Synthesis of bis-α-amino acids through proline catalyzed asymmetric α-amination of higher homologs of Garner's aldehyde

Article abstract of DOI:10.1016/j.tet.2014.10.048

A very convenient synthesis of bis-α-amino acids from the higher homologs of Garner's aldehyde is reported. The key step is proline catalyzed asymmetric amination of the aldehydes using dibenzylazodicarboxylate. The aldehydes used are either commercially available or can easily be prepared from aspartic or glutamic acid. One of the two chiral centers in the bis-amino acids comes from the aldehyde and the other one is generated through the proline catalyzed reaction, which were high yielding and proceeded with very high diastereoselectivity (93-99%). The reported route offers a general method for the synthesis of the title compounds with desired stereochemical outcome.

Full text of DOI:10.1016/j.tet.2014.10.048

Tetrahedron 70 (2014) 9554e9563
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of bis-
a-amino acids through proline catalyzed
asymmetric
a
-amination of higher homologs of Garner’s aldehyde
*
Ramu Petakamsetty, Ram Pada Das, Ramesh Ramapanicker
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very convenient synthesis of bis-a-amino acids from the higher homologs of Garner’s aldehyde is
Received 1 September 2014
Received in revised form 6 October 2014
Accepted 22 October 2014
Available online 29 October 2014
reported. The key step is proline catalyzed asymmetric amination of the aldehydes using dibenzylazo-
dicarboxylate. The aldehydes used are either commercially available or can easily be prepared from
aspartic or glutamic acid. One of the two chiral centers in the bis-amino acids comes from the aldehyde
and the other one is generated through the proline catalyzed reaction, which were high yielding and
proceeded with very high diastereoselectivity (93e99%). The reported route offers a general method for
the synthesis of the title compounds with desired stereochemical outcome.
Keywords:
Unusual amino acids
Organocatalysis
Ó 2014 Elsevier Ltd. All rights reserved.
Asymmetric amination
Proline catalyzed reaction
1. Introduction
cystine and has been used as a structural replacement for cystine in
biologically active peptides.2
Bis-
a
-amino acids, 1 are involved in a number of very vital
The importance of these molecules has resulted in a number of
reports dealing with their synthesis. Synthetic strategies based on
olefin metathesis and metal mediated cross coupling reactions of
chiral precursors predominate the available syntheses of these
molecules.3 Procedures based on stereoselective and stereospecific
transformations are also available.4 Most of these procedures are
limited to the synthesis of 1a and/or 1b or their specific lower
analogs and general methods available for the synthesis of 1 of any
length are limited. Very recently, Soloshonok et al. have reported
functions in various microorganisms (Fig. 1) and two of the most
commonly discussed examples are diaminopimelic acid (1a) and
diaminosuberic acid (1b). Compound 1a plays an important role in
bacterial biosynthesis of L-lysine and provides structural stability to
the peptidoglycan units of bacterial cell walls by functioning as
cross-linking units between polysaccharides.1 The absence of a 1a
based biosynthetic pathway in mammals has spurred an interest in
the synthesis and study of 1a and related analogs. Compound 1b on
the other hand, has received attention for its structural similarity to
a general procedure for the synthesis of bis-a-amino acids through
bis-alkylation of 2 equiv of a glycine equivalent using suitable
dihalogenated reagents.5 We report here an easy and efficient
procedure for the synthesis of 1 with various chain lengths from the
higher homologs, 2 of Garner’s aldehyde through proline catalyzed
asymmetric a
-amination (Scheme 1).6 The strategy reported here is
based on using a starting material with one of the stereo centers
fixed and generating the second one using an asymmetric func-
tionalization. The current method provides the opportunity to
generate two different diastereomers of the target compounds
from the same aldehyde using
(Scheme 1).
L or D-proline as the catalyst
Fig. 1. Bis-a-amino acids.
2. Results and discussion
The methodology is based on the assumption that aldehydes 2
are ideal starting materials for the synthesis of 1 through proline
* Corresponding author. Tel.: þ91 512 2596684; fax: þ91 512 259 7436; e-mail
address: rameshr@iitk.ac.in (R. Ramapanicker).
catalyzed asymmetric a
-hydrazination6,7 followed by reduction to
http://dx.doi.org/10.1016/j.tet.2014.10.048
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
9555
Scheme 1. Synthesis of bis-a-amino acids through asymmetric amination of aldehydes, 2.
get asymmetric
a
-amino alcohols, which in turn can be converted
yielded the other diastereomer, 30 with equally high selectivity
(Table 1), which was expected from similar reports available in the
literature.10 However, the reaction of 2a, with dibenzylazodi-
to the title compounds. The required starting materials, 2 are
commercially available or can easily be synthesized from aspartic or
glutamic acid (Scheme 2).8 The derivatives 2a and 2b are prepared
carboxylate in the presence of
ceeded without any diastereoselectivity. We assume that the
presence of an adjacent chiral center to the -CH2 and steric factors
D-proline was very slow and pro-
directly from L-aspartic and L-glutamic acids. A chain extension of
2a and 2b through Wittig reaction followed by reduction gives the
aldehydes 2c and 2d, respectively. Homologating 2c further as
above yielded the aldehyde 2e.
a
resulting from it could have resulted in the differential reaction of
2a. A similar difference in reactivity of an oxygenated analog of 2a
Scheme 2. Synthesis of the aldehydes 2.
Asymmetric electrophilic
explored strategy for the synthesis of
the proline catalyzed
a
-amination of aldehydes is a widely
in L- and D-proline catalyzed amination reactions were earlier re-
a
-amino acids in general and
ported by Greck et al.10b The reactions proceeded smoothly and the
isolated products were the major isomers in each case and were
obtained in very high yields. The presence of a number of diaster-
eotopic groups, a flexible oxazolidine ring and the possibility of
having rotamers resulting from the geometry of the Boc group in 3
and 30 yielded very complex 1H and 13C NMR spectra for them at
room temperature. The 1H NMR spectra of these compounds
recorded at 90 ꢀC in DMSO-d6 were simpler and easy to interpret.
The hydrazine derivatives 3 and 30 were reduced with Raney-Ni/
H2 (CH3OH/CH3CO2H, 30 ꢀC, 16 h) to get the 2-amino alcohol de-
rivatives, which were treated with (Boc)2O and were isolated as the
N-Boc derivatives 4 and 40 in excellent yields (Table 2). Oxidation of
the primary alcohol group to the carboxylic acid, followed by
a
-functionalization of aldehydes using dialkyl
azodicarboxylates is a particularly effective method,6,7,9 which we
presumed could yield us the targeted compounds. Accordingly, 2
was treated with dibenzylazodicarboxylate (1 equiv) in the pres-
ence of L
-proline (10 mol %, 0e30 ꢀC, CH3CN, 3 h) followed imme-
diately with reduction of the aldehyde function to the primary
alcohol (NaBH4, C2H5OH) to get the hydrazine derivatives 3 in very
high yields and diastereoselectivity (Table 1). The diastereomeric
ratio of these compounds was estimated using chiral HPLC and was
established by comparing the chromatograms with that of a 1:1
mixture of the diastereomers obtained through reactions catalyzed
by DL-proline. Using D-proline instead of the L-isomer as a catalyst

9556
R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
Table 1
Asymmetric a-hydrazination of 2
Entry
Aldehyde 2
Catalyst
Yielda (%)
3(S,R)/30(S,S)b
1
2
3
4
5
6
7
8
9
n¼0, 2a
n¼1, 2b
n¼1, 2b
n¼2, 2c
n¼2, 2c
n¼3, 2d
n¼3, 2d
n¼4, 2e
n¼4, 2e
L
-Proline
-Proline
91
93
94
95
95
97
95
96
97
96:4
97:3
3:97
99:1
4:96
98:2
6:94
93:7
3:97
L
D
-Proline
-Proline
-Proline
-Proline
-Proline
-Proline
L
D
L
D
L
D
-Proline
a
Isolated yield.
Estimated from chiral HPLC.
b
Table 2
Synthesis of the amino esters 5 and 50
No
Hydrazine derivative
N-Boc amino alcohol (% yield)a
Amino ester (% yield)a
1
2
3
4
5
6
7
8
9
3a
3b
3b0
3c
4a (85)
4b (86)
4b0 (86)
4c (87)
4c0 (88)
4d (88)
4d0 (87)
4e (88)
4e0 (85)
5a (82)
5b (85)
5b0 (85)
5c (83)
5c0 (84)
5d (84)
5d0 (85)
5e (80)
5e0 (81)
3c0
3d
3d0
3e
3e0
a
Isolated yield.
esterification using diazomethane yielded the
a
-amino esters 5 and
oxazolidine group with TFA (7% in CH3OH) provided the dia-
minohydroxy esters 6 and 60 in high yields (Table 3). Oxidation of
the primary hydroxyl group in 6 and 60, followed by the esterifi-
cation of the carboxylic acid group with diazomethane yielded the
50 in very good yields (Table 2). Our initial attempts were to hy-
drolyze the oxazolidine group in 4, and to oxidize both the primary
hydroxy groups together using Jones’ reagent. Although the start-
ing materials were consumed, the reactions yielded very polar
mixtures and the diaminodicarboxylic acids could not be isolated.
The amino esters 5 and 50 bearing an oxazolidine group were
converted to the target molecules in two steps. Acidolysis of the
targeted bis-a-amino acids 1 as their N-Boc protected methyl ester
derivatives 7 and 70 (Table 3). However, the reaction did not pro-
ceed as expected for 5a, acidolysis of this derivative gave the dia-
mino lactone 8 (Scheme 3).

R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
9557
Table 3
Synthesis of the bis-a
-amino esters 7 and 70
No
Amino ester
Diaminohydroxy ester (% yield)a
Bis-a
-amino esters (% yield)a
1
2
3
4
5
6
7
8
5b
5b0
5c
6b (90)
6b0 (89)
6c (90)
6c0 (88)
6d (91)
6d0 (92)
6e (93)
6e0 (94)
7b (86)
7b0 (86)
7c (85)
7c0 (84)
7d (86)
7d0 (85)
7e (86)
7e0 (87)
5c0
5d
5d0
5e
5e0
a
Isolated yield.
The stereochemical outcomes of the reactions were confirmed
from the X-ray crystal structure of 7c (Fig. 2).11 All the meso de-
rivatives, 7 synthesized using
L-proline were optically inactive as
expected. The asymmetric -hydrazination of 2 should be following
a
a very ordered transition state similar to the one proposed by List
and Jorgensen.6 The orientation of the carboxylic acid function of
proline decides the outcome of the reaction and thus the stereo-
chemistry of the products. While
L
-proline prefers the attack on the
re-face, the reaction using
D
-proline proceeds on the si-face.6
3. Conclusions
In conclusion, we have achieved a very efficient synthesis of
a,
a
0-diaminodiacids in their protected forms starting from aspartic
or glutamic acids using organocatalytic asymmetric a-amination as
the key step. The method is very general and can be applied for the
synthesis of both diastereomers of the diaminodiacids, by choosing
the suitable isomer of proline as the catalyst. The strategy can be
Scheme 3. Cyclization of 5a to the diamino lactone 8.
Fig. 2. X-ray crystal structure of 7c.11

9558
R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
used for making diaminodiacids of any length, which is a definite
advantage.
(br s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.58 (br s, 1H), 1.92 (br s, 1H), 3.37
(br s, 1H), 3.42 (br s, 1H), 3.67e3.68 (m, 1H), 3.79e3.89 (m, 1H), 4.08
(m, 1H), 4.23 (br s, 1H), 5.08 (s, 4H), 7.30 (s, 10H), 8.91 (br s,
4. Experimental section
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d¼27.2, 27.8, 28.4, 54.5,
54.7, 61.8, 66.7, 67.1, 67.3, 67.7, 79.4, 93.2, 93.4, 127.6, 128.0, 128.2,
128.5, 128.8, 128.9, 136.8, 151.7, 156.0 ppm; HRMS (ESI-TOF) m/z:
[MþNa]þ calcd for C29H39N3NaO8 580.2635; found: 580.2634.
4.1. General experimental methods
All the commercially available reagents were used directly
without any further purification. All the reactions were carried out
under inert atmosphere unless otherwise mentioned. Acetonitrile
was distilled out initially from phosphorus pentoxide and sub-
sequently from calcium hydride; dichloromethane was distilled out
from calcium hydride. Yields reported are for compounds purified
using column chromatography. All the reactions were monitored by
analytical thin layer chromatography carried out on 0.25 mm Merck
silica gel plates (60F-254) using UV light as a visualizing agent and
ninhydrin as a staining agent. Merck silica gel (particle size 60e120
and 100e200 mesh) was used for column chromatography. All
proton NMR spectra were recorded at either 400 or 500 MHz using
a Jeol spectrometer and 13C NMR spectra were run at 100 or
125 MHz. 1H NMR splitting pattern was designated as singlet (s),
doublet (d), doublet of doublet (dd), triplet (t) and multiplet (m),
broad singlet (br s). IR spectra were recorded as neat for liquids and
as KBr pellets for solids. High-resolution mass spectra were ob-
tained using a Waters Q/Tof Premier micromass HAB 213 spec-
trometer with an ESI source. Optical rotation was measured using
4.2.3. Dibenzyl 1-((S)-1-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-3-hydroxypropan-2-yl)hydrazine-1,2-
dicarboxylate 3b0. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
25
(1.05 g, 94%); [
a]
þ25.0 (c 0.2, CHCl3); IR nmax (thin film): 3469,
D
3258,1718,1693 cmꢂ1; 1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d¼1.36
(br s, 3H), 1.38 (s, 9H), 1.42 (s, 3H), 1.66 (br s, 1H), 1.76 (br s, 1H),
3.38e3.48 (m, 2H), 3.73 (br s, 1H), 3.81e3.83 (m, 1H), 4.01 (br s, 1H),
4.25 (br s, 1H), 5.08 (s, 4H), 7.27e7.30 (m, 10H), 9.09 (br s, 1H) ppm;
13C NMR (DMSO-d63, 125 MHz):
d¼27.1, 28.0, 28.5, 55.6, 58.5, 60.9,
66.7, 66.9, 67.1, 67.3, 67.7, 79.4, 93.1, 127.7, 127.9, 128.2, 128.3, 128.5,
128.8, 128.9, 136.8, 151.3, 155.7, 157.0, ppm; HRMS (ESI-TOF) m/z:
[MþNa]þ calcd for C29H39N3NaO8 580.2635; found 580.2634.
4.2.4. Dibenzyl 1-((R)-4-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-1-hydroxybutan-2-yl)hydrazine-1,2-
dicarboxylate 3c. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
25
(1.09 g, 95%); [
a
]
ꢂ8.0 (c 0.2, CHCl3); IR nmax (thin film): 3471,
D
3261, 1719, 1698 cmꢂ1
¼1.34e1.44 (m, 15H), 1.46e1.63 (m, 4H), 3.28e3.33 (m, 1H),
3.40e3.44 (m, 1H), 3.66 (br s, 1H), 3.79e3.82 (m, 1H), 4.03e4.05 (m,
1H), 4.20 (br s,1H), 5.08 (s, 4H), 7.28 (s,10H), 9.10 (br s,1H) ppm; 13
NMR (DMSO-d6, 125 MHz):
57.6, 60.0, 60.9, 61.7, 61.9, 66.3, 66.6, 66.9, 67.1, 67.3, 67.6, 79.1, 79.5,
92.9, 93.1, 127.5, 127.6, 127.8, 128.2, 128.4, 128.5, 128.8, 128.9, 136.6,
136.9,151.6,151.8,156.1,156.3,157.2,158.5 ppm; HRMS (ESI-TOF) m/
z: [MþNa]þ calcd for C31H43N3O8 594.2791; found 594.2795.
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
6.0 mL cell with a 10 dm path length and are reported as [
a
]
25 (c in
d
D
g per 100 mL solvent). The diastereoselectivity was determined by
chiral HPLC analysis using Daicel chiralpack IA-3 column with
254 nm UV detector and by using a mixture of isopropanol and n-
hexane as eluant at 25 ꢀC.
C
d
¼23.6, 25.0, 25.4, 27.1, 27.9, 28.5, 57.4,
4.2. General procedure for the asymmetric
aldehydes
a-hydrazination of
The aldehyde, 2 (2 mmol,1 equiv) in dry acetonitrile (15 mL) was
4.2.5. Dibenzyl 1-((S)-4-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-1-hydroxybutan-2-yl)hydrazine-1,2-
treated with dibenzylazodicarboxylate (0.59 g, 2 mmol, 1 equiv)
and proline (either
D
or
L
, 0.02 g, 10 mol %) at 0 ꢀC. The mixture was
dicarboxylate 3c0. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
25
stirred for 2 h and the temperature was raised to 20 ꢀC over a period
of 1 h. The mixture was stirred until the color changed from yellow
to colorless (1e2 h) and was cooled to 0 ꢀC and then treated with
sodium borohydride (0.05 g) in ethanol (15 mL). Then stirring was
continued for 5 min and the reaction was quenched with saturated
ammonium chloride solution (20 mL). Organic layer was extracted
with ethyl acetate (3ꢁ30 mL) and the combined organic phases
were dried over anhydrous Na2SO4, filtered, concentrated, and
purified by column chromatography using ethyl acetate and pe-
troleum ether of suitable composition.
(1.09 g, 95%); [
a
]
þ18.6 (c 0.22, CHCl3); IR nmax (thin film): 3471,
D
3261, 1719, 1698 cmꢂ1
¼1.38e1.46 (m, 15H), 1.50e1.73 (m, 4H), 3.32e3.37 (m, 1H),
3.40e3.45 (m, 1H), 3.62 (br s, 1H), 3.76e3.81 (m, 1H), 4.03e4.08 (m,
1H), 4.18 (br s,1H), 5.09 (s, 4H), 7.29 (s,10H), 9.01 (br s,1H) ppm; 13
NMR (DMSO-d6, 125 MHz):
27.7, 27.9, 28.5, 29.3, 29.5, 30.0, 30.8, 56.6, 56.8, 60.1, 60.5, 60.9, 61.1,
61.3, 61.6, 61.7, 66.6, 66.9, 67.2, 67.4, 67.6, 79.2, 79.5, 93.1, 93.3,127.6,
127.8, 128.2, 128.5, 128.8, 128.9, 136.6, 136.8, 151.8, 152.0, 156.1,
156.3, 157.1, 158.6 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
C
d
¼22.5, 23.4, 24.0, 24.5, 24.7, 26.8, 27.1,
C31H43N3O8 594.2791; found 594.2795.
4.2.1. Dibenzyl 1-((R)-1-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-2-hydroxyethyl)hydrazine-1,2-
dicarboxylate 3a. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
4.2.6. Dibenzyl 1-((R)-5-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-1-hydroxypentan-2-yl)hydrazine-1,2-
(0.97 g, 91%); [
a
]
25 ꢂ12.7 (c 2.83, CHCl3); IR nmax (thin film): 3469,
dicarboxylate 3d. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
D
3258, 1718, 1693 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
(1.13 g, 97%); [
a
]
ꢂ16.8 (c 0.28, CHCl3); IR nmax (thin film): 3463,
25
D
d
¼1.36e1.45 (m, 15H), 3.54e4.21 (m, 6H), 5.06e5.10 (m, 4H),
7.30e7.36 (m, 10H), 8.95 (br s, 1H) ppm; 13C NMR (DMSO-d6,
125 MHz):
3265, 1718, 1694 cmꢂ1 1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
;
d
¼1.12e1.22 (m, 2H), 1.34e1.51 (m, 15H), 1.43e1.51 (m, 4H), 3.28 (br
d
¼28.2, 28.4, 56.2, 59.8, 60.2, 64.8, 66.4, 67.1, 67.4, 67.7,
s, 1H), 3.35e3.39 (m, 2H), 3.64e3.82 (m, 2H), 4.05e4.18 (m, 2H),
79.7, 81.0, 93.8, 127.6, 127.9, 128.3, 128.7, 128.8, 128.9, 129.0, 136.5,
136.5, 137.0, 153.7, 155.9, 157.0, 157.1 ppm; HRMS (ESI-TOF) m/z:
[MþH]þ calcd for C28H38N3O8: 544.2659; found 544.2655.
5.07 (s, 4H), 7.29 (s, 10H), 9.02 (br s, 1H) ppm; 13C NMR (DMSO-d6,
90 ꢀC, 125 MHz):
d¼22.9, 28.3, 28.5, 28.7, 57.2, 57.5, 60.9, 66.9, 67.4,
79.3, 79.5, 93.1, 127.5, 127.9, 128.0, 128.2, 128.3, 128.4, 128.5, 128.6,
128.9, 129.0, 136.8, 137.0, 151.8, 156.3 ppm; HRMS (ESI-TOF) m/z:
[MþNa]þ calcd for C31H43N3O8 608.2498; found 608.2495.
4.2.2. Dibenzyl 1-((R)-1-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-3-hydroxypropan-2-yl)hydrazine-1,2-
dicarboxylate 3b. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
4.2.7. Dibenzyl-1-((S)-5-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-1-hydroxypentan-2-yl)hydrazine-1,2-
dicarboxylate3d0. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
25
(1.05 g, 93%); [
a
]
ꢂ13.1 (c 0.16, CHCl3); IR nmax (thin film): 3469,
D
3258,1718,1693 cmꢂ1; 1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d¼1.37

R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
9559
25
(1.16 g, 95%); [
a
]
þ11.9 (c 0.42, CHCl3); IR nmax (thin film): 3463,
28.5, 28.6, 54.3, 55.0, 57.5, 60.9, 61.8, 65.2, 65.3, 78.0, 78.2, 79.6,
79.6, 80.0, 93.4, 93.8,151.9,153.3,155.5,155.7 ppm; HRMS (ESI-TOF)
m/z: [MþH]þ calcd for C17H33N2O6 361.2339; found 361.2335.
D
3265, 1718, 1694 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.12e1.22 (m, 2H), 1.34e1.51 (m, 15H), 1.43e1.51 (m, 4H), 3.28 (br
s, 1H), 3.35e3.39 (m, 2H), 3.64e3.82 (m, 2H), 4.05e4.18 (m, 2H),
5.07 (s, 4H), 7.29 (s, 10H), 9.12 (br s, 1H) ppm; 13C NMR (DMSO-d6,
4.3.2. (S)-tert-Butyl 4-((R)-2-(tert-butoxycarbonylamino)-3-
90 ꢀC, 125 MHz):
d
¼22.9, 28.3, 28.5, 28.7, 57.2, 57.5, 60.9, 66.9, 67.4,
hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate 4b. Rf¼0.3
79.3, 79.5, 93.1, 127.5, 127.9, 128.0, 128.2, 128.3, 128.4, 128.5, 128.6,
128.9, 129.0, 136.8, 137.0, 151.8, 156.3 ppm; HRMS (ESI-TOF) m/z:
[MþNa]þ calcd for C31H43N3O8 608.2498; found 608.2495.
(petroleum ether/EtOAc, 3:2); oily liquid (0.64 g, 86%); [
a
;
]
25 ꢂ11.79
D
(c 0.195, CHCl3); IR nmax (thin film): 3355, 1695 cmꢂ1
1H NMR
(DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.35 (s, 9H), 1.37 (s, 3H), 1.39 (s, 9H),
1.44 (s, 3H), 1.47e1.61 (m, 2H), 3.23e3.33 (m, 3H), 3.62e3.64 (m,
1H), 3.72e3.74 (m, 1H), 3.84e3.87 (m, 1H), 4.18 (br s, 1H), 5.94 (br
4.2.8. Dibenzyl 1-((R)-6-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-1-hydroxyhexan-2-yl)hydrazine-1,2-
s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼23.5, 24.9, 27.1, 27.3,
dicarboxylate 3e. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
28.1, 28.5, 28.7, 28.7, 29.6, 30.5, 34.9, 36.8, 50.5, 55.1, 55.2, 57.2,
60.9, 61.1, 64.1, 64.2, 66.4, 66.9, 77.9, 78.0, 79.0, 79.1, 79.5, 92.9,
93.0, 93.1, 151.3, 151.4, 151.6, 151.7, 155.9, 157.0 ppm; HRMS (ESI-
TOF) m/z: [MþNa]þ calcd for C18H34N2NaO6 397.2315; found
397.2313.
25
(1.06 g, 96%); [
a
]
ꢂ4.2 (c 0.23, CHCl3); IR nmax (thin film): 3472,
D
3275, 1719, 1695 cmꢂ1 1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
;
d
¼1.14e1.25 (m, 4H),1.33e1.38 (m, 15H),1.44e1.56 (m, 4H), 3.28 (br
s, 1H), 3.37 (br s, 2H), 3.59e3.68 (m, 2H), 3.81e3.82 (m,
1H),4.02e4.05 (m, 1H), 5.07 (s, 4H), 7.30 (s, 10H), 9.03 (br s,
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d¼23.5, 24.9, 26.0, 27.1,
4.3.3. (S)-tert-Butyl 4-((S)-2-(tert-butoxycarbonylamino)-3-
28.0, 28.5, 32.6, 33.5, 57.1, 57.4, 59.4, 60.9, 61.6, 61.9, 66.4, 66.5, 66.8,
67.1, 67.3, 79.0, 79.5, 92.9, 93.1, 127.5, 127.7, 127.8, 128.1, 128.3, 128.4,
128.6, 128.8, 128.8, 128.9, 136.6, 136.9, 137.0, 151.5, 151.7, 156.2,
156.3, 157.0, 158.5 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate4b0. Rf¼0.3
(petroleum ether/EtOAc, 3:2); oily liquid (0.64 g, 86%); [
a
;
]
25 þ17.18
D
(c 0.19, CHCl3); IR nmax (thin film): 3355, 1695 cmꢂ1
1H NMR
(DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.37 (s, 9H), 1.39 (s, 3H), 1.41 (s, 9H),
C
32H46N3O8 600.3285; found 600.3281.
1.46 (s, 3H), 1.51e1.65 (m, 2H), 3.24e3.34 (m, 3H), 3.63e3.65 (m,
1H), 3.73e3.75 (m, 1H), 3.86e3.89 (m, 1H), 4.19 (br s, 1H), 5.95 (br s,
4.2.9. Dibenzyl 1-((S)-6-((S)-3-(tert-butoxycarbonyl)-2,2-
dimethyloxazolidin-4-yl)-1-hydroxyhexan-2-yl)hydrazine-1,2-
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d¼23.5, 24.9, 27.1, 27.3,
28.1, 28.5, 28.7, 28.7, 29.6, 30.5, 34.9, 36.8, 50.5, 55.1, 55.2, 57.2, 60.9,
61.1, 64.1, 64.2, 66.4, 66.9, 77.9, 78.0, 79.0, 79.1, 79.5, 92.9, 93.0, 93.1,
151.3, 151.4, 151.6, 151.7, 155.9, 157.0 ppm; HRMS (ESI-TOF) m/z:
[MþNa]þ calcd for C18H34N2NaO6 397.2315; found 397.2313.
dicarboxylate 3e0. Rf¼0.3 (petroleum ether/EtOAc, 7:3); oily liquid
25
(1.16 g, 97%); [
a
]
þ15.5 (c 0.45, CHCl3); IR nmax (thin film): 3463,
D
3273, 1716, 1694 cmꢂ1 1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
;
d
¼1.14e1.25 (m, 4H),1.38e1.39 (m, 15H),1.42e1.57 (m, 4H), 3.29 (br
s, 1H), 3.37e3.40 (br s, 1H), 3.59e3.70 (m, 2H), 3.82e3.85 (m,
1H),4.01e4.07 (m, 1H), 5.08 (s, 4H), 7.30 (s, 10H), 8.99 (br s,
4.3.4. (S)-tert-Butyl 4-((R)-3-(tert-butoxycarbonylamino)-4-
hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate
4c. Rf¼0.3
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d¼23.5, 24.9, 26.0, 27.1,
(petroleum ether/EtOAc, 3:2); oily liquid (0.85 g, 87%); [
a
]
25 ꢂ13.9
D
28.0, 28.5, 32.9, 33.6, 57.0, 57.1, 57.4, 59.5, 60.9, 61.6, 61.9, 66.4, 66.6,
67.0, 67.1, 67.3, 67.3, 79.0, 79.5, 79.7, 92.9, 93.1, 127.5, 127.8, 128.1,
128.3, 128.3, 128.4, 128.6, 128.8, 128.8, 128.9, 136.6, 136.9, 136.9,
137.0, 151.6, 151.6, 156.2, 156.3, 157.0, 157.1, 158.6 ppm; HRMS (ESI-
TOF) m/z: [MþNa]þ calcd for C32H46N3O8 622.3104; found
622.3109.
(c 0.23, CHCl3); IR nmax (thin film): 3355, 1695 cmꢂ1
;
1H NMR
(DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.36 (s, 9H), 1.37 (s, 3H), 1.40 (s, 9H),
1.44 (s, 3H), 1.43e1.65 (m, 4H), 3.25e3.34 (m, 3H), 3.64e3.66 (m,
1H), 3.70 (br s, 1H), 3.83e3.86 (m, 1H), 4.21 (br s, 1H), 6.00 (br s,
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼23.4, 24.8, 27.1, 28.0,
28.7, 28.7, 29.6, 30.2, 52.7, 52.9, 57.4, 57.6, 64.0, 64.2, 66.2, 66.8, 77.8,
79.0, 79.5, 92.8, 93.1, 151.6, 155.9 ppm; HRMS (ESI-TOF) m/z:
[MþNa]þ calcd for C19H36N2NaO6 411.2471; found 411.2473.
4.3. General procedure for the preparation of N-Boc protected
amino alcohols 4 from the corresponding hydrazino alcohols 3
4.3.5. (S)-tert-Butyl 4-((S)-3-(tert-butoxycarbonylamino)-4-
Freshly prepared Raney-nickel (around 0.80 g, pre-washed with
absolute ethanol) was added to the stirred solution of 3 (2 mmol) in
dry methanol (15 mL) followed with 40 drops of acetic acid. The
reaction mixture was hydrogenated at atmospheric pressure for
16 h at 30 ꢀC. After complete disappearance of starting material on
TLC, the reaction mixture was passed over Celite and concentrated.
The crude amines were protected as Boc derivatives using the fol-
lowing procedure, before purification.
hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate
4c0. Rf¼0.3
(petroleum ether/EtOAc, 3:2); oily liquid (0.85 g, 87%); [
a
]
25 þ12.12
D
(c 0.33, CHCl3); IR nmax (thin film): 3355, 1695 cmꢂ1
;
1H NMR
(DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.35 (s, 9H), 1.37 (s, 3H), 1.40 (s, 9H),
1.45 (s, 3H), 1.43e1.70 (m, 4H), 3.27e3.33 (m, 3H), 3.62e3.64 (m,
1H), 3.71 (br s, 1H), 3.84e3.87 (m, 1H), 4.20e4.21 (m, 1H), 5.98 (br s,
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼23.5, 24.8, 27.0, 28.1,
28.5, 28.7, 29.4, 30.3, 52.7, 57.4, 63.9, 66.5, 66.9, 77.8, 79.1, 79.1, 79.4,
Boc anhydride (2 mmol) was added drop wise to the stirred
solution of the crude amine (0.48 g, 2.2 mmol) and NaHCO3 (0.55 g,
6 mmol) in THF at 0 ꢀC. Stirring was continued for 12 h, filtered,
concentrated, and purified by column chromatography (3:7, ethyl
acetate/pet ether mixture).
92.9, 93.1, 151.6, 155.9 ppm; HRMS (ESI-TOF) m/z: calcd for
C
19H36N2NaO6 [MþNa]þ: 411.2471; found: 411.2473.
4.3.6. (S)-tert-Butyl 4-((R)-4-(tert-butoxycarbonylamino)-5-
hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate 4d. Rf¼0.3
(petroleum ether/EtOAc, 3:2); oily liquid (0.69 g, 87%); [a]
25 15.7 (c
D
4.3.1. (S)-tert-Butyl 4-((R)-1-(tert-butoxycarbonylamino)-2-
0.14, CHCl3); IR nmax (thin film): 3355, 1695 cmꢂ1; 1H NMR (DMSO-
d6, 90 ꢀC, 500 MHz):
hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylate
4a. Rf¼0.3
d
¼1.23e1.26 (m, 2H), 1.35 (s, 9H), 1.37 (s, 3H),
(petroleum ether/EtOAc, 3:2); oily liquid (0.61 g, 85%); [
a
]
25 ꢂ24.7
1.39 (s, 9H), 1.43 (s, 3H), 1.43e1.58 (m, 4H), 3.24e3.34 (m, 3H),
3.60e3.67 (m, 1H), 3.71 (br s, 1H), 3.84e3.89 (m, 1H), 4.20 (br s, 1H),
D
(c 0.21, CHCl3); IR nmax (thin film): 3356, 1698 cmꢂ1
;
1H NMR
(DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.34 (s, 9H), 1.39 (s, 3H), 1.42 (s, 9H),
5.99 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d¼22.7, 23.4,
1.45 (s, 3H), 3.41 (br s, 2H), 3.66 (br s, 1H), 3.80e3.83 (m, 1H),
3.88e3.90 (m, 1H), 3.97 (br s, 1H), 4.40 (br s, 1H), 5.67 (br s,
24.9, 27.1, 27.9, 28.5, 28.7, 31.3, 32.9, 33.9, 52.5, 57.2, 57.4, 64.1, 66.5,
67.0, 77.7, 79.1, 79.5, 92.9, 93.1, 151.6, 151.7, 155.9 ppm; HRMS (ESI-
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d¼23.0, 24.5, 26.2, 27.1,

9560
R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
TOF) m/z: [MþNa]þ calcd for C20H38N2NaO6 425.2628; found
reaction mixture was concentrated and purified by column
chromatography.
425.2622.
4.3.7. (S)-tert-Butyl 4-((S)-4-(tert-butoxycarbonylamino)-5-
4.4.1. (S)-tert-Butyl 4-((R)-1-(tert-butoxycarbonylamino)-2-
methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate
hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate 4d0. Rf¼0.3
(petroleum ether/EtOAc, 3:2); oily liquid (0.69 g, 87%); [
a
;
]
25 þ11.53
5a. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.64 g, 82%);
D
25
(c 0.26, CHCl3); IR nmax (thin film): 3355, 1695 cmꢂ1
1H NMR
[
a
]
ꢂ14.9 (c 0.26, CHCl3); IR nmax (thin film): 3355, 1745,
D
(DMSO-d6, 90 ꢀC, 500 MHz):
1.37 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.47e1.53 (m, 2H), 1.57e1.63
(m, 2H), 3.27e3.36 (m, 3H), 3.63 (dd, J¼8.5 Hz, J¼1.8 Hz, 1H), 3.73
d
¼1.17e1.30 (m, 2H), 1.35 (s, 9H),
1698 cmꢂ1
¼1.22e1.42 (m, 24H), 3.60 (s, 3H), 3.87e4.02 (m, 3H), 4.35 (br s,
1H), 6.57 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
24.2, 26.0, 26.8, 28.4, 28.5, 52.3, 54.7, 58.4, 58.7, 64.3, 79.1, 80.0,
80.4, 93.7, 93.9, 151.6, 152.5, 155.4, 155.6, 171.5 ppm; HRMS (ESI-
TOF) m/z: [MþH]þ calcd for C18H33N2O7 389.2288; found 389.2284.
;
1H NMR (DMSO-d6DMSO-d6, 90 ꢀC, 500 MHz):
d
d
¼22.8,
(m, 1H), 3.84e3.87 (m, 1H), 4.18 (br s, 1H), 5.93 (br s, 1H) ppm; 13
C
NMR (DMSO-d6, 125 MHz):
d
¼22.4, 23.4, 24.8, 27.1, 27.8, 28.5, 28.7,
31.4, 33.0, 34.0, 52.6, 52.7, 57.1, 57.3, 64.1, 66.5, 67.1, 77.7, 79.0, 79.4,
92.9, 93.1, 151.6, 151.7, 155.9 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ
calcd for C20H38N2NaO6 425.2628; found 425.2622.
4.4.2. (S)-tert-Butyl 4-((R)-2-(tert-butoxycarbonylamino)-3-
methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate
4.3.8. (S)-tert-Butyl 4-((R)-5-(tert-butoxycarbonylamino)-6-
5b. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.68 g, 85%);
25
hydroxyhexyl)-2,2-dimethyloxazolidine-3-carboxylate
4e. Rf¼0.3
[a
]
ꢂ10.2 (c 0.19, CHCl3); IR nmax (thin film): 3355, 1745,
D
25
(petroleum ether/EtOAc, 3:2); oily liquid (0.73 g, 88%); [
a
]
þ19.0
1698 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.35 (s, 9H),
D
(c 0.21, CHCl3); IR nmax (thin film): 3356, 1694 cmꢂ1
;
1H NMR
1.38 (s, 3H), 1.40 (s, 9H), 1.45 (s, 3H), 1.90 (br s, 2H), 3.61 (s, 3H),
(DMSO-d6, 90 ꢀC, 500 MHz):
1.37 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.43e1.60 (m, 4H), 3.23e3.35
(m, 3H), 3.62e3.64 (m, 1H), 3.71e3.72 (m, 1H), 3.84e3.87 (m, 1H),
4.17 (br s, 1H), 5.93 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼1.20e1.28 (m, 4H), 1.36 (s, 9H),
3.70e3.75 (m, 1H), 3.84e3.87 (m, 2H), 4.01 (br s, 1H), 6.67 (br s,
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼23.3, 24.7, 27.2, 27.9,
28.4, 28.6, 38.1, 51.3, 52.4, 55.0, 66.4, 66.7, 78.7, 79.5, 79.8, 93.3,
151.3, 151.7 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
d
¼23.5, 24.8, 24.9, 25.8, 26.0, 27.1, 28.5, 28.7, 31.4, 33.7, 33.7, 52.4,
C19H34N2NaO7 425.2264; found 425.2261.
52.5, 57.0, 57.1, 64.1, 66.9, 66.9, 67.0, 77.7, 79.0, 79.4, 92.9, 93.1, 151.5,
151.7, 155.9; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for C21H40N2NaO6
439.2784; found 439.2781.
4.4.3. (S)-tert-Butyl 4-((S)-2-(tert-butoxycarbonylamino)-3-
methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate
5b0. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.68 g, 85%);
25
4.3.9. (S)-tert-Butyl 4-((S)-5-(tert-butoxycarbonylamino)-6-
[a
]
þ17.18 (c 0.25, CHCl3); IR nmax (thin film): 3355, 1745,
D
hydroxyhexyl)-2,2-dimethyloxazolidine-3-carboxylate
(petroleum ether/EtOAc, 3:2); oily liquid (0.73 g, 85%); [
(c 0.15, CHCl3); IR nmax (thin film): 3356, 1694 cmꢂ1
(DMSO-d6, 90 ꢀC, 500 MHz):
1.37 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.42e1.61 (m, 4H), 3.23e3.36
(m, 3H), 3.62e3.64 (m, 1H), 3.70e3.72 (m, 1H), 3.84e3.87 (m, 1H),
4.17 (br s, 1H), 5.94 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
4e0. Rf¼0.3
1698 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.35 (s, 9H),
25
a
]
þ13.3
1.38 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 2.05 (br s, 2H), 3.61 (s, 3H),
D
;
1H NMR
3.72e3.74 (m, 1H), 3.81e3.86 (m, 2H), 3.98 (br s, 1H), 6.92 (br s,
d
¼1.23e1.29 (m, 4H), 1.36 (s, 9H),
1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
28.6, 31.8, 35.8, 52.3, 52.5, 55.5, 67.2, 78.8, 79.5, 93.1, 151.4, 155.2,
173.2 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for C19H34N2NaO7
425.2264; found 425.2261.
d
¼23.4, 24.8, 27.3, 28.4,
d
¼23.5, 24.9, 26.0, 27.1, 28.5, 28.7, 31.4, 33.8, 52.5, 57.1, 57.5, 64.1,
66.4, 66.9, 77.7, 79.0, 79.4, 92.9, 93.1, 151.5, 151.7, 155.9 ppm; HRMS
(ESI-TOF) m/z: [MþNa]þ calcd for C21H40N2NaO6 439.2784; found
439.2781.
4.4.4. (S)-tert-Butyl 4-((R)-3-(tert-butoxycarbonylamino)-4-
methoxy-4-oxobutyl)-2,2-dimethyloxazolidine-3-carboxylate
5c. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.55 g, 83%);
25
[
a
]
ꢂ15.38 (c 0.26, CHCl3); IR nmax (thin film): 3353, 1746,
D
4.4. Procedure for the oxidation of N-Boc protected amino
alcohols 4 to the corresponding amino carboxylic acid methyl
esters 5
1697 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.35 (s, 9H),
1.36 (s, 3H), 1.38 (s, 9H), 1.44 (s, 3H), 1.49e1.69 (m, 4H), 3.59 (s, 3H),
3.61e3.66 (m, 1H), 3.73 (br s, 1H), 3.82e3.87 (m, 1H), 3.93 (br s, 1H),
6.85 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼27.1, 27.9,
Pyridinium dichromate (7.51 g, 21.4 mmol) was added to the
stirred solution of N-Boc protected amino alcohol (2 mmol) in dry
DMF (8 mL) under nitrogen at 30 ꢀC and stirring was continued for
6 h. After complete disappearance of the starting material on TLC,
the reaction was quenched by adding water (50 mL) and the mix-
ture was extracted diethyl ether (2ꢁ50 mL). The ether solution was
extracted with 10% NaHCO3 solution (2ꢁ30 mL), the aqueous ex-
tracts containing the carboxylate salts were combined and acidified
with saturated KHSO4 solution and was extracted with diethyl
ether (2ꢁ30 mL). The ether layers were combined, dried over an-
hydrous Na2SO4, and concentrated under reduced pressure. The
crude carboxylic acids were converted to the methyl ester de-
rivatives using diazomethane before purification.
N-Nitroso methyl urea (1 g) was added to a stirred of mixture of
60% KOH solution (25 mL) and diethyl ether (15 mL) at 0 ꢀC and was
stirred for 5 min. Color of the ether layer changes to yellow in-
dicating the presence of diazomethane. The ether layer was sepa-
rated and passed through KOH pellets. This solution of
diazomethane in ether was added to the crude solution of car-
boxylic acids in ether. Esterification was finished within 5 min. The
28.3, 28.4, 28.5, 28.5, 28.7, 28.7, 28.9, 28.9, 30.1, 51.9, 52.1, 54.4, 56.8,
56.9, 57.1, 57.2, 66.9, 67.1, 67.3, 78.8, 79.4, 93.3, 93.3, 151.8, 151.8,
155.8, 173.1, 173.2 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
C
20H36N2NaO7 439.2420; found 439.2423.
4.4.5. (S)-tert-Butyl 4-((S)-3-(tert-butoxycarbonylamino)-4-
methoxy-4-oxobutyl)-2,2-dimethyloxazolidine-3-carboxylate
5c0. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.71 g, 84%);
25
[
a
]
þ35.2 (c 0.17, CHCl3); IR nmax (thin film): 3353, 1746,
D
1697 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.35 (s, 9H),
1.36 (s, 3H), 1.38 (s, 9H), 1.44 (s, 3H), 1.49e1.69 (m, 4H), 3.59 (s, 3H),
3.61e3.66 (m, 1H), 3.73 (br s, 1H), 3.82e3.87 (m, 1H), 3.93 (br s, 1H),
6.85 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
d
¼27.1, 27.9,
28.3, 28.4, 28.5, 28.5, 28.7, 28.7, 28.9, 28.9, 30.1, 51.9, 52.1, 54.4, 56.8,
56.9, 57.1, 57.2, 66.9, 67.1, 67.3, 78.8, 79.4, 93.3, 93.3, 151.8, 151.8,
155.8, 173.1, 173.2 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
C
20H36N2NaO7 439.2420; found 439.2423.
4.4.6. (S)-tert-Butyl 4-((R)-4-(tert-butoxycarbonylamino)-5-
methoxy-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate

R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
9561
5d. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.75 g, 84%);
1.98e2.02 (m, 2H), 3.03 (br s, 1H), 3.60e3.65 (m, 3H), 3.70 (s, 3H),
4.37e4.39 (m,1H), 5.02 (d, J¼7.9 Hz,1H), 5.64 (d, J¼7.9 Hz,1H) ppm;
25
[
a]
þ3.75 (c 0.16, CHCI3); IR nmax (thin film): 3353, 1746,
D
1697 cmꢂ1 1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
;
d
¼1.23e1.33 (m,
13C NMR (CDCl3, 125 MHz):
d
¼28.3, 28.4, 33.7, 48.9, 51.0, 52.5, 64.6,
2H), 1.35 (s, 9H), 1.37 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.46e1.68 (m,
4H), 3.60 (s, 3H), 3.63 (dd, J¼8.85, 1.85 Hz, 1H), 3.73 (br s, 1H),
3.84e3.87 (m, 1H), 3.90e3.94 (m, 1H), 6.72 (br s, 1H) ppm; 13C NMR
79.9, 80.1, 155.7, 156.0, 173.0 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ
calcd for C16H30N2NaO7 385.1959; found 385.1954.
(DMSO-d6, 125 MHz):
d
¼22.5, 23.4, 24.8, 27.1, 27.9, 28.5, 28.6, 31.0,
4.5.2. (2S,4S)-Methyl 2,4-bis(tert-butoxycarbonylamino)-5-
33.3, 52.1, 52.1, 53.9, 57.0, 66.6, 67.0, 78.6, 79.1, 79.5, 93.0, 93.2,151.5,
hydroxypentanoate 6b0. Rf¼0.4 (petroleum ether/EtOAc, 1:1); oily
151.8, 156.0, 173.6 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
liquid (0.65 g, 90%); [
a
]
25 þ13.0 (c 0.23, CHCl3); IR nmax (thin film):
D
C
21H39N2O7 431.2757; found 431.2753.
3354, 1741, 1692 cmꢂ1; 1H NMR (CDCl3, 500 MHz):
d
¼1.41 (s, 18H),
1.81e2.05 (m, 2H), 3.60e3.67 (m, 3H), 3.72 (s, 3H), 4.25 (m,1H), 5.17
4.4.7. (S)-tert-Butyl 4-((S)-4-(tert-butoxycarbonylamino)-5-
methoxy-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate
(br s, 1H), 5.43 (br s, 1H) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼28.3,
28.4, 29.7, 34.3, 49.9, 51.0, 52.6, 64.9, 79.9, 80.3, 155.7, 156.2,
173.1 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for C16H30N2NaO7
385.1959; found 385.1954.
5d0. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.75 g,
25
85%); [
a
]
þ24.1 (c 0.29, CHCl3); IR nmax (thin film): 3353,
D
1746, 1697 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.27e1.34 (m, 2H), 1.36 (s, 9H), 1.39 (s, 3H), 1.40 (s, 9H), 1.46
4.5.3. (2R,5S)-Methyl 2,5-bis(tert-butoxycarbonylamino)-6-
(s, 3H), 1.53e1.71 (m, 4H), 3.61 (s, 3H), 3.64 (dd, J¼8.85,
1.85 Hz, 1H), 3.74 (br s, 1H), 3.86e3.88 (m, 1H), 3.91e3.95 (m,
1H), 6.72 (br s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz):
hydroxyhexanoate 6c. Rf¼0.4 (petroleum ether/EtOAc, 1:1); pale
yellow solid; mp 57e60 ꢀC (0.61 g, 90%); [
a
]
D
25 ꢂ9.6 (c 0.23, CHCl3);
IR nmax (KBr): 3359, 1744, 1698 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d
¼22.6, 23.4, 24.9, 27.1, 28.1, 28.7, 28.8, 31.1, 33.4, 52.3, 52.5,
d
¼1.41 (s, 18H), 1.46e1.69 (m, 2H), 1.87e2.02 (m, 2H), 2.72 (br s, 1H)
54.2, 57.2, 66.8, 67.2, 78.8, 79.1, 79.5, 93.0, 93.2, 151.7, 151.9,
3.54e3.59 (m, 3H), 3.71 (s, 3H), 4.25e4.26 (m, 1H), 4.87 (d,
J¼7.90 Hz, 1H), 5.21 (d, J¼6.7 Hz, 1H) ppm; 13C NMR (CDCl3,
156.1, 173.7 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
C
21H39N2O7 431.2757; found 431.2753.
125 MHz):
d
¼27.5, 28.3, 28.4, 29.5, 52.4, 53.5, 65.4, 79.7, 80.1, 155.6,
156.4, 173.1 ppm; HRMS (ESI-TOF) m/z: calcd for C17H33N2O7
4.4.8. (S)-tert-Butyl 4-((R)-5-(tert-butoxycarbonylamino)-6-
methoxy-6-oxohexyl)-2,2-dimethyloxazolidine-3-carboxylate
377.2288; found 377.2285.
5e. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.75 g, 80%);
4.5.4. (2S,5S)-Methyl 2,5-bis(tert-butoxycarbonylamino)-6-
25
[
a]
þ18.75 (c 0.16, CHCl3); IR nmax(thin film): 3353, 1746,
hydroxyhexanoate 6c0. Rf¼0.4 (petroleum ether/EtOAc, 1:1); oily
D
25
1697 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.19e1.30 (m,
liquid (0.61 g, 90%); [
a
]
D
þ8.6 (c 0.23, CHCl3); IR nmax (thin film):
4H), 1.35 (s, 9H), 1.37 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.46e1.65 (m,
4H), 3.60 (s, 3H), 3.63 (dd, J¼8.8, 1.85 Hz, 1H), 3.71 (br s, 1H),
3.84e3.87 (m, 1H), 3.90e3.95 (m, 1H), 6.72 (br s, 1H) ppm; 13C NMR
3354, 1741, 1692 cmꢂ1; 1H NMR (CDCl3, 500 MHz):
1.57e2.14 (m, 4H), 2.76 (br s, 1H), 3.54e3.61 (m, 3H), 3.71 (s, 3H),
d
¼1.41 (s, 18H),
4.79e4.88 (m, 1H), 5.16 (br s, 1H) ppm; 13C NMR (CDCl3, 125 MHz):
(DMSO-d6, 125 MHz):
d
¼23.4, 24.8, 25.4, 25.6, 25.8, 27.1, 27.9, 28.6,
d
¼27.4, 28.3, 28.4, 29.5, 52.1, 52.4, 53.2, 65.3, 79.7, 80.1, 155.6, 156.3,
29.5, 31.10, 32.2, 33.4, 52.1, 52.2, 53.7, 53.9, 56.9, 57.0, 57.2, 57.3,
66.3, 66.5, 66.8, 66.9, 78.6, 79.1, 79.5, 92.9, 92.9, 93.1, 93.1, 151.5,
151.7, 156.0, 173.7 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
173.2 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C17H33N2O7
377.2288; found 377.2286.
C
22H40N2NaO7 467.2733; found 467.2733.
4.5.5. (2R,6S)-Methyl 2,6-bis(tert-butoxycarbonylamino)-7-
hydroxyheptanoate 6d. Rf¼0.4 (petroleum ether/EtOAc, 1:1); oily
4.4.9. (S)-tert-Butyl 4-((S)-5-(tert-butoxycarbonylamino)-6-
methoxy-6-oxohexyl)-2,2-dimethyloxazolidine-3-carboxylate
liquid (0.71 g, 91%); [
a
]
25 ꢂ10.0 (c 0.10, CHCl3); IR nmax (thin film):
D
3357, 1740, 1689 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d
¼1.28e1.35
5e0. Rf¼0.5 (petroleum ether/EtOAc, 4:1); oily liquid (0.75 g, 81%);
(m, 2H), 1.41 (s, 18H), 1.54e1.82 (m, 4H), 3.56 (m, 3H), 3.71 (s,
3H), 4.30 (m, 1H), 4.92 (m, J¼3.95 Hz, 1H), 5.18 (m, J¼9 Hz,
25
[
a
]
þ13.33 (c 0.15, CHCl3); IR nmax(thin film): 3353, 1746,
D
1697 cmꢂ1
;
1H NMR (DMSO-d6, 90 ꢀC, 500 MHz):
d
¼1.19e1.33 (m,
1H) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼21.5, 28.3, 28.4, 30.3,
4H), 1.35 (s, 9H), 1.37 (s, 3H), 1.39 (s, 9H), 1.44 (s, 3H), 1.47e1.67 (m,
4H), 3.60 (s, 3H), 3.63 (dd, J¼8.85, 1.50 Hz, 1H), 3.71 (br s, 1H),
3.84e3.87 (m, 1H), 3.90e3.94 (m, 1H), 6.72 (br s, 1H) ppm; 13C
33.1, 52.2, 52.4, 52.5, 64.4, 79.5, 80.2, 155.9, 156.3, 173.3 ppm;
HRMS (ESI-TOF) m/z: [MþNa]þ calcd for C18H34N2NaO7 413.2264;
found 413.2263.
NMR (DMSO-d6, 125 MHz):
d
¼23.4, 25.4, 25.7, 25.9, 27.1, 27.1, 28.6,
28.6, 31.0, 33.4, 52.1, 52.2, 53.8, 53.8, 57.1, 57.3, 66.5, 66.9, 78.6,
79.1, 79.5, 92.9, 93.1, 150.2, 151.6, 156.0, 173.7 ppm; HRMS (ESI-
TOF) m/z: [MþNa]þ calcd for C22H40N2NaO7 467.2733; found
467.2733.
4.5.6. (2S,6S)-Methyl 2,6-bis(tert-butoxycarbonylamino)-7-
hydroxyheptanoate 6d0. Rf¼0.4 (petroleum ether/EtOAc, 1:1);
white solid; mp 81e85 ꢀC (0.71 g, 92%); [ 25 4.34 (c 0.23, CHCl3); IR
a]
D
nmax (KBr): 3357, 1741, 1691 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d
¼1.28e1.35 (m, 2H), 1.40 (s,18H), 1.46e1.75 (m, 4H), 2.61 (br s,1H),
4.5. General procedure for the conversion of 5 to 6 (ox-
azolidine ring opening)
3.53e3.59 (m, 3H), 3.70 (s, 3H), 4.23 (br s, 1H), 4.85 (m, J¼4.6 Hz,
1H), 5.19 (m, J¼6.1 Hz,1H) ppm; 13C NMR (CDCl3, 125 MHz):
¼21.8,
d
28.4, 28.4, 30.7, 32.6, 52.2, 52.4, 53.0, 65.9, 79.6, 80.0, 155.7, 156.7,
173.4 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for C18H34N2NaO7
413.2264; found 413.2269.
The oxazolidine derivatives 5 (2 mmol) were treated with 25 mL
of 7% trifluoroacetic acid in MeOH at 0 ꢀC under nitrogen. After
stirring the reaction mixture for 16 h at 30 ꢀC, the mixture was
concentrated under reduced pressure and purified by column
chromatography (1:1 ethyl acetate and petroleum ether).
4.5.7. (2R,7S)-Methyl 2,7-bis(tert-butoxycarbonylamino)-8-
hydroxyoctanoate 6e. Rf¼0.4 (petroleum ether/EtOAc, 1:1); pale
yellow solid; mp 90e95 ꢀC (0.75 g, 93%); [
a]
25 ꢂ12.5 (c 0.24, CHCl3);
D
4.5.1. (2R,4S)-Methyl 2,4-bis(tert-butoxycarbonylamino)-5-
IR nmax (KBr): 3360, 1744, 1691 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
hydroxypentanoate 6b. Rf¼0.4 (petroleum ether/EtOAc, 1:1); oily
d
¼1.18e1.35 (m, 4H), 1.41 (s, 18H), 1.49e1.87 (m, 4H), 2.62 (br s, 1H),
3.50e3.62 (m, 3H), 3.71 (s, 3H), 4.25e4.26 (m, 1H), 4.70 (br s, 1H),
5.05 (br s, 1H) ppm; 13C NMR (CDCl3, 125 MHz):
¼25.1, 25.5, 28.3,
25
liquid (0.65 g, 90%); [
a
]
ꢂ3.5 (c 0.28, CHCl3); IR nmax (thin film):
D
3354, 1741, 1692 cmꢂ1; 1H NMR (CDCl3, 500 MHz):
d
¼1.41 (s, 18H),
d

9562
R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
28.4, 29.7, 31.3, 32.6, 52.3, 52.6, 53.3, 65.8, 79.6, 79.9, 155.5, 156.5,
173.4 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C19H37N2O7
405.2601; found 405.2605.
TOF) m/z: [MþNa]þ calcd for C19H34N2NaO8 441.2213; found
441.2212.
4.6.6. (2S,6S)-Dimethyl-2,6-bis(tert-butoxycarbonylamino)heptane-
4.5.8. (2S,7S)-Methyl 2,7-bis(tert-butoxycarbonylamino)-8-
dioate 7d0. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid (0.71 g,
25
hydroxyoctanoate 6e0. Rf¼0.4 (petroleum ether/EtOAc, 1:1); oily
86%); [
a
]
þ9.4 (c 0.42, CHCl3); IR nmax (thin film): 3364, 1744,
liquid (0.75 g, 93%); [
a
]
þ2.8 (c 0.34, CHCl3); IR nmax(thin film):
1714 cmꢂD1; 1H NMR (CDCl3, 500 MHz):
d
¼1.20e1.27 (m, 2H), 1.33 (s,
25
3356, 1741, 1691 cmꢂ1; 1DH NMR (CDCl3, 500 MHz):
d
¼1.17e1.33 (m,
18H), 1.55e1.70 (m, 4H), 3.62 (s, 6H), 4.14 (m, 2H), 5.17 (d, J¼7.3 Hz,
4H), 1.40 (s, 18H), 1.44e1.74 (m, 4H), 2.83 (br s, 1H), 3.54e3.59 (m,
3H), 3.70 (s, 3H), 4.25e4.26 (m, 1H), 4.75 (br s, 1H), 5.09 (d,
2H) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼21.4, 28.3, 32.0, 52.2, 53.0,
79.7, 155.6, 173.2 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
J¼6.7 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz):
d¼25.1, 25.4, 28.3,
C19H35N2O8 419.2393; found 419.2390.
28.4, 29.7, 31.3, 32.6, 52.3, 52.6, 53.2, 65.5, 79.6, 80.0, 155.5, 156.4,
173.4 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C19H37N2O7
405.2601; found 405.2604.
4.6.7. (2R,7S)-Dimethyl-2,7-bis(tert-butoxycarbonylamino)octane-
dioate 7e. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid (0.75 g,
25
87%); [
a]
0.0 (c 0.31, CHCl3); IR nmax (thin film): 3362, 1744,
D
1714 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d¼1.27e1.34 (m, 4H),
4.6. Oxidation of N-Boc protected amino alcohols 6 to the bis-
amino acid derivatives 7
1.21e1.34 (m, 4H), 1.40 (s, 18H), 1.52e1.59 (m, 2H), 1.73e1.74 (m,
2H), 3.69 (s, 6H), 4.23e4.24 (m, 2H), 5.04 (d, J¼7.0 Hz, 2H) ppm; 13
C
NMR (CDCl3, 125 MHz):
d
¼24.9, 28.3, 32.5, 52.3, 53.2, 79.9, 155.4,
Oxidation of N-Boc protected amino alcohols 6 to the bis-amino
acid derivatives 7 was carried out using the same procedure that
was used for the oxidation of 4 to 5.
173.3 ppm; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C20H37N2O8
432.2550; found 433.2556.
4.6.8. (2S,7S)-Dimethyl-2,7-bis(tert-butoxycarbonylamino)octane-
4.6.1. (2R,4S)-Dimethyl-2,4-bis(tert-butoxycarbonylamino)pentane-
dioate 7e0. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid (0.75 g,
25
dioate 7b. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid (0.67 g,
87%); [
a
]
þ14.6 (c 0.47, CHCl3); IR nmax (thin film): 3363, 1744,
86%); [
a
]
0.00 (c 0.24, CHCl3); IR nmax (thin film): 3354, 1741,
1715 cmꢂD1; 1H NMR (CDCl3, 500 MHz):
d
¼1.25e1.33 (m, 4H), 1.38 (s,
25
D
1692 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d
¼1.42 (s, 18H), 2.23 (t,
18H), 1.51e1.72 (m, 4H), 3.68 (s, 6H), 4.22e4.23 (m, 2H), 5.04 (d,
J¼5.75 Hz, 2H), 3.73 (s, 3H), 4.31 (br s, 2H), 5.25 (br s, 2H) ppm; 13
C
J¼7.6 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz):
¼24.9, 28.3, 32.5,
d
NMR (CDCl3, 125 MHz):
d
¼28.2, 28.3, 29.7, 34.7, 50.8, 52.6, 80.3,
52.2, 53.3, 79.9, 155.4, 173.3 ppm; HRMS (ESI-TOF) m/z: [MþH]þ
155.4, 172.5 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
calcd for C20H37N2O8 433.2550; found 433.2556.
C
17H30N2NaO8 413.1900; found 413.1902.
4.6.9. (3R,4S)-3,4-Di(tert-butoxycarbonylamino)dihydrofuran-
4.6.2. (2S,4S)-Dimethyl-2,4-bis(tert-butoxycarbonylamino)pentane-
2(3H)-one 8. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid
25
dioate 7b0. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid
(0.52 g, 85%); [
a]
ꢂ40.7 (c 2.7, CHCl3); IR nmax (thin film): 3355,
D
25
(0.67 g, 86%); [
a
]
þ20.68 (c 0.29, CHCl3); IR nmax (thin film):
1787, 1693 cmꢂ1
3.96e4.13 (m, 2H), 4.37 (br s, 1H), 4.78 (br s, 1H), 5.28 (d, J¼5.7 Hz,
1H), 6.00 (br s, 1H) ppm; 13C NMR (CDCl3, 100 MHz):
;
1H NMR (CDCl3, 400 MHz):
d¼1.42 (s, 18H),
D
3354, 1741, 1692 cmꢂ1
18H), 2.23 (t, J¼5.75 Hz, 2H), 3.73 (s, 3H), 4.31 (br s, 2H), 5.25
(br s, 2H) ppm; 13C NMR (CDCl3, 125 MHz):
;
1H NMR (CDCl3, 500 MHz):
d
¼1.42 (s,
d
¼28.3, 28.3,
d
¼28.2, 28.3, 29.7,
54.8, 55.3, 70.1, 80.4, 81.4, 155.9, 156.6, 172.4 ppm; HRMS (ESI-TOF)
34.7, 50.8, 52.6, 80.3, 155.4, 172.5 ppm; HRMS (ESI-TOF) m/z:
m/z: [MþNa]þ calcd for C14H24N2NaO6 339.1532; found 339.1533.
[MþNa]þ calcd for C17H30N2NaO8 413.1900; found 413.1902.
Acknowledgements
4.6.3. (2R,5S)-Dimethyl-2,5-bis(tert-butoxycarbonylamino)hex-
anedioate 7c. Rf¼0.3 (petroleum ether/EtOAc, 4:1); crystalline solid
The authors thank Department of Science and Technology,
Ministry of Science and Technology for financial support (grant
number: SR/FT/CS-12/2011) and R.P. thanks University Grants
Commission for a senior research fellowship.
25
(0.69 g, 85%); mp 120e125 ꢀC; [
a]
0.0 (c 0.31, CHCl3); IR nmax
D
(KBr): 3361, 1741, 1714 cmꢂ1; 1H NMR (CDCl3, 500 MHz):
18H), 1.54e1.92 (m, 4H), 3.72 (s, 6H), 4.30 (m, 2H), 5.04 (d, J¼6.1 Hz,
d¼1.39 (s,
2H) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼28.3, 28.9, 52.4, 52.9, 80.1,
155.4, 172.9 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for
Supplementary data
C
18H32N2NaO8 427.2056; found 427.2053.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.10.048.
4.6.4. (2S,5S)-Dimethyl-2,5-bis(tert-butoxycarbonylamino)hex-
anedioate 7c0. Rf¼0.3 (petroleum ether/EtOAc, 4:1); white solid;
mp 81e85 ꢀC (0.69 g, 85%); [
a
]
25 þ17.3 (c 0.23, CHCl3); IR nmax (KBr):
D
References and notes
3361, 1741, 1714 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d
¼1.37 (s, 18H),
1.58e1.89 (m, 4H), 3.73 (s, 6H), 4.28 (m, 2H), 5.07 (br s, 2H) ppm;
1. (a) Cox, R. J. Nat. Prod. Rep. 1996, 13, 29e43; (b) Cox, R. J.; Sutherland, A.; Ve-
deras, J. C. Bioorg. Med. Chem. 2000, 8, 843e871.
2. (a) Walker, R.; Yamanaka, T.; Sakakibara, S. Proc. Natl. Acad. Sci. U.S.A. 1974, 71,
1901e1905; (b) Nutt, R. F.; Verber, D. F.; Saperstein, R. J. Am. Chem. Soc. 1980,
102, 6539e6545.
13C NMR (CDCl3, 125 MHz):
d
¼28.3, 28.9, 52.5, 53.2, 80.1, 155.4,
172.8 ppm; HRMS (ESI-TOF) m/z: [MþNa]þ calcd for C18H32N2NaO8
427.2056; found 427.2053.
3. (a) Elaridi, J.; Patel, J.; Jackson, W. R.; Robinson, A. J. J. Org. Chem. 2006, 71,
7538e7545; (b) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2004, 69,
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4.6.5. (2R,6S)-Dimethyl-2,6-bis(tert-butoxycarbonylamino)heptane-
dioate 7d. Rf¼0.3 (petroleum ether/EtOAc, 4:1); oily liquid
25
(0.71 g, 86%); [
a
]
0.0 (c 0.28, CHCl3); IR nmax (thin film): 3361,
D
1741, 1714 cmꢂ1
;
1H NMR (CDCl3, 500 MHz):
d
¼1.22e1.38 (m,
2H), 1.41 (s, 18H), 1.57e1.79 (m, 4H), 3.71 (s, 6H), 4.25e4.26 (m,
2H), 5.05 (d, J¼6.4 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼21.1, 28.3, 32.2, 52.3, 53.1, 80.0, 155.5, 173.1 ppm; HRMS (ESI-

R. Petakamsetty et al. / Tetrahedron 70 (2014) 9554e9563
9563
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~
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11. CCDC-1001499 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.