A general electron transfer reduction of lactones using SmI 2-H2O

Article abstract of DOI:10.1039/c2ob00017b

Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI ₂-H₂O and a Lewis base to tune the redox properties of the complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.

Full text of DOI:10.1039/c2ob00017b

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COMMUNICATION
A general electron transfer reduction of lactones using SmI2–H2O†‡
Michal Szostak, Karl D. Collins, Neal J. Fazakerley, Malcolm Spain and David J. Procter*
Received 3rd January 2012, Accepted 30th January 2012
DOI: 10.1039/c2ob00017b
Herein we describe a strategy for the selective, electron trans-
fer reduction of lactones of all ring sizes and topologies using
SmI2–H2O and a Lewis base to tune the redox properties of
the complex. The current protocol permits instantaneous
reduction of lactones to the corresponding diols in excellent
yields, under mild reaction conditions and with useful che-
moselectivity. We demonstrate the broad utility of this trans-
formation through the reduction of complex lactones and
sensitive drug-like molecules. Sequential electron transfer
reactions and syntheses of deuterated diols are also
described.
Samarium diiodide (SmI2, Kagan’s reagent) is the most con-
venient-to-use single electron transfer reagent available in the
laboratory.1 Of particular note is the ability of SmI2 to operate
Fig. 1 Reduction of unactivated cyclic and acyclic esters using SmI2–
through either one-electron or two-electron reductive pathways,
or complex pathways involving both modes of activation. These
pathways often proceed with exquisite control of structure and
stereochemistry and are frequently utilised to furnish bond dis-
connections that are impossible to achieve with other reagents.2
Although SmI2-mediated transformations of aldehydes and
ketones have been widely employed to access alcohols and to
initiate reductive couplings to form challenging C–C bonds, the
analogous reactions of esters and lactones have long been
thought to lie outside the reducing range of SmI2.1,2
H2O.
Recently, impressive progress has been made in the mechanis-
tic understanding, development and application of proton donors
and Lewis bases as additives for use with SmI2.3 These additives
have played a key role in expanding the chemistry of SmI2 by
fine-tuning the redox properties of the reagent to enable a par-
ticular transformation or to target a specific group of substrates.
In 2008, we reported that activation of SmI2 by excess H2O
facilitated the unprecedented reduction of six-membered lactones
through the formation of unusual ketyl-type radical intermediates
(Fig. 1a).4 Attempts to extend the reaction to other lactones
(using H2O or other proton sources as activating additives)
Fig. 2 Reductive cyclisations of ketyl radicals A and B generated in
lactone reductions using SmI2–H2O.
School of Chemistry, University of Manchester, Oxford Road,
Manchester, M13 9PL, UK. E-mail: david.j.procter@manchester.ac.uk;
Fax: +44 (0)161 2754939; Tel: +44 (0)161 2751425; http://people.man.
ac.uk/~mbdssdp2/
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
resulted in low or no reactivity. Our interest in new strategies for
synthesis involving atypical intermediates accessed using SmI2
and protic additives has also led us to develop the first reduction
of aliphatic esters and acids using SmI2 (Fig. 1b).5 Key to the
success of this transformation was the finding that the addition
of a Lewis base to SmI2–H2O afforded a powerful single electron
‡Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/c2ob00017b
5820 | Org. Biomol. Chem., 2012, 10, 5820–5824
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Table 1 Reduction of unactivated lactones with SmI2–H2O–Et3N
Entry
1
1
Lactone
Yield (%)
97
Entry
9
1
Lactone
Yield (%)
99
1a
1i
2
3
1b
1c
98
93
10
11
1j
87
97
1k
4
5
1d
1e
87
99
12
13
1l
92
99
1m
6
7
1f
85
92
14
15
1n
1o
88
93
1g
8
1h
90
16
1p
99
reductant that allowed efficient transformation of simple acyclic
esters via acyl radical equivalents (Fig. 1b).
couplings and radical cascades to afford complex molecular
architectures (Fig. 2).7–9 Straightforward access to ketyl inter-
mediates from other ring-sizes of lactone would significantly
expand the scope of the reductive coupling of lactones using
SmI2–H2O in organic synthesis.
As predicted, the addition of triethylamine to SmI2–H2O gave
a reagent system capable of reducing a broad range of lactone
substrates (Table 1).10 Six-, five-, seven-, eight- and sixteen-
membered lactones (entries 1–7) and sterically-hindered sub-
strates, whose reduction typically proved problematic with our
original SmI2–H2O system (see, Table ESI-1 in ESI‡11 for com-
parison between the two systems and additional examples), were
amenable to the current protocol and provided the desired diols
We hypothesised that a similar SmI2–H2O–amine system
could facilitate the direct manipulation of lactones that are
unreactive to our previously reported SmI2–H2O conditions
(Fig. 1a).6 Specifically, capitalising on the finely-tuned redox
properties of the SmI2–H2O–amine complex, we reasoned that
lactones of other ring sizes, lactones featuring steric hindrance
close to the carbonyl group and conformationally-locked,
bridged lactones could be selectively activated towards the
reduction (Fig. 1c).1,2,5 We have already demonstrated that ketyl-
type radicals derived from six-membered lactone templates
readily participate in unprecedented, stereoselective reductive
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Scheme 1 Selective reduction of lovastatin using SmI2–H2O–Et3N.
in good yields after short reaction times (entries 3, 8–9). To
further explore the substrate scope, we tested the reduction of a
variety of saturated and unsaturated lactones (entries 10–16).
Importantly, the reduction shows good functional group toler-
ance: olefin and aryl-containing substrates (entries 5, 10–14),
bicyclic lactones, and sterically-demanding lactones with more
complex carbon skeletons (entries 15–16), all gave diol products
in high yield. Notably, all reductions using SmI2–H2O–NEt3
demonstrated considerably higher reaction rates and gave
superior yields to reductions using our previously reported proto-
col with SmI2–H2O.
Scheme 2 Lactone reduction in the synthesis of a model of the A ring
of pseudolaric acid B.
Mild reaction conditions and selectivity are important features
of the reduction and make our method complementary to exist-
ing procedures.12 To demonstrate the selectivity possible, we
subjected lovastatin, a cholesterol-lowering drug bearing a six-
membered lactone and an acyclic ester in a sensitive carbocyclic
skeleton, to our reaction conditions (Scheme 1). We were
delighted to find that the reduction using SmI2–H2O–Et3N pro-
ceeded with complete selectivity for the lactone moiety. No pro-
ducts resulting from alternative reduction pathways were
detected. Furthermore, the mild conditions associated with the
protocol permitted the isolation of the desired product in high
yield.13
Scheme 3 Sequential reactions of lactones using SmI2–H2O–Et3N.
The ultimate test for any new method is its application in the
synthesis of complex natural products.14 In this context, we have
exploited lactone reduction using SmI2–H2O–Et3N in the selec-
tive synthesis of a model of the functionalized A ring of pseudo-
laric acid B (Scheme 2). Reduction of the 5-membered lactone
5,15 a lactone prone to retro-aldol reaction, gave the diol 6 in an
excellent 91% yield with full retention of stereochemical integ-
rity. It is worth noting that conventional methods of reduction
resulted only in decomposition products, demonstrating the
potential of our method for the manipulation of sensitive
molecules.
We next explored the potential of using lactones as substrates
for sequential processes mediated by electron transfer (Scheme 3).
Although tandem, one-pot and sequential reactions proceeding
via ionic and radical mechanism have attracted considerable
interest in the last decade, tandem reactions based on electron
transfer processes and involving two different functional groups
have received less attention.16,17 The one-pot reduction of mul-
tiple functional groups has obvious potential for streamlining
synthetic routes. For example, lactones 8 (containing unactivated
olefins) and lactones 10 (bearing aromatic rings at the δ-position)
underwent sequential reduction to give fully saturated diols (after
lactone and olefin reduction) and primary alcohols (after lactone
reduction and deoxygenation), respectively. These one-pot reac-
tions provide attractive alternatives to multi-step procedures.18
Scheme 4 Synthesis of deuterated alcohols from lactones using
SmI2–D2O–Et3N.
Since the reduction involves aqueous conditions, with SmI2–
H2O playing a key mechanistic role in the protonation of anions
formed during the course of the reaction, in a preliminary study,
we have investigated the potential of using deuterium oxide as
an inexpensive and non-toxic deuterium source (Scheme 4).19
As expected, the corresponding deuterated diol 2a-D2 was
formed from 1a in quantitative yield, with >99% deuterium
incorporation, establishing a new approach to the introduction of
deuterium at the α-position of aliphatic alcohols.
A plausible mechanism for the lactone reduction is presented
in Scheme 5. Activation of the lactone carbonyl by coordination
to SmI2–H2O and electron transfer generates the first radical
anion that is then protonated. A subsequent series of electron
and proton transfers gives a final anionic intermediate that is pro-
tonated by H2O to furnish diol. The first ketyl radical intermedi-
ate generated by electron transfer from SmI2 to the lactone
carbonyl group has the potential to be utilised in reductive coup-
lings (see Fig. 2).
5822 | Org. Biomol. Chem., 2012, 10, 5820–5824
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3371; (f) K. C. Nicolaou, S. P. Ellery and J. S. Chen, Angew. Chem., Int.
Ed., 2009, 48, 7140; (g) M. Szostak and D. J. Procter, Angew. Chem., Int.
Ed., 2011, 50, 7737; (h) A. Dahlén and G. Hilmersson, Eur. J. Inorg.
Chem., 2004, 3393; (i) R. A. Flowers, II, Synlett, 2008, 1427;
( j) C. Beemelmanns and H. U. Reissig, Chem. Soc. Rev., 2011, 40, 2199;
(k) H. Y. Harb and D. J. Procter, Synlett, 2012, 23, 6.
3 For selected examples, see: (a) T. K. Hutton, K. Muir and D. J. Procter,
Org. Lett., 2002, 4, 2345; (b) T. K. Hutton, K. Muir and D. J. Procter,
Org. Lett., 2003, 5, 4811; (c) C. E. McDonald, J. D. Ramsey,
D. G. Sampsell, J. A. Butler and M. R. Cecchini, Org. Lett., 2010, 12,
5178; (d) P. R. Chopade, E. Prasad and R. A. Flowers, II, J. Am. Chem.
Soc., 2004, 126, 44; (e) E. Prasad and R. A. Flowers, II, J. Am. Chem.
Soc., 2005, 127, 18093; (f) J. A. Teprovich Jr., M. N. Balili, T. Pintauer
and R. A. Flowers, II, Angew. Chem., Int. Ed., 2007, 46, 8160;
(g) D. V. Sadasivam, P. K. S. Antharjanam, E. Prasad and R. A. Flowers,
II, J. Am. Chem. Soc., 2008, 130, 7228; (h) K. A. Choquette,
D. V. Sadasivam and R. A. Flowers, II, J. Am. Chem. Soc., 2010, 132,
17396; (i) D. V. Sadasivam, J. A. Teprovich Jr., D. J. Procter and
R. A. Flowers, II, Org. Lett., 2010, 12, 4140; ( j) A. Tarnopolsky and
S. Hoz, J. Am. Chem. Soc., 2007, 129, 3402; (k) M. Amiel-Levy and
S. Hoz, J. Am. Chem. Soc., 2009, 131, 8280; (l) S. K. Upadhyay and
S. Hoz, J. Org. Chem., 2011, 76, 1355; (m) C. M. Jensen, K. B. Lindsay,
R. H. Taaning, J. Karaffa, A. M. Hansen and T. Skrydstrup, J. Am. Chem.
Soc., 2005, 127, 6544; For a recent breakthrough in the elucidation of the
role of NiI2 in SmI2 chemistry, see: (n) K. A. Choquette, D. V. Sadasivam
and R. A. Flowers, II, J. Am. Chem. Soc., 2011, 133, 10655.
Scheme 5 Mechanism of lactone reduction using SmI2–H2O–Et3N.
Preliminary observations on the mechanism and features of
lactone reduction, are listed below (see, ESI‡ for details11): (a) A
primary kinetic isotope effect kH/kD of 1.2 was determined for
six-membered lactone 1a indicating that proton transfer is not
involved in the rate limiting step. (b) As illustrated in Scheme 4,
the reduction of 1a with SmI2–D2O gave 2a-D2, suggesting that
anions are generated and protonated by H2O during a series of
single electron transfers. (c) Complete selectivity for lactone 1a
is observed in competition experiments with primary aliphatic
esters suggesting that initial electron transfer is rate-limiting. (d)
The reaction of six-membered lactone 1a is instantaneous (reac-
tion complete in <30 s). (e) The relative rates of the reduction of
5-, 6-, 7-membered lactones are: 6 > 7 > 5. (f) Both additives
(H2O and amine) are required for the reaction, with no reactivity
observed in the absence of water and insignificant conversions
detected in the absence of amine. (g) The optimal ratio of SmI2–
H2O–amine required to form the active complex is 1 : 1 : 2. This
is consistent with literature precedent.10 (h) Amines other than
Et3N can be used in the reaction to deliver the products in com-
parable yields. (i) In agreement with our previous observations,
water is the proton source of choice when compared to the use of
other protic co-solvents known to strongly coordinate to SmI2.
In summary, we have introduced an approach for the selective
reduction of lactones of all sizes and topologies using SmI2–
H2O as a single electron reductant. The value of this transform-
ation has been highlighted by the selective manipulation of
complex and/or sensitive molecules and by the orchestration of
one-pot sequential reactions. We expect that this method will be
of broad utility for the selective reduction of lactones under mild
conditions. Application of the radical-anion intermediates
formed in the reduction in reductive C–C bond formation will be
described shortly.
4 L. A. Duffy, H. Matsubara and D. J. Procter, J. Am. Chem. Soc., 2008,
130, 1136.
5 (a) M. Szostak, M. Spain and D. J. Procter, Chem. Commun., 2011, 47,
10254; (b) M. Szostak, M. Spain and D. J. Procter, Org. Lett., 2012, 14,
840.
6 For a review of selective reductions using SmI2–H2O, see: M. Szostak,
M. Spain, D. Parmar and D. J. Procter, Chem. Commun., 2012, 48, 330.
7 D. Parmar, L. A. Duffy, D. V. Sadasivam, H. Matsubara, P. A. Bradley,
R. A. Flowers, II and D. J. Procter, J. Am. Chem. Soc., 2009, 131, 15467.
8 D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley and
D. J. Procter, J. Am. Chem. Soc., 2011, 133, 2418.
9 For reduction and reductive cyclisations of cyclic 1,3-diesters with SmI2–
H2O, see: (a) G. Guazzelli, S. De Grazia, K. D. Collins, H. Matsubara,
M. Spain and D. J. Procter, J. Am. Chem. Soc., 2009, 131, 7214;
(b) K. D. Collins, J. M. Oliveira, G. Guazzelli, B. Sautier, S. De Grazia,
H. Matsubara, M. Helliwell and D. J. Procter, Chem.–Eur. J., 2010, 16,
10240; (c) B. Sautier, S. E. Lyons, M. E. Webb and D. J. Procter, Org.
Lett., 2012, 14, 146.
10 For seminal work on the addition of amines to SmI2–H2O, see:
(a) W. Cabri, I. Candiani, M. Colombo, L. Franzoi and A. Bedeschi, Tet-
rahedron Lett., 1995, 36, 949; (b) A. Dahlén and G. Hilmersson, Tetrahe-
dron Lett., 2002, 43, 7197; For selected examples, see: (c) A. Dahlén and
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G. Hilmersson, J. Am. Chem. Soc., 2005, 127, 8340; (g) T. A. Davis,
P. Chopade, G. Hilmersson and R. A. Flowers, II, Org. Lett., 2005, 7,
119; (h) A. Dahlén, Å. Nilsson and G. Hilmersson, J. Org. Chem., 2006,
71, 1576; (i) T. T. Ankner and G. Hilmersson, Tetrahedron, 2009, 65,
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2010, 46, 7596; (k) T. Ankner and G. Hilmersson, Org. Lett., 2009, 11,
503.
11 The ESI‡ contains: (a) Table ESI-1,‡ comparing lactone reduction
with SmI2–H2O and SmI2–H2O–Et3N systems (b) detailed information
regarding mechanistic studies on lactone reduction using SmI2–H2O–
Et3N.
Acknowledgements
We thank the EPRSC, AstraZeneca and GSK for support.
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2 For general reviews on SmI2, see: (a) H. B. Kagan, Tetrahedron, 2003,
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This journal is © The Royal Society of Chemistry 2012
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15 H. Y. Harb, K. D. Collins, J. V. Garcia Altur, S. Bowker, L. Campbell and
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18 To the best of our knowledge, reduction of unactivated olefins has not
been reported with SmI2. Studies on this interesting process are currently
underway in our group.
17 For recent selected examples of tandem reactions promoted by SmI2, see:
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19 Concellón has studied the use of SmI2–D2O in the reduction
of α,β-unsaturated derivatives of carboxylic acids, however this
reagent system has not been used for the synthesis of useful 1,1-
dideuterated alcohols: (a) J. M. Concellón, P. L. Bernad and
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