Facile Stereoselective Approach to Diverse Spiroheterocyclic Tetrahydropyrans: Concise Synthesis of (+)-Broussonetine G and H

Article abstract of DOI:10.1002/anie.201907353

A highly diastereoselective copper-catalyzed multicomponent cyclization of exocyclic enol ethers/enamines with methylene malonate and aldehydes has been developed to furnish spiroheterocyclic tetrahydropyrans in high yields with greater than 95:5 d.r. Thi

Full text of DOI:10.1002/anie.201907353

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Accepted Article
Title: Facile Stereoselective Approach to Diverse Spiroheterocyclic
Tetrahydropyrans: Concise Synthesis of (+)-Broussonetine G and
H
Authors: Li Zhou, Shu-Yang Yu, Yong Tang, and Lijia Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907353
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10.1002/anie.201907353
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Facile Stereoselective Approach to Diverse Spiroheterocyclic
Tetrahydropyrans: Concise Synthesis of (+)-Broussonetine G and
H
Li Zhou, Shu-Yang Yu, Yong Tang and Lijia Wang*
Abstract:
A
highly diastereoselective copper catalyzed multi-
Intermolecular reactions are vested in more facility in the
construction of diverse spiroketals from simple starting materials
in views of step economy. In fact, as early as 1988, Pale and
coworkers pioneered a two-step synthesis strategy involving a
silver ion catalyzed intramolecular cyclization of ω-acetylenic
alcohols followed by a Lewis acid catalyzed hetero-Diels-Alder
(HDA) reaction for the build of unsaturated spiroketals (Scheme
1a).[6-7] Recent years, with similar strategy,[8-9] remarkable
progress has been made by Barluenga[8a] and Xu[8b] respectively,
in terms of employing noble metals, such as Pd and Au,
cooperated with different Lewis acids as catalysts to achieve [6,5]-
spiroketalizations between alkynols and salicylaldehyde
derivatives or oxa-dienophiles. McDonald and co-workers
developed a rhodium-catalyzed alkyne cyclotrimerization strategy
to synthesize the spiroglycoside from bisalkynylcarbohydrate
derivatives (Scheme 1b)[10]. These above-mentioned methods
provide effective protocols for the construction of [6,5]-
spiroketals.[11] In contrast, for [6,6]-spiroketals, which are also
core structures of a series of biologically active natural products,
the reported intermolecular examples are still challenging. For
example, Feng and co-workers developed an elegant
gold(I)/nickel(II) relay catalysis on the synthesis of spiroketals with
alkynyl alcohols and keto esters.[9b] They found that by employing
hex-5-yn-1-ol instead of pent-4-yn-1-ol, the yield of the
corresponding [6,6]-spiroketal was dramatically decreased from
94% to 50% compared with the [6,5]-spiroketal product, probably
due to the fact that the intramolecular alkynols cyclization step is
gradually more difficult with the longer carbon chain. Thus, facile
approaches to variable spiroheterocyclic tetrahydropyran,
especially containing larger rings or complicated structures, are
still very limited. In this study, we conceived a new tandem
cyclization protocol for a base metal catalyzed stereoselective
spiroketalization (Scheme 1c).
components tandem cyclization of exocyclic enol ethers/enamines
with methylene malonate and aldehydes has been developed to
furnish the spiroheterocyclic tetrahydropyrans in high yields with
>95/5 dr. This method is very practical that 36 examples reacted
smoothly over a very broad range of aldehydes and many different
exo-vinyl heterocycles. By applying the newly developed method, the
total synthesis of (+)-broussonetine G and formal synthesis of (+)-
broussonetine H were achieved in a concise way.
Spiroheterocyclic tetrahydropyran motifs widely exist in natural
products.[1-2] These compounds with diverse structures are
endowed with various biological activities.[3] For example, (+)-
broussonetine G and H, which containing [6,5]- and [6,6]-
spiroketal fragments, were potent glycosidase inhibitors;[3a]
virgatolide C with a [6,6]-spiroketal core showed cytotoxicity
against HeLa cells;[3b] penicitrinine A bearing N,O-spiroketal
structure was found anti-proliferative activity on multiple tumor
types.[3c] For a long time, the synthesis of such compounds has
been mainly focused on the intramolecular cyclization strategy,[4-
5]
which depends on designing elaborate substrates that usually
require long linear routes to prepare. Thus, developing general
methods for the rapid construction of these motifs from simple
starting materials are highly in demand.
Figure 1. Bioactive Molecules with Spiroheterocyclic Tetrahydropyran Motifs.
[*]
L. Zhou, S.-Y. Yu, Prof. Dr. Y. Tang, Prof. Dr. L. Wang
The State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, CAS, University of Chinese
Academy of Sciences
345 Lingling Lu, Shanghai 200032, China
Prof. Dr. L. Wang
School of Chemistry and Molecular Engineering, East China Normal
University
500 Dongchuan Rd.,Shanghai 200241
E-mail: ljwang@chem.ecnu.edu.cn
Scheme 1. Intermolecular Approaches to Build Spiroheterocyclic
Tetrahydropyrans.
Supporting information for this article is given via a link at the end of
the document
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A diverse range of spiroheterocyclic tetrahydropyranes can be
constructed with high efficiency and diastereoselectivity from
various exocyclic enol ethers/enamines, methylene malonate and
a very wide scope of aldehydes. Applying this method, the total
synthesis of (+)-broussonetine G, the formal synthesis of (+)-
broussonetine H, as well as the core structure framing of natural
product cycloethaliacumarin[12] were completed in a concise way.
Herein, we report the preliminary results.
Table 1. Substrate Scope of Aldehydes
Recent years, we have developed a series of cyclization
reactions by employing methylene malonate (2a) as synthetic
building block.[13] In this study, exocyclic enol ether (1a),
methylene malonate (2a) and 2-naphthaldehyde (3a) were initially
reacted with 10 mol % of InCl3 as catalyst in dichloromethane
(DCM) at -50 oC, leading to the desired spiroketal (4a) in only 8%
yield (Scheme 2). Further screening on the reaction conditions
was carried out [14] and the in situ generated Cu(PF6)2 from CuBr2
and AgPF6 was found to be the best catalyst, giving 4a in 98%
o
yield with >95/5 dr at -78 C after 24 h. It was worth to mention
that both CuBr2 and AgPF6 could not promote the current reaction
at -78 oC. The relative configuration of 4a was confirmed by X-ray
crystallography.[15]
Scheme 2. Tandem reaction of exocyclic enol ether (1a), methylene malonate
(2a) and 2-naphthaldehyde (3a) with different Lewis acids.
Under the optimized reaction conditions, the substrate scope
of the reaction was investigated as summarized in Table 1. A very
wide range of aldehydes were found as suitable substrates, even
those with sensitive functional groups. Aromatic aldehydes
bearing substituents at different positions of the phenyl groups,
such as 2-MeO, 4-Cl and 2-Br groups, led to spiroketals 4b-4d in
83-91% yields with >95/5 dr. Aromatic aldehydes containing
easily transformed functional groups, such as 4-bpin, 4-hydoxy
and formyl groups, were tolerated, providing 4e-4g in up to 87%
yield with >95/5 dr. In addition, 2-formylthiophene and 3-
formylindole were also suitable reaction candidates, giving the 4h
and 4k in high yields with >95/5 dr, respectively. This method
could also deliver spiroketals with olefin moiety. For examples,
when 4-methoxycinnamaldehyd, 2-hexenal and crotonaldehyde
were employed as substrates, 4j-4l were obtained in 88-93%
yields with excellent diastereoselectivities. With 3-butenal as
substrate, 4m was afforded in 73% yield with >95/5 dr.
Remarkably, aliphatic aldehydes were totally compatible with the
current reaction system. Various aliphatic aldehydes, including 2-
phenylacetaldehyde, butyraldehyde, cyclohexanaldehyde and 5-
bromopentanal were employed, and high yields with >95/5 dr
were achieved to give 4n-4q. Furthermore, spiroketal 4r bearing
a ferrocene moiety could also be prepared by using this method
in 84% yield with >95/5 dr.
Further study shown that this method was compatible with
various exocyclic enol ethers. As shown in Table 2, the enol
ethers, bearing two phenyl groups at the five-membered ring,
could give 4s and 4t in 88-91% yields with >95/5 dr. Compared
with those previously reported strategies that involving noble
metal catalysed intramolecular cyclization of alkynols, the current
method broke the limitation of the five-membered ring enol ether
substrates. Six-membered exocyclic enol ethers were very good
substrates, which could react with a broad range of aldehydes
smoothly including both aromatic and aliphatic aldehydes (4u-4z,
80-99% yields, >95/5 dr). It was found that the excellent
diastereoselectivity was controlled by
a
thermodynamic
process.[14] Seven-membered exocyclic enol ethers, and even 13-
membered enol ethers, were also suitable substrates, leading to
the 4aa and 4bb in 92% and 58% yields with excellent
diastereoselectivities, respectively. Furthermore, these good
performances were observed not only for enol ethers, but also for
exocyclic enamines, and the corresponding products 4cc-4ee
were obtained in good to high yields with excellent dr values for
both aromatic and aliphatic aldehydes. Remarkably, in order to
test the practicability of this reaction on transforming complex
molecules at late stage in organic synthesis, asymmetric
reactions on modifying the (R)-(+)-sclareolide were carried out.
With 2-naphthaldehyde, the resulting optically active product (+)-
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Table 3. Construction of Tetracyclic Spiroketals with Salicylaldehydes.
sclareolide-spiro was obtained in 95% yield with 90/10 dr (>95/5
dr, after recrystallization). This reaction could even serve as a
flexible toolbox that could easily joint two complex moieties by one
tetrahydropyranic cycle. With a lithocholic acid derived aldehyde,
the (R)-(+)-sclareolide was connected with a steroid moiety to
give the corresponding optically active product (+)-sclareolide-
spiro-(+)-steroid in 73% yield with 88/12 dr. The relative
configurations of 4u and (+)-sclareolide-spiro were confirmed by
X-ray crystallography.[15] These examples shown a high degree of
remote stereocontrol in a thermodynamic process.
Table 2. Substrate Scope of 1.
Inspired by the synthetic efficiency to form spiroketals of the
current method, we tried to apply it to construct the basic
skeletons of biologically active natural products (+)-broussonetine
G and H.[3a] In Scheme 3, the catalyst loading could be decreased
to 1 mol %, and the scale-up tandem cyclization reactions with
both five- and six- membered ring enol ethers were applied as the
key step to build the 4m and 4x with excellent diastereoselectivity.
The two enantiomers (+)-4m and (-)-4m could be easily separated
by preparative high-performance liquid chromatography (HPLC).
[14] (+)-4m was then treated with LiCl to give mono-decarboxylated
products (+)-6m, followed by a hydrolysis reaction, affording (+)-
7m in 97% yield. The carboxyl group was removed through a
Barton ester free-radical reaction, and the resulting (+)-8m was
then connected with an arabinofuranose derived synthetic
intermediate 9[16] by employing Hoveyda-Grubbs(II) catalyst to
Moreover, when salicylaldehydes were employed as
substrates, the spiroketalization followed by an intramolecular
transesterification occurred to give the corresponding tetracyclic
spiroketals 5a-5c in 65-73% yields with excellent dr value. It is
worth to mention that those tetracyclic spiroketals are core
structure of natural product cycloethaliacumarin.[12] The relative
configuration of 5c was confirmed by X-ray crystallography.[15]
Scheme 3. Gram-scale synthesis, total synthesis of (+)-broussonetine G and
formal synthesis of (+)-broussonetine H. Reagents and conditions: a. Cu(PF6)2,
DCM; b. LiCl, H2O, dimethyl sulfoxide (DMSO), 130 oC; c. LiOH·H 2O,
MeOH/H2O, 50 oC; d. dipyrithione, n-Bu3P, n-Bu3SnH, dark, benzene at rt for 3
h, then azodiisobutyronitrile (AIBN) at 80 oC; e. Hoveyda-Grubbs(II), DCM, 55
oC; f. Pd/C, H2, MeOH, HCl (aq), rt.
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into 8x, which could be transformed to (+)-broussonetine H in two
steps by a known procedure. [2e]
In summary, the first stereoselective multi-components
tandem cyclizations of exocyclic enol ethers/enamines,
methylene malonate and aldehydes were developed catalyzed by
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a
copper (II) catalyst to furnish the spiroheterocyclic
tetrahydropyrans in up to 99% yields with >95/5 dr. The reaction
has a broad substrate scope that includes 36 examples. A very
wide range of aldehydes, as well as different exo-vinyl
heterocycles can all work well. This newly developed method was
competent in modifying complex molecules at late stage, and was
applied to the total synthesis of (+)-broussonetine G and formal
synthesis of (+)-broussonetine H. The spiroketal was transformed
to (+)-broussonetine G in a linear sequence of 6 steps from 3-
butenal with 10.1% overall yield. Further application of this
reaction is still underway in our laboratory.
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We thank the NSFC (Nos. 21432011, 21772224), the CAS (Nos.
QYZDY-SSW-SLH016, XDB20000000, 2017301), and the
STCSM (Nos. 17JC1401200, 17ZR1436900) for the financial.
Keywords: spiroketal • diastereoselectivity • copper catalyst •
tandem cyclization • (+)-broussonetine G
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[15] CCDC 1921542 (4a), 1921543 (4u), 1921546 (5c) and 1921531 ((+)-
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COMMUNICATION
Li Zhou, Shu-Yang Yu, Yong Tang, Lijia
Wang *
Page No. – Page No.
Facile Stereoselective Approach to
Diverse Spiroheterocyclic
Tetrahydropyrans: Concise Synthesis
of (+)-Broussonetine G and H
General method! An effective diastereoselective spiroketalization has been realized
over a broad range of aldehydes in up to 99% yield with >95/5 dr. This method was
applied to the total synthesis of (+)-broussonetine G and formal synthesis of (+)-
broussonetine H.
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