Lactone radical cyclizations and cyclization cascades mediated by SmI 2-H2O

Article abstract of DOI:10.1021/ja3047975

Unsaturated lactones undergo reductive radical cyclizations upon treatment with SmI₂-H₂O to give decorated cycloheptanes in a single highly selective operation during which up to three contiguous stereocenters are generated. Furthermore, cascade processes involving lactones bearing two alkenes, an alkene and an alkyne, or an allene and an alkene allow "one-pot" access to biologically significant molecular scaffolds with the construction of up to four contiguous stereocenters. The cyclizations proceed by the trapping of radical anions formed by electron transfer reduction of the lactone carbonyl.

Full text of DOI:10.1021/ja3047975

Article
pubs.acs.org/JACS
Lactone Radical Cyclizations and Cyclization Cascades Mediated by
SmI2−H2O
Dixit Parmar,† Hiroshi Matsubara,‡ Kieran Price,† Malcolm Spain,† and David J. Procter*,†
†School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
‡Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
S
* Supporting Information
ABSTRACT: Unsaturated lactones undergo reductive radical
cyclizations upon treatment with SmI2−H2O to give decorated
cycloheptanes in a single highly selective operation during
which up to three contiguous stereocenters are generated.
Furthermore, cascade processes involving lactones bearing two
alkenes, an alkene and an alkyne, or an allene and an alkene
allow “one-pot” access to biologically significant molecular
scaffolds with the construction of up to four contiguous stereocenters. The cyclizations proceed by the trapping of radical anions
formed by electron transfer reduction of the lactone carbonyl.
radical acceptors allows an additional stereocenter bearing an
additional substituent to be constructed.6 The bicyclic motifs
2c−e form the centerpiece of a number of biologically
important natural products including pseudolaric acid B,7a,b
englerin A,7c−j phorbol, prostratin, 12-deoxyphorbol-13-phenyl-
acetate (DPP),7k−n and mediterraneol B7o (Figure 1).
1. INTRODUCTION
Carbonyl reduction is a fundamental transformation that
underpins synthetic chemistry.1 The rerouting of carbonyl
reduction through less-conventional intermediates allows new
selectivity and reactivity to be exploited. For example, our
recent work on metal-mediated electron transfer2 has resulted
in unprecedented selectivity in the reduction of lactones,3a−c
cyclic 1,3-diesters,3d−g and acyclic esters and acids.3h,i
Furthermore, we have shown for the first time that the radical
anions formed by electron transfer to the ester carbonyl group
can be exploited in additions to alkenes.3b,d−f The lanthanide
reductant samarium diiodide (SmI2),4 activated by H2O,5 was
used to achieve electron transfer in these studies. The use of
H2O is crucial because it coordinates to samarium(II),
increasing the reduction potential of the metal and providing
a proximal proton source for the quenching of intermediates.5
Here we report in full our studies on the formation of
oxygenated cycloheptanes 2a,b by reductive cyclization of
alkenyl, alkynyl, and allenyllactones 1a,b using SmI2−H2O
(Scheme 1).6 In particular, we disclose for the first time that the
cyclization of allenyllactones 1b delivers highly decorated
cycloheptanes 2b in a single, often highly selective operation
during which three stereocenters are generated. Furthermore,
treatment of lactones bearing two alkenes, an alkene and an
alkyne, or an allene and an alkene, 1c−e, with SmI2−H2O
results in cascade cyclizations involving four or six electron
transfer steps that generate two rings and up to four
stereocenters and deliver complex molecular architectures
2c−e in a single step. The cyclizations are triggered by the
generation and trapping of radical anions formed from the ester
carbonyl by electron transfer. In the case of allenyllactones 1b,
stereochemistry is constructed, post-cyclization, by a relay from
center to center around the ring, with a high level of
diastereocontrol that is not possible in analogous cyclizations
of alkenyl or alkynyllactones 1a.6 Furthermore, the use of allene
2. RESULTS AND DISCUSSSION
We began by studying the behavior of readily prepared8
alkenyllactones 3a−e with SmI2−H2O. Pleasingly, cycloheptan-
1,4-diols 4a−e were obtained in moderate to good yield as a
mixture of diastereoisomers (Scheme 2). In addition, the
cyclization of 3f gave 4f as a mixture of four diastereoisomers
after elimination of a thiyl radical.
Efficient cyclization was also observed in the case of
alkenyllactones 3g−n bearing 5-alkyl substituents. In this
case, crude cycloheptan-1,4-diol products were oxidized to
the corresponding hemiketals 5g−n so that diastereoisomeric
ratios resulting from the carbon−carbon bond-forming step
could be easily determined (Scheme 3). Moderate diasterocon-
trol (75:25 to 86:14 dr) was observed in the cyclizations of
substrates bearing aryl-substituted alkenes. The relative
configuration of the major diastereoisomers was assigned on
the basis of X-ray crystallographic analyses of 5k and 5m
(Scheme 3).9
As in our previous studies, the addition of H2O to SmI2 was
crucial to the success of the reaction.3,5 For example, treatment
of lactone 3g with SmI2 in the absence of H2O led to the
recovery of starting material. As little as 10 equiv of H2O (with
respect to SmI2) led to significant reductive cyclization,
although the use of 100 equiv gave the best yield of 4g. The
mechanism of the cyclization of alkenyllactones is shown in
Received: May 17, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 1. Decorated Cycloheptane Scaffolds from the
Reductive Cyclizations of Unsaturated Lactones with SmI2−
H2O
Scheme 2. Lactone Radical Cyclizations To Form
Cycloheptan-1,4-diols
a
a
Conditions: SmI2 (8 equiv), THF, H2O (100 equiv with respect to
b
SmI2), RT, 5−20 h. The dr values give the ratio of the major
diastereoisomer to the sum of the other diastereoisomers. Mixture of
c
4 diastereoisomers.
Scheme 3. Lactone Radical Cyclizations To Form
Cycloheptan-1,4-diols and Oxidation to the Corresponding
a
Hemiketals
a
Conditions: SmI2 (8 equiv), THF, H2O (100 equiv with respect to
b
c
SmI2), RT, 5−20 h. Yields for two steps. Ratio of two
diastereoisomers.
Scheme 4. Proposed Mechanism for the Reductive
Cyclizations of Alkenyllactones
Figure 1. Selected natural products possessing [5.3.0] or [4.2.1]
bicyclic ring systems.
Scheme 4 for representative substrate 3m. Activation of the
lactone by coordination to Sm(II) and electron transfer
generates an anomerically stabilized axial radical anion 6.10
Cyclization then takes place with the major product appearing
to arise from a transition state in which the alkene assumes an
endo-orientation relative to the heterocyclic ring. The ring-open
form 7 of the resultant hemiketal intermediate is then reduced
further by Sm(II) to give a second ketyl radical anion and a
final electron transfer from Sm(II) gives an organosamarium
that is protonated by H2O. The amount of SmI2 (approximately
8 equiv) used is consistent with the four-electron mechanism; a
B
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
2-fold excess of reagent is used to ensure reactions are
complete.
compared with the analogous cyclization of an alkenyllactone
(Scheme 6A).
Attempts to isolate the hemiketal (or cycloheptanone)
intermediates by the use of fewer equivalents of SmI2 were
unsuccessful: a mixture of starting material and cycloheptan-
1,4-diols were obtained in low yield. To unequivocally
determine whether the cyclization proceeded through an
ester-derived radical anion such as 6, lactone 3g and lactol 8
were exposed to the conditions for cyclization. While lactone
3g underwent smooth cyclization and reduction to yield diol
4g, lactol 8 underwent reduction to acyclic diol 9 with no trace
of cyclization observed (Scheme 5). Thus, it is clear that
cyclization involves an ester-derived ketyl radical anion (cf. 6)
rather than a more conventional, aldehyde-derived ketyl radical
anion.
Therefore, in our search for more stereoselective routes to
decorated cycloheptanes, we prepared alkynyllactones 10a,b.
Upon treatment with SmI2−H2O in THF, 10a,b underwent
efficient reductive cyclization. Subsequent oxidation of the
crude cycloheptan-1,4-diols then gave hemiketals 5g and 5o in
good overall yield and with improved diastereoselectivity
(Scheme 7; see also Scheme 3).
Scheme 7. Radical Cyclizations of Alkynyllactones Followed
a
by Oxidation To Give Hemiketals
Scheme 5. Exploring the Nature of the Radical Anion
Involved in Cyclization
a
Conditions: SmI2 (8 equiv), THF, H2O (100 equiv with respect to
b
c
SmI2), RT, 20 h. Yields for two steps. Ratio of two diastereoisomers.
The cyclization of alkynyllactones proceeds via hemiketals 11
and enones 12 that are reduced13 further to radical anions 13.
Further reduction and protonation then generates samarium
enolates11 14 (alternatively, protonation of 13 on oxygen,
electron transfer and proton transfer may lead to 14).5l
Protonation of the enolate then determines the stereoselectivity
of the process. Cycloheptanone intermediates are then reduced
further to give cycloheptan-1,4-diols 4 (Scheme 8).
Although the reductive cyclization of alkenyllactones was
found to proceed efficiently, the diastereoselectivity of the
process was modest. We proposed that analogous cyclizations
of alkynyl- and allenyllactones might deliver cyclic products
with improved levels of stereocontrol because stereochemistry
in such processes would be generated by protonation of
samarium enolates11 post-cyclization, rather than during seven-
membered ring formation (vide infra). Computational studies12
were carried out to compare cyclizations involving alkynes and
allenes with those of alkenyllactones (Scheme 6). Pleasingly,
calculations suggested that the cyclizations of axial radical
anions3b,d−f,10 derived from model alkynyl and allenyllactones
by electron transfer would be possible (Scheme 6B,C). The
cyclization of allenyllactones appeared to be particularly facile
Scheme 8. Proposed Mechanism for the Reductive
Cyclizations of Alkynyllactones
Scheme 6. Computational Studies on the Cyclization of
Alkenyl, Alkynyl, and Allenyllactones
We proposed that seven-membered ring products would be
delivered with a further improvement in diastereoselectivity by
the analogous cyclizations of allenyllactones. With allene14
radical acceptors,15 we proposed that stereochemistry would be
constructed in an efficient relay around the ring (vide infra) and
deliver high diastereoselectivities not possible using analogous
alkenyl and alkynyllactones. Furthermore, the use of allene
radical acceptors would allow an additional stereocenter bearing
an additional substituent to be constructed during the
cyclizations.
To explore the first ester−allene radical cyclizations, a range
of allenyllactones was prepared by allenylmetal addition to δ-
ketoesters followed by lactonization.16 Upon treatment with
SmI2−H2O in THF at room temperature, allenyllactones 15
underwent cyclization to give cycloheptan-1,4-diols 16 in high
yield and with high diastereoselectivity. In the cyclization of
substrates bearing aryl substituents, essentially complete
C
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
diastereocontrol was observed in the construction of three
stereocenters (Table 1). Variation of substituents on the
Scheme 9. Proposed Mechanism for the Reductive
Cyclizations of Allenyllactones
Table 1. Cycloheptan-1,4-diols from the Reductive
a
Cyclizations of Allenyllactones
b
c
entry
R1
R2
C6H5
R3
product yield (%)
dr
1
2
3
4
5
6
7
8
9
10
Me
Me
Me
Me
Me
Me
Me
Me
Cy
H
H
H
H
H
H
H
H
H
Me
16a
16b
16c
16d
16e
16f
16g
16h
16i
68
99
63
97
67
98
86
78
62
66
>95:5
>95:5
>95:5
93:7
4-OMeC6H4
2-BrC6H4
3-MeC6H4
3-ClC6H4
Me
>95:5
86:14
66:34
80:20
>95:5
86:14
Et
hemiketal 20. Reduction of the enone moiety13 generates a
second radical anion 22 that undergoes diastereoselective
protonation at the β-position. A further reduction then gives
samarium(III) enolate11 23 that undergoes diastereoselective
protonation at the α-position. (Alternatively, protonation of 22
on oxygen, electron transfer, and proton transfer may lead to
23).5l Finally, the cycloheptanone intermediate (in equilibrium
with the corresponding hemiketal) is reduced to give 16, with
high diastereocontrol, via a third radical anion 24 (Scheme 9).
Thus, reduction of the intermediate enone allows stereo-
chemical information to be passed from carbon to carbon, post-
cyclization, in the newly formed cycloheptane ring. The high
diastereoselectivity observed in the protonation steps may arise
from the bulky nature of the Sm(II)−H2O complex5,5k,m or its
coordination to the hydroxyl group on the cycloheptane ring in
22 and 23.
4-MeC6H4
4-OMeC6H4
C6H5
d
Me
16j
a
Conditions: SmI2 (8 equiv), THF, H2O (500 equiv with respect to
b
c
d
1
SmI2), RT. Isolated yield. Determined by H NMR. Reaction was
carried out on a 2:1 diastereoisomeric mixture of 15j.
lactone and at the internal and terminal positions of the allene
was tolerated. For 15j, diastereoisomers at the allene chiral axis
showed similar reactivity to give 16j. The relative configuration
1
of the products was determined by H NMR and by X-ray
crystallographic analysis of related products (vide infra).
In contrast to our studies on alkenyllactones, in allenyllac-
tone substrates 17 bearing bulky substituents on the internal
double bond of the allene or at the δ-position of the lactone,
the use of less SmI2−H2O allowed the hemiketal products 18 of
a four-electron process to be isolated in moderate to good yield
and in high diastereoisomeric excess (Table 2).
The cyclizations of allenyllactones proceed according to the
mechanism outlined in Scheme 9. Electron transfer to the ester
carbonyl from SmI2−H2O generates axial radical anion
19,3b,d−f,10 which undergoes cyclization. Further reduction
and protonation steps, then give enone 21, via opening of
Having studied the cyclizations of alkenyl, alkynyl, and
allenyllactones, we speculated that the location of unsaturated
groups at both the 5- and 2-positions of the lactone scaffold in
generic substrates such as 25 should allow both radical anion
intermediates 26 and 27 to be trapped resulting in the
formation of bicyclic tertiary alcohols 28 (Scheme 10).
Scheme 10. Proposed Lactone Radical Cyclization Cascades
Using SmI2−H2O
Table 2. Cyclopheptanone Hemiketals from the Reductive
Cyclizations of Allenyllactones
a
b
c
entry
R1
R2
C6H5
product
yield (%)
dr
d
1
2
3
4
5
6
Me
Me
Me
Me
Ph
18a
18b
18c
18d
18e
18f
27
>95:5
>95:5
>95:5
93:7
e
SiMe3
SiMe2Ph
SiMe2vinyl
Me
64
78
e
87
f
90
f
75:25
83:17
Calculations12 suggested that selective reductive cyclization
cascades of lactones 25 possessing cis relative configurations
should be possible (Figure 2). For example, considering
theoretical substrate 29, the relative activation energy for 5-
exo-trig cyclization of the lactone-derived radical anion
involving the alkene attached to the 5-position of the lactone
ring was calculated to be ∼6 kJ mol−1, whereas 5-exo-trig
Ph
Et
77
a
Conditions: SmI2 (4 equiv), THF, H2O (500 equiv with respect to
b
c
d
1
SmI2), RT. Isolated yield. Determined by H NMR. X-ray crystal
structure on the keto form (see Supporting Information). Major
product was diol 16a. X-ray crystal structure (see Supporting
e
f
Information). Characterized as a mixture of keto and hemiketal forms.
D
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 11. (A) The Effect of Relative Configuration in
Lactone 30 on the Sequence Integrity of a Cyclization
Cascade and (B) Cyclization Cascades of Alkenyllactones
Using SmI2−H2O
Figure 2. Calculations To Assess the Feasibility of Cyclization
Cascades.
Scheme 12. Mechanism and Stereochemical Course of the
Cascade Cyclization of Lactone cis-30
cyclization of the lactone-derived radical anion (after radical
inversion) involving the alkene attached to the 2-position of the
ring was calculated to have a much higher relative activation
energy (∼28 kJ mol−1).12 Thus, generic substrate cis-29 should
selectively undergo a “right then left” cyclization cascade to give
a bicyclic product as outlined in Scheme 10.
To explore the predicted impact of relative configuration in
the lactone substrate on the sequence integrity of the
cyclization cascade, cis-30 and trans-30 were treated with
SmI2−H2O. As predicted, cis-30 underwent efficient cascade
cyclization to give 31 in 71% yield as a separable 3:1 mixture of
two diastereoisomers, while the attempted cascade reaction of
trans-30 misfired, and cyclopentanol 32 was obtained as a
mixture of diastereoisomers (Scheme 11A). The relative
configuration of 31 was determined by X-ray crystallographic
analysis.9 Lactone substrates 33−37 bearing cis-orientated
alkene/alkyne chains were prepared8 and exposed to SmI2−
H2O. In all cases, efficient cascade cyclization resulting in a
rapid increase in molecular complexity was observed. The
lactone cyclization cascades gave bicyclic products 38−42 with
good diastereocontrol and diastereoisomeric products were
readily separable (Scheme 11B).
The ability of both cis and trans isomers of allenyllactones 43
to undergo efficient cyclization cascades, compared with the
requirement for the cis-relative configuration in lactone 30, can
be rationalized by considering the conformation of lactones
43a, for example, and 30. Assuming cyclizations involve radical
anions in chair conformations with the radical acceptor at the 5-
position of the lactone ring assuming a pseudo-axial orientation,
cyclization of trans-30 requires the adoption of an inaccessible,
high-energy conformation with both substituents pseudo-axial.
In contrast, cis-30 undergoes cyclization through an accessible
conformation in which the 2-substituent adopts a pseudo-
equatorial orientation (Scheme 14).
In allenyllactones 43a, the presence of a methyl substituent at
the 5-position of the lactone ring renders accessible reactive
conformations in which the 5-allenyl substituent adopts a
pseudoaxial orientation for both cis and trans isomers and thus
both isomers undergo efficient cascade processes.
The mechanism and stereochemical course of the cascade
cyclization for lactone cis-30 is shown in Scheme 12.
We have also investigated cyclization cascades of allenyllac-
tones. Pleasingly, treatment of substrates 43 with SmI2−H2O
gave highly decorated bicyclic products 44 bearing four new
stereocenters in high yield and with high diastereoselectivity
(Scheme 13). Importantly, in contrast to observations made
during studies involving lactone 30, both cis and trans-fused
bicyclic products 44 could be obtained by programing the
correct relative configuration into the starting allenyllactone 43.
E
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 13. Reductive Cyclization Cascades of cis- or trans-
Allenyllactones to give [5.3.0] Bicyclic Ring Systems
Scheme 15. Reductive Cyclization Cascades of
Allenyllactones to give [4.2.1] Bicyclic Ring Systems
3. CONCLUSIONS
In summary, electron transfer from SmI2−H2O to the carbonyl
group of alkenyl and alkynyllactones triggers cyclization to give
cycloheptan-1,4-diols with moderate diastereocontrol. In
contrast, cyclizations involving allenyllactones allow decorated
cycloheptanes to be constructed in a single, highly diaster-
eoselective operation during which three stereocenters are
generated. The generation of stereochemistry, post-cyclization,
in a relay around the ring is key to the high diastereoselectivities
that are observed. When two alkenes, an alkene and an alkyne,
or an allene and an alkene are appropriately positioned in the
substrate, radical cascade cyclizations, utilizing two radical anion
intermediates, are possible. The cyclization cascades allow
access to complex molecular architectures in a single reaction
using a simple, readily-available reagent.
a
Yield based on recovered hemiketal. In some cases, hemiketal
products of a stalled process were isolated as byproducts. These
intermediates resulting from the first cyclization stage could be isolated
and converted to the cascade products by treatment with SmI2−H2O.
Scheme 14. The Impact of Lactone Conformation on the
Feasibility of Cyclization Cascades
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data,
details of calculations, and X-ray crystal structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
david.j.procter@manchester.ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC Pharma initiative and Pfizer for the award
of a project studentship (D.P.) and Paul A. Bradley for
discussions.
Finally, we have also investigated the feasibility of cyclization
cascades of allenyllactones 45. Pleasingly, treatment of
substrates 45a,b with SmI2−H2O gave bicyclo[4.2.1]nonanes
46a,b in moderate yield (Scheme 15).
The high sequence integrity observed in all lactone
cyclization cascades is a result of the high rate of cyclization
of the ester-derived ketyl radical anion and the radical acceptor
at the 5-position of the lactone ring.
REFERENCES
■
(1) (a) Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 8, pp 1, 235, 283.
(b) Hedberg, C. In Modern Reduction Methods; Andersson, P. G.,
Munslow, I. J., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, Germany, 2008, p 107. (c) Gladiali, S.; Taras, R. In Modern
Reduction Methods; Andersson, P. G., Munslow, I. J., Eds.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008, p 135.
F
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(d) Nakamura, K.; Matsuda, T. In Modern Reduction Methods;
Andersson, P. G., Munslow, I. J., Eds.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2008, p 209.
Lee, H. Y.; Munger, J. D., Jr.; Wilhelm, R. S.; Williams, P. D. J. Am.
Chem. Soc. 1989, 111, 8957. (l) Lee, K.; Cha, J. K. J. Am. Chem. Soc.
2001, 123, 5590. (m) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am.
Chem. Soc. 1997, 119, 7897. (n) Wender, P. A.; Kee, J.-M.;
Warrington, J. M. Science 2008, 320, 649. (o) Kakiuchi, K.;
Nakamura, I.; Matsuo, F.; Nakata, M.; Ogura, M.; Tobe, Y.;
Kurosawa, H. J. Org. Chem. 1995, 60, 3318.
(8) See the Supporting Information for experimental details.
(9) See the Supporting Information for CCDC numbers and X-ray
crystal structures.
(10) The higher stability of axial radicals, arising from the anomeric
effect, is reflected in the transition state, leading to a higher rate of
formation. (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. (d) Crich,
D.; Lim, L. B. J. Chem. Soc., Perkin Trans. 1 1991, 2209.
(e) Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. J. Org.
Lett. 2001, 3, 807.
(11) For a review of the chemistry of Sm(III) enolates, see: Rudkin, I.
M.; Miller, L. C.; Procter, D. J. Organomet. Chem. 2008, 34, 19.
(12) Calculations do not take into account the presence of Sm(III).
See the Supporting Information for details of calculations.
(13) For early examples of the conjugate reduction of enones and
enoates using SmI2, see: (a) Inanaga, J.; Handa, Y.; Tabuchi, T.;
Otsubo, K.; Yamaguchi, M.; Hanamoto, T. Tetrahedron Lett. 1991, 32,
6557. (b) Cabrera, A.; Alper, H. Tetrahedron Lett. 1992, 33, 5007.
(c) Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997, 38, 2121.
(14) (a) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; Vols. 1 and 2. (b) Ma, S.
Chem. Rev. 2005, 105, 2829. (c) Ma, S. Aldrichimica Acta 2007, 40, 91.
(d) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 795. (e) Yu, S.;
Ma, S. Chem. Commun. 2011, 47, 5384.
(2) Metal-mediated radical reactions: Gansauer; Bluhm, A. H. Chem.
̈
Rev. 2000, 100, 2771.
(3) (a) Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc.
2008, 130, 1136. (b) Parmar, D.; Duffy, L. A.; Sadasivam, D. V.;
Matsubara, H.; Bradley, P. A.; Flowers, R. A., II; Procter, D. J. J. Am.
Chem. Soc. 2009, 131, 15467. (c) Szostak, M.; Collins, K. D.;
Fazakerley, N. J.; Spain, M.; Procter, D. J. Org. Biomol. Chem. 2012, 10,
5820. (d) Guazzelli, G.; De Grazia, S.; Collins, K. D.; Matsubara, H.;
Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 7214. (e) Collins,
K. D.; Oliveira, J.; Guazzelli, G.; Sautier, B.; De Grazia, S.; Matsubara,
H.; Helliwell, M.; Procter, D. J. Chem.Eur. J. 2010, 16, 10240.
(f) Sautier, B.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Org. Lett. 2012,
14, 146. (g) Szostak, M.; Spain, M.; Procter, D. J. Nat. Protoc. 2012, 7,
970. (h) Szostak, M.; Spain, M.; Procter, D. J. Chem. Commun. 2011,
47, 10254. (i) Szostak, M.; Spain, M.; Procter, D. J. Org. Lett. 2012, 14,
840.
(4) For recent reviews on the use of SmI2, see: (a) Harb, H. Y.;
Procter, D. J. Synlett 2012, 23, 6. (b) Szostak, M.; Procter, D. J. Angew.
Chem., Int. Ed. 2011, 50, 7737. (c) Procter, D. J.; Flowers, R. A., I. I.;
Skrydstrup, T. Organic Synthesis using Samarium Diiodide: A Practical
Guide; RSC Publishing: Cambridge, U.K., 2010. (d) Nicolaou, K. C.;
Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140.
(e) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607. (f) Kagan,
́
H. B. Tetrahedron 2004, 59, 10351. (g) Dahlen, A.; Hilmersson, G.
Eur. J. Inorg. Chem. 2004, 3393. (h) Edmonds, D. J.; Johnston, D.;
Procter, D. J. Chem. Rev. 2004, 104, 3371. (i) Steel, P. G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2727. (j) Kagan, H. B.; Namy, J. L. In
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed.;
Springer: Berlin, 1999; pp 155. (k) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321. For a detailed study of the preparation of
SmI2, see: (l) Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2012,
77, 3049.
(15) For examples of allenes as radical acceptors in SmI2-mediated
reactions: (a) Gillmann, T. Tetrahedron Lett. 1993, 34, 607.
(b) Holemann, A.; Reissig, H. U. Org. Lett. 2003, 5, 1463.
̈
(c) Holemann, A.; Reissig, H. U. Chem.Eur. J. 2004, 10, 5493.
̈
(5) For a review of selective reductions using SmI2−H2O, see:
(a) Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem. Commun.
2012, 48, 330. For selected studies on the role of alcohols and water
in SmI2-mediated reactions, see: (b) Hasegawa, E.; Curran, D. P. J.
Org. Chem. 1993, 58, 5008. (c) Hutton, T. K.; Muir, K. W.; Procter, D.
J. Org. Lett. 2003, 5, 4811. (d) Chopade, P. R.; Prasad, E.; Flowers, R.
A., II. J. Am. Chem. Soc. 2004, 126, 44. (e) Prasad, E.; Flowers, R. A., II.
J. Am. Chem. Soc. 2005, 127, 18093. (f) Sadasivam, D. V.; Teprovich, J.
A., Jr.; Procter, D. J.; Flowers, R. A., II. Org. Lett. 2010, 12, 4140.
(g) Yacovan, A.; Bilkis, I.; Hoz, S. J. Am. Chem. Soc. 1996, 118, 261.
(h) Tarnopolsky, A.; Hoz, S. Org. Biomol. Chem. 2007, 5, 3801.
(i) Tarnopolsky, A.; Hoz, S. J. Am. Chem. Soc. 2007, 129, 3402.
(j) Amiel-Levy, M.; Hoz, S. J. Am. Chem. Soc. 2009, 131, 8280.
(k) Upadhyay, S. K.; Hoz, S. J. Org. Chem. 2011, 76, 1355.
(l) Rozental, E.; Hoz, S. Tetrahedron 2009, 65, 10945. (m) Farran,
H.; Hoz, S. Org. Lett. 2008, 10, 865.
(d) Molander, G. A.; Cormier, E. P. J. Org. Chem. 2005, 70, 2622.
(16) See the Supporting Information for details of substrate
synthesis. The allenylation of unactivated ketones has little precedent.
For selected examples of indium-mediated addition of propargyl
bromides to activated ketones to form allenes, see: (a) Alcaide, B.;
Almendros, P.; Aragoncillo, C.; Rodriguez-Acebes, R. J. Org. Chem.
2001, 66, 5208. (b) Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J.
Org. Chem. 2005, 70, 3198. (c) Lee, P. H.; Kim, H.; Lee, K. Adv. Synth.
Catal. 2005, 347, 1219. (d) Alcaide, B.; Almendros, P.; Rodriguez-
Acebes, R. J. Org. Chem. 2006, 71, 2346. (e) Kim, S.; Lee, K.;
Seomoon, D.; Lee, P. H. Adv. Synth. Catal. 2007, 349, 2449. (f) Park,
J.; Kim, S. H.; Lee, P. H. Org. Lett. 2008, 10, 5067. (g) Li, J.; Fu, C.;
Chen, G.; Chai, G.; Ma, S. Adv. Synth. Catal. 2008, 350, 1376.
(6) For a preliminary account of the cyclization of alkenyllactones,
see: Parmar, D.; Price, K.; Spain, M.; Matsubara, H.; Bradley, P. A.;
Procter, D. J. J. Am. Chem. Soc. 2011, 133, 2418.
(7) (a) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2007, 129,
14556. (b) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008,
130, 16424. (c) Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.;
̈
̈
Gessner, V. H.; Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed.
2009, 48, 9105. (d) Zhou, Q.; Chen, X.; Ma, D. Angew. Chem., Int. Ed.
2010, 49, 3513. (e) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2010, 49, 3517. (f) Nicolaou, K. C.; Kang, Q.; Ng, S. Y.;
Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132, 8219. (g) Xu, J.; Caro-
Diaz, E. J. E.; Theodorakis, E. A. Org. Lett. 2010, 12, 3708. (h) Li, Z.;
Nakashige, M.; Chain, W. J. J. Am. Chem. Soc. 2011, 133, 6553.
(i) Radtke, L.; Willot, M.; Sun, H.; Ziegler, S.; Sauerland, S.;
Strohmann, C.; Frohlich, R.; Habenberger, P.; Waldmann, H.;
̈
Christmann, M. Angew. Chem., Int. Ed. 2011, 50, 3998. (j) Ushakov,
D. B.; Navickas, V.; Strobele, M.; Maichle-Mossmer, C.; Sasse, F.;
̈
̈
Maier, M. E. Org. Lett. 2011, 13, 2090. (k) Wender, P. A.; Kogen, H.;
G
dx.doi.org/10.1021/ja3047975 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX