Catalaytic isomerization of 1,5-enynes to bicyclo[3.1.0]hexenes

Article abstract of DOI:10.1021/ja046248w

The cycloisomerization of 1,5-enynes catalyzed by cationic triphenylphosphinegold(I) complexes produces bicyclo[3.1.0]hexenes. Substitution at all positions of the 1,5-enyne is tolerated, leading to a wide range of bicyclo[3.1.0]hexane structures, includi

Full text of DOI:10.1021/ja046248w

Published on Web 08/13/2004
Catalaytic Isomerization of 1,5-Enynes to Bicyclo[3.1.0]hexenes
Michael R. Luzung, Jordan P. Markham, and F. Dean Toste*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California-Berkeley,
Berkeley, California 94720
Received June 24, 2004; E-mail: fdtoste@berkeley.edu
Table 1. Au(I)-Catalyzed Synthesis of Bicyclo[3.1.0]hexenesa
Transition metal-catalyzed isomerization and rearrangement
reactions of unsaturated systems provide access to structural motifs
not accessible through their thermal counterparts. This is exempli-
fied by the numerous applications of transition metal-catalyzed
Alder-ene reactions of 1,6- and 1,7-enynes for the synthesis of
cyclopentyl and cyclohexyl ring systems.1 The corresponding
skeletal rearrangements of simple 1,5-enynes are much less studied.
Berson and co-workers conjectured that the thermal rearrangement
of 1,5-enyne 1 proceeds via bicyclo[3.1.0]hexene 2 to afford toluene
and triene 3 as the major constituents of a complex mixture.2 Scat-
tered reports of transition metal-catalyzed isomerizations of 1,5-en-
ynes3 exist; however, these generally employ enol ethers as the
ene component.4,5 While enols are expected to be excellent nucleo-
philes,6 we were intrigued by the possibility that metal-alkyne
complexes could be electrophilic enough to react even with simple
olefins and catalyze processes related to the thermal rearrangement.
To this end, treatment of 1,5-enyne 4 with 1 mol % palladium-
(II) or platinum(II) complexes returned mainly starting material (eq
2). Both silver(I) tetrafluoroborate and triphenylphosphinegold(I)
chloride failed to catalyze the rearrangement of 4. On the other
hand, the combination of these two complexes7 rapidly (5 min)
and cleanly produced bicyclo[3.1.0]hexene8 5, an olefin isomer of
the proposed intermediate (2) in the thermal isomerization. In sharp
contrast to the gold(I)-catalyzed cyclizations of ω-alkynyl â-ke-
toesters,9 none of the competing 5-exo-dig cyclization to afford an
exo-methylene product was observed. Finally, gold(III) chloride also
catalyzed this reaction, however, with significantly lower conver-
sion. On the other hand, 5% AuCl3 with 15% AgOTf gave complete
conversion; however, this was accompanied by a substantial amount
of decomposition.
a Reaction conditions: 0.5 M 1,5-enyne in dichloromethane, rt. b Dia-
stereomeric ratio determined by 1H NMR. c Starting material (19%) was
recovered.
Terminal and internal alkynyl substrates (entry 4) react with equal
facility, the latter producing an allylic quaternary center. Substrates
containing either 1,1- (entry 5) or 1,2-disubstituted (entries 8-10)
olefins cleanly undergo the gold(I)-catalyzed isomerization. For
example, 3 mol % triphenylphosphinegold(I) hexafluoroantimonate
smoothly catalyzes the formation of 13 by the rearrangement of
1,1-disubstituted olefin 12.
To gain insight into the mechanism of this transformation, we
studied the stereochemical course of the rearrangement. We found
that the gold(I)-catalyzed reaction of substrates containing 1,2-
disubstituted olefins is stereospecific. For example, (E)-olefin 18
selectively affords trans-cyclopropane 19 (entry 8), while (Z)-olefin
20 produces a 97:3 mixture of diastereomers in favor of cis-
cyclopropane 21 (entry 9). Additionally, enantioenriched 1,5-enyne
22 is isomerized to 23 with excellent chirality transfer (entry 10).12
Finally, deuterium-labeled 1,5-enyne 24 underwent gold(I)-catalyzed
conversion to a bicyclo[3.1.0]hexene (25) in which the deuterium
was selectively incorporated at the vinyl position (eq 3).
A range of 1,5-enynes undergo the triphenylphosphinegold(I)-
catalyzed rearrangement (Table 1). The propargylic position can
be unsubstituted (entry 6) or substituted with aryl (entries 1-5) or
alkyl substituents (entries 8 and 9). Additionally, potentially
nucleophilic aromatic groups (entry 2) do not interfere with the
reaction.10 Introduction of an alkyl group at the allylic position is
also tolerated, producing bicyclo[3.1.0]hexene 15 as a 10:1 mixture
of diastereomers11 (entry 6). The rearrangement proceeds when the
1,5-enyne (16) is unsubstituted at both the allylic and propargylic
positions, albeit with slightly decreased efficiency (entry 7).
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10.1021/ja046248w CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Mechanistic Proposal for Au(I)-Catalyzed
Cycloisomerization
On the basis of these data, we propose the process detailed in
Scheme 1 as the most likely mechanism for this transformation.
Coordination of cationic gold(I) to the alkyne followed by nucleo-
philic addition of the pendant olefin produces cyclopropylcarbinyl13
cation 27, which may have some gold(I) carbene character (28).
The bicyclo[3.1.0]hexene product is generated by a 1,2-hydrogen
shift onto a cation or a gold(I) carbene. The stereoselectivity and
stereospecificity of the reaction can be accounted for by considering
half-chair transition states, with the large groups occupying
pseudoequatorial positions, similar to those proposed for the
acetylenic Cope rearrangement.14
The proposed mechanism suggests that cationic intermediate 27/
28 could potentially be trapped in the presence of a nucleophile.
In accord with this hypothesis, cyclohexenyl methyl ether 30 was
produced when the gold(I)-catalyzed reaction of enyne 29 was
carried out in methanol (eq 4).15 Notably, for this reaction the
presence of a quaternary carbon at the propargylic position is
necessary to prevent competing formation of the bicyclo[3.1.0]-
hexene; however, in the absence of nucleophile, a 1,2-alkyl shift
is observed. For example, 1,5-enynes 31a and 31b undergo a gold-
(I)-catalyzed tandem cycloisomerization-ring enlargement process16
to afford tricyclic structure 32a and 32b in 72 and 66% yield,
respectively (eq 5).
References
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(7) In general, lower yields of bicyclo[3.1.0]hexenes were obtained when PPh3-
AuOTf (generated from PPh3AuMe/TfOH or PPh3AuCl/AgOTf) was
employed as the catalyst.
(8) For a review on bicyclo[n.1.0]alkenes, see: Billups, W. E.; Haley, M.
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(11) Major diastereomer was assigned on the basis of the NOE measurements
detailed in Supporting Information.
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In conclusion, we have developed a transition metal-catalyzed
rearrangement of 1,5-enynes that produces bicyclo[3.1.0]hexenyl
products that are isomeric to those produced as intermediates in
the thermal reaction. The gold(I)-catalyzed reaction can be con-
ducted under “open-flask” conditions and as such can be combined
with our rhenium-catalyzed propargylic allylation17 to provide a
one-pot synthesis of bicyclo[3.1.0]hexenes from propargyl alcohols
(eq 6). This carbon-carbon bond-forming reaction provides a
stereospecific method for the synthesis of a variety of cyclopropane
containing carbocycles, including tricyclic structures prepared by
a tandem cycloisomerization-ring enlargement reaction. Develop-
ment of gold(I)-catalyzed18 carbon-carbon bond-forming reactions,
including an enantioselective version of this cycloisomerization, is
ongoing and will be reported in due course.
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, Merck Research Laboratories, and Amgen,
Inc., for financial support. The Center for New Directions in Organic
Synthesis is supported by Bristol-Myers Squibb as a Sponsoring
Member and Novartis Pharma as a Supporting Member.
(17) Luzung, M. R.; Toste, F. D. Toste J. Am. Chem. Soc. 2003, 125, 15760.
(18) For a review of Au-catalyzed reactions, see: (a) Dyker, G. Angew. Chem.,
Int. Ed. 2000, 39, 4237. (b) Hashmi, A. S. K. Gold Bull. 2003, 23, 3.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA046248W
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