Stereoselective Radical Cyclization Cascades Triggered by Addition of Diverse Radicals to Alkynes to Construct 6(5)-6-5 Fused Rings

Article abstract of DOI:10.1021/acs.orglett.6b02599

Cascade radical cyclization of alkynyl ketones with various carbon- and heteroatom-centered radical precursors via a sequential radical addition/1,5-H radical shift/5-exo-trig/radical cyclization process was realized for the first time. This method provides a strategically novel and step-economical protocol for diversity-oriented synthesis of a wide range of carbocyclic and heterocyclic 6(5)-6-5 fused ring systems with three contiguous stereocenters, including a quaternary carbon in high yields with excellent chemo- and diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.6b02599

Letter
pubs.acs.org/OrgLett
Stereoselective Radical Cyclization Cascades Triggered by Addition
of Diverse Radicals to Alkynes To Construct 6(5)−6−5 Fused Rings
Lin Huang,† Liu Ye,† Xiao-Hua Li,† Zhong-Liang Li, Jin-Shun Lin, and Xin-Yuan Liu*
Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: Cascade radical cyclization of alkynyl ketones
with various carbon- and heteroatom-centered radical precursors
via a sequential radical addition/1,5-H radical shift/5-exo-trig/
radical cyclization process was realized for the first time. This
method provides a strategically novel and step-economical
protocol for diversity-oriented synthesis of a wide range of
carbocyclic and heterocyclic 6(5)−6−5 fused ring systems with
three contiguous stereocenters, including a quaternary carbon in high yields with excellent chemo- and diastereoselectivity.
omplex carbon- or heteroatom-containing n−6−5 fused
ring systems (n = 5 or 6) with multiple stereocenters are
privileged structural motifs found in natural products and
pharmaceutical compounds with important biological properties
(Figure 1). For example, pycnanthuquinones A−C display
unactivated alkynes is an especially attractive approach for the
direct functionalization of alkynes as the alkyne is an easily
accessible building block.6 In this context, initiated by pioneering
works of Heiba and Dessau,7d Curran,7e−g Renaud,7h−j and
others, the tandem H atom translocation/cyclization process
triggered by vinyl radical intermediates7 has attracted consid-
erable attention for constructing a wide range of five-membered
rings. Inspired by these seminal works and driven by our
continued interest in the area of radical chemistry,8 we
envisioned that such inherently high-energy σ-type vinyl
radicals,7 which could be in situ generated from addition of a
variety of radicals to unactivated alkynes, would provide a driving
force to undergo cascade 1,5-H radical shift/5-exo-trig/radical
cyclization process (Scheme 1).
C
Figure 1. Representative natural products with a 6−6−5 fused ring.
Scheme 1. Synthetic Strategy
antihyperglycemic activity in mice.1 (−)-Epipodophyllotoxin
represents the aglycon of the potent clinical antitumor drugs
etoposide and teniposide for the treatment of small cell lung
cancer and Kaposi’s sarcoma.2 Therefore, considerable efforts
have been devoted to the development of new and simple
methods for the construction of such fused tricyclic frameworks.3
Although significant progress has been made, some crucial and
challenging issues are far from being fully addressed, such as
limited product scope, step-economy and starting material
accessibility, and achievement of high degrees of stereocontrol in
these stereocenter-abundant systems. Development of a new and
efficient protocol for diversity-oriented synthesis of functionally,
skeletally, and stereochemically diverse tricyclic scaffolds is
highly desired.
Ingenious design and applications of radical cascade
cyclizations have emerged as a powerful strategy to construct
complex molecular scaffolds.4 Note that several cascade
cyclizations have been efficiently applied to the total synthesis
of complex natural products, such as scholarisine A,5a
barbiturates,5b and ophiobolin sesterterpene.5c However,
addition of carbon- and heteroatom-centered radicals to
Herein, we report a new, efficient, and general cascade radical
cyclization protocol for diversity-oriented synthesis of carbocy-
clic and heterocyclic fused tricyclic frameworks with three
contiguous stereocenters, including a quaternary carbon from
readily available alkynyl ketones, in which three new carbon−
carbon bonds and two rings are simultaneously formed in a
cascade process in high yields with excellent chemo- and
Received: August 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02599
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
diastereoselectivity. In the context of a diversity-oriented
synthesis of fused tricyclic frameworks, the current protocol
displays some exceptional advantages. (1) Functional group
diversity: a variety of carbon- and heteroatom-centered radical
sources, including trifluoromethyl, difluoromethyl, perfluoroalk-
yl, and sulfonyl radical, are compatible. (2) Skeleton diversity:
various carbocyclic and heterocyclic 6(5)−6−5 fused ring
systems are easily collected. (3) Efficient control of chemo-
and diastereoselectivity of multiple stereocenters is realized
under mild synthetic conditions from easily available acyclic
precursors.
Scheme 3. Substrate Scope of Alkynyl Ketones
Selective incorporation of a CF3 group into drug molecules
may lead to significant improvement in the drug’s pharmacoki-
netic properties, binding selectivity, and metabolic stability.9 We
began our investigation by exploring a radical trifluoromethyla-
tion system6b,d,f using the model reaction of alkynyl ketone 1a
with Togni’s reagent 2a (Scheme 2; see Table S1 for details).10
Scheme 2. Optimization of Model Reaction
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), DBN (20 mol
b
%), solvent (4 mL) at 80 °C for 12 h under argon. Yield of isolated
product. DBN (10 mol %) for 24 h. DBN (20 mol %) for 24 h; 20%
c
d
of 1p was recovered.
only 10 mol % of DBN as the catalyst. Notably, internal alkyne 1p
bearing a methyl group proved to be a suitable substrate, giving
3p in 50% yield along with 20% recovery of 1p. The structure and
relative configuration of 3l were further confirmed by X-ray
crystallographic analysis (Scheme 3).
To expand the synthetic utility of this methodology, we next
focused on other more sterically hindered alkynyl 1,3-dicarbonyl
substrates, which would offer a novel and promising method to
synthesize cyclopenta[b]hydronaphthalenes with three contig-
uous stereocenters including a quaternary carbon (Scheme 4).
Since copper salts were used to activate 2a to generate the CF3
radical, different Cu(I) salts were first examined as the catalysts.
In the presence of these catalysts, reaction of 1a with 2a gave the
desired products 3a and 3a′ in 78−81% total yields with almost
complete chemoselectivity after 24 h. However, only poor
diastereoselectivity was observed in all cases. To improve the
diastereoselectivity, we evaluated different pyridine-based
bidentate ligands but with little improvement. Finally, inspired
by the success of our recently developed organic base-catalyzed
radical trifluoromethylation of alkenes,8b,d we envisioned that an
organic base may be a suitable catalyst to realize such cyclizations
via a SET process to activate 2a. We screened a series of
phosphines and amines under otherwise identical conditions.
Use of DBN resulted in a significantly increased diastereose-
lectivity of up to 14:1 with 73% yield. Furthermore, an obvious
solvent effect was observed, and the best results (81% yield with
>20:1 dr) were obtained with CH3CN as the solvent. The
observed excellent diastereoselectivity using DBN might be
attributed to its strong basicity, which could epimerize 3a′ to give
the more stable cis-fused 3a.
a b
,
Scheme 4. Substrate Scope of Alkynyl 1,3-Dicarbonyls
With the optimized conditions, we next investigated the
substrate scope of alkynyl ketones with diverse substituents
(Scheme 3). A variety of alkynyl aryl ketones, bearing either
electron-donating groups (R = CH3, OMe) or electron-
withdrawing groups (R = Br, Cl, CN, NO2) at the para position
of the phenyl ring, reacted smoothly with 2a, affording 3b−3g in
66−88% yields with excellent diastereoselectivity. Substrate with
meta-substituent (3-Br) in the phenyl ring gave two regioisomers,
3h and 3h′, in 85% yield with a regioselectivity of 3:1. This
reaction shows excellent compatibility with disubstituted phenyl
and heteroaromatic groups, yielding the 6−6−5 fused ring 3i and
5−6−5 fused ring 3j in 83 and 65% yields. Furthermore,
substrates bearing other tethered groups, such as malononitrile-
and oxygen-tethered 1k−1m, were also well-tolerated to give
final products 3k−3m in 52−72% yields. Most importantly, 1n
and 1o without any tether were also applicable to this process,
affording 3n and 3o in 64 and 84% yields, respectively, even with
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), DBN (10 mol
b
%), solvent (4 mL) at 80 °C for 48 h under argon. Yield of isolated
product. TBD (10 mol %) for 48 h. TBD = 1,5,7-triazabicyclo[4.4.0]-
dec-5-ene.
c
After systematic optimization of different reaction parameters,
we found that 1q with a 1,3-diketone group was efficiently
converted to 3q in 61% yield with excellent diastereoselectivity
with 10 mol % of TBD. A variety of functional groups including
1,3-diketone (1r) and β-ketone ester (1s,1t) were also
compatible with the current system in the presence of TBD or
DBN, affording 3r−3t in 55−65% yield with excellent
diastereoselectivity. Most importantly, 1u with a diester-tethered
B
DOI: 10.1021/acs.orglett.6b02599
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Letter
group was also suitable, and 3u bearing densely multiple
substituents was isolated in 89% yield.
To further evaluate the practicality of the process, reaction was
carried out on a gram scale. There was no change in reactivity and
almost no influence on the chemical yield and stereoselectivity
(1.24 g, 86% yield along with >20:1 dr for 3d) (Scheme S1, eq 1).
Reduction of 3e by NaBH4 generated the desired product with
four contiguous stereocenters (Scheme S1, eq 2), an important
structural motif presented in biologically active pycnanthuqui-
nones A−C (Figure 1).
We next extended other radical precursors. In recent years,
visible-light-driven photoredox catalysis has become an eco-
friendly and powerful tool for the generation of various radical
species.11 As expected, reaction of 1c and 1e with p-
toluenesulfonyl chloride (4) under visible light photoredox
catalysis conditions12 delivered sulfonyl-containing fused rings in
good yields with poor diastereoselectivity. Diastereoselectivity
was significantly improved to >20:1 after in situ treatment of the
reaction mixture with DBN at 60 °C for 6 h (Scheme 5). For
To gain more insight into the reaction mechanism, a series of
control experiments were performed. We recently developed N-
hydroxyphthalimide for reduction of 2a to generate CF3 and
short-lived phthalimide-N-oxyl radical (PINO).8e The reaction
of PINO with alkyl radical C (Scheme 1) provides 13 in 94%
yield with PINO−CF3 14 in 36% yield (Scheme S2) when
alkynyl ketone 11 with a methyl group was used as the substrate
under the standard conditions. These results also support that C
was generated through a cascade radical process triggered by
addition of radicals to alkyne. An isotopic experiment supported
that the 1,5-H radical shift process, established by Renaud,7h−j
might be involved in this transformation (Scheme S3).
Scheme 5. Substrate Scope with Sulfonyl Chlorides
On the basis of these results and previous reports,7,8
a
proposed pathway for the formation of fused rings including a
quaternary carbon is depicted in Scheme 7. Initially, a variety of
Scheme 7. Plausible Catalytic Cycle
a
Reaction conditions: 1 (0.2 mmol), 4 (0.4 mmol), Na2HPO4 (0.4
mmol), [Ir] = [Ir(dtbbpy)(ppy)2PF6 (1 mol %)], EA (4 mL), blue
b
c
LED at rt for 12 h under argon. Yield of isolated product. The dr
ratio was obtained when the crude mixture was further treated with
d
DBN (1.2 mmol) at 60 °C for 6 h. Reaction conditions: 1 (0.2
mmol), 6 (0.4 mmol), Na2HPO4 (0.4 mmol), lr(ppy)3 (1 mol %), EA
(4 mL), blue LED at rt for 12 h under argon. Yield of isolated product.
sterically hindered alkynyl 1,3-dicarbonyl substrates 1u−1w,
fused ring compounds 5u−5w were obtained in 62−73% yields
with excellent diastereoselectivity under standard conditions
without any organic base. The structure and relative config-
uration of 5u were further confirmed by X-ray crystallographic
analysis (Scheme 5). Success of C4F9 radical installation to
generate 7c, 7u, and 7w in 63−73% yields with >20:1 dr achieved
with perfluorobutanesulfonyl chloride (6)13 via extrusion of
sulfur dioxide under similar reaction conditions demonstrates the
utility of the present methodology to introduce a perfluoroalkyl
group to fused ring systems via a radical process (Scheme 5).
To further expand this methodology and in light of the
increasing importance of the difluoromethylene group (CF2) in
drug and agrochemical design,9 we investigated the reaction of
alkynyl ketones with EtO2CCF2I 8 as the radical precursor14
under visible light photoredox catalysis conditions. Gratifyingly,
under the reaction conditions similar to those of Scheme 5, the
CF2-incorporated cyclopenta[b]hydronaphthalenes 9c and 9e
were obtained via CF2 radical-initiated cascade cyclization in
moderate yields with excellent diastereoselectivity (Scheme 6).
radicals could be generated in situ under different reaction
conditions. In situ generated radical species attack alkyne,
affording a nascent σ-type vinyl radical intermediate A, followed
by 1,5-H radical shift to generate a lower-energy carbonyl-
stabilized radical B.8 Once formed, B undergoes 5-exo-trig
cyclization via Ts1 or Ts2 to form C′ or C, respectively. As 5-exo-
trig cyclization is expected to be rapid and reversible in the
presence of multiple radical-stabilizing carbonyl groups,15
C
having a pseudoequatorial A group would undergo an radical
cyclization via Ts3 due to less steric reasons, which enables
excellent diastereocontrol to give intermediate D. Finally,
deprotonation of D to give E followed by single-electron
oxidation takes place to furnish the final product.6e,16 An
alternative pathway via single-electron oxidation and deproto-
nation cannot be ruled out.6 However, the origin of excellent
diastereoselectivity observed in this reaction remains unclear and
deserves further detailed studies.
Scheme 6. Substrate Scope with EtO2CCF2I
In conclusion, we have successfully developed the first cascade
radical cyclization of easily available alkynyl ketones via a
sequential 1,5-H radical shift/5-exo-trig/radical cyclization
process triggered by radical trifluoromethylation, sulfonylation,
C
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reaction provides a new facile and straightforward approach for
the diversity-oriented synthesis of carbocyclic and heterocyclic
fused tricyclic frameworks with three contiguous stereocenters,
including a quaternary carbon in high yields, with excellent
chemo- and diastereoselectivity. To the best of our knowledge,
this is the first example using in situ generated vinyl radicals as the
key intermediate in cascade radical cyclizations for the
construction of 6(5)−6−5 fused rings, which would provide a
particularly advantageous alternative to the traditional tandem H
atom translocation/cyclization process triggered by vinyl
radicals.7
ASSOCIATED CONTENT
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X-ray data for 3l (CIF)
X-ray data for 5u (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Den
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*E-mail: liuxy3@sustc.edu.cn.
Author Contributions
†L.H., L.Y., and X.-H.L. contributed equally to this work.
Notes
(8) (a) Yu, P.; Lin, J.-S.; Li, L.; Zheng, S.-C.; Xiong, Y.-P.; Zhao, L.-J.;
Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed. 2014, 53, 11890. (b) Yu, P.;
Zheng, S.-C.; Yang, N.-Y.; Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed.
2015, 54, 4041. (c) Huang, L.; Lin, J.-S.; Tan, B.; Liu, X.-Y. ACS Catal.
2015, 5, 2826. (d) Yang, N.-Y.; Li, Z.-L.; Ye, L.; Tan, B.; Liu, X.-Y. Chem.
Commun. 2016, 52, 9052. (e) Huang, L.; Zheng, S.-C.; Tan, B.; Liu, X.-Y.
Org. Lett. 2015, 17, 1589.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Foundation
of China (Nos. 21572096, 21302088), Shenzhen overseas high
level talents innovation plan of technical innovation project
(KQCX20150331101823702), and Shenzhen special funds for
the development of biomedicine, Internet, new energy, and new
material industries (JCYJ20150430160022517) is greatly
appreciated.
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