One-pot synthesis of the tetracyclic framework of the aromatic erythrina alkaloids from simple furans

Article abstract of DOI:10.1021/ol401582e

Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2-pyrrolidinone formation, cycliz

Full text of DOI:10.1021/ol401582e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
One-pot Synthesis of the Tetracyclic
Framework of the Aromatic Erythrina
Alkaloids from Simple Furans
Dimitris Kalaitzakis, Tamsyn Montagnon, Eirini Antonatou, and
Georgios Vassilikogiannakis*
Department of Chemistry, University of Crete, Vasilika Vouton, 71003 Iraklion,
Crete, Greece
vasil@chemistry.uoc.gr
Received June 5, 2013
ABSTRACT
Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction
sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2-pyrrolidinone formation, cyclization of the pendant
aldehyde moiety and an N-acyliminium ion formation and terminates with a Pictet-Spengler-type aromatic substitution. The method has been used
to achieve a rapid and highly effective formal synthesis of erysotramidine.
The aromatic (D ring) erythrina alkaloids (Figure 1)
have long captured researchers’ imaginations due to their
characteristic and wide-ranging profile which combines
a complex web of biogenetic relationships, potent bio-
logical activities, and synthetically challenging polycyclic
molecular architectures.1 Strategies for the assembly of their
tetracyclic frameworks are, as expected, numerous,2À4 but
right from the outset,5 construction of the C5ÀC13 bond
(completing the C-ring, Figure 1) by means of a Pictet-
Spengler-type cyclization (in which an N-acyliminium ion6
acts as the electrophile in a substitution reaction with the
aromatic moiety) has emerged as a particularly versatile
approach.2,3,5 The aromatic erythrina alkaloids can be
subdivided into two categories, the dienoid type (1 and 2,
Figure 1), which have a diene unit spanning the A and B
rings, and the alkenoid type (3 and 4, Figure 1), which
have a single isolated double bond in the A ring. Despite
the existence of a large body of synthetic work targeting
both the dienoid and alkenoid erythrina alkaloids, only
very rarely have researchers successfully constructed all
the requisite nonaromatic rings (A, B and C) in the same
reaction sequence.7 Herein, we report the successful
development of such a process that delivers the entire
erythrinane skeleton in one synthetic operation, using
(3) For selected example syntheses of aromatic erythrina alkaloids of
the past decade using a Pictet-Spengler/NAI cyclization for C5-C13
bond formation, see: (a) Ogawa, S.; Iida, N.; Tokunaga, E.; Shiro, M.;
Shibata, N. Chem.;Eur. J. 2010, 16, 7090. (b) Juma, B.; Adeel, M.;
Villinger, A.; Reinke, H.; Spannenberg, A.; Fischer, C.; Langer, P. Adv.
€
Synth. Catal. 2009, 351, 1073. (c) Tietze, L. F.; Tolle, N.; Kratzert, D.;
Stalke, D. Org. Lett. 2009, 11, 5230. (d) Zhang, F.; Simpkins, N. S.;
€
Blake, A. J. Org. Biomol. Chem. 2009, 7, 1963. (e) Tietze, L. F.; Tolle, N.;
Noll, C. Synlett 2008, 525. (f) Zhang, F.; Simpkins, N. S.; Wilson, C.
Tetrahedron Lett. 2007, 48, 5942. (g) Padwa, A.; Wang, Q. J. Org. Chem.
2006, 71, 7391. (h) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601. (i) Gao,
S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, Y.; Fan, X.;
Zhang, S. Org. Lett. 2006, 8, 2373. (j) Blake, A. J.; Gill, C.; Greenhalgh,
D. A.; Simpkins, N. S.; Zhang, F. Synthesis 2005, 3287. (k) Allin, S. M.;
Streetley, G. B.; Slater, M.; James, S. L.; Martin, W. P. Tetrahedron Lett.
2004, 45, 5493. (l) El Bialy, S. A. A.; Braun, H.; Tietze, L. F. Angew.
Chem., Int. Ed. 2004, 43, 5391. (m) Padwa, A.; Lee, H. I.; Rashatasakhon,
P.; Rose, M. J. Org. Chem. 2004, 69, 8209. (n) Lee, H. I.; Cassidy, M. P.;
Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 5067. (o) Gill, C.;
Greenhalgh, D. A.; Simpkins, N. S. Tetrahedron Lett. 2003, 44, 7803.
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2003, 59, 4953. (q) Chikaoka, S.; Toyao, A.; Ogasawara, M.; Tamura, O.;
Ishibashi, H. J. Org. Chem. 2003, 68, 312. (r) Abelman, M. M.; Curtis,
J. K.; James, D. R. Tetrahedron Lett. 2003, 44, 6527.
(1) (a) Dyke, S. F.; Quessy, S. N. In The Alkaloids; Rodrigo, R. G. A.,
Ed.; Academic Press: New York, 1981; Vol. 18, pp 1À98. (b) Sano, T.;
Tsuda, Y. In The Alkaloids; Cordell, G. A., Ed; Academic Press: New York,
1996; Vol. 48, pp 249À337.
(2) For a review of the strategies used, see: Reimann, E. Synthesis
Pathways to Erythrina Alkaloids and Erythrina Type Compounds. In
Progress in the chemistry of organic natural products; Herz, W., Falk, H.,
Kirby, G. W., Eds.; Springer-Verlag/Wien: Austria, 2007; Vol. 88, pp 1À62.
r
10.1021/ol401582e
XXXX American Chemical Society

Scheme 1. Mechanistic Rationale for the Proposed One Step
Synthesis of Erythrinanes from Simple Furans
Figure 1. Selected erythrina alkaloids (with an aromatic D ring).
exceptionally mild reaction conditions. The one-pot
reaction sequence involves, but is by no means limited
to, an N-acyliminium ion (NAI) formation and a Pictet-
Spengler-type reaction and begins from simple and
readily accessible furan precursors. It is important for
the efficiency of the process that there is no lengthy
substrate synthesis beforehand (Scheme 1). The devel-
opment of this novel process was facilitated by our
recent discovery of a new way to access NAIs beginning
with singlet oxygen-mediated furan photooxygenation.8
This one-pot reaction sequence is notable particularly
for its concise and rapid increase in molecular complexity
from a very simple starting point (outlined mechanistically
in Scheme 1). In this way it exhibits a very high degree of
step-9 and atom-economy10 and this feature, in combina-
tion with its utilization of the selective green reagent,
singlet oxygen, to mediate the changes with precision and
minimal waste, mean that it succeeds in attaining many of
the recently established criteria for an ideal synthesis.11
Furthermore, it intrinsically exhibits a number of other
unique and highly advantageous characteristics. First, the
1,4-dielectrophile (B, Scheme 1) accessed by singlet oxygen
oxidation of a furan (A f B in itself a mild and highly
selective process with broad functional group tolerance)
is of a specific nature such that the subsequent conden-
sation with an amine (B f E) can be achieved under
milder conditions than when other 1,4-dielectrophiles of
a more classical nature are used.6 This endows the over-
all process with broad enough functional group toler-
ance to allow a sensitive aldehyde moiety to be carried
through to the end of the sequence whereby intermediate
E is converted into F (Scheme 1). Second, the way this
one-pot process has been designed allows us first to
exploit the enamide’s (E) nucleophilicity and then the
NAI’s (F) electrophilicity. Since interconversion of the
enamide E and NAI F is relatively easy (via protonation/
deprotonation), it should be noted that a reversal in
the order of reactivity would terminate this particular
sequence without construction of the A-ring of the
erythrinane skeleton; so the relative reactivity (between
the C-ring forming reaction and A-ring forming reaction)
(4) For selected example syntheses of aromatic erythrina alkaloids of
the past decade not using a Pictet-Spengler/NAI cyclization for C5ÀC13
bond formation, see: (a) Joo, J. M.; David, R. A.; Yuan, Y.; Lee, C. Org.
Lett. 2010, 12, 5704. (b) Tuan, L. A.; Kim, G. Bull. Korean Chem. Soc.
2010, 31, 1800. (c) Liang, J.; Chen, J.; Liu, J.; Li, L.; Zhang, H. Chem.
Commun. 2010, 46, 3666. (d) Onoda, T.; Takikawa, Y.; Fujimoto, T.;
Yasui, Y.; Suzuki, K.; Matsumoto, T. Synlett 2009, 1041. (e) Yoshida,
Y.; Mohri, K.; Isobe, K.; Itoh, T.; Yamamoto, K. J. Org. Chem. 2009,
74, 6010. (f) Stanislawski, P. C.; Willis, A. C.; Banwell, M. G. Chem.
Asian J. 2007, 2, 1127. (g) Shimizu, K.; Takimoto, M.; Sato, Y.; Mori, M.
J. Organomet. Chem. 2006, 691, 5466. (h) Stanislawski, P. C.; Willis,
A. C.; Banwell, M. G. Org. Lett. 2006, 8, 2143. (i) Kim, G.; Kim, J. H.;
Lee, K. Y. J. Org. Chem. 2006, 71, 2185. (j) Yasui, Y.; Suzuki, K.;
Matsumoto, T. Synlett 2004, 619. (k) Fukumoto, H.; Esumi, T.;
Ishihara, J.; Hatakeyama, S. Tetrahedron Lett. 2003, 44, 8047. (l)
Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2003, 5, 2323.
(5) For the earliest pioneering synthetic approaches, see: (a) Belleau,
B. J. Am. Chem. Soc. 1953, 75, 5765. (b) Mondon, A. Angew. Chem.
1956, 68, 578. (c) Prelog, V. Angew. Chem. 1957, 69, 33.
(6) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff,
C. A. Chem. Rev. 2004, 104, 1431.
(7) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org. Chem.
1998, 63, 1144.
(8) (a) Kalaitzakis, D.; Montagnon, T.; Alexopoulou, I.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2012, 51, 8868.
(b) Kalaitzakis, D.; Montagnon, T.; Antonatou, E.; Bardajı, N.;
Vassilikogiannakis, G. Chem.;Eur. J. 2013, 10.1002/chem.201301571.
(9) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
(11) (a) Young, I. S; Baran, P. S. Nat. Chem. 2009, 1, 193. (b) Gaich,
T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657. (c) Newhouse, T.; Baran,
P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010. For the first
introduction to the “ideal synthesis” concept, see: (d) Hendrickson, J. B.
J. Am. Chem. Soc. 1975, 97, 5784.
(10) Trost, B. M. Science 1991, 254, 1471.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. One Step Synthesis of Erythrinanes from Simple
Furans
Scheme 3. Formic Acid-mediated Double Electrophilic
Aromatic Substitution
with those already reported in the literature.3c,j Thus, we
had succeeded in finding the first conditions that would
convert simple furan 5 into the intact erythrinane skeleton
in a one-pot process. Furthermore, we had achieved a
racemic formal synthesis of erysotramidine 1 (Figure 1) by
a late stage intersection with Simpkins’ asymmetric total
synthesis.3d,j More specifically, erythrinane 10 is just four
steps from erysotramidine 1 using the chemistry developed
previously (Simpkins3d,j and Padwa3n).
It was subsequently found that AlCl3 (4 equiv) was also
a successful mediator of the desired reaction. In this
case, however, we isolated tetracycle 11. The result of this
modification was fortuitous, because tetracycle 11 has an
A-ring double bond positioned correctly for the alkenoid
aromatic erythrinane alkaloids such as 3-demethoxyery-
thratidinone 3 and erythramine 4 (Figure 1), to enhance
the versatility of this newly developed chemistry.
needed to be right to ensure success. Our investigations,
delineated below, have established the conditions needed
to achieve the desired results and have shown how changes
to those employed in the Pictet-Spengler step can be used
to tailor the outcome to access both dienoid and alkenoid
erythrina structures, as desired.
Furyl aldehyde 512 was usedassubstrate inthe searchfor
optimized reaction conditions (Scheme 2). In the first part
of the one-pot process, 5 was subjected to a standard set of
photooxygenation conditions8 and then condensed with
amine 6 to furnish the enamide 7 which cyclized sponta-
neously to afford the fused bicycle and NAI-precursor 8.
Thiswas thentreatedinsituwithoneofarangeofBrønsted
and Lewis acids. Treatment with TFA (0.5 equiv, rt, 30
min) yielded an aromatized product oxindole 9. Likewise,
neatformicacidgaveacomplex mixture of desiredproduct
10 (as its formate ester) and undesired byproducts. How-
ever, when we turned our attention toward Lewis acids,
the reaction immediately took on the desired profile.
When BF3•OEt2 (3 equiv) was introduced at À78 °C,
at the appropriate moment in the one-pot procedure
(i.e., when tlc analysis indicated the presence of cyclized
compound 8), and the reactants were stirred for 16 h,
tetracyclic compound 10 was isolated12 in a remarkable
57% yield. The spectroscopic data of 10 are in full agreement
We next sought to investigate how the outcome of this
one-pot process might be affected if we made the A-ring
formation less favorable relative to the Pictet-Spengler-
type aromatic substitution (C-ring formation, Scheme 3).
To this end, we subjected aldehyde 1212 (with one less
carbon in the side chain when compared to aldehyde 5) to
several variations of the cascade reaction sequence condi-
tions. In this case, formic acid turned out to be the acid of
choice, as other acids (BF3•OEt2, AlCl3 and TFA) tested
led to complex mixtures of products and starting material.
When formic acid was employed, however, we observed
interesting results; after 2 h at room temperature, aldehyde
14 was isolated (yield 65%) showing that the Pictet-
Spengler-type cyclization now occurred in preference to
formation of a [5,5]-fused bicycle via cyclization of the
intermediate 2-pyrrolidinone 13 onto the aldehyde func-
tionality. Furthermore, if the temperature applied to this
stage of the one-pot sequence was elevated to reflux,
tetracycle 15 was isolated (overall yield 53%). In this case,
the aromatic moiety had undergone two successive
(12) For full details of synthesis of these compounds and all one-pot
procedures, see Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

acid-catalyzed electrophilic aromatic substitutions;the
first with the NAI and the second with the aldehyde func-
tionality, followed by dehydration. Thus, once again the
aldehyde moiety has been conserved through a complex
cascade reaction sequence until itwas neededtoparticipate
in a final ring forming reaction completing the synthesis of
an intricate tetracycle.
In conclusion, a new, mild and highly efficient erythri-
nane synthesis is presented. Starting with very simple and
readily accessible furan substrates, the erythrinane tetra-
cycle could be rapidly accessed in one synthetic operation.
The mechanistically complex (but operationally simple)
one-pot reaction sequence employed, began with singlet
oxygen-mediated oxidation of the initial furan substrate
and continued via condensation of the resultant 1,4-dielec-
trophile with an amine; cyclization of the resultant
enamide, acid-catalyzed N-acyliminium ion formation
and Pictet-Spengler aromatic substitution completed the
sequence. The method has been used to achieve a formal
synthesis of erysotramidine, the shortness and high overall
yield of which are without precedent.
Acknowledgment. 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
Supporting Information Available. Experimental proce-
dures, full spectroscopic data and copies of 1Hand13CNMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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