A Mixed-Ligand Chiral Rhodium(II) Catalyst Enables the Enantioselective Total Synthesis of Piperarborenine B

Article abstract of DOI:10.1002/anie.201600766

A novel, mixed-ligand chiral rhodium(II) catalyst, Rh₂(S-NTTL)₃(dCPA), has enabled the first enantioselective total synthesis of the natural product piperarborenine B. A crystal structure of Rh₂(S-NTTL)₃(dCPA) r

Full text of DOI:10.1002/anie.201600766

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International Edition: DOI: 10.1002/anie.201600766
German Edition: DOI: 10.1002/ange.201600766
Enantioselective Synthesis
A Mixed-Ligand Chiral Rhodium(II) Catalyst Enables the
Enantioselective Total Synthesis of Piperarborenine B
Robert A. Panish, Srinivasa R. Chintala, and Joseph M. Fox*
Abstract: A novel, mixed-ligand chiral rhodium(II) catalyst,
Rh2(S-NTTL)3(dCPA), has enabled the first enantioselective
total synthesis of the natural product piperarborenine B. A
crystal structure of Rh2(S-NTTL)3(dCPA) reveals a “chiral
crown” conformation with a bulky dicyclohexylphenyl acetate
ligand and three N-naphthalimido groups oriented on the same
face of the catalyst. The natural product was prepared on large
scale using rhodium-catalyzed bicyclobutanation/ copper-
catalyzed homoconjugate addition chemistry in the key step.
The route proceeds in ten steps with an 8% overall yield and
92% ee.
T
ruxillate and truxinate natural products exhibit diverse
biological activities. These molecules and their derivatives
display potential as therapeutic leads in areas including
oncology, neurology, infectious diseases, and respiratory
diseases.[1] Despite the significant number of natural lead
compounds, the underrepresentation[2] of cyclobutane-con-
taining drugs is a reflection of an area in organic chemistry
where concise, general and stereoselective methods for
cyclobutane synthesis are still needed.
Figure 1. Cyclobutane-containing natural products and drug leads.
Piperarborenine B,
a cyclobutane-containing natural
product isolated from Piper arborescens, has exhibited
activity against P-388, A-549, and HT-29 cancer cell lines
(IC50 = 0.13, 1.4, and 2.4 mm, respectively).[3] Other cyclo-
butane-containing natural products such as incarvillateine,[4,5]
pauferrol A[1d] and the synthetic SB-FI-26[6] have also exhib-
ited exciting biological activities, with the cyclobutane core
proving to be an essential feature.
There are several ways to access truxillate and truxinate
natural products, but most are focused on the preparation of
compounds with symmetrical cyclobutane cores. The photo-
chemical [2+2] reaction has factored significantly in the total
synthesis of symmetrical truxillic acid and related deriva-
tives,[7] including elegant solutions from crystal engineering[8]
and advances from redox photocatalysis.[9] Alternatively,
truxinic acid derivatives have been formed in modest
diastereoselectivity by [2+2] photocycloaddition in flow.[10]
However, direct photodimerization is extremely limited for
the construction of cyclobutane natural products where the
core is chiral and the alkene precursors are non-equivalent
such as the compounds displayed in Figure 1.[8b]
À
In recent years, catalytic C H activation methods have
factored prominently in the elaboration of cyclobutane
natural products.[11] Recently, Baran has shown that racemic
tri- and tetrasubstituted cyclobutanes can be prepared from
disubstituted cyclobutanes through sequential arylation and
vinylation reactions,[12] using directing groups and catalytic
conditions originally developed by Daugulis[11b,13] and also
popularized by Chen.[14] Baranꢀs synthesis of piperarboreni-
ne B showcased sequential cyclobutane C(sp ) H activation
to construct the unsymmetrical truxillate core. This approach
provided racemic piperarborenine B in 7% overall yield in 7
steps.
Several enantioselective approaches to unsymmetrical
cyclobutane cores have been described in recent years.[15–20]
Tang has reported the synthesis of the initially assigned
structures of pipercyclobutanamide A and piperchabamide G
via RhI-catalyzed conjugate addition of arylboronic acid to
a cyclobutenoate derived from enantiospecific cyclopropane
ring expansion.[15] Rh2(5S-MEPY)4-catalyzed cyclopropana-
tion was used to set the stereochemistry of the core in 80% ee.
This study revised the assignments to the six-membered ring
isomers chabamide and nigramide F, respectively.
3
À
[*] R. A. Panish, S. R. Chintala, Prof. J. M. Fox
Department of Chemistry and Biochemistry, University of Delaware
Newark, DE 19716 (USA)
Recently, our group has introduced a modular new
approach to chiral cyclobutane synthesis involving tandem
RhII-catalyzed enantioselective “bicyclobutanation”[21]/ CuI-
catalyzed homoconjugate addition of a-cinnamyl-a-diazoest-
E-mail: jmfox@udel.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600766.
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Scheme 1. Bicyclobutanation/homoconjugate addition strategy for
enantioselective cyclobutane synthesis.
Scheme 3. An efficient route to the substituted diazoester, 3.
ers (Scheme 1).[22,23] Inspired by the unique bioactivities of
a number of cyclobutane-containing natural products, we
sought to demonstrate the power of our strategy for
enantioselective synthesis of unsymmetrical cyclobutanes.
Additionally, we realized this would potentially enable rapid
diversification of complex cyclobutanes for SAR studies.
Herein, we report the first enantioselective total synthesis of
piperarborenine B (1). Critical to the synthesis was the
development of a new, chiral RhII-carboxylate complex that
catalyzes the key bicyclobutanation step with high enantio-
selectivity and turnover number. Additional key aspects of
the synthesis include improved “on water” conditions for
mol%).[24] Treatment of ketoester 2 with p-ABSA, and
NaOH in a mixture of acetonitrile/H2O provided the desired
diazoester 3 in 47% yield over three steps. This three step
process for diazoester synthesis was accomplished in one day
and represents an efficient new strategy for a-allyl-a-diazo-
ester synthesis.
Recently, our group[22] and that of Davies[21] have
described complementary catalyst systems for enantioselec-
tive bicyclobutanation. Our system provides access to tert-
butyl bicyclobutane carboxylates that can be combined in situ
with Grignard reagents to produce functionalized, enantio-
merically enriched cyclobutanes.[22] In our previous work, we
described Rh2(S-NTTL)4 as an effective catalyst for bicyclo-
butanation in terms of enantioselectivity and yield. However,
our efforts to apply this catalyst produced the bicyclobutane
intermediate 4 in only 84% ee (Scheme 4). Screening efforts
with other symmetrical catalysts were unsuccessful (see
Supporting Information for full optimization table).
À
cyclobutane C H activation and a streamlined route that was
used to produce the natural product on 400 mg scale in only
one week from veratraldehyde.
Retrosynthetically, we envisioned the a-truxillate core of
À
7 arising from a Baran late stage C H activation using
a properly installed directing group (Scheme 2). The stereo-
triad 5 would be constructed using our previously developed
enantioselective bicyclobutanation/ homoconjugate addition
chemistry. The required diazoester 3 would arise from
commercially available veratraldehyde using a Tsuji–Trost
allylation in a key step.
Scheme 4. RhII-catalyst screening and enantioselective synthesis of
vinylcyclobutane, 5.
Scheme 2. Retrosynthetic strategy for the enantioselective synthesis of
piperarborenine B.
Recently, our group described the mixed-ligand RhII-
catalyst, Rh2(S-PTTL)3(TPA), a dirhodium paddlewheel
complex that is substituted by three chiral ligands and one
achiral ligand.[25] This catalyst displayed superior results in
certain enantioselective cyclopropanation, cyclopropenation
and indole functionalization reactions. Our computational
and crystallographic studies showed that it adopts a “chiral
crown” conformation, where the N-phthalimido groups are
all presented on the same face. In the bicyclobutanation of 3,
Rh2(S-PTTL)3(TPA) gave the bicyclobutane 4 in a promising
60% ee. We speculated that replacing TPA with a ligand that
The synthesis commenced by developing a synthesis of the
diazoester (3). Several efficient routes to the compound were
developed (see supporting information). In the most time and
scale efficient route (Scheme 3), veratraldehyde was treated
with vinylMgBr to provide a vinyl alcohol that was shown to
be an effective substrate for an “on water” Tsuji–Trost
allylation of tert-butyl acetoacetate using Pd(OAc)2 (2
mol%), PPh3 (10 mol%), and adamantoic acid (10
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makes non-covalent contacts between the chiral ligand and
a separable diastereomer derived from the minor diastereo-
mer of 5.
substrate may be beneficial to asymmetric induction. We
further speculated that a large achiral ligand may rigidify the
chiral crown arrangement of the chiral ligands. Accordingly
À
Initial attempts at C H activation using known condi-
tions[12a] (Ar-I, Pd(OAc)2, Ag2CO3, tert-BuOH, 758C) pro-
vided the arylated product in 45% yield and incomplete
conversion of starting material. Gratifyingly, we discovered
that the yield was significantly improved by running the
reaction “on water”.[26] Thus, the combination of 3,4,5-
trimethoxyiodobenzene, Pd(OAc)2, PivOH, and K2CO3 on
we designed
a
new mixed-ligand RhII-catalyst, Rh2(S-
NTTL)3(dCPA), which contains a bulky dicyclohexylpheny-
lacetate group (dCPA) as the achiral ligand. A crystal
structure of Rh2(S-NTTL)3(dCPA) revealed that the chiral
crown conformation was conserved with the bulky dCPA
ligand. As shown in Figure 2, the N-naphthalimido groups are
water gave the desired cyclobutane
7 in 69% yield
(Scheme 5). These conditions avoid the use of Ag2CO3 and
Figure 2. X-ray crystal structure of Rh2(S-NTTL)3(dCPA).[28]
oriented on the same face of the catalyst with the sterically
demanding tert-butyl groups on the opposite face blocking
reactivity on the bottom face of the catalyst. Indeed, this new
mixed-ligand complex gave 92% ee and 79% yield of the
bicyclobutane. With this optimal catalyst in hand, we used it in
the key step in a one-pot bicyclobutanation/ homoconjugate
addition sequence to assemble the core of piperarborenine B.
Hence, treatment of diazoester 3 with 0.1 mol % Rh2(S-
NTTL)3(dCPA) at À788C in toluene followed by cuprate
addition using CuBr·SMe2, PPh3, and 2-methyl-1-propenyl-
magnesium bromide in THF provided the desired trisubsti-
tuted cyclobutane 5 in 69% yield, 92% ee and 4:1 d.r. after
kinetic protonation with BHT.
In order to set the desired stereochemical relationship of
the cyclobutane ring, kinetic protonation with a bulky proton
source was required. BHT was an effective proton source
providing the desired diastereomer in 4:1 d.r..[22] An even
higher 6:1 d.r. was obtained with the sterically demanding 2,6-
di(adamantan-1-yl)-4-(tert-butyl)phenol, but unfortunately
this high selectivity was poorly reproducible upon scale up.
For this reason, BHT was chosen for large scale synthesis of
the enantiomerically enriched cyclobutane 5, which was
prepared in gram quantities.
À
Scheme 5. Directing group installation, Pd-catalyzed C H activation
and hydrolysis via lithium hydroperoxide.
also proceed considerably faster with full consumption of
starting material after 12 h (as opposed to 45% yield and
80% conversion after 36 h in tert-BuOH at 758C). Running
the reaction neat led to a slightly diminished 56% yield.
Interestingly, microwave heating at 1008C resulted in 55%
yield with incomplete conversion after only 20 minutes but
was not further investigated due to scalability limitations of
our microwave reactor.
The directing group was removed by converting to the
Boc-amide followed by hydrolysis with lithium hydroperox-
ide.[12a,27] The remaining tert-butylester monoacid was treated
with TFA to afford the diacid 8. The synthesis of piperarbor-
enine B was completed by dihydropyridinone addition to in
situ generated diacyl chloride in 75% yield (Scheme 6).
We next sought to install the amide directing group to
À
facilitate subsequent Pd-catalyzed C H activation. The
carboxylate functionality was unveiled by an ozonolysis/
Pinnick oxidation sequence. First, vinylcyclobutane 5 was
treated with O3 in the presence of 1,3,5-trimethoxybenzene,
an additive found to suppress over-oxidation of the electron-
rich 1,2-dimethoxyphenyl group. After reductive quench with
PPh3, the aldehyde intermediate was oxidized to the carbox-
ylic acid by Pinnick oxidation. The crude carboxylic acid was
used in a HATU-enabled coupling with 2-(methylthio)aniline
to install the desired directing group providing cyclobutane 6
in 66% yield, along with an additional 14% yield of
Scheme 6. Completion of piperarborenine B.
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In conclusion, the highly efficient, enantioselective total
synthesis (8% overall yield) can be completed in only one
week to produce 400 mg of the natural product, piperarbor-
enine B. Key features include a new protocol for a-allyl-a-
diazoester synthesis that can be completed in one day while
avoiding unstable intermediates. A new mixed-ligand RhII-
catalyst was designed, synthesized and demonstrated to be
effective for the key bicyclobutanation step in 92% ee with
only 0.1 mol % of the catalyst. This catalytic enantioselective
reaction can be employed in a one-pot bicyclobutanation/
homoconjugate addition cascade to establish the cyclobutane
À
core. “On water” conditions for cyclobutane C H activation
were found to be particularly effective in forming the
truxillate core. The use of aqueous media factored prom-
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À
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Acknowledgements
We thank the NSF (CHE 1300329, CHE 0840401, CHE-
1229234, CHE-1048367) for funding and the NIH
(P20GM104316,
P30GM110758,
S10RR026962-01,
S10OD016267-01) for instrumentation. R.A.P. thanks NIH
T32GM008550 for a training grant. We are grateful to Glenn
Yap for the determining the crystal structure of Rh2(S-
NTTL)3(dCPA).
Keywords: bicyclobutane · chiral rhodium catalyst ·
homoconjugate addition · piperarborenine B ·
strained molecules
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Received: January 22, 2016
Published online: March 15, 2016
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