Total synthesis of methyl l-daunosaminide hydrochloride via chiral 1,3-oxazine

Article abstract of DOI:10.1016/j.tet.2014.02.033

Total synthesis of methyl l-daunosaminide hydrochloride was achieved from readily available l-tyrosine. Key steps in this strategy were palladium(0) catalyzed stereoselective intramolecular oxazine formation and catalytic hydrogenation of oxazine intermed

Full text of DOI:10.1016/j.tet.2014.02.033

Tetrahedron 70 (2014) 2570e2575
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of methyl
1,3-oxazine
L
-daunosaminide hydrochloride via chiral
,
,
Tian Jin a y, Jin-Seok Kim a y, Yu Mu a, Seok-Hwi Park a, Xiangdan Jin a, Jong-Cheol Kang a,
Chang-Young Oh a b, Won-Hun Ham a
,
,
*
a School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b Yonsung Fine Chemicals Co., Ltd, 129-9 Suchon-ri, Jangan-myeon, Hwaseong-si, Gyeonggi-do 445-944, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 January 2014
Received in revised form 12 February 2014
Accepted 13 February 2014
Available online 21 February 2014
Total synthesis of methyl L-daunosaminide hydrochloride was achieved from readily available L-tyrosine.
Key steps in this strategy were palladium(0) catalyzed stereoselective intramolecular oxazine formation
and catalytic hydrogenation of oxazine intermediate. This paper reported 1H and 13C NMR data of
- and
-anomer of methyl -daunosaminide hydrochloride.
a
b
L
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
L-Daunosamine
anti,syn-Oxazine
Diastereoselectivity
Palladium
1. Introduction
3-Amino-2,3,6-trideoxysugars were found in nature as struc-
tural constituent of glycosidic and oligosaccharide antibiotics.1
L-Daunosamine 1 (3-amino-2,3,6-trideoxy-L-lyxo-hexose) is a gly-
cosidic component of a number of important anthracycline anti-
biotics, such as daunomycin 32 and adriamycin 4,3 which exhibit
impressive activity against a broad range of experimental and
human tumor types (Fig. 1).2,4
Various synthetic methods of 3-amino-2,3,6-trideoxyhexoses
from both sugar and nonsugar starting materials have been docu-
mented due to their synthetic interest of controlling the chirality in
the absence of neighboring groups at C-2, which affect the ste-
reochemistry at the anomeric position.5 In recent representative
publications, Liu et al. demonstrated a highly efficient synthesis of
Fig. 1. Structure of L-daunosamine (1), methyl L-daunosaminide hydrochloride (2), and
anthracycline antibiotics.
et al. described total synthesis of 2,3,6-trideoxy-3-aminohexo
pyranoses via photochemically induced acyl nitrene aziridination
reaction followed by regioselective hydrogenolytic cleavage of the
aziridine as key steps.5e
L
-epi-daunosamine glycosides via BF3$OEt2 promoted tandem
hydroamination and glycosylation on a protected scaffold.5a Fries-
tad et al. reported the sequence of asymmetric dihydroxylation and
a regio-reversed Wacker oxidation via the application of silicon-
tethered vinyl addition under tin-free thiyl radical conditions
complete a synthesis of L
-daunosamine derivatives.5b Also, Lowary
2. Results and discussion
As part of an ongoing research program aimed at developing
asymmetric total syntheses of biologically active compounds,6
we recently described a facile strategy for the preparation of
* Corresponding author. Tel.: þ82 31 290 7706; fax: þ82 31 292 8800; e-mail
address: whham@skku.edu (W.-H. Ham).
y
Both authors contributed equally to this work.
DAB-1 and D-fagomine via palladium(0) catalyzed stereoselective
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.033

T. Jin et al. / Tetrahedron 70 (2014) 2570e2575
2571
intramolecular oxazine formation and catalytic hydrogenation.6d
As continuation of our previous works, we herein describe an
The stereochemistry of the oxazine obtained above was eluci-
dated by 1H NMR spectroscopy. The relative configuration of each
diastereomer of the oxazine products, obtained after the silica gel
column separation, was determined by a comparison of their cou-
pling constants and a measurement of NOE effect. The large cou-
pling constant of J4,5¼6.0 Hz as in anti,syn-oxazine 6, was caused by
the pseudo-diaxial relationship between the two adjacent protons
in six-membered ring. The small coupling constants of J5,6¼3.5 Hz
as in anti,syn-oxazine 6, are typically because of the pseudo-axial-
equatorial relationship between the two adjacent protons in six-
membered ring. NOE enhancement for compound 6 is shown be-
low: there is 8.82% NOE between H5 and H6, 0.29% between H5 and
H4, but no NOE effective between H4 and H6 (Fig. 2).
asymmetric total synthesis of methyl
chloride 2, the daunosamine derivative, which results in report of
NMR spectroscopic data of its - and -anomer, starting from
commercially available -tyrosine via palladium(0) catalyzed ster-
L-daunosaminide hydro-
a
b
L
eoselective intramolecular oxazine formation followed by catalytic
hydrogenation of oxazine intermediate as key steps.
Retrosynthetically, we envisioned that methyl L-daunosaminide
hydrochloride 2 (Scheme 1) could be generated from lactone 5
through reduction and deprotection. Lactone 5 would come from
anti,syn-oxazine 6 through a process involving ozonolysis, sub-
sequent tributyltin hydride-mediated reduction, ruthenium cata-
lyzed oxidation, and catalytic hydrogenation of oxazine
intermediate with concomitant lactonization. In turn, the anti,syn-
oxazine 6 could be prepared by the diastereoselective reduction of
amino ketone 7 followed by intramolecular cyclization. The amino
ketone 7 could be easily achieved from commercially available
L
-tyrosine according to the known procedure.7
Fig. 2. Coupling constants and NOE spectroscopic data of 6.
Also, anti,syn-oxazine 6 has almost similar 1H NMR patterns to
previously reported benzyl oxazine compounds.6e Protons of the
terminal olefin and H5 have peaks at 6.0 and 3.73 ppm, respectively.
In addition, the coupling constant of the newly generated chiral
center (H5eH6) of compound 6 has the similar value 3.5 Hz, com-
pared to all anti,syn-oxazines previously reported and the stereo-
chemistry was finally confirmed by its conversion into methyl
L-daunosaminide hydrochloride 2.
Scheme 1. Retrosynthetic analysis.
Total synthesis of methyl -daunosaminide hydrochloride 2 is
L
described in Scheme 3. The terminal olefin in compound 6 was
converted to the alcohol 9 by ozonolysis followed by reduction with
NaBH4. Primary alcohol 9 was treated with tosyl chloride in the
presence of Et3N and DMAP in dichloromethane to afford the
tosylate 10 in good yield. Then, tosylate 10 was treated with lithium
bromide in N,N-dimethylformamide (DMF) to afford bromide 11.
Bromide 11 was subjected to a radical reduction [tributyltin hydride
(Bu3SnH), catalytic 2,20-azobis(isobutyronitrile) (AIBN)] to afford 12
in 75% yield.9 Oxidation of p-methoxyphenyl group of 12 with
RuCl3 (0.1 equiv) and NaIO4 (17 equiv) in CCl4/CH3CN/H2O (2:2:3)10
gave the sequence of catalytic hydrogenation6b,c and in situ lacto-
nization.11 Subsequent reduction of the lactone 5 using DIBAL-H
gave the protected lactol 14 as an 1.3:1 mixture of anomers in
93%. The assignment of relative stereochemistry for protected lactol
14 was made on the basis of the 1H NMR spectra (Fig. 3). The two
small coupling constants (equatorialeequatorial interaction and
The chelation-controlled hydride reduction of 7 using lithium
tri-tert-butoxyaluminum hydride yielded anti-amino alcohol with
excellent stereoselectivity (anti/syn>10:1 by 1H NMR spectros-
copy).6 The secondary alcohol was then protected with the silyl
ether with tert-butyldimethylsilyl chloride (TBSCl) and imidazole in
N,N-dimethylformamide (DMF) to afford the cyclization precursor
8 in 92% yield. Under the conditions of Pd(PPh3)4, NaH, and n-Bu4NI
in THF at 0 ꢀC, stereoselective intramolecular cyclization of the allyl
chloride 8 afforded anti,syn-oxazine 6 and anti,anti-oxazine 60 as
a 10:1 mixture (1H NMR spectroscopy) in 72% yield (Scheme 2).8
equatorialeaxial interaction) of 14a between protons H-1 (
dd) and H-3 of 2.5 Hz, and between H-1 and H-2 of 2.5 Hz exhibited
by -anomeric proton are consistent with an axial disposition of the
hydroxyl group. A large coupling constant (axialeaxial interaction)
between protons H-1 ( 4.79, ddd) and H-3 of 9.5 Hz, confirmed
that this was the -anomer, 14b. The coupling pattern of anomeric
hydrogen of protected lactol 14 shows good agreements with the
d 5.34,
a
d
b
coupling pattern of anomeric hydrogen of N-benzoyl L-daunos-
amine reported by Grasselli et al.12
Finally, removal of the Boc and TBS groups under acidic condi-
tion (6 N HCl, MeOH, rt) afforded methyl -daunosaminide hydro-
chloride 2 as a 3:1 mixture of anomers. The assignment of relative
Scheme 2. Reagents and conditions: (a) LiAlH(OtBu)3, ꢁ78 ꢀC, 85%; (b) TBSCl, imid-
azole, DMF, rt, 92%; (c) Pd(PPh3)4, NaH, n-Bu4NI, THF, 0 ꢀC, 72%.
L

2572
T. Jin et al. / Tetrahedron 70 (2014) 2570e2575
compared to the reported value, ½a D25
ꢂ
ꢁ140 (c 1.0, MeOH),5l con-
firmed the absolute configuration of 2. The net result was synthesis
from a linear sequence of 11 steps from the amino ketone 7 in 9.9%
overall yield for methyl -daunosaminide hydrochloride 2.
L
3. Conclusions
We have demonstrated the total synthesis of methyl
saminide hydrochloride 2 starting from readily available
L
-dauno-
L
-tyrosine
via palladium-catalyzed stereoselective intramolecular oxazine
formation followed by catalytic hydrogenation of oxazine in-
termediate. Also, we have reported structural identification of its
a
- and
pattern of the anomeric hydrogen in the 1H NMR spectra of methyl
-daunosaminide hydrochloride enabled determination of the
b-anomer by NMR spectroscopic data, clearly. The coupling
L
anomeric configuration. Further extension of this work to the
syntheses of structurally related natural products are in progress.
4. Experimental
4.1. General information
Optical rotations were measured with a polarimeter in the
solvent specified. 1H and 13C NMR spectroscopic data were recor-
ded with FT-NMR 125, 175, 500 or 700 MHz. Chemical shift values
are reported in parts per million relative to TMS or CDCl3, as the
internal standard, and coupling constants are reported in Hertz. IR
spectra were measured with a FT-IR spectrometer. Mass spectro-
scopic data were obtained with Jeol JMS 700 high resolution mass
spectrometer of magnetic sectordelectric sector double focusing
analyzer. Flash chromatography was executed using mixtures of
ethyl acetate and hexane as the eluents. Unless otherwise noted,
all nonaqueous reactions were carried out under an argon atmo-
sphere with commercial grade reagents and solvents. Tetrahy-
drofuran (THF) was distilled from sodium and benzophenone
(indicator). Methylene chloride (CH2Cl2) was distilled from cal-
cium hydride.
Scheme 3. Reagents and conditions: (a) O3, MeOH, ꢁ78 ꢀC then NaBH4, 0 ꢀC, 86%; (b)
TsCl, Et3N, DMAP, CH2Cl2, rt, 89%; (c) LiBr, DMF, 60 ꢀC, 84%; (d) Bu3SnH, AIBN, toluene,
100 ꢀC, 75%; (e) NaIO4, RuCl3, CCl4/CH3CN/H2O¼2:2:3, rt; (f) CH2N2, EtOH, rt, 76%, for
two steps; (g) Pd(OH)2, H2, Boc2O, hexane/MeOH¼2:3, rt, 68%; (h) DIBAL-H, THF,
ꢁ78 ꢀC, 93%; (i) 6 N HCl, MeOH, rt, 76%.
4.1.1. N-((2S,3R,E)-3-((tert-Butyldimethylsilyl)oxy)-6-chloro-1-(4-
methoxyphenyl)hex-4-en-2-yl)benzamide (8). LiAlH(OtBu)3 (1.0 M
solution in THF, 0.91 mL, 0.91 mmol) was added to a solution of 7
(216 mg, 0.60 mmol) in EtOH (6 mL) at ꢁ78 ꢀC. After the reaction
mixture was stirred at the same temperature for 3 h, aqueous citric
acid (10%,1 mL) was added. The resulting mixture was warmed to rt
and extracted with EtOAc (30 mLꢃ2). The organic layers were
combined, washed with brine (10 mL), dried over MgSO4, filtered,
and concentrated in vacuo to give the crude product. The crude
material was purified by chromatography on a silica gel column
(hexanes/EtOAc, 3:1) to give the anti-amino alcohol (185 mg, 85%,
anti/syn>10:1 by 1H NMR spectroscopy) as a white solid; mp
Fig. 3. Stereochemical identification of protected lactol 14 and methyl L-daunosami-
nide hydrochloride 2.
150e152 ꢀC; ½a 2D5
ꢁ38.41 (c 0.4, CHCl3); Rf¼0.25 (hexanes/EtOAc,
ꢂ
2:1); IR (neat) nmax¼3358, 2944, 2832, 1453, 1033, 636 cmꢁ1
;
1H
NMR (500 MHz, CDCl3)
d
2.84 (dd, J¼9.0, 14.5 Hz, 1H), 2.94 (dd,
stereochemistry for 2 was made on the basis of the 1H NMR spectra.
The mixed NMR spectrum of 2 shows two isomeric signals. One of
them shows a good agreement with the chemical shift and coupling
J¼5.0, 14.0 Hz, 1H), 3.77 (s, 3H), 3.97 (br s, 1H), 4.05e4.07 (m, 2H),
4.38e4.44 (m, 2H), 5.88 (dd, J¼5.5, 15.5 Hz, 1H), 5.98 (dtd, J¼1.0, 7.0,
15.0 Hz, 1H), 6.22 (d, J¼7.5 Hz, 1H), 6.83e6.85 (m, 2H), 7.14e7.15 (m,
2H), 7.35e7.38 (m, 2H), 7.45e7.49 (m, 1H), 7.58e7.60 (m, 2H); 13C
pattern of
constants of 2a between protons H-1 (
exhibited by proton H-1 in the -anomer are consistent with an
a
-anomer reported by Davies et al.5k The small coupling
d
4.85, d) and H-3 of 2.8 Hz
NMR (125 MHz, CDCl3)
d 35.1, 44.4, 55.5, 56.8, 73.8, 114.4, 127.2,
a
128.8, 128.9, 129.5, 130.3, 132.0, 133.4, 134.2, 158.7, 169.0; HRMS
(FABþ) calcd for C20H22ClNO3 [MþH]þ 360.1366, found 360.1370.
TBSCl (160 mg, 1.06 mmol) and imidazole (72 mg, 1.06 mmol)
were added to a stirred solution of the alcohol (319 mg, 0.89 mmol)
in anhydrous DMF (3 mL) at rt under argon. The reaction mixture
was stirred at rt for 12 h, then quenched with H2O (10 mL), and
extracted with EtOAc (50ꢃ2 mL). The organic layer was washed
with H2O and brine, dried over MgSO4, and concentrated in vacuo.
axial disposition of the hydroxyl group. The assignment of the
minor isomer described unknown by Sibi et al.5l was made on the
basis of the 1H NMR spectrum, indicating that this is the
b
-anomer.
A large coupling constant between protons H-1 (
d 4.51, d) and H-3
of 11.9 Hz and a small coupling constant between protons H-1 and
H-2 of 2.8 Hz, exhibited that H-1 is an axial disposition indicating
b
-anomer, 2b. The optical rotation 2, ½a D25
ꢁ142 (c 0.9, MeOH),
ꢂ

T. Jin et al. / Tetrahedron 70 (2014) 2570e2575
2573
The residue was purified by silica gel column chromatography
(hexanes/EtOAc, 10:1) to give 8 (387 mg, 92%) as a white solid; mp
(0.11 mL 0.85 mmol), and DMAP (5 mg, 0.043 mmol) were added to
a solution of alcohol 9 (188 mg, 0.43 mmol) in anhydrous CH2Cl2
(4 mL) at rt under argon. The reaction mixture was stirred at rt for
6 h. The reaction was quenched with saturated aqueous NH4Cl
solution (2 mL), and the resulting mixture was extracted with
CH2Cl2 (15ꢃ2 mL). The organic layer was washed with brine, dried
over MgSO4, and the solvent was evaporated in vacuo. The residue
was purified by flash column chromatography (hexanes/EtOAc,
10:1) to afford 10 (226 mg, 89%) as a white solid; mp 115e117 ꢀC;
108e110 ꢀC; ½a 2D5
ꢁ21.64 (c 2.5, CHCl3); Rf¼0.76 (hexanes/EtOAc,
ꢂ
2:1); IR (neat) nmax¼3332, 2948, 2832, 1637, 1513, 1451, 1249, 1033,
837, 778, 695 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
ꢁ0.04 (s, 3H), 0.09
(s, 3H), 0.90 (s, 9H), 2.84 (dd, J¼9.0, 14.5 Hz, 1H), 2.94 (dd, J¼5.5,
14.5 Hz, 1H), 3.75 (s, 3H), 4.05 (d, J¼6.0 Hz, 2H), 4.38 (dddd, J¼3.5,
5.0, 9.0, 9.0 Hz, 1H), 4.50 (dd, J¼4.0, 4.0 Hz, 1H), 5.87 (dd, J¼5.0,
15.5 Hz, 1H), 5.92 (td, J¼6.0, 16.0 Hz, 1H), 6.04 (d, J¼8.5 Hz, 1H),
6.80e6.82 (m, 2H), 7.13e7.14 (m, 2H), 7.36e7.46 (m, 3H), 7.58e7.60
½
a 2D5
ꢂ
ꢁ21.84 (c 1.3, CHCl3); Rf¼0.35 (hexanes/EtOAc, 6:1); IR (neat)
(m, 2H); 13C NMR (125 MHz, CDCl3)
d
ꢁ4.8, ꢁ4.0, 18.4, 26.1, 34.0,
nmax¼3381, 2947, 2833, 1662, 1452, 1115, 1032, 678 cmꢁ1
;
1H NMR
44.6, 55.5, 55.5, 73.4, 114.2, 126.9, 128.0, 128.8, 130.2, 130.3, 131.6,
134.8, 134.8, 158.4, 167.2; HRMS (FABþ) calcd for C26H36ClNO3Si
[MþH]þ 474.2231, found 474.2227.
(500 MHz, CDCl3)
d
ꢁ0.12 (s, 3H), ꢁ0.10 (s, 3H), 0.77 (s, 9H), 2.41 (s,
3H), 2.56 (dd, J¼8.5, 14.0 Hz, 1H), 2.96 (dd, J¼6.0, 14.0 Hz, 1H), 3.58
(ddd, J¼3.5, 6.0, 8.0 Hz, 1H), 3.79 (dd, J¼3.0, 3.0 Hz, 1H), 3.81 (s, 3H),
4.21 (dd, J¼7.5, 10.5 Hz, 1H), 4.25 (dd, J¼4.5, 11.0 Hz, 1H), 4.43 (ddd,
J¼2.5, 4.0, 7.0 Hz, 1H), 6.86e6.88 (m, 2H), 7.15e7.17 (m, 2H),
7.29e7.36 (m, 4H), 7.41e7.44 (m, 1H), 7.79e7.84 (m, 4H); 13C NMR
4.1.2. (4S,5S,6S)-5-((tert-Butyldimethylsilyl)oxy)-4-(4-
methoxybenzyl)-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine
(6). NaH (55% in mineral oil, 37 mg, 1.56 mmol) and n-Bu4NI
(288 mg, 0.78 mmol) were added to a stirred solution of allyl
chloride 8 (370 mg, 0.78 mmol) in anhydrous THF (3.9 mL) at 0 ꢀC.
After stirred for 5 min, Pd(PPh3)4 (90 mg, 0.078 mmol) was added
to the mixture and stirring was allowed to continue for 12 h at the
same temperature. The reaction mixture was filtered through a pad
of silica and then evaporated under reduced pressure to give the
crude product. Purification of this material by silica gel chroma-
tography (hexanes/EtOAc, 30:1) gave 6 (246 mg, 72%) as a colorless
(125 MHz, CDCl3)
d
ꢁ4.7, ꢁ4.5, 18.1, 21.9, 25.8, 40.7, 55.5, 60.3, 64.9,
69.1, 72.0, 114.2, 127.6, 128.2, 130.1, 130.3, 130.7, 130.7, 132.9, 133.4,
145.2, 153.0, 158.6; HRMS (FABþ) calcd for C32H41NO6SSi [MþH]þ
596.2502, found 596.2500.
4.1.3. (4S,5S,6R)-6-(Bromomethyl)-5-((tert-butyldimethylsilyl)oxy)-
4-(4-methoxybenzyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazine
(11). LiBr (37 mg, 0.42 mmol) was added to a stirred solution of 10
(125 mg, 0.21 mmol) in anhydrous DMF (2 mL) at rt under argon.
The reaction mixture was refluxed for 12 h and then quenched with
H2O (2 mL). The aqueous layer was extracted with EtOAc
(10ꢃ2 mL). The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (hexanes/EtOAc, 20:1) to afford 11
oil; ½a 2D5
ꢁ62.82 (c 0.5, CHCl3); Rf¼0.77 (hexanes/EtOAc, 3:1); IR
ꢂ
(neat) nmax¼3382, 2948, 2833, 1661, 1452, 1115, 1032, 697 cmꢁ1; 1H
NMR (500 MHz, CDCl3)
d
0.00 (s, 6H), 0.87 (s, 9H), 2.78 (dd, J¼7.5,
13.5 Hz, 1H), 2.84 (dd, J¼6.3, 14.0 Hz, 1H), 3.54 (ddd, J¼6.0, 6.0,
7.5 Hz,1H), 3.73 (dd, J¼3.5, 5.5 Hz,1H), 3.77 (s, 3H), 4.69 (ddd, J¼1.5,
3.5, 5.0 Hz, 1H), 5.26 (td, J¼1.5, 12.0 Hz, 1H), 5.30 (td, J¼1.5, 17.5 Hz,
1H), 5.99 (ddd, J¼5.0, 10.5, 15.5 Hz, 1H), 6.84e6.85 (m, 2H),
7.22e7.23 (m, 2H), 7.33e7.41 (m, 3H), 7.95e7.96 (m, 2H); 13C NMR
(75 mg, 84%) as a white solid; mp 208e210 ꢀC; ½a D25
ꢁ32.36 (c 2.5,
ꢂ
CHCl3); Rf¼0.5 (hexanes/EtOAc, 10:1); IR (neat) nmax¼3384, 2949,
2836, 1651, 1452, 1115, 1023, 702 cmꢁ1; 1H NMR (500 MHz, CDCl3)
(125 MHz, CDCl3)
d
ꢁ4.5, ꢁ4.1, 18.2, 26.0, 39.9, 55.5, 59.5, 68.3, 75.6,
d
ꢁ0.12 (s, 3H), ꢁ0.07 (s, 3H), 0.81 (s, 9H), 2.52 (dd, J¼9.0, 14.0 Hz,
114.0, 117.7, 127.6, 128.2, 130.6, 130.9, 131.3, 133.5, 133.8, 152.9,
158.4; HRMS (FABþ) calcd for C26H35NO3Si [MþH]þ 438.2464,
found 438.2462.
1H), 3.11 (dd, J¼5.0, 13.5 Hz, 1H), 3.55 (dd, J¼7.0, 10.0 Hz, 1H), 3.58
(dd, J¼7.0, 10.0 Hz, 1H), 3.71 (ddd, J¼2.5, 5.5, 9.0 Hz, 1H), 3.80 (s,
3H), 3.98 (dd, J¼2.0, 2.5 Hz, 1H), 4.33 (dt, J¼2.0, 6.5 Hz, 1H),
6.87e6.89 (m, 2H), 7.18e7.20 (m, 2H), 7.36e7.45 (m, 3H), 7.94e7.96
4.1.2.1. ((4S,5S,6S)-5-((tert-Butyldimethylsilyl)oxy)-4-(4-
methoxybenzyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)methanol
(9). A solution of the oxazine 6 (515 mg, 1.18 mmol) in anhydrous
MeOH (10 mL) was cooled to ꢁ78 ꢀC. O3 was passed through the
solution until the starting material had been consumed (TLC anal-
ysis). The resulting blue solution was purged with oxygen for
10 min, and then NaBH4 (53 mg, 1.41 mmol) was added. After
stirring the mixture at rt for 30 min, saturated aqueous NH4Cl was
added. The reaction mixture was extracted with EtOAc, and the
organic layer was washed with brine, dried over anhydrous MgSO4,
and then concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexanes/EtOAc, 4:1) to af-
(m, 2H); 13C NMR (125 MHz, CDCl3)
d
ꢁ4.6, ꢁ4.5, 18.1, 25.9, 30.1,
41.0, 55.5, 61.2, 64.6, 73.9, 114.3, 127.6, 128.3, 130.3, 130.7, 130.7,
133.6, 153.8, 158.6; HRMS (FABþ) calcd for C25H34BrNO3Si [MþH]þ
506.1553, found 506.1567.
4.1.4. (4S,5S,6S)-5-((tert-Butyldimethylsilyl)oxy)-4-(4-
methoxybenzyl)-6-methyl-2-phenyl-5,6-dihydro-4H-1,3-oxazine
(12). A stirred solution of bromide 11 (69 mg, 0.14 mmol), n-
Bu3SnH (76 mL, 0.27 mmol), and AIBN (2 mg, 0.014 mmol) in toluene
(1 mL) was heated to 100 ꢀC. After 12 h, the reaction mixture was
cooled to rt and concentrated in vacuo. The residue was purified by
flash column chromatography (hexanes/EtOAc, 20:1) to afford 12
ford alcohol 9 (450 mg, 86%) as a colorless oil; ½a D25
ꢂ
ꢁ45.36 (c 0.7,
(44 mg, 75%) as a colorless oil; ½a D25
ꢁ52.13 (c 1.2, CHCl3); Rf¼0.20
ꢂ
CHCl3); Rf¼0.33 (hexanes/EtOAc, 4:1); IR (neat) nmax¼3381, 2947,
(hexanes/EtOAc, 20:1); IR (neat) nmax¼3382, 2947, 2833,1662,1452,
2833, 1662, 1452, 1115, 1032, 659 cmꢁ1; 1H NMR (500 MHz, CDCl3)
1115, 1032, 695 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
ꢁ0.05 (s, 3H),
d
ꢁ0.08 (s, 3H), ꢁ0.06 (s, 3H), 0.82 (s, 9H), 2.12 (br s, 1H), 2.59 (dd,
ꢁ0.04 (s, 3H), 0.86 (s, 9H), 1.33 (d, J¼6.5 Hz, 3H), 2.68e2.73 (m, 1H),
2.91e2.95 (m, 1H), 3.63e3.66 (m, 2H), 3.80 (s, 3H), 4.33 (dq, J¼3.0,
6.5 Hz, 1H), 6.86e6.88 (m, 2H), 7.21e7.23 (m, 2H), 7.34e7.42 (m,
J¼8.5, 14.0 Hz, 1H), 3.02 (dd, J¼6.5, 14.0 Hz, 1H), 3.67 (ddd, J¼3.0,
6.5, 8.5 Hz, 1H), 3.80 (s, 3H), 3.85 (m, 2H), 3.93e3.97 (m, 1H), 4.30
(ddd, J¼3.0, 4.0, 7.0 Hz, 1H), 6.86e6.88 (m, 2H), 7.18e7.20 (m, 2H),
7.36e7.44 (m, 3H), 7.94e7.96 (m, 2H); 13C NMR (125 MHz, CDCl3)
3H), 7.93e7.94 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
ꢁ4.5, ꢁ4.4,
16.2, 18.2, 26.0, 40.7, 55.5, 60.0, 67.8, 70.7, 114.0, 127.5, 128.1, 130.4,
130.8, 131.2, 134.3, 154.0, 158.4; HRMS (FABþ) calcd for C25H35NO3Si
[MþH]þ 426.2464, found 426.2462.
d
ꢁ4.6, 18.1, 25.9, 40.9, 55.5, 60.7, 63.1, 65.9, 74.5, 114.2, 127.5, 128.3,
130.7, 133.9, 153.8, 158.6; HRMS (FABþ) calcd for C25H35NO4Si
[MþH]þ 442.2414, found 442.2416.
4.1.5. Methyl 2-((4S,5S,6S)-5-((tert-butyldimethylsilyl)oxy)-6-
methyl-2-phenyl-5,6-dihydro-4H-1,3-oxazin-4-yl)acetate
(13). NaIO4 (743 mg, 3.47 mmol) and RuCl3 (4 mg, 0.020 mmol)
were added to a cooled (0 ꢀC) solution of compound 12 (87 mg,
4.1.2.2. ((4S,5S,6S)-5-((tert-Butyldimethylsilyl)oxy)-4-(4-
methoxybenzyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)methyl 4-
methylbenzenesulfonate (10). TsCl (97 mg, 0.51 mmol), Et3N

2574
T. Jin et al. / Tetrahedron 70 (2014) 2570e2575
0.20 mmol) in a mixed solvent system (CCl4/CH3CN/H2O¼1:1:1.5,
3.5 mL) The reaction mixture was stirred for 6 h at rt, quenched
with brine (2 mL), and filtered through a Celite pad. The filtrate was
concentrated in vacuo to give the crude carboxylic acid, which was
used without purification in the next reaction. To an ethereal so-
lution of CH2N2 was added dropwise a stirred solution of the above
crude product in Et2O (2 mL) until the reaction mixture turned
yellow. The mixture was stirred for 2 h at rt. Evaporation of solvents
yielded crude compound. The residue was purified by flash column
chromatography (hexanes/EtOAc, 10:1) to provide 13 (59 mg, 76%)
4.1.8. (2S,3S,4S)-4-Amino-6-methoxy-2-methyltetrahydro-2H-py-
ran-3-ol hydrochloride (2). HCl (6 N solution, 0.2 mL) was added to
a solution of above lactol (21 mg, 0.058 mmol) in MeOH (1 mL), and
the reaction mixture was stirred at rt for 10 h. The solvent was then
removed in vacuo. The residue was purified by silica gel column
chromatography (CHCl3/MeOH, 5:1) to give 2 (9 mg, 76%) as a white
solid; ½a 2D5
ꢂ
ꢁ142 (c 0.9, MeOH); mp 185e188 ꢀC; Rf¼0.2 (CHCl3/
MeOH, 5:1); IR (neat) nmax¼3455e3279, 3062e2770 cmꢁ1; HRMS
(FABþ) calcd for C7H16ClNO3 [MꢁCl]þ 162.1130, found 162.1127.
a
-Anomer: 1H NMR (700 MHz, pyridine-d5)
d
1.39 (d, J¼6.3 Hz,
as a colorless oil; ½a D25
ꢂ
ꢁ44.51 (c 0.7, CHCl3); Rf¼0.42 (hexanes/
3H), 2.42 (dd, J¼4.2, 12.6 Hz, 1H), 2.49 (ddd, J¼2.8, 12.6, 12.6 Hz,
1H), 3.27 (s, 3H), 3.93 (q, J¼6.3 Hz, 1H), 4.23 (d, J¼11.9 Hz, 1H),
4.48e4.50 (br s, 1H), 4.81 (d, J¼2.1 Hz, 1H); 13C NMR (175 MHz,
EtOAc, 6:1); IR (neat) nmax¼3382, 2947, 2883,1663, 1452,1115,1032,
696 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 0.10 (s, 3H), 0.12 (s, 3H), 0.90
(s, 9H), 1.36 (d, J¼6.5 Hz, 3H), 2.55 (dd, J¼7.5, 15.0 Hz, 1H), 2.62 (dd,
J¼6.5, 15.0 Hz, 1H), 3.74 (s, 3H), 3.80 (dd, J¼3.5, 6.0 Hz, 1H), 3.92
(ddd, J¼6.5, 6.5, 6.5 Hz, 1H), 4.35 (dq, J¼4.0, 6.5 Hz, 1H), 7.32e7.41
pyridine-d5) d 17.1, 29.4, 47.8, 54.2, 66.4, 67.2, 97.7.
b
-Anomer: 1H NMR (700 MHz, pyridine-d5)
d
1.43 (d, J¼6.3 Hz,
3H), 2.37 (ddd, J¼11.9,11.9,11.9 Hz,1H), 2.62 (dd, J¼2.8,12.6 Hz,1H),
3.47 (s, 3H), 3.68e3.71 (q, J¼5.6 Hz,1H), 4.07 (d, J¼12.6 Hz,1H), 4.40
(br s, 1H), 4.51e4.53 (dd, J¼1.4, 9.8 Hz, 1H); 13C NMR (175 MHz,
(m, 3H), 7.89e7.91 (m, 2H); 13C NMR (125 MHz, CDCl3)
15.5, 18.2, 25.9, 39.6, 51.9, 54.3, 68.3, 71.5, 127.6, 128.1, 130.6, 133.8,
154.2, 172.3; HRMS (FABþ) calcd for C20H31NO4Si [MþH]þ 378.2101,
found 378.2099.
d
ꢁ4.5, ꢁ4.3,
pyridine-d5)
d 17.1, 31.4, 50.8, 55.8, 66.8, 71.9, 101.1.
Acknowledgements
4.1.6. tert-Butyl (2S,3S,4S)-3-(tert-butyldimethylsilyloxy)-2-methyl-
6-oxotetrahydro-2H-pyran-4-ylcarbamate (5). A stirred solution of
compound 13 (80 mg, 0.21 mmol) in a 3:2 mixture of hexane and
MeOH (5 mL) was stirred at rt for 12 h under an atmosphere of
hydrogen in the presence of a catalytic quantity of 20% palladium
hydroxide on charcoal (37 mg, 0.053 mmol) and (Boc)2O (234 mg,
1.06 mmol). The catalyst was then removed by filtration through
Celite, and the solvents were evaporated under reduced pressure.
The resulting residue was purified by flash column chromatography
(hexanes/EtOAc, 2:1) to afford a lactone 5 (52 mg, 68%) as a white
This research was supported by the National Research Foundation
of Korea (NRF) through the Basic Science Research Program. Further
support by the South Korean Ministry of Education, Science and
Technology (2011-0029199, 2010-0022900) and Yonsung
Fine Chemicals Corporation is appreciated. The Samsung Dream
Scholarship Foundation grant to T.J. is gratefully acknowledged.
The Global Ph.D. Fellowship grants to S.H.P. are gratefully
acknowledged.
solid; mp 107e109 ꢀC; ½a D25
ꢁ10.91 (c 1.5, CHCl3); Rf¼0.33 (hexanes/
ꢂ
Supplementary data
EtOAc, 2:1); IR (neat) nmax¼3358, 2947, 2832, 1663, 1453, 1033,
658 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 0.00 (s, 3H), 0.12 (s, 3H), 0.93
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.033. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
(s, 9H), 1.35 (d, J¼6.5 Hz, 3H), 1.45 (s, 9H), 2.49 (dd, J¼12.0, 17.5 Hz,
1H), 2.71 (dd, J¼6.5, 17.5 Hz, 1H), 3.99 (s, 1H), 4.01e4.07 (m, 1H),
4.42 (q, J¼6.5 Hz, 1H), 4.47 (d, J¼7.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3)
d
ꢁ4.1, ꢁ3.9, 18.1, 18.5, 26.1, 28.6, 31.4, 49.1, 69.2, 80.6, 169.2;
HRMS (FABþ) calcd for C17H34NO5Si [MþH]þ 360.2206, found
References and notes
360.2204.
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1007e1010.
4.1.7. tert-Butyl ((2S,3S,4S)-3-(tert-butyldimethylsilyloxy)-6-hydroxy-
2-methyltetrahydro-2H-pyran-4-yl)carbamate (14). DIBAL-H (1.0 M,
0.22 mL) was added to a stirred solution of 5 (66 mg, 0.18 mmol) in
anhydrous THF (2 mL) at ꢁ78 ꢀC. The reaction mixture was stirred
for 2 h at ꢁ78 ꢀC and then was quenched by the addition of satu-
rated sodium potassium tartrate at ꢁ78 ꢀC. The resulting mixture
was extracted with EtOAc (10ꢃ2 mL). The organic layer was washed
with brine, dried over MgSO4, and the solvent was evaporated in
vacuo. The residue was purified by flash column chromatography
(hexanes/EtOAc, 2:1) to afford protected lactol 14 (62 mg, 93%) as
4. (a) Horton, D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227e240; (b) Grethe, G.;
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F.; William, R.; Wang, F.; Ma, J.; Ji, L.; Liu, X. Org. Lett. 2011, 13, 652e655; (b)
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a white solid; mp 106e108 ꢀC; ½a D25
ꢁ5.0 (c 1.0, CHCl3); Rf¼0.27
ꢂ
(hexanes/EtOAc, 2:1); IR (neat) nmax¼3358, 2945, 2832, 1667, 1452,
1115, 1033, 658 cmꢁ1; HRMS (FABþ) calcd for C17H35NO5Si [MþH]þ
362.2363, found 362.2361.
a
-Anomer: 1H NMR (500 MHz, CDCl3)
d 0.08 (s, 6H), 0.95 (s, 9H),
1.13 (d, J¼6.5 Hz, 3H), 1.44 (s, 9H), 1.62e1.66 (m, 1H), 1.81e1.89 (m,
1H), 2.38 (br, 1H), 4.10 (m, 2H), 4.49 (d, J¼9.0 Hz, 1H), 5.34 (dd,
J¼2.5, 2.5 Hz,1H); 13C NMR (125 MHz, CDCl3)
d
ꢁ3.6, ꢁ3.5,18.1,18.2,
6. (a) Jin, T.; Mu, Y.; Kim, G. W.; Kim, S. S.; Kim, J. S.; Huh, S. I.; Lee, K. Y.; Joo, J. E.; Ham,
W. H. Asian J. Org. Chem. 2012, 1, 232e237; (b) Mu, Y.; Kim, J. Y.; Jin, X.; Park, S. H.;
Joo, J. E.; Ham, W. H. Synthesis 2012, 44, 2340e2346; (c) Mu, Y.; Jin, T.; Kim, G. W.;
Kim, J. S.; Kim, S. S.; Tian, Y. S.; Oh, C. Y.; Ham, W. H. Eur. J. Org. Chem. 2012,
2614e2620; (d) Kim, J. Y.; Mu, Y.; Jin, X.; Park, S. H.; Pham, V. T.; Song, D. K.; Lee, K.
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28.6, 28.6, 30.5, 46.7, 67.0, 71.3, 92.0, 155.1.
b
-Anomer: 1H NMR (500 MHz, CDCl3)
d 0.09 (s, 6H), 0.96 (s, 9H),
1.21 (d, J¼6.5 Hz, 3H), 1.44 (s, 9H), 1.60e1.66 (m, 1H), 1.81e1.89 (m,
1H), 2.90 (d, J¼7.0 Hz, 1H), 3.54 (q, J¼6.5 Hz, 1H), 3.60 (d, J¼2.0 Hz,
1H), 3.71e3.76 (m, 2H), 4.59 (d, J¼9.0 Hz, 1H), 4.79 (ddd, J¼2.5, 7.0,
7. The requisite a,b-unsaturated ketone 6 was prepared in high yield from the
9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
34.1, 50.6, 70.1, 72.3, 94.9, 155.1.
d
ꢁ4.1, 18.7, 18.7, 26.3, 26.4,
commercially available
scheme.
L-tyrosine by the five steps sequence shown in following

T. Jin et al. / Tetrahedron 70 (2014) 2570e2575
2575
8. (a) Joo, J. E.; Pham, V. T.; Tian, Y. S.; Chung, Y. S.; Oh, C. Y.; Lee, K. Y.; Ham, W. H.
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T.; Ham, W. H. Eur. J. Org. Chem. 2007, 1586e1593.
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Pipper, C. B.; Madsen, R. Eur. J. Org. Chem. 2009, 3387e3395.
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3936e3938.
11. Bernadat, G.; George, N.; Couturier, C.; Masson, G.; Schlama, T.; Zhu, J. Synlett
2011, 576e578.
Reagents and conditions: (a) SOCl2, MeOH, reflux, (b) BzCl, Et3N, MeOH, 0 ꢀC,
(c) K2CO3, MeI, DMF, 93% three steps; (d) MeNHOMe$HCl, AlMe3, CH2Cl2, 90%;
(e) 15, MeLi$LiBr, ꢁ78 ꢀC, 79%.
12. Fronza, G.; Fuganti, C.; Grasselli, P. J. Chem. Soc., Perkin Trans. 1 1982, 885e891.