Rapid synthesis of polyprenylated acylphloroglucinol analogs via dearomative conjunctive allylic annulation

Article abstract of DOI:10.1021/ja5060302

Polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. Herein, we present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via double decarboxylative allylation (DcA) of acylphloroglucinol scaffolds to access allyl-desoxyhumulones followed by dearomative conjunctive allylic alkylation (DCAA).

Full text of DOI:10.1021/ja5060302

Article
pubs.acs.org/JACS
Open Access on 07/25/2015
Rapid Synthesis of Polyprenylated Acylphloroglucinol Analogs via
Dearomative Conjunctive Allylic Annulation
Alexander J. Grenning, Jonathan H. Boyce, and John A. Porco, Jr.*
Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590
Commonwealth Ave., Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: Polyprenylated acylphloroglucinols (PPAPs)
are structurally complex natural products with promising
biological activities. Herein, we present a biosynthesis-inspired,
diversity-oriented synthesis approach for rapid construction of
PPAP analogs via double decarboxylative allylation (DcA) of
acylphloroglucinol scaffolds to access allyl-desoxyhumulones
followed by dearomative conjunctive allylic alkylation
(DCAA).
dearomative prenylation and (b) alkene-intercepted prenylation
(Scheme 1).1 Union of the prenyl fragments with the
INTRODUCTION
■
Polyprenylated acylphloroglucinol (PPAP) natural products
including nemorosone, clusianone, and hyperforin are structur-
ally complex molecules having promising chemotherapeutic
properties (Figure 1).1,2 As such, their laboratory syntheses
Scheme 1. Biosynthetic Hypothesis for PPAP’s
phloroglucinol at either the 2- and 4-positions or the 4- and
6-positions yields nemorosone (arbitrary absolute configuration
shown) or clusianone, respectively. Generally speaking, this
isomeric difference is referred to as “type A” and “type B”
throughout this family. Thus, hyperforin is a “type A” PPAP
through union of the phloroglucinol core to a geranyl fragment
(dearomatization) and a prenyl cation (cascade bicyclo[3.3.1]-
nonane assembly). Although the biosynthesis is efficient and
complexity generating, it has yet to be realized in a laboratory
setting.3
We hypothesized that Pd-catalyzed dearomative conjunctive
allylic annulation (DCAA) of desoxyhumulones 1 and 2-
methylene-1,3-propanediol derivative 2 would serve as an
efficient biosynthesis-inspired, diversity-oriented strategy to
access a plethora of PPAP analogs 3 possessing many of the
essential structural features for bioactivity (Scheme 2).2 Such an
approach to PPAP core structures would take advantage of
biosynthetic, innate reactivity8,9 (phloroglucinol dearomatiza-
tion, allylic alkylation) and utilize the predictably reactive
reagent 2 which has been utilized extensively in conjunctive
Figure 1. Representative PPAP natural products.
have received considerable attention.3 PPAPs are highly
regarded for their biological activities1 which include
anticancer,2b−e,g,h antiviral,2f and antibacterial2i properties.
Bottlenecks toward their applications in disease treatment are
stability issues,4 synthetic challenges,3 and promiscuous bio-
logical activity.1e Thus, medicinal chemistry and biological
evaluation of novel analogs within the PPAP family are of high
interest but have been underdeveloped.3m,5 With these
challenges in mind, we sought to develop a route that was
both chemically efficient and applicable to diversity-oriented
synthesis (DOS).6
As expertly penned by Mulzer in a recent review,7 there are
numerous tactics to render a given synthesis efficient including
biosynthetic considerations. By considering a biosynthetic
hypothesis for a natural product, often innate reactivity can
be exploited, ideally resulting in an efficient synthetic strategy.
In the case of PPAPs, the molecules are presumed to be derived
from three building blocks: a desoxyhumulone substrate such as
1 and two additional prenyl cation equivalents which react
distinctly to assemble the bicyclo[3.3.1]nonane core via (a)
Received: June 16, 2014
Published: July 25, 2014
© 2014 American Chemical Society
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Scheme 2. A Biosynthesis-Inspired DOS Approach to PPAP
Analogs
Scheme 5. Double DcA/Formal Claisen Rearrangement
specificity of the DcA process.15,16 The Pd-catalyst could then
trigger a “formal” Claisen rearrangement under mild conditions
via allyl phenyl ether ionization17 and concomitant C-allylation
to provide product 1a (Scheme 5).
To examine the possibility for a mild Pd-catalyzed double
decarboxylative allylation/Claisen rearrangement sequence
yielding desoxyhumulones 1, we prepared the requisite starting
material 6a in >95% yield from 2-benzoylphloroglucinol 4a and
allyl chloroformate.18 Excitingly, we found that a highly efficient
reaction of 6a to the desired product 1a occurred using 1 mol
% Pd(PPh3)4 in cyclohexane (CyH) at 75 °C for 2h (Table 1,
bond-forming processes.10 Herein, we report our initial
discoveries enabling the rapid construction of diverse PPAP
analogs for biological evaluation through this modular and step-
economic sequence.
ALLYL-DESOXYHUMULONE SCAFFOLD
SYNTHESIS VIA DOUBLE DECABOXYLATIVE
ALLYLATION
■
In order to realize a diversity-oriented approach to PPAP-type
structures, it was necessary to establish a modular, scalable, and
robust route to allyl-desoxyhumulone scaffolds 1. The synthesis
of allyl desoxyhumulone 1a, a common intermediate en route
to the natural products plukenetione A, 7-epi-nemorosone, and
(−)-clusianone (Scheme 3A),3g,l,p has been achieved by direct
Table 1. Development of Double DcA/Formal Claisen
Rearrangement
Scheme 3. Utility and Challenges Associated with Allyl-
Desoxyhumulone 1a
entry
solvent
temp (°C) time (h) product yield (%) [conv. (%)]
a
1
2
3
4
5
CyH
CyH
75
75
2
1a
7a
7a
7a
1a
87
b
b
b
5 min
[100]
[100]
[100]
CH2Cl2
THF
40
1
1
1
66
a
toluene
110
64
a
b
Isolated yields after silica gel chromatography. Percent conversion as
1
determined by H NMR analysis.
entry 1). Of note, reaction for 5 min under the same conditions
resulted in complete conversion to the O-allylated byproduct
7a confirming its intermediacy en route to product 1a.
Regarding other solvents, CH2Cl2 and THF yielded only O-
allylated products (Table 1, entries 3 and 4), whereas toluene
was also found to be a competent solvent for desoxyhumulone
scaffold synthesis (Table 1, entry 5).
C-allylation of 2-acylphloroglucinol 4a with allyl bromide in
low yield due to overalkylation11 or by selective O-allylation
then Claisen rearrangement requiring temperatures exceeding
200 °C (Scheme 3B).
Generally speaking, allylated phenols 5 can be accessed
through high-temperature (>200 °C) or Lewis acid promoted
[3,3]-allyl phenyl ether Claisen rearrangements (Scheme 4).12
To confirm that Pd(PPh3)4 is involved in the mild allyl aryl
ether Claisen rearrangement, we prepared 7a via DcA of 6a and
resubjected it to the reaction conditions sans the palladium
catalyst. Not surprisingly, no conversion was observed. Upon
addition of the palladium catalyst under the optimized
conditions (cyclohexane, 75 °C), conversion to 1a commences
(Scheme 6).
Scheme 4. Alternative Approaches to C-allylated phenols
Scheme 6. Requirement of Pd(0) for [3,3]-Allyl Aryl Ether
Claisen Rearrangement
Due to the sensitivity of acylphloroglucinols and desoxyhumu-
lones, we wondered if a relatively low-temperature and neutral
formal allyl phenyl ether Claisen rearrangement could be
achieved via Pd(0)-catalysis. As shown in Scheme 5, we
envisioned access to desoxyhumulones via Pd-catalyzed
decarboxylative allylation (DcA)13 which should controllably
generate diallyl phenyl ether14 7a in accord with the site-
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Regarding the scope of allyl-desoxyhumulone synthesis via
double DcA/formal Claisen rearrangement, phloroglucinols
with a variety of 2-acyl groups were found to be compatible
coupling partners (Scheme 7A). For example, desoxyhumu-
Scheme 8. Related Scaffolds for Pd-Catalyzed DcA
Scheme 7. Scope of Allyl-Desoxyhumulone Synthesis
Claisen rearrangement regardless of the reaction duration
(Scheme 8A). In addition, the double DcA/Claisen rearrange-
ment was extended to the chrysin-derived flavone scaffold 9a
under slightly modified conditions (Scheme 8B). From the
commercially available flavone chrysin, we prepared 6,8-
diallylchrysin20 1n without silica gel chromatography in 99%
yield over the two-step sequence via intermediate 9a.
BIOSYNTHESIS-INSPIRED, DIVERSITY-ORIENTED
SYNTHESIS OF PPAP ANALOGS
■
With a variety of desoxyhumulone scaffolds 1a−1j in hand,
many of which were prepared in multigram quantities, we next
turned to the development of the key dearomative conjunctive
allylic annulation (DCAA) to provide a diversified set of PPAP
analogs. Using the model coupling reaction between 1a and 2,
we began our quest for the optimal Pd catalyst, solvent, and
reaction conditions (Table 2). Mono-methyl allyl desoxyhumu-
Table 2. Development of DCAA
entry
solvent
temp (°C) time (h)
catalyst
yield (%)
lones 1a−1d having 2-benzoyl-, acetyl-, isobutyryl-, and
isovaleroyl groups were prepared. Internal allylic substitution
proceeded as desired to afford products 1e and 1f; however,
terminally substituted allylic coupling partners (e.g., cinnamyl
and prenyl) afforded complex mixtures.19 Excitingly, the
reaction could be extended to related aromatic starting
materials such as resorcinol 1g and orcinols 1h−1j.
Importantly, a variety of large-scale (gram−multigram scale)
reactions were performed for each of the compatible scaffolds
identified (phloroglucinols 1a/d, resorcinol 1g, and orcinol
1h). All multigram scale reactions were successful with reduced
catalyst loading (0.25 mol % Pd(PPh3)4) at an increased
concentration (0.5 M in cyclohexane). To broaden substrate
scope and further enhance the diversity of PPAP analogs for
our investigation, we also removed the O-methyl group on 1a,
1b, and 1d with BBr3 to access the unprotected variants 1k−1m
(Scheme 7B).
a
c
1
CyH
toluene
DCE
75
100
80
0.5
1
Pd(PPh3)4
87
81
b
d
2
Pd/BINAP
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd/BINAP
Pd/BINAP
e
3
4
5
6
7
0.5
0.5
0.5
24
24
trace
e
toluene
THF
80
trace
e
65
trace
CyH
75
68
80
THF
65
a
b
c
Standard conditions A. Standard conditions B. 2.5 mol %
d
Pd(PPh3)4. 2 mol % Pd2dba3, 4 mol % rac-BINAP, premixed in
e
reaction solvent for 10 min, Δ. Determined by 1H NMRof the crude
reaction mixture.
lone 1a was chosen as an initial scaffold as it was thought, based
on our previous studies,3g that the methyl ether would direct
the annulation to the 2- and 4-positions of the substrate (“type
A” annulation).
In addition to the synthesis of desoxyhumulones 1a−1m via
DcA/formal Claisen rearrangement, we also investigated the
synthesis of related scaffolds (Scheme 8). Interestingly, we
found that the mono-allyl phenyl carbonate 8a only underwent
DcA to provide allyl phenyl ether 8b under the optimized
conditions and did not undergo formal allyl phenyl ether [3,3]-
We ultimately identified two standard conditions (A and B,
Table 2, entries 1 and 2) that were utilized throughout our
studies to construct PPAP analogs. Standard conditions A
(Pd(PPh3)4, cyclohexane) were found to be highly solvent
dependent as related conditions in DCE, toluene, and THF did
not produce the desired product (Table 2, entries 3−5).
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Standard conditions B (Pd/BINAP) appeared to be more
tolerant to solvent choice, though reaction times were found to
be significantly longer in lower boiling solvents such as
cyclohexane and THF (Table 2, entries 6 and 7).
Scheme 10. “Type B” PPAP Analogs via DCAA
Interestingly, using either the methylated (1a−1f, Scheme
7A) or the nonmethylated (1k−1m, Scheme 7B) desoxy-
humulone scaffolds, either “type A” or “type B” PPAP
structures could be selectively prepared (Schemes 9 and 10,
Scheme 9. “Type A” PPAP Analogs via DCAA
A and B” PPAPs 3 as shown for prenylated variants 3ca
(Scheme 9B) and 3ma (Scheme 10B) in excellent yields. All
products 3 led to selective prenylation of the monosubstituted
allyl groups leaving the exo-methylene intact.22 Removal of the
methyl enol ether could be accomplished in good yield
revealing the vinylogous acid functionality commonly found in
PPAP natural products (Scheme 9B). We opted to store the
vinylogous acid 3ca as its dicyclohexyl ammonium salt, and the
“type B” scaffolds 3k−3m were stored as potassium salts18,3p
due to their enhanced stability and shelf life.4
We also found that alkyl substitution at C4 and C6 was
important for success of the DCAA reaction (Scheme 11).
Scheme 11. Importance of Alkyl Substitution at Both C4 and
C6
respectively). O-Methyldesoxyhumulones 1a−1f reacted under
standard conditions A (Table 2, entry 1) to yield “type A”
PPAP analogs 3a−3f in excellent yields (Scheme 9A). The
reaction tolerated both allyl (3a−3d) and β-methylallyl (3e and
3f) substitution at C4 and C6. Pleasingly, the nonmethylated
desoxyhumulones 1k−1m exclusively provided “type B”
annulation adducts 3k−3m under modified conditions via
regioselective cyclization at the more nucleophilic C4 and C6
positions (Scheme 10A).3c We discovered that increased
reaction times, lower temperatures, and larger catalyst
(Pd2dba3/BINAP) loadings were required for successful
cyclization to the “type B” core as low yields were obtained
using standard conditions A or B. As one possible explanation,
the nucleophilic phenolate moiety at C5 may bind to binary
palladium(0) more effectively than BINAP resulting in loss of
catalytic activity.21 Pleasingly, our general purification proce-
dure developed for dearomatized phloroglucinols and PPAP
derivatives3p,18 allowed access to bicyclo[3.3.1]nonanes 3k−3m
along with their potassium salts18 in high yields without the use
of silica gel chromatography (Scheme 10A).
While the standard allyl-desoxyhumulone 1a underwent clean
reaction under the optimized conditions to afford 3a, neither
the proteo-(4a) or the chlorinated (10a) variants reacted with
conjunctive reagent 2 under standard conditions A or B, likely
due to a combination of steric and electronic influences.
From the successful studies on allyl-desoxyhumulones 1a−1f
(Scheme 9) and 1k−1m (Scheme 10), we reasoned that other
scaffolds bearing at least a resorcinol oxygenation pattern, an
acyl group, and alkyl substituents at C4 and C6 should also
undergo the desired DCAA process. We proceeded to test our
hypothesis by further broadening our investigation to construct
a diverse set of resorcinol- and orcinol-derived PPAP analogs
via DCAA (Scheme 12). Excitingly, we discovered that
resorcinol derivative 1g and orcinol derivatives 1h−1j yielded
“type A” PPAP analogs 3g−3j lacking a vinylogous acid moiety
(Scheme 12, eqs 1 and 2). Moreover, the structure of DCAA
product 3h was unequivocally determined by X-ray crystallog-
raphy (Figure 2).18 Diallyl-chrysin 1n exclusively afforded “type
Moreover, using the Grubbs second-generation catalyst, we
could also conveniently access prenylated analogs of both “type
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patterns. The mixture likely arises from the intermediate anion
reacting through either major- or minor-contributing resonance
structures, which can be reasoned by the fact that keto-
stabilized allyl anions prefer to react at the most-stabilized
position.25 Finally, lupulone derivative 12a yielded a PPAP
analog bearing gem-diallyl substitution (Scheme 12, eq 5).26
In conclusion, we have achieved a biosynthesis-inspired,
diversity-oriented synthesis approach to both “type A and B”
PPAP analogs. Through the use of two consecutive Pd-
catalyzed reactions, double DcA/Claisen rearrangement and a
DCAA, we can rapidly prepare PPAP molecules for biological
evaluation. The reaction is applicable to a number of electron-
rich aromatic substrates bearing a resorcinol or phloroglucinol
substitution pattern. Further studies including construction of
highly diverse PPAP-inspired chemical libraries for biological
studies and development of asymmetric DCAA are currently in
progress and will be reported in due course.
Scheme 12. Other Scaffolds That Undergo DCAA
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
porco@bu.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial Support from the National Institutes of Health
(GM073855) and Boston University is greatly acknowledged.
We thank Professor Nigel Simpkins (University of Birmingham,
UK) for helpful discussions. NMR (CHE-0619339) and MS
(CHE-0443618) facilities at Boston University are supported
by the NSF. Research at the Center for Chemical Methodology
and Library Development at Boston University (CMLD-BU) is
supported by NIH grant GM-067041.
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major, 63% yield) and “type B” (3o-minor, 27% yield) fusion
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