Sequential aminodiene Diels-Alder approach to the ergoline skeleton

Article abstract of DOI:10.1021/jo0508797

Through a novel sequence of aminodiene Diels-Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a tran

Full text of DOI:10.1021/jo0508797

Sequential Aminodiene Diels-Alder Approach to the Ergoline
Skeleton
Albert Padwa,* Scott K. Bur,† and Hongjun Zhang
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received May 2, 2005
Through a novel sequence of aminodiene Diels-Alder reactions, several substituted amidofurans
were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system
is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an
intramolecular Diels-Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered
such that it participates in the cycloaddition as the 2π component. A convenient way to construct
the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular
carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal’s
diene. The presence of this activating group not only prevents the isomerization of the advanced
ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle’s
ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the
corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl
triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling
with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately,
our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene
amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid.
Introduction
Indole alkaloids constitute a major family of natural
products whose structural diversity and broad pharma-
cological activity have made them both synthetically
interesting and medicinally important.1 The ergot alka-
loids have also attracted a great deal of interest, in part
because they possess the widest spectrum of biological
activity found in any family of natural products.2-4
† NIH Postdoctoral Fellow, Grant GM20666. Current address:
Gustavus Adolphus College, Saint Peter, MN.
(1) Saxton, J. E. Nat. Prod. Rep. 1993, 10, p 349.
FIGURE 1. Some typical ergot alkaloids.
(2) (a) Ninomiya, I.; Kiguchi, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, CA, 1990; Vol. 38, pp 1-156. (b) Rehacek,
Z.; Sajdi, P. Ergot Alkaloids: Chemistry, Biological Effects, Biotech-
nology; Elsevier Science: Amsterdam, 1990.
(3) Stadler, P. A.; Gigar, K. A. In Natural Products and Drug
Development; Krogsgaard-Larsen, P., Christensen, S. B., Koffod, H.,
Eds.; Munksgaard: Copenhagen, Denmark, 1984; p 467.
(4) (a) Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F.
J. Am. Chem. Soc. 2001, 123, 5918. (b) Lee, K. L.; Goh, J. B.; Martin,
S. F. Tetrahedron Lett. 2001, 42, 1635. (c) Banfield, S. C.; Kerr, M. A.
Synlett 2001, 436. (d) Yokoyama, Y.; Osanai, K.; Mitsuhashi, M.;
Kondo, K.; Murakami, Y. Heterocycles 2001, 55, 653. (e) Kren, V.;
Weignerova´. L.; Kuzma, M.; Jegorov, A.; Sedmera, P. Heterocycles 2001,
55, 1045.
Lysergic acid (1) has been a major synthetic target, since
it possesses the fundamental nucleus of this class of
alkaloids, as do the analogous derivatives Lisuride (4)
(an anti-prolactin drug) and Pergolide (5) (an anti-
Parkinson’s drug) (Figure 1).
The substituents present on the core tetracycle of the
ergots change the biological response from psychotropic
(LSD, 2) to oxytocic (ergonovine, 3).5 Several derivatives
in which the D ring is variably substituted are used
clinically as labor-inducing agents as well as anti-
10.1021/jo0508797 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/15/2005
J. Org. Chem. 2005, 70, 6833-6841
6833

Padwa et al.
SCHEME 1. Selective Synthesis of A Ring
Derivatives
FIGURE 2. Biological properties of ergot structures.
migraine, analgesic, and anti-Parkinson’s therapeutics.5
The clinical success of these synthetic derivatives has
prompted keen interest in derivatives that are substi-
tuted around the aryl A ring, though little has been
reported in terms of general synthetic strategies to access
these structures. For example, compounds with the
general structure 6 have antihypertensive, anti-Parkin-
son, and prolactin-inhibiting activities, while compounds
represented by 7 are analgesic and cell protective agents
(Figure 2).6 One particularly interesting example that
illustrates the potential of A ring derivatives is the
difference in 5-hydroxytryptamine (5-HT, serotonin) re-
ceptor selectivities for compounds 8 and 9.7 Compounds
of type 8, which contain a tert-butyl group on C(13),
exhibit a selectivity for the 5-HTIA receptor. Molecules
of type 9, on the other hand, which possess a tert-butyl
group on C(14), show selectivity for the 5-HT2 family of
receptors. Without any substitution on the A ring, there
is little selectivity between the two classes of receptors.
Selective synthesis of A ring derivatives requires either
a regioselective modification of an indole core or de novo
construction of the indole moiety. Methods for the
modification of indoles are complicated by the inherent
regiochemical preferences dictated by electronic factors.
For example, the synthesis of 8 and 9 was accomplished
by electrophilic alkylation of the aryl ring by exposing a
synthetic intermediate to tert-butyl cation, followed by
separation of the regioisomers (Scheme 1).7 When the
methyl lysergate derivative 10, which contains a thiom-
ethyl residue to protect the more electrophilic 2-position
of the indole, was exposed to a mixture of tert-butyl
acetate and trifluoroacetic acid, it gave rise to 11 (65%)
and 12 (15%). A strategy in which the indole is con-
structed with the appropriate substitution would offer
an advantage in the synthesis of compounds containing
substituents on C(12)-C(14).
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,9
an electrophilic cyclization,10 or a tandem radical reac-
tion.11
The first total synthesis of lysergic acid (1) was
published by Kornfeld, Woodward, and colleagues in
1954.12 Since the original synthesis, racemic lysergic acid
((()-1) has been prepared by 10 different groups,13 but
the number of publications dealing with the synthetic
efforts toward (()-1 is much higher. Among these ap-
proaches one can find about a dozen methods attempting
to construct the ergoline ring, some of which were
successful and others remaining at the level of at-
tempt.4,14 A critical intermediate in the Kornfeld-Wood-
ward synthesis was a compound that became affection-
ately known as Kornfeld’s ketone (14).12 Over the past
several decades many of the synthetic studies dealing
with ergot structures focus on both Uhle’s (13)8,15 and
Kornfeld’s (14) ketones16 as convenient synthetic inter-
mediates (Figure 3). Methodologies that conveniently
(9) Oppolzer, W.; Francotte, E.; Ba¨ttig, K. Helv. Chim. Acta 1981,
64, 478.
(10) Ralbovsky, J. L.; Scola, P. M.; Sugino, E.; Burgos-Garcia, C.;
Weinreb, S. M.; Parvez, M. Heterocycles 1996, 43, 1497.
(11) O¨ zlu, Y.; Cladingboel, D. E.; Parsons, P. J. Tetrahedron 1994,
50, 2183.
(12) (a) Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.;
Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1954, 76, 5256. (b)
Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison,
D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087.
(13) For leading references, see: (a) Moldvai, I.; Temesva´ri-Major,
E.; Incze, M.; Szentirmay, E.; Ga´cs-Baltz, E.; Sza´ntay, C. J. Org. Chem.
2004, 69, 5993. (b) Hendrickson, J. B.; Wang, J. Org. Lett. 2004, 6, 3.
(14) (a) Marino, J. P., Jr.; Osterhout, M. H.; Padwa, A. J. Org. Chem.
1995, 60, 2704. (b) Sader-Bakaouni, L.; Charton, O.; Kunesch, N.;
Tillequin, F. Tetrahedron 1998, 54, 1773.
This existence of useful drugs and the potential for
discovery of new therapeutics has sustained much inter-
est in the synthesis of the ergot template. The majority
of synthetic approaches have utilized the method first
developed by Uhle to effect an intramolecular Friedel-
Crafts cyclization, in which the indole was masked as
an indoline moiety.8 This strategy imposes the necessity
of reoxidizing the indoline to an indole at a later stage of
the synthesis,3 usually a difficult and inefficient process.
(15) Teranishi, K.; Hayashi, S.; Nakatsuka, S.-I.; Goto, T. Synthesis
1995, 506.
(16) (a) Armstrong, V. W.; Coulton, S.; Ramage, R. Tetrahedron Lett.
1976, 4311. (b) Kurihara, T.; Terada, T.; Yoneda, R. Chem. Pharm.
Bull. 1986, 34, 442. (c) Kurihara, T.; Terada, T.; Harusawa, S.; Yoneda,
R. Chem. Pharm. Bull. 1987, 35, 4793. (d) Matsubara, Y.; Yoneda, R.;
Harusawa, S.; Kurihara, T. Chem. Pharm. Bull. 1988, 36, 1597. (e)
Cacchi, S.; Ciatti, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1988,
29, 3117. (f) Okide, G. B. Tetrahedron 1993, 49, 9517. (g) Carr, M. A.;
Creviston, P. E.; Hutchison, D. R.; Kennedy, J. H.; Khau, V. V.; Kress,
T. J.; Leanna, M. R.; Marshall, J. D.; Martinelli, M. J.; Peterson, B.
C.; Varie, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8640. (h)
Waldvogel, E.; Engeli, P.; Ku¨sters, E. Helv. Chim. Acta 1997, 80, 2084.
(5) Somei, M.; Yokoyama, Y.; Murakami, Y. In The Alkaloids;
Academic Press: San Diego, CA, 2000; Vol. 54, pp 191-257.
(6) Yamamoto, I.; Itoh, M.; Shimojo, M.; Yamiya, Y.; Mukaihira, T.;
Akada, Y. WO9745410, 1997.
(7) Mantegani, S.; Brambilla, E.; Caccia, C.; Damiani, G.; Fornaretto,
M. G.; McArthur, R. A.; Varasi, M. Bioorg. Med. Chem. Lett. 1998, 8,
1117.
(8) Uhle, F. C. J. Am. Chem. Soc. 1949, 71, 761.
6834 J. Org. Chem., Vol. 70, No. 17, 2005

Diels-Alder Approach to the Ergoline Skeleton
SCHEME 3. Consecutive [4 + 2] Cycloadditionsa
FIGURE 3. Uhle’s and Kornfeld’s ketones.
SCHEME 2. Strategic Diels-Alder Disconnections
a Reagents: (a) NaH, 2,3-dibromopropene, DMF, 0 °C; 70%; (b)
Pd(PPh3)4, CO, i-Pr2EtN, MeOH, 100 °C; 70%; (c) 19, CH3CN, heat;
(d) HF‚pyr, 25 °C; (e) PhMe, heat; 60%; (f) TFA, CH2Cl2, room
temperature; (g) KOTMS, Et2O, room temperature; (h) Pb(OAc)4,
DMF, 0 °C; 58%.
synthesize these tricycles have become important tools
for medicinal chemists. Consequently, much attention
has been centered on approaches that construct indoles,
particularly 3,4-disubstituted indoles.17 Because of the
potential presented by A ring ergot analogues, new
tactical strategies that can selectively generate polysub-
stituted indoles and also allow for the rapid construction
of substituted analogues of 13 and 14 would be of
particular use to the medicinal community.
developed by Rawal and co-workers.21 Consequently, the
key amidofuran 17 was imagined to be derived from an
appropriately substituted furan 18 and diene 1922 via an
intermolecular [4 + 2] cycloaddition.
Initial studies on the simple allyl system 18 (R1 ) H;
R2 ) CO2-t-Bu) confirmed that an electron-withdrawing
group was necessary to activate the olefin toward cy-
cloaddition with Rawal’s diene. Unfortunately, attempts
to acylate the (tert-butyloxy)carbonyl-protected 2-amid-
ofuran 1823 with acryloyl chloride failed to provide useful
material. Furan 20 could, however, be alkylated with 2,3-
dibromopropene to give the vinyl bromide 21 in 83% yield
(Scheme 3). Palladium-catalyzed carbonylation of 21 in
the presence of methanol provided the acrylate derivative
22 (68%), which was required for the intermolecular
aminodiene cycloaddition reaction. Heating a mixture of
Rawal’s diene 19 and 22 in anhydrous CH3CN at reflux
for 2 h furnished a separable 2:1 mixture of diastereo-
meric amines 23 in 70% yield. The use of anhydrous CH3-
CN was critical to the yield, as wet CH3CN led to
significant decomposition of both reactants. Exposing the
mixture of 23 to HF at 0 °C unmasked the enone
functionality to give 24. Because furan 24 slowly under-
went an intramolecular Diels-Alder reaction during
isolation attempts, the crude furan was simply heated
at reflux in toluene for 30 min to effect the cycloaddition,
ring opening, and dehydration cascade that provides the
desired tricyclic ketone 25 in 80% yield from 23. Alter-
natively, a protocol in which the intermolecular Diels-
Alder reaction is followed by immediate addition of HF
to the reaction mixture at 0 °C furnished 25 in 60%
Results and Discussion
As part of our ongoing program dealing with the
intramolecular Diels-Alder reaction of 2-amidofurans,18
we had previously noted that polysubstituted dihydroin-
doles could easily be prepared.19 It occurred to us that
the strategic deployment of this methodology could
furnish a tricyclic ketone similar to Kornfeld’s ketone 14
in relatively few steps and in a manner that would form
the aromatic moiety in a particularly novel way. To
demonstrate the feasibility of such an approach to the
ergot core, a model study was initiated.20
The formation of tricyclic ketone 15 was envisioned to
come about from a ring opening and dehydration of the
oxabicyclic 16 (Scheme 2). In turn, this oxabicycle is the
result of an intramolecular Diels-Alder reaction of
amidofuran 17 with a cyclohexenone moiety tethered
such that it participates in the cycloaddition as the 2π
component. A convenient way to construct the cyclohex-
enone is to make use of some aminodiene chemistry
(17) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(18) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1997, 62, 4088. (b) Padwa, A.; Brodney, M. A.; Dimitroff, M. J.
Org. Chem. 1998, 63, 5304. (c) Padwa, A.; Dimitroff, M.; Waterson, A.
G.; Wu, T. J. Org. Chem. 1998, 63, 3986. (d) Padwa, A.; Brodney, M.
A.; Satake, K.; Straub, C. S. J. Org. Chem. 1999, 64, 4617.
(19) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J. Org.
Chem. 1999, 64, 3595.
(21) (a) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org.
Chem. 2000, 65, 9059. (b) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J.
Org. Chem. 1999, 64, 3039.
(22) Kozmin, S. A.; He, S.; Rawal, V. Org. Synth. 2001, 78, 152. This
reagent has recently become commercially available.
(23) Padwa, A.; Brodney, M. A.; Lynch, S. M. Org. Synth. 2001, 78,
202.
(20) For a preliminary report of this work, see: Bur, S. K.; Padwa,
A. Org. Lett. 2002, 4, 4135.
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Padwa et al.
SCHEME 4. Intramolecular Amino Furan
Cycloadditionsa
SCHEME 5. Bromination of a Kornfeld’s Ketone
Analog
isomerization of advanced ergoline intermediates to a
naphthalene system but could also be leveraged for an
oxidation to provide Uhle’s ketone (13). Accordingly, we
developed a three-step protocol to convert 25 to 13. First,
treatment of 25 with trifluoroacetic acid cleaved the
carbamate group. This was followed by hydrolysis of the
methyl ester with potassium trimethylsilanolate to pro-
vide the potassium salt of the carboxylic acid.24 Finally,
exposure of the crude salt to lead tetraacetate in wet
DMF effected an oxidative decarboxylation25 without
purifying any of the intermediates.
The reactivity of 25 appears to be similar to that of
Kornfeld’s ketone 14. For example, when 25 was treated
with phenyltrimethylammonium tribromide (PTT) in
THF, bromide 38 was isolated as a separable mixture
(7:1) of diastereomers favoring the equatorial bromide in
85% yield (Scheme 5).26 Interestingly, the bromide de-
rived from Kornfeld’s ketone 14 is exclusively isolated
as the axial isomer 39,12b while 40, a similar substrate
that possesses an angular methyl group, is only isolated
as the equatorial bromide.16
a Reagents: (a) NaH, 2,3-dibromopropene, DMF, 0 °C; (b)
Pd(PPh3)4, CO, i-Pr2EtN, MeOH, 10 °C; (c) 19, CH3CN, heat; HF,
-20 °C; (d) PhMe, heat.
overall yield from 22. Although Danishefsky’s diene also
participates in this sequence of events, higher tempera-
tures (150 °C, sealed tube) and longer reaction times (12
h) were necessary in order to induce the intermolecular
cycloaddition, and lower overall yields (30%) of 25 were
obtained from 22 on employing this diene.
Several analogues of 25 were prepared using differ-
ently substituted furyl carbamates. Following the same
general sequence of reactions, the sodium salts of furans
26-28 were first alkylated with 2,3-dibromopropene to
give 29-31 in moderate to good yields (43-97%). Pal-
ladium-mediated carbonylation of 29 and 30 in methanol
provided 32 and 33 in ca. 60% yield (Scheme 4). When
the (benzyloxy)carbonyl-substituted derivative 31 was
subjected to similar conditions, but using a toluene/benzyl
alcohol solvent mixture instead of methanol, the benzyl
ester 34 was obtained in 40% yield. In the key reaction
sequence, 32-34 were converted to 35-37 by reaction
with Rawal’s diene 19 followed by exposure to HF and
thermolysis of the intermediate enones (e.g. 24). The
substitution pattern of 35 and 36 is significant in that
ergot derivatives based upon 35 are not available through
electrophilic alkylation, and those based upon 36 are the
minor isomers of electrophililc alkylation (vide supra).
Several features of the cascade sequence outlined in
Scheme 3 are worth noting. (1) The use of the aminodiene
chemistry developed by Rawal and co-workers allows for
the enantioselective synthesis of these ketones by select-
ing a chiral amine for the formation of a diene reactant
analogous to 19.21a (2) The carbomethoxy functionality,
required to activate the olefin toward cycloaddition with
diene 19, also serves as a protecting group that prevents
the known aromatization of advanced ergoline intermedi-
ates to a naphthalene system.12b (3) This sequence also
allows for independent substitution of the aryl ring as
in ketones 35 and 36, a feature rarely exploited by other
methodologies.
With a viable approach to substituted derivatives of
Kornfeld’s ketone established, we next turned our atten-
tion to the elaboration of these derivatives toward ergot
natural products. In our initial studies, we found that
ketone 25 could be easily transformed into triflate 41 in
89% yield by the action of triflic anhydride in the
presence of 4-methyl-2,6-di-tert-butylpyridine (Scheme 6).
Subsequent cross coupling of 41 with N-methylpropri-
olamide27 could be accomplished via palladium catalysis
to afford 42 in 87% yield. Alternatively, 41 could be
carbonylated under a CO atmosphere in the presence of
methanol to provide the diester 43 in good yield. Cis
hydrogenation of the alkynyl group present in 42 was
expected to give the (Z)-dienamide 44, which we hoped
would undergo cyclization to furnish the ergoline skeleton
45. Hydrogenation of 42 over palladium on carbon
poisoned with quinoline provided 44 in 56% yield, but
unfortunately we could not find any conditions to effect
the cyclization of 44 to give 45. Exposure of 44 to various
bases, for example, produced an intractable mixture
1
whose H NMR spectra lacked resonances attributable
With a successful procedure for the formation of a
Kornfeld’s ketone analogue (i.e., 25), we next examined
the conversion of dihydroindole 25 to Uhle’s ketone (13).
The angular carbomethoxy group, required to activate
the olefin toward cycloaddition with diene 19, was seen
to fulfill two functions. It would not only prevent the
(24) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(25) Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279.
(26) Stereochemical assignments are based upon coupling constants
for the C(4) proton in each diastereomer.
(27) Hay, L. A.; Koenig, T. M.; Ginah, F. O.; Copp, J. D.; Mitchell,
D. J. Org. Chem. 1998, 63, 5050.
6836 J. Org. Chem., Vol. 70, No. 17, 2005

Diels-Alder Approach to the Ergoline Skeleton
SCHEME 6. Cross-Coupling of Ketone 25 with
SCHEME 8. Synthesis of Acrylic Acid Ethyl Ester
48
N-Methylpropriolamidea
SCHEME 9. Palladium-Mediated Heck Coupling
of Triflate 41
a Reagents and yields: (a) Tf2O, 4-methyl-2,6-di-tert-butylpy-
ridine, CH2Cl2, -78 °C f -20 °C, 48 h, 89%; (b) (PPh3)2Pd(OAc)2,
NaOAc, N-methylpropiolamide, DMF, 60 °C, 90 min, 87%; (c)
Pd(PPh3)4, CO, i-Pr2EtN, MeOH, 50 °C, 3 h; (d) H2, Pd(C),
quinoline, 25 °C, 56%.
SCHEME 7. Synthesis of Modified Lysergic
Systems by Intramolecular Conjugate Addition
Reactions
between 41 and acrylate derivative 48, since a related
transformation had been described in the literature.16e
Our intention was to cleave the [2-(trimethylsilyl)ethoxy]-
carbonyl (Teoc) group29 and cyclize the resulting second-
ary amine to the desired ergoline core 50. The required
acrylate derivative 48 for the Heck reaction was obtained
by a three-step sequence comprising the trapping of the
anion of 51 with formaldehyde to give the hydroxymethyl
derivative 52, conversion of 52 into the mesylate 53, and
an elimination reaction on crude 53 to give 48 (Scheme
8).
Unfortunately, the palladium-mediated Heck coupling
of 41 and acrylate 48 in the presence of Et3N delivered
the isomeric vinylogous enamido ester 54 in yields
comparable to that obtained by Cacchi.16e When 54 was
treated with TBAF, it afforded a 1.5:1 mixture of the E
(55) and Z (56) stereoisomers of the deprotected enamino
ester in good yield. The structure of 55 was unequivocally
established by an X-ray crystal structure. Apparently, the
presence of the angular carbomethoxy group affects the
regioselectivity of the reductive elimination step so that
the vinylogous enamido ester 54 is the preferred olefin
formed (Scheme 9).
In conclusion, while we were ultimately thwarted at
the last stage of our ergoline synthesis by an uncoopera-
tive Heck reaction, there is no question that the sequen-
tial aminodiene Diels-Alder cycloaddition method has
shown its potential for the preparation of various ergot
alkaloids. In one operation, the ABC core skeleton is
assembled and the method also allows for the indepen-
dent substitution on the aryl A ring, a feature rarely
exploited by other methodologies. Investigation into the
range of substituents that are allowed as well as the
to 45. Irradiation with a medium-pressure Hg lamp
returned the starting materials, and reaction with Me3O‚
BF4 led to extensive decomposition. A literature search
failed to disclose any related cyclizations of dienamides;
therefore, we decided to change our approach to the
ergoline skeleton.
Unsaturated esters of type 46 have previously been
obtained by Ramage28 in nine steps from Kornfeld’s
ketone (14) and were shown to constitute promising
intermediates in the synthesis of modified lysergic sys-
tems (47) via intramolecular conjugate addition reactions
(Scheme 7). Given the success of the palladium-catalyzed
transformations of the vinyl triflate 41, we chose to
examine an alternate method to prepare the related
compound 49 by using a sequence similar to that em-
ployed by Cacchi for establishing the D ring of the
ergoline skeleton.16e The envisaged building block 49 was
to be obtained from a palladium-catalyzed reaction
(28) Ramage, R.; Armstrong, V. W.; Coulton, S. Tetrahedron 1981,
37, 157.
(29) Carpino, L. A.; Tsao, J.-H.; Ringsdorf, H.; Fell, E.; Hettrich, G.
J. Chem. Soc., Chem. Commun. 1978, 358.
J. Org. Chem, Vol. 70, No. 17, 2005 6837

Padwa et al.
g, 0.02 mmol), and N,N-diisopropylethylamine (0.26 g, 2 mmol)
in MeOH (1 mL) was heated at 100 °C under a CO atmosphere
(250 psi) for 18 h. The mixture was cooled to room tempera-
ture, diluted with ether (10 mL), and washed with a saturated
aqueous NaHCO3 solution. The organic layer was dried over
MgSO4 and concentrated under reduced pressure. Purification
by flash silica gel chromatography using an EtOAc/hexane (1:
19) mixture as the eluent afforded the desired ester.
application of the method to the synthesis of several ergot
alkaloids is currently being explored.
Experimental Section
General Procedure for the Alkylation of Furyl Car-
bamates. To a solution of furan-2-yl carbamate (10 mmol) in
DMF (20 mL) at 0 °C was added NaH (60% dispersion, 0.44 g,
11 mmol). The mixture was stirred at 0 °C for 1 h, and then
2,3-dibromopropene (2.6 g, 13 mmol) was added. Stirring was
continued for 1 h, and the reaction mixture was partitioned
between H2O (50 mL) and ether (50 mL). The layers were
separated, and the aqueous layer was extracted with ether.
The combined organic layer was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. The result-
ant oil was subjected to flash silica gel chromatography using
an EtOAc/hexane mixture as the eluent.
tert-Butyl N-(2-Bromo-2-propenyl)-N-(2-furyl)carbam-
ate (21). By the general experimental procedure, the reaction
of furanyl carbamate 20 (14.6 g, 80.0 mmol), NaH (60%
dispersion, 3.5 g, 88 mmol), and 2,3-dibromopropene (20.8 g,
104 mmol) in DMF (160 mL) gave 21 (20 g, 83%). IR (neat):
2978, 2932, 1720, and 1613 cm-1. 1H NMR (300 MHz): δ 1.46
(s, 9H), 4.39 (s, 2H), 5.55 (d, 1H, J ) 1.7 Hz), 5.77 (dd, 1H, J
) 3.2 and 1.7 Hz) 6.09 (brs, 1H), 6.33 (dd, 1H, J ) 3.1 and 2.2
Hz), and 7.17 (d, 1H, J ) 1.7 Hz). 13C NMR (75 MHz): δ 28.3,
56.0, 82.1, 101.8, 109.6, 111.1, 117.5, 128.9, 138.5, and 147.8.
Anal. Calcd for C12H16NO3Br: C, 47.84; H, 5.36; N, 4.65.
Found: C, 47.71; H, 5.30; N, 4.52.
tert-Butyl N-(2-Bromo-2-propenyl)-N-(5-methylfur-2-
yl)carbamate (29). By the general experimental procedure,
the reaction of furanyl carbamate 2630 (1.9 g, 9.4 mmol), NaH
(60% dispersion, 0.4 g, 10.3 mmol), and 2,3-dibromopropene
(2.4 g, 12.2 mmol) in DMF (20 mL) gave 29 (1.4 g, 47%). IR
(neat): 2979, 2928, 1721, 1628, and 1575 cm-1. 1H NMR (300
MHz): δ 1.45 (s, 9H), 2.21 (s, 3H), 4.34 (s, 2H), 5.54 (dd, 1H,
J ) 1.9 and 1.0 Hz), 5.78 (d, 1H, J ) 1.4 Hz), 5.89 (dd, 1H, J
) 1.9 and 0.7 Hz), and 5.94 (brs, 1H). 13C NMR (75 MHz): δ
13.8, 28.3, 56.4, 81.9, 103.2, 106.8, 117.4, 129.0, 145.9, 148.3,
and 153.8. Anal. Calcd for C13H18NO3Br: C, 49.52; H, 5.76;
N, 4.44. Found: C, 49.28; H, 5.80; N, 4.19.
tert-Butyl N-[2-(Carboxymethyl)-2-propenyl]-N-(2-fu-
ryl)carbamate (22). By the general procedure, the reaction
of furanyl carbamate 21 (13.7 g, 45.0 mmol), Pd(PPh3)4 (1.0 g,
0.9 mmol), and N,N-diisopropylethylamine (11.6 g, 90 mmol)
in MeOH (45 mL) gave 22 (8.6 g, 68%). IR (neat): 1716, 1639,
1
and 1614 cm-1. H NMR (300 MHz): δ 1.43 (s, 9H), 3.72 (s,
3H), 4.43 (t, 1H, J ) 1.6 Hz), 5.71-5.72 (m, 1H), 5.99 (brs,
1H), 6.25-6.32 (m, 2H), and 7.12 (dd, 1H, J ) 1.9 and 1.0 Hz).
13C NMR (75 MHz): δ 28.3, 49.3, 52.1, 81.8, 101.1, 111.1, 125.5,
136.3, 138.2, 148.5, 153.7, and 166.5. HRMS: calcd for C14H19-
NO5, 281.126 32; found, 281.126 07.
tert-Butyl N-[2-(Carboxymethyl)-2-propenyl]-N-(5-me-
thylfur-2-yl)carbamate (32). By the general procedure, the
reaction of furanyl carbamate 29 (1.4 g, 4.4 mmol), Pd(PPh3)4
(0.1 g, 0.09 mmol), and N,N-diisopropylethylamine (1.1 g, 8.8
mmol) in MeOH (5 mL) gave 32 (0.75 g, 58%). IR (neat): 1720,
1625, 1575, and 1476 cm-1 1H NMR (300 MHz): δ 1.43 (s,
.
9H), 2.20 (s, 3H), 3.73 (s, 3H), 4.39 (t, 2H, J ) 1.6 Hz), 5.74
(m, 1H), 5.82-5.90 (m, 2H), and 6.29 (m, 1H). 13C NMR (75
MHz): δ 13.8, 28.3, 49.6, 52.1, 81.6, 102.5, 106.7, 125.5, 136.3,
146.6, 148.0, 154.1, and 166.6. HRMS: calcd for C15H21NO5,
295.141 97; found, 295.140 69.
tert-Butyl N-[2-(Carboxymethyl)-2-propenyl]-N-(3-me-
thylfur-2-yl)carbamate (33). By the general procedure, the
reaction of furanyl carbamate 30 (0.35 g, 1.1 mmol), Pd(PPh3)4
(0.03 g, 0.02 mmol), and N,N-diisopropylethylamine (0.28 g,
2.2 mmol) in MeOH (1 mL) gave 33 (0.19 g, 59%). IR (neat):
1719, 1646, 1508, and 1475 cm-1. 1H NMR (300 MHz): δ 1.40
(s, 9H), 1.86 (s, 3H), 3.71 (s, 3H), 4.37 (brs, 2H), 5.83 (s, 1H),
6.16 (d, 1H, J ) 1.9 Hz), 6.28 (d, 1H, J ) 1.0 Hz), and 7.09 (d,
1H, J ) 1.9 Hz). 13C NMR (75 MHz): δ 9.7, 28.3, 49.2, 52.0,
81.2, 112.1, 113.2, 126.8, 136.2, 138.4, 144.3, 154.2, and 166.5.
HRMS: calcd for C15H21NO5: 295.141 97. Found: 295.142 42.
Benzyl N-(2-(Carboxybenzyl)-2-propenyl)-N-(fur-2-yl)-
carbamate (34). A mixture of furanyl carbamate 31 (1.6 g,
4.6 mmol), Pd(PPh3)4 (0.11 g, 0.09 mmol), benzyl alcohol (1.5
g, 13.8 mmol), and N,N-diisopropylethylamine (1.2 g, 9.2
mmol) in toluene (4 mL) was heated to 100 °C under a CO
atmosphere (1 atm) for 18 h. The mixture was cooled to room
temperature, diluted with ether, and washed with a saturated
aqueous NaHCO3 solution. The organic layer was dried over
MgSO4, and the mixture was concentrated under reduced
pressure. Purification of the residue by flash silica gel chro-
matography using an EtOAc/hexane (1:19) mixture as the
eluent afforded 34 (0.7 g, 39%). IR (neat): 3033, 2954, 1720,
1612, and 1499 cm-1. 1H NMR (300 MHz): δ 4.57 (s, 2H), 5.19
(s, 2H), 5.20 (s, 2H), 5.79 (s, 1H), 6.05 (s, 1H), 6.33-6.34 (m,
1H), 6.38 (s, 1H), 7.18 (m, 1H), and 7.32-7.35 (m, 10H). 13C
NMR (75 MHz): δ 49.9, 66.9, 68.2, 101.5, 102.8, 106.3, 111.3,
126.7, 128.0, 128.5, 128.8, 132.6, 136.0, 136.9, 139.1, 140.4,
147.7, 154.9, and 165.7. HRMS: calcd for C23H21NO5,
391.141 97; found, 391.142 18.
General Procedure for the Sequential Diels-Alder
Cascade. A mixture of furyl acrylate (1 mmol), Rawals’ diene
19 (0.27 g, 1.2 mmol), and CH3CN (1 mL) was heated at reflux
for 2 h. The mixture was cooled to 0 °C, and then a solution of
HF‚pyr (0.09 g, 3.0 mmol) in CH3CN (3 mL) was added. The
reaction mixture was stirred at 0 °C for 2 h and then
partitioned between a saturated aqueous NaHCO3 solution and
EtOAc. The layers were separated, and the aqueous layer was
extracted with EtOAc. The combined organic layer was dried
over MgSO4, and the mixture was concentrated under reduced
pressure. The crude residue was dissolved in toluene and the
solution heated at reflux for 2 h. The mixture was cooled to
tert-Butyl N-(2-Bromo-2-propenyl)-N-(3-methylfur-2-
yl)carbamate (30). By the general experimental procedure,
the reaction of furanyl carbamate 2731 (1.5 g, 7.5 mmol), NaH
(60% dispersion, 0.33 g, 8.3 mmol), and 2,3-dibromopropene
(2.0 g, 9.8 mmol) in DMF (25 mL) gave 30 (1.2 g, 52%). IR
(neat): 2976, 2920, 1713, and 1641 cm-1 1H NMR (300
.
MHz): δ 1.40 (brs, 9H), 1.92 (s, 3H), 4.33 (brs, 2H), 5.52 (s,
1H), 5.81 (s, 1H), 6.18 (d, 1H, J ) 1.8 Hz), and 7.11 (d, 1H, J
) 1.7 Hz). 13C NMR (75 MHz): δ 10.0, 28.3, 56.1, 81.5, 112.7,
113.3, 118.5, 128.8, 138.6, 143.7, and 154.1. Anal. Calcd for
C13H18NO3Br: C, 49.52; H, 5.76; N, 4.44. Found: C, 49.35; H,
5.61; N, 4.36.
Benzyl N-(2-Bromo-2-propenyl)-N-(fur-2-yl)carbamate
(31). By the general experimental procedure, the reaction of
furanyl carbamate 28 (1.0 g, 4.6 mmol), NaH (60% dispersion,
0.13 g, 5.5 mmol), and 2,3-dibromopropene (1.1 g, 5.5 mmol)
in DMF (10 mL) gave 31 (1.5 g, 97%). IR (neat): 2959, 1719,
1612, and 1504 cm-1. 1H NMR (300 MHz): δ 4.48 (s, 2H), 5.22
(s, 2H), 5.57 (m, 1H), 5.79 (s, 1H), 6.30 (s, 1H), 6.37 (dd, 1H,
J ) 3.4 and 2.0 Hz), and 7.33 (s, 5H). 13C NMR (75 MHz): δ
56.6, 68.3, 103.4, 11.3, 118.6, 127.9, 128.3, 128.4, 128.7, 130.7,
132.5, 136.1, 139.3, 147.1, and 155.0. Anal. Calcd for C15H14-
NO3Br: C, 53.73; H, 4.21; N, 4.18. Found: C, 53.59; H, 4.07;
N, 4.31.
General Procedure for Carbonylation of Vinyl Bro-
mide. A mixture of vinyl bromide (1 mmol), Pd(PPh3)4 (0.023
(30) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J. Org.
Chem. 1999, 64, 3595.
(31) Yakushijin, K.; Suzuki, R.; Hattori, R.; Furukawa, H. Hetero-
cycles 1981, 16, 1157.
6838 J. Org. Chem., Vol. 70, No. 17, 2005

Diels-Alder Approach to the Ergoline Skeleton
room temperature and concentrated under reduced pressure.
Purification by flash silica gel chromatography using an
EtOAc/hexane (2:8) mixture as the eluent afforded the pure
product.
of diasteromers. The major (equatorial) diastereomer (1.2 g,
61%) showed the following spectral properties. IR (neat): 1734,
1705, 1698, 1615, 1596 cm-1. 1H NMR (300 MHz): δ 1.55 (brs,
9H), 2.66 (t, 1H, J ) 12.6 Hz), 1.74 (dd, 1H, J ) 12.6 and 5.8
Hz), 3.70 (s, 3H), 3.77 (d, 1H, J ) 11.0 Hz), 4.64 (brd, 1H, J )
11 Hz), 4.99 (dd, 1H, J ) 12.6 and 5.8 Hz), 7.37 (t, 1H, J ) 7.8
1-[(tert-Butyloxy)carbonyl]-2a-carbomethoxy-5-keto-
1,2,2a,3,4,5-hexahydrobenz[cd]indole (25). By the general
procedure, furanyl carbamate 22 (0.28 g, 1.0 mmol) was
reacted with Rawal’s diene 19 (0.27 g, 1.2 mmol), followed by
exposure to HF‚pyr (0.09 g, 3.0 mmol) in 3 mL of CH3CN to
give 25 (0.2 g, 60%). Mp: 166-167 °C. IR (film): 1733, 1706,
Hz), 7.52 (dd, 1H, J ) 7.8 and 0.8 Hz), and 7.91 (brs, 1H). 13
C
NMR (75 MHz): δ 28.5, 43.5, 48.0, 50.6, 53.7, 59.1, 82.3, 119.7,
120.1, 120.4, 128.7, 130.8, 136.0, 142.4, 152.0, 172.3, and 189.5.
Anal. Calcd for C18H20BrNO5: C, 52.70; H, 4.91; N, 3.41.
Found: C, 52.65; H, 4.77; N, 3.50.
1689, 1614, and 1596 cm-1 1H NMR (300 MHz): δ 1.79 (s,
.
9H), 2.12-2.24 (m, 1H), 2.63-2.71 (m, 3H), 3.67 (s, 3H), 3.76
(d, 1H, J ) 11.1 Hz), 4.62 (brd, J ) 11.1 Hz), 7.34 (t, 1H, J )
7.9 Hz), 7.47 (dd, 1H, J ) 7.9 and 0.8 Hz), and 7.89 (brs, 1H).
13C NMR (75 MHz): δ 28.6, 32.3, 35.8, 49.6, 53.3, 59.8, 81.9,
119.3, 119.5, 130.2, 136.5, 141.9, 152.2, 173.3, and 195.9. Anal.
Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.02; H, 6.44; N, 4.12.
1-[(tert-Butyloxy)carbonyl]-2a-carbomethoxy-5-keto-
8-methyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole (35). By
the general procedure, furanyl carbamate 32 (0.75 g, 2.5 mmol)
was reacted with Rawal’s diene 19 (0.74 g, 3.3 mmol), followed
by exposure to HF‚pyr (0.21 g, 7.5 mmol) in 10 mL of CH3CN
to give 35 (0.33 g, 39%). Mp: 133-134 °C. IR (film): 1727,
1712, 1685, 1614, and 1590 cm-1. 1H NMR (300 MHz): δ 1.50
(s, 9H), 1.88-1.99 (m, 1H), 2.36 (s, 3H), 2.57-2.82 (m, 3H),
3.65 (s, 1H), 3.70 (d, 1H, J ) 11.8 Hz), 4.81 (d, 1H, J ) 11.8
Hz), 7.18 (dd, 1H, J ) 8.2 and 0.5 Hz), and 7.51 (d, 1H, J )
8.2 Hz). 13C NMR (75 MHz): δ 20.1, 28.2, 30.6, 35.6, 50.0, 52.9,
63.2, 81.4, 121.7, 127.5, 132.4, 135.3, 140.9, 141.9, 153.7, 172.5,
and 196.0. Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N,
4.06. Found: C, 65.94; H, 6.84; N, 4.24.
1-[(tert-Butyloxy)carbonyl]-2a-carbomethoxy-5-keto-
6-methyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole (36). By
the general procedure, furanyl carbamate 33 (0.19 g, 0.65
mmol) was reacted with Rawal’s diene 19 (0.19 g, 0.85 mmol)
followed by exposure to HF‚pyr (0.06 g, 2 mmol) in 2 mL of
CH3CN to give 36 (0.08 g, 37%). Mp: 127-127.5 °C. IR
(neat): 1731, 1705, 1680, 1608, and 1585 cm-1. 1H NMR (300
MHz): δ 1.54 (s, 9H), 2.11-2.19 (m, 1H), 2.56 (s, 3H), 2.60-
2.68 (m, 3H), 3.66 (s, 3H), 3.72 (d, 1H, J ) 11.2 Hz), 4.58 (brd,
1H, J ) 11.2 Hz), 7.11 (d, 1H, J ) 8.2 Hz), and 7.78 (brs, 1H).
13C NMR (75 MHz): δ 20.7, 28.3, 31.5, 36.6, 49.9, 52.9, 59.3,
81.4, 118.9, 127.9, 132.7, 133.6, 137.0, 139.9, 151.9, 173.4, and
196.8. Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06.
Found: C, 66.14; H, 6.63; N, 4.05.
The minor (axial) diastereomer (0.18 g, 9%) exhibited the
following spectral properties. Mp: 144-145 °C. IR (film): 1735,
1
1706, 1694, 1597, 1478, and 1461 cm-1. H NMR (300 MHz):
δ 1.56 (s, 9H), 2.76 (dd, 1H, J ) 15.1 and 5.2 Hz), 3.26 (d, 1H,
J ) 15.1 Hz), 3.71 (s, 3H), 3.76 (d, 1H, J ) 11.3 Hz), 4.53 (d,
1H, J ) 11.3 Hz), 4.70 (dd, 1H, J ) 5.2 and 1.7 Hz), 7.41 (t,
1H, J ) 7.9 Hz), 7.59 (dd, 1H, J ) 7.9 and 0.7 Hz), and 7.96
(brs, 1H). 13C NMR (75 MHz): δ 28.5, 40.6, 44.5, 47.4, 53.7,
61.4, 82.4, 120.2, 120.7, 128.1, 130.7, 136.0, 142.6, 152.1, 174.0,
and 188.7. Anal. Calcd for C18H20BrNO5: C, 52.70; H, 4.91;
N, 3.41. Found: C, 52.92; H, 4.98; N, 3.43.
1-[(tert-Butyloxy)carbonyl]-2a-(carboxymethyl)-5-[(tri-
fluoromethyl)sulfonyl]-1,2,2a,3-tetrahydrobenz[cd]in-
dole (41). To a solution of ketone 25 (0.5 g, 1.5 mmol) and
2,6-di-tert-butyl-4-methylpyridine (0.37 g, 1.8 mmol) in CH2-
Cl2 (5 mL) at -78 °C was added triflic anhydride (0.5 g, 1.8
mmol). The mixture was stirred at -78 °C for 30 min, and it
was then warmed to -20 °C. After it was stirred at -20 °C
for 48 h, the solution was quenched with a saturated aqueous
NaHCO3 solution. The layers were separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layer
was dried over MgSO4 and concentrated under reduced pres-
sure. The resulting solid was subjected to flash silica gel
chromatography using an EtOAc/hexane (1:9) mixture as the
eluent to give triflate 41 as a white solid (0.56 g, 89%). Mp:
132-133 °C. IR (film): 1736, 1706, 1634, 1619, and 1583 cm-1
.
1H NMR (300 MHz): δ 1.55 (s, 9H), 2.64 (dd, 1H, J ) 16.8
and 2.2 Hz), 3.14-3.28 (m, 1H), 3.62 (s, 3H), 3.80 (d, 1H, J )
11.5 Hz), 4.49 (brs, 1H), 5.91 (brd, 1H, J ) 5.0 Hz), 6.95 (d,
1H, J ) 7.9 Hz), 7.29 (t, 1H, J ) 7.9 Hz), and 7.70 (brs, 1H).
13C (75 MHz): δ 28.5, 32.0, 47.5, 53.2, 60.1, 82.1, 114.7, 116.1,
117.1, 118.8 (q, J ) 320.7), 126.7, 128.6, 130.5, 141.9, 146.5,
152.2, and 173.8. 19F NMR (282 MHz): δ -74.58 (s, 3F). Anal.
Calcd for C19H20F3NO7S: C, 49.24; H, 4.35; N, 3.02. Found:
C, 49.23; H, 4.31; N, 2.96.
1-[(tert-Butyloxy)carbonyl]-2a-(carboxymethyl)-5-(N-
methylpropriolamid-3-yl)-1,2,2a,3-tetrahydrobenz[cd]in-
dole (42). A solution of triflate 41 (0.25 g, 0.5 mmol),
N-methylpropriolamide (0.06 g, 0.7 mmol), NaOAc (0.18 g, 2.2
mmol), and Pd(OAc)2(PPh3)2 (8 mg) in DMF (2 mL) was stirred
for 90 min. The reaction mixture was cooled to room temper-
ature and was partitioned between H2O and ether. The layers
were separated, and the aqueous layer was extracted with
ether. The combined organic layer was successively washed
with H2O and brine, dried over MgSO4, and concentrated
under reduced pressure. The resulting solid was subjected to
flash silica gel chromatography using an EtOAc/hexane (3:7)
mixture as the eluent to give 42 (0.19 g, 88%) as a white foam.
1-[(Benzyloxy)carbonyl]-2a-carbomethoxy-5-keto-
1,2,2a,3,4,5-hexahydrobenz[cd]indole (37). By the general
procedure, furanyl carbamate 34 (0.39 g, 1.0 mmol) was
reacted with Rawal’s diene 19 (0.29 g, 1.3 mmol) followed by
exposure to HF‚pyr (0.09 g, 3.0 mmol) in 3 mL of CH3CN to
give 37 (0.17 g, 39%). Mp: 99-99.5 °C. IR (neat): 2953, 1716,
1687, 1596, and 1476 cm-1. 1H NMR (300 MHz): δ 2.18 (ddd,
1H, J ) 12.4, 10.5 and 7.9 Hz), 2.58-2.69 (m, 3H), 3.83 (d,
1H, J ) 11.5 Hz), 4.73 (brd, 1H, J ) 10.5), 5.12 (s, 2H), 5.12-
5.29 (m, 2H), 7.15-7.18 (m, 1H), 7.29 (t, 1H, J ) 3.2 Hz), 7.39
(s, 9H), 7.53 (d, 1H, J ) 7.7 Hz), and 7.97 (brs, 1H). 13C NMR
(75 MHz): δ 32.0, 35.7, 49.9, 59.7, 67.8, 119.8, 128.0, 128.4,
128.7, 128.9, 130.4, 135.3, 136.0, 136.9, 142.3, 152.8, 172.3,
and 195.7. Anal. Calcd for C27H23NO5: C, 73.46; H, 5.25; N,
3.17. Found: C, 73.41; H, 5.25; N, 3.13.
4-Bromo-1-[(tert-butyloxy)carbonyl]-2a-(carboxyme-
thyl)-5-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole (38).
To a solution of ketone 25 (1.7 g, 5.1 mmol) in dry THF (30
mL) was added a solution of phenyltrimethylammonium
tribromide (1.9 g, 5.1 mmol) in THF (30 mL). The mixture was
stirred for 2 h at room temperature for 3 h, and then H2O was
added. The layers were separated, and the aqueous layer was
extracted with ether. The combined organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
resulting solid was subjected to flash silica gel chromatography
using EtOAc/hexane (3:15) as the eluent to afford a 7:1 mixture
IR (film): 3295, 2215, 1733, 1701, 1652, 1568, and 1538 cm-1
.
1H NMR (300 MHz): δ 1.53 (brs, 9H), 2.43 (dd, 1H, J ) 17.5
and 2.6 Hz), 2.85 (d, 3H, J ) 4.8 Hz), 3.18 (dd, 1H, J ) 17.5
and 6.4 Hz), 3.58 (s, 3H), 3.76 (d, 1H, J ) 11.5 Hz), 4.43 (brs,
1H), 6.43 (dd, 1H, J ) 6.4 and 2.6 Hz), 6.45-6.49 (m, 1H),
7.02 (d, 1H, J ) 8.2 Hz), 7.21 (t, 1H, J ) 7.7 Hz), 7.62 (brs,
1H). 13C NMR (75 MHz): δ 26.8, 28.6, 32.9, 47.2, 53.1, 60.6,
81.2, 81.9, 85.3, 115.1, 117.9, 119.5, 126.7, 129.3, 130.3, 137.6,
141.5, 152.4, 154.2, and 173.7. Anal. Calcd for C22H24N2O5: C,
66.64; H, 6.11; N, 7.87. Found: C, 66.51; H, 5.87; N, 7.93.
1-[(tert-Butyloxy)carbonyl]-2a,5-(dicarboxymethyl)-
1,2,2a,3-tetrahydrobenz[cd]indole (43). A mixture of tri-
flate 41 (0.1 g, 0.22 mmol), Pd(PPh3)4 (0.005 g, 0.004 mmol),
J. Org. Chem, Vol. 70, No. 17, 2005 6839

Padwa et al.
and N,N-diisopropylethylamine (0.06 g, 0.4 mmol) in MeOH
(1 mL) was heated at 50 °C for 3 h. The reaction mixture was
cooled, filtered, and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography using
EtOAc/hexane (1:9) as the eluent to give 43 (0.06 g, 73%) as a
white solid. Mp: 145-146 °C. 1H NMR (300 MHz): δ 1.56 (brs,
9H), 2.46 (dd, 1H, J ) 17.3 and 2.4 Hz), 3.30 (dd, 1H, J ) 17.3
and 5.4 Hz), 3.60 (s, 3H), 3.79 (d, 1H, J ) 11.5 Hz), 3.81 (s,
3H), 4.33-4.54 (m, 1H), 7.13 (d, J ) 4.8 Hz), 7.26 (t, 1H, J )
7.8 Hz), 7.54 (d, 1H, J ) 7.8 Hz), and 7.67 (brs, 1H). 13C NMR
(75 MHz; two rotamers): δ 28.6, 29.9, 32.6, 47.1, 47.9, 52.1,
53.1, 59.9, 60.4, 77.4, 81.3, 82.2, 114.8, 119.7, 128.4, 128.7,
130.0, 138.9, 139.3, 141.1, 141.9, 152.2, 152.6, 165.9, 173.4,
and 173.8. Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N,
3.75. Found: C, 64.22; H, 6.31; N, 3.69.
MHz, CDCl3): δ 0.02 (s, 9H), 0.95 (dd, 2H, J ) 9.2 and 8.0
Hz), 1.22 (t, 3H, J ) 7.0 Hz), 2.66-2.92 (m, 4H), 3.42-3.81
(m, 5H), and 4.07-4.14 (m, 4H). 13C NMR (CDCl3, 100 MHz):
δ -1.4, 14.2, 17.8, 35.1, 45.8, 46.9, 59.6, 60.9, 64.3, 158.0, and
172.7.
2-{[Methyl((2-(trimethylsilanyl)ethoxy)carbonyl)amino]-
ethyl}acrylic Acid Ethyl Ester (48). To a solution of 2.5 g
(8.2 mmol) of alcohol 52 and 2.6 mL (18.0 mmol) of Et3N at 0
°C was added 1.0 g (9.0 mmol) of mesyl chloride. After it was
stirred at room temperature for 1 h, the reaction mixture was
quenched with a saturated NaHCO3 solution and extracted
with EtOAc. The combined organic layer was washed with H2O
and brine and dried over MgSO4. The solvent was removed
under reduced pressure, and the resultant residue was dis-
solved into 20 mL of benzene, followed by the addition of 1.2
mL (9.0 mmol) of DBU. After it was stirred at room temper-
ature for 30 min, the reaction mixture was quenched with a
saturated NaHCO3 solution and extracted with EtOAc. The
combined organic layer was washed with H2O and brine, and
dried over MgSO4. The solvent was removed under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 1.5 g (64%) of 48 as a colorless oil. IR
(neat): 1705, 1299, 1249, 1151, and 839 cm-1. 1H NMR (CDCl3,
400 MHz): δ 0.02 (brs, 5H), 0.02 (brs, 4H), 0.93-1.02 (m, 2H),
1.29 (t, 3H, J ) 7.2 Hz), 2.88 (brd, 3H, J ) 6.8 Hz), 4.08-4.23
(m, 6H), 5.52 (brs, 0.55H), 5.58 (brs, 0.45H), and 6.27 (brs,
1H). 13C NMR (CDCl3, 100 MHz): δ -1.3, 14.3, 18.0, 34.7, 35.0,
49.3, 49.7, 61.0, 63.9, 124.6, 125.3, 136.1, 136.3, 157.0, and
166.4. HRMS: calcd for C13H25NO4Si, 287.1553; found, 287.1550.
5-{2-(Ethoxycarbonyl)-3-[methyl-((2-(trimethylsilanyl)-
ethoxy)carbonyl)amino]allyl}-3H-benzo[cd]indole-1,2a-
dicarboxylic Acid 1-tert-Butyl Ester 2a-Methyl Ester
(54). To a solution of 0.47 g (1.0 mmol) of triflate 41 and 0.3
g (1.1 mmol) of the Teoc-protected acrylic acid ethyl ester 48
in 6 mL of DMF was added 24 mg (0.1 mmol) of Pd(OAc)2, 53
mg (0.2 mmol) of PPh3, and 0.35 mL (2.5 mmol) of Et3N. The
reaction mixture was heated to 65 °C for 12 h, quenched with
H2O, and extracted with ether. The combined organic layer
was washed with H2O and brine and dried over MgSO4. The
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to give 0.12
g (21%) of 54 as a yellow oil. IR (neat): 1731, 1701, 1386, 1331,
1250, 1203, and 1160 cm-1. 1H NMR (CDCl3, 400 MHz): δ 0.06
(s, 9H), 1.05-1.09 (m, 3H), 1.25 (t, 3H, J ) 7.2 Hz), 1.55 (brd,
9H), 2.36 (brd, 1H, J ) 16.8 Hz), 3.01-3.10 (m, 1H), 3.13 (s,
3H), 3.38 (brd, 1H, J ) 18.4 Hz), 3.56 (s, 3H), 3.72 (brd, 1H, J
) 16.8 Hz), 3.77 (brd, 1H, J ) 11.6 Hz), 4.17 (q, 2H, J ) 7.2
Hz), 4.28-4.32 (m, 2H), 4.36-4.50 (m, 1H), 5.53 (brs, 1H), 6.94
(d, 1H, J ) 8.0 Hz), 7.20-7.32 (m, 1.5H), 7.65 (brs, 0.5H), and
8.20 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -1.3, 14.5, 15.5,
17.8, 28.0, 28.6, 32.6, 33.9, 47.4, 48.2, 52.8, 53.2, 59.9, 60.6,
65.8, 66.1, 77.4, 81.2, 82.0, 110.3, 114.3, 115.8, 122.4, 122.8,
128.7, 129.9, 132.9, 135.7, 141.1, 152.3, 155.1, 168.8, and 174.2.
HRMS: calcd for [C31H44N2O8Si + H+], 601.2840; found,
601.2943.
1-[(tert-Butyloxy)carbonyl]-2a-(carboxymethyl)-5-(N-
methylpropenamid-3-yl)-1,2,2a,3-tetrahydrobenz[cd]in-
dole (44). A mixture of alkyne 42 (0.17 g, 0.4 mmol), quinoline
(0.22 g, 1.7 mmol), and 10% Pd/C (0.05 g) in EtOAc (4 mL)
was stirred at room temperature under a hydrogen blanket
(1 atm) for 1 h. The mixture was filtered through Celite,
washed with aqueous HCl (1 M), dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue
was subjected to flash silica gel chromatography using an
EtOAc/hexane (7:3) mixture as the eluent to give 44 (0.1 g,
56%) as a yellow foam. IR (film): 3307, 2975, 1726, 1703, 1652,
1614, and 1568 cm-1 1H NMR (300 MHz): δ 1.56 (s, 9H),
.
2.46-2.54 (m, 4H), 3.04 (dd, 1H, J ) 17.2 and 6.4 Hz), 3.70 (s,
3H), 3.80 (d, 1H, J ) 11.8 Hz), 4.57 (brs, 1H), 6.00-6.04 (m,
1H), 6.02 (d, 1H, J ) 12.5 Hz), 6.56-6.60 (m, 1H), 6.83 (d,
1H, J ) 8.0 Hz), 7.23 (t, 1H, J ) 8.0 Hz), and 7.62 (brs, 1H).
13C NMR (75 MHz): δ 26.2, 28.6, 33.4, 47.4, 53.1, 59.7, 82.1,
114.6, 117.4, 127.7, 128.0, 130.3, 132.0, 134.1, 141.5, 150.4,
152.4, 156.8, 167.3, and 174.4. HRMS: calcd for C22H26N2O5,
398.184 17; found, 398.183 37.
3-{Methyl[(2-(trimethylsilanyl)ethoxy)carbonyl]amino}-
propionic Acid Ethyl Ester (51). To a solution containing
2.0 g (15 mmol) of 3-(methylamino)propionic acid ethyl ester32
and 4.2 mL (30 mmol) of Et3N in 10 mL of CH2Cl2 at 25 °C
was added dropwise a solution of 2-(trimethylsilyl)ethyl car-
bonochloridate33 in 5 mL of CH2Cl2. After it was stirred at room
temperature for 2 h, the reaction mixture was quenched with
H2O and extracted with CH2Cl2. The combined organic layer
was washed with H2O and brine and dried over MgSO4. The
solvent was removed under reduced pressure, and the crude
residue was subjected to flash silica gel chromatography to
give 2.9 g (71%) of 51 as a colorless oil. IR (neat): 1735, 1698,
1250, 1180, 861, and 839 cm-1. 1H NMR (600 MHz, CDCl3): δ
0.02 (s, 9H), 0.98 (t, 2H, J ) 8.1 Hz), 1.24 (t, 3H, J ) 6.9 Hz),
2.53 (brt, 2H, J ) 8.4 Hz), 2.89 (brd, 3H, J ) 7.2 Hz), 3.51
(brd, 2H, J ) 7.2 Hz), 4.10 (q, 2H, J ) 6.9 Hz), and 4.14 (t,
2H, J ) 8.1 Hz). 13C NMR (CDCl3, 150 MHz): δ -1.3, 14.3,
17.9, 18.1, 33.2, 33.6, 34.9, 35.1, 44.9, 45.5, 60.7, 63.7, 63.8,
156.7, 171.9, and 172.2.
2-(Hydroxymethyl)-3-{methyl[(2-(trimethylsilanyl)-
ethoxy)carbonyl]amino}propionic Acid Ethyl Ester (52).
To a solution of 9.8 mmol of freshly prepared LDA in 20 mL
of THF at -78 °C was added dropwise a solution of 2.5 g (8.9
mmol) of the Teoc-protected propionic acid ethyl ester 51 in
10 mL of THF. After the mixture was stirred at -78 °C for 45
min, formaldehyde gas (20 equiv), generated by heating dry
paraformaldehyde at 150 °C, was added to the enolate solution.
The reaction mixture was warmed to room temperature,
quenched with a saturated NH4Cl solution, and extracted with
EtOAc. The combined organic layer was washed with H2O and
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 2.5 g (92%) of 52 as a colorless oil. IR
(E)- and (Z)-5-[2-(Ethoxycarbonyl)-3-(methylamino)-
allyl]-3H-benzo[cd]indole-1,2a-dicarboxylic Acid 1-tert-
Butyl Ester 2a-Methyl Ester (55 and 56). To a solution of
0.08 g (0.13 mmol) of ester 54 in 4 mL of THF was added 0.8
g of dry 4 Å sieves, followed by the dropwise addition of 0.2
mL (0.2 mmol) of TBAF (1.0 M in THF) at 0 °C. After it was
stirred for 30 min, the reaction mixture was quenched with a
saturated NaHCO3 solution and extracted with ether. The
organic layer was washed with H2O and brine and dried over
MgSO4. The NMR spectrum of the crude residue showed that
it contained a 1.5:1 mixture of compounds 55 and 56. An
analytical sample of the E isomer 55 was obtained by recrys-
tallization from CH2Cl2/MeOH and corresponded to a white
1
(neat): 1733, 1701, 1683, 1250, and 839 cm-1. H NMR (400
1
solid. Mp: 190-192 °C. H NMR (CDCl3, 400 MHz): δ 1.26
(t, 3H, J ) 7.2 Hz), 1.56 (m, 9H), 2.36 (dd, 1H, J ) 16.0 and
3.2 Hz), 2.87 (d, 1H, J ) 4.8 Hz), 3.02 (brd, 1H, J ) 13.2 Hz),
3.30 (brd, 1H, J ) 16.8 Hz), 3.54 (m, 1H), 3.59 (s, 3H), 3.76 (d,
(32) Holley, R. W.; Holley, A. D. J. Am. Chem. Soc. 1949, 71, 2124.
(33) Shute, R. E.; Rich, D. H. Synthesis 1987, 346.
6840 J. Org. Chem., Vol. 70, No. 17, 2005

Diels-Alder Approach to the Ergoline Skeleton
1H, J ) 16.0 Hz), 4.09-4.22 (m, 2H), 4.41 (m, 2H), 5.76 (brs,
1H), 6.99 (d, 1H, J ) 8.0 Hz), 7.22 (m, 1.5H), 7.39 (d, 1H, J )
13.6 Hz), and 7.60 (brs, 0.5H).
of Health (Grant No. GM 059384) for generous support
of this work. We thank our colleague, Dr. Kenneth
Hardcastle, for his assistance with the X-ray crystal-
lographic studies together with Grant Nos. NSF CHE-
9974864 and NIH S10-RR13673.
The minor Z isomer 56 was obtained as a pale yellow oil.
1H NMR (CDCl3, 400 MHz): δ 1.25 (t, 3H, J ) 7.2 Hz), 1.57
(m, 9H), 2.37 (brd, 1H, J ) 14.4 Hz), 2.88 (d, 3H, J ) 4.8 Hz),
3.06 (brd, 1H, J ) 16.0 Hz), 3.05 (brd, 1H, J ) 16.0 Hz), 3.36
(brd, 1H, J ) 16.0 Hz), 3.62 (s, 3H), 3.78 (brd, 1H, J ) 12.0
Hz), 4.10-4.20 (m, 2H), 4.42 (m, 2H), 5.68 (brs, 1H), 6.45 (brd,
1H, J ) 13.2 Hz), 6.89 (brd, 1H, J ) 7.6 Hz), 7.21 (brs, 1H),
and 7.63 (brs, 1H).
Supporting Information Available: Figures giving an
Ortep drawing for 55 and NMR spectra for 22, 32-34, 44, 48,
51, 52, and 54-56 and a CIF file giving crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org. The authors have also deposited atomic
coordinates for these structures with the Cambridge Crystal-
lographic Data Centre.
Acknowledgment. We appreciate the financial sup-
port provided by the National Science Foundation
(Grant No. CHE-0450779) and the National Institutes
JO0508797
J. Org. Chem, Vol. 70, No. 17, 2005 6841