A novel sequential aminodiene Diels-Alder strategy for the rapid construction of substituted analogues of Kornfeld's ketone.

Article abstract of DOI:10.1021/ol0268992

Through a novel sequence of aminodiene Diels-Alder reactions, amidofurans 18a-c were converted to tricyclic ketones 21a-c in moderate to good yields. Ketone 21a could be converted to Uhle's ketone (6) by cleaving the tert-butyl carbamate and oxidatively r

Full text of DOI:10.1021/ol0268992

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4135-4137
A Novel Sequential Aminodiene
Diels−Alder Strategy for the Rapid
Construction of Substituted Analogues
of Kornfeld’s Ketone
Scott K. Bur† and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received September 13, 2002
ABSTRACT
Through a novel sequence of aminodiene Diels−Alder reactions, amidofurans 18a−c were converted to tricyclic ketones 21a−c in moderate
to good yields. Ketone 21a could be converted to Uhle´’s ketone (6) by cleaving the tert-butyl carbamate and oxidatively removing the methyl
ester. Tricycle 21a readily underwent bromination to give 22. Formation of the corresponding enol triflate 25 followed by carbonylation gave
ester 27, which was then coupled with N-methyl propriolamide to furnish 26.
Indole alkaloids constitute a major family of natural products
whose structural diversity and broad pharmacological activity
have made them both synthetically interesting and medici-
nally important.1 The ergot alkaloids, of which lysergic acid
(1) is representative, are particularly important as they
possess the widest spectrum of biological activity found in
any family of natural products.2 Small variations in the
substituents present on the core tetracycle change the
biological response from psychotropic (LSD, 2) to oxytocic
(ergonovine, 3). Several synthetic derivatives are used
9 are analgesic and cell protective agents.5 The position of
the tert-butyl group (R) in indole 10 strongly impacts on
the selectivity of these molecules for 5-HT1A vs 5-HT2
receptors.6
Many of the synthetic studies dealing with ergot structures
focus on Uhle´’s (6)7,8 and Kornfeld’s (7)9-11 ketones, and
methodologies that efficiently construct these tricycles have
been important tools for medicinal chemists. Consequently,
clinically as antimigrain (lisuride), analgesic (metergoline,
4), and anti-Parkinsonian (pergolide, 5) therapeutics, to name
just a few.3
The clinical success of these synthetic derivatives has
prompted keen interest in indoles that are substituted around
the aryl A ring. For example, compounds with the general
structure 8 have antihypertensive, antiparkinson, and pro-
lactin-inhibiting activities,4 while compounds represented by
† NIH postdoctoral Fellow; grant GM20666.
(4) Jones, J. H. U.S. 4238486, 1980.
(5) Yamamoto, I.; Itoh, M.; Shimojo, M.; Yumiya, Y.; Mukaihira, T.;
Akada, Y. WO 9745410, 1997.
(6) Mantegani, S.; Brambilla, E.; Enzo, C.; Damiani, G.; Fornaretto, M.
G.; McArthur, R. A.; Varisi, M. Bioorg. Med. Chem. Lett. 1998, 8, 1117-
1122.
(1) Saxton, J. E. Nat. Prod. Rep. 1993, 10, 349-395.
(2) Ninomiya, I.; Kigichi, T. In The Alkaoids; Brossi, A., Ed.; Academic
Press: San Diego, CA, 1990; Vol. 38, pp 1-156.
(3) Somei, M.; Yokoyama, Y.; Murakami, Y. In The Alkaloids; Academic
Press: San Diego, CA, 2000; Vol. 54, pp 191-257.
10.1021/ol0268992 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/25/2002

Accordingly, the tert-butyloxycarbonyl protected 2-amido-
furan 16a (R1, R2 ) H)17 was first alkylated with 2,3-
dibromopropene to give vinyl bromide 17 (Scheme 2).
Scheme 2a
much attention has been centered on synthetic methods that
construct indoles, particularly 3,4-disubstituted indoles.12
New procedures that can selectively generate polysubstituted
indoles and also allow for the rapid construction of substi-
tuted analogues such as 6 or 7 would be of particular use to
the medicinal community.
As part of our ongoing program dealing with the intra-
molecular Diels-Alder reaction of 2-amidofurans,13 we had
previously noted that polysubstituted dihydroindoles could
easily be prepared.14 It occurred to us that the strategic
deployment of this methodology could fashion a tricyclic
ketone similar to Kornfeld’s ketone 7 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.
The formation of tricyclic ketone 11 was envisioned to
come about from a ring opening and dehydration of an
oxabicycle 12 (Scheme 1). In turn, this oxabicycle is the
Scheme 1. Strategic Sequential 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) 15, CH3CN,
4; (d) HF, 25 °C; (e) PhMe 4; 60% (f) TFA, CH2Cl2, rt; (g)
KOTMS, Et2O, rt; (h) Pb(OAc)4, DMF, 0 °C, 58%.
Palladium-catalyzed carbonylation of 17 in the presence of
methanol provided the acrylate derivative 18 that was
required for the intermolecular aminodiene cycloaddition
reaction. Heating a mixture of 15 and 18 in CH3CN at reflux
for 2 h furnished a 2:1 mixture of diastereomeric amines 19
(10) (a) Armstrong, V. W.; Coulton, S.; Ramage, R. Tetrahedron Lett.
1976, 4311-4314. (b) Kurihara, T.; Terada, T.; Yoneda, R. Chem. Pharm.
Bull. 1986, 34, 442-443. (c) Kurihara, T.; Terada, T.; Harusawa, S.;
Yoneda, R. Chem. Pharm. Bull. 1987, 35, 4793-4802. (d) Matsubara, Y.;
Yoneda, R.; Harusawa, S.; Kurihara, T. Chem. Pharm. Bull. 1988, 36,
1597-1600. (e) Cacchi, S.; Ciattini, G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1988, 29, 3117-3120. (f) Okide, G. B. Tetrahedron 1993, 49, 9517-
9524. (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-
8653.
result of an intramolecular Diels-Alder reaction of amido-
furan 13 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 recently developed by
Rawal.15 Consequently, the key amidofuran 13 was imagined
to be derived from an appropriately substituted furan 14 and
diene 1516 via an intermolecular [4+2]-cycloaddition.
(11) For an interesting derivative of 7 see: Waldvogel, E.; Engeli, P.;
Kusters, E. HelV. Chim. Acta 1997, 80, 2084-2099.
(12) Gribble, G. W. J. Chem. Soc., Perkin. Trans. 1 2000, 1045-1075.
(13) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem.
1997, 62, 4088-4096. (b) Padwa, A.; Brodney, M. A.; Dimitroff, M. J.
Org. Chem. 1998, 63, 5304-5305. (c) Padwa, A.; Dimitroff, M.; Waterson,
A. G.; Wu, T. J. Org. Chem. 1998, 63, 3986-3997. (d) Padwa, A.; Brodney,
M. A.; Satake, K.; Straub, C. S. J. Org. Chem. 1999, 64, 4617-4626.
(14) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998, 63,
3986-3937.
(7) Uhle, F. C. J. Am. Chem. Soc. 1949, 71, 761-766.
(8) Teranishi, K.; Hayashi, S.; Natkatsuka, S.-i.; Goto, T. Synthesis 1995,
506-508.
(9) (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, 5256-5257. (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.
(15) (a) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org.
Chem. 2000, 65, 9059-9068. (b) Kozmin, S. A.; Janey, J. M.; Rawal, V.
H. J. Org. Chem. 1999, 64, 3039-3052.
4136
Org. Lett., Vol. 4, No. 23, 2002

that was immediately treated with HF at room temperature
to unmask the enone 20. Because furan 20 slowly underwent
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 21a. Although Danishefsky’s diene also participates
in this sequence of events, higher temperatures (150 °C,
sealed tube) and longer reaction times (12 h) were necessary
to induce the intermolecular cycloaddition and lower overall
yields (30%) of 21a were obtained from 18 using this diene.
In a similar manner, amidofurans 16b18 and 16c19 were
converted to dihydroindoles 21b and 21c.
Scheme 3a
Several features of this sequence are significant: The use
of the aminodiene chemistry developed by Rawal and co-
workers allows for the enantioselective synthesis of these
ketones by selecting a chiral amine for the formation of a
diene reactant analogous to 15.15a The carbomethoxy func-
tionality, required to activate the olefin toward cycloaddition
with 15, also serves as a protecting group that prevents the
known aromatization of advanced ergoline intermediates to
a naphthalene system.9b This sequence also allows for
independent substitution of the aryl ring as in ketones 21b,c,
a feature rarely exploited by other methodologies.
a Reagents: (a) PTT, THF, rt; 85%; (b) Tf2O, 4-methyl-2,6-di-
tert-butylpyridine, CH2Cl2, -78 to -20 °C, 48 h; 89%; (c)
(PPh3)2Pd(OAc)2, NaOAc, N-methylpropriolamide, DMF, 60 °C,
90 min, 87%; (d) Pd(PPh3)4, CO, i-Pr2EtN, MeOH, 50 °C, 3 h.
Ketone 21a was easily converted to Uhle´'s ketone (6) by
a three-step procedure without purifying any of the inter-
mediates. Treatment of 21a with trifluoroacetic acid cleaved
the carbamate group. This was followed by hydrolysis of
the methyl ester with potassium trimethylsilylanolate so as
to provide the potassium salt of the carboxylic acid.20 Finally,
exposure of the crude salt to lead tetraacetate in wet DMF
effected an oxidative decarboxylation to furnish 6 in 60%
overall yield from 21a.21
Ketone 21a was also transformed into triflate 25 in 89%
yield by the action of triflic anhydride in the presence of
4-methyl-2,6-di-tert-butylpyridine. Subsequent cross coupling
of 25 with N-methylpropriolamide23 could be accomplished
via palladium catalysis to afford 26 in 87% yield. Alterna-
tively, 25 could be carbonylated under a CO atmosphere in
the presence of methanol to provide diester 27 in good yield.
In summary, a novel method for constructing analogues
of Kornfeld’s tricyclic ketone has been developed that relies
on two sequential aminodiene Diels-Alder reactions to
fashion the aromatic A ring. Investigation into the range of
substituents that are allowed as well as the application of
this methodology to the synthesis of ergot alkaloids is
currently underway, and results will be disclosed in due
course.
The reactivity of 21a appears to be similar to that of 7.
For example, when 21a was treated with phenyl-trimethyl-
ammonium tribromide (PTT) in THF,9f bromide 22 was
isolated as a separable mixture (7:1) of diastereomers
favoring the equatorial bromide in 85% yield.22 Interestingly,
the bromide derived from 7 is exclusively isolated as the
axial isomer 23,9b while 24, a similar substrate that possesses
an angular methyl group, is only isolated as the equatorial
bromide.11
(16) Kozmin, S. A.; He, S.; Rawal, V. H. Org. Synth. 2001, 78, 152-
159. This reagent has recently become commercially available.
(17) Padwa, A.; Brodney, M. A.; Lynch, S. M. Org. Synth. 2000, 78,
202-211.
(18) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J. Org.
Chem. 1999, 64, 3595-3607.
(19) Yakushijin, K.; Suzuki, R.; Hattori, R.; Furukawa, H. Heterocycles
1981, 16, 1157-1160.
Acknowledgment. We thank the National Institutes of
Health (GM59384 and GM60003) for generous support of
this work. We acknowledge the use of shared instrumentation
provided by grants from the NIH and NSF.
(20) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(21) Kochi, J. K. Org. React. 1972, 19, 279-421.
(22) Stereochemical assignments are based upon coupling constants for
the C(4) proton in each diastereomer.
(23) Hay, L. A.; Koenig, T. M.; Ginah, F. O.; Copp, J. D.; Mitchell, D.
J. Org. Chem. 1998, 63, 5050-5058.
Supporting Information Available: Spectral character-
ization for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0268992
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