Short, enantioselective total synthesis of sceptrin and ageliferin by programmed oxaquadricyclane fragmentation

Article abstract of DOI:10.1002/anie.200503374

(Chemical Equation Presented) Absolutely without auxiliaries: The enantioselective syntheses of both enantiomers of the dimeric pyrrole-imidazole alkaloids sceptrin and ageliferin have been achieved by a non-auxiliary-based route, which allows assignment

Full text of DOI:10.1002/anie.200503374

Angewandte
Chemie
Asymmetric Synthesis
DOI: 10.1002/anie.200503374
Short, Enantioselective Total Synthesis of Sceptrin
and Ageliferin by Programmed Oxaquadricyclane
Fragmentation**
Phil S. Baran,* Ke Li, Daniel P. OꢀMalley, and
Christos Mitsos
Dedicated to Professor David I. Schuster
on the occasion of his 70th birthday.
The marine-derived dimeric pyrrole-imidazole alkaloids
sceptrin (1) and ageliferin (2) are endowed with intriguing
molecular architectures and a range of useful bioactivities
(Scheme 1).[1] The enantioselective synthesis of a dimeric
pyrrole-imidazole alkaloid has yet to be reported, partly
because of the intrinsic difficulty associated with handling
multiply charged nitrogen-containing intermediates.[2]
Scheme 1. The structures of sceptrin (1) and ageliferin (2). TFA=tri-
fluoroacetate.
We recently described practical syntheses of both 1 and 2
in their racemic form[3,4] by the use of an oxaquadricyclane
fragmentation to generate the cyclobutane core of 1. Since the
mechanism of this reaction remained ill-defined,[5] it was
unclear how, or even if, stereochemical information in an
oxaquadricyclane could be transferred to the product cyclo-
butane. Indeed, preliminary screens using numerous enan-
tioenriched oxaquadricyclanes (3, Scheme 2) under a variety
of acidic conditions led to cyclobutanes which were either
racemic or showed a considerable loss of optical activity.
Racemic oxaquadricyclanes were also evaluated with chiral
acids and auxiliaries, but to no avail. Further investigation was
warranted because of the lack of viable alternatives for the
enantioselective synthesis of tetrasubstituted cyclobutanes.[6]
Herein, we report the details of a unique method for the
enantioselective synthesis of tetrasubstituted cyclobutanes by
programmed fragmentation of an oxaquadricyclane, and the
Scheme 2. Unsuccessfulattempts at enantioseel ctive fragmentation of
an oxaquadricyclane.
application of this method to the first asymmetric synthesis of
both enantiomers of sceptrin and ageliferin.
The synthesis commenced with the enzymatic desymmet-
rization[7] of meso-diester 4[3a] using pig liver esterase (PLE) to
provide monoester 5 in quantitative yield and 75% ee
(Scheme 3). The ee value was determined by 1H NMR
spectroscopic analysis of the amide derived from (S)-a-
methylbenzylamine (absolute configuration determined by
X-ray analysis of the ammonium salt derived from the same
amine and 5). Formation of a benzylamide using DMT-MM[8]
afforded the monobenzylamide 6 in 92% yield. Remarkably,
cis,trans,trans-cyclobutane 10 was formed in 50% overall
yield and 75% ee when amide 6 was irradiated to form
oxaquadricyclane 7 and directly treated with H2SO4 in THF/
MeOH (1:1). Amide (ꢀ)-10 is nearly enantiopure (> 95% ee)
after a single recrystallization. The use of a benzylamide was
critical to achieve complete transfer of chirality. A mild and
chemoselective debenzylation/esterification of the robust
secondary amide in 10 and epimerization to the all-trans
stereochemistry were necessary to access (ꢀ)-13. Treatment
of 10 with TsOH and MeOH in toluene at 1058C[9]
accomplished all three tasks in a single pot to afford (ꢀ)-13
in 90% yield. The ease with which this amide is hydrolyzed is
likely due to assistance by the nearby cis-methyl ketone, as
depicted in structure 12 (simple secondary amides are not
converted into methyl esters under these conditions).
[*] Prof. Dr. P. S. Baran, Dr. K. Li, D. P. O’Malley, Dr. C. Mitsos
Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
[**] 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, respec-
tively. We are grateful to Biotage for a generous donation of
microwave process vials that were used extensively during these
studies and to the Department of Defense and the Hertz
Foundation for pre-doctoral fellowships (D.P.O.). Financial support
for this work was provided by The Scripps Research Institute,
Amgen, Dupont, Eli Lilly, GlaxoSmithKline, Roche, the Searle
Scholarship Fund, and NIH/NIGMS (GM-073949).
Supporting information for this article (detailed experimental
procedures, copies of all spectral data, and full characterization) is
available on the WWW under http://www.angewandte.org or from
the author.
Angew. Chem. Int. Ed. 2006, 45, 249 –252
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
249

Communications
Scheme 4. Enantioselective Synthesis of nat-1 and nat-2. Reagents and
conditions: a) 1. DMT-MM (1.05 equiv), DMAP (0.05 equiv), iPrOH,
558C, 3 h; 2. LiOH (1.2 equiv), THF/H2O (1:1), 2 h; 3. DMT-MM
(1.05 equiv), BnNH2 (1.05 equiv), THF, 3 h, 80% (3 steps); b) hu,
THF, 72 h, then H2SO4, THF/MeOH (1:1), 3 h, 45–50%; c) recrystalli-
zation from hexanes/EtOAc (1:1), then pTsOH (4.0 equiv), MeOH
(20 equiv), toluene, 1058C, sealed tube, 12 h, 50%. DMAP=4-di-
methylaminopyridine.
directly converted into the amide 14 in 80% overall yield,
without purification, by sequential formation of an ester,
selective saponification of the methyl ester, and formation of
an amide. Amide 14 was amenable to the same reaction
sequence used for 6 (Scheme 3) and furnished cyclobutane 17
with complete conservation of optical activity. Following
recrystallization (> 95% ee), epimerization, and transesteri-
fication to (+)-13, the synthesis of nat-(ꢀ)-sceptrin ([a]D =
ꢀ11.7 (MeOH, c = 0.12, HCl salt)) and (ꢀ)-ageliferin ([a]D =
ꢀ10.0 (MeOH, c = 0.03, TFA salt)) was completed. Both the
sign and magnitude of the optical rotation of sceptrin changes
depending on the counteranion (synthetic ent-sceptrin bishy-
drochloride had [a]D = + 16.0 (MeOH, c = 0.25, HCl salt),
while the bistrifluoroacetate salt had [a]D = ꢀ23.5 (MeOH,
c = 0.75, no literature value available). This unusual reversal
of optical rotation and the fact that the literature measure-
ments for 1 and 2 are variable necessitated the use of circular
dichroism to verify the assignments (Figure 1). The fact that
(ꢀ)-2 can be derived from (ꢀ)-1 is consistent with the
suggestion that the former may be produced from the latter in
nature or that they share common intermediates in the
biosynthetic pathway.[2,3b]
Scheme 3. Enantioselective Synthesis of ent-1 and ent-2. Reagents and
conditions: a) PLE (50 unitmmolꢀ1), acetone/phosphate buffer (pH 8),
238C, 1 week, 100%, 75% ee; b) BnNH2 (1.05 equiv), DMT-MM
(1.05 equiv), THF, 3 h, 92%; c) hu, 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, 1058C, sealed
tube, 12 h, 50%. Bn=benzyl, THF=tetrahydrofuran; TsOH=toluene-
sulfonic acid, DMT-MM=4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-
morpholinium chloride.
The absolute configuration of (ꢀ)-13 was verified by
conversion into sceptrin[3a] and comparison with a natural
sample, which revealed that ent-sceptrin (1) had been
synthesized ([a]D = + 16.0 (MeOH, c = 0.25, HCl salt),
lit. [1][ a]D = ꢀ7.4 (MeOH, c = 1.2, HCl salt)). Exposure of
ent-sceptrin (1) to microwave irradiation[3b] led to ent-
ageliferin (2; [a]D = + 8.0 (MeOH, c = 0.05, TFA salt), natural
product [a]D = ꢀ10.0 (MeOH, c = 0.1, TFA salt)).[3] The
absolute configuration of 2 can now be assigned as depicted
in Scheme 1.
The cascade rearrangement of oxaquadricyclanes to
cyclobutanes was initially discovered by McInnes and co-
workers,[5a] who proposed a mechanism involving the initial
fragmentation of the oxa bridge with water. The cascade was
The naturally occurring forms of 1 and 2 could be
prepared as outlined in Scheme 4. Thus, monoacid 5 was
250
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 249 –252

Angewandte
Chemie
prone to a variety of other rearrangements under acidic
conditions.[5c] This method proceeds in an operationally
simple, scalable, and direct manner and represents the first
solution for the nontrivial problem of the enantioselective
construction of a tetrasubstituted cyclobutane which does not
rely upon chiral auxiliaries.[6,11]
In summary, the first enantioselective syntheses of the
dimeric pyrrole-imidazole alkaloids sceptrin (1) and ageli-
ferin (2) have been accomplished (18% overall for (ꢀ)-1
from commercially available compounds). Notably, column
chromatography (on 10 and 17) and HPLC (to separate 1
from 2) only need to be performed once during the entire
sequence. These syntheses have enabled the assignment of the
absolute configuration of 2, provided insight into the mech-
anism of the remarkable oxaquadricyclane!cyclobutane
rearrangement, and opened up an enantioselective route to
other complex alkaloids in this family.[12]
Received: September 23, 2005
Published online: November 30, 2005
Keywords: asymmetric synthesis · cascade reactions ·
.
enantioselectivity · natural products · rearrangement
[1]a) Sceptrin: R. P. Walker, D. J. Faulkner, D. Van Engen, J.
Clardy, J. Am. Chem. Soc. 1981, 103, 6772 – 6773; b) Ageliferin:
P. A. Keifer, R. E. Schwartz, M. E. S. Koker, R. G. Hughes, Jr.,
D. Rittschof, K. L. Rinehart, J. Org. Chem. 1991, 56, 2965 – 2975.
[2]For reviews, see H. Hoffmann, T. Lindel, Synthesis 2003, 1753 –
1783; D. E. N. Jacquot, T. Lindel, Current Org. Chem. 2005, 9,
1551 – 1565.
[3]a) P. S. Baran, A. L. Zografos, D. P. OꢀMalley, J. Am. Chem. Soc.
2004, 126, 3726 – 3727; b) P. S. Baran, D. P. OꢀMalley, A. L.
Zografos, Angew. Chem. 2004, 116, 2728 – 2731; Angew. Chem.
Int. Ed. 2004, 43, 2674 – 2677.
Figure 1. Top: Circular dichroism (CD) spectra of natural (ꢀ)-sceptrin
(green), synthetic (ꢀ)-sceptrin (blue), and synthetic (+)-sceptrin (red)
in water (0.2 mm). Bottom: Circular dichroism (CD) spectra of natural
(ꢀ)-ageliferin (green), synthetic (ꢀ)-ageliferin (red), and synthetic (+)-
ageliferin (blue) in water (0.35 mm). All measurements were recorded
at 258C.
later studied by Nelsen and Calabrese,[5b] who posited an
alternative mechanism initiated by fragmentation of a cyclo-
propyl ring to form an oxocarbonium ion (see 8 and 16). After
the work of Nelsen and Calabrese, little notice was taken of
this reaction until it was adopted in the synthesis of sceptrin.[3]
Success of an enantioselective variant relied on the assump-
tion that the configuration of the final product is controlled by
the order of the enolization (or protonation) of the carbonyl
groups in the first fragmentation. For example, the major
enantiomer (10) resulting from the fragmentation of 7 is
produced by initial enolization of the benzylamide
(Scheme 3), whereas the minor enantiomer (ent-10) would
be produced by initial enolization of the ester. This result fits
with the results of theoretical predictions that have found that
enols of amides are more stable than those of carboxylic acids
or esters.[10] The selective fragmentation of 7 to amide enol 8 is
followed by tautomerization (protonation from the convex
face) and capture by water to furnish 9. Immediate fragmen-
tation leads to the stable cis,trans,trans-cyclobutane 10. The
efficiency and complete transfer of chirality observed in these
reactions (6!10 and 14!17) is surprising given the complex-
ity of this mechanism, the difficulties encountered at the
outset (see above), and the fact that oxaquadricyclanes are
[4]For a recent synthesis of ( ꢁ )-1, see V. B. Birman, X.-T. Jiang,
Org. Lett. 2004, 6, 2369 – 2371; for studies toward 2, see Ref. [2]
and Y. He, Y. Chen, H. Wu, C. J. Lovely, Org. Lett. 2003, 5, 3623 –
3626; I. Kawasaki, N. Sakaguchi, N. Fukushima, N. Fujioka, F.
Nikaido, M. Yamashita, S. Ohta, Tetrahedron Lett. 2002, 43,
4377 – 4380.
[5]a) J. Laing, A. W. McCulloch, D. G. Smith, A. G. McInnes, Can.
J. Chem. 1971, 49, 574 – 582; b) S. F. Nelsen, J. C. Calabrese, J.
Am. Chem. Soc. 1973, 95, 8385 – 8388; c) for a review of
oxaquadricyclane chemistry, see W. Tochtermann, G. Olsson,
Chem. Rev. 1989, 89, 1203 – 1214.
[6]The use of chiral auxiliaries in [2 + 2]cycloadditions was shown
to be only partially stereoselective with cinnamate derivatives,
see D. Haag, H.-D. Sharf, J. Org. Chem. 1996, 61, 6127 – 6135; for
a review, see E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003, 103,
1449 – 1483.
[7]a) M. Ohno, Y. Ito, T. Shibata, K. Adachi, H. Sawai, Tetrahedron
1984, 40, 145 – 151; b) R. Bloch, E. Guibe-Jampel, C. Girard,
Tetrahedron Lett. 1985, 26, 4087 – 4090; for a review of meso
compounds in synthesis, see R. Hoffmann, Angew. Chem. 2003,
115, 1128 – 1142; Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109.
[8]4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride: M. Kunishima, C. Kawachi, J. Morita, K. Terao, F.
Iwasaki, S. Tani, Tetrahedron 1999, 55, 13159 – 13170.
[9]C.-Y. Chern, Y.-P. Huang, W. M. Kan, Tetrahedron Lett. 2003, 44,
1039 – 1041.
Angew. Chem. Int. Ed. 2006, 45, 249 –252
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
251

Communications
[10]N. Heinrich, W. Koch, G. Frenking, H. Schwarz, J. Am. Chem.
Soc. 1986, 108, 593 – 600; R. E. Rosenberg, J. Org. Chem. 1998,
63, 5562 – 5567.
[11]For an example of a cyclobutane with vicinal quaternary centers
(18) that can be made using this method, see the Supporting
Information.
[12]CCDC-281469 (chiral ammonium salt of 5) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
252
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 249 –252