Regioselective ring-opening of amino acid-derived chiral aziridines: An easy access to cis-2,5-disubstituted chiral piperazines

Article abstract of DOI:10.1002/asia.201000554

An efficient four-step synthetic strategy for cis-2,5-disubstituted chiral piperazines derived from amino-acid-based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF₃·OEt₂)-mediated ring-opening of less-reactive N-Ts chiral aziridines by α-amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)-piperazinomycin. The pied piperazines: A four-step efficient synthetic strategy for cis-2,5-disubstituted chiral piperazines derived from amino acid-based aziridines is described. The key reaction steps are the highly regioselective BF₃·OEt₂ mediated ring-opening of less-reactive N-Ts chiral aziridines by α-amino acid methyl ester hydrochlorides, followed by a Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)-piperazinomycin. Copyright

Full text of DOI:10.1002/asia.201000554

DOI: 10.1002/asia.201000554
Regioselective Ring-Opening of Amino Acid-Derived Chiral Aziridines: an
Easy Access to cis-2,5-Disubstituted Chiral Piperazines
Krishnananda Samanta and Gautam Panda*[a]
Dedicated to Professor S. Chandrasekaran on the ocassion of his 65th birthday
Abstract: An efficient four-step synthetic strategy for cis-2,5-disubstituted chiral
piperazines derived from amino-acid-based aziridines is described. The key steps
in this strategy are the highly regioselective boron trifluoride diethyl etherate
(BF3·OEt2)-mediated ring-opening of less-reactive N-Ts chiral aziridines by a-
amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This
protocol has been used in an attempt to construct the piperazine core framework
of natural product (+)-piperazinomycin.
Keywords: amino acids · cycliza-
tion · heterocycles · natural prod-
ucts · regioselectivity
Introduction
metric synthesis of chiral piperazines is obtained by the re-
duction of substituted mono- and diketopiperazines,[10,11]
which are again obtained either from chiral building blocks
or by asymmetric synthesis using a chiral auxiliary.
Nitrogen-containing heterocycles, such as piperazines, have
been extensively used as pharmaceutical agents. Designed
piperazine scaffolds exhibiting a wide range of biological ac-
tivities[1], including 5HT-anxiolytics,[2] dopamine D3 agents[3]
acting on central nervous system (CNS) receptors,[4] human
immunodeficiency virus (HIV) protease inhibitors,[1b] for ex-
ample, indinavir, antimicrobial agents such as pefloxacin
and related quinolones,[5] and antihypertensive agent[6], is
considered to be an important
Ring-opening of aziridines with a variety of nucleophiles
in the presence of Lewis acids has been well-explored.[12]
However, a careful survey of the literature did not reveal
many studies concerning ring-opening of amino acid-derived
aziridines with amino acids[13–15] as the nucleophile. In most
of the reported, ring-opening reactions of aziridines, strong
electron-withdrawing groups such as nosyl, and para-nitro-
benzyloxycarbonyl groups (pNZ) were used as protecting
groups for the nitrogen atom, thereby giving rise to a mix-
ture of diastereoisomers.[13] Furthermore, N-Nosyl bearing
aziridines are significantly more reactive than their N-Tosyl
(N-Ts) ones.[16]
We have been working on the synthesis and biology of S-
amino-acid-based chiral heterocycles and natural product-
like molecules.[17] In the present paper, we have developed a
novel methodology to construct cis-2,5-disubstituted chiral
piperazines through a highly regioselective ring-opening of
less-reactive N-Ts chiral aziridines by employing a-amino
acid methyl ester hydrochlorides. To demonstrate the practi-
cal applicability of this method, it was applied toward the
synthesis of (+)-piperazinomycin, which is isolated from
Streptoverticillium olivoreticuli Neoenacticus,[8] and it has an-
timicrobial and antifungal activity. The overall structure of
(+)-piperazinomycin has a cis-2,5-disubstituted piperazine
core and a 14-membered para- and meta-cyclophane diaryl
privileged structure in drug dis-
covery.[1]
Furthermore,
a
number of bioactive natural
products containing a chiral pi-
perazine spacer, such as ecte-
naiscidin 743,[7] piperazinomy-
cin,[8] and dragmacines[9] are
also reported.
However, methods for the
synthesis of chiral piperazines[10]
are abundant. Generally, asym-
[a] K. Samanta, Dr. G. Panda
Division of Medicinal and Process Chemistry
Central Drug Research Institute
Lucknow-226001, UP (India)
Fax : (+91)522-2623405
E-mail: gautam.panda@gmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000554.
Chem. Asian J. 2011, 6, 189 – 197
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
189

FULL PAPERS
ether structural subunit. Few synthetic efforts have been di-
of (S)-2-benzyl-1-tosylaziridine 3b with S-phenylalanine
methyl ester hydrochloride 4b was carried out to optimize
the reaction conditions (see Table 1). The best result was ob-
tained when 3b was treated with 4b (3 equiv), BF3·OEt2
(1.0 equiv), and triethylamine (Et3N; 1 equiv) in tetrahydro-
furan (THF) at 608C for four days. The yield of the reaction
remains unchanged even with the use of 1.1 equiv of
BF3.OEt2. However, with the reaction temperature is in-
creased to 658C, the yield decreased from 58% to 42%
(Table 1, entry 10). The isolation of a single isomer indicates
that ring-opening of the aziri-
rected for piperazinomycin[18]
.
Results and Discussion
Retrosynthetic analysis of piperazines and piperazinomycin
are illustrated in Scheme 1. We envisioned that the chiral pi-
perazine could be constructed from intermediate B, which
could be obtained from boron trifluoride diethyl etherate
dine was highly regioselective,
and the nucleophilic attack oc-
curred from the less-hindered
side of the ring.
By using these optimized
conditions, aziridine ring-open-
ing with different amino acid
ester salts was explored. For all
aziridines and amino acid ester
salts, the desired ring-opening
products were obtained in mod-
erate to good yields with high
regioselectivity (Table 2). The
yield of aziridine ring-opening
reaction increases when the
alkyl group of the aziridine and
the nucleophile are both the
Scheme 1. Retrosynthetic analysis of cis-2,5-disubstituted chiral piperazines and natural product (+)-piperazi-
nomycin.
(BF3.OEt2)-mediated regioselective ring-opening of chiral
aziridines with amino acid methyl ester hydrochloride D,
followed by mesylation, and ester reduction of the inter-
mediate C.
Table 1. Optimization of the regioselective aziridine ring-opening reac-
tion conditions.
Natural product piperazinomycin could be obtained from
piperazine core E by an intramolecular Ullmann-type mac-
rocyclization reaction; this core could be synthesized from F
and G by synthetic sequences mentioned above.
Entry Nu[a]/E+[b]/BF3·OEt2/Et3N Solvent
T
t
Yield [%][c]
First, the synthesis of the chiral aziridine was performed.
Chiral aziridines were prepared in good yields from a-
amino acids following four synthetic steps; these steps in-
volved esterification of acids, tosylation on amines, LiBH4
reduction of ester groups, followed by a Mitsunobu cycliza-
tion (Scheme 2). Now with chiral aziridine 3 in hand, the
stage was set to implement the crucial BF3·OEt2-mediated
regioselective ring-opening of N-tosyl aziridine with S-
amino acid methyl ester hydrochloride. First, ring-opening
1
2
3
4
5
6
7
8
1.0/1/0.1/1
1.0/1/0.1/1
1.5/1/0.5/1
2.0/1/0.5/1
2.0/1/0.5/1
2.0/1/0.5/1
2.0/1/1.0/1
3.0/1/1.0/1
3.0/1/1.1/1
3.0/1/1.1/1
THF
THF
THF
THF
DCM
DCM
THF
THF
THF
THF
RT
1 day
0
0
0
408C 2 days
RT 2 days
408C 3 days
RT 3 days
408C 4 days
608C 4 days
608C 4 days
608C 4 days
658C 4 days
25
trace
15
48
58
58
42
9
10
[a] Nucleophile amino acids; [b] E+ aziridines; [c] Isolated yield based on
3.
same (Table 2, entry 1, 2, 3, and 7). To the best of our
knowledge, it was the first detailed study of a BF3·OEt2-
mediated regioselective ring-opening of amino acid-derived
less-reactive N-Ts chiral aziridines with amino acids as the
nucleophile. In each case, the chiral starting material was re-
covered in 10–20% yield.
Scheme 2. Synthesis of chiral aziridine 3. Reagents and conditions:
a) SOCl2, MeOH, 7 h; b) Et3N, TsCl, 1 h; c) LiBH4, dry THF; 1 h;
d) PPh3, DEAD, THF, 08C.
With this result in hand, our next objective was to com-
plete the synthesis of cis-2,5-disubstituted piperazines
190
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Chem. Asian J. 2011, 6, 189 – 197

Regioselective Ring Opening of Amino Acid-Derived Chiral Aziridines
Table 2. Synthesis of the intermediate 5 by chiral aziridine ring opening
with amino acids methyl ester hydrochlorides.
ture afforded cis-2,5-disubstituted chiral piperazines 8a–g in
70–85% yield.
Having obtained this promising result, our objective was
to synthesize the cis-2,5-disubstituted piperazine ring frame-
work of natural product (+)-piperazinomycin with an idea
of completing the total synthesis. Retrosynthetic analysis
suggests that the intermediate F could be constructed from
l-tyrosine methyl ester hydrochloride (Scheme 1). Synthesis
was commenced from commercially available l-tyrosine
methyl ester hydrochloride 9 (Scheme 4). First, 9 was treat-
ed with Boc2O in the presence of NaHCO3 in ethanol to
obtain Boc-protected amino ester 10 with 96% yield, and
then the phenolic-OH group was methylated by using
K2CO3/methyl iodide in dimethylformamide (DMF), and
this afforded 11 in 97% yield. Boc deprotection of 11 fur-
nished the retrosynthetic intermediate G, which was used in
the aziridine ring-opening reaction of F (Scheme 1). I2/
Ag2SO4 was utilized for mono iodination (ortho to methoxy
group) of the aromatic ring in 11 to afford 12 in 74% yield.
The Boc group was deprotected by treatment with HCl
(6 N) in methanol to obtain 13, and subsequent tosyl protec-
tion by using standard conditions gave 14 in good yield
(41% based on three steps). The ester group of 14 was re-
duced to carbinol in the presence of LiBH4 in THF to give
15 in 87% yield. Finally, Mitsunobu cyclization of 15 fur-
nished (S)-2-(3-iodo-4-methoxybenzyl)-1-tosylaziridine 16 in
76% yield.
Entry
3
4
R
R1
Product Yield [%][a]
1
2
3
4
5
6
7
8
3a 4a CH3
3b 4b CH2Ph
3c 4c CH
3c 4b CH
3c 4a CH
3a 4c CH3
3d 4d CH2-indole,
3e 4b CH2CH
CH3
CH2Ph
CH
CH2Ph
CH3
5a
5b
5c
5d
5e
5 f
5g
61
58
66
36
25
G
G
E
G
CH
CH2-indole,
28
54
(CH3)2 CH2Ph
trace
[a] Isolated yield based on 3.
With aziridine 16 and intermediate G in hand, construc-
tion of piperazinomycin was undertaken (Scheme 5). Regio-
selective ring opening of aziridine 16 with G proceeded
smoothly with the optimized conditions to give a single
isomer 17 in 59% yield. Selective mesylation of secondary
amine 17 afforded 18 in 73% yield. Furthermore, reduction
of the ester in 18 with LiBH4 gave carbinol 19 in 85% yield.
Finally, Mitsunobu cyclization of 19 in the presence of
DEAD/PPh3 furnished the cis-2,5-disubstituted piperazine
core 20 of the natural product piperazinomycin in 74%
yield. Two aromatic methoxy groups were demethylated by
using BBr3 (1m) in dry DCM to afford 21 in 64% yield.
Now, the stage was set for the challenging 14-membered
macrocyclic ether linkage bond construction by an Ullmann-
type macrocyclization reaction. Ether linkage bond forma-
tion was carried out in accordance with the previously re-
ported sequence.[18b] Frustratingly, the ring-cyclization prod-
uct was not isolated. A range of reagents and conditions
were also investigated without cyclization, which gave
mostly decomposition or recovery of starting material. Fail-
ure of the Ullmann macrocyclization reaction has now given
us a challenge to find a way out to complete the total syn-
thesis of (+)-piperazinomycin. As a representative example,
the tosyl group of the cis-2,5-disubstituted chiral piperazine
8c was selectively deprotected by using sodium naphthaleni-
de[17l] as a reducing agent, and this provided 22 with 64%
yield, which gives scope for further structural diversification
(Scheme 6).
Scheme 3. Synthesis of cis-2,5-disubstituted chiral piperazines. Reagents
and conditions: a) dry pyridine, MsCl, 12 h, 65–75% yield; b) LiBH4
(2M), dry THF, 1 h, 85–95% yield; c) PPh3, DEAD, dry THF, 08C, 1 h,
70–85% yield.
(Scheme 3). First, we attempted the intramolecular Mitsuno-
bu cyclization of 7 with an unprotected secondary amine,
and this afforded an inseparable mixture. Then, we decided
to selectively protect the secondary amine of 5a–g. Thus,
treatment of 5a–g with mesyl chloride in a minimum
volume of dry pyridine at room temperature gave the de-
sired result. A variety of reagents and conditions were ex-
amined, such as tert-butyl dicarbonate (Boc2O), Et3N, di-
chloromethane (DCM); Boc2O, Et3N–pyridine (1:1); Boc2O,
4-dimethylaminopyridine (DMAP), DCM; tosyl chloride
(TsCl), Et3N, DCM, TsCl, and pyridine, but these conditions
did not afford the desired product. An alternate procedure
developed by Franzyk and co-workers would be to protect
the secondary amine of 5a–g by microwave-assisted[10d]
easily removable carbamate groups. Next, mesyl-protected
6a–g were treated with LiBH4 in dry tetrahydrofuran (THF)
to obtain carbinols 7a–g in 85–95% yield. Final Mitsunobu
cyclization[19] of 7a–g with diethylazodicarboxylate (DEAD)
and triphenylphosphine (Ph3P) for 1 hour at room tempera-
Chem. Asian J. 2011, 6, 189 – 197
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191

G. Panda et al.
FULL PAPERS
dex column (250ꢁ4 mm, 5 mm) using
water and acetonitrile as an eluent at
*
30 C.
Selected Experimental and Spectral
Data
5: Et3N (1 equiv) was added to
a
stirred solution of N-tosyl-protected
aziridine 3 (1 equiv) and 4 (3 equiv) in
anhydrous THF (20 mL) at 08C. The
reaction mixture was stirred at the
same temperature for an additional
5 minutes and then BF3.OEt2 (1 equiv)
was added at 08C. It was warmed to
room temperature and then stirred for
an additional 1 hour. Then, the mix-
ture was refluxed at 608C for 4 days.
The reaction mixture was diluted with
water and the aqueous layer was ex-
tracted with ethyl acetate (3ꢁ50 mL).
The organic phases were combined,
dried over anhydrous Na2SO4, and
concentrated in vacuo, and the crude
product was purified by column chro-
matography on silica gel using eluent
EtOAc/hexane (3.5:6.5) to afford
product 5.
Scheme 4. Synthesis of (S)-2-(3-iodo-4-methoxybenzyl)-1-tosylaziridine 16 from l-tyrosine. Reagents and con-
ditions: a) NaHCO3, Boc2O, EtOH, 2 h, 96%; b) K2CO3, MeI, DMF, 2 h, 97%; c) HCl (6N), MeOH; d) I2,
Ag2SO4, MeOH, 2 h; e) HCl (6N), MeOH; f) TsCl, Et3N, dry DCM, 1 h, 41% yield based on three steps;
g) LiBH4, THF, 2 h, 87% yield; h) PPh3, DEAD, 1 h, 76% yield.
(S)-Methyl-2((S)-2-(4-methylphenyl-
sulfonamido)propylamino)propanoate
(5a): Colorless oil (61%); Rf =0.52
(6.0:4.0, hexane/EtOAc); IR (neat):
n˜max =3434, 3023, 1732, 1635, 1216,
765 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
TMS): d=7.77–7.74 (m, 2H; 2CH), 7.30–7.27 (m, 2H; 2H), 5.34 (bs, 1H;
Conclusions
NH), 3.70 (s, 3H; CH3), 3.24–3.07 (m, 2H; 2CH), 2.68–2.62 (m, 1H;
3
CHH), 2.45 (s, 3H; CH3), 2.31–2.24 (m, 1H; CHH), 1.24 (d, JH,H =7 Hz,
3H; CH3), 1.09 ppm (d, 3JH,H =6.3 Hz, 3H; CH3); 13C NMR (50 MHz,
CDCl3, TMS): d=175.4, 142.7, 138.2, 129.5, 127.4, 56.6, 52.8, 51.8, 49.6,
21.6, 19.5, 19.0 ppm; MS (ESI): m/z (%): 315 (100) [M+H]+; elemental
analysis: calcd (%) for C14H22N2O4S: C 53.48, H 7.05, N 8.91; found:
C 53.51, H 7.12, N 8.96.
In summary, we have developed an efficient four-step strat-
egy that provides straightforward access to a number of cis-
2,5-disubstituted enantiomerically pure chiral piperazines.
The key steps in this strategy are BF3·OEt2-promoted regio-
selective ring-opening of amino acid-derived N-Ts aziridines
with different amino acid methyl ester hydrochlorides, and
an intramolecular Mitsunobu cyclization. 2,5-disubstituent
variation of the piperazine core was achieved by using dif-
ferent substituted aziridines and amino acid methyl ester hy-
drochlorides. This protocol has been used in an attempt to
synthesize the piperazine ring framework of the natural
product (+)-piperazinomycin.
(S)-Methyl-2-((S)-2-(4-methylphenylsulfonamido)-3-phenyl)propylami-
no)-3-phenylpropanoate (5b): Colorless oil (58%); Rf =0.51 (6.5:3.5,
hexane/EtOAc); IR (neat): n˜max =3432, 3021, 2361, 1725, 1630, 1218,
766 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.66–7.63 (m, 2H;
;
2CH), 7.31–7.20 (m, 5H; 5CH), 7.14–7.10 (m, 5H; 5CH), 6.88–6.85 (m,
2H; 2CH), 5.43–5.41 (m, 1H; NH), 3.64 (s, 3H, CH3), 3.33–3.23 (m, 2H;
2CH), 2.96–2.89 (m, 1H; 1CH), 2.80–2.56 (m, 4H, 4CH), 2.43 (s, 3H;
CH3), 2.26–2.20 ppm (m, 1H; CH); 13C NMR (75 MHz, CDCl3, TMS):
d=174.2, 142.5, 137.9, 137.33, 137.29, 129.4, 129.3, 129.2, 128.4, 128.3,
127.2, 126.7, 126.3, 62.9, 55.0, 51.6, 49.7, 39.4, 39.0, 21.5 ppm; MS (ESI):
m/z (%): 467 (100) [M+H]+; elemental analysis calcd (%) for
C26H30N2O4S: C 66.93, H 6.48, N 6.00; found: C 66.99, H 6.58, N 6.05.
(S)-Methyl-3-methyl-2-((S)-3-methyl-2-(4-methylphenylsulfonamido)bu-
tylamino)butanoate (5c): Light yellow semi-solid (66%); Rf =0.51
(8.0:2.0, hexane/EtOAc); IR (KBr): n˜max =3378, 3023, 2958, 2361, 1720,
Experimental Section
General Remarks
1437, 1325, 774 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.77–7.74
;
(m, 2H; 2CH), 7.31–7.28 (m, 2H; 2CH), 5.09–5.07 (m, 1H; NH), 3.69 (s,
3H; CH3), 2.95–2.87 (m, 1H; CH), 2.84–2.82 (m, 1H; CH), 2.58 (dd,
3JH,H =12.0 Hz, 2JH,H =4.7 Hz, 1H; CHH), 2.42 (s, 3H; CH3), 2.21 (dd,
3JH,H =12.0 Hz, 2JH,H =7.9 Hz, 1H; CHH), 2.09–1.96 (m, 1H; CH), 1.90–
1.76 (m, 1H; CH), 0.89–0.80 ppm (m, 12H, 4CH3); 13C NMR (75 MHz,
CDCl3, TMS): d=175.0, 143.2, 137.3, 129.5, 127.2, 67.5, 59.1, 51.5, 47.7,
31.5, 29.6, 21.5, 19.2, 18.3, 18.2, 17.6 ppm; MS (ESI): m/z (%): 371 (100)
[M+H]+; elemental analysis calcd (%) for C18H30N2O4S: C 58.35, H 8.16,
N 7.56; found: C 58.41, H 8.18, N 7.65.
All chemicals were purchased from Sigma–Aldrich (Milwaukee, Wiscon-
sin, USA). Melting points were determined on COMPLAB melting point
apparatus and are uncorrected. IR spectra were recorded on a Perkin–
Elmer FTIR RXI spectrophotometer. 1H NMR and 13C NMR spectra
were recorded on a Brucker DPX200 or DPX300 spectrometer using the
deuterated chloroform (CDCl3) as
a
solvent. Tetramethylsilane
(0.00 ppm) served as an internal standard in 1H NMR and CDCl3
(77.0 ppm) in 13C NMR. Chemical shifts are expressed in parts per mil-
lion (ppm). Mass spectra were recorded on a JEOL SX 102 spectrometer.
Elemental analyses were done on Varian EL-III CH N analyzer (Germa-
ny). The enantiomeric excess was determined with a LichroCART Chira-
(S)-Methyl-2-((S)-3-methyl-2-(4-methylphenylsulfonamido)butylamino)-
3-phenylpropanoate (5d): Colorless oil (36%); Rf =0.51 (7.5:2.5, hexane/
192
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Chem. Asian J. 2011, 6, 189 – 197

Regioselective Ring Opening of Amino Acid-Derived Chiral Aziridines
IR (neat): n˜max =3394, 3022, 2960,
1739, 1674, 1218, 1159, 764 cmꢀ1
;
1H NMR (300 MHz, CDCl3, TMS):
d=7.77–7.74 (m, 2H; 2CH), 7.30–7.27
(m, 2H; 2CH), 5.23 (bs, 1H; NH),
3
3.69 (s, 3H; CH3), 3.20 (q, JH,H
=
7.0 Hz, 1H; CH), 2.96–2.94 (m, 1H;
CH), 2.55–2.49 (m, 1H; CH), 2.42–
2.36 (m, 4H; CH3, CH), 1.94–1.85 (m,
1H; CH), 1.18 (d, 3JH,H =7.0 Hz, 3H;
CH3), 0.82 (d, 3JH,H =7.03 Hz, 3H;
CH3), 0.79 ppm (d, 3JH,H =6.9 Hz, 3H;
CH3); 13C NMR (75 MHz, CDCl3,
TMS): d=175.6, 143.1, 137.4, 129.4,
127.2, 58.8, 56.4, 51.8, 47.1, 29.7, 21.4,
18.6, 18.2, 17.9 ppm; MS (ESI): m/z
(%): 343 (100) [M+H]+; elemental
analysis: calcd (%) for C16H26N2O4S:
C 56.12,
H 7.65,
N 8.18;
found:
C 56.18, H 7.69, N 8.25.
(S)-Methyl-3-methyl-2-((S)-2-(4-meth-
ylphenylsulfonamido)propylamino)-
butanoate (5 f): Colorless oil (28%);
Rf =0.50 (7.5/2.5, hexane/EtOAc); IR
(neat): n˜max =3405, 3021, 2961, 1738,
1216,
1158,
763 cmꢀ1
;
1H NMR
(300 MHz, CDCl3, TMS): d=7.78–7.74
(m, 2H; 2CH), 7.32–7.29 (m, 2H;
2CH), 5.29 (bs, 1H; NH), 3.70 (s, 3H;
CH3), 3.06–3.05 (m, 1H; CH), 2.88–
2.86 (m, 1H; CH), 2.72–2.66 (m, 1H;
CHH), 2.43 (s, 3H; CH3), 2.16–2.09
(m, 1H; CHH), 1.92–1.81 (m, 1H;
3
CH), 1.13 (d, JH,H =6.4 Hz, 3H; CH3),
0.92 (d, 3JH,H =6.7 Hz, 3H; CH3),
0.87 ppm (d, 3JH,H =6.8 Hz, 3H; CH3);
MS (ESI): m/z (%): 343 (100)
[M+H]+; elemental analysis calcd (%)
for C16H26N2O4S: C 56.12, H 7.65,
N 8.18; found: C 56.21, H 7.63, N 8.26.
Scheme 5. Cis-2,5-disubstituted piperazine core of the (+)-piperazinomycin. Reagents and conditions:
a) BF3·OEt2, Et3N, 608C, 4 d, 59% yield; b) pyridine, MsCl, 12h, 73% yield; c) LiBH4, THF, 2 h, 85% yield;
d) PPh3, DEAD, 1h, 74% yield; e) BBr3, DCM, -788C!RT, 18 h, 64% yield.
(S)-Methyl-2-((S)-3-(1H-indol-3-yl)-2-
(4-methylphenylsulfonamido)propyl
amino)-3-(1H-indol-3-yl) propanoate
(5g): Colorless oil (54%); Rf =0.50
(6.0/4.0, hexane/EtOAc); IR (neat): n˜max =3413, 3020, 2930, 1726, 1641,
1216, 766 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=8.28 (bs, 1H;
;
NH), 7.97 (bs, 1H; NH), 7.59–7.56 (m, 3H; 3CH), 7.39–7.36 (m, 1H;
CH), 7.28–7.07 (m, 7H; 7CH), 6.99–6.96 (m, 2H; 2CH), 6.53 (s, 1H;
CH), 5.38 (bs, 1H; NH), 3.66 (s, 3H; CH3), 3.52–3.44 (m, 1H; CH), 3.37
(bs, 1H; CH), 3.20–3.14 (m, 1H; CHH), 3.02–2.85 (m, 3H; CH2, CHH),
2.79–2.72 (m, 1H; CHH), 2.34–2.31 ppm (m, 4H; CH3, CHH); 13C NMR
(75 MHz, CDCl3, TMS): d=175.0, 143.0, 137.0, 136.3, 136.1, 129.4, 127.4,
127.3, 126.9, 123.1, 122.9, 122.1, 121.8, 119.5, 119.3, 118.6, 111.4, 111.1,
111.0, 110.8, 61.9, 53.7, 51.9, 50.0, 28.9, 28.7, 21.4 ppm; MS (ESI): m/z
(%): 545 (100) [M+H]+, 567 (10) [M+H]+; elemental analysis calcd (%)
for C30H32N4O4S: C 66.15, H 5.92, N 10.29; found: C 66.19, H 5.98,
N 10.38.
Scheme 6. Deprotection of the tosyl group 8c. Reagents and conditions:
a) Na, napthalene, -788C, 15 min, 64% yield.
EtOAc); IR (neat): n˜max =3389, 3024, 2961, 1740, 1331, 1217, 1158,
764 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.73–7.71 (m, 2H;
;
2CH), 7.31–7.25 (m, 5H; 5CH), 7.13–7.11 (m, 2H; 2CH), 5.11–5.09 (m,
1H; NH), 3.66 (s, 3H; CH3), 3.35–3.31 (m, 1H; CH), 2.94–2.75 (m, 3H;
CH2, CH), 2.52 (dd, 3JH,H =12.2 Hz, 2JH,H =4.7 Hz, 1H; CHH), 2.43 (s,
6: Compound 5 (1 equiv) was dissolved in anhydrous pyridine (3 mL),
and then it was cooled at 08C, followed by the addition of methane sulfo-
nyl chloride (2.5 equiv), and was continuously stirred for 12 hours at
room temperature. The pyridine was removed under vacuum. After the
usual work-up, the crude product was chromatographed on silica gel with
the eluent EtOAc/hexane (4.5:5.5) to afford the title compound 6.
3H; CH3), 2.30 (dd, 3JH,H =12.2 Hz, 2JH,H =6.9 Hz, 1H; CHH), 1.93–1.80
3
(m, 1H; CH), 0.78 (d, 3JH,H =7.0 Hz, 3H; CH3), 0.73 ppm (d, JH,H
=
6.8 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, TMS): d=174.4, 143.1,
137.5, 137.0, 129.4, 129.08, 128.97, 128.5, 127.2, 127.0, 126.8, 62.9, 58.8,
51.7, 47.4, 39.4, 29.5, 21.4, 18.3, 17.8 ppm; MS (ESI): m/z (%): 419 (100)
[M+H]+; elemental analysis calcd (%) for C22H30N2O4S: C 63.13, H 7.22,
N 6.69; found: C 63.21, H 7.26, N 6.61.
(S)-Methyl-2-(N-((S)-2-(4-methylphenylsulfonamido)propyl)methyl
sulfonamido)-3-phenylpropanoate (6a): Colorless oil (71%); Rf =0.50
(6.0:4.0, hexane/EtOAc); IR (neat): n˜max =3439, 3023, 1739, 1637, 1217,
(S)-Methyl-2-((S)-3-methyl-2-(4-methylphenylsulfonamido)butylamino)-
propanoate (5e): Colorless oil (25%); Rf =0.51 (6.5:3.5, hexane/EtOAc);
765 cmꢀ1
;
1H NMR (300 MHz, CDCl3, TMS): d=7.79–7.77 (m, 2H;
3
2CH), 7.31–7.28 (m, 2H; 2CH), 5.97–5.95 (m, 1H; NH), 4.43 (q, JH,H
=
Chem. Asian J. 2011, 6, 189 – 197
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
193

G. Panda et al.
FULL PAPERS
7.4, Hz, 1H; CH), 3.73 (s, 3H; CH3), 3.40–3.32 (m, 1H; CH), 3.30–3.22
(m, 1H; CHH), 3.12–3.06 (m, 1H; CHH), 2.94 (s, 3H; CH3), 2.41 (s, 3H;
CH3), 1.09–1.05 ppm (m, 6H; 2CH3); 13C NMR (50 MHz, CDCl3, TMS):
d=172.1, 143.2, 137.4, 129.5, 127.3, 56.1, 52.5, 50.2, 49.8, 38.9, 21.4, 19.7,
16.5 ppm; MS (ESI): m/z (%): 393 (100) [M+H]+; elemental analysis
calcd (%) for C15H24N2O6S2: C 45.90, H 6.16, N 7.14; found: C 45.97,
H 6.25, N 7.03.
2CH), 7.31–7.27 (m, 2H; 2CH), 6.20–6.18 (m, 1H; NH), 3.86–3.80 (m,
1H; CHH), 3.59–3.34 (m, 4H; CHH, CH2, CH), 3.24–3.08 (m, 1H; CH),
2.91 (s, 3H; CH3), 2.40 (s, 3H; CH3), 1.03–0.95 ppm (m, 6H; 2CH3);
13C NMR (75 MHz, CDCl3, TMS): d=143.5, 137.1, 129.7, 127.1, 63.4,
55.9, 49.8, 48.1, 40.0, 21.4, 18.9, 14.9 ppm; MS (ESI): m/z (%): 365 (100)
[M+H]+; elemental analysis calcd (%) for C14H24N2O5S2: C 46.13, H 6.64,
N 7.69; found: C 46.21, H 6.58, N 7.78.
(S)-Methyl-2-(N-((S)-2-(4-methylphenylsulfonamido)-3-phenylpropyl)me-
thylsulfonamido)-3-phenylpropanoate (6b): Colorless oil (72%); Rf =
0.50 (6.0:4.0, hexane/EtOAc); IR (neat): n˜max =3430, 3022, 2929, 2366,
N-((S)-1-(N-((S)-1-Hydroxy-3-methylbutan-2-yl)methylsulfonamido)-3-
methyl- butan-2-yl)-4-methylbenzenesulfonamide (7c): Colorless oil
(93%); Rf =0.51 (7.0:3.0, hexane/EtOAc); IR (neat): n˜max =3514, 3280,
1732, 1216, 763 cmꢀ1 1H NMR (200 MHz, CDCl3, TMS): d=7.64–7.60
;
3025, 2966, 1323, 1153, 760 cmꢀ1 1H NMR (300 MHz, CDCl3): d=7.78–
;
(m, 2H; 2CH), 7.26–7.15 (m, 9H; 9CH), 7.04–7.01 (m, 3H; 3CH), 5.49–
5.47 (m, 1H; NH), 4.50–4.42 (m, 1H; CH), 3.50–3.47 (m, 4H; CH3, CH),
3.37–3.29 (m, 2H; CH2), 2.81–2.78 (m, 2H; CH2), 2.74–2.69 (m, 4H; CH3,
CHH), 2.42–2.39 (m, 1H; CHH), 2.34 ppm (s, 3H; CH3); MS (ESI): m/z
(%): 567 (100) [M+Na]+; elemental analysis calcd (%) for C27H32N2O6S2:
C 59.54, H 5.92, N 5.14; found: C 59.50, H 5.81, N 5.21.
7.75 (m, 2H; 2CH), 7.31–7.28 (m, 2H; 2CH), 6.02–6.00 (m, 1H; NH),
3.94–3.90 (m, 1H; CHH), 3.77–3.71 (m, 1H; CHH), 3.66–3.58 (m, 1H,
CH), 3.49–3.37 (m, 2H; CH2), 3.04 (s, 3H; CH3), 2.84 (bs, 1H; CH), 2.43
(s, 3H; CH3), 1.92–1.79 (m, 3H; 2CH, OH), 0.99–0.96 (m, 6H; 2CH3),
0.83 (d, 3JH,H =6.9 Hz, 3H; CH3), 0.65 ppm (d, 3JH,H =7.0 Hz, 3H; CH3);
13C NMR (75 MHz, CDCl3, TMS): d=143.4, 138.3, 129.6, 126.9, 66.4,
62.0, 58.0, 44.6, 41.6, 30.9, 27.8, 21.5, 20.9, 20.1, 17.7, 16.3 ppm; MS (ESI):
m/z (%): 421 (45) [M+H]+, 443 (100) [M+Na]+; elemental analysis calcd
(%) for C18H32N2O5S2: C 51.40, H 7.67, N 6.66; found: C 51.46, H 7.75,
N 6.74.
(S)-Methyl-3-methyl-2-(N-((S)-3-methyl-2-(4-methylphenylsulfonamido)-
butyl)methylsulfonamido)butanoate (6c): Colorless oil (71%); Rf =0.50
(7.5:2.5, hexane/EtOAc); IR (neat): n˜max =3389, 3026, 2965, 1738, 1327,
1
1152, 763 cmꢀ1; H NMR (300 MHz, CDCl3, TMS): d=7.77–7.75 (m, 2H;
2CH), 7.30–7.27 (m, 2H; 2CH), 5.30–5.28 (m, 1H; NH), 3.97–3.94 (m,
1H; CH), 3.83 (s, 3H; CH3), 3.74–3.61 (m, 2H; CH, CHH), 3.20–3.11 (m,
1H; CHH), 3.05 (s, 3H; CH3), 2.42 (s, 3H; CH3), 2.10–1.93 (m, 1H; CH),
1.90–1.77 (m, 1H; CH), 0.92–0.89 (m, 6H; 2CH3), 0.84 (d, 3JH,H =7.0 Hz,
3H; CH3), 0.66 ppm (d, 3JH,H =7.0 Hz, 3H; CH3); 13C NMR (50 MHz,
CDCl3, TMS): d=172.4, 143.1, 138.6, 129.5, 126.9, 66.0, 57.6, 52.4, 44.1,
40.4, 29.6, 28.2, 21.4, 19.5, 19.2, 17.7, 16.0 ppm; MS (ESI): m/z (%): 449
(100) [M+H]+; elemental analysis calcd (%) for C19H32N2O6S2: C 50.87,
H 7.19, N 6.24; found: C 50.92, H 7.31, N 6.27.
N-((S)-1-(N-((S)-1-Hydroxy-3-phenylpropan-2-yl)methylsulfonamido)-3-
methyl butan-2-yl)-4-methylbenzenesulfonamide (7d): Colorless semi-
solid (89%); Rf =0.51 (6.5:3.5, hexane/EtOAc); IR (KBr): n˜max =3513,
3024, 2958, 1216, 763 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.81–
;
7.77 (m, 2H; 2CH), 7.32–7.18 (m, 8H; 8CH), 5.65–5.62 (m, 1H; NH),
3.95–3.86 (m, 1H; CHH), 3.66–3.65 (m, 2H; CHH, CH), 3.45–3.37 (m,
2H; CH, CHH), 3.22–3.14 (m, 1H; CHH), 2.87 (s, 3H; CH3), 2.68–2.61
3
(m, 2H; CH2), 2.35 (s, 3H; CH3), 1.97–1.92 (m, 1H; CH), 0.85 (d, JH,H
=
7.0 Hz, 3H; CH3), 0.69 ppm (d, 3JH,H =7.1 Hz, 3H; CH3); 13C NMR
(75 MHz, CDCl3, TMS): d=143.6, 137.9, 137.5, 129.7, 129.1, 128.8, 128.7,
127.3, 127.0, 126.9, 126.8, 62.9, 61.8, 58.3, 45.0, 40.0, 36.8, 29.6, 21.4, 17.5,
17.0 ppm; MS (ESI): m/z (%): 469 (100) [M+H]+; elemental analysis
calcd (%) for C22H32N2O5S2: C 56.38, H 6.88, N 5.98; found: C 56.46,
H 6.83, N 5.86.
(S)-Methyl-2-(N-((S)-3-methyl-2-(4-methylphenylsulfonamido)butyl)me-
thylsulfonamido)-3-phenylpropanoate (6d): Colorless oil (69%); Rf =
0.51 (7.5:2.5), hexane/EtOAc); IR (neat): n˜max =3384, 3025, 2959, 1733,
1214, 1160, 762 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.87–7.84
;
(m, 2H; 2CH), 7.37–7.30 (m, 5H; 5CH), 7.21–7.18 (m, 2H; 2CH), 5.39–
5.37 (m, 1H; NH), 4.60–4.54 (m, 1H; CH), 3.68 (s, 3H; CH3), 3.46–3.43
(m, 1H; CH), 3.37–3.31 (m, 2H; CH2), 3.12–3.04 (m, 1H; CHH), 2.79 (s,
3H; CH3), 2.65–2.58 (m, 1H; CHH), 2.41 (s, 3H, CH3), 2.15–2.06 (m,
1H; CH), 0.92 (d, 3JH,H =7.0 Hz, 3H; CH3), 0.73 ppm (d, 3JH,H =7.0 Hz,
3H; CH3); MS (ESI): m/z (%): 497 (100) [M+H]+; elemental analysis
calcd (%) for C23H32N2O6S2: C 55.62, H 6.49, N 5.64; found: C 55.71,
H 6.56, N 5.68.
N-((S)-1-((S)-1-Hydroxypropan-2-ylamino)-3-methylbutan-2-yl)-4-
methyl- benzene sulfonamide (7e): Colorless oil (88%); Rf =0.51
(6.5:3.5, hexane/EtOAc); IR (neat): n˜max =3518, 3021, 2963, 1216, 1158,
765 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.79–7.76 (m, 2H;
;
2CH), 7.32–7.29 (m, 2H; 2CH), 5.74–5.71 (m, 1H; NH), 3.90–3.79 (m,
1H; CHH), 3.63–3.61 (m, 2H; CHH, CH), 3.51–3.44 (m, 1H; CHH),
3.36–3.30 (m, 1H; CHH), 3.05–2.97 (m, 4H; CH3, CHH), 2.42 (s, 3H;
CH3), 1.93–1.82 (m, 1H; CH), 1.08 (d, 3JH,H =6.9 Hz, 3H; CH3), 0.82 (d,
3JH,H =7.0 Hz, 3H; CH3), 0.70 ppm (d, 3JH,H =6.9 Hz, 3H; CH3); MS
(ESI): m/z (%): 315 (100) [M+H]+; elemental analysis calcd (%) for
C15H26N2O3S: C 57.30, H 8.33, N 8.91; found: C 57.37, H 8.38, N 8.96.
(S)-Methyl-2-(N-((S)-3-(1H-indol-3-yl)-2-(4-methylphenylsulfonamido)-
propyl)methylsulfonamido)-3-(1H-indol-3-yl) propanoate (6 g): Colorless
oil (67%); Rf =0.50 (5.5:4.5, hexane/EtOAc); IR (neat): n˜max =3416,
3022, 2931, 1734, 1632, 1216, 763 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
TMS): d=8.14 (bs, 1H; NH), 8.07 (bs, 1H; NH), 7.64–7.62 (m, 2H;
2CH), 7.48 (d, 3JH,H =7.8 Hz, 1H; CH), 7.39–7.30 (m, 3H; 3CH), 7.21–
7.06 (m, 6H; 6H), 6.93 (bs, 1H; CH), 6.88 (bs, 1H; CH), 5.57–5.56 (m,
1H; NH), 4.68–4.63 (m, 1H; CH), 3.71–3.70 (m, 1H; CH), 3.55–3.48 (m,
4H; CH3, CHH), 3.42–3.37 (m, 1H; CHH), 3.02–2.92 (m, 3H; CH2,
CHH), 2.67 (m, 3H; CH3), 2.48 (dd, 3JH,H =14.3 Hz, 2JH,H =6.6 Hz, 1H;
CHH), 2.15 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3, TMS): d=
171.1, 143.4, 136.4, 136.3, 136.0, 129.5, 127.2, 127.1, 126.7, 123.2, 123.1,
122.2, 122.1, 119.71, 119.67, 118.7, 118.4, 111.25, 111.18, 110.6, 110.0, 60.6,
54.0, 52.2, 48.9, 38.3, 29.0, 26.6, 21.3 ppm; MS (ESI): m/z (%): 623 (26)
[M+H]+, 645 (100) [M+Na]+; elemental analysis calcd (%) for
C31H34N4O6S2: C 59.79, H 5.50, N 9.00; found: C 59.88, H 5.56, N 9.11.
N-((S)-1-((S)-1-Hydroxy-3-methylbutan-2-ylamino)propan-2-yl)-4-
methyl- benzenesulfonamide (7 f): Colorless oil (86%); Rf =0.50 (6.5:3.5,
hexane/EtOAc); IR (neat): n˜max =3516, 3023, 2961, 1217, 1158, 761 cmꢀ1
;
1H NMR (300 MHz, CDCl3, TMS): d=7.78–7.76 (m, 2H, 2CH), 7.33–
7.30 (m, 2H, 2CH), 6.38 (bs, 1H, NH), 3.92–3.87 (m, 1H; CHH), 3.71–
3.64 (m, 2H, CHH, CH), 3.48–3.32 (m, 2H; CHH, CH), 3.02–2.93 (m,
4H; CH3, CHH), 2.43 (s, 3H; CH3), 1.81–1.69 (m, 1H; CH), 0.98–
0.94 ppm (m, 9H; 3CH3); MS (ESI): m/z (%): 315 (100) [M+H]+; ele-
mental analysis calcd (%) for C15H26N2O3S: C 57.30, H 8.33, N 8.91;
found: C 57.36, H 8.38, N 8.96.
N-((S)-1-(N-((S)-1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl) methylsulfon
amido)-3-(1H-indol-3-yl)propan-2-yl)-4-methylbenzenesulfonamide (7 g):
Colorless semi-solid (89%); Rf =0.50 (1:1, hexane/EtOAc); IR (KBr):
7: A solution of LiBH4 (2m; 1.5 equiv) was added to a stirred solution of
6 (1 equiv) in anhydrous THF (10 mL) at 08C. It was stirred at room tem-
perature for 3 hours and was quenched by ethyl acetate followed by
water at 08C. After the usual work-up, the crude product was chromato-
graphed on silica gel with MeOH/CHCl3 (1.5:8.5) as an eluent to furnish
compound 7 (85–95%).
1
n˜max =3508, 3428, 2930, 1637, 1219, 770 cmꢀ1; H NMR (300 MHz, CDCl3,
TMS): d=8.23 (bs, 1H; NH), 8.06 (bs, 1H; NH), 7.70–7.67 (m, 2H;
2CH), 7.50 (d, 3JH,H =7.8 Hz, 1H; CH), 7.34–7.31 (m, 3H; 3CH), 7.21–
7.06 (m, 6H; 6CH), 6.90 (d, 3JH,H =2.0 Hz, 1H; CH), 6.65 (d, JH,H
=
3
2.0 Hz, 1H; CH), 5.96–5.95 (m, 1H; NH), 3.93–3.87 (m, 1H; CHH),
3.72–3.70 (m, 1H; CHH), 3.43–3.24 (m, 3H; CH2, CH), 3.12–3.05 (m,
2H; CH2), 2.88–2.80 (m, 1H; CH), 2.60 (s, 3H; CH3), 2.49–2.48 (m, 1H;
CH), 2.32–2.29 (m, 2H; CH2), 2.10 ppm (s, 3H; CH3); 13C NMR
(75 MHz, CDCl3, TMS): d=143.6, 136.3, 136.1, 129.6, 127.1, 126.8, 123.3,
N-((S)-1-(N-((S)-1-Hydroxypropan-2-yl)methylsulfonamido)propan-2-yl)-
4-methylbenzenesulfonamide (7a): Colorless oil (91%); Rf =0.51
(3.0:7.0, MeOH/CHCl3); IR (Neat): n˜max =3503, 3022, 1324, 1216,
768 cmꢀ1
;
1H NMR (300 MHz, CDCl3, TMS): d=7.77–7.74 (m, 2H;
194
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 189 – 197

Regioselective Ring Opening of Amino Acid-Derived Chiral Aziridines
122.7, 122.1, 119.6, 118.7, 118.6, 111.4, 111.3, 110.6, 61.4, 60.8, 54.4, 47.2,
39.0, 29.2, 26.6, 21.2 ppm; MS (ESI): m/z (%): 617 (100) [M+Na]+; ele-
mental analysis calcd (%) for C30H34N4O5S2: C 60.58, H 5.76, N 9.42;
found: C 60.65, H 5.75, N 9.51.
(75 MHz, CDCl3, TMS): d=143.7, 137.6, 129.8, 127.1, 59.1, 51.5, 47.0,
42.3, 38.8, 21.5, 19.1, 18.1, 17.4 ppm; MS (ESI): m/z (%): 375 (100)
[M+H]; elemental analysis calcd (%) for C16H26N2O4S2: C 51.31, H 7.00,
N 7.48; found: C 51.39, H 7.06, N 7.56.
8: DEAD (1.2 equiv) in THF was added dropwise to a stirred solution of
(1 equiv) and triphenylphosphine (1.2 equiv) in anhydrous THF
ACHTUNGTRENNUNG
7
(15 mL) under N2 at 08C, and the reaction mixture was stirred for 1 hour.
The triphenylphosphine oxide was filtered off with a mixture of hexane/
diethylether 1:1, and the crude product was chromatographed on silica
gel to furnish 8 in 75–85% yield.
(neat): n˜max =3421, 3022, 2966, 1216, 759 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, TMS): d=7.70–7.67 (m, 2H; 2CH), 7.34–7.31 (m, 2H; 2CH),
3.80–3.73 (m, 1H; CH), 3.69–3.56 (m, 2H; 2CH), 3.46–3.31 (m, 2H;
2CH), 2.92–2.81 (m, 4H; CH3, CH), 2.44 (s, 3H; CH3), 2.18–2.07 (m, 1H;
CH), 1.16 (d, 3JH,H =6.1 Hz; 3H; CH3), 1.00 (d, 3JH,H =6.8 Hz, 3H; CH3),
ACHTUNGTRENNUNG(2S,5S)-2,5-Dimethyl-1-(methylsulfonyl)-4-tosylpiperazine (8a): Colorless
semi-solid (76%); Rf =0.51 (6.0:4.0, hexane/EtOAc); ½aꢁ2D5 =+136.4 (c=
0.10, MeOH); HPLC analysis: ee>99 (tR =8.1 min, CH3CN/H2O); IR
3
0.97 ppm (d, JH,H =6.9 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, TMS):
(neat): n˜max =3428, 3022, 1217, 761 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
d=143.7, 136.6, 129.9, 127.0, 59.9, 51.3, 46.9, 43.4, 40.3, 21.5, 19.3, 17.7,
17.5 ppm; MS (ESI): m/z (%): 375 (100) [M+H]+, 397 (17) [M+NH4]+;
elemental analysis calcd (%) for C16H26N2O4S2: C 51.31, H 7.00, N 7.48;
found: C 51.35, H 7.05, N 7.42.
TMS): d=7.69–7.66 (m, 2H; 2CH), 7.32–7.29 (m, 2H; 2CH), 3.89–3.74
(m, 2H; CH2), 3.53–3.47 (m, 2H; CH2), 3.12–3.01 (m, 2H; 2CH), 2.81 (s,
3H; CH3), 2.42 (s, 3H; CH3), 1.24 (d, 3JH,H =5.7 Hz, 3H; CH3), 1.14 ppm
3
(d, JH,H =6.4 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, TMS): d=143.7,
3,3’-((2S,5S)-1-(Methylsulfonyl)-4-tosylpiperazine-2,5-diyl)bis(methyl
ene)bis-(1H-indole) (8g): Light yellow semi-solid (77%); Rf =0.50
(7.0:3.0, hexane/EtOAc); ½aꢁ2D5 =+7.8 (c=0.11, MeOH); HPLC analysis:
ee>99 (tR =11.9 min, CH3CN/H2O); IR (neat): n˜max =3418, 3022, 2931,
136.8, 129.8, 126.9, 51.2, 50.7, 47.0, 46.6, 39.0, 21.4, 17.4, 16.9 ppm; MS
(ESI): m/z (%): 347 (64) [M+H]+, 369 (100) [M+Na]+; elemental analy-
sis calcd (%) for C14H22N2O4S2: C 48.53, H 6.40, N 8.09; found: C 48.61,
H 6.43, N 8.18.
1638, 1216, 762 cmꢀ1 1H NMR (300 MHz, CDCl3): d=8.33 (bs, 2H,
;
2NH), 7.69–7.62 (m, 4H; 4CH), 7.38–7.34 (m, 2H; 2CH), 7.25–7.14 (m,
6H; 6CH), 6.96 (d, 3JH,H =1.8 Hz, 1H; CH), 6.93 (d, 3JH,H =1.8 Hz, 1H;
CH), 4.17–4.12 (m, 1H; CH), 3.94–3.92 (m, 1H; CH), 3.40–3.10 (m, 8H;
8CH), 2.66 (s, 3H; CH3), 2.40 ppm (s, 3H; CH3); 13C NMR (75 MHz,
CDCl3, TMS): d=143.8, 136.2, 136.1, 136.0, 132.1, 131.9, 129.9, 128.6,
128.5, 127.33, 127.26, 127.0, 123.5, 121.9, 119.54, 119.46, 118.9, 118.7,
111.32, 111.28, 110.2, 110.0, 55.2, 55.1, 43.9, 43.4, 37.9, 29.2, 29.0,
21.4 ppm; MS (ESI): m/z (%): 577 (10) [M+H]+, 599 (100) [M+Na]+; el-
emental analysis calcd (%) for C30H32N4O4S2: C 62.48, H 5.59, N 9.71;
found: C 62.57, H 5.61, N 9.79.
ACHTUNGTRENNUNG(2S,5S)-2,5-Dibenzyl-1-(methylsulfonyl)-4-tosylpiperazine (8b): Colorless
oil (78%); Rf =0.52 (6.5:3.5, hexane/EtOAc); ½aꢁ2D5 =ꢀ92.7 (c=0.088,
MeOH), HPLC analysis: ee>99 (tR =8.8 min, CH3CN/H2O); IR (neat):
1
n˜max =3382, 3021, 2926, 2364, 1216, 769 cmꢀ1; H NMR (300 MHz, CDCl3,
TMS): d=7.63–7.60 (m, 2H; 2CH), 7.34–7.24 (m, 8H; 8CH), 7.14–7.06
(m, 4H; 4CH), 4.15–4.11 (m, 1H; CHH), 3.94–3.91 (m, 1H; CHH), 3.41–
3.33 (m, 2H; 2CH), 2.99–2.76 (m, 6H; 2CH2, CH2), 2.68 (m, 3H; CH3),
2.46 ppm (s, 3H; CH3); 13C NMR (50 MHz, CDCl3, TMS): d=143.4,
137.1, 136.3, 136.1, 129.8, 129.6, 129.4, 128.7, 128.6, 127.3, 126.9, 55.7,
55.4, 43.6, 43.3, 39.4, 39.2, 38.9, 21.6 ppm; MS (ESI): m/z (%): 499 (100)
[M+H]+; elemental analysis calcd (%) for C26H30N2O4S2: C 62.62, H 6.06,
N 5.62; found: C 62.53, H 6.18, N 5.68.
(S)-Methyl 2-((S)-3-(3-iodo-4-methoxyphenyl)-2-(4-methylphenylsulfon
amido)propylamino)-3-(4-methoxyphenyl)propanoate (17): The proce-
dure was followed as described for the preparation of 5. Colorless oil
(59%); Rf =0.51 (5.5:4.5, hexane/EtOAc); IR (neat): n˜max =3455, 3021,
A
(8c):
White solid (82%); Rf =0.51 (7.5:2.5, hexane/EtOAc); m.p.: 122–1258C;
½aꢁ2D5 =+31.3 (c=0.096, MeOH); HPLC analysis: ee>99 (tR =10.3 min,
CH3CN/H2O); IR (neat): n˜max =3401, 3026, 2966, 1466, 1334, 1151,
2360, 1729, 1217, 766 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.62–
;
7.59 (m, 2H; 2CH), 7.31–7.22 (m, 3H; CH), 7.08–7.05 (m, 2H; 2CH),
6.90–6.85 (m, 3H; 3CH), 6.61 (d, 3JH,H =8.5 Hz, 1H; CH), 5.12–5.10 (m,
1H; NH), 3.84 (s, 3H; OCH3), 3.81 (s, 3H; OCH3), 3.69 (s, 3H; CH3),
752 cmꢀ1 1H NMR (300 MHz, CDCl3, TMS): d=7.74–7.71 (m, 2H;
;
2CH), 7.33–7.30 (m, 2H; 2CH), 4.11–4.03 (m, 1H; CHH), 3.89–3.64 (m,
3H; CHH, CH2), 3.09–2.93 (m, 5H; CH3, CH2), 2.43 (s, 3H; CH3), 2.22–
3.32 (dd, 3JH,H =7.7 Hz, 2JH,H =5.6 Hz, 1H; CH), 3.18–3.16 (m, 1H; CH),
3
2.91 (dd, 3JH,H =13.6 Hz, 2JH,H =5.5 Hz, 1H; CHH), 2.75 (dd, JH,H
=
3
1.97 (m, 2H; 2CH), 0.94–0.90 (m, 6H; 2CH3), 0.86 (d, JH,H =7.1 Hz, 3H,
13.7 Hz, 2JH,H =7.8 Hz, 1H; CHH), 2.67–2.58 (m, 3H; CH2, CHH), 2.43
(s, 3H; CH3), 2.31–2.25 ppm (m, 1H; CHH); 13C NMR (75 MHz, CDCl3,
TMS): d=174.6, 158.5, 156.8, 143.2, 139.9, 137.0, 131.4, 130.4, 130.1,
129.5, 129.0, 127.0, 114.0, 110.6, 86.0, 63.1, 56.3, 55.3, 55.0, 51.9, 50.0, 38.6,
37.6, 21.6 ppm; MS (ESI): m/z (%): 653 (90) [M+H]+, 675 (100)
[M+Na]+; elemental analysis calcd (%) for C28H33IN2O6S: C 51.54,
H 5.10, N 4.29; found: C 51.58, H 5.21, N 4.36.
CH3), 0.80 ppm (d, 3JH,H =6.9 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3,
TMS): d=143.6, 137.8, 129.8, 126.9, 58.8, 57.8, 41.0, 40.6, 40.0, 31.7, 31.3,
21.5, 18.7, 18.6, 16.1, 15.8 ppm; MS (ESI): m/z (%): 403 (34) [M+H]+,
420 (100) [M+NH4]+; elemental analysis calcd (%) for C18H30N2O4S2:
C 53.70, H 7.51, N 6.96; found: C 53.76, H 7.63, N 6.98.
ACHTUNGTRENNUNG(2S,5S)-2-Benzyl-5-iso-propyl-1-(methylsulfonyl)-4-tosylpiperazine (8d):
Colorless oil (74%); Rf =0.51 (7.5:2.5, hexane/EtOAc); ½aꢁ2D5 =+15.21
(c=0.094, MeOH); HPLC analysis: ee>99 (tR =11.4 min, CH3CN/H2O);
IR (neat): n˜max =3389, 3026, 2966, 1335, 1216, 1152, 756 cmꢀ1; NMR
(200 MHz, CDCl3, TMS): d=7.62–7.58 (m, 2H; 2CH), 7.27–7.18 (m, 7H;
7CH), 3.98–3.89 (m, 2H; CH2), 3.67–3.52 (m, 2H, 2CH), 3.02–2.72 (m,
7H, CH3, 2CH2), 2.41 (s, 3H; CH3), 1.97–1.87 (m, 1H; CH), 0.80–
0.71 ppm (m, 6H; 2CH3); 13C NMR (75 MHz, CDCl3, TMS): d=143.6,
137.3, 135.8, 129.7, 129.4, 128.5, 126.93, 126.87, 58.2, 54.9, 44.0, 40.4, 39.8,
39.2, 30.9, 21.4, 18.6, 16.2 ppm; MS (ESI): m/z (%): 451 (100) [M+H]+;
elemental analysis calcd (%) for C22H32N2O4S2: C 58.64, H 6.71, N 6.22;
found: C 58.57, H 6.76, N 5.29.
(S)-Methyl 2-(N-((S)-3-(3-iodo-4-methoxyphenyl)-2-(4-methylphenylsul-
fonamido)propyl)methylsulfonamido)-3-(4-methoxyphenyl)propanoate
(18): The procedure was followed as described for the preparation of 6.
Colorless oil (73%); Rf =0.45 (5.5:4.5, hexane/EtOAc); IR (neat): n˜max
=
3425, 3022, 2363, 1730, 1217, 766 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
TMS): d=7.58–7.55 (m, 2H; 2CH), 7.40 (d, 3JH,H =1.9 Hz, 1H; CH),
3
7.20–7.18 (m, 2H; 2CH), 7.09–7.06 (m, 2H; 2CH), 7.00 (dd, JH,H
=
3
8.2 Hz, 2JH,H =1.9 Hz, 1H; CH), 6.84–6.81 (m, 2H; 2CH), 6.62 (d, JH,H
=
8.4 Hz, 1H; CH), 5.29–5.27 (m, 1H; NH), 4.59–4.53 (m, 1H; CH), 3.86
(s, 3H; OCH3), 3.78 (s, 3H; OCH3), 3.64 (s, 3H; CH3), 3.49–3.27 (m, 3H;
CH2, CH), 2.94–2.87 (m, 2H; CH2), 2.68 (s, 3H; CH3), 2.61–2.54 (m, 2H;
CH2), 2.37 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3, TMS): d=
171.2, 158.7, 156.9, 143.3, 139.8, 136.3, 131.1, 130.2, 130.1, 129.5, 128.0,
127.1, 114.1, 110.7, 86.1, 62.0, 56.2, 55.2, 54.9, 52.5, 48.7, 38.5, 37.7, 35.1,
21.6 ppm; MS (ESI): m/z (%): 731 (100) [M+H]+; elemental analysis
calcd (%) for C29H35IN2O8S2: C 47.67, H 4.83, N 3.83; found: C 47.61,
H 4.91, N 3.86.
ACHTUNGTRENNUNG(2S,5S)-2-iso-Propyl-5-methyl-4-(methylsulfonyl)-1-tosylpiperazine (8e):
Colorless oil (76%); Rf =0.51 (7.5:2.5, hexane/EtOAc); ½aꢁ2D5 =ꢀ159.5
(c=0.099, MeOH); HPLC analysis: ee>99% (tR =8.8 min, CH3CN/
H2O); IR (neat): n˜max =3423, 3023, 2973, 1217, 757 cmꢀ1 1H NMR
;
(300 MHz, CDCl3, TMS): d=7.75–7.72 (m, 2H; 2CH), 7.33–7.31 (m, 2H;
2CH), 4.36–4.29 (m, 1H; CH), 3.90–3.70 (m, 2H; 2CH), 3.61–3.52 (m,
1H; CH), 3.37–3.35 (m, 2H; CH2), 2.84 (s, 3H; CH3), 2.44 (s, 3H; CH3),
3
2.14–2.02 (m, 1H; CH), 1.23 (d, 3JH,H =6.2 Hz, 3H; CH3), 0.91 (d, JH,H
=
N-((S)-1-(N-((S)-1-Hydroxy-3-(4-methoxyphenyl)propan-2-yl)methylsul-
fonamido)-3-(3-iodo-4-methoxyphenyl) propan-2-yl)-4-methylbenzenesul-
6.8 Hz, 3H; CH3), 0.86 ppm (d, 3JH,H =6.8 Hz, 3H; CH3); 13C NMR
Chem. Asian J. 2011, 6, 189 – 197
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
195

G. Panda et al.
FULL PAPERS
fonamide (19): The procedure was followed as described for the prepara-
tion of 7. Colorless semi-solid (85%); Rf =0.51 (4.5:5.5, hexane/EtOAc);
Acknowledgements
IR (neat): n˜max =3454, 3149, 2938, 2364, 1508, 1318, 1249, 1149, 761 cmꢀ1
;
This research project (NO. SR/S1/OC-74/2009) was supported by the De-
partment of Science and Technology, New Delhi, India. K.S. thanks
Sonia for the preparation of the starting materials and CSIR for provid-
ing the fellowship (NET-SRF). Instrumental facilities from SAIF, CDRI
(communication no. 7984), Lucknow is acknowledged.
1H NMR (300 MHz, CDCl3, TMS): d=7.61–7.58 (m, 2H; 2CH), 7.37 (d,
3JH,H =1.9 Hz, 1H; CH), 7.21–7.18 (m, 2H; 2CH), 7.06–6.98 (m, 3H;
3CH), 6.83–6.80 (m, 2H; 2CH), 6.62 (d, 3JH,H =8.3 Hz, 1H; CH), 5.77–
5.75 (m, 1H; NH), 3.84 (s, 3H; OCH3), 3.78 (s, 3H; OCH3), 3.58–3.43
(m, 3H; CH2, CH), 3.33–3.31 (m, 2H; CH2), 2.83–2.75 (m, 4H; CH3,
CH), 2.66–2.44 (m, 4H; 2CH2), 2.34 ppm (s, 3H; CH3); 13C NMR
(75 MHz, CDCl3, TMS); d=158.5, 156.9, 143.5, 139.8, 136.5, 131.2, 130.3,
130.0, 129.7, 129.5, 127.0, 114.1, 110.8, 86.1, 62.7, 61.9, 56.3, 55.5, 55.2,
47.9, 39.4, 37.8, 35.6, 21.5 ppm; MS (ESI): m/z (%): 703 (100) [M+H]+;
elemental analysis calcd (%) for C28H35IN2O7S2: C 47.86, H 5.02, N 3.99;
found: C 47.79, H 5.06, N 3.92.
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(S)-2-(4-Methoxybenzyl)-1-(methylsulfonyl)-4-tosylpiperazine compound
with 4-ethyl-2-iodo-1-methoxybenzene (1:1) (20): The procedure was fol-
lowed as described for the preparation of 8. Colorless oil (74%); Rf =
0.51 (6.5:3.5, hexane/EtOAc); IR (neat): n˜max =3426, 3021, 2928, 1511,
1335, 1217, 768 cmꢀ1
;
1H NMR (300 MHz, CDCl3, TMS): d=7.64–7.61
3
(m, 2H; 2CH), 7.39 (d, JH,H =1.8 Hz, 1H; CH), 7.32–7.30 (m, 2H; 2CH),
7.07–7.03 (m, 3H; 3CH), 6.84–6.81 (m, 2H; 2CH), 6.70 (d, 3JH,H =8.4 Hz,
1H; CH), 4.14–4.09 (m, 2H; 2CH), 3.88 (s, 3H; OCH3), 3.82 (s, 3H;
OCH3), 3.48–3.39 (m, 2H; CH2), 2.95–2.71 (m, 9H; CH3, 3CH2),
2.45 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3, TMS): d=158.5,
157.1, 143.9, 140.0, 136.6, 130.5, 130.4, 130.0, 127.9, 127.0, 114.0, 110.9,
86.0, 56.3, 55.8, 55.2, 55.0, 43.4, 43.2, 39.0, 38.3, 37.5, 21.5 ppm; MS (ESI):
m/z (%): 723 (100) [M+Na]+; elemental analysis calcd (%) for
C29H37IN2O6S2: C 49.71, H 5.32, N 4.00; found: C 49.77, H 5.35, N 4.12.
(S)-4-((1-(Methylsulfonyl)-4-tosylpiperazin-2-yl)methyl)phenol
com-
pound with 4-ethyl-2-iodophenol (1:1) (21): BBr3 (1.28 mL, 1m) was
added dropwise to a stirred solution of 18 (220 mg, 0.32 mmol) in dry
DCM (8 mL) under an atmosphere of N2 at ꢀ788C. It was warmed to
room temperature and stirred for 18 hours. The reaction was quenched
with water (1 mL), followed by the usual work-up, and purified by
column chromatography (6.0:4.0, hexane/EtOAc) to afford 19 (135 mg,
25
64%) as a light yellow oil. Rf =0.46 (5.5/4.5, hexane/EtOAc); ½aꢁD
=
+31.5 (c=0.10, MeOH); HPLC analysis: ee>99 (tR =10.6 min, CH3CN/
H2O); IR (neat): n˜max =3421, 2926, 2360, 1327, 1150, 757 cmꢀ1 1H NMR
[6] D. Giardina, U. Gulini, M. Massi, M. G. Piloni, P. Pompei, G. Ra-
faiani, C. Melchiorre, J. Med. Chem. 1993, 36, 690.
;
(300 MHz, CDCl3, TMS): d=7.66–7.64 ( m, 2H; 2CH), 7.34–7.31 (m,
2H; 2CH), 7.20 (d, 3JH,H =1.5 Hz, 1H; CH), 6.97–6.94 (m, 2H; 2CH),
6.88–6.73 (m, 4H; 4CH), 4.18–4.11 (m, 1H; CH), 3.93–3.91 (m, 1H; CH),
3.51–3.40 (m, 2H; CH2), 2.85–2.70 (m, 9H; CH3, 3CH2), 2.45 ppm (s, 3H;
CH3); 13C NMR (75 MHz, CDCl3, TMS): d=154.7, 154.0, 144.1, 139.0,
136.7, 131.1, 130.7, 130.1, 129.6, 127.5, 126.9, 115.5, 115.1, 85.3, 55.6, 54.6,
43.2, 43.1, 39.1, 38.2, 37.2, 21.5 ppm; MS (ESI): m/z (%): 695 (100)
[M+Na]+; elemental analysis calcd (%) for C27H33IN2O6S2: C 48.21,
H 4.95, N 4.16, found: C 48.26, H 4.98, N 4.23.
[7] a) K. L. Rinehart, T. G. Holt, N. L. Fregeau, P. A. Keifer, G. R.
Wilson, T. J. Perun, Jr., R. Sakai, A. G. Thompson, J. G. Stroh, L. S.
Shield, D. S. Seigler, L. H. Li, D. G. Martin, C. J. P. Grimmelikhuij-
zen, G. Gꢃde, J. Nat. Prod. 1990, 53, 771; b) J. D. Scott, R. M. Wil-
liams, Chem. Rev. 2002, 102, 1669; c) J. F. Gonzꢂlez, L. Salazar, E.
de La Cuesta, C. AvendaÇo, Tetrahedron 2005, 61, 7447.
[8] S. Tamai, M. Kaneda, S. Nakamura, J. Antibiot. 1982, 35, 1130.
[9] S. A. Morris, R. J. Andersen, Tetrahedron 1990, 46, 715.
[10] a) A. Viso, R. F. de La Pradilla, A. Flores, A. Gracia, M. Tortosa,
M. L. Lꢄpez-Rodrꢅguez, J. Org. Chem. 2006, 71, 1442; b) F. Crestey,
M. Witt, J. W. Jaroszewski, H. Franzyk, J. Org. Chem. 2009, 74,
5652; c) F. Crestey, M. Witt, K. Frydenvang, D. Stærk, J. W. Jaros-
zewski, H. Franzyk, J. Org. Chem. 2008, 73, 3566; d) L. K. Ottesen,
C. A. Olsen, M. Witt, J. W. Jaroszewski, H. Franzyk, Chem. Eur. J.
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Husson, J. Org. Chem. 1997, 62, 1016; b) C. J. Dinsmore, D. C. Be-
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6586; d) P. Maity, B. Konig, Org. Lett. 2008, 10, 1473; e) C. L. Lenci-
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19, 1689.
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Chen, F. A. Davis, Aziridines and Epoxides in Organic Synthesis
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d) M. K. Ghorai, D. Shukla, K. Das, J. Org. Chem. 2009, 74, 7013;
e) M. K. Ghorai, A. Kumar, D. P. Tiwari, J. Org. Chem. 2010, 75,
137.
ACHTUNGTRENNUNG(2S,5S)-2,5-Di-iso-propyl-1-(methylsulfonyl)piperazine (22): Finely chop-
ped sodium metal (171.3 mg, 7.45 mmol) and naphthalene (1.05 g,
8.2 mmol) were dissolved in dry THF (10 mL) and stirred for 2 hours
until a dark-green color appeared. The desired THF solution of 8c
(150 mg, 0.37 mmol) was cooled to ꢀ788C and then a solution of Na-nap-
thalenide was added dropwise to the reaction mixture by using a syringe
until a dark-green color persisted and was stirred for 15 minutes at
ꢀ788C. The reaction was quenched with 1–2 drops of water to discharge
the green color, followed by the usual work-up, and the crude product
was purified by column chromatography (3.0:7.0, MeOH/CHCl3) to fur-
nish 22 (59 mg, 63.8%) as a colorless oil. Rf =0.46 (2.0.8.0, MeOH/
CHCl3); ½aꢁ2D5 =+71.5 (c=0.11, MeOH); HPLC analysis: ee>99 (tR =
7.7 min, CH3CN/H2O); IR (neat): n˜max =3393, 3022, 2385, 1520, 1216,
1
3
763 cmꢀ1; H NMR (300 MHz, CDCl3, TMS): d=3.65 (dd, JH,H =14.0 Hz,
2JH,H =2.6 Hz, 1H; CHH), 3.31 (dd, 3JH,H =10.4 Hz, 2JH,H =3.4 Hz, 1H;
CHH), 3.19–3.15 (m, 1H; CH), 2.89–2.72 (m, 5H; CH3, NH, CH), 2.42–
2.24 (m, 2H; CH2), 1.63–1.48 (m, 2H; CH2), 0.98–0.92 ppm (m, 12H;
4CH3); 13C NMR (75 MHz, CDCl3, TMS): d=60.5, 59.2, 46.7, 44.4, 41.1,
31.0, 24.8, 19.9, 19.7, 18.53, 18.49 ppm; MS (ESI): m/z (%): 249 (100)
[M+H]+; elemental analysis calcd (%) for C11H24N2O2S: C 53.19, H 9.74,
N 11.28; found: C 53.27, H 9.71, N 11.22.
196
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Received: August 11, 2010
Published online: November 12, 2010
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