Short Total Synthesis of (±)-γ-Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction

Article abstract of DOI:10.1002/chem.201700143

An intramolecular acylal cyclisation (IAC) approach to the synthesis of a range of bicyclic heterocycles is reported. As an example of the utility of the IAC reaction, the methodology was applied in a protecting-group-free five-step total synthesis of (±)-γ-lycorane, incorporating a new intramolecular Heck addition reaction to generate the pentacyclic core structure of the natural product in good yield.

Full text of DOI:10.1002/chem.201700143

A Journal of
Accepted Article
Title: A Short Total Synthesis of (±)-Lycorane by a Sequential
Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck
Addition Reaction
Authors: Alessandra Monaco, Blanka R Szulc, Zenobia X Rao, Marta
Barniol-Xicota, Moussa Sehailia, Bruno Borges, and Stephen
Hilton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201700143
Link to VoR: http://dx.doi.org/10.1002/chem.201700143
Supported by

10.1002/chem.201700143
Chemistry - A European Journal
COMMUNICATION
A Short Total Synthesis of (±)--Lycorane by a Sequential
Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck
Addition Reaction
Alessandra Monaco,[a] Blanka R. Szulc,[a] Zenobia X. Rao,[a] Marta Barniol-Xicota,[b] Moussa Sehailia,[a]
Bruno M. A. Borges[a] and Stephen T. Hilton*[a]
Due to their potent and wide ranging activities and their
associated structural complexity, they have accordingly attracted
significant efforts towards their syntheses,9-15 including radical
cyclisation, aminocyclisation, intramolecular addition reactions
and several metal-catalyzed amidations amongst others.9-16
Despite the structural diversity of both classes of compound and
the wide array of synthetic methods used in their syntheses, many
have focused on the synthesis of the dihydroindolenone core 11,
due to its ready elaboration to either of the core structures of
erythrina (1-3) or lycorane alkaloids (4-10) (Figure 2).10,16,17
Abstract: An intramolecular acylal cyclisation (IAC) approach to the
synthesis of a range of bicyclic heterocycles is reported. As an
example of the utility of the IAC reaction, the methodology was applied
in a protecting-group free five-step total synthesis of (±)--lycorane,
incorporating a novel intramolecular Heck addition reaction to
generate the pentacyclic core structure of the natural product in good
yield.
Heterocycles based on indole and substituted hydroindole
derivatives are found in an array of natural products and have
been heavily exploited in medicinal chemistry due to their potent
and wide-ranging biological activities.1 Examples of natural
product alkaloids incorporating this bicyclic motif include the
erythrina and lycorane alkaloid families which display potent and
wide ranging biological activities.1-3 Erythrina derived compounds
1-3, display anxiolytic, anticonvulsant, sedative, antidepressive
and antiepileptic effects,4-6 whilst lycorane derivatives as
exemplified by 4-10 display central nervous system effects,
acethylcolinesterase inhibition, antimalarial, analgesic and anti-
inflammatory activity.7,8 Lycorane alkaloids have also been shown
to display significant antiproliferative activity in various cancer cell
lines including melanoma, multiple melanoma, leukaemia,
carcinoma, lymphoma, glioblastoma and non-small cell lung
cancer (Figure 1).7,8
Figure 2. The hydroindolenone 11 intermediate used in the synthesis of both
lycorane and erythratin.
As a result of the structural complexities and potent
biological activities associated with each class of compound, we
were interested in the development of novel methodology to
access molecules related to the bicyclic core 11 as a route to both
classes of compound.18,19 We were also cognizant of the need to
develop a flexible route which would facilitate the synthesis of a
range of analogues for biological testing. In a previous approach
to the erythratin core 12, we had developed a facile two-step
domino cyclisation process, which focused on a Lewis acid
mediated intramolecular acylal cyclisation (IAC) via intermediate
13 (Scheme 1).18-21 We were therefore interested in the possibility
that in the case of an N-benzyl substituted analogue (n = 1), the
intermediate iminium ion 13 would not undergo a further
intramolecular addition reaction with the aryl moiety, but would
instead undergo tautomerisation to the intermediate 16, which
with a suitably designed precursor could undergo radical
cyclisation to generate the lycorane core 15 as per literature
precedent and is outlined below (Scheme 1).16
Figure 1. Natural products based on the erythratin 1-3 and lycorane cores 4-10.
[a]
Dr A. Monaco, Dr B. R. Szulc, Miss Z. X. Rao, Dr M. Sehailia, Mr B.
M. A. Borges, Dr S. T. Hilton
UCL School of Pharmacy
University College London
29-39 Brunswick Square, London, WC1N 1AX, United Kingdom
E-mail: s.hilton@ucl.ac.uk
[b]
Dr Marta Barniol-Xicota
Laboratori de Quꢀmica Farmacꢁutica (Unitat Associada al CSIC),
Facultat de Farmꢂcia, and Institute of Biomedicine (IBUB),
Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028,
Spain
Scheme 1. Proposed synthetic route to both the erythratin 12 and lycorane 15
cores.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700143
Chemistry - A European Journal
COMMUNICATION
To investigate our hypothesis that both classes of
compound could be accessed using this approach via simple
variation of the N-substituent and to explore the synthesis of a
range of bicyclic heterocycles related to compound 16, we first
reacted benzylamine 17 with cyclohexanone under Dean and
Stark water removal conditions. Intermediate 18 was
subsequently reacted with diacetoxyacetyl chloride 19, in the
presence of pyridine using our previously published methodology
to give the intramolecular acylal cyclisation precursor 20a in 86%
yield.18-21 On reaction with BF3.OEt2 (5 equiv.) and heating the
reaction mixture in the microwave (Biotage Initiator) at 65 C for
15 minutes, the reaction did not give the expected bicyclic
heterocycle 16, but instead led to formation of dihydroindolenone
21a in good yield (78%) (Scheme 2).
predominant, it is likely that the intermediate bicyclic acetate - 24
(obtained after reaction of the nucleophilic enamine with the
oxonium ion) is unstable and readily undergoes hydride loss to
give 25. Further activation via BF3 and loss of acetate followed by
tautomerisation provides a ready mechanistic route to the
dihydroindolenone core 21a.
Following the success in the formation of the bicyclic
dihydroindolenone core 21a, we next elected to explore the scope
of this reaction in the synthesis of a range of closely related
analogues through simple variation of the initial ketone
component in order to explore the scope of the reaction with
variation of ring size and incorporation of substituents on the aryl
ring in order to develop an advanced intermediate towards the
synthesis of the lycorane core 15. The desired cyclisation
precursors 20b-20h were prepared in good yields (55-97%) as
shown below (Scheme 3).
Scheme 3. Formation of bicyclic heterocycle cyclisation precursor analogues.
Compounds 20b and 20d were chosen to explore the effect
of different ring sizes on the reaction outcome, whilst other
cyclisation precursors were selected to explore the effects of
electron-donating substituents on the aromatic ring as an
approach towards the total synthesis of (±)--Lycorane 5. All
reactions were heated in the microwave at 65 °C for 15 minutes
as per the formation of the initial bicyclic dihydroindolenone 21a
and the results are shown below (Scheme 4).
Scheme 2. Cyclisation via an Intramolecular Acylal Cyclisation reaction to give
the bicyclic core – 21a and a proposed mechanism for formation.
Whilst obtention of the dihydroindolenone 21a was
unexpected as we had anticipated that product 16 would be
This article is protected by copyright. All rights reserved.

10.1002/chem.201700143
Chemistry - A European Journal
COMMUNICATION
excellent yield (72%). Reaction with boron trifluoride diethyl
etherate as per standard conditions gave the bicyclic
dihydroindolenone 33 in 87% yield (Scheme 5).
Scheme 5. Synthesis of (±)--lycorane cyclisation precursor 34.
Attempts to synthesize lycorane from the bicyclic precursor 33
under previous analogous radical conditions led to degradation of
the starting material in all cases.16 We attributed this to the
inherent stability of the conjugated double bond and therefore
sought an alternative approach. We were therefore intrigued by a
novel palladium-mediated intramolecular Heck reaction with the
conjugated amidic carbonyl and as such, elected to explore a
range of Heck coupling conditions with 33 (Scheme 6).23
Scheme 4. Formation of bicyclic core analogues.
As can be seen above, all compounds gave good yields of
the bicyclic core structures (21b-21h) following intramolecular
acylal cyclisation. The formation of the bicyclic fused [3.3.0] and
[5.3.0] ring systems in compounds 21b and 21d showed a
reduction in yield (65% and 60% respectively) when compared
with the initial cyclisation to give 21a. The extended conjugated
tricyclic compound was also obtained in good yield (71%), with
the double bond undergoing a hydride shift to give the more
thermodynamically stable compound 21f.22 Incorporation of an
electron donating group on the N-benzyl substituent as
exemplified by 21c and others was also very well tolerated with
good yields obtained in all cases 45-75%. Pleasingly, compound
21g which is an advanced synthetic intermediate towards (±)--
lycorane 5, was also obtained in excellent yield (75%). With the
successful demonstration of the formation of the cyclized
compounds which are suitable for elaboration to lycorane
analogues, attention then focused on the total synthesis of (±)--
lycorane 5 to demonstrate the flexibility of our IAC approach. In
order to access the core structure of lycorane and synthesize the
B-ring of the tetracyclic core via our planned radical cyclisation
mediated route, we required a halogen atom on the N-benzyl
substituent. As such, piperonylamine 29 was reacted with
bromine in acetic acid to give 30 in 80% yield. Generation of the
free base, followed by condensation with cyclohexanone and
diacetoxyacetyl chloride 19 gave the cyclisation precursor 32 in
Scheme 6. Synthesis of the pentacyclic (±)--lycorane core 34 via an
intramolecular Heck cyclisation.
Initial reaction of the cyclisation precursor 33 under Heck
cyclisation conditions using palladium diacetate as catalyst in
dioxane, gave the cyclized product 34 albeit in low yield (5%)
(Table 1, Entry 1).23 Optimization of the reaction conditions via
use of triphenylphosphine palladium dichloride as catalyst and
heating the reaction in the microwave at 150 °C for one hour
afforded the Heck cyclisation product in good yield (74%) (Table
1, Entry 4).23
Table 1. Heck cross-coupling optimization.
Entry
Solvent
Dioxane
DMF
Time
30 min.
1h.
Catalyst
Pd(OAc)2
Yield %
1
2
3
4
5
Pd(OAc)2
20
15
74
DMF
1h.
Pd(OAc)2
DMF
1h.
(PPh3)2PdCl2
This article is protected by copyright. All rights reserved.

10.1002/chem.201700143
Chemistry - A European Journal
COMMUNICATION
Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier,
Oxford, 2008, 353-388.
Following efficient formation of the pentacyclic core of
lycorane, we next sought to complete the total synthesis of (±)--
Lycorane 5. Hydrogenation of the conjugated double bonds in 34
via use of an H-cube hydrogenation flow reactor using a mixture
of ethanol and ethyl acetate as solvent to aid solubility, with a flow
rate of 0.5 mL/ min and 10% palladium on charcoal as catalyst at
65 °C and 60 bar pressure gave the reduced product 35 in almost
quantitative yield (97%). Reduction following literature precedent
using lithium aluminium hydride completed the synthetic route to
give the total synthesis of (±)--Lycorane 5 in 85% yield (Scheme
7).16e
[2]
[3]
a) U. P. De Albuquerque, P. M. De Medeiros, A. L. S. De Almeida, J. M.
Monteiro, E. M. D. F.L. Neto, J. G. De Melo, J. P. Dos Santos, J.
Ethnopharm. 2007, 114, 325-354; b) Y. Tsuda, T. Sano in The Alkaloids,
Vol 48 (Ed.: G. A. Cordell), Academic Press, New York, 1996, 249-337.
a) B. Deng, L. Ye, H. Yin, Y. Liu, S. Hu and B. Li, J. Chromatogr. B 2011,
879, 927-932; b) X. Li, H.-Y. Yu, Z.-Y. Wang, H.-F. Pi, P. Zhang and H.-
L. Ruan, Fitoterapia 2013, 88, 82-90; c) W.-M. Wu, Y.-Y. Zhu, H.-R. Li,
H.-Y. Yu, P. Zhang, H.-F. Pi and H.-L. Ruan, J. Asian Nat. Prod. Res.
2013, 16, 192-199; d) S.-D. Huang, Y. Zhang, H.-P. He, S.-F. Li, G.-H.
Tang, D.-Z. Chen, M.-M. Cao, Y.-T. Di and X.-J. Hao, Chin. J. Nat. Med.
2013, 11, 406-410.
[4]
[5]
G. M. Onusic, R. L. Nogueira, A. M. S. Pereira, M. B. Viana, Braz. J. Med.
Biol. Res. 2002, 35, 473-477.
S. M. M. Vasconcelos, N. M. Lima, G. T. M. Sales, G. M. A. Cunha, L. M.
V. Aguiar, E. R. Silveira, A. C. P. Rodrigues, D. S. Macedo, M. M. F.
Fonteles, F. C. F. Sousa, G. S. B. Viana, J. Ethnopharmacol. 2007, 110,
271-274.
[6]
[7]
a) J. O. A. Flausino, A. M. Pereira, V. D. S. Bolzani, R. L. Nunes-de-
Souza, Biol. Pharm. Bull. 2007, 30, 375-378; b) P. Setti-Perdigão, M. A.
R. Serrano, O. A. Flausino, V. S. Bolzani, M. Z. P. Guimarães, N. G.
Castro, PloS ONE 2013, 8, e82726; c) J. Sarris, E. McIntyre, D. Camfield,
CNS Drugs 2013, 27, 207-219.
a) Z.-M. Liu, X.-Y. Huang, M.-R. Cui, X.-D. Zhang, Z. Chen, B.-S. Yang
and X.-K. Zhao, Fitoterapia 2015, 101, 188-193; b) B. Hao, S.-F. Shen
and Q.-J. Zhao, Molecules 2013, 18, 2458-2468; c) J. McNulty, J. J. Nair,
J. R. L. Little, J. D. Brennan, J. Bastida, Bioorg. Med. Chem. Lett. 2010,
20, 5290-5294; d) M. R. Herrera, A. K. Machocho, R. Brun, F. Viladomat,
C. Codina, J. Bastida, Planta Med. 2001, 67, 191-193.
Scheme 7. Total synthesis of (±)--lycorane 5.
In summary, we have developed a novel five-step route to the
total synthesis of (±)--Lycorane 5, which is based on a novel
sequential intramolecular acylal cyclisation/ Heck addition
approach. In addition, we have shown that by variation of the
starting ketone or the N-benzyl substituent of the precursor, we
will be able to generate a number of substituted analogues as
demonstrated by the efficient formation of the bicyclic core. Our
approach is readily adaptable to incorporation of heteroatom
substituents and further studies on these are under way in our
laboratories and will be reported in due course.
[8]
a) D. Lamoral-Theys, A. Andolfi, G. Van Goietsenoven, A. Cimmino, B.
Le Calvé, N. Wauthoz, V. Mégalizzi, T. Gras, C. Bruyère, J. Dubois, V.
Mathieu, A. Kornienko, R. Kiss and A. Evidente, J. Med. Chem. 2009,
52, 6244-6256; b) W. E. Campbell, J. J. Nair, D. W. Gammon, C. Codina,
J. Bastida, F. Viladomat, P. J. Smith and C. F. Albrecht, Phytochemistry
2000, 53, 587-591; c) X.-S. Liu, J. Jiang, X.-Y. Jiao, Y.-E. Wu, J.-H. Lin
and Y.-M. Cai, Cancer Lett. 2009, 274, 16-24; d) P. Wang, H.-H. Yuan,
X. Zhang, Y.-P. Li, L.-Q. Shang and Z. Yin, Molecules 2014, 19, 2469-
2480; e) M. Jokhadze, L. Eristavi, J. Kutchukhidze, A. Chariot, L.
Angenot, M. Tits, O. Jansen and M. Frédérich, Phytother. Res. 2007, 21,
622-6240; f) J. J. Nair, J. Staden, J. Bastida, Curr. Med. Chem. 2016, 23,
161-185; g) J. McNulty, J. J. Nair, M. Singhi, D. J. Crankshaw, A. C.
Holloway, J. Bastida, Bioorg. Med. Chem. Lett. 2009, 19, 3233-3237; h)
J. McNulty, J. J. Nair, J. Bastida, S. Pandey, C. Griffin, Phytochemistry
2009, 70, 913-919; i) Z. Jin, Nat. Prod. Res. 2005, 22, 111-126.
For recent examples see: a) A. Padwa, H. I. Lee, P. Rashatasakhon, M.
Rose, J. Org. Chem. 2004, 69, 8209-8218; b) M. A. Ledreau, D.
Desmaele, F. Dumas, J. d'Angelo, J. Org. Chem. 1993, 58, 2933-2935;
c) C. L’Homme, M. Ménard, J. Org. Chem. 2014, 79, 8481-8485; d) J. M.
Joo, R. A. David, Y. Yuan, C. Lee, Org. Lett. 2010, 12, 5704-5707; d) J.
X. Liang, J. B. Chen, J. P. Liu, L. Li, H. B. Zhang, Chem. Commun. 2010,
46, 3666-3668; e) T. Onoda, Y. Takikawa, T. Fujimoto, Y. Yasui, K.
Suzuki, T. Matsumoto, Synlett 2009, 1041-1046; f) Y. Yoshida, K. Mohri,
K. Isobe, T. Itoh, K. Yamamoto, J. Org. Chem. 2009, 74, 6010-6015.
Acknowledgements
This work was gratefully supported by an FNS visiting
postdoctoral fellowship grant to A.M. [P2GEP2_151840] and a
Leverhulme Trust project grant [F/01 232/A]. We thank the
EPSRC UK National Mass Spectrometry Facility at Swansea
University for spectroscopic services.
[9]
Keywords: Erythrina • Lewis acid • Lycorane • tandem cyclisation
• Heck
[1]
a) A. J. Clark, Chem. Soc. Rev. 2002, 31, 1-11; b) D. O'Hagan, Nat.
Prod. Rep. 2000, 17, 435-446; c) M. d’Ischia, A. Napolitano and A.
Pezzella, in Comprehensive Heterocyclic Chemistry III, eds. A. R.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700143
Chemistry - A European Journal
COMMUNICATION
[10] For examples see: a) B. Juma, M. Adeel, A. Villinger, H. Reinke, A.
Spannenberg, C. Fischer, P. Langer, Adv. Synth. Catal. 2009, 351, 1073-
1079; b) P. C. Stanislawski, A. C. Willis, M. G. Banwell Org. Lett. 2006,
8, 2143-2146; c) G. Kim, J. H. Kim, K. Y. Lee, J. Org. Chem. 2006, 71,
2185-2187; d) Y. Yasui, K. Suzuki, T. Matsumoto, Synlett 2004, 619-622;
d) D. Kalaitzakis, T. Montagnon, E. Antonatou, G. Vassilikogiannakis,
Org. Lett. 2013, 15, 3714-3717; e) S. Ogawa, N. Iida, E. Tokunaga, M.
Shiro, N. Shibata, Chem. Eur. J. 2010, 16, 7090-7095; f) L. F. Tietze, N.
Tolle, D. Kratzert, D. Stalke, Org. Lett. 2009, 11, 5230-5233; g) F. Z.
Zhang, N. S. Simpkins, A. J. Blake, Org. Biomol. Chem. 2009, 7, 1963-
1979; h) A. Padwa, Q. Wang, J. Org, Chem. 2006, 71, 7391-7402; i) H.
Ishibashi, K. Sato, M. Ikeda, H. Maeda, S. Akai, Y. Tamura, J. Chem.
Soc. Perkin Trans. 1 1985, 605-609; j) Y.-M. Zhao, P. Gu, Y.-Q. Tu, H.-
J. Zhang, Q.-W. Zhang, C.-A. Fan, J. Org. Chem. 2010, 75, 5289-5295.
[11] a) S. R. Angle, J. P. Boyce, Tetrahedron Lett. 1995, 36, 6185-6188; b)
K. Nishimura, N. Fukuyama, T. Yashuhara, M. Yamashita, T. Sumiyoshi,
Y. Yamamoto, K. –I Yamada, K. Tomioko, Tetrahedron 2015, 71, 7222-
7226; c) Y. Wang, H. Lu, P. –F. Xu, Acc. Chem. Res. 2015, 48, 1832-
1844; d) I. A. Andreev, N. K. Ratmanova, A. M. Novoselov, D. S. Belov,
I. F. Seregina, A. V. Kurkin, Chem. Eur. J. 2016, 22, 7262-7267; e) Z.
Sun, M. Zhou, X. Li, X. Meng, F. Peng, H. Zhang, Z. Shao, Chem. Eur.
J. 2014, 20, 6112-6119; f) Y. –G. Jung, S. –C. Lee, H. –K. Cho, N. B.
Darvatkar, J. –Y. Song, C. –G. Cho, Org. Lett. 2013, 15, 132-135; g) D.
Liu, L. Ai, A. Zhao, J. Chen, H. Zhang, J. Liu, Org. Biomol. Chem. 2014,
12, 3191-3200; h) E. S. Conner, K. E. Crocker, R. G. Fernando, F. R.
Fronczek, G. G. Stanley, J. R. Ragains, Org. Lett. 2013, 15, 5558-5561.
[12] a) G. Li, J. –H. Xie, J. Hou, S. –F. Zhu, Q. –L. Zhou, Adv. Synth. Catal.
2013, 355, 1597-1604; b) C. Liu, J. –H. Xie, Y. –L. Li, J. –Q. Chen, Q. –
L. Zhou, Angew. Chem. Int. Ed. 2013, 52, 593-596; c) Y. Wang. Y. –C.
Luo, H. –B. Zhang, P. –F. Xu, Org. Biomol. Chem. 2012, 10, 8211-8215;
d) S. Rajkumar, K. Shankland, G. D. Brown, A. J. A. Cobb, Chem. Sci.
2012, 3, 584-588; e) R. J. Huntley, R. L. Funk, Tetrahedron Lett. 2011,
52, 6671-6674; f) B. D. Chapsal, I. Ojima, Org. Lett. 2006, 8, 1395-1398;
g) K. Tomooka, M. Suzuki, K. Uehara, M. Shimada, T. Akiyama Synlett
2008, 2518-2522; h) B. –C. Hong, R. Y. Nimje, M. –F. Wu, A. A. Sadani,
Eur. J. Org. Chem. 2008, 1449-1457; i) L. Dong, Y. –J. Xu, W. –C. Yuan,
X. Cui, L. –F. Cun, L. –Z. Gong, Eur. J. Org. Chem. 2006, 4093-4105.
[13] a) H. Fujioka, K. Murai, Y. Ohba, H. Hirose, Y. Kita, Chem. Commun.
2006, 832-834; b) L. Dong, Y. –J. Xu, L. –F. Cun, X. Cui, A. –Q. Mi, Y. –
Z. Jiang, L. –Z. Gong, Org. Lett. 2005, 7, 4285-4288; c) S. Gao, Y. Q.
Tu, Z. Song, A. Wang, X. Fan, Y. Jiang, J. Org. Chem. 2005, 70, 6523-
6525; d) T. Yasuhara, K. Nishimura, E. Osafune, O. Muraoka, K.
Tomioka,, Chem. Pharm. Bull. 2004, 52, 1109-1113; e) T. Yasuhara, E.
Osafune, K. Nishimura, M. Yamashita, K.-I. Yamada, O. Muraoka, K.
Tomioka Tetrahedron Lett. 2004, 3043-3045; f) A. Padwa, J. D. Ginn, S.
K. Bur, C. K. Eidell, S. M. Lynch, J. Org. Chem. 2002, 67, 3412-3424; g)
A. Padwa, M. A. Brodney, S. M. Lynch, J. Org. Chem. 2001, 66, 1716-
1724; h) M. G. Banwell, J. E. Harvey, D. R. Hockless, J. Org. Chem.
2000, 65, 4241-4250.
Organometallic Chem. 1998, 567, 101-117; c) A. Padwa, M. A. Brodney,
M. Dimitroff, J. Org. Chem. 1998, 63, 5304-5305; d) L. S. Beall, A. Padwa
Tetrhedron Lett. 1998, 39, 4159-4162; e) J. H. Rigby, M. E. Mateo
Tetrahedron 1996, 52, 10569-10582; f) M. G. Banwell, A. W. Wu, J.
Chem. Soc. Perkin Trans 1 1994, 2671-2672; g) H. Yoshizaki, H. Satoh,
Y. Sato, S. Nukui, M. Shibasaki, M. Mori, J. Org. Chem. 1995, 60, 2016-
2021; h) D. B. Grotjahn, K. P. C. Vollhardt, Synthesis 1993, 579-605; i)
V. K. Mishra, P. C. Ravikumar, M. E. Maier, Tetrahedron 2016, 72, 6499-
6509; j) E. Ghiradi, R. Griera, M. Piccichè, E. Molins, I. Fernández, J.
Bosch, M. Amat, Org. Lett. 2016, 18, 5836-5839.
[15] a) W. H. Pearson, J. M. Schkeryantz, J. Org. Chem. 1992, 57, 6783-
6789; b) D. Pérez, E. Guitlán, L. Castedo, Tetrahedron Lett. 1992, 33,
2407-2408; c) C. –L. Wang, W. C. Ripka, P. N. Confalone, Tetrahedron
Lett. 1984, 25, 4613-4616; d) J. –E. Bäckvall, P. G. Andersson, G. B.
Stone, A. Gogoll, J. Org. Chem. 1991, 56, 2988-2993; e) H.
Higashiyama, T. Honda, H. Otomasu, T. Kametani, Planta Medica 1983,
48, 268-271; f) H. Iida, Y. Yuasa, C. Kibayashi, J. Am. Chem. Soc. 1978,
78, 3598-3599; g) N. Ueda, T. Tokuyama, T. Sakan, Bull. Chem. Soc.
Jpn. 1966, 39, 2012-2014; h) K. Kotera, Tetrahedron 1961, 12, 248-261.
[16] a) A. F. Parsons, D. A. J. Williams, Tetrahedron 2000, 56, 7217-7228; b)
L. D. Miranda, S. Z. Zard, Org. Lett. 2002, 4, 1135-1138; c) M. Ikeda, S.
Ohtani, T. Sato, H. Ishibashi, Synthesis 1998, 1803-1806; d) J. Cossy,
L. Tresnard, D. G. Pardo, Eur. J. Org. Chem. 1999, 1925-1933; e) J.
Cassayre, S. Z. Zard, Synlett 1999, 501-503; f) S. A. A. E Bialy Nat. Prod.
Res. 2008, 22, 1176-1188.
[17] a) H. Ishibashi, K. Kodama, M. Higuchi, O. Muraoka, G. Tanabe, Y.
Takeda, Tetrahedron 2001, 57, 7629-7637; b) W. K. Goh, D. S. Black,
N. Kumar, Tetrahedron Lett. 2007, 48, 9008-9011.
[18] A. Monaco, A. E. Aliev and S. T. Hilton, Chem. Eur. J. 2015, 21, 13909–
13912.
[19] a) B. R. Szulc, B. C. Sil, A. Ruiz, S. T. Hilton, Eur. J. Org. Chem. 2015,
34, 7438-7442; b) B. R. Szulc, A. Ruiz, S. T. Hilton, 2014,
WO2014181101-A1.
[20] a) B. C. Sil, S.T. Hilton, Synlett 2013, 2563-2566; b) A. E. Aliev, S. T.
Hilton, W. B. Motherwell, D. L. Selwood, Tetrahedron Lett. 2006, 47,
2387-2390.
[21] K. M. Cook, S. T. Hilton, J. Mecinovic, W. B. Motherwell, W. D. Figg, C.
J. Schofield, J. Biol. Chem. 2009, 284, 26831-26838.
[22] M. Ikeda, S. Ohtani, T. Yamamoto, T. Sato, H. Ishibashi, J. Chem. Soc.
Perkin Trans. 1, 1998, 1763-1768.
[23] a) Z. –H. Shao, H. –B. Zhang, Chin. J. Org. Chem. 2005, 25, 282-289; b)
E. Coya, N. Sotomayor, E. Lete Adv. Synth. Catal. 2015, 357, 3206-
3214; c) C. Blázquez-Barbadillo, E. Aranzamendi, E. Coya, E. Lete, N.
Sotomayor, H. González-Díaz RSC Adv. 2016, 6, 38602-38610.
[14] a) P. Magnus, J. M. Bailey, M. J. Porter, Tetrahedron 1999, 55, 13927-
13936; b) H. Rudler, A. Parlier, M. Rudler, J. Vaissermann, J.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700143
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Alessandra Monaco,[a] Blanka R.
Szulc,[a] Zenobia X. Rao,[a] Marta
Barniol-Xicota,[b] Moussa Sehailia,[a]
Bruno M. A. Borges[a] and Stephen T.
Hilton*[a]
Page No. – Page No.
A novel approach to the total
synthesis of -lycorane: The pentacyclic structure of the natural product (±)--
lycorane was synthesized via a novel sequential Lewis acid mediated
intramolecular acylal cyclisation (IAC)/ Heck coupling approach. Using this,
methodology, a range of bicyclic heterocycles were also synthesised in good yields
demonstrating the potential of the IAC reaction to access complex heterocycles.
A Short Total Synthesis of (±)--
Lycorane by a Sequential
Intramolecular Acylal Cyclisation
(IAC) and Intramolecular Heck
Addition Reaction
This article is protected by copyright. All rights reserved.