Enantioselective total syntheses of manzamine A and related alkaloids

Article abstract of DOI:10.1021/ja0202964

As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2] cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These experiments clearly demonstrated that the geometry of the internal double bond and the presence of an electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75), ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured a novel domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core embodied in these alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to form the 13- and 8-membered rings leading to Z-72 and 74, the latter of which was quickly elaborated into ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially available starting materials with the longest linear sequence being 21 steps.

Full text of DOI:10.1021/ja0202964

Published on Web 06/22/2002
Enantioselective Total Syntheses of Manzamine A and
Related Alkaloids
John M. Humphrey, Yusheng Liao, Amjad Ali, Tobias Rein, Yue-Ling Wong,
Hui-Ju Chen, Anne K. Courtney, and Stephen F. Martin*
Contribution from the Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
Received February 26, 2002
Abstract: As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series
of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2]
cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These
experiments clearly demonstrated that the geometry of the internal double bond and the presence of an
electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation
of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75),
ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured
a novel domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core embodied in these
alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical
operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to
form the 13- and 8-membered rings leading to Z-72 and 74, the latter of which was quickly elaborated into
ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following
literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially
available starting materials with the longest linear sequence being 21 steps.
Introduction
that manzamine A exhibits potent antimalarial and antituber-
culosis activity.5
The manzamines constitute a growing and important family
of structurally complex indole alkaloids that have been isolated
from marine sponges of the genera Haliclona and Pellina found
off the coast of Okinawa.1 Manzamine A (1) attracted consider-
able attention because of its potent antitumor activity and was
the first member of this group of alkaloids to be isolated.2 After
this exciting discovery, a number of related alkaloids including
manzamine B (2), manzamine C (3), keramaphidin B (4), and
ircinal A (5)3 were isolated. Baldwin has proposed a novel
biosynthetic pathway to the manzamine alkaloids and has
supported this hypothesis by demonstrating that key reactions
are indeed viable in the laboratory.4 Interest in the manzamine
alkaloids has been further stimulated by the recent discoveries
* Corresponding author. E-mail: sfmartin@mail.utexas.edu.
(1) For reviews, see: (a) Tsuda, M.; Kobayashi, J. Heterocycles 1997, 46, 765.
(b) Matzanke, N.; Gregg, R.; Weinreb, S. Org. Prep. Proc. Intl. 1998, 30,
1. (c) Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201.
(2) (a) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
Soc. 1986, 108, 6404. (b) Nakamura, H.; Deng, S.; Kobayashi, J.; Ohizumi,
Y.; Tomotake, Y.; Matsuzaki, T.; Hirata, Y. Tetrahedron Lett. 1987, 28,
621.
(3) Kondo, K.; Shigemori, H.; Kikuchi, Y.; Ishibashi, M.; Sasaki, T.; Kobayashi,
J. J. Org. Chem. 1992, 57, 2480.
(4) (a) Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059. (b)
Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee, V.;
Spring, D. R.; Whitehead, R. C.; Boughtflower, R. J.; Mutton, I. M.; Upton,
R. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 2661. (c) Baldwin, J. E.;
Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee, V.; Spring, D. R.;
Whitehead, R. C. Chem Eur. J. 1999, 5, 3154.
The combination of the complex and unusual structure of
manzamine A (1) and its promising biological activity has
inspired numerous synthetic investigations.6 Despite these
extensive efforts, the only two reports of its synthesis via ircinal
9
8584
J. AM. CHEM. SOC. 2002, 124, 8584-8592
10.1021/ja0202964 CCC: $22.00 © 2002 American Chemical Society

Total Syntheses of Manzamine and Related Alkaloids
A R T I C L E S
Scheme 1
synthesis of trisubstituted homoallylic amines and dienes that
might be applied to the preparation of 9, and one such technique
was invented during the course of our studies.10 The underlying
viability of the key intramolecular Diels-Alder reaction to form
the tricyclic ABC core with its attendant stereochemistry was
not well precedented. There were only a few examples of
intramolecular Diels-Alder reactions of vinylogous amides as
dienophiles, and none of these had the connectivity of 8.11
Whether such dienophiles were electron rich or poor had not
been probed experimentally. Equally challenging were the
problems posed by the construction of the 13- and 8-membered,
unsaturated nitrogen heterocyclic rings with Z-olefins. Hence,
toward the goal of exploring new chemistry associated with the
synthesis of the manzamines, a series of model studies were
first undertaken.
Discussion and Results
A (5), which had been previously converted into 1 by Koba-
yashi,3 have been recorded by Winkler and ourselves.7,8 Herein
we report the details of our work leading to the enantioselective
syntheses of manzamine A and ircinal A.8,9
Initial Model Studies. The first phase of our investigations
was specifically designed to probe the feasibility and stereo-
chemical outcome of intramolecular Diels-Alder reactions to
produce the tricyclic ABC core of the manzamines. Toward this
end, a series of trienes having different geometries and substitu-
tion on the internal double bond were prepared by coupling
geometrically defined dienes with requisite dienophilic com-
ponents related to 10. The dienol 12 was first prepared in an
unoptimized variation of a reaction developed by Kocienski for
the stereoselective synthesis of alkenes (Scheme 2).12 The
tosylate derived from 12 was treated with benzylamine to give
13. The corresponding 3-unsubstituted diene 14 was prepared
by reaction of benzylamine with a known dienic tosylate.13
In our retrosynthetic analysis of 5 (Scheme 1), we envisioned
that the tricyclic intermediate 6 would be a key intermediary
objective. Indeed, most of the approaches to ircinal A and related
alkaloids have targeted the ABC tricyclic core as the initial goal.
R1 would be any group that could be transformed into an
aldehyde, and the paired substituents R2/R3 and R4/R5 would
be suitably functionalized for elaboration into the 13- and
8-membered rings, respectively. This advanced intermediate
would in turn evolve from 7, which we reasoned would be
accessible via the intramolecular Diels-Alder reaction of triene
8. Assembly of 8 simply required coupling substituted diene 9
with chiral dienophile 10.
Scheme 2
In undertaking the synthesis of a complex natural product
such as manzamine A, there are typically many uncertainties
and steps for which there may be little or no precedent.
Consequently, preliminary studies must be conducted to estab-
lish the viability of key steps. Because discovering new
chemistry should be a paramount objective of exercises in total
synthesis, the approach should be planned to optimize op-
portunities for developing new methods and techniques. Indeed,
analysis of the basic plan set forth in Scheme 1 reveals several
opportunities to explore new chemistry. The first of these
involved developing a general method for the stereoselective
(5) (a) Ang, K. K. H.; Holmes, M. J.; Higa, T.; Hamann, M. T.; Kara, U. A.
K. Antimicrob. Agents Chemother. 2000, 44, 1645. (b) El Sayed, K. A.;
Kelly, M.; Kara, U. A. K.; Ang, K. K. H.; Katsuyama, I.; Dunbar, D. C.;
Khan, A. A.; Hamann, M. T. J. Am. Chem. Soc. 2001, 123, 1804.
(6) For selected studies, see: (a) Kamenecka, T.; Overman, L. Tetrahedron,
1994, 35, 4279. (b) Pandit, U.; Borer, B.; Bieraugel, H. S. Pure Appl. Chem.
1996, 68, 659. (c) Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39,
837. (d) Brands, K.; DiMichele, L. Tetrahedron Lett. 1998, 39, 1677. (e)
Li, S.; Kosemura, S.; Yamamura, S. Tetrahedron 1998, 54, 6661. (f) Li,
S.; Yamamura, S. Tetrahedron 1998, 54, 8691. (g) Nakagawa, M.;
Torisawa, Y.; Uchida, H.; Nishida, A. J. Synth. Org. Chem., Jpn. 1999,
57, 112. (h) Uchida, H.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 1999,
40, 113. (i) Coldham, I.; Crapnell, K. M.; Fernandez, J.-C.; Haxell, T. F.
N.; Treacy, A. B.; Coles, S. J.; Hursthouse, M. B.; Moseley, J. D. Chem.
Commun. 1999, 1757. (j) Bland, D.; Chambournier, G.; Dragan, V.; Hart,
D. J. Tetrahedron 1999, 55, 8953. (k) Clark, J. S.; Townsend, R. J.; Blake,
A. J.; Teat, S. J.; Johns, A. Tetrahedron Lett. 2001, 42, 3235. (l) Herdemann,
M.; Al-Mourabit, A.; Martin, M.-T.; Marazano, C. J. Org. Chem. 2002,
67, 1890. (m) Magnus, P.; Fielding, M. R.; Wells, C.; Lynch, V.
Tetrahedron Lett. 2002, 43, 947.
The dienophile component 16 was then fabricated from 15
by a straightforward sequence of reactions and coupled via its
acid chloride with 13 and 14 to give the trienic substrates 17a,b
(Scheme 3). When 17a was heated (toluene, sealed tube, 180
°C bath temperature), a mixture (ca. 2:1) of the two cycloadducts
18a, which possesses the tricyclic ABC subunit of manzamine
A, and 19a was obtained (81%). The structures of 18a and 19a
(10) Neipp, C. E.; Humphry, J. M.; Martin, S. F. J. Org. Chem. 2001, 66, 531.
(11) (a) Morgans, D. J., Jr.; Stork, G. Tetrahedron Lett. 1979, 1959. (b) Kraus,
G. A.; Raggon, J.; Thomas, P. J.; Bougie, D. Tetrahedron Lett. 1988, 29,
5605. (c) Kuehne, M. E.; Bornmann, W. G.; Earley, W. G.; Marko, I. J.
Org. Chem. 1986, 51, 2913.
(12) (a) Kocienski, P.; Wadman, S.; Cooper, K. J. Am. Chem. Soc. 1989, 111,
2363. (b) Kocienski, P.; Barber, C. Pure Appl. Chem. 1990, 62, 1933.
(13) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J. Org. Chem.
1983, 48, 5170.
(7) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425.
(8) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc.
1999, 121, 866.
(9) For preliminary accounts of other parts of this work, see: (a) Martin, S.
F.; Rein, T.; Liao, Y. Tetrahedron Lett. 1991, 32, 6481. (b) Martin, S. F.;
Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691.
9
J. AM. CHEM. SOC. VOL. 124, NO. 29, 2002 8585

A R T I C L E S
Humphrey et al.
Scheme 3
feasibility of a key step in our projected synthesis of 1. How-
ever, prior to implementing such a cycloaddition in this venture,
it was necessary to discover a more stereoselective variant. In
this context, it was known that the intramolecular [4 + 2]
cycloadditions of trienes having Z internal double bonds gave
cis-cycloadducts with high selectivity because of geometric
constraints.16 We therefore set to the task of preparing the
Z-trienes 28a,b to ascertain whether they would undergo
efficient cyclization to produce the desired cis-fused products
18a,b.
The dienol 25 was first prepared from δ-valerolactone by an
unoptimized sequence proceeding via the unsaturated lactone
24 (Scheme 4). It was perhaps noteworthy that 23 was converted
via its enolate into 24 without excessive â-elimination. The
conversion of 24 into 25 was effected in analogy with prior art
from our laboratory,13 and the syntheses of 26 and 27 by
reactions of benzylamine with the corresponding precursor
hexadienyl tosylates occurred without difficulty.
Scheme 4
were initially based upon nOe studies, but these relative
stereochemical assignments were later verified by single-crystal
X-ray analyses of the derived quaternary salts 20 and 21.14
Similarly we found that heating 17b produced a mixture (2:3)
of 18b and 19b, the structures of which were tentatively assigned
based upon their NMR spectra. For example, nOe difference
experiments showed a nOe between the hydrogen atoms at C(24)
and C(26) of 19b that was absent in 18b.15 A large coupling
constant of 13.4 Hz also indicated a trans diaxial arrangement
between the C(24)-H and the axial proton at C(23) of 19b.
The fortuitous overlap of the signals for the hydrogen atoms at
C(24) and C(12) in 18b unfortunately rendered it impossible to
obtain a coupling constant between the C(24)-H and either of
the protons at C(23). The 13C NMR spectra of 18a,b and 19a,b
were also diagnostic of the relative stereochemistry in that the
signals for the C(24) and C(26) carbon atoms in 18a,b were
slightly downfield from the corresponding carbon atoms in
19a,b, and signals for the C(25) carbon atoms in 19a,b were
downfield from those in 18a,b.
We briefly probed the effects of using Lewis acids and found
that cyclizations of both 17a and 17b proceeded more readily
in the presence of EtAlCl2. Moreover, there was a slight increase
in the stereoselectivity of the acid-catalyzed reaction favoring
formation of the cis-hydroisoquinolines 18a,b over the corre-
sponding trans-isomers 19a,b in ratios of 6:1 and 3:2, respec-
tively.
The foregoing experiments not only demonstrated that
vinylogous imides could participate as dienophiles in intramo-
lecular Diels-Alder reactions, but they also established the
The unsaturated amines 27 and 26 were then coupled with
the acid chloride derived from 16 to give the corresponding
trienes 28a and 28b (Scheme 5). Heating 28a in refluxing
mesitylene surprisingly gave a mixture (4:1:7) of the three
cycloadducts 18a, 19a, and 29a; 29a was a mixture (3:1) of
two diastereomers. When 28a was heated in toluene at reflux
in the presence of EtAlCl2 (1.5 equiv), a mixture (ca. 8:1) of
18a and 19a was obtained in 70% combined yield. The
substituted triene 28b was much less prone to undergo intramo-
lecular Diels-Alder reactions. For example, 28b was relatively
stable at temperatures up to about 150 °C, although it did cyclize
upon heating to 200 °C to give primarily 29b. It also cyclized
(16) For example, see: (a) Oppolzer, W.; Fehr, C.; Warneke, J. HelV. Chim.
Acta 1977, 60, 48. (b) Boeckman, R. K., Jr.; Alessi, T. R. J. Am. Chem.
Soc. 1982, 104, 3216. (c) Pyne, S. G.; Hensel, M. J.; Fuchs, P. L. J. Am.
Chem. Soc. 1982, 104, 5719. (d) Yoshioka, M.; Nakai, H.; Ohno, M. J.
Am. Chem. Soc. 1984, 106, 1133. (e) Wattanasin, S.; Kathawala, F. G.;
Boeckman, R. K., Jr. J. Org. Chem. 1985, 50, 3810.
(14) Lynch, V. M.; Liao, Y.-S.; Martin, S. F.; Davis, B. E. Acta Crystallogr.
1992, C48, 1703.
(15) Numbering of all compounds corresponds to that for manzamine A.
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Total Syntheses of Manzamine and Related Alkaloids
A R T I C L E S
Scheme 5
Scheme 6
upon heating at 150 °C in the presence of EtAlCl2 (1.1 equiv)
to give poor yields (<20%) of 18b together with recovered
starting material (>60%).
subsequent N-deprotection gave 33. The amino diene 33 was
then coupled with the acid chloride derived from 16 to give
34, which underwent facile and efficient cyclization upon
heating to give 35 as the only isolable product. Hence, activation
of the diene with an ester group enabled the [4 + 2] cycload-
dition to proceed to the virtual exclusion of deleterious diene
isomerization pathways. The structure of the tricycle 35 was
initially based upon nOe studies; however, this assignment was
unequivocally confirmed by X-ray analysis of the crystalline
salt 36, which was prepared from 35 by sequential hydride
reduction (DIBAL-H) and methylation (MeI).
The successful intramolecular [4 + 2] cycloaddition of 34
clearly established the efficacy of our basic strategy for the
synthesis of the manzamine ABC ring core. Moreover, the fact
that an electron-withdrawing group on the dienic component
facilitated the reaction was consistent with our preliminary
hypothesis that the vinylogous imide would behave as an
electron-rich dienophile in the Diels-Alder reaction. There
remained, however, several major issues that needed to be
addressed prior to embarking upon the syntheses of 5 and 1.
For example, we had not yet established a workable provision
for an enantioselective synthesis of the target alkaloids. We had
also not formulated specific tactics that would optimally enable
us to construct the 8- and 13-membered rings. It was now time
to focus upon solving these problems.
Forming the trans-hydroisoquinolines 19a and 19b by in-
tramolecular Diels-Alder cyclizations of 28a and 28b was
implausible based upon transition state analysis and prior art.16
Rather it seemed more likely that these cycloadducts were
produced by cyclizations of E-trienes 17a,b that were formed
in situ by acid-catalyzed isomerizations of 28a,b. Supporting
this hypothesis, we found that 28a underwent partial equilibra-
tion to 17a in the presence of catalytic amounts of EtAlCl2
(toluene, 72 h, 40 °C; ca. 30% conversion). The formation of
29a,b presumably arose from the cyclizations of 30a,b that
would be formed by a 1,5-hydrogen shift of 28a,b, but we were
unable to confirm this conjecture by isolating or detecting 30a,b
in the reaction mixtures.
Second Generation Model Studies. In these initial investiga-
tions, we established the underlying viability of intramolecular
[4 + 2] cycloadditions of trienes containing a vinylogous imide
dienophile for constructing the ABC tricyclic core of the
manzamine alkaloids. However, the reactions examined were
neither facile nor sufficiently stereoselective to meet the
demands of the total synthesis of 1. It then occurred to us that
the vinylogous imide might behave as an electron-rich dieno-
phile, and therefore the presence of an electron-withdrawing
group on the diene at C(10) might both facilitate the key
cycloaddition and render it more stereoselective. To evaluate
this hypothesis, we synthesized the trienic substrate 34 (Scheme
6). The R-bromo unsaturated ester 32 was first prepared in 93%
yield by stereoselective Wittig olefination of the known aldehyde
3117 with carbomethoxybromomethylidene triphenylphospho-
rane;18 the corresponding E-isomer was also isolated in about
4% yield. Stille coupling of 32 with vinyl tributylstannane and
The commercially available pyroglutaminol 37 emerged as
an attractive starting material because the absolute stereochem-
istry in 37 corresponds to that at C(34) in the manzamine
alkaloids. We anticipated that this stereocenter would serve as
the pivotal stereochemical control element for introducing all
the remaining stereocenters. In the event, 37 was converted in
two steps into 38.19 Subsequent elaboration of 38 by sequential
acylation, hydrogenolysis, and a hydride reduction under
(17) Pandit, U. K.; Brands, K. M. J. Heterocycles 1990, 30, 257.
(18) Denney, D. B.; Ross, S. T. J. Org. Chem. 1962, 27, 998.
(19) The enantiomer of 38 is known: Pickering, L.; Malhi, B. S.; Coe, P. L.;
Walker, R. T. Nucleosides & Nucleotides 1994, 13, 1493.
9
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A R T I C L E S
Humphrey et al.
Scheme 7
E Ring Synthesis by Ring-Closing Metathesis. Having thus
completed the concise, enantioselective assembly of the tricyclic
ABC ring core 42 and the derived ketone 45, it remained to
address the equally important issue of developing a tactic for
annelating the eight-membered azocine E ring. The methodology
then available for effecting such constructions was largely
limited to the two obvious possibilities of Wittig and reductive
coupling reactions. However, the opportunity for developing
new chemistry with such tactics seemed minimal, and hence
we were attracted contemporaneously to the timely report by
Grubbs, who had just revealed a novel route to monocyclic
nitrogen and oxygen heterocycles (5- to 7-membered rings) via
the ring-closing metathesis (RCM) of R,ω-dienes.22 Following
this exciting lead, we quickly conducted a series of experiments
and established for the first time that fused azabicyclic systems,
including those containing 8-membered rings, could be formed
by the RCM of dienes having a nitrogen atom in the chain
linking the two olefinic subunits (Scheme 8);23 both the Schrock
molybdenum catalyst 4824 and the Grubbs ruthenium catalyst
4925 were used effectively with different substrates.
Scheme 8
conditions that enabled concomitant dehydration provided the
unsaturated carboxylic acid 40 (Scheme 7). The acid chloride
derived from 40 was then coupled with the diene 33 to give
41. Cyclization of 41 proceeded smoothly to deliver the tricyclic
ABC ring intermediate 42 as the only isolable product. The
structure of 42 was assigned by NMR spectroscopy, including
COSY and nOe experiments, and comparison of its NMR
spectra and those of its deprotected derivative 44 (see Figure
1) with those of 35, the structure of which had been previously
established by X-ray analysis of 36. Removal of the N-Boc
group from 41 afforded 43, which underwent cyclization to
furnish 44 upon heating overnight at 80 °C. The facility of this
intramolecular Diels-Alder reaction lends further support to
our original hypothesis that the vinylogous imide serves as an
electron-rich dienophile in these cyclizations.
It was apparent at this juncture that monocyclic and bicyclic
nitrogen heterocycles could be readily accessed via RCM
reactions. However, such cyclizations had never been used in
the context of natural product synthesis, and the viability of
performing metathesis reactions with highly functionalized
substrates was completely unknown. We thus converted 44 in
four simple operations into the complex RCM substrate 51
(Scheme 9). When 51 was heated in the presence of the Schrock
catalyst 48, it did indeed undergo facile and efficient cyclization
to deliver the tetracyclic product 52 in good yield. It was then
obvious that RCM reactions held forth considerable promise in
synthetic organic chemistry.
(20) For example, see: (a) Pearson, A. J.; Han, G. R. J. Org. Chem. 1985, 50,
2791. (b) Muzart, J. Tetrahedron Lett. 1987, 28, 4665. (c) Chidambaram,
N.; Chandrasekaran, S. J. Org. Chem. 1987, 52, 5048. (d) Åkermark, B.;
Larsson, E. M.; Oslob, J. D. J. Org. Chem. 1994, 59, 5729. (e) Grennberg,
H.; Simon, V.; Ba¨ckvall, J.-E. J. Chem. Soc., Chem. Commun. 1994, 265-
266. (f) Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922. (g)
Campbell, E.; Martin, J. J.; Bordner, J.; Kleinman, E. F. J. Org. Chem.
1996, 61, 4806.
Figure 1. Selected nOes for 44.
Ultimately, it would be necessary to functionalize C(12) to
enable fabrication of the 13-membered ring, so we thought it
would be prudent to ascertain whether selective allylic oxidation
at C(12) might be achieved. This oxidation proved somewhat
troublesome, however, and a number of reagents and conditions
were screened with minimal success.20 We did discover in one
preliminary experiment that reaction of 42 with excess CrO3 in
the presence of 3,5-dimethylpyrazole provided the desired
unsaturated ketone 45, albeit in modest yield.21
(21) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43,
2057.
(22) Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc. 1992, 114, 7324.
(23) (a) Martin, S. F.; Liao, Y.; Chen, H.-J.; Pa¨tzel, M.; Ramser, M. Tetrahedron
Lett. 1994, 35, 6005. (b) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao,
Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251.
(c) Fellows, I.; Kaelin, D. E.; Martin, S. F. J. Am. Chem. Soc. 2000, 122,
10781.
(24) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.;
O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875.
(25) Schwab, P. E.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
100.
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Total Syntheses of Manzamine and Related Alkaloids
A R T I C L E S
Scheme 9
Scheme 10
selectivity to give 55 in 91% yield together with small quantities
(7%) of the corresponding E-isomer. Subsequent selective
removal of the nitrogen protecting group with trimethylsilyl
triflate followed by precipitation of the amine with p-toluene-
sulfonic acid afforded the tosylate salt 56 as a stable crystalline
solid.27
The pyrrolidine 57, which served as the precursor of the
requisite chiral dienophile, was prepared in virtually quantitative
yield by a convenient one-pot procedure involving the carboxy-
lation and reduction of the imide 38 (Scheme 11). Although
the carboxylic acid derived from 57 could be isolated, it was
unstable and suffered facile decarboxylation, whereas the sodium
salt 57 could be stored without noticeable decomposition.
Sequential reaction of 57 with oxalyl chloride (2.5 equiv) and
The successes of these early experiments convincingly
validated several key aspects of our strategy for the synthesis
of the manzamine alkaloids. In particular, we had shown that
an intramolecular [4 + 2] cycloaddition of a dienic vinylogous
imide related to 8 provided an expeditious entry to the ABC
tricyclic core. We had also discovered that a RCM reaction of
an R,ω-diene could be implemented to form the eight-membered
E ring in a highly functionalized setting. These accomplishments
notwithstanding, we recognized that the tetracyclic ABCE
subunit 52 was not ideally endowed for facile transformation
into ircinal A (5), and further refinements of our approach were
needed.
Scheme 11
Synthesis of the ABC Ring Subunit. We evaluated various
options that might lead to an improved synthesis of the ABC
ring precursor of manzamine A, and several promising tactics
emerged from these deliberations. In our preliminary work, an
N-benzyl group was ever present on N(21). If this protecting
group were replaced at the outset with a functionalized alkyl
side chain that could be directly utilized in forming the 13-
membered D ring, several unnecessary steps would be elimi-
nated. A five-carbon chain terminated by a protected alcohol
group seemed well-suited to the task. Further streamlining of
the sequence would eventuate if the Stille and Diels-Alder
reactions were performed in a tandem process to fabricate the
ABC ring core in a single step from a monocyclic precursor.
Toward realizing these collective objectives, we prepared the
diene precursor 56 (Scheme 10). The known protected amino
alcohol 53,26 which was prepared in one step from commercially
available 5-aminopentan-1-ol, was first silylated, and the
resulting carbamate was allowed to react with an excess of
acrolein in the presence of camphorsulfonic acid to give the
aldehyde 54. Wittig olefination of 54 then proceeded with high
(26) Miyashita, M.; Sato, H.; Yoshikoshi, A.; Toki, T.; Matsushita, M.; Irie,
H.; Yanami, T.; Kikuchi, Y.; Takasaki, C.; Nakajima, T. Tetrahedron Lett.
1992, 33, 2833.
(27) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
9
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A R T I C L E S
Humphrey et al.
then the free base of 56 afforded 58 (79% overall yield), thereby
setting the stage for the critical domino Stille/Diels-Alder
reaction. Reaction of 58 with vinyl tributylstannane in the
presence of Pd(0) afforded the triene 59, which underwent an
intramolecular [4 + 2] cycloaddition upon continued heating
to give solely 60 in 68% overall yield. In this novel sequence,
three new carbon-carbon bonds are produced in a single opera-
tion, and the lone stereocenter in 58 defined the absolute and
relative stereochemistry at the three newly formed stereocenters.
Formation of D and E Rings by RCM. With the key
tricyclic intermediate 60 in hand, the stage was set for
elaborating the 8- and 13-membered rings. Although there was
little precedent for forming 13-membered rings via ring-closing
metathesis,29 we were intrigued by the possibility that both rings
might be formed by sequential RCM reactions, perhaps even
in a single synthetic transformation. As the first step in this
direction, it was necessary to introduce a carbonyl group at C(12)
in 60 via allylic oxidation. Optimizing this oxidation using the
Salmond protocol we had employed to convert 42 to 45 proved
somewhat troublesome, but we eventually discovered that using
a large excess of CrO3 (20 equiv) and 3,5-dimethylpyrazole (30
equiv) provided 61 in 63% yield (80% based upon recovered
60) (Scheme 12).21 Use of equimolar ratios of chromium trioxide
and dimethylpyrazole led to the formation of imide side
products.30
Thus, simultaneous desilylation of the two hydroxyl groups in
61 (84%) and Swern oxidation31 of the intermediate bis-alcohol
furnished a dialdehyde (89%) that underwent a double “salt-
free” Wittig reaction under carefully controlled conditions to
give 62 (63%).32 When the Wittig reaction was conducted with
other bases and solvents (e.g., n-BuLi/THF, NaH/DMSO, etc.),
there was incomplete methylenation of the aldehyde function
at C(33), and some methylenation of the ketone at C(12) was
observed. Even under optimized conditions, small quantities (1-
5%) of the trimethylene derivative of 62 were typically isolated.
Global reduction of the carbonyl groups in 62 followed by
oxidation of the allylic alcohol functions in the resulting diol
with Dess-Martin periodinane33 gave 63 in 53% overall yield.
To probe the feasibility of effecting a double RCM reaction
to construct the pentacyclic skeleton of ircinal A in a single
operation, it remained to introduce the alkenyl side chains onto
C(12) and N(27). Toward this end, 63 was first transformed
into 65 by an unoptimized sequence of reactions involving
N-deprotection, N-acylation, and acetal formation (Scheme 13).
Stereoselective addition of 3-butenyllithium34 to 65 then fur-
nished 66. Despite our naive optimism, several exploratory
Scheme 13
Scheme 12
The two protected primary alcohols in 61 were then refunc-
tionalized in parallel fashion to optimize the overall efficiency.
(28) For example, see: Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437.
(29) For example, see: (a) Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit,
U. K. Tetrahedron Lett. 1994, 35, 3191. (b) Kamenecka, T. M. Studies
Towards the Enantioselective Total Synthesis of Manzamine A, Dissertation,
University of California at Irvine, 1996.
(30) For example, see also: Blay, G.; Cardona, L.; Garcia, B.; Garcia, C. L.;
Pedro, J. R. Tetrahedron Lett. 1997, 38, 8257.
(31) Tidwell, T. T. Synthesis 1990, 857.
(32) Sreekumar, C.; Darst, K. P.; Still, W. C. J. Org. Chem. 1980, 45, 4260.
(33) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Meyer, S.
D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
9
8590 J. AM. CHEM. SOC. VOL. 124, NO. 29, 2002

Total Syntheses of Manzamine and Related Alkaloids
A R T I C L E S
Scheme 14
attempts to induce the double RCM of 66 using the Grubbs’
ruthenium catalyst 49 afforded no detectable amounts of the
desired pentacyclic skeleton of ircinal A. Rather, an inseparable
mixture was isolated that contained two compounds tentatively
identified as the isomeric tetracyclic olefins 67. In a subsequent
experiment, we discovered that 65 underwent rapid RCM in
the presence of Grubbs’ catalyst 49 to give 68 as a mixture (ca
1:1) of geometric isomers; the structure of 68 was assigned upon
1
extensive H NMR and COSY spectral experiments and mass
spectrometry. Addition of 3-butenyllithium to 68 provided a
compound that was identical (TLC and MS) to 67, thereby
providing further support for the proposed structure of 67. The
preferential formation of a 15-membered ring by the ring-closing
metatheses of 65 and 66 was somewhat surprising for entropic
reasons and because we had found that an eight-membered ring
was readily produced by the RCM of the closely related
substrate 51 (see Scheme 9). Thus, these results serve as a
reminder of the problems that may be encountered when
preparing eight-membered rings via RCM.
Our inability to marshal a double RCM to form the 8- and
13-membered rings simultaneously simply meant that it would
be necessary to elaborate these rings in a serial fashion. Toward
this end, the aldehyde function in 63 was selectively protected
as a dimethyl acetal to give 69 in 84% yield (Scheme 14). Reac-
tion of 69 with 3-butenyllithium followed by quenching at -78
°C provided 70. In a preliminary experiment, we discovered
that 70 cyclized in the presence of the ruthenium catalyst 49 to
give a 13-membered ring, but the reaction was both sluggish
and low-yielding. On the other hand, the cyclic carbamate 71,
which was formed by treating 69 with 3-butenyllithium at -78
°C and allowing the reaction to warm to -20 °C prior to
quenching, underwent facile RCM with 49 to furnish a mixture
of geometric isomers (Z/E ) ca. 8:1) from which Z-72 was
isolated in 67% yield. The structure of E-72 was unequivocally
established by X-ray crystallography. The preferential formation
of the Z-isomer stands in contrast to the vast majority of RCM
macrocyclizations that afford E-isomers as the major products.35
Because there was evidence that free amines were incompatible
with 49,36 it is perhaps noteworthy that catalyzing the RCM of
71 with 49 proceeded equally well irrespective of whether the
tertiary amino function was protonated.
Hydrolysis of the cyclic carbamate in Z-72 followed by
N-acylation gave 73 (75% overall yield), thereby setting the
stage for forming the eight-membered E ring of the ircinal A
skeleton. Although we had previously found that 51 and other
1,9-dienes readily cyclized via RCM to give fused azocines,9b,23
our experience inducing a double RCM with 66 (vide supra)
suggested that the cyclization of 73 to provide 74 might be
problematic. This was indeed the case, and forming the E ring
proved to be the most difficult step in the synthesis. Under the
best conditions identified, cyclization of 73 with an excess of
the ruthenium catalyst 49 followed by an aqueous acid workup
gave 74 in 26% overall yield.37 Promoting the RCM with the
Schrock molybdenum catalyst 48, which has sometimes been
used with substrates having tertiary alcohol groups,38 gave lower
yields of cyclized product. To assess whether the presence of
the tertiary hydroxyl or amino groups in 73 might be interfering
with the RCM, these functions were protected by trimethylsi-
lylation and protonation, respectively; however, cyclizations of
these derivatives of 73 in the presence of either 48 or 49 were
no more efficient. Because of rapidly dwindling supplies of 73,
we were unable to explore further the underlying reasons for
the difficulties associated with forming the 8-membered ring
in 74 via RCM. Perhaps the proximal double bond in the 13-
membered ring is involved in competitive metathesis pathways,
but this hypothesis remains to be evaluated.
Completion of the Total Synthesis of Manzamine Alka-
loids. Reduction of 74 with DIBAL-H gave ircinol A (75)
(63%),39,40 which was oxidized with Dess-Martin periodinane
to deliver synthetic ircinal A (5) (89%) (Scheme 15). The
(34) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404. (b) Negishi,
E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406.
(35) See Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blandra, G. Chem. Eur. J. 2001,
7, 5286 and references therein.
(36) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115,
9856.
(37) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(38) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 3800. (b)
Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746.
(39) Tsuda, M.; Kawasaki, N.; Kobayashi, J. Tetrahedron 1994, 50, 7957.
9
J. AM. CHEM. SOC. VOL. 124, NO. 29, 2002 8591

A R T I C L E S
Humphrey et al.
Scheme 15
A (75) and ircinal A (5). The synthesis of 5 required a total of
24 operations from commercially available starting materials,
and the longest linear sequence was only 21 steps. The concise
approach detailed herein highlights a novel strategy for as-
sembling the tricyclic ABC ring core by a domino Stille/Diels-
Alder reaction. An unusual aspect of the key intramolecular
Diels-Alder cycloaddition was the use of a vinylogous N-acyl
urea as the dienophile. The synthesis of these complex indole
alkaloids also demonstrates the power and versatility of RCM
reactions for constructing 13- and 8-membered heterocyclic rings
in highly functionalized settings, although the potential limita-
tions of using RCM for forming 8-membered rings are also
evident. Whether these deficiencies may be overcome with more
recent generations of RCM catalysts or other experimental
tactics must be established by further experimentation. Other
applications of RCM to the syntheses of alkaloid natural
products are being broadly pursued in our laboratories, and the
results of these investigations will be reported in due course.
synthetic ircinal A thus obtained gave a 1H NMR spectrum that
was consistent with that of natural material, a 13C NMR
spectrum that matched the published data,3 and a specific
rotation that corresponded to previous reports {[R]D +48° (c
0.07, CHCl3); lit.3 [R]D +48° (c 2.9, CHCl3); lit.7 [R]D +46° (c
)0.23, CHCl3)}. Inasmuch as we did not have an authentic
sample of ircinal A, the identity of synthetic 5 was established
by converting a small quantity into 1 following the published
protocol of Kobayashi;3 the material thus obtained exhibited
Acknowledgment. We thank the National Institutes of Health
(GM 25439), the Robert A. Welch Foundation, Pfizer, Inc, and
Merck Research Laboratories for their generous support of this
research. We thank Professor C. W. Jefford (University of
Geneva) and J. Kobayashi (Hokkaido University) for generous
1
the same properties (TLC, HPLC, H NMR, HRMS) as an
authentic sample of natural manzamine A.
1
samples of manzamine A and Professor Kobayashi for a H
Conclusions
NMR spectrum of ircinal A.
We have thus completed the enantioselective syntheses of
manzamine A (1) and the related manzamine alkaloids ircinol
Supporting Information Available: Experimental and full
characterization of all new compounds (PDF) and X-ray data
(CIF) for compounds 20, 36, and E-72. This material is available
free of charge via the Internet at http://pubs.acs.org.
(40) The positive optical rotation originally observed for the reduction product
(DIBAL-H) of natural ircinal A that led to the assignment of the antipodal
structure for natural ircinol A has recently been reexamined by Professor
Kobayashi and found to be incorrect (personal communication). Natural
ircinol A and ircinal A thus have the same absolute configuration.
JA0202964
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8592 J. AM. CHEM. SOC. VOL. 124, NO. 29, 2002