Samarium(II)-mediated reactions of γ,δ-unsaturated ketones. Cyclization and fragmentation processes

Article abstract of DOI:10.1021/ol0260472

(Matrix Presented) On treatment with samarium(II) iodide, γ,δ-unsaturated ketones undergo very different processes depending upon the nature of the reaction conditions. Employing samarium(II) iodide and MeOH, functionalized syn-cyclopentanol products are obtained stereoselectively. Mechanistic studies suggest that this cyclization occurs via a sequential reduction/intramolecular aldol reaction. With samarium(II) iodide and HMPA, products of a 4-exo-trig cyclization and of an interesting fragmentation reaction are observed.

Full text of DOI:10.1021/ol0260472

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2345-2347
Samarium(II)-Mediated Reactions of
γ,δ-Unsaturated Ketones. Cyclization
and Fragmentation Processes
Thomas K. Hutton, Kenneth Muir, and David J. Procter*
Department of Chemistry, The Joseph Black Building, UniVersity of Glasgow,
Glasgow G12 8QQ, U.K.
daVidp@chem.gla.ac.uk
Received April 19, 2002
ABSTRACT
On treatment with samarium(II) iodide, γ,δ-unsaturated ketones undergo very different processes depending upon the nature of the reaction
conditions. Employing samarium(II) iodide and MeOH, functionalized syn-cyclopentanol products are obtained stereoselectively. Mechanistic
studies suggest that this cyclization occurs via a sequential reduction/intramolecular aldol reaction. With samarium(II) iodide and HMPA,
products of a 4-exo-trig cyclization and of an interesting fragmentation reaction are observed.
Samarium(II) iodide continues to enjoy widespread applica-
tion throughout organic synthesis.1 We have previously
reported that γ,δ-unsaturated aldehydes, such as 1, undergo
stereoselective 4-exo-trig cyclization on treatment with
samarium(II) iodide to give anti-cyclobutanols in good yield
(Scheme 1).2,3 We have since applied our reaction in the first
synthetic studies on Pestalotiopsin A.4
results of our studies into the reaction of γ,δ-unsaturated
ketones with samarium(II) iodide.
As previously mentioned, treatment of γ,δ-unsaturated
aldehyde 1 with samarium(II) iodide in the presence of
MeOH gave anti-cyclobutanol 2 with complete diastereo-
control in 65% yield.2 However, we were intrigued to find
that under our standard conditions employing samarium(II)
iodide in THF and MeOH (4:1), the corresponding methyl
ketone 4a gave none of the expected cyclobutanol, instead
giving cyclopentanol 5a (45%), accompanied by the acyclic
reduction product 6a (44%) (Scheme 1).
Scheme 1a
(1) For reviews on the use of samarium(II) iodide in organic synthesis,
see: (a) Soderquist, J. A. Aldrichimica Acta 1991, 24, 15. (b) Molander,
G. A. Chem. ReV. 1992, 92, 29. (c) Molander, G. A. Org. React. 1994, 46,
211. (d) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (e)
Molander, G. A.; Harris C. R. Tetrahedron 1998, 54, 3321. (f) Krief, A.;
Laval, A.-M. Chem. ReV. 1999, 99, 745. (g) Steel, P. G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2727.
a Reagents and conditions: (i) SmI2, THF/MeOH (4:1), 0 °C
(2) (a) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett.
1999, 40, 4913. (b) Johnston, D.; McCusker, C. F.; Muir, K.; Procter, D. J.
J. Chem. Soc., Perkin Trans. 1 2000, 681.
(3) Prior to our work, a single example of such a cyclization had been
described by Weinges: Weinges, K.; Schmidbauer, S. B.; Schick, H. Chem.
Ber. 1994, 127, 1305.
We have sought to extend the chemistry to the cyclization
of the corresponding ketones, such as methyl ketone 4a, thus
allowing the stereoselective synthesis of even more highly
substituted cyclobutanols. Here we report the preliminary
(4) Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J. Org. Lett.
2001, 2001.
10.1021/ol0260472 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/19/2002

unsuccessful, as in line with our previous observations2
reducing the amount of MeOH employed led to a dramatic
decrease in the efficiency of the reaction and only a slight
increase in the ratio of 5a to 6a. Cyclizations of 4b-d were
carried out under our standard conditions; the results are
shown in Table 2. The proportion of cyclopentanol product
obtained clearly varies according to the size of the ketone
substituent (Table 2). Although the combined overall yields
of 5 and 6 remained approximately constant, the product ratio
decreased from 1:1 for the cyclization of 4a, to only a trace
of 5c being observed from the cyclization of the isopropyl
ketone 4c.
Table 1.a
R
RM
3
4
Me
Et
iPr
Bn
cPr
MeLi‚LiBr
EtMgCl
iPrMgCl
BnMgCl
cPrMgBr
3a (74%)
3b (45%)
3c (76%)
3d (51%)
3e (65%)
4a (88%)
4b (57%)
4c (44%)
4d (82%)
4e (53%)
In all cases, cyclopentanol products were obtained as single
diastereoisomers. To ascertain the stereochemistry of the
cyclization products, 5a was reduced (LiAlH4, THF, 0 °C,
80%) and the resulting diol 7 was converted to mono-p-
nitrobenzoate 8 (p-O2NC6H4COCl, pyridine, rt, 77%). X-ray
crystallographic analysis of 85 thus confirmed the syn
stereochemistry of 5a. The stereochemistry of the cyclopen-
tanols 5b-d was inferred from this observation.
Cyclopropyl ketone 4e was prepared in order to investigate
the mechanism of cyclization to form “5-endo-type” prod-
ucts. The isolation of byproducts 6 suggested that the reaction
might proceed via initial conjugate reduction of the R,â-
unsaturated ester,6 protonation, and a second reduction to
give an intermediate samarium(III) enolate that could either
undergo cyclization via an intramolecular aldol reaction,7 to
give cyclopentanols 5, or be protonated to give acyclic
reduction products 6. The alternative, direct 5-endo radical
cyclization mechanism appeared less likely.
a Reagents and conditions: (i) RM, THF, -78 °C. (ii) (COCl)2, DMSO,
NEt3, CH2Cl2, -78 °C then Ph3PCHCO2Et.
To investigate further this switch in reactivity, a series of
γ,δ-unsaturated ketones was prepared. Ketone substrates
4a-e were prepared from γ-butyrolactone by dimethylation,
DIBALH reduction to the lactol, and subsequent ring opening
of the lactol with appropriate alkylmetal reagents. Diols 3a-e
were obtained in the yields indicated in Table 1. One-pot
Swern oxidation and Wittig reaction then gave the desired
ketones 4a-e in good overall yield (Table 1).
Employing methyl ketone 4a as our test substrate, it was
found that under the standard conditions used for the
analogous aldehyde cyclizations, an approximately 1:1
mixture of cyclopentanol 5a and the acyclic reduction
product 6a was obtained in 89% (Table 2). In an attempt to
In the cyclization of cyclopropyl ketone 4e, if the reaction
proceeded through the generation of a ketyl-radical anion,
the cyclopropinyl radical anion formed from 4e would be
expected to undergo rapid fragmentation.8 The fragmentation
of cyclopropyl ketones on treatment with samarium(II) iodide
has been exploited previously in both synthetic9 and mecha-
Table 2.a
(5) Crystal data for 8: C16H21NO5, M ) 307.34, monoclinic, space group
P21/c, a ) 10.4932(3), b ) 13.0916(4) Å, c ) 12.2594(4) Å, â ) 111.410-
(1)°, V ) 1567.9(1) Å3, T ) 100 K, Z ) 4, Dc ) 1.302 Mg m-3, µ ) 0.097
mm-1, F(000) ) 656. 21, 423 reflections measured, 6788 unique (Rint
)
0.04) used in refinement. R1[4438 with I > 2σ(I)] ) 0.050, wR2(all data)
) 0.136 after adjusting 250 parameters, |∆F| < 0.41 e Å-3. CCDC reference
number 184372. Programs used: SHELX97sPrograms for Crystal Structure
Analysis (Release 97-2). Sheldrick, G. M. Institu¨t fu¨r Anorganische Chemie
der Universita¨t, Tammanstrasse 4, D-3400 Go¨ttingen, Germany, 1998.
WinGXsA Windows Program for Crystal Structure Analysis. Farrugia, L.
J. J. Appl. Crystallogr. 1999, 32, 837.
(6) The conjugate reduction of R,â-unsaturated carbonyl compounds with
SmI2 is well-precedented: (a) Inanaga, J.; Sakai, S.; Handa, Y.; Yamaguchi,
M.; Yokoyama, Y. Chem. Lett. 1991, 2117. (b) Cabrera, A.; Alper, H.
Tetrahedron Lett. 1992, 33, 5007. (c) Fujita, Y.; Fukuzumi, S.; Otera, J.
Tetrahedron Lett. 1997, 38, 2121.
(7) Cabrera has reported the cyclodimerization of R,â-unsaturated
ketones, which proceeds via a similar intramolecular aldol reaction: (a)
Cabrera, A.; Rosas, N.; Alvarez, C.; Sharma, P.; Toscano, A.; Salmo´n, M.;
Arias, J. L. Polyhedron 1996, 15, 2971. (b) Cabrera, A.; Le Lagadec, R.;
Sharma, P.; Arias, J. L.; Toscano, R. A.; Velasco, L.; Gavin˜o, R.; Alvarez,
C.; Salmo´n, M. J. Chem. Soc., Perkin Trans. 1 1998, 3609.
(8) It has recently been shown that ring opening is significantly faster
for radical anions derived from aliphatic cyclopropyl ketones than for the
corresponding neutral cyclopropinyl radicals. Stevenson, J. P.; Jackson, W.
F.; Tanko, J. M. J. Am. Chem. Soc. 2002, 124, 4271.
a Typical reaction conditions: to a solution of SmI2 (0.1 M in THF) (4
equiv) at 0 °C was added MeOH (resultant solution, 4:1 THF/MeOH), and
the solution was stirred for 10 min. Ketone substrate (1 equiv) in THF
(0.75 mL) was then added, and the solution was stirred at 0 °C for 1-2 h.
optimize the formation of the cyclopentanol 5a, the quantity
of proton source was reduced. This proved to be largely
(9) Batey, R. A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32,
6211.
2346
Org. Lett., Vol. 4, No. 14, 2002

Scheme 2a
Scheme 3a
a Reagents and conditions: (i) SmI2 (0.1 M in THF) 3 equiv,
t
HMPA 6 equiv, BuOH 3 equiv, THF, 0 °C.
Interestingly, in addition to small amounts of cyclization
products, 4d gave known ketone 14 (∼30%), and methyl
ketone 13 gave known lactone 15 as the major products
(30%) (Figure 1). These experiments suggest that either the
a Reagents and conditions: (i) SmI2 (0.1 M in THF), THF/MeOH
(4:1), 0 °C
nistic10 contexts. Treatment of cyclopropyl ketone 4e with
samarium(II) iodide gave 5e (15%) and 6e (42%) and
additionally, iodide 9 (5%) and fragmented ketone 10 (10%)
(Scheme 2).
The isolation of 5e, in which the cyclopropyl group is
intact, suggests that the cyclization does not proceed via a
ketyl-radical anion. We believe iodide 9 arises from 5e by
cyclopropyl ring-opening and elimination. Fragmented ketone
10 appears to arise from reduction of 6e. This experiment
therefore suggests that the cyclization proceeds via a
sequential reduction/intramolecular aldol mechanism.11,12
Changing the reaction conditions was found to dram-
atically alter the course of the reaction. Employing HMPA
as an additive and using t-BuOH as a proton source,
ketone 4a underwent 4-exo-trig cyclization to give syn-
cyclobutanol products 11 and 12 in moderate yield. No trace
of cyclopentanol products was observed under these condi-
tions.
It is clear that the switch in reaction conditions brings
about a change in mechanism. SmI2/HMPA/t-BuOH may
promote ketyl-radical anion formation and subsequent
4-exo-trig cyclization onto the alkene, or alternatively, the
formation of a dianion from the R,â-unsaturated ester may
lead to a 4-exo-trig anionic cyclization onto the ketone. The
latter may be the more plausible explanation, as the increased
reactivity of the dianion in HMPA and the lower concentra-
tion of proton source would be expected to promote
cyclization.
Figure 1.
ketyl-radical anion13 or the dianion formed from the R,â-
unsaturated ester undergoes fragmentation under these reac-
tion conditions. A possible mechanism for the fragmentation
would involve R,â-C-C bond cleavage in either intermediate
to give a samarium(III) enolate and an extended samarium-
(III) enolate, which are then protonated. This fragmentation
process appears to account for the low yield observed in the
4-exo-trig cyclization of 4a (Scheme 3).
In conclusion, treatment of γ,δ-unsaturated ketones with
samarium(II) iodide in the presence of MeOH results in a
stereoselective cyclization to give functionalized syn-cyclo-
pentanols. Mechanistic studies suggest the cyclization pro-
ceeds via a sequential reduction/intramolecular aldol process.
Employing HMPA and t-BuOH as additives results in a
dramatic switch in the reaction pathway, and products of
4-exo-trig cyclization and of fragmentation are obtained.
Further investigations to increase the synthetic potential of
these processes are currently underway in our laboratories.
In an attempt to discover the fate of the remaining mass
from the reaction shown in Scheme 3, higher molecular
weight substrates 4d and methyl ketone 13 were treated with
samarium(II) iodide under identical conditions.
Acknowledgment. We thank the EPSRC (T.K.H., grant
GR/N02481) for financial support.
Supporting Information Available: X-ray crystal struc-
ture and crystallographic data for 8, experimental procedures
and full characterization data for compounds 3a-e, 4a-e,
5a-e, 6a-e, 7-13. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112.
(b) Curran, D. P.; Gu, X.; Zhang, W.; Dowd, P. Tetrahedron 1997, 53,
9023. (c) McKerlie, F.; Procter, D. J.; Wynne, G. Chem. Commun. 2002,
584.
(11) Sequential conjugate reduction-aldol cyclizations using Stryker’s
reagent have recently been reported: Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng,
K.-F. Org. Lett. 2001, 1901.
OL0260472
(12) The syn-selectivity of the cyclisation is in agreement with the
observed syn-selectivity of the processes reported by Cabrera and Chiu (refs
7 and 11, respectively).
(13) For a related fragmentation, see: Haque, A.; Ghosh, S. Chem.
Commun. 1997, 2039. For an additional example, see ref 1b, page 47.
Org. Lett., Vol. 4, No. 14, 2002
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