Gold(I)-catalyzed synthesis of dihydropyrans

Article abstract of DOI:10.1021/ja061344d

A trinuclear gold(I)-oxo complex, [(Ph₃PAu)₃O]BF₄, serves as the catalyst for the stereocontrolled synthesis of 2-hydroxy-3,6-dihydropyrans from propargyl vinyl ethers. Importantly, the rearrangement proceeds with excellen

Full text of DOI:10.1021/ja061344d

Published on Web 06/02/2006
Gold(I)-Catalyzed Synthesis of Dihydropyrans
Benjamin D. Sherry, Lisa Maus, Brian Ngo Laforteza, and F. Dean Toste*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720
Received February 24, 2006; E-mail: fdtoste@uclink.berkeley.edu
Table 1. Au(I)-Catalyzed Pyran Synthesis
The stereoselective preparation of pyran-containing molecules
is a continuing challenge in organic synthesis.1 Cascade sequences
that afford the pyran framework from an acyclic precursor, with
the concurrent installation of multiple stereocenters, offer a
particularly attractive approach.2,3 Our recent finding of a gold(I)-
catalyzed propargyl Claisen rearrangement4 prompted us to consider
nucleophilic addition to the proposed oxocarbenium intermediate
(A)5 as a complimentary method for the stereoselective synthesis
of dihydropyrans (eq 1). We anticipated that formation of the
â-allenic aldehyde could be competitive with the trapping of A;
however, A may be re-formed by subsequent 6-endo-trig hetero-
cyclization of the aldehyde onto the allene. To execute this tandem
propargyl Claisen rearrangement/heterocyclization, the Au(I) com-
plex must catalyze two distinct reactions by sequential activation
of an alkyne and an allene.6,7
a Isolated as a 1-1.3:1 mixture of anomers after purification by column
chromatography.
they failed to undergo the subsequent heterocyclization to deliver
useful yields of the desired pyran product.10 The propargyl position
was also tolerant of substitution, including linear, branched, and
oxygenated substituents (entries 6-8). Furthermore, an electron-
rich alkene (entry 9) and N-tosyl indole (entry 10)-derived substrates
showed high selectivity for the desired pyran formation.
We have previously demonstrated that the gold(I)-catalyzed
propargyl Claisen rearrangement proceeds to afford allenes with
excellent diastereocontrol and chirality transfer from the propargyl
ether stereocenter. On the basis of these results, we hypothesized
that the gold(I)-catalyzed reaction might provide a stereoselective
synthesis of pyrans. Gratifyingly, (E)-1,2-disubstituted enol ethers
rearranged stereoselectively to give 3,6-syn-substituted pyrans as
a 4-6:1 mixture of anomers (eq 3).11 Moreover, gold(I)-catalyzed
rearrangement of enantioenriched ether 5f affords pyran 6f with
only a minor decrease in the enantiomeric excess.12
A fundamental obstacle to accessing pyrans by this approach is
the tendency of allenes to undergo preferential 5-exo-dig cycliza-
tions (eq 1).7,8 Therefore, at the outset of this work, we sought to
define a system wherein cyclization would occur with the opposite
regiochemical outcome. Subjecting propargyl vinyl ether 2 to our
previously reported conditions for the [(Ph3PAu)3O]BF4 (1)-
catalyzed propargyl Claisen rearrangement led to formation of
expected allenic aldehyde 3.4a Gratifyingly resubjecting 3 to the
Au(I) catalyst, but in wet dioxane9 rather than methylene chloride,
led to formation of desired 2-hydroxy-3,6-dihydropyran 4. Confident
that heterocyclization could follow the desired 6-endo-trig pathway,
the Claisen/heterocyclization cascade for the synthesis of pyrans
directly from 2 was examined. To this end, reaction of propargyl
vinyl ether with 1 mol % of Au(I) catalyst 1 in wet dioxane led to
formation of desired pyran 4 in 86% yield.
Having demonstrated the efficient generation of pyrans directly
from an enol ether starting material, we set out to define the scope
of this Au(I)-catalyzed reaction (Table 1). Substitution at the alkyne
terminus was well tolerated, encompassing linear (entries 1, 2, and
6-10), branched (entry 5), and cyclic groups (entries 3 and 4).
Additionally, primary tosylate (entry 1) and nitrile (entry 2) were
compatible with the Au(I) catalyst. While terminal alkynes are
viable substrates for the gold(I)-catalyzed Claisen rearrangement,4a
We envisioned that replacing water with a pendant alcohol as
nucleophile might provide a stereoselective entry into spiroketals.6h,13
To this end, 5,6- (10a) and 6,6-spiroketals (10b) were generated
in good yield and with excellent diastereocontrol from the reaction
of alcohols 9a,b with 1 mol % of Au(I)-oxo catalyst 1. Further-
more, treatment of enantiomerically enriched propargyl vinyl ether
11 led to the formation of spiroketal 12 with complete chirality
transfer. Therefore from a linear precursor, in a single step, the
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J. AM. CHEM. SOC. 2006, 128, 8132-8133
10.1021/ja061344d CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
bicyclic spiroketal framework is established with complete stereo-
control over three centers and an alkene functional group in the
product that could be engaged in post-cyclization diastereoselective
transformations.
financial support. B.D.S. thanks Eli Lilly & Co. for a graduate
fellowship. L.M. thanks the German National Academic Foundation.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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On the basis of these results, we envision two plausible pathways
for this transformation. Both initiate by Au(I) coordination to the
alkyne and addition of the pendant enol ether to afford cationic in-
termediate A (eq 1). In one case, intermolecular trapping of A by
water or alcohol generates the pyran directly, after protonation of the
vinyl gold intermediate. Alternatively, Grob-type fragmentation of
A to an allenic aldehyde, followed by 6-endo-trig addition of the
aldehyde, regenerates A, which can be trapped by water or alcohol.15
To investigate this hypothesis, propargyl vinyl ether 16 bearing a
pendant aldehyde was prepared. Subjecting 16 to the optimized
reaction conditions led to a 3.3:1.0 mixture of 18:19. Alternatively,
when dialdehyde 17 was subjected to the Au(I) catalyst, a 1.0:9.4
mixture of 18:19 was obtained. Taken together, these results suggest
a mechanism wherein fragmentation of A occurs at a rate slower
than, but competitive with, direct nucleophilic trapping (eq 9).
(9) Reaction in CH2Cl2 gave only allenyl aldehyde 2 even the presence of
water. THF and dioxane afforded the desired pyran in 14 and 4 h,
respectively. Reactions in DME returned only starting material.
(10) Gold(I)-catalyzed reaction of a terminal alkyne (Table 1, 5 R1 ) Ph-
(CH2)2, R2 ) H) afforded a 1:1.6:0.5 ratio of the desired dihydropyran:
furan:8aan unidentified aldehyde.
(11) Relative stereochemistry was ascertained through nOe analysis; see
Supporting Information for details.
(12) The enantiomeric excess of pyran 6f was determined after in situ reduction
to the corresponding allylic alcohol (see Supporting Information for
details).
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(15) An alternative mechanism in which gold(I) catalyzes the addition of the
hemiacetal, not the aldehyde, to the allene is also possible. See: (a) Asao,
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In conclusion, we have developed a gold(I)-catalyzed method
for the stereocontrolled synthesis of 2-hydroxy-3,6-dihydropyrans
from propargyl vinyl ethers. This reaction is amenable to the
synthesis of spirocyclic compounds from appropriately function-
alized precursors. Efforts aimed at elucidating the mechanism of
this transformation and applications of this methodology in natural
product synthesis are ongoing and will be reported in due course.
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, NIHGMS (R01 GM073932-01), Merck
Research Laboratories, Bristol-Myers Squibb, Amgen Inc., DuPont,
GlaxoSmithKline, Eli Lilly & Co., Pfizer, and AstraZeneca for
JA061344D
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