Intermolecular radical reaction of O, Se-acetals generated via seleno-Pummerer rearrangement

Article abstract of DOI:10.1021/ol301482f

A new general protocol for the synthesis of O,Se-acetals using the seleno-Pummerer reaction has been developed, and their radical-based two- and three-component coupling reactions were studied. The three-component coupling employed the O,Se-acetal, cyclopentenone, and an allylstannane derivative, and enabled stereoselective installations of α-acyloxy alkyl and functionalized allyl groups to generate the 2,3-trans-disubstituted cyclopentanone in a single operation. The obtained highly functionalized structure was used as an intermediate for facile assembly of the zedoarondiol carboskeleton.

Full text of DOI:10.1021/ol301482f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Intermolecular Radical Reaction of O,Se-
Acetals Generated via Seleno-Pummerer
Rearrangement
Daisuke Urabe, Hiroki Yamaguchi, Ayumi Someya, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
inoue@mol.f.u-tokyo.ac.jp
Received May 30, 2012
ABSTRACT
A new general protocol for the synthesis of O,Se-acetals using the seleno-Pummerer reaction has been developed, and their radical-based two-
and three-component coupling reactions were studied. The three-component coupling employed the O,Se-acetal, cyclopentenone, and an
allylstannane derivative, and enabled stereoselective installations of R-acyloxy alkyl and functionalized allyl groups to generate the 2,3-trans-
disubstituted cyclopentanone in a single operation. The obtained highly functionalized structure was used as an intermediate for facile assembly
of the zedoarondiol carboskeleton.
Radical-based carbonꢀcarbon bond formation has long
been recognized as a powerful and practical methodology
for total synthesis of complex natural products because it
exhibits high product yield and chemoselectivity under
mild reaction conditions.1 Among such transformations,
we have been particularly interested in three-component
radical reactions that enable single-step formation of two
new CꢀC bonds.2 These multicomponent couplings are
suitable for efficient assembly of functionalized carboske-
letons, since the reactions maximize the buildup of struc-
tural and functional complexity while minimizing the
number of synthetic operations.3
R-Oxygenated alkyl radicals are extremely useful reac-
tive intermediates for incorporation of oxygen-substituted
sp3 carbon centers onto CdC double bonds and thus are
applicable for the construction of multiply oxygenated
carboskeletons of natural products. O,Se-Acetals have
been employed as reliable precursors of R-oxygenated
radicals, as they are more chemically stable than R-alkoxy
alkylhalides (O,X-acetals, X = Cl, Br, or I) and more
reactive than O,S-acetals. Accordingly, O,Se-acetals were
utilized as versatile substrates for radical cyclizations.4,5
However, intermolecular reactions of O,Se-acetals re-
mained unexplored in comparison to their intramolecular
counterparts.6 Here we report the development of a new
efficient protocol for synthesis of O,Se-acetals and their
two- and three-component radical reactions. The present
three-component reaction allows one-step attachments of
(4) For
a recent review on organoselenium compounds, see:
Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J. Org. Chem. 2009, 1649.
(5) For representative examples of intramolecular radical reactions
of O,Se-acetals: (a) Beckwith, A. L. J.; Pigou, P. E. J. Chem. Soc., Chem.
Commun. 1986, 85. (b) Rawal, V. H.; Singh, S. P.; Dufour, C.; Michoud,
C. J. Org. Chem. 1993, 58, 7718. (c) Sasaki, M.; Inoue, M.; Noguchi, T.;
Takeichi, A.; Tachibana, K. Tetrahedron Lett. 1998, 39, 2783. (d)
Kumamoto, H.; Ogamino, J.; Tanaka, H.; Suzuki, H.; Haraguchi, K.;
Miyasaka, T.; Yokomatsu, T.; Shibuya, S. Tetrahedron 2001, 57, 3331.
(e) Yamashita, S.; Ishihara, Y.; Morita, H.; Uchiyama, J.; Takeuchi, K.;
Inoue, M.; Hirama, M. J. Nat. Prod. 2011, 74, 357.
(6) For application of intermolecular radical reaction of cyclic O,Se-
acetals in the context of C-glycosylation, see: (a) Abel, S.; Linker, T.;
Giese, B. Synlett 1991, 171. (b) Haraguchi, K.; Tanaka, H.; Saito, S.;
Yamaguchi, K.; Miyasaka, T. Tetrahedron Lett. 1994, 35, 9721. (c)
SanMartin, R.; Tavassoli, B.; Walsh, K. E.; Walter, D. S.; Gallagher, T.
Org. Lett. 2000, 2, 4051. (d) Abe, H.; Shuto, S.; Matsuda, A. J. Am.
Chem. Soc. 2001, 123, 11870. (e) Liu, Y.; Gallagher, T. Org. Lett. 2004, 6,
2445. (f) Woodward, H.; Smith, N.; Gallagher, T. Synlett 2010, 869. For
a review, see: (g) Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett
1998, 700.
(1) For a recent review, see: Rowlands, G. J. Tetrahedron 2010, 66,
1593.
(2) Urabe, D.; Yamaguchi, H.; Inoue, M. Org. Lett. 2011, 13, 4778.
(3) For a recent review, see: Tojino, M.; Ryu, I. Free-radical-
mediated Multicomponent Coupling Reactions. In Multicomponent
ꢀ
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH Verlag: Weinheim,
2005; pp 169ꢀ198.
r
10.1021/ol301482f
XXXX American Chemical Society

two functionalized carbon chains in a stereoselective fashion,
and the generated structures will serve as advanced inter-
mediates for synthesis of highly oxygenated natural products.
Pummerer reactions have not been fully exploited, mainly
due to competing facile olefination of the selenoxide via syn-
elimination.9 In fact, selenoxide 6, which was synthesized
from selenide 5 by treatment with m-CPBA at ꢀ78 °C,
underwent elimination at 80 °C within 20 min, clearly
demonstrating the thermal instability of 6. On the other
hand, wefound thatacetylation at room temperature using
a reagent mixture of acetic anhydride and sodium acetate
completely converted 6 to selenonium salt 8, which did not
undergo anti-elimination at 80 °C. Instead, heating of 8 at
80 °C in the same flask resulted in the high-yielding
formation of O,Se-acetal 9 through the desired seleno-
Pummerer rearrangement (85% yield from 5). Reactions
of selenoxide 6 with Bz2O and Piv2O were also realized
without causing elimination, and the obtained selenonium
salts were converted to R-benzoyloxy and R-pivaloyloxy
phenylselenides 10 (86% yield) and 11 (85% yield), respec-
tively, at 120 °C.
Scheme 1. Plan for Three-Component Coupling Reaction
Scheme 2. Seleno-Pummerer Reaction vs syn-Elimination
Our scenario for the three-component reaction between
1, 2, and 3 is illustrated in Scheme 1. O,Se-Acetal 1 would
generate alkyl radical A by homolytic cleavageof the CꢀSe
bond. The nucleophilic R-oxygenated carbon radical A is
expected to selectively react with electron-deficient cyclo-
alkenone 2 in the presence of electron-rich tin reagent
3 to generate electron-deficient radical B. The R3 group
of 3 would then be introduced from the opposite side of the
new carbon chain of B, producing trans-disubstituted
carbocycle 4 in a diastereoselective fashion. Using this
methodology, the ring structures ofthe oxygenated natural
products such as zedoarondiol and prostaglandin E1 could
be prepared from simple cycloalkenone 2 in a single step.
Importantly, this attractive three-component reaction
would be realized only when the radical intermediates A,
B, and n-Bu3Sn• preferentially react with the components
2, 3, and 1, respectively.
To apply O,Se-acetals to intermolecular reactions, it was
a prerequisite for us to develop a concise and general
protocol for their preparation (Scheme 2). In this context,
we decided to employ a seleno-Pummerer reaction5d,7,8
because its application would deliver various R-acyloxy
phenylselenides from the corresponding phenylselenoxides
under neutral conditions. To date, however, seleno-
Having optimized the preparative method of the O,Se-
acetals, we demonstrated the high applicability of the
seleno-Pummerer reaction using a variety of selenides 12
(Table 1). Acetoxy phenylselenide 13a was prepared from
12a without affecting the acid-labile TBS protective group
(entry 1). O,Se-Acetals 13b and 13c were generated from
homobenzyl selenide 12b and homoallyl selenide 12c,
respectively (entries 2 and 3), even though syn-elimination
of the produced selenoxides would afford the stable con-
jugated olefins.10 Furthermore, more sterically congested
12d, 12e, and 12f were transformed to 13d, 13e, and 13f,
respectively, under the same conditions (entries 4ꢀ6). It
was practically important that the radical donors 9, 10, 11,
and 13aꢀf were chemically stable upon silica gel purifica-
tion and irradiation using a desk lamp and necessitated no
special precautions in handling.
(7) (a) Galambos, G.; Simonidesz, V. Tetrahedron Lett. 1982, 23,
4371. (b) Fukuyama, T.; Robins, B. D.; Sachleben, R. A. Tetrahedron
Lett. 1981, 22, 4155. (c) Marshall, J. A.; Royce, R. D., Jr. J. Org. Chem.
1982, 47, 693. (d) Schreiber, S. L.; Santini, C. J. Am. Chem. Soc. 1984,
106, 4038. (e) Emery, F.; Vogel, P. Synlett 1995, 420.
(8) For selected papers on synthesis of O,Se-acetals by other meth-
ods, see: (a) Dumont, W.; Krief, A. Angew. Chem., Int. Ed. 1977, 16, 540.
(b) Keck, G. E.; Tafesh, A. M. Synlett 1990, 257. (c) Nishiyama, Y.;
Yamamoto, H.; Nakata, S.; Ishii, Y. Chem. Lett. 1993, 841. (d)
Surowiec, K.; Fuchigami, T. J. Org. Chem. 1992, 57, 5781. (e) Tingoli,
M.; Temperini, A.; Testaferri, L.; Tiecco, M. Synlett 1995, 1129. (f)
Myers, A. G.; Gin, D. Y.; Rogers, D. H. J. Am. Chem. Soc. 1993, 115,
2036. See also refs 5 and 6.
Next, we explored the intermolecular CꢀC bond forma-
tion between O,Se-acetals and various electron-deficient
(9) Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett.
1973, 14, 1979.
(10) The low yield of 12c is attributable to the concomitant formation
of 1,3-butadiene, which was not detected due to its volatility.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Syntheses of O,Se-Acetals
Table 2. Intermolecular CꢀC Bond Formation of
O,Se-Acetalsa,b
a A 1:1 epimeric mixture at the acetoxy-substituted carbon center.
olefins under the reductive conditions (Table 2). The nucleo-
philic R-acyloxy carbon radicals were effectively generated
from Ac (9), Bz (10), and Piv derivatives (11) by treatment
with n-Bu3SnH and catalytic AIBN at 80 °C, and all
the radicals smoothly reacted with acrylonitrile 14a to pro-
duce 15a, 16a, and 17a, respectively (entries 1ꢀ3).11 In these
reactions, slow addition of n-Bu3SnH and AIBN by a syringe
pump prevented the direct reduction of the transient R-
alkoxy carbon radicals by n-Bu3SnH, and maximized yields
of the adducts.12 Under the same conditions, coupling of 9
with both methyl acrylate 14b and 1-cyanovinyl acetate 14c
efficiently afforded 15b and 15c, respectively (entries 4 and 5).
exo-Olefin 14d functioned as a radical acceptor for 9, leading
to 2,3-trans-substituted γ-lactone 15d with complete stereo-
control at C2 (entry 6).13 Finally, the carbon chain was
successfully attached to the cyclic alkenones. Coupling be-
tween 9 and cyclopentenone 14e gave rise to 3-substituted
cyclopentanone 15e in 70% yield (entry 7), while reaction of
cyclohexenone 14f with 9 afforded 15f in 22% yield (entry 8).
The intermolecular reactions of O,Se-acetals were then
extended to the three-component coupling (Table 3).14
a Conditions: 9ꢀ11 (1.0 equiv), 14 (1.5 equiv), n-Bu3SnH (2.0 equiv),
AIBN (0.4 equiv), benzene (0.02 M), 80 °C. n-Bu3SnH and AIBN
(0.2 equiv) were added by syringe pump over 1 h. b A 1:1 epimeric
mixture at the acetoxy-substituted carbon center. c Conditions: 9 (1.0
equiv), 14 (5.0 equiv), n-Bu3SnH (6.0 equiv), AIBN (0.4 equiv), benzene
(0.02 M), 80 °C. n-Bu3SnH and AIBN (0.2 equiv) were added by syringe
pump over 3 h. d Reduced product of 9 was obtained as the major product.
Cyclopentenones 14e and 14g were selected as acceptors
of the R-oxygenated radicals, and electron-rich allyl tribu-
tylstannane derivatives 18ꢀ20 were used as the trapping
agents. Slow addition of allyl tributyltin 18 and AIBN to
the refluxing solution of 9 and 14e in benzene successfully
suppressed direct allylation of the R-alkoxy carbon radical
and exclusively generated 2,3-trans-disubstitued cyclopen-
tanone 21e13 in 68% yield (entry 1).
When the radical acceptor 14g was applied to these
conditions (entry 2), 2,3-trans-3,4-trans-trisubstituted cy-
clopentanone 21g was produced (46% yield),13 indicating
that the preexisting stereochemistry of 14g influenced the
selective introduction of the two new stereocenters on the
five-membered ring of 21g. Moreover, functionalized allyl
tributyltin derivatives 1915 and 2016 participated in the
three-component reactions. Upon treatment with 9 and
14e at 110 °C in the presence of V-40, 19 and 20 were
transformed to 22e (68% yield, entry 3) and 23e (59%
yield, entry 4),13 respectively, both of which have branched
carbon chains at C2. Stereoselective formation of the
(11) Reaction of 9 and ethyl vinyl ether, an electron-rich olefin, only
gave the reduced product of 9, indicating nucleophilic character of the
R-acyloxy carbon radical.
(12) The reaction between 9 and 14a without using a syring pump
afforded 15a (63% yield) and the reduced product (18% yield).
(13) See the Supporting Information for structural determination.
(14) For related examples of three-component radical couplings, see:
(a) Mizuno, K.; Ikeda, M.; Toda, S.; Otsuji, Y. J. Am. Chem. Soc. 1988,
110, 1288. (b) Curran, D. P.; Shen, W.; Zhang, J.; Heffner, T. A. J. Am.
Chem. Soc. 1990, 112, 6738. (c) Toru, T.; Watanabe, Y.; Tsusaka, M.;
Gautam, R. K.; Tazawa, K.; Bakouetila, M.; Yoneda, T.; Ueno, Y.
Tetrahedron Lett. 1992, 33, 4037. (d) Keck, G. E.; Kordik, C. P.
Tetrahedron Lett. 1993, 34, 6875. (e) Sibi, M. P.; Chen, J. J. Am. Chem.
Soc. 2001, 123, 9472. (f) Schaffner, A. P.; Sarkunam, K.; Renaud, P.
Helv. Chim. Acta 2006, 89, 2450.
Org. Lett., Vol. XX, No. XX, XXXX
C

2,3-trans-disubstituted cyclopentanones 21ꢀ23 proved
that the substrates and the radical intermediates reacted
in the expected order as depicted in Scheme 1 and demon-
strated the efficiency and generality of the present three-
component process using O,Se-acetals.
Scheme 3. Construction of Bicyclo[5.3.0]decene of
Zedoarondiol
Table 3. Three-Component Radical-Coupling Reactionsa
metathesis of 24 using the Grubbs’ second-generation
catalyst19 gave rise to the tetrasubstituted cycloheptene
25 in 45% yield for three steps.
In conclusion, we developed a general protocol for
synthesis of O,Se-acetals using the seleno-Pummerer re-
arrangement and demonstrated their mild, yet powerful,
radical-based two- and three-component coupling reac-
tions. The R-acyloxy carbon radicals generated from the
O,Se-acetals functioned as nucleophilic radicals, and re-
liably reacted with electron-deficient olefins, resulting in
installation of R-acyloxy alkyl groups. Furthermore, a
three-component radical reaction of the O,Se-acetals, cy-
clopentenones, and allylstannane derivatives installed two
differently functionalized carbon chains in a single step, and
was an especially useful method for rapidly increasing
complexity of the molecules. The synthetic significance of
the three-component reaction was also exemplified by the
four-step assembly of the carboskeleton of zedoarondiol
from the three simple starting materials. Applications of
the developed chemistry to the total synthesis of highly
complex natural products are currently underway in our
laboratory.
a A 1:1 epimeric mixture at the acetoxy-substituted carbon center.
b Conditions: 9, 14e, 18, AIBN, benzene (0.1 M), 80 °C. 18 and AIBN
(0.2 equiv) were added by syringe pump over 3 h. c Conditions: 9, 14g, 18,
AIBN, toluene (0.1 M), 110 °C. 18 and AIBN (0.2 equiv) were added by
d
syringe pump over 3 h. Conditions: 9, 14e, 19 or 20, V-40 [1,10-
azobis(cyclohexane-1-carbonitrile)], toluene (0.1 M), 110 °C. 19 or 20
and V-40 (0.2 equiv) were added by syringe pump over 3 h.
Acknowledgment. This research was financially supported
by the Funding Program for Next Generation World-Leading
Researchers (JSPS) to M.I. and a Grant-in-Aid for Young
Scientists (B) (JSPS) to D.U. We thank T. Ishiyama in our
laboratory for synthesis of 14d.
By taking advantage of the densely functionalized na-
ture of the three-component adduct 23e, the trans-fused
bicyclo[5.3.0]decene structure 25 of anti-inflammatory
zedoarondiol17 (Scheme 1) was constructed in three steps
(Scheme 3). Selective removal of the TBDPS group of 23e,
followed by olefin formation through syn-elimination of
theselenoxide,18 affordeddiene24. Finally, thering closing
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra of all newly synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(15) (a) Weigand, S.; Bruckner, R. Synthesis 1996, 475. (b) Vloon,
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(16) Trost, B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985, 107, 1778.
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Cho, W.; Nam, J.-W.; Kang, H.-J.; Windono, T.; Seo, E.-K.; Lee, K.-T.
Int. Immunopharmacol. 2009, 9, 1049.
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1485.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX