Efficient asymmetric synthesis of N-protected-β-aryloxyamino acids via regioselective ring opening of serine sulfamidate carboxylic acid

Article abstract of DOI:10.1039/c4ob01047g

First regioselective ring opening of serine derived cyclic sulfamidate by hard nucleophiles like ArONa is developed, where β-elimination of serine sulfamidate ester by stronger nucleophiles is overcome by reversal of the electronic effect of the carboxyla

Full text of DOI:10.1039/c4ob01047g

Organic &
Biomolecular Chemistry
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Efficient asymmetric synthesis of N-protected-
β-aryloxyamino acids via regioselective ring
opening of serine sulfamidate carboxylic acid†
Cite this: Org. Biomol. Chem., 2014,
12, 6507
Rajesh Malhotra,a Tushar K. Dey,a,b Swarup Dutta,b Sourav Basu*b and
Saumen Hajra*c
First regioselective ring opening of serine derived cyclic sulfamidate by hard nucleophiles like ArONa is
developed, where β-elimination of serine sulfamidate ester by stronger nucleophiles is overcome by
reversal of the electronic effect of the carboxylate anion. This method provides easy and direct access to
a variety of N-Boc- and N-PMB protected β-aryloxy-α-amino acids with complete retention of enantio-
purity in moderate to high yields.
Received 21st May 2014,
Accepted 19th June 2014
DOI: 10.1039/c4ob01047g
www.rsc.org/obc
equivalents to aziridines, the former is more advantageous
over the latter in terms of reactivity and selectivity.6 A wide
Introduction
β-Aryloxy-α-amino acids are important unnatural amino acids variety of nucleophiles are used for the regioselective opening
present in and precursor to many bioactive natural products1,2 of the sulfamidate of serine.6–11 Wei and Lubell studied the
and pharmaceuticals.3 Serine is commonly used as a chiral regioselective ring opening of serine derived cyclic sulfamidate
substrate for the synthesis of β-aryloxyamino acids and their ester with a variety of nucleophiles, where β-elimination and
derivatives. The nucleophilic substitution reaction of fluoro- partial to complete loss of enantiopurity were the major pro-
nitroarenes with serine and its dipeptide has efficiently been blems.8 Lanthionines were efficiently synthesized by Cobb and
utilized for the synthesis of cyclopeptide alkaloids with a Vederas via regioselective ring opening of serine sulfamidate
β-aryloxyamino acid unit, where a number of additional steps ester with N-protected cysteine ester.9 Cohen and Halcomb
are needed to remove the surplus nitro-group.2 The Mitsunobu reported the elegant synthesis of S-linked glycosyl amino acids
reaction of ArOH with N-protected serine ester provides low to from the serine derived cyclic sulfamidates with 1-thio-sugar.10
moderate yields of β-aryloxy amino acid esters and it was Recently Varma et al. described the synthesis of a dithiocarba-
found that N-protection is crucial to get the desired Mitsunobu mate side chain containing unnatural α-amino acids by a
products.4 Regio- and stereoselective ring opening of aziridine one-pot reaction of in situ generated dithiocarbamate anions
with ArOH to obtain β-aryloxyamino acids has also been with serine derived sulfamidate ester.11 Similarly regioselective
reported.5
ring opening of serine derived sulfamidate with ArOH may
Development of a general and direct method for the syn- provide the aryloxyamino acids. However, ring opening of
thesis of unnatural amino acids from an easily accessible serine derived sulfamidates with oxy-nucleophiles like phenols
chiral precursor is highly desirable. Thus an alternative and has not been explored, may be due to the tendency for β-elimi-
efficient method could be regioselective ring opening of cyclic nation. We have overcome the problem and thus describe here
sulfamidates of serine. Though sulfamidates are synthetic efficient and direct synthesis of N-protected-β-aryloxy-α-amino
acids from the cyclic sulfamidate of serine with a free
carboxylic acid group.
aDepartment of Chemistry, Guru Jambheshwar University of Science and Technology,
Hisar, Haryana 125001, India
bTCG Life Sciences Ltd, Saltlake, Kolkata 700091, India.
E-mail: sourav@chembiotek.com; Fax: (+91)-33-23673058; Tel: (+91)-33-23673151
cDepartment of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur
Results and discussion
721302, India. E-mail: shajra@chem.iitkgp.ernet.in; Fax: (+91)-3222-282252;
A potential limitation of the serine derived sulfamidate 1 is the
propensity to undergo elimination, affording compound 2′
(Scheme 1). It is almost exclusive in the case of strong nucleo-
Tel: (+91)-3222-283340
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
and LC-MS for all the compounds 1, 4, 6, 9 and 10 and HPLC chromatograms of
philes. Thus sulfamidate 1 could not be utilized for the
compounds 6a–6d, 6h–6j, 6l–6m, 6o, 10d, 10j and 10q. See DOI: 10.1039/
c4ob01047g
opening with stronger nucleophiles like oxy-anions. We also
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Table 1 Screening of solvents, base and temperature for the ring
opening of sulfamidate 4 with PhOH 5a
Entry
Base
Solvent
T (°C)
Yielda (%)
eeb (%)
Scheme 1 β-Elimination of sulfamidate ester 1 with hard nucleophiles.
1
2
3
4
5
6
7
8
NaH
NaH
NaH
K2CO3
Cs2CO3
NaH
K2CO3
Cs2CO3
THF
THF
THF
THF
25
0
−15
25
0
25
25
25
<5
49
57
NR
<5
40
NR
20
ND
>99
>99
—
—
ND
—
THF
Dioxane
Dioxane
Dioxane
ND
a Isolated yield of amino acid 6a over two steps. b ee was determined by
chiral HPLC. ND: not determined.
Fig. 1 Electronic effects of sulfamidate ester
anion 1’.
1 and carboxylate
The sulfamidate carboxylic acid 4 was reacted with phenol
in the presence of different bases and with variation of sol-
vents as well (Table 1). We are delighted to report that NaH
(60% in oil) was found to work well in THF and dioxane at
0 °C and rt, respectively, and provided the desired N-Boc-β-
phenoxyamino acid 6a in moderate yields (entries 2 and 6). When
the reaction in THF was performed at −15 °C, it afforded an
improved yield of compound 6a (entry 3). The reactions in
DMF using three bases gave traces of product 6a (not shown in
Table 1). The optical purity of 6a was determined by HPLC ana-
lysis, which showed complete retention of enantiopurity.
Having set the optimized reaction conditions, we explored
the scope of this ring opening reaction with a panel of substi-
tuted phenols (Table 2). We are pleased to report that the
majority of phenols work very well. In general sterically
hindered and electron-deficient less reactive phenols were found
to work well at 0 °C. Alkyl substituted phenols containing an
ethyl group at the 3- or 4-position provided good yields of
β-aryloxyamino acids 6b and 6c, respectively, at −15 °C (entries
2 and 3). The ortho-effect was not prominent for 2,3-dimethyl-
phenol 5d rather it gave the highest yield among the alkyl sub-
stituted phenols (entry 4). We are delighted to find that
bulky o-tert-butylphenol also underwent smooth reaction and
afforded the acid 6e in 53% yield, but the corresponding meta-
substituted phenol gave a lower yield (entries 5 and 6). A pro-
minent ortho-steric effect was observed for 2,6-dimethylphenol
5g and afforded the amino acid 6g in low yield (entry 7). More
electron rich substrates like alkoxy substituted phenols 5h–5j
were found to work very well and provided high yields of
amino acids 6h–6j (entries 8–10). α-Naphthol 5k behaves
similar to phenol and gave a moderate yield of the desired
amino acid 6k (entry 11). Electronically different substituents
along with the ortho-steric effect did not affect the reaction of
4-chloro-2-methoxyphenol 5l with sulfamidate 4 and acted
more like an electron-rich substrate affording very good yield
of 6l (entry 12). Halogenated phenols 5m and 5n are compara-
Scheme 2 Synthesis of serine derived cyclic sulfamidate acid 4.
found that when sulfamidate 1 (R = Bn) was reacted with
sodium phenoxide generated from phenol in THF, it exclu-
sively afforded the elimination product 2′ in 85% yield; no
trace of compound 2 was detected. The combined electron-
withdrawing effects of the ester and the sulfonyl unit attached
to N, O might be making the α-methine proton of 1 more
acidic. Thus a stronger nucleophile, in turn hard base, acts
more like the latter and abstracts the proton resulting in elimi-
nation leading to 2′. It is presumed that the electronic effect
of the ester might be reversed if it transforms to a carboxylate
ion 1′ (Fig. 1). We, therefore, intended to prepare the N-Boc-
sulfamidate of L-serine with free carboxylic acid 4. An EtOAc
solution of serine sulfamidate ester 1 upon hydrogenation in
the presence of Pd/C under 1 atm pressure gave compound 4,
which was directly used without any purification (Scheme 2).
Instead of EtOAc, when the hydrogenation was carried out in
MeOH, it showed a cleaner reaction profile as found in 1H
NMR spectrum analysis of the crude product. Sulfamidate 1
was prepared from N-Boc serine benzyl ester 3 (Scheme 2).6,10
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Table 2 Synthesis of N-Boc-β-aryloxyamino acids 6 from sulfamidate 4
Table 3 One-pot synthesis of aryloxy amino acids 6
Entry
ArOH
5
Product 6
Yielda (%)
eeb (%)
Entry ArOH
5
Product 6 Yielda (%) eeb (%)
1
2
PhOH
5a
5c
5i
6a
6c
6i
58
62
70
46
>99
>99
>99
NDe
1
2
3
PhOH
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
57
68
66
70
53
26
20
70
66
70
40
75
39
51
52
53
>99
>99
>99
98
4-EtC6H4OH
2-EtOC6H4OH
2-ClC6H4OH
3-EtC6H4OH
4-EtC6H4OH
2,3-Me2C6H3OH
2-tBuC6H4OH
3-tBuC6H4OH
2,6-Me2C6H3OH
2,3-(MeO)2C6H3OH
2-EtOC6H4OH
4-MeOC6H4OH
1-Naphthol
3
4c,d
5n
6n
4
a Isolated yield of amino acid 6 over two steps. b ee was determined by
chiral HPLC. c The reaction was performed at 0 °C. d Along with 8% of
des-chloro product 6a. e ND: not determined.
5c
6c
7c
8
NDe
NDe
NDe
>99
>99
9
10
11
12
13c
14c,d
15c
16
5j
5k
6j
6k
6l
98.5
NDe
>99
>99
NDe
>99
NDe
4-Cl-2-MeOC6H3OH 5l
2-FC6H4OH
2-ClC6H4OH
4-CNC6H4OH
4-PhC6H4OH
5m 6m
5n
5o
5p
6n
6o
6p
a Isolated yield of amino acid 6. b ee was determined by chiral HPLC.
c The reaction was performed at 0 °C. d R-Isomer, obtained from
D-serine derived sulfamidate acid. e ND: not determined.
Scheme 3 Plausible route towards decomposition of sulfamidate 4.
tively electron-deficient and react with sulfamidate 4 at 0 °C.
Yields of the amino acids 6m and 6n increase from o-fluoro to
o-chloro, respectively, probably due to the electronic effect
(entries 13 and 14). We are delighted to report that electron-
deficient 4-cyanophenol 5o also underwent smooth reaction at
0 °C (entry 15) and 4-phenylphenol 5p gave moderate yield of
amino acid 6p (entry 16). The formation of elimination pro-
ducts 2a′ (R = H) was noticed for the less reactive phenols and
it enhances with the decrease in the reactivity of the phenols.
Also to note is that no desired ring opening products were
obtained for the highly sterically hindered 2,6-di-tert-butyl-
phenol and electron-deficient pentachlorophenol (C6Cl5OH),
rather the elimination product 2a′ was exclusively isolated
(>80%; not shown in Table 2).
We also observed that the freshly prepared sulfamidate 4
always provided better yields of aryloxyamino acids 6. Preser-
vation of sulfamidate 4 for overnight at 5 °C reduces 20–30%
of yields of 6. Also to note is that evaporation of EtOAc and
MeOH after hydrogenation must be done at rt or lower. The
sulfamidate 4 undergoes decomposition at 40 °C and above to
other compounds as found in 1H NMR analysis. This impelled
us to study a one-pot synthesis of the aryloxyamino acid via
in situ generated sulfamidate 4. For this purpose, a THF
solution of sulfamidate 1 was hydrogenated in the presence of
Pd/C under 1 atm pressure. After complete debenzylation,
hydrogen was replaced with N2 and the suspended mixture
was successively treated with PhOH (1.0 equiv.) and NaH (60%
in oil; 2.05 equiv.) at −15 °C. We are delighted to report that it
provided the desired amino acid 6a in 58% yield without any
loss of enantiopurity. The one-pot method was generalized
Scheme 4 Synthesis of N-PMB-sulfamidate carboxylic acid 9.
with a few phenols and gave moderate to good yields of amino
acids 6 (Table 3). Chlorophenol also afforded the desired
product 6n along with a minor amount of the des-chloro
product 6a.
One of the plausible routes towards decomposition of sulfa-
midate 4 might be decarboxylative ring opening (Scheme 3),
where the electron-withdrawing Boc functionality might have
facilitated the decomposition. Replacement of the Boc group
with an electron-donating protecting group like p-methoxyben-
zyl (PMB) may reduce the propensity to undergo decarboxyla-
tive ring opening.
Thus the N-PMB sulfamidate 9 was prepared from N-PMB-
serine sulfamidate ester 8 (Scheme 4).10 The sulfamidate 9 was
found to be quite stable at rt even for a month. Ring opening
of the sulfamidate 9 was tested with 4-ethylphenol 5c and NaH
(60% in oil) under the standard developed conditions. It is
found to work well at 0 °C and provided very good yield of
amino acid 10c (Table 4; entry 1). Ring opening reaction of 9
was generalized with electronically and sterically different
phenols obtaining N-PMB protected aryloxyamino acids 10
in high yields (entries 2–7). Electron-rich phenols underwent
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too. A wide variety of substituted phenols were tested for the
ring opening reaction, which showed a minute temperature
effect. The method is also suitable for one-pot synthesis
of these unnatural amino acids via in situ generated serine
sulfamidate carboxylic acid.
Table 4 Synthesis of N-PMB aryloxyamino acids 10
Time
(h)
Product
10
Yielda
(%)
eeb
(%)
Experimental
General
Entry
ROH
5
1
2
3
4
5
6
7
8
4-EtC6H4OH
5c
5d
5f
5g
5j
5m
5o
5q
4
4
7
7
4
7
7
7
10c
10d
10f
10g
10j
10m
10o
10q
79
80
54
36
80
51
68
16
NDc
>99
NDc
NDc
>99
NDc
NDc
>99
All reactions were conducted using oven-dried glassware under
an atmosphere of argon (Ar) or nitrogen (N2). Commercial
grade reagents were used without further purification. Solvents
were dried and distilled following usual protocols.
Column chromatography was carried out using silica gel
(100–200 mesh). TLC was performed on aluminium-backed
plates coated with Silica gel 60 with F254 indicator. The 1H
NMR spectra were recorded at 400 MHz and 13C NMR spectra
were recorded at 100 MHz using CDCl3 and DMSO-d6. 1H NMR
chemical shifts are expressed in parts per million (δ) relative to
CDCl3 (δ = 7.26) and DMSO-d6 (δ = 2.49); 13C NMR chemical
shifts are expressed in parts per million (δ) relative to the
CDCl3 resonance (δ = 77.0) and DMSO-d6 (δ = 39.7). High
resolution mass spectra (HRMS) were measured with a QTOF I
(quadrupole–hexapole TOF) mass spectrometer with an
orthogonal Z-spray–electro-spray interface. HPLC analyses of
compound 6 were done by Cellulose-2 (4.6 × 250 mm) and
Chiralpak AD-H (4.6 × 250 mm) columns using SFC (Supercriti-
cal Fluid Chromatography) and that of compound 10 were
done using a Cellulose-1 (4.6 × 250 mm) column. Specific
optical rotation values were measured on a polarimeter. Sulf-
amidates 1 and 8 were prepared by following the literature
procedures.7,10
2,3-Me2C6H3OH
3-tBuC6H4OH
2,6-Me2C6H3OH
4-MeOC6H4OH
2-FC6H4OH
4-CNC6H4OH
n-C8H17OH
a Isolated yield of amino acid 10. b ee was determined by chiral HPLC.
c ND: not determined.
smooth reaction and provided high yields of N-protected aryl-
oxyamino acids 10c, 10d and 10j (entries 1, 2 and 5). Sterically
hindered phenols 5f and 5g on reaction with sulfamidate 9
gave better yields (entries 3 and 4) than the sulfamidate 4
(Table 2; entries 6 and 7). Electron-deficient phenols 5m and
5o afforded moderate to good yields of aryloxyamino acids
10m and 10o (entries 6 and 7).
Regio-selective ring opening of the sulfamidates 4 and 9
were also tested with alkoxides generated from n-octanol, iso-
propanol and tert-butanol under standard reaction conditions.
N-Boc-sulfamidate 4 led exclusively to the elimination product
2a′ (R = H). N-PMB-sulfamidate 9 showed 10–30% of the
desired ring opening products in LC-MS along with a mixture
of uncharacterised compounds. As branching of the alcohols
increases the reactions become more and more messy. Only
n-octyloxyamino acid 10q could be isolated in pure form by
preparative HPLC in 16% yield with complete retention of
enantiopurity (Table 4; entry 8).
4(S)-Benzyl-3-tert-butyl-1,2,3-oxathiazolidine-3,4-dicarboxylate-
2,2-dioxide 1 [serine sulfamidate] (1). Dry CH2Cl2 (230 mL,
5.0 mL mmol−1) and thionyl chloride (8.3 mL, 2.5 equiv.) were
placed in a round-bottomed flask under an argon atmosphere.
Then N-Boc benzyl ester of serine 3 (13.4 g, 45.37 mmol) in
CH2Cl2 (450 mL, 10 mL mmol−1) was dropwise added to the
reaction mixture at −40 °C and stirring was continued for
30 min. Pyridine (18.7 mL, 5.1 equiv.) was added to the reac-
tion mixture and slowly raised to rt. After 1 h, the reaction was
Conclusion
In summary, the electronic effect of the carboxylate anion and quenched with ice-water (450 mL), washed with sodium bi-
ester of serine derived cyclic sulfamidate plays a pivotal role carbonate (450 mL) and brine (450 mL) successively, dried over
towards their reactions with hard nucleophiles. This led us to sodium sulfate, evaporated to get the crude sulfamidate
develop the first regioselective ring opening of serine derived (16.5 g), which was used for the next step. To the crude
cyclic sulfamidate with phenols. The method provides easy compound in acetonitrile (290 mL) were added RuCl3·H2O
and direct access to non-racemic N-protected-β-aryloxyamino (0.220 g, 0.97 mmol, 0.02 equiv.), NaIO4 (16.0 g, 74.8 mmol,
acids in moderate to very good yields with complete preser- 1.6 equiv.) and water (290 mL) at 0 °C and stirred. After 1 h,
vation of enantiopurity. Both enantiomers of the unnatural the reaction mixture was quenched with satd NaHCO3
amino acids can be obtained from sulfamidates derived from (300 mL), extracted with ethyl acetate (3 × 400 mL), washed
L- and D-serine. N-Protection of serine sulfamidate carboxylic with brine (500 mL), dried over sodium sulfate, and purified
acid takes a crucial role in the stability and reactivity. N-PMB- by column chromatography to get a white solid of sulfamidate
serine sulfamidate carboxylic acid 9 is more stable than the 1 (10.43 g, 64%); m.p. 120–122 °C. 1H NMR (400 MHz, CDCl3):
N-Boc compound 4. In general the former gave better yields of 7.41–7.28 (m, 5H), 5.33 (d, J = 12.1 Hz, 1H), 5.24 (d, J =
aryloxyamino acids 6 and it also provided β-alkoxy amino acid 12.1 Hz, 1H), 4.85–4.83 (m, 1H), 4.79–4.75 (m, 1H), 4.69–4.66
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(m, 1H), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3): 166.9, 147.9, dried over sodium sulfate, and purified by column chromato-
134.3, 128.7 (2C), 128.6 (2C), 128.3, 86.2, 68.4, 67.4, 57.5, 27.7 graphy to get the amino acid 6a (0.138 g, 58%).
(3C). LC-MS (ESI): 355.8 [M − H]+, [α]D25 = −26.3 (c 0.51, DCM).
(S)-2-((tert-Butoxycarbonyl)amino)-3-phenoxypropanoic acid
HRMS (ESI): calcd for C15H19NNaO7S, 380.0780 m/z [M + Na]+, (6a). Yield 57%; light yellow semi-solid; 1H NMR (400 MHz,
found 380.0780. From D-serine: white solid, m.p. 120–122 °C. DMSO-d6): δ 7.28 (t, J = 7.8 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H),
[α]2D5 = +26.4 (c = 0.51, DCM).
6.96–6.91 (m, 3H), 4.35–4.34 (m, 1H), 4.23–4.19 (m, 2H), 1.39
3(S)-(tert-Butoxycarbonyl)-1,2,3-oxathiazolidine-4-carboxylic (s, 9H). 13C NMR (100 MHz, DMSO-d6): δ 171.3, 158.0, 155.3,
acid-2,2-dioxide (4). To the compound 1 (0.30 g, 0.84 mmol) 129.4 (2C), 120.8, 114.5 (2C), 78.2, 67.2, 53.3, 28.0 (3C). LC-MS
in ethyl acetate (4.0 mL) was added 10% Pd/C (0.030 g) and the (ESI): 280.0 [M − H]−. HPLC analysis: Cellulose-2 (4.6 ×
suspended mixture was stirred under a hydrogen balloon at rt 250 mm) 5μ, (MeOH + 0.5% IPA) containing 82% CO2, 2.0 mL
for 30 min. The reaction mixture was filtered through a celite min−1, 220 nm, tr (major) 5.75, tr (minor) 6.98, >99% ee,
bed to remove the palladium and the filtrate was evaporated at [α]D25
rt under reduced pressure to get sulfamidate carboxylic acid 4 C14H19NNaO5 304.1161 m/z [M + Na]+, found 304.1161.
= +42.2 (c 1.02, MeOH). HRMS (ESI): calcd for
as a gummy liquid, which was directly used for the next step
within an hour.
From D-serine: light yellow semi-solid; HPLC analysis: Cellu-
lose-2 (4.6 × 250 mm) 5μ, (MeOH + 0.5% IPA) containing 82%
1H NMR (400 MHz, DMSO-d6): δ 13.83 (br s, 1H), 4.98 (dd, CO2, 2.0 mL min−1, 220 nm, tr (major) 6.98, tr (minor) 5.77,
J = 8.8, 3.4 Hz, 1H), 4.89 (m, 2H), 1.50 (s, 9H); (400 MHz, >99% ee, [α]2D5 = −42.0 (c 1.10, MeOH).
d6-acetone): δ 5.04 (dd, J = 6.8, 1.8 Hz, 1H), 4.97 (dd, J = 9.6,
6.8 Hz, 1H), 4.88 (dd, J = 9.6, 1.8 Hz, 1H), 1.50 (s, 9H).
(S)-2-((tert-Butoxycarbonyl)amino)-3-(3-ethylphenoxy)-propionic
acid (6b). Yield 68%; light yellow solid; m.p. 78–80 °C;
Instead of EtOAc, hydrogenation was also carried out in 1H NMR (400 MHz, DMSO-d6): δ 12.86 (br s, 1H), 7.19–7.16 (m,
MeOH. The 1H NMR spectrum of the crude sulfamidate 4 2H), 6.80–6.71 (m, 3H), 4.36–4.31 (m, 1H), 4.18–4.16 (m, 2H),
showed a better reaction profile. 1H NMR (400 MHz, MeOH- 2.56 (q, J = 7.6 Hz, 2H), 1.38 (s, 9H), 1.16 (t, J = 7.6 Hz, 3H).
d4): δ 4.91 (dd, J = 6.8, 1.6 Hz, 1H), 4.85 (dd, J = 9.5, 6.8 Hz, 1H, 13C NMR (100 MHz, DMSO-d6): δ 171.5, 158.2, 155.4, 145.4,
along with peak of HOD), 4.76 (dd, J = 9.5, 1.6 Hz), 1.52 129.3, 120.5, 114.2, 111.6, 78.3, 67.2, 53.4, 28.2 (3C), 28.1, 15.6
(s, 9H). 13C NMR (100 MHz, MeOH-d4): 170.34, 149.8, 86.7, LC-MS (ESI): 308.2 [M − H]−. HPLC analysis: Cellulose-2 (4.6 ×
69.7, 59.1, 28.2. ELSD-MS (ESI): 266.0 [M − H]−. [α]D25 = −24.3 250 mm) 5μ, (MeOH + 0.5% IPA) containing 80% CO2, 2 mL
(c 0.53, MeOH). HRMS (ESI): calcd for C8H13NNaO7S 290.0310 min−1, 220 nm, tr (major) 4.98, tr (minor) 6.17, >98% ee,
m/z [M + Na]+, found 290.0310.
[α]2D5
= +33.7 (c 1.00, MeOH). HRMS (ESI): calcd for
C16H23NNaO5, 332.1474 m/z [M + Na]+, found 332.1489. From
D-serine: HPLC analysis: Cellulose-2 (4.6 × 250 mm) 5μ, (MeOH
+ 0.5% IPA) containing 80% CO2, 2 mL min−1, 220 nm, tr
General procedure for ring opening of sulfamidate acid 4 with
phenol
To a suspended solution of NaH (60% in oil; 0.105 g, (major) 6.12, tr (minor) 5.07, >99% ee, [α]2D5 = −33.4 (c 1.06,
2.6 mmol) in THF (3.0 mL), phenol 5a (0.083 g, 0.88 mmol) MeOH).
was added at 0 °C. The reaction mixture was stirred for 10 min
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-ethylphenoxy)-propionic
and then it was brought to −15 °C. Serine sulfamidate acid 4 acid (6c). Yield 66%; light yellow semi-solid, 1H NMR
(0.224 g, 0.84 mmol) in dry THF (1.0 mL) was slowly added to (400 MHz, DMSO-d6): δ 7.13–7.09 (m, 3H), 6.82 (d, J = 8.5 Hz,
it at −15 °C. After 4 h, the reaction mixture was acidified 2H), 4.31–4.29 (m, 1H), 4.15–4.14 (m, 2H), 2.54 (q, J = 7.5 Hz,
(pH 2; monitored by pH paper) by addition of NaHSO4. Then 2H), 1.38 (s, 9H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz,
it was extracted with ethyl acetate (3 × 20 mL), the combined DMSO-d6): δ 171.5, 156.2, 155.4, 136.2, 128.7 (2C), 114.5 (2C),
organic layers were washed with brine (100 mL), dried over 78.3, 67.4, 53.4, 28.2 (3C), 27.3, 15.9. LC-MS (ESI): 308.2
sodium sulfate, and purified by column chromatography to get [M − H]−. HPLC analysis: Cellulose-2 (4.6 × 250 mm) 5μ,
the β-phenoxy-α-amino acid 6a (0.136 g, 57%).
(MeOH + 0.5% IPA) containing 80% CO2, 2 mL min−1, 220 nm,
tr (major) 5.13, tr (minor) 6.6, >98% ee, [α]2D5 = +38.4 (c 1.18,
MeOH). HRMS (ESI): calcd for C16H23NNaO5, 332.1474 m/z
[M + Na]+, found 332.1502. From D-serine: HPLC analysis:
General procedure for one pot synthesis of aryloxyamino
acid 6
To the sulfamidate 1 (0.30 g, 0.84 mmol) in THF (4.0 mL) was Cellulose-2 (4.6 × 250 mm) 5μ, (MeOH + 0.5% IPA) containing
added 10% Pd/C (0.030 g) and the reaction mixture was stirred 80% CO2, 2 mL min−1, 220 nm, tr (major) 6.57, tr (minor) 5.08,
under hydrogen (1 atm) at rt for 30 min. TLC shows complete >99% ee, [α]2D5 = −38.2 (c 1.12, MeOH).
consumption of starting 1. The hydrogen balloon was replaced
(S)-2-((tert-Butoxycarbonyl)amino)-3-(2,3-dimethylphenoxy)-
with N2, phenol 5a (0.083 g, 0.88 mmol) and NaH (60% in oil; propionic acid (6d). Yield 70%; off white solid, m.p.
1
0.105 g, 2.6 mmol) were then successively added to the reac- 114–116 °C; H NMR (400 MHz, DMSO-d6): δ 12.88 (br s, 1H),
tion mixture at −15 °C and stirred. After 4 h, the reaction 7.17 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.77–6.74
mixture was acidified (pH 2 monitored by pH paper) by (m, 2H), 4.43–4.38 (m, 1H), 4.18 (dd, J = 9.6, 4.0 Hz, 1H), 4.10
addition of NaHSO4. Then it was filtered through a celite bed (dd, J = 9.6, 6.8 Hz, 1H), 2.19 (s, 3H), 2.03 (s, 3H), 1.39 (s, 9H).
and the filtrate was extracted with ethyl acetate (3 × 20 mL), 13C NMR (100 MHz, DMSO-d6): δ 171.4, 155.9, 155.3, 137.2,
the combined organic layers were washed with brine (100 mL), 125.8, 124.5, 122.3, 109.3, 78.2, 67.8, 53.3, 28.1 (3C), 19.5, 11.2.
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LC-MS (ESI): 307.8 [M − H]−. HPLC analysis: Chiralpak AD-H min−1, 210 nm, tr (major) 2.13, tr (minor) 3.89, >99% ee,
(4.6 × 250 mm) 5μ, (MeOH + IPA) containing 80% CO2, 3.0 mL [α]2D5 = −40.1 (c 2.77, MeOH).
min−1, 210 nm, tr (major) 2.12, tr (minor) 1.73; 98% ee. [α]2D5
=
(S)-2-((tert-Butoxycarbonyl)amino)-3-(2-ethoxyphenoxy)-propionic
+43.4 (c 1.28, MeOH). HRMS (ESI): calcd for C16H23NNaO5, acid (6i). Yield 66%; light yellow semi-solid; 1H NMR
332.1474 m/z [M + Na]+, found 332.1502. From D-serine: off (400 MHz, DMSO-d6): δ 12.88 (br s, 1H), 7.03 (d, J = 8.2 Hz,
white semi-solid, HPLC analysis: Chiralpak AD-H (4.6 × 1H), 6.99–6.96 (m, 2H), 6.94–6.90 (m, 1H), 6.89–6.85 (m, 1H),
250 mm) 5μ, (MeOH + IPA) containing 80% CO2, 3.0 mL 4.32–4.29 (m, 1H), 4.18 (d, J = 5.2 Hz, 2H), 4.00 (q, J = 7.0 Hz,
min−1, 210 nm, tr (major) 1.7, tr (minor) 2.12, >99% ee, [α]2D5
−44.5 (c 0.95, MeOH).
=
2H), 1.39 (s, 9H), 1.31 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 171.5, 155.3, 148.8, 148.0, 122.1, 121.1, 115.7,
(S)-2-((tert-Butoxycarbonyl)amino)-3-(2-tert-butylphenoxy)- 114.5, 78.3, 68.9, 64.1, 53.5, 28.1 (3C), 14.7. LC-MS (ESI): 324.0
propionic acid (6e). Yield 53%; light brown semi-solid; [M − H]−. HPLC analysis: Cellulose-2 (4.6 × 250 mm) 5μ,
1H NMR (400 MHz, DMSO-d6): δ 13.0 (br s, 1H), 7.20 (d, J = (MeOH + 0.5% IPA) containing 80% CO2, 2.0 mL min−1
,
6.6 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 220 nm, tr (major) 6.14, tr (minor) 10.56, >99% ee, [α]D25
=
6.92 (d, J = 8.1 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H), 4.49–4.45 +23.6 (c 0.88, MeOH). HRMS (ESI): calcd for C16H23NNaO6,
(m, 1H), 4.27 (dd, J = 9.5, 3.8 Hz, 1H), 4.15 (dd, J = 9.5, 7.1 Hz, 348.1423 m/z [M + Na]+, found 348.1440. From D-serine: HPLC
1H), 1.38 (s, 9H), 1.30 (s, 9H). 13C NMR (100 MHz, DMSO-d6): analysis: Cellulose-2 (4.6 × 250 mm) 5μ, (MeOH + 0.5% IPA)
δ 171.5, 156.6, 155.1, 137.2, 127.0, 126.2, 120.4, 111.9, Containing 80% CO2, 2.0 mL min−1, 220 nm, tr (major) 10.59,
78.2, 67.0, 53.3, 34.3, 29.7 (3C), 28.1 (3C). LC-MS (ESI): tr (minor) 6.19, >99% ee. [α]2D5 = −23.4 (c 0.94, MeOH).
336.2 [M − H]−. [α]2D5 = +33.2 (c 0.58, MeOH). HRMS (ESI):
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-methoxyphenoxy)-
calcd for C18H27NNaO5, 360.1787 m/z [M + Na]+, found propionic acid (6j). Yield 70%; greenish semi-solid; 1H NMR
360.1787. (400 MHz, DMSO-d6): δ 12.87 (br s, 1H), 7.15 (d, J = 8.2 Hz,
(S)-2-((tert-Butoxycarbonyl)amino)-3-(3-tert-butylphenoxy)- 1H), 6.85 (AB quasi t, J = 9.7 Hz, 4H), 4.34–4.30 (m, 1H),
propionic acid (6f). Yield 26%; light brown solid, m.p. 4.16–4.12 (m, 2H), 3.69 (s, 3H), 1.38 (s, 9H). 13C NMR
1
108–110 °C; H NMR (400 MHz, DMSO-d6): δ 12.90 (br s, 1H), (100 MHz, DMSO-d6): δ 171.4, 155.3, 153.6, 152.0, 115.6 (2C),
7.20 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 114.5 (2C), 78.2, 67.9, 55.2, 53.4, 28.1 (3C). LC-MS (ESI): 310.0
8.0 Hz, 1H), 6.89 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.34 (m, 1H), [M − H]−. HPLC analysis: Chiralpak AD-H (4.6 × 50 mm) 5μ,
4.22–4.18 (m, 2H), 1.39 (s, 9H), 1.25 (s, 9H). 13C NMR (MeOH + IPA) containing 80% CO2, 3.0 mL min−1, 220 nm,
(100 MHz, DMSO-d6): 171.3, 157.8, 155.2, 152.2, 128.9, 117.7, tr (major) 2.45, tr (minor) 2.06, 98.5% ee, [α]2D5 = +33.7 (c 1.01,
112.2, 110.8, 78.1, 67.2, 53.3, 34.2, 30.9 (3C), 28.0 (3C). LC-MS MeOH). HRMS (ESI): calcd for C15H21NNaO6, 334.1267 m/z
(ESI): 336.2 [M − H]−. [α]2D5 = +35.8 (c 1.04, MeOH). HRMS [M + Na]+, found 334.1266. From D-serine: brown semi-solid,
(ESI): calcd for C18H27NNaO5, 360.1787 m/z [M + Na]+, found HPLC analysis: Chiralpak AD-H (4.6 × 250 mm) 5μ, (MeOH +
360.1816.
(S)-2-((tert-Butoxycarbonyl)amino)-3-(2,6-dimethylphenoxy)- 2.06, tr (minor) 2.45, >99% ee, [α]2D5 = −33.8 (c 0.99, MeOH).
propionic acid (6g). Yield 20%; colourless semi-solid; 1H NMR
(S)-2-((tert-Butoxycarbonyl)amino)-3-(naphthalen-1-yloxy)-
IPA) containing 80% CO2, 3.0 mL min−1, 220 nm, tr (major)
(400 MHz, DMSO-d6): δ 12.9 (br s, 1H), 7.07 (d, J = 8.3 Hz, 1H), propionic acid (6k). Yield 40%; brown semi-solid, 1H NMR
7.01–6.99 (m, 2H), 6.93–6.89 (m, 1H), 4.32 (m, 1H), 4.01–3.95 (400 MHz, DMSO-d6): δ 8.20 (d, J = 8.2 Hz, 1H), 7.85 (d, J =
(m, 2H), 2.21 (s, 6H), 1.36 (s, 9H). 13C NMR (100 MHz, DMSO- 8.0 Hz, 1H), 7.53–7.34 (m, 5H), 6.94 (d, J = 7.5 Hz, 1H), 4.60
d6): δ 171.4, 155.2, 154.5, 130.3 (2C), 128.6 (2C), 123.8, 78.2, (m, 1H), 4.41–4.33 (m, 2H), 1.41 (s, 9H). 13C NMR (100 MHz,
70.7, 54.1, 28.0 (3C), 15.6 (2C). LC-MS (ESI): 308.6 [M − H]−. DMSO-d6): 171.4, 155.4, 153.6, 133.9, 127.2, 126.4, 126.1,
[α]2D5
C16H23NNaO5, 332.1474 m/z [M + Na]+, found 332.1474.
= +25.4 (c 1.03, MeOH). HRMS (ESI): calcd for 125.0, 124.8, 121.8, 120.1, 105.1, 78.2, 67.9, 53.3, 28.1 (3C).
LC-MS (ESI): 330.2 [M − H]−. [α]D25 = +46.3 (c 1.30, MeOH).
(S)-2-((tert-Butoxycarbonyl)amino)-3-(2,3-dimethoxyphenoxy)- HRMS (ESI): calcd for C18H21NNaO5, 354.1317 m/z [M + Na]+,
propionic acid (6h). Yield 70%; light yellow semi-solid; found 354.1349.
1H NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 7.15 (d, J =
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-chloro-2-methoxy-
8.3 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), phenoxy)-propionic acid (6l). Yield 75%; light yellow semi-
1
6.64 (d, J = 8.4 Hz, 1H), 4.39–4.35 (m, 1H), 4.22 (dd, J = 9.8, solid; H NMR (400 MHz, DMSO-d6): δ 7.05–7.02 (m, 1H), 6.97
3.9 Hz, 1H), 4.15 (dd, J = 9.8, 7.2 Hz, 1H), 3.75 (s, 3H), 3.64 (d, J = 8.6 Hz, 1H), 6.91 (dd, J = 8.5, 2.2 Hz, 1H), 4.30–4.26
(s, 3H), 1.38 (s, 9H). 13C NMR (100 MHz, DMSO-d6): δ 171.5, (m, 1H), 4.20–4.13 (m, 2H), 3.79 (s, 3H), 1.38 (s, 9H). 13C NMR
155.4, 153.2, 151.9, 138.0, 123.6, 106.9, 106.0, 78.3, 68.3, 60.0, (100 MHz, DMSO-d6): δ 171.3, 155.3, 150.1, 146.6, 125.2, 120.1,
55.8, 53.4, 28.2 (3C). LC-MS (ESI): 339.8 [M − H]−. HPLC ana- 115.4, 112.7, 78.3, 68.6, 55.9, 53.4, 28.1 (3C). LC-MS (ESI):
lysis: Chiralpak AD-H (4.6 × 250 mm) 5μ, (MeOH + IPA) con- 344.0 [M − H]−. HPLC analysis: Cellulose-2 (4.6 × 250 mm) 5μ,
taining 80% CO2, 3.0 mL min−1, 210 nm, tr (major) 3.88, (MeOH + 0.5% IPA) containing 80% CO2, 2.0 mL min−1
,
tr (minor) 2.15, >99% ee. [α]2D5 = +40.0 (c 2.99, MeOH). HRMS 220 nm, tr (major) 6.27, tr (minor) 8.84, >98% ee, [α]D25 = +35.7
(ESI): calcd for C16H23NNaO7, 364.1372 m/z [M + Na]+, found (c 2.81, MeOH). HRMS (ESI): calcd for C15H20ClNNaO6,
364.1384. From D-serine: HPLC analysis: Chiralpak AD-H (4.6 × 368.0877 m/z [M + Na]+, found 368.0895. From D-serine: light
250 mm) 5μ, (MeOH + IPA) containing 80% CO2, 3.0 mL yellow semi-solid, HPLC analysis: Cellulose-2 (4.6 × 250 mm)
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5μ, (MeOH + 0.5% IPA) containing 80% CO2, 2.0 mL min−1
,
(4S)-N-(p-Methoxybenzyl)-2,2-dioxo-1,2,3-oxathiazolidione-
220 nm, tr (major) 8.68, tr (minor) 6.3, >99% ee, [α]2D5 = −35.4 4-carboxylic acid (9). To the protected sulfamidate 8 (0.30 g,
(c 2.54, MeOH).
0.79 mmol) in ethyl acetate was added 10% Pd/C (0.070 g). The
(S)-2-((tert-Butoxycarbonyl)amino)-3-(2-fluorophenoxy)-pro- reaction mixture was stirred under a hydrogen balloon at rt for
1
pionic acid (6m). Yield 39%; light yellow semi-solid; H NMR 1 h. The reaction mixture was filtered through a celite bed and
(400 MHz, DMSO-d6): δ 12.91 (br s, 1H), 7.22–7.09 (m, 4H), the filtrate was evaporated under reduced pressure to get the
6.98–6.94 (m, 1H), 4.36–4.34 (m, 1H), 4.31–4.21 (m, 2H), 1.36 sulfamidate carboxylic acid 9 as a sticky liquid, which was
(s, 9H). 13C NMR (100 MHz, DMSO-d6): δ 171.2. 155.3, 151.7 used for the next step without further purification. 1H NMR
(d, J = 242.5 Hz), 146.0 (d, J = 10.4 Hz), 124.7 (d, J = 3.8 Hz), (400 MHz, CDCl3): δ 7.33 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz,
121.5 (J = 6.8 Hz), 116.0 (d, J = 17.8 Hz), 115.3, 78.3, 68.3, 53.3, 2H), 4.67 (dd, J = 8.9, 4.1 Hz, 1H), 4.59 (quasi t, J = 8.2 Hz, 1H),
28.1. LC-MS (ESI): 298.2 [M − H]−. HPLC analysis: Cellulose-2 4.51 (d, J = 14.1 Hz, 1H), 4.41 (d, J = 14.1 Hz, 1H), 4.12–4.06
(4.6 × 250 mm) 5μ, (MeOH + 0.5% IPA) containing 80% CO2, (m, 1H), 3.80 (s, 3H); 1H NMR (400 MHz, DMSO-d6): δ 13.5
2.0 mL min−1, 216 nm, tr (major) 4.97, tr (minor) 6.02, >99% (br s, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 4.76
ee; [α]2D5 = +28.1 (c 1.60, MeOH). HRMS (ESI): calcd for (quasi t, J = 8.3 Hz, 1H), 4.67 (dd, J = 9.0, 4.6 Hz, 1H), 4.40
C14H18FNNaO5, 322.1067 m/z [M + Na]+, found 322.1077. From (d, J = 14.4, 1H), 4.41–4.29 (m, 1H), 4.30 (d, J = 14.4 Hz, 1H),
D-serine: HPLC analysis: Cellulose-2 (4.6 × 250 mm) 5μ, 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.7, 159.9, 130.8
(MeOH + 0.5% IPA) containing 80% CO2, 2.0 mL min−1
,
(2C), 125.1, 114.3 (2C), 67.4, 57.4, 55.3, 49.8. LC-MS (ESI):
216 nm, tr (major) 6.02, tr (minor) 5.09, >99% ee, [α]2D5 = −27.9 286.3 [M − H]−, [α]D25 = −36.0 (c 1.01, MeOH).
(c 1.65, MeOH).
General procedure of ring opening reaction of sulfamidate
9 with ArOH
(R)-2-((tert-Butoxycarbonyl)amino)-3-(2-chlorophenoxy)-pro-
pionic acid (6n). Yield 51%; obtained from D-serine; yellow
semi-solid; 1H NMR (400 MHz, DMSO-d6): δ 7.40 (d, J = 7.8 Hz, To 4-methoxyphenol 5j (0.104 g, 0.84 mmol, 1.05 equiv.) in dry
1H), 7.27 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.06 (d, J = THF (4.0 mL) was added NaH (60% in oil; 0.100 g, 2.5 mmol,
8.1 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 4.44–4.39 (m, 1H), 4.32 3.1 equiv.) at 0 °C and stirred for 5 min. Sulfamidate acid 9
(dd, J = 9.8, 3.8 Hz, 1H), 4.24 (dd, J = 9.8, 7.3 Hz, 1H), 1.38 (0.228 g, 0.79 mmol, 1.0 equiv.) in dry THF (2.0 mL) was added
(s, 9H). 13C NMR (100 MHz, DMSO-d6): δ 171.1, 155.2, 153.5, and stirring was continued at 0 °C. After 4 h, the reaction
129.9, 128.2, 121.9, 121.6, 114.2, 78.3, 68.3, 53.2, 28.1 (3C). mixture was acidified (pH 2; monitored by pH paper) by
LC-MS (ESI): 314.2 [M − H]−. [α]D25 = −33.1 (c 1.01, MeOH). addition of NaHSO4 and extracted with ethyl acetate (3 ×
HRMS (ESI): calcd for C14H18ClNNaO5, 338.0771 m/z 15 mL). The combined organic layers were washed with brine,
[M + Na]+, found 338.0771.
dried over sodium sulfate, filtered, and purified by column
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-cyanophenoxy)-pro- chromatography using MeOH–DCM to give amino acid 10j
panoic acid (6o). Yield 52%; brown semi-solid; 1H NMR (0.21 g, 80%).
(400 MHz, DMSO-d6): δ 12.98 (br s, 1H), 7.76 (d, J = 8.7 Hz,
(S)-3-(4-Ethylphenoxy)-2-((4-methoxybenzyl)amino)-propanoic
1
2H), 7.29 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 4.40–4.36 acid (10c). Yield 79%; white solid, m.p. 178–180 °C; H NMR
(m, 1H), 4.32–4.29 (m, 2H), 1.38 (s, 9H). 13C NMR (100 MHz, (400 MHz, DMSO-d6): δ 7.40 (d, J = 8.5 Hz, 2H), 7.13 (d, J =
DMSO-d6): δ 171.0, 161.5, 155.3, 134.1 (2C), 118.9, 115.6 (2C), 8.4 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H), 8.86 (d, J = 8.4 Hz, 2H),
103.1, 78.3, 67.7, 53.1, 28.1 (3C). LC-MS (ESI): 305.0 [M − H]−. 4.31 (d, J = 3.5 Hz, 2H), 4.11–4.06 (m, 2H), 3.92 (m, 1H), 3.75
HPLC analysis: Cellulose-2 (4.6 × 250 mm) 5μ, (MeOH + 0.5% (s, 3H), 2.53 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H).
IPA) containing 80% CO2, 2.0 mL min−1, 246 nm, tr (major) 13C NMR (100 MHz, DMSO-d6): δ 168.0, 159.6, 155.6, 136.7,
6.22, tr (minor) 7.15, >98% ee, [α]2D5 = +35.0 (c 1.06, MeOH). 131.6 (2C), 128.6 (2C), 123.8, 114.5 (2C), 113.8 (2C), 65.8, 58.1,
HRMS (ESI): calcd for C15H18N2NaO5, 329.1113 m/z [M + Na]+, 55.1, 49.3, 27.2, 15.8. LC-MS (ESI): 330.2 [M + H]+, HRMS (ESI):
found 329.1113. From D-serine: HPLC analysis: Cellulose-2 calcd for C19H23NNaO4, 352.1525 m/z [M + Na]+, found
(4.6 × 250 mm) 5μ, (MeOH + 0.5% IPA) containing 80% CO2, 352.1519. [α]2D5 = +23.0 (c 0.168, MeOH).
2.0 mL min−1, 246 nm, tr (major) 7.09, tr (minor) 6.21,
(S)-3-(2,3-Dimethylphenoxy)-2-((4-methoxybenzyl)amino)-pro-
panoic acid (10d). Yield 80%; off white solid, m.p.
>99% ee, [α]2D5 = −34.8 (c 1.00, MeOH).
(S)-3-([1,1′-Biphenyl]-4-yloxy)-2-((tert-butoxycarbonyl)amino)- 184–186 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.36 (d, J = 8.4
propanoic acid (6p). Yield 53%; light yellow solid, m.p. Hz, 2H), 7.01 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H),
1
124–126 °C; H NMR (400 MHz, DMSO-d6): δ 12.91 (br s, 1H), 6.78–6.75 (m, 2H), 4.25–4.20 (m, 2H), 4.01 (AB q, J = 13.0 Hz,
7.61–7.59 (m, 4H), 7.43 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.62 (m, 1H), 2.2 (s, 3H), 2.06 (s, 3H). 13C
1H), 7.22 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 4.40–4.35 NMR (100 MHz, DMSO-d6): δ 168.4, 159.2, 155.8, 137.4, 130.9
(m, 1H), 4.28–4.24 (m, 2H), 1.39 (s, 9H). 13C NMR (100 MHz, (2C), 126.2, 125.9, 124.5, 122.5, 113.9 (2C), 109.3, 67.7, 59.3,
DMSO-d6): δ 171.3, 157.7, 155.3, 139.6, 132.9, 128.7 (2C), 127.6 55.1, 49.6, 19.7, 11.5. LC-MS (ESI): 330.3 [M + H]+, HPLC analy-
(2C), 126.6, 126.1 (2C), 114.9 (2C), 78.2, 67.4, 53.3, 28.1 (3C). sis: Cellulose-1 (4.6 × 250 mm) 5μ, MeOH, 3.0 mL min−1
,
LC-MS (ESI): 356.2 [M − H]−. [α]2D5 = +44.2 (c = 0.99, MeOH). 225 nm, tr (major) 2.78, tr (minor) 3.98, >99% ee, HRMS (ESI):
HRMS (ESI): calcd for C20H23NNaO5, 380.1474 m/z [M + Na]+, calcd for C19H23NNaO4, 352.1525 m/z [M + Na]+, found
found 380.1474.
352.1525. [α]2D5 = +20.0 (c 0.252, MeOH). From D-serine: HPLC
Org. Biomol. Chem., 2014, 12, 6507–6515 | 6513
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analysis: Cellulose-1 (4.6 × 250 mm) 5μ, MeOH, 3.0 mL min−1
,
103.4, 67.0, 58.5, 55.1, 49.4. LC-MS (ESI): 325.4 [M + H]+,
225 nm, tr (major) 3.95, tr (minor) 2.78, >99% ee.
HRMS (ESI): calcd for C18H18N2NaO4, 349.1164 m/z [M + Na]+,
(S)-3-(3-(tert-Butyl)phenoxy)-2-((4-methoxybenzyl)amino)-pro- found 349.1164. [α]2D5 = +25.0 (c 0.1006, MeOH).
panoic acid (10f). Yield 54%; white solid, m.p. 162–164 °C;
(S)-2-((4-Methoxybenzyl)amino)-3-(octyloxy)-propanoic acid
1H NMR (400 MHz, DMSO): δ 7.39 (d, J = 8.4 Hz, 2H), 7.21 (10q). Yield 16%; white solid, m.p. 182–184 °C; 1H NMR
(t, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), (400 MHz, MeOD): δ 7.40 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.6 Hz,
6.90 (m, 1H), 6.75 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 4.31 (d, J = 2H), 4.19 (s, 2H), 3.83–3.79 (m, 2H), 3.64–3.61 (m, 1H), 3.45
3.6 Hz, 2H), 4.11–4.03 (m, 2H), 3.74 (s, 3H), 3.72 (m, 1H), (t, J = 6.6 Hz, 2H), 1.59–1.54 (m, 2H), 1.29 (m, 10H), 0.89 (t, J =
1.25 (s, 9H), 13C NMR (100 MHz, DMSO-d6):
δ
168.1, 6.4, 3H), 13C NMR (100 MHz, MeOD + CDCl3): δ 169.7, 160.9,
159.2, 157.6, 152.2, 130.9 (2C), 128.9, 125.6, 117.9, 113.7 131.5 (2C), 123.4, 114.4 (2C), 71.6, 68.4, 60.9, 54.8, 31.9, 29.5,
(2C), 112.1, 110.9, 66.7, 58.9, 54.9, 49.3, 34.3, 30.9 (3C). LC-MS 29.4, 29.3, 26.1, 22.6, 13.4. LC-MS (ESI): 336.2 [M − H]−, HPLC
(ESI): 356.2 [M − H]−, HRMS (ESI): calcd for C21H27NNaO4, analysis: Cellulose-2 (4.6 × 250 mm) 5μ, (MeOH) containing
380.1838 m/z [M + Na]+, found 380.1838. [α]D25 = +17.0 (c 0.10, 20% CO2, 1.999 mL min−1, 232 nm, tr (major) 2.48, tr (minor)
MeOH).
3.1, >99% ee; HRMS (ESI): calcd for C19H31NO4Na, 360.2151
(S)-3-(2,6-Dimethylphenoxy)-2-((4-methoxybenzyl)amino)- m/z [M + Na]+, found 360.2151. From D-serine: HPLC analysis:
propanoic acid (10g). Yield 36%; white solid, m.p. 210–212 °C; Cellulose-2 (4.6 × 250 mm) 5μ, (MeOH) containing 20% CO2,
1H NMR (400 MHz, DMSO-d6): δ 7.37 (d, J = 8.5 Hz, 2H), 7.0 1.999 mL min−1, 232 nm, tr (major) 3.11, tr (minor) 2.49,
(d, J = 7.4 Hz, 2H), 6.95–6.89 (m, 3H), 4.06–4.00 (m, 2H), >99% ee.
3.97–3.94 (m, 2H), 3.75 (s, 3H), 3.51 (m, 1H), 2.20 (s, 6H).
13C NMR (100 MHz, DMSO + TFA): δ 168.0, 159.9, 153.5, 132.0
(2C), 130.4 (2C), 128.9 (2C), 124.6, 123.0, 114.0 (2C), 67.7, 58.6,
55.1, 49.3, 15.8 (2C). LC-MS (ESI): 328.2 [M − H]−, HRMS (ESI):
calcd for C19H23NNaO4, 352.1525 m/z [M + Na]+, found
352.1525.
Acknowledgements
We thank DBT (BIPP), New Delhi (sanction no. 102/IFD/SAN/
1191/2009-2010) for providing financial support. The authors
are thankful to the referees for their constructive scientific
comments and suggestions.
(S)-2-((4-Methoxybenzyl)amino)-3-(4-methoxyphenoxy)-pro-
panoic acid (10j). Yield 80%; white solid, m.p. 178–180 °C;
1H NMR (400 MHz, DMSO-d6): δ 7.43 (d, J = 8.3 Hz, 2H), 6.97
(d, J = 8.3 Hz, 2H), 6.93–6.86 (m, 4H), 4.35 (m, 2H), 4.21–4.12
(m, 3H), 3.76 (s, 3H), 3.69 (s, 3H). 13C NMR (100 MHz, DMSO-
d6): δ 168.0, 159.8, 154.1, 151.5, 132.1 (2C), 123.3, 115.9 (2C),
114.6 (2C), 113.9 (2C), 66.1, 57.8, 55.4, 55.2, 49.2. LC-MS (ESI):
332.2 [M + H]+, HPLC analysis: Cellulose-1 (4.6 × 250 mm) 5μ,
MeOH, 3.0 mL min−1, 225 nm, tr (major) 4.83, tr (minor) 5.16,
>99% ee, [α]2D5 = +26.0 (c 0.127, MeOH). HRMS (ESI): calcd for
C18H21NNaO5, 354.1317 m/z [M + Na]+, found 354.1317. From
D-serine: HPLC analysis: Cellulose-1 (4.6 × 250 mm) 5μ,
MeOH, 3.0 mL min−1, 225 nm, tr (major) 5.18, tr (minor) 4.95,
>99% ee.
Notes and references
1 For review: D. C. Gournelis, G. G. Laskaris and
R. Verpoorte, Nat. Prod. Rep., 1997, 14, 75; U. Schmidt,
A. Lieberknecht and E. Haslinger, in The Alkaloids, ed.
A. Brossi, Academic Press, New York, 1985, vol. 26, p. 299;
M. M. Joullié and R. F. Nutt, in Alkaloids: Chemical and Bio-
logical Perspectives, ed. S. W. Pelletier, Wiley, New York,
1985, vol. 3, p. 113.
(S)-3-(2-Fluorophenoxy)-2-((4-methoxybenzyl)amino)-propanoic
acid (10m). Yield 51%; white solid, m.p. 169–171 °C; H NMR
2 M. Pays, F.-X. Jarreau, X. Lusinchi and R. Goutdref, Ann.
Chim., 1966, 83; T. T.-Laib, J. Chastanet and J. Zhu, J. Am.
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1
(400 MHz, DMSO-d6): δ 7.36 (d, J = 8.5 Hz, 2H), 7.24–7.10
(m, 3H), 6.99–6.96 (m, 1H), 6.92 (d, J = 8.5 Hz, 2H), 4.39–4.29
(m, 2H), 4.04–3.97 (m, 2H), 3.75 (s, 3H), 3.31 (m, 1H),
13C NMR (100 MHz, DMSO-d6): δ 169.1, 159.0, 151.7 (d, J =
251.5 Hz), 145.8 (d, J = 10.4 Hz), 130.6 (2C), 126.5, 124.7 (d, J =
2.5 Hz), 121.4 (d, J = 6.8 Hz), 115.9 (d, J = 17.8 Hz), 115.2, 113.7
(2C), 69.9, 59.9, 54.9, 49.5; LC-MS (ESI): 318.0 [M − H]−, HRMS
(ESI): calcd for C17H18FNO4Na, 342.1118 m/z [M + Na]+, found
342.1118. [α]2D5 = +21.0 (c 0.10, MeOH).
3 K. Urbahns, M. Härter, A. Vaupel, M. Albers, D. Schmidt,
U. Brüggemeier, B. S.-Ludwig, C. Gerdes and H. Tsujishita,
Bioorg. Med. Chem. Lett., 2003, 13, 1071; S. B. Hoyt,
C. London, H. Ok, E. Gonzalez, J. L. Duffy, C. Abbadie,
B. Dean, J. P. Felix, M. L. Garcia, N. Jochnowitz,
B. V. Karanam, X. Li, K. A. Lyons, E. McGowan,
D. E. MacIntyre, W. J. Martin, B. T. Priest, M. M. Smith,
R. T.-Guth, V. A. Warren, B. S. Williams, G. J. Kaczorowskid
and W. H. Parsons, Bioorg. Med. Chem. Lett., 2007, 17,
6172.
(S)-3-(4-Cyanophenoxy)-2-((4-methoxybenzyl)amino)-propanoic
1
acid (10o). Yield 68%, white solid, m.p. 170–174 °C; H NMR
(400 MHz, DMSO-d6): δ 7.79 (d, J = 8.6 Hz, 2H), 7.39 (d, J =
8.6 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H),
4.43 (m, 2H), 4.08 (AB q, J = 13.0 Hz, 2H), 3.90 (m, 1H), 3.75
(s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 167.7, 161.2, 159.4,
134.2 (2C), 131.3 (2C), 125.1, 119.0, 115.7 (2C), 113.9 (2C),
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W. Wuc, Y. Yang and M. Xu, Tetrahedron Lett., 2011, 52,
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