Concise Total Syntheses of (±)-Joubertiamine, (±)- O -Methyljoubertiamine, (±)-3′-Methoxy-4′- O -methyljoubertiamine, (±)-Mesembrane, and (±)-Crinane

Article abstract of DOI:10.1055/s-0035-1561583

A method to access cis-3a-aryloctahydroindole alkaloids has been developed through a key strategy involving Eschenmoser-Claisen rearrangement of allylalcohol. This approach gives us an opportunity to access the all-carbon quaternary center required for ci

Full text of DOI:10.1055/s-0035-1561583

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
M. K. Das et al.
Paper
Synthesis
Concise Total Syntheses of (±)-Joubertiamine, (±)-O-Methyl-
joubertiamine, (±)-3′-Methoxy-4′-O-methyljoubertiamine,
(±)-Mesembrane, and (±)-Crinane
R
Mrinal Kanti Das
Me
NMe2
+
Subhadip De
Shubhashish
Alakesh Bisai*
MeO OMe
(DMA-DMA)
R = 4-OMe, (
R = 3,4-(OMe)2, (
R–R = 3,4-OCH2O-, (
)
)
OH
)
MeO
Eschenmoser–Claisen
rearrangement
OMe
H
H
Department of Chemistry, Indian Institute of Science
Education and Research Bhopal, Bhopal Bypass Road,
Bhauri, Bhopal 462 066, Madhya Pradesh, India
alakesh@iiserb.ac.in
H
OR
R
N
Me
(
)-mesembrane
and
NMe2
NMe2
O
O
H
O
H
N
O
R = 4-OMe
R = 3,4-(OMe)2
R–R = 3,4-OCH2O
R = H; ( )-joubertiamine
R = Me; ( )-O-methyl-
joubertiamine
H
(
)-crinane
Received: 26.12.2015
Accepted after revision: 22.02.2016
Published online: 18.03.2016
groups: seco-mesembrane alkaloids (1), such as jouberti-
amine (1a),1 O-methyljoubertiamine (1b), 3′-methoxy-4′-
O-methyljoubertiamine (1c), and dihydrojoubertiamine
(1d), and cis-3a-aryloctahydroindole alkaloids (2)2 such as
mesembrane (2a), mesembranol (2b), mesembrine (2c).2
The common structural feature of these classes of alka-
loids is the presence of an all-carbon quaternary stereocen-
ter;3 hence, it is quite reasonable to believe that they origi-
nated through a common biosynthetic pathway.4 In addi-
tion to their interesting architecture, the cis-3a-
aryloctahydroindole skeleton constitutes the core structure
of many alkaloids with impressive diversity of biological ac-
tivities.4 Their biological potential was significantly mani-
fested by their antiviral, antitumor, anticholinergic and
anti-HIV properties.5 Therefore, in recent years consider-
able effort has been directed toward the synthesis of Scele-
tium alkaloids.1
DOI: 10.1055/s-0035-1561583; Art ID: ss-2015-z0741-op
Abstract A method to access cis-3a-aryloctahydroindole alkaloids has
been developed through a key strategy involving Eschenmoser–Claisen
rearrangement of allylalcohol. This approach gives us an opportunity to
access the all-carbon quaternary center required for cis-3a-aryloctahy-
droindole alkaloids. Subsequent simple allylic oxidation of Eschenmos-
er–Claisen products and synthetic elaborations (reductions/oxidations)
enabled the total syntheses of the title compounds to be completed in
good yields in a few steps. The strategic viability was further tested in
the total syntheses of Amaryllidaceae alkaloids (±)-mesembrane and
(±)-crinane. Towards this end, we synthesized advanced intermediate
keto-aldehydes from Eschenmoser–Claisen rearrangement products
through iodolactonization followed by elaboration involving reduction
and oxidation steps.
Keywords Eschenmoser–Claisen rearrangement, all-carbon quaterna-
ry centers, allylic oxidation, alkaloids
The alkaloids of the Amaryllidaceae family (Figure 2)
also have interesting architecture with an all-carbon qua-
ternary stereocenter.6 These alkaloids drew the attention of
the synthetic community because of their intriguing physi-
ological activities.7 Plants belonging to the Amaryllidaceae
family are herbaceous perennials that grow from bulbs. The
Sceletium alkaloids1 of the family Aizoaceae (1a–d and
2a–c; Figure 1) represent an interesting class of alkaloids
with an all-carbon quaternary stereocenter. Most of the
bases that have been characterized belong to two different
OMe
OH
OR
OMe
MeO
MeO
MeO
OMe
OMe
OMe
H
H
O
H
H
H
H
HO
NMe2
NMe2
N
N
N
NMe2
Me
Me
Me
O
O
O
R = H; joubertiamine (1a)
R = Me; O-methyljouber-
tiamine (1b)
3'-methoxy-4'-O-methyl- dihdrojoubertiamine (1d)
joubertiamine (1c)
(+)-mesembrane (2a)
(+)-mesembranol (2b)
(+)-mesembrine (2c)
Figure 1 Selected seco-mesembrane 1a–d and mesembrane 2a–c alkaloids
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. K. Das et al.
Paper
Synthesis
OH
O
OR
O
OMe
OMe
MeO
H
H
HO
HO
H
H
H
H
OH
H
O
O
OH
O
O
H
OR
H
OMe
R
H
N
N
N
N
N
Me
N
Me
OH
(+)-haemanthamine (3e)
H
O-methylnorbelladine (5)
R = H; (+)-crinane (3a)
R = OH; (+)-elwesine (3b)
R = -CH2-; (+)-crinine (3c)
R = Me; (+)-maritidine (3d)
(−)-galanthamine (4a)
(−)-lycoramine (4b)
Figure 2 The Amaryllidaceae alkaloids 3a–e and 4a–b, and biosynthetic precursor, O-methylnorbelladine (5)
family consists of about 60 genera, whose 800 species are
widely distributed in several countries around the world.
They are also cultivated as ornamental plants for their
beautiful flowers and for the production of volatile oil.
Among all Amaryllidaceae alkaloids, the crinine-type alka-
loids, which have the 5,10b-ethanophenanthridine skeleton
as the core structure, represented by crinane 3a, elwesine
3b, crinine 3c, martidine 3d, and haemanthamine 3e, have
received considerable attention, since they have been re-
ported to possess antiviral, and anticancer activities (Figure
2).8 These activities, together with their intriguing struc-
tures, have brought a major impetus for synthetic explora-
tion in this direction from organic chemists across the
globe.
Biogenetically, crinane (3a) type alkaloids are closely re-
lated to other major Amaryllidaceae family natural prod-
ucts, such as galanthamine 4a and lycoramine 4b, as they
are all derived from the same precursor O-methylnorbella-
dine 5 (Figure 2).9 These alkaloids display vicinal quaterna-
ry and tertiary carbon stereocenters3 with a fused pyrroli-
dine ring, as common structural features, the stereochemi-
cal incorporation of which is indeed a challenge. Several
approaches have been developed to synthesize this skele-
ton, which includes a quaternary carbon.10 The incorpora-
tion of this sterically congested quaternary center is the
critical element in the total synthesis of crinine-type alka-
loids, and a number of synthetic approaches have emerged
to solve this challenging problem.11
Recently, we envisaged a strategy to access alkaloids
having the cis-3a-aryloctahydroindole skeleton with a steri-
cally congested quaternary carbon center located at the hy-
droindolone bridgehead (C-3a) position.12 Herein, we delin-
eate a unified approach to the seco-mesembrane alkaloids
1a–c, mesembrane alkaloids 2a, and crinane alkaloids 3a
through a key Eschenmoser–Claisen rearrangement of allyl-
ic alcohol of type 7 (Scheme 1), which permits an iodolac-
tonization process for the divergent introduction of a range
of functionality to address the total synthesis of several
congeners of this family.
Structurally, Sceletium alkaloids of seco-mesembrane
and mesembrane classes of alkaloids (see 1 and 2, Figure 1)
have an interesting all-carbon quaternary stereocenter,1,2
whereas Amaryllidaceae alkaloids, with a 5,10b-ethano-
phenanthridine skeleton (3a–e, Figure 2), possess a struc-
ture that may be regarded as a carbocyclic six-membered
ring, an appended aryl substituent, and a five-membered,
nitrogen-containing ring annulated onto a carbocyclic six-
membered ring.
We hypothesized that an Eschenmoser–Claisen rear-
rangement of 3-(4-methoxyphenyl)cyclohex-2-enol (7a), 3-
(3,4-dimethoxyphenyl)cyclohex-2-enol (7b), and 3-(3,4-
methylenedioxyphenyl)cyclohex-2-enol (7c) could be an
excellent strategic platform to install the all-carbon quater-
nary stereocenter required for a unified strategy for the
construction of Sceletium and Amaryllidaceae alkaloids
shown in Figure 1 and Figure 2. Our retrosynthetic analysis
is shown in Scheme 1. A simple allylic oxidation of products
from Eschenmoser–Claisen rearrangement (6a–c) can pro-
vide a simple route to the complete skeleton of seco-
mesembrane alkaloids (Scheme 1).
Retrosynthetically, we also thought that the advanced
intermediate ketoaldehydes 9a and 9b would lead to a uni-
fied pathway to access both mesembrane (2a) and crinane
(3a) type alkaloids (Scheme 1). Ketoaldehydes 9a and 9b
could be synthesized from a complete reduction of iodolac-
tones 10a and 10b, respectively, which could be accessed
from iodolactonization13 of dimethylamides 6b and 6c. The
latter can be accessed from Eschenmoser–Claisen rear-
rangement14 of 3-(aryl)cyclohex-2-enols 7a–c (Scheme 1).
At this stage we hypothesized that, because [3,3]-sigma-
tropic rearrangements follow a completely stereospecific
reaction, enantioenriched 3-(aryl)cyclohex-2-enols 7a–c
would easily allow our approach to be conducted in an
asymmetric manner. Compounds 7a–c can be obtained
from the reduction of 3-aryl-2-cyclohexenones 8a–c,
which, in turn, can be obtained from vinylogous ester 11
through a well-known Stork–Danheiser sequence.15
Moving forward with our proposed strategy, our first
task was to synthesize 3-(aryl)cyclohex-2-enols (±)-7a–c
required for the Eschenmoser–Claisen rearrangement. To-
wards this, we carried out the Stork–Danheiser sequence
on compound 11 by using arylmagnesium bromides to af-
ford 3-aryl-2-cyclohexenones 8a–c in 73–85% yields
(Scheme 2). The latter were then reduced under Luche re-
duction16 to access 3-(aryl)cyclohex-2-enols (±)-7a–c in
92–96% yields. With allyl alcohols 7a–c in hand, we sought
conditions to effect the key [3,3]-sigmatropic rearrange-
ment for the synthesis of 1-dimethylacetamide-1-aryl-2-
cyclohexenes 6a–c (Table 1), with an all-carbon quaternary
stereocenter. Eschenmoser–Claisen rearrangement17,18 of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. K. Das et al.
Paper
Synthesis
OMe
OMe
OMe
R = H;
joubertiamine (1a)
R = Me;
O-methyl-
joubertiamine (1b)
NMe2
OH
O
O
6a
7a
8a
OR
OR
OR
OR
OR
OR
3'-methoxy-4'-methyl-
joubertiamine (1c)
NMe2
OH
R = Me, 7b
O
O
R = Me, 6b
R–R = -CH2-, 6c
R = Me, 8b
R–R = -CH2-, 8c
R–R = -CH2-, 7c
OR
OR
OR
OR
( )-mesembrane (2a)
( )-crinane (3a)
R = Me, 6b
R–R = -CH2-, 6c
O
O
O
O
I
R = Me, 9a
R = Me, 10a
R–R = -CH2-, 9b
R–R = -CH2-, 10b
Scheme 1 Retrosynthetic analysis of (±)-1a–c, (±)-2a, and (±)-3a
N,O-ketene acetals is a fundamental concerted process that
yields γ,δ-unsaturated amides, which are of great use in
natural product synthesis.19 This process allows the forma-
tion of a carbon–carbon bond at the β-position to a nitro-
gen atom of N,O-ketene acetals.
At the outset, we started optimization of Eschenmoser–
Claisen rearrangement by using 3-(3,4-dimethoxyphe-
nyl)cyclohex-2-enol (7b) as a model substrate with the di-
methyl acetal of dimethylacetamide (DMA-DMA) in differ-
ent solvents under reflux; the results are summarized in Ta-
R
R
O
OMe
CeCl3.7H2O
OMe
ArMgBr
THF, 0 °C, 12 h
NaBH4, MeOH
O
92–96%
73–85%
OH
O
11
R = H, 8a; 85%
R = H, 7a; 92%
R = OMe, 8b; 73%
R = OMe, 7b; 96%
O
O
O
O
O
CeCl3.7H2O
ArMgBr
THF, 0 °C, 12 h
NaBH4, MeOH
O
96%
85%
OH
O
11
8c
7c
Scheme 2 Synthesis of 3-(aryl)cyclohex-2-enols (±)-7a–c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

D
M. K. Das et al.
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Synthesis
ble 1. Preliminary studies indicate that two equivalents of
dimethylacetal of DMA-DMA in different solvents furnished
product 6b in only 26–49% yields (entries 1–3). After ex-
haustive optimization, it was observed that six equivalents
of DMA-DMA was also not sufficient for optimal conditions
(up to 53% of 6b was obtained) when reactions were carried
out in toluene, xylene, or mesitylene (entries 4–6). By in-
creasing the amount of DMA-DMA to 10 equivalents, it was
observed that 6b could be obtained in maximum 73% yields
in mesitylene heated to reflux (entries 7–9).
Gratifyingly, it was seen that Eschenmoser–Claisen rear-
rangement of 7b could be effected smoothly at 180 °C with-
out any solvent to give 6b in 92% yield (Table 1, entry 10).
Under these conditions, 3-(aryl)cyclohex-2-enols (±)-7a
and (±)-7c also afforded products in 90 and 83% isolated
yields, respectively (entries 11 and 12). However, use of an
excess (10 equiv) of DMA-DMA in Eschenmoser–Claisen re-
arrangement of 7b under heating led us to consider the use
of a microwave-assisted reaction as an alternative method.
Table 1 Optimization of Eschenmoser–Claisen Rearrangement of 3-(3,4-Dimethoxy)cyclohex-2-enols (±)-7ba
R
R
solvent, temp.
time
Me
NMe2
+
MeO OMe
DMA-DMA
up to 92% yield
NMe2
OH
O
R = 4-OMe, ( )-7a
R = 3,4-(OMe)2, ( )-7b
R–R = 3,4-OCH2O-, ( )-7c
R = 4-OMe, ( )-6a
R = 3,4-(OMe)2, ( )-6b
R–R = 3,4-OCH2O-, ( )-6c
Entry
7
DMA-DMA (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7a
7c
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7a
7b
7c
2
2
toluene
xylene
110
24
26 (6b)c
42 (6b)c
49 (6b)c
47 (6b)c
50 (6b)c
53 (6b)
61 (6b)
66 (6b)
73 (6b)
92 (6b)
90 (6a)
83 (6c)
65 (6a)
81 (6a)
74 (6a)
92 (6a)
89 (6a)
72 (6a)
74 (6a)
63 (6a)
87 (6b)
89 (6c)
71 (6a)
74 (6b)
69 (6a)
130
24
3
2
mesitylene
toluene
xylene
150
24
4
6
110
16
5
6
130
16
6
6
mesitylene
toluene
xylene
150
16
7
10
10
10
10
10
10
5
110
12
8
130
12
9
mesitylene
–
150
12
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
180
12
–
180
12
–
180
12
toluene
xylene
110 (MW)
140 (MW)
170 (MW)
200 (MW)
200 (MW)
200 (MW)
200 (MW)
200 (MW)
200 (MW)
200 (MW)
200
10 min
20 min
15 min
10 min
15 min
15 min
15 min
30 min
10 min
10 min
2
5
5
mesitylene
xylene
5
5
mesitylene
xylene
3
3
mesitylene
xylene
2
5
xylene
5
xylene
5
xylene
5
xylene
200
2
5
xylene
200
2
a Reaction was conducted with (±)-7a–b (0.25 mmol) and solvent (2 mL) unless noted otherwise.
b Isolated yield after column chromatography.
c (±)-7b was recovered in 28–37%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
M. K. Das et al.
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Synthesis
Towards this, we continued our optimization of the
Eschenmoser–Claisen rearrangement by using 3-(4-meth-
oxyphenyl)cyclohex-2-enol (7a) as model substrate in a mi-
crowave-assisted process in different solvents (Table 1, en-
tries 13–22). The use of five equivalents DMA-DMA was
sufficient to afford 6a in 92% yield in only 10 minutes at
200 °C in xylene (entries 13–17). However, it was observed
that reducing the amount of DMA-DMA led to a drop in the
isolated yield of 6a to 74 and 63% when three and two
equivalents of DMA-DMA, respectively, was used (entries
19 and 20). Under the optimized conditions, allylalcohols
7b and 7c afforded products 6b and 6c, respectively, in 87–
89% yields (entries 21 and 22).
Having accomplished the synthesis of (±)-6a–c, we at-
tempted to manipulate the cyclohexene double bond to-
ward the synthesis of more decorated cyclohexenones
(Scheme 3). For this purpose, we carried out allylic oxida-
tions of the intermediate (±)-6a with pyridinium dichro-
mate (PDC) in the presence of tert-butyl hydroperoxide to
afford enone (±)-12a in 86% yield, which, on subsequent
lithium aluminum hydride mediated reduction, provided
(±)-13a in 90% yield with approximately 1:1 diastereomeric
ratio.20 Manganese dioxide mediated oxidation of allylalco-
hol (±)-13a completed the total synthesis of (±)-O-methyl-
joubertiamine (±)-1b in 63% yield, from which the total
synthesis of (±)-joubertiamine (±)-1a was accomplished in
88% yield by treatment with BBr3 (Scheme 3).
Along similar lines, PDC oxidation21 of (±)-6b,c afforded
enones (±)-12b,c in 60–62% yield, which, on subsequent re-
duction using lithium aluminum hydride provided allylal-
cohols (±)-13b,c in 80–87% yield with approximately 1:1 dr
(Scheme 4). The latter were then oxidized with MnO2 to
complete the total synthesis of 3′-methoxy-4′-O-methyl-
joubertiamine (±)-1c and related structure (±)-14 in 67–
75% yields.
We then turned our attention to the total syntheses of
(±)-mesembrane (±)-2a and (±)-crinane (±)-3a; for these it
was required to functionalize the 2-position of the cyclo-
hexene ring of (±)-6b,c. Towards this end, iodolactonization
of 1-dimethylacetamido-1-aryl cyclohexenes (±)-6b,c in
the presence of iodine in a mixture of THF and water pro-
vided iodolactone intermediates (±)-10a,b in 85–86% yield
(Scheme 5). Iodolactones (±)-10a,b, upon treatment with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base, fur-
nished alkenes (±)-15a,b in excellent yields. The latter could
be used as advanced intermediates for the synthesis of a va-
riety of Amaryllidaceae alkaloids. However, for the total
synthesis of (±)-mesembrane (2a) and (±)-crinane (3a),
γ-keto aldehydes (±)-9a,b were required. Towards this end,
iodolactones (±)-10a,b were reduced in the presence of
OMe
OMe
OMe
PDC, tBuOOH
PhH, r.t., 18 h
LiAlH4, THF
80 °C, 20 h
90%
dr 1:1
86%
NMe2
NMe2
NMe2
O
HO
O
O
( )-6a
( )-12a
( )-13a
OMe
OH
BBr3, CH2Cl2
–78 °C, 1 h
MnO2, CH2Cl2
r.t., 16 h
( )-13a
NMe2
88%
63%
NMe2
O
O
( )-O-methyljoubertiamine (1b)
( )-joubertiamine (1a)
Scheme 3 Total synthesis of (±)-O-methyljoubertiamine (1b) and (±)-joubertiamine (1a)
OR
OR
OR
OR
OR
OR
PDC, tBuOOH
PhH, r.t., 18 h
OR
OR
LiAlH4, THF
80 °C, 20 h
MnO2, CH2Cl2
r.t., 16 h
80–87%
dr 1:1
67–75%
60–62%
NMe2
NMe2
NMe2
NMe2
O
O
HO
O
O
R = Me, ( )-6b
R–R = -CH2-, ( )-6c
R = Me, ( )-12b
R–R = -CH2-, ( )-12c
R = Me, ( )-13b
R–R = -CH2-, ( )-13c
R = Me, ( )-3'-methoxy-4'-O-methyl-
joubertiamine ( )-1c
R–R = -CH2-, ( )-14
Scheme 4 Total syntheses of 3′-methoxy-4′-O-methyljoubertiamine (1c) and related structure 14
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. K. Das et al.
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Synthesis
OR
OR
OR
OR
OR
OR
I2, THF–H2O
(1:1), 60 °C, 4 h
DBU, PhMe
110 °C, 5 h
92–94%
85–86%
O
O
NMe2
O
O
O
I
R = Me, ( )-6b
R = Me, ( )-10a; 86%
R = Me, ( )-15a; 94%
R–R = -CH2-, ( )-6c
R–R = -CH2-, ( )-10b; 85%
R–R = -CH2-, ( )-15b; 92%
LiAlH4, THF
70 °C, 12 h
90–92%
OR
OR
OR
(COCl)2, DMSO
Et3N, CH2Cl2,
OR
–78 °C to r.t., 1 h
89–92%
OH
O
OH
O
R = Me, ( )-16a; 90%
R–R = -CH2-, ( )-16b; 92%
R = Me, ( )-9a; 89%
R–R = -CH2-, ( )-9b; 92%
Scheme 5 Synthesis of keto aldehydes (±)-9a,b
Table 2 Optimization of Reductive Amination of (±)-9aa
LiAlH4 to afford 1,4-diols (±)-16a,b in quantitative yield
(Scheme 5). Among various oxidation procedures investi-
gated to synthesize γ-keto aldehydes (±)-9a,b, we found
that Swern oxidation22 of 1,4-diols (±)-16a,b afforded (±)-
9a,b in the highest yield (89–92%; Scheme 5). Optimization
studies were further conducted to carry out reductive ami-
nation of model γ-keto aldehyde (±)-9a to complete the to-
tal synthesis of (±)-mesembrane (2a). The optimization
studies are summarized in Table 2. Initially, reductive ami-
nation of (±)-9a was carried out in the presence of two
equivalents of ammonium acetate and four equivalents of
sodium cyanoborohydride in solvents such as MeOH, EtOH,
and THF in the presence of one equivalent of trifluoroacetic
acid and acetic acid.
To our delight, we found that cis-3a-aryloctahydroin-
dole (±)-17a could be obtained in 32–89% isolated yields
(Table 2, ). Following further optimization, we were pleased
to find that secondary amine (±)-17a could be obtained in
83–85% yields when reductive amination was carried out in
the presence of only 10 mol% of each trifluoroacetic acid
(TFA) and acetic acid (AcOH) (entries 7 and 8). Gratifyingly,
on further reducing the amount of catalyst to 5 mol%, we
found that cis-3a-aryloctahydroindole (±)-17a could be ob-
tained in 82–84% in the presence of 5 mol% of each TFA and
AcOH, respectively (entries 9 and 10), whereas, 2 mol% of
each TFA and AcOH afforded cis-3a-aryloctahydroindole
(±)-17a in 69–71% in one day (entries 11 and 12).
OMe
MeO
OMe
protic acid
OMe
+ NaBH3CN
+ NH4OAc
solvent, 25 °C
time
H
O
N
H
O
(
)-9a
(
)-17
Entry
Acid
Solvent
Time (h)
Yield (%)b
1
TFA (1 equiv)
AcOH (1 equiv)
TFA (1 equiv)
AcOH (1 equiv)
TFA (1 equiv)
AcOH (1 equiv)
TFA (10 mol%)
AcOH (10 mol%)
TFA (5 mol%)
MeOH
MeOH
EtOH
MeOH
THF
12
12
10
10
18
18
16
16
19
19
24
24
72
75
89
88
35
32
83
85
84
82
69
71
2
3
4
5
6
THF
7
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
8
9
10
11
12
AcOH (5 mol%)
TFA (2 mol%)
AcOH (2 mol%)
a Reaction conditions: (±)-9a (0.20 mmol), NH4OAc (2.0 equiv), NaBH3CN
(4.0 equiv), solvent (2 mL), 0–25 °C, inert atmosphere.
b Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

G
M. K. Das et al.
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Synthesis
RO
RO
RO
OR
ClCOOMe
NaHCO3
OR
CbzCl
NaHCO3
OR
H
H
H
O
79–85%
82–83%
O
N
N
N
H
OBn
OMe
R = Me, ( )-18a
R–R = -CH2-, ( )-19a
R = Me, ( )-17a
R–R = -CH2-, ( )-17b
R = Me, ( )-18b
R–R = -CH2-, ( )-19b
LiAlH4, THF
61–64%
LiAlH4, THF
79–85%
70 °C, 12 h
70 °C, 12 h
RO
RO
OR
OR
H
H
N
Me
N
Me
R = Me, ( )-2a; mesembrane
R–R = -CH2-, ( )-20
R = Me, ( )-2a; mesembrane
R–R = -CH2-, ( )-20
Scheme 6 Total synthesis of (±)-mesembrane (2a)
Continuing our studies, carbamates (±)-18a,b were syn-
thesized in 82–85% yields from cis-3a-aryloctahydroindole
(±)-17a by treatment with chloromethylformate and benzyl
chloroformate in the presence of NaHCO3 (Scheme 6).
In fact, carbamates (±)-18a,b could serve as potential
precursors for the synthesis of the tricyclic core with addi-
tional amide functionality (see Scheme 6, red arrows) relat-
ed to many Amaryllidaceae alkaloids (3a–c; Figure 2)
through a Bischler–Napieralski type process.23 For the total
synthesis of (±)-mesembrane (±)-2a, we then carried out
LiAlH4-mediated reduction of carbamates (±)-18a,b to af-
ford (±)-2a in 64–79% yield (Scheme 6).
A similar reductive amination was carried out with
γ-keto aldehyde (±)-9b in the presence of 10 mol% of each
TFA and AcOH, which afforded cis-3a-aryloctahydroindole
(±)-17b in 84–88% yield in 24 hours (Scheme 7). As found
for the earlier case, reductive amination of γ-keto aldehyde
(±)-9b also afforded (±)-17b in 84–88% yield in 24 hours
only in the presence of 5 mol% of each TFA and AcOH
(Scheme 7). Similar to carbamates (±)-18a,b, carbamates
(±)-19a,b were also synthesized in 79–83% yields from (±)-
17b by treatment with chloromethylformate and benzyl
chloroformate in the presence of NaHCO3, which, on reduc-
tion using LiAlH4, afforded cis-3a-aryloctahydroindole (±)-
20 in 61–85% (Scheme 6). However, for a direct total syn-
thesis of (±)-mesembrane 2a from γ-keto aldehyde (±)-9a,
reductive amination was carried out using methylamine
with sodium cyanoborohydride (NaBH3CN) in the presence
of protic acids such as TFA and AcOH. Thus, the total syn-
thesis of (±)-mesembrane (±)-2a was accomplished in 79–
88% yield (Scheme 8). Along similar lines, we also synthe-
sized cis-3a-aryloctahydroindole (±)-20 in 78–91% isolated
yields.
OMe
MeO
OMe
OMe
protic acid, EtOH
0–25 °C
H
NaBH3CN
MeNH2
+
+
79–88%
O
N
Me
(
O
(
)-9a
( )-2a
)-mesembrane
10 mol% AcOH: 86%
10 mol% TFA: 88%
5 mol% AcOH: 79%
5 mol% TFA: 80%
O
O
O
O
O
O
H+, EtOH
O
O
protic acid, EtOH
H
0–25 °C, 24 h
NaBH3CN
NH4OAc
+
+
0–25 °C
H
NaBH3CN
MeNH2
+
+
84–88%
78–91%
O
O
N
N
H
Me
O
O
(
)-17b
(
)-9b
(
)-9b
( )-20
10 mol% AcOH: 84%
10 mol% TFA: 88%
5 mol% AcOH: 81%
5 mol% TFA: 83%
10 mol% AcOH: 87%
10 mol% TFA: 91%
5 mol% AcOH: 78%
5 mol% TFA: 82%
Scheme 7 Reductive amination of (±)-9b
Scheme 8 Total synthesis of (±)-mesembrane (2a)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

H
M. K. Das et al.
Paper
Synthesis
let), q (quartet), m (multiplet), br (broad). IR spectra were recorded
with a FT-IR system (Spectrum BX) and are reported in frequency of
absorption (cm–1). Only selected IR absorbencies are reported. High-
resolution mass spectrometry (HRMS) data were recorded with a
MicrOTOF-Q-II (Bruker) mass spectrometer using MeOH as solvent.
O
O
O
THF
40 °C, 30 h
H
(
H
O
N
+
I
72%
N
N
H
(
)-17b
)-crinane (3a)
Stork–Danheiser Sequence Followed by Luche Reduction of Vinyl-
ogous Esters; General Procedure
Scheme 9 Total synthesis of (±)-crinane (±)-3a
A flame-dried round-bottom flask was charged with vinylogous ester
11 (20.0 mmol, 1.0 equiv) and anhydrous THF (30 mL) and cooled to
0 °C. To this solution, aryl magnesium bromide (24.0 mmol, 1.2 equiv)
in anhydrous THF (20 mL) was added dropwise over 10 min by using a
syringe. After stirring for 6–8 h at r.t., the reaction was quenched by
the addition of 1 M HCl (20 mL) at 0 °C. The reaction mixture was
stirred and warmed to r.t. over 3 h, then neutralized by the addition
of sat. aq NaHCO3. The resulting mixture was extracted with EtOAc
(4 × 30 mL) and the combined organic layers were dried over Na2SO4
and concentrated under vacuum. The crude product was purified by
flash chromatography (hexanes–EtOAc) to give 3-arylcyclohexenone
8.
We then shifted our attention to developing a concise
synthesis of (±)-crinane (±)-3a. Towards this end, a variety
of conditions were investigated to affect Pictet–Spengler re-
actions with formalin, paraformaldehyde, and 1,3,5-triox-
ane without success. Finally, cis-3a-aryloctahydroindole
(±)-17b was reacted with Eschenmoser’s salt (N,N-dimeth-
ylmethyleneammonium iodide),11d in THF at 40 °C for 30
hours to complete the total synthesis of (±)-crinane (±)-3a
(Scheme 9).
In conclusion, we have described a general approach to
a number of Sceletium alkaloids of the family Aizoaceae and
the Amaryllidaceae alkaloids, featuring an Eschenmoser–
Claisen rearrangement as the key step to install the all-
carbon quaternary stereocenter. By utilizing the aforemen-
tioned strategy, we have demonstrated the total syntheses
of (±)-joubertiamine (1a), (±)-O-methyljoubertiamine (1b),
and (±)-3′-methoxy-4′-O-methyljoubertiamine (1c), and
Amaryllidaceae alkaloids mesembrane (2a) and crinane
(3a). We believe that this method could be extended to oth-
er structural types of Amaryllidaceae alkaloids. Importantly,
as allylic alcohols of type 7a–c could easily be accessed in
entioenriched form through either resolution or by em-
ploying CBS (Corey–Bakshi–Shibata) reduction,24 our strat-
egy could also be adapted to an enantioselective version.
Further application of the methodology described herein is
under investigation in our laboratories and will be reported
in due course.
In a round-bottom flask, 3-aryl-cyclohexenone 8 (20.0 mmol, 1.0
equiv) was dissolved in MeOH (40 mL), and CeCl3·7 H2O (8.94 g, 24.0
mmol, 1.2 equiv) was added. The reaction mixture was stirred at r.t.
for 15 min and then cooled to 0 °C. NaBH4 (912 mg, 24.0 mmol, 1.2
equiv) was then added over 15 min and the reaction mixture was
stirred. Upon completion (TLC, ca. 30 min) the reaction was quenched
with sat. aq NH4Cl (10 mL). After stirring vigorously for 30 min, the
solvent was removed under reduced pressure, H2O (20 mL) was added
and the crude reaction mixture was extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were washed with sat. aq NaCl
(20 mL), dried over Na2SO4, and concentrated under reduced pressure.
The crude product was purified by flash chromatography to provide
allylic alcohol 7.
4′-Methoxy-3,4,5,6-tetrahydro-[1,1′-biphenyl]-3-ol [(±)-7a]
Yield: 3.2 g (78% yield over two steps); white solid; mp 59–60 °C; Rf =
0.35 (EtOAc–hexane, 30%).
IR (film): 3390, 3035, 2999, 2933, 2051, 1887, 1606, 1574, 1505,
1454, 1343, 1279, 1250, 1181, 1037, 911 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.8 Hz, 2 H), 6.81 (d, J =
8.8 Hz, 2 H), 6.03–6.02 (m, 1 H), 4.33 (d, J = 3.5 Hz, 1 H), 3.75 (m, 3 H),
2.77 (br s, 1 H), 2.39–2.25 (m, 2 H), 1.92–1.84 (m, 2 H), 1.70–1.58 (m,
2 H).
13C NMR (100 MHz, CDCl3): δ = 159.0, 139.0, 133.9, 126.4, 125.2,
113.7, 66.3, 55.2, 31.7, 27.5, 19.6.
Chemicals and reagents were purchased from commercial sources
and used without further purification. Unless otherwise stated, reac-
tions were performed in oven-dried glassware fitted with rubber sep-
ta under an inert atmosphere and were stirred with Teflon-coated
magnetic stirring bars. THF and toluene were distilled over sodi-
um/benzophenone ketyl. Dichloromethane, chloroform, and dichlo-
roethane were distilled over calcium hydride. All other solvents such
as DMF, MeCN, and MeOH were used as received. Thin-layer chroma-
tography was performed using Silicagel 60 F-254 precoated plates
(0.25 mm) and visualized by UV irradiation, anisaldehyde stain, and
other stains. Silicagel of particle size 100–200 mesh was used for
flash chromatography. 1H and 13C NMR spectra were recorded with
400, 500 MHz spectrometers (Bruker) with 13C operating frequencies
of 100, 125 MHz, respectively. Chemical shifts (δ) are reported in ppm
relative to the residual solvent (CDCl3) signal (δ = 7.26 ppm for 1H and
δ = 77.0 ppm for 13C). Data for 1H NMR spectra are reported as fol-
lows: chemical shift (multiplicity, coupling constants, number of hy-
drogen). Abbreviations are as follows: s (singlet), d (doublet), t (trip-
Microwave-Assisted Eschenmoser–Claisen Rearrangement; Gener-
al Procedure
Alcohol (±)-7 (generally in 0.25 mmol scale, 1.0 equiv) was charged
with N,N-dimethylacetamide dimethyl acetal (183 μL, 1.25 mmol, 5.0
equiv) and p-xylene (2 mL) in a sealed tube at r.t. After sealing, the
reaction mixture was heated under microwave irradiation for 10 min
(power = 300 W, ramp time = 6 min, ramp to temperature = 200 °C,
hold time = 4 min, stirring high). After 10 min, the reaction mixture
was concentrated under reduced pressure and purified by flash col-
umn chromatography to give amide 6.
2-(4′-Methoxy-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-N,N-di-
methylacetamide [(±)-6a]
Yield: 63 mg (92%); yellow gel; Rf = 0.25 (EtOAc–hexane, 50%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. K. Das et al.
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IR (film): 2930, 2835, 2056, 1888, 1634, 1502, 1394, 1249, 1183,
1139, 1035, 982, 827, 745 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.8 Hz, 2 H), 6.78 (d, J =
8.8 Hz, 2 H), 6.13 (dd, J = 1.9, 10.3 Hz, 1 H), 5.83 (td, J = 3.5, 10.2 Hz,
1 H), 3.72 (s, 3 H), 2.77 (s, 3 H), 2.70 (s, 3 H), 2.64 (t, J = 11.0 Hz, 1 H),
2.04–1.86 (m, 4 H), 1.57–1.49 (m, 1 H), 1.37–1.27 (m, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 1.0, 10.3 Hz, 1 H), 6.78 (s,
1 H), 6.73 (s, 2 H), 6.12 (d, J = 10.3 Hz, 1 H), 5.92 (s, 2 H), 2.90 (s, 3 H),
2.84 (s, 3 H), 2.40–2.30 (m, 2 H), 2.28–2.14 (m, 2 H), 1.52–1.43 (m,
1 H), 1.40–1.37 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 199.1, 169.5, 156.1, 148.0, 146.3,
137.1, 128.8, 119.7, 108.2, 106.9, 101.2, 44.0, 42.9, 37.6, 36.3, 35.5,
34.4.
.
13C NMR (100 MHz, CDCl3): δ = 170.7, 157.5, 139.6, 133.3, 127.8,
127.7, 113.3, 55.1, 45.0, 41.5, 37.7, 36.6, 35.3, 25.2, 18.8.
HRMS (ESI): m/z [M + H]+ calcd for [C17H19NO4 + H]+: 302.1387; found:
302.1396.
HRMS (ESI): m/z [M + H]+ calcd for [C17H23NO2 + H]+: 274.1802; found:
274.1829.
Synthesis of Amines (±)-13a–c; General Procedure
To a suspension of LiAlH4 (327 mg, 8.63 mmol, 4.0 equiv) in THF (40
mL) at 0 °C was added a solution of enone 12a–c (2.16 mmol, 1.0
equiv) in THF (20 mL). The reaction mixture was allowed to warm to
r.t., and the flask was fitted with a water condenser, heated to 80 °C
and heated to reflux for 20 h. The mixture was cooled to r.t., then to
0 °C and the reaction was quenched with EtOAc, basified with 4N
NaOH solution and extracted with EtOAc (3 × 25 mL). The combined
organic extracts were washed with sat. aq NaCl (30 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude product
was purified by flash chromatography to provide amines 13a–c.
Allylic Oxidation; General Procedure
In an oven-dried round-bottom flask, amide 6a–c (0.731 mmol, 1.0
equiv) was dissolved in anhydrous benzene (6 mL). To this solution,
oven-dried Celite was added and the mixture was stirred vigorously.
Pyridinium dichromate (3.66 mmol, 5.0 equiv) and tert-butylhydro-
peroxide solution (6.0 M in decane, 3.66 mmol, 5.0 equiv) were added
to the reaction mixture at r.t. and stirring was continued for 18 h.
Celite and black tar was filtered out and washed continuously with
CH2Cl2 (50 mL) and the crude product was purified by flash chroma-
tography to afford enone 12a–c.
1-(2-(Dimethylamino)ethyl)-4′-methoxy-1,2,3,4-tetrahydro-[1,1′-
biphenyl]-4-ol (13a)
2-(4′-Methoxy-4-oxo-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-N,N-
dimethylacetamide [(±)-12a]
Yield: 559 mg (90%); colorless oil; Rf = 0.10 (EtOAc with one drop
Et3N).
Yield: 180 mg (86%); yellowish gel; Rf = 0.20 (EtOAc–hexane, 75%).
IR (film): 3091, 2959, 2910, 1818, 1700, 1635, 1431, 1400, 1199,
IR (film): 3361, 2940, 2862, 2824, 2779, 1608, 1511, 1436, 1245,
1041, 811, 714 cm–1
.
1249, 1182, 1035, 948, 831, 709 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58 (dd, J = 1.3, 10.3 Hz, 1 H), 7.21 (d,
J = 8.9 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.13 (d, J = 10.3 Hz, 1 H), 3.77
(s, 3 H), 2.84 (d, J = 5.1 Hz, 6 H), 2.80–2.66 (m, 2 H), 2.43–2.20 (m,
4 H).
13C NMR (100 MHz, CDCl3): δ = 199.1, 169.6, 158.3, 156.4, 135.1,
128.7, 127.5, 114.0, 55.3, 44.1, 42.5, 37.6, 36.0, 35.4, 34.5.
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.7 Hz, 1 H), 7.16 (d, J =
8.7 Hz, 1 H), 6.81 (dd, J = 2.3, 8.8 Hz, 2 H), 5.95 (s, 1 H), 5.86 (s, 1 H),
4.22–4.10 (m, 1 H), 3.76 (s, 3 H), 2.13 (s, 6 H), 2.10–1.96 (m, 2 H),
1.94–1.70 (m, 5 H), 1.62–1.57 (m, 1 H), 1.40–1.22 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 157.7, 157.7, 138.6, 138.3, 136.3,
134.8, 131.5, 129.8, 127.9, 127.6, 113.6, 113.5, 67.1, 64.3, 55.2, 55.2,
55.1, 45.5, 45.5, 41.6, 39.9, 39.4, 35.0, 32.7, 28.9, 28.4.
HRMS (ESI): m/z [M + Na]+ calcd for [C17H21NO3 + Na]+: 310.1414;
found: 310.1427.
HRMS (ESI): m/z [M + H]+ calcd for [C17H25NO2 + H]+: 276.1958; found:
276.1982.
2-(3′,4′-Dimethoxy-4-oxo-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-
N,N-dimethylacetamide [(±)-12b]
4-(Benzo[d][1,3]dioxol-5-yl)-4-[2-(dimethylamino)ethyl]cyclo-
hex-2-enol (13c)
Yield: 201 mg (60%); yellow oil; Rf = 0.24 (EtOAc).
IR (film): 3444, 2935, 1644, 1519, 1463, 1410, 1257, 1177, 1146,
Yield: 203 mg (80%); colorless oil; Rf = 0.10 (MeOH–CH2Cl2, 10%).
1025, 901, 857, 809 cm–1
.
IR (film): 3391, 2939, 2863, 2826, 1644, 1503, 1487, 1432, 1238,
1H NMR (400 MHz, CDCl3): δ = 7.58 (dd, J = 1.1, 10.3 Hz, 1 H), 6.85–
6.79 (m, 3 H), 6.13 (d, J = 10.3 Hz, 1 H), 3.84 (d, J = 1.4 Hz, 6 H), 2.84 (s,
6 H), 2.46–2.18 (m, 4 H), 1.26–1.21 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 199.1, 169.6, 156.2, 148.9, 147.9,
135.6, 128.7, 118.7, 111.1, 110.1, 56.0, 55.9, 44.1, 42.7, 37.6, 36.0,
35.4, 34.6.
1039, 936, 813, 735 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.81 (d, J = 1.2 Hz, 1 H), 6.75–6.70 (m,
2 H), 5.90 (s, 2 H), 5.90–5.81 (m, 2 H), 4.20 (d, J = 6.0 Hz, 1 H), 2.13 (s,
6 H), 2.11–1.96 (m, 4 H), 1.90–1.68 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 147.7, 145.6, 140.6, 134.6, 131.7,
120.2, 107.7, 107.4, 100.9, 67.2, 55.1, 45.5, 42.1, 40.0, 35.2, 28.8.
HRMS (ESI): m/z [M + Na]+ calcd for [C18H23NO4 + Na]+: 340.1519;
found: 340.1546.
HRMS (ESI): m/z [M + H]+ calcd for [C17H23NO3 + H]+: 290.1751; found:
290.1757.
2-{1-(benzo[d][1,3]dioxol-5-yl)-4-oxocyclohex-2-en-1-yl}-N,N-di-
methylacetamide [(±)-12c]
Procedure for Selective Reduction20
In an oven-dried round-bottle flask compound (±)-12a (60 mg, 0.208
mmol, 1.0 equiv) in anhydrous THF (4 mL) was charged with reducing
agent (LiBH4 or LiEt3BH; 0.46 mmol, 2.2 equiv] at 0 °C under a N2 at-
mosphere. The reaction mixture was stirred for 1–2 h at the same
temperature, then the reaction was quenched with sat. aq NH4Cl and
the mixture was diluted with EtOAc (10 mL). The combined organic
Yield: 219 mg (62%); yellow gel; Rf = 0.28 (EtOAc–hexane, 75%).
IR (film): 3054, 2927, 1837, 1675, 1641, 1488, 1434, 1400, 1240,
1040, 934, 814 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. K. Das et al.
Paper
Synthesis
layers were washed with water and brine, and dried over anhydrous
Na2SO4. After removal of the solvent, the crude material was purified
by flash chromatography.
1H NMR (400 MHz, CDCl3): δ = 7.04 (d, J = 10.3 Hz, 1 H), 6.75 (s, 1 H),
6.68 (q, J = 8.1 Hz, 2 H), 6.08 (d, J = 10.2 Hz, 1 H), 5.90 (s, 2 H), 2.32–
2.16 (m, 5 H), 2.12 (s, 6 H), 2.10–2.02 (m, 1 H), 1.99–1.86 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 199.3, 155.1, 148.1, 146.3, 137.0,
129.4, 120.0, 108.0, 107.0, 101.1, 55.1, 45.5, 43.1, 39.4, 36.5, 34.4.
HRMS (ESI): m/z [M + H]+ calcd for [C17H21NO3 + H]+: 288.1594; found:
288.1623.
2-(4-Hydroxy-4′-methoxy-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-
yl)-N,N-dimethylacetamide (13d)
Yield: 49 mg (82%); colorless gel; Rf = 0.15 (EtOAc–hexane, 75%).
IR (film): 3393, 2929, 2883, 1622, 1515, 1478, 1398, 1248, 1059,
912 cm–1
.
Total Synthesis of (±)-Joubertiamine (1a)
1H NMR (400 MHz, CDCl3): δ = 7.23–7.21 (m, 2 H), 6.81–6.78 (m, 2 H),
6.21 (d, J = 10.2 Hz, 1 H), 5.85 (d, J = 10.2 Hz, 1 H), 4.22 (br s, 1 H), 3.74
(s, 3 H), 2.78 (s, 3 H), 2.74 (s, 3 H), 2.68–2.59 (m, 2 H), 2.04–1.94 (m,
4 H), 1.82 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.4, 157.7, 138.5, 135.2, 131.2,
127.6, 113.5, 67.0, 55.2, 44.6, 41.8, 37.8, 35.4, 34.4, 28.8.
In an oven-dried, long-neck, round-bottle flask, BBr3 (307 μL, 0.307
mmol, 3.5 equiv) was added to a solution of (±)-1b (24 mg, 0.088
mmol, 1.0 equiv) in anhydrous CH2Cl2 (1.5 mL) at –78 °C under a N2
atmosphere. The reaction mixture was stirred for 1 h at the same
temperature, then the reaction was quenched with water at 0 °C and
the mixture was diluted with CH2Cl2 (5 mL). The combined organic
layers were washed with water and brine, and dried over anhydrous
Na2SO4. After removal of the solvent, the crude material was purified
by flash chromatography to afford (±)-1a.
General Procedure for Allylic Oxidation
MnO2 (6.91 mmol, 20.0 equiv) was added to a stirred solution of allyl-
ic alcohol (0.345 mmol, 1.0 equiv) in anhydrous CH2Cl2 (5 mL) in
Celite (200 mg) at r.t. under an argon atmosphere. The reaction mix-
ture was stirred at r.t. for 16 h. Upon completion of the reaction
(monitored by TLC), the reaction mixture was filtered with CH2Cl2
and purified by flash chromatography to provide enone 1 and 14.
1-[2-(Dimethylamino)ethyl]-4′-hydroxy-2,3-dihydro-[1,1′-biphe-
nyl]-4(1H)-one [(±)-1a]
Yield: 20 mg (88%); white solid; mp 158–160 °C; Rf = 0.1 (MeOH–
CH2Cl2, 10%).
IR (film): 3382, 2999, 2860, 1681, 1608, 1511, 1463, 1386, 1250,
1184, 1097, 1034, 894, 830 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.04 (t, J = 10.1 Hz, 3 H), 6.45 (d, J =
8.2 Hz, 2 H), 6.10 (d, J = 10.2 Hz, 1 H), 2.34–2.03 (m, 14 H).
.
1-[2-(Dimethylamino)ethyl]-4′-methoxy-2,3-dihydro-[1,1′-biphe-
nyl]-4(1H)-one [(±)-1b]
Yield: 59 mg (63%); colorless gel; Rf = 0.15 (EtOAc with one drop
13C NMR (100 MHz, CDCl3): δ = 199.4, 155.9, 155.0, 132.8, 129.2,
Et3N).
127.7, 115.9, 54.3, 44.8, 42.6, 39.0, 36.3, 34.5, 29.7.
HRMS (ESI): m/z [M + H]+ calcd for [C16H21NO2 + H]+: 260.1645; found:
IR (film): 3036, 2946, 2832, 2771, 2860, 2054, 1684, 1609, 1580,
1463, 1386, 1250, 1184, 1097, 895, 831 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 8.7 Hz, 2 H), 7.11 (d, J =
10.3 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 2 H), 6.13 (d, J = 10.3 Hz, 1 H), 3.78 (s,
3 H), 2.36–2.19 (m, 4 H), 2.15 (s, 6 H), 2.12–1.93 (m, 4 H).
260.1666.
3a-(3,4-Dimethoxyphenyl)-1-methyloctahydro-1H-indole
13C NMR (100 MHz, CDCl3): δ = 199.5, 158.3, 155.5, 135.1, 129.3,
[Mesembrane; (±)-2a]
127.7, 114.0, 55.3, 55.2, 45.6, 42.7, 39.4, 36.4, 34.5.
Yield: 17 mg (88%); colorless gel; Rf = 0.45 (1 mL MeOH + 30 mL
CH2Cl2 + 1 mL Et3N).
HRMS (ESI): m/z [M + H]+ calcd for [C17H23NO2 + H]+: 274.1802; found:
274.1802.
IR (film): 2932, 2856, 1589, 1519, 1464, 1410, 1326, 1257, 1148,
1030, 805 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.94–6.90 (m, 2 H), 6.84–6.81 (m, 1 H),
3.89 (s, 3 H), 3.88 (s, 3 H), 3.28–3.23 (m, 1 H), 2.59 (br s, 1 H), 2.33 (s,
3 H), 2.32–2.29 (m, 1 H), 1.96–1.80 (m, 4 H), 1.67–1.65 (m, 3 H), 1.50–
1.45 (m, 2 H), 1.39–1.36 (m, 1 H).
1-[2-(Dimethylamino)ethyl]-3′,4′-dimethoxy-2,3-dihydro-[1,1′-bi-
phenyl]-4(1H)-one [(±)-1c]
Yield: 70 mg (67% over two steps); colorless oil; Rf = 0.30 (MeOH–
CH2Cl2, 10%).
13C NMR (100 MHz, CDCl3): δ = 148.6, 146.8, 140.3, 118.9, 110.7,
110.6, 68.7, 55.9, 55.8, 54.4, 47.5, 41.0, 40.7, 36.1, 23.7, 22.9, 20.4.
IR (film): 2945, 2861, 2832, 1681, 1606, 1514, 1463, 1203, 1180,
1149, 833, 768 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for [C17H25NO2 + H]+: 276.1958; found:
276.1965.
1H NMR (400 MHz, CDCl3): δ = 7.11 (dd, J = 4.1, 10.2 Hz, 1 H), 6.86 (dt,
J = 3.4, 5.2 Hz, 1 H), 6.82–6.76 (m, 2 H), 6.17–6.12 (m, 1 H), 3.85 (s,
3 H), 3.78 (s, 3 H), 2.34–2.18 (m, 4 H), 2.16 (d, J = 4.2 Hz, 6 H), 2.12–
1.97 (m, 4 H).
2,3,4,4a-Tetrahydro-1H,6H-5,11b-ethano[1,3]dioxolo[4,5-
j]phenanthridine [Crinane; (±)-3a]
HRMS (ESI): m/z [M + H]+ calcd for [C18H25NO3 + H]+: 304.1907; found:
304.1929.
An oven-dried, round-bottom flask was charged with (±)-11b (21 mg,
0.082 mmol, 1.0 equiv) in anhydrous THF (7 mL). To the reaction mix-
ture, Eschenmoser’s salt (23 mg, 0.124 mmol, 1.5 equiv) was added
and the reaction mixture was heated at 40 °C for 30 h. Upon comple-
tion of the reaction (monitored by TLC), THF was removed under vac-
uum and EtOAc (10 mL) and 1 M NaOH was added until the solution
became basic. The organic phases were combined and dried over an-
4-(Benzo[d][1,3]dioxol-5-yl)-4-[2-(dimethylamino)ethyl]cyclo-
hex-2-enone [(±)-14]
Yield: 75 mg (75%); yellow oil; Rf = 0.12 (EtOAc with one drop Et3N).
IR (film): 2946, 2820, 2773, 2052, 1850, 1681, 1612, 1485, 1388,
1238, 1171, 1097, 1038, 934, 813 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
M. K. Das et al.
Paper
Synthesis
hydrous K2CO3 and concentrated under vacuum. The crude product
was purified by flash chromatography with basic alumina to give
amine 3a.
3861. (g) Hoshino, O.; Ishizaki, M.; Sawaki, S.; Yuasa, M.;
Umezawa, B. Chem. Pharm. Bull. 1988, 36, 3373. (h) Asaoka, M.;
Fujii, N.; Takei, H. Chem. Lett. 1988, 1655. (i) Taber, D. F.; Mack, J.
F.; Rheingold, A. L.; Geib, S. J. J. Org. Chem. 1989, 54, 3831.
(3) (a) Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis; Christoffers, J.; Baro, A., Eds.; Wiley-VCH:
Weinheim, 2005. (b) For numerous examples, see: Nicolaou, K.
C.; Sorensen, E. J. Classics in Total Synthesis, 1st ed.; Wiley-VCH:
Weinheim, 1996. (c) Nicolaou, K. C.; Snyder, S. A. Classics in
Total Synthesis II, 1st ed.; Wiley-VCH: Weinheim, 2003. For
reviews, see: (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem. Int.
Ed. 1998, 37, 388. (e) Christoffers, J.; Mann, A. Angew. Chem. Int.
Ed. 2001, 40, 4591. (f) Trost, B. M.; Jiang, C. H. Synthesis 2006,
369. (g) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347,
1473.
Yield: 16 mg (72%); light-yellow gel; Rf = 0.40 (MeOH–CH2Cl2, 10%).
IR (film): 2929, 2916, 2881, 1649, 1484, 1454, 1238, 1040, 935,
867 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.69 (s, 1 H), 6.43 (s, 1 H), 5.86 (s, 2 H),
4.31 (d, J = 16.8 Hz, 1 H), 3.72 (d, J = 16.8 Hz, 1 H), 3.27–3.34 (m, 1 H),
2.74–2.83 (m, 2 H), 2.31–2.34 (m, 1 H), 2.15–2.22 (m, 1 H), 1.70–1.84
(m, 6 H), 1.56–1.61 (m, 1 H), 1.47–1.51 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 146.1, 145.5, 142.3, 126.2, 106.2,
103.3, 100.6, 57.3, 62.1, 51.9, 42.8, 37.9, 29.0, 27.6, 24.4, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for [C16H19NO2 + H]+: 258.1489; found:
258.1497.
(4) (a) Jeffs, P. M. In The Alkaloids; Vol. 19; Rodrigo, R. G. A., Ed.;
Academic Press: New York, 1981, 1–80. (b) Martin, S. F. In The
Alkaloids; Vol. 30; Brossi, A., Ed.; Academic Press: New York,
1987, 251–376. (c) Jeffs, P. M. In MTP International Review of
Science, Alkaloids, Organic Chemistry, Series One; Vol. 9; Hey, D.
H.; Wiesner, K. F., Eds.; Butterworth: London, 1973, 273–318.
(5) (a) Lin, L.-Z.; Hu, S.-F.; Chai, H.-B.; Pengsuparp, T.; Pezzuto, J. M.;
Cordell, G. A.; Ruangrungsi, N. Phytochemistry 1995, 40, 1295.
(b) For a detailed report on chemistry, biology, and medicinal
potential of narciclasine and its congeners, see: Kornienko, A.;
Evidente, A. Chem. Rev. 2008, 108, 1982.
OMe
OMe
reducing agent
0 °C to 25 °C, 1–2 h
75–82%
dr 4:1
NMe2
NMe2
O
O
HO
O
(
)-12a
(
)-13d
Scheme 10
(6) For reviews on Amaryllidaceae alkaloids, see: (a) Martin, S. F.
The Alkaloids; Vol. 30; Brossi, A., Ed.; Academic: New York, 1987,
251–376. (b) Hoshino, O. The Alkaloids; Cordell, G. A., Ed.; Aca-
demic: New York, 1998. (c) Tsuda, Y. Heterocycles 1978, 10, 555.
(d) Lewis, J. R. Nat. Prod. Rep. 2002, 19, 223. (e) Jin, Z.; Li, Z.;
Hyang, R. Nat. Prod. Rep. 2002, 19, 454. (f) Jin, Z. Nat. Prod. Rep.
2005, 22, 111. (g) Jin, Z. Nat. Prod. Rep. 2009, 26, 363.
Acknowledgment
Financial support from the Department of Science and Technology
(DST) through FAST-TRACK scheme (SB/FT/CS-54/2011) and the
(7) (a) Overman, L. E.; Mendelson, L. T. J. Am. Chem. Soc. 1981, 103,
5579. (b) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53,
3184. (c) Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63,
3607. (d) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett.
2006, 8, 4755. (e) Zhang, F.-M.; Tu, Y.-Q.; Liu, J.-D.; Fan, X.-H.;
Shi, L.; Hu, X.-D.; Wang, S.-H.; Zhang, Y.-Q. Tetrahedron 2006,
62, 9446. (f) McNulty, J.; Nair, J. J.; Codina, C.; Bastida, J.; Pandey,
S.; Gerasimoff, J.; Griffin, C. Phytochemistry 2007, 68, 1068.
(8) (a) Papas, T. S.; Sandhaus, L.; Chirigos, M. A.; Furusawa, E. Bio-
chem. Biophys. Res. Commun. 1973, 52, 88. (b) Furusawa, E.;
Furusawa, S.; Sokugawa, L. Chemotherapy 1983, 29, 294.
(c) Furusawa, E.; Lum, M. K. M.; Furusawa, S. Chemotherapy
1981, 27, 277. (d) Abdel-Halim, O. B.; Morikawa, T.; Ando, S.;
Matsuda, H.; Yoshikawa, M. J. Nat. Prod. 2004, 67, 1119.
(e) Likhitwitayawuld, K.; Angerhofer, C. K.; Chai, H.; Pezzuto, J.
M.; Cordell, G. A.; Ruangrungsi, N. J. Nat. Prod. 1993, 56, 1331.
(f) Houghton, P. J.; Agbedahunsi, J. M.; Adegbulugbe, A. Phyto-
chemistry 2004, 65, 2893.
Council
of
Scientific
and
Industrial
Research
(CSIR)
[02(0013)/11/EMR-II], Govt. of India is gratefully acknowledged.
M.K.D. and S.D. thank the CSIR, New Delhi, for Senior Research Fel-
lowships (SRF). We sincerely thank the Department of Chemistry, IIS-
ER Bhopal for infrastructure.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561583.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L