Catalytic asymmetric protonation of achiral lithium enolates mediated by a chiral tetraamine ligand with water as a proton source

Article abstract of DOI:10.1016/S0040-4039(99)01912-7

Catalytic protonation of achiral lithium enolates (derived from 2- substituted-1-tetralones), mediated by a chiral tetraamine ligand [(R,R)- N,N'-bis[1-phenyl-2-(1-piperidinyl)ethyl]-1,3-propanediamine (0.10 equiv.)], was achieved with high enantioselecti

Full text of DOI:10.1016/S0040-4039(99)01912-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 209–213
Catalytic asymmetric protonation of achiral lithium enolates
mediated by a chiral tetraamine ligand with water as
a proton source
Yasuhiro Yamashita, Yoshihiro Emura, Kazunori Odashima and Kenji Koga ∗,†
Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 9 September 1999; revised 29 September 1999; accepted 1 October 1999
Abstract
Catalytic protonation of achiral lithium enolates (derived from 2-substituted-1-tetralones), mediated by a
chiral tetraamine ligand [(R,R)-N,N0-bis[1-phenyl-2-(1-piperidinyl)ethyl]-1,3-propanediamine (0.10 equiv.)], was
achieved with high enantioselectivity (up to 93% ee) by using water (10% aqueous citric acid) as a proton source.
A possible mechanism of highly efficient catalytic turnover of the chiral tetraamine ligand is discussed. © 1999
Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric reactions; enantioselection; protonation; catalysis; enolates; cyclic ketones.
Asymmetric protonation of achiral enolates affords a method of high synthetic versatility for convert-
ing racemic α-substituted carbonyl compounds to the optically active ones.1 Following the pioneering
work by Duhamel et al.,2 many examples including catalytic approaches3 have been reported to date.
We have made efforts for enantioselective protonation which featured the use of chiral multidentate
ligands in the presence of LiBr.4a,b By using ligand (R)-1, protonation of lithium enolates 5a–c derived
from the corresponding 2-substituted-1-tetralones (3a–c) via the trimethylsilyl (TMS) enol ethers (4a–c)
(Scheme 1) was achieved with high enantioselectivities, not only under stoichiometric conditions (up
to 91% ee)4a but also under catalytic conditions (up to 83% ee with 0.2 equiv. of 1).4b Meanwhile, in
the course of our study on catalytic enantioselective alkylation (quaternization) of 5a by using ligand
(R,R)-2 (0.10 equiv.),5 we frequently observed high asymmetric induction (72–91% ee) for the recovered
ketones (3a) after aqueous workup, showing the possibility of using water as an effective proton source
for catalytic enantioselective protonation. The versatility of such a system as well as fundamental interest
prompted us to carry out detailed investigation of catalytic enantioselective protonation mediated by
∗
†
Corresponding author. Tel: +81-743-72-6170; fax: +81-743-72-6179; e-mail: kkoga@ms.aist-nara.ac.jp
Present address: Research and Education Center for Materials Science, Nara Institute of Science and Technology,
Takayama-cho, Ikoma-shi, Nara 630-0101, Japan.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01912-7

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(R,R)-2. Highly efficient enantioselective protonation with a large excess of water as a proton source was
achieved in upto 93% ee under catalytic conditions [0.10 equiv. of (R,R)-2].
Scheme 1. Enantioselective protonation. (i) MeLi-LiBr (1.0 equiv.), Et2O, rt, 1.5 h; (ii) chiral amine [+achiral additive (2.0
equiv.)], toluene, −20°C, 40 min; (iii) achiral proton source, −45°C→room temperature
Table 1 shows the results of enantioselective protonation of lithium enolates (5a–c), derived from 3a–c
(racemate) via 4a–c, to give the corresponding optically active ketones under stoichiometric and catalytic
conditions (Scheme 1).6,7 The reactions were carried out in the presence of 1.0 equiv. of LiBr at the initial
stage of the reaction.8
Under the conditions similar to those employed previously for (R)-1 in the reaction from 4a to (S)-3a
(91% ee by quenching with acetic acid at −78°C),4a tetraamine ligand (R,R)-2 gave a comparatively high
enantioselectivity (91% ee, data not shown in Table 1). However, to our surprise, essentially the same
result was obtained with a large excess of water (10% aqueous citric acid), added in one portion (ca. 3
s) as a proton source in place of acetic acid. Furthermore, when the chiral ligand (R,R)-2 was reduced
to substoichiometric amounts, the enantioselectivity did not decrease substantially, showing an efficient
catalytic turnover with water as a proton source (entries 1–3).9,10 An examination of the effect of added
achiral bidentate ligands (entries 4–8) revealed that the enantioselectivity could be retrieved to nearly
that attained under the stoichiometric conditions (entry 1, 93% ee) by carrying out the reactions in the
presence of appropriate bidentate ligands (7b–d). The highest enantioselectivity was obtained with ligand
7c having a tetramethylene bridge (entry 7, 89% ee). The enantioselectivity was mostly retained when
neutral water was used as a proton source (entry 9, 86% ee) but decreased substantially when acetic acid
was used (entry 10, 56% ee). The enantioselectivity was slightly improved by adding the achiral diamine
before the chiral tetraamine (entry 7 versus 11). The amount of the chiral tetraamine could be reduced
to 0.025 equiv. without substantial decrease in the enantioselectivity (entry 11–14). For other substrates,
an enantioselectivity comparable to that for 4a (R=Me; entry 11, 93% ee) was observed for 4b (R=Bun;
entry 15, 90% ee) but not for substrate 4c with a benzyl substituent (entry 16, 54% ee). In all cases,
the preferred direction of protonation was the same as that in the protonation mediated by (R)-14a,b and
opposite from that in the alkylation mediated by (R)-1,4a,7c,11a (R,R)-25 or related ligands.11a,b
A possible mechanism of catalytic turnover of the chiral ligand is shown in Scheme 2. Of the two
protonation processes, step D (nonenantioselective process) will be suppressed substantially in a two-
phase system compared to a homogeneous system using acetic acid as a proton source. In contrast,
step C (enantioselective process) in a two-phase system may not be suppressed as markedly as step D
because the more hydrophilic nature of the chiral tetraamine ligand compared to the achiral diamine
ligand makes the complex with the former more favorable for an interfacial protonation process that
may predominate in a two-phase system. A possible role of achiral bidentate ligand such as 7c is
deaggregation of unreacted lithium enolates by complexation (step A), facilitating the ligand exchange

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Table 1
Enantioselectivities of protonation mediated by chiral tetraamine ligand (R,R)-2a
(step B) and making the formation (regeneration) of a highly reactive chiral complex8 faster than the
nonenantioselective protonation process (step D).
Scheme 2. A proposed catalytic cycle

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In conclusion, highly enantioselective catalytic protonation of lithium enolates was achieved in upto
93% ee with a large excess of water as a proton source by chiral tetraamine (R,R)-2, particularly
when used together with achiral diamine 7c. As interesting examples in view of this point, catalytic
enantioselective protonation using a limited amount of water as a proton source3a as well as that using
two-phase systems composed of a tetrahydrofuran/fluorocarbon media3c have been reported recently.
Compared to these examples, the present protonation system is quite unusual in the sense that high
enantioselectivities can be achieved with a large excess of water as a proton source in a usual workup
procedure. This characteristic aspect may provide a new possibility of ligand design for efficient catalytic
turnover in protonation.
Acknowledgements
This work was supported by Grants from CREST and from the Ministry of Education, Science, Sports
and Culture, Japan.
References
1. For recent reviews, see: (a) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566–2587. (b) Yanagisawa, A.; Ishihara, K.;
Yamamoto, H. Synlett 1997, 411–420.
2. (a) Duhamel, L.; Plaquevent, J.-C. Tetrahedron Lett. 1977, 2285–2288. (b) Duhamel, L.; Plaquevent, J.-C. J. Am. Chem.
Soc. 1978, 100, 7415–7416.
3. In addition to the literatures cited in Ref. 1a,b, see the following examples for recent studies of catalytic enantioselective
protonation: (a) Sugiura, M.; Nakai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2366–2368. (b) Vedejs, E.; Kruger, A. W.
J. Org. Chem. 1998, 63, 2792–2793. (c) Takeuchi, S.; Nakamura, Y.; Ohgo, Y.; Curran, D. P. Tetrahedron Lett. 1998, 39,
8691–8694.
4. (a) Yasukata, T.; Koga, K. Tetrahedron: Asymmetry 1993, 4, 35–38. (b) Riviere, P.; Koga, K. Tetrahedron Lett. 1997, 38,
7589–7592.
5. Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 1999, 40, 2803–2806.
6. The general experimental procedure for enantioselective protonation is as follows: Under argon atmosphere, TMS enol
ether 4a–c (1.0 mmol) was treated with a solution of methyllithium (MeLi) (1.0 mmol) in diethyl ether containing LiBr
(1.1 mmol) (purchased from Kanto Chemical, Tokyo, Japan) at room temperature for 1.5 h. Toluene (11.5 mL) was added,
and the reaction mixture was cooled to −20°C and stirred for 10 min. Then a solution of chiral amine (1.0 mmol or catalytic
amount) in toluene [3.0 mL; added dropwise within 2 min and rinsed with toluene (1.0 mL×2)] and achiral additive (2.0
mmol; added neat) were added, and the mixture was stirred for an additional 40 min at this temperature. After the whole
was cooled to −45°C and stirred for 20 min, the proton source [10% aqueous citric acid (10 mL), water (10 mL), or
AcOH (1.2 equiv.)], without precooling, was added in one portion (ca. 3 s), and the mixture was allowed to warm to room
temperature. The organic layer was separated and the aqueous layer was extracted with diethyl ether (20 mL×2). The
combined organic layers were washed successively with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL×1), dried over
anhyd MgSO4, filtered and concentrated in vacuo to give a crude oil, which was purified by column chromatography (silica
gel 15 g, hexanes:ether=50:1) to afford the target compound as a pale yellow oil. This oil was analyzed by HPLC (Daicel
Chiralcel OJ or OD-H) to determine the enantiomeric excess.
7. The absolute configurations of chiral ketones (S)-3a,7a,b (S)-3b,4a and (R)-3c7c are known. (a) Jaouen, G.; Meyer, A. J.
Am. Chem. Soc. 1975, 97, 4667–4672. (b) Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger, M. J.
Am. Chem. Soc. 1981, 103, 3081–3087. (c) Murakata, M.; Nakajima, M.; Koga, K. J. Chem. Soc., Chem. Commun. 1990,
1657–1658.
8. Such a condition has been shown to be essential for obtaining high enantioselectivities in protonation4a,b as well as in
other types of reactions8a,b mediated by related ligands. The effect of lithium salt is possibly due to the formation of a
highly reactive ternary complex composed of the chiral ligand, lithium enolate and LiBr.8a–f For related discussions, see
the following review articles and references cited therein: (a) Koga, K. Pure Appl. Chem. 1994, 66, 1487–1492. (b) Koga,
K.; Shindo, M. J. Synth. Org. Chem., Jpn. 1995, 53, 1021–1032. (c) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27,

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1624–1654. (d) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach, D. Synthesis
1993, 1271–1290. See also: (e) Yanagisawa, A.; Kikuchi, T.; Kuribayashi, T.; Yamamoto, H. Tetrahedron 1998, 54,
10253–10264. (f) Asensio, G.; Aleman, P.; Gil, J.; Domingo, L. R.; Medio-Simon, M. J. Org. Chem. 1998, 63, 9342–9347.
9. The reproducibility of the protonation experiments under the catalytic conditions of entry 7 was that, although the ee
ranged from 80 to 89%, the values close to 89% ee were obtained in most cases.
10. An additional fact supporting the effectiveness of water as a proton source is that the catalytic protonation with (R)-1 in
place of (R,R)-2 under the catalytic condition of entry 11 also induced a moderate enantioselectivity (74% ee).
11. (a) Murakata, M.; Yasukata, T.; Aoki, T.; Nakajima, M.; Koga, K. Tetrahedron 1998, 54, 2449–2458. (b) Imai, M.;
Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am. Chem. Soc. 1994, 116, 8829–8830.