C–H-Activation approach towards the core structure of the alkaloid γ-lycorane

Article abstract of DOI:10.1016/j.tet.2016.08.061

With a view towards the synthesis of lycorane-like structures several N-(pivaloyloxy)benzamides were reacted with cyclohexa-1,3-diene in presence of a rhodium(III) catalyst which resulted via C–H activation in the corresponding tetrahydrophenanthridinones

Full text of DOI:10.1016/j.tet.2016.08.061

Accepted Manuscript
C–H-Activation approach towards the core structure of the alkaloid γ-lycorane
Vivek Kumar Mishra, Ponneri C. Ravikumar, Martin E. Maier
PII:
S0040-4020(16)30846-8
10.1016/j.tet.2016.08.061
TET 28042
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 July 2016
Revised Date: 19 August 2016
Accepted Date: 21 August 2016
Please cite this article as: Mishra VK, Ravikumar PC, Maier ME, C–H-Activation approach towards the
core structure of the alkaloid γ-lycorane, Tetrahedron (2016), doi: 10.1016/j.tet.2016.08.061.
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C–H-Activation approach towards the core
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structure of the alkaloid γ-lycorane
Vivek Kumar Mishraa, Ponneri C. Ravikumarb,*, Martin E. Maiera,*
aInstitut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076
Tübingen, Germany
bSchool of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar,
Jatni Campus, Khurda, Odisha 752050, India

1
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Tetrahedron
journal homepage: www.elsevier.com
C–H-Activation approach towards the core structure of the alkaloid γ-lycorane
Vivek Kumar Mishraa, Ponneri C. Ravikumarb, and Martin E. Maiera,
aInstitut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
bSchool of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Jatni Campus, Khurda, Odisha 752050, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
With a view towards the synthesis of lycorane-like structures several N-(pivaloyloxy)-
benzamides were reacted with cyclohexa-1,3-diene in presence of a rhodium(III) catalyst which
resulted via C–H activation in the corresponding tetrahydrophenanthridinones 12a-d and 19.
Subsequently, various strategies were explored to convert these tricyclic phenanthridinones to
the tetracyclic core structure of the lycoranes. While radical based approaches were not
successful, we were able to form ring D (pyrrolidine ring) by a nickel catalyzed reaction,
resulting in alkaloid derivatives 39 and 40.
Available online
Keywords:
C–H-activation
lycorane
2009 Elsevier Ltd. All rights reserved
.
alkaloid
hydroboration
cyclization
———
Corresponding author. Tel.: +49 7071 2975247; fax: +49 7071 295137; e-mail: martin.e.maier@uni-tuebingen.de
Corresponding author. Tel.: +91 674 249 4321; fax: +91 674 249 4004; e-mail: pcr@niser.ac.in

2
Tetrahedron
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1. Introduction
With the advent of Rh(III)-catalyzed synthesis of fused
heterocycles from N-hydroxybenzamide derivatives and alkenes,
a new approach to lycorane analogs based on route c seemed
possible (Scheme 2). Thus, extending on the example reported by
Guimond et al.11,12,13 who described the annulation of N-
(pivaloxyloxy)benzamide 10a with cyclohexa-1,3-diene to
tetrahydrophenanthridinone 12a, the synthesis of lycorane-like
structures seemed possible by annexing the D-ring to a properly
substituted tetrahydrophenanthridinone.
Among alkaloids derived from phenylalanine and tyrosine,
amaryllidaceae alkaloids, hold a prominent place among natural
products. They comprise eight different ring systems, with
lycorine (1) representing one of them (Figure 1).1 Alkaloids
related
to
lycorine
feature
a
tetracyclic
pyrrolo[d,e]phenanthridine core structure (galanthan ring
system). Some of these alkaloids seem to have interesting
biological activity. Thus, lycorine (1), displays plant growth
inhibiting properties. Another structurally related alkaloid is (+)-
fortucine (2) which features a cis-B/C-ring junction. Its correct
absolute configuration could recently be determined by total
synthesis.2 During degradation studies on lycorine the
deoxygenated derivative called α-lycorane (3) was obtained.3
Besides the trans-cis- (α) and the trans-trans- (β), the cis-cis-
isomer [γ-lycorane (5)] has also been prepared.4 While not
biologically active, the lycoranes are timeless synthetic targets
for demonstrating potential new strategies towards such
polycyclic alkaloids.
HO
O
O
N
N
A
H
H
D
MeO
Scheme 2. Possible route to lycorane derivatives via Rh(III)-
catalyzed C–H-activation on benzamide derivatives with
annulation of cyclohexadienes followed by formation of ring
D.
H
H
C
HO
HO
OH
lycorine (1)
(+)ꢀfortucine (2)
However, this would require to study the effect of substituted
O
O
O
O
O
N
H
N
N
benzamide
derivatives
on
this
rhodium(III)-catalyzed
H
H
phenanthridinone synthesis. In this paper we describe our results
of this study and investigations toward D-ring formation.
O
H
H
H
H
H
H
ꢀlycorane (3)
ꢀlycorane (5)
4
ꢀlycorane ( )
2. Results and discussion
Figure 1. Structures of alkaloids with galanthan ring system.
With a view towards the synthesis of lycorane using this
strategy, 3,4-dialkoxy-substituted N-(pivaloyloxy)-benzamide
10b was prepared as a model compound. The synthesis of this
amide from vanillin is summarized in Scheme 3. Thus,
benzylation of 4-hydroxy-3-methoxy-benzaldehyde (vanillin, 14)
to benzyl ether14 15 was followed by oxidation15 of the aldehyde
function to benzoic acid16 16. For the conversion of benzoic acid
16 to N-pivaloyloxy)amide 10b two variants were explored. In
the first one, acid 16 was converted to ethyl benzoate17 17 under
alkylating conditions. Subsequent reaction of 17 with
hydroxylamine led to hydroxamic acid 18.18 A final reaction with
pivalic anhydride provided benzamide derivative 10b. The
second variant utilizes the acid chloride, derived from 16. Its
reaction with, O-pivaloylhydroxylamine,19 generated from its
triflate salt with Na2CO3 gave amide 10b as well.
The main strategies towards lycoranes 6 can be grouped
according to formation of the final ring (Scheme 1). Thus, major
approaches path through 7-phenyl-octahydro-1H-indole
derivatives 7 (route a) and close ring B, for example by Pictet-
Spengler cyclization.5 Alternatively, 1-benzyloctahydro-1H-
indole derivatives 8 have served as advanced intermediates prior
to formation of the B-ring (route b).6 These major strategies then
distinguish themselves in the synthetic strategies towards the key
octahydroindole derivatives. A quite unique synthesis of lycorine
(1) features an intramolecular Diels-Alder reaction to
simultaneously create the B and C rings.7 There are two
syntheses of lycoranes where the pyrrolidine ring D is formed in
the final step by reductive amination and ketone alkylation,
respectively, from derivatives of 9 (route c).8,9,10
Scheme 1. Major strategies for formation of the last ring of
the galanthan ring system.

3
cyclohexadiene (11). These other N-(pivaloyloxy)benzamides
ACCEPTED MANUSCRIPT
were prepared analogously to 10b as described in the Supporting
Information. The optimized conditions (2.5 mol% of catalyst, 0.5
equiv of (CsOAc, EtOH 0 °C to rt, 36 h) were then applied to
benzamides 10a–10e. The results are summarized in Scheme 4.
With the exception of 12b, all annulations proceeded in quite
good yields. In all cases essentially only the cis-fused products
were obtained (dr > 98:02). A surprising result was obtained with
the amide 10e derived from 3,4-(methylendioxy)benzoic acid. In
this case only the isomer resulting from activation of 2-H was
observed. This was clearly evident from observation of two
doublets for the aromatic protons. As is known, the electron-
donating effect of the methylenedioxy function is significantly
reduced due to conformational reasons, since the free election
pairs of the oxygen atoms cannot be in line with the π-system.
Moreover, the steric demand of the methylenedioxy group might
be less. Similar regioselectivtiy has been observed for other
Rh(III)-catalyzed reactions of 10e.21 Therefore, access to the
lycorane skeleton would not be possible from 10e via this
strategy. Thus, it seems that electronic factors govern the
regiochemistry in the C–H activation step.
Scheme 3. Synthesis of benzamide derivative 10b from
vanillin (14).
With amide 10b a brief survey of reaction conditions (amount
of catalyst [Cp*RhCl2]2,20 solvent) was carried out (Table 1). In
methanol the reaction led to successful C–H activation, cross-
coupling and cyclization. However, despite relatively high
catalyst loadings (up to 5 mol%) the yield of tricyclic amide 12b
did not exceed 20%. Acetonitrile as solvent was even worse with
a 10% yield of 12b in presence of 5 mol% catalyst. Much better
results were obtained in ethanol as solvent. Here up to 55% of
12b (2.5 mol% of catalyst) could be obtained.
Table 1. Screening of conditions for the rhodium(III)-
catalyzed synthesis of phenanthridinone 12b.
Scheme 4. Rhodium(III)-catalyzed synthesis of
phenanthridinones 12a–12d and 19 using the optimized
conditions from Table 1.
entry
mol% of
catalyst
solvent
yield of 12b (%)
1
2
3
4
5
6
7
8
9
5
MeOH
MeOH
MeOH
MeCN
MeCN
MeCN
EtOH
20
20
10
10
5
Accordingly, studies towards formation of ring D were carried
out with tetrahydrophenanthridinones 12c and 12d. However,
this turned out to be rather difficult. Some of these experiments
with 12c and 12d are summarized in Scheme 5. Thus, reduction
of the amide function of 12 with the reagent combination
LiAlH4/AlCl3 led to secondary amines 20.22 The structure of
20c·HCl was secured by X-ray analysis, which proved the B/C-
cis-function (Scheme 5). Amines 20c and 20d could be acylated
with bromoacetyl bromide to the corresponding amides 21.
However, neither radical conditions23 nor reaction in presence of
Pd(OAc)2 (30 mol%), tBu3P (40 mol%), Et3N (2 equiv), toluene,
110 °C, 12 h, led to the desired tetracycles 22c or 22d. Rather
decomposition of these bromoacetamides with the formation of a
complex mixture was observed.
2.5
1
5
2.5
1
0
5
50
55
40
2.5
1
EtOH
EtOH
In a larger scale reaction besides the cis-product 12b a small
amount of the corresponding trans-fused compound could be
isolated (cis/trans = 98:02). As can be seen, the C–H activation is
regioselective with the insertion taking place only at 6-H.
With a view towards delineating the scope of this reaction,
various 3,4-dialkoxy-substituted N-(pivaloyloxy)benzamides
10c-10e were prepared (Scheme 4) and then reacted with

4
Tetrahedron
a)
benzoylperoxide as radical initiator led to formation of the
O
ACCEPTED MANUSCRIPT
intermediate acyl radical followed by decarbonylation and
MeO
H
H
MeO
RO
H
H
N
AlCl3, LiAlH4
N
formation of N-methylamide 28.
THF, 40 °C
8 h
RO
H
Our next plans focused on derivatization reactions of the
double bond of ring C. This might open additional options for
creation of ring D. Initially, amine 20d was converted to
sulfonamides 29a–29c (Scheme 6). As it turned out,
hydroboration24 of the double bond was highly selective, with the
borane attacking the double bond at the more hindered position.
The alcohol derivatives were not further purified but rather
oxidized to the α-aminoketone derivatives 30a–30c using the
Dess-Martin periodinane reagent. The regiochemistry of the
H
12c R = Et
12d R = Me
20c R = Et (60%)
20d R = Me (75%)
O
MeO
RO
Br
N
H
Bu3SnH, AIBN
BrCH2COBr
CH2Cl2, rt
4 h
H
benzene, T
1
21c
21d
R = Et (99%)
R = Me (99%)
hydroboration was inferred from the H NMR spectra. Indicative
O
MeO
RO
of the regiochemistry was the signal for 4a-H in alcohol 30a-OH
which appeared as a doublet of doublet (δ = 3.90, J = 8.0, 4.0
Hz). The hydroboration was also diastereoselective. While this
was not further investigated, we assume attack of the borane from
the exo face, syn to 4a-H and 10b-H. For the other regioisomer a
multiplet would be expected instead. In order to attach ring D,
extension of the ketone by a suitable C2-building block is
required. Reaction of the two ketones 30a and 30c with methyl 2-
(triphenylphosphoranylidine) acetate gave the desired enoates
31a and 31c, respectively. However, the yields were too low to
be of practical value.
N
H
H
H
22c R = Et
22d R = Me
20c—HCl
b)
O
O
H
MeO
MeO
Cl
ClCH2C(O)Cl
Bu3SnH, AIBN
N
12d
12d
DMAP, MeCN
2 d (69%)
benzene,
(83%)
T
H
23
O
O
MeO
MeO
NaH, BrCH2CO2tBu
(PhSe)2, nBu3P
N
12d
H
OR
CH2Cl2, reflux
24 h (84%)
DMF, 0 °C to rt
60 min (63%)
H
R = tBu
24
HCl (g), CH2Cl2
0 °C to rt, 2 h
25 R = H
O
O
O
SePh
MeO
MeO
MeO
MeO
Bu3SnH, AIBN
N
H
N
H
O
benzene,
T
H
H
H
26
27
O
Scheme 6. Conversion of tricyclic amine 20d to sulfonamides
29a–29c and the regioselective hydroboration of the ring C
double bond.
MeO
MeO
Me
Bu3SnH, (PhCO2)2
N
26
H
benzene, T, 3 h
(63%)
H
28
In order to check whether the protecting group on the nitrogen
influences the regiochemistry of the hydroboration reaction,
amine 20d was converted to the carbamates 32a–32c (Scheme 7).
Subjecting these carbamates to the hydroboration/oxidation
sequence led to the α-aminoketone derivatives 33a–33c,
respectively. Carbamate 33c was deprotected under acid
conditions giving amine salt 34. After its acylation with 2-
bromoacetyl bromide the obtained 2-bromoacetamide 35 was
subjected to conditions for a Reformatsky reaction. However
instead of the desired intramolecular aldol reaction, only
reductive dehalogenation to acetamide 36 could be observed. The
reasons for the failure of the above-mentioned cyclizations are
unclear, as visual inspection of amine 20c indicates that
cyclization of an amide derivative via attack at the double bond
should be possible. Most likely, the tricyclic ring system already
Scheme 5. a) Reduction of amides 12c,d to amines 20c,d and
attempts to form lactams 22c,d by radical cyclization. X-ray
structure of amine 20c (as hydrochloride) showing the cis-
fusion. b) Attempts to cyclize amide derivatives 23 and 26 to
the corresponding galanthan ring systems.
Diacylamine 23, obtained from amide 12d, underwent
cleavage of the acylic amide bond upon reaction with Bu3SnH
given back the starting amide. (Scheme 5). As it is known that
phenyl selenoesters can serve as precursors for acyl radicals,
selenoester 26 was prepared from amide 12d in three steps.
However, reaction of 26 with Bu3SnH in presence of AIBN did
not lead to the desired tetracyclic compound. Here only starting
material (16 mg of 25 mg) was recovered. Using

5
Br
5
N
suffers from some strain so the additional ring D would increase
the ring strain even more.
ACCEPTED MANUSCRIPT
MeO
8
MeO
MeO
NH—HCl
Br
H
H
Br
MeO
NaH, THF
rt, 1 h (65%)
O
H
H
H
1
MeO
MeO
MeO
—
H
NH HCl
N
OR
20d
38
Cl(C=O)OR
MeO
a) Ni(cod)2, Et3N
MeCN, rt, 15 min
Et3N, CH2Cl2
0 °C to rt
H
H
MeO
MeO
N
H
b) Me3SiCN, 3 h (80%)
20d
32a R = Et (94%)
32b
H
H
R = Bn (39%)
32c R = tBu (89%)
39
CN
O
H
i) NaBH4, BF3—OEt2
THF
MeO
MeO
a) Ni(cod)2, Et3N
N
OR
MeO
MeO
MeCN, rt, 15 min
N
H
O
ii) H2O2/NaOH
iii) DMP, CH2Cl2
38
H
H
b) Et3SiH, 3 h (70%)
H
33a R = Et (74%)
40
33b R = Bn (30%, from 20d)
Scheme 8. Conversion of amine 20d to 5-(2-bromoallyl)-
hexahydrophenanthridine derivative 38 and its nickel-
mediated cyclization to 4-methylene-octahydro-1H-
pyrrolo[3,2,1-de]phenanthridines 39 and 40.
33c
R = tBu (75%)
MeO
CF3CO2H
BrCH2COBr
NH—HX
33c
H
Et3N, CH2Cl2
rt, 1 h (65%)
O
H
CH2Cl2, rt
MeO
4 h
3. Conclusion
34
O
In this paper we present a new approach to lycorane-like
structures that relies on the fusion of substituted benzamide
derivatives with cyclohexadiene by C–H-activation. After
reduction of the tricyclic secondary amine, N-allylation with 2-
bromoallyl bromide and Ni-induced cyclization led to the
tetracyclic γ-lycorane analogs 39 and 40. In the course of this
study we discovered a strong influence of the type of the 3,4-
dialkoxy substituents on the regiochemistry of the C–H-
activation. While for the non-constrained N-(pivaloyloxy)
benzamides activation of 6-H takes place, with 3,4-
methylendioxyamide 10e insertion occurs selectively at 2-H.
Furthermore N-protected phenanthridine derivatives 29 and 32
MeO
N
Br
a) Zn, DMF, rt
or
b) RhCl(PPh3)3, Et2Zn
THF, 0 °C
H
O
MeO
H
35
O
O
MeO
MeO
MeO
N
N
H
H
and not
O
MeO
H
OH
H
36
37
[a) 48%, b) 56%]
Scheme 7. Conversion of tricyclic amine 20d to carbamates
32a–32c, their regioselective hydroboration of the ring C
double bond followed by oxidation to ketones 33a–33c, and
attempts on intramolecular Reformatsky reaction of keto
amide 35.
underwent
a regioselective hydroboration/oxidation to the
corresponding α-aminoketone compounds.
4. Experimental section
4.1. Preparation of catalyst [Cp*RhCl2]2
Eventually we turned to transition metal catalyzed cyclization
where the cyclization would be initiated from a vinylmetal
species. Accordingly, amine 20d was alkylated with 2-
bromoallyl bromide to yield allylamine 38 (Scheme 8). With this
substrate successful cyclization was observed in presence of
Ni(cod)2, Et3N and a suitable nucleophile, like trimethylsilyl
cyanide or triethylsilane.25 This way the two tetracyclic
compounds 39 and 40 were obtained. Both feature the cis/cis-ring
fusion of the γ-lycorane ring system. Brief attempts at
epoxidation or oxidative cleavage (O3) were unsuccessful.
To a stirred solution of RhCl3 (0.5 g, 1.95 mmol) in MeOH
(12 mL) was added excess pentamethylcyclopentadiene (0.5 mL).
The mixture was reflux for 21 h, cooled to room temperature,
filtered through sintered funnel, washed with diethylether (2 × 5
mL), dried under vacuum to give the rhodium catalyst (1.02 g,
85%) as dark brown powder.20
4.2. Preparation of O-pivaloyl hydroxamic acids
4.2.1. (Procedure 1, via hydroxamic acid)
(a) To a stirred solution of ethyl benzoate (1.0 equiv) and
hydroxylamine hydrochloride (4.0 equiv) in MeOH (2 mL per
mmol of benzoate) was added KOH solution (1
M in methanol,
5.0 equiv) in a dropwise fashion. The resulting solution was
stirred 48 h at room temperature. Thereafter most of the MeOH
was distilled out in vacuo and the solid residue was dissolved in a
mixture of acetic acid/water (1/1, 4 mL per mmol of benzoate).
The mixture was extracted with EtOAc (3 × 5 mL (per mmol of
benzoate)). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo to provide
the crude hydroxamic acid which was washed with diethyl ether
(5 mL per mmol of benzoate) to afford the pure hydroxamic acid
as transparent solid.
(b) To the suspension of hydroxamic acid (1.0 equiv) in
CH2Cl2 (5 mL per mmol of acid) was added pivalic anhydride

6
Tetrahedron
(0.8 equiv). The resulting mixture was stirred for 16 h at room
128.1 (Ar), 128.7 (Ar), 136.2 (Ar), 149.7 (Ar), 151.9 (Ar), 177.3
ACCEPTED MANUSCRIPT
temperature. The reaction mixture was diluted with saturated
NaHCO3 (4 mL per mmol of acid) and extracted with EtOAc (2 ×
5 mL (per mmol of acid)). The combined organic layers were
washed with saturated NaHCO3 solution (4 mL per mmol of
acid), dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
to afford the pure O-pivaloyl hydroxamic acid.
(CONH), 177.7 (tBuCO2); HRMS (ESI): calcd for C20H23NO5
[M+Na]+ 380.14684, found 380.14715.
4.2.6. 4-Ethoxy-3-methoxy-N-
(pivaloyloxy)benzamide (10c)
Prepared from the corresponding benzoic acid (1.00 g, 5.09
mmol) according to procedure 2. The crude product was purified
by flash chromatography (ethyl acetate/petroleum ether, 1:5) to
give pure N-(pivaloyloxy)benzamide 10c (1.5 g, 98%) as
4.2.2. Procedure 2 (reaction of acid chloride with
O-pivaloylhydroxylamine)
1
colorless solid. H NMR (400 MHz, CDCl3): δ = 1.28 (s, 9H,
To a solution of benzoic acid (1.0 equiv) in dry CH2Cl2 (3 mL
per mmol of acid) was added SOCl2 (5.0 equiv) at room
temperature followed by the addition of a catalytic amount of
DMF (4 drops per 10 mmol of acid). The mixture was refluxed
for 8 h. After cooling, solvent and excess reagent were removed
in vacuo to afford the crude acid chloride, which was used in the
next step without further purification.
O-Pivaloylhydroxylamine triflate19 (1.2 equiv) was added to a
biphasic mixture of Na2CO3 (2.0 equiv) in EtOAc/H2O (9 mL per
mmol of acid chloride, 2:1). To the cooled mixture containing the
pivaloylhydroxylamine at 0 °C was added crude acid chloride
(1.0 equiv) in EtOAc (1 mL per mmol of acid chloride) dropwise.
The reaction mixture was allowed to reach room temperature
within 5 h. The layers were separated and the aqueous layer was
extracted with EtOAc (2 × 10 mL (per mmol of acid chloride)).
The combined organic layers were dried over Na2SO4, filtered
and concentrated in vacuo to provide. The crude product was
purified by flash chromatography to afford pure O-pivaloyl
hydroxamic acid.
OPiv), 1.41 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.79 (s, 3H, OMe),
4.05 (q, J = 7.1 Hz, OCH2CH3), 6.71-6.77 (m, 1H, Ar), 7.29-7.35
(m, 2H, Ar), 9.79 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): δ =
14.4 (OCH2CH3), 26.9 (OPiv), 38.3 (tBu), 55.7 (OMe), 64.2
(OCH2CH3), 110.5 (Ar), 111.17 (Ar), 120.5 (Ar), 122.7 (Ar),
148.9 (Ar), 151.8 (Ar), 166.5 (CONH), 177.0 (tBuCO2); HRMS
(ESI): calcd for C15H21NO5 [M+Na]+ 318.13119, found
318.13121.
4.2.7. 3,4-(Dimethoxy)-N-(pivaloyloxy)benzamide
(10d)
Prepared either from the corresponding N-hydroxybenzamide
(3.00 g, 15.2 mmol, procedure 1) or the benzoic acid (3.0 g,
14.48 mmol, procedure 2). The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 1:3) to give
pure N-(pivaloyloxy)benzamide26 10d (3.70 g, 86%, procedure 1;
3.70 g, 80%, procedure 2) as colorless solid. 1H NMR (400 MHz,
CDCl3): δ = 1.24 (s, 9H, OPiv), 3.75 (s, 3H, OMe), 3.78 (s, 3H,
OMe), 6.65-6.73 (m, 1H, 5-H), 7.26-7.36 (m, 2H, 2-H, 3-H), 9.65
(br, 1H, NH); 13C NMR (100 MHz, CDCl3): δ = 26.8 (OPiv),
38.2 (tBu), 55.6 (OMe), 55.7 (OMe), 110.1 (Ar), 110.2 (Ar),
120.5 (Ar), 122.9 (Ar), 148.6 (Ar), 152.2 (Ar), 166.3 (CONH),
176.9 (tBuCO2); HRMS (ESI): calcd for C14H19NO5 [M+Na]+
304.11554, found 304.11566.
4.2.3. 4-(Benzyloxy)-N-hydroxy-3-
methoxybenzamide (18)
Prepared from benzoic acid 16 (300 mg, 1.05 mmol)
according to procedure 1 (a). The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 1:2) to give
4.2.8. N-(pivaloyloxy) benzo[d][1,3]dioxole-5-
carboxamide (10e)
1
hydroxamic acid 18 (280 mg, 95%) as colorless solid. H NMR
(400 MHz, DMSO-d6): δ = 3.78 (s, 3H, OMe), 5.11 (s, 2H,
CH2Ph), 7.1 (d, J = 8.3 Hz, 1H, Ar), 7.28-7.47 (m, 7H, Ar); 13C
NMR (100 MHz, DMSO-d6): δ = 55.8 (OMe), 70.0 (CH2Ph),
110.6 (C-5), 112.8 (C-2), 120.1 (C-6), 125.4 (Ar), 128.14 (Ar),
128.3 (Ar), 128.7 (Ar), 136.9 (Ar), 148.8 (Ar), 150.3 (Ar), 164.2
(CONHOH); HRMS (ESI): calcd for C15H15NO4 [M+Na]+
296.08933, found 296.08989.
Prepared from the corresponding benzoyl chloride (500 mg,
2.71 mmol) according to procedure 2. The crude product was
purified by flash chromatography (ethyl acetate/petroleum ether,
1:3) to give pure N-(pivaloyloxy)benzamide21 10e (650 mg, 90%)
1
as colorless solid. H NMR (400 MHz, CDCl3): δ = 1.31 (s, 9H,
OPiv), 5.99 (s, 2H, OCH2O), 6.76 (d, J = 8.3 Hz, 5-H), 7.21 (d, J
= 2.0 Hz, 2-H), 7.22 (dd, J = 8.3, 2.0 Hz, 1H, 6-H), 9.58 (s, 1H,
NH); 13C NMR (100 MHz, CDCl3): δ = 26.9 (OPiv), 38.5 (tBu),
101.8 (OCH2O), 107.8 (C-5), 108.1 (C-2), 122.6 (C-6), 124.6
(Ar), 147.9 (Ar), 151.2 (Ar), 166.2 (CONH), 177.1 (tBuCO2);
HRMS (ESI): calcd for C13H15NO5 [M+Na]+ 288.08424, found
288.08450.
4.2.4. N-(Pivaloyloxy)benzamide11 (10a)
Prepared from the corresponding N-hydroxybenzamide (850
mg, 6.20 mmol) according to procedure 1 (b). The crude product
was purified by flash chromatography (ethyl acetate/petroleum
ether, 1:10) to give pure N-(pivaloyloxy)benzamide 10a (1.260 g,
92%) as colorless solid. 1H NMR (400 MHz, CDCl3): δ = 1.34 (s,
9H, OPiv), 7.39-7.46 (m, 2H, Ar), 7.50-7.57 (m, 1H, Ar), 7.76-
7.82 (m, 2H, Ar), 9.48 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3): δ = 27.0 (OPiv), 38.4 (tBu), 127.4 (Ar), 128.8 (Ar),
130.8 (Ar), 132.6 (Ar), 166.7 (CONH), 177.0 (tBuCO2).
4.3. Rhodium catalyzed annulation (Procedure 3)
An oven dried, cooled Schlenk tube under N2, was charged
with N-(pivaloyloxy)benzamide (1.0 equiv), [Cp*RhCl2]2 (2.5
mol%), CsOAc (50 mol%) and dry EtOH (1 mL per mmol of
amide). The mixture was cooled to 0 °C, whereupon 1,3-
cyclohexadiene (1.3 equiv) was added in one shot. The screw cap
was closed tightly under positive pressure of N2 followed by
stirring of the reaction mixture at room temperature for 35 h
(TLC control). The mixture was concentrated in vacuo and the
residue purified by flash chromatography to afford the pure
annulation product.
4.2.5. 4-(Benzyloxy)-3-methoxy-N-
(pivaloyloxy)benzamide (10b)
Prepared from N-hydroxybenzamide 18 (250 mg, 0.91 mmol)
according to procedure 1 (b). The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 1:5) to give
pure N-(pivaloyloxy)benzamide 10b (240 mg, 75%) as yellow
1
solid. H NMR (400 MHz, CDCl3): δ = 1.35 (s, 9H, OPiv), 3.91
4.3.1. 1,4a,5,10b-Tetrahydrophenanthridin-6(2H)-
one (12a)
Prepared from N-(pivaloyloxy)benzamide 10a (100 mg, 0.45
mmol) according to procedure 3. TLC showed consumption of
(s, 3H, OMe), 5.21 (s, 2H, CH2Ph), 6.87 (d, J = 8.6 Hz, 1H, 5-H),
7.28-7.47 (m, 7H, Ar), 9.24 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3): δ = 27.0 (OPiv), 38.4 (tBu), 56.1 (OMe), 70.84 (CH2Ph),
111.0 (C-5), 112.7 (C-2), 120.3 (C-6), 123.5 (Ar), 127.2 (Ar),

7
starting material after 19 h. The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 1:1) to give
120.0 (Ar), 124.4 (C-4), 132.2 (Ar), 136.6 (C-3), 148.0 (Ar),
ACCEPTED MANUSCRIPT
152.5 (Ar), 164.9 (CONH); HRMS (ESI): calcd for C15H17NO3
pure phenanthridinone11 12a (74 mg, 82%) as colorless solid. H
[M+Na]+ 282.11006, found 282.11030.
1
NMR (400 MHz, CDCl3): δ = 1.62-1.73 (m, 1H, 1-H), 1.88-2.05
(m, 1H, 2-H), 2.10-2.28 (m, 2H, 1-H, 2-H), 2.92 (td, J = 3.8, 12.2
Hz, 1H, 10b-H), 4.22-4.30 (m, 1H, 4a-H), 5.79 (ddt, J = 2.1, 4.5,
9.3 Hz, 1H, 4-H), 5.94-6.06 (m, 1H, 3-H), 6.26 (s, br, 1H, NH),
6.23 (d, J = 7.5 Hz, 1H, Ar), 7.33 (td, J = 1.1, 7.6 Hz, 1H, Ar),
7.46 (td, J = 1.3, 7.5 Hz, 1H, Ar), 8.06 (dd, J = 1.2, 7.8 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl3): δ = 25.0 (C-2), 25.1 (C-1),
37.7 (C-10b), 47.9 (C-4a), 124.4 (Ar), 127.0 (Ar), 127.2 (Ar),
127.5 (Ar), 127.9 (Ar) 132.2 (C-4), 132.5 (C-3), 142.7 (Ar),
165.4 (CONH); HRMS (ESI): calcd for C13H13NO [M+Na]+
222.08893, found 222.08894.
4.3.5. 7a,8,9,11a-Tetrahydro-[1,3]dioxolo[4,5-
k]phenanthridin-6(7H)-one (19)
Prepared from N-(pivaloyloxy)benzamide 10e (500 mg, 2.00
mmol) according to procedure 3. TLC showed consumption of
starting material after 35 h. The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 4:1) to give
1
pure phenanthridinone 19 (435 mg, 89%) as colorless solid. H
NMR (400 MHz, CDCl3): δ = 1.69-1.78 (m, 1H, 11-H), 1.80-
1.97 (m, 1H, 11-H), 2.14-2.26 (m, 2H, 10-H2), 2.98-3.12 (m, 1H,
11a-H), 4.14-4.26 (m, 1H, 7a-H), 5.68-5.85 (m, 2H, 8-H, NH),
6.00-6.11 (m, 1H, 9-H), 6.02 (d, J = 1.3 Hz, 2-H), 6.79 (d, J = 1.3
Hz, 2-H), 6.79 (d, J = 8.2 Hz, 1H, 4-H), 7.68 (d, J = 8.3 Hz, 1H,
5-H); 13C NMR (100 MHz, CDCl3): δ = 22.6 (C-10), 25.2 (C-11),
32.4 (C-11a), 47.6 (C-7a), 101.9 (C-2), 107.1 (C-4), 121.7 (Ar),
123.4 (C-5), 123.9 (Ar), 124.0 (C-8), 132.6 (C-9), 143.9 (Ar),
150.6 (Ar), 164.6 (CONH); HRMS (ESI): calcd for C14H13NO3
[M+Na]+ 266.07876, found 266.07918.
4.3.2. 9-(Benzyloxy)-8-methoxy-1,4a,5,10b-
tetrahydrophenanthridin-6(2H)-one (12b)
Prepared from N-(pivaloyloxy)benzamide 10b (50 mg, 0.14
mmol) according to procedure 3. TLC showed consumption of
starting material after 39 h. The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 1:1) to give
pure phenanthridinone 12b (26 mg, 55%) as slightly yellow
4.4. Reduction of the tetrahydrophenanthridinones to
hexahydrophenanthridines (Procedure 4)
1
solid. H NMR (400 MHz, CDCl3): δ = 1.54-1.65 (m, 1H, 1-H),
1.82-1.97 (m, 1H, 1-H), 2.06-2.26 (m, 2H, 1-H), 2.78 (td, J = 3.3,
12.1 Hz, 1H, 10a-H), 3.92 (s, 3H, OMe), 4.21 (m, 1H, 4a-H),
5.20 (OCH2Ph), 5.57 (s, br, NH), 5.68-5.78 (m, 1H, 4-H), 5.94-
6.05 (m, 1H, 3-H), 6.70 (s, 1H, 10-H), 7.28-7.34 (m, 1H, Ar),
7.34-7.41 (m, 2H, Ar), 7.41-7.48 (m, 2H, Ar), 7.58 (s, 1H, 7-H);
13C NMR (100 MHz, CDCl3): δ 24.9 (C-2), 25.0 (C-1), 37.4 (C-
10b), 48.2 (C-4a), 56.1 (OMe), 70.9 (OCH2Ph), 110.4 (C-7),
111.6 (C-10), 120.4 (Ar), 124.4, 127.2, 128.0, 128.6, 132.2,
136.2, 136.4, 148.6 (Ar), 151.6 (Ar), 164.9 (CONH); HRMS
(ESI): calcd for C21H21O3 [M+H]+ 336.159420, found
336.159327.
To a cooled (0 °C) solution of AlCl3 (1 equiv) in THF (10 mL
per mmol AlCl3) under N2 was added LiAlH4 (3 equiv). The
mixture was allowed to stir at room temperature for 1 h, before it
was added dropwise via cannula to a separately stirred solution of
the amide (1 equiv) in THF (20 mL per mmol of amide). The
reaction mixture was allowed to reach room temperature within 1
h. Then the flask was moved to a preheated oil bath (40 °C) and
the mixture stirred for 8 h. Thereafter, the reaction mixture was
cooled to 0 °C and quenched with saturated NH4Cl solution (10
mL per mmol of AlCl3). The organic layer was separated and the
aqueous semisolid washed with diethyl ether (10 mL per mmol of
amide). The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The crude material
was dissolved in diethyl ether (10 mL per mmol of amide) and
4.3.3. 9-Ethoxy-8-methoxy-1,4a,5,10b-
tetrahydrophenanthridin-6(2H)-one (12c)
Prepared from N-(pivaloyloxy)benzamide 10c (100 mg, 0.34
mmol) according to procedure 3. TLC showed consumption of
starting material after 20 h. The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 2:1) to give
cooled to 0 °C, then ethereal HCl (3M, 0.5 mL per mmol of
amide) was added dropwise. The white solid amine salt which
precipitated, was collected by filtration through a G4 frit. It was
found to be of sufficient purity.
1
pure phenanthridinone 12c (75 mg, 81%) as colorless solid. H
NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 6.8 Hz, 3H,
OCH2CH3), 1.58-1.68 (m, 1H, 1-H), 1.82-1.95 (m, 1H, 1-H),
2.11-2.21 (m, 2H, 2-H), 2.78 (td, J = 3.3, 12.4 Hz, 1H, 10a-H),
3.87 (s, 3H, OMe), 4.11 (q, J = 6.8 Hz, 2H, OCH2CH3), 4.18-
4.23 (m, 1H, 4a-H), 5.72-5.80 (m, 1H, 4-H), 5.93-6.01 (m, 1H, 3-
H), 6.40 (s, 1H, NH), 6.65 (s, 1H, 10-H), 7.51 (s, 1H, 7-H); 13C
NMR (100 MHz, CDCl3): d = 14.6 (OCH2CH3), 24.9 (C-2), 25.1
(C-1), 37.4 (C-10b), 48.1 (C-4a), 56.0 (OMe), 64.3 (OCH2CH3),
110.0 (C-7), 110.2 (C-10), 119.6 (Ar), 124.3 (C-4), 132.0 (Ar),
136.5 (C-3), 148.1 (Ar), 151.9 (Ar), 165.4 (CONH).
4.4.1. 9-Ethoxy-8-methoxy-1,2,4a,5,6,10b-
hexahydrophenanthridin-5-iumchloride (20c)
Prepared from tetrahydrophenanthridinone 12c (127 mg, 0.46
mmol) according to procedure 4 to give pure hydrochloride 20c
1
(115 mg, 80%) as colorless solid. H NMR (400 MHz, CD3OD):
δ = 1.40 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.79-1.91 (m, 1H, 1-H),
2.04-2.12 (m, 1H, 1-H), 2.16-2.35 (m, 2H, 2-H), 3.16 (dt, J = 4.3,
12.1 Hz, 1H, 10b-H), 3.82 (s, 3H, OMe), 4.06 (q, J = 7.1 Hz, 3H,
OCH2CH3, 4a-H), 4.28 (dd, J = 11.4, 15.4 Hz, 2H, 6-H), 5.86-
5.93 (m, 1H, 4-H), 6.28-6.34 (m, 1H, 3-H), 6.79 (s, 1H, 10-H),
6.93 (s, 1H, 7-H); 13C NMR (100 MHz, CD3OD): δ = 15.2
(OCH2CH3), 25.8 (C-2), 27.8 (C-1), 35.5 (C-10b), 45.2 (C-6),
52.2 (C-4a), 56.7 (OMe), 65.8 (OCH2CH3), 110.7 (C-7), 114.2
(C-10), 120.5 (Ar), 122.0 (C-4), 129.2 (Ar), 138.2 (C-3), 150.2
(Ar), 150.3 (Ar); HRMS (ESI): calcd for C16H22ClNO2 [M]+
260.164505, found 260.164354.
4.3.4. 8,9-Dimethoxy-1,4a,5,10b-
tetrahydrophenanthridin-6(2H)-one (12d)
Prepared from N-(pivaloyloxy)benzamide 10d (500 mg, 1.78
mmol) according to procedure 3. TLC showed consumption of
starting material after 55 h. The crude product was purified by
flash chromatography (ethyl acetate/petroleum ether, 4:1) to give
pure phenanthridinone 12d (325 mg, 70%) as slightly brown
1
solid. H NMR (400 MHz, CDCl3): δ = 1.61-1.71 (m, 1H, 1-H),
4.4.2. 8,9-Dimethoxy-1,2,4a,5,6,10b-
1.84-1.99 (m, 1H, 1-H), 2.15-2.24 (m, 2H, 2-H), 2.82 (td, J = 4.0,
12.4 Hz, 1H, 10b-H), 3.91 (s, 3H, OMe), 3.91 (s, 3H, OMe), 4.23
(t, J = 4.0 Hz, 1H, 4a-H), 5.72-5.84 (m, 2H, 4-H, NH), 5.97-6.05
(m, 1H, 3-H), 6.67 (s, 1H, 10-H), 7.51 (s, 1H, 7-H); 13C NMR
(100 MHz, CDCl3): δ = 24.9 (C-2), 25.2 (C-1), 37.7 (C-10b),
48.2 (C-4a), 56.0 (OMe), 56.1 (OMe), 109.3 (C-7), 109.9 (C-10),
hexahydrophenanthridin-5-iumchloride (20d)
Prepared from tetrahydrophenanthridinone 12d (500 mg, 1.90
mmol) according to procedure 4 to give pure hydrochloride 20d
1
(425 mg, 75%) as colorless solid. H NMR (400 MHz, CD3OD):
δ = 1.77-1.93 (m, 1H, 1-H), 2.04-2.17 (m, 1H, 1-H), 2.18-2.37
(m, 2H, 2-H), 3.18 (dt, J = 4.0, 12.0 Hz, 1H, 10b-H), 3.82 (s, 3H,

8
Tetrahedron
ACCEPTED MANUSCRIPT
OMe), 3.84 (s, 3H, OMe), 4.02-4.10 (m, 1H, 4a-H), 4.29 (dd, J
µL, 0.57 mmol, 1.5 equiv) was added. Then the reaction mixture
= 14.4, 15.7 Hz, 2H, 6-H), 5.84-5.91 (m, 1H, 4-H), 6.28-6.37 (m,
1H, 3-H), 6.78 (s, 1H, 10-H), 6.95 (s, 1H, 7-H); 13C NMR (100
MHz, CD3OD): δ = 25.8 (C-2), 27.8 (C-1), 35.6 (C-10b), 45.2
(C-6), 52.3 (C-4a), 56.6 (OMe), 56.7 (OMe), 110.5 (C-7), 112.9
(C-10), 120.5 (Ar), 121.9 (C-4), 129.3 (Ar), 138.3 (C-3), 150.2
(Ar), 151.0 (Ar); HRMS (ESI): calcd for C15H20ClNO2 [M+Na]+
246.14886, found 246.14873.
was warmed to room temperature within 45 min. The reaction
mixture was diluted with water (30 mL) and the aqueous phase
was basified (10% NaOH, 5 mL) and extracted with ether (5 × 10
mL). The combined ether extracts were washed with saturated
NaCl solution, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/ethyl acetate, 3:1) to provide
pure N-alkyation product 24 (90 mg, 63%) as an amorphous
solid. Rf = 0.6 (petroleum ether/ethyl acetate, 1:1). 1H NMR (400
MHz, CDCl3): d = 1.45 (s, 9H, tBu), 1.70-1.80(m, 1H, 1-H),
2.03-2.20 (m, 3H, 1-H, 2-H), 2.99-3.09 (m, 1H, 10b-H), 3.86 (d,
J = 17.2 Hz, 1H, NCH2CO), 3.89 (s, 3H, OMe), 3.91 (s, 3H,
OMe), 4.33 (m, 1H, 4a-H), 4.70 (d, J = 17.2 Hz, 1H, NCH2CO),
5.66-5.72 (m, 1H, 4-H), 5.91-5.99 (m, 1H, 3-H), 6.67 (s, 1H, 10-
H), 7.58 (s, 1H, 7-H); 13C NMR (100 MHz, CDCl3): δ = 24.3 (C-
2), 24.4 (C-1), 28.0 (tBu), 36.7 (C-10b), 46.0 (NCH2CO), 53.5
(C-4a), 56.0 (OMe), 81.6 (C-(CH3)3), 108.5 (C-7), 110.7 (C-10),
120.6 (Ar), 123.8 (C-4), 132.6 (C-3), 135.2 (Ar), 147.8 (Ar),
152.2 (Ar), 164.3 (CON), 169.0 (CO2tBu); HRMS (ESI): calcd
for C21H27NO5 [M+Na]+ 396.17814, found 396.17849.
4.5. Preparation of α-haloamides from amine hydrochlorides
(Procedure 5)
To a stirred solution of the amine·HCl (1 equiv) and
trimethylamine (2 equiv) in THF (3 mL per mmol of salt) at 0 °C
was added 2-bromoacetyl bromide (2 equiv). The stirred reaction
mixture was allowed to reach room temperature within 1 h. For
work-up the mixture was diluted with saturated NaHCO3 solution
(20 mL per mmol of salt) and extracted with Et2O (3 × 15 mL
(per mmol of salt). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
amide was purified by flash chromatography (petroleum
ether/ethyl acetate, 3:1) to provide pure product.
4.5.4. 2-(8,9-Dimethoxy-6-oxo-2,4a,6,10b-
tetrahydrophenanthridin-5(1H)-yl)acetic acid (25)
4.5.1. 2-Bromo-1-(9-ethoxy-8-methoxy-2,4a,6,10b-
tetrahydrophenanthridin-5(1H)-yl)ethan-1-one
(21c)
Through a solution of ester 24 (67 mg, 0.18 mmol) in CH2Cl2
(5 mL) was bubbled HCl gas at 0 °C for 5 h. The solution was
stirred for additional 1.5 h at 0 °C, warmed to room temperature
over 30 min, and evaporated to dryness. This way acid 25 was
Prepared from amine hydrochloride 20c (50 mg, 0.16 mmol)
according to procedure 5 to give pure bromoacetylamide 21c (67
mg, 99%) as brown solid. Rf = 0.5 (petroleum ether/ethyl acetate,
1:1); 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ = 1.43
(t, J = 7.1 Hz, 3H, OCH2CH3), 1.68-1.93 (m, 2H, 1-H, 2-H),
1.93-2.09 (m, 1H, 1-H), 2.21-2.43 (m, 1H, 2-H), 3.16-3.43 (m,
1H, 10b-H), 3.81 (s, 3H, OMe), 4.00-4.23 (m, 5H, OCH2CH3,
CH2Br, 4a-H), 4.40-4.64 (m, 1H, 6-H), 5.12-5.46 (m, 1H, 6-H),
5.46-5.58 (m, 1H, 4-H), 5.70-5.85 (m, 1H, 3-H), 6.54 (s, 1H, 7-
H), 6.80 (s, 1H, 10-H); 13C NMR (100 MHz, CDCl3): δ = 14.8,
20.1, 25.3, 33.1, 34.4, 40.7, 41.1, 41.5, 44.6, 48.6, 53.4, 55.8,
64.5, 64.6, 108.5, 108.9, 111.0, 111.2, 124.4, 125.2, 125.6, 126.0,
132.1, 132.6, 147.3, 147.7, 147.8, 148.0, 165.3 (CO); HRMS
(ESI): calcd for C18H22BrNO3 [M]+ 402.067527, found
402.067526.
1
obtained as a white solid in pure form. H NMR (400 MHz,
CD3OD): δ = 1.73-1.92 (m, 1H, 1-H), 2.08-2.30 (m, 3H, 1-H, 2-
H), 3.06-3.22 (m, 1H, 10b-H), 3.84 (s, 3H, OMe), 3.89 (s, 3H,
OMe), 4.07 (d, J = 17.4 Hz, 1H, NCH2CO), 4.35-4.42 (m, 1H,
4a-H), 4.62 (d, J = 17.4 Hz, 1H, NCH2CO), 5.74-5.81 (m, 1H, 4-
H), 5.94-6.01 (m, 1H, 3-H), 6.91 (s, 1H, 10-H), 7.41 (s, 1H, 7-H);
13C NMR (100 MHz, CD3OD): δ = 25.3 (C-2), 25.3 (C-1), 37.7
(C-10b), 46.0 (NCH2CO), 55.8 (C-4a), 56.6 (OMe), 56.7 (OMe),
110.5 (C-7), 111.8 (C-10), 121.4 (Ar), 124.9 (C-4), 133.9 (C-3),
137.6 (Ar), 149.5 (Ar), 154.5 (Ar), 166.3 (CON), 173.1 (CO2H).
4.5.5. Se-phenyl 2-(8,9-dimethoxy-6-oxo-
2,4a,6,10b-tetrahydrophenanthridine-5(1H)-
yl)ethaneselenoate (26)
4.5.2. 2-Bromo-1-(8,9-dimethoxy-2,4a,6,10b-
tetrahydrophenanthridin-5(1H)-yl)ethan-1-one
(21d)
(PhSe)2 (60 mg, 0.20 mmol, 1.5 equiv) was added to a
solution of acid 25 in CH2Cl2 (10 mL). The solution was cooled
to 0 °C before n-Bu3P (66 µL, 0.26 mmol, 2.0 equiv) was added.
The reaction mixture was refluxed for 24 h, poured into water (20
mL) and then the mixture was extracted with CH2Cl2 (3 × 10
mL). The combined extracts were washed with saturated NaCl
solution, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The crude product was purified by flash
chromatography (petroleum ether/ethyl acetate, 3:1) to provide
pure selenoester 26 (50 mg, 84%), as an amorphous solid. Rf =
Prepared from amine hydrochloride 20d (200 mg, 0.71 mmol)
according to procedure 5 to give pure bromoacetylamide 21d
(145 mg, 56%) as brown solid. Rf = 0.2 (petroleum ether/ethyl
acetate, 1:1); 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ
= 1.66-1.92 (m, 2H, 1-H, 2-H), 1.93-2.11 (m, 1H, 1-H), 2.22-2.48
(m, 1H, 2-H), 3.13-3.48 (m, 1H, 10b-H), 3.81 (s, 3H, OMe), 3.84
(s, 3H, OMe), 3.97-4.24 (m, 1H, 4a-H), 4.15 (s, 2H, CH2Br),
4.43-4.83 (m, 1H, 6-H), 5.12-5.45 (m, 1H, 6-H), 5.46-5.60 (m,
1H, 4-H), 5.71-5.88 (m, 1H, 3-H), 6.53 (s, 1H, 7-H), 6.78 (s, 1H,
10-H); 13C NMR (100 MHz, CDCl3): δ = 20.1, 25.3, 33.2, 34.4,
40.7, 41.1, 41.4, 44.6, 48.6, 53.4, 55.7, 56.0, 108.2, 108.7, 109.2,
109.5, 124.4, 125.1, 125.6, 125.9, 132.1, 132.6, 148.1, 148.5,
165.4 (CO); HRMS (ESI): calcd for C17H20BrNO3 [M+Na]+
388.05188, found 388.05197.
1
0.5 (petroleum ether/ethyl acetate, 1:1); H NMR (400 MHz,
CDCl3): δ = 1.75-1.94 (m, 1H, 1-H), 2.06-2.28 (m, 3H, 1-H, 2-
H), 3.18-3.37 (m, 1H, 10b-H), 3.91 (s, 3H, OMe), 3.93 (s, 3H,
OMe), 4.11 (d, J = 16.9 Hz, 1H, NCH2CO), 4.37-4.44 (m, 1H,
4a-H), 5.05 (d, J = 16.9 Hz, 1H, NCH2CO), 5.64-5.73 (m, 1H, 4-
H), 5.92-6.01 (m, 1H, 3-H), 6.72 (s, 1H, 10-H), 7.32-7.40 (m,
3H, Ar), 7.46-7.53 (m, 2H, Ar), 7.62 (s, 1H, 7-H); 13C NMR (100
MHz, CDCl3): δ = 23.8 (C-2), 24.3 (C-1), 36.2 (C-10b), 54.7
(NCH2CO), 56.0 (OMe), 56.05 (OMe), 56.5 (C-4a), 108.3 (C-7),
110.8 (C-10), 120.1 (Ar), 123.4 (C-4), 125.4 (Ar), 128.9 (C-3),
129.1 (Ar),129 (Ar), 131.4 (Ar), 132.8 (Ar), 135.0 (Ar), 136.0
(Ar), 148.0 (Ar), 152.6 (Ar), 164.8 (CON), 199.0 (COSePh);
HRMS (ESI): calcd for C23H23NO4Se [M+Na]+ 480.06845, found
480.06836.
4.5.3. tert-Butyl 2-(8,9-dimethoxy-6-oxo-
2,4a,6,10b-tetrahydrophenanthridin-5(1H)-
yl)acetate (24)
Sodium hydride (20 mg, 0.50 mmol, 1.3 equiv, 60%
dispersion in mineral oil) was added to a stirred, cold (0 °C)
solution of amide 12d (100 mg, 0.38 mmol) in dry DMF (2 mL).
The solution was allowed to warm to room temperature for 20
min and then cooled to 0 °C, before tert-butyl bromoacetate (86

9
4.5.6. 8,9-Dimethoxy-5-methyl-1,4a,5,10b-
tetrahydrophenanthridin-6(2H)-one (28)
(d, J = 16.2 Hz, 1H, 6-H), 4.56 (d, J = 16.2 Hz, 1H, 6-H), 4.81-
ACCEPTED MANUSCRIPT
4.89 (m, 1H, 4a-H), 5.34-5.43 (m, 1H, 4-H), 5.68-5.79 (m, 1H, 3-
H), 6.52 (s, 1H, 7-H), 6.76 (s, 1H, 10-H), 7.58-7.70 (m, 3H, Ar),
8.01-8.08 (m, 1H, Ar); 13C NMR (100 MHz, CDCl3): δ = 20.1
(C-2), 25.5 (C-1), 33.9 (C-10b), 43.5 (C-6), 52.9 (C-4a), 55.8
(OMe), 56.0 (OMe), 108.4 (C-7), 109.4 (C-10), 124.7 (Ar), 124.2
(Ar), 124.7 (Ar), 126.2 (Ar), 130.7 (C-4), 131.7 (C-3), 133.1
(Ar), 133.3 (Ar), 133.7 (Ar), 147.4 (Ar), 147.9 (Ar), 148.3 (Ar);
HRMS (ESI): calcd for C21H22N2O6S [M+Na]+ 453.10908, found
453.10940.
To a boiling solution of compound selenoester 26 (16 mg,
0.035 mmol) in benzene (2 mL) was added dropwise a solution
of Bu3SnH (14 µL, 0.052 mmol, 1.5 equiv), and benzoyl
peroxide (2 mg, 0.008 mmol, 23 mol%) in benzene (1 mL) over 1
h by employing a syringe pump. After complete addition, the
reaction mixture was further refluxed for 2 h. The solvent was
evaporated in vacuo, and the residue diluted with Et2O (3 mL).
This solution was washed with 10% aqueous solution of KF (2 ×
5 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography
(petroleum ether/ethyl acetate, 1:2) to provide N-methylamide 28
(6 mg, 63%), as a colorless solid. Rf = 0.1 (petroleum ether/ethyl
4.6.3. 8,9-Dimethoxy-5-((4-nitrophenyl)sulfonyl)-
1,2,4a,5,6,10b-hexahydrophenanthridine (29c)
Prepared from amine hydrochloride 20d (100 mg, 0.35 mmol)
according to procedure 6 to give pure sulfonamide 29c (140 mg,
99%) as yellow amorphous solid. Rf = 0.2 (petroleum ether/ethyl
acetate, 2:1); 1H NMR (400 MHz, CDCl3): δ = 1.62-1.73 (m, 1H,
1-H), 1.74-1.85 (m, 1H, 2-H), 1.85-1.98 (m, 1H, 1-H), 2.18-2.31
(m, 1H, 2-H), 2.99-3.13 (m, 1H, 10b-H), 3.80 (s, 3H, OMe), 3.82
(s, 3H, OMe), 4.23 (d, J = 15.9 Hz, 1H, 6-H), 4.64 (d, J = 15.9
Hz, 1H, 6-H), 4.81-4.89 (m, 1H, 4a-H), 5.14-5.21 (m, 1H, 4-H),
5.67-5.75 (m, 1H, 3-H), 6.49 (s, 1H, 7-H), 6.66 (s, 1H, 10-H),
7.97 (d, J = 8.8 Hz, 2H, Ar), 8.26 (d, J = 8.8 Hz, 2H, Ar); 13C
NMR (100 MHz, CDCl3): δ = 20.1 (C-2), 25.5 (C-1), 33.8 (C-
10b), 43.4 (C-6), 52.8 (C-4a), 55.8 (OMe), 56.0 (OMe), 108.4
(C-7), 109.4 (C-10), 124.7 (Ar), 124.2 (Ar), 124.7 (C-4), 126.5
(Ar), 128.2 (Ar), 133.5 (C-3), 146.4 (Ar), 147.6 (Ar), 148.5 (Ar),
149.8 (Ar); HRMS (ESI): calcd for C21H22N2O6S [M+Na]+
453.10908, found 453.10940.
1
acetate, 1:1); H NMR (400 MHz, CDCl3): δ = 1.79-1.92(m, 1H,
1-H), 2.02-2.15 (m, 2H, 1-H, 2-H), 2.16-2.27 (m, 1H, 2-H), 3.14
(s, 3H, NCH3), 3.17-3.28 (m, 1H, 10b-H), 3.91 (s, 3H, OMe),
3.92 (s, 3H, OMe), 4.08-4.20 (m, 1H, 4a-H), 5.64-5.75 (m, 1H, 4-
H), 5.78-5.90 (m, 1H, 3-H), 6.71 (s, 1H, 10-H), 7.60 (s, 1H, 7-H);
13C NMR (100 MHz, CDCl3): δ = 22.9 (C-2), 24.0 (C-1), 32.2
(NCH3), 35.3 (C-10b), 56.0 (OMe), 56.2 (C-4a), 107.9 (C-7),
110.7 (C-10), 121.5 (Ar), 124.5 (C-4), 130.6 (C-3), 133.4 (Ar),
147.8 (Ar), 151.9 (Ar), 164.1 (CON); HRMS (ESI): calcd for
C16H19NO2 [M+Na]+ 296.12571, found 296.12582.
4.6. Preparation of sulfonamides from amine hydrochlorides
(Procedure 6)
To a cooled (0 °C) suspension of amine·HCl (1.0 equiv) in
CH2Cl2 (9 mL per mmol of hydrochloride) were added Et3N (2.0
equiv) and arylsulfonyl chloride (1.5 equiv). The stirred reaction
mixture was allowed reach room temperature within 2 h.
Thereafter, saturated NaHCO3 solution (9 mL per mmol of
hydrochloride) was added. After separation of the layers the
aqueous layer was extracted with CH2Cl2 (2 × 9 mL per mmol of
hydrochloride). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by flash chromatography to afford the pure
sulfonamides.
4.7. Preparation of carbamates from amine hydrochlorides
(Procedure 7)
To a cooled (0 °C) suspension of amine·HCl (1.0 equiv) in
CH2Cl2 (9 mL per mmol of hydrochloride) were added Et3N (2.0
equiv) and the corresponding chloroformate (2.0 equiv) or Boc2O
(2.5 equiv). The stirred reaction mixture was allowed reach room
temperature within 1 h (in case chloroformate) or 2 h (in case of
Boc2O), respectively. Thereafter, saturated NaHCO3 solution (9
mL per mmol of hydrochloride) was added. After separation of
the layers the aqueous layer was extracted with CH2Cl2 (2 × 9
mL per mmol of hydrochloride). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The residue was purified by flash chromatography to
afford the pure carbamates.
4.6.1. 8,9-Dimethoxy-5-tosyl-1,2,4a,5,6,10b-
hexahydrophenanthridine (29a)
Prepared from amine hydrochloride 20d (305 mg, 1.03 mmol)
according to procedure 6 to give pure sulfonamide 29a (435 mg,
99%) as colorless solid. Rf = 0.3 (petroleum ether/ethyl acetate,
2:1); 1H NMR (400 MHz, CDCl3): δ = 1.55-1.83 (m, 2H, 1-H, 2-
H), 1.85-1.98 (m, 1H, 1-H), 2.18-2.31 (m, 1H, 2-H), 2.38 (s, 3H,
SO2CH2Ph), 3.07-3.21 (m, 1H, 10b-H), 3.81 (s, 6H, 2 OMe), 4.13
(d, J = 15.6 Hz, 1H, 6-H), 4.59 (d, J = 15.6 Hz, 1H, 6-H), 4.76-
4.88 (m, 1H, 4a-H), 5.10-5.20 (m, 1H, 4-H), 5.56-5.73 (m, 1H, 3-
H), 6.48 (s, 1H, 7-H), 6.69 (s, 1H, 10-H), 7.22 (d, J = 8.0 Hz, 2H,
Ar), 7.69 (d, J = 8.0 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3): δ
= 20.2 (C-2), 21.4 (Me), 25.5 (C-1), 34.0 (C-10b), 43.2 (C-6),
52.4 (C-4a), 55.7 (OMe), 56.0 (OMe), 108.4 (C-8), 109.4 (C-10),
124.7 (Ar), 125.2 (C-4), 126.5 (Ar), 127.1 (Ar), 129.6 (Ar), 132.6
(C-3), 137.4 (Ar), 143.2 (Ar), 147.3 (Ar), 148.2 (Ar); HRMS
(ESI): calcd for C22H25NO4S [M+Na]+ 422.13965, found
422.13960.
4.7.1. Ethyl 8,9-dimethoxy-2,4a,6,10b-
tetrahydrophenanthridine-5(1H)-carboxylate (32a)
Prepared from amine hydrochloride 20d (10 mg, 0.03 mmol)
according to procedure 7 to give pure carbamate 32a (9 mg,
94%) as colorless amorphous solid. Rf = 0.5 (petroleum
ether/ethyl acetate, 2:1); 1H NMR (400 MHz, CDCl3): δ = 1.27 (t,
J = 7.1 Hz, 3H, OCH2CH3), 1.71-1.91 (m, 2H, 1H, 2-H), 1.94-
2.08 (m, 1H, 1-H), 2.28-2.38 (m, 1H, 2-H), 3.19-3.29 (m, 1H,
10b-H), 3.83 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.18 (q, J = 7.1
Hz, 3H, OCH2, 6-H) 4.81 (d, J = 15.7 Hz, 1H, 6-H), 4.96-5.28
(m, 1H, 4a-H), 5.44-5.55 (m, 1H, 4-H), 5.65-5.78 (m, 1H, 3-H),
6.52 (s, 1H, 7-H), 6.81 (s, 1H, 10-H); 13C NMR (100 MHz,
CDCl3): δ = 14.7 (OCH2CH3), 20.3 (C-2), 25.3 (C-1), 33.5 (C-
10b), 42.2 (C-6), 50.3 (C-4a), 55.8 (OMe), 56.1 (OMe), 61.5
(OCH2), 108.5 (C-7), 109.5 (C-10), 127.3 (C-4), 131.2 (C-3),
147.4 (Ar), 148.0 (Ar), 155.4 (CO).
4.6.2. 8,9-Dimethoxy-5-((2-nitrophenyl)sulfonyl)-
1,2,4a,5,6,10b-hexahydrophenanthridine (29b)
Prepared from amine hydrochloride 20d (350 mg, 1.01 mmol)
according to procedure 6 to give pure sulfonamide 29b (377 mg,
87%) as yellow amorphous solid. Rf = 0.2 (petroleum ether/ethyl
acetate, 2:1); 1H NMR (400 MHz, CDCl3): δ = 1.63-1.87 (m, 2H,
1-H, 2-H), 1.93-2.03 (m, 1H, 1-H), 2.25-2.37 (m, 1H, 2-H), 3.26-
3.36 (m, 1H, 10b-H), 3.82 (s, 3H, OMe), 3.83 (s, 3H, OMe), 4.39
4.7.2. Benzyl 8,9-Dimethoxy-2,4a,6,10b-
tetrahydrophenanthridine-5(1H)-carboxylate (32b)
Prepared from amine hydrochloride 20d (100 mg, 0.34 mmol)
according to procedure 7 to give pure carbamate 32b (50 mg,
39%) as colorless amorphous solid. Rf = 0.2 (petroleum

10
Tetrahedron
4.8.2. 8,9-Dimethoxy-5-((4-nitrophenyl)sulfonyl)-
ether/ethyl acetate, 2:1); 1H NMR (400 MHz, CDCl3): δ =
ACCEPTED MANUSCRIPT
1,2,3,4,4a,5,6,10b-octahydrophenanthridin-4-ol
1.69-1.90 (m, 2H, 1-H, 2-H), 1.91-2.09 (m, 1H, 1-H), 2.26-2.41
(m, 2H, 2-H), 3.18-3.35 (m, 1H, 10b-H), 3.82 (s, 3H, OMe), 3.85
(s, 3H, OMe), 4.21 (d, J = 16.0 Hz, 1H, 6-H), 4.84 (d, J = 16.0
Hz, 1H, 6-H), 5.02-5.26 (m, 1H, 4a-H), 5.17 (s, 2H, OCH2Ph),
5.46-5.55 (m, 1H, 4-H), 5.67-5.77 (m, 1H, 3-H), 6.52 (s, 1H, 7-
H), 6.81 (s, 1H, 10-H), 7.28-7.34 (m, 1H, Ar), 7.35-7.44 (m, 4H,
Ar); 13C NMR (100 MHz, CDCl3): δ = 20.2 (C-2), 25.2 (C-1),
33.4 (C-10b), 42.3 (C-6), 50.4 (C-4a), 55.7 (OMe), 56.0 (OMe),
67.2 (OCH2Ph), 108.5 (C-7), 109.4 (C-10), 127.6 (C-4), 128.4
(Ar), 128.9 (Ar), 131.8 (C-3), 136.6 (Ar), 147.3 (Ar), 148.0 (Ar),
155.4 (CO); HRMS (ESI): calcd for C23H25NO4 [M+Na]+
402.16758, found 402.16774.
(30c-OH)
Prepared from alkene 29c (120 mg, 0.29 mmol) according to
procedure 8 to give alcohol 30c-OH (80 mg, 63%) as yellow
solid. Rf = 0.4 (petroleum ether/ethyl acetate, 1:1); 1H NMR (400
MHz, CDCl3): δ = 1.15-1.30 (m, 1H), 1.34-1.48 (m, 1H), 1.54-
1.75 (m, 3H), 1.97-2.08 (m, 1H), 2.31-2.43 (m, 1H), 3.01-3.10
(m, 1H, 4a-H), 3.5 (td, J = 10.4, 4.5 Hz, 1H, 4-H), 3.81 (s, 3H,
OMe), 3.83 (s, 3H, OMe), 3.90 (dd, J = 10.1, 5.0 Hz, 1H, 4a-H),
4.40 (d, J = 16.4 Hz, 1H, 6-H), 4.72 (d, J = 16.4 Hz, 1H, 6-H),
6.53 (s, 1H, 7-H), 6.67 (s, 1H, 10-H), 8.04 (d, J = 8.8 Hz, 2H,
Ar), 8.28 (d, J = 8.8 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3): δ
= 19.3 (C-2), 27.7 (C-1), 34.5 (C-3), 36.8 (C-10b), 43.5 (C-6),
55.9 (OMe), 56.0 (OMe), 60.9 (C-4), 66.2 (C-4a), 108.6 (C-7),
108.7 (C-10), 123.2 (Ar), 124.2 (Ar), 126.1 (Ar), 128.3 (Ar),
146.2 (Ar), 147.8 (Ar), 148.5 (Ar).
4.7.3. Ethyl 8,9-Dimethoxy-2,4a,6,10b-
tetrahydrophenanthridine-5(1H)-carboxylate (32c)
Prepared from amine hydrochloride 20d (173 mg, 0.68 mmol)
according to procedure 7 to give pure carbamate 32c (210 mg,
89%) as colorless amorphous solid. Rf = 0.3 (petroleum
4.9. Oxidation of the secondary alcohols to the corresponding
ketones using Dess-Martin periodinane (Procedure 9)
1
ether/ethyl acetate, 2:1); H NMR (400 MHz, CDCl3): δ = 1.47
(s, 9H, OtBu), 1.69-1.89 (m, 2H, 1-H, 2-H), 1.91-2.06 (m, 1H, 1-
H), 2.26-2.38 (m, 1H, 2-H), 3.16-3.26 (m, 1H, 10b-H), 3.83 (s,
3H, OMe), 3.84 (s, 3H, OMe), 4.12 (d, J = 16.7 Hz, 6-H), 4.75
(d, J = 16.7 Hz, 1H, 6-H), 4.87-5.20 (m, 1H, 4a-H), 5.41-5.53 (m,
1H, 4-H), 5.63-5.76 (m, 1H, 3-H), 6.52 (s, 1H, 7-H), 6.81 (s, 1H,
10-H); 13C NMR (100 MHz, CDCl3): δ = 20.3 (C-2), 25.4 (C-1),
28.4 (OtBu), 33.6 (C-10b), 42.2 (C-6), 55.7 (OMe), 56.0 (C-4a),
56.1 (OMe), 79.8 (OtBu), 108.6 (C-7), 109.5 (C-10), 127.6 (C-4),
130.8 (C-3), 147.3 (Ar), 147.9 (Ar), 154.8 (CO). HRMS (ESI):
calcd for C20H27NO4 [M+Na]+ 368.18323, found 368.18325.
To a stirred solution of alcohol (1 equiv) in CH2Cl2 (50 mL
per mmol of alcohol) was added DMP (1.5 equiv) and the
mixture was allowed to stir at room temperature for 1.5 h. Then it
was diluted with saturated NaHCO3 solution (30 mL per mmol of
alcohol) and concentrated sodium thiosulfate solution (30 mL per
mmol of alcohol). This mixture was stirred until both the organic
and aqueous layers appeared clear. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (2 ×
30 mL per mmol of alcohol). The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
Purification of the residue by flash chromatography afforded the
pure ketone.
4.8. Directed hydroboration of arylsulfonyl)-
hexahydrophenanthridines 29 and carbamates 32 (Procedure 8)
4.9.1. 8,9-Dimethoxy-5-tosyl-2,3,4,4a,5,6,10b-
hexahydrophenanthridin-4-(1H)-one (30a)
Prepared from alcohol 30a-OH (120 mg, 0.30 mmol)
according to procedure 9 to give ketone 30a (98 mg, 79%) as
colorless solid. Rf = 0.5 (petroleum ether/ethyl acetate, 1:1); H
NMR (400 MHz, CDCl3): δ = 1.45-1.96 (m, 2H, 2-H), 2.07-2.24
(m, 1H, 1-H), 2.25-2.36 (m, 2H, 1-H, 3-H), 2.42 (s, 3H, CH3),
2.52-2.66 (m, 1H, 3-H), 3.59-3.72 (m, 1H, 10b-H), 3.81 (s, 3H,
OMe), 3.84 (s, 3H, OMe), 4.47 (d, J = 15.2 Hz, 1H, 6-H), 4.58
(d, J = 15.2 Hz, 1H, 6-H), 4.79 (d, J = 5.6 Hz, 1H, 4a-H), 6.49 (s,
1H, 7-H), 6.70 (s, 1H, 10-H), 7.29 (d, J = 8.1 Hz, 2H, Ar), 7.73
(d, J = 8.1 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3): δ = 21.4
(C-1), 21.5 (CH3), 27.6 (C-2), 41.0 (C-3), 41.1 (C-10b), 44.2 (C-
6), 55.7 (OMe), 56.0 (OMe), 62.5 (C-4a), 108.1 (C-7), 108.8 (C-
10), 124.5 (Ar), 125.0 (Ar), 127.4 (Ar), 129.4 (Ar), 136.2 (Ar),
143.3 (Ar), 148.0 (Ar), 148.1 (Ar), 205.1 (CO); HRMS (ESI):
calcd for C22H25NO5S [M+Na]+ 438.13456, found 438.13454.
To a magnetically stirred suspension of NaBH4 (6.0 equiv) in
dry THF (3 mL per mmol of NaBH4) was added neat BF3·OEt2
(5.5 equiv) at 0 °C. The reaction mixture was allowed to stir at
room temperature for 30 min before the alkene 29 or 32 (1.0
equiv) respectively, in dry THF (30 mL per mmol of alkene) was
added dropwise to the mixture at 0 °C. Thereafter, the mixture
was allowed to reach room temperature within 1.5 h. For work-
1
up 3
N aqueous NaOH (30 mL per mmol of alkene) and 30%
H2O2 (30 mL per mmol of alkene) were added sequentially to the
reaction mixture at 0 °C. The mixture was stirred at room
temperature for 5 h, before it was extracted with Et2O (3 × 50 mL
per mmol of alkene). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo.
Purification of the residue by flash chromatography gave the pure
secondary alcohol.
4.8.1. 8,9-Dimethoxy-5-tosyl-1,2,3,4,4a,5,6,10b-
octahydrophenanthridin-4-ol (30a-OH)
4.9.2. 8,9-Dimethoxy-5-((4-nitrophenyl)sulfonyl)-
2,3,4,4a,5,6,10b-hexahydrophenanthridin-4-(1H)-
one (30c)
Prepared from alkene 29a (220 mg, 0.55 mmol) according to
procedure 8 to give alcohol 30a-OH (206 mg, 90%) as colorless
solid. Rf = 0.4 (petroleum ether/ethyl acetate, 1:1); 1H NMR (400
MHz, CDCl3): δ = 1.11-1.26 (m, 1H, 2-H), 1.29-1.43 (m, 1H, 2-
H), 1.48-1.68 (m, 2H, 1-H), 1.94-2.05 (m, 1H, 3-H), 2.23-2.33
(m, 1H, 3-H), 2.36 (s, 3H, CH3), 2.87-2.98 (m, 1H, 10b-H), 3.44
(td, J = 10.6, 4.8 Hz, 1H, 4-H), 3.80 (s, 3H, OMe), 3.81 (s, 3H,
OMe), 3.90 (dd, J = 8.0, 4.0 Hz, 1H, 4a-H), 4.41 (d, J = 16.0 Hz,
1H, 6-H), 4.64 (d, J = 16.0 Hz, 1H, 6-H), 6.53 (s, 1H, 7-H), 6.64
(s, 1H, 10-H), 7.23 (d, J = 8.1 Hz, 2H, Ar), 7.71 (d, J = 8.1 Hz,
2H, Ar); 13C NMR (100 MHz, CDCl3): δ = 19.2 (C-2), 21.5
(CH3), 27.6 (C-1), 33.9 (C-3), 36.0 (C-10b), 43.5 (C-6), 55.8
(OMe), 56.0 (OMe), 60.6 (C-4), 66.3 (C-4a), 108.6 (C-7), 108.9
(C-10), 123.8 (Ar), 126.4 (Ar), 127.1 (Ar), 129.7 (Ar), 137.0
(Ar), 143.5 (Ar), 147.6 (Ar), 148.2 (Ar).
Prepared from alcohol 30c-OH (50 mg, 0.10 mmol) according
to procedure 9 to give ketone 30c (47 mg, 99%) as yellow
amorphous solid, Rf = 0.5 (petroleum ether/ethyl acetate, 1:1); 1H
NMR (400 MHz, CDCl3): δ = 1.54-1.61 (m, 1H, 2-H), 1.82-1.92
(m, 1H, 2-H), 2.12-2.34 (m, 3H, 1-H, 3-H), 2.56-2.67 (m, 1H, 3-
H), 3.70-3.77 (m, 1H, 10b-H), 3.80 (s, 3H, OMe), 3.83 (s, 3H,
OMe), 4.39 (d, J = 14.6 Hz, 1H, 6-H), 4.68 (d, J = 14.6 Hz, 1H,
6-H), 4.85 (d, J = 6.1 Hz, 1H, 4a-H), 6.48 (s, 1H, 7-H), 6.70 (s,
1H, 10-H), 8.00 (d, J = 8.8 Hz, 2H, Ar), 8.34 (d, J = 8.8 Hz, 2H,
Ar); 13C NMR (100 MHz, CDCl3): δ = 21.4 (C-1), 27.6 (C-2),
40.9 (C-10b), 41.0 (C-3), 44.3 (C-6), 55.8 (OMe), 56.1 (OMe),
62.8 (C-4a), 108.1 (C-7), 108.8 (C-10), 124.1 (Ar), 124.3 (Ar),

11
4.9.5. 9,10-Dimethoxy-4-methylene-
128.6 (Ar), 144.9 (Ar), 148.4 (Ar), 150.0 (Ar), 204.9 (CO).
HRMS (ESI): calcd for C21H22N2O7S [M+Na]+ 469.10399, found
469.10415.
ACCEPTED MANUSCRIPT
2,3,3a,3a,1,4,5,7,11b-octahydro-1H-pyrrolo[3,2,1-
de]phenanthridine-3-carbonitrile (39)
To a solution of Ni(COD)2 (149 mg, 0.54 mmol, 2.0 equiv) in
dry acetonitrile (1 mL), at room temperature and under nitrogen
atmosphere, was added a solution of vinyl bromide 38 (100 mg,
0.27 mmol) and Et3N (117 µL, 0.81 mmol, 3.0 equiv) in dry
acetonitrile (1 mL). The reaction mixture was stirred at room
temperature for about 15 min, resulting in a color change from
yellow to black. When all starting material had been consumed
(checked by TLC), the quencher TMSCN (100 µL, 0.66 mmol,
2.5 equiv) was added and the mixture stirred for additional 3 h. It
was filtered through Celite and the filter cake washed several
times with CH2Cl2. The filtrate was washed with saturated
Na2CO3 solution. The organic layer was dried over Na2SO4,
filtered and concentrated in vacuo. Purification of the residue by
flash chromatography (CH2Cl2/MeOH, 9/1) afforded the
cyclization product 39 (67 mg, 80%) as yellow solid. Rf = 0.6
(CH2Cl2/MeOH, 9:1); 1H NMR (400 MHz, CDCl3): δ = 1.68 (tt, J
= 3.3, 13.6 Hz, 1H, 1-H), 1.75-2.87 (m, 1H, 2-H), 1.91-2.02 (m,
1H, 1-H), 2.02-2.13 (m, 1H, 2-H), 2.68 (t, J = 4.8 Hz, 1H, 3a-H),
2.72-2.82 (m, 2H, 3-H, 11b-H), 2.94 (d, J = 14.1 Hz, 1H, 5-H),
3.00-3.07 (m, 1H, 3b-H), 3.28 (d, J = 14.1 Hz, 1H, 5-H), 3.82 (s,
3H, OMe), 3.84 (s, 3H, OMe), 4.09 (d, J = 14.4 Hz, 1H, 7-H),
4.11 (d, J = 14.4 Hz, 1H, 7-H), 5.08 (s, 1H, 4-CH2), 5.13 (s, 1H,
4-CH2), 6.52 (s, 1H, 11-H), 6.62 (s, 1H, 8-H); 13C NMR (100
MHz, CDCl3): δ = 26.6 (C-3), 27.3 (C-2), 31.1 (C-1), 38.1 (C-
11b), 44.8 (C-3a), 55.7 (C-7), 55.89 (OMe), 55.92 (OMe), 59.5
(C-5), 61.1 (C-3b), 107.6 (4-CH2), 109.2 (C-8), 111.2 (C-11),
121.6 (CN), 126.0 (Ar), 129.9 (Ar), 147.5 (Ar), 147.6 (Ar), 148.4
(C-4); HRMS (ESI): calcd for C19H22N2O2 [M+H]+ 311.17540,
found 311.17548.
4.9.3. 5-(2-Bromoacetyl)-8,9-dimethoxy-
2,3,4a,5,6,10b-hexahydrophe-nanthridin-4(1H)-one
(35)
To a cooled (0 °C) stirred solution of carbamate 33c (30 mg,
0.08 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL). The
reaction mixture was allowed to stir at room temperature for 4 h.
Excess solvent and TFA were removed on a rotavapor in vacuo
and the residual TFA was removed by adding several times
CH2Cl2 and concentration of the solution in vacuo to give the
solid amine salt, which was directly used in next step without
further purification.
To a cooled (0 °C) solution of salt and Et3N (36 µL, 0.25
mmol, 3 equiv) in CH2Cl2 (1 mL) was added bromoacetyl
bromide (8 µL, 0.10 mmol, 1.2 equiv) dropwise. The stirred
reaction mixture was allowed to reach room temperature within 1
h. For work-up, the mixture was treated with saturated NaHCO3
(2 mL), and this mixture was extracted with Et2O (3 × 2mL). The
combined organic layers was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. The crude amide was purified
by flash chromatography (petroleum ether/ethyl acetate, 2:1) to
provide pure amide 35 (20 mg, 65% over two steps) as yellow
solid. Rf = 0.3 (petroleum ether/ethyl acetate, 2:1); 1H NMR (400
MHz, CDCl3, mixture of rotamers): δ = 1.53-1.81 (m, 2H, 2-H),
1.82-2.01 (m, 1H, 2-H), 2.13-2.27 (m, 2H, 1-H), 2.28-2.46 (m,
2H, 1-H, 3-H), 2.54-2.75 (m, 1H, 3-H), 3.52-3.67 (m, 1H, 10b-
H), 3.78-3.86 (6H, 2 OMe), 3.90-4.08 (s, 1H, COCH2Br), 4.14-
4.31 (m, 1H, COCH2Br), 4.59-4.73 (m, 1H, 6-H), 4.76-4.92 (m,
1H, 6-H), 5.44 (d, J = 6.1 Hz, 1H, 4a-H), 6.52-6.59 (1H, 7-H),
6.68-6.75 (1H, 10-H); 13C NMR (100 MHz, CDCl3): δ = 21.0,
21.1, 25.9, 26.1, 27.0, 27.2, 38.9, 40.8, 41.2, 45.4, 45.8, 55.8,
55.8, 56.0, 56.1, 59.6, 59.64, 107.8, 107.9, 108.8, 109.2, 123.5,
124.4, 124.5, 124.7, 124.7, 148.3, 148.4, 166.5, 166.8, 205.1,
205.2; HRMS (ESI): calcd for C17H20BrNO4 [M+Na]+
404.04679, found 404.04670.
4.9.6. 9,10-Dimethoxy-4-methylene-
2,3,3a,3a,1,4,5,7,11b-octahydro-1H-pyrrolo[3,2,1-
de]phenanthridine (40)
To a solution of Ni(COD)2 (149 mg, 0.54 mmol, 2.0 equiv) in
dry acetonitrile (1 mL), at room temperature and under nitrogen
atmosphere, was added a solution of vinyl bromide 38 (100 mg,
0.27 mmol) and Et3N (117 µL, 0.81 mmol, 3.0 equiv) in dry
acetonitrile (1 mL). The reaction mixture was stirred at room
temperature for about 15 min, resulting in a color change from
yellow to black. When all starting material had been consumed
(checked by TLC), the quencher Et3SiH (137 µL, 0.85 mmol, 3.2
equiv) was added and the mixture stirred for additional 3 h. It
was filtered through Celite and the filter cake washed several
times with CH2Cl2. The filtrate was washed with saturated
Na2CO3 solution. The organic laywer was dried over Na2SO4,
filtered and concentrated in vacuo. Purification of the residue by
flash chromatography (CH2Cl2/MeOH, 9/1) afforded the
cyclization product 40 (54 mg, 70%) as yellow solid. Rf = 0.5
(CH2Cl2/MeOH, 9:1); 1H NMR (400 MHz, CDCl3): δ = 1.23-1.48
(m, 3H, 3-H, 2-H), 1.55-1.80 (m, 3H, 2-H, 1-H), 2.48-2.59 (m,
2H, 3a-H, 11b-H), 2.64-2.75 (m, 1H, 3b-H), 2.83 (d, J = 14.0 Hz,
1H, 5-H), 3.20 (d, J = 14.0 Hz, 1H, 5-H), 3.75 (s, 3H, OMe), 3.78
(s, 3H, OMe), 3.88 (d, J = 14.0 Hz, 1H, 7-H), 3.97 (d, J = 14.0
Hz, 1H, 7-H), 4.81 (s, 1H, 4-H), 4.82 (s, 1H, 4-H), 6.45 (s, 1H,
11-H), 6.57 (s, 1H, 8-H); 13C NMR (100 MHz, CDCl3): δ = 24.8
(C-2), 29.8 (C-3), 31.4 (C-1), 38.5 (C-11b), 43.5 (C-3a), 55.8
(OMe), 56.4 (C-7), 59.9 (C-5), 62.9 (C-3b), 103.9 (4-CH2), 109.2
(C-8), 111.3 (C-11), 125.7 (Ar), 131.5 (Ar), 147.2 (Ar), 147.6
(Ar), 152.2 (C-4); HRMS (ESI): calcd for C18H23NO2 [M+H]+
286.18016 found 286.18043.
4.9.4. 5-(2’-Bromoallyl)-8,9-dimethoxy-
1,2,4a,5,6,10b-hexahydro phenanthridine (38)
To a stirred solution of amine·HCl 20d (110 mg, 0.34 mmol)
in DMF (1 mL) was added NaH (60% dispersion in oil, 35 mg,
0.85 mmol, 2.5 equiv) and bromoallyl bromide (51 µL, 0.51
mmol, 1.5 equiv). The reaction mixture was allowed to stir at
room temperature for 1 h, before it was cooled to 0 °C and
quenched with H2O (2 mL). The mixture was extracted with
EtOAc (3 × 3mL). The combined organic layers were was
washed with H2O (3 × 3 mL) and saturated NaCl solution (3 mL),
drieed with anhydrous Na2SO, filtered, and concentrated in
vacuo. Purification of the residue by flash chromatography
(petroleum ether/ethyl acetate, 3:1) provided pure allylamine 38
(80 mg, 65%) as yellow oil. Rf = 0.6 (petroleum ether/ethyl
acetate, 1:1); 1H NMR (400 MHz, CDCl3): δ = 1.80-1.89 (m, 1H,
1-H), 1.92-2.03 (m, 2H, 2-H), 2.11-2.24 (m, 1H, 1-H), 2.92-3.01
(m, 1H, 10b-H), 3.40 (d, J = 16.0 Hz, 1H, 1'-H), 3.46-3.50 (m,
1H, 4a-H), 3.53 (d, J = 16.0 Hz, 1H, 1'-H), 3.58 (d, J = 15.2 Hz,
1H, 6-H), 3.81 (s, 3H, OMe), 3.84 (d, J = 15.2 Hz, 6-H), 3.85 (s,
3H, OMe), 5.57 (s, 1H, 3'-H), 5.71-5.79 (m, 1H, 4-H), 5.82-5.89
(m, 1H, 3-H), 5.91 (s, 1H, 3'-H), 6.48 (s, 1H, 10-H), 6.74 (s, 1H,
7-H); 13C NMR (100 MHz, CDCl3): δ = C-2), 26.6 (C-1), 35.2
(C-10b), 51.3 (C-6), 55.7 (OMe), 55.9 (C-1'), 56.0 (OMe), 60.9
(C-4a), 109.0 (C-7), 110.2 (C-10), 117.8 (C-2'), 126.0 (C-3'),
126.6 (Ar), 129.1 (Ar), 131.7 (C-4), 132.1 (C-3), 147.1 (Ar),
147.8 (Ar).
Acknowledgments

12
Tetrahedron
ACCEPTED MANUSCRIPT
Financial support by the Deutscher Akademischer
Austauschdienst (DAAD) for a fellowship to V. K. M. is
gratefully acknowledged. The authors would like to acknowledge
networking contribution by the COST Action CM1407
"Challenging organic syntheses inspired by nature - from natural
products chemistry to drug discovery".
6674; (o) Jung, Y.-G.; Lee, S.-C.; Cho, H.-K.; Darvatkar, N.
B.; Song, J.-Y.; Cho, C.-G. Org. Lett. 2012, 15, 132-135; (p)
Wang, Y.; Luo, Y.-C.; Zhang, H.-B.; Xu, P.-F. Org. Biomol.
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Supplementary data
General information, some procedures not included in the
main part and copies of NMR spectra. Supplementary data
associated with this article can be found in the online version, at
doi:
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