Facile synthesis of 2,3,6,11-tetrahydro-1H,5H-indolizino[8,7-b]indole-11b- carboxylic acid methyl ester via a 9-BBN-mediated tertiary lactam reduction

Article abstract of DOI:10.1080/00397910802238684

A facile synthesis of 2,3,6,11-tetrahydro-1H,5H-indolizino[8,7-b]indole- 11b-carboxylic acid methyl ester, a versatile intermediate utilized in the synthesis of indole alkaloids, was achieved in two steps. Condensation of tryptamine with dimethyl α-ketoglutarate led to the formation of the corresponding indolizino[8,7-b]indolone ester, which subsequently underwent an efficient lactam reduction with 9-BBN to generate the tertiary amine ester in good yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802238684

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Facile Synthesis of 2,3,6,11-
Tetrahydro-1H,5H-
indolizino[8,7-b]indole-11b-
Carboxylic Acid Methyl Ester
via a 9-BBN-Mediated Tertiary
Lactam Reduction
Demosthenes Fokas a & Zhimin Wang a
a Department of Chemistry, ArQule, Inc., Woburn,
Massachusetts, USA
Version of record first published: 14 Oct 2008
To cite this article: Demosthenes Fokas & Zhimin Wang (2008): Facile Synthesis of
2,3,6,11-Tetrahydro-1H,5H-indolizino[8,7-b]indole-11b-Carboxylic Acid Methyl Ester
via a 9-BBN-Mediated Tertiary Lactam Reduction, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:21,
3816-3822
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Synthetic Communications1, 38: 3816–3822, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238684
Facile Synthesis of 2,3,6,11-Tetrahydro-1H,
5H-indolizino[8,7-b]indole-11b-Carboxylic Acid
Methyl Ester via a 9-BBN-Mediated Tertiary
Lactam Reduction
Demosthenes Fokas and Zhimin Wang
Department of Chemistry, ArQule, Inc., Woburn, Massachusetts, USA
Abstract: A facile synthesis of 2,3,6,11-tetrahydro-1H,5H-indolizino[8,7-b]
indole-11b-carboxylic acid methyl ester, a versatile intermediate utilized in the
synthesis of indole alkaloids, was achieved in two steps. Condensation of trypta-
mine with dimethyl a-ketoglutarate led to the formation of the corresponding
indolizino[8,7-b]indolone ester, which subsequently underwent an efficient lactam
reduction with 9-BBN to generate the tertiary amine ester in good yield.
Keywords: 9-BBN, Dimethyl a-ketoglutarate, lactam reduction, tryptamine
Indole alkaloids continue to be the target of scientific investigations
because of their interesting physiological, biological, and structural pro-
perties.[1] They offer unique opportunities to explore a wide range of
chemistry and biology space in the pursuit of new bioactive agents. In
our search to design indole alkaloid-based screening libraries for drug
discovery, we recently developed a strategy for the synthesis of structu-
rally diverse 7-aryl-octahydroazonino[5,4-b]indoles via a three-compo-
nent reaction utilizing indolizinoindoles, chloroformates, and aromatic
nucleophiles.[2] Treatment of indolizinoindole 1 with chloroformate 2,
in the presence of an aromatic nucleophile 3, resulted in the production
of 7-aryl-octahydroazonino[5,4-b]indole 4 via a chloroformate-induced
Received January 15, 2008.
Address correspondence to Demosthenes Fokas, Department of Materials
Science and Engineering, University of Ioannina, Ioannina 45110, Greece
(current address). E-mail: dfokas@cc.uoi.gr
3816

9-BBN Reduction of a Tetracyclic Lactam Ester
3817
Scheme 1. 7-Aryl-octahydroazonino[5,4-b]indoles via a three-component reaction.
fragmentation of the b-tetrahydrocarboline (THC) ring, followed by
insertion of the appropriate nucleophile to the azoninoindole nucleus
(Scheme 1). Considering that a number of 7-substituted-azonino[5,4-
b]indoles have exhibited a wide range of biological properties as central
nervous system (CNS) stimulants, antidepressants, anti-inflammatories,
diuretics, and anti-ulcer agents,[3] we surmised that access to libraries of
structurally diverse azonino[5,4-b]indoles might facilitate the search for
new bioactive agents.
The chemistry described in Scheme 1 is amenable to high-throughput
solution-phase parallel synthesis and could provide access to screening
libraries of 7-aryl-octahydroazonino[5,4-b]indoles with general structure
4. However, to be able to proceed with the library synthesis, we required
large amounts of both indolizinoindoles 1a and 1b. There are several
reports in the literature that describe the racemic[4] as well as the asym-
metric[5] synthesis of indolizinoindole 1b. Compound 1b in large quanti-
ties can be obtained with the Corsano–Algieri protocol, which involves
the condensation of tryptamine with a-ketoglutaric acid in AcOH fol-
lowed by a LiAlH4 reduction of the resulting tetracyclic lactam.[4a] The
synthesis of optically active amine 1a was first reported by Magnus et
al.[6] in their studies directed toward the synthesis of vinblastine-vincris-
tine models.[7] It was prepared in four steps in an overall yield of 30%,
starting from either of the two antipodes of tryptophan p-toluenesulfonic
acid salt and dimethyl a-ketoglutarate 6. This route utilizes a Barton
radical decarboxylation of the Pictet–Spengler tetracyclic adduct to yield
lactam 7, followed by a Raney nickel desulfurization of thiolactam 9.
Also, the synthesis of racemic amine 1a, which was successfully utilized
in the synthesis of strychnine, was reported to proceed in a similar
fashion starting from tryptamine instead (Scheme 2).[8]
Before we embarked on the large-scale synthesis of 1a according to
Scheme 2, we wanted to test the feasibility of this route on a gram scale.
When we attempted the Pictet–Spengler reaction of tryptamine hydro-
chloride 5 with dimethyl a-ketoglutarate 6 in MeOH, we observed the
formation of tetracyclic lactam 7 in 53% yield and its decarboxylated by-
product 8 in 19% yield. Treatment of lactam 7 with Lawesson’s reagent[9]

3818
D. Fokas and Z. Wang
Scheme 2. Thiolactam reduction route to 1a.
produced thiolactam 9, which was then subjected, without purification, to
a Raney nickel desulfurization to generate racemic 1a in 55% yield for the
two-step sequence (Scheme 2). Indeed, 1a was prepared in three steps from
tryptamine hydrochloride in an overall yield of 29%.
Although the thiolactam reduction route described in Scheme 2
could provide access to significant amounts of tetracyclic amine 1a, the
use of a large excess of the pyrophoric Raney nickel was deemed sub-
optimal. The Ni2B=H2 reagent system,[10] prepared in situ from
NiCl2 ꢀ 6H2O and NaBH4, could serve as a viable alternative to Raney
nickel given its successful use in the desulfurization of similar indolic sys-
tems.[11] However, the need for a large excess of nickel chloride and
NaBH4 coupled with the problems associated with the handling and dis-
posal of nickel salts, rendered this reduction protocol unattractive. There-
fore, the search for a facile and user-friendly method of amide reduction,
in the presence of the ester group, was deemed necessary. Furthermore,
the chromatographic separation of lactam 7 from the decarboxylated
by-product 8 would render the large-scale synthesis of amine 1a cumber-
some. Thus, optimization of the Pictet–Spengler step was required to
eliminate the formation of the decarboxylated by-product 8.
Indeed, we found that treatment of tryptamine-free base 10 with
a-ketoester 6 in AcOH resulted in the clean formation of tetracyclic lac-
tam 7 in 86% yield. The use of a borane reagent for the chemoselective
reduction of the tertiary lactam 7 seemed a viable alternative. For exam-
ple, 9-borabicyclo[3.3.1]nonane (9-BBN) was reported to efficiently
reduce tertiary amides and appeared to be an attractive candidate for this
transformation.[12] Indeed, when lactam 7 was treated with 9-BBN (3.2
equiv), the desired amine 1a was formed cleanly in 85% yield. Compound
1a was prepared in two steps from tryptamine-free base in an overall yield
of 73% (Scheme 3).
The method in Scheme 3 represents a facile synthesis of tetracyclic
amine 1a, a versatile intermediate that could be utilized in the synthesis
of indole alkaloids as well as several biologically interesting azonino

9-BBN Reduction of a Tetracyclic Lactam Ester
3819
Scheme 3. Entry to 1a via a 9-BBN-mediated reduction of a tertiary lactam.
[5,4-b]indoles. It involves an efficient reduction of a tertiary lactam with 9-
BBN in the presence of an ester group. Although the described synthesis is
racemic, the combination of Magnus’ Pictet–Spengler=radical decarboxy-
lation protocol with the 9-BBN reduction of the intermediate indoli-
zino[8,7-b]indolone ester would enhance the synthesis of large quantities
of optically active 1a.
EXPERIMENTAL
Improved Synthesis of Tetracyclic Lactam 7
A solution of tryptamine 10 (16.2 g, 0.10 mol) and dimethyl a-ketogluta-
rate 6 (19.4 g, 0.11 mol) in AcOH (300 mL) was stirred at 120 ꢁC under
reflux for 3 h. The reaction mixture was cooled to room temperature,
and the solvent was then evaporated in vacuo. The resulting residue
was dissolved in CHCl3 (300 mL), and the chloroform solution was
washed with water (2 ꢂ 150 mL). The organic phase was dried over
Na2SO4 and concentrated in vacuo to give the crude amide 7, which
was then treated with hot t-butyl methyl ether under stirring. The result-
ing suspension was cooled and then filtered to give a solid, which was
subsequently washed with cold t-butyl methyl ether and dried under
vacuum to afford 24.4 g (86%) of lactam 7 as a pale brown solid. Com-
1
pound 7 exhibited H NMR (300 MHz, CDCl3) spectral data identical
with the data reported in the literature.[6]
Reduction of 7 to Tetracyclic Amine 1a
A solution of lactam 7 (8.53 g, 0.030 mol) and 9-BBN dimer (11.7 g,
0.048 mol) in THF (100 mL) was stirred at 65 ꢁC for 1 h. The reaction

3820
D. Fokas and Z. Wang
mixture was cooled to room temperature and then treated with MeOH
(30 mL) and 2 M HCl in Et2O (30 mL). The mixture was stirred at room
temperature for 1 h and then concentrated in vacuo. The resulting residue
was partitioned between EtOAc (200 mL) and 3 M aqueous HCl
(100 mL). The aqueous phase was separated, and the organic phase
was washed with 3 M aqueous HCl (2 ꢂ 50 mL). The combined aqueous
phase was neutralized with solid NaHCO3 and then extracted with
EtOAc (2 ꢂ 100 mL). The combined organic phase was dried over
Na2SO4 and concentrated in vacuo to afford 6.9 g (85%) of amine 1a
1
as a brown solid. H NMR (300 MHz, CDCl3) d 8.20 (s, 1 H), 7.50 (d, 1
H, J ¼ 7.5 Hz), 7.35 (d, 1 H, J ¼ 7.8 Hz), 7.18 (t, 1 H, J ¼ 7.0 Hz), 7.10
(t, 1 H, J ¼ 7.0 Hz), 3.78 (s, 3 H), 3.40–3.33 (m, 2 H), 3.15 (m, 1 H),
3.02–2.88 (m, 2 H), 2.59–2.45 (m, 2 H), 2.35–2.22 (m, 1 H), 1.95 (m, 1
H), 1.72 (m, 1 H). MS (ESþ) m=z for C16H18N2O2: calcd. 270.14; found
271.05 (M þ H). We have noticed that the authors in Ref. 6 missed two
multiplet peaks: one at 2.59–2.35 ppm and the other at 2.35–2.22 ppm,
corresponding to two and one aliphatic proton, respectively. The
remainder of the spectral data is identical with the data reported therein.
ACKNOWLEDGMENTS
The authors thank ArQule’s Analytical Department for the mass spectra
analysis of the compounds described in the article.
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