Gold(I)-Catalyzed Angle Strain Controlled Strategy to Furopyran Derivatives from Propargyl Vinyl Ethers: Insight into the Regioselectivity of Cycloisomerization

Article abstract of DOI:10.1021/acs.orglett.5b03641

A unique strategy for the regiospecific synthesis of bicyclic furopyran derivatives has been developed via a gold(I)-catalyzed propargyl-Claisen rearrangement/6-endo-trig cyclization of propargyl vinyl ethers. The introduction of angle strain into the substrates significantly altered the reaction's regioselectivity. Insight into the regioselectivity of the cycloisomerization was obtained with density functional theory calculations. (Chemical Equation).

Full text of DOI:10.1021/acs.orglett.5b03641

Letter
pubs.acs.org/OrgLett
Gold(I)-Catalyzed Angle Strain Controlled Strategy to Furopyran
Derivatives from Propargyl Vinyl Ethers: Insight into the
Regioselectivity of Cycloisomerization
Shengfei Jin, Chongguo Jiang, Xiaoshi Peng, Chunhui Shan, Shanshan Cui, Yuanyuan Niu,†,‡
†
,‡
†,‡
†,‡
§
†,‡
†
,‡
,§
,†,‡
,†,‡
Yang Liu, Yu Lan,* Yongxiang Liu,* and Maosheng Cheng*
†Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education,
Shenyang 110016, P. R. China
‡
Institute of Drug Research in Medicine Capital of China, Benxi 117000, P. R. China
§
School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
*
S Supporting Information
ABSTRACT: A unique strategy for the regiospecific synthesis
of bicyclic furopyran derivatives has been developed via a
gold(I)-catalyzed propargyl-Claisen rearrangement/6-endo-trig
cyclization of propargyl vinyl ethers. The introduction of angle
strain into the substrates significantly altered the reaction’s
regioselectivity. Insight into the regioselectivity of the
cycloisomerization was obtained with density functional theory
calculations.
old-catalyzed cycloisomerizations have been developed
cases, the 5-exo-dig (trig) mode dominates the cyclizations
compared with 6-endo-dig (trig), which is mainly attributed to
4
G
into important and integral transformations over the past
1
decades, which can afford unique carbocycles and heterocycles
stereoelectronic factors and geometry of the cyclization
transition states. Though the exo products have lower intrinsic
barriers than the endo competitors from a stereoelectronic
aspect, preferences for exo-dig (trig) closure can be over-
shadowed by additional factors, such as strain in one of the
products, which can tip the balance in favor of the endo
from simple acyclic precursors such as easily accessed enynes,
among which propargyl vinyl ethers have been utilized to
2
synthesize a wide range of products. Mechanistically, a 6-endo-
dig addition of the enol ether onto gold(I)−alkyne complex
followed by Grob-type fragmentation to afford the β-allenic
carbonyl intermediates (or its tautomeric enol forms) was
widely accepted in the propargyl vinyl ether mediated
5
products. The postulation “when the length and nature of
linking chain enables the terminal atoms to achieve the required
2a−c,e
rearrangement reactions (Scheme 1).
trajectories” for the bond formation suggested by Baldwin
6
The chemo- and regioselectivities in the cycloisomerizations
have been important issues. Various attempts have been
conducted to regulate regioselectivity involving the modifica-
emphasized stereoelectronic factors. The favorable trajectories
for cyclizations indicated a maximized orbital overlap. However,
intrinsic stereoelectronic preferences can be masked by
thermodynamic factors that may exert an influence on the
3
tion of the substrates, reagents, catalysts, and solvents. In most
5
,7
activation barrier. These two factors are not always sufficient
8
,9
for dominating the selectivity. Strain effects have been used
Scheme 1. Angle-Strain-Controlled Distinct
Regioselectivities of Gold-Catalyzed Cyclizations
to favor the formation of larger cycles previously in anionic and
9
radical cyclizations, and we were interested in expanding this
concept to Au-catalyzed cycloisomerizations. We therefore
hypothesized that the introduction of further angle strain into
the vinyl ether fragment to increase the ring strain may exert an
influence on the geometry of the transition states leading to an
alternative regioselective cyclization.
Received: December 23, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To test the hypothesis, we synthesized a propargyl γ-
butyrolactone-2-enol ether and observed the cyclization mode
of this strained substrate at the catalysis of gold(I) species. As
expected, the regioselectivity of the cyclization was changed
totally to yield a furopyran derivative exclusively (the
conditions screening is described in the Supporting Information
(
SI)) (Scheme 1).
The exciting results encouraged us to examine the generality
10
of the reaction with a series of synthetic substrates (Figure 1).
Figure 2. Scope of the cyclic vinyl moieties.
propargyl γ-butyrolactone-3-enol ether substrate (Figure 2, 3c).
The ketone substrates also afforded the pyrans with a single
diastereoselectivity (Figure 2, 4d,e). It is worth mentioning that
the formation of migrated products in propargyl coumarin
ethers substrates was highly substrate dependent (Figure 2,
4
g,h).
The mechanistic proposal for the formation of pyran
outlined in Scheme 2 was supported by the previous research
a
Scheme 2. Proposed Mechanism of the Cyclizations
Figure 1. Scope of the alkyne substitutions. Reactions with 1c and 1d
were run at rt for 5 min.
Aromatic and heteroaromatic substituted alkyne substrates
were first investigated, and good yields were obtained (Figure 1,
2
a−e). The substrates with an alkyl-substituted alkyne gave the
pyran with an unexpected 1,3-hydrogen migration after
cyclization (Figure 1, 2f). The detailed mechanism and
computational study of this migration step are shown as Figure
S2 in the SI. To prove the generality of the migration, the
substrates with different alkyne alkyl substitutions were
synthesized and examined under the standard conditions, and
the corresponding hydrogen shift products were formed in
excellent yields with relatively good diastereoselectivity (E/Z =
a
The values in parentheses are given in kcal/mol and represent the
relative free energies calculated by using the M11 method in DCE.
4
:1) (Figure 1, 2g−i). The substrate with cyclohexyl group gave
a hydrogen shift product (Figure 1, 2j), while the cyclopropyl-
substituted alkyne substrate gave a normal pyran product
exclusively with no hydrogen shift (Figure 1, 2k). Electron-
withdrawing groups such as acetoxyl and chloro groups were
attached to α-methylene at the terminal alkyne position:
nonmigrated pyrans were isolated as the only products in each
case (Figure 1, 2l and 2m).
The functional group tolerances were further examined by
utilizing cyclic fragments with similar angle strains. The
propargyl β-tetronic acid ether substrates afforded the
corresponding pyran products in satisfactory yields (Figure 2
entries 4a−c). However, the geometry of the newly formed
alkenes changed from an E/Z mixture into an exclusive E
isomer (Figure 1, 2h and 2i; Figure 2 4a and 4b). There was no
hydrogen migration in propargyl γ-butyrolactone-2-enol ether
substrate (Figure 1, 1m); however, total migration occurred in
on gold(I)-catalyzed furan formation and our experimental
2a−c,e
results.
A 6-endo-dig addition of the enol ether of 1n onto
gold(I)−alkyne complex 1n-1 results in the formation of
intermediate 1n-2, which collapses into the β-allenic ketone 1n-
1
3 (the actual intermediate 1d-3 was confirmed by the H NMR
spectrum of the crude reaction mixture and also consistent with
11
previous reports which could be transformed into the product
2d smoothly under the standard conditions; see the SI). Then a
gold(I)-catalyzed keto−enol tautomerism, followed by 6-endo-
dig cyclization, finally delivers pyran 2n.
In order to pursue an intrinsic explanation on the unusual
regioselectivity of the reaction, a systematic study assisted by
computational chemistry was performed. As shown in Scheme
2 (detailed free energy profiles were shown in Figure S1),
12
density functional theory (DFT) method M11, is employed
to elucidate the mechanism of this reaction. In our DFT study,
B
DOI: 10.1021/acs.orglett.5b03641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
regioselectivity is controlled by the nucleophilc addition step
from intermediate 1n-4 to 1n-5 shown in Scheme 2.
To gain insight into the selectivity, theoretical models for the
nucleophilic cycloaddition step are listed in Table 1. The
between complex CP4d and CP4d′ showed that the reactivities
of terminal carbon and internal carbon in allene moiety are
close (entry 5).
To further clarify the regioselectivity, key bond angles are
listed in Table 1. For the noncyclic substrates as shown in entry
3, there are no obvious differences of bond angle change in
cyclization between transition state TS4b-5b and TS4b-7b
Table 1. Reactivity and Regioselectivity for the Selected
a
Intermediates
(
7.9° between A and A , 4.6° between A and A ). In entry 4,
3 5 4 6
the changes of bond angles for intermediate CP4c are also
similar to that of entry 3 in both transition states. However, in
intermediate CP4, the bond angle A2 is 109.6°, which is 20.0°
less than that in CP4b because of the strain of the furanone
ring. When the nucleophilic addition takes place on internal
carbon via transition state TS4-7, the bond angles of A5 and A6
are 114.8° and 111.1°, respectively. Geometry information
indicates that furanone ring restricts the increasing of bond
angle A6 and the decreasing of bond angle A5; therefore, the
formation of the furofuran-type adduct is unfavorable. In
another case, when the nucleophilic addition occurs on
terminal carbon in the allene moiety via transition state TS4-
5
, the bond angles A3 and A4 are 126.5° and 110.5°,
respectively. The less strain effect leads to a lower activation
free energy via transition state TS4-5. Therefore, in our
reported gold(I)-catalyzed formation of pyrans from propargyl
vinyl ethers, the strain of furanone moiety leads to the
formation of furopyran type product.
We explored the application of this strategy to the synthesis
of isopatulin 2o, an analogue of patulin with antimicrobial
properties against some microorganisms. An expected tandem
cyclization/deprotection followed by an enol−keto tautomeri-
zation occurred to give 2o with a moderate yield when the
synthesized substrate was subjected to the standard conditions
(
Scheme 3). This unique approach allowed a rapid assembly of
13
isopatulin and its derivatives in a two-step sequence.
Scheme 3. Gold(I)-Catalyzed Synthesis of Isopatulin
In conclusion, a gold(I)-catalyzed propargyl-Claisen rear-
rangement/6-endo-trig tandem cyclization strategy for furopyr-
an derivatives has been developed. Notably, ring strain acts as
an indispensable factor to alter the regioselectivity from 5-exo-
trig to 6-endo-trig. The interplay of electronic and steric
contributions to the transition states for 5-exo-trig and 6-endo-
trig cyclizations of theoretical models was also analyzed by DFT
calculation, which provided results consistent with the
experimental findings.
a
The values of relative activation free energies and activation
enthalpies (in parentheses) are given in kcal/mol.
ASSOCIATED CONTENT
■
*
S
Supporting Information
relative free energies for transition states showed that the
furopyran-type adducts will be the major products in the cyclic
substrates with both electron-deficient and -rich allene moieties
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03641.
(
entries 1 and 2), while on the contrary, the furofuran-type
adducts will be the major products for the noncyclic substrates
entries 3 and 4). Moreover, an intermolecular reaction model
Experimental procedures, compound characterization
data, and computational details (PDF)
(
C
DOI: 10.1021/acs.orglett.5b03641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J. Org. Chem. 1994, 59, 7876. (c) Benati, L.; Leardini, R.; Minozzi, M.;
Nanni, D.; Spagnolo, P.; Zanardi, G. J. Org. Chem. 2000, 65, 8669.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
*
(d) Marion, F.; Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095.
E-mail: lanyu@cqu.edu.cn.
E-mail: yongxiang.liu@syphu.edu.cn.
E-mail: mscheng@syphu.edu.cn.
(e) Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.;
Alabugin, I. V. Org. Lett. 2004, 6, 2457. (f) Alabugin, I. V.; Gilmore, K.;
Patil, S.; Manoharan, M.; Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J.
Am. Chem. Soc. 2008, 130, 11535.
Notes
(9) (a) Bharucha, K. N.; Marsh, R. M.; Minto, R. E.; Bergman, R. G.
The authors declare no competing financial interest.
J. Am. Chem. Soc. 1992, 114, 3120. (b) Matzger, A. J.; Vollhardt, K. P.
C. Chem. Commun. 1997, 1415. (c) Alabugin, I. V.; Manoharan, M. J.
Am. Chem. Soc. 2005, 127, 12583. (d) Vasilevsky, S. F.;
Mikhailovskaya, T. F.; Mamatyuk, V. I.; Salnikov, G. E.;
Bogdanchikov, G. A.; Manoharan, M.; Alabugin, I. V. J. Org. Chem.
ACKNOWLEDGMENTS
This research was supported by the National Natural Science
Foundation of China (Grant Nos. 21202103, 2137226, and
■
2
009, 74, 8106. (e) Vasilevsky, S. F.; Gold, B.; Mikhailovskaya, T. F.;
5
1302327), the Natural Science Foundation of Liaoning
Alabugin, I. V. J. Phys. Org. Chem. 2012, 25, 998. (f) Alabugin, I. V.;
Gilmore, K. Chem. Commun. 2013, 49, 11246.
Province of China (Grant No. 2014020080), and Liaoning
Province Education Administration of China (Grant No.
L2014386). We thank the Program for Innovative Research
Team of the Ministry of Education and Program for Liaoning
Innovative Research Team in University and Chinese Academy
of Sciences.
(10) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(b) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127.
(11) (a) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 8132. (b) Gille, A.; Rehbein, J.; Hiersemann, M.
Org. Lett. 2011, 13, 2122. (c) Yang, W. B.; Hashmi, A. S. K. Chem. Soc.
Rev. 2014, 43, 2941.
(
(
12) Peverati, R.; Truhlar, D. G. J. Phys. Chem. Lett. 2011, 2, 2810.
13) For the other synthetic methods for isopatulin, see: (a) Puetzer,
REFERENCES
■
(
2
1) (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348,
271. (b) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200.
B.; Nield, C. H.; Barry, R. H. J. Am. Chem. Soc. 1945, 67, 832.
b) Lykakis, I. N.; Zaravinos, I.-P.; Raptis, C.; Stratakis, M. J. Org.
Chem. 2009, 74, 6339.
(
(
(
c) Jimen
́
́
̃
ez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326.
d) Cheong, P. H.; Morganelli, P.; Luzung, M. R.; Houk, K. N.; Toste,
F. D. J. Am. Chem. Soc. 2008, 130, 4517. (e) Belmont, P.; Parker, E.
Eur. J. Org. Chem. 2009, 2009, 6075. (f) Horino, Y.; Yamamoto, T.;
Ueda, K.; Kuroda, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2809.
(
g) Hashmi, A. S. K. Pure Appl. Chem. 2010, 82, 1517. (h) Zheng, H.;
Adduci, L. L.; Felix, R. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2014,
3, 7904. (i) Belger, K.; Krause, N. Eur. J. Org. Chem. 2015, 2015, 220.
2) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
5978. (b) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7,
925. (c) Cao, H.; Jiang, H. F.; Yao, W. J.; Liu, X. H. Org. Lett. 2009,
1, 1931. (d) Tejedor, D.; Mendez-Abt, G.; Cotos, L.; Ramirez, M. A.;
́
5
(
1
3
1
́
García-Tellado, F. Chem. - Eur. J. 2011, 17, 3318. (e) Tejedor, D.;
Cotos, L.; García-Tellado, F. Org. Lett. 2011, 13, 4422. (f) Tejedor, D.;
Cotos, L.; García-Tellado, F. J. Org. Chem. 2013, 78, 8853. (g) Vidhani,
D. V.; Krafft, M. E.; Alabugin, I. V. Org. Lett. 2013, 15, 4462.
(
3
(
h) Vidhani, D. V.; Krafft, M. E.; Alabugin, I. V. J. Org. Chem. 2014, 79,
52. (i) Zhu, Z. B.; Kirsch, S. F. Chem. Commun. 2013, 49, 2272.
j) Hosseyni, S.; Su, Y.; Shi, X. Org. Lett. 2015, 17, 6010.
3) (a) Amijs, C. H. M.; Lopez-Carrillo, V.; Raducan, M.; Per
Galan, P.; Ferrer, C.; Echavarren, A. M. J. Org. Chem. 2008, 73, 7721.
b) Mauleon, P.; Zeldin, R. M.; Gonzalez, A. Z.; Toste, F. D. J. Am.
(
́
́
ez-
́
(
Chem. Soc. 2009, 131, 6348. (c) Hickman, A. J.; Sanford, M. S. ACS
Catal. 2011, 1, 170. (d) Gross, E.; Liu, J. H.-C.; Toste, F. D.; Somorjai,
G. A. Nat. Chem. 2012, 4, 947. (e) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J.
Am. Chem. Soc. 2012, 134, 17412. (f) Wang, T.; Shi, S.; Vilhelmsen, M.
H.; Zhang, T.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Chem. -
Eur. J. 2013, 19, 12512. (g) Issa, J. P.; Bennett, C. S. J. Am. Chem. Soc.
2
014, 136, 5740. (h) Larsen, C. R.; Erdogan, G.; Grotjahn, D. B. J. Am.
Chem. Soc. 2014, 136, 1226.
4) (a) Lebœuf, D.; Simonneau, A.; Aubert, C.; Malacria, M.;
Gandon, V.; Fensterbank, L. Angew. Chem., Int. Ed. 2011, 50, 6868.
b) Gai, R. M.; Schumacher, R. F.; Back, D. F.; Zeni, G. Org. Lett.
012, 14, 6072. (c) Jha, R. R.; Aggarwal, T.; Verma, A. K. Tetrahedron
(
(
2
Lett. 2014, 55, 2603. (d) Thirupathi, N.; Kumar, Y. K.; Kant, R.;
Reddy, M. S. Adv. Synth. Catal. 2014, 356, 1823.
(5) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513.
(6) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(7) (a) Marcus, R. A. J. Chem. Phys. 1956, 24, 966. (b) Marcus, R. A.
Annu. Rev. Phys. Chem. 1964, 15, 155. (c) Marcus, R. A. J. Phys. Chem.
968, 72, 891. (d) Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am.
Chem. Soc. 2011, 133, 12608.
8) (a) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110,
796. (b) Grissom, J. W.; Klingberg, D.; Meyenburg, S.; Stallman, B. L.
1
(
4
D
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