Sequential Csp3-H arylation and olefination: Total synthesis of the proposed structure of pipercyclobutanamide a

Article abstract of DOI:10.1002/anie.201203897

Hip to be square: A strategy for assembling tetrasubstituted cyclobutanes is reported in the context of a short, protecting-group-free synthesis of the proposed structure of pipercyclobutanamide A. The route features sequential C-H functionalizations on an unactivated cyclobutane wherein C-C bonds to aryl and styryl groups are made one by one in a stereocontrolled fashion. DG=directing group. Copyright

Full text of DOI:10.1002/anie.201203897

Angewandte
Chemie
DOI: 10.1002/anie.201203897
Natural Products
À
Sequential Csp3 H Arylation and Olefination: Total Synthesis of the
Proposed Structure of Pipercyclobutanamide A**
Will R. Gutekunst, Ryan Gianatassio, and Phil S. Baran*
Our laboratory recently reported the synthesis of the
pseudodimeric cyclobutane natural products piperarboreni-
ne B (1; Figure 1a) and piperarborenine D (proposed struc-
À
ture, 2) through a sequential cyclobutane C H arylation
strategy.[1,2] This approach led to both the concise preparation
of these molecules (6–7 steps) and the structural reassignment
of piperarborenine D (revised structure, 3). While the piper-
arborenines are the simplest examples of heterodimeric
cyclobutane natural products isolated from pepper plants,
a number of other heterodimers have been isolated, and they
all arise from a formal [2+2] cycloaddition of piperine-like
monomers (4) having varying oxidation states and chain
lengths.[3] Looking to extend our C H functionalization
À
strategy to more complex members of the family, our
attention turned to the pipercyclobutanamides (5 and 6).
The pipercyclobutanamides were first isolated by Fuji-
wara and co-workers in 2001 from the fruits of the black
pepper plant, Piper nigrum, though no biological activity was
reported at that time.[3a] In 2006, Tezuka and co-workers
reisolated pipercyclobutanamide A (5) and demonstrated
a selective inhibition of cytochrome P450 2D6 (CYP2D6).[3c]
These heterodimers represent a greater synthetic challenge
than the piperarborenines (1,3) because of the presence of
four different substituents on the cyclobutane ring. Both of
these natural products contain an unusual cis unsaturated
amide, and pipercyclobutanamides A (5) and B (6) contain
styrene and styryl diene motifs, respectively. Viewing these
À
molecules as an opportunity to develop cyclobutane C H
olefination chemistry, a synthetic strategy was devised and the
retrosynthetic analysis of pipercyclobutanamide A (5) is
shown in Figure 1b. First, the cis alkene is transformed into
an aldehyde through a stereocontrolled olefination reaction.
The aldehyde could then be deconstructed to a directing
group (DG) and the amide into a methyl ester using standard
Figure 1. a) Selected heterodimeric cyclobutane natural products.
b) Retrosynthesis of pipercyclobutanamide A (5).
functional group manipulations to provide intermediate 7.
Applying the strategy developed for the piperarborenines,
À
this intermediate could be prepared through a series of
The direct olefination of Csp2 H bonds has been known
since the seminal work of Fujiwara and Moritani in the late
À
epimerizations and Csp3 H functionalizations on the desym-
metrized cyclobutane dicarboxylate 8.
1960s,[4] but few examples exist for the direct olefination of
unactivated Csp3 H bonds. During a study towards the
[5]
À
teleocidin natural products, Sames and co-workers coupled an
unactivated methyl group with a vinyl boronic acid, though
the sequence proceeded through a discretely isolated palla-
dacycle.[5e] The first catalytic example was reported in 2010 by
Yu and co-workers.[5a] A highly electron-deficient anilide
directing group was employed to couple acrylate derivatives
[*] W. R. Gutekunst, R. Gianatassio, Prof. Dr. P. S. Baran
Department of Chemistry, The Scripps Research Institute
10650 North Torrey Pines Road, La Jolla, CA, 92037 (USA)
E-mail: pbaran@scripps.edu
[**] We are grateful to Dane Holte for technical assistance. Financial
support for this work was provided by the NIH/NIGMS (GM-
073949) and the NSF for a predoctoral fellowship to W.R.G.
À
directly to unactivated methyl and cyclopropyl C H bonds.
Chen and co-workers later reported the coupling of cyclic
À
vinyl iodides with methylene C H bonds using Daugulisꢀ
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203897.
picolinamide directing group under palladium catalysis.[5d]
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Encouraged by this result in particular, a styrenyl iodide was
chosen as the first coupling partner to examine for the
synthesis of pipercyclobutanamide A (5).[6]
Investigations started with the preparation of the requisite
cyclobutane starting material 12 (Scheme 1). By applying the
methodology developed previously for the piperarborenine
natural products, methyl coumalate (9) underwent a photo-
chemical 4p electrocyclization at reduced temperature to give
the photopyrone 10.[7] This unstable intermediate was imme-
diately hydrogenated and coupled to 8-aminoquinoline[8] in
cyclobutane that is quite strained and, to our knowledge,
there are no other general methods for the controlled
construction of this stereochemical array on a cyclobutane.
À
Given the modularity of this sequential C H functional-
ization strategy, a monoarylation reaction could take place
with a subsequent olefination reaction to reach the end goal.
When the standard monoarylation conditions were applied to
the reaction of cyclobutane 12 with 1-iodo-3,4-methylene-
dioxybenzene, poor conversion was observed as a result of the
methylenedioxy ring (3,4-dimethoxyiodobenzene as a cou-
pling partner performed well). Pivalic acid proved to be an
effective additive, and when the reaction was performed in
tBuOH at high concentration, an acceptable yield of 14 was
obtained (54%, 1.00 g scale). Because of the facile double
olefination observed in the preparation of 13, the monoary-
À
a single operation to give the desired C H olefination
precursor 12 in 54% overall yield. The olefination reaction
was initially studied with (2-iodovinyl)benzene as a model
coupling partner. The use of reaction conditions originally
developed for monoarylation [with hexafluoroisopropanol
(HFIP) as the solvent and pivalic acid] resulted in low
conversion and significant amounts of decomposition. Switch-
ing the solvent to toluene improved the reaction considerably
to give the bis(olefinated) cyclobutane 13 as the major
product in 50% yield. This result is in contrast to our previous
work on the piperarborenines in which an epimerization
À
lated 14 was directly subjected to the C H olefination
reaction with the styrenyl iodide 15. Optimizing the reaction
was straightforward, thus employing catalytic Pd(OAc)2 in
the presence of 1.5 equivalents of AgOAc with toluene as the
solvent gave the all-cis cyclobutane 16 in 59% yield (480 mg
scale). Pivalic acid as an additive retarded the reaction rate,
and protic solvents such as tBuOH and HFIP were inferior,
thereby giving low conversion and substantial decomposition,
respectively.
À
event was required to allow an efficient second C H
functionalization on the cyclobutane ring. The reason for
this direct bis(olefination) is unclear, but it may simply be that
the vinyl iodide is smaller than the aryl iodide, thereby leading
to a more facile second reaction. Furthermore, 13 is an all-cis
With the sequential functionalization product 16 in hand,
the relative stereochemistry needed to be altered to the all-
Scheme 1. Total synthesis of the proposed structure of pipercyclobutanamide A (5). Reagents and conditions: a) 450-W Hanovia lamp, Pyrex filter,
CH2Cl2, 158C, 96 h; then H2, Pt/C, 4 h; then 8-aminoquinoline (1.2 equiv), EDC (1.2 equiv), 0 to 238C, 3 h, 54%. b) (2-iodovinyl)benzene
(3.0 equiv), Pd(OAc)2 (0.15 equiv), AgOAc (3.0 equiv), PhMe, 808C, 12 h, 50%. c) Pd(OAc)2 (0.15 equiv), Ag2CO3 (1.0 equiv), PivOH (1.0 equiv),
1-iodo-3,4-methylenedioxybenzene (2.0 equiv), tBuOH, 858C, 15 h, 54%. d) 15 (2 equiv), Pd(OAc)2 (0.15 equiv), AgOAc (1.5 equiv), PhMe, 808C,
10 h, 59%. e) NaOMe (2.0 equiv), MeOH/THF (1:4), 458C, 2 h, then 1n NaOH, 1 h. f) DIBAL (3.5 equiv), THF, À788C, 0.5 h. g) piperidine
(3.0 equiv), T3P (1.5 equiv), CH2Cl2, 238C, 15 min, 40–45% (3 steps). h) 21 (1.5 equiv), KOtBu (1.5 equiv), THF, À788C to 08C, 2 h, 80%.
DIBAL=diisobutylaluminium hydride, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, T3P=propylphosphonic anhydride, THF=tetrahy-
drofuran.
2
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trans configuration found in the natural product. This was
anticipated to be a facile process given the strained nature of
the all-cis stereochemistry and the thermodynamically down-
hill path to the desired all-trans product. Experimentally, this
was verified through the use of two equivalents of sodium
methoxide with C1 epimerization occurring rapidly at room
temperature (< 1 min). Upon warming the reaction mixture
to 458C, the methyl ester (C3) epimerizes over two hours and
fully hydrolyzes after the addition of aqueous sodium
hydroxide to give acid 18. Without further purification, 18
was treated with excess DIBAL to transform the amino-
quinoline directing group directly into an aldehyde. By
employing the free carboxylic acid in this reaction, the
correct oxidation state found in the natural product is
maintained with the carboxylate anion acting as an innate
protecting group.[9] Additionally, the direct reduction of
secondary amides to aldehydes with DIBAL has limited
precedent, and the success of this reaction is likely the result
of the chelating nature of the aminoquinoline motif.[10]
Furthermore, this presents a new method for the cleavage
of this amide directing group and avoids the extremes of pH
and heat, thus expanding the synthetic utility of the Daugulis
methodology[6, 8a] if found to be general. Moving forward with
the crude aldehyde 19, piperidine was used as both a base and
a coupling partner in the reaction with T3P to provide amide
20 in 40–45% yield upon isolation after three steps (114–
386 mg scale).
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3965 – 3972.
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[9] This strategy was inspired by Bartonꢀs clever use of enolate
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To complete the synthesis of pipercyclobutanamide A (5),
only an olefination reaction remained. This transformation
was accomplished through the use of Andoꢀs methodology for
cis-selective unsaturated amide synthesis.[11] Treatment of the
aldehyde 20 with the Ando phosphonate (21) in the presence
of tBuOK resulted in an approximately 5:1 cis/trans mixture
of easily separable olefin isomers, thus giving the desired
pipercyclobutanamide A (5) in 80% yield upon isolation
1
(100 mg scale). Unfortunately, the H and 13C NMR data did
not match the spectrum reported for the natural product.[12]
The concise synthesis of the proposed structure of
pipercyclobutanamide A (5) further demonstrates the power
À
of C H functionalization logic in synthesis to provide
substantial amounts of complex cyclobutanes (7 steps, 5
chromatographic purifications, 5% overall yield, > 100 mg
prepared). The sequence features mostly skeleton-forming
transformations, is protecting-group-free,[13] and has only one
concession step (DIBAL reduction) leading to an ideality of
85%.[14] Salient features of the synthesis include: 1) the first
À
example of C H olefination on an unactivated cyclobutane
ring; 2) stereocontrolled access to highly strained all-cis
cyclobutanes; 3) direct conversion of aminoquinoline
amides directly to aldehydes; and 4) the use of a carboxylate
anion as an innate protecting group in an amide reduction.
[10] a) F. U. Schmitz, V. W.-F. Tai, R. Rai, C. D. Roberts, A. D. M.
Abadi, S. Baskaran, I. Slobodov, J. Maung, M. L. Neitzel
(Genelabs Technologies, Inc.), WO 2009023179, 2009; other
methods for the direct reduction of secondary amides to
aldehydes: b) G. Pelletier, W. S. Bechara, A. B. Charette, J.
Am. Chem. Soc. 2010, 132, 12817 – 12819; c) S. Bower, K. A.
Kreutzer, S. L. Buchwald, Angew. Chem. 1996, 108, 1662 – 1664;
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Chem. Soc. 2007, 129, 3408 – 3419.
Received: May 21, 2012
Published online: && &&, &&&&
À
Keywords: C H functionalization · natural products ·
palladium · small rings · synthesis design
.
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[11] K. Ando, S. Nagaya, Y. Tarumi, Tetrahedron Lett. 2009, 50,
5689 – 5691.
Liu, M. Zhang, T. P. Wyche, G. N. Winston-McPherson, T. S.
Bugni, W. Tang, Angew. Chem. 2012, DOI: 10.1002/
ange.201203379; Angew. Chem. Int. Ed. 2012, DOI: 10.1002/
anie.201203379.
[12] While this work was in progress, we became aware of the elegant
studies of the Tang group whose first and asymmetric synthesis
of 5 indicated that the natural product is misassigned and that
the real pipercyclobutanamide A is actually the constitutionally
isomeric cyclohexene containing natural product chabamide: R.
[13] I. S. Young, P. S. Baran, Nat. Chem. 2009, 1, 193 – 205.
[14] T. Gaich, P. S. Baran, J. Org. Chem. 2010, 75, 4657 – 4673.
4
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Natural Products
W. R. Gutekunst, R. Gianatassio,
P. S. Baran*
&&&& — &&&&
À
Sequential Csp3 H Arylation and
Olefination: Total Synthesis of the
Proposed Structure of
Pipercyclobutanamide A
Hip to be square: A strategy for assem-
bling tetrasubstituted cyclobutanes is
reported in the context of a short, pro-
tecting-group-free synthesis of the pro-
posed structure of pipercyclobutanami-
functionalizations on an unactivated
À
cyclobutane wherein C C bonds to aryl
and styrenyl groups are made one by one
in a stereocontrolled fashion. DG=
directing group.
À
de A. The route features sequential C H
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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