Efficient construction of a doubly functionalized trisoxazole derivative relevant to the synthesis of the novel telomerase inhibitor telomestatin and its analogues

Article abstract of DOI:10.1055/s-2006-926415

An efficient construction of a suitably functionalized trisoxazole derivative related to telomestatin was developed from L-serine, which involved three sequential oxazoline cyclization-oxidation steps in an overall yield of 11% in a linear sequence of twelve steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926415

PAPER
1289
Efficient Construction of a Doubly Functionalized Trisoxazole Derivative
Relevant to the Synthesis of the Novel Telomerase Inhibitor Telomestatin
and its Analogues
C
onstruction o
h
f
a
Doubly F
i
unctio
t
a
Trisoxazol
l
e
K. Chattopadhyay,* Suman Biswas, Benoy K. Pal
Department of Chemistry, University of Kalyani, Kalyani-741235, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
Received 4 July 2005; revised 28 November 2005
This paper is respectfully dedicated to Professor Gerald Pattenden, Nottingham University, UK
within the 24-membered macrocyclic ring of 2 could be
retrosynthetically dissected along the designated rings ‘A’
and ‘E’ through the structures 3–5 (Scheme 1) into a func-
tionalized trisoxazole unit 6 based on the formation of ox-
azoline and thiazoline rings from the dehydrative
cyclization of the corresponding b-hydroxy amides and
thioamides, respectively. Dimerization of 6 by intermo-
lecular amide bond formation is expected to provide b-hy-
droxy amide 5 which on cyclodehydration followed by
oxidation should lead to the suitably functionalized hep-
taoxazole ring system 4. The latter, after suitable depro-
tection, should upon macro-cyclization provide the cyclic
b-hydroxy amide 3b which could be converted to the cor-
responding thioamide 3a. Cyclodehydration of the latter
should provide the target structure 2. In this paper, we
wish to report an efficient construction of the doubly func-
tionalized trisoxazole unit 6 in its protected form 18.
Our synthesis started from the known6 L-serine-derived
Garner’s ester 7, which was hydrolyzed to the correspond-
ing acid 8 (Scheme 2). The latter on condensation with
methyl L-serinate in the presence of DCC and HOBt led to
the dipeptide 9 in good yield. Various reagents are known7
to convert b-hydroxy amides to oxazolines but the mild-
ness of the diethylaminosulfur trifluoride (DAST) mediat-
ed cyclization procedure8 has made it attractive in recent
years for the synthesis of oxazole-containing natural prod-
ucts.9 Indeed, the conversion of the hydroxy amide 9 to
the oxazoline 10 proceeded smoothly and the latter was
obtained as a single diastereomer indicating that negligi-
ble racemization10 occurred. Oxidation11 of 10 with bro-
motrichloromethane in the presence of DBU smoothly led
to the mono-oxazole derivative 11 as a colorless solid in a
yield of 50% from the starting acid 8. Compound 11 had
spectroscopic properties similar to those of racemic 11 re-
ported by Pattenden and co-workers.12
Abstract: An efficient construction of a suitably functionalized
trisoxazole derivative related to telomestatin was developed from
L-serine, which involved three sequential oxazoline cyclization–ox-
idation steps in an overall yield of 11% in a linear sequence of
twelve steps.
Key words: heterocycles, chiral pool, oxidations, peptides, ox-
azoles
A recent addition to the expanding family1,2 of oxazole-
and thiazole-containing bioactive natural products is the
novel telomerase inhibitor telomestatin 1 (Figure 1)
isolated3 from Streptomyces anulatus 3533-SV4. It has
been demonstrated that telomestatin specifically inhibits
telomerase without affecting other enzymes like DNA-
polymerase and reverse transcriptase, possibly through
interacting4 with the G-quadruplex structure of telomers.
The combination of the unprecedented and unique chem-
ical structure along with its unusual and useful biological
activity has rendered telomestatin an attractive synthetic
target as well as a candidate for the design and synthesis
of analogues relevant to anti-cancer drug development.5
We became interested in the synthesis and biological eval-
uation of 6,9-demethyltelomestatin (2) as a possible ana-
logue of telomestatin (Figure 1).
We envisioned that the octacyclic array of seven 2,4-di-
substituted oxazole rings and a thiazoline ring contained
R
6
O
S
N
N
O
9
N
O
O
N
R
N
O
N
The mono-oxazole ester 11 was then hydrolyzed to the
corresponding acid 12, which was condensed13 with
L-Ser-OMe·HCl to provide b-hydroxy amide 13 in good
yield. Sequential dehydrative cyclization with DAST and
oxidation under Williams protocol11 then led to the bisox-
azole derivative 15 through the intermediate oxazole-ox-
azoline 14. Compound 15 was obtained as a colorless
solid in 47% yield from the starting mono-oxazole deriv-
ative 11.
N
N
O
O
1, R = Me
2, R = H
Figure 1
SYNTHESIS 2006, No. 8, pp 1289–1294
x
x
.
x
x
.2
0
0
6
Advanced online publication: 28.03.2006
DOI: 10.1055/s-2006-926415; Art ID: T09705SS
© Georg Thieme Verlag Stuttgart · New York

1290
S. K. Chattopadhyay et al.
PAPER
OH
OPG
O
O
O
X
S
A
CO2R
N
N
N
N
N
NHPG
H
O
O
O
N
N
N
O
O
O
N
O
O
N
N
N
O
N
O
N
O
N
N
O
N
N
N
N
N
E
N
N
O
E
E
O
O
O
O
O
3a, X = S
3b, X = O
4
2
OPG
OPG
GPHN
OR
O
O
N
O
CO2R
N
GPHN
O
N
O
O
N
N
O
O
N
N
N
O
O
N
O
N
NH2
OH
N
O
H
N
N
HO2C
O
O
OH
6
5
Scheme 1
Conversion of the bisoxazole 15 into trisoxazole deriva- pot synthesis to 18. The latter was obtained as a colorless
tive 18 was achieved by repetition of the sequence de- powder in an overall yield of 47% from the bisoxazole de-
tailed above, that is, saponification to 16, condensation rivative 15 and in an overall yield of 11% from the starting
with L-Ser-OMe·HCl leading to the b-hydroxy amide 17, Garner’s acid 8.
followed by its cyclodehydration, and oxidation in a one-
OH
O
O
CO2Me
CO2R
N
N
H
CO2Me
iv
iii
ii
N
N
O
O
N
O
83%
Boc
79%
Boc
80%
Boc
9
10
O
7, R = Me
8, R = H
i, 96%
O
N
O
N
N
Boc
Boc
CO2R
O
iii
iv
ii
N
O
N
O
N
79%
81%
76%
Boc
H
N
N
CO2Me
OH
11, R = Me
12, R = H
O
i, 96%
CO2Me
O
14
13
O
O
N
O
N
O
N
N
Boc
N
Boc
Boc
N
O
iii, iv
68%
ii
O
N
74%
N
O
N
H
N
CO2R
CO2Me
OH
O
N
O
O
CO2Me
17
O
15, R = Me
16, R = H
i, 94%
18
Scheme 2 Reagents: (i) LiOH, THF–H2O; (ii) L-Ser-OMe·HCl, Et3N, DCC, HOBt; (iii) DAST; (iv) BrCCl3, DBU.
Synthesis 2006, No. 8, 1289–1294 © Thieme Stuttgart · New York

PAPER
Construction of a Doubly Functionalized Trisoxazole
1291
Several syntheses14 of the trisoxazole ring system have
appeared in the literature mainly because of the preva-
lence of this unique ring system in the ulapualide family
of natural products. Most of the published procedures
have involved elaborating a mono-oxazole into a bisox-
azole and then into a trisoxazole in a linear stepwise fash-
ion, an elegant exception14d being Pattenden’s convergent
approach to this ring system. The present synthesis, al-
though linear in nature, proceeds in good yield and there-
fore has the potential to provide adequate material suitable
for application to the synthesis of structures related to te-
lomestatin.
[a]D –26 (c 0.3, CHCl3).
IR (neat): 3429, 2981, 1748, 1680, 1479, 1368, 1250, 1067 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.07 (br s, 1 H), 4.63 (br s, 1 H),
4.38 (br s, 1 H), 4.18–4.09 (m, 2 H), 3.97–3.86 (m, 2 H), 3.78 (s, 3
H), 1.67 (s, 3 H), 1.53 (s, 3 H), 1.48 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 171.0 (s), 170.4 (s), 152.5 (s), 94.4
(s), 81.3 (s), 65.8 (t), 62.1 (d), 60.2 (t), 54.6 (d), 52.3 (q), 27.9 (q),
25.9 (q), 22.7 (q).
Anal. Calcd for C15H26N2O7: C, 52.01; H, 7.57; N, 8.09. Found: C,
52.33; H, 7.41; N, 8.28.
(S)-Methyl 2-[(S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]-4,5-dihydrooxazole-4-carboxylate (10)
DAST (0.42 mL, 3.20 mmol) was added dropwise over 15 min to a
stirred solution of hydroxy amide 9 (1.0 g, 2.90 mmol) in anhyd
CH2Cl2 (15 mL) at –78 °C under Ar and stirring was continued for
1 h. The reaction was quenched with solid K2CO3 (0.55 g, 4.0
mmol) and the reaction temperature was allowed to rise to r.t. over
1.5 h. The solution was diluted with CH2Cl2 (25 mL) and washed se-
quentially with a sat. aq solution of NaHCO3 (2 × 25 mL), H2O (25
mL), and brine (10 mL), dried (Na2SO4), filtered, and the filtrate
was concentrated in vacuo to leave the crude product as a light yel-
low viscous liquid, which was purified by chromatography (PE–
EtOAc, 4:1) to provide the product 10 (0.76 g, 80%) as a colorless
solid.
Optical rotations were recorded in spectroscopic grade CHCl3,
CH2Cl2, or MeOH on a Jasco DIP-370 polarimeter. IR spectra were
recorded on a Perkin-Elmer Spectrum-1 spectrophotometer pur-
1
chased through a DST-FIST grant. H and 13C NMR spectra were
recorded on a Bruker DRX-300 spectrometer at I.I.C.B., Calcutta.
Chemical shifts are recorded relative to residual CHCl3 or TMS.
NMR data of the major rotamer are detailed. MS were recorded on
a JEOL-JMS 600 instrument from I.I.C.B., Calcutta or C.D.R.I.,
Lucknow. Elemental analyses were also obtained from the same in-
stitute. Petroleum ether (PE) refers to the fraction with a bp range
60–80 °C. Silica gel (60–120 mesh) purchased from Spectrochem,
India was used for column chromatography.
Mp 95 °C (EtOAc–PE); [a]D –6.6 (c 0.7, CHCl3).
IR (KBr): 2979, 1742, 1660, 1479, 1383, 1291, 1057 cm–1.
(S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidine-4-
carboxylic Acid (8)
1H NMR (CDCl3, 300 MHz): d = 4.81–4.74 (m, 1 H), 4.66–4.61 (m,
1 H), 4.52–4.49 (m, 2 H), 4.20–4.03 (m, 2 H), 3.79 (s, 3 H), 1.66 (s,
3 H), 1.58 (s, 3 H), 1.41 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 171.6 (s), 168.7 (s), 152.1 (s), 95.4
(s), 80.6 (s), 68.6 (t), 67.9 (d), 57.7 (t), 54.8 (d), 52.4 (q), 28.4 (q),
25.4 (q), 24.4 (q).
Solid LiOH·H2O (0.68 g, 16.20 mmol) was added in one portion to
a stirred solution of 7 (2.0 g, 7.72 mmol) in THF–H2O (4:1, 40 mL)
and stirring was continued for 4 h. EtOAc (50 mL) was added and
the resulting solution was acidified to pH 2 with 2 N HCl at 0–5 °C.
The aqueous layer was separated and extracted with EtOAc (2 × 50
mL). The combined organic extract was washed with brine (25 mL),
dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo
to leave the crude product as a colorless viscous oil (1.82 g, 96%),
which was used without further purification. A small portion was
purified for characterization by chromatography (PE–EtOAc, 1:3).
Anal. Calcd for C15H24N2O6: C, 54.87; H, 7.37; N, 8.53. Found: C,
55.11; H, 7.61; N, 8.19.
(S)-Methyl 2-[3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-
4-yl]oxazole-4-carboxylate (11)
IR (neat): 2981, 1708, 1479, 1395, 1250, 1054 cm–1.
DBU (0.52 g, 3.40 mmol) was added dropwise over 5 min to a
stirred solution of oxazoline 10 (1.0 g, 3.05 mmol) in anhyd CH2Cl2
(25 mL) at 0 °C under nitrogen, stirring was continued for 16 h, and
the reaction temperature was allowed to rise to r.t. The mixture was
washed with a sat. aq solution of NH4Cl (2 × 25 mL) and the sepa-
rated aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The
combined organic extract was washed with brine (25 mL), dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo to
leave a brownish mass, which was purified by chromatography
(PE–EtOAc, 3:1) to provide the oxazole 11 (0.83 g, 83%) as a col-
orless solid.
1H NMR (CDCl3, 300 MHz): d = 9.19 (br s, 1 H), 4.52–4.40 (m, 1
H), 4.22–4.14 (m, 2 H), 1.67 (s, 3 H), 1.54 (s, 3 H), 1.51 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 175.9 (s), 152.5 (s), 95.0 (s), 80.6
(s), 66.0 (t), 58.9 (d), 28.1 (q), 24.7 (q), 24.1 (q).
Anal. Calcd for C11H19NO5: C, 53.87; H, 7.81; N, 5.71. Found: C,
54.11; H, 8.08; N, 6.03.
(S)-tert-Butyl 4-{[(S)-3-Hydroxy-1-methoxy-1-oxopropan-2-
yl]carbamoyl}-2,2-dimethyloxazolidine-3-carboxylate (9)
Et3N (3.50 mL, 25.0 mmol) was added dropwise over 15 min to a
stirred suspension of L-Ser-OMe·HCl (1.1 g, 7.10 mmol) in anhyd
CH2Cl2 (40 mL) at 0 °C under N2. Then the acid 7 (1.70 g, 7.0
mmol) and HOBt (1.0 g, 7.40 mmol) were added sequentially and
the resulting mixture was stirred for 15 min after which a solution
of DCC (1.60 g, 7.8 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise over 15 min. The resulting mixture was stirred at the same
temperature for 1 h, the reaction temperature was allowed to rise to
r.t., and stirred for 18 h. The precipitated urea was filtered off and
the filtrate was washed sequentially with a sat. aq solution of
NaHCO3 (30 mL), HCl (3%, 30 mL), H2O (30 mL), and brine (30
mL), dried (Na2SO4), filtered, and the filtrate was concentrated in
vacuo to leave the crude product as a light yellow viscous liquid,
which was purified by chromatography (PE–EtOAc, 3:1) to provide
the product 9 (1.91 g, 79%) as a foam.
Mp 124 °C (EtOAc–PE); [a]D –103 (c 0.1, CHCl3).
IR (KBr): 3135, 2991, 1701, 1460, 1369, 1265, 1099 cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.21 (s, 1 H), 5.18–5.07 (m, 1 H),
4.29–4.18 (m, 2 H), 3.93 (s, 3 H), 1.74 (s, 3 H), 1.60 (s, 3 H), 1.29
(s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 164.1 (s), 161.3 (s), 151.0 (s),
143.7 (d), 133.5 (s), 95.2 (s), 80.6 (s), 67.4 (t), 55.1 (d), 52.2 (q),
28.1 (q), 25.3 (q), 24.0 (q).
MS (EI): m/z (%) = 326 (M+, 21), 311 (M+ – CH3, 62), 253 (M+ –
OCMe3, 63), 211 (M+– NBoc, 100).
Anal. Calcd for C15H22N2O6: C, 55.21; H, 6.79; N, 8.58. Found: C,
55.07; H, 6.96; N, 8.43.
Synthesis 2006, No. 8, 1289–1294 © Thieme Stuttgart · New York

1292
S. K. Chattopadhyay et al.
PAPER
(S)-2-[3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl]-
oxazole-4-carboxylic Acid (12)
phy (PE–EtOAc, 1:1) to provide the product 14 (0.38 g, 79%) as a
colorless foam.
Solid LiOH·H2O (0.27 g, 6.4 mmol) was added in one portion to a
stirred solution of 11 (1.0 g, 3.10 mmol) in THF–H2O (4:1, 15 mL)
and stirring was continued for 4 h. EtOAc (25 mL) was added and
the resulting solution was acidified to pH 2 with 2 N HCl at 0–5 °C.
The aqueous layer was separated and extracted with EtOAc (2 × 25
mL). The combined organic extract was washed with brine (25 mL),
dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo
to leave the crude product as a colorless solid (0.92 g, 96%), which
was recrystallized from EtOAc to give the product as a colorless
powder.
[a]D +4.0 (c 1.4, CHCl3).
IR (CHCl3): 2981, 1745, 1707, 1660, 1441, 1385, 1252, 1048 cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.16 (s, 1 H), 5.18–5.07 (m, 1 H),
4.94 (t, J = 8.2 Hz, 1 H), 4.73–4.67 (m, 1 H), 4.59 (t, J = 9.2 Hz, 1
H), 4.28–4.23 (m, 1 H), 4.15–4.12 (m, 1 H), 3.80 (s, 3 H), 1.73 (s, 3
H), 1.59 (s, 3 H), 1.30 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 171.0 (s), 164.2 (s), 159.8 (s),
151.0 (s), 141.2 (d), 130.3 (s), 95.1 (s), 80.6 (s), 69.4 (t), 68.3 (t),
67.5 (d), 55.0 (d), 52.7 (q), 28.1 (q), 25.2 (q), 23.9 (q).
Mp 140 °C; [a]D –82.2 (c 0.5, CHCl3).
IR (neat): 2972, 1718, 1687, 1378, 1275, 1096 cm–1.
Anal. Calcd for C18H25N3O7: C, 54.68; H, 6.37; N, 10.63. Found: C,
54.94; H, 6.51; N, 10.40.
1H NMR (CDCl3, 300 MHz): d = 8.29 (s, 1 H), 6.20 (br s, 1 H),
5.23–5.14 (m, 1 H), 4.31–4.26 (m, 1 H), 4.19–4.11 (m, 1 H), 1.75
(s, 3 H), 1.70 (s, 3 H), 1.30 (s, 9 H).
Methyl 2-{2-[(S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]oxazol-4-yl}oxazol-4-carboxylate (15)
DBU (0.21 mL, 1.40 mmol) was added dropwise over 5 min to a
stirred solution of oxazole-oxazoline 14 (0.5 g, 1.26 mmol) in anhyd
CH2Cl2 (15 mL) at 0 °C under N2, stirring was continued for 16 h,
and the reaction temperature was allowed to rise to r.t. The solution
was washed with a sat. aq solution of NH4Cl (2 × 10 mL) and the
separated aqueous layer was extracted with CH2Cl2 (2 × 20 mL).
The combined organic extract was washed with brine (25 mL),
dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo
to leave the crude product as a light yellow solid, which was puri-
fied by recrystallization from EtOAc to provide bisoxazole 15 (0.40
g, 81%) as a colorless solid.
Anal. Calcd for C14H20N2O6: C, 53.84; H, 6.45; N, 8.97. Found: C,
54.16; H, 6.66; N, 8.68.
(S)-tert-Butyl 4-(4{[(S)-3-Hydroxy-1-methoxy-1-oxopropan-2-
yl]carbamoyl}oxazol-2-yl)-2,2-dimethyloxazolidine-3-carbox-
ylate (13)
Et3N (1.9 mL, 13.3 mmol) was added dropwise over 15 min to a
stirred suspension of L-Ser-OMe·HCl (0.86 g, 5.6 mmol) in anhyd
CH2Cl2 (20 mL) at 0 °C under N2. The acid 12 (1.0 g, 3.20 mmol)
and HOBt (0.67 g, 4.91 mmol) were added sequentially and the re-
sulting mixture was stirred for 15 min, then a solution of DCC (0.93
g, 4.50 mmol) in anhyd CH2Cl2 (8 mL) was added dropwise over 15
min. The resulting mixture was stirred at the same temperature for
1 h, the reaction temperature was allowed to rise to r.t., and stirred
for 18 h. The precipitated urea was removed by filtration, the filtrate
was washed sequentially with a sat. aq solution of NaHCO3 (20
mL), HCl (3%, 2 × 20 mL), H2O (25 mL), and brine (20 mL), dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo to
leave the crude product as a light yellow viscous liquid, which was
purified by chromatography (PE– EtOAc, 1:1) to provide the prod-
uct 13 (1.01 g, 76%) as a foam.
Mp 144 °C; [a]D 19.9 (c 0.1 CHCl3).
IR (KBr): 2984, 1734, 1702, 1639, 1457, 1377, 1274, 1096 cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.34 (s, 1 H), 8.30 (s, 1 H), 5.21–
5.09 (m, 1 H), 4.31–4.24 (m, 2 H), 3.95 (s, 3 H), 1.61 (s, 3 H), 1.45
(s, 3 H), 1.28 (s, 9 H).
13C NMR (75 MHz): d = 164.7 (s), 161.3 (s), 157.1 (s), 151.0 (s),
143.8 (d), 139.3 (d), 134.3 (s), 130.3 (s), 95.2 (s), 80.6 (s), 67.4 (t),
55.1 (d), 52.3 (q), 28.3 (q), 25.2 (q), 24.1 (q).
UV (CHCl3): lmax = 247.2 nm.
MS (EI): m/z (%) = 393 (M+, 9), 378 (12), 337 (61), 278 (M+ –
NBoc, 100).
[a]D –41 (c 0.2, CHCl3).
IR (neat): 3410, 2981, 1748, 1703, 1457, 1379, 1250, 1063 cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.20 (s, 1 H), 7.78 (d, J = 7.4 Hz,
1 H), 5.12–5.01 (m, 1 H), 4.81–4.77 (m, 1 H), 4.26–4.23 (m, 1 H),
4.13–4.05 (m, 2 H), 3.97–3.94 (m, 1 H), 3.79 (s, 3 H), 3.39 (br s, 1
H), 1.75 (s, 3 H), 1.60 (s, 3 H), 1.31 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 170.4 (s), 163.3 (s), 160.5 (s),
151.9 (s), 141.6 (d), 135.6 (s), 95.0 (s), 81.3 (s), 67.1 (t), 62.6 (t),
54.8 (d), 54.3 (d), 52.5 (q), 28.1 (q), 26.1 (q), 23.9 (q).
Anal. Calcd for C18H23N3O7: C, 54.96; H, 5.89; N, 10.68. Found: C,
55.12; H, 6.03; N, 10.92.
2-(2-[(S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-4-
yl]oxazol-4-yl}oxazol-4-carboxylic Acid (16)
Solid LiOH·H2O (0.23 g, 5.48 mmol) was added in one portion to a
stirred solution of bisoxazole ester 15 (1.0 g, 2.54 mmol) in THF–
H2O (4:1, 15 mL) and stirring was continued for 6 h. EtOAc (50
mL) was added and the resulting solution was acidified to pH 2 with
2 N HCl at 0–5 °C. The aqueous layer was separated and extracted
with EtOAc (2 × 25 mL). The combined organic extract was
washed with brine (25 mL), dried (Na2SO4), filtered, and the filtrate
was concentrated in vacuo to leave the crude product as a colorless
solid (0.93 g, 94%), which was recrystallized from CH2Cl2 to give
the product as a colorless powder.
Anal. Calcd for C18H27N3O8: C, 52.29; H, 6.58; N, 10.16. Found: C,
52.46; H, 6.81; N, 10.54.
(S)-Methyl 2-{2-[(S)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-
oxazolidin -4-yl]oxazol-4-yl}-4,5-dihydrooxazole-4-carboxylate
(14)
DAST (0.20 mL, 1.44 mmol) was added dropwise over 15 min to a
stirred solution of hydroxy amide 13 (0.5 g, 1.21 mmol) in anhyd
CH2Cl2 (10 mL) at –78 °C under Ar and stirring was continued for
1 h. The reaction was quenched with solid K2CO3 (0.25 g, 1.8
mmol) and then the reaction temperature was allowed to rise to r.t.
over 1.5 h. The reaction mixture was diluted with CH2Cl2 (25 mL)
and washed sequentially with a sat. aq solution of NaHCO3 (2 × 25
mL), H2O (25 mL), and brine (10 mL), dried (Na2SO4), filtered, and
the filtrate was concentrated in vacuo to leave the crude product as
a light yellow viscous liquid, which was purified by chromatogra-
Mp 182 °C; [a]D –73 (c 0.21, CHCl3).
IR (neat): 3137, 1714, 1689, 1380, 1273, 1096 cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.39 (s, 1 H), 8.35 (s, 1 H), 5.24–
5.13 (m, 1 H), 4.32–4.27 (m, 2 H), 1.77 (s, 3 H), 1.61 (s, 3 H), 1.29
(s, 9 H).
Anal. Calcd for C17H21N3O7: C, 53.82; H, 5.58; N, 11.08. Found: C,
54.16; H, 5.77; N, 11.26.
Synthesis 2006, No. 8, 1289–1294 © Thieme Stuttgart · New York

PAPER
Construction of a Doubly Functionalized Trisoxazole
1293
(S)-tert-Butyl 4-[4-(4-{[(S)-3-Hydroxy-1-methoxy-1-oxopropan-
2-yl]carbamoyl}oxazol-2-yl)oxazol-2-yl]-2,2-dimethyloxazoli-
dine-3-carboxylate (17)
Et3N (1.0 mL, 9.9 mmol) was added dropwise over 15 min to a
stirred suspension of L-Ser-OMe·HCl (0.47 g, 3.0 mmol) in anhyd
CH2Cl2 (10 mL) at 0 °C under N2. Then the acid 16 (0.55 g, 1.45
mmol) and HOBt (0.36 g, 2.66 mmol) were added sequentially and
the resulting mixture was stirred for 15 min. A solution of DCC
(0.51 g, 2.47 mmol) in anhyd CH2Cl2 (4 mL) was added dropwise
(s), 130.0 (s), 95.3 (s), 80.7 (s), 67.4 (t), 55.1 (d), 52.3 (q), 28.1 (q),
25.3 (q), 24.1(q).
MS (EI): m/z (%) = 460 (M+, 17), 404 (26), 345 (100).
UV (CH2Cl2): lmax (e) = 244 nm (13170).
Anal. Calcd for C21H24N4O8: C, 54.78; H, 5.25; N, 12.17. Found: C,
54.55; H, 5.40; N, 12.29.
over 15 min, the resulting mixture was stirred at the same tempera- Acknowledgment
ture for 1 h, the reaction temperature was allowed to rise to r.t., and
Financial assistance from DST, New Delhi (Grant No SR/S1/OC-
24/2002) is gratefully acknowledged.
then stirred for 18 h. The precipitated urea was removed by filtra-
tion, the filtrate was washed sequentially with a sat. aq solution of
NaHCO3 (2 × 20 mL), HCl (3%, 2 × 20 mL), H2O (25 mL), and
brine (20 mL), dried (Na2SO4), filtered, and the filtrate was concen-
trated in vacuo to leave the crude product as a light yellow viscous
liquid, which was purified by chromatography (PE– EtOAc, 1:2) to
provide the product 17 (0.52 g, 74%) as a colorless solid.
References
(1) For reviews see: (a) Pattenden, G. J. Heterocycl. Chem.
1992, 29, 607. (b) Wipf, P. Chem. Rev. 1995, 95, 2115.
(c) Faulkner, D. Nat. Prod. Rep. 2002, 29, 1. (d) Yeh, V. S.
C. Tetrahedron 2004, 60, 11995.
(2) For some examples, see: (a) Gonzalez, M. A.; Pattenden, G.
Angew. Chem. Int. Ed. 2003, 42, 1255. (b) Krebs, O.;
Taylor, R. J. K. Org. Lett. 2005, 7, 1063. (c) Bagley, M. C.;
Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J. J. Org.
Chem. 2005, 70, 1389. (d) Bagley, M. C.; Bashford, K. E.;
Hesketh, C. L.; Moody, C. J. J. Am. Chem. Soc. 2000, 122,
3301. (e) Mann, E.; Kessler, H. Org. Lett. 2003, 5, 4567.
(f) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew.
Chem. Int. Ed. 2003, 42, 4961.
Mp 194 °C; [a]D –20.8 (c 1.1, CHCl3).
IR (neat): 3420, 3390, 2932, 1751, 1655, 1440, 1390, 1218, 913
cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.27 (s, 1 H), 8.24 (s, 1 H), 7.79
(d, J = 7.6 Hz, 1 H), 5.23–5.13 (m, 1 H), 4.88–4.85 (m, 1 H), 4.33–
4.28 (m, 1 H), 4.17–4.03 (m, 3 H), 3.82 (s, 3 H), 2.58 (br s, 1 H),
1.65 (s, 3 H), 1.59 (s, 3 H), 1.30 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 170.8 (s), 165.4 (s), 160.8 (s),
157.1 (s), 154.1 (s), 142.0 (d), 139.8 (d), 137.4 (s), 130.5 (s), 95.7
(s), 81.2 (s), 67.9 (t), 63.5 (t), 55.6 (d), 53.2 (d), 49.9 (q), 28.6 (q),
25.7 (q), 25.2 (q).
(3) Shin-Ya, K.; Weirzba, K.; Matsuo, K.; Ohtani, T.; Yamada,
Y.; Furihata, K.; Hayakawa, Y.; Seto, H. J. J. Am. Chem.
Soc. 2001, 123, 1262.
MS (EI): m/z (%) = 480 (M+, 19), 462 (11), 424 (22), 365 (100).
(4) Kim, M. Y.; Vankayalapati, H.; Shin-Ya, K.; Weirzba, K.;
Hurley, L. H. J. Am. Chem. Soc. 2002, 124, 2098.
(5) (a) Kim, M. Y.; Gleason-Guzman, M.; Izbicka, E.; Nishioka,
D.; Hurley, L. H. Cancer Res. 2003, 63, 3247.
Anal. Calcd for C21H28N4O9: C, 52.50; H, 5.87; N, 11.66. Found: C,
52.77; H, 6.18; N, 11.91.
Methyl 2-(2-{2-[(S)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-
oxazolidin-4-yl]oxazol-4-yl}oxazol-4-yl)oxazole-4-carboxylate
(18)
(b) Nakajima, A.; Tauchi, T.; Sashida, G.; Sumi, M.; Abe,
K.; Yamamoto, K.; Ohyashiki, J. H.; Ohyashiki, K.
Leukemia 2003, 17, 560. (c) Sumi, M.; Tauchi, T.; Sashida,
G.; Nakajima, A.; Gotoh, A.; Shin-Ya, K.; Ohyashiki, J. H.;
Ohyashiki, K. Int. J. Oncol. 2004, 24, 1481. (d) Shamma,
M. A.; Reis, R. J. S.; Li, C.; Koley, H.; Hurley, L. H.;
Andersson, K. C.; Munshi, N. C. Clin. Cancer Res. 2004, 10,
770.
DAST (75 mL, 0.57 mmol) was added dropwise to a stirred solution
of the b-hydroxy amide 17 (0.20 g, 0.416 mmol) at –78 °C under Ar
and stirring was continued for 1.5 h. The reaction was quenched
with solid K2CO3 (92 mg, 0.67 mmol) and the reaction temperature
was allowed to rise to r.t. over 1 h. The solution was diluted with
CH2Cl2 (15 mL) and washed sequentially with a sat. aq solution of
NaHCO3 (15 mL), H2O (25 mL), and brine (10 mL), dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo to
leave the crude product as a light yellow powder. A solution of the
crude product (197 mg) in anhyd CH2Cl2 (6 mL) was cooled to 0 °C
and DBU (72 mL, 0.48 mmol) followed by BrCCl3 (50 mL, 0.51
mmol) were added sequentially. The mixture was stirred at 3–4 °C
for 12 h and then quenched with a sat. solution NH4Cl (10 mL). The
separated aqueous layer was extracted with CH2Cl2 (2 × 15 mL) and
the combined organic extract was dried (Na2SO4), filtered, and the
filtrate was concentrated. Purification of the residue by chromato-
graphy (PE–EtOAc, 1:2) provided the trisoxazole derivative 18
(129 mg, 68% over two steps) as a colorless powder.
(6) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
(b) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N.
Synthesis 1994, 31.
(7) (a) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(b) Wipf, P.; Miller, C. P.; Hayes, G. B. Tetrahedron 1998,
54, 6987. (c) Evans, D. A.; Peterson, G. S.; Johnson, J. S.;
Barnes, D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem.
1998, 63, 4541. (d) Rajaram, S.; Sigman, M. S. Org. Lett.
2002, 4, 3399. (e) DeRoy, P. L.; Charette, A. B. Org. Lett.
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D. R. Org. Lett. 2000, 2, 1165. (b) Burrell, G.; Evans, J. M.;
Jones, G. E.; Stemp, G. Tetrahedron Lett. 1990, 31, 3649.
(c) Lafargue, P.; Guenot, P.; Lellouche, J.-P. Heterocycles
1995, 41, 947.
Mp 218–220 °C (EtOAc); [a]27D –64.5 (c 0.1, CHCl3).
IR (KBr): 3132, 1717, 1645, 1377, 1093, 976, 726 cm–1.
(9) (a) Williams, D. R.; Brooks, D. A.; Berliner, M. A.; Reeves,
J. T. J. Am. Chem. Soc. 1999, 121, 4924. (b) Williams, D.
R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.;
Reeves, J. T. Angew. Chem. Int. Ed. 2003, 42, 1258.
(c) Wipf, P.; Uto, Y. J. Org. Chem. 2000, 65, 1037.
(10) Boden, C. D. J.; Pattenden, G.; Ye, T. Synlett 1995, 417.
1H NMR (300 MHz, CDCl3): d = 8.44 (s, 1 H), 8.33 (s, 2 H), 5.23–
5.14 (m, 1 H), 4.32–4.14 (m, 2 H), 3.95 (s, 3 H), 1.78 (s, 3 H), 1.61
(s, 3 H), 1.30 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 164.8 (s), 161.2 (s), 156.4(s),
151.0 (s), 143.6 (d), 139.6 (s), 139.4 (d), 139.2 (d), 134.3 (s), 130.8
Synthesis 2006, No. 8, 1289–1294 © Thieme Stuttgart · New York

1294
S. K. Chattopadhyay et al.
PAPER
(11) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A.
Tetrahedron Lett. 1997, 38, 331.
(12) Chattopadhyay, S. K.; Kempson, J.; McNeil, A.; Pattenden,
G.; Reader, M.; Rippon, D. E.; Waite, D. J. Chem. Soc.,
Perkin Trans. 1 2000, 2415.
(14) (a) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990,
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(e) Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61, 6496.
(13) Although the chirality of serine is destroyed in subsequent
steps we preferred to use L-serine to avoid diastereomeric
problems.
Synthesis 2006, No. 8, 1289–1294 © Thieme Stuttgart · New York