Asymmetric Synthesis of a Fused Tricyclic Hydronaphthofuran Scaffold by Desymmetric [2+2+2] Cycloaddition

Article abstract of DOI:10.1002/anie.201911071

A rhodium(I)-BINAP-catalyzed highly enantioselective [2+2+2] cycloaddition of enynes with alkynes has been developed. Diverse fused tricyclic hydronaphthofuran scaffolds with three consecutive stereogenic centers were constructed in one step from easily a

Full text of DOI:10.1002/anie.201911071

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Accepted Article
Title: Asymmetric Synthesis of a Fused tricyclic Hydronaphthofuran
Scaffold by Desymmetric [2+2+2] Cycloaddition
Authors: Qi Teng, Wenxiu Mao, Dong Chen, Zhen Wang, Chen-Ho
Tung, and Zhenghu Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911071
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10.1002/anie.201911071
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Asymmetric Catalysis
Asymmetric Synthesis of a Fused tricyclic Hydronaphthofuran Scaffold
by Desymmetric [2+2+2] Cycloaddition
Qi Teng, Wenxiu Mao, Dong Chen, Zhen Wang, Chen-Ho Tung, and Zhenghu Xu*
Dedicated to Professor Li-Xin Dai on the occasion of his 95th birthday
Abstract: A rhodium(I)-BINAP-catalyzed highly enantioselective
of terminal alkynes could lead to a fused tricylic scaffold, formed
[2+2+2] cycloaddition of enynes with alkynes has been developed. in an enantioselective fashion with chiral phosphine ligands
Diverse fused tricyclic hydronaphthofuran scaffolds with three
consecutive stereogenic centers were constructed in one step
from easily available materials with excellent chemo-, regio-,
diastereo-, and enantioselectivities. Notable features of these
reactions include 100% atom-economy, very broad scope, and
mild reaction conditions.
(Scheme 1b). However, this type of transformation has not been
reported to date. The major challenge may be the formation of
rhodium acetylide. This would be followed by alkyne insertion and
a fast desymmetric Michael addition to generate the bicyclic
hydrobenzofuran product (5). Lin and Tian et al.[9a] and our
group[9b] have recently independently reported this reactivity. This
type of desymmetric cascade reaction leading to bicyclic scaffolds
has been well studied.[10] Another challenge is how to realize the
desymmetric oxidative cyclization on Rh(I) and control the
regioselectivity of alkyne insertion to form 3 or 4. We envisioned
that with a rational selection of substrates, rhodium catalyst and
chiral phosphine ligands and appropriate reaction conditions, the
desired desymmetric oxidative cyclization mode may survive the
competitive Rh(I)-acetylide insertion-Michael addition pathway to
generate a chiral fused tricyclic scaffold. In this paper, we report
our preliminary results.
Chiral tricyclic hydronaphthofuran scaffolds are found in many
bioactive natural products, such as azadirachtin,[1a] momilactone
A,[1b] nagilactone F,[1c] and commercial pharmaceuticals such as
oxycontin (Scheme 1a). Their unique structures have also led to
their use as key synthetic intermediates in the total synthesis of
many terpenoid natural products.[2] Traditional approaches to the
synthesis of these tricyclic skeletons often requires numerous
reaction steps[1,2] and the establishment of multiple chiral centers
in these stepwise reactions is challenging. Direct synthesis of
such fused tricyclic scaffolds by an asymmetric catalytic reaction
involving readily available starting materials in a step-economic
and atom-economic manner is a notable advance. In 2014,
Alemán reported an organocatalyzed intramolecular Diels-Alder
reaction of cyclohexadienone tethered alkenals leading to a fused
tricyclic hydronaphthofuran scaffold in one step with high
enantioselectivity.[3] Recently, Ogoshi et al. reported accessing
this scaffold by means of an elegant Ni(cod)2-catalyzed
desymmetric cycloaddition of cyclohexadienone with activated
alkene chalcones.[4] Novel transformations with excellent stero-
control, wide applications and general scope are still in high
demand for molecular diversity and complexity.[5]
.
Forming multiple bonds stereoselectively to contruct
structurally complex molecules in a single step has always been
pursued in organic synthesis. Rh(I)-catalyzed asymmetric high-
order cyclization of enynes or diynes with other unsaturated
components has been developed as a powerful strategy with
which to build complex polycyclic structures.[6,7] We questioned if
an enantioselective desymmetric[8] oxidative cyclization of cyclo-
hexadienone alkynes tethered to Rh(I), followed by the insertion
[]
Q. Teng, W. Mao, D. Chen, Z. Wang, Prof. Dr. C. -H. Tung, Prof. Dr.
Z. Xu
Scheme 1. Asymmetric synthesis of a tricyclic hydronaphthofuran scaffold
and important biologically active compounds with a hydronaphthofuran core.
Key Lab for Colloid and Interface Chemistry of Education Ministry,
Department of Chemistry, Shandong University
No. 27 South Shanda Road, Jinan, 250100 (China)
E-mail: xuzh@sdu.edu.cn
The enyne (1a) was easily synthesized in one step by the
oxidative reaction of commerically available para-substituted
phenols. To test our hypothesis, the reaction of 1a with a terminal
alkyne (2a) in the presence of various rhodium catalysts was
examined (Table 1). In our previously described DCE/MeOH co-
solvent system,[9b] Rh(I)Cl/BINAP catalyst failed to deliver any
products (entries 1,2). When a cationic catalyst, Rh(cod)2BF4 was
employed, the bicyclic hydrobenzofuran product (5a) was the
Prof. Dr. Z. Xu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai, 200032, China
Supporting information for this article is available at
http://www.angewandte.org or from the author.
1
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10.1002/anie.201911071
Angewandte Chemie International Edition
Next we investigated the scope of this reaction in order to
establish a general method with which to synthesize fused
tricyclic scaffolds. As shown in Table 2, various enynes were
reacted with phenyl acetylene (2a) under the optimized conditions.
Substrates bearing various aliphatic groups such as ethyl,
isopropyl, diverse functionalized aliphatic groups, or a phenyl
group at the quaternary carbon center all reacted with 2a to give
the corresponding fused tricyclic compounds in high yields with
excellent regioselectivities and 97->99% ee values (3ba-3ga).
When the terminal methyl group was changed to an ethyl group,
another regioisomer (4ha) was the major product. These results
indicates that steric hindrance plays a very important role in the
regioselectivity of this reaction. The phenyl- substituted enyne
was almost unreactive and 4ia was isolated in low yield with 96%
ee. A nitrogen-tethered enyne was also prepared and reacted
with 2a at room temperature, regioisomer (4ja) was obtained as
the major isomer with over 99% ee.
major prodouct, and the target tricyclic product (3a) was isolated
in 24% yield (entry 3). It is impossible to generate 3a from 5a,
suggesting the desymmetric oxidative cyclization on Rh(I) is
possible. To further optimize the reaction conditions, the effect of
the solvent was investigated (entries 3-7). It was observed that
when protic solvent methanol was absent, 5a was not formed.
Chlorine-containing solvents gave better results, and the reaction
in CH2Cl2 led to the formation of product 3a with >99% ee in 77%
yield at room temperature (entry 5). Only trace amount of another
regioisomer (4a) was observed in this reaction. Other solvents
such as toluene and THF all produced inferior results (entries 6,
o
7). Increasing the reaction temperature to 40 C led to a much
higher yield of 85% with >99% ee in dichloroethane solution when
BINAP was used as the ligand (entry 8). Other commonly used
chiral bisphosphine ligands were also screened (entries 8-13) and
the most simple and generally used BINAP ligand proved to be
the best. Further increase in the temperature to 60 oC led to
slightly decreased yield and enantioselectivity (entry 14).
Increasing the concentration of both substrates with relatively
lower catalyst loading led to the formation of product 3a in 92%
yield and >99% ee. These reaction conditions were concluded to
be optimal (entry 15). Application of Ni(cod)2 in the place of the
rhodium catalyst failed to produce any desired product (entry 16).
Table 2. Substrate Scope of 1,6-enynes.[a]
Table 1. Optimization of reaction conditions.[a]
[a] Standard conditions were employed. Isolated yields were reported. [b] 80 oC.
[c] [Rh] (10 mol%), and ligand (10 mol%), rt, 40h.
The scope of alkynes was investigated extensively. As
summarized in Table 3, many chiral fused tricyclic
hydronaphthofurans were synthesized in good yields with
excellent enantioselectivity. For para-substituents in the aromatic
alkynes such as halogen (3ac-3ae), or electron-donating methyl
or methoxyl groups (3ab,3af), the regioisomer (3) was produced
in excellent yields with excellent regioselectivity and over 97% ee.
The absolute configuration of compound 3a was established as
(S,S,S) by X-ray diffraction of a single crystal of its pure
enantiomer.[11] Strong electron-withdrawing groups such as
trifluoromethyl (4ag), cyano (4ah), nitro (4ai) or an ester group
(4aj) at the para-position of the phenyl ring all led to the formation
of regioisomer 4 in good yields with excellent selectivity with the
same catalyst under slightly more dilute conditions. The structure
of 4 was characterized by NMR spectroscopy and further
confirmed by x-ray diffraction of a single crystal obtained from
racemic 4ai. Other 3-methyl (3ak) or free hydroxyl aromatic
compounds (3al), naphthyl (3am), thienyl (3an) and cyclohexenyl
(3ao) substituted terminal alkynes all produced regioisomer 3 in
good yields with 97-99% ee. Aliphatic alkynes reacted smoothly,
producing the corresponding fused tricyclic products with over
99% ee. Functional groups such as cyclopropyl, free hydroxyl,
and halogen are all tolerated. Boc-protected propargyl amine was
amenable to this transformation, giving the regioisomer (4au) as
the major product in 37% yield with 99% ee. Internal alkynes are
less reactive and there is competitive homodimerization of
enynes. Internal alkynes also reacted smoothly to give the
corresponding fused tricyclic compounds (3av, 3aw) in good
[a] Reaction conditions: A mixture of 1a (0.1 mmol), 2a (0.2 mmol), [Rh] (10
mol%), and ligand (10 mol%), solvent (2 mL). [b] Isolated yields of 3a were
reported, 3a/4a > 20/1. [c] Determined by HPLC analysis using a chiral
stationary phase. [d] 1a (0.2 mmol), 2a (0.4 mmol), Rh(cod)BF4 (5 mol%), and
L1 (5 mol%). IRr = 1,3-bis(2,6-diisopropyl-phenyl)imidazol-2-ylidene.
2
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10.1002/anie.201911071
Angewandte Chemie International Edition
yields with >99% ee when the loading of internal alkyne was
increased slightly to inhibit enyne homodimerization.
loss of enantiomeric purity was observed in all the above
transformations.
Table 3. Substrate Scope of Alkynes.[a]
Scheme 2. De novo construction of chiral tricyclic penta-substituted benzenoid
by [1.5]-H migration.
[a] Standard conditions were employed. Isolated yields were reported. [b] A
mixture of 1a (0.1 mmol), 2a (0.2 mmol), [Rh] (10 mol%), and ligand (10 mol%),
solvent (8 mL). [c] 80 oC. [d] 4 eqivalents of internal alkynes were used.
Scheme 3. Transformations to various unsaturated hydronaphthofurans.
The enone and diene moieties in the fused tricyclic structure
in the products are useful synthetic handles for further
transformations (Schemes 2, 3). In a gram-scale experiment,
product 3a was isolated in 82% yield with > 99% ee with only 2.5
mol% catalyst loading (Scheme 3). Upon treatment of 3 with NaH
under nitrogen atmosphere at room temperature, double bond
isomerization led to the formation of chiral tricyclic benzene
derivatives in 10 minutes, the structure of the product being
confirmed by X-ray crystallography (Scheme 2). Diverse
functionalized penta-substituted tricyclic benzene derivatives (6a-
6r) could be produced efficiently by this mild reaction. The
reaction may proceed via base-promoted enolization and [1,5]-H
migration. A one-pot cycloaddition/[1,5]-H migration aromatization
sequence could produce the tricyclic benzenoid compound (6r) in
62% yield with over 99% ee. This method offers an elegant
approach to the de novo construction of chiral penta-substituted
benzene derivatives.[12] Direct reduction of the ketone group in 3a
produced the allylic alcohol (7) in 80% yield with 8/1 dr (Scheme
3). Through DDQ oxidation, the tricyclic compound (8) was
formed in 65% yield. When 3a was treated with DBU under
aerobic conditions, epoxide 9 was isolated in 92% yield. The
structure and absolute configuration of 9 was established by X-
ray crystallography (Scheme 3). Epoxide 9 is a useful synthetic
intermediate, and could be transformed into the methoxyl-
substituted enone (10) by treatment with NaOMe in methanol. No
Scheme 4. Deuteration experiments.
Deuteration experiments were conducted to gain insight into the
reaction mechanism (Scheme 4). The deuterated alkynes 2a-D
and 2g-D were subjected to the reaction under standard
conditions or with added methanol, Deuterium was 100% retained
in both type of products [eq. (1, 2)]. Upon addition of MeOD to the
standard reaction of 2a and 2g, the tricyclic products were
foundto be deuterium-free [eq. (4, 5)]. However, the hydrogen of
α-methylene group of the by-product (5a) originated in the solvent
[eq. (3, 5)]. These results indicated Rh(I) acetylide is involved in
the formation of byproduct 5a, but is not formed in this [2+2+2]
cycloaddition reaction. Based on these experiments and previous
3
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10.1002/anie.201911071
Angewandte Chemie International Edition
reports,[7] a plausible catalytic cycle is proposed in Scheme 5.
Firstly, a desymmetric oxidative cyclization of 1a with Rh(I)/BINAP
occurs, leading to a chiral rhodacyclopentene (A), which could
exist in equilibrium with its enolate structure (A’). Alkyne
coordination followed by insertion to the triple bond generates the
rhodacycle C or C'. Because of the steric hindrance between the
R groups in the alkyne and ketone moieties, formation of C from
B is favored, and subsequent reductive elimination gives product
3, regenerating the Rh(I) catalyst (Path A). However, strong
electron-withdrawing groups may stabilize intermediate C' and
deliver the isomer 4 as the major product (Path B).
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Scheme 5. Proposed reaction mechanism.
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In summary, we have developed a new [2+2+2] cycloaddition
reaction to access the fused tricyclic hydronaphthofuran scaffold
with excellent chemo-, regio-, diastereo-, and enantioselectivity. A
desymmetric oxidative cyclization involving Rh(I) and subsequent
regioselective alkyne insertion mechanism is proposed for the
formation of two regioisomers. Prominent features of this
approach include use of easily available chiral BINAP ligands,
100% atom economy, a very broad substrate scope, and mild
reaction conditions. Further development of this desymmetric
cycloaddition strategy is in progress in our laboratory.
Acknowledgements
[11] CCDC 1938461(3a), 1943438 (4ai), 1915702(6a) and 1915701 (9)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] For de novo construction of benzene, see: a) Z. Lu, Y. Li, J. Deng, A. Li,
Nat. Chem. 2013, 5, 679; b) J. Li, P. Yang, M. Yao, J. Deng, A. Li, J. Am.
Chem. Soc. 2014, 136, 16477.
We are grateful for financial support from the Natural Science
Foundation of China (no. 21572118, 21971149) and Tang scholar
award and the Fundamental Research Funds of Shandong
University.
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Keywords: cycloaddition reactions ·asymmetric
catalysis · Desymmetric · rhodium
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Deslongchamps, J. Org. Chem. 2002, 67, 5269; c) S. Hanessian, N.
Boyer, G. J. Reddy, B. Deschênes-Simard, Org. Lett. 2009, 11, 4640.
4
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10.1002/anie.201911071
Angewandte Chemie International Edition
Synthetic Methods
Qi Teng, Wenxiu Mao, Dong Chen,
Zhen Wang, Chen-Ho Tung, and
Zhenghu Xu*
Page – Page
Asymmetric Synthesis of a Fused
tricyclic Hydronaphthofuran Scaffold
by
Desymmetric
[2+2+2]
Cycloaddition
A rhodium(I)-BINAP-catalyzed, highly enantioselective [2+2+2] cycloaddition of enynes
with alkynes has been developed. Diverse fused tricyclic hydronaphthofuran scaffolds
with three consecutive stereogenic centers were constructed in one step from easily
available materials with excellent chemo-, regio-, diastereo-, and enantioselectivity.
Notable features of these reactions include 100% atom-economy, very broad scope, and
mild reaction conditions
5
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