Catalytic enantioselective alkylative dearomatization-annulation: Total synthesis and absolute configuration assignment of hyperibone K

Article abstract of DOI:10.1021/ja1057828

The asymmetric total synthesis of the polyprenylated acylphloroglucinol hyperibone K has been achieved using an enantioselective alkylative dearomatization-annulation process. NMR and computational studies were employed to probe the mode of action of a chiral phase-transfer (ion pair) catalyst.

Full text of DOI:10.1021/ja1057828

Published on Web 09/10/2010
Catalytic Enantioselective Alkylative Dearomatization-Annulation: Total
Synthesis and Absolute Configuration Assignment of Hyperibone K
Ji Qi, Aaron B. Beeler, Qiang Zhang, and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment (CMLD-BU),
Boston UniVersity, Boston, Massachusetts 02215
Received June 30, 2010; E-mail: porco@bu.edu
dearomatization processes have been reported, chiefly involving
Abstract: The asymmetric total synthesis of the polyprenylated
acylphloroglucinol hyperibone K has been achieved using an
enantioselective alkylative dearomatization-annulation process.
NMR and computational studies were employed to probe the
oxidation chemistry,10 with more limited studies reported involving
alkylative dearomatization.11 Our approach was inspired by a recent
report from O’Donnell and co-workers12 involving tandem conju-
gate addition-elimination using a chiral phase-transfer catalyst13
mode of action of a chiral phase-transfer (ion pair) catalyst.
derived from Cinchona alkaloids. We focused our initial studies
on enantioselective dearomatization/alkylation of 7 with R-acetoxy
The polyprenylated acylphloroglucinols (PPAPs) are a unique
enal 9.7 We first evaluated a number of chiral catalysts (8a-g,
natural product class bearing the highly substituted and oxygenated
Figure 2) which were prepared from readily available Cinchona
bicyclo[3.3.1]nonane-1,3,5-trione framework (Figure 1). Clusianone
alkaloids. In initial experiments, we found that the desired
(1) and its C7 epimer 2, isolated from the floral resins of the Clusia
dearomatization-annulation process using O-allyl-N-(9-anthrace-
species, have been shown to have cancer chemopreventive activity1
nylmethyl)cinchonidinium bromide (8a,14 Figure 2) (CsOH ·H2O,
as well as inhibit HIV infection.2 Hyperibone K (3)3 and its
4 Å MS, CH2Cl2, -50 °C) proceeded smoothly to afford adaman-
structural isomer plukenetione A (4)4 (absolute stereochemistries
tane 5 in moderate yield (68%) and ee (75%) (Table 1, entry 1).15
unassigned) possess highly functionalized and unusual adamantane
However, a stoichiometric amount of catalyst 8a was required to
cores. In light of their challenging structures and promising
promote the reaction at -50 °C.
biological activities, the PPAP family has garnered significant
interest. Recently, asymmetric syntheses of (+)-clusianone (1)5 and
(-)-hyperforin (3)6 were reported. In a previous study,7 we reported
the synthesis of (()-clusianone (1) employing a tandem alkylative
dearomatization-annulation process. In this Communication, we
report development of an enantioselective dearomatization-annulation
protocol employing chiral phase-transfer (ion pair) catalysis and
its application to the enantioselective synthesis of hyperibone K.
Figure 2. Dearomatization-alkylation using Cinchona alkaloid-derived
Figure 1. Polyisoprenylated acylphloroglucinol natural products.
Scheme 1. Retrosynthetic Analysis for Hyperibone K
catalysts.
Table 1. Enantioselective Dearomatization of Clusiaphenone B
Using Various Phase Transfer Catalysts
Aldehyde
(1.05 equiv)
catalyst
(25 mol %)
time
(h)
yield
(%)
ee
(%)
Entry
1
9
8a
(1 equiv)
8b
15
68
75 (27R)
2
3
4
5
6
7
8
9
9
9
9
9
10
10
10
10
22
22
22
22
10
10
10
10
41
22
68 (27R)
11 (27R)
20 (27R)
84 (27R)
76 (27R)
86 (27R)
90 (27R)
-60 (27S)
8c
Our approach to hyperibone K (Figure 1, 3) leverages a concise
access to adamantane 57 (Scheme 1). We envisioned that 3 may
be derived from allylic alcohol 6 by Lewis acid-promoted intramo-
lecular cation cyclization.8 Allylic alcohol 6 may be derived from
base-promoted retro-aldol/vinyl metal addition9 of adamantane 5,
the latter which may be derived from alkylative dearomatization
of clusiaphenone B (7).
8d
∼10
8e
48
8b
65
61
71
53
8e
8f
8g
Enantioselective approaches to clusianone, hyperibone K, and
other PPAPs required development of an asymmetric alkylative
dearomatization-alkylation process. A number of enantioselective
Recently, dimeric Cinchona alkaloid-derived phase-transfer
catalysts have been reported,16 which show very high reactivity
and enantioselectivity in transformations including asymmetric
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C O M M U N I C A T I O N S
alkylations16a,d and nucleophilic epoxidation.16c Accordingly, we
first evaluated several reported dimeric catalysts (8b-d, Figure 2).
Interestingly, we found that reactions catalyzed by the meta-
substituted dimer 8b (entry 2) afforded 5 in promising enantiomeric
excess (68% ee) at a catalyst loading of 25 mol %. Catalysts with
ortho- and para-substitution (8c and 8d) showed poor enantiose-
lectivity (11% ee and 20% ee). Through extensive structural
modifications of the meta-dimeric catalyst, we identified the benzyl
ether dimer 8e which afforded 5 in moderate yield and good
enantiomeric excess (48% yield, 84% ee).
We also evaluated heptanoate aldehyde 10 which displayed better
reactivity having improved yields and shorter reaction times (Table
1, entries 6-9). Further modification of catalyst 8e by replacing
the vinyl group with a 2-methylpropenyl moiety (catalyst 8f, entry
8) led to improvement of enantioselectivity (90% ee). Use of (+)-
cinchonine-derived catalyst 8g afforded the opposite enantiomeric
product (27S), albeit with lower enantioselectivity (-60% ee). We
were able to unambiguously determine the absolute configuration
of adamantane (-)-5 by single crystal X-ray analysis after conver-
sion to p-bromobenzoate ester 11 (Figure 3).15,17
Figure 4. Allylic cation intermediate 13.
Accordingly, initial 1H NMR studies were conducted which
indicated that, under standard reaction conditions (both achiral and
chiral phase transfer catalysts), 80-90% of clusiaphenone B 7 exists
in a dearomatized enolate form (cf. 14-17, Figure 5).15,19 Accord-
ingly, we propose that the dearomatized enolate is likely the reactive
species interacting with the catalyst.
Figure 5. Dearomatized acylphloroglucinols 14-17.
We next turned our attention to elucidating the catalyst conforma-
1
tion. H and 13C NMR analysis of dimeric catalyst 8e indicated that
the catalyst adopts a C2 symmetrical conformation which is in
agreement with a previously reported crystal structure of a related
dimeric Cinchona alkaloid-derived catalyst.16c We utilized NOESY
experiments in conjunction with conformational analysis (mixed Monte
Carlo Multiple Minimum (MCMM)/Low-Mode Conformational Search
(LMCS)) to determine likely conformations of catalyst 8e in solution.
By surveying the generated low energy conformations corresponding
to key NOE interactions, we identified a single conformation (Figure
6) which was further optimized using DFT (B3LYP-63-1g). We also
compared NOESY data of 8e both alone and with substrate 7 allowing
us to ascertain that the catalyst conformation did not shift significantly
upon substrate complexation.15
Figure 3. Determination of the absolute configuration of 5.
Scheme 2. Total Synthesis of (-)-Hyperibone K
Our synthetic approach to hyperibone K (3) features a retro-
aldol/addition process and is shown in Scheme 2. Dearomatization-
annulation of 7 and aldehyde 10 proceeded smoothly to produce
(-)-5 (71%, 90% ee). Treatment of 5 with LDA, followed by
addition of 2-methyl-1-propenyl magnesium bromide,18 afforded allylic
alcohol 6 which was produced from the retro-aldol intermediate 12
followed by addition of 2-methyl-propenyl magnesium bromide.
Intramolecular cation cyclization of 6 catalyzed by Sc(OTf)38 suc-
cessfully afforded (-)-3 in moderate yield (50% yield, two steps), thus
establishing the absolute configuration of natural (+)-3. The high (>20:
1) diastereoselectivity observed in the cyclization may be explained
by analysis of cationic intermediate 13 which indicates a likely
preference for conformation 13a wherein the allylic cation is situated
away from the gem-dimethyl moiety (Figure 4).
Although we developed an efficient catalyst system for enantiose-
lective dearomatization-annulation, the mechanism and mode of action
for the phase-transfer (ion pair) catalyst remained unsolved. To further
understand the catalyst mode of action, we considered a two-stage
approach which would utilize both experimental and computational
information. Stage 1 involved understanding the identity of the reactive
substrate and relevant conformation(s) for the catalyst. Stage 2 involved
elucidation of the substrate and catalyst complex leading to the
observed enantiomer (-)-5.
Figure 6. Optimized conformation of catalyst 8e with key NOEs.
Stage 2 relied on use of computational molecular docking to generate
binding poses of the catalyst substrate complex. Literature reports have
indicated the possibility of this approach highlighted by an example
from Deslongchamps and co-workers who have utilized reverse
docking to explore the configurational space of a flexible organocatalyst
around a rigid catalyst-free transition state.20 We utilized CDOCKER
(a CHARMM-based docking program) to systematically pose the
flexible substrate (acylphloroglucinol) within a static catalytic site and
conduct low-level energy calculations for each pose. We also combined
these studies with ROESY data of the substrate catalyst complex which
illuminated key intermolecular interactions.15
As there are several possible enolates which may be operative
(cf. Figure 5), we conducted docking studies on each. Docking
experiments provided over 100 poses for enolates 14-17 bound
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C O M M U N I C A T I O N S
to 8e which were quickly reduced to a single pose for each enolate
through a series of criteria: (1) correlation with ROESY data; (2)
potential for ion-pair interactions (2-4 Å); and (3) substrate
availability for Michael addition. The selected pose for each enolate
was further optimized by DFT (B3LYP-63-1g).15 Poses meeting
most of these criteria for each substrate were very similar regarding
placement of the dearomatized enolate in the catalyst cavity.
Utilizing a pose which meets all of the criteria above, we developed
a working model for the phase-transfer (ion pair) catalyst-mediated
dearomatization-annulation with 8e and enolate 15 (Figure 7). The
preferred binding mode appears to be one in which the para-enolate
oxygen is placed near a quaternary nitrogen center to form a tight ion
pair and the dearomatized cyclohexadienone is aligned near the top
of the aromatic linker. The lower energy poses situate the substrate
such that the pseudoaxial proton derived from dearomatization is
oriented away from the catalyst (Figure 7a).15 In this orientation,
substrates 15 and 17 appear to have more optimal ion pairing (Figure
7a) with the more accessible ammonium center while substrates 14
and 16 are situated such that the charge bearing oxygen is paired with
the less accessible ammonium center.15 The pose illustrated in Figure
7 also satisfies the major intermolecular interactions identified by
ROESY experiments (Figure 7a).15 Furthermore, poses utilizing
substrates 15 and 17 may lead to the correct stereochemical outcome
((-)-5) while poses with 14 and 16 would afford the opposite
configuration.15 Based on the model of catalyst 8e and substrate 15, it
is apparent that a key binding element involves hydrophobic interaction
of a substrate prenyl group in a hydrophobic cleft of the catalyst formed
by the vinyl and O-benzyl groups (Figure 7b), both of which were
shown to be critical for enantioselectivity (cf. Table 1).17
(ion pair) catalysts. The total synthesis and absolute configuration
assignment of hyperibone K have been achieved by application of the
asymmetric dearomatization process. NMR and computational studies
were employed to illuminate the mode of action for the phase-transfer
(ion pair) catalyst. Further studies utilizing molecular docking for a
mechanistic understanding of phase-transfer catalysis are ongoing and
will be reported in due course.
Acknowledgment. We thank the National Institutes of Health
(GM-073855), the National Science Foundation (0848082), Merck
Research Laboratories, and Wyeth for research support; Dr. Sujata
Bardhan (Boston University) for providing catalysts and helpful
discussions; and Dr. Paul Ralifo (Boston University) for assistance
with NMR experiments. We thank the NSF for the high resolution
mass spectrometer (CHE-0443618) used in this work.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. X-ray crystal structure
coordinates and files in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Figure 7. Proposed Binding Model of Catalyst 8e and 15. (a) Key
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In summary, we have developed an enantioselective alkylative
dearomatization-annulation process using dimeric chiral phase-transfer
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