Synthesis of 5-(3-indolyl)oxazole natural products. Structure revision of Almazole D

Article abstract of DOI:10.1016/j.tet.2010.03.109

The synthesis and utility of β-oxotryptamine and β-oxytryptophan ester synthons provide a convenient entry to 5-(3-indolyl)oxazole natural products leading to a structure revision of almazole D.

Full text of DOI:10.1016/j.tet.2010.03.109

Tetrahedron 66 (2010) 4888–4893
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 5-(3-indolyl)oxazole natural products. Structure revision
of Almazole D
*
Fumiko Miyake, Michinao Hashimoto, Sorasaree Tonsiengsom, Kenichi Yakushijin, David A. Horne
Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and utility of
b-oxotryptamine and
b
-oxytryptophan ester synthons provide a convenient
Received 15 February 2010
Received in revised form 28 March 2010
Accepted 29 March 2010
Available online 2 April 2010
entry to 5-(3-indolyl)oxazole natural products leading to a structure revision of almazole D.
Ó 2010 Published by Elsevier Ltd.
Keywords:
Oxazole
Synthesis
Natural products
Antibiotics
O
RO
1
1. Introduction
N
3
105.7
O
O
Almazole D (1) is a secondary metabolite isolated from red alga
that possesses potent antibacterial activity against Gram-negative
bacteria such as Serratia marcescens and Salmonella typhi LXD.1
These and related pathogenic bacteria are of high concern due to
the increasing number of infectious cases, virulence, and resistance
to antibiotics. The structure elucidation of 1 has been reported by
Pietra and co-workers in which chemical modification studies
involving the treatment of 1 with diazomethane yielded methyl-
ated analog 2. Comparison of NMR data obtained for 1 and 2 with
those for almazole C (3)2 led to the proposed structure 1 for
almazole D. In this report, we describe the results of our synthetic
efforts in this area for which a structure revision of almazole D is
proposed.
N
N
N
H
N
H
N
3
almazole C ( )
almazole D ( ) R=H (C3 δ=105.1)
2
R=CH3 (C3 d=103.9)
O2C
N
105.4
N
O
H
115.6
N
O
O
N
N
N
H
H
H
martefragin A (4)
prealmazole C (5)
2. Results and discussion
and martefragin A (4).4 Indoles based on an oxotryptamine motif
such as prealmazole C (5)2 typically have C3 chemical shift values in
the range of 113–116 ppm. This holds true for a number of oxo-
tryptamine derivatives that we have investigated, particularly
those found in the bisindole alkaloid series.3 Additionally, the for-
mation of almazole D (1) from a biosynthetic viewpoint involving
One piece of data that remained at odds with proposed structure
1 is the 13C chemical shift value of the indole C3. The reported value
for C3 of 1 and 2 are 105.05 (s) and 103.90 (s) ppm, respectively.
Upon examining related indole derivatives reported in the litera-
ture as well as those synthesized by our laboratory,3 these values
are more consistent with 5-(3-indolyl)oxazole structures that lack
a carbonyl substituent at C3 and better correspond to almazole C (3)
tryptophan and N,N-dimethyl-L-phenylalanine would require an
unprecedented oxidative deamination event to explain the extra
carbonyl group and hydroxyl moiety contained in the oxazole ring.
Based on these observations, we concluded that the original
structure 1 proposed for almazole D is likely misassigned and that
* Corresponding author. Tel.: þ1 626 471 7310; fax: þ1 626 930 5410; e-mail
address: dhorne@coh.org (D.A. Horne).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.03.109

F. Miyake et al. / Tetrahedron 66 (2010) 4888–4893
4889
the correct structure of the antibiotic is 5-(3-indolyl)oxazole 6. This
new structure is also more reasonable from a biosynthetic view-
point as delineated for martefragin A (4).4
Next, using optically pure N,N-dimethyl-
L
-phenylalanine (11),
diethylphosphoryl cyanide (DEPC)10 facilitated acylation with 8
23
23
producing prealmazole C (5), [
a]
þ99 (c 0.27, MeOH) (lit.2
[a]
D
D
þ38, c 0.25, MeOH) (Scheme 2). It should be noted that a large
discrepancy in specific rotation exists between our work and that
reported by Pietra and co-workers. Treatment of 5 with POCl3 at
23 ꢀC for one day did not produce appreciable amounts of almazole
O2C
N
C (3); however, heating the reaction to 60 ꢀC for two days produced
O
23
good yields of 3, [
a]
þ156 (c 0.27, MeOH). At 90 ꢀC, almazole C (3)
D
N
N
can be obtained in shorter reaction time but the higher tempera-
H
23
ture afforded 3 in lower optical purity ([
a
]
þ91, c 0.27, MeOH). The
D
revised structure of
almazole D (6)
optical purity of 3 resulting from both sets of reaction conditions
was also evaluated by NMR analysis in the presence of (R)-Mosher’s
acid.11 Under 60 ꢀC cyclization conditions, >97% enantiomeric
product purity was obtained as indicated by the presence of a single
methyl signal seen at
epimerization was evident in the product by the presence of two
d
2.86 ppm in CDCl3. At 90 ꢀC, however,
Our synthetic studies began with almazole C (3), a related sec-
ondary metabolite isolated from red alga. Structure 3 was pre-
viously confirmed through synthesis in which a Robinson–Gabriel2
methyl signals at
d
2.86 and 2.84 ppm.
cyclization served as the key oxazole forming step. The optical
CO2H
DEPC
NMe2
23
rotation, however, reported for the natural material [
a
]
þ168
prealmazole C (5)
8
+
D
(c 1.08, MeOH) is significantly higher than the synthesized material
23
[
a]
þ138 (c 0.1, MeOH).2 One possibility to account for this
D
11
POCl3
60 ºC
discrepancy is epimerization of the dimethylamino center during
cyclization. While the Robinson–Gabriel method is one of the most
widely used procedures for the preparation of oxazoles,5 cyclo-
3
almazole C ( )
dehydrations of chiral
a-acylamino ketones having epimerizable
centers often pose a problem under these conditions.6 Thus, one of
the key objectives of this study not only involves the structure
confirmation of almazole D but the preparation of two key syn-
thons, oxo-tryptamine (8) and -tryptophan ester (13) and their use
in a Robinson–Gabriel approach to chiral, non-racemic oxazole
synthesis.
Scheme 2.
Our attention next turned to the synthesis of oxazole 6, the
revised structure proposed for almazole D. The synthesis required
the preparation of oxotryptophan methyl ester 13 (Scheme 3). This
was achieved through hydrolysis of oxazole 12, which is easily
obtained from the cycloaddition of methyl isocyanoacetate and acyl
nitrile 7.12 Acid hydrolysis of 12 produced oxotryptophan 13 (75%)
and minor amounts oxotryptamine 8 (5%), which occurred through
decarboxylation.
In a previous communication,3 the reduction of indole-3-
carbonyl nitrile (7)7 produced oxotryptamine (8), which is an
important synthon found in many structural motifs of biologically
active natural products. This procedure enables the convenient
preparation of 8 in large quantities. With 8 in hand, initial studies
were directed at examining reaction conditions necessary to effect
the Robinson–Gabriel cyclization which is typically performed at
elevated temperatures. Acylation of 8 with the corresponding acid
chloride produced ketoamides 9a–d. Treatment of 9a–d with POCl3
at room temperature produced excellent yields of streptomyces
and/or streptoverticillium metabolites pimprinethine (10a),8 WS-
30581A (10b),9 WS-30581B (10c),9 and unnatural analog (10d)
(Scheme 1).
MeO2C
O
N
NH2
NC
MeO2C
O
HCl
MeOH
7
CO2Me
N
H
N
H
12
13
Scheme 3.
While Vinograd and co-workers13 reported the keto–enol tau-
tomeric behavior of oxotryptophan ethyl ester (13a/13b) (Eq. 1)
(prepared in two steps from ethyl -keto- -(3-indolyl)propionate)
b
b
O
O
in pyridine-d5 and/or MeOH-d4, we were unable to observe different
tautomeric species in the 1H NMR spectrum of 13 in a variety of
solvents (pyridine-d5, CDCl3, DMSO-d6, and MeOH-d4) as well as in
the 13C NMR spectrum measured in DMSO-d6. The methine hydro-
gen, however, did undergo rapid deuterium exchange in the pres-
NH2
H2
CN
RCOCl
Pd/C
AcOH
N
H
N
H
8
7
ence of D2O. While it is reported that some a-C-acylamino acid ester
hydrochlorides exist predominantly as the enol tautomer observed
by1HNMRmeasurementsin DMSO-d6,12 wefound theindoleanalog
13$HCl resides predominantly in the keto form in both MeOH-d4 and
DMSO-d6 as evidenced by their 1H and 13C NMR spectra.
O
N
H
R
N
POCl3
23 ºC
O
R
O
N
H
N
H
H
9
10a-d
O
O
O
O
a
R = CH2CH3
b R = CH2CH2CH3
OEt
OEt
ð1Þ
c R = CH2(CH2)2CH3
NH2
NH2
N
H
N
H
d
R = CH=C(CH3)2
13b
Scheme 1.
13a

4890
F. Miyake et al. / Tetrahedron 66 (2010) 4888–4893
DEPC coupling of 13 with N,N-dimethyl-
L
-phenylalanine (11) pro-
In summary, we have demonstrated the utility of the Robinson–
Gabriel oxazole synthesis with chiral, non-racemic ketoamides.
In addition, a convenient preparation of b-oxotryptophan methyl
ester has been developed. These investigations have led to a struc-
ture revision of the antibiotic, almazole D.
duced a 1:1 diastereomeric mixture of amides 14. Although each
diastereomer is initially separable by column chromatography,
significant epimerization was observed upon standing in DMSO-d6.
Treatment of 14 with POCl3 (60 ꢀC, seven days) afforded oxazole 15
23
[
a]
þ115 (c 0.13, MeOH) and recovered starting material in w1:1
D
ratio. Cyclization of 14 was significantly slower than prealmozole C
(5) presumably due to greater steric hindrance. Complete disap-
pearance of starting material was observed at higher temperatures
(90 ꢀC, two days), however, significant epimerization occurred as
3. Experimental section
3.1. General methods
evidenced by the presence of two -NMe2 product signals at
d 2.97
Unless otherwise noted, materials were obtained from com-
mercial suppliers and used without further purification except for
solvents, which were dried and distilled. POCl3 and acid chlorides
were freshly distilled before use. All reactions were carried out
under inert atmosphere (N2) unless otherwise specified. Silica gel
and 2.95 ppm (CDCl3) in the presence of (R)-Mosher’s acid. Direct
comparison of 1H and 13C NMR spectra of 15 and methylated
almazole D 2 revealed a perfect match, suggesting a structure
revision for 2 to 15. Further evidence for this revision can be found
in the hydrolysis of ester 15, which produced carboxylic acid 16
upon acidification with HCl. The neutral (or zwitterionic) form 17
can be obtained through flash chromatography (Scheme 4).
(particle size 32–63
m) was used for flash chromatography.
3.1.1. -Oxotryptamine (8). A mixture of indolyl-3-carbonyl nitrile
b
(7) (5.0 g, 29 mmol) and 10% Pd/C (1.5 g) in 150 mL of acetic acid
was stirred under a balloon of hydrogen. After 16 h, the reaction
mixture was filtered over Celite and the filtrate concentrated under
reduced pressure. The resulting residue was dissolved in ethanol
containing concd HCl (5% by volume). Concentration under vacuo
yielded 7$HCl as a reddish-brown solid (4.6 g, 90%). 1H NMR
N
O
H
N
11
POCl3
13
O
DEPC
N
H
CO2Me
14
(300 MHz, DMSO-d6)
d
12.45 (1H, br s), 8.50 (1H, d, J¼2.9 Hz), 8.36
O
(2H, br s), 8.15 (1H, dd), 7.52 (1H, dd), 7.23 (2H, tdꢁ2), 4.34 (2H, d,
MeO2C
J¼5.1 Hz), 3.42 (2H, s) ppm. Compound 7 (free base): 1H NMR
N
N
RO
(300 MHz, DMSO-d6)
d 12.45 (1H, br s), 8.31 (1H, s), 8.17 (1H, br s),
O
O
NaOH
7.46 (1H, dd), 7.22–7.15 (2H, m), 3.89 (2H, br s) ppm; 13C NMR
(75 MHz, DMSO-d6) 195.3 (s), 136.5 (s), 133.0 (d), 125.4 (s), 122.7
N
N
N
H
N
H
d
(d), 121.6 (d), 121.2 (d), 114.3 (s), 112.1 (d), 48.2 (t) ppm; MS m/z
(relative intensity)¼175 (Mþþ1, 100), 144 (30); HRMS calcd for
C10H11N2O (Mþþ1): 175.0871; found:175.0869.
15
16
R=H, HCl salt
17 R=H
R=Na
6
Scheme 4.
3.1.2. N-[2-(1H-Indole-3-yl)-2-oxo-ethyl]-alkylamide 9. General pro-
Both the 1H and 13C NMR spectra of 17 (MeOH-d4) as well as the
cedure A. To a stirred solution of
b-oxotryptamine 3 (0.30 g,
UV spectrum in the presence of NaOH (1.5 equiv) were identical
(Fig. 1) to corresponding spectra obtained for almazole D (1) iso-
lated from natural sources.
1.7 mmol) in 20 mL of THF and triethylamine (0.18 mL, 2.5 mmol)
was added acid chloride (1.9 mmol) dropwise at 23 ꢀC. The re-
action mixture was stirred for 30 min and concentrated. The
Figure 1. 13C NMR spectra of almazole in MeOH-d4. A. Natural material B. Synthetic material.

F. Miyake et al. / Tetrahedron 66 (2010) 4888–4893
4891
residual product was dissolved in 100 mL of ethyl acetate, washed
with brine (2ꢁ50 mL), dried (MgSO4), and filtered. Concentration
of the filtrate under reduced pressure afforded indole-oxo-
alkylamide 9. The product was filtered and washed with methy-
lene chloride.
(0.17 mL, 1.4 mmol) was added and the resulting solution was
allowed to warm to 23 ꢀC. After 12 h, the reaction mixture was
concentrated under vacuum. The residual product was dissolved in
100 mL ethyl acetate, washed with brine (2ꢁ50 mL), dried (MgSO4),
and filtered. Concentration under vacuum afforded a residue that
was purified by flash chromatography (CH2Cl2/MeOH 39:1) to give
prealmazole C (5) (0.38 g, 85% yield) as a solid; mp 141–143 ꢀC; 1H
3.1.3. N-[2-(1H-Indole-3-yl)-2-oxo-ethyl]-propionamide (9a). General
procedure A was used to prepare indole-oxo-alkylamide 9a from
propionyl chloride (0.17 g, 1.9 mmol). Upon concentration under
vacuum, compound 9a crystallized as a light yellow solid (0.34 g,
NMR (300 MHz, CDCl3)
d 9.65 (1H, br s), 8.32–8.29 (1H, m), 7.88
(1H, d, J¼3.1 Hz), 7.83 (1H, br t, J¼4.5 Hz), 7.42–7.37 (1H, m),
7.32–7.15 (7H, m), 4.63 (1H, dd, J¼18.2, 5.0 Hz), 4.51 (1H, dd, J¼18.2,
4.6 Hz), 3.41 (1H, dd, J¼7.7, 5.8 Hz), 3.22 (1H, dd, J¼13.8, 7.7 Hz),
3.01 (1H, dd, J¼13.8, 5.8 Hz), 2.42 (6H, s) ppm. 1H NMR (300 MHz,
85%); mp 221–223 ꢀC; IR (KBr) 3299, 3188, 1662, 1616, 1439 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6)
d 11.98 (1H, br s), 8.40 (1H, d,
J¼3.1 Hz), 8.16–8.13 (1H, m), 8.06 (1H, bt, J¼5.4 Hz) 7.48–7.45 (1H,
DMSO-d6)
d
11.99 (1H, br s), 8.42 (1H, d, J¼2.4 Hz), 8.16–8.10 (2H,
m), 7.24–7.15 (2H, m), 4.44 (2H, d, J¼5.6 Hz), 2.18 (2H, q, J¼7.6 Hz),
m), 7.49–7.46 (1H, m), 7.24–7.13 (7H, m), 4.53 (1H, dd, J¼17.4,
5.8 Hz), 4.36 (1H, dd, J¼17.4, 5.3 Hz), 3.38 (2H, dd, J¼8.1, 5.9 Hz),
2.99 (1H, dd, J¼13.6, 8.1 Hz), 2.80 (1H, dd, J¼13.6, 5.9 Hz), 2.31 (6H,
1.03 (3H, t, J¼7.6 Hz) ppm; 13C NMR (75 MHz, DMSO-d6)
d 190.4 (s),
173.2 (s), 136.4 (s), 133.5 (d), 125.4 (s), 122.8 (d), 121.8 (d), 121.1 (d),
114.1 (s), 112.1 (d), 45.6 (t), 28.4 (t), 10.0 (q) ppm; MS m/z (relative
intensity)¼231 (Mþþ1, 100), 175 (10), 154 (10), 144 (25), 114 (20);
HRMS calcd for C13H15N2O2 (Mþþ1): 231.1134; found: 231.1133.
s) ppm. 1H NMR (300 MHz, acetone-d6)
d 11.15 (1H, br s), 8.35 (1H,
d, J¼3.2 Hz), 8.32–8.26 (1H, m), 7.72 (1H, br s), 7.56–7.50 (1H, m),
7.33–7.11 (7H, m), 4.65 (1H, dd, J¼18.0, 5.5 Hz), 4.50 (1H, dd, J¼18.0,
4.9 Hz), 3.45 (1H, dd, J¼7.6, 5.8 Hz), 3.16 (1H, dd, J¼13.7, 7.6 Hz),
2.92 (1H, dd, J¼13.7, 5.8 Hz), 2.39 (6H, s) ppm; 13C NMR (100.1 MHz,
3.1.4. N-[2-(1H-Indole-3-yl)-2-oxo-ethyl]-butyramide (9b). General
procedure A was used to prepare indole-oxo-alkylamide 9b from
butyryl chloride (0.20 g, 1.9 mmol) affording compound 3b (0.36 g,
acetone-d6)
d 190.0 (s), 171.7 (s), 140.9 (s), 137.2 (s), 133.1 (d), 129.7
(dꢁ2), 128.5 (dꢁ2), 126.2 (s), 126.1 (d), 123.5 (d), 122.4 (d), 122.1 (d),
115.2 (s), 112.4 (d), 70.7 (d), 46.1 (t), 41.9 (qꢁ2), 33.3 (t) ppm; MS
m/z (relative intensity)¼350 (Mþþ1, 40), 307 (5), 258 (10), 148
(100); HRMS calcd for C21H24N3O2 (Mþþ1): 350.1868; found:
350.1871.
87%): 1H NMR (300 MHz, DMSO-d6)
d 11.97 (1H, br s), 8.40 (1H, d,
J¼3.1 Hz), 8.16–8.13 (1H, m), 8.08 (1H, br t, J¼5.7 Hz) 7.48–7.44 (1H,
m), 7.24–7.15 (2H, m), 4.44 (2H, d, J¼5.7 Hz), 2.16 (2H, t, J¼7.3 Hz),
1.55 (2H, q, J¼7.3 Hz), 0.89 (3H, t, J¼7.3 Hz) ppm; 13C NMR (75 MHz,
DMSO-d6)
d 190.4 (s), 172.3 (s), 136.4 (s), 133.5 (d), 125.4 (s), 122.8
(d), 121.8 (d), 121.1 (d), 114.1 (s), 112.1 (d), 45.6 (t), 37.2 (t), 18.7 (t),
13.6 (q) ppm; MS m/z (relative intensity)¼245 (Mþþ1, 100), 175
(15), 144 (25), 77 (10); HRMS calcd for C14H17N2O2 (Mþþ1):
245.1290; found: 245.1286.
3.1.8. 3-(2-Alkyl-oxazole-5-yl)-1H-indole (10). General procedure B.
A mixture of 9 (w0.5 mmol) in 5 mL of POCl3 was stirred at 23 ꢀC.
The reaction was allowed to proceed overnight and concentrated
under reduced pressure. The residual product was dissolved in
50 mL of ethyl acetate, washed with saturated aqueous NaHCO3
(50 mL), brine (2ꢁ50 mL), dried (MgSO4), and filtered. Concentra-
tion of the filtrate under reduced pressure gave alkyl oxazole indole
10. The product was filtered and washed with ether.
3.1.5. Pentanoic acid [2-(1H-indole-3-yl)-2-oxo-ethyl]-amide (9c). General
procedure A was used to prepare indole-oxo-alkylamide 9c from
valeryl chloride (0.23 g, 1.9 mmol) affording compound 9c (0.37 g,
84%); mp 207–210 ꢀC; IR (KBr) 3320, 3190, 1653, 1626, 1436 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6)
d
11.97 (1H, br s), 8.40 (1H, d,
3.1.9. 3-(2-Ethyl-oxazole-5-yl)-1H-indole (10a). General procedure B
was used to prepare alkyl oxazole indole 10a from 9a (0.10 g,
0.43 mmol) affording compound 10a (0.082 g, 90%); mp 161–
J¼2.9 Hz), 8.16–8.13 (1H, m), 8.08 (1H, br t, J¼5.3 Hz) 7.47–7.45
(1H, m), 7.23–7.15 (2H, m), 4.43 (2H, d, J¼5.7 Hz), 2.18 (2H, t,
J¼7.3 Hz), 1.51 (2H, m), 1.29 (2H, m), 0.87 (3H, t) ppm; 13C NMR
163 ꢀC; IR (KBr) 3456, 3175, 2368, 2344, 1634 cmꢂ1 1H NMR
;
(75 MHz, DMSO-d6)
d
190.4 (s), 172.4 (s), 136.4 (s), 133.5 (d), 125.4
(300 MHz, CDCl3)
d
8.77 (1H, br s), 7.86–7.83 (1H, bd, J¼8.3 Hz), 7.52
(s), 122.8 (d), 121.8 (d), 121.1 (d), 114.1 (s), 112.1 (d), 45.6 (t), 35.0 (t),
27.5 (t), 21.8 (t), 13.8 (q) ppm; MS m/z (relative intensity)¼259
(Mþþ1, 100), 175 (20), 159 (5), 144 (30), 136 (10); HRMS calcd for
C15H19N2O2 (Mþþ1): 259.1446; found: 259.1144.
(1H, d, J¼2.4 Hz), 7.45–7.42 (1H, bd, J¼8.6 Hz), 7.31–7.22 (2H, bq),
7.17 (1H, s), 2.89 (2H, q), 1.42 (3H, t); 13C NMR (75 MHz, CDCl3)
d
163.8 (s), 147.3 (s), 136.3 (s), 124.1 (s), 122.9 (d), 121.6 (d), 120.8 (d),
119.9 (d), 119.6 (d), 111.6 (d), 105.9 (s), 21.7 (t), 11.3 (q); MS m/z
(relative intensity)¼213 (Mþþ1, 100), 154 (5), 136 (5); HRMS calcd
for C13H13N2O (Mþþ1): 213.1028; 213.1028.
3.1.6. 3-Methyl-but-2-enoic acid [2-(1H-indole-3-yl)-2-oxo-ethyl]-
amide (9d). General procedure A was used to prepare indole-oxo-
alkylamide 9d from 3,3-dimethylacryloyl chloride (0.22 g,
1.9 mmol) affording compound 9c (0.36 g, 81%); mp 230–233 ꢀC; IR
3.1.10. 3-(2-Propyl-oxazol-5-yl)-1H-indole (10b). General procedure
B was used to prepare alkyl oxazole indole 10b from 9b (0.10 g,
0.40 mmol) affording compound 10b (0.08 g, 88% yield); mp
(KBr) 3333, 3220, 1626, 1515, 1435 cmꢂ1
DMSO-d6)
;
1H NMR (300 MHz,
11.98(1H, br s), 8.41(1H, d, J¼3.0 Hz), 8.16–8.14 (1H, m),
d
161–163 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 11.52 (1H, br s), 7.82
8.03 (1H, br t, J¼5.7 Hz) 7.49–7.46 (1H, m), 7.24–7.16 (2H, m), 5.8
(1H, br d J¼7.7 Hz), 7.72 (1H, d, J¼2.6 Hz), 7.46 (1H, br d,
J¼7.8 Hz), 7.28 (1H, s), 7.19 (1H, br t, J¼7.7 Hz), 7.13 (1H, br t,
J¼7.7 Hz), 2.76 (2H, t), 1.76 (2H, m), 0.97 (3H, t); 13C NMR
(1H, s), 4.47 (2H, d, J¼5.8 Hz), 2.08 (3H, s), 1.80 (3H, s) ppm; 13C
NMR (75 MHz, DMSO-d6)
d 190.6 (s), 166.2 (s), 148.8 (s), 136.4 (s),
133.5 (d), 125.4 (s), 122.8 (d), 121.8 (d), 121.1 (d), 118.9 (d), 114.1 (s),
112.1 (d), 45.4 (t), 26.8 (q), 19.3 (q) ppm; MS m/z (relative
intensity)¼257 (Mþþ1, 100), 75 (10), 159 (5), 144 (25), 82 (40);
HRMS calcd for C15H17N2O2 (Mþþ1): 257.1290; found: 257.1283.
(75 MHz, DMSO-d6) d 161.5 (s), 147.2 (s), 136.3 (s), 123.5 (s), 122.9
(d), 122.1 (d), 120.0 (d), 119.4 (d), 119.0 (d), 112.0 (d), 103.9 (s),
29.3 (t), 20.1 (t), 13.5 (q); MS m/z (relative intensity)¼227 (Mþþ1,
100), 154 (5), 136 (5); HRMS calcd for C14H15N2O (Mþþ1):
227.1184; found: 227.1186.
3.1.7. 1-Benzyl-3-[2-(1H-indole-3-yl)-2-oxo-ethyl]-1-isopropyl-urea
(5). To
1.3 mmol) in 100 mL of THF under nitrogen was added triethyl-
amine (0.27 mL, 1.95 mmol) at 0 ꢀC. After 30 min, N,N-dimethyl-
phenylalanine (0.27 g, 1.4 mmol) and diethyl pyrocarbonate
a
stirred solution of
b
-oxotryptamine 3$HCl (0.50 g,
3.1.11. 3-(2-Butyl-oxazol-5-yl)-1H-indole (10c). General procedure B
was used to prepare alkyl oxazole indole 10c from 9c (0.10 g,
0.38 mmol) affording compound 10c (0.079 g, 86% ꢂy1ield); mp
;
1H NMR
L-
122–124 ꢀC; IR (KBr) 3456, 3128, 2368, 2344, 1632 cm

4892
F. Miyake et al. / Tetrahedron 66 (2010) 4888–4893
(300 MHz, DMSO-d6)
d
11.50 (1H, br s), 7.80 (1H, br d, J¼7.6 Hz), 7.70
(relative intensity)¼332 (Mþþ1, 55), 287 (100), 240 (30), 136 (45),
107 (15); HRMS calcd for C21H22N3O (Mþþ1): 332.1763; found:
332.1761.
(1H, d, J¼2.6 Hz), 7.44 (1H, br d, J¼7.8 Hz), 7.26 (1H, s), 7.18 (1H, br t,
J¼7.6 Hz), 7.11 (1H, br t, J¼7.6 Hz), 2.78 (2H, t), 1.72 (2H, m), 1.38
(2H, m), 0.91 (3H, t); 13C NMR (75 MHz, DMSO-d6)
d 161.6 (s), 147.2
(s), 136.3 (s), 123.5 (s), 122.9 (d), 122.0 (d), 120.0 (d), 119.4 (d), 119.0
(d), 112.0 (d), 103.9 (s), 28.7 (t), 27.0 (t), 21.6 (t), 13.6 (q); MS m/z
(relative intensity)¼241 (Mþþ1, 100), 211 (5), 144 (5), 136 (5), 107
(5); HRMS calcd for C15H17N2O (Mþþ1): 241.1341; found: 241.1340.
3.1.15. Methyl 5-(3-indolyl) oxazole-4-carboxylate (12). To a stirred
solution of 7 (1.0 g, 5.9 mmol) in 50 mL of THF at 0 ꢀC was dropwise
added
a-isocyanoacetate (0.65 mL, 7.1 mmol) and DBU (1.1 mL,
7.1 mmol). The mixture was stirred at room temperature for 10 h,
and concentrated. The resulting residue was dissolved in 50 mL
ethyl acetate, washed with water (3ꢁ30 mL), brine (50 mL), and
dried (MgSO)4. Filtration and evaporation afforded a residue, which
was chromatographed over silica gel, eluted with hexane/ethyl
acetate 3:2 to give 12 in 1.0 g, 70% yield. Mp 140–142 ꢀC; IR (KBr)
3.1.12. 3-[(2-Methyl-propenyl)-oxazol-5-yl]-1H-indole
(10d). General procedure B was used to prepare alkyl oxazole indole
10d from 9d (0.10 g, 0.39 mmol) affording compound 10d (0.081 g,
87% yield); mp 128–131 ꢀC; IR (KBr) 3166, 2368, 2344, 1631 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6)
d
11.56 (1H, br s), 7.84 (1H, br d,
3300, 1699, 1571, 1416 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d 11.96
J¼7.8 Hz), 7.74 (1H, d, J¼2.8 Hz), 7.45 (1H, br d, J¼8.2 Hz), 7.43
(1H, br s), 8.66 (1H, d, J¼3.0 Hz), 8.45 (1H, s), 8.05 (1H, br d,
J¼7.4 Hz), 7.53 (1H, br d, J¼7.2 Hz), 7.24 (1H, td, J¼7.3, 1.8 Hz), 7.19
(1H, td, J¼7.3, 1.8 Hz), 3.84 (3H, s); 13C NMR (100.1 MHz, DMSO-d6)
(1H, s), 7.18 (1H, br t, J¼7.8 Hz), 7.12 (1H, br t, J¼7.8 Hz), 6.19 (1H, s),
2.23 (3H, s), 1.96 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d 158.3 (s),
146.2 (s), 144.1 (s), 136.4 (s), 123.5 (s), 123.2 (d), 122.1 (d), 120.2 (d),
120.1 (d), 119.4 (d), 112.1 (d), 111.3 (d), 103.8 (s), 26.7 (q), 20.3 (q);
MS m/z (relative intensity)¼238(Mþþ1, 100), 209 (3), 182 (3), 168
(3), 144 (5), 136 (3); HRMS calcd for C15H15N2O (Mþþ1): 239.1184;
found: 239.1182.
d 163.5 (s), 154.9 (s), 149.6 (d),136.9 (s), 130.9 (d), 125.6 (s), 122.6 (s),
123.5 (d), 121.3 (d), 121.9 (d), 113.3 (d), 103.0 (s), 52.4 (q); MS m/z
(relative intensity)¼242 (Mþþ1, 100), 211 (60), 154 (45), 136 (33);
HRMS calcd for C13H12N2O3 (Mþþ1): 244.0848; found: 244.0845.
3.1.16.
b-Oxotryptophan methyl ester (13). Methyl 5-(3-indolyl)
3.1.13. {1-[5-(1H-Indol-3-yl)-oxazol-2-phenyl-ethyl}-dimethyl-
amine (10e). A mixture of 9e (0.10 g, 0.29 mmol) in 5 mL of POCl3
was stirred at 80 ꢀC for 2 h. Concentration under vacuo afforded
a residue that was dissolved in 50 mL of ethyl acetate, washed
with saturated aqueous NaHCO3 (50 mL), brine (3ꢁ50 mL), dried
(MgSO4), and filtered. Upon concentration of the filtrate under
reduced pressure, 10e crystallized from the solution. The product
was collected by filtration and washed with hexane and ether to
give 9e (0.048 g, 50% yield); mp 115–117 ꢀC; 1H NMR (300 MHz,
oxazole-4-carboxylate 12 (0.8 g, 3.3 mmol) was dissolved in the
mixture of methanol (30 mL) and hydrochloric acid (3 mL). The
mixture was stirred at 60 ꢀC for three days and concentrated.
Methanol was removed by evaporation and the reaction mixture
was purified by flash chromatography using a 19:1–9:1 gradient of
CH2Cl2/MeOH (NH3) as the eluent to
(0.58 g, 2.51 mmol, 76%) as a brown solid. Compound 13 free base;
IR (KBr) 3342, 3277, 1736, 1651, 1618, 1521 cmꢂ1 1H NMR
(300 MHz, DMSO-d6) 12.14 (1H, br s), 8.47 (1H, s), 8.17–8.11 (1H,
b-oxotryptophan methyl ester
;
d
CDCl3)
d
8.48 (1H, br s), 7.84–7.81 (1H, br d, J¼7.3 Hz), 7.52 (1H, d,
m), 7.51–7.48 (1H, m), 7.26–7.18 (2H, m), 5.03 (1H, s), 3.59 (3H, s),
J¼2.6 Hz), 7.45–7.43 (1H, br d, J¼5.7 Hz), 7.21 (1H, s), 7.32–7.14
(7H, m), 4.09 (1H, dd, J¼9.6, 5.5 Hz), 3.42 (1H, dd, J¼13.5, 9.6 Hz),
3.24 (1H, dd, J¼13.5, 5.5 Hz), 2.43 (6H, s). 1H NMR (400 MHz,
3.36 (1H, q), 2.38 (2H, br s), 1.08 (1H, t); 13C NMR (100.1 MHz,
DMSO-d6)
d 190.7 (s), 172.7 (s), 137.5 (s), 136.7 (d), 126.5 (s), 124.1
(d), 123.0 (d), 122.1 (d), 115.1 (s), 113.2 (d), 61.3 (d), 53.4 (q). Com-
CDCl3)
d
8.68 (1H, br s), 7.85 (1H, br d, J¼7.5 Hz), 7.54 (1H, d,
pound 13$HCl salt; mp 165–170 ꢀC; 1H NMR (300 MHz, DMSO-d6)
J¼2.4 Hz), 7.46 (1H, br d, J¼7.7 Hz), 7.24 (1H, s), 7.34–7.17 (7H, m),
4.13 (1H, dd, J¼9.7, 5.3 Hz), 3.45 (1H, dd, J¼13.5, 9.7 Hz), 3.28 (1H,
dd, J¼13.5, 5.3 Hz), 2.47 (6H, s). 1H NMR (300 MHz, acetone-d6)
d
12.75 (1H, d, J¼2.6 Hz), 9.03 (2H, s), 8.74 (1H, d, J¼3.3 Hz),
8.15–8.12 (1H, m), 7.57–7.54 (1H, m), 7.31–7.23 (2H, m), 3.71 (3H, s),
3.36 (1H, q),1.08 (1H, t); 13C NMR (100.1 MHz, DMSO-d6)
182.5 (s),
d
d
10.67 (1H, br s), 7.90–7.88 (1H, br d, J¼7.2 Hz), 7.74 (1H, d,
166.5 (s), 139.1 (d), 137.7 (s), 126.3 (s), 124.6 (d), 123.7 (d), 121.9 (d),
114.5 (s), 113.7 (d), 57.9 (d), 54.5 (q); HRMS calcd for C13H13N2O3
(Mþþ1): 233.0926; found: 233.0922.
J¼2.6 Hz), 7.52–7.49 (1H, br d, J¼5.8 Hz), 7.26 (1H, s), 7.29–7.10
(7H, m), 4.08 (1H, dd, J¼9.2, 6.1 Hz), 3.38 (1H, dd, J¼13.6, 9.1 Hz),
3.20 (1H, dd, J¼13.6, 6.1 Hz), 2.36 (6H, s); 13C NMR (75 MHz,
acetone-d6)
d
160.4 (s), 148.4 (s), 139.6 (s), 137.2 (s), 129.6 (dꢁ2),
3.1.17. N-(N,N-Dimethyl-
L
-phenylalanyl)-
b
-oxotryptophan
methyl
128.5 (dꢁ2), 126.4 (d), 124.6 (s), 123.2 (d), 122.8 (d), 120.7 (d),
112.3 (d), 105.4 (s), 64.6 (d), 41.5 (qꢁ2), 37.0 (t); MS m/z (relative
intensity)¼332 (Mþþ1, 55), 287 (100), 240 (30), 136 (45), 107
(15); HRMS calcd for C21H22N3O (Mþþ1): 332.1763; found:
332.1766.
ester (14). To a stirred solution of
b
-oxotryptamine 8$HCl (1.0 g,
4.27 mmol) in 100 mL of THF was added triethylamine (1.79 mL,
12.28 mmol) at 0 ꢀC, and the solution was stirred for 30 min. To the
mixture was then added diethyl pyrocarbonate (0.69 mL,
4.69 mmol), the mixture was stirred for 30 min. To the mixture was
added N,N-dimethyl-L-phenylalanine (0.90 g, 4.70 mmol) and stir-
3.1.14. Almazole C (3). A mixture of 5 (0.1 g, 0.29 mmol) in 5 mL of
POCl3 was stirred at 60 ꢀC for two days. Concentration under
reduced pressure afforded a residue that was dissolved in 50 mL of
ethyl acetate, washed with saturated aqueous NaHCO3 (50 mL),
brine (3ꢁ50 mL), dried (MgSO4), and filtered. Upon concentration
of the filtrate under reduced pressure, 3 crystallized from the
solution. The product was filtrated and washed with hexane and
ether to give 3 in 0.045 g, 50% yield: mp 115–117 ꢀC; 1H NMR
red at 23 ꢀC under nitrogen. After 12 h, the reaction was concen-
trated under vacuum. The residual product was dissolved in 100 mL
ethyl acetate, and washed with brine (2ꢁ50 mL), and dried
(MgSO4). Filtration and evaporation afforded a residue, which was
chromatographed over silica gel, eluted with DCM/MeOH 49:1 to
give 14 in 1.05 g, 60% yield: compound 14 Down; IR (KBr) 3366,
3250, 1751, 1654, 1647, 1498 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
.
d
12.15 (1H, br s), 8.69–8.66 (1H, br d, J¼7.7 Hz), 8.26 (1H, d,
(300 MHz, acetone-d6)
d
10.67 (1H, br s), 7.90–7.88 (1H, br d,
J¼1.8 Hz), 8.11–8.08 (1H, br d, J¼7.7 Hz), 7.52–7.49 (1H, br d,
J¼7.7 Hz), 7.27–7.01 (6H, m), 5.90 (1H, d, J¼7.7 Hz), 3.64 (3H, s), 3.51
(1H, dd, J¼8.6, 5.6 Hz), 2.95 (1H, dd, J¼13.4, 8.6 Hz), 2.74 (1H, dd,
J¼7.2 Hz), 7.74 (1H, d, J¼2.6 Hz), 7.52–7.49 (1H, br d, J¼5.8 Hz), 7.26
(1H, s), 7.29–7.10 (7H, m), 4.08 (1H, dd, J¼9.2, 6.1 Hz), 3.38 (1H, dd,
J¼13.6, 9.1 Hz), 3.20 (1H, dd, J¼13.6, 6.1 Hz), 2.36 (6H, s); 13C NMR
J¼13.2, 5.6 Hz), 2.30 (3H, s); 13C NMR (100.1 MHz, DMSO-d6)
d 186.4
(75 MHz, acetone-d6)
d
160.4 (s), 148.4 (s), 139.6 (s), 137.2 (s), 129.6
(s), 171.2 (s), 169.4 (s), 140.1 (s), 137.6 (s), 137.1 (d), 129.9 (d), 128.8
(d), 126.6 (d), 126.4 (d), 124.3 (d), 123.2 (d), 122.0 (d), 114.6 (s), 113.3
(d), 68.5 (d), 59.2 (d), 53.2 (q), 42.2 (q), 34.7 (t). Compound 14 Up;
(dꢁ2), 128.5 (dꢁ2), 126.4 (d), 124.6 (s), 123.2 (d), 122.8 (d), 120.7
(d), 112.3 (d), 105.4 (s), 64.6 (d), 41.5 (qꢁ2), 37.0 (t); MS m/z

F. Miyake et al. / Tetrahedron 66 (2010) 4888–4893
4893
1H NMR (300 MHz, DMSO-d6)
d
12.22 (1H, br s), 8.68–8.65 (1H, br d,
(3H, s) ppm; 13C NMR (75 MHz, CD3OD-d6)
d
167.2 (s), 156.8 (s),
J¼7.7 Hz), 8.48 (1H, d, J¼2.7 Hz), 8.14–8.11 (1H, br d, J¼7.7 Hz),
7.52–7.49 (1H, br d, J¼7.7 Hz), 7.27–7.01 (6H, m), 5.97 (1H, d,
J¼7.7 Hz), 3.59 (3H, s), 3.51 (1H, dd, J¼8.6, 5.6 Hz), 2.96 (1H, dd,
J¼13.4, 8.6 Hz), 2.78 (1H, dd, J¼13.2, 5.6 Hz), 2.20 (3H, s); 13C NMR
153.3 (s), 137.6 (s), 136.7 (s), 129.8 (d), 129.2 (dꢁ2), 128.6 (dꢁ2),
126.8 (d), 125.6 (s), 122.5 (s), 120.9 (d), 120.7 (d), 111.9 (s), 103.6 (s),
65.0 (d), 41.3 (qꢁ2), 36.9 (t); MS m/z (relative intensity)¼391
(Mþþ1, 12), 376 (90), 331 (100), 307 (70), 284 (35), 219 (18), 148
(40); HRMS calcd for C22H22N3O3 (Mþþ1): 376.1662; found:
376.1661.
(100.1 MHz, DMSO-d6) d 186.6 (s), 171.4 (s), 169.2 (s), 140.1 (s), 137.6
(s), 137.2 (d), 129.9 (d), 128.9 (d), 126.7 (d), 126.4 (d), 124.3 (d), 123.2
(d), 122.0 (d), 114.6 (s), 113.3 (d), 68.5 (d), 59.2 (d), 53.3 (q), 42.3(q),
34.7 (t); MS m/z (relative intensity)¼408 (Mþþ1, 58), 316 (20), 154
(75), 148 (100); HRMS calcd for C23H26N3O4 (Mþþ1): 408.1923;
found: 408.1921.
3.1.21. Almazole D, 2-[1-(dimethylamino)-2-phenylethyl]-5-(3-in-
23
dolyl)oxazole-4-carboxylic acid sodium salt (6). [
a
]
þ31, UV lmax
D
(MeOH) 208, 278, 310 nm. 1H NMR (400 MHz, CD3OD-d6, NaOH in
D2O)
d
8.71 (1H, s), 8.06 (1H, br s, J¼7.4 Hz), 7.47 (1H, br d, J¼7.4 Hz),
3.1.18. Almazole D methyl ester; methyl 2-[1-(dimethylamino)-2-
phenylethyl]-5-(3-indolyl)oxazole-4-carboxylate (15). A mixture of
14 (0.4 g, 0.98 mmol) in 5 mL of POCl3 was stirred at 60 ꢀC. The
mixture was stirred for seven days, and concentrated. The residual
product was dissolved in 50 mL of ethyl acetate, washed with
saturated aqueous NaHCO3 (3ꢁ50 mL) and washed with brine
(2ꢁ50 mL), and dried (MgSO4). Filtration and evaporation afforded
a residue, which was chromatographed over silica gel, eluted with
DCM/MeOH 49:1 to give 15 as colorless solid in 0.19 g, 50% yield
7.24–7.09 (7H, m), 4.08 (1H, dd, J¼10.8, 4.7 Hz), 3.48 (1H, dd, J¼13.1,
11.0 Hz), 3.31 (1H, dd, J¼13.1, 4.7 Hz); 13C NMR (100.1 MHz,
CD3OD-d6, NaOH in D2O)
d 169.5 (s), 157.4 (s), 151.2 (s), 138.0 (s),
136.7 (s), 129.19 (s), 129.15 (dꢁ2), 129.09 (d), 128.5 (dꢁ2), 126.7 (d),
125.7 (s), 122.2 (d), 120.9 (d), 120.7 (d), 120.5 (d), 111.8 (d), 104.1 (s),
65.3 (d), 41.6 (qꢁ2), 37.3 (t).
Acknowledgements
and recovered starting material: compound 15 mp 135–139 ꢀC,
Financial support from Chugai Pharmaceutical Co. is gratefully
acknowledged. The authors thank Professor Graziano Guella
providing authentic spectra of natural almazole D for spectral
comparison.
23
[
a]
þ115 (c 0.105, MeOH). UV lmax (MeOH) 203, 218, 254, 272,
D
331 nm. IR (KBr) 3333, 2380, 2345, 1690, 1588, 1568, 1458 cmꢂ1; 1H
NMR (300 MHz, CD3OD-d6) 8.71 (1H, s), 8.15–8.11 (1H, m), 7.51–
d
7.48 (1H, m), 7.29–7.20 (2H, m), 7.20–7.10 (5H, m), 4.87 (3H, s), 4.13
(1H, dd, J¼10.7, 5.1 Hz), 3.90 (2H, s), 3.46 (1H, dd, J¼13.3, 10.7), 3.30
(3H, dd, J¼13.3, 5.1 Hz), 2.46 (3H, s); 13C NMR (75 MHz, CD3OD-d6)
Supplementary data
d
163.2 (s), 158.5 (s), 155.7 (s), 137.8 (s), 136.8 (s), 130.4 (d), 129.0
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.109.
(dꢁ2), 128.5 (dꢁ2), 126.7 (d), 125.4 (s), 122.9 (d), 121.8 (s), 121.4 (d),
120.7 (d), 112.1 (d), 102.9 (s), 65.0 (d), 51.2 (q), 41.4 (qꢁ2), 37.0 (t);
MS m/z (relative intensity)¼390 (Mþþ1, 23), 345 (77), 298 (100),
154 (50), 148 (49); HRMS calcd for C23H25N3O3 (Mþþ1): 391.1897;
found: 391.1898.
References and notes
1. N’Diaye, I.; Guella, G.; Mancini, I.; Pietra, F. Tetrahedron Lett. 1996, 37,
3049–3050.
3.1.19. Almazole D; 2-[1-(N,N-dimethyl)-2-phenylethyl]-5-(3-in-
dolyl)oxazole-4-carboxylic acid (16). To the mixture of methanol
(15 mL) and 3 N aqueous KOH solution (2 mL) was added 15 (0.1 g,
0.26 mmol) at room temperature for 10 h. The pH of resulting
mixture was adjusted to 4 by addition of concd HCl and white
precipitates 16 were formed. The precipitation was filtered and
washed with water. Almazole D 16$HCl was converted to free base
17 by flash chromatography (DCM/MeOH–NH3 4:6) in 0.09 g, 90%
yield. The addition of 1 N of NaOH solution to free base 17 provided
almazole D 6 in 85 mg, 85% yield.
2. Guella, G.; Mancini, I.; N’Diaye, I.; Pietra, F. Helv. Chim. Acta 1994, 77, 1999–2006.
3. (a) Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.; Fujita, D.; Kiuchi, F.;
Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 1527–1529; (b) Nishida, A.; Fuwa, M.;
Fujikawa, Y.; Nakahata, E.; Furuno, A.; Nakagawa, M. Tetrahedron Lett. 1998,
39, 5983–5986; (c) Nishida, A.; Fuwa, M.; Naruto, S.; Sugano, Y.; Saito, H.;
Nakagawa, M. Tetrahedron Lett. 2000, 41, 4791–4794.
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5. Boyd, G. V. Sci. Synth. 2002, 11, 383–479.
6. A mild cyclodehydration procedure of a-acylamino ketones with epimerizable
centers has been reported using Ph3P and I2. Wipf, P.; Miller, C. P. J. Org. Chem.
1993, 58, 3604–3606.
7. Hogan, I. T.; Sainsbury, M. Tetrahedron 1984, 40, 681–682.
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549–555; (b) Koyama, Y.; Yokose, K.; Dolby, L. J. Agric. Biol. Chem. 1981, 45,
1285–1287; (c) Yoshioka, T.; Mohri, K.; Oikawa, Y.; Yonemitsu, O. J. Chem. Res.,
Miniprint 1981, 2252–2281; (d) Doyle, K.; Moody, C. J. Synthesis 1994,
1021–1022.
9. (a) Umehara, K.; Yoshida, K.; Okamoto, M.; Iwami, M.; Tanaka, H.; Kohsaka, M.;
Imanaka, H. J. Antibiot. 1984, 37, 1153–1160; (b) Structure revision of APHEs:
Kelly, T. R.; Fu, Y.; Xie, R. L. Tetrahedron Lett. 1999, 40, 1857–1860.
10. Yamada, S.; Kasai, Y.; Shioiri, T. Tetrahedron Lett. 1973, 1595–1598.
11. (a) Baxter, C. A. R.; Richards, H. C. Tetrahedron Lett. 1972, 3357–3358; (b) Belvisi,
L.; Gennari, C.; Poli, G.; Scolastico, C.; Salom, B. Tetrahedron: Asymmetry 1993, 4,
273–280; (c) Pellegrini, C.; Strassler, C.; Weber, M.; Borschberg, H.-J. Tetrahe-
dron: Asymmetry 1994, 5, 1979–1992.
3.1.20. Almazole D; 2-[1-(N,N-dimethyl)-2-phenylethyl]-5-(3-in-
dolyl)oxazole-4-carboxylic acid (16)-HCl salt. 1H NMR (300 MHz,
CD3OD-d6)
d
8.71 (1H, s), 7.86 (1H, br d, J¼7.4 Hz), 7.46 (1H, br d,
J¼7.4 Hz), 7.30–7.15 (7H, m), 5.18 (1H, t, J¼8.1 Hz), 4.88 (3H, s), 3.64
(1H, d, J¼8.2 Hz), 3.13 (3H, s) ppm; 13C NMR (75 MHz, CD3OD-d6)
d
163.8 (s), 156.9 (s), 151.9 (s), 136.8 (s), 134.1 (s), 131.3 (d), 129.3
(dꢁ2), 129.1 (dꢁ2), 127.9 (d), 125.2 (s), 123.6 (s), 123.1 (d), 121.5 (d),
120.7 (d), 112.1 (d), 102.4 (s), 64.0 (d), 40.8 (qꢁ2), 35.0 (t); com-
pound 17 free base: UV lmax (MeOH) 212, 271, 330 nm. IR (KBr)
3421, 2362, 2342, 1618, 1597 cmꢂ1 1H NMR (300 MHz, CD3OD-d6)
;
12. Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura, K.; Matsumoto, K. J. Org. Chem.
1973, 38, 3571–3575.
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d
8.71 (1H, s), 8.07–8.05 (1H, m), 7.47–7.44 (1H, m), 7.24–7.09 (7H,
m), 4.26 (1H, dd, J¼10.8, 4.8 Hz), 3.48 (1H, dd, J¼13.0, 10.8 Hz), 2.54