Novel approach to the lundurine alkaloids: Synthesis of the tetracyclic core

Article abstract of DOI:10.1021/ol201980r

The tetracyclic core of the lundurine family of alkaloids has been synthesized by a novel approach that features a double ring-closing olefin metathesis to form the five-and eight-membered rings.

Full text of DOI:10.1021/ol201980r

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5104–5107
Novel Approach to the Lundurine Alkaloids:
Synthesis of the Tetracyclic Core
Suvi T. M. Orr, Jianhua Tian, Meike Niggemann, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin,
Texas 78712, United States
sfmartin@mail.utexas.edu
Received July 22, 2011
ABSTRACT
The tetracyclic core of the lundurine family of alkaloids has been synthesized by a novel approach that features a double ring-closing olefin
metathesis to form the five-and eight-membered rings.
Lundurine A (1) and lundurine B (2) belong to a small
but important family of hexacyclic alkaloids that was first
isolated in 1995 from Kopsia K. tenuis.1 These alkaloids are
characterized by a unique propellane structure that com-
prises a dihydroindole ring fused with eight- and three-
membered rings. Because of its limited availability, it
was not until 2004 that lundurine B was found to exhibit
potent in vitro activity toward B16 melanoma cells (IC50 of
2.8 μg/mL); it is also effective in circumventing multidrug
resistance in vincristine-resistant KB cells.2 Lundurine B is
thus important as a potential anticancer agent. There are
no reported syntheses of any of the lundurines to date,
although a few approaches to the skeleton have been
reported.3
be anticipated in this step owing to the stereochemistry
at the preformed quaternary center at C(16). Similar
Scheme 1. Retrosynthetic Analysis
Our retrosynthetic analysis of lundurine B is depicted in
Scheme 1. We envisioned that the cyclopropane ring could
be constructed via a copper(I)-catalyzed, intramolecular
cyclopropanation of an intermediate as 3 followed by a
selective deoxygenation using a modified WolffÀKishner
procedure.4 High facial selectivity in this cyclization would
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r
10.1021/ol201980r
Published on Web 09/02/2011
2011 American Chemical Society

intramolecular cyclopropanations of the C(2)ÀC(3) dou-
ble bond of indoles with diazo ester in the presence of
transition-metal catalysts are known.5 The diazoketone
moiety of 3 would then arise from the corresponding ester
group in 4 via hydrolysis followed by diazomethylation.
The tetracycle 4, a key intermediate in our plan, would be
accessed via an enantioselective, double ring-closing me-
tathesis (RCM) reaction involving the tetraene 5.6À8 In-
deed, the inspiration for utilizing an RCM for the synthesis
of the lundurines owes its origin to our long-standing
interest in using RCM as a key construction for alkaloid
synthesis.9 Assembly of compound 5 would require cou-
pling of the 2-vinyl indolylethanol derivative 6, the amine
7, and a suitable electrophile such as 8 or 9.
Scheme 2
Lundurine B possesses an N-carbomethoxy group, but
we had some concerns regarding the stability of this moiety
during some transformations that we anticipated might be
involved as we worked out the synthetic details. We thus
decided to conduct our exploratory studies with an N-tosyl
group that could be easily removed at a later stage.
Accordingly, we initiated our investigations by protecting
the primary hydroxyl group in 10, which was prepared
according to a known procedure, to give 11 (Scheme 2).10
Bromination of the protected indolyl ethanol with N-
bromosuccinimide (NBS) selectively afforded the 2-bro-
moindole derivative 12 in 78% yield. It should be noted
that dibromination of the indole ring, which is the major
side reaction in this step, could be suppressed by slow
addition of NBS to a solution of 11. Treatment of 12 with
NaHMDS followed by p-toluenesulfonyl chloride cleanly
provided the tosyl-protected indolyl bromide 13 in 81%
yield. Subsequent Suzuki-type cross coupling of 13 with
trivinylboroxane (14) delivered the 2-vinylindole 15, which
underwent facile fluoride-induced deprotection of the
TBDPS group to furnish 16 in 90% yield.
The next stepof the synthesis required preparation ofthe
amine 7 (Scheme 3). Bisalkylations of the imine anion
derived from 17 have been reported to provide geminally
dialkylated glycine derivatives.11 Accordingly, the com-
mercially available glycine Schiff base 17, which can be
easily prepared,12 was subjected to reaction with 2 equiv of
phenylvinyl sulfoxide and a stoichiometric amount of
K2CO3 according to a literature procedure.9 However,
the monoalkylated compound was obtained as the only
product in 80% yield. Because this compound could not be
further transformed to 18 by resubjection to these reaction
conditions, a modified protocol was developed. We even-
tually discovered that when a stoichiometric amount of
t-BuOK was employed as the base under phase-transfer
conditions, the desired bisalkylated product 18 could be iso-
lated in 86% yield. Hydrolysis of the diphenylimine moiety
was achieved by stirring 18 in THF in the presence of aque-
ous HCl at room temperature for 1 h to give the requisite
amine 7 in 89% yield.
(6) For some leading examples of enantioselective RCM, see:
(a) Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5,
4899–4902. (b) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem.
Soc. 2006, 128, 1840–1846. (c) Lee, A.; Malcomson, S. J.; Puglisi, A.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 5153–
5157. (d) Sattely, E. S.; Meek, S. J.; Malcomson, S. J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943–953. (e) Tiede, S.;
Scheme 3
€
Berger, A.; Schlesiger, D.; Rost, D.; Luhl, A.; Blechert, S. Angew. Chem.,
Int. Ed. 2010, 49, 3972–3975.
(7) For an example of a RCM of a tetraene, see: Wallace, D. J.;
Cowden, C. J.; Kennedy, D. J.; Ashwood, M. S.; Cottrell, I. F.; Dolling,
U.-H. Tetrahedron Lett. 2000, 41, 2027–2029.
(8) For reviews of applications of RCM to the synthesis of hetero-
cycles, see: (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–
2238. (b) Compain, P. Adv. Synth. Catal. 2007, 349, 1829–1846.
(9) (a) Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett.
1994, 35, 691–694. (b) Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F.
J. Am. Chem. Soc. 2000, 122, 10781–10787. (c) Humphrey, J. M.; Liao,
Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin,
S. F. J. Am. Chem. Soc. 2002, 124, 8584–8592. (d) Washburn, D. G.;
Heidebrecht, R. W., Jr.; Martin, S. F. Org. Lett. 2003, 5, 3523–3525.
(e) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867–8878.
(f) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60,
7301–7314. (g) Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733–
5735. (h) Deiters, A.; Pettersson, M.; Martin, S. F. J. Org. Chem. 2006,
71, 6547–6561. (i) Kummer, D. A.; Brenneman, J. B.; Martin, S. F.
Tetrahedron 2006, 62, 11437–11449. (j) Simila, S. T. M.; Martin, S. F.
J. Org. Chem. 2007, 72, 5342–5349. (k) Deck, J. A.; Martin, S. F. Org.
Lett. 2010, 12, 2610–2613.
With the alcohol 16 and amine 7 in hand, the secondary
amine 19 was readily prepared in 89% yield over two steps
by sequential oxidation of 16 to the corresponding alde-
hyde with 2-iodoxybenzoic acid (IBX) and reductive ami-
nation with 7 in the presence of NaBH(OAc)3 (Scheme 4).
Amine19wasthenheated ina microwavereactortoinduce
(11) Opio, J. O.; Labidalle, S.; Galons, H; Micoque, M. Synth.
Commun. 1991, 21, 1743–1754.
(12) (a) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663–
2666. (b) Danner, P.; Bauer, M.; Phukan, P.; Maier, M. E. Eur. J. Org.
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Org. Lett., Vol. 13, No. 19, 2011
5105

pyrolytic elimination and afford the key intermediate
triene 20 in 69% yield.
was formed that shut down the catalytic cycle and precluded
an RCM.14 Toward obviating this potential problem,
we conducted the RCM in the presence of Ti(OÀi-Pr)4
(30 mol %),14b albeit to no avail.
Reasoning that the tertiary amine derived from 20 might
not suffer the same fate, we turned our attention to a
synthesis of lundurine B, which lacks a lactam function in
the five-membered ring. Accordingly, the tetraene 23 was
prepared in excellent yield by allylation of 20 with allyl
bromide (Scheme 6). Grubbs I, Grubbs II, HoveydaÀ
Grubbs II, and Schrock catalysts all promoted the RCM
cyclization of 23, but the yields of 24 were best using the
less reactive Grubbs I catalyst. Grubbs I, Grubbs II, and
Schrock catalysts promoted the cyclization of 24 to 25, but
the cyclization with the former gave the best yield. Increas-
ing the catalyst loading or using the hydrochloride salt of
either 23 or 24, a tactic that sometimes proves advanta-
geous for cyclizations of bis-olefinic, tertiary amines,8b did
not improve the yield. Although 25 could also be obtained
in a one-pot procedure using Grubbs I catalyst, the overall
yield was not as high.
Scheme 4
With a view toward preparing lundurine A (1), which
has an unsaturated lactam moiety in the five-membered
ring, triene 20wastreated withcrotonylchloride inCH2Cl2
in the presence of Et3N to deliver the tetraene 21 in 72%
yield (Scheme 5). Unfortunately, when 21 was heated with
Grubbs I catalyst in refluxing CH2Cl2 or benzene or at
various temperatures with microwave heating, none of the
desired tetracyclic compound 22 was isolated. Grubbs II
catalyst was also examined as a catalyst as were other
RCM catalysts, including the Schrock catalyst and the
StewartÀGrubbs catalyst,13 but none of these afforded
detectable amounts of 22. Use of Grubbs II catalyst in
refluxing benzene provided small amounts of a tricyclic
compound having an eight-membered ring, perhaps aris-
ing from initial loading of the catalyst onto the vinylindole
moiety, but further experiments were not pursued because
of the low yields. We hypothesized that an unreactive
metalÀcarbene chelate involving the amide oxygen atom
Scheme 6
Scheme 5
With the tetracycle 25 in hand, we turned our atten-
tion to its conversion to lundurine B (2). Catalytic
hydrogenation of 25 (Pd/C, 1 atm H2) gave 26 by
(13) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592.
(14) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446–452. (b) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130–9136. (c) Arisawa, M.; Nishida, A.; Nakagawa, M.
J. Organomet. Chem. 2006, 691, 5109–5121.
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Org. Lett., Vol. 13, No. 19, 2011

highly selective reduction of the double bond in the
eight-membered ring (Scheme 7); no reduction of the
olefin in the five-membered ring was observed under
these conditions. Subsequent saponification of 26
with K2CO3 in MeOH/H2O (2:1) at 80 °C provided
acid 27 in 93% yield.
Scheme 7
Preliminary experiments to convert the acid 27 into
diazoketone 28 have been unsuccessful. For example,
sequential treatment of 27 with isobutyl chloroformate
at À20 °C and then diazomethane at 0 °C according to
Wardrop’s protocol15 did not provide 28. Attempts to
activate the carboxyl function using thionyl chloride or
oxalyl chloride under mild conditions followed by reaction
with diazomethane were also unsuccessful. Mixtures of
starting material, unidentifiable products, and small
amounts of a side product that appeared to be the pyrrole
29 were typically isolated. The pyrrole 29 is presumably
formed by decarbonylation of the activated carboxylic
acid moiety, giving an iminium intermediate that tauto-
merizes to give the pyrrole. It has been shown that activa-
tion of tertiary amino acids may lead to the formation of
iminium ions via decarbonylation, but reported conditions
that result in such fragmentations are typically more
forcing.16,17
to access a prochiral divinyl moiety in 20 and a two-step
RCM procedure to form the five-and eight-membered
rings of the lundurine skeleton. We are currently exploring
several other approaches to the lundurines that will enable
the RCM with a chiral catalyst and that will avoid the
problematic steps to generate a diazoketone. The results of
those investigations will be disclosed in due course.
In summary, we have developed a novel route to the
tetracyclic framework of lundurine B (2). Notable features
of the approach are a high-yielding reductive amination
of a 2-vinylindole-3-acetaldehyde derived from alcohol
16 with a geminally substituted glycine derivative 7, fol-
lowed by a thermal elimination of phenylsulfoxide groups
Acknowledgment. We thank the National Institutes of
Health (GM 25439 and GM 31077) and the Robert A. Welch
Foundation (F-0652) for their generous support of this
work. M.N. is grateful to the German Academic Exchange
Service (DAAD) for a postdoctoral fellowship. We also
thank Mr. Yuichi Yasuhara (Kyoto University) for
help in preparing starting materials. We are also grateful
to Dr. Richard Pederson (Materia, Inc.) for providing
metathesis catalysts used in these studies.
(15) Wardrop, D. J.; Forslund, R. E. Tetrahedron Lett. 2002, 43, 737–
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J. Am. Chem. Soc. 1976, 98, 7448–7449. (b) Martin, S. F.; Barr, K. J.;
Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121, 6990–6997.
(17) For example, see: (a) van Tamelen, E. E.; Oliver, L. K. Bioorg.
Chem. 1976, 5, 309–326. (b) Ambra, T. E. D.; Estep, K. G.; Bell, M. R.;
Eissenstat, M. A.; Josef, K. A.; Ward, S. J.; Haycock, D. A.; Baizman,
E. R.; Casiano, F. M.; Beglin, N. C.; Chippari, S. M.; Grego, J. D.;
Kullnig, R. K.; Daley, G. T. J. Med. Chem. 1992, 35, 124–135.
Supporting Information Available. Experimental pro-
1
cedures, spectral data, and copies of H and 13C NMR
spectra for key compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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