Synthesis of chiral 2-oxazolidinones, 2-oxazolines, and their analogs

Article abstract of DOI:10.1016/j.tet.2007.07.044

Chiral five-membered ring 2-oxazolidinones and six-membered ring 1,3-oxazinan-2-ones are synthesized from the corresponding amino alcohols with complete inversion or retention of stereochemistry. Chiral 5-substituted 2-oxazolines and 6-substituted 2-oxazi

Full text of DOI:10.1016/j.tet.2007.07.044

Tetrahedron 63 (2007) 10034–10041
Synthesis of chiral 2-oxazolidinones, 2-oxazolines,
and their analogs
*
Jean-Rene Ella-Menye and Guijun Wang
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Received 19 March 2007; revised 8 July 2007; accepted 13 July 2007
Available online 19 July 2007
Abstract—Chiral five-membered ring 2-oxazolidinones and six-membered ring 1,3-oxazinan-2-ones are synthesized from the corresponding
amino alcohols with complete inversion or retention of stereochemistry. Chiral 5-substituted 2-oxazolines and 6-substituted 2-oxazines are
also synthesized from the same starting materials with inversion of stereochemistry through an intramolecular SN2 reaction. These compounds
are useful intermediates in organic synthesis and crucial building blocks for many pharmaceutical compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
been great interests in developing their effective syntheses.
The preparations of optically pure cyclic carbamates include
the conversion of a chiral hydroxyl amide by Hofmann
rearrangement14 and the carbonylation reaction of chiral
1,3-amino alcohols.15 Many examples are available for the
synthesis of cyclic carbamates from chiral amino alcohols
with retention of stereochemistry.16–29 There are fewer
methods for the preparation of cyclic carbamates with
opposite stereochemistry to the starting amino alcohol deriv-
atives.19,30–33 For the preparation of the opposite stereoiso-
mers, the hydroxyl group is usually converted to a better
leaving group through mesylation or Mitsunobu reaction,
and the nitrogen is derivatized with Boc2O or CbzCl. The
SN2 cyclization from the displacement of the activated
hydroxyl group affords the cyclic carbamate with opposite
stereochemistry.
Nitrogen and oxygen containing heterocycles, such as cyclic
carbamates and oxazolines, are important intermediates in
organic synthesis and useful building blocks for biologically
active compounds. For example, the (S)-5-aminomethyl
2-oxazolidinone (1) is the core structure in antibacterial
agent linezolid (3),1,2 which is the first member of the syn-
thetic oxazolidinone antibiotics3–7 effective against resistant
Gram-positive bacterial infection. The six-membered ring
1,3-oxazinan-2-one (2) derivatives also exhibit biological
activities, such as anti-inflammatory,8 anti-thrombotic,9
and antibacterial activities.10 These heterocycles can be syn-
thesized from amino alcohols or related starting materials.
Another class of heterocyclic compounds that can be inter-
converted from amino alcohols is the oxazolines.11,12 They
are also important pharmacophores in many drug molecules
including the natural product 4, which has antibiotic
activity.13 Besides being important building blocks for
the preparation of biologically active compounds, the
1,3-oxazinan-2-ones, 2-oxazolidinones, and 2-oxazolines
are also used as chiral auxiliaries or as protected forms of
amino alcohols in the synthesis of complex molecules.
A general precursor for oxazoline synthesis is a b-hydroxy
amide. The hydroxyl group is usually converted to a better
leaving group such as a sulfonate or halide, then an intra-
molecular SN2 cyclization reaction gives the corresponding
oxazoline. Many chiral 1,2-amino alcohols can be prepared
from naturally occurring a-amino acids, and the oxazolines
formed from these amino alcohols are 2,4-disubstituted ox-
azolines. Relatively fewer 5-substituted 2-oxazolines have
been synthesized because of the lack of accessibility of the
Because of the importance of these heterocycles as pharma-
ceutical core structures in asymmetric synthesis, there have
O
O
O
O
HN
O
H
N
O
N
O
O
O
HN
O
N
N
NH2
NH2
O
F
HO
1
2
3
4
* Corresponding author. Tel.: +1 504 280 1258; fax: +1 504 280 6860; e-mail: gwang2@uno.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.044

J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
10035
corresponding amino alcohols. There are also fewer six-
membered ring 2-oxazines comparing to five-membered
ring oxazolines, for the same reason as above, 1,3-amino
alcohols are less accessible than the amino acid derived
1,2-amino alcohols, which are used often in the synthesis
of 2-oxazolines.
When the amide contains a hydrogen atom such as in com-
pound 8a (R¼H), under the same mild basic conditions, the
2,5-disubstituted oxazoline 10 with inverted stereochemistry
was obtained. The oxazoline was then hydrolyzed to give the
amino alcohol 11 ([a]2D5 +15.3, EtOH, c 1.10), which has
inverted stereochemistry compared to compound 6a ([a]D25
ꢀ15.9, EtOH, c 1.00). Because the oxazoline 10 is formed
through an intramolecular reaction, it is expected to have
high integrity of stereochemistry. Therefore, the stereo-
chemistry of the amino alcohol 6a can be inverted through
a four-step sequence as shown in Scheme 1.
(S)-3-Hydroxy-g-butyrolactone is a commercially available
compound that can be synthesized readily from starch or
lactose.34 The lactone has been converted to chiral (S)-1,2-
amino alcohols, (S)-1,3-amino alcohols, and their deriva-
tives via efficient methods.14,35 These chiral amino alcohols
have structures that are complementary to those of natural
amino acids derived amino alcohols. As part of our effort
in synthesizing chiral building blocks that are useful in
drug discovery, we devised new routes for several chiral
heterocycles from intermediates generated from (S)-3-
hydroxy-g-butyrolactone. These chiral heterocycles include
5-substituted 2-oxazolines, 6-substituted 2-oxazines, and
both enantiomers of 5-trityloxymethyl-2-oxazolidinones
and 6-trityloxymethyl-1,3-oxazinan-2-ones.
In the preparation of the six-membered ring analogs, the
trityl protected amino alcohols 12b and 12c were used as
starting materials. These compounds are synthesized by
reacting (S)-3-hydroxy-g-butyrolactone with amines to pro-
duce the corresponding dihydroxyl butyramides followed by
the reduction of the trityl protected amides with lithium
aluminum hydride.15 As shown in Scheme 2, by a similar
method as for the five-membered ring oxazolidinone syn-
thesis, the amino alcohols 12 were converted to the trifluoro-
acetamide 13. From compounds 13b and 13c, direct acyl
transfer cyclization under anhydrous basic conditions led
to the formation of (S)-1,3-oxazinan-2-ones 14b ([a]D25
+32.5, EtOAc, c 1.03), and 14c ([a]2D5 +29.0, EtOAc, c
1.01) in excellent yields. This demonstrated the feasibility
of converting the amino alcohols into cyclic carbamates
using trifluoroacetamide intermediate through elimination
of the trifluoromethyl group. To prepare the carbamates
with opposite stereochemistry, the mesylates 15b and 15c
were treated with potassium carbonate to afford the cycliza-
tion products 16b ([a]D25 ꢀ31.9, EtOAc, c 1.03) and 16c
([a]2D5 ꢀ28.6, EtOAc, c 1.00) in moderate yields. Although
the reaction suffered from lower yields, the optical purities
of the oxazinanones with inverted stereochemistry are over
99% ee.37
2. Results and discussions
For the preparation of the five-membered ring compounds,
we started from the trityloxymethyl oxazolidinones 5a and
5b. These can be prepared from (S)-3-hydroxyl-g-butyrol-
actone according to literature procedures.9,14 Compound 5
was decarbonylated by refluxing with NaOH in a mixture
of THF, ethanol, and water to give the trityl protected amino
alcohol 6 in excellent yield. The amino alcohol 6 was then
treated with trifluoroacetic anhydride at low temperature to
give the corresponding amide 7, followed by mesylation of
the free hydroxyl group in 7 to give the intermediate 8.
The mesylate 8b (R¼Me) was cyclized to N-methyl-
oxazolidinone 9 ([a]2D5 ꢀ41.0, EtOAc, c 1.00) under basic
condition using potassium carbonate in DMF. Compound 9
has a stereochemistry opposite to that of the starting material
5b ([a]2D5 +40.9, EtOAc, c 1.00). The cyclization to the ox-
azolidinone occurred through intramolecular SN2 displace-
ment of the mesylate and subsequent rearrangement. The
yield for the transformation is excellent with complete inver-
sion of stereochemistry.36 In this four-step sequence, the
chirality of the oxazolidinone starting material is inverted.
The six-membered ring 2-oxazine homolog 17 can be syn-
thesized by a similar method as the synthesis of 2-oxazoline
10. The mesylate 15a was converted to the 2-oxazine 17 and
the hydrolysis of 17 using cesium carbonate gave the amino
alcohol 18 with excellent yield. The isolated product amino
alcohol 18 ([a]2D5 +15.0, EtOH, c 1.00) has reasonable good
optical purity as compared to the optical rotation data of
compound 12a ([a]2D5 ꢀ15.7, EtOH, c 1.01).
O
OH
OH
(F3CCO)2O
R
N
NaOH
O
NHR
TrO
CF3
TrO
NR
K2CO3, THF
EtOH, H2O
TrO
O
7a, R = H, 78%
7b, R = Me, 72%
6a, R = H, 100%
6b, R = Me, 84%
5a, R = H
5b, R = Me
MsCl, DIPEA
CH2Cl2, 0 °C
O
OMs
CF3
8b
R
N
OH
NaOH, reflux
O
TrO
CF3
8a
N Me
K2CO3
DMF,
O
TrO
NH2
60%
TrO
N
TrO
K2CO3
DMF,
94%
O
11
9
8a, R = H, 91%
8b, R = Me, 95%
10
92%, 99% ee
Scheme 1. Synthesis of trityl protected 2-oxazoline 10 and the oxazolidinone 9.

10036
J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
O
O
O
R
R
OH NHR
(CF3CO)2
MsCl, DIPEA
CH2Cl2, 0 °C
K2CO3
R
N
O
OMs N
CF3
OH
N
CF3
TrO
TrO
K2CO3, THF
TrO
TrO
DMF or
DMSO
12a, R = H,
12b, R = Me
12c, R = Bn
13a, R = H, 76%
13b, R = Me, 86%
13c, R = Bn, 79%
16b, R = Me, 55%,
99%ee
16c, R = Bn, 63%
15a, R = H, 94%
15b, R = Me, 95%
15c, R = Bn, 94%
13b NaH, THF
13c, LiOH, DMF
K2CO3
DMF
78%
15a
O
R
CF3
OH NH2
Cs2CO3/EtOH
O
N
O
N
TrO
TrO
Reflux
98%
TrO
14b, R = Me, 90%
14c, R = Bn, 89%
18
17
Scheme 2. Synthesis of both enantiomers of trityl protected 1,3-oxazinan-2-ones (14 and 16) and oxazine 17.
The intramolecular SN2 cyclizations in the six-membered
ring formation suffered lower yields than the five-
3. Conclusions
membered ring system. Several attempts using different
bases, solvents, and lengths of reaction time failed to im-
prove the yield of the 1,3-oxazinan-2-ones. The N-benzyl
derivative 16c was obtained in 63% yield from the corre-
sponding mesylate 15c, then we synthesized the N-methyl
derivatives considering that the substituents on the nitro-
gen might affect the reaction outcome. The reaction of N-
methyl derivative afforded poorer yield than the N-benzyl
derivative. Compound 15b in DMF treated with potassium
carbonate and other bases only gave a small amount (20%)
of the desired product 16b with a large percentage of
decomposition. When the reaction was done in DMSO
with K2CO3 as the base, the desired product was obtained
with a 55% yield. Therefore, this rearrangement reaction is
perhaps more effective for the formation of five-membered
ring system.
We have developed an efficient method to convert chiral
trityl protected 3-amino-1,2-propane diol and 4-amino-1,2-
butane diol to the corresponding optically pure cyclic carba-
mate derivatives. Direct acyl transfer reactions under basic
conditions led to cyclic carbamates with retention of stereo-
chemistry; while intramolecular SN2 cyclization yielded
2-oxazolidinones or 1,3-oxazinan-2-ones with inversion of
stereochemistry. The direct acyl transfer cyclization using
trifluoroacetamide intermediate can be used as a complemen-
tary method to cyclizations using t-Boc or Cbz carbamates
as intermediates to synthesize cyclic carbamates. The intra-
molecular SN2 cyclization methods can be used to synthe-
size oxazolidinones with inverted stereochemistry. Chiral
2,5-disubstituted oxazolines and 2,6-disubstituted oxazines
were also synthesized from the corresponding amino alco-
hols. Hydrolysis of these heterocycles yielded amino alco-
hols with opposite configuration to that of the starting
materials. The effective synthesis of these chiral heterocy-
cles allows feasible access to a variety of biologically active
compounds including antibacterial agents.
In the direct acyl transfer reaction leading to the cyclic car-
bamate with the same stereochemistry as the starting mate-
rial, the cyclization occurred presumably by nucleophilic
addition to the carbonyl group followed by elimination. Sim-
ilar reactions are commonly used in the formation of cyclic
carbamates, these include using a t-Boc or Cbz derivative of
the amines. For the SN2 cyclization reaction leading to het-
erocycles with opposite stereochemistry, a possible mecha-
nism is shown in Scheme 3 using the oxazolidinone as an
example. The first step here is the displacement of the mesyl-
ate and maybe through the formation of an unstable inter-
mediate 19. The second step involves the attack of a base
to the intermediate 19, a hydroxide ion or other base present
in the reaction attacks the carbon-2 and gives the tetrahedral
intermediate 20, which then undergoes elimination to afford
the 2-oxazolidinone 9.
4. Experimental section
4.1. General
4.1.1. (S)-3-Methyl-5-(trityloxymethyl)oxazolidin-2-one
5b. (S)-5-(Trityloxymethyl)oxazolidin-2-one 5a (118 mg,
0.328 mmol) was dissolved in anhydrous THF (5 mL). The
reaction flask was cooled to 0 ꢁC and potassium tert-butox-
ide (74.0 mg, 0.660 mmol) was added to the solution, which
was stirred for 1 h. Iodomethane (0.051 mL, 0.819 mmol)
was added to the mixture and the reaction was stirred at
OH -
CF3
CF3
N
O
CF3
HO
O
MsO
-OMs
O
CF3
K2CO3
O
-HCF3
N
N
TrO
TrO
9
DMSO TrO
N
TrO
8b
19
20
Scheme 3. A possible mechanism for the formation of oxazolidinone.

J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
10037
room temperature for 2 h after which NMR of the crude mix-
ture showed that all starting material had been transformed.
The reaction flask was cooled to 0 ꢁC and the reaction was
quenched with cold methanol. The solvents were evaporated
and the crude residue was taken up in dichloromethane. The
solid residue was filtered out and the solvent was evaporated
to afford a crude residue that was purified on silica gel
with a solvent system of hexane/CH2Cl2/THF 8:1:1. The
pure product was isolated as a white solid (108 mg,
0.290 mmol). Yield: 88%. Mp 157–158 ꢁC, [a]D25 +40.9
(EtOAc, c 1.00). 1H NMR (CDCl3, 250 MHz); d 7.49–7.22
(m, 15H), 4.56 (m, 1H), 3.49 (t, 1H, J¼8.7 Hz), 3.34 (m,
2H), 3.22 (dd, 1H, J¼10.2, 4.5 Hz), 2.89 (s, 3H). 13C
NMR (CDCl3, 62.5 MHz); d 158.1, 143.4, 128.5, 127.9,
127.2, 86.8, 71.7, 64.3, 48.8. 30.9. HRMS calcd for
C24H23NO3 [M+H]+ 374.1756, found 374.1748.
and washed with water twice. The dichloromethane was then
evaporated and the crude mixture purified on SiO2 gel using
a gradient of solvent of pure hexane to hexane/CH2Cl2/THF
6:3:1. The pure product was obtained as an off-white solid
(1.01 g, 2.33 mmol). Yield: 78%. Mp 98–100 ꢁC, [a]D25
ꢀ19.2 (EtOH, c 1.03). 1H NMR (CDCl3, 250 MHz);
d 7.41–7.12 (m, 15H), 7.04 (br s, 1H), 3.82 (m, 1H), 3.49
(m, 1H), 3.23 (dd, 1H, J¼12.8, 5.9 Hz), 3.17 (dd, 1H,
J¼9.1, 4.1 Hz), 3.08 (dd, 1H, J¼9.1, 5.4 Hz), 3.00 (br s,
1H). 13C NMR (CDCl3, 75 MHz); d 157.5 (q, C]O,
2J¼36.5 Hz), 143.2, 128.4, 127.9, 127.2, 115.7 (q, CF3,
1J¼287.9), 87.0, 68.8, 64.9, 42.7. HRMS calcd for
C24H22F3NO3 [M+Na]+ 452.1449, found 452.1440.
4.1.5. (S)-2,2,2-Trifluoro-N-(2-hydroxy-3-(trityloxy)-
propyl)-N-methylacetamide 7b. (S)-1-(Methylamino)-3-
(trityloxy)propan-2-ol 6b (172 mg, 0.495 mmol) was
dissolved in anhydrous THF (4 mL) and the reaction was
cooled to ꢀ20 ꢁC. DIPEA (0.431 mL, 2.47 mmol) was ad-
ded and the reaction was stirred for 5 min. Trifluoroacetic
anhydride (0.077 mL, 0.545 mmol) was then added and the
reaction was stirred for about 40 min at ꢀ20 ꢁC. The solvent
was evaporated to dryness and the crude residue was purified
on silica gel with a solvent system of hexane/CH2Cl2/THF
20:1:1. The clean product was isolated as a brown oil
(158 mg, 0.356 mmol). Yield: 72%, [a]2D5 ꢀ17.7 (EtOAc, c
4.1.2. (S)-1-Amino-3-trityloxy-2-propanol 6a. (S)-5-Trityl-
oxymethyl-2-oxazolidinone 5a (2.00 g, 5.56 mmol) was
dissolved in a (1:1) mixture of ethanol and THF (40 mL).
Sodium hydroxide (1.35 g, 33.8 mmol) in distilled water
(10 mL) was added dropwise to the solution. The mixture
was refluxed overnight. The solvents were evaporated and
the residue taken up in THF. A precipitate was formed and
filtered out. The solution was concentrated to dryness under
vacuum and the crude was dried on the vacuum pump with-
out further purification to afford a white semi-solid (1.85 g,
1
1.01). H NMR (CDCl3, 250 MHz); d 7.49–7.23 (m, 15H),
1
5.55 mmol). Yield: 100%. [a]2D5 ꢀ15.9 (EtOH, c 1.00). H
4.08 (m, 1H), 3.61 (dd, 1H, J¼13.9, 3.6 Hz), 3.51 (dd, 1H,
J¼13.6, 7.9 Hz), 3.30 (dd, 1H, J¼9.5, 4.8 Hz), 3.17 (m,
1H), 3.16 (s, 3H). 13C NMR (CDCl3, 62.5 MHz); d (major
tautomer) 157.9 (q, C]O, 2J¼35.9 Hz), 143.4, 128.5,
127.9, 127.2, 116.4 (q, CF3, 1J¼287.6 Hz), 87.0, 69.3,
65.2, 53.1, 36.7 (q, CH3, 4J¼3.7 Hz); (minor tautomer)
NMR (CDCl3, 400 MHz); d 7.47–7.21 (m, 15H), 3.75 (m,
1H), 3.15 (d, 2H, J¼5.0 Hz), 2.77 (m, 2H), 2.09 (br s, 3H).
13C NMR (CDCl3, 100 MHz); d 143.8, 128.6, 127.8,
127.1, 86.6, 71.3, 65.6, 44.4. HRMS calcd for C22H23NO2
[M+Na]+ 356.1651, found 356.1626.
2
157.8 (q, C]O, J¼35.9 Hz), 143.3, 128.5, 127.9, 127.3,
4.1.3. (S)-1-(Methylamino)-3-(trityloxy)propan-2-ol
6b. (S)-3-Methyl-5-(trityloxymethyl)oxazolidin-2-one 5b
(154 mg, 0.412 mmol) was dissolved in a mixture of THF
and ethanol (2 mL each). Lithium hydroxide (100 mg,
4.18 mmol) and sodium hydroxide (85.0 mg, 2.12 mmol)
were dissolved in water (4 mL) and added to the solution.
The mixture was refluxed for 48 h and the solvents were
evaporated. The crude residue was taken up in THF and
the insoluble salts were filtered out; the THF was evaporated
and the crude product was purified on silica gel with a gradi-
ent of hexane/CH2Cl2 1/9 to CH2Cl2/methanol 9:1. The
product was obtained as a light brown semi-solid (120 mg,
0.345 mmol). Yield: 84%. [a]2D5 ꢀ14.2 (EtOAc, c 1.00). 1H
NMR (CDCl3, 250 MHz); d 7.47–7.19 (m, 15H), 3.90 (m,
1H), 3.17 (m, 2H), 2.67 (m, 2H), 2.42 (s, 3H), 2.34 (br s,
2H). 13C NMR (CDCl3, 62.5 MHz); d 143.8, 128.6, 127.7,
126.9, 86.6, 68.6, 66.2, 54.3, 35.9. HRMS calcd for
C23H25NO2 [M+H]+ 348.1964, found 348.1961.
116.5 (q, CF3, 1J¼287.9 Hz), 87.1, 69.7, 65.4, 53.2 (q,
4
CH2N, J¼2.1 Hz), 35.9. HRMS calcd for C25H24F3NO3
[M+Na]+ 466.1606, found 466.1614.
4.1.6. (S)-1-(2,2,2-Trifluoroacetamido)-3-(trityloxy)pro-
pan-2-yl-methanesulfonate 8a. (S)-2,2,2-Trifluoro-N-
(2-hydroxy-3-(trityloxy)propyl)acetamide 7a (880 mg,
2.05 mmol) was dissolved in anhydrous dichloromethane
(20 mL). The solution was cooled to 0 ꢁC and methanesulfo-
nate chloride (0.24 mL, 3.09 mmol) was added. After 1 min,
diisopropylethylamine (1.00 mL, 5.74 mmol) was added
and the mixture was stirred for 40 min. Ice-water (2–
3 mL) was added to quench the reaction and the organic
phase was separated. Dichloromethane was evaporated and
the crude mixture purified on SiO2 gel using a gradient of
pure hexane to hexane/CH2Cl2/THF 8:1:1. The pure product
was obtained as a white solid (948 mg, 1.87 mmol). Yield:
1
91%. Mp 118–119 ꢁC, [a]2D5 ꢀ10.1 (EtOAc, c 1.04). H
NMR (CDCl3, 250 MHz); d 7.37–7.18 (m, 15H), 6.83 (br
s, 1H), 4.75 (m, 1H), 3.71 (m, 1H), 3.47 (m, 1H), 3.39 (dd,
1H, J¼11.3, 4.4 Hz), 3.27 (dd, 1H, J¼10.9, 5.5 Hz), 2.97
(s, 3H). 13C NMR (CDCl3, 75 MHz); d 157.6 (q, C]O,
2J¼38.4 Hz), 142.9, 128.4, 128.1, 127.5, 115.6 (q, CF3,
1J¼287.9 Hz), 87.5, 78.2, 63.3, 40.9, 38.4. HRMS calcd
for C25H24F3NO5S [M+Na]+ 530.1225, found 530.1219.
4.1.4. (S)-2,2,2-Trifluoro-N-(2-hydroxy-3-(trityloxy)pro-
pyl)acetamide 7a. (S)-1-Amino-3-(trityloxy)propan-2-ol
6a (1.00 g, 3.00 mmol) was dissolved in anhydrous THF
(25 mL). The mixture was stirred at 0 ꢁC for about 5 min
then potassium carbonate (2.5 g, 18.1 mmol) was added to
the solution. After another 5 min, trifluoroacetic anhydride
(0.50 mL, 3.54 mmol) was added and the mixture was stirred
for 30 min at 0 ꢁC. The solution was diluted with CH2Cl2
and K2CO3 was filtered out. The organic solvents were evap-
orated on the rotovap, the crude mixture taken up in CH2Cl2
4.1.7. (S)-1-(2,2,2-Trifluoro-N-methylacetamido)-3-(tri-
tyloxy)propan-2-yl-methanesulfonate 8b. (S)-2,2,2-Tri-
fluoro-N-(2-hydroxy-3-(trityloxy)propyl)-N-methylacetamide

10038
J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
7b (336 mg, 0.758 mmol) was dissolved in anhydrous di-
chloromethane (10.0 mL). The solution was stirred at 0 ꢁC
for 5 min and methanesulfonyl chloride (0.100 mL,
1.29 mmol) followed by DIPEA (0.400 mL, 2.29 mmol)
was added to the mixture and the reaction was stirred at
0 ꢁC for 30 min. The solvent was evaporated to dryness
and the crude residue purified on silica gel with a solvent
system of hexane/dichloromethane/THF 10:1:1 to afford
a white solid (375 mg, 0.720 mmol). Yield: 95%. Mp 47–
48 ꢁC, [a]D25 ꢀ8.4 (EtOAc, c 1.00). 1H NMR (CDCl3,
250 MHz); d 7.97–7.26 (m, 15H), 7.25 (br s,1H), 5.00 (m,
1H), 3.75 (dd, 1H, J¼14.2, 4.0 Hz), 3.63 (dd, 1H, J¼14.2,
8.2 Hz), 3.47 (dd, 1H, J¼11.1, 3.5 Hz), 3.31 (dd, 1H, J¼
11.1, 5.6 Hz), 3.20 (s, 3H), 3.00 (s, 3H). 13C NMR
(CDCl3, 62.5 MHz); d (major tautomer) 157.7 (q, C]O,
2J¼36.5 Hz), 143.0, 128.5, 128.0, 127.9, 116.1 (q, CF3,
1J¼287.7 Hz), 87.5, 78.0, 63.4, 51.2, 38.4, 36.9 (q, CH3,
4J¼3.8 Hz); (minor tautomer) 157.8 (q, C]O, 2J¼
CH2Cl2 and the solid salts were filtered out. The solvent
was evaporated and the crude product was purified on
SiO2 gel using a solvent system of CH2Cl2/MeOH 95:5. After
drying under vacuum a colorless semi-solid was obtained
(43.0 mg, 0.129 mmol). Yield: 60%. [a]2D5 +15.3 (EtOH, c
1
1.10). H NMR (CDCl3, 300 MHz); d 7.48–7.19 (m, 15H),
3.79 (m, 1H), 3.17 (m, 5H), 2.84 (m, 1H), 2.72 (m, 1H).
13C NMR (CDCl3, 75 MHz); d 143.7, 128.6, 127.8, 126.9,
86.6, 70.6, 65.6, 44.2.
4.1.11. (S)-4-(Benzylamino)butane-1,2-diol 12c. (S)-
(160 mg,
N-Benzyl-3-hydroxy-4-(trityloxy)butanamide
0.354 mmol) was dissolved in anhydrous THF (4 mL). Lith-
ium aluminum hydride (41.0 mg, 1.08 mmol) was added at
0 ꢁC and the mixture was stirred for 48 h. The mixture was
cooled to 0 ꢁC and the reaction was quenched by addition
of cold methanol and water. The aluminum salts formed
were filtered out, and after concentration, the crude product
was purified on silica gel with a gradient of CH2Cl2/hexane
9:1 to CH2Cl2/MeOH 20:1. The pure product was dried on
vacuum pump and obtained as a white solid (109 mg,
1
38.4 Hz), 142.9, 128.4, 128.1, 127.5, 116.2 (q, CF3, J¼
288.7 Hz), 87.6, 77.9, 63.3, 50.2, 38.7, 35.6. HRMS calcd
for C26H26F3NO5S [M+Na]+ 544.1381, found 544.1392.
1
0.249 mmol). Yield: 70%. H NMR (CDCl3, 400 MHz);
4.1.8. (R)-3-Methyl-5-(trityloxymethyl)oxazolidin-2-one
9. (S)-1-(2,2,2-Trifluoro-N-methylacetamido)-3-(trityloxy)-
propan-2-yl-methanesulfonate 8b (87.0 mg, 0.167 mmol)
was dissolved in DMF (4.00 mL). Potassium carbonate
(92.0 mg, 0.667 mmol) was added and the solution was
stirred at 120 ꢁC for 45 min. K2CO3 was filtered out and
the solvent was evaporated to dryness under nitrogen and
then under vacuum. The pure product was obtained as a white
solid (57.0 mg, 0.153 mmol). Yield: 92%. Mp 154–155 ꢁC,
[a]2D5 ꢀ41.0 (EtOAc, c 1.00). 1H NMR (CDCl3, 250 MHz);
d 7.46–7.22 (m, 15H), 4.60 (m, 1H), 3.55 (t, 1H, J¼
8.7 Hz), 3.35 (m, 2H), 3.22 (dd, 1H, J¼10.2, 4.6 Hz), 2.90
(s, 3H). 13C NMR (CDCl3, 62.5 MHz); d 158.1, 143.4,
128.5, 127.9, 127.2, 86.7, 71.7, 48.8, 30.9. HRMS calcd
for C24H23NO3 [M+H]+ 374.1756, found 374.1764.
d 7.49–7.22 (m, 20H), 4.05 (m, 1H), 3.77 (dd, 2H, J¼19.4,
13.1 Hz), 3.22 (dd, 1H, J¼9.0, 5.7 Hz), 3.06 (dd, 1H,
J¼9.0, 5.8 Hz), 2.94 (m, 1H), 2.81 (m, 1H), 1.81 (m, 1H),
1.65 (m, 1H). 13C NMR (CDCl3, 100 MHz); d 144.0,
139.3, 128.6, 128.4, 128.1, 127.7, 127.1, 126.9, 86.3, 71.9,
67.4, 53.7, 47.4, 32.2. HRMS calcd for C30H31NO2
[M+H]+ 438.2433, found 438.2418.
4.1.12. (S)-2,2,2-Trifluoro-N-(3-hydroxy-4-(trityloxy)-
butyl)-acetamide 13a. (S)-4-Amino-1-(trityloxy)butan-2-ol
12a (583 mg, 1.68 mmol) was dissolved in anhydrous THF
(10.0 mL). Pyridine (0.405 mL, 5.03 mmol) was added to
the solution, which was stirred for 30 min. Trifluoroacetic
anhydride (0.475 mL, 3.36 mmol) was added to the mixture
and after stirring for another 30 min, the reaction was
quenched with ice-water (2 mL). The solvent was then evap-
orated and the crude residue was dissolved in CH2Cl2 and
washed twice with water and once with brine. The organic
phase was then evaporated and the crude residue was puri-
fied on SiO2 gel using a gradient of pure hexane to hex-
ane/CH2Cl2/THF 9:1:1. The pure product was obtained as
a white solid (565 mg, 1.27 mmol). Yield: 76%. Mp 80–
82 ꢁC, [a]D25 +16.3 (CH2Cl2, c 1.04). 1H NMR (CDCl3,
250 MHz); d 7.60 (br s, 1H), 7.48–7.24 (m, 15H), 3.93 (m,
1H), 3.65 (m, 1H), 3.32 (m, 1H), 3.21 (dd, 1H, J¼9.5,
3.8 Hz), 3.13 (m, 1H), 2.93 (br s, 1H), 1.63 (m, 2H). 13C
NMR (CDCl3, 62.5 MHz); d 157.1 (q, C]O, 2J¼36.5 Hz),
4.1.9. (R)-2-(Trifluoromethyl)-5-(trityloxymethyl)-ox-
azoline 10. (S)-1-(2,2,2-Trifluoroacetamido)-3-(trityloxy)-
propan-2-yl-methanesulfonate 8a (106 mg, 0.210 mmol)
was dissolved in anhydrous N,N-dimethylformamide
(10.0 mL). Potassium carbonate (60.0 mg, 0.434 mmol)
was added and the solution was stirred at 85 ꢁC for 1 h.
K2CO3 was then filtered out and DMF evaporated. The crude
mixture was clean enough after drying under vacuum and did
not require purification. The product was obtained as a white
solid (81.6 mg, 0.198 mmol). Yield: 94%. Mp 180–182 ꢁC,
[a]2D5 ꢀ43.5 (EtOAc, c 1.00). 1H NMR (CDCl3, 300 MHz);
d 7.50–7.26 (m, 15H), 4.99 (m, 1H), 4.07 (m, 1H), 3.93
(dd, 1H, J¼14.3, 6.6 Hz), 3.21 (dd, 1H, J¼10.7, 4.7 Hz). 13C
1
143.5, 128.5, 127.9, 127.2, 115.9 (q, CF3, J¼287.9 Hz),
86.9, 70.7, 67.3, 37.9, 30.9. HRMS calcd for C25H24F3NO3
[M+Na]+ 466.1606, found 466.1598.
2
NMR (CDCl3, 75 MHz); d 155.2 (q, C]N, J¼39.9 Hz),
1
143.3, 128.5, 127.9, 127.2, 116.4 (q, CF3, J¼274.4 Hz),
86.7, 81.3, 64.3, 56.4. HRMS calcd for C24H20F3NO2
[M+Na]+ 412.1524, found 412.1542.
4.1.13. (S)-2,2,2-Trifluoro-N-(3-hydroxy-4-(trityloxy)bu-
tyl)-N-methylacetamide 13b. This compound was prepared
via a similar method as the one used for the synthesis of 13a.
Compound 12b (300 mg, 0.830 mmol) was used as the start-
ing material. The crude product was purified on silica gel
with a solvent system of hexane/CH2Cl2/THF 15:1:1. The
pure product was obtained as a white solid (318 mg,
0.700 mmol). Yield: 86%. Mp 106–107 ꢁC, [a]D25 ꢀ14.0
(EtOAc, c 1.00). 1H NMR (CDCl3, 250 MHz); d 7.52–7.23
(m, 15H), 3.73 (m, 2H), 3.43 (m, 1H), 3.20 (m, 2H), 3.10
4.1.10. (R)-1-Amino-3-(trityloxy)propan-2-ol 11. (R)-2-
(Trifluoromethyl)-5-(trityloxymethyl)-oxazoline
10
(88.9 mg, 0.216 mmol) was dissolved in a mixture of THF
and EtOH (5.00 mL each). Sodium hydroxide (94.0 mg,
2.35 mmol) was dissolved in 2 mL of H2O and added to
the solution. The reaction was refluxed for 14 h then the sol-
vents were evaporated. The crude residue was taken up in

J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
10039
(s, 2H), 2.98 (s, 1H), 2.84 (br s, 1H), 1.71 (m, 2H). 13C NMR
(CDCl3, 62.5 MHz); d (major tautomer) 156.9 (q, C]O,
2J¼35.7 Hz), 143.6, 128.5, 127.7, 126.9, 116.3 (q, CF3,
3.8 Hz), 30.2; (minor tautomer) 156.7 (q, C]O, 2J¼
35.7 Hz), 143.5, 128.4, 127.8, 127.0, 116.4 (q, CF3,
1J¼287.6 Hz), 86.7, 68.2, 67.3, 46.4, 34.5, 32.0. HRMS
calcd for C26H26F3NO3 [M+Na]+ 480.1762, found
480.1764.
167–168 ꢁC, [a]2D5 +29.0 (EtOAc, c 1.01). 1H NMR
(CDCl3, 250 MHz); d 7.52–7.25 (m, 20H), 4.60 (dd, 2H,
J¼21.1, 14.9 Hz), 4.43 (m, 1H), 3.43 (dd, 1H, J¼9.7,
4.7 Hz), 3.23 (m, 3H), 2.10 (m, 1H), 1.96 (m, 1H). 13C
NMR (CDCl3, 100 MHz); d 153.5, 143.4, 136.5, 128.5,
128.4, 127.9, 127.7, 127.5, 127.0, 86.6, 75.7, 64.6, 52.4,
43.2, 24.5. HRMS calcd for C31H29NO3 [M+H]+
464.2226, found 464.2222.
4
1J¼287.7 Hz), 86.6, 67.9, 67.4, 46.5, 35.0 (q, CH3, J¼
4.1.17. (S)-4-(2,2,2-Trifluoroacetamido)-1-(trityloxy)-
butan-2-yl-methanesulfonate 15a. (S)-2,2,2-Trifluoro-N-
(3-hydroxy-4-(trityloxy)butyl)-acetamide 13a (486 mg,
1.10 mmol) was dissolved in anhydrous CH2Cl2 (10.0 mL).
The solution was cooled to 0 ꢁC. Methanesulfonyl chloride
(0.130 mL, 1.67 mmol) was added, followed by diisopropyl-
ethylamine (0.570 mL, 3.30 mmol). The mixture was stirred
at 0 ꢁC for 30 min and some ice-water was added to quench
the reaction. The solution was diluted with dichloromethane
and washed twice with water. The organic solvent was evap-
orated and the crude residue purified on SiO2 gel using a gra-
dient of pure hexane to hexane/CH2Cl2/THF 8:1:1. The pure
product was obtained as a colorless semi-solid (536 mg,
4.1.14. (S)-N-Benzyl-2,2,2-trifluoro-N-(3-hydroxy-4-(tri-
tyloxy)butyl)-acetamide 13c. This compound was prepared
via a similar method as the one used for the synthesis of
13a. Compound 12c (88.6 mg, 0.202 mmol) was used as
the starting material. The crude product was purified on sil-
ica gel with a solvent system of hexane/CH2Cl2/THF 15:1:1.
The pure product was obtained as a white solid (85.0 mg,
0.159 mmol). Yield: 79%. Mp 139–140 ꢁC, [a]D25 ꢀ16.8
(EtOAc, c 1.00). 1H NMR (CDCl3, 250 MHz); d 7.47–7.21
(m, 20H), 4.67 (m, 2H), 3.74 (m, 1H), 3.56 (m, 1H), 3.40
(m, 1H), 3.17 (m, 1H), 3.10 (m, 1H), 1.74 (m, 2H). 13C
NMR (CDCl3, 62.5 MHz); d (major tautomer) 157.3 (q,
C]O, 2J¼35.7 Hz), 143.5, 134.8, 128.7, 128.5, 127.9,
1
1.03 mmol). Yield: 94%. [a]2D5 ꢀ17.7 (EtOAc, c 1.00). H
1
127.8, 127.2, 127.1, 116.5 (q, CF3, J¼287.9 Hz), 86.7,
NMR (CDCl3, 250 MHz); d 7.45–7.22 (m, 15H), 7.18 (br
s, 1H), 4.61 (m, 1H), 3.59 (m, 1H), 3.38 (m, 2H), 3.27 (m,
1H), 3.02 (s, 3H), 1.81 (m, 2H). 13C NMR (CDCl3,
68.1, 67.2, 49.4, 43.4, 30.3; (minor tautomer) 157.3 (q,
C]O, 2J¼35.7 Hz), 143.7, 135.4, 128.9, 128.7, 128.1,
1
2
127.9, 127.2, 127.1, 116.6 (q, CF3, J¼287.9 Hz), 86.8,
62.5 MHz); d 157.3 (q, C]O, J¼36.5 Hz), 143.0, 128.4,
4
68.4, 67.3, 50.9 (q, CH2Ph, J¼3.1 Hz), 43.7 (q, CH2N,
128.0, 127.4, 115.7 (q, CF3, 1J¼287.9 Hz), 87.6, 79.7,
65.4, 38.6, 35.4, 30.6. HRMS calcd for C26H26F3NO5S
[M+Na]+ 544.1381, found 544.1368.
4J¼2.9 Hz), 32.2. HRMS calcd for C32H30F3NO3 [M+Na]+
556.2075, found 556.2090.
4.1.15. (S)-3-Methyl-6-(trityloxymethyl)-1,3-oxazinan-
2-one 14b. (S)-2,2,2-Trifluoro-N-(3-hydroxy-4-(trityloxy)-
butyl)-N-methylacetamide 13b (54.0 mg, 0.118 mmol) was
dissolved in anhydrous DMF (5.00 mL). Lithium hydroxide
(31.0 mg, 1.30 mmol) was added and the solution was stirred
at 65 ꢁC for 12 h. The organic solvent was evaporated and
the crude mixture taken up in CH2Cl2. The solid LiOH
was filtered out and the solvent evaporated under nitrogen.
The crude residue was purified on silica gel with a solvent
system of hexane/THF/CH2Cl2 15:1:1. The pure product
was isolated as white crystals (41.2 mg, 0.106 mmol). Yield:
90%. Mp 160.5–161 ꢁC, [a]2D5 +32.5 (EtOAc, c 1.03).
(CDCl3, 400 MHz); d 7.45–7.19 (m, 15H), 4.34 (m, 1H),
3.35 (dd, 1H, J¼9.8, 4.7 Hz), 3.31 (dd, 1H, J¼11.5,
5.7 Hz), 3.21 (m, 2H), 2.97 (s, 3H), 2.08 (m, 1H), 1.97 (m,
1H). 13C NMR (CDCl3, 100 MHz); d 153.6, 143.5, 128.6,
127.8, 127.1, 86.8, 75.7, 64.7, 46.1, 36.5, 24.6. HRMS calcd
for C25H25NO3 [M+Na]+ 410.1732, found 410.1737.
4.1.18. (S)-4-(2,2,2-Trifluoro-N-methylacetamido)-1-(tri-
tyloxy)butan-2-yl-methanesulfonate 15b. This compound
was prepared via a similar method as the one used for the
synthesis of 15a. Compound 13b (194 mg, 0.424 mmol)
was used as the starting material. The crude product was pu-
rified on silica gel with a solvent system of hexane/CH2Cl2/
THF 15:1:1. The pure product was obtained as a brown oil
(215 mg, 0.401 mmol). Yield: 95%. [a]2D5 +5.8 (EtOAc, c
1
1.05). H NMR (CDCl3, 250 MHz); d 7.47–7.24 (m, 15H),
4.77 (m, 1H), 3.42 (m, 4H), 3.10 (s, 2H), 3.04 (s, 2H), 3.03
(s, 1H), 2.99 (s, 1H), 1.98 (m, 2H). 13C NMR (CDCl3,
62.5 MHz); d (major tautomer) 156.9 (q, C]O, 2J¼
1
35.7 Hz), 143.1, 128.5, 127.9, 127.3, 116.3 (q, CF3, J¼
287.7 Hz), 87.4, 79.6, 64.9, 46.0, 38.7, 35.2 (q, CH3,
2
4J¼3.9 Hz), 28.7; (minor tautomer) 156.9 (q, C]O, J¼
35.7 Hz), 143.0, 128.4, 128.0, 127.4, 116.4 (q, CF3,
1J¼287.3 Hz), 87.5, 78.7, 64.5, 45.7 (q, CH2N, 4J¼2.9 Hz),
38.6, 34.6, 30.7. HRMS calcd for C27H28F3NO5S [M+Na]+
558.1538, found 558.1532.
4.1.16. (S)-3-Benzyl-6-(trityloxymethyl)-1,3-oxazinan-
2-one 14c. (S)-N-Benzyl-2,2,2-trifluoro-N-(3-hydroxy-4-
(trityloxy)butyl)-acetamide 13c (156 mg, 0.292 mmol) was
dissolved in anhydrous THF (4.00 mL). The mixture was
cooled to 0 ꢁC and sodium hydride (14.0 mg, 0.583 mmol)
was added. The solution was stirred for 20 min and
quenched by addition of methanol. The solvent was evapo-
rated and the crude mixture was taken up in CH2Cl2. The or-
ganic solvent was washed with H2O three times, separated
from the aqueous solvent and dried on Na2SO4. After filtra-
tion, the solvent was evaporated and the residue was dried
under vacuum. The pure product (120 mg, 0.260 mmol)
was obtained without further purification. Yield: 89%. Mp
4.1.19. (S)-4-(N-Benzyl-2,2,2-trifluoroacetamido)-1-(tri-
tyloxy)butan-2-yl-methanesulfonate 15c. This compound
was prepared via a similar method as the one used for the
synthesis of 15a. Compound 13c (1.03 g, 1.93 mmol) was
used as the starting material. The crude product was purified
on silica gel with a solvent system of hexane/CH2Cl2/THF
15:1:1. The pure product was obtained as a colorless semi-
solid (1.11 g, 1.81 mmol). Yield: 94%. [a]2D5 +3.50 (EtOAc,
c 1.03). 1H NMR (CDCl3, 250 MHz); d 7.43–7.14 (m, 20H),
4.67 (m, 1H), 4.60 (m, 2H), 3.33 (m, 2H), 3.26 (m, 2H), 2.98
(s, 3H), 1.94 (m, 2H). 13C NMR (CDCl3, 62.5 MHz); d (ma-
2
jor tautomer) 157.1 (q, C]O, J¼35.1 Hz), 143.1, 134.4,

10040
J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
129.0, 128.9, 128.4, 127.9, 127.4, 127.3, 116.4 (q, CF3,
1J¼287.9 Hz), 87.2, 78.5, 64.5, 49.6, 42.9, 38.7, 28.7; (minor
tautomer) 157.7 (q, C]O, 2J¼35.1 Hz), 143.1, 135.1, 129.0,
128.9, 128.3, 128.1, 127.4, 127.3, 116.5 (q, CF3, 1J¼
288 Hz), 87.4, 78.5, 64.6, 51.2, 42.8, 38.6, 30.8. HRMS calcd
for C33H32F3NO5S [M+Na]+ 634.1851, found 634.1853.
1J¼276.4 Hz), 87.2, 75.9, 65.6, 42.2, 23.8. HRMS calcd
for C25H22F3NO2 [M+H]+ 426.1681, found 426.1672.
4.1.23. (R)-4-Amino-1-(trityloxy)butan-2-ol 18. (R)-2-
(Trifluoromethyl)-6-(trityloxymethyl)-5,6-dihydro-4H-1,3-
oxazine 17 (65.6 mg, 0.154 mmol) was dissolved in absolute
ethanol (6 mL). Cesium carbonate (0.500 g, 1.53 mmol) dis-
solved in 2.00 mL of water was added to the solution, which
was refluxed for 36 h. The solvents were evaporated and the
crude mixture was taken up in CH2Cl2. The insoluble salts
were filtered out and the organic phase was washed once
with water. After drying on Na2SO4, the solvent was evapo-
rated and after drying under vacuum, the product was ob-
tained as a colorless semi-solid (52.6 mg, 0.151 mmol).
4.1.20. (R)-3-Methyl-6-(trityloxymethyl)-1,3-oxazinan-
2-one 16b. (S)-4-(2,2,2-Trifluoro-N-methylacetamido)-1-
(trityloxy)butan-2-yl-methanesulfonate
15b
(147 mg,
0.247 mmol) was dissolved in anhydrous DMSO
(4.00 mL). Potassium carbonate (114 mg, 0.825 mmol)
was added and the solution was stirred at 120 ꢁC for 3 h.
The mixture was cooled to room temperature, diluted with
CH2Cl2, and washed with cold water three to four times.
The dichloromethane was evaporated and the crude mixture
was purified on silica gel with a solvent system of hexane/
CH2Cl2/THF 12:1:1. The pure product was isolated as
a white solid (58.0 mg, 0.150 mmol). Yield: 55%. Mp
163–164 ꢁC, [a]2D5 ꢀ31.9 (EtOAc, c 1.03). 1H NMR
(CDCl3, 400 MHz); d 7.45–7.20 (m, 15H), 4.33 (m, 1H),
3.35 (dd, 1H, J¼9.7, 4.7 Hz), 3.30 (dd, 1H, J¼10.9,
5.5 Hz), 3.21 (m, 2H), 2.96 (s, 3H), 2.07 (m, 1H), 1.96 (m,
1H). 13C NMR (CDCl3, 100 MHz); d 153.6, 143.5, 128.6,
127.8, 127.1, 86.7, 75.7, 64.7, 46.0, 36.5, 24.6. HRMS calcd
for C25H25NO3 [M+H]+ 388.1913, found 388.1897.
1
Yield: 98%. [a]2D5 +15.0 (EtOH, c 1.00). H NMR (CDCl3,
250 MHz); d 7.53–7.19 (m, 16H), 4.02 (m, 1H), 3.18 (dd,
1H, J¼9.1, 6.1 Hz), 3.08 (dd, 1H, J¼9.1, 5.4 Hz), 2.95 (m,
1H), 2.85 (m, 1H), 1.67 (m, 1H), 1.55 (m, 1H). 13C NMR
(CDCl3, 62.5 MHz); d 143.9, 128.6, 127.8, 126.9, 86.4,
71.2, 67.6, 38.9, 35.1.
Acknowledgements
This work was supported in part by American Heart Asso-
ciation grant #0430285N.
References and notes
4.1.21. (R)-3-Benzyl-6-(trityloxymethyl)-1,3-oxazinan-
2-one 16c. (S)-4-(N-Benzyl-2,2,2-trifluoroacetamido)-
1-(trityloxy)butan-2-yl-methanesulfonate 15c (600 mg,
0.980 mmol) was dissolved in anhydrous DMF (5.00 mL)
and potassium carbonate (0.542 g, 3.92 mmol) was added
to the solution. The mixture was stirred at 120 ꢁC for 20 h.
The organic was evaporated under nitrogen overnight and
the residue taken up in CH2Cl2. The solid K2CO3 was fil-
tered out and the solution concentrated to dryness. The crude
product was purified on silica gel with a gradient of hexane/
THF 19:1 to hexane/CH2Cl2/THF 8:1:1. The pure product
was dried under vacuum and obtained as a white solid
(281 mg, 0.606 mmol). Yield: 63%. Mp 166–167 ꢁC, [a]D25
1. Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed. 2003, 42,
2010–2023.
2. Brickner, S. J. Curr. Pharm. Des. 1996, 2, 175–194.
3. Gravestock, M. B. Curr. Opin. Drug. Discov. Devel. 2005, 8,
469–477.
4. Bush, K.; Macielag, M.; Weidner-Wells, M. Curr. Opin.
Microbiol. 2004, 7, 466–476.
5. Renslo, A. R.; Luehr, G. W.; Gordeev, M. F. Bioorg. Med.
Chem. Lett. 2006, 14, 4227–4240.
6. Hutchinson, D. K. Curr. Top. Med. Chem. 2003, 3, 1021–1042.
7. Hollingsworth, R. I.; Wang, G.; Padmakumar, R.; Mao, J.;
Zhang, H.; Dai, Z.; Puthuparampil, K. PCT Int. Appl.
WO03106413 A, 2003; Chem. Abstr. 2003, 140, 59633.
8. Yamana, K.; Suzuki, N.; Takahama, A.; Ine, S. Jpn.
Kokai Tokkyo Koho JP 179572, 2002; Chem. Abstr. 2002,
137, 57555.
1
ꢀ28.6 (EtOAc, c 1.00). H NMR (CDCl3, 250 MHz); d
7.52–7.23 (m, 20H), 4.58 (dd, 2H, J¼21.9, 14.9 Hz), 4.39
(m, 1H), 3.42 (dd, 1H, J¼9.7, 4.8 Hz), 3.23 (m, 1H), 3.15
(m, 2H), 1.97 (m, 2H). 13C NMR (CDCl3, 62.5 MHz);
d 153.5, 143.4, 136.5, 128.5, 128.4, 127.8, 127.7, 127.4,
127.0, 86.6, 75.7, 64.6, 52.3, 43.2, 24.4. HRMS calcd for
C31H29NO3 [M+H]+ 464.2226, found 464.2232.
9. Jin, F.; Confalone, P. N. PCT Int. Appl. WO0000481, 2000,
119 pp; Chem. Abstr. 2000, 132, 78560.
10. Wang, G.; Ella-Menye, J. R.; Sharma, V. Bioorg. Med. Chem.
Lett. 2005, 16, 2177–2181.
4.1.22. (R)-2-(Trifluoromethyl)-6-(trityloxymethyl)-5,6-
dihydro-4H-1,3-oxazine 17. (S)-4-(2,2,2-Trifluoroacet-
11. Wong, G. S. K.; Wu, W. 2-Oxazolines. In The Chemistry of
Heterocyclic Compounds; Palmer, D. C., Ed.; Oxazoles:
Synthesis, Reactions, and Spectroscopy, Part B; John Wiley
& Sons: Hoboken, NJ, 2004; Vol. 60, pp 331–528.
12. Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichim Acta
2003, 36, 39–50.
13. Sasaki, T.; Otani, T.; Yoshida, K.-I.; Unemi, N.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1997, 50, 881–883.
14. Wang, G.; Hollingsworth, R. I. Tetrahedron: Asymmetry 2000,
11, 4429–4432.
amido)-1-(trityloxy)butan-2-yl-methanesulfonate
15a
(91.5 mg, 0.175 mmol) was dissolved in anhydrous dime-
thylformamide (5.00 mL). Potassium carbonate (97.0 mg,
0.702 mmol) was added and the solution stirred at 85 ꢁC
for 45 min. The solvent was then evaporated under nitrogen
and the crude mixture purified on SiO2 gel using a solvent
system of hexane/CH2Cl2/THF 8:1:1. The pure product
was obtained as an off-white solid (58.4 mg, 0.137 mmol).
Yield: 78%. Mp 106–108 ꢁC, [a]D25 ꢀ46.1 (CH2Cl2, c
1
1.03). H NMR (CDCl3, 250 MHz); d 7.49–7.21 (m, 15H),
15. Ella-Menye, J. R.; Sharma, V.; Wang, G. J. Org. Chem. 2005,
70, 463–469.
16. Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124,
12–13.
4.42 (m, 1H), 3.54 (m, 2H), 3.27 (m, 2H), 1.89 (m, 2H).
13C NMR (CDCl3, 62.5 MHz); d 148.4 (q, C]N,
2J¼38.4 Hz), 143.9, 129.0, 128.4, 127.6, 117.2 (q, CF3,

J.-R. Ella-Menye, G. Wang / Tetrahedron 63 (2007) 10034–10041
10041
17. Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am.
Chem. Soc. 2002, 124, 12934–12935.
34. Hollingsworth, R. I.; Wang, G. Chem. Rev. 2000, 100, 4267–
4282.
18. Crich, D.; Ranganathan, K.; Rumthao, S.; Shirai, M. J. Org.
Chem. 2003, 68, 2034–2037.
35. Wang, G.; Hollingsworth, R. I. J. Org. Chem. 1999, 64, 1036–
1038.
19. Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre,
P.; Sambri, L. Org. Lett. 2005, 7, 1983–1985.
20. Bergmeier, S. C.; Katz, S. J. J. Comb. Chem. 2002, 4, 162–166.
21. Kim, S. W.; Lee, J. G.; Lee, E. J.; Park Choo, H.-Y.; Yoo, C. Y.;
Lee, D. Y.; Roh, K. R.; Kim, E. K. J. Comb. Chem. 2004, 6,
851–854.
22. Buchstaller, H.-P. J. Comb. Chem. 2003, 5, 789–793.
23. Hancock, M. T.; Pinhas, A. R. Tetrahedron Lett. 2003, 44,
5457–5460.
24. Miller, A. W.; Nguyen, S. T. Org. Lett. 2004, 6, 2301–2304.
25. Park, C. S.; Kim, M. S.; Sim, T. B.; Pyun, D. K.; Lee, C. H.;
Choi, D.; Lee, W. K.; Chang, J.-W.; Ha, H.-J. J. Org. Chem.
2003, 68, 43–49.
26. Spino, C.; Tremblay, M.-C.; Gobdout, C. Org. Lett. 2004, 6,
2801–2804.
36. A small amount of compounds 5b and 9 was deprotected using
TFA to remove the trityl group and the free alcohol treated with
Mosher’s acid chloride to form the corresponding esters 24 and
25. Integration of the signals on the 1H NMR spectrum of the
crude reaction products allowed us to confirm the optical purity
1
with the optical rotation data. The crude 500 MHz H NMR
spectrum of compound 24 indicated no presence of diastereo-
mer, the chemical shifts of protons a and b are: d (ppm), 4.76
0
(br s, Ha), 4.58 (d, 1H, Hb, J¼0, 11.7 Hz), 4.41 (dd, Hb ,
J¼3.9, 11.7 Hz), compound 25: 4.78 (br s, Ha), 4.58 (dd, 1H,
0
Hb, J¼2.9, 12.2 Hz), 4.37 (dd, Hb , J¼3.9, 12.2 Hz), a small
doublet impurity signal at 4.41 estimated less than 1% of
0
the Hb integration indicates that the purity of the enantiomer
is 99%.
O
O
27. Osa, Y.; Hikima, Y.; Sato, Y.; Takino, K.; Ida, Y.; Hirono, S.;
Nagase, H. J. Org. Chem. 2005, 70, 5737–5740.
28. Hein, J. E.; Geary, L. M.; Jaworski, A. A.; Hultin, P. G. J. Org.
Chem. 2005, 70, 9940–9946.
O
a
CF3
MeO
O
a
Me
CF3
O
N
MeO
Me
O
N
O
b
b
O
29. ten Holte, P.; Thijs, L.; Zwanenburg, B. Org. Lett. 2001, 3,
1093–1095.
24
25
30. Dinsmore, C. J.; Mercer, S. P. Org. Lett. 2004, 6, 2885–2888.
31. Benedetti, F.; Norbedo, S. Tetrahedron Lett. 2001, 41, 10071–
10074.
32. Madhusudhan, G.; Om Reddy, G.; Ramanatham, J.; Dubey,
P. K. Tetrahedron Lett. 2003, 44, 6323–6325.
33. Ghosh, A.; Shin, D.; Mathivanan, P. Chem. Commun. 1999,
1025–1026.
37. A small amount of compounds 14b, 16b, and their 1:1 mixture
was converted to the corresponding hydroxyl trifluoromethyl
ester derivatives by treating with TFA and trifluoroacetic anhy-
dride. GC analysis of the derivatives using cyclodextrin column
indicates that the optical purities of compounds 14b and 16b
are both over 99% ee, there is no detectable presence of the
opposite isomer.