Total synthesis of (±)-trigonoliimine C via oxidative rearrangement of an unsymmetrical bis-tryptamine

Article abstract of DOI:10.1021/ja203960b

We report the first total synthesis of (±)-trigonoliimine C, a member of a family of structurally complex alkaloids, in 10 steps from tryptamine and 6-methoxytryptamine. Our convergent synthetic strategy relies on a selective oxidative rearrangement of an unsymmetrical 2,2′-bis- tryptamine.

Full text of DOI:10.1021/ja203960b

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Total Synthesis of (()-Trigonoliimine C via Oxidative Rearrangement
of an Unsymmetrical Bis-Tryptamine
Xiangbing Qi, Hongli Bao, and Uttam K. Tambar*
Department of Biochemistry, Division of Chemistry, The University of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States
S Supporting Information
b
Scheme 1. Alternative Biosynthetic Hypothesis for the
Trigonoliimines
ABSTRACT: We report the first total synthesis of (()-
trigonoliimine C, a member of a family of structurally com-
plex alkaloids, in 10 steps from tryptamine and 6-methox-
ytryptamine. Our convergent synthetic strategy relies on a
selective oxidative rearrangement of an unsymmetrical 2,20-
bis-tryptamine.
lkaloids with oxidatively rearranged indole substructures are
A
abundant in nature.1 These unique molecular architectures
present synthetic challenges for chemists and inspire the devel-
opment of new methods.2 The trigonoliimines are a family of
alkaloids isolated in 2010 that exemplify the structural intrigue
presented by oxidatively rearranged indole systems.3 These natural
products possess unprecedented polycyclic structures that ap-
pear to arise from the union of two heteroaromatic subunits. In
addition to reporting the anti-HIV-1 activity of the trigonolii-
mines in the original isolation paper, Hao and co-workers pro-
posed a biosynthesis that commenced with the coupling of
tryptamine and kynuramine.4 We envisioned an alternative
biogenetic origin that exploits the latent symmetry of these
alkaloids and may be relevant to the biosynthesis of many other
indole natural products (Scheme 1). This hypothesis involves an
oxidative arylꢀaryl coupling of two tryptamine derivatives to
generate unsymmetrical 2,20-binary tryptamine 1, which is con-
verted to trigonoliimine scaffolds 2ꢀ4 through a series of selec-
tive oxidative rearrangements.5
Scheme 2. Symmetry-Guided Retrosynthetic Analysis of
Trigonoliimine C (4)
In this communication, we describe a concise and convergent
total synthesis of (()-trigonoliimine C (4) that is guided by our
new biosynthetic hypothesis for this family of natural products.
We have developed unprecedented selective methods to oxida-
tively functionalize either indole ring system in unsymmetrical
conjugated bis-indoles. Given the prevalence of alkaloids that can
conceptually arise from the selective mono-oxidation and rear-
rangement of unsymmetrical conjugated binary indole systems,1,2
our strategy may provide a general route to complex natural
product architectures that possess this element of structural
symmetry.
Our retrosynthetic analysis for trigonoliimine C was based on
the assumption that bis-indole 7 could be converted selectively to
mono-oxidized hydroxyindolenine 6, followed by a Wagnerꢀ
Meerwein [1,2]-shift6 to generate indoxyl 5 (Scheme 2). While
the tandem indole oxidation/WagnerꢀMeerwein [1,2]-shift is a
well-established method in alkaloid synthesis for constructing
oxindoles,7 the selective generation of indoxyl products is less
developed.8 Moreover, we were interested in employing this
strategy for the conversion of a 2,20-binary indole such as 7 into
sterically congested, indole-substituted indoxyl 5. This rearran-
gement process would address the major synthetic challenges of
this alkaloid, which include the dense polycyclic scaffold and the
fully substituted tertiary carbinamine stereocenter.
To test the feasibility of our synthetic strategy for trigonolii-
mine C, we explored the oxidative rearrangement of model 2,20-
indole dimer 9 (Scheme 3). Phthalimide protected tryptamine 8 was
subjected to a two-step metal-free oxidative coupling protocol to
Received: April 29, 2011
Published: June 14, 2011
r
2011 American Chemical Society
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generate dimer 9,9 which was treated with oxaziridine 1010 to yield
mono-oxidized hydroxyindolenine 11. In the presence of Sc(OTf)3
and dimethylformamide as solvent, hydroxyindolenine 11 was
converted selectively to indoxyl 12.11 The efficient synthesis of
indoxyl 12 bode well for our retrosynthetic strategy of trigonolii-
mine C, given its similarity to the proposed indoxyl intermediate 5.
Motivated by the success of our model studies in the genera-
tion ofindoxyl12, we commenced our synthesis of trigonoliimine C
with the convergent assembly of unsymmetrical bis-indole 7
(Scheme 4). Boc-protected tryptamine 14 was constructed in a
short series of steps from 6-methoxytryptamine 13. This inter-
mediate was then subjected to a Boc-directed lithiation/stanny-
lation sequence, which resulted in the formation of stannylindole
15. Bis-indole 7 was synthesized in good yield under Stille cross-
coupling conditions between stannylindole 15 and bromoindole
16, which was assembled from tryptamine in two steps. Inter-
estingly, formation of the C2-bis-indole linkage was accompanied
by concomitant cleavage of the Boc directing group to unveil the
deprotected binary tryptamine 7.
Scheme 3. Synthesis of Model Indoxyl 12
Once we had access to bis-indole 7, we attempted several
mono-oxidation reactions with the expectation that the electron-
rich 6-methoxyindole system would be oxidized preferentially
over the indole system (6 vs 17, Table 1). To our surprise,
exposure of unsymmetrical bis-indole 7 to a diverse set of
oxidants led to the formation of the undesired mono-oxidation
product 17 as the major product (e.g., entries 1ꢀ3).12 For
example, in the presence of oxaziridine 10, which was utilized
in our model studies, the undesired hydroxyindolenine 17 was
generated in a ratio of 6:1 (entry 2). We also observed that
certain oxidation protocols formed both hydroxyindolenines 6
and 17 in approximately equimolar amounts (entries 4ꢀ7). We
were particularly intrigued by the facile mono-oxidation of 7
under an atmosphere of O2 (entry 6) and even ambient air (entry 7).
Gratifyingly, after considerable experimentation we discovered
that iodine(III) reagents such as PhI(OAc)2 and PhI(TFA)2
preferentially produced the desired hydroxyindolenine 6 (entries
8 and 9). The favorable oxidation of the methoxy-substituted
indole system was attributed to the formation of covalent adduct
18, which would be susceptible to intermolecular nucleophilic
attack by a molecule of water.13 While several attempts were
made to realize an enantioselective mono-oxidation of unsym-
metrical bis-tryptamine 7 with chiral iodine(III) reagents, the
addition of water at C3 of the methoxyindole system, which is
remote to the chiral framework of the oxidant, resulted in little to
no enantioselectivity.14,15 Nevertheless, we now had methods to
selectively mono-oxidize either the electron-poor (entry 2) or
electron-rich (entry 9) aromatic system of an unsymmetrical
conjugated binary indole.
Scheme 4. Assembly of Unsymmetrical Binary Tryptamine 7
With a selective synthesis of hydroxyindolenine 6 in hand, we
explored its rearrangement under the conditions developed for
Table 1. Selective Oxidation of Unsymmetrical Binary Tryptamine 7
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Table 2. Selective WagnerꢀMeerwein [1,2]-Shift To Generate Indoxyl 5
Scheme 5. Unexpected Hydroxyl Migration between Indole
Systems
the rearrangement of model hydroxyindolenine 11 (Table 2).
Unexpectedly, exposure to Sc(OTf)3 in dimethylformamide did
not yield the desired indoxyl 5. Instead, the isomeric indoxyl
19 was formed (entry 1), presumably through a transfer of the
hydroxyl functionality from the 6-methoxyindole fragment to the
unfuctionalized indole fragment via the putative dihydrofuran
intermediate 21 (Scheme 5).16,17 Although this hydroxyl migra-
tion may have also occurred in our model studies (Scheme 3), it
was inconsequential for pseudosymmetric hydroxyindolenine
11. Unfortunately, the formation of the undesired indoxyl 19
was deleterious for our efforts to synthesize trigonoliimine C,
since we could not determine a straightforward method to
convert this unexpected indoxyl into the indole natural product.
In addition, subjection of hydroxyindolenine 17 to these reaction
conditions resulted in the same indoxyl product 19, without any
hydroxyl migration (Scheme 5).
While the Sc(OTf)3 mediated conditions did not generate the
desired rearrangement product, Brønsted acids proved to be more
promising. For example, a small amount of the desired indoxyl 5
was generated in the presence of HCO2H and PhMe as solvent,
with considerable formation of undesired and thermodynami-
cally more stable oxindole 20 (entry 2). Unfortunately, the use of
HCO2H also yielded large amounts of reduced bis-indole 7
(entries 2ꢀ3), which most likely formed by formic acid reduc-
tion of hydroxyindolenine 6.18 The use of Brønsted acids that are
not hydride sources, such as HCl, improved the efficiency of
indoxyl formation (entries 4ꢀ5), but considerable amounts of
bis-indole 7 were still generated, presumably by decomposition
of dimethylformamide to HCO2H.19 Fortunately, by simply
switching to dimethylacetamide as solvent, we eliminated the
formation of HCO2H and exclusively formed the desired indoxyl
5 (entry 6).
To complete the synthesis of trigonoliimine C, we examined
numerous methods to assemble the strained seven-membered Schiff
base of the natural product. While most conditions for intramole-
cular imine formation were unsuccessful, eventually we discovered
that deprotection of the phtahlimide group and subsequent
Ti(Oi-Pr)4 mediated cyclization efficiently converted intermedi-
ate 5 into (()-trigonoliimine C (Scheme 6). The spectroscopic
data obtained for our synthetic sample of 4 were identical with
the data reported by Hao in the original isolation paper.
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Scheme 6. Total Synthesis of (()-Trigonoliimine C (4)
(5) Similar oxidative arylꢀaryl couplings to generate oxidatively
labile C2-indole dimers are proposed in the biosynthesis of staurospor-
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Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993, 115, 8867–8868. (f) Liu, Y.;
McWhorter, W. W., Jr. J. Org. Chem. 2003, 68, 2618–2622.
(7) For some seminal examples of oxidation/WagnerꢀMeerwein
[1,2]-shift in oxindole synthesis, see: (a) Ito, M.; Clark, C. W.;
Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001,
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In conclusion, we have developed the first convergent total
synthesis of the alkaloid (()-trigonoliimine C in 10 steps from
tryptamine and 6-methoxytryptamine. Our strategy relies on a
selective mono-oxidation of 2,20-bis-tryptamine 7, followed by a
WagnerꢀMeerwein [1,2]-shift to indoxyl 5. We have discovered
methods to oxidize either the electron-poor or electron-rich
indole system in an unsymmetrical conjugated binary indole,
which may have a broader impact for the construction of other
structurally complex indole alkaloids. The application of this
strategy to the other trigonoliimines, the synthesis of unnatural
analogs, and the exploration of biological activity for these
alkaloids are ongoing interests in our group.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
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dures and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Commun. 1977, 25–26.
’ AUTHOR INFORMATION
(11) Movassaghi recently reported an elegant use of Sc(OTf)3 to
convert a bis-indole into oxindole: Movassaghi, M.; Schmidt, M. A.;
Ashenhurst, J. A. Org. Lett. 2008, 10, 4009–4012.
(12) The structures of isomers 6 and 17 were confirmed by X-ray
crystallography. See Supporting Information.
Corresponding Author
uttam.tambar@utsouthwestern.edu
(13) When we subjected bis-phthalyl protected unsymmetrical 6-MeO
2,20-bis-tryptamine to the optimized oxidation conditions (Table 1,
entry 9), the electron-rich indole ring was still oxidized preferentially
(albeit in a diminished ratio of 4:1). This suggests that both the methoxy
substituent and the formamide influence the high selectivity during
mono-oxidation of 7. See Supporting Information for details.
(14) See Supporting Information for details of our attempts to use
chiral iodine(III) reagents in the enantioselective mono-oxidation of bis-
tryptamine 7. While enantioselective iodine(III) mediated additions of
intramolecular nucleophiles have been reported, difficulties associated
with enantioselective iodine(III)-mediated additions of intermolecular
nucleophiles such as water persist: Quideau, S.; Lyvinec, G.; Marguerit,
M.; Bathany, K.; Ozanne-Beaudenon, A.; Buffeteau, T.; Cavagnat, D.;
Chꢀenedꢀe, A. Angew. Chem., Int. Ed. 2009, 48, 4605–4609.
’ ACKNOWLEDGMENT
Financial support was provided by the Robert A. Welch
Foundation (Grant I-1748) and the W. W. Caruth, Jr. Endowed
Scholarship. Prasanta Das is acknowledged for experimental
assistance.
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