBSCl (5.75 g, 0.038 mmol) and the reaction was
stirred at the same temperature for 4 h. The reaction was
diluted with EtOAc (50 mL) and quenched with cold water
(50 mL). The organic layer was extracted with EtOAc (3 x 50
mL) and the combined organic layers were concentrated in
vacuo. The residue was placed on a high vacuum manifold to
afford methyl α-D-6-O-silylgalactopyranoside as colorless
compound. It was subjected to filter column to remove
unreacted silyl reagent.
To the stirred solution of above crude compound (9.74 g,
0.032 mmol) in THF at 0 °C, was added sodium hydride (3.8
g, 0.158 mmol) in portion wise followed by dropwise addition
of benzyl bromide by using dropping funnel. The reaction was
shifted to room temperature and allowed to stir for overnight.
After completion of the reaction, the reaction mixture was
quenched with methanol and then it was evaporated in
rotavapour to a solid mass. After that it was diluted with
EtOAc, and washed with water and brine solution. The
combined organic layers were dried on Na2SO4 and
concentrated in vacuum. The crude material was subjected to
silica gel column chromatography by using EtOAc/Hexane
(1:9) as a solvent to obtain a pure compound 17 in 85% yield
(16 g, 0.028 mmol). Rf 0.4 (1/4, EtOAc/ Hexane). [α]D22 +31.5
(c 0.1, CHCl3). IR (Neat): νmax= 3117, 2986, 1721, 1630,
Scheme 4: Attempts to the preparation of (+)-lycoricidine 1.
Reagents and conditions: (a) Pd/C (10%), Na2CO3,
DME:H2O (1:1), 50 °C6 h, 88%. (b) DIBAL-H, THF, -78 °C,
3 h, 85% (c) MsCl, Et3N, dry DCM, 0 °C-RT (d) NaN3, DMF,
RT, 24 h, 83% (over two steps). (e) (i) PPh3, THF-H2O, RT.
(ii) ClCO2Me, DMAP, DCM, RT, 78%. (f) Tf2O, DMAP, dry
DCM, 0 °C to RT, 12 h, 62%. (g) BCl3, DCM, 0 °C, 6 h, 55%.
4. Experimental Section
4.1. General
1
1415, 1205, 1120 cm-1. H (400 MHz, CDCl3): δ 7.24-7.40
The organic solvents were made anhydrous by standard
methods before their use. TLC plates coated with silica gel
(60F-254) 2.5 × 5 cm and 0.25 mm thickness were used to
monitor the progress of the reaction. Visualization of the spots
was done by spraying the plate with Ce(SO4)2 (1% in 2N
H2SO4) and subsequent charring over hot plate. Silica gel (60–
120 mesh) and silica gel (230-400 mesh) were used for
column chromatography. All the intermediates were
characterized by NMR, IR, ESI-HRMS and the identifications
of known compounds were done by comparing their optical
rotation with those reported in the literature. NMR
experiments were recorded in CDCl3 and CD3OD at 25 ºC.
Chemical shift values are given on δ scale with reference to
TMS at 0.00 ppm for proton and carbon. The reference CDCl3
appeared at 77.26 ppm for 13C NMR. NMR spectra were
recorded on Bruker Avance 400 MHz spectrometer at 400
MHz (1H) and 100 MHz (13C). Optical rotations were
determined on HORIBA, high sensitive polarimeter, SEPA-
300 using a 1 dm cell at 17 ºC-32 ºC in chloroform;
(m, 15H), 4.96 (d, J=15.2 Hz, 1H), 4.81-4.88 (m, 2H), 4.67-
4.75 (m, 3H), 4.55-4.60 (m, 1H), 4.03 (dd, J1=3.56, J2=9.42
Hz 1H), 3.91-3.94 (m, 2H), 3.68-3.72 (m, 1H), 3.57-3.64 (m,
2H), 3.36 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H). 13C (100 MHz,
CDCl3): δ 139.14, 139.05, 138.81, 128.59, 128.55, 128.42,
128.37, 128.33, 127.89, 127.74, 98.97, 79.42, 76.76, 75.39,
74.99, 73.77, 73.51, 71.27, 62.21, 55.41, 26.11, 18.42, -5.16, -
5.24. ESI-HRMS: m/z [M+Na]+ calcd for C34H46NaO6Si+
601.2961, measured 601.2950.
(2S,3R,4S,5R)-3,4,5-tris(benzyloxy)-2-(iodomethyl)-6-
methoxytetrahydro-2H-pyran (Compound 19): TBAF
(28.5 mL,1.0 M solution in THF, 0.028 mmol) was added
drop wise to a stirred solution of compound 17 (11 g, 0.019
mmol) in THF (10 mL) at 0 °C and the stirring was continued
for 3 h. After completion of the reaction, the mixture was
quenched with water and the organic layer was separated. The
aqueous layer was extracted with EtOAc (3 x 30 mL) and the
7

combined organic layers were dried over Na2SO4. The solvent
obtain a pure compound 19 in 90% yield over two steps (17 g,
0.03 mmol).
ACCEPTED MANUSCRIPT
was removed under reduced pressure and the crude reaction
mixture was used for iodination without its column
purification.
(3R,4S,5R)-3,4,5-tris(benzyloxy)-2-methoxy-6-
methylenetetrahydro-2H-pyran (Compound 13): BuOK
t
To the above stirred solution of crude compound (5.5 g, 0.012
mmol) in toluene were added PPh3 (4.6 g, 0.02 mmol),
imidazole (1.6 g, 0.02 mmol) and molecular iodine (4.5 g,
0.02 mmol) at room temperature. The temperature of the
reaction was raised to 70 °C and stirring was continued for 2
h. After completion of the reaction, the mixture was quenched
with Na2S2O3.5H2O. The aqueous layer was extracted with
EtOAc (3 x 20 mL). The combined organic layers were dried
over Na2SO4 and the solvent was evaporated in vacuum. The
crude compound was subjected to column chromatography
(EtOAc/Hexane, 8:92) to obtain a pure compound 19 in 80%
yield (9.4 g, 0.02 mmol) over two steps. Rf 0.4 (1/5, EtOAc/
(1.04 g, 9.3 mmol) was added to a stirred solution of iodide 19
(3 g, 0.01 mmol) in THF (40 mL) in portion wise at 0 °C over
2 h and the reaction was allowed to stir at room temperature
for 24 h. The reaction mixture was diluted with ethyl acetate
(50 mL) and the organic layer was washed with H2O (2 x 25
mL) followed by brine solution (2 x 25 mL). The organic
layer was separated, dried (Na2SO4), and concentrated under
reduced pressure to give a residue. Its silica gel column
chromatography furnished pure olefin 13 in 85% yield (2 g,
0.005 mmol). Rf 0.4 (1/5, EtOAc/ Hexane). [α]D22 +7.6 (c 0.2,
CHCl3). IR (Neat): νmax =3020, 2361, 1663, 1216, 1051 cm-1.
1H (400 MHz, CDCl3): δ 7.17-7.29 (m, 15H), 4.53-4.93 (m,
9H), 3.82-3.96 (m, 1H), 3.45-3.54 (m, 1H), 3.34-3.41 (m,
4H), 3.21-3.28 (m, 1H). 13C (100 MHz, CDCl3): δ 153.89,
138.79, 138.27, 138.25, 128.74, 128.70, 128.64, 128.60,
128.24, 127.98, 127.94, 127.85, 99.30, 97.07, 79.76, 76.02,
75.99, 75.59, 74.72, 73.84, 73.68, 55.75. ESI-HRMS: m/z
[M+H]+ calcd for C28H31O5+ 447.2171, measured 447.2160.
22
Hexane). [α]D +25.5 (c 0.3, CHCl3). IR (Neat): νmax=3015,
1
2930, 2855, 1645, 1472, 1216, 1014 cm-1. H (400 MHz,
CDCl3): δ 7.24-7.41 (m, 15 H), 5.03 (d, J=11.08, 1H), 4.62-
4.91 (m, 6H),4.0-4.03 (m, 2H), 3.91-3.94 (m, 1H), 3.82-3.86
(m, 1H), 3.41 (s, 3H), 3.22 (dd, J1=7.53, J2=9.98 Hz, 1H),
3.07 (dd, J1=6.21, J2=9.98 Hz, 1H). 13C (100 MHz, CDCl3): δ
138.89, 138.61, 138.50, 128.67, 128.35, 128.05, 128.01,
127.85, 127.76, 99.09, 79.31, 76.24, 76.05, 75.26, 73.85,
71.54, 55.98, 3.8. ESI-HRMS: m/z [M+Na]+ calcd for
C28H31INaO5+ 597.1114, measured 597.1105.
(4S,5R,6R)-4,5,6-tris(benzyloxy)cyclohex-2-en-1-one
(Compound 21): To a stirred suspension of the exocyclic
olefin 13 (900 mg, 2.02 mmol) in acetone/water (30 mL, 2:1,
v/v) at room temperature was added Mercury (II)
trifluoroacetate (90 mg, 0.220 mmol). The reaction mixture
was allowed to stir for overnight, after completion the
reaction, the solvent was concentrated at reduced pressure to a
residue. Then it was dissolved in ethyl acetate (30 mL) and
washed with water (3 x 15 mL) and brine (3 x 15 mL)
solutions. The combined organic layers were dried over
Na2SO4 and evaporated under reduced pressure to obtain clear
oil (890 mg), which was used without further purification.
Procedure for the preparation of 19 directly from 15: To a
solution of methyl α- D-glucopyranoside 15 (5.00 g, 25.8
mmol) in toluene (500 mL) at room temperature was added
triphenylphosphine (10.1 g, 38.6 mmol) followed by
imidazole (5.30 g, 3.00 mmol) and iodine (9.15 g, 1.40 mmol)
and the reaction was heated to 70 ºC for 2 h. It was cooled to
room temperature and water (50 mL) was added to it. The
resulting mixture was stirred vigorously for 10 min. The
organic layer was extracted with water (1 X 50 mL) and the
combined aqueous layers were concentrated in vacuo. The
residue was placed on a high vacuum manifold to afford 11.0
Triethyl amine (2.5 mL) and methanesulfonyl chloride (0.64
mL, 4.6 mmol) were added to the above crude residue (890
mg) dissolved in DCM (15 mL) at 0 °C. The reaction mixture
was shifted to room temperature and continued the stirring for
2 h. The reaction was quenched with saturated aqueous
solution of NH4Cl (15 mL) and the resulting solution was
extracted with DCM (4 x 15 mL). The organic layers were
dried over Na2SO4 and the solvent was removed under
reduced pressure to a residue, which on silica gel column
chromatography furnished the enone 21 in 72% yield (585
mg, 1.41 mmol) over two steps. Rf 0.4 (1/4, EtOAc/ Hexane).
g of methyl α-D-6-deoxy-6-iodoglucopyranoside as an off-
white solid.
To the above crude compound (11 g, 0.035 mmol) in THF at
0 °C, was added sodium hydride (4.2 g, 0.175 mmol) in
portion wise for 30 min followed by dropwise addition of
benzyl bromide by using dropping funnel at the same
temperature. The reaction was warmed to room temperature
and allowed to stir for overnight. The reaction mixture was
diluted with methanol followed by evaporation of the solvent
in rotavapour to a solid mass. It was dissolved in EtOAc, and
washed with water and brine solution. The combined organic
layers were dried over Na2SO4 and concentrated in vacuum.
The crude material was subjected to silica gel column
chromatography by using EtOAc/Hexane (1:9) as a solvent to
22
[α]D +137.6 (c 0.2, CHCl3). IR (neat): νmax =3020, 2361,
1
1693, 1648, 1216, 1024 cm-1. H (400 MHz, CDCl3): δ 7.27-
7.34 (m, 15H), 6.77 (dd, J1=3.18, J2=10.20 Hz, 1H), 5.99 (d,
J=10.31 Hz, 1H), 4.80-4.83 (m, 1H), 4.52-4.72 (m, 5H), 4.42
(bs, 1H), 4.23-4.24 (m, 1H), 3.95-3.97 (m, 1H). 13C (100
MHz, CDCl3): δ 196.34, 138.13, 138.00, 137.80, 128.76,
128.62, 128.61, 128.29, 128.23, 128.09, 128.05, 80.23, 79.16,
8

75.35, 73.47, 72.94, 72.63. ESI-HRMS: m/z [M+Na]+ calcd
vacuum. The crude was subjected to column chromatography
(EtOAc/Hexane 12:88) to obtain a pure compound.
ACCEPTED MANUSCRIPT
for C27H26NaO4+ 437.1729, measured 437.1722.
(4R,5R,6S)-2-(benzo[d][1,3]dioxol-5-yl)-4,5,6-
General procedure for the α-iodination of compounds 10
and 11: K2CO3 (664 mg, 4.8 mol) and DMAP (10 mg, 0.08
mmol) were added to the stirred solution of 2-cyclohexenone
derivative 20 or 21 (1.6 g, 0.004 mmol) in a 1:1 mixture of
THF/H2O at 0 °C then continue the stirring at the same
temperature for 10 min. A series of colours were observed
before finally turning to brown. After that, I2 (1.22 g, 0.005
mol) was added slowly to avoid forming a solid mass at the
bottom of the flask. The reaction turned black and was stirred
for 12 h open to the atmosphere at room temperature. Then
the mixture was partitioned between EtOAc and washed
sequentially with 0.1 M aqueous HCl, saturated aqueous
Na2S2O3.5H2O, and brine solutions. The combined organic
layers were dried (Na2SO4) and concentrated. The residue was
subjected to silica gel column chromatography to afford a
pure 2-iodoenone.
tris(benzyloxy)cyclohex-2-en-1-one (Compound 22): The
compound 22 was obtained in 83% yield (171 mg, 0.30
mmol) after column purification. Column eluent:
EtOAc/hexane (18:72, v/v). Rf 0.3 (1/3, EtOAc/ Hexane);
[α]D22 +32.4 (c 0.3, CHCl3). IR (KBr): νmax=3021, 1746, 1644,
1
1217, 1072 cm-1. H (400 MHz, CDCl3): δ 7.17-7.28 (m,
15H), 6.59-6.71 (m, 2H), 6.46 (d, J=7.55 Hz, 2H), 5.88 (s,
2H), 5.01-5.04 (m, 1H), 4.91-4.94 (m, 1H), 4.66-4.80 (m,
4H), 4.38 (dd, J1=2.12, J2=8.08 Hz, 1H), 3.94-4.09 (m, 2H);
13C (100 MHz, CDCl3): δ 196.16, 148.88, 144.37, 143.52,
138.39, 138.33, 137.97, 137.87, 135.85, 128.78, 128.62,
128.49, 128.37, 128.26, 128.17, 128.07, 128.01, 108.86,
103.17, 101.81, 84.72, 84.42, 78.80, 75.81, 74.74, 73.90. ESI-
+
HRMS: m/z [M+H]+ calcd for C34H31O6 535.2121, found
535.2135.
(4S,5R,6R)-2-(benzo[d][1,3]dioxol-5-yl)-4,5,6-
(4R,5R,6S)-4,5,6-tris(benzyloxy)-2-iodocyclohex-2-en-1-
tris(benzyloxy)cyclohex-2-en-1-one (Compound 24): The
compound 24 was obtained in 88% yield (880 mg, 1.64
mmol). Rf 0.5 (1/4, EtOAc/ Hexane) [α]D +50.6 (c 0.1,
one (Compound 10): 89% yield (1.7 g, 0.0035 mmol) as a
yellow oil. Rf 0.5 (1/4, EtOAc/ Hexane). [α]D +286.1 (c
22
22
0.77, CHCl3); IR (neat): νmax =3427, 3022, 2927, 2363, 1698,
1
1218 cm-1; H NMR (400 MHz, CDCl3): δ 7.57 (d, J=3.5 Hz,
CHCl3). IR (KBr): νmax =3018, 2954, 2855, 1702, 1542, 1183,
1025 cm-1. 1H (400 MHz, CDCl3): δ 7.24-7.39 (m, 15H), 6.71-
6.79 (m, 4H), 5.89 (s, 2H), 5.02-504 (m, 1H), 4.92-4.95 (m,
1H), 4.63-4.80 (m, 4H), 4.37-4.39 (m, 1H), 3.95-4.10 (m,
2H). 13C (100 MHz, CDCl3): δ 196.30, 148.10, 147.73,
144.04, 138.47, 138.32, 138.04, 137.94, 128.81, 128.65,
128.54, 128.47, 128.40, 128.27, 128.18, 128.10, 128.03,
122.59, 109.40, 108.40, 101.43, 84.77, 84.50, 78.83, 75.85,
1H), 7.39-7.26 (m, 15H), 4.82-4.56 (m, 6H), 4.40-4.34 (m,
2H), 4.01 (dd, 1H, J1=3.0, J2=6.8 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 190.6, 154.9, 138.1, 137.8, 137.6, 128.9,
128.8, 128.5, 128.4, 128.3, 103.9, 78.7, 78.4, 75.4 , 73.9, 73.7,
+
73.0; ESI-HRMS: m/z [M]+ calcd for C27H25IO4 540.0798,
found 540.0798.
+
74.74, 73.87. ESI-HRMS: m/z [M+H]+ calcd for C34H31O6
(4S,5R,6R)-4,5,6-tris(benzyloxy)-2-iodocyclohex-2-en-1-
one (Compound 11): 91% yield (1.89 g, 0.004 mmol) as a
yellow oil. Rf 0.5 (1/4, EtOAc/ Hexane). [α]D +155.3 (c
535.2121, found 535.2115.
22
General procedure for 7 or 8: Enone 22 or 24 (350 mg,
0.655 mmol) was dissolved in dry THF (4.0 mL), cooled to –
78 °C under argon and 0.5 mL of DIBAL-H (1M solution in
dichloromethane or hexanes) was added. The mixture was
allowed to stir for two hours, warmed to room-temperature
and EtOAc (1.0 mL) was added, followed by 3N HCl (0.3
mL) and water (5.0 mL). The mixture was extracted with
EtOAc (3 x 20 mL). Organic phase was separated, washed
with brine (3 x 20 mL), dried (Na2SO4), and solvent removed
under vacuum.
0.15, CHCl3). IR (neat): νmax =3028, 2924, 2865, 1698, 1593,
1083, 1015 cm-1. 1H (400 MHz, CDCl3): δ 7.49 (d, J=3.79 Hz,
1H), 7.25-7.38 (m, 15H), 4.81-4.84 (m, 1H), 4.49-4.64 (m,
5H), 4.39 (d, J=2.40 Hz, 1H), 4.33 (bs, 1H), 3.96 (dd,
J1=2.32, J2=5.36 Hz, 1H). 13C (100 MHz, CDCl3): δ 190.43,
154.25, 137.84, 137.52, 137.45, 128.84, 128.67, 128.41,
128.36, 128.19, 128.15, 128.09, 103.38, 79.88, 78.00, 73.46,
73.15, 72.97. ESI-HRMS: m/z [M+Na]+ calcd for
C27H25INaO4+ 563.0695, found 563.0670.
General procedure for the synthesis of 22 and 24: To a
stirred solution of 2-iodoenone 10 or 11 (1.1 g, 0.002 mmol)
in DME and H2O (1:1, 10 mL) were added Na2CO3 (431 mg,
4.07 mol), boronate 9 (675 mg, 4.07 mmol), and 10% Pd/C
(100 mg, 5 mol %). The mixture was stirred for the 4 h at
room temperature. After completion of the reaction, Pd/C was
filtered, and the filtrate was diluted with H2O (10 mL) and
extracted with Et2O (3 x 15 mL). The collected organic
extracts were dried over Na2SO4 and concentrated under
(1S,4R,5R,6R)-2-(benzo[d][1,3]dioxol-5-yl)-4,5,6-
tris(benzyloxy)cyclohex-2-en-1-ol (Compound 7): The
compound 22 was obtained in 79% yield (171 mg, 0.30
mmol) after column purification. Column eluent:
EtOAc/hexane (18:72, v/v). Rf 0.3 (1/3, EtOAc/ Hexane).
22
[α]D +73.7 (c 0.2, CHCl3). IR (Neat): νmax =3432, 3020,
1
2959, 2363, 1637, 1216, 1044 cm-1. H (400 MHz, CDCl3): δ
7.22-7.30 (m, 15H), 6.65 (s, 1H,), 6.46-6.48 (m, 2H), 5.85-
5.94 (m, 3H), 4.77-4.93 (m, 3H), 4.59-4.70 (m, 4H), 4.16-4.25
9

(m, 1H), 3.80-3.83 (m, 1H), 3.52-3.68 (m, 1H). 13C (100
MHz, CDCl3): δ 149.23, 143.68, 139.67, 138.27, 135.40,
135.36, 133.94, 128.83, 128.78, 128.62, 128.59, 128.24,
128.13, 127.98, 127.84, 127.82, 126.71, 106.62, 101.51,
Na2SO4 and the solvent was removed under reduced pressure
to a residue, which was used directly for the azidation without
purification.
ACCEPTED MANUSCRIPT
NaN3 (109 mg, 0.17 mmol) was added to the above crude
solution of mesylate compound in anhydrous DMF (5 mL)
and the resulting mixture was stirred under nitrogen
atmosphere at 18 °C for 10 h then diluted with diethyl ether
(30 mL). The separated organic layer was washed with water
(5 X 10 mL) then dried over Na2SO4, filtered and
concentrated under reduced pressure to give a yellow oil.
Subjection of this material to flash column chromatography
(20% v/v ethyl acetate/hexanes) and concentration of the
relevant fractions gave the title compound 6 in 83% yield
(362 mg, 0.6 mmol) as a clear, colorless oil. Rf 0.3 (1/4,
100.90, 80.04, 79.78, 79.35, 75.37, 75.21, 73.42, 72.61, 71.99,
68.33.
537.2277, found 537.2262;
+
ESI-HRMS: m/z [M+H]+ calcd for C34H33O6
(1S,4S,5R,6S)-2-(benzo[d][1,3]dioxol-5-yl)-4,5,6-
tris(benzyloxy)cyclohex-2-en-1-ol (Compound 8): Pure
compound was obtained in 85% yield (298 mg, 0.26 mmol)
by using silica gel column chromatography. Rf0.5 (1/3,
22
EtOAc/ Hexane). [α]D +45.0 (c 0.1, CHCl3). IR (Neat): νmax
1
=3427, 3022, 2927, 2363, 1698, 1218 cm-1; H (400 MHz,
CDCl3): δ 7.25-7.40 (m, 15H), 7.02-7.04 (m, 2H), 6.76-6.78
(m, 1H), 5.39-5.95 (m, 3H), 4.69-4.82 (m, 4H), 4.57-4.66 (m,
2H), 427-4.29 (m, 1H), 4.03-4.04 (m, 1H), 3.96-3.97 (m, 1H),
3.30 (d, J= 10.61 Hz, 1H); 13C (100 MHz, CDCl3): δ 147.94,
147.54, 141.33, 138.55, 138.14, 133.64, 128.72, 128.16,
127.98, 122.27, 120.65, 108.34, 107.46, 101.28, 79.00, 75.86,
73.57, 72.15, 67.60. ESI-HRMS: m/z [M+H]+ calcd for
C34H33O6+ 537.2277, found 537.2259.
22
EtOAc/ Hexane). [α]D -66.4 (c 0.1, CHCl3). IR (Neat): νmax
1
=3128, 2824, 2160, 1710, 1593, 1283, 1115 cm-1. H (400
MHz, CDCl3): δ 7.29-7.37 (m, 15H), 6.76-6.85 (m, 3H), 5.99
(d, J=3.54 Hz, 1H), 5.96 (s, 2H), 4.64-4.81 (m, 6H), 4.45 (d,
J=5.12 Hz, 1H), 4.29-4.31 (m, 1H), 3.98 (dd, J1=2.16, J2=5.48
Hz, 1H), 3.87 (dd, J1=2.16, J2=5.79 Hz, 1H). 13C (100 MHz,
CDCl3): δ 148.08, 147.80, 138.75, 138.53, 138.40, 138.25,
132.85, 128.72, 128.70, 128.68, 128.21, 128.11, 128.08,
127.99, 120.45, 108.47, 107.29, 101.45, 78.52,75.24, 73.13,
72.89, 72.45, 61.29. ESI-HRMS: m/z [M+Na]+ calcd for
C34H31N3NaO5+ 584.2161, found 584.2155.
(1S,4R,5R,6R)-2-(benzo[d][1,3]dioxol-5-yl)-4,5,6-
tris(benzyloxy)cyclohex-2-en-1-yl
2,2,2-
trichloroacetimidate (Compound 5): To the stirred solution
of compound 7 (130 mg, 0.243 mmol) in dry DCM was added
the trichloroacetonitrile (0.045 mL, 0.036 mmol) and DBU
(0.054 mL, 0.036 mmol) at ice cold conditions. Then the
reaction mixture was stirred for 3 h at room temperature.
After completion of the reaction, solvent was evaporated in
rota vapour. The crude mixture was subjected to silica gel
column chromatography to obtain pure compound 5 in 90%
yield. Rf 0.5 (1/5, EtOAc/ Hexane). [α]D22 +72 (c 0.2, CHCl3).
IR (Neat): νmax =3100, 3055, 2899, 2100, 1655, 1190 cm-1; 1H
(400 MHz, CDCl3): δ 7.20-7.31 (m, 15 H), 6.81-6.88 (m, 3H),
6.69 (d, J=8.67 Hz, 1H), 6.08 (d, J= 3.83 Hz, 1H), 5.87 (s,
2H), 5.34 (dd, J1=2.25, J2=9.85 Hz, 1H), 4.78 (t, J=11.52 Hz,
2H), 4.59-4.67 (m, 3H), 4.52-4.55 (m, 1H), 4.10-4.11 (m,
1H), 3.74-3.76 (m, 2H); 13C (100 MHz, CDCl3): δ 162.29,
147.68, 147.56, 138.72, 138.40, 138.36, 137.79, 131.99,
128.70, 128.60, 128.53, 128.23, 128.02, 127.90, 127.86,
127.61, 120.59, 108.23, 107.50, 101.24, 91.65, 83.40, 82.67,
79.88, 78.40, 75.65, 72.87; ESI-HRMS: m/z [M+H]+ calcd for
C36H33Cl3NO6+ 680.1373, found 680.1390.
methyl ((1R,4S,5R,6S)-2-(benzo[d][1,3]dioxol-5-yl)-4,5,6-
tris(benzyloxy)cyclohex-2-en-1-yl)carbamate (4): To the
stirred solution of azide 6 (20 mg, 0.0356 mmol) in THF (3
mL) was added the PPh3 (19 mg, 0.07 mmol) and 2 drops of
water. The resulting mixture was continued for stirring for 3
h. After completion of the reaction, it was concentrated under
reduced pressure and the residue was dissolved in DCM (5
mL). The resulting solution was dried over Na2SO4, filtered
and concentrated under reduced pressure to obtain a crude
amine which was used directly without purification for the
next step.
A solution of methyl chloroformate (0.2 mL, 0.12 mmol) and
DMAP (20 mg, 0.16 mmol) were added slowly to a
vigorously stirred mixture of the above crude amine (20 mg,
0.03 mmol) in CH2C12 (3 ml). The reaction mixture was then
allowed to stir at 18 °C for a further 3 h and afterward water
(4 mL) and CH2Cl2 (4 ml) were added to it. The separated
organic phase was washed with water (1 x20 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure.
The residue was subjected to silica gel column
chromatography to obtain a pure compound 4 in 78% (16 mg,
0.027 mmol) over two steps. Rf 0.3 (1/4, EtOAc/ Hexane).
5-((3S,4R,5S,6R)-6-azido-3,4,5-tris(benzyloxy)cyclohex-1-
en-1-yl)benzo[d][1,3]dioxole (Compound 6):Triethyl amine
(0.13 mL, 1.5 mmol) and methanesulfonyl chloride (0.12 mL,
1.42 mmol) were added to the alcohol 8 (400 mg, 0.71 mmol)
dissolved in DCM (15 mL) at 0 °C. The reaction mixture was
shifted to room temperature and continued the stirring for 2 h.
The reaction was quenched with saturated aqueous solution of
NaHCO3 (15 mL) and the resulting solution was extracted
with DCM (4 x 15 mL). The organic layers were dried over
22
[α]D +61.8 (c 0.2, CHCl3). IR (Neat): νmax =3018, 2931,
1
2231, 1742, 1584, 1216, 1152 cm-1. H (400 MHz, CDCl3): δ
7.18-7.28 (m, 15H), 6.82 (d, J=9.6 Hz, 1H), 6.47-6.48 (m,
2H), 6.04 (d, J=2.37 Hz, 1H), 5.86-5.88 (m, 2H), 5.09 (dd,
J1=5.31, J2=9.39 Hz, 1H), 4.72-4.75 (m, 1H), 4.61-4.65 (m,
10

5H), 4.16-4.17 (m, 1H), 3.86-3.89 (m, 1H), 3.77-3.79 (m,
105.04, 103.90, 74.25, 70.68, 70.63, 53.26; ESI-HRMS: m/z
(M+H)+ calcd. for C14H14NO6+ 292.0816, found: 292.0829.
ACCEPTED MANUSCRIPT
4H). 13C (100 MHz, CDCl3): δ 149.09, 143.65, 138.32,
137.99, 137.78, 136.57, 135.50, 132.55, 128.73, 128.68,
128.39, 128.29, 128.19, 128.15, 128.09, 128.03, 125.64,
106.07, 101.80, 100.86, 79.15, 78.59, 76.45, 74.25, 74.14,
72.23, 56.71. ESI-HRMS: m/z [M+H]+ calcd for
C36H35NNaO7+ 616.2311, found 616.2355.
Acknowledgements
This work was supported by Department of Science and
Technology [DST, grant no. SB/S1/OC-28/2014]. We are
thankful to Mr A. K. Pandey for technical assistance, SAIF,
CSIR-CDRI, for providing spectral data and Dr. H. M.
Gauniyal from SAIF, CSIR-CDRI for providing COSY and
NOESY NMR spectra. P. S. thanks CSIR for awarding Senior
(2S,3R,4S,4aR)-2,3,4-tris(benzyloxy)-3,4,4a,5-tetrahydro-
[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one
(Compound
25): To a solution of methyl carbamate 4 (55 mg 0.09 mmol)
and DMAP (35 mg, 0.3 mmol) in CH2Cl2 (4 mL) cooled to -
10 °C was added trifluoromethanesulfonic anhydride (0.7 mL,
0.4 mmol). The reaction mixture was stirred for 5 h at -10 °C
to -5 °C and further continued for 12 h at 0 °C. After total
consumption of starting material (TLC analysis), the solvents
were removed under reduced pressure, and THF (2 mL) was
added. The reaction mixture was cooled to 0 °C and two drops
of 2 M aq HCl was added. The mixture was stirred for 2 h,
and solid sodium bicarbonate was added. The solvent was
removed under reduced pressure and the residue purified by
flash column chromatography affording lactam 25 as a yellow
oil (13.8 mg, 62%); Rf 0.1 (ethyl acetate/hexanes, 2:1); IR
(Neat): νmax =3490, 2940, 2858, 1660, 1613 cm-1; [α]D22 +22.4
Research
Fellowship.
CDRI
manuscript
number
125/2017/AKS.
Electronic Supplementary Information (ESI) available online.
References:
[1] (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1987; Vol. 30, p 251; (b)
Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 1998; Vol. 51, p 323; (c) Jin, Z. Nat. Prod.
Rep. 2003, 20, 606.
[2] (a) Fuganti, C.; Mazza, M. J. Chem. Soc., Chem.
Commun. 1972, 239; (b) Carrasco, L.; Fresno, M.; Vasquez,
D. FEBS Lett. 1975, 52, 236–239; (c) Jimenez, A.; Sanchez,
L.; Vasquez, D. FEBS Lett. 1975, 55, 53–56; (d) Baez, A.;
Vasquez, D. Biochim. Biophys. Acta 1975, 518, 95–103; (e)
Jimenez, A.; Santos, A.; Alonso, G.; Vasquez, D. Biochim.
Biophys. Acta 1976, 425, 342–348.
[3] (a) Pettit, G. R.; Melody, N. J. Nat. Prod. 2005, 68, 207;
(b) McNulty, J.; Larichev, V.; Pandey, S. Bioorg. Med. Chem.
Lett. 2005, 15, 5315; (c) Pettit, G. R.; Eastham, S. A.;
Melody, N.; Orr, B.; Herald, D. L.; McGregor, J.; Knight, J.
C.; Doubek, D. L.; Pettit, G. R., III; Garner, L. C.; Bell, J. A.
J. Nat. Prod. 2006, 69, 7.
1
(c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H),
7.18-7.27 (m, 15H), 7.04 (s, 1H), 6.01-6.02 (m, 1H), 5.85 (dd,
J1=1.26, J2=4.78 Hz, 2H), 5.06 (dd, J1=5.10, J2=9.44 Hz, 1H),
4.71-4.74 (m, 1H), 4.57-4.66 (m, 5H), 4.15-4.17 (m, 1H), 3.87
(dd, J1=4.53, J2=6.58 Hz, 1H), 3.79-3.81 (m, 1H); 13C (100
MHz, CDCl3): δ 161.37, 148.02, 147.87, 138.40, 138.08,
137.82, 136.73, 132.21, 128.73, 128.69, 128.37, 128.28,
128.23, 128.14, 128.06, 128.02, 125.42, 120.47, 108.42,
107.19, 101.38, 78.98, 78.27, 76.32, 74.14, 74.05, 72.16,
52.07; ESI-HRMS: m/z (M+Na)+ calcd. for C35H31NNaO6
+
584.2049, found: 584.2055.
[4] (a) Ohta, S.; Kimoto, S. Tetrahedron Lett. 1975, 2279; (b)
Ohta, S.; Kimoto, S. Chem. Pharm. Bull. 1976, 24, 2969; (c)
Ohta, S.; Kimoto, S. Chem. Pharm. Bull. 1976, 24, 2977; (d)
Paulsen, H.; Stubbe, M. Tetrahedron Lett. 1982, 23, 3171; (e)
Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535; (f)
Ugarkar, B. G.; DaRe, J.; Schubert, E. M. Synthesis 1987,
715; (g) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett.
1991, 32, 4525; (h) Chida, N.; Ohtsuka, M.; Ogawa, S. J. Org.
Chem. 1993, 58, 4441; (i) Hudlicky, T.; Olivo, H. F. J. Am.
Chem. Soc. 1992, 114, 9694; (j) Hudlicky, T.; Olivo, H. F.;
McKibben, B. J. Am. Chem. Soc. 1994, 116, 5108; (i) Martin,
S. F.; Tso, H.-H. Heterocycles 1993, 35, 85; (j) Keck, G. E.;
Wager, T. T. J. Org. Chem. 1996, 61, 8366; (k) Keck, G. E.;
Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999,
121, 5176; (l) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247
and Padwa, A.; Zhang, H. J. Org. Chem. 2007, 72, 2570; (m)
Matveenko, M.; Kokas, O. J.; Banwell, M. G.; Willis, A. C.
Org. Lett. 2007, 9, 3683; (n) Yadav, J. S.; Satheesh, G.;
Murthy, C. V. S. R. Org. Lett. 2010, 12, 2544; (o) Bera, S.;
Das, S. K.; Saha, T.; Panda, G. Tetrahedron Lett. 2015, 56,
(+)-Lycoricidine (1): To the stirred solution of above lactam
25 (32 mg) dissolved in dry DCM (2 mL) at 0 °C was added
BCl3 (0.4 mL, 1 M solution in DCM) under argon atmosphere
and stirring of the reaction mixture was continued at same
temperature for 4 h. After completion of reaction, methanol (2
mL) was added to the reaction mixture. Solvent evaporation
of reaction mixture at reduced pressure furnished a residue,
which was purified using silica gel column chromatography to
afford a pure compound (+)-lycoricidine 1 as a white solid in
55% yield (8 mg); Rf0.5 (1/4, MeOH/ DCM). m.p 220-223
22
°C; (lit4n. m.p 217-221 °C); [α]D +187 (c 0.50, pyridine);
[lit4n [α]D +180 (c 0.45, pyridine)]; IR (KBr): νmax =3380,
22
1
2923, 1712, 1643, 1470, 1396, 1129, 1032 cm-1; H NMR
(400 MHz, CD3OD): δ 7.39 (s, 1H), 7.15 (s, 1H), 6.15-6.17
(m, 1H), 6.05 (d, J = 1.0 Hz, 1H), 6.02(d, J = 1.0 Hz, 1H),,
4.34 (dd, J1=2.6, J2=8.5 Hz, 1H), 4.22 (dd, J1 =2.6, J2=4.8 Hz,
1H), 3.88-3.95 (m, 2H); 13C (100 MHz, CD3OD): δ 166.23,
153.24, 149.90, 133.88, 133.10, 124.08, 123.20, 108.62,
11

146; (p) Cai, S-L; Yuan, B-H; Jiang, Y-X; Lin, G-Q; Sun, X-
ACCEPTED MANUSCRIPT
W. Chem. Commun., 2017, 53, 3520-3523; (q) Kato, M.;
Yasui, K.; Yamanaka, M.; Nagasawa, K. Asian J. Org. Chem.
2016, 5, 380-388.
[5] (a) Saidhareddy, P.; Ajay, S.; Shaw, A. K. RSC Adv.,
2014, 4, 4253–4259; (b) Saidhareddy, P.; Shaw, A. K. RSC
Adv., 2015, 5, 29114–29120.
[6] (a) Sagar, R.; Reddy L. V. R.; Shaw, A. K. Tetrahedron
Asymmetry, 2006, 17, 1189-1198; (b) Sagar, R.; Reddy, L. V.
R.; Saquib, M.; Kumar, B.; Shaw, A. K.; Tetrahedron
Asymmetry, 2006, 17, 3294–3299; (c) Reddy, L. V. R.; Roy,
A. D.; Roy R.; Shaw, A. K. Chem. Commun., 2006, 3444–
3446; (d) Husain, I.; Saquib, M.; Kumar, V.; Kumar, B.;
Shaw, A. K. J. Org. Chem. 2011, 76, 8930-8943.
[7] (a) Arora, I.; Kashyap, V. K.; Singh, A. K.; Dasgupta, A.;
Kumar, B. and Shaw, A. K. Org. Biomol. Chem., 2014, 12,
6855; (b) Das, P.; Kundooru, S.; Pandole, R.; Sharma, S. K.;
Singh, B. N. and Shaw, A. K. Tetrahedron: Asymmetry 2016,
27, 101; (c) Das, P.: Ajay, S.; Shaw, A. K. Tetrahedron Lett.
2017, 58, 419; (d) Das, P.: Ajay, S.; Shaw, A. K. Synthesis
2016, 48, 3753; (e) Ajay, S.; Saidhareddy, P.; Shaw, A. K.
Synthesis 2016, 48, 1191; (f) Ajay, S.; Arora, I.; Saidhareddy,
P.; Shaw, A. K. Synlett 2016, 27, 2721; (g) Arora, I.; Sharma,
S.; Shaw, A. K. RSC Adv., 2016, 6, 13014.
[8] a) Banwell, M. G.; Cowden, C. J.; Gable, R. W. J. Chem.
Soc. Perkin Trans. 1994, 1, 3515; b) Banwell, M. G.; Bisset,
B. D.; Busato, S.; Cowden, C. J.; Hockless, D. C. R.; Holman,
J. W.; Read, R. W.; Wu, A. W. J. J. Chem. Soc. Chem.
Commun. 1995, 2551.
[9] Lee, J. C.; Francis, S.; Dutta, D.; Gupta, V.; Yang, Y.;
Zhu, J-Y.; Tash, J. S.;Schonbrunn, E.; Georg, G. I. J. Org.
Chem., 2012, 77, 3082-3098.
[10] Miller, J. N.; Pongdee, R. Tetrahedron Lett. 2013, 54,
3185–3187.
[11] Imuta, S.; Tanimoto, H.; Momose, M. K.; Chida, N.
Tetrahedron 2006, 62, 6926-6944.
[12] Kumar, V.; Das, P.; Ghosal, P.; Shaw, A. K.
Tetrahedron, 2011, 67, 4539-4546.
[13] Taber, D. F.; Berry, J. F. J. Org. Chem. 2013, 78,
8437−8441.
[14] (a) Felpin, F-X. J. Org. Chem. 2005, 70, 8575-8578; (b)
Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun.
1979, 866−867.
[15] (a) Honzumi, M.; Taniguchi, T.; Ogasawara, K. Org.
Lett. 2001, 3, 1355-1358; (b) Stereochemistry of the newly
formed -center (C4) in 7 was established by its detailed 2D
NMR spectroscopy studies (COSY, NOESY).
[16] (a) Matveenko, M.; Willis, A. C.; BanwellL. M. G. Aust.
J. Chem. 2009, 62, 64–68; (b) Overman, E.; Carpenter, N. E.
Org. React. 2005, 66, 1; (c) Kürti, L.; Czakó, B. Strategic
Applications of Named Reactions in Organic Synthesis 2005,
pp. 322–333 (Elsevier Academic Press: Burlington, MA); (d)
Danishefsky, S.; Lee, J. Y. J. Am. Chem, Soc. 1989, 111,
4829-4837.
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