Switching between Novel Samarium(II)-Mediated Cyclizations by a Simple Change in Alcohol Cosolvent

Article abstract of DOI:10.1021/ol0358399

(Equation Presented) γ,δ-Unsaturated ketones undergo two very different stereoselective cyclization reactions mediated by samarium(II) iodide depending upon the alcohol cosolvent used in the reaction. Switching between an unprecedented aldol spirocyclizat

Full text of DOI:10.1021/ol0358399

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4811-4814
Switching between Novel
Samarium(II)-Mediated Cyclizations by a
Simple Change in Alcohol Cosolvent
Thomas K. Hutton, Kenneth W. Muir, and David J. Procter*
Department of Chemistry, The Joseph Black Building, UniVersity of Glasgow,
Glasgow, G12 8QQ Scotland
daVidp@chem.gla.ac.uk
Received September 23, 2003
ABSTRACT
γ,δ-Unsaturated ketones undergo two very different stereoselective cyclization reactions mediated by samarium(II) iodide depending upon the
alcohol cosolvent used in the reaction. Switching between an unprecedented aldol spirocyclization and a novel cyclobutanol-forming process
can be achieved simply by changing the alcohol cosolvent from methanol to tert-butyl alcohol.
It is well appreciated that the outcome of many samarium(II)
iodide1 reactions can be influenced by the use of additives
and cosolvents.2 Common examples of the use of additives
include the addition of HMPA or DMPU to increase the
reduction potential of the reagent and the use of alcohol
cosolvents to quench intermediate anions in reactions.2 In
general, however, the role of additives in samarium(II)-
mediated organic reactions is still poorly understood. In this
Letter we report how a simple class of unsaturated ketones
can be directed down either of two distinct, stereoselective
reaction pathways, simply by the choice of the alcohol
cosolvent under otherwise identical reaction conditions.
role played by the alcohol cosolvent in achieving a satisfac-
tory reaction outcome.3,4c
We have recently reported that on treatment with SmI2 in
THF and MeOH, γ,δ-unsaturated ketones 1 give a mixture
of syn-cyclopentanols and acyclic conjugate reduction prod-
ucts such as 2 and 3, respectively.5
Scheme 1a
We have previously described the stereoselective synthesis
of cyclobutanols using a Sm(II)-mediated 4-exo-trig cycliza-
tion of aldehydes,3 and have applied the process in target
synthesis.4 During these studies we have noted the important
a Reagents and conditions: (i) SmI2, THF-MeOH (4:1), 0 °C,
89%, 2:3, 1:1.
(1) For reviews on the use of samarium(II) iodide in organic synthesis:
(a) Soderquist, J. A. Aldrichimica Acta 1991, 24, 15. (b) Molander, G. A.
Chem. ReV. 1992, 92, 29. (c) Molander, G. A. Org. React. 1994, 46, 211.
(d) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (e) Molander,
G. A.; Harris C. R. Tetrahedron 1998, 54, 3321. (f) Krief, A.; Laval, A.-
M. Chem. ReV. 1999, 99, 745. (g) Steel, P. G. J. Chem. Soc., Perkin Trans.
1 2001, 2727.
(2) Kagan, H.; Namy, J. L. Lanthanides: Chemistry and Use in Organic
Synthesis; Kobayashi, S., Ed.; Springer: New York, 1999.
(3) (a) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett.
1999, 40, 4913. (b) Johnston, D.; McCusker, C. F.; Muir, K.; Procter, D. J.
J. Chem. Soc., Perkin Trans. 1 2000, 681.
In addition, we have shown that cyclopentanols such as 2
are formed by a sequential conjugate reduction/intramolecular
aldol reaction.5 Although not immediately of synthetic value,
the formation of syn-cyclopentanols such as 2 prompted us
to examine the Sm(II)-mediated cyclizations of γ,δ-unsatu-
rated ketones more closely. At the outset of our investigation,
we were delighted to find that unsaturated lactone substrate
10.1021/ol0358399 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/13/2003

unsaturated lactone moiety present in the cyclization sub-
strates. Lactone phosphonate 16 was prepared from δ-
valerolactone using the method of Weimer,8 while lactam
phosphonate 17 was prepared from N-benzylpyrrolidinone
using a modified literature procedure (Figure 1).9
Scheme 2a
a Reagents and conditions: (i) SmI2, THF-MeOH (4:1), 0 °C,
63%.
4 underwent cyclization to give syn-spirocycle 5 in 63% yield
(Scheme 2).
Figure 1.
X-ray crystallographic analysis confirmed the syn stereo-
chemistry of 5.6 Thus, in the spirocyclization of 4, two
stereocenters are formed, including one quaternary center,
with complete stereocontrol. In addition, the carbon-carbon
bond-forming step occurs with relative efficiency despite
acute steric congestion around the reacting centers.
A range of simpler substrates, lacking the gem-dimethyl
group, were prepared to probe the generality of the spiro-
cyclization process. Thus, substrates 6-10 were conveniently
prepared from tetrahydrofuran-2-ol by ring opening with an
alkylmetal reagent and one-pot Swern oxidation/Wittig
reaction with (1-butyrolactonylidine)triphenylphosphorane,
in line with our previously reported route.5 On exposure to
our standard conditions, ketones 6-10 underwent smooth
cyclization to give the corresponding spirocyclic cyclo-
pentanols 117 and 12-15 in moderate to good yield (Scheme
3).
Treatment of keto aldehydes 18-20 with lactone phos-
phonate 16 gave isomeric mixtures of keto-olefins 21-23
in moderate yield (Scheme 4). The stereoselectivity of
olefinations with 16 was found to depend markedly on the
reaction conditions employed and the substrate. Similarly,
treatment of keto aldehyde 18 with lactam phosphonate 17
gave lactam cyclization substrate 24E/Z in moderate yield
(Scheme 5).
Scheme 4a
Scheme 3a
a Reagents and conditions: (i) 16, K2CO3, 18-C-6, THF, rt, 16
h.
On treatment with SmI2 in THF and MeOH, 21E under-
went efficient cyclization to give methyl ester 25, the product
of spirocyclization followed by opening of the lactone ring
with MeOH (Scheme 6). Interestingly, the cyclization of 21Z
and mixtures of 21E and 21Z gave identical results.10
a Reagents and conditions: (i) SmI2, THF-MeOH (4:1), 0 °C.
X-ray crystallographic analysis of 156 again confirmed the
syn stereoselectivity of the spirocyclization process.
To investigate the facile conjugate reduction/aldol spiro-
cyclization sequence further, we sought to modify the
Scheme 5a
(4) (a) Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J. Org.
Lett. 2001, 3, 2001. (b) Johnston, D.; Couche´, E.; Edmonds, D. J.; Muir,
K.; Procter, D. J. Org. Biomol. Chem. 2003, 328. (c) Edmonds, D. J.; Muir,
K. W.; Procter, D. J. J. Org. Chem. 2003, 68, 3190.
(5) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345.
(6) See Supporting Information for X-ray crystal structures and crystal-
lographic data.
a Reagents and conditions: (i) 17, KHMDS (0.5 M in toluene),
18-C-6, THF, -78 °C to room temperature, 18 h, 24E 53% and
24Z 16%.
(7) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987,
109, 453.
4812
Org. Lett., Vol. 5, No. 25, 2003

Scheme 6a
Scheme 8a
a Reagents and conditions: (i) SmI2, THF-MeOH (4:1), 0 °C,
81%.
a Reagents and conditions: (i) SmI2, THF-tBuOH (4:1), 0 °C.
Unfortunately, the cyclization of lactam substrate 24E gave
the spirocycle 26 in low yield (∼10%).
served when t-BuOH was employed in the cyclizations of
other related substrates. On treatment with SmI2 in THF and
t-BuOH, substrates 6, 7, 8, 22E/Z, and 23E/Z all underwent
cyclization to give cyclobutanol-derived products as the sole
cyclized products in moderate yield (Scheme 8). The structure
of 30 was confirmed by conversion to the corresponding
p-nitrobenzoate 35, fractional recrystallization, and X-ray
crystallographic analysis on a single diastereoisomer.6
The cyclization of cyclopropyl ketone substrate 10 in
t-BuOH was carried out to investigate the mechanism of the
four-membered ring-forming reaction. In substrate 10, the
cyclopropyl ring acts as a mechanistic probe for the formation
of a ketyl radical anion from the ketone carbonyl group.11
Treatment of 10 with SmI2 in THF and t-BuOH gave 36 in
which the cyclopropyl ring was intact, thus suggesting
cyclization to give 36 does not proceed via formation of a
ketyl radical anion (Scheme 9). When taken in conjunction
In an attempt to prevent the lactone ring-opening by the
cosolvent in the cyclization of 21, we investigated the use
of less nucleophilic cosolvents in the SmI2-mediated cy-
clization. To our surprise, the use of EtOH as a cosolvent
gave three products: ethyl ester 27, spirocycle 28, and
cyclobutane product 29 (Scheme 7). Using propan-2-ol as a
cosolvent gave mostly 29 with a small amount of spirocycle
28. Interestingly, the use of t-BuOH completed the switch
from five-membered ring formation to four-membered ring
formation and 29 was obtained as the sole product (Scheme
7).
Scheme 7
Scheme 9a
a Reagents and conditions: (i) SmI2, THF-tBuOH (4:1), 0 °C,
70%.
Thus, simply by changing the cosolvent from MeOH to
t-BuOH, the SmI2-mediated cyclization of 21 switches
between five-membered ring and four-membered ring forma-
tion.
We were eager to see if the same dramatic switch to the
formation of four-membered ring products would be ob-
with our previous observations,5,10 we believe the mechanistic
switch observed on changing the cosolvent from MeOH to
t-BuOH can be best explained from the mechanistic outline
shown in Scheme 10.
Reduction of the R,â-unsaturated moiety gives radical
anion 37. In MeOH, the â-anion is protonated rapidly,
whereas in t-BuOH, the rate of protonation is sufficiently
slow to allow cyclization to give cyclobutanol products. In
both processes, Sm(III)-enolates are then formed by a second
reduction. In the MeOH pathway, the enolate then undergoes
aldol cyclization to give syn-cyclopentanols.12
(8) Jackson, J. A.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem. 1989,
54, 4750.
(9) Tay, M. K.; About-Jaudet, E.; Collignon, N.; Savignac, P. Tetrahedron
1989, 45, 4415.
(10) This again suggests that the cyclization proceeds via sequential
conjugate reduction/aldol cyclization as the stereochemical outcome and
the efficiency of ketyl-olefin cyclizations generally depends on the initial
olefin geometry: (a) Enholm, E. J.; Trivellas, A. Tetrahedron Lett. 1989,
30, 1063. (b) Enholm, E. J.; Trivellas, A. J. Am. Chem. Soc. 1989, 111,
6463. (c) Enholm, E. J.; Satici, H.; Trivellas, A. J. Org. Chem. 1989, 54,
5841. See also ref 4.
(11) Stevenson, J. P.; Jackson, W. F.; Tanko, J. M. J. Am. Chem. Soc.
2002, 124, 4271.
Org. Lett., Vol. 5, No. 25, 2003
4813

Under either set of conditions, none of the alternative
cyclization product was isolated. The dramatic switch in the
reaction outcome is summarized in Scheme 11 for five
substrates. Partitioning between the two reaction pathways
may result from the differing rates of protonation of a radical
anion intermediate.
Scheme 10
Scheme 11
Acknowledgment. We thank the EPSRC (T.K.H., Grant
GR/N02481) for financial support. We thank Kenny
McDougall and Lisa Sloan for carrying out the cyclizations
of 9 (to give 14) and 10 (to give 15), respectively.
In summary, γ,δ-unsaturated ketones undergo two very
different, stereoselective cyclization reactions mediated by
samarium(II) iodide depending upon the alcohol cosolvent
used in the reaction. Clean switching between an un-
precedented aldol spirocyclization and a stereoselective
cyclobutanol-forming process can be achieved simply by
changing the alcohol cosolvent from MeOH to t-BuOH.
Supporting Information Available: Experimental pro-
cedures and data for all new compounds, as well as 1H and
13C NMR spectra and X-ray structures and crystallographic
data for 5, 15, and 35. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Alternatively, divergence may result from differing rates of pro-
tonation of a dianion intermediate formed after two-electron reduction.
OL0358399
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Org. Lett., Vol. 5, No. 25, 2003