Asymmetric preparation of new N, N -dialkyl-2-amino-1,1,2-triphenylethanol catalysts and a kinetic resolution in the addition of diethylzinc to flavene-3-carbaldehydes

Article abstract of DOI:10.1055/s-0032-1318301

Enantiopure N,N-dialkyl-(S)-2-amino-1,1,2-triphenylethanols were prepared using a new synthetic methodology and tested for their ability to catalyze the enantioselective addition of diethylzinc to aldehydes. The structural modification of N-substituents of the catalysts led us to identify N-methyl-N-(S)-1-phenyl-ethyl-substituted 4d as an effective catalyst for the addition. Also disclosed is a kinetic resolution of racemic flavene-3- carbaldehydes with the chiral catalyst.

Full text of DOI:10.1055/s-0032-1318301

630▌
LETTER
lAettserymmetric Preparation of New N,N-Dialkyl-2-amino-1,1,2-triphenylethanol
Catalysts and a Kinetic Resolution in the Addition of Diethylzinc to Flavene-3-
carbaldehydes
New N,N-Dialkyl-2-amino-1,1,2-triphenylethanol Catalysts
Seock Yong Kang, Jinho Baek, Yi Kyung Ko, Chan Im, Yong Sun Park*
Department of Chemistry and KFnSC, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea
Fax +82(2)34365382; E-mail: parkyong@konkuk.ac.kr
Received: 18.12.2012; Accepted after revision: 01.02.2013
the α-bromo carbon center via dynamic resolution of two
Abstract: Enantiopure N,N-dialkyl-(S)-2-amino-1,1,2-triphenyl-
diastereomeric α-bromo-α-phenyl acetates 1 and 2.3 This
ethanols were prepared using a new synthetic methodology and test-
nucleophilic substitution readily enabled us to fine-tune
N-substitution through the use of various amine nucleo-
ed for their ability to catalyze the enantioselective addition of
diethylzinc to aldehydes. The structural modification of N-substitu-
ents of the catalysts led us to identify N-methyl-N-(S)-1-phenyl- philes.
ethyl-substituted 4d as an effective catalyst for the addition. Also
disclosed is a kinetic resolution of racemic flavene-3-carbaldehydes
with the chiral catalyst.
The previous studies by Pericàs et al. have revealed that 2-
piperidino-1,1,2-triphenylethanol provides excellent en-
antioselectivity in the addition of dialkylzinc to aldehydes
and structural changes in the N,N-dialkyl substituents
have important chemical consequences.2c–f In order to fur-
ther understand the influence of the N-alkyl substituents
on the catalytic properties, we have prepared four differ-
ent chiral catalysts 4a–d having different N-benzyl sub-
stituents.
Key words: addition, asymmetric catalysis, chirality, enantioselec-
tivity, kinetic resolution
A great deal of effort has been devoted to the development
of efficient chiral catalysts for catalytic asymmetric reac-
tions. Among the various types of chiral catalysts ex-
plored, β-amino alcohols have proven to be especially
efficient for the addition of organometallic reagents to
carbonyl compounds.1 In particular, 2-amino-1,1,2-tri-
substituted ethanols are known as some of the most effi-
cient chiral catalysts for the addition of dialkylzinc to
aldehydes.2 However, the preparation of the optically pure
catalysts is not a trivial task, and fine-tuning of their struc-
tures for optimal catalytic behavior requires carefully con-
trolled synthetic strategies. Thus, it is of interest to
develop a practical synthesis of new catalysts, based on
processes that are compatible with structural diversity.
O
Br
1 Xc = diacetone-D-glucose
Xc
2 Xc = (R)-pantolactone
Ph
(αRS)
R1R2NH
with 2
DIPEA
TBAI
3a R1 = R2 = Bn
92%, 99:1 dr
O
3b R1 = Bn, R2 = Me
R2R1N
O
56%, 91:9 dr
O
Herein, we report the asymmetric syntheses of new N,N-
dialkyl-2-amino-1,1,2-triphenylethanols using a dynamic
resolution mediated by a chiral auxiliary in the nucleo-
philic substitution of α-bromo esters. The application of
the synthesized catalysts to the addition of diethylzinc to
aldehydes, a typical catalytic asymmetric benchmark re-
action, is also discussed. Furthermore, we present a suc-
cessful example of kinetic resolution of racemic flavene-
3-carbaldehyde by addition of diethylzinc.
3c R1 = (R)-phenylethyl, R2 = H
66%, 99:1 dr
Ph
O
3d R1 = (S)-phenylethyl, R2 = H
71%, 99:1 dr
(αS)
1. MeI, Et3N (for 3c,d)
2. PhMgBr
72–31% yield
Ph
Me
N
OH
OH
Ph
Ph
Ph
Ph
Ph
N
Our strategy for the synthesis of enantiopure N,N-dialkyl-
2-amino-1,1,2-triphenylethanols involves an asymmetric
nucleophilic substitution of α-bromo esters with an amine
nucleophile followed by Grignard addition as shown in
Scheme 1. In the nucleophilic substitution with amine nu-
cleophiles, the chiral information of a chiral auxiliary is
efficiently transferred to the new C–N bond formation at
Ph
Ph
Ph
Ph
Ph
4a
4b
Me
N
OH
Me
N
OH
Ph
Ph
Ph
Ph
(S)
Ph
(R)
Me
Ph
Me
4d
4c
SYNLETT 2013, 24, 0630–0634
Advanced online publication: 25.02.2013
Scheme 1 Asymmetric preparation of chiral catalysts 4a–d
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318301; Art ID: ST-2012-U1080-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
New N,N-Dialkyl-2-amino-1,1,2-triphenylethanol Catalysts
631
We first used diacetone-D-glucose as a chiral auxiliary for product with an ee of 96%, while N-(R)-1-phenylethyl-
the asymmetric syntheses of N-substituted amino esters substituted catalyst 4c led to low conversion and poor en-
via dynamic kinetic resolution of α-bromo esters.4 The antioselectivity. Simple structural modifications of the N-
treatment of a 1:1 diastereomeric mixture of α-bromo-α- alkyl substituents of 4a–d had a significant impact on the
phenyl acetate 1 with dibenzylamine, benzylmethyl- stereochemical outcome of the addition.
amine, (R)-1-phenylethylamine, and (S)-1-phenylethyl-
Table 1 Enantioselective Addition of 4-Chlorobenzaldehyde
amine in the presence of tetrabutyl ammonium iodide
(TBAI) and diisopropyl ethylamine (DIPEA) gave the
O
OH
L*
Et
substitution products in diastereomeric ratios (dr) of 92:8,
92:8, 94:6, and 94:6, respectively. In an effort to improve
the stereoselectivity, we also examined a series of substi-
tution reactions of (R)-pantolactone-derived α-bromo-α-
phenyl acetate 2.5 Nucleophilic substitutions of 2 were
conducted under the same reaction conditions as those
used for α-bromo ester 1. Much higher stereoselectivities
were observed with dibenzylamine, (R)-1-phenylethyl-
amine, and (S)-1-phenylethylamine to produce 3a, 3c, and
3d in a diasteromeric ratio of 99:1 in 92–66% yields as
shown in Scheme 1. Meanwhile, no substantial difference
in stereoselectivity was found in the reaction with benzyl-
methylamine to afford 3b (91:9 dr). The subsequent re-
duction of 3a and 3b using an excess of PhMgBr in THF
furnished the expected β-dialkylamino alcohols 4a and
4b. Enantiopure chiral catalyst (S)-4a was easily isolated
in 72% yields by flash column chromatography, and enan-
tiopure (S)-4b was obtained in 31% yield by recrystalliza-
tion. Chiral HPLC analysis of catalysts 4a,b confirmed
that no racemization had taken place in the reaction with
excess PhMgBr. The N-methylation of 3c and 3d with
methyl iodide was efficiently carried out in DMF using
triethylamine as the base. Subsequent treatment with ex-
cess PhMgBr completed the synthesis of enantiopure chi-
ral catalysts (R,S)-4c and (S,S)-4d in 34% and 41% overall
yields.6
4-ClC6H4
H
2Zn
4-ClC6H4
Entrya
Solvent
Catalyst
(mol%)
Temp
Conv.
(%)b
ee
(%)c,d
1
2
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
toluene
4a (5)
4b (5)
4c (5)
4d (5)
4d (5)
4d (5)
4d (5)
4d (5)
4d (3)
4d (2)
4d (1)
4d (5)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0 °C
13
98
6
92
32
96
94
96
26
94
93
89
86
94
3
20
4
100
100
100
27
5
6
n-hexane
THF
7
8
Et2O
100
90
9
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
10
11
12
93
92
36
a Reactions run for 5 h.
b Conversion (%) was determined by 1H NMR analysis of the reaction
mixture.
c Determined by CSP-HPLC (Chiralcel OJ-H).
d Absolute configuration (R) assigned by comparison with known elu-
tion order reported in the literature.2
Chiral catalysts 4a–d were initially tested in the enantio-
selective addition of diethylzinc to 4-chlorobenzaldehyde
as shown in Table 1. Reactions were performed with two
equivalents of diethylzinc and 5 mol% of the catalyst in t-
BuOMe at room temperature for five hours. When 4-chlo-
robenzaldehyde was added to the mixture of diethylzinc
and N,N-dibenzyl-substituted chiral catalyst 4a, 1-(4-
chlorophenyl)-1-propanol was obtained with an enantio-
meric excess (ee) of 6% and low conversion after five
hours7 (Table 1, entry 1). In contrast, the reaction of chiral
catalyst 4b having N-benzyl and N-methyl groups showed
promising results, in which the aldehyde was completely
consumed after five hours with a much higher enantio-
meric excess of 92% (Table 1, entry2). It is speculated,
based on previous studies of β-amino alcohol–ethylzinc
complexes,2,8 that the success of chiral catalyst 4b might
rely on the steric difference between the N-methyl and N-
benzyl groups. When more sterically demanding N-1-
phenylethyl-substituted chiral catalysts 4c and 4d were
subjected to the same reaction conditions, the additional
stereogenic center of the N-1-phenylethyl substituents had
a remarkable effect on the enantioselectivity (Table 1, en-
tries 3 and 4). It was found that N-(S)-1-phenylethyl-sub-
stituted catalyst 4d was more effective to give the R
To obtain optimal conditions for the reaction of N-methyl-
N-(S)-1-phenylethyl-substituted catalyst 4d, we examined
experimental parameters such as solvent, molar ratio of
the catalyst, and reaction temperature as shown in entries
5–12 (Table 1). Among the solvents examined, n-hexane
was found to give the same enantioselectivity as t-BuOMe
for chiral catalyst 4d, and the reaction in THF gave the
lowest enantioselectivity (26% ee) with 5 mol% catalyst
loading (Table 1, entries 6 and 7). Decreasing the catalyst
loading to 3 mol% was not satisfactory and gave a slightly
lower ee of 93% (Table 1, entry 9). Significant decrease in
enantioselectivity was observed in the reactions with 2
mol% and 1 mol% of 4d (Table 1, entries 10 and 11). We
found that the reaction at 0 °C took place slowly with a
slightly abated enantioselectivity (Table 1, entry 12).
Thus, the use of two equivalents of diethylzinc in t-
BuOMe at room temperature with 5 mol% catalyst load-
ing was taken as the optimal conditions for the addition
with 4d.
With the identification of chiral catalyst 4d as an effective
catalyst for the stereoselective addition of diethylzinc to
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 630–634

632
S. Y. Kang et al.
LETTER
4-chlorobenzaldehyde, the substrate scope of the enan- Given the high levels of enantioselectivity attained in the
tioselective reaction was examined as shown in Table 2. asymmetric addition of diethylzinc to various aldehydes
The reactions of 4-bromobenzaldehyde, 4-fluorobenzal- with chiral catalyst 4d, we examined whether racemic fla-
dehyde, 4-cyanobenzaldehyde, 4-trifluoromethylbenzal- vene-3-carbaldehydes 5a–h bearing an additional chiral
dehyde, and 4-methylbenzaldehyde provided the center at the 2-position might be good substrates for kinet-
corresponding (R)-propanols with almost the same enan- ic resolution (Table 3). To the best of our knowledge,
tioselectivity as the reaction with 4-chlorobenzaldehyde there is no successful example of kinetic resolution of ra-
(Table 2, entries 1–5). However, the reaction of 4-meth- cemic aldehydes by addition with dialkylzinc.9 The fla-
oxybenzaldehyde resulted in the decreased enantioselec- vene (2-phenyl-2H-chromene) structural core is a
tivity of 80% ee (Table 2, entry 6). Among the reactions of widespread element in natural flavonoids, and the devel-
2- or 3-substituted benzaldehydes, high stereoselectivities opment of asymmetric synthetic strategies for highly
were observed in the reactions with 2-methoxy-, 3-meth- functionalized flavenes is of considerable interest.10,11 Ef-
oxy-, and 3-bromobenzaldehydes, whereas mild drops in ficient kinetic resolution in the addition to flavene-3-carb-
stereoselectivity were seen with 2-bromobenzaldehyde, aldehydes can allow both the unconverted aldehydes 5
3-methylbenzaldehyde, 1-naphthaldehyde, and 2-naph- and flavenyl alcohols 6 and 7 to be obtained in highly en-
thaldehyde (Table 2, entries 7–13). Also, lower enantiose- antioenriched forms.
lectivities of 80% ee and 79% ee were observed in the
reactions of both cinnamaldehyde and α-methylcinnamal-
When racemic flavene-3-carbaldehyde 5a was treated
with diethylzinc and chiral catalyst 4d for three hours, the
dehyde (Table 2, entries 14 and 15). Curiously, a much
addition proceeded in 51% conversion to provide a diaste-
lower enantioselectivity was observed in the reaction with
reomeric mixture (79:21 dr) of 3-flavenyl-substituted pro-
panols 6a and 7a with 93% ee and 95% ee, respectively.
benzaldehyde (Table 2, entry 16).
Kinetic resolution in the asymmetric addition favoring
(S)-5a proceeded with a selectivity factor (s) of 5, where
Table 2 Reactions of Various Aldehydes with Chiral Catalyst 4d
OH
ligand 4d (5 mol%)
Et2Zn, t-BuOMe, r.t.
the unreacted (R)-flavene-3-carbaldehyde 5a was recov-
ered with 52% ee as shown in Table 3 (entry 1).11,12 Based
on the R-configuration of the recovered aldehyde and the
assumption that the re-face of flavene-3-carbaldehyde is
preferentially attacked to form the (R)-propanol, the abso-
lute configurations of the major enantiomers of 6a and 7a
are provisionally assigned as (2S,1′R) and (2R,1′R), re-
spectively.13
O
R
R
H
Entrya
R
Conv. (%)b
ee (%)c,d
1
2
4-BrC6H4
4-FC6H4
92
100
100
89
52
80
70
95
81
99
53
84
90
95
72
40
94
90
94
93
91
80
91
95
92
86
88
85
87
80
79
55
3
4-NCC6H4
4-F3CC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
3-MeOC6H4
3-BrC6H4
2-BrC6H4
3-MeC6H4
1-Naph
We then probed the influence of the substituent on the fla-
vene scaffold. When the kinetic resolution of flavenes 5b–
d having different 2-aryl groups was explored using chiral
catalyst 4d, similar results to those of the reaction of 5a
were obtained with selectivities of 4–6 (Table 3, entries 2–
4). The high enantioselectivity and relatively low diaste-
reoselectivity indicates that the stereocontrol is mainly
governed by the chirality of the catalyst and that the ste-
reogenic center at the 2-position of the flavene scaffold
plays only a minor role in the reactions of 5a–d.14 In addi-
tion, the same experimental procedure was applied to the
kinetic resolution of flavenes 5e–h having 4-chloro sub-
stituent. The reaction of 5e for three hours showed 46%
conversion with chiral catalyst 4d and produced a diaste-
reomeric mixture (98:2 dr) of 6e and 7e with 72% ee and
83% ee, respectively (Table 3, entry 5). The analogous re-
actions of 4-chloro-substituted flavene carbaldehydes 5f–
h gave similar results as shown in entries 6–8 (Table 3), in
which higher diastereoselectivity was obtained, but with
lower enantioselectivity in comparison with the reactions
of 5a–d. Notably high efficiency in kinetic resolution was
obtained with 4-chloro substituted flavenes 5e–h, afford-
ing selectivity values ranging from 12 to 9.15 Limited re-
sults indicate that the 4-chloro substituent exerts some
impact on the stereoselectivity, and the substrate-con-
trolled addition is more operative in the reactions of 5e–h,
4
5
6
7
8
9
10
11
12
13
14
15
16
2-Naph
(E)-PhCH=CH
(E)-PhCH=C(Me)
Ph
a Reactions run for 5 h.
b Conversion (%) was determined by 1H NMR analysis of the reaction
mixture.
c Determined by CSP-HPLC (Chiralcel OB-H or OJ-H).
d Absolute configuration (R) assigned by comparison with known elu-
tion order reported in the literature.2
Synlett 2013, 24, 630–634
© Georg Thieme Verlag Stuttgart · New York

LETTER
New N,N-Dialkyl-2-amino-1,1,2-triphenylethanol Catalysts
633
Table 3 Kinetic Resolution of Flavene-3-carbaldehydes 5a–h
X
OH
X
X
OH
Ar
(1'R)
(1'R)
CHO
Ar
ligand 4d (5 mol%)
Et2Zn, t-BuOMe
O
O
Ar
O
(2R)
7a–h
(2S)
racemate
5a–h
6a–h
Entrya
1
Aldehyde
Conv. (%)b
ee (%) of recovered (R)-5c Selectivity factor sd dr of 6/7b
ee (%)c
5a Ar = Ph, X = H
51
61
54
40
46
64
46
47
52
63
48
40
60
95
61
61
5
4
79:21
77:23
72:28
84:16
98:2
6a 93
7a 95
2
3
4
5
6
7
8
5b Ar = 4′-MeOC6H4, X = H
5c Ar = 2′-MeOC6H4, X = H
5d Ar = 4′-ClC6H4, X = H
5e Ar = Ph, X = Cl
6b 94
7b 96
4
6c 96
7c 97
6
6d 89
7d 89
9
6e 72
7e 83
5f Ar = 4′-MeOC6H4, X = Cl
5g Ar = 2′-MeOC6H4, X = Cl
5h Ar = 4′-ClC6H4, X = Cl
12
12
11
95:5
6f 75
7f 76
98:2
6g 87
7g 74
97:3
6h 79
7h 99
a Reactions run for 3 h at r.t. with 2 equiv of diethylzinc.
b Conversion (%) was determined by direct 1H NMR analysis of the crude mixture.
c The ee values were determined by CSP-HPLC.
d Selectivity (s) values represent an average of at least two experiments, while conversion and ee are for specific cases.
detailed experimental procedures and characterization data (NMR
contrary to the strong catalyst-controlled enantiodifferen-
tiation observed in the reactions of 5a–d.
spectra and HPLC chromatogram).SnoIufproi
m
tgioSratnnugIifo
maoirt
r
pt
In summary, we have reported a novel synthetic method
for N,N-dialkyl 2-amino-1,1,2-triphenyl ethanol catalysts
and developed a new efficient chiral catalyst 4d for the ad-
ditions of diethylzinc to aldehydes. In addition, we pre-
sented the first example of catalytic kinetic resolution of
racemic aldehydes in the reaction with dialkylzinc. The
interesting kinetic resolution affords densely functional-
ized flavene derivatives that can be transformed into more
complex molecules. Further investigation of the extension
of the kinetic resolution to various racemic aldehydes and
its application to the syntheses of biologically interesting
molecules is under way.
References and Notes
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Acknowledgment
This work was supported by Seoul R&BD Program (WR090671)
and Basic Science Research Program through the National Re-
search Foundation of Korea (NRF) funded by the Ministry of Edu-
cation, Science and Technology (2012R1A1A2004794).
Supporting Information for this article is available online at
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 630–634

634
S. Y. Kang et al.
LETTER
anhyd MgSO4, filtered, and concentrated in vacuo.
Chromatographic separation on silica gel (eluent hexane–
EtOAc) afforded the enantioenriched ethanols, and the
enantioselectivity of the products was measured by HPLC
with chiral columns using racemic material as a standard
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To a solution of 1:1 diastereomeric mixture of 2-bromo-2-
phenylacetic acid (R)-pantolactone ester 2 in dry CH2Cl2
(0.1 M) at r.t. was added (S)-1-phenylethylamine (1.2 equiv),
TBAI (1.0 equiv), and DIPEA (1.0 equiv). After the
resulting reaction mixture was stirred at r.t. for 12 h, the
solvent was evaporated, and the crude material was purified
by column chromatography on silica gel to give 3d in 71%
yield with 99:1 dr. To a solution of 3d in DMF at r.t., MeI
(2.0 equiv) and DIPEA (1.2 equiv) were added slowly. The
resulting reaction mixture was stirred at r.t. for 24 h. After
the mixture was concentrated, the crude product was
dissolved in anhyd THF. To the solution of the product was
added a solution of PhMgBr (4.0 equiv). The reaction was
then allowed to proceed at r.t. for 24 h. The reaction was
quenched by the addition of 1 M aq HCl and extracted with
EtOAc. The combined organic extracts were dried with
anhyd MgSO4, filtered, and concentrated in vacuo.
Chromatographic separation on silica gel afforded the chiral
catalyst 4d with 41% yield. 1H NMR (400 MHz, CDCl3):
δ = 7.25–6.87 (m, 20 H), 5.68 (s, 1 H), 4.98 (s, 1 H), 3.49 (q,
J = 6.8 Hz, 1 H), 1.88 (s, 3 H), 1.15 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.7, 146.1, 142.6, 138.4,
131.0, 128.2, 128.1, 127.9, 127.5, 127.3, 127.0, 126.8,
126.4, 126.3, 125.4, 125.3, 79.1, 74.0, 59.8, 35.3, 15.5.
HRMS: m/z calcd for C29H30NO [M+ + 1]: 408.2327; found:
408.2329..
(9) For reviews on kinetic resolution of racemic aldehydes in
oxidation and Horner–Wadsworth–Emmons reactions, see:
(a) Minato, D.; Nagasue, Y.; Demizu, Y.; Onomura, O.
Angew. Chem. Int. Ed. 2008, 47, 9458. (b) Pedersen, T. M.;
Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.; Bodmann,
K.; Reiser, O. Org. Lett. 2000, 2, 535.
(10) (a) Magar, D. R.; Chen, K. Tetrahedron 2012, 68, 5810.
(b) Das, B. C.; Mohapatra, S.; Campbell, P. D.; Nayak, S.;
Mahalingam, S. M.; Evans, T. Tetrahedron Lett. 2010, 51,
2567. (c) Lee, M. H.; Choi, E. T.; Kim, D.; Lee, Y. M.; Park,
Y. S. Eur. J. Org. Chem. 2008, 5630. (d) Konoike, T.;
Matsumura, K.-i.; Yorifuji, T.; Shinomoto, S.; Ide, Y.; Ohya,
T. J. Org. Chem. 2002, 67, 7741. (e) Hardouin, C.; Burgaud,
L.; Valleix, A.; Doris, E. Tetrahedron Lett. 2003, 44, 435.
(11) The absolute configuration of 5a was assigned by
comparison of CSP-HPLC retention time with the reported
value in the following references: (a) Sundén, H.; Ibrahem,
I.; Zhao, G.-L.; Eriksson, L.; Córdova, A. Chem. Eur. J.
2007, 13, 574. (b) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.;
Jiang, W.; Wei, S.; Wang, W. Chem. Commun. 2007, 507.
(c) Govender, T.; Hojabri, L.; Moghaddam, F. M.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2006, 17, 1763.
(12) The selectivity factor (s) was estimated using the equation,
s = kS/kR = ln[(1 – C)(1 – ee)]/ln[(1 – C)(1 + ee)], where ee is
the enantiomeric excess of unconverted aldehyde 5 and the
conversion (C) determined by 1H NMR of reaction mixture.
(13) The absolute configuration at the 2-position of major
enantiomers of 6a and 7a was confirmed by the reaction of
highly enantioenriched (R)-5a with diethylzinc.
(7) General Procedure for the Addition of Diethylzinc to
Aldehydes
Diethylzinc (1.0 M in toluene, 2.0 equiv) was added to a
solution of chiral catalyst (0.05 equiv) and aldehyde (1.0
equiv) in t-BuOMe at 0 °C. The homogeneous solution was
stirred at r.t. for 5 h (3 h for kinetic resolution). The reaction
was quenched by addition of 1 M aq HCl and extracted with
CHCl3. The combined organic extracts were dried with
(14) Vedejs, E.; Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974.
(15) The use of commercially available (S)-2-piperidino-1,1,2-
triphenylethanol for the kinetic resolution of flavenes 5e–h
gave selectivity values ranging from 4 to 6.
Synlett 2013, 24, 630–634
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