Diastereocontrol by trialkylaluminums in the synthesis of tetrahydrofurans via radical cyclization

Article abstract of DOI:10.1021/ol016429s

(matrix presented) The influence of various Lewis acids in the radical cyclization of β-allyloxyalkyl phenyl selenides was investigated. Whereas the unperturbed cyclization afforded trans-2,4-disubstituted tetrahydrofurans as the major products (cis/trans ≈ 1/4.5), cyclization in the presence of trialkylaluminums (3 equiv) afforded predominantly (cis/trans ≈ 7/1) the corresponding cis-isomers.

Full text of DOI:10.1021/ol016429s

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3459-3462
Diastereocontrol by Trialkylaluminums
in the Synthesis of Tetrahydrofurans via
Radical Cyclization
Cecilia Ericsson and Lars Engman*
Department of Organic Chemistry, Institute of Chemistry, Uppsala UniVersity,
Box 531, S-751 21, Uppsala, Sweden
lars.engman@kemi.uu.se
Received July 13, 2001
ABSTRACT
The influence of various Lewis acids in the radical cyclization of â-allyloxyalkyl phenyl selenides was investigated. Whereas the unperturbed
cyclization afforded trans-2,4-disubstituted tetrahydrofurans as the major products (cis/trans ≈ 1/4.5), cyclization in the presence of
trialkylaluminums (3 equiv) afforded predominantly (cis/trans ≈ 7/1) the corresponding cis-isomers.
In addition to metal-mediated synthesis, radical chemistry
has emerged during the last 15 years as one of the most
interesting methods for carbon-carbon bond formation.1
Once it was established that radical reactions are often “well-
behaved” in the sense that chemo- and regioselectivity can
be controlled without much difficulty, the attention was
focused (and still is) on the stereoselectivity of radical
transformations.2 Whereas enantioselective reactions of
radicals are still rare, diastereoselectivity control in acyclic
systems has seen remarkably rapid progress recently.3
Diastereoselective reactions of cyclic radicals are also not
uncommon. The vast majority of stereoselective radical
reactions are 5-exo-cyclizations of variously substituted
(including oxa and aza analogues) 5-hexenyl radicals.
Diastereoselectivity in these systems is primarily governed
by conformational and steric effects as described by the
Beckwith-Houk transition state model.4 Thus, 1- or 3-sub-
stituted 5-hexenyl radicals afford predominantly cis-disub-
stituted products, whereas 2- and 4-substituted derivatives
give the corresponding trans-isomers in excess. Selectivity
rarely exceeds 4/1 in favor of the major diastereomer, though.
Significant perturbation of Beckwith-Houk selectivities can
be obtained by Lewis acid complexation5 or by the stereo-
chemical influence of the anomeric effect.6 By variation of
(1) Giese, B. Radicals in Organic Synthesis: Formation of C-C bonds;
Pergamon Press: Oxford, 1986. Regitz, M., Giese, B., Eds. Houben-Weyl,
Methoden der Organishen Chemie, Band E19a, C-Radikale, Teil 1+2; Georg
Thieme Verlag: Stuttgart, 1989. Curran, D. P. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, p 715 and 779. Motherwell, W. B.; Crich, D.
Free Radical Chain Reactions in Organic Synthesis; Academic Press:
London, 1992. Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic
Chemistry; Wiley: Chichester, 1995.
(2) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions - Concepts, Guidelines and Synthetic Applications; VCH:
Weinheim, 1996. See also: Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut,
J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301.
(3) For representative examples, see: Easton, C. J.; Merrett, M. C.
Tetrahedron 1997, 53, 1151. Guindon, Y.; Slassi, A.; Rancourt, J.; Bantle,
G.; Bencheqroun, M.; Murtagh, L.; Ghiro, EÄ .; Jung, G. J. Org. Chem. 1995,
60, 288. Morikawa, T.; Washio, Y.; Harada, S.; Hanai, R.; Kayashita, T.;
Nemoto, H.; Shiro, M.; Taguchi, T. J. Chem. Soc., Perkin Trans. 1 1995,
271. Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme, D.;
Renaud, J.; Robinson, G.; Lavalle´e, J.-F.; Slassi, A.; Jung, G.; Rancourt, J.
J. Org. Chem. 1994, 59, 1166. Porter, N. A.; Carter, R. L.; Mero, C. L.;
Roepel, M. G.; Curran, D. P. Tetrahedron 1996, 52, 4181. Porter, N. A.;
Scott, D. M.; Lacher, B.; Giese, B.; Zeitz, H. G.; Lindner, H. J. J. Am.
Chem. Soc. 1989, 111, 8311. Crich, D.; Davies, J. W. Tetrahedron Lett.
1987, 28, 4205. Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800. Sibi, M.
P.; Shay, J. J.; Ji, J. Tetrahedron Lett. 1997, 38, 5955. Sibi, M. P.; Ji, J.;
Wu, J. H.; Gu¨rtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996, 118, 9200.
Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117, 11029.
(4) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem.
Commun. 1980, 482. Beckwith, A. L. J.; Lawrence, T.; Serelis, A. K. J.
Chem. Soc., Chem. Commun. 1980, 484. Beckwith, A. L. J.; Schiesser, C.
H. Tetrahedron 1985, 41, 3925. Spellmeyer, D. C.; Houk, K. N. J. Org.
Chem. 1987, 52, 959.
10.1021/ol016429s CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/05/2001

the steric bulk of the N-substituent, we recently were able
to control diastereoselectivity in the preparation of 2,4-
disubstituted pyrrolidines via radical cyclization.7
Table 1. Radical Cyclization in the Presence of Various Lewis
Acids
In the present paper we report attempts to control dia-
stereoselectivity in the synthesis of tetrahydrofurans via
radical cyclization. The preparation of radical cyclization
precursors involved regioselective ring-opening of epoxides
with benzeneselenolate, followed by O-allylation (Scheme
1).8
Lewis acid (3 equiv)
yielda (%)
cis/trans-ratio
-
77
1/4.5
Ni(acac)2
(C6F5)3B
BF3‚OEt2
Ti(O-i-Pr)4
TiCl4
GaCl3
MeAlCl2
Et2AlCl
Zn(OTf)2
Me2AlOPhg
Me3Al
Et3Al
i-Bu3Al
0b
Scheme 1. Synthesis of Radical Precursors
0b
34 (56c)
25 (69c)
0d
1/3.5
1/4
0e
0e
26e
75
64
74
79
69
4.5/1
1/4
1/4.1
5.8/1
5.1/1
6.8/1
f
With the perspective to perturb Beckwith-Houk diaste-
reoselectivity by O-complexation, the photoinduced radical
cyclization of compound 1a (Table 1) in the presence of
AIBN9 and n-Bu3SnH was then studied in the presence of 3
equiv of various Lewis acids.10 In the absence of an additive,
this reaction is moderately trans-selective (cis/trans ) 1/4.5).
To our disappointment, certain Lewis acids prevented
initiation of the radical reaction (Ni(acac)2, (C6F5)3B) or made
the reaction proceed with very low conversion (BF3‚OEt3,
Ti(O-i-Pr)4). Lewis acids containing a nucleophilic group
(TiCl4, MeAlCl2, Et2AlCl, GaCl3) converted the starting
material either into the corresponding â-chloroselenide
(TiCl4) or into allylbenzene (GaCl3, Et2AlCl, and MeAlCl2).
Other Lewis acids did not seem to affect the diastereo-
selectivity at all (Zn(OTf)2, Me2AlOPh).
a Isolated yield. b Only starting material was recovered. c On the basis
of consumed starting material. d 2-Chloro-3-phenylpropyl phenyl selenide
was formed. e Allylbenzene was formed. f Only partly dissolved. g The
reaction was performed in toluene. One equivalent of phenol was added to
Me3Al at -78 °C before selenide, AIBN, and n-Bu3SnH were added.
presence of 1.5, 3, 6, and 12 equiv of Me3Al, Et3Al, or i-Bu3-
Al (Table 2). As shown, the cis/trans-ratio was approximately
Table 2. Radical Cyclization of Compound 1a in the Presence
The best results were obtained with trialkylaluminums. In
the presence of 3 equiv of i-Bu3Al, 2-benzyl-4-methyltetra-
hydrofuran (2a) was isolated in 69% yield as a 6.8/1-mixture
of cis- and trans-isomers. To examine the effects of
increasing amounts of Lewis acid on diastereoselectivity,
radical cyclization of compound 1a was performed in the
of Various Trialkylaluminums
Lewis acid
equiv
yielda of 2a (%)
cis/trans-ratio
Me3Al
Me3Al
Me3Al
Me3Al
Et3Al
1.5
3
6
12
1.5
6
84
74
60
55 (85b)
87
81
80
71
69
2.1/1
5.8/1
7.6/1
7.8/1
4.7/1
6.3/1
7.1/1
3.5/1
6.8/1
6.9/1
6.9/1
Et3Al
(5) Renaud, P.; Andrau, L.; Schenk, K. Synlett 1999, 1462. Delouvrie´,
B.; Fensterbank, L.; Lacoˆte, E.; Malacria, M. J. Am. Chem. Soc. 1999, 121,
11395. Molander, G. A.; McWilliams, J. C.; Noll, B. C. J. Am. Chem. Soc.
1997, 119, 1265. Sibi, M. P.; Ji, J. J. Am. Chem. Soc. 1996, 118, 3063.
Nishida, M.; Ueyama, E.; Hayashi, H.; Ohtake, Y.; Yamaura, Y.; Yanagi-
numa, E.; Yonemitsu, O.; Nishida, A.; Kawahara, N. J. Am. Chem. Soc.
1994, 116, 6455. Feldman, K. S.; Romanelli, A. L.; Ruckle, Jr, R. E.; Jean,
G. J. Org. Chem. 1992, 57, 100. For a general review on the use of Lewis
acids in free radical reactions, see: Renaud, P.; Gerster, M. Angew. Chem.,
Int. Ed. 1998, 37, 2562.
Et3Al
12
1.5
3
6
12
i-Bu3Al
i-Bu3Al
i-Bu3Al
i-Bu3Al
45
55
a Isolated yield. b Reaction time ) 30 h (instead of 15 h); a second portion
of AIBN and Bu3SnH was added after 15 h.
(6) Villar, F.; Renaud, P. Tetrahedron Lett. 1998, 39, 8655. Beckwith,
A. L. J.; Page, D. M. J. Org. Chem. 1998, 63, 5144.
(7) Besev, M.; Engman, L. Org. Lett. 2000, 2, 1589.
(8) Engman, L.; Gupta, V. J. Org. Chem. 1997, 62, 157.
4/1 using 1.5 equiv of the trialkylaluminum. The ratio then
increased slowly by further addition of Lewis acid. Contrary
to our expectations, the sterically most demanding i-Bu3Al
did not increase diastereoselectivity beyond those values
recorded for Me3Al and Et3Al.
The poor conversion of starting material was a drawback
with Me3Al and i-Bu3Al. When 12 equiv of Me3Al was used,
the yield dropped to 55%. However, if the reaction time was
extended to 30 h and a second portion of AIBN and n-Bu3-
(9) Low-temperature initiation using Et3Al and a small amount of O2
was also tried. Although the diastereoselectivities were further improved
(cis/trans ) 15/1 for compound 2a at -78 °C in toluene with 3 equiv of
Et3Al), the reactions never did proceed to full conversion.
(10) Maruoka and co-workers have reported a remarkable template effect
of ATPH [aluminum tris(2,6-diphenylphenoxide)] in the preparation of
2-methyl-3-butyltetrahydrofuran by radical cyclization. In the absence of
the Lewis acid, the trans isomer was formed with high selectivity (cis/
trans ) 3/97) whereas in the presence of ATPH the cis isomer predominated
(cis/trans ) 92/8). Ooi, T.; Hokke, Y.; Maruoka, K. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1181.
3460
Org. Lett., Vol. 3, No. 22, 2001

Table 3. Radical Cyclization in the Absence/Presence of 3 equiv of Et3Al
a Isolated yield. b NMR yield (volatile products). c endo/exo-Ratio of cis-fused products. d In additon, 21% of trans-fused products was also obtained. e In
addition, 12% of trans-fused products was also obtained.
SnH was added after 15 h, 85% of the desired product was
isolated. Conversion was not a problem with Et3Al. There-
fore, radical cyclization of a few other substrates was studied
in the absence or presence of 3 equiv of Et3Al (Table 3).
Replacing the benzyl group in the radical precursor for a
butyl gave a slightly better cis-selectivity (Table 3, entry 1).
Compound 1c (derived from a 1,2-disubstituted epoxide)
upon cyclization afforded the 2,3,4-trisubstituted tetrahydro-
furan 2c as a mixture of exo- and endo-isomers. In the
presence of triethylaluminum, formation of the endo-isomer
was highly favored (endo/exo ) 11.4/1) as compared with
the unperturbed reaction (endo/exo ) 1/3.2). A similar
dramatic reversion of diastereoselectivity was observed in
the cyclization of the cyclooctene oxide derived radical
precursor 1d (Table 3, entry 3). The influence of triethyl-
aluminum on diastereoselectivity in the synthesis of 3,4-
disubstituted tetrahydrofurans was also investigated (Table
3, entry 4). As expected, diastereoselectivity was much less
changed in favor of the cis-isomer in the presence of the
Lewis acid.
Since compounds 5 and 6 are Lewis acid sensitive, they
underwent hydrolysis during reaction/workup and none of
the desired products of radical cyclization was isolated
(Scheme 2).
Our results with 2,4-disubstituted tetrahydrofurans may be
rationalized using the Beckwith-Houk transition state model.
In the absence of trialkylaluminum, transition state A (TS
A), where the R-group is equatorial, is favored over TS C
(Scheme 3). If the Lewis acid is complexed to oxygen, the
Scheme 3. Transition States Considered in the Synthesis of
Tetrahydrofurans via Radical Cyclization
Scheme 2
R-group is forced to adopt an axial position (TS D favored
over TS B), resulting in formation of the cis-isomer. In
support of this hypothesis, compound 1a when submitted to
radical cyclization in THF containing 3 equiv of Et3Al
Org. Lett., Vol. 3, No. 22, 2001
3461

by assuming a cis-decalin-like transition state (Scheme 4,
left). Complexation by triethylaluminum from above either
directs cyclization to occur via a boat conformer (Scheme
4, right) or via the other chair to give endo-2c.
Scheme 4. Transition States Considered in the Formation of
Compound 2c
In conclusion, it was possible to substantially perturb
Beckwith-Houk diastereoselectivity in the radical cyclization
synthesis of tetrahydrofurans by addition of trialkylalumi-
nums.
Acknowledgment. Financial support by the Swedish
Natural Science Research Council is gratefully acknowl-
edged.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
afforded the trans-isomer (cis/trans ) 1/5.1) as the major
product in 85% yield. Since THF competes with the substrate
for Et3Al, no Lewis acid effect is observed.
The preferential formation of the exo-isomer of compound
2c in the unperturbed cyclization reaction may be explained
OL016429S
3462
Org. Lett., Vol. 3, No. 22, 2001