Cascade radical cyclisations of methylenecyclopropyl ketones - Synthesis of bicyclo-[3.2.1]-octanes

Article abstract of DOI:10.1016/S0040-4039(02)01329-1

Samarium diiodide mediated cyclisation of methylenecyclopropyl ketones, readily prepared from β-ketoesters provides a simple route to bicyclo-[3.2.1]-octanes.

Full text of DOI:10.1016/S0040-4039(02)01329-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6201–6203
Cascade radical cyclisations of methylenecyclopropyl
ketones—synthesis of bicyclo-[3.2.1]-octanes
Alexandre C. Saint-Dizier and Jeremy D. Kilburn*
Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 17 May 2002; accepted 28 June 2002
Abstract—Samarium diiodide mediated cyclisation of methylenecyclopropyl ketones, readily prepared from b-ketoesters provides
a simple route to bicyclo-[3.2.1]-octanes. © 2002 Elsevier Science Ltd. All rights reserved.
We have previously shown that cyclisations of
methylenecyclopropylpropyl radicals provides an
efficient method for the generation of methylenecyclo-
hexyl radicals, via a 5-exo cyclisation and ‘endo’ open-
ing of the resulting cyclopropylmethyl radical (e.g.
2“4).1 The methylenecyclohexyl radicals so formed can
be used in further radical cyclisations leading to bicyclic
products.2 Radical cascades of this type, initiated by
ketyl radicals, can be particularly efficient and can be
highly diastereoselective.3 We reasoned that cyclisations
of methylenecyclopropyl ketones, such as 1, with a
suitably placed alkene radical trap could provide a
route to bicyclo-[3.2.1]-octanes,4 a common structural
component of many natural products such as the kau-
renoids and gibberellins (Scheme 1).
The required methylenecyclopropyl ketones were read-
ily prepared from simple b-ketoesters by mono- or
dialkylation with allyl bromide, protection of the
ketone, conversion of the ester to an aldehyde, addition
of methylenecyclopropyl lithium, and finally deprotec-
tion of the ketal. Using this sequence the methylenecy-
Scheme 1.
Scheme 2.
Keywords: methylenecyclopropane; samarium diiodide; cyclisation.
* Correponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01329-1

6202
A. C. Saint-Dizier, J. D. Kilburn / Tetrahedron Letters 43 (2002) 6201–6203
Scheme 3.
Scheme 4.
structure of the major diastereoisomer of 16 was deter-
mined by comparison of NMR data and NOE experi-
ments with that obtained for 15.9 The stereoselectivity
can be understood by assuming chelation of the Sm3+
by both the ketyl oxygen and the alcohol10 leading to
the chair intermediate 14 with an allyl group held axial,
and in the appropriate orientation for further cyclisa-
tion (Scheme 4).
clopropyl ketoalcohols 8–10 were prepared in good
overall yields (Scheme 2). Ketoalcohols 8 and 10 were
both obtained as a mixture of four diastereoisomers
(ꢀ9:9:1:1), from which the two major diastereoisomers,
having a syn relationship between the resulting hydroxy
and allyl groups, could be separated. Ketoalcohol 9 was
obtained as a 1:1 mixture, of two diastereoisomers.
Alcohol 7 was also converted to the corresponding
iodide, which was displaced with methylenecyclopropyl
lithium and deprotected, to give ketone 11 as a 3:1
mixture of diasteroisomers.
In conclusion, methyl ketones incorporating
a
methylenecyclopropane can be used in SmI2 mediated
cascade cyclisations to provide the bicyclooctane skele-
ton with excellent stereocontrol, although the presence
of an alcohol group in the substrate, to chelate to the
ketyl samarium, appears to be essential for efficient
cyclisation.
Cyclisation of phenyl ketone 10 was not successful
under any of the conditions tried5 (slow addition of
t
ketone to SmI2, in the presence of BuOH (2 equiv.)
and HMPA (10 equiv.) in THF6 at 0 or −78°C; slow
addition to SmI2 in THF/MeOH (4:1)7 at 0 or −78°C;
reverse addition of SmI2 to the ketone under similar
solvent conditions) and led only to the reduced diol 12
and ketone 13 (Scheme 3), presumably formed by a
retroaldol reaction, catalysed by Lewis acidic Sm3+.
Similarly, attempted cyclisation of 11, led to a complex
mixture of products from which no bicyclic product
could be identified.
The methyl ketones
8 and 9, however, cyclised
efficiently to produce the desired bicyclooctanes 15 and
16, with almost complete control of the stereochemistry
(Scheme 4). Cyclisation of ketone 8 was best carried out
by slow addition of the ketone to 2 equiv. of SmI2, in
the presence of tBuOH (2 equiv.) and HMPA (10
equiv.) in THF at 0°C and gave 15 in 71% yield and as
a 9:1 ratio of diastereoisomers. Cyclisation of ketone 9,
on the other hand was best carried out with 4 equiv. of
SmI2 at −78°C to give bicyclic product 16 in 53% yield
and as a 6:1 ratio of diastereoisomers.
The structure of the major diastereoisomer of 15 was
determined by X-ray crystallography8 (Fig. 1) and the
Figure 1. X-Ray crystal structure of 15.

A. C. Saint-Dizier, J. D. Kilburn / Tetrahedron Letters 43 (2002) 6201–6203
6203
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