Rhodium(III)-catalyzed intramolecular redox-neutral annulation of tethered alkynes: Formal total synthesis of (±)-goniomitine

Article abstract of DOI:10.1002/chem.201403973

A Rh^III-catalyzed intramolecular redox-neutral atom-economic annulation of a tethered alkyne has been developed to efficiently construct 2-amidealkyl indoles with completely reversed regioselectivity by a C-H activation pathway. Furthermore, us

Full text of DOI:10.1002/chem.201403973

DOI: 10.1002/chem.201403973
Communication
&
Organic Chemistry
Rhodium(III)-Catalyzed Intramolecular Redox-Neutral Annulation
of Tethered Alkynes: Formal Total Synthesis of (Æ)-Goniomitine
[
a]
Bing Zhou,* Juanjuan Du, Yaxi Yang, and Yuanchao Li*
Despite remarkable progress, there remain some major chal-
lenges: 1) The reactions with arylalkyl acetylenes give only 2-
aryl-3-alkyl substituted indoles and no 2-alkyl-3-aryl substituted
III
Abstract: A Rh -catalyzed intramolecular redox-neutral
atom-economic annulation of a tethered alkyne has been
developed to efficiently construct 2-amidealkyl indoles
with completely reversed regioselectivity by a CÀH activa-
[5a–e,7]
indoles could be formed.
2) An additional issue is the
poor regioselectivities (ca. 1:1 to 2:1) when unsymmetrical di-
III
tion pathway. Furthermore, using the Rh -catalyzed CÀH
[
5a,b]
alkyl or diaryl acetylenes were employed.
Recognizing
activation/annulation as a key step, a one-pot synthesis of
pyrido[1,2-a]indoles has also been developed and applied
to a highly efficient formal total synthesis of (Æ)-goniomi-
tine.
III
these limitations and with our continued interest in Rh -cata-
[8]
lyzed CÀH functionalization, we became interested in the in-
tramolecular annulation reaction of an alkyne-tethered phenyl-
hydrazine (Scheme 1c). The successful development of this
method would not only overcome the mentioned restrictions,
but also give a redox-neutral and regioselective synthesis of 2-
amidealkyl-substituted indoles, which could be readily convert-
ed into pyrido[1,2-a]indole scaffolds that are found in a variety
Indoles are ubiquitous structural motifs in natural products,
[
1]
marketed drugs, and other functional molecules. Therefore,
there is a continued interest in the development of new meth-
[
9–16]
[9]
of biologically active natural products
including Strychnos,
[
2]
[10]
[11a]
[12]
ods to selectively access indole derivatives. Among them,
transition-metal-catalyzed oxidative CÀH/NÀH cyclization has
emerged as a powerful and distinct approach to this structural
moiety due to its high efficiency,
Kopsia, Melodinus henryi,
Gonioma Malagasy, Hunteria
[13]
[14]
[15]
eburnean,
Aspidosperma,
Vinca minor L,
and Alstonia
[16]
angustofolia alkaloid families (Figure 1). Herein, we success-
selectivity, and easy availability
[
3]
(
Scheme 1a). This method has
opened up a new avenue in
[
4]
indole synthesis. However, stoi-
chiometric amounts of metal ox-
II
I
idants, such as Cu and Ag salts,
are generally required, thus gen-
erating undesired waste and lim-
iting the substrate scope as
[
5]
well. Recently, an oxidizing–
directing-group strategy has
emerged as an attractive alterna-
tive, allowing annulation reac-
tions under redox-neutral reac-
tion conditions and also show-
ing the clear advantages of high
selectivity, functional-group tol-
erance as well as an improved
Scheme 1. Indole synthesis by CÀH activation.
level
of
6,7]
reactivity
[
III
(Scheme 1b).
fully develop this Rh -catalyzed intramolecular annulation of
arylhydrazines with a tethered alkyne by CÀH activation. This
methodology was used to finish the formal total synthesis of
goniomitine.
[
a] Dr. B. Zhou, Dr. J. Du, Dr. Y. Yang, Prof. Y. Li
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica
Chinese Academy of Sciences, 555 Zu Chong Zhi Road
Shanghai 201203 (P. R. China)
We initially evaluated the reaction of substrate 1a with
[
RhCl (Cp*)]2
(Cp*=1,2,3,4,5-pentamethylcyclopentadienyl)
under different conditions (see Table S1 in the Supporting In-
formation). When 1a was treated with [RhCl (Cp*)] (2.5 mol%)
2
E-mail: zhoubing2012@hotmail.com
ycli@mail.shcnc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403973.
2
2
and CsOAc (20 mol%) in MeOH at 708C for 12 h, no product
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KIE value of 1.0 indicated that
CÀH bond cleavage might not
be involved in the rate-limiting
[19]
step.
On the basis of the
above-mentioned results, a tenta-
tive mechanism for the Rh-cata-
lyzed annulation reaction is pro-
III
posed (Scheme 3). First, a Rh -
catalyzed ortho-directed CÀH
bond cleavage occurs to form in-
termediate A, followed by coor-
dination and alkyne insertion to
give seven-membered rhodacy-
cle B. Then a rearrangement pre-
sumably occurs to provide
Figure 1. Representative biologically active natural products bearing a pyrido[1,2-a]indole core.
was detected. However, when one equivalent of
AcOH was added, 30% of product 2a was obtained
(for the structure, see Scheme 2). Other acids, such as
PivOH and dichloroacetic acid, did not improve the
yield of 2a. Next, we tested various solvents, such as
PhMe, THF, CH CN, 1,4-dioxane, and 1,2-dichloro-
3
ethane. DCE as the solvent proved to be optimal, im-
proving the yield of 2a to 82%. The use of other ace-
tate salts, such as NaOAc, AgOAc, and KOAc de-
creased the yield of 2a and other metal catalysts like
[
RuCl (p-cymene)] and [IrCl (Cp*)] failed to provide
2 2 2 2
the product 2a.
Next the optimized conditions were used to survey
the scope of the reaction with various substrates
(Scheme 2). Diverse functional groups were tolerated
on the ortho, meta, and para positions of the ethynyl-
phenyl substituent, including electron-donating (2c,
2
d, 2h, 2i) and -withdrawing (2b, 2e, 2 f, 2g)
groups, all providing their corresponding products in
60% yield. Remarkably, in this methodology, the
>
alkyl-substituted (or ethoxybenzyl-substituted) alkyne
produced only one regioisomer, indole 2j. This regio-
selectivity is superior to other reported intermolecu-
lar versions in which a 1.2:1 regioselectivity was ob-
[
5b,17]
served.
stituent also tolerated either electron-donating or
withdrawing substitutions at its para (2h–i), meta
2k–l), and ortho (2m) positions. Meta-substituted
Furthermore, the phenylhydrazine sub-
-
(
derivatives underwent this annulation reaction only
at the sterically more accessible CÀH bond (2k, 2l).
Naphthalene-2-ylhydrazine substrate was well tolerat-
ed, yielding 2n and demonstrating the versatility of
this annulation. Notably, the reversed regioselectivity
[
18]
of this method,
provides a good complement to previously reported
producing 2-alkyl-3-aryl indoles,
[
5a–e,7]
methods that form 2-aryl-3-alkyl-indoles
offers great potential for indole synthesis.
and
To probe the reaction mechanism, an intermolecu-
lar competition experiment between protio and deu-
Scheme 2. Substrate scope: Conditions: 1 (0.2 mmol), [RhCl
2 2
(Cp*)] (0.005 mmol), CsOAc
(
0.04 mmol), AcOH ( 0.2 mmol), and DCE (1 mL) at 708C for 6 h under an argon
teron 1a was carried out [Eq. (1)] and an observed atmosphere. Yield of isolated product.
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amethyldisilazide (LiHMDS) and ethyl bromide afford-
ed 4j in 90% yield. Addition of the propanol group
to the same carbon was accomplished by treatment
of 4j with LHMDS and (3-bromopropoxy)(tert-butyl)-
dimethylsilane, and a subsequent deprotection with
tetra-n-butylammonium fluoride (TBAF) yielding the
alcohol 5j in 66% yield. Mitsunobu reaction of 5j
provided azide 6j, and subsequent reduction of 6j
with LiAlH gave 7j in good yield. Finally, deprotec-
4
[
22]
tion of 7j afforded (Æ)-goniomitine.
Thus, the
formal total synthesis of racemic goniomitine was
completed in seven steps from phenylhydrazine 1j.
In summary, we have developed a mild and effi-
III
cient Rh -catalyzed redox-neutral CÀH activation/
intramolecular annulation of alkyne-tethered arylhy-
drazines to prepare 2-amidealkyl indoles. This reac-
tion does not require any external oxidant and fea-
tures high reverse regioselectivity, which offers
a good complement to previous methods. Further-
III
more, using the Rh -catalyzed CÀH activation/annula-
tion as a key step, a one-pot synthesis of pyrido[1,2-
a]indoles has also been developed and applied to
a highly efficient formal total synthesis of (Æ)-gonio-
mitine. Considering the valuable structure of the
products, we expect this intramolecular annulation
reaction to gain broad synthetic utility.
Scheme 3. Proposed mechanism.
a more stable six-membered rhodacycle C, which undergoes
reductive elimination and oxidative addition to form intermedi-
ate D. Protonation of D yields
the desired indole 2a and regen-
III
erates the Rh catalyst. Alterna-
tively, C could undergo an acyl-
amino migration to give a cyclic
V
[20]
Rh nitrene intermediate E, fol-
lowed by a reductive elimination
and protonation to deliver
III
indole 2a and Rh catalyst.
The synthetic utility of the in-
tramolecular redox-neutral annu-
lation reaction was exemplified
by a successful one-pot synthe-
[
9–16]
sis of pyrido[1,2-a]indoles 3
directly
from
alkynes
[
21]
1
(Scheme 4).
For example,
treatment of alkynes 1 under
our optimized reaction condi-
tions, and subsequent treatment
with dioxane/HCl (0.1m) in one-
pot gave the desired pyrido[1,2-
a]indoles 3 in good yields.
Utility of our methodology is Scheme 4. One-pot synthesis of pyrido[1,2-a]indoles 3 from arylhydrazines 1.
further demonstrated by its ap-
plication in a seven-step formal
total synthesis of (Æ)-goniomitine (Scheme 5). Thus, annulation
of 1j under our optimized reaction conditions and subsequent
treatment with dioxane/HCl in one-pot afforded the pyrido-
[1,2-a]indole 3j in 58% yield. Treatment of 3j with lithium hex-
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Communication
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[
Keywords: CÀH activation · goniomitine · indoles · redox-
neutral · total synthesis
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COMMUNICATION
&
Organic Chemistry
B. Zhou,* J. Du, Y. Yang, Y. Li*
& – &&
&
Rhodium(III)-Catalyzed Intramolecular
Redox-Neutral Annulation of Tethered
Alkynes: Formal Total Synthesis of
III
CÀH activation: A Rh -catalyzed intra-
tion pathway (see scheme). A one-pot
synthesis of pyrido[1,2-a]indoles has
also been developed and applied to
a highly efficient formal total synthesis
of (Æ)-goniomitine.
(Æ)-Goniomitine
molecular redox-neutral atom-economic
annulation of a tethered alkyne has
been developed to efficiently construct
2
-amidealkyl indoles with completely re-
versed regioselectivity by a CÀH activa-
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!