An efficient entry to highly substituted chiral 2-oxopiperazines from α-amino acids via iodocyclization

Article abstract of DOI:10.1016/j.tet.2012.09.109

A short and stereoselective route for the synthesis of 2-oxopiperazines is presented starting from different naturally abundant α-amino acids. The key synthetic steps involved amide coupling, Wittig reaction, HWE olefination, aza-Michael reaction, iodocyc

Full text of DOI:10.1016/j.tet.2012.09.109

Tetrahedron 68 (2012) 10114e10121
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
An efficient entry to highly substituted chiral 2-oxopiperazines from a-amino
acids via iodocyclization
*
Amit Kumar Jana, Sanjit Kumar Das, Gautam Panda
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2012
Received in revised form 11 August 2012
Accepted 27 September 2012
Available online 3 October 2012
A short and stereoselective route for the synthesis of 2-oxopiperazines is presented starting from dif-
ferent naturally abundant -amino acids. The key synthetic steps involved amide coupling, Wittig re-
action, HWE olefination, aza-Michael reaction, iodocyclization. This new pathway involving first report of
iodocyclization to construct chiral substituted 2-oxopiperazines furnished final compounds in good
yields.
a
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The piperazine moiety is very often found as important phar-
macophore in a large number of biologically active molecules, in-
cluding 5HTanxiolytics,1 dopamine D3 agents,2 Bcl-2 inhibitors,3
cytochrome c inhibitor,4 CNS compounds,5 and HIV protease in-
hibitors,6 antiproliferative agents,7 quinolone antibiotics8 etc.
The nitrogen-containing heterocycles offer a convenient core
from which many compounds can be derived through convergent
synthesis.9 In this respect, piperazine is an important building block
for generating libraries of compounds for the study of structure
activity relationships (SAR).9 Not only piperazine, but their keto
analogues (oxopiperazine) also play an important role in drug de-
velopment and found to be present in the core structure of many
important bioactive natural products.10e19 Particularly, the exis-
tence of substituted chiral 2-oxopiperazine nucleus in the skeleton
of numerous natural products, such as pseudotheonamides A1 and
A2 1e2,10,11 (ꢀ)-A agelastatin A 3,12e14 marcfortine B 4,15 the Pha-
kellin group 5e7,16e18 and guadinomine C2 819 (Fig. 1) make them
attractive targets. In addition, their crucial role in peptidomimetic
chemistry for the discovery of novel, bioactive small molecules20e24
is well established. Thus, oxopiperazines have gained a lot of im-
portance as conformationally restricted peptidomimetics,25 as
fragments of natural products of diverse structural complexity and
biological activities,26 and also have been examined as ligands in
enantioselective catalysis.27 In case of peptidomimetic drugs, ex-
cellent examples, having 2-oxopiperazine template that con-
formationally mimics the dipeptide moiety, essentially include
constrained substance P analogues,28 farnesyltransferase (FTase)29
* Corresponding
author.
E-mail
addresses:
gautam.panda@gmail.com,
gautam_panda@cdri.res.in (G. Panda).
Fig. 1. Some important representatives of 2-oxopiperazines.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.109

A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
10115
and protein geranylgeranyltransferase-I (PGGTase-I)30 inhibitors,
compounds with dual farnesyltransferase/geranylgeranyltrans-
ferase-I inhibitory activity,31 elastase,32 factor Xa,33 renin34e36
and BACE137 inhibitors, melanocortin receptors (MCRs) ago-
nists,21 fibrinogen glycoprotein IIbeIIIa,22,38 and neuropeptide S
(NPS) receptor39,40 antagonists.
Furthermore, bioactive drugs used for the treatment of central
nervous system diseases are also highly enriched with the
substituted oxopiperizines.5 Besides; they are equally potential as
cancer chemotherapeutic agents,20,41 and are promising candidates
for the treatment and prevention of numerous diseases, such as
rheumatoid arthritis,32 depression,28 sexual disfunctions21 or ve-
nous and arterial thrombosis.33
Because of their profound importance, many research groups
were engaged in establishing efficient route to synthesize oxopi-
perazines.9a,42 Despite this, there is a challenge to generate an ef-
ficient scalable route to substituted chirally pure 2-oxopiperazines.
Our group is engaged to develop new synthetic methodology for
the synthesis of chiral heterocycles and their bioevolution43 and in
continuation of this project, we wish to present here an elegant
path to synthesize densely substituted chirally pure 2-
CH2Cl2 to furnish compounds (15aef) in excellent chemical yields
(84e95%), which were subjected to LiAlH4 mediated reduction of
the ester functionality to furnish alcohols (12aef) with very good
yields (78e84%) within 1 h. In the next step, the derived alcohols
(12aef) were oxidized via Swern oxidation using oxalyl chloride/
DMSO/DIPEA to provide aldehydes (16aef), which were sub-
sequently transformed into the olefinic compounds 11aef in good
yields (67e72%, over two steps) utilizing methyl Wittig reaction in
presence of Ph3PCH3I/KHMDS in 2 h. Now the stage was set for the
crucial iodocyclization reaction to obtain the 2-oxopiperazine de-
rivative 10aef. The crucial iodocyclization reaction of these olefinic
compounds 11aef in the presence of K2CO3 (3 equiv)/I2 (3 equiv) in
CH3CN delivered the targeted 2-oxopiperazine derivatives 10aef in
satisfactory yields (76e88%) (Scheme 2).
oxopiperazines from commercially available a-amino acids utiliz-
ing amide coupling, methyl Wittig and iodocyclization44 as the key
reaction steps.
To further explore our synthetic methodology, we targeted the
natural product piperazirum, a novel bioactive alkaloid from Arum
palaestinum Boiss.45 Piperazirum 9 was active against all examined
cultured human cell lines using the SRB method,46 such as A549
(non-small cell lung, ED50¼4.26ꢁ0.2
m
M), SK-OV-3 (ovary,
ED50¼1.38ꢁ0.1
m
M), SK-MEL-2 (melanoma, ED50¼0.51ꢁ0.1 M)
m
Scheme 2. Synthesis of chiral 2-oxopiperazine derivatives 10aef.
and HCT-15 (colon, ED50¼2.47ꢁ0.3
2. Results and discussions
2.1. Retrosynthetic analysis
mM).
It is believed that the iodocyclization reaction took place
through the favoured six-membered cyclic transition state (TS-2,
Fig. 2) compared to the disfavoured TS-1 due to the presence of
steric interaction between R2 and Boc substituents. The regiose-
lective 6-exo-tet cyclization mode provided the desired compounds
where the newly generated stereocenter should be in syn fashion
with the adjacent one. The other stereoisomers were isolated in
very negligible yields via TS-1, which is energetically unfavourable.
To further support the stereochemistry in the cyclic compounds, we
have done COSY experiment with one of the 2-oxopiperazine de-
rivative 10f where the coupling constant value (J 5.19 Hz) between
Ce5H and Ce6H clearly proved that the two adjacent H’s are in syn
fashion. Again, the kinetically favoured regioselective six-mem-
bered cyclization predominates over the seven-membered cycli-
zation, which is kinetically unfavoured and expectedly seven-
membered cyclic products were not found in any case (Table 1).
The retrosynthetic analysis suggests that the target 2-
oxopiperazine derivatives, 10aef can be accessed via crucial dia-
stereoselective iodocyclization reaction from the olefinic in-
termediates 11aef, which in turn can be obtained from the alcohols
12aef through Swern oxidation followed by methyl Wittig re-
action. The intermediate alcohols 12aef can easily be furnished by
amide coupling among different amino acid counter parts
(Scheme 1).
Scheme 1. Retrosynthetic analysis of 2-oxopiperazine derivatives.
2.2. Synthesis of 2-oxopiperazine derivatives
To achieve the synthesis of various 2-oxopiperazine derivatives,
we have taken different naturally abundant
a-amino acids as
starting materials. First, a number of amino acid methyl ester hy-
drochlorides (14aef) were coupled with Boc protected amino acids
(13aef) through peptide coupling in presence of TBTU/Et3N in dry
Fig. 2. Model for the diastereoselective iodocyclization reaction.

10116
A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
Table 1
Synthesized 2-oxopiperazine derivatives
25
Entry
R1
R2
Compound no.
2-Oxopiperazine derivatives
Overall yield (%)
39.8
[a
] in CH3OH
D
de (%)a
1
eCH2CH(CH3)2
eCH(CH3)2
10a
ꢀ24.7, (c 0.30)
ꢀ14.2, (c 0.41)
>99
2
3
4
eCH(CH3)2
eCH(CH3)2
10b
10c
10d
40.8
39.8
48.4
>99
>99
>99
eCH2Ph
eCH2Ph
ꢀ10.8, (c 0.42)
ꢀ14.7, (c 0.35)
eCH2Ph
eCH2CH(CH3)2
5
6
eCH2CH(CH3)2
eCH2Ph
10e
10f
42.0
42.5
ꢀ7.2, (c 0.51)
ꢀ23.7, (c 0.18)
>99
>99
eCH2Ph
eCH(CH3)CH2CH3
7
eCH2CH(CH3)2
eCH(CH3)2
10g
36.1
þ24.6, (c 0.40)
>99
a
Diastereomeric excess.
After successful achievement of the synthesis of 2-
oxopiperazine derivatives, we turned our attention to achieve the
synthesis of another kind of 2-oxopiperazines through aza-Michael
cyclization. For the said purpose, we performed a model study on
one of the previously prepared aldehyde 16a.
CO2Et
H
Ph3P=CHCO2Et,
H
N
N
CHO
BocHN
BocHN
dry CH2Cl2,
oC-rt, 3 h,
86%
O
16a
O
0
17a
Thus, aldehyde 16a was transformed into a,b-unsaturated ester
17a through HornereWadswortheEmmons olefination in the
presence of Ph3P]CHCO2Et in dry CH2Cl2 in 2 h in excellent yield
(86%) and then Boc was removed by the treatment of TFA to fur-
nish free amine. Now the stage was set for the essential aza-
Michael cyclization to furnish desired 2-ketopiperazine 18a. This
cyclization was examined in presence of different types of bases
(DBU, DABCO, K2CO3) and Lewis acids (BF3eOEt2, TiCl4). Un-
fortunately, the yields are very low (10e25%) except little bit
improved in the case of DBU (35%). Nonetheless, we could achieve
the chirally pure 2-oxopiperazines 18a albeit in low yield
(Scheme 3).
H
N
1. TFA, CH2Cl2,
O
NaHCO3
s
s
CO2Et
2. DBU, CH3CN,
35%
N
H
18a
Scheme 3. Synthesis of 2-oxopiperazine 18a.
3. Conclusions
The synthetic methodology described above was also re-
peated with the (R)-amino acid in order to synthesize the
target molecule piperazirum 9. Thus (R)-leucine and (R)-valine
provided the 2-oxopiperazie derivative 10g, which could be
utilized for total synthesis of the natural product, piper-
azirum. Efforts in this direction are currently underway
(Scheme 4).
In summary, we have developed a scalable synthetic route to
2-oxopiperazine derivatives involving amide coupling, Wittig
olefination, aza-Michael reaction and iodocyclization as the key
reaction steps. Iodocyclization played a crucial role to the for-
mation of 2-oxopiperazine scaffolds resulting in good yield and
this is the first report towards the synthesis of this type of cyclic
skeletons.

A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
10117
4.1.1.2. (S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-
methylbutanamido)-3-methylbutanoate (15b). Yield 84%; mp
140 ꢃC; Rf (20% EtOAc/Hexane) 0.53; [
a
]
D
22 ꢀ10.9 (c 0.31, CH3OH); IR
(KBr) 3331, 3077, 2970, 2365, 1751, 1648, 1551, 1177, 1016 cmꢀ1
;
dH
(300 MHz, CDCl3) 6.51 (1H, d, J 8.13 Hz, NHBoc), 5.14 (1H, d, J
8.61 Hz, NHCO), 4.54 (1H, dd, J1 8.64 Hz, J2 5.01 Hz, CHNHBoc),
3.96e3.91 (1H, m, CHCO2Me), 3.73 (3H, s, OMe), 2.22e2.12 (2H, m,
CHMe2), 1.44 (9H, s, CMe3), 0.98e0.90 (12H, m, Me2CH); dC
(75 MHz, CDCl3) 172.1, 171.6, 155.7, 79.7, 60.0, 57.0, 52.0, 31.1, 30.5,
28.2, 19.1, 18.8; m/z (ESI) 275.0 (100%), 331.9 (35%, MHþ), 353.1
(90%); HRMS (ESI): MHþ, found 331.2237 C16H31N2O5 requires
331.2233.
4.1.1.3. (S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-
Scheme 4. Synthesis of 2-oxopiperazine 10g.
phenylpropanamido)-3-phenylpropanoate (15c). Yield 90%; mp
112 ꢃC; Rf (20% EtOAc/Hexane) 0.56; [
a]
22 ꢀ4.2 (c 0.30, CH3OH); IR
D
4. Experimental
(KBr) 3485, 1743, 1660, 1365, 1170, 763 cmꢀ1
;
dH (300 MHz, CDCl3)
7.18e7.08 (8H, m, ArH), 6.93e6.90 (2H, m, ArH), 6.39 (1H, d, J
7.26 Hz, NHBoc), 4.99 (1H, d, J 5.34 Hz, CHNHBoc), 4.70 (1H, d, J
7.26 Hz, CHCO2Me), 4.27 (1H, s, NHCO), 3.56 (3H, s, OMe),
3.01e2.93 (4H, m, CH2Ph), 1.30 (9H, s, CMe3); dC (50 MHz, CDCl3)
171.3,170.7,155.1,136.4,135.5,129.2, 129.1,128.5, 128.4, 127.0,126.8,
80.1, 55.6, 53.2, 52.1, 38.2, 37.8, 28.1; m/z (ESI) 370.1 (100%), 427.2
(50%, MHþ), 449.2 (95%); HRMS (ESI): MHþ, found 427.2237
C24H31N2O5 requires 427.2233.
4.1. General methods
Organic solvents were dried by standard methods. All the
products were characterized by 1H, 13C, two-dimensional homo-
nuclear COSY (correlation spectroscopy), IR, ESI-MS, HRMS. Ana-
lytical TLC was performed using 2.5ꢂ5 cm plates coated with
a 0.25 mm thickness of silica gel (60F254), visualization was ac-
complished with iodine and under UV lamp. Column chromatog-
raphy was performed using silica gel (60e120 and 100e200 mesh).
NMR spectra were recorded on Bruker Avance DPX 200FT, Bruker
Robotics, Bruker DRX 300 and 400 Spectrometers at 200, 300 MHz
(1H) and 50, 75 MHz (13C). Experiments were recorded in CDCl3 at
4.1.1.4. (S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-
phenylpropanamido)-4-methylpentanoate (15d). Yield 95%; mp
105 ꢃC; Rf (20% EtOAc/Hexane) 0.50; [
a
]
D
22 ꢀ10.5 (c 0.40, CH3OH); IR
(KBr) 3334, 2971, 2365, 1751, 1683, 1642, 1552, 1178, 1021 cmꢀ1
;
dH
25 ꢃC. Chemical shifts are given on the
d
scale and are referenced to
(300 MHz, CDCl3) 7.21e7.11 (5H, m, ArH), 6.45 (1H, d, J 7.29 Hz,
NHBoc), 5.09 (1H, d, J 8.10 Hz, CHNHBoc), 4.47 (1H, dd, J1 7.86 Hz, J2
4.80 Hz, CHCO2Me), 4.30 (1H, br s, NHCO), 3.60 (3H, s, OMe),
3.04e2.95 (2H, m, CH2Ph), 1.53e1.37 (3H, m, CH2CHMe2), 1.32 (9H,
s, CMe3), 0.83e0.80 (6H, m, Me2CH); dC (50 MHz, CDCl3) 172.7,
170.9, 155.3, 136.5, 129.2, 128.4, 126.7, 80.0, 55.4, 52.1, 50.6, 41.3,
38.0, 28.1, 24.5, 22.6; m/z (ESI) 337.2 (100%), 393.3 (30%, MHþ),
415.4 (90%); HRMS (ESI): MHþ, found 393.2385 C21H33N2O5 re-
quires 393.2389.
the TMS at 0.00 ppm for proton. For 13C NMR reference CDCl3
appeared at 77.16 ppm. IR spectra were recorded on PerkineElmer
881 and FTIR-8210 PC Shimadzu Spectrophotometers. Mass spectra
were recorded on a JEOL JMS-600H high resolution spectrometer
using EI mode at 70 eV. Optical rotations were determined on an
Autopol III polarimeter using a 1 dm cell at 25 ꢃC in methanol as the
solvent; concentrations mentioned are in g/100 ml.
4.1.1. General procedure for amide coupling of amino acids. To an ice
cooled solution of N-Boc protected amino acids 13aeg (4.32 mmol)
in dry CH2Cl2 (25 ml), TBTU (6.48 mmol) and Et3N (6.26 mmol) were
added under N2 atmosphere. Then the reaction mixture was stirred
for 30 min at the same temperature. After that amino acid methyl
ester hydrochlorides, 14aeg (6.48 mmol) and Et3N (6.48 mmol)
were added. The whole mixture was stirred for 1 h at room tem-
perature and water was added, the organic layer was separated, and
the aqueous phase was extracted thrice with CH2Cl2 (3ꢂ50 ml). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, filtered and then concentrated under reduced pres-
sure to obtain yellow crude product. The crude product was purified
over silica gel column chromatography to furnish corresponding
dipeptides 15aeg as colourless solid in 84e95% yield.
4.1.1.5. (S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-4-
methylpentanamido)-3-phenylpropanoate (15e). Yield 89%; mp
22
87 ꢃC; Rf (20% EtOAc/Hexane) 0.51; [
a
]
ꢀ9.5 (c 0.21, CH3OH); IR
D
(KBr) 3335, 2974, 2366, 1755, 1688, 1644, 1551, 1178, 1025 cmꢀ1
; dH
(300 MHz, CDCl3) 7.18e7.16 (3H, m, ArH), 7.05e7.02 (2H, m, ArH)
6.47 (1H, d, J 6.84 Hz, NHBoc), 4.77 (2H, d, J 6.93 Hz, CH), 4.01 (1H,
br s, NHCO), 3.63 (3H, s, OMe), 3.11e2.97 (2H, m, CH2Ph), 1.88 (1H,
buried s, CHMe2), 1.57e1.53 (2H, m, CH2CH), 1.36 (9H, s, CMe3),
0.85e0.82 (6H, m, Me2CH); dC (50 MHz, CDCl3) 172.1, 171.6, 155.4,
135.7, 129.2, 128.4, 127.0, 79.9, 56.8, 52.9, 51.8, 41.1, 37.8, 28.2, 24.6,
22.8; m/z (ESI) 337.2 (100%), 393.1 (35%, MHþ), 415.4 (90%); HRMS
(ESI): MHþ, found 393.2385 C21H33N2O5 requires 393.2389.
4.1.1.6. (2S,3R)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-
4.1.1.1. (S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-4-
phenylpropanamido)-3-methylpentanoate (15f). Yield 88%; mp
methylpentanamido)-3-methylbutanoate (15a). Yield 93%; mp
115 ꢃC; Rf (20% EtOAc/Hexane) 0.58; [
a
]
22 ꢀ15.5 (c 0.30, CH3OH); IR
D
143 ꢃC; Rf (20% EtOAc/Hexane) 0.52; [
a
]
22 ꢀ14.5 (c 0.50, CH3OH); IR
(KBr) 3336, 2981, 2375, 1761, 1693, 1652, 1562, 1179, 1031 cmꢀ1
;
dH
D
(KBr) 3338, 2977, 2366, 1759, 1688, 1645, 1551, 1179, 1020 cmꢀ1
;
dH
(300 MHz, CDCl3) 7.19e7.11 (5H, m, ArH), 6.47 (1H, d, J 7.95 Hz,
NHBoc), 5.11 (1H, d, J 7.86 Hz, CHNHBoc), 4.43 (1H, dd, J1 8.34 Hz, J2
5.16 Hz, CHCO2Me), 4.30 (1H, d, J 4.77 Hz, NHCO), 3.60 (3H, s, OMe),
2.98 (2H, d, J 5.94 Hz, CH2Ph), 1.77e1.72 (1H, m, CHMeEt), 1.33 (9H,
s, CMe3), 1.08e0.98 (2H, m, CH2Me), 0.82e0.74 (6H, m, CH3); dC
(75 MHz, CDCl3) 171.5, 171.1, 155.2, 136.6, 129.0, 128.0, 126.3, 79.4,
56.2, 55.3, 51.5, 37.8, 37.3, 27.9, 24.7, 14.9, 11.1; m/z (ESI) 337.2
(100%), 393.2 (30%, MHþ), 415.6 (90%); HRMS (ESI): MHþ, found
393.2384 C21H33N2O5 requires 393.2389.
(300 MHz, CDCl3) 6.74 (1H, br, s, NHBoc), 5.10 (1H, br, s, NHCO), 4.49
(1H, dd, J1 8.76 Hz, J2 5.04 Hz, CHCH2), 4.12 (1H, s, CHCO2Me), 3.69
(3H, s, OMe), 2.13 (1H, dd, J1 12.09 Hz, J2 6.63 Hz, CHMe2), 1.65e1.58
(2H, m, CH2CHMe2), 1.49e1.46 (1H, m, CHCMe2), 1.40 (9H, s, CMe3),
0.91e0.85 (12H, m, Me2CH); dC (75 MHz, CDCl3) 173.3, 171.7, 155.9,
80.3, 63.7, 57.2, 53.5, 40.5, 28.8, 28.2, 24.7, 22.8, 19.5; m/z (ESI) 289.2
(100%), 345.3 (55%, MHþ), 367.4 (90%); HRMS (ESI): MHþ, found
345.2384 C17H33N2O5 requires 345.2389.

10118
A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
4.1.1.7. (R)-Methyl 2-((R)-2-(tert-butoxycarbonylamino)-4-
CH3OH); IR (KBr) 3462, 3336, 2966, 2365, 1659, 1535, 1383,
1049, 693 cmꢀ1
dH (300 MHz, CDCl3) 7.33e7.22 (5H, m, ArH),
6.04 (1H, d, J 8.04 Hz, NHBoc), 5.26 (1H, d, J 7.56 Hz, NHCO),
4.30 (1H, d, 6.69 Hz, CHNHBoc), 3.95 (1H, d, 3.00 Hz,
methylpentanamido)-3-methylbutanoate (15g). Yield 91%; mp
;
136 ꢃC; Rf (20% EtOAc/Hexane) 0.52; [
a
]
22 þ14.2 (c 0.50, CH3OH); IR
D
(KBr) 3335, 2970, 2368, 1755, 1691, 1647, 1555, 1179, 1018 cmꢀ1
;
dH
J
J
(300 MHz, CDCl3) 7.22 (1H, d, J 7.53 Hz, NHBoc), 5.71 (1H, d, J
7.44 Hz, CHNHBoc), 4.47e4.43 (1H, m, CHCO2Me), 4.22 (1H, d, J
4.38 Hz, NHCO), 3.64 (3H, s, OMe), 2.08 (1H, dd, J1 11.91 Hz, J2
6.03 Hz, CHMe2), 1.58e1.49 (3H, m, CH2CHMe2), 1.35 (9H, s,
CMe3),0.85 (12H, d, J 5.04 Hz, CH3); dC (50 MHz, CDCl3) 172.5, 172.0,
155.6, 79.7, 56.8, 52.9, 51.8, 40.6, 31.0, 28.1, 24.5, 22.7, 18.7; m/z (ESI)
289.1 (100%), 345.1 (55%, MHþ), 367.0 (90%); HRMS (ESI): MHþ,
found 345.2386 C17H33N2O5 requires 345.2389.
CHCH2OH), 3.47e3.39 (2H, m, CH2OH), 3.11e2.98 (2H, m,
CH2Ph), 2.57 (1H, buried s, OH) 1.51 (1H, dd, J1 13.29 Hz, J2
6.63 Hz, CHMe2), 1.41 (9H, s, CMe3), 1.30e1.27 (2H, m,
CH2CHMe2), 0.87 (6H, d, J 6.45 Hz, CH3); dC (50 MHz, CDCl3)
171.4, 155.4, 136.7, 129.2, 128.4, 126.7, 80.1, 65.0, 56.0, 49.7, 39.7,
38.3, 28.1, 24.5, 22.9; m/z (ESI) 309.2 (60%), 365.1 (70%, MHþ),
387.2 (90%); HRMS (ESI): MHþ, found 365.2438 C20H33N2O4
requires 365.2440.
4.1.2. General procedure of ester reduction. To an ice cooled solution
of ester 15aef (2.90 mmol) in dry THF (30 ml), LiAlH4 (3.19 mmol)
was added slowly, and was allowed to stir at room temperature for
1 h. After completion of the reaction, it was quenched by slow
addition of ethyl acetate and water. The aqueous layer was
extracted with ethyl acetate thrice (3ꢂ50 ml), the combined or-
ganic layer was washed with brine, dried over anhydrous Na2SO4,
and solvent was removed under reduced pressure and subjected to
silica jel column chromatography to obtain the alcohols 12aeg in
78e84% yield.
4.1.2.5. tert-Butyl (S)-1-((S)-1-hydroxy-3-phenylpropan-2-
ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (12e). Yield 82%;
22
mp 111 ꢃC; Rf (30% EtOAc/Hexane) 0.49; [
a
]
ꢀ17.5 (c 0.42,
D
CH3OH); IR (KBr) 3462, 3336, 2966, 2365, 1659, 1535, 1383,
1049, 693 cmꢀ1
;
dH (300 MHz, CDCl3) 7.19e7.15 (5H, m, ArH),
6.72 (1H, br s, NHBoc), 5.07 (1H, br s, NHCO), 4.04 (2H, s,
CHNH), 3.54 (2H, d, J 11.25 Hz, CH2OH), 3.23 (1H, br s, OH), 2.80
(2H, d, J 6.63 Hz, CH2Ph), 1.52 (3H, br s, CH2CHMe2), 1.35 (9H, s,
CMe3), 0.82 (6H, s, CH3); dC (50 MHz, CDCl3) 172.9, 155.8, 137.7,
129.2, 128.4, 126.4, 80.1, 63.1, 53.4, 52.7, 41.0, 36.7, 28.2, 24.6,
22.7; m/z (ESI) 309.4 (60%), 365.2 (70%, MHþ), 387.2 (90%);
HRMS (ESI): MHþ, found 365.2443 C20H33N2O4 requires
365.2440.
4.1.2.1. tert-Butyl (S)-1-((S)-1-hydroxy-3-methylbutan-2-
ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (12a). Yield 79%;
22
mp 122 ꢃC; Rf (30% EtOAc/Hexane) 0.48; [
a
]
D
ꢀ18.9 (c 0.30,
CH3OH); IR (KBr) 3327, 2977, 2369, 1685, 1639, 1537, 1397, 1254,
4.1.2.6. tert-Butyl (S)-1-((2S,3R)-1-hydroxy-3-methylpentan-2-
1179, 1024, 644 cmꢀ1
;
dH (300 MHz, CDCl3) 6.62 (1H, d, J 6.93 Hz,
ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (12f). Yield 81%;
22
NHBoc), 5.13 (1H, br s, CHNHBoc), 4.08 (1H, d, J 3.27 Hz, NHCO),
3.67 (3H, br s, CHCH2OH), 3.19 (1H, s, OH), 1.95e1.84 (1H, m,
CHMe2), 1.69e1.62 (2H, m, CH2CH), 1.56e1.50 (1H, m, CHMe2), 1.43
(9H, s, CMe3),0.96e0.90 (12H, m, CH3); dC (50 MHz, CDCl3) 173.3,
156.0, 80.3, 63.6, 57.1, 53.5, 40.5, 28.2, 24.7, 22.8, 19.5, 18.6; m/z (ESI)
261.1 (100%), 317.2 (30%, MHþ), 339.1 (40%); HRMS (ESI): MHþ,
found 317.2435 C16H33N2O4 requires 317.2440.
mp 124 ꢃC; Rf (30% EtOAc/Hexane) 0.51; [
a
]
D
ꢀ18.5 (c 0.40,
CH3OH); IR (KBr) 3466, 3333, 2962, 2365, 1652, 1537, 1384, 1041,
690 cmꢀ1
;
dH (300 MHz, CDCl3) 7.23e7.15 (5H, m, ArH), 6.06 (1H, d,
J 8.34 Hz, NHBoc), 5.20 (1H, d, J 7.38 Hz, NHCO), 4.24 (1H, d, J
6.90 Hz, CHNHBoc), 3.61 (1H, d, J 3.57 Hz, CHCHMeEt), 3.42 (2H, s,
CH2OH), 3.05e2.91 (2H, m, CH2Ph), 2.46 (1H, br s, OH),1.46e1.34
(11H, m), 1.01e0.88 (1H, m, CHMeEt), 0.77e0.75 (6H, m, CH3); dC
(50 MHz, CDCl3) 171.6, 155.5, 136.7, 129.2, 128.6, 126.9, 80.3, 62.9,
56.3, 55.9, 38.3, 35.1, 28.1, 25.2, 15.3, 11.1; m/z (ESI) 309.3 (60%),
365.2 (70%, MHþ), 387.4 (90%); HRMS (ESI): MHþ, found 365.2444
C20H33N2O4 requires 365.2440.
4.1.2.2. tert-Butyl (S)-1-((S)-1-hydroxy-3-methylbutan-2-
ylamino)-3-methyl-1-oxobutan-2-ylcarbamate (12b). Yield 83%;
mp 145 ꢃC; Rf (30% EtOAc/Hexane) 0.53; [
a
]
D
22 ꢀ9.8 (c 0.15, CH3OH);
IR (KBr) 3323, 2968, 2365, 1686, 1635, 1532, 1369, 1298, 1176, 1020,
647 cmꢀ1
;
dH (300 MHz, CDCl3) 6.23 (1H, d, J 6.06 Hz, NHBoc), 5.00
4.1.2.7. tert-Butyl (R)-1-((R)-1-hydroxy-3-methylbutan-2-
(1H, d, J 4.74 Hz, NHCO), 3.79e3.74 (1H, m, CHNHBoc), 3.64e3.57
(3H, m, CHCH2OH), 2.17 (1H, buried s, OH), 1.83e1.79 (2H, m,
CHMe2), 1.37 (9H, s, CMe3),0.92e0.85 (12H, m, CH3); dC (50 MHz,
CDCl3) 172.4, 156.0, 79.8, 63.1, 60.7, 56.9, 30.2, 28.6, 28.1, 19.4, 19.2;
m/z (ESI) 247.0 (100%), 303.9 (60%, MHþ), 325.1 (15%); HRMS (ESI):
MHþ, found 303.2287 C15H31N2O4 requires 303.2284.
ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (12g). Yield 78%;
22
mp 120 ꢃC; Rf (30% EtOAc/Hexane) 0.48; [
a
]
þ18.8 (c 0.26,
D
CH3OH); IR (KBr) 3325, 2970, 2366, 1688, 1635, 1534, 1392, 1250,
1176, 1027, 649 cmꢀ1
;
dH (300 MHz, CDCl3) 6.60 (1H, d, J 6.99 Hz,
NHBoc), 5.12 (1H, br s, NHCO), 4.08 (1H, d, J 4.05 Hz, CHNHBoc),
3.69e3.60 (3H,m, CHCH2OH), 3.07 (1H,buried s, OH),1.89 (1H, dd, J1
13.2 Hz, J2 6.6 Hz, CHMe2), 1.69e1.62 (2H, m, CH2CH), 1.56e1.50
(1H, m, CHMe2 (leucine)), 1.43 (9H, s, CMe3),0.95e0.90 (12H, m,
CH3); dC (50 MHz, CDCl3) 173.3, 155.9, 80.3, 63.6, 57.1, 53.4, 40.5,
28.8, 28.2, 24.7, 22.8, 19.4; m/z (ESI) 261.2 (100%), 317.1 (30%, MHþ),
339.1 (40%); HRMS (ESI): MHþ, found 317.2436 C16H33N2O4 requires
317.2440.
4.1.2.3. tert-Butyl (S)-1-((S)-1-hydroxy-3-phenylpropan-2-
ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (12c). Yield 80%;
22
mp 145 ꢃC; Rf (30% EtOAc/Hexane) 0.53; [
a
]
ꢀ13.3 (c 0.31,
D
CH3OH); IR (KBr) 3461, 3335, 2963, 2363, 1658, 1532, 1386, 1048,
698 cmꢀ1
;
dH (300 MHz, CDCl3) 7.21e7.04 (10H, m, ArH), 6.01 (1H,
d, J 7.23 Hz, NHBoc), 5.02 (1H, d, J 7.02 Hz, NHCO), 4.19 (1H, d, J
6.78 Hz, CHNHBoc), 4.01e3.99 (1H, m, CHCH2OH), 3.35 (2H, br s,
CH2OH), 2.91 (2H, d, J 7.05 Hz, CH2Ph), 2.70e2.67 (2H, m, CH2Ph)
2.38 (1H, buried s, OH) 1.33 (9H, s, CMe3); dC (75 MHz, CDCl3) 171.2,
155.4, 137.4, 136.7, 129.2, 129.1, 128.6, 128.5, 126.9, 126.5, 80.3, 63.1,
56.2, 52.6, 38.6, 36.7, 28.2; m/z (ESI) 343.0 (50%), 399.0 (80%, MHþ),
421.2 (95%); HRMS (ESI): MHþ, found 399.2288 C23H31N2O4 re-
quires 399.2284.
4.1.3. General procedure for Swern oxidation. In an inert atmo-
sphere, (COCl)2 (4.74 mmol) was taken in dry CH2Cl2 (10 ml) cooled
to ꢀ78 ꢃC, dry DMSO (9.48 mmol) was added slowly. After 15 min,
previously prepared alcohols 12a-g (3.16 mmol) in dry CH2Cl2
(20 ml) was added slowly. The reaction mixture was allowed to stir
at the same temperature for 30 min, then DIPEA (12.64 mmol) was
added. The reaction was then allowed to stir at the same temper-
ature for 1.5 h. After completion, the reaction was quenched with
slow addition of NH4Cl solution, the aqueous layer was extracted
with CH2Cl2 (3ꢂ30 ml), the combined organic layer was washed
with brine, dried over anhydrous Na2SO4, and solvent was removed
4.1.2.4. tert-Butyl (S)-1-((S)-1-hydroxy-4-methylpentan-2-
ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (12d). Yield 84%;
22
mp 129 ꢃC; Rf (30% EtOAc/Hexane) 0.52; [
a
]
ꢀ15.3 (c 0.34,
D

A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
10119
under reduced pressure to furnish the crude aldehydes 16aeg,
which was used in the next step without further purification.
CH3); dC (50 MHz, CDCl3) 170.3, 155.4, 138.2, 136.7, 129.4, 128.6,
126.8, 114.4, 80.2, 56.1, 49.5, 43.9, 38.3, 28.2, 24.5, 22.7; m/z (ESI)
304.1 (80%), 361.2 (40%, MHþ), 383.2 (40%); HRMS (ESI): MHþ,
found 361.2488 C21H33N2O3 requires 361.2491.
4.1.4. General procedure for Wittig reaction. To a solution of meth-
yltriphenylphosphonium iodide (4.77 mmol) in dry THF (10 ml)
under N2 atmosphere, KHMDS solution (0.5 M in toluene)
(3.97 mmol) was added slowly at ꢀ78 ꢃC and stirred for 1 h. After
the development of the deep yellow coloured solution, previously
prepared aldehydes 16aeg (1.59 mmol) in dry THF (15 ml) was
added slowly to the reaction mixture at the same temperature and
was allowed to stir for 2 h. After completion of the reaction, satd
solution of ammonium chloride was added, extracted with ethyl
acetate (3ꢂ20 ml). The combined organic layer was washed with
brine solution, dried over anhydrous Na2SO4 and then solvent was
removed under reduced pressure. The crude product was purified
over silica gel column chromatography to furnish corresponding
olefin 11aeg as colourless solid in 67e72% yield.
4.1.4.5. tert-Butyl (S)-4-methyl-1-oxo-1-((S)-1-phenylbut-3-en-
2-ylamino)pentan-2-ylcarbamate (11e). Yield 72%; mp 123 ꢃC; Rf
22
(15% EtOAc/Hexane) 0.58; [
a
]
ꢀ14.8 (c 0.20, CH3OH); IR (KBr)
D
3296, 2968, 2375, 1666, 1527, 1292, 1177, 698 cmꢀ1
; dH
(300 MHz, CDCl3) 7.27e7.16 (5H, m, ArH), 6.16 (1H, d, J 7.8 Hz,
NHBoc), 5.85e5.76 (1H, m, CH]CH2), 5.16e5.06 (2H, m, CH2]),
4.95e4.74 (2H, m, CHNHBoc, NHCO), 4.04e3.99 (1H, m, CHCH]
CH2), 2.91e2.80 (2H, m, CH2Ph), 1.62e1.54 (2H, m, CH2CHMe2),
1.42 (9H, s, CMe3), 1.34e1.30 (1H, m, CHCH2Me2), 0.92e0.83
(6H, m, CH3); dC (50 MHz, CDCl3) 171.8, 155.6, 137.2, 129.4,
129.3, 128.3, 126.5, 115.0, 80.0, 53.1, 51.9, 41.0, 28.2, 24.5, 22.6,
22.2; m/z (ESI) 304.5 (100%), 361.3 (10%, MHþ), 383.2 (75%);
HRMS (ESI): MHþ, found 361.2494 C21H33N2O3 requires
361.2491.
4.1.4.1. tert-Butyl (S)-4-methyl-1-((S)-4-methylpent-1-en-3-
ylamino)-1-oxopentan-2-ylcarbamate (11a). Yield 67%; mp 126 ꢃC;
22
Rf (15% EtOAc/Hexane) 0.62; [
a
]
ꢀ16.8 (c 0.35, CH3OH); IR (KBr)
4.1.4.6. tert-Butyl (S)-1-((3R,4R)-4-methylhex-1-en-3-ylamino)-
D
3299, 2976, 2367, 1652, 1527, 1293, 1174, 693 cmꢀ1
;
dH (300 MHz,
1-oxo-3-phenylpropan-2-ylcarbamate (11f). Yield 71%; mp 115 ꢃC;
22
CDCl3) 6.34 (1H, s, NHBoc), 5.78e5.70 (1H, m, CH]CH2), 5.17e5.03
(3H, m, CH2], CHNHBoc), 4.33e4.31 (1H, m, CHCH]CH2), 4.11 (1H,
br s, NHCO), 1.84e1.68 (3H, m, CH2CHMe2, CHMe2), 1.48e1.47 (1H,
m, CHMe2 (leucine)),1.43 (9H, s, CMe3), 0.95e0.87 (12H, m, CH3); dC
(50 MHz, CDCl3) 172.0, 155.9, 136.8, 115.4, 80.2, 56.3, 40.8, 32.1, 28.3,
24.8, 22.1, 18.7, 17.9; m/z (ESI) 257.3 (100%), 313.1 (25%, MHþ), 336.2
(40%); HRMS (ESI): MHþ, found 313.2489 C17H32N2O3 requires
313.2491.
Rf (15% EtOAc/Hexane) 0.62; [
a
]
ꢀ15.8 (c 0.60, CH3OH); IR (KBr)
D
3297, 2972, 2371, 1660, 1526, 1299, 1175, 696 cmꢀ1
; dH (300 MHz,
CDCl3) 7.20e7.12 (5H, m, ArH), 5.91 (1H, d, J 8.36 Hz, NHBoc),
5.56e5.45 (1H, m, CH]CH2), 5.13e4.78 (3H, m, CH2], NHCO), 4.25
(2H, br s, CHCH]CH2, CHCH2), 2.99 (2H, d, J 6.66 Hz, CH2Ph), 1.33
(11H, s, CMe3, CH2Me), 0.99e0.87 (1H, m, CHMeEt), 0.81e0.69 (6H,
m, CH3); dC (50 MHz, CDCl3) 170.4, 155.4, 136.7, 135.7, 129.3, 128.5,
126.7, 115.7, 80.1, 56.1, 55.5, 38.4, 38.2, 28.1, 25.0, 14.8, 11.4; m/z (ESI)
304.9 (100%), 361.2 (10%, MHþ), 383.1 (75%); HRMS (ESI): MHþ,
found 361.2496 C21H33N2O3 requires 361.2491.
4.1.4.2. tert-Butyl (S)-3-methyl-1-((S)-4-methylpent-1-en-3-
ylamino)-1-oxobutan-2-ylcarbamate (11b). Yield 69%; mp 89 ꢃC;
22
Rf (15% EtOAc/Hexane) 0.62; [
a
]
ꢀ12.8 (c 0.34, CH3OH); IR (KBr)
4.1.4.7. tert-Butyl (R)-4-methyl-1-((R)-4-methylpent-1-en-3-
D
3291, 2982, 2361, 1670, 1536, 1289, 1165, 691 cmꢀ1
;
dH (300 MHz,
ylamino)-1-oxopentan-2-ylcarbamate (11g). Yield 67%; mp 98 ꢃC;
22
CDCl3) 6.11 (1H, d, J 8.64 Hz, NHBoc), 5.80e5.69 (1H, m, CH]CH2),
5.18e5.12 (3H, m, CH2], CHNHBoc), 4.37e4.32 (1H, m, CHCH]
CH2), 3.88e3.83 (1H, m, CHMe2), 2.15 (1H, d, J 4.17 Hz, NHCO),
1.85e1.74 (1H, m, CHMe2), 1.44 (9H, s, CMe3), 0.97e0.88 (12H, m,
CH3); dC (75 MHz, CDCl3) 171.1, 155.9, 136.6, 115.5, 79.8, 56.4, 32.0,
30.2, 28.2, 19.4, 18.7, 18.0; m/z (ESI) 242.1 (80%), 299.5 (30%, MHþ),
322.3 (65%); HRMS (ESI): MHþ, found 299.2337 C16H31N2O3 re-
quires 299.2335.
Rf (15% EtOAc/Hexane) 0.63; [
a]
þ16.9 (c 0.31, CH3OH); IR (KBr)
D
3295, 2974, 2366, 1655, 1521, 1291, 1175, 698 cmꢀ1
; dH (300 MHz,
CDCl3) 6.21 (1H, br s, NHBoc), 5.73e5.62 (1H, m, CH]CH2),
5.09e5.03 (2H, m, CH2]), 4.90 (1H, br s, NHCO), 4.26e4.23 (1H, m,
CHNHBoc), 4.01 (1H, br s, CHCH]CH2), 1.83 (1H, s, CHMe2, CHMe2),
1.76e1.69 (1H, m, CHMe2), 1.40 (2H, m, CH2CHMe2) 1.36 (9H, s,
CMe3), 0.86e0.80 (12H, m, CH3); dC (75 MHz, CDCl3) 172.1, 156.0,
136.8, 115.5, 80.5, 56.3, 32.1, 29.6, 28.3, 24.8, 22.8, 18.7, 17.8; m/z
(ESI) 257.1 (100%), 313.2 (25%, MHþ), 336.1 (40%); HRMS (ESI): MHþ,
found 313.2487 C17H33N2O4 requires 313.2491.
4.1.4.3. tert-Butyl (S)-1-oxo-3-phenyl-1-((S)-1-phenylbut-3-en-
2-ylamino)propan-2-ylcarbamateas (11c). Yield 70%; mp 140 ꢃC; Rf
(15% EtOAc/Hexane) 0.61; [
a
]
D
22 ꢀ4.3 (c 0.26, CH3OH); IR (KBr) 3293,
4.1.5. General procedure for iodocyclization. To an ice cooled solu-
tion of starting olefinic compounds 11aeg (0.59 mmol) in aceto-
nitrile (5 ml), K2CO3 (1.77 mmol) was added followed by I2
(1.77 mmol) in argon atmosphere and keep stirring for 2 h. After
the completion of reaction I2 was quenched by satd Na2S2O3 solu-
tion and extracted with ethyl acetate (3ꢂ25 ml), the combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
solvent was removed under reduced pressure and the crude
product was subjected to column chromatography to furnish the
oily cyclic compounds 10aeg in 76e88%.
2975, 2363, 1653, 1520, 1290, 1170, 695 cmꢀ1
;
dH (300 MHz, CDCl3)
7.27e7.01 (10H, m, ArH), 5.82 (1H, d, J 7.14 Hz, NHBoc), 5.70e5.59
(1H, m, CH]CH2), 5.04e4.83 (3H, m, CH2], CHNHBoc), 4.69 (1H, s,
NHCO), 4.27 (1H, d, J 6.9 Hz, CHCH2Ph), 2.99 (2H, d, J 5.97 Hz,
CH2Ph), 2.83e2.70 (2H, m, CH2Ph), 1.39 (9H, s, CMe3); dC (50 MHz,
CDCl3) 170.3, 155.2, 136.8, 129.4, 128.6, 128.3, 126.9, 126.6, 115.3,
80.2, 56.0, 51.9, 40.9, 38.3, 28.2; m/z (ESI) 338.9 (100%), 395.2 (20%,
MHþ), 417.1 (30%); HRMS (ESI): MHþ, found 395.2332 C24H31N2O3
requires 395.2335.
4.1.4.4. tert-Butyl (S)-1-((S)-5-methylhex-1-en-3-ylamino)-1-
4.1.5.1. (3S,6S)-tert-Butyl 2-(iodomethyl)-6-isobutyl-3-isopropyl-
oxo-3-phenylpropan-2-ylcarbamate (11d). Yield 69%; mp 115 ꢃC;
5-oxopiperazine-1-carboxylate (10a). Yield 70%; Rf (10% EtOAc/
22
22
Rf (15% EtOAc/Hexane) 0.60; [
a
]
ꢀ7.8 (c 0.45, CH3OH); IR (KBr)
Hexane) 0.61; [
a
]
ꢀ24.7 (c 0.30, CH3OH); IR (Neat) 3498, 3242,
D
D
3293, 2971, 2370, 1658, 1523, 1291, 1179, 695 cmꢀ1
;
dH (300 MHz,
2995, 2363, 1649, 1454, 1122, 1029, 672 cmꢀ1
; dH (300 MHz,
CDCl3) 7.30e7.19 (5H, m, ArH), 5.73 (1H, d, J 7.74 Hz, NHBoc),
5.62e5.51 (1H, m, CH]CH2), 5.10e4.88 (3H, m, CH2], NHCO),
4.47e4.43 (1H, m, CHNHBoc), 4.29 (1H, dd, J1 14.7 Hz, J2 7.2 Hz,
CHCH]CH2), 3.07e3.04 (2H, m, CH2Ph), 1.56e1.47 (1H, m, CHMe2),
1.41 (9H, s, CMe3), 1.30e1.25 (2H, m, CH2CHMe2), 0.89e0.86 (6H, m,
CDCl3) 5.01e4.93 (1H, m, NH), 4.45e4.32 (1H, m, CHCH2CHMe2),
4.28e4.23 (1H, m, CHCH2I), 3.63e3.56 (1H, m, CHCHMe2),
3.24e3.17 (2H, m, CH2I), 1.82e1.50 (4H, m, 2CHMe2, CH2CHMe2),
1.44 (9H, s, CMe3), 0.96e0.90 (12H, m, CH3); dC (75 MHz, CDCl3)
166.6, 155.2, 80.5, 80.3, 79.4, 47.4, 42.8, 32.1, 28.2, 24.7, 21.9, 18.2,

10120
A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
8.2; m/z (ESI) 383.3 (60%), 439.1 (100%, MHþ), 461.2 (20%); HRMS
4.1.5.7. (3R,6R)-tert-Butyl 2-(iodomethyl)-6-isobutyl-3-isopropyl-
(ESI): MHþ, found 439.1454 C17H32IN2O3 requires 439.1458.
5-oxopiperazine-1-carboxylate (10g). Yield 76%; Rf (10% EtOAc/
22
Hexane) 0.62; [
a
]
D
þ24.6 (c 0.40, CH3OH); IR (Neat) 3497, 3243,
4.1.5.2. (3S,6S)-tert-Butyl 2-(iodomethyl)-3,6-diisopropyl-5-
2994, 2362, 1643, 1451, 1120, 1028, 679 cmꢀ1
; dH (300 MHz, CDCl3)
oxopiperazine-1-carboxylate (10b). Yield 71%; Rf (10% EtOAc/Hex-
4.87 (1H, s, NH), 4.29 (1H, d, J 5.43 Hz, CHNBoc), 4.20e4.16 (1H, m,
CHCH2I), 3.52 (1H, d, J 5.25 Hz, CHNH), 3.19e3.08 (2H, m, CH2I),
1.71e1.67 (2H, m), 1.55e1.45 (2H, m), 1.37 (9H, s, CMe3), 0.89e0.83
(12H, m, CH3); dC (75 MHz, CDCl3) 166.7, 155.3, 80.6, 79.5, 47.4, 42.3,
32.1, 29.6, 28.2, 24.7, 21.9, 18.2, 8.2; m/z (ESI) 338.1 (60%), 439.9
(100%, MHþ), 461.3 (20%); HRMS (ESI): MHþ, found 439.1455
C17H32IN2O3 requires 439.1458.
22
ane) 0.61; [
a
]
ꢀ14.2 (c 0.41, CH3OH); IR (Neat) 3492, 3245,
dH (300 MHz,
9.09 Hz, NH), 4.31e4.24 (2H, m,
D
2999, 2368, 1646, 1452, 1128, 1022, 672 cmꢀ1
CDCl3) 5.05 (1H, d,
;
J
CHCH2CHMe2, CHCH2I), 3.61e3.57 (1H, m, CHCHMe2), 3.22e3.19
(2H, m, CH2I), 2.18e2.09 (1H, m, CHMe2), 1.82e1.71 (1H, m,
CHMe2), 1.44 (9H, s, CMe3), 1.01e0.91 (12H, m, CH3); dC (75 MHz,
CDCl3) 165.3, 155.6, 80.9, 79.4, 53.9, 32.2, 30.9, 28.2, 19.0, 18.3,
17.6, 7.9; m/z (ESI) 369.0 (100%), 425.9 (100%, MHþ), 447.9 (10%);
HRMS (ESI): MHþ, found 425.1306 C16H30IN2O3 requires
425.1301.
4.1.6. Procedure for HornereWadswortheEmmons olefination. To an
ice cooled solution of the aldehyde 16a (3.18 mmol) in dry CH2Cl2
(30 ml), Wittig reagent Ph3P]CHCO2Et (4.13 mmol) was added and
then allowed to stir at room temperature for 2 h. After completion
of the reaction, solvent was removed under reduced pressure to
obtain the crude product, which was purified by column chroma-
4.1.5.3. (2S,5S)-tert-Butyl 2,5-dibenzyl-6-(iodomethyl)-3-
oxopiperazine-1-carboxylate (10c). Yield 69%; Rf (10% EtOAc/Hex-
ane) 0.60; [
a
]
22 ꢀ10.8 (c 0.42, CH3OH); IR (Neat) 3492, 3245, 2998,
tography to furnish the desired
yield.
a,b-unsaturated ester 17a in 86%
D
2365, 1642, 1455, 1119, 1029, 676 cmꢀ1
;
dH (300 MHz, CDCl3)
7.29e7.15 (10H, m, ArH), 5.14e5.03 (1H, m), 4.65 (1H, br, s),
4.28e4.22 (1H, m), 3.95 (1H, d, J 6.12 Hz), 3.28e2.63 (6H, m, CH2Ph,
CH2I), 1.42 (9H, s, CMe3); dC (50 MHz, CDCl3) 165.0, 155.4, 138.1,
136.2, 129.7, 129.5, 128.8, 128.5, 128.3, 126.8, 82.9, 79.8, 72.9, 49.9,
41.7, 29.7, 28.5, 7.1; m/z (ESI) 464.1 (60%), 521.1 (80%, MHþ), 543.3
(70%); HRMS (ESI): MHþ, found 521.1304 C24H30IN2O3 requires
521.1301.
4.1.6.1. (S,E)-Ethyl 4-((S)-2-(tert-butoxycarbonylamino)-4-
methylpentanamido)-5-methylhex-2-enoate (17a). Yield 86%; Rf
22
(25% EtOAc/Hexane) 0.51; [
a]
ꢀ15.9 (c 0.51, CH3OH); IR (KBr)
D
3113, 2996, 2233, 1656, 1371, 1019, 770 cmꢀ1
; dH (300 MHz, CDCl3)
7.02 (1H, d, J 7.59 Hz, NH), 6.81 (1H, dd, J1 15.66 Hz, J2 5.40 Hz, CH]
CHCO2Et), 5.86 (1H, d, J 15.60 Hz, CHCO2Et), 5.36 (1H, d, J 6.60 Hz,
NH), 4.48e4.42 (1H, m), 4.15e4.07 (3H, m), 1.85e1.75 (1H, m,
CHMe2), 1.59e1.45 (3H, m, CH2CHMe2), 1.36 (9H, s, CMe3), 1.20 (3H,
t, J 7.11 Hz, CH3CH2O), 0.87e0.81 (12H, m, CH3); dC (75 MHz, CDCl3)
172.2, 166.1, 156.0, 146.6, 121.6, 79.1, 60.3, 54.9, 40.2, 32.1, 29.6, 28.2,
24.7, 22.8, 18.9, 17.85; m/z (ESI) 284.1 (60%), 385.2 (100%, MHþ),
407.1 (30%); HRMS (ESI): MHþ, found 385.2698 C20H37N2O5 re-
quires 385.2702.
4.1.5.4. (2S,5S)-tert-Butyl 2-benzyl-6-(iodomethyl)-5-isobutyl-3-
oxopiperazine-1-carboxylate (10d). Yield 67%; Rf (10% EtOAc/Hex-
ane) 0.63; [
a
]
22 ꢀ14.7 (c 0.35, CH3OH); IR (Neat) 3497, 3246, 2993,
D
2364, 1642, 1458, 1120, 1022, 679 cmꢀ1
;
dH (300 MHz, CDCl3)
7.30e7.14 (5H, m, ArH), 5.05 (1H, br s, NH), 4.62e4.60 (1H, m,
CHCH2Ph), 4.19e4.14 (1H, m, CHCH2I), 3.76e3.72 (1H, m,
CHCH2CHMe2), 3.22e3.03 (4H, m, CH2Ph, CH2I), 1.82e1.72 (2H, m,
CH2CHMe2), 1.40 (9H, s, CMe3) 1.28e1.25 (1H, m, CHMe2),
0.95e0.88 (6H, m, CH3); dC (50 MHz, CDCl3) 164.4, 155.2, 136.5,
129.6, 128.4, 126.9, 84.4, 79.8, 70.0, 49.9, 45.7, 38.8, 28.3, 24.5, 22.9,
6.86; m/z (ESI) 431.1 (60%), 487.1 (80%, MHþ), 510.2 (20%); HRMS
(ESI): MHþ, found 487.1455 C21H32IN2O3 requires 487.1458.
4.1.7. Procedure for aza-Michael reaction. To an ice cooled solution
of 17a (2.34 mmol) in dry CH2Cl2 (10 ml), 1:1 TFA in CH2Cl2 (10 ml)
was added and allowed to stir at room temperature for 30 min. After
completion of the reaction, solvent was removed and the crude
residue was utilized in the next step without further purification.
The crude product obtained in the previous step was dissolved in
CH3CN (5 ml), cooled to 0 ꢃC and then DBU (0.26 mmol) was added.
Thereaction mixturewasallowed to stirat roomtemperaturefor 8h.
Water was added and the aqueous layer was extracted with ethyl
acetate thrice, the combined organic layer was washed with brine,
dried over anhydrous Na2SO4, solvent was removed under reduced
pressure. The crude product was purified by column chromatogra-
phy to furnish the cyclic product 18a in 26% over two steps.
4.1.5.5. (3S,6S)-tert-Butyl 3-benzyl-2-(iodomethyl)-6-isobutyl-5-
oxopiperazine-1-carboxylate (10e). Yield 66%; Rf (10% EtOAc/Hex-
22
ane) 0.62; [
a
]
ꢀ7.2 (c 0.51, CH3OH); IR (Neat) 3491, 3242, 2993,
D
2364, 1648, 1455, 1122, 1021, 675 cmꢀ1
; dH (300 MHz, CDCl3)
7.25e7.10 (5H, m, ArH), 4.91e4.88 (1H, m, NH), 4.34e4.32 (1H, m,
CHCH2CHMe2), 4.16e4.14 (1H, m, CHCH2Ph), 3.99e3.95 (1H, m,
CHCH2I), 3.01e2.65 (4H, m, CH2I, CH2Ph), 1.65e1.43 (3H, m,
CH2CHMe2), 1.37 (9H, s), 0.90e0.84 (6H, m, CH3); dC (75 MHz,
CDCl3) 166.9, 155.0, 136.5, 129.5, 128.5, 126.7, 82.0, 79.6, 72.6, 42.7,
41.2, 35.3, 28.3, 24.5, 22.7, 7.3; m/z (ESI) 431.1 (50%), 487.9 (100%,
MHþ), 510.1 (10%); HRMS (ESI): MHþ, found 487.1460 C21H32IN2O3
requires 487.1458.
4.1.7.1. Ethyl-2-((3S,6S)-6-isobutyl-3-isopropyl-5-oxopiperazin-
2-yl)acetate (18a). Rf (60% EtOAc/Hexane) 0.42; [
a
]
22 ꢀ26.8 (c 0.61,
D
CH3OH). IR (Neat) 3305, 3213, 2979, 2119, 1692, 1375, 1223, 1026,
768 cmꢀ1
; dH (300 MHz, CDCl3) 6.30 (1H, s), 4.20e4.12 (2H, m),
3.49e3.38 (2H, m), 2.93e2.91 (1H, m), 2.57e2.54 (2H, m),1.93e1.55
(5H, m), 1.27 (3H, t, J 7.14 Hz), 0.99e0.88 (12H, m); dC (75 MHz,
CDCl3) 173.6, 171.5, 62.0, 60.7, 52.8, 46.8, 40.6, 36.9, 30.4, 24.1, 23.4,
19.5, 14.1; m/z (ESI) 285.2, 20%, MHþ; HRMS (ESI): MHþ, found
285.2175 C15H29N2O3 requires 285.2178.
4.1.5.6. (2S,5S)-tert-Butyl 2-benzyl-5-sec-butyl-6-(iodomethyl)-
3-oxopiperazine-1-carboxylate (10f). Yield 70%; Rf (10% EtOAc/
22
Hexane) 0.64; [
a]
ꢀ23.7 (c 0.18, CH3OH); IR (Neat) 3497, 3246,
D
2993, 2364, 1642, 1458, 1120, 1022, 679 cmꢀ1
; dH (300 MHz, CDCl3)
7.19e7.15 (5H, m, ArH), 5.06 (1H, d, J 6.75 Hz, NH), 4.55 (1H, d, J
6.30 Hz, CHCH2Ph), 4.19 (1H, dd, J1 10.89 Hz, J2 5.40 Hz, CHCH2I),
3.52 (1H, d, J 5.19 Hz, CHNH), 3.10e2.89 (4H, m, CH2I, CH2Ph),
1.44e1.40 (1H, m, CHMeEt), 1.32 (9H, s, CMe3), 1.04e0.92 (2H, m,
CH2CH3), 0.83e0.71 (6H, m); dC (75 MHz, CDCl3) 165.1, 155.0, 136.3,
129.4, 128.3, 126.8, 80.97, 79.7, 76.2, 49.8, 38.9, 38.6, 28.3, 25.1, 14.5,
11.6, 7.9; m/z (ESI) 431.1 (60%), 487.0 (100%, MHþ), 510.3 (10%);
HRMS (ESI): MHþ, found 487.1465 C21H32IN2O3 requires 487.1458.
Acknowledgements
Financial support from Department of Science and Technology
(SR/S1/OC-74/2009), New Delhi, India is highly acknowledged.
Amit and Sanjit thank CSIR for providing fellowships (NET-JRF and
NET-SRF). Instrumental facilities from SAIF, CDRI, Lucknow is ac-
knowledged. This is CDRI communication no 8327.

A.K. Jana et al. / Tetrahedron 68 (2012) 10114e10121
10121
31. Dinsmore, C. J.; Zartman, C. B.; Bergman, J. M.; Abrams, M. T.; Buser, C. A.;
Culberson, J. C.; Davide, J. P.; Ellis-Hutchings, M.; Fernandes, C.; Graham, S. L.;
Hartman, G. D.; Huber, H. E.; Lobell, R. B.; Mosser, S. D.; Robinson, R. G.; Wil-
liams, T. M. Bioorg. Med. Chem. Lett. 2004, 14, 639e643.
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.09.109.
32. Seibel, J.; Brown, D.; Amour, A.; Macdonald, S. J.; Oldham, N. J.; Schofield, C. J.
Bioorg. Med. Chem. Lett. 2003, 13, 387e389.
33. Su, T.; Yang, H.; Volkots, D.; Woolfrey, J.; Dam, S.; Wong, P.; Sinha, U.;
Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2003, 13, 729e732.
34. Holsworth, D. D.; Powell, N. A.; Downing, D. M.; Cai, C.; Cody, W. L.; Ryan, J. M.;
Ostroski, R.; Jalaie, M.; Bryant, J. W.; Edmunds, J. J. Bioorg. Med. Chem. 2005, 13,
2657e2664.
References and notes
1. Ward, S. E.; Harrington, F. P.; Gordon, L. J.; Hopley, S. C.; Scott, C. M.; Watson, J.
M. J. Med. Chem. 2005, 48, 3478e3480.
35. Powell, N. A.; Clay, E. H.; Holsworth, D. D.; Bryant, J. W.; Ryan, J. M.; Jalaie, M.;
Zhang, E.; Edmunds, J. J. Bioorg. Med. Chem. Lett. 2005, 15, 2371e2374.
36. Holsworth, D. D.; Cai, C.; Cheng, X.-M.; Cody, W. L.; Downing, D. M.; Erasga, N.;
Lee, C.; Powell, N. A.; Edmunds, J. J.; Stier, M.; Jalaie, M.; Zhang, E.; McConnell,
P.; Ryan, J. M.; Bryant, J.; Li, T.; Kasani, A.; Hall, E.; Subedi, R.; Rahim, M.; Maiti,
S. Bioorg. Med. Chem. Lett. 2006, 16, 2500e2504.
37. Cumming, J. N.; Le, T. X.; Babu, S.; Carroll, C.; Chen, X.; Favreau, L.; Gaspari, P.;
Guo, T.; Hobbs, D. W.; Huang, Y.; Iserloh, U.; Kennedy, M. E.; Kuvelkar, R.; Li, G.;
Lowrie, J.; McHugh, N. A.; Ozgur, L.; Pan, J.; Parker, E. M.; Saionz, K.; Stamford,
A. W.; Strickland, C.; Tadesse, D.; Voigt, J.; Wang, L.; Wu, Y.; Zhang, L.; Zhang, Q.
Bioorg. Med. Chem. Lett. 2008, 18, 3236e3241.
2. Leopoldo, M.; Lacivita, E.; Colabufo, N. A.; Contino, M.; Berardi, F.; Perrone, R. J.
Med. Chem. 2005, 48, 7919e7922.
3. Bruncko, M.; Oost, T. K.; Belli, B. A.; Ding, H.; Joseph, M. K.; Kunzer, A.;
Martineau, D.; McClellan, W. J.; Mitten, M.; Ng, S.-C.; Nimmer, P. M.;
Oltersdorf, R.; Park, C.-M.; Petros, A. M.; Shoemaker, A. R.; Song, X.; Wang, X.;
Wendt, M. D.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H.; Elmore, S. W. J. Med.
Chem. 2007, 50, 641e662.
4. Bombrun, A.; Gerber, P.; Casi, G.; Terradillos, O.; Antonsson, B.; Halazy. J. Med.
Chem. 2003, 46, 4365e4368.
5. Jacobsen, E. J.; Stelzer, L. S.; TenBrink, R. E.; Belonga, K. L.; Carter, D. B.; Im, H. K.;
Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D.; Zhong, W.-Z.;
Mickelson, J. W. J. Med. Chem. 1999, 42, 1123e1144.
38. Kitamura, S.; Fukushi, H.; Miyawaki, T.; Kawamura, M.; Konishi, N.; Terashita,
Z.-I.; Naka, T. J. Med. Chem. 2001, 44, 2438e2450.
39. Okamura, N.; Habay, S. A.; Zeng, J.; Chamberlin, A. R.; Reinscheid, R. K. J.
Pharmacol. Exp. Ther. 2008, 325, 893e901.
6. Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Welss, K. M.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 1994, 35, 673e676.
7. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nat. Rev. Drug. Discov.
40. Zhang, Y.; Gilmour, B. P.; Navarro, H. A.; Runyon, S. P. Bioorg. Med. Chem. Lett.
2002, 1, 493e502.
2008, 18, 4064e4067.
8. Miyamoto, T.; Matsumoto, J.; Chiba, K.; Egawa, H.; Shibamori, K.; Minamida, A.;
Nishimura, Y.; Okada, H.; Kataoka, M. J. Med. Chem. 1990, 33, 1645e1656.
9. (a) Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 329e332; (b) Nakhla, J. S.;
Wolfe, J. P. Org. Lett. 2007, 9, 3279e3282.
41. Bergman, J. M.; Abrams, M. T.; Davide, J. P.; Greenberg, I. B.; Robinson, R. G.;
Buser, C. A.; Huber, H. E.; Koblan, K. S.; Kohl, N. E.; Lobell, R. B.; Graham, S. L.;
Hartman, G. D.; Williams, T. M.; Dinsmore, C. J. Bioorg. Med. Chem. Lett. 2001, 11,
1411e1415.
10. Gurjar, M. K.; Karmakar, S.; Mohapatra, D. K.; Phalgune, U. D. Tetrahedron Lett.
42. (a) Reginato, G.; Credico, B. D.; Andreotti, D.; Mingardi, A.; Paiob, A.;
Donatib, D. Tetrahedron: Asymmetry 2007, 18, 2680e2688; (b) Lencina, C. L.;
Klimpt, A. D.; Sonnet, P. Tetrahedron: Asymmetry 2008, 19, 1689e1697; (c)
Mohamed, N.; Bhatt, U.; Just, G. Tetrahedron Lett. 1998, 39, 8213e8216; (d)
2002, 43, 1897e1900.
11. Shioiri, T.; Irako, N. Chem. Lett. 2002, 130e131.
12. Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621e623.
13. Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054e6055.
14. Dickson, D. P.; Wardrop, D. J. Org. Lett. 2009, 11, 1341e1344.
15. Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086e3087.
16. Jacquot, D. E. N.; Hoffmann, H.; Polborn, K.; Lindel, T. Tetrahedron Lett. 2002, 43,
3699e3702.
17. Chung, R.; Yu, E.; Incarvito, C. D.; Austin, D. J. Org. Lett. 2004, 6, 3881e3884.
18. Wang, S.; Romo, D. Angew. Chem., Int. Ed. 2008, 47, 1284e1286.
19. Hirose, T.; Sunazuka, T.; Tsuchiya, S.; Tanaka, T.; Kojima, Y.; Mori, R.; Iwatsuki,
M.; Omura, S. Chem.dEur. J. 2008, 14, 8220e8238.
20. Dinsmore, J. C.; Bergman, J. M.; Wei, D. D.; Zartman, C. B.; Davide, J. P.;
Greenberg, I. B.; Liu, D.; O’Neill, T. J.; Gibbs, J. B.; Koblan, K. S.; Kohl, N. E.; Lobell,
R. B.; Chen, I.-W.; McLoughlin, D. A.; Olah, T. V.; Graham, S. L.; Hartman, G. D.;
Williams, T. M. Bioorg. Med. Chem. Lett. 2001, 11, 537e540.
21. Tian, X.; Mishra, R. K.; Switzer, A. G.; Hu, X. E.; Kim, N.; Mazur, A. W.; Ebetino, F.
H.; Wos, J. A.; Crossdoersen, D.; Pinney, B. B.; Farmer, J. A.; Sheldon, R. J. Bioorg.
Med. Chem. Lett. 2006, 16, 4668e4673.
ꢀ
Risi, C. D.; Pela, M.; Pollini, G. P.; Trapella, C.; Zanirato, V. Tetrahedron:
Asymmetry 2010, 21, 255e274; (e) Mohamed, N.; Bhatt, U.; Just, G. Tetrahe-
dron Lett. 1997, 38, 3679e3682; (f) Kha, N. M.; Cano, M.; Balasubramanian, S.
Tetrahedron Lett. 2002, 43, 2439e2443; (g) Viso, A.; Pradill, R. F.; Flores, A.;
García, A. Tetrahedron 2007, 63, 8017e8026; (h) Viso, A.; Pradilla, R. F.;
ꢁ
Flores, A.; García, A.; Tortos, M.; Lopez-Rodríguez, M. L. J. Org. Chem. 2006,
71, 1442e1448.
43. (a) Mishra, J. K.; Panda, G. Synthesis 2005, 1881e1887; (b) Mishra, J. K.; Rao, J. S.;
Sastry, G. N.; Panda, G. Tetrahedron Lett. 2006, 47, 3357e3360; (c) Shagufta;
Panda, G. Org. Biomol. Chem. 2007, 5, 360e366; (d) Mishra, J. K.; Panda, G. J.
Comb. Chem. 2007, 9, 321e338; (e) Mishra, J. K.; Garg, P.; Dohare, P.; Kumar, A.;
Siddiqi, M. I.; Ray, M.; Panda, G. Bioorg. Med. Chem. Lett. 2007, 17, 1326e1331; (f)
Srivastava, A. K.; Panda, G. Chem.dEur. J. 2008, 14, 4675e4688; (g) Srivastava,
A. K.; Das, S. K.; Panda, G. Tetrahedron 2009, 65, 5322e5327; (h) Parai, M. K.;
Panda, G. Tetrahedron Lett. 2009, 50, 4703e4705; (i) Samanta, K.; Chakravarti,
B.; Mishra, J. K.; Dwivedi, S. K. D.; Nayak, L. V.; Choudhry, P.; Bid, H. K.; Konwar,
R.; Chattopadhyay, N.; Panda, G. Bioorg. Med. Chem. Lett. 2010, 20, 283e287; (j)
Mishra, J. K.; Samanta, K.; Jain, M.; Dikshit, M.; Panda, G. Bioorg. Med. Chem. Lett.
2010, 20, 244e247; (k) Das, S. K.; Srivastava, A. K.; Panda, G. Tetrahedron Lett.
2010, 51, 1483e1485; (l) Samanta, K.; Panda, G. Org. Biomol. Chem. 2010, 8,
2823e2828; (m) Samanta, K.; Panda, G. ChemdAsian J. 2011, 189e197; (n)
Samanta, K.; Srivastava, N.; Saha, S.; Panda, G. Org. Biomol. Chem. 2012, 10,
1553e1564.
22. Sugihara, H.; Fukushi, H.; Miyawaki, T.; Imai, Y.; Terashita, Z.-I.; Kawamura, M.;
Fujisawa, Y.; Kita, S. J. Med. Chem. 1998, 41, 489e502.
23. Pohlmann, A. R.; Guillaume, D.; Quirion, J.-C.; Husson, H.-P. J. Pept. Res.1997,51,116e120.
24. Herrero, S.; Garcia-Lopez, M. T.; Latorre, M.; Cenarruzabeitia, E.; Rio, J. D.;
Herranz, R. J. Org. Chem. 2002, 67, 3866e3873.
25. (a) Gonzalez-Vera, J. A.; Garcia-Lopez, M. T.; Herranz, R. J. Org. Chem. 2005, 70,
€
3660e3666; (b) Rubsam, F.; Mazitschek, R.; Giannis, A. Tetrahedron 2000, 56,
8481e8487; (c) Nefzi, A.; Giulianotti, M. A.; Houghten, R. A. Tetrahedron 2000,
44. (a) Bruni, E.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. Tetrahedron Lett.
1989, 30, 1679e1682; (b) Balko, T. W.; Brinkmeyer, R. S.; Terando, N. H. Tet-
rahedron Lett. 1989, 30, 2045e2048; (c) Creeke, P. I.; Mellor, J. M. Tetrahedron
Lett. 1989, 30, 4435e4438; (d) Noguchi, M.; Okada, H.; Watanabe, M.;
Moriyama, H.; Nakamura, O.; Kakehi, A. Heterocycl. Commun. 1996, 2,
361e370; (e) Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.; Kakehi, A.
Tetrahedron 1996, 52, 2827e2838; (f) Kitagawa, O.; Fujita, M.; Li, H.; Taguchi,
T. Tetrahedron Lett. 1997, 38, 615e618; (g) Yanada, R.; Kaieda, A.; Yanada, K.;
Takemoto, Y. Heterocycles 2005, 66, 101e106; (h) Arnold, M. A.; Duron, S. G.;
Gin, D. Y. J. Am. Chem. Soc. 2005, 127, 6924e6925; (i) Dennis, M.; Hall, L. M.;
Murphy, P. J.; Thornhill, A. J.; Nash, R.; Winters, A. L.; Hursthouse, M. B.; Light,
M. E.; Horton, P. Tetrahedron Lett. 2003, 44, 3075e3080; (j) Bera, S.; Panda, G.
ACS Comb Sci. 2012, 14, 1e4.
56, 3319e3326.
26. (a) Govek, S. P.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 9468e9469; (b)
€
Jacquot, D. E. N.; Zollinger, M.; Lindel, T. Angew. Chem., Int. Ed. 2005, 44,
2295e2298; (c) Williams, R. M.; Cao, J.; Tsujishima, H. Angew. Chem., Int. Ed.
2000, 39, 2540e2544.
27. (a) Eriksson, J.; Arvidsson, P. I.; Davidsson, O. Chem.dEur. J. 1999, 5, 2356e2361;
(b) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Org. Lett. 2006, 8, 6139e6142;
(c) Itsuno, S.; Matsumoto, T.; Sato, D.; Inoue, T. J. Org. Chem. 2000, 65,
5879e5881; (d) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 8,
3045e3048.
28. Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65,
2484e2493.
29. Dinsmore, C. J.; Bergman, J. M.; Bogusky, M. J.; Culberson, J. C.; Hamilton, K. A.;
Graham, S. L. Org. Lett. 2001, 3, 865e868.
45. Desouky, S. K. E.; Ryu, S. Y.; Kim, Y. K. Tetrahedron Lett. 2007, 48, 4015e4017.
46. Skehan, P.; Streng, R.; Scudiero, D.; Monks, A.; Mc-Mahon, J.; Visitica, D. J. Natl.
Cancer Inst. 1990, 82, 1107e1112.
30. Peng, H.; Carrico, D.; Thai, V.; Blaskovich, M.; Bucher, C.; Pusateri, E. E.; Sebti, S.
M.; Hamilton, A. D. Org. Biomol. Chem. 2006, 4, 1768e1784.