Use of a Catalytic Chiral Leaving Group for Asymmetric Substitutions at sp3-Hybridized Carbon Atoms: Kinetic Resolution of β-Amino Alcohols by p-Methoxybenzylation

Article abstract of DOI:10.1002/anie.201607208

A catalytic strategy was developed for asymmetric substitution reactions at sp³-hybridized carbon atoms by using a chiral alkylating agent generated in situ from trichloroacetimidate and a chiral phosphoric acid. The resulting chiral p-methoxybenzyl phosphate selectively reacts with β-amino alcohols rather than those without a β-NH functionality. The use of an electronically and sterically tuned chiral phosphoric acid enables the kinetic resolution of amino alcohols through p-methoxybenzylation with good enantioselectivity.

Full text of DOI:10.1002/anie.201607208

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607208
German Edition: DOI: 10.1002/ange.201607208
Asymmetric Catalysis
Use of a Catalytic Chiral Leaving Group for Asymmetric Substitutions
at sp3-Hybridized Carbon Atoms: Kinetic Resolution of b-Amino
Alcohols by p-Methoxybenzylation
Yusuke Kuroda, Shingo Harada, Akinori Oonishi, Hiroki Kiyama, Yousuke Yamaoka, Ken-
ichi Yamada,* and Kiyosei Takasu*
Abstract: A catalytic strategy was developed for asymmetric
substitution reactions at sp3-hybridized carbon atoms by using
a chiral alkylating agent generated in situ from trichloroacet-
imidate and a chiral phosphoric acid. The resulting chiral p-
methoxybenzyl phosphate selectively reacts with b-amino
alcohols rather than those without a b-NH functionality. The
use of an electronically and sterically tuned chiral phosphoric
acid enables the kinetic resolution of amino alcohols through
p-methoxybenzylation with good enantioselectivity.
A
dvances in asymmetric synthesis rely on the development
of new catalytic methods that provide an array of versatile
enantioselective transformations. Substitution at sp3-hybrid-
ized carbon atoms is one of the most fundamental trans-
formations in organic synthesis. For this class of reaction,
catalytic asymmetric induction is generally achieved by taking
advantage of noncovalent interactions such as ion pairing or
hydrogen bonding between chiral catalysts and substrates.[1]
One attractive approach based on covalent interactions
involves a chiral leaving group (Figure 1A).[2,3] The chiral
source (X*) is directly bonded to the electrophile (R) in the
substitution step, which allows highly enantioselective trans-
formations to be achieved. However, this strategy relies on
the use of stoichiometric amounts of chiral sources, which is
a drawback.
Figure 1. Use of a chiral leaving group for asymmetric substitution
reactions.
phosphate as a leaving group can be generated in situ from
a chiral phosphoric acid and an appropriate trichloroacetimi-
date. The generated alkylating agent undergoes asymmetric
substitution under the control of the chiral leaving group and
À
enantioselectively gives Nu* R as the product, with regen-
eration of the catalyst.[7] Although this strategy for asymmet-
ric transformations (nucleophilic catalysis) is common for
reactions at unsaturated sp2-hybridized carbon atoms, such as
acylation[8] or allylic substitution,[9] the corresponding reac-
tion at saturated sp3-hybridized carbon atoms is unexplored.
Our investigations commenced with the reactivity of the
phosphate as a leaving group (Scheme 1). Initially, phenethyl
alcohol (2a) was treated with PMB-2,2,2-trichloroacetimidate
(3) and a catalytic amount of diphenyl phosphate (1a) in
chloroform at room temperature in the presence of powdered
4A molecular sieves (MS) but was found to be unreactive. To
our delight, when N-Ns-protected 2-aminoethanol 2b was
subjected to the same reaction conditions, p-methoxybenzy-
lation proceeded to give 4b in 73% yield. Since N-methylated
Recently, we developed a chiral phosphoric acid catalyzed
intramolecular SN2’ reaction in which trichloroacetimidate
was used as a leaving group that could be activated by
a Brønsted acid through hydrogen-bonding interactions.[4,5]
During the study, we observed a substitution reaction of an
allylic trichloroacetimidate with a chiral phosphoric acid to
afford the corresponding organophosphate.[6] This finding is
the basis of our strategy for overcoming the drawback
mentioned above, that is, the use of a catalytic chiral leaving
group (Figure 1B). An alkylating agent bearing a chiral
[*] Dr. Y. Kuroda, Dr. S. Harada, A. Oonishi, H. Kiyama, Dr. Y. Yamaoka,
Prof. Dr. K. Yamada, Prof. Dr. K. Takasu
À
amino alcohol 2c was completely unreactive, the N H
Graduate School of Pharmaceutical Sciences
Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: kay-t@pharm.kyoto-u.ac.jp
functionality plays an important role in accelerating the p-
methoxybenzylation.
We next turned our attention to whether the chiral
organophohsphate could provide enantioinduction in the
substitution reaction. In light of the initial results, we chose
the kinetic resolution of amino alcohols 5 through p-
methoxybenzylation (Table 1) as a test reaction. The kinetic
resolution of racemic secondary alcohols through enantiose-
lective protection is an important process, and many cata-
Prof. Dr. K. Yamada
Current address: Graduate School of Pharmaceutical Sciences,
Tokushima University
Shomachi, Tokushima 770–8505 (Japan)
E-mail: yamak@tokushima-u.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607208.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
group increased the s value to 7.7 (Table 1, entry 7). The
reaction at a lower concentration (0.1m) of 5e resulted in
a synthetically useful s value of 8.6 (Table 1, entry 8).
Solvent screening showed that fluorobenzene improves
the reaction rate (see the Supporting Information). The
enantiomerically enriched alcohol (S)-5e was recovered in
29% yield with 96% ee (s = 8.8; Table 2, entry 1) under these
conditions.[21] The use of amino alcohol 5 f, which bears an
electron-deficient aromatic ring, substantially increased the
reaction rate while preserving the selectivity (Table 2,
entry 2). The s values for kinetic resolutions using amino
Scheme 1. A preliminary study on the reactivity of PMB diphenylphos-
1
phate.[a] [a] Yields were determined by H NMR analysis using Ph3CH
Table 2: Substrate scope of the kinetic resolution.[a]
as an internal standard. PMB=4-methoxybenzyl. MS=molecular
sieves, Ns=2-nitrobenzenesulfonyl.
lytic[10,11] and enzymatic methods[12] have been developed for
this purpose. Despite the widespread use of the PMB group in
synthetic organic chemistry, there is no report of enantiose-
lective p-methoxybenzylation of alcohols,[13] in contrast to
acylation,[8,14] silylation,[15,16] and acetalization.[17] A solution
of Ns amino alcohol 5a, PMB trichloroacetimidate (3;
0.5 equiv), and (R)-binaphthol-derived phosphoric acid
1b[18] (10 mol%) in chloroform was stirred at room temper-
ature in the presence of powdered 4A MS. However, the
chiral PMB phosphate derived from 1b and 3 was so
unreactive that PMB ether 6a was not produced even after
48 h (Table 1, entry 1).[19] To overcome this, we used our
previously reported catalyst 1c,[11b] which bears nitro groups
at the 6,6’-positions of the binaphthol backbone and has
enhanced leaving-group ability. The use of 1c significantly
increased the reactivity, but without enantioinduction (selec-
tivity factor (s) = 1.2;[20] Table 1, entry 2). Screening of con-
ventional N-protecting groups showed that 5d, which bears
a benzyloxycarbonyl (Cbz) group, gave higher s values
(Table 1, entries 2–5). Catalyst 1d, which bears cyclohexyl
(Cy) groups instead of isopropyl groups, improved the
selectivity (entry 6). Further investigation of N-protecting
groups showed that the use of a 9-fluorenyloxycarbonyl (Foc)
Entry
Amino alcohol
R
Recovered 5
s[d]
5
% yield[b]
e.r.[c]
1
Ph
4-ClC6H4
Cy
5e
5 f
5g
5h
29
32
29
36
97:3
97:3
95:5
98:2
8.7
8.7
12
2[e]
3[f]
4[f]
t-Bu
18
5[e]
6[f]
7[f]
5i
5j
5k
42
40
34
97:3
20
32
14
>99:1
98:2
Unsuccessful substrates (No reaction under the optimal conditions)
[a] Reactions were carried out on a 0.1 mmol scale. [b] Yield of isolated
product. [c] Determined by HPLC on a chiral stationary phase. [d] Based
on theoretical conversion and the e.r. of recovered 5. [e] Using CHCl3 as
a solvent for 4 d. [f] Using 15 mol% of (R)-1d.
Table 1: Optimization of reaction conditions for the kinetic resolution of 5 through p-methoxybenzylation.[a]
Entry
1
5 (PG)
6
% conv.[b]
s
1
2
3
4
5
6
1b
1c
1c
1c
1c
1d
1d
1d
5a (Ns)
5a (Ns)
5b (Bz)
5c (Fmoc)
5d (Cbz)
5d (Cbz)
5e (Foc)
5e (Foc)
6a
6a
6b
6c
6d
6d
6e
6e
0
–
50
42
48
50
47
43
26
1.2
1.2
2.1
3.4
4.6
7.7
8.6
7
8[c]
[a] Reaction conditions: 5 (0.1 mmol), 3 (0.05 mmol), 1 (0.01 mmol), and MS 4A (50 mg) in CHCl3 (0.4 mL). PG=protecting group. [b] Calculated
from ee values, determined by HPLC on a chiral stationary phase, of 6 and recovered 5. [c] Conducted at a concentration of 0.1 M.
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
alcohols with secondary and tertiary alkyl substituents at the
stereogenic center were higher than those for reactions using
amino alcohols bearing aromatic rings, but the reaction rates
were lower (Table 2, entries 3 and 4). Various functional
groups, for example, nitrile and ester groups, were tolerated
under the reaction conditions; amino alcohols 5i and 5j were
resolved with good selectivities (Table 2, entries 5 and 6). It is
worth noting that acetal 5k, which is potentially sensitive to
acids, was inert under these conditions (entry 7). The
developed method could not be applied to 2-aminocycloal-
kanols 5l, 5m, or tertiary alcohol 5n, presumably due to steric
hindrance at the carbon atoms adjacent to a hydroxyl group
or NH functionality.
In situ formation of the PMB phosphate was confirmed
using 1H NMR spectroscopy (Figure 2a). When (R)-1d
(1 equiv) was added to a solution of 3 in CDCl3, the 2H
Figure 3. Chem3D perspective view of transition state structures
TSmajor (which gives (R)-6e) and TSminor (which gives (S)-6e) at the
ONIOM (B3LYP/6-31G**:HF/3-21G) level of theory.
the Supporting Information for details). TSmajor and TSminor
,
which give (R)- and (S)-6e, respectively, are shown in
À
Figure 3. The lengths of the breaking and forming C O
bonds in TSmajor were 2.73 and 2.47 ꢀ, respectively, thus
indicating that a loose SN2 mechanism is involved. Reactions
with 1-phenylethanol and the N-methylated analogue 5o,
which has no adjacent NH functionality, failed. The two
=
=
hydrogen bonds, OH···O P (1.81 ꢀ) and NH···O P (2.14 ꢀ)
are thus probably important in stabilizing the TS (Scheme 2).
Analysis of the ONIOM energies sheds light on the
mechanism of the observed asymmetric induction. The
ONIOM high-layer energy of TSmajor, which only reflects the
energy of the reaction center and the hydrogen bonds (see the
Supporting Information for details), is more stable than that
of TSminor by 1.33 kcalmolÀ1. This can probably be attributed
to the distorted arrangement of the reacting hydroxy, PMB,
and phosphate moieties in TSminor, which is caused by steric
repulsion between the Foc moiety and one of the cyclohexyl
groups. The calculated DDG between TSmajor and TSminor was
1.26 kcalmolÀ1 at the M06-2X/6-31G**/CPCM (CHCl3)//
ONIOM (B3LYP/6-31G**:HF/3-21G) level of theory, which
corresponds to 8.3:1 selectivity at room temperature. This is in
good agreement with the experimental results.
Figure 2. Mechanistic studies: a) 1H NMR spectrum of chiral PMB
phosphate A and b) kinetic resolution of 5e with A.
singlet signal from the benzylic proton of 3 at 5.3 ppm (open
circle) disappeared within 5 min, and two 1H triplet signals
(solid circles) appeared at 4.9 and 4.3 ppm, with concomitant
formation of trichloroacetamide (solid square). This result
clearly indicates the formation of PMB phosphate A, in which
the two benzylic protons are diastereotopic and show spin
coupling with each other as well as with the phosphorus atom.
We performed a stoichiometric reaction to confirm that A is
an actual intermediate (Figure 2b). Racemic 5e was added to
a solution of A, which was prepared in situ by mixing 3
(0.5 equiv) and (R)-1d (0.5 equiv) in the presence of 4A MS.
The kinetic resolution proceeded with an s value comparable
to that for the catalytic reaction (Table 1, entry 8). These
results verify the reaction pathway shown in Figure 1B.
The transition state (TS) geometries were calculated at
the ONIOM (B3LYP/6-31G**:HF/3-21G) level of theory (see
Scheme 2. Control experiments.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
[6] It is known that glycosylation of phosphoric acids using
trichloroacetimidates proceeds in the absence of acid catalysts:
R. R. Schmidt, M. Stumpp, Liebigs Ann. Chem. 1984, 680.
[7] Proposed nucleophilic catalysis of chiral Brønsted acids in
asymmetric intramolecular allylic substitution: a) N. D. Shapiro,
V. Rauniyar, G. L. Hamilton, J. Wu, F. D. Toste, Nature 2011,
470, 245; b) Z. Sun, G. A. Winschel, P. M. Zimmerman, P.
Nagorny, Angew. Chem. Int. Ed. 2014, 53, 11194; Angew. Chem.
2014, 126, 11376.
[8] C. E. Mꢁller, P. R. Schreiner, Angew. Chem. Int. Ed. 2011, 50,
6012; Angew. Chem. 2011, 123, 6136, and references therein.
[9] B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921.
[10] a) E. Vedejs, M. Jure, Angew. Chem. Int. Ed. 2005, 44, 3974;
Angew. Chem. 2005, 117, 4040; b) H. Pellissier, Adv. Synth.
Catal. 2011, 353, 1613.
In summary, we have developed a novel strategy for
catalytic asymmetric substitution reactions using chiral orga-
nophosphates generated in situ from phosphoric acids and
trichloroacetimidate. This strategy makes use of a chiral
phosphoric acid as a leaving group, which is an alternative
catalytic mode to the conventional hydrogen-bond donor[22]
or counteranion.[23] The first kinetic resolution of amino
alcohols through p-methoxybenzylation was achieved with
this strategy by using the novel chiral phosphoric acid 1d.
NMR studies and a stoichiometric reaction verified a mech-
anism based on a catalytic leaving group, which had pre-
viously been proposed based on MS observations[7a] and DFT
calculations.[7b]
[11] Our recent contributions: a) S. Kuwano, S. Harada, B. Kang, R.
Oriez, Y. Yamaoka, K. Takasu, K. Yamada, J. Am. Chem. Soc.
2013, 135, 11485; b) S. Harada, S. Kuwano, Y. Yamaoka, K.
Yamada, K. Takasu, Angew. Chem. Int. Ed. 2013, 52, 10227;
Angew. Chem. 2013, 125, 10417; c) K. Yamada, A. Oonishi, Y.
Kuroda, S. Harada, H. Kiyama, Y. Yamaoka, K. Takasu,
Tetrahedron Lett. 2016, 57, 4098.
[12] a) E. Schoffers, A. Golebiowski, C. R. Johnson, Tetrahedron
1996, 52, 3769; b) U. Hanefeld, Org. Biomol. Chem. 2003, 1,
2405; c) A. Ghanem, H. Y. Aboul-Enein, Tetrahedron: Asym-
metry 2004, 15, 3331.
Experimental Section
General Procedure: To a stirred suspension of racemic amino alcohol
5
(0.100 mmol), 4-methoxybenzyl 2,2,2-trichloroacetimidate
3
(22.6 mg, 80.0 mmol), and 4A molecular sieves (50 mg) in solvent
(1 mL), (R)-1d (10 or 15 mol%) was added and the resulting mixture
was stirred at RT for the indicated time. The reaction was quenched
by the addition of MeOH (5 mL), and then the solvent was removed
under reduced pressure. After flash-column chromatography on silica
gel (hexane/AcOEt 9:1 to 6:4), PMB ether 6 and amino alcohol 5
were obtained. The enantiomeric excess was determined by HPLC
analysis with a chiral stationary phase.
[13] Pd-catalyzed asymmetric p-methoxybenzylation of azlactones:
a) B. M. Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2012, 134,
5778; b) B. M. Trost, L. C. Czabaniuk, Chem. Eur. J. 2013, 19,
15210.
[14] Chiral phosphoric acid-catalyzed enantioselective acylations:
a) C. Wang, H.-W. Luo, L.-Z. Gong, Synlett 2011, 992; b) G. Lu,
V. B. Birman, Org. Lett. 2011, 13, 356; c) H. Mandai, K. Murota,
K. Mitsudo, S. Suga, Org. Lett. 2012, 14, 3486; d) G. Qabaja, J. E.
Wilent, A. R. Benavides, G. E. Bullard, K. S. Peterson, Org. Lett.
2013, 15, 1266.
[15] Recent examples: a) S. Y. Park, J.-W. Lee, C. E. Song, Nat.
Commun. 2015, 6, 7512; b) K. Hyogo, S. Gandhi, M. V.
Gemmeren, B. List, Synlett 2015, 1093; c) N. Manville, H.
Alite, F. Haeffner, A. M. Hoveyda, M. L. Snapper, Nat. Chem.
2013, 5, 768, and references therein.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Num-
bers JP16H05073, JP26460005, MEXT KAKENHI Grant
Numbers JP26105732 in Advanced Molecular Transforma-
tions by Organocatalysts, JP16H01147 in Middle Molecular
Strategy, and AMED Platform for Drug Discovery, Infor-
matics, and Structural Life Science. Y.K. thanks JSPS for
a research fellowship for young scientists (JP14J07965).
[16] A review: S. Rendler, M. Oestreich, Angew. Chem. Int. Ed. 2008,
47, 248; Angew. Chem. 2008, 120, 254.
[17] Chiral phosphoric acid-catalyzed enantioselective acetaliza-
Keywords: asymmetric catalysis · b-amino alcohols ·
Brønsted acid catalysis · kinetic resolution ·
substitution reactions
ˇ
´
tions: a) I. Coric, S. Vellalath, B. List, J. Am. Chem. Soc. 2010,
ˇ
´
132, 8536; b) I. Coric, S. Mꢁller, B. List, J. Am. Chem. Soc. 2010,
132, 17370; c) I. Coric, B. List, Nature 2012, 483, 315; d) Z. Sun,
G. A. Winschel, A. Borovika, P. Nagorny, J. Am. Chem. Soc.
ˇ
´
ˇ
´
2012, 134, 8074; e) J. H. Kim, I. Coric, S. Vellalath, B. List,
Angew. Chem. Int. Ed. 2013, 52, 4474; Angew. Chem. 2013, 125,
4570; f) T. Kimura, M. Sekine, D. Takahashi, K. Toshima, Angew.
Chem. Int. Ed. 2013, 52, 12131; Angew. Chem. 2013, 125, 12353;
g) E. Mensah, N. Camasso, W. Kaplan, P. Nagorny, Angew.
Chem. Int. Ed. 2013, 52, 12932; Angew. Chem. 2013, 125, 13170;
h) T. Yamanaka, A. Kondoh, M. Terada, J. Am. Chem. Soc. 2015,
137, 1048; i) J. H. Kim, I. Coric, C. Palumbo, B. List, J. Am.
Chem. Soc. 2015, 137, 1778; j) Y. Y. Khomutnyk, A. J. Argꢁelles,
G. A. Winschel, Z. Sun, P. M. Zimmerman, P. Nagorny, J. Am.
Chem. Soc. 2016, 138, 444.
[1] Catalytic Asymmetric Synthesis, 3rd ed. (Ed.: I. Ojima), Wiley,
Hoboken, 2010.
[2] Pioneering works: a) P. G. Duggan, W. S. Murphy, J. Chem. Soc.
Chem. Commun. 1974, 263; b) J. M. Wilson, D. J. Cram, J. Am.
Chem. Soc. 1982, 104, 881; c) P. Duhamel, J. Y. Valnet, J. J.
Eddine, Tetrahedron Lett. 1982, 23, 2863; d) S. Sakane, J.
Fujiwara, K. Maruoka, H. Yamamoto, J. Am. Chem. Soc. 1983,
105, 6154.
ˇ
´
[18] S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. Int. Ed. 2005,
44, 7424; Angew. Chem. 2005, 117, 7590.
[3] A review: S. D. Lepore, D. Mondal, Tetrahedron 2007, 63, 5103.
[4] Y. Kuroda, S. Harada, A. Oonishi, Y. Yamaoka, K. Yamada, K.
Takasu, Angew. Chem. Int. Ed. 2015, 54, 8263; Angew. Chem.
2015, 127, 8381.
[5] For pioneering works in the field of chiral phosphoric acids, see:
a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int.
Ed. 2004, 43, 1566; Angew. Chem. 2004, 116, 1592; b) D.
Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356.
[19] A Screening of the conventional chiral phosphoric acids was
conducted. See the Supporting Information for details.
[20] Enantioselectivity in kinetic resolution is expressed by the
selectivity factor s, which is defined as the ratio of reaction rates
for the fast- and the slow-reacting enantiomers of the starting
material. In simple first-order kinetics, s = kfast/kslow = ln[(1ÀC)-
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
(1Àee’)]/ln[(1ÀC)(1 + ee’)] = ln[1ÀC(1 + ee)]/ln[1ÀC(1Àee)]
Schenker, M. Freund, S. B. Tsogoeva, Org. Biomol. Chem. 2010,
8, 5262; d) M. Terada, Synthesis 2010, 1929.
and C = ee’/(ee’’ + ee), where C is conversion, and ee and ee’’ are
the enantiomeric excesses of the product and the recovered
starting material, respectively: a) H. B. Kagan, J. C. Fiaud, Top.
Stereochem. 1988, 18, 249; b) see Ref. [10a].
[23] a) J. Lacour, D. Moraleda, Chem. Commun. 2009, 7073; b) R. J.
Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4, 603;
c) M. Mahlau, B. List, Angew. Chem. Int. Ed. 2013, 52, 518;
Angew. Chem. 2013, 125, 540; d) K. Brak, E. N. Jacobsen,
Angew. Chem. Int. Ed. 2013, 52, 534; Angew. Chem. 2013, 125,
558.
[21] The absolute configuration of recovered (S)-5e was determined
by comparing the specific rotation with that derived from
a known compound with established stereochemistry (see the
Supporting Information). For all the other compounds, the
absolute configuration was tentatively assigned by analogy.
[22] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713;
b) M. Terada, Chem. Commun. 2008, 4097; c) A. Zamfir, S.
Received: July 26, 2016
Revised: August 16, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
Y. Kuroda, S. Harada, A. Oonishi,
H. Kiyama, Y. Yamaoka, K. Yamada,*
K. Takasu*
&&&& — &&&&
Use of a Catalytic Chiral Leaving Group
for Asymmetric Substitutions at sp3-
Hybridized Carbon Atoms: Kinetic
Resolution of b-Amino Alcohols by p-
Methoxybenzylation
By your leave: A strategy for asymmetric
substitutions based on the use of a cata-
lytic chiral leaving group was demon-
strated with a chiral phosphate generated
in situ from trichloroacetimidate and
a chiral phosphoric acid. An electronically
and sterically tuned chiral phosphoric
acid was developed to enable the kinetic
resolution of amino alcohols through p-
methoxybenzylation with good enantio-
selectivity.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!