Gold(I)-Catalyzed Cyclization-3-Aza-Cope-Mannich Cascade and Its Application to the Synthesis of Cephalotaxine

Article abstract of DOI:10.1021/acs.orglett.1c01323

The discovery of a new gold(I)-catalyzed cascade reaction involving cyclization onto a vinylammonium, 3-aza-Cope rearrangement, and Mannich cyclization is reported. A variety of fused nitrogen heterocycles were prepared from simple cyclic tertiary amines using 1-5 mol % of a AuCl(PPh3)/Ag[C5(CN)5] cocatalyst system. The developed reaction was used in a study aimed at synthesizing cephalotaxine. A five-step operation from norhydrastinine provided demethylcephalotaxinone in 39.1% overall yield, which was transformed to (-)-cephalotaxine in two steps.

Full text of DOI:10.1021/acs.orglett.1c01323

pubs.acs.org/OrgLett
Letter
Gold(I)-Catalyzed Cyclization−3-Aza-Cope−Mannich Cascade and Its
Application to the Synthesis of Cephalotaxine
Takeo Sakai,* Chise Okumura, Masatoshi Futamura, Naotaka Noda, Akari Nagae, Chiharu Kitamoto,
Madoka Kamiya, and Yuji Mori
Cite This: Org. Lett. 2021, 23, 4391−4395
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ABSTRACT: The discovery of a new gold(I)-catalyzed cascade
reaction involving cyclization onto a vinylammonium, 3-aza-Cope
rearrangement, and Mannich cyclization is reported. A variety of
fused nitrogen heterocycles were prepared from simple cyclic tertiary
amines using 1−5 mol % of a AuCl(PPh3)/Ag[C5(CN)5] cocatalyst
system. The developed reaction was used in a study aimed at
synthesizing cephalotaxine. A five-step operation from norhydrasti-
nine provided demethylcephalotaxinone in 39.1% overall yield, which
was transformed to (−)-cephalotaxine in two steps.
intermediate 5 followed by Mannich cyclization to afford 3-
ascade reactions are useful and interesting to organic
Cchemists as they furnish complex compounds from aminocyclopentanone 6. The structure of 6 is entirely different
from the common 3-acylpyrrolidine skeleton 3 of the 2-aza-
Cope−Mannich product. Therefore, the 3-aza-Cope−Mannich
reaction is potentially a powerful tool for the synthesis of many
organic compounds that cannot be accessed using the 2-aza-
Cope−Mannich reaction. However, the 3-aza-Cope−Mannich
reaction has only been reported on a few occasions,3 and its
usefulness in synthesis has not yet been established, possibly
because vinylammonium 4 is somewhat more difficult to
prepare than iminium 1.
Recently, we prepared a spirovinylammonium using ion-pair
extraction with the C5Ph(CN)4 anion, and reported an
example of the 3-aza-Cope−Mannich cascade to afford tricyclic
aminoketone.4 The success of this reaction initiated our study
into new cascade reactions involving in situ generated
vinylammoniums. The intramolecular addition of tertiary
amines to alkynes, arynes, allenes, or ketimines is a good
method for generating vinylammoniums, and such intermedi-
ates have been used to synthesize nitrogen macrocycles
through 3-aza-Cope rearrangements.5 Gold(I) catalysts oper-
ate as soft Lewis acids that can activate alkynes for addition
reactions6 with primary or secondary amines providing cyclic
enamines,7 and vinylammonium intermediates have been
proposed in the gold(I)-catalyzed reactions of aziridines8 or
simple molecules in single experimental operations. Natural
and pharmaceutical compounds are more efficiently synthe-
sized using cascade reactions because fewer synthetic steps are
involved.1 For example, many natural alkaloids have been
synthesized using 2-aza-Cope−Mannich cascades,2 in which
the [3,3]-sigmatropic rearrangement of an iminium 1 and
subsequent Mannich cyclization of an enol-iminium inter-
mediate 2 affords a 3-acylpyrrolidine 3 as a common product
skeleton (Scheme 1). The 2-aza-Cope−Mannich reaction has
been synonymous with the “aza-Cope−Mannich reaction” for
a long time, despite the existence of another positional
analogue, namely, the 3-aza-Cope−Mannich reaction. In this
version, vinylammonium 4 is a common starting structure,
which undergoes a [3,3]-shift to give enol ether-iminium
Scheme 1. Preparing Different Core Skeletons Using the 2-
Aza- and 3-aza-Cope−Mannich Cascades
Received: April 17, 2021
Published: May 13, 2021
https://doi.org/10.1021/acs.orglett.1c01323
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4391−4395
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Letter
sulfonamides.9 Hence, we designed cyclic tertiary amino alkyne
7 as a substrate for the cascade reaction, in which
intramolecular cyclization of the tertiary amine to the alkyne
provides vinylammonium 8. We anticipated that 8 will undergo
3-aza-Cope rearrangement to iminium 9, with subsequent
Mannich cyclization furnishing tricyclic nitrogen heterocycles
10 and 11 (Scheme 2). Fused nitrogen skeletons related to
Scheme 2. 3-Aza-Cope−Mannich Cascade and Natural
Products with Fused Tricyclic Skeletons
these tricyclic skeletons appear in many alkaloids, and the
cascade reaction outlined in Scheme 2 is potentially useful for
the synthesis of these natural products. Cephalotaxine,10
serratinine,11 and stemonamine12 contain the tricyclic system
exemplified by 10 and 11, while the skeletons of lepadiformine
A13 and lycospidine A14 include homologated versions of
them. Herein, we report the new cascade reaction shown in
Scheme 2 and a short synthesis of (−)-cephalotaxine.
We began our study by screening the reaction conditions
using alkynyl amine 7a (Figure 1). We first examined the
AuCl(PPh3)/AgOTf catalytic system. To our delight, three
isomers 10a, cis-11a, and trans-11a, all of which are products of
the desired cascade reaction, were obtained in 67% total yield
(entry 1). Examining various silver salts15 disclosed that silver
pentacyanocyclopentadienide (Ag[C5(CN)5], AgPCCP)16
with a C5-symmetrical superacid conjugate base gave the
best result in this reaction (entry 4). No cascade reaction
products were obtained in the absence of a gold or silver salt
(entries 7 and 9). Use of Ph3PAuNTf2 did not increased
product yields (entry 8). A gold salt bearing an electron-
deficient phosphine led to a significantly lower product yield
(entry 10), while the catalyst bearing a bulky phosphine or a
carbene afforded the product in slightly lower yields (entries
11−12). The reaction was performed in 1,2-dichloroethane on
an isolable scale in the presence of 1 mol % AuCl(PPh3) and
Ag[C5(CN)5] at a higher temperature to give products 10a,
cis-11a, and trans-11b in good total yields (eq 1).
The substrate scope of the reaction is shown in Figure 2.
Azepanes, piperidines, and benzoazepanes (10a−d and 11a−
d) were obtained in good total yields by the cascade reaction.
Moreover, the reaction successfully furnished systems involv-
ing cyclic enol ethers, namely, dihydropyrans, dihydrofurans,
and 1,4-dioxenes (10f,g and 11e−g). Notably, the uncon-
jugated isomer 11e was exclusively formed with the substrate
bearing tetrahydropyran ring. 1,3-Dimethyldioxolene product
10h was obtained in only 7% yield because the acetonide
group was lost during the reaction. Interestingly, in the
presence of Et3N, enone 12 was obtained as the product, which
was presumably formed by triethylamine-mediated elimination
Figure 1. Screening reaction conditions using substrate 7a. Yields for
10a, cis-11a, and trans-11a for entries 1−12 were determined by H
NMR spectroscopy using 1,2-dichloroethane as an internal standard.
1
of acetone from iminium and the Mannich cyclization as
shown in A (eq 2). Lower reactivity and product yield were
observed when a TBS enol ether was used instead of a methyl
enol ether. In addition, partial N-alkylation of product 10i by
1,2-dichloroethane (solvent) gave chloride 13. Substrates
bearing four-atom tethers between their amines and alkynes
required higher temperatures and gave products 10j,k and
11j−l in lower yields. While, substrate 7m with a two-atom
tether underwent endo cyclization onto vinyl ammonium
intermediate, subsequent 3-aza-Cope rearrangement and
Mannich cyclization gave tricyclic products 14 and 15 (eq
3). Substrate 7n bearing a 2-ethynylbenzyl group provided
products 16 and 17 through gold-catalyzed 6-endo cyclization
(eq 4). We used optically enriched starting substrates in the
reactions for 10b,c, 11b,c, and 11l, respectively; however, all
reaction products showed very low specific optical rotations,
indicating that racemization occurred during the reaction. We
currently assume that racemization occurs by the ring-flip of
the macrocycle in iminium intermediate 9. Complete isomer-
ization to 10 or 11, or hydrolysis to corresponding ketones
were not successful yet. For example, attempted hydrolysis of a
mixture of enol ethers 10d and 11d using TsOH·H2O in
acetone produced a macrocyclic enone through a retro aza-
Michael reaction (for detail, see Supporting Information).
We next prepared cephalotaxine in a short sequence using
the developed cascade reaction. Cephalotaxine is a pentacyclic
alkaloid isolated from the plum yew Cephalotaxus harringto-
nii.10 Omacetaxine mepesuccinate (homoharringtonine), an
ester derivative, shows significant cytotoxicity against leukemia
cells17 and was developed as a pharmaceutical drug against
chronic myeloid leukemia.18 Furthermore, cephalotaxine has
recently been found to inhibit Zika infection by impeding viral
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Scheme 3. Seven-Step Synthesis of (−)-Cephalotaxine
as the major product under the standard reaction conditions in
1,2-dichloroethane. After carefully examining the reaction
conditions, the desired isomer 23 was predominantly formed
in preference to the conjugated isomer 24 in the presence of 4
equiv of TsNH2 in tert-butanol as the solvent.25 Oxidation with
m-CPBA under acidic conditions occurred smoothly at 0 °C to
give demethylcephalotaxinone (25). The rearrangement of 22
was carried on the gram scale, which yielded more than 400
mg of 25. It is worth mentioning that 25 was synthesized from
norhydrastinine (18) in only five steps in 39.1% overall yield.
The total synthesis of (−)-cephalotaxine was completed
following a known two-step transformation including enol
ether formation26 and Noyori’s asymmetric transfer hydro-
genation.22l We next examined optically active substrate
(+)-22 (98% ee), which was isolated by chiral-phase HPLC;
rearranged products (−)-23 and (−)-24 were obtained
without racemization, in contrast to the results obtained for
the reactions to 10b,c, 11b,c, and 11l, all of which underwent
significant racemization. Presumably, the gold(I)-catalyzed
cyclization is reversible and the 3-aza-Cope rearrangement
advances via a chair-type transition state 26. The chiral center
at the β-position of iminium intermediate 27 plays an
anchoring role that prevents racemization through the ring-
flip of the macrocycle. Oxidation of (−)-23 with m-CPBA
afforded (+)-25, also a known intermediate in the synthesis of
natural (−)-cephalotaxine.26
Figure 2. Substrate Scope
replication and stability.19 Since the first total synthesis by
Weinreb,20 many research groups have reported total syntheses
of cephalotaxine (including formal total syntheses).21,22
However, a more efficient total synthesis is necessary for the
development of cephalotaxine derivatives.
Norhydrastinine (18)23 was employed as the starting
material in our total synthesis, and alkylation with iodide 19
gave cyclic iminium salt 20 (Scheme 3). Nucleophilic addition
of vinyllithium 21,24 and subsequent deprotection of the TMS
group with TBAF provided 22. Undesired 24, in which the
enol ether and the benzene ring are conjugated, was obtained
In conclusion, we developed a new cascade reaction
involving the gold(I)-catalyzed cyclization of a tertiary amine
onto a terminal alkyne, the 3-aza-Cope rearrangement of a
vinylammonium, and Mannich cyclization. Tricyclic hetero-
cycles found in many natural alkaloids were constructed from
simple cyclic amines bearing alkynyl side chains and enol ether
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(c) Pelissier, H. Asymmetric Metal Catalysis in Enantioselective Domino
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moieties. Screening gold ligands and silver counterions
revealed that the AuCl(PPh3)/Ag[C5(CN)5] cocatalyst system
is most effective in providing good total yields of fused
heterocycles. The cascade reaction shows broad substrate
scope for both the cyclic amine moiety and the enol ether
group. Cascade reactivity was observed to be lower when four-
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norhydrastinine (18). Further studies of reactions using
vinylammoniums and synthetic studies into other natural
alkaloids are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
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https://pubs.acs.org/doi/10.1021/acs.orglett.1c01323.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Takeo Sakai − Faculty of Pharmacy, Meijo University, Nagoya
468-8503, Japan; orcid.org/0000-0002-9006-8249;
Email: sakait@meijo-u.ac.jp
Authors
Chise Okumura − Faculty of Pharmacy, Meijo University,
Nagoya 468-8503, Japan
Masatoshi Futamura − Faculty of Pharmacy, Meijo
University, Nagoya 468-8503, Japan
Naotaka Noda − Faculty of Pharmacy, Meijo University,
Nagoya 468-8503, Japan
Akari Nagae − Faculty of Pharmacy, Meijo University, Nagoya
468-8503, Japan
Chiharu Kitamoto − Faculty of Pharmacy, Meijo University,
Nagoya 468-8503, Japan
Madoka Kamiya − Faculty of Pharmacy, Meijo University,
Nagoya 468-8503, Japan
Yuji Mori − Faculty of Pharmacy, Meijo University, Nagoya
468-8503, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01323
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by Grant-in-Aids for
Scientific Research (C) (19K06983 and 20K05503) from the
Japan Society for the Promotion of Science (JSPS), the
Research Foundation for Pharmaceutical Sciences, and
Ichihara International Scholarship Foundation. We thank Ms.
Tatsuko Sakai (Meijo University) for performing the elemental
analysis.
(12) Iizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. X-Ray
crystallographic determination of the structure of stemonamine, a new
alkaloid from Stemona japonica miq.: isolation of isostemonamine. J.
Chem. Soc., Chem. Commun. 1973, 125−126.
(13) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren,
J.; Weber, J. F.; Boukef, K. Lepadiformine, a new marine cytotoxic
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