Employing lactams for the unprecedented enantiopure synthesis of non-natural amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2011.11.047

The enantiopure non-natural amino acids¹ have been synthesized by insitu generation of iminium and iminium triflates from lactams using triflic anhydride in pyridine buffered media. These molecules with remote chiral centers may be useful in synthesis of natural product particularly Kopsia derived alkaloids.

Full text of DOI:10.1016/j.tet.2011.11.047

Tetrahedron 68 (2012) 1272e1279
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Employing lactams for the unprecedented enantiopure synthesis of non-natural
amino acid derivatives
*
Imran A. Khan, Anil K. Saxena
Division of Medicinal and Process Chemistry Division, Central Drug Research Institute (CDRI), CSIR, Chattar Manzil Palace, MG Road, Lucknow 226001, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
The enantiopure non-natural amino acids1 have been synthesized by insitu generation of iminium and
iminium triflates from lactams using triflic anhydride in pyridine buffered media. These molecules with
remote chiral centers may be useful in synthesis of natural product particularly Kopsia derived alkaloids.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 19 August 2011
Received in revised form 10 October 2011
Accepted 17 November 2011
Available online 25 November 2011
Keywords:
Thiazoline
Thiazolination
Iminium
Chiral center
Oxepane
1. Introduction
thiazolines are sometimes not obtained, especially with acid-
sensitive or racemization prone substrates. There are reports
Thiazoline is one of the most common heterocycle found in
many bioactive natural products of peptide origin.2 This sub-
structure offers conformational rigidity and caters as a recogni-
that at low temperature in a buffered medium with excess pyr-
idine, iminium, and imino triflates can be generated and reacted
with amino thiols to allow efficient access to thiazolines without
any racemization. Pioneering studies by Ghosez and others10
have demonstrated that iminium (2) and imino triflates (3) can
be generated by the treatment of tertiary or secondary amides
with triflic anhydride (Tf2O). Chaerette and Chua9h,11 reasoned
that subsequent addition of amino thiols to such highly elec-
trophilic species may lead to the formation of thiazoline under
tolerable conditions to most of the functional groups and chiral
centers (Fig. 2).
tion site for DNA, RNA, and protein binding.3 The
b-turn
structure is formed by intramolecular hydrogen bonding in
a tripeptide substructure at the protein surface, and is well
recognized ligand by various receptors.4 The low molecular-
weight compounds, especially those incorporating thiazoline
mimic the b-turn substructure of natural polypeptide ligands to
overcome the pharmacokinetic disadvantages of peptide li-
gands.5 These molecules are of current interest due to their
presence in numerous interesting natural products and in cata-
lyst designing.6 The thiazoline has an advantage of electrophilic
addition at exomethine position followed by quenching with
various alkyl halides and subsequent reduction to substituted 2-
methyl thiazolidine. These 2-methyl thiazolidines can provide 2-
alkyl substituted aldehydes and carboxylic acids on cleavage
with mercuric chloride7 and on acidic hydrolysis,8 respectively.
(Fig. 1) Even though numerous methodologies are available for
the synthesis of thiazolines6b,9 but high yields of substituted
* Corresponding author. Tel.: þ91 522 2612411 18, (4268, 2624273 Direct); fax:
þ91 522 2623405, 2623938; e-mail addresses: anilsak@gmail.com, ak_saxena@
cdri.res.in (A.K. Saxena).
Fig. 1. Reactivity and synthetic application of 2-thiazoline.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.047

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
1273
Table 2
The summarized results of the thiazolination employed on the derivatives of
pyroglutamide
L-
(i) 1.3 eq Tf2O
in DCM buffered
with Py (3.0 eq),
-60oC
R
n
NCbz
n
O
N
R1
N
H N
2
(ii)
R1
SH (1.3eq)
S
R
-40oC-0oC
(iii) Cbz-Cl (1.5eq)
Na2CO3
11a-d
12a-d
Compd
R
R1
Tf2O
Time (h)
Yield (%)
12a
12b
12c
12d
CH3
CH3
H
CH3CO
COOCH3
CH3CO
1.3
1.5
1.3
1.4
2.5
1.5
4.0
3.5
65
74
68
70
H
COOCH3
In this reaction there was no racemization at the C (a) of amidic
Fig. 2. Schematic representation of iminium and iminium triflates reacting with amino
thiols resulting to respective thiazoline.
center when thiazolination was carried out in (2S,4S)-methyl-4-
methyl-5-oxopyrrolidine-2-carboxylate (12aed). In order to gen-
eralize it we used (R)/(S)-ethyl 3-(1-benzyl-3-ethyl-2-
oxopiperidin-3-yl)propanoate (15 and 17) to give the respective
thiazolinized product in quantitative with the retention of config-
uration (Table 3). The substrates 15 and 17 used in this reaction
were synthesized using Desmaele’s approach.13
2. Result and discussion
In view of the importance of substrates bearing remote chiral
center in the synthesis of natural products, it appeared of interest to
explore the possibility of generating iminium and iminium triflates
from different hither to unexplored cyclic amides (lactams). The
optimal conditions involved an initial activation of the lactam by
the slow addition of Tf2O to the lactam to avoid the formation of N-
triflylpyridinium triflates,12 which are less reactive for O-sulfony-
lation of lactam due to the exotherm in anhydrous dichloro-
methane containing pyridine, which is present to neutralize any
adventitious acid. Stronger bases than pyridine might form a con-
jugate acid that would be too weak to the addition of the amine on
to the thioimidate or for the elimination of the amine residue.
The methodology has been successfully extended to larger lac-
tam ring viz. valero- and capro-lactam for the generation of the
respective 4-(4,5-dihydrothiazol-2-yl) butan-1-amine (10c) and 5-
(4,5-dihydrothiazol-2-yl) pentan-1-amine (10e) in 72% and 64%
yield, respectively (Table 1). The reaction was found equally effi-
cient for tertiary lactam (Table 2). It was a general observation that
on continuing the reaction for longer time there was an increase in
the yield. In view of the poor stability of the free amino derivatives,
the amino group was protected as carbamate.
Table 3
Results obtained with the lactam possessing chiral center at the
a
-C (15 and 17 were
synthesized using Desmaele’s method)
R
Tf2O
Time (h)
Yield (%)
16a
16b
18a
18b
H
1.3
1.5
1.3
1.5
7.0
6.0
7.8
5.5
64
72
74
75
COOCH3
H
COOCH3
Table 1
The obtained after thiazolination mediated ring opening using triflic anhydride in
the presence of pyridine
Since the thiazolination of lactam was equally facile similar to
the case of amides, the comparison of amide and lactam reactivity
toward the reaction conditions was made on (R)-N-methyl-pyro-
glutamide (19) (Fig. 3, Tables 4 and 5) as it possesses both lactam
and simple amide functionalities within the same molecule. Thus
the reaction of 19 with 1.3 equiv of Tf2O and 1.0 equiv of amino thiol
resulted in the formation of 5-(4,5-dihydrothiazol-2-yl)pyrrolidin-
2-one (20) only as a single product indicating that the reaction
preferably took place at amide than lactam. Whereas, the increase
in the amount of Tf2O to 2ꢀ1.3 equiv resulted in the thiazolination
of both the amide and lactam to give (R)-1,3-bis(4,5-
dihydrothiazol-2-yl)propan-1-amine (21, Table 4).When the ex-
periment was carried out with the weinreb amide analogue N-
methoxy-1-dimethyl-5-oxopyrrolidine-2-carboxamide (22) the
terminal thiazolinization was superseded by the formation of open
chain thiazoline counterpart as the isolated (R)-4-(4,5-
Compd
n
R
Time (h)
Yield (%)
10a
10b
10c
10d
10e
1
1
2
2
3
H
CH3
H
CH3
H
3.5
4.0
3.5
4.0
3.5
5.0
72
78
64
67
57
68
dihydrothiazol-2-yl)-N-methoxy-N-methyl-2
(methylamino)-
butanamide (24) was obtained as the major product, the ratio of the

1274
I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
for thiazolination at lactam. Therefore, in the presence of 2.5 equiv
of triflic anhydride dithazolinated product was obtained. Whereas,
in the complementary case of weinreb amide analogue where
ΔG4z1/2ΔG3 favored the formation of open chain thiazoline
derivative.
The above described novel ring opening strategy could be im-
plicated in the synthesis of molecules possessing remote chiral
centers, which may be envisaged as crucial starting substrate for
the total synthesis of natural product viz. alkaloids derived from the
genus Kopsia.14 The Desmaele’s method of synthesizing lactam
having substitutions at the third carbon center, which can be ac-
complished stereoselectively by an elegant incorporation of (R/S) a-
methyl benzyl amine as a chiral auxiliary. A new application of
Desmaele’s method for generating stereoselectively R- and S-ethyl-
7-(benzylamino)-4-(4,5-dihydrothiazol-2-yl)-4-ethyl heptanoate
(16a and 18a) from the corresponding R- and S-ethyl 3-(1-benzyl-3-
ethyl-2-oxopiperidin-3-yl)propanoate (15 and 17) via triflic anhy-
dride mediated thiazolination has been explored (Table 4). The
products 16a and 18a have an advantage that they possess easily
transformable groups at three terminals, which can be explored in
the generation of chemical libraries of non-natural amino acid
derivatives of medicinal importance. To begin with the 16a and 18a
were used to prepare 2-oxoazepanes (25 and 26, Fig. 4) possessing
chiral center at C-5 as such scaffolds are of pharmaceutical
importance.15
Fig. 3. Representation of the free energy for the two possibilities of thiazolination in
the case of pyroglutamide (19) and its weinreb analogue (22). aMethyl ester cysteine
hydrochloride was employed in place 2-amino ethanethiol resulted to the formation of
the respective thiazolinized products (20.1 and 21.1) and showed similar reactivity
(details are given in Supplementary data).
Table 4
Summary of the obtained results when pyroglutamide was subjected to the
thiazolination
O
i,ii
Tf2O
Time (h)
Yield (%)a
BnN
60%
N
S
16a
Compd 20
1.3 equiv
1.5
2.5
3.5
34
59
65
25
Compd 21
O
3.0 equiv
2.0
3.0
4.0
40
54
68
i
i,i
BnN
%
64
N
S
18a
a
The yield shown are determined after the Cbz-protection due to the instability
of the free amino products the NMR details of the protected products are denoted as
20p and 21.1p (details are given in Supplementary data).
26
Fig. 4. Synthesis of 2-oxoazepane derivative by Lactamization. Reagent and condi-
tions: (i) Pd (10% on activated charcoal), methanol, 2.5 h 94% (ii) Al(Me)3 (1.5 equiv, 25%
solution in hexane), benzene and DCM, 8 h, ꢁ10ꢂ to 0 ꢂC.
Table 5
The amount of amide and lactam thiazolination and obtained when weinreb amide
derivative of pyroglutamide was thiazolinized
Tf2O
1.5
Time (h)
Yield (%)a
Thus the presented novel method for the preparation of non-
natural amino acids may be considered as an important tool in
deriving molecules of targeted importance.
Compd 23
Compd 24
4.0
5.0
6.0
16
21
24
49
58
64
a
3. Conclusion
Isolated yield.
In conclusion we have successfully developed a methodology of
thiazolination using lactam as starting material and extended this
methodology in developing non-natural amino acids possessing
remote chiral centers. In addition we have found a procedure for
the selective thiazolination in the molecules possessing both lac-
tam and amide, which can be explored further. The applications of
this method toward the synthesis of Rhazinilam and Arbolocine are
underway and will be reported in due course.
two products (24:23) was 3:1 based on the isolated yields. This
offers scope for the further investigation on the selectivity in the
reactivity of amidic linkage.
In order to account for this selectivity the computational
studies for the probable energetics of the two possible fates of
thiazolination with pyroglutamide were performed and a com-
parison of the free energy change for the two possibilities of O-
triflation (i) at lactam and (ii) at terminal amide was done using
RHF 3-21G and RHF 6-31G basis set (Table 4 and Fig. 3). The op-
timization of the structure was accomplished and the relative
values of free energy change were calculated on two hybrid basis
set RHF 3-21G//RHF 6-31G and RHF 3-21G//Becke3LYP. Since, the
free energy change G1 and G2 for the terminal and lactam, re-
spectively, were almost equal, i.e., ΔG2zΔG1 therefore the possi-
bility of thiazolination at the amidic linkage was nearly the same
4. Experimental section
4.1. General information
In general, all reagents and solvents were of commercial quality
and were used without further purification. IR spectra (nmax in
cmꢁ1) of the compounds were recorded on PerkineElmer’s FT-IR

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
1275
RX1 PC spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on Bruker Supercon Magnet Avance DRX-300 spectrom-
eters (operating at 300 MHz for 1H and 75 MHz for 13C) in deu-
1676.4, 1637.4 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.41e7.05 (m, 5H,
ArH), 5.38 (s, 2H, benzyCH2), 4.12e3.77 (m, 2H, NCH2), 3.63e3.33 (m,
2H, SCH2), 3.08 (q, J¼7.6 Hz, 2H, NHCH2), 2.64e2.23 (m, 2H, CH2),
CH2); 13C NMR (50 MHz, CDCl3)
171.67,
a
terated solvents with TMS as internal reference (chemical shifts
d
in
1.76 (qd, J¼7.9 Hz, 1.6, 2H,
b
d
ppm, J in Hz). Electro Spray Ionization Mass spectra (ESI-MS) were
recorded on Thermo Lcq Advantage Max-IT, 6520 Accurate-mass Q-
TOF LC/MS Agilant and JEOL, JMS T100LC Accu TOF. Elemental
analyses were performed on Carlo Erba EA-1108 micro analyzer/
Vario EL-III C H N S analyzer. All compounds were analyzed of C, H,
N and the results obtained were within ꢃ0.4% of calculated values.
The reaction progress was routinely monitored by thin layer
chromatography (TLC) on pre-coated silica gel plates (Aldrich).
Column chromatography was performed over Merck silica gel
(100e200 mesh). All compounds were characterized by TLC, 1H
NMR and 13C NMR, MS and HRMS. Elemental analyses data meet
the criteria of ꢄ95% purity. All chemicals and solvents were pro-
cured from SigmaeAldrich/Merck, India Ltd.
157.78, 137.09, 128.32, 128.32, 128.17, 128.17, 128.16, 66.69, 60.84,
41.22, 36.20, 28.84, 24.57; HRMS(ES) calcd for C14H18N2O2S (Mþ)
278.1089 found 278.1077 m/z.
4.2.3. 3-(4,5-Dihydrothiazol-2-yl)-N-methylpropan-1-amine
(10b0). The crude product obtained using similar procedure (a) is
purified using column chromatography (30% EtOAc/hexane) to give
10b (64.0 mg, 80%) as yellowish oil; Rf 0.36 (30% EtOAc/hexane); IR
(neat) 3254, 1640, 1213 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
3.99 (dd,
J¼10.4, 3.8 Hz, 2H, NCH2), 3.47 (dd, J¼10.3, 3.8 Hz, 2H, SCH2), 2.51
(dq, J¼16.4, 7.7 Hz, 7H, NCH3, NCH2,
aCH2), 1.95e1.42 (m, 2H, bCH2),
1.15 (s,1H, NH); Due unstable nature of the compound 13C NMR was
precluded.; HRMS (ES) calcd for C7H14N2S (Mþ) 158.0878, found
158.0874.
4.2. General experimental procedure for the thiazolination of
secondary and tertiary lactams (Table 1, entry 1)
4.2.4. Benzyl 3-(4,5-dihydrothiazol-2-yl)propyl(methyl)carbamate
(10b). The crude product obtained using general procedure is puri-
fied using column chromatography (5% EtOAc/hexane) to give the
title compound 10b (41.0 mg, 78%) as yellowish oil; Rf 0.54 (5% EtOAc/
hexane); IR(neat) 1651, 1635, 935 cmꢁ1; 1H NMR (300 MHz, CDCl3)
(a) Pyrrolidone (85 mg, 1 mmol), DCM (10 ml) and pyridine
(235 ml, 3.0 mmol) are mixed in a dry 25 ml double necked R.B flask
under nitrogen atmosphere. The resulting solution is cooled to
ꢁ65 ꢂC and then neat triflic anhydride (229
m
l, 1.3 mmol) is added
d
7.58e6.91 (m, 5H, ArH), 5.36 (s, 2H, benzylCH2), 4.05e3.74 (m, 2H,
NCH2), 3.76e3.38 (m, 3H, SCH2, NHCHH), 3.23e2.92 (m, 4H, NHCHH,
NCH3), 2.61e2.12 (m, 2H,
CH2), 1.84 (qd, J¼7.9, 1.5 Hz, 2H,
CH2); 13
NMR (75 MHz, CDCl3) 171.67, 156.07, 137.09, 128.32, 128.32, 128.17,
slowly to the solution. After completion of the addition of Tf2O, the
reaction mixture is allowed to warm up to ꢁ40 ꢂC (approx.1.5 h)
then gradually cooled to ꢁ60 ꢂC and added 2-amino ethanethiol
a
b
C
d
(130 mg, 1.7 mmol) followed by addition of another 235
m
l
128.17, 128.16, 76.98, 67.05, 60.84, 49.53, 36.20, 34.62, 29.16, 21.08;
ESI-MS: 293.4 (Mþþ1), Elemental analysis of C15H20N2O2S calcd. C,
61.62; H, 6.89; N, 9.58 found C, 61.56; H, 6.79; N, 9.48.
(3.0 mmol) of pyridine and warmed the reaction mixture to ꢁ30 ꢂC
and is allowed to stir for another hour at the same temperature and
then allowed to stir for 1.5 h at room temperature. After the opti-
mum completion of the reaction (as per TLC), the reaction mixture
is then filtered through silica bed (60e120 mesh) and eluted with
diethyl ether. The ethereal filtrate is concentrated and purified
using Flash chromatography to obtain thiazolinized product (10a0)
as yellow colored oil. (In a general observation these products are
sensitive to aqueous acid and are not stable enough at room tem-
perature therefore protection of free amino terminal as carbamate
is performed.)
4.2.5. Benzyl 4-(4,5-dihydrothiazol-2-yl)butylcarbamate (10c). The
crude product obtained using condition A is purified using column
chromatography (5% EtOAc/hexane) to give the title compound 10c
(47.0 mg, 64%) yellowish oil; Rf 0.60 (5% EtOAc/hexane); IR (neat)
1655.8, 1637, 1243, 935 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.53e6.97 (m, 5H, ArH), 5.37 (s, 2H, benzylCH2), 4.01 (t, J¼5.8 Hz,
2H, NCH2), 3.47 (t, J¼5.8 Hz, 2H, SCH2), 3.04 (t, J¼7.5 Hz, 2H,
NHCH2), 2.44 (t, J¼5.3 Hz, 2H,
CH2), 1.87e1.37 (m, 4H, CH2CH2); 13
NMR (75 MHz, CDCl3) 171.67, 157.78, 137.09, 128.31, 128.17, 76.98,
a
C
(b) The ethereal filtrate was taken in a 25 ml R.B. flask and added
d
TEA (187
m
l, 1.3 mmol) at 0 ꢂC, followed by the addition of benzyl
66.69, 60.84, 41.51, 36.20, 30.65, 28.92, 24.03.; HRMS(ES) calcd for
chloroformate (186
m
l, 1.5 mmol) or di-tert-butyl carbonate (344
m
l,
C15H20N2O2S (Mþ), 292.1245, found 292.1223 m/z.
1.5 mmol) and then allowed the reaction mixture to stir at room
temperature for 10e14 h. After the completion of reaction in vacuo
distillation is carried out a deep yellow colored crude product was
obtained. The desired Cbz or Boc protected thiazolinized product
was purified with flash chromatography on silica gel as light yellow
colored oil in quantitative yield. (10a).
4.2.6. Benzyl
4-(4,5-dihydrothiazol-2-yl)butyl(methyl)carbamate
(10d). The crude product obtained using general procedure is puri-
fied using flash chromatography (5% EtOAc/hexane) to give 10d
(40.0 mg, 70%) as yellowish oil; Rf 0.64 (5%EtOAc/hexane); IR(neat)
1654, 1635, 1212, 1195 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.67e6.83
(m, 5H, ArH), 5.35 (s, 2H, benzyCH2), 4.00 (t, J¼5.8 Hz, 2H, NCH2),
4.2.1. 3-(4,5-Dihydrothiazol-2-yl)propan-1-amine (10a0). The crude
product obtained using the general procedure is purified using
flash chromatography (15% EtOAc/hexane) to give the title com-
pound 10a0 (41.0 mg, 78%) as light yellowish oil; Rf 0.26 (30% EtOAc/
3.73e3.52 (m, 2H, SCH2), 3.43 (t, J¼5.8 Hz, 2H, NHCH2), 3.08 (s, 3H,
NCH3), 2.99e2.76 (m, 1H,), 2.42 (t, J¼5.6 Hz, 2H,
aCH2), 1.82e1.11 (m,
4H, CH2CH2);13C NMR (75 MHz, CDCl3)
d 171.67,156.07,137.09,128.31,
128.17, 76.98, 67.05, 60.84, 50.93, 36.20, 34.62, 30.65, 26.35, 23.91;
hexane); IR (neat) 3345, 2765, 2324, 1637, 1106 cmꢁ1
;
1H NMR
3.85 (t, J¼5.7 Hz, 2H, NCH2), 3.36 (t, J¼5.7 Hz,
2H, SCH2), 2.69 (t, J¼7.5 Hz, 2H, NH2CH2), 2.44 (dd, J¼12.0 Hz, 4.3,
HRMS (ES) calcd for C16H22N2O2S(Mþ) 306.4231 found 306.4228 m/z.
(300 MHz, CDCl3)
d
4.2.7. Benzyl 5-(4,5-dihydrothiazol-2-yl)pentylcarbamate (10e). The
crude product obtained using general procedure for the insitu
carbamylation is purified using flash chromatography (5% EtOAc/
hexane) to give 10e (45.0 mg, 57%) as dirty yellow oil; Rf 0.62 (5%
2H, aCH2), 2.10 (s, 2H, NH2), 2.04e1.58 (m, 2H, bCH2); Due to in-
stability of compound 13C NMR was precluded; HRMS (ES) calcd for
C6H12N2S (Mþ) 144.0721 found 144.0754 m/z.
EtOAc/hexane) IR (neat) 1658, 1627, 1245, 935 cmꢁ1 1H NMR
;
4.2.2. Benzyl 3-(4,5-dihydrothiazol-2-yl)propylcarbamate (10a). The
crude product obtained using general procedure of carbamylation as
using 10a0 as starting material is purified using flash chromatogra-
phy (5% EtOAc/hexane) to give the title compound 10a (57.0 mg, 72%)
as light yellowish colored oil; Rf 0.76 (10% EtOAc/hexane); IR (neat)
(300 MHz, CDCl3) d 7.67e6.87 (m, 5H, ArH), 5.38 (s, 2H, benzylCH2),
4.11 (dd, J¼9.6, 3.4 Hz, 2H, NCH2), 3.87 (s, 1H, NH), 3.62 (dd, J¼9.6,
3.4 Hz, 2H, SCH2), 3.07 (td, J¼7.4, 3.1 Hz, 2H, NHCH2), 2.35 (t,
J¼7.7 Hz, 2H,
CDCl3)
a
CH2), 1.98e1.06 (m, 6H, 3CH2).13C NMR (75 MHz,
171.67, 157.78, 137.09, 128.31, 128.17, 76.98, 66.69, 60.84,
d

1276
I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
41.51, 36.20, 30.65, 29.49, 26.64, 25.73; HRMS(ES) calcd for
MS:217.2 (Mþ1), 201.2 (MꢁNH2); HRMS (ES) calcd for
C9H16N2O2S (Mþ) 216.0932, found 216.0940 m/z.
C16H22N2O2S (Mþ), 306.1402, found 306.1421 m/z.
4.2.8. (R)-5-(4,5-Dihydrothiazol-2-yl)-3-(methylamino)pentan-2-
one (12a0). The crude product obtained using general procedure is
purified using column chromatography (5% EtOAc/hexane) to give
the title compound 12a0 (70.0 mg, 72%) as yellowish oil; IR (neat)
4.2.13. (R)-Ethyl 2-(benzyloxycarbonylamino)-4-(4,5-dihydrothiazol-
2-yl)butanoate (12d). The crude product obtained using general
procedure of insitu carbamoylation is purified using flash chro-
matography (5% EtOAc/hexane) to give 12d (35.0 mg, 70%) as yel-
3435, 2932, 1720, 1654, 1616 cmꢁ1; Rf 0.28 (8% EtOAc/hexane); ½a D20
ꢅ
lowish oil; Rf 0.56 (8% EtOAc/hexane); ½a D19
ꢁ37.2 (c 1.0, CHCl3); IR
ꢅ
þ12.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d
4.00 (t, J¼6.4 Hz,
(neat) 3230, 2926, 1645, 1632 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
2H, NCH2), 3.41 (t, J¼6.4 Hz, 2H, SCH2), 2.85 (t, J¼5.6 Hz, 1H, NHCH),
d
7.45e6.84 (m, 5H, ArH), 5.40 (s, 2H, benzylCH2), 4.88e4.63 (m, 1H,
2.55 (s, 3H, NCH3), 2.52e2.29 (m, 2H,
aCH2), 2.15 (s, 3H, CH3),
NHCH), 4.16 (q, J¼5.9 Hz, 2H, OCH2), 3.77e3.49 (m, 2H, NCH2),
2.11e1.80 (m, 2H,
b
CH2); Due to the unstability of 12a0 13C NMR is
3.48e3.26 (m, 2H, SCH2), 2.55e2.17 (m, 4H, aCH2bCH2), 1.36 (t,
precluded; HRMS (ES) calcd for C9H16N2OS (Mþ), 200.0983, found
J¼6.0 Hz, 3H, CH3), 0.94 (s, 1H, NH); 13C NMR (75 MHz, CDCl3)
200.1234 m/z.
d 173.12, 170.73, 159.04, 136.99, 128.33, 128.20, 76.97, 67.05, 64.76,
61.79, 52.79, 40.06, 30.10, 28.42, 14.69; HRMS (ES) calcd for
4.2.9. (S)-tert-Butyl-1-(4,5-dihydrothiazol-2-yl)-4-oxopentan-3-
yl(methyl)carbamate (12a). The crude product obtained using
general procedure for insitu carbamylation is purified using flash
chromatography (5% EtOAc/hexane) to give 12a (68.0 mg, 65%) as
yellowish oil; Rf 0.58 (5% EtOAc/hexane); IR (neat) 2943, 2929,1720,
C17H22N2O4S (Mþ): 186.1494, found 186.1488 m/z.
4.2.14. (S)-Ethyl-7-(benzylamino)-4-(4,5-dihydrothiazol-2-yl)-4-
ethylheptanoate (16a0). The crude product obtained using condi-
tion A is purified using column chromatography (5% EtOAc/hexane)
to give the title compound 16a0 (41.0 mg, 72%) yellowish oil; Rf 0.74
1666, 1654, 1414, 1108 cmꢁ1; ½a D20
ꢅ
þ43.5 (c 1.0, CHCl3); 1H NMR
a 20
(300 MHz, CDCl3)
d
4.36 (t, J¼6.6 Hz, 1H, NCH), 3.88 (t, J¼5.7 Hz, 2H,
(14% EtOAc/hexane); ½ ꢅD þ65 (c 1.0, CHCl3); IR (neat) 3434, 1752,
NCH2), 3.37 (t, J¼5.7 Hz, 2H, SCH2), 3.09 (s, 3H, NCH3), 2.59e2.29 (m,
2H, CH2), 2.28e1.84 (m, 5H, COCH3,
CH2), 1.51 (s, 9H. 3CH3); 13C
NMR (75 MHz, CDCl3) 204.71, 170.74, 156.80, 80.96, 76.98, 66.83,
1637 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.23 (m, 5H, ArH),
a
b
4.35e3.82 (m, 2H, benzylCH2), 3.55 (dd, J¼9.5, 3.4 Hz, 4H, OCH2,
NCH2), 2.62 (td, J¼7.4, 2.9 Hz, 4H, SCH2, CH2), 2.44e2.00 (m, 6H,
CH2, alkylH), 1.86 (td, J¼6.7, 4.0 Hz, 2H, alkylH), 1.82e1.44 (m, 2H,
alkylH), 1.37 (t, J¼5.9 Hz, 3H, COOCH2CH3), 1.01 (t, J¼6.6 Hz, 3H,
CH2CH3); 13C NMR (75 MHz, CDCl3)
174.42, 171.87, 140.76, 128.30,
d
a
64.76, 40.06, 32.66, 29.79, 28.41, 28.13, 25.83 ESI-MS 301.1 (MþH);
Elemental analysis: calcd for C14H24N2O3S C, 55.97; H, 8.05; N, 9.32;
found C, 55.93; H, 8.01; N, 9.26; HRMS (ES) calcd 300.1508, found
300.1515.
b
d
127.52, 126.58, 76.98, 65.11, 61.18, 52.12, 50.49, 49.15, 41.45, 40.13,
38.15, 36.51, 30.56, 23.96, 14.70, 8.20; HRMS (ES) calcd for
C21H32N2O2S (Mþ), 376.2184, found 376.2491 m/z.
4.2.10. (R)-Ethyl-2-((benzyloxycarbonyl) (methyl)amino)-4-(4,5-
dihydrothiazol-2-yl)butanoate (12b). The crude product obtained
using condition A is purified using flash chromatography (5%
EtOAc/hexane) to give 12b (50.0 mg, 74%) as yellowish oil; Rf 0.62
4.2.15. (S)-Ethyl-7-(benzyl(benzyloxycarbonyl)amino)-4-(4,5-
dihydrothiazol-2-yl)-4-ethylheptanoate (16a). The crude product
obtained using general procedure is purified using flash chroma-
tography (5% EtOAc/hexane) to give 16a (35.0 mg, 64%) as yellowish
(5% EtOAc/hexane); ½a D20
ꢅ
þ16.5 (c 1.0, CHCl3); IR (neat) 1735.3,
1640.4, 1615, 1323.8, 937.9 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.76e6.63 (m, 5H, ArH), 5.36 (s, 2H, benzylCH2), 4.40e4.26 (m, 1H,
oil; Rf 0.78 (5% EtOAc/hexane); ½a D20
ꢅ
þ132.7 (c 1.0, CHCl3); IR (neat)
NCH), 4.20 (q, J¼6.0 Hz, 2H, OCH2), 4.05 (t, J¼6.8 Hz, 2H, NCH2), 3.61
(t, J¼6.8 Hz, 2H, SCH2), 3.01 (s, 3H, NCH3), 2.44e2.10 (m, 4H,
CH2CH2), 1.37 (t, J¼6.0 Hz, 3H, OCH2CH3); 13C NMR (75 MHz, CDCl3)
1735, 1685, 1647 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.24 (dd,
J¼8.7 Hz, 2.7, 10H, ArH), 5.41 (s, 2H, benzylCH2), 4.70 (s, 1H, ben-
zylCHH), 4.31 (s, 1H, benzylCHH), 4.16 (q, J¼5.9 Hz, 2H, COCH2CH3),
3.88e3.63 (m, 2H, NCH2), 3.45 (ddd, J¼12.7, 8.2, 3.0 Hz, 3H, SCH2,
NCbzCHH), 3.15 (t, J¼4.5 Hz, 2H, COCH2), 2.47e1.97 (m, 4H),
1.94e1.46 (m, 3H), 1.39 (dd, J¼7.4, 4.4 Hz, 3H), 1.00 (t, J¼6.6 Hz, 3H,
d
171.80, 170.74, 155.47, 136.99, 128.33, 128.20, 76.98, 67.42, 64.76,
61.80, 60.49, 40.06, 32.66, 29.79, 28.47, 14.70.; HRMS (ES) calcd for
C18H24N2O4S (Mþ), 364.1456, found 364.1389 m/z.
COOCH2CH3); 13C NMR (75 MHz, CDCl3)
d 174.42, 171.87, 155.86,
4.2.11. (S)-Benzyl 1-(4,5-dihydrothiazol-2-yl)-4-oxopentan-3-
ylcarbamate (12c). The crude product obtained using condition A
is purified using column chromatography (5% EtOAc/hexane) to
give 12c (82.0 mg, 68%) as greenish yellow oil; Rf 0.65 (5% EtOAc/
137.78, 136.99, 128.62, 128.47, 128.33, 128.20, 127.51, 76.98, 67.42,
65.11, 61.18, 50.49, 48.41, 47.60, 42.43, 40.13, 38.15, 36.51, 30.56,
21.81, 14.70, 8.20; HRMS (ES) calcd for C29H38N2O4S (Mþ), 510.2552,
found 510.2561 m/z.
hexane); IR (neat) 1705, 1632, 1609, 1321, 920 cmꢁ1
;
1H NMR
7.21 (d, J¼8.5 Hz, 5H, ArH), 5.39 (s, 2H, ben-
zylCH2), 4.72e4.24 (m, 1H, NHCH), 4.20e3.76 (m, 3H, NCH2, NH),
3.76e3.21 (m, 2H, SCH2), 2.67e1.62 (m, 7H,
CH2bCH2, COCH3); 13
NMR (75 MHz, CDCl3) 207.17, 170.74, 159.05, 136.99, 128.33,
(300 MHz, CDCl3)
d
4.2.16. (S)-Ethyl-7-(benzylamino)-4-(4,5-dihydrothiazol-2-yl)-4-
ethylheptanoate (16b). The crude product obtained using above
mentioned general procedure is purified using column chroma-
tography (5% EtOAc/hexane) to give 16b (61.0 mg, 72%); Rf 0.72 (14%
a
C
d
128.33, 128.21, 128.21, 128.18, 67.06, 64.76, 58.07, 40.06, 28.43,
28.32, 27.13; HRMS (ES) calcd for C16H20N2O3S (Mþ) 320.4066,
found 320.4054 m/z.
EtOAc/hexane); IR (neat) 1728, 1632, 1345, 917 cmꢁ1 1H
;
NMR(300 MHz, CDCl3)
d
7.30 (d, J¼2.3 Hz, 5H, ArH), 5.41 (d,
J¼2.8 Hz, 2H, OCH2), 4.80e3.96 (m, 2H, NCH2), 3.84 (s, 4H, ben-
zylCH2), 3.71e3.24 (m, 2H, SCH2), 3.04 (dd, J¼6.1, 4.5 Hz, 2H,
4.2.12. (R)-Ethyl
2-amino-4-(4,5-dihydrothiazol-2-yl)butanoate
NHCH2), 2.65e1.22 (m, 4H, CH2CH2), 0.99 (t, J 6.5 Hz, 1H, CH3); 13
C
(12d0). The crude product obtained using condition A is purified
NMR (75 MHz, CDCl3) d 184.63, 174.41, 172.85, 155.86, 137.78,
using flash chromatography (30% EtOAc/hexane) to give 12d0
136.99, 128.61, 128.47, 128.33, 128.20, 127.51, 74.04, 67.41, 61.17,
52.17, 50.67, 48.41, 47.59, 42.43, 38.15, 36.51, 35.23, 30.55, 21.80,
14.69, 8.20; HRMS (ES) calcd for C21H32N2O2S (Mþ) 376.2184, found
376.2176 m/z.
(41.0 mg, 68%) as yellowish oil; Rf 0.14 (35% EtOAc/hexane); ½a D20
ꢅ
þ11.1 (c 1.0, CHCl3); IR(neat) 3440, 1735, 1640, 1356 cmꢁ1; 1H NMR
(300 MHz, CDCl3)
d
4.19 (q, J¼6.0 Hz, 2H, OCH2), 4.06e3.85 (m, 2H,
NCH2), 3.71e3.37 (m, 3H, NH2, NH2CH), 2.57e2.32 (m, 2H, SCH2),
2.14 (ddd, J¼15.4, 8.9, 6.3 Hz, 2H, CH2), 1.38 (t, J¼6.0 Hz, 3H, CH3);
Unstable for longer time therefore 13C NMR were precluded; ESI-
a
4.2.17. (R)-Ethyl-7-(benzylamino)-4-(4,5-dihydrothiazol-2-yl)-4-
ethylheptanoate (18a0). The crude product obtained using condition

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
1277
A is purified using column chromatography (5% EtOAc/hexane) to
give the title compound 18a0 (54.0 mg, 80%) yellowish oil; Rf 0.52
30.49, 30.49, 28.42; HRMS(ES) calcd for C17H21N3O2S2 (MþH),
364.10752, found 364.1065 m/z.
(10% EtOAc/hexane); ½a D20
ꢅ
ꢁ64.2 (c 1.0, CHCl3); IR(neat) 3434, 1752,
1637 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.51e6.86 (m, 5H, ArH),
4.2.22. (S)-Methyl 2((R)-5-oxopyrrolidin-2-yl)-4,5-dihydrothiazole-
4-carboxylate (20.1). The crude product obtained using general
procedure is purified using flash chromatography (18% EtOAc/
hexane) to give 20.1 (41.0 mg, 62%) as yellowish oil; Rf 0.52 (10%
4.46e3.90 (m, 4H, OCH2, benzylCH2), 3.90e3.65 (m, 2H, NCH2),
3.60e3.28 (m, 2H, SCH2), 2.92e2.23 (m, 4H, NHCH2, COCH2),
2.23e1.97 (m, 3H, COCH2CH2, NHCH2CHH), 1.93e1.48 (m, 4H,
NH(CH2)2CH2, CH2CH3), 1.48e1.17 (m, 5H, NHCH2CHH, OCH2CH3),
0.99 (t, J¼6.6 Hz, 3H, CH2CH3); Due to the unstability of the com-
pound 13C NMR was precluded; HRMS(ES) calcd for C21H32N2O2S
(Mþ), 376.2184, found 376.2171 m/z.
EtOAc/hexane); ½a D24
þ52.1 (c 1.0, CHCl3); IR(neat) 3243, 2935,
ꢅ
2100, 1732, 1653, 1634, 1616, 1105 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
5.10 (t, J¼8.0 Hz, 1H, CHCOOCH3), 4.71e4.38 (m, 1H,
aCH),
4.29e3.89 (m, 2H), 3.86 (s, 3H, OCH3), 2.70 (tdd, J¼9.7, 6.9, 4.2 Hz,
1H, SCHH), 2.54e2.38 (m, 2H, SCHH, COCHH), 2.38e2.08 (m, 3H,
4.2.18. (R)-Ethyl-7-(benzyl(benzyloxycarbonyl)amino)-4-(4,5-
dihydrothiazol-2-yl)-4-ethylheptanoate (18a). The crude product
obtained using general procedure is purified using flash chroma-
tography (5% EtOAc/hexane) to give 18a (54.0 mg, 74%); Rf 0.78 (5%
COCHH, COCHHCH2); 13C NMR (75 MHz, CDCl3)
d 177.84, 172.85,
170.74, 76.98, 75.57, 56.92, 52.17, 35.53, 31.08, 30.41; ESI-MS 229.4
(MþH); Elemental analysis calcd for C9H12N2O3S C, 47.35; H, 5.30;
N, 12.27; found C, 46.35; H, 5.40; N, 11.47; HRMS (ES) calcd for
C9H12N2O3S(Mþ) 228.0569 found 228.0554.
EtOAc/hexane); ½a D20
ꢅ
ꢁ130.1 (c 1.0, CHCl3); IR (neat) 1735, 1685,
1647 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.58e6.87 (m, 10H, ArH),
5.37 (s, 2H, benzylCH2), 4.50 (d, J¼32.6 Hz, 2H, benzylCH2), 4.16 (q,
J¼6.0 Hz, 2H, OCH2), 3.99e3.66 (m, 2H, NCH2), 3.51 (ddd, J¼7.1, 3.4,
2.2 Hz, 3H, SCH2, NCHH), 3.19 (t, J¼7.2 Hz, 1H, NCHH), 2.42e1.86 (m,
4.2.23. (R)-5-(4,5-Dihydrothiazol-2-yl)pyrrolidin-2-one
(21). The
crude product obtained using general procedure is purified using
column chromatography (5% EtOAc/hexane) to give 21 (48.0 mg,
a 20
5H, COCH2,
COOCH2CH3,
a
CH2), 1.86e1.58 (m, 3H), 1.53e1.20 (m, 5H,
68%) as yellowish oil; Rf 0.32 (10% EtOAc/hexane); ½ ꢅD þ29.2 (c 1.0,
b
CH2), 1.02 (t, J¼6.6 Hz, 3H, CH2CH3); 13C NMR
CHCl3); IR (neat) 3233, 3009, 2903, 2121, 1632, 1616, 1509,
(75 MHz, CDCl3)
d
174.41, 171.87, 155.86, 137.78, 136.99, 128.62,
1123 cmꢁ1; 1H NMR (300 MHz, CDCl3)
4.01 (t, J¼5.8 Hz, 2H, NCH2), 3.60 (t, J¼5.8 Hz, 2H, SCH2), 2.87e2.54
(m,1H, COCHH), 2.55e2.38 (m, 2H, COCHH, COCHHCHH), 2.38e2.04
(m, 1H, COCHHCHH), 1.63 (s, 1H, NH); 13C NMR (75 MHz, CDCl3)
d
4.56 (t, J¼7.5 Hz, 1H,
aCH),
128.47, 128.33, 128.20, 127.51, 67.41, 65.11, 61.17, 50.48, 48.41, 47.59,
42.43, 40.12, 38.15, 36.51, 30.55, 21.80, 14.69, 8.20; HRMS (ES) calcd
for C29H38N2O4S (Mþ), 510.2552, found 510.2421 m/z.
d
177.84, 163.74, 76.98, 64.80, 57.36, 40.02, 31.08, 30.41; HRMS (ES)
4.2.19. (S)-Ethyl-7-(benzyl(benzyloxycarbonyl)amino)-4-(4,5-
dihydrothiazol-2-yl)-4-ethylheptanoate (18b). The crude product
obtained using general procedure is purified using flash chroma-
tography (5% EtOAc/hexane) to give 18b (61.0 mg, 75%); Rf 0.78 (5%
EtOAc/hexane); IR (neat) 1738, 1689, 1632, 935; 1H NMR (300 MHz,
calcd for C7H10N2OS (Mþ) 170.05138, found 169.9901 m/z.
4.2.24. (4S,40S)-Dimethyl 2,20-((R)-1-aminopropane-1,3-diyl)-bis(4,5-
dihydrothiazole-4-carboxylate) (21.1). The crude product obtained
using general procedure is purified using column chromatography
(5% EtOAc/hexane) to give 21.1 (37.0 mg, 62%) as yellowish oil; Rf 0.22
CDCl3)
d
7.29 (m, 10H, ArH), 5.42 (d, J¼2.8 Hz, 3H, benzylCH2,
benzylCHH), 4.94e4.27 (m, 2H, NCH2), 4.11 (t, J¼5.9 Hz, 2H, OCH2),
(10% EtOAc/hexane); ½a D20
þ19.2 (c 1.0, CHCl3); IR (neat) 3435, 1717,
ꢅ
3.85 (s, 1H, benzylCHH), 3.73e3.26 (m, 2H, SCH2), 3.08 (dd, J¼6.4,
1709, 1632,1609,1435,1215.4,1107 cmꢁ1; 1H NMR (300 MHz, CDCl3)
3.5 Hz, 2H, NCH2), 2.11 (d, J¼3.6 Hz, 4H, COCH2,
aCH2), 1.78e0.61
d
6.08 (t, J¼4.4 Hz, 1H, CHCOOCH3), 5.19 (dd, J¼12.0, 8.0 Hz, 1H,
(m, 12H, alkylH); 13C NMR (75 MHz, CDCl3)
d
184.63, 174.41, 172.85,
CHCOOCH3), 4.82 (t, J¼7.8 Hz, 1H, NH2CH), 4.35 (t, J¼3.3 Hz,1H), 3.84
(s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.74e3.43 (m, 2H, SCH2), 2.64e2.29
(m, 3H, SCH2,), 2.22e1.99 (m, 2H, CH2); HRMS (ES) calcd for
C13H19N3O4S2 (Mþ) 345.0817 found 345.0831 m/z.
155.86, 137.78, 136.99, 128.61, 128.47, 128.33, 128.20, 127.51, 74.04,
67.41, 61.17, 52.17, 50.67, 48.41, 47.59, 42.43, 38.15, 36.51, 35.23,
30.55, 21.80, 14.69, 8.20; HRMS(ES) calcd for C29H38N2O4S (Mþ)
510.2552, found 510.2546 m/z.
4.2.25. (S)-Methyl 2-((R)-1-methyl-5-oxopyrrolidin-2-yl)-4,5-
dihydrothiazole-4-carboxylate (21p). The crude product obtained
using general procedure is purified using column chromatography
(5% EtOAc/hexane) to give the title compound 21p (41.0 mg, 62%)
4.2.20. (R)-1,3-Bis(4,5-dihydrothiazol-2-yl)propan-1-amine
(20). The crude product obtained using general procedure is pu-
rified using column chromatography (25% EtOAc/hexane) to give
the desired compound 20 (31.0 mg, 65%) as yellowish oil; Rf 0.18
yellowish oil; Rf 0.28 (10% EtOAc/hexane); ½a D20
ꢅ
þ65.2 (c 1.0, CHCl3);
(30% EtOAc/hexane); ½a D20
ꢅ
(c 1.0) n.d.; 1H NMR (300 MHz, CDCl3)
IR(neat) 1750, 1743.2, 1632 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 5.64
d
5.40 (t, J¼3.4 Hz, 1H,
a
CH), 4.27 (t, J¼7.0 Hz, 2H, NCH2), 3.72 (t,
(t, J¼9.2 Hz, 1H, NCHCOOMe), 4.72e4.33 (m, 1H, NCH), 4.16 (dd,
J¼12.4, 9.2 Hz, 2H, SCH2), 4.02e3.66 (m, 4H, OCH3, COCHH), 2.88 (s,
3H, NCH3), 2.62e1.92 (m, 3H, COCHH, COCH2CH2). 13C NMR
J¼6.2 Hz, 2H, NCH2), 2.96 (dd, J¼9.8, 4.1 Hz, 4H, 2SCH2), 2.53e2.33
(m, 2H, dCH2), 2.35e2.10 (m, 2H, b
CH2); Due to instability 13C were
precluded IR(neat) 3421, 1623, 1617, 1412, 1109 cmꢁ1; HRMS(ES)
(75 MHz, CDCl3) d 176.53, 173.82, 172.85, 76.98, 75.57, 58.56, 52.17,
calcd for C9H15N3S2 (MþH) 229.0707, found 229.0013 m/z.
35.53, 29.90, 28.59, 28.08. HRMS (ES) calcd for C10H14N2O3S (Mþ),
242.2947, found 242.3045 m/z.
4.2.21. (R)-Benzyl 1,3-bis(4,5-dihydrothiazol-2-yl)propylcarbamate
(20p). The crude product obtained using condition A is purified
using column chromatography (15% EtOAc/hexane) to give the title
compound 20p (41.0 mg, 62%) as yellowish oil; Rf 0.48 (EtOAc/
4.2.26. (4S,40S)-Dimethyl 2,20-((R)-1-(benzyloxycarbonylamino)-pro-
pane-1,3-diyl)bis(4,5-dihydrothiazole-4-carboxylate)
(21.1p). The
crude product obtained using general procedure is purified using
hexane); ½a 2D0
ꢅ
þ8.4 (c 1.0, CHCl3) (uncorrected); IR(neat) 3232,
column chromatography (5% EtOAc/hexane) to give 21.1p (45.0 mg,
2929, 1662, 1647, 1632, 1424 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
68%) as yellowish oil; Rf 0.52 (7% EtOAc/hexane); ½a D20
þ32.1 (c 1.0,
ꢅ
d
7.51e6.87 (m, 5H, ArH), 5.35 (s, 2H, benzylCH2), 4.80 (t, J¼7.3 Hz,
CHCl3); IR (neat) 3234, 2938, 1754, 1723, 1634, 1624, 1616 cmꢁ1; 1H
1H, NCH), 3.97 (dd, J¼10.3, 3.7 Hz, 2H, NCH2), 3.68e3.26 (m, 4H,
NCH2, SCH2), 2.88 (t, J¼5.9 Hz, 2H, SCH2), 2.70e2.25 (m, 3H,
NCbzCHCHH, NCbzCHCH2CH2), 2.09 (dt, J¼11.9, 5.9 Hz, 1H,
NMR (300 MHz, CDCl3) d 7.58e6.86 (m, 5H, ArH), 5.61e5.10 (m, 2H,
benzylCH2), 4.88 (t, J¼8.0 Hz, 2H, NCH, NCH), 4.19e3.51 (m, 2H),
3.07e2.59 (m, 1H, CH), 2.56e2.31 (m, 1H), 2.15 (ddd, J¼7.5, 6.1,
NCbzCHCHH); 13C NMR (75 MHz, CDCl3)
d
170.73, 165.67, 159.04,
4.9 Hz, 1H), 0.97 (s, 6H). 13C NMR (75 MHz, CDCl3)
d 174.95, 172.85,
136.99, 128.33, 128.20, 76.97, 67.05, 64.78, 51.06, 40.05, 40.02,
169.58,159.04,136.99,128.33,128.20, 76.97, 75.56, 67.05, 52.17, 51.15,

1278
I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
51.15, 35.87, 35.53, 30.49, 28.32; HRMS (ES) calcd for C21H25N3O6S2
33.72, 20.96, 8.20; HRMS (ES) calcd for C19H26N2OS 330.1766 found
330.1772 m/z.
(Mþ), 479.1184, found 479.1162 m/z.
4.2.27. (R)-5-(4,5-Dihydrothiazol-2-yl)-1-methylpyrrolidin-2-one
(23.1). The crude product obtained using general procedure is
purified using flash chromatography (5% EtOAc/hexane) to give
4.3.2. (R)-1-Benzyl-5-(4,5-dihydrothiazol-2-yl)-5-ethylazocan-2-one
(26). The crude product obtained using procedure mentioned in
Section 4.3 and purified using flash chromatography (5% EtOAc/
hexane) to give 26 (44.0 mg, 64%) as yellowish oil; Rf 0.54 (15%
23.1 (21.0 mg, 60%) yellowish oil; Rf 0.42 (10% EtOAc/hexane); ½a D20
ꢅ
þ22.2 (1.0, CHCl3) (uncorrected); IR(neat) cmꢁ1:1756.4, 1627.9; 1H
EtOAc/hexane); IR (neat) 1679, 1639, 1339, 935 cmꢁ1 1H NMR
;
NMR (300 MHz, CDCl3)
d
4.29e4.11 (m, 1H,
a
CH), 3.97 (t, J¼5.8 Hz,
(300 MHz, CDCl3)
d
7.26 (dt, J¼1.4, 0.7 Hz, 5H, ArH), 4.66e4.33 (m,
2H, NCH2), 3.53 (t, J¼5.8 Hz, 2H, SCH2), 2.95 (s, 3H, NCH3),
2H, benzylCH2), 4.30e3.79 (m, 2H, NCH2), 3.79e3.10 (m, 4H, SCH2,
NCH2), 2.89 (dd, J¼8.5, 3.2 Hz, 2H, COCH2), 2.28e1.26 (m, 8H,
NCH2CH2CH2, CH2CH3, COCH2CH2), 1.18e0.50 (m, 3H, CH3); 13C
NMR values corroborates with the proton spectra of 25; HRMS (ES)
calcd for C19H26N2OS 330.1766 found 330.1762 m/z.
2.63e2.27 (m, 3H, COCH2, COCH2CHH), 2.27e1.99 (m, 1H,
COCH2CHH). 13C NMR (75 MHz, CDCl3)
d 176.53, 163.70, 76.98,
64.80, 58.07, 40.02, 29.90, 28.59, 28.08; HRMS (ES) calcd for
C8H12N2OS (Mþ), 184.2586, found 184.2491 m/z.
4.2.28. (R)-Benzyl 4-(4,5-dihydrothiazol-2-yl)-1-(methoxy-(methyl)
amino)-1-oxobutan-2-yl(methyl)carbamate (24). The crude product
obtained using general procedure is purified using column chro-
matography (5% EtOAc/hexane) to give 24 (41.0 mg, 62%) as yel-
Acknowledgements
I.A.K. is thankful to UGC, New Delhi, for the award of SRF and
SAIF-CDRI for the spectral and elemental analysis facilities and also
acknowledges Mr. R.K. Purushottam, Mr. D.N. Viswakarma, Mr. A.S.
Khushwaha, and Mr. Zahid Ali for technical support. The CDRI
communication number allotted to this manuscript is 8165.
lowish oil; ½a 2D0
ꢅ
þ53.1 (c 1.0, CHCl3); IR (neat) 2958, 2874.2, 1667.3,
1653, 1465, 1414, 1175.5, 1102 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.59e6.92 (m, 5H, ArH), 5.31 (s, 2H, benzylCH2), 4.44 (t, J¼7.5 Hz,
1H, NCH), 3.99e3.68 (m, 5H, NCH3, NCH2), 3.39 (t, J¼5.8 Hz, 2H,
SCH2), 3.28 (s, 3H, OCH3), 3.01 (s, 3H, NCH3), 2.47 (t, J¼5.5 Hz, 2H,
Supplementary data
a
CH2), 2.28e1.94 (m, 2H, b
CH2); 13C NMR (75 MHz, CDCl3)
d
176.27, 170.74, 155.47, 136.99, 128.33, 128.20, 76.98, 67.42, 64.76,
Spectral details of all compounds. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.11.047.
57.58, 56.85, 40.06, 32.96, 32.66, 29.79, 28.68; ESI-MS 380.3
(MþH); HRMS (ES) calcd for C18H25N3O4S(Mþ) 379.1566 found
379.1557 m/z.
References and notes
4.3. Detailed procedure for the synthesis of oxepane rings
1. (a) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645;
(b) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517;
(c) Kotha, S. Acc. Chem. Res. 2003, 36, 342; (d) Rilatt, I.; Caggiano, L.; Jackson, R.
F. W. Synlett 2005, 2701; (e) Kotha, S.; Halder, S. Synlett 2010, 337; (f) Solo-
shonok, V. A.; Sorochinsky, A. E. Synthesis 2010, 20, 2319.
A dry, 50-ml, two-necked, round-bottomed flask equipped
with a reflux condenser fitted with a nitrogen inlet at its top,
a rubber septum, and a magnetic stirring bar is charged with
10 ml of benzene (Ref. 16) and flushed briefly with nitrogen, after
which 2.2 ml (0.57 mmol) of a 25% solution of trimethylaluminum
in hexane is injected through the septum into the flask. The
solution is stirred and cooled in an iceesalt bath at ꢁ10ꢂ to ꢁ15ꢂ,
255 mg (0.549 mmol), dissolved in 1 ml DCM of debenzylated 16a
(Ref. 16) is added slowly with a syringe. Twenty minutes after the
addition is completed, the cooling bath is removed, and the con-
tents of the flask are allowed to stir and warm slowly to room
temperature over a 45 min period. The resulting solution is
allowed to stir for 22 h at room temperature, and hydrolyzed by
slow and cautious addition of 0.85 ml (0.55 mmol) of 0.67 M
hydrochloric acid. The upper organic layer is separated, and the
aqueous layer is extracted with three 25 ml portions of ethyl
acetate. The organic extracts are combined, washed with brine
solution, dried with anhydrous magnesium sulfate, and evapo-
rated under reduced pressure. The crude thus obtained was pu-
rified by flash chromatography (EtOAc/hexane 5:95) afforded 25
in 178.3 mg (75%).
2. (a) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Corbett, T. H.; Valeriote, F. A. J.
Am. Chem. Soc. 1990, 112, 8195; (b) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.
Tetrahedron Lett. 1991, 32, 2593; (c) Bayer, A.; Freund, S.; Nicholson, G.; Jung, G.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1336; (d) Yorgey, P.; Lee, J.; Koerdel, J.;
Vivas, E.; Warner, P.; Jebaratnam, D.; Kolter, R. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 4519; (e) For an annual review see: Lewis, J. R. Nat. Prod. Rep. 2000, 17, 57.
3. (a) Minster, D. K.; Jordis, U.; Evans, D. L.; Hecht, S. M. J. Org. Chem. 1978, 43,
1624; (b) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1992, 57, 5566; (c) Fu-
kuyama, T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449; (d) Parsons, R. L.; Heathcock,
C. H. Tetrahedron Lett. 1994, 35, 1379; (e) Parsons, R. L. J.; Heathcock, C. H.
Tetrahedron Lett. 1994, 35, 1383; (f) For a review see: Wipf, P. Chem. Rev. 1995,
95, 2115; (g) Parsons, R. L. J.; Heathcock, C. H. Synlett 1996, 1168; (h) Wipf, P.;
Xu, W. J. Org. Chem. 1996, 61, 6556; (i) Wipf, P.; Venkatraman, S. Synlett 1997, 1;
(j) Kuriyama, N.; Akaji, K.; Kiso, Y. Tetrahedron 1997, 53, 8323; (k) White, J. D.;
Kim, T.-S.; Nambu, M. J. Am. Chem. Soc. 1997, 119, 103; (l) Ino, A.; Hasegawa, Y.;
Murabayashi, A. Tetrahedron Lett. 1998, 39, 3509; (m) Akaji, K.; Kiso, Y. Tetra-
hedron 1999, 55, 10685.
4. (a) Watkins, D.; Mohan, S.; Koudelka, G. B.; Williams, L. D. J. Mol. Biol. 2010, 396,
1145; (b) McDowell, R. S.; Gadek, T. R. J. Am. Chem. Soc. 1992, 114, 9245.
5. (a) For review see: Salam, A. M.; Suwaidi, J. A. Expert Opin. Invest. Drugs 2002, 11,
1645.
6. (a) Frump, J. A. Chem. Rev. 1971, 71, 483; (b) Gaumont, A.-C.; Gulea, M.; Levillain,
J. Chem. Rev. 2009, 109, 1371; (c) Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8,
2115; (d) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade,
A. F. Chem. Rev. 2009, 109, 2703; (e) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.;
Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015.
4.3.1. (S)-1-Benzyl-5-(4,5-dihydrothiazol-2-yl)-5-ethylazocan-2-one
(25). The crude product obtained using procedure mentioned in
Section 4.3 is purified using flash chromatography (5% EtOAc/hex-
ane) to give 25 (178.3 mg, 60%) as glassy yellow solid; mp 78 ꢂC; Rf
0.54 (15% EtOAc/hexane); IR (neat) 1680, 1635, 1342, 935 cmꢁ1; 1H
7. (a) Meyers, A. I.; Durandetta, J. L. J. Org. Chem. 1975, 40, 2021; (b) Meyers, A. I.;
Durandetta, J. L.; Munavu, R. J. Org. Chem. 1975, 40, 2025; (c) Reuman, M.;
Meyers, A. I. Tetrahedron 1985, 41, 837.
8. Martin, R. B.; Lowey, S.; Elson, E. L.; Edsall, J. T. J. Am. Chem. Soc. 1959, 81, 5089.
9. (a) Kwiatkowski, S.; Crocker, P. J.; Chavan, A. J.; Imai, N.; Haley, B. E.; Watt, D. S.;
Ho, R.-j. Tetrahedron Lett. 1990, 31, 2093; (b) Boyce, R. J.; Mulkueen, G. C.;
Pattenden, G. Tetrahedron Lett. 1994, 35, 5705; (c) Ramasamy, K. S.; Bandaru, R.;
Averett, D. J. Org. Chem. 2000, 65, 5849; (d) Yamakuchi, M.; Matsunaga, H.;
Tokuda, R.; Ishizuka, T.; Nakajima, M.; Kunieda, T. Tetrahedron Lett. 2005, 46,
4019; (e) Vorbruggen, H.; Krolikiewicz, K. Tetrahedron Lett. 1981, 22, 4471; (f)
North, M.; Pattenden, G. Tetrahedron 1990, 46, 8267; (g) Katritzky, A. R.; Cai, C.;
Suzuki, K.; Singh, S. K. J. Org. Chem. 2004, 69, 811; (h) Charette, A. B.; Chua, P. J.
Org. Chem. 1998, 63, 908; (i) Fukuhara, T.; Hasegawa, C.; Hara, S. Synthesis 2007,
NMR (300 MHz, CDCl3)
d 7.51e6.94 (m, 5H, ArH), 4.46 (s, 2H, ben-
zylCH2), 3.92 (dd, J¼9.6, 3.5 Hz, 2H, NCH2), 3.69e3.33 (m, 3H, SCH2,
NCHH), 3.33e2.99 (m, 1H, NCHH), 2.85 (td, J¼5.6, 1.2 Hz, 2H,
COCH2), 2.10e1.12 (m, 8H, NCH2CH2CH2, CH2CH3, COCH2CH2), 0.99
(t, J¼6.5 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3)
d 177.79, 171.87,
~
137.78, 128.61, 128.49, 127.51, 65.11, 48.84, 47.16, 40.12, 39.07, 36.51,
10, 1528; (j) Fernandez, X.; Fellous, R.; Dunach, E. Tetrahedron Lett. 2000, 41,

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 1272e1279
1279
3381; (k) Raman, P.; Razavi, H.; Kelly, J. W. Org. Lett. 2000, 2, 3289; (l) Wenker,
H. J. Am. Chem. Soc. 1935, 57, 1079; (m) Jagodzinski, T. S. Chem. Rev. 2003, 103,
197.
Kitajima, M.; Matsuzaki, T.; Hashimoto, S.; Nagaoka, M.; Zhang, R.; Takayama, H.
J. Nat. Prod. 2009, 72, 204.
15. (a) Long, R. D.; Moeller, K. D. J. Am. Chem. Soc. 1997, 119, 12394; (b)
Trancard, D.; Tout, J. B.; Giard, T.; Chichaoui, I.; Cahard, D.; Plaquevent, J.-C.
Tetrahedron Lett. 2000, 41, 3843; (c) Gutierrez Rodríguez, M.; García Lopez,
M. T.; Herranz, R. Tetrahedron 2004, 60, 5177; (d) Kotha, S.; Khedkar, P.
Synthesis 2008, 18, 2925; (e) Takahashi, K.; Midori, M.; Kawano, K.; Ishi-
hara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244; (f) Wishka,
D. G.; Bedard, M.; Brighty, K. E.; Buzon, R. A.; Farley, K. A.; Kooistra, J.;
Lewis, J. G.; O’Dowd, H.; Samardjiev, I. J.; Samas, B.; Yalamanchi, G.; Noe,
M. C. J. Org. Chem. 2011, 76, 1937.
16. The hydrogenation was carried out using Pd/C (10 mol %,) in dried methanol in
Parr assembly the selective hydrogenation of Cbz was obtained within
30e40 min on longer duration of hydrogen atmosphere causes the complete
removal of both Cbz and benzyl group.
10. (a) Falmagne, J. B.; Escudero, J.; Taleb-Saharaoui, S.; Ghosez, L. Angew. Chem., Int.
Ed. Engl. 1981, 20, 879; (b) Barbaro, G.; Battaglia, A.; Bruno, C.; Giorgianni, P.;
Guerrini, A. J. Org. Chem. 1996, 61, 8480; (c) Sisti, N. J.; Fowler, F. W.; Grierson, D.
S. Synlett 1991, 816; (d) Sisti, N. J.; Zeller, E.; Grierson, D. S.; Fowler, F. W. J. Org.
Chem. 1997, 62, 2093; (e) Thomas, E. W. Synthesis 1993, 767.
11. Charette, A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245.
12. (a) Periasamy, M. Arkivoc 2002, vii,151; (b) Kaoi, H. Chem. Pharm. Bull. 2002, 50, 301.
€
13. (a) Desmaele, D.; Mekouar, K.; d’Angelo, J. J. Org. Chem. 1997, 62, 3890; (b)
€
Mekouar, K.; Ambroise, L.; Desmaele, D.; d’Angelo, J. Synlett May 1995, 529.
14. (a) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam,
T. S. J. Nat. Prod. 2007, 70, 1783; (b) Gan, C. Y.; Low, Y. Y.; Etoh, T.; Hayashi, M.;
Komiyama, K.; Kam, T. S. J. Nat. Prod. 2009, 72, 2098; (c) Wu, Y.; Suehiro, M.;