Biomimetic dehydrogenative diels-alder cycloadditions: Total syntheses of brosimones A and B

Article abstract of DOI:10.1002/anie.201302847

Passing (H₂) gas: Concise syntheses of the natural products brosimones A and B have been achieved using sequential dehydrogenative Diels-Alder (DHDA) cycloadditions. The syntheses employ either Pt/C-cyclopentene or DDQ to effect dehydrogenation of prenylchalcone substrates in combination with silver nanoparticles to promote subsequent Diels-Alder cycloadditions. Copyright

Full text of DOI:10.1002/anie.201302847

Angewandte
Chemie
Communications
Natural Product Synthesis
C. Qi, H. Cong, K. J. Cahill, P. Mꢀller,
R. P. Johnson,
J. A. Porco*
&&&& — &&&&
Biomimetic Dehydrogenative Diels–Alder
Cycloadditions: Total Syntheses of
Brosimones A and B
Passing (H2) gas: Concise syntheses of
the natural products brosimones A and B
have been achieved using sequential
dehydrogenative Diels–Alder (DHDA)
cycloadditions. The syntheses employ
either Pt/C-cyclopentene or DDQ to effect
dehydrogenation of prenylchalcone sub-
strates in combination with silver nano-
particles to promote subsequent Diels–
Alder cycloadditions.
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DOI: 10.1002/anie.201302847
Natural Product Synthesis
Biomimetic Dehydrogenative Diels–Alder Cycloadditions:
Total Syntheses of Brosimones A and B**
Chao Qi, Huan Cong, Katharine J. Cahill, Peter Mꢀller, Richard P. Johnson, and John A. Porco
Jr.*
Nature creates an intriguing array of molecular architectures
that has attracted extensive investigations on natural product
identification, origin, biological activities, and chemical syn-
thesis.[1] In particular, biosynthetic studies have inspired
elegant biomimetic total synthesis of natural products.[2]
Herein, we report biomimetic syntheses of the natural
products brosimones A and B featuring multicatalytic,[3]
dehydrogenative Diels–Alder (DHDA) cycloadditions[4] of
2’-hydroxychalcones.
Scheme 1. Proposed biosynthesis of artonin I (1).
Prenylflavonoid Diels–Alder natural products,[5] mainly
isolated from the root bark of mulberry trees (Morus alba),
are biosynthetically derived from electron-rich 2’-hydroxy-
chalcone dienophiles and flavonoid dienes. Pioneering studies
by Nomura and co-workers have determined that the
requisite diene subunits arise from prenyl groups in nature.
In one key experiment,[6] the natural product artonin I (1) was
isolated from Morus alba cell extract after both prenylated
flavone 2 and chalcone 3 were fed to cell culture (Scheme 1).
As part of our continuing interest[7] in the total synthesis
of prenylflavonoid Diels–Alder and related natural prod-
ucts,[8] we have recently reported silica-supported silver
nanoparticles (AgNPs)[9] as a highly efficient catalyst for
[4+2] cycloadditions of 2’-hydroxychalcones. Inspired by the
aforementioned biosynthesis studies, further investigation
was directed to the development of catalysts that enable
biomimetic DHDA cycloadditions employing prenyl groups
as diene precursors. In this regard, we envisioned tandem
reactions that employ one catalyst system to promote
dehydrogenation of prenyl groups to 1,3-substituted
dienes[10] in combination with silica-supported AgNPs to
catalyze Diels–Alder cycloadditions of chalcone dienophiles
and in situ-generated dienes.
Brosimones A (4)[11] and B (5)[12] were both isolated from
the plant Brosimopsis oblongifolia in Brazil and feature
dimeric structures derived from prenyl chalcone
7
(Scheme 2). The intriguing biosynthetic relationship and
structures of the brosimones, in particular the [3.3]metacy-
clophane core[13] of 4, underscores the compounds as attrac-
tive targets for further development of DHDA cycloadditions.
Our initial studies began with model reactions using
prenyl chalcone 8. After screening a number of catalysts and
oxidants,[14] we observed that the desired dehydrogenative
cycloaddition was catalyzed by a mixture of platinum on
activated carbon (Pt/C)[15] and silica-supported AgNPs in an
ambient air atmosphere (Table 1, entry 1), which afforded
cycloadducts exo-9 and endo-10 in 52% combined yield. We
also examined hydrogen scavengers for transfer dehydrogen-
ation, including cyclopentene[16] (entry 3) and norbornene[17]
(entry 6). Use of cyclopentene afforded the best yield and
mass balance and was chosen as the optimal hydrogen
[*] C. Qi,[+] H. Cong,[+] Prof. Dr. J. A. Porco Jr.
Department of Chemistry and Center for Chemical Methodology
and Library Development (CMLD-BU), Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
E-mail: porco@bu.edu
K. J. Cahill, Prof. Dr. R. P. Johnson
Department of Chemistry, University of New Hampshire
Durham, NH 03824 (USA)
P. Mꢀller
Department of Chemistry, Massachusetts Institute of Technology
Boston, MA 02139 (USA)
[+] These authors contributed equally to this work.
[**] Financial support from the NIH (GM-099920), NSF (CHE-0910826),
and AstraZeneca (graduate fellowship to H.C.) is gratefully
acknowledged. We thank Dr. Jeffery Bacon (Boston University) for X-
ray crystal structure analyses, Prof. Irene Messana (University of
Cagliari) for providing authentic spectra for natural brosimones, and
Mark Muncey (Gilson) for assistance with the Gilson PLC 2020.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302847.
Scheme 2. Biomimetic synthetic design for brosimones A and B.
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Table 1: Development of the initial methodology employing a model
brosimone B were in agreement with those reported by
prenylchalcone.[a]
Messana and co-workers for the natural product.[12] Methyl-
ation of 5 afforded protected derivative 14, the structure of
which was determined by X-ray crystal-structure analysis.[20]
We next studied dehydrogenative cycloaddition of exo-12
to access brosimone A (4) (Scheme 4). Treatment of exo-12
Entry
Hydrogen scavenger
Conversion[b]
endo-10/exo-9[b]
1
air (1 atm)
O2 (1 atm)
88% (52%)[c]
79% (60%)[c]
66% (61%)[c]
<10%
52:48
57:43
42:58
–
72:28
50:50
55:45
2[d]
3
cyclopentene (9 equiv)
cyclopentene (9 equiv)
cyclopentene (9 equiv)
norbornene (10 equiv)
none
4[e]
5[f]
6
38% (8%)[c]
76% (44%)[c]
40% (18%)[c]
7
[a] See the Supporting Information for experimental details. [b] Based on
integration of signals in the 1H NMR spectrum. [c] Yield of isolated
product shown in parentheses. [d] 5 mol% Pt/C, 0.1 mol% AgNP. [e] In
the absence of Pt/C. [f] In the absence of AgNPs.
scavenger. Control experiments showed that reactions with
cyclopentene did not proceed without Pt/C (entry 4) and were
significantly less efficient in the absence of AgNPs (entry 5).
The use of AgNP catalyst also promotes enhanced formation
of the desired exo diastereomer 9 (entries 3 and 5), which may
be explained by conversion of endo-10 to exo-9 under AgNP-
catalyzed conditions.[14] Use of Lewis acids such as BF3·Et2O
and AgOTf in place of the AgNPs afforded trace amounts of
dehydrogenative cycloaddition products.[14]
Scheme 4. Dehydrogenative cycloadditions to access cycloadducts exo-
endo-15, 16, and exo-exo-19. a) DDQ (1.6 equiv), AgNP (0.3 mol%),
PhCl, 908C, 48 h, exo-endo-15, 17%, 16, 34%; b) DDQ (1.5 equiv),
AgNP (0.3 mol%), PhCl, 1308C, 72 h, 62%, d.r. >20:1; c) AgNP
(0.3 mol%), PhCl, 1308C, 48 h, 95%; d) AgNP (0.4 mol%), PhCl,
1308C, 48 h, 84%.
With a model reaction established, DHDA cycloaddition/
dimerization of 11 using the optimized Pt/C-AgNP conditions
with cyclopentene as H2 scavenger afforded the cycloadducts
exo-12 and endo-13 (1.2:1) in 64% yield.[14] Transfer hydro-
genolysis of exo-12 was accomplished employing 1,4-cyclo-
hexadiene as hydrogen donor to afford brosimone B (5) with
the trisubstituted olefin remaining intact (Scheme 3).[18] Use
of ammonium formate[19] as additive was found to further
accelerate the hydrogenolysis. Spectral data for synthetic
with catalytic Pt/C and AgNPs in combination with cyclo-
pentene as H2 scavenger did not lead to substantial formation
of desired cycloadducts, even at temperatures up to 1308C.
After screening a series of reaction parameters, we found that
in the presence of excess 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ)[4f,21] and AgNPs as catalyst, exo-12 was
converted into the cycloadduct exo-endo-15[22] in 17% yield
using chlorobenzene as solvent at 908C. Furthermore, the
DDQ adduct 16 was isolated in 34% yield, which further
supported the intermediacy of diene 17.[23] In a similar
fashion, treatment of prenylchalcone 11 with DDQ in the
absence of AgNPs afforded DHDA adduct 18 in 55% yield
and 5:1 d.r., with no exo-12 or endo-13 observed (Scheme 5,
major endo diastereomer shown). The structure and stereo-
chemistry of 18 were confirmed by X-ray crystallography.[20]
Further experiments revealed that increasing the reaction
temperature (1308C) for DHDA of exo-12 in the presence of
Scheme 3. Synthesis of brosimone B. a) Pt/C (10 mol%), AgNP
(0.2 mol%), cyclopentene, 1,2-dichloroethane (DCE), 1108C, 48 h,
64%, endo-13:exo-12=1:1.2; b) Pd/C (40 mol%), HCO2NH4 (2 equiv),
1,4-cyclohexadiene, acetone, 408C, 24 h, 85%; c) K2CO3, Me2SO4,
acetone, 408C, 4 h, 15%. Bn=benzyl.
Scheme 5. DDQ-derived cycloadduct formation. a) DDQ (2.1 equiv),
DCE, 908C, 24 h, 55%, d.r. =5:1.
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AgNPs predominantly afforded exo-exo-cycloadduct 19 in
62% yield (Scheme 4). Replacement of AgNPs with Lewis
acids led to inferior results. Substantial decomposition
occurred with BF3·Et2O, Cu(OTf)2,[24] or In(OTf)3
as
[25]
Lewis acids; a 7% yield of 19 was obtained using AgOTf
(20 mol%) as catalyst. Cycloadduct 19 was not observed in
a control experiment with silica gel at 1308C, demonstrating
the utility of AgNPs to access brosimone A derivative 19.[14]
Further studies showed that DDQ adduct 16 could be
converted into exo-exo-19 in 84% yield under AgNP-
catalyzed conditions, which suggested tandem retro-Diels–
Alder/Diels–Alder processes[8a] consistent with temperature-
dependent stereoselectivity affording exo-endo-15 (kineti-
cally favored product) and exo-exo-19 (thermodynamically
favored product). Moreover, exo-endo-15 was converted
exclusively into exo-exo-19 under AgNP-promoted conditions
at 1308C. A control experiment without AgNPs also showed
trace conversion of 15 to 19, reinforcing the fact that AgNPs
may facilitate tandem retro-Diels–Alder/Diels–Alder pro-
cesses.
Final hydrogenolysis of exo-exo-19 afforded brosimone A
(4) in 91% yield (Scheme 6). Methylation of 4 afforded
hexamethylether 20, which allowed unambiguous structure
and stereochemical assignments for synthetic brosimone A
(4) based on X-ray crystallography.[20] The X-ray structure of
20 revealed a C2-symmetric syn-[3,3]metacyclophane[26] struc-
ture with slightly distorted aromatic rings[13] (f Ca-Cb-Cc-Cd =
6.48).
Our previous studies provided strong evidence for an
electron-transfer mechanism for AgNP-catalyzed Diels–
Alder cycloadditions.[9a] A simplified computational model
for AgNP-catalyzed cycloadditions was constructed using the
corresponding diene of substrate 14, which was found to have
similar reactivity to hexabenzylether 12 (Scheme 7).[14] Den-
sity functional theory was used to predict the energetics of
cycloaddition by different mechanisms. The lowest barriers
were observed for a process that involved one electron
substrate oxidation, deprotonation of the phenol, and com-
plexation of the resultant radical with AgI on the surface of
Scheme 7. Model reactions for calculations. a) DDQ (1.5 equiv), AgNP
(0.2 mol%), PhCl, 1308C, 72 h, 72%; b) DDQ (1.5 equiv), AgNP
(0.2 mol%), PhCl, 908C, 48 h, 15%; c) AgNP (0.2 mol%), PhCl,
1308C, 48 h, 94%.
the AgNPs.[27] Figure 1 shows the energetics of stepwise
intramolecular cycloadditions[28] to yield the observed cyclo-
adducts. Our predicted reaction energetics and calculated
transition states[14] support the observation that the exo-endo-
syn stereoisomer (exo-endo-15, Scheme 4) is the kinetic
product, which may be converted to the more thermodynami-
cally stable exo-exo-syn diastereomer (exo-exo-19, Scheme 4)
through cycloreversion. Pathways to exo-exo-anti and exo-
endo-anti products (Scheme 7), which were not observed
experimentally, lie at higher energy.[14]
In summary, we have developed biomimetic, dehydrogen-
ative Diels–Alder (DHDA) cycloadditions that have enabled
concise syntheses of the natural product brosimone B and the
[3.3]metacyclophane natural product brosimone A. The syn-
Scheme 6. Synthesis of brosimone A. a) Pd/C (60 mol%), HCO2NH4
(2 equiv), HCO2H, 1,4-cyclohexadiene, acetone, 408C, 24 h, 91%;
b) K2CO3, MeI, acetone, 408C, 12 h, 13%.
Figure 1. B3LYP/LANL2DZ energetics of AgNP-catalyzed cycloaddi-
tions.
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[9] For [4+2] cycloadditions with AgNPs, see: a) H. Cong, C. F.
theses employ Pt/C-cyclopentene or DDQ to effect dehydro-
genation of prenylchalcones in combination with silver nano-
particles to promote subsequent Diels–Alder cycloaddition.
Experiments confirmed the formation of a kinetic exo-endo
diastereomer of a protected form of brosimone A, which
could be converted to a thermodynamic exo-exo isomer using
AgNPs at higher temperature. Density functional theory was
used to predict the energetics of AgNP-catalyzed cycloaddi-
tions; the lowest barriers were observed for a process
involving one electron oxidation, phenol deprotonation, and
complexation of the resultant radical with AgI on the surface
of the AgNP. Further applications of dehydrogenative Diels–
Alder cycloadditions and reaction development using silver
nanoparticles are ongoing and will be reported in due course.
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Received: April 5, 2013
Revised: May 24, 2013
Published online: && &&, &&&&
Keywords: brosimone · dehydrogenative cycloaddition ·
.
Diels-Alder cycloaddition · nanoparticle catalysts ·
natural product synthesis
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