Applications of vinylogous Mannich reactions. Total syntheses of the Ergot alkaloids rugulovasines A and B and setoclavine

Article abstract of DOI:10.1021/ja010577w

Concise syntheses of the Ergot alkaloids rugulovasine A (3a), rugulovasine B (3b), and setoclavine (2) have been completed by strategies that feature inter- and intramolecular vinylogous Mannich reactions as the key steps. Thus, the first synthesis of 3a,

Full text of DOI:10.1021/ja010577w

5918
J. Am. Chem. Soc. 2001, 123, 5918-5924
Applications of Vinylogous Mannich Reactions. Total Syntheses of
the Ergot Alkaloids Rugulovasines A and B and Setoclavine
Spiros Liras, Christopher L. Lynch, Andrew M. Fryer, Binh T. Vu, and
Stephen F. Martin*
Contribution from the Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
ReceiVed March 2, 2001
Abstract: Concise syntheses of the Ergot alkaloids rugulovasine A (3a), rugulovasine B (3b), and setoclavine
(2) have been completed by strategies that feature inter- and intramolecular vinylogous Mannich reactions as
the key steps. Thus, the first synthesis of 3a,b commenced with the conversion of the known indole 17 into
24 via the addition of the furan 22 to the iminium ion 21, which was generated in situ from the aldehyde 19.
Cyclization of 24 by a novel SRN1 reaction followed by removal of the N-benzyl group furnished a mixture
(1:2) of 3a and 3b. In an alternative approach to these alkaloids, the biaryl 35 was reduced with DIBAL-H to
give an intermediate imine that underwent spontaneous cyclization via an intramolecular vinylogous Mannich
addition to provide 36a,b. N-Methylation of the derived benzyl carbamates 37a,b followed by global deprotection
gave a mixture (2:1) of rugulovasines A and B (3a,b). Setoclavine (2) was then prepared from the biaryl 41
using a closely related intramolecular vinylogous Mannich reaction to furnish the spirocyclic lactones 42a,b.
These lactones were subsequently transformed by hydride reduction and reductive methylation into the ergoline
derivatives 43a,b, which were in turn converted into 2 by deprotection and solvolytic 1,3-rearrangement of
the allylic hydroxyl group.
Introduction
Scheme 1
The indole alkaloids of the Ergot family have attracted the
attention of synthetic chemists for decades.1 Certainly the most
well-known representative of this class is lysergic acid (1),2,3
but other members have also played important roles on the stage
of natural products chemistry. One such alkaloid is setoclavine
(2), which is structurally related to 1,3,4 whereas the rugu-
lovasines A and B (3a,b)5,6 represent novel structural types
within this family.
racemic form, and they were observed to interconvert upon
warming.6 To account for these unusual facts, it was proposed
that 3a and 3b underwent interconversion via the achiral
intermediate 4 (Scheme 1). That this hypothesis was indeed
feasible was later convincingly demonstrated by Rebek, who
first prepared rugulovasine A in optically pure form and studied
its equilibration to form a mixture of racemic 3a and 3b.7
The cyclization of 4 to give either 3a or 3b constitutes one
of the early examples of a class of carbon-carbon bond forming
reactions that is generally known as the vinylogous Mannich
reaction.8 Various combinations of linear and cyclic iminium
ions and enol derivatives may participate in vinylogous Mannich
additions, and we have actively exploited such constructions in
developing tactics and strategies for the concise syntheses of a
Most natural products are typically isolated as single enan-
tiomers, but rugulovasines A and B were both isolated in
(1) For an excellent review of the Ergot alkaloids, see: Ninomiya, I.;
Kiguchi, T. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego,
CA, 1990; Vol. 38, pp 1-156.
(2) For selected syntheses of lysergic acid, see: (a) 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, 3087-3114. (b) Oppolzer,
W.; Francotte, E.; Battig, K. HelV. Chim. Acta 1981, 64, 478-481. (c)
Ninomiya, I.; Hashimoto, C.; Kiguchi, T.; Naito, T. J. Chem. Soc., Perkin
Trans. 1 1985, 941-948. (d) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar,
G. Tetrahedron Lett. 1988, 29, 3117-3120. (e) Saa´, C.; Crotts, D. D.; Hsu,
G.; Vollhardt, K. P. C. Synlett 1994, 487-488.
(6) Cole, R. J.; Kirksey, J. W.; Clardy, J.; Eickman, N.; Weinreb, S. M.;
Singh, P.; Kim, D. Tetrahedron Lett. 1976, 3849-3852.
(7) (a) Rebek, J.; Shue, Y.-K. J. Am. Chem. Soc. 1980, 102, 5426-
5427. (b) Rebek J.; Shue, Y.-K.; Tai, D. F. J. Org. Chem. 1984, 49, 3540-
3545.
(8) For reviews of the Mannich and vinylogous Mannich reactions, see:
(a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. Engl.
1998, 37, 1044-1070. (b) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu,
G. Chem. ReV. 2000, 100, 1929-1972. (c) Rassu, G.; Zanardi, F.; Battistini,
L.; Casiraghi, G. Chem. Soc. ReV. 2000, 29, 109-118. (d) Bur, S. K.; Martin
S. F. Tetrahedron 2001, 57, 3221-3242.
(3) Rebek, J., Jr.; Tai, D. F.; Shue, Y.-K. J. Am. Chem. Soc. 1984, 106,
1813-1819.
(4) Kornfeld, E. C.; Bach, N. J. Chem. Ind. (London) 1971, 1233-1234.
(5) Abe, M.; Ohmono, S.; Ohashi, T.; Tabuchi, T. Agric. Biol. Chem.
1969, 33, 469-471.
10.1021/ja010577w CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/01/2001

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5919
Scheme 2
Scheme 3
number of complex alkaloid natural products.9 When 2-alkoxy-
furans 6 are employed as the nucleophiles in additions to
iminium ions 5, aminoalkyl butenolides 7 are produced, and
the two new stereocenters are often created with good diaste-
reoselectivity (Scheme 2). Significantly, this type of vinylogous
Mannich reaction leads directly to the molecular framework
found in 3a,b and other alkaloids containing derivatized
butyrolactone rings as structural subunits. The transformation
of the Mannich adducts 7 into hydroxy dihydropyridones 8, or
other substituted piperidines such as the one present in 4, then
requires a ring expansion that proceeds via an O f N acyl
transfer. When the reacting partners in the vinylogous Mannich
reaction are linked by joining R3 and R4, the spirobicyclic ring
system 7 initially produced may be elaborated via a lactone-
lactam rearrangement to give a fused nitrogen heterocycle 8.
A combination of the efficiency and the stereoselectivity of
vinylogous Mannich reactions ultimately determines their
general utility in alkaloid synthesis. However, the stereochem-
istry of the addition is not a factor in applying this construction
to the syntheses of the Ergot alkaloids because there is no 1,2-
amino alcohol array in 1 and 2, and both possible stereochemical
relationships are found in the naturally occurring diastereomers
3a and 3b. Hence, we envisioned that a vinylogous Mannich
addition might be advantageously employed as a key step in
designing a novel and efficient entry to 3a,b and 2 (Scheme 3).
The essence of the plan requires elaboration of the butenolide
10, which corresponds to the rugulovasines A and B (3a,b) if
R3 ) Me, into 1 and 2. A pivotal intermediate in this sequence
would likely be the lactam 9, which could be generated from
10 by a lactone-lactam rearrangement. There are two reaction
manifolds that can lead to 10. The first of these involves
cyclization of 11, which in turn would be formed by the
intermolecular vinylogous Mannich reaction of the iminium ion
13 and the silyloxy furan 14 (path a). The second pathway
features the intramolecular vinylogous Mannich reaction of 12
(path b). A number of potential precursors of the iminium ion
12 may be formulated, but all require the intermediacy of a
biaryl intermediate that is functionally related to 15, which
should be accessible via a palladium-catalyzed coupling reaction
that would form bond c. The reduction of this general plan to
the total syntheses of rugulovasines A and B (3a,b) and
setoclavine (2) constitutes the substance of this report.10
Intermolecular Vinylogous Mannich Approach to Rugu-
lovasines A and B. The syntheses of 3a and 3b commenced
with converting 4-bromoindole 1611 into the 3-indolylacetonitrile
derivative 17 in 71% overall yield using a one-pot procedure
that is a slight modification of known methods.12 The indole
nitrogen of 17 was then protected as a tert-butyl carbamate,
whereupon the nitrile function was reduced using diisobutyl-
aluminum hydride to give the aldehyde 19, which was used
without purification. If the indole N-H was not protected prior
to hydride reduction, the resulting aldehyde was not particularly
stable and decomposed quickly upon storage.13 Although other
carbamates could be introduced onto the indole, they were more
readily cleaved in the hydride reduction step.
The stage was now set to examine the critical vinylogous
Mannich reaction, but the initial experiments were somewhat
(9) For some examples, see: (a) Martin, S. F.; Benage, B.; Geraci, L.
S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991, 113, 6161-
6171. (b) Martin, S. F.; Corbett, J. W. Synthesis 1992, 55-57. (c) Martin,
S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236-3242.
(d) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem. Soc.
1996, 118, 9804-9805. (e) Martin, S. F.; Bur, S. K. Tetrahedron Lett. 1997,
38, 7641-7644. (f) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J.
Am. Chem. Soc. 1999, 121, 6990-6997. (g) Martin, S. F.; Bur, S. K.
Tetrahedron 1999, 55, 8905-8914. (h) Martin, S. F.; Lopez, O. D.
Tetrahedron Lett. 1999, 40, 8949-8953. (i) Martin, S. F.; Chen, K. X.;
Eary, C. T. Org. Lett. 1999, 1, 79-81. (j) Bur, S. K.; Martin, S. F. Org.
Lett. 2000, 2, 3445-3447.
(10) For a preliminary account of a portion of this work, see: Martin,
S. F.; Liras, S. J. Am. Chem. Soc. 1993, 115, 10450-10451.
(11) 4-Bromoindole was prepared from 2-bromo-6-nitrotoluene. See:
Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106-
5110.
(12) (a) Somei, M.; Kizu, K.; Kunimoto, M.; Yamada, F. Chem. Pharm.
Bull. 1985, 33, 3996-3708. (b) Patel, M. K.; Fox, R.; Taylor, P. D.
Tetrahedron 1996, 52, 1835-1840.
(13) For example, see: Burkard, S.; Borschberg, H.-J. HelV. Chim. Acta
1989, 72, 254-263.

5920 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Liras et al.
discouraging. For example, when 19 was treated sequentially
with methylamine and then the silyloxyfuran 22 under a variety
of conditions, none of the desired adduct 23 was isolated.
Aldimines derived from unhindered primary amines were known
to be relatively unstable, so this result was not entirely
surprising. We soon discovered that condensation of the crude
aldehyde 19 with benzylmethylamine gave an intermediate
enamine that underwent facile reaction with the silyloxyfuran
22 in the presence of camphorsulfonic acid to furnished a
mixture (1:2) of diastereomeric adducts 24 in 45% overall yield
from the nitrile 18. Lewis acids were not found to be effective
promoters of this vinylogous Mannich reaction that presumably
proceeded via the iminium ion 21.
Scheme 4
With the aminoalkyl butenolides 24 in hand, the second key
construction was at hand. The question now to be addressed
was whether an intramolecular SRN1 reaction could be used to
create the hindered spirocyclic lactone moiety and to complete
the construction of the rugulovasine skeleton. Such processes
have enjoyed only limited application in the total synthesis of
complex natural products,14,15 and success was by no means
assured. Nevertheless, we were delighted to discover that
irradiation of 24 in refluxing ammonia in the presence of freshly
sublimed potassium tert-butoxide proceeded smoothly to deliver
an inseparable mixture (1:2) of N-benzyl rugulovasines A and
B 25a,b in 51% yield. The desired cyclization also proceeded
fortuitously with concomitant removal of the tert-butyl carbam-
ate group, thereby obviating the need for a separate deprotection
step. Although we did not explore the mechanistic details to
any great extent, the transformation 24 f 25a,b appeared to
occur by an SRN1 mechanism, because several attempts to effect
the cyclization in the absence of light under the typical reaction
conditions required for aryne-type reactions (LDA, THF, -23
to 25 °C) did not provide any of the expected product.16
The final step of the synthesis required removal of the
N-benzyl protecting group from 25a,b, and this task proved to
be more challenging than originally anticipated. Attempted
debenzylation of 25a,b under oxidative conditions17 or using
various chloroformates, including R-chloroethyl chloroformate
and vinyl chloroformate,18 either returned starting material or
gave mixtures of products. At least part of the problem in this
deprotection was attributed to the free indolic N-H in 25a,b
as the N-Boc derivative of 24 was readily debenzylated with
1-chloroethyl chloroformate in an exploratory experiment.
However, reintroduction of an indolic nitrogen protecting group
would have added steps to the synthesis and hence was not very
appealing in the context of developing a concise approach to
the target alkaloids. Eventually, we found that N-debenzylation
of the hydrochloride salt of 25a,b proceeded smoothly by
hydrogenolysis using Pearlman’s catalyst to give a mixture (1:
2) of the rugulovasines A and B (3a,b) in 74% yield. The
spectral characteristics of 3a and 3b were identical with those
of authentic samples.19
Intramolecular Vinylogous Mannich Approach to Rugu-
lovasines A and B. Having demonstrated the viability of an
intermolecular vinylogous Mannich reaction as a key step in
the syntheses of the rugulovasines A and B, we were interested
in examining the intramolecular variant that corresponded to
the putative biomimetic pathway for their interconversion
(Scheme 1). To establish the feasibility of inducing the key
cyclization, a simple model study was first conducted. The
stannyl furan 26 was prepared in 78% yield from commercially
available 2-methoxyfuran. Coupling of 26 with the bromoindole
17 under Stille conditions afforded the biaryl 27, N-protection
of which gave 28 in 84% overall yield (Scheme 5). The original
plan was to reduce the nitrile function of 28 to generate the
aldehyde 29, condensation of which with methylamine was then
expected to give the imine 30 (R ) Me) that would then undergo
acid-catalyzed cyclization to furnish 31. However, when 28 was
treated with DIBAL-H and the reaction subjected to a standard
aqueous workup, an unexpectedly facile intramolecular vi-
nylogous aldol reaction occurred to give a mixture of the
epimeric alcohols 32; none of the expected aldehyde 29 was
isolated.
The observation that rugulovasines A and B interconverted
via reversible vinylogous Mannich reactions suggested that 32
might undergo a reVerse vinylogous aldol reaction to give the
aldehyde 29. The question that naturally arose was whether the
29 thus produced might be trapped in situ with methylamine to
give the imine 30 (R ) Me), which could then cyclize
spontaneously to furnish the desired 31. However, reaction of
32 with methylamine under a variety of conditions afforded no
detectable amounts of 31.
(14) For a review of SRN1 reactions, see: Norris, R. K. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, pp 451-482.
(15) (a) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson,
T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507-2516.
(b) Goehring, R. R. Tetrahedron Lett. 1992, 33, 6045-6048.
(16) Flann, C. J.; Overman, L. E.; Sarkar, A. K. Tetrahedron Lett. 1991,
32, 6993-6996.
(17) (a) Monkovic, I.; Wong, H.; Bachand, C. Synthesis 1985, 770-
773. (b) Gao, X.; Jones, R. A. J. Am. Chem. Soc. 1987, 109, 1275-1278.
(18) For example, see: Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau,
M.; Malfroot, T. J. J. Org. Chem. 1984, 49, 2081-2082 and references
therein.
(19) We thank Professor Julius Rebek (The Scripps Research Institute)
for spectra of rugulovasines A and B.

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5921
Scheme 5
Scheme 6
was ultimately found to be a stepwise one. Thus, reaction of
36a,b with benzyl succinimidyl carbonate20 gave a mixture of
the carbamates 37a,b, which were N-methylated under standard
conditions to afford the protected rugulovasines 38a,b in 85%
overall yield. Global deprotection of 38a,b using 30% HBr in
HOAc gave 3a and 3b in a single operation, but the unoptimized
yield was only about 50%. On the other hand, the two protecting
groups could be removed sequentially to give a mixture (2:1)
of 3a and 3b in 74% overall yield. The ordering in this
deprotection sequence appeared to be critical as several attempts
to remove the Cbz group first by hydrogenolysis were ac-
companied by variable amounts of over reduction and formation
of the saturated butyrolactone. It is perhaps noteworthy that this
second approach to the rugulovasines gave a mixture (2:1) of
3a and 3b in which 3a was the major product, whereas the
intramolecular SRN1 reaction afforded a mixture (1:2) in which
3b was the major product.
Synthesis of Setoclavine. The foregoing experiments clearly
established the viability of both inter- and intramolecular
vinylogous Mannich reactions to provide quick access to the
rugulovasines A and B (3a,b). We then turned our attention to
the associated question of whether it would be possible to
convert the spirocyclic butyrolactone subunit found in 3a,b into
the fully fused tetracyclic ring system found in lysergic acid
(3) and setoclavine (2) via a lactone-lactam rearrangement (cf.
Scheme 1). Precedent for this key transformation may be found
in a report by Rebek, who induced such an acyl transfer in a
related dihydroindole system.3 However, effecting the analogous
conversion of 33, which possesses an aromatic indole ring, into
39 proved to be more difficult than anticipated. After consider-
able experimentation, we discovered that heating 33 with
N-methyl-p-toluenesulfonamide in the presence of DBU in a
sealed tube gave the desired tetracycle 39 in 78% yield.21
Unfortunately, despite numerous efforts, we have thus far been
Owing to the facility with which the aldehyde 29 cyclized, it
occurred to us that it might be possible to trap the intermediate
imine 30 (R ) H) that was first generated upon reduction of
the nitrile group in 28. After some experimentation, we found
that reduction of 28 with DIBAL-H followed by the addition
of anhydrous silica gel prior to aqueous workup furnished the
vinylogous Mannich adduct 33 (R ) H) as a mixture (ca. 2:1)
of diastereomers in 77% yield. The established precedent for
the rugulovasines to undergo reversible vinylogous Mannich
reactions prompted us to expose 33 to excess methylamine in
an attempt to prepare the N-methyl analogue 31 (R ) Me).
However, a number of preliminary experiments in which 33
was treated with methylamine were unavailing, and it was
apparent that other tactics would ultimately have to be developed
to introduce the N-methyl group required in the rugulovasines.
The discovery that hydride reduction of the nitrile group in
28 generated an imine that underwent spontaneous vinylogous
Mannich reaction inspired a simple plan for the syntheses of
the rugulovasines 3a and 3b. The furyl stannane 34, which was
obtained from 2-triisopropylsilyloxy-3-methylfuran9f by sequen-
tial metalation and stannylation with Bu3SnCl, was coupled with
17 via a Stille reaction. It was necessary to conduct this Stille
reaction in the presence of base to suppress protiodestannylation
of 34. When the Stille coupling was complete, the indole
nitrogen was protected by simply adding (Boc)2O, 4,4-(di-
methylamino)pyridine (DMAP), and Et3N directly to the reaction
mixture to give 35 in 94% overall yield from 17. Hydride
reduction (DIBAL-H) of 35 followed by the addition of
anhydrous silica gel and an aqueous workup then delivered a
mixture (2:1) of diastereomeric adducts 36a,b in 71% yield.
Variable amounts (10-15%) of the adducts lacking the N-Boc
group were also produced in this reaction.
Several methods for effecting the monomethylation of 36 in
a single operation were explored, but the most efficient protocol
(20) Paquet, A. Can. J. Chem. 1982, 60, 976-980.

5922 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Liras et al.
Scheme 7
Scheme 8
unable to convert compounds related to 39 efficiently into any
of the naturally occurring Ergot alkaloids. Consequently, we
elected to examine another tactic for transforming spirocyclic
vinylogous Mannich adducts related to 33 into the fused ergoline
ring system.
We had found that the indolic N-Boc protecting group was
somewhat labile under the conditions required to transform 35
into 36a,b via hydride reduction/vinylogous Mannich cycliza-
tion. Hence, to avoid adventitious N-deprotection during the
synthesis of setoclavine, the bromoindole 17 was protected as
its N-tosyl derivative 40 (73% yield). Starting 17 was invariably
recovered in about 15-20% yield, but when the conditions were
varied in attempts to force the reaction to completion, other
side reactions intervened. The transformation of 40 into the
biaryl intermediate 41 via a Stille reaction and the subsequent
tandem hydride reduction/vinylogous Mannich reaction pro-
ceeded smoothly to give the spirocyclic butenolides 42a,b in
76% overall yield. Reduction of 42a,b with DIBAL-H provided
an intermediate amino lactol that underwent facile isomerization
and dehydration to generate a mixture of epimeric dihydropy-
ridines. Although the two dihydropyridines could be separated
by chromatography and characterized, they were routinely
reduced with excess NaBH3CN in the presence of 38% aqueous
formaldehyde to give a mixture of the diastereomeric amino
alcohols 43a and 43b in 41% and 29% overall yields,
respectively.
The N-tosyl protecting group was readily removed from 43a,b
by reduction with magnesium in MeOH. However, the diaster-
eomeric alcohols thus produced underwent facile solvolysis and
rearrangement, and setoclavine (2) was isolated as the major
product. Two other products that were formed in this depro-
tection step were tentatively identified as the methyl ether 44
and the tertiary alcohol 45. Armed with the knowledge that the
acid-catalyzed rearrangements of compounds related to 44 and
of 45 had been shown to give setoclavine,3,22 we treated the
crude mixture obtained upon deprotection of 43a,b with aqueous
acid and obtained setoclavine (2) in 64% overall yield; the
setoclavine thus obtained gave spectral data identical with those
reported.
intermolecular vinylogous Mannich addition of the furan 22 to
the iminium ion 21 furnished 24, thereby setting the stage for
an unusual SRN1 reaction that delivered a mixture of N-benzyl
rugulovasines A and B; subsequent debenzylation afforded 3a
and 3b. In the alternative approach to these alkaloids, the biaryl
35 was reduced with DIBAL-H to give an intermediate imine
that spontaneously underwent an intramolecular vinylogous
Mannich addition to provide a mixture of 36a,b that was readily
transformed into 3a and 3b. The related intramolecular vi-
nylogous Mannich cyclization of 41 to give 42 was exploited
as a pivotal step in the synthesis of setoclavine (2); the novel
skeletal reorganization of 42 leading to 2 is also noteworthy.
These syntheses of 2, 3a, and 3b further establish the utility of
vinylogous Mannich reactions for the preparation of complex
alkaloid natural products, and other applications of these general
processes to alkaloid synthesis are in progress, the results of
which will be reported in due course.
Conclusions
Concise syntheses of the Ergot alkaloids rugulovasine A (3a),
rugulovasine B (3b), and setoclavine (2) have been completed.
The novel strategy that was developed for their syntheses
featured inter- and intramolecular vinylogous Mannich reactions
as key constructions. In the first approach to 3a and 3b, the
Selected Experimental Procedures
4-Bromo-3-[2-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)-2-[methyl-
(phenylmethyl)amino]ethyl]-1H-indole-1-carboxylic Acid, 1,1-Di-
methylethyl Ester (24). A solution of DIBAL-H (3.2 mL, 1.0 M
solution in CH2Cl2) was added dropwise to a solution of nitrile 18 (0.82
g, 2.45 mmol) in CH2Cl2 (25 mL) at -78 °C. The mixture was stirred
at -78 °C for 45 min and then at room temperature for 5 h. Saturated
aqueous Rochelle’s salt (20 mL) was added, and the mixture was poured
into saturated aqueous NH4Cl (20 mL). After the mixture was stirred
for 10 min, H2O (20 mL) was added. The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The
(21) (a) Drummond, J. T.; Johnson, G. Tetrahedron Lett. 1988, 29, 1653-
1656. (b) Bon, E.; Bigg, D. C. H.; Bertrand, G. J. Org. Chem. 1994, 59,
4035-4036. (c) Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem.
Soc. 1996, 118, 3055-3056.
(22) (a) Bach, N. J.; Kornfeld, E. C. Tetrahedron Lett. 1974, 3225-
3228. (b) Bernardi, L.; Gandini, E.; Temperilli, A. Tetrahedron 1974, 30,
3447-3450.

Applications of Vinylogous Mannich Reactions
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5923
combined organic layers were washed with brine (20 mL), dried
(MgSO4), and concentrated under reduced pressure to give 0.75 g (91%)
of crude 19 that was used in the next step without further purification.
MHz) δ 174.4, 150.7, 134.1, 126.6, 126.5, 123.1, 119.4, 115.3, 111.4,
110.3, 88.5, 63.1, 35.1, 29.7, 25.4, 10.9.
1
For rugulovasine B (3b): H NMR (300 MHz) 8.08 (br s, 1 H),
A solution of benzylmethylamine (0.24 g, 2.0 mmol) in CH2Cl2 (5
mL) was added dropwise to a stirred solution of crude 19 (0.75 g, 2.22
mmol) in CH2Cl2 (15 mL) at room temperature, and stirring was
continued for 8 h. The solvents were removed under reduced pressure
to afford the corresponding enamine (0.88 g, 1.99 mmol), which was
immediately dissolved in benzene (4 mL) containing silyloxyfuran 22
(0.843 g, 3.98 mmol), and camphorsulfonic acid (0.463 g, 1.99 mmol).
The resulting reaction was heated under reflux for 1 h and cooled to
room temperature. EtOAc (20 mL) was added, the organic solution
was washed with saturated aqueous NaHCO3 (1 × 15 mL), and the
aqueous layer was back-extracted with EtOAc (15 mL). The combined
organic layers were washed with brine (2 × 15 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was purified by
flash chromatography with hexanes/EtOAc (6:1) to afford 0.61 g (45%
from 18) of a diastereomeric mixture (2:1) of 24. A small amount of
the major component was separated by HPLC: 1H NMR (300 MHz)
δ 8.15 (d, J ) 7.8 Hz, 1 H), 7.37 (s, 1 H), 7.29 (d, J ) 7.8 Hz, 1 H),
7.2-7.0 (m, 7 H), 6.99 (s, 1 H), 5.27 (br s, 1 H), 3.85 (d, J ) 13.9 Hz,
1 H), 3.62 (d, J ) 13.9 Hz, 1 H), 3.58-3.45 (m, 1 H), 3.18-3.02 (m,
1 H), 2.37 (s, 3 H), 1.82 (d, J ) 1.5 Hz, 3 H), 1.63 (s, 9 H); 13C NMR
(75 MHz) δ 174.6, 148.9, 148.1, 139.2, 137.1, 129.7, 128.4, 128.3,
128.1, 127.2, 126.8, 126.7, 125.0, 117.4, 114.5, 113.8, 84.1, 80.7, 64.1,
58.6, 38.1, 28.1, 22.3, 10.6; IR (CH2Cl2) 1754, 1753 cm-1; mass
spectrum (CI) m/z 541.1535 (C28H31BrN2O4 + H requires 541.1525),
441 (base), 230, 182.
7.37 (br s, 1 H), 7.32 (d, J ) 8.2 Hz, 1 H), 7.18 (t, J ) 8.0 Hz, 1 H),
7.03 (br s, 1 H), 6.87 (d, J ) 7.3 Hz, 1 H), 3.37-3.25 (m, 2 H), 3.05
(dd, J ) 15.3, 6.4 Hz, 1 H), 2.46 (s, 3 H), 2.05 (d, J ) 1.6 Hz, 3 H);
13C NMR (75 MHz) δ 174.2, 150.9, 134.0, 129.4, 128.1, 123.2, 119.9,
114.9, 111.2, 109.1, 88.2, 63.6, 34.8, 29.7, 24.4, 10.8.
Tributyl(5-triisopropylsiloxy-4-methyl-2-furanyl)stannane (34).
To a stirred solution of 3-methyl-2-triisopropylsilyloxyfuran9f (0.97 g,
3.8 mmol) and TMEDA (2.69 g, 3.5 mL, 23.1 mmol) in anhydrous
hexane (40 mL) at -5 °C was added 1.1 M sec-BuLi in cyclohexane
(3.6 mL, 3.6 mmol) over 10 min. After stirring for 6.5 h, freshly distilled
Bu3SnCl (1.29 g, 1.08 mL, 4.0 mmol) was added, and the reaction
mixture was stirred for 18 h at -5 °C. The mixture was then
concentrated under reduced pressure, and the residue was distilled under
vacuum (240 °C Kugelrohr oven temperature, 0.2 mmHg) to afford a
2.03 g (94%) of 34 as a yellow oil: 1H NMR (300 MHz) δ 6.29 (s, 1
H), 1.82 (s, 3 H), 1.60-1.48 (comp, 6 H), 1.35-1.19 (comp, 9 H),
1.09-0.85 (comp, 33 H); 13C NMR (75 MHz) δ 157.4, 146.5, 126.5,
91.4, 29.0, 27.3, 17.6, 13.7, 12.4, 10.0, 8.4; IR (CHCl3) 2957, 2927,
2869, 1651, 1487, 1464 cm-1; mass spectrum (CI) m/z 542.2766
[C26H52O2Si118Sn requires 542.2752], 544 (base), 542, 289, 255.
3-Cyanomethyl-1-[(4-methylphenyl)sulfonyl]-4-(4-methyl-5-triiso-
propylsiloxy-2-furanyl)-1H-indole (41). The bromide 40 (1.106 g,
2.843 mmol) was dissolved in degassed toluene (55 mL), and the furan
34 (2.007 g, 3.696 mmol), K2CO3 (393 mg, 2.843 mmol), and Pd-
(PPh3)4 (164 mg, 0.142 mmol) were added. The resulting mixture was
heated under reflux for 3 h and then allowed to cool to room
temperature. The solvent was removed under reduced pressure to give
a residue that was purified by flash chromatography on silica gel eluting
with 2:1 (v/v) hexanes/Et2O to give nitrile 41 (1.512 g, 95%) as a pale
yellow oil; 1H NMR (250 MHz) δ 7.95 (d, J ) 8.2 Hz, 1 H), 7.79 (d,
J ) 8.4 Hz, 2 H), 7.73 (s, 1 H), 7.33-7.17 (comp, 4 H), 6.16 (s, 1 H),
3.69 (d, J ) 1.2 Hz, 2 H), 2.35 (s, 3 H), 1.89 (s, 3 H), 1.35-1.16 (m,
1 H), 1.06 (d, J ) 6.7 Hz); 13C NMR (75.5 MHz) δ 153.2, 145.3,
139.6, 135.9, 134.8, 130.0, 127.0, 125.7, 125.0, 125.3, 124.9, 124.6,
117.4, 113.7, 113.0, 112.1, 94.4, 21.5, 17.5, 16.4, 12.3, 8.6; IR (CHCl3)
1600 cm-1; mass spectrum (CI) m/z 563.2411 [C31H39SSiN2O4 (M +
1) requires 563.2400], (base), 313.
N-Benzylrugulovasines A and B (25a,b). To a solution of sublimed
potassium tert-butoxide (84 mg, 0.75 mmol) in distilled NH3 (24 mL)
at reflux was added 24 (54 mg, 0.10 mmol). The resulting yellow-
orange solution was then irradiated externally (Pyrex filter) with a
Hanovia 450-W mercury lamp for 1.25 h. Solid NH4Cl (50 mg) was
then slowly added to the reaction mixture, and the ammonia was
allowed to evaporate. EtOAc (25 mL) was added and the organic layer
was washed with brine (2 × 5 mL). The aqueous layer was washed
with EtOAc (2 × 10 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by flash chromatography with hexanes/EtOAc (3:1) to afford
18 mg (51%) of 25a and 25b as an inseparable (1:2) mixture: 1H NMR
(300 MHz) δ 8.00 (br s, 1 H), 7.31-7.04 (comp, 8 H), 6.97-6.37 (m,
1 H), 6.86 (d, J ) 7.2 Hz, 0.66H), 6.70 (d, J ) 7.2 Hz, 0.33 H), 3.85-
3.59 (comp, 2 H), 3.51-3.12 (comp, 3 H), 2.40 (s, 1 H), 2.21 (s, 2 H),
2.11 (d, J ) 1.3 Hz, 1 H), 1.87 (d, J ) 1.3 Hz, 2 H); 13C NMR (75
MHz) δ 175.1, 174.8, 151.3, 148.9, 139.8, 139.6, 134.1, 134.0, 130.3,
128.7, 128.6, 128.3, 128.2, 128.0, 126.9, 126.8, 125.9, 123.3, 122.9,
118.8, 118.5, 115.5, 114.1, 111.6, 110.8, 110.5, 88.7, 86.7, 67.5, 65.1,
60.2, 59.8, 39.8, 39.5, 29.7, 21.1, 19.1, 10.9, 10.7; IR (CH2Cl2) 1748,
1602 cm-1; mass spectrum, m/z 358.1686 (C23H22N2O2 requires
358.1681), 105, 91 (base).
4-Amino-3,4-dihydro-4′-methyl-1-[(4-methylphenyl)sulfonyl]-
spiro[benz[cd]indole-5(1H)-2′-[(5′H)-furan-5′-one]] (42a,b). To a cold
(-78 °C) solution of the nitrile 41 (627 mg, 1.116 mmol) in CH2Cl2
(20 mL) was added a 1.0 M solution of DIBAL-H in CH2Cl2 (2.8 mL,
2.789 mmol). After the reaction was stirred at -78 °C for 45 min, the
cooling bath was removed and the reaction was stirred at room
temperature for 4 h. The reaction was diluted with CH2Cl2 (15 mL),
and anhydrous (dried at 180 °C under high vacuum for 18 h) silica gel
(ca. 10 g) was added in one portion under Ar at room temperature.
The mixture was vigorously stirred for 5 min at room temperature,
and then a saturated aqueous solution of Rochelle’s salt (6 mL) was
added. The mixture was stirred vigorously for 10 min, and the solids
were then removed by vacuum filtration through a pad of Celite. The
pad was washed successively with EtOAc (2 × 200 mL) and MeOH
(50 mL). The combined filtrate and washings were dried (Na2SO4),
and the solvents were removed under reduced pressure. The residue
was purified by flash chromatography on silica gel eluting with 9:1
(v/v) EtOAc/MeOH to give a mixture of 42a and 42b (345 mg, 76%)
as a colorless oil: 1H NMR (250 MHz, ∼2:1 mixture of diastereoiso-
mers) δ 7.84 (d, J ) 8.3 Hz, 0.67 H), 7.82 (d, J ) 8.3 Hz, 0.33 H),
7.73 (d, J ) 8.4 Hz, 0.67 H), 7.73 (d, J ) 8.4 Hz, 0.67 H), 7.72 (d, J
) 8.4 Hz, 1.33 H), 7.28-7.17 (comp, 4 H), 7.10 (s, 0.33 H), 7.03 (s,
0.67 H), 6.94 (d, J ) 7.3 Hz, 1 H), 3.48 (dd, J ) 8.9, 4.5 Hz, 0.33 H),
3.32 (dd, J ) 8.5, 4.5 Hz, 0.67 H), 3.20 (dd, J ) 16.5, 4.5 Hz, 0.33
H), 3.09 (dd, J ) 15.6, 4.5 Hz, 0.67 H), 2.85 (dd, J ) 15.6, 8.5 Hz,
0.67 H), 2.73 (dd, J ) 16.5, 8.9 Hz, 0.33 H), 2.29 (s, 3 H), 1.99 (d, J
) 1.2 Hz, 2 H), 1.95 (d, J ) 1.4 Hz, 1 H); 13C NMR (75.5 MHz, ∼2:1
mixture of diastereoisomers) δ 173.7, 149.2, 148.6, 145.0, 135.0, 133.3,
130.7, 129.9, 128.8, 128.6, 127.4, 126.8, 126.6, 125.8, 125.7, 121.1,
119.6, 118.5, 115.7, 114.2, 113.7, 87.8, 87.3, 54.8, 54.0, 28.5, 27.6,
Rugulovasines A and B (3a,b). The hydrochloride salt of 25a,b
was prepared by adding ethanolic HCl to a solution of 25a,b (20 mg,
0.056 mmol) in EtOH (0.3 mL) containing 20% Pd(OH)2/C (15 mg).
The resulting mixture was stirred under H2 (1 atm) at room temperature
for 9 h. The catalyst was removed by suction filtration through a pad
of Celite, and the pad was washed with EtOH (2 mL). The combined
filtrate and washings were concentrated under reduced pressure, and
the residue was dissolved in EtOAc (10 mL). This solution was washed
with saturated aqueous NaHCO3 (10 mL), and the aqueous layer was
back-extracted with EtOAc (2 × 5 mL). The combined organic layers
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with EtOAc to
afford 11 mg (74% yield) of a mixture (1:2 by 1H NMR) of rugulovasine
A (3a) and rugulovasine B (3b). Pure samples of each were then
obtained by repeated flash chromatography using EtOAc as the eluant.
For rugulovasine A (3a): 1H NMR (300 MHz) δ 8.05 (br s, 1 H),
7.31 (d, J ) 8.2 Hz, 1 H), 7.16 (d, J ) 1.4 Hz, 1 H), 7.16 (t, J ) 7.7
Hz, 1 H), 7.00 (br s, 1 H), 6.87 (d, J ) 7.2 Hz, 1 H), 3.28 (dd, J )
14.8, 3.4 Hz, 1 H), 3.17 (dd, J ) 7.5, 4.0 Hz, 1 H), 3.04 (dd, J ) 15.1,
7.4 Hz, 1 H), 2.49 (s, 3 H), 2.05 (d, J ) 1.4 Hz, 3 H); 13C NMR (75

5924 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Liras et al.
21.4, 10.7; IR (CHCl3) 1759 cm-1; mass spectrum (CI) m/z 409.1227
[C22H21SN2O4 (M + 1) requires 409.1222], (base), 255.
2.58-2.52 (m, 1 H), 2.52 (s, 3 H), 2.31 (s, 3 H), 1.61 (s, 3 H); 13C
NMR (125.7 MHz) δ 144.7, 135.5, 135.5, 134.5, 133.1, 129.8, 128.0,
126.7, 126.5, 126.3, 119.9, 118.4, 117.3, 112.3, 70.1, 64.9, 52.8, 41.2,
21.5, 20.2, 14.8; IR (CHCl3) 1602 cm-1; mass spectrum (CI) m/z
409.1589 [C23H25SN2O3 (M + 1) requires 409.1586] (base), 391.
Setoclavine (2). A solution of the crude mixture of alcohols 43a,b
(20 mg, 0.049 mmol) in MeOH (1.5 mL) containing Mg powder (12
mg, 0.490 mmol) was stirred at room temperature for 1.5 h. The mixture
was then acidified with 1 N HCl (aq) (2 mL). Saturated aqueous
NaHCO3 (5 mL) was then added, and the mixture was extracted with
CHCl3 (3 × 5 mL). The combined organic layers were washed with
saturated brine (5 mL), dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by flash chromatography on
silica gel eluting with EtOAc/MeOH (5:1) to give setoclavine (2) (8
mg, 64%) as a white solid: mp 210-215 °C dec (lit.23 mp 215-217
°C dec); 1H NMR (500 MHz) δ 7.90 (br s, 1 H), 7.23-7.17 (comp, 3
H), 6.90 (t, J ) 1.8 Hz, 1 H), 6.39 (s, 1 H), 3.53 (dd, J ) 14.5, 5.7 Hz,
1 H), 3.06 (ddd, J ) 11.5, 5.7 Hz, 1.8 Hz, 1 H), 3.01 (br s, 1 H), 2.80
(dd, J ) 11.4, 1.3 Hz, 1 H), 2.68 (ddd, J ) 14.5, 12.8, 1.8 Hz, 1 H),
2.56 (s, 3 H), 2.52 (d, J ) 11.4 Hz, 1 H), 1.35 (s, 3 H); 13C NMR
(125.5 MHz) δ 135.9, 133.9, 127.7, 127.0, 126.6, 123.3, 118.3, 112.6,
8,9-Didehydro-6,8-dimethyl-1-[(4-methylphenyl)sulfonyl]ergoline-
10-ol (43a,b). A 1.0 M solution of DIBAL-H in CH2Cl2 (420 µL, 0.420
mmol) was added dropwise to a solution of the butenolides 42a,b (49
mg, 0.120 mmol) in THF (2 mL) at -78 °C. The reaction was stirred
at -78 °C for 2 h, and MeOH (40 µL) was then added cautiously. The
mixture was allowed to warm to room temperature, a saturated solution
of aqueous NH4Cl (4 drops) was added, and the mixture was then stirred
vigorously for 30 min. The solids were removed by vacuum filtration,
and the filtrate was concentrated under reduced pressure. The crude
dihydropyridine thus obtained was immediately dissolved in CH3CN
(2 mL) under argon, and NaCNBH3 (30 mg, 0.480 mmol) and AcOH
(4 drops) were added. The reaction was stirred at room temperature
for 2 h, whereupon a 38% aqueous solution of formaldehyde (6 drops)
was added followed by further portions of NaCNBH3 (30 mg, 0.420
mmol) and AcOH (4 drops). The reaction was stirred at room
temperature for 14 h and then made basic with saturated aqueous
NaHCO3 (3 mL). The mixture was extracted with CHCl3 (2 × 10 mL),
and the combined extracts were washed with H2O (5 mL) and saturated
brine (5 mL), dried (MgSO4), and concentrated under reduced pressure.
Although further purification of this residue was unnecessary for the
next step, the diastereomeric alcohols could be separated and purified
by flash chromatography on silica gel eluting with 11:1 (v/v) EtOAc/
MeOH to give the more polar 43a (20 mg, 41%) as pale yellow oil
110.8, 109.9, 66.6, 66.5, 63.3, 43.6, 27.2, 24.8; IR (CHCl3) 3483 cm-1
;
mass spectrum (CI) m/z 254.1411 [C16H18N2O (M) requires 254.1419],
237 (base), 154.
1
and its epimer 43b (14 mg, 29%) as a pale yellow oil. For 43a: H
Acknowledgment. We thank the National Institutes of
Health (GM 25439), The Robert A. Welch Foundation, Pfizer
Inc., and Merck Research Laboratories for financial support.
We also thank Mr. David Kaelin for experimental assistance.
NMR (500 MHz) δ 7.82 (dd, J ) 8.2, 0.6 Hz, 1 H), 7.72 (d, J ) 8.4
Hz, 2 H), 7.38 (d, J ) 7.2 Hz, 1 H), 7.33-7.30 (m, 1 H), 7.22 (d, J )
2.0 Hz, 1 H), 7.16 (dd, J ) 8.4, 0.6 Hz, 2 H), 6.34 (s, 1 H), 3.20 (d,
J ) 16.5 Hz, 1 H), 3.05 (dd, J ) 14.7, 4.4 Hz, 1 H), 2.82-2.75 (comp,
2 H), 2.46 (dd, J ) 12.0, 4.4 Hz, 1 H), 2.43 (s, 3 H), 2.31 (s, 3 H),
1.73 (s, 3 H); 13C NMR (125.7 MHz) δ 144.7, 136.2, 135.5, 133.7,
132.1, 129.8, 129.1, 126.7, 125.4, 123.1, 119.9, 118.5, 117.7, 113.3,
67.0, 65.9, 61.0, 40.9, 21.5, 21.4, 20.5; IR (CHCl3) 1601 cm-1; mass
spectrum (CI) m/z 409.1579 [C23H25SN2O3 (M + 1) requires 409.1586]
(base), 391. For 43b: 1H NMR (500 MHz) δ 7.76 (dd, J ) 8.0, 0.8
Hz, 1 H), 7.71 (d, J ) 8.4 Hz, 2 H), 7.41 (d, J ) 7.4 Hz, 1 H), 7.36-
7.32 (m, 1 H), 7.17 (dd, J ) 8.4, 0.6 Hz, 2 H), 7.14 (dd, J ) 1.8 Hz,
1 H), 5.53 (s, 1 H), 3.09-3.04 (comp, 2 H), 2.93-2.88 (comp, 2 H),
Supporting Information Available: Experimental proce-
dures and complete characterization (1H and 13C NMR, IR, and
mass spectral data) for compounds 18, 19, 26-28, 33a,b, and
35-40 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA010577W
(23) Horwell, D. C.; Verge, J. P. Phytochemistry 1979, 18, 519.