Concise synthesis of the erythrina alkaloid 3-demethoxyerythratidinone via combined rhodium catalysis

Article abstract of DOI:10.1021/ol102535u

The total synthesis of the erythrina alkaloid 3-demethoxyerythratidinone has been achieved via a strategy based on combined rhodium catalysis. The catalytic tandem cyclization effected by the interplay of alkynyl and vinylidene rhodium species allows for

Full text of DOI:10.1021/ol102535u

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5704-5707
Concise Synthesis of the Erythrina
Alkaloid 3-Demethoxyerythratidinone via
Combined Rhodium Catalysis
Jung Min Joo,† Ramoncito A. David,† Yu Yuan,† and Chulbom Lee*,‡
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544,
United States, and Department of Chemistry, Seoul National UniVersity,
Seoul 151-747, South Korea
chulbom@snu.ac.kr
Received October 19, 2010
ABSTRACT
The total synthesis of the erythrina alkaloid 3-demethoxyerythratidinone has been achieved via a strategy based on combined rhodium catalysis.
The catalytic tandem cyclization effected by the interplay of alkynyl and vinylidene rhodium species allows for efficient access to the A and
B rings of the tetracyclic erythrinane skeleton in a single step. The synthesis also features rapid preparation of the requisite precursor for the
double ring closure and thus has been completed in only 7 total steps in 41% overall yield.
Erythrinanes (1) and homoerythrinanes (2) are a large class
of structurally diverse natural products isolated from tropical
and subtropical plants of the Erythrina genus that have long
been used for various indigenous medicines (Figure 1).1
These plant-derived alkaloids exhibit a wide range of
pharmacological effects such as hypotensive, sedative,
hypnotic, anticonvulsive, CNS depressing, and curare-like
properties. Structurally, four rings are fused with the A/C
spiro juncture to constitute the distinctive 6-5-6-n and 6-5-
7-n skeletons with considerable structural variance in the D
ring. Thus, not surprisingly, this unique molecular architec-
ture along with interesting biological activities of erythrina
alkaloids has stimulated a number of chemical synthesis
investigations.2
Figure 1. Erythrina alkaloids.
one ring via sequential or tandem cyclization that facilitates rapid
access to the archetypal tetracyclic core.3 However, rarely have
these strategies been explored for simultaneous construction of
the A and B rings despite the fact that the 6-5 fused system
constitutes a “conserved subunit” for all members of erythrina
Among the synthetic efforts toward erythrina alkaloids,
notable are the approaches involving synthesis of more than
† Princeton University.
‡ Seoul National University.
(2) For a recent review on the synthesis of erythrina alkaloids, 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 1-62.
(1) (a) Dyke, S. F.; Quessy, S. N. In The Alkaloids; Rodrigo, R. G. A.,
Ed.; Academic Press: New York, 1981; Vol. 18, pp 1-98. (b) Sano, T.;
Tsuda, Y. In The Alkaloids; Cordell, G. A., Ed; Academic Press: New York,
1996; Vol. 48, pp 249-337.
10.1021/ol102535u  2010 American Chemical Society
Published on Web 11/19/2010

Scheme 1
.
Retrosynthetic Analysis
Scheme 2. Synthesis of Iodoenyne 6a
alkaloids.4 Thus, it would be of potentially broad interest to
develop synthetic routes that are amenable for both the
erythrinane and homoerythrinane series. Herein, we report a
concise total synthesis of 3-demethoxyerythratidinone (3),5,6 in
which a combined rhodium(I) catalysis enables tandem
annulation of the A and B rings of the erythrinane skeleton
and thus greatly simplifies the synthesis.7
Our synthetic plan arose from the notion that diene 4
possessing the essential framework of the target 3 might be
readily accessed from enyne 6 via a catalytic domino process
involving a transition metal unsaturated carbene (vinylidene,
e.g. 5) complex as an intermediate (Scheme 1). Based on
(3) For selected recent examples, see: (a) Tietze, L. F.; To¨lle, N.;
Kratzert, D.; Stalke, D. Org. Lett. 2009, 11, 5230. (b) Fukumoto, H.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2006,
45, 2731. (c) El Bialy, S. A. A.; Braun, H.; Tietze, L. F. Angew. Chem.,
Int. Ed. 2004, 43, 5391.
our recent studies on combined rhodium catalysis,8 it was
envisioned that 6 could be mobilized to undergo C-C bond
formations at both the R- and ꢀ-positions of its alkyne
moiety, thus establishing the A/B ring system in one step.
In this scenario, a single catalyst would have to mediate the
two distinct bond-forming events, the ꢀ-alkylation and enyne
cycloisomerization. The requisite haloenyne 6 for the double
ring closure was then anticipated to be easily assembled from
the three commercially available building blocks, 7, 8, and
9, in a straightforward manner without extensive engineering.
With the plan to evaluate the tandem A/B approach, our
studies commenced with the construction of the C and D
rings (Scheme 2). Thus, homoveratrylamine (7) was first
acylated with pentenoyl chloride (8), and the resulting amide
was subjected to Bischler-Napieralski conditions to afford
isoquinoline 10 in quantitative yield.9 For the introduction
of the requisite halide and alkyne groups, a sequence
involving N-alkylation and iminium addition was carried out.
Thus, treatment of isoquinoline 10 with the silyl protected
iodoethanol 9a followed by addition of an ethynyl Grignard
reagent to N-alkyliminium ion 11a provided the desired
propargyl amine 12a in high yield.10 After removal of the
(4) (a) Westling, M.; Smith, R.; Livinghouse, T. J. Org. Chem. 1986,
51, 1159. (b) Padwa, A.; Hennig, R.; Kappe, C. C.; Reger, T. S. J. Org.
Chem. 1998, 63, 1144.
(5) Isolation: Barton, D. H. R.; Gunatilaka, A. A. L.; Letcher, R. M.;
Lobo, A. M. F. T.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1973,
874
.
(6) For reports on the total synthesis of 3-demethoxyerythratidinone,
see: (a) Zhang, F.; Simpkins, N. S.; Blake, A. J. Org. Biomol. Chem. 2009,
7, 1963. (b) Zhang, F.; Simpkins, N. S.; Wilson, C. Tetrahedron Lett. 2007,
48, 5942. (c) Padwa, A.; Wang, Q. J. Org. Chem. 2006, 71, 7391. (d)
Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron Lett.
1998, 39, 8995. (e) Hosoi, S.; Ishida, K.; Sangai, M.; Tsuda, Y. Chem.
Pharm. Bull. 1992, 40, 3115. (f) Tsuda, Y.; Sakai, Y.; Nakai, A.; Kaneko,
M.; Ishiguro, Y.; Isobe, K.; Taga, J.; Sano, T. Chem. Pharm. Bull. 1990,
38, 1462. (g) Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ishikawa,
K.; Ikeda, M. Chem. Pharm. Bull. 1990, 38, 907. (h) Wasserman, H. H.;
Amici, R. M. J. Org. Chem. 1989, 54, 5843. (i) Irie, H.; Shibata, K.;
Matsuno, K.; Zhang, Y. Heterocycles 1989, 29, 1033. (j) Danishefsky, S. J.;
Panek, J. S. J. Am. Chem. Soc. 1987, 109, 917. (k) Tanaka, H.; Shibata,
M.; Ito, K. Chem. Pharm. Bull. 1984, 32, 1578. (l) Tsuda, Y.; Nakai, A.;
Ito, K.; Suzuki, F.; Haruna, M. Heterocycles 1984, 22, 1817. For reports
on the formal synthesis, see: (m) Liang, J.; Chen, J.; Liu, J.; Li, L.; Zhang,
H. Chem. Commun. 2010, 46, 3666. (n) Gao, S.; Tu, Y. Q.; Hu, X.; Wang,
S.; Hua, R.; Jiang, Y.; Zhao, Y.; Fan, X.; Zhang, S. Org. Lett. 2006, 8,
2373. (o) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601. (p) Allin, S. M.;
Streetley, G. B.; Slater, M.; James, S. L.; Martin, W. P. Tetrahedron Lett.
2004, 45, 5493. (q) Chikaoka, S.; Toyao, A.; Ogasawara, M.; Tamura, O.;
Ishibashi, H. J. Org. Chem. 2003, 68, 312. (r) Sano, T.; Toda, J.; Ohshima,
T.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40, 873
.
(7) Portions of this work are taken from preliminary studies: (a) Joo,
J. M. Ph.D. Dissertation, Princeton University, NJ, October 2008. (b) David,
R. A. A.B. Dissertation, Princeton University, NJ, June 2008.
(8) Joo, J. M.; Yuan, Y.; Lee, C. J. Am. Chem. Soc. 2006, 128, 14818.
(9) For a similar sequence to prepare a dihydroisoquinoline, see: Ho,
W.-B.; Broka, C. J. Org. Chem. 2000, 65, 6743.
Org. Lett., Vol. 12, No. 24, 2010
5705

TBDPS group, the resultant alcohol 12b was then converted
into iodide 6a, thereby procuring the key haloenyne inter-
mediate 6 (X ) I) of our synthesis. Alternatively, it was
found that this sequence could be more efficiently performed
by using 2-iodoethanol (9b), with which N-alkylation of 10
led to the formation of the cyclic ammonium salt 13 from
the incipient iminium isomer 11b.11 The alkynylation of 13
appeared to involve a Grignard addition reaction to an
iminium salt of type 11 (R ) MgBr) arising from the cyclic
N,O-ketal 14,12 which could be isolated under basic condi-
tions. Through this protecting group-free route, homovera-
trylamine (7) was expediently advanced to alcohol 12b in 4
stages with only one purification step.
Figure 2. Possible byproducts.
heated at 85 °C for 2 h in the presence of 3 equivalents of
triethylamine.13 This N-alkylation was found to take place
to a significant degree even at a low reaction temperature in
either DMF or CH3CN (ca. 50% at 25 °C in 1 h).
With iodoenyne 6a in hand, we set out to examine the
possibility of effecting its double ring closure by rhodium
catalysis (Scheme 3). When iodide 6a was subjected to the
The serious setback faced in initial studies prompted us
to probe a range of parameters affecting the outcome of the
key cyclization. Our focus was first placed on the base effect
because of the unexpected detrimental role played by
triethylamine in the reaction of 6a. However, a set of
screening experiments varying the nature as well as amount
of the base did not lead to amelioration, with the highest
yield still resulting from the reaction employing triethy-
lamine.14 Given that the rapid N-alkylation was mainly
responsible for the low yield of 4, attempts were made to
reduce the rate of this substitution process (Table 1).
Scheme 3. Rhodium-Catalyzed Tandem Cyclization of 6a
standard conditions derived from our previous study,8 the
tandem cyclization did occur to generate the desired tetra-
cyclic diene 4, but only in 36% yield. In contrast to our
previous experience where the reaction times ranged from 6
to 24 h, 6a was completely consumed within 1 h. The
formation of diene 15, the simple cycloisomerization product
without ꢀ-alkylation, was not detected (Figure 2). In addition,
a rapid decomposition process seemed to be operative
independent of the desired product formation, a problem not
encountered before.
Table 1. Leaving Group and Solvent Effectsa
entry
reactant
X
solvent
time
yieldb
1
2
3
4
6a
6a
6b
6c
6d
6b
6b
6a
I
I
Br
Cl
OTs
Br
Br
I
DMF
1 h
1 h
1 h
1 h
1 h
14 h
8 h
12 h
36%
29%
39%
9%c
11%
49%
47%
70%
CH3CN
CH3CN
CH3CN
CH3CN
THF
In light of these observations, a series of control experi-
ments were carried out to identify the side reaction pathway.
These tests revealed that the loss of 6a was due almost
exclusively to its reaction with triethylamine that gave the
quaternary ammonium salt 16, whereas 6a was unaffected
by other reaction components. Indeed, clean conversion of
6a to 16 in quantitative yield was observed when it was
5
6
7d
8
THF
THF
a All reactions were performed with 0.20 mmol of halide 6, 0.40 mmol
of Et3N, 0.01 mmol of [Rh(COD)Cl]2, and 0.04 mmol of P(4-F-C6H4)3 at
85 °C in the solvent indicated (0.1 M). b Isolated yield. c Unreacted 6c was
recovered in 20%. d Reaction was carried out in the presence of 0.02 mmol
of tetrabutylammonium iodide.
(10) (a) For a review on addition reactions to iminium salts, see:
Paukstelis, J. V.; Cook, A. G. Ternary iminium salts. In Enamines: Synthesis,
Structure and Reactions; Cook, G. A., Ed.; Marcel Dekker: New York,
1988; pp 275-346. For a similar sequence to prepare 2,2-disubstituted
isoquinolines, see: (b) Ohkubo, M.; Kuno, A.; Katsuta, K.; Ueda, Y.;
Shirakawa, K.; Nakanishi, H.; Nakanishi, I.; Kinoshita, T.; Takasugi, H.
Chem. Pharm. Bull. 1996, 44, 95.
Although a maximum yield of 39% was obtained from the
reaction of bromide 6b, substrates with a poor leaving group,
6c (X ) Cl) and 6d (X ) OTs), in general, gave rise to
inferior results (entry 1 vs entries 2-5). On the other hand,
significant improvement came from the solvent screening,
which revealed THF to be more efficient than CH3CN or
(11) Interestingly, the reaction employing 1,2-diiodoethane did not result
in a similar N-alkylation, but instead led to iodinium-induced cyclization
of the alkenylimine to give an iodoiminium salt. See Supporting Informa-
tion.
(12) For a review on addition reactions of N,O-acetals, see: (a) Yamazaki,
N.; Kibayashi, C. J. Synth. Org. Chem. Jpn. 2003, 61, 38. For selected
examples of the addition of alkynyl Grignard reagents to N,O-acetals, see:
(b) Caldwell, J. J.; Craig, D. Angew. Chem., Int. Ed. 2007, 46, 2631. (c)
Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem.
2003, 68, 1919. (d) Poerwono, H.; Higashiyama, K.; Takahashi, H. J. Org.
Chem. 1998, 63, 2711.
(13) Resubjection of 16 to the rhodium-catalyzed tandem cyclization
conditions resulted only in the recovery of the starting material.
(14) See Supporting Information for the detailed results of the base
screening experiments.
5706
Org. Lett., Vol. 12, No. 24, 2010

DMF (entries 6-8). Thus, the cyclization reaction of 6a in
THF could afford 4 in 70% yield. These results formed a
stark contrast to our previous findings, in which the use of
THF solvent did not induce ꢀ-alkylation but instead rendered
only the simple cycloisomerization product such as 15 at
room temperature. It would seem that although the rates of
formation of 4 and 16 were both decelerated in THF (entries
1 and 2 vs entries 6-8), the intermolecular N-alkylation
producing the undesired 16 was slowed down much more
than the intramolecular ꢀ-alkylation en route to the desired
4. This solvent effect might be a consequence of differential
product solvation in entropic origin: in a relatively nonpolar
medium as THF vis-a`-vis CH3CN and DMF, the bimolecular
N-alkylation process forming the ammonium salt 16 involves
a higher degree of charge development in the transition state
and thus is disfavored.
catalyzed dihydroxylation and periodate-mediated glycol
cleavage was thus performed on diene 4 to furnish
3-demethoxyerythratidinone (3), whose spectroscopic data
matched the literature values in all aspects.
In summary, we have accomplished a total synthesis of
3-demethoxyerythratidinone based on a tandem strategy
emanating from the combined rhodium catalysis. In this
approach, the A/B ring system of the erythrinane skeleton
is constructed in one step mediated by a single catalyst. Also
notable is the rapid assembly of the key intermediate from
simple commercial materials in a highly convergent manner.
These features allow the synthesis to be completed in only
7 total steps with an overall yield of 41%. Our work
represents the first example of an application of the C-C
bond-forming metal vinylidene catalysis to natural product
synthesis, wherein an alkynyl group catalytically undergoes
novel ꢀ-alkylation and formal C-H insertion in tandem to
effect double ring closure.
With the tetracyclic framework established through the
catalytic tandem cyclization, the final stage of the total
synthesis entailed excision of the methylene unit from 4
(Scheme 4). The single-pot oxidation combining osmium-
Acknowledgment. We thank the NSF (CHE 518559) and
the NIH (R01GM073065) for support of this research and
Bristol-Myers Squibb for the graduate fellowship to J.M.J.
The National Research Foundation of Korea (NRF) is
gratefully acknowledged for the support through the Basic
Research Laboratory (BRL) Program.
Scheme 4. Completion of the Total Synthesis of 3
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL102535U
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