Spiroquinazoline support studies: methods for the preparation of imidazoloindolines from oxindoles

Article abstract of DOI:10.1016/j.tet.2006.06.103

Two methods for the annulation of glycine to the 1 and 2 positions of oxindoles are described. The first method involves introduction of an α-azidoacetyl group on the oxindole nitrogen followed by an intramolecular Staudinger reaction to complete the annu

Full text of DOI:10.1016/j.tet.2006.06.103

Tetrahedron 62 (2006) 8748–8754
Spiroquinazoline support studies: methods for the preparation
of imidazoloindolines from oxindoles
!
*
Yomadis A. Ortiz Barbosa, David J. Hart and Nabi A. Magomedov
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA
Received 24 April 2006; revised 27 June 2006; accepted 29 June 2006
Available online 25 July 2006
Abstract—Two methods for the annulation of glycine to the 1 and 2 positions of oxindoles are described. The first method involves intro-
duction of an a-azidoacetyl group on the oxindole nitrogen followed by an intramolecular Staudinger reaction to complete the annulation.
The second method involves acylation of the oxindole nitrogen with an N-Cbz–glycine derivative followed by reduction of the oxindole
carbonyl group and subsequent cyclization to provide an imidazoloindoline.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Imidazoloindolines appear as a substructure in a variety
of alkaloids including the tryptoquivalines,1 asperlicins,2
and fumiquinazolines.3 Several years ago we hoped to
accomplish the synthesis of structurally unique alkaloid
spiroquinazoline (2)4 from the spirooxindole alkaloid
alantrypinone (1) via reductive annulation of a glycine resi-
due to the 1 and 2 positions of an oxindole (Fig. 1).5,6 In
Figure 1. Alantrypinone (1) and Spiroquinazoline (2).
support of this idea we developed several methods for
accomplishing this task. This paper describes the results of
these studies and introduces p-nitrophenyl 2-azidoacetate
An alternative method for converting 3 into 7 involved initial
acylation of the anion derived from 3 with p-nitrophenyl
N-Cbz–glycinate10 to provide imide 8 in 88% yield. It is
notable that in structurally related N-acyl oxindoles with
gem-dimethyl substitution at Ca, the N-Cbz group readily
adds to the oxindole carbonyl group.11 Compound 8 exists
entirely in the acyclic form as shown in Scheme 1. It was
speculated that treatment of 8 with triethylsilane in the pres-
ence of an appropriate acid might effect sequential cycliza-
tion of the glycine derived nitrogen onto the oxindole
carbonyl group, ionization of the resulting carbinol, and
reduction of the resulting N-acyliminium ion to provide
7.10 In reality, treatment of 8 with triethylsilane (4 equiv)
in dichloromethane/trifluoroacetic acid (10:1) provided
only deacylation product 3. Treatment of 8 with boron tri-
fluoride etherate (8 equiv) and triethylsilane (2 equiv) in
dichloromethane at room temperature returned only the
starting imide. On the other hand, saturation of a dichloro-
methane solution of 8 with BF3 gas at ꢀ78 ꢁC in the pres-
ence of triethylsilane (2 equiv), followed by gradual
addition of another 4 equiv of triethylsilane and an aqueous
workup, gave carbinol 9 in 79% yield. Treatment of 9 with
p-toluenesulfonicacidinbenzeneprovided10andhydrogeno-
lysis of the N-Cbz group provided 7 in 98% overall yield.
as a new reagent for the N-acylation of amides.
2. Results and discussion
Our initial studies focused on the transformation of 3,3-di-
methyloxindole (3) to imidazoloindoline 7 and involved an
intramolecular Staudinger reaction largely developed by
Eguchi for use in heterocycle synthesis (Scheme 1).6,7
Thus, the anion derived from deprotonation of known oxin-
dole 38 was acylated using a-chloroacetyl chloride to provide
4 in 90% yield. Treatment of 4 with sodium azide in DMSO
gave 5 in 70% yield along with 10% of oxindole 3. Thus
imide N-deacylation is a minor problem in this reaction.
Treatment of 5 with triphenylphosphine provided the
expected intramolecular Staudinger product 6 in 92% yield.
Borch reduction of 6 with sodium cyanoborohydride com-
pleted the desired four-step annulation and provided 7 in
quantitative yield.9
* Corresponding author. Tel.: +1 614 292 1677; fax: +1 614 292 1685;
e-mail: hart@chemistry.ohio-state.edu
Deceased February 7, 2006.
!
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.103

Y. A. Ortiz Barbosa et al. / Tetrahedron 62 (2006) 8748–8754
8749
chloride and anthracene provided acid chloride 11. Reduc-
tion of 11 with lithium aluminum hydride provided alcohol
12 in 91% overall yield from anthracene.12 Swern oxidation
of 12 provided 13 in 75% yield,13,14 and treatment of 13 with
phenylhydrazine in the presence of boron trifluoride etherate
gave indole 14 in 63% yield.15 The regiochemistry of the
indole was established using difference NOE experiments.
For example irradiation of Ha led to enhancement of the
signal for the adjacent methylene and irradiation of Hb led
to enhancement of the indole NH. Ring contraction of 14
to oxindole 16 was accomplished using a standard procedure
followed by reduction of the intermediate aryl bromide 15
using platinum on carbon.5,16 It is notable that H4 of the
oxindole aromatic ring in 15 appeared as an upfield singlet
(d 5.0), as one would expect based on its position relative
to the dihydroanthracene substructure, and as observed for
the analogous proton in 21-epi-alantrypinone.5 The chemical
shift of this proton served as an analytical landmark through
the remainder of the chemistry described in this paper.
We next examined the intramolecular Staudinger annulation
protocol as described in Scheme 3.6 Acylation of the anion
derived from 16 with chloroacetyl chloride provided imide
17 in 40% yield. Treatment of 17 with sodium azide in
DMSO, however, failed to provide the desired azide 18.
Only oxindole 16 was obtained in 66% yield. Thus
N-deacylation was more problematic with 17 than with sub-
strate 4 (Scheme 1). Introduction of the azido group in the
acylating agent circumvented this problem. Rather than
using the well known, but hazardous, azidoacetyl chloride
as an acylating agent,17 we decided to examine p-nitrophenyl
azidoacetate (19) as an acylating agent. This new crystalline
reagent was prepared by DCC coupling of azidoacetic acid18
with p-nitrophenol in 64% yield. Sequential treatment of
Scheme 1. Two methods for preparing 7 from oxindole 3: (a) n-BuLi, THF,
ꢀ78 ꢁC; ClCH2COCl (5 equiv), ꢀ78 ꢁC; (b) NaN3 (4 equiv), DMSO, rt,
20 min; (c) Ph3P (1.1 equiv), PhH, rt, 2 h; (d) NaBH3CN, MeOH, aq HCl,
pH 4, rt; (e) n-BuLi, THF, ꢀ78 ꢁC; CbzNHCH2CO2PNP (1.5 equiv),
ꢀ78 ꢁC; (f) Et3SiH (6 equiv), BF3 (excess), CH2Cl2, ꢀ78 ꢁC; (g) p-TsOH
monohydrate, PhH, 80 ꢁC, 30 min and (h) H2 (1 atm), 10% Pd/C, EtOAc,
3 h.
Our next studies focused on a substrate more closely related
to alantrypinone. Thus oxindole 16 was prepared as shown in
Scheme 2.6 The Diels–Alder reaction between acryloyl
Scheme 2. Preparation of oxindole 16.
Scheme 3. Preparation of 21.

8750
Y. A. Ortiz Barbosa et al. / Tetrahedron 62 (2006) 8748–8754
oxindole 16 with n-BuLi and 19 provided 18 in 40% yield.
Treatment of 18 with a slight excess of triphenylphosphine
in benzene at room temperature gave a 37% yield of crystal-
line cyclization product 20 along with 11% of oxindole 16.
Thus, imide deacylation, as with 4 and 17, was once again
a problem. It is also notable that 20 underwent nearly com-
plete conversion to anthracene upon standing in CDCl3 for
2 h. Nonetheless, reduction of 20 using the Borch conditions
provided 21 and the corresponding C2 epimer in 78% yield as
a 5:1 mixture, respectively.9 Pure 21 (43%) and its epimer
(4%) were isolated and difference NOE experiments were
used to assign stereochemistry at C2. For example, irradia-
tion of Hc in 21 showed an enhancement of 3.7% at Hd and
of 2.5% at the NH. On the other hand, irradiation of Hc in
the C2 diastereomer of 21 showed an enhancement of 3.3%
at Hb and of 2.0% at the NH.
(9.50 mmol) of freshly distilled chloroacetyl chloride was
added in one portion. The reaction mixture was stirred at
ꢀ78 ꢁC for 1 h, and then partitioned between 120 mL of
ethyl acetate and 30 mL of water. The organic layer was
sequentially washed with two 40-mL portions of saturated
aqueous NaHCO3, 30 mL of water, dried (MgSO4), and con-
centrated in vacuo. The residue was recrystallized from
a mixture of CH2Cl2 and hexanes to give 260 mg (58%) of
4 as a white crystalline solid. The mother liquor was concen-
trated and the residue was flash chromatographed over 10 g
of silica gel (EtOAc/hexanes, 1:3) to give additional 140 mg
(32%) of 4: mp 139.0–140.0 ꢁC (recrystallized from
1
CH2Cl2/hexanes); H NMR (CDCl3, 300 MHz) d 1.46 (s,
6H, 2CH3), 4.86 (s, 2H, CH2Cl), 7.23–7.26 (m, 2H, ArH),
7.28–7.37 (m, 1H, ArH), 8.24 (ddd, J¼8.1, 0.9, 0.9 Hz,
1H, H7).
Attempts to apply the annulation methods described above
for the conversion of alantrypinone to spiroquinazoline
have thus far met with failure. For example, the method
that relies on the regioselective reduction of imide 8 provides
a complex mixture of unidentifiable products when applied
to an appropriate alantrypinone derivative. Perhaps this is
not surprising given the presence of numerous Lewis basic
sites present in such derivatives. Although we were able to
prepare appropriate cyclization substrates from alantrypi-
none, we were not able to accomplish the key aza-Wittig
reaction. Instead, the deacylation reaction mentioned above
became dominant reaction pathway.
3.1.2. 1-(Azidoacetyl)-3,3-dimethyl-2-indolinone (5). To
a vigorously stirred solution of 435 mg (1.68 mmol) of 4 in
8 mL of DMSO was added 438 mg (6.73 mmol) of NaN3
in one portion. The reaction mixture was stirred at room tem-
perature for 20 min, then poured into 30 mL of water, and
extracted with 150 mL of ethyl acetate. The organic solution
was washed with four 30-mL portions of water, dried
(MgSO4), and concentrated invacuo to give an orange liquid,
which solidified under high vacuum (1 mm of Hg). The solid
was flash chromatographed over 15 g of silica gel (Et2O/hex-
anes, 1:3, then 1:2) to provide 380 mg (85%) of azide 5 as
a white solid in addition to 43 mg (10%) of oxindole 3. An
analytically pure sample of 5 as a white crystalline solid
(300 mg or about 80% recovery) was obtained by recrystal-
lization from a mixture of Et2O and hexanes: mp 101–
In spite of this disappointment, the research described herein
does provide two routes to analogs of spiroquinazoline. The
stereochemical course of the reduction of 20 is also notable
and suggests that stereochemical problems may accompany
attempts to access spiroquinazoline via reduction of an
acylimine. In addition, it was found that compound 10 was
a weak inhibitor of Substance-P binding to the human
NK-1 receptor, the biological activity that has (in part)
rendered spiroquinazoline an interesting target for total
synthesis.19 Nonetheless, the quest for other methods (and
variations of the methods described herein) for converting
alantrypinone to spiroquinazoline and related alkaloids20
continues in our laboratories.
1
102 ꢁC; IR (KBr) 2172, 2110, 1757, 1712, 1606 cmꢀ1; H
NMR (CDCl3, 300 MHz) d 1.45 (s, 6H, 2CH3), 4.62 (s,
2H, COCH2), 7.23–7.27 (m, 2H, ArH), 7.28–7.38 (m, 1H,
ArH), 8.28 (ddd, J¼8.1, 0.9, 0.9 Hz, 1H, H7); 13C NMR
(acetone-d6, 75.5 MHz) d 25.5 (q), 45.2 (s), 55.1 (t), 117.0
(d), 123.5 (d), 126.5 (d), 128.9 (d), 136.5 (s), 139.4 (s),
170.1 (s), 182.7 (s); mass-spectrum (EI), m/z (relative inten-
sity) 244 (M+, 16), 161 (100); Anal. calcd for C12H12N4O2:
C, 59.05; H, 4.96. Found: C, 59.18; H, 4.90.
3.1.3. 2,9-Dihydro-9,9-dimethyl-3H-imidazo[1,2-a]-
indole-3-one (6). To a stirred solution of 220 mg
(0.90 mmol) of azide 5 in 6 mL of benzene was added
260 mg (0.99 mmol) of solid triphenylphosphine in one por-
tion. The reaction mixture was stirred at room temperature
for 2 h, after which time TLC (silica gel, EtOAc/hexanes,
1:1) indicated complete consumption of starting material.
The reaction mixture was concentrated in vacuo and the resi-
due was flash chromatographed over 50 g of silica gel
(EtOAc/hexanes, 2:1) to give 165 mg (92%) of imidazoline
6 as a white solid. Sublimation at 1 mm of Hg and 100 ꢁC
provided an analytically pure sample of 6 as a white crystal-
line solid: mp 138–139 ꢁC (sublimed); IR (KBr) 1731, 1673,
1665, 1610 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d 1.56 (s, 6H,
2CH3), 4.53 (s, 2H, COCH2), 7.19 (ddd, J¼7.5, 7.5, 1.2 Hz,
1H, ArH), 7.29 (ddd, J¼7.5, 1.2, 0.6 Hz, 1H, ArH), 7.31
(ddd, J¼7.5, 7.5, 1.4 Hz, 1H, ArH), 7.60 (dm, J¼7.8 Hz,
1H, ArH); 13C NMR (CDCl3, 75.5 MHz) d 26.3 (q), 40.6
(s), 66.2 (t), 112.8 (d), 123.4 (d), 125.6 (d), 128.5 (d),
134.3 (s), 140.9 (s), 174.8 (s), 176.7 (s); mass-spectrum
(EI), m/z (relative intensity) 200 (M+, 44), 172 (100); Anal.
3. Experimental
3.1. General
All compounds were prepared as racemic mixtures. Melting
points are uncorrected. Solvents were dried using standard
protocols. All carbon multiplicities (s¼C, d¼CH, t¼CH2,
and q¼CH3) were determined using DEPT techniques.
COSY and NOE experiments were used to support NMR
peak assignments. Mass spectra were recorded using EI
(electron impact) or ESI (electrospray ionization) techniques
as indicated.
3.1.1. 1-(Chloroacetyl)-3,3-dimethyl-2-indolinone (4). To
a stirred solution of 310 mg (1.90 mmol) of oxindole 38 in
12 mL of dry THF, cooled to ꢀ78 ꢁC, was added dropwise
1.66 mL (2.66 mmol) of a 1.6 M solution of n-BuLi in hex-
anes over a period of 3 min. After 10 min at ꢀ78 ꢁC, 757 mL

Y. A. Ortiz Barbosa et al. / Tetrahedron 62 (2006) 8748–8754
8751
calcd for C12H12N2O: C, 72.03; H, 6.05. Found: C, 72.12; H,
6.29.
J¼8.1, 0.9, 0.9 Hz, 1H, H7); 13C NMR (DMSO-d6,
75.5 MHz) d 25.4 (q), 44.7 (s), 47.4 (t), 67.2 (t), 116.7 (d),
122.3 (d), 125.8 (d), 128.2 (d), 128.4 (d), 128.6 (d), 135.2
(s), 136.5 (s), 138.2 (s), 156.6 (s), 170.4 (s), 182.1 (s) (one
doublet was not seen due to overlap with other peaks);
mass-spectrum (EI), m/z (relative intensity) 352 (M+, 0.15),
161 (100); Anal. calcd for C20H20N2O4: C, 68.22; H, 5.72.
Found: C, 68.05; H, 5.71.
3.1.4. 1,2,9,9a-Tetrahydro-9,9-dimethyl-3H-imidazo[1,2-
a]indole-3-one (7). From 6: to a stirred solution of 145 mg
(0.725 mmol) of imidazoline 6, a tiny amount of bromo-
cresol green (just to get a green solution), and 45 mg
(0.750 mmol) of NaBH3CN (addition of hydride changes
green solution color to blue) in 10 mL of MeOH was added
dropwise 1 N aqueous HCl until the solution became yellow
(4–5 drops). Addition of HCl was continued whenever the
yellow solution turned blue. The reaction mixture was stirred
for 1 h at room temperature, after which time TLC (silica gel,
Et2O/Et3N, 95:5) still showed the presence of starting mate-
rial. Additional NaBH3CN (45 mg, 0.75 mmol) was added
until starting material was completely consumed. The reac-
tion mixture was partitioned between 150 mL of EtOAc
and 20 mL of saturated aqueous NaHCO3. The organic layer
was washed with 15 mL of water, dried (MgSO4), and con-
centrated in vacuo. The residue was chromatographed over
14 g of flash silica gel (Et2O/Et3N, 95:5) to give 146 mg
(100%) of 7 as a white solid. From 10: to a solution of
18 mg (0.054 mmol) of 10 in 5 mL of ethyl acetate was
added 20 mg of 10% Pd/C. The mixture was stirred at
room temperature under 1 atm of H2 for 3 h. Then the reac-
tion mixture was passed through a 1-cm pad of Celite and
concentrated in vacuo to give 11 mg (100%) of amine 7 as
a white solid. The hydrochloride of 7 was readily obtained
as a white crystalline solid by passing dry HCl through a
solution of 7 in ether. Hydrochloride: mp 203–204 ꢁC
(dec) (Et2O). Free base: mp 91.5–92.5 ꢁC; IR (KBr) 3304,
3.1.6. Benzyl [[(2-hydroxy-3,3-dimethyl-1-indolinyl)car-
bonyl]-methyl]carbamate (9). A solution of 81 mg
(0.23 mmol) of imide 8 and 80 mL (0.49 mmol) of Et3SiH
in 8 mL of CH2Cl2, cooled to ꢀ78 ꢁC, was saturated with
gaseous BF3. The resulting mixture was stirred at ꢀ78 ꢁC
for 2 h. TLC (EtOAc/hexanes, 1:1) indicated the presence
of starting material. Two 20-mL (0.12 mmol) portions of
Et3SiH were added over a period of 1 h to achieve complete
consumption of starting material. The reaction mixture was
poured into 100 mL of EtOAc and washed with two
30-mL portions of saturated aqueous NaHCO3. The organic
layer was dried (MgSO4) and concentrated in vacuo to give
85 mg of colorless amorphous residue. The residue was flash
chromatographed over 12 g of silica gel (EtOAc/hexanes,
1:2, then 1:1) to give 65 mg (79%) of 9 as a white solid (9
solidifies very slowly): mp 136–137 ꢁC: IR (KBr) 3395,
3385, 1699, 1673, 1598 cmꢀ1 1H NMR (Me2CO-d6,
;
300 MHz) d 1.21 (s, 3H, CH3), 1.44 (s, 3H, CH3), 4.36
(dd, J¼17.1, 5.6 Hz, 1H, COCHNH), 4.44 (dd, J¼17.1,
5.6 Hz, 1H, COCHHNH), 5.12 (s, 2H, OCH2), 5.50 (d,
J¼8.3 Hz, 1H, CHOH, exchangeable), 5.56 (d, J¼8.3 Hz,
1H, CHOH), 6.46 (dt, J¼5.6 Hz, 1H, NH), 7.06 (ddd,
J¼7.4, 7.4, 1.1 Hz, 1H, ArH), 7.19 (ddd, J¼7.7, 7.7,
1.4 Hz, 1H, ArH), 7.23 (dm, J¼7.4 Hz, 1H, ArH), 7.27–
7.42 (m, 5H, ArH), 8.08 (br d, J¼7.2 Hz, 1H, ArH); 13C
NMR (Me2CO-d6, 75.5 MHz) d 20.0 (q), 29.8 (q), 44.4 (t),
45.8 (s), 66.9 (t), 91.9 (d), 117.1 (d), 123.2 (d), 124.9 (d),
128.2 (d), 128.7 (d), 129.2 (d), 138.2 (s), 140.1 (s), 141.2
(s), 157.6 (s), 169.4 (s), one doublet was not seen due to
overlap with other signals; mass-spectrum (EI), m/z (relative
intensity) 354 (M+, 3.5), 91 (100); Anal. calcd for
C20H22N2O4: C, 67.83; H, 6.26. Found: C, 67.57; H, 6.37.
3253, 1708, 1693, 1604 cmꢀ1
;
1H NMR (MeCN-d3,
300 MHz) d 1.02 (s, 3H, CH3), 1.36 (s, 3H, CH3), 2.71
(br s, 1H, NH), 3.55 (d, J¼15.7 Hz, 1H, CHH), 3.94 (d,
J¼15.7 Hz, 1H, CHH), 5.21 (s, 1H, NHCH), 7.12 (tm, J¼
7.8 Hz, 1H, ArH), 7.2–7.26 (m, 2H, ArH), 7.38 (d,
J¼7.8 Hz, 1H, ArH); 13C NMR (C6D6, 75.5 MHz) d 23.7
(q), 24.9 (q), 44.6 (s), 54.5 (t), 88.5 (d), 116.2 (d), 123.4
(d), 125.4 (d), 128.4 (d), 138.0 (s), 143.6 (s), 170.9 (s);
mass-spectrum (EI), m/z (relative intensity) 202 (M+, 100);
Anal. calcd for C12H15ClN2O (hydrochloride): C, 60.54;
H, 6.35. Found: C, 60.30; H, 6.26.
3.1.7. Benzyl 2,3,9,9a-tetrahydro-9,9-dimethyl-3-oxo-
1H-imidazo[1,2-a]indole-3-carboxylate (10). To a solution
of 194 mg (0.54 mmol) of 9 in 30 mL of benzene was added
10 mg (10 mol %) of p-toluenesulfonic acid monohydrate.
The resulting mixture was refluxed for 30 min after which
time TLC (EtOAc/hexanes, 1:1) indicated complete con-
sumption of starting material. The reaction mixture was
cooled to room temperature, passed through a 1-cm pad of
basic alumina (Brockman activity II), and concentrated in
vacuo to give 180 mg (98%) of imidazolidine 10 as a thick
colorless liquid slowly solidifying into a white solid: mp
3.1.5. Benzyl [[(3,3-dimethyl-2-oxo-1-indolinyl)car-
bonyl]-methyl]carbamate (8). To a stirred solution of
175 mg (1.09 mmol) of oxindole 3 in 5 mL of dry THF,
cooled to ꢀ78 ꢁC, was added dropwise 885 mL of a 1.6 M
solution of n-BuLi in hexanes over a period of 2 min. After
10 min at ꢀ78 ꢁC, a solution of 538 mg (1.63 mmol) of
p-nitrophenyl N-Cbz–glycinate (10) in 3 mL of THF was
added by cannula. The reaction mixture was stirred at
ꢀ78 ꢁC for 20 min, and then left to warm to room tempera-
ture. After 4 h at room temperature, the reaction mixture
was dissolved in 150 mL of ethyl acetate and washed with
two 20-mL portions of 1 M aqueous sodium carbonate.
The organic layer was dried (MgSO4), concentrated invacuo,
and the residue was flash chromatographed over 14 g of silica
gel (EtOAc/hexanes, 1:3, then 1:2) to give 336 mg (88%) of
imide 8 as a white crystalline solid: mp 118.5–119.0 ꢁC; IR
67–68 ꢁC; IR (KBr) 1725, 1712, 1604 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz, 60 ꢁC) d 1.02 (s, 3H, CH3), 1.58 (br s,
3H, CH3), 4.18 (dd, J¼16.4, 1.8 Hz, 1H, COCHNH), 4.45
(d, J¼16.4 Hz, 1H, COCHHN), 5.22 (1/2 of AB quartet, J¼
12.2 Hz, 1H, OCHH), 5.27 (1/2 of AB quartet, J¼12.2 Hz,
1H, OCHH), 5.62 (d, J¼1.8 Hz, 1H, NCHN), 7.14–7.20
(m, 2H, ArH), 7.26 (ddd, J¼7.6, 5.5, 3.6 Hz, 1H, ArH),
7.34–7.41 (m, 5H, ArH), 7.51 (ddd, J¼7.6, 0.9, 0.9 Hz,
1H, ArH); 13C NMR (CDCl3, 75.5 MHz, 60 ꢁC) d 23.3 (q),
24.5 (q), 45.9 (s), 52.9 (t), 68.1 (t), 87.1 (d), 116.7 (d),
1
(KBr) 3434, 1756, 1724, 1699 cmꢀ1; H NMR (CDCl3,
300 MHz) d 1.45 (s, 6H, 2CH3), 4.70 (d, J¼5.6 Hz, 2H,
CH2NH), 5.17 (s, 2H, OCH2), 5.52 (br s, 1H, NH), 7.23–
7.26 (m, 2H, ArH), 7.27–7.38 (m, 6H, ArH), 8.23 (ddd,

8752
Y. A. Ortiz Barbosa et al. / Tetrahedron 62 (2006) 8748–8754
123.2 (d), 126.3 (d), 128.1 (d), 128.4 (d), 128.7 (d), 128.8 (d),
136.1 (s), 136.5 (s), 142.8 (s), 154.5 (s), 167.3 (s); mass-spec-
trum (EI), m/z (relative intensity) 336 (M+, 7), 91 (100);
Anal. calcd for C20H20N2O3: C, 71.46; H, 6.00. Found: C,
71.27; H, 5.99.
NMR (DMSO-d6, 62 MHz) d 39.9 (t), 43.5 (d), 51.8 (s),
52.0 (d), 111.1 (d), 112.7 (s), 123.0 (d), 123.9 (d), 125.41
(d), 125.49 (d), 126.0 (d), 126.5 (d), 126.8 (d), 127.1 (d),
130.5 (d), 136.6 (s), 139.6 (s), 141.14 (s), 141.16 (s), 144.1
(s), 144.2 (s), 179.2 (s) (one aromatic CH obscured by sol-
vent); exact mass (ESI) calcd for C23H16N79BrNa+: m/z
424.0307, observed; m/z 424.0329.
3.1.8. Indole 14. To a stirred solution of 9.0 g (38.5 mmol)
of aldehyde 13 in 100 mL of tetrahydrofuran was added
3.78 mL (4.16 g, 38.5 mmol) of phenylhydrazine. The reac-
tion mixture was stirred for 10 min after which 6.82 mL
(7.64 g, 53.85 mmol) of BF3$Et2O was added dropwise
over a period of 10 min. The reaction mixture was heated
at 80 ꢁC with stirring for 3.5 h. The reaction mixture was par-
titioned between 150 mL of chloroform and 35 mL of satu-
rated aqueous sodium bicarbonate. The organic layer was
washed with two 50-mL portions of saturated aqueous
sodium bicarbonate and two 50-mL portions of water. The
combined aqueous layers were extracted with 70 mL of chlo-
roform. The combined organic phases were dried (MgSO4)
and concentrated under reduced pressure to afford 11 g of
a dark orange solid. This solid was purified by column chro-
matography over 400 g of silica gel (sample loaded in
CH2Cl2 and eluted with hexanes/CH2Cl2, 99:1; then hex-
anes/CH2Cl2, 2:1; then EtOAc) to give 7.44 g (63%) of
indole 14 as a white solid: mp 295–296.5 ꢁC; IR (KBr)
3.1.10. Oxindole 16. To a stirred solution of 1.0 g
(3.26 mmol) of indole 14 in 100 mL of a mixture of THF/
TFA/H2O (60:20:20) cooled to 3 ꢁC was added 1.16 g
(6.51 mmol) of N-bromosuccinimide. The reaction was
allowed to reach room temperature and stirred for 16 h after
which it was filtered. The filtrate was partitioned between
150 mL of saturated aqueous sodium bicarbonate and
200 mL of ethyl acetate. The organic layer was washed
with two 50-mL portions of saturated aqueous sodium bicar-
bonate and two 40-mL portions of water, dried (MgSO4), and
concentrated under reduced pressure to afford 1.17 g of bro-
mooxindole 15 as a beige solid. To a stirred solution of 1.15 g
(2.71 mmol) of bromooxindole 15 in 770 mL of methanol
was added 4.64 g (56.6 mmol) sodium acetate, 9.3 mL
(9.76 g, 162.6 mmol) of acetic acid and 0.9 g of 5% platinum
on carbon. The system was placed under a hydrogen atmo-
sphere for 72 h. The reaction mixture was filtered through
a short pad of Celite 545 and the filtrate was concentrated
to give a white solid. The solid was partitioned between
200 mL of ethyl acetate and 50 mL of water. The organic
layer was washed with five 40-mL portions of water, dried
(MgSO4) and concentrated under reduced pressure to afford
0.99 g(83%) of oxindole 16 as awhite solid: mp 215–216 ꢁC;
IR (KBr) 3231, 1718 cmꢀ1; 1H NMR (DMSO-d6, 400 MHz)
d 1.83 (dd, J¼13.1, 2.0 Hz, 1H, CH2), 2.05 (dd, J¼13.1,
2.0 Hz, 1H, CH2), 4.04 (s, 1H, CH), 4.58 (t, J¼5.2 Hz, 1H,
CHCH2), 5.05 (d, J¼8.0 Hz, 1H, ArH), 6.55 (t, J¼7.0 Hz,
1H, ArH), 6.78 (d, J¼7.8 Hz, 1H, ArH), 6.98 (d, J¼7.0 Hz,
1H, ArH), 7.08 (m, 4H, ArH), 7.18 (d, J¼6.0 Hz, 1H,
ArH), 7.23 (td, J¼8.1, 1.0 Hz, 1H, ArH), 7.33 (d, J¼
6.0 Hz, 1H, ArH), 7.48 (d, J¼8.0 Hz, 1H, ArH), 10.25 (br
s, 1H, ArH); 13C NMR (DMSO-d6, 125 MHz) d 39.6 (t),
43.3 (d), 51.0 (s), 51.8 (d), 108.9 (d), 120.4 (d), 122.6 (d),
123.3 (d), 123.6 (d), 124.9 (d), 125.0 (d), 125.5 (d), 126.0
(d), 126.2 (d), 126.3 (d), 127.5 (d), 133.9 (s), 139.7 (s),
141.0 (s), 141.4 (s), 143.8 (s), 144.0 (s), 179.4 (s); exact
mass (ESI) calcd for C23H17NONa+: m/z 346.1202, found:
m/z 346.1200.
1
3388 cmꢀ1; H NMR (CDCl3, 500 MHz) d 3.22 (d, J¼
3.7 Hz, 2H, CH2), 4.47 (t, J¼3.6 Hz, 1H, CHCH2), 4.78 (s,
1H, CH), 6.98 (t, J¼9.0 Hz, 1H, ArH), 7.05 (t, J¼9.0 Hz,
1H, ArH), 7.13 (t, J¼8 Hz, 2H, ArH), 7.15 (t, J¼8.5 Hz,
2H, ArH), 7.21 (d, J¼7 Hz, 1H, ArH), 7.28 (m, 3H, ArH),
7.46 (d, J¼6 Hz, 2H, ArH), 7.96 (br s, 1H, NH); 13C NMR
(CDCl3, 100 MHz) d 31.1 (t), 46.4 (d), 47.4 (d), 104.4 (s),
111.0 (d), 117.8 (d), 119.9 (d), 121.6 (d), 124.4 (d), 126.5
(d), 127.0 (d), 127.2 (d), 130.1 (s), 134.5 (s), 136.5 (s),
141.6 (s), 144.7 (s); exact mass (ESI) calcd for
C23H17NNa+: m/z 330.1259, observed: m/z 330.1253. Anal.
calcd for C23H17N: C, 89.86; H, 5.58; N, 4.56. Found: C,
89.71; H, 5.82; N, 4.61.
3.1.9. Bromooxindole 15. To a stirred solution of 107.5 mg
(0.35 mmol) of indole 14 in 15 mL of a mixture of THF/TFA/
H2O (7:4:4) cooled to 3 ꢁC was added 62 mg (0.35 mmol) of
N-bromosuccinimide. The reaction was allowed to stir for
1.5 h at 2–3 ꢁC after which another 62 mg (0.35 mmol) of
N-bromosuccinimide was added. The reaction was allowed
to stir for a total of 7.5 h at 2–3 ꢁC. The reaction mixture
was partitioned between 50 mL of saturated aqueous sodium
bicarbonate and 200 mL of ethyl acetate. The organic layer
was washed with two 50-mL portions of water, dried
(MgSO4), and concentrated under reduced pressure to afford
121 mg of a beige solid. This material was normally used in
subsequent reactions without further purification. For char-
acterization purposes this solid was purified by column chro-
matography over 15 g of flash silica (eluted with hexanes/
ethyl acetate 9:1, then 4:1) to give 57 mg (53%) of bromo-
spirooxindole 15 as a white solid: mp 208–211 ꢁC; IR
3.1.11. p-Nitrophenyl a-azidoacetate (19). To a solution of
0.92 g (9.12 mmol) of azidoacetic acid in 10 mL of dichloro-
methane was added 1.15 g (8.29 mmol) of p-nitrophenol and
50 mg (0.415 mmol) of 4-dimethylaminopyridine. The solu-
tion was stirred for 5 min and 1.80 g (9.12 mmol) of DCC in
5 mL of dichloromethane was added dropwise over a period
of 30 min. The mixture was stirred for 2 h at room tempera-
ture. The resulting mixture was filtered and the filtrate was
concentrated to give a yellow solid. The residue was purified
by recrystallization from 90 mL of hexanes/ether (2:1) to
give 1.17 g (64%) of p-nitrophenyl a-azidoacetate (19) as
a white solid: mp 81–82.5 ꢁC; IR (KBr) 3111, 2115, 1763,
1
(KBr) 1716, 1614 cmꢀ1; H NMR (DMSO-d6, 400 MHz)
d 1.84 (dd, J¼11.2, 3.0 Hz, 1H, CH2), 2.03 (dd, J¼11.2,
3.0 Hz, 1H, CH2), 4.08 (s, 1H, CH), 4.60 (t, J¼8.2 Hz, 1H,
CHCH2), 5.01 (d, J¼2.1 Hz, 1H, ArH), 6.75 (d, J¼8.1 Hz,
1H, ArH), 7.08 (m, 4H, ArH), 7.19 (dd, J¼10.2, 2.0 Hz,
1H, ArH), 7.25 (m, 2H, ArH), 7.34 (d, J¼1.2 Hz, 1H,
ArH), 7.50 (d, J¼7.0 Hz, 1H, ArH), 10.4 (s, 1H, NH); 13C
1
1616 cmꢀ1; H NMR (CDCl3, 300 MHz) d 4.19 (s, 2H,
COCH2), 7.33–7.38 (m, 2H, ArH), 8.27–8.33 (m, 2H,
ArH); 13C NMR (CDCl3, 75.5 MHz) d 50.4 (t), 122.3 (d),
125.4 (d), 145.8 (s), 154.7 (s), 166.3 (s); mass-spectrum

Y. A. Ortiz Barbosa et al. / Tetrahedron 62 (2006) 8748–8754
8753
(EI), m/z (relative intensity) 222 (M+, 2), 109 (100); Anal.
calcd for C8H6N4O4: C, 43.28; H, 2.72. Found: C, 43.37;
H, 2.69.
22 mL of methanol, was added four drops of bromocresol
green indicator solution (0.04 g of the indicator in 100 mL
of 95% EtOH and 0.1 M aqueous NaOH until blue) and
21 mg (315 mmol) of sodium cyanoborohydride. The reac-
tion was kept at pH 4, maintaining the yellow color by the
dropwise addition of 3 N aqueous hydrochloric acid. The
reaction was stirred at room temperature for 5.5 h. The reac-
tion mixture was partitioned between 200 mL of ethyl ace-
tate and 60 mL of saturated aqueous sodium bicarbonate.
The organic layer was washed with two 50-mL portions of
saturated aqueous sodium bicarbonate and 30 mL of water,
dried (MgSO4), and concentrated under reduced pressure.
The residue was chromatographed over 30 g of silica (loaded
in EtOAc and eluted with EtOAc/hexanes, 1:3) to give
24.8 mg (43%) of imidazoloindoline 21 as a white solid,
18.2 mg of a 7:4:1 mixture of imidazoloindoline 21, the C2
epimers of 21 and oxindole 16, respectively, and 2 mg
(4%) of the C2 epimer of 21 as a white solid. Imidazoloindo-
3.1.12. Imide 18. To a stirred solution of 76 mg (0.24 mmol)
of spirooxindole 16 in 4 mL of tetrahydrofuran cooled to
ꢀ70 ꢁC was added 195 mL (0.27 mmol) of n-butyllithium
(1.3 M in hexanes). The solution was stirred for 20 min
and then 68 mg (0.31 mmol) of p-nitrophenyl a-azidoacetate
(19) in 2 mL of tetrahydrofuran was added. The reaction
mixture was stirred at ꢀ70 ꢁC for 30 min, then at room tem-
perature for 2 h. The reaction mixture was partitioned
between 60 mL of ethyl acetate and 20 mL of water. The
organic layer was washed with three 20-mL portions of
water, dried (MgSO4), and concentrated under reduced pres-
sure to afford 150 mg of solid. This solid was purified by col-
umn chromatography over 5 g of silica (eluted with EtOAc/
hexanes, 1:8, then 1:4) to give 33 mg (40%) of imide 18 as
a white solid: mp 169–171 ꢁC (dec); IR (KBr) 2120, 1753,
1
line 21: mp 259.5–260 ꢁC (dec); IR 3432, 1708 cmꢀ1; H
1
1716 cmꢀ1; H NMR (CDCl3, 250 MHz) d 1.94 (dd, J¼
NMR (C6D6, 500 MHz) d 0.43 (br s, 1H, NH), 1.70 (dd,
J¼12.9, 2.1 Hz, 1H, CH2), 2.10 (dd, J¼12.9, 2.1 Hz, 1H,
CH2), 3.13 (d, J¼14.3 Hz, 1H, CH2N), 3.41 (d, J¼
14.3 Hz, 1H, CH2N), 4.01 (t, J¼2.3 Hz, 1H, CHCH2), 4.14
(s, 1H, CHAr2), 4.52 (s, 1H, CHNH), 5.22 (d, J¼7.5 Hz,
1H, ArH), 6.53 (td, J¼7.7, 0.8 Hz, 1H, ArH), 6.62 (d,
J¼7.3 Hz, 1H, ArH), 6.88 (t, J¼7.8 Hz, 1H, ArH), 6.95
(m, 5H, ArH), 7.09 (d, J¼7.2 Hz, 2H, ArH), 7.87 (d,
J¼7.7 Hz, 1H, ArH); 13C NMR (C6D6, 125 MHz) d 45.0
(d), 45.8 (t), 50.3 (d), 52.3 (s), 54.2 (t), 88.6 (d), 114.3 (d),
122.9 (d), 123.3 (d), 123.7 (d), 125.2 (d), 125.5 (d), 125.6
(d), 125.8 (d), 126.3 (d), 127.2 (d), 137.5 (s), 141.3 (s),
142.0 (s), 142.5 (s), 145.1 (s), 145.6 (s), 168.5 (s), the
remaining two aromatic carbons (CH) were obscured by
the benzene; exact mass (ESI) calcd for C25H20N2ONa+:
m/z 387.1473, found: m/z 387.1547. Anal. calcd for
C25H20N2O: C, 82.38; H, 5.54; N, 7.69. Found: C, 82.32;
H, 5.82; N, 7.67. C2 epimer of 21: mp 265–267 ꢁC (dec);
1H NMR (C6D6, 400 MHz) d 0.40 (br s, 1H, NH), 1.24
(dd, J¼12.5, 2.2 Hz, 1H, CH2), 2.98 (dd, J¼12.5, 3.2 Hz,
1H, CH2), 3.06 (d, J¼1.2 Hz, 2H, CH2), 3.75 (s, 1H, CH),
3.94 (t, J¼2.6 Hz, 1H, CHCH2), 4.82 (br s, 1H, CHNH),
6.13 (d, J¼7.6 Hz, 1H, ArH), 6.65 (td, J¼7.6, 1.1 Hz, 1H,
ArH), 6.80 (m, 2H, ArH), 6.93 (m, 2H, ArH), 7.05 (m, 5H,
ArH), 7.85 (d, J¼8.0 Hz, 1H, ArH); 13C NMR (C6D6,
125 MHz) d 39.4 (t), 44.9 (d), 52.9 (t), 53.2 (s), 54.5 (d),
85.3 (d), 114.9 (d), 123.2 (d), 124.3 (d), 124.8 (d), 125.0
(d), 125.5 (d), 125.7 (d), 126.3 (d), 126.5 (d), 126.7 (d),
127.5 (d), 138.4 (s), 140.4 (s), 140.9 (s), 141.2 (s), 144.7
(s), 146.3 (s), 168.6 (s), the remaining aromatic carbon was
obscured by the benzene; exact mass (ESI) calcd for
C25H20N2ONa+: m/z 387.1473, found: m/z 387.1461.
12.6, 2.8 Hz, 1H, CH2), 2.26 (dd, J¼12.6, 2.8 Hz, 1H,
CH2), 3.96 (s, 1H, CHAr2), 4.39 (s, 2H, CH2N3), 4.47 (t, J¼
2.3 Hz, 1H, CHCH2), 5.25 (d, J¼7.6 Hz, 1H, ArH), 6.78 (d,
J¼7.3 Hz, 1H, ArH), 6.85 (d, J¼8.3 Hz, 1H, ArH), 7.12 (m,
6H, ArH), 7.35 (m, 2H, ArH), 8.13 (d, J¼8.1 Hz, 1H, ArH);
13C NMR (CDCl3, 62 MHz) d 41.1 (t), 44.2 (d), 52.4 (s), 53.9
(d), 54.6 (t), 115.8 (d), 123.1 (d), 123.5 (d), 124.0 (d), 125.0
(d), 125.7 (d), 125.9 (d), 126.8 (d), 126.9 (d), 127.1 (d), 128.3
(d), 132.7 (s), 138.1 (s), 138.4 (s), 139.1 (s), 143.3 (s), 143.8
(s), 168.4 (s), 179.2 (s) (one aromatic CH obscured by sol-
vent); exact mass (ESI) calcd for C25H18N4O2Na+: m/z
429.1321, found: m/z 429.1302.
3.1.13. N-Acylamidine 20. To a stirred solution of 129 mg
(0.32 mmol) of azide 18 in 4 mL of benzene was added
127 mg (0.47 mmol) of triphenylphosphine in 2 mL of benz-
ene. The mixture was stirred for 20 h. The resulting precip-
itate was collected by suction filtration to give 35 mg (32%)
of imidazolinone 20 as a white solid. The filtrate was concen-
trated in vacuo to give a mixture of oxindole 16, triphenyl-
phosphine oxide and N-acylamidine 20. The mixture was
purified by column chromatography over 10 g of silica
(eluted with EtOAc/Hexanes, 1:2) to give 13 mg (11%) of
oxindole 16 and 5.9 mg (5%) of N-acylamidine 20 as a white
solid: mp 202–203 ꢁC (dec); IR (KBr) 1737, 1654 cmꢀ1; 1H
NMR (C6D6, 400 MHz) d 1.85 (dd, J¼12.6, 2.8 Hz, 1H,
CH2CH), 2.32 (dd, J¼12.6, 2.8 Hz, 1H, CH2CH), 3.60 (s,
1H, CHAr2), 3.92 (d, J¼22 Hz, 1H, CH2C]O), 4.05 (d,
J¼22 Hz, 1H, CH2C]O), 4.13 (t, J¼2.6 Hz, 1H, CHCH2),
5.44 (d, J¼8.1 Hz, 1H, ArH), 6.62 (d, J¼7.3 Hz, 1H,
ArH), 6.83 (d, J¼8.1 Hz, 1H, ArH), 6.97 (m, 2H, ArH),
7.08 (m, 4H, ArH), 7.17 (s, 1H, ArH), 7.76 (d, J¼7.8 Hz,
1H, ArH), the remaining ArH was obscured by the benzene;
13C NMR (C6D6, 125 MHz) d 42.9 (t), 44.7 (d), 48.0 (s), 53.6
(d), 65.7 (t), 112.1 (d), 123.4 (d), 123.6 (d), 124.2 (d), 125.2
(d), 125.7 (d), 125.8 (d), 126.7 (d), 127.0 (d), 126.98 (d),
135.7 (s), 138.8 (s), 139.4 (s), 140.5 (s), 143.9 (s), 144.5
(s), 172.3 (s), 174.5 (s), the remaining two aromatic carbons
(CH) were obscured by the benzene; exact mass (ESI) calcd
for C25H18N2O+: m/z 362.1413, found: m/z 362.1445.
Acknowledgements
We wish to acknowledge the National Institutes of Health for
support of this research.
Supplementary data
3.1.14. Imidazoloindolines 21 and 2-epi-21. To a stirred
solution of 57 mg (157 mmol) of imidazolinone 20 in
Experimental procedures for the preparation of 12 and 13,
and 1H and 13C NMR spectra of most compounds are

8754
Y. A. Ortiz Barbosa et al. / Tetrahedron 62 (2006) 8748–8754
Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am.
Chem. Soc. 1994, 116, 11143.
8. Burns, B.; Grigg, R.; Santhakumar, V.; Sridharan, V.;
Stevenson, P.; Wokarum, T. Tetrahedron 1992, 48, 7297.
9. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2897.
available as supplementary material. Supplementary data
associated with this article can be found in the online
version, at doi:10.1016/j.tet.2006.06.103.
References and notes
10. Wolman, Y.; Ladkany, D.; Frankel, M. J. Chem. Soc. C 1967,
689.
11. Buchi, G.; DeShong, P. R.; Katsumura, S.; Sugimura, Y. J. Am.
Chem. Soc. 1979, 101, 5084.
1. Clardy, J.; Springer, J. P.; Buchi, G.; Matsuo, K.; Wightman, R.
J. Am. Chem. Soc. 1975, 97, 663; Buchi, G.; Luk, K. C.; Kobbe,
B.; Townsend, J. M. J. Org. Chem. 1977, 42, 244.
12. Alder, K.; Windemuth, E. Chem. Ber. 1938, 71, 1939.
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480.
14. Chung, Y.; Duerr, B. F.; McKelvey, T. A.; Nanjappan, P.;
Czarnik, A. W. J. Org. Chem. 1989, 54, 1018.
15. Rodriguez, J. G.; Benito, Y.; Temprano, F. J. Heterocycl. Chem.
1985, 22, 1207.
16. Pellegrini, C.; Strassler, C.; Weber, M.; Borschbert, H.-J.
Tetrahedron: Asymmetry 1994, 5, 1979.
17. Bose, A. K.; Anganeyulu, B. Chem. Ind. 1966, 903; Hoppe, D.;
Kloft, M. Liebigs Ann. Chem. 1980, 1512; Ghosh, A.; Miller,
J. J.; Richardson, S. K.; Savela, G. C. Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley:
Chichester, UK, 1995; Vol. 1, p 218.
2. Chang, R. S. L.; Lotti, V. J.; Monaghan, R. L.; Birnbaum, J.;
Stapley, E. O.; Goetz, M. A.; Abers-Schonberg, G.; Patchett,
A. A.; Liesch, J. M.; Hemsens, O. D.; Springer, J. P. Science
1985, 230, 177.
3. Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.;
Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.;
Singu, T. Tetrahedron Lett. 1992, 33, 1621; Takahashi, C.;
Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda,
Y.; Numata, A. J. Chem. Soc., Perkin Trans. 1 1995, 2345.
4. Barrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471; Larsen,
T. O.; Frydenvang, K.; Frisvad, J. C.; Christophersen, C.
J. Nat. Prod. 1998, 61, 1154.
5. Hart, D. J.; Magomedov, N. A. Tetrahedron Lett. 1999, 40,
5429.
18. Dyke, J. M.; Broves, A. P.; Morris, A.; Ogden, J. S.; Dias, A. A.;
Oliveira, A. M. S.; Costa, M. L.; Barros, M. T.; Cabral, M. H.;
Moutinho, A. M. C. J. Am. Chem. Soc. 1977, 119, 1979.
19. We thank Stafford McLean (Pfizer) for evaluating displace-
ment of 125I-Bolton Hunter labeled SP bound to the human
HK-1 receptor by 10 (IC50¼2.75 mM) and other compounds
prepared in our laboratory.
20. Proenca Barros, F. A.; Rodrigues-Filho, E. Biochem. Syst. Ecol.
2005, 33, 257; Larsen, T. O.; Petersen, B. O.; Duus, J. O.;
Sorensen, D.; Frisvad, J. C.; Hansen, M. E. J. Nat. Prod.
2005, 68, 871; Ariza, M. R.; Larsen, T. O.; Petersen, B. O.;
Duus, J. O.; Christophersen, C.; Barrero, A. F. J. Nat. Prod.
2001, 64, 1590.
6. Hart, D. J.; Magomedov, N. A. J. Am. Chem. Soc. 2001, 123,
5892.
7. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635;
Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45,
6375; Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron
1989, 45, 6386; Takeuchi, H.; Yanagida, S.; Ozaki, T.;
Hagiwara, S.; Eguchi, S. J. Org. Chem. 1989, 54, 431; Gajda,
T.; Koziara, A.; Osowska-Pacewicka, K.; Zawadzki, S.;
Zwierzak, A. Synth. Commun. 1992, 22, 1929; Hickey,
D. M. B.; Mackenzie, A. R.; Moody, C. J.; Rees, C. W.
J. Chem. Soc., Perkin Trans. 1 1987, 921; Stegmann, H. B.;
Stocker, F.; Wax, G. Synthesis 1981, 816; He, F.; Foxman,
B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417;