A concise total synthesis of (?)-γ-lycorane via an aromatic C[sbnd]H alkylation of unactivated secondary alkyl iodide

Article abstract of DOI:10.1016/j.tetlet.2020.151733

A concise and straightforward total synthetic approach towards lycorine-type alkaloid (?)-γ-lycorane has been achieved in 7 steps. The key feature of the route is the employment of a palladium-catalyzed aromatic C[sbnd]H alkylation of unactivated secondary alkyl iodide. The synthetic protocols also involve a palladium-catalyzed deracemization of allylic carbonate, a Johnson-Claisen rearrangement and an iodocyclization.

Full text of DOI:10.1016/j.tetlet.2020.151733

Journal Pre-proofs
A concise total synthesis of (-)-γ-lycorane via an aromatic C-H alkylation of
unactivated secondaryalkyl iodide
Yiying Pang, Hesheng Xiao, Wentao Ou, Xuesong Zhang, Xiaoji Wang,
Shuangping Huang
PII:
S0040-4039(20)30156-8
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151733
TETL 151733
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 January 2020
7 February 2020
11 February 2020
Please cite this article as: Pang, Y., Xiao, H., Ou, W., Zhang, X., Wang, X., Huang, S., A concise total synthesis
of (-)-γ-lycorane via an aromatic C-H alkylation of unactivated secondaryalkyl iodide, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.151733
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Graphical Abstract
A concise total synthesis of (-)-γ-lycorane via
an aromatic C-H alkylation of unactivated
secondary alkyl iodide
Leave this area blank for abstract info.
Yiying Panga, Hesheng Xiaoa, Wentao Oua, Xuesong Zhanga, Xiaoji Wanga,b* and Shuangping Huangc,*

1
Tetrahedron Letters
A concise total synthesis of (-)-γ-lycorane via an aromatic C-H alkylation of
unactivated secondary alkyl iodide
Yiying Panga, Hesheng Xiaoa, Wentao Oua, Xuesong Zhanga, Xiaoji Wanga,b* and Shuangping Huangc,*
a School of Life Science, Jiangxi Science and Technology Normal University
b School of Chemical Engineering and Energy Technology, Dongguan University of Technology
c College of Biomedical Engineering, Taiyuan University of Technology
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise and straightforward total synthetic approach towards lycorine-type alkaloid (-)-γ-
lycorane has been achieved in 7 steps. The key feature of the route is the employment of a
palladium-catalyzed aromatic C-H alkylation of unactivated secondary alkyl iodide. The
synthetic protocols also involve a palladium-catalyzed deracemization of allylic carbonate, a
Johnson-Claisen rearrangement and an iodocyclization.
Available online
Keywords:
(-)-γ-lycorane
natural product
total synthesis
2009 Elsevier Ltd. All rights reserved.
aromatic C-H alkylation
Introduction
Being rich in bioactive natural alkaloids, amaryllidaceae
family of plants, such as daffodils and smowdrops, play an
important role in natural product research.[1] As a large class of
subclass of amaryllidaceae alkaloids, the lycorine-type alkaloids
with
tetracyclic
pyrrolo[d,e]phenanthridine
frameworks
(galanthan ring system, Figure 1), usually possessing potent and
wide-range biological activities have accordingly attracted
considerable attention of communities of medicinal and synthetic
chemistry.[2] Among these alkaloids, the difference of structures
is mainly focusing on the cis- or trans- configuration and the
diverse oxidation states of B/C/D ring. Although no apparently
useful pharmaceutical properties
were demonstrated,
nevertheless, γ-lycorane was one of the molecules of
amaryllidaceae family with highest interesting,[3] which might be
due to that synthesis of γ-lycorane deemed to demonstrate the
suitability of the developed synthetic methodology or that
synthesis of γ-lycorane could lay the important foundation of
other more complex lycorine-type compounds with cis-B/C, C/D
rings. As part of our ongoing interesting in research on natural
alkaloids with complex structure and potent biological
activities,[4] we are interesting in developing an efficient and
practical synthetic approach to access lycorine-type alkaloids.
Herein, we presented a highly concise tactic for total synthesis of
(-)-γ-lycorane.
Figure 1. Structures of some lycorine-type alkaloids.
Our retrosynthetic analysis of (-)-γ-lycorane was briefly
outlined in Scheme 1. Recently, prof. Alexanian described a
catalytic palladium-catalyzed C-H alkylation using unactivated
alkyl halides and a variety of arenes and heteroarenes to deliver
carbocyclic and heterocyclic products.[5] However, there were
fewer applications using this methodology on total synthesis of
complex natural product[6]. Inspired by their methodology, we
hypohtesized that (-)-γ-lycorane would be obtained via an
intramolecular aromatic C-H alkylation from unactivated
secondary alkyl iodide 1. The precursor iodide 1 was assumed to
be derived from amine intermediate 2 through an intramolecular

2
Tetrahedron Letters
°C, 91%; (d) i, MeOH, r.t., 4 h; ii, NaBH4, 0 °C, 4 h, 84% (over
two steps).
iodocyclization, which would undergo a substrate-controlled
process to give the desired cis-5,6 ring (C/D ring). Amine 2 was
devised to be assembled through a reductive amination, hence,
the retrosynthetic route was readily disconnected to amine 3 and
aldehyde 4. For aldehyde 4, it should be readily converted from
commercially 2-cyclohexen-1-ol 5.
With 2 in hand, our next step was to construct the cis 5,6-ring
(cis-octahydro-1H-indole ring) of 1. Therefore, compound 2
was then subjected to an intramolecular iodocyclization with
different electrophilic iodine source. As shown in Table 1, a
series of conditions reported in the literatures to construct cis-
octahydro-1H-indole ring were conducted. When treated with N-
iodosuccinimide (NIS) either in DCM or tetrahydrofuran
(THF),[11] compound 1 could be obtained in 84% or 76% yields
(entries 1, 2). Additive such as iodine was used,[12] and no
improvement of yield was observed (entry 3). We also subjected
amine 2 to iodocyclization with I2/ K2CO3, in DCM at room
temperature,[13] satisfactorily, delivering a higher yield (90%).
Table 1. Examination of intramolecular iodocyclization to
construct cis-octahydro-1H-indole ring.
temperature
(°C)
yield
(%)a
entry
1
iodide
NIS
solvent
THF
0-rt
0-rt
-78
0-rt
84
76
73
90
Scheme 1. Retrosynthetic analysis of (-)-γ-lycorane.
Results and discussion
2
3
4
NIS
DCM
DCM
DCM
As depicted in Scheme 2, the synthesis of (-)-γ-lycorane was
initiated by using commercially 2-cyclohexen-1-ol 5. The chiral
element of the synthesis was introduced via a palladium-
catalyzed deracemization of allylic carbonate following Gais’s
strategy.[7] According to the standard procedure in the literature,
the (S)-2-cyclohexen-1-ol (S-5) was obtained in gram-scale in
good yield and enatioselectivity (90%, 97% ee value) in the
mixture of dichloromethane (DCM) and water (DCM/H2O,
solvent v/v=9:1). With compound S-5 in hand, we conducted a
Johnson-Claisen rearrangement to install the acetic acid residue
to cyclohexene at the allylic position.[8] Upon treatment with
excess triethyl orthoacetate in the presence of catalytic o-
nitrophenol in refluxing xylene for 12 hours, (S)-2-cyclohexen-1-
NIS/I2
I2/K2CO3
a Yield based on isolation by column chromatography.
At this stage, retrosynthetically, we needed to construct the B
ring to achieve the natural product (-)-γ-lycorane via the
aromatic C-H alkylation from unactivated alkyl secondary iodide
1. Hence, as displayed in Table 2, a series of representative
conditions reported in the literature were conducted.[5, 14] When
treated with Pd(OAc)2 in 1,4-dioxone in the presence of Cs2CO3,
(-)-γ-lycorane was obtained in about 30% yield, accompanying
with almost the same amount of regioisomer 7 (entry 1).
However, the ratio of the desired product (-)-γ-lycorane and the
unexpected regioisomer 7 was nearly 1:1, which was determined
by NMR spectra. This might be contribute to the almost equal
reaction activities between the ortho-position and the para-
position at 1,3-benzodioxole ring (on the base of the bottom
oxygen atom). Pd(PPh3)4 was found an effective catalyst to the
aromatic C-H alkylation of alkyl iodide 1 in the presence of
either K3PO4 or Cs2CO3 at 100 °C using 1,4-dioxone as the
solvent, and total yield of (-)-γ-lycorane and 7 could be up to
about 90%, however, with no change of regioselectivity.
Increasing the loading of Pd(PPh3)4 could not improve the yield
and regioselectivity of the desired natural product (entries 2-5).
When changing the solvent to PhCF3, the same result was
observed (entry 6). The physical and spectral data (1H, 13C) of (-
)-γ-lycorane from our lab were in agreement with those reported
in the literature.[3n]
ol
and triethyl orthoacetate was smoothly and
stereoselectively converted into ester 6 in 85% yield. The ester
group was then reduced to homoallylic aldehyde 4 smoothly
using diisobutylaluminum hydride (DIBAL-H) in the solvent of
DCM at -78 °C (91%). According to the retrosynthetic strategy
for constructing secondary amine 2, aldehyde 4 was then subject
to reductive
amination with known
amine 3,4-
methylenedioxybenzylamine.[9] After stirring at room
temperature for 4 hours, the resulting solution of aldehyde 4 and
amine 3 in MeOH was cooled down to 0 °C and subsequently
treated with sodium borohydride to give intermediate 2 in 84%
yield from aldehyde 4.[10]
Table 2. Examination of aromatic C-H alkylation of
unactivated secondary alkyl iodide.
Scheme 2. Asymmetic synthesis of intermediate 2. Reaction and
conditions: (a) ref. 1, 90%, 97% ee; (b) triethyl orthoacetate, o-
nitrophenol, xylene, reflux, 12 h, 85%; (c) DIBAL-H, DCM, -78
entry
conditions
yield
Ratiob

3
(%)a
61
((-)-γ-lycorane:7)
carbonate,
a
Johnson-Claisen rearrangement and an
0.1 equiv. Pd(OAc)2,
2.0 equiv. Cs2CO3, 1,4-
dioxone, 100 °C
iodocyclization. This synthetic strategy provides an alternative
route to lycorine-type alkaloids. Further studies on the
application of this approach to natural products containing
alkaloids with tetracyclic pyrrolo[d,e]phenanthridine units are in
progress and will be disclosed in due course.
1
~1:1
0.1 equiv. Pd(Ph3)4, 2.0
equiv. K3PO4, 1,4-
dioxone, 100 °C
2
entry
3
91
~1:1
yield
(%)a
Ratiob
((-)-γ-lycorane:7)
Acknowledgment
conditions
We thank the National Science Foundation of China
(21062088, 21562020) and the Science and Technology Plan
Project of Jiangxi Province (No. 20151BBG70028,
20142BBE50006) for the funding support.
0.2 equiv. Pd(Ph3)4, 2.0
equiv. K3PO4, 1,4-
dioxone, 100 °C
89
90
91
88
~1:1
~1:1
~1:1
~1:1
0.1 equiv. Pd(Ph3)4, 2.0
equiv. Cs2CO3, 1,4-
dioxone, 100 °C
4
5
6
A. Supplementary data
0.2 equiv. Pd(Ph3)4, 2.0
equiv. Cs2CO4, 1,4-
dioxone, 100 °C
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/....
0.1 equiv. Pd(Ph3)4, 2.0
equiv. Cs2CO3, PhCF3,
100 °C
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a Yield based on isolation by column chromatography.
b The ratio was determined by NMR spectra..
The above result demonstrated that the two ortho-position of
benzyl group would be both attacked in the reaction. The
regioselectivity was according with the Cossy’s observation,[3o]
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Figure 2. Proposed mechanism of palladium-catalyzed aromatic
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In summary, we have successfully achieved a concise and
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catalyzed aromatic C-H alkylation of unactivated secondary
alkyl iodide. To the best of our knowledge, the present synthetic
route is the shortest approach to (-)-γ-lycorane compared with all
other total syntheses that had been published. The protocol also
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Highlights
A concise total synthesis of (-)-γ-lycorane.
The shortest synthetic approach in only 7
steps.
Palladium-catalyzed aromatic C-H alkylation
to generate ring B.
Intramolecular iodocyclization to construct the
cis- 5,6-ring.