Palladium-mediated transannular cyclizations of medium-ring olefinic enolsilanes

Article abstract of DOI:10.1016/j.tetlet.2005.09.125

Medium-ring olefinic ketone and lactone enolsilanes were subjected to palladium(II)-mediated cycloalkenylation conditions. Diverse bicyclic ring products were obtained in moderate to good yields. The effect of olefin geometry and ring size is discussed.

Full text of DOI:10.1016/j.tetlet.2005.09.125

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8149–8152
Palladium-mediated transannular cyclizations
of medium-ring olefinic enolsilanes
b
a
Andrew S. Kende,a, Clara E. Mota Nelson and Sebastien Fuchs
*
´
aDepartment of Chemistry, University of Rochester, PO Box 270216, Rochester, NY 14627, USA
bPPG Industries Inc., Allison Park, PA 15101, USA
Received 14 September 2005; revised 19 September 2005; accepted 20 September 2005
Available online 7 October 2005
Abstract—Medium-ring olefinic ketone and lactone enolsilanes were subjected to palladium(II)-mediated cycloalkenylation condi-
tions. Diverse bicyclic ring products were obtained in moderate to good yields. The effect of olefin geometry and ring size is
discussed.
Ó 2005 Elsevier Ltd. All rights reserved.
Palladium(II)-mediated cyclization of olefinic enol
ethers is a powerful and reasonably general method
for cycloalkenylation reactions in which a new car-
bon–carbon bond is formed from the enolic center to
an alkene. First observed by Saegusa et al. in 1979,1 this
reaction was soon shown to be an efficient route to
numerous bridged and spirocyclic bicycloalkenones2
and subsequently exploited as a key step in the synthesis
of several natural products.3
OTBDMS
TBDMSO
1
2
OTBDMS
1
OTBDMS
1
10
10
3
4
While the scope of these palladium-mediated cycloalke-
nylations has been the subject of several detailed sur-
veys,4 we are unaware of such cyclizations in which
both the enolsilane and the olefin are in the same ring.
We now report the course of such reactions in selected
medium-ring enolsilanes represented by the cyclonona-
dienes 1 and 2, the cyclodecadienes 3 and 4, and the lac-
tone derivatives 5 and 6 (Scheme 1).
OTBDMS
O
TBDMSO
O
5
6
Scheme 1.
Whereas the silylations8 of symmetrical nine-membered
ketone precursors to 1 and 2 can form only one possi-
ble enolsilane regioisomer, the 10-membered ketones
are known to undergo regioselective silylation in the
1,10 position.9 The silylations of the macrolactones
12 and 13 were carried out in a slightly different
manner.10
The olefinic ketone precursors to enolsilanes 1–4 were
prepared by known procedures.5 The olefinic lactone
precursors 12 and 13 to ketene acetals 5 and 6 were ob-
tained by macrolactonization, after semi-hydrogenation
of the readily available x-hydroxyalkynoic acids 7 and 8
(Scheme 2).6 Each ring system required a different lact-
onization method to achieve sufficient yields of the very
volatile lactone products.7
The transannular cyclizations11 of the 2 nine-membered
enolsilanes 1 and 2 using stoichiometric Pd(OAc)2 led,
respectively, to two different bicyclo[4.3.0]ketones in
good yields (Scheme 3). (E)-Cycloalkene enolsilane 1
produced the a,b-unsaturated ketone 14,12 whereas the
(Z)-cycloalkene enol silyl ether 2 led to the cis-bicy-
cloalkenone 15.13
Keywords: Palladium(II)-mediated cycloalkenylation; Cyclization;
Medium-ring enolsilanes; Bicyclic ketones/lactones.
*
Corresponding author. Tel.: +1 585 275 4236; fax: +1 585 276
0205; e-mail: kende@chem.rochester.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.125

8150
A. S. Kende et al. / Tetrahedron Letters 46 (2005) 8149–8152
O
CO2R
CO2R
H2, Pd/Ba2SO4
82-93%
OH
macrolactonization
41-46%
OH
O
n
n
n
9 R=Me, n=1
10 R=H, n=1
11 n=2
7 R=Me, n=1
8 R=H, n=2
12 n=1
13 n=2
NaOH
Scheme 2.
OTBDMS
O
leads upon syn palladium b-hydride elimination to the
bicycloalkenone 15.
Pd(OAc)2
MeCN/CH2Cl2
70%
For the 10-membered ring substrates 3 and 4, both
(E)- and (Z)-cycloalkenes produced the trans-bicyclo-
[4.4.0]ketones 1917 and 2018 in moderate yields (Scheme
5). These regioisomeric products were obtained in differ-
ent ratios depending on the olefin geometry of the sub-
strates. Thus, the cyclization of the (E)-cycloalkene
enolsilane 3 gave compounds 19 and 20 in a ratio of
1:1.3, whereas the (Z)-cycloalkene enolsilane 4 produced
these compounds in a 7.5:1 ratio.
1
14
O
H
TBDMSO
Pd(OAc)2
MeCN/CH2Cl2
93%
H
2
15
Scheme 3.
Palladium(II)-mediated cyclization was unsuccessful
when ketene acetals 5 and 6 were treated with Pd(OAc)2.
Only starting ketene-acetal was recovered after 16 h.
The reaction was then carried out with the more electro-
philic palladium trifluoroacetate instead of palladium
acetate. Under these conditions, the reaction product
depended dramatically on ring size (Scheme 6). For
the nine-membered reactant 5, the sole product was
the a,b-unsaturated lactone 21.19 Such dehydrogenation
is a well established side reaction of certain enolsilanes
under Pd(OAc)2 treatment.1 In the case of the 10-mem-
bered ketene acetal 6, Pd(O2CCF3)2 treatment led to the
bicyclic enol lactone 2220,21 and recovered lactone 13.
The structure of 22 was established by 500 MHz 1H
NMR through extensive decoupling of each ring proton
and by oxidative degradation to the known cis cyclopen-
tane diacid 23.22 This diacid had identical melting point,
IR, 1H, and 13C NMR spectra with an authentic sample
The observed regioselectivities in the above reactions are
consistent with the mechanism we had previously envi-
sioned for the palladium(II)-mediated cycloalkenyla-
tion.3a,14 As recently reiterated by Toyota and Ihara,4a
this mechanism comprises a backside nucleophilic attack
by the double bond of the enol-TBS derivative upon the
Pd-coordinated exocyclic olefin.15 Examination of Dre-
iding models of the substrates 1 and 2 during cyclization
predicts that they should lead, respectively, to two differ-
ent sigma-bonded palladium intermediates, namely 16
and 18 (Scheme 4). In the case of the bicyclic intermedi-
ate 16, in which two hydrogens are available for syn pal-
ladium b-hydride elimination,16 the ketone 17 appears
to form, which by subsequent enolization, gives the
a,b-unsaturated ketone 14 as the only isolated product.
On the other hand, the bicyclic intermediate 18, with the
palladium anti to the hydrogen of the ring junction,
O
H
OTBDMS
O
H
H
15
Pd(OAc)2
H
O
O
H
Pd
1
16
14
17
O
O
TBDMSO
H
H
Pd(OAc)2
H
H
15
H
18
Pd
2
Scheme 4.

A. S. Kende et al. / Tetrahedron Letters 46 (2005) 8149–8152
8151
O
H
H
OTBDMS
OTBDMS
19
Pd(OAc)2
Pd(OAc)2
+
MeCN/CH2Cl2
56%
MeCN/CH2Cl2
52%
O
H
4
3
H
20
Scheme 5.
TBDMSO
O
Pd(O2CCF3)2
O
O
MeCN/CH2Cl2
72%
5
21
O
OTBDMS
O
1) O3
H
H
H
COOH
COOH
O
2) DMS
Pd(O2CCF3)2
MeCN/CH2Cl2
3) NaClO2,
H2NSO3H
H
22 (45%)
6
23
61%
+
O
O
H
O
H
13 (49%)
24
Scheme 6.
Toyota, M.; Rudyanto, M.; Ihara, M. J. Org. Chem. 2002,
67, 3374–3386.
of 23 independently prepared from the readily available
ketone 24.23,24
5. Marvell, E. N.; Whalley, W. Tetrahedron Lett. 1970, 509–
512; Holt, D. A. Tetrahedron Lett. 1981, 22, 2243–2246;
Kato, T.; Kondo, H.; Nishino, M.; Tanaka, M.; Hata, G.;
Miyake, M. Bull. Chem. Soc. Jpn. 1980, 53, 2958–2961;
Lange, G. L.; Hall, T.-W. J. Org. Chem. 1974, 39, 3819–
3822.
Our results suggest that such transannular cycloalkenyl-
ations in certain medium rings are reasonably efficient
and offer potential as a strategic element in the synthesis
of polycyclic natural products.
6. For the preparation of the compound 7, see: Adams, J.;
Rokach, J. Tetrahedron Lett. 1984, 25, 35–38; The starting
material 8 was prepared by the alkylation of 5-bromo-
valeric acid with the lithium dianion of 3-butyn-1-ol
following the procedure of Ames, D. E.; Covell, A. N.;
Goodburn, T. G. J. Chem. Soc. 1963, 5889–5893.
7. The nine-membered lactone 12 was isolated in 46% yield
from the hydroxyacid 10 by using the 2-thiopyridyl
ester method: Corey, E. J.; Nicolaou, K. C. J. Am. Chem.
Soc. 1974, 96, 5614–5616. MukaiyamaÕs procedure was
used to prepare the 10-membered lactone 13 (41%):
Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976,
49–50.
8. Silylations of the ketone precursors were typically carried
out by adding a solution of the ketone in dry THF to
lithium diisopropylamide (1.1 equiv) in dry THF at
À78 °C. After stirring 1 h at this temperature, a solution
of DMPU (2 equiv) and TBDMSOTf (1.1 equiv) in dry
THF was added and the reaction mixture was allowed to
References and notes
1. Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa,
T. J. Am. Chem. Soc. 1979, 101, 494–496.
2. Kende, A. S.; Roth, B.; Sanfilipo, P. J. J. Am. Chem. Soc.
1982, 104, 1784–1785; Kende, A. S.; Battista, R. A.;
Sandoval, S. B. Tetrahedron Lett. 1984, 25, 1341–1344;
Toyota, M.; Majo, V. J.; Ihara, M. Tetrahedron Lett.
2001, 42, 1555–1558.
3. (a) Kende, A. S.; Roth, B.; Sanfilipo, P. J.; Blacklock, T. J.
J. Am. Chem. Soc. 1982, 104, 5808–5810; (b) Shibasaki,
M.; Mase, T.; Ikegami, S. J. Am. Chem. Soc. 1986, 108,
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1991, 32, 5911–5914; (d) Toyota, M.; Sasaki, M.; Ihara,
M. Org. Lett. 2003, 5, 1193–1195.
4. (a) Toyota, M.; Ihara, M. Synlett 2002, 1211–1222; (b)
Toyota, M. Rev. Heteroat. Chem. 1999, 21, 231–255; (c)

8152
A. S. Kende et al. / Tetrahedron Letters 46 (2005) 8149–8152
warm to 0 °C. After 1 h, the reaction mixture was
16. Heck, R. F. Acc. Chem. Res. 1979, 12, 146–151; Sato, Y.;
Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33,
2593–2596, see also Ref. 3c.
quenched with an aqueous saturated solution of sodium
bicarbonate, extracted with hexanes, and the organic layer
washed with an aqueous saturated solution of sodium
bicarbonate and brine. The crude yellow oil was purified
by chromatography (silica gel treated with 1% triethyl-
amine in hexanes, 100% hexanes).
17. Spectroscopic data for 19 (1H, 13C NMR, IR, and MS)
were in accord with those of an authentic sample
independently synthesized according to the following
procedures: Oppolzer, W.; Snowden, R. L.; Simmons, D.
P. Helv. Chim. Acta 1981, 64, 2002–2021; Gras, J.-L.;
Bertrand, M. Tetrahedron Lett. 1979, 4549–4552.
18. Spectroscopic data (1H, 13C NMR, and IR) for 20 were in
agreement with literature data: Jones, J. B.; Dodds, D. R.
Can. J. Chem. 1987, 65, 2397–2404.
9. Schreiber, S. L.; Hawley, R. C. Tetrahedron Lett. 1985, 26,
5971–5974.
10. Silylations of the macrolactones were carried out with
HMPA (1.1 equiv) instead of DMPU. The lithium enolate
was trapped with TBDMSCl (1.1 equiv) and slowly
warmed to room temperature. After chromatography,
the very unstable ketene acetals 5 and 6 were used
immediately in the palladium(II) reactions.
19. Spectroscopic data for 21: 1H NMR (CDCl3): d 1.85–2.00
(m, 2H), 2.22–2.30 (m, 2H), 4.20–4.25 (m, 2H), 5.45–5.55
(m, 2H), 5.92 (d, 1H, J = 11 Hz), 6.41–6.50 (m, 1H). GC/
MS (m/e, 70 eV): M+ = 138 (9%), 121, 110, 91, 80, 79
(100%), 68, 53, 41.
11. Cyclizations were typically carried out by addition of a
solution of silyl enol ether in acetonitrile/dichlorometh-
ane, to a solution of palladium acetate (1.0 equiv) in
acetonitrile. After stirring for 16 h under argon at room
temperature, the black solution was evaporated to dryness
under reduced pressure, diluted with hexanes, and filtered
through a plug of Florisil. The filtrate was concentrated,
and the resulting yellow oil purified by chromatography
(silica gel, gradient hexanes 100%—hexanes–ethyl acetate
9:1).
1
20. Spectroscopic data for 22: H NMR (CDCl3): d 1.27 (m,
1H), 1.55 (m, 1H), 1.70–1.80 (m, 2H), 1.95 (m, 1H), 2.17
(m, 2H), 2.31 (m, 1H), 2.69 (m, 1H), 3.15 (m, 1H), 5.66
(dd, 1H, J = 6.1 Hz), 6.40 (d, 1H, J = 6.1 Hz). IR (CHCl3
solution): 2945, 2840–2920, 1740, 1120 cmÀ1. MS (m/e,
70 eV): M+ = 152, 124, 109, 95, 83, 81, 69, 68, 67.
21. The chemical shifts and coupling constants of the vinylic
protons of 22 as well as the infrared maximum for the
carbonyl groupwere consistent with literature data:
12. Spectroscopic data (1H, 13C NMR, and MS) of cycliza-
tion product 14 were identical to those from an authentic
sample obtained during the preparation of the substrate
2.
´
Astudillo, L.; Galindo, A.; Gonzalez, A. G.; Mansilla,
H. Heterocycles 1993, 36, 1075–1080.
22. Ayral-Kaloustian, S.; Wolff, S.; Agosta, W. C. J. Org.
Chem. 1978, 43, 3314–3318.
23. For the preparation of ketone 24, see: Boeckman, R. K.,
Jr. Tetrahedron Lett. 1977, 4281–4284.
24. The compound 23 was obtained in two steps from 24, first
by generating the kinetic enolate of 24 with LDA
(1.2 equiv) in dry THF and trapping with TMSCl
(1.2 equiv), and then by the same oxidative degradation
used to transform 22 to 23, with an overall yield of 39%.
13. Spectroscopic data (1H, 13C NMR, IR, and MS) for 15
were in agreement with literature data: Redmond, K.;
Carpenter, B. K. J. Org. Chem. 1997, 62, 5668–5669;
Hudlicky, T.; Koszyk, F. J.; Dochwat, D. M.; Cantrell, G.
L. J. Org. Chem. 1981, 46, 2911–2915.
14. Kende, A. S.; Wustrow, D. J. Tetrahedron Lett. 1985, 26,
5411–5414.
15. For an alternative mechanistic picture, see Ref. 3c.