Synthesis of bis(indole) alkaloids from Arundo donax: The ynindole diels-alder reaction, conformational chirality, and absolute stereochemistry

Article abstract of DOI:10.1002/anie.201407336

Bis(indole) alkaloids from Arundo donax were synthesized using the first ynindole Diels-Alder reaction. The alkaloids are chiral, having stable enantiomeric conformations with half-lives of racemization of t1/2 = 4150-25100 seconds at room temperature. Th

Full text of DOI:10.1002/anie.201407336

Angewandte
Chemie
DOI: 10.1002/anie.201407336
Natural Product Synthesis
Synthesis of Bis(indole) Alkaloids from Arundo donax: The Ynindole
Diels–Alder Reaction, Conformational Chirality, and Absolute
Stereochemistry**
Jingjin Chen, Andrew J. Ferreira, and Christopher M. Beaudry*
Abstract: Bis(indole) alkaloids from Arundo donax were
synthesized using the first ynindole Diels–Alder reaction. The
alkaloids are chiral, having stable enantiomeric conformations
with half-lives of racemization of t1/2 = 4150–25100 seconds at
room temperature. Their absolute stereochemistry was deter-
mined using the exciton chirality method.
3
I
n molecules lacking sp -hybridized stereogenic carbon
atoms such as biaryls and cyclophanes, identification of
chirality is not straightforward. In such molecules, chirality
means the molecules have relatively long half-lives of
racemization. In this context, chirality has been defined as
those molecules which possess a half-life of 1000 seconds or
longer. Predicting half-lives of enantiomeric conformations
of molecules using computational methods is not straightfor-
[
1,2]
[
3]
Figure 1. Bis(indole) alkaloids from Arundo donax.
[
4]
À1
ward because small (1.4 kcalmol ) changes in the racemiza-
approximately 0.001 to 0.1 seconds, and is not consistent
[
11,12]
tion barrier result in a change of an order of magnitude in the
with the barrier calculated by Khuzhaev.
[
5]
racemization half-life. As a result, molecules lacking
stereocenters could have unnoticed chirality. In such cases,
chemical synthesis and experimental determination of the
racemization half-life would be required to unambiguously
demonstrate the presence of chirality. Described herein is
such an investigation for a family of indole alkaloids.
The CÀN biaryl axis of 1–4 is flanked by three non-
hydrogen substituents, and such substitution patterns often
[
1]
lead to chirality in biphenyls. Moreover, typical CÀN bonds
which connect azoles with phenyl rings are shorter (1.419–
[
13]
[14]
1.430 ꢁ) than CÀC bonds in biphenyls (1.482–1.507 ꢁ),
and would bring the large substituents closer, and could
enhance steric effects.
Arundo donax is a grass native to Asia and it has been
[
6]
used in folk medicine since ancient times. More recently, it
has been used as the source of reeds for woodwind instru-
ments, has been evaluated as a biofuel, and it can be an
We decided to prepare the A. donax alkaloids and
measure their racemization half-lives. The alkaloids 1–4
could arise from the glyoxamide 7 (Scheme 1). We envisioned
7 as the product of a Diels–Alder cascade of 8, which displays
an amino-furan diene and an ynindole (N-alkynyl indole)
dienophile. The intermediate 8 may arise from coupling of the
[
7]
invasive species. In 2002–2004 Khuzhaev and co-workers
isolated six bis(indole) natural products (1–6; Figure 1) from
[
8,9]
the root ball of A. donax.
They display a 4-indoyl-indole
molecular architecture, and as such, represent a unique class
of bis(indole) natural products. Khuzhaev hypothesized that
arundamine (3) is achiral based on computational analysis of
[
10,11]
CÀN bond rotation.
Despite Khuzhaevꢀs hypothesis, we suspected the alka-
loids from A. donax possess stable enantiomeric conforma-
1
tions. Tabulated H NMR chemical shifts for the alkaloids
reveal that the geminal methylene protons are chemical-shift
inequivalent. This feature is diagnostic for racemization half-
1
lives which are longer than the H NMR timescale of
[
+]
[+]
[
*] Dr. J. Chen, A. J. Ferreira, Prof. Dr. C. M. Beaudry
Department of Chemistry, Oregon State University
Corvallis, OR 97331 (USA)
E-mail: christopher.beaudry@oregonstate.edu
+
[
] These authors contributed equally to this work.
[**] Financial Support from Oregon State University is acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407336.
Scheme 1. Retrosynthetic analysis of the A. donax alkaloid. Boc=tert-
butoxycarbonyl.
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indole 9 and alkyne 10. Notably, this strategy constructs the
central CÀN linkage prior to synthesis of the bis(indole)
Table 1: Ynindole Diels–Alder substrates.
architecture. It was envisioned that the coupling of an indole
NH and a terminal alkyne would be smoother than cross-
coupling of two functionalized indole building blocks.
Amino-furan dienes have been used in Diels–Alder
[
15]
reactions, but ynindoles are unknown as dienophiles. The
lack of Diels–Alder reactivity of ynindoles could be attributed
to a paucity of methods for their construction. Recently
however, metal-catalyzed coupling of an indole with a bro-
Entry
1
Indole
Product
Yield [%]
54
[
16]
[17]
moalkyne
or a propiolic acid
to form ynindoles was
12
reported. In 2008, Stahl and co-workers reported a synthesis
of an ynindole from 3-carbomethoxy indole (11) and a simple
[
18]
terminal alkyne. All high-yielding ynindole formations use
indoles substituted with electron-withdrawing groups. Possi-
bly, the electron-withdrawing substituent renders the indole
sufficiently acidic to be deprotonated under the reaction
conditions.
[
a]
a]
2
3
n.r.
n.r.
0
0
[
Provided we could synthesize 8, we considered whether or
not it would undergo intramolecular Diels–Alder cycloaddi-
tion. The amino-furan functionality is known to be an
electron-rich diene. We expected the alkyne to be electron
poor based on the inductive electron-withdrawing ability of
the indole. However, the electronic preference of ynindoles in
Diels–Alder reactions was completely unknown. Nitrogen-
substitued alkynes such as ynanimes are among the most
4
8
57
[
a] Starting material was recovered unchanged. DMSO=dimethylsulf-
oxide, n.r.=no reaction.
[
19]
electron-rich dienophiles. However, the electron pair on
the nitrogen atom of the ynidole participates in the aroma-
ticity of the indole, and may not be available for resonance
donation. Furthermore, the indole nitrogen lone pair would
activate only one of two orthogonal p systems of the alkyne,
thus leaving the remaining p bond for normal-electron-
demand Diels–Alder cycloaddition. Such considerations
offered a compelling reason to investigate the Diels–Alder
reactivity of 8.
Functional-group manipulations were used to complete
the synthesis of the alkaloids (Scheme 3). The intermediate 7
was converted into the bis(indole) 15. Acylation of 15 gave
the bis(glyoxamide) 16. Indole glyoxamides can be cleanly
reduced to tryptamines using several hydride reducing agents
[
22]
such as LiAlH4. However, identifying reaction conditions
for clean reduction of 16 was surprisingly difficult. After
considerable experimentation, it was found that exhaustive
reduction of 16 could be achieved with borane. The initial
[
20]
[23]
The alkyne 10 was prepared in four steps from Boc-
product of the reduction appears to be a boron complex,
[
21]
protected 2-aminofuran.
Coupling of 10 with 11 using
which can be hydrolyzed to 17. Hydrogenolysis of 17 in acetic
acid removes the benzyl ether to give arundamine (3).
copper in DMSO gave the ynindole 12 in good yield (Table 1).
Indole or dimethyl tryptamine did not couple with 10,
presumably because they are not sufficiently acidic. We
then coupled 10 with 9, which is synthetically equivalent to
dimethyl tryptamine and contains an electron-withdrawing
substituent at the indole 3-position.
[
24,25]
Hydrogenolysis of 17 in methanol gave arudanine (1).
Acylation of arundamine gave arundacine (2). Arundarine (4)
was formed by Pictet–Spengler reaction of the intermediate
[
20]
18.
We then investigated the chiral properties of the alkaloids.
We evaluated the Diels–Alder reactivity of 8. Gratify-
ingly, it underwent clean high-yielding cycloaddition to give
the phenol 7 at mild temperatures (1508C; Scheme 2).
Presumably, the reaction proceeds via 13 which fragments
to give the acyliminium ion 14. Tautomerization then gives 7.
No intermediates were observed or isolated in the reaction.
Gratifyingly, 1–4 were cleanly resolved on chiral HPLC.
Arundamine enantiomers (3) were separated for polarimetry
and circular dichroic (CD) analysis. The dextrorotatory
enantiomer, (+)-arundamine, was analyzed by CD spectros-
copy (Figure 2). It exhibited a positive first Cotton effect and
negative second Cotton effect (l = 234 and 222 nm, respec-
[26,27]
tively). The exciton chirality method
+)-arundamine enantiomer possesses the aR absolute ste-
reochemistry.
An enantiopure sample of (+)-arundamine underwent
indicates this
(
slow racemization at room temperature. The first-order rate
À4 À1
constant was krac = 1.67 ꢂ 10 s , which corresponds to a half-
life of t1/2 = 4150 s (1.15 h) and a free energy of activation for
À1
racemization of 23.3 kcalmol .
The HPLC resolution, analysis of CD data, and measure-
ment of racemization rate was conducted for the remaining
Scheme 2. Reagents and conditions: a) 1508C, toluene (sealed tube).
2
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Figure 3. Racemization rates, specific rotations, and absolute configu-
rations of the A. donax alkaloids.
mization energies result in comparatively large differences in
racemization half-life.
Scheme 3. Reagents and conditions: a) BnBr, K CO , DMF; b) TFA,
2
3
In conclusion, the first synthesis of the Arundo donax
alkaloids was accomplished using the first Diels–Alder
reaction of the ynindole functional group. Synthetic material
was used to determine the racemization half-life, free energy
of activation for racemization, and absolute configuration of
the molecules. The molecules are chiral, with half-lives of
racemization at 258C of 4150–25100 seconds. Whether such
molecules are biosynthesized in enantioenriched form or
whether such molecules with modest racemization rates can
be implicated in time-sensitive biological processes is the
subject of our current research.
CH Cl ; c) MnO , acetone, 358C; d) 1. (COCl) , THF; 2. HNMe , H O;
2
2
2
2
2
2
e) 1. BH ·DMS, THF, reflux; 2. MeOH, reflux; f) H , Pd/C, AcOH;
3
2
g) H , Pd/C, (CH O) , MeOH; h) Ac O, MeOH; i) CH O(aq), AcOH.
2
2
n
2
2
DMF=N,N-dimethylformamide, DMS=dimethylsulfide, TFA=tri-
fluoroacetic acid, THF=tetrahydrofuran.
Received: July 17, 2014
Revised: August 14, 2014
Published online: && &&, &&&&
Keywords: alkynes · chirality · cycloaddition · natural products ·
.
total synthesis
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Natural Product Synthesis
J. Chen, A. J. Ferreira,
C. M. Beaudry*
&&&& — &&&&
Synthesis of Bis(indole) Alkaloids from
Arundo donax: The Ynindole Diels–Alder
Reaction, Conformational Chirality, and
Absolute Stereochemistry
Conformational chirality: Bis(indole)
alkaloids from Arundo donax were syn-
thesized using the first ynindole Diels–
Alder reaction. The alkaloids are chiral,
having stable enantiomeric conforma-
tions with half-lives of racemization of t1/
=4150–25100 seconds at room tem-
perature. Their absolute stereochemistry
was determined using the exciton chir-
ality method.
2
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!