Preparative and mechanistic studies toward the rational development of catalytic, enantioselective selenoetherification reactions

Article abstract of DOI:10.1021/ja106837b

A systematic investigation into the Lewis base catalyzed, asymmetric, intramolecular selenoetherification of olefins is described. A critical challenge for the development of this process was the identification and suppression of racemization pathways available to arylseleniranium ion intermediates. This report details a thorough study of the influences of the steric and electronic modulation of the arylselenenyl group on the configurational stability of enantioenriched seleniranium ions. These studies show that the 2-nitrophenyl group attached to the selenium atom significantly attenuates the racemization of seleniranium ions. A variety of achiral Lewis bases catalyze the intramolecular selenoetherification of alkenes using N-(2-nitrophenylselenenyl)succinimide as the electrophile along with a Bronsted acid. Preliminary mechanistic studies suggest the intermediacy of ionic Lewis base-selenium(II) adducts. Most importantly, a broad survey of chiral Lewis bases revealed that 1,1′-binaphthalene-2,2′-diamine (BINAM)-derived thiophosphoramides catalyze the cyclization of unsaturated alcohols in the presence of N-(2-nitrophenylselenenyl)succinimide and methanesulfonic acid. A variety of cyclic seleno ethers were produced in good chemical yields and in moderate to good enantioselectivities, which constitutes the first catalytic, enantioselective selenofunctionalization of unactivated olefins.

Full text of DOI:10.1021/ja106837b

Published on Web 10/20/2010
Preparative and Mechanistic Studies toward the Rational
Development of Catalytic, Enantioselective
Selenoetherification Reactions
Scott E. Denmark,* Dipannita Kalyani, and William R. Collins
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801, United States
Received July 30, 2010; E-mail: sdenmark@illinois.edu
Abstract: A systematic investigation into the Lewis base catalyzed, asymmetric, intramolecular seleno-
etherification of olefins is described. A critical challenge for the development of this process was the
identification and suppression of racemization pathways available to arylseleniranium ion intermediates.
This report details a thorough study of the influences of the steric and electronic modulation of the
arylselenenyl group on the configurational stability of enantioenriched seleniranium ions. These studies
show that the 2-nitrophenyl group attached to the selenium atom significantly attenuates the racemization
of seleniranium ions. A variety of achiral Lewis bases catalyze the intramolecular selenoetherification of
alkenes using N-(2-nitrophenylselenenyl)succinimide as the electrophile along with a Brønsted acid.
Preliminary mechanistic studies suggest the intermediacy of ionic Lewis base-selenium(II) adducts. Most
importantly, a broad survey of chiral Lewis bases revealed that 1,1′-binaphthalene-2,2′-diamine (BINAM)-
derived thiophosphoramides catalyze the cyclization of unsaturated alcohols in the presence of N-(2-
nitrophenylselenenyl)succinimide and methanesulfonic acid. A variety of cyclic seleno ethers were produced
in good chemical yields and in moderate to good enantioselectivities, which constitutes the first catalytic,
enantioselective selenofunctionalization of unactivated olefins.
Introduction
intermediate, followed by inter- or intramolecular nucleophilic
attack at the carbon to release the isolated product (Scheme 1).8
The selenofunctionalization of unactivated olefins represents
an important method for the rapid introduction of vicinal
functional groups, often with concomitant formation of rings
and stereocenters.1 Generally these transformations are char-
acterized by the pairwise addition of a carbon or a heteroatomic
selenium(II) electrophile and a nucleophile to an isolated double
bond.2 A diverse array of 1,2-difunctionalized products can be
obtained from these transformations through the large number
of different combinations of nucleophiles and selenium(II)
precursors.3-7 The mechanism of this family of reactions is
believed to involve the formation of a discrete seleniranium ion
These transformations are stereospecific and as such afford the
product via anti addition of the electrophile and the nucleophile.
Scheme 1
(1) (a) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Product
Synthesis; CIS: Philadelphia, 1984. (b) Paulmier, C. Selenium Reagents
and Intermediates in Organic Synthesis; Pergamon Press: Oxford,
1986. (c) Liotta, D., Ed. Organoselenium Chemistry; Wiley: New York,
1987; Chap. 1 and 2, pp 1-163. (d) Back, T. G. In The Chemistry of
Organic Selenium and Tellurium Compounds; Patai, S., Ed.; Wiley:
New York, 1987; Vol. 2, pp 94-215. (e) Back, T. G., Ed. Organose-
lenium ChemistrysA Practical Approach; Oxford University Press:
Oxford, 1999. (f) Tiecco, M., In Topics in Current Chemistry:
Organoselenium Chemistry; Wirth, T., Ed.; Springer: Heidelberg, 2000;
pp 7-54. (g) Petragnani, N.; Stefani, H. A.; Valduga, C. J. Tetrahedron
2001, 57, 1411–1448. (h) Ranganathan, S.; Muraleedharan, K. M.;
Vaish, N. K.; Jayaraman, N. Tetrahedron 2004, 60, 5273–5308.
(2) (a) Schmid, G. H.; Garratt, D. G. Tetrahedron 1978, 34, 2869–2872.
(b) Luh, T. Y.; So, W. H.; Cheung, K. S.; Tam, S. W. J. Org. Chem.
1985, 50, 3051–3053.
The most commonly utilized selenofunctionalization reactions
for the synthesis of complex natural and non-natural compounds
are intramolecular selenoetherifications and selenolactoniza-
tions.9 These reactions involve the interception of the selen-
iranium ion by a pendant alcohol or carboxylic acid to generate
(5) Kozikowski, A. P.; Sorgi, K. L.; Schmiesing, R. J. J. Chem. Soc.,
Chem. Commun. 1980, 477–479.
(6) Tomoda, S.; Takeuchi, Y.; Nomura, Y. J. Chem. Soc., Chem. Commun.
1982, 871–872.
(7) Toshimitsu, A.; Uemura, S.; Okano, M. J. Chem. Soc., Chem. Commun.
1982, 87–89.
(3) Hassner, A.; Amarasekara, A. S. Tetrahedron Lett. 1987, 28, 5185–
5188.
(8) (a) Garratt, D. G.; Schmid, G. H. Can. J. Chem. 1974, 52, 1027–
1028. (b) Schmid, G. H.; Garratt, D. G. Tetrahedron Lett. 1975, 16,
3991–3994. (c) Borodkin, G. I.; Chernyak, E. I.; Shakirov, M. M.;
Gatilov, Y. V.; Rybalova, T. V.; Shubin, V. G. J. Org. Chem. USSR
1990, 26, 1163–1179.
(4) (a) Denis, J. N.; Vicens, J.; Krief, A. Tetrahedron Lett. 1979, 29, 2697–
2700. (b) Scarborough, R. M.; Smith, A. B.; Barnette, W. E.; Nicolaou,
K. C. J. Org. Chem. 1979, 44, 1742–1744.
9
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10.1021/ja106837b  2010 American Chemical Society

Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
cyclic ethers or lactones, respectively. Once introduced, the
organoselenium moiety provides a versatile intermediate for
further structural manipulation. Specifically, the C-Se bond can
stabilize R-carbanions,10 serve as a radical precursor,11 or
undergo syn oxidative elimination via the selenoxide.12 Ulti-
mately, the facile installation and subsequent elaboration of
organoselenium functionalities in this manner allows for the
rapid generation of structurally and stereochemically rich ring
systems from simple olefins. As such, electrophilic selenofunc-
tionalizations of alkenes have found widespread use as key steps
in the total synthesis of complex biologically active molecules.1
As part of a broadly based program for the development of
asymmetric transformations mediated by main-group elements,17
heavier chalcogens (S, Se, Te) have been identified as elements
for which a rich chemistry is extant, albeit with a dearth of
catalytic, asymmetric variants.18 We describe here the inspira-
tion, design, development, and mechanistic study of the first
catalytic, asymmetric selenoetherification of unactivated olefins
by harnessing the paradigm of “Lewis base activation of Lewis
acids”.19
Background
1. Lewis Base Catalysis. The concept of “Lewis base activa-
tion of Lewis acids” has been successfully exploited in the
development of a myriad of catalytic, asymmetric reactions.19
In general, these transformations involve the in situ generation
of the catalytically active adduct of a Lewis basic donor and a
Lewis acid acceptor, characterized by three-center, four-electron
(3c-4e) hypervalent bonds (Scheme 2).20 In the limit of
polarization, ionization of one of the acceptor ligands can
generate a cationic Lewis acid. As depicted in Scheme 2, such
complex formation enhances the electrophilicity of the nascent
Lewis acid, thereby providing the chemical potential for
reactivity. Furthermore, the use of a chiral Lewis base generates
a chiral adduct, which allows for asymmetric induction via the
activated species. This concept has been most effectively applied
to catalytic, asymmetric reactions involving silicon-based Lewis
acids (e.g., SiCl4).21 However, recent work from these labora-
tories and others has demonstrated that this form of catalysis
can be applied to the reactions of Group 17 Lewis acids as
well,22,23 such as halofunctionalization of alkenes. Catalytic,
asymmetric selenofunctionalization of unactivated alkenes
presents yet another opportunity for the application of Lewis
base catalysis, in this case with Group 16 Lewis acids.
Despite the established synthetic utility of these selenofunc-
tionalization reactions, there is no report on a catalytic,
enantioselective variant of these transformations.13 To date, the
synthesis of enantiomerically enriched selenofunctionalized
products has relied upon either the presence of stereogenic
centers on the olefin substrate14 or the use of chiral selenylating
agents.15 Although both of these strategies have allowed for
highly diastereoselective selenofunctionalizations, they do have
drawbacks that limit their efficiency, cost effectiveness, and
widespread application. The former approach necessitates the
requirement of an appropriately positioned stereocontrolling
element on the olefin substrate, which might not be readily
accessible in the context of complex molecule synthesis. The
latter strategy often requires lengthy syntheses of enantiomeri-
cally pure selenium electrophiles as well as the use of expensive
chiral modifiers in stoichiometric amounts. Hence, the develop-
ment of catalytic, enantioselective selenofunctionalization reac-
tions remains an important challenge in organic chemistry.16
(9) (a) Campos, M. D. M.; Petragnani, N. Chem. Ber. 1960, 93, 317–
320. (b) Clive, D. L. J.; Chittattu, G. J. Chem. Soc., Chem. Commun.
1977, 484–485. (c) Nicolaou, K. C.; Lysenko, Z. J. Am. Chem. Soc.
1977, 99, 3185–3187. (d) Nicolaou, K. C.; Seitz, S. P.; Sipio, W. J.;
Blount, J. F. J. Am. Chem. Soc. 1979, 101, 3884–3893. (e) Clive,
D. L. J.; Russell, C. G.; Chittattu, G.; Singh, A. Tetrahedron 1980,
36, 1399–1408.
Scheme 2
(10) (a) Petragnani, N.; Ferraz, H. M. C. Synthesis 1978, 476–478. (b)
Reich, H. J. Acc. Chem. Res. 1979, 12, 22–30.
(11) (a) Clive, D. L. J.; Chittattu, G. J.; Farina, V.; Kiel, W. A.; Menchen,
S. M.; Russell, C. G.; Singh, A.; Wong, C. K.; Curtis, N. J. J. Am.
Chem. Soc. 1980, 102, 4438–4442. (b) Kraus, G. A.; Taschner, M. J.
J. Org. Chem. 1980, 45, 1175–1176. (c) Bachi, M. D.; Hoornaert, C.
Tetrahedron Lett. 1981, 22, 2693–2694. (d) Burke, S. D.; Fobare,
W. F.; Armistead, D. M. J. Org. Chem. 1982, 47, 3348–3350.
(12) (a) Jones, D. N.; Mundy, D.; Whitehou, R. D. J. Chem. Soc., Chem.
Commun. 1970, 86–87. (b) Reich, H. J.; Wollowitz, S.; Trend, J. E.;
Chow, F.; Wendelborn, D. F. J. Org. Chem. 1978, 43, 1697–1705.
(13) (a) Wirth, T.; Hauptli, S.; Leuenberger, M. Tetrahedron: Asymmetry
1998, 9, 547–550. (b) Tiecco, M.; Carlone, A.; Sternativo, S.; Marini,
F.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46, 6882–
6885.
A hypothetical catalytic cycle for selenofunctionalization of
olefins using a Lewis base catalyst and a selenium(II) source is
depicted in Figure 1. Following the concept articulated above,
the weak selenium(II) electrophile will combine with a chiral
Lewis base to form adduct 1. Such a chirally modified and
kinetically activated complex can potentially discriminate the
enantiotopic faces of a prochiral alkene to afford a diastereo-
enriched seleniranium ion (3). Finally, nucleophilic capture of
(14) Rodriguez-Escrich, C.; Olivella, A.; Urp´ı, F.; Vilarrasa, J. Org. Lett.
2007, 9, 989–992.
(15) (a) Deziel, R.; Goulet, S.; Grenier, L.; Bordeleau, J.; Bernier, J. J.
Org. Chem. 1993, 58, 3619–3621. (b) Deziel, R.; Malenfant, E. J.
Org. Chem. 1995, 60, 4660–4662. (c) Deziel, R.; Malenfant, E.;
Thibault, C.; Frechette, S.; Gravel, M. Tetrahedron Lett. 1997, 38,
4753–4756. (d) Fragale, G.; Neuberger, M.; Wirth, T. Chem. Commun.
1998, 1867–1868. (e) Wirth, T. Tetrahedron 1999, 55, 1–28. (f) Wirth,
T. Angew. Chem., Int. Ed. 2000, 39, 3740–3749. (g) Tiecco, M.;
Testaferri, L.; Marini, F.; Bagnoli, L.; Santi, C.; Temperini, A.;
Sternativo, S.; Tomassini, C. Phosphorus, Sulfur Silicon 2005, 180,
729–740. (h) Browne, D. M.; Wirth, T. Curr. Org. Chem. 2006, 10,
1893–1903.
(17) (a) Fukuzawa, S.-I.; Takahashi, K.; Kato, H.; Yamazaki, H. J. Org.
Chem. 1997, 62, 7711–7716. (b) Denmark, S. E.; Stavenger, R. A.
Acc. Chem. Res. 2000, 33, 432–440. (c) Denmark, S. E.; Fujimori, S.
In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Wein-
heim, 2004; Vol. 2, Chap. 7.
(18) (a) Finet, J.-P. Ligand Coupling Reactions with Heteroaromatic
Compounds; Pergamon: Oxford, 1998. (b) Chemistry of HyperValent
Compounds; Akiba, K., Ed.; Wiley-VCH: Weinheim, 1999. (c) Main
Group Metals in Organic Synthesis; Yamamoto, H., Oshima, K., Eds.;
Wiley-VCH: Weinheim, 2005; Vols. 1 and 2.
(16) Ongoing work in these laboratories involves the development of equally
challenging catalytic, enantioselective thiofunctionalization of olefins.
For preliminary mechanistic work toward this goal, see: (a) Denmark,
S. E.; Collins, W. R.; Cullen, M. D. J. Am. Chem. Soc. 2009, 131,
3490–3491. (b) Denmark, S. E.; Vogler, T. Chem. Eur. J. 2009, 15,
11737–11745.
(19) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–
1638.
(20) (a) Gutmann, V. The Donor-Acceptor Approach to Molecular
Interactions; Plenum Press: New York, 1978. (b) Jensen, W. B. The
Lewis Acid-Base Concept; Wiley-Interscience: New York, 1980.
9
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PCy3(S), hexamethylphosphorous triamide (HMPT), hexameth-
ylphosphoramide (HMPA), HMPA(S), and HMPA(Se) served
as efficient catalysts for this transformation. Importantly, the
selenolactonization was completely suppressed when it was
conducted with the in situ generated pyridinium carboxylate of
5, indicating the need for a Brønsted acid coactivator in these
reactions.
Scheme 3
The successful demonstration of a Lewis base catalyzed
selenolactonization reaction set the stage for the development
of catalytic, enantioselective variants of this and other seleno-
functionalizations.26 The selenolactonization reactions were
investigated with a wide variety of enantioenriched Lewis bases,
a small subset of which are shown in Scheme 4. The products
were obtained in good to excellent yields; however, in all cases
the products were racemic! Although it is possible that none
of the chiral Lewis bases were suitable for stereoinduction, this
seemed unlikely because of the structural diversity of catalysts
that were investigated. Importantly, control experiments dem-
onstrated that enantioenriched seleno lactone product 7 obtained
via an alternative route did not racemize under the reaction
conditions. Hence, the failure to obtain any asymmetric induc-
tion using chiral Lewis bases demanded a careful understanding
of processes that could be subverting the formation of enantio-
enriched products.
Figure 1. Hypothetical catalytic cycle for Lewis base catalyzed seleno-
functionalization of olefins.
the seleniranium ion at carbon would release the product 4 and
regenerate the Lewis base catalyst.
The feasibility of this catalytic cycle is predicated on the well-
documented formation of 3c-4e hypervalent bonds between
Lewis bases and electrophilic selenium(II) reagents to generate
complexes analogous to 1 (Figure 1, step i).24 Importantly, it is
the enhanced electrophilicity at the central atom of the proposed
adduct 1 (Figure 1) relative to that in the parent Lewis acid
RSeX that is expected to minimize any contribution from RSeX
to the overall reaction rate. More significantly, in the case of
the chiral, nonracemic complex 1, the enhanced kinetic
potency of adduct 1 relative to the achiral Lewis acid is
critical to achieve high levels of asymmetric induction in
these transformations.15
2. Preliminary Studies. The critical proof of principle toward
achieving the desired transformation depicted in Figure 1 was
secured in 2007, in the first example of a Lewis base catalyzed
selenolactonization reaction (Scheme 3).25 The combination of
an unsaturated acid (5) with N-phenylselenenylsuccinimide
(NPSS, 6) in the presence of substoichiometric amounts (10
mol %) of a Lewis base afforded seleno lactone 7 in excellent
yields. A variety of Lewis bases such as 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone (DMPU), DMPU(S), PPh3(S),
Scheme 4
(21) (a) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002,
124, 13405–13407. (b) Denmark, S. E.; Beutner, G. L.; Wynn, T.;
Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774–3789.
(22) (a) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
2010, 132, 1232–1233. (b) Denmark, S. E.; Burk, M. T. Proc. Nat.
Acad. Sci. U.S.A. 2010. in press.
(23) (a) Mellegaard-Waetzig, S. R.; Wang, C.; Tunge, J. A. Tetrahedron
2006, 62, 7191–7198. (b) Sakakura, A.; Ukai, A.; Ishihara, K. Nature
2007, 445, 900–903. (c) Ahmad, S. M.; Braddock, D. C.; Cansell, G.;
Hermitage, S. A. Tetrahedron Lett. 2007, 48, 915–918. (d) Zhang,
W.; Xu, H. D.; Xu, H.; Tang, W. J. Am. Chem. Soc. 2009, 131, 3832–
3833. (e) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B.
J. Am. Chem. Soc. 2010, 132, 3298–3300. (f) Zhang, W.; Zheng, S.;
Liu, N.; Werness, J. B.; Guzel, I. A.; Tang, W. J. Am. Chem. Soc.
2010, 132, 3664–3665.
(24) (a) Boyle, P. D.; Godfrey, S. M.; McAuliffe, C. A.; Pritchard, R. G.;
Sheffield, J. M. Chem. Commun. 1999, 2159–2160. (b) Godfrey, S. M.;
Ollerenshaw, R. T. A.; Pritchard, R. G.; Richards, C. L. J. Chem.
Soc., Dalton Trans. 2001, 508–509. (c) Barnes, N. A.; Godfrey, S. M.;
Halton, R. T. A.; Mustaq, I.; Pritchard, R. G. J. Chem. Soc., Dalton
Trans. 2006, 4795–4804. (d) Barnes, N. A.; Godfrey, S. M.; Halton,
R. T. A.; Mushtaq, I.; Pritchard, R. G.; Sarwar, S. J. Chem. Soc.,
Dalton Trans. 2006, 1517–1523.
3. Challenges. The stereodetermining step for the Lewis base
catalyzed asymmetric selenolactonization of alkene 5 is most
likely the formation of the seleniranium ion.27 The formation
of racemic seleno lactone products with all the chiral Lewis
(26) Collins, W. R. Ph.D. thesis, University of Illinois, Urbana-Champaign,
(25) Denmark, S. E.; Collins, W. R. Org. Lett. 2007, 9, 3801–3804.
2009.
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Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
bases investigated was attributed to the racemization of the
intermediate seleniranium ion prior to intramolecular capture
by the pendant acid. Racemization of the seleniranium ion
requires epimerization of both of the carbon-selenium bonds
simultaneously or in rapid succession.28 Mechanistically, this
process could occur by attack of a nucleophile on the selenium
atom of the seleniranium ion instead of the carbon atom to yield
an alkene and an achiral selenium species (Scheme 5). The
subsequent redelivery of the electrophilic selenium species to
the olefin would diminish or eliminate any enantioenrichment.
The two most likely candidates for causing racemization by this
pathway under these selenolactonization reaction conditions are
the pendant nucleophile, namely the carboxylate anion (Scheme
5, path a), and the alkene (Scheme 5, path b).
of ꢀ-hydroxy selenides with triflic acid in acetonitrile is highly
sensitive to the nature of the aryl group on the selenium atom.32
Increased steric hindrance around the selenium atom increases
the enantiospecificities, as exemplified by the reaction of
substrates 15a-d (Scheme 6c). Furthermore, almost complete
enantiospecificity is observed in the seleno-Ritter reaction of
15e, bearing the electron-deficient 2-trifluoromethylphenylse-
lenenyl group.
Scheme 6
Scheme 5
Configurational scrambling of seleniranium ions by nucleo-
philes has been well documented in the literature.29 For example,
Gruttadauria and co-workers have shown that the reaction of
diastereomerically enriched seleno alcohols 9a and 9b both
afforded 10 after elimination of water (Scheme 6a).29d,e This
result is explained by invoking fast equilibration of 11a to 11b
via reversible selenylation-deselenylation by the pendant
alcohol. Similarly, Wirth has reported that the reaction of
diastereomerically enriched 12 with triflic acid in methanol
generated a significant amount (25%) of ether 13b via
deselenylation-selenylation of the initially generated selenira-
nium ion 14a (Scheme 6b).30 Finally, Toshimitsu has demon-
strated that the enantiospecificity31 of the seleno-Ritter reaction
As detailed below, both computational and experimental
studies have unambiguously demonstrated the feasibility of
olefin transfer to iranium ions. The computationally calculated
barrier for direct transfer of olefins to thiiranium ions is relatively
(27) Alternatively, as in Wirth’s system, capture could be stereodetermining
and cannot be ruled out at this time.
(28) (a) Schmid, G. H.; Garratt, D. G. In The Chemistry of Double Bonded
Functional Groups, Supplement A, Part 2; Patai, S. Ed.; Wiley: New
York, 1977; pp 854-866. (b) Garratt, D. G.; Kabo, A. Can. J. Chem.
1980, 58, 1030–1041. (c) Pannecoucke, X.; Outurquin, F.; Paulmier,
C. Eur. J. Org. Chem. 2002, 995–1006.
(30) (a) Wirth, T.; Fragale, G.; Spichty, M. J. Am. Chem. Soc. 1998, 120,
3376–3381. (b) Spichty, M.; Fragale, G.; Wirth, T. J. Am. Chem. Soc.
2000, 122, 10914–10916.
(31) The term “enantiospecificity” [es ) (eeproduct/eestarting material) × 100%]
provides a convenient method for describing the conservation of
configurational purity of a reaction.
(29) (a) Rouessac, F.; Zamarlik, H. Tetrahedron Lett. 1981, 22, 2643–
2646. (b) Harusawa, S.; Imazu, T.; Takashima, S.; Araki, L.; Ohishi,
H.; Kurihara, T.; Yamamoto, Y.; Yamatodani, A. Tetrahedron Lett.
1999, 40, 2561–2564. (c) Mihelich, E. D. J. Am. Chem. Soc. 1990,
112, 8995–8997. (d) Gruttadauria, M.; Aprile, C.; Riela, S.; Noto, R.
Tetrahedron Lett. 2001, 42, 2213–2215. (e) Aprile, C.; Gruttadauria,
M.; Amato, M. E.; D’anna, F.; Lo Meo, P.; Riela, S.; Noto, R.
Tetrahedron 2003, 59, 2241–2251.
(32) (a) Toshimitsu, A.; Ito, M.; Uemura, S. J. Chem. Soc., Chem. Commun.
1989, 530–531. (b) Toshimitsu, A.; Nakano, K.; Mukai, T.; Tamao,
K. J. Am. Chem. Soc. 1996, 118, 2756–2757. (c) Toshimitsu, A.;
Terada, M.; Tamao, K. Chem. Lett. 1997, 733–734. (d) Okamoto, K.;
Nishibayashi, Y.; Uemura, S.; Toshimitsu, A. Tetrahedron Lett. 2004,
45, 6137–6139. (e) Toshimitsu, A. Phosphorus, Sulfur Silicon 2005,
180, 935–937.
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low (11 kcal/mol).33 Additionally, in 2009, the first spectroscopic
observation of the direct transfer of selenium cations from one
olefin to another was reported from these laboratories (Scheme
7).16a For example, seleniranium ion 16a reacted rapidly and
completely with alkene (E)-17 to generate 16b and (Z)-17.
Scheme 8
Scheme 7
of an olefin to investigate any racemization pathways introduced
by the alkene.
The initial studies focused on accessing enantioenriched
seleniranium ions tethered to an alcohol (instead of an acid)
because of their ease of accessibility. It was envisioned that
carbonates 20 could serve as suitable precursors to the desired
seleniranium ions for several reasons (Scheme 9). First, they
could be readily accessed with diverse aryl groups on the
selenium atom. Second, Brønsted acid activation of carbonates
in conjunction with anchimeric assistance from the selenium
atom could generate the desired enantioenriched seleniranium
ions in situ with concomitant extrusion of carbon dioxide
(Scheme 9). Subsequent invertive displacement at the benzylic
position by the tethered alcohol in 21 would produce the
3-arylselenotetrahydrofurans 22. Finally, the only byproduct in
the formation of the seleniranium ion is carbon dioxide,
precluding any complications with additional nucleophiles in
solution.
4. Objectives of this Study. The realization of Lewis base
catalyzed, enantioselective selenofunctionalization reactions is
contingent on the suppression of the above-mentioned racem-
ization pathways available to seleniranium ions (Scheme 5). In
recognition of this fundamental requirement for success, the
goals for this program were the following:
(1) to systematically elucidate the effect of the electronic and
steric properties of the selenium atom on the configurational
stability of seleniranium ions analogous to 8 (Scheme 5);
(2) to judiciously select a selenium(II) electrophile with
optimum steric and electronic properties for Lewis base
catalyzed selenofunctionalization to minimize racemization of
putative seleniranium ion intermediates; and
Scheme 9
(3) to demonstrate the application of the selected electrophile
toward the development of Lewis base catalyzed asymmetric
selenofunctionalization of unactivated olefins.
Results
1. Configurational Stability of Seleniranium Ions. 1.1. Strat-
egy. The first phase of these studies was the investigation of
the effect that the steric and electronic environment at the
selenium atom had on the configurational stability of selen-
iranium ions bearing a tethered nucleophile. As such, enan-
tioenriched seleniranium ions tethered to a nucleophile with
diverse sterically and electronically differentiated arylselenenyl
groups in the absence of any other nucleophile were needed
(Scheme 8). Because seleniranium ions are not stable in the
presence of even weak nucleophiles for any spectroscopically
observable period of time, they had to be generated in situ.34
The enantiomeric purity of product 19, formed upon capture
by the tethered nucleophile, would provide insight into the
relative rates of ring closure versus deselenylation of 18 (Scheme
8). If the nucleophile preferentially attacks the seleniranium ion
18 at the carbon, then the products will be formed with preserved
configurational purity (Scheme 8, path b). If, instead, the
nucleophile attacks at the selenium atom of 18, the enantiopurity
will be lost via deselenylation pathways, and the enantioen-
richment of product 19 will be compromised (Scheme 8, path
a). Additionally, this study could be performed in the presence
1.2. Synthesis of Carbonates. The synthetic strategy to access
the desired arylseleno carbonates with diverse electronic and
steric environments at the selenium atom is outlined in Scheme
10. The desired (3R,4S)-arylseleno carbonates 25a-g were
obtained in modest to good yields. The enantiomeric ratios (er’s)
of the carbonates were assumed to be the same as those of
epoxide 23 (93:7).35
1.3. Choice of Brønsted Acid for the Carbonate Opening.
The execution of the proposed carbonate-opening experiments
required a Brønsted acid that generated the seleno ethers at
appreciable rates (Scheme 9). Additionally, to attribute the
results of the experiment solely to the configurational stability
of the intermediate seleniranium ions, it was imperative to ensure
that the acid did not racemize the seleno ether products. Thus,
the configurational stability of 3-arylselenotetrahydrofurans
toward Brønsted acids was investigated. Because the racem-
ization of seleno ethers requires the acid-assisted formation of
seleniranium ions, it is reasonable to posit that the stability of
3-phenylseleno-2-phenyltetrahydrofuran 28a (Scheme 11) closely
reflects that of other seleno ethers with electron-rich selenenyl
(33) (a) Solling, T. I.; Wild, S. B.; Radom, L. Chem. Eur. J. 1999, 5, 509–
514. For seleniranium ions, see: (b) Borodkin, G. I.; Chernyak, E. I.;
Shakirov, M. M.; Shubin, V. G. Russ. J. Org. Chem. 1997, 33, 470–
471. (c) Borodkin, G. I.; Chernyak, E. I.; Shakirov, M. M.; Shubin,
V. G. Russ. J. Org. Chem. 1998, 34, 1563–1568.
(35) The er’s of 25a and 25f were checked against the racemates and were
found to be 95:5 and 96:4, respectively. Therefore, it is reasonable to
assume that the er’s of 25b-e and 25g are not significantly different
than that of the starting epoxide 23.
(34) Denmark, S. E.; Edwards, M. G. J. Org. Chem. 2006, 71, 7293–7306.
9
15756 J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010

Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
Table 1. Configurational Stability of 28a toward Brønsted Acids
Scheme 10
acid,
equiv
conc,
M
time,
h
es,a
%
entry
1
2
3
4
CF3SO3H, 0.1
CH3SO3H, 0.1
CH3SO3H, 0.1
CF3CO2H, 0.1
CF3CO2H, 0.1
CF3CO2H, 1.0
0.01
0.01
0.01
0.01
0.10
0.10
0.5
0.5
3
24
24
24
0
100
77
100
100
0
5b c
,
6b c
,
a Determined by CSP-SFC analysis. b The er of the starting seleno
ether was >99:1. c Conducted in CDCl3.
moieties. Additionally, racemization of ethers containing electron-
deficient selenenyl groups should be further attenuated under
otherwise identical conditions because of destabilization of the
corresponding selenium cations. As such, the enantioenriched
3-phenylselenotetrahydrofuran 28a was synthesized in >99:1 er,
as determined by chiral stationary phase, supercritical fluid
chromatographic (CSP-SFC) analysis of the product (Scheme
11).
required an equivalent amount of TFA or methanesulfonic acid
(MsOH) (Table 2, entries 4-7). Importantly, control experi-
ments showed that, unlike seleno ether 28a, 28d-f did not
racemize to any significant extent with an equivalent amount
of TFA. Hence, the enantiomeric ratios of 28d-f solely reflect
the relative configurational stability of the intermediate seleni-
ranium ions without contribution from the product racemization.
Both electron-deficient and sterically hindered arylselenenyl
groups were modestly effective at preventing racemization of
seleniranium ions (entries 3-5), whereas electron-rich (entry
1) and -neutral (entry 2) substrates resulted in nearly racemic
products. As shown in Table 2, arylseleno ethers 28f and 28g
were obtained with the highest enantiospecificities, suggesting
that the 2-nitrophenyl and 2,6-bis(trifluoromethyl)phenyl
groups37 (entries 6 and 7, respectively) are most effective at
preventing the racemization of the corresponding seleniranium
ions in the presence of a tethered nucleophile.
Scheme 11
Next, selenide 28a was treated with 10 mol % of Brønsted
acids of varying pKa values36 at 25 °C in dichloromethane. As
summarized in Table 1, racemization of 28a was highly
dependent on the acid strength. Triflic acid (pKa in DMSO )
-14) and methanesulfonic acid (pKa in DMSO ) -2.6) led to
significant racemization of 28a (Table 1, entries 1 and 3).
Gratifyingly, 28a was configurationally stable in the presence
of trifluoroacetic acid (pKa in DMSO ) -0.25) over 24 h, thus
making it the acid of choice for the carbonate-opening studies
(Table 1, entries 4 and 5).
1.4. Carbonate Opening Experiments. Treatment of the
arylseleno carbonates 25a-g with trifluoroacetic acid (TFA)
led to the formation of cyclic ethers at varying rates and with
variable enantiospecificities (Table 2). The enantiopurity of the
3-arylselenotetrahydrofurans thus formed was determined by
CSP-SFC analysis. The enantiospecificities (es’s) of these
transformations were obtained by comparing the enantiomeric
excess of the carbonate substrates and the 3-arylselenotetrahy-
drofuran products.31 On the basis of the working mechanistic
hypothesis for these reactions, the major enantiomer of the
seleno ethers formed from completely stereospecific carbonate
opening would be of 2R,3S absolute configuration. Whereas 10
mol % of TFA was sufficient to generate significant amounts
of 3-arylselenotetrahydrofurans from electron-rich seleno car-
bonates 25a-c over 24 h (Table 2, entries 1-3), the reaction
of arylseleno carbonates bearing electron-deficient aryl groups
Table 2. Carbonate-Opening Experiments
acid,
equiv
conv,a
%
es,
%
entry
aryl
carbonate
ether
erb
c
4-MeOC6H4
Ph
25b
25a
25c
25d
25e
25f
TFA, 0.1
TFA, 0.1
TFA, 0.1
TFA, 1.0
TFA, 1.0
TFA, 1.0
28b
28a
28c
46 52.5:47.5
17 57.4:42.6 17
48 62.8:37.2 30
5
1
2
3
4
5
6
7
c
c
2,4,6-(i-Pr)3C6H2
4-CF3C6H4
2-CF3C6H4
2-NO2C6H4
2,6-(CF3)2C6H3
c
28d 100 61.8:38.2 27
28e 100 67.2:32.8 40
c
c
28f
54 93.6:6.4 >99
94 93.7:6.3 >99
d
25g
MsOH, 1.0 28g
a
1
Conversion determined by monitoring reaction progress by H NMR
spectroscopy. b Determined by CSP-SFC analysis. c Reaction time was
24 h. d Reaction time was 2 h.
To determine whether the 2-nitrophenylseleniranium ion was
stable to racemization via olefin transfer of selenium cations,
carbonate 25f was treated with TFA (1.0 equiv) in the presence
of trans-4-phenyl-3-buten-1-ol (29) (1.0 equiv) (Scheme 12a).
The decreased enantiospecificity of this reaction versus that in
Table 2, entry 6, implies that 29 effects the racemization of the
(36) (a) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1883–1885. (b) Bordwell, F. G.; Bares, J. E.; Bartmess,
J. E.; Drucker, G. E.; Gerhold, J.; McCollum, G. J.; Van der Puy, M.;
Vanier, N. R.; Matthews, W. S. J. Org. Chem. 1977, 42, 326–332.
(37) A >100% es was observed for the reactions for which es is reported
as >99%. This is likely because the er’s of carbonate in these cases
were higher than the assumed er (93:7).
9
J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010 15757

A R T I C L E S
Denmark et al.
Scheme 1237
selenoetherification were performed at lower temperatures or
by syringe pump addition of the substrate.16
On the basis of the previous report from these laboratories
on the ability of NPSS (6) to promote selenolactonization under
catalysis with Lewis bases, N-(2-nitrophenylselenenyl)succin-
imide (34) was selected as the selenenylating reagent for
subsequent investigations. Electrophile 34 was easily obtained
in good yield following the synthetic sequence analogous to
that used for the synthesis of N-phenylselenenylsuccinimide.40
Allylation of 32, followed by reaction of 33 with N-chlorosuc-
cinimide, afforded 34 as an air- and moisture-stable solid
(Scheme 13).41
Scheme 13
3. Selenoetherification with Achiral Lewis Bases. The car-
bonate-opening experiments gave insight into the racemization
of seleniranium ions in the presence of a tethered alcohol (not
an acid). Although Lewis base catalysis for selenolactonization
had been demonstrated,25 catalysis of the corresponding seleno-
etherification had not. Thus, before implementing the use of
chiral Lewis bases with 34, it was deemed prudent to establish
suitable reaction conditions for catalysis with simple Lewis
bases. The observation that the tethered carboxylic acid moiety
in substrate 5 serves as the Brønsted acid for these reaction was
critical for the development of selenoetherifications (Scheme
4). Combination of substrate 29 with 34 and HMPA(S) did not
afford any of the desired 3-arylselenotetrahydrofuran product
(Table 3, entry 1). Gratifyingly, however, the use of TFA
resulted in good to excellent conversions42 of 29 to 28f in the
presence of a variety of achiral Lewis base catalysts (Table 3,
entries 3 and 5-10). Importantly, acetic acid was completely
ineffective in promoting this transformation (Table 3, entry 2).
Additionally, reactions with MsOH generally proceeded faster
than with TFA under otherwise identical conditions (Table 3,
entries 4 versus 3). The thiophosphoryl Lewis bases (Table 3,
entries 3 and 8-10) were more effective than the corresponding
phosphoryl oxides (HMPA) (Table 3, entry 6), selenophosphoryl
(HMPA(Se)) (Table 3, entry 5), or a phosphorus(III) catalyst
(HMPT) (Table 3, entry 7). Importantly, 28f was not formed in
the absence of the Lewis base catalyst with or without TFA
(Table 3, entries 11 and 12).
intermediate seleniranium ion to some extent. To distinguish
whether the double bond or the hydroxy group in 29 is
responsible for this racemization, the carbonate opening of 25f
was performed in the presence of 1-butanol. This reaction
generated arylseleno ether 28f with high enantiospecificity
(Scheme 12b), suggesting that the erosion of specificity in
Scheme 12a is mediated by the olefin of 29. This racemization
was further investigated by a crossover experiment in which
the opening of 25f was conducted in the presence of trans-5-
phenyl-4-penten-1-ol (30) (Scheme 12c). In this system, two
different products, 28f and 31, resulted from the capture of the
seleniranium ions generated by carbonate opening and olefin
transfer, respectively. The lack of enantioselectivity for the
formation of seleno ether 31 confirmed that the attenuated
selectivity in Scheme 12a results from olefin transfer of
seleniranium ions to olefins.38
2. Selection and Synthesis of the Electrophile for Lewis
Base Catalyzed Selenoetherifications. The carbonate-opening
study (Table 2) suggested that the 2-nitrophenyl and the 2,6-
bis(trifluoromethyl)phenylseleniranium ions are the most con-
figurationally stable intermediates among all the precursors
tested. These results are particularly significant because they
suggest that the use of 2-nitrophenylselenenyl or 2,6-bis(tri-
fluoromethyl)phenylselenenyl electrophiles in place of NPSS
(6) in the chiral Lewis base catalyzed selenofunctionalization
reactions might furnish enantioenriched products (Scheme 4).
The 2-nitrophenylselenenyl electrophiles were selected for
several reasons. First, the 2-nitrophenyl diselenide precursor for
the synthesis of 2-nitrophenylselenenyl electrophiles is com-
mercially available and is readily prepared in multigram
quantities in good yields from 2-nitrophenylselenocyanate.39
Second, the 2-nitrophenylselenenyl group has been extensively
used in synthesis.1a Finally, the olefin-to-olefin transfer observed
with the 2-nitrophenylselenenyl carbonate (Scheme 12a) could
potentially be minimized further if the catalytic, enantioselective
4. Selenoetherification with Chiral Lewis Bases. At this
juncture, the ability of 2-nitrophenyl groups to significantly
attenuate the racemization of the corresponding seleniranium
ions was firmly secured. The critical task ahead was to validate
the hypothesis that the identification and suppression of race-
mization pathways available to seleniranium ions was the key
to the development of Lewis base catalyzed asymmetric
(40) Hori, T.; Sharpless, K. B. J. Org. Chem. 1979, 44, 4208–4210.
1
(41) For a reference on H, 13C, 15N, 17O, and 77Se NMR of selenamides
bearing 2-nitrophenyl groups, see: Paulmier, C.; Lerouge, P.; Out-
urquin, F.; Chapelle, S.; Granger, P. Magn. Reson. Chem. 1987, 25,
955–959.
(38) The ratio of 28f to 31 could not be determined by 1H NMR
spectroscopic analysis of the crude reaction mixture due to overlapping
resonances. However, 1H NMR spectroscopic analysis of the isolated
product showed approximately a 2:1 ratio of 28f:31.
(39) Casar, Z.; Leban, I.; Majcen-Le Marechal, A.; Lorcy, D. J. Chem.
Soc., Perkin Trans. 1 2002, 1568–1573.
(42) The major side product in these reactions results from trifluoroacetyl-
ation of the alcohol of the alkenol. Conversions were calculated by
monitoring the relative integrations of the diagnostic peaks of the olefin
substrate, the seleno ether product, and the trifluoroacetylated side
1
product in H NMR spectra of unpurified reaction mixtures.
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Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
Table 3. Achiral Lewis Base Survey with 34
the morpholine-derived thiophosphoramide catalyst (R)-35m,
which was thus selected for further optimization.
In the next phase of optimization, MsOH was used in place
of TFA. The reaction of 29 and 34 with (R)-35m as the catalyst
afforded similar enantioselectivities with significantly faster
reaction rates (Table 4, entry 1). Lowering the reaction tem-
perature to -12 °C led to increased selectivity, albeit with only
partial conversion after 24 h (Table 4, entry 2).42 Additionally,
syringe pump addition of the substrate resulted in only a small
increase in selectivity (Table 4, entry 3).
conv,a
%
entry
acid
Lewis base
3.5 h
24 h
1
2
3
4
5
6
7
8
none
AcOH
TFA
MsOH
TFA
TFA
TFA
TFA
TFA
HMPA(S)
HMPA(S)
HMPA(S)
HMPA(S)
HMPA(Se)
HMPA
0
0
73
100
21
0
0
95
-
72
trace
85
-
-
75
0
Table 4. Optimization of Selenoetherification with (R)-35m
trace
45
HMPT
Ph3P(S)
Cy3P(S)
DMPU(S)
none
none
none
100b
100
12
9
10
11
12
13
TFA
none
TFA
time,
h
temp,
°C
conv,a
%
entry
erb
0
trace
3
trace
38
1
0.33
24
14
25
-12
25
100
50
100
68:32
73:27
69:31
MsOH
2
3c
a Conversion of 29 to 28f determined by 1H NMR spectroscopic
analysis of the reaction mixture. b Complete conversion within 1.5 h.
a Conversion of 29 to 28f determined by 1H NMR spectroscopic
analysis of the reaction mixture. b Determined by CSP-SFC analysis of
the product. c 20 mol % of catalyst used, and the substrate was added
via syringe pump addition over 14 h.
selenoetherification reactions. In anticipation of testing this
premise, the successful demonstration of Lewis base catalyzed
selenoetherification using the 2-nitrophenylselenenyl-containing
electrophile 34 set the stage to embark on the crucial experi-
ments implementing the use of chiral Lewis bases. A wide
variety of chiral, nonracemic Lewis bases, including phosphine
sulfides, thiophosphoramides, and thioureas, were efficient at
catalyzing the selenoetherification of 29 (see Supporting Infor-
mation, Figure S1). In general, the reactions proceeded with
good to excellent conversions of 29 to 28f after 24 h, as
determined by 1H NMR spectroscopic analysis of crude reaction
mixtures.42 Although, disappointingly, the products were race-
mic in most cases, we were pleased to discover that the 1,1′-
binaphthalene-2,2′-diamine (BINAM)-derived thiophosphor-
amide (R)-35a delivered the first nonracemic sample of 28f in
a modest 61.6:38.4 enantiomeric ratio (Figure 2). The use of
the NPSS electrophile with (R)-35a as the catalyst led to seleno
ether 28a in nearly racemic form (er 54:46), thus emphasizing
the importance of the 2-nitrophenyl moiety for enantioselectivity.
At this point, the reaction conditions in Table 4, entry 1, were
deemed sufficient to explore the generality of this transformation
with respect to other substrates. Gratifyingly, those conditions
could be applied to a number of trans disubstituted olefins to
obtain the trans products in excellent yields and diastereo-
selectivities (>20:1), with modest to good enantioselectivities
(Table 5). The reactions of olefinic substrates bearing an alkyl
group at the terminal position were more enantioselective than those
with a phenyl substituent (Table 5, entries 1 and 2 versus 3 and
4). Additionally, (E)-36 and (E)-39 afforded a mixture of endo
and exo cyclization products. Finally, the cis-3-arylselenotetra-
hydrofuran 42 was obtained in good yields and high diastereo-
selectivity (>20:1) from the reaction of the cis-olefin (Z)-29,
albeit in racemic form. The absolute configuration of the major
enantiomer of product 28f was determined to be 2R,3S by
comparison of its CSP-SFC trace with that of the same product
obtained from the carbonate-opening experiment. The absolute
configurations of the other products are assigned by analogy.
5. Mechanistic Studies on the Selenoetherification with
N-(2-Nitrophenylselenenyl)succinimide. BINAM-derived thio-
phosphoramides have enabled the discovery of the first catalytic,
asymmetric selenocyclization reaction. To foster future design
of catalysts with higher activity and selectivity, an understanding
of the reactive intermediates involved in these transformations
was initiated. As detailed in the preceding sections, the
thiophosphoryl Lewis bases exhibit exquisite activity in cata-
lyzing the selenoetherification reactions with 34. The catalyti-
cally active intermediate postulated in these transformations is
the Lewis acid-base adduct between the electrophile and the
Lewis base. Although several phosphorus(III)-selenium(II)
adducts have been spectroscopically characterized,24 analogous
studies on complex formation between phosphorus(V) Lewis
bases and selenium(II) Lewis acids are not known. Accordingly,
the identification of acid-base adduct formation between
thiophosphoramides and 34 was undertaken. Additionally, the
effect of the strength of the Lewis bases and Brønsted acids on
The modest but promising result with N-(2-nitrophenylselen-
enyl)succinimide and (R)-35a prompted an examination of other
thiophosphoramide catalysts with structural variations. As shown
in Figure 2, the use of selenophosphoramide (R)-35b in place
of (R)-35a led to racemic 28f. The lower enantiomeric ratio
(50:50) of the product obtained using (R)-35c versus (R)-35d
suggests that substitution at the 3,3′ positions is detrimental to
enantioselectivity. The replacement of the methyl group on the
internal nitrogen with an ethyl group (R)-35e resulted in
decreased selectivity. Additionally, the thiophosphoramidite
catalyst (R)-35f led to poor conversion (15%) to 28f over 3 days.
Finally, a variety of cyclic and acyclic dialkylamino groups,
including N-methylphenylamino (R)-35g, diethylamino (R)-35h,
pyrrolidino (R)-35i, azepino (R)-35j, indolino (R)-35k, tetra-
hydroquinolino (R)-35l, and morpholino (R)-35m, were intro-
duced in place of piperidine. These thiophosphoramide catalysts
((R)-35g-m) resulted in good conversions of 29 to 28f, albeit
with modest effects of these peripheral modifications on enantio-
selectivity. The highest selectivity, 66:34, was obtained using
9
J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010 15759

A R T I C L E S
Denmark et al.
Figure 2. Catalytic, asymmetric selenoetherification with BINAM-derived thiophosphoramides.
the rate and equilibrium position of adduct formation was
examined to elucidate the origin of the effect of these parameters
on the catalytic reaction.
showed a broad resonance around δ 60 ppm, implying that the
species observed were fluxional. When the 31P NMR spectrum
was recorded at -50 °C, two sharp, well-resolved signals
corresponding to HMPA(S) (δ 82 ppm) and a new species (δ
62 ppm) could be observed in a 2.0:1.0 ratio. On the basis of
the similarity of shifts of the 31P resonance of the new species
and the HMPT-NPSS complex (δ 60 ppm), and the previously
reported HMPA(S)-dihalogen43 and HMPA(Se)-dihalogen
adducts,44 the new species is most likely the ionized complex
43 depicted in Scheme 14.
These studies began by examining the 1H, 31P, and 77Se NMR
spectra of the stoichiometric reaction between the phosphorus(V)
Lewis bases and 34. A 1.0:1.0 mixture of HMPA(S) with 34 in
CDCl3 at room temperature did not produce spectroscopically
observable changes. However, the addition of MsOH (1.0 equiv)
to this solution led to instantaneous observation of new
resonances in both the 1H NMR and the 31P NMR spectra (see
1
Supporting Information). The H NMR spectrum clearly de-
picted four new signals in the aromatic region, corresponding
to the 2-nitrophenyl moiety. Integration of the new resonances
to those of 34 revealed a 2.0:1.0 ratio favoring the new species.
Importantly, this ratio remained constant over 24 h. 31P NMR
spectroscopic analysis of this mixture at room temperature
(43) Cross, W. I.; Godfrey, S. M.; Jackson, S. L.; McAuliffe, C. A.;
Pritchard, R. G. J. Chem. Soc., Dalton Trans. 1999, 2225–2230.
(44) Godfrey, S. M.; Jackson, S. L.; McAuliffe, C. A.; Pritchard, R. G.
J. Chem. Soc., Dalton Trans. 1997, 4499–4502.
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Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
Table 5. Substrate Scope for Catalytic, Asymmetric
Selenoetherification with (R)-35m
acid-base equilibria as a function of the strength of the Brønsted
acids. The reaction between HMPA(S) and 34 with TFA in place
of MsOH under otherwise identical conditions also resulted in
the formation of a new complex (44) (Scheme 15). The 31P
NMR (δ 63 ppm) and 77Se NMR (δ 587 ppm) resonances of
44 were very similar to those observed in the experiment with
MsOH. However, in contrast to the reaction with MsOH, this
experiment produced a 0.9:1.0 mixture of 44 to 34. Additionally,
treatment of this mixture with alkene (E)-29 proceeded at a
slightly slower rate, leading to a 74% conversion of (E)-29 to
28f in 1 h at room temperature. Importantly, 31P NMR signals
at δ 62 and 63 ppm were the only observable signals in the
HMPA(S)-catalyzed 2-nitrophenylselenoetherification of (E)-
29 with MsOH and TFA, respectively, suggesting the relevance
of these stoichiometric reactions to the catalytic transformations.
Scheme 15
Finally, the stoichiometric reaction between the morpholine-
derived chiral thiophosphoramide (R)-35m and electrophile 34
was investigated to glean insights on the effect of the Lewis
base strength. Thiophosphoramide is a weaker Lewis base than
HMPA(S) because the lone pairs on the internal nitrogen atoms
of (R)-35m are in conjugation with the binaphthyl ring. A 1.0:
1.0 mixture of (R)-35m and 34 and MsOH (1.0 equiv) in CDCl3
at room temperature resulted in a 0.28:1.0 (31P) mixture of the
putative complex 45 to 34, as determined by 31P NMR
spectroscopic analysis (Scheme 16). Importantly, the unfavorable
equilibrium for the complexation with (R)-35m is manifested
in the catalytic reaction, in which the resonance at δ 87 ppm
(R)-35m is the only spectroscopically observable phosphorus
species. 31P NMR spectroscopic analysis of the reaction revealed
two separate, broad resonances at δ 87 and 65 ppm, corre-
sponding to (R)-35m and 45, respectively. The observation of
two separate resonances at room temperature suggests the
diminished fluxional behavior of these species relative to the
HMPA(S) system. As was the case with HMPA(S), the
resonances in the 31P NMR spectrum sharpened at -50 °C. The
77Se NMR spectrum also revealed the existence of two major
species with signals at δ 723 and 620 ppm. Subsequent reaction
with olefin (E)-29 led to quantitative formation of 28f in 1 h at
room temperature.
a Aryl ) 2-nitrophenyl. b Reaction conditions: alkene (1.0 mmol), 34
(1.1 mmol), MsOH (1.0 equiv), (R)-35m (0.1 mmol), CHCl3 (0.1 M), 25
°C. c Exo:endo ratios determined by 1H NMR spectroscopic analysis of
the crude reaction mixture. d Determined by CSP-SFC analysis.
Scheme 14
The absence of selenium satellites in the 31P NMR spectra
suggests a small 2JSe-P for complex 43.45 Furthermore, the 77Se
NMR spectra also showed two sharp singlets at δ 723 ppm (34)
and δ 582 ppm (43) at room temperature and -50 °C.
Importantly, the upfield shifts of complex 43 relative to
HMPA(S) and 34 in the 31P and 77Se NMR spectra, respectively,
are similar to those observed for known Lewis base-
selenium(II)43 and Lewis base-halogen adducts.44 Addition of
olefin (E)-29 (1.1 equiv) to this mixture at room temperature
resulted in the quantitative (with respect to the electrophile 34)
formation of 28f within 1 h, with concomitant regeneration of
HMPA(S) (sharp signal at δ 82 ppm in the 31P NMR spectrum).
Next, a similar study with TFA in place of MsOH was
conducted to gain insight into the position of these Lewis
Scheme 16
Discussion
1. Configurational Stability of Seleniranium Ions. The reac-
tion of carbonates 25a-g with a Brønsted acid proceeded with
varying enantiospecificities to generate the 3-arylselenotetra-
(45) Duddeck, H. Prog. Nucl. Magn. Reson. Spectrosc. 1995, 27, 1–323.
9
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A R T I C L E S
Denmark et al.
hydrofurans 28a-g (Table 2). If the conversion of the carbonates
to the seleno ethers proceeded without racemization of the
intermediate seleniranium ion, the 3-arylselenotetrahydrofurans
would consequently be produced with complete enantiospeci-
ficity. If, instead, the intermediate seleniranium ions underwent
racemization, the enantiopurity of the tetrahydrofuran products
would be compromised.
Figure 3. Hypervalent bonding between the nitro group and the selenium
center in 2-nitrobenzeneselenenyl halides.
Previous reports suggest that electron-deficient and sterically
hindered arylselenenyl groups are effective at attenuating the
racemization of the corresponding seleniranium ions (Scheme
6c).32 Electron-deficient aryl groups on the selenium atom
enhance the electrophilicity of the benzylic carbon via induc-
tively polarizing electron density away from the carbon. This
polarization thereby attenuates the racemization by increasing
the propensity of nucleophilic capture at carbon. On the other
hand, sterically encumbering aryl groups suppress racemization
by preventing nucleophilic attack at the selenium atom. The
results of the carbonate-opening studies are confluent with these
observations (Table 2). Whereas the ring-opening of arylseleno
carbonates 25a and 25b, bearing electron-neutral, electron-rich,
and sterically undemanding aryl groups, led to the formation
of nearly racemic 3-arylselenotetrahydrofurans 28a and 28b,
respectively (Table 2, entries 2 and 1), the reaction of 25d,
bearing a 4-trifluoromethyl group, proceeded with modest
enantiospecificity (es ) 27%). Additionally, the sterically
congested 2,4,6-triisopropylphenyl group in 25c also generated
3-arylselenotetrahydrofuran 28c with modest enantiospecificity
(Table 2, entry 3). These results suggested that a combination
of steric and electronic influences was needed to prevent
racemization of seleniranium ions. Consistent with this hypoth-
esis, the reaction of arylseleno carbonate 25g, bearing the 2,6-
bis(trifluoromethylphenyl)selenenyl group, occurred with com-
plete enantiospecificity (Table 2, entry 7). Importantly, the
modest enantiospecificity observed in the formation of 28e with
a 2-trifluoromethylphenylselenenyl group (Table 2, entry 5)
revealed that both trifluoromethyl groups in 25g were necessary
to prevent racemization. Interestingly, however, the ring-opening
of 2-nitrophenylselenenyl-containing precursor 25f also pro-
ceeded with high enantiospecificity (Table 2, entry 6). The
significantly enhanced enantiospecificity of this reaction versus
that of carbonate 25e (Table 2, entry 5) could be a result of the
increased electron-withdrawing nature of the nitro group versus
the trifluoromethyl group (σparaCF3 ) 0.46, σparaNO2 ) 0.71).46
The 2-nitrophenyl group might also be preventing racemization
by blocking a coordination site on the selenium.47 Intramolecular
bonding between the nitro group and the selenium atom has
been cited as the reason for the significantly slower rates of
nucleophilic substitution reactions of 2-nitrobenzeneselenenyl
halides relative to those of benzeneselenenyl halides (Figure
3).48,49
4-phenyl-3-buten-1-ol ((E)-29) exhibited a modest erosion of
enantiospecificity as a result of racemization of the intermediate
seleniranium ion via arylselenenyl cation transfer (Scheme 12a).
Two limiting mechanisms can be envisioned for this transfer
in which either the arylselenenium ion departs unassisted from
the seleniranium ion (dissociative, Scheme 17a) or another
alkene assists in the deselenylation process (associative, Scheme
17b). The formation of racemic 31 in the crossover experiment
in Scheme 12c does not distinguish between these possibilities.
However, the calculated enthalpic barrier (32.2 kcal/mol) for
the direct dissociation of uncoordinated selenium cations from
seleniranium ions is prohibitively high at room temperature in
the gas phase.50 This factor, along with the recent report from
these laboratories on the modest enantiospecificity that is
observed for thiiranium ion transfer to an olefin, supports an
associative mechanism for olefin transfer to selenium cations.16b
Scheme 17
2. Selenoetherifications Catalyzed by Achiral Lewis Bases.
2.1. Mechanistic Hypothesis. The central tenet of the mecha-
nistic hypothesis for Lewis base catalyzed selenofunctionaliza-
tion of olefins is that the catalytically active species is a Lewis
base coordinated, cationic arylselenium species such as 1 (Figure
1). This postulate is supported by the results of both the catalytic
and stoichiometric selenoetherification reactions and is discussed
below. The stoichiometric reaction between thiophosphoramides
(HMPA(S) and (R)-35m) and electrophile 34 in the presence
of a Brønsted acid effected the formation of the Lewis
base-selenium(II) complexes 43-45 (Schemes 14-16). The
ionic nature of the complexes is suggested by the similarity of
the chemical shifts in the 31P NMR spectra (δ 62, 63, and 65
ppm) to those of [(Me2N)3PdSesMe]+SbCl6- (δ 63.2 ppm).51
Furthermore, a previous report from these laboratories has
demonstrated the feasibility for the complexation of HMPT with
NPSS to generate the ionic complex 46 (Scheme 18).25
Complexes 43-45 reacted with olefin (E)-29 to furnish the
3-selenoaryltetrahydrofuran 28f. Additionally, complexes 43 and
44 are the resting states of the catalyst in the HMPA(S)-
Although these studies established the configurational stability
of 2-nitrophenylseleniranium ions in the presence of a tethered
hydroxyl group, it was deemed prudent to demonstrate their
stability under pseudocatalytic conditions in which seleniranium
ions are generated in low concentration in relation to the parent
alkene. The carbonate opening of 25f in the presence of trans-
(46) Ritchie, C. D. Prog. Phys. Org. Chem. 1964, 2, 323–400.
(47) Eriksen, R.; Hauge, S. Acta Chem. Scand. 1972, 26, 3153–3164.
(48) Lindgren, B. Acta Chem. Scand. B 1977, 31, 1–6.
(49) (a) Austad, T. Acta Chem. Scand. 1975, 29, 895–906. (b) Austad, T.
Acta Chem. Scand. 1976, 30, 579–585. (c) Austad, T. Acta Chem.
Scand. 1977, 31, 227–231. (d) Austad, T. Acta Chem. Scand. 1977,
31, 93–103.
(50) Wang, X.; Houk, K. N.; Spichty, M.; Wirth, T. J. Am. Chem. Soc.
1999, 121, 8567–8576.
(51) Krawczyk, E.; Skowronska, A.; Michalski, J. J. Chem. Soc., Dalton
Trans. 2002, 4471–4478.
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Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
2.2. Analysis of the Effect of the Bronsted Acid Strength
on the Catalytic Reaction Rates. The equilibrium position for
complex formation in the stoichiometric reactions of 34 with
HMPA(S) was sensitive to the strength of the Brønsted acid
employed. Whereas the equilibrium in the reaction of HMPA(S)
and 34 with MsOH (1.0 equiv) favored the ionized complex 43
(Scheme 14), the analogous reaction with TFA (1.0 equiv)
slightly favored free HMPA(S) (Scheme 15). Because the rates
of the catalyzed reactions are faster with MsOH than with TFA
(Table 3, entries 3 and 4), the results of the stoichiometric studies
suggest that the rate of catalytic selenoetherification is dependent
on the concentration of the ionized complex 48 (Figure 4). This
conclusion is further corroborated by the need for a significantly
stronger acid (TFA or MsOH) in reactions with the weaker
electrophile 34 (Table 3) than with NPSS (AcOH) (see Sup-
porting Information). Previous reports have demonstrated that
nucleophilic substitution reactions of 2-nitrobenzeneselenenyl
halides proceeds 106 times slower that those of benzeneselenenyl
halides. This difference in reactivity is attributed to the
intramolecular n-σ* interaction between the selenium atom and
an oxygen of the nitro group (Figure 3).49 As such, the less
reactive electrophile 34 requires a stronger acid to form the
ionized complex in concentrations that would allow the catalytic
reactions to proceed at observable rates.
promoted selenoetherification. These data suggest the potential
of a hypervalent Lewis base-selenium complex as a key
intermediate in these transformations. Importantly, a crucial
component for the stoichiometric complexation of 34 with
HMPA(S) (or (R)-35m) to proceed is a Brønsted acid. These
results support the observation that both a Lewis base and a
Brønsted acid are required for significant rates of catalytic
selenoetherification with 34 (Table 3), indicating a critical role
of a Brønsted acid coactivator in these reactions.
Scheme 18
Taken together, these data allow the formulation of a self-
consistent mechanism for the Lewis base catalyzed seleno-
etherifications (Figure 4). The cycle commences with the
reversible binding of the Lewis base to the selenimide to form
adduct 47. Protonation of the succinimide in 47 generates the
putative reactive intermediate 48. Subsequent formation of the
seleniranium ion 49 and nucleophilic capture releases the prod-
uct and regenerates the Lewis base catalyst. A slight modifica-
tion of this mechanism involves protonation of the succinimide
prior to binding of the Lewis base with strong acids (TFA or
MsOH). In either case, species 48 is proposed to be the key
reactive intermediate. Importantly, the proposed acid-assisted
removal of the succinimide in the coordinatively saturated
intermediate 47 is likely necessary to allow for the binding of
the olefin and the subsequent reaction to occur (Figure 4, step
ii). A similar mechanism has been postulated previously for the
Lewis base catalyzed selenolactonizations.25
2.3. Analysis of the Effect of the Lewis Base Strength on
Catalytic Reaction Rates. A variety of Lewis bases were
effective at catalyzing the selenoetherification with 34. However,
the rates of these reactions were highly dependent on the
polarizability of the donor atom and the substituent attached to
it (Table 3). The reactivity trend of the Lewis bases in the order
of decreasing rates of selenoetherification is Ph3PS > Cy3PS >
HMPA(S) > HMPA(Se) > DMPU(S) > HMPA. Previous reports
have shown that the rate of nucleophilic SN2 displacement of
halides from arylselenenyl halides decreases in the order Se
donor > S donor > O donor.49 Consistent with these reports,
the softer chalcogens donors, namely HMPA(Se) and HMPA(S),
were much more effective than HMPA in the selenoetherifica-
tion reactions. However, unlike the nucleophilic substitutions
of arylselenenyl halides, reactions promoted by the stronger
Lewis base, HMPA(Se), were significantly slower than those
with HMPA(S). Additionally, the above trend implies that the
rate of the selenoetherification is inversely proportional to the
Brønsted/Lewis basicity of the catalyst. Among the thiophos-
phoryl catalysts, this behavior is exemplified by the fastest and
the slowest rates for Ph3PS and HMPA(S), respectively.52
Additionally, reaction with a strong Lewis base such as HMPT
is relatively slow. Two scenarios can be envisaged to explain
these results on the basis of the postulated mechanism for these
transformations. First, the strong Brønsted acids required for
selenoetherification with 34 might be protonating the stronger
Lewis bases (also Brønsted bases), rendering them less available
for the formation of the catalytically active ionized complex
48 (Figure 4). However, this reasoning is not consistent with
the stoichiometric reactions of thiophosphoryl Lewis bases and
34. The stoichiometric complexation of HMPA(S) with 34
proceeded to a greater extent with MsOH than with TFA
(Scheme 14 versus 15). Moreover, the equilibria for Lewis
(52) (a) Henderson, W. A., Jr.; Streuli, C. A. J. Am. Chem. Soc. 1960, 82,
5791–5794. (b) Matrosov, E. I.; Tsvetkov, E. N.; Mironova, Z. N.;
Malevannaya, R. A.; Kabachnik, M. I. Russ. Chem. Bull. 1975, 24,
1231–1234. (c) Li, T. S.; Lough, A. J.; Morris, R. H. Chem. Eur. J.
2007, 13, 3796–3803.
Figure 4. Proposed catalytic cycle for Lewis base catalyzed selenoetheri-
fication.
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A R T I C L E S
Denmark et al.
base-selenium(II) complexation lies far to the left for the
weaker Lewis base (R)-35m (Scheme 14 versus 16).
stereospecificity of these selenoetherification reactions (Table
5, entries 1-4 versus 5). Importantly, these results suggest that
the Lewis base catalyzed selenoetherification reactions proceed
via discrete cyclic seleniranium ion intermediates, analogous
to the uncatalyzed transformations.1f
A second explanation to reconcile the results of the stoichio-
metric and the catalytic reactions is that the activation barrier
for the reaction with weaker Lewis bases is lower than that with
stronger Lewis bases. To postulate a reason for the different
activation barriers, an understanding of the rate-determining step
is critical. On the basis of the preceding discussions, it is
reasonable to posit that the ionized complex 48 (Figure 4) is
involved at or before the turnover-limiting step of the catalytic
cycle. The rate-determining step for the addition of benzene-
selenenyl halides to alkenes is believed to be the formation of
the seleniranium ion.2,8 Hence, it is reasonable to propose that
the rate-determining step of the Lewis base catalyzed seleno-
etherification involves the reaction of the alkene with the ionized
complex 48. In this scenario, the influence of the Lewis base
strength on the activation barriers for the reaction could stem
from the varying energies required for the seleniranium ion
formation between complex 48 and the olefin (Figure 4).53 In
the transition state for seleniranium ion formation, both the olefin
and the Lewis base are in competition for the positive charge
on the selenium atom. The higher energy needed for the
association of olefins to adducts with stronger Lewis bases
increases the barrier for seleniranium ion formation and thus
consequently decreases the rate of the overall transformation.
3. Selenoetherification Catalyzed by Chiral Lewis Bases.
3.1. Effect of Catalyst Structure. The diversity of the Lewis
bases that catalyzed the selenoetherification reactions with N-(2-
nitrophenylselenenyl)succinimide enabled a good deal of ver-
satility in the design of potential chiral catalysts. A broad survey
of catalyst structure was critical because the constitutional and
stereochemical details of the Lewis base-selenium(II) complex
as well as the precise trajectory of the approach of the olefin to
the ionized adduct are unknown. Most of the initial catalysts
were chosen because of the demonstrated efficiency of their
analogues in other asymmetric transformations. However, among
all the chiral Lewis bases investigated thus far, only the BINAM-
derived thiophosphoramide catalysts led to the formation of
seleno ethers in nonracemic form. Additionally, structural
variations on the BINAM backbone led to only modest effects
on enantioselectivity (Figure 2). The morpholine-derived thio-
phosphoramide (R)-35m generated the 3-arylselenotetrahydro-
furans with the highest, albeit still modest, enantioselectivity
at appreciable rates and was thus employed to explore the
generality of this transformation. Substrates were chosen to
evaluate the effect of conjugation ((E)-29 and (E)-30 versus (E)-
36 and (E)-39), tether length ((E)-29 versus (E)-30), and alkene
geometry ((E)-29 versus (Z)-29) on the rate, yield, site-
selectivity, stereospecificity, and enantioselectivity of these
transformations (Table 5). These results and their implications
are discussed in detail below. The insights gleaned from these
studies are critical for an understanding of the transition state
structure as well as for the future design of catalyst structures
for these transformations.
3.3. Effect of Olefin Structure on Constitutional Site
Selectivity. The conjugated alkenols (E)-29 and (E)-30 afforded
28f and 31, respectively, by nucleophilic capture of the
intermediate seleniranium ion at the benzylic position. This site
selectivity is believed to be a result of the greater stability of
the incipient positive charge on benzylic carbons (Table 5,
entries 1 and 2). In contrast, nonconjugated alkenes (E)-36 and
(E)-39 led to mixtures of constitutional isomers arising from
competitive exo and endo cyclization modes (Table 5, entries
3 and 4). Importantly, the exo and endo products do not
interconvert under the reaction conditions, thus assuring that
the product ratios were the result of kinetically controlled
selectivity (see the Supporting Information). The preference for
5-exo versus 6-endo cyclization observed with (E)-36 and (E)-
39 is confluent with the calculated activation barriers for
cyclization of seleniranium ions derived from nonconjugated
alkenes tethered to a hydroxy group (5-endo > 6-endo > 5-exo).54
Additionally, the constitutional site preference for furan forma-
tion in nonconjugated alkenols is typical for a variety of
selenocyclizations.1g
3.4. Effect of Olefin Structure on Enantioselectivity. The
enantioselectivity of this reaction was highly dependent on the
substrate structure. As is the case in asymmetric selenofunc-
tionalizations with chiral selenides,50 the varying steric demands
presented by the substitution patterns and the geometry of the
olefins dictate the intrinsic facial selectivity of the catalyst for
different substrates. The exact nature of the factors influencing
the facial selectivities in the stereodetermining transition
structure is unknown at this time.
In addition to the intrinsic facial selectivities for different
olefins, the enantioselectivities will also be influenced by the
rates of intramolecular capture of the different seleniranium ion
intermediates. This contribution arises because the carbonate-
opening studies showed that the 2-nitrophenyl group does not
completely suppress arylselenenium cation transfer to olefins
(Scheme 12). Thus, higher enantioselectivities would be ex-
pected in reactions of substrates for which cyclization is faster
than racemization by arylselenenium cation transfer. The varying
degrees of nonbonding interactions associated with the transfer
process for different alkenols may in part be influencing the
enantioselectivities in the Lewis base catalyzed selenoetherifi-
cations. This conclusion is consistent with reports by Modena
and co-workers, who have demonstrated that the rate of
nucleophilic attack at the sulfur of thiiranium ions by disulfides
is sensitive to the substitution pattern on the ring carbons.55 In
general, for trans-substituted thiiranium ions, the sterically bulky
substituents on the carbons attenuate the degree of nucleophilic
attack at the sulfur, thereby allowing for product formation by
attack at the carbon atoms. However, the lack of asymmetric
induction for the selenoetherification of cis-alkenol (Z)-29 (Table
5, entry 5) cannot be explained on the basis of these arguments
because the extent of nucleophilic attack at the carbon is
postulated to be significantly greater for cis-thiiranium ions than
for their trans counterparts.56 Hence, the observed lack of
3.2. Stereospecificity. The reaction of cis- and trans-alkenols
with catalyst (R)-35m and electrophile 34 furnished the products
in excellent yields in 4 h at room temperature (Table 5). The
exclusive formation of cis- and trans-tetrahydrofurans and
pyrans from cis- and trans-olefins, respectively, exemplifies the
(53) For analogy in silicon chemistry, see: Denmark, S. E.; Eklov, B. M.;
Yao, P. J.; Eastgate, M. D. J. Am. Chem. Soc. 2009, 131, 11770–
11787.
(54) (a) Gruttadauria, M.; Noto, R. Tetrahedron Lett. 1999, 40, 8477–8481.
(b) Gruttadauria, M.; Lo Meo, P.; Noto, R. Tetrahedron 2001, 57,
1819–1826.
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Catalytic, Enantioselective Selenoetherification of Olefins
A R T I C L E S
enantioselectivity for (Z)-29 likely stems from the poor facial
selectivity of the catalyst for cis-alkenols.
of racemization of seleniranium ion intermediates in these
transformations. An investigation of the effect of the steric and
electronic nature of the aryl group on the selenium atom on the
configurational stability of in situ generated, enantioenriched
arylseleniranium ions revealed that the 2-nitrophenyl-bearing
seleniranium ion is significantly stabilized toward racemization
by nucleophiles. This result culminated in the selection of N-2-
nitrophenylselenosuccinimide as the selenylating agent of choice
for the development of catalytic, enantioselective selenoetheri-
fications. A thorough screen of catalyst structures revealed that
the BINAM-derived thiophosphoramides are able to catalyze
the enantioselective selenoetherification of a variety of olefins
in modest to good enantioselectivities. Among the catalysts
examined, the thiophosphoryl(V) Lewis bases are the most
efficient at catalyzing the selenoetherifications. Additionally,
these reactions are sensitive to the strength of the Brønsted acids
employed. Preliminary mechanistic studies support the inter-
mediacy of hypervalent Lewis acid-base adducts in these
transformations. Furthermore, these studies suggest that both
the concentration of the putative Lewis base-selenium(II)
intermediates and their reactivity toward olefins are playing a
role in dictating the overall rate of the catalytic selenoetherifi-
cation reactions. In all, the study described herein exemplifies
the importance of understanding the mechanistic underpinnings
governing chemical transformations to bring to fruition novel
forms of reactivity.
The higher enantioselectivities for reactions of nonconjugated
alkenols (E)-36 and (E)-39 (Table 5, entries 3 and 4) could be
attributed to faster closure to nonstabilized, alkyl-substituted
seleniranium ions versus the benzylic seleniranium intermediates
for (E)-29 and (E)-30 (Table 5, entries 1 and 2). Furthermore,
consistent with the higher activation barrier for 5-endo versus
6-endo cyclization, the enantiomeric purity of the 5-endo product
28f (Table 5, entry 1) is lower than that of the 6-endo product
31 (Table 5, entry 2). Contrary to expectations, however, 5-exo
product 37 had a lower enantiomeric ratio than the correspond-
ing 6-endo constitutional isomer 38 (Table 5, entry 3). This
discrepancy can be reconciled if the intrinsic rates of closure
are overridden by the effect of the Lewis base on the relative
rates of various cyclization modes. Importantly, for this argu-
ment to hold, the Lewis base must be present in the coordination
sphere of the selenium atom at the time of intramolecular capture
of the seleniranium intermediate.22b
3.5. Speculation on the Transition-State Structure. The
absolute configuration of the major enantiomer of the seleno
ethers formed under catalysis with (R)-35m was confirmed to
be 2R,3S. A plausible transition-state structure for the approach
of the olefin to the Lewis base-34 adduct is illustrated in Figure
5. The selenium-aryl bond is perpendicular to the plane of the
three-membered ring on the basis of the calculated structures
for seleniranium and thiiranium ions.50,55a Additionally, the
approximate T-shaped structure of the Lewis acid-base adduct
is implied on the basis of similar geometries of the ionic
HMPT-selenium(II) adducts.24a Two critical features of this
transition state are the involvement of a seleniranium ion and
the presence of the Lewis base. These features corroborate the
experimentally observed stereospecificity and the enantioselec-
tivity of these transformations, respectively. Importantly, the
details of the transition-state structure are limited by the lack
of knowledge on both the constitutional and stereochemical
details of the Lewis base-selenium(II) adduct as well as the
precise trajectory of the approach of the olefin to the complex.
As such, the proposed transition-state structure will guide the
computational modeling to elucidate these details for future
development of catalyst architectures to engender enhanced
enantioselectivities for the Lewis base catalyzed selenoetheri-
fication reactions.
Having demonstrated the feasibility of Lewis base catalyzed
asymmetric selenoetherifications, it is now possible to undertake
the challenge of rationalizing the origin of enantioselectivities
in these transformations. As such, future efforts will focus on
extensive computational modeling to achieve this goal. Fur-
thermore, the lessons gleaned from these studies will be applied
to expanding the scope and selectivities for the selenofunction-
alization of olefins by novel catalyst design. Most importantly,
these investigations will be invaluable for the development of
a broader class of catalytic, enantioselective chalcogen func-
tionalization reactions of alkenes.
Acknowledgment. We are grateful to the National Institutes
of Health (R01 GM82535) and the National Science Foundation
(NSF CHE-0717989) for financial support. W.R.C. thanks Johnson
& Johnson PRI for a graduate fellowship. We thank Dr. T. Vogler
for assistance in catalyst preparations and T. W. Wilson, M. T.
Burk, and D. J. P. Kornfilt for helpful discussions.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA106837B
Figure 5. Transition structure hypothesis for catalytic, asymmetric seleno-
etherification.
(55) (a) Lucchini, V.; Modena, G.; Pasquato, L. J. Chem. Soc., Chem.
Commun. 1994, 1565–1566. (b) Fachini, M.; Lucchini, V.; Modena,
G.; Pasi, M.; Pasquato, L. J. Am. Chem. Soc. 1999, 121, 3944–3950.
(c) Destro, R.; Lucchini, V.; Modena, G.; Pasquato, L. J. Org. Chem.
2000, 65, 3367–3370.
Conclusion and Outlook
This full account traces the conceptual development, proof
of principle, exploration of scope, and mechanistic investigation
of the first catalytic, asymmetric selenofunctionalization of
unactivated olefins. Critical to this success was the suppression
(56) (a) Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1988,
110, 6900–6901. (b) Lucchini, V.; Modena, G.; Pasi, M.; Pasquato,
L. J. Org. Chem. 1997, 62, 7018–7020. (c) Pasquato, L.; Modena, G.
Chem. Commun. 1999, 1469–1470.
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