Total synthesis of dimeric pyrrole-imidazole alkaloids: Sceptrin, ageliferin, nagelamide E, oxysceptrin, nakamuric acid, and the axinellamine carbon skeleton

Article abstract of DOI:10.1021/ja069035a

The dimeric pyrrole imidazole natural products are a growing class of alkaloids with exotic connectivity, unique topologies, high nitrogen content, and exciting bioactivities. This full account traces the evolution of a strategy that culminated in the fir

Full text of DOI:10.1021/ja069035a

Published on Web 03/22/2007
Total Synthesis of Dimeric Pyrrole-Imidazole Alkaloids:
Sceptrin, Ageliferin, Nagelamide E, Oxysceptrin, Nakamuric
Acid, and the Axinellamine Carbon Skeleton
Daniel P. O’Malley, Ke Li, Michael Maue, Alexandros L. Zografos, and
Phil S. Baran*
Contribution from the Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received December 17, 2006; E-mail: pbaran@scripps.edu
Abstract: The dimeric pyrrole imidazole natural products are a growing class of alkaloids with exotic
connectivity, unique topologies, high nitrogen content, and exciting bioactivities. This full account traces
the evolution of a strategy that culminated in the first total syntheses of several members of this family,
including sceptrin, ageliferin, nagelamide E, nakamuric acid (and its methyl ester), and oxysceptrin. Details
on the fascinating conversion of sceptrin to ageliferin, which has been used to produce gram quantities of
this sensitive natural product, are provided. In addition, the first enantioselective total synthesis of sceptrin
and ageliferin are reported by programming the fragmentation of an oxaquadricyclane. A hallmark of our
approach to this family of alkaloids is the minimal use of protecting groups despite the presence of 10
nitrogen atoms in the target compounds. Thus, the fundamental chemistry of the 2-aminoimidazole
heterocycle was explored without masking its innate reactivity. Insights gained during these explorations
led to total syntheses of oxysceptrin and nakamuric acid and a successful construction of the carbon skeleton
of axinellamine.
Introduction
two hymenidin (2) subunits. The family of dimeric pyrrole-
imidazole alkaloids has since grown to include the ageliferins
The mysteries of natural product biosynthesis can often be
solved like jigsaw puzzles if enough “pieces”, or members of a
related family, can be found. Contemplating the relationship
between members of a family of related natural products can
often guide chemists to a reasonable retrosynthesis.1 Even when
these presumed “biosynthetic” relationships do not reflect the
true metabolic pathway followed in the source organism, they
can provide a useful heuristic for synthetic analysis, as was the
case with Woodward’s hypothesis for the biosynthesis of
strychnine.2 This synthetic program toward the dimeric pyrrole-
imidazole alkaloids (Figure 1) has been inspired by the unique
hypothesis that sceptrin (1) could serve as a precursor to other
related alkaloids.
(3),4 axinellamines (4-7),5 palau’amines,6 nagelamides,7 mas-
sadine (8),8 and the noncyclized mauritiamine.9 The recent
isolation of the “tetrameric” stylissadine A (9) and tetrabromo-
styloguanidine (10) by Ko¨ck10a,b and Quinn10c holds the promise
of even more exciting discoveries to come.
In addition to their ornate structures, these molecules also
possess a diverse range of potentially useful biological proper-
ties. Sceptrin is a potent antibacterial as well as an antiviral,
antihistiminic, and antimuscarinic agent.3,6b Ageliferin also
(4) (a) Keifer, P. A.; Koker, M. E. S.; Schwartz, R. E.; Hughes, R. G., Jr.;
Rittschof, D.; Rinehart, K. L. 26th Interscience Conference on Antimicrobial
Agents and Chemotherapy, New Orleans, Sep. 28-Oct. 1, 1986, No. 1281.
(b) Rinehart, K. L. Pure Appl. Chem. 1989, 61, 525-528. (c) Kobayashi,
J.; Tsuda, M.; Murayama, T.; Nakamura, H.; Ohizuma, Y.; Ishibashi, M.;
Iwamura, M.; Ohta, T.; Nozoe, S. Tetrahedron 1990, 46, 5579-5586. (d)
Williams, D. H.; Faulkner, D. J. Tetrahedron 1996, 52, 5381-5390.
(5) Urban, S.; Leone, P. de A.; Carroll, A. R.; Fechner, G. A.; Smith, J.; Hooper,
J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731-735.
(6) (a) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993,
115, 3376-3377. (b) Kinnel, R. B.; Gehrken, H.-P.; Swali, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281-3286.
(7) Endo, T.; Tsuda, M.; Okada, T.; Mitsuhashi, S.; Shima, H.; Kikuchi, K.;
Mikami, Y.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2004, 67, 1262-
1267; we are grateful to Prof. Kobayashi for providing NMR spectra of
compound 43.
(8) Nishimura, S.; Matsunaga, S.; Shibazaki, M.; Suzuki, K.; Furihata, K.; van
Soest, R. W. M.; Fusetani, N. Org. Lett. 2003, 5, 2255-2257.
(9) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Nat. Prod. 1996, 59,
501-503.
(10) (a) Grube, A.; Ko¨ck, M. Org. Lett. 2006, 8, 4675-4678. (b) Grube, A.;
Ko¨ck, M. Angew. Chem., Int. Ed. 2007, 46, 2320-2324. (c) Buchanan,
M. S.; Carroll, A. R.; Addepalli, R.; Avery, V. M.; Hooper, J. N. A.; Quinn,
R. J. J. Org. Chem., published online Feb 22, 2007 (http://dx.doi.org/
10.1021/jo062007q).
The isolation of sceptrin (1) in 1981 by Faulkner and Clardy3a
was the first report of a pyrrole-imidazole alkaloid containing
(1) For some examples, see: (a) Nicolaou, K. C.; Snyder, S. A. Classics in
Total Synthesis II; Wiley-VCH: Weinheim, 2003; p 639. For recent
examples from this laboratory, see: (b) Baran, P. S.; Shenvi, R. A. J. Am.
Chem. Soc. 2006, 128, 14028-14029. (c) Baran, P. S.; Hafensteiner, B.
D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. J. Am. Chem. Soc.
2006, 128, 8678-8693. (d) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc.
2005, 127, 15394-15396.
(2) For a detailed discussion of the “Woodward Fission”, see: Berson, J. A.
Chemical DiscoVery and the Logicians’ Program; Wiley-VCH: Weinheim,
2003; Chapter 8 and references therein.
(3) (a) Walker, R. P.; Faulkner, D. J.; Van Engen, D.; Clardy, J. J. Am. Chem.
Soc. 1981, 103, 6772-6773. (b) Cafieri, F.; Carnuccio, R.; Fattorusso, E.;
Taglialatela-Scafati, O.;Vallefuoco, T. Biorg. Med. Chem. Lett. 1997, 7,
2283-2288. (c) Shen, X.; Perry, P. L.; Dunbar, C. D.; Kelly-Borges, M.;
Hamann, M. T. J. Nat. Prod. 1988, 61, 1302-1303. (d) Rosa, R.; Silva,
W.; Escalona de Motta, G.; Rodriguez, A. D.; Morales, J. J.; Ortiz, M.
Experientia 1992, 885-887.
9
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Total Synthesis of Dimeric Pyrrole−Imidazole Alkaloids
A R T I C L E S
Figure 1. Pyrrole-imidazole alkaloids and proposed synthetic relationships.
possesses antibiotic and antiviral activity and is a useful agent
for the study of actin-myosin contractile systems.4 The nage-
lamides have also been identified as possessing antibacterial
activity, and nagelamide G is also an inhibitor of protein
phosphatase 2A.7 Nakamuric acid (11) and its methyl ester (12)
both exhibit antibiotic activity against Bacillus subtilis,11 while
oxysceptrin (13) exhibits both antibacterial and antiviral activ-
ity.12 Some biological activity has been observed for the
pyrrole-imidazole alkaloids possessing cyclopentane cores, but
full investigation has been hampered by a lack of sufficient
material.
Despite a flurry of synthetic activity in this area,13 there have
been relatively few successful syntheses of members of this
family. Horne and co-workers completed mauritiamine,14 and
Ohta et al. prepared a non-natural methylated derivative of
ageliferin.15 Recently, we16 and Birman17 reported racemic
syntheses of sceptrin. We have also reported the conversion of
sceptrin to ageliferin18 and nagelamide E19 and an enantiose-
lective synthesis of sceptrin and ageliferin.20
A hallmark of our final approach to this family of alkaloids
is the minimal use of protecting group manipulations21 despite
the presence of 10 nitrogen atoms in the target compounds.
Thus, the fundamental chemistry of the 2-aminoimidazole
heterocycle was explored without masking its innate reactivity.
In some cases, this required the development of unconventional
strategies since most reactions needed to be performed in water.
(11) Eder, C.; Proksch, P.; Wray, V.; van Soest, R. W. M.; Ferdinandus, E.;
Pattisina, L. A.; Sudarsono. J. Nat. Prod. 1999, 62, 1295-1297.
(12) (a) Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.; Rittschof,
D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965-2975. (b) Kobayashi,
J.; Tsuda, M.; Ohizumi, Y. Experientia 1991, 47, 301-304.
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O’Malley et al.
Figure 2. First generation retrosynthesis of sceptrin.
Scheme 1. Synthesis of Mesylate 19a
a Reagents and conditions: (a) see ref 22; (b) NaH (4.0 equiv), DME; then BnBr (2.0 equiv), 20 °C, 32 h, 87%; (c) DIBAL (6.5 equiv), CH2Cl2, 0 f 20
°C, 24 h, quantitative; (d) MsCl (28 equiv), py, 0 °C, 3 h, quantitative. DME ) 1,2-dimethoxyethane, DIBAL ) diisobutylaluminum hydride, py ) pyridine.
First Generation Approach to Sceptrin
The insights gained during these explorations led to total
syntheses of oxysceptrin, nakamuric acid (and its methyl ester),
and a successful construction of the carbon skeleton of axinel-
lamine. This full account details our studies in this area setting
the stage for the construction of the most complex members of
this intriguing alkaloid family.
Having identified sceptrin (1) as the keystone to a synthetic
program toward the other dimeric pyrrole-imidazole alkaloids,
a synthesis capable of providing sceptrin in large quantities was
required. The initial retrosynthesis, shown in Figure 2, was based
upon the known dimerization of allyl urocanate (14, R′ ) allyl)
to form all-trans cyclobutane 15.22 From 15, simple functional
group manipulations could install the required pyrrole amide
sidechains, leaving only amination of the imidazoles to complete
the natural product.
(13) (a) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am.
Chem. Soc. 1997, 7159-7160. (b) Starr, J. T.; Koch, G.; Carreira, E. M.
J. Am. Chem. Soc. 2000, 122, 8793-8794. (c) Dilley, A. S.; Romo, D.
Org. Lett. 2001, 3, 1535-1538. (d) Belanger, G.; Hong, F.-T.; Overman,
L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle. W. C. J. Org. Chem. 2002,
67, 7880-7883. (e) Lovely, C. J.; Du, H.; Rasika Dias, H. V. Heterocycles
2003, 60, 1-7. (f) Koening, S. G.; Miller, S. M.; Leonard, K. A.; Lo¨we,
R. S.; Chen, B. C.; Austin, D. J. Org. Lett. 2003, 5, 2203-2206. (g) Lovely,
C. J.; Du, H.; He, Y.; Rasika Dias, H. V. Org. Lett. 2004, 6, 735-738. (h)
Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559-9568. (i) Garrido-
Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.; Doundoulakis, T.;
Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765-769. (j) Dransfield,
P. J.; Wang, S.; Dilley, A.; Romo, D. Org. Lett. 2005, 7, 1679-1682. (k)
Tan, X.; Chen, C. Angew. Chem., Int. Ed. 2006, 45, 4345-4348. (l) Du,
H.; He, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965-992. (m) Gergely,
J.; Morgan, J. B.; Overman, L. E. J. Org. Chem. 2006, 71, 9144-9152.
(n) Dransfield, P. J.; Dilley, A. S.; Wang, S.; Romo, D. Tetrahedron 2006,
62, 5223-5247. (o) Krishnamoorthy, P.; Sivappa, R.; Du, H.; Lovely, C.
J. Tetrahedron 2006, 62, 10555-10566. For reviews, see: (p) Hoffmann,
H.; Lindel, T. Synthesis 2003, 1753-1783. (q) Jacquot, D. E. N.; Lindel,
T. Curr. Org. Chem. 2005, 9, 1551-1565. (r) Lanman, B. A.; Overman,
L. E. Heterocycles 2006, 70, 557-570.
As expected, esterification of commericially available ura-
canic acid (16, Scheme 1) followed by benzophenone-sensitized
photodimerization22 proceeded in good yield to give all-trans
cyclobutane 15. Interestingly, attempts at photodimerization of
the methyl ester analogue of 14 under similar conditions gave
a mixture of stereoisomers. Benzyl protection of the imidazoles
and DIBAL reduction of the esters gave diol 18 in high yield.
Although formation of bis-mesylate 19 proceeded in excellent
yield, 19 proved unexpectedly resistant to nucleophilic attack
(18) Baran, P. S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int. Ed.
2004, 43, 2674-2677.
(14) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997, 62, 7918-
7919.
(19) Northrop, B. H.; O’Malley, D. P.; Zografos, A. L.; Baran, P. S.; Houk, K.
N. Angew. Chem., Int. Ed. 2006, 45, 4126-4130.
(15) (a) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka, N.; Nikaido. F.;
Yamashita. M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377-4380. (b)
Kawasaki, I.; Sakaguchi, N.; Khadeer, A.; Yamashita, M.; Ohta, S.
Tetrahedron 2006, 62, 10182-10192.
(20) Baran, P. S.; Li, K.; O’Malley, D. P.; Mitsos, C. Angew. Chem., Int. Ed.
2006, 45, 249-252.
(21) For an example, see: (a) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature
2007, 446, 404-408. For a review, see: (b) Hoffmann, R. W. Synthesis
2006, 3531-3541.
(16) Baran, P. S.; Zografos, A. L.; O’Malley, D. P. J. Am. Chem. Soc. 2004,
126, 3726-3727.
(17) Birman, V. B.; Jiang, X.-T. Org. Lett. 2004, 6, 2369-2371.
(22) D’Auria, M.; Raicoppi, R. Photochem. Photobiol. 1998, 112, 145-148.
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Scheme 2. Failed Attempts To Elaborate Mesylate 19
Scheme 5. Failed Dimerization Attempts
23, as a prelude to preparing amine 21 via reductive amination,
also proved unexpectedly difficult.
The imidazole subunits were similarly resistant to function-
alization; although 18 could readily be protected as its bis silyl
ether 24 (Scheme 4), attempts to deprotonate the imidazole at
C-2 and quench with an electrophilic azide source23 failed to
give 25. After a screen for alternative dimerization partners
carrying functionality that might prove more amenable to
modification (Scheme 5) failed to provide any promising leads,
it became apparent that a completely new strategy was required.
Scheme 3. Failed Attempts To Elaborate Alcohol 18
Second Generation Approach to Sceptrin
A new strategy was devised with the cyclobutane ketoazide
26 as a key intermediate (Figure 3). From this intermediate,
three logical pathways could lead to sceptrin. In pathway A,
the 2-aminoimidazole would be elaborated first from bromoke-
tone 27, followed by reduction of the azides of intermediate 28
and attachment of the bromopyrrole amides. In pathway B, the
azides would be reduced and acylated first to give 29 and then
the 2-aminoimidazole would be installed on intermediate 30.
Pathway C represented a hybrid of these routes in which a
protected amine would be installed on the methyl group of the
ketone as a placeholder for the 2-aminioimidazole, as in 31,
before reduction and acylation of the azide to yield 32. Key
intermediate 26 could be obtained by simple functional group
manipulations from ketoester 34 via diol 33.
Scheme 4. Failure To Aminate Imidazole 24a
Ketoester 34 was a known compound, obtained via fragmen-
tation of oxaquadricyclane 35,24 formed from the union of 2,5-
dimethylfuran and dimethyl acetylenedicarboxylate. In addition
to promising rapid, diastereoselective access to the cyclobutane
core of sceptrin, this route would facilitate the exploration of
oxaquadricyclane chemistry. Although there had been some
interest in these unusual, highly strained species from a physical
organic perspective,24 the initial research had lain dormant for
over 30 years without application in synthetic chemistry.
Enlisting this reaction in the synthesis of sceptrin would
represent an interesting alternative to the traditional methods
of cyclobutane synthesis: intermolecular [2 + 2] dimerization
and linking two alkenes with a disposable tether prior to
intramolecular [2 + 2] cyclization.
a Reagents and conditions: (a) NaH (12 equiv), TBSOTf (6.0 equiv),
DMF, 20 °C, quantitative. DMF ) N,N-dimethylformamide.
(Scheme 2). Reaction with sodium azide failed to form 20, as
did attempts to form amine 21 or amide 22 directly.
Alcohol 18 also proved remarkably intransigent (Scheme 3);
attempts to form azide 20 or amide 22 via Mitsonobu displace-
ment proved fruitless. Although triflation of 18 appeared to
proceed via thin layer chromatography, attempts to form 20,
22, or amine 21 by direct displacement of this putative triflate
were unsuccessful, as were attempts to isolate the triflate and
confirm its structure. Finally, the oxidation of 18 to aldehyde
Although the synthesis of oxaquadricyclane 35 had already
been reported,24 extensive effort was spent developing stream-
(23) Spagnolo, P.; Zanirato, P. J. Org. Chem. 1978, 43, 3539-3541.
(24) (a) Laing, J.; McCulloch, A. W.; Smith, D. G.; McInnes, A. G. Can. J.
Chem. 1971, 49, 574-582. (b) Nelson, S. F.; Calabrese, J. C. J. Am. Chem.
Soc. 1973, 95, 8385-8388. (c) For a review of oxaquadricyclane chemistry,
see: Tochterman, W.; Olsson, G. Chem. ReV. 1989, 89, 1203-1214.
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Figure 3. Second generation retrosynthesis of sceptrin.
lined conditions to facilitate large-scale synthesis (Scheme 6).
By using a slight excess of 2,5-dimethylfuran in the Diels-
Alder reaction, oxabicycle 36 could be obtained in quantitative
yield. In the [2 + 2] cyclization to form oxaquadricyclane 35,
it was found that switching the solvent from diethyl ether to
THF not only accelerated the reaction but also avoided potential
complications due to the low boiling point of ether. The highly
unstable 35 was taken on in crude form to the fragmentation
step. The known procedure for the fragmentation of oxaquad-
ricylane 35 gave only low yield and required repeated prepara-
tive thin layer chromatography to obtain cyclobutane 34 cleanly.
As this was clearly not a viable option to support extensive
synthetic efforts, a more expedient procedure was needed. It
was found that the addition of diethyl ether after evaporation
of methanol would cause the precipitation of cyclobutane 34 in
ca. 50% yield, allowing expedient access to multigram quantities
of 34.
With the all-trans cyclobutane framework in place, 26 proved
easily obtainable. Protection of the ketone moieties of 34 as
the corresponding methyl ketals and DIBAL reduction furnished
diol 33 in quantitative yield. Although the reduction initially
appeared to generate many products by TLC analysis, it was
discovered that this was caused by the newly formed alcohol
cyclizing into the ketal during the quenching of excess DIBAL.
A simple workup in 70% aqueous acetic acid provided diol 33
without recourse to chromatographic purification. Mesylation
of the diol and displacement with sodium azide gave the key
azide 26 in sufficient purity to be used without purification.
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Scheme 6. Synthesis of Key Intermediate 26a
a Reagents and conditions: (a) DMAD (1.0 equiv), 2,5-dimethylfuran (1.2 equiv), 1,4-dioxane, 100 °C, 12 h, quantitative; (b) 450 W Hanovia lamp, THF,
24 h, quantitative; (c) H2SO4, MeOH, 24 h, 50%; (d) (i) MeOH, CH(OMe)3 (14 equiv), TsOH (0.15 equiv), 50 °C, 24 h; (ii) DIBAL (6.0 equiv), CH2Cl2,
-78 °C, 1.5 h, then AcOH, H2O, 10 min, quantitative; (e) (i) MsCl (4.4 equiv), py 0f20 °C, 1 h; (ii) NaN3 (6.0 equiv), DMF, 50 °C, 24 h, quantitative.
DMAD ) dimethyl acetylenedicarboxylate, THF ) tetrahydrofuran, DIBAL ) diisobutylaluminum hydride, DMF ) N,N-dimethylformamide.
Scheme 7. Attempt To Synthesize Sceptrin via Intermediate 28a
a Reagents and conditions: (a) (i) MeOH, CH(OMe)3 (14 equiv), TsOH (0.15 equiv), 50 °C, 24 h; (ii) PTT (2.1 equiv), THF/MeOH/CH(OMe)3 2:1:0.1,
20 °C, 2 h; AcOH(aq), 50 °C, 12 h, 92%; (b) NaN(CHO)2 (6 equiv), MeCN, 18 h, 20 °C; (c) MeOH, HCl (1% v/v), 16 h; (d) H2NCN (80 equiv), H2O, 140
°C µwave, 3 min, 80% from 37. PTT ) phenyltrimethylammonium tribromide, THF ) tetrahydrofuran.
Given the unexpected difficulties in performing functional
group modifications on the superficially similar cyclobutane 18,
it was decided that all three routes from 26 to sceptrin outlined
in Figure 3 should be pursued simultaneously, in the event
similar roadblocks were encountered. The first steps of pathway
A (initial construction of the 2-aminoimidazole) proceeded quite
smoothly. Ketalization of 26 under standard conditions (Scheme
7), followed by bromination of the crude ketal with phenyltri-
methyl ammonium tribromide,25 gave bromoketone 37 in 92%
yield. Displacement with sodium diformamide26 gave 31, which
was hydrolyzed with aqueous HCl to give 38 and reacted with
cyanamide27 to form 28 in 80% yield over three steps, thereby
completing installation of the 2-aminoimidazole, along with
5-10% of an oxazole byproduct. Attempts to reduce the azide
and install the necessary bromopyrrole amide resulted in
complex mixtures from which only trace quantities of product
could be obtained. Reduction of intermediate 31 (pathway C)
appeared successful, but no acylated products could be obtained.
Further attempts at resolving these issues were obviated by the
success of an alternative pathway. It should be noted here,
however, that the subsequently reported synthesis of sceptrin
by Birman17 proceeded from 37 via a Boc protected analogue
of 28.
As early attempts to handle 2-aminoimidazole containing
compounds revealed their intractable nature, deferring the
installation of this ring until the final stages of the synthesis
seemed advantageous. Accordingly, initial attachment of the
bromopyrrole was pursued as outlined in Scheme 8. Protection
of the ketone as the ketal, followed by reduction with Lindlar
catalyst28 and acylation with 39,29 gave 40 in 70% yield.
Compound 40 fortuitously precipitated from acetonitrile in pure
form during the course of the acylation, eliminating the need
for chromatography. Attempts to functionalize the methyl group
of 40 or its ketone analogue ran afoul of selectivity issues.
Competitive halogenation at the R-methine position and the
pyrrole as well as polybromination of the methyl groups
thwarted most attempts at halogenation. This was further
complicated by the dimeric nature of 40, which meant that the
(25) Marquet, A.; Jacques, J. Tetrahedron Lett. 1959, 1, 24-26.
(26) Han, Y.; Hu, H. Synthesis 1990, 122-124.
(27) Lancini, G. C.; Lazzari, E.; Arioli, V.; Bellani, P. J. Med. Chem. 1969, 12,
775-780.
(28) Corey, E. J.; Nicolaou, K. C.; Balanson, R. D.; Machida, Y. Synthesis 1975,
590-591.
(29) Kitamura, C.; Yamashita, Y. J. Chem. Soc., Perkin Trans. 1 1997, 1443-
1447.
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Scheme 8. Completion of Sceptrina
a Reagents and conditions: (a) (i) MeOH, CH(OMe)3 (14 equiv), TsOH (0.15 equiv), 50 °C, 24 h; (ii) H2 (1 atm), Lindlar catalyst, MeOH, 12 h; (iii) 39
(2.2 equiv), MeCN, 4 h, 70% from 26; (b) BnNMe3ICl2 (3.3 equiv), THF, 60 °C, 1.75 h, 97%; (c) NaN(CHO)2 (5.5 equiv), 35 °C, 40 h; (d) HCl, MeOH,
20 °C, 16 h; (e) H2NCN, H2O, 95 °C, 4 h, 72% from 41. THF ) tetrahydrofuran.
desired functionalization would have to occur twice on the same
molecule to obtain the desired product. Attempts to purify the
complex mixtures resulting from standard R-functionalization
protocols or to selectively react the desired product directly from
the mixture met with little or no success. After much experi-
mentation, a solution involving benzyl trimethylammonium
dichloriodate was devised. Although this reagent was known
to slowly chlorinate ketones,30 it had not previously been
employed on ketals. When carefully monitored and quenched,
heating ketal 40 with this reagent in tetrahydrofuran (THF) at
60 °C gave desired chloroketone 41 in nearly quantitative yield.
Interestingly, if methanol and trimethyl orthoformate were
included in the solvent mixture, the dimethyl ketal of 41 was
obtained directly. This reaction presumably takes place via
chlorination of the methyl enol ether derived from the ketal.
The previously applied protocol for aminoimidazole formation
was now used: reaction with sodium diformamide gave 32,
which was hydrolyzed with methanolic HCl to give 49. Finally,
reaction with cyanamide completed the first total synthesis of
sceptrin in 72% from chloroketone 41. Thus a total synthesis
of sceptrin which proceeds rapidly and in high yield from
dimethyl acetylenedicarboxylate and 2,5-dimethylfuran has been
developed.
such as maleimide but does not dimerize under thermal
conditions. Close examination of isolation literature33 indicated
that crude sponge extracts typically contained far more sceptrin
than any other dimeric oroidin derivative, which led to the
hypothesis that sceptrin could function as a biosynthetic
precursor to ageliferin.
Sceptrin and ageliferin are related by a formal [1,3] sigma-
tropic rearrangement followed by a double bond isomerization.
Orbital symmetry considerations indicate that a concerted
transformation of this nature would have to occur under
photochemical conditions, so initial experiments centered on
UV irradiation of sceptrin. Extended irradiation with a 5.5 W
UV lamp (pyrex filter) had no observable effect, while use of
a 450 W Hanovia lamp caused rapid decomposition. Attempts
at effecting a stepwise transformation with conventional heating
were likewise fruitless. Attempts to increase the reactivity of
sceptrin by forming the free base simply accelerated decomposi-
tion. Ultimately, microwave irradiation proved to be the key to
transforming sceptrin into ageliferin. Initial small-scale (e5 mg)
experiments using sceptrin bis-hydrochloride led to a mixture
of sceptrin (1) and ageliferin (3)18 (Scheme 9) upon heating to
200 °C for 2 min. HPLC separation of the mixture gave
ageliferin in 40% yield, along with ca. 50% recovered sceptrin.
Attempts to scale up this reaction gave inconsistent results.
It was discovered that a third compound was formed in the
reaction, albeit in low yield (in an approximately 1:20 ratio to
ageliferin). Qualitatively, the amount of this compound present
appeared to increase with extended heating. Inspection of the
1H NMR spectrum revealed that it was remarkably similar to
ageliferin, although the shifts of several protons were slightly
different. The compound was tentatively assigned as an epimer
of ageliferin. Based on mechanistic considerations, the attach-
ment of the pendent 2-aminoimidazole was believed to be the
epimeric position, although initially the matter was not studied
in detail. Subsequently, Kobayashi et al. reported the isolation
Conversion of Sceptrin to Ageliferin
With a route to sceptrin in hand, ageliferin was selected as
the next target. The reigning biosynthetic hypothesis at this point
was that ageliferin arose from enzyme-catalyzed Diels-Alder
dimerization of hymenidin (2).4,31 However, cursory examination
of oroidin indicated that the electronic nature of its alkene moiety
would be poorly suited to function as a dienophile in a Diels-
Alder reaction. This has been recently confirmed by Lindel et
al.,32 who found that bromooroidin (hymenidin) undergoes
Diels-Alder reactions in moderate yield with active dienophiles
(30) Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Fujisaki, S.; Maeno, K.;
Okamoto, T. Synthesis 1988, 545-546.
(31) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
(32) Po¨verlein, C.; Breckle, G.; Lindel, T. Org. Lett. 2006, 8, 819-821.
(33) Assmann, M.; Ko¨ck, M. Z. Naturforsch. C 2002, 57, 157-160; Assmann,
M.; Lichte, E.; Ko¨ck, M. Proceedings of the 6th International Sponge
Symposium 2004, 187-193.
9
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Total Synthesis of Dimeric Pyrrole−Imidazole Alkaloids
A R T I C L E S
Scheme 9. Synthesis of Ageliferin and Nagelamide Ea
a Reagents and conditions: (a) H2O, 200 °C µwave; see text for details.
2-aminoimidazole. The formation of nagelamide E can be
accounted for either by inversion of the radical center prior to
recombination or by epimerization of ageliferin under the
reaction conditions.
The completion of ageliferin and nagelamide E represents
the first synthesis of these molecules as well as the first use of
the vinylcyclobutane rearrangement in natural products synthe-
sis. This procedure has proven to be both robust and scalable;
it has allowed the synthesis of ageliferin and dibromoageliferin
in gram quantities.
Synthesis of Oxysceptrin, Nakamuric Acid, and
Nakamuric Acid Methyl Ester
Having synthesized ageliferin and nagelamide E, which
possess the same level of oxidation as sceptrin, questions
remained as to the viability of sceptrin as a synthetic precursor
for more highly oxidized members of the pyrrole-imidazole
family, such as oxysceptrin (13), nakamuric acid (11), massadine
(8), and the axinellamines (4-7). Although the structural
homology of sceptrin to oxysceptrin and nakamuric acid is
readily apparent, its relationship to massadine and the axinel-
lamines is less obvious. Furthermore, although the relationship
of oxysceptrin and nakamuric acid to sceptrin appeared to be
quite simple, there was no guarantee that an attempt to
synthesize them from sceptrin would prove nearly as simple or
even possible.
Figure 4. Dihydroxylated 2-aminoimidazoles as synthetic intermediates.
of the nagelamides,7 a series of dimeric pyrrole-imidazole
alkaloids. Surprisingly, nagelamide E (43, Scheme 9), isolated
in a 1:24 ratio to ageliferin, possessed the same structure as the
“epi-ageliferin” isolated from the conversion of sceptrin to
ageliferin.19 It was subsequently discovered that resubjection
of purified ageliferin or nagelamide to the reaction conditions
resulted in a mixture of the two, which stabilized at a ratio of
approximately 2:1 in favor of ageliferin after 7 min of heating.
Examining this family of natural products, it is apparent that
a dihydroxylated 2-aminoimidazole of type 44 (Figure 4),
formed by oxidation of the parent aminoimidazole 45, could
serve as a precursor to all the various guanidine rings identified
thus far. Oxidative cleavage of the diol would lead to bis-
acylated guanidine 46, which could in turn be hydrolyzed to
the carboxylic acid 47, analogous to that found in nakamuric
acid (11). Alternatively, expulsion of H2O from 44 would set
the stage for a hydroxyl group assisted [1,2] shift to form 48.
If R ) H, this would form the aminoimidazolinone present in
oxysceptrin (13). Oxysceptrin could also be formed by elimina-
tion of H2O followed by tautomerization of the resulting
hydroxyaminoimidazole. Alternatively, if R ) R1 ) cyclohexyl,
the same [1,2] shift would initiate a ring contraction to a spiro
[5.5] system 48 (R ) R1 ) -C4H8-), reminiscent of the
axinellamines (4-7) and massadine (8).13c,j,n Similarly, if R was
a strained ring such as a cyclobutane, expulsion of H2O could
initiate a Demjanov-like ring expansion.35 Stereoselective
Further examination of the reaction conditions led to the
discovery of an unexpected counterion dependence in the
conversion of sceptrin to ageliferin. The acetate and formate
salts of sceptrin proved far superior to the trifluoroacetate and
initially used hydrochloride salts in terms of speed and conver-
sion. The use of sceptrin bis-acetate provided far more consistent
results upon scale-up as well, giving a 50% yield of ageliferin,
along with 28% of nagelamide E and 12% recovered sceptrin.
The thermal rearrangement of vinyl cyclobutanes has been
reported previously, although all prior instances of this reaction
involved simple hydrocarbon substrates and thermolysis at
temperatures in excess of 300 °C. It has been determined that
these reactions proceed through diradical intermediates.34 Given
the highly functionalized nature of 1 and the significantly lower
temperature at which its rearrangement occurs, there was a
possibility that the rearrangement of sceptrin progresses through
an alternative pathway. However, computational studies19
indicate that the rearrangement of 1 likely proceeds via radical
scission of the cyclobutane bond, followed by 6-endo-trig
recombination and olefin isomerization to rearomatize the
(35) (a) Corey, E. J.; Liu, K. Tetrahedron Lett. 1997, 38, 7491-7494. (b) Fitjer,
L.; Majewski, M.; Kanshik, A.; Egert, E.; Sheldrick, G. M. Tetrahedron
Lett. 1986, 27, 3603-3606. (c) Fadel, A.; Salau¨n, J. Tetrahedron 1985,
41, 413-420. (d) Jahangir; Fisher, L. E.; Clark, R. D.; Muchowski, J. M.
J. Org. Chem. 1989, 54, 2992-2996. (e) Feline, T. C.; Mellows, G. J.
Chem. Soc., Chem. Commun. 1974, 63-64. (f) Ohfune, Y.; Shirahama,
H.; Matsumoto, T. Tetrahedron Lett. 1976, 2795-2796.
(34) Leber, P. A.; Baldwin, J. E. Acc. Chem. Res. 2002, 35, 279-287; see also
references cited in ref 19.
9
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A R T I C L E S
O’Malley et al.
Scheme 10. Synthesis of Oxysceptrin, Nakamuric Acid, and Nakamuric Acid Methyl Estera
a Reagents and conditions: (a) see text; (b) aq. AcOH, 140 °C, 30 min, 65%; (c) 1.2 equiv of NaIO4, pH 5 buffer (AcOH/NaOAc), 60%; (d) 1.2 equiv
of NaIO4, pH 8 buffer (0.1 M phosphate buffer), 85%; (e) LiOH, THF/H2O ) 1:1, quantitative; (f) MeOH/HCl, 80 °C, 1 h, 80%.
quenching of the resulting cyclopentyl cation would form 49,
the massadine ring system.
increased amounts of tetrahydroxylated byproducts resulting
from oxidation of the second aminoimidazole. This reaction
likely occurs by epoxidation of the aminoimidazole to form
intermediate 51, followed by ring opening of the epoxide to
iminium 52. Attack of H2O then affords diol 50.
Although this plan would allow rapid access to this family
of highly complex alkaloids, significant questions remained
about its feasibility. Natural products containing guanidines or
2-aminoimidazoles have historically been approached either by
deferring their installation until the final stages of the synthesis
or by completely masking their reactivity through protection.13
Since Nature apparently manipulates these species with ease,
our goal was to learn about their innate reactivity and avoid
any kind of protection.21 This decision added a new level of
practical difficulty since all reactions would have to be
performed in protic solvents and chromatography would be quite
challenging. Although 2-aminoimidazoles had previously been
oxidized to bis-alkoxy imidazoles and thence converted to
aminoimidazolinones,36 it was unclear if the precedent set on
these relatively simple molecules could be translated to sceptrin.
The presence of the pyrrole subunits raised the issue of
chemoselectivity, and the dimeric nature of sceptrin required
the site-selective oxidation of only one of the two 2-aminoimi-
dazoles.
With key intermediate 50 in hand, the next step was to effect
dehydration to oxysceptrin (13). The diol mixture 50 proved to
1
be labile when evaporated to dryness. In fact, the H NMR of
50 (after purification by prep HPLC) indicated the presence of
a significant quantity (ca. 20-30%) of oxysceptrin (13). In order
to drive the reaction to completion, microwave irradiation of
50 at 140 °C in aqueous acetic acid induced the required [1,2]-
hydride shift (or simple dehydration/tautomerization) to com-
plete the synthesis of oxysceptrin in 65% yield. We were able
to confirm the isolation chemists’ observation12 that oxysceptrin
exists as a 1:1 mixture of epimers at the imidazolinone
stereocenter.
Initial attempts to elicit oxidative cleavage of diol 50 to
nakamuric acid (11) were stymied by the instability of the
substrate under oxidizing conditions. After considerable explora-
tion, periodate-based oxidation protocols on diol 50 were
developed to controllably direct cleavage to 11 or 12. Thus, by
running the reaction in pH 5 buffer (AcOH/NaOAc), nakamuric
acid (11) could be obtained in 60% yield, along with 20%
recovered 50. Nakamuric acid methyl ester (12) could be
obtained by instead using pH 8 buffer (0.1 M phosphate) and
methanol in order to dissolve 50 (85% yield, along with 10%
11). Under oxidizing conditions, a pH window of 4.5-8.0 results
in diol cleavage while reactions outside of this range lead to
extensive decomposition. Based on LC/MS data, these reactions
Gratifyingly, exposure of sceptrin (1) to a variety of oxidizing
agents provided the corresponding dihydroxy compound 50 as
an inconsequential mixture of four diastereomers (Scheme 10).
Operationally, it was found that aqueous peracetic acid was the
optimum oxidant, giving 50% yield of 50, along with 35%
recovered starting material. Although this reaction could be
induced to proceed further, attempts to do so resulted in
(36) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63, 1248-
1253.
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Total Synthesis of Dimeric Pyrrole−Imidazole Alkaloids
A R T I C L E S
It was reasoned that the same driving force that had stymied
efforts to induce ring expansion of sceptrin by promoting hydride
shift would be beneficial in the ring contraction of systems of
type 59 (Scheme 11) to type 60. This approach is reminiscent
of the proposal of Scheuer et al. for the biosynthesis of
palau’amine;6b Romo13c,j,n and Lovely13e,g,l,o have also reported
approaches to palau’amine and axinellamine based on contrac-
tion of a cyclohexene. Thus, dihydroxylation of ageliferin (3)
was attempted. Although our ability to dihydroxylate sceptrin
was encouraging, the unsymmetrical nature of ageliferin com-
plicated matters, as the dialkylated 2-aminoimidazole would
have to be oxidized in preference to the monoalkylated ring.
A screening of various oxidants found that magnesium
monoperoxyphthalate (MMPP) in H2O oxidized ageliferin most
cleanly, providing the somewhat unstable diol 59 as a single,
unassigned diastereomer in 32% isolated yield after preparative
HPLC. Inducing rearrangement of diol 59 proved to be a greater
challenge. Many conditions resulted in fragmentation to pre-
sumed diketone 61 as the major product. Basic reaction media
were found to suppress this fragmentation; microwave irradiation
of diol 59 in 5% aqueous NaHCO3 provided spirocycle 60 in
31% yield. Operationally, it was found that telescoping these
two operations into one step greatly improved yields; addition
of saturated aqueous NaHCO3 to crude diol 59 and subjecting
the resulting suspension to microwave irradiation directly
provided spirocycle 60 in 36% overall yield from ageliferin.
The connectivity and stereochemistry of compound 60 were
confirmed by HMQC and ROESY analysis in rigorously dried
DMSO-d6. Unfortunately, the stereochemistry of 60 is epimeric
to massadine and the axinellamines at the spriro ring juncture.
Figure 5. Attempts at ring expansion of model system 26.
proceed via a bis-acylated guanidine species (see 46, Figure
4). Nakamuric acid (11) and its methyl ester (12) are readily
interconvertible; hydrolysis of 12 with LiOH provided 11 in
quantitative yield, while careful esterification of 11 with HCl
in methanol furnished 12 in 80% yield (diazomethane is not
chemoselective for the carboxylic acid).
Although the 1H NMR spectroscopic data of both nakamuric
acid (11) and its methyl ester (12) matched nicely with that
published by Proksch and co-workers,11 there were some minor
discrepancies with the assignments of the 13C NMR data. Using
HMQC (1H-13C correlation, see Supporting Information) it was
determined that three carbon atoms were incorrectly assigned
including one carbon atom which was actually underneath the
solvent peak (DMSO-d6).
Synthesis of the Axinellamine Carbon Skeleton
Attempts to induce ring expansion of sceptrin (1) to com-
pounds of type 44 were less successful. The facility of
dehydration to generate oxysceptrin (13) prevented the formation
of the requisite cyclopentyl carbocation. Seeking to determine
if the failure of 50 to undergo ring expansion was due solely to
the facility of the hydride shift to form oxysceptrin, or if the
cyclobutane was intrinsically resistant to ring expansion, a series
of model studies on ketoazide 26 was undertaken (Figure 5).
Most attempts at Lewis or Brønsted acid initiated ring expansion
to cyclopentane 53 yielded only recovered starting material or
nonspecific decomposition. One notable exception was the
reaction of 26 with SbCl5, which formed aldehyde 54 in 20%
yield. Although the conversion of azides to aldehydes under
strong Brønsted acid conditions is known,37 to the best of our
knowledge, this is the first report of such a transformation
initiated by a Lewis acid. Attempts to use ketal 55 to induce a
ring expansion were likewise unsuccessful; most conditions
simply resulted in deketalization to 26. Reduction of 26 with
NaBH4 gave alcohol 56 as a mixture of diastereomers. However,
reactions of 56 proved no more fruitful; exposure to HCl resulted
in conversion to chloride 57 rather than ring expansion. The
derived mesylate 58 changed from a 3:1 mixture of diasteromers
to a 1:1 mixture upon heating in toluene. As this epimerization
must have occurred via cation formation and recombination, it
was clear that the cyclobutane was reluctant to undergo ring
expansion, even in the presence of a cation on an adjacent
carbon. In light of these results, it was clear that ring expansion
of sceptrin would be unlikely without significant structural
modifications, so a new strategy was devised.
Asymmetric Synthesis of Sceptrin and Ageliferin
Although the previously discussed syntheses of sceptrin and
ageliferin allowed rapid and efficient access to these alkaloids
in racemic form, prospects for the development of an asym-
metric synthesis were uncertain. There is a general scarcity of
methods for the synthesis of enantiopure cyclobutanes,38 and
most of the existing procedures depend on the attachment of a
stoichiometric chiral auxiliary prior to [2 + 2] dimerization.
This is undesirable from the perspectives of both atom and step
economy as well as potentially costly if the auxiliary is
expensive and/or not amenable to recycling. The use of an
oxaquadracyclane fragmentation to generate the all-trans cy-
clobutane core of sceptrin posed an exciting challenge; despite
a number of elegant studies,23 the mechanism of this physical
organic oddity remained ill-defined. Without a definitive
understanding of this reaction, it was unclear how, or even if,
stereochemical information in an oxaquadracyclane could be
transferred to the product cyclobutane. The task was further
complicated by the fact that the absolute configuration of
ageliferin was unknown.
The cascade rearrangement of oxaquadricyclanes to cyclobu-
tanes was initially discovered by McInnes and co-workers,23a
who proposed a mechanism involving the initial fragmentation
of the oxo bridge with water. The cascade was later studied by
Nelsen,23b who posited an alternative mechanism initiated by
fragmentation of a cyclopropyl ring to form an oxocarbonium
ion. After the work of Nelsen, little notice was taken of this
reaction until it was adapted for use in the synthesis of sceptrin.
(37) Schultz, A. G.; Ravichandran, R. J. Org. Chem. 1980, 45, 5009-5011.
(38) Lee-Ruff, E.; Mladenova, G. Chem. ReV. 2003, 103, 1449-1483.
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4771

A R T I C L E S
O’Malley et al.
Scheme 11. Synthesis of the Axinellamine Carbon Skeletona
a Reagents and conditions: see text.
In addition to allowing enantioselective access to sceptrin and
ageliferin, developing a variant of this reaction for the synthesis
of enantiomerically pure cyclobutanes would shed light on the
mechanism of this intriguing transformation.
In an attempt to ascertain what modifications to oxaquadri-
cyclane 35 ought to be made to effect an enantioselective
fragmentation, the potential mechanisms of the reaction were
analyzed. McInnes et al. proposed a mechanism which was
initiated by attack of water to rupture the oxo bridge, forming
intermediate 62 (path A in Figure 6).23a Fragmentation of the
cyclopropane rings was proposed to occur with retention of
stereochemistry at one ester bearing cyclobutane carbon and
inversion at the other. It was suggested that this was the result
of intramolecular protonation at one carbon and intermolecular
protonation at the other. The resulting cis-acetyl compound 63
would then isomerize under the reaction conditions to give the
product all-trans cyclobutane 34. An alternative mechanism
(path B in Figure 6), similar to the one suggested by Nelsen,23b
is initiated by the opening of a cyclopropane ring to form an
ester enol intermediate such as 64. Capture of this intermediate
by water and tautomerization of the ester enol to a position trans
to the other ester forms 65, which then fragments to the cis-
acetyl cyclobutane 63 and epimerizes to 34.
Careful analysis of the McInnes mechanism reveals that the
stereochemistry of the product cyclobutane is governed by the
carbon which is protonated in an intramolecular sense. In
intermediate 62, only the alcohol resulting from the oxo bridge
is properly situated to effect intramolecular protonation, so the
final stereochemistry of the product is determined by which face
of the oxaquadracyclane is attacked by water to initiate the
fragmentation. Although the initiation step in this proposal
seemed somewhat improbable, it was of some concern, as
inducing facial selectivity by modification of the carbonyl units
would be a difficult proposition indeed. In the alternative
mechanism, however, the configuration of the final product is
Figure 6. Mechanistic proposals for the transformation of oxaquadricyclane
35 to cyclobutane 34.
controlled by the order of carbonyl enolization in the fragmenta-
tion (see Scheme 13). Synthesizing a derivative of 35 possessing
two types of carbonyls with distinct enolization energies would
therefore be the key to obtaining a diastereoselective fragmenta-
tion. Although there is presently a paucity of experimental data
concerning the relative stabilities of ester and amide enols,
theoretical predictions indicate that enols of amides are more
9
4772 J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007

Total Synthesis of Dimeric Pyrrole−Imidazole Alkaloids
A R T I C L E S
Scheme 12. Screening of Conditions for Diastereoselective Oxaquadricyclane Fragmentationa
a Reagents and conditions: (a) isobutyl chloroformate, Et3N, CH2Cl2, 0 °C then (S)-R-methylbenzylamine, 90%; (b) hν, THF; (c) Table 1.
Table 1. Optimization of Fragmentation Conditions on Substrate
stable than those of carboxylic acids or esters. Heinrich and
70
co-workers calculated that the energy difference between the
keto and enol forms of acetic acid was 35.6 kcal/mol, while
that of acetamide was 33.3 kcal/mol.39a More recently, Rosen-
berg calculated that the ∆H of enolization was 16.0 kcal/mol
for methyl acetate, while that of acetamide was calculated to
be 14.1 kcal/mol.39b As the highly unstable oxaquadricyclane
yielda
35 was clearly not amenable to modification, Diels-Alder
entry
acid
solvent
dr (71:71
′
)
(%)
product 36 was identified as the optimal stage for installing the
necessary functionality. An amide of type 66 (Scheme 13) was
therefore targeted.
1
2
3
4
H2SO4
H2SO4
H2SO4
H2SO4
HCl
Yb(OTf)3
Sc(OTf)3
none
THF/MeOH 1:1
THF/H2O 1:1
H2O/MeOH 1:1
MeOH
THF/MeOH 1:1
THF/MeOH 1:1
THF/MeOH 1:1
THF/MeOH 1:1
7:1
4:1
5:1
4.7:1
4.7:1
5.2:1
n.d.
n.d.
57
66
57
58
35
62
0
Inspired by encouraging literature precedent for the enzymatic
desymmetrization of similar meso intermediates,40 pig liver
esterase (0.1 M pH 8 phosphate buffer, acetone, 20 °C) was
used to furnish the monoester 67 (Scheme 13) in quantitative
5
6b
7
8c
0
1
yield and 75% ee as determined by H NMR of the (S)-R-
a Isolated yield. b Reaction run at 60 °C. c Reaction run at 100 °C.
methylbenzylamine-derived amide. The absolute configuration
was determined by X-ray analysis of the salt 68 formed by the
same amine and carboxylic acid 67. Having succeeded in
enantioselectively differentiating the carbonyl units of 36, the
next major task was finding conditions for the enantiospecific
fragmentation of the derived oxaquadricyclane. Would the
chirality of the oxiquadricyclane translate into the fragmented
product? In order to answer this question, the chiral amide 69
was prepared as depicted in Scheme 12. After photolysis (to
form 70) and rearrangement to cyclobutanes 71 and 71′, the
resulting dr can be rapidly ascertained by 1H NMR. As shown
in Table 1, the use of H2SO4 emerged as the optimum acid in
terms of overall yield and diastereoselectivity.
Having determined conditions for diastereospecific fragmen-
tation of oxaquadricyclanes, the enantioselective synthesis
proceeded as outlined in Scheme 13. Acid 67 was converted to
benzyl amide 66 with DMT-MM in 92% yield. UV irradiation
gave oxaquadricyclane 72, which was immediately subjected
to fragmentation. Cyclobutane 73 was obtained in 50% overall
yield and 75% ee, which represents complete retention of chiral
information from 72. This fragmentation presumably proceeds
via initial enolization of the amide to form 74, followed by
quenching of the resulting carbocation to form 75. Fragmentation
of the remaining cyclopropane then gives 73. Before continuing,
amide 73 was recrystalized to upgrade the ee to >95%.
Conversion to key ketoester 34 now required only epimerization
of one ketone side chain and methanolysis of the benzyl amide.
These transformations could be accomplished in one pot by
heating 73 with toluenesulfonic acid and methanol to 105 °C
in toluene.41 The methanolysis of the amide under these
unusually mild conditions can be explained by invoking
intramolecular assistance from the methyl ketone in epimerized
cyclobutane 76, as illustrated in intermediate 77. The config-
uration of ketoester (-)-34 was assigned by conversion to
sceptrin by the method described previously. Comparison to a
natural sample of sceptrin bishydrochloride revealed that ent-
sceptrin had been synthesized ([R]D ) +16.0 (MeOH, c ) 0.25,
HCl salt), lit.3 [R]D ) -7.4 (MeOH, c ) 1.2, HCl salt)). As
the optical rotation of sceptrin was found to vary with the nature
of its counterion (vide infra), this assignment was confirmed
by circular dichroism analysis (see Supporting Information). The
ent-sceptrin thus obtained was then subjected to the previously
developed conditions for conversion to ageliferin (vide supra),
yielding (+)-ent-ageliferin ([R]D ) +8.0 (MeOH, c ) 0.05,
TFA salt), natural product [R]D ) -10.0 (MeOH, c ) 0.1, TFA
salt)). This allowed the determination of the absolute configu-
ration of ageliferin as depicted in Scheme 13 and the correlation
of the absolute configurations of sceptrin and ageliferin.
The transformation of oxaquadricyclane 72 into cyclobutane
73 supports the mechanistic pathway shown in Scheme 13 and
pathway B of Figure 6; initial enolization of the amide in
accordance with theoretical predictions accounts for the stere-
ochemisty observed in product 73. As the stereospecifity of this
reaction is difficult to rationalize using the mechanism illustrated
in pathway A, these results strongly support the initiation of
the reaction by the enolization of a carbonyl moiety.
With this conclusion in mind, the logical way to obtain nat-
sceptrin was to switch the location of the amide and ester groups
in oxaquadricyclane 72. This was accomplished by esterification
(39) (a) Heinrich, N.; Koch, W.; Frenking, G.; Schwarz, H. J. Am. Chem. Soc.
1986, 108, 593-600. (b) Rosenberg, R. E. J. Org. Chem. 1998, 63, 5562-
5567.
(40) (a) Ohno, M.; Ito, Y.; Shibata, T.; Adachi, K.; Sawai, H. Tetrahedron 1984,
40, 145-151. (b) Bloch, R.; Guibe-Jampel, E.; Girard, C. Tetrahedron Lett.
1985, 26, 4087-4090; for a review of meso compounds in synthesis, see:
(c) Hoffmann, R. Angew. Chem., Int. Ed. 2003, 42, 1096-1109.
(41) Chern, C.-Y.; Huang, Y.-P.; Kan, W. M. Tetrahedron Lett. 2003, 44, 1039-
1041.
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4773

A R T I C L E S
O’Malley et al.
Scheme 13. Enantioselective Synthesis of (+)- and (-)- Sceptrin and Ageliferina
a Reagents and conditions: (a) PLE (50 unit/mmol), acetone/phosphate buffer (pH 8), 23 °C, 1 week, 100%, 75% ee; (b) BnNH2 (1.05 equiv), DMT-MM
(1.05 equiv), THF, 3 h, 92%; (c) hυ, THF, 72 h, then H2SO4, THF/MeOH (1:1), 3 h, 45 - 50%; (d) recrystallization from hexanes/EtOAc (1:1), then TsOH
(4.0 equiv), MeOH (20 equiv), toluene, 105 °C, sealed tube, 12 h, 50%; (e) BnNH2 (1.05 equiv), DMT-MM (1.05 equiv), THF, 3 h, 92%; (f) hυ, THF, 72
h, then H2SO4, THF/MeOH (1:1), 3 h, 45 - 50%; (g) recrystallization from hexanes/EtOAc (1:1), then TsOH (4.0 equiv), MeOH (20 equiv), toluene, 105
°C, sealed tube, 12 h, 50%. PLE ) pig liver esterase, THF ) tetrahydrofuran; TsOH ) toluenesulfonic acid, DMT-MM ) 4-(4,6-dimethoxy-1,3,5-triazin-
2-yl)-4-methylmorpholinium chloride.
of enzyme product 67 with 2-propanol, selective hydrolysis of
the methyl ester, and benzyl amide formation to give 78 in 80%
yield. Using the previously applied cyclization and fragmentation
conditions gave cyclobutane 79 in 50% yield and 75% ee,
presumably through the intermediacy of 80-82. Crystallization
of 79 then increased the ee to >95%. Heating with toluene-
sulfonic acid and methanol under the conditions used for 73
proceeded analogously through 83 and 84 with simultaneous
transesterification of the isopropyl ester to give (+)-34. As
from (-)-34 (obtained directly from HPLC purification) was
measured, it was found to an optical rotation that was both larger
and of the opposite direction than expected based on data
reported for the hydrochloride salt ([R]D ) -23.5 (MeOH, c )
0.75, TFA salt)). Although not completely unprecedented,42 the
dependence of the sign of optical rotation upon the identity of
the counterion was entirely unexpected.
Conclusion
expected, (+)-34 was elaborated to (-)-nat-sceptrin ([R]D
-11.7 (MeOH, c ) 0.12, HCl salt)) and (-)-nat-ageliferin ([R]D
) -10.0 (MeOH, c ) 0.03, TFA salt)).
The determination of the absolute configuration of these
compounds was not without complication, however. When the
optical rotation of ent-sceptrin bistrifluoroacetate synthesized
)
This full account has traced the development of a successful
strategy for the total synthesis of sceptrin from the initial failure
of an allyl urocanate dimerization route to an ultimately
successful oxaquadricyclane fragmentation strategy. Along the
(42) Hart, F. A.; Mann, F. G. J. Chem. Soc. 1957, 2828-2830.
9
4774 J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007

Total Synthesis of Dimeric Pyrrole−Imidazole Alkaloids
A R T I C L E S
way, a new method for the R-chlorination of ketals was
developed to confront unexpected chemo- and regioselectivity
issues. This synthesis also contained a unique application of
the oxaquadricyclane fragmentation cascade to total synthesis.
Following our biosynthetic hypothesis, sceptrin was then
converted into the related natural products ageliferin (3) and
nagelamide E (43) via the first example of a vinyl cyclobutane
rearrangement in natural products synthesis. Computational
studies19 support a stepwise radical mechanism for this interest-
ing transformation.
Extension of this biosynthetic hypothesis coupled with a
desire to avoid protecting groups led to the examination of the
chemistry of hydroxylated aminoimidazoles.21 Following pro-
posed biogenetic relationships and using the empirical intel-
ligence gathered led to the first syntheses of oxysceptrin,
nakamuric acid, and nakamuric acid methyl ester. These
syntheses proceed from sceptrin quickly and without masking
the reactivity of the 2-aminoimidazole with protecting groups.
The axinellamine carbon skeleton was likewise obtained from
ageliferin by harnessing the innate reactivity of 2-aminoimida-
zoles.
hypothesis that sceptrin is the biosynthetic precursor of ageliferin.
The enantioselective synthesis of sceptrin via enzymatic de-
symmetrization and an oxaquadricyclane fragmentation repre-
sents an interesting alternative to traditional templated [2 + 2]
cyclization approaches to enantioselective cyclobutane synthesis.
Efforts to synthesize the remaining members of this class of
thought-provoking marine alkaloids are currently underway.
Acknowledgment. We thank Dr. D. H. Huang and Dr. L.
Pasternack for NMR spectroscopic assistance, and Dr. G.
Siuzdak and Dr. R. Chadha for mass spectrometric and X-ray
crystallographic assistance, respectively. We are grateful to
Biotage for a generous donation of microwave process vials
used extensively during these studies, to the U.S. Department
of Defense and the Hertz Foundation for predoctoral fellowships
(D.P.O.), and to the German Academic Exchange Service
(DAAD) for a postdoctoral fellowship (M.M.). Financial support
for this work was provided by The Scripps Research Institute,
Amgen, Astra Zeneca, Bristol-Myers Squibb, Dupont, Eli Lilly,
GlaxoSmithKline, Roche, the Searle Scholarship Fund, the
Alfred Sloan Foundation, and NIH/NIGMS (GM-073949).
Finally, mechanistic consideration of the oxaquadricyclane
fragmentation allowed the enantioselective synthesis of both
enantiomers of sceptrin and ageliferin. This study represented
the first enantioselective synthesis of any dimeric pyrrole-
imidazole alkaloid and allowed the assignment of ageliferin’s
absolute configuration. The fact that the absolute configurations
of sceptrin and ageliferin match lends further credence to the
Supporting Information Available: Full characterization,
including copies of 1H and 13C NMR spectra, and experimental
procedures for selected compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA069035A
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