Non-enzymatic diastereoselective asymmetric desymmetrization of 2-benzylserinols giving optically active 4-benzyl-4-hydroxymethyl-2- oxazolidinones: Asymmetric syntheses of α-(hydroxymethyl)phenylalanine, N-Boc-α-methylphenylalanine, cericlamine and BIRT-377

Article abstract of DOI:10.1016/j.tet.2012.06.090

A reaction of (S)-2-benzyl-2-(α-methylbenzyl)amino-1,3-propanediol (S)-4a and 2-chloroethyl chloroformate, and the subsequent addition of DBU gave (4R,αS)-4-benzyl-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone (4R)-5a (92% de) via a diastereoselective asymmetric desymmetrization process. Debenzylation of (4R)-5a using trifluoromethanesulfonic acid and anisole in MeNO₂ gave (R)-4-benzyl-4-hydroxymethyl-2-oxazolidinone (R)-15a, which was converted into (R)-(α-hydroxymethyl)phenylalanine (7) in two steps. N-Boc-α-methylphenylalanine (8), cericlami0ne (9) and BIRT-377 (10) were also synthesized using these asymmetric desymmetrization and debenzylation.

Full text of DOI:10.1016/j.tet.2012.06.090

Tetrahedron 68 (2012) 8033e8045
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Non-enzymatic diastereoselective asymmetric desymmetrization
of 2-benzylserinols giving optically active 4-benzyl-4-hydroxymethyl-2-
oxazolidinones: asymmetric syntheses of
a-(hydroxymethyl)phenylalanine,
N-Boc- -methylphenylalanine, cericlamine and BIRT-377
a
*
*
Shigeo Sugiyama , Satoshi Arai, Keitaro Ishii
Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A reaction of (S)-2-benzyl-2-(
oformate, and the subsequent addition of DBU gave (4R,
benzyl)-2-oxazolidinone (4R)-5a (92% de) via
a
-methylbenzyl)amino-1,3-propanediol (S)-4a and 2-chloroethyl chlor-
S)-4-benzyl-4-hydroxymethyl-3-( -methyl-
diastereoselective asymmetric desymmetrization
process. Debenzylation of (4R)-5a using trifluoromethanesulfonic acid and anisole in MeNO2 gave (R)-4-
benzyl-4-hydroxymethyl-2-oxazolidinone (R)-15a, which was converted into (R)-( -hydroxymethyl)
phenylalanine (7) in two steps. N-Boc- -methylphenylalanine (8), cericlami0ne (9) and BIRT-377 (10)
were also synthesized using these asymmetric desymmetrization and debenzylation.
Received 16 February 2012
Received in revised form 20 June 2012
Accepted 21 June 2012
a
a
a
Available online 4 July 2012
a
a
Keywords:
Asymmetric desymmetrization
Serinol
Ó 2012 Elsevier Ltd. All rights reserved.
Oxazolidinone
Debenzylation
Fractional crystallization
Cyclic carbonate
1. Introduction
Stereoselective construction of quaternary carbon stereocenters
is one of the most important techniques for organic synthesis. Many
methods have been developed to construct asymmetric centers of
quaternary carbon, especially for the synthesis of optically active
quaternary
a
-amino acids.1 For example, optically active 4,4-
Scheme 1. Desymmetrization of serinol derivatives A (*: chiral center).
disubstituted-2-oxazolidinones have been synthesized asymmet-
rically and then converted to 2,2-disubstituted 2-aminoethanols2
and
a,a
-disubstituted amino acids.3 Enzymatic asymmetric
serinol derivatives to give the corresponding 2-oxazolidinones
diastereoselectively. We selected benzyl groups for the sub-
stituent at 2-position of serinol 1 and investigated the diaster-
eoselective asymmetric desymmetrization of serinol (S)-4a to
afford 2-oxazolidinone (4R)-5a (Scheme 3), because few enzy-
matic6 or chemical7 desymmetrizations of 2-benzylserinol
desymmetrization of prochiral compounds are frequently used for
this purpose. Desymmetrization of 2-substituted serinols A giving
optically active monoacyl 2-substituted serinols B (R3¼acyl group)
has been reported (Scheme 1).4
We are investigating new synthetic methods of optically active
2-oxazolidinones and their related reactions.5 In the previous paper
we reported asymmetric desymmetrization of N-(a-methylbenzyl)
serinol 1 using 2-chloroethyl chloroformate (CCF) and DBU to give
4-hydroxymethyl-2-oxazolidinone 2 in 94% de (Scheme 2).5b We
considered that this reaction would be applied to 2-substituted
* Corresponding authors. Tel.: þ81 42 495 8791; fax: þ81 42 495 8783; e-mail
addresses: sugiyama@my-pharm.ac.jp (S. Sugiyama), ishiikei@my-pharm.ac.jp
(K. Ishii).
Scheme 2. Reported diastereoselective asymmetric desymmetrization of serinol 1.
Reaction conditions: (a) CCF, Py, CH2Cl2, rt, then DBU, 1 ꢀC to rt.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.090

8034
S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
derivatives have been reported. This type of compounds would be
was ca. 1:1 as confirmed by 1H NMR analysis of the crude material,
and was not changed by the use of toluene or THF as a reaction
solvent or benzyl chloride instead of benzyl bromide (entry 2).
C-Benzylation of N-acylaminomalonates7a,13 and N,N-dialkyl-
aminomalonate14 has been performed successfully. However, the
selective C-benzylation of (S)-11 was found to be difficult be-
a key intermediate for the asymmetric synthesis of a-substituted
phenylalanines (e.g., 78 and 88d,9), as well as of pharmaceuticals,
such as the selective 5-HT uptake inhibitor cericlamine (9)10 and
lymphocyte function-associated antigen-1 (LFA-1) antagonist BIRT-
377 (10)11 (Fig. 1).
cause the
a-methylbenzylamino group of (S)-11 is also active as
a nucleophilic group. Moreover, C-benzyl aminomalonate (S)-12a
could not be separated from N-benzyl aminomalonate 13 with
silica gel column chromatography. We investigated another
isolation method and found that the desired compound (S)-12a
was easy to isolate by fractional crystallization. After the mix-
ture of (S)-12a and 13 was dissolved in Et2O and treated with
a solution of 4 mol/L HCl in dioxane, fortunately C-alkyl ami-
nomalonate hydrogen chloride (S)-12a-HCl was precipitated
selectively in 45% yield from (S)-11 (entry 1). After a NaHCO3
aq/CHCl3 partition to give free amine (S)-12a (97%), the ester
groups were reduced with LiAlH4 to afford 2-benzylserinol (S)-
4a (89%, entry 1). Benzylserinol (R)-4a was also synthesized
from diethyl bromomalonate according to this procedure using
crude aminomalonate (R)-11 (entry 3).
Scheme 3. Diastereoselective asymmetric desymmetrization in this study.
According to this procedure, 2-benzylserinols (S)-4b and (R)-4c
were synthesized from aminomalonates (S)-11 and (R)-11 using
3,4-dichlorobenzyl bromide and 4-bromobenzyl bromide, re-
spectively (entries 4e7). Aminomalonate (S)-11 was benzylated
with 3,4-dichlorobenzyl bromide (entry 4) and chloride (entries 5
and 6) in the presence of potassium tert-butoxide in DMF to afford
2-amino-2-benzylmalonate (S)-12b. The crude (S)-12b was con-
verted to (S)-12b-HCl to be purified by fractional crystallization.
After recovery of pure free amine (S)-12b from (S)-12b-HCl, the
malonate (S)-12b was converted to 2-benzylserinol (S)-4b (entry 6).
Benzylserinol (R)-4c was also obtained by this method from ami-
nomalonate (R)-11 using 4-bromobenzyl bromide (entry 7). Thus,
2-benzylserinols 4 were synthesized easily via C-benzylation of
aminomalonates 11, fractional crystallization of 12-HCl, and re-
duction of the ester groups (Table 1). This method is an easily
handled and low-cost method for a large scale synthesis of
2-benzylserinols 4.
Fig. 1. Synthetic targets.
In this paper, we report a new synthetic method of obtaining
optically active 4-benzyl-4-hydroxymethyl-2-oxazolidinones (4R)-
5a using the asymmetric desymmetrization of 2-benzylserinols
(S)-4a (Scheme 3). This methodology was applied for other 2-
benzylserinols possessing 3,4-dichlorobenzyl and 4-bromobenzyl
groups instead of benzyl group to synthesize corresponding opti-
cally active 4-benzyl-4-hydroxymethyl-2-oxazolidinones. We also
2.2. Asymmetric desymmetrization of 2-benzylserinols
Next, we investigated the formation of 4-benzyl-4-
hydroxymethyl-2-oxazolidinone (4R)-5a from 2-benzylserinol (S)-
4a (Table 2). In the previous paper, we used CCF in CH2Cl2 to give
a diastereomeric mixture of two monocarbonates (ca. 1:1) of ser-
inol 1, and then this mixture was treated with DBU to form an
optically active 2-oxazolidinone 2 in 94% de (Scheme 2).5b First,
these reaction conditions were examined using 2-benzylserinol (S)-
4a, and the desired 2-oxazolidinone (4R)-5a was given in 40% yield
and 88% de (entry 1). Reactions of (S)-4a in THF (entry 2) and Et2O
(entry 3) were also tested; however, the yields (28 and 20%) and
diastereoselectivities (78 and 82% de) were lower than those of the
reaction in CH2Cl2. Identical results to entry 1 were given using a 5-
g scale of 2-benzylserinol (S)-4a and CCF in CH2Cl2. The diaster-
eoselectivity of (4R)-5a before recrystallization was 88% de, and
(4R)-5a was given in 47% yield after recrystallization of the crude
material (entry 4). The reaction using DMAP and Et3N instead of
pyridine5c gave (4R)-5a in 69% yield and 92% de (entry 7).
The oxazolidinones (4R)-5b and (4S)-5c were also synthesized
by means of CCF with pyridine (entries 5 and 6) or with DMAP and
Et3N (entries 8 and 9). The yields of (4R)-5b and (4S)-5c using
DMAP and Et3N were better than those using pyridine. The reaction
of (R)-4a with 1,10-carbonylbis-1H-imidazole (CDI)5a gave (4S)-5a
and (4R)-6a in 84% yield and in 40% de (entry 10). The reaction of
4aec with N,N0-disuccinimidyl carbonate (DSC)5b gave the prod-
ucts 5aec and 6aec in 84e53% yield and 0e24% de (entries 11e13).
investigated the synthesis of
cericlamine (9),10 BIRT-377 (10)11 and N-Boc-(
anine (8)8d,9 from the oxazolidinones. In the synthesis of 9 and 10,
debenzylation of the N- -methylbenzyl groups without dehaloge-
a
-(hydroxymethyl)phenylalanine 7,8
-methyl)phenylal-
a
a
nation of the halogenated phenyl groups were also focused on.
2. Results and discussion
2.1. Synthesis of 2-benzylserinols
Benzylserinol (S)-4a was synthesized as follows (Table 1).
Aminomalonate (S)-1112 was benzylated with benzyl bromide and
potassium tert-butoxide in DMF (entry 1). Although desired
C-benzyl aminomalonate (S)-12a was obtained by this method,
undesired N-benzyl aminomalonate 13 (Fig. 2) was also formed. A
reaction using 2 equiv of potassium tert-butoxide and benzyl bro-
mide gave no N,C-dibenzyl compound 14.y The ratio of (S)-12a/13
y
Although we synthesized diethyl N-Boc-(a-methylbenzyl)aminomalonate from
11 and (Boc)2O in 71% yield and investigated its C-benzylation using BnBr with
bases (t-BuOK and NaH) in DMF at room temperature, no C-benzyl product was
obtained. Thus, reactivity of the C-2 carbon of N-protected diethyl (
aminomalonates was decreased extremely by the N-protective groups.
a-methylbenzyl)

S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
8035
Table 1
Synthesis of serinols (S)-4a,b and (R)-4a,c
Entry
Aminomalonate 11
Benzyl halide
Benzylation and fractional crystallization
Partition and reduction
X
R3
R4
12-HCl
Yield (%)
4
Yielda (%)
1
2
3
4
5
6
7
(S)-11
(S)-11
(R)-11
(S)-11
(S)-11c
(S)-11d
(R)-11
Br
Cl
Br
Br
Cl
Cl
Br
H
H
H
Cl
Cl
Cl
H
H
H
H
Cl
Cl
Cl
Br
(S)-12a-HCl
(S)-12a-HCl
(R)-12a-HCl
(S)-12b-HCl
(S)-12b-HCl
(S)-12b-HCl
(R)-12c-HCl
45
39
(S)-4a
d
84
d
89
d
d
77
55
31b
30
(R)-4a
d
27
35
47
d
(S)-4b
(R)-4c
a
The yield was calculated from aminomalonate HCl salt 12-HCl.
This yield was calculated from diethyl bromomalonate (see Experimental 4.1.4).
(S)-11 (2 mmol) was used.
b
c
d
(S)-11 (111 mmol) was used.
As shown here, optically active 4-benzyl-4-hydroxymethyl-2-
oxazolidinones 5aec were synthesized from diethyl bromomalo-
nate (11) by the four-step synthesis without tedious purifications.
2.3. Synthesis of (R)-
a-(hydroxymethyl)phenylalanine, (S)-N-
Boc- -methylphenylalanine, cericlamine and BIRT-377
a
We found that oxazolidinones 5aec were easy to synthesize
diastereoselectively and easy to separate from side products 6aec
with recrystallization or silica gel column chromatography. To show
Fig. 2. N-Benzyl and N,C-dibenzyl compounds 13 and 14. (Compound 14 have not been
obtained.)
Table 2
Formation of 2-oxazolidinones 5aec and 6aec from 2-benzylserinols 4aec
Entry
Materiala
Conditions
Reagent
Results
Solvent
Base-1
Base-2
Product
Yieldb (%)
Ratio (de, %)b
1
2
3
4
5
6
7
8
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4b
(R)-4c
(S)-4a
(S)-4b
(R)-4c
(R)-4a
(S)-4a
(S)-4b
(R)-4c
CCF
CCF
CCF
CCF
CCF
CCF
CCF
CCF
CCF
CDI
DSC
DSC
DSC
CH2Cl2
THF
Et2O
Py
Py
Py
Py
Py
Py
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
d
(4R)-5a, (4S)-6a
(4R)-5a, (4S)-6a
(4R)-5a, (4S)-6a
(4R)-5a, (4S)-6a
(4R)-5b, (4S)-6b
(4S)-5c, (4R)-6c
(4R)-5a, (4S)-6a
(4R)-5b, (4S)-6b
(4S)-5c, (4R)-6c
(4S)-5a, (4R)-6a
(4R)-5a, (4S)-6a
(4R)-5b, (4S)-6b
(4S)-5c, (4R)-6c
40c
28c
20c
47e
45
40
69
68
71
84
86
87
53
94:6 (88)d
89:11 (78)d
91:9 (82)d
94:6 (88)d
96:4 (92)
94:6 (88)
96:4 (92)
95:5 (90)
95:5 (90)
70:30 (40)
51:49 (2)
62:38 (24)
50:50 (0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
MeCN
MeCN
MeCN
DMAP, Et3N
DMAP, Et3N
DMAP, Et3N
Et3N
d
9
10
11
12
13
d
d
d
d
a
The reactions were carried out using 7.9 mg of (S)-4a in entries 1e3. (See Experimental for other entries.).
Estimated from the isolated products of 5aec and 6aec otherwise noted.
b
c
The yields were calibrated with the internal standard (triphenylmethane) by 1H NMR integration.
The ratio of the products was estimated by the integral values of their 1H NMR spectra before purification.
Isolated yield of (4R)-5a only.
d
e

8036
S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
the utility of 2-oxazolidinones 5aec as intermediates for the syn-
theses of bioactive compounds, we first remove the -methyl-
a
benzyl group from 2-oxazolidinones (Scheme 4). Debenzylations of
(4R)- and (4S)-5a by the use of trifluoromethanesulfonic acid
15
(TfOH) and anisole in MeNO2 gave oxazolidinones (R)- and (S)-
15a in high yield, respectively. Debenzylation of (4R)-5b and (4S)-
5c possessing halogens on their C-benzyl groups were also pro-
ceeded smoothly without dehalogenation to give (R)-15b and (S)-
15c, respectively (Scheme 4). After the debenzylation, the hydroxyl
groups were tosylated using TsCl in pyridine to afford corre-
sponding tosylates (S)-16a, (S)-16b and (R)-16c. Tosylate (R)-16a
and mesylate (R)-16d were synthesized via another route from
(4S)-5a. Tosylation and mesylation of oxazolidinone (4S)-5a were
proceeded slowly but smoothly to give the corresponding tosylate
17a and mesylate 17b, respectively. Their debenzylation gave (R)-
16a and (R)-16d in good yield.
Scheme 5. Synthesis of (R)-a-(hydroxymethyl)phenylalanine (7). Reagents and con-
ditions: (a) RuCl3, NaIO4, MeCN, CCl4, H2O, rt; (b) 6 mol/L HCl aq, reflux.
21. Oxidation of the hydroxymethyl group of 21 gave N-Boc-a-
methylphenylalanine (8) as an optically pure form (>99% ee
checked by HPLC analysis).
Scheme 6. Reduction of sulfonates and synthesis of N-Boc-(a-methyl)phenylalanine
(8). Reagents and conditions: (a) NaBH4, DMSO, 100 ꢀC; (b) (Boc)2O, Et3N, DMAP, THF,
rt; (c) Cs2CO3, MeOH, rt; (d) RuCl3, NaIO4, MeCN, CCl4, H2O, rt.
Finally, tosylate (S)-16b and (R)-16c were converted to N-
methyl-3-phenyl-2-aminopropanols 22 and 23, respectively, by
treatment of LiAlH4 in Et2O.17 Cericlamine (9) was obtained after N-
methylation20 of 22, and BIRT-377 (10) was obtained after reaction
of 23 with 3,5-dichlorophenylisocyanate and then oxidation of the
hydroxymethyl group of 24 (Scheme 7). In this Ru-oxidation, we
realized that AcOEt/H2O21 was a good solvent system to prevent the
formation of 4-bromobenzoic acid, which was formed from 24
during the oxidation in CCl4/MeCN/H2O.16
The reaction of 2-benzylserinols 4 and CCF using DBU gave
oxazolidinones 5 with high diastereoselectivities (Table 2, entries
4e9). These reaction pathways from 4 to 5 would be identical to
those from serinol 1 to oxazolidinone 2 (Scheme 2) via cyclic car-
bonate 25a and then proposed bicyclic intermediate 26a (Fig. 3).5b
Therefore, 25b would be formed from serinols 4 and CCF, and then
converted to bicyclic intermediate 26b. The benzyl group of 26b
was located at the opposite site of the reaction site and would have
no effect on the diastereoselectivities. On the other hand, the re-
action of 2-benzylserinols 4 and DSC gave oxazolidinones 5 and 6
with poor diastereoselectivities (Table 2, entries 11e13). The ser-
inols 4 reacted with DSC and then would give oxazolidinones di-
rectly without forming cyclic carbonate 25b and bicyclic
intermediate 26b as we had shown the reaction of 1 and DSC.5b
Cyclic carbonate 25a is also formed form serinol 1 using CDI.5a
The reaction of serinol 4 and CDI would give oxazolidinones 5
and 6 via 25b and 26b, and direct cyclization.15
Scheme 4. Synthesis of sulfonates. Reagents and conditions: (a) TfOH [1.0 equiv for
(4R)-5a and 17a,b, 1.5 equiv for the other 5aec], anisole, MeNO2, 50 or 100 ꢀC; (b) TsCl,
Py, rt; (c) MsCl, Py, rt.
To determine the stereochemistry of (4S)-5a, we synthesized
(R)-a
-(hydroxymethyl)phenylalanine (7) from (S)-15a. Oxidation16
of the hydroxymethyl group of 2-oxazolidinone (S)-15a followed
by acidic hydrolysis of the 2-oxazolidinone ring of 18 gave the de-
sired (R)-amino acid 7 (Scheme 5). The absolute configuration of
the (R)-amino acid 7 was determined by comparison of the specific
rotation, ½a 2D1
ꢁ
ꢂ16.4 (c 1.0, H2O), with the reported value, ½a D20
ꢁ
þ16.4 (c 0.89, H2O), of the corresponding (S)-amino acid.9b There-
fore, the stereochemistry of (4S)-5a was determined to be 4S,aR.
(S)-N-Boc-a-Methylphenylalanine (8) was synthesized from the
oxazolidinone (S)-16a as follows (Scheme 6); tosylate (S)-16a was
treated with NaBH4 in DMSO in 100 ꢀC17 to afford (S)-4-benzyl-4-
methyl-2-oxazolidinone [(S)-19]. Demesylation of 16b also
gave (R)-19 in good yield. Oxazolidinone (S)-19 was converted to
N-Boc-2-oxazolidinone (S)-20, and the oxazolidinone ring of (S)-20
was cleaved with Cs2CO3 in MeOH19 to afford N-Boc-aminoalcohol
3. Conclusion
In conclusion, we report a simple and practical route to enan-
tioenriched 4-benzyl-2-oxazolidinones (R)- and (S)-15a possessing
a quaternary carbon through the non-enzymatic diastereoselective

S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
8037
(HRMS) were taken on a JEOL JMS-DX302 spectrometer using
glycerol as a matrix of positive FABMS otherwise noted. Column
chromatography was performed with silica gel 60 (spherical,
40e50
mm, Kanto Chemical). Analytical TLC was performed on
plates pre-coated with 0.25 mm layer of silica gel 60 F254 (Merck) or
on those of RP-18 F254s (Merck).
4.1. Synthesis of aminomalonate hydrochlorides 12aec-HCl
(Table 1)
4.1.1. Synthesis of (S)-12a-HCl using benzyl bromide (entry
1). Aminomalonate (S)-1112 (17.0 g, 60.9 mmol) was dissolved in
DMF (152 mL), and t-BuOK (13.7 g, 122 mmol) was added por-
tionwise to the DMF solution at room temperature. After being
stirred for 30 min, the mixture was cooled using an ice bath, and
benzyl bromide (20.8 g, 122 mmol) was added dropwise to the
mixture. After the resulting mixture was stirred for 18 h at room
temperature, the reaction mixture was diluted with H2O (170 mL)
and extracted with Et2O (170 mL, three times). The extracts were
combined, dried over MgSO4, filtered, and concentrated in vacuo.
This oil was dissolved in Et2O (500 mL) again, and 4 mol/L solution
of hydrogen chloride in dioxane (16.7 mL) was added to the ether
solutionwithvigorouslystirring. Crystallinematerial was precipitated
in the mixture, and the resulting mixture was filtered through a glass
filter to give (S)-12a-HCl as white-ivory powder (11.0 g, 45%). (The
filtrate containing 13-HCl was used in 4.2.3 to afford 13.)
For spectral analysis, pure (S)-12a-HCl was prepared by fol-
lowing procedure; benzylmalonate (S)-12a (296 mg), which was
obtained from (S)-12a-HCl described in 4.2.1 was dissolved in Et2O
(5 mL) and the solution was extracted with 10% HCl aq (10 mL).
After the aqueous layer was separated and allowed to stand for
30 min at room temperature, colorless crystalline material was
precipitated, and the material was collected by filtration to give
pure (S)-12a-HCl (165 mg).
Scheme 7. Syntheses of cericlamine (9) and BIRT-377 (10). Reagents and conditions:
(a) LiAlH4, solvent (Et2O for 16b and THF for 16c), reflux; (b) HCHO, NaBH4, TFA, THF, rt;
(c) 3,5-dichlorophenylisocyanate, NaH, THF, rt; (d) RuCl3, NaIO4, AcOEt, H2O, rt.
4.1.2. Diethyl 2-benzyl-N-(S)-(a-methylbenzyl)aminomalonate hy-
drochloride [(S)-12a-HCl]. Colorless powder; mp 111e113 ꢀC. ½a D26
ꢁ
ꢂ40.2 (c 0.3, CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.70 (2H, d,
J¼7.1 Hz, Ar), 7.31e7.40 (6H, m, Ar), 7.21e7.25 (2H, m, Ar), 4.67 (1H,
q, J¼6.8 Hz, PhCH), 4.20 (2H, q, J¼7.1 Hz, OCH2), 4.13 (1H, d,
J¼14.2 Hz, PhCHH), 3.90 (1H, dq, J¼10.8, 7.2 Hz, OCHH), 3.85 (1H, d,
J¼14.2 Hz, PhCHH), 3.68 (1H, dq, J¼10.8, 7.6 Hz, OCHH), 1.96 (3H, d,
J¼6.3 Hz, Me), 1.28 (3H, t, J¼7.1 Hz, OCH2Me), 1.09 (3H, t, J¼7.1 Hz,
Fig. 3. The first and second intermediates 25 and 26 for the reaction in Table 2.
desymmetrization of readily available 2-benzylserinols (S)- and (R)-
4a and the debenzylation of 3-a-methylbenzyl-2-oxazolidinones
(4R)- and (4S)-5a using TfOH and anisole in MeNO2. 2-
Benzylserinols (S)-4b and (R)-4c possessing halogenated phenyl
groups were also applied for the diastereoselective desymmetri-
zation to give oxazolidinones (4R)-5b and (4S)-5c, respectively.
Debenzylation using TfOH and anisole in MeNO2 was also useful for
OCH2Me). 13C NMR (100 MHz, CDCl3)
d
: 164.5 (C]O ꢃ2), 145.9 (Ar,
C), 132.4 (Ar, C), 130.3 (Ar, CH ꢃ2), 129.1 (Ar, CH), 128.8 (Ar, CH ꢃ2)
128.6 (Ar, CH ꢃ2),128.2 (Ar, CH ꢃ2),127.9 (Ar, CH), 71.4 (NCBn), 63.5
(CH2O), 63.3 (CH2O), 59.7 (PhCHN), 39.3 (PhCH2), 22.4 (PhCHMe),
13.9 (Me), 13.7 (Me). IR (KBr) cmꢂ1: 1750. MS (FAB) m/z: 370
[(Mþ1ꢂHCl)þ]. Anal. Calcd for C22H28ClNO4: C, 65.01; H, 6.95; N,
3.45. Found: C, 64.87; H, 6.96; N, 3.25.
3-(
sessing 3,4-dichlorobenzyl and 4-bromobenzyl groups. Optically
active -(hydroxymethyl)phenylalanine (7), N-Boc- -methyl-
a-methylbenzyl)-2-oxazolidinones (4R)-5b and (4S)-5c pos-
a
a
phenylalanine (8), cericlamine (9), and BIRT-377 (10) were syn-
thesized from the corresponding oxazolidinones (S)- and (R)-15a,
(R)-15b, and (S)-15c, respectively. Application of other 2-
substituted serinols instead of 2-benzylserinols 4 in the diaster-
eoselective asymmetric desymmetrization giving 2-substituted 2-
oxazolidinones is underway, and will be reported in due course.
4.1.3. Synthesis of (S)-12a-HCl using benzyl chloride (entry
2). Aminomalonate hydrochloride (S)-12a-HCl (9.50 g, 39%) was
also synthesized from aminomalonate (S)-11 (17.0 g, 60,9 mmol)
using benzyl chloride (15.4 g, 122 mmol) according to the pro-
cedure described in 4.1.1.
4.1.4. Synthesis of (R)-12a-HCl from a crude (R)-11 (entry 3). A
4. Experimental
mixture of triethylamine (7.91 g, 78.2 mmol) and (R)-(þ)-
a-meth-
ylbenzylamine (9.48 g, 78.2 mmol) was added to a mixture of diethyl
bromomalonate (92% purity, Aldrich, 20.3 g, 78.1 mmol as 92%
purity) in MeCN (78 mL) at room temperature, and the resulting
mixture was stirred for 18 h at room temperature. After the reaction
mixture was filtered, the filtrate was concentrated in vacuo. The
residue was diluted with Et2O and washed with saturated aqueous
NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo to
Melting points were measured with Yanaco MP-3 apparatus and
are uncorrected. Optical rotations were determined on a JASCO DIP-
140 polarimeter. NMR spectra were obtained a JEOL JNM-GSX400
(1H NMR: 400 MHz and 13C NMR: 100 MHz) spectrometers using
tetramethylsilane as an internal standard. IR spectra were recorded
on a Hitachi 215 spectrophotometer. MS and high-resolution MS

8038
S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
give a crude (R)-1112 (22.3 g) as brown oil, which was used without
further extraction for the synthesis of (R)-12a-HCl using t-BuOK
(17.6 g, 15.7 mmol), DMF (200 mL) and benzyl bromide (26.8 g,
157 mmol) according to the procedure described in 4.1.1 to afford
(R)-12a-HCl as white-ivory powder (9.77 g, 31% from diethyl bro-
purification. For spectral analysis, (R)-12a was prepared by fol-
lowing procedure; the pure salt (S)-12a-HCl (68.6 mg, 169 mol),
m
which was obtained for the spectrum analysis in 4.1.1, was dis-
solved in CHCl3 and the solution was washed with saturated
aqueous NaHCO3. The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo to give pure (S)-12a (62.4 mg, quant.) as
momalonate). ½a D23
ꢁ
þ40.3 (c 1.0, CHCl3). 1H NMR spectrum was good
agreement with that of (S)-12a-HCl.
colorless oil. Rf value; 0.32 (RP-18, MeOH/H2O, 9:1). ½a D20
ꢂ1.9 (c 1.3,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.15e7.33 (10H, m, Ar), 4.02
4.1.5. Synthesis of (S)-12b-HCl (entries 4e6). According to the
procedure described in 4.1.1, (S)-12b-HCl (215 mg, 27%) was
obtained from (S)-11 (500 mg, 1.79 mmol) and 3,4-dichlorobenzyl
chloride (700 mg, 3.58 mmol) (entry 4). (S)-12b-HCl (240 mg,
31%) was also obtained from (S)-11 (500 mg, 1.79 mmol) and 3,4-
dichlorobenzyl bromide (859 mg, 3.58 mmol) (entry 5) or from
(S)-11 (30.7 g, 110 mmol) and 3,4-dichlorobenzyl chloride (43.0 g,
220 mmol) (entry 6).
(1H, q, J¼6.8 Hz, PhCH), 3.960 (1H, q, J¼7.1 Hz, OCHH), 3.959 (1H, q,
J¼7.1 Hz, OCHH), 3.84 (1H, dq, J¼10.7, 7.1 Hz, OCHH), 3.56 (1H, dq,
J¼10.7, 7.1 Hz, OCHH), 3.40 (1H, d, J¼14.4 Hz, PhCHH), 3.19 (1H, d,
J¼14.4 Hz, PhCHH), 1.35 (3H, d, J¼6.8 Hz, Me), 1.15 (3H, t, J¼7.1 Hz,
OCH2Me), 1.05 (3H, t, J¼7.1 Hz, OCH2Me). 13C NMR (100 MHz, CDCl3)
d: 170.0 (C]O), 169.6 (C]O), 145.6 (Ar, C), 135.5 (Ar, C), 129.9 (Ar,
CH ꢃ2), 127.9 (Ar, CH ꢃ2), 127.8 (Ar, CH ꢃ2) 126.7 (Ar, CH ꢃ2), 126.6
(Ar, CH ꢃ2), 126.5 (Ar, CH), 70.1 (NCBn), 61.4 (CH2O), 61.1 (CH2O),
53.2 (PhCHN), 38.6 (PhCH2), 26.4 (PhCHMe), 14.0 (Me), 13.8 (Me). IR
(film) cmꢂ1: 1740. MS (FAB) m/z: 370 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C22H28NO4, 370.2019; found, 370.2019.
4.1.6. Diethyl (S)-2-(3,4-dichlorobenzyl)-2-(a-methylbenzyl)amino-
malonate hydrochloride [(S)-12b-HCl]. White-ivory powder, mp
82e84 ꢀC. ½a 2D8
ꢁ
ꢂ38.7 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3)
d:
7.74 (2H, d, J¼7.1 Hz, Ar), 7.31e7.40 (4H, m, Ar), 7.26 (1H, d,
J¼8.3 Hz, Ar), 7.17 (1H, dd, J¼8.3, 2.0 Hz, Ar), 4.79 (1H, q, J¼6.8 Hz,
PhCH), 4.10e4.16 (2H, m, OCH2), 4.10 (1H, d, J¼14.6 Hz, PhCHH),
3.97 (1H, d, J¼13.9 Hz, PhCHH), 3.62e3.70 (1H, m, OCHH),
3.51e3.40 (1H, m, OCHH), 2.03 (3H, d, J¼6.8 Hz, Me), 1.20 (3H, t,
J¼7.1 Hz, OCH2Me), 1.02 (3H, t, J¼7.1 Hz, OCH2Me). 13C NMR
4.2.2. Diethyl 2-benzyl-N-(R)-(a-methylbenzyl)aminomalonate [(R)-
12a] (entry 3). Aminomalonate (R)-12a (8.47 g, 97%) was also
synthesized according to the procedure described in 4.2.1 from (R)-
12a-HCl (9.62 g). ½a D27
ꢁ
þ1.9 (c 1.0, CHCl3). 1H NMR spectrum was
good agreement with that of (S)-12a.
(100 MHz, CDCl3)
d: 164.5 (C]O), 163.5 (C]O), 136.6 (Ar, C), 133.6
4.2.3. Diethyl N-benzyl-N-(S)-(a-methylbenzyl)aminomalonate (13).
(Ar, C), 132.5 (Ar, CH), 131.9 (Ar, C), 131.6 (Ar, C), 130.1 (Ar, CH), 129.8
(Ar, CH), 129.1 (Ar, CH) 128.7 (Ar, CH ꢃ2), 128.6 (Ar, CH ꢃ2), 70.9
(NCBn), 63.3 (CH2O), 63.2 (CH2O), 59.6 (PhCHN), 38.7 (PhCH2), 23.0
(PhCHMe), 13.8 (Me), 13.6 (Me). IR (KBr) cmꢂ1: 1740. MS (FAB) m/z:
438 [(MꢂHClþ1)þ]. HRMS (FAB) m/z: calcd for C22H26Cl2NO4:
438.1239. Found: 438.1246. Anal. Calcd for C22H26Cl3NO4: C, 55.60;
H, 5.52; N, 2.95. Found: C, 56.05; H, 5.54; N, 2.81.
The filtrate containing 13-HCl in Et2O, which had been given from
the mixture of (S)-12 and 13 in Et2O as described in 4.1.1, was
washed with saturated aqueous NaHCO3, dried over MgSO4, fil-
tered, and concentrated in vacuo to give a brown oil (20.5 g). A
small amount of the oil (601 mg) was chromatographed on silica
gel (hexane/AcOEt, 9:1) to give a pure 13 (248 mg) as a colorless oil.
Thus, the brown oil (20.5 g) had been containing 8.45 g (38%) of 13.
Rf value; 0.34 (RP-18, MeOH/H2O, 9:1). ½a D27
ꢁ
ꢂ10.5 (c 0.5, CHCl3). 1H
4.1.7. Synthesis of (R)-12c-HCl (entry 7). Aminomalonate hydro-
chloride (R)-12c-HCl (11.0 g, 47%) was synthesized from (R)-11
(13.6 g, 48.6 mmol) and 4-bromobenzyl bromide (24.3 g,
97.2 mmol) (entry 7) according to the procedure described in 4.1.1.
NMR (400 MHz, CDCl3)
d
: 7.53 (2H, d, J¼7.6 Hz, Ar), 7.46 (2H, d,
J¼8.0 Hz, Ar), 7.41e7.20 (6H, m, Ar), 4.25e4.05 (8H, m, OCH2 ꢃ2,
PhCH2, PhCHeNCH),1.29 (3H, d, J¼6.8 Hz, Me), 1.25 (3H, t, J¼7.2 Hz,
OCH2Me), 1.21 (3H, t, J¼7.19 Hz, OCH2Me). 13C NMR (100 MHz,
CDCl3) d: 169.4 (C]O), 168.8 (C]O), 143.0 (Ar, C), 140.6 (Ar, C),
4.1.8. Diethyl
(R)-2-(4-bromobenzyl)-2-(
a
-methylbenzyl)amino-
128.3 (Ar, CH ꢃ2), 128.1 (Ar, CH ꢃ2), 128.0 (Ar, CH ꢃ2), 127.5 (Ar, CH
ꢃ2), 126.9 (Ar, CH), 126.7 (Ar, CH), 64.4 (CH), 61.3 (CH2), 61.2 (CH2),
58.0 (CH), 53.2 (CH2), 16.9 (Me), 14.2 (Me ꢃ2). IR (film) cmꢂ1: 1730.
MS (EI) m/z: 370 (Mþ1)þ. HRMS (EI) m/z: calcd for C22H27NO4,
369.1941; found, 369.1936.
malonate hydrochloride [(R)-12c-HCl]. White-ivory powder, mp
94e96 ꢀC. ½a 2D5
ꢁ
þ40.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d:
7.67 (2H, d, J¼6.8 Hz, Ar), 7.33e7.59 (5H, m, Ar), 7.22 (2H, d, J¼8.0 Hz,
Ar), 4.62 (1H, q, J¼6.8 Hz, PhCH), 4.05 (1H, d, J¼6.8 Hz, OCHH), 4.03
(1H, d, J¼6.8 Hz, OCHH), 3.96 (1H, d, J¼14.0 Hz, ArCHH), 3.80e3.88
(1H, m, OCHH), 3.77 (1H, d, J¼14.0 Hz, ArCHH), 3.59e3.67 (1H, m,
OCHH), 1.95 (3H, d, J¼6.8 Hz, Me), 1.20 (3H, t, J¼6.8 Hz, OCH2Me),
4.2.4. Diethyl (S)-2-(3,4-dichlorobenzyl)-2-(a-methylbenzyl)amino-
malonate [(S)-12b] (entry 6). Aminomalonate (S)-12b (14.9 g, 89%)
was obtained from aminomalonate hydrochloride (S)-12b-HCl
(18.0 g). This material was used at the next reaction without further
1.04 (3H, t, J¼6.8 Hz, OCH2Me). 13C NMR (100 MHz, CDCl3)
d: 164.6
(C]O), 164.5 (C]O), 137.5 (Ar, C), 132.20 (Ar, C), 132.17 (Ar, CH ꢃ2),
131.4 (Ar, CH ꢃ2),129.0 (Ar, CH),128.7 (Ar, CH ꢃ2),128.4 (Ar, CH ꢃ2),
121.8 (Ar, C), 71.0 (NCCH2Ar), 63.2 (CH2O), 63.1 (CH2O), 59.0
(PhCHN), 38.3 (ArCH2), 22.8 (PhCHMe),13.8 (Me),13.7 (Me). IR (KBr)
cmꢂ1: 1750. MS (FAB) m/z: 448 [(MꢂHClþ1)þ]. HRMS (FAB) m/z:
calcd for C22H27BrNO4: 448.1123. Found: 448.1121.
purification; a colorless oil. ½a D26
ꢁ
þ21.3 (c 1.1, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 7.29 (5H, d-like m, Ar), 7.18e7.23 (2H, m, Ar),
6.97 (1H, dd, J¼8.4, 2.0 Hz, Ar), 4.08 (2H, q-like m, PhCHþOCHH),
3.87 (2H, m, OCH2), 3.59 (1H, m, OCHH), 3.29 (1H, d, J¼14.7 Hz,
PhCHH), 3.06 (1H, d, J¼14.7 Hz, PhCHH), 2.56 (1H, br s, NH), 1.38
(3H, d, J¼6.8 Hz, Me), 1.21 (3H, t, J¼7.1 Hz, OCH2Me), 1.06 (3H, t,
4.2. C-Benzylaminomalonates 12aec and N-benzyl
aminomalonate (Table 1)
J¼7.1 Hz, OCH2Me). 13C NMR (100 MHz, CDCl3)
: 169.4 (C]O ꢃ2),
d
145.3 (Ar, C), 136.0 (Ar, C), 132.0 (Ar, CH), 131.6 (Ar, C), 130.6 (Ar, C),
129.6 (Ar, CH), 129.3 (Ar, CH), 128.0 (Ar, CH ꢃ2), 126.8 (Ar, CH) 126.5
(Ar, CH ꢃ2), 70.1 (NCCH2Ar), 61.8 (CH2O), 61.4 (CH2O), 53.3
(PhCHN), 37.2 (ArCH2), 26.4 (PhCHMe), 14.1 (Me), 13.9 (Me). IR
(CHCl3) cmꢂ1: 1760,1200,1040. MS (FAB) m/z: 438 [(Mþ1)þ]. HRMS
(FAB) m/z: calcd for C22H26Cl2NO4: 438.1239. Found: 438.1245.
4.2.1. Diethyl 2-benzyl-N-(S)-(a-methylbenzyl)aminomalonate [(S)-
12a] (entry 1). HCl salt (S)-12a-HCl (11.6 g, 28.6 mmol) was treated
with saturated aqueous NaHCO3 (200 mL), and the mixture was
extracted with Et2O (once with 100 mL and twice with 50 mL). The
extracts were combined, dried over MgSO4, filtered, and concen-
trated in vacuo to give (S)-12a as brown viscous oil (10.2 g, 97%).
This material was used at the next reaction without further
4.2.5. Diethyl
(R)-2-(4-bromobenzyl)-2-(a-methylbenzyl)amino-
malonate [(R)-12c] (entry 7). Aminomalonate (R)-12c (8.40 g, 82%)

S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
8039
was obtained from aminomalonate hydrochloride (R)-12c-HCl
(11.0 g). This material was used at the next reaction without further
J¼13.6 Hz, PhCHH), 1.26 (3H, d, J¼6.4 Hz, Me). 13C NMR (100 MHz,
CDCl3) d: 147.5 (Ar, C), 137.1 (Ar, C), 132.1 (Ar, CH), 131.8 (Ar, C), 130.2
purification; anyellowoil. ½a D22
ꢁ
ꢂ3.7 (c 1.0, CHCl3).1HNMR (400 MHz,
(Ar, C), 129.8 (Ar, CH ꢃ2), 128.7 (Ar, CH ꢃ2), 127.1 (Ar, CH), 125.7 (Ar,
CH ꢃ2), 62.9 (OCH2), 62.7 (OCH2), 61.3 (NCCH2Ar), 51.5 (PhCHN),
36.9 (ArCH2), 26.9 (Me). IR (neat) cmꢂ1: 3450, 3380, 1480, 1410,
1150, 1050. MS (FAB) m/z: 354 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for
C18H22Cl2NO2: 354.1028. Found: 354.1033.
CDCl3)
d
: 7.33 (2H, d, J¼9.2 Hz, Ar), 7.17e7.31 (5H, m, Ar), 7.02 (2H, d,
J¼8.4 Hz, Ar), 4.03 (1H, d, J¼6.8 Hz, OCHH), 3.99 (1H, d, J¼7.2 Hz,
OCHH), 3.95 (1H, q, J¼7.2 Hz, PhCH), 3.80e3.88 (1H, m, OCHH),
3.53e3.61 (1H, m, OCHH), 3.32 (1H, d, J¼14.4 Hz, ArCHH), 3.10 (1H, d,
J¼14.4 Hz, ArCHH), 1.36 (3H, d, J¼6.4 Hz, Me), 1.17 (3H, t, J¼7.2 Hz,
OCH2Me), 1.05 (3H, t, J¼7.2 Hz, OCH2Me). 13C NMR (100 MHz, CDCl3)
4.3.4. (R)-2-(4-Bromobenzyl)-2-(a-methylbenzyl)amino-1,3-
d: 169.8 (C]O), 169.6 (Ar, C]O), 145.5 (Ar, C), 134.7 (Ar, C), 131.6 (Ar,
propanediol [(R)-4c]. Crude benzylserinol (R)-4c (6.4 g) was
obtained from C-benzyl aminomalonate (R)-12c (8.34 g,18.6 mmol)
as a dark brown solid according to the procedure described in 4.3.1.
This solid was recrystallized from EtOH to give a pure (R)-4c (3.12 g,
46%). The residue was purified with silica gel column chromatog-
raphy (hexane/AcOEt, 3:7) to give a pure (R)-4c (1.41 g, total 4.53 g,
CH ꢃ2),130.9 (Ar, CH ꢃ2), 128.0 (Ar, CH ꢃ2), 126.7 (Ar, CH),126.6 (Ar,
CH ꢃ2), 120.7 (Ar, C), 70.1 (NCCH2Ar), 61.7 (CH2O), 61.3 (CH2O), 53.3
(PhCHN), 37.8 (ArCH2), 26.5 (PhCHMe), 14.1 (Me), 13.9 (Me). IR (neat)
cmꢂ1: 2970,1730,1490. MS (FAB) m/z: 448 [(Mþ1)þ]. HRMS (FAB) m/
z: calcd for C22H27BrNO4: 448.1123. Found: 448.1131.
67%); colorless powder, mp 127e128 ꢀC. ½a D18
þ74.5 (c 0.9, CHCl3).
ꢁ
4.3. Synthesis of 2-benzylserinols 4aec (Table 1)
1H NMR (400 MHz, CDCl3)
d: 7.25e7.40 (7H, m, Ar), 7.08 (2H, d,
J¼8.3 Hz, Ar), 4.05 (1H, q, J¼6.6 Hz, PhCH), 3.15e3.30 (4H, m, OCH2
4.3.1. (S)-2-Benzyl-2-(a-methylbenzyl)amino-1,3-propanediol [(S)-
ꢃ2), 2.74 (1H, d, J¼13.2 Hz, ArCHH), 2.67 (1H, d, J¼13.2 Hz, ArCHH),
4a]. LiAlH4 (5.07 g, 134 mmol) was added slowly to a solution of
C-benzyl aminomalonate (S)-12a (9.85 g, 26.7 mmol) in Et2O
(134 mL, 0.2 mol/L) with cooling by use of an ice bath. The mixture
was stirred for 2.5 h with cooling. H2O/THF (1:1, 10.2 mL) was
added dropwise carefully, and 15% NaOH aq (5.1 mL) and then H2O
(5.1 mL) were added to the mixture. The resulting mixture was
stirred for 2 h at room temperature and filtered through a glass
filter. The solid was washed with Et2O. The filtrate was extracted
with 10% HCl aq three times (40 mLꢃ1 and 20 mLꢃ2). The aqueous
layer was alkalined (ca. pH 11) with NaOH and extracted with Et2O
three times (40 mLꢃ1 and 20 mLꢃ2). The organic extracts were
combined, washed with H2O twice (40 mLꢃ2), dried over MgSO4
and evaporated in vacuo to afford benzylserinol (S)-4a (6.42 g, 84%)
as brown viscous oil. This oil was used at the next reaction without
further purification. For spectral analysis, the benzylserinol (S)-4a
(99.9 mg) was purified with silica gel column chromatography
(hexane/AcOEt, 3:7) to give a pure (S)-4a (73.9 mg) as colorless oil.
1.36 (3H, d, J¼6.6 Hz, Me). 13C NMR (100 MHz, CDCl3)
d: 147.7 (Ar,
C), 135.8 (Ar, C), 132.1 (Ar, CH ꢃ2), 131.1 (Ar, CH ꢃ2), 128.8 (Ar, CH
ꢃ2), 127.2 (Ar, CH),125.7 (Ar, CH ꢃ2),120.3 (Ar, C), 63.3 (OCH2), 62.9
(OCH2), 61.4 (NCCH2Ar), 51.6 (PhCHN), 37.6 (PhCH2), 27.1 (Me). IR
(CHCl3) cmꢂ1: 1635. MS (FAB) m/z: 364 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C18H23BrNO2: 364.0912. Found: 364.0921.
4.4. Synthesis of 2-oxazolidinones 5 and 6 (Table 2)
4.4.1. Test of the solvents (entries 1e3). CCF (3.0
added to a solution of (S)-4a (7.9 mg, 29 mol), pyridine (2.3
29 mol) and triphenylmethane (1.3 mg, an internal standard) in
CH2Cl2, THF, or Et2O (0.29 mL) at room temperature. After being
stirred for 16 h at room temperature, DBU (13 L, 87 mol) was
m
L, 29
m
mol) was
m
m
L,
m
m
m
added to the mixture, and the resulting mixture was stirred for
4 h at room temperature. The reaction mixture was poured into
saturated aqueous NH4Cl and extracted with Et2O. The extracts
were combined, dried over MgSO4, filtered and, concentrated in
vacuo. The yields and ratios were estimated with the internal
standard (triphenylmethane) by 1H NMR integration in CDCl3.
Characteristic signals (CDCl3): d5a¼4.82 ppm, d6a¼4.44 ppm, and
dPh3CH¼5.55 ppm.
½
a 2D7
ꢁ
ꢂ73.6 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.19e7.42
(10H, m, Ar), 4.10 (1H, q, J¼11.2 Hz, PhCH), 3.24 (1H, d, J¼11.2 Hz,
OCHH), 3.30 (1H, d, J¼11.2 Hz, OCHH), 3.25 (1H, d, J¼11.2 Hz,
OCHH), 3.23 (1H, d, J¼11.2 Hz, OCHH), 2.80 (1H, d, J¼13.3 Hz,
PhCHH), 2.71 (1H, d, J¼13.3 Hz, PhCHH), 1.37 (3H, d, J¼6.6 Hz, Me).
13C NMR (100 MHz, CDCl3)
d: 147.7 (Ar, C), 136.7 (Ar, C), 130.3 (Ar,
CH ꢃ2), 128.7 (Ar, CH ꢃ2), 128.1 (Ar, CH ꢃ2), 127.0 (Ar, CH), 126.3
(Ar, CH), 125.8 (Ar, CH ꢃ2), 63.7 (OCH2), 63.3 (OCH2), 61.4 (NCBn),
51.6 (PhCHN), 38.2 (PhCH2), 27.0 (Me). IR (film) cmꢂ1: 3400, 3330,
2925, 1455, 1040. MS (FAB) m/z: 286 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C18H24NO2, 286.1808; found, 286.1810.
4.4.2. Synthesis of 5aec using CCF and pyridine (entries 4e6). Entry
4; CCF (2.70 g, 18.9 mmol) was added to a mixture of benzylserinol
(S)-4a (5.13 g, 18.0 mmol) and pyridine (1.49 g, 18.9 mmol) in
CH2Cl2 (180 mL) at room temperature. After being stirred for 15 h at
room temperature, the mixture was cooled to 2 ꢀC (internal tem-
perature) by use of an ice bath. DBU (8.63 g, 56.7 mmol) was added
dropwise to the mixture, and the resulting mixture was stirred for
6 h at this temperature. The reaction mixture was washed twice
with 10% HCl aq (40 mL and 20 mL) and once with saturated
aqueous NaHCO3 (40 mL), dried, filtered, and concentrated in vacuo
to give a dark brown solid. This solid was recrystallized from AcOEt
(70 mL) to give (4R)-5a (2.31 g) as colorless needles. The filtrate was
concentrated in vacuo to give a mixture of dark brown viscous oil
and solid. This mixture was suspended with Et2O (10 mL), and the
solid was collected with filtration and then recrystallized from
AcOEt (11 mL) to give (4R)-5a as colorless needles (0.31 g, total
2.62 g, 47%).
Entry 5; a crude dark brown solid containing (4R)-5b was
obtained from benzylserinol (S)-4b (10.0 g, 28.2 mmol) according
to the procedure described in 4.4.2. This solid was recrystallized
from AcOEt (70 mL) to give (4R)-5b as colorless needles (2.51 g).
The filtrate was concentrated in vacuo to give a mixture of dark
brown viscous oil and solid. This mixture was suspended with Et2O
(10 mL), and the solid was collected with by filtration and
4.3.2. (R)-2-Benzyl-2-(a-methylbenzyl)amino-1,3-propanediol [(R)-
4a]. Benzylserinol (R)-4a (5.37 g, 89%) was also synthesized via (R)-
12a (8.18 g, 22.1 mmol) according to the procedure described in
4.3.1. ½a 2D6
ꢁ
þ70.1 (c 1.0, CHCl3). 1H NMR spectrum data was good
agreement with those of (S)-4a.
4.3.3. (S)-2-(3,4-Dichlorobenzyl)-2-(a-methylbenzyl)amino-1,3-
propanediol [(S)-4b]. Benzylserinol 4b (10.4 g, 87%) was obtained
from C-benzyl aminomalonate (S)-12b (14.9 g, 33.9 mmol) as
a brown viscous oil according to the procedure described in 4.3.1.
This oil was used at the next reaction without further purification.
For spectral analysis, the benzylserinol (S)-4b (182 mg) was
purified with silica gel column chromatography (hexane/AcOEt,
1:1) to give a pure (S)-4b (106 mg); an yellow oil. ½a D28
ꢂ59.6 (c 2.1,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.08e7.30 (8H, m, Ar), 3.95
(1H, q, J¼6.4 Hz, PhCH), 3.18 (1H, d, J¼11.2 Hz, OCHH), 3.16 (1H, d,
J¼10.8 Hz, OCHH), 3.08 (1H, d, J¼11.2 Hz, OCHH), 3.03 (1H, d,
J¼10.8 Hz, OCHH), 2.63 (1H, d, J¼13.6 Hz, PhCHH), 2.57 (1H, d,

8040
S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
recrystallized from AcOEt (11 mL) to give (4R)-5b as colorless
needles (1.59 g). The residue was chromatographed on silica gel
(hexane/AcOEt, 1:1) to give (4R)-5b (0.45 g, total 4.55 g, 43%) and
(4S)-6b (202 mg, 2%).
Entry 6; a crude dark brown solid containing (4S)-5c was
obtained from benzylserinol (R)-4c (300 mg, 0.82 mmol) according
to the procedure described in 4.4.2. This solid was recrystallized
from EtOH to give (4S)-5c as colorless needles (52.6 mg). The fil-
trate was concentrated in vacuo to give a mixture of dark brown
viscous oil and solid. The residue (390 mg) was purified with silica
gel column chromatography (CHCl3/MeOH, 9:1) to give (4S)-5c
(76.3 mg, total 129 mg, 40%).
Ar), 7.35e7.38 (2H, m, Ar), 7.23e7.31 (4H, m, Ar), 7.02e7.04 (2H, m,
Ar), 4.80 (1H, q, J¼7.3 Hz, PhCH), 4.23 (1H, d, J¼8.8 Hz, COCHH), 3.88
(1H, d, J¼8.8 Hz, COCHH), 3.69 (1H, d, J¼11.7 Hz, DOCHH), 3.57 (1H,
d, J¼11.8 Hz, DOCHH), 3.08 (1H, d, J¼13.7 Hz, PhCHH), 2.79 (1H, d,
J¼13.4 Hz, PhCHH), 1.90 (3H, d, J¼7.3 Hz, Me). 13C NMR (100 MHz,
CDCl3)
d
: 157.2 (C]O), 142.3 (Ar, C), 134.3 (Ar, C), 129.9 (Ar, CH ꢃ2),
128.6 (Ar, CH ꢃ2), 128.5 (Ar, CH ꢃ2), 127.5 (Ar, CH), 127.2 (Ar, CH
ꢃ3), 67.9 (CH2), 65.9 (C), 64.4 (CH2), 52.6 (CH), 40.9 (CH2), 19.9 (Me).
IR (CHCl3) cmꢂ1: 1735. MS (EI) m/z: 280 [(MꢂCH2OH)þ, 4%], 220
[(MꢂBn)þ, 45], 176 (11), 116 (14), 105 (100). MS (FAB) m/z: 312
[(Mþ1)þ]. Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50.
Found: C, 73.45; H, 6.89; N, 4.37.
4.4.3. Reactions of 4aec using CCF, DMAP, and Et3N (entries
4.4.7. (4R,aS)-4-Benzyl-4-hydroxymethyl-3-(a-methylbenzyl)-2-
7e9). Entry 7; CCF (322
benzylserinol (S)-4a (888 mg, 3.11 mmol), DMAP (19.1 mg,
156 mol) and Et3N (431 L, 3.11 mmol) in CH2Cl2 (31 mL) at room
m
L, 3.11 mmol) was added to a mixture of
oxazolidinone [(4R)-5a]. Oxazolidinone (4R)-5a was synthesized
according to the method described in 4.4.3. ½a D30
ꢁ
þ55.0 (c 0.3,
m
m
CHCl3).
temperature. After being stirred for 15 h at room temperature, the
mixture was cooled by use of an ice bath. DBU (1.40 mL, 9.33 mmol)
was added dropwise to the mixture, and the resulting mixture was
stirred for 6 h at this temperature. The reaction mixture was
washed with 10% HCl aq and saturated aqueous NaHCO3, dried,
filtered, and concentrated in vacuo. The residue was chromato-
graphed on silica gel to give (4R)-5a (636 mg, 66%) and (4S)-6a
(27.0 mg, 2.8%).
4.4.8. (4R,
a
R)-4-Benzyl-4-hydroxymethyl-3-(
a
-methylbenzyl)-2-
oxazolidinone [(4R)-6a]. Colorless needles, mp 173e175 ꢀC (AcOEt).
Rf value; 0.49 (silica gel, hexane/AcOEt, 1:1). ½a D22
ꢂ12.1 (c 0.6,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.59e7.61 (2H, m, Ar),
7.28e7.39 (6H, m, Ar), 7.21e7.23 (2H, m, Ar), 4.44 (1H, q, J¼7.3 Hz,
PhCH), 4.25 (1H, d, J¼8.8 Hz, COCHH), 4.05 (1H, d, J¼8.8 Hz,
COCHH), 3.60 (1H, dd, J¼12.5, 4.2 Hz, HOCHH), 3.32 (1H, dd, J¼12.5,
9.5 Hz, HOCHH), 3.03 (1H, d, J¼14.2 Hz, PhCHH), 2.94 (1H, d,
J¼13.7 Hz, PhCHH), 1.87 (3H, d, J¼7.3 Hz, Me), 1.01 (1H, dd, J¼9.5,
Entry 8; reaction conditions in entry 8 were identical with those
in entry 7 and used for serinol (S)-4b (286 mg).
Entry 9; a crude dark brown solid containing (4S)-5c was
obtained from benzylserinol (R)-4c (1.94 g, 5.34 mmol) according
to the procedure described in 4.4.3. This solid was recrystallized
from AcOEt to give (4S)-5c as colorless needles (1.14 g). The filtrate
was concentrated in vacuo to give a mixture of dark brown viscous
oil and solid. The residue (1.14 g) was purified with silica gel column
chromatography (CHCl3/MeOH, 9:1) to give (4S)-5c (276 mg, total
1.41 g, 68%) and (4R)-6c (56.5 mg, 3.4%).
4.2 Hz, OH). 1H NMR (400 MHz, CDCl3 with D2O)
d: 7.59 (2H, d,
J¼7.1 Hz, Ar), 7.30e7.39 (6H, m, Ar), 7.21e7.23 (2H, m, Ar), 4.45 (1H,
q, J¼7.3 Hz, PhCH), 4.25 (1H, d, J¼8.5 Hz, COCHH), 4.05 (1H, d,
J¼8.8 Hz, COCHH), 3.59 (1H, d, J¼12.5 Hz, DOCHH), 3.31 (1H, d,
J¼12.5 Hz, DOCHH), 3.03 (1H, d, J¼13.9 Hz, PhCHH), 2.94 (1H, d,
J¼13.9 Hz, PhCHH), 1.87 (3H, d, J¼7.3 Hz, Me). 13C NMR (100 MHz,
CDCl3)
d
: 157.3 (C]O), 143.3 (Ar, C), 134.1 (Ar, C), 130.0 (Ar, CH ꢃ2),
129.2 (Ar, CH ꢃ2), 128.7 (Ar, CH ꢃ2), 128.0 (Ar, CH), 127.4 (Ar, CH),
126.5 (Ar, CH ꢃ2), 67.2 (CH2), 66.4 (C), 64.2 (CH2), 52.9 (CH), 39.7
(CH2), 21.0 (Me). IR (CHCl3) cmꢂ1: 1740. MS (FAB) m/z: 312
[(Mþ1)þ]. Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50.
Found: C, 72.96; H, 6.74; N, 4.24.
4.4.4. Reaction of 4a with CDI (entry 10). CDI (85 mg, 0.52 mmol)
was added to
0.522 mmol) in THF (13 mL) at room temperature. After the mixture
was stirred for 6 h at room temperature, DBU (233 L, 1.56 mmol)
a solution of benzylserinol (S)-4a (149 mg,
m
was added to the mixture. The resulting mixture was stirred for 15 h
at room temperature. The reaction mixture was poured into satu-
rated aqueous NH4Cl and extracted with AcOEt. The extracts were
combined, dried, filtered, and concentrated in vacuo. The residue
was chromatographed on silica gel (hexane/AcOEt, 3:7) to give (4S)-
5a (96.1 mg, 59%) and (4R)-6a (41.2 mg, 25%).
4.4.9. (4R,aS)-4-(3,4-Dichlorobenzyl)-4-hydroxymethyl-3-(a-
methylbenzyl)-2-oxazolidinone [(4R)-5b]. Colorless needle, mp
159e160 ꢀC (AcOEt). ½a 2D1
ꢁ
ꢂ108 (c 0.9, MeOH). 1H NMR (400 MHz,
CD3OD)
d
: 7.56 (2H, d, J¼7.2 Hz, Ar), 7.26e7.83 (4H, m, Ar), 7.06 (1H,
d, J¼2.0 Hz, Ar), 6.81 (1H, dd, J¼8.0, 2.0 Hz, Ar), 4.75 (1H, q,
J¼7.2 Hz, PhCH), 4.10 (1H, d, J¼8.8 Hz, COCHH), 3.89 (1H, d,
J¼8.8 Hz, COCHH), 3.70 (1H, dd, J¼7.2, 4.0 Hz, HOCHH), 3.62 (1H,
dd, J¼7.2, 4.0 Hz, HOCHH), 3.00 (1H, d, J¼9.6 Hz, PhCHH), 2.74 (1H,
d, J¼9.6 Hz, PhCHH), 2.10 (1H, t, J¼4.0 Hz, OH),1.88 (3H, d, J¼7.2 Hz,
4.4.5. Reaction of 4aec with DSC (entries 11e13). DSC (500 mg,
1.97 mmol) was added to a solution of benzylserinol (S)-4a (563 mg,
1.97 mmol) in MeCN (20 mL) at room temperature. After being
stirred for 15 h at room temperature, the reaction mixture was
concentrated in vacuo. The residue was chromatographed on silica
gel (hexane/AcOEt, 1:4) to give (4S)-6a (274 mg, 45%) and (4R)-5a
(249 mg, 41%). This reaction conditions were used for the reaction of
serinol (S)-4b (1.01 g) and (R)-4c (89 mg) (entries 12 and 13).
Me).13C NMR (100 MHz, CD3OD)
d: 157.1 (C]O),142.2 (Ar, C),134.6
(Ar, C),132.5 (Ar, C),131.8 (Ar, CH),131.5 (Ar, C),130.3 (Ar, CH),129.2
(Ar, CH), 128.7 (Ar, CH ꢃ2), 127.6 (Ar, CH), 127.2 (Ar, CH ꢃ2), 67.7
(NCBn), 65.7 (OCH2C), 64.5 (HOCH2C), 52.9 (PhCHN), 39.3 (PhCH2),
20.1 (Me). IR (CHCl3) cmꢂ1: 1700. MS (FAB) (Magic bullet) m/z: 380
[(Mþ1)þ]. HRMS (FAB) (Magic bullet) calcd for C19H20NO3Cl2:
380.0822. Found: 380.0828. Anal. Calcd for C19H19Cl2NO3: C, 60.01;
H, 5.04; N, 3.68. Found: C, 59.96; H, 5.13; N, 3.49.
4.4.6. (4S,aR)-4-Benzyl-4-hydroxymethyl-3-(a-methylbenzyl)-2-
oxazolidinone [(4S)-5a]. Colorless needles, mp 186e188 ꢀC (AcOEt).
Rf value; 0.27 (silica gel, hexane/AcOEt, 1:1). ½a D28
ꢁ
ꢂ59.7 (c 1.0,
4.4.10. (4S,aS)-4-(3,4-Dichlorobenzyl)-4-hydroxymethyl-3-(a-
methylbenzyl)-2-oxazolidinone [(4S)-6b]. Colorless needle, mp
CHCl3). 1H NMR (400 MHz, CDCl3)
d
: 7.58e7.60 (2H, m, Ar),
7.35e7.39 (2H, m, Ar), 7.23e7.31 (4H, m, Ar), 7.02e7.04 (2H, m, Ar),
4.82 (1H, q, J¼7.3 Hz, PhCH), 4.23 (1H, d, J¼9.0 Hz, COCHH), 3.88
(1H, d, J¼8.8 Hz, COCHH), 3.70 (1H, dd, J¼11.7, 4.2 Hz, HOCHH), 3.57
(1H, dd, J¼11.7, 6.6 Hz, HOCHH), 3.09 (1H, d, J¼13.7 Hz, PhCHH),
2.79 (1H, d, J¼13.7 Hz, PhCHH), 1.91 (3H, d, J¼7.3 Hz, Me), 1.64 (1H,
127e128 ꢀC. ½a 2D2
ꢁ
ꢂ23.5 (c 0.8, MeOH). 1H NMR (400 MHz, CDCl3)
d
: 7.57 (2H, d, J¼7.2 Hz, Ar), 7.29e7.43 (5H, m, Ar), 7.08 (1H, dd,
J¼8.0, 2.0 Hz, Ar), 4.46 (1H, q, J¼6.8 Hz, PhCH), 4.15 (1H, d,
J¼8.8 Hz, COCHH), 4.02 (1H, d, J¼8.8 Hz, COCHH), 3.54 (1H, d,
J¼12.0 Hz, HOCHH), 3.33 (1H, d, J¼12.0 Hz, HOCHH), 3.00 (1H, d,
J¼14.0 Hz, PhCHH), 2.89 (1H, d, J¼14.0 Hz, PhCHH), 1.89 (3H, d,
m, OH). 1H NMR (400 MHz, CDCl3 with D2O)
d: 7.57e7.59 (2H, m,

S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
8041
J¼6.8 Hz, Me). 13C NMR (100 MHz, CDCl3)
d
: 157.0 (C]O), 143.1 (Ar,
was synthesized from (4R)-5a (500 mg, 1.60 mmol) using tri-
fluoromethanesulfonic acid (240 mg, 1.60 mmol) and anisole
(894 mg, 8.00 mmol) in MeNO2 (8.0 mL) according to the method
C), 134.4 (Ar, C), 132.8 (Ar, C), 131.9 (Ar, CH), 131.8 (Ar, C), 130.6 (Ar,
CH), 129.2 (Ar, CH ꢃ3), 128.0 (Ar, CH), 126.5 (Ar, CH ꢃ2), 67.0
(OCH2), 66.1 (NCCH2Ar), 64.3 (OCH2), 53.1 (NCHPh), 38.4 (CH2Ar),
21.1 (Me). IR (CHCl3) cmꢂ1: 1740, 1205, 1060. MS (FAB) m/z: 380
[(Mþ1)þ]. HRMS (FAB) m/z: calcd for C19H20NO3 (Mþ1): 380.0820.
Found: 380.0817.
described in 4.5.1. ½a D30
þ25.4 (c 0.7, CHCl3).
ꢁ
4.5.3. (R)-4-(3,4-Dichlorobenzyl)-4-hydroxymethyl-2-oxazolidinone
[(R)-15b]. Oxazolidinone (R)-15b (213 mg, 98%) was obtained from
(4R)-5b (300 mg 0.79 mmol) according to the procedure described
4.4.11. (4S,
a
R)-4-(4-Bromobenzyl)-4-hydroxymethyl-3-(
a
-methyl-
in 4.5.1; colorless powder, mp 128e130 ꢀC. ½a D25
þ30.5 (c 0.7, EtOH).
ꢁ
benzyl)-2-oxazolidinone [(4S)-5c]. Colorless needles, mp 197e198 ꢀC.
1H NMR (400 MHz, CD3OD)
d: 7.43e7.46 (2H, m, Ar), 7.19e7.21 (1H,
½
a 2D4
ꢁ
ꢂ85.9 (c 0.3, MeOH). 1H NMR (400 MHz, CD3OD)
d: 7.56 (2H, d,
m, Ar), 4.26 (1H, d, J¼9.2 Hz, COCHH), 4.15 (1H, d, J¼9.2 Hz,
COCHH), 3.54 (1H, d, J¼11.2 Hz, HOCHH), 3.50 (1H, d, J¼11.2 Hz,
HOCHH), 2.89 (1H, d, J¼14.0 Hz, ArCHH), 2.80 (1H, d, J¼14.0 Hz,
J¼7.6 Hz, Ar), 7.32e7.36 (3H, m, Ar), 7.28 (2H, d, J¼8.0 Hz, Ar), 6.85
(2H, d, J¼8.0 Hz, Ar), 4.70 (1H, q, J¼6.8 Hz, PhCH), 4.23 (1H, d,
J¼8.8 Hz, COCHH), 4.02 (1H, d, J¼8.8 Hz, COCHH), 3.82 (1H, d,
J¼11.2 Hz, HOCHH), 3.55 (1H, d, J¼11.2 Hz, HOCHH), 2.89 (1H, d,
J¼13.9 Hz, ArCHH), 2.78 (1H, d, J¼13.9 Hz, ArCHH), 1.84 (3H, d,
ArCHH). 13C NMR (100 MHz, CD3OD)
d: 161.2 (C]O), 137.4 (Ar, C),
133.3 (Ar, CH), 132.9 (Ar, C), 131.8 (Ar, C), 131.2 (Ar, CH), 131.1 (Ar,
CH), 71.4 (OCH2), 66.8 (OCH2), 63.1 (NCCH2Ar), 40.5 (ArCH2). IR
(CHCl3) cmꢂ1: 1720. MS (FAB) m/z: 276 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C11H12Cl2NO3: 276.0194. Found: 276.0195.
J¼6.8 Hz, Me). 13C NMR (100 MHz, CD3OD)
d: 159.7 (C]O), 144.1 (Ar,
C), 135.3 (Ar, C), 133.0 (Ar, CH ꢃ2), 132.2 (Ar, CH ꢃ2), 129.3 (Ar, CH
ꢃ2), 128.5 (Ar, CH ꢃ2), 128.2 (Ar, CH), 121.8 (Ar, C), 69.4 (OCH2), 67.5
(NCCH2Ar), 64.6 (HOCH2), 53.5 (PhCHN), 40.0 (ArCH2), 20.2 (Me). IR
(KBr) cmꢂ1: 1700. MS (FAB) m/z: 390 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C19H21BrNO3: 390.0705. Found: 390.0706.
4.5.4. (S)-4-(4-Bromobenzyl)-4-hydroxymethyl-2-oxazolidinone
[(S)-15c]. Oxazolidinone (S)-15c (0.89 g, 83%) was obtained from
(4S)-5c (1.48 g, 3.79 mmol) according to the procedure described in
4.5.1; colorless powder, mp 149e151 ꢀC. ½a D26
ꢂ36.1 (c 0.5, CHCl3).
ꢁ
4.4.12. (4R,
a
R)-4-(4-Bromobenzyl)-4-hydroxymethyl-3-(
a
-meth-
1H NMR (400 MHz, CD3OD)
d
: 7.46 (2H, d, J¼8.4 Hz, Ar), 7.19 (2H, d,
ylbenzyl)-2-oxazolidinone [(4R)-6c]. Colorless crystals, mp
J¼8.4 Hz, Ar), 4.24 (1H, d, J¼11.2 Hz, COCHH), 4.15 (1H, d, J¼11.2 Hz,
COCHH), 3.54 (1H, d, J¼7.2 Hz, HOCHH), 3.49 (1H, d, J¼7.2 Hz,
HOCHH), 2.87 (1H, d, J¼14.0 Hz, ArCHH), 2.79 (1H, d, J¼14.0 Hz,
128e130 ꢀC. ½a 2D1
ꢁ
ꢂ1.4 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d:
7.58 (2H, d, J¼7.1 Hz, Ar), 7.48 (2H, dt, J¼6.6, 1.7 Hz, Ar), 7.37 (2H, m,
Ar), 7.28e7.33 (1H, m, Ar), 7.11 (2H, dt, J¼8.3, 1.7 Hz, Ar), 4.45 (1H, q,
J¼7.1 Hz, PhCH), 4.17 (1H, d, J¼8.8 Hz, OCHH), 4.02 (1H, d, J¼8.8 Hz,
OCHH), 3.56 (1H, dd, J¼12.2, 4.2 Hz, HOCHH), 3.31 (1H, dd, J¼12.2,
8.8 Hz, HOCHH), 3.00 (1H, d, J¼13.9, ArCHH), 2.89 (1H, d, J¼14.2 Hz,
ArCHH), 1.87 (3H, d, J¼7.1 Hz, Me), 1.15 (1H, dd, J¼8.8, 4.2 Hz, OH).
ArCHH). 13C NMR (100 MHz, CD3OD)
d: 161.3 (C]O), 135.8 (Ar, C),
133.3 (Ar, CH ꢃ2), 132.3 (Ar, CH ꢃ2), 121.8 (Ar, C), 71.4 (OCH2), 66.9
(OCH2), 63.2 (NCCH2Ar), 40.9 (ArCH2). IR (KBr) cmꢂ1: 1760. MS
(FAB) m/z: 276 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for C11H13BrNO3:
286.0079. Found: 286.0075.
13C NMR (CDCl3,100 MHz)
d: 157.1 (C]O),143.1 (C, Ar),133.2 (C, Ar),
131.8 (CH ꢃ2, Ar), 131.6 (CH ꢃ2, Ar), 129.1 (CH2 ꢃ2, Ar), 128.0 (CH,
Ar), 126.5 (CH2 ꢃ2), 121.5 (C, Ar), 67.0 (OCH2), 66.1 (C), 64.2 (OCH2),
53.0 (CH), 38.9 (CH2), 21.1 (Me). IR (KBr) cmꢂ1: 3438, 1721. MS (FAB)
m/z: 390 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for C19H21BrNO3 (Mþ1):
390.0705. Found: 390.0703.
4.6. Tosylation of 15aec
4.6.1. (S)-(4-Benzyl-2-oxazolidinon-4-yl)methyl p-toluenesulfonate
[(S)-16a]. p-Toluenesulfonyl chloride (400 mg, 2.10 mmol) was
added to
a solution of 2-oxazolidinone (R)-15a (175 mg,
0.84 mmol) in pyridine (2.1 mL) at 0 ꢀC. The reaction mixture was
stirred for 6 h at room temperature. Pyridine was removed in
vacuo. The residue was dissolved in CH2Cl2, and washed with 10%
HCl aq. The aqueous layer was extracted twice with CH2Cl2. The
extracts were combined, dried over MgSO4, and concentrated in
vacuo. The residue was purified with silica gel column chroma-
tography (hexane/AcOEt, 1:1) to give (S)-16a (268 mg, 88%). Col-
4.5. Debenzylation of 5aec
4.5.1. (S)-4-Benzyl-4-hydroxymethyl-2-oxazolidinone [(S)-15a]. Tri-
fluoromethanesulfonic acid (462 mg, 3.08 mmol) was added to
a mixture of 2-oxazolidinone (4S)-5a (640 mg 2.06 mmol) and ani-
sole (1.15 g, 10.3 mmol) in MeNO2 (20.5 mL). After the mixture was
stirred for 6 h at 50 ꢀC, the reaction mixture was diluted with CH2Cl2
and washed with saturated aqueous NaHCO3. The aqueous layer was
extracted twice with CH2Cl2. The extracts were combined, dried over
MgSO4, and concentrated in vacuo. The residue (1.1 g) was purified
with silica gel column chromatography (AcOEt) to give (S)-15a
(358 mg, 84%, >99% ee detected by HPLC). Colorless needles, mp
orless amorphous foam. ½a D22
ꢁ
þ29.3 (c 0.2, MeOH). 1H NMR
(500 MHz, CDCl3)
d
: 7.80 (2H, d, J¼8.2 Hz, Ar), 7.38 (2H, d, J¼8.2 Hz,
Ar), 7.28 (3H, m, Ar), 7.09 (2H, m, Ar), 5.50 (1H, s, NH), 4.20 (1H, d,
J¼9.2 Hz, CO2CHH), 4.15 (1H, d, J¼9.2 Hz, CO2CHH), 3.91 (1H, d,
J¼9.8 Hz, CHHOTs), 3.71 (1H, d, J¼9.8 Hz, CHHOTs), 3.00 (1H, d,
J¼13.7 Hz, PhCHH), 2.89 (1H, d, J¼14.0 Hz, PhCHH), 2.48 (3H, s, Me).
118e121 ꢀC. ½a 2D6
ꢁ
ꢂ24.3 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3)
d
:
13C NMR (125 MHz, CDCl3)
d: 157.7 (C]O), 145.7 (C), 133.4 (C), 132.0
7.23e7.33 (4H, m, Ar), 7.18e7.20 (2H, m, Ar), 6.40 (1H, s, NH), 4.25
(1H, d, J¼8.8 Hz, COCHH), 4.20 (1H, d, J¼8.8 Hz, COCHH), 3.56 (1H, d,
J¼11.5 Hz, HOCHH), 3.47 (1H, d, J¼11.7 Hz, HOCHH), 2.93 (1H, d,
J¼13.9 Hz, PhCHH), 2.84 (1H, d, J¼13.7 Hz, PhCHH). 13C NMR
(C), 130.2 (CH ꢃ2), 130.0 (CH ꢃ2), 129.0 (CH ꢃ2), 128.0 (CH ꢃ2),
127.8 (CH), 71.1 (CH2), 70.3 (CH2), 59.6 (C), 41.0 (CH2), 21.7 (Me). IR
(film) cmꢂ1: 1770. MS (FAB) m/z: 362 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C18H20NO5S, 362.1063; found, 362.1061.
(100 MHz, CDCl3)
d: 159.7 (C]O), 134.5 (Ar, C), 130.1 (Ar, CH ꢃ2),
128.6 (Ar, CH ꢃ2), 127.2 (Ar, CH), 71.0 (OCH2), 65.7 (OCH2), 62.2
(NCBn), 41.3 (PhCH2). IR (KBr) cmꢂ1: 1750. MS (FAB) m/z: 208
[(Mþ1)þ]. HRMS (FAB) m/z: calcd for C11H14NO3: 208.0974. Found:
208.0969. HPLC conditions: Chiralcel OD-H column eluted with
hexane/2-propanol (7:3) at 0.5 mL/min using UV detector at
254 nm. Retention time: tR¼13.1 min and tS¼15.1 min.
4.6.2. (S)-[4-(3,4-Dichlorobenzyl)-2-oxazolidinon-4-yl]methyl p-tol-
uenesulfonate [(S)-16b]. p-Toluenesulfonate (S)-16b (306 mg, 98%)
was obtained from (R)-15b (200 mg, 0.72 mmol) according to the
procedure described in 4.6.1; colorless amorphous foam. ½a D25
þ2.3
ꢁ
(c 1.2, CHCl3). 1H NMR (400 MHz, CDCl3)
d
: 7.77 (2H, d, J¼8.4 Hz, Ar),
7.24e7.37 (3H, m, Ar), 6.99 (1H, dd, J¼8.4, 1.6 Hz, Ar), 6.82 (1H, d,
J¼14.4 Hz, Ar), 4.17 (1H, d, J¼9.2 Hz, COCHH), 4.12 (1H, d, J¼9.2 Hz,
COCHH), 3.96 (1H, d, J¼10.0 Hz, TsOCHH), 3.88 (1H, d, J¼10.0 Hz,
TsOCHH), 2.94 (1H, d, J¼14.0 Hz, ArCHH), 2.92 (1H, d, J¼14.0 Hz,
4.5.2. (R)-4-Benzyl-4-hydroxymethyl-2-oxazolidinone [(R)-15a].
Oxazolidinone (R)-15a (226 mg, 68%, >99% ee detected by HPLC)

8042
S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
ArCHH), 2.45 (3H, s, Me). 13C NMR (100 MHz, CDCl3)
d: 158.1 (C]O),
141.9 (C, Ar),132.8 (C, Ar),129.6 (CH ꢃ2, Ar),128.9 (CH ꢃ2, Ar),128.6
(CH ꢃ2, Ar), 127.8 (CH, Ar), 127.6 (CH, Ar), 127.0 (CH ꢃ2, Ar), 68.1
(OCH2), 67.7 (OCH2), 64.1 (C), 52.9 (CH), 41.2 (CH2), 38.0 (Me), 20.1
(Me). IR (KBr) cmꢂ1: 2360, 1749, 1456, 1419. MS (FAB) m/z: 390
[(Mþ1)þ], 286, 105. HRMS (FAB) m/z: calcd for C20H23NO5S:
390.1376. Found 390.1383. Anal. Calcd for C20H23NO5S: C, 61.68; H,
5.95; N, 3.60. Found: C, 61.12; H, 5.88; N, 3.50.
145.5 (Ar, C), 133.7 (Ar, C), 132.5 (Ar, C), 131.9 (Ar, CH), 131.7 (Ar, C),
131.5 (Ar, C), 130.5 (Ar, CH ꢃ2), 130.0 (Ar, CH), 129.4 (Ar, CH), 127.7
(Ar, CH ꢃ2), 70.8 (OCH2), 70.4 (OCH2), 59.7 (NCCH2Ar), 39.8 (ArCH2)
21.8 (Me). IR (CHCl3) cmꢂ1: 1800, 1720, 1680, 1600. MS (FAB) m/z:
430 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for C18H18NO5Cl2S: 430.0283.
Found: 430.0283.
4.6.3. (R)-[4-(4-Bromobenzyl)-2-oxazolydinon-4-yl]methyl p-tolue-
nesulfonate [(R)-16c]. p-Toluenesulfonate (R)-16c (1.16 g, 95%) was
obtained from (S)-15c (793 mg, 2.77 mmol) according to the pro-
4.6.6. (4S)-4-Benzyl-2-oxo-oxazolidin-4-ylmethyl p-toluene-4-
sulfonate [(R)-16a]. TfOH (31 mL, 0.35 mmol) was added to a mix-
ture of tosylate 17a (163 mg, 0.351 mmol) and anisole (190 mg,
1.76 mmol) in MeNO2 (1.8 mL) at room temperature. The resulting
mixture was stirred for 1 h at 100 ꢀC. After being cooled to room
temperature, the reaction mixture was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2. The extracts were
combined, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was chromatographed on silica gel (hexane/AcOEt, 1:1)
to afford (R)-16a as a colorless amorphous foam (115 mg, 91%).
cedure described in 4.6.1; colorless amorphous form. ½a D25
þ6.2
ꢁ
(c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3)
d
: 7.78 (2H, d, J¼8.3 Hz, Ar),
7.38e7.41 (4H, m, Ar), 6.98 (1H, d, J¼8.3 Hz, Ar), 4.16 (1H, d,
J¼9.2 Hz, COCHH), 4.14 (1H, d, J¼9.2 Hz, COCHH), 3.89 (1H, d,
J¼14.0 Hz, TsOCHH), 3.84 (1H, d, J¼14.0 Hz, TsOCHH), 2.96 (1H, d,
J¼13.9 Hz, ArCHH), 2.85 (1H, d, J¼13.9 Hz, ArCHH), 2.48 (3H, s, Me).
13C NMR (100 MHz, CDCl3)
d: 157.4 (C]O), 145.7 (Ar, C), 132.2 (Ar,
C), 132.0 (Ar, CH ꢃ2), 131.7 (Ar, C), 131.5 (Ar, CH ꢃ2), 130.1 (Ar, CH
ꢃ2), 127.9 (Ar, CH ꢃ2), 121.1 (Ar, C), 70.9 (OCH2), 70.2 (OCH2), 59.5
(NCCH2Ar), 40.5 (ArCH2) 21.9 (Me). IR (neat) cmꢂ1: 1760, 1370,1180,
1040. MS (FAB) m/z: 440 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for
C18H18BrNO3: 440.0167. Found: 440.0181.
½
a 2D1
ꢁ
ꢂ32.6 (c 0.8, MeOH).
4.6.7. (4S)-4-Benzyl-2-oxo-oxazolidin-4-ylmethyl methanesulfonate
[(R)-16d]. Mesylate (R)-16d (84.2 mg, 87%) was synthesized from
mesylate 17b (132 mg, 0.34 mmol) according to the procedure from
17a to (R)-16a. Colorless solid, mp 170e175 ꢀC. ½a D24
ꢂ31.8 (c 0.2,
ꢁ
4.6.4. (4R,
a
R)-4-Benzyl-3-(
a
-methylbenzyl)-2-oxo-oxazolidin-4-
MeOH). 1H NMR (400 MHz, CD3OD)
d: 7.32e7.35 (2H, m, Ar),
ylmethyl p-toluene-4-sulfonate (17a). p-Tolunenesulfonyl chloride
(TsCl) (367 mg, 1.93 mmol) was added to a solution of (4S)-5a
(200 mg, 0.644 mol) in pyridine (1.5 mL). The reaction mixture was
stirred for four days. After the work up described in 4.6.1, the crude
product was purified with silica gel chromatography (hexane/
AcOEt, 7:3 then 3:7) to afford 17a (256 mg, 86%) as colorless solid,
7.26e7.29 (3H, m, Ar), 4.27 (1H, d, J¼9.3 Hz, OCHH), 4.25 (1H, d,
J¼10.5 Hz, OCHH), 4.24 (1H, d, J¼9.3 Hz, OCHH), 4.22 (1H, d,
J¼10.5 Hz, OCHH), 3.15 (3H, s, Me), 2.99 (1H, d, J¼13.9 Hz, PhCHH),
2.89 (1H, d, J¼13.9 Hz, PhCHH). 13C NMR (100 MHz, CD3OD)
d: 135.4
(C, Ar), 131.4 (CH ꢃ2, Ar), 129.4 (CH ꢃ2, Ar), 128.2 (CH, Ar), 73.1
(OCH2), 70.8 (OCH2), 61.5 (C), 41.4 (CH2), 37.3 (Me). IR (KBr) cmꢂ1
:
mp 118e120 ꢀC. ½a D19
ꢁ
ꢂ10.6 (c 0.98, CHCl3). 1H NMR (400 MHz,
3354, 3026, 2936, 1752, 1351, 1179, 1036, 999. MS (FAB) m/z: 286
[(Mþ1)þ]. HRMS (FAB) m/z: calcd for C12H16NO5S: 286.0750. Found:
286.0753. Anal. Calcd for C12H15NO5S: C, 50.52; H, 5.30; N, 4.91.
Found: C, 50.63; H, 5.59; N, 4.64.
CDCl3)
d
: 7.81 (2H, d, J¼8.3 Hz, Ar), 7.51 (2H, d, J¼7.1 Hz, Ar), 7.39
(2H, d, J¼7.8 Hz, Ar), 7.34 (2H, t, J¼7.3 Hz, Ar), 7.27e7.29 (1H, m,
Ar), 7.18e7.24 (3H, m, Ar), 6.93e6.95 (2H, m, Ar), 4.53 (1H, q,
J¼7.1 Hz, PhCH), 4.21 (1H, d, J¼9.3 Hz, OCHH), 4.11 (1H, d,
J¼10.3 Hz, OCHH), 3.98 (1H, d, J¼10.3 Hz, OCHH), 3.69 (1H, d,
J¼9.3 Hz, OCHH), 3.09 (1H, d, J¼13.7 Hz, PhCHH), 2.75 (1H, d,
J¼PhCHH), 2.48 (3H, s, Me), 1.78 (3H, d, J¼7.1 Hz, Me). 13C NMR
4.7. Synthesis of (R)-a-(hydroxymethyl)phenylalanine (7)
4.7.1. (R)-(4-Benzyl-2-oxo-4-oxazolidine)carboxylic acid (18).
RuCl3$nH2O (9.9 mg) and NaIO4 (1.52 g, 7.09 mmol) were added to
a stirred mixture of 2-oxazolidinone (S)-15a (358 mg, 1.73 mmol)
in CCl4/MeCN/H2O16 (2:2:3, 17 mL). The mixture was stirred vig-
orously at room temperature for 5 h. The reaction mixture was
filtered through a pad of Celite, and the filtrate was concentrated
in vacuo. The residue (372 mg) was purified with silica gel column
chromatography (AcOEt) to give 18 (187 mg, 49%). Colorless
(100 MHz, CDCl3) d: 156.2 (C]O), 145.6 (C, Ar), 142.1 (C, Ar), 133.0
(C, Ar), 131.8 (C, Ar), 130.0 (CH ꢃ2), 129.7 (CH ꢃ2), 128.8 (CH ꢃ2),
128.5 (CH ꢃ2), 127.8 (CH ꢃ2), 127.6 (CH, Ar), 127.5 (CH, Ar), 127.1
(CH ꢃ2, Ar), 69.5 (OCH2), 67.8 (OCH2), 63.9 (C), 53.1 (CH), 40.5
(CH2), 21.9 (Me), 20.0 (Me). IR (KBr) cmꢂ1: 2360, 1761, 1446, 1413,
1371, 1270, 1189, 1096. MS (FAB) m/z: 466 [(Mþ1)þ], 312, 208, 105.
HRMS (FAB) m/z: calcd for C26H27NO5S: 466.1689. Found:
466.1679. Anal. Calcd for C26H27NO5S: C, 67.08; H, 5.85; N, 3.01.
Found: C, 67.06; H, 6.03; N, 2.97.
needles, mp 201e203 ꢀC. ½a D17
ꢁ
ꢂ14.1 (c 0.4, MeOH). 1H NMR
(400 MHz, CDCl3)
d
: 7.25e7.30 (5H, m, Ar), 4.55 (1H, d, J¼9.3 Hz,
OCHH), 4.31 (1H, d, J¼9.0 Hz, OCHH), 3.20 (1H, d, J¼13.7 Hz,
4.6.5. (4S,aR)-4-Benzyl-3-(a-methylbenzyl)-2-oxo-oxazolidin-4-
PhCHH), 13.9 (1H, d, J¼13.9 Hz, PhCHH). 13C NMR (100 MHz,
ylmethyl methanesulfonate (17b). Methanesulfonyl chloride (MsCl)
(1.93 mmol, 221 mg) was added to a solution of oxazolidinone (4S)-
5a (200 mg, 0.644 mmol) in pyridine (1.5 mL) at 0 ꢀC. After being
stirred 15 h at room temperature, the reaction mixture was diluted
with AcOEt and washed with water, 10% hydrochloric acid, satu-
rated aqueous NaHCO3, and brine, consequently. The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The
residue was chromatographed on silica gel (hexane/AcOEt, 3:7)
to afford 17b (223 mg, 89%). Colorless solid, mp 137e142 ꢀC.
CDCl3) d: 164.8 (C]O), 151.0 (C]O), 125.9 (Ar, C), 121.7 (Ar, CH
ꢃ2), 119.8 (Ar, CH ꢃ2), 118.7 (Ar, CH), 64.2 (OCH2), 56.5 (NCBn),
33.7 (PhCH2). IR (CHCl3) cmꢂ1: 1750, 1600. MS (EI) m/z: 221 (Mþ,
4.8%), 175 (3.4), 130 (4.4), 91 (100). HRMS (EI) m/z: calcd for
C11H11NO4: 221.0688. Found: 221.0693.
4.7.2. (R)-2-Amino-3-hydroxy-2-benzylpropionic acid [(R)-a-(hy-
droxymethyl)phenylalanine] (7). A solution of 2-oxazolidinone 18
(101 mg, 0.46 mmol) in 6 mol/L HCl aq (4.6 mL) was refluxed for
12 h. The reaction mixture was concentrated. The residue was di-
luted with H2O and washed three times with CH2Cl2. The aqueous
layer was concentrated in vacuo to give a residue (100 mg). The
residue (77.0 mg) was purified through a DOWEX 50 WeX8
(100e200 mesh) column eluting with 5% aqueous ammonia to give
a pure 7 (65.0 mg, 84%). Colorless powder, mp 261e263 ꢀC (de-
½
a 1D9
ꢁ
ꢂ11.4 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.55 (2H, d,
J¼7.8 Hz, Ar), 7.36 (2H, t, J¼7.1 Hz, Ar), 7.25e7.31 (4H, m, Ar),
6.98e7.31 (4H, m, Ar), 4.57 (1H, q, J¼7.1 Hz, PhCH), 4.32
(d, J¼10.7 Hz, OCHH), 4.30 (1H, d, J¼10.7 Hz, OCHH), 4.13
(d, J¼10.5 Hz, OCHH), 3.96 (d, J¼9.3 Hz, OCHH), 3.08 (3H, s, SO2Me),
3.04 (1H, d, J¼13.7 Hz, PhCHH), 2.85 (1H, d, J¼13.9 Hz, PhCHH), 1.91
(3H, d, J¼7.1 Hz, Me). 13C NMR (100 MHz, CDCl3)
d: 156.5 (C]O),
compose). ½a 2D1
ꢁ
ꢂ16.4 (c 1.0, H2O) {(S)-form,9b
½
a 2D0
ꢁ
þ16.4 (c 0.89,

S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
8043
H2O)}. 1H NMR (400 MHz, D2O)
d
: 7.37e7.42 (3H, m, Ar), 7.27 (2H, d,
79.9 (C), 69.8 (CH2), 57.3 (C), 41.1 (CH2), 28.5 (Me ꢃ3), 23.3 (Me).
IR (CHCl3) cmꢂ1: 1700, 1500, 1370, 1160. MS (FAB) m/z: 266
[(Mþ1)þ]. HRMS (FAB) m/z: calcd for C15H24NO3, 266.1757; found,
266.1756.
J¼6.8 Hz, Ar), 4.05 (1H, d, J¼12.0 Hz, OCHH), 3.78 (1H, d, J¼12.0 Hz,
OCHH), 3.26 (1H, d, J¼14.2 Hz, CHHPh), 2.97 (1H, d, J¼14.4 Hz,
CHHPh). 13C NMR (100 MHz, D2O)
d: 173.6 (C]O), 133.8 (Ar, C),
130.2 (Ar, CH), 129.2 (Ar, CH ꢃ2), 128.1 (Ar, CH ꢃ2), 67.4 (NCPh) 64.5
(OCH2), 38.3 (CH2Ph). MS (FAB) m/z: 196 [(Mþ1)þ]. HRMS (FAB) m/
z: calcd for C10H14NO3: 196.0974. Found: 196.0966.
4.8.5. (S)-N-Boc-a-methylphenylalanine (8). To a solution of N-Boc-
aminoalcohol 21 (47.8 mg, 0.18 mmol) in CCl4/MeCN/H2O (2:2:3,
0.91 mL) was added NaIO4 (158 mg, 0.74 mmol) and RuCl3$nH2O
(1.1 mg) under stirring vigorously at room temperature for 8 h. The
reaction mixture was diluted with AcOEt, washed with water. The
aqueous layer was extracted with AcOEt twice. The organic layers
were combined, dried over MgSO4, and concentrated in vacuo. The
residue was purified with silica gel column chromatography (CHCl3)
to give 8 (24.3 mg, 48%, >99% ee detected by HPLC). Colorless powder,
4.8. Synthesis of N-Boc-a-methylphenylalanine (8)
4.8.1. (S)-4-Benzyl-4-methyl-2-oxazolidinone
[(S)-19]. NaBH4
(40.9 mg, 1.08 mmol) was added to a solution of oxazolidinone (S)-
16a (196 mg, 0.54 mmol) in DMSO (1.4 mL), and the mixture was
stirred for 3 h at 100 ꢀC.17 After cooling to rt, the reaction mixture
was diluted with Et2O and washed with 10% HCl aq. The organic
layer was separated, dried over MgSO4, and concentrated in vacuo.
The residue was purified with silica gel column chromatography
(hexane/AcOEt, 1:1) to give (S)-19 (74.1 mg, 71%). Colorless plate,
mp 119e121 ꢀC, ½a D27
ꢁ
þ12.6 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d
: 7.24e7.27 (3H, m, Ar), 7.14 (2H, d, J¼6.79 Hz, Ar), 5.08(1H, br, s, NH),
3.30 (2H, s, ArCH2), 1.56 (3H, s, Me), 1.47 (9H, s, t-Bu). 13C NMR
(100 MHz, CDCl3) : 178.2 (C]O),154.7 (C]O),135.9 (Ar, C),130.1 (Ar,
d
mp 82e86 ꢀC. ½a 2D6
ꢁ
þ28.2 (c 0.3, EtOH). {(R)-form,18
½
a 2D5
ꢁ
ꢂ28.8 (c
CH ꢃ2), 128.1 (Ar, CH ꢃ2), 126.8 (Ar, CH), 71.9 (t-Bu, C), 60.3 (NCBn),
41.4 (PhCH2), 28.5 (t-Bu, Me ꢃ3), 23.7 (Me). IR (CHCl3) cmꢂ1: 3440,
2950, 1720, 1500, 1460, 1380, 1180. MS (FAB) m/z: 280 [(Mþ1)þ].
HRMS (FAB) m/z: calcd for C15H21NO4: 280.1549. found: 280.1540.
HPLC conditions: Chiralcel OD-H column eluted with hexane/2-
propanol/trifluoroacetic acid (90:10:0.1) at 0.5 mL/min using UV
detector at 254 nm. Retention time: tR¼8.1 min and tS¼9.3 min. (RS)-
1.548, EtOH)}. 1H NMR (400 MHz, CDCl3)
d: 7.92e7.37 (3H, m, Ar),
7.17e7.24 (2H, m, Ar), 5.66 (1H, br s, NH), 4.28 (1H, d, J¼8.4 Hz,
COCHH), 4.07 (1H, d, J¼8.4 Hz, COCHH), 2.90 (1H, d, J¼13.4 Hz,
PhCHH), 2.83 (1H, d, J¼13.4 Hz, PhCHH), 1.32 (3H, s, Me). 13C NMR
(100 MHz, CDCl3)
d
: 158.5 (C]O), 135.1 (Ar, C), 130.0 (Ar, CH ꢃ2),
128.5 (Ar, CH ꢃ2), 127.1 (Ar, CH), 75.3 (OCH2), 58.1 (NCPh), 46.3
(PhCH2), 27.9 (Me). IR (CHCl3) cmꢂ1: 1720, 1695, 1390. MS (EI) m/z:
191 (Mþ, 0.5%), 100 [(MꢂBn)þ, 100], 91 (16), 56 (28). HRMS (EI) m/z:
calcd for C11H13NO2, 191.0947; found, 191.0951.
N-Boc-a-methylphenylalanine was synthesized from (RS)-a-meth-
ylphenylalanine (Aldrich) and used for the HPLC analysis.
4.9. Synthesis of cericlamine (9)
4.8.2. (R)-4-Benzyl-4-methyl-2-oxazolidinone [(R)-19]. Reductive
demesylation of (R)-16d (61.3 mg, 0.215 mmol) was carried out
according to the procedure described in 4.8.1 to afford (R)-19
4.9.1. (S)-3-(3,4-Dichlorophenyl)-2-methyl-2-methylamino-1-
propanol (22). LiAlH4 (71.1 mg, 1.78 mmol) was added carefully to
a solution of the oxazolidinone (S)-16b (255 mg, 0.59 mmol) in
Et2O (3.0 mL, 0.2 mol/L) with cooling by use of an ice bath.18 The
(35.3 mg, 86%). ½a D26
ꢂ22.7 (c 0.7, EtOH).
ꢁ
4.8.3. (S)-4-Benzyl-3-tert-butoxycarbonyl-4-methyl-2-oxazolidinone
[(S)-20]. A mixture of oxazolidinone (S)-19 (74.1 mg, 0.39 mmol),
Boc2O (0.77 g, 3.51 mmol), triethylamine (118 mg, 1.17 mmol) and
DMAP (24.4 mg, 0.20 mmol) in THF (0.78 mL) was stirred for 3.5 h at
room temperature. The reaction mixture was diluted with water and
extracted with AcOEt twice. The extracts were combined, dried over
MgSO4, and concentrated in vacuo. The residue was purified with
silica gel column chromatography (hexane/AcOEt, 3:2) to give (S)-20
mixture was refluxed for 3 h. After cooling, H2O/THF (1:1, 142
was added dropwise carefully, and 15% NaOH aq (70 L) and then
water (105 L) were added to the mixture successively. The
mL)
m
m
resulting mixture was stirred for 2 h at room temperature and fil-
tered through a glass filter. The solid was washed with Et2O. The
filtrate was extracted three times with 10% HCl aq. The aqueous
layers were combined, made basic (pH¼ca. 11) with sodium hy-
droxide and extracted three times with Et2O. The organic extracts
were combined, washed twice with H2O, dried over MgSO4, and
concentrated in vacuo. The residue was chromatographed on silica
gel (CHCl3/MeOH, 7:3) to give a pure 22 (92.8 mg, 63%); colorless
(94.0 mg, 83%). Colorless oil. ½a D28
ꢁ
þ65.2 (c 1.7, CHCl3). 1H NMR
(500 MHz, CDCl3) d: 7.33e7.26 (3H, m, Ar), 7.16e7.14 (2H, m, Ar), 4.27
(1H, d, J¼8.6 Hz, OCHH), 3.77 (1H, d, J¼8.9 Hz, OCHH), 3.32 (1H, d,
J¼13.7 Hz, PhCHH), 2.96 (1H, d, J¼13.7 Hz, PhCHH), 1.61 (9H, s, tBu),
powder, mp 111e112 ꢀC. ½a D22
ꢁ
þ3.5 (c 0.4, CHCl3). 1H NMR
1.59 (3H, s, Me).13C NMR (125 MHz, CDCl3)
d: 152.4 (C]O),149.8 (C]
(400 MHz, CDCl3)
d
: 7.35 (1H, d, J¼8.3 Hz, Ar), 7.28 (1H, d, J¼2.0 Hz,
O), 135.0 (C), 130.0 (CH ꢃ2), 128.8 (CH ꢃ2), 127.5 (CH), 83.9 (C), 71.1
Ar), 7.03 (1H, dd, J¼8.3, 2.0 Hz, Ar), 3.30 (1H, d, J¼10.7 Hz, CHHOH),
3.24 (1H, d, J¼10.7 Hz, CHHOH), 2.69 (1H, d, J¼13.2 Hz, CHHAr),
2.63 (1H, d, J¼13.2 Hz, CHHAr), 2.36 (3H, s, NMe), 0.98 (3H, s, Me).
(CH2), 62.3 (C), 42.8 (CH2), 28.2 (Me ꢃ3), 24.7 (Me). IR (CHCl3) cmꢂ1
:
1810, 1730, 1350, 1330, 1170, 1090. MS (FAB) m/z: 292 [(Mþ1)þ].
HRMS (FAB) m/z: calcd for C16H22NO4, 292.1550; found, 292.1540.
13C NMR (100 MHz, CDCl3)
d: 137.7 (Ar, C), 132.0 (Ar, CH), 131.9 (Ar,
C), 130.3 (Ar, C), 129.9 (Ar, CH), 129.7 (Ar, CH), 65.0 (HOCH2), 56.8
4.8.4. (S)-2-(tert-Butoxycarbonyl)amino-2-methyl-3-phenylpropan-
1-ol (21). To a solution of N-Boc-oxazolidinone 20 (82.5 mg,
0.28 mmol) in MeOH (2.8 mL) was added Cs2CO3 (45.6 mg,
0.14 mmol) at room temperature,19 and the resulting mixture was
stirred for 4 h. After the neutralization with saturated aqueous
citric acid, the product was extracted with AcOEt three times. The
extracts were combined, dried over MgSO4, and concentrated in
vacuo. The residue was purified with silica gel column chroma-
tography (hexane/AcOEt, 4:1) to give 21 (58.4 mg, 78%). Colorless
(NCCH2Ar), 41.2 (ArCH2), 28.2 (NMe), 20.3 (Me). IR (CHCl3) cmꢂ1
:
2930,1475,1135,1040. MS (FAB) m/z: 248 [(Mþ1)þ]. HRMS (FAB) m/
z: calcd for C11H16Cl2NO: 248.0609. Found: 248.0604.
4.9.2. (S)-3-(3,4-Dichlorophenyl)-2-dimethylamino-2-methyl-1-
propanol (cericlamine) (9). To a solution of propanol 22 (68.0 mg,
0.27 mmol) inTHF (2.2 mL) were added paraformaldehyde (81.1 mg,
2.70 mmol) and NaBH4 (102 mg, 2.7 mmol).20 Then a solution of TFA
(1.10 mL,14.3 mmol) inTHF (6.5 mL) was added dropwise (10 drops/
min) under stirring vigorously at room temperature over 30 min,
and the resulting mixture was stirred for 18 h at room temperature.
The reaction mixture was diluted with H2O and made basic with
sodium hydroxide. The basic mixture was extracted three times
with AcOEt. The extracts were combined, dried over MgSO4, and
needle, mp 65e67 ꢀC.
(400 MHz, CDCl3)
½
a 2D8
ꢁ
ꢂ72.4 (c 1.0, CHCl3). 1H NMR
d
: 7.21e7.19 (5H, m, Ar), 4.20 (1H, br s, NH),
3.69 (2H, s, CH2O), 3.18 (1H, d, J¼13.4 Hz, PhCHH), 2.80 (1H, d,
J¼13.6 Hz, PhCHH), 1.47 (9H, s, tBu). 13C NMR (125 MHz, CDCl3)
d:
156.0 (C]O), 136.8 (C), 130.5 (CH ꢃ2), 128.0 (CH ꢃ2), 126.4 (CH),

8044
S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
concentrated in vacuo. The residue (71.8 mg) was purified with silica
gel column chromatography (CHCl3/MeOH, 9:1) to give a pure 9
1.2 mL). The mixture was stirred vigorously at room temperature
for 20 h. The reaction mixture was filtered through Celite, and the
filtrate was concentrated in vacuo. The residue (32.0 mg) was pu-
rified with silica gel column chromatography (hexane/AcOEt, 1:1)
(62.1 mg, 86%). Colorless powder, mp 65e67 ꢀC. ½a D16
þ6.4 (c 0.6,
ꢁ
EtOH) {Ref., ½a 2D2
ꢁ
þ6.3 (c 1.0, EtOH)10a}. 1H NMR (400 MHz, CDCl3)
d:
7.33 (1H, d, J¼8.3 Hz, Ar), 7.27 (1H, d, J¼2.0 Hz, Ar), 7.05 (1H, dd,
J¼8.3, 2.0 Hz, Ar), 3.28 (1H, d, J¼10.8 Hz, CHHOH), 3.22 (1H, d,
J¼10.8 Hz, CHHOH), 2.74 (1H, d, J¼12.8 Hz, CHHAr), 2.64 (1H, d,
J¼12.8 Hz, CHHAr), 2.35 (6H, s, NMe2), 0.89 (3H, s, Me). 13C NMR
to give a pure 12 (16.5 mg, 55%); colorless powder. ½a D17
ꢂ133.5
ꢁ
(c 0.2, EtOH) {Ref., ½a D25
ꢁ
ꢂ134.3 (c 1.0, EtOH)11d}. 1H NMR (400 MHz,
CDCl3)
d
: 7.44 (2H, d, J¼6.4 Hz, Ar), 7.26e7.29 (1H, m, Ar), 6.94 (2H,
d, J¼8.8 Hz, Ar), 6.85 (2H, d, J¼1.6 Hz, Ar), 3.09 (1H, d, J¼16.4 Hz,
(100 MHz, CDCl3) d: 138.2 (Ar, C), 132.1 (Ar, CH), 131.8 (Ar, C), 130.3
ArCHH), 3.07 (3H, s, NMe), 2.97 (1H, d, J¼14.0 Hz, ArCHH), 1.62 (3H,
(Ar, C), 129.9 (Ar, CH), 129.8 (Ar, CH), 63.9 (HOCH2), 60.5 (NCCH2Ar),
38.4 (ArCH2), 38.1 (NMe2), 15.8 (Me). IR (CHCl3) cmꢂ1: 2950, 1480,
1140, 1050. MS (FAB) m/z: 262 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for
C12H18Cl2NO: 262.0765. Found: 262.0760.
s, Me). 13C NMR (100 MHz, CDCl3)
d: 173.1 (C]O), 153.3 (C]O),
134.9 (Ar, C ꢃ2), 132.9 (Ar, C), 132.7 (Ar, C), 131.7 (Ar CH ꢃ2), 131.0
(Ar, CH ꢃ2), 128.2 (Ar, CH), 124.4 (Ar, CH ꢃ2), 121.9 (Ar, C), 65.7
(NCMe), 40.9 (CH2Ar), 25.5 (NMe), 21.2 (Me). IR (CHCl3) cmꢂ1: 1720.
MS (FAB) m/z: 441 [(Mþ1)þ]. HRMS (FAB) m/z: calcd for
C18H16BrCl2N2O2: 440.9772. Found: 440.9780.
4.10. Synthesis of BIRT-377 (10)
4.10.1. (R)-3-(4-Bromophenyl)-2-methyl-2-methylamino-1-propanol
(23). LiAlH4 (297 mg, 7.44 mmol) was added carefully to a solution
of the oxazolidinone (R)-16c (1.09 g, 2.48 mmol) in THF (12.4 mL)
with cooling by use of an ice bath.18 The mixture was refluxed for
Acknowledgements
The authors wish to thank the staff of the Analysis Center of
Meiji Pharmaceutical University for performing the elemental
analysis (Ms. S. Kubota) and mass spectra (Ms. T. Koseki). We are
also grateful to Ms. S. Akiba and Mr. H. Hotaka for their technical
assistance. This work was supported by a grant from the High-Tech
Research Center Project, the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan (S081043).
3 h. After cooling, H2O/THF (1:1, 600
mL) was added dropwise
carefully, and 15% NaOH aq (300 L) and then water (450
m
mL) were
added to the mixture successively. The resulting mixture was stir-
red for 19 h at room temperature and filtered through a glass filter.
The solid was washed with AcOEt. The filtrate was washed twice
with water. The organic layer was dried over MgSO4, and concen-
trated in vacuo. The residue (498 mg) was chromatographed on
silica gel (CHCl3/MeOH, 7:3) to give a pure 23 (428 mg, 67%); col-
Supplementary data
orless powder, mp 144e146 ꢀC. ½a D27
ꢁ
ꢂ1.4 (c 1.0, CHCl3). 1H NMR
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.090.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
(400 MHz, CDCl3)
d
: 7.35 (1H, d, J¼8.3 Hz, Ar), 7.28 (1H, d, J¼2.0 Hz,
Ar), 7.03 (1H, dd, J¼8.3, 2.0 Hz, Ar), 3.30 (1H, d, J¼10.7 Hz, CHHOH),
3.24 (1H, d, J¼10.7 Hz, CHHOH), 2.69 (1H, d, J¼13.2 Hz, CHHAr),
2.63 (1H, d, J¼13.2 Hz, CHHAr), 2.36 (3H, s, NMe), 0.98 (3H, s, Me).
13C NMR (100 MHz, CDCl3)
d: 137.7 (Ar, C), 132.0 (Ar, CH), 131.9 (Ar,
References and notes
C), 130.3 (Ar, C), 129.9 (Ar, CH), 129.7 (Ar, CH), 65.0 (HOCH2), 56.8
(NCCH2Ar), 41.2 (ArCH2), 28.2 (NMe), 20.3 (Me). IR (neat) cmꢂ1
:
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2007, 1487e1495; (c) Bella, M.; Gasperi, T. Synthesis 2009, 10, 1583e1614; (d)
Cativiela, C.; Ordonez, M. Tetrahedron: Asymmetry 2009, 20, 1e63; (e) Mosey, R.
A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymmetry 2008, 19, 2755e2762.
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Hoshino, A.; Kinbara, A. Tetrahedron 2006, 62, 4103e4109; (g) Donohoe, T. J.;
Rigby, C. L.; Thomas, R. E.; Nieuwenhuys, W. F.; Bhatti, F. L.; Cowley, A. R.; Bhalay,
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2940, 1500, 1420. MS (FAB) m/z: 258 [(Mþ1)þ]. HRMS (FAB) m/z:
calcd for C11H17BrNO: 258.0494. Found: 258.0503.
4.10.2. (R)-1-(1-(4-Bromophenyl)-3-hydroxy-2-methylpropan-2-yl)-
3-(3,5-dichlorophenyl)-1-methylurea (24). Propanol 23 (157 mg,
0.61 mmol) was added portionwise to a stirred solution of sodium
hydride (ca. 60% oil suspension, 48.8 mg, ca. 1.22 mmol) in THF
(6.1 mL), followed by an addition of 3,5-dichlorophenylisocyanate
(239 mg, 1.22 mmol). The reaction mixture was stirred for 4 h at
room temperature. The reaction mixture was diluted with AcOEt,
washed with saturated aqueous NaCl. The aqueous layer was
extracted three times with AcOEt. Theextractswere combined, dried
over MgSO4, and concentrated in vacuo. The residue (290 mg) was
chromatographed on silica gel (hexane/AcOEt, 9:1) to give a pure 24
ꢀ
(183 mg, 67%); colorless powder, mp 163e165 ꢀC. ½a D22
þ12.2 (c 2.0,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3)
d
: 7.41 (1H, d, J¼8.4 Hz, Ar),
7.25e7.28 (3H, m, Ar), 6.95e6.99 (3H, m, Ar), 3.59 (1H, d, J¼8.8 Hz,
CHHOH), 3.31 (1H, d, J¼9.2 Hz, CHHOH), 2.90 (3H, s, N-Me), 2.88 (1H,
d, J¼15.2 Hz, CHHAr), 2.73 (1H, d, J¼13.6 Hz, CHHAr),1.40 (3H, s, Me).
13C NMR (100 MHz, CDCl3)
d: 155.8 (C]O), 141.7 (Ar, C), 134.8 (Ar, C
ꢃ2), 134.2 (Ar, C), 131.6 (Ar, CH ꢃ2), 131.3 (Ar, CH ꢃ2), 121.8 (Ar, CH),
121.3 (Ar, C), 115.2 (Ar, CH ꢃ2), 57.6 (NCCH2Ar), 53.3 (HOCH2), 42.6
(ArCH2), 25.3 (NMe), 24.2 (Me). IR (neat) cmꢂ1: 2940,1500,1420. MS
(FAB) m/z: 427 [(MꢂH2Oþ1)þ]. HRMS (FAB) m/z: calcd for
C18H18BrCl2N2O (MꢂH2Oþ1): 426.9980. Found: 426.9979.
8. Recent publications of asymmetric synthesis of a-(hydroxymethyl)phenylala-
nine: (a) Jew, S.-s.; Lee, Y.-J.; Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.;
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dimethylimidazolidine-2,4-dione
(BIRT-377)
(10). RuCl3$nH2O
(1.8 mg) and NaIO4 (62.0 mg, 0.29 mmol) were added to a stirred
solution of urea 24 (30.5 mg, 0.07 mmol) in AcOEt/H2O21 (5:1,

S. Sugiyama et al. / Tetrahedron 68 (2012) 8033e8045
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