Stereocontrol in radical cyclization: Change in rate-determining step

Article abstract of DOI:10.1021/ol101370x

Intramolecular cyclization of an α-carbon radical of ester carrying a chiral 2,4-pentanediol tether shows low stereoselectivity when the radical carbon has an alkyl substituent, while the selectivity becomes high to give a single stereoisomer (>99% pure)

Full text of DOI:10.1021/ol101370x

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3626-3629
Stereocontrol in Radical Cyclization:
Change in Rate-Determining Step
Siddiki S. M. A. Hakim and Takashi Sugimura*
Graduate School of Material Science, UniVersity of Hyogo, 3-2-1, Kohto,
Kamigori, Ako-gun, Hyogo 678-1297, Japan
sugimura@sci.u-hyogo.ac.jp
Received June 14, 2010
ABSTRACT
Intramolecular cyclization of an r-carbon radical of ester carrying a chiral 2,4-pentanediol tether shows low stereoselectivity when the radical
carbon has an alkyl substituent, while the selectivity becomes high to give a single stereoisomer (>99% pure) when the substituent is an aryl
group. The difference in the selectivity is attributable to the change in the rate-determining step from the conformational process to the
cyclization.
The radical is synthetically useful because of its reactive
nature, allowing expected reactions involving an unpaired
electron irrespective of coexisting functional groups that can
react with polar reagents.1 For the same reason, the reaction
control by a polar interaction is not usually workable for a
neutral radical species. To realize a stereocontrolled radical
reaction, many reaction systems have been developed by
incorporating a proper steric fence,2 although sufficiently
stereocontrolled reactions for asymmetric synthesis are
limited.3,4 We have reported an efficient tandem reaction
including radical cyclization using a detachable chiral
auxiliary (Scheme 1).5
Scheme 1
.
Tandem Reaction via Radical Cyclization Using a
2,4-Pentanediol Tether
(1) (a) Renaud, R.; Sibi, M. P., Eds. Radicals in Organic Synthesis;
Wiley-VCH: Verlag, 2001; Vols. 1 and 2. (b) Gans¨auer, A., Ed. Radicals
in Synthesis; Springer: Verlag, 2006; I and II.
The product yield was very high (up to 94%), but the
stereoselectivity at the cyclization step was very poor (dr )
ca. 1:1).6 We found a reason for the low selectivity, and a
solution to address it will be reported herein.
(2) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1995.
(3) (a) Zimmerman, J.; Sibi, M. P. Radicals in Synthesis; Gansa¨uer, A.,
Ed.; Springer: Verlag, 2006; I, pp 107-162. (b) Bertelsen, S.; Nielsen, M.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 7356–7359
.
(4) For selected recent examples, see: (a) Lee, J. C. H.; Hall, D. G.
J. Am. Chem. Soc. 2010, 132, 5544–5545. (b) Um, J. M.; Gutierrez, O.;
Schoenebeck, F.; Houk, K. N.; MacMillan, W. C. J. Am. Chem. Soc. 2010,
132, 6001–6005. (c) Jang, H. Y.; Hong, J. B.; MacMillan, W. C. J. Am.
Chem. Soc. 2007, 129, 7004–7005. (d) Miyabe, H.; Asada, R.; Toyoda, A.;
Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45, 5863–5866. (e) Yang, D.;
Zheng, B. F.; Gao, Q.; Gu, S.; Zhu, N. Y. Angew. Chem., Int. Ed. 2006,
(5) (a) Sugimura, T.; Nagano, S.; Tai, A. Tetrahedron Lett. 1997, 38,
3574–3548. (b) Nagano, N.; Hakim, S. S. M. A.; Sugimura, T. Bull. Chem.
Soc. Jpn. 2007, 80, 2011–2013.
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B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, J. K.; Trach,
F. Organic Reactions; Paquette, L. A., Ed.; John Wiley: New York, NY,
1996; Vol. 48, Chapter 2, pp 301-856. (c) Giese, B. Angew. Chem., Int.
Ed. Engl. 1989, 28, 969–980.
45, 255–258
.
10.1021/ol101370x  2010 American Chemical Society
Published on Web 07/21/2010

To investigate the stereoselectivity of the cyclization step,
the radical intermediate was generated by reductive debro-
mination of R-bromoester 1. As preliminary studies, ef-
ficiency of the reaction, a debromination-cyclization-ter-
mination sequence (Scheme 2), was examined with 1a-c
The diastereomeric tethered substrates 1b and 1f showed
similar selectivity, which is totally unexpected because the
two methyl groups on the tether should work cooperatively
or competitively depending on the relative configurations.
It is also unusual that the lower reaction temperature did
not give any higher stereoselectivity; e.g., the reaction of
1b at -50 °C gave 2b of 31% de (20% yield). Here, we
have reached a working hypothesis that activation energy
for the cyclization step to generate the new chiral center does
not govern the product selectivity.
Scheme 2.
Product Yields in Tethered Radical Cyclizationa
Stereoselectivity can be rationalized by slow change of
the conformations of the generated radical intermediate.9
Figure 1 shows a general case of the secondary R-carbon
a Conditions. Method A: Bu3SnH/AIBN/80 °C. Method B: NaBH4/
Bu3SnCl/365 nm.
Figure 1. Pre-equilibration for cyclization of the R-radical of ester.
under two reaction conditions, use of a stoichiometric amount
of Bu3SnH with AIBN in benzene under reflux (method A)
and a catalytic amount of Bu3SnCl with NaBH4 in ethanol
under photolysis (method B).7
By method A, a considerable amount of the Michael-type
tin-adducts of the acrylate were formed, and expected 2a-c
were obtained only in 0-12% yields. In contrast, method B
using a limited amount of tin reagent resulted in good yields
of 2b and 2c, although the primary bromide 1a did not give
2a, leading predominantly to the simple substitution of
hydrogen for bromine.
radical of ester. Since steric repulsions between R4 and the
different oxygens are similar, the equilibration is not shifted
to one side, in contrast to the R-carbon radicals of amide.10
In a diastereoselective reaction of chiral substrates, both the
conformers are directed to give the same stereoisomer if
the reaction is stereocontrolled by the chiral R4 group, but
the stereodirection between the conformers becomes opposite
if the chiral R3 group controls.11 Activation energy for the
conformational change of a typical secondary R-carbon
radical of ester was reported to be 11-12 kcal/mol,12 which
could be larger than those for the cyclization with 1b and
1d-f, which correspond to the R3-controlled reaction.
The reaction rate for the cyclization through the 2,4-
pentanediol tether was experimentally evaluated using a
radical clock (Scheme 4).13 When 1g or 1h was treated under
the reductive debromination conditions of method B, gener-
Secondary bromides 1d,e were converted to 2d,e by
method B in very high yields of 80-92% (Scheme 3). The
Scheme 3. Stereoselectivity with Secondary Substrates
(8) (a) Sugimura, T. In Recent Research Developments in Organic
Chemistry; Pandalai, S. G., Ed.; Transworld: Tribundrum, 1998; Vol. 2, pp
47-54. (b) Sugimura, T. Eur. J. Org. Chem. 2004, 1185–1192.
(9) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Orgnic
Compounds; Wiley: New York, 1994; pp 647-655.
(10) (a) Curran, D. P.; Shen, W.; Zhang, J.; Heffner, T. A. J. Am. Chem.
Soc. 1990, 112, 6738–6740. (b) Porter, N. A.; Bryer, R.; Swann, E.; Nally,
J.; Pradhan, J.; Allen, T.; McPhail, A. T. J. Am. Chem. Soc. 1991, 113,
7002–7010. (c) Porter, N. A.; Rosenstein, I. J.; Breyer, R. A.; Bruhnke,
J. D.; Wu, W.-X.; McPhail, A. T. J. Am. Chem. Soc. 1992, 114, 7664–
7676. (d) Hiroi, K.; Maneko, M.; Ishii, M.; Kato, F. Tetrahedron: Asymmetry
2003, 14, 2875–2878.
(11) (a) Yang, D.; Xu, M.; Bian, M. Y. Org. Lett. 2001, 3, 111–114.
(b) Chen, M-. Y.; Fang, J-. M.; Tsai, Y-. M.; Yeh, R-. L. J. Chem. Soc.,
Chem.Commun. 1991, 1603–1604, and references therein.
(12) Strub, W.; Roduner, E.; Fischer, H. J. Phys. Chem. 1987, 91, 4379–
4383.
stereoselectivities were very poor to give 0-44% de,
irrespective of the size of R1. These poor stereoselectivities
are exceptional for the 2,4-pentanediol tethered reactions.8
(13) Newcomb, M.; Filipkowski, M. A.; Johnson, C. C. Tetrahedron
Lett. 1995, 36, 3643–3646. See also Newcomb, M. Tetrahedron 1993, 49,
1151–1176.
(7) Curran, D. P. Synthesis 1988, 417–439, and 489-513.
Org. Lett., Vol. 12, No. 16, 2010
3627

Scheme 4. Competitive Intermolecular Cyclization Reaction with the Radical Clock Reaction
ated radicals underwent a quick formation of the five-
membered ring at the rate of 2 × 105 s-1.13 From the reaction
of 1g carrying (2R,4R)-tether, two products 2g and 3g were
obtained at a ratio of 1:1 in more than 70% total yield. Thus,
the two competitive intramolecular reactions should occur at a
similar rate. In the case of 1h carrying (2S,4R)-tether, only 2h
was obtained in more than 70% yield, but 3h or its derivative
Scheme 5.
Stereoselectivity with Arene-Substituted Substratesa
1
was undetected (<5% deduced from H NMR). From these
observations, the radical cyclization rates via the tether are
concluded to be 2 × 105 s-1 for 1g and >4 × 106 s-1 for 1h.
The rates can be converted to the activation Gibbs energies of
10 kcal mol-1 and <8 kcal mol-1, respectively, which are
comparable to or lower than the activation energies expected
for the conformational change of the radical intermediates.12
Thus, the stereoselectivity is governed by the conformer ratio
of the radical intermediate, in contrast to the implication from
the Curtin-Hammett principle.14,15
Rotation of the radical intermediate about the CO-C• R1
bond in Scheme 2 becomes faster when the radical is
delocalized to the R1 group and conjugation with the carbonyl
becomes weak. The delocalization also affects the reactivity
of the radical to reduce the cyclization rate. Both the effects
could work, in crossing the Curtin-Hammett borderline, to
control the selectivity by the activation energy at the
cyclization step. To attain the radical delocalization, the
aromatic group was introduced (R1 ) Ar). By the treatment
of phenyl-substituted 1i and 1j by method B, 89% de of 2i
and >99% de of 2j were obtained in moderate yields (Scheme
5). Configuration of the newly generated chiral centers was
assigned to be S for 2i and R for 2j by chemical correlation
with (+)-(S)-2-phenylglutaric acid.16 The moderately high
selectivity with the (2R,4R)-tether (1k-1m) and very high
selectivity with the (2S,4R)-tether (1n-1p) were also ob-
served for the production of 2k-p.
a Conditions. Method A: Bu3SnH/AIBN/80 °C. Method B: NaBH4/
Bu3SnCl/365 nm. Method C: Bu3SnH/365 nm.
amount of Bu3SnH under the photolysis conditions at rt to give
85% of 2i and 60% of 2j (method C).
Expected geometries for the radical cyclization reactions
are shown in Scheme 6. They seem to cause minimum strains
both at the tether part and the addition sites.
The low yields with the aryl-substituted substrates should be
due to the low reactivity of the radicals generated. The yields
were improved by using a stoichiometric amount of Bu3SnH.
That is, the reactions of 1i and 1j with AIBN at 80 °C (method
A) resulted in higher yields than those by method B. Further
improvement in the yields was achieved using a stoichiometric
Scheme 6. Expected Conformations for the Cyclization Reactionsa
(14) Conformation of the radical intermediate generated from 1b is
confirmed to be independent of the configuration at the bromide carbon.
That is, the reaction with stereochemically pure 1b prepared from (S)-R-
bromoisovaleric acid gave the same diastereomer ratio of 31% de (54%
yield) as those with the diastereomeric mixture, and thus, chirality in 1b is
not transferred to 2b.
a Conformation A is for the major isomer of 2i, B is for the minor of
2i, and C is for the predominant isomer of 2j.
3628
Org. Lett., Vol. 12, No. 16, 2010

In the present report, the intramolecular radical reaction using
the 2,4-pentanediol tether was shown to be stereouncontrolled
if the cyclization is quicker than the conformational isomer-
ization, but this problem was dissolved by a proper substitution
at the radical center. The essential stereocontrollability of the
2,4-pentanediol tether for intramolecular reactions was con-
firmed to be very high even for the quick reaction, and
sufficiently strong stereocontrol is attained when the confor-
mational change is still fast.
Acknowledgment. We thank Professor Emeritus Tadashi
Okuyama of University of Hyogo for his helpful discussions.
Supporting Information Available: Experimental pro-
cedure and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(15) For other conformation-controlled radical reactions, see: (a) Taaning,
R. H.; Lindsy, K. B.; Shciott, B.; Daasbjerg, K.; Skrydstrup, T. J. Am. Chem.
Soc. 2009, 131, 10253–10262. (b) Guthrie, D. B.; Curran, D. P. Org. Lett.
2009, 11, 249–251.
(16) Evans, D. A.; Sheidt, K. A.; Johnston, J. N.; Willes, M. C. J. Am.
Chem. Soc. 2001, 123, 4480–4491. See Supporting Infromationfor the
details.
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