U.S. patent application number 10/001611 was filed with the patent office on 2002-06-27 for synthesis of cc-1065/duocarmycin analogs.
This patent application is currently assigned to The Scripps Research Institute. Invention is credited to Boger, Dale L..
Application Number | 20020082424 10/001611 |
Document ID | / |
Family ID | 22079548 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082424 |
Kind Code |
A1 |
Boger, Dale L. |
June 27, 2002 |
Synthesis of CC-1065/duocarmycin analogs
Abstract
The dihydroindole C-ring found in CC-1065/duocarmycin analogs is
formed by the 5-exo-trig radical cyclization of an aryl halide onto
a tethered vinyl chloride forming with chlorine installed as a
suitable leaving group for subsequent cyclopropane
spirocyclization. The versatility of this approach is disclosed in
the context of six CC-1065/duocarmycin analogs previously
synthesized in this laboratory.
Inventors: |
Boger, Dale L.; (La Jolla,
CA) |
Correspondence
Address: |
THE SCRIPPS RESEARCH INSTITUTE
OFFICE OF PATENT COUNSEL, TPC-8
10550 NORTH TORREY PINES ROAD
LA JOLLA
CA
92037
US
|
Assignee: |
The Scripps Research
Institute
10550 N. Torrey Pine Road
La Jolla
CA
92307
|
Family ID: |
22079548 |
Appl. No.: |
10/001611 |
Filed: |
October 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10001611 |
Oct 30, 2001 |
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09581049 |
Jul 10, 2000 |
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09581049 |
Jul 10, 2000 |
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PCT/US98/25992 |
Dec 8, 1998 |
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60067960 |
Dec 8, 1997 |
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Current U.S.
Class: |
546/63 ;
548/421 |
Current CPC
Class: |
C07D 215/54 20130101;
C07D 471/04 20130101; C07D 209/08 20130101; C07D 487/04 20130101;
C07C 271/28 20130101 |
Class at
Publication: |
546/63 ;
548/421 |
International
Class: |
C07D 471/02 |
Claims
What is claimed:
1. A method for the synthesis of a dihydroindole C-ring of a
CC-1065/duocarmycin analog wherein the method comprises the steps
of: Step A: alkylating an aryl halide with 1,3-dichloropropene and
a catalytic amount of n-tetrabutylammonium iodide for forming a
vinyl chloride; then Step B: cyclizing the vinyl chloride of said
step A under conditions using tribuytyl tin hydride, catalytic AIBN
and toluene as the solvent for forming the dihydroindole C-ring of
the CC-1065/duocarmycin analog.
2. A compound represented by the following structure: 5
3. A compound represented by the following structure: 6
4. A compound represented by the following structure: 7
5. A compound represented by the following structure: 8
6. A compound represented by the following structure: 9
7. A compound represented by the following structure: 10
8. A compound represented by the following structure: 11
9. A compound represented by the following structure: 12
10. A compound represented by the following structure: 13
11. A compound represented by the following structure: 14
12. A compound represented by the following structure: 15
13. A compound represented by the following structure: 16
14. A compound represented by the following structure: 17
15. A compound represented by the following structure: 18
16. A compound represented by the following structure: 19
17. A compound represented by the following structure: 20
18. A compound represented by the following structure: 21
Description
DESCRIPTION
[0001] 1. Technical Field
[0002] The present invention relates to a method for the synthesis
of the dihydroindole C-ring found in CC-1065/duocarmycin analogs.
More particularly, the invention comprises the 5-exo-trig radical
cyclization of an aryl halide onto a tethered vinyl chloride
forming the dihydroindole C-ring with chlorine installed as a
suitable leaving group for subsequent cyclopropane
spirocyclization. The versatility of this approach is examined in
the context of six CC-1065/duocarmycin analogs previously
synthesized in this laboratory.
[0003] 2. Background
[0004] CC-1065 (1; Chidester et al. J. Am. Chem. Soc. 1981, 1-3,
7629) and the duocarmycins 2 (Ichimura et al. J. Antibiot. 1990,
43, 1037) and 3 (Takahashi et al. J. Antibiot. 1988, 41, 1915;
Yasuzawa et al. Chem. Pharm. Bull. 1995, 43, 378) are the parent
members of a potent class of antitumor antibiotics that derive
their biological properties through reversible, sequence selective
alkylation of DNA (For a review of mechanistic aspects see: Boger,
et al. Angew. Chem., Int. Ed. Engl. 1996, 35, 230).
[0005] Since their disclosure, synthetic efforts have focused on
the natural products as well as a great number of rationally
designed analogs (For a review of synthetic efforts see: Boger et
al. Chem. Rev., 1997, 97, 787). These analogs have served define
the fundamental principles underlying the relationships between
structure, chemical reactivity and biological properties within
this family, and have advanced the understanding of the origin of
sequence selectivity and the catalysis of the DNA alkylation
reaction by 1-3 (Boger et al. J. Am. Chem. Soc. 1997, 119, 4977;
Boger et al. J. Am. Chem. Soc. 1997, 119, 4987; Boger et al. Biorg.
Med. Chem. 1997, 5, 263; Warpehoski et al. J. Am. Chem. Soc. 1994,
116, 7573; Warpehoski et al. J. Am. Chem. Soc. 1995, 117,
2951).
[0006] Common synthetic routes to many of the duocarmycin and
CC-1065 analogs incorporate the same transformation via a four step
procedure highlighted by an in-situ trap of a primary radical with
TEMPO (TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy free radical)
followed by its reductive removal and conversion to the chloride as
depicted for the synthesis of CBI (Boger et al. J. Org. Chem. 1995,
60, 1271) as illustrated in FIG. 4.
[0007] It would be beneficial to have a more direct and higher
yielding transformation to obtain the dihydroindole C-ring found in
CC-1065/duocarmycin analogs. What is needed, therefore, is an
efficient and general method for the synthesis of the dihydroindole
C-ring found in CC-1065/duocarmycin analogs with less steps than
the standard four step TEMPO procedure as described above.
SUMMARY OF THE INVENTION
[0008] One aspect of the invention is directed to a 2 step
synthesis of the dihydroindole C-ring found in CC-1065/duocarmycin
analog. An aryl halide is alkylated with 1,3-dichloropropene and a
catalytic amount of n-tetrabutylammonium iodide for forming a vinyl
chloride. The vinyl chloride is then cyclized under conditions
using tribuytyl tin hydride, catalytic AIBN and toluene as the
solvent for forming the dihydroindole C-ring of the
CC-1065/duocarmycin analog.
[0009] Another aspect of the invention is directed to the following
compounds: 1
DESCRIPTION OF FIGURES
[0010] FIG. 1 shows CC-1065 (1) and the duocarmycins (2) and (3).
The compounds are parent members of a potent class of antitumor
antibiotics.
[0011] FIG. 2 shows CBI (4) (S), CPyI (6), desmethyl-CPI (7),
iso-CBI (8), and the mitomycin-hybrid (9) which are compounds of
interest in this application.
[0012] FIG. 3 shows the novel intramolecular aryl radical
cyclization onto a tethered vinyl chloride to install the
dihydroindole C ring with chlorine installed as a suitable leaving
group for subsequent cyclopropane spirocyclization.
[0013] FIG. 4 shows the standard four step procedure highlighted by
an in-situ trap of a primary radical with TEMPO
(TEMPO=2,2,6,6-tetramethyl-1- -piperidinyloxy free radical)
followed by its reductive removal and conversion to the chloride as
depicted for the synthesis of CBI.
[0014] FIG. 5 illustrates the transformation from compound 10a to
12a and the subsequent formation of a cyclopropyl ring.
[0015] FIG. 6 shows a table which illustrates the results of the
two-step synthesis of 3-chloro-methylindolines with the following
conditions: a NaH, 1,3-dichloropropene, DMF, 25.degree. C.; b NaH,
1,3-dichloropropene, nBu.sub.4NI, DMF, 25.degree. C.; c AIBN
(cat.), Bu.sub.3SnH, benzene, 60-75.degree. C.; d AIBN (cat.),
Bu.sub.3SnH, toluene, 90.degree. C. wherein each compound uses the
same transformation as shown in FIG. 6.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The invention is directed to a two-step transformation
directed to the synthesis of 6 CC-1065/duocarmycin analogs using a
novel intramolecular aryl radical cyclization onto a vinyl chloride
to form the dihydroindole C-ring found in 6 CC-1065/duocarmycin
analogs. This transformation represents a potential two-step
improvement to the synthetic route to many other analogs, which
most recently incorporated the same transformation via a four step
procedure highlighted by an in-situ trap of a primary radical with
TEMPO (TEMPO=2,2,6,6-tetramethyl-1- -piperidinyloxy free radical)
followed by its reductive removal and conversion to the chloride as
depicted for the synthesis of CBI (Boger et al. J. Org. Chem. 1995,
60, 1271) as illustrated in FIG. 4.
[0017] Patel et al. describes the synthesis of an analog named
Oxa-duccarmycln SA which utilizes a novel intramolecular aryl
radical cyclization onto a tethered vinyl chloride to install the
dihydroindole C ring with chlorine installed as a suitable leaving
group for subsequent cyclopropane spirocyclization as described in
FIG. 3.
[0018] Application of this improved two-step transformation to the
synthetic routes reported for a number of the analogs synthesized
in this laboratory would serve to establish the versatility of this
approach to the synthesis of CC-1065 and duocarmycin analogs.
[0019] With this goal in mind, the C-ring construction for CBI (4;
Boger et al. J. Org. Chem. 1995, 60, 1271, CCBI (5; Boger et al. J.
Org. Chem. 1996, 61, 4894), CPyI (6), desmethyl-CPI (7), iso-CBI
(8), and the mitomycin-hybrid (9) was investigated. The
appropriately functionalized aryl halides (10a-g), which were
obtained either through direct electrophilic halogenation (entries
1-5) or directed ortho metallation (entries 6 and 7) and halide
quench, were alkylated with 1,3 dichloropropene to complete the
radical cyclization precursors (11a-g) in high yields. Treatment
with Bu.sub.3SnH and a catalytic amount of AIBN
(AIBN=2,2'-azobisisobutyronitrile) with heating in benzene or
toluene very cleanly effected 5-exo-trig radical cyclization to
form the 3-chloromethyl indoline C-ring present in each of the
analogs (12a-g) as illustrated in FIG. 6.
[0020] This two-step transformation works well with benzene,
naphthalene, indole and quinoline derivatives, aryl iodides as well
as aryl bromides, with little to no deterioration in the
consistently high yields for both steps. Brief optimization efforts
revealed that higher yields may sometimes be obtained with addition
of n-Bu.sub.4NI to the alkylation reaction, as well as substitution
of toluene and higher reaction temperature for benzene. It was
observed, as also noted by Patel et al. that deoxygenation of the
solvent prior to radical cyclization may enhance both the rate and
yield of the reaction.
[0021] In summary, this novel intramolecular aryl radical
cyclization onto a vinyl chloride, as introduced by Patel, was
successfully applied to the C-ring synthesis of 6
CC-1065/duocarmycin analogs. This application has effectively
shortened the synthesis of each of these analogs by two steps.
Clearly the versatility of this approach, combined with the high
conversions for both steps, assure its use in future rational
analog design in the CO-1065/duocarmycin family of antitumor
antibiotics.
[0022] While a preferred form of the invention has been shown in
the drawings and described, since variations in the preferred form
will be apparent to those skilled in the art, the invention should
not be construed as limited to the specific form shown and
described, but instead is as set forth in the following claims.
Experimental Protocals
[0023] General .sup.1H and .sup.13C nmr spectra were recorded
either on a Bruker AM-250, a Bruker AMX-400 or a Bruker AMX-500
spectrometer. Residual protic solvent CHCl.sub.3,
(.delta..sub.H=7.26 ppm, .delta..sub.c=77.0), d.sub.4-methanol
(.delta..sub.H=3.30 ppm, .delta..sub.c=49.0) and D.sub.2O
(.delta..sub.H=4.80 ppm, .delta..sub.c (of CH.sub.3CN)=1.7 ppm) or
TMS (.delta..sub.H=0.00 ppm) were used as internal reference.
Coupling constants were measured in Hertz (Hz). HRMS were recorded
using FAB method in a m-nitrobenzylalcohol (NBA) matrix doped with
NaI or CsI. Infra-red spectra were recorded on a Perkin-Elmer FTIR
1620 spectrometer. Enantiomeric excess was determined by HPLC using
a Daicel Chemical Industries CHIRALPAK AD column. Optical rotations
were measured with an Optical Activity AA-1000 polarimeter. Melting
points were taken on a Thomas Hoover capillary melting point
apparatus and are uncorrected. Column chromatography was performed
on Merck Kieselgel 60 (230-400 mesh). Analytical thin layer
chromatography was performed using pre-coated glass-backed plates
(Merck Kieselgel F.sub.254) and visualized by cerium
molybdophosphate or ninhydrin. Diethyl ether, tetrahydrofuran (THF)
and toluene (PhCH.sub.3) were distilled from sodium-benzophenone
ketyl, dichloromethane (DCM) and acetonitrile from calcium hydride.
Other solvents and reagents were purified by standard procedures if
necessary.
[0024] General Experimental Procedure for Individual Synthesis of
12a-g as Shown in FIG. 6:
[0025] A solution of the aryl iodide (one of 10a-g as shown in FIG.
6 obtained from the sources or conditions as described herein; aryl
iodide is obtained from the following sources:) in anhydrous DMF
(0.1 M) at 0.degree. C. was treated with NaH (2.0 equiv.) in small
portions. The resulting suspension was stirred 15 min and treated
with neat 1,3-dichloropropene (5.0 equiv) in a slow dropwise
manner, followed by catalytic Bu.sub.4NI (0.1 equiv.;
n-tetrabutylammonium iodide). The reaction mixture was warmed to
25.degree. C. and stirred for 12 h. The reaction mixture was
quenched with the addition of 5% aqueous NaHCO.sub.3, and the
aqueous layer was extracted with EtOAc. The combined organic
extracts were washed with H.sub.2O, dried (Na.sub.2SO4) and
concentrated under reduced pressure. The crude was purified by
flash column chromatography. A solution of one of 11a-g in
anhydrous benzene (0.1M; alternatively substitution of toluene and
higher reaction temperature can optimize yield, due to higher
temperatures) was treated with Bu.sub.3SnH (1.05 equiv.) and
catalytic AIBN (0.1 equiv.) and deoxygenated with a stream of dry
N, gas. The solution was heated to 80.degree. C. for 2 h and
concentrated in vacuo. The crude was purified by flash column
chromatography to form one of compounds 12a-g.
[0026] Synthesis of Cyclopropane via Spirocyclization.
[0027] The chlorine group of the dihydroindole C-ring is installed
as a suitable leaving group for cyclopropane spirocyclization.
Methodologies for subsequent spirocyclization and further aklyation
of the resultant cyclopropane C-ring system to the DNA portion of
CC-1065 and the duocarmycins is well known in the art. A
representative spirocyclization is accomplished via treatment of
12(a-g) with NaH (3 equiv, THF, 0.degree. C., 30 min) to provide
(4-9; as shown in FIG. 2). Similarly, acid-catalyzed deprotection
of 12(a-g) (3N HCl-EtOAc, 25.degree. C., 20 min) followed by
spirocyclization of the crude indoline hydrochloride salt upon
exposure to 5% aqueous NaHCO.sub.3-THF (1:1, 25.degree. C., 1.5 h,
93%) can also provide (4-9; as shown in FIG. 2).
[0028] Synthesis of Compounds 4-9 as Shown in FIG. 2
[0029] A solution of 12(a-g; one of the compounds in FIG. 6;
obtained from the sources or conditions as described herein) (1.5
mg, 4.1 .mu.mol) in tetrahydrofuran-dimethylformamide (3:1, 200
.mu.L) at 0.degree. C. under N.sub.2 was treated with suspension of
NaH (0.5 mg, 60% in an oil dispersion, 12 .mu.mol, 3 equiv). The
reaction mixture was allowed to stir at 0.degree. C. and for 30 min
before the addition of pH 7 phosphate buffer (0.2 M, 250 .mu.L) and
2 mL of tetrahydrofuran. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. Chromatography
(SiC.sub.2, 20-30% Ethylacetate-hexane gradient elution) afforded
(4-9; as shown in FIG. 2): Alternative Spyrocyclization: 12(a-g;
one of the compounds)(5 mg, 1.37 .mu.mol) was treated with
anhydrous 3N HCl-Ethylacetate (0.4 mL) at 24.degree. C. for 20 min.
The solvent was removed in vacuo to afford the crude, unstable
amine hydrochloride. This residue was treated with 5% aqueous
NaHC.sub.3 (0.4 mL) and tetrahydrofuran (0.4 mL) at 24.degree. C.
under N.sub.2, and the two phase mixture was stirred for 1.5 h
(24.degree. C.). The reaction mixture was extracted with
Ethylacetate (3.times.2 mL) and the combined extracts were washed
with H.sub.2O (2 mL), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. Chromatography (SiO.sub.2, 10% CH.sub.3OH--CH.sub.2Cl.sub.2)
afforded (4-9; as shown in FIG. 2). 2
[0030] 2,4-(Dimethoxy)-3-(methyl)-methoxymethyl Phenyl Ether
(101).
[0031] A solution of 2,4-(dimethoxy)-3-methylphenol (1.0 g, 5.95
mmol) in 60 mL of anhydrous DMF at 0.degree. C. was treated with
NaH (357 mg, 9.91 mmol) in several portions over 5 min. After 10
min, BU.sub.4NI (219 mg, 0.60 mmol) was added followed by the
dropwise addition of ClCH.sub.2OCH.sub.3 (0.68 EL, 8.91 mmol). The
reaction mixture was stirred at 25.degree. C. for 36 h before the
reaction was quenched by the slow addition of 30 mL of H.sub.2O.
The aqueous layer was extracted with EtOAc (3 (30 mL). The organic
layers were combined, washed with 10% aqueous NaHCO.sub.3 (50 mL)
and H.sub.2O (4 (20 mL), dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure. Flash chromatography (SiO.sub.2, 3 (10 cm,
10% EtOAc/hexane) provided 101 (1.11 g, 88%) as a light yellow oil:
.sup.1H NMR (CDCl.sub.3, 250 MHz) .delta. 6.92 (d, J=8.8 Hz, 1H),
6.51 (d, J=8.8 Hz, 1H), 5.13 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H)
3.50 (s, 3H), 2.13 (s, 3H); .sup.13C NMR (CDCl.sub.3, 62.5 MHz)
.delta. 153.5, 149.2, 144.3, 121.0, 114.4, 105.3, 96.0, 60.4, 56.0,
55.7, 8.9; IR (film) .nu..sub.max 2937, 2833, 1595, 1487, 1440,
1420 cm.sup.-1 ; FABHRMS (NBA) m/z 212.1040 (C.sub.11H.sub.6O.sub.4
requires 212.1049).
[0032] 2,4-(Dimethoxy)-3-(methyl)-5-(nitro)-methoxymethyl Phenyl
Ether (102).
[0033] A solution of 101 (1.11 g, 5.21 mmol) in 18 mL freshly
distilled Ac.sub.2O at 0.degree. C. was treated with
Cu(NO.sub.3).sub.2.circle-soli- d.2.5 H.sub.2O (2.41 g, 10.4 mmol)
in several portions over 5 min. The reaction mixture was stirred
for 2 h at 0.degree. C., then 1 h at 25.degree. C. before the
reaction was poured over H.sub.2O (50 mL) and extracted with EtOAc
(3 (30 mL). The combined organic layers were washed with saturated
aqueous NaCl (50 mL), dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure. The crude light yellow oil (1.18 g, 88%)
was carried on to the next transformation: .sup.1H NMR (CDCl.sub.3,
250 MHz) .delta. 7.54 (s, 1H), 5.18 (s, 2H), 3.87 (s, 3H), 3.81 (s,
3H), 3.48 (s, 3H), 2.21 (s, 3H); .sup.13C NMR (CDCl.sub.3, 62.5
MHz) .delta. 153.0, 147.8, 145.8, 138.9, 128.2, 110.5, 95.3, 61.8,
60.5, 56.2, 9.5; IR (film) .nu..sub.max 2942, 2829, 1522, 1481,
1344, 1280, 1246 cm.sup.-1 ; FABHRMS (NBA) m/z 258.0977
(C.sub.11H.sub.15NO.sub.6+H.sup.+ requires 258.0978).
[0034] 5-(Amino)-2,4-(dimethoxy)-3-(methyl)-methoxymethyl Phenyl
Ether (103).
[0035] A solution of 102 (1.18 g, 4.57 mmol) in 90 mL moist ether
(8:2:1 Et.sub.2O:EtOH:H.sub.2O) was cooled to 0.degree. C., and
treated with freshly prepared Al-Hg (1.23 g Al, 45.7 mmol) in small
1 (1 cm pieces. The reaction mixture was stirred vigorously for 0.5
h at 0 (C, then 1 h at 25 (C. The reaction mixture was then
filtered through Celite, and the Celite was washed thoroughly with
Et.sub.2O (5 (20 mL). The solution was then washed with saturated
aqueous NaCl (100 mL), dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure to afford 103 (0.88 g, 85%) as a crude brown
oil, which was immediately carried on to the next step: .sup.1H NMR
(CDCl.sub.3, 250 MHz) .delta. 6.42 (s, 1H), 5.11 (s, 2H), 3.70 (s,
3H), 3.66 (s, 3H), 3.56 (m, 2H), 3.47 (s, 3H) 2.16 (s, 3H);
.sup.13C NMR (CDCl.sub.3, 250 MHz) .differential. 147.0, 140.4,
140.3, 135.8, 125.4, 102.0, 95.4, 60.6, 59.4, 56.0, 9.34; IR (film)
.nu..sub.max 3446, 3359, 2935, 2826, 1617, 1492, 1358 cm.sup.-1;
ESIMS m/z 228 (C.sub.11H.sub.17NO.sub.4+H.sup.+requires 228).
[0036]
[N-(tert-Butyloxycarbonyl)amino]-2,4-(dimethoxy)-5-(methoxymethoxy)-
-3-methylbenzene (104).
[0037] A solution of crude 102 (0.88 g, 3.85 mmol) in 40 mL
anhydrous THF was treated with BOC.sub.2O (1.73 g, 7.72 mmol) and
the reaction mixture was warmed at reflux (65 (C) for 18 h. The
solvents were removed under reduced pressure, and flash
chromatography (SiO.sub.2, 3 (10 cm, 10% EtoAc/hexane) provided
pure 104 as a yellow oil (0.96 g, 76%): .sup.1H NMR (CDCl.sub.3,
250 MHz) .delta. 7.72 (br s, 1H), 6.86 (br s, 1H), 5.18 (s, 2H),
3.75 (s, 3H), 3.67 (s, 3H), 3.51 (s, 3H), 2.19 (s, 3H), 1.50 (s,
9H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 152.7, 146.4,
143.6, 141.6, 127.8, 124.8, 105.3, 95.5, 80.4, 60.5, 60.4, 56.4,
28.3, 9.5; IR (film) .nu..sub.max 3437, 3341, 2977, 2935, 1731,
1519, 1454, 1422, 1397 cm.sup.-1; FABHRMS (NIBA/CsI) m/z 460.0723
(C.sub.16H.sub.25NO.sub.6+Cs.s- up.+ requires 460.0736).
[0038]
[N-(Tert-Butyloxycarbonyl)amino]-2,4-(dimethoxy)-6-(iodo)-5-(m
ethoxymethoxy)-3-methyl Benzene (10 g). A solution of 104 (0.55 g,
1.67 mmol) in 6.6 mL anhydrous THF was cooled to -25 (C and treated
with TMEDA (0.94 mL, 6.18 mmol) followed by n-BuLi (2.5 mL of a 2.5
M solution in hexane, 6.18 mmol) in a slow dropwise manner. The
resulting gold solution stirred for 2 h at -25 (C. The reaction
mixture was treated with 1-chloro-2-iodoethane (0.45 mL, 6.18 mmol)
and stirred for 15 min at 25 (C. The reaction was diluted with
H.sub.2O (50 mL) and extracted with Et.sub.2O (3 (30 mL), and the
combined organic extracts were washed with saturated aqueous NaCl,
dried (Na.sub.2SO.sub.4), and concentrated under reduced pressure.
Flash chromatography (SiO.sub.2, 2.5 (10 cm, 20% EtOAc/hexane)
yielded 11g (560 mg, 74%) as a colorless oil: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 5.99 (br s, 1H), 5.10 (s, 2H), 3.75
(s, 3H), 3.69 (s, 3H), 3.65 (s, 3H), 2.17 (s, 3H), 1.49 (s, 9H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 153.6, 151.8, 150.5,
146.9, 129.3, 126.7, 99.1, 95.8, 80.6, 60.5, 60.3, 58.5, 28.3, 9.8;
IR (film) .nu..sub.max 3321, 2975, 2936, 1722, 1485, 1455, 1390
cm.sup.-1; FABHRMS (NSA/CsI) m/z 585.9688
(C.sub.16H.sub.24INO.sub.6+Cs.sup.+ requires 585.9703).
[0039]
[N-(tert-Butyloxycarbonyl)-N-(3-chloro-2-propen-1-yl)amino]-2,
4-(dimethoxy)-6-(iodo)-5-(methoxymethoxy)-3-methylbenzene
(11g).
[0040] A solution of 10g (0.610 g, 1.34 mmol) in 13.4 mL anhydrous
DMF was cooled to 0 (C, and treated with NaH (60% dispersion in
oil, 121 mg, 4.03 mmol) in small portions. The resulting suspension
was stirred for 15 min and treated with neat 1,3-dichloropropene
(0.52 mL, 5.5 mmol) in a slow dropwise manner, followed by
catalytic n-Bu.sub.4NI (50.0 mg, 0.13 mmol). The reaction mixture
was warmed to 25 (C and stirred for 3 h. The reaction mixture was
quenched with the addition of saturated aqueous NaHCO.sub.3 (50
mL)), and the aqueous layer was extracted with EtOAc (3 (30 mL).
The combined organic extracts were washed with H.sub.2O (4 (50 mL),
dried (Na.sub.2SO.sub.4), and concentrated under reduced pressure.
Flash chromatography (SiO.sub.2, 3 (10 cm, 0-20% EtoAc/hexane
gradient) yielded 11 g (0.681 g, 96%) as a colorless mixture of
rotamers: .sup.1H NMR (CDCl.sub.3, 400 MHz) 2:1 rotamers .delta.
6.15-6.03 (m, 1H), 6.00-5.90 (m, 1H), 5.11-5.03 (m, 2H), 4.17-3.87
(m, 2H), 3.77 and 3.74 (s, 3H), 3.65 and 3.63 (s, 3H), 3.627 and
3.622 (s, 3H), 2.14 and 2.13 (s, 3H), 1.50 and 1.34 (s, 9H);
.sup.13C NMR (CDCl.sub.31 100 MHz) rotamers .delta. 153.65 and
153.62, 152.8 and 152.1, 151.0 and 150.7, 147.0 and 146.7, 134.5
and 134.0, 129.5 and 129.0, 127.0 and 126.7, 121.0 and 120.6, 99.0,
97.7 and 97.3, 80.8 and 80.6, 60.5 and 60.4, 60.3 and 60.2, 58.5
and 58.4, 50.4, 48.8, 28.3 and 28.2, 9.9; IR (film) .nu..sub.max
2973, 2936, 1704, 1456, 1366 cm.sup.-1; FABHRMS (NBA/CsI) m/z
659.9655 (C.sub.19H.sub.27ClINO.sub.6+Cs.sup.+ requires 659.9626).
3
[0041] 3-Bromo-8-hydroxy-6-nitroquinoline (210).
[0042] A solution of 2-bromoacrolein (5 g, 37.0 mmol, 1 equiv) in
110 mL glacial acetic acid at 25.degree. C. was titrated to the
appearance of a faint reddish color with bromine (ca. 5.9 g, 37.0
mmol, 1 equiv). 2-Hydroxy-4-nitroaniline (209, 5.7 g, 37.0 mmol, 1
equiv) was added, and the solution was gradually heated to 100 (C.
The solution was cooled to 25 (C after one hour. Filtering and
neutralization of the precipitate with 1 M sodium phosphate buffer
(pH 7, Na.sub.2HPC.sub.4-NaH.sub.2PO.sub- .4) afforded 9.2 g (9.95
g theoretical, 92%) of 210 as a light yellow solid: mp 240-241 (C;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.93 (d, L=2.0 Hz, 1H),
8.50 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.18 (s, 1H), 7.92
(s, J=2.3 Hz, 1H); .sup.13C NMR (DMSO, 62.5 MHz) .delta. 155.1,
152.1, 146.3, 139.5, 139.1, 128.7, 119.1, 113.5, 105.1; IR (film)
(.sub.max 3408 (br), 3089, 1587, 1553, 1519, 1476, 1389, 1350,
1297, 1263, 1210, 1133, 1079, 929, 931, 839, 804, 734, 633
cm.sup.-1; ESIMS m/z 269 (M+H.sup.+, C.sub.9H.sub.3BrO requires
269); Anal. Calcd for C.sub.9H.sub.3BrO: C, 40.18; H, 1.87; N,
10.41. Found: C, 40.21; H, 1.91; N, 9.98.
[0043] 8-(Benzyloxy)-3-bromo-6-nitroquinoline (211). A solution of
210
[0044] (13.7 g, 51 mmol, 1 equiv) in anhydrous DMF (150 mL) was
cooled to 4 (C under nitrogen and treated with KI (1.7 g, 10 mmol,
0.2 equiv) and sodium hydride (60% dispersion in oil, 2.24 g, 56
mmol, 1.1 equiv). Benzyl bromide (7.3 mL, 6.1 mmol, 1.2 equiv) was
added after 30 min and the reaction was allowed to warm to 25 (C.
After 24 h, the reaction volume was reduced by one-third in vacuo
and EtOAc (200 mL) was added. The reaction mixture was poured on
H.sub.2O (200 mL) and extracted with EtOAc (3 (100 mL). The
combined organic extracts were washed with saturated aqueous NaCl
(1 (40 ml), dried (Na.sub.2SO.sub.4) and concentrated. Flash
chromatography (SiO.sub.2, 5.5 (20 cm, 50-100%
CH.sub.2Cl.sub.2-hexane) afforded 211 (15.63 g, 18.32 g
theoretical, 85%) as a yellow solid: mp 170 (C; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.06 (d, J=2.2 Hz, 1H), 8.44 (d,
J=2.2 Hz, !H), 8.25 (d, J=2.2 Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.52
(app d, J=7.4 Hz, 2H), 7.38 (m, 2H), 7.32 (m, 1H), 5.47 (s, 2H);
.sup.13C NMR (CDCl.sub.3, 62.5 MHz) .delta. 155.4, 153.3, 146.4,
140.3, 138.8, 135.0, 128.7 (2C), 128.6, 128.4 (2C), 127.5, 119.9,
115.1, 103.3, 71.4; IR (film) (.sub.max 3082, 3055, 2933, 2871,
1609, 1567, 1519, 1476, 1450, 1375, 1338, 1311, 1252, 1135, 1093,
976, 912, 842, 741 cm.sup.-1; FABHRMS (NBA/NaI) m/z 359.0040
(M+H.sup.+, C.sub.16H.sub.11BrN.sub.2O.sub.3 requires 359.0031).
Anal. Calcd for C.sub.16H.sub.11BrN.sub.2O.sub.3: C, 53.50; H,
3.09; N, 7.80. Found: C, 53.81; H, 3.23; N, 7.48.
[0045] 8-(Benzyloxy)-3-bromo-6-N-(tert-butyloxycarbonyl)
Aminoquinolin e (212).
[0046] A solution of 211 (200 mg, 0.56 mmol, 1 equiv) in EtOAc (1.1
mL) at 25 (C was treated with SnCl.sub.2-2H.sub.2O (628 mg, 2.78
mmol, 5 equiv). The reaction mixture was heated to 70 (C under
nitrogen until an orange slurry formed (ca. 0.5 h). After cooling
to 25 (C, the reaction mixture was poured on ice and made basic
with 1N NaOH. The aqueous layer was filtered and extracted with
EtOAc (3 (15 mL). The combined organic layers were treated with
saturated aqueous NaCl (1 (10 mL), dried (Na.sub.2SO.sub.4) and
concentrated. The yellow solid was placed under vacuum for 0.5h and
then dissolved in anhydrous dioxane (5 mL) and treated with
di-tert-butyl dicarbonate (490 mg, 2.25 mmol, 4.0 equiv) and
triethylamine (156 .mu.L, 1.12 mmol, 2.0 equiv). The reaction
mixture was warmed to 70.degree. C. under argon for one day. After
cooling, the solvent was removed in vacuo. Chromatography
(SiC.sub.2, 3 (13 cm, 25% EtOAc-hexane) afforded 212 (179 mg, 240
mg theoretical, 74%) as a light yellow solid: mp 162 (C; .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 8.77 (d, J=2.0 Hz, 1H), 8.13 (d,
J=2.5 Hz, 1H), 7.47 (app d, J=7.5 Hz, 2H), 7.42 (d, J=2.0 Hz, 1H),
7.35 (m, 2H), 7.28 (m, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.61 (s, 1H),
5.37 (s, 2H), 1.51 (s, 9H); .sup.13C NMR (CDCl.sub.3, 125 MHz)
.delta. 154.9, 152.4, 148.3, 137.9, 136.3, 136.2, 135.4, 131.0,
128.6 (2C), 128.0, 127.3 (2C), 118.6, 104.7, 103.6, 81.1, 70.9,
28.3 (3C); IR (film) (.sub.max 3354, 2971, 2919, 1807, 1766, 1724,
1621, 1450, 1367, 1310, 1253, 1217, 1160, 1123, 1061, 843, 771,
699, 657 cm.sup.-1; FABHRMS (NBA/CsI) m/z 429.0825 (M+H.sup.+,
C.sub.21H.sub.21BrN.sub.2O.sub- .3 requires 429.0814).
[0047] n-Buty18-(benzyloxy)-6-N-(tert-butyloxycarbonyl)
Aminoquinoline -3-carboxylate (213).
[0048] A solution of 212 (4.4 g, 10.1 mmol, 1 equiv) in 85 mL
n-BuOH was cooled to -78 (C and degassed under vacuum.
Pd(PPh.sub.3).sub.4 (1.2 g, 1.0 mmol, 0.1 equiv) and n-Bu.sub.3N
(2.9 mL, 12.1 mmol, 1.2 equiv) were added and the solution was
purged with nitrogen. The reaction mixture was then flushed with
carbon monoxide and then slowly heated to 100 (C under a CO
atmosphere. Upon complete reaction (ca. 12 h), 50 mL H.sub.2O and
50 mL saturated aqueous NH.sub.4Cl were added. The organic layer
was separated and the aqueous layer was extracted with EtOAc (3 50
mL). The combined organic layers were washed with saturated aqueous
NaCl (1 (40 mL), dried (Na.sub.2SO.sub.4) and concentrated.
Chromatography (SiC.sub.2, 5.5 (20 cm, 25% EtOAc-hexane) afforded
213 (3.55 g, 4.55 g theoretical, 78%) as a yellow solid: mp 135-136
(C; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.31 (d, J=2.0 Hz,
1H), 8.66 (d, J=2.1 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.49 (app d,
J=7.4 Hz, 2H), 7.35 (app t, J=7.2 Hz, 2H), 7.29 (m, 1H), 7.11 (d,
J=2.1 Hz, 1H), 6.64 (br s, 1H), 5.39 (s, 2H), 4.38 (t, J=6.6 Hz,
2H), 1.78 (m, 2H), 1.52 (s, 9H), 1.49 (m, 2H, buried under 1.52
ppm), 0.98 (t, J=7.4 Hz, 3H); .sup.13C NMR (acetone d.sub.6, 100
MHz) 67 165.7, 155.7, 153.5, 146.8, 139.8, 139.5, 137.8, 137.7,
129.5, 129.1 (2C), 128.6, 128.4 (2C), 124.8, 107.1, 106.9, 80.4,
71.2, 65.5, 31.3, 28.3 (3C), 19.8, 13.9. IR (film) (.sub.max 3222,
3049, 2958, 2930, 2876, 1717, 1617, 1544, 1503, 1430, 1362, 1271,
1239, 1157, 1065 cm.sup.-1; FABHRMS (NBA/CsI) m/z 451.2249
(M+H.sup.+, C.sub.26H.sub.30N.sub.2O.sub.5 requires 451.2233).
[0049] Methyl-8-(benzyloxy)-6-N-(tert-butyloxycarbonyl)
Aminoquinoline -3-carboxylate (214).
[0050] A solution of 213 (2.9 g, 6.4 mmol, 1.0 equiv) in 70 mL MeOH
was cooled to 4 (C under nitrogen and treated with LiOMe (275 mg,
7.1 mmol, 1.1 equiv). The reaction mixture was allowed to warm to
25 (C after 20 min. Upon complete reaction (ca. 1.5 h), 100 mL
H.sub.2O was added. The organic layer was separated and the aqueous
layer was extracted with EtOAc (3 (30 mL). The organic layers were
combined, washed with saturated aqueous NaCl (1 (30 mL), dried
(Na.sub.2SO.sub.4) and concentrated. Chromatography (SiO.sub.2, 5
(19 cm, 25-30% EtOAc-hexane) afforded 214 (2.39 g, 2.63 g
theoretical, 91%) as a yellow solid: mp 173-174 (C; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.29 (d, J=2.0 Hz, 1H), 8.66 (d,
J=2.1 Hz, 1H), 7.56 (d, J=1.8 Hz, 1H,), 7.45 (m, 2H), 7.30 (m, 2H),
7.25 (m, 1H), 7.18 (d, J=2.0 Hz, 1H), 6.85 (s, 1H), 5.36 (s, 2H),
3.98 (s, 3H), 1.50 (s, 9H); .sup.13C NMR (CDCl.sub.3, 125 MHz)
.delta. 165.9, 154.6, 152.6, 146.9, 138.6, 137.9, 137.8, 136.0,
128.5, 128.4 (2C), 127.9, 127.3 (2C), 123.8, 106.5, 105.5, 80.8,
70.8, 52.4, 28.2 (3C); IR (film) (.sub.max 3333, 3241, 2974, 1723,
1621, 1580, 1539, 1497, 1431, 1390, 1364, 1277, 1231, 1164, 1126,
1103, 1062, 1000, 882, 846, 795, 749, 697, 662 cm.sup.-1; FABHRMS
(NBA/CsI) m/z 409.1773 (M+H.sup.+, C.sub.23H.sub.24N.sub.2O.sub.5
requires 409.1763).
[0051] Methyl
8-(benzyloxy)-6-[N-(tert-butyloxycarbonyl)amino]-5-iodoquino-
line-3-carboxylate (10c).
[0052] A solution of 214 (2.13 g, 5.2 mmol, 1 equiv) in 85 mL of a
1:1 mixture of THF-CH.sub.3OH was cooled to 4 (C and treated with
40 mg TsOH (or H.sub.2SO.sub.4) in 0.5 mL THF. N-Iodosuccinimide
(1.4 g, 6.2 mmol, 1.2 equiv) in 10 mL THF was then slowly added
over 10 min. After 1.5 h, the reaction mixture was warmed to 25 (C
and then stirred 45 h. Upon complete reaction, 100 mL saturated
aqueous NaHCO.sub.3, 100 mL Et.sub.2O, and 100 mL H.sub.2O were
added. The organic layer was separated and the aqueous layer was
extracted with Et.sub.2O (3 (50 mL) and EtOAc (1 (50 mL). The
organic layers were combined, washed with saturated aqueous
NaHCO.sub.3 (1 (50 mL) and saturated aqueous NaCl (1 (50 mL), dried
(Na.sub.2SO.sub.4) and concentrated. Chromatography (SiO.sub.2, 5
(19 cm, hexanes then 30% EtOAc-hexane) provided 10c (2.34 g, 2.78 g
theoretical, 84%, typically 80-88%) as a yellow solid: mp 182-183
(C; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.27 (d, J=1.9 Hz,
1H), 8.96 (d, J=1.9 Hz, 1H), 8.40 (s, 1H), 7.58 (m, 2H), 7.36 (m,
2H), 7.27 (m, 1H), 7.26 (s, 1H), 5.43 (s, 2H), 4.01 (s, 3H), 1.55
(s, 9H); .sup.13C NMR (CDCl.sub.3, 62.5 MHz) .delta. 165.4, 155.0,
152.3, 147.6, 141.9, 139.8, 139.7, 135.8, 129.6, 128.5 (2C), 128.1,
128.0 (2C), 125.1, 105.6, 81.7, 78.4, 71.1, 52.6, 28.2 (3C); IR
(film) (.sub.max 3384, 2974, 1723, 1595, 1554, 1498, 1431, 1400,
1359, 1328, 1262, 1226, 1149, 995, 754 cm.sup.-1; FABHRMS (NBA/CsI)
m/z 535.0743 (M+H.sup.+, C.sub.23H.sub.23IN.sub.2O.sub.5 requires
535.0730). 4
[0053] N.sup.5,1-Dibenzoyl-5-amino-7-(benzyloxy)-4-iodoindole
(305).
[0054] The above indole (118 g, 0.26 mmol) was stirred in THF (1
mL) and toluenesulfonic acid (26mg, 0.13 mmol) was added. The
solution was cooled to 0.degree. C. and N-iodosuccinimide (71 mg,
0.312 mmol) in THF (1 mL) was added. The reaction was allowed to
warm to 25.degree. C. over 1 hr. After 16h, a further portion of
N-iodosuccinimide (15mg, 0.065 mmol) was added and the reaction was
stirred for a further 24hr. Saturated sodium bicarbonate solution
(1 mL) and water (4 mL) were then added and the resulting mixture
was extracted with chloroform (3.times.5 mL). The organic layers
were combined, dried (MgSO.sub.4) and volatiles were removed under
reduced pressure. The residue was purified by flash column
chromatography (silica, ethyl acetate/hexane 3:7, 2.5.times.15 cm)
and crystallized from ethyl acetate to give the expected product
(305) as a yellow solid (67 mg, 45%); .sup.1H NMR .delta. (ppm)
(CDCl.sub.3) 8.15 (s, 1H, NH), 7.99 (d, 2H J=Hz), 7.64 (d, 2H,
J=Hz), 7.58-7.47 (m, 4H, ArH), 7.30-7.17 (m, 5H, ArH), 6.58 (d, 1H,
J=3.6 Hz), 4.92 (s, 2H). 13C NMR .delta. (ppm) 168, 165.5, 147.3,
136.2, 135.8, 134.9, 134.7, 134.1, 132.2, 132.1,129.8, 129.6,
129.5, 129.0, 128.4, 128.3, 128.2, 127.8, 127.7, 127.1, 127.0,
122.4, 110.6, 102.1, 71.9, 70.6 IR (neat) .nu..sub.max 3058, 1703,
1678, 1598, 1332, 1279, 1237, 695 cm.sup.-1 Mass Spectrum (FAB,
NAB/CsI) 705 (M.sup.++Cs.sup.+)
[0055] N.sup.5-Benzoyl-5-amino-7-(benzyloxy)-4-iodoindole
(310).
[0056] The above iodo-compound (305) (193 mg, 0.34 mmol) was
stirred in dichloromethane (10 mL). Sodium methoxide in methanol
(0.523 mL, 1.04 mmol) was added and the solution was stirred at RT
for 10 min. Water (50 mL) and ethyl acetate (50 mL) were added and
organic layer was separated, dried (MgSO.sub.4) and evaporated to
give the crude product. Chromatography (2.times.15 cm SiO.sub.2,
ethyl acetate/hexanes 1:3) gave the pure compound (142 mg, 89%), Rf
0.2 (SiO.sub.2, ethyl acetate/hexanes 1:3) as a colourless solid:
.sup.1H NMR (CDCl.sub.3, 400 MHz) 8.61 (s, 1H, NH), 8.31(s, 1H,
NH), 8.05 (s, 1H), 8.00 (d, 1H, J=6.8 Hz), 7.53 (m, 5H), 7.37 (m,
3H), 7.21 (dd, 1H, J=2.8, 1.4 Hz), 6.43 (dd, 1H, J=2.7, 1.2 Hz),
5.28 (s, 2H); IR (neat) .nu..sub.max 3290, 3010, 1658, 1573, 1535,
1355 cm.sup.-1; FABHRMS (NBA-CsI) m/z 600.9408. (M+Cs.sup.+,
C.sub.22H.sub.17IN.sub.2O.sub.2 requires 600.9389).
[0057] N.sup.5-Benzoyl-N.sup.5,
1-di-(tert-butoxycarbonyl)-5-amino-7-(benz- yloxy)-4-iodoindole
(311).
[0058] Di-tert-butyl dicarbonate (687 mg, 3.16 mmol) and DMAP (128
mg, 1.04 mmol) were added to a stirred solution of compound 310
(255 mg, 0.54 mmol) in dichloromethane (6 mL). After 30 min at RT
the solution was directly subjected to chromatography (2.times.15
cm SiO.sub.2, ethyl acetate/hexane 1:4) to give the pure product
(390 mg, 93%) as a colorless oil (Rf 0.80, SiO.sub.2, ethyl
acetate/hexane 1:3); .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.81 (d, 2H,
J=6.9 Hz), 7.55 (d, 1H, J=3.6 Hz), 7.45 (m, 5H), 7.31 (m, 3H), 6.82
(s, 1H), 6.57 (d, 1H, J=3.6 Hz), 5.15 (s, 2H), 1.47 (s, 9H), 1.22
(s, 9H); FABHRMS (NBA-CsI) m/z 801.0402 (M+Cs.sup.+,
C.sub.32H.sub.33IN.sub.2O.sub.6 requires 801.0438).
[0059] N.sub.5,
1-Di-(tert-butoxycarbonyl)-5-amino-7-(benzyloxy)-4-iodoind- ol e
(10d).
[0060] Sodium methoxide in methanol (2M, 0.224 mL, 0.44 mmol) was
added to a stirred solution of compound (311) (150 mg, 0.22 mmol)
in dichloromethane (5 mL). After 10 min at RT, water (25 mL) and
ethyl acetate (25 mL) were added and the organic layer was
separated. The aqueous layer was extracted with ethyl acetate (25
mL) and the combined organic layers were dried (MgSO.sub.4) and
concentrated. Chromatography (2.times.15 cm SiO.sub.2, gradient
elution ethyl acetate/hexanes 1:9 to ethyl acetate/hexanes 1:3)
gave the pure compound (102 mg, 82%), Rf 0.8 (SiO.sub.2,, ethyl
acetate/hexanes 1:3) as a colourless oil: .sup.1H NMR (CDCl.sub.13,
400 MHz) 7.83 (br s, 1H, NH), 8.00 (d, 1H, J=6.8 Hz), 7.53 (m, 3H
(1H+2H), 7.37 (m, 3H), 6.84 (br s, 1H), 6.45 (d, 1H, J=3.4 Hz),
5.21 (s, 2H), 1.54 (s, 9H), 1.45 (s, 9H);IR (neat) .nu..sub.max
3395, 2977, 1759, 1727, 1603, 1577, 1517, 1367, 1346, 1228, 1154,
1111 cm.sup.-1; FABHRMS (NBA-CsI) m/z 697.0176 (M+Cs.sup.+,
C.sub.25H.sub.29IN.sub.2O.sub.5 requires 697.0176).
[0061] N.sup.5-(3-Chloro-2-propen-1-yl)-N.sup.5,
1-di-((tert-butyloxy)carb- onyl)-5-amino-7-(benzyloxy)-4-iodoindole
(11d).
[0062] Sodium hydride (22 mg, 0.54 mmol, 3 eq, 60% dispersion) was
added to a stirred solution of compound (10d) (100 mg, 0.18 mmol)
in DMF (5 mL). After 15 min at RT, E/Z-1,3-dichloropropene (0.025
mL, 0.27 mmol) was added. The solution was stirred at Rt for 1 hr.
Water (50 mL) and ethyl acetate (50 mL) were then added and the
organic layer was separated. The aqueous layer was extracted with
ethyl acetate (50 mL) and the combined organic layers were dried
(MgSO.sub.4) and concentrated. Chromatography (2.times.15 cm
SiO.sub.2, ethyl acetate/hexanes 1:9) gave the pure compound (75.4
mg, 66%) as a mixture of E and Z isomers: .sup.1H NMR (CDCl.sub.13,
400 MHz) major rotamer 7.47 (br s, 1H), 7.36 (m, 5H), 6.53 (m, 1H),
6.00 (m, 2H), 5.17 (s, 2H), 4.51 (m, 1H), 4.11 (m, 1H), 1.54 (s,
9H), 1.25 (s, 9H); IR (neat) .nu..sub.max 2976, 1759, 1701, 1630,
1570, 1367, 1157 cm; FABHRMS (NBA-CsI) m/z 771.0125 (M+Cs.sup.-,
C.sub.28H.sub.32ClIN.sub.2O.sub.5 requires 771.0099)
* * * * *