Regiocontrol of radical cyclization by Lewis acids. Efficient synthesis of optically active functionalized cyclopentanes and cyclohexanes

Article abstract of DOI:10.1021/ol0067890

(equation presented) Treatment of α-alkylidenelactones 3a-d with Bu₃SnH and a catalytic amount of Et₃B effected a 5-exo radical cyclization preferentially to provide the corresponding 1 and 2 in a ratio of 70:30 to 100:0. Meanwhile,

Full text of DOI:10.1021/ol0067890

ORGANIC
LETTERS
2001
Vol. 3, No. 1
67-69
Regiocontrol of Radical Cyclization by
Lewis Acids. Efficient Synthesis of
Optically Active Functionalized
Cyclopentanes and Cyclohexanes
Kwangho Kim, Sentaro Okamoto, and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received October 27, 2000
ABSTRACT
Treatment of r-alkylidenelactones 3a−d with Bu3SnH and a catalytic amount of Et3B effected a 5-exo radical cyclization preferentially to
provide the corresponding 1 and 2 in a ratio of 70:30 to 100:0. Meanwhile, the reaction of 3a and 3b in the presence of Et2AlCl proceeded via
a 6-endo cyclization pathway predominantly to afford 2a and 2b with 90% and 92% regioselectivity, respectively.
There are many biologically important compounds that have
a chiral five- or six-membered carbocyclic ring in their
structure as the main unit or a subunit, and thus, development
of an asymmetric approach to these ring skeletons has
attracted much interest. Herein reported is an efficient method
for synthesizing optically active cyclopentane and cyclohex-
ane compounds 1 and 2, which have plural stereogenic
centers. Compounds 1 and 2 might find utility as a chiral
building block for synthesizing a variety of cyclopentanes
and cyclohexanes, respectively, by taking advantage of the
reactivity of the existing lactone functional group.
The preparation of 3 was carried out according to the
reaction sequence shown in Scheme 2. Thus, the Sharpless
asymmetric epoxidation of (E)-6-(tert-butyldimethylsilyl-
oxy)hex-2-ene-1-ol followed by protection of the hydroxy
group as benzyl ether afforded 4 with 95% ee in 82% yield.2
The epoxide ring opening of 4 with an acetylenic anion
affording 5 under several different reaction conditions
revealed that the conditions shown in Scheme 2 afforded
the best and satisfactory regioselectivity. Thus, the ring-
opening reaction of 4 with 2 equiv of RCtCAlEt2 in the
presence of 1 equiv of Me3Al in hexane proceeded with
regioselectivity of 92:8, 95:5, 95:5, or 87:13, respectively,
where R is Me, Bu, Ph, or SiMe3.3 The compound 5 was
then converted to the ethyl carbonate 6, which in turn was
treated with a divalent titanium reagent Ti(O-i-Pr)4/
The characteristic features of our approach to 1 and/or 2,
which are summarized in Scheme 1 in a retrosynthetic way,
involve an efficient synthesis of R-alkylidene lactones 3 by
a Ti(II)-mediated intramolecular nucleophilic acyl substitu-
tion reaction of 6 (readily prepared from optically active
epoxy alcohol derivative 4) and the intramolecular radical
cyclization of 3, regiocontrolled by selection of the reaction
conditions.1
(1) For radical-mediated substituted cycloalkane construction: Zhu, Q.;
Qiao, L.-X.; Wu, Y.; Wu, Y.-L. J. Org. Chem. 1999, 64, 2428 and references
therein.
(2) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
10.1021/ol0067890 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/12/2000

The results of radical cyclization of 3 thus produced using
a Bu3SnH/Et3B reagent6 are summarized in Table 1 (entries
Scheme 1
Table 1. Radical Cyclization of 3a
2i-PrMgX4 to afford, as expected, the intramolecular nu-
cleophilic acyl substitution reaction product 7.5 From 7, the
compound 3 was prepared according to conventional reaction
sequences. Although all transformations for conversion of 5
to 3 were carried out without separation of the regioisomer
of 5, the compounds 3 were obtained, after column chro-
1
matography, with >95% chemical purity (checked by H
NMR). Thus, in conclusion, the compounds 3, where R is a
methyl, butyl, phenyl, or trimethylsilyl group, i.e., 3a, 3b,
3c, and 3d, were prepared from 4 and the corresponding
alkyne in 37%, 39%, 41%, and 39% overall yield, respec-
tively.
1-4). It can be seen from the table that the substrates with
an alkyl substituent at the sp2-carbon, 3a and 3b, afforded a
mixture of the corresponding 1 and 2 where the former was
formed preferentially in a ratio of 70:30 for 3a and 90:10
for 3b. Meanwhile, the compounds 3c and 3d having a
phenyl and a trimethylsilyl substituent, respectively, furnished
only the 5-exo cyclized product 1. The predominant or
exclusive production of five-membered compounds 1 might
be explained by the well-known fact that 5-exo-cyclization
takes preference over 6-endo-cyclization for the radical
cyclization reaction.7 However, as radical addition to R,â-
unsaturated carbonyl compounds has a tendency to proceed
Scheme 2a
(3) The ring-opening reaction of the corresponding epoxy alcohol with
BuCtCAlEt2 under the Nozaki conditions (Suzuki, T.; Saimoto, H.;
Tomioka, H.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982, 23, 3597)
proceeded in 60% yield with 70:30 regioselectivity, while the reaction of
4 with BuCtCLi in the presence of a stoichiometric amount of BF3‚OEt2
(Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391) or a catalytic
amount of Me3Al (Ooi, T.; Kagoshima, N.; Ichikawa, H.; Maruoka, K. J.
Am. Chem. Soc. 1999, 121, 3228) did not take place.
(4) Reviews for synthetic reactions mediated by the titanium(II) re-
agent: Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511.
Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753. Sato, F.; Urabe, H.;
Okamoto, S. Chem. ReV. 2000, 100, 2835.
(5) For a Ti(II)-mediated synthesis of R-alkylidenelactones from alkynyl
carbonates: Kasatkin, A.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1995,
36, 6075. Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. J. Am. Chem.
Soc. 1996, 118, 2208. Mincheva, Z. P.; Gao, Y.; Sato, F. Tetrahedron Lett.
1998, 39, 7947.
(6) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109,
2547.
68
Org. Lett., Vol. 3, No. 1, 2001

via a conjugate addition pathway,8 the reaction of 3 afforded
conjugate addition products 2 also, though they are 6-endo
cyclized products, and the amount of 2 was increased in
proportion to the decrease of the steric requirement of the
substituent R at the â-position of the carbonyl group from a
phenyl or a trimethylsilyl to a butyl and to a methyl group
as shown in Table 1.9 Thus, in conclusion, the radical
cyclization of 3 provided cyclopentanes 1 highly selectively
or exclusively, except for the case where R is a methyl group.
As the starting compounds 3 are readily preparable and the
resulting 1 is highly functionalized, we believe that the
present finding opens up a new efficient and practical access
to five-membered carbocyclic compounds, even for the case
where R is a methyl group.
alkyl group has been developed. We believe that 1 and 2
might find wide use as starting compounds for synthesizing
a variety of optically active five- or six-membered car-
bocycles including natural products. To show such possibil-
ity, we have prepared cyclohexane derivatives possessing a
quaternary stereocenter, the construction of which has
attracted much interest (Scheme 3).15 Thus, successive
Scheme 3a
With a selective conversion of 3 to cyclopentanes 1 in
hand, our next concern was the possibility of their selective
conversion to cyclohexane compounds 2. Recently, radical
reactions in the presence of Lewis acids have been investi-
gated by several research groups,10 including our group,11
and it has been revealed that use of Lewis acids affects the
reaction rates and the stereoselectivity. We anticipated that
the regiochemistry of the radical cyclization of 3 might also
be influenced by Lewis acids, although to the best of our
knowledge, there are only two precedents for the case of
intermolecular reaction12 and no precedent for intramolecular
reaction.13 The results of the radical reaction in the presence
of Et2AlCl (1.5 equiv) are shown in entries 5 and 6 in Table
1. To our satisfaction, the cyclization of 3a and 3b proceeded
with excellent regioselectivity of better than 90:10 furnishing
the corresponding 2 as the major product; however, 3c and
3d did not afford the 6-endo-cyclized product at all.14 The
highly predominant production of a 6-endo-cyclized product
from 3a and 3b might be explained by assuming that the
complexation of the carbonyl group in 3 with Et2AlCl
increases the electron-withdrawing nature of the carbonyl
group, thus making the conjugate addition pathway a lower-
energy process.
treatment of 2a with LDA and MeI furnished the methylated
lactone 8 as the sole diastereomer. From the compound 8,
triol 9, diol 10, lactone 11 and keto aldehyde 12 were
prepared by conventional reaction sequences.16 The diol 10
obtained here was reported to serve as a key intermediate
for preparation of bakkenolides by Greene et al.,17 and its
In conclusion, a new efficient method for synthesizing
optically active cyclopentanes 1 where R is an alkyl, aryl,
or trimethylsilyl group and cyclohexanes 2 where R is an
spectroscopic data and [R]D value ([R]25 +13.0 (c 0.62,
D
CHCl3), lit.17b [R]20 +13 (c 1.0, CHCl3)) were in good
D
agreement with those reported.
(7) Review: Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV.
1991, 91, 1237.
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture (Japan) for financial support.
We also thank Dr. Yun Gao and Mr. Katsuhiro Miyakoshi
for their assistance in an early stage of this work.
(8) Review: Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753.
Selective 6-endo-cyclization of 5-carbomethoxy-5-hexenyl radicals via a
conjugate addition pathway was reported: Della, E. W.; Kostakis, C.; Smith,
P. A. Org. Lett. 1999, 1, 363. See also: Sibi, M. P.; Ji, J. J. Am. Chem.
Soc. 1996, 118, 3063. Tararov, V. I.; Kuznetzov, N. Y.; Bakhmutov, V. I.;
Ikonnikov, N. S.; Bubnov, Y. N.; Khrustalev, V. N.; Saveleva, T. F.;
Belokon, Y. N. J. Chem. Soc., Perkin Trans. 1 1997, 3101.
(9) One reviewer suggested that regiospecific production of 5-exo product
for the case of 3c and 3d might lie in product radical stability (such as
benzyl and R-silyl radicals).
Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Review for use of Lewis acids in radical reactions: Renaud, P.;
Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562.
OL0067890
(11) Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, F. J.
Org. Chem. 1995, 60, 3576. Urabe, H.; Kobayashi, K.; Sato, F. J. Chem.
Soc., Chem. Comm. 1995, 1043-1044.
(12) Vionnet, J.-P.; Schenk, K.; Renaud, P. HelV. Chim. Acta 1993, 76,
2490. Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 274.
(13) In comparison with intermolecular reaction, a change in regiose-
lectivity in intramolecular reaction seems to be more difficult, since it needs
to overcome the stereoelectronic effect.
(15) Fuji, K. Chem. ReV. 1993, 93, 2037.
(16) Although the conversion of 2a was carried out in the presence of
8% of 1a, due to the difficulty of the separation by column chromatography,
pure 10, 11 and 12 were obtained after purification by column chromatog-
raphy.
(17) (a) Greene, A. E.; Depres, J. P.; Coelho, F.; Brocksom, T. J. J.
Org. Chem. 1985, 50, 3945, (b) Greene, A. E.; Coelho, F.; Depres, J. P.;
Brocksom, T. J. Tetrahedron Lett. 1988, 29, 5661.
(14) The reaction mainly resulted in reduction of the olefin and iodo
moieties.
Org. Lett., Vol. 3, No. 1, 2001
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