A convergent synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists

Article abstract of DOI:10.1016/S0040-4020(01)00367-2

A practical synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists which features a palladium-catalyzed Larock indole synthesis and a palladium-catalyzed Suzuki-Miyaura sequence to install the 2-position aryl substitue

Full text of DOI:10.1016/S0040-4020(01)00367-2

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 5233±5241
A convergent synthesis of ꢀS)-b-methyl-2-aryltryptamine based
gonadotropin releasing hormone antagonists
Thomas F. Walsh,p Richard B. Toupence, Feroze Ujjainwalla,
Jonathan R. Young and Mark T. Goulet
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, USA
Dedicated to Professor Barry M. Trost, with friendship and gratitude, on the occasion of his 60th birthday
Received 16 February 2001; revised 14 March 2001; accepted 15 March 2001
AbstractÐA practical synthesis of 0S)-b-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists which features a
palladium-catalyzed Larock indole synthesis and a palladium-catalyzed Suzuki±Miyaura sequence to install the 2-position aryl substituent is
reported. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
0SAR) studies. These efforts established the importance of
methyl substitution on the 2-position phenyl group, the
preference for a carboxamide at the 5-position of the indole
nucleus, and identi®ed several potency enhancing trypt-
amine sidechains. Additionally, the discovery of the 0S)-b-
methyl substituent on the 3-position side chain has particu-
lar signi®cance for its unique contribution to receptor bind-
ing speci®city.7 We became interested in further exploring
the SAR of the indole substituents. In particular, we sought
to evaluate the consequence on receptor binding af®nity of a
3,4,5-trimethylphenyl substituent at the indole 2-position
0e.g. 2), since this substituent had afforded signi®cant
potency enhancement when it was incorporated at the
3-position in our quinolone series of GnRH antagonists.5d
Gonadotropin Releasing Hormone 0GnRH) is a decapeptide
produced in the hypothalamus, which interacts with speci®c
membrane-associated GnRH receptors on gonadotroph cells
of the pituitary. Peptidic antagonists of GnRH receptors are
undergoing clinical development for their ability to block
the subsequent secretion of the pituitary hormones luteiniz-
ing hormone and follicle-stimulating hormone which
follows upon activation of the GnRH receptor by its
hormone.1 Luteinizing hormone released by the pituitary
is primarily responsible for the regulation of gonadal steroid
production in both sexes, therefore, GnRH antagonists
can achieve a gender-independent suppression of gonadal
steroid hormones to castrate levels. This reversible suppres-
sion of the pituitary-gonadal axis offers therapeutic bene®t
for the management of several pathological states exacer-
bated by these hormones such as hormone-dependent
cancers, endometriosis, and precocious puberty.2,3
The original preparation of 2-aryltryptamines used in our
laboratories was based upon a Fisher indole synthesis. The
key step involved reaction of a 4-substituted phenylhydra-
zine with a substituted 3-chloropropyl phenyl ketone to
afford the desired 2-aryltryptamine as a minor product and
a tetrahydropyridazine side product which predominated.
Unfortunately, when the 4-position substituent on the
phenylhydrazine was an electron releasing group, the
yield for the tryptamine in this reaction was further reduced
to approximately 15%. The low yield for this step was a
In 1998, researchers from Takeda described a non-peptidic
GnRH receptor antagonist which demonstrated for the ®rst
time that an orally bioavailable therapeutic agent in this
class might be developed.4 More recent reports from our
laboratories have described the discovery and pharmaco-
logical characterization of two new classes of potent, non-
peptidic GnRH receptor antagonists based upon 3-aryl-
quinolone5 and 2-aryltryptamine6 scaffolds. This latter series
of antagonists, exempli®ed by compound 1 0Fig. 1), has
been the subject of extensive structure±activity relationship
Keywords: antagonists; asymmetric synthesis; boron heterocycles; gonado-
tropin; indoles; Larock reactions; receptors; Suzuki reactions.
p
Corresponding author. Tel.: 11-732-594-5232; fax: 11-732-594-2210;
e-mail: thomas_walsh@merck.com
Figure 1. Gonadotropin releasing hormone antagonists 1 and 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00367-2

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T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
Scheme 1. Retrosynthetic analysis for GnRH antagonists related to 1.
particular concern to us when we attempted to incorporate
the 0S)-b-methyl substituent in the tryptamine sidechain.
As a consequence, we also sought to develop a more con-
vergent and high yielding synthesis for this series of
compounds to support our SAR studies.
shown retrosynthetically in Scheme 1. Alternatively, inter-
mediate 3 might be obtained from compounds 4 and the
more readily available aryl halides or tri¯ates using the
Suzuki±Miyaura coupling protocol.9 It was expected that
the 0S)-b-methyl-2-iodotryptophols 04) would be available
from 0S)-b-methyl-2-triethylsilyltryptophols 5 by an iodo-
desilylation reaction, and that these latter compounds 05)
could be prepared using the Larock indole synthesis.10 In
fact, the Larock cyclization of ortho-iodoanilines 06) with
triethylsilylacetylene partners has been reported to proceed
with high chemical yields and excellent regiochemical
control.11 Finally, we recognized that the requisite
silylacetylene 7 could be obtained from 0R)-3-benzyloxy-
2-methylpropanal12 010) via a Corey±Fuchs ethynylation
sequence.13 Herein, we report the realization of this synthetic
strategy and illustrate it with the synthesis of the 3,4,5-
trimethylphenyl substituted GnRH antagonist 2 0Fig. 1).
2. Results and discussion
A previous report from this laboratory documented the
utility of the palladium-catalyzed cross-coupling reaction
of 2-bromotryptamines with arylboronic acids to afford 2-
aryltryptamines.8 We envisioned that GnRH antagonists
related to 1 might be synthesized from 0S)-b-methyl-2-aryl-
tryptophol derivatives 03), which could also be prepared by
palladium-catalyzed cross-coupling reactions of 0S)-b-
methyl-2-iodotryptophols 4 with arylboronic acids as
Scheme 2. Synthesis of alkynylsilane 7. 0a) cyclohexane±CCl4 02:1), benzyl 2,2,2-trichloroacetimidate, CF3SO3H 0cat.), rt, 16 h, 74%. 0b) LiAlH4, THF, rt,
4 h, 89%. 0c) 0i) 0COCl)2, DMSO, CH2Cl2, 2608C; 0ii) i-Pr2NEt. 0d) PPh3, CBr4, CH2Cl2, 0±58C, 15 min, 81% 02 steps). 0e) 0i) n-BuLi, THF, 2788C, 1 h; 0ii)
Et3SiCl, 0±108C, 1 h, 94%.
Scheme 3. Synthesis of ortho-iodoanilines 6a and b. 0a) NaH, THF, CH3I, 108C±rt, 1 h, 90%. 0b) H2 045 psig), 10% Pd/C, EtOH, rt, 1.5 h, 99%. 0c) ICl,
CaCO3, MeOH±H2O, rt, 30 min, 93%. 0d) NaOH, MeOH, 608C, 4 h, 97%. 0e) 0i) 0COCl)2, DMF 0cat.), toluene, 808C; 0ii) amine´HCl 16, Et3N, CH2Cl2, rt,
12 h, 96%. 0f) H2 045 psig), 10% Pd/C, EtOH, rt, 1 h, 100%. 0g) ICl, CaCO3, MeOH±H2O, rt, 30 min, 97%.

T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
5235
Scheme 4. Larock synthesis of 0S)-b-methyltryptophol derivatives 19a and 19b. 0a) Pd0OAc)2, PPh3, LiCl, K2CO3, DMF, 1008C, 16 h. Yield:19a, 89%; 19b,
72%.
The synthesis of 0S)-04-benzyloxy-3-methylbut-1-ynyl)-
triethylsilane 07) is illustrated in Scheme 2. Commercially
available methyl 0R)-02)-3-hydroxy-2-methylpropionate 8
was protected as its O-benzyl ether14 with benzyl 2,2,2-
trichloroacetimidate then reduced to the alcohol 9 with
lithium aluminum hydride. Reoxidation of 9 using the
Swern±Moffatt procedure15 afforded the previously
reported aldehyde12 10, which was immediately subjected
to reaction with carbon tetrabromide and triphenyl-
phosphine using the Corey conditions13 to provide dibro-
moole®n 11 in 81% yield for the two steps. Treatment of
11 with 2 equivalents of n-butyllithium followed by addition
of chlorotriethylsilane then afforded 7 in 94% yield.
afforded by incorporating the desired amide early in the
synthesis justi®ed using this reaction for the synthesis of
GnRH antagonist 2.
With the Larock indole synthesis of 0S)-b-methyltryptophol
derivatives 19b established, we next turned our attention
towards introduction of the 2-position phenyl group.
Silver-assisted iododesilylation18 of the silyl intermediate
19b proceeded in excellent yield to afford iodide 20, in
which the 2-iodo group is ideally suited to serve as the
electrophilic component in
a subsequent palladium-
catalyzed cross-coupling reaction. Commercially available
3,4,5-trimethylphenol offered convenient access to the
boronic acid derivative 21 suitable for the proposed cross-
coupling with 20. The phenol was ®rst converted to its
tri¯ate using tri¯uoromethanesulfonic anhydride in pyridine
in 80% yield. The resulting tri¯ate was submitted to a
palladium-catalyzed reaction with bis0pinacolato)diboron
which furnished 4,4,5,5-tetramethyl-2-03,4,5-trimethyl-
phenyl)-1,3,2-dioxaborolane 021) in 98% yield. Boronate
21 underwent a Suzuki cross-coupling reaction with 2-
iodoindole 20 0Scheme 5) using 0dppf)palladium0II)
dichloride as catalyst in 96% yield which afforded the 2-
arylindole 22 and completed construction of the carbon
skeleton of the target compounds.
Two ortho-iodoanilines 06a,b) were prepared as shown in
Scheme 3 and subsequently evaluated in the Larock indole
synthesis. Ethyl 04-nitrophenyl)acetate 012) was gem-
dimethylated to afford ester 13 as previously described.6e,16
Catalytic hydrogenation of 13 followed by reaction of the
resulting aniline with iodine monochloride and calcium car-
bonate in aqueous methanol11 gave ortho-iodoaniline 6a in
over 90% for the two latter steps. The amide-substituted
ortho-iodoaniline 6b was prepared in four steps beginning
with the hydrolysis of ester 13. The resulting carboxylic acid
15 was converted to its acid chloride using oxalyl chloride
in toluene in the presence of a catalytic amount of dimethyl-
formamide. Reaction of the intermediate acid chloride with
7-azabicyclo[2.2.1]heptane hydrochloride 016)17 afforded
amide 17 in 96% yield. Catalytic hydrogenation of 17,
followed by iodination of the resulting aniline 18 as
described above provided the amido-substituted ortho-
iodoaniline 6b.
The ®nal steps for the synthesis of GnRH antagonist 2 are
illustrated in Scheme 5. The indole nitrogen was protected
as its tert-butylcarbamate 023) and the O-benzyl ether was
removed from the sidechain by catalytic hydrogenolysis to
provide tryptophol 24. We then examined several methods
for the conversion of tryptophol 24 to tryptamine deriva-
tives. While the displacement of leaving groups derived
from less sterically hindered tryptophols with amine nucleo-
philes is precedented,9 these methods were unsuccessful
using tryptophol 24. As an alternative, we found that 24
smoothly underwent a Mitsunobu reaction with zinc
azide±pyridine complex19 in 93% yield to afford a primary
azide 025). Reduction of the azide using catalytic hydro-
genation conditions in turn provided tryptamine 26.
Incorporation of the pyridylethyl sidechain was accomp-
lished using a Fukuyama±Mitsunobu process.20 The ®rst
step of this process was to convert tryptamine 26 to its 2,4-
dinitrobenzenesulfonamide derivative 27 under Schotten±
Baumann conditions. Reaction of sulfonamide 27 with 4-02-
hydroxyethyl)pyridine in the presence of diethylazodicar-
boxylate and triphenylphosphine in benzene afforded a
tertiary sulfonamide which was directly deprotected by n-
propylamine in methylene chloride to afford the secondary
amine 28 in 76% yield for the two steps. Finally, removal of
the tert-butylcarbamate protecting group from intermediate
We next turned our attention towards examination of the
Larock indole synthesis of the ortho-iodoanilines 6a and b
with alkynylsilane 7. Reaction of 6a and 7 in dimethyl-
formamide at 1008C using catalytic palladium acetate
05 mol%) and triphenylphosphine 05 mol%) in the presence
of one equivalent of lithium chloride and 2.5 equivalents of
potassium carbonate afforded after 14 h, an excellent 89%
yield of the 2-silylindole 19a with no regioisomeric product
detected. In fact, at an early stage of our investigations, we
examined the Larock reaction of ortho-iodoaniline 6a and
an alkynylsilane related to 7 bearing a tert-butyl protecting
group on the alcohol instead of the O-benzyl ether. In that
example, we observed a nearly quantitative yield of the
corresponding 2-silylindole. When ortho-iodoaniline 6b
was subjected to reaction with 7 under identical conditions,
2-silylindole 19b was isolated in 72% yield 0Scheme 4).
Although the diminished yield obtained in this case was
somewhat disappointing, we felt that the convergence

5236
T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
Scheme 5. Completion of the synthesis of GnRH antagonist 2. 0a) AgBF4, ICl, MeOH±THF 01:1), 08C, 15 min, 92%. 0b) 0dppf)PdCl2´CH2Cl2, toluene±EtOH±
2 M Na2CO3 07:2:1), 858C, 15 h, 96%. 0c) 0BOC)2O, DMAP, CH2Cl2, rt, 2 h. 0d) H2 040 psig), 10% Pd/C 0Degussa E101), EtOH, rt, 3 h, 94% 02 steps). 0e)
Zn0N3)2´2 Pyr, DEAD, PPh3, imidazole, CH2Cl2, rt, 24 h, 90%. 0f) H2 01 atm), 10% Pd/C, EtOH, rt, 15 h, 95%. 0g) 2,4-dinitrobenzenesulfonyl chloride,
CH2Cl2, sat. aq. NaHCO3, 08C to rt, 30 min, 93%. 0h) 4-02-hydroxyethyl)pyridine, DEAD, PPh3, C6H6, rt, 1 h. 0i) n-PrNH2, CH2Cl2, rt, 30 min, 76% 02 steps).
0j) CF3CO2H, CH2Cl2, rt, 12 h, 94%.
28 using tri¯uoroacetic acid followed by puri®cation using
reversed-phase HPLC afforded the targeted GnRH antago-
nist 2 as its tri¯uoroacetic acid salt in 94% yield.
reaction mixture was stirred under a nitrogen atmosphere
and cooled to 2788C with an external dry ice±acetone bath.
A solution of methyl sulfoxide 029.607 g; 0.379 mol) in
85 mL CH2Cl2 was then added over 5 min to the reaction
mixture via cannula. After the addition, the reaction was
stirred an additional 5 min and then a solution of 31.048 g
00.172 mol) of 0S)-3-benzyloxy-2-methylpropan-1-ol 09)12
in 170 mL CH2Cl2 was added via cannula. When the second
addition was completed, the reaction mixture was stirred for
15 min at 2788C then 111.32 g 00.861 mol) of N,N-diiso-
propylethylamine was added via syringe. The reaction
mixture was stirred an addition 15 min at 2788C, the cool-
ing bath was removed and the reaction was allowed to
warm. When the internal temperature had reached 2158C,
350 mL of a 10% aqueous NaHSO4 solution was slowly
added and the mixture was transferred to a separatory
funnel. The organic layer was separated, washed with
aqueous NaHSO4 02£250 mL), saturated brine, dried
0MgSO4), ®ltered and evaporated. The residue was used
immediately in the next step without further puri®cation.
3. Conclusions
In summary, we have described a convergent synthesis for
analogs of GnRH antagonist 1 which proceeds in 15 steps
and an acceptable 20% overall yield from commercially
available 0R)-02)-3-hydroxy-2-methylpropionate. Since the
protodesilylation of 2-silyltryptophols related to 19a and b
has been previously described,11 the synthetic strategy
described herein is also applicable for the preparation of
pharmaceutically interesting tryptophol or tryptamine
derivatives with branched sidechains and devoid of the 2-
position aryl group.
4. Experimental
4.1.2. ꢀS)-4-Benzyloxy-1,1-dibromo-3-methylbut-1-ene ꢀ11).
An oven-dried three-necked 2 L round bottom ¯ask was
equipped with a mechanical stirrer, a thermometer, a nitro-
gen inlet, and a septum. The ¯ask was charged with
180.71 g 00.689 mol) of triphenylphosphine and 925 mL
of CH2Cl2. The reaction mixture was stirred under a nitrogen
atmosphere and cooled to 0±58C with an external ice-water
4.1. Data for compounds
4.1.1. ꢀS)-3-Benzyloxy-2-methylpropanal ꢀ10). An oven-
dried three-necked 2 L round bottom ¯ask was equipped
with a mechanical stirrer, a thermometer, a nitrogen inlet,
and a septum. The ¯ask was charged with 24.050 g
00.189 mol) of oxalyl chloride and 425 mL CH2Cl2. The

T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
5237
bath. The septum was then removed and 114.25 g
00.344 mol) of carbon tetrabromide was added in portions
through the open neck of the ¯ask at a rate that maintained
the temperature of the reaction mixture below 208C. After
the addition was complete, the reaction was stirred for 1 h
then a solution of the 0S)-3-benzyloxy-2-methylpropanal
010)12 prepared in the preceding step dissolved in 150 mL
of CH2Cl2 was added via cannula over a 5 min period. The
reaction mixture was stirred under nitrogen for an additional
1 h and allowed to warm to room temperature. A separate
10 L three-necked round bottom ¯ask was equipped with a
mechanical stirrer and charged with 4 L of hexane. The
stirrer was started and the crude reaction mixture was intro-
duced as a slow stream, which resulted in formation of a
granular precipitate. After the transfer was complete, the
reaction mixture was ®ltered and the solids were carefully
washed with hexane. The ®ltrate was evaporated in vacuo
and additional solids were deposited. The residue was resus-
pended in hexane, ®ltered and evaporated, then puri®ed by
Kugelrohr distillation to afford 46.54 g 081% two steps) of a
colorless oil.
stir bar was charged with a solution of 27.176 g 00.131 mol)
of the aniline 14 dissolved in 250 mL methanol, 19.685 g
00.197 mol) calcium carbonate, and 125 mL water. The
heterogeneous mixture was vigorously stirred at room
temperature and 23.416 g 00.144 mol) of iodine mono-
chloride dissolved in 10 mL methanol was added dropwise.
The reaction became warm and was allowed to cool to room
temperature while stirring for 30 min. The reaction mixture
was partitioned between EtOAc and 5% aqueous sodium
thiosulfate. The organic layer was separated, washed with
water, saturated brine, then dried 0MgSO4), ®ltered and
evaporated. The residue was puri®ed on a silica gel ¯ash
chromatography column eluted with CHCl3. Evaporation of
the puri®ed fractions and drying in vacuo afforded 093%) of
a nearly colorless oil.
1H NMR 0500 MHz, CDCl3) d: 1.17 0t, Jˆ7.0 Hz, 3H), 1.49
0s, 6H), 3.85±4.10 0brs, 2H), 4.08 0q, Jˆ7.0 Hz, 2H), 6.68
0d, Jˆ8.5 Hz, 1H), 7.10 0dd, Jˆ2.0, 8.5 Hz, 1H), 7.58 0d,
Jˆ2.0 Hz, 1H) ppm; 13C NMR 0125 MHz, CDCl3) d: 14.05,
26.43 02C), 45.22, 60.79, 84.19, 114.50, 126.99, 136.02,
136.53, 145.15, 176.48 ppm; MS 0ES) m/z: 334.0 [MH1].
1H NMR 0500 MHz, CDCl3) d: 1.10 0d, Jˆ7.0 Hz, 3H),
2.78±2.86 0m, 1H), 3.38±3.45 0m, 2H), 4.54 0d,
Jˆ15.5 Hz, 1H), 4.56 0d, Jˆ15.5 Hz, 1H), 6.35 0d,
Jˆ9.0 Hz, 1H), 7.28±7.41 0m, 5H) ppm; 13C NMR
0125 MHz, CDCl3) d: 15.85, 38.74, 72.95, 73.02, 88.83,
127.51 02C), 127.58, 128.35 02C), 138.21, 141.13 ppm;
MS 0CI, NH3) m/z: 351.9 [M1NH41].
4.1.5. 4-[2-ꢀ7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-
2-oxoethyl]-2-iodoaniline ꢀ6b). A 500 mL round bottom
¯ask equipped with a magnetic stir bar was charged with
a solution of 16.525 g 00.064 mol) of the aniline 18
dissolved in 130 mL methanol, 9.603 g 00.096 mol) calcium
carbonate, and 65 mL water. The heterogeneous mixture
was vigorously stirred at room temperature and 11.423 g
00.070 mol) of iodine monochloride dissolved in 5 mL
methanol was added dropwise. The reaction became warm
and was allowed to cool to room temperature while stirring
for 30 min. The reaction mixture was partitioned between
EtOAc and 5% aqueous sodium thiosulfate. The organic
layer was separated, washed with water, saturated brine,
then dried 0MgSO4), ®ltered and evaporated. The product
was puri®ed by recrystallization from ether±hexane to
afford 23.840 g 097%) of a tan solid.
4.1.3. ꢀS)-ꢀ4-Benzyloxy-3-methylbut-1-ynyl)triethylsilane
ꢀ7). An oven-dried 250 mL single-necked round bottom
¯ask was equipped with a magnetic stir bar and a septum
then charged with 12.086 g 036.2 mmol) of dibromoole®n
11 and 45 mL of anhydrous THF. The reaction mixture was
stirred at 2788C under a nitrogen atmosphere and 28.9 mL
of a 2.5 M solution of n-butyllithium in hexanes 031.0 mmol)
was added dropwise via syringe over 15 min. The reaction
mixture was stirred at 2788C for 1 h, then warmed to room
temperature and stirred for an additional 1 h. The reaction
mixture was then recooled to 08C with an external ice-water
bath and 6.98 mL 06.27 g; 41.6 mmol) of chlorotriethyl-
silane was added to the reaction mixture via syringe. The
reaction mixture was stirred an additional 1 h at 0±108C,
then quenched with excess 10% aqueous NaHSO4. The
mixture was diluted with water and the organic product
extracted into EtOAc. The organic layer was washed with
water 03£25 mL), saturated brine, then dried 0MgSO4),
®ltered, and evaporated. The residue was puri®ed by Kugel-
rohr distillation to afford 9.833 g 094%) of the title
compound as a colorless oil.
1H NMR 0400 MHz, CDCl3) d: 1.14±1.40 0m, 6H), 1.43 0s,
6H), 1.45±1.72 0m, 2H), 3.62±3.68 0brs, 1H), 4.65±4.73
0brs, 3H), 6.78 0d, Jˆ8.4 Hz, 1H), 7.05 0dd, Jˆ2.0,
8.4 Hz, 1H), 7.52 0d, Jˆ2.0 Hz, 1H) ppm; 13C NMR
0125 MHz, CDCl3) d: 27.93 02C), 28.81 02C), 30.01 02C),
46.22, 53.79, 55.78, 84.41, 114.87, 126.44, 135.69, 138.62,
144.79, 171.68 ppm; MS 0ES) m/z: 385.0 [MH1].
4.1.6. Ethyl 2-[3-[ꢀ1S)-2-ꢀbenzyloxy)-1-methylethyl]-2-
ꢀtriethylsilyl)-1H-indol-5-yl]-2-methylpropanoate ꢀ19a).
An oven-dried 50 mL round bottom ¯ask equipped with a
magnetic stir bar was charged sequentially with 1.660 g
04.98 mmol) of iodoaniline 6a, 2.300 g 07.97 mmol) of alky-
nylsilane 7, 1.722 g 012.5 mmol) potassium carbonate,
0.211 g 04.98 mmol) lithium chloride, 0.065 g 00.25 mmol)
triphenylphosphine, 25 mL anhydrous DMF and 0.056 g
00.25 mmol) of palladium acetate. The atmosphere in the
¯ask was replaced with dry nitrogen and the reaction
mixture was stirred and heated at 1008C with an external
oil bath for 14 h. The reaction mixture was then cooled to
room temperature and partitioned between EtOAc and
water. The organic layer was separated, washed with
water 03£), saturated brine, then dried 0MgSO4), ®ltered
1H NMR 0400 MHz, CDCl3) d: 0.57 0q, Jˆ8.0 Hz, 6H), 0.98
0t, Jˆ8.0 Hz, 9H), 1.22 0d, Jˆ7.2 Hz, 3H), 2.78 0m, 1H),
3.37 0dd, Jˆ6.0, 9.2 Hz, 1H), 3.56 0dd, Jˆ6.0, 9.2 Hz, 1H),
4.54 0d, Jˆ9.6 Hz, 1H), 4.57 0d, Jˆ9.6 Hz, 1H), 7.26±7.36
0m, 5H) ppm; 13C NMR 0125 MHz, CDCl3) d: 4.49 03C),
7.43 03C), 17.99, 27.76, 72.95, 74.23, 82.07, 110.21, 127.46
02C), 127.49, 128.29 02C), 138.37 ppm; MS 0ES) m/z: 289.1
[MH1].
4.1.4. Ethyl 2-ꢀ4-amino-3-iodophenyl)-2-methylpropano-
ate ꢀ6a). A 1 L round bottom ¯ask equipped with a magnetic

5238
T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
and evaporated. The residue was puri®ed on a silica gel ¯ash
chromatography column eluted with 10% EtOAc±hexane.
Evaporation of the puri®ed fractions afforded 2.190 g 089%)
of a pale yellow to colorless oil.
was ®ltered and the precipitate was washed thoroughly
with EtOAc. The combined EtOAc solutions were washed
sequentially with 10% aqueous sodium thiosulfate, water,
saturated brine, then dried 0MgSO4), ®ltered and evapo-
rated. The residue was puri®ed on a silica gel ¯ash chroma-
tography column eluted with 35% EtOAc±hexane.
Evaporation of the puri®ed fractions and drying in vacuo
afforded 1.956 g 092%) of a light yellow solid.
1H NMR 0500 MHz, CDCl3) d: 0.83 0q, Jˆ8.0 Hz, 6H), 0.94
0t, Jˆ8.0 Hz, 9H), 1.15 0t, Jˆ7.0 Hz, 3H), 1.49 0d,
Jˆ7.0 Hz, 3H), 1.55 0s, 3H), 1.56 0s, 3H), 3.28±3.36 0m,
1H), 3.62 0dd, Jˆ5.0, 9.5 Hz, 1H), 3.87 0t, Jˆ9.5 Hz, 1H),
4.07 0q, Jˆ7.0 Hz, 2H), 4.51 0s, 2H), 7.10 0dd, Jˆ1.5,
8.5 Hz, 1H), 7.20±7.32 0m, 6H), 7.57 0d, Jˆ1.5 Hz, 1H),
7.78 0brs, 1H) ppm; 13C NMR 0125 MHz, CDCl3) d: 3.72
03C), 7.41 03C), 14.12, 18.26, 27.00, 27.09, 34.45, 46.26,
60.58, 72.89, 74.95, 110.86, 117.11, 120.27, 127.02, 127.40
02C), 127.62 02C), 128.25 02C), 131.53, 135.26, 137.89,
138.66, 177.35 ppm; MS 0ES) m/z: 494.0 [MH1].
1H NMR 0500 MHz, CDCl3) d: 1.02±1.35 0brm, 6H), 1.47
0d, Jˆ7.0 Hz, 3H), 1.56 0s, 3H), 1.57 0s, 3H), 1.55±1.70
0brm, 2H), 3.32±3.39 0m, 1H), 3.57±3.65 0brs, 1H),
3.72±3.83 0m, 2H), 4.53 0d, Jˆ15.0 Hz, 1H), 4.56 0d,
Jˆ15.0 Hz, 1H), 4.72±4.82 0brs, 1H), 7.08 0dd, Jˆ1.5,
8.5 Hz, 1H), 7.27 0d, Jˆ8.5 Hz, 1H), 7.25±7.35 0m, 5H),
7.32 0d, Jˆ1.5 Hz, 1H), 7.52 0s, 1H), 8.47 0brs, 1H) ppm;
13C NMR 0125 MHz, CDCl3) d: 17.14, 28.31, 28.66, 28.80
02C), 29.82 02C), 34.75, 47.09, 53.81, 55.74, 72.70, 74.15,
78.67, 110.73, 114.84, 119.39, 122.51, 126.22, 127.32,
127.43 02C), 128.19 02C), 137.14, 138.12, 138.44,
172.66 ppm; MS 0ES) m/z: 557.1 [MH1].
4.1.7. 5-[2-ꢀ7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-
2-oxoethyl]-3-[ꢀ1S)-2-ꢀbenzyloxy)-1-methylethyl]-2-
ꢀtriethylsilyl)-1H-indole ꢀ19b). An oven-dried 250 mL
round bottom ¯ask equipped with a magnetic stir bar and
a
septum, was charged sequentially with 7.188 g
018.7 mmol) of iodoaniline 6b, 9.188 g 031.8 mmol) of
alkynylsilane 7, 6.463 g 046.8 mmol) potassium carbonate,
0.793 g 018.7 mmol) lithium chloride, 0.245 g 00.94 mmol)
triphenylphosphine, 100 mL anhydrous DMF and 0.210 g
00.94 mmol) of palladium acetate. The atmosphere in the
¯ask was replaced with dry nitrogen, and the reaction
mixture was stirred and heated at 1008C with an external
oil bath for 16 h. The reaction mixture was then cooled to
room temperature and partitioned between EtOAc 0250 mL)
and water 0250 mL). The organic layer was separated,
washed with water 03£), saturated brine, then dried
0MgSO4), ®ltered and evaporated. The residue was puri®ed
on a silica gel ¯ash chromatography column eluted with
35% EtOAc±hexane. Evaporation of the puri®ed fractions
afforded 7.326 g 072%) of an off-white crystalline solid.
4.1.9.
4,4,5,5-Tetramethyl-2-ꢀ3,4,5-trimethylphenyl)-
1,3,2-dioxaborolane ꢀ21). A 100 mL round bottom ¯ask
equipped with a magnetic stirring bar was charged sequen-
tially with 2.587 g 09.64 mmol) 3,4,5-trimethylphenyl tri¯ate,
2.694 g 010.6 mmol) bis0pinacolato)diboron, 50 mL anhy-
drous methyl sulfoxide, 2.840 g 028.9 mmol) potassium
acetate, and 0.236 g 00.29 mmol) [1,10-bis0diphenylphos-
phino)ferrocene]dichloro-palladium0II)´CH2Cl2 complex.
The reaction mixture was stirred at 808C under a nitrogen
atmosphere for 2 h, then cooled to room temperature and
partitioned between EtOAc and water. The resulting emul-
sion was ®ltered through Celite and the clari®ed layers were
separated. The organic layer was washed with saturated
brine, dried 0MgSO4), ®ltered and evaporated. The residual
oil was puri®ed by ®ltration through a silica gel pad eluted
with 5% EtOAc±hexane. Evaporation of the ®ltrate afforded
2.340 g 098%) of a white crystalline solid.
1H NMR 0500 MHz, CDCl3) d: 0.87 0q, Jˆ7.5 Hz, 6H), 0.96
0t, Jˆ7.5 Hz, 9H), 0.98±1.34 0brm, 6H), 1.47 0d, Jˆ7.0 Hz,
3H), 1.50±1.72 0brm, 2H), 1.52 0s, 3H), 1.53 0s, 3H),
3.27±3.36 0m, 1H), 3.55±3.64 0m, 2H), 3.83 0t, Jˆ9.0 Hz,
1H), 4.47 0d, Jˆ12.0 Hz, 1H), 4.53 0d, Jˆ12.0 Hz, 1H),
4.66±4.78 0brs, 1H), 7.06 0dd, Jˆ1.5, 8.5 Hz, 1H),
7.21±7.32 0m, 6H), 7.48 0s, 1H), 7.79 0s, 1H) ppm; 13C
NMR 0125 MHz, CDCl3) d: 3.76 03C), 7.46 03C), 18.31,
28.43, 28.56 02C), 28.79, 29.96 02C), 34.51, 47.13, 53.66,
55.69, 72.90, 74.99, 111.00, 117.13, 119.38, 127.28, 127.37,
127.49, 127.54 02C), 128.23 02C), 131.81, 136.86, 137.87,
138.64, 172.75 ppm; MS 0ES) m/z: 545.1 [MH1].
1H NMR 0400 MHz, CDCl3) d: 1.35 0s, 12H), 2.20 0s, 3H),
2.30 0s, 6H), 7.47 0s, 2H) ppm; 13C NMR 0125 MHz, CDCl3)
d: 15.64, 20.29 02C), 24.82 04C), 83.52 02C), 133.88 04C),
135.78, 138.76 ppm; MS 0EI) m/z: 246.2 [M1].
4.1.10. 5-[2-ꢀ7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-
2-oxoethyl]-3-[ꢀ1S)-2-ꢀbenzyloxy)-1-methylethyl]-2-ꢀ3,4,5-
trimethylphenyl)-1H-indole ꢀ22). A 100 mL round bottom
¯ask equipped with a magnetic stir bar was charged with
2.527 g 04.54 mmol) of iodoindole 20 and 1.677 g
06.81 mmol) of boronate 21. Toluene 013 mL) and ethanol
05.2 mL) were added and the reaction mixture was stirred at
room temperature until the solids had dissolved, then
0.185 g 00.23 mmol) [1,10-bis0diphenylphosphino)ferro-
cene]dichloro-palladium0II) complex with CH2Cl2 was
added and the atmosphere in the ¯ask was replaced with
dry nitrogen. The reaction mixture was then stirred and
heated to 808C with an external oil bath and ®nally
2.6 mL of a 2.0 M aqueous sodium carbonate was added
dropwise. The reaction mixture was stirred at 808C for
15 h, then cooled to room temperature and partitioned
between EtOAc and 10% aqueous NaHSO4. The organic
layer was separated, washed with saturated brine, dried
4.1.8. 5-[2-ꢀ7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-
2-oxoethyl]-3-[ꢀ1S)-2-ꢀbenzyloxy)-1-methylethyl]-2-
iodo-1H-indole ꢀ20). A 100 mL round bottom ¯ask
equipped with a magnetic stir bar was charged with
2.092 g 03.84 mmol) of the silylindole 19b dissolved in
7.0 mL THF. Methanol 07.0 mL) was added, followed by
0.822 g 04.22 mmol) of silver tetra¯uoroborate. The reac-
tion mixture was stirred at room temperature until homo-
genous, then cooled to 08C with an external ice-water bath.
A solution of 0.686 g 04.22 mmol) of iodine monochloride
in 5.0 mL methanol was then added over 5 min to the vigor-
ously stirred mixture. After 15 min, the reaction mixture

T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
5239
0MgSO4), ®ltered and evaporated. The residual oil was puri-
®ed on a silica gel ¯ash chromatography column eluted with
35% EtOAc±hexane. Evaporation of the puri®ed fractions
and drying in vacuo afforded 2.397 g 096%) of a tan amor-
phous solid.
1H NMR 0500 MHz, CDCl3) d: 1.08±1.40 0brm, 6H), 1.22
0s, 9H), 1.30 0d, Jˆ7.0 Hz, 3H), 1.52±1.75 0brm, 2H), 1.59
0s, 3H), 1.60 0s, 3H), 2.24 0s, 3H), 2.33 0s, 6H), 3.25±3.31
0m, 1H), 3.58±3.75 0brs, 1H), 3.75 0dd, Jˆ6.5, 10.5 Hz,
1H), 3.87 0dd, Jˆ6.5, 10.5 Hz, 1H), 4.68±4.85 0brs, 1H),
6.92±7.20 0brs, 2H), 7.30 0dd, Jˆ1.5, 9.0 Hz, 1H), 7.51 0d,
Jˆ1.5 Hz, 1H), 8.20 0d, Jˆ9.0 Hz, 1H) ppm; 13C NMR
0125 MHz, CDCl3) d: 15.21, 16.67, 20.51 02C), 27.38
03C), 28.32, 28.50, 28.86 02C), 29.99 02C), 34.38, 47.18,
53.74, 55.73, 66.50, 82.83, 115.23, 116.79, 120.24,
121.03, 128.17, 129.08 02C), 130.59, 134.57, 135.40,
135.73 02C), 137.95, 140.65, 150.09, 172.31 ppm; MS
0ES) m/z: 558.4 [MH1].
1H NMR 0500 MHz, CDCl3) d: 1.02±1.34 0brm, 6H), 1.43
0d, Jˆ7.0 Hz, 3H), 1.46±1.72 0brm, 2H), 1.54 0s, 3H), 1.55
0s, 3H), 2.21 0s, 3H), 2.31 0s, 6H), 3.49±3.57 0m, 1H),
3.59±3.68 0brs, 1H), 3.74±3.85 0m, 2H), 4.45 0d,
Jˆ14.0 Hz, 1H), 4.47 0d, Jˆ14.0 Hz, 1H), 4.67±4.78 0brs,
1H), 7.09 0dd, Jˆ1.5, 8.5 Hz, 1H), 7.19 0s, 2H), 7.21±7.29
0m, 6H), 7.53 0d, Jˆ1.5 Hz, 1H), 7.87 0brs, 1H) ppm; 13C
NMR 0125 MHz, CDCl3) d: 15.27, 17.96, 20.66 02C),
28.44, 28.68, 28.87 02C), 29.98 02C), 31.88, 47.17, 53.71,
55.72, 72.82, 75.03, 111.00, 114.60, 117.15, 119.18, 127.46,
127.62 02C), 127.91, 128.06 02C), 128.36 02C), 130.26,
134.95, 135.13, 136.11, 136.89 02C), 137.42, 138.82,
172.82 ppm; MS 0ES) m/z: 549.2 [MH1].
4.1.13. tert-Butyl 5-[2-ꢀ7-azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-3-[ꢀ1S)-2-azido-1-methylethyl]-2-
ꢀ3,4,5-trimethylphenyl)-1H-indole-1-carboxylate ꢀ25). A
100 mL round bottom ¯ask equipped with a magnetic stir
bar was sequentially charged with 2.071 g 03.71 mmol) of
the alcohol 24, 2.280 g 07.41 mmol) of zinc azide pyridine
complex, 3.889 g 014.8 mmol) of triphenylphosphine,
1.009 g 014.8 mmol) imidazole, and 40 mL CH2Cl2. The
reaction mixture was stirred under an atmosphere of dry
nitrogen and cooled to 08C with an external ice-water
bath. Diethylazodicarboxylate 02.34 mL, 14.8 mmol) was
added dropwise over 5 min, then the reaction mixture was
allowed to warm to room temperature and it was stirred for
an additional 24 h. The reaction mixture was diluted with
CH2Cl2 and ®ltered, then the ®ltrate was washed with 10%
aqueous NaHSO4. The organic layer was separated, dried
0MgSO4), ®ltered, evaporated and the residue was puri®ed
on a silica gel ¯ash chromatography column eluted with
35% EtOAc±hexane. Evaporation of the puri®ed fractions
and drying in vacuo afforded 1.949 g 090%) of a white
amorphous solid.
4.1.11. tert-Butyl 5-[2-ꢀ7-azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-3-[ꢀ1S)-2-ꢀbenzyloxy)-1-methyl-
ethyl]-2-ꢀ3,4,5-trimethylphenyl)-1H-indole-1-carboxyl-
ate ꢀ23). A 100 mL round bottom ¯ask was equipped with a
magnetic stir bar and charged with 2.250 g 04.10 mmol) of
the indole 22, 0.601 g 04.92 mmol) of 4-dimethylamino-
pyridine and 12 mL CH2Cl2. The reaction mixture was
stirred at room temperature and 1.074 g 04.92 mmol) of
di-tert-butyl dicarbonate was added in portions over
5 min. The reaction mixture was stirred for 4 h at room
temperature, then evaporated in vacuo. The residue was
dissolved in EtOAc and washed successively with 10%
aqueous NaHSO4, saturated brine, then dried 0MgSO4),
®ltered and evaporated to afford a white amorphous
solid which was used in the next step without further
puri®cation.
1
IR 0®lm) nmax: 2973, 2096, 1727, 1628 cm21; H NMR
0400 MHz, CDCl3) d: 1.05±1.40 0brm, 6H), 1.18 0s, 9H),
1.26 0d, Jˆ7.2 Hz, 3H), 1.55±1.75 0brm, 2H), 1.55 0s, 3H),
1.56 0s, 3H), 2.20 0s, 3H), 2.29 0s, 6H), 2.98±3.07 0m, 1H),
3.58±3.65 0brs, 1H), 3.68±3.75 0m, 1H), 3.80±3.87 0m, 1H),
4.70±4.76 0brs, 1H), 6.86±6.96 0brs, 2H), 7.28 0dd, Jˆ1.6,
8.8 Hz, 1H), 7.47 0d, Jˆ1.6 Hz, 1H), 8.16 0d, Jˆ8.8 Hz,
1H) ppm; 13C NMR 0125 MHz, CDCl3) d: 15.23, 18.05,
20.47 02C), 27.37 03C), 28.32, 28.48, 28.89 02C), 29.98
02C), 31.90, 47.17, 53.75, 55.75, 56.10, 82.85, 115.39,
116.42, 120.21, 120.98, 127.95, 129.00 02C), 130.48,
134.66, 135.31, 135.79 02C), 137.50, 140.67, 150.06,
172.29 ppm; MS 0ES) m/z: 584.7 [MH1].
1H NMR 0500 MHz, CDCl3) d: 1.04±1.42 0brm, 6H), 1.22
0s, 9H), 1.32 0d, Jˆ7.0 Hz, 3H), 1.55±1.78 0brm, 2H), 1.57
0s, 3H), 1.58 0s, 3H), 2.23 0s, 3H), 2.30 0s, 6H), 3.14±3.22
0m, 1H), 3.60±3.78 0m, 3H), 4.41 0d, Jˆ12.0 Hz, 1H), 4.43
0d, Jˆ12.0 Hz, 1H), 4.70±4.84 0brm, 1H), 6.94 0brs, 2H),
7.22±7.33 0m, 6H), 7.51 0d, Jˆ1.5 Hz, 1H), 8.18 0d,
Jˆ9.0 Hz, 1H) ppm; 13C NMR 0125 MHz, CDCl3) d:
15.15, 17.21, 20.41 02C), 27.33 03C), 28.22, 28.51, 28.84
02C), 29.93 02C), 31.71, 47.10, 53.65, 55.66, 72.56, 74.09,
82.57, 115.10, 116.91, 120.78, 121.36, 127.23, 127.25 02C),
128.12 02C), 128.45, 129.09 02C), 130.76, 134.27, 135.29,
135.44 02C), 136.95, 138.49, 140.34, 150.15, 172.32 ppm;
MS 0ES) m/z: 649.3 [MH1].
4.1.14. tert-Butyl 3-[ꢀ1S)-2-amino-1-methylethyl]-5-[2-
ꢀ7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-
2-ꢀ3,4,5-trimethylphenyl)-1H-indole-1-carboxylate ꢀ26).
A 50 mL round bottom ¯ask equipped with a magnetic
4.1.12. tert-Butyl 5-[2-ꢀ7-azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-3-[ꢀ1S)-2-hydroxy-1-methylethyl]-
2-ꢀ3,4,5-trimethylphenyl)-1H-indole-1-carboxylate ꢀ24).
A 250 mL Parr hydrogenation ¯ask was charged with a
solution of 2.375 g 03.66 mmol) of the benzyl ether 23 in
30 mL ethanol and 0.225 g of 10% palladium on carbon
catalyst 0Degussa E101) was added. The mixture was hydro-
genated in a Parr apparatus under a 40 psig hydrogen atmos-
phere at room temperature for 2 h. The mixture was then
®ltered and evaporated in vacuo to afford 2.155 g 094%, 2
steps) of an amorphous solid.
stir bar was charged with
a solution of 1.949 g
03.34 mmol) of the azide 25 in 20 mL EtOH and 250 mg
of 10% Pd/carbon catalyst was added. The reaction mixture
was stirred under hydrogen 01 atm) for 15 h, then, diluted
with methanol, ®ltered and evaporated. The residue was
puri®ed on a silica gel ¯ash chromatography column eluted
with 5% MeOH±CHCl3. The puri®ed fractions were
combined, evaporated and dried in vacuo to afford 1.768 g
095%) of a white amorphous solid.

5240
T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
IR 0®lm) nmax: 2974, 1723, 1627 cm21; 1H NMR 0400 MHz,
CDCl3) d: 1.04±1.38 0brm, 6H), 1.18 0s, 9H), 1.27 0d,
Jˆ7.2 Hz, 3H), 1.56 0s, 6H), 1.55±1.74 0brm, 2H), 2.19
0s, 3H), 2.28 0s, 6H), 2.74±2.85 0m, 2H), 2.94±3.02 0m,
1H), 3.60±3.65 0brs, 1H), 4.68±4.75 0brs, 1H), 6.90 0brs,
2H), 7.25 0dd, Jˆ1.6, 8.8 Hz, 1H), 7.46 0d, Jˆ1.6 Hz, 1H),
8.16 0d, Jˆ8.8 Hz, 1H) ppm; 13C NMR 0125 MHz, CDCl3)
d: 15.17, 18.12, 20.47 02C), 27.34 03C), 28.32, 28.40, 28.82
02C), 29.96 02C), 35.42, 47.12, 47.21, 53.69, 55.68, 82.70,
115.18, 116.85, 120.88, 121.41, 128.06, 129.06 02C),
130.80, 134.43, 135.37, 135.68 02C), 137.57, 140.50,
150.07, 172.27 ppm; MS 0ES) m/z: 558.6 [MH1].
CH2Cl2. The solution was stirred under a nitrogen atmos-
phere at room temperature and 1.0 mL 012.2 mmol) of n-
propylamine was added via syringe. The reaction mixture
was stirred an additional 30 min, then evaporated in vacuo.
The residue was puri®ed on a silica gel ¯ash chroma-
tography column eluted with 5% MeOH±CHCl3. The puri-
®ed fractions were combined, evaporated and dried in vacuo
to afford 0.334 g 076% overall) of an amorphous powder.
1H NMR 0500 MHz, CDCl3) d: 1.02±1.35 0m, 6H), 1.20 0s,
9H), 1.28 0d, Jˆ6.5 Hz, 3H), 1.53±1.72 0brm, 2H), 1.55 0s,
3H), 1.58 0s, 3H), 2.17 0s, 3H), 2.25 0s, 6H), 2.52±2.71 0m,
4H), 2.75±2.81 0m, 1H), 2.95±3.40 0m, 2H), 3.57±3.72 0brs,
1H), 4.68±4.78 0brs, 1H), 6.83 0brs, 2H), 6.88 0d, Jˆ5.5 Hz,
2H), 7.27 0dd, Jˆ2.0, 8.5 Hz, 1H), 7.49 0d, Jˆ2.0 Hz, 1H),
8.17 0d, Jˆ8.5 Hz, 1H), 8.39 0d, Jˆ5.5 Hz, 2H) ppm; 13C
NMR 0125 MHz, CDCl3) d: 15.21, 18.70, 20.51 02C), 27.40
03C), 27.98, 28.96 03C), 29.91 02C), 31.25, 35.42, 47.18,
49.38, 53.75, 54.32, 55.70, 82.84, 115.22, 116.84, 120.91,
121.51, 123.84 02C), 128.12, 128.98 02C), 130.59, 134.47,
135.43, 135.65 02C), 137.29, 140.54, 148.97, 149.56 02C),
150.07, 172.26 ppm; MS 0ES) m/z: 663.4 [MH1].
4.1.15. tert-Butyl 5-[2-ꢀ7-azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-2-ꢀ3,5-dimethylphenyl)-3-ꢀꢀ1S)-2-
{[ꢀ2,4-dinitrophenyl)sulfonyl]amino}-1-methylethyl)-
1H-indole-1-carboxylate ꢀ27). A 25 mL round bottom ¯ask
equipped with a magnetic stir bar was charged with a solu-
tion of 1.105 g 01.98 mmol) of the amine 26 in 6 mL CH2Cl2
and 6 mL of saturated aqueous NaHCO3. The mixture was
stirred at 08C with an external ice-water bath and 0.581 g
02.18 mmol) of 2,4-dinitrobenzenesulfonyl chloride was
added in portions. The reaction was stirred for 30 min
while warming to room temperature, then it was partitioned
between EtOAc and water. The organic layer was separated,
washed with saturated brine, then dried 0MgSO4), ®ltered
and evaporated. The residue was puri®ed on a silica gel ¯ash
chromatography column eluted with 35% EtOAc±hexane.
The puri®ed fractions were combined, evaporated and dried
in vacuo to afford 1.451 g 093%) of a bright yellow powder.
4.1.17. ꢀ2S)-2-[5-[2-ꢀ7-Azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-2-ꢀ3,4,5-trimethylphenyl)-1H-indol-
3-yl]-N-ꢀ2-pyridin-4-ylethyl)propan-1-amine, tri¯uoro-
acetic acid salt ꢀ2). A 10 mL round bottom ¯ask equipped
with a magnetic stir bar and a septum was charged with a
solution of 0.303 g 00.46 mmol) of the BOC-protected in-
dole 28 in 1.0 mL CH2Cl2. Tri¯uoroacetic acid 01.0 mL;
13.0 mmol) was added and the reaction mixture was stirred
under a nitrogen atmosphere at room temperature for 12 h.
The mixture was concentrated in vacuo, redissolved in
2.0 mL methanol±water 01:1) and puri®ed on a Waters 15
1H NMR 0500 MHz, CDCl3) d: 1.02±1.36 0brm, 6H), 1.18
0s, 9H), 1.21 0d, Jˆ7.5 Hz, 3H), 1.44±1.72 0brm, 2H), 1.50
0s, 3H), 1.59 0s, 3H), 2.21 0s, 3H), 2.29 0s, 6H), 2.92±3.02
0m, 1H), 3.30±3.37 0m, 1H), 3.54±3.68 0brm, 2H), 4.64±
4.78 0brs, 1H), 5.29 0t, Jˆ5.5 Hz, 1H), 6.81 0s, 2H), 7.27
0dd, Jˆ1.5, 8.5 Hz, 1H), 7.34 0d, Jˆ1.5 Hz, 1H), 7.81 0d,
Jˆ8.5 Hz, 1H), 8.07 0d, Jˆ8.5 Hz, 1H), 8.26 0dd, Jˆ2.0,
8.5 Hz, 1H), 8.50 0d, Jˆ2.0 Hz, 1H) ppm; 13C NMR
0125 MHz, CDCl3) d: 15.25, 17.88, 20.45 02C), 27.34
03C), 27.37, 28.83 02C), 29.42, 29.85 02C), 32.01, 47.17,
48.46, 53.81, 55.76, 83.36, 115.39, 116.43, 119.01,
120.24, 121.21, 127.00, 128.79 02C), 131.71, 135.04,
135.23, 136.12 02C), 137.96, 139.55, 140.90, 147.45,
149.19, 149.75, 172.10 ppm; MS 0ES) m/z: 788.2 [MH1].
Ê
micron 100 A, C18 DeltaPak 030£300 mm) reversed phase
HPLC column eluted with 60% water±40% acetonitrile
containing 0.1% TFA. The puri®ed fractions were combined
and lyophilized to afford 0.339 g 094%) of an amorphous
white powder.
1
Data for free base of 2: H NMR 0500 MHz, CDCl3) d:
0.98±1.34 0m, 6H), 1.41 0d, Jˆ7.5 Hz, 3H), 1.52±1.72
0brm, 2H), 1.56 0s, 3H), 1.58 0s, 3H), 2.19 0s, 3H), 2.29 0s,
6H), 2.52±2.76 0m, 4H), 2.87±2.91 0m, 1H), 3.07±3.13 0m,
1H), 3.35±3.44 0m, 1H), 3.60±3.72 0brs, 1H), 4.66±4.78
0brs, 1H), 6.82 0d, Jˆ6.0 Hz, 2H), 7.10 0s, 2H), 7.13 0dd,
Jˆ1.5, 8.5 Hz, 1H), 7.30 0d, Jˆ8.5 Hz, 1H), 7.55 0d,
Jˆ1.5 Hz, 1H), 7.99 0brs, 1H), 8.33 0d, Jˆ6.0 Hz,
2H) ppm; 13C NMR 0125 MHz, CDCl3) d: 15.28, 19.31,
20.71 02C), 28.16, 28.94 02C), 29.12, 29.67 02C), 31.32,
35.47, 47.19, 49.45, 53.71, 55.04, 55.72, 110.96, 114.20,
116.84, 119.02, 123.86 02C), 127.31, 127.78 02C), 129.90,
134.95, 135.04, 136.60, 136.74 02C), 137.33, 149.11,
149.42 02C), 172.70 ppm; MS 0ES) m/z: 563.4 [MH1].
4.1.16. tert-Butyl 5-[2-ꢀ7-azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-3-{ꢀ1S)-1-methyl-2-[ꢀ2-pyridin-4-
ylethyl)amino]ethyl}-2-ꢀ3,4,5-trimethylphenyl)-1H-in-
dole-1-carboxylate ꢀ28). A 25 mL round bottom ¯ask
equipped with a magnetic stir bar was charged with
0.528 g 00.67 mmol) of the sulfonamide 27, 0.140 g 01.14
mmol) of 4-02-hydroxyethyl)pyridine, 0.299 g 01.14 mmol)
triphenylphosphine, and 7.0 mL benzene. The resulting
solution was stirred at room temperature under a nitrogen
atmosphere and 179 mL 00.198 g; 1.14 mmol) of diethyl-
azodicarboxylate was added via syringe over 2 min. The
reaction mixture was stirred at room temperature for 1 h,
then concentrated in vacuo and the residue was puri®ed on a
silica gel ¯ash chromatography column eluted with 75%
EtOAc±hexane. The puri®ed fractions were combined,
evaporated and dried in vacuo, then transferred to a
25 mL round bottom ¯ask and dissolved in 1.0 mL
Acknowledgements
We thank Drs Cheng-yi Chen and Richard D. Tillyer of the
Department of Process Research, Merck Research Labora-
Â
tories for helpful discussions, Drs Andre Giroux and Petpi-
boon Prasit of the Merck-Frosst Centre for Therapeutic
Research for a generous gift of bis0pinacolato)diboron, Mr

T. F. Walsh et al. / Tetrahedron 57 02001) 5233±5241
5241
Lo, J.-L.; Yang, Y.-T.; Cheng, K.; Smith, R. G.; Fisher, M. H.;
Wyvratt, M. J.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2001,
11, 1073±1076. 0d) Lin, P.; Parikh, M.; Lo, J.-L.; Yang, Y.-T.;
Cheng, K.; Smith, R. G.; Fisher, M. H.; Wyvratt, M. J.; Goulet,
M. T. Bioorg. Med. Chem. Lett. 2001, 11, 1077±1080.
0e) Ashton, W. T.; Sisco, R. M.; Yang, Y.-T.; Lo, J.-L.;
Yudkovitz, J. B.; Cheng, K.; Goulet, M. T. Bioorg. Med.
Chem. Lett. 2001 0submitted for publication). 0f) Ashton,
W. T.; Sisco, R. M.; Yang, Y.-T.; Lo, J.-L.; Yudkovitz, J. B.;
Gibbons, P. H.; Mount, G. R.; Ren, R. N.; Butler, B. S.;
Cheng, K.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2001
0submitted for publication).
Glenn Reynolds for the preparation of iodoaniline 6b, Dr
Gerard Kieczykowski for the preparation of silylacetylene
7, and Mrs Amy Bernick for mass spectrometry analysis.
Helpful discussions with Drs Peter Lin and Robert DeVita
during the preparation of this manuscript are also gratefully
acknowledged.
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