Highly Enantioselective Rhodium-Catalyzed Cross-Addition of Silylacetylenes to Cyclohexadienone-Tethered Internal Alkynes

Article abstract of DOI:10.1021/acs.orglett.9b00249

The first highly enantioselective rhodium-catalyzed cross-addition of silylacetylenes to cyclohexadienone-tethered internal alkynes has been achieved via a tandem process: regioselective alkynylation of the internal alkynes and subsequent intramolecular conjugate addition to the cyclohexadienones, affording the cis-hydrobenzofuran frameworks with good yields (up to 88% yield) and excellent enantioselectivities (90%-96% ee). This mild reaction showed perfect atom economy and broad functional group tolerance. Furthermore, a gram-scale experiment and diverse further conversions of the cyclization products were also presented.

Full text of DOI:10.1021/acs.orglett.9b00249

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Enantioselective Rhodium-Catalyzed Cross-Addition of
Silylacetylenes to Cyclohexadienone-Tethered Internal Alkynes
Chang-Lin Duan,†,§,⊥ Yun-Xuan Tan,‡,⊥ Jun-Li Zhang,† Shiping Yang,§ Han-Qing Dong,∥
Ping Tian,*,†,‡ and Guo-Qiang Lin*,†,‡
†The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of
Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
‡Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
§Department of Chemistry, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China
∥Arvinas, Inc., 5 Science Park 395 Winchester Avenue, New Haven, Connecticut 06511, United States
S
* Supporting Information
ABSTRACT: The first highly enantioselective rhodium-
catalyzed cross-addition of silylacetylenes to cyclohexadie-
none-tethered internal alkynes has been achieved via a tandem
process: regioselective alkynylation of the internal alkynes and
subsequent intramolecular conjugate addition to the cyclo-
hexadienones, affording the cis-hydrobenzofuran frameworks
with good yields (up to 88% yield) and excellent
enantioselectivities (90%−96% ee). This mild reaction showed
perfect atom economy and broad functional group tolerance.
Furthermore, a gram-scale experiment and diverse further
conversions of the cyclization products were also presented.
withdrawing group, and electron-deficient alkenes or isocya-
he carbon−carbon triple bond is an important and
Tpractical structure unit in modern organic synthesis nates (Scheme 1b).7e Notably, none of these alkynylative
because it could be functionalized using various methods.1
tandem reactions of internal alkynes generated chiral products.
To the best of our knowledge, the enantioselective alkynylative
tandem reactions of internal alkynes have not been reported yet.
Herein, we disclose the first chemo-, regio-, and enantioselective
rhodium-catalyzed alkynylation/intramolecular-conjugate-addi-
tion tandem reaction between silylacetylenes and cyclo-
hexadienone-tethered internal alkynes (Scheme 1c).
As part of our continuous efforts on transition-metal-catalyzed
tandem desymmetrization reactions of cyclohexadienones,8,9 we
envision that this rhodium-catalyzed alkynylative tandem
reaction would face three major challenges. The first is the
chemoselectivity: the rhodium acetylide should undergo cross-
addition with internal alkynes rather than conjugate addition to
enones. The second is the regioselectivity: such addition should
take place at outer sites of internal alkynes rather than inner
ones. The last is the enantioselectivity: a suitable catalytic system
should be found to effectively distinguish the prochiral
cyclohexadienones during the intramolecular 1,4-addition
(Scheme 1c).
The transition-metal-catalyzed direct alkynylation of unsatu-
rated compounds with a terminal alkyne has been widely
investigated and become an efficient, attractive, and atom-
economical tool to introduce an alkyne moiety.2−6 Among these,
the regio- and stereoselective cross-addition of terminal alkynes
to internal alkynes has been extensively developed using
palladium,6a,b,f,a,b,f,i−k iridium,6c rhodium,6d,e,g nickel,6g and
cobalt6h catalysts (Scheme 1a). However, such hydroalkynyla-
tion of internal alkynes could only construct a single carbon−
carbon bond. The simultaneous formation of two carbon−
carbon bonds, i.e., the alkynylative tandem reactions of internal
alkynes with terminal alkynes, are relatively uncommon.7 In
1997, Trost and co-workers reported the cross-trimerization of
1-phenylsulfonyl-1-propyne with either propargyl alcohol or
phenylacetylene in the presence of a palladium catalyst.7a In this
case, the initial cross-coupling adduct further reacted with the
excessive 1-phenylsulfonyl-1-propyne. Then, Ogata, Fukuzawa,
and co-workers demonstrated nickel-catalyzed highly regio-,
chemo-, and stereoselective cross-trimerization, in which bulky
triisopropylsilylacetylene could react with two internal alkynes
(either the same or different).7b,c Recently, Tanaka and co-
workers realized an extraordinary rhodium-catalyzed highly
chemoselective three-component cross-addition of terminal
silylacetylenes, activated internal alkynes bearing an electron-
With these considerations in mind, a series of privileged chiral
ligands and rhodium precatalysts were screened for the
rhodium-catalyzed cross-addition of terminal silylacetylene 2a
Received: January 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00249
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Strategic Design
Table 1. Selected Optimization Studies
to cyclohexadienone-tethered internal alkyne 1a, and selected
results were summarized in Table 1.10 The use of (S)-Binap
(L1) as a ligand and [Rh(coe)2Cl]2 as a precatalyst afforded the
desired alkynylative cyclization product 3aa with good yield and
high enantioselectivity (Table 1, entry 1). Next, several
bisphosphine ligands including (R)-Segphos (L2), (S)-
DTBM-Segphos (L3), (R,R)-Ph-BPE (L4), and (R,Sp)-Josiphos
(L5) were tested. Only L2 could offer a satisfactory result with
an enantioselectivity up to 96% ee (Table 1, entries 2−5).
Moreover, the chiral diene ligand L6 failed to give the desired
product,11 which is probably because the Rh/diene catalyst has a
shorter lifetime and quickly loses its catalytic activity during the
reaction (Table 1, entry 6).2p Then, the reaction yield could be
further improved to 70% when the rhodium precatalyst was
switched to Rh(nbd)2BF4 (Table 1, entries 7−8). Increasing or
decreasing the loading of 2a had no obvious effect on the yield
and enantioselectivity (Table 1, entries 9−10). In addition,
lowering the reaction temperature resulted in a big erosion of the
yield (Table 1, entry 11). More importantly, the desired
alkynylative cyclization product 3aa could not be detected in the
absence of Cs2CO3, indicating the essential role of the base
additives in this catalytic system (Table 1, entry 12).
With the optimized reaction conditions in hand, the scope of
the cyclohexadienone-tethered internal alkynes 1 was examined.
Various R1 substituents in the cyclohexadienone-tethered
internal alkynes 1, such as a simple alkyl, cyclohexyl, sterically
hindered adamantyl, benzyl, vinyl, allyl, and phenyl group, could
be well tolerated, and the reactions proceeded smoothly with
good to high yields (60%−88%) and excellent enantioselectiv-
ities (Scheme 2, 3aa−3ka, 90%−96% ee). Furthermore, diverse
functional groups, such as ester, silyl ether, sulfonyl ester, and
halogens (Cl, Br, I), were well tolerant, and the corresponding
alkynylative cyclization products could be obtained with great
enantioselectivities (Scheme 2, 3la−3ra, 90%−94% ee). As for
substrate 1s derived from estrone, L2 and ent-L2 ligands led to
similar yields, but with opposite diastereoselectivities, revealing
that the formation of diastereomers in this case was completely
controlled by the chiral ligand. To our delight, alkyl- and phenyl-
a
b
Reactions were performed under an Ar atmosphere. Determined by
c
1H NMR analysis of unpurified mixtures. Determined by HPLC
analysis. At 60 °C. In the absence of Cs2CO3.
d
e
substituted internal alkynes were also feasible, and only the
phenyl-substituted substrate resulted in a slight decrease of the
yield (Scheme 2, 3ua). More surprisingly, the R2 substituents
containing alkyl ether, ester, and silyl ether were also compatible
in this reaction, affording the corresponding alkynylative
cyclization products with good yields and favorable enantiose-
lectivities (Scheme 2, 3va−3ya, 63%−73% yields, 92%−94%
ee). As for terminal alkyne substrate 1z, the desired cyclization
product was also obtained, albeit with a 22% yield and 70% ee
(Scheme 2, 3za).
Next, several terminal alkynes 2 were evaluated (Scheme 3).
When trimethylsilylacetylene (2b), tert-butyl acetylene (2e),
and methyl propiolate (2f) were individually applied to this
reaction, no desired products were detected due to the
homodimerization as the main side reaction for these less
bulky terminal alkynes.2b The larger substituents including SiEt3
and Si(t-Bu)Me2 at silylacetylenes could still generate the
desired products with moderate yields and excellent enantiose-
lectivities (Scheme 3, 3ac−3ad, 59%−68% yields, 90%−92%
ee).
To demonstrate the synthetic utility of this rhodium-catalyzed
alkynylative cyclization reaction, a gram-scale experiment was
carried out, and the corresponding cyclization product 3aa was
isolated with good yield and constant enantioselectivity
(Scheme 4). Then, several transformations of 3aa were
conducted to display the applications of the alkynyl unit.
B
DOI: 10.1021/acs.orglett.9b00249
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of 1,6-Enynes
Scheme 4. Gram-Scale Experiment and Several
Transformations
1-bromo-4-iodobenzene proceeded smoothly to form the aryl-
substituted internal alkyne.12 The triazole product 6aa could be
easily obtained through a copper-catalyzed click reaction
between 4aa and benzyl azide.13 Moreover, the terminal alkyne
4aa could undergo silver-mediated bromination to afford 7aa in
high yield.14 Finally, in order to determine the absolute
configurations of the cyclization products, 3ma was converted
to a known chiral tricyclic product (R,R,R)-4ma through a two-
step sequence including removal of the acetyl group in 3ma and
a simultaneous oxa-Michael addition under basic conditions and
a subsequent ozonation reaction.8a,15
In conclusion, we have developed the first highly chemo-,
regio-, and enantioselective rhodium-catalyzed alkynylation/
intramolecular conjugate addition tandem reaction between
terminal silylacetylenes and cyclohexadienone-tethered internal
alkynes. This tandem process showed perfect atom economy
and broad functional group tolerance and could conveniently
afford optically pure cis-hydrobenzofuran skeletons containing a
versatile silylacetylene fragment. Additionally, the cyclization
products could be readily applied to diverse further function-
alizations. Further studies on the transition-metal-catalyzed
tandem desymmetrization reactions of cyclohexadienone-
tethered alkynes are underway and will be disclosed in due
course.
a
b
Reactions were performed under an Ar atmosphere. Yield of
c
isolated product 3. Determined by HPLC analysis.
a
Scheme 3. Scope of Silylacetylenes
a
b
ASSOCIATED CONTENT
* Supporting Information
■
Reactions were performed under an Ar atmosphere. Yield of
c
S
isolated product 3. Determined by HPLC analysis.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00249.
Protodesiliconation of 3aa with TBAF afforded the terminal
alkyne 4aa, which could undergo diverse transformations. For
example, Sonogashira coupling of the terminal alkyne 4aa with
Experimental procedures, spectra for all new compounds
(PDF)
C
DOI: 10.1021/acs.orglett.9b00249
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2008, 3405. (c) Xu, H.-D.; Zhang, R.-W.; Li, X.; Huang, S.; Tang, W.;
Hu, W.-H. Org. Lett. 2013, 15, 840. (d) Trost, B. M.; Masters, J. T.
Chem. Soc. Rev. 2016, 45, 2212. (e) Zhou, Y.; Zhang, Y.; Wang, J. Org.
Biomol. Chem. 2016, 14, 6638. (f) Liang, Q.; Osten, K. M.; Song, D.
Angew. Chem., Int. Ed. 2017, 56, 6317. (g) Xu, D.; Sun, Q.; Quan, Z.;
Wang, X.; Sun, W. Asian J. Org. Chem. 2018, 7, 155.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tianping@sioc.ac.cn; tianping@shutcm.edu.cn.
*E-mail: lingq@sioc.ac.cn.
ORCID
(6) For selected transition-metal-catalyzed alkynylation of internal
alkynes, see: (a) Trost, B. M.; Chan, C.; Ruhter, G. J. Am. Chem. Soc.
̈
Shiping Yang: 0000-0001-7527-4581
Ping Tian: 0000-0002-5612-0664
Author Contributions
⊥C.-L.D. and Y.-X.T. contributed equally.
1987, 109, 3486. (b) Chen, L.; Li, C.-J. Tetrahedron Lett. 2004, 45,
2771. (c) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. Adv. Synth. Catal.
2005, 347, 872. (d) Ito, J.; Kitase, M.; Nishiyama, H. Organometallics
2007, 26, 6412. (e) Nishimura, T.; Guo, X.-X.; Ohnishi, K.; Hayashi, T.
Adv. Synth. Catal. 2007, 349, 2669. (f) Tsukada, N.; Ninomiya, S.;
Aoyama, Y.; Inoue, Y. Org. Lett. 2007, 9, 2919. (g) Matsuyama, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 3576.
(h) Sakurada, T.; Sugiyama, Y.-K.; Okamoto, S. J. Org. Chem. 2013, 78,
3583. (i) Liu, G.; Kong, W.; Che, J.; Zhu, G. Adv. Synth. Catal. 2014,
356, 3314. (j) Babu, M. H.; Dwivedi, V.; Kant, R.; Reddy, M. S. Angew.
Chem., Int. Ed. 2015, 54, 3783. (k) Trost, B. M.; Masters, J. T.; Taft, B.
R.; Lumb, J. P. Chem. Sci. 2016, 7, 6217.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was generously provided by the NSFC (Nos.
21871184, 21572251, and 21572253), the SMEC (No. 2019-
01-07-00-10-E00072), the STCSM (No. 18401933500), the
973 Program (No. 2015CB856600), and the CAS (Nos. XDB
20020100 and QYZDY-SSW-SLH026).
(7) For selected transition-metal-catalyzed alkynylative tandem
reactions of internal alkynes, see: (a) Trost, B. M.; Sorum, M. T.;
̈
Chan, C.; Harms, A. E.; Ruhter, G. J. Am. Chem. Soc. 1997, 119, 698.
(b) Ogata, K.; Murayama, H.; Sugasawa, J.; Suzuki, N.; Fukuzawa, S.-i.
J. Am. Chem. Soc. 2009, 131, 3176. (c) Ogata, K.; Sugasawa, J.;
Fukuzawa, S.-i. Angew. Chem., Int. Ed. 2009, 48, 6078. (d) Shibata, Y.;
Tanaka, K. Angew. Chem., Int. Ed. 2011, 50, 10917. (e) Hoshino, Y.;
Shibata, Y.; Tanaka, K. Angew. Chem., Int. Ed. 2012, 51, 9407.
(8) For a selection of our work on transition-metal-catalyzed
desymmetrization of cyclohexadienones, see: (a) He, Z.-T.; Tian, B.;
Fukui, Y.; Tong, X.; Tian, P.; Lin, G.-Q. Angew. Chem., Int. Ed. 2013, 52,
5314. (b) Liu, P.; Fukui, Y.; Tian, P.; He, Z.-T.; Sun, C.-Y.; Wu, N.-Y.;
Lin, G.-Q. J. Am. Chem. Soc. 2013, 135, 11700. (c) Fukui, Y.; Liu, P.;
Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.; Lin, G.-Q. J. Am. Chem. Soc.
2014, 136, 15607. (d) He, Z.-T.; Tang, X.-Q.; Xie, L.-B.; Cheng, M.;
Tian, P.; Lin, G.-Q. Angew. Chem., Int. Ed. 2015, 54, 14815. (e) Tan, Y.-
X.; Tang, X.-Q.; Liu, P.; Kong, D.-S.; Chen, Y.-L.; Tian, P.; Lin, G.-Q.
Org. Lett. 2018, 20, 248.
(9) For selected recent work by other groups on transition-metal-
catalyzed desymmetrization of cyclohexadienones, see: (a) Tello-
Aburto, R.; Kalstabakken, K. A.; Harned, A. M. Org. Biomol. Chem.
2013, 11, 5596. (b) Keilitz, J.; Newman, S. G.; Lautens, M. Org. Lett.
2013, 15, 1148. (c) Kalstabakken, K. A.; Harned, A. M. Tetrahedron
2014, 70, 9571. (d) He, C.; Zhu, C.; Dai, Z.; Tseng, C.-C.; Ding, H.
Angew. Chem., Int. Ed. 2013, 52, 13256. (e) Clarke, C.; Incerti-Pradillos,
C. A.; Lam, H. W. J. Am. Chem. Soc. 2016, 138, 8068. (f) Kumar, R.;
Hoshimoto, Y.; Tamai, E.; Ohashi, M.; Ogoshi, S. Nat. Commun. 2017,
8, 32. (g) Chen, J.; Han, X.; Lu, X. Angew. Chem., Int. Ed. 2017, 56,
14698. (h) Zhou, X.; Pan, Y.; Li, X. Angew. Chem., Int. Ed. 2017, 56,
8163. (i) Lu, H.; Fan, Z.; Xiong, C.; Zhang, A. Org. Lett. 2018, 20, 3065.
(j) Shu, T.; Zhao, L.; Li, S.; Chen, X.-Y.; von Essen, C.; Rissanen, K.;
Enders, D. Angew. Chem., Int. Ed. 2018, 57, 10985. (k) Liu, B.; Li, J.; Hu,
P.; Zhou, X.; Bai, D.; Li, X. ACS Catal. 2018, 8, 9463.
REFERENCES
■
(1) For selected recent reviews, see: (a) Stang, P. J.; Diederich, F.
Modern Acetylene Chemistry; Wiley-VCH: Weinheim, 1995. (b) Scho-
bert, H. Chem. Rev. 2014, 114, 1743. (c) Trost, B. M.; Li, C.-J. Modern
Alkyne Chemistry; Wiley-VCH: Weinheim, 2015.
(2) For selected transition-metal-catalyzed alkynylation of alkenes,
see: (a) Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am.
Chem. Soc. 2005, 127, 9682. (b) Nishimura, T.; Guo, X.-X.; Uchiyama,
N.; Katoh, T.; Hayashi, T. J. Am. Chem. Soc. 2008, 130, 1576.
(c) Nishimura, T.; Tsurumaki, E.; Kawamoto, T.; Guo, X.-X.; Hayashi,
T. Org. Lett. 2008, 10, 4057. (d) Fillion, E.; Zorzitto, A. K. J. Am. Chem.
Soc. 2009, 131, 14608. (e) Nishimura, T.; Sawano, T.; Hayashi, T.
Angew. Chem., Int. Ed. 2009, 48, 8057. (f) Nishimura, T.; Tokuji, S.;
Sawano, T.; Hayashi, T. Org. Lett. 2009, 11, 3222. (g) Nishimura, T.;
Sawano, T.; Tokuji, S.; Hayashi, T. Chem. Commun. 2010, 46, 6837.
(h) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132,
10275. (i) Nishimura, T.; Sawano, T.; Ou, K.; Hayashi, T. Chem.
Commun. 2011, 47, 10142. (j) Fan, B.-M.; Yang, Q.-J.; Hu, J.; Fan, C.-
L.; Li, S.-F.; Yu, L.; Huang, C.; Tsang, W. W.; Kwong, F. Y. Angew.
Chem., Int. Ed. 2012, 51, 7821. (k) Sawano, T.; Ashouri, A.; Nishimura,
T.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 18936. (l) Sawano, T.; Ou,
K.; Nishimura, T.; Hayashi, T. Chem. Commun. 2012, 48, 6106.
(m) Fan, B.; Xu, J.; Yang, Q.; Li, S.; Chen, H.; Liu, S.; Yu, L.; Zhou, Y.;
Wang, L. Org. Lett. 2013, 15, 5956. (n) Harada, A.; Makida, Y.; Sato, T.;
Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2014, 136, 13932. (o) Bai,
X.-Y.; Wang, Z.-X.; Li, B.-J. Angew. Chem., Int. Ed. 2016, 55, 9007.
(p) Dou, X.; Huang, Y.; Hayashi, T. Angew. Chem., Int. Ed. 2016, 55,
1133. (q) Wang, Z.-X.; Bai, X.-Y.; Yao, H.-C.; Li, B.-J. J. Am. Chem. Soc.
2016, 138, 14872. (r) Wang, Z.-X.; Bai, X.-Y.; Li, B.-J. Synlett 2017, 28,
509. (s) Bai, X.-Y.; Zhang, W.-W.; Li, Q.; Li, B.-J. J. Am. Chem. Soc.
2018, 140, 506. (t) Chen, Y.; Wang, Z.-X.; Li, Q.; Xu, L.-J.; Li, B.-J. Org.
Chem. Front. 2018, 5, 1815. (u) Choo, K. L.; Lautens, M. Org. Lett.
2018, 20, 1380.
(10) For more details, see the Supporting Information.
(11) (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem.
Soc. 2007, 129, 5336. (b) Tian, P.; Dong, H.-Q.; Lin, G.-Q. ACS Catal.
2012, 2, 95.
(12) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(13) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(14) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E.
L. Org. Lett. 2004, 6, 1151.
(3) For selected transition-metal-catalyzed alkynylation of 1,3-dienes,
see: (a) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410.
(b) Shirakura, M.; Suginome, M. Angew. Chem., Int. Ed. 2010, 49, 3827.
(4) For selected transition-metal-catalyzed alkynylation of allenes, see:
(a) Nishimura, T.; Guo, X.-X.; Hayashi, T. Chem. - Asian J. 2008, 3,
1505. (b) Sawano, T.; Ou, K.; Nishimura, T.; Hayashi, T. J. Org. Chem.
2013, 78, 8986. (c) Grugel, C. P.; Breit, B. Org. Lett. 2018, 20, 1066.
(d) Pradhan, T. R.; Kim, H. W.; Park, J. K. Angew. Chem., Int. Ed. 2018,
57, 9930.
(15) The absolute configuration of 3ma was determined to be (S,S)-
(−) by correlation with 4ma.
(5) For selected transition-metal-catalyzed dimerization of terminal
alkynes, see: (a) Yang, C.; Nolan, S. P. J. Org. Chem. 2002, 67, 591.
(b) Katagiri, T.; Tsurugi, H.; Satoh, T.; Miura, M. Chem. Commun.
D
DOI: 10.1021/acs.orglett.9b00249
Org. Lett. XXXX, XXX, XXX−XXX