Synthesis of γ-oxo γ-aryl and γ-aryl α-amino acids from aromatic aldehydes and serine

Article abstract of DOI:10.1002/ejoc.201201128

γ-Oxo α-amino acids and γ-aryl α-amino acids are compounds with very interesting biological properties and are active components of many drug molecules. Oxo amino acids are also used as synthetic precursors for a number of unnatural amino acids and amino alcohols. We report a very efficient synthesis of such compounds through the coupling of aromatic dithianes, prepared from aromatic aldehydes and an iodide derivative of serine. The dithiane groups in compounds thus obtained can be either hydrolyzed or reduced to generate 4-oxo-4-aryl or 4-aryl 2-amino butanol derivatives, respectively, which, on further transformations, can be converted into the title compounds. Starting with L-serine provides the corresponding D-amino acids with complete enantiopurity. The reported method is economically viable and complements the existing methods, which rely largely on cross-coupling reactions.

Full text of DOI:10.1002/ejoc.201201128

FULL PAPER
DOI: 10.1002/ejoc.201201128
Synthesis of γ-Oxo γ-Aryl and γ-Aryl α-Amino Acids from Aromatic
Aldehydes and Serine
Shibin Chacko[a] and Ramesh Ramapanicker*[a]
Keywords: Synthetic methods / Amino acids / Oxidation / Hydrolysis / Aldehydes / Reduction
γ-Oxo α-amino acids and γ-aryl α-amino acids are com- pounds thus obtained can be either hydrolyzed or reduced to
pounds with very interesting biological properties and are
active components of many drug molecules. Oxo amino acids
are also used as synthetic precursors for a number of unnatu-
ral amino acids and amino alcohols. We report a very efficient
synthesis of such compounds through the coupling of aro-
matic dithianes, prepared from aromatic aldehydes and an
iodide derivative of serine. The dithiane groups in com-
generate 4-oxo-4-aryl or 4-aryl 2-amino butanol derivatives,
respectively, which, on further transformations, can be con-
verted into the title compounds. Starting with
L-serine pro-
vides the corresponding -amino acids with complete enanti-
D
opurity. The reported method is economically viable and
complements the existing methods, which rely largely on
cross-coupling reactions.
their synthesis from chiral starting materials most com-
monly derived from serine, aspartic, or glutamic acids.
Most of these procedures are based on metal-catalyzed
cross-coupling reactions.[8] The most recently reported
strategy towards the synthesis of homophenylalanine deriv-
atives is through sequential allylic amination and vinylic
arylation of olefins reported by White and co-workers.[9]
The large number of reports, spanning over a decade, dem-
onstrates the importance of efficient methodologies for the
synthesis of these compounds and is also an indication that
no single strategy has so far been enough to satisfy the
growing needs for synthesizing these derivatives with vary-
ing functional groups. However, dedicated reports on the
synthesis of γ-oxo α-amino acids are very limited.[10]
The use of dithiane derivatives of aldehydes to reverse
the polarity around an electrophilic carbon atom is very
well established. The anions derived from such dithianes
react readily with aliphatic iodides and the products on hy-
drolysis yield unsymmetrical ketones. The dithiane deriva-
tives could also be hydrogenolyzed to generate the corre-
sponding alkanes. Herein, we report an efficient method for
the synthesis of γ-oxo γ-aryl α-amino acids and γ-aryl α-
amino acids starting from the dithiane derivatives of aro-
matic aldehydes and an iodo compound 1, derived from
serine.
Introduction
γ-Aryl α-amino acids, generally referred to as homo-
phenylalanine derivatives, form a class of unnatural amino
acids of particular interest because of their vital biological
activity. One of the major clinical applications of these com-
pounds is in the treatment of hypertension and congestive
heart failure through the inhibition of angiotensin-con-
verting enzyme (ACE).[1] Lisinopril, benazepril, enalapril,
imidapril, and temocapril are examples of homophenylala-
nine derivatives used as ACE inhibitors.[2] The γ-oxo deriva-
tives of such amino acids are also found in biological sys-
tems, although not commonly in proteins. l-Kinurenine is
a typical example of an γ-oxo α-amino acid, which is associ-
ated with the catabolism of tryptophan.[3] The γ-oxo α-
amino acids can also be used as very valuable synthetic pre-
cursors, especially for the synthesis of γ-hydroxy amino ac-
ids.[4] These unnatural amino acid residues are sometimes
generated as an artifact during peptide synthesis and are
occasionally shown to have better biological activity than
the parent peptide.[5]
The indubitable importance of homophenylalanine
amino acids has resulted in a number of methods being
reported for their synthesis. Methods are available for the
synthesis of these compounds from achiral starting materi-
als using asymmetric catalysis[6] or using chiral auxiliaries.[7]
However, much effort has been directed towards achieving
Results and Discussion
[a] Department of Chemistry, Indian Institute of Technology
Kanpur,
The synthesis was initiated by converting l-Serine into
the iodide derivative 1, using reported procedures.[11] The
aromatic dithianes 2, prepared from the corresponding al-
dehydes and propane dithiol,[12] were treated with nBuLi to
generate the corresponding anions and subsequent addition
of iodide 1 over a period of 15 min to these anions yielded
208016 Kanpur, Uttar Pradesh, India
Fax: +91-5122597436
E-mail: rameshr@iitk.ac.in
Homepage: http://home.iitk.ac.in/~rameshr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201128.
7120
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γ-Oxo γ-Aryl and γ-Aryl α-Amino Acids
the coupling products 3 in very good yield (Scheme 1, (TFA) in MeOH to obtain the N-protected amino alcohol
Table 1). The maximum yields were obtained when the reac- derivatives 4 (Scheme 2). The use of larger amounts of TFA
tion was carried out at –20 °C in tetrahydrofuran (THF). resulted in the deprotection of the Boc group and was delib-
Although the reaction was equally effective at lower tem- erately avoided. The dithiane group in 4 was hydrolyzed to
peratures (–40 °C) the reaction times were longer. Increas- obtain the keto amino alcohol derivatives 5 in quantitative
ing the reaction temperature to 0 °C or increasing the rate yields using NaHCO3/I2.[13] The use of sodium hydrogen
of addition of 1 resulted in partial dehydroiodination of 1. carbonate and iodine to carry out this transformation is
very high-yielding and conveniently mild. The keto amino
alcohols 5 are very interesting compounds in themselves
and can be used as valuable synthetic precursors. The γ-
hydroxy ketones 5 exist in equilibrium with the correspond-
ing cyclic hemiacetals in solution, which was evident from
1
the H NMR spectra; the percentage of the cyclized form
Scheme 1. Reaction of the iodide derivative of serine 1 with aro-
depends on the nature of the aryl group. Derivatives with
more electron-deficient aryl groups showed a higher ten-
dency to exist as the cyclic derivatives. Our initial efforts
focused on hydrolyzing the dithiane prior to cleavage of the
oxazolidine group. Although the dithiane could be cleaved
very effectively from 3, subsequent hydrolysis of the oxazol-
idine group with TFA in methanol yielded mixtures of
products. The primary alcohol group in 5 was very easily
oxidized using pyridinium dichromate (PDC) in N,N-di-
methylformamide (DMF) to give the corresponding car-
boxylic acids in excellent yields (Scheme 2). These condi-
tions were the most ideal for converting 5 into the corre-
sponding γ-oxo α-amino acid derivatives 6, and the condi-
tions were mild enough not to cause any side reactions of
the ketone or to lead to deprotection of the N-Boc group.
The reaction conditions were suitable for all the examples
studied (Table 2). Most importantly, the transformations
did not result in racemization of the starting materials and
the products were obtained with very high enantiopurity.
This was confirmed by preparing a racemic mixture of the
oxo amino acid 6h starting from dl-serine and comparing
its chiral HPLC profile with that of 6h synthesized from l-
serine. The racemic derivative resolved into two peaks
whereas the chiral derivative showed only a single peak,
demonstrating complete enantiopurity. HPLC profiles of
other derivatives recorded under the same conditions also
yielded only single peaks.
matic dithianes 2.
Table 1. Reaction of the iodide derivative of serine 1 with aromatic
dithianes 2.
[a] Isolated yield.
Scheme 2. Synthesis of γ-oxo α-amino acids.
Dithiane derivatives 3 are masked keto amino alcohols.
The hydrolysis of the dithiane derivative and opening of
A very simple modification of the steps used for the syn-
the oxazolidine moiety followed by oxidation of the alcohol thesis of 6 could be used to obtain the γ-aryl α-amino acid
could give the corresponding oxo amino acids. The oxazol- derivatives 9 (Scheme 3). The reduction of the dithiane
idine rings in 3 were cleaved using 7% trifluoroacetic acid group in 3, instead of its hydrolysis, was the only change
Eur. J. Org. Chem. 2012, 7120–7128
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S. Chacko, R. Ramapanicker
FULL PAPER
Table 2. Synthesis of γ-oxo α-amino acids.
Scheme 3. Synthesis of γ-aryl α-amino acids.
Table 3. Synthesis of γ-aryl α-amino acids.
[a] Isolated yield.
required in the synthetic sequence. A number of reagents
are available for the reduction of a dithiane function to the
corresponding methylene group. We used NaBH4/
NiCl2·6H2O in a mixture of methanol and THF for very
efficient conversion of 3 into the corresponding reduced
products 7.[14] The oxazolidine ring in 7 was then cleaved
using TFA in MeOH to gain the N-protected amino alcohol
8. The primary hydroxyl group in 8 was oxidized to the
corresponding carboxylic acid using PDC in DMF to ob-
tain the amino acid derivatives 9, as expected (Scheme 3,
Table 3). However, the dithiane derivative 3h, which con-
tains a thiophenyl group, could not be converted into the
corresponding γ-aryl α-amino acid using this sequence of
reactions. In this case, the conditions used for reducing 3 to
the corresponding methylene group was sufficient to result
in the reduction of the thiophene group.
[a] Isolated yield.
responding alkene was the only product that could be iso-
lated. The dithiane derivative of 4-nitrobenzaldehyde did
not give the expected product on treatment with nBuLi and
1.
Conclusions
Overall, the synthesis of the γ-oxo α-amino acid deriva-
tives 6 from 3 was slightly more efficient than the synthesis
We have developed a very simple and effective method
of the γ-aryl α-amino acid derivatives 9. These reactions for the synthesis of γ-oxo α-amino acids and γ-aryl α-amino
could not be carried out with aliphatic dithianes. The acids from serine with very high enantiopurity. The use of
anions generated from aliphatic dithianes using nBuLi were dithiane derivatives of common aromatic aldehydes is a
basic enough to induce dehydroiodination of 1 and the cor- simpler and more cost effective alternative to many of the
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γ-Oxo γ-Aryl and γ-Aryl α-Amino Acids
1
(KBr): ν = 2975, 1694, 1386 cm–1. H NMR (CDCl , 500 MHz): δ
˜
available procedures. Whereas most of the available synthe-
ses use metal-catalyzed cross-coupling reactions to intro-
duce an aromatic group into the amino acid side chain, our
method uses a nucleophilic substitution reaction. The pro-
cedure reported here has the added advantage of providing
both γ-oxo γ-aryl and γ-aryl amino acids from the same
synthetic intermediate. The existing methods rely largely on
expensive reagents, whereas the current method uses very
easily available, inexpensive starting materials and well-es-
tablished chemistry, which could allow wider application.
Like the other syntheses reported in literature, the use of l-
serine yields the corresponding d-amino acids.
3
(mixture of rotamers) = 7.94 (m, 2 H), 7.40 (m, 2 H), 7.28 (m, 1
H), 4.19–4.01 (m, 1 H), 3.45 (m, 1 H), 2.97–2.47 (m, 6 H), 2.32–
2.03 (m, 1 H), 1.92 (m, 2 H), 1.47 (br. s, 15 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ (mixture of rotamers) = 151.5, 141.4, 129.1,
127.4, 93.2, 92.6, 80.4, 80.1, 67.4, 57.8, 57.5, 54.2, 54.0, 48.1, 47.3,
28.8, 28.5, 27.6, 25.0 ppm. HRMS (ESI): m/z calcd. for
C21H31NO3S2 [M + H+] 410.1824; found 410.1829.
3-Boc-Protected 2,2-Dimethyl-4-[(2-p-tolyl-1,3-dithian-2-yl)methyl]-
oxazolidine (3b): Column chromatography (petroleum ether/
EtOAc, 98:2); white solid (1.01 g, 80%); m.p. 108–110 °C. IR
1
(KBr): ν = 3003, 1691, 1386 cm–1. H NMR (CDCl , 500 MHz): δ
˜
3
(mixture of rotamers) = 7.80 (m, 2 H), 7.18 (m, 2 H), 4.17–4.01
(m, 1 H), 3.4 (m, 1 H), 2.98–2.49 (m, 5 H), 2.34 (s, 3 H), 2.28–2.07
(m, 1 H), 1.91 (m, 2 H), 1.37 (br. s, 15 H) ppm. 13C NMR (CDCl3,
125 MHz): δ (mixture of rotamers) = 151.6, 138.1, 137.1, 129.8,
128.9, 93.1, 92.6, 80.4, 80.09, 67.4, 57.6, 54.3, 54.0, 48.1, 28.8, 28.5,
27.6, 25.08, 21.0 ppm. HRMS (ESI): m/z calcd. for C22H33NO3S2
[M + Na+] 446.18; found 446.1809.
Experimental Section
General Remarks: All the chemicals were purchased from commer-
cial sources and were used without further purification. 1H and 13
C
NMR spectra were recorded either with a 400 MHz (100 MHz for
3-Boc-Protected 2,2-Dimethyl-4-{[2-(4-isopropylphenyl)-1,3-dithian-
2-yl]methyl}oxazolidine (3c): Column chromatography (petroleum
13C) or with a 500 MHz (125 MHz for 13C) NMR spectrometer at
1
25 °C. The H NMR signals are referenced to tetramethylsilane (δ
ether/EtOAc, 98:2); clear oil (1.05 g, 78%). IR (thin film): ν = 2962,
˜
= 0.00 ppm) and the 13C NMR peaks are referenced to residual
CHCl3 signal (δ = 77.0 ppm). The chemical shifts are reported in
parts per million and coupling constants are given in Hz. The mul-
tiplicities are assigned as s (singlet), d (doublet), t (triplet), br. s
(broad singlet), dd (double doublet), and m (multiplet). High-reso-
lution mass spectra were obtained with a Q/TOF spectrometer
equipped with an ESI source. IR spectra were recorded with an
FTIR instrument and melting points and optical rotations were
recorded with digital instruments. The analytical HPLC were per-
formed using a normal-phase chiral column with n-hexane and 2-
propanol as eluent. Column chromatography was performed using
100–200 mesh silica gel and appropriate mixtures of petroleum
ether and ethyl acetate were used as eluent.
1
1697, 1386 cm–1. H NMR (CDCl3, 500 MHz): δ (mixture of rota-
mers) = 7.82 (d, J = 8.55 Hz, 2 H), 7.21 (d, J = 8 Hz, 2 H), 4.19–
4.00 (m, 1 H), 3.42 (m, 1 H), 2.93–2.52 (m, 7 H), 2.30–2.09 (m, 2
H), 1.91 (m, 2 H), 1.38 (br. s, 15 H), 1.24 (d, J = 8.85 Hz, 6 H) ppm.
13C NMR (CDCl3, 125 MHz): δ (mixture of rotamers) = 151.6,
148.1, 138.6, 128.9, 127.1, 93.1, 92.5, 80.44, 80.09, 67.33, 57.7,
57.33, 54.3, 54.0, 48.0, 31.6, 31.0, 28.8, 27.6, 25.1, 24.0 ppm.
HRMS (ESI): m/z calcd. for C24H37NO3S2 [M + H+] 452.2293;
found 452.2291.
3-Boc-Protected 2,2-Dimethyl-4-{[2-(4-methoxyphenyl)-1,3-dithian-
2-yl]methyl}oxazolidine (3d): Column chromatography (petroleum
ether/EtOAc, 96:4); clear oil (1.11 g, 85%). IR (thin film): ν = 2978,
˜
1695, 1387, 1251 cm–1. 1H NMR (CDCl3, 500 MHz): δ (mixture of
rotamers) = 7.82 (m, 2 H), 6.88 (m, 2 H), 4.16 (m, 1 H), 3.8 (s, 3
H), 3.45 (m, 1 H), 2.9–2.8 (m, 1 H), 2.7–2.5 (m, 4 H), 2.3–2.1 (m,
2 H), 1.9 (m, 2 H), 1.45 (br. s, 15 H) ppm. 13C NMR (CDCl3,
125 MHz): δ (mixture of rotamers) = 158.7, 151.5, 132.7, 130.3,
114.2, 92.5, 93.1, 80.4, 80.3, 67.3, 55.3, 54.2, 53.9, 48.1, 47.2, 28.8,
28.4, 27.6, 25.0 ppm. HRMS (ESI): m/z calcd. for C22H33NO4S2
[M + H+] 440.1929; found 440.1922.
HPLC Analysis of Amino Acid Derivatives: The γ-oxo amino acid
6h was prepared from l and dl-serine separately and HPLC analy-
ses of the products were performed with a normal-phase chiral col-
umn. The racemic product resolved into two different peaks with
tR = 9.8 and 16.8 min. The d-isomer prepared from l-serine gave
a single peak (tR = 9.8 min) in the chromatogram and there was
no peak corresponding to the other isomer, confirming the reten-
tion of the configuration throughout the synthetic sequence. Chiral
HPLC was performed on two other products 6a and 6d, and both
yielded peaks corresponding to a single enantiomer. The chromato-
grams are provided in the Supporting Information.
3-Boc-Protected 2,2-Dimethyl-4-{[2-(3,4-dimethoxyphenyl)-1,3-di-
thian-2-yl]methyl}oxazolidine (3e): Column chromatography (petro-
leum ether/EtOAc, 95:5); clear oil (1.08 g, 77%). IR (thin film): ν
˜
= 2931, 1695, 1387, 1026 cm–1. 1H NMR (CDCl3, 500 MHz): δ
(mixture of rotamers) = 7.48 (m, 2 H), 6.84 (m, 1 H), 4.15–4.01
(m, 1 H), 3.87 (s, 6 H), 3.47 (m, 1 H), 2.99–2.52 (m, 6 H), 2.17–
2.09 (m, 1 H), 1.91 (m, 2 H), 1.49, 1.33 (2ϫ br. s, 15 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ (mixture of rotamers) = 151.5, 149.3,
149.2, 148.2, 133.6, 133.5, 121.6, 121.2, 112.1, 111.8, 111.2, 111.1,
111.0, 93.0, 92.6, 80.4, 80.1, 67.4, 57.0, 57.2, 56.1, 55.9, 54.3, 54.0,
48.1, 47.2, 29.7, 28.8, 28.5, 27.7, 25.0 ppm. HRMS (ESI): m/z calcd.
for C23H35NO5S2 [M + Na+] 492.1854; found 492.1856.
Umpolung Reaction of Iodide 1 with Dithianes 2. General Procedure:
Aromatic dithiane 1 (5 mmol) was dissolved in anhydrous THF
(10 mL) and cooled to –20 °C, and nBuLi (5.5 mmol, 3.4 mL, 1.6 m
in hexane) was added dropwise. The reaction mixture became
orange (indicating the formation of the anion) and was stirred for
40 min at –20 °C. Iodide 1 (3 mmol) in THF (3 mL) was added
over a period of 15 min and stirring was continued. The reaction
was monitored by TLC until complete disappearance of the iodide
was observed (1 to 1.5 h). The reaction was quenched with a satu-
rated solution of NH4Cl (10 mL) and extracted with EtOAc (3ϫ
50 mL). The organic layers were pooled, dried with anhydrous
Na2SO4, and the solvent was removed under vacuum. The crude
product 3 was purified by column chromatography.
3-Boc-Protected 2,2-Dimethyl-4-{[2-(4-fluorophenyl)-1,3-dithian-2-
yl]methyl}oxazolidine (3f): Column chromatography (petroleum
ether/EtOAc, 98:2); solid (0.99 g, 77%); m.p. 104–106 °C. IR
(KBr): ν = 2980, 2936, 1689, 1385 cm–1. 1H NMR (CDCl3,
˜
500 MHz): δ (mixture of rotamers) = 7.89 (m, 2 H), 7.03 (m, 2 H),
4.13–3.99 (m, 1 H), 3.49–3.33 (m, 1 H), 3.08–2.93 (m, 1 H), 2.72–
2.05 (m, 6 H), 1.90 (m, 2 H), 1.40 (br. s, 15 H) ppm. 13C NMR
3-Boc-Protected 2,2-Dimethyl-4-[(2-phenyl-1,3-dithian-2-yl)methyl]-
oxazolidine (3a): Column chromatography (petroleum ether/
EtOAc, 98:2); white solid (1.07 g, 87%); m.p. 112–114 °C. IR (CDCl3, 125 MHz): δ (mixture of rotamers) = 162.9, 160.4, 151.4,
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S. Chacko, R. Ramapanicker
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137.6, 130.7, 115.7, 93.2, 92.5, 80.3, 80.0, 67.5, 57.5, 56.7, 54.2,
53.9, 48.2, 47.4, 31.0, 28.8, 27.5, 24.9 ppm. HRMS (ESI): m/z calcd.
for C21H30FNO3S2 [M + H+] 428.1729; found 428.1721.
(s, 6 H), 1.22 (m, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
152.2,138.7, 129.4, 128.3, 126.6, 93.7, 79.4, 66.8, 57.7, 35.3, 33.8,
32.4, 29.8, 28.5, 24.0 ppm. HRMS (ESI): m/z calcd. for C21H33NO3
[M + H+] 348.2539; found 348.2535.
3-Boc-Protected 2,2-Dimethyl-4-({[2-(3-chlorophenyl)-1,3-dithian-2-
3-Boc-Protected 2,2-Dimethyl-4-(4-methoxyphenethyl)oxazolidine
yl]methyl}methyl)oxazolidine (3g): Column chromatography (petro-
(7d): Column chromatography (petroleum ether/EtOAc, 96:4); clear
leum ether/EtOAc, 98:2); solid (1.00 g, 76%); m.p. 113–115 °C. IR
oil (273 mg, 83%). IR (thin film): ν = 2978, 2934, 1696, 1389 cm–1.
1
(KBr): ν = 2919, 1690, 1386 cm–1. H NMR (CDCl , 500 MHz): δ
˜
˜
3
1H NMR (CDCl3, 500 MHz): δ = 7.09 (m, 2 H), 6.81 (m, 2 H),
3.94–3.76 (m, 6 H), 2.53 (m, 2 H), 2.10–1.72 (m, 2 H), 1.45 (br. s,
15 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 157.8, 152.1, 151.7,
133.4, 129.2, 113.9, 93.7, 93.1, 80.0, 79.4, 66.8, 57.6, 57.0, 55.3,
35.5, 34.8, 31.9, 28.5 ppm. HRMS (ESI): m/z calcd. for C19H29NO4
[M + Na+] 358.1994; found 358.1998.
(mixture of rotamers) = 7.97–7.85 (m, 3 H), 7.32 (m, 1 H), 4.20–
4.02 (m, 1 H), 3.63–3.40 (m, 2 H), 3.18–2.97 (m, 1 H), 2.70–2.44
(m, 5 H), 1.92 (m, 2 H), 1.40 (br. s, 15 H) ppm. 13C NMR (CDCl3,
125 MHz): δ (mixture of rotamers) = 151.5, 143.9, 134.9, 130.1,
128.9, 127.6, 126.9, 93.2, 92.7, 80.6, 79.9, 67.7, 66.5, 57.2, 56.8,
54.0, 31.0, 28.8, 28.5, 27.6, 24.7 ppm. HRMS (ESI): m/z calcd. for
C21H30ClNO3S2 [M + Na+] 466.1253; found 466.1253.
3-Boc-Protected 2,2-Dimethyl-4-(3,4-dimethoxyphenethyl)oxazolid-
ine (7e): Column chromatography (petroleum ether/EtOAc, 95:5);
3-Boc-Protected 2,2-Dimethyl-4-{[2-(thiophen-2-yl)-1,3-dithian-2-
yl]methyl}oxazolidine (3h): Column chromatography (petroleum
ether/EtOAc, 98:2); orange solid (0.95 g, 76%); m.p. 138–140 °C.
clear oil (277 mg, 76%). IR (thin film): ν = 2927, 1693, 1515,
˜
1
1029 cm–1. H NMR (CDCl3, 500 MHz): δ = 6.72 (m, 3 H), 3.86
IR (KBr): ν = 3068, 1694, 1385 cm–1. 1H NMR (CDCl , 500 MHz):
(s, 3 H), 3.83 (s, 3 H), 3.92–3.76 (m, 3 H), 2.55 (m, 2 H), 1.85 (m,
2 H), 1.47 (s, 9 H), 1.42 (s, 6 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 156.5, 148.9, 147.3, 134.1, 120.2, 111.7, 111.3, 93.7,
79.7, 65.9, 57.9, 55.9, 55.8, 33.5, 32.4, 31.0, 28.4 ppm. HRMS
(ESI): m/z calcd. for C20H31NO5 [M + Na+] 388.2100; found
388.2101.
˜
3
δ (mixture of rotamers) = 7.23 (m, 2 H), 6.96 (m, 1 H), 4.25–4.09
(m, 1 H), 3.55 (m, 1 H), 2.94–2.6 (m, 5 H), 2.55–2.35 (m, 1 H),
2.18 (m, 1 H), 1.94 (m, 2 H), 1.48 (br. s, 15 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ (mixture of rotamers) = 151.5, 149.7, 128.3,
127.7, 127.3, 93.2, 92.6, 80.5, 80.1, 67.3, 54.0, 53.4, 48.8, 48.4, 28.8,
28.5, 28.0, 24.8 ppm. HRMS (ESI): m/z calcd. for C19H29NO3S3
[M + H+] 416.1388; found 416.1385.
3-Boc-Protected 2,2-Dimethyl-4-(4-fluorophenethyl)oxazolidine (7f):
Column chromatography (petroleum ether/EtOAc, 96:4); clear oil
(255 mg, 79%). IR (thin film): ν = 2979, 1696, 1510, 1389 cm–1. 1H
Reduction of Dithianes 3a–h. Typical Procedure:[14] To a stirred
solution of dithiane 3 (1 mmol) in MeOH/THF (8:2, 10 mL),
NiCl2·6H2O (1.66 g, 7 mmol) was added at 0 °C and the mixture
was vigorously stirred for 5 min; NaBH4 (0.76 g, 20 mmol) was
added to this mixture in small portions over a period of 5 min. The
temperature was allowed to come to room temp. (30 °C) and the
progress of the reaction was monitored by TLC. On complete dis-
appearance of the starting material, the reaction was quenched by
the addition of saturated NaHCO3 (10 mL) and the crude product
was extracted with dichloromethane (3ϫ 15 mL). The crude solu-
tion containing the product was dried by passing through a bed of
anhydrous Na2SO4 and the oxazolidine derivatives 7 were further
purified by column chromatography.
˜
NMR (CDCl3, 500 MHz): δ = 7.12 (m, 2 H), 6.95 (m, 2 H), 3.9–
3.74 (m, 3 H), 2.58 (m, 2 H), 2.09–1.70 (m, 2 H), 1.47, 1.42 (2ϫ
br. s, 15 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 162.4, 160.3,
152.3, 151.6, 137.2, 129.7, 115.2, 93.8, 93.3, 79.9, 79.7, 66.6, 57.4,
56.8, 35.4, 34.8, 31.9, 28.0 ppm. HRMS (ESI): m/z calcd. for
C18H26FNO3 [M + Na+] 346.1794; found 346.1796.
3-Boc-Protected
2,2-Dimethyl-4-(3-chlorophenethyl)oxazolidine
(7g): Column chromatography (petroleum ether/EtOAc, 96:4); clear
oil (278 mg, 82%). IR (thin film): ν = 2979, 1696, 1389 cm–1. 1H
˜
NMR (CDCl3, 500 MHz): δ = 7.15 (m, 4 H), 3.92–3.76 (m, 3 H),
2.59 (m, 2 H), 1.94 (m, 2 H), 1.41 (br. s, 15 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 156.4, 143.6, 134.4, 129.8, 128.5, 126.6,
126.2, 93.3, 79.7, 66.7, 57.5, 35.0, 32.4, 31.0, 28.5 ppm. HRMS
(ESI): m/z calcd. for C18H26ClNO3 [M + Na+] 362.1499; found
362.1499.
Acidolysis of the Oxazolidine Rings in 3 and 7; Typical Procedure:[8c]
Oxazolidinone 3 or 7 (2 mmol) was cooled to 0 °C and a solution
of trifluoroacetic acid (7%) in methanol (5 mL) was added drop-
wise. The reaction was monitored by TLC until complete disap-
pearance of the starting material was observed, and was then neu-
tralized with NaHCO3 (1 g). The solution was filtered and the fil-
trate was concentrated under vacuum. Crude N-protected amino
alcohols 4 and 8 were purified by column chromatography.
3-Boc-Protected 2,2-Dimethyl-4-phenethyloxazolidine (7a): Column
chromatography (petroleum ether/EtOAc, 98:2); white solid
(250 mg, 82%); m.p. 125–128 °C. IR (KBr): ν = 2977, 1691,
˜
1
1388 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.21 (m, 5 H), 3.94–
3.72 (m, 3 H), 2.62 (m, 2 H), 2.16–1.81 (m, 2 H), 1.43 (s, 9 H), 1.3
(s, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 151.7, 141.7,
128.5, 125.9, 93.7, 80.1, 66.8, 57.6, 35.3, 34.7, 32.8, 27.6 ppm.
HRMS (ESI): m/z calcd. for C18H27NO3 [M + Na+] 328.1889;
found 328.1884.
3-Boc-Protected
2,2-Dimethyl-4-(4-methylphenethyl)oxazolidine
(7b): Column chromatography (petroleum ether/EtOAc, 98:2);
white solid (255 mg, 80%); m.p. 123–124 °C. IR (thin film): ν =
˜
2-(tert-Butyloxycarbonylamino)-3-(2-phenyl-1,3-dithian-2-yl)propan-
1-ol (4a): Column chromatography (petroleum ether/EtOAc, 4:1);
2977, 1698, 1388 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.081 (m,
4 H), 3.84 (m, 3 H), 2.56 (m, 2 H), 2.30 (s, 3 H), 1.95 (m, 2 H),
1.47 (s, 9 H), 1.25 (s, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 152.2, 138.6, 135.5, 129.2, 128.3, 93.7, 79.5, 66.8, 35.5, 31.9, 29.7,
28.5, 21.0 ppm. HRMS (ESI): m/z calcd. for C19H29NO3 [M + Na+]
342.204; found 342.2047.
colorless oil (627 mg, 85%). IR (thin film): ν = 3375, 2975, 1693,
˜
1
1170 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.90 (d, J = 7.7 Hz,
2 H), 7.37 (d, J = 7.7 Hz, 2 H), 7.25 (d, J = 7.3 Hz, 1 H), 3.61 (m,
1 H), 3.41 (d, J = 3.72 Hz, 1 H), 2.70 (m, 4 H), 2.26 (m, 2 H), 1.92
(m, 2 H), 1.36 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
155.8, 141.3, 129.0, 128.9, 128.5, 128.4, 127.4, 76.6, 66.4, 57.2, 49.8,
46.0, 28.45, 27.7, 24.0 ppm. HRMS (ESI): m/z calcd. for
C18H27NO3S2 [M + H+] 370.1511; found 370.1510.
3-Boc-Protected 2,2-Dimethyl-4-(4-isopropylphenethyl)oxazolidine
(7c): Column chromatography (petroleum ether/EtOAc, 98:2); clear
oil (288 mg, 83%). IR (thin film): ν = 2960, 2870, 1699, 1388 cm–1.
˜
1H NMR (CDCl3, 500 MHz): δ = 7.12 (m, 4 H), 3.93–3.76 (m, 3
2-(tert-Butyloxycarbonylamino)-4-phenylbutan-1-ol (8a): Column
H), 2.88 (m, 1 H), 2.56 (m, 2 H), 1.98 (m, 2 H), 1.47 (s, 9 H), 1.25
chromatography (petroleum ether/EtOAc, 8:2); white solid
7124
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7120–7128

γ-Oxo γ-Aryl and γ-Aryl α-Amino Acids
(493 mg, 93%); m.p. 78–80 °C. IR (KBr): ν = 3374, 1686,
oil (519 mg, 88%). IR (thin film): ν = 3361, 2926, 1685, 1247 cm–1.
˜
˜
1
1516 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.27 (m, 2 H), 7.18 1H NMR (CDCl3, 500 MHz): δ = 7.08 (m, 2 H), 6.81 (m, 2 H),
(m, 3 H), 4.69 (br., 1 H), 3.66 (m, 2 H), 3.56 (m, 1 H), 2.68 (m, 2 4.72 (br. s, 1 H), 3.76 (s, 3 H), 3.64 (m, 2 H), 3.54 (m, 1 H), 2.618
H), 1.78 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): (m, 2 H), 1.73 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3,
δ = 156.5, 141.5, 128.5, 128.3, 126.1, 79.7, 65.9, 52.5, 33.3, 32.4,
28.4 ppm. HRMS (ESI): m/z calcd. for C15H23NO3 [M + Na+]
288.1576; found 288.1574.
125 MHz): δ = 157.8, 156.6, 133.5, 129.2, 113.9, 79.8, 65.9, 55.3,
52.3, 33.5, 31.4, 28.4 ppm. HRMS (ESI): m/z calcd. for C16H25NO4
[M + Na+] 318.1681; found 318.1684.
2-(tert-Butyloxycarbonylamino)-3-(2-p-tolyl-1,3-dithian-2-yl)- 2-Boc-amino-3-[2-(3,4-dimethoxyphenyl)-1,3-dithian-2-yl]propan-1-
propan-1-ol (4b): Column chromatography (petroleum ether/ ol (4e): Column chromatography (petroleum ether/EtOAc, 6:4);
EtOAc, 4:1); colorless oil (636 mg, 83%). IR (thin film): ν = 3360, white solid (746 mg, 87%); m.p. 85–87 °C. IR (KBr): ν = 3380,
˜
˜
1
2981, 1690, 1160 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.76 (d, 2932, 1691, 1510 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.46 (dd,
J = 8.4 Hz, 2 H), 7.17 (d, J = 8.3 Hz, 2 H), 3.61 (m, 1 H), 3.41 J1 = 9.1, J2 = 2.45 Hz, 1 H), 7.44 (d, J = 2.45 Hz, 1 H), 6.85 (d, J
(dd, J1 = 11.02, J2 = 3.5 Hz, 1 H), 3.36 (dd, J1 = 10.87, J2 = 5.0 Hz,
= 9.0 Hz, 1 H), 4.39 (br., 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.64 (m,
1 H), 2.70 (m, 4 H), 2.33 (s, 3 H), 2.25 (m, 2 H), 1.92 (m, 2 H), 1.3
1 H), 3.41 (dd, J1 = 11.6, J2 = 4.2 Hz, 1 H), 3.37 (dd, J1 = 11.1, J2
(s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 155.5, 138.1, = 5.1 Hz, 1 H), 2.70 (m, 4 H), 2.23 (m, 2 H), 1.93 (m, 2 H), 1.35
137.0, 129.6, 128.4, 79.5, 66.4, 57.0, 49.8, 45.8, 28.4, 27.7, 27.5,
25.0, 21.0 ppm. HRMS (ESI): m/z calcd. for C19H29NO3S2 [M +
Na+] 406.1487; found 406.1485.
(s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 155.9, 149.0,
148.1, 133.4, 121.1, 111.7, 110.9, 79.6, 66.6, 57.2, 56.0, 55.8, 49.8,
46.1, 28.3, 27.8, 27.6, 25.0 ppm. HRMS (ESI): m/z calcd. for
C20H31NO5S2 [M + Na+] 452.154; found 452.1548.
2-(tert-Butyloxycarbonylamino)-4-p-tolylbutan-1-ol (8b): Column
chromatography (petroleum ether/EtOAc, 8:2); white solid 2-(tert-Butyloxycarbonylamino)-4-(3,4-dimethoxyphenyl)butan-1-ol
(430 mg, 77%); m.p. 80–82 °C. IR (thin film): ν = 3383, 2925, 1688, (8e): Column chromatography (petroleum ether/EtOAc, 7:3); clear
1170 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.06 (m, 4 H), 4.7 oil (565 mg, 87%). IR (thin film): ν = 3360, 2927, 1687, 1516 cm–1.
˜
˜
(br., 1 H), 3.64 (m, 2 H), 3.54 (m, 1 H), 2.63 (m, 2 H), 2.30 (s, 3
1H NMR (CDCl3, 500 MHz): δ = 6.74 (m, 3 H), 3.85 (s, 3 H), 3.83
H), 1.75 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): (s, 3 H), 3.67 (m, 2 H), 3.54 (m, 1 H), 2.61 (m, 2 H), 1.75 (m, 2
δ = 156.6, 138.4, 129.2, 128.3, 79.7, 66.0, 52.6, 33.4, 32.2, 28.4,
21.0 ppm. HRMS (ESI): m/z calcd. for C16H25NO3 [M + H+]
280.1913; found 280.1918.
H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 156.3,
148.08, 147.1, 133.9, 120.1, 111.7, 79.7, 66.0, 56.0, 55.9, 52.4, 33.5,
32.0, 28.4 ppm. HRMS (ESI): m/z calcd. for C17H27NO5 [M + Na+]
348.1787; found 348.1780.
2-(tert-Butyloxycarbonylamino)-3-[2-(4-isopropylphenyl)-1,3-di-
thian-2-yl]propan-1-ol (4c): Column chromatography (petroleum
2-(tert-Butyloxycarbonylamino)-3-[2-(4-fluorophenyl)-1,3-dithian-
2-yl]propan-1-ol (4f): Column chromatography (petroleum ether/
EtOAc, 7.5:2.5); white solid (619 mg, 80%); m.p. 88–90 °C. IR
ether/EtOAc, 4:1); solid (700 mg, 85%); m.p. 96–98 °C. IR (KBr):
1
ν = 3395, 2960, 1691, 1170 cm–1. H NMR (CDCl , 400 MHz): δ
˜
3
= 7.72 (d, J = 8.2 Hz, 2 H), 7.16 (d, J = 8.2 Hz, 2 H), 4.40 (m, 1
(KBr): ν = 3412, 3270, 1675, 1157 cm–1 1H NMR (CDCl3,
.
˜
H), 3.32 (m, 2 H), 2.84 (m, 1 H), 2.6 (m, 4 H), 2.1 (m, 2 H), 1.87
500 MHz): δ = 7.88 (m, 2 H), 7.04 (m, 2 H), 4.37 (br. s, 1 H), 3.63
(m, 2 H), 1.3 (s, 9 H), 1.18 (d, J = 11.6 Hz, 6 H) ppm. 13C NMR (m, 1 H), 3.43 (dd, J1 = 11.6, J2 = 4.2 Hz, 1 H), 3.38 (dd, J1
=
(CDCl3, 125 MHz): δ = 155.5, 147.9, 138.5, 128.4, 126.9, 79.6, 66.4,
57.0, 49.9, 45.6, 33.6, 28.4, 27.4, 27.6, 25.0, 24.0, 23.9 ppm. HRMS
(ESI): m/z calcd. for C21H33NO3S2 [M + H+] 412.1980; found
412.1987.
11.0, J2 = 5.1 Hz, 1 H), 2.68 (m, 4 H), 2.23 (m, 2 H), 1.93 (m, 2
H), 1.36 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 162.8,
160.9, 155.7, 137.0, 130.6, 130.6, 115.7, 115.5, 79.7, 66.5, 56.7, 49.5,
46.2, 28.7, 27.7, 24.8 ppm. HRMS (ESI): m/z calcd. for
C18H26FNO3S2 [M + Na+] 410.1234; found 410.1236.
2-(tert-Butyloxycarbonylamino)-4-(4-isopropylphenyl)butan-1-ol
(8c): Column chromatography (petroleum ether/EtOAc, 8:2); clear
2-(tert-Butyloxycarbonylamino)-4-(4-fluorophenyl)butan-1-ol (8f):
oil (497 mg, 81%). IR (thin film): ν = 3362, 2959, 2926, 1687 cm–1.
Column chromatography (petroleum ether/EtOAc, 7:3); clear oil
˜
1H NMR (CDCl3, 500 MHz): δ = 7.12 (m, 4 H), 3.67 (m, 2 H),
3.55 (m, 1 H), 2.85 (s, 1 H), 2.63 (m, 2 H), 1.77 (m, 2 H), 1.44 (s,
9 H), 1.22 (m, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 156.5,
146.6, 138.5, 128.2, 126.3, 79.6, 60.2, 52.5, 33.6, 33.3, 31.9, 28.3,
24.1 ppm. HRMS (ESI): m/z calcd. for C18H29NO3 [M + Na+]
330.2045; found 330.2046.
(537 mg, 95%). IR (thin film): ν = 3357, 1687, 1510, 1169 cm–1. 1H
˜
NMR (CDCl3, 500 MHz): δ = 7.10 (m, 2 H), 6.93 (m, 2 H), 4.86
(br. s, 1 H), 3.60 (m, 2 H), 3.51 (m, 1 H), 2.62 (m, 2 H), 1.72 (m,
2 H), 1.42 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 162.3,
160.4, 156.5, 137.2, 129.8, 115.3, 79.7, 65.5, 52.3, 33.5, 31.6,
28.4 ppm. HRMS (ESI): m/z calcd. for C15H22FNO3 [M + Na+]
306.1481; found 306.1479.
2-(tert-Butyloxycarbonylamino)-3-[2-(4-methoxyphenyl)-1,3-di-
thian-2-yl]propan-1-ol (4d): Column chromatography (petroleum
2-(tert-Butyloxycarbonylamino)-3-[2-(3-chlorophenyl)-1,3-dithian-
ether/EtOAc, 4:1); colorless oil (678 mg, 85%). IR (thin film): ν = 2-yl]propan-1-ol (4g): Column chromatography (petroleum ether/
˜
3382, 2932, 1691, 1510 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
7.75 (d, J = 9.05 Hz, 2 H), 6.84 (d, J = 9.05 Hz, 2 H), 3.76 (s, 3
H), 3.57 (m, 1 H), 3.37 (dd, J1 = 22, J2 = 4.3 Hz, 1 H), 3.31 (dd,
J1 = 22.9, J2 = 5.0 Hz, 1 H), 2.65 (m, 4 H), 2.24 (dd, J1 = 14.6, J2
EtOAc, 7.5:2.5); colorless oil (693 mg, 86%). IR (thin film): ν =
˜
3399, 2976, 1808, 1689, 1368 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 7.92 (s, 1 H), 7.81 (d, J = 6 Hz, 1 H), 7.31 (m, 1 H), 7.24 (m,
1 H), 4.49 (br. s, 1 H), 3.64 (m, 1 H), 3.4 (m, 2 H), 2.66 (m, 4 H),
= 4.0 Hz, 1 H), 2.17 (dd, J1 = 15.0, J2 = 4.0 Hz, 1 H), 1.87 (m, 2 2.33 (m, 2 H), 1.93 (m, 2 H), 1.37 (s, 9 H) ppm. 13C NMR (CDCl3,
H), 1.32 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 158.6,
155.9, 132.9, 129.8, 114.1, 79.6, 66.5, 56.8, 55.4, 49.8, 46.05, 28.4,
27.7, 27.5, 25.0 ppm. HRMS (ESI): m/z calcd. for C19H29NO4S2
[M + Na+] 422.1436; found 422.1437.
125 MHz): δ = 155.7, 143.9, 134.8, 130.1, 128.9, 127.6, 127.0, 79.7,
66.6, 56.8, 49.5, 46.1, 28.4, 27.8, 27.6, 24.7 ppm. HRMS (ESI): m/z
calcd. for C18H26ClNO3S2 [M + Na+]: 426.0945, found 426.0940.
2-(tert-Butyloxycarbonylamino)-4-(4-chlorophenyl)butan-1-ol (8g):
2-(tert-Butyloxycarbonylamino)-4-(4-methoxyphenyl)butan-1-ol Column chromatography (petroleum ether/EtOAc, 75:25); clear oil
(8d): Column chromatography (petroleum ether/EtOAc, 8:2); clear
(568 mg, 95%). IR (thin film): ν = 3346, 2976, 1686, 1170 cm–1. 1H
˜
Eur. J. Org. Chem. 2012, 7120–7128
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7125

S. Chacko, R. Ramapanicker
FULL PAPER
NMR (CDCl3, 500 MHz): δ = 7.16 (m, 4 H), 3.64 (m, 2 H), 3.55 28.4, 28.3, 24.0, 23.7 ppm. HRMS (ESI): m/z calcd. for C18H27NO4
(m, 1 H), 2.65 (m, 2 H), 1.77 (m, 2 H), 1.43 (s, 9 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 156.3, 143.6, 134.1, 129.7, 128.6,
126.7, 126.6, 79.8, 65.7, 52.3, 33.1, 32.1, 28.4 ppm. HRMS (ESI):
m/z calcd. for C15H22ClNO3 [M + Na+] 322.1186; found 322.1188.
[M + Na+] 344.1838; found 344.1831.
3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-(4-methoxyphenyl)-
butan-1-one (5d): Column chromatography (petroleum ether/
EtOAc, 4:1); white solid (550 mg, 89%); m.p. 64–66 °C. IR (KBr):
2-(tert-Butyloxycarbonylamino)-3-[2-(thiophen-2-yl)-1,3-dithian-2-yl- ν = 3356, 2982, 1681, 1171 cm–1. H NMR (CDCl , 500 MHz): δ
1
˜
3
]propan-1-ol (4h): Column chromatography (petroleum ether/
(equilibrium with cyclic hemiketal) = 7.96 (d, J = 8.9 Hz,2 H), 7.58
EtOAc, 7.5:2.5); orange solid (675 mg, 90%); m.p. 100–102 °C. IR (m, 1 H), 7.40–7.25 (m), 6.91–6.42 (m), 5.39 (br., 1 H), 4.10 (m, 1
(KBr): ν = 3357, 2964, 1695, 1115 cm–1 1H NMR (CDCl3, H), 3.85 (s, 3 H), 3.81 (s), 3.72 (d, J = 4.0 Hz, 2 H), 3.25 (m, 2 H),
.
˜
500 MHz): δ = 7.28 (m, 1 H), 7.24 (m, 1 H), 6.95 (m, 1 H), 4.55 1.43 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ (equilibrium
(m, 1 H), 3.73 (m, 1 H), 3.42–3.47 (m, 2 H), 2.93 (m, 1 H), 2.73 with cyclic hemiketal) = 197.9, 163.9, 159.0, 156.4, 154.0, 141.4,
(m, 1 H), 2.22 (m, 1 H), 2.00 (m, 1 H), 1.85 (m, 1 H), 1.39 (s, 9
130.7, 129.8, 125.3, 124.1, 114.1, 114.06, 113.9, 111.6, 103.45, 79.8,
64.6, 60.5, 55.6, 55.4, 49.8, 39.3, 28.4 ppm. HRMS (EI): m/z calcd.
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 155.9, 149.3, 128.6,
127.5, 127.1, 79.7, 66.6, 53.6, 49.7, 47.4, 28.5, 28.2, 27.9, for C16H23NO5 [M + Na+] 332.1474; found 332.1472.
24.71 ppm. HRMS (ESI): m/z calcd. for C16H25NO3S3 [M + Na+]
3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-(3,4-dimethoxyphen-
yl)butan-1-one (5e): Column chromatography (petroleum ether/
398.0894; found 398.0897.
Hydrolysis of the Dithiane in 4. General Procedure:[13] To a solution
of dithiane derivative 4 (2 mmol) in acetonitrile (5 mL), saturated
NaHCO3 (5 mL) was added and the mixture was cooled to 0 °C.
Iodine (2.0 g, 8 mmol, 4 equiv.) was added in small portions to the
above solution. The reaction mixture was stirred vigorously and
allowed to attain room temp. (30 °C). After 1 h, the reaction was
quenched by adding a saturated solution of Na2S2O3 (5 mL) and
the product was extracted with diethyl ether (3 ϫ 25 mL). The
crude ether solution of hydroxy ketone 5 was washed with brine,
dried with anhydrous Na2SO4, concentrated under vacuum, and
purified by column chromatography.
EtOAc, 1:1); clear oil (637 mg, 94%). IR (thin film): ν = 3379, 2974,
˜
1683, 1021 cm–1. 1H NMR (CDCl3, 500 MHz): δ (equilibrium with
cyclic hemiketal) = 7.62 (d, J = 8.25 Hz, 1 H), 7.51 (s, 1 H), 6.88
(d, J = 8.25 Hz, 1 H), 5.37 (br. s, 1 H), 4.08 (m, 1 H), 3.92 (s, 3
H), 3.91 (s, 3 H), 3.74 (d, J = 2.4 Hz, 2 H), 3.33 (m, 1 H), 3.20 (m,
1 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ (equilib-
rium with cyclic hemiketal) = 197.9, 156.1, 153.9, 153.7, 149.7,
148.5, 141.5, 129.9, 124.2, 123.2, 116.6, 111.7, 111.3, 110.1, 107.2,
103.7, 79.8, 64.5, 63.4, 56.2, 56.07, 56.02, 55.9, 49.9, 39.3, 29.7,
28.4, 28.3 ppm. HRMS (ESI): m/z calcd. for C17H25NO6 [M + Na+]
362.1580; found 362.1591.
3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-phenylbutan-1-one 3-(tert-Butyloxycarbonylamino)-1-(4-fluorophenyl)-4-hydroxy-
(5a): Column chromatography (petroleum ether/EtOAc, 3:1); white
butan-1-one (5f): Column chromatography (petroleum ether/
solid (519 mg, 93%); m.p. 78–80 °C. IR (thin film): ν = 3360, 1680,
EtOAc, 7:3); white solid (552 mg, 93%); m.p. 68–70 °C. IR (KBr):
˜
1
1580 cm–1. 1H NMR (CDCl3, 500 MHz): δ (equilibrium with cyclic
hemiketal) = 7.96 (d, J = 9.15 Hz, 2 H), 7.65 (m, 1 H), 7.56 (t, J
= 7.4 Hz, 2 H), 7.36 (t, J = 7.4 Hz, 2 H), 7.34 (m, 1 H), 6.63 (m,
1 H), 5.38 (br. s, 1 H), 4.10 (m, 1 H), 3.74 (d, J = 4.6 Hz, 2 H),
ν = 3359, 2967, 1685, 1529 cm–1. H NMR (CDCl , 500 MHz): δ
˜
3
(equilibrium with cyclic hemiketal) = 8.00 (m, 2 H), 7.12 (m, 2 H),
5.33 (br. s, 1 H), 4.09 (m, 1 H), 3.75 (d, J = 4.3 Hz, 2 H), 3.34 (d,
J = 14.4 Hz, 1 H), 3.23 (dd, J1 = 16.5, J2 = 6.0 Hz, 1 H), 1.40 (s,
3.30 (m, 2 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ (equilibrium with cyclic
(equilibrium with cyclic hemiketal) = 199.3, 156.5, 142.1, 136.1,
133.5, 130.9, 128.7, 128.7, 128.3, 127.4, 111.7, 105.2, 79.8, 64.5,
49.6, 39.6, 28.4, 28.3 ppm. HRMS (ESI): m/z calcd. for C15H21NO4
[M + Na+] 302.1368; found 302.1365.
hemiketal) = 197.7, 167.09, 165.0, 156.1, 142.1, 133.2, 131.1,
131.04, 125.6, 125.5, 116.0, 115.8, 115.6, 111.7, 104.7, 79.9, 64.4,
49.6, 39.5, 28.4, 28.3 ppm. HRMS (ESI): m/z calcd. for
C15H20FNO4 [M + Na+] 320.1274; found 320.1274.
3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-p-tolylbutan-1-one 3-(tert-Butyloxycarbonylamino)-1-(3-chlorophenyl)butan-4-hydroxy-
(5b): Column chromatography (petroleum ether/EtOAc, 3:1); white 1-one (5g): Column chromatography (petroleum ether/EtOAc, 7:3);
solid (551 mg, 94%); m.p. 60–64 °C. IR (KBr): ν = 3365, 1685,
white solid (557 mg, 89%); m.p. 78–80 °C. IR (KBr): ν = 3359,
˜
˜
1578 cm–1. 1H NMR (CDCl3, 500 MHz): δ (equilibrium with cyclic
hemiketal) = 7.83 (d, J = 8.05 Hz, 2 H), 7.54 (d, J = 8.3 Hz, 2 H),
7.42 (m), 7.24 (d, J = 8.3 Hz, 2 H), 6.57 (d, J = 3.4 Hz, 1 H), 6.43
(m), 4.11 (m, 1 H), 3.73 (d, J = 4.3 Hz), 3.26 (m, 2 H), 2.39 (s, 3
3063, 1687, 1529 cm–1. 1H NMR (CDCl3, 500 MHz): δ (equilib-
rium with cyclic hemiketal) = 7.92 (m, 1 H), 7.84 (m, 1 H), 7.63 (1
H), 7.52 (m, 2 H), 7.46 (m, 1 H), 7.40 (m, 2 H), 7.25 (m, 2 H), 6.6
(m, 1 H), 6.46 (m, 1 H), 4.11 (m, 1 H), 3.75 (d, J = 4.0 Hz, 2 H),
H), 2.34 (s, 3 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): 3.26 (m, 2 H), 1.43 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
δ (equilibrium with cyclic hemiketal) = 199.0, 156.5, 154.2, 144.5,
141.7, 137.2, 134.3, 129.5, 129.46, 129.4, 128.2, 116.1, 104.2, 79.8,
64.5, 49.7, 39.5, 28.4, 28.3, 21.7, 21 ppm. HRMS (ESI): m/z calcd.
for C16H23NO4 [M + Na+] 316.1525; found 316.1523.
(equilibrium with cyclic hemiketal) = 197.9, 156.4, 152.5, 142.6,
138.2, 135.1, 134.6, 133.4, 130.1, 129.9, 128.3, 127.2, 126.4, 123.8,
121.8, 111.9, 106.1, 79.8, 64.4, 49.49, 39.7, 28.4, 28.29 ppm. HRMS
(ESI): m/z calcd. for C15H20ClNO4 [M + Na+] 336.0979; found
336.0970.
3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-(4-isopropylphenyl)-
butan-1-one (5c): Column chromatography (petroleum ether/
3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-(thiophen-2-yl)butan-
1-one (5h): Column chromatography (petroleum ether/EtOAc,
EtOAc, 7:3); white solid (571 mg, 89%); m.p. 60–62 °C. IR (KBr):
1
ν = 3374, 2964, 1683, 1170 cm–1. H NMR (CDCl , 500 MHz): δ
7.5:2.5); white solid (518 mg, 91%); m.p. 66–68 °C. IR (KBr): ν
˜
˜
3
(equilibrium with cyclic hemiketal) = 7.90 (d, J = 8 Hz, 2 H), 7.58
(d, J = 7.7 Hz, 2 H), 7.43 (m, 1 H), 7.32 (m, 1 H), 7.23 (m, 1 H),
= 3361, 1680, 1643, 1525 cm–1. 1H NMR (CDCl3, 500 MHz): δ
(equilibrium with cyclic hemiketal) = 7.79 (m, 1 H), 7.65 (d, J =
6.70 (m, 1 H), 6.58 (m, 2 H), 6.44 (m, 1 H), 5.38 (br., 1 H), 4.5 (m, 4.8 Hz, 1 H), 7.38–7.02 (m), 6.48–6.42 (m), 5.3 (br. s, 1 H), 4.09
1 H), 3.75 (m, 1 H), 3.750 (m, 1 H), 3.28 (m, 1 H), 2.9 (m, 1
H) ppm. 13C NMR (CDCl3, 125 MHz): δ (equilibrium with cyclic
hemiketal) = 199.1, 156.5, 155.2, 154.2, 148.2, 141.7,134.6, 128.6,
(m, 1 H), 3.74 (m, 2 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ (equilibrium with cyclic hemiketal) = 192.2, 156.0,
144.1, 141.6, 135.1, 134.6, 133.4, 133.2, 128.5, 127.6, 124.1, 122.6,
127.0, 127, 126.9, 126.8, 123.9, 116.6, 79.8, 64.6, 49.7, 34.3, 33.3, 111.7, 105.0, 79.8, 64.4, 62.6, 49.9, 49.2, 40.4, 38.6, 28.4, 28.3 ppm.
7126
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7120–7128

γ-Oxo γ-Aryl and γ-Aryl α-Amino Acids
HRMS (ESI): m/z calcd. for C13H19NO4S [M + Na+] 308.09324;
found 308.0940.
2-(tert-Butyloxycarbonylamino)-4-(4-isopropylphenyl)butanoic Acid
(9c): Column chromatography (petroleum ether/EtOAc, 6:4); clear
oil (565 mg, 88%). [α]D = –8.66 (c = 1.07, CHCl3). IR (thin film):
Oxidation of the Primary Alcohols 5 and 8; General Procedure:[8c]
The N-protected amino alcohol 5 or 8 (2 mmol) was dissolved in
anhydrous DMF (20 mL) and pyridinium dichromate (7.5 g,
20 mmol, 10 equiv.) was added at room temp. (30 °C). The reaction
mixture was stirred for 15 h then quenched with water (10 mL).
The carboxylic acids were extracted from the crude solution with
diethyl ether (3ϫ 25 mL); the ether solutions were pooled together
and washed with brine (2ϫ 25 mL), dried with anhydrous Na2SO4,
and concentrated under reduced pressure. The crude products 6 or
9 were purified by column chromatography.
1
ν = 3344, 2959, 1703, 1020 cm–1. H NMR (CDCl , 500 MHz): δ
˜
3
= 7.13 (m, 4 H), 5.11 (br. s, 1 H), 4.26 (m, 1 H), 2.87 (m, 1 H),
2.69 (m, 2 H), 2.68 (m, 2 H), 1.45 (s, 9 H), 1.23 (m, 6 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 177.1, 155.7, 146.7, 138.0, 128.4,
126.3, 80.3, 53.3, 37.2, 33.8, 32.0, 29.8, 24.1 ppm. HRMS (ESI):
m/z calcd. for C18H27NO4 [M + Na+] 344.1838; found 344.1839.
2-(tert-Butyloxycarbonylamino)-4-(4-methoxyphenyl)-4-oxobutanoic
Acid (6d): Column chromatography (petroleum ether/EtOAc, 4:1);
colorless oil (517 mg, 80%). [α]D = –45.76 (c = 0.740, CHCl3). IR
(thin film): ν = 3381, 2925, 1712, 1675, 1169 cm–1 1H NMR
.
˜
2-(tert-Butyloxycarbonylamino)-4-oxo-4-phenylbutanoic Acid (6a):
Column chromatography (petroleum ether/EtOAc, 1:1); clear oil
(CDCl3, 500 MHz): δ = 7.90 (d, J = 8.9 Hz, 2 H), 6.91 (d, J =
8.8 Hz, 2 H), 5.69 (br. s, 1 H), 4.69 (m, 1 H), 3.85 (s, 3 H), 3.69
(dd, J1 = 17.8, J2 = 4.4 Hz, 1 H), 3.46 (dd, J1 = 18.3, J2 = 3.0 Hz,
1 H), 1.45 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 196.6,
176.2, 164.1, 155.8, 130.7, 129.1, 113.9, 80.3, 55.6, 49.5, 40.5,
28.0 ppm. HRMS (ESI): m/z calcd. for C16H21NO6 [M + Na+]
346.1267; found 346.1263.
(492 mg, 84%). [α]D = –39.29 (c = 0.780, CHCl ). IR (thin film): ν
˜
3
= 3357, 2978, 1687, 1164 cm–1. H NMR (CDCl3, 500 MHz): δ =
1
7.95 (d, J = 7.4 Hz, 2 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.45 (t, J =
7.7 Hz, 2 H), 5.68 (br. s, 1 H), 4.72 (m, 1 H), 3.74 (dd, J1 = 18.1,
J2 = 3.8 Hz, 1 H), 3.41 (d, J = 3.72 Hz, 1 H), 3.53 (dd, J1 = 18.0,
J2 = 4.0 Hz, 1 H), 1.4 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 198.0, 176.3, 155.8, 136.0, 133.8, 128.8, 128.3, 80.3, 60.5, 49.5,
40.5, 28.3 ppm. HRMS (ESI): m/z calcd. for C15H19NO5 [M + Na+]
316.1161; found 316.1161.
2-(tert-Butyloxycarbonylamino)-4-(4-methoxyphenyl)butanoic Acid
(9d): Column chromatography (petroleum ether/EtOAc, 6:4); clear
oil (544 mg, 88%). [α]D = –8.92 (c = 0.291, CHCl3). IR (thin film):
1
ν = 3330, 2926, 1714, 1513 cm–1. H NMR (CDCl , 500 MHz): δ
˜
3
2-(tert-Butyloxycarbonylamino)-4-phenylbutanoic Acid (9a): Col-
umn chromatography (petroleum ether/EtOAc, 6:4); clear oil
= 7.09 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 5.08 (br. s,
1 H), 4.23 (m, 1 H), 3.76 (s, 3 H), 2.04 (m, 2 H), 1.43 (s, 9 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 176.9, 158.0, 155.5, 132.7, 129.4,
113.8, 80.1, 55.2, 52.9, 34.0, 30.9, 28.1 ppm. HRMS (ESI): m/z
calcd. for C16H23NO5 [M + Na+] 332.1474; found 332.1473.
(519 mg, 93%). [α]D = –7.06 (c = 1.41, CHCl ). IR (thin film): ν =
˜
3
3327, 3028, 1716, 1166 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
7.26 (m, 2 H), 7.18 (m, 3 H), 5.10 (br. s, 1 H), 4.26 (m, 1 H), 2.70
(m, 2 H), 1.99 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 176.7, 155.2, 140.1, 128.5, 128.5, 125.9, 80.1, 53.0,
34.0, 31.7, 28.3 ppm. HRMS (ESI): m/z calcd. for C15H21NO4 [M
+ H+] 280.1549; found 280.1549.
2-(tert-Butyloxycarbonylamino)-4-(3,4-dimethoxyphenyl)-4-oxo-
butanoic Acid (6e): Column chromatography (petroleum ether/
EtOAc, 4:6); colorless oil (593 mg, 84%). [α]D = –86.1 (c = 0.770,
CHCl ). IR (thin film): ν = 3385, 1710, 1650, 1165 cm–1. 1H NMR
˜
3
2-(tert-Butyloxycarbonylamino)-4-oxo-4-p-tolylbutanoic Acid (6b):
Column chromatography (petroleum ether/EtOAc, 1:1); clear oil
(CDCl3, 500 MHz): δ = 7.52–7.44 (m, 2 H), 6.84 (m, 1 H), 5.75
(br. s, 1 H), 4.64 (m, 1 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.65 (d, J =
15.2 Hz, 1 H), 3.49 (d, J = 15.3 Hz, 1 H), 5.65 (br. s, 1 H), 1.37 (s,
9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 196.9, 176.5, 155.8,
153.8, 149.0, 129.3, 123, 114.1, 110.0, 80.1, 56.1, 55.9, 50.0, 40.6,
28.7 ppm. HRMS (ESI): m/z calcd. for C17H23NO7 [M + Na+]
376.137; found 376.1372.
(522 mg, 85%). [α]D = –81.44 (c = 0.920, CHCl ). IR (thin film): ν
˜
3
= 3360, 2985, 1690, 1160 cm–1. H NMR (CDCl3, 500 MHz): δ =
1
7.82 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 5.69 (br. s, 1
H), 4.69 (m, 1 H), 3.7 (dd, J1 = 18.0, J2 = 3.7 Hz, 1 H), 3.49 (dd,
J1 = 18.0, J2 = 3.7 Hz, 1 H), 2.38 (s, 3 H), 1.40 (s, 9 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 197.6, 176.1, 155.8, 144.7, 133.6,
129.4, 128.4, 80.3, 49.5, 40.8, 28.3, 21.1 ppm. HRMS (ESI): m/z
calcd. for C16H21NO5 [M + Na+] 330.1317; found 330.1312.
2-(tert-Butyloxycarbonylamino)-4-(3,4-dimethoxyphenyl)butanoic
Acid (9e): Column chromatography (petroleum ether/EtOAc, 7:3);
clear oil (542 mg, 80%). [α]D = –25.4 (c = 0.328, CHCl3). IR (thin
film): ν = 3346, 2932, 1714, 1516, 1159 cm–1. 1H NMR (CDCl3,
˜
2-(tert-Butyloxycarbonylamino)-4-p-tolylbutanoic Acid (9b): Col-
500 MHz): δ = 6.73 (m, 3 H), 5.06 (br. s, 1 H), 4.24 (m, 1 H), 3.84
(s, 3 H), 3.83 (s, 3 H), 2.65 (m, 2 H), 2.05 (m, 2 H), 1.44 (s, 9
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 177.1, 155.7, 148.5,
umn chromatography (petroleum ether/EtOAc, 6:4); clear oil
(545 mg, 93%). [α]D = –7.88 (c = 1.01, CHCl ). IR (thin film): ν =
˜
3
3333, 2924, 1716, 1167 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
7.07 (m, 4 H), 5.12 (br. s, 1 H), 4.24 (m, 1 H), 2.66 (m, 2 H), 2.3
(s, 3 H), 2.06 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 177.0, 155.7, 137.7, 135.6, 129.2, 128.3, 80.3, 53.3,
34.3, 31.2, 28.3, 21.0 ppm. HRMS (ESI): m/z calcd. for C16H23NO4
[M + Na+] 316.1525; found 316.1524.
146.8, 133.1, 120.3, 111.8, 111.2, 80.3, 55.9, 55.8, 53.1, 34.3, 31.3,
+
28.3 ppm. HRMS (ESI): m/z calcd. for C17H25NO6 [M + NH4
]
357.2026; found 357.2029.
2-(tert-Butyloxycarbonylamino)-4-(4-fluorophenyl)-4-oxobutanoic
Acid (6f): Column chromatography (petroleum ether/EtOAc, 1:1);
colorless oil (588 mg, 88%). [α]D = –44.8 (c = 0.71, CHCl3). IR
2-(tert-Butyloxycarbonylamino)-4-(4-isopropylphenyl)-4-oxo-
butanoic Acid (6c): Column chromatography (petroleum ether/
EtOAc, 1:1); colorless oil (529 mg, 79%). [α]D = –45.3 (c = 0.302,
(thin film): ν = 3357, 1686, 1158 cm–1 1H NMR (CDCl3,
.
˜
500 MHz): δ = 7.95 (m, 2 H), 7.10 (m, 2 H), 5.69 (br. s, 1 H), 4.70
(m, 1 H), 3.70 (m, 1 H), 3.45 (m, 1 H), 1.39 (s, 9 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 196.4, 176.1, 165.1, 155.8, 132.5,
131.09, 131.01, 116.02, 115.8, 80.4, 65.9, 49.5, 40.8, 28.3 ppm.
HRMS (ESI): m/z calcd. for C15H18FNO5 [M + Na+] 334.1067;
found 334.1060.
CHCl ). IR (thin film): ν = 3416, 2963, 1682, 1164 cm–1. 1H NMR
˜
3
(CDCl3, 400 MHz): δ = 7.80 (d, J = 8.3 Hz, 2 H), 7.21 (d, J =
7.84 Hz, 2 H), 5.65 (br., 1 H), 4.63 (m, 1 H), 3.66 (m, 1 H), 3.46
(m, 1 H), 2.86 (m, 1 H), 1.34 (s, 9 H), 1.17 (d, J = 6.8 Hz, 6 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 197.6, 176.2, 155.8, 133.9, 128.6,
126.8, 80.2, 60.6, 49.5, 40.8, 34.38, 27.4, 22.77 ppm. HRMS (ESI):
m/z calcd. for C18H25NO5 [M + Na+] 358.1633; found: 358.1633.
2-(tert-Butyloxycarbonylamino)-4-(4-fluorophenyl)butanoic Acid
(9f): Column chromatography (petroleum ether/EtOAc, 70:30);
Eur. J. Org. Chem. 2012, 7120–7128
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7127

S. Chacko, R. Ramapanicker
FULL PAPER
clear oil (421 mg, 71%). [α]D = –11.42 (c = 1.3, CHCl3). IR (thin
Acknowledgments
film): ν = 3321, 1715, 1510, 1160 cm–1 1H NMR (CDCl3,
.
˜
500 MHz): δ = 7.12 (m, 2 H), 6.92 (m, 2 H), 5.12 (br. s, 1 H), 4.33–
4.12 (m, 1 H), 2.67 (m, 2 H), 2.04 (m, 2 H), 1.44 (s, 9 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 177.07, 162.4, 160.5, 155.7, 136.3,
129.9, 115.4, 80.4, 53.1, 34.2, 30.9, 28.3 ppm. HRMS (ESI): m/z
calcd. for C15H20FNO4 [M + Na+] 320.1274; found 320.1274.
The authors thank IIT Kanpur for financial support (IITK/CHM/
20100070). S. C. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for a Junior Research Fellowship.
[1] B. J. Bhuyan, G. Mugesh, Curr. Sci. 2011, 101, 881–887.
[2] a) D. W. Cushman, M. A. Ondetti, Nat. Med. 1999, 5, 1110–
1112; b) A. A. Patchett, E. Harris, E. W. Tristram, M. J.
Wyvratt, M. T. Wu, D. Taub, E. R. Peterson, T. J. Ikeler, J.
ten Broeke, L. G. Payne, D. L. Ondeyka, E. D. Thorsett, W. J.
Greenlee, N. S. Lohr, R. D. Hoffsommer, H. Joshua, W. V. Ru-
yle, J. W. Rothrock, S. D. Aster, A. L. Maycock, F. M. Robin-
son, R. Hirschmann, Nature 1980, 288, 280–283.
[3] O. Hayaishi, R. Y. Stanier, J. Bacteriol. 1951, 62, 691–709.
[4] A. F. Zahoor, U. Kazmaier, Synthesis 2011, 3020–3026.
[5] F. Berree, K. Chang, A. Cobas, H. Rapoport, J. Org. Chem.
1996, 61, 715–721.
[6] Y. Xie, R. Lou, Z. Li, A. Mi, Y. Jiang, Tetrahedron: Asymmetry
2000, 11, 1487–1494.
[7] M. Yamada, N. Nagashima, J. Hasegawa, S. Takahashi, Tetra-
hedron Lett. 1998, 39, 9019–9022.
[8] a) M. Suhartono, A. E. Schneider, G. Durner, M. W. Gobel,
Synthesis 2010, 293–303; b) W. Barfoot, J. E. Harvey, M. N.
Kenworthy, J. P. Kilburn, M. Ahmed, R. J. K. Taylor, Tetrahe-
dron 2005, 61, 3403–3417; c) P. N. Collier, A. D. Campbell, I.
Patel, T. M. Raynham, R. J. K. Taylor, J. Org. Chem. 2002, 67,
1802–1815; d) M. Sabat, C. R. Johnson, Org. Lett. 2000, 2,
1089–1092.
2-(tert-Butyloxycarbonylamino)-4-(3-chlorophenyl)-4-oxobutanoic
Acid (6g): Column chromatography (petroleum ether/EtOAc, 1:1);
colorless oil (549 mg, 84%). [α]D = –42.2 (c = 0.90, CHCl3). IR
(thin film): ν = 3373, 2977, 1692, 1164 cm–1. 1H NMR (CDCl3,
˜
500 MHz): δ = 7.89 (s, 1 H), 7.8 (d, J = 7.15 Hz, 1 H), 7.52 (d, J
= 7.45 Hz, 1 H), 7.39 (t, J1 = 7.7, J2 = 7.7 Hz, 1 H), 5.67 (br. s, 1
H), 4.72 (m, 1 H), 3.69 (dd, J1 = 17.4 Hz, J2 = 3.4 Hz, 1 H), 3.53
(dd, J = 17.5 Hz, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 196.7, 176.2, 155.7, 137.4, 135.1, 133.7, 130.1, 128.3,
126.3, 80.0, 57.0, 49.3, 41.1, 28.0 ppm. HRMS (ESI): m/z calcd. for
C15H18ClNO5 [M + H+] 328.0959; found 328.0952.
2-(tert-Butyloxycarbonylamino)-4-(3-chlorophenyl)butanoic Acid
(9g): Column chromatography (petroleum ether/EtOAc, 75:25);
clear oil (526 mg, 84%). [α]D = –12.87 (c = 0.466, CHCl3). IR (thin
film): ν = 3346, 2976, 1686, 1170 cm–1 1H NMR (CDCl3,
.
˜
500 MHz): δ = 7.12 (m, 4 H), 5.12 (br. s, 1 H), 4.25 (m, 1 H), 2.69
(m, 2 H), 2.07 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 156.3, 143.6, 134.1, 129.7, 128.6, 126.6, 126.7, 79.8,
65.7, 52.3, 33.1, 32.1, 28.4 ppm. HRMS (ESI): m/z calcd. for
C15H20ClNO4 [M + Na+] 336.097; found 336.0979.
[9] C. Jiang, D. J. Covell, A. F. Stepan, M. S. Plummer, M. C.
White, Org. Lett. 2012, 14, 1386–1389.
2-(tert-Butyloxycarbonylamino)-4-oxo-4-(thiophen-2-yl)butanoic
Acid (6h): Column chromatography (petroleum ether/EtOAc, 1:1);
colorless oil (526 mg, 88%). [α]D = –44.07 (c = 0.720, CHCl3). IR
[10] A. S. Golubev, N. Sewald, K. Burger, Tetrahedron 1996, 52,
14757–14776.
(thin film): ν = 3373, 1707, 1659, 1415, 1163 cm–1 1H NMR
.
˜
[11] A. Ollivier, M. Goubert, A. Tursun, I. Canet, M.-E. Sinibaldi,
ARKIVOC 2010, 9, 108–126.
[12] H. Firouzabadi, N. Iranpoor, H. Hazarkhani, J. Org. Chem.
2001, 66, 7527–7529.
[13] Followed a previously described procedure, see: M. J. Gaunt,
A. S. Jessiman, P. Orsini, H. R. Tanner, D. F. Hook, S. V. Ley,
Org. Lett. 2003, 5, 4819–4822.
[14] J. M. Khurana, D. Magoo, Synth. Commun. 2010, 40, 2908–
2913.
(CDCl3, 500 MHz): δ = 7.73 (m, 1 H), 7.62 (m, 1 H), 7.09 (m, 1
H), 5.7 (br. s, 1 H), 4.65 (m, 1 H), 3.63 (d, J = 16.6 Hz, 1 H),
3.47 (d, J = 17.2 Hz, 1 H), 1.38 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 190.0, 176.0, 155.7, 143.0, 134.4, 133.0, 128.3, 80.2,
67.9, 49.6, 41.2, 28.3 ppm. HRMS (ESI): m/z calcd. for
C13H17NO5S [M + Na+] 322.0725; found 322.0723.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra and chiral HPLC chroma-
tograms.
Received: August 19, 2012
Published Online: November 2, 2012
7128
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Eur. J. Org. Chem. 2012, 7120–7128