Gold-catalyzed assembly of heterobicyclic systems

Article abstract of DOI:10.1021/ja051110e

We have described an efficient gold-catalyzed double cyclization of 1,5-enynes to afford a range of heterobicyclic compounds, including oxabicylclo[3.2.1]octenes, azabicyclo[3.2.1]octenes, oxaspiro[5.4]decene, azaspiro[5.4]decene, oxaspiro[5.5]undecene, o

Full text of DOI:10.1021/ja051110e

Published on Web 04/21/2005
Gold-Catalyzed Assembly of Heterobicyclic Systems
Liming Zhang and Sergey A. Kozmin*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received February 21, 2005; E-mail: skozmin@uchicago.edu
Table 1. Gold-Catalyzed Synthesis of Heterobicyclic Alkenes
Gold-based chemoselective alkyne activation is emerging as an
attractive strategy for the development of an arsenal of new catalytic
processes.1 Due to the exceptional alkynophilicity of gold, such
reactions generally proceed under exceedingly mild conditions
enabling the formation of new carbon-carbon and carbon-
heteroatom bonds with high turnover efficiency.2,3 In this com-
munication, we describe an efficient gold-catalyzed synthesis of
heterobicyclic alkenes as a result of the 6-endo-dig carbocyclizations
of 1,5-enynes with a concomitant intramolecular formation of either
C-O or C-N bonds. The most notable aspect of this process is a
mild and chemoselective metal-based alkyne activation, which
enables rapid assembly of a range of heterobicyclic products with
high efficiency and excellent diastereoselectivity.
In the course of our investigation of gold-catalyzed cycloisomer-
ization of 1,5-enynes,4 we discovered that treatment of enyne 1
with either a Au(I) or Au(III) catalytic promoter afforded a new
product that was identified as 6-oxabicyclo[3.2.1]octene 2 (Scheme
1).5-7 The optimized protocol entailed a brief exposure of alcohol
Scheme 1
1 to a catalytic amount of AuCl3 in MeCN, which furnished alkene
2 in 89% yield. The use of Au(PPh3)Cl in combination with AgClO4
proved to be equally effective. To rule out a possible involvement
of the conjugate Brønsted acid in the alkyne activation,8 alcohol 1
was treated with a substoichiometric amount of HCl in the absence
of AuCl3. The observed reaction was significantly slower and
afforded exclusively tetrahydrofuran 3. The outcome of this
experiment demonstrated unambiguously that gold-based catalysis
was uniquely responsible for chemoselective alkyne activation.
Our investigation of the generality and scope of the reaction is
summarized in Table 1. Subjection of enynes 4 and 6 to the general
protocol utilizing AuCl3 efficiently afforded the expected bicyclic
products 5 and 7, respectively, indicating that aryl substitution of
the enyne was well tolerated (entries 1 and 2). To probe the
requirement of the quaternary center at the C(3), we subjected
alcohol 8 to the standard protocol (entry 3). While the efficiency
of the reaction utilizing AuCl3 was moderate, the use of Au(PPh3)-
Cl and AgClO4 afforded the oxabicyclic alkene 9 in 89% yield.
Treatment of sulfonamide 10 with AuCl3 resulted in efficient
assembly of azabicyclo[3.2.1]octene 11 (entry 4). This finding is
particularly noteworthy as it provides the first example of efficient
interception of a cationic intermediate formed in a gold-catalyzed
process by a sulfonamide-based nucleophile.9 When alcohol 12
a Method A: Enyne (0.1 mmol) was dissolved in MeCN (2 mL) and
treated with AuCl3 (5 µmol). The resulting solution was stirred at 20 °C
for 1 h and treated with Et3N (50 µL). The solvent was removed under
reduced pressure, and the crude product was purified by flash chromatog-
raphy on silica gel. b Method B: Enyne (0.1 mmol) was dissolved in CH2Cl2
(2 mL) and treated with [Au(PPh3)]ClO4 (5 µmol) generated from
Au(PPh3)Cl and AgClO4. The resulting solution was stirred at 20 °C for 1
h. The product was obtained similarly as described above. c Refers to isolated
yields of spectroscopically pure products that were fully characterized by
NMR, IR, and MS.
(entry 5) was treated with [Au(PPh3)]ClO4, oxaspiro[5.4]decene 13
was obtained in 86% yield. Cyclization of the corresponding
sulfonamide 14 efficiently afforded azaspiro[5.4]decene 15 (entry
6). Finally, enyne 16 armed with a chain-extended alcohol ef-
ficiently furnished the spirocyclic ether 17 (entry 7).
To examine the formation of fused heterobicycloalkenes, alcohol
18, containing trisubstituted E-alkene, was treated with 10 mol %
of AuCl3 to successfully afford a strained trans-oxabicyclo[4.3.0]-
nonene 1910 with excellent diastereoselectivity (eq 1).11 Additional
studies demonstrated the diastereospecific nature of this double
cyclization allowing to access either the cis- or trans-fused bicyclic
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C O M M U N I C A T I O N S
ethers.12 Double cyclization of one-carbon extended trisubstituted
Z-alkene 20 (eq 2) afforded exclusively cis-oxabicyclo[4.4.0]decene
21 (dr > 97:3). Finally, subjection of sulfonamide 22 to [Au(PPh3)]-
ClO4 furnished trans-oxabicyclo[4.3.0]nonene 23 with excellent
efficiency and diastereoselectivity (eq 3).
In summary, we have developed an efficient gold-catalyzed
double cyclization of simple 1,5-enynes armed with either oxygen-
or nitrogen-based nucleophiles. This mild catalytic process provides
an efficient access to oxa- and azabicyclic alkenes containing
bridged, fused, and spirocyclic architectures. Furthermore, the
assembly of fused oxabicycloalkenes proceeds diastereospecifically,
strongly suggesting a concerted nature of this double cyclization.
Acknowledgment. Partial support of this work was provided
by the NSF CAREER (CHE-0447751). S.A.K. thanks the Dreyfus
Foundation for a Teacher-Scholar Award, Amgen for a New
Investigator’s Award, and GlaxoSmithKline for a Chemistry
Scholars Award. S.A.K. is a fellow of the Alfred P. Sloan
Foundation. We thank Michael Schramm for X-ray analysis.
Supporting Information Available: Full characterization of new
compounds and selected experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
The diastereospecific course of the double cyclization can be
viewed as either a concerted process A or a stepwise route involving
nucleophilic opening of the cyclopropyl gold carbene intermediate
B (Scheme 2). Release of the proton from C followed by
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Scheme 2
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protodemetalation of the alkenyl gold complex D affords the
observed bicyclic ether. While gold carbenes of type B have been
implicated as reactive intermediates in 5-exo-dig,2f 6-exo-dig,6 and
6-endo-dig cyclizations,2k,l,4 our results strongly indicate that the
double cyclization is a highly concerted process, which results in
anti addition of the alkyne and the nucleophile to the alkene. Indeed,
successful cyclization of sulfonamide 10 (Table 1, entry 4) indicates
significant carbocationic character at the C(5), which is more
consistent with a concerted reaction manifold. Furthermore, the
cyclization of alcohol 8 (Table 1, entry 3) proceeded without any
observed formation of an alternative [3.1.0] bicyclic alkene2k,l as a
result of hydride migration and elimination from the gold carbene
intermediate of type B.
Interestingly, subjection of trisubstituted E-alkene 24 (eq 4) to
10 mol % of AuCl3 afforded unexpectedly tetrahydrofuran 25 as
an exclusive anti-Markovnikov reaction product (dr > 97:3).13 The
outcome of this experiment can be rationalized by a strained nature
of the alternative trans-oxabicyclo[4.4.0]decene product, changing
the reaction course to the 5-endo-dig cyclization.
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fused bicyclic ether.
(11) Bicyclic ether 19 was produced as a 9:1 mixture of trans:cis diastereomers
corresponding to the 9:1 mixture E:Z geometrical isomers of alkene 18.
(12) Subjection of the 2:1 mixture E:Z geometrical isomers of alkene 18 to
AuCl3 (10 mol %) afforded a 2:1 mixture of trans:cis-fused bicyclic ethers
19, which were separated and fully characterized. See Supporting
Information for details.
(13) The structure of 25 was verified by X-ray crystallography. See Supporting
Information for details.
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