Lewis Acid Promoted Phenylseleno Group Transfer Tandem Radical Cyclization Reactions

Article abstract of DOI:10.1021/ol025750n

matrix presented A new Lewis acid promoted phenylseleno group transfer tandem radical cyclization method was developed. In the presence of Lewis acids such as Yb(OTf)₃ or Mg(Cl0₄)₂, under photolysis condition at low temper

Full text of DOI:10.1021/ol025750n

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1239-1241
Lewis Acid Promoted Phenylseleno
Group Transfer Tandem Radical
Cyclization Reactions
Dan Yang,* Qiang Gao, and On-Yi Lee
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, P. R. China
yangdan@hku.hk
Received February 20, 2002
ABSTRACT
A new Lewis acid promoted phenylseleno group transfer tandem radical cyclization method was developed. In the presence of Lewis acids
such as Yb(OTf)3 or Mg(ClO ) , under photolysis condition at low temperature (−45 °C), various unsaturated r-phenylseleno â-keto amides
4 2
underwent radical cyclization reactions to give monocyclic or bicyclic products in a highly efficient, regioselective, and stereoselective manner.
Since its discovery more than a decade ago, atom or group
transfer radical cyclization has become a powerful tool for
the synthesis of cyclic compounds.1 Recently we discovered
a chiral Lewis acid catalyzed bromo atom-transfer radical
cyclization method for the synthesis of 2,3-disubstituted
cyclic ketones (eq 1).2 Here we report a new Lewis acid
There are two known pathways for the cyclization of
R-phenylseleno 1,3-dicarbonyl compounds: the ionic path-
way promoted by Lewis acids (eq 2),5 and the radical
pathway under photolysis condition (eq 3).6 After screening
promoted phenylseleno group transfer radical cyclization
method3 and its successful application to tandem cyclization
reactions for the construction of various bicyclic ring
skeletons.4
several 1,3-dicarbonyl compounds and heteroatom/group
combinations, we found unsaturated R-phenylseleno â-keto
(1) (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986,
108, 2489-2490. (b) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54,
3140-3157. (c) Curran, D. P.; Chen, M.-S.; Kim, D. J. Am. Chem. Soc.
1989, 111, 6265-6276. (d) Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong,
C. M.; Chang, C.-T. J. Am. Chem. Soc. 1989, 111, 8872-8878. (e) Curran,
D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746-2750. (f) For a recent
review, see: Byers, J. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, Chapter 1.5.
(2) Yang. D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K. J. Am.
Chem. Soc. 2001, 123, 8612-8613.
(3) For an recent review on the use of Lewis acids in free radical
reactions, see: (a) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998,
37, 2562-2579. For recent examples of Lewis acid promoted atom transfer
radical reactions, see: (b) Mero, C. L.; Porter, N. A. J. Am. Chem. Soc.
1999, 121, 5155-5160. (c) Clark, A. J.; Campo, F. D.; Deeth, R. J.; Filik,
R. P.; Gatard, S.; Hunt, N. A.; Lastecoueres, D.; Thomas, G. H.; Verlhac,
J.-B.; Wongtap, H. J. Chem. Soc., Perkin Trans. 1 2000, 671-680. (d)
Kitagawa, O.; Yamada, Y.; Fujiwara, H.; Taguchi, T. J. Org. Chem. 2002,
67, 922-927.
10.1021/ol025750n CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/03/2002

amides suitable radical precursors since they are stable and
easy to prepare and purify.7 For compound 1a, several
reaction conditions were examined (Table 1). At 6 °C and
Table 2. Lewis Acid Promoted Phenylseleno Group Transfer
Monocyclization Reactionsa
Table 1. Effect of Lewis Acids on the Phenylseleno Group
Transfer Radical Cyclization Reaction of 1aa
Lewis
acid
initiating temp time prod-
solvent condition (°C)
(h) uct yieldb
entry
1
2
3
4
5
6
Mg(ClO4)2 CH2Cl2
CH2Cl2 hν
Mg(ClO4)2 CH2Cl2 hν
6
-45
-45
1
5
4.5
3a
nr
2a
2a
2a
2a
70%
53%
40%
74%
80%
Mg(ClO4)2 toluene Et3B/O2 -78 to 0 10
Mg(ClO4)2 toluene hν
-50
-45
9
2
c
Yb(OTf)3 CH2Cl2 hν
a Unless otherwise indicated, the reaction was irradiated with UV light
at -45 °C in CH2Cl2 and 1 equiv of Lewis acid was added. b Ratio of
epimers. c 0.6 equiv. d Et2O was used as the solvent. e 4 Å molecular sieves
was added.
a Unless otherwise indicated, 1.0 equiv of Lewis acid was used. b Isolated
yield. c 0.6 equiv.
in the presence of Mg(ClO4)2 (1 equiv), only the six-
membered-ring compound 3a was formed in 70% yield
(entry 1), which is believed to be the ionic cyclization
product.5 No reaction took place at -45 °C when the reaction
mixture was irradiated with UV light in the absence of Lewis
acid (entry 2). In contrast, with the addition of 1 equiv of
Yb(OTf)3 or Mg(ClO4)2, the desired product 2a could be
obtained by using either UV light or Et3B/O2 to initiate the
radical reaction (entries 3-6). It was noteworthy that at lower
temperatures (-50 or -45 °C), the ionic side reactions were
effectively suppressed and no compound 3a was formed.
With a catalytic amount of Yb(OTf)3 (0.6 equiv) as catalyst
(entry 6), the best yield (80%) was achieved under photolysis
condition at -45 °C in CH2Cl2. Clearly Lewis acids
promoted this phenylseleno group transfer radical cyclization
reaction. By complexation with 1,3-dicarbonyl groups, Lewis
acids can make the R-radical more electron-deficient and
therefore activate it toward addition to unactivated alkenes.
Various unsaturated R-phenylseleno â-keto amide sub-
strates (1b-e) were then tested under the above radical
cyclization condition (Table 2). Cyclization of 1b gave
exclusively the 6-endo product 2b as a mixture of epimers
in 68% yield (entry 1). In contrast, Byers and co-workers
obtained a 3:1 mixture of 6-endo and 5-exo products for the
cyclization of the corresponding â-keto ester under sunlamp
irradiation without the addition of Lewis acids (eq 3).6a
Substrate 1c failed to cyclize when treated under the standard
photolysis condition (1.0 equiv of Yb(OTf)3 or Mg(ClO4)2
in CH2Cl2). When the solvent was changed to Et2O and 0.6
equiv of Yb(OTf)3 was added, the 6-exo cyclization product
2c was formed in 56% yield (entry 2). Substrate 1d has two
cyclization modes, i.e., 6-exo and 7-endo, but only the 6-exo
product was isolated in 80% yield (entry 3). For the
cyclization of 1e, the R-radical intermediate attacked the less
substituted side of the alkene to form the seven-membered-
ring amide 2e exclusively (entry 4).8 These results demon-
strate that excellent regioselectivity can be achieved for the
Lewis acid promoted phenylseleno group transfer radical
cyclization reactions.
It is known in the literature that the phenylseleno group
transfer is slower than the I or Br atom transfer, and this
feature makes the phenylseleno group transfer especially
suitable for tandem cyclization reactions.1f,9 By applying the
above monocyclization method to a series of diene substrates
(1f-j), we expected to obtain various bicyclic phenylseleno
(4) For recent reviews on radical tandem cyclization reactions, see: (a)
McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224-
2248. (b) Malacria, M. Chem. ReV. 1996, 96, 289-306.
(5) Jackson, W. P.; Ley, S. V.; Morton, J. A. Tetrahedron Lett. 1981,
22, 2601-2604.
(6) (a) Byers, J. H.; Gleason, T. G.; Knight, K. S. J. Chem. Soc., Chem.
Commun. 1991, 354-356. For examples of phenylseleno group transfer
radical cyclization reactions, see: (b) Back, T. G.; Gladstone, P. L. Synlett
1993, 699-700. (c) Ryu, I.; Muraoka, H.; Kambe, N.; Komatsu, M.; Sonoda,
N. J. Org. Chem. 1996, 61, 6396-6403. (d) Pandey, G.; Rao, K. S. S. P.;
Rao, K. V. N. J. Org. Chem. 1996, 61, 6799-6804. (e) Abazi, S.; Rapado,
L. P.; Schenk, K.; Renaud, P. Eur. J. Org. Chem. 1999, 477-483. For a
recent review, see: (f) Renaud, P. In Organoselenium Chemistry: Modern
DeVelopments in Organic Synthesis; Wirth, T., Ed.; Springer: Berlin, 2000;
pp 81-112.
(7) Rosenstein, I. J.; Tynan, T. A. Tetrahedron Lett. 1998, 39, 8429-8432.
1240
Org. Lett., Vol. 4, No. 7, 2002

group transfer products. Once generated, the R-radicals of
â-keto amides would undergo endo-cyclization to attack the
less substituted side of the internal alkene group, yielding
cyclic tertiary alkyl radical intermediates. At this stage, the
slow rate of phenylseleno group transfer would allow enough
time for the formation of the second carbon-carbon bond
before the radical chain is terminated. Subsequent group
transfer would be accomplished when the bicyclic alkyl
radical abstracts the phenylseleno group from another
substrate. This was indeed the case for the tandem cyclization
reactions of substrates 1f-j (Table 3). Despite the difference
the highly regioselective formation of the exocyclic CdC
bond. In contrast, oxidative radical cyclization of similar
unsaturated â-keto esters without R-SePh group using
Mn(OAc)3 and Cu(OAc)2 resulted in a mixture of exo- and
endo-cyclic olefinic products.11 After the cyclization of 1h
(entry 5), cis-6,5-fused ring product 2h was isolated in high
yield (80%) as a mixture of epimers (R:â ) 1:3.6). In
addition, cis-7,5-fused ring skeleton was constructed in good
yield as a pair of epimers (entries 6 and 7). A small amount
of alkene 5 (7%), arising from elimination of bicylic alkyl
radical intermediate, was also formed in the cyclization
reaction of 1j (entry 7). Presumably the bulky geminal methyl
groups of 1j hindered the abstraction of the PhSe group from
another substrate molecule. Oxidative elimination of selenide
2j afforded 5, a potential intermediate for the total synthesis
of the potent antibacterial agent guanacastepene.12
Table 3. Lewis Acid Promoted Tandem Phenylseleno Group
Transfer Reactionsa
In conclusion, the Lewis acid promoted phenylseleno
group transfer radical cyclization represents an efficient,
regioselective, and stereoselective tool for the formation of
monocyclic and bicyclic compounds that are important core
structures of many biologically interesting natural products.
Future efforts will be directed at developing the enantio-
selective version of these reactions.13
Acknowledgment. This work was supported by The
University of Hong Kong and Hong Kong Research Grants
Council. We thank Dr. N.-Y. Zhu for X-ray analysis. D.Y.
acknowledges the Bristol-Myers Squibb Foundation for an
Unrestricted Grant in Synthetic Organic Chemistry and the
Croucher Foundation for a Croucher Senior Research Fol-
lowship.
a Reaction conditions: 1 equiv of Lewis acid, hν, -45 °C, CH2Cl2. b 4
Å MS was added. c 0.6 equiv. d In the absence of MS, the reaction took 5
h to complete and the yield was 74%. e Ratio of epimers (R:â).
in the second ring formation, i.e., 6-endo for 1f and 6-exo
for 1g, both cyclization products 2f and 2g possessed the
trans-decalin skeleton with four stereocenters set up in one
step (entries 1-4). Slightly better yield of 2f was obtained
when Yb(OTf)3 was used as the Lewis acid instead of
Mg(ClO4)2 (entry 1 vs entry 2). Oxidative elimination of
PhSe group from 2f provided the exocyclic olefinic com-
pound 4, a core structure found in many naturally occurring
bioactive terpenoids, such as andrographolide,10a subglutinol,10b
and the candelalides.10c A notable feature of this reaction is
Supporting Information Available: Experimental details
and X-ray data of compounds 2f and â-5. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL025750N
(10) (a) Puri, A.; Saxena, R.; Saxena, R. P.; Saxena, K. C.; Srivastava,
V.; Tandon, J. S. J. Nat. Prod. 1993, 56, 995-999. (b) Lee, J. C.;
Lobkovsky, E.; Pliam, N. B.; Strobel, G.; Clardy, J. J. Org. Chem. 1995,
60, 7076-7077. (c) Singh, S. B.; Zink, D. L.; Dombrowski, A. W.; Dezeny,
G.; Bills, G. F.; Felix, J. P.; Slaughter, R. S.; Goetz, M. A. Org. Lett. 2001,
3, 247-250.
(11) (a) Snider, B. B.; Mohan, R.; Kates, S. A. Tetrahedron Lett. 1987,
28, 841-844. (b) Yang, D.; Xu, M. Org. Lett. 2001, 3, 1785-1788.
(12) (a) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569-572.
(b) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3, 2399-2402.
(13) For an excellent review on enantioselective radical reactions, see:
Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163-171.
(8) When Mg(ClO4)2 was used as the Lewis acid, the addition of 4 Å
molecular sieves led to faster reaction and higher yield
(9) Curran, D. P.; Martin-Esker, A. A.; Ko, S.-B.; Newcomb, M. J. Org.
Chem. 1993, 58, 4691-4695.
Org. Lett., Vol. 4, No. 7, 2002
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