NMR studies on the structure of a lithium amide-chiral diether complex for an asymmetric reaction

Article abstract of DOI:10.1016/j.tet.2013.03.036

The combination of a chiral diether ligand and a lithium benzyl(trimethylsilyl)amide is a powerful lithium amide reagent for asymmetric conjugate amination of enoate in a toluene solvent. The structure of the chiral diether-lithium amide complex in soluti

Full text of DOI:10.1016/j.tet.2013.03.036

Tetrahedron 69 (2013) 3836e3840
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
NMR studies on the structure of a lithium amideechiral diether
complex for an asymmetric reaction
,
b
a,
*
Yasutomo Yamamoto a , Hiroyuki Nasu , Kiyoshi Tomioka
*
a Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
b Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of a chiral diether ligand and a lithium benzyl(trimethylsilyl)amide is a powerful
lithium amide reagent for asymmetric conjugate amination of enoate in a toluene solvent. The structure
of the chiral dietherelithium amide complex in solution was analyzed by low-temperature NMR. 6Li
NMR suggested the formation of a cyclic heterodimer. The stereochemical pathway is predictable based
on the structure of the lithium amideechiral diether complex.
Received 22 February 2013
Accepted 12 March 2013
Available online 15 March 2013
Keywords:
Lithium amide
Ó 2013 Elsevier Ltd. All rights reserved.
Asymmetric aza-Michael reaction
NMR
1. Introduction
diether in other types of asymmetric reactions has also been reported
by other research groups.21
The dimethyl ether of (R,R)- and (S,S)-1,2-dihydroxy-1,2-
diphenylethane 1 is a powerful and widely applicable chiral exter-
nal ligand1 for asymmetric reactions of lithiated reagents, such as
organolithium,2 lithium enolate, and lithium amide.3 Since the first
report on the utility of chiral diether 1 in the catalytic and stoichio-
metric asymmetric conjugate addition of organolithiums to un-
saturated imines,4 further applications to an asymmetric SNAr
reaction giving biaryls,5 a conjugate addition to enoates,6 an asym-
metric addition to imines,7 an enantioselective opening of oxiranes
and oxetanes,8 an asymmetric HornereWadswortheEmmons re-
action,9 and natural Amaryllidaceae alkaloid total synthesis10 have
been developed. The utility was further extended to the reaction of
lithium enolate, and an asymmetric Mannich-type reaction with
imines,11 asymmetric Peterson reaction,12 asymmetric Michael re-
action with enones13 and enoates,14 and its application to the total
synthesis of marine natural products bearing quaternary carbons15
have been reported. It was an unexpected discovery that a ternary
complex of lithium enolate with lithium amide as well as diether li-
gand 1 is a more reactive enolate reagent than enolateediether and
enolateelithium amide binarycomplexes.16 Lithium amide17 has also
become a powerful chiral nitrogen nucleophile in the conjugate ad-
Formation of lithiated reagentechiral diether 1 complex 2 was
conceptually designed, as shown in Fig. 1, and experimentally sup-
ported by the variety of highly efficient asymmetric reactions de-
scribed above. The two methyl groups on the oxygen atom situate up
and down face of the five-membered chelation because of trans-
arrangement toward the phenyl group. If a reaction occurs upon
coordination to lithium, the two methyl groups support the closest
stereocontrolling groups. Proof of concept, however, should be
demonstrated by a structure study of the lithiated reagentechiral
diether 1 complex 2. Also, studies on the structure are important to
understand the stereochemical control in these asymmetric re-
actions. Therefore, we investigated the structure of the lithiated ester
enolateechiral diether 1 complex using NMR technology. It is im-
portant to note that a ternary complex of lithium ester enolate with
chiral diether and lithium amide is the most reactive enolate reagent
in a toluene solvent.22 Because lithium amide is widely used as a base
or a nitrogen nucleophile in organic synthesis,23,24 structural studies
of the lithium amideechiral diether complex are also important.
We previously developed a chiral diether 1-mediated asym-
metric conjugate addition reaction of lithium benzyl(trimethylsilyl)
dition reaction with enoates, giving b
-amino acid derivatives.18,19
Application to the asymmetric total synthesis of natural indole-
alkaloids was the subject of our recent study.20 The utility of
* Corresponding authors. Tel.: þ81 774 65 8676; fax: þ81 774 65 8658; e-mail
addresses:
yayamamo@dwc.doshisha.ac.jp
(Y.
Yamamoto),
tetrahedron@
dwc.doshisha.ac.jp, tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
Fig. 1. Lithium reagentechiral diether 1 complex 2.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.036

Y. Yamamoto et al. / Tetrahedron 69 (2013) 3836e3840
3837
amide 3 with tert-butyl cinnamate 4 in a toluene solvent to give b-
aminoester 6a in 93% yield with 92% ee.18,25 A tandem alkylation
reaction of the nucleophilic lithium enolate intermediate 5 with
alkyl halide was possible to efficiently construct two adjacent chiral
centers 6b (Scheme 1).18d,20 The conceptual basis of these asym-
metric transformations is the putative five-membered chelate 7a of
lithium amide and ligand 1, around which a chiral environment was
effectively created, as shown in 7b (Fig. 2). In this paper, we focused
on the NMR behavior of the lithium amide 3-diether 1 complex in
toluene solvent and the relation to stereochemical control in
asymmetric conjugate amination.
Scheme 1. Asymmetric conjugate amination reaction of 3 mediated by 1.
1
Chart 1. H NMR spectra (toluene-d8, e100 ꢁC) of the 1e3 complex.
respectively, which also suggested the formation of binary complex
1e3 (K). At the same time, Ce and Cf of uncomplexed 3 were ob-
served. These results strongly supported the existence of both of
1e3 and uncomplexed 1, as shown in 1H NMR (Chart 1D).
The number of connected 6Li and 15N atoms can be analyzed by
6Li and 15N NMR.28 We then prepared 6Li and 15N-labeled lithium
amide 3, and measured 6Li NMR.29
Fig. 2. Putative binary complex 7 of 1 and 3.
6Li NMR of [6Li,15N]-3, prepared from n-Bu6Li and [15N]-8,
showed a triplet signal at ꢀ40 ꢁC (Chart 4L), which is indicative of
NeLieN connectivity and the existence of a cyclic dimer.30 Lower-
ing the temperature to below ꢀ80 ꢁC changed a complex signal to
a signal comprising mainly two triplets with overlapping compo-
nents (M, N). Cis- and trans-cyclic dimers 9 and 10 are possible
structures (Fig. 3),31 and these stereoisomeric cyclic dimers give
two triplet signals, consistent with the 6Li NMR of [6Li,15N]-3 at ꢀ80
and ꢀ100 ꢁC (M, N). In the 1:1 mixture of 1 and [6Li,15N]-3 at
ꢀ80 ꢁC, a triplet signal appeared (O), indicative of NeLieN con-
nectivity. At ꢀ100 ꢁC, three triplets appeared from a complex signal
2. Results and discussion
We performed 1H NMR analysis of lithium amide 3 in toluene-
d8 at ꢀ100 ꢁC. Treatment of benzyl(trimethylsilyl)amine
8
(Chart 1A) with 1 equiv of a hexane solution of n-BuLi indicated
that methyl protons Ha and benzyl protons Hb of 8 were shifted to
Hc and Hd, as shown in blue, respectively (B). Upon addition of
1 equiv of diether 1 (C) to the solution of 3 in toluene-d8, new
peaks He2 (two peaks) and Hf2, derived from methyl and methine
protons of 1, and downfield shifted Hc2 and Hd2 of 3 appeared (D),
strongly supporting the coordination of 1 to 3.26 He and Hf of
coordination-free 1 were also observed, and most of 1 seemed to
coordinate to 3 based on a He2/He integration ratio of 4/1. The split
of He2 of 1 and Hd2 of 3 suggests that the two methyl groups of 1
and the benzyl protons of 3 were not equivalent at this tempera-
ture. At an elevated temperature, e40 ꢁC, similar 1H NMR shifts of
Hc and Hd of 3 and He and Hf of 1 were observed (Chart 2EeG).
Protons of non-coordinated diether 1 were not observed at all in
the 1:1 mixture of 1 and 3, indicating that the coordination and
dissociation equilibrium of 1 with 3 was a faster process than the
NMR time scale at ꢀ40 ꢁC.27
Analysis by 13C NMR at ꢀ100 ꢁC (Chart 3) indicated the forma-
tion of lithium amide 3 (I) from amine 8 (H) with n-BuLi by
a downfield shift of Ca and Cb to Cc and Cd, respectively. In the 1:1
mixture of 1e3, new peaks Cc2 and Cd2 of 3 and Ce2 and Cf2 of 1
appeared, as shown in red, and their chemical shifts were different
from that of Ce, Cf, Cc, and Cd of uncomplexed 1 (J) and 3 (I),
1
Chart 2. H NMR spectra (toluene-d8, e40 ꢁC) of the 1e3 complex.

3838
Y. Yamamoto et al. / Tetrahedron 69 (2013) 3836e3840
Fig. 3. Plausible cis- and trans-dimers 9 and 10, and heterodimers 11 and 12.
In a diether 1-mediated asymmetric conjugate addition of 3
with enoate 4 (Scheme 1), binary complexes 11 and 12 were first
generated. The next step would be the coordination of carbonyl
oxygen of enoate 4 to lithium atoms of the binary complex. Lithium
atoms of heterocyclic dimers 11 and 12, however, are sterically
hindered and therefore dissociation to the monomeric complex
would be required for the conjugate addition to proceed. As shown
in Scheme 2, enoate 4 coordinates to lithium atoms to avoid the
steric repulsion of the two methyl groups of 1, and therefore the
reaction proceeded from the Re-face of 4 to give (R)-6a with the
observed absolute configuration.
13
Chart 3. C NMR spectra (toluene-d8, e100 ꢁC) of 1e3 complex.
(P).32 The lithium signals in chart P appeared to be in a higher field
than those in chart N, indicating that lithium atoms in the mixture
of 1 and 3 are relatively electron-rich by the coordination of 1 to the
lithium atoms of 3.
Two forms, 9 and 10, of 3 are possible to constitute the cyclic
heterodimers 11 and 12 by adding coordinating 1 to lithium (Fig. 3).
The methyl groups of 1 would be positioned to avoid steric re-
pulsion against the adjacent phenyl groups. The two lithium atoms
of 11 are equivalent, whereas those of 12 are not equivalent. Three
triplet signals in Chart 4P would correspond to Li2 of 11 and Li3 and
Li4 of 12. With regard to the four methyl groups in 11 and 12, two
methyls of each heterodimer are close to the N-benzyl group (Me1
of 11 and Me4 of 12), and the others are close to the TMS groups
(Me2 of 11 and Me3 of 12). This is likely the reason for the non-
equivalence of He2 and Ce2 in 1H and 13C NMR at ꢀ100 ꢁC, re-
spectively (Chart 1D, 3K).
Scheme 2. Plausible stereochemistry of an asymmetric conjugate amination reaction.
3. Conclusion
A binary complex of lithium amide 3 and chiral diether 1 was
analyzed by 1H, 13C, and 6Li NMR, and formation of a cyclic dimer
was suspected based on 6Li NMR using [6Li,15N]-3. Although the
observed structure was not confirmed to represent real active
species, the present studies provide mechanistic insight into the
asymmetric reaction mediated by chiral diether 1.
4. Experimental
4.1. General
All NMR samples were prepared in a flask and transferred to an
NMR tube via cannula before measurement. All NMR tubes were
dried under vacuum at 100 ꢁC for 1 h, sealed with septa, and filled
with argon gas before use. Toluene-d8 was distilled from sodium/
benzophenone. All NMR experiments were recorded on a 500-MHz
spectrometer with a variable-temperature unit. Measuring fre-
quencies were 500 MHz (1H), 125 MHz (13C), and 73 MHz (6Li). 1H
and 13C chemical shifts in toluene-d8 were referenced to the solvent
signals at d 2.09 and d
20.4, respectively. 6Li spectra were referenced
to external 0.3 M 6LiCl in MeOH-d4 0.0). n-Bu6Li33 and N-ben-
(d
zyltrimethylsilylamine34 was prepared according to reported
procedures.
Chart 4. 6Li NMR spectra (toluene-d8, variable temperature) of the 1e3 complex.

Y. Yamamoto et al. / Tetrahedron 69 (2013) 3836e3840
3839
4.2. Preparation of isotope-labeled materials
4.3.4. Amine 8 in toluene-d8. A 0.20 M solution in toluene-d8 was
prepared in a round bottom flask and transferred to a dry NMR tube
via cannula.
4.2.1. [15N]-Benzamide. [15N]-Benzylamine was prepared according
to the reported procedure.35 15NH4Cl (min 98 atom % 15N, 10.1 g,
0.185 mol) was dissolved in water (140 mL), and benzene (20 mL)
was added. The flask was cooled in an ice bath, followed by the
addition of aqueous 4 M NaOH (100 mL, 0.4 mol) and then a solu-
tion of benzoyl chloride (21.8 mL, 0.188 mol) in benzene (800 mL).
The mixture was stirred for 1.5 h at room temperature, and then
cooled in an ice bath. The precipitated white solid was collected by
filtration and recrystallized from EtOH (19 mL), giving [15N]-ben-
zamide as colorless plates (18.9 g, 83%, >98 atom % 15N calcd by
EIMS) of mp 127.5e130.5 ꢁC. 1H NMR (CDCl3): 5.97e6.23 (2H, m),
7.44e7.47 (2H, m), 7.53 (1H, tt, J¼7.3, 1.4), 7.81e7.83 (2H, m). 13C
NMR (CDCl3): 127.4 (CH), 128.6 (CH), 132.0 (CH), 133.4 (C, d, J¼8.3),
169.7 (C, d, J¼14.5). EIMS m/z: 122 (Mþ).
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Young Scientists (B), and a Grant-in-Aid for Scientific Research (A)
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
References and notes
1. Tomioka, K. Synthesis 1990, 541e549.
2. (a) Tomioka, K. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, Germany, 2000; Chapter 12, pp 491e505; (b) Iguchi, M.; Yamada,
K.; Tomioka, K. In Topics in Organometallic Chemistry; Hodgson, D. M., Ed.;
Springer: Berlin, Heidelberg, Germany, 2003; Vol. 5, pp 37e59.
3. (a) Tomioka, K. Yakugaku Zasshi 2004, 124, 43e53; (b) Yamataka, H.; Yamada,
K.; Tomioka, K. In The Chemistry of Organolithium Compounds; Rappoport, Z., Ed.
Marek, I., Ed.; John Wiley & Sons: Chichester, United Kingdom, 2004; Vol. 1,
pp 901e940; (c) Tomioka, K. In Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Ed.; Springer: Berlin, Heidelberg, Germany, 2004; pp 109e124; Supple-
ment to 31.1; (d) Tomioka, K.; Yamamoto, Y.; Yamada, K. In Comprehensive
Chirality; Carreira, E. M., Ed.Yamamoto, H., Ed.; Elsevier: Amsterdam, The
Netherlands, 2012; Vol. 3, pp 626e654.
4. (a) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111, 8266e8268; (b)
Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63, 9351e9357.
5. Shindo, M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc. 1992, 114, 8732e8733.
6. (a) Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron Lett. 1993, 34, 681e682; (b)
Asano, Y.; Iida, A.; Tomioka, K. Tetrahedron Lett. 1997, 38, 8973e8976.
7. Hasegawa, M.; Taniyama, D.; Tomioka, K. Tetrahedron 2000, 56, 10153e10158.
8. Mizuno, M.; Kanai, M.; Iida, A.; Tomioka, K. Tetrahedron: Asymmetry 1996, 7,
2483e2484.
9. Mizuno, M.; Fujii, K.; Tomioka, K. Angew. Chem., Int. Ed. 1998, 37, 515e517.
10. (a) Yamada, K.; Yamashita, M.; Sumiyoshi, T.; Nishimura, K.; Tomioka, K. Org.
Lett. 2009, 11, 1631e1633; (b) Yamada, K.; Mogi, Y.; Mohamed, M.-A.; Takasu, K.;
Tomioka, K. Org. Lett. 2012, 14, 5868e5871.
11. Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997,
119, 2060e2061.
12. Iguchi, M.; Tomioka, K. Org. Lett. 2002, 4, 4329e4331.
13. Iguchi, M.; Doi, H.; Hata, S.; Tomioka, K. Chem. Pharm. Bull. 2004, 52, 125e129.
14. Yamamoto, Y.; Suzuki, H.; Yasuda, Y.; Iida, A.; Tomioka, K. Tetrahedron Lett. 2008,
49, 4582e4584.
15. Yamamoto, Y.; Yasuda, Y.; Nasu, H.; Tomioka, K. Org. Lett. 2009, 11, 2007e2009.
16. Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron 1999, 55, 11219e11228.
17. Pettersen, D.; Amedjkouh, M.; Ahlberg, P. In The Chemistry of Organolithium
Compounds; Rappoport, Z., Ed.Marek, I., Ed.; John Wiley & Sons: Chichester,
United Kingdom, 2006; Vol. 2, pp 411e476.
18. (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc. 2003,
125, 2886e2887; (b) Doi, H.; Sakai, T.; Yamada, K.; Tomioka, K. Chem. Commun.
2004, 1850e1851; (c) Sakai, T.; Doi, H.; Kawamoto, Y.; Yamada, K.; Tomioka, K.
Tetrahedron Lett. 2004, 45, 9261e9263; (d) Sakai, T.; Kawamoto, Y.; Tomioka, K.
J. Org. Chem. 2006, 71, 4706e4709; (e) Sakai, T.; Doi, H.; Tomioka, K. Tetrahedron
2006, 62, 8351e8359; (f) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yama-
moto, Y.; Tomioka,, K. Tetrahedron 2013, 69, 3264e3273.
4.2.2. [15N]-Benzylamine. A solution of [15N]-benzamide (8.4 g,
0.069 mol) in THF (100 mL) was added to a suspension of LiAlH4
(7.8 g, 0.206 mol) in THF (300 mL) over 5 min at 0 ꢁC, and the
mixture was refluxed for 2 h. After cooling to 0 ꢁC, water (8 mL),15%
NaOH (8 mL) and water (24 mL) were added, and the mixture was
stirred for 3 min at room temperature. The solid was filtered and
the filtered gray cake was washed with THF (100 mLꢂ2); then the
combined filtrates were dried over Na2SO4. Concentration followed
by distillation (83e85 ꢁC/28 mmHg) gave [15N]-benzylamine as
a colorless oil (6.31 g, 85%). 1H NMR (CDCl3): 1.40 (2H, br s), 3.87
(2H, s), 7.24 (1H, m), 7.30e7.35 (4H, m).
4.2.3. [15N]-N-Benzyl(trimethylsilyl)amine ([15N]-8). A solution of
[
15N]-benzylamine (5.5 mL, 50 mmol) in dry THF (50 mL) was
cooled in an ice-salt bath (ca. e15 ꢁC). n-BuLi (1.54 M in hexane,
32.5 mL, 50 mmol) was added to the solution over 5 min and the
mixture was stirred for 1 h at 0 ꢁC. TMSCl (6.35 mL, 50 mmol) was
added to the pink suspension over 2 min at 0 ꢁC. After stirring for
1 h at room temperature, benzene (50 mL) was added to the re-
action mixture to precipitate LiCl, which was removed by filtration.
Concentration of the filtrate followed by distillation (80e82 ꢁC/
8 mmHg) gave [15N]-N-benzyl(trimethylsilyl)amine ([15N]-8) as
a colorless oil (6.81 g, 76%). 1H NMR (C6D6): 0.05 (9H, s), 0.41 (1H, dt,
J¼75.7, 8.1), 3.78 (2H, d, J¼7.9), 7.11 (1H, t, J¼7.0), 7.19e7.25 (4H, m).
13C NMR (C6D6): 0.1 (CH3), 46.2 (CH2, d, J¼8.4), 126.6 (CH), 127.3
(CH), 128.4 (CH), 144.7 (C). IR: 3402, 1250. HRMSeDART m/z:
[MþH]þ calcd for C10H18 15NSi, 181.1179; found, 181.1186.
4.3. Preparation of NMR samples
4.3.1. Binary complex of 1e3 in toluene-d8. A dry round bottom
flask was equipped with a stir bar and filled with argon by evacu-
ation and refilled three times. Amine 8 (90.0 mg, 0.5 mmol) and
toluene-d8 (1.4 mL) were added at room temperature and the
mixture was cooled to ꢀ78 ꢁC. n-BuLi (1.54 M in hexane, 0.33 mL,
0.5 mmol) was added over 2 min and the mixture was stirred for
0.5 h at ꢀ78 ꢁC. A solution of diether 1 (121.2 mg, 0.5 mmol) in
toluene-d8 (1.0 mL) was added to the solution over 3 min. The
mixture was stirred for 0.5 h at ꢀ78 ꢁC and then transferred to a dry
NMR tube via cannula.
19. (a) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820e2822; (b) Rico, J. G.;
Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. J. Org. Chem. 1993, 58, 7948e7951; (c)
Enders, D.; Wahl, H.; Bettray, W. Angew. Chem., Int. Ed. Engl. 1995, 34, 455e457;
(d) Sewald, N.; Hiller, K. D.; Helmreich, B. Liebigs Ann. 1995, 925e928; (e) Bull,
S. D.; Davies, S. G.; Robert, P. M.; Savory, E. D.; Smith, A. D. Tetrahedron 2002, 58,
4629e4642 Reviews: (f) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25,
117e128; (g) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991e8035; (h) Xu, L. W.;
Xia, G. G. Eur. J. Org. Chem. 2005, 633e639; (i) Davies, S. G.; Smith, A. D.; Price,
P. D. Tetrahedron: Asymmetry 2005, 16, 2833e2891; (j) Krishna, P. R.;
Sreeshailam, A. ,; Srinivas, R. Tetrahedron 2009, 65, 9657e9672; (k) Enders, D.;
Wang, C.; Liebich, J. X. Chem.dEur. J. 2009, 15, 11058e11076; (l) Wang, J.; Li, P.;
Choy, P. Y.; Chan, A. S. C.; Kwong, F. Y. ChemCatChem 2012, 4, 917e925; (m)
Davies, S. G.; Fletcher, A. ,M.; Roberts, P. M.; Thomson, J. E. Tetrahedron:
Asymmetry 2012, 23, 1111e1153.
4.3.2. Lithium amide 3 in toluene-d8. The lithium amide 2 solution
was prepared from amine 8 (90.0 mg, 0.5 mmol) and n-BuLi (1.54 M
in hexane, 0.33 mL, 0.5 mmol) in toluene-d8 (2.4 mL) at ꢀ78 ꢁC, and
transferred to a dry NMR tube via cannula.
20. (a) Suzuki, M.; Kawamoto, Y.; Sakai, T.; Yamamoto, Y.; Tomioka, K. Org. Lett.
2009, 11, 653e655; (b) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto,
Y.; Tomioka, K. J. Org. Chem. 2012, 77, 7212e7222; (c) Harada, S.; Sakai, T.;
Takasu, K.; Yamada, K.; Yamamoto, Y.; Tomioka, K. Chem.dAsian J. 2012, 7,
2196e2198.
21. For example, see the review and recent applications. (a) Okano, K. Tetrahedron
2011, 67, 2483e2512; (b) Perron, Q.; Alexakis, A. Adv. Synth. Catal. 2010, 352,
2611e2620.
22. Yamamoto, Y.; Yasuda, Y.; Oulyadi, H.; Maddaluno, J.; Tomioka, K. Tetrahedron
2010, 66, 2470e2473.
4.3.3. Diether 1 in toluene-d8. A 0.20 M solution in toluene-d8/
hexane (8/1) was prepared in a round bottom flask and transferred
to a dry NMR tube via cannula.

3840
Y. Yamamoto et al. / Tetrahedron 69 (2013) 3836e3840
23. Hilmersson, G.; Granander, J. In The Chemistry of Organolithium Compounds;
29. 15N NMR of [15N]-6 was a singlet signal at 14.0 ppm, [6Li,15N]-3 was a broad
singlet at 19.3 ppm, and 1e[6Li,15N]-3 was a broad singlet at 19.4 ppm. Contrary
to our expectations, the connectivity of 6Li and 15N was unclear in these ex-
periments because no 6Lie15N coupling was observed.
30. Higher oligomers such as cyclic trimers and tetramers are also possible. Based
on the NMR studies of LiHMDS, the aggregation state is greatly influenced by
the solvent; the ratio of higher oligomer/dimer is 1:1 in pentane and 1/11 in
toluene Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1996, 118, 2217e2225.
31. Lithium cyclohexyl(isopropyl)amide in THF forms both cis- and trans-cyclic
dimers Galiano-Roth, A. S.; Michaelides, E. M.; Collum, D. B. J. Am. Chem. Soc.
1988, 110, 2658e2660; Lithium cyclohex-1-en-1-yl(phenyl)amide also forms
cis- and trans-cyclic dimers at low THF concentrations, whereas monomers are
predominant in neat THF Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D.
B. J. Am. Chem. Soc. 1990, 112, 4069e4070.
Rappoport, Z., Ed.Marek, I., Ed.; John Wiley
& Sons: Chichester, United
Kingdom, 2006; Vol. 2, pp 381e409.
24. NMR studies of solution-state structure of chiral lithium amides: (a) Aoki, K.;
Noguchi, H.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1993, 34, 5105e5108; (b)
Aoki, K.; Tomioka, K.; Noguchi, H.; Koga, K. Tetrahedron 1997, 53, 13641e13656;
ꢀ
(c) Corruble, A.; Davoust, D.; Desjardins, S.; Fressigne, C.; Giessner-Prettre, C.;
Harrison-Marchand, A.; Houte, H.; Lasne, M.-C.; Maddaluno, J.; Oulyadi, H.;
ꢀ
Valnot, J.-Y. J. Am. Chem. Soc. 2002, 124, 15267e15279; (d) Pate, F.; Duguet, N.;
ꢀ
Oulyadi, H.; Harrison-Marchand, A.; Fressigne, C.; Valnot, J.-Y.; Lasne, M.-C.;
Maddaluno, J. J. Org. Chem. 2007, 72, 6982e6991; (e) Li, D.; Sun, C.; Williard, P.
G. J. Am. Chem. Soc. 2008, 130, 11726e11736; (f) Li, D.; Keresztes, I.; Hopson, R.;
Williard, P. G. Acc. Chem. Res. 2009, 42, 270e280; (g) Lecachey, B.; Duguet, N.;
ꢀ
Oulyadi, H.; Fressigne, C.; Harrison-Marchand, A.; Yamamoto, Y.; Tomioka, K.;
Maddaluno, J. Org. Lett. 2009, 11, 1907e1910; (h) Kagan, G.; Li, W.; Li, D.;
Hopson, R.; Williard, P. G. J. Am. Chem. Soc. 2011, 133, 6596e6602.
32. Chemicalshiftand coupling constantof 6Lisignals in chart N:
d
1.89 (t, lJNeLi¼5.2),1.
39 (t, lJNeLi¼5.5). Chart P: 0.83 (t, lJNeLi¼3.5), 1.06 (t, lJNeLi¼3.7), 1.11 (t, lJNeLi¼3.7).
Based on computational studies, the 6Lie15N coupling constant of the tetra-
coordinated lithium ion is smaller than that of tri- or dicoordinated lithium ions
Koizumi, T.; Morihashi, K.; Kikuchi, O. Bull. Chem. Soc. Jpn. 1996, 69, 305e309.
33. Gawley, R. E.; Klein, R.; Ashweek, N. J.; Coldham, I. Tetrahedron 2005, 61,
3271e3280.
25. In this reaction, the presence of TMSCl was highly effective to give b-amino-
ester 6a with 97% ee and 97% yield (see Ref. 18a).
26. Superscript ‘2’ of Hc2, Hd2, He2 and Hf2 represents the protons of binary com-
plexes 1e3.
27. By increasing the amount of 1 from 1 equiv to 2 equiv with respect to 2 in the
1H NMR at e40 ꢁC, Hc2 and Hd2 were shifted close to Hc and Hd of non-
coordinated 1, but Hc and Hd themselves were not observed. The results also
indicated the rapid coordination/dissociation of 1 with 3 at ꢀ40 ꢁC.
28. Collum, D. B. Acc. Chem. Res. 1993, 26, 227e234.
34. Watanabe, Y.; Nishiyama, K.; Zhang, K.; Okuda, F.; Kondo, T.; Tsuji, Y. Bull. Chem.
Soc. Jpn. 1994, 67, 879e882.
€
35. Reich, H. J.; Goldenberg, W. S.; Gudmundsson, B. O.; Sanders, A. W.; Kulicke, K.
J.; Simon, K.; Guzei, I. A. J. Am. Chem. Soc. 2001, 123, 8067e8079.