Studies on the mechanism, selectivity, and synthetic utility of lactone reduction using SmI2 and H2O

Article abstract of DOI:10.1021/ja906396u

Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI₂, activation of the lanthanide reagent by H₂O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI₂-H₂O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI₂-H₂O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.

Full text of DOI:10.1021/ja906396u

Published on Web 09/18/2009
Studies on the Mechanism, Selectivity, and Synthetic Utility of
Lactone Reduction Using SmI2 and H2O
Dixit Parmar,† Lorna A. Duffy,† Dhandapani V. Sadasivam,‡ Hiroshi Matsubara,§
Paul A. Bradley,| Robert A. Flowers II,‡ and David J. Procter*,†
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester, M13 9PL, United
Kingdom, Department of Chemistry, Lehigh UniVersity, Seeley G. Mudd Building, Bethlehem,
PennsylVania 18015, Department of Chemistry, Graduate School of Science, Osaka Prefecture
UniVersity, Sakai, Osaka 599-8531, Japan, and DiscoVery Chemistry, Pfizer Global R & D,
Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
Received July 30, 2009; E-mail: david.j.procter@manchester.ac.uk
Abstract: Although simple aliphatic esters and lactones have long been thought to lie outside the reducing
range of SmI2, activation of the lanthanide reagent by H2O allows some of these substrates to be manipulated
in an unprecedented fashion. For example, the SmI2-H2O reducing system shows complete selectivity for
the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction
has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest
that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical
intermediates formed during lactone reduction with SmI2-H2O can be exploited in cyclizations to give cyclic
ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of
ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.
Introduction
example of ester-alkene radical cyclizations in which the ester
carbonyl acts as an acyl radical equivalent.3
The rerouting of synthetic transformations through less-
conventional intermediates opens up unexplored reaction space
where new selectivity and reactivity may be discovered and
exploited. For example, diverting fundamental transformations
of the carbonyl groupstransformations carried out routinely in
academic and industrial laboratoriessthrough intermediates with
stabilities and reactivities different to those intermediates
typically encountered during the conversion presents opportuni-
ties to identify new selective reactions of carbonyl compounds.
Here we report a full account of our synthetic and mechanistic
studies on a ring size-selective reduction of lactones using
During studies on a SmI2-mediated stereoselective spirocy-
clization,4 we found that exposure of spirocyclic lactone 1 to
excess SmI2 in THF, employing H2O as a cosolvent, gave triol
2. Although Kamochi and Kudo had described the reduction of
carboxylic acids5a and aryl esters5b using SmI2-H2O, the
reduction of unactivated aliphatic esters and lactones with SmI2
had not been reported.5 Spirocyclic lactones 3 and 5 also
underwent reduction to give the corresponding triols in good
yield. Importantly, the ꢀ-hydroxyl group present in these
substrates was found to not play a crucial role6 in the activation
of the lactone carbonyl group, and less-functionalized 6-mem-
bered lactones also underwent reduction to the corresponding
diols in good yield (Figure 1).
1
SmI2 -H2O2 and report for the first time that radical intermedi-
ates formed during lactone reduction with SmI2-H2O can be
exploited in cyclizations to give cyclic ketone products with
high diastereoselectivity. The cyclization constitutes the first
(3) Cossy has described the radical cyclization of unsaturated esters using
sodium-ammonia but proposes that radicals at a lower oxidation state
(cf. 17 Scheme 3) are involved: (a) Cossy, J. Gille, B. Bellosta, V. J.
Org. Chem. 1998, 63, 3141. Srikrishnaha’s reported the anionic
cyclization of unsaturated esters using lithium-ammonia: (b) Srikrishna,
A.; Ramasastry, S. S. V. Tetrahedron Lett. 2004, 45, 379. See also ref
2b.
† University of Manchester.
‡ Lehigh University.
§ Osaka Prefecture University.
| Pfizer Global R & D.
(1) Metal-mediated radical reactions: (a) Gansa¨uer, 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) Skrydstrup, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 345. (f) Molander, G. A.; Harris, C. R. Tetrahedron
1998, 54, 3321. (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.
(j) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607.
(2) For a preliminary account of this work, see: (a) Duffy, L. A.; Matsubara, H.;
Procter, D. J. J. Am. Chem. Soc. 2008, 130, 1136We have recently reported
the selective reductions and cyclizations of cyclic-1,3-diesters using SmI2-
H2O: (b) Guazzelli, G.; De Grazia, S.; Collins, K. D.; Matsubara, H.; Spain,
M.; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 7214.
(4) (a) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811.
(b) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345. (c)
Guazzelli, G.; Duffy, L. A; Procter, D. J. Org. Lett. 2008, 10, 4291.
(5) Kamochi and Kudo have described the reduction of aryl carboxylic
acid derivatives using the reagent: (a) Kamochi, Y.; Kudo, T. Chem.
Lett. 1991, 893. (b) Kamochi, Y.; Kudo, T. Chem. Lett. 1993, 1495.
Marko´ has recently exploited the SmI2-mediated reduction of aryl esters
in a deoxygenation procedure: (c) Lam, K.; Marko´, I. E. Org. Lett.
2008, 10, 2773. Marko´ has recently exploited the SmI2-mediated
reduction of aryl esters in the removal of ester protecting groups: (d)
Lam, K.; Marko, I. E. Org. Lett. 2009, 11, 2752.
(6) (a) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem.
1999, 64, 2172. (b) Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc.
2002, 124, 6357.
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Parmar et al.
Scheme 2. Selective Lactonization to “Switch-On” the Reactivity of
an Ester Carbonyl Group
to ‘switch-on’ the reactivity of an ester carbonyl group, making
it receptive to electron-transfer from Sm(II). To explore this
idea, diester 10, possessing ester groups with similar reactivity
toward conventional hydride reducing agents, was prepared. (An
ethyl ester group and a methyl ester group were chosen to
facilitate monitoring of the selectivity of reactions involving
10.) As expected, treatment of 10 with SmI2-H2O gave no
reaction and 10 was recovered in quantitative yield. Selective
lactonization of ester B upon treatment with acid, however,
activated ester B toward reduction and treatment with
SmI2-H2O gave diol 11 in 83% yield (Scheme 2). The overall
sequence corresponds to a selective reduction of ester B in the
presence of ester A.
Figure 1. Reduction of 6-membered lactones to the corresponding diols/
triols with SmI2-H2O. (Conditions: SmI2 (7 equiv), THF, H2O (150 equiv),
rt, 3-30 h.)
Scheme 1. Selective Reductions of 6-Membered Lactones Using
SmI2-H2O (1:1 Mixture of Substrates)
Studies to elucidate the mechanism of the reduction and to
understand the ring size-selectivity observed have been carried
out. The reduction of 1 and 8 with SmI2-D2O gave 2-D, D
and 9-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. Activation of the lactone by coordination to Sm(II)
and electron-transfer generates radical anion 12 that is then
protonated.8 A second electron transfer generates carbanion 149
that is quenched by the H2O cosolvent. Lactol 15 is in
equilibrium with hydroxy aldehyde 16 and is reduced by a third
electron-transfer from Sm(II) to give a ketyl radical anion 17.
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).
As shown in Figure 1, lactone reduction was possible in
substrates bearing ester substituents. A series of competition
experiments has been carried out to illustrate further the
chemoselectivity observed with the SmI2-H2O reagent system.
Mixtures of lactones were prepared and treated with SmI2-H2O.
In all cases, no reduction products arising from 5, 7 and
8-membered lactones were observed while 6-membered lactones
were reduced smoothly (Scheme 1). Modified SmI2 reagent
systems employing additives (HMPA, DMPU, LiBr)1i were also
ineffective for the reduction of other lactones.
The enhanced reactivity of SmI2, enabling the reduction of
lactones, 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.7 Flowers
has since shown that H2O produces larger rate enhancements
than alcohols in the reduction of acetophenone with SmI2,8a and
has used UV-vis spectra of SmI2 with H2O to illustrate that a
unique reductant is formed at high concentrations of H2O.8a,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 equivalents of H2O.8
A kinetic study was initiated to determine the role of each
reactant in the lactone reduction. Rate studies were performed
using stopped-flow spectrophotometry under pseudo-first-order
conditions with substrate in excess. 5-Decanolide was chosen
as a representative model substrate for kinetic studies and rates
were obtained by monitoring the decay of the SmI2-H2O
complex at 560 nm. A plot of observed rate constant (kobs) with
concentration for the reduction of 5-decanolide is shown in
Figure 2. The rate constant for the reduction of 5-decanolide
with SmI2-H2O was found to be 7.4 ( 0.1 × 10-3 M-1 s-1
.
The rate order of 5-decanolide was 1.1 ( 0.1 (Figure 3) and
the rate order of the SmI2-H2O complex was found to be 1, as
determined by the fractional times method as well as the initial
rates method (see Supporting Information).10
To determine the role of water under the concentrations used
in the reactions, kobs values for the reduction of 5-decanolide
were monitored with increasing concentration of water from
100 to 180 equivalents with respect to [SmI2] and no appreciable
Results and Discussion
The selectivity of the SmI2-H2O reagent system for 6-mem-
bered lactones suggests that selective lactonization can be used
(7) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008.
(8) (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.
(9) For a discussion of the conformation of related radicals and orga-
nosamariums, see: Skrydstrup, T.; Jarreton, O.; Mazeas, D.; Urban,
D.; Beau, J.-M. Chem.sEur. J. 1998, 4, 655.
(10) Espenson, J. H. Chemical Kinetics and Reaction Mechanisms, 2nd
ed.; McGraw Hill: New York, 1995; p 32.
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Lactone Reduction Using SmI2 and H2O
A R T I C L E S
Scheme 3. Mechanism of the Reduction of Lactones Using SmI2-H2O
Scheme 4. Investigating the Origin of the Ring Size-Selectivity
effects consistent with proton transfer are greater than 2.11
Furthermore, the lack of influence of H2O concentration under
the reaction conditions on the rate of reduction shows that proton
transfer is not involved in the rate equation.
Overall, these kinetic studies show that the initial electron
transfer from the SmI2-H2O complex to substrate is the rate
limiting step as shown in eq 1.
Figure 2. Plot of kobs vs [5-decanolide]. SmI2 ) 10 mM, H2O ) 150 equiv,
5-decanolide ) 45-70 equiv, T ) 30.0 ( 0.1 °C. Rate constant ) 7.4 (
-d[SmI2-H2O]/dt ) k[SmI2-H2O][5-decanolide] (1)
0.1 × 10-3 M-1 s-1
.
The complete selectivity of the reducing system for 6-mem-
bered lactones over 5, 7 and 8-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 18 and 19, intermediates in the reductions, are both
rapidly reduced, in high yield, by SmI2-H2O (Scheme 4).
For 6-membered lactones, we believe that reduction generates
a radical anion intermediate 12 that is stabilized by interaction
with the lone-pairs on both the endocyclic and exocyclic
oxygens.12 Such interactions are known to be more pronounced
in 6-membered rings than in other, conformationally more labile,
ring systems. It appears that the greater stability of the radical
anion 12, compared to analogous radicals formed from the
reduction of 5, 7 and 8-membered lactones, promotes the initial
reduction step.13 This hypothesis is supported by the observation
that 2-oxabicyclo[2,2,2]octan-3-one 20, from which an inter-
mediate radical-anion would be unable to adopt the chair
conformation necessary for optimal stabilization, is not reduced
by SmI2-H2O (Scheme 5).
Figure 3. Plot of ln(kobs) vs ln[5-decanolide]. SmI2 ) 10 mM, H2O ) 150
equiv, 5-decanolide ) 45-70 equiv, T ) 30.0 ( 0.1 °C. Rate order ) 1.1
( 0.1.
Calculated, relatiVe reaction energies, not taking into account
the impact of Sm(II) and Sm(III) ions, lend further support to
increase in the rate values were observed over this range (see
Supporting Information). A deuterium isotopic study was carried
out to further analyze the role of H2O in the system. The rate
of 5-decanolide reduction was monitored using 150 equiv of
D2O in place of H2O. This study provided a kH/kD value of 1.5.
The impact of deuterium is likely the result of a secondary
kinetic isotope effect due to differential coordination of H2O
and D2O with Sm(II). Typically, primary deuterium isotope
(11) Espenson, J. H. Chemical Kinetics and Reaction Mechanisms, 2nd
ed.; McGraw Hill: New York, 1995; pp 217-218.
(12) 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.
(13) 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. Thermodynamics 1990, 22, 885. (b) Galli, C.; Mandolini, L.
Eur. J. Org. Chem. 2000, 3117.
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Scheme 5. Support for the Importance of a Radical Anomeric Effect (1:1 Mixture of Substrates)
Scheme 6. Calculations on the Reduction of Lactones Using SmI2-H2O
Scheme 7. Potential to Intercept the Radical-Anions from Lactone Reduction
Scheme 8. Preliminary Studies on the Cyclization of Lactones Using SmI2-H2O
the importance of the first electron-transfer to the lactone
carbonyl group. Calculations suggest that the first electron-
transfer to the lactone carbonyl is endothermic (>100 kJ mol-1)
in all cases. The relative reaction energy of this step for
6-membered lactones, however, is calculated to be 116 kJ mol-1,
about 25-26 kJ mol-1 lower than those involving 5- and
7-membered rings (Scheme 6). (The relative reaction energy
for the first electron-transfer to bicyclic lactone 20 is calculated
to be 147.4 kJ mol-1). The second electron transfer is lower in
energy and similar for all systems, agreeing with kinetic studies
showing that the first electron-transfer is the rate-determining
step. The calculated lowest energy conformation of the radical
anion derived from a 6-membered anion suggests that the radical
does indeed adopt a pseudoaxial orientation apparently enjoying
stabilization by an anomeric effect. Activation of the lactone
by coordination to Sm(II) and electrostatic stabilization of the
product radical-anion by coordination to Sm(III)14 is likely to
render these reductions more favorable than the calculated,
relative reaction energies suggest.
intermediate 22 could be prevented from collapsing, the
interception of radical-anions 21 to give cyclic ketones 23 would
correspond to an unprecedented acyl radical-type cyclization
of lactones (Scheme 7).
We began by investigating the behavior of lactones 24,
bearing alkene radical acceptors, in the presence of SmI2-H2O.
Although diol 25a was the major product from the reduction
of the lactone 24a, we were pleased to also isolate cyclopen-
tanone 26a and cyclopentanol 27a, as mixtures of diastereoi-
somers and in low yield (Scheme 8). Treatment of lactone 24b,
containing a more reactive alkene radical acceptor, gave a higher
yield of cyclization products 26b and 27b (48%). Importantly,
diol 25b was not isolated. These early experiments illustrated
the feasibility of carrying out ester-alkene radical cyclizations
using lactones and SmI2-H2O.2b,16
We envisaged that the introduction of a Lewis basic group
capable of coordination to Sm(III), for example an adjacent ester
substituent, would stabilize the hemiketal intermediates (cf. 22)
We considered that radical-anion intermediates 21 (cf. 12)
on the reaction path might be trapped by an alkene tethered to
the lactone scaffold.15 Provided that the proposed hemiketal
(15) Calculations suggested that the cyclization of the first radical (cf. 12
in Scheme 3) and of the second radical (cf. 17 in Scheme 3) on the
reaction pathway should both be possible. See Supporting Information.
(16) For an imide-alkene cyclization, see: Taaning, R. H.; Thim, L.; Karaffa,
J.; Campan˜a, A. G.; Hansen, A.-M.; Skrydstrup, T. Tetrahedron 2008,
64, 11884.
(14) Farran, H.; Hoz, S. Org. Lett. 2008, 10, 4875.
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A R T I C L E S
Table 1. Lactones as Acyl Radical-Equivalents in Cyclizations Using SmI2-H2O
a
Diastereoisomeric ratios were determined by H NMR. Reaction conditions: SmI2 (5 equiv), H2O (500 equiv), THF, rt, 5 min. b Yields are based on
1
recovered starting material (see Supporting Information). 10-15% of cyclopentanol was also obtained. c Relative stereochemistry of the major
diastereoisomer was determined by NOE experiments on a derivative (see Supporting Information). d Relative stereochemistry of the major
diastereoisomer was confirmed by X-ray crystallography.
thus preventing collapse to the cyclopentanone and over-
reduction to cyclopentanol products. Cyclization of a range of
lactones 28-38 bearing a carboethoxy group R to the lactone
carbonyl group gave cyclopentanone products 39-49 in moder-
ate to high diastereoisomeric excess (7:1 dr to >95:5 dr) with
no over reduction to the corresponding cyclopentanols (Table
1). The cyclization of substrates possessing aryl substituents
on the alkene proceeded in excellent yield while substrates
bearing unactivated alkenes also underwent efficient cyclization
in some cases. In addition to preventing over-reduction, the
R-ethoxycarbonyl group in lactones 28-38 promotes reduction
of the lactone carbonyl by coordination to Sm(II) and improves
the diastereoselectivity of the cyclizations through organization
of the transition structures by coordination to the radical-anion
intermediate (Vide infra).
In line with our previous observations on the selectivity of
the SmI2-H2O reagent system, no products resulting from
reduction of the ethyl ester substituents were observed. In
addition, five-membered lactone substrate 50 (Scheme 9)
(analogous to six-membered lactone 30) was recovered un-
changed after exposure to SmI2-H2O, reaffirming the ring size-
selectivity of lactone reduction and confirming that cyclization
of these substrates is initiated by reduction of the lactone
carbonyl rather than by reduction of the alkene.
A possible mechanism for the cyclizations is given in Scheme
9. Activation of the lactone by coordination to Sm(II) and
electron-transfer generates radical anion 51 (cf. 21 in Scheme
7). Cyclization of equatorial radical 52-equat through an
electronically favored18 anti-transition structure then gives
organosamarium 53, after reduction of the radical formed upon
cyclization. Chelated hemiketal product 54 appears to be stable
under the reaction conditions thus preventing collapse to the
ketone and over reduction to give cyclopentanol products
(Scheme 9).
The relative stereochemistry of the major cyclization products
was determined by NOE studies on a derivative of 44 (see
Supporting Information) and by X-ray crystallographic analysis
of 49.17
(17) For X-ray crystallographic data and CCDC number, see Supporting
Information.
(18) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073.
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Scheme 9. Possible Mechanism of Lactone Cyclization Using SmI2-H2O
The reduction of 30 with SmI2-D2O gave 41-D in 65% yield.
Interestingly, 41-D was obtained as a 7:1 diastereoisomeric
mixture at the benzylic position, suggesting that one diastere-
oisomeric benzylsamarium predominates prior to protonation
in the final stage of the reaction. The preference for one
diastereoisomeric benzylsamarium may arise from coordination
to the ring oxygen (cf. 53, Scheme 9).
To examine the mechanistic proposal in Scheme 9, a kinetic
study was performed to determine the role of each reactant. Rate
studies were performed under pseudo-first-order conditions
similar to those employed for 5-decanolide. Lactone ester 30
was chosen as a representative model substrate for kinetic studies
and rates were obtained by monitoring the decay of the
SmI2-H2O complex at 560 nm. Reduction of 30 was too fast
to be studied under pseudo-first-order conditions at room
temperature, so the rate studies were carried out at 0.0 ( 0.1
°C. A plot of observed rate constant (kobs) with concentration
for the reduction of lactone ester 30 is shown in Figure 4. The
rate constant for the reduction of lactone ester 30 with
SmI2-H2O was found to be 3.14 ( 0.18 × 101 M-1 s-1. The
rate order of lactone ester 30 was 1.06 ( 0.01 (Figure 4) and
the rate order of the SmI2-H2O complex was found to be 1, as
determined by the fractional times method as well as the initial
rates method (see Supporting Information).10
A deuterium isotope study was carried out to further analyze
the role of H2O in this system. The rate of reduction of 30 was
monitored using 150 equiv of D2O in place of H2O. This study
provided a kH/kD value of 1.27. The impact of deuterium is likely
the result of a secondary kinetic isotope effect due to differential
coordination of H2O and D2O with Sm(II) as shown for
5-decanolide (Vide supra).
These kinetic studies show that the initial electron transfer
from the SmI2-H2O complex to substrate 30 is the rate limiting
step as shown in eq 2. The significantly faster rate of reduction
of 30 is likely due to two factors: (1) chelation of SmI2
(formation of 51 in Scheme 9), and (2) rapid cyclization of the
initially formed radical anion with the pendant alkene.
-d[SmI2-H2O]/dt ) k[SmI2-H2O][substrate]
(2)
Previous mechanistic studies have shown that esters ꢀ to a
reducible functional group substantially increase the rate of
reduction through a chelation-controlled pathway.6b More recent
mechanistic studies have shown that ketones containing a
pendant alkene are reduced 2-3 orders of magnitude faster than
the parent substrate.19 Overall, the present kinetic studies and
previous mechanistic work on structurally similar systems are
fully consistent with the mechanistic hypothesis set out in
Scheme 9.
Conclusion
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 6-membered lactones
are converted to the corresponding diols. Experimental and
computational studies suggest the selectivity originates from the
initial electron-transfer to the lactone carbonyl and that anomeric
stabilization of the radical-anion formed is an important factor
in determining reactivity. In addition to the selectivity of the
reagent system, SmI2 is commercially available, or convenient
to prepare, easy to handle, operates at ambient temperature, and
does not require toxic cosolvents or additives, making the
transformation an attractive addition to the portfolio of reduc-
tions. Lactones can also be used in reductive C-C bond
formation through cyclization of the radicals formed by one
electron reduction, generating cyclic ketones (or ketals) often
with high diastereoselectivity. The cyclizations constitute the
Figure 4. Plot of kobs vs [lactone ester 30]. SmI2 ) 10 mM, Water ) 150
equiv, lactone ester 30 ) 10-20 equiv, T ) 0.0 ( 0.1 °C. Rate constant
(19) Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, E.; Flowers, R. A.,
) 3.14 ( 0.18 × 101 M-1 s-1
.
II J. Am. Chem. Soc. 2008, 130, 7228.
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Lactone Reduction Using SmI2 and H2O
A R T I C L E S
first examples of ester-alkene radical cyclizations in which the
ester carbonyl acts as an acyl radical equivalent.
Supporting Information Available: Experimental procedures,
1
characterization data and H and 13C spectra, X-ray crystal-
lographic data, details of calculations and rate studies. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We thank the EPSRC for the award of a
project studentship (L.A.D.), the EPSRC Pharma initiative and
Pfizer for the award of a project studentship (D.P.). R.A.F. thanks
the National Science Foundation (CHE-0844946) for support of
the work at Lehigh University.
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