A ring size-selective reduction of lactones using SmI2 and H2O

Article abstract of DOI:10.1021/ja078137d

The SmI₂-H₂O reducing system shows complete selectivity for six-membered lactones over other classes of lactone and esters. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electro

Full text of DOI:10.1021/ja078137d

Published on Web 01/10/2008
A Ring Size-Selective Reduction of Lactones Using SmI2 and H2O
Lorna A. Duffy,† Hiroshi Matsubara,‡ and David J. Procter*,†
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester, M13 9PL, U.K., and Department of
Chemistry, Graduate School of Science, Osaka Prefecture UniVersity, Sakai, Osaka 599-8531, Japan
Received October 24, 2007; E-mail: david.j.procter@manchester.ac.uk
The discovery of reagent systems that allow the selective
manipulation of functional groups is crucial for advancements in
synthesis. Of particular value are reagent systems that allow
functional groups with apparently similar reactivities to be distin-
guished by the re-routing of transformations through less-
conventional intermediates. Here we report that the reducing system
1
SmI2 -H2O not only differentiates between the carbonyl groups
of esters and lactones but also shows complete ring size-selectiVity2
for six-membered lactones.
During studies on a SmI2-mediated1 stereoselective spirocycliza-
tion we found that the treatment of methyl ketone 1 with SmI2 in
Figure 1. Reduction of six-membered lactones to the corresponding diols/
THF, employing H2O as a cosolvent, gave spirocyclic lactone 2a
as a single diastereoisomer in 70% yield.3 When an excess of SmI2
was used, triol 3a was obtained in 30% yield in addition to the
expected lactone 2a (Scheme 1). Although Kamochi and Kudo have
described the reduction of carboxylic acids4a and aryl esters4b using
SmI2-H2O the reduction of unactivated aliphatic esters or lactones
with SmI2 has not been reported.
triols with SmI2-H2O. Conditions: SmI2 (7 equiv), THF, H2O (150 equiv),
room temp, 3-30 h.
Scheme 2. Selective Reductions of Six-Membered Lactones
Scheme 1. Sequential Spirocyclization-Reduction Using
SmI2-H2O
Treatment of lactone 2a with SmI2-H2O at room temperature
gave triol 3a in 71% (Figure 1) thus showing 2a to be an
intermediate in the production of 3a from 1. Spirocyclic lactones
2b and 2c also underwent reduction to give the corresponding triols
in good yield. Importantly, the â-hydroxyl group present in these
substrates was found not to be playing a crucial role5 in the
activation of the lactone carbonyl group and less-functionalized six-
membered lactones also underwent reduction to the corresponding
diols with yields ranging from 72% to 90% (Figure 1).
We have carried out a series of experiments to illustrate the
chemoselectivity observed with the SmI2-H2O reagent system.
Mixtures of esters and lactones were prepared and treated with
SmI2-H2O. In all cases, no reduction products arising from esters
or five, seven, and eight-membered lactones were observed while
six-membered lactones were reduced smoothly (Scheme 2). Modi-
fied SmI2 reagent systems employing additives (HMPA, DMPU,
LiBr)1i were also ineffective for the reduction of other lactones.
The enhanced reactivity of SmI2 observed in our studies is due
to activation of the reagent by the H2O cosolvent. Hasegawa and
Curran first proposed that H2O accelerated reactions using SmI2
by increasing the reduction potential of the reagent in addition to
acting as a proton source.6
Flowers has since shown that H2O produces larger rate enhance-
ments than alcohols in the reduction of acetophenone with SmI2,7a
and has used UV-vis spectra of SmI2 with H2O to illustrate that a
unique reductant is formed at high concentrations of H2O.7a,b
Flowers has also shown that the reduction potential of SmI2 (-1.3
V) increases to a maximum of -1.9 V on the addition of up to
500 equiv of H2O.7
We have carried our preliminary studies to elucidate the
mechanism of the reduction and to understand the ring size-
selectivity observed. The reduction of 2a and 4 with SmI2-D2O
gave 3a-D,D and 5-D,D, respectively, suggesting that anions are
generated and protonated by H2O during a series of single electron
transfers. A possible mechanism for the transformation is given in
Scheme 3.
† University of Manchester.
‡ Osaka Prefecture University.
9
1136
J. AM. CHEM. SOC. 2008, 130, 1136-1137
10.1021/ja078137d CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
about 25-26 kJ mol-1 lower than those involving five and seven-
membered rings (Scheme 4).11 The second electron transfer is lower
in energy and similar for all systems, suggesting the first electron-
transfer is the rate-determining step.
Scheme 3. Mechanism for the Reduction of Lactones Using
SmI2-H2O
In summary, the first reduction of lactones to diols using SmI2-
H2O has been carried out. The reagent system is selective for the
reduction of lactones over esters, furthermore, it displays complete
ring size-selectivity in that only six-membered lactones are
converted to the corresponding diols. Experimental and computa-
tional studies suggest the selectivity originates from the initial
electron-transfer to the lactone carbonyl. In addition to the selectivity
of the reagent system, SmI2 is commercially available, or convenient
to prepare,1 easy to handle, and does not require any toxic cosolvents
or additives, making the transformation an attractive addition to
the portfolio of reductions. We are currently harnessing the
intermediate radicals formed during the reduction and exploiting
the ring size-selective transformation in new strategies for synthesis;
for example, selective lactonization will be exploited to “switch
on” the reactivity of one ester group in the presence of others.
Activation of the lactone by coordination to Sm(II) and electron-
transfer generates radical anion 6 that is then protonated.8 A second
electron transfer generates carbanion 8 that is quenched by the H2O
cosolvent. Lactol 9 is in equilibrium with hydroxy aldehyde 10
and is reduced by a third electron-transfer from Sm(II) to give a
ketyl radical anion 11. A final electron-transfer from Sm(II) gives
an organosamarium that is protonated by H2O. The amount of SmI2
(approximately 7 equiv) required experimentally is consistent with
the amount predicted by the proposed mechanism (4 equiv). The
complete selectivity of the reducing system for six-membered
lactones over five, seven, and eight-membered lactones appears to
have its origin in the rate of the initial electron-transfer to the lactone
carbonyl. This is illustrated by the observation that lactols 12 and
13, intermediates in the reductions, are both rapidly reduced, in
high yield, by SmI2-H2O (Scheme 4).
Acknowledgment. We thank the EPSRC for the award of a
project studentship (L.A.D.).
Supporting Information Available: Additional experiments, ex-
perimental conditions, characterization data, and details of calculations.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
Scheme 4. Investigating the Origin of the Selectivity
(1) Metal-mediated radical reactions: (a) Gansauer, A.; Bluhm, H. Chem.
ReV. 2000, 100, 2771. Recent reviews on the use of SmI2 in synthesis:
(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) Kagan, H. B.
Tetrahedron 2003, 59, 10351. (h) Edmonds, D. J.; Johnston, D.; Procter,
D. J. Chem. ReV. 2004, 104, 3371. (i) Dahle´n, A.; Hilmersson, G. Eur. J.
Inorg. Chem. 2004, 3393.
(2) Limited selectivity has been observed in ketone reductions using Al/Hg.
Hulce, M.; LaVaute, T. Tetrahedron Lett. 1988, 29, 525.
(3) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811.
(4) (a) Kamochi, Y.; Kudo, T. Chem. Lett. 1991, 893. (b) Kamochi, Y.; Kudo,
T. Chem. Lett. 1993, 1495.
For six-membered lactones, we believe that reduction generates
a radical anion intermediate 6 that is stabilized by interaction with
the lone-pairs on both the endocyclic and exocyclic oxygens.9 Such
interactions are known to be more pronounced in six-membered
rings than in other, conformationally more labile, ring systems. It
appears that the greater stability of the radical anion 6, compared
to analogous radicals formed from the reduction of five, seven,
and eight-membered lactones, promotes the initial reduction step.10
This hypothesis is supported by the observation that 2-oxabicyclo-
[2.2.2]octan-3-one, where an intermediate radical-anion would be
unable to adopt the chair conformation necessary for stabilization,
is not reduced. Calculations lend further support and suggest the
first electron-transfer to the lactone carbonyl is endothermic (>100
kJ mol-1) in all cases. The reaction energy of this step for six-
(5) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem. 1999,
64, 2172.
(6) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008.
(7) (a) Chopade, P. R.; Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc.
2004, 126, 44. (b) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2005,
127, 18093. (c) Enemaerke, R. J.; Daasbjerg, K.; Skrydstrup, T. Chem.
Commun. 1999, 343.
(8) Grobelny, Z.; Stolarzewicz, A.; Maercker, A. J. Org. Chem. 2005, 70,
8201.
(9) Axial radicals are preferred due to the anomeric effect. For selected
examples, see: (a) Malatesta, V.; Ingold, K. U. J. Am. Chem. Soc. 1981,
103, 609. (b) Giese, B.; Dupuis, J. Tetrahedron Lett. 1984, 25, 1349. (c)
Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
(10) Relief of ring strain is a less-satisfactory explanation, see: (a) Leitao, M.
L. P.; Pilcher, G.; Meng-Yan, Y. J.; Brown, J. M.; Conn, A. D. J. Chem.
Thermodyn. 1990, 22, 885. (b) Galli, C.; Mandolini, L. Eur. J. Org. Chem.
2000, 3117.
(11) The reaction energy for the first electron-transfer to 2-oxabicyclo[2.2.2]-
octan-3-one is calculated to be 147.4 kJ/mol.
membered lactones, however, is calculated to be 116 kJ mol-1
,
JA078137D
9
J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1137