Improved stereoselectivity in intramolecular SN2′ cyclization through use of mechanistic principles

Article abstract of DOI:10.1055/s-2006-958956

Valine and alanine were converted into the corresponding α-hydroxy-β-amino acids through intramolecular S_N2′ cyclization. The novel cyclization protocol relied upon the use of N-benzyl-protected carbamates derived from α-amino acids. Georg Thie

Full text of DOI:10.1055/s-2006-958956

PAPER
209
Improved Stereoselectivity in Intramolecular SN2¢ Cyclization through Use of
Mechanistic Principles
I
mprove
d
Stereoselectiv
o
ity in Intram
o
olecular
S
2
¢
CycliD
zation uck Seo,a Marcus J. Curtis-Long,b Seong Hun Jeong,a Tae Hong Jun,a Min Suk Yang,a Ki Hun Park*a
N
a
Fax +82(55)7570178; E-mail: khpark@gshp.gsnu.ac.kr
Woodview, 12 New Road, Nafferton, East Yorkshire, YO25 4JP, UK
b
Received 28 August 2006; revised 17 October 2006
acids containing bulky side chains, but has, sadly, been of
low utility in substrates possessing smaller side chains
(valine and alanine). The objective of the work reported
here has been to extend this methodology to allow stereo-
selective synthesis of ABHAs possessing smaller side
chains. We will also discuss the mechanistic features of
the cyclization transition state as elucidated during this
work.
Abstract: Valine and alanine were converted into the correspond-
ing a-hydroxy-b-amino acids through intramolecular SN2¢ cycliza-
tion. The novel cyclization protocol relied upon the use of N-
benzyl-protected carbamates derived from a-amino acids
Key words: oxazolidin-2-one, intramolecular cyclization, stereo-
selectivity, A(1,3) strain, a-hydroxy-b-amino acids
Synthesis of the substrates began with chemoselective re-
duction of N-Boc-N-Bn-protected a-amino esters 3a and
3b with lithium aluminum hydride (Scheme 1).[4] Swern
oxidation of the resulting (2-hydroxyethyl)carbamates 4a
and 4b furnished chiral aldehydes, which underwent an E-
selective Horner–Wadsworth–Emmons reaction that af-
forded allylic carbamates 5a and 5b. Finally, chemoselec-
tive reduction of the ester moiety with diisobutyl-
aluminum hydride generated the cyclization precursors,
allylic alcohols 6a and 6b (Scheme 1).
The derivatization of a-amino acids continues to be a vi-
brant and fruitful area of chemical endeavor because of
the high optical purity and varied reactivity of these start-
ing materials.1 a-Amino acids have been converted effi-
ciently into enantiopure amino epoxides,2 amino
alcohols,3 amino diols,4 and a wide range of unsaturated
intermediates, as well as into b-amino acids. b-Amino
acids5 are of great chemical significance, and the huge in-
terest in this field has been reflected in the publication of
a number of recent reviews on both the general chemical
function and the synthesis of this class of compound.6
However, despite their abundance in important bioactive
compounds such as Taxol,7 highly selective routes to a-
hydroxy-b-amino acids (ABHAs; e.g., 1 and 2, Figure 1)
are much rarer, because the controlled generation of two
or more stereogenic centers is required. We were able to
show that the derivatization of diastereo- and enantiomer-
ically pure oxazolidinones constitutes a powerful route to
ABHAs.4,8
O
R
R
i
OMe
Boc
OH
Boc
N
N
Bn
Bn
4a R = iPr
4b R = Me
3a R = iPr
3b R = Me
ii
O
R
R
OH
iii
OEt
OH
OH
N
N
OH
OH
Bn
Boc
Bn
Boc
6a R = iPr
6b R = Me
5a R = iPr
5b R = Me
NH2
O
NH2
O
2
1
Scheme 1 Reagents and conditions: (i) see ref. 4; (ii) (a) Swern oxi-
dation; (b) (EtO)2P(O)CH2CO2Et (2 equiv), NaH (2 equiv), dry THF,
0 °C to r.t., 82% yield; (iii) DIBAL-H (3.0 equiv), THF, –78 °C, 85%
yield.
Figure 1 Target compounds
This methodology is based on the conversion of a-amino
acids into oxazolidin-2-ones through cyclization of (4-hy-
droxybutenyl)carbamates, in which the hydroxy group
(nucleofuge) has been activated as a sulfonate prior to an
internal SN2¢ cyclization.4 This cyclization strategy has
been highly effective for substrates derived from a-amino
Under our previously reported conditions, namely the use
of trifluoromethanesulfonic anhydride in pyridine at
–78 °C, allylic alcohols 6c and 6f (R2 = H) gave the corre-
sponding oxazolidinones 7 in 1:2 and 1:5 cis/trans selec-
tivities, respectively (Table 1, entries 1 and 4). However,
when the steric bulk at nitrogen was increased by
N-methylation (6d and 6g, R2 = Me), the cyclization pro-
ceeded slightly more selectively, to afford the oxazolidi-
SYNTHESIS 2007, No. 2, pp 0209–0214
x
x
.
x
x
.2
0
0
7
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958956; Art ID: F13406SS
© Georg Thieme Verlag Stuttgart · New York

210
W. D. Seo et al.
PAPER
3
1
none products 7 in improved cis/trans ratios (Table 1,
entries 2 and 5). We subsequently investigated the effect
of the more sterically demanding N-benzyl substituent (6e
and 6h, R2 = Bn) upon the selectivity (Table 1, entries 3
and 6). Triflation/cyclization of alanine derivative 6e and
valine derivative 6h led to a dramatic improvement in the
selectivities, with the corresponding trans-oxazolidinones
7 forming in 15:1 and an excellent 99:1 dr, respectively
(Table 1, entries 3 and 6).
R1
R2
4
OH
2
N
Boc
syn-pentane
interaction
when R2 > H
OtBu
R2
R1
N
OtBu
O
R2
R1
H
H
N
O
minimize
syn-pentane
interactions
H
H
OTf
TfO
H
Table 1 Optimization of the SN2¢ Cyclization Step
B
A
minimize
A(1,3) strain
R1
R1
R1
R2
OH
Tf2O, py
R2
N
O
R2
N
O
+
R1
R1
N
CH2Cl2, –78 °C
Boc
O
O
R2
N
O
6
R2
N
O
trans-7
cis-7
O
O
Entry
Substrate 6 R1
R2
H
dra
1:2
1:4
Yieldb (%)
Figure 2 Model explaining increased anti selectivity when R2 = Bn
1
2
3
4
5
6
6c
6d
6e
6f
Me
65
70
85
76
83
85
Me
Me
i-Pr
i-Pr
i-Pr
Me
Bn
H
nally, the amino group was deprotected by hydrogenolysis
to give (2R,3S)-14 and (2R,3S)-211 in 90% yield
(Scheme 2).
1:15
1:5
O
6g
6h
Me
Bn
1:8
R
OH
R
1:99
i
Bn
N
O
Bn
N
O
a The dr (cis/trans) was determined by 1H NMR integration.
b Isolated yield.
O
O
8a R = iPr
8b R = Me
7a R = iPr
7b R = Me
Previously, our consideration of the mechanism of the cy-
clization, as well as molecular modeling studies led us to
conclude that minimization of A(1,3) strain9 by eclipsing
of C(2)H and C(4)H is a probable cause for the observed
trans selectivity in the case of substrates possessing bulky
R1 substituents. However, we noted that for efficient
A(1,3) strain control, a substituent bulkier than a proton is
generally required in the 2-position (Figure 2) to achieve
good selectivity, and this seems to be the grounds for low
selectivity when R1 is small. However, as our results ver-
ify, when R2 becomes an alkyl group, an extra interaction
occurs, which destabilizes the transition state leading to
the cis product. This interaction may be described as a
syn-pentane interaction between the N–R2 bond and the
olefin. This new interaction is expected to stabilize B over
A, even when R1 is small enough to allow for significant
C(3)–C(4) bond rotation in the absence of other factors.10
(S)
(R)
ii
OH
OH
iii
S
R
OH
R
OH
R
NH2
O
NH
Bn
O
(2R,3S)-1 R = iPr
(2R,3S)-2 R = Me
9a R = iPr
9b R = Me
Scheme 2 Reagents and conditions: (i) (a) OsO4 (10%), NMO (2
equiv), acetone, r.t., 24 h, 90% yield; (b) NaIO4 (1.5 equiv), EtOH–
H2O, 2:1, r.t., 2 h, 80% yield; (c) KMnO4 (1.2 equiv), K2CO3 (2.1
equiv), THF–H2O, 2:1, r.t., 1 h, 75% yield; (ii) 4 M KOH, EtOH,
60 °C, 85% yield; (iii) H2, MeOH, r.t., 90% yield.
The relative stereochemistry within the target molecules 1
and 2 was determined by 2D-NOESY experiments on ox-
azolidinone 7a and 7b, both of which showed a weak cor-
relation between C(4)H and C(5)H. Vicinal coupling
constants between C(4)H and C(5)H (J4,5) are also consis-
tent with this analysis (Figure 3).
The conversion of the oxazolidinone products into the
corresponding ABHAs was next undertaken (Scheme 2).
Dihydroxylation of the vinyl substituent on 7a and 7b is
achieved with osmium tetroxide followed by cleavage in
the presence of periodate, and subsequent oxidation with
potassium permanganate yielded acids 8a and 8b
(Scheme 2). The oxazolidinone ring within these products
was easily cleaved, without epimerization at the C(5)-po-
sition, by reflux in aqueous potassium hydroxide, to give
N-benzyl-protected ABHAs 9a and 9b in 85% yield. Fi-
To prove the enantiomeric purities of the product AHBAs,
compounds (2R,3S)-1 and (2R,3S)-2 were converted first
into the N-Boc-protected methyl ester derivatives 10 and
12,12 and then into the Mosher’s esters 11 and 13
(Scheme 3).4 Analysis of the 19F NMR spectra of the
Mosher’s esters and comparison with a sample synthe-
sized from racemic a-methoxy-a-(trifluoromethyl)phenyl-
Synthesis 2007, No. 2, 209–214 © Thieme Stuttgart · New York

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Improved Stereoselectivity in Intramolecular SN2¢ Cyclization
211
tert-Butyl (S)-Benzyl[1-(hydroxymethyl)-2-methylpropyl]car-
bamate (4a)
O
O
H
H
1
O
2
5
O
Compound 4a was prepared as described in a literature procedure.4
N
N
4
3
[a]D20 –23.1 (c 1.0, CHCl3).
IR (KBr): 3450, 3125, 1732 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (m, 6 H), 1.42 (s, 9 H), 1.82
(m, 1 H), 3.53 (s, 1 H), 3.60 (m, 2 H), 4.08 (d, J = 9.2 Hz, 1 H), 4.83
(d, J = 9.2 Hz, 1 H), 7.26–7.49 (m, 5 H).
weak
NOE
weak
NOE
H
H
Ph
Ph
7a
J4,5 = 3.6 Hz
7b
J4,5 = 4.2 Hz
Figure 3 NOESY correlation and coupling constants of oxazolidi-
nones 7a and 7b
13C NMR (75 MHz, CDCl3): d = 18.5, 19.5, 28.4, 29.2, 58.0, 63.7,
72.6, 79.4, 128.1, 128.8, 135.3, 156.8.
acetic acid (MTPA) showed that the enantiomeric ratio of
the two AHBAs formed in this protocol were >99:1. The
absolute configuration was inferred from the known abso-
lute configuration of the starting a-amino acids.
Anal. Calcd for C17H27NO3: C, 69.59; H, 9.28; N, 4.77. Found: C,
68.57; H, 9.26; N, 4.79.
tert-Butyl (S)-Benzyl(2-hydroxy-1-methylethyl)carbamate (4b)
Compound 4b was obtained by the same procedure as that used for
compound 4a.
Oil; [a]D20 +5.6 (c 2.0, CHCl3).
OH
OMTPA
OMe
OMe
i
ii
1a
IR (KBr): 3356, 2978, 1720 cm–1.
NH
Boc
O
NH
O
Boc
1H NMR (300 MHz, CDCl3): d = 1.14 (d, J = 6.9 Hz, 3 H), 1.45 (m,
9 H), 3.50 (m, 2 H), 4.00 (d, J = 5.7 Hz, 1 H), 4.41 (m, 2 H), 7.23–
7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.7, 28.4, 48.8, 54.9, 65.6, 80.4,
127.1, 128.5, 139.5, 156.7.
11
10
OH
OMTPA
OMe
OMe
i
ii
1b
NH
Boc
O
NH
O
Boc
Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C,
67.91; H, 8.72; N, 5.26.
13
12
Scheme 3 Preparation of diastereomeric Mosher’s esters 11 and 13.
Reagents and conditions: (i) (a) HCl, MeOH, r.t., 10 h, 80% yield; (b)
Boc2O, Na2CO3, MeOH, r.t., 24 h, 85% yield; (ii) (R)-(+)-MTPA
(Mosher’s acid), DCC, MeCN, r.t., 12 h, 87% yield.
Ethyl (2E,4S)-4-[Benzyl(tert-butoxycarbonyl)amino]-5-methyl-
hex-2-enoate (5a)
A soln of NaH (0.7 g, 16.5 mmol) in THF (20 mL) was added to
(EtO)2P(O)CH2CO2Et (3.3 mL, 16.5 mmol) at 0 °C. The mixture
was vigorously stirred until clear and then the corresponding alde-
hyde 4a (prepared as described in the literature4) (2.4 g, 8.2 mmol)
was slowly added at –40 °C. After 30 min, the resulting mixture was
warmed to r.t. over 2 h. The mixture was quenched with sat. aq
NaHCO3 (20 mL) and extracted with EtOAc (3 × 15 mL). The com-
bined organic layers were washed with brine and dried (Na2SO4).
The solvent was evaporated and the residue was chromatographed
(silica gel, hexane–EtOAc, 6:1); this gave compound 5a as a solid.
Yield: 2.4 g (81%); mp 72.6–73.4 °C; [a]D20 –15.2 (c 0.7, CHCl3).
IR (KBr): 3162, 2978, 1750 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.74–0.87 (m, 6 H), 1.28 (m, 2 H),
1.45 (m, 9 H), 2.04 (m, 1 H), 4.19 (m, 2 H), 4.27 (d, J = 15.2 Hz, 1
H), 4.47 (d, J = 15.1 Hz, 1 H), 5.78 (d, J = 15.7 Hz, 1 H), 6.85 (dd,
J = 6.0, 15.8 Hz, 1 H), 7.20–7.32 (m, 5 H).
In conclusion, we have synthesized two enantiopure
ABHAs using a novel cyclization protocol relying upon
the use of N-benzyl-protected carbamates derived from a-
amino acids. Our study has not only brought about consid-
erable new mechanistic understanding of this potentially
highly useful system, but also extended the range of viable
substrates to include branched and unbranched aliphatic
side chains. We aim to apply these ideas to further devel-
opment of this protocol by the synthesis of natural prod-
ucts, and by investigating its use in more complex
systems.
All non-aqueous reactions were carried out under an inert N2 atmo-
sphere. Et3N, DMSO, and CH2Cl2 were distilled from CaH2. All re-
actions were monitored by TLC on commercially available glass-
backed plates. Column chromatography was carried out on 230–400
mesh silica gel. During the workup of reaction mixtures, the final
soln before evaporation was washed with brine and dried over an-
hyd Na2SO4. IR spectra were recorded on a Bruker IFS 66 spec-
trometer. 1H and 13C NMR spectra were measured relative to TMS
in CDCl3, MeOD, and D2O unless otherwise noted, and recorded on
an Avance-300 or a Bruker DRX-500 spectrometer; the 2D NMR
experiments were conducted on a Bruker DRX-500 spectrometer.
EI-HRMS was carried out on a JEOLJMS-700 mass spectrometer.
Elemental analyses were performed on a Leco CHNS-932 instru-
ment. Optical rotations were measured on a Perkin–Elmer polari-
meter 343.
13C NMR (75 MHz, CDCl3): d = 14.2, 22.3, 22.4, 24.6, 28.4, 40.9,
60.4, 77.2, 80.3, 121.8, 127.0, 128.3, 147.4, 155.7, 166.2.
Anal. Calcd for C21H31NO4: C, 69.78; H, 8.64; N, 3.87. Found: C,
69.76; H, 8.65; N, 3.85.
Ethyl (2E,4S)-4-[Benzyl(tert-butoxycarbonyl)amino]pent-2-
enoate (5b)
Compound 5b was obtained by the same procedure as that used for
compound 5a.
Oil; [a]D20 –8.4 (c 1.0, CHCl3).
IR (KBr): 3145, 2955, 1720 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25–1.43 (m, 6 H), 1.43 (m, 9 H),
4.19 (m, 3 H), 4.50 (d, J = 9.2 Hz, 1 H), 5.79 (d, J = 15.7 Hz, 1 H),
6.90 (dd, J = 3.8, 15.8 Hz, 1 H), 7.21–7.33 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.2, 17.5, 28.3, 60.4, 77.5, 80.4,
120.9, 126.9, 128.4, 148.7, 155.5, 166.2.
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212
W. D. Seo et al.
PAPER
Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C,
68.42; H, 8.15; N, 4.21.
1H NMR (300 MHz, CDCl3): d = 1.09 (d, J = 13.2 Hz, 3 H), 3.74
(m, 1 H), 4.05 (d, J = 15.2 Hz, 1 H), 4.80 (d, J = 15.2 Hz, 1 H), 4.91
(m, 1 H), 5.43 (m, 1 H), 5.82 (m, 2 H), 7.28–7.38 (m, 5 H).
tert-Butyl Benzyl[(1S,2E)-4-hydroxy-1-isopropylbut-2-
enyl]carbamate (6a)
To a soln of allylic ester 5a (2.0 g, 5.5 mmol) in CH2Cl2 (27 mL)
was added DIBAL-H (16.6 mmol, 3 equiv) at –78 °C and then the
mixture was stirred for 10 min at the same temperature. The mixture
was quenched with 10% NaOH (5 mL) and filtered. The filtrate was
evaporated and chromatographed (silica gel, hexane–EtOAc, 2:1).
13C NMR (75 MHz, CDCl3): d = 13.7, 45.7, 53.2, 78.1, 120.0, 127.9,
128.8, 131.2, 133.6, 136.0, 157.7.
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.85; H, 6.96; N, 6.43.
(4S,5R)-3-Benzyl-4-isopropyl-2-oxooxazolidine-5-carboxylic
Acid (8a)
Yield: 1.5 g (85%); oil; [a]D20 –14.2 (c 1.0, CHCl3).
To a stirred soln of 7a (0.4 g, 1.6 mmol) and NMO (0.4 g, 3.3 mmol)
in acetone–H2O (10:1, 11 mL) at r.t. was added aq OsO4 (cat.). The
mixture was stirred at r.t. overnight and quenched with aq 10%
Na2SO3, and extracted with CHCl3 (3 × 5 mL). The organic phase
was dried and concentrated under reduced pressure to give the cor-
responding diol, which was used in the next step without further pu-
rification. To a soln of the diol (1.4 mmol) in EtOH–H2O (2:1, 6
mL) was added NaIO4 (0.6 g, 2.9 mmol) at r.t. After stirring for 2 h,
the reaction mixture was evaporated and filtered with EtOAc. The
residue was oxidized with KMnO4 (0.4 g, 2.8 mmol) and K2CO3
(0.4 g, 2.8 mmol) in THF–H2O (2:1, 6 mL). After 30 min, the reac-
tion was quenched by the addition of 5% citric acid (6 mL), and then
extracted with EtOAc (4 × 10 mL). The organic layer was concen-
trated and the residue was chromatographed (silica gel, CH2Cl2–
MeOH, 5:1).
IR (KBr): 3458, 2970, 1440 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.84 (s, 6 H), 1.41 (s, 9 H), 2.01
(m, 1 H), 3.94 (m, 2 H), 4.02 (m, 1 H), 4.25 (d, J = 15.5 Hz, 1 H),
4.49 (d, J = 15.4 Hz, 1 H), 5.60 (m, 2 H), 7.17–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 19.5, 20.4, 28.9, 30.1, 49.0, 62.9,
77.2, 79.8, 126.7, 128.1, 130.0, 139.7, 155.8.
Anal. Calcd for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C,
71.42; H, 9.16; N, 4.36.
tert-Butyl Benzyl[(1S,2E)-4-hydroxy-1-methylbut-2-enyl]car-
bamate (6b)
Compound 6b was obtained by same procedure as that used for
compound 6a.
Oil; [a]D20 –36.0 (c 2.0, CHCl3).
Yield: 0.28 g (74%); oil; [a]D20 –46.0 (c 1.0, MeOH).
IR (KBr): 3155, 2910, 1714, 1595 cm–1.
IR (KBr): 3480, 2958, 1418 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.92 (dd, J = 6.9, 16.9 Hz, 6 H),
2.09 (m, 1 H), 3.61 (t, J = 3.4 Hz, 1 H), 4.07 (d, J = 15.4 Hz, 1 H),
4.62 (d, J = 3.6 Hz, 1 H), 4.88 (d, J = 15.2 Hz, 1 H), 7.14–7.38 (m,
5 H).
13C NMR (125 MHz, CDCl3): d = 14.6, 17.4, 27.9, 46.2, 62.7, 70.9,
127.8, 128.1, 128.9, 135.0, 157.4, 172.5.
1H NMR (300 MHz, CDCl3): d = 1.23 (d, J = 15.0 Hz, 3 H), 1.49 (s,
9 H), 2.28 (s, 1 H), 4.04 (m, 2 H), 4.33 (m, 2 H), 5.69 (m, 2 H), 7.20–
7.31 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 17.9, 28.4, 47.2, 62.9, 79.9, 126.6,
128.2, 132.2, 140.1, 155.8.
Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C,
70.05; H, 8.64; N, 4.80.
Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.85; H, 6.50; N, 5.34.
(4S,5S)-3-Benzyl-4-isopropyl-5-vinyloxazolidin-2-one (7a)
To a soln of allyl alcohol 6a (0.6 g, 2.5 mmol) in CH2Cl2 (13 mL)
was added pyridine (0.61 mL, 7.5 mmol) and then diluted Tf2O (0.8
mL, 5.0 mmol) in CH2Cl2 at –78 °C. After being stirred for 0.5 h at
–78 °C, the reaction mixture was quenched with sat. aq NaHCO3
(20 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic layers were washed with brine and dried (Na2SO4). The sol-
vent was evaporated and the residue was chromatographed (silica
gel, hexane–EtOAc, 3:1).
Yield: 0.5 g (85%); oil; [a]D20 –28.3 (c 0.8, CHCl3).
IR (KBr): 3145, 1724, 1455 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89–0.98 (m, 6 H), 2.06 (m, 1 H),
3.20 (t, J = 4.3 Hz, 1 H), 3.99 (d, J = 15.2 Hz, 1 H), 4.63 (d, J = 4.8
Hz, 1 H), 4.90 (d, J = 15.2 Hz, 1 H), 5.23 (d, J = 10.9 Hz, 1 H), 5.71
(m, 1 H), 7.25–7.37 (m, 1 H).
(4S,5R)-3-Benzyl-4-methyl-2-oxooxazolidine-5-carboxylic Acid
(8b)
Compound 8b was obtained by the same procedure used for 8a.
Oil; [a]D20 –2.5 (c 2.0, CHCl3).
IR (KBr): 3122, 2940, 1721 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 (d, J = 3.7 Hz, 3 H), 3.78 (t,
J = 7.4 Hz, 1 H), 4.17 (d, J = 9.2 Hz, 1 H), 4.50 (d, J = 3.7 Hz, 1 H),
4.75 (d, J = 9.2 Hz, 1 H), 7.26–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 19.1, 46.4, 54.7, 128.4, 128.5,
129.3, 135.5, 157.4, 171.7.
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.25; H, 5.58; N, 5.94.
(2R,3S)-3-(Benzylamino)-2-hydroxy-4-methylpentanoic Acid
(9a)
13C NMR (75 MHz, CDCl3): d = 14.9, 17.5, 27.6, 45.9, 63.8, 74.4,
117.6, 127.9, 127.9, 128.8, 159.1.
To a soln of 8a (0.5 g, 1.9 mmol) in EtOH (2 mL) was added 4 M
KOH (4 mL), and the mixture was stirred for 4 h at 60 °C. The mix-
ture was washed with Et2O (20 mL) and the aqueous layer was acid-
ified (pH 2) and extracted with Et2O (3 × 5 mL). The combined
organic layers were washed with brine (5 mL) and dried (Na2SO4).
The solvent was evaporated and the residue was chromatographed
(silica gel, CH2Cl2–acetone, 1:1).
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.42; H, 7.80; N, 5.72.
(4S,5S)-3-Benzyl-4-methyl-5-vinyloxazolidin-2-one (7b)
Compound 7b was obtained by the same procedure as that used for
compound 7a.
Oil; [a]D20 –0.6 (c 2.0, CHCl3).
20
Yield: 0.38 g (85%); solid; mp 214–216 °C; [a]D –2.6 (c 1.0,
MeOH).
IR (KBr): 3165, 1735, 1447 cm–1.
IR (KBr): 3432, 3010, 1724, 1595 cm–1.
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Improved Stereoselectivity in Intramolecular SN2¢ Cyclization
213
1H NMR (500 MHz, MeOD): d = 0.92 (dd, J = 6.9, 16.9 Hz, 6 H),
2.09 (m, 1 H), 3.61 (t, J = 3.4 Hz, 1 H), 4.07 (d, J = 15.4 Hz, 1 H),
4.62 (d, J = 3.6 Hz, 1 H), 4.88 (d, J = 15.2 Hz, 1 H), 7.14–7.38 (m,
5 H).
dried over Na2SO4. The solvent was evaporated and the residue was
chromatographed (silica gel, hexane–EtOAc, 4:1); this gave com-
pound 11 as an oil, and care was taken to avoid mechanical separa-
tion of the diastereomers.
13C NMR (125 MHz, MeOD): d = 14.6, 17.4, 27.9, 46.2, 62.7, 70.9,
Yield: 47 mg (85%).
127.8, 128.1, 128.9, 135.0, 157.4, 172.5.
1H NMR (500 MHz, CDCl3): d = 0.88 (m, 6 H), 1.43 (s, 10 H), 3.55
(s, 3 H), 3.69 (s, 3 H), 3.94 (m, 1 H), 4.52 (d, J = 10.3 Hz, 1 H), 5.34
(s, 1 H), 7.45 (m, 3 H), 7.70 (m, 2 H).
Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C,
65.82; H, 8.05; N, 5.91.
13C NMR (125 MHz, CDCl3): d = 19.7, 19.8, 28.6, 30.4, 53.0, 56.1,
(2R,3S)-3-(Benzylamino)-2-hydroxybutanoic Acid (9b)
Compound 9b was obtained by the same procedure used for 9a.
Solid; mp 250–252 °C; [a]D20 +3.3 (c 0.5, MeOH).
IR (KBr): 3458, 3102, 1765 cm–1.
74.2, 80.1, 127.9, 128.8, 130.2, 132.4, 155.7, 166.4, 168.6.
19F NMR (473 MHz, CDCl3): d = –72.08 (s, >99%, CF3), –72.48 (s,
<1%, CF3).
1H NMR (300 MHz, MeOD): d = 1.34 (m, 3 H), 3.59 (m, 1 H), 4.22–
4.30 (m, 3 H), 7.45–7.91 (m, 5 H).
Acknowledgment
This work was supported by the Korea Science and Engineering
Foundation (KOSEF) through the Regional Animal Industry Re-
search Center at Jinju National University, Jinju, Korea. We are also
grateful for the financial support of the Brain Korea 21 Program.
13C NMR (75 MHz, MeOD): d = 13.8, 45.7, 63.6, 78.7, 127.9,
128.0, 128.8, 136.1, 171.7.
Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C,
63.12; H, 7.21; N, 6.71.
(2R,3S)-3-Amino-2-hydroxy-4-methylpentanoic Acid (1)
Compound 9a (18 mg, 0.08 mmol) was hydrogenated with 20%
Pd(OH)2/C in MeOH (3 mL) at r.t. for 12 h. The reaction mixture
was filtered and evaporated. The residue was dissolved in MeOH (3
mL) and mixed with Dowex 50W-X8 (0.5 g). The mixture was fil-
tered and then washed with MeOH. The remaining residue was di-
luted with 3 N NH4OH soln (5 mL). The soln was evaporated and
then co-evaporated with toluene; this gave 1 as a solid.
Yield: 10 mg (90%); mp 208–209 °C; [a]D20 –11.5 (c 0.5, MeOH).
IR (KBr): 3434, 2955, 1620 cm–1.
1H NMR (300 MHz, D2O): d = 0.97 (m, 6 H), 1.77 (m, 1 H), 3.45 (t,
J = 6.5 Hz, 1 H), 4.07 (d, J = 4.8 Hz, 1 H).
13C NMR (75 MHz, D2O): d = 15.5, 17.8, 28.4, 49.8, 71.3, 174.6.
References
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(2R,3S)-3-Amino-2-hydroxybutanoic Acid (2)
Compound 2 was obtained as a solid by the same procedure used for
1.
Mp 218–219 °C; [a]D20 +21.4 (c 1.0, H2O).
IR (KBr): 3410, 2930, 1640 cm–1.
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40.33; H, 7.60; N, 11.75.
(R)-(+)-Methyl 3-[(tert-Butoxycarbonyl)amino]-4-methyl-2-
[(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)oxy]pen-
tanoate (11)
The preparation of 11 is described as a representative example.
DCC (47 mg, 0.23 mmol) was added to a soln of (R)-(+)-MTPA in
MeCN (1.0 mL); this immediately resulted in the formation of a
white precipitate of N,N-dicyclohexylurea. After this mixture had
stirred at r.t. for 30 min, the resulting soln of the MTPA anhydride
was filtered through a pipette capped with cotton wool, and added
to (R)-10 (30 mg, 0.12 mmol). The resulting clear colorless soln was
stirred at r.t. for 20 h and then quenched with sat. aq NaHCO3 (5
mL). The reaction mixture was extracted with CHCl3 (3 × 10 mL).
The combined organic layers were washed with brine (5 mL) and
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Synthesis 2007, No. 2, 209–214 © Thieme Stuttgart · New York

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W. D. Seo et al.
PAPER
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Synthesis 2007, No. 2, 209–214 © Thieme Stuttgart · New York