Pt-catalyzed tandem epoxide fragmentation/pentannulation of propargylic esters

Article abstract of DOI:10.1021/ja061549m

A Pt-catalyzed pentannulation of propargylic esters containing an epoxide moiety has been developed. The present transformation achieves the formation of cyclopentenone products as single diastereomers in good yields. The observed products likely form fro

Full text of DOI:10.1021/ja061549m

Published on Web 05/06/2006
Pt-Catalyzed Tandem Epoxide Fragmentation/Pentannulation of
Propargylic Esters
Brian G. Pujanauski, B. A. Bhanu Prasad, and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received March 6, 2006; E-mail: rsarpong@berkeley.edu
Scheme 1
The development of new pentannulation reactions continues to
be an important pursuit in synthetic organic chemistry due to the
prevalence of five-membered rings in natural products. While var-
ious traditional approaches such as the Nazarov,1 Pauson-Khand,2
and Karpf-Dreiding3 reactions have provided access to pentacyclic
structures, there remains a need to develop more efficient organic
transformations in this regard.4,5 Recently we reported a Pt-catalyzed
pentannulation reaction, an example of which is outlined in eq 1.6
Table 1. Cycloisomerization of Epoxide Substratesa
In these reactions, readily obtained propargylic esters such as 1
are converted to highly functionalized indenes (2) under platinum
catalysis, presumably via the intermediacy of a metallocarbenoid.7
With the success of these processes, we sought to develop other
bond forming transformations of propargylic esters. We envisioned
a substrate such as 3 (Scheme 1) could undergo Pt-catalyzed 5-exo-
dig cyclization to produce 4. Zwitterion 4 could give rise to
metallocarbenoid 5, which should be electrophilic enough to be
attacked by the epoxide oxygen. The resulting strained intermediate
6 should then undergo bond isomerization to yield pyran 7, which
may exist in equilibrium with the ring-opened tautomer, 8, via an
oxa-6π electrocyclization. We theorized that acetoxy-bearing di-
enone 8 would, in turn, cyclize to the pentannulated product 9.8
The requisite substrates to test this hypothesis (e.g., 3) were rea-
dily prepared in three steps in high overall yield, albeit as a mixture
of diastereomers.9 To our delight, exposure of a 3:1 diastereomeric
mixture of propargylic acetate 3 to catalytic Pt(II) gave a single
diastereomer of pentannulated bicyclic product 9 in 72% yield. As
shown in Table 1, this reaction is general for a range of propargylic
esters using an optimized set of conditions (10 mol % PtCl2, 0.10
M in PhMe, 100 °C). Various ring sizes readily participate in this
epoxide fragmentation pentannulation reaction (entries 1, 2, and
4) and lead to good yields of the desired bicyclic products. Methyl,
ethyl, and benzyl esters are all easily tolerated at the terminus of
the alkyne (entry 2). Likewise, propargylic acetates, benzoates, and
pivalates are transformed to the pentannulated products (entry 3)
in comparable yields. Additionally, acyclic compounds serve as
competent substrates in the cycloisomerization to afford function-
alized cyclopentenone products (entries 6 and 7).
We sought to extend the scope of this transformation by em-
ploying substrates that bear substituents other than alkyl carboxyl-
ates at the terminus of the alkyne. Our studies utilized epoxides
10, 13, and 16 (see eqs 2, 3, and 4, respectively).11 Under our op-
timized conditions (see Table 1), 10 was converted over 6 h to the
desired bicycle 11a/b (60% yield)12 along with pyran isomer 12
(19% yield). In contrast, 13 gave only trace conversion under the
same conditions. However, under the protocol first reported by Ya-
mamoto (10 mol % PtCl2, 20 mol % cyclooctadiene, 0.2 M in Ph-
Me, 100 °C, 6 h),13 propargylic acetate 13 was transformed to
dienone 14 in 65% yield.14,15 Additional heating (12 h) under the
same reaction conditions resulted in the net loss of AcOH and
a Reaction conditions: 10 mol % PtCl2, 0.10 M in PhMe, 100 °C. b Only the
major diastereomer of the substrate is shown although syn/anti mixtures were
used.10 c Only a single diastereomer of the product was obtained in each case.
formation of bicyclic dienone 15 as the sole product. Furthermore,
under the Yamamoto conditions, terminal alkyne 16 was smoothly
converted in high yield to the pentannulated product 17.16
Subsequent studies with the p-chlorobenzoate substrate 18
(Scheme 2) led to a 3:1 mixture of pentannulated bicycle 19 and
pyran 20, respectively, under our standard reaction conditions.
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10.1021/ja061549m CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Acknowledgment. The authors are grateful to U.C. Berkeley,
Eli Lilly, and GlaxoSmithKline (New Faculty award to R.S.) for
generous financial support. The authors also thank Dr. Herman van
Halbeek for extensive NMR assistance and Drs. Fred Hollander
and Allen Oliver for crystallographic data.
Supporting Information Available: Experimental details and
characterization data for all new compounds are available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For recent reviews, see: (a) Tius, M. A. Eur. J. Org. Chem. 2005, 2193-
2206. (b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577-7606.
(2) For a recent review, see: Geis, O.; Schma¨lz, H.-G. Angew. Chem., Int.
Ed. 1998, 37, 911-914.
(3) Karpf, M.; Dreiding, A. S. HelV. Chim. Acta 1979, 62, 852-856.
(4) For seminal examples of pentannulations, see: (a) Rautenstrauch, V. J.
Org. Chem. 1984, 49, 950-952. (b) Mainetti, E.; Mourie´s, V.; Fenster-
bank, L.; Malacria, M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002,
41, 2132-2135.
Scheme 2
(5) For recent examples of pentannulations, see: (a) Shintani, R.; Okamoto,
K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 2872-2873. (b) Yamabe,
H.; Mizuno, A.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2005, 127,
3248-3249. (c) Shi, X.; Gorin, D.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 5802-5803. (d) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128,
1442-1443.
(6) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem. Soc.
2005, 127, 12468-12469.
(7) For early examples of metallocarbenoids generated from propargylic
acetates, see: (a) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am.
Chem. Soc. 2004, 126, 8654-8655. (b) Miki, K.; Ohe, K.; Uemura, S. J.
Org. Chem. 2003, 68, 8505-8513. (c) Harrak, Y.; Biaszykowski, C.;
Benard, M.; Cariou, K.; Mainetti, E.; Mourie´s, V.; Dhimane, A.-L.;
Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004, 126, 8656-8657.
(8) To the best of our knowledge, transformations of the type 8f9 are
unprecedented.
Bicycle 19 provided single crystals suitable for X-ray crystal-
(9) For complete synthesis details, see Supporting Information and (a) Marson,
C. M.; Harper, S. J. Org. Chem. 1998, 63, 9223-9231. (b) Marson, C.
M.; Harper, S.; Oare, C. A.; Walsgrove, T. J. Org. Chem. 1998, 63, 3798-
3799.
lography (Figure 1).
(10) For a definition of syn/anti and assignment of major diastereomer, see:
Marson, C. M.; Benzies, D. W. M.; Hobson, A. D. Tetrahedron 1991,
47, 5491-5506.
(11) For experimental details of the synthesis of substrates 10, 13, and 16, see
Supporting Information.
(12) Obtained as an inseparable mixture (1:1.2) of 11a and 11b, respectively.
(13) (a) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022-15023. (b) Subsequent studies have revealed PtCl2 alone
effects the conversion 13f15 over prolonged heating ()12 h).
(14) The conversion 13f14 likely proceeds via 24, which results from an
initially formed allenyl intermediate 23. For Pt(II)-catalyzed reactions of
propargylic esters bearing a phenyl at the alkyne terminus, see: Cariou,
K.; Mainetti, E.; Fensterbank, L.; Malacria, M. Tetrahedron 2004, 60,
9745-9755.
Figure 1. ORTEP illustration of cyclopentenone 19 with thermal ellipsoids
drawn at 50% probability (hydrogens are omitted).
As shown in the ORTEP depiction of 19,17 a syn stereochemical
relationship is evident between the bridgehead hydrogen and the
p-chlorobenzoate moiety. Interestingly, re-exposure of pyran 20 to
the reaction conditions afforded 19 exclusively upon heating over
10 h.18
On the basis of these observations, and in accordance with our
proposed mechanism (Scheme 1), the pentannulated bicyclic pro-
ducts (e.g., 19) likely arise from pyran intermediates such as 20.19
This may occur through an initial oxa-6π-electrocyclization to yield
21 followed by C-C bond formation with attendant acyl shift via
the presumed intermediate 22. The relative stereochemistry of the
resulting vicinal stereocenters can be accounted for by a conrotatory
4π electrocyclic ring closure in the C-C bond-forming step.
In conclusion, we have developed an efficient method for pen-
tannulation using acyloxy-functionalized pyrans that evolve from
readily available propargylic esters. Utilizing a range of epoxides,
pentannulation is achieved using PtCl2 to obtain bicycles containing
a tertiary stereocenter. To the best of our knowledge, this work
represents the first example of the use of pyrans such as 20 in the
construction of carbon-carbon bonds. Further studies to probe the
mechanism of this transformation and broaden the scope to include
enantio- and diastereoselective examples and applications thereof
in natural product synthesis are currently ongoing and will be
reported in due course.
(15) Substrates similar to 13 bearing either a cyclopropane or 1-cyclohexene
at the terminus of the alkyne demonstrated analogous reactivity.
(16) The secondary propargylic acetate 25 bearing a terminal alkyne is also
efficiently converted to cyclopentenone 26 under Pt(II) catalysis.
(17) The ORTEP depiction of 19 is enantiomeric to the structure drawn in
Scheme 2. Stereoviews and crystallographic data are in the Supporting
Information.
(18) In the absence of PtCl2, pyran 20 remained unchanged upon heating.
(19) Isolation of pyran isomer 12 (eq 2) and subsequent 1H NMR studies with
10 also corroborate this hypothesis. Using propargylic acetate 10 as
substrate (0.1 M in PhMe, 10 mol % PtCl2) and monitoring aliquots of
the reaction mixture at 3-h intervals, initially observed proton resonances
characteristic of dienone and pyran intermediates converged over 10 h at
100 °C to resonances corresponding to bicycles 11a and 11b.
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