Highly stereoselective intramolecular SN2′ cyclization yielding chiral oxazolidin-2-ones: General route to α-hydroxy-β-amino acids

Article abstract of DOI:10.1055/s-2005-872264

Intramolecular nucleophilic attack onto allylsulfonates promoted by silica gel acting as an acid catalyst provides expedient stereoselective access to 4,5-difunctionalized oxazolidin-2-ones. Precursors were prepared efficiently from enantiopure α-amino ac

Full text of DOI:10.1055/s-2005-872264

LETTER
2289
Highly Stereoselective Intramolecular SN2¢ Cyclization Yielding Chiral
Oxazolidin-2-ones: General Route to a-Hydroxy-b-amino Acids
a
-Hydroxy-
b-amino
Aco
ids o Duck Seo,a Marcus J. Curtis-Long,b Jin Hyo Kim,a Jong Keun Park,c Ki Min Park,d Ki Hun Park*a
b
c
d
Trout Beck, Wansford, Driffield, East Yorkshire, YO25 8NX, UK
Department of Chemical Education, Gyeongsang National University, Jinju 660-701, South Korea
The research Institute of Natural Science, Gyeongsang National University, Jinju 660-701, South Korea
Fax +82(55)7570178; E-mail: khpark@gshp.gsnu.ac.kr
Received 21 June 2005
highly useful in their own right. In this way, such a meth-
odology constitutes a transformation for the synthesis of
enantioenriched a-hydroxy-b-amino acids. The synthesis
of the carbamate began with N-Boc-protected a-amino
Abstract: Intramolecular nucleophilic attack onto allylsulfonates
promoted by silica gel acting as an acid catalyst provides expedient
stereoselective access to 4,5-difunctionalized oxazolidin-2-ones.
Precursors were prepared efficiently from enantiopure a-amino
acids and subsequent manipulation of the oxazolidin-2-ones yielded ester 1. Reduction by LiAlH4 of 2, followed by Swern
enantiopure a-hydroxy-b-amino acids.
oxidation furnished an aldehyde intermediate, which was
set up for a Horner–Wadsworth–Emmons reaction to in-
stall the allylic carbamate 3 required for the cyclization
step. Regioselective DIBAL reduction afforded allylic
alcohol 4, which was activated for the final ring forming
step using a range of different activating groups and
conditions (Scheme 2).
Key words: oxazolidin-2-one, intramolecular SN2¢ cyclization,
AHPBA, silica gel, a-hydroxy-b-amino acids
The stereoselective transformation of homochiral a-ami-
no acids remains an active area of research on account of
their high optical purity giving scope for further manipu-
lation into other useful compounds in high enantiomeric
excesses.1 In amino acid chemistry, many efforts focus on
generating enantiomerically pure amino alcohols, many
of which are considered biologically active, which also
can be converted to biologically important compounds.2
Thus, the transformation of a-amino acids to oxazolidin-
2-ones is also attractive because oxazolidin-2-ones are
amino alcohol equivalents and show potent bioactivity as
well.3 Despite the various practical transformations of ox-
azolidin-2-ones from amino alcohols,4 aziridines,5 allyl
alcohols,6 and allyl amines,7 there are but a few synthetic
routes involving a direct chiral induction step.8 We found
that a chiral oxazolidin-2-one possessing a vinyl group on
the 5 position could be generated by internal cyclization
of chiral carbamate onto an allylic cation (Scheme 1).
O
Bn
Bn
Bn
i
OCH3
OH
ii
NH
NH
BOC
BOC
2
1
O
Bn
iii
OH
OEt
NH
BOC
NH
BOC
4
3
Scheme 2 Reagents and conditions: i) LiAlH4 (2.0 equiv), anhyd
THF, 0 °C, 1 h, 90%; ii) (a) (COCl)2 (2.8 equiv), DMSO (4 equiv),
Et3N (8 equiv), anhyd CH2Cl2, –78 °C; (b) triethylphosphonoacetate
(2 equiv), NaH (2 equiv), anhyd THF, 0 °C to r.t., 80%; iii) DIBAL
(3.0 equiv), THF, –78 °C, 81%.
O
Initially, the hydroxyl group was activated by mesylation.
In the first set of conditions, a thermal induced cyclization
was tested, and whilst the desired product formed, the
selectivity for trans versus cis was low (2:1) and the yield
was less than optimal.
NH2
O
HN
R
O
α-Amino acid
R
OH
OH
Scheme 1
Assuming a polar transition state, where the mesylate is
effectively partially bonded to an allylic cation, it was
decided that formation of an ion pair could assist the
departure of the nucleofuge, while giving some bias for
the elimination; accordingly, trichloroacetimidate was
screened.9 In the standard thermal cyclization, the de was
slightly more favorable than with the tosylate, however,
copper was used to augment the leaving group capacity of
the Schiff base which was unable to increase the level of
This methodology is appealing not only because it derives
from chiral amino alcohols, an ideal basis for an asymmet-
ric synthetic scheme, but also because the products are
protected a-hydroxy-b-amino acid derivatives, which are
SYNLETT 2005, No. 15, pp 2289–2292
Advanced online publication: 03.08.2005
DOI: 10.1055/s-2005-872264; Art ID: U18905ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
9
.2
0
0
5

2290
W. D. Seo et al.
LETTER
selectivity to the required level, even though the dr in- Me, the dr decreased rapidly. For the smallest group, Me,
creased.
the dr was of no great significance (Table 2).
Therefore, two enantiomers of a chiral organocatalyst
were screened separately.10 Although the dr was indepen-
dent of the organocatalyst used, it none the less increased,
which we believe is due to stablization of the nascent me-
sylate in the transition state, silica gel was screened, and it
was found that the dr increased to 9:1 in favor of the trans
product (Scheme 3). This highly selectivity is believed to
be due to bounded protons and the steric effect of the het-
erogeneous catalyst (amorphous silica gel). Changing the
nucleofuge to the tosylate, lowered the yield and dr, the
former at least probably being due to the lower stability of
the tosylate compared to the mesylate.
Figure 1
The cis/trans stereostructures of oxazolidin-2-ones were
determined by NOESY experiments and with the aid of
the X-ray crystal structure of 6d (Figure 1).11 Comparison
of coupling constants of J4,5 clearly indicates the differ-
ence between cis-4,5-disubstituted (J4,5 = 4.7–7.7 Hz) and
trans-4,5-disubstituted oxazolidin-2-one (J4,5 = 4.2–7.3
Hz).
O
O
5% silica gel
HN
OtBu
HN
R
O
4
5
CH3CN, reflux
OMs
R
6
5
Boc
HN
Hb
Hb
Ha
Scheme 3
OMs
OMs
Ph
Ph
NH Hc
Boc
Ha
ϕ = 178°
Hc
(A)
Finally, this trend was extended when the triflate, a com-
pound of low stability, gave only a trace of the desired
product (Table 1). The optimized protocol was then ex-
tended by repetition to a range of substrates derived from
naturally occurring a-amino acids. In the case of substitu-
ents containing more bulky side chains, Bn and Ph, the drs
were good to excellent, however, as the size decreased to
(B)
ϕ = 69°
∆E = 0 kcal/mol
(∆E = 5 kcal/mol)
Top
tBuO
O
H
HN
OMs
Ph
OMs
Ph
H
HN
O
tBuO
Table 1 Intramolecular Hydroxylation of Amino Allylic Alcoholsa
Bottom
O
O
O
O
Bn
+
HN
Bn
O
HN
Bn
O
OR
HN
O
HN
Ph
O
NH
Boc
4 5
Ph
6d
7d
H
H
H
H
Yield (%)b Ratioc
4,5-trans
4,5-cis
Entry
R
Conditions
ϕ : Dihedral angle of Ha and Hb
∆E: Relative energy of ϕ = 178° and ϕ = 69° in 5a
1
2
3
4
5
6
7
Ms
Ms
Ms
Ts
Silica gel, reflux, 5 h
Reflux, 24 h
79
9:1
2:1
4:1
6:1
70
Figure 2
Organocatalyst,e 2 h
Silica gel, reflux, 5 h
CH2Cl2, –78 °C
60
45
It is generally accepted that cis-oxazolidin-2-ones have
larger coupling constants than trans.12 The stereoselectiv-
ity in the case of the formation of the 4,5-trans systems
arises from attack of the carbonyl oxygen of the Boc
group from the top (Si) face of the prochiral center of the
allylsulfonate group. Thus, an SN2¢ reaction resulted in the
highly stereoselective intramolecular cyclization. The
geometric structures of compound 5a were theoretically
optimized by Hartree–Fock/6-31G* level.13 The energy of
the trans-conformer A (j = 178°) was 5 kcal/mol lower
compared with that of the cis-conformer B (j = 69°;
Figure 2). Whilst there seems to be some theoretical basis
for a bias for the ground state to adopt the preferred reac-
Tff
trace
68
–
d
TCAg
TCA
DMSO, reflux, 2 h
(CF3SO3Cu)2, 3 h
3:1
6:1
70
a All reactions were carried out in CH3CN.
b Isolated yield.
c Determined by 1H NMR integration.
d Not determined.
e (+)-Cinchonine or (–)-cinchonidine.
f Trifluoromethanesulfonyl.
g Trichloroacetimidate.
Synlett 2005, No. 15, 2289–2292 © Thieme Stuttgart · New York

LETTER
a-Hydroxy-b-amino Acids
2291
Table 2 Silica Gel Promoted Oxazolidinonation of Amino Allyl Mesylatea
Entry
1
Allyl alcohol adduct
Oxazolidin-2-one
Ratiob
99:1
Yieldc
85%
O
Ph
OMs
NH
Boc
HN
Ph
O
5a
6a
6b
6b
2
99:1
65%
O
O
OTf
N
Boc
O
N
N
5b
3
4
5
6:1
9:1
6:1
65%
79%
70%
OMs
N
Boc
O
O
5c
Ph
OMs
NH
Boc
HN
O
Ph
5d
6d
O
OMs
HN
O
NH
Boc
5e
6e
6
2:1
75%
O
OMs
NH
Boc
HN
O
5f
6f
a All reactions were refluxed in anhyd CH3CN.
b Determined by integration of the 1H NMR spectroscopy.
c Isolated yield.
tive conformation, the standard A1,3 strain model is in monstrated in the synthesis of a-hydroxy-b-amino acid,
general applicable to Z double bonds.14 In this way, it (2R,3S)-AHPBA 9.
seems that there may be some steric effect in the transition
state, which retard the formation of the syn product as R
increases in size.
O
O
ii
i
HN
Bn
O
HN
Bn
O
The utility of this methodology can be shown by the use
of the oxazolidin-2-one as a protecting group of the amino
alcohol functionality. Oxidation of the vinyl group using
OsO4, followed by periodate cleavage, in the presence of
KMnO4 yielded acid 8. Oxazolidin-2-one ring was easily
cleaved by refluxing with KOH to give (2R,3S)-3-amino-
2-hydroxy-4-phenyl butanoic acid (AHPBA; 9) in 86%
yield (Scheme 4). The spectroscopic data and optical
rotation for 9 are consistent with those reported.15 In
conclusion, an expedient route to enantiomerically pure
oxazolidin-2-ones has been developed using non-toxic
conditions in a short number of steps, with excellent
selectivity when strain is maximized. The potential for
derivatization of the oxazolidin-2-one has also been de-
OH
6d
7
OH
OH
O
OH
iii
Ph
HN
Bn
O
NH2
HCl
9
O
OH
8
O
(2R,3S)-AHPBA
Scheme 4 Reagents and conditions: i) OsO4 (10%), NMO (2
equiv), acetone, r.t, 24 h; ii) (a) NaIO4 (1.5 equiv), EtOH–H2O 2:1,
r.t., 2 h; (b) KMnO4 (1.2 equiv), K2CO3 (2.1 equiv), THF–H2O 2:1,
r.t., 1 h, 80%; iii) 4 N KOH, EtOH, reflux to r.t., 24 h, 86%
Synlett 2005, No. 15, 2289–2292 © Thieme Stuttgart · New York

2292
W. D. Seo et al.
LETTER
(5) (a) Lucarini, S.; Tomasini, C. J. Org. Chem. 2001, 66, 727.
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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.
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Synlett 2005, No. 15, 2289–2292 © Thieme Stuttgart · New York