New synthesis of chiral 1,3-oxazinan-2-ones from carbohydrate derivatives

Article abstract of DOI:10.1021/jo040224q

(Chemical Equation Presented) Chiral 1,3-oxazinan-2-ones are useful intermediates in synthesizing pharmaceutical compounds and amino alcohols. In this paper, we report a new synthetic method to chiral 6-hydroxymethyl 1,3-oxazinan-2-ones and their analogue

Full text of DOI:10.1021/jo040224q

New Synthesis of Chiral 1,3-Oxazinan-2-ones from Carbohydrate
Derivatives
Jean-Rene Ella-Menye, Vibha Sharma, and Guijun Wang*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
gwang2@uno.edu
Received June 30, 2004
Chiral 1,3-oxazinan-2-ones are useful intermediates in synthesizing pharmaceutical compounds
and amino alcohols. In this paper, we report a new synthetic method to chiral 6-hydroxymethyl
1,3-oxazinan-2-ones and their analogues from carbohydrate derivatives. The synthesis was
accomplished by the reaction of optically pure 3-hydroxy-γ-butyrolactone with a primary amine to
give an amide, which was reduced and carbonylated to give the desired compound class.
Introduction
alcohols.8-10 1,3-Oxazinan-2-ones 5 and 6 are important
heterocycles that are present in several biologically active
natural products such as maytansine and its
analogues.11-13 1,3-Oxazinan-2-one derivatives exhibit a
variety of biological activities, and they are being ex-
plored as antiinflammatory agents and as agents for
treating ulcers, allergies, asthma, arthritis, and diabe-
tes.13 Some 6-phenyl-1,3-oxazinan-2-ones (7) have phos-
phodiesterase IV inhibitory effects and have been shown
to be remedies for inflammatory diseases and antiasth-
matics.14 1,3-Oxazinan-2-ones have been used as key
intermediates in Woodward’s total synthesis of erythro-
mycin A,9 in the synthesis of thrombolytics (8),15 and in
the synthesis of liquid crystal devices.16 The six-mem-
bered 1,3-oxazinan-2-one ring systems have also been
used as chiral auxiliaries or other chiral control ele-
ments,17,18 although they are not used as extensively as
Small chiral molecules are very important building
blocks for pharmaceutical compounds. Chiral 5-substi-
tuted 2-oxazolidinones (1 and 2; Chart 1) and the
analogous 6-substituted 1,3-oxazinan-2-ones (3 and 4) are
important core structures in many drug molecules and
useful intermediates in the synthesis of chiral amino
alcohols. The 5-(hydroxymethyl)- and 5-(aminomethyl)-
2-oxazolidinones 1 and 2 are important in the preparation
of oxazolidinone antibacterial agents.1 Representative
oxazolidinone antibiotics include linezolid (5; Zyvox) and
eperezolid (6). Oxazolidinones have been used in the
synthesis of chiral amino alcohols such as the beta-
blocker carvedilol.2 There has been great interest in
developing efficient syntheses toward 2-oxazolidinones.3,4
We and others have developed several efficient synthetic
methods toward the synthesis of chiral 5-substituted
2-oxazolidinones.5-7 The homologous six-membered cyclic
carbamate 1,3-oxazinan-2-ones are also useful intermedi-
ates in synthesizing natural products and 1,3-amino
(8) Bernet, B.; Bishop, P. M.; Caron, M.; Kawamata, T.; Roy, B. L.;
Ruest, L.; Sauve, G.; Soucy, P.; Deslongchamps, P., Can. J. Chem. 1985,
63, 2818-2820.
(9) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward,
D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen,
C. H.; Chenevert, R. B.; Fliri, A.; Frobel, K.; et al. J. Am. Chem. Soc.
1981, 103, 3213-3215.
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Kallen, J.; Meingassner, J. G.; Nuninger, F.; Weitz-Schmidt, G. PCT
Int. Appl. WO 0048989, 2000; Chem. Abstr. 2000, 133, 177065.
(11) Gormley, G., Jr.; Chan, Y. Y.; Fried, J. J. Org. Chem. 1980, 45,
1447-1454.
(12) Larson, G. M.; Schaneberg, B. T.; Sneden, A. T. J. Nat. Prod.
1999, 62, 361-363.
(13) Cassady, J. M.; Chan, K. K.; Floss, H. G.; Leistner, E. Chem.
Pharm. Bull. 2004, 52, 1-26.
(14) Yamana, K.; Suzuki, N.; Takahama, A.; Ine, S. Jpn. Kokai
Tokkyo Koho JP 2002179572, 2002; Chem. Abstr. 2002, 137, 57555.
(15) Jin, F.; Confalone, P. N. PCT Int. Appl. (119 pp) WO 2000000481,
2000; Chem. Abstr. 2000, 132, 78560.
* To whom correspondence should be addressed. Tel: 504-280-1258.
Fax: 504-280-6860.
(1) 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.
(2) Pittelkow, T.; Fischer, E.; Treppendahl, S. P. PCT Int. Appl. WO
2001087837, 2001; Chem. Abstr. 2001, 136, 5898.
(3) Brickner, S. J. Curr. Pharm. Design 1996, 2, 175-194.
(4) Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed. 2003, 42,
2010-2023.
(5) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; et al. Org. Process
Res. Dev. 2003, 7, 533-546.
(6) Wang, G.; Hollingsworth, R. I. Tetrahedron: Asymmetry 2000,
11, 4429-4432.
(7) Hollingsworth, R. I.; Wang, G. Chem. Rev. 2000, 100, 4267-4282.
10.1021/jo040224q CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/17/2004
J. Org. Chem. 2005, 70, 463-469
463

Ella-Menye et al.
CHART 1
SCHEME 1. Synthesis of
N-Aryl-1,3-oxazinan-2-ones from Aspartic Acid
SCHEME 2. Synthesis of 1,3-Oxazinan-2-one by
Iodoaminocyclization
cyclization reactions,23-25 a trans-sulfamoylation through
sulfamide intermediates,26 selenium-mediated cyclization
of amino alcohol with carbon monoxide,27 rearrangement
from cyclic sulfates,28 intramolecular Michael additions,29
asymmetric dihydroxylation of homoallylic amines,30 and
a Hoffmann rearrangement of a primary amide to form
the carbamate.31 The iodoaminocyclization reaction is
highly stereoselective when using a homoallyl carbamate
with a chiral center at the homoallylic position (Scheme
2).23
The chiral 1,3-oxazinan-2-ones 3 and 4 are useful in
drug development toward new therapeutic agents. They
are also useful in organic syntheses as chiral auxiliaries
or as intermediates for synthesizing 1,3-amino alcohols.
Because of these potential applications and as part of our
interest in synthesizing new chiral heterocyclic deriva-
tives as therapeutic agents, we developed a novel method
to synthesize these chiral six-membered-ring carbamates
from carbohydrate derivatives.
the homologous 2-oxazolidinones. This is probably due
to the difficulties in synthesizing chiral 1,3-oxazinan-2-
ones. Besides inducing chirality, the 1,3-oxazinan-2-ones
were also used as aminopropylation agents19 and as
intermediates for the preparation of amino alcohols.20
Chiral versions of the homologous 6-substituted 1,3-
oxazinan-2-ones are difficult to synthesize. There are not
many available syntheses for chiral 1,3-oxazinan-2-ones
in the literature. One chiral pool approach method
utilizes aspartic acid as the starting material (Scheme
1); an epoxide containing Cbz-protected arylamine was
obtained as an intermediate (9), and then the epoxide
ring was opened by sodium azide and cyclization of the
hydroxyl group with the Cbz group gave the desired 1,3-
oxazinan-2-one 11.21 A short synthesis for 1,3-oxazinan-
2-ones was accomplished by reductive amination of
2-deoxy-D-ribose followed by cyclization of the aryl chlo-
roformate derivatized amine.22 Other methods to syn-
thesize 1,3-oxazinan-2-ones include halogen-mediated
Results and Discussions
We have designed and carried out the syntheses of
these important chiral compounds from the carbohydrate
(23) Fujita, M.; Kitagawa, O.; Suzuki, T.; Taguchi, T. J. Org. Chem.
1997, 62, 7330-7335.
(24) Jorda-Gregori, J. M.; Gonzalez-Rosende, M. E.; Cava-Montesi-
nos, P.; Sepulveda-Arques, J.; Galeazzi, R.; Orena, M. Tetrahedron:
Asymmetry 2000, 11, 3769-3777.
(16) Takiguchi, T.; Iwaki, T.; Tokanou, G.; Kosaka, Y.; Nakamura,
S. JP9151179, 1997; Chem. Abstr. 1997, 127, 42427.
(17) Abbas, T. R.; Cadogan, J. I. G.; Doyle, A. A.; Gosney, I.; Hodgson,
P. K. G.; Howells, G. E.; Hulme, A. N.; Parsons, S.; Sadler, I. H.
Tetrahedron Lett. 1997, 38, 4917-4920.
(25) Muehlstaedt, M.; Meusinger, R.; Olk, B.; Weber, L.; Widera,
R. J. Prakt. Chem. 1986, 328, 309-313.
(26) Dewynter, G.; Abdaoui, M.; Regainia, Z.; Montero, J.-L. Tetra-
hedron 1996, 52, 14217-14224.
(27) Sonoda, N.; Yamamoto, G.; Natsukawa, K.; Kondo, K.; Murai,
S. Tetrahedron Lett. 1975, 16, 1969-1972.
(18) Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Gould, R. O.;
Hodgson, K. G.; McDougall, D. Tetrahedron 1998, 54, 9765-9784.
(19) Poindexter, G. S.; Strauss, K. M. Synth. Commun. 1993, 23,
1329-1338.
(28) Kemp, S. J.; Bao, J. G.; Pedersen, S. F. J. Org. Chem. 1996,
61, 7162-7167.
(29) Hirama, M.; Nishizaki, I.; Shigemoto, T.; Itoˆ, S. J. Chem. Soc.,
Chem. Commun. 1986, 393-394.
(20) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. Chem.
Lett. 1988, 87-90.
(30) Walsh, P. J.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett.
1993, 34, 5545-5548.
(21) Lohray, B. B.; Baskaran, S.; Reddy, B. Y.; Rao, K. S. Tetrahe-
dron Lett. 1998, 39, 6555-6556.
(31) Hilborn, J. W.; Lu, Z.-H.; Jurgens, A. R.; Fang, Q. K.; Byers,
P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2001, 42, 8919-
8921.
(22) Ross, B. C. U.S. Patent 4107435, 1977; Chem. Abstr. 1977, 88,
7304.
464 J. Org. Chem., Vol. 70, No. 2, 2005

Chiral 1,3-Oxazinan-2-ones
SCHEME 3. Synthesis of Chiral 1,3-Oxazinan-2-ones from Lactone 12
CHART 2
derivative (S)-3-hydroxy-γ-butyrolactone (12; Scheme 3).
Starting from optically pure lactone 12,32 ring opening
with amines led to the dihydroxybutyramide 13 quanti-
tatively.33 The diol was selectively protected with a trityl
group to increase the hydrophobicity of the compound.
This is necessary for the reduction step when the R group
is a small alkyl group. Without a protecting group, the
reduction product is too polar and it is hard to recover it
from the reaction mixture. The trityl group showed
excellent selectivity to the primary hydroxyl group,
although some small amount of diprotected byproduct can
be obtained after a prolonged period of stirring. Reduction
of the protected amide 14 using LiAlH4 in THF gave the
corresponding intermediate amino alcohol 15 in excellent
yield. Cyclization of the intermediate 15 using carbonyl
diimidazole gave the protected 1,3-oxazinan-2-ones 16 in
70-93% yield. Attempts at using Cbz-protected amine
and using the carbonyl group of the Cbz group to form
the carbamate ring resulted in a lower yield. The trityl
protecting group was removed quantitatively using TFA
in dichloromethane. The primary hydroxyl group in 17
can then be converted to an amino group by converting
it to the mesylate 18 and displacing the mesylate by
benzylamine in DMSO at 60-80 °C. The benzyl protect-
ing group in 19 can be removed by catalytic hydrogena-
tion to give the corresponding 6-(aminomethyl)-1,3-
oxazinan-2-ones.
copy. The 1,3-oxazinan-2-ones are stable under neutral
conditions. Heating at over 85 °C for 48 h resulted in
almost no decomposition of pure compound 19b in
DMSO. Addition of benzylamine to the sample did not
cause rearrangement of compound 19b either. However,
addition of potassium carbonate promoted the rearrange-
ment in the presence of benzylamine. In the absence of
benzylamine, K2CO3 promoted the rearrangement to
completion after 18 h of heating at >85 °C. This indicated
that participation of a nonbulky base is important to the
reaction. We also carried out the rearrangement reaction
for compound 19a cleanly in DMSO using 2 equiv of
potassium carbonate at 100 °C for 24 h. A possible
mechanism of the formation of 20 is shown in Scheme 4.
A base B- (such as hydroxide) molecule attacks the
carbamate and opens up the six-membered ring, forming
the tetrahedral intermediate 21, and cyclization with the
neighboring 6-benzylamino group leads to the formation
of a five-membered-ring carbamate, the oxazolidinone 20.
Besides the five-membered-ring oxazolidinone, another
possible rearrangement product could be the seven-
membered urea 22 (Chart 2) by cleavage of the C-O bond
instead of the C-N bond. However, this possibility is
ruled out for the above rearrangement reaction on the
The displacement product is mainly the direct SN2
displacement product 19 when using DMSO as solvent
and 2-2.5 equiv of benzylamine at 60-80 °C. However,
we found that when the temperature is higher than 85
°C and in the presence of potassium carbonate, a signifi-
cant quantity of compound 20 was obtained. This is
presumably obtained from rearrangement of the 1,3-
oxazinan-2-one 19. To understand the requirement for
the rearrangement, we monitored the compound 19b (R
) CH2CH3) in d6-DMSO at >85 °C by 1H NMR spectros-
1
basis of both H and 13C NMR spectral data. The five-
(32) Hollingsworth, R. I. Biotech. Annu. Rev. 1996, 2, 281-287.
(33) Wang, G.; Hollingsworth, R. I. J. Org. Chem. 1999, 64, 1036-
1038.
membered ring is also thermodynamically more stable
than the seven-membered ring. The amine 20a has a
J. Org. Chem, Vol. 70, No. 2, 2005 465

Ella-Menye et al.
FIGURE 1. 1H NMR spectra of compounds 19a (bottom), neutral amine 20a (middle), and protonated amine 23 (top). All spectra
were obtained in CDCl3.
SCHEME 4. Possible Mechanism of the Rearrangement from Six-Membered to Five-Membered Carbamates
Promoted by Base
certain solubility (∼10 mg/mL) in water, and it is easily
protonated. The protonated form 23 would exhibit changes
of chemical shifts for the methyl a and methylenes b and
c. The 1H NMR spectra of the three compounds are shown
in Figure 1. If the seven-membered-ring urea 22 is the
rearrangement product, the 1H NMR chemical shifts for
the methyl a and methylene b should not change signifi-
cantly, since the chemical environments for a and b are
essentially the same in 19a and 22. However, if the
methine proton d moved downfield from 4.34 ppm in 19a
to 4.68 ppm in the rearrangement product. This is strong
evidence that the structure 22 is not the rearrangement
product, in which the methine proton d is expected to
have a chemical shift around 4.0 ppm. Furthermore, the
absorptions for a and b in the ammonium salt 23 should
move downfield in comparison to the signals for the
neutral form 20a. For the urea, addition of acid will not
affect the chemical shifts of a and b significantly. As
shown in Figure 1, the chemical shifts of the groups close
to the nitrogen have significantly moved downfield after
addition of acid: methyl a shifted from 2.38 to 2.60 ppm,
and methylene b shifted from 2.68 to 3.01 ppm. We have
1
rearrangement product is the amine 20a, then the H
NMR absorptions of a and b should change significantly.
This is what we have observed, as shown in Figure 1.
The chemical shift for methyl a moved upfield from 2.94
ppm in 19a to 2.38 ppm, and the methylene group b also
shifted upfield from 2.78 ppm in 19a to 2.68 ppm. The
1
also compared the H and 13C spectral data to those for
existing 2-oxazolidinones,6 and the similarities of the five-
466 J. Org. Chem., Vol. 70, No. 2, 2005

Chiral 1,3-Oxazinan-2-ones
temperature for 6-8 h. After concentrating on a rotavaporator,
the excess methylamine can be removed by washing with
hexane, and the last trace of solvent and methylamine can be
removed on a vacuum pump. The crude product was obtained
as a brown viscous liquid (26.6 g, 0.20 mol, 100%) and was
used directly in the second step without further purification.
SCHEME 5. Proposed Synthesis of the New
Oxazolidinone Building Block 25
25
[R]D ) -25.9° (c 1.08, EtOH). 1H NMR (D2O, 400 MHz; δ
(ppm)): 3.94 (m, 1H), 3.48 (dd, 1H, J ) 11.72, 3.9 Hz), 3.38
(dd, 1H, J ) 11.7, 6.8 Hz), 2.61 (s, 3H), 2.32 (dd, J ) 14.7, 3.9
Hz), 2.22 (dd, J ) 14.7, 8.8 Hz). 13C NMR (CD3OD, D2O, 100
MHz; δ (ppm)): 175.1, 70.1, 69.2, 40.8, 26.9.
(S)-N-Ethyl-3,4-dihydroxybutyramide (13b). Yield: 99%,
25
yellow crystals. Mp: 59.0-61.0 °C. [R]D ) -26.7° (c 1.07,
1
EtOH). H NMR (CDCl3, 400 MHz; δ (ppm)): 5.69 (bs, 1H),
4.07 (m, 1H), 2.41 (dd, 1H, J ) 15.6, 8.8 Hz), 2.31 (dd, 1H, J
) 15.6, 3.9 Hz), 3.67 (m, 1H), 3.51 (m, 1H), 3.29 (m, 2H), 1.14
(t, 3H, J ) 7.3 Hz). 13C NMR (D2O, 5% CD3OD, 100 MHz; δ
(ppm)): 174.2, 70.1, 66.2, 40.9, 35.6, 14.6.
membered-ring absorption data confirmed that the struc-
ture 20a is the correct product. The above results confirm
our hypothesis that the rearrangement product is the
five-membeed-ring 2-oxazolidinone 20, not the seven-
membered-ring urea 22.
The formation of 20 is another method of synthesizing
chiral oxazolidinones that have stereochemistry opposite
to that of the Hoffmann rearrangement method from
13c.6 The rearrangement product 20 can be used to
synthesize 2-oxazolidinones with an alkene functional
group by oxidation of the amine (after converting to a
tertiary amine and treatment with hydrogen peroxide)
followed by Cope elimination (Scheme 5). The 2-oxazo-
lidinone 25 after Cope elimination can be used as a
general building block in the synthesis of 2-oxazolidinone
derivatives. Substituted 2-oxazolidinones can be obtained
by electrophilic addition to the double bonds.
(S)-3-Hydroxy-N-methyl-4-(trityloxy)butyramide (14a).
3,4-Dihydroxy-N-methylbutyramide (13a; 19.41 g, 0.146 mol)
was dissolved in 52 mL of anhydrous DMF under N2. Trityl
chloride (49 g, 0.175 mol) and pyridine (35 mL, 0.438 mol) were
added to the solution, which was then stirred at room tem-
perature for 24-36 h. The reaction was quenched by addition
of ice water (100 mL) to the solution. The water was decanted,
and the solid precipitate was dissolved in EtOAc (150 mL).
The organic phase was washed several times with 30 mL of
water and finally with 30 mL of brine. After drying with Na2-
SO4, the ethyl acetate was removed on a rotavaporator and
58 g of the crude product was obtained as an off-white solid.
The crude product can be purified by flash chromatography
on silica gel using a gradient of the solvent system hexane/
ethyl acetate (3:1 to 1:1). The pure product was obtained as a
white crystalline material. Mp: 107.0-108.0 °C. [R]D25 ) -18.3°
1
(c 1.12, EtOAc). H NMR (CDCl3, 400 MHz; δ (ppm)): δ 7.40
(d, 6H, J ) 7.8 Hz), 7.19-7.34 (m, 9H), 5.98 (bs, 1H), 4.14 (m,
1 H), 3.55 (s, 1 H), 3.15 (dd, 1H, J ) 9.8, 5.9 Hz), 3.10 (m, 1H),
2.72 (d, 3 H, J ) 4.9 Hz), 2.40 (dd, 1H, J ) 15.6, 2.9 Hz), 2.31
(dd, 1H, J ) 15.6, 8.8 Hz). 13C NMR (CDCl3, 100 MHz; δ
(ppm)): 172.3, 143.5, 128.4, 127.6, 126.9, 86.4, 67.8, 66.6, 39.4,
25.9. HRMS (m/z): calcd for C24H25NO3Na+ [M + Na]+,
398.1732; found, 398.1746. IR (CHCl3; cm-1): 3347, 3015, 1653,
1550, 1491, 1448, 1217, 1074, 758.
Conclusions
We have developed a new efficient method to synthe-
size chiral 6-substituted 1,3-oxazinan-2-ones from (S)-3-
hydroxy-γ-butyrolactone. The reaction scheme is straight-
forward and efficient and offers complete retention of
stereochemistry. We also discovered that, under basic
conditions, heat can promote the rearrangement of the
six-membered-ring 1,3-oxazinan-2-ones to the more stable
five-membered-ring 2-oxazolidinones. The product 2-ox-
azolidinone has stereochemistry opposite to that of the
2-oxazolidinone synthesized by a Hoffmann rearrange-
ment. This method allows us to synthesize chiral core
structures with complementary stereocenters, since the
priority order is switched. The efficient syntheses of these
chiral carbamates are important in the preparation of
biologically active pharmaceutical compounds. The syn-
thesis also provides intermediates for synthesizing chiral
amino alcohol derivatives.
(S)-N-Ethyl-3-hydroxy-4-(trityloxy)butyramide (14b).
Yield: 95% (0.05 mol scale) after purification using hexane/
25
ethyl acetate (1:1). Rf ) 0.3. White solid. Mp: 119.0 °C. [R]D
) -19.1° (c 1.11, EtOAc). 1H NMR (CDCl3, 400 MHz; δ
(ppm)): 7.50-7.16 (m, 15H), 5.90 (bs, 1H), 4.16 (m, 1H), 3.52
(bs, 1H), 3.23 (m, 2H), 3.13 (m, 2H), 2.38 (dd, 1H, J ) 15.63,
2.93 Hz), 2.31 (dd, 1H, J ) 15.6, 7.8 Hz), 1.08 (t, J ) 6.8 Hz,
3H). 13C NMR (CDCl3, 100 MHz; δ (ppm)): 171.5, 143.7, 128.6,
127.8, 127.1, 86.7, 68.0, 66.6, 39.6, 34.2, 14.7. HRMS (m/z):
calcd for C25H27NO3Na+ [M + Na]+, 412.1889; found, 412.1909.
IR (CHCl3; cm-1): 3444, 3372, 3062, 3017, 2934, 2878, 1651,
1533, 1448, 1217, 1074, 758 cm-1
.
(S)-3-Hydroxy-4-(trityloxy)butyramide (14c). Yield after
purification: 90%. Mp: 107.5-108.5 °C. [R]D25 ) -18.4° (c 1.00,
1
EtOAc). H NMR (CDCl3, 400 MHz; δ (ppm)): 7.41 (d, 6H, J
) 7.8 Hz), 7.34-7.19 (m, 9H), 6.06 (bs, 1H), 5.64 (bs, 1H), 4.15
(m, 1H), 3.45 (bs, 1H), 3.16 (d, 2H, J ) 5.9 Hz), 2.37 (m, 2H).
13C NMR (CDCl3, 100 MHz; δ (ppm)): 174.1, 143.6, 128.5,
127.8, 127.1, 86.8, 67.7, 66.7, 39.2. IR (CHCl3; cm-1): 3494,
3408, 3019, 2929, 2878, 1675, 1594, 1492, 1448, 1217, 1075,
742.
(S)-4-(Methylamino)-1-(trityloxy)butan-2-ol (15a). 3-Hy-
droxy-N-methyl-4-(trityloxy)butyramide (14a; 55.0 g, 0.146
mol) was dissolved in anhydrous THF (240 mL), and the
reaction flask was cooled to 0 °C in an ice-salt bath. LiAlH4
(16.50 g, 0.434 mol) was added to the flask at 0 °C under dry
N2. The ice bath was removed after the generation of hydrogen
settled down. The mixture was stirred at room temperature
for 12-18 h, after which time the reaction is essentially
Experimental Section
General procedure for the synthesis when R ) Me is used
as an illustration for the procedure. The compounds with R )
Et, H are synthesized by a similar method. The characteriza-
tion data for the N-ethyl analogues and R ) H are given and
1
the H and 13C NMR spectra are given in the supplementary
section. Melting point (uncorrected) was measured using
Fisher-Jones.
(S)-3,4-Dihydroxy-N-methylbutyramide (13a). Com-
pounds 13a-c were obtained by similar methods given in the
literature.21 The lactone (20.2 g, 0.20 mol) and methylamine
(77.65 g, 1.0 mol, 40 wt % in water) were mixed at room
J. Org. Chem, Vol. 70, No. 2, 2005 467

Ella-Menye et al.
(S)-6-((Trityloxy)methyl)-1,3-oxazinan-2-one (16c).
25
complete, on the basis of NMR spectroscopy. The reaction
mixture was then cooled in an ice bath, and the reducing agent
was quenched by adding 50 mL of a 1:1 mixture of MeOH and
H2O. The white precipitate that formed after addition of water
and MeOH was removed by vacuum filtration, and the filtrate
was extracted several times with CHCl3. The combined organic
phase was dried using Na2SO4 overnight. The solvent was
removed on a rotavaporator, and the residue was dried on a
vacuum pump. The crude product was obtained as an off-white
solid (51.35 g, 0.142 mol, 97%) and was used directly in the
next step without further purification. A small amount was
purified by chromatography. Mp: 120.0 °C. [R]D25 ) -19.0° (c
1.02, EtOH). 1H NMR (CDCl3, 400 MHz; δ (ppm)): 7.45 (d,
6H, J ) 6.8 Hz), 7.28 (t, 6H, J ) 7.8 Hz), 7.21 (t, 3H, J ) 6.8
Hz), 4.00 (m, 1H), 3.47 (bs, 2H), 3.17 (dd, 1H, J ) 9.8, 5.9 Hz),
3.00 (dd, 1H, J ) 9.8, 5.9 Hz), 2.83 (m, 1H), 2.73 (m, 1H), 2.36
(s, 3H), 1.75 (m, 1H), 1.59 (m, 1H). 13C NMR (CDCl3, 100 MHz;
δ (ppm)): 144.0, 128.6, 127.6, 126.8, 86.2, 71.6, 67.4, 49.8, 85.9,
31.8. HRMS ES+ (m/z): calcd for C24H27NO2 [M + 1]+,
362.2120; found, 362.2127. IR (CHCl3; cm-1): 3318, 3061, 3011,
2929, 2872, 1598, 1491, 1448, 1217, 1075, 766.
Yield: 70%. Mp: 182.5-183.5 °C. [R]D ) +20.8° (c 1.01,
1
EtOAc). H NMR (CDCl3, 400 MHz; δ (ppm)): 7.60-7.18 (m,
15H), 7.42 (d, 6H, J ) 7.8 Hz), 7.29 (t, 6H, J ) 7.8 Hz), 7.21
(d, 3H, J ) 7.8 Hz), 5.25 (bs, 1H), 4.38 (m, 1H), 3.34 (m, 3H),
3.23 (dd, 1H, J ) 9.8, 5.9 Hz), 2.03 (dd, 1H, J ) 12.7, 2.9 Hz),
1.92 (m, 1H), 1.55 (bs, 1H). 13C NMR (CDCl3, 100 MHz; δ
(ppm)): 154.46, 143.5, 128.5, 127.9, 127.1, 86.8, 76.1, 64.7, 38.7,
23.6. IR (CHCl3; cm-1): 3448, 3261, 3062, 3018, 2939, 2882,
1707, 1490, 1450, 1292, 1217, 1110, 1079, 750.
(S)-6-(Hydroxymethyl)-3-methyl-1,3-oxazinan-2-one
(17a). The solution of 3-methyl-6-((trityloxy)methyl)-1,3-ox-
azinan-2-one (16a; 5 g, 0.013 mol) in a mixture of TFA and
CH2Cl2 (20 mL, 1:1) was stirred for 12 h at room temperature.
The TFA and the solvent were evaporated to dryness on a
rotavaporator. Ice water was then added to the viscous liquid
residue, and a solid precipitate formed. The solid was removed
by vacuum filtration, and the water phase was extracted with
hexane to remove a trace amount of trityl compound. The
water phase was then evaporated on an oil pump, and MeOH
was added to the product and then evaporated several times.
The product was obtained as a light brown viscous liquid (1.9
g, 0.013 mol) and was used directly in the next step. Yield:
(S)-4-(Ethylamino)-1-(trityloxy)butan-2-ol(15b). Yield:
73.0% (unoptimized yield). White crystals. Mp: 109.0-110.0
100%. [R]25 ) +75.6° (c 1.09, EtOH). 1H NMR (CDCl3, 400
25
D
°C. [R]D ) -17.7° (c 1.07, EtOH), HRMS (m/z): calcd for
MHz; δ (ppm)): 4.29 (m, 1H), 3.74 (dd, 1H, J ) 11.7, 3.9 Hz),
3.65 (dd, 1 H, J ) 11.7, 4.9 Hz), 3.38 (m, 1H), 3.22 (m, 1H),
2.95 (s, 3H), 2.77 (bs, 1H), 1.97 (m, 2H). 13C NMR (CDCl3, 100
MHz; δ (ppm)): 154.0, 77.5, 63.7, 46.0, 36.3, 23.3. HRMS ES+
(m/z): calcd for C6H12NO3 [M + 1]+, 146.0817; found, 146.0820.
IR (CHCl3; cm-1): 3381, 3009, 2939, 1677, 1499, 1450, 1256,
1079, 756.
C25H30NO2 [M + 1]+, 376.2277; found, 376.2281. 1H NMR
(CDCl3, 400 MHz; δ (ppm)): 7.50-7.16 (m, 15H), 4.00 (m, 1H),
3.16 (dd, 1H, J ) 8.8, 5.9 Hz), 2.98 (dd, 1H, J ) 8.8, 5.9 Hz),
2.90 (m, 1H), 2.76 (m, 1H), 2.62 (m, 2H), 1.80-1.70 (m, 1H),
1.58 (m, 1H), 1.07 (t, 2H, J ) 7.3 Hz). 13C NMR (CDCl3, 100
MHz; δ (ppm)): 144.1, 128.7, 127.7, 126.9, 86.4, 72.0, 67.5,
47.7, 43.8, 31.9, 14.8. IR (CHCl3; cm-1): 3062, 3019, 2972,
1491, 1448, 1216, 1075, 757.
(S)-3-Ethyl-6-(hydroxymethyl)-1,3-oxazinan-2-one (17b).
25
Yield: quantitative. [R]D ) +64.1° (c 0.91, EtOH). HRMS
(S)-4-Amino-1-(trityloxy)butan-2-ol (15c). Yield: 93%
Mp: 104.0-106.0 °C. [R]D25 ) -16.0° (c 1.01, EtOH). 1H NMR
(CDCl3, 400 MHz; δ (ppm)): 7.62-7.18 (m, 15H), 3.98 (m, 1H),
3.14 (dd, 1H, J ) 8.8, 5.9 Hz), 3.04 (dd, 1H, J ) 8.8, 4.9 Hz),
2.95 (m, 1H), 2.82 (m, 1H), 1.65 (m, 1H), 1.53 (m, 1H). 13C NMR
(CDCl3, 100 MHz; δ (ppm)): 143.8, 128.4, 127.5, 126.7, 86.2,
70.3, 67.6, 39.3, 35.1. IR (CHCl3; cm-1): 3377, 3061, 3015,
ES+ (m/z): calcd for C7H14NO23 [M + 1]+, 160.0974; found,
160.0972. 1H NMR (CDCl3, 400 MHz; δ (ppm)): 4.28 (m, 1H),
3.79 (m, 1H), 3.66 (m, 1H), 3.38 (m, 3H), 3.26 (dd, 1H, J )
5.9, 2.9 Hz), 1.95 (m, 2H), 1.16 (t, 3H, J ) 6.8 Hz). 13C NMR
(CDCl3, 100 MHz; δ (ppm)): 153.5, 77.5, 63.6, 43.8, 43.4, 23.3,
12.0. IR (CHCl3; cm-1): 3393, 3013, 2927, 1664, 755.
(S)-Methanesulfonic Acid 3-Methyl-2-oxo-1,3-oxazinan-
6-yl Methyl Ester (18a). 6-(Hydroxymethyl)-3-methyl-1,3-
oxazinan-2-one (17a; 1.87 g, 0.013 mol) was dissolved in dry
dichloromethane (20 mL). Pyridine (12 mL, 0.156 mol) and
methanesulfonyl chloride (5 mL, 0.065 mol) were added, and
the solution was stirred at room temperature for 12 h. NaHCO3
(5 g, 0.059 mol) was then added to the flask, and the mixture
was stirred for 30 min, after which time the solvent was
removed on a rotavaporator. The residue was cooled in an ice
bath and water (30-40 mL) was added to quench the unre-
acted sulfonyl chloride. The water phase was extracted using
EtOAc (30 mL, five times). The combined organic extracts were
dried using Na2SO4, and the solvent was evaporated to give
the crude product as a dark brown solid (2.38 g, 0.011 mol).
Yield: 83%. Mp: 81.5-82.0 °C. [R]D25 ) +59.1° (c 1.14, EtOAc).
1H NMR (CDCl3, 400 MHz; δ (ppm)): 4.49 (m, 1H), 4.34 (dd,
1H, J ) 11.7, 3.9 Hz), 4.30 (dd, 1H, J ) 11.7, 3.9 Hz), 3.42 (m,
1H), 3.27 (m, 1H), 3.08 (s, 3H), 2.98 (s, 3H), 2.04 (m, 2H). 13C
NMR (CDCl3, 100 MHz; δ (ppm)): 152.5, 73.9, 69.6, 45.6, 37.5,
36.3, 23.2. HRMS (m/z): calcd for C7H13NO5S [M + 1]+,
224.0593; found, 224.0583. IR (CHCl3; cm-1): 3019, 2942, 1693,
2929, 2873, 1596, 1491, 1448, 1217, 1073, 767 cm-1
.
(S)-3-Methyl-6-((trityloxy)methyl)-1,3-oxazinan-2-
one (16a). 4-(Methylamino)-1-(trityloxy)butan-2-ol (15a; 10.89
g, 0.030 mol) was dissolved in anhydrous THF or dioxane (50
mL). After the compound 15a was completely dissolved,
carbonyldiimidazole (9.98 g, 0.06 mol) was added to the flask
and the solution was stirred with refluxing for 24 h. The
solvent was evaporated on the rotavaporator, and the remain-
ing solid was extracted in EtOAc. The organic phase was
washed with about 10 mL of H2O several times and with 30
mL of brine. The EtOAc phase was concentrated on the
rotavaporator to afford a brown solid that was purified by SiO2
chromatography (hexane/ethyl acetate 5:1-3:1-1:1). The puri-
fied product was obtained as a white crystalline solid (10.87
g, 0.028 mol). Yield: 93%. Mp: 161.0-162.0 °C. [R]D25 ) +36.2
1
(c 1.08, EtOAc). H NMR (CDCl3, 400 MHz): δ 7.42 (d, 6H, J
) 6.8 Hz), 7.32-7.20 (m, 9 H), 4.32 (m, 1H), 3.32 (m, 1H), 3.21
(m, 1H), 2.96 (s, 3H), 2.07 (m, 1H), 1.96 (m. 1H). 13C NMR
(CDCl3, 100 MHz): δ 153.3, 143.3, 128.3, 127.56, 126.9, 86.5,
75.4, 64.5, 45.8, 36.2, 24.3. HRMS ES+ (m/z): calcd for C25H26-
NO3 [M + 1]+, 388.1913; found, 388.1928. IR (CHCl3; cm-1):
3061, 3018, 2938, 2880, 1690, 1494, 1448, 1217, 1083, 760.
1496, 1448, 1356, 1177, 756 cm-1
.
(S)-Methanesulfonic Acid 3-Ethyl-2-oxo-1,3-oxazinan-
6-yl Methyl Ester (18b). After purification by chromatogra-
(S)-3-Ethyl-6-((trityloxy)methyl)-1,3-oxazinan-2-one
25
phy, white crystal. Yield: 92%. Mp: 68.0-70.0 °C. [R]25
)
(16b). Yield: 79%. White crystals. Mp: 141.0-142.0 °C. [R]D
D
) +26.7° (c 1.07, EtOAc). HRMS (m/z): calcd for C26H28NO3
[M + 1]+, 402.2069; found, 402.2079. 1H NMR (CDCl3, 400
MHz; δ (ppm)): 7.52-7.16 (m, 15H), 4.32 (m, 1H), 3.42-3.26
(m, 4H), 3.24-3.14 (m, 2H), 2.10 (m, 1H), 1.93 (m, 1H), 1.12
(t, 3H, J ) 6.8 Hz). 13C NMR (CDCl3, 100 MHz; δ (ppm)):,
153.0, 143.5, 128.6, 127.8, 127.1, 86.7, 75.5, 64.7, 44.0, 43.4,
24.7, 12.1. IR (CHCl3; cm-1): 3062, 3019, 2982, 2938, 1685,
1491, 1450, 1280, 1217, 1094, 763.
+52.2° (c 1.14, EtOAc). HRMS ES+ (m/z): calcd for C8H16-
1
NO5S [M + 1]+, 238.0749; found, 238.0745. H NMR (CDCl3,
400 MHz; δ (ppm)): 4.47 (m, 1H), 4.34 (dd, 1H, J ) 11.7, 3.9
Hz), 4.30 (dd, 1H, J ) 11.7, 4.9 Hz), 3.38 (m, 3H), 2.29 (m,
1H), 3.08 (s, 3H), 2.10-1.92 (m, 2H), 1.15 (t, 3H, J ) 6.8 Hz).
13C NMR (CDCl3, 100 MHz; δ (ppm)): 152.1, 73.9, 69.5, 44.2,
43.2, 37.8, 23.6, 12.1. IR (CHCl3; cm-1): 3436, 3020, 1694,
1491, 1456, 1217, 758 cm-1
.
468 J. Org. Chem., Vol. 70, No. 2, 2005

Chiral 1,3-Oxazinan-2-ones
(S)-6-((Benzylamino)methyl)-3-methyl-1,3-oxazinan-2-
one (19a). Methanesulfonic acid 3-methyl-2-oxo-1,3-oxazinan-
6-yl methyl ester (18a; 0.81 g, 3.67 mmol) and benzylamine
(0.8 mL, 8 mmol) were dissolved in anhydrous DMSO (10 mL).
The mixture was stirred at 75-80 °C for 48 h under an
anhydrous atmosphere. The reaction mixture was cooled to
room temperature, and ice water (10-20 mL) was added to
the flask. The water phase was extracted several times with
dichloromethane. The combined organic phase was dried using
Na2SO4 and concentrated on a rotavaporator to remove the
solvent and give the crude product as a yellow viscous liquid.
The crude compound was purified by silica gel chromatography
using a gradient solvent system (hexane/THF, 9:1; hexane/
CH2Cl2/THF, 6:3:1; CH2Cl2/MeOH, 9.9:0.1). The product was
(S)-3-Benzyl-5-(2-(methylamino)ethyl)oxazolidin-2-
one (20a). 6-((Benzylamino)methyl)-3-methyl-1,3-oxazinan-2-
one (19a; 0.16 g, 0.0007 mol), anhydrous DMSO (5 mL), and
K2CO3 (0.2 g, 0.0014 mol) were mixed and stirred at 95-100
°C for 24 h. The 1H NMR spectrum indicated complete
conversion to the five-membered-ring product. The flask was
cooled to room temperature, and ice water (5 mL) was added
to the solution. The water phase was then extracted with
CH2Cl2 several times. The combined organic phase was
concentrated on a rotavaporator, and the yellow liquid ob-
tained was purified by SiO2 chromatography (hexane/THF, 9:1;
hexane/CH2Cl2/THF, 6:3:1; CH2Cl2/MeOH, 9.9:0.1) to give the
pure product as a light brown viscous liquid. Isolated yield:
1
0.13 g, 80%. [R]25 ) +68.5° (c 1.00, EtOH). H NMR (CDCl3,
D
obtained as a light brown viscous liquid (0.77 g, 3.3 mmol).
1
Yield: 91%. [R]25 ) +68.2° (c 1.07, EtOH). H NMR (CDCl3,
400 MHz; δ (ppm)): 7.36-7.21 (m, 5H), 4.57 (m, 1H), 4.41 (d,
1H, J ) 14.7 Hz), 4.36 (d, 1H, J ) 14.7 Hz), 3.47 (t, 1H, J )
8.8 Hz), 3.03 (t, 1H, J ) 7.8 Hz), 2.69 (t, 2H, J ) 6.8 Hz), 2.38
(s, 3H), 1.88 (m, 1H), 1.74 (m, 1H), 1.62 (bs, 1H). 13C NMR
(CDCl3, 100 MHz; δ (ppm)): 158.0, 135.7, 128.8, 128.1, 127.9,
72.3, 49.4, 48.3, 47.5, 36.4, 35.1. HRMS (m/z): calcd for
C13H19N2O2 [M + 1]+, 235.1447; found, 235.1449. IR (CHCl3;
cm-1): 3018, 2936, 1742, 1493, 1442, 1217, 756.
D
400 MHz; δ (ppm)): 7.24-7.13 (m, 5H), 4.34 (m, 1H), 3.77 (m,
2H), 3.34 (m, 1H), 3.17 (m, 1H), 2.94 (s, 3H), 2.80 (dd, 1H, J )
12.7, 6.8 Hz), 2.75 (dd, 1H, J ) 12.7, 3.9 Hz), 1.92 (m, 2H),
1.83 (bs, 1H). 13C NMR (CDCl3, 100 MHz; δ (ppm)): 153.7,
139.4, 128.3, 128.0, 127.0, 76.3, 53.5, 52.3, 46.2, 36.3, 25.0.
HRMS (m/z): calcd for C13H19N2O2 [M + 1]+, 235.1447; found,
235.1447. IR (CHCl3; cm-1): 3330, 3009, 2938, 1690, 1496,
1449, 1409, 1354, 754.
(S)-6-((Benzylamino)methyl)-3-ethyl-1,3-oxazinan-2-
one (19b). The reaction temperature was 65 °C, and the time
was 36 h (crude yield 96%; 1H NMR spectroscopy indicated
quantitative conversion). Isolated pure compound yield: 78%
Acknowledgment. We are grateful for the generous
gift of 3-hydroxy-γ-butyrolactone starting material from
Prof. Rawle I. Hollingsworth. We also acknowledge
financial support by CAGNO (Cancer Association of
Greater New Orleans) and the startup fund from the
University of New Orleans.
after column purification (solvent gradient hexane/CH2Cl2 6:1
25
and then hexane/CH2Cl2/THF 6:3:1 to 3:5:2 to 0:6:1). [R]D
)
+55.3° (c 0.64, EtOH). HRMS ES+ (m/z): calcd for C14H21N2O2
[M + 1]+, 249.1603; found, 249.1597. 1H NMR (CDCl3, 400
MHz; δ (ppm)): 7.40-7.18 (m, 5H), 4.34 (m, 1H), 3.80 (d, 1H,
J ) 12.7 Hz), 3.76 (d, 1H, J ) 12.7 Hz), 3.34 (m, 2H), 3.20 (m,
1H), 2.81 (dd, 1H, J ) 12.7, 6.8 Hz), 2.76 (dd, 1H, J ) 12.7,
4.9 Hz), 1.94 (m, 2H), 1.85 (s, 1H), 1.13 (t, 3H, J ) 6.8 Hz).
13C NMR (CDCl3, 100 MHz; δ (ppm)): 153.2, 139.8, 128.4,
128.1, 127.0, 76.4, 53.7, 52.6, 44.0, 43.6, 25.3, 12.1. IR (CHCl3;
cm-1): 3472, 2974, 2934, 1682, 1492, 1455, 1282, 1221, 1095,
755.
Supporting Information Available: 1H and 13C NMR
spectra of compounds 13a-20a, 13b-19b, 14c-16c, and
protonated 20a. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO040224Q
J. Org. Chem, Vol. 70, No. 2, 2005 469