Singlet-Oxygen-Initiated Tandem Transformation of 2-Hexylfuran to the Natural Alkaloids Glochidine and Glochidicine

Article abstract of DOI:10.1002/ejoc.201600524

A synthesis of the imidazole alkaloids glochidine and glochidicine is presented. These natural products were prepared by the photooxygenation of a readily accessible alkylfuran precursor using histamine as a nitrogen source. By tailoring the choice of the photosensitizer as well as the conditions used for the cyclization of an N-acyliminium intermediate, the tandem reaction sequence could be manipulated to afford each of the natural products independently and as desired.

Full text of DOI:10.1002/ejoc.201600524

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
DOI: 10.1002/ejoc.201600524
Communication
Sustainable Synthesis
Singlet-Oxygen-Initiated Tandem Transformation of 2-Hexyl-
furan to the Natural Alkaloids Glochidine and Glochidicine
Georgios I. Ioannou,[a] Dimitris Kalaitzakis,[a] and Georgios Vassilikogiannakis*[a]
Abstract: A synthesis of the imidazole alkaloids glochidine and ing the choice of the photosensitizer as well as the conditions
glochidicine is presented. These natural products were pre- used for the cyclization of an N-acyliminium intermediate, the
pared by the photooxygenation of a readily accessible alkyl- tandem reaction sequence could be manipulated to afford each
furan precursor using histamine as a nitrogen source. By tailor- of the natural products independently and as desired.
Introduction
Imidazole alkaloids are a subclass of nitrogen-containing aro-
matic polycycles.[1] Normally, the heterocyclic aromatic ring of
these compounds is biogenetically derived from the amino acid
histidine or its decarboxylated counterpart histamine.[2] Natu-
rally occurring imidazole alkaloids have been isolated from a
number of specific plants,[2] or marine organisms[3]. Despite the
broad structural diversity exhibited by these natural products,
examples of histamine analogues containing a γ-lactam scaffold
are limited to the alkaloids obtained from the trees Cynometra
spp.[4] and Glochidion philippicum.[5] In the latter case, along
Scheme 1. Imidazole alkaloids from the plant Glochidion philippicum.
with the two lactam isomers glochidine (1) and glochidicine (2)
(Scheme 1), the histamine derivative N-(4-oxodecanoyl)-
tate access to nitrogen-containing polycycles and, thus, in the
histamine (3)[5] as well as the alkaloid N-cinnamoylhistamine (4)
synthesis of natural alkaloids.[10] In many instances, the compet-
(Scheme 1)[6] were also isolated from the leaves of this New
itive carbon–carbon (irreversible) and carbon–heteroatom (re-
Guinean tree. In reality, compound 3 can be considered to be
versible) bond formations at the same site of the molecule have
the biogenetic precursor to both of these interrelated alkaloids,
been manipulated in order to selectively construct either the
glochidine (1) and glochidicine (2). This assumption was vali-
dated by the isolation report, which describes how compounds
thermodynamic or the kinetic product, respectively.[7,11] Control
of these competing cationic cyclizations must also be consid-
ered for the synthesis of glochidine (1) and glochidicine (2), as
1 and 3 could be transformed into glochidicine (2) upon being
subjected to refluxing acetic acid.[5] Predictably, glochidicine (2)
the pendent imidazole ring bears both a nitrogen and a carbon
was reported to be very stable in this acidic environment. Like-
nucleophile.
wise, the only reported synthesis of these natural products also
revealed that glochidine (1) and glochidicine (2) can be ob-
tained from the histamine amide 3 by a site-selective N-acyl-
Results and Discussion
iminium cyclization.[7]
From our experience in applying N-acyliminium intramolecular
cyclizations to nitrogen-polycycle formation,[12] we envisioned
that the natural alkaloids glochidine (1) and glochidicine (2)
might be very rapidly synthesized using a set of highly sustain-
able and mild conditions. The proposed scenario (detailed in
Scheme 2) is based on the ability of singlet oxygen to initiate
cascade reaction sequences.[13] More specifically, the one-step
synthesis has been designed to start from the photooxygen-
ation of the easily accessible 2-hexylfuran (5) (using visible light
irradiation from an LED strip) followed by in situ reduction (5
→ 6) (Scheme 2). It was our intention that the enal 7 so-formed
would then react intermolecularly with the primary amino
group of histamine to afford the corresponding 2-pyrrolidinone
The N-acyliminium ion (NAI) is one of the most important
reactive species in organic synthesis.[8] This electrophile may be
formed in the presence of an acid catalyst and is key to the
rapid construction of a myriad of alkaloid structures when it
reacts with an appropriate nucleophile.[8] As part of an intramo-
lecular Pictet–Spengler cyclization reaction (C–C bond form-
ing),[9] NAI intermediates have been utilized frequently to facili-
[a] Department of Chemistry, University of Crete
Vasilika Vouton, 71003 Iraklion, Crete, Greece
E-mail: vasil@chemistry.uoc.gr
www.chemistry.uoc.gr/vassilikogiannakis
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600524.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Communication
8.[12] It was anticipated that the subsequent acid-catalyzed N- For instance, starting the procedure with RB as photosensitizer
acyliminium generation (9) (Scheme 2) would open up two dif- and refluxing the solution of 8 in formic acid the oxidized ana-
ferent 6-endo cyclization pathways. Kinetic conditions would be logue 10 was produced along with the desired product 2 in a
expected to favor the nitrogen attack (path a, N–C bond forma- 2:3 ratio (Scheme 4).[12b] The replacement of RB with Methylene
tion) in order to afford glochidine (1), while the carbon attack Blue (MB) led to the oxidized product 11 (Scheme 4) by a pro-
(path b, C–C bond formation) might be promoted under ther- ton-coupled electron-transfer reaction (PCET).[14]
modynamic conditions in order to obtain glochidicine (2).
Scheme 2. Proposed scenario for the synthesis of glochidine and glochidicine
from 2-hexylfuran. PS: photosensitizer.
Scheme 4. Transformation of intermediate pyrrolidinone 8 into the unsatu-
rated lactams 10 or 11. PT: proton transfer, ET: electron transfer.
To begin testing our hypotheses, we conducted the photo-
These unsuccessful attempts to exclusively synthesize glo-
oxygenation of 2-hexylfuran (5, in a 40 m
M
methanolic solution)
chidicine (2) prompted us to investigate the conditions that
would prevent the oxidation of 8. In accordance with our recent
mechanistic studies,[14a] we supposed that this PCET mecha-
nism was favored by protic solvents since the enol form of inter-
mediate 8 (8i, Scheme 4) would be stabilized by hydrogen-
bonding with the solvent thus accelerating the proton transfer
to the base (e.g., histamine) and the electron transfer to MB
(Scheme 4). Consequently, we might be able to prevent this
oxidation reaction by selecting the appropriate non-hydrogen-
bonding solvent. Applying this logic, we proceeded to add the
histamine in dichloromethane instead of methanol, and, im-
pressively, this procedural change led to the exclusive formation
in the presence of Rose Bengal (RB, 10–4
M) as a photosenzitizer.
Using an LED strip source (14.4 W/m) the reaction was complete
in only 5 min. Subsequent reduction of the hydroperoxide moi-
ety by Me2S (45 min) followed by addition of commercially
available histamine (1 equiv.) led to the exclusive formation of
1
2-pyrrolidinone 8 (1 h, as indicated by the crude HNMR spec-
trum) (Scheme 3). Without purification of 8, we proceeded to
investigate the next N-acyliminium-mediated cyclization step.
Specifically, it was found that by exchanging the solvent
(MeOH) with formic acid and stirring the solution at room tem-
perature for 18 h, the nitrogen attack (path a, Scheme 2) could
be promoted, thus affording the kinetic product glochidine (1)
in 62 % isolated yield (Scheme 3).
of
8 without the presence of any oxidized lactam 11
(Scheme 5). From here, we continued with the cyclization step,
and 8 (produced under these conditions specifically) was sub-
jected to refluxing formic acid, which led to the successful for-
mation of the thermodynamic natural product glochidicine (2)
in 58 % isolated yield (Scheme 5).
Scheme 3. Synthesis of glochidine from 2-hexylfuran.
With the synthesis of glochidine (1) accomplished, our atten-
tion now shifted to the synthesis of glochidicine (2). Various
reaction conditions were applied in an attempt to successfully,
and exclusively, form this related natural product by the Pictet–
Spengler cyclization step of intermediate 8 (path b, Scheme 2).
Scheme 5. Synthesis of glochidicine from 2-hexylfuran.
2 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Communication
Conclusions
Keywords: N-Acyliminium ions · Alkaloids · Glochidine ·
The synthesis of the natural alkaloids glochidine (1) and glo- Glochidicine · Imidazole · Pictet-Spengler reactions · Singlet
chidicine (2) has been presented. Their synthesis started from oxygen
2-hexylfuran, which was effectively transformed into the natural
alkaloids using singlet oxygen as oxidant and histamine as a
nitrogen source. The outcome of the tandem reaction sequence
was successfully controlled by judicious choice of both the pho-
tosensitizer and the solvent.
[1] L. Maat, H. C. Beyerman in The Alkaloids: Chemistry and Pharmacology,
vol. 22 (Ed.: A. Brossi), Elsevier, New York, 1984, pp. 281–333.
[2] A. P. Santos, P. R. H. Moreno in Natural Products, vol. 1 (Eds.: K. G. Rama-
wat, J. M. Mérillon), Springer-Verlag, Berlin–Heidelberg, 2013, pp. 861–
882.
[3] H. Fujioka, Y. Kita in Natural Products, vol. 1 (Eds.: K. G. Ramawat, J. M.
Mérillon), Springer-Verlag, Berlin–Heidelberg, 2013, pp. 264–278.
[4] a) F. Khuong-Huu, X. Monseur, G. Ratle, G. Lukacs, R. Goutarel, Tetrahe-
dron Lett. 1973, 14, 1757–1760; b) L. Tchissambou, M. Bénéchie, F.
Khuong-Huu, Tetrahedron Lett. 1978, 19, 1801–1802; c) P. G. Waterman,
D. F. Faulkner, Phytochemistry 1981, 20, 2765–2767; d) L. Tchissambou,
M. Bénéchie, F. Khuong-Huu, Tetrahedron 1982, 38, 2687–2695.
[5] a) S. R. Johns, J. A. Lamberton, Chem. Commun. (London) 1966, 312–313;
b) S. R. Johns, J. A. Lamberton, Aust. J. Chem. 1967, 20, 555–560.
[6] J. S. Fitzgerald, Aust. J. Chem. 1964, 17, 375–378.
Experimental Section
General Method: 2-Hexylfuran (5; 0.5 mmol) was dissolved in
methanol (12.5 mL, 40 m
M
) containing catalytic amounts of Rose
Bengal or Methylene Blue (10–4
M). Oxygen (baloon) was gently
bubbled through the solution, while it was irradiated with white
LEDs (strip, 14.4 W/m, 50 Lm/W). The reaction was monitored by
TLC. After completion of the reaction (5 min), Me2S (2.0 mmol) was
added (in methanol when targeting glochidine, or in dichloro-
methane for glochidicine), and the reaction mixture was stirred for
45 min. Then, histamine (0.5 mmol) was added (in methanol when
targeting glochidine, or in dichloromethane for glochidicine), and
the solution was stirred at room temperature for a further 1 h. After
the formation of the 2-pyrrolidinone 8, the solvent was replaced
with HCOOH, and the solution was stirred at room temperature for
18 h for glochidine (1), or at reflux for 18 h for glochidicine (2).
Afterwards, the mixtures were concentrated in vacuo, and the final
products were purified by flash column chromatography (silica gel;
EtOAc → acetone/EtOAc, 1:1) to afford glochidine (1; 62 % yield) or
glochidicine (2; 58 % yield).
[7] Y. S. Lee, S. H. Kim, S. H. Jung, S. J. Lee, H. Park, Heterocycles 1994, 37,
303–309.
[8] a) W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56, 3817–3856;
b) B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi, C. A. Maryanoff,
Chem. Rev. 2004, 104, 1431–1628; c) A. Yazici, S. G. Pyne, Synthesis 2009,
339–368; d) U. Martínez-Estibalez, A. Gómez-SanJuan, O. García-Calvo, E.
Aranzamendi, E. Lete, N. Sotomayor, Eur. J. Org. Chem. 2011, 3610–3633;
e) A. Daïch, A. Ghinet, B. Rigo in Comprehensive Organic Synthesis, vol. 2
(Eds.: P. Knochel, G. A. Molander), Elsevier, Oxford, 2014, pp. 682–742.
[9] a) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030–2036; b)
E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797–1842; c) J. Stöckigt, A. P.
Antonchick, F. Wu, H. Waldmann, Angew. Chem. Int. Ed. 2011, 50, 8538–
8564; Angew. Chem. 2011, 123, 8692–8719.
[10] a) H. Abdelkafi, B. Nay, Nat. Prod. Rep. 2012, 29, 845–869; b) Y. Wang, L.
Zhu, Y. Zhang, R. Hong, Angew. Chem. Int. Ed. 2011, 50, 2787–2790;
Angew. Chem. 2011, 123, 2839–2842; c) S. N. Gaskell, L. J. Duffy, S. M.
Allin, Nat. Prod. Commun. 2008, 3, 1825–1838; d) I. T. Raheem, P. S. Thiara,
E. A. Peterson, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404–13405.
[11] For selective examples, see: a) M. Jida, O.-M. Soueidan, B. Deprez, G.
Laconde, R. Deprez-Poulain, Green Chem. 2012, 14, 909–911; b) S. M.
Allin, J. M. R. Towler, M. R. J. Elsegood, B. Saha, P. C. Bulman, Synth.
Commun. 2012, 42, 872–882; c) J.-F. Fleury, P. Netchitaïlo, A. Daïch, Synlett
2011, 1821–1826; d) A. A. Bahajaj, M. H. Moore, J. M. Vernon, Tetrahedron
2004, 60, 1235–1246.
[12] a) D. Kalaitzakis, T. Montagnon, I. Alexopoulou, G. Vassilikogiannakis,
Angew. Chem. Int. Ed. 2012, 51, 8868–8871; Angew. Chem. 2012, 124,
8998–9001; b) D. Kalaitzakis, T. Montagnon, E. Antonatou, N. Bardají, G.
Vassilikogiannakis, Chem. Eur. J. 2013, 19, 10119–10123; c) D. Kalaitzakis,
T. Montagnon, E. Antonatou, G. Vassilikogiannakis, Org. Lett. 2013, 15,
3714–3717; d) D. Kalaitzakis, E. Antonatou, G. Vassilikogiannakis, Chem.
Commun. 2014, 50, 400–402; e) D. Kalaitzakis, T. Montagnon, G. I. Ioan-
nou, E. Antonatou, G. Vassilikogiannakis, ARCIVOC 2015, (iii), 154–166.
[13] T. Montagnon, D. Kalaitzakis, M. Triantafyllakis, M. Stratakis, G. Vassilikogi-
annakis, Chem. Commun. 2014, 50, 15480–15498.
1
Glochidine (1): H NMR (500 MHz, CDCl3): δ = 7.45 (s, 1 H), 6.76 (s,
1 H), 4.31 (ddd, J = 13.5, 6.4, 2.1 Hz, 1 H), 3.08 (ddd, J = 13.3, 11.1,
5.9 Hz, 1 H), 2.91–2.80 (m, 2 H), 2.63–2.47 (m, 3 H), 2.41 (m, 1 H),
1.94 (m, 2 H), 1.34–1.20 (m, 8 H), 0.85 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 173.4, 132.2, 125.0, 124.7, 78.4, 41.5,
33.4, 31.4 (2 C), 29.8, 28.8, 23.6, 22.4, 20.1, 13.9 ppm. HRMS (TOF
ESI): calcd. for C15H24N3O [M + H]+ 262.1914; found 262.1917.
Glochidicine (2): 1H NMR (500 MHz, CDCl3): δ = 8.95 (br. s, 1 H),
7.53 (s, 1 H), 4.39 (dd, J = 13.3, 6.5 Hz, 1 H), 3.08 (td, J = 12.4, 5.0 Hz,
1 H), 2.78 (ddd, J = 15.5, 11.5, 6.5 Hz, 1 H), 2.59 (m, 2 H), 2.35 (m, 2
H), 2.14 (m, 1 H), 1.91 (m, 1 H), 1.77 (m, 1 H), 1.41 (m, 1 H), 1.34–
1.20 (m, 7 H), 0.84 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 174.3, 138.8, 134.1, 122.1, 63.5, 39.5, 34.6, 31.6, 31.2,
29.7, 29.5, 24.0, 22.5, 21.8, 14.0 ppm. HRMS (TOF ESI): calcd. for
C15H24N3O [M + H]+ 262.1914; found 262.1915.
Acknowledgments
[14] a) D. Kalaitzakis, A. Kouridaki, D. Noutsias, T. Montagnon, G. Vassilikogian-
nakis, Angew. Chem. Int. Ed. 2015, 54, 6283–6287; Angew. Chem. 2015,
127, 6381–6385; b) D. Kalaitzakis, D. Noutsias, G. Vassilikogiannakis, Org.
Lett. 2015, 17, 3596–3599.
The research leading to these results has received funding from
the European Research Council under the European Union's
Seventh Framework Programme (FP7/2007-2013)/ERC Grant
Agreement No. 277588 as well as from the European Union's
Seventh Framework Programme (FP7/2007-2013)/Marie Curie
ITN Grant Agreement No. 316975).
Received: April 27, 2016
Published Online: ■
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Communication
Sustainable Synthesis
G. I. Ioannou, D. Kalaitzakis,
G. Vassilikogiannakis* ....................... 1–4
Singlet-Oxygen-Initiated
Tandem
Transformation of 2-Hexylfuran to
the Natural Alkaloids Glochidine
and Glochidicine
A singlet-oxygen-triggered, one-step gen source. The outcome of this cas-
synthesis of the imidazole alkaloids cade reaction sequence was effectively
glochidine and glochidicine is pre- controlled by tailoring the choice of
sented. These natural products were both the photosensitizer as well as the
derived from the readily accessible 2- conditions for the cyclization of the N-
hexylfuran using histamine as a nitro- acyliminium intermediate.
DOI: 10.1002/ejoc.201600524
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim