Total synthesis of (±)-Lycorine from the endo -cycloadduct of 3,5-dibromo-2-pyrone and (E)-β-borylstyrene

Article abstract of DOI:10.1021/ol502792p

A new synthetic route to (±)-lycorine, starting from the endo-cycloadduct of 3,5-dibromo-2-pyrone and (E)-β-borylstyrene, is reported. Boronate oxidation and a set of reactions including face-selective epoxidation provided the pivotal C1-OH group and C3/C3a double bond.

Full text of DOI:10.1021/ol502792p

Letter
pubs.acs.org/OrgLett
Total Synthesis of ( )-Lycorine from the Endo-Cycloadduct of 3,5-
Dibromo-2-pyrone and (E)‑β-Borylstyrene
Hyeong-Seob Shin, Yong-Geun Jung, Hyun-Kyu Cho, Yong-Gyu Park, and Cheon-Gyu Cho*
Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro, Seongdong-gu,
Seoul 133-791, Korea
S
* Supporting Information
ABSTRACT: A new synthetic route to ( )-lycorine, starting
from the endo-cycloadduct of 3,5-dibromo-2-pyrone and (E)-β-
borylstyrene, is reported. Boronate oxidation and a set of
reactions including face-selective epoxidation provided the
pivotal C1-OH group and C3/C3a double bond.
ycorine is a naturally occurring alkaloid widespread in the
Amaryllidaceae family of plants with a long history of use in
Scheme 1. Oxidative Functionalization of Ring C
L
traditional medicine.1 In connection with the natural product
based drug development, lycorine has received renowned
attention for its potent antitumor, antiviral, and anticholinester-
ase activities.2 Structurally, lycorine has a tetracyclic pyrrolo-
[de]phenanthridine ring system with four contiguous stereogenic
centers on ring C (Figure 1). Due to the C3/C3a double bond,
Figure 1. Selected pyrrolo[de]phenanthridine natural alkaloids.
ring C is in the same oxidation state as the aromatic A ring and
thus susceptible to aromatization, imposing additional challenges
in the synthesis. Not surprisingly, there are only a handful total
syntheses reported in the literature,3 despite efforts since the
structural determination.4
The problem in the synthesis arises from the installation of the
anti-oriented vicinal hydroxyl groups, as exemplified in some
early synthetic endeavors (Scheme 1). Tsuda and co-workers
elaborated a synthetic route utilizing epoxide 2. Subsequent
transformation to allylic alcohol 3 allowed the first total synthesis
of lycorine. Nonetheless, their route became obsolete due to the
inefficient low yielding synthesis of the cyclohexene 1. As an
alternative, Torssell and co-workers proceeded along the path by
way of more readily accessible cyclohexene intermediate 5.
However, it fared worse, because of the poor yield in the
synthesis of allylic alcohol 7. Another low-yielding acid-catalyzed
allylic transposition reaction delivered acetate 8 in 35% yield.
With no further improvement availed, many synthetic works
reported thereafter often ended up at the stage of cyclohexene 5
(known as Torssell’s intermediate).5
As a part of our ongoing studies exploring the utility of 3,5-
dibromo-2-pyrone in target-oriented synthesis,6 we have
demonstrated that lactam 12, accessed from bicyclolactone 11,
the cycloadduct of 3,5-dibromo-2-pyrone 9, and dienophile 10,
could be readily converted into 1-deoxylycorine (Scheme 2).6b
However, the direct application to the synthesis of lycorine
would be unattractive as the C1-OH installation may require the
conversion of lactam 12 to Torssell’s intermediate 5. In this
Received: September 22, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Scheme 2. Previous Synthesis of 1-Deoxylycorine
Scheme 4. Synthesis of Bicyclic Lactam Epoxide 24
context, we envisaged the pivotal C1-OH of lycorine could be
established in a similar way as in our previous synthesis of
pancratistatin using (E)-β-borylstyrene 14 for the Diels−Alder
reaction with 3,5-dibromo-2-pyrone 7. The boryl group of endo-
cycloadduct 15 was then oxidized to install the C1-OH group of
pancratistatin.6a Herein we wish to report our successful
integration of two synthetic strategies that allows an efficient
total synthesis of ( )-lycorine (16 → 17 → lycorine) (Scheme
3).
Scheme 3. Boronate as a Synthetic Equivalent of C1-OH
Group of Pancratistatin and Lycorine
However, further manipulation of epoxide 24 encountered a
deadlock, as the epoxide ring opening with phenyl selenide anion
afforded an inseparable mixture of two regioisomeric diols 25a
and 25b (3:2, Scheme 5). Evidently, there is little selectivity on
the nucleophilic attack at C2 vs C3.
Scheme 5. Epoxide Opening Reaction of 24
The synthesis commenced with the preparation of dienophile
16 from alkyne 18 by following the process reported previously
(Scheme 4).6a,7 The Diels−Alder cycloaddition with 3,5-
dibromo-2-pyrone 9 proceeded in a highly endo-selective fashion
to give bicyclolactone 19 in 74% yield. Oxidation of the boronate
group and Zn-mediated reductive removal of both Br groups
gave rise to alcohol 20 in 60% overall yield. The hydroxyl group
was then protected as PMB ether before the acidic methanolysis
of the lactone bridge to afford ester 21 (70% yield over two
steps). Subsequent Eschenmoser−Claisen rearrangement was
carried out under microwave irradiation conditions to provide
amide 22 in 86% yield.6b,8 Ester hydrolysis followed by Curtius
rearrangement and acidic hydrolysis gave lactam 23 in 42% total
yield over three steps from amide 22. Epoxidation of the allylic
double bond with mCPBA proceeded in a highly selective
manner, efficiently directed by the pseudo-equatorial allylic
hydroxyl group, to afford epoxide 24 as a single product in 83%
yield.9 Notably, no reaction was observed, when subjected to
vanadium-catalyzed epoxidation [t-BuOOH, VO(acac)2
(cat.)].10
We envisaged the undesired α-face attack at C2 that gives
epoxide opening product 25b could be suppressed if the
equatorial hydroxyl group was replaced by a large axially oriented
substituent. Toward this end, epoxide 24 was employed in a
Mitsunobu reaction with 4-nitro-benzoic acid to give rise to
benzoate 26. As expected, the axial 4-nitrobenzoate group
effectively blocked the nucleophilic reaction at the C2 carbon and
resulted in the exclusive formation of a C3-opening product (26
→ 27, Scheme 6). During the reaction, the 4-nitro-benzoyl group
was concomitantly cleaved off. The unstable diol 27 was
immediately converted into diacetate 28 (82% overall yield
from epoxide 27).
For the end-game synthesis, we adapted the route developed
by Sano and co-workers to build ring B prior to the installation of
the C3−C3a double bond.3f In fact, the synthesis in reverse order
proved to be ineffective.3d Subjection to Pictet−Spengler
reaction conditions allowed a rapid construction of ring B (28
→ 29, Scheme 7). Subsequent selenoxide elimination reaction
B
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Organic Letters
Letter
Scheme 6. Oxidative Functionalization of Ring C
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Scheme 7. End Game Synthesis of Lycorine
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generated the C3/C3a double bond, which provided tetracyclic
lactam 30 in 71% over two steps. LiAlH4 reduction of lactam 31
in THF gave rise to lycorine.11 Because of poor solubility in
standard organic solvents, the lycorine product was converted
into diacetate 31 for the structural confirmation.
In summary, we have developed a new synthetic route to
( )-lycorine starting from the endo-cycloadduct of 3,5-dibromo-
2-pyrone and (E)-β-borylstyrene. Boronate oxidation and a set of
reactions including face-selective epoxidation provided the
pivotal C1-OH group and C3/C3a double bond. We are
currently pursuing enantioselective syntheses of the Amaryllida-
ceae type alkaloids including (−)-lycorine with the development
of catalytic asymmetric Diels−Alder reactions of 3,5-dibromo-2-
pyrone.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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*E-mail: ccho@hanyang.ac.kr.
Notes
(11) Actual yield was not measured due to the low solubility. The same
reduction was reported in the literature, furnishing ( )-lycorine in 49%
isolation yield (ref 3f).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the grants from the National
Research Foundation of Korea (2012R1A2A4A01005064 and
2012M3A7B4049661).
C
dx.doi.org/10.1021/ol502792p | Org. Lett. XXXX, XXX, XXX−XXX