Total synthesis and structural revision of the piperarborenines: When photochemistry meets C-H activation

Article abstract of DOI:10.1002/anie.201108592

Activate and reiterate: The activation of C(sp³)-H bonds is a highly desirable transformation because molecular complexity can be increased at the expense of the most simple and readily available organic linkage. In recent contributions this ap

Full text of DOI:10.1002/anie.201108592

Angewandte
Chemie
DOI: 10.1002/anie.201108592
Total Synthesis
Total Synthesis and Structural Revision of the
Piperarborenines: When Photochemistry Meets C H
Activation**
Frꢀdꢀric Frꢀbault and Nuno Maulide*
À
À
C H activation · cyclobutanes · photochemistry ·
piperarborenines · total synthesis
T
he piperarborenines, isolated from the stems of the
In 2004, Kibayashi et al. described the first enantioselec-
tive total synthesis of (À)-incarvillateine (3).[4] A few years
later, Bergman and Ellman,[5] as well as Jia and co-workers,[6]
reported independent total syntheses using a similar approach
to construct the cyclobutane core. The synthetic focus of these
different strategies was placed on the assembly of the bicyclic
alkaloid moiety, whilst the construction of the tetrasubstituted
cyclobutane ring relied on Kibayashiꢀs elegant topochemical
[2+2] photodimerization of the ferulic acid derivative 4
(Scheme 1).[4] Key to the success of this strategy was the
realization that subtle structural factors, at loci as remote
from the reactive center as the oxygen substituents in the aryl
moiety of 4 (cf. tosyl substituent), can have a dramatic impact
on the crystal packing arrangement and thus on the outcome
of the photodimerization process.[4]
creeping shrub Piper arborescens,[1] are members of a class
of quasi-dimeric monoterpene alkaloids characterized by a
tetrasubstituted cyclobutane ring. Closely related to the
piperarborenines, but structurally more complex, is the
incarvillateine family of natural products,[2] in which the
dihydropyridone is replaced by an elaborate bicyclic piper-
idine moiety containing five contiguous stereocenters (Fig-
ure 1). Interestingly, structure–activity relationship studies
performed on 3 and derivatives thereof suggest that the
cyclobutyl moiety plays a crucial role in the expression of
biological activity.[3]
Scheme 1. Kibayashi’s topochemical [2+2] photodimerization of ferulic
acid derivative 4.[4]
While this topochemical [2+2] photodimerization ap-
proach is a very powerful tool for the synthesis of symmetrical
cyclobutanes such as incarvillateine (3), several issues arise
when two distinct olefins are brought together, including
homodimerization, orientation (head-to-head versus head-to-
tail) and double-bond isomerization.[7] Nonsymmetrical tar-
gets, such as the piperarborenines, thus pose significant
hurdles to such a strategy. In spite of remarkable advances
in crystal engineering and solid-state photochemistry, which
have provided elegant routes towards stereodefined cyclo-
butanes,[8] photo-heterodimerizations of alkenes are still
rare.[9]
Figure 1. Structures of the piperarborenines and incarvillateine.
[*] Dr. F. Frꢀbault, Dr. N. Maulide
Max-Planck-Institut fꢁr Kohlenforschung
Recently Baran et al. described a strategy to circumvent
those limitations and access unsymmetrical cyclobutane
natural products, based on an innovative metal-catalyzed
Kaiser-Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
E-mail: maulide@mpi-muelheim.mpg.de
Homepage: http://www.kofo.mpg.de/maulide
3
[10]
À
C(sp ) H functionalization of cyclobutanes. The state-of-
[**] We thank the Max-Planck Society and the Max-Planck-Institut fꢁr
Kohlenforschung, the European Research Council (grant 278872),
and the Deutsche Forschungsgemeinschaft (grant MA-4861/3-1)
for generous support.
the-art work of Daugulis and co-workers in the cross-coupling
reaction of C(sp ) H bonds with aryl iodides
Baran and Gutekunst to prepare the piperarborenines by
3
[11]
À
inspired
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Angewandte
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means of two sequential, unprecedented cyclobutane C H
arylations directed by suitable pre-existing carboxylate func-
tionality.
The synthetic pathway to the 1,3-dicarboxylate cyclo-
butane 8 exploited commercially available methyl coumalate
6 and required only two steps to reach the desired inter-
mediate as a single diastereoisomer (Scheme 2). This expedi-
tious one-pot sequence involves a photochemical 4p-electro-
ysis,[14] followed by conversion of the resulting dicarboxylic
acid to the diimide.
À
In a similar fashion, the route to piperarborenine D (2)
began with selective epimerization at C-3 of the common
intermediate 10 using KMHDS as a base (Scheme 4). The
remarkable selectivity afforded by diverse bases for the
À
Scheme 2. Synthesis of cyclobutane precursor 9 for C H activations.
DCM=dichloromethane, EDC=1-ethyl-3-(3-dimethylaminopropyl)car-
bodiimide.
cyclization of 6 to give the bicyclic lactone 7,[12] followed by
two successive reductions by hydrogenolysis. Subsequent
introduction of a directing group, 2-aminothioanisole, set
Scheme 4. Total synthesis and structural revision of piperarborenine D
(15). KHMDS=potassium hexamethyldisilazide.
À
the stage for C H activations of cyclobutane 9. This directing
group has comparable efficiency to the most widely employed
8-aminoquinoline, whilst being easier to hydrolyze.[11b] After
extensive optimization of the reaction conditions, 3,4,5-
epimerization of different acidic stereocenters is noteworthy
and probably results from the ability propensity (or not) of
each base to generate an amide N-bound anion. The resulting
diastereomerically pure cyclobutane 13 underwent a second
À
trimethoxyiodobenzene was coupled with a C H bond of
amide 9 in the presence of a catalytic amount of palladiu-
m(II)acetate to give the trisubstituted cyclobutane 10 in
moderate yield (Scheme 3). The all-syn selectivity that results
from the stereodirecting effect of the aromatic amide as well
as the almost complete absence of overarylation products are
distinctive features of this impressive transformation.
À
C H arylation with 3,4-dimethoxyiodobenzene, and again
HFIP and PivOH were found to be critical additives. Treat-
ment of 14 with KOH in refluxing EtOH effected complete
epimerization at C-1 as well as full hydrolysis to the
dicarboxylic acid, which was then converted to the originally
proposed structure of piperarborenine D (2) by coupling with
dihydropyridone.
1
Owing to inconsistencies between the H and 13C NMR
spectra of synthetic piperarborenine D (2) and the literature
data,[1a] the authors proposed a revised unsymmetrical head-
to-head type dimer structure for this natural product (15).
This newly proposed structure was confirmed by chemical
synthesis, which was achieved through intramolecular [2+2]
photocycloaddition of a mixed cinnamic anhydride. Cyclo-
butane 15 displayed spectroscopic properties fully in accord
with those published.
The first pivotal operation in Baranꢀs total synthesis of the
piperarborenines is the very concise access to 1,3-dicarbox-
ylate cyclobutane 8, showcasing the power of pyrone photo-
chemistry to deliver four-membered-ring products in stereo-
defined and atom-economical fashion. The innovative use of
Scheme 3. Total synthesis of piperarborenine B (1). Boc=tert-butyl-
oxycarbonyl.
À
The addition of both hexafluoroisopropanol (HFIP) and
pivalic acid was found to play a crucial role in the course of
the reaction.[13] Selective epimerization of 10 at C-1 using
LiOtBu in toluene gave predominantly the desired cyclo-
butane 11, which was further arylated with 3,4-dimethoxyio-
dobenzene under conditions similar to those previously
employed (interestingly, HFIP and PivOH no longer provided
sequential, programmed cyclobutane C H activations is the
À
crux of this synthetic approach. Various aspects of these C H
functionalization steps merit further comment. First: the
ability of the directing group (combined with additives) to
activate exclusively one methylene group during the first
arylation reaction and the preference for C H insertion into
the methylene group over the tertiary benzylic C H bond in
the second C H arylation, which are both striking. Second:
the particularly high yield of the coupling giving 14 (compare
with the analogous preparation of 10 and 12), which is
À
À
À
À
any beneficial effects for this C H arylation). The total
synthesis of piperarborenine B (1) was completed after three
further steps, including simultaneous amide and ester hydrol-
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Angewandte
Chemie
probably a consequence of stereoelectronically unfavorable
effects by the b-disposed C-3 ester moiety. Third: the
[1] a) F.-P. Lee, Y.-C. Chen, J.-J. Chen, I.-L. Tsai, I.-S. Chen, Helv.
Chim. Acta 2004, 87, 463 – 468; b) I.-L. Tsai, F.-P. Lee, C.-C. Wu,
C.-Y. Duh, T. Ishikawa, J.-J. Chen, Y.-C. Chen, H. Seki, I.-S.
Chen, Planta Med. 2005, 71, 535 – 542.
À
synthetically useful yields achieved in those C H arylations
which, though perhaps modest (ca. 50% in two cases) from an
absolute point of view, accompany spectacular increases in
complexity en route to the natural product targets. It is the
latter point which perhaps best defines the promise and
[2] Y.-M. Chi, W.-M. Yan, J.-S. Li, Phytochemistry 1990, 29, 2376 –
2378.
[3] M. Nakamura, Y.-M. Chi, W.-M. Yan, A. Yonezawa, Y.
Nakasugi, T. Yoshizawa, F. Hashimoto, J. Kinjo, T. Nohara, S.
Sakurada, Planta Med. 2001, 67, 114 – 117.
[4] M. Ichikawa, M. Takahashi, S. Aoyagi, C. Kibayashi, J. Am.
Chem. Soc. 2004, 126, 16553 – 16558.
[5] A. S. Tsai, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2008,
130, 6316 – 6317.
À
challenge of C H functionalization methodologies, which are
clearly at a stage ripe for synthetic applications, but still
allowing room for further development and discovery. In
particular, the achievement of the Baran group along with
another recent report by Yu et al. suggest that the use of a
cyclic rigid template, in the form of
a
cyclopropane
[6] F. Zhang, Y. Jia, Tetrahedron 2009, 65, 6840 – 6843.
[7] a) F. D. Lewis, S. L. Quillen, P. D. Hale, J. D. Oxman, J. Am.
Chem. Soc. 1988, 110, 1261 – 1267; b) R. B. Filho, M. P. De S-
ouza, M. E. O. Mattos, Phytochemistry 1981, 20, 345 – 346.
[8] a) M. D. Cohen, G. M. J. Schmidt, J. Chem. Soc. 1964, 2000 –
2013; b) V. Ramamurthy, K. Venkatesan, Chem. Rev. 1987, 87,
433 – 481; c) A. Natarajan, V. Ramamurthy, The chemistry of
cyclobutanes, Vol. 1 (Eds.: Z. Rappoport, J. F. Libeman), Wiley,
Chichester, 2005, pp. 807 – 872.
(Scheme 5)[15] or cyclobutane ring, to enforce selective C H
manipulation is a strategy with considerable potential in
synthesis.
À
[9] For a recent example, see: J. Du, T. P. Yoon, J. Am. Chem. Soc.
2009, 131, 14604 – 14605.
[10] W. R. Gutekunst, P. S. Baran, J. Am. Chem. Soc. 2011, 133,
19076 – 19079.
[11] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc.
2005, 127, 13154 – 13155; b) D. Shabashov, O. Daugulis, J. Am.
Chem. Soc. 2010, 132, 3965 – 3972.
[15]
À
Scheme 5. Yu’s C H activation of cyclopropanes.
[12] a) H. Javaheripour, D. C. Neckers, J. Org. Chem. 1977, 42, 1844 –
1850. For recent applications of 4p-electrocyclisation of pyrones,
see: b) F. Frꢁbault, M. Luparia, M. T. Oliveira, R. Goddard, N.
Maulide, Angew. Chem. Int. Ed. 2010, 49, 5672 – 5676.
[13] a) M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496 –
16497; b) M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
14570 – 14571.
3
À
This remarkable sequential C(sp ) H arylation approach
to cyclobutane natural products certainly paves the way for
future exploitation and raises the exciting possibility of the
modular assembly of diverse analogues for biological testing.
[14] D. A. Evans, P. H. Carter, C. J. Dinsmore, J. C. Barrow, J. L.
Catz, D. W. Kung, Tetrahedron Lett. 1997, 38, 4335 – 4538.
[15] M. Wasa, K. M. Engle, D. W. Lin, E. J. Yoo, J.-Q. Yu, J. Am.
Chem. Soc. 2011, 133, 19598 – 19601.
Received: December 6, 2011
Published online: February 13, 2012
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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