Dual enantioselective control using D-phenylglycine-L-proline-derived catalysts for the enantioselective addition of diethylzinc to aldehyde

Full text of DOI:10.1002/bkcs.10621

Note
DOI: 10.1002/bkcs.10621
BULLETIN OF THE
S. Y. Kang and Y. S. Park
KOREAN CHEMICAL SOCIETY
Dual Enantioselective Control using D-phenylglycine-L-proline-derived
Catalysts for the Enantioselective Addition of Diethylzinc to Aldehyde
*
Seock Yong Kang and Yong Sun Park
Department of Chemistry, Konkuk University, Seoul 143-701, Korea. *E-mail: parkyong@konkuk.ac.kr
Received June 15, 2015, Accepted September 24, 2015, Published online December 21, 2015
Keywords: Asymmetric synthesis, Dipeptide, Chiral catalyst, Dual stereoselectivity, Dialkylzinc
Dipeptide-derived catalysts are of great interest in various
asymmetric transformations because of their short and simple
preparation and easy modification of their modular structure
by using different α-amino acids.1 However, the methodolo-
gies using catalysts derived from naturally occurring L-amino
acids are often limited by the need for the preparation of both
enantiomers of the desired product. This problem has recently
been overcome by structural modification of the nonchiral
components of the catalysts.2 The dual enantioselective con-
trol using catalysts derived from a single enantiomeric precur-
sordeserves further attention asithas thepotential toopennew
avenues in asymmetric synthesis. Herein, we report the devel-
opment of novel catalysts derived from D-phenylglycine-L-
proline (D-Phg-L-Pro) dipeptide and the achievement of dual
stereocontrol in the addition of diethylzinc to aldehydes.
Werecently reportedthefirstexampleofdipeptide-catalyzed
enantioselective addition of dialkylzinc to aldehydes. N,N-
dibenzyl substituted D-Phg-L-Pro dipeptide derivatives 1 and
2 depicted in Figure 1 had been identified as effective catalysts
for the addition of dimethylzinc (Me2Zn) and diethylzinc
(Et2Zn), respectively.3 Encouraged by these results, we have
tested the efficiency of catalyst 1 for the ethylation of
p-bromobenzaldehyde with diethylzinc (Et2Zn) as shown in
Table 1. The ethylation was initially conducted at room temper-
ature in toluene in the presence of 0.1 equiv of catalyst and
3.0 equiv of diethylzinc. The transformations catalyzed by
1proceededtoyield(S)-1-(p-bromophenyl)propanolwithgood
conversionandanenantiomericratio(er)of21:79(entry1).The
observed enantioselectivity is much lower than the previously
reported er of 5:95 with catalyst 2 (entry 2).
Pro dipeptide analog 3 in 85% yield with >99:1 diastereomeric
ratio (dr). When 3 was used as a catalyst for the addition of
diethylzinc under the same conditions, dipeptide derivative
3 failed to induce a noticeable enantioselectivity (entry 3).
Next, the methoxycarbonyl group of 3 was converted to a
diphenyl hydroxymethyl group. Treatment of 3 with PhMgBr
inTHF providedproticalcohol 4 whichwastested asa catalyst
for the addition of Et2Zn to aldehydes. We are surprised to
observe that the reaction using catalyst 4 gave 1-(p-bromophe-
nyl)propanol (5) with a significantly enhanced enantioselec-
tivity of 84:16 er in favor of the (R)-enantiomer (entry 4).
However, a substantial amount of benzyl alcohol 6 was pro-
duced as the byproduct (Table 1, entries 1–4).5 The diphenyl
substituted hydroxymethyl moiety clearly affected the enan-
tioselectivity of the product when the original source of chiral-
ity was kept unchanged. The development of synthetic
methodologiestopreparebothenantiomersusingasinglechiral
source of D-Phg-L-Pro dipeptide would be highly desirable.6
The solvent played an important role in the enantioselectiv-
ity of the process when using catalyst 4. In n-hexane, the reac-
tion showed a much higher chemoselectivity (5:6 = 92:8)
with a slightly reduced enantioselectivity of 82:18 er (entry
5). The use of diethylether significantly decreased the chemos-
electivity, whereas methyl tert-butyl ether (MTBE) gave a
moderate chemoselectivity with an improved enantioselectiv-
ity of 89:11 er (entries 6–7). To our delight, lowering the tem-
ꢀ
perature to −10 C increased the enantioselectivity up to 96:4
er, whereas a slightly decreased enantioselectivity was
ꢀ
observed when the reaction was performed at −20 C. More-
over, optimization of the temperature significantly improved
the chemoselectivity to 95:5 (5:6), minimizing the undesired
reduction to benzyl alcohol (entry 9). Therefore, the reaction
conditions of entry 9 were chosen as the optimal conditions for
the following studies.
In order to investigate the effect of N-terminal amino acid on
the enantioselectivity, four different AA-L-Pro dipeptide-
derived catalysts 7–10 were tested as shown in Table 2. When
D-Phgofcatalyst4wasreplacedbyL-Phg,asignificantlylower
er was observed (entry 1). Interestingly, when Gly-L-Pro cata-
lyst 8 was examined, no stereoselectivity was observed (entry
2). The above results indicated that an appropriate matching
of the two chiral centers is required to achieve high enantios-
electivity. In order to further examine the synergic effect of
thetwochiralcentersofthedipeptide, catalysts9and10derived
In our efforts to improve asymmetric induction in the ethy-
lation with catalyst 1, we attempted to modify the catalytic
properties of dipeptide catalyst 1 by introducing different
N-alkyl and C-terminal functional groups. At the outset, in
order to modify the coordinating ability of the amino group,
we replaced the bulky N,N-dibenzylamino moiety with a
piperidyl group. As shown in Scheme 1, dipeptide derivative
3 was easily prepared according to the synthetic methodology
previously developed by our group for asymmetric synthesis
of dipeptide analogs.4
Treatment of the diastereomeric mixture (ca. 50:50) of
N-(α-bromo-α-phenylacetyl)-L-proline methyl ester with
piperidine in the presence of diisopropylethylamine (DIEA)
and tetrabutylammonium iodide (TBAI) afforded D-Phg-L-
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KOREAN CHEMICAL SOCIETY
Figure 1. D-Phg-L-Pro dipeptide-derived catalysts for the additionof
dialkylzinc.
Table 1. Dipeptide-derived catalysts for asymmetric addition of
diethylzinc to 4-bromophenylaldehyde.
Scheme 1. Preparation of D-Phg-L-Pro dipeptide-derived catalysts.
substituted benzaldehydes, high enantioselectivities were
obtained with 3-bromobenzaldehyde, 3-chlorobenzaldehyde,
3,4-dichlorobenzaldehyde, and 2-naphthaldehyde, whereas a
noticeable dropinerwasobservedwithelectron-rich 3-methyl
substituted benzaldehyde (entry 10). Moreover, the reactions
of 1-naphthaldehyde and 2-bromobenzaldehyde showed
decreased er values compared with the reactions using 2-
naphthaldehyde and 3-bromobenzaldehyde (entries 13–14).
Theseresultsindicatethat theenantioselectivityofthereaction
with 4 greatly depends on the nature and position of the sub-
stituents on the aromatic ring.
Inordertogainsomeinsight intothemechanismoftheaddi-
tion, we performed nonlinear effect studies for the addition of
diethylzinc to 4-bromobenzaldehyde with catalyst 4. When
catalyst 4 is used, no asymmetric amplification or depletion
is observed. The linear correlation between the ee of the prod-
uct and the ee of catalyst 4 indicates that dimeric species con-
taining two units of the dipeptide catalyst are not involved.7
Based on the observed results, we propose a fused tetracyclic
transition state structure shown in Figure 2.8
Conversion
(%)a
Erb,c
(R:S)
Entry Catalyst Conditions
5:6
1
2
3
4
5
1
2
3
4
4
Toluene, rt, 18 h
Toluene, rt, 18 h
Toluene, rt, 18 h
Toluene, rt, 10 h
n-hexane, rt,
92
93
90
99
99
76:24 21:79
99:1 5:95
85:15 49:51
76:24 84:16
92:8 82:18
10 h
6
7
8
4
4
4
Ether, rt, 10 h
MTBE, rt, 10 h
MTBE, 0 C,
96
99
90
61:39 83:17
83:17 89:11
86:14 90:10
ꢀ
10 h
ꢀ
9
4
MTBE, −10 C,
84
95:5 96:4
10 h
Determined by 1H NMR analysis of the reaction mixture.
Determined by CSP-HPLC (Chiralcel OB-H).
Absolute configuration assigned by comparison with known elution
order.
a
b
c
We havedeveloped a novel D-Phg-L-Pro dipeptide-derived
catalyst (4) for the addition of diethylzinc to aromatic alde-
hydes. We also disclosed an effective chiral switching by sim-
ply modifying nonchiral part of D-Phg-L-Pro dipeptide. In
contrast to the ethylation with catalysts 1 and 2, the use of cat-
alyst 4 led to the formation of products with opposite config-
uration with up to 98:2 er. Further investigations are in
progress to elucidate the mechanism of dual asymmetric
induction and to explore the potential application of the
dipeptide-derived catalysts to other transformations.
from D-Ala and L-Ala, respectively, were prepared and applied
in the addition of diethylzinc to p-bromobenzaldehyde. In reac-
tions with both alanine-derived catalysts, despite the opposite
chirality of alanine, (R)-enantiomer was obtained as major
product with slightly different enantioselectivities (entries
3 and 4). These findings suggest thatthe anionicformofthe cat-
alyst could bind the zinc atom in a fashion which brings
them into closer proximity to the R1 substituent.7 Next, we
examinedthe effect ofthe R2 substituentsofthe hydroxymethyl
group of the catalyst on the stereoselectivity of the reaction.
When catalysts 11–13 with three different aryl substituents
were employed under the same conditions, lower enantioselec-
tivities were observed (entries 5–7).
With the optimal conditions in hand, catalyst 4 was then
used in the asymmetric addition of diethylzinc to other aro-
matic aldehydes (Table 3). Excellent enantioselectivities
(>90:10 er) were observed for various 4-substituted benzalde-
hydes, except for the electron-rich 4-methoxy substituted
benzaldehyde (entries 1–7). The reactions with 3- or 2-
substituted benzaldehydes were also tested under the same
conditions (entries 8–14). Among the reactions of 3-
Experimental
General Procedure for the Preparation of Chiral Catalysts
N-[(R)-α-Phenyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydro-
xyldiphenylmethyl)pyrrolidine (4). To a solution of diaster-
eomeric mixture of N-(α-bromo-α-phenylacetyl)-L-proline
alkyl ester in dry CH2Cl2 (0.1 M) at room temperature was
added piperidine (1.2 equiv), TBAI (1.0 equiv), and DIEA
(1.0 equiv). The resulting reaction mixture was stirred at room
temperature for 12 h. The solvent in mixture was evaporated
and the crude product was purified by column chromatography
on silica gel to give 3. To a solution of 3 in THF (0.5 M) was
Bull. Korean Chem. Soc. 2016, Vol. 37, 108–111
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KOREAN CHEMICAL SOCIETY
Table 2. Effects of R1 and R2 substituents of catalysts.
Entrya
R1 (AA)
R2
Catalyst
Conversionb (%)
5:6
Erc (R:S)
1
2
3
4
5
6
7
a
(S)-Ph (L-Phg)
H (Gly)
Ph
Ph
Ph
Ph
7
8
9
10
11
12
13
92
63
91
90
95
89
92
97:3
70:30
94:6
92:8
95:5
95:5
96:4
41:59
51:49
89:11
70:30
93:7
(R)-CH3(D-Ala)
(S)-CH3(L-Ala)
(R)-Ph (D-Phg)
(R)-Ph (D-Phg)
(R)-Ph (D-Phg)
4-Cl-Ph
4-t-Bu-Ph
3,5-(CH3)2-Ph
83:17
94:6
Reactions run for 10 h in t-BuOMe.
b
c
Determined by 1H NMR analysis of the reaction mixture.
Determined by CSP-HPLC (Chiralcel OB-H).
Table 3. Reactions with aromatic aldehydes.
Figure 2. Proposed transition state structure for the addition of
diethylzinc with catalyst 4.
Entrya,b
Ar
Conversionc (%)
Erd (R:S)e
The combined organic extracts were dried with anhydrous
MgSO4, filtered and concentrated in vacuo. Chromatographic
separation on silica gel afforded 4 with >99:1 dr in 78% yield.
1H NMR (CDCl3, 400 MHz) 7.42–7.22 (m, 15H), 7.07 (s,
1H), 5.06 (t, J = 7.2 Hz, 1H), 3.91 (s, 1H), 3.65–3.59 (m,
1H), 3.20–3.13 (m, 1H), 2.18 (br, 4H), 1.88–1.82 (m, 2H),
1.53–1.33 (m, 7H), 1.04–0.98 (m, 1H); 13C NMR (CDCl3,
100 MHz) 173.7, 146.3, 143.4, 135.5, 129.4, 128.6, 128.4,
128.2, 127.9, 127.6, 127.5, 127.2, 126.8, 81.5, 74.7, 68.1,
52.5, 48.2, 29.7, 25.8, 24.4, 23.4.
1
2
3
4
5
6
7
8
4-Cl-Ph
4-I-Ph
4-F-Ph
4-CN-Ph
4-NO2-Ph
4-CF3-Ph
4-MeO-Ph
3-Br-Ph
93
90
91
98
99
97
54
99
95
88
87
88
82
82
95:5
91:9
90:10
96:4
95:5
90:10
74:26
97:3
9
3-Cl-Ph
94:6
10
11
12
13
14
a
3-Me-Ph
3,4-dichloro-Ph
2-Naph
1-Naph
2-Br-Ph
85:15
90:10
98:2
92:8
83:17
N-[(S)-α-Phenyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydroxy-
diphenylmethyl)pyrrolidine (7). The solution of N-Boc-L-
phenylglycine in CH2Cl2 was treated with L-proline methyl
ester (1.0 equiv), DCC (N,N0-Dicyclohexylcarbodiimide,
1.0 equiv), and DMAP (4-Dimethylaminopyridine, 0.1
equiv). The mixture was stirred for 1 h as a white precipitate
formed. The mixture was filtered, concentrated and chromato-
graphed to afford N-Boc-L-Phg-L-Pro-OMe. To a solution of
the dipeptide in CH2Cl2 was added TFA (20% v/v,
TFA/CH2Cl2). The mixture was stirred for 1 h before it was
concentrated and re-dissolved in CH2Cl2. The solution was
washed with saturated NaHCO3 solution, dried over MgSO4,
filtered and concentrated. For N,N-dialkylation, the unpurified
dipeptide was dissolved in DMF and diisopropylethyl amine
(5 equiv) was then added slowly. After stirring for 1 h, 1,5-
Reactions run for 10 h in t-BuOMe.
b
c
d
e
In all reactions, the chemoselectivity is >95:5.
Determined by 1H NMR analysis of the reaction mixture.
Determined by CSP-HPLC.
Absolute configuration assigned by comparison with known elution
order.3,5
ꢀ
added PhMgBr (1.0 M in THF, 3 equiv) at 0 C, and the reac-
tion mixture was stirred at room temperature for 24 h.
The reaction was quenched with saturated NH4Cl solution
and the aqueous layer was extracted with EtOAc (5 mL × 3).
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dibromopentane (3 equiv) was added and further stirred for
12 h. After quenching with water, the resulting mixture was
extracted using ethyl acetate. The combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by column chromatography
and the solution was stirred for 1 h in t-BuOMe (0.1 M of sub-
strate) at room temperature. After adding 1.0 equiv of alde-
ꢀ
hyde, the homogeneous solution was stirred at −10 C for
10 h. The reaction was quenched by addition of 1 M aqueous
HClandextracted withCHCl3. Thecombinedorganicextracts
were dried with anhydrous MgSO4, filtered and concentrated
in vacuo. Chromatographic separation on silica gel afforded
the enantioenriched propanols and the enantioselectivity of
the products were measured by HPLC with chiral column.3,5
1
on silica gel to give 7 in 56% yield. H NMR (CDCl3,
400 MHz) 7.43–6.88 (m, 15H), 6.65 (s, 1H), 5.38–5.35 (m,
1H), 4.06 (s, 1H), 3.58–3.53 (m, 1H), 2.67–2.63 (m, 1H),
2.38 (br, 4H), 2.07–2.02 (m, 1H), 1.90–1.85 (m, 1H),
1.62–1.39 (m, 7H), 0.52–0.49 (m, 1H); 13C NMR (CDCl3,
100 MHz) 174.3, 146.6, 143.1, 129.7, 128.7, 128.5, 128.2,
127.9, 127.7, 127.2, 127.1, 126.9, 125.8, 82.2, 73.8, 66.1,
53.0, 47.9, 28.7, 25.8, 24.5, 23.1.
Acknowledgments. This work was supported by Basic Sci-
ence Research Program through the National Research Foun-
dation of Korea (NRF) funded by the Ministry of Education
(2012R1A1A2004794 and 2014R1A1A2057279).
N-[(R)-α-Methyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydroxy-
diphenylmethyl)pyrrolidine (9). The same procedure as for
1
References
7 was followed with D-alanine to afford 9 in 45% yield. H
NMR (CDCl3, 400 MHz) 7.45–7.24 (m, 10H), 6.98 (s, 1H),
5.16–5.12 (m, 1H), 3.52–3.34 (m, 3H), 2.43–2.31 (br, 4H),
2.05–1.92 (m, 2H), 1.55–1.25 (m, 7H), 1.13 (d, J = 6.8 Hz,
3H), 0.95–0.88 (m, 1H); 13C NMR (CDCl3, 100 MHz)
175.9, 146.6, 143.5, 128.2, 127.9, 127.8, 127.7, 127.4,
127.2, 81.5, 67.6, 62.9, 50.0, 48.8, 29.6, 26.5, 24.4, 23.5, 9.97.
N-[(R)-α-Phenyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydro-
xydi(4-chlorophenyl)methyl) pyrrolidine (11). The same
procedure as for 4 was followed with p-Cl-PhMgBr to afford
11 in 49% yield. 1H NMR (CDCl3, 400 MHz) 7.40–7.23 (m,
14H), 4.93 (t, J = 7.6 Hz, 1H), 3.90 (s, 1H), 3.81–3.76 (m,
1H), 3.19–3.12 (m, 1H), 2.17–2.08 (br, 4H), 1.92–1.70 (m,
2H), 1.52–1.40 (m, 7H), 1.29–1.18 (m, 1H); 13C NMR
(CDCl3, 100 MHz) 173.7, 144.2, 141.6, 135.1, 133.4,
133.3, 129.3, 129.2, 128.9, 128.7, 128.3, 128.1, 127.9,
127.8, 80.6, 75.0, 68.7, 52.4, 48.2, 30.0, 25.8, 24.4, 23.7.
N-[(R)-α-Phenyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydro-
xydi(4-t-butylphenyl)methyl) pyrrolidine (12). The same
procedure as for 4 was followed with p-t-Bu-PhMgBr to afford
12 in 46% yield. 1H NMR (CDCl3, 400 MHz) 7.45–7.24 (m,
13H), 6.86 (s, 1H), 5.09 (t, J = 7.2 Hz, 1H), 3.93 (s, 1H),
3.63–3.57 (m, 1H), 3.13–3.07 (m, 1H), 2.24 (br, 4H),
1.88–1.84 (m, 2H), 1.55–1.27 (m, 25H), 1.09–1.01 (m, 1H);
13C NMR (CDCl3, 100 MHz) 173.6, 149.9, 143.4, 140.4,
135.6, 129.4, 129.0, 128.6, 128.2, 127.7, 127.3, 124.7, 124.2,
81.4, 74.6, 67.7, 52.5, 48.1, 34.4, 31.3, 29.6, 25.8, 24.5, 23.3.
N-[(R)-α-Phenyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydro-
xydi(3,4-dimethylphenyl)methyl) pyrrolidine (13). The
same procedure as for 4 was followed with 3,5-Me2PhMgBr
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1
to afford 13 in 56% yield. H NMR (CDCl3, 400 MHz)
7.45–6.88 (m, 11H), 5.04–5.01 (m, 1H), 3.86 (s, 1H),
3.59–3.54 (m, 1H), 3.22–3.15 (m, 1H), 2.31–2.13 (m, 16H),
1.90–1.83 (m, 2H), 1.55–1.35 (m, 7H), 1.04–1.00 (m, 1H);
13C NMR (CDCl3, 100 MHz) 173.5, 146.3, 143.4, 137.1,
136.6, 135.7, 129.3, 129.2, 128.7, 128.6, 128.2, 126.0,
125.5, 81.4, 74.5, 68.1, 52.7, 43.3, 29.8, 25.8, 24.5, 23.3, 21.6.
General Procedure for the Enantioselective Addition of
Diethylzinc to Aldehydes. Diethylzinc (1.0 M in hexanes,
3.0 equiv) was added to a solution of a catalyst (0.1 equiv)
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Bull. Korean Chem. Soc. 2016, Vol. 37, 108–111
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