Samarium diiodide coupling of enones: A remarkable cascade sequence

Article abstract of DOI:10.1021/ol049563w

Equation presented. Treatment of cyclic enones with SmI₂ in THF/MeOH (4:1) led to tricyclic diol products in one step and, in the case of enone 7, gave the tetracycle 13 as a single diastereoisomer in up to 67percent yield.

Full text of DOI:10.1021/ol049563w

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1943-1945
Samarium Diiodide Coupling of Enones:
A Remarkable Cascade Sequence
Dean M. Howells, Sarah M. Barker, Faye C. Watson, Mark E. Light,
Michael B. Hursthouse, and Jeremy D. Kilburn*
School of Chemistry, UniVersity of Southampton, Southampton, UK SO17 1BJ
jdk1@soton.ac.uk
Received March 9, 2004
ABSTRACT
Treatment of cyclic enones with SmI2 in THF/MeOH (4:1) led to tricyclic diol products in one step and, in the case of enone 7, gave the
tetracycle 13 as a single diastereoisomer in up to 67% yield.
Samarium diiodide is a remarkably versatile single-electron-
transfer reducing agent and is used in many synthetic
transformations.1 However, a detailed mechanistic under-
standing of these reactions is complicated by the different
pathways, involving radical and/or anionic intermediates, that
the reactions might follow.2
Among its many applications, the treatment of R,â-
unsaturated carbonyl compounds with SmI2 can lead to
reduction of the CdC double bond or homodimerization to
give 1,6-dicarbonyl compounds.3-7 Thus, Cabrera3 and
others4 have shown that treatment of acyclic enones such as
1 with SmI2 in the presence of HMPA leads to dimerization,
followed by an intramolecular aldol reaction, to give cyclo-
pentanols such as 3 (Scheme 1). Under the same conditions,
Cabrera reported that cyclic enones 4 only undergo a simple
homodimerization to give 5, without the subsequent intra-
molecular aldol reaction. Treatment of enones in the presence
t
of a proton source (HMPA, BuOH), on the other hand,
resulted only in the reduction of the CdC double bond.7
The initial step in these reactions involves single-electron
transfer to the enone to give a delocalized ketyl radical 2.
Proposed mechanisms for the dimerization presume that this
radical either couples with another radical or adds at the 1,4-
positions of another enone. If this is the case we reasoned
that it might be possible to trap the first formed radical with
a suitably tethered alkene to provide a novel cyclization
pathway. To test this possibility, we prepared allyloxy enone
(1) (a) Kagan, H. B. Tetrahedron 2003, 59, 10351. (b) Krief, A.; Laval,
A.-M. Chem. ReV. 1999, 99, 745. (c) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321.
(2) See ref 1 and also: (a) Curran, D. P.; Gu X.; Zhang, W.; Dowd, P.
Tetrahedron 1997, 53, 9023. (b) Curran, D. P.; Fevig, T. L.; Jasperse, C.
P.; Totleben, M. J. Synlett 1992, 943.
(3) (a) Cabrera, A.; Le Lagadec, R.; Sharma, P.; Arias, J. L.; Toscano,
R. A.; Velasco, L.; Gavin˜o, T.; Alvarez, C.; Salmo´n, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 3609. (b) Cabrera, A.; Rosas, N.; Sharma, P.; Le
Lagadec, R.; Velasco, L.; Salmo´n, M.; Arias, J. L. Synth. Commun. 1998,
28, 1103.
Scheme 1
(4) Zhou, L.; Zhang, Y. Synth. Commun. 2000, 30, 597.
(5) Cyclodimerization of dicinnamoylferrocenes: Jong S.-J.; Fang, J.-
M. Org. Lett. 2000, 2, 1947.
(6) Homodimerization of R,â-unsaturated esters and other R,â-unsaturated
carbonyl compounds: see ref 3a and references therein. See also: (a)
Cabrera, A.; Alper, H. Tetrahedron Lett. 1992, 33, 5007. (b) Inanaga, J.;
Handa, Y.; Tabuchi, T.; Otsubo, K.; Yamaguchi, M.; Hanamoto, T.
Tetrahedron Lett. 1991, 32, 6557.
(7) Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997, 38, 2121.
10.1021/ol049563w CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/08/2004

7 from commercially available diketone 6, according to
Pirrung’s protocol8 (Scheme 2).
Scheme 2
When 7 was treated with SmI2 in the presence of HMPA
(cf. Cabrera3), in THF, a complex mixture of products was
obtained. A similar result was obtained in the absence of
HMPA or when a proton source was added (tBuOH, 2 equiv).
However, when 7 was added (over 10 min) to a solution of
2.5 equiv of SmI2 in a mixed THF/MeOH (4:1) solvent
system9 at -78 °C, a new compound 13 was obtained in
45% yield and as a single diastereoisomer (Scheme 3). The
Figure 1. Crystal structure of tetracycle 13.
If the reaction proceeds by 1,4-addition of a radical
intermediate (e.g., 8) to another enone, then this pathway
should be suppressed by slow addition of 7 to the SmI2
solution, since a low concentration of the enone substrate
would be maintained. However, the outcome of the reaction
was unaffected by the rate of addition of 7 to the SmI2
solution (addition over 1 min gave a 62% yield of 13;
addition over 6 h gave a 60% yield of 13). Conversely, slow
addition of SmI2 to a dilute solution of 7 in should reduce
the opportunity for the buildup of the initially formed radical,
which might dimerize by radical-radical combination.
However, addition of SmI2 (as a solution in THF) to a
solution of 7 in THF/MeOH again yielded the tetracyclic
product 13 (up to 61% yield), but no other products could
be identified from the reaction mixture.
Scheme 3
One explanation for the observed results is that the
anticipated cyclization of the delocalized ketyl radical onto
the pendant alkene is reversible and thermodynamically
unfavorable, although, even if this is the case, it is surprising
structure of 13 was established by X-ray crystallography
(Figure 1).10 Addition of 7 to 4 equiv of SmI2 gave 13 in an
increased yield of 67%.
(10) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 232459. Data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
Crystal data for 1: C18H28O4, Mr ) 308.40, T ) 120(2) K, triclinic, space
group P-1, a ) 9.6537(19), b ) 10.664(2), c ) 15.994(3) Å, R ) 94.77(3),
â ) 97.10(3), γ ) 90.01(3)°, V ) 1628.2(6) Å3, Fcalc ) 1.258 g cm-3, µ
) 0.087 mm-1, Z ) 4, reflections collected 9719, independent reflections
3783 (Rint ) 0.1274), final R indices [I > 2σI] R1 ) 0.1287, wR2 ) 0.3349,
R indices (all data) R1 ) 0.2082, wR2 ) 0.3785. The above average R
factors are a result of the poor diffraction properties of the crystal, and the
two molecules in the asymmetric unit differ in the orientation of the prop-
2-en-1-ol groups.
Tetracycle 13 presumably arises from initial dimerization
followed by an intramolecular aldol reaction. The resulting
ketone can then be further reduced to give a ketyl radical
that undergoes a conventional 5-exo cyclization onto the
pendant allyl ether (Scheme 3).
(8) Pirrung, M. C.; Chang, V. K.; DeAmicis, C. V. J. Am. Chem. Soc.
1989, 111, 5824.
(9) (a) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett.
1999, 40, 4913. (b) Watson, F. C.; Kilburn, J. D. Tetrahedron Lett. 2000,
41, 10341.
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Org. Lett., Vol. 6, No. 12, 2004

that none of the cyclized products 9 or 10 was isolated under
any of the conditions used. Alternatively, it may be that initial
reaction of the enone with SmI2 generates a complex (e.g.,
with coordination of both the ketyl oxygen and allylic radical
species to samarium metal) that is unreactive toward dimer-
ization or radical cyclizations. Reduction of this species, by
a further single-electron transfer, would then give an anionic
organosamarium intermediate that cannot cyclize onto the
pendant, unactivated alkene, but does undergo a Michael
addition to another equivalent of enone, followed by an
intramolecular aldol reaction, etc.
gave a ∼2:1 mixture of tricyclic alcohols 15 and 16 in good
overall yield with the diastereoisomer ratio only slightly
affected by the reaction temperature. Cyclopentenone gave
tricyclic alcohols 17 and 18 with significant diastereoselec-
tivity when the reaction was carried out at 0 °C but little
selectivity when carried out at -78 °C. Mesityl oxide, on
the other hand, gave a 1:1 mixture of alcohols 19 and 20 at
0 °C but predominantly alcohol 19 at -78 °C. Methyl vinyl
ketone and acetylcyclohexene, however, did not yield any
cyclic products under these conditions.
In conclusion, the SmI2-mediated tandem cyclodimeriza-
tion of enones can be extended to cyclic enones by using
THF/MeOH solvent mixtures. This is a striking example of
the significant differences that can be achieved with SmI2-
mediated reactions by varying solvent and additives,9,14 and
clearly the use of THF/MeOH is preferable to the use of
HMPA as an additive. In addition, we have used the reaction
for the efficient construction of a highly functionalized
tetracyclic product 10, in a reaction that involves the
formation of three carbon-carbon bonds and five quaternary
centers in a completely stereoselective manner.
When the optimal reaction conditions (addition of the
enone to 4 equiv of SmI2 in THF/MeOH (4:1)) were used,
simple enones (both cyclic and acyclic) also underwent the
dimerization-aldol sequence (Scheme 4).11
Scheme 4
Acknowledgment. We thank Professor Richard Whitby
for useful discussions concerning the mechanism of the
dimerization.
Supporting Information Available: Experimental pro-
cedures for SmI2-mediated cyclodimerization of enones in
THF/MeOH, characterization data for compounds 13 and
15-20, and X-ray crystallographic data for 15, 16, and 19
and the p-nitrobenzoate derived from 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049563W
(12) Stereoselective reduction of â-hydroxy ketones using SmI2: Keck,
G. E.; Wagner, C. A.; Sell, T.; Wager, T. T. J. Org. Chem. 1999, 64, 2172.
(13) Structure and stereochemistry of 15, 16, and 19 were established
by X-ray crystallography. The structure and stereochemistry of 17 was
established by X-ray crystallography of the derived p-nitrobenzoate, and
thus 18 is assumed by analogy to 16. Structure and stereochemistry of 20
was established by oxidation of 19 and 20 to a common â-hydroxyketone.
Full experimental details and X-ray crystallographic data are provided in
the ESI.
In each case this leads to a single diastereomeric ketone
intermediate that is further reduced to a secondary alcohol
with varying diastereoselectivity.12,13 Thus, cyclohexenone
(11) Reverse-addition procedure (i.e., adding SmI2, as a solution in THF,
to a solution of cyclohexenone or cyclopentenone in THF/MeOH) also
yielded the tricyclic diols 15-18 as the only isolable products, but in lower
yields (50-65%).
(14) For a detailed study on the role of proton donors in SmI2-mediated
reductions, see: Chopade, P. R.; Prasad, E.; Flowers, R. A., II. J. Am. Chem.
Soc. 2004, 126, 44.
Org. Lett., Vol. 6, No. 12, 2004
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