N-benzyl-protection of amino acid derivatives by reductive alkylation with α-picoline-borane

Article abstract of DOI:10.1055/s-0029-1218707

A convenient method for N-protection of amino acid derivatives with a benzyl group by reductive alkylation of amino acid derivatives with α-picoline-borane is described. Amino acid esters or amino alcohols were treated with aryl aldehydes in methanol/acetic acid in the presence of -picoline-borane to give N-benzyl-protected amino acid derivatives in good yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218707

PAPER
1673
N-Benzyl-Protection of Amino Acid Derivatives by Reductive Alkylation with
a-Picoline-Borane
Yasushi Kawase,a Takehiro Yamagishi,a Teruo Kutsuma,a Tadashi Kataoka,b Kimio Ueda,c Takeo Iwakuma,c
Tadashi Nakata,d Tsutomu Yokomatsu*a
a
School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(42)6763239; E-mail: yokomatu@toyaku.ac.jp
Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan
Development Laboratory, Junsei Chemical Co., LTD, 1-6 Ohmano-cho, Koshigaya, Saitama 343-0844, Japan
b
c
d
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 19 January 2010; revised 1 March 2010
and the reaction was applied to the one-pot synthesis of
Abstract: A convenient method for N-protection of amino acid de-
alkoxyamine derivatives from various carbonyl com-
rivatives with a benzyl group by reductive alkylation of amino acid
derivatives with a-picoline-borane is described. Amino acid esters
or amino alcohols were treated with aryl aldehydes in methanol/
pounds.11 In a continuation of our studies on the applica-
tion of pic-BH3, we describe here a convenient method for
acetic acid in the presence of a-picoline-borane to give N-benzyl- N-benzyl-protection of amino acid derivatives, including
protected amino acid derivatives in good yields.
substrates such as methionine derivatives for which the
traditional methods for N-benzylation are not applicable,
by reductive alkylation using a-pic-BH3 (Equation 1).
Key words: amino acid esters, amino alcohols, benzylation, pro-
tecting groups, reductions
(O)n
(O)n
OR2
R1
R1
ArCHO
The protection of amino acids is an essential process in
their derivatization and, thus, numerous methods for their
protection with various kinds of protective groups have
been reported.1 The number of protective methods for N-
benzylation of amino acid derivatives is quite low, even
though N-benzyl-protected amino acids, especially N,N-
dibenzylamino acid derivatives, are useful chiral building
blocks for the synthesis of optically active b-amino alco-
hols.2,3 The latter compounds are widely found in biolog-
ically active compounds and natural products, as well as
being useful synthetic tools as simple N-masked amino
acids.4 For example, N-benzyl-protected amino acids have
been synthesized by direct alkylation with a benzyl halide
under basic conditions.5 This procedure, however, cannot
be applied to amino acids with a side-chain containing a
hetero-atom.2,6a Another approach is reductive alkylation
of amino acids with benzaldehyde using mild reducing
reagents such as sodium cyanoborohydride,6 pyridine–
borane (pyr-BH3),7 and others. These reagents, however,
have some problems from the viewpoint of process chem-
istry due to their toxicity or instability.8
OR2
Ar
Ar
N
NH2
N
n = 0, 1
2 = H, Me
BH3
R
(α-pic-BH3)
Equation 1
First, we examined the reaction of L-phenylalanine methyl
ester (1) with benzaldehyde using a-pic-BH3 as a model
reaction in order to optimize the conditions for N-benzyl-
protection of amino acid derivatives (Equation 2,
Table 1). A mixture of 1 and one equivalent of benzalde-
hyde was treated with one equivalent of a-pic-BH3 in a
methanol/acetic acid mixture (10:1) at room temperature
for two hours, to give N-monobenzyl-L-phenylalanine
methyl ester (3) in excellent yield (entry 1). We optimized
reaction conditions for N,N-dibenzylation by varying the
amounts of benzaldehyde and a-pic-BH3. When the reac-
tion was carried out with two equivalents of benzaldehyde
in the presence of one equivalent of a-pic-BH3, the de-
sired N,N-dibenzyl-L-phenylalanine methyl ester (2) was
produced in 53% yield, along with 3 (45% yield; entry 2).
Even when the amount of a-pic-BH3 was increased to two
equivalents, the ratio of 2 to 3 hardly changed (entry 3).
On the other hand, using three equivalents of benzalde-
hyde in the presence of 1.5 equivalents of a-pic-BH3, gave
2 in 78% yield. In this reaction, mono-benzylation product
3 was not detected (entry 4), although, benzyl alcohol was
also produced in 13% yield, along with unreacted benz-
aldehyde in 2% yield (relative to starting amounts of
benzaldehyde). These observations mean the rate-deter-
mining step in this reaction is the formation of an iminium
Picoline–borane (pic-BH3) reagents have received much
attention as more convenient alternatives for reductive
amination/alkylation, because they are non-explosive at
temperatures up to100 °C and have longer shelf-lives than
pyr-BH3.9 Kikugawa et al. reported on reductive amina-
tion of carbonyl compounds with a-picoline–borane (a-
pic-BH3).10 Recently, we also reported on a-pic-BH3-me-
diated reductive alkoxyamination of carbonyl compounds
SYNTHESIS 2010, No. 10, pp 1673–1677
x
x.
x
x
.
2
0
1
0
Advanced online publication: 24.03.2010
DOI: 10.1055/s-0029-1218707; Art ID: F01410SS
© Georg Thieme Verlag Stuttgart · New York

1674
Y. Kawase et al.
PAPER
NH2
α-pic-BH3
NBn2
COOMe
NHBn
COOMe
Ph
+ PhCHO
+
Ph
Ph
COOMe
MeOH–AcOH (10:1)
r.t.
1
2
3
Equation 2
Table 2 N,N-Protection of Amino Acid Estersa
ion in the second benzylation. In addition, the rate of re-
duction for the imine and iminium ion might be relatively
high compared to that of benzaldehyde under the applied
conditions.
Run Amine R
Ar
Product Yield
(%)
1
2
3
4
5
4
5
6
7
1
i-Bu
Ph
Ph
Ph
9
79
Table 1 Reaction of L-Phenylalanine Methyl Ester (1) and Benzal-
dehyde with a-pic-BH3
i-Pr
10
11
12
60b
91
HOCH2
Entry
PhCHO a-pic-BH3 Time
Yield of 2a Yield of 3a
(equiv)
(equiv)
(h)
(%)
(%)
MeS(CH2)2 Ph
PhCH2
77 (>99% ee)c
77
1
2
3
4
1
2
2
3
1
2
0
94
4-MeOC6H4 13
1
19
19
2
53
60
78
45
40
0
a Reaction conditions: aldehyde (3 equiv), a-pic-BH3 (1.5 equiv), r.t.
b Mono-benzylated product was isolated in a 37% yield.
c Optical purity was determined by 1H NMR analysis of a-methoxy-
a-(trifluoromethyl)phenylacetic acid (MTPA) esters of the corre-
sponding amino alcohol.
2
1.5
Under the optimized conditions, using three equivalents
of benzaldehyde and 1.5 equivalents of a-pic-BH3, other
amino acid esters were also benzylated (Equation 3); the
results are summarized in Table 2. N,N-Dibenzylation of
aliphatic amino acid esters proceeded in good yields (en-
tries 1 and 2). However, the reaction of L-valine methyl
ester (5), which is sterically congested around the amino
group, gave N-benzyl-L-valine methyl ester along with
N,N-dibenzyl-L-valine methyl ester (10; entry 2). Amino
acid esters with a side-chain containing a hetero-atom,
such as L-serine methyl ester (6) and L-methionine methyl
ester (7), could also be converted into the corresponding
N,N-dibenzylamino acid esters 11 and 12 in good yields
without racemization (entries 3 and 4). No by-products
except for mono-N-benzylation products and benzyl alco-
hol were detected for these reactions. To the best of our
knowledge, this is the first example of the synthesis of
N,N-dibenzyl methionine derivatives.2 When anisalde-
hyde was used for the reductive alkylation of 1 in place of
rived from amino acids as illustrated in Equation 4; the re-
sults are summarized in Table 3. For N,N-dibenzylation
of the amino alcohols, 2.5 equivalents of benzaldehyde
was sufficient. N,N-Diprotection products 20 and 21, with
o-substituted benzyl groups, were obtained under the
same conditions by using 2-methylbenzaldehyde and 2-
methoxybenzaldehyde, respectively (entries 4 and 5).
Doubly protected a-aminoaldehydes with o-substituted
benzyl groups have been reported to be better substrates
than the corresponding dibenzyl-protected a-aminoalde-
hydes regarding the selectivity in non-chelation addition
through the Felkin–Anh type transition state.13 For N,N-
dibenzylation of the amino alcohols, competitive forma-
tion of N,O-acetals is conceivable, if the reduction rate of
the initially formed imines is low. However, no such by-
products derived from N,O-acetals were detected for these
reactions.
benzaldehyde,
N,N-bis(4-methoxybenzyl)-protected
ArCHO
NH2
Ar
N
Ar
product 13 was produced in 77% yield (entry 5); in this
case, it is worth noting that the protecting groups can usu-
ally be readily removed by oxidative treatment.12
OH
OH
α-pic-BH3
MeOH–AcOH (10:1)
R
R
17–21
14–16
Equation 4
ArCHO
NH2
COOMe
Ar
N
Ar
α-pic-BH3
MeOH–AcOH (10:1)
The reaction conditions described here were applicable to
the g-amino alcohol derived from the b-amino acid, i.e.,
b-alaninol (22), to give N,N-dibenzyl-b-alaninol (23) in
good yield (Scheme 1).
R
R
COOMe
9–13
4–8
Equation 3
We also examined N-benzylation of the amino group in
cyclic amino acid derivatives under similar conditions.
Thus, L-proline derivatives 24 and 25 were respectively
converted into 26 and 27 using 1.5 equivalents of benzal-
dehyde and a-pic-BH3 in good yields (Scheme 1).
Optically active N,N-dibenzyl-2-amino alcohols are also
important chiral building blocks for the synthesis of opti-
cally active b-amino alcohols.2 Thus, we tried to extend
this method to N,N-dibenzylation of amino alcohols de-
Synthesis 2010, No. 10, 1673–1677 © Thieme Stuttgart · New York

PAPER
Reductive Alkylation with a-Picoline-Borane
1675
Table 3 N,N-Protection of Amino Alcohols 14–16a
with EtOAc (3 × 10 mL). The combined extract was washed with
sat. aq NaCl (3 × 10 mL) and dried over MgSO4. After removal of
MgSO4 by filtration, the filtrate was concentrated in vacuo and the
residue was purified by silica gel column chromatography (hexane–
EtOAc, 50:1→5:1) to give 2.
Run Amine
R
Ar
Ph
Ph
Product Yield
(%)
1
14
PhCH2
i-Bu
17
85
(>99% ee)b
Yield: 527 mg (78%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 2.99 (dd, J = 14.0, 8.3 Hz, 1 H),
3.12 (dd, J = 7.2, 14.0 Hz, 1 H), 3.54 (d, J = 14.0 Hz, 2 H), 3.67
(dd, J = 8.3, 7.2 Hz, 1 H), 3.73 (s, 3 H), 3.95 (d, J = 14.0 Hz, 2 H),
7.16–7.27 (m, 15 H).
MS (ESI, MeOH): m/z = 360 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C24H26NO2: 360.1694; found:
2
3
4
5
15
16
14
14
18
71
69
68
64
MeS(CH2)2 Ph
19
20
PhCH2
PhCH2
2-MeC6H4
2-MeOC6H4 21
360.1957.
a Reaction conditions: aldehyde (2.5 equiv), a-pic-BH3 (1.5 equiv),
1H NMR spectrum of 2 was identical with that reported in the liter-
r.t.
ature.14
b Optical purity was determined by 1H NMR analysis of MTPA esters
of 17.
Methyl N-Benzyl-L-phenylalaninate
Benzaldehyde (1 equiv) was used as described above to give the ti-
tle compound.
PhCHO (1.5 equiv)
Bn
Yield: 94%; colorless oil.
N
OH
H2N
OH
1H NMR (300 MHz, CDCl3): d = 2.96 (d, J = 7.0 Hz, 2 H), 3.54 (t,
J = 7.0 Hz, 1 H), 3.63 (d, J = 13.1 Hz, 1 H), 3.65 (s, 3 H), 3.81 (d,
J = 13.1 Hz, 1 H), 7.15–7.31 (m, 10 H).
α-pic-BH3 (1.5 equiv)
MeOH–AcOH (10:1)
r.t., 2 h
Bn
23
22
83%
MS (ESI, MeOH): m/z = 270 [M + H]+.
PhCHO (1.5 equiv)
HRMS-ESI: m/z [M + H]+ calcd for C17H20NO2: 270.1494; found:
270.1475.
R
R
N
N
α-pic-BH3 (1.5 equiv)
MeOH–AcOH (10:1)
r.t., 2 h
H
Bn
1H NMR spectrum was identical with that reported in the litera-
24 R = COOMe
25 R = CH2OH
26 86%
27 75%
ture.15
Scheme 1
Methyl N,N-Dibenzyl-L-leucinate (9)
Prepared from L-leucine methyl ester hydrochloride (3).
Yield: 79%; colorless oil; [a]D20 –104.81 (c 0.82, CHCl3).
IR (neat): 1733 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.59 (d, J = 0.64 Hz, 3 H), 0.81 (d,
J = 6.6 Hz, 3 H), 1.43–1.54 (m, 1 H), 1.64–1.79 (m, 2 H), 3.39 (dd,
J = 8.6, 6.0 Hz, 1 H), 3.50 (d, J = 13.8 Hz, 2 H), 3.75 (s, 3 H), 3.91
(d, J = 13.8 Hz, 2 H), 7.21–7.37 (m, 10 H).
In conclusion, because of its simplicity, the safety features
of a-pic-BH3, and its applicability to various kinds of ami-
no acid derivatives, we believe that the method presented
in this paper will contribute to N-benzyl-protection of
amino acid derivatives in process chemistry. Especially,
this method is effective for N-benzyl-protection of sub-
strates having a side-chain containing a heteroatom, such
as methionine derivatives, which are difficult to protect by
traditional methods.
13C NMR (75.5 Hz, CDCl3): d = 21.5, 23.2, 24.3, 38.7, 50.9, 54.5,
58.7, 126.9, 128.2, 128.9, 139.7, 173.8.
Methyl N,N-Dibenzyl-L-valinate (10)
Prepared from L-valine methyl ester hydrochloride (5) in a manner
analogous to that of 2.
All melting points are uncorrected. IR spectra were measured di-
rectly on an NaCl plate or in KBr disks. 1H NMR spectra were mea-
sured at 300 or 400 MHz in CDCl3 using TMS as an internal
standard. 13C NMR spectra were measured at 75.5 or 100 MHz in
CDCl3. The chemical sifts of 13C NMR spectra were recorded rela-
tive to the central resonance of CDCl3 (d = 77.0 ppm). Mass spectra
were measured by electrospray ionization.
Yield: 60%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.93 (d, J = 6.5 Hz, 3 H), 1.02 (d,
J = 6.5 Hz, 3 H), 2.12–2.20 (m, 1 H), 2.87 (d, J = 10.8 Hz, 1 H),
3.28 (d, J = 14.0 Hz, 2 H), 3.78 (s, 3 H), 3.99 (d, J = 14.0 Hz, 2 H),
7.21–7.54 (m, 10 H).
MS (ESI, MeOH): m/z = 312 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C20H26NO2: 312.1964; found:
Methyl N,N-Dibenzyl-L-phenylalaninate (2); Typical Proce-
dure
To a solution of L-phenylalanine methyl ester hydrochloride (1; 406
mg, 1.88 mmol) in MeOH (2.5 mL) at 0 °C, was added Et3N (0.26
mL, 1.88 mmol), and the mixture was stirred for 10 min at the same
temperature under an N2 atmosphere. To the mixture was succes-
sively added a solution of benzaldehyde (599 mg, 2.82 mmol) in
MeOH (2.5 mL), then AcOH (0.5 mL) and a-pic-BH3 (302 mg, 2.82
mmol) at 0 °C. The mixture was stirred for 2 h at r.t. and concentrat-
ed in vacuo. The residue was treated with 10% HCl (2.5 mL) at 0 °C
and the mixture was stirred at r.t. for 30 min. The mixture was bas-
ified with 25% aq Na2CO3 (10 mL) and the whole was extracted
312.1948.
In this preparation, methyl N-benzyl-L-valinate ester was also iso-
lated in 37% yield as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.93 (d, J = 6.2 Hz, 3 H), 0.95 (d,
J = 6.6 Hz, 3 H), 1.87–1.96 (m, 1 H), 3.02 (d, J = 6.0 Hz, 1 H), 3.59
(d, J = 13.1 Hz, 1 H), 3.72 (s, 3 H), 3.83 (d, J = 13.1 Hz, 1 H), 7.22–
7.36 (m, 5 H).
MS (ESI, MeOH): m/z = 222 [M + H]+.
Synthesis 2010, No. 10, 1673–1677 © Thieme Stuttgart · New York

1676
Y. Kawase et al.
PAPER
HRMS-ESI: m/z [M + H]+ calcd for C13H20NO2: 222.1494; found:
MS (ESI, MeOH): m/z = 220 [M + H]+.
222.1480.
HRMS-ESI: m/z [M + H]+ calcd for C13H28NO2: 220.1338; found:
220.1332.
1H NMR spectra of 10 and methyl N-benzyl-L-valinate were identi-
cal with those reported in the literature.16,17
1H NMR spectrum of 26 was identical with that reported in the lit-
erature.16
Methyl N,N-Dibenzyl-L-serinate (11)
Prepared from L-serine methyl ester hydrochloride (6) in a manner
analogous to that of 2.
Yield: 91%; colorless oil; [a]D25 –121.88 (c 1.38, CHCl3).
Preparation of N,N-Dibenzylamino Alcohols from Amino Alco-
hols; Typical Procedure for the Synthesis of N,N-Dibenzyl-L-
phenylalaninol (17)
To a solution of L-phenylalaninol (14; 284 mg, 1.88 mmol) in
MeOH (2.5 mL) were successively added a solution of benzalde-
hyde (499 mg, 4.70 mmol) in MeOH (2.5 mL), then AcOH (0.5 mL)
and a-pic-BH3 (302 mg, 2.82 mmol) were added at 0 °C. The mix-
ture was stirred for 2 h at r.t. and concentrated in vacuo. The residue
was treated with 10% HCl (2.5 mL) at 0 °C and the mixture was
stirred at r.t. for 30 min. The mixture was basified with 25% aq
Na2CO3 (10 mL) and the whole was extracted with EtOAc (3 × 10
mL). The combined extracts were washed with sat. aq NaCl (3 × 15
mL) and dried over MgSO4. After removal of MgSO4 by filtration,
the filtrate was concentrated in vacuo and the residue was purified
by silica gel column chromatography (n-hexane–EtOAc,
10:1→8:1) to give 17.
IR (neat): 3228, 1732 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.57 (dd, J = 7.5, 7.5 Hz, 1 H),
3.68 (d, J = 13.4 Hz, 2 H), 3.73–3.78 (m, 2 H), 3.80 (s, 3 H), 3.91
(d, J = 13.4 Hz, 2 H), 7.24–7.38 (m, 10 H).
13C NMR (75.5 MHz, CDCl3): d = 51.4, 54.7, 59.3, 61.7, 127.4,
128.4, 128.9, 138.6, 171.7.
MS (ESI, MeOH): m/z = 300 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C18H22NO3: 300.1600; found:
300.1586.
Methyl N,N-Dibenzyl-L-methioninate (12)
Prepared from L-methionine methyl ester hydrochloride (7) in a
manner analogous to that of 2.
Yield: 77%; colorless oil; [a]D20 –99.95 (c 0.94, CHCl3).
Yield: 527 mg (85%); colorless oil; mp 71–73 °C.
1H NMR (300 MHz, CDCl3): d = 2.44 (dd, J = 12.8, 9.4 Hz, 1 H),
3.02–3.15 (m, 2 H), 3.50 (d, J = 13.3 Hz, 2 H), 3.31–3.56 (m, 2 H),
3.94 (d, J = 13.3 Hz, 2 H), 7.10–3.15 (m, 2 H).
IR (neat): 1730 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.97 (s, 3 H), 1.96–2.02 (m, 2 H),
2.36–2.45 (m, 1 H), 2.56–2.63 (m, 1 H), 3.48 (dd, J = 7.3 Hz, 1 H),
3.55 (d, J = 13.8 Hz, 2 H), 3.76 (s, 3 H), 3.89 (d, J = 13.8 Hz), 7.21–
7.35 (m, 10 H).
13C NMR (75.5 MHz, CDCl3): d = 15.4, 29.4, 31.0, 51.3, 55.0, 60.0,
127.2, 128.6, 129.0, 139.5, 173.2.
MS (ESI, MeOH): m/z = 332 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C23H26NO: 332.2014; found:
332.2021.
1H NMR spectrum of 17 was identical with that reported in the lit-
erature.18
MS (ESI, MeOH): m/z = 344 [M + H]+.
N,N-Dibenzyl-L-leucinol (18)
Prepared from L-leucinol (15) in a manner analogous to that of 17.
HRMS-ESI: m/z [M + H]+ calcd for C20H25NO2S: 344.1684; found:
344.1679.
Yield: 71%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.85 (d, J = 5.8 Hz, 3 H), 0.92 (d,
J = 5.9 Hz, 3 H), 1.13–1.19 (m, 1 H), 1.50–1.53 (m, 2 H), 2.82–
2.86 (m, 1 H), 3.36 (d, J = 13.3 Hz, 2 H), 3.37–3.51 (m, 2 H), 3.81
(d, J = 13.3 Hz, 2 H), 7.21–7.34 (m, 10 H).
MS (ESI, MeOH): m/z = 298 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C20H28NO: 298.2171; found:
Methyl N,N-Bis(4-methoxybenzyl)-L-phenylalaninate (13)
Prepared using 4-methoxybenzaldehyde instead of benzaldehyde in
a manner analogous to that of 2.
Yield: 77%; colorless oil; [a]D25 –64.24 (c 0.45, CHCl3).
IR (neat): 1730 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.97 (dd, J = 14.0, 8.4 Hz, 1 H),
3.10 (dd, J = 14.0, 7.1 Hz, 1 H), 3.43 (d, J = 13.7, 2 H), 3.64–3.69
(m, 1 H), 3.73 (s, 3 H), 3.79 (s, 6 H), 3.86 (d, J = 13.7 Hz, 2 H), 6.78
(d, J = 8.6 Hz, 4 H), 6.99–7.02 (m, 2 H), 7.06 (d, J = 8.6 Hz, 4 H),
7.21–7.24 (m, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 35.6, 51.0, 53.5, 55.2, 61.9,
113.5, 126.2, 128.1, 129.4, 129.7, 131.3, 138.2, 158.5, 172.8.
298.2149.
1H NMR spectrum of 18 was identical with that reported in the lit-
erature.19
N,N-Dibenzyl-L-methioninol (19)
Prepared from L-methioninol (16) in a manner analogous to that of
17.
MS (ESI, MeOH): m/z = 420 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C26H30NO4: 420.2175; found:
Yield: 69%; colorless oil; [a]D19 +103.96 (c 0.86, CHCl3).
IR (neat): 3432 cm–1.
420.2153.
1H NMR (400 MHz, CDCl3): d = 1.49–1.58 (m, 1 H), 1.97–2.05 (m,
1 H), 2.11 (s, 3 H), 2.40–2.52 (m, 2 H), 2.88–2.95 (m, 2 H), 3.46 (d,
J = 13.3 Hz, 2 H), 3.48–3.51 (m, 1 H), 3.80 (d, J = 13.3 Hz, 2 H),
7.22–7.31 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 15.8, 25.5, 32.0, 53.5, 58.6, 61.0,
127.4, 128.6, 129.1, 139.3.
MS (ESI, MeOH): m/z = 316 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C19H26NOS: 316.1735; found:
Methyl N-Benzyl-L-prolinate (26)
Prepared from L-proline methyl ester hydrochloride (24) using
benzaldehyde (1.5 equiv) and a-pic-BH3 in a manner analogous to
that of 17.
Yield: 86%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.76–2.00 (m, 3 H), 2.10–2.18 (m,
1 H), 2.35–2.43 (m, 1 H), 3.03–3.09 (m, 1 H), 3.25 (dd, J = 8.8,
6.2 Hz, 1 H), 3.58 (d, J = 12.7 Hz, 1 H), 3.65 (s, 3 H), 3.89 (d,
J = 12.7 Hz, 1 H), 7.23–7.34 (m, 5 H).
316.1727.
Synthesis 2010, No. 10, 1673–1677 © Thieme Stuttgart · New York

PAPER
Reductive Alkylation with a-Picoline-Borane
1677
N,N-Bis(2-methylbenzyl)-L-phenylalaninol (20)
Prepared using 3-methylbenzaldehyde instead of benzaldehyde in a
manner analogous to that of 17.
Yield: 68%; colorless oil; [a]D25 +58.22 (c 0.44, CHCl3).
References
(1) Greene, T. W.; Wutz, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J. Wiley: New York, 1999.
(2) Review on the synthesis of optically active b-amino alcohols
from N,N-dibenzylamino acid derivatives, see: Reetz, M. T.
Chem. Rev. 1999, 99, 1121.
(3) (a) Santella, J. B.; Gardner, D. S.; Yao, W.; Shi, C.; Reddy,
P.; Tebben, A. J.; DeLucca, G. V.; Wacker, D. A.; Watson,
P. S.; Welch, P. K.; Wadman, E. A.; Davies, P.; Solomon, K.
A.; Graden, D. M.; Yeleswaram, S.; Mandlekar, S.; Kariv, I.;
Decicco, C. P.; Ko, S. S.; Carter, P. H.; Duncia, J. V. Bioorg.
Med. Chem. Lett. 2008, 18, 576. (b) Andres, J. M.; Pedrosa,
R.; Perez-Encarbo, A. Tetrahedron Lett. 2006, 47, 5317.
(c) Goff, N. L. C.-L.; Audin, P.; Paris, J.; Cazes, B.
Tetrahedron Lett. 2002, 43, 6325. (d) Andres, J. M.;
Pedrosa, R.; Perez, A.; Perez-Encabo, A. Tetrahedron 2001,
57, 8521.
IR (neat): 3444 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.52 (dd, J = 13.3, 10.4 Hz, 1 H),
3.05–3.11 (m, 1 H), 3.22 (dd, J = 3.9, 13.3 Hz, 1 H), 3.33 (dd,
J = 10.6, 4.6 Hz, 1 H), 3.55 (dd, J = 10.6, 10.6 Hz, 1 H), 3.61 (d,
J = 13.1 Hz, 2 H), 3.90 (d, J = 13.1 Hz, 2 H), 7.10–7.31 (m, 13 H).
13C NMR (100 MHz, CDCl3): d = 30.9, 31.3, 51.0, 60.5, 61.1,
125.9, 126.3, 127.4, 128.0, 129.0, 130.6, 130.7, 136.5, 137.1, 139.3.
MS (ESI, MeOH): m/z = 360 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C25H30NO: 360.2327; found:
360.2315.
N,N-Bis(2-methoxybenzyl)-L-phenylalaninol (21)
Prepared using 2-methoxybenzaldehyde instead of benzaldehyde in
a manner analogous to that of 17.
(4) Chandrasekhar, S.; Venkat Reddy, M. Tetrahedron 2000,
56, 1111.
(5) (a) Tao, J.; Hu, S.; Tian, Q.; Nayyar, N.; Babu, S.
Tetrahedron: Asymmetry 2005, 16, 699. (b) Xue, C.-B.; He,
X.; Roderick, J.; Corbett, R. L.; Decicco, C. P. J. Org. Chem.
2002, 67, 865. (c) Laib, T.; Zhu, J. Tetrahedron Lett. 1999,
40, 83. (d) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons,
W. A.; Martin, V. S. J. Org. Chem. 1998, 63, 3741.
(e) Gmeiner, P.; Junge, D.; Kartner, A. J. Org. Chem. 1994,
59, 6766.
(6) (a) Gmeiner, P.; Lerche, H. Heterocycles 1990, 31, 9.
(b) Gmeiner, P. Tetrahedron Lett. 1990, 31, 5717.
(7) Khan, N. M.; Arumugam, V.; Balasubramanian, S.
Tetrahedron Lett. 1996, 37, 4819.
25
Yield: 64%; colorless crystals; mp 103–105 °C; [a]D +50.86 (c
0.47, CHCl3).
IR (neat): 3435 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.42 (dd, J = 13.1, 10.5 Hz, 1 H),
3.01–3.07 (m, 1 H), 3.18 (dd, J = 13.1, 3.5 Hz, 1 H), 3.26 (dd,
J = 10.7, 4.7 Hz, 1 H), 3.54 (dd, J = 10.7, 10.7 Hz, 1 H), 3.66 (d,
J = 13.2 Hz, 2 H), 3.81 (s, 6 H), 3.89 (d, J = 13.2 Hz, 2 H), 6.83–
6.90 (m, 4 H), 7.09–7.26 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 31.6, 48.0, 55.3, 60.7, 61.7,
110.4, 120.5, 127.4, 128.4, 128.5, 129.1, 131.2, 139.9, 158.0.
(8) Thermal stability of pyr-BH3, see: (a) Baldwin, R. A.;
Washburn, R. M. J. Org. Chem. 1961, 26, 3549. (b)Brown,
H. C.; Domash, L. J. Am. Chem. Soc. 1956, 78, 5384.
(9) Thermal stabilities of a- and g-picoline-borane were
examined. They were non-explosive at 100 °C and did not
decompose under ambient conditions over two years judging
from the HPLC analysis of the products.
MS (ESI, MeOH): m/z = 392 [M + H]+.
HRMS-ESI: m/z calcd for C25H30NO3: 392.2226; found: 392.2227.
N,N-Dibenzyl-3-aminopropanol (23)
Prepared from 3-aminopropanol (22) in a manner analogous to that
of 17.
(10) Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y.
Yield: 83%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.73–1.80 (m, 2 H), 2.65 (t,
J = 5.8 Hz, 2 H), 3.65 (t, J = 5.3 Hz, 2 H), 7.23–7.37 (m, 10 H).
Tetrahedron 2004, 60, 7899.
(11) Kawase, Y.; Yamagishi, T.; Kutsuma, T.; Ueda, K.;
Iwakuma, T.; Nakata, T.; Yokomatsu, T. Heterocycles 2009,
78, 463.
(12) N,N-Di(p-methoxy)-benzylation of a-amino acids with 4-
methoxybenzyl chloride, see: Hanessian, S.; Parthasaraphy,
S.; Mauduit, M. J. Med. Chem. 2003, 46, 34.
1H- and 13C NMR spectra was identical with that reported in the lit-
erature.20
N-Benzyl-L-prolinol (27)
(13) Anh, N. T. Top. Curr. Chem. 1980, 88, 145.
(14) Hoffman, R. V.; Tao, J. J. Org. Chem. 1997, 62, 2292.
(15) Garuer, P.; Kaniskan, U. Tetrahedron Lett. 2005, 46, 5181.
(16) Gray, D.; Concellon, C.; Gallagher, T. J. Org. Chem. 2004,
69, 4849.
(17) Ando, A.; Shioiri, T. Tetrahedron 1989, 45, 4969.
(18) Ng, J. S.; Przybyla, C. L.; Liu, C.; Yen, J. C.; Mullner, W.;
Weyker, C. L. Tetrahedron 1995, 51, 6397.
Prepared from L-prolinol (25) using benzaldehyde (1.5 equiv) and
a-pic-BH3 in a manner analogous to that of 17.
Yield: 75%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.64–1.98 (m, 4 H), 2.26–2.34 (m,
1 H), 2.71–2.77 (m, 1 H), 2.95–3.01 (m, 1 H), 3.36 (d, J = 13.0 Hz,
1 H), 3.43 (dd, J = 10.8, 2.0 Hz, 1 H), 3.67 (dd, J = 10.8, 3.4 Hz,
1 H), 3.97 (d, J = 13.0 Hz, 1 H), 7.28–7.33 (m, 5 H).
MS (ESI, MeOH): m/z = 192 [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C12H18NO: 192.1388; found:
(19) Metro, T.-X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007,
72, 6556.
(20) Almient, G. M.; Balducci, D.; Battoni, A.; Calraresi, M.;
Portzi, G. Tetrahedron: Asymmetry 2007, 18, 2695.
(21) Zhu, L.; Cheng, L.; Zhang, Y.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 2737.
192.1382.
1H NMR spectrum of 27 was identical with that reported in the lit-
erature.21
Synthesis 2010, No. 10, 1673–1677 © Thieme Stuttgart · New York