Hydroxyl-directed cyclizations of 1,6-enynes

Article abstract of DOI:10.1021/ol200157x

The palladium-catalyzed, hydroxyl-directed cyclization reactions of 1,6-enynes provide a highly diastereoselective process for the syntheses of stereochemically defined cyclopentanes. Consistently high levels of cis-selectivity are possible using homoprop

Full text of DOI:10.1021/ol200157x

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1517–1519
Hydroxyl-Directed Cyclizations of
1,6-Enynes
Andrew M. Camelio, Thomas Barton, Fenghai Guo, Travis Shaw, and Dionicio Siegel*
Department of Chemistry and Biochemistry, The University of Texas at Austin,
1 University Station, Austin, Texas 78712, United States
dsiegel@cm.utexas.edu
Received January 18, 2011
ABSTRACT
The palladium-catalyzed, hydroxyl-directed cyclization reactions of 1,6-enynes provide a highly diastereoselective process for the syntheses of
stereochemically defined cyclopentanes. Consistently high levels of cis-selectivity are possible using homopropargyl alcohols in contrast to the
corresponding propargyl alcohols. Hydroborylative enyne cyclizations coupled with this directing group effect provide a useful method for the
syntheses of multifaceted compounds bearing all carbon quaternary centers.
The intuitive implementation and reliability of substrate-
directed reactions makes them ideal transformations for
complex molecule syntheses. The noncovalent interactions
that direct these reactions provide outcomes that oppose the
typically repulsive effects of adjacent substituents.1 The
ability to diastereoselectively perform the cyclization reac-
tions of 1,6-enynes provides an added attribute to this
already useful transformation.2 Recently, the use of ester
functionalities as directing groups has provided remarkable
control, allowing alternative products to be formed depend-
ing on the metal catalyst used.2c Herein we report the
pronounced directing group effects of homopropargyl alco-
hols on the borylative cyclization reactions of 1,6-enynes.
In the course of our efforts to develop a synthetic route
to stolonidiol, a marine derived diterpenoid capable of
inducing the biosynthesis of choline acetyltransferase
(ChAT),3,4 we plan to implement a key Pd-catalyzed enyne
cyclization to form the 5- and 11-membered rings of the
natural product in a single operation. To test the potential
directing effect of homopropargyl alcohol within our
system on the enyne cyclization we examined the reaction
using a borylative enyne cyclization.5 The initial study
examined the cyclization reaction of homopropargyl alco-
hol 1 which was shown to proceed with good diastereo-
selectivity (10:1), providing the cis-product 2 as the major
diastereomer (eq 1).
To test the generality of this diastereocontrol several
cyclization substrates, propargyl and homopropargyl al-
cohols, were synthesized and subjected to the borylative
cyclization. The addition of acetylide anions into 4-methyl-
4-pentenal (3) provided the corresponding propargyl alco-
hols represented by 4 (Scheme 1).6,7 In addition to provid-
ing access to the corresponding homopropargylic system
these alcohols were used to study the diastereoselectivities
possible using propargyl alcohols as directing groups.
(1) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
(2) For review, see: (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (b)
^
Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008,
47, 4268. Recent example of an ester directed enyne cyclizations:
(c) Trost, B. M.; Ferreira, E. M.; Gutierrez, A. C. J. Am. Chem. Soc.
2008, 130, 16176.
(3) (a) Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.; Inouye, Y.
Tetrahedron Lett. 1987, 28, 5673. (b) Yabe, T.; Yamada, H.;
Shimomura, M.; Miyaoka, H.; Yamada, Y. J. Nat. Prod. 2000, 63, 433.
(4) Miyaoka, H.; Baba, T.; Mitome, H.; Yamada, Y. Tetrahedron
Lett. 2001, 42, 9233.
(5) (a) Marco-Martinez, J.; Lopez-Carrillo, V.; Bunuel, E.; Simancas,
R.; Cardenas, D. J. J. Am. Chem. Soc. 2007, 129, 1874. (b) Marco-
~
~
Martinez, J.; Bunuel, E.; Munoz-Rodriguez, R.; Cardenas, D. J. Org.
ꢀ
Lett. 2008, 10, 3619.
r
10.1021/ol200157x
2011 American Chemical Society
Published on Web 02/11/2011

Table 2. Diastereoselective, Borylative Enyne Cyclizations of
Homopropargyl Alcoholsa
Scheme 1
Alternatively, conversion of the alcohols to either propar-
gyl bromides or mesylates generated precursors for reac-
tions with either formaldehyde or acetone, yielding a series
of homopropargyl alcohols exemplified by 7 and 8. Barb-
ier-type reactions with formaldehyde were optimally per-
formed using indium, formalin, and bromides 5 providing
Table 1. Diastereoselective, Borylative Enyne Cyclizations of
Propargyl Alcoholsa
a Yields quoted are isolated yields. Stereoselectivities were deter-
mined by 1H NMR spectroscopy of the crude mixture. The relative
stereochemistries were determined by NOE measurements and X-ray
crystallography.
the primary alcohols 7.8 The reaction of the propargyl
mesylates 11 with acetone was accomplished using diethyl
zinc and tetrakis(triphenylphosphine)palladium, forming
the corresponding tertiary alcohol products 9.9
The cyclization reactions of propargyl alcohols and
ethers using the palladium catalyzed borylative cyclization
were examined using substrates 9-14 (Table 1).5 Treat-
ment of the propargyl alcohols with palladium acetate,
methanol, and bis(pinicolato)diborane provided the cy-
clized products with no to moderate selectivity and vari-
able yields. To facilitate the determination of the ratios of
the products, the boronate esters were oxidized using basic
solutions of hydrogen peroxide generating the correspond-
ing diol products.10 Propargyl alcohol 9 proved to be
(6) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55,
4144.
(7) Wakefield, B. J. Organolithium Methods; Academic: London, 1988;
pp 32-44.
(8) Chan, T.-H.; Li, C.-J. Tetrahedron 1999, 55, 11149.
(9) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
a Yields quoted are isolated yields. Stereoselectivities were deter-
mined by 1H NMR spectroscopy of the crude mixture, with relative
stereochemistries determined by NOE measurements.
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Org. Lett., Vol. 13, No. 6, 2011

unreactive under the cyclization conditions; however, the
corresponding methyl ether 10 formed the expected prod-
ucts in 57% yield and as a 1:1 mixture of isomers. Enyne 11
provided the corresponding diols in 91% yield (2.5:1 ratio
cis/trans), and enyne 12 proved nonselective in the cycliza-
tion reaction proceeding with a yield of 46%. An interest-
ing exception in the propargyl alcohol series, the TMS
substituted alkyne 13 cyclized providing an 8.5:1 cis/trans
ratio of products in good yield. The related methyl ether 14
proveda poor candidateforcyclization andgenerateda 1:1
ratio of diastereomers.
alcohols also provide a handle for carbon bond formation.
The conversion of homoallyl alcohol 2 to acetophenone 21
through a palladium-catalyzed retro-allylationprovides an
example of a useful carbon-carbon bond forming trans-
formation (eq 2).11
The cyclizations of the homopropargyl alcohols using
the ligandless palladium conditions provided the cis-
product with good to excellent diastereoselectivities and
moderate to good yields (Table 2). Enyne 15 cyclized
providing the cis product as the major isomer in a ratio
of 10:1 (cis/trans) in 75% yield. Substrates with additional
substitution on the alkyne, 16 and 17, generated the
cyclized products with excellent selectivity in excess of
19:1. The cyclizations of tertiary alcohols 1 and 19 were
accomplished with good and excellent selectivities, respec-
tively, demonstrating the strong directing effect from the
homopropargyl position. The sterically congested enyne
18 proved resistant to the reaction conditions returning
unchanged starting material. Cyclization of silyl ether 20
resulted in a nonselective reaction providing support for
the importance of the alcohol in directing the reaction.
Aside from reactions of the boronate esters gene-
rated through the course of the reactions the homoallylic
The directing effects of propargyl alcohols have proven
variable; however, the cyclizations of homopropargyl
alcohols proceed with high levels of diastereoselectivity.
The directing group effects of the homopropargyl alcohols
leads to the cis-placement of the boronate esters even when
sterically congested tertiary alcohols are used as directing
groups. Starting from simple precursors the boronic esters
and diol products are expected to provide new, stereoche-
mically defined compounds for complex molecule
synthesis.
Acknowledgment. The authors are grateful for the
financial support by the Welch Foundation (F-1694),
Texas Institute for Drug and Diagnostic Development,
and The University of Texas at Austin.
Supporting Information Available. Detailed experi-
mental procedures and full spectroscopic characteriza-
tion data for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(10) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81, 247.
(11) (a) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am.
Chem. Soc. 2006, 128, 2210. (b) Iwasaki, M.; Hayashi, S.; Hirano, K.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 4463.
Org. Lett., Vol. 13, No. 6, 2011
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