A new approach to cyclohexenes and related structures

Article abstract of DOI:10.1039/b001119n

Intermolecular radical addition of a xanthyl phosphonoacetate to a γ,δ-enone gives rise to an adduct suitable for a base induced Horner-Emmons ring closure to a cyclohexene derivative, optionally after the reductive removal of the xanthate group.

Full text of DOI:10.1039/b001119n

A new approach to cyclohexenes and related structures
Nathalie Cholleton,a Isabelle Gauthier-Gillaizeau,b Yvan Sixa and Samir Z. Zard*ab
a Institut de Chimie des Substances Naturelles, C. N. R. S., 91198 Gif-Sur-Yette, France.
E-mail: sam.zard@icsn.cnrs-gif.fr
b Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Received (in Liverpool, UK) 9th February 2000, Accepted 25th February 2000
Published on the Web 15th March 2000
Intermolecular radical addition of a xanthyl phosphonoace-
tate to a g,d-enone gives rise to an adduct suitable for a base
induced Horner–Emmons ring closure to a cyclohexene
derivative, optionally after the reductive removal of the
xanthate group.
xanthate group in the final product represents a very useful
handle since it provides an entry into the exceptionally rich
chemistry of sulfur. The ring size of the starting cyclic ketone
may of course be modified as illustrated by the conversion of
cycloheptanone 2d into bicyclo [5.4.0] derivative 5c. Fused 6–7
ring systems are found in some terpene families, such as the
sandresolides, the tiglianes (e.g. phorbol), and the daph-
nanes.7
One important feature of this approach is that the unsaturated
ketone precursors are readily available, either by direct
allylation of the corresponding enolate or through the powerful
Claisen rearrangement. The latter route is especially interesting,
since it can provide substituted substrates with controlled
relative (and sometimes absolute) sterochemistry of adjacent
chiral centres.8 Compound 2d was thus obtained by heating
together 1-methoxy-2-methylcyclohexene and crotyl alcohol in
the presence of trifluoroacetic acid.8 Application of the same
sequence gave 5d with a defined relative stereochemistry, again
in good overall yield (Scheme 1).
If a 2-allyl cyclopentanedione component is employed, the
sequence now provides a ready access to the ubiquitous
hydrindane backbone. This is illustrated by the conversion of
2e, prepared by allylation of 2-methylcyclopentane-1,3-dione
with allyl bromide9 followed by ketalisation of one of the
ketone groups, into 5e, as outlined in Scheme 2. This route is
significantly shorter than that previously reported for an
analogue of 5e.10 The presence of the olefin allows access to the
trans-hydrindane system through catalytic reduction.10 For the
ethyl derivative 2f, the Horner–Emmons reaction was per-
formed after acid mediated cleavage of the ketal group but
The construction of rings often hinges on the ability to attach
together two reacting partners, which are then made to undergo
an intramolecular combination under suitable conditions.1 In
some cases, such as in the classical Robinson annelation, both
the attachment and cyclisation require similar reaction condi-
tions and can sometimes be accomplished concomittantly. This,
however, imposes various constraints in terms of selectivity that
must be addressed.1b More frequently, one or both of the
reacting functions have to be protected and then unmasked just
before the cyclisation step. A more concise approach would be
to combine an intermolecular assembly process with a ring
closure proceeding through two different mechanisms and
operating under orthogonal sets of conditions: the two reacting
units are thus rapidly brought together whilst avoiding cumber-
some protection–deprotection steps. In view of the importance
of ring structures in essentially all classes of natural products,
numerous combinations of reactions have therefore been
exploited to construct mono- and poly-cyclic derivatives.1 Here,
we describe the use of an intermolecular radical addition to an
unactivated olefin in conjunction with an intramolecular
Horner–Emmons reaction to rapidly access various cyclohex-
ene containing architectures.
Unlike intermolecular C–C bond formation involving radical
additions to activated (usually electrophilic) olefins, clean
bimolecular additions to simple alkenes are not generally easy
to accomplish using common radical processes.2 The rate of the
addition step is often too slow to allow it to compete
successfully with other pathways open to the radical inter-
mediate. In stannane based chemistry for example, premature
hydrogen abstraction from the organotin hydride is difficult to
avoid.3 This limitation may be lifted to a large extent by using
the dithiocarbonate (xanthate) transfer reaction we have
developed over the past few years.4 The main competing
pathway is degenerate: the intermediate radicals acquire an
extended effective lifetime and are thus able to interact with
comparatively unreactive traps. For our present purpose, the
reaction of xanthate 15 derived from triethyl phosphonoacetate
with a g,d-enone would provide in one step the desired
combination of functionality for a subsequent intramolecular
Horner–Emmons ring closure (Scheme 1). Indeed, heating
2-allyl-2-methylcyclohexanone 2a (1.08 mmol) with xanthate 1
(2.17 mmol) in refluxing 1,2-dichloroethane (2 mL) in the
presence of a small amount of lauroyl peroxide (16 mol%) as
initiator under an inert atmosphere delivered the expected
adduct 3a in (80%) yield (Scheme 1). Reductive removal of the
xanthate group with tributylstannane and base-induced (NaH/
THF) cyclisation finally gave bicyclic derivative 5a in high
overall yield. The Horner–Emmons reaction may, if desired, be
performed whilst keeping the xanthate group. In this way, 3a
was efficiently converted into 5b by exposure to a combination
of potassium carbonate and 18-crown-6 in toluene.6 The initial
NaH/THF system did not prove suitable in this case. The
Scheme 1 Reagents and conditions: i, EtOCSSK, acetone; ii, lauroyl
peroxide (0.1–0.2 equiv.), 1,2-dichloroethane, reflux; iii, Bu3SnH (AlBN),
toluene, reflux; iv, NaH, THF; v, K2CO3/18-crown-6, toluene, reflux.
DOI: 10.1039/b001119n
Chem. Commun., 2000, 535–536
This journal is © The Royal Society of Chemistry 2000
535

latter is displayed in Scheme 3. Addition of xanthate 1 to N-
allylglutarimide followed by removal of the xanthate group
using lauroyl peroxide/isopropyl alcohol gave the requisite
adduct 4g in 42% overall yield. We have previously described
the use of this reagent combination as a an economical and
ecologically more acceptable alternative to organotin hydides
for reductively removing xanthates and related groups.14
Treatment of 4g with NaH/THF induced ring closure to furnish
5g in 43% yield. This compound is in principle an immediate
precursor of lupinine.15 The moderate yield in the cyclisation
step must be contrasted with the sole literature precedent of a
Wittig–Horner-type cyclisation on a glutarimide motif, reported
to proceed in only 19%.16
In summary, we have described a new, short and flexible
strategy for accessing cyclohexenes and related structures. The
key radical addition to the unactivated terminal olefin occurs
under mild, neutral conditions, that are compatible with most
functional groups encountered in modern synthesis.
We thank Dr Philippe Mackiewicz (Aventis, Romainville,
France) for a generous gift of 2-ethylcyclopentane-1,3-dione.
Notes and references
Scheme 2 Reagents and conditions: i, lauroyl peroxide (10–20 mol%)
cyclohexane, reflux; ii, Bu3SnH (AlBN), toluene, reflux; iii, NaH, THF; iv,
(a) p-TSA, acetone; (b) K2CO3/18-crown-6, toluene, 80 °C.
1 A. Varmer and R. B. Grossman, Tetrahedron, 1999, 55, 13 867; M. E.
Jung, Tetrahedron, 1976, 32, 1; R. E. Gawley, Synthesis, 1976, 777.
2 D. P. Curran, in Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon Press, Oxford, 1991, vol. 4, pp. 715–831; B.
Giese, Radicals in Organic Synthesis: Formation of Carbon–Carbon
Bonds, Pergamon Press, Oxford, 1986; W. P. Neumann, Synthesis,
1987, 665; D. P. Curran, Synthesis, 1988, 417, 489.
3 See, for example: D. P. Curran, J. Xu and E. Lazzarini, J. Am. Chem.
Soc., 1995, 117, 6603.
4 For a review, see: S. Z. Zard, Angew. Chem., Int. Ed. Engl., 1997, 36,
672.
5 Xanthate 1 was obtained by reaction of ethyl potassium xanthate with
triethyl phosphochloroacetate, itself obtained by chlorination of diethyl
phosphonoacetate according to the procedure of C. E. McKenna and
L. A. Khawli, J. Org. Chem., 1986, 51, 5467.
6 P. A. Aristoff, J. Org. Chem., 1981, 46, 1954.
7 A. D. Rodriguez, C. Ramirez and I. I. Rodriguez, Tetrahedron Lett.,
1999, 40, 7621; P. A. Wender, K. D. Rice and M. E. Schnute, J. Am.
Chem. Soc., 1997, 119, 7897; P. A. Wender, C. A. Jesudason, H.
Nakahira, N. Tamura, A. L. Tebbe and Y. Ueno, J. Am. Chem. Soc.,
1997, 119, 12 976 and references therein.
8 M. Sugiura and T. Nakai, Tetrahedron Lett., 1996, 37, 7991.
9 H. Schick, H. Schwarz and A. Finger, Tetrahedron, 1982, 38, 1279.
10 T. Manda¨ı, T. Kojima and J. Tsuji, J. Org. Chem., 1994, 59, 5847.
11 S. Schwartz, S. Ring, G. Weber, G. Teichmu¨ller, H.-J. Palure, C.
Pfeiffer, B. Undeutsch, B. Erhart and D. Grawe, Tetrahedron, 1994, 50,
10 709 and references therein.
12 E. J. Corey and A. X. Huang, J. Am. Chem. Soc., 1999, 121, 710.
13 For a recent review on non-classical Wittig-type reactions, see: P.
Murphy and S. E. Lee, J. Chem. Soc., Perkin Trans. 1, 1999, 3049.
14 A. Liard, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1996, 37,
5877; B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1998, 39,
9435.
Scheme 3 Reagents and conditions: i, lauroyl peroxide (8 mol%),
1.2-dichloroethane, reflux; ii, lauroyl peroxide (1.46 mol. equiv.), isopropyl
alcohol, reflux; iii, NaH (4.0 equiv.), THF, reflux.
without removal of the xanthate. Ring closure took place only
on the ketone group leading to the least congested isomer, 5f,
with the xanthate in the equatorial orientation and in a location
corresponding to the important C-11 position in steroids. There
are several clinically useful steroid drugs with the unnatural
C-13 ethyl group and some, such as the third-generation
contraceptive Desogestrel, also contain a substituent at C-11.11
Surprisingly, a Robinson-type annulation to construct the
C-ring in this series was recently reported to fail.12
15 For an approach to indolizidine and quinolizidine alkaloids using such
intermediates, see: S. A. Miller and A. R. Chamberlain, J. Am. Chem.
Soc., 1990, 112, 8100.
Finally, the possibility of performing a non-classical Horner–
Emmons reaction13 on an imide may be exploited as an entry to
indolizidine and quinolizidine alkaloids. An example of the
16 T. Minami, K. Watanabe and K. Hirakawa, Chem. Lett., 1986, 2027.
Communication b001119n
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Chem. Commun., 2000, 535–536