Enantioselective formal synthesis of (?)-aurantioclavine using Pd-catalyzed cascade cyclization and organocatalytic asymmetric aziridination

Article abstract of DOI:10.1016/j.tetlet.2018.01.033

The enantioselective formal synthesis of (?)-aurantioclavine is described. The core tricyclic skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The stereocenter was constructed by a highly enantioselective organocatal

Full text of DOI:10.1016/j.tetlet.2018.01.033

Accepted Manuscript
Enantioselective formal synthesis of (–)-aurantioclavine using Pd-catalyzed
cascade cyclization and organocatalytic asymmetric aziridination
Shun-ichi Nakano, Yasumasa Hamada, Tetsuhiro Nemoto
PII:
S0040-4039(18)30057-1
https://doi.org/10.1016/j.tetlet.2018.01.033
TETL 49620
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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21 November 2017
27 December 2017
11 January 2018
Please cite this article as: Nakano, S-i., Hamada, Y., Nemoto, T., Enantioselective formal synthesis of (–)-
aurantioclavine using Pd-catalyzed cascade cyclization and organocatalytic asymmetric aziridination, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.033
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Enantioselective formal synthesis of ( -
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aurantioclavine using Pd-catalyzed cascade
cyclization and organocatalytic asymmetric
aziridination
Shun-ichi Nakano, Yasumasa Hamada and Tetsuhiro Nemoto*

1
Tetrahedron Letters
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Enantioselective formal synthesis of (–)-aurantioclavine using Pd-catalyzed cascade
cyclization and organocatalytic asymmetric aziridination
Shun-ichi Nakanoa, Yasumasa Hamadaa, and Tetsuhiro Nemotoa,b ∗
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
b Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
The enantioselective formal synthesis of (−)-aurantioclavine is described. The core tricyclic
skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The
stereocenter was constructed by a highly enantioselective organocatalytic asymmetric
aziridination reaction.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
−)
(
-Aurantioclavine
Cascade reaction
Indole
Organocatalysis
Palladium
The ergot alkaloid (−)-aurantioclavine (1) was isolated from
Penicillium aurantiovirens by Kozlovskii and co-workers in
1981.1 This natural product possesses an azepane ring bridging
the C3- and C4-positions of the indole, and a stereogenic center
on the benzylic position. The absolute stereochemistry was
determined to be R by Stoltz and co-workers in 2008.2 (–)-
Aurantioclavine is a biosynthetic intermediate of the complex
polycyclic alkaloid, communesins, which exhibit a variety of
bioactivities.3 Thus, (−)-aurantioclavine is an attractive synthetic
target for organic chemists. In addition to the synthesis of
methods of this class are based on intramolecular Larock indole
synthesis,5a,b Rh-catalyzed intramolecular dearomatizing [3+2]
annulation of α-imino Rh-carbenoids,5c,d and Rh-catalyzed C-H
activation.5e–g As part of our ongoing studies aimed at developing
an efficient synthetic method for 3,4-fused tricyclic indole
derivatives,7 we reported a synthetic method based on a
palladium-catalyzed Heck insertion to an allene–allylic amination
cascade (Scheme 1).7a The reaction products, 3,4-fused 3-
alkylidene indolines, could be transformed to the corresponding
indole derivatives by treating them with acid. We hypothesized
−)
racemic aurantioclavine, several enantioselective total syntheses
4
−)
of ( -aurantioclavine have been reported.
that the enantioselective total synthesis of ( -aurantioclavine
would be realized using the present palladium catalysis in
combination with an organocatalytic asymmetric aziridination of
α,β-unsaturated aldehydes developed by our group.8 Herein we
−)
( -
report the formal enantioselective total synthesis of
aurantioclavine based on our synthetic methods.
Figure 1. (–)-Aurantioclavine and communesin F.
Efficient synthetic methods of 3,4-fused tricyclic indole
skeletons are in high demand in synthetic organic and medicinal
chemistry because of the ubiquity of this tricyclic structure in
bioactive molecules.5,6 Recent efforts have focused on developing
catalytic synthetic methods for this skeleton using easily prepared
anilinic or aromatic substrates in place of expensive 4-
haloindoles or their derivatives. Representative synthetic
———
∗ Corresponding author. Tel./fax: +81 43 226 2920; e-mail: tnemoto@chibaa-u.jp (T. Nemoto)

2
Tetrahedron
Scheme 1. Pd-catalyzed cascade cyclization to construct 3,4-
fused tricyclic indole skeletons.
The retrosynthetic analysis is shown in Scheme 2. The prenyl
moiety was constructed using the vinyl precursor in some
previous syntheses. Therefore, compound I was set as the key
intermediate for this work.9 We envisioned that compound I
would be accessible from 3,4-fused tricyclic indole derivative II
bearing a side-chain at the benzylic position, which would be
synthesized by Pd-catalyzed cascade cyclization using allene-
tethered iodoaniline derivative III. We envisioned that chiral
amine derivative III would be prepared from chiral aziridine 4,
which in turn could be synthesized by an organocatalytic
asymmetric aziridination of α,β−unsaturated aldehyde 2 with
tert-butyl p-toluenesulfonyloxy carbamate 3.
Scheme 3. Synthesis of N-Boc protected amine 10 using
organocatalytic asymmetric aziridination.
We next examined the synthesis of a substrate for the Pd-
catalyzed cascade cyclization (Scheme 4). Although direct
allenylation
of
10
with
buta-2,3-dien-1-yl
4-
methylbenzenesulfonate (allenyl tosylate) was examined first, the
desired product was not obtained. Thus, the Boc group was
converted into a tosyl group by standard protocols and compound
11 was obtained in 84% yield in two steps. Compound 11 was
then treated with allenyl tosylate in DMF under basic conditions
to furnish 12 in 70% yield (98% yield based on the recovered
starting material). Reduction of the nitro group followed by
protection of the resulting amine with a tosyl group afforded the
cyclization precursor 13 in 94% yield (2 steps). The cascade
cyclization was performed using 10 mol% of Pd(dba)2, 24 mol%
of P(2-furyl)3, and 4 equiv of K2CO3 in DMSO at 90 °C. The
corresponding tricyclic alkylidene indoline derivative 14 was not
obtained at all, however, and elimination of the tosylamido
moiety occurred to form compound 15 exclusively, probably due
to acidity of the α-proton of the methyl ester.
Scheme 2. Retrosynthetic analysis of (–)-aurantioclavine.
Our synthesis began with commercially available 2-iodo-3-
nitrobenzoic acid 5 (Scheme 3). A carboxylic acid moiety was
converted into aldehyde via a two-step process involving
BH3·THF reduction and MnO2 oxidation. Aldehyde 6 was then
reacted with trimethyl phosphonoacetate to give trans-α,β-
unsaturated ester 7 in 76% overall yield. After conversion of the
ester moiety to aldehyde (82% yield in 2 steps), the obtained
α,β−unsaturated aldehyde 2 was applied to organocatalytic
asymmetric aziridination.10 The reaction proceeded in the
presence of 10 mol % of (S)-L-proline-derived chiral amine
catalyst 8,11 1.2 equiv of 3, and 3 equiv of sodium acetate,
affording chiral aziridine derivative 4. The subsequent
transformation from 4 to β−amino ester derivative 10 could be
performed in a single-pot reaction by adding 10 mol % of
triazolium salt 9 and methanol to the reaction mixture, producing
N-Boc protected amine 10 in 96% yield.10d,12 Enantiomeric
excess (98% ee) was determined by chiral HPLC analysis.
Scheme 4. Synthesis of a substrate for the Pd-catalyzed cascade
cyclization.

3
2. (a) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y.
To prevent the observed side reaction, ester moiety in 13 was
converted into the corresponding TBS-protected alcohol 16 via
DIBAL-H reduction in 83% yield (2 steps) (Scheme 5). Pd-
catalyzed cascade cyclization was then examined using the TBS-
protected substrate under the optimum conditions and tricyclic
alkylidene indoline derivative 17 was obtained in 77% yield.13
Isomerization of 17 into the 3,4-fused tricyclic indole derivative
was achieved by treatment with 30 equiv of TFA and subsequent
removal of the TBS group by TBAF provided compound 18 in
98% yield (2 steps). Dehydration of 18 using 2-nitrophenyl
selenocyanate followed by elimination under oxidative
conditions afforded 19 in 77% yield. Both tosyl groups were
removed by Birch reduction and protection of the two nitrogen
atoms with a Boc group afforded Yang’s known intermediate 20
in 70% yield (2 steps).4h, 14 The NMR data were identical to those
reported by Yang et al. The enantiomeric excess of 20 (98% ee)
was determined by chiral HPLC analysis. Because the synthetic
route from 20 to (–)-aurantioclavine 1 was established, we
achieved a formal enantioselective synthesis.
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Org. Lett. 2014, 16, 3900.
6. For other representative synthetic methods of 3,4-fused indole
derivatives, see: (a) Greshock, T. J.; Funk, R. L. J. Am. Chem.
Soc. 2006, 128, 4946; (b) Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H.
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Hayashi, M.; Xu, D.; Hamajima, A.; Hamada, Y. Tetrahedron:
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9. Dimethylation of II, followed by dehydration of the corresponding
tertiary alcohol, can be a possible synthetic route for 1. Stoltz and
co-workers already reported that, however, dehydration of such
tertiary alcohol gave a mixture of inseparable olefin isomers. See,
reference 2a.
Scheme 5. Formal enantioselective total synthesis of (–)-
aurantioclavine.
In conclusion, we achieved
synthesis of (−)-aurantioclavine. The core tricyclic skeleton was
synthesized using Pd-catalyzed Heck insertion–allylic
amination cascade as the key step. The stereocenter was
constructed by highly enantioselective organocatalytic
a formal enantioselective
10. For representative examples of organocatalytic asymmetric
aziridination of α,β−unsaturated aldehydes and ketones using 3 as
a nucleophile, see: (a) Pesciaioli, F.; De Vincentiis, F.; Galzerano,
P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P.
Angew, Chem., Int. Ed. 2008, 47, 8703; (b) Deiana, L.; Zhao, G.-
L.; Lin, S.; Dziedzic, P.; Zhang, Q.; Leijonmarck, H.; Córdova, A.
Adv. Synth. Catal. 2010, 352, 3201; (c) De Vincentiis, F.;
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.;
Galzerano, P.; Melchiorre, P. Chem. Asian J. 2010, 5, 1652; (d)
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Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett.
2011, 13, 5744.
a
a
asymmetric aziridination reaction. This work successfully
demonstrated the synthetic utility of our methods. Further studies
on the application of these methods to the synthesis of bioactive
natural products are underway.
Acknowledgments
11. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew, Chem., Int. Ed. 2005, 44, 794; (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew, Chem., Int. Ed. 2005, 44, 4212; (c)
For a review, see: Jensen, K. L.; Dickmeiss, G.; Jiang, H.;
Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
12. (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
8126; (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Córdova,
A. Angew, Chem., Int. Ed. 2007, 46, 778; (c) Jiang, H.; Gschwend,
B.; Albrecht, L.; Jørgensen, K. A. Org. Lett. 2010, 12, 5052.
13. We also examined the cascade cyclization using a primary alcohol
derivative. The reaction was very slow, however, and the target
This work was supported financially by JSPS KAKENHI Grant
Number 15K07850 (T.N.), JSPS Research Fellowship for Young
Scientist 17J01154 (S.N.), and grant from Global and Prominent
Research, Chiba University.
References and notes
1. Kozlovskii, A. G.; Solov’eva, T. F.; Sahkarovskii, V. G.; Adanin,
V. M. Dokl. Akad. Nauk. SSSR. 1981, 260, 230.

4
Tetrahedron
molecule was obtained in only trace amount. We expected that
coordination of the hydroxyl group to the palladium catalyst
resulted in the low reactivity.
Supplementary Material
Supplementary data associate with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tetlet.
14. Although prenylation of the vinyl moiety in 19 was investigated
using Yang’s stepwise method, the desired product was obtained
in only 7% yield.

5
Highlights
−)
The enantioselective formal synthesis of ( -
aurantioclavine was achieved.
The core skeleton was synthesized using a Pd-
catalyzed cascade cyclization.
The stereocenter was constructed by a
organocatalytic asymmetric aziridination.