Copper-Catalyzed Aerobic Oxidative Cyclization Cascade to Construct Bridged Skeletons: Total Synthesis of (?)-Suaveoline

Article abstract of DOI:10.1002/anie.201902155

Based on the discovery of copper-catalyzed cyclopropanol ring-opening addition to iminium ions, an unprecedented catalytic aerobic C?H oxidation/cyclopropanol cyclization cascade using CuCl₂ as the multifunctional catalyst and air as the oxidant was developed to construct the azabicyclo[3.3.1]nonane skeleton, which is widespread in natural products and medicines. Using this method, concise asymmetric total synthesis of the indole alkaloid (?)-suaveoline was achieved. This study not only provides an efficient, low-cost, and environmentally benign method for constructing such bridged frameworks, but also enriches the realm of cyclopropanol chemistry and C?H functionalization.

Full text of DOI:10.1002/anie.201902155

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Accepted Article
Title: Copper-Catalyzed Aerobic Oxidative Cyclization Cascade to
Construct Bridged Skeletons: Total Synthesis of (−)-Suaveoline
Authors: Qiuyuan Tan, Zhao Yang, Dan Jiang, Yuegang Cheng, Jiao
Yang, Song Xi, and Min Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902155
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10.1002/anie.201902155
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Copper-Catalyzed Aerobic Oxidative Cyclization Cascade to
Construct Bridged Skeletons: Total Synthesis of (−)-Suaveoline
Qiuyuan Tan, Zhao Yang, Dan Jiang, Yuegang Cheng, Jiao Yang, Song Xi, and Min Zhang*
Abstract: Based on the discovery of copper-catalyzed
cyclopropanol ring-opening addition to iminium ions, an
unprecedented catalytic aerobic C−H oxidation/cyclopropanol
cyclization cascade using CuCl2 as the multifunctional catalyst and
air as the oxidant has been developed to construct the
azabicyclo[3.3.1]nonane skeleton, which is widespread in natural
products and medicines. Using this method, concise asymmetric
total synthesis of the indole alkaloid (−)-suaveoline has been
achieved. This study not only provides an efficient, low-cost, and
environmentally benign protocol for constructing such bridged
frameworks, but also enriches the realm of cyclopropanol chemistry
and C−H functionalization.
cyclopropanol ring-opening cyclization[10,11] of 2 could give the
azabicyclo[3.3.1]nonane 4 with a ketone functionality, ideally,
using a single catalyst to catalyze both the two elementary steps
and air as the oxidant (Scheme 1c). This proposal has several
potential advantages. Chiral cyclopropanol 2 with a dictating
stereogenic carbon center can be conveniently prepared in one
step by Kulinkovich cyclopropanation of ester 1,[10a] which can
be easily prepared from amino acids in two steps. The great
advances in the area of cross-dehydrogenative coupling (CDC)
of tetrahydroisoquinoline with nucleophiles made by Li,
Murahashi, Wang, Liu, and others indicate the feasibility of the
initial C–H oxidation step to generate iminium ion 3.[12] In
addition, previous studies showing that cyclopropanol acts as a
homoenolate equivalent to undergo single- or two-electron ring-
opening reactions indicate the possibility of the second
cyclization step.[10,11] Structurally, the flat N-aryl group of 2 first
functionalizes to facilitate the initial C–H oxidation, and then to
force the cyclopropanol group to take a pseudo-axial orientation
prerequisite for cyclization to the iminium ion to minimize the
A1,2-strain,[13a] while the homologous A1,3-strain controlling factor
is more often used to construct the bridged structures.[7b,13]
The azabicyclo[3.3.1]nonane motif is widely distributed in
natural products and medicines. Some selected representatives
are shown in Scheme 1a. Granisetron (Sancuso®) is a serotonin
5-HT3 receptor antagonist that was approved by FDA in 2008 to
prevent nausea and vomiting induced by chemotherapy or
radiotherapy in cancer treatment.[1] Naturally occurring alkaloid
ajmaline (Gilurytmal®) is used as a diagnostic drug to induce
arrhythmic contraction in patients suspected of having Brugada
syndrome.[2] Ajmaline, sarpagine, and suaveoline along with
other over 150 congeners are principally isolated from plants of
the Apocynaceae family with medicinal significance.[3]
Neocaryachine, a typical member of the over 30 known pavine
alkaloids, exhibits low nanomolar antiproliferative activity in
tumor cell lines.[4]
The biological significance and architectural complexity of
the natural products containing the azabicyclo[3.3.1]nonane core
structure have made them highly pursued synthetic targets for
decades.[5–8] Cook and co-workers[6] have accomplished elegant
synthesis of several indole alkaloids with this structural feature
using Dieckmann condensation strategy to construct the bridged
framework. Efficient strategies also include Martin’s biomimetic
synthesis
and
olefin
metathesis,[7a–c]
Kwon’s
[4+2]-
annulation/Friedel-Crafts acylation,[7d] Gaich’s [5+2]-dipolar
cycloaddition/ring-enlargment,[7e−g] and other methods.[7–8]
Despite these advances, most of the existing methods require
multiple functional group pre-installations and transformations
(Scheme 1b), whereas greener strategies, namely, C–H
functionalization,[9] that benefit from minimal functional group
manipulations remain underexplored.
We envisioned that catalytic tandem C–H oxidation and
[*]
Q.-Y. Tan,[+] Z. Yang,[+] D. Jiang, Y.-G. Cheng, J. Yang, S. Xi, and
Prof. M. Zhang
Chongqing Key Laboratory of Natural Product Synthesis and Drug
Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331 (China).
Scheme 1. Background and study synopsis
E-mail: minzhang@cqu.edu.cn.
Prof. M. Zhang
School of Chemistry and Chemical Engineering, Chongqing
University, Chongqing 401331 (China).
These authors contributed equally to this work.
Although this proposal is feasible in principle, there are
several inherent issues that need to be addressed. First,
successful electrophilic trapping of cyclopropanol with carbonyl
compounds remains scarce, and nucleophilic addition to iminium
[+]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201902155
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ions or imines has not been reported, other than formation of a
challenging bridged structure.[10,11] Second, most of the existing
Compounds fused with heteroaryl groups, such as thienyl and
furyl groups, both smoothly reacted (4p and 4q). Changing the
N-activating group from PMP to Ph did not affect the reaction
outcome, giving 4r in 60% yield. The relative and absolute
configurations of the bridged products were assigned based on
X-ray crystallographic analysis of the derivative of 4a.[14]
The substrate scope was further expanded to include
structurally more diversified cyclopropanols (Table 2). 2s with an
alkyl group at C3 is also a viable substrate, generating 4s with a
bridgehead quaternary stereogenic center.[15] Remarkably, in
addition to azabicyclo[3.3.1]nonane, this method is also capable
of forming a medium-sized azabicyclo[4.3.1]decane framework,
as showncased by 4t.
C−H
functionalizations
of
tetrahydroisoquinoline-type
compounds are limited to intermolecular reactions with common
nucleophiles, and there are no precedents that form bridged
structures.[12] Third, cyclopropanol is prone to react under
oxidative conditions, which could result in complications.[10,11]
The key to the success of this proposal is to identify a
multifunctional catalytic system that can catalyze the initial C–H
oxidation step without prematurely interfering with the labile
cyclopropanol unit, and, more importantly, is capable of
promoting the unexplored cyclopropanol ring-opening addition to
the in situ formed iminium ion.
After extensive investigation of various reaction
parameters,[14] CuCl2/air/CHCl3 or DMF/60 °C were determined
to be the best choice of reaction conditions, providing 4a in 65%
yield from 2a and thus experimentally validating the feasibility of
the proposal (Table 1). In addition, this reaction can be also
performed on gram-scale in an open flask, providing 4a in 55%
yield.[14] We then explored the generality of this method. As
shown in Table 1, substrates with electronically different
substituents, such as F, Cl, Br, MeO-, and Me, at the 6-position
of the phenyl ring readily participated in the oxidative cyclization
(4b–4f). Substrates with phenyl rings bearing two oxygen
substituents resulted in slightly better yields (4g and 4h).
Halogen atoms or methyl and methoxyl groups at the 5-, 7-, and
8-positions of the phenyl ring are also tolerated (4i–4n),
providing products with handles for further elaboration.
The catalytic role of the copper catalyst in oxidation of
tetrahydroisoquinolines to iminium ions has been well-studied,[12]
but ring-opening addition of cyclopropanol to iminium ions or
imines remains underexplored.[10,11] In this context, two
questions need to be answered: 1) Is the copper catalyst
involved in cyclopropanol ring-opening cyclization to the iminium
ions? 2) What mechanism operates? To understand the reaction
mechanism and further extend the substrate scope,
cyclopropanols with extra substituents on the cyclopropane ring
were investigated (Table 2, 4u–4w). Two possible cyclopropanol
ring-opening mechanisms could be involved: breaking the less
substituted bond A or more substituted bond B. It has been
demonstrated that the radical cyclopropanol ring-opening
process favors breaking bond B to provide a more substituted
and thus more stable radical intermediate, while formation of the
metallo-homoenolate tends to break bond A to generate the less
substituted metallo-homoenolate.[10,11f,g,k,l] In our case, bond B
was selectively cleaved to generate 4u and 4v (X-ray)[14] with an
alkyl group and 4w with a gem-dimethyl group at C11 as the
Table 1: Substrate scope with respect to the aryl groups.[a]
only isolated products, which indicates that
cyclopropanol ring-opening mechanism is operating.
a
radical
Table 2: Substrate scope with respect to the cyclopropanol units.[a]
[a] As in Table 1 unless otherwise stated. Using Cu(acac)2/TBHP for 4s;
using CH3CN as the solvent for 4u and 4v.
Along with the above experimental observations, extra
mechanistic studies were performed (Scheme 2a). Shortening
the reaction time of 2a from 24 to 0.5 h, 6a was isolated as the
main product in 80% yield. The structure of 6a was verified by
comparison with the oxidation product of 2a with 5 and X-ray
[a] Typical Conditions: 2 (0.1 mmol), CuCl2 (0.02 mmol), air balloon, DMF or
CHCl3 (1 mL), 60 °C, 4–48 h.
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crystallographic analysis.[14] Subjecting purified 6a to the
standard oxidative cyclization conditions (condition I) gave 4a in
65% yield, whereas omitting CuCl2 generated no 4a. Rigorous
removal of oxygen gave a similar yield of 4a within the same
operating time profile (condition II), indicating that oxygen is not
essential for the cyclopropanol ring-opening cyclization step.
Using CuCl as the catalyst under argon resulted in a negligible
amount of 4a (condition III), while using CuCl under air gave 5%
yield of 4a,[14] indicating that CuCl is not effective to induce the
cyclopropanol ring-opening cyclization process and the higher
oxidation state of the copper catalyst (i.e. CuCl2) is required.
Performing this reaction with Lewis acids, such as Et2AlCl,
EtAlCl2, BF3·OEt2, and TiCl4, produced no 4a (condition IV),
further highlighting the crucial role of the copper catalyst.
Addition of 3 equiv of the radical inhibitor TEMPO into the
reaction mixture inhibited formation of 4a (condition V).
radical-stabilizing factor. Single-electron transfer from CuI to
intermediate D regenerates CuII to complete catalytic cycle B
and give product 4a. Catalytic cycle B is time-consuming, and it
is overall redox-neutral with no external oxidant involved.
To test the synthetic utility of this methodology, the total
synthesis of indole alkaloid suaveoline was then performed
(Scheme
3).[8,16]
Suaveoline
contains
an
azabicyclo[3.3.1]nonane central substructure annelated to
pyridyl and indolyl rings at both sides. Starting with the
commercially available (S)-homoserine 7, a sequence of N-
arylation/esterification and N-alkylation afforded 10 in good yield.
Swern oxidation and Wittig olefination of 10 gave 11 as an
inconsequential mixture of E/Z isomers, which set the stage for
the pivotal oxazole–olefin Diels–Alder reaction to construct the
pyridine ring.[8e,f,17] The microwave-assisted Diels–Alder reaction
efficiently occurred to give 12 in 65% yield with 95% ee. The
standard Kulinkovich cyclopropanation protocol (Ti(OiPr)4,
EtMgBr) produced cyclopropanol 13 in 85% yield. The N-atom of
pyridine as a potential copper-coordination site did not result in
any problems, and exposure of 13 to the standard oxidative
cyclization conditions generated 4x in 55% yield with 95% ee,
which indicates that there is no erosion of the enantiopurity in
the Kulinkovich cyclopropanation and oxidative cyclization steps.
Finally, Fisher indole synthesis taking advantage of the ketone
functionality and subsequent removal of the PMP group gave
(−)-suaveoline in good yield with high optical purity (95% ee).
Scheme 2. Mechanistic studies and proposed reaction mechanism.
On the basis of the above experimental results and previous
mechanistic studies,[11f,g,12k,m] we propose a plausible reaction
mechanism in Scheme 2b. Essentially, the copper catalyst plays
dual catalytic roles for the initial C−H oxidation and subsequent
cyclopropanol ring-opening cyclization steps, corresponding to
the catalytic cycles A and B, respectively. In the C−H oxidation
step, CuII oxidizes substrate 2a to iminium ion A, which
undergoes rapid O-cyclization to form aza-acetal 6a with the
cyclopropane ring untouched, and the CuI catalyst is then
oxidized back to CuII by air to complete catalytic cycle A.[12k,m]
This step is rapid and can be done in minutes. Thereafter, CuII
enters catalytic cycle B and first acts as a Lewis acid to open the
aza-acetal to form iminium ion B. To minimize the A1,2-strain, the
metallo-cyclopropanol would take a pseudo-axial orientation to
facilitate the cyclization.[13a] Radical ring opening of the metallo-
cyclopropanol moiety generates CuI and radical intermediate
C,[11f,g] which undergoes intramolecular radical addition to the
iminium ion to form radical cation D with the PMP group as the
Scheme 3. Total synthesis of (−)-suaveoline. Reagents and conditions: a)
PMPI, CuI, K2CO3, DMSO, 100 °C, then MeI, room temperature, 55%; b) 9,
K2CO3, CH3CN, 60 °C, 84%; c) (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C; d) nPr-
PPh3.Br, nBuLi, THF, −78 °C, E/Z=1:3, 50% from 10; e) MW, DMSO, 200 °C,
65%; f) Ti(OiPr)4, EtMgBr, THF, 0 °C, 85%; g) CuCl2, air balloon, CHCl3, 60 °C,
55%; h) 14, HCl, MeOH, 70 °C, 89%; i) H5IO6, H2SO4, MeCN/H2O, rt, 75%.
In conclusion, the first Cu-catalyzed aerobic C−H
oxidation/cyclopropanol ring-opening cyclization cascade has
been
developed
to
efficiently
construct
the
azabicyclo[3.3.1]nonane framework, which is widespread in
natural products and medicines, culminating in a concise total
synthesis of (−)-suaveoline. The initial C−H oxidation and
subsequent cyclopropanol ring-opening cyclization steps share
the same CuCl2 catalyst. This method features inexpensive
chiral starting materials (amino acids), catalyst (CuCl2), and
oxidant (air), as well as mild conditions, broad substrate scope,
and high-value bridged products. The method is based on the
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opening manner, therefore, enriching the cyclopropanol
chemistry and C−H functionalization.
Acknowledgements
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This work was supported by NSFC (21672029, 21871033) and
CSTC (2018jcyjAX0421).
Keywords: cyclopropanol • C–H functionalization • cross-
dehydrogenative coupling • bicyclo[3.3.1]nonane • total
synthesis
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Entry for the Table of Contents
COMMUNICATION
Qiuyuan Tan, Zhao Yang, Dan Jiang,
Yuegang Cheng, Jiao Yang, Song Xi,
and Min Zhang*
Page No. – Page No.
Copper-Catalyzed Aerobic Oxidative
Cyclization Cascade to Construct
Bridged Skeletons: Total Synthesis of
(−)-Suaveoline
A new catalytic aerobic C−H oxidation/cyclopropanol ring-opening cyclization
cascade using CuCl2 as the multifunctional catalyst and air as the oxidant has been
developed to construct the bridged azabicyclo[3.3.1]nonane frameworks. Using this
reaction as the key step, a concise asymmetric total synthesis of the indole alkaloid
(−)-suaveoline has been achieved.
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