Highly diastereoselective alkylation of the Dellaria oxazinone template with bifunctional electrophiles

Article abstract of DOI:10.1081/SCC-120021497

This study investigates the efficiency of alkylation of the Dellaria oxazinone glycinate template with sensitive bifunctional electrophiles. In addition to improved access to the template, triflate/halide bifunctional combinations provided good yields (85-93%) of highly diastereoselective alkylation products.

Full text of DOI:10.1081/SCC-120021497

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Highly Diastereoselective Alkylation of the Dellaria
Oxazinone Template with Bifunctional Electrophiles
Gregory H. P. Roos a & Kim A. Dastlik b
a Chemistry Department , Sultan Qaboos University , Sultanate of Oman
b Chemistry Department , Murdoch University , Perth, Western Australia
Published online: 17 Aug 2006.
To cite this article: Gregory H. P. Roos & Kim A. Dastlik (2003) Highly Diastereoselective Alkylation of the Dellaria Oxazinone
Template with Bifunctional Electrophiles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:13, 2197-2208, DOI: 10.1081/SCC-120021497
To link to this article: http://dx.doi.org/10.1081/SCC-120021497
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2197–2208, 2003
Highly Diastereoselective Alkylation of the
Dellaria Oxazinone Template with
Bifunctional Electrophiles
2
Gregory H. P. Roos1, and Kim A. Dastlik
*
1Chemistry Department, Sultan Qaboos University,
Sultanate of Oman
2Chemistry Department, Murdoch University, Perth,
Western Australia
ABSTRACT
This study investigates the efficiency of alkylation of the Dellaria
oxazinone glycinate template with sensitive bifunctional electro-
philes. In addition to improved access to the template, triflate/halide
bifunctional combinationsprovided good yields(85–93%) of highly
diastereoselective alkylation products.
As part of a programme directed at natural product synthesis, we
had a need to investigate the highly diastereoselective alkylation of a
*Correspondence: Gregory H. P. Roos, Chemistry Department, Sultan
QaboosUniveritsy, Box 36 Al-Khoud 123, Sultanate of Oman; E-mail:
groos@squ.edu.om.
2197
DOI: 10.1081/SCC-120021497
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2198
Roos and Dastlik
suitable chiral glycine enolate synthon. The literature abounds with many
auxiliary-[1] and template-based[2] methodologiesaimed at thisend. Due
to considerations of subsequent manipulations of the intermediate pro-
ducts, we specifically sought a protocol that would allow the release of
the amino acid productsunder very mild conditions. In particular, it was
hoped that the unmasking of the amino acid could be combined with
subsequent cyclization (Sch. 1). After evaluation of reported alkylation
methodologies, yields and cleavage procedures, the Dellaria and
Santarsiero[3] oxazinone template 1 was selected for this purpose.
Initially some difficulty was experienced in reproducing the template
preparation by the reported method. However, simple modification of the
original route (Sch. 2) produced a highly reproducible ‘‘one-pot’’
protocol which was amenable to useful laboratory scales (>20 g).[4] In
thisway, both enantiomeric templateswere available in high purity
in 73–80% overall yield. The related enantiomeric templates 2, containing
–NBoc were also prepared.
Literature alkylations of these and the Williams’ templates indicated
high yields and diastereoselectivity with activated electrophiles (e.g.,
methyl-, allyl-, and benzylbromides). Efficiency dropped dramatically
Scheme 1. Analysis of the template-cyclization approach.
Scheme 2. Oxazinone preparation.

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Alkylation of Dellaria Oxazinone
2199
with less activated systems (e.g., n-butyliodide). In addition, usually at least
3–10 equiv. of electrophile were required to ensure significant alkylation.
Initial studies were conducted with a range of 1,4-di-X substituted
butane electrophiles( X ¼ Br, I, OMs, OTs). These proved to be largely
unsuccessful, with only the diiodide showing any reactivity.[5] Similar low
reactivity wasobesrved with both homoallyl bromide or iodide.
However, a single clean product could be isolated in 40% yield from
the latter system when 15-crown-5 was employed as an additive.
Following a report by Uenishi et al.,[6] the utility of triflate asa
leaving group wasexplored. The required functionalized triflateswere
readily accessed from 3-buten-1-ol (for homoallyl triflate) and THF
(for the 4-halo-1-triflates). These reactive substrates proved to be stable
at low temperature (À4ꢀC) for periodsup to a week.
Alkylation of the templates 1 and 2 with the homoallyl, chloro, and
bromo triflates( ꢁ1.25 equiv.) reproduceably provided high yieldsof dia-
stereomerically pure products (Table 1). The iodo triflate, on the other
hand, led to multiple products. No trace of the alternative diastereomers
could be detected either by HPLC or NMR.
To confirm the pattern of configurational assignments (Sch. 3),
(S,S )-3a (R ¼ homoallyl; Z ¼ Cbz) wasconverted in 89% (H /Pd-C) to
2
(S )-norleucine 4 with [a]D 22.9ꢀ (Lit.[7] 22.8ꢀ). In a similar reaction,
(S,S )-3c (R ¼ bromobutyl, Z ¼ Cbz) afforded a small amount of (S )-
Table 1. Diastereoselective alkylation of oxazinones 1 and 2.
Template
E
3%
Config/[a]D
(R)-1
(S )-1
(R)-1
93
92
85
(R,R) À 146ꢀ
(S,S ) þ 145ꢀ
(R,R) À 136ꢀ
OTf
OTf
Cl
Cl
Br
Br
Cl
Cl
Br
Br
OTf
(S )-1
(R)-1
(S )-1
(R)-2
(S )-2
(R)-2
(S )-2
83
90
90
95
93
80
81
(S,S ) þ 136ꢀ
(R,R) À 128ꢀ
(S,S ) þ 129ꢀ
(R,R) À 145ꢀ
(S,S ) þ 144ꢀ
(R,R) À 133ꢀ
(S,S ) þ 133ꢀ
OTf
OTf
OTf
OTf
OTf
OTf
OTf

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2200
Roos and Dastlik
Scheme 3. Hydrogenation of selected alkylation products.
norleucine 4 (12%) along with the expected (S )-pipecolic acid 5 (45%)
with [a]D À25.9ꢀ (Lit.[8] À25.8ꢀ).
EXPERIMENTAL
General
Nuclear magnetic resonance spectra were recorded on a Bruker
Advance DPX-300 (1H, 300 MHz; 13C, 75.5 MHz). All spectra were run
in deuterochloroform at ambient (25ꢀC) temperature with tetramethyl-
silane as an internal standard unless stated otherwise.
High-resolution mass spectra were measured on a VG Autospec
Mass Spectrometer. High-pressure liquid chromatography was carried
out on a GBC LC 1150 system using a 25 cm Chiracell OD or an Alltech
Econosil C18 column. The detector was a Knauer variable wavelength
monitor set at 254 nm. Infrared spectra were recorded on a Perkin Elmer
1720-X Fourier Transform Spectrometer as KBr discs (solids) or as thin
films(liquidsand o)i.ls Melting pointswere determined on
an Electrothermal melting point apparatusand are uncorrected.
Optical rotationswere obtained on an Optical Activity PolAAr 2001
polarimeter. Thin layer chromatography wascarried out on aluminium

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Alkylation of Dellaria Oxazinone
2201
platescoated with Kieeslgel 60 F 254. Radial chromatography wasper-
formed on a Harrison Research Ltd. ‘‘Chromatotron’’ with coatings of
Merck silica gel 60 PF254
.
Hexanesrefersto the fraction of petroleum ditsillate that boilsin
the range 65ꢀC–70ꢀC, ether refersto diethyl ether. Sodium bicarbonate
and brine solutions were used as saturated solutions at ambient tempera-
ture. Magnesium and sodium sulphate drying agents were oven-dried at
200ꢀC for 3 h (and cooled in a vacuum desiccator) prior to use. All solvents
were distilled prior to use. All quoted yields refer to isolated compounds
obtained after chromatography, distillation or recrystallization.
(R )-2,3,5,6-Tetrahydro-5-phenyl-N-(benzyloxycarbonyl)-4H-
1,4-oxazine-2-one (R)-1
(R )-Phenylglycinol (1.37 g, 0.01 mol) was suspended in dry THF
(20 mL) with dry triethylamine (1.21 g, 1.65 mL, 0.012 mol) and cooled
to 0ꢀC under a stream of N2. Ethyl bromoacetate (2.00 g, 1.33 mL,
0.012 mol) wasadded and the reaction tsirred for 3 h (0 ꢀC ! rt). The
reaction wascooled in ice, filtered, and the filter cake washedꢀwith cold
THF (10 mL). The combined organicswere concentrated (45 C) and the
residue taken up in CH2Cl2 (20 mL) and NaHCO3 (40 mL). Benzyl
chloroformate (1.88 g, 1.65 mL, 0.011 mol) wasadded dropwies and
the reaction vigorously stirred for 1 h. The phases were separated,
the aqueousphaes wahsed with CH 2Cl2 (3 Â 20mL) and the combined
organicswashed with brine (10 mL), dried (Na 2SO4), and concentrated.
The residue was diluted with toluene (100 mL), pTSA (0.19 g, 0.001 mol)
added and the solvent slowly distilled (down to ꢂ5 mL) at atmospheric
pressure. The remaining toluene was evaporated (rotorvap.) and the
residue taken up in ether (100 mL). The ether was washed with water
(25 mL), dried (MgSO4), and concentrated to ꢂ5 mL. The product
(2.47 g, 80%) crystallized on cooling, sometimes by trituration with
hexanes(1–2 mL): m.p. 123–123.5 ꢀC (CH2Cl2/ether); Lit.[3] m.p.
21
D
97–98ꢀC (acetone/ether). IR (KBr) 1773, 1695 cmÀ1. ½aŠ
À56.6ꢀ

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2202
Roos and Dastlik
(c ¼ 1.0, CHCl3). 1H NMR (CDCl3, 60ꢀC) ꢀ 7.36–7.15 (m, 10H, Ph),
5.22 (t, 1H, J ¼ 4.5 Hz, H5), 5.14 (d, 1H, J ¼ 12.3 Hz, PhCHHO-),
5.08 (d, 1H, J ¼ 12.3 Hz, PhCHHO-), 4.64 (d, 1H, J ¼ 18 Hz, H3),
4.59 (dd, 1H, J ¼ 4.3 and 12 Hz, H6), 4.50 (dd, 1H, J ¼ 5.3 and
12 Hz, H6), 4.20 (d, 1H, J ¼ 18 Hz, H3). 13C NMR ꢀ 167, 155, 137,
136, 129, 129, 128, 126, 70, 68.2, 54.1, 44.8.
(S )-2,3,5,6-Tetrahydro-5-phenyl-N-(benzyloxycarbonyl)-4H-
1,4-oxazine-2-one (S )-1
The (S )-enantiomer wasderived in a ismilar manner from ( S )-
21
phenylglycinol: ½aŠ 56.4 (c ¼ 1.0, CHCl3). All spectroscopic and physical
D
data were identical to the above.
(R )-2,3,5,6-Tetrahydro-5-phenyl-N-(tert-butyloxycarbonyl)-
4H-1,4-oxazine-2-one (R)-2
A similar method to that of the Lit.[3] wasfollowed (0.01 mol scale of
(R)-phenylglycinol) with the alkylation reaction time being shortened to
3 h. The product (1.35 g, 49%, unoptimized) wasrecrytsallized from
ether/hexanesasneedl:es m.p. 87–89
ꢀC; Lit.[3] m.p. 87–88ꢀC
21
D
(EtOAc/hexanes). IR (KBr) 1761, 1671 cmÀ1. ½aŠ À67.5ꢀ (c ¼ 1.0,
CHCl3). H NMR (CDCl3, 60ꢀC) ꢀ 7.39–7.21 (m, 5H, Ph), 5.17 (m, 1H,
1
H5), 4.58 (dd, 1H, J ¼ 5.9 and 12 Hz, H6), 4.15(d, 1H, J ¼ 18 Hz, H3),
1.33 (s, 9H, tert-butyl). 13C NMR ꢀ 167, 154, 138, 129, 128, 126, 81.7,
70.0, 54.2, 44.6, 28.2.
(S )-2,3,5,6-Tetrahydro-5-phenyl-N-(tert-butyloxycarbonyl)-
4H-1,4-oxazine-2-one (S )-2
The (S )-enantiomer wasderived in a ismilar manner from ( S )-
phenylglycinol: ½aŠ þ67.5ꢀ (c ¼ 1.0, CHCl3). All spectroscopic and
21
D
physical data were identical to the above.
General Procedure for the Preparation of Triflates
K2CO3 (1.10 g, 8 mmol) wasadded to a three necked flask fitted with
a nitrogen inlet/outlet, a rubber septum and a glass stopper. The flask was

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Alkylation of Dellaria Oxazinone
2203
flame dried then cooled to À50ꢀC, under a gentle flow of N2. Dry CH2Cl2
(10 mL), triflic anhydride (2.1 mL, 12.5 mmol), and DMAP (0.122 g,
1 mmol) were added sequentially to the stirred mixture. After 10 min,
the alcohol[9] (10 mmol, neat) wasadded and the reaction tsirred for
1 h. CH2Cl2 (10 mL) and H2O (5 mL) were added, the layersesparated
and the aqueousphase extracted with further CH 2Cl2 (5 mL). The com-
bined CH2Cl2 fractionswere dried (MgSO 4) and concentrated (rotorvap.
at 40ꢀC). The residue was distilled in a Kugelrohr apparatus to produce
the triflate as a colorless oil. All triflates were stored under nitrogen in the
fridge and were stable for up to a week (although some discoloration did
occur). All proved too unstable for successful microanalysis.
3-Butenyl-1-trifluoromethanesulphonate
Seventy two percent distilled. This product had physical and spectro-
scopic details that were identical to that reported in the Lit.[10]
4-Bromobutanol-1-trifluoromethanesulphonate
Seventy percent distilled: b.p. 75ꢀC at 0.03 mm Hg. 1H NMR
(CDCl3) ꢀ 4.59 (m, 2H, H1), 3.46 (m, 2H, H4), 2.02 (m, 4H, H2 and
H3). 13C NMR ꢀ 119, 76.6, 43.7, 28.2, 27.9.
4-Chlorobutanol-1-trifluoromethanesulphonate
Seventy nine percent distilled: b.p. 65ꢀC at 0.04 mm Hg. H NMR
1
(CDCl3) ꢀ 4.60 (m, 2H, H1), 3.62 (m, 2H, H4), 2.00 (m, 4H, H2 and H3).
13C NMR ꢀ 119, 76.7, 43.8, 28.2, 26.7.
4-Iodobutanol-1-trifluoromethanesulphonate
Fifty six percent distilled (x2): b.p. 90ꢀC at 0.025 mm Hg. IR (Thin
film) 1246, 1208, 1144 cmÀ1. HRMS calcd. for C5H8IF3O3S: 331.9191.
1
Found: 331.9188. H NMR (CDCl3) ꢀ 4.53 (m, 2H, H1), 3.22 (m, 2H,
H4), 2.00 (m, 4H, H2 and H3). 13C NMR ꢀ 119, 76.1, 33.8, 30.1, 28.8.

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Roos and Dastlik
General Procedure for Alkylation of Oxazinones
To a flame dried three-necked flask, under a gentle stream of nitro-
gen, wasadded the template 1 or 2 and dry DME (4 mL). After complete
dissolution, the flask was cooled to À78ꢀC and a solution of NaHMDS
(1.0 mL of a 1 M solution in THF) added via syringe. The mixture was
stirred for 0.5 h, treated dropwise with freshly distilled triflate (1.25 mmol,
neat) and stirring continued for 2 h. The reaction was quenched by the
addition of EtOAc (20 mL) and brine (5 mL). The layerswere separated
and the aqueousphase re-extracted with EtOAc (5 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue was
applied to a 2 mm Chromatatron plate and eluted with EtOAc in hexanes
(20 ! 50%).
(3R,5R)-2,3,5,6-Tetrahydro-3-(1-butenyl)-5-phenyl-N-
(benzyloxycarbonyl)-4H-1,4-oxazine-2-one (R,R)-3a
Ninety three percent, recrystallized from ether/hexanes: m.p.
21
165–165.5ꢀC. IR (KBr) 1757, 1707 cmÀ1. ½aŠ À146ꢀ (c ¼ 1.0, CHCl3).
D
1H NMR (CDCl3, 60ꢀC) ꢀ 7.32–6.99 (m, 10H, Ph), 5.81 (m, 1H, H50),
5.13–4.99 (m, 5H, H50 and H6 and PhCH2O-), 4.85 (dd, 1H, J ¼ 4.4 and
9.5 Hz, H3), 4.77 (dd, 1H, J ¼ 3 and 11.9 Hz, H6), 4.41 (dd, 1H, J ¼ 1.5
and 11.9 Hz, H6), 2.26–1.86 (m, 4H, H30 and H40). 13C NMR ꢀ 168, 154,
139, 136, 136, 129, 128, 126, 116, 69.8, 67.9, 56.9, 55.0, 33.8, 29.8. Anal.
calcd. for C22H23NO4: C 72.58; H 6.34; N 3.83. Found: C 72.08; H 6.24;
N 3.82%.
(3S,5S )-2,3,5,6-Tetrahydro-3-(1-butenyl)-5-phenyl-N-
(benzyloxycarbonyl)-4H-1,4-oxazine-2-one (S,S)-3a
The (3S,5S )-enantiomer waspurified in analogousfahsion (92%)
½aŠ þ145ꢀ (c ¼ 1, CHCl3). All other spectroscopic and physical data
22
D
were identical to the above.
(3R,5R )-2,3,5,6-Tetrahydro-3-(4-chlorobutyl)-5-phenyl-N-
(benzyloxy-carbonyl)-4H-1,4-oxazin-2-one (R,R )-3b
Eighty five percent, recrystallized from ether: m.p. 95–96ꢀC. IR (KBr)
22
D
1
1760, 1703 cmÀ1. ½aŠ À136ꢀ (c ¼ 1.0, CHCl3). H NMR (CDCl3, 60ꢀC)
ꢀ 7.28 (m, 6H, Ph), 7.08 (m, 4H, Ph), 5.13 (br s, 1H, H5), 5.09 (d, 1H,

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Alkylation of Dellaria Oxazinone
2205
J ¼ 12 Hz, PhCHHO), 4.99 (d, 1H, J ¼ 12 Hz, PhCHHO), 4.80 (m, 1H,
H3), 4.74 (dd, 1H, J ¼ 3.0 and 12 Hz, H6), 4.39 (d, 1H, J ¼ 12 Hz, H6),
3.49 (t, 2H, J ¼ 6.5 Hz, H60), 2.06 (m, 1H, H30), 1.93–1.72 (m, 3H, H30 and
H50), 1.62 (m, 2H, H40). 13C NMR ꢀ 168, 154, 139, 136, 129, 128, 125, 69.8,
67.6, 56.8, 54.6, 44.4, 33.9, 33.2, 22.9. Anal. calcd. for C22H24ClO4: C
65.75, H 6.02, N 3.49, Found: C 65.55, H 6.05, N 3.45%.
(3S,5S )-2,3,5,6-Tetrahydro-3-(4-chlorobutyl)-5-phenyl-N-
(benzyloxycarbonyl)-4H-1,4-oxazin-2-one (S,S )-3b
The (3S,5S )-enantiomer waspurified in analogousfahsion (83%).
½aŠ þ136ꢀ (c ¼ 1.0, CHCl3). All other spectroscopic and physical data
22
D
were identical to the above.
(3R,5R )-2,3,5,6-Tetrahydro-3-(4-bromobutyl)-5-phenyl-N-
(benzyloxycarbonyl)-4H-1,4-oxazin-2-one (R,R )-3c
Ninety percent, recrystallized from ether/hexanes: m.p. 90–92ꢀC. IR
22
D
1
(KBr) 1759, 1701 cmÀ1; ½aŠ À128ꢀ (c ¼ 1.0, CHCl3). H NMR (CDCl3,
60ꢀC) ꢀ 7.28 (m, 6H, Ph), 7.08 (m, 4H, Ph), 5.13 (br.s, 1H, H5), 5.08 (d, 1H,
J ¼ 12 Hz, PhCHH), 4.98 (d, 1H, J ¼ 12 Hz, PhCHH), 4.80 (m, 1H, H3),
4.72 (dd, 1H, J ¼ 3.0 and 12 Hz, H6), 4.37 (d, 1H, J ¼ 12 Hz, H6), 3.34 (t,
2H, J ¼ 6.6 Hz, H60), 2.06 (m, 1H, H30), 1.94–1.73 (m, 3H, H30 and H50),
1.63 (m, 2H, H40). 13C NMR ꢀ 167, 153, 138, 135, 128, 127.5, 127, 125, 68.8,
66.8, 56.0, 53.8, 32.5, 31.7, 30.9, 23.4. Anal. calcd. for C22H24BrNO4: C
59.20, H 5.42, N 3.14. Found: C 59.10, H 5.40, N 3.07%.
(3S,5S )-2,3,5,6-Tetrahydro-3-(4-bromobutyl)-5-phenyl-N-
(benzyloxycarbonyl)-4H-1,4-oxazin-2-one (S,S )-3c
The (3S,5S )-enantiomer waspurified in analogousfahsion (90%).
½aŠ þ129ꢀ (c ¼ 1.0, CHCl3). All other spectroscopic and physical data
22
D
were identical to the above.
(3R,5R)-2,3,5,6-Tetrahydro-3-(4-chlorobutyl)-5-phenyl-N-
(tert-butoxycarbonyl)-4H-1,4-oxazin-2-one (R,R)-3d
Ninety five percent, recrystallized from ether: m.p. 169–172ꢀC (dec).
22
D
IR (KBr) 1754, 1698 cmÀ1
.
½aŠ À145ꢀ (c ¼ 1.0, CHCl3). 1H NMR

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2206
Roos and Dastlik
(CDCl3, 60ꢀC) ꢀ 7.29 (m, 3H, Ph), 7.08 (m, 2H, Ph), 5.05 (br.s, 1H, H5),
4.81 (m, 1H, H3), 4.76 (dd, 1H, J ¼ 3.0 and 11.8 Hz, H6), 4.39 (d, 1H,
J ¼ 11.8 Hz, H6), 3.55 (t, 2H, H60), 2.05 (m, 1H, H30), 1.88 (m, 3H, H30
and H50), 1.68 (m, 2H, H40), 1.28 (s, 9H, tert-butyl). 13C NMR ꢀ 169, 154,
140, 129, 128, 126, 81.5, 69.9, 56.8, 54.9, 44.4, 34.0, 32.0, 28.2, 23.3. Anal.
calcd. for C19H26ClNO4: C 62.03, H 7.12, N 3.81. Found: C 62.15, H 7.13,
N 3.73%.
(3S,5S )-2,3,5,6-Tetrahydro-3-(4-chlorobutyl)-5-phenyl-N-(tert-
butoxycarbonyl)-4H-1,4-oxazin-2-one (S,S)-3d
The (3S,5S)-enantiomer (S,S)-3d wasgenerated in analogousfashion
(93%). ½aŠ þ144ꢀ (c ¼ 1.0, CHCl3). All other spectroscopic and physical
23
D
data were identical to the above.
(3R,5R )-2,3,5,6-Tetrahydro-3-(4-bromobutyl)-5-phenyl-N-
(tert-butoxycarbonyl)-4H-1,4-oxazin-2-one (R,R )-3e
Eighty percent, recrystallized from ether: m.p. 152–156ꢀC (dec). IR
22
D
1
(KBr) 1754, 1699 cmÀ1. ½aŠ À133ꢀ (c ¼ 1.0, CHCl3). H NMR (CDCl3,
60ꢀC) ꢀ 7.28 (m, 3H, Ph), 7.09 (m, 2H, Ph), 5.06 (br s, 1H, H5), 4.80 (m,
1H, H3), 4.76 (dd, 1H, J ¼ 3.0 and 11.9 Hz, H6), 4.40 (d, 1H, J ¼ 11.9 Hz,
H6), 3.42 (t, 2H, J ¼ 11 Hz, H60), 2.05–1.90 (m, 4H, H30 and H50), 1.68
(m, 2H, H40), 1.28 (s, 9H, tert-butyl). 13C NMR ꢀ 169, 153, 140, 129, 128,
125, 81.4, 69.7, 56.1, 54.9, 33.4, 33.1, 31.9, 28, 24.4. Anal. calcd. for
C19H26BrNO4: C 55.35, H 6.36, N 3.40. Found: C 55.37, H 6.34, N 3.40%.
(3S,5S )-2,3,5,6-Tetrahydro-3-(4-bromobutyl)-5-phenyl-N-
(tert-butoxycarbonyl)-4H-1,4-oxazin-2-one (S,S)-3e
The (3S, 5S )-enantiomer (S,S )-3e wasgenerated in analogous
fashion. ½aŠ þ133ꢀ (c ¼ 1.0, CHCl3). All spectroscopic and physical
22
D
data were identical to the above.
L-(Q)-Norleucine (S )-4
Alkene (S,S )-3a (0.182 g, 0.5 mmol) was dissolved in methanol
(10 mL) containing TFA (1 drop) and exhaustively (24 h) hydrogenated

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Alkylation of Dellaria Oxazinone
2207
at 55 psi pressure over 10% Pd-C (0.182 g). The catalyst was removed
by filtration and the filtrate concentrated. The concentrate wasdi-s
solved in water (2 mL) and applied to an ion exchange column
(Dowex 50X2). The column waseluted with ammonium hydroxide
(1 N, 200 mL) and the eluant concentrated to give (S )-4 asa colorles
22
D
22
D
powder (0.058 g, 89%): ½aŠ þ22.9ꢀ (c ¼ 0.5, 6 N HCl). Lit.[7] ½aŠ
þ22.8ꢀ (c ¼ 0.46, 6 N HCl).
L-(À)-Pipecolic Acid (S )-5 and L-(Q)-Norleucine (S )-4
Bromo derivative (S )-3c (0.223 g, 0.5 mmol) was dissolved in metha-
nol (10 mL) containing TFA (1 drop) and exhaustively (24 h) hydroge-
nated at 55 psi pressure over 10% Pd-C (0.182 g). The palladium catalyst
wasremoved by filtration and the filtrate concentrated. The concentrate
was dissolved in water (2 mL) and applied to an ion exchange column
(Dowex 50X2). The column waseluted with ammonium hydroxide (1 N,
200 mL) and 5 mL aliquotscollected and concentrated to drynessto
afford firstly (S )-4 (0.008 g, 12%), followed by (S )-5 (0.029 g, 45%):
22
D
22
D
½aŠ À25.9ꢀ (c ¼ 1.0, H2O). Lit.[8] ½aŠ À25.8ꢀ (c ¼ 1.0, H2O).
ACKNOWLEDGMENT
The authors acknowledge the support of Murdoch University for
thiswork.
REFERENCES
1. For recent general compilations see (a) Roos, G.H.P. Alkylation
and related reactions. Compendium of Chiral Auxiliary Applications;
Academic Press: London, 2002; Vol. 1, 218; (b) Seyden-Penne, J.
Alkylation and related reactions. Chiral Auxiliariesand
Ligandsin Aysmmetric Syntheis
1995; 157.
; Wiley-Interscience: New York,
2. (a) Williams, R.M. Synthesis of Optically Active a-Amino Acids;
Baldwin, J.E., Magnus, P.D., Eds.; Pergamon Press: Oxford, 1989;
Vol. 7; (b) Seebach, D.; Sting, A.R.; Hoffman, M. Angew. Chem. Int.
Ed. Engl. 1996, 35, 2708.
3. (a) Dellaria, J.F.; Santarsiero, B.D. Tetrahedron Lett. 1988, 29, 6079;
(b) Dellaria, J.F.; Santarsiero, B.D. J. Org. Chem. 1989, 54, 3916.

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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2208
Roos and Dastlik
4. Dastlik, K.A.; Roos, G.H.P.; Giles, R.G.F. Tetrahedron:
Asymmetry 1996, 7, 2525.
5. Whilst reaction monitoring indicated a single major product,
extensive decomposition prevented further characterization.
6. Uenishi, J.; Tatsumi, Y.; Kobayashi, N.; Yonemitsu, O.
Tetrahedron Lett. 1995, 36, 5909.
7. Baldwin, J.E.; Spivey, A.C.; Schofield, C.J.; Sweeney, J.B.
Tetrahedron 1993, 49, 6309.
8. Hockless, D.C.R.; Mayadunne, R.C.; Wild, S.B. Tetrahedron:
Asymmetry 1995, 6, 3031.
9. For the general approach to the haloalcohols, see: Shea, K.J.;
Burke, L.D. J. Org. Chem. 1988, 53, 318.
10. Xu, Y.-C.; Wulff, W.D. J. Org. Chem. 1987, 52, 3263.
Received in the USA November 8, 2002