Gold-Catalyzed Tandem 1,3-Migration/Double Cyclopropanation of 1-Ene-4,n-diyne Esters to Tetracyclodecene and Tetracycloundecene Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b02404

A synthetic method that relies on Au(I)-catalyzed tandem 1,3-acyloxy migration/double cyclopropanation of 1-ene-4,9-diyne and 1-ene-4,10-diyne esters to construct the respective architecturally challenging tetracyclodecene and tetracycloundecene derivatives is described. Achieved under mild reaction conditions, the transformation was shown to be robust with a wide variety of substitution patterns tolerated to give the two members of the carbocyclic family in good to excellent yields and as a single regio- and diastereomer.

Full text of DOI:10.1021/acs.orglett.6b02404

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Tandem 1,3-Migration/Double Cyclopropanation of
1‑Ene-4,n‑diyne Esters to Tetracyclodecene and Tetracycloundecene
Derivatives
Cuili Chen,† Yongzhen Zou,† Xianxiao Chen,† Xiaoxiang Zhang,† Weidong Rao,*,†
and Philip Wai Hong Chan*,‡,§
†Jiangsu Key Laboratory of Biomass-based Green Fuels and Chemicals, College of Chemical Engineering, Nanjing Forestry
University, Nanjing 210037, China
‡School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
§Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom
S
* Supporting Information
ABSTRACT: A synthetic method that relies on Au(I)-catalyzed
tandem 1,3-acyloxy migration/double cyclopropanation of 1-ene-4,9-
diyne and 1-ene-4,10-diyne esters to construct the respective
architecturally challenging tetracyclodecene and tetracycloundecene
derivatives is described. Achieved under mild reaction conditions, the
transformation was shown to be robust with a wide variety of
substitution patterns tolerated to give the two members of the
carbocyclic family in good to excellent yields and as a single regio- and diastereomer.
Scheme 1. Gold-Catalyzed Reaction Pathways of 1,n-Diyne
Esters
old-catalyzed cycloisomerization of 1,n-diynes has become
Gone of the most efficient and versatile synthetic strategies
for the rapid construction of highly functionalized cyclic
compounds in a single step.1−7 Within the field, this has included
examples that have exploited the propensity of 1,n-diyne esters to
undergo 1,2- and 1,3-acyloxy migration and further reactivity to
give a variety of synthetically valuable products, as shown in
Scheme 1.2−7 For example, we recently reported a synthetic
route to tricyclic bridged hexenones and heptenones involving
the gold(I)-catalyzed 1,3-acyloxy migration/metallo-Nazarov
cyclization and respective formal [4 + 2]-cyclization and
cyclopropanation/Cope rearrangement of 1,11-diene-3,9-diynye
esters.5b As part of an ongoing program to develop this catalytic
tactic for carbocyclic synthesis, we were drawn to the potential
reactivity of 1-ene-4,9-diyne and 1-ene-4,10-diyne esters, the
chemistry of which has so far remained unexplored.6 We
anticipated the gold-activated species II generated from Au(I)-
catalyzed 1,3-acyloxy migration of the substrate would be
susceptible to a pathway involving 1,4-enallene cycloisomeriza-
tion followed by 1,2-hydride migration.7 Subsequent 1,6-enyne
rearrangement of the resulting putative bicyclo[3.1.0]hexenyl
gold adduct III might then be expected to provide the respective
tetracyclodecene and tetracycloundecene ring systems.8,9 Here-
in, we describe the details of this chemistry that provides an
expedient and chemoselective approach to these two potentially
useful carbocycles possessing four quaternary carbon centers at
the ring junctions in good to excellent yields and as single regio-
and diastereomers.
a
a
Het = heteroaryl group.
1).10 This initially revealed that treatment of the starting material
with 5 mol % of gold(I) phosphine catalyst A in 1,2-
dichloroethane at 80 °C for 24 h afforded the tetracycloundecene
To test the feasibility of our hypothesis, the 1-ene-4,10-diyne
4-nitrobenzoate 1a, prepared from 5-hexynoic acid, was selected
as the model substrate to establish the reaction conditions (Table
Received: August 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
1
catalyst
reaction time (h)
2a
3a
A
A
A
B
C
D
24
24
24
30
72
24
24
48
48
83
91
c
2
d
3
96
4
5
6
7
8
9
73
71
68
7
Ph3PAuNTf2
Rh(COD)2BF4
Pd(PPh3)2Cl2
51
e
e
a
All reactions were performed at the 0.2 mmol scale with catalyst/1a
b
c
ratio = 1:20 in (CH2Cl)2 at 80 °C. Isolated yield. Reaction carried
d
out in the presence of 4 Å MS (100 mg). Reaction carried out at
e
room temperature. No reaction based on TLC analysis and 1H NMR
measurements of the crude mixture.
product 2a as a single regio- and diastereomer in 83% yield (entry
1). The structure and relative stereochemistry of the tetracarbo-
cycle was unambiguously ascertained by NMR measurements
and X-ray single-crystal analysis.11 The introduction of 4 Å
molecular sieves (MS) to the reaction conditions was found to
lead to an increase in product yield from 83 to 91% (entry 2).
The analogous control reaction at room temperature, on the
other hand, was found to give the bicyclo[3.1.0]hexene adduct 3a
in 96% yield (entry 3). In our hands, lower product yields of 68−
73% along with increased reaction times were observed on
repeating the reaction with the more sterically crowded Au(I)
complexes B and C or the NHC−Au(I) (NHC = N-heterocyclic
carbene) complex D in place of A as the catalyst (entries 4−6).
However, the analogous control experiment with Ph3PAuNTf2 as
the catalyst gave a mixture of 2a and 3a in yields of 7 and 51%
(entry 7). No reaction was detected in control experiments with
the metal complexes Rh(COD)2BF4 and Pd(PPh3)2Cl2 as the
catalyst (entries 8 and 9). On the basis of the above results, the
cycloisomerization of 1a in the presence of Au(I) complex A (5
mol %) as the catalyst in 1,2-dichloroethane at 80 °C for 24 h was
deemed to provide the optimum reaction conditions.
With the optimal conditions in hand, we first strived to assess
the generality of the procedure for a series of 1-ene-4,10-diyne
esters, and the results are summarized in Figure 1. Overall, these
reactions illustrated that the Au(I) complex A-catalyzed
conditions were broad and afforded a diverse array of
tetracycloundecenes containing a variety of substitution patterns
in 41−91% yield from the corresponding substrates 1b−w.
Reactions of starting esters containing an Ac (1b) or Piv (1c)
instead of a PNB migrating group were found to be well-
tolerated, furnishing the corresponding tetracarbocycles 2b and
2c in 77 and 82% yield, respectively. Likewise, the cyclization of
substrates bearing a monosubstituted allyl motif (1d) or a tertiary
Figure 1. Gold(I)-catalyzed 1,3-migration/double cycloisomerization
of 1-ene-4,10-diyne esters 1b−w. All reactions were performed on a 0.2
mmol scale with a catalyst/1 ratio = 1:20 and 4 Å MS (100 mg) at 80 °C
for 24 h. Values in parentheses denote isolated product yields. Reaction
time: (a) 48 h, (b) 72 h.
sulfonamide (1e), acetyl (1f), aryl ether (1g,h), or malonate
(1i,j) group at the R2 position were shown to proceed well, giving
the corresponding dicyclopropanes 2d−j in 41−88% yield. The
presence of an electron-donating (1k,l,n) or electron-with-
drawing (1m,o) substituent at the 4- or 3,5-positions of the
phenyl group at the R3 position of the substrate was also found to
have no appreciable influence on the course of the reaction. In
these experiments, the corresponding tetracyclic products 2k−o
were provided in yields of 71−91%. Similarly, starting materials
with a pendant sterically demanding aryl group, as in 2p−r, a
heteroaryl (1s−v) motif at the same position, or a 1,3-enyne unit
(1w) gave the corresponding carbocycles 2p−w in 44−83%
yield.
We next turned our attention to evaluating the scope of the
Au(I) complex A-catalyzed procedure to assemble the
tetracyclodecene ring system from 1-ene-4,9-diyne 4-nitro-
benzoates (Figure 2). Under the optimized reaction conditions,
this revealed experiments with substrates containing an isoprenyl
motif (1x) or an acetyl (1y), phenyl ether (1z), or malonate (1α)
group on the alkene bond gave the corresponding cyclic products
2x−α in 62−85% yield. It was also pleasing to find the starting
nitrobenzoates 1β and 1γ, containing a sterically bulky 2-9H-
fluorenyl group, to proceed well upon application of the Au(I)
complex A-mediated method and afforded the tetracyclodecene
derivatives 2β and 2γ in yields of 77 and 64%.
B
DOI: 10.1021/acs.orglett.6b02404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Tentative Mechanism for the Gold(I)-Catalyzed
1,3-Migration/Double Cycloisomerization of 1-Ene-4,10-
diyne Esters
Figure 2. Gold(I)-catalyzed 1,3-migration/double cycloisomerization
of 1-ene-4,9-diyne esters 1x−γ. All reactions were performed on a 0.2
mmol scale with a catalyst/1 ratio = 1:20 and 4 Å MS (100 mg) at 80 °C
for 24 h. Values in parentheses denote isolated product yields.
In this work, the conversion of two tetracycloundecene
examples to their tricyclic ketone derivatives was also examined
(Scheme 2). Subjecting compound 2a to K2CO3 in methanol at
Scheme 2. Base-Mediated Methanolysis of 2a and 2d
control experiments detailed in Table 1, entries 3 and 7. It is
also further supported by our findings in a control reaction
showing 2a being furnished in 95% yield on treating 3a with 5
mol % of gold(I) phosphine complex A as the catalyst and 4 Å
MS in 1,2-dichloroethane at 80 °C for 24 h (Scheme 4).
room temperature was found to give the anticipated
tricycloundecenone 4a in 93% yield.7b Under similar reaction
conditions, the based-mediated methanolysis of 2d afforded 4d
in 88% yield, the structure of which was determined by both
NMR measurements and X-ray crystallography.11
Scheme 4. Control Experiment with 3a
A tentative mechanism for the present gold(I)-catalyzed 1-
ene-4,9-diyne and 1-ene-4,10-diyne ester cycloisomerization
transformations is outlined in Scheme 3. With 1a as a
representative example, this might involve initial selective
activation of the alkynyl ester moiety of the substrate by the
gold(I) complex. This initiates 1,3-acyloxy migration of the
resulting gold-coordinated species IV to produce the allenic ester
V, which upon further activation by the metal catalyst gives the
allenic gold species II that is susceptible to 1,4-enallene
cycloisomerization. Subsequent 1,2-hydride migration of the
resulting presumed gold carbenoid species VII, obtained via the
cationic cyclohexenyl intermediate VI, followed by deauration
would furnish the bicyclo[3.1.0]hexene 3a.7b Further activation
of the remaining pendant alkyne moiety in the newly formed
cyclopropane adduct by the gold(I) complex would provide the
gold-coordinated analogue III put forward in Scheme 1. This is
the active species that undergoes the second cyclopropanation
step involving cycloisomerization of the 1,6-enyne motif to give
the putative gold carbenoid complex IX via the carbocationic
cycloheptenyl species VIII.8,9 Regeneration of the gold(I)
catalyst and delivery of the tetracycloundecene product 2a
might then occur as VIII becomes susceptible to a 1,2-hydride
shift and deauration. The proposed involvement of the
bicyclo[3.1.0]hexene intermediate 2a posited in Schemes 1 and
3 would be in good agreement with the isolation of the
cyclopropane-fused five-membered ring adduct isolated in
In summary, we have developed an approach to tetracyclo-
decene and tetracycloundecene derivatives with four quaternary
carbon centers at the ring junctions from gold(I)-catalyzed
tandem 1,3-acyloxy migration/double cyclopropanation of 1-
ene-4,9-diyne and 1-ene-4,10-diyne esters. The utility of the
present method to the two members of carbocyclic family was
shown by the conversion of two examples to their ketone
derivatives, which are also potentially useful building blocks in
organic synthesis.12 Efforts to explore the synthetic applications
of the present reactions are currently underway and will be
reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02404.
C
DOI: 10.1021/acs.orglett.6b02404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Soc. 2015, 137, 6350. (c) Li, D.; Rao, W.; Tay, G. L.; Ayers, B. J.; Chan, P.
Detailed experimental procedures, characterization data
and 1H and 13C NMR spectra for all starting materials and
products (PDF)
W. H. J. Org. Chem. 2014, 79, 11301. (d) Yu, Y.; Yang, W.; Pflasterer, D.;
̈
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2014, 53, 1144. (e) Yu, Y.; Yang,
W.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2013, 52,
7586. (f) Rao, W.; Sally; Koh, M. J.; Chan, P. W. H. J. Org. Chem. 2013,
78, 3183. (g) Hashmi, A. S. K.; Yang, W.; Yu, Y.; Hansmann, M. M.;
Rudolph, M.; Rominger, F. Angew. Chem., Int. Ed. 2013, 52, 1329.
(h) Chen, M.; Liu, J.; Wang, L.; Zhou, X.; Liu, Y. Chem. Commun. 2013,
49, 8650.
X-ray data for 2a (CIF)
X-ray data for 4d (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
(6) Recent examples by us: refs 4a, d, g, and 5a−c.
*E-mail: weidong@njfu.edu.cn.
*E-mail: phil.chan@monash.edu; p.w.h.chan@warwick.ac.uk.
(7) (a) Horino, Y.; Yamamoto, T.; Ueda, K.; Kuroda, S.; Toste, F. D. J.
Am. Chem. Soc. 2009, 131, 2809. (b) Buzas, A.; Gagosz, F. J. Am. Chem.
Soc. 2006, 128, 12614.
Notes
(8) Selected reviews of Au-catalyzed 1,n-enyne cycloisomerizations:
The authors declare no competing financial interest.
(a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232. (b) Furstner,
̈
A. Chem. Soc. Rev. 2009, 38, 3208. (c) Jimen
́
ez-Nunez, E.; Echavarren, A.
́
̃
ACKNOWLEDGMENTS
M. Chem. Rev. 2008, 108, 3326. (d) Michelet, V.; Toullec, P. Y.; Genet
J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. (e) Zhang, L.; Sun, J.;
Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271.
̂
,
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21502093 and 21302096), the
Natural Science Foundation of Jiangsu Province (Grant Nos.
BK20150871 and BK20130962), the Project Fund from the
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD) and Top-Notch Academic
Programs Project of Jiangsu Higher Education Institutions
(TAPP) (to W.R.), and a Discovery Project Grant
(DP160101682) from the Australian Research Council (to
P.W.H.C.).
(9) Selected examples of gold-catalyzed 1,6-enyne cycloisomeriza-
tions: (a) Hosseyni, S.; Wojtas, L.; Li, M.; Shi, X. J. Am. Chem. Soc. 2016,
138, 3994. (b) Teller, H.; Furstner, A. Chem. - Eur. J. 2011, 17, 7764.
̈
(c) Deschamps, N. M.; Elitzin, V. I.; Liu, B.; Mitchell, M. B.; Sharp, M. J.;
Tabet, E. A. J. Org. Chem. 2011, 76, 712. (d) Chen, Z.; Zhang, Y.-X.;
Wang, Y.-H.; Zhu, L.-L.; Liu, H.; Li, X.-X.; Guo, L. Org. Lett. 2010, 12,
3468. (e) Nieto-Oberhuber, C.; Lop
Chem. Soc. 2005, 127, 6178. (f) Nieto-Oberhuber, C.; Lop
M. P.; Cardenas, D. J.; Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2005, 44, 6146. (g) Furstner, A.; Stelzer, F.; Szillat, H. J.
́
ez, S.; Echavarren, A. M. J. Am.
́
ez, S.; Munoz,
̃
́
̃
̈
Am. Chem. Soc. 2001, 123, 11863. (h) Men
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2001,
123, 10511.
́
dez, M.; Munoz, M. P.;
̃
REFERENCES
■
́
(1) Selected general reviews on gold catalysis: (a) Zheng, Z.; Wang, Z.;
Wang, Y.; Zhang, L. Chem. Soc. Rev. 2016, 45, 4448. (b) Wei, Y.; Shi, M.
ACS Catal. 2016, 6, 2515. (c) Dorel, R.; Echavarren, A. M. Chem. Rev.
2015, 115, 9028. (d) Jia, M.; Bandini, M. ACS Catal. 2015, 5, 1638. (e)
Gold Catalysis: An Homogeneous Approach; Toste, F. D., Michelet, V.,
Eds.; Imperial College Press: London, 2014. (f) Obradors, C.;
Echavarren, A. M. Acc. Chem. Res. 2014, 47, 902. (g) Hashmi, A. S. K.
Acc. Chem. Res. 2014, 47, 864. (h) Corma, A.; Leyva-Perez, A.; Sabater,
M. J. Chem. Rev. 2011, 111, 1657. (i) Gorin, D. J.; Sherry, B. D.; Toste, F.
D. Chem. Rev. 2008, 108, 3351.
(2) Selected reviews on gold-catalyzed cycloisomerization of propargyl
esters: (a) Ayers, B. J.; Chan, P. W. H. Synlett 2015, 26, 1305.
(b) Fensterbank, L.; Malacria, M. Acc. Chem. Res. 2014, 47, 953.
(c) Kazem Shiroodi, R.; Gevorgyan, V. Chem. Soc. Rev. 2013, 42, 4991.
(d) Shu, X.-Z.; Shu, D.; Schienebeck, C. M.; Tang, W. Chem. Soc. Rev.
2012, 41, 7698. (e) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 2010,
692. (f) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750.
(3) Reviews on gold-catalyzed cycloisomerization of 1,n-diyne
derivatives: (a) Asiri, A. M.; Hashmi, A. S. K. Chem. Soc. Rev. 2016,
45, 4471. (b) Day, D. P.; Chan, P. W. H. Adv. Synth. Catal. 2016, 358,
1368.
(10) For synthesis of 1 and gold(I) complexes A−D, see the
Supporting Information.
(11) CCDC 1496251 (2a) and CCDC 1496253 (4d) 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) Selected examples: (a) White, A. M.; Pierens, G. K.; Skinner-
Adams, T.; Andrews, K. T.; Bernhardt, P. V.; Krenske, E. H.; Mollo, E.;
Garson, M. J. J. Nat. Prod. 2015, 78, 1422. (b) Hodgson, D. M.; Salik, S.;
Fox, D. J. J. Org. Chem. 2010, 75, 2157. (c) Xiong, J.; Tan, N.-H.; Ji, C.-J.;
Lu, Y.; Gong, N.-B. Tetrahedron Lett. 2008, 49, 4851. (d) Wu, B.;
Kashiwagi, T.; Kuroda, I.; Chen, X. H.; Tebayashi, S.-I.; Kim, C.-S.
Biosci., Biotechnol., Biochem. 2008, 72, 611. (e) Nagashima, F.; Kishi, K.;
Hamada, Y.; Takaoka, S.; Asakawa, Y. Phytochemistry 2005, 66, 1662.
(f) Von Reus, S. H.; Wu, C.-L.; Muhle, H.; Koenig, W. A. Phytochemistry
2004, 65, 2277. (g) Mitome, H.; Shirato, N.; Miyaoka, H.; Yamada, Y.;
van Soest, R. W. M. J. Nat. Prod. 2004, 67, 833.
(4) Recent examples of gold(I)-catalyzed reactions of 1,n-diyne
carbonates and esters proceeding via an initial 1,2-acyloxy migration
step: (a) Yan, J.; Tay, G. L.; Neo, C.; Lee, B. R.; Chan, P. W. H. Org. Lett.
2015, 17, 4176. (b) Liu, J.; Chen, M.; Zhang, L.; Liu, Y. Chem. - Eur. J.
2015, 21, 1009. (c) Lauterbach, T.; Higuchi, T.; Hussong, M. W.;
Rudolph, M.; Rominger, F.; Mashima, K.; Hashmi, A. S. K. Adv. Synth.
Catal. 2015, 357, 775. (d) Rao, W.; Chan, P. W. H. Chem. - Eur. J. 2014,
20, 713. (e) Lauterbach, T.; Ganschow, M.; Hussong, M. W.; Rudolph,
M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2014, 356, 680.
(f) Oh, C. H.; Kim, J. H.; Piao, L.; Yu, J.; Kim, S. Y. Chem. - Eur. J. 2013,
19, 10501. (g) Rao, W.; Koh, M. J.; Li, D.; Hirao, H.; Chan, P. W. H. J.
Am. Chem. Soc. 2013, 135, 7926. (h) Lauterbach, T.; Gatzweiler, S.;
Nosel, P.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal.
̈
2013, 355, 2481.
(5) Recent examples of gold(I)-catalyzed reactions of 1,n-diyne
carbonates and esters proceeding via an initial 1,3-acyloxy migration
step: (a) Rao, W.; Boyle, J. W.; Chan, P. W. H. Chem. - Eur. J. 2016, 22,
6532. (b) Rao, W.; Susanti, D.; Ayers, B. J.; Chan, P. W. H. J. Am. Chem.
D
DOI: 10.1021/acs.orglett.6b02404
Org. Lett. XXXX, XXX, XXX−XXX