Chiral ammonium betaines as ionic nucleophilic catalysts

Article abstract of DOI:10.1002/anie.201002315

Catalyst debut: The chiral ammonium betaine 1 has been successfully applied to the asymmetric Steglich rearrangement as an ionic nucleophilic catalyst. The catalyzed reaction results in record levels of product enantioselectivity, and has a broad substrate scope. M.S. = molecular sieves, Troc = 2,2,2-trichloroethoxycarbonyl. (Figure Presented)

Full text of DOI:10.1002/anie.201002315

Angewandte
Chemie
DOI: 10.1002/anie.201002315
Nucleophilic Catalysis
Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts**
Daisuke Uraguchi, Kyohei Koshimoto, Shuhei Miyake, and Takashi Ooi*
Asymmetric nucleophilic catalysis has been extensively
studied over the last several decades and plays an increasingly
important role in modern asymmetric synthesis.[1] The general
definitive feature of this catalysis is that a Lewis basic catalyst
reacts with a substrate to give a reactive ionic intermediate
through the formation of a new covalent bond, which will be
eventually cleaved by the elimination of the catalyst. In this
respect, an anionic molecule could function as a potentially
more nucleophilic catalyst for initiating the reaction, com-
pared to the commonly utilized electronically neutral mole-
cules, but it generates a rather stable intermediate bearing no
charge (see below). Hence, research toward exploiting the
reactivity of anionic molecules for the development of a new
type of nucleophilic catalysis, that is, enantioselective ionic
nucleophilic catalysis, has met with limited success.[2,3]
We recently introduced the chiral ammonium betaine 1 as
a new, yet intriguing structural motif as an organic molecular
catalyst.[4,5] The basic character of its anionic site (aryloxylate)
Scheme 1. Working hypothesis for the Steglich rearrangement with an
onium aryloxide (Q+OArꢀ) as an ionic nucleophilic catalyst. Left cycle:
a conventional intermolecular onium salt. Right cycle: an intramolecu-
lar onium salt such as chiral ammonium betaine of type 1.
pioneering work in this field was reported by Ruble and Fu
for a synthetic analogue of DMAP.[9a] However, the use of an
ionic nucleophile, such as onium aryloxylate (Q+OArꢀ), in
this reaction has been difficult, probably because of the
presumed low reactivity of the in situ generated, electroni-
cally neutral aryl ester (R’COOAr) toward the onium enolate
A (left cycle). In contrast, in the betaine catalysis, the rate-
limiting carbon–carbon bond formation would proceed in a
pseudo-intramolecular manner, and the unique ion-pair
intermediate B could have the potential to not only circum-
vent the reactivity problem but also induce an unprecedented
level of stereocontrol (right cycle). Herein, we present the
highly enantioselective Steglich rearrangement using chiral
ammonium betaines as nucleophilic ionic catalysts.
The reaction was generally conducted by the addition of a
1,4-dioxane solution of 2-tert-butyl-4-benzyl-5-oxazolyl 2,2,2-
trichloroethyl carbonate (2a) to a stirred mixture of 1 (2
mol%) and powdered 4 ꢀ molecular sieves[10] in 1,4-dioxane
at 258C.[11] Since an initial attempt with 1a[4] as a catalyst
showed its ineffectiveness in terms of both reactivity and
stereoselectivity, we prepared 1b, which lacks a substituent at
the 3 position of the aryloxylate moiety (R2) to bring out the
inherent nucleophilicity of the aryloxy anion. As expected,
the rearrangement in the presence of 1b proceeded cleanly to
give the desired product 3a in 93% yield, and with an
enantiomeric excess of 93% (Scheme 2).[12] Notably, the
characteristic yellow color of betaine 1b instantaneously
lightened with the addition of one drop of a solution of 2a,
which implies the formation of the intermediate B. Indeed,
the analysis of this mixture by ESI/MS methods showed a
peak corresponding to acylated 1b (m/z 592), thus corrobo-
and the hydrogen-bonding capability of its conjugate acid
(arylhydroxide) appeared to be the key features for realizing
highly enantioselective Mannich-type reactions. Given that
the aryloxylate functionality has a nucleophilic character, we
envisioned that 1 could be evolved into a chiral nucleophile
after appropriate structural manipulations.[6]
Acyl transfer reactions by means of nucleophilic catalysts
are the fundamental molecular transformation in synthetic
organic chemistry. Among these reactions, the Steglich
rearrangement,[7] which is the rearrangement of 5-oxazolyl
carbonate into 4-carboxyazlactones, offers an attractive
process for establishing
a tetrasubstituted stereogenic
center, and also serves as a model system for evaluating the
efficiency of chiral nucleophilic catalysts (Scheme 1);[8,9] the
[*] Dr. D. Uraguchi, K. Koshimoto, S. Miyake, Prof. Dr. T. Ooi
Department of Applied Chemistry
Graduate School of Engineering, Nagoya University
Furo-cho B2-3(611), Chikusa, Nagoya 464-8603 (Japan)
Fax: (+81)52-789-3338
E-mail: tooi@apchem.nagoya-u.ac.jp
[**] This work has been supported by the Sumitomo Foundation, the
Global COE program in Chemistry of Nagoya University, and the
Tatematsu Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002315.
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carbonyl)oxazolones 3 in high chemical yields with uniformly
excellent and record levels of enantioselectivity. It should be
emphasized that enol carbonates bearing a sterically demand-
ing a substituent such as the valine-derived substrate, a
challenging substrate so far, can be accommodated by
simply increasing the reaction temperature to 408C (entry 5).
In the present system, the stereoselectivity was strongly
dependent upon substrate concentration, and it was of critical
importance to maintain a low concentration of 2 to achieve an
excellent enantiomeric excess. In fact, enantioselectivity was
decreased to 87% ee when the reaction was performed by
adding 1d to a solution of 2a under otherwise identical
reaction conditions. This observation could provide an addi-
tional mechanistic clue to the 1d-catalyzed Steglich rear-
rangement, that is, the existence of two reaction pathways.
One is a highly stereoselective, pseudo-intramolecular bond-
formation reaction (Scheme 3, cycle I), and the other is a less
Scheme 2. Steglich rearrangement catalyzed by 1. Bn=benzyl,
Troc=2,2,2-trichloroethoxycarbonyl.
rating our conjecture. After a while, without the addition of
more 2a, the original yellow color gradually returned,
indicating the regeneration of the betaine 1b, which was
also verified by the detection of protonated 1b (m/z 418) in
the ESI/MS measurements. This unique phenomenon would
support the validity of the proposed reaction mechanism and
confirm that the carbon–carbon bond formation is the rate-
limiting step in this catalysis.[9a] Interestingly, the installation
of an electron-withdrawing aromatic unit, such as the para-
trifluoromethylphenyl (1c) or 3,5-bis(trifluoromethyl)phenyl
(1d) group, on the naphthyl unit that possesses a pendent
ammonium cation (R1) led to and enhancement of the
catalytic efficiency; this enhancement was visually observed
as the reaction mixture retained its yellow color throughout
the reaction. The enantioselectivity was synchronously
improved to 95% ee and 97% ee when using 1c and 1d,
respectively.
With the optimized catalyst structure in hand, the general
applicability of the asymmetric catalysis of the Steglich
rearrangement by 1d was investigated using a series of
amino acid derived enol carbonates 2; the representative
examples are listed in Table 1. Substrates with simple alkyl
(entries 1–5), substituted benzylic (entries 6–8), or function-
alized alkyl side chains (entries 9 and 10) were efficiently
transformed into the corresponding 4-(2,2,2-trichloroethoxy-
Scheme 3. Possible reaction pathways for the Steglich rearrangement
catalyzed by 1.
stereoselective intermolecular reaction of the chiral ammo-
nium enolate B with 2 (cycle II). To assess the involvement of
cycle II, the reactivity of 2 as an acyl transfer reagent toward
ammonium enolates was evaluated by the experiment shown
in Scheme 4. The rearrangement of 2a was carried out in a
similar manner in the presence of the in situ generated ion-
pair, tetrabutylammonium b-naphthoxide (20 mol%),[13]
which afforded 3a in 85% yield together with the 2,2,2-
trichloroethyl b-naphthyl carbonate 4 (15% yield). The
concomitant isolation of 4 in amounts comparable to that of
the catalyst used, clearly indicates that 3a was mainly
produced through the reaction of 2a-derived tetrabutylam-
monium enolate with 2a itself. Therefore, chiral ammonium
enolate B could also react with 2, and this intermolecular
bond-forming process would compete with the pseudo-intra-
molecular reaction of B. This is probably the origin of the
concentration dependence of the stereoselectivity, and the
Table 1: Substrate scope.[a]
Entry
R
3
Yield [%][b]
ee[c] [%]
1
CH3
3b
3c
3d
3e
3 f
3g
3h
3i
99
99
96
97
94
98
97
96
91
95
96
96
96
97
95
97
96
95
94
96
2
CH3CH2
3
4
CH3(CH2)3
(CH3)2CHCH2
(CH3)2CH
p-CH3OC6H4CH2
p-ClC6H4CH2
o-FC6H4CH2
CH3O(CH2)2
CH3S(CH2)2
5[d]
6
7
8
9
10
3j
3k
[a] Unless otherwise noted, the reactions were performed on 0.25 mmol
scale in 2.5 mL of 1,4-dioxane with 4 ꢀ M.S. at 258C. See the Supporting
Information for more details. [b] Yields of isolated products are reported.
[c] Enantiomeric excesses were determined by HPLC analysis using a
chiral stationary phase. Absolute configurations of 3b–k were assigned
by analogy to 3a. [d] The reaction was carried out at 408C.
Scheme 4. In situ generated TBAOb-Naph as the catalyst for the
reaction of 2a.
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2429 – 2431; Angew. Chem. Int. Ed. 2005, 44, 2377 – 2379;
addition of the substrate to the catalyst solution is crucial for
allowing the pseudo-intramolecular process to predominate
as it essentially relies on the ion-pair nature of 1.
In conclusion, the nucleophilic nature of chiral ammoni-
um betaines has been revealed and successfully applied to the
an enantioselective Steglich rearrangement. This new, yet
attractive function of ammonium betaines as ionic nucleo-
philic catalysts opens new opportunities for the development
of asymmetric nucleophilic catalysis.
c) M. R. Nahm, J. R. Potnick, P. S. White, J. S. Johnson, J. Am.
Chem. Soc. 2006, 128, 2751 – 2756; d) M. R. Garrett, J. C. Tarr,
J. S. Johnson, J. Am. Chem. Soc. 2007, 129, 12944 – 12945.
[3] X. Yang, V. B. Birman, Org. Lett. 2009, 11, 1499 – 1502, and
references therein.
[4] D. Uraguchi, K. Koshimoto, T. Ooi, Chem. Commun. 2010, 46,
300 – 302.
[5] D. Uraguchi, K. Koshimoto, T. Ooi, J. Am. Chem. Soc. 2008, 130,
10878 – 10879.
[6] Lewis basic character of aryloxy anion had been used for the
activation of silyl nucleophile in an intermolecular ammonium
salt catalysis; see: a) T. Tozawa, H. Nagao, Y. Yamane, T.
Mukaiyama, Chem. Asian J. 2007, 2, 123 – 134; b) H. Nagao, Y.
Kawano, T. Mukaiyama, Bull. Chem. Soc. Jpn. 2007, 80, 2406 –
2412, and references therein.
[7] W. Steglich, G. Hꢃfle, Tetrahedron Lett. 1970, 11, 4727 – 4730.
[8] For review, see: A. Moyano, N. El-Hamdouni, A. Atlamsani,
Chem. Eur. J. 2010, 16, 5260 – 5273.
[9] a) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532 –
11533; b) S. A. Shaw, P. Aleman, E. Vedejs, J. Am. Chem. Soc.
2003, 125, 13368 – 13369; c) J. G. Seitzberg, C. Dissing, I. Søtofte,
P.-O. Norrby, M. Johannsen, J. Org. Chem. 2005, 70, 8332 – 8337;
d) S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P. Va, E.
Vedejs, J. Am. Chem. Soc. 2006, 128, 925 – 934; e) H. V. Nguyen,
D. C. D. Butler, C. J. Richards, Org. Lett. 2006, 8, 769 – 772; f) E.
Busto, V. Gotor-Fernꢂndez, V. Gotor, Adv. Synth. Catal. 2006,
348, 2626 – 2632; g) C. Joannesse, C. P. Johnston, C. Concellꢄn,
C. Simal, D. Philp, A. D. Smith, Angew. Chem. 2009, 121, 9076 –
9080; Angew. Chem. Int. Ed. 2009, 48, 8914 – 8918.
Experimental Section
A magnetic stirrer bar and 4 ꢀ molecular sieves (100 mg) were placed
in a test tube under argon atmosphere. The 4 ꢀ M.S. were then dried
with a heat gun under reduced pressure for 5 min and the test tube
was refilled with argon. Ammonium betaine 1d (2.77 mg,
0.005 mmol) and 1,4-dioxane (1.0 mL) were added to the test tube
successively under argon atmosphere at 258C. A solution of 2a
(101.7 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) was then added to the
yellow mixture dropwise over 15 min. Upon completion of the
addition, the reaction mixture was additionally stirred for 10 min,
after which a 0.5m solution of trifluoroacetic acid in toluene (20.0 mL)
was introduced. The reaction mixture was filtered with CHCl3 to
remove the 4 A M.S. and the filtrate was concentrated. The crude
residue was purified by column chromatography on silica gel using n-
hexane/ethyl acetate (50:1!5:1) to afford 3a (95.6 mg) in 94% yield
and the enantiomeric excess of 3a was measured by HPLC analysis
(DAICEL CHIRALPAK AS-H) (97% ee).
[10] The addition of 4 ꢀ molecular sieves was crucial for avoiding
protonation of reactive ammonium enolate by a small amount
(< 5%) of water which was contaminated from slightly hygro-
scopic onium salt 1.
Received: April 19, 2010
Published online: July 7, 2010
[11] Under the representative conditions, we also attempted the
reactions of benzyl and phenyl carbonate derivatives with 1d as
a catalyst, which gave unsatisfactory results: benzyl carbonate
analogue of 2a; [a low conversion (408C for 30 min)]; phenyl
carbonate analogue of 2a [76% yield with 83% ee (258C for
30 min)].
Keywords: asymmetric synthesis · betaines · heterocycles ·
nucleophilic catalysis · rearrangement
.
[1] Reviews: a) S. France, D. J. Guerin, S. J. Miller, T. Lectka, Chem.
Rev. 2003, 103, 2985 – 3012; b) R. P. Wurz, Chem. Rev. 2007, 107,
5570 – 5595; c) D. Enders, O. Niemeier, A. Henseler, Chem. Rev.
2007, 107, 5606 – 5655; d) N. Marion, S. Dꢁez-Gonzꢂlez, S. P.
Nolan, Angew. Chem. 2007, 119, 3046 – 3058; Angew. Chem. Int.
Ed. 2007, 46, 2988 – 3000; e) S. E. Denmark, G. L. Beutner,
Angew. Chem. 2008, 120, 1584 – 1663; Angew. Chem. Int. Ed.
2008, 47, 1560 – 1638.
[12] The absolute configuration of 3a was determined by X-ray
diffraction analysis after derivatization (CCDC 772979 contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif). See the Supporting Information for details.
[13] The generation of tetrabutylammonium b-naphthoxide in solu-
[2] a) X. Linghu, J. R. Potnick, J. S. Johnson, J. Am. Chem. Soc.
2004, 126, 3070 – 3071; b) M. R. Nahm, X. Linghu, J. R. Potnick,
C. M. Yates, P. S. White, J. S. Johnson, Angew. Chem. 2005, 117,
1
tion was confirmed by H NMR analysis.
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