Total synthesis and structural revision of the piperarborenines via sequential cyclobutane C-H arylation

Article abstract of DOI:10.1021/ja209205x

A strategy for the construction of unsymmetrical cyclobutanes using C-H functionalization logic is demonstrated in the total synthesis of piperarborenine B and piperarborenine D (reported structure). These syntheses feature a new preparation of cis-cyclob

Full text of DOI:10.1021/ja209205x

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pubs.acs.org/JACS
Total Synthesis and Structural Revision of the Piperarborenines via
Sequential Cyclobutane CꢀH Arylation
Will R. Gutekunst and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
ABSTRACT: A strategy for the construction of unsymme-
trical cyclobutanes using CꢀH functionalization logic is
demonstrated in the total synthesis of piperarborenine B
and piperarborenine D (reported structure). These synthe-
ses feature a new preparation of cis-cyclobutane dicarbox-
ylates from commercially available coumalate starting ma-
terials and a divergent approach to the controlled cis or trans
installation of the two distinct aryl rings found in the natural
products using the first example of cyclobutane CꢀH
arylation. The structure of piperarborenine D is reassigned
to a head-to-head dimer, which was synthesized using an
intramolecular [2+2] photocycloaddition strategy.
imeric, cyclobutane-containing natural products comprise a
D
small yet diverse family with a variety of biological activities.1
Although no “[2+2]-ase” has been identified, it is generally
presumed that such compounds originate from the direct
coupling of the parent monomeric olefins in Nature. From the
vantage point of synthetic strategy, cyclobutanes derived from
such a heterodimerization are quite difficult to prepare in a
controlled fashion. For example, dictazole A (1) and the piper-
arborenines (2aꢀ2c, 3aꢀ3c) are pseudosymmetrical cyclobu-
tane natural products that are only differentiated by remote
substituents (Figure 1A).2 While a direct [2+2] photocycloaddi-
tion is an appealing route for coupling two similar yet distinct
olefins, this strategy is problematic for several reasons, including
homodimerization, orientation (head-to-head versus head-
to-tail), and E/Z isomerization, leading to a variety of possible
structural and stereochemical outcomes.3 While crystal engineer-
ing and solid-state photochemistry techniques have provided
stereodefined access to some cyclobutane classes,4 examples of
direct heterodimerization of isolated olefins to form cyclobu-
tanes are rare and are generally limited in scope.5 In this Com-
munication, the first catalytic, transition metal-mediated CꢀH
functionalization of cyclobutanes is reported as an alternative to
[2+2] cycloaddition for the preparation of pseudosymmetrical
cyclobutane structures.6,7 It is further shown for the first time that
sp3 CꢀH arylation reactions can be conducted sequentially to
access a set of stereoisomeric natural products in a practical and
divergent fashion.8
Figure 1. General CꢀH activation strategy for unsymmetrical cyclo-
butane natural products: 2a, piperarborenine A (R1 = R2 = H); 2b,
piperarborenine B (R1 = H, R2 = OMe); 2c, piplartine dimer A (R1 = R2 =
OMe); 3a, piperarborenine C (R1 = OMe, R2 + R3 = OCH2O); 3b,
piperarborenine D (R1 = H, R2 = R3 = OMe); 3c, piperarborenine E (R1 =
H, R2 + R3 = OCH2O).
head-to-tail dimerization of piplartine-type monomers with
varying degrees of oxidation on the aryl rings. While considering
new strategies toward these cyclobutane natural products, the
use of the pre-existing carboxylate functionality to guide sequen-
tial CꢀH arylations directly onto the cyclobutane ring was
envisioned, as depicted in Figure 1. Furthermore, if these aryla-
tions could be performed sequentially, the problems of pseudo-
symmetry and stereochemistry would be greatly simplified. While
CꢀH arylation reactions on cyclobutane rings have hitherto not
been reported,9 the pioneering studies of Daugulis and co-workers
to cross-couple sp3 CꢀH bonds with aryl iodides appeared to be
suitable for our endeavors.10
The retrosynthesis of piperarborenine B (2b) and piperarbor-
enine D (3b) is outlined in Figure 1B. The imide motifs found in
the natural products were viewed as latent carboxylate-based
directing groups for CꢀH functionalization, and, therefore, the
dimethoxybenzene ring was replaced with a simple CꢀH bond.
Monoarylated cyclobutane 4 was chosen as a divergent inter-
mediate that could access both piperarborenine stereoisomers.
Through selective epimerization of the C-1 or C-3 stereocenter,
followed by a second CꢀH arylation, the synthesis of either
The piperarborenines (2aꢀ2c, 3aꢀ3c) were isolated from the
stems of the creeping shrub Piper arborescens and exhibit in vitro
cytotoxicity against P-388, HT-29, and A549 cancer cell lines
(IC50 < 4 μg/mL).2c This family of natural products can be
classified into two distinct stereochemical classes: cisꢀtransꢀcis
(2aꢀ2c) and transꢀtransꢀtrans (3aꢀ3c), both arising from the
Received: September 29, 2011
Published: November 08, 2011
r
2011 American Chemical Society
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Scheme 1. Total Synthesis of Piperarborenine B (2b) and Piperarborenine D (3b)a
a Reagents and conditions: (a) 450-W Hanovia lamp, Pyrex filter, DCM, 15 °C, 96 h; then H2, Pt/C, 5 h; then 2-aminothioanisole, EDC, 0 to 23 °C, 3 h,
61%; (b) 9 (2.0 equiv), Pd(OAc)2 (0.15 equiv), Ag2CO3 (1.5 equiv), PivOH (1.0 equiv), HFIP, 90 °C, 36 h, 52%; (c) LiOtBu (1.0 equiv), PhMe, 50 °C,
36 h, 79% (>10:1 dr); (d) 12 (2.0 equiv), Pd(OAc)2 (0.15 equiv), Ag2CO3 (1.0 equiv), tBuOH, 75 °C, 36 h, 46%; (e) Boc2O, DMAP, MeCN, 5 h, 90%;
(f) LiOH, H2O2, THF/H2O, 50 °C, 24 h, 83%; (g) (COCl)2, DMF, THF, 2 h; 14 (3 equiv), PhMe, 4-Å MS, 80 °C, 12 h, 77%; (h) KHMDS (2.25 equiv),
THF, ꢀ15 °C, 3 min then aq NH4Cl, 65ꢀ80%; (i) 12 (2.0 equiv), Pd(OAc)2 (0.10 equiv), Ag2CO3 (1.0 equiv), PivOH (1.0 equiv), HFIP, 75 °C, 24 h,
81%; (j) NaOH, EtOH, 100 °C, 24 h, 86%; (k) (COCl)2, DMF, CHCl3, 2 h; 14 (3 equiv), PhMe, 4-Å MS, 80 °C, 4 h, 78%.
natural product could be envisioned. The all-cis cyclobutane 4
would arise from a controlled, single CꢀH arylation performed
on a symmetrical cyclobutane derived from acid 5. Although
double arylation of this substrate could easily derail this plan, it
was rationalized that the cis orientation of the ester and the
directing group would hinder the rate of the second arylation
due to steric and conformational effects. Furthermore, despite
the seemingly simple appearance of carboxylic acid 5, the liter-
ature preparation requires a lengthy, 8-step, nonstereocontrolled
sequence,11 making the first challenge a new synthesis of 1,3-
substituted cyclobutane dicarboxylates.
the anticipated overarylated product. After significant optimiza-
tion, the addition of hexafluoroisopropanol (HFIP) and pivalic
acid15 was found to be critical to the success of the reaction. This
allowed the desired cyclobutane 10 to be isolated in 52% yield
(1.0 g scale) with only trace amounts of overarylated byproduct
formed.
With the key intermediate 10 secured, efforts were directed
toward its divergent epimerization. Treatment with LiOtBu in a
nonpolar solvent selectively epimerized the C-1 stereocenter to
give cyclobutane 11 in 79% yield (1.6 g scale) with less than 10%
of undesired epimerization products observed. Alternatively, C-3
can be selectively inverted by treatment of 10 with 2.25 equiv of
KHMDS, followed by a quench of the resulting dianion with
ammonium chloride. The initial amide NꢀH deprotonation
allowed for exclusive ester enolate generation, giving 15 as a
single product and diastereomer in 65ꢀ80% yield,16 with its
relative stereochemistry confirmed by X-ray crystallographic
analysis.
With conditions secured to access either epimer, attention was
then turned to the second arylation event. To this end, epimer
11 underwent a second CꢀH arylation reaction with 3,4-
dimethoxyiodobenzene (12) in 46% yield (1.1 g scale) when
t-BuOH was employed as a solvent at high concentration (1 M).
Exclusive selectivity was observed for CꢀH insertion into the
methylene CꢀH bond over the tertiary benzylic CꢀH bond.17
Curiously, HFIP and pivalic acid, critical in the first CꢀH
arylation, resulted in inefficient cross-coupling for this substrate.
All that remained to complete the synthesis of piperarborenine
B (2b) was the conversion of the ester and the directing groups
into dihydropyridone rings. Using conditions developed by Evans
Maulide’s creative work on cyclobutene synthesis12a and
pioneering experiments by Corey on pyrone photochemistry12b
inspired the selection of methyl coumalate (6)13 as a potential
entry to acid 5. Since photochemical 4π electrocyclization to
intermediate photopyrone 7 is known,12c only two reductions
would be required to reach the desired product 5. After some
experimentation, hydrogenation with Pt/C as a catalyst was
found to reduce the photopyrone 7 to the desired carboxylic
acid 5 as a single diastereomer (Scheme 1). An EDC coupling
merged the directing group, 2-aminothioanisole,14 to the car-
boxylic acid and provided the CꢀH arylation substrate 8 (relative
stereochemistry confirmed by X-ray crystallographic analysis).
Notably, each step in this sequence was performed with DCM as
the solvent, allowing all three reactions to be telescoped as a
single operation in 61% isolated yield (1.0 g scale).
The selective CꢀH cross-coupling of 8 with 3,4,5-trimethoxy-
iodobenzene (9) proved to be a formidable challenge. Under
most conditions, the reaction was plagued with substantial
decomposition, poor catalyst turnover, and varying amounts of
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Scheme 2. Structural Revision of Piperarborenine Da
this particular substrate simply decomposed under most condi-
tions tested. After a small screen of photosensitizers and solvents,
20-acetonaphthone21 in acetonitrile furnished the desired photo-
product, albeit in low yield. The intermediate anhydride was
immediately converted into the corresponding dibenzyl ester
(20) for purification, and it was isolated in 21% yield over two
steps. Hydrogenolysis of the benzyl esters and coupling of the
crude diacid chloride to lithium salt 22 generated a product that
was spectroscopically identical to that reported for piperarbor-
enine D (21) in 32% yield.22
The short routes to 2b and 3b (7 steps, 7% overall yield; 6
steps, 12% overall) demonstrate the power of guided7g CꢀH
functionalization logic to enable a fundamentally new approach
to cyclobutane natural product synthesis. Notable elements of
the synthesis include the following: (1) a one-step, stereocon-
trolled preparation of 8 from methyl coumalate (6); (2) the first
example of catalytic transition metal-mediated CꢀH activation
on a cyclobutane ring; (3) the first example of sequential sp3
CꢀH arylation reactions performed in natural product synthesis;
(4) divergent epimerization of 10 to access both proposed
piperarborenine stereoisomers; and (5) reassignment of the
transꢀtransꢀtrans piperarborenines (3aꢀ3c) to head-to-head
cyclobutane dimers (e.g., 21).
a Reagents and conditions: (a) 17, 18, acetone, 5 min, 98%; (b) 450-W
Hanovia lamp, Pyrex filter, MeCN, 2-acetonaphthone (4 equiv), 48 h;
EDC (1.5 equiv), BnOH (3 equiv), DMAP (0.1 equiv), 12 h, 21% (over
2 steps); (c) Pd/C, H2, THF, 4 h, 98%; (d) (COCl)2, DMF, DCM, 4 h;
THF, 22, 0.5 h, 0 °C, 32%.
for mild amide bond hydrolysis,18 the directing group was car-
bamoylated (91%, 1.8 g scale) and cleaved with lithium hydro-
peroxide (83%, 1.8 g scale). Fortunately, the methyl ester also
hydrolyzed under these reaction conditions, and the carefully
constructed stereotetrad remained intact. After conversion of
both carboxylic acids to the corresponding acid chlorides and
heating with dihydropyridone (14) in the presence of 4-Å molec-
ular sieves,19 piperarborenine B (2b) was generated in 77%
isolated yield (100 mg scale) and matched the reported spectral
and experimental data.2b
In order to prepare the stereoisomeric piperarborenine D
(3b), epimer 15 was subjected to a second round of CꢀH
arylation with 12 to provide the desired compound 16 in 81%
isolated yield. The facility with which 15 was found to undergo a
second CꢀH arylation supports the proposed role of the methyl
ester stereochemistry during the previous monoarylation reac-
tion. Interestingly, pivalic acid and HFIP were once again pivotal
for the efficiency of this cross-coupling. Refluxing 16 with sodium
hydroxide in ethanol resulted in complete C-1 epimerization and
full hydrolysis to the bis-carboxylic acid in 86% yield. Conversion
to the bis-acid chloride and coupling with dihydropyridone (14)
resulted in the proposed structure of piperarborenine D (3b) in
78% yield; however, the obtained 1H and 13C NMR spectra did
not match the data given for 3 in the isolation paper.2c
A reexamination of the original spectral data revealed a
number of inconsistencies with the proposed structure, the most
glaring being the excessive number of 13C NMR peaks for a
compound that contains a σv plane of symmetry. Thus, an
unsymmetrical head-to-head type dimer (21) that is consistent
with the reported data was proposed, and its preparation was
pursued in order to confirm its structure. A simple, albeit un-
optimized, synthesis of this heterodimeric structure was devised
using an anhydride as a temporary tether for an intramolecular
[2+2] photocycloaddition (Scheme 2). The mixed anhydride
(19) was prepared in 98% yield by reacting 3,4-dimethoxycinna-
moyl chloride (17) with sodium 3,4,5-trimethoxycinnamate (18) in
acetone. While similar cinnamic anhydrides have been reported in the
literature to undergo facile intramolecular [2+2] photocycloaddition,20
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization data for all reaction and products, including 1H
NMR and 13C NMR spectra and CIF files. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
pbaran@scripps.edu
’ ACKNOWLEDGMENT
Financial support for this work was provided by the NIH/
NIGMS (GM-073949) and NSF (predoctoral fellowship to
W.R.G.). We thank Prof. A. Rheingold and Dr. Curtis E. Moore
for X-ray crystallographic measurements.
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