Synthesis and PET oxidative cyclization of silyl enol ethers: Build-up of quasi-steroidal carbocycles

Article abstract of DOI:10.1016/S0040-4039(02)02491-7

PET oxidative cyclization of silyl enol ethers carrying suitable side chains with olefinic double bonds results in the stereoselective formation of carbocycles. Two model compounds for investigating the influence of silyl enol ether ring size are synthesi

Full text of DOI:10.1016/S0040-4039(02)02491-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 45–48
Synthesis and PET oxidative cyclization of silyl enol ethers:
build-up of quasi-steroidal carbocycles
Jens O. Bunte,a Stefanie Rinne,a Christian Scha¨fer,a Beate Neumann,b Hans-Georg Stammlerb and
Jochen Mattaya,*
aOrganische Chemie I, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Postfach 100131, 33501 Bielefeld, Germany
bAnorganische Chemie III, Abteilung fu¨r Ro¨ntgenstrukturanalyse, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Postfach 100131,
33501 Bielefeld, Germany
Received 30 October 2002; revised 6 November 2002; accepted 7 November 2002
Abstract—PET oxidative cyclization of silyl enol ethers carrying suitable side chains with olefinic double bonds results in the
stereoselective formation of carbocycles. Two model compounds for investigating the influence of silyl enol ether ring size are
synthesized. Furthermore the synthesis of a quasi-steroidal carbocycle with an unnatural configuration is presented. © 2002
Elsevier Science Ltd. All rights reserved.
The chemistry of electron deficient compounds is a
major topic in recent research.1 Silyl enol ethers repre-
sent a class of electron rich, non-aromatic compounds,
which form reactive radical cations on one electron
oxidation. There is a wide range of methods available
to carry out one-electron oxidations on silyl enol ethers.
Various metal ions like Ce(IV),2 V(V),3 other chemical
oxidants like XeF2,4 or 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone,5 anodic oxidation6 and photoinduced
electron transfer (PET)7 can be used.
Besides processes like further oxidation,5,7a,8 the
intramolecular reaction with double bonds is the most
important reaction of these electron deficient intermedi-
ates (Scheme 1).2,6a,7d,e
In our group, the PET oxidation of silyl enol ethers and
subsequent ring closure reactions have been thoroughly
investigated.7d–f In the course of this research, the regio-
and stereoselective build-up of carbocycles turned out
to be an aspect of synthetic importance. On basis of
these findings, we planned a synthesis of steroid-like
carbocycles by a cascade cyclization of silyl enol ethers.
The key structure of this synthetic strategy is a silyl
enol ether moiety embedded in a carbocycle with a
stereogenic center adjacent to the double bond (Scheme
1). This controls the stereochemistry of the stereogenic
centers built up in the cyclization reaction.
Though silyl enol ethers derived from cyclic ketones
have become an important class of precursors in
organic chemistry, there are only a few general methods
available for their selective synthesis.9 One of the best-
known ways for the regioselective build-up of the silyl
enol ether double bond is the 1,4-addition of
organocopper reagents to enones in the presence of
trimethylsilyl chloride.10 We employed this reaction for
the addition of a methyl group to the desired enone.
For the synthesis of the enone we used the lithiation of
an iodide and addition of this organometallic interme-
diate to a cyclic vinylic ester.11
Scheme 1. Formation of silyl enol ether radical cation and
ring closure reaction.
* Corresponding author.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02491-7

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J. O. Bunte et al. / Tetrahedron Letters 44 (2003) 45–48
With this strategy on hand we have a flexible synthetic
route towards variations of both ring size and side
chain of the silyl enol ether.
The synthetic procedure was applied to the syntheses of
silyl enol ethers 1 and 2 (Scheme 2) as model systems
for investigating the influence of the silyl enol ether ring
size on the stereochemistry of the cyclization.
Iodide 3 was synthesized from cyclohexanone by
known methods.12 Enones 4 and 5 were synthesized by
the described method in 60 and 61% isolated yields,
respectively.
Silyl enol ethers 1 (74% yield) and 2 (85% yield) were
obtained as racemic mixtures.
The PET oxidative cyclization of the six-membered ring
silyl enol ether 2 with DCA (9,10-dicyano-anthracene)
as sensitizer leads to the formation of two
diastereomeric products 7 and 8 in a 90:10 ratio (49%
combined isolated yield). Both cyclization products
have the same 4a-4b-transoid ring connection (Scheme
3) resulting from a completely selective attack of the
radical cation moiety of the initial radical cation on the
cyclohexene double bond leading to the intermediate
radical cation 6. The remaining stereogenic center 8a is
generated by the saturation of the intermediate radical
function in 6 from different sides of the molecule
(Scheme 3). Here a second selectivity is observed yield-
ing the 90:10 ratio of the products.
Scheme 3. PET oxidative cyclization of 2.
In contrast, the cyclization of 1 with DCA as sensitizer
leads to the formation of the diastereomeric products 9,
10 and 11 with a 41:31:28 ratio in 42% combined
isolated yield (Scheme 4).
Obviously the change in ring size has a large effect on
the selectivity of the cyclization reaction. Products 9
and 10 are formed in analogy to 7 and 8. Product 11 is
formed by an attack of the radical cation on the
Scheme 4. PET oxidative cyclization of 1.
cyclohexene double bond with both rings almost
stacked, leading to a 9b-9a-cisoid ring connection. This
mode of ring closure does not occur in the reaction of
2 and only yields one isolable product from the satura-
tion of intermediate radical function,13 presumably due
to greater differences in transition state energies in the
two possible saturation pathways.
The structure determination of 1–5 and 7–11 has been
accomplished with NMR spectroscopy (1H, 13C, DEPT,
HSQC, HMBC), MS(EI), HRMS and IR. The assign-
ment of configuration in the cyclization products 7, 8,
9–11 has been carried out with NMR spectroscopy by
NOESY experiments in combination with determina-
tion of all necessary 1H/1H coupling constants and
comparison of these results with the geometry of the
possible diastereomeric cyclization products obtained
by calculation of conformer distributions on semi-
empirical level (AM1).
To explore the possibilities of syntheses of steroidal
tetracycles by cascade cyclizations of silyl enol ether
radical cations, we chose a silyl enol ether with a
Scheme 2. Syntheses of model silyl enol ethers 1 and 2.

J. O. Bunte et al. / Tetrahedron Letters 44 (2003) 45–48
47
six-membered ring and a side chain derived from (S)-
perillyl alcohol 12 (Scheme 5). Iodide 13 was synthesized
in 53% yield from 12 in analogy to known methods.14
The described strategy leads to the formation of enone
14 (64% yield) and silyl enol ether 15 (84% yield) as an
inseparable mixture of the two diastereomers.
In conclusion, we presented a new synthetic strategy for
building up polycyclic carbon frameworks by cascade
cyclization utilizing silyl enol ethers as a source of
reactive radical cations. The syntheses of two sets of
model compounds for investigating the influence of silyl
enol ether ring size revealed interesting stereochemical
features. The underlying mechanism with regard to the
stereoselectivity of the ring closure reaction and the
saturation mechanism are subject to current research.
Furthermore, by cascade cyclization a carbon backbone
is accessible that represents an unnatural quasi-steroid
concerning the attachment of the 19-methyl group18 and
the C/D-cis ring juncture. Both features are hard to
synthesize by other means. This cascade cyclization
shows a remarkable stereoselectivity, which makes it a
useful way of preparing these molecules with stereo-
chemical features not available by established methods.
PET oxidative cyclization in a solvent mixture of aceto-
nitrile and propionitrile with DCA as sensitizer results
in the formation of three products 16,15 1716 and 18 in
a 47:41:12 ratio. The combined isolated yield is 28%.
The two major products 15 and 16 are formed from one
of the two diastereomeric silyl enol ethers 14. Com-
pounds 16 and 17 are generated by the same modes of
cyclization in the two ring closure steps and the same
mode of saturation of the remaining radical function.
The first ring closure can be seen in analogy to the
cyclization of 2, the second ring closure results from an
attack of the tertiary radical center on the trisubstituted
cyclohexene double bond. For this type of radical
cyclization reaction other authors have also observed a
trans,anti-stereochemistry.17
Supplementary material
Analytical data for compounds 1–5, 7–18. Synthetic
schemes and analytical data for the synthesis of 13 from
12 are available from the author.
Compounds 16 and 17 have been isolated from a
mixture of cyclization products by preparative HPLC
and fractional crystallization. Byproduct 18 was
obtained as an inseparable mixture with 17 only. 13C
NMR and DEPT were measured, revealing the same
carbon backbone as in 16 and 17. Presumably 18 is the
result of a different mode of saturation of one of the
diastereomeric intermediate radicals.
Acknowledgements
Financial support by the Ministerium fu¨r Schule, Wis-
senschaft und Forschung des Landes Nordrhein-
Scheme 5. PET oxidative cascade cyclization of 1.

48
J. O. Bunte et al. / Tetrahedron Letters 44 (2003) 45–48
Westfalen (MSWF-NRW), the Deutsche Forschungsge-
meinschaft (DFG), the Fonds der Chemischen Industrie
and the Innovationsfonds der Universita¨t Bielefeld is
gratefully acknowledged. We also thank the state of
Nordrhein-Westfalen for granting a predoctoral schol-
arship for J.O.B.
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