Au(I)-catalyzed efficient synthesis of functionalized bicyclo[3.2.0] heptanes

Article abstract of DOI:10.1021/ja802294t

An efficient Au(I)-catalyzed synthesis of highly strained and functionalized bicyclo[3.2.0]heptanes is developed. Subsequent couplings with various nucleophiles offer additional structural features/complexity. These one-pot, three-component reactions are proposed to proceed via a key 1,3-dipolar cycloaddition between a Au carbenoid-containing carbonyl ylide and ethyl vinyl ether. Copyright

Full text of DOI:10.1021/ja802294t

Published on Web 05/09/2008
Au(I)-Catalyzed Efficient Synthesis of Functionalized Bicyclo[3.2.0]heptanes
Guotao Li, Xiaogen Huang, and Liming Zhang*
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received March 28, 2008; E-mail: lzhang@unr.edu
Cycloaddition reactions are essential tools for organic synthesis,
offering not only substrate flexibility but also rapid increase of
molecular complexity. Au/Pt catalysts1 have been employed to
generate reactive intermediates for cycloaddition reactions, including
Diels-Alder reaction,2 1,3-dipolar cycloaddition,3 and [4 + 3]
cycloadditions.4 These reactions are often followed by cascade
transformations involving the regeneration of metal catalysts,
Figure 1. ORTEP depiction of compound 8i and natural products
therefore rendering further functionalization and/or additional
structural complexities. However, this novel and powerful approach
has only been realized in limited cases.2–4 Herein, we report a Au(I)-
catalyzed 1,3-dipolar cycloaddition, leading to efficient formation
of functionalized, highly strained bicyclo[3.2.0]heptanes,5 a struc-
tural motif present in various natural products including repraesentin
F6a and kelsoene6b (Figure 1).
containing the bicyclo[3.2.0]heptane skeleton.
Scheme 1. Initial Discovery
We reported previously that 1-(1-phenylethynyl)cyclopropyl
methyl ketone7 (1, Scheme 1) underwent various IPrAuNTf2-
catalyzed8 [4 + 2] annulations via a proposed Au-containing all
carbon 1,4-dipole intermediate.9 During the study, we noticed a
different reaction outcome when ethyl vinyl ether was used as
dipolarophile at room temperature.10 Instead of the anticipated
tetrasubstituted furan product, two acid-sensitive compounds were
formed highly efficiently,11 and attempts to purify them using even
Et3N-treated silica gel column led to subpure materials as a mixture.
2D TLC revealed that they decomposed on the plate into three
stable, separable compounds. Consequently, treating the reaction
mixture with regular silica gel led to the isolation and characteriza-
tion of all those compounds (i.e., 3, 4, and 5), which shared a
strained bicyclo[3.2.0]heptane skeleton (Scheme 1). We concluded
that the initially formed products were the diastereomers of enone
2 and their ready decomposition into bicycles 3, 4, and 5 must be
due to partial release of the ring strains in 2. To avoid the isolation
problem, the reaction mixture upon the complete consumption of
1 in 15 min was concentrated to remove excess ethyl vinyl ether,
and the residue was treated with TsOH (20 mol %) in acetone/
H2O (7/1, 2 mM). Hydroxyenone 4 was isolated in 93% yield, while
hydroxyketone 3 was not observed and only a negligible amount
of aldehyde 5 was formed. Although both PtCl2 and AuCl3 also
catalyzed this reaction, higher catalyst loadings (10 mol %) were
required.12
The mechanism for the formation of hydroxyenone 4 is proposed
in Scheme 2. It begins with a 5-endo-dig cyclization of the carbonyl
group onto the Au-activated C-C triple bond, forming an oxocar-
benium intermediate A. Different from our previous study9 where
A undergoes cyclopropane ring opening and aromatization, a
resonance structure of A, i.e., B,3a,b,f is a Au(I) carbenoid-containing
carbonyl ylide and can undergo 1,3-dipolar cycloaddition with ethyl
vinyl ether, forming bridged bicycle C. 1,2-Alkyl migration
followed by bridge opening then results in the formation of
spirobicyclic cation E. Ring enlargement of the cyclopropane ring
forms the bicyclo[3.2.0]heptane skeleton and subsequent elimination
of the Au catalyst forms enone 2. Treatment of 2 with Brønsted
acid should generate cation G as one of possible intermediates,
Scheme 2. Proposed Mechanism via a 1,3-Dipolar Cycloaddition
which can be trapped by H2O and affords hydroxyketone 3 upon
tautomerization of 6 or enone 4 via EtOH elimination. We anticipate
that hydroxyketone 3 can be readily converted to enone 4 under
acidic conditions. Of note, the formation of aldehyde 5 is the result
of a second molecule of ethyl vinyl ether reacting with 2 under
acidic conditions.
This expedient excess to highly strained and functionalized
bicyclo[3.2.0]heptanes can be readily expanded to other ketone
substrates. As shown in Table 1, various substituents at the carbonyl
group were allowed. In particular, substrates with linear alkyl (entry
1) and functionalized linear alkyl (entries 4 and 5) groups underwent
this reaction in good to excellent efficiency. Sterically more
demanding benzyl group (entry 6) and alkyl groups including
isobutyl (entry 2) and isopropyl (entry 3) slowed this reaction, and
slightly elevated reaction temperatures were required; moreover,
the yields were lower. To our delight, this reaction also worked
with aldehyde 7g (entry 7) and phenone 7h (entry 8) in fair yields.
Surprisingly, in the case of 7h, the [4 + 2] annulation9 previously
9
6944 J. AM. CHEM. SOC. 2008, 130, 6944–6945
10.1021/ja802294t CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope Study
Subsequent couplings with various nucleophiles offer additional
structural features/complexity. These one-pot, three-component
reactions are proposed to proceed via a key 1,3-dipolar cycloaddition
between Au carbenoid-containing carbonyl ylides and ethyl vinyl
ether.
Acknowledgment. Generous financial supports from ACS PRF
(43905-G1), ORAU and Merck are appreciated. L.Z. thanks Prof.
Vince Catalano for helping with the X-ray structure. The acquisition
of an NMR spectrometer and upgrade of an existing NMR
spectrometer was funded by NSF CHE-0521191, and the X-ray
diffractometer purchase was supported by NSF Grant CHE-
0226402.
a Isolated yield. b Reaction temperature: 40 °C. c TBAF (2 equiv) was
added to complete desilylation. d The [4 + 2] product was isolated at
30%. e The ethoxyenone diastereomers initially formed were isolated in
59% and 12% yield, respectively. f Yield of 12 was 14%.
observed only with dipolarophiles other than ethyl vinyl ether
occurred, and 4-ethoxy-1,3-diphenyl-4,5,6,7-tetrahydroisobenzo-
furan was isolated in 30% yield; moreover, the ethoxyenone
diastereomers initially formed were stable on column, and their
characterization offered support for the structure assignment of 2.
The alkyne terminus could accommodate different substituents
including n-butyl (entry 11), MOM (entry 12) and aryl groups of
electron-rich (entries 9) and electron-deficient (entry 10) well.
Surprisingly, 14% of aldehyde 12 (see eq 5) was isolated in entry
12, which is likely due to the presence of a chelating R-methoxy-
ketone moiety. To our delight, the structure of 8i was elucidated
by X-ray crystallography (Figure 1), confirming our previous
structure assignments. Substrates with a methyl or a phenyl
substitution at the cyclopropane ring, however, did not furnish
expected bicyclo[3.2.0]heptane products. Besides ethyl vinyl ether,
tert-butyl vinyl ether could be used but the reaction was slower.
The formation of aldehyde enone 5 (Scheme 1) suggests that
the ring juncture of 2 proximal to the carbonyl group is highly
susceptible toward nucleophilic attacks and groups other than OH
can be readily installed. Indeed, when MeOH instead of H2O was
used, methyl ether 9 was formed in 93% yield (eq 2). In addition,
a hydride and an allyl group can be readily delivered, yielding
reduced enone 10 (eq 1) and allyl enone 11 (eq 3) in excellent
yields. Moreover, the yield of aldehyde 5 can be improved
dramatically to 81% upon the addition of Me2AlCl (1 equiv) and
extra ethyl vinyl ether. These reactions constitute efficient one-
pot, 3-component couplings, offering rapid excess to highly strained
and functionalized bicyclo[3.2.0]heptanes. Unexpectedly, when
MOM-substituted 7l was treated with PtCl2, aldehyde 12 was
obtained essentially pure without chromatography after acidic
hydrolysis and workup (eq 5). The lack of 8l is interesting and
suggests that PtCl2 is more acidic than IPrAuNTf2 (entry 12).
Compound 12, though sensitive to silica gel, was easily cyclized
under basic conditions to afford delicate tricyclic dienone 13 in
63% yield, demonstrating the synthetic utility of this chemistry.
In summary, we have developed an efficient Au(I)-catalyzed
synthesis of highly strained and functionalized bicyclo[3.2.0]heptanes.
Supporting Information Available: Experimental procedures,
compound characterization data and cif file. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(10) Without the addition of ethyl vinyl ether, ketone 1 did not undergo
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