An efficient synthesis of l-3,4,5-trioxygenated phenylalanine compounds from l-tyrosine

Article abstract of DOI:10.1016/j.tet.2013.02.079

A new strategy for the synthesis of l-3,4,5-trioxygenated phenylalanine derivatives from l-tyrosine is developed for the first time. The approach, featuring the transformation of aryl diiodide to bis-phenol via a one-pot procedure including lithiation, boronation, and oxidation, is highly practical. By this robust protocol, N-protected l-3,5-bis(tert-butyldimethylsilyloxy)-4- methoxy-phenylalanine and l-3,4,5-trimethoxy-phenylalanine derivatives were obtained from l-tyrosine in 9 steps with 36-40% overall yields.

Full text of DOI:10.1016/j.tet.2013.02.079

Tetrahedron 69 (2013) 3565e3570
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An efficient synthesis of -3,4,5-trioxygenated phenylalanine
L
compounds from
L-tyrosine
,
,
,b,
*
Ruijiao Chen a y, Hao Liu a y, Xiubing Liu a, Xiaochuan Chen a
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy for the synthesis of L-3,4,5-trioxygenated phenylalanine derivatives from L-tyrosine is
Received 10 December 2012
Received in revised form 12 February 2013
Accepted 22 February 2013
Available online 27 February 2013
developed for the first time. The approach, featuring the transformation of aryl diiodide to bis-phenol via
a one-pot procedure including lithiation, boronation, and oxidation, is highly practical. By this robust
protocol, N-protected
L-3,5-bis(tert-butyldimethylsilyloxy)-4-methoxy-phenylalanine and
L
-3,4,5-
trimethoxy-phenylalanine derivatives were obtained from
yields.
L-tyrosine in 9 steps with 36e40% overall
Keywords:
Trioxygenated phenylalanine
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
L-Tyrosine
Asymmetric synthesis
Aryl dilithium
Bis-phenol
1. Introduction
a comparable antitumor activity to Et 743 and may be a more
economical therapeutic agent.5b,8
L-3,4,5-Trioxygenated phenylalanines 1 are an important class of
Therefore the development of methods for the synthesis of
nonproteinogenic amino acids, which are frequently found in bi-
ologically active molecules as privileged structural fragments. For
example (Fig. 1), TMC-2 compounds, produced by Aspergillus oryzae
A374, are potent dipeptidyl peptidase IV inhibitors with high se-
lectivity.1 Natural bicyclic hexapeptide RA-XVIII (3) and the dimmer
show a strong antitumor activity.2 As a novel series of proteasome
inhibitors, peptide 4 and their derivatives are opening a potential
new approach in cancer therapy.3 The tunichromes, a kind of re-
ducing blood pigments from Sea Squirts, harbored in cells that take
L
-3,4,5-trioxygenated phenylalanine compounds has attracted the
attention of organic chemists. In 1996, Corey et al. described the first
approach tothis kindof -amino acidderivatives via a chiral rhodium-
L
catalyzed asymmetric hydrogenation of benzylic enamine as key
part in a variety of physiological responses.4 Moreover, protected
L-
3,4,5-trioxygenated phenylalanine 6 and its corresponding alde-
hyde derivative 7 (Fig. 2) are key coupling partners in the asym-
metric syntheses of marine tetrahydroisoquinoline alkaloids and
analogues, such as ecteinascidin 743 (Et 743, 8), phthalascidin 650
(Pt 650, 9), and saframycin A (10).5 These alkaloids possess re-
markable antitumor and antimicrobial activity:6 Et 743 is approved
by the European Commission as an anticancer agent for the patient
with advanced soft-tissue sarcomas.7 Pt 650, a structurally sim-
plified synthetic analogue of Et 743, was found to display
* Corresponding author. Tel.: þ86 28 85412095; fax: þ86 28 85413712; e-mail
address: chenxc@scu.edu.cn (X. Chen).
Fig. 1. L-3,4,5-Trioxygenated phenylalanines and representative related bioactive
compounds.
y
These individuals contributed equally to this work.
0040-4020/$ e see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.079

3566
R. Chen et al. / Tetrahedron 69 (2013) 3565e3570
poor yield in the last stage this short route lost its value in practical
synthesis.
Scheme 1. The initial strategy on the synthesis of 15 via a key BaeyereVilliger oxi-
dation of 12.
Intrigued by the reported methods on transformation of aryl ha-
lides to the phenols via a copper-mediated hydroxylation process,16
we intended to utilize aryl dihalide intermediates to synthesize
Fig. 2. Synthetic segments for several tetrahydroisoquinoline alkaloids.
L
-3,4,5-trioxygenated phenylalanine compounds (Scheme 2). Iodin-
ation of
-tyrosine with ICl17 followed by protection of amino group
smoothly gave -N-Boc-3,5-diiodo-tyrosine 16, which was subjected
to the esterification and the etherification in one-pot leading to 17 in
72% overall yield for three steps. Methyl ester 17 also could be
step, by which 6 was synthesized in 10 steps from methyl 3,5-
L
dihydroxy-4-methoxybenzoate.5a Jackson and co-workers synthe-
L
sized L-3,4,5-trimethoxy-phenylalanine ester derivative by a palla-
dium catalyzed coupling reaction between serine-derived
organozinc reagent and 3,4,5-trimethoxyiodobenzene.9 Laumen
obtained from L-tyrosine in four steps with 48% overall yield accord-
ing to Sanda’s procedure.18 The methyl ester group in 17 was reduced
with lithium borohydride to provide alcohol 18. Protection of
hydroxyl group as MOM ether gave 19. Similarly, 3,5-dibromo ana-
et al. prepared N-acetyl protected L-3,4,5-trimethoxy-phenylalanine
by way of enzymatic resolution hydrolysis of the corresponding ra-
cemic amino acid esters.10 Although these elegant strategies for the
enantioselective synthesis of L-3,4,5-trioxygenated phenylalanine
compounds have been developed successfully, exploitation of new
synthetic route with lower cost and simpler procedure is still very
logue 21 also prepared from 11 or the known L-3,5-dibromo-tyro-
sine19 by the same procedure. According to literature, copper-
catalyzed hydroxylation of 19 and 21 was next attempted. Un-
fortunately, the reaction conditions (refluxing in aqueous hydroxide
solution) are too harsh for the sensitive substrates, such as 19 and 21.
t-Butyloxycarbomate(Boc)asamineprotectinggroup, whichisstable
to usual alkalic conditions, was cleaved in the reaction under these
conditions. Only small amount of monohydroxylated product with
free amino group was detected, and di-hydroxylated compound 22
was not produced.
significant. As a cheap natural amino acid,
L-tyrosine (11), was
employed to synthesize nonproteinogenic amino acids like
L-3-
hydroxy-4-methoxy-5-methylphenylalanine and phenylalanol by
us11 and other groups.12 However, to the best of our knowledge, the
synthesis of
L-3,4,5-trioxygenated phenylalanine compounds from L-
tyrosine has not been described in the literature. Hereinwe report the
concise transformation of
derivatives.
L-tyrosine to these unnatural amino acid
2. Results and discussion
Our initially attempted strategy was based on key BaeyereVilliger
oxidation of the substituted isophthalaldehyde derivative 12
(Scheme 1). N-protection of L-tyrosine as Cbz group followed by
a base-catalyzed phenolic aldol reaction with excessive formalde-
hyde furnished the known bishydroxymethylated compound 1313 in
71%yield. Esterificationof thecarboxylic acidand etherification of the
phenol proceeded in one-pot by treatment of 13 with Me2SO4 to give
14. Oxidation of diol 14 to the corresponding dicarbaldehyde 12 was
then investigated. However, the substituted isophthalaldehyde 12
was obtained at most in 30% yield under the attempted conditions
including DesseMartin periodinane, IBX, PCC, MnO2, and Swern ox-
idation protocols,14 even though diol 14 was consumed thoroughly.
Furthermore, the subsequent conversion of 12 to bis-phenol 15 by
a sequence involving BaeyereVilliger oxidation and hydrolysis of
formyl group was also disappointed. Treatment of 12 with various
BaeyereVilliger oxidation conditions15 always lead to a complex
mixture, which is stirred in aqueous methanol in the presence of
K2CO3 to just yield a trace amount of the desired 15. Because of the
Scheme 2. The preparation of dihalides 19 and 21 from L-tyrosine.

R. Chen et al. / Tetrahedron 69 (2013) 3565e3570
3567
Thus, we adopted an alternative protocol for the trans-
formation of aryl halides to phenols by oxidation of the formed
borate intermediate,20 although dihalide substrates employed in
this transformation are rare and simple.21 The one-pot procedure
involved three reaction stage including lithiation, boronation, and
oxidation at two positions on the aryl ring. The investigation re-
sults showed that diiodide 19 was more easier converted to the
aryl dilithium species than dibromide 21 at lithiation stage
(Scheme 3). When the dibromide substrate 21 was applied, con-
siderable material still remained in aryl monolithiation stage in
the metalation even the n-butyllithium was improved to 5 equiv.
After treatment of 19 with 3.2 equiv n-butyllithium, the iodine
atoms could be exchanged thoroughly to produce the resultant
aryl dilithium. However, the subsequent reaction of the aryl
dilithium with trimethyl bromate proceeded so difficultly that the
desirable bis-phenol 22 was obtained as a minor product only in
18% yield from 19 together with mono-phenol compound 23 as
major product (53% yield) after oxidation. Presumably, the lith-
iation of the acidic amide NH group may disturb the boronation.
To avoid the above situation, protection of the vicinal OeH and
CONeH functionalities in 18 and 20 as oxazolidine ring with 2,2-
dimethoxypropane (2,2-DMP) furnished 25 and 29, respectively.
To our delight, following the similar procedure the desired bis-
phenol 26 was obtained from diiodide 25 in 80% yield along
with a small amount of inseparable monohydroxylated mixture 27
and 28, the ratio of which is judged by integration of the peaks in
1H NMR spectrum. In contrast, when dibromide 29 is recruited as
material to prepare 26, the result is still unsatisfactory because
the formation of the same dianion from 29 is much harder than
from 25.
groups in 26 with TBSCl gave silyl ether 31. Selective hydrolysis of
oxazolidine in the presence of a catalytic amount of TsOH furnished
the desired alcohol 32. Oxidation of primary hydroxy to carboxylic
acid using TEMPO (0.2 equiv) and [bis(acetoxy)-iodo]benzene
(BAIB) as co-oxidant22 proceeded smoothly to afford the desired
amino acid 33 in 95% yield. On the other hand, 32 was converted N-
protected amino aldehyde 34 by DesseMartin periodinane or
Swern oxidation protocol with high yield. O-Methylation of bis-
phenol 26 then followed by the similar procedures afforded an-
other useful trioxygenated phenylalanine derivative 36.
Scheme 4. Conversion of bis-phenol 26 to L-3,4,5-trioxygenated phenylalanine de-
rivative 33, 34, and 36.
With bis-phenol 26 in hand, the subsequent transformation
becomes easy to achieve (Scheme 4). Protection of the two phenol
3. Conclusions
In summary, we developed a new approach to the synthesis of
protected
commercial and cheap
such as 25 was employed as a key step. Through this approach,
three -3,4,5-trioxygenated phenylalanine derivatives 33, 34, and
L-3,4,5-trioxygenated phenylalanine derivatives from
L-tyrosine. Bishydroxylation of the diiodide,
L
36 were obtained in nine steps with 36e40% overall yield. Our
approach has several advantages: (1) Reagents and materials,
which are expensive or need additionally be prepared are seldom
involved. (2) High yields are achieved in the whole synthesis. (3)
The employed reactions are easy to operate and be scaled up. (4) It
is conveniently extended to the synthesis of other
L-3,4,5-
trioxygenated phenylalanine derivatives by selectively manipulat-
ing the hydroxyl-protective groups on the phenols. The robust
preparation procedure of L-3,4,5-trioxygenated phenylalanine de-
rivatives would greatly improve the ease of synthesis and the
overall yield of many structurally related bioactive compounds.
4. Experimental
4.1. General
Solvents for reaction were distilled prior to use: Ether and tet-
rahydrofuran were distilled from Na/benzophenone, CH2Cl2, an-
hydrous CH3CN from CaH2. All reagents were obtained from
commercial suppliers unless otherwise stated. IR spectra were
recorded on a commercial spectrophotometer. Optical rotations
T
were reported as follows: [
a
]
(c g/100 mL, in solvent). 1H NMR
D
spectra were recorded on commercial instruments (400 or
600 MHz) with TMS as the internal standard. Data are reported as
follows: chemical shift, multiplicity (s¼singlet, d¼doublet,
t¼triplet, m¼multiplet, br¼broad), coupling constants (Hertz),
Scheme 3. Investigation on the bishydroxylation of several aryl dihalides by oxidation
of the borate intermediate.

3568
R. Chen et al. / Tetrahedron 69 (2013) 3565e3570
integration. 13C NMR data were collected on commercial in-
struments (100 or 150 MHz) with complete proton decoupling.
Chemical shifts are reported in parts per million from the tetra-
methylsilane with the solvent resonance as internal standard.
HRMS spectra were recorded using a commercial apparatus and
methanol or Dichloromethane was used to dissolve the sample.
117.9, 79.8, 63.4, 60.6, 53.4, 36.1, 28.4; HRMS (ESIþ): m/z [MþNa]þ
calcd for C15H21Br2NO4Na: 459.9735; found: 459.9740.
4.5. (S)-tert-Butyl-1-(3,5-diiodo-4-methoxyphenyl)-3-(me-
thoxymethoxy) propan-2-ylcarbamate 19
4.2. (S)-Methyl-2-(tert-butoxycarbonylamino)-3-(3,5-diiodo-
4-methoxyphenyl)propanoate 17
To an ice-cooled solution of compound 18 (7.1 g, 13.3 mmol) in
dry CH2Cl2 (67 mL), DIPEA (3.9 mL, 33.3 mmol) was added at 0 ꢀC
under argon atmosphere. After 2 min. MOMCl (1.8 mL, 23.9 mmol)
was added and the reaction mixture was allowed to stir at room
temperature for 10 h. After completion of the reaction, water was
added, organic layer was separated and aqueous phase was
extracted with CH2Cl2 (3ꢁ50 mL). The combined organic layer was
washed with brine (50 mL), dried with anhydrous Na2SO4, filtered,
and then concentrated under reduced pressure to obtain reddish
crude product. This crude product was purified over silica gel col-
umn chromatography to give the pure compound 19 as a pale
yellow oil (6.9 g, 90%). IR (neat) nmax: 3355, 2931, 2822, 1701, 1514,
L-Tyrosine 11 (5.14 g, 28.4 mmol) was dissolved in 73 mL of
glacial AcOH and heated to 40 ꢀC. Then 3.2 mL of ICl in 23 mL of
glacial AcOH was added dropwise to the reaction. The mixture was
heated at 80 ꢀC for 8 h. Then the solvent was evaporated and the
residue was dissolved in MeOH/H2O (2:1, 87 mL), and NaHCO3
(8.3 g, 99.3 mmol), Boc2O (7.3 mL, 34.1 mmol) were added. The
resulting mixture was stirred overnight at room temperature. The
solvent was evaporated and the residue was diluted with H2O
(60 mL), extracted with ethyl acetate (3ꢁ80 mL). The combined
organic layer was dried with Na2SO4, filtered, and the solvent
evaporated in vacuo. The crude was taken up in dry CH3CN
(142 mL) were added (CH3)2SO4 (8.1 mL, 85.2 mmol) and anhydrous
K2CO3 (11.8 g, 85.2 mmol), and the resulting mixture was stirred at
60 ꢀC for 5 h. The solvent removed in vacuo, and the water (150 mL)
was added. The mixture was extracted with ethyl acetate
(3ꢁ100 mL). The combined organic layer was dried with Na2SO4
and concentrated. This crude product was purified over silica gel
column chromatography to give the compound 17 as a pale yellow
1461, 1249, 1169, 1038, 997, 705 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
(ppm) 7.59 (s, 2H), 4.93 (d, J¼8.4 Hz, 1H), 4.59 (m, 2H), 3.83 (m,
1H), 3.78 (s, 3H), 3.45 (dd, J¼3.6, 10.0 Hz, 1H), 3.41 (dd, J¼4.0,
10.0 Hz, 1H), 3.36 (s, 3 H), 2.70 (m, 2H), 1.39 (s, 9H); 13C NMR
(100 MHz, CDCl3): d (ppm) 157.3, 155.2, 140.6, 138.2, 96.9, 90.4, 79.5,
68.2, 60.7, 55.6, 51.3, 36.1, 28.4; HRMS (ESIþ): m/z [MþNa]þ calcd for
C17H25I2NO5Na: 599.9720; found: 599.9716.
powder (11.5 g, 72% over three steps). Mp 73e75 ꢀC, [
a
]
26 þ71 (c 1.1,
D
in CHCl3); IR(neat) nmax: 3370, 2975, 1712, 1504, 1462, 1362, 1250,
4.6. (S)-tert-Butyl(1-(3,5-dibromo-4-methoxyphenyl)-3-(me-
thoxymethoxy)propan-2-yl)carbamate 21
1166, 1057, 996, 706 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.47
(s, 2H), 5.19 (d, J¼8 Hz, 1H), 4.42 (m, 1H), 3.74 (s, 3H), 3.67 (s, 3H),
2.98 (dd, J¼5.4, 13.8 Hz, 1H), 2.81 (dd, J¼6.7, 13.7 Hz, 1H), 1.35 (s,
Compound 21 was prepared from 20 with the similar procedure
to 19. Yield: 91%; IR (neat) nmax: 3351, 2931, 1709, 1540, 1470, 1259,
9H); 13C NMR (100 MHz, CDCl3):
d (ppm) 171.6, 157.6, 154.8, 140.4,
136.2, 90.3, 79.9, 60.5, 54.1, 52.4, 36.3, 28.2; HRMS (ESIþ): m/z
[MþNa]þ calcd for C16H21I2NO5Na: 583.9407; found: 583.9411.
1169, 1039, 738 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d (ppm) 7.34 (s,
2H), 4.93 (d, J¼8.3 Hz, 1H), 4.60 (m, 2H), 3.85 (m, 1H), 3.82 (s, 3H),
3.47 (dd, J¼3.6, 10.0 Hz, 1H), 3.42 (dd, J¼4.1, 10.0 Hz, 1H), 3.36 (s,
3H), 2.72 (m, 2H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3):
d (ppm)
4.3. (S)-tert-Butyl-1-(3,5-diiodo-4-methoxyphenyl)-3-
hydroxypropan-2-ylcarbamate 18
155.3, 152.6, 137.1, 133.5, 117.9, 96.9, 79.6, 68.3, 60.6, 55.6, 51.4, 36.7,
28.4; HRMS (ESIþ): m/z [MþNa]þ calcd for C17H25Br2NO5Na:
503.9997; found: 503.9994.
To a solution of the compound 17 (8.3 g, 14.8 mmol) in anhy-
drous THF (74 mL), and LiBH4 (11.1 mL, 22.2 mmol) was added
under argon atmosphere. The resulting mixture was stirred over-
night at rt, and methanol (1 mL)was added. Then the solvent was
evaporated and the residue was diluted with H2O (50 mL),
extracted with ethyl acetate (3ꢁ30 mL), and dried (Na2SO4). After
concentration and column chromatography, the amino alcohol 18
4.7. (S)-tert-Butyl 4-(3,5-diiodo-4-methoxybenzyl)-2,2-dim-
ethyloxazolidine-3-carboxylate 25
2-Methoxypropene (5.9 mL, 48.0 mmol) was added to a solution
of the compound 18 (5.2 g, 9.6 mmol) in acetone (20 mL). To
(7.50 g, 95%) was isolated as a white gel; [
a
]
26 ꢂ2 (c 1.0, in CHCl3); IR
D
(neat) nmax: 3345, 2974, 2933, 1686, 1528, 1462, 1366, 1250, 1168,
a
stirred solution was added TsOH monohydrate (17 mg,
999, 704 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d (ppm) 7.62 (s, 2H), 4.88
0.096 mmol). The reaction mixture was refluxed for 3 h. When the
reaction was complete, by TLC analysis, the solution was evapo-
rated in vacuo. The residue was dissolved in ethyl acetate (75 mL)
and washed with aqueous NaHCO3 (2ꢁ30 mL). The organic layer
was dried with anhydrous Na2SO4 and evaporated in vacuo and the
(d, J¼5.5 Hz, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.64 (m, 1H), 3.54 (m,
1H), 2.73 (d, J¼6.9 Hz, 2H), 2.67 (br s, 1H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3): d (ppm) 157.4, 156.0, 140.6, 138.3, 90.5, 79.9, 63.6,
60.8, 53.5, 35.6, 28.5; HRMS (ESIþ): m/z [MþNa]þ calcd for
C15H21I2NO4Na: 555.9458; found: 555.9450.
residue purified by column chromatography to afford the com-
26
pound 25 as a pale yellow oil (5.12 g, 93%). [
a
]
þ34 (c 1.8, in
D
4.4. (S)-tert-Butyl-1-(3,5-dibromo-4-methoxyphenyl)-3-
hydroxypropan-2-ylcarbamate 20
CHCl3); IR (neat) nmax: 2977, 2935, 2875,1697, 1463, 1389, 1254, 997,
847, 706 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
(ppm) 7.63 (s, 1H), 7.57
(s, 1H), 4.08e3.86 (m, 1H), 3.80 (s, 3H), 3.78 (d, J¼5.7 Hz, 1H), 3.68
(d, J¼9.1 Hz, 1H), 3.06e2.89 (m, 1H), 2.59e2.50 (m, 1H), 1.60e1.40
Compound 20 was synthesized from
L
-tyrosine with the similar
26
procedure to 18. [
2976, 1680, 1529, 1467, 1366, 1253, 1167, 1005, 706 cmꢂ1
(400 MHz, CDCl3):
(ppm) 7.34 (s, 2H), 5.09 (d, J¼8 Hz, 1H), 3.81 (s,
3H), 3.74 (m, 1H), 3.59 (m, 2H), 3.42 (br s, 1 H), 2.74 (m, 2H), 1.35 (s,
9H); 13C NMR (100 MHz, CDCl3):
(ppm) 156.0, 152.5, 137.1, 133.4,
a
]
ꢂ36 (c 1.2, in CHCl3); IR (neat) nmax: 3342,
(m, 6H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3):
d (ppm) 152.8,
D
;
1H NMR
152.7, 152.1, 151.5, 137.3, 137.2, 133.5, 133.3, 118.2, 118.0, 94.2, 93.7,
80.4, 79.9, 66.1, 65.7, 60.6, 58.7, 38.5, 37.2, 28.5, 28.4, 27.4, 26.9, 24.4,
23.2; HRMS (ESIþ): m/z [MþH]þ calcd for C18H26I2NO4: 573.9951;
found: 573.9954.
d
d

R. Chen et al. / Tetrahedron 69 (2013) 3565e3570
3569
4.8. (S)-tert-Butyl-4-(3,5-dibromo-4-methoxybenzyl)-2,2-
4.11. (S)-tert-Butyl(1-(3,5-bis((tert-butyldimethylsilyl)oxy)-4-
dimethyloxazolid-ine-3-carboxylate 29
methoxyphenyl)-3-hydroxypropan-2-yl)carbamate 32
Compound 29 was prepared from 20 with the similar pro-
To a solution of compound 31 (0.40 g, 0.69 mmol) in methanol
(15 mL) was added PTSA hydrate (3 mg, 0.014 mmol) at room
temperature. The reaction mixture was stirred overnight, and
saturated aqueous solution of NaHCO3 (5 mL) was used to quench
the reaction. Methanol was removed under reduced pressure and
the aqueous residue was extracted with ethyl acetate (3ꢁ30 mL).
The combined organic phases were washed with brine (30 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The
cedure to 25. Yield: 94%; [
a
]
D
26 ꢂ26 (c 0.9, in CHCl3); IR (neat) nmax
:
2977, 2933, 2872, 1698, 1473, 1387, 1260, 999, 848, 738 cmꢂ1
;
1H
NMR (400 MHz, CDCl3):
d (ppm) 7.36 (s, 1H), 7.29 (s, 1H),
4.02e3.89 (m, 1H), 3.82 (s, 3H), 3.79 (m, 1H), 3.67 (d, J¼9.2 Hz, 1H),
3.06e2.89 (m, 1H), 2.61e2.52 (m, 1H), 1.58 (s, 1.5H), 1.48 (s, 12H),
1.42 (s, 1.5H); 13C NMR (100 MHz, CDCl3):
d (ppm) 157.6, 157.5,
152.2, 151.5, 140.7, 140.5, 138.6, 138.4, 94.3, 93.7, 90.7, 90.5, 80.5,
80.0, 66.2, 65.7, 60.8, 58.8, 38.1, 36.7, 28.6, 28.5, 27.5, 26.9, 24.5,
23.3; HRMS (ESIþ): m/z [MþNa]þ calcd for C18H25Br2NO4Na:
500.0048; found: 500.0046.
residue was purified by flash chromatography on silica gel to give
27
compound 32 (0.34 g, 92%) as a colorless oil. [
a
]
ꢂ6 (c 1.6, in
D
CH2Cl2); IR (neat) nmax: 3439, 2932, 2859, 1695, 1576, 1495, 1433,
1253, 1173, 1093, 834 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
(ppm)
6.34 (s, 2H), 4.70 (d, J¼7.2 Hz, 1H), 3.78 (br s, 1H), 3.69 (s, 3H), 3.63
4.9. (S)-tert-Butyl-4-(3,5-dihydroxy-4-methoxybenzyl)-2,2-
dimethyloxazoli-dine-3-carboxylate 26
(m, 1H), 3.53 (m, 1H), 2.65 (m, 2H), 1.42 (s, 9H), 0.99 (s, 18H), 0.16 (s,
12H); 13C NMR (100 MHz, CDCl3):
d (ppm) 156.2, 149.7, 141.6, 132.8,
115.6, 79.6, 64.6, 59.9, 53.4, 36.9, 28.4, 25.7, 18.3, ꢂ4.6; HRMS
(ESIþ): m/z [MþH]þ calcd for C27H52NO6Si2: 542.3333; found:
542.3329.
To a solution of compound 25 (1.3 g, 2.3 mmol) in dry ether
(23 mL) at ꢂ78 ꢀC, n-BuLi (2.6 mL, 2.0 M solution in hexane,
5.2 mmol) was added dropwise under argon atmosphere. After
2 h, B(OMe)3 (2.5 mL, 23.0 mmol) was added to the mixture all at
once. The solution was allowed to warm to 35 ꢀC, stirred for
overnight and then cooled to 0 ꢀC. The reaction mixture was
treated with AcOH (1.3 mL, 23.0 mmol) and 30% H2O2 (2.3 mL,
23.0 mmol), and further stirred overnight. The reaction was
quenched with NH4Cl aq and worked up. The organic layer was
dried with anhydrous Na2SO4, evaporated in vacuo and the res-
4.12. (S)-3-(3,5-Bis((tert-butyldimethylsilyl)oxy)-4-
methoxyphenyl)-2-((tert-butoxycarbonyl)amino) propanoic
acid 33
To a solution of compound 32 (66 mg, 0.12 mmol) in CH3CN/
H2O (1:1, 1.6 mL) was added TEMPO (3.8 mg, 0.024 mmol) and
phenyliodonium diacetate (85 mg, 0.26 mmol) at room tempera-
ture. After stirring for 5 h, the mixture was filtered through a short
pad of Celite and then concentrated in vacuo. The residue was
diluted with ethyl acetate (200 mL) and washed with brine
(50 mL), dried over anhydrous Na2SO4. The combined filtrates
were concentrated in vacuo and the residue was purified by flash
idue purified by silica gel column chromatography to afford
27
compound 26 (0.65 g, 80%) as a colorless oil. [
a
]
ꢂ45 (c 1.0, in
D
CHCl3); IR (neat) nmax: 3376, 2979, 2936, 2877, 1695, 1596, 1395,
1251, 1100, 1062, 850 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
(ppm)
6.43 (s, 1H), 6.34 (s, 1H), 6.13 (br s, 2H), 4.00 (m, 1H), 3.87 (s, 1H),
3.76 (m, 2H), 3.05 (dd, J¼2.5, 13.2 Hz, 0.5H), 2.97 (dd, J¼2.8,
12.8 Hz, 0.5H), 2.45 (dd, J¼12.2, 23.4 Hz, 1H), 1.63 (s, 1.5H), 1.57 (s,
1.5H), 1.52 (s, 4.5H), 1.50 (s, 4.5H), 1.49 (s, 1.5H), 1.47 (s, 1.5H); 13C
chromatography on silica gel to give the compound 33 (63 mg,
27
95%) as a colorless oil. [
a
]
þ11 (c 1.6, in CH2Cl2); IR (neat) nmax
:
D
NMR (100 MHz, CDCl3):
d
(ppm) 152.4, 151.8, 149.4, 149.3, 135.0,
3383, 2933, 2860, 1700, 1576, 1433, 1388, 1255, 1174, 1099,
134.7, 133.4, 133.3, 109.0, 108.8, 94.1, 93.8, 80.9, 80.0, 66.1, 65.7,
60.9, 60.8, 59.0, 58.9, 39.3, 38.1, 28.5, 28.4, 27.6, 26.9, 24.5, 23.3;
HRMS (ESIþ): m/z [MþNa]þ calcd for C18H27NO6Na: 376.1736;
found: 376.1732.
835 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
(ppm) 10.80 (br s, 1H),
6.53 (m, 0.3H), 6.36 (s, 0.5H), 6.32 (s, 1.5H), 4.94 (d, J¼8.1 Hz, 0.7H),
4.53 (m, 0.7H), 4.32 (m, 0.3H), 3.69 (s, 3H), 3.01 (dd, J¼5.2, 14.0 Hz,
1H), 2.89 (dd, J¼6.4, 13.9 Hz, 0.7H), 2.73 (dd, J¼9.3, 13.4 Hz, 0.3H),
1.41 (s, 6H), 1.35 (s, 3H), 0.99 (s, 18H), 0.15 (s, 12H); 13C NMR
(100 MHz, CDCl3):
d (ppm) 176.7, 176.4, 156.5, 155.4, 149.8, 142.1,
4.10. (S)-tert-Butyl-4-(3,5-bis((tert-butyldimethylsilyl)oxy)-4-
methoxybenzyl)-2,2-dimethyloxazolidine-3-carboxylate 31
141.9, 131.7, 130.9, 115.8, 81.5, 80.2, 60.0, 56.2, 54.2, 38.9, 37.3, 32.0,
28.4, 28.2, 25.8, 18.4, ꢂ4.5; HRMS (ESIþ): m/z [MþNa]þ calcd for
C27H49NO7Si2Na: 578.2945; found: 578.2950.
To a solution of compound 26 (0.49 g, 1.4 mmol) in DMF
(2.8 mL) was added imidazole (0.21 g, 3.1 mmol) and tert-
butyldimethylsilyl chloride (0.45 g, 3.1 mmol) at 0 ꢀC. The re-
action mixture was stirred at room temperature for 5 h and then
diluted with ethyl acetate (100 mL) and water (50 mL). Layers
were separated and the aqueous phase was extracted with ethyl
acetate (20 mL). The combined organic phases were washed with
brine (10 mL), dried over anhydrous Na2SO4 and the residue
4.13. (S)-tert-Butyl(1-(3,5-bis((tert-butyldimethylsilyl)oxy)-4-
methoxyphenyl)-3-oxopropan-2-yl)carbamate 34
To a solution of the compound 32 (60 mg, 0.11 mmol) in DCM
(2 mL), DesseMartin periodinane (DMP, 51 mg, 0.12 mmol) was
added at room temperature. The reaction mixture was stirred for
3 h and then added with saturated aqueous sodium bicarbonate
solution (NaHCO3, 5 mL). Layers were separated, and the aqueous
layer was extracted with DCM (2ꢁ10 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by flash chromatography on silica
purified by silica gel column chromatography to afford com-
27
pound 31 (0.76 g, 94%) as a colorless oil. [
a
]
ꢂ28 (c 1.7, in
D
CH2Cl2); IR (neat) nmax: 2932, 2858, 1719, 1577, 1495, 1254, 1092,
1010, 834 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
(ppm) 6.35 (s, 2H),
3.96 (m, 1H), 3.76 (m, 2H), 3.69 (s, 3H), 3.02 (m, 1H), 2.44 (m, 1H),
1.64 (s, 1.5H), 1.58 (s, 1.5H), 1.53 (s, 9H), 1.49 (s, 1.5H), 1.46 (s,
1.5H), 0.99 (s, 18H), 0.15 (s, 12H); 13C NMR (100 MHz, CDCl3):
gel to provide 34 (55 mg, 93%) as an oil. [
a
]
27 þ7 (c 0.96, in CHCl3);
D
IR (neat) nmax: 3433, 2930, 2857, 1714, 1576, 1432, 1360, 1254, 1167,
d
(ppm) 152.2, 151.7, 149.8, 149.6, 141.6, 140.6, 137.1, 133.8, 116.0,
1093, 834 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d (ppm) 9.59 (s, 1H),
115.8, 94.1, 93.3, 80.1, 79.7, 66.1, 65.8, 60.1, 60.0, 59.5, 58.9, 39.3,
38.0, 28.7, 28.5, 27.0, 26.5, 26.1, 25.8, 24.7, 23.3, 18.4, ꢂ3.2, ꢂ4.6;
HRMS (ESIþ): m/z [MþNa]þ calcd for C30H55NO6Si2Na: 604.3466;
found: 604.3460.
6.29 (s, 2H), 5.01 (d, J¼5.8 Hz, 1H), 4.31 (m, 1H), 3.69 (s, 3H), 3.67
(m, 1H), 2.95 (m, 1H), 1.44 (s, 9H), 0.99 (s, 18H), 0.15 (s, 12H); 13C
NMR (100 MHz, CDCl3):
d (ppm) 199.7, 155.5, 150.0, 142.1,
130.8, 115.8, 80.3, 60.6, 60.1, 35.1, 28.4, 25.8, 18.4, ꢂ4.5; HRMS

3570
R. Chen et al. / Tetrahedron 69 (2013) 3565e3570
(ESIþ): m/z [MþNa]þ calcd for C27H49NO6Si2Na: 562.2996; found:
Supplementary data
562.2999.
Copies of 1H and 13C NMR spectra. Supplementary data related to
this article can be found at http://dx.doi.org/10.1016/j.tet.2013.02.079.
4.14. (S)-tert-Butyl (1-hydroxy-3-(3,4,5-trimethoxyphenyl)
propan-2-yl)carbamate 35
References and notes
To a solution of 26 (0.18 g, 0.51 mmol) in dry CH3CN (5.1 mL)
were added (CH3)2SO4 (0.15 mL, 1.6 mmol) and anhydrous K2CO3
(0.22 g, 1.6 mmol), and the resulting mixture was stirred at 60 ꢀC for
5 h. The solvent removed in vacuo, and the water (40 mL) was
added. The mixture was extracted with ethyl acetate (3ꢁ25 mL).
The combined organic layer was dried with Na2SO4, filtered, and
the solvent evaporated in vacuo. The residue was taken up in
methanol (15 mL) was added PTSA hydrate (4.5 mg, 0.021 mmol) at
room temperature. The reaction mixture was stirred overnight, and
saturated aqueous solution of NaHCO3 (5 mL) was used to quench
the reaction. Methanol was removed under reduced pressure and
the aqueous residue was extracted with ethyl acetate (3ꢁ30 mL).
The combined organic phases were washed with brine (30 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The
1. (a) Nonaka, N.; Asai, Y.; Nishio, M.; Takahashi, K.; Okuda, T.; Tanaka, S.; Sugita,
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residue was purified by flash chromatography on silica gel to give
15
compound 35 (0.14 g, 78% over two steps) [
a
]
ꢂ14 (c 0.5, in
D
CH2Cl2); IR(neat) vmax: 3357, 2936, 1685, 1592, 1509, 1458, 1422,
1367, 1242, 1168, 1127, 1051, 780 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
(ppm) 6.43 (s, 2H), 4.85 (d, J¼5.0 Hz,1H), 3.85 (s, 6H), 3.85 (m,1H),
3.82 (s, 3H), 3.68 (br d, J¼10.5 Hz, 1H), 3.59 (dd, J¼4.5, 10.4 Hz, 1H),
ꢀ
~
2.79 (m, 2H), 2.62 (br s,1H),1.42 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
(ppm) 156.1, 153.2, 136.5, 133.6, 106.1, 79.7, 64.2, 60.9, 56.0, 53.5,
37.7, 28.4; HRMS (ESIþ): m/z [MþH]þ calcd for C17H28NO6:
342.1917; found: 342.1912.
11. Chen, R.; Zhu, D.; Hu, Z.; Zheng, Z.; Chen, X. Tetrahedron: Asymmetry 2002, 21,
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4.15. (S)-2-((tert-Butoxycarbonyl)amino)-3-(3,4,5-trime-
thoxy-phenyl)propanoic acid 36
To a solution of compound 35 (53 mg, 0.14 mmol) in CH3CN/H2O
(1:1, 1.6 mL) was added TEMPO (4.4 mg, 0.028 mmol) and phe-
nyliodonium diacetate (100 mg, 0.31 mmol) at room temperature.
After stirring for 5 h, the mixture was filtered through a short pad of
Celite and then concentrated in vacuo. The residue was diluted with
ethyl acetate (200 mL) and washed with brine (50 mL), dried over
anhydrous Na2SO4. The combined filtrates were concentrated in
vacuo and the residue was purified by flash chromatography on
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silica gel to give the compound 36 (50 mg, 92%). [
a
]
15 þ13 (c 0.4, in
D
MeOH); IR(neat) vmax: 3350, 2930, 1712, 1592, 1508, 1459, 1423,
1244, 1165, 1128, 1012, 780 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
(ppm) 6.40 (s, 2H), 6.39 (d, 0.3H), 5.00 (d, J¼7.7 Hz, 0.7H), 4.60 (m,
17. Faul, M. M.; Winneroski, L. L.; York, J. S.; Reinhard, M. R.; Hoying, R. C.; Gritton,
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(dd, J¼6.8, 13.9 Hz, 0.7H), 2.87 (m, 0.3H), 1.43 (s, 6.3H), 1.26 (s,
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2.7H); 13C NMR (100 MHz, CDCl3):
d (ppm) 176.0, 155.4, 153.2, 137.0,
131.5, 106.4, 106.2, 80.4, 60.8, 56.1, 54.3, 38.1, 28.3, 28.0; HRMS
(ESIþ): m/z [MþNa]þ calcd for C17H25NO7Na: 378.1529; found:
378.1535.
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Acknowledgements
We thank Sichuan University Analytical and Testing Center as
well as Prof. Xiaoming Feng group for NMR determination. This
work was supported by grants from the National Natural Science
Foundation of China (20802045, 21172153 and J1103315/J0104), the
National Basic Research Program of China (973 Program, No.
2012CB833200).
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