One pot synthesis of amino acid derived chiral disubstituted morpholines and 1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences

Article abstract of DOI:10.1039/c1ob05462g

A new one-pot synthetic strategy is described for the synthesis of enantiomerically pure cis-3,5-disubstituted morpholines and 3,6-disubstituted 1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences. This new strategy describes how epoxy alco

Full text of DOI:10.1039/c1ob05462g

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 7365
www.rsc.org/obc
PAPER
One pot synthesis of amino acid derived chiral disubstituted morpholines and
1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences†
Krishnananda Samanta and Gautam Panda*
Received 23rd March 2011, Accepted 22nd June 2011
DOI: 10.1039/c1ob05462g
A new one-pot synthetic strategy is described for the synthesis of enantiomerically pure
cis-3,5-disubstituted morpholines and 3,6-disubstituted 1,4-oxazepanes via tandem aziridine/epoxide
ring opening sequences. This new strategy describes how epoxy alcohols could act as both a nucleophile
and an electrophile in a tandem fashion and undergo intermolecular regioselective ring opening of
chiral aziridines for the first time.
Introduction
The design and synthesis of chiral heterocycles has received a lot
of attention in synthetic organic chemistry due to their diverse
applications as drug candidates,1 materials,2 and for catalysis.3
Among them, morpholine structural units are generally used
in pharmaceutical industry, the World Drug Index cites 100
drugs containing a morpholine core. Morpholine containing
Fig. 1 Some bioactive morpholines derivatives.
structural units exhibit a wide range of biological activites,4
including antidepressant,5 1, antioxidant,6 serotonin agonist, NK-
derivatives are still not reported. Very recently, our group reported
a new route to 1,4-oxazepanes and 1,4-diazepanes from Garner
aldehyde.15b Herein, we disclosed base promoted one pot syn-
thesis of cis-3,5-disubstituted morpholines and 3,6-disubstituted
1,4-oxazepanes via tandem aziridine/epoxide ring opening
1 and NK-2 receptor antagonist, and antifungal,7b 2 and GABAB
receptor antagonist7c,d 3, Fig. 1. Furthermore, heterocycles con-
taining nitrogen and oxygen, such as oxazepanes have been
important synthetic targets for synthetic and medicinal chemists,8
because of their diverse biological properties.9 1,4-Oxazepane
sequences.
structural frameworks can be found in natural products such as
As a three-member-ring heterocycle, both aziridine and epoxide
neurotoxin batrachotoxin.10 Recently, Shankaran and coworkers
have ring strain and readily undergo ring opening reaction with
reported the synthesis and biological evaluation of oxazepane,
different types of nucleophiles.16 In the present paper we shown
diazepane, and thiazepane derivatives as nitric oxide synthase
that chiral epoxy alcohols could act as both a nucleophile and
inhibitor.11 The amino acids derived oxazepane units are also
an electrophile in tandem fashion and undergo regioselective ring
important building blocks for the synthesis of peptide nucleic
opening of chiral aziridines.
acids (PNAs) to control the biological function in the desired
In our work, we reasoned that initial base mediated conversion
of epoxy alcohol to alkoxide anion (Scheme 1) itself could act as
the nucleophile A and might undergo regioselective ring opening of
aziridine B to yield C as a fleeting intermediate. Next, sulfonamide
anion of the intermediate C might proceed nucleophilic ring
opening of epoxide (either path a or b, or both) to give either
product D or E or mixture of both D and E.
manner.12
We have been working on the synthesis and biology of S-amino
acid–base chiral heterocyles and natural product-like molecules.13
We are interested in developing new methodology to construct
chiral heterocycles for biological evaluation.13h,i Towards this
objective, we chose to synthesize enantiomerically pure amino
acids derived morpholines and 1,4-oxazepanes for which not
many practical methods are known.11,14,15 Moreover, one pot
synthetic approaches towards chiral morpholine and oxazepane
Medicinal and Process Chemistry Division, CSIR, Central Drug Re-
search Institute, Lucknow, 226001, UP, India. E-mail: gautam.panda@
gmail.com, gautam_panda@cdri.res.in; Fax: +91-522-2623405; Tel: +91-
522-2612411-18, Ext. 4385, 4603
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05462g
Scheme 1 Our hypothesis.
This journal is The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7365–7371 | 7365
©

View Article Online
the anion is more naked than that complexed to the potassium.
This observation suggested that a polar solvent was necessary for
the reaction.
Results and discussion
To test our hypothesis, first NaH promoted ring opening of
N-Ts aziridine 4 with R-glycidol 5 was carried out in DMSO
at room temperature (Scheme 2). Aziridine 4 was prepared
according to our reported procedure.16 To our delight, the starting
materials were fully consumed within 15 min, as confirmed by
Next, our challenge was to separate the two isomers. On the basis
of the above aforementioned results, we confirmed that the initial
ring opening of aziridine with alkoxide anion A of R-glycidol was
highly regioselective. The reaction occurred at the least hindered
carbon due to the steric bulk of the epoxide ring. However, final
intramolecular epoxide ring opening by sulfonamide anion gave
possibility of two isomers (path a & b, Scheme 1). According to
our hypothesis (Scheme 1), a mixture of primary and secondary
carbinol bearing substituted morpholines and oxazepanes were
formed, respectively. In an effort to separate the compounds, the
mixture was treated with TBDMSiCl (1 equiv), imidazole in dry
DCM for 30 min at room temperature (Scheme 3).
1
TLC monitoring, and a new spot was detected. From H NMR
analysis, ratio of 2.1 : 1 mixture of two products was found which
were inseparable on silica gel column chromatography. Next, our
expected product was assigned by mass spectroscopy analysis.
From MS (ESI) spectrum, one peak was found at m/z 314 (M +
H)+ ion that indicates that the reaction proceeded smoothly via one
pot tandem aziridine/epoxide ring opening sequences because, the
exact mass of the compounds 6 and 7 are found to be 313.13 amu.
Scheme 3 Separation of inseparable isomers.
Scheme 2 One pot synthesis of disubstituted morpholine and 1,4-ox-
azepane derivatives.
We were delighted to find that more reactive primary carbinol of
6 was readily protected with TBDMS group and easily separated
using silica gel column chromatography with 44% yield. From
1H NMR spectrum analysis, formation of 3.8 : 1 mixture of 8
and 9 was found. Under this condition secondary carbinol of
7 was also prone to react with TBDMSiCl. Pure compound 7
was isolated with 48% yield at room temperature based on 4.
Next, we decided to optimize the reaction temperature to avoid
the unwanted TBDMS protection of 7. After several attempts,
(Table 2) a reproducible result was obtained, when the inseparable
mixture was treated with TBDMSiCl at 0 ◦C for 20 min. When the
reaction was performed at -10 ◦C, 100% pure morpholine 8 (13%)
was obtained along with 56% recovery of starting materials 6 & 7
(Table 2, entry 2). Using this optimized condition (entry 3), two
isomers were separated that were confirmed by 1H and 13C NMR
analysis.
Our next objective was to optimize the reaction conditions
(Table 1) in order to improve the yield and regioselectivity. Chiral
aziridine 4 and R-glycidol 5 were chosen as model substrates.
The best result was obtained when the reaction was performed
t
in the presence of 1.2 equiv BuOK in DMSO with 70% yield
(Table 1, Entry 6). It is noted that the yield of the product was
improved, but the regioselectivity remained unchanged. There was
no formation of product when the reaction was carried out at
0
◦C in THF, DMF or DMSO. Again, when the reaction was
t
performed in THF, promoted by NaH or BuOK, no desired
product was detected (Table 1, Entry 2 & 7). In THF, it is probable
that the alkoxide anion of R-glycidol is bound to potassium as a
tight ion pair (supported by literature precedent17) that did not
allow intermolecular nucleophilic attack on the aziridine ring. In
polar solvent like DMSO, DMF the reaction facilitates because
Table 1 Optimization of the reaction conditionsa
Entry
Base (equiv)
Solvent
T/◦C
Time
%Yieldb
drc
1
2
3
4
5
6
7
8
9
NaH (4)
NaH (4)
DMSO
THF
THF
DMSO
DMSO
DMSO
THF
DMF
DMF
RT
RT
RT
RT
15 min
180 min
180 min
45 min
60 min
10 min
60 min
40 min
20 min
56
0
0
Trace
0
70
0
0
2.1 : 1
K2CO3 (1.5)
K2CO3 (1.5)
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
0 ◦
C
RT
RT
2.1 : 1
2.1 : 1
0 ◦
C
RT
63
a Reaction conditions: 4 (1 equiv), 5 (1 equiv). b Combined yield of 6 & 7 based on 4. c dr values determined by 1H NMR analysis of the crude product.
7366 | Org. Biomol. Chem., 2011, 9, 7365–7371
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 2 Optimization of the reaction temperature
Table 3 Ring opening reaction of aziridines (12) with R-glycidol pro-
moted by tBuOKa
T/◦C
Time
Ratio 8 : 9a
8, %yieldb
Entry
Aziridine
R
13(%)b
14(%)b
Entry
1
2
3
4
5
12a
12b
12c
12d
12e
CH2CH(CH3)2
CH(CH3)CH2CH3
CH2-indole
NFc
NF
NF
13a (22.7)
13b (25)
14a (74)
14b (65)
14c (63)
14d (43.7)
14e (39)
1
2
3
-20
-10
0
120 Min
60 Min
20 Min
0 : 0
100 : 0
100 : 0
0
13c
25.7d
d
CH3
CH2C6H5(OMe)e
a Ratio was determined by 1H NMR analysis. b Isolated yield based on 4.
c recovery of starting materials 6 & 7 (56%). d isolated yield of pure 7 at
0 ◦C (46.6%) based on 4 (See exp. section).
a Reaction conditions: 12 (1 equiv), 5 (1 equiv). b Isolated yield based on
12. c NF means not formed. d Inseparable mixtures were formed. Yields
are given after separation based on 12d (see exp. section.). e Compounds
are separated on silica gel column chromatography.
To further ensure the formation of 6 and 7, some functional
group manipulation was carried out on the compounds (Scheme 4
and Scheme 5). TBDMS group of the separated compound 8 was
deprotected by TBAF to afford primary carbinol 6 in 85% yield.
Next, carbinol 6 was protected with a mesyl group using standard
conditions to obtain 10, which gives scope for further structural
diversification.
in accordance with the above mentioned optimized condition
(Table 2, entry 3).
However, to confirm the stereochemistry of those products, a 2D
NMR experiment was carried out (see ESI†). In compound 14d
(Fig. 2), the locations of all the protons were confirmed on the basis
of the COSY spectrum. The cis relationship between Ha-3/Ha-2
(Jcis = 4.2 Hz), Ha-6/Ha-5 (Jcis = 4.3 Hz) and trans relationship
between Ha-6/Hb-7 (Jtrans = 8.7 Hz) was deduced from the vicinal
coupling constant value. The absolute configuration of C-6 was
determined on the basis of the NOESY correlations between
Ha-2/Ha-7, Hb-2/Hb-7, Ha-5/Ha-3, Hb-7/Hb-5, Hb-2/CH3-3,
Hb-5/CH3-3 and Hb-7/CH3-3. The absolute configuration of 14d
is (3S, 6S) which was also supported by our proposed hypothesis.
Scheme 4 Synthesis of 10.
Scheme 5 Synthesis of 11.
Similarly, compound 7 was treated with mesyl chloride in the
presence of a minimum volume of pyridine, but did not furnish 11,
giving recovery of starting material which indicates the presence
of less reactive secondary carbinol group. This above experiment
proves the formation of primary (CH2OH) and secondary carbinol
(CHOH) bearing six and seven member morpholine and 1,4-
oxazepane derivatives which was also supported by DEPT spec-
trum analysis (see ESI†).
Fig. 2 Confirmation of stereochemistry by NOE contacts from NOESY
Experiment of 14d (400 MHz, CDCl3).
Next, the scope of this tandem aziridine/epoxide ring opening
reactions was then explored. A wide range of chiral monosubsti-
tuted aziridines were investigated (Table 3).
Based on the above results, a plausible mechanism was proposed
(Scheme 6). First, BuOK mediated conversion of R-glycidol
t
All aziridines reacted well in the tandem process to fur-
nish products with moderate to good yield as revealed in
Table 3. Surprisingly, sec-butyl, iso-butyl and indole-substituted
aziridines gave only seven member oxazepane derivatives that
were confirmed from 1H and 13C NMR spectroscopy analy-
sis. It was further confirmed through treatment with TBDM-
SiCl at 0 ◦C (Table 2, entry 3) and no TBDMS protected
product was detected. However, mixture of both isomers was
obtained for methyl, benzyl-substituted aziridines. Methyl sub-
stituted aziridine afforded an inseparable mixture of isomers
on silica gel column chromatography which was separated
to oxygen nucleophile A, which underwent highly regioselective
aziridine ring opening to produce another nitrogen nucleophile C
as a fleeting intermediate. Afterwards, there would be two probable
pathways (path a & b) to form the desired molecules. Interestingly,
aziridines 12a–c showed a similar kind of reactivity to follow path
b, giving 1,4-oxazepane derivatives 14a–c.
However, aziridines 12d–e followed path a & b, leading to the
formation of mixture of isomers. To rationalize the formation of six
and seven member chiral heterocycles, we focused our attention on
the intermediate C. Probably, depending on the stability of C and
activation of the epoxide ring due to non covalent interaction with
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7365–7371 | 7367
©

View Article Online
Experimental
General methods
IR spectra were recorded on a Perkin-Elmer FT-IR RXI spec-
trometer. 1H NMR and 13C NMR spectra were recorded on
1
Brucker DPX-200 (operating at 200 MHz for H and 50 MHz
for 13C) or DPX-300 (operating at 300 MHz for 1H and 75 MHz
for 13C) spectrometer using CDCl3 as solvent. Tetramethylsilane
(0.00 ppm) served as an internal standard in 1H NMR and CDCl3
(77.0 ppm) in 13C NMR. All spectra were recorded at 25 ◦C.
Coupling constants (J values) are given in hertz (Hz). Chemical
shifts are expressed in parts per million (ppm). Mass spectra
were recorded using electron spray ionization (ESMS). Glycerol
or m-nitro benzyl alcohol was used as matrix. Reactions were
monitored on silica gel TLC plates (coated with TLC grade silica
gel). Detecting agents used (for TLC) were iodine vapors and/or
spraying with an aqueous solution of vanillin in 10% sulfuric
acid followed by heating at 150 ◦C. Column chromatography was
performed over silica gel (100–200 mesh) procured from Qualigens
(India) using freshly distilled solvents. The diastereomeric excess
was determined by LichroCART Chiradex column (250 ¥ 4
mm), (R,R)-Whelk-01) column using iso-propanol/acetonitrile,
flow rate 0.50 mL min-1 and for 14d hexane/acetonitrile, flow rate
0.80 mL min-1 as eluent at 20 ◦C.
Scheme 6 Proposed plausible mechanism.
potassium ion, the above results could be explained. For aziridines
12a–c, large steric interaction between tosyl and alkyl groups
disfavored six members T.S (see C1, Scheme 6) that allowed path
b to provide 1,4-oxepane derivatives. In case of 12d & 4, probably,
the large distance between tosyl and alkyl groups minimized the
steric interaction (see C2) in comparison to 14a–c that helps to
stabilize C and high reactivity of epoxide ring follows path a &
b giving the mixture of isomers. For benzyl substituted aziridines
12e, probably, p–p stacking interaction and epoxide reactivity is
the driving force to follow the path a & b to furnish separable
isomers. It is worth noting that yield of formation of seven member
oxazepane is more favored than six member morpholine.
The tosyl group of the selected molecules 7 & 8 were deprotected
(Scheme 7) by using sodium naphthalenide 13l in dry THF with 65%
& 63% yield, respectively.
Experimental procedures and characterization data
Experimental procedure for the synthesis of chiral aziridines 4,
12a–d & 12e
The chiral aziridines are prepared in our previously reported
procedure.17
(S)-2-iso-Propyl-1-tosylaziridine 4. Colorless solid; mp 78–
82 ◦C; yield, 47% (four steps); Rf 0.50 (8.5/1.5, hexane/ethyl
acetate); [a]2D5 = +4.4 (c 0.1, CHCl3); IR (neat, cm-1): 3298, 3024,
2964, 1463, 1321, 1158, 758; 1H NMR (200 MHz, CDCl3) d 7.79–
7.75 (m, 2H), 7.30–7.26 (m, 2H), 2.55–2.43 (m, 5H), 2.02–2.00 (m,
1H), 1.46–1.30 (m, 1H), 0.89 (d, 3H, J = 6.6), 0.79 (d, 3H, J = 6.6);
13C NMR (75 MHz, CDCl3) d 143.8, 135.8, 129.4, 128.2, 45.8,
32.4, 30.1, 21.6, 19.6, 19.2; MS (ESI): m/z 240 [M+H]+.
(S)-2-iso-Butyl-1-tosylaziridine 12a. Colorless oil; yield, 45%
(four steps); Rf 0.50 (8.5/1.5, hexane/ethyl acetate); [a]2D5 = +24.1
(c 0.11, CHCl3); IR (neat, cm-1): 3291, 3021, 2958, 1462, 1159,
764; 1H NMR (200 MHz, CDCl3) d 7.83–7.80 (m, 2H), 7.34–7.32
(m, 2H), 2.82–2.74 (m, 1H), 2.63–2.61 (m, 1H), 2.44 (s, 3H), 2.03–
2.01 (m, 1H), 1.67–1.56 (m, 1H), 1.35–1.30 (m, 2H), 0.889–0.885
(m, 6H); 13C NMR (75 MHz, CDCl3) d 144.3, 135.0, 129.5, 127.8,
40.3, 38.9, 33.9, 26.6, 22.6, 21.8, 21.5; MS (ESI): m/z 254 [M+H]+.
Scheme 7 Tosyl group deprotection of 7 & 8.
In conclusion, a new one pot synthetic strategy for the synthesis
of enatiomerically pure cis-3,5-disubstituted morpholines and 3,6-
disubstituted 1,4-oxazepanes is described from S-amino acids
derived aziridines and R-glycidol via tandem aziridine/epoxide
ring opening sequences. A plausible reaction mechanism was
proposed and it was also rationalized that formation of six
member morpholine and seven member 1,4-oxazepane derivatives
depending on chiral aziridines. This new strategy describes how
epoxy alcohols could act as both nucleophile and electrophile
in a tandem process and undergo intermolecular regioselective
ring opening of aziridines for the first time. Further scope of this
methodology is being investigated in our laboratory.
(S)-3-((1-Tosylaziridin-2-yl)methyl)-1H-indole 12c. Colorless
oil; yield, 46% (four steps); Rf 0.50 (7.0/3.0, hexane/ethyl acetate);
[a]2D5 = +8.6 (c 0.06, CHCl3); IR (neat, cm-1): 3408, 3021, 2923,
1
1320, 1218, 1158, 762; H NMR (300 MHz, CDCl3) d 8.03 (bs,
1H), 7.68–7.66 (m, 2H), 7.48 (d, 1H, J = 7.8), 7.32 (d, 1H, J = 8.1),
7.21–7.06 (m, 4H), 6.996–6.990 (m, 1H), 3.11–2.99 (m, 2H), 2.86
(dd, 1H, J1 = 6.5, J2 = 14.9), 2.72 (d, 1H, J = 6.6), 2.40 (s, 3H),
2.22–2.21 (m, 2H); 13C NMR (75 MHz, CDCl3) d 144.1, 136.0,
7368 | Org. Biomol. Chem., 2011, 9, 7365–7371
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
134.6, 129.3, 127.6, 127.1, 122.3, 121.9, 119.3, 118.5, 111.1, 111.0,
40.6, 33.3, 27.1, 21.5; MS (ESI): m/z 327 [M+H]+.
4.62 min, CH3CN/iso-propanol); IR (neat, cm-1): 3513, 3271,
2958, 1463, 1158, 758; H NMR (300 MHz, CDCl3) d 7.76–7.73
1
(m, 2H), 7.27–7.24 (m, 2H), 5.14–5.12 (m, 1H), 3.54 (dd, 1H, J1 =
2.7, J2 = 11.5), 3.38 (dd, 1H, J1 = 4.2, J2 = 9.8), 3.25–3.07 (m,
(S)-2-Methyl-1-tosylaziridine 12d. Colorless semi-solid; yield,
42% (four steps); Rf 0.51 (8.0/2.0, hexane/ethyl acetate); [a]D25
-13.1 (c 0.1, CHCl3); IR (neat, cm-1): 3291, 3027, 2958, 1457,
3H), 2.98–2.95 (m, 1H), 2.72–2.69 (m, 1H), 2.49 (dd, 1H, J1
=
2.7, J2 = 5.0), 2.38 (s, 3H), 1.87–1.83 (m, 1H), 0.84–0.80 (m, 6H);
13C NMR (50 MHz, CDCl3) d 143.2, 137.8, 129.5, 127.0, 78.1,
74.7, 71.1, 64.6, 47.4, 26.4, 21.4, 19.6, 19.5; MS (ESI): m/z 314
[M+H]+, 336 [M+Na]+.
1
1320, 1158, 759; H NMR (200 MHz, CDCl3) d 7.83–7.79 (m,
2H), 7.34–7.30 (m, 2H), 2.88–2.74 (m, 1H), 2.61–2.57 (m, 1H),
2.43 (s, 3H), 2.02–1.99 (m, 1H), 1.23 (d, 3H, J = 5.5); 13C NMR
(75 MHz, CDCl3) d 144.3, 135.3, 129.6, 127.7, 35.7, 34.6, 21.5,
16.7; MS (ESI): m/z 212 [M+H]+.
(3R,5S)-5-iso-Propyl-4-tosylmorpholin-3-yl)methanol 6. Col-
orless oil; yield, 21.7% (based on 4); Rf 0.50 (7.0/3.0, hexane/ethyl
acetate); [a]2D5 = +25.61 (c 0.010, MeOH), IR (neat, cm-1): 3421,
2922, 2857, 1463, 1218, 767; 1H NMR (300 MHz, CDCl3) d 7.74–
7.71 (m, 2H), 7.34–7.32 (m, 2H), 3.92–3.75 (m, 4H), 3.66–3.62 (m,
1H), 3.37 (dd, 1H, J1 = 3.5, J2 = 10.8), 3.03 (dd, 1H, J1 = 3.7, J2 =
11.9), 2.94 (dd, 1H, J1 = 4.2, J2 = 11.7), 2.45 (s, 3H), 2.31 (bs, 1H),
(S)-2-(4-Methoxybenzyl)-1-tosylaziridine 12e. First, phenolic-
OH group of L-tyrosine methyl ester hydrochloride was methylated
and then aziridine was synthesized in accordance with our
previously reported sequence.17
Experimental procedure for the synthesis of 6 & 7
2.12–2.03 (m, 1H), 1.15 (d, 3H, J = 6.7), 0.98 (d, 3H, J = 6.5); 13
C
To a stirred solution of chiral aziridine 4 (500 mg, 2.09 mmol) and
R-glycidol (0.14 mL, 2.09 mmol) in anhydrous DMSO (10 mL)
was added BuOK (281 mg, 2.51 mmol) and then the mixture
NMR (50 MHz, CDCl3) d 143.6, 138.0, 130.0, 126.8, 66.6, 65.2,
62.8, 59.1, 53.7, 29.5, 21.5, 20.6, 20.4; MS (ESI): m/z 314 [M+H]+.
t
was stirred for 5–15 min at RT. After completion of reaction,
the reaction mixture was diluted with water and aqueous layer
was extracted with AcOEt (2 ¥ 50 mL). Removal of solvent
under vacuum and column chromatography of the crude product
on silica gel with AcOEt-hexane (2.5 : 7.5) as eluent to furnish
inseparable mixture of 6 & 7 (458 mg, 70% yield) as a colorless oil.
Experimental procedure for the synthesis of 10
The compound 6 (85 mg, 0.27 mmol) was dissolved in 1.5 mL
anhydrous pyridine, and then it was cooled at 0 C, followed by
◦
addition of methane sulfonyl chloride (0.06 mL, 0.81 mmol). Then
it was continuous stirred for 12 h. The pyridine was quenched with
dil HCl and then diluted with 30 mL water. The aqueous layer was
extracted with ethyl acetate (2 ¥ 50 mL) and dried over anhydrous
sodium sulphate. The solvent was removed under vacuum and
the crude product was then chromatographed over silica gel with
eluent AcOEt-Hexane (3.5 : 6.5) to afford the title compound 10
(80 mg, 75%) as a colorless oil.
Separation of inseparable isomers (6 & 7). To a stirred solution
of mixture compounds (6 & 7) (458 mg, 1.46 mmol) in anhydrous
DCM (10 mL) were added TBDMSiCl (220 mg, 1.46 mmol) and
imidazole (149 mg, 2.19 mmol) at 0 ◦C. The resulting solution was
stirred for 20 min at the same temperature. The reaction mixture
was diluted with water and then aqueous layer was extracted with
DCM (2 ¥ 50 mL). Removal of solvent under vacuum and column
chromatography of the crude product on silica gel with AcOEt-
hexane to furnish TBDMS-protected 8 (230 mg, 25.7% yield)
based on 4 as colorless oil and 7 (305 mg, 46.6% yield) based
on 4 as a colorless oil.
(3S,5S)-5-iso-Propyl-4-tosylmorpholin-3-yl)methylmethane-
sulfonate 10. Colorless oil; yield, 75%; Rf 0.52 (7.5/2.5, hex-
ane/ethyl acetate); [a]D25 = +15.21 (c 0.098, MeOH), HPLC
analysis: de > 99 (tR = 4.63 min, CH3CN/H2O); IR (neat, cm-1):
1
3421, 3028, 2922, 1635, 1349, 1170, 768; H NMR (300 MHz,
CDCl3) d 7.74–7.71 (m, 2H), 7.36–7.33 (m, 2H), 4.52–4.46 (m,
1H), 4.33 (dd, 1H, J1 = 5.2, J2 = 9.5), 3.95–3.76 (m, 3H), 3.37 (dd,
1H, J1 = 3.4, J2 = 11.2), 3.09 (s, 3H), 3.01–2.94 (m, 2H), 2.46 (m,
2H), 2.03–1.95 (m, 1H), 1.11 (dd, 1H, J = 6.8), 1.00 (d, 3H, J = 6.3);
13C NMR (50 MHz, CDCl3) d 143.8, 137.6, 130.0, 129.7, 127.0,
126.8, 67.4, 66.5, 64.6, 58.7, 50.5, 37.4, 29.7, 21.4, 20.5, 20.3; MS
(ESI): m/z 348 [M+-CH(CH3)2], 392 [M+H]+.
Next, to a stirred solution of 8 (230 mg, 0.54 mmol) in anhydrous
THF (10 mL) under an atmosphere of N2, was added TBAF (1
M) (0.64 mL) dropwise at 0 ◦C. The reaction mixture was stirred
for 25 min at the room temperature The reaction mixture was
diluted with water and extracted with ethyl acetate (2 ¥ 50 mL).
Removal of solvent under vacuum and column chromatography
of the crude product on silica gel with AcOEt-hexane to furnish 6
(142 mg, 84.5% yield) as colorless oil and 21.7% yield based on 4.
Experimental procedure for the synthesis of 14a–c
(3S,5S)-3-((tert-Butyldimethylsilyloxy)methyl)-5-iso-propyl-4-
tosylmorpholine 8. Colorless oil; yield, 25.7% (based on 4); Rf
0.51 (9.0/1.0, hexane/ethyl acetate); IR (neat, cm-1): 3431, 2958,
The procedure was followed as described for6 & 7.
(3S,6S)-3-iso-Butyl-4-tosyl-1,4-oxazepan-6-ol 14a. Colorless
oil; yield, 74%; Rf 0.52 (7.5/2.5, hexane/ethyl acetate); [a]D25
-62.9 (c 0.105, MeOH); HPLC analysis: de > 99 (tR = 4.66 min,
CH3CN/iso-propanol); IR (neat, cm-1): 3510, 3276, 2957, 1461,
1328, 1157, 759; 1H NMR (200 MHz, CDCl3) d 7.81–7.77 (m, 2H),
7.33–7.30 (m, 2H), 4.95–4.91 (m, 1H), 3.66–3.59 (m, 1H), 3.39–
3.18 (m, 4H), 3.08–3.00 (m, 1H), 2.82–2.75 (m, 1H), 2.57–2.53 (m,
1H), 2.44 (s, 3H), 1.66–1.53 (m, 1H), 1.39–1.33 (m, 2H), 0.85 (d,
3H, J = 6.6), 0.76 (d, 3H, J = 6.4); 13C NMR (50 MHz, CDCl3) d
143.1, 138.2, 129.5, 127.0, 72.9, 71.8, 51.8, 50.5, 44.0, 41.5, 24.2,
1
2863, 1638, 1218, 761; H NMR (300 MHz, CDCl3) d 7.74–7.72
(m, 2H), 7.34–7.31 (m, 2H), 3.92–3.84 (m, 3H), 3.75 (dd, 1H, J1 =
4.3, J2 = 8.7), 3.56–3.50 (m, 1H), 3.32 (dd, 1H, J1 = 3.3, J2 = 10.7),
3.01 (dd, 1H, J1 = 3.7, J2 = 11.8), 2.88 (dd, 1H, J1 = 3.5, J2 = 11.8),
2.45 (s, 3H), 2.06–1.94 (m, 1H), 1.10 (d, 1H, J = 6.7), 0.98 (d, 1H,
J = 6.4), 0.90 (s, 9H), 0.08 (s, 6H); MS (ESI): m/z 428 [M+H]+.
(3S,6S)-3-iso-Propyl-4-tosyl-1,4-oxazepan-6-ol 7. Colorless
oil; yield, 46.6% (based on 4); Rf 0.51 (7.0./3.0, hexane/ethyl
acetate); [a]2D5 = +6.8 (c 0.1, MeOH); HPLC analysis: de > 99 (tR =
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7365–7371 | 7369
©

View Article Online
22.7, 21.8, 21.4; MS (ESI): m/z 254 [M+-OH, CH2CH(CH3)2], 310
(8.5/1.5, hexane/ethyl acetate); IR (neat, cm-1): 3438, 2953, 2862,
1634, 1219, 1098, 768; H NMR (300 MHz, CDCl3) d 7.73–7.70
1
[M+-OH], 327.9 [M+H]+, 344.9 [M+NH4]+.
(m, 2H), 7.32–7.29 (m, 2H), 4.04–3.81 (m, 4H), 3.68–3.59 (m, 2H),
3.23–3.18 (m, 1H), 3.11–3.06 (m, 1H), 2.43 (s, 3H), 1.33 (d, 3H,
J = 7.0), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (50 MHz, CDCl3) d
143.3, 138.3, 129.8, 126.7, 70.5, 65.2, 62.7, 53.5, 47.6, 25.9, 21.5,
21.4, 18.2, -5.3, -5.5; MS (ESI): m/z 400 [M+H]+, 421.7 [M+Na]+.
(3S,6S)-3-sec-Butyl-4-tosyl-1,4-oxazepan-6-ol 14b. Colorless
oil; yield, 65%; Rf 0.51 (7.5/2.5, hexane/ethyl acetate); [a]2D5 -2.23
(c 0.101, MeOH); HPLC analysis: de > 99 (tR = 4.67 min,
CH3CN/iso-propanol); IR (neat, cm-1): 3431, 3290, 2965, 1328,
1217, 1159, 768; 1H NMR (300 MHz, CDCl3) d 7.78–7.75 (m, 2H),
7.30–7.28 (m, 2H), 4.97–4.94 (d, 1H), 3.59–3.54 (m, 1H), 3.44–3.39
(m, 1H), 3.28–3.15 (m, 3H), 3.02–2.97 (m, 1H), 2.76–2.73 (m, 1H),
2.53–2.50 (m, 1H), 2.42 (s, 3H), 1.70–1.61 (m, 1H), 1.55–1.44 (m,
1H), 1.12–0.99 (m, 1H), 0.84 (d, 3H, J = 7.2), 0.82 (d, 3H, J =
6.7); 13C NMR (75 MHz, CDCl3) d 143.2, 138.2, 129.5, 127.1,
71.8, 70.2, 57.6, 50.6, 44.1, 36.5, 25.3, 21.5, 15.1, 11.5; MS (ESI):
m/z 254 [M+-OH, CH2CH(CH3)2], 310 [M+-OH], 328 [M+H]+,
345 [M+NH4]+.
(3S,6S)-3,6-Dimethyl-4-tosyl-1,4-oxazepane 14d. Colorless
oil; yield, 43.7% (based on 12d); Rf 0.51 (7.5/2.5, hexane/ethyl
acetate); [a]2D5 = +35.7 (c 0.101, MeOH); HPLC analysis: de
> 99 (tR = 17.75 min, hexane/CH3CN); IR (neat, cm-1): 3429,
1
3021, 2932, 2870, 1331, 1155, 764; H NMR (300 MHz, CDCl3)
d 7.72–7.70 (m, 2H), 7.32–7.29 (m, 2H), 4.16–4.11 (m, 2H),
3.93–3.78 (m, 2H), 3.75–3.69 (m, 2H), 3.56 (dd, 1H, J1 = 4.1, J2 =
12.7), 3.09 (dd, 1H, J1 = 8.7, J2 = 15.1), 2.43 (s, 3H), 2.28 (bs, 1H),
1.03 (d, 3H, J = 6.7); 13C NMR (50 MHz, CDCl3) d 143.3, 137.8,
129.7, 126.8, 77.5, 77.4, 70.5, 53.6, 46.8, 21.4, 15.1; MS (ESI):
m/z 272 [M+H+-CH3], 308 [M+Na]+.
(3S,6S)-3-((1H-Indol-3-yl)methyl)-4-tosyl-1,4-oxazepan-6-ol
14c. Colorless oil; yield, 63%; Rf 0.51 (6.5/3.5, hexane/ethyl
acetate); [a]2D5 -64.6 (c 0.105, MeOH); HPLC analysis: de > 99
(tR = 4.74 min, CH3CN/iso-propanol); IR (neat, cm-1): 3413, 2985,
1700, 1429, 1226, 1155, 764; 1H NMR (200 MHz, CDCl3) d 8.24
(bs, 1H), 7.56–7.52 (m, 2H), 7.29–6.97 (m, 7H), 5.30–5.24 (m, 1H),
5.01–4.85 (m, 3H), 3.75–3.33 (m, 3H), 2.80 (bs, 2H), 2.36 (s, 4H);
13C NMR (75 MHz, CDCl3) d 142.8, 136.2, 129.3, 127.2, 126.6,
123.3, 121.8, 119.3, 118.3, 111.2, 109.9, 77.2, 70.5, 69.7, 53.4, 52.2,
29.6, 21.9; MS (ESI): m/z 401 [M+H]+.
((3R,5S)-5-Methyl-4-tosylmorpholin-3-yl)methanol 13a. Col-
orless oil; yield, 22.7% (based on 12d); Rf 0.51 (7.5/2.5, hex-
ane/ethyl acetate); [a]2D5 -12.46 (c 0.106, MeOH); HPLC analysis:
de > 99 (tR = 4.98 min, CH3CN/iso-propanol); IR (neat, cm-1):
3429, 2931, 2858, 1468, 1219, 764; 1H NMR (300 MHz, CDCl3);
d 7.73–7.70 (m, 2H), 7.32–7.29 (m, 2H), 3.91–3.83 (m, 4H), 3.75–
3.72 (m, 1H), 3.57–3.53 (m, 1H), 3.23–3.12 (m, 2H), 2.43 (s, 3H),
1.38 (d, 3H, J = 7.0); 13C NMR (75 MHz, CDCl3) d 143.5, 138.0,
129.9, 126.6, 70.4, 65.7, 63.0, 53.4, 47.8, 21.4, 21.0; MS (ESI): m/z
286 [M+H]+.
Experimental procedure for the synthesis of 13a & 14d
To a stirred solution of chiral aziridine 12d (580 mg, 2.74 mmol)
and R-glycidol (0.18 mL, 2.74 mmol) in anhydrous DMSO (10 mL)
was added tBuOK (369 mg, 3.29 mmol) and then the mixture was
stirred for 5 min at RT. Same work-up procedure was followed
as described for 6 & 7 and column chromatography of the crude
product on silica gel with AcOEt-hexane (3.5 : 6.5) as eluent to
furnish inseparable mixture (494 mg, 63% yield) as a colorless oil.
Experimental procedure for the synthesis of 13b & 14e
To a stirred solution of chiral aziridine 12e (480 mg, 1.51 mmol)
and R-glycidol (0.10 mL, 1.51 mmol) in anhydrous DMSO (7 mL)
was added tBuOK (203 mg, 1.81 mmol) and then the mixture was
stirred for 5 min at RT. Same work-up procedure was followed as
described for 6 & 7 and column chromatography of the crude
product on silica gel with AcOEt-hexane furnished separable
mixture of 13b (147 mg, 25% yield) and 14e (233 mg, 39% yield)
as a colorless oil. Combine yield is 64%.
Separation of inseparable isomers
To a stirred solution of mixture compounds (494 mg, 1.73 mmol)
in anhydrous DCM (10 mL) were added TBDMSiCl (260.7 mg,
1.73 mmol) and imidazole (176 mg, 2.59 mmol) at 0 ◦C. The
resulting solution was stirred for 20 min at the same temperature.
Same work-up procedure was followed as described for 6 & 7 and
column chromatography of the crude product on silica gel with
AcOEt-hexane to furnish TBDMS-protected morpholine (296 mg,
27% yield) based on 12d as colorless oil and 14d (342 mg, 43.7%
yield) based on 12d as a colorless oil.
Next, to a stirred solution of TBDMS-protected morpholine
(296 mg, 0.74 mmol) in anhydrous THF (10 mL) under atm◦osphere
of N2, was added TBAF (1 M) (0.89 mL) dropwise at 0 C. The
reaction mixture was stirred for 30 min at the room temperature.
The reaction mixture was diluted with water and extracted with
ethyl acetate (2 ¥ 50 mL). Removal of solvent under vacuum and
column chromatography of the crude product on silica gel with
AcOEt-hexane to furnish 13a (178 mg, 84.3% yield) as colorless
oil and 22.7% yield based on 12d.
((3R,5S)-5-(4-Methoxybenzyl)-4-tosylmorpholin-3-yl) methanol
13b. Rf 0.51 (7.5/2.5, hexane/ethyl acetate); [a]2D5 -21.6 (c 0.105,
MeOH); HPLC analysis: de > 99 (tR = 4.76 min, CH3CN/iso-
propanol); IR (neat, cm-1): 3420, 2927, 2363, 1611, 1221, 771; 1H
NMR (300 MHz, CDCl3) d 7.67–7.64 (m, 2H), 7.24–7.22 (m, 2H),
6.97–6.73 (m, 2H), 3.78 (s, 3H), 3.69–3.64 (m, 1H), 3.51–3.47 (m,
1H), 3.38–3.26 (m, 3H), 3.11–3.06 (m, 1H), 2.82–2.72 (m, 3H),
2.59–2.56 (m, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) d
158.2, 143.1, 137.5, 130.2, 129.5, 128.9, 126.9, 113.8, 71.7, 71.4,
55.1, 54.7, 50.5, 44.1, 37.1, 21.4; MS (ESI): m/z 414 [M+Na]+, 430
[M+K]+.
(3S,6S)-3-(4-Methoxybenzyl)-4-tosyl-1,4-oxazepan-6-ol
14e.
Rf 0.49 (7.5/2.5, hexane/ethyl acetate); [a]2D5 -19.0 (c 0.109,
MeOH); HPLC analysis: de > 99 (tR = 4.95 min, CH3CN/iso-
propanol); IR (neat, cm-1): 3445, 2362, 1631, 1220, 771; 1H
NMR (300 MHz, CDCl3) d 7.58–7.56 (m, 2H), 7.24–7.21 (m,
2H), 6.97–6.94 (m, 2H), 6.75–6.72 (m, 2H), 4.19–4.10 (m, 2H),
3.88–3.76 (m, 7H), 3.58 (dd, 1H, J1 = 3.6, J2 = 12.7), 3.19 (dd, 1H,
(3S,5S)-3-((tert-Butyldimethylsilyloxy)methyl)-5-methyl-4-tos-
ylmorpholine. Colorless oil; yield, 27% (based on 12d); Rf 0.53
7370 | Org. Biomol. Chem., 2011, 9, 7365–7371
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
J1 = 6.9, J2 = 15.0), 2.86 (dd, 1H, J1 = 8.9, J2 = 13.5), 2.65 (dd,
1H, J1 = 6.0, J2 = 13.6), 2.42 (s, 3H); 13C NMR (50 MHz, CDCl3)
d 158.3, 143.2, 137.4, 130.1, 129.6, 129.2, 126.8, 113.9, 75.0, 71.1,
59.9, 55.1, 47.4, 35.0, 21.4; MS (ESI): m/z 121 [CH2C6H4OMe]+,
391.9 [M+H]+ 414 [M+Na]+, 433 [M+2H+Na]+.
2 (a) J. Sanchez-Quesada, M. R. Ghadiri, H. Bayley and O. Braha, J. Am.
Chem. Soc., 2000, 122, 1175; (b) D. T. Bong, T. D. Clark, J. R. Granja
and M. R. Ghadiri, Angew. Chem., Int. Ed., 2001, 40, 988.
3 E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58, 2481.
4 For a review on the synthesis and biological significance of C-
substituted morpholines, see: (a) R. Wijtmans, M. K. S. Vink, H. E.
Schoemaker, F. L. van Delft, R. H. Blaauw and F. P. J. T. Rutjes,
Synthesis, 2004, 641.
5 E. H. F. Wong, M. S. Sonders, S. G. Amara, P. M. Tinholt, M. F. P.
Piercey, W. P. Hoffmann, D. K. Hyslop, S. Franklin, R. D. Porsolt, A.
Bonsignori, N. Carfagna and R. A. McArthur, Biol. Psychiatry, 2000,
47, 818.
6 (a) M. C. Chrysselis, E. A. Rekka and P. N. Kourounakis, J. Med.
Chem., 2000, 43, 609; (b) M. C. Chrysselis, E. A. Rekka, I. C. Siskou and
P. N. Kourounakis, J. Med. Chem., 2002, 45, 5406; (c) C. Guilloneau, Y.
Charton, Y. Ginot, M. Fouquier-d’Herouel, M. Bertrand, B. Lockhart,
P. Lestage and S. Goldstein, Eur. J. Med. Chem., 2003, 38, 1.
7 (a) H. Dieckmann, M. Stockmaier, R. Kreuzig and M. Bahadir,
Fresenius’ J. Anal. Chem., 1993, 345, 784; (b) J. A. H. Lainton, M.
C. Allen, M. Burton, S. Cameron, T. R. G. Edwards, G. Harden, R.
Hogg, W. Leung, S. Miller, S. S. Morrish, S. M. Rooke and B. Wendt, J.
Comb. Chem., 2003, 5, 400 and references cited therein; (c) D. Enders,
O. Meyer, G. Raabe and J Runsink, Synthesis, 1994, 66–72; (d) R Dave
and N. A. Sasaki, Org. Lett., 2004, 6, 15–18.
8 (a) H. Ohno, H. Hamaguchi, M. Ohata, S. Kosaka and T. Tanaka, J.
Am. Chem. Soc., 2004, 126, 8744; (b) L. Banfi, A. Basso, G. Guanti, N.
Kielland, C. Repetto and R. Riva, J. Org. Chem., 2007, 72, 2151.
9 (a) K. Ø. Audouze, E. Nielsen and D. Peters, J. Med. Chem., 2004, 47,
3089; (b) G. Sharma, J. Y. Park and M. S. Park, Bioorg. Med. Chem.
Lett., 2008, 18, 3188; (c) S. Y. Ablordeppey, R. B. Altundas, X. Y. Zhu,
E. V. K. S. Kumar, T. Jackson, A. Khan and B. L. Roth, Bioorg. Med.
Chem., 2008, 16, 7291.
General experimental procedure for the synthesis of 15 & 16.
Finely chopped sodium metal (12 equiv) and naphthalene (14
equiv) were dissolved in 7 mL dry THF. The reaction mixture
was stirred for 2 h, until a dark green color was appeared. The
◦
desired THF solution of 7 & 8 were cooled to -78 C and then
Na-napthalenide solution was added dropwise to the reaction
mixture via a syringe, until a dark green color was persisted.
The reaction mixture was stirred for 15 min at -78 ◦C and
then it was quenched by adding 1–2 drops water to discharge
the green color. The reaction mixture was diluted with water
and then extracted with EtOAc (3 ¥ 50 mL) and the organic
layer was dried over anhydrous Na2SO4, concentrated under vac-
uum and the column chromatography (eluent = MeOH/CHCl3,
0.6 : 9.4) of crude product over silica gel furnished 15 &
16.
(3S,6S)-3-iso-Propyl-1,4-oxazepan-6-ol 15. Brown oil; yield,
65%; Rf 0.25 (6.5/3.5, hexane/ethyl acetate); IR (neat, cm-1): 3443,
1
2963, 1632, 1367, 771; H NMR (300 MHz, CDCl3) d 4.03–4.01
(m, 2H), 3.93–3.84 (m, 1H), 3.68–3.53 (m, 2H), 3.17–3.14 (m, 1H),
2.41–2.37 (m, 1H), 2.09–2.02 (m, 1H), 1.07 (d, 3H, J = 6.8), 1.00
(d, 3H, J = 6.7); 13C NMR (75 MHz, CDCl3) d 72.3, 67.8, 57.3,
28.4, 18.9, 18.5; MS (ESI): m/z 144 [M+2H-OH]+.
10 (a) T. J. Grinsteiner and Y. Kishi, Tetrahedron Lett., 1994, 45, 8333;
(b) T. J. Grinsteiner and Y. Kishi, Tetrahedron Lett., 1994, 45, 8337.
11 K. Shankaran, K. L. Donnelly, S. K. Shah, C. G. Caldwell, P. Chen, W.
K. Hagmann, M. MacCoss, J. L. Humes, S. G. Pacholok, T. M. Kelly,
S. K. Grant and K. K. Wong, Bioorg. Med. Chem. Lett., 2004, 14, 5907.
12 (a) P. Wittung, P. E. Nielsen, O. Buchardt, M. Egholm and B. Norde´n,
Nature, 1994, 368, 561; (b) K. E. Nelson, M. Levy and S. L. Miller,
Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 3868.
(3S,5S)-3-((tert-Butyldimethylsilyloxy)methyl)-5-isopropyl-4-
tosylmorpholine 16. Brown oil; yield, 63%; Rf 0.35 (6.5/3.5,
hexane/ethyl acetate); IR (neat, cm-1): 3402, 2366, 1584, 1261,
1
13 (a) J. K. Mishra and G. Panda, Synthesis, 2005, 1881; (b) J. K. Mishra,
J. S. Rao, G. N. Sastry and G. Panda, Tetrahedron Lett., 2006, 47, 3357;
(c) Shagufta and G. Panda, Org. Biomol. Chem., 2007, 5, 360; (d) J. K.
Mishra and G. Panda, J. Comb. Chem., 2007, 9, 321; (e) J. K. Mishra,
P. Garg, P. Dohare, A. Kumar, M. I. Siddiqi, M. Ray and G. Panda,
Bioorg. Med. Chem. Lett., 2007, 17, 1326; (f) A. K. Srivastava and G.
Panda, Chem.–Eur. J., 2008, 14, 4675; (g) A. K. Srivastava, S K. Das and
G. Panda, Tetrahedron, 2009, 65, 5322; (h) M. K. Parai and G. Panda,
Tetrahedron Lett., 2009, 50, 4703; (i) K. Samanta, B. Chakravarti, J. K.
Mishra, S. K. D. Dwivedi, L. V. Nayak, P. Choudhry, H. K. Bid, R.
Konwar, N. Chattopadhyay and G. Panda, Bioorg. Med. Chem. Lett.,
2010, 20, 283; (j) J. K. Mishra, K. Samanta, M. Jain, M. Dikshit and
G. Panda, Bioorg. Med. Chem. Lett., 2010, 20, 244; (k) S K. Das, A.
K. Srivastava and G. Panda, Tetrahedron Lett., 2010, 51, 1483; (l) k.
Samanta and G. Panda, Org. Biomol. Chem., 2010, 8, 2823.
14 (a) M. L. Leathen, B. R. Rosen and J. P. Wolfe, J. Org. Chem., 2009, 74,
5107 and references cited therein; (b) L. Wang, Q. B. Liu, D. S. Wang,
X. Li, H. W. Han, W. J. Xiao and Y. G. Zhou, Org. Lett., 2009, 11, 1119.
15 (a) S. M. Clark and H. M. I. Osborn, Tetrahedron: Asymmetry, 2004,
15, 3643; (b) S K. Das, A. K. Srivastava and G. Panda, Tetrahedron
Lett., 2010, 51, 1483.
1131, 775; H NMR (300 MHz, CDCl3) d 3.85–3.79 (m, 2H),
3.74–3.69 (m, 3H), 3.62–3.54 (m, 3H), 2.00–1.94 (m, 1H), 0.96 (d,
3H, J = 7.3), 0.95 (d, 3H, J = 6.9); MS (ESI): m/z 274 [M+H]+,
298 [M+2H+Na]+.
Acknowledgements
This research project was supported by Department of Science
and Technology (SR/S1/OC-74/2009), New Delhi, India. Krish-
nananda thanks Dr A. Ravishankar for helpful discussion about
2D NMR and CSIR for providing fellowship (NET-SRF). This
has CDRI communication no 8086.
Notes and references
1 (a) J. Taunton, J. L. Collins and S. L. Schreiber, J. Am. Chem. Soc.,
1996, 118, 10412; (b) P. J. Murray, M. Kranz, M. Ladlow, S. Taylor, F.
Berst, A. B. Holmes, K. N. Keavey, A. Jaxa-Chamiec, P. W. Seale, P.
Stead, R. J. Upton, S. L. Croft, W. Clegg and M. R. J. Elsegood, Bioorg.
Med. Chem. Lett., 2001, 11, 773.
16 K. Samanta and G. Panda, Chem.–Asian J., 2011, 6, 189 references
cited therein.
17 G. B. Payne, J. Org. Chem., 1962, 27, 3819.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7365–7371 | 7371
©