Free radical reactions for heterocycle synthesis. Part 5: Formation of novel bridged spirolactones by double cyclizations

Article abstract of DOI:10.1016/S0040-4039(01)01090-5

Novel bridged spirolactones have been synthesized via double radical cyclization of enol ester radicals.

Full text of DOI:10.1016/S0040-4039(01)01090-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5617–5620
Free radical reactions for heterocycle synthesis. Part 5:
Formation of novel bridged spirolactones by double cyclizations
Wei Zhang* and Georgia Pugh
Lead Discovery, DuPont Crop Protection, Stine-Haskell Research Center, Newark, DE 19714, USA
Received 6 April 2001; accepted 11 June 2001
Abstract—Novel bridged spirolactones have been synthesized via double radical cyclization of enol ester radicals. © 2001 Elsevier
Science Ltd. All rights reserved.
Free radical cyclizations can be designed to undergo a
tandem (cascade) sequence.1 This strategy has been
widely used in the synthesis of fused polycyclic
compounds2 such as quinanes,3 steroids,4 and alka-
loids.5 Synthesis of bridged or spirocyclic systems by
this approach, however, received relatively less atten-
tion.1,6 We now report here a double cyclization
sequence that leads to formation of novel tetracyclic
systems containing both spiro and bridged rings.
access more complex heterocyclic systems. In order to
undertake a systematic study, we purposely selected
aryl and alkyl bromides that have allyl groups at two
different positions of the a,b-unsaturated cyclic
ketones. These compounds can be easily prepared by
coupling of the allylated 1,3-cyclohexanediones with
appropriate carboxylic acids followed by flash column
chromatography to separate the different O-acylation
products (Scheme 1).
In recent years, we have focused on the development of
a general methodology to construct heterocyclic sys-
tems based on radical annulations of o-bromoben-
zoates.7 One of its applications is the synthesis of
spirolactones by intramolecular radical Michael addi-
tions (Eq. (1)).7b,c Extending the scope of this reaction
by designing a double cyclization sequence allows us to
(1)
Scheme 1.
* Corresponding author. Current address: Fluorous Technologies, Inc., 970 William Pitt Way, Pittsburgh, PA 15238, USA. Fax: 1-412-826-3053;
e-mail: w.zhang@fluorous.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01090-5

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W. Zhang, G. Pugh / Tetrahedron Letters 42 (2001) 5617–5620
With these enol esters in hand, we carried out a series
of (Me3Si)3SiH mediated radical cyclizations. Using 2a
or 4a as substrates, the initial radicals undergo double
cyclizations, first by intramolecular Michael addition to
form stabilized intermediate radicals 6 or 8, followed by
5-exo cyclization onto the alkene to give bridged spiro-
lactones 7 or 9 (Scheme 2). Reaction of 2a generates 7
as a mixture of two diastereomers, whereas reaction of
4a affords dicyclization product 9 along with monocyc-
lization product 10. Formation of 7 suggests that the
spirocyclization (11 to 6) is stereoselective where the
newly-formed CꢀC bond is trans to the vinyl group
(Scheme 3). Subsequent 5-exo cyclization (6 to 12) is
less selective probably due to free rotation around the
allylic CꢀC single bond and gives a mixture of
diastereomers. The structures of 7-exo and 7-endo are
confirmed by X-ray structure analyses (Fig. 1).
Reactions using substrates 2b or 4b that both have a
2-methylallyl side chain also afford dicyclization prod-
ucts. In these two cases, the spirocyclization is followed
by a cyclization of 6-endo instead of 5-exo. The bridged
spirolactones 148 and 15 are both single diastereomers
(Scheme 4).
Scheme 2.
Scheme 3.
Figure 1. X-Ray structures of 7-exo and 7-endo.

W. Zhang, G. Pugh / Tetrahedron Letters 42 (2001) 5617–5620
5619
Scheme 4.
The reaction of enol esters 5a produces only monocy-
clization products 17 (Scheme 5, A). Steric hindrance
probably disfavors the second cyclization of 5-exo.
This result is consistent with the report by Simpkins in
the synthesis of spiroethers.9 Addition of a methyl
group to the allyl side chain (5b) induces the second
cyclization of 6-endo (Scheme 5, B). In this case, ade-
quate amount of dicyclization product 1910 is formed
as a single diastereomer.11 This result implies that
spirocyclization of radical 21, 6-endo cyclization of
radical 18, and subsequent H-atom transfer from
(Me3Si)3SiH to 22 go through a stereoselective path-
way (Scheme 6). The structure of 19 is confirmed by
X-ray structure analysis (Fig. 2).
In conclusion, we have demonstrated that several
novel bridged spirolactones can be prepared by
tandem radical cyclizations of a,b-unsaturated cyclo-
hexanone derivatives bearing an appropriate allyl side
chain.
Scheme 5.
Scheme 6.

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W. Zhang, G. Pugh / Tetrahedron Letters 42 (2001) 5617–5620
Figure 2. X-Ray structure of compound 19.
Acknowledgements
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The authors thank William Marshall for X-ray struc-
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