Total Synthesis of cis-Clavicipitic Acid from Asparagine via Ir-Catalyzed C-H bond Activation as a Key Step

Article abstract of DOI:10.1002/chem.201502300

4-Substituted tryptophan derivatives and the total synthesis of cis-clavicipitic acid were achieved in reactions in which Ir-catalyzed C-H bond activation was a key step. The starting material for these reactions is asparagine, which is a cheap natural amino acid. The reductive amination step from the 4-substituted tryptophan derivative gave cis-clavicipitic acid with perfect diastereoselectivity.

Full text of DOI:10.1002/chem.201502300

DOI: 10.1002/chem.201502300
Communication
&
Synthetic Methods
Total Synthesis of cis-Clavicipitic Acid from Asparagine via Ir-
Catalyzed CÀH bond Activation as a Key Step
Yu-ki Tahara,[a] Mamoru Ito,[a] Kyalo Stephen Kanyiva,[b] and Takanori Shibata*[a, c]
Abstract: 4-Substituted tryptophan derivatives and the
total synthesis of cis-clavicipitic acid were achieved in re-
actions in which Ir-catalyzed CÀH bond activation was
a key step. The starting material for these reactions is as-
paragine, which is a cheap natural amino acid. The reduc-
tive amination step from the 4-substituted tryptophan de-
rivative gave cis-clavicipitic acid with perfect diastereose-
lectivity.
Clavicipitic acid (1) is an ergot alkaloid that has been isolated
from Claviceps strain SD-58 and Claviceps fusiformis as a mixture
of cis- and trans-isomers.[1] The unique tricyclic azepinoindole
system has attracted synthetic chemists, and various strategies
have been developed for its total syntheses.[2,3] Clavicipitic acid
(1) has a 4-substituted tryptophan skeleton, which was used as
the key intermediate for the total synthesis of clavicipitic acid
(1)[3f] and other alkaloids,[4,5] but the introduction of a substitu-
ent at the C-4 position is generally difficult compared with
other positions on the indole ring of tryptophan derivatives.
The three typical approaches to 4-substituted tryptophan de-
Scheme 1. Approaches to the synthesis to 4-substituted tryptophan deriva-
tives.
rivatives are shown in Scheme 1: Pd-catalyzed indole synthesis
by the coupling of o-haloanilines with aldehydes having an
amino acid moiety (Scheme 1a);[5] amino acid synthesis by the
enantioselective alkylation of N-(diphenylmethylene)glycine
tert-butyl ester with 3-(bromomethyl)indoles using a chiral
Transition metal-catalyzed CÀH bond activation has attract-
phase-transfer catalyst (Scheme 1b);[3e] Pd-catalyzed CÀH alke-
ed much attention, because pre-activation of the substrate is
nylation at the C-4 position of tryptophan using trifluorome-
thylsulfonamide as a directing group (Scheme 1c).[6] We envi-
sioned that the indole skeleton of clavicipitic acid (1) could
readily be obtained via intramolecular cyclodehydration initiat-
ed by the CÀH bond activation of b-keto aniline, which can be
derived from asparagine (Scheme 1d).
unnecessary, thus realizing shorter and more atom-economical
syntheses of complex molecules.[7] To date, the direct CÀH
bond activation strategy has been used in key steps for the
total synthesis of natural products and pharmaceuticals.[7j] Our
group has focused on the Ir-catalyzed synthetic transforma-
tions initiated by CÀH bond activation.[8,9] For example, we re-
ported intramolecular cyclodehydration via sp2 CÀH bond
cleavage for the synthesis of 4-substituted benzoheteroles
such as benzofuran and indole derivatives.[10,11] Herein we
report the use of this protocol for the synthesis of 4-substitut-
ed tryptophan derivatives (Scheme 1d), and the conversion of
one of the obtained derivatives into clavicipitic acid (1).
[a] Y. Tahara, M. Ito, Prof. Dr. T. Shibata
Department of Chemistry and Biochemistry
School of Advanced Science and Engineering
Waseda University, Shinjuku, Tokyo 169-8555(Japan)
E-mail: tshibata@waseda.jp
Our retro-synthetic strategy is shown in Scheme 2. cis-Clavi-
cipitic acid (1) would be accessible from the 4-substituted tryp-
tophan derivative 10 by intramolecular reductive amination.
Compound 10 would be converted from b-keto aniline deriva-
tive 9b by our originally developed intramolecular cyclodehy-
dration. We considered that substrate 9b could be readily pre-
pared from commercially available Cbz-l-aspartic acid a-
[b] Dr. K. S. Kanyiva
International Center for Science and Engineering Programs (ICSEP)
Waseda University, Shinjuku, Tokyo 169-8555 (Japan)
[c] Prof. Dr. T. Shibata
ACT-C (Japan) Science and Technology Agency (JST)
4-1-8 Honcho Kawaguchi, Saitama, 332-0012 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502300.
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chloride, trimethylsilyldiazomethane, and aqueous hydrobro-
mic acid in 87% yield. Subsequent nucleophilic substitution of
a-keto bromide 6 with 1-(3-aminophenyl)-3-methylbut-2-en-1-
one (7)[13] in the presence of potassium carbonate gave b-keto
aniline 8b in 83% yield.
Next, we examined the Ir-catalyzed cyclodehydration of b-
keto aniline 8 via CÀH bond activation for the synthesis of 4-
substituted tryptophan derivatives 9 (Table 1). We chose b-keto
aniline 8a as a model substrate, which has an acetyl group as
a directing group (DG), and submitted it to an intramolecular
reaction in the presence of an Ir catalyst prepared from
[Ir(cod)2]BARF and rac-BINAP at 1358C in chlorobenzene
(PhCl).[10a] The desired 4-substituted tryptophan 9a was ob-
tained in moderate yield (entry 1). When b-keto aniline 8b,
which has a 3,3-dimethyl acryloyl group as a directing group,
was used, the corresponding 4-substituted tryptophan 9b was
obtained in 79% yield (entry 2).[14] The high yield was also ach-
ieved even by using a smaller amount of the catalyst, albeit
with a longer reaction time. The reaction of b-keto aniline 8c
derived from the R-form of the amino acid also proceeded
smoothly to give the 4-substituted R-tryptophan derivative 9c,
which is the opposite enantiomer of 9b (entry 3). b-Keto
phenol ether could be also used in the present transformation,
Scheme 2. Retrosynthetic analysis of cis-clavicipitic acid.
methyl ester (5; Z-Asp-OMe), or cheaper asparagine (2; Asn),
which is a natural amino acid.
We inititated our synthesis by the transformation of com-
mercially available Asn (2) to Z-Asp-OMe 5 (Scheme 3). The car-
bobenzoxylation of 2 with benzyl chloroformate (CbzCl) and
sodium carbonate gave Z-Asn-OH 3.[12a] Subsequent methyl
esterification proceeded in the presence of thionyl chloride in
methanol.[12b] Transformation from amide to carboxylic acid
using tert-butyl nitrite afforded 5.[12c,d]
Table 1. Cyclodehydration via Ir-catalyzed CÀH bond activation for the
synthesis of 4-substituted tryptophan derivatives 9.
The synthesis of b-keto aniline 8b, which is a substrate of
the key reaction, is depicted in Scheme 4. a-Keto bromide 6
was prepared by Arndt–Eistert synthesis from 5 using thionyl
Entry
1
A
DG
Substrate
Time, Yield
NH
8a
2
NH
8b
Scheme 3. Synthesis of Z-Asp-OMe 5 from Asn (2).
3
4
NH
8c
O
8d
[a] Catalyst (5 mol%) was used.
Scheme 4. Synthesis of b-keto aniline 8b.
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and the reaction of 8d afforded 4-substituted (3-benzofuranyl)
alanine derivative 9d in 84% (entry 4). These results indicate
that Ir-catalyzed cyclodehydration is a versatile protocol for the
synthesis of 4-functionalized tryptophan derivatives including
its oxygen analogue.
We next turned our attention to the the construction of the
tricyclic azepinoindole skeleton by an intramolecular reductive
amination, where ketimine would be formed between the car-
bonyl moiety of the 3,3-dimethyl acryloyl group and the amino
moiety of the amino acid (Table 2).[2g] We first deprotected the
Scheme 5. Synthesis of cis-clavicipitic acid.
In conclusion, we have developed a new approach to the
synthesis of 4-substituted tryptophane derivatives 9 by cyclo-
dehydration via Ir-catalyzed CÀH bond activation. We further
achieved the total synthesis of the cis-clavicipitic acid (1) from
asparagine (2) via this original Ir-catalyzed reaction and intra-
molecular reductive amination in a few steps. Our synthesis
started from a commercially available and cheap compound,
and realized higher atom-efficiency through the minimum use
of protecting groups. Further studies for the use of our origi-
nally developed CÀH bond activation in natural product syn-
theses are underway in our laboratory.
Table 2. Intramolecular reductive amination for the synthesis of cis-clavi-
cipitic acid methyl ester 11.[a]
Acknowledgements
This work was supported by Grant-in-aid for Scientific Research
on Innovative Area, “Molecular Activation Directed toward
Straightforward Synthesis”, MEXT, JST, ACT-C, and Grants for Ex-
cellent Graduate School (Practical Chemical Wisdom), Waseda
University, MEXT, Japan.
Entry
Reductant
X [equiv]
Additive
Yield [%]
1
2
3
4
5
NaBH(OAc)3
NaBH(OAc)3
NaBH3CN
NaBH(OAc)3
NaBH(OAc)3
1.4
1.4
1.4
2.8
4.2
none
Et3N
Et3N
Et3N
Et3N
N. D.
21
N. D.
46
53
[a] N.D.=not determined.
Keywords: 4-substituted tryptophan derivatives
activation · clavicipitic acid · iridium · total synthesis
·
CÀH
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Received: June 12, 2015
Published online on July 14, 2015
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