Enantiospecific synthesis of (r)-4-amino-5-oxo-1,3,4,5- tetrahydrobenz[cd]indole, an advanced intermediate containing the tricyclic core of the ergots

Article abstract of DOI:10.1021/jo981723s

We report a new strategy for the enantiospecific synthesis of (R)-4- amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole. This compound is an advanced intermediate which contains the tricyclic core of many of the tetracyclic ergot alkaloids. Our method involves the initial synthesis of D-4- bromotryptophan from the coupling of an indolyllithium species with a masked serinal. The α-amino position was protected with an N-trityl group, ensuring the enantiomeric integrity of this position during the ensuing organometallic cyclization reaction. Stabilization of the tricycle was accomplished by protecting the indole nitrogen with a BOC group or by reducing the α-amino ketone to the corresponding β-amino alcohol.

Full text of DOI:10.1021/jo981723s

J . Org. Chem. 1999, 64, 225-233
225
En a n tiosp ecific Syn th esis of
(R)-4-Am in o-5-oxo-1,3,4,5-tetr a h yd r oben z[cd ]in d ole, a n Ad va n ced
In ter m ed ia te Con ta in in g th e Tr icyclic Cor e of th e Er gots
Clarence R. Hurt, Ronghui Lin, and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received August 24, 1998
We report a new strategy for the enantiospecific synthesis of (R)-4-amino-5-oxo-1,3,4,5-tetrahy-
drobenz[cd]indole. This compound is an advanced intermediate which contains the tricyclic core of
many of the tetracyclic ergot alkaloids. Our method involves the initial synthesis of D-4-
bromotryptophan from the coupling of an indolyllithium species with a masked serinal. The R-amino
position was protected with an N-trityl group, ensuring the enantiomeric integrity of this position
during the ensuing organometallic cyclization reaction. Stabilization of the tricycle was accomplished
by protecting the indole nitrogen with a BOC group or by reducing the R-amino ketone to the
corresponding â-amino alcohol.
Ch a r t 1
In tr od u ction
Of interest due to their remarkable pharmacological
properties, the ergot alkaloids1 have often been the source
for the development of new drugs.2 Lysergic acid (1)
(Chart 1) has been a major synthetic target since it
possesses the fundamental nucleus of this class of
alkaloids as do analogous derivatives, e.g., pergolide (2,
an anti-Parkinson’s drug) and lisuride (3, an anti-
prolactin drug).
This existence of useful drugs and the potential for
discovery of new ergot-based therapeutics has sustained
much interest in the development of an enantiospecific
synthesis of the ergot template. The majority of synthetic
approaches have utilized the method first developed by
Uhle to effect an intramolecular Friedel-Crafts cycliza-
tion in which the indole was masked as an indoline
moiety.3 These strategies imposed the necessity of reoxi-
dizing the indoline to an indole at a later stage in the
synthesis,2 usually a difficult and inefficient process.
Several groups attempted to avoid the problems associ-
ated with the reoxidation of an advanced indoline inter-
mediate by maintaining the indole moiety while effecting
the formation of the tricyclic system through intramo-
lecular cyclizations employing a Diels-Alder reaction,4
an electrophilic cyclization,5 or a tandem radical reac-
tion.6 More recently, 1-pivaloylindole-3-propionic acid was
used as a substrate for intramolecular Friedel-Crafts
cyclization.7 The pivaloyl group in the 1-position pre-
vented cyclization at the 2-position and led to the
formation of Uhle’s ketone. In our hands, this methodol-
ogy failed when applied to various tryptophan deriva-
tives.8
We now report an efficacious route to the tricyclic core
of the ergot nucleus. We describe the racemic and
enantiospecific syntheses of 4-amino-5-oxo-1,3,4,5-tet-
rahydrobenz[cd]indole (C), a key precursor for lysergic
acid and some of its derivatives.9 The formation of ketone
C results from the intramolecular cyclization of 4-bro-
motryptophan B. In the racemic version, 4-bromogramine
served as the intermediate10 which was then converted
to (()-4-bromotryptophan. The enantiospecific pathway
involved the formation of D-4-bromotryptophan from
4-bromoindole and L-serine (Figure 1). Previous methods
for the asymmetric synthesis of 4-bromotryptophan have
relied on either resolution of the racemic mixture11 or an
enzymatic coupling of indoles and serine.12
(1) Rehacek, Z.; Sajdl, P. Ergot Alkaloids: Chemistry, Biological
Effects, Biotechnology; Elsevier Science Publishers: Amsterdam, 1990.
(2) Stadler, P. A.; Gigar, K. A. Natural Products and Drug Develop-
ment; Krogsgaard-Larsen, P., Christensen, S. B., Koffod, H., Eds.;
Munksgaard: Copenhagen, 1984; p 463.
(3) (a) Uhle, F. C. J . Am. Chem. Soc. 1949, 71, 761. (b) Kornfeld, E.
C.; Fornefeld, E. J .; Kline, G. B.; Mann, M. J .; Morrison, D. E.; J ones,
R. G.; Woodward, R. B. J . Am. Chem. Soc. 1956, 78, 3087. (c) Ninomiya,
I.; Kiguchi, T. The Alkaloids; Brossi, A., Ed.; Academic Press: San
Diego, 1990; Vol. 38, Chapter 1.
(4) Oppolzer, W.; Francotte, E.; Ba¨ttig, K. Helv. Chim. Acta 1981,
64, 478.
(5) Ralbovsky, J . L.; Scola, P. M.; Sugino, E.; Burgos-Garcia, C.;
Weinreb, S. M.; Parvez, M. Heterocycles 1996, 43, 1497.
(6) O¨ zlu, Y.; Cladingboel, D. E.; Parson, P. J . Tetrahedron 1994, 50,
2183.
(7) (a) Teranishi, K.; Hayashi, S.; Nakatsuka, S.; Goto, T. Tetrahe-
dron Lett. 1994, 35, 8173. (b) Teranishi, K.; Hayashi, S.; Nakatsuka,
S.; Goto, T. Synthesis 1994, 506.
(8) Similar results were reported by Tani, M.; Matsumoto, S.; Aida,
Y.; Arikawa, S.; Nakane, A.; Yokoyama, Y.; Murakami, Y. Chem.
Pharm. Bull. 1994, 42, 443.
(9) (a) Flaugh, M. E.; Mullen, D. L.; Fuller, R. W.; Mason, N. R. J .
Med. Chem. 1988, 31, 1746. (b) Leanna, M. R.; Martinelli, M. J .; Varie,
D. L.; Kress, T. J . Tetrahedron Lett. 1989, 30, 3935. (c) Martinelli, M.
J .; Leanna, M. R.; Varie, D. L.; Peterson, B. C.; Kress, T. J .; Wepsiec,
J . P.; Khau, V. V. Tetrahedron Lett. 1990, 31, 7579. (d) Varie, D. L.
Tetrahedron Lett. 1990, 31, 7583.
(10) (a) Iwao, M. Heterocycles 1993, 36, 29. (b) Iwao, M.; Motoi, O.
Tetrahedron Lett. 1995, 36, 5929. (c) Nettekoven, M.; Psiorz, M.;
Waldmann, H. Tetrahedron Lett. 1995, 36, 1425.
10.1021/jo981723s CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1998

226 J . Org. Chem., Vol. 64, No. 1, 1999
Hurt et al.
F igu r e 1. Proposed synthesis of protected (R)-4-amino-5-oxo-1,3,4, 5-tetrahydrobenz[cd]indole.
Sch em e 1. Syn th esis of (()-4-Br om otr yp top h a n
4-Bromogramine (7) was treated with diethyl N-for-
mamidomalonate and a catalytic amount of sodium
hydroxide to give indolyl malonate 8 in an 87% yield.
Through a series of deprotection reactions, (()-4-bromo-
tryptophan (9) was realized in quantitative yield. Ester
hydrolysis was carried out with an aqueous NaOH/THF
solution to give the corresponding carboxylate salts.
Acidification and subsequent mono-decarboxylation re-
sulted from slowly adding AcOH and heating the reaction
at reflux for 24 h. The final removal of the formyl group
from the R-amino nitrogen was effected by heating the
suspension in aqueous 3 M HCl for 24 h. At this point
the pH of the reaction mixture was slowly adjusted to
6.0 with aqueous 1 M KOH, leading to precipitation of
(()-4-bromotryptophan (9) in quantitative yield. The
overall yield of (()-4-bromotryptophan from gramine was
72%.
P r ep a r a tion of Ser in a l 12. Our plan for the synthe-
sis of enantiopure tryptophan derivatives required an
indole with the potential for attachment at the 3-position
of a side chain which possessed (a) a configurationally
stable R-amino group and (b) a carboxylic acid surrogate
at the terminus. The use of L-serine-derived reagents to
introduce the required functionality appeared to be an
obvious solution.14 L-Serine would provide the three-
carbon unit possessing an R-amino group, and it would
be joined via its carbonyl to a 3-lithioindole derivative,
thus providing D-tryptophan-configured derivatives. To
ensure enantiomeric integrity at the R-amino position,
the amine was protected with a 9-phenylfluorenyl group
(Pf), and the reported isoxazolidide 10 was prepared.15
The primary alcohol was then protected as its MOM ether
in 96% yield to give isoxazolidide 11. Direct reaction of
11 with the 3-lithioindole to form the ketone was unsuc-
cessful;16 however, serinal 12, prepared in 96% yield by
reduction of 11 with LAH, reacted readily with the
3-lithioindoles.
Resu lts a n d Discu ssion
Syn th esis of Ra cem ic 4-Br om otr yp top h a n . The
synthesis of racemic tryptophan analogues has been
discussed on a number of occasions, but rarely have the
4-halogen-substituted compounds been presented.13 One
method that showed considerable promise employed
gramine to direct the substitution of electrophiles into
the 4-position through an intermediate organometallic
reagent.10 This method provided a practical route to the
synthesis of (()-4-bromotryptophan (Scheme 1), with
gramine as an inexpensive, readily available starting
material. The indole nitrogen of gramine was protected
with TIPSCl to give gramine 5 in a 96% yield. Gramine
5 then was treated with t-BuLi in Et2O, leading to anion
formation at the 4-position; quenching with 1,2-dibro-
moethane gave an 87% yield of bromogramine 6. The silyl
protecting group was then removed with a THF solution
of TBAF leading to bromogramine 7 in a 99% yield. Thus
our yields leading to the formation of 4-bromogramine
were somewhat higher than those reported.10
Syn th esis of N-BOC-4-br om o-3-lith ioin d ole a n d
Rea ction w ith Ser in a l 12. The synthesis of the indole
portion of the tryptophan derivatives required the ability
to selectively generate an anion at C-3 of the nitrogen-
protected 4-bromoindole, which would react with serine
aldehyde 12. The halogenation of 4-bromoindole (13)
appeared to offer a possible solution. Bromoindole 13 was
prepared as described;17 however, attempts to brominate
13 at C-3 with bromine under a variety of conditions
failed to produce the desired 3,4-dibromoindole.18 Alter-
natively, when 13 was treated with pyridinium bromide
perbromide, the unstable 3,4-dibromoindole (14) was
produced.19 The crude material was immediately N-
(11) Sakagami, Y.; Manabe, K.; Aitani, T.; Thiruvikraman, S. V.;
Marumo, S. Tetrahedron Lett. 1993, 34, 1057.
(12) Kitajima, N.; Watanabe, S.; Takeda, I. Chem. Abstr. 1974, 80,
106876g.
(13) (a) Rydon, H. N.; Tweddle, J . C. J . Chem. Soc. 1955, 77, 3499.
(b) Hengartner, U.; Batcho, A. D.; Blount, J . F.; Leimgruber, W.;
Larscheid, M. E.; Scott, J . W. J . Org. Chem. 1979, 44, 3748. (c)
Prasitpan, N.; J ohnson, M. E.; Currie, B. L. Synth. Commun. 1990,
20, 3459. (d) Spadoni, G.; Balsamini, C.; Bedini, A.; Duranti, E.;
Tontini, A. J . Heterocycl. Chem. 1992, 29, 305. (e) Chung, J . Y. L.;
Wasicak, J . T.; Nadzan, A. M. Synth. Commun. 1992, 22, 1039. (f)
Howell, D. C.; Nichols, P. D.; Ratcliffe, G. S.; Roberts, E. J . Org. Chem.
1994, 59, 4418. (g) Holzapfel, C. W.; Gildenhuys, P. J . S. African J .
Chem. 1977, 30, 125.
(14) Sardina, F. J .; Rapoport, H. Chem. Rev. 1996, 96, 1825.
(15) Lubell, W. D.; Rapoport, H. J . Org. Chem. 1989, 54, 3824.
(16) Ha¨ner, R. Unpublished results, this laboratory.
(17) Moyer, M. P.; Shiurba, J . F.; Rapoport, H. J . Org. Chem. 1986,
51, 5106.
(18) Bocchi, V.; Palla, G. Synthesis 1982, 1096.

(R)-4-Amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole
J . Org. Chem., Vol. 64, No. 1, 1999 227
protected with BOC2O, and an 80% yield of 15 over the
two steps was realized.
aromatic bromide was retained and the yield was nearly
quantitative. With the effective deprotection of the N-
BOC group, the original deoxygenation conditions were
invoked with alcohols 17 and gave 50-60% of the desired
bromoindole 20. Speculating that deprotonation of the
indole nitrogen would enhance the deoxygenation pro-
cess, we added 120 mol % of DMAP to the reaction of
alcohol 17 with BH3‚THF, increasing the yield of bro-
moindole to 91%.
Regioselective metal-halogen exchange at the C-3
bromide then became the hurdle. Several factors were
examined in order to achieve this selective exchange. Of
primary importance was the rate of addition, as almost
complete kinetic control was realized by bolus addition
of n-BuLi to the reaction mixture containing dibromoin-
dole 15. Formation of the 3-lithio species proceeded with
greater than 95% regioselectivity.20 When the rate of
addition of the alkyllithium was decreased, a methanol
quench led to a mixture of three products: N-BOC-indole,
N-BOC-3-bromoindole, and N-BOC-4-bromoindole.
The second factor which influenced the selectivity of
the halogen-metal exchange was temperature control.
Significant exothermic problems with reactions of more
than 1 mmol were overcome by direct addition of liquid
nitrogen to the reaction mixture, along with an external
dry ice-acetone bath. Under this protocol, as the bolus
addition of n-BuLi was initiated, the internal tempera-
ture of the reaction mixture gradually rose to -82 °C,
but never exceeded -78 °C. In this way, the anion was
generated exclusively at the 3-position from the 3,4-
dibromoindole without recourse to the 3-iodo-4-bromoin-
dole derivative.21 The 3-lithio anion of 15 then reacted
readily with serinal 12 to give an 85% yield of a 2.5:1
mixture of diastereomeric alcohols 16.
D-4-Br om otr yp top h a n . With the diastereomeric mix-
ture of alcohols in hand, two transformations remained:
reduction of the â-secondary alcohol to methylene and
oxidation of the primary alcohol to carboxyl. Initially, we
planned to oxidize the diastereomeric alcohols to the
corresponding ketone 18, followed by reductive deoxy-
genation with BH3‚THF to give methylene intermediate
20.22 Oxidizing the mixture of alcohols 16 with chromium
trioxide produced ketone 18 in an 86% yield; however,
removal of the N-BOC group from 18 led to the unex-
pected loss of bromide at C-4 and formation of 19. The
N-deprotection of ketone 18 was carried out with metha-
nolic sodium methoxide at room temperature. When an
acidic medium was used, again bromide was lost along
with cleavage of the MOM and BOC groups. Since
deprotection of the BOC group can lead to the generation
of tert-butyl radicals23 which might be responsible for the
loss of the bromide, free radical scavengers24 were
introduced prior to initiation of the reaction; debromi-
nation still occurred. The same conditions for deprotec-
tion of the N-BOC group of 1-BOC-4-bromoindole led to
a 1:1 mixture of 4-bromoindole and indole; addition of
free radical scavengers totally prevented debromination.
We have no explanation for this dramatic difference in
behavior.
Proceeding to the target tryptophan 9, bromoindole 20
was reprotected with BOC2O and the MOM group was
removed selectively from 21 with anhydrous 1 M HCl in
EtOAc to give primary alcohol 22. Alcohol 22 was
oxidized stepwise to aldehyde and then to carboxylic acid.
Initial attempts to oxidize the primary alcohol directly
to the carboxylic acid led to poor yields;25 however,
26
oxidation
of 22 gave aldehyde 23 in 86% yield. The
carboxylic acid 24 was then realized in 69% yield by
oxidation with NaClO2.27 D-(+)-4-Bromotryptophan was
obtained through the deprotection of both the BOC and
the phenylfluorenyl protecting groups28 on treatment
with TMSOTf/Et3SiH in refluxing dichloroethane to give
a 95% yield of D-(+)-4-bromotryptophan. This process is
delineated in Scheme 2.
Cycliza tion to 4-Am in o-5-oxo-1,3,4,5-tetr a h yd r o-
ben z[cd ]in d ole. Since it had already been established
that protection of the indole nitrogen was not necessary
for the generation of regioisomerically pure lithiated
indoles by metal-halogen exchange,17 protecting groups
on the R-amino group were evaluated for their effect on
yield and maintenance of enantiomeric integrity (Scheme
3). Having previously examined a variety of N-protecting
groups at the R-amino position for the intramolecular
cyclization reaction,29 we found the trityl group to be the
most effective, as it not only aided in maintaining the
solubility of the trianion which was formed but it also
provided total protection of the stereocenter.
To attach the trityl group, (+)-4-bromotryptophan ((+)-
9) was treated with excess TrBr in the presence of
triethylamine to give the bis-O,N-trityl derivative 25.
Selective cleavage of the O-trityl ester to N-trityl acid
26 was achieved in 80% yield by simply heating at 50 °C
in THF/MeOH/H2O. Alternatively, (+)-9 was esterified
with TMSCl and MeOH to provide a 96% yield of the
methyl ester 27 as its hydrochloride,30 which then was
treated with TrCl and N-methylmorpholine to give a 96%
yield of the N-trityl R-amino-protected methyl ester 28.
Hydrolysis of the methyl ester with LiOH‚H2O in dioxane
and water required refluxing and gave acid 26 after 96
h in quantitative yield. Both methods were employed for
preparing (R)-4-bromo-R-N-trityltryptophan (26) since it
was our key intermediate and total enantiomeric integ-
rity was required. Although the R-N-trityl group should
be sufficient to avoid epimerization during ester hydroly-
Failure to convert the keto group of 18 to methylene
necessitated direct reductive replacement of the second-
ary alcohol, with or without derivatization. In contrast
to the behavior of ketone 18, when the alcohols 16 were
treated with a methanolic solution of NaOMe, the
(25) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(26) Corey, E. J .; Kim, C. U. J . Am. Chem. Soc. 1972, 94, 7586.
(27) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(28) (a) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1987, 109,
236. (b) Christie, B. D.; Rapoport, H. J . Org. Chem. 1985, 50, 1239.
(29) The protecting groups employed were Pf, BOC, acetyl, and Bs.
Low yields were obtained with the acetyl, BOC and Bs ranging from
15 to 50%. The Pf-protected system did not cyclize. Initial reactions
with the N-acetyl compound were performed by R. Ha¨ner, this
laboratory.
(19) Brennan, M. R.; Erickson, K. L.; Szmalc, F. S.; Tansey, M. J .;
Thornton, J . M. Heterocycles 1986, 24, 2879.
(20) The alkyllithium was added via cannula with a rapid stream
of nitrogen over a period of 5-30 s.
(21) Harrington, P. J .; Hegedus, L. S. J . Org. Chem. 1984, 49, 2657.
(22) Stu¨cky, G.; Davis, D. Unpublished results, this laboratory.
(23) (a) Perkins, M. J .; Roberts, B. P. J . Chem. Soc, Chem. Commun.
1973, 173. (b) Evans, C. A. Aldrichimica Acta 1979, 12, 23.
(24) The free radical scavengers employed were N-nitrosobenzene
and N-tert-butyl-R-phenylnitrone purchased from Aldrich.
(30) Brook, M. A.; Chan, T. H. Synthesis 1983, 201.

228 J . Org. Chem., Vol. 64, No. 1, 1999
Sch em e 2. Syn th esis of D-(+)-4-Br om otr yp top h a n
Hurt et al.
Sch em e 3. Syn th esis a n d An a lysis of D-(+)-4-Br om otr yp top h a n Der iva tivesa
a
Both racemic and R compounds were prepared; only the R forms are shown.
sis,28 the drastic conditions required for the generation
approach was found to be 99% er on the basis of HPLC
analysis of derivatives 29. These results were consistent
with independent chiral HPLC analysis of compound 28.
Initially, bromotryptophan 26 was deprotonated at -78
°C with approximately 250 mol % of n-BuLi to remove
the three acidic protons. With the trityl group on the
R-amino group, the reaction remained homogeneous.
Addition of 250 mol % of t-BuLi at -78 °C initiated the
metal-halogen exchange for formation of the 4-lithio
species, which in turn led to the cyclization to ketone 30.
The reaction was allowed to warm slowly to room
temperature before it was quenched to give ketone 30 in
of acid 26 from ester 28 led us to develop the alternative
path, (+)-9 f 25 f 26. The enantiomeric purity of each
of the intermediates was examined by derivatization of
common intermediate 27 with (R)-(+)-R-methylbenzyl-
isocyanate to form 29 as a diastereomeric mixture,
separable on HPLC analysis. For example, compound 26
was first transformed to 28 quantitatively by reaction
with CH2N2 and then to 27, also quantitatively, by
selective deprotection with TFA. The enantiomeric purity
of 26 obtained by the second approach was found to range
from 97 to 99% er, while that obtained by the first

(R)-4-Amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole
J . Org. Chem., Vol. 64, No. 1, 1999 229
Sch em e 4. Syn th esis of Tr icyclic r-Am in o
Con clu sion
Keton ea
We have developed a direct and efficient strategy for
the enantiospecific snthesis of (R)-4-amino-5-oxo-1,3,4,5-
tetrahydrobenz[cd]indole, the tricyclic core of the ergot
alkaloids. This route relies upon the ability to perform
an intramolecular cyclization reaction via metal-halogen
exchange with the substrate D-4-bromotryptophan, which
was synthesized in an enantiospecific fashion from L-
serine. We have also established the racemic syntheses
of both 4-bromotryptophan and the corresponding tricy-
clic ketone. These new routes allow for the enantiospecific
syntheses of ergot derivatives and avoid the previously
commonly employed intermediacy of indolines and their
subsequent reoxidation to indoles.
Exp er im en ta l Section
Gen er a l. Glassware was flame dried before use and cooled
to room temperature under a nitrogen atmosphere. THF and
Et2O were distilled from sodium/benzophenone; CH3CN, DIEA,
TEA, CH2Cl2, 1,2-DCE, toluene, and TMSCl were distilled from
CaH2; MeOH was distilled from Mg; N-methylmorpholine
(NMM) and 1,2-dibromoethane were distilled prior to use.
Final solutions before evaporation were dried over MgSO4, and
chromatography was carried out using (a) 70-230 or (b) 230-
400 mesh silica gel. IR spectra were taken in CHCl3, and NMR
spectra were taken in CDCl3, unless otherwise noted. 1H
coupling constants, J , are reported in hertz.
a
Both (() and (+) compounds were prepared; only the (+) form
is shown.
4-Br om ogr a m in e (7). Bromogramine 6 (3.5 g, 8.55 mmol)10
was dissolved in THF (75 mL) and stirred under nitrogen as
a solution of TBAF (9.00, 1.0 M in THF, 9.00 mmol) was added
dropwise over 5 min. The reaction was stirred at room
temperature for 4 h before it was poured into ice water (100
mL) and extracted with EtOAc (3 × 100 mL) and dried. The
organic layer was filtered and evaporated to give the crude
product (2.12 g, 99%) which was used directly in the next
reaction.
60-65% yield. To avoid any deprotonation at the benzylic
position, the reaction temperature was lowered to -100
°C.31 Thus, by deprotonating, followed by the metal-
halogen exchange of bromotryptophan 26 at -105 °C, the
yield of ketone 30 was increased to 80% (Scheme 4).
The desamino tricyclic ketone (Uhle’s ketone) related
to 30 has been shown to be unstable.32 We found R-amino
ketone 30 to be very susceptible to air oxidation; it is
better stored as its relatively stable BOC derivative 31
(prepared in 94% yield). The enantiomeric ratio of 31 was
found to be 99.5/0.5 by chiral HPLC analysis, established
by comparison with the corresponding racemic material.
Exposure of BOC ketone 31 to air slowly transformed it
in 100% yield to the corresponding R-amino R,â-unsatur-
ated ketone 32 with a half-life (t1/2) of 14 days based on
1H NMR analysis in CDCl3. The completely deprotected
racemic amino ketone corresponding to 30 has been
reported to be unstable.33 Thus, the tricyclic R-amino
ketone 30 should be used directly after preparation; it
was converted to the corresponding â-amino alcohol 33,
prepared by reducing the R-amino ketone 30 stereospe-
cifically with NaBH4. The cis configuration of the â-amino
alcohol 33 was assigned on the basis of the assumption
that the R-N-trityl group would direct nucleophilic attack
from the opposite side and was supported by the observed
small coupling constant on the two adjacent protons. The
various forms 30, 31, and 33 of the tricyclic ketone afford
attractive and versatile intermediates, from which the
synthesis of a variety of ergot derivatives can be envis-
aged.
r-N-For m yl-r-(eth oxycar bon yl)-4-br om otr yptoph an (8).
4-Bromogramine (7, 16.8 g, 66.4 mmol) was suspended in
toluene (300 mL) followed by addition of a catalytic amount
of NaOH (300 mg, 7.5 mmol) while stirring under nitrogen.
To this mixture was added diethyl formamidomalonate (15.5
g, 76.3 mmol), and the reaction mixture was heated at reflux
for 24 h and then cooled to room temperature and dissolved
in EtOAc (500 mL). The organic layer was washed with 1 M
H3PO4 (3 × 300 mL) and brine (2 × 300 mL), dried, filtered,
and evaporated. The residue was titurated in hot MeOH (150
mL), allowed to cool to room temperature, filtered, and dried
under vacuum to give 25.1 g (92% yield) of 8 as a beige solid:
1
mp 204-205 °C; H NMR (DMSO-d6) δ 1.08 (t, J ) 7.1, 6H),
3.98 (s, 2H), 4.04-4.14 (m, 4H), 6.94 (t, J ) 7.76, 7.9, 1H),
7.15 (d, J ) 7.6, 1H), 7.19 (s, 1H), 7.37 (d, J ) 1.33, 1H), 8.04
(s, 1H), 8.8 (s, 1H), 11.4 (br, 1H); 13C NMR (DMSO-d6) δ 13.6,
27.8, 61.7, 66.1, 107.5, 111.3, 112.8, 121.9, 123.3, 124.8, 126.0,
137.2, 160.7, 167.1. Anal. Calcd for C17H19BrN2O5: C, 49.7;
H, 4.7; N, 6.8. Found: C, 49.8; H, 4.6; N, 6.9.
(()-4-Br om otr yp top h a n [(()-9]. To indolylmalonate 8
(3.00 g, 7.27 mmol) in THF (18 mL) was added a solution of
NaOH (1.02 g, 25.5 mmol) in water (30 mL), and the mixture
was stirred at room temperature for 24 h. Acetic acid (6 mL)
was added dropwise over 5 min, the resulting mixture was
heated at reflux for 24 h and then cooled to room temperature,
and the organic phase was evaporated. To the remaining
aqueous layer was added 3 M HCl (30 mL), and the reaction
mixture was refluxed for 24 h and then cooled to room
temperature, whereupon a white precipitate formed. The
suspension was placed in an ice bath, and the pH was adjusted
to 6.0 with 2 M KOH. The white solid formed was filtered off,
washed with water, and then dried overnight under vacuum
to give 2.05 g (99% yield) of (()-9 as a beige solid: mp 287-
(31) (a) Parham, W. E.; J ones, L. D.; Sayed, Y. J . Org. Chem. 1975,
40, 2394. (b) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982,
15, 300.
(32) (a) Grob, C. A.; Voltz, J . Helv. Chim. Acta 1950, 33, 1796. (b)
Grob, C. A.; Hofer, B. Helv. Chim. Acta 1952, 35, 2095. (c) Grob, C. A.;
Payot, P. Helv. Chim. Acta 1953, 36, 839. (d) Grob, C. A.; Hofer, B.
Helv. Chim. Acta 1953, 36, 847.
1
289 °C; H NMR (DMSO-d6) δ 3.18-3.24 (dd, J ) 9.65, 5.13,
(33) Stoll, A.; Rutschmann, J .; Petrzilka, T. Helv. Chim. Acta 1950,
33, 2257.
1H), 3.65-3.7 (dd, J ) 9.65, 5.13, 1H), 3.65-3.7 (dd, J ) 5.41,

230 J . Org. Chem., Vol. 64, No. 1, 1999
Hurt et al.
9.36, 1H), 4.13 (br, 1H), 7.00 (d, J ) 7.83, 1H), 7.2 (d, J )
7.48, 1H), 7.35 (d, J ) 2.33, 1H), 7.42 (d, J ) 8.06, 1H), 8.34
(s, 1H), 11.5 (d, J ) 2.04, 1H); 13C NMR (DMSO-d6) δ 27.3,
53.9, 107.6, 111.7, 112.7, 122.5, 122.9, 124.8, 127.7, 138.2,
170.8. Anal. Calcd for C11H11BrN2O2: C, 46.7; H, 3.9; N, 9.9.
Found: C, 46.5; H, 4.1; N, 9.6.
8.22 (d, J ) 8.36, 1H); 13C NMR 100 MHz) δ 28.1, 84.9, 114.0,
114.6, 125.4, 125.9, 127.2, 135.8, 148.2; IR (CDCl3) 3050, 2980,
1735, 1460, 1412 cm-1. Anal. Calcd for C13H13Br2NO2: C, 41.6;
H, 3.5; N, 3.7. Found: C, 41.7; H, 3.4; N, 3.7.
4-Br om o-1-(ter t-bu tyloxyca r bon yl)-3-[1(RS)-h yd r oxy-
2(R)-((9-p h en yl-9-flu or en yl)a m in o)-3-(m eth oxym eth oxy)-
p r op yl]in d ole (16). Dibromoindole 15 (1.7 g, 4.0 mmol) was
dissolved in 50 mL of THF, and the solution was cooled to -78
°C. Liquid nitrogen was introduced directly into the reaction
mixture over a period of 2-5 min, reducing the internal
temperature to -95 °C. When the reaction mixture had become
homogeneous, n-BuLi (2.04 mL, 4.4 mmol), precooled to -78
°C in 5 mL of THF, was added over a 2-5 min interval. The
internal temperature of the reaction immediately rose to -78
°C, and after 90 min at this temperature, a solution of aldehyde
(12, 1.5 g, 4.0 mmol) in 5 mL of THF, precooled to -78 °C,
was added via cannula. After 4 h at -75 °C, the reaction was
poured into saturated NH4Cl (50 mL) and extracted with Et2O
(3 × 75 mL). The combined organic layer was washed with
brine (100 mL), dried, filtered, and evaporated to give an oil.
Chromatography (4:1, hexanes/EtOAc) led to 2.19 g (82%,
diastereomer ratio, 2.5:1) in several fractions. First diastere-
omer 16a : 1.56 g; mp 102-103 °C; [R]25D +111° (c 1.02, CHCl3);
1H NMR δ 1.62 (2, 9H), 2.92 (dd, J ) 3.98, 5.82, 1H), 3.23 (s,
3H), 3.37-3.30 (m, 2H), 4.42 (dd, J ) 6.46, 27.1, 2H), 4.66 (br,
1H), 4.81 (d, J ) 4.56, 1H), 6.99 (t, J ) 8.15, 1H), 7.67-7.14
(m, 15H), 7.73 (d, J ) 7.46, 1H), 8.11 (d, J ) 8.11, 1H); 13C
NMR δ 28.1, 55.4, 55.5, 66.4, 66.7, 72.7, 83.9, 96.5, 113.7, 114.2,
119.9, 120.8, 124.7, 124.9, 125.2, 125.6, 125.8, 126.7, 127.2,
127.6, 127.7, 128.1, 128.4, 128.6, 137.1, 139.9, 141.6, 145.4,
149.1, 149.5; IR (CDCl3): 3400, 3100, 2940, 1725, 1465, 1440,
1360 cm-1. Anal. Calcd for C37H37BrN2O5: C, 66.4, H, 5.6, N,
4.2. Found: C, 66.6; H, 5.8; N, 4.1. Second diastereomer 16b:
630 mg; [R]25D +151° (c 1.02, CHCl3); mp 101-103 °C; 1H NMR
δ 1.68 (s, 9H), 2.8-2.75 (m, 2H), 3.31 (s, 3H), 4.43 (AB, J )
6.3, 57.6, 2H), 4.72 (s, 1H), 5.59 (d, J ) 2.97, 1H), 6.37 (d, J )
7.53, 1H), 6.48 (t, J ) 7.48, 1H), 7.50-6.98 (m, 12H), 7.66-
7.55 (m, 2H), 8.21 (d, J ) 7.87, 1H); 13C NMR δ 28.1, 55.5,
69.4, 69.7, 72.0, 83.9, 96.6, 113.2, 114.3, 119.3, 119.9, 121.8.
124.1, 124.7, 125.0, 125.8, 126.1, 127.0, 127.1, 127.3, 127.4,
127.5, 127.7, 128.1, 128.3, 137.2, 139.7, 140.4, 145.0, 148.1,
149.0, 150.9.
3-O-(Meth oxym eth yl)-2-N-(9-ph en yl-9-flu or en yl)am in o-
L-ser in e Isoxa zolid id e (11). The isoxazolidide 10 (8.5 g, 21.3
mmol)15 was dissolved in CH2Cl2 (250 mL) and stirred under
nitrogen as DIEA (23.0 mL, 145 mmol) was added dropwise.
The resulting solution was stirred for 5 min, MOMCl (6.82
mL, 89.5 mmol) was added dropwise over 5 min, and the
reaction was stirred at room temperature for another 20 h.
The reaction mixture was washed with 1 M H3PO4 (3 × 200
mL), and the combined aqueous layers were washed with CH2-
Cl2 (2 × 200 mL). The organic layers were combined and
washed with saturated NaCl (2 × 300 mL), dried, filtered, and
evaporated. Chromatography (EtOAc) of the residue gave 9.37
g (99% yield) as a light yellow oil: [R]24D -189° (c 2.15, CHCl3);
1H NMR δ 1.75-2.10 (m, 2H), 2.50-2.70 (m, 1H), 3.10-3.40
(m, 2H), 3.28 (s, 3H), 3.52-3.60 (m, 5H), 4.52 (s, 2H), 7.17-
7.45 (m, 11H), 7.66 (t, J ) 7.16, 2H); 13C NMR δ 26.7, 42.8,
52.5, 55.0, 68.1, 70.4, 73.0, 96.1, 119.4, 119.6, 125.4, 126.0,
127.0, 127.9, 128.1, 128.2, 139.5, 141.3, 149.3, 149.7, 173.5.
Anal. Calcd for C27H28N2O4: C, 73.0; H, 6.4; N, 6.3. Found:
C, 72.9; H, 6.5; N, 6.5.
3-O-(Meth oxym eth yl)-2-N-(9-ph en yl-9-flu or en yl)am in o-
L-ser in a l (12). To isoxazolidide 11 (3.00 g, 6.78 mmol) dis-
solved in THF (100 mL) and cooled to 0 °C with stirring under
nitrogen was added dropwise a solution of LAH (300 mg, 7.9
mmol) dissolved in THF (40 mL) over 15 min at 0 °C. This
mixture was stirred for an additional 30 min at 0 °C, then
poured over ice cold saturated KHSO4 (100 mL) and ice (50
g), and extracted with Et2O (3 × 100 mL). The combined
organic layer was washed successively with ice cold KHSO4
(2 × 200 mL), saturated NaHCO3 (2 × 200 mL), H2O (200 mL),
and brine (250 mL), then dried, filtered, and evaporated.
Chromatography (EtOAc) of the residue gave 2.42 g (96% yield)
of aldehyde 12 as a yellow oil: [R]24D -32.0° (c 1.0, CHCl3); 1H
NMR δ 2.72 (dt, J ) 4.5, 0.7, 1H), 3.24 (s, 3H), 3.23-3.50 (m,
2H), 3.59 (dd, J ) 10.0, 4.5, 1H), 4.4 (s, 2H), 7.20-7.69 (m,
13H), 9.4 (d, J ) 0.7, 1H); 13C NMR δ 55.2, 61.8, 67.5, 72.8,
96.3, 119.9, 120.0, 125.2, 125.3, 126.1, 127.3, 127.9, 128.0,
128.3, 128.5, 128.7, 140.4, 140.6, 144.3, 148.9, 149.3, 202.6.
Anal. Calcd for C24H23NO3: C, 77.2; H, 6.2; N, 3.8. Found: C,
76.9; H, 6.5; N, 3.8.
4-Br om o-3-[1(RS)-h yd r oxy-2(R)-((9-p h en yl-9-flu or en -
yl)a m in o)-3-(m eth oxym eth oxy)p r op yl]in d ole (17). To al-
cohol 16 (500 mg, 0.77 mmol) dissolved in THF (20 mL) and
stirred under nitrogen at room temperature was added a
solution of NaOMe (generated from Na, 88 mg, 3.85 mmol, in
MeOH, 3 mL) via cannula. The reaction was stirred for 1 h at
room temperature, after which saturated NH4Cl (5 mL) and
brine (5 mL) were added, the mixture was extracted with Et2O
(2 × 25 mL), and the organic layer was washed with brine (50
mL), dried, filtered, and evaporated. Chromatography (50%
EtOAc/hexanes) of the residue led to 430 mg (99% yield) of a
mixture of isomers. Diastereomer 17a : 307 mg; mp 102-103
°C; [R]25D +101° (c 1.02, CHCl3); 1H NMR δ 2.89 (dd, J ) 4.18,
5.62, 1H), 3.23 (m, 3H), 3.41-3.29 (m, 2H), 4.41 (q, J ) 6.45,
18.7, 2H), 4.66 (br, 1H), 4.86 (d, J ) 3.58, 1H), 6.85 (t, J )
7.87, 1H), 7.01 (dd, J ) 0.82, 6.79, 1H), 7.47-7.14 (m,
13H),7.67 (d, J ) 7.54, 1H), 7.74 (d, J ) 7.55, 1H), 8.38 (s,
1H); 13C NMR δ 55.4, 56.0, 60.4, 66.7, 72.8, 96.5, 110.2, 113.8,
116.2, 119.8, 120.0, 122.3, 123.4, 123.5, 124.7, 125.2, 125.6,
125.8, 127.2, 127.6, 128.1, 128.4, 128.5, 128.6, 137.5, 140.0,
141.7, 145.7, 149.3, 149.4. Anal. Calcd for C32H29BrN2O3: C,
67.5; H, 5.1; N, 4.9. Found: C, 66.9; H, 5.5; N, 4.5. Diastere-
N-BOC-3,4-d ibr om oin d ole (15). 4-Bromoindole (13, 23.5
g, 120 mmol)17 was dissolved in pyridine (470 mL) and cooled
to 0 °C as it was stirred under nitrogen. After 10 min, a
solution of pyridinium bromide perbromide (45.4 g, 127 mmol,
90% techical grade) in pyridine (235 mL) was added dropwise
over 15 min. Upon completion of the addition, ice water (600
mL) was added and the reaction mixture was extracted with
Et2O (3 × 800 mL). The organic layer was washed with 3 M
phosphoric acid (3 × 800 mL), followed by saturated NaHCO3
(3 × 800 mL) and brine (2 × 800 mL). The organic layer was
dried, filtered, and evaporated to give 14 as a dark oil (31.0
g). Dibromide 14 is unstable, especially on warming, and
1
should be used directly after isolation: H NMR δ 7.02 (t, J
) 7.88, 1H), 7.24 (d, J ) 2.74, 1H), 7.31 (dd, 2H), 8.32 (br,
1H); 13C NMR δ90.7, 111.1, 113.8, 123.2, 123.7, 125.5, 125.6,
136.2.
The above freshly prepared 14 was immediately dissolved
in THF (590 mL), and the resulting solution was stirred under
nitrogen. Triethylamine (4.00 mL), DMAP (2.94 g, 24.4 mmol),
and (BOC)2O (34.7 g, 159 mmol) were added successively, and
the reaction mixture was stirred under nitrogen for 14 h.
Evaporation under reduced pressure was followed by re-
solution of the residue in Et2O (1200 mL) which was washed
with saturated NH4Cl (2 × 800 mL) followed by saturated
NaHCO3 (3 × 800 mL) and brine (2 × 800 mL). The organic
layer was dried, filtered, and evaporated. Chromatography (5%
EtOAc/hexanes) of the oily residue led to 40.8 g (91% yield
from 13) of 15 as a white solid: mp 80 °C; 1H NMR δ 1.66 (s,
9H), 7.16 (t, J ) 8.18, 1H), 7.43 (d, J ) 7.76, 1H), 7.69 (s, 1H),
omer 17b: 123 mg; mp 101-103 °C; [R]25 +167.5° (c 1.00,
D
CHCl3); 1H NMR δ 2.65 (dd, J ) 3.44, 6.35, 1H), 2.74 (br, 1H),
3.07 (br, 1H), 3.17 (d, J ) 9.6, 1H), 3.25 (s, 3H), 4.31 (br, 1H),
4.40 (AB, J ) 6.45, 47.1, 2H), 5.63 (d, J ) 5.33, 1H), 6.47 (d,
J ) 7.43, 1H), 6.57 (t, J ) 7.52, 1H), 6.89 (t, J ) 7.91, 1H),
6.95 (d, J ) 2.11, 1H), 7.44-7.07 (m, 10H), 7.56 (d, J ) 7.55,
1H), 7.65 (d, J ) 7.94, 1H), 8.53 (s, 1H); 13C NMR δ 55.5, 56.9,
68.6, 72.3, 96.7, 110.4, 113.5, 117.5, 119.4, 119.9, 122.4, 124.1,
124.2, 125.0, 125.1, 125.2, 126.1, 127.1, 127.5, 127.6, 127.9,
128.2, 128.3, 137.6, 140.1, 140.4, 145.1, 148.4, 151.0.

(R)-4-Amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole
J . Org. Chem., Vol. 64, No. 1, 1999 231
4-Br om o-1-(ter t-b u t yloxyca r b on yl)-3-[1-oxo-2(R)-((9-
p h en yl-9-flu or en yl)a m in o)-3-(m eth oxym eth oxy)p r op yl]-
in d ole (18). To a solution of CrO3 (1.5 g) in H2O (1.5 mL),
cooled to 5 °C, was added pyridine (10 mL) over 20 min to
give an orange solution. Alcohol 16 (500 mg, 0.75 mmol) was
dissolved in pyridine (10 mL), the cold bath was removed from
the CrO3 solution, and the alcohol solution was added drop-
wise. The mixture was stirred for 96 h at room temperature
and then cooled to 0 °C, and 2 M H3PO4 (20 mL) was added.
The mixture was washed with EtOAc (3 × 30 mL), and the
combined organic layer was then washed with brine (2 × 100
mL), dried, filtered, and evaporated to give an oil. Chroma-
tography (hexanes/EtOAc, 2:1) led to 430 mg (86% yield) of a
yellow oil that solidified: [R]23D -77.8 (c 1.02, CHCl3); mp 74-
2.87-2.69 (m, 3H), 3.02-2.89 (m, 2H), 3.15-3.06 (m, 1H), 3.29
(s, 3H), 4.42 (q, J ) 6.36, 21.2, 2H), 6.51 (d, J ) 7.51, 1H),
6.66 (t, J ) 6.76, 1H), 7.43-7.04 (m, 12H), 7.58 (d, J ) 7.54,
1H), 7.67 (d, J ) 6.85, 1H), 8.18 (d, J ) 8.2, 1H); 13C NMR δ
28.2, 31.0, 53.2, 55.2, 70.2, 72.6, 83.8, 96.6, 114.2, 114.3, 118.6,
119.4, 119.9, 124.7, 124.9, 125.3, 126.1, 126.4, 126.9, 127.0,
127.4, 127.5, 127.7, 128.0, 128.2, 128.9, 136.9, 139.9, 140.7,
145.7, 149.1, 149.5, 150.9. Anal. Calcd for C37H37BrN2O4: C,
68.0; H, 5.7; N, 4.3. Found: C, 67.7; H, 5.8; N, 4.4.
4-Br om o-1-(ter t-bu tyloxyca r bon yl)-3-[2(R)-((9-p h en yl-
9-flu or en yl)a m in o)-3-h yd r oxyp r op yl]in d ole (22). Bro-
moindole 21 (5.0 g, 7.65 mmol) was dissolved in 1 M HCl in
EtOAc (200 mL) precooled to 0 °C, and the solution was stirred
under nitrogen. The reaction mixture was allowed to warm to
room temperature over 1 h, stirred for 4 h, and poured into
ice and saturated NaHCO3 (150 mL). The EtOAc layer was
separated, and the aqueous phase was extracted with Et2O (3
× 100 mL). The combined organic layers were washed with
brine (2 × 100 mL), dried, filtered, and evaporated. Chroma-
tography (33% EtOAc/hexanes) of the residue led to 4.00 g
(86% yield) of 22 as a white foam: [R]23D -14.9° (c 1.00, CHCl3);
1H NMR δ 1.66 (s, 9H), 2.75 (m, 3H), 2.92 (d, J ) 7.15, 2H),
3.03 (d, J ) 9.13, 1H), 6.34 (d, J ) 7.52, 1H), 6.63 (dt, J ) 1.1,
6.46, 1H), 7.37-7.02 (m, 12H), 7.73-7.59 (m, 2H), 8.15 (d, J
) 8.25, 1H); 13C NMR δ 28.1, 55.0, 62.8, 72.8, 84.2, 114.2,
114.3, 117.2, 119.7, 120.1, 124.6, 125.1, 125.4, 125.9, 126.5,
127.1, 127.4, 127.7, 128.1, 128.4, 128.8, 137.1, 140.1, 140.7,
143.7, 148.2, 148.9. Anal. Calcd for C35H33N2BrO3: C, 69.0;
H, 5.5; N, 4.6. Found: C, 68.5; H, 5.9; N, 4.2.
1
76 °C; H NMR δ 1.71 (s, 9H), 3.18 (s, 3H), 3.38 (t, J ) 5.52,
1H), 3.52 (d, J ) 5.7, 2H), 3.87 (br, 1H), 4.43 (q, J ) 6.42,
5.28, 2H), 6.84 (s, 1H), 6.97 (t, J ) 7.5, 1H), 7.5-7.1 (m, 13H),
7.72 (d, J ) 7.41, 1H), 8.11 (d, J ) 8.4, 1H); 13C NMR δ 28.0,
55.2, 61.1, 70.5, 73.1, 85.2, 96.5, 114.1, 114.5, 119.4, 119.7,
121.1, 125.7, 126.0, 126.3, 126.6, 127.1, 127.7, 128.0, 128.1,
128.2, 128.4, 129.0, 130.3, 136.8, 139.7, 140.9, 144.2, 148.1,
149.2, 149.7, 198.1; IR (CDCl3) 3300, 2920, 1740, 1680, 1560,
1460, 1415, 1255 cm-1. Anal. Calcd for C37H35BrN2O5: C, 66.6;
H, 5.3; N, 4.2. Found: C, 66.5; H, 5.3; N, 4.1.
3-[1-Oxo-2(R)-((9-p h en yl-9-flu or en yl)a m in o)-3-(m et h -
oxym eth oxy)p r op yl]in d ole (19). Ketone 18 (350 mg, 0.527
mmol) was dissolved in THF (10 mL) and stirred under
nitrogen as a solution of NaOCH3 (generated from Na, 37 mg,
1.6 mmol, in 5 mL of CH3OH) was added via cannula. The
reaction was stirred at room temperature for 2 h before it was
diluted with EtOAc (25 mL) and hydrolyzed with 1 M H3PO4
(20 mL). The aqueous layer was washed with EtOAc (2 × 30
mL), and the combined organic layer was washed with brine
(75 mL), dried, and filtered. The solvent was evaporated to
give a yellow oil: 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H),
3.35-3.6 (m, 3H), 4.4 (d, J ) 2.0, 2H), 6.52 (d, J ) 3.0, 1H),
6.8 (t, J ) 7.5, 1H)6.9 (t, J ) 7.8, 1H), 7.0-7.7 (m, 14H), 8.3
(m, 2H), 9.4 (s, 1H).
4-Br om o-3-[2(R)-((9-ph en yl-9-flu or en yl)am in o)-3-(m eth -
oxym eth oxy)p r op yl]in d ole (20). Alcohol 17 (2.5 g, 4.4
mmol) and DMAP (670 mg, 5.5 mmol) were dissolved in THF
(90 mL), and the resulting solution was stirred under nitrogen
and cooled to 0 °C. To this mixture was added a solution of
BH3‚THF (22.0 mL, 22.0 mmol, 1 M) dropwise over 1 h after
which the reaction was stirred at 0 °C for 72 h. Ten milliliters
of H2O/AcOH (1:1) were slowly added to the reaction mixture
at 0 °C, and it was then allowed to warm to room temperature
and heated at reflux for 2 min. The mixture was poured into
ice water (100 mL) and extracted with Et2O (3 × 75 mL). The
combined organic layer was washed with saturated NaHCO3
(4 × 150 mL) and brine (2 × 100 mL), dried, filtered, and
evaporated to a residue which was chromatographed (50%
4-Br om o-1-(ter t-bu tyloxyca r bon yl)-3-[2(R)-((9-p h en yl-
9-flu or en yl)a m in o)-3-oxop r op yl]in d ole (23). A solution of
NCS (300 mg, 2.24 mmol) in toluene (10 mL) was cooled to 0
°C and stirred under nitrogen as DMS (0.2 mL, 2.72 mmol)
was added dropwise. The mixture was stirred for another 30
min at 0 °C and then cooled to -25 °C, and bromo alcohol 22
(400 mg, 0.66 mmol), dissolved in toluene (10 mL), was added
via cannula. The reaction mixture was stirred at -25 °C for 6
h, Et3N (0.32 mL, 2.22 mmol) was added dropwise over 5 min,
and the mixture was stirred for an additional 10 min at -25
°C. After being warmed to room temperature and stirred for
1 h, it was poured into H2O (50 mL) and extracted with brine
(100 mL), dried, filtered, and evaporated. Chromatography of
the residue (20% EtOAc/hexanes) led to 340 mg (86% yield) of
23 as a white solid consisting of rotamers: [R]23 +41.3° (c
D
1
1.00, CHCl3); mp 73-74 °C; H NMR δ major 1.68 (s), minor
1.64 (s, 9H), 3.64-3.28 (m, 4H), 7.18 (t, J ) 7.59, 1H), 7.96-
7.53 (m, 12H), major 8.69 (d, J ) 8.07), minor 8.60 (d, J ) 8.0,
1H), 9.87 (d, J ) 1.7, 1H); 13C NMR δ 28.0, 28.2, 62.2, 72.8,
83.8, 84.2, 114.1, 114.3, 114.4, 115.8, 118.4, 119.1, 119.6, 119.8,
119.9, 124.3, 124.7, 125.1, 125.7, 125.8, 126.1, 126.6, 126.8,
126.9, 127.0, 127.1, 127.2, 127.5, 127.7, 127.9, 128.0, 128.1,
128.3, 128.4, 128.7, 137.1, 140.3, 140.7, 143.9, 148.7, 148.8,
148.9, 203.5. Anal. Calcd for C35H31N2BrO3: C, 69.2; H, 5.1;
N, 4.6. Found: C, 69.5; H, 5.5; N, 4.4.
EtOAc/hexanes) to give 2.20 (91% yield) of 20 as a white
1
solid: mp 69-72 °C; [R]25 +98 °C (c 1.0, CHCl3); H NMR δ
D
2.91-2.72 (m, 3H), 3.11-3.07 (m, 2H), 3.27 (s, 3H), 4.40 (q, J
) 6.33, 1.89, 2H), 6.56 (q, J ) 6.51, 0.98, 1H), 7.39-6.92 (m,
13H), 7.58 (d, J ) 7.49, 1H), 7.65 (d, J ) 7.44, 1H), 8.07 (s,
1H); 13C NMR δ 14.1, 30.9, 53.7, 55.3, 70.4, 72.8, 96.6, 110.3,
114.5, 114.6, 119.4, 119.9, 122.6, 123.9, 124.9, 125.0, 125.5,
126.0, 126.2, 126.9, 127.4, 127.7, 128.0, 128.1, 137.6, 140.2,
140.5, 145.9, 149.6, 150.9. Anal. Calcd for C32H29BrN2O2: C,
69.4; H, 5.3; N, 5.1. Found: C, 69.8; H, 5.5; N, 4.9.
4-Br om o-1-(ter t-bu tyloxyca r bon yl)-3-[2(R)-((9-p h en yl-
9-flu or en yl)a m in o)-3-(m et h oxym et h oxy)p r op yl]in d ole
(21). To a solution of bromoindole 20 (900 mg, 1.62 mmol) in
THF (20 mL) stirred under nitrogen were added DMAP (470
mg, 0.54 mmol), Et3N (4.0 mL, 28.7 mmol), and (BOC)2O (600
mg, 2.89 mmol) successively, and the reaction was stirred for
4 h at room temperature. The solvent was evaporated, and
the residue was dissolved in Et2O (100 mL) which was washed
with saturated NH4Cl (2 × 50 mL), saturated NaHCO3 (2 ×
50 mL), and brine (75 mL). Drying, filtering, and evaporating
(R)-4-Br om o-1-(ter t-bu tyloxyca r bon yl)-r-N-(9-p h en yl-
9-flu or en yl)tr yp top h a n (24). A solution of aldehyde 23 (1.00
g, 1.65 mmol) in CH3CN (15 mL), t-BuOH (51 mL), and
2-methyl-2-butene (10 mL) was stirred rapidly as it was cooled
to 0 °C. A solution of NaClO2 (1.15 g, 12.7 mmol) and NaH2-
PO4 (1.81 g, 1.28 mmol) in H2O (20 mL) was added dropwise
over a period of 10 min at 0 °C, and the mixture was then
partitioned between EtOAc (100 mL) and brine (60 mL). The
organic layer was washed with 1 M Na2S2O4 (2 × 75 mL),
dried, filtered, and evaporated. Purification of the residue by
chromatography (2:1:0.3, hexanes/EtOAc/AcOH) led to 700 mg
(69% yield) of 24 as a tan solid: mp 123-125 °C; [R]22D +55.9°
(c 1.0, CHCl3); 1H NMR δ 1.67 (s, 9H), 3.21-3.00 (m, 3H), 6.18
(d, J ) 7.34, 1H), 6.49 (t, J ) 7.38, 1H), 7.35-7.01 (m, 12H),
7.51 (d, J ) 7.48, 1H), 7.60 (d, J ) 7.45, 1H), 8.19 (d, J ) 7.88,
1H); 13C NMR δ 13.9, 15.1, 22.3, 28.2, 30.1, 34.1, 57.4, 65.8,
72.7, 84.2, 114.0, 144.4, 116.2, 119.4, 119.9, 123.9, 125.1, 125.7,
125.9, 126.1, 126.7, 127.2, 127.3, 127.6, 127.9, 128.3, 128.5,
128.8, 136.9, 140.2, 140.8, 143.7 147.1, 148.3, 148.9, 177.6.
Anal. Calcd for C35H31N2BrO4: C, 67.4; H, 5.0; N, 4.5. Found:
C, 67.4; H, 5.4; N, 4.6.
left
a residue which was chromatographed (20% EtOAc/
hexanes), giving 1.02 g (95% yield) of 21 as a white solid: [R]23
D
+144.7° (c 1.03, CHCl3); mp 62-64 °C; 1H NMR δ 1.69 (s, 9H),

232 J . Org. Chem., Vol. 64, No. 1, 1999
Hurt et al.
1
(R)-4-Br om otr yp top h a n [(R)-9]. Tryptophan 24 (4.0 g, 6.4
mmol) was dissolved in DCE (100 mL) and stirred under
nitrogen as Et3SiH (3.16 mL), 22.4 mmol) and TMSOTf (5.6
mL, 32.1 mmol) were added successively. The mixture was
heated at reflux for 1 h and then cooled to room temperature.
The solvent was evaporated, the residue was suspended in
hexane (350 mL) which was decanted, and the resulting
residue was suspended in 1 M HCl (75 mL) and heated at
reflux for 2 h. The mixture was cooled to room temperature
and then cooled in an ice bath as a solution of 1 M KOH was
added dropwise until the pH was 6.0. The water was evapo-
rated, and the residue was suspended in hot MeOH and then
filtered. The filtrate was evaporated, and the solid was
titurated with EtOAc, filtered off, and dried under vacuum
overnight to give 1.72 g (95% yield) as a light brown solid. The
246-247 °C; [R]24 +8.7° (c 1.0, MeOH); H NMR (DMSO-d6)
D
δ 3.23 (AB, J ) 6.65, 7.97, 49.4, 8.4, 6.2, 8.45, 2H), 3.65 (s,
3H), 4.17 (t, J ) 7.44, 1H), 6.99 (t, J ) 7.85, 1H), 7.18 (d, J )
7.85, 1H), 7.18 (d, J ) 7.4, 1H), 7.40 (m, 2H), 8.7 (br, 1H),
11.6 (s, 1H); 13C NMR (DMSO-d6) δ 27.0, 52.6, 53.9, 107.1,
111.5, 112.4, 122.3, 122.8, 124.6, 127.6, 137.9, 169.5. Anal.
Calcd for C12H14ClN2O2: C, 43.2; H, 4.2; N, 8.4. Found: C, 43.2;
H, 4.3; N, 8.3.
(R)-4-Br om o-r-N-tr ityltr yp top h a n Meth yl Ester (28).
4-Bromotryptophan methyl ester hydrochloride [(R)-27, 4.6 g,
13.79 mmol] was suspended in 1,2-dichloroethane (200 mL)
and stirred under nitrogen as Et3N (9.24 mL, 65.84 mmol) was
added dropwise at room temperature. To this mixture was
added TrCl (4.0 g, 14.32 mmol) in dichloroethane (30 mL) via
cannula, and the resulting mixture was stirred for 48 h at room
temperature. Methanol (3.0 mL) was added, and stirring was
continued for 1 h at room temperature before the organic layer
was evaporated. The residue was dissolved in a mixture of
CHCl3/IPA (3:1, 250 mL) washed with water (3 × 150 mL) and
brine (2 × 150 mL), dried, filtered, and evaporated. The residue
was chromatographed (33% EtOAc/hexanes) to give 7.1 g (96%
spectroscopic properties were identical to those of (()-9: [R]24
D
+27.6 (c 1.02, 1 M HCl); mp 288-290 °C.
(R)-4-Br om o-r-N-tr ityltr yp top h a n Tr ityl Ester (25).
Bromotryptophan [(R)-9] (906 mg, 3.2 mmol) was dissolved
in dry DMF (5.0 mL) with stirring under nitrogen at room
temperature. After cooling to 0 °C, Et3N (1.78 mL, 12.8 mmol)
was then added dropwise. To the resultant solution was
further added a solution of trityl bromide (2.28 g, 7.04 mmol)
in CHCl3 (10 mmol). The reaction mixture was stirred for 15
min and then allowed to warm to room temperature. After
stirring at room temperature for 2 h, the mixture was
evaporated. The crude product could be directly subjected to
selective hydrolysis of the trityl ester to give compound 26.
By column chromatography with EtOAc/hexane, 1:3, pure 25
yield) of 28 as a white solid: mp 205-206 °C; [R]24 -31.2° (c
D
1.0, CHCl3); 1H NMR δ 2.74 (d, J ) 10.8, 1H), 2.9 (s, 3H), 3.36
(AB, J ) 8.1, 6.0, 5.59, 6.9, 7.3, 2H), 3.85 (m, 1H), 6.96 (t, J )
7.84, 1H), 7.0 (d, J ) 2.3, 1H), 7.07-7.09 (m, 9H), 7.10-7.23
(m, 2H), 7.36-7.38 (m, 6H), 8.21 (s, 1H); 13C NMR δ 32.3, 51.1,
58.4, 70.8, 110.4, 112.4, 114.3, 122.7, 123.9, 125.5, 125.8, 126.2,
127.5, 128.9, 137.41, 145.9, 175.9. Anal. Calcd for C31H27
BrN2O2: C, 69.0; H, 5.0; N, 5.2. Found: C, 69.0; H, 5.2; N,
5.0.
-
1
could be obtained as a white foam (2.60 g, 90%): H NMR δ
2.42 (dd, J ) 6.4m 15.3, 1H), 2.56 (d, 1H), 3.25 (dd, J ) 6.9,
15.3, 1H), 3.94 (m, 1H), 6.61 (s, 1H), 6.90-7.45 (m, 33H), 8.26
(s, 1H); 13C NMR δ 30.2, 58.0, 71.5, 90.5, 110.5, 111.8, 114.2,
122.4, 123.7, 124.9, 125.5, 126.4, 127.1, 127.2, 127.5, 127.7,
127.9, 128.3, 128.7, 137.3, 142.8, 146.1, 146.8, 172.8.
The er was shown to be 99:1 by chiral HPLC (Chirobiotic V
column, 80% methyl tert-butyl ether/20% hexane/0.05% DMF;
1.0 mL/min at 245 nm, 45 °C, tR 9.6 min for D-enantiomer, tR
10.3 min for L-enantiomer).
Detritylation of 28 to amino ester 27 was effected by treating
28 (40 mg, 74 µmol), dissolved in CH2Cl2 (2 mL) and stirred
under nitrogen, with Et3SiH (14 mL, 0.089 mmol) and TFA
(35 mL, 0.445 mmol), added successively. The reaction mixture
was stirred at room temperature for 30 min, evaporated, and
chromatographed, eluting with 5% MeOH/EtOAc to give 27
(22 mg, 100%), identical to 27 obtained from (+)-9.
(R)-4-Br om o-r-N-tr ityltr yp top h a n (26). F r om (R)-25. To
a solution of 25 (0.72 g, 0.94 mmol) in THF (35 mL) were added
MeOH (10 mL) and H2O (10 mL). The resultant THF (35 mL)
was stirred at 50-55 °C for 14 h and evaporated, and the
residue was chromatographed with EtOAc/hexane, 1:1, to give
acid 26 (395 mg, 80%): mp 181 °C (dec); [R]24 -20.2° (c 1.0,
D
THF); 1H NMR (DMSO-d6) δ 3.12-3.26 (m, 2H), 3.38 (br, 1H),
3.56 (m, 1H), 6.98 (t, J ) 7.8, 1H), 7.03-7.07 (m, 1H), 7.14 (d,
J ) 7.45, 1H), 7.22-7.25 (m, 1H), 7.38 (d, J ) 2.3, 1H), 7.42
(d, J ) 7.7, 1H), 11.3 (s, 1H), 11.55 (br, 1H); 13C NMR (DMSO-
d6) δ 31.8, 57.8, 70.2, 110.9, 111.1, 113.2, 121.8, 122.6, 125.5,
126.0, 127.3, 127.4, 128.5, 137.7, 146.1, 176.1. Anal. Calcd for
Author: Please check wording of above paragraph.
F or m a tion of Ur ea 29. Alternative evidence for enantio-
meric purity was obtained by adding to a solution of amino
ester 27 (18 mg, 64 µmol) in THF (1 mL) under nitrogen (R)-
(+)-R-methylbenzyl isocyanate (9.0 mg, 65 µmol). The reaction
mixture was stirred at room temperature for 30 min and then
evaporated, and the residue was directly subjected to HPLC
analysis (EtOAc/hexane, 2:1, 1 mL/min at 254 nm, tR 16 min
for D-enantiomer, tR 18 min for l-enantiomer): 1H NMR δ 1.32
(d, 3H), 3.36 (dd, 1H), 3.62 (dd, 1H), 3.68 (s, 3H), 4.56 (d, 1H),
4.69 (t, 1H), 4.79 (m, 1H), 4.83 (d, 1H), 6.98 (s, 1H), 7.00 (t,
1H), 7.10-7.40 (m, 7H), 8.4 (br, 1H).
C
30H25BrN2O2: C, 68.6; H, 4.8; N, 5.3. Found: C, 68.2; H, 5.0;
N, 5.2.
F r om (R)-28. The ester (R)-28 (6.9 g, 12.84 mmol) was
dissolved in 1,4-dioxane (160 mL) and stirred rapidly at room
temperature as a solution of LiOH‚H2O (5.5 g, 141 mmol) in
water (60 mL) was added. The resulting mixture was heated
at reflux for 96 h and then cooled to room temperature, and
the organic layer was evaporated. The remaining aqueous
phase was cooled to 0 °C, ice cold 1.0 M H3PO4 (100 mL) was
added, and the resulting mixture was extracted with a mixture
of CHCl3/IPA (4:1, 3 × 100 mL). The combined organic layer
was washed with 1 M H3PO4 (3 × 100 mL), water (2 × 100
mL), and brine (2 × 100 mL). Drying, filtering, and evaporat-
ing gave 6.75 g (100% yield) of 26.
For the determination of HPLC efficacy, (()-27, (()-28, and
(()-29 were prepared as described above for the single enan-
tiomers to provide HPLC controls.
4(R)-N-Tr ityla m in o-5-oxo-1,3,4,5-tetr a h yd r oben z[cd ]-
in d ole [(R)-30]. (R)-Bromo-R-N-trityltryptophan 26 (1.00 g,
1.90 mmol) was dissolved in THF (25 mL) and cooled to -100
°C (liquid nitrogen, pentane bath) with stirring under nitrogen.
To this solution was added n-BuLi (2.6 mL, 2.14 M in hexanes,
5.7 mmol) dropwise over 5 min, maintaining the temperature
below -100 °C. After the reaction mixture was stirred at -105
°C for 2 h, a solution of t-BuLi (2.3 mL, 1.7 M in pentane, 3.9
mmol) was added dropwise over 8 min, maintaining the
internal temperature at -100 °C by direct addition of liquid
N2. The resulting reaction mixture was stirred at -100 °C for
1 h before it was allowed to slowly warm to -78 °C, where it
was stirred for 1 h and then allowed to slowly warm to 0 °C.
After remaining at 0 °C for 1 h, the reaction was allowed to
warm to room temperature and the solution was stirred for
an additional 4 h, then poured into saturated NaHCO3 (25 mL)
and extracted with EtOAc (3 × 40 mL). The organic layers
were combined, washed with brine (2 × 50 mL), dried, filtered,
and evaporated. The residue was chromatographed (33%
Esterification of acid 26 with CH2N2 gave a quantitative
yield of methyl ester 28 with an er identical to that of ester
28 prepared from 27.
(R)-4-Br om otr yp top h a n Meth yl Ester Hyd r och lor id e
(27). Bromotryptophan [(R)-9] (3.00 g, 10.6 mmol) was sus-
pended in MeOH (50 mL) with stirring under nitrogen at room
temperature as TMSCl (3.00 mL, 23.3 mmol) was added
dropwise. The now homogeneous reaction mixture was heated
at reflux for 48 h, after which it was cooled to room temper-
ature and evaporated. The solid residue was dissolved in hot
MeOH (20 mL), then Et2O (180 mL) was added, and a white
precipitate formed. After being cooled in an ice bath, the solid
was filtered off and washed with Et2O. Drying overnight under
vacuum gave 3.39 g (96% yield) of ester hydrochloride 27: mp

(R)-4-Amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole
J . Org. Chem., Vol. 64, No. 1, 1999 233
EtOAc/hexane) to give 650 mg (80% yield) of (R)-30 as an off-
(4R ,5S )-4-N -Tr it yla m in o-5-h yd r oxy-1,3,4,5-t e t r a h y-
d r oben z[cd ]in d ole [(4R,5S)-33]. (R)-4-Bromo-R-N-trityltryp-
tophan (26, 0.25 g, 0.48 mmol) was dissolved in THF (6.3 mL)
and cooled to -100 °C (liquid nitrogen, pentane bath) with
stirring under nitrogen. To this solution was added n-BuLi
(250 mol %, 0.48 mL, 2.5 M in hexane, 1.20 mmol) dropwise
over 5 min maintaining the temperature below -100 °C by
direct addition of liquid N2. After the reaction mixture was
stirred at -105 °C for 2 h, a solution of t-BuLi (0.70 mL, 1.7
M in pentane, 1.20 mmol) was added dropwise over 10 min.
The resulting reaction mixture was stirred at -100 °C for 1 h
before it was allowed to slowly warm to -78 °C, where it was
stirred for 5 h and then allowed to slowly warm to -15 °C
over a period of 2 h. After stirring at -15 °C for 5 h, the
reaction mixture was poured into a cooled pH 7.0 buffer
solution (10 mL) and extracted with CH2Cl2 (3 × 40 mL), and
the combined organic layer was dried, filtered, and evaporated.
The residue was dissolved in MeOH (5.0 mL), the resultant
solution was cooled to -40 °C, and to this solution was added
150 mg of NaBH4 portionwise over 10 min. The reaction
mixture was then allowed to warm to room temperature over
1 h, poured into a cooled pH 7.0 phosphate buffer solution,
and extracted with CH2Cl2 (3 × 40 mL). The combined organic
layer was dried, filtered, evaporated, and chromatographed
(33% EtOAc/hexane) to give 144 mg (70% yield) of (4R,5S)-
33. Recrystallization from CHCl3/hexane afforded a white solid
white solid: mp 194-196 °C; [R]24 -73.2° (c 1.0, THF); 1H
D
NMR δ 2.53 (dd, J ) 6.7, 15.4, 1H), 2.80 (m, 1H), 3.73 (dd, J
) 6.7, 11.6, 1H), 4.2 (br, exchangeable with D2O, 1H), 6.67 (s,
1H), 7.05-7.28 (m, 1H), 7.45 (d, J ) 6.9, 1H), 7.57 (d, J ) 7.3,
6H), 8.39 (s, 1H); 13C NMR δ 30.2, 61.0, 71.3, 109.8, 115.6,
115.7, 120.7, 122.6, 126.4, 126.6, 127.7, 127.8, 128.0, 128.9,
131.0, 134.2, 146.4, 148.5, 198.5.
1-(ter t-Bu t yloxyca r b on yl)-4(R)-N-t r it yla m in o-5-oxo-
1,3,4,5-tetr a h yd r oben z[cd ]in d ole [(R)-31]. To tricyclic ke-
tone (R)-30 (950 mg, 2.21 mmol), dissolved in THF (20 mL)
and stirred rapidly under nitrogen, were added successively
NMM (1.0 mL, 9.10 mmol), DMAP (20 mg, 0.16 mmol), and
BOC2O (550 mg, 2.52 mmol). The resulting solution was stirred
at room temperature for 2 h, then diluted with Et2O (50 mL)
and washed with 1 M H3PO4 (3 × 50 mL), NaHCO3 (2 × 70
mL), and brine (2 × 50 mL). The organic layer was dried,
filtered, and evaporated. Chromatography (25% EtOAc/hex-
ane) of the residue led to 1.10 g (94% yield) of (R)-31 as a light
yellow solid: mp 106-108 °C; [R]24D-81.2° (c 0.95, CHCl3); 1H
NMR δ 1.64 (s, 9H), 2.47 (dd, J ) 6.6, 9.3, 1H), 2.73 (m, 1H),
3.67 (q, J ) 6.6, 5.1, 1H), 4.17 (s, 1H), 7.2 (t, J ) 7.2, 1H),
7.26-7.6 (m, 17H), 8.05 (br, 1H); 13C NMR δ 28.2, 29.9, 60.4,
71.3, 84.0, 114.4, 118.8, 120.0, 121.7, 125.2, 125.8, 126.5, 127.9,
128.9, 133.7, 146.3, 149.6, 197.4. Anal. Calcd for C35H32N2O3:
C, 79.5; H, 6.1; N, 5.3. Found: C, 79.4; H, 6.4; N, 5.1.
which by HPLC and NMR was found to be a single diastere-
1
omer: mp 182-183 °C; [R]22 -28.4° (c 1.0, CHCl3); H NMR
Chiral HPLC: er 99.5/0.5 (Chirobiotic T column, 50%
hexane/methyl tert-butyl ether, 0.5 mL/min at 250 nm, ambi-
ent temperature, tR 11.8 min for D-enantiomer, tR 13.3 for
L-enantiomer). To provide a sample for development of the
HPLC protocol, (()-31 was prepared in exactly the same way.
Upon standing exposed to the atmosphere, 31 was slowly
oxidized to the corresponding R,â-unsaturated ketone, 1-(ter t-
bu tyloxyca r bon yl)-4-N-tr ityla m in o-5-oxo-1,5d ih yd r oben -
z[cd ]in d ole (32): mp 180-182 °C (dec); 1H NMR δ 1.64 (s,
9H), 5.82 (s, 1H), 6.84 (s, 1H), 7.20-7.40 (m, 17H), 8.10 (d, J
) 7.6, 1H); 13C NMR δ 28.1, 71.0, 84.2, 102.7, 114.7, 119.9,
122.3, 124.3, 126.1, 126.5, 126.9, 127.9, 128.0, 128.3, 128.9,
129.1, 141.0, 144.6, 146.3, 179.9. Anal. Calcd for C35 H30
N2O3: C: 79.8; H, 5.7; N, 5.3. Found: C, 79.9; H, 5.8; N, 5.2.
D
δ 1.57 (br, exchangeable with D2O, 1H), 1.93 (dd, J ) 5.1, 15.4,
1H), 2.55 (dd, J ) 3.4, 15.5, 1H), 3.21 (m, 1H), 4.65 (d, J )
5.0, 1H), 6.61 (s, 1H), 7.05-7.59 (m, 18H), 7.85 (s, 1H); 13C
NMR δ 24.5, 55.0, 71.0, 71.7, 110.2, 110.3, 116.8, 119.4, 123.0,
125.9, 126.3, 127.8, 127.9, 128.7, 130.7, 133.7, 146.9. Anal.
Calcd for C30H26N2O: C, 83.7; H, 6.1; N, 6.5. Found: C, 83.3;
H, 6.4; N, 6.5.
Ack n ow led gm en t. We thank Al Mical of the Du-
Pont Pharmaceutical Company for his most generous
and expert assistance in determining the enantiomeric
ratios by chiral HPLC.
J O981723S