Asymmetric α-allylation of α-branched aldehydes with allyl alcohols by synergistic catalysis using an achiral palladium complex and a chiral primary amino acid

Article abstract of DOI:10.1055/s-0033-1340901

Highly enantioselective direct α-allylation of α-branched aldehydes with simple allyl alcohols was achieved by the combined use of an achiral transition-metal catalysis with a palladium complex and a chiral organocatalysis with a readily obtainable primary α-amino acid. Various α-allylated aldehydes possessing a stereocontrolled quaternary carbon stereogenic center were synthesized in high yields with high enantioselectivity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340901

SPECIAL TOPIC
▌1367
sApesciyalmtopmic etric α-Allylation of α-Branched Aldehydes with Allyl Alcohols by
Synergistic Catalysis Using an Achiral Palladium Complex and a Chiral
Primary Amino Acid
Asymmetric α-Allylation of α-Branched Aldehydes
Masanori Yoshida,*a,b Erika Masaki,b Tatsuaki Terumine,b Shoji Haraa,b
a
Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University, Kita 13-jo Nishi 8, Kita-ku, Sapporo,
Hokkaido 060-8628, Japan
b
Molecular Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Kita 13-jo Nishi
8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
Fax +81(11)7066557; E-mail: myoshida@eng.hokudai.ac.jp
Received: 26.12.2013; Accepted after revision: 12.02.2014
papers; however, it is still a challenge to achieve α-al-
Abstract: Highly enantioselective direct α-allylation of α-branched
lylation of α-branched aldehydes by asymmetric catalysis
aldehydes with simple allyl alcohols was achieved by the combined
for the construction of a quaternary carbon stereogenic
use of an achiral transition-metal catalysis with a palladium com-
plex and a chiral organocatalysis with a readily obtainable primary
center with high enantioselectivity.6,7
α-amino acid. Various α-allylated aldehydes possessing a stereo-
controlled quaternary carbon stereogenic center were synthesized in
transition-metal catalysis has attracted the attention of
high yields with high enantioselectivity.
In recent years, the combined use of organocatalysis and
synthetic organic chemists, since the synergistic catalysis
Key words: aldehydes, allylation, amino acids, asymmetric cataly-
enables a bond-forming reaction to proceed easily by ac-
sis, palladium
tivating both an electrophile and a nucleophile.8 By the
synergistic use of organocatalysis and transition-metal ca-
talysis for allylation reactions, Córdova’s group achieved
In the synthesis of complex organic molecules, such as
direct α-allylation of aldehydes using a multicatalyst sys-
natural organic compounds and pharmaceuticals, the ste-
tem consisting of a palladium complex and a secondary
reoselective construction of a quaternary carbon stereo-
amine, but the substrate scope did not extend to α-
genic center is frequently required to obtain the intended
structure. Although asymmetric carbon–carbon bond for-
mation at a tertiary carbon atom is a straightforward pro-
branched aldehydes.9a As for the direct asymmetric α-al-
lylation of α-branched aldehydes, the groups of List9b,c
and Carreira9d successfully carried out the reaction by
cedure to obtain a quaternary carbon atom, steric
synergistic catalysis using a palladium complex and a chi-
repulsion between the reactants often makes it difficult
ral Brønsted acid with an amine (List) or by synergistic
when the reactants have insufficient reactivity. Therefore,
catalysis using an iridium complex and a cinchona alka-
various approaches have been attempted to enhance the
loid derived primary amine (Carreira). It is notable that
reactivity of reactants in the formation of a carbon–carbon
both of the reactions can be carried out using simple allyl
alcohols directly for the generation of the π-allyl–palladi-
um complexes without transformation into reactive allyl
bond proceeding at a tertiary carbon atom.1,2 We recently
achieved the highly enantioselective construction of a
quaternary carbon stereogenic center by organocatalytic
compounds, such as allyl esters. Very recently, we also re-
asymmetric Michael addition of α-branched aldehydes to
ported that using the catalyst combination of an achiral
palladium complex and a chiral primary amino acid was
effective for the direct asymmetric α-allylation of α-
branched aldehydes; however, allyl esters, which produce
nitroalkenes using L-phenylalanine lithium salt as the cat-
alyst for the activation of the aldehydes by formation of an
enamine intermediate.3,4
Among various carbon–carbon bond forming reactions, a stoichiometric amount of acid as a waste byproduct,
allylation reaction using a reactive π-allyl–palladium were used to generate π-allyl–palladium complexes in our
complex, which is generated from a palladium(0) catalyst method.9e,10
and an allyl compound, is known as the Tsuji–Trost al-
lylation reaction and it is a widely used method in organic
In our continued efforts to achieve asymmetric α-al-
lylation of α-branched aldehydes, we found that the reac-
synthesis, since the reaction generally proceeds under
tion can be carried out with simple allyl alcohols under
mild reaction conditions to give allylated products in high
very mild reaction conditions. By using a synergistic cat-
alyst system consisting of O-(tert-butyldimethylsilyl)-L-
threonine (1a) and Pd(PPh3)4 (2a), the allylation reaction
of 2-phenylpropanal (3a) with allyl alcohol (4a) proceed-
yields.5–7 An asymmetric version of this reaction was
achieved using palladium catalysts with chiral phosphine
ligands, and it has been documented in detail in previous
ed smoothly in toluene at room temperature to give al-
SYNTHESIS 2014, 46, 1367–1373
Advanced online publication: 17.03.2014
DOI: 10.1055/s-0033-1340901; Art ID: SS-2013-C0838-OP
© Georg Thieme Verlag Stuttgart · New York
lylated product (R)-5a in high yield with high
enantioselectivity (Scheme 1). Encouraged by this result,
we carried out the optimization of the reaction conditions
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1368
M. Yoshida et al.
SPECIAL TOPIC
using aldehyde 3a and allyl alcohol (4a) as model sub- moserine 1k were then employed in the allylation reac-
strates.
tion,11,12 and we found O-TBS-L-threonine 1a gave a
promising result in terms of enantioselectivity (see also
Scheme 1). With these results in mind, we synthesized
more sterically hindered primary amino acids such as O-
TBS-3-hydroxy-D-valine 1l and its analogue 1m from L-
serine for the allylation reaction. Fortunately, we found
that catalyst 1l drastically improved the enantioselectivity
of the reaction without decreasing the chemical yield of
5a. Thus, catalyst 1l was chosen as the amino acid catalyst
for further investigations.
CO2H
NH2
TBSO
CHO
CHO
1a (20 mol%)
OH
+
Ph
3a
Ph
Pd(PPh3)4 (2a; 5 mol%)
toluene
4a
(2.5 equiv)
(R)-5a
25 °C, 24 h
82%, 79% ee
Scheme 1 Allylation reaction of an α-branched aldehyde with allyl
alcohol in the presence of a primary amino acid and palladium com-
plex combined catalyst
Table 2 Screening of Amino Acid Catalysts 1 for the Allylation Re-
action of 3a with 4aa
Entry Amino acid catalyst 1
Yieldb (%) of 5a eec (%)
A brief solvent screen indicated that only aromatic sol-
vents, such as benzene and toluene, are suitable for the al-
lylation reaction, since other solvents, such as methanol,
dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile,
tetrahydrofuran, and haloalkanes, resulted in low conver-
sion and/or low enantioselectivity (Table 1). Thus, tolu-
ene was chosen as the solvent for further investigations.
CO2H
NH2
1
2
1b
1c
50
45
28
46
CO2H
NH2
Table 1 Solvent Screen for the Allylation Reaction of 3a with 4a in
the Presence of 1a and 2aa
CO2H
NH2
3
4
1d
1e
86
64
78
51
Entry
Solvent
Yieldb (%)
eec (%)
CO2H
NH2
1
2
3
4
5
6
7
8
9
MeOH
MeCN
DMSO
DMF
82
45
–
trace
trace
trace
44
–
CO2H
NH2
CO2H
5
1f
44
7
–
THF
50
66
–
6
7
8
1g
1h
1i
28
81
82
7
N
H
CH2Cl2
CHCl3
benzene
toluene
8
trace
74
CO2H
NH2
TBSO
70
70
81
79
CO2H
NH2
82
TBDPSO
a Reaction conditions: 1a (0.1 mmol), 2a (0.025 mmol), 3a (0.5
mmol), 4a (1.25 mmol), solvent (1 mL), 25 °C, 24 h, argon atmo-
sphere.
CO2H
NH2
b Isolated yield of 5a based on 3a.
TBDPSO
TBDPSO
9
1j
78
70
c Determined by chiral HPLC analysis.
77d
95d
92d
We then carried out a catalyst screen of amino acids for
the allylation reaction of 3a with 4a (Table 2). An exami-
nation of the use of common primary α-amino acids 1b–f
indicated that the enantioselectivity of the allylation reac-
tion is strongly affected by the bulkiness of the side chain
of amino acids, and relatively sterically hindered amino
acids give better enantioselectivities. As was the case with
the enamine-based organocatalysis of α-branched alde-
hydes with an amino acid salt catalyst in our previous
works,4 a secondary amine catalyst, L-proline 1g, could
not promote the present allylation reaction efficiently, and
a large amount of the starting material 3a was recovered.
O-Silylated L-serines 1h,i, L-threonines 1a,j, and D-β-ho-
10
11
12
1k
1l
76
84
87
H2N
CO2H
CO2H
NH2
CO2H
NH2
TBSO
TBSO
1m
a Reaction conditions: 1 (0.1 mmol), 2a (0.025 mmol), 3a (0.5 mmol),
4a (1.25 mmol), toluene (1 mL), 25 °C, 24 h, under argon.
b Isolated yield of 5a based on 3a.
c Determined by chiral HPLC analysis.
d (S)-Enantiomer.
Synthesis 2014, 46, 1367–1373
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Asymmetric α-Allylation of α-Branched Aldehydes
1369
Next we carried out a screening of palladium catalysts and Under the optimized reaction conditions, we investigated
their ligands for the allylation reaction of 3a with 4a in the the substrate scope of the allylation reaction with various
presence of amino acid catalyst 1l (Table 3). The use of α-branched aldehydes (Table 4). Allylation reactions with
palladium(II) acetate (2b) with triphenylphosphine gave a a 2-arylpropanal possessing an electron-donating group
result similar to that of 2a, and the amount of triphe- (methyl) or an electron-withdrawing group (chloro) in the
nylphosphine could be reduced to three equivalents for para- or meta-position of the aromatic ring were complet-
palladium(II) acetate (2b) without reducing enantioselec- ed within 24–72 hours to give allylated products in good
tivity (entries 1–4). It was found that bidentate ligands yields with high enantioselectivity, although no reaction
such as 1,3-bis(diphenylphosphino)propane (dppp) and was observed from that with ortho-substituted substrates
1,4-bis(diphenylphosphino)butane (dppb) did not pro- (entries 2–7). Likewise, 2-(4-fluorophenyl)propanal (3h)
mote the allylation reaction efficiently, while 1,2-bis(di- and 2-(naphthalen-2-yl)propanal (3i) provided the corre-
phenylphosphino)ethane (dppe) gave allylated product 5a sponding allylated products 5h and 5i, respectively, in
in a good yield (entries 5–7). Although 1,1′-bis(diphe- good yields with high enantioselectivity (entries 8 and 9).
nylphosphino)ferrocene (dppf) was also found to be a The allylation reaction with a hetero aromatic substrate, 2-
good ligand for the promotion of the allylation reaction, it (thiophen-2-yl)propanal (3j), gave the desired allylated
resulted in a slightly lower enantioselectivity than that of product 5j in good yield, though the enantioselectivity
triphenylphosphine (entry 8). Since both racemic and chi- was moderate (entry 10). 2-Phenylbutanal (3k) was also
ral forms of BINAP gave the same enantiomer of allylated found to be a good substrate giving allylated product 5k
product 5a with very similar enantiomeric excess, we with high enantioselectivity; however, the reaction was
found that the stereocontrol of the present allylation reac- very slow (entry 11). The present allylation reaction can
tion greatly depends on the chirality of an amino acid cat- be applied to the reaction with a substituted allyl alcohol,
alyst (entries 9–11). In addition, it was confirmed that trans-cinnamyl alcohol (4b), and (E)-2-methyl-2,5-diphe-
both an amino acid catalyst and a palladium catalyst are nylpent-4-enal (6) was obtained in high yield with good
required to promote the allylation reaction (entries 12 and enantioselectivity (entry 12). In this reaction, no genera-
13).
tion of regio- and geometric isomers was observed. Un-
fortunately, the allylation reaction with an α,α-dialkyl-
substituted aldehyde, 2-cyclohexylpropanal (3l), resulted
in no reaction, in contrast to the successful results ob-
tained from that with α-arylpropanal (entry 13).
Table 3 Screening of Palladium Catalyst 2 for the Allylation Reac-
tion of 3a with 4a in the Presence of 1la
Entry Pd catalyst 2
Ligand (mol%)
Yieldb (%) eec (%)
In conclusion, we have found that asymmetric α-allylation
of α-branched aldehydes with simple allyl alcohols can be
carried out by the synergistic use of an achiral palladium
complex, Pd(OAc)2–PPh3, and a chiral primary amino
acid, O-TBS-3-hydroxy D-valine, which was synthesized
from L-serine. The allylation reaction proceeded smoothly
under mild reaction conditions to give various α-allylated
aldehydes possessing a stereocontrolled quaternary car-
bon stereogenic center in high yields with high enantiose-
lectivity. Further investigations of the present allylation
reaction including mechanistic studies and substrate
scope expansion with ketones are under way in our group.
1
2
Pd(PPh3)4 (2a)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
Pd(OAc)2 (2b)
none
none
84
84
83
85
74
n.r.
18
84
52
52
69
11
n.r.
95
95
95
94
94
–
Ph3P (20)
Ph3P (15)
Ph3P (12)
dppe (10)
dppp (10)
dppb (10)
dppf (10)
3
4
5
6
7
94
93
94
93
95
–
8
9
(±)-BINAP (10)
(S)-BINAP (10)
(R)-BINAP (10)
Ph3P (15)
none
Amino acids 1b–g are commercially available. O-Silylated L-ser-
ines 1h,i,11 L-threonines 1a,j,11 and D-β-homoserine 1k12 were syn-
thesized according to the literature. 3-(tert-Butyldimethylsiloxy)-D-
valine (1l) and O-(tert-butyldimethylsilyl)-3,3-diethyl-D-serine
(1m) were synthesized from L-serine. Palladium catalysts 2 and
phosphine ligands were purchased and used without purification.
Aldehyde 3a is commercially available. Other aldehydes 3b–l were
prepared according to the literature.13 Allyl alcohols 4 are commer-
cially available. Aldehydes 3, allyl alcohols 4, and solvents were
used after distillation. IR spectra were recorded using a Jasco
FT/IR-410 spectrophotometer. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Jeol JNM-A400II, JNM-
ECX400P, or JNM-ECS400 FT NMR; chemical shifts, δ are refer-
enced to TMS (CDCl3 and CD3OD). EI and ESI HRMS were mea-
sured on a Jeol JMS-T100GCv or a Thermo Exactive spectrometer.
Specific rotation was measured by a Horiba SEPA-500 polarimeter.
10
11
12d
13e
–
a Reaction conditions: 1a (0.1 mmol), 2 (0.025 mmol), 3a (0.5 mmol),
4a (1.25 mmol), ligand, toluene (1 mL), 25 °C, 24 h, under argon.
b Isolated yield of 5a based on 3a; n.r. = no reaction.
c Determined by chiral HPLC analysis.
d The reaction was carried out in the absence of 1l.
e The reaction was carried out in the absence of 2 and a ligand.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1367–1373

1370
M. Yoshida et al.
SPECIAL TOPIC
Table 4 Substrate Scope
R1
CHO
1l
OH
CHO
R1 R2
R3
+
R3
R2
Pd(OAc)2 (2b), Ph3P
toluene
3
4a
5
Entry
3
R1
R2
Ph
R3
Time (h)
Product
Yieldb (%)
eec (%)
1
2
3a
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
Ph
H
24
72
24
–
5a
5b
5c
–
83
76
95
94
95
–
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-FC6H4
2-naphthyl
2-thienyl
Ph
3
89
4
n.r.
90
5
72
72
–
5e
5f
–
95
96
–
6
90
7
3g
3h
3i
n.r.
83
8
24
24
72
72
72
–
5h
5i
5j
5k
6
95
94
72
95
85
–
9
88
10
11
12e
13
3j
77
3k
3a
3l
32d
91
Me
Me
Ph
Cy
–
n.r.
a Reaction conditions: 1l (0.1 mmol), 2a (0.025 mmol), Ph3P (0.075 mmol), 3 (0.5 mmol), 4a (1.25 mmol), toluene (1 mL), 25 °C, under argon.
b Isolated yield of 5 based on 3; n.r. = no reaction
c Determined by chiral HPLC analysis.
d Conversion: 71%
e trans-Cinnamyl alcohol (4b, 1.25 mmol) was used instead of 4a.
Melting points are measured with a Yanagimoto micro melting
point apparatus and are uncorrected. HPLC was carried out using a
Jasco PU-2089 Plus intelligent pump and a UV-2075 Plus UV de-
tector.
2-Methyl-2-(4-methylphenyl)pent-4-enal (5b)9b,e
Oil; yield: 71.5 mg (76%); Rf = 0.69 (n-hexane–Et2O, 4:1); [α]589
+80.4 (c 1.0, CHCl3, 94% ee).
1H NMR (400 MHz, CDCl3): δ = 1.42 (s, 3 H), 2.34 (s, 3 H), 2.58–
2.71 (m, 2 H), 5.01–5.08 (m, 2 H), 5.50–5.60 (m, 1 H), 7.13–7.14
(m, 2 H), 7.19–7.21 (m, 2 H), 9.50 (s, 1 H).
22.5
(S)-2-Methyl-2-phenylpent-4-enal (5a); Typical Procedure
In a 7-mL vial, 2-phenylpropanal (3a, 67 mg, 0.5 mmol) and allyl
alcohol (4a, 72.5 mg, 1.25 mmol) were successively added to a mix-
ture of Pd(OAc)2 (2b, 5.6 mg, 0.025 mmol), Ph3P (19.7 mg, 0.075
mmol), 3-(tert-butyldimethylsiloxy)-D-valine (1l, 24.7 mg, 0.1
mmol), and toluene (1 mL). Then the atmosphere in the vial was re-
placed with argon, and the mixture was stirred for 24 h at 25 °C. The
resulting mixture was filtered through a small plug of silica gel
(Et2O; 3 × 2 mL) and concentrated under reduced pressure. (S)-2-
Methyl-2-phenylpent-4-enal (5a) was isolated by column chroma-
tography (silica gel, hexane–Et2O, 19:1) as a clear oil; yield: 72.2
mg (83%); 95% ee (chiral HPLC analysis); the absolute configura-
tion was determined by comparison of the specific rotation with that
in the literature;9b,c,e Rf = 0.69 (n-hexane–Et2O, 4:1); [α]58919.6 +79.8
(c 1.0, CHCl3, 95% ee).
13C NMR (100 MHz, CDCl3): δ = 18.8, 20.9, 40.5, 53.2, 118.5,
127.1, 129.6, 133.3, 136.3, 137.1, 202.0.
2-Methyl-2-(3-methylphenyl)pent-4-enal (5c)9b,e
Oil; yield: 83.7 mg (89%); Rf = 0.69 (n-hexane–Et2O, 4:1); [α]589
+78.7 (c 1.0, CHCl3, 95% ee).
1H NMR (400 MHz, CDCl3): δ = 1.43 (s, 3 H), 2.36 (s, 3 H), 2.59–
2.72 (m, 2 H), 5.02–5.09 (m, 2 H), 5.50–5.61 (m, 1 H), 7.05–7.12
(m, 3 H), 7.28–7.30 (m, 1 H), 9.50 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.8, 21.6, 40.5, 53.5, 118.5,
124.1, 127.9, 128.1, 128.7, 133.3, 138.5, 139.3, 202.0.
23.2
2-(4-Chlorophenyl)-2-methylpent-4-enal (5e)9c,e
Oil; yield: 93.6 mg (90%); Rf = 0.66 (n-hexane–Et2O, 4:1); [α]589
+74.6 (c 1.0, CHCl3, 95% ee).
1H NMR (400 MHz, CDCl3): δ = 1.43 (s, 3 H), 2.58–2.69 (m, 2 H),
5.03–5.08 (m, 2 H), 5.46–5.57 (m, 1 H), 7.17–7.19 (m, 2 H), 7.34–
7.37 (m, 2 H), 9.49 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.8, 40.6, 53.3, 119.0, 128.6,
129.0, 132.7, 133.4, 137.9, 201.4.
23.4
1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 3 H), 2.60–2.72 (m, 2 H),
5.01–5.08 (m, 2 H), 5.49–5.60 (m, 1 H), 7.24–7.31 (m, 3 H), 7.37–
7.41 (m, 2 H), 9.52 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.7, 40.5, 53.5, 118.5, 127.0,
127.2, 128.7, 133.1, 139.3, 201.7.
Spectroscopic data of 5 are in agreement with those in the litera-
ture.9b,c,e
Synthesis 2014, 46, 1367–1373
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Asymmetric α-Allylation of α-Branched Aldehydes
1371
2-(3-Chlorophenyl)-2-methylpent-4-enal (5f)9e
Oil; yield: 93.6 mg (90%); Rf = 0.66 (n-hexane–Et2O, 4:1); [α]589
+66.1 (c 1.0, CHCl3, 96% ee).
1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 3 H), 2.58–2.70 (m, 2 H),
5.04–5.10 (m, 2 H), 5.47–5.58 (m, 1 H), 7.11–7.14 (m, 1 H), 7.24–
7.34 (m, 3 H), 9.51 (s, 1 H).
bath was then removed, and the mixture was stirred for 4 h at r.t.
The resulting mixture was washed with Et2O (2 × 50 mL) and acid-
ified to pH 2 with aq 3 M HCl. The obtained solution was extracted
with EtOAc (1 × 100 mL and 3 × 50 mL). The combined organic
phase was washed with brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was dissolved in MeOH
(150 mL), and SOCl2 (8.5 mL, 117 mmol) was then added dropwise
to the solution at 0 °C under an N2 atmosphere. The mixture was
stirred for 10 min at 0 °C, the ice-water bath was then removed, and
the mixture was stirred overnight at r.t. The resulting solution was
then concentrated under reduced pressure, dissolved in Et2O (150
mL), washed with cold sat. NaHCO3, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The obtained crude material
was purified by column chromatography (silica gel, hexane–
EtOAc, 1:1 to 1:3) to give the product (16.8 g, 66 mmol, 66%, 2
steps).
23.5
13C NMR (100 MHz, CDCl3): δ = 18.8, 40.6, 53.6, 119.1, 125.5,
127.4, 127.6, 130.0, 132.6, 134.9, 141.6, 201.2.
2-(4-Fluorophenyl)-2-methylpent-4-enal (5h)9e
Oil; yield: 79.7 mg (83%); Rf = 0.69 (n-hexane–Et2O, 4:1); [α]589
+76.1 (c 1.0, CHCl3, 95% ee).
1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 3 H), 2.58–2.70 (m, 2 H),
5.03–5.08 (m, 2 H), 5.48–5.58 (m, 1 H), 7.05–7.09 (m, 2 H), 7.21–
7.25 (m, 2 H), 9.49 (s, 1 H).
19.9
13C NMR (100 MHz, CDCl3): δ = 20.3, 42.1, 54.5, 117.1 (d, J = 21.7
Hz), 120.2, 130.3 (d, J = 7.9 Hz), 134.3, 136.5 (d, J = 3.0 Hz), 163.4
(d, J = 246.3 Hz), 203.0.
(S)-2-(Benzyloxycarbonylamino)-3-methylbutane-1,3-diol
In a 3-necked round-bottomed flask equipped with a condenser, Mg
(6.5 g, 266 mmol) was dried under an N2 atmosphere, and anhyd
Et2O (60 mL) was then added to the reaction vessel. A solution of
MeI (16.6 mL, 266 mmol) in anhyd Et2O (75 mL) was added drop-
wise so as to maintain reflux, and the mixture was stirred for 1 h at
r.t. The mixture was then cooled to 0 °C with an ice-water bath, and
a solution of N-(benzyloxycarbonyl)-L-serine methyl ester (10.8 g,
43 mmol) anhyd Et2O (50 mL) was added slowly over 2 h. The ice-
water bath was removed, and the mixture was stirred for 1.5 h at r.t.
Sat. NH4Cl (100 mL) was added slowly to the mixture at 0 °C, and
the resulting mixture was extracted with EtOAc (3 × 150 mL). The
combined organic phases were washed with brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The obtained
crude material was purified by column chromatography (silica gel,
hexane–EtOAc, 1:1 to EtOAc only) to give the product (6.33 g, 25
mmol, 59%).
2-Methyl-2-(naphthalen-2-yl)pent-4-enal (5i)9b,e
Oil; yield: 98.6 mg (88%); Rf = 0.69 (n-hexane–Et2O, 4:1); [α]589
20.1
+120.5 (c 1.0, CHCl3, 94% ee).
1H NMR (400 MHz, CDCl3): δ = 1.56 (s, 3 H), 2.70–2.85 (m, 2 H),
5.02–5.11 (m, 2 H), 5.52–5.62 (m, 1 H), 7.36–7.38 (m, 1 H), 7.48–
7.52 (m, 2 H), 7.71–7.72 (m, 1 H), 7.83–7.87 (m, 3 H), 9.59 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.9, 40.5, 53.8, 118.7, 125.0,
126.26, 126.28, 126.4, 127.5, 128.0, 128.6, 132.4, 133.1, 133.4,
136.8, 202.0.
2-Methyl-2-(thiophen-2-yl)pent-4-enal (5j)9b,e
Oil; yield: 69.3 mg (77%); Rf = 0.71 (n-hexane–Et2O, 4:1); [α]589
20.1
+21.0 (c 1.0, CHCl3, 72% ee).
1H NMR (400 MHz, CDCl3): δ = 1.51 (s, 3 H), 2.69 (d , J = 7.2 Hz,
2 H), 5.09–5.16 (m, 2 H), 5.60–5.71 (m, 1 H), 6.92 (dd, J = 1.2, 3.6
Hz, 1 H), 7.04 (dd, J = 3.6, 5.2 Hz, 1 H), 7.31 (dd, J = 1.2, 5.2 Hz,
1 H), 9.49 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 19.9, 41.4, 52.1, 119.2, 125.2,
125.4, 127.4, 132.5, 144.1, 199.6.
N-(Benzyloxycarbonyl)-3-hydroxy-D-valine
To a solution of (S)-2-(benzyloxycarbonylamino)-3-methylbutane-
1,3-diol (6.33 g, 25 mmol) in MeCN (50 mL), phosphate buffer (pH
6.5, 50 mL), and TEMPO (0.67 g, 4.3 mmol) were added at r.t. The
mixture was warmed to 35 °C, NaClO2 solution [prepared from
NaClO2 (1.8 g, 20 mmol), H2O (40 mL), and phosphate buffer (pH
6.5, 20 mL)] and NaClO solution [prepared from aq NaClO solution
(5%, 13 mL), H2O (20 mL), and phosphate buffer (pH 6.5, 13 mL)]
were added to the mixture at the same time with stirring over 1 h.
The mixture was stirred for a further 4 h at 35 °C, and then, the re-
sulting solution was acidified to pH 2 with 3 M HCl at 0 °C. The ob-
tained mixture was extracted with EtOAc (1 × 200 mL and 4 × 100
mL). The combined organic phases were concentrated under re-
duced pressure, dissolved in cold sat. NaHCO3, and washed with
EtOAc (2 × 100 mL). The resulting aqueous solution was acidified
to pH 2 with H3PO4 at 0 °C, saturated with NaCl, and extracted with
EtOAc (4 × 100 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated under reduced pressure to give
the product (5.76 g, 21.6 mmol, 86%).
2-Ethyl-2-phenylpent-4-enal (5k)9e
Oil; yield: 30.1 mg (32%); Rf = 0.69 (n-hexane–Et2O, 4:1); [α]589
19.4
+48.6 (c 0.745, CHCl3, 95% ee).
1H NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 7.3 Hz, 3 H), 1.96–2.06
(m, 2 H), 2.66–2.79 (m, 2 H), 5.03–5.12 (m, 2 H), 5.49–5.60 (m, 1
H), 7.23–7.42 (m, 5 H), 9.52 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.9, 24.5, 36.1, 57.4, 118.3, 127.3,
127.6, 128.7, 132.9, 138.4, 202.4.
2-Methyl-2,5-diphenylpent-4-enal (6)9b,e
Oil; yield: 113.8 mg (91%); Rf = 0.58 (n-hexane–Et2O, 4:1);
[α]58920.0 +102.3 (c 1.0, CHCl3, 85% ee).
1H NMR (400 MHz, CDCl3): δ = 1.50 (s, 3 H), 2.76–2.87 (m, 2 H),
5.94 (dt, J = 7.5, 15.9 Hz, 1 H), 6.41 (d, J = 15.9 Hz, 1 H), 7.17–7.34
(m, 8 H), 7.39–7.44 (m, 2 H), 9.58 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.9, 39.9, 54.1, 124.9, 126.1,
127.17, 127.24, 127.4, 128.5, 128.9, 133.6, 137.2, 139.4, 202.0.
N-(Benzyloxycarbonyl)-3-hydroxy-D-valine Benzyl Ester
To a solution N-(benzyloxycarbonyl)-3-hydroxy-D-valine (5.73 g,
21.4 mmol) in DMF (80 mL), K2CO3 (5.92 g, 42.8 mmol), KI (0.36
g, 2.1 mmol), and BnBr (2.55 mL, 21.4 mmol) were added at 0 °C,
and the mixture was stirred for 1 h at the same temperature. The
mixture was stirred overnight at r.t., and the resulting solution was
poured into H2O (200 mL) and extracted with a mixture of hexane–
EtOAc (1:1, 3 × 100 mL). The combined organic phases were
washed with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. The obtained crude material was purified by col-
umn chromatography (silica gel, hexane–EtOAc, 4:1 to 2:1) to give
the product (5.26 g, 14.7 mmol, 69%).
Synthesis of 3-(tert-Butyldimethylsiloxy)-D-valine (1l)9e and O-
(tert-Butyldimethylsilyl)-3,3-diethyl-D-serine (1m)
N-(Benzyloxycarbonyl)-L-serine Methyl Ester
To a slurry of L-serine (10.5 g, 100 mmol) in H2O (100 mL),
NaHCO3 (21.0 g, 250 mmol), and THF (50 mL) were added succes-
sively at 0 °C with cooling of the reaction vessel in an ice-water
bath. The mixture was stirred for 30 min, benzyl chloroformate
(15.5 mL, 110 mmol) was added dropwise at 0 °C. The ice-water
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1367–1373

1372
M. Yoshida et al.
SPECIAL TOPIC
N-(Benzyloxycarbonyl)-3-(tert-butyldimethylsiloxy)-D-valine
Benzyl Ester (Protected 1l)
IR (KBr): 1637 cm–1 (C=O).
1H NMR (400 MHz, CD3OD): δ = 0.19 (s, 6 H), 0.92 (s, 9 H), 0.98
(t, J = 7.4 Hz, 3 H), 1.01 (t, J = 7.5 Hz, 3 H), 1.64–1.78 (m, 2 H),
1.90–2.01 (m, 2 H), 3.58 (s, 1 H).
13C NMR (100 MHz, CD3OD): δ = –1.7, –1.6, 8.4, 9.4, 19.6, 26.7,
30.5, 30.7, 61.6, 80.6, 171.2.
HRMS (ESI): m/z [M + H]+ calcd for C13H30NO3Si: 276.1990;
found: 276.1988.
To a solution of N-(benzyloxycarbonyl)-3-hydroxy-D-valine benzyl
ester (5.26 g, 14.7 mmol) in anhyd CH2Cl2 (10 mL), 2,6-lutidine
(3.44 mL, 29.6 mmol) and TBSOTf (6.8 mL, 29.6 mmol) were add-
ed at 0 °C under an N2 atmosphere. The mixture was stirred for 5
min at 0 °C, then for a further 2.5 h at r.t. The resulting solution was
poured into aq NH4Cl (15%, 30 mL), saturated with NaCl, and ex-
tracted with Et2O (1 × 50 mL, 2 × 25 mL). The combined organic
phases were washed with brine, dried (MgSO4), filtered, and con-
centrated under reduced pressure. The obtained crude material was
purified by column chromatography (silica gel, hexane–EtOAc–
CH2Cl2, 8:1:2) to give protected 1l (6.69 g, 14.2 mmol, 97%) as oil;
with 99% ee [HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH, 98:2,
Acknowledgment
This work was supported in part by a Grant-in Aid for Scientific Re-
search on Innovative Areas ‘Advanced Molecular Transformations
by Organocatalysts’ from MEXT, Japan (KAKENHI No.
24105501) and MEXT, Japan, program ‘Strategic Molecular and
Materials Chemistry through Innovative Coupling Reactions’ of
Hokkaido University.
21.7
1.0 mL/min, 254 nm): tR = 11.6 (major), 9.2 min (minor)]; [α]589
+3.8 (c 1.0, CHCl3).
IR (neat): 1731 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 3 H), 0.06 (s, 3 H), 0.81
(s, 9 H), 1.29 (s, 3 H), 1.34 (s, 3 H), 4.22 (d, J = 9.8 Hz, 1 H), 5.10–
5.20 (m, 4 H), 5.53 (d, J = 9.8 Hz, 1 H), 7.34–7.36 (m, 10 H).
13C NMR (100 MHz, CDCl3): δ = –2.43, –2.38, 17.9, 25.6, 27.6,
27.9, 63.3, 66.86, 66.88, 74.9, 127.9, 128.0, 128.3, 128.4, 128.5,
135.2, 136.3, 156.2, 170.1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (ESI): m/z [M + Na]+ calcd for C26H37NNaO5Si: 494.2333;
found: 494.2336.
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In a round-bottomed flask, N-(benzyloxycarbonyl)-3-(tert-butyldi-
methylsiloxy)-D-valine benzyl ester (6.69 g, 14.2 mmol) was added
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IR (neat): 1731, 1744 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 3 H), 0.10 (s, 3 H), 0.85–
0.91 (m, 15 H), 1.54–1.69 (m, 4 H), 4.40 (d, J = 10.0 Hz, 1 H), 5.07–
5.24 (m, 4 H), 5.51 (d, J = 10.0 Hz, 1 H), 7.34–7.36 (m, 10 H).
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28.8, 29.1, 59.9, 66.8, 66.9, 80.9, 127.9, 128.0, 128.3, 128.4,
128.46, 128.49, 135.3, 136.5, 156.3, 170.5.
HRMS (ESI): m/z [M + Na]+ calcd for C28H41NNaO5Si: 522.2646;
found: 522.2646.
O-(tert-Butyldimethylsilyl)-3,3-diethyl-D-serine (1m)
White solid; mp 181–182 °C; [α]58921.8 +2.9 (c 0.5, MeOH).
Synthesis 2014, 46, 1367–1373
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Asymmetric α-Allylation of α-Branched Aldehydes
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1367–1373