SmI2-H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades

Article abstract of DOI:10.1039/c4cc05404k

The SmI₂-H₂O reagent system mediates challenging 5-exo/6-exo lactone radical cascade cyclisations that deliver carbo[5.4.0]bicyclic motifs in a diastereoselective, one-pot process that establish two new carbocyclic rings and four ste

Full text of DOI:10.1039/c4cc05404k

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SmI2–H2O-mediated 5-exo/6-exo lactone radical
cyclisation cascades†
Irem Yalavac,a Sarah E. Lyons,a Michael R. Webbb and David J. Procter*a
Cite this: Chem. Commun., 2014,
50, 12863
Received 14th July 2014,
Accepted 15th August 2014
DOI: 10.1039/c4cc05404k
www.rsc.org/chemcomm
The SmI2–H2O reagent system mediates challenging 5-exo/6-exo
lactone radical cascade cyclisations that deliver carbo[5.4.0]bicyclic
motifs in a diastereoselective, one-pot process that establish two
new carbocyclic rings and four stereocentres.
Cascade processes have the potential to assemble complex
molecular architectures in a single synthetic operation.1 If such
processes can be mediated by simple, commercial reagents and
can be harnessed to deliver structures possessing important
biological or physical properties they become even more desirable.
We have recently exploited carbonyl reduction by the well-known
2–4
electron-transfer reductant SmI2
to trigger cascade processes
that deliver natural and unnatural product structural motifs.5
For example, we have used a dialdehyde cyclisation cascade to
deliver the tricyclic skeleton of the antibacterial natural product
pleuromutilin,5d,e and have prepared novel organic materials
and bioactive targets using cascades involved phase-tag
removal and cyclisation.5f–h Of most relevance to the current
study, we have used SmI2–H2O6,7 to trigger cyclisation cascades
of alkenyl- and allenyllactone substrates that allow one-pot
access to [5.3.0] and [4.2.1]bicyclic motifs found in biologically
important natural products (Scheme 1A).5a,b The lactone radical
Scheme 1 (A) Lactone radical cyclisation cascades terminated by 5-exo-
cyclisations; (B) this work: lactone radical cyclisation cascades terminated
by challenging 6-exo-cyclisations.
cyclisation cascades explored to date have in common a final allenyllactones, stereochemistry is constructed, post-cyclisation,
radical 5-exo-cyclisation event.5a,b In this study we report the by a relay from centre to centre around the ring, with a high level
evaluation of lactone radical cyclisation cascades terminated by far of diastereocontrol that is not possible in analogous cyclisations of
less usual and more challenging 6-exo-cyclisations8 (Scheme 1B). alkenyl or alkynyllactones.5b Furthermore, the use of allene radical
The new cascades allow one-pot access to carbo[5.4.0]bicyclic acceptors allows an additional stereocenter bearing an additional
motifs found in important natural product targets such as phorbol substituent to be introduced to the complex products 2.5b
and prostratin.9
Our investigations began with diastereoisomeric lactones 1a,
We chose to study the feasibility of 5-exo/6-exo lactone radical prepared by adapting our previously reported route.5a,b Pleasingly,
cyclisation cascades of allenyllactone substrates 1. In the case of treatment of trans-allenyllactone trans-1a bearing an unactivated
terminal alkene with SmI2–H2O gave cascade product 2a as a single
diastereoisomer in 10% yield with monocyclisation product 3a
obtained as the major product in 33% yield. Monocyclisation
product 3a arises from competing reduction of the radical-anion
a School of Chemistry, University of Manchester, Oxford Road, Manchester,
M13 9PL, UK. E-mail: david.j.procter@manchester.ac.uk
b Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage,
intermediate required for 6-exo-cyclisation (cf. 8 in Fig. 3). In line
Herts, SG1 2NY, UK
with our previous observations,5a,b cis-allenyllactone cis-1a yielded a
† Electronic supplementary information (ESI) available. CCDC 1009956 and
1012766. See DOI: 10.1039/c4cc05404k
complex mixture of products (Scheme 2).‡
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Fig. 1 X-ray crystal structure of 2b.
Scheme 2
monocyclisation product 4b showing that, as expected, the 6-exo-
cyclisation is the slow component in the cascade.§ The relative
stereochemistry of 2b was confirmed by X-ray crystallographic
analysis (Fig. 1).11
Given the relative scarcity of literature precedent for 6-exo-trig
ketyl-olefin cyclisations mediated by SmI2 involving simple
alkenes,8 the isolation of 2a, albeit in low yield, was surprising
and we attempted to increase the efficiency of the cascade by the
installation of a radical stabilizing aryl group on the tethered
alkene. Allenyllactone trans-1b was therefore prepared and its
behaviour upon exposure to SmI2–H2O was studied (Table 1).
Pleasingly, cascade product 2b was obtained as a single
diastereoisomer in almost all cases. As expected the amount
of water additive used had an effect on the transformation
(entries 1–3): at lower concentrations of H2O, intermediate
ketone 4b was obtained as the major product, while at higher
concentrations of water, lower conversion was observed. The latter
observation can be explained by considering the saturation of the
Sm(II) centre at high concentrations of water thus preventing
coordination to the substrate and inner sphere electron transfer.10
The highest reaction conversion and yield of 2b was obtained using
an excess of SmI2 (36% of 2b – corresponding to an average of 84%
for the six bond forming events) (entry 4). Somewhat surprisingly, the
order of addition had little impact on the process: addition of
substrate to SmI2–H2O proved as effective as the addition of SmI2 to
the substrate and H2O (cf. entry 1 and 5). Finally, quenching
the reaction after 0.5, 6 and 17 h (entries 6–8) led to the formation
of increasing amounts of cascade product 2b at the expense of
We next studied the cascade cyclisation of a series of trans-
allenyllactone substrates trans-1b–f with different substituents
on the alkene moiety (Scheme 3). Bicyclic cascade products 2b–f
were obtained as single diastereoisomers in moderate overall
isolated yield for the 6-electron-process. Treatment of trans-1b
with SmI2–D2O gave 2b-D4 illustrating that anions are generated and
protonated during the 6-electron cascade process. Interestingly,
deuteration at the benzylic position occurs to give a single
diastereoisomer suggesting that a configurationally stable
benzylic organosamarium is formed and quenched during the
cascade.7b Reduceable substituents such as trifluoromethyl (2c),
bromo (2d) and chloro (2f) were tolerated and no over-reduction
products were observed in these cases (Scheme 3).
In an attempt to facilitate the challenging 6-exo-trig-ketyl-
olefin cyclisation we prepared allenyllactone trans-1g bearing a
Table 1 Optimisation studies
Entry SmI2 (eq.) H2O (eq.) Time (h) Conv.a (%) 2ba (%) 4ba (%)
1b
2b
3b
4b
5c
6b
7b
8b
8
8
8
16
8
8
4000
800
17
17
17
17
17
0.5
6
86
96
64
100
96
31
19
11
16
36
24
0
4
13
9
8
9
8
14
7
8000
4000
4000
4000
4000
4000
8
8
93
95
15
22
17
a
NMR yields from crude spectra using 2,3,5,6-tetrachloronitrobenzene
b
as a standard. 30 min addition of SmI2 to H2O and substrate at rt.
c
Scheme 3
Inverse addition: 30 min addition of substrate to SmI2–H2O at rt.
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undergoes selective 6-exo-trig cyclisation on to the alkene to
give 2b as a single diastereoisomer after a further reduction and
a protonation (Fig. 3).5a,b
In summary, allenyllactones bearing a tethered alkene
undergo 5-exo/6-exo radical cyclisation cascades that deliver
carbo[5.4.0]bicyclic motifs in a diastereoselective, one-pot process
using the commercially-available reagent SmI2 in the presence of
H2O. The cascades establish two new carbocyclic rings and four
stereocentres in moderate overall yield for the 6-electron-process.
Further studies on these and other complexity-generating cascade
processes are underway in our laboratories.
Scheme 4
Notes and references
‡ Treatment of cis-1b with SmI2–H2O gave a complex mixture of
products from which a cascade product could be isolated as a single
unknown diastereoisomer in 10% yield.
§ The low mass balance reported is due to difficulties isolating the
cascade products from monocyclisation by-products (e.g. ketones,
hemi-ketals and alcohols [diastereoisomeric at the new hydroxyl bearing
centre]).
Fig. 2 Additional substrates investigated.
gem-dimethyl group. Surprisingly, treatment of trans-1g with
SmI2–H2O returned starting material with no trace of 2g. This is
consistent with the reversible formation of sterically-hindered
ketyl-radical anion 5 (Scheme 4).10
Attempted cascade cyclisation of allenyllactone trans-1h, bearing
a tethered alkyne, and alkenyllactone trans-1i gave products of
monocyclisation (Fig. 2). These observations again show the
challenge presented by these cascades: 6-exo-dig cyclisations
(trans-1h) and 6-exo-trig cyclisations of ketones derived from
alkenyllactone cyclisations (trans-1i) are inefficient.5a,b
Fig. 3 sets out a proposed mechanism and the stereochemical
course for the successful 5-exo/6-exo cascade cyclisations of allenyll-
actones trans-1b–f. For example, reduction of trans-1b with SmI2–
H2O gives axial radical anion 6 that undergoes 5-exo-cyclisation on
to the allene to give unsaturated ketal 7 after a further reduction
and a protonation. Selective conjugate reduction of the enone, in
equilibrium with 7, then gives ketone 4b as a single diastereo-
isomer. Finally, reduction of 4b gives radical anion 8 that
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12866 | Chem. Commun., 2014, 50, 12863--12866
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