Rapid access to polyprenylated phloroglucinols via alkylative dearomatization-annulation: Total synthesis of (±)-clusianone

Article abstract of DOI:10.1021/ja0762339

A concise approach to the bicyclo[3.3.1]nonane framework of the polyprenylated phloroglucinol natural products utilizing a tandem alkylative dearomatization-annulation sequence is described. Syntheses of (±)-clusianone and a complex adamantane framework h

Full text of DOI:10.1021/ja0762339

Published on Web 09/29/2007
Rapid Access to Polyprenylated Phloroglucinols via Alkylative
Dearomatization-Annulation: Total Synthesis of (()-Clusianone1
Ji Qi and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment (CMLD-BU),
Boston UniVersity, Boston, Massachusetts 02215
Received August 18, 2007; E-mail: porco@bu.edu
A number of polyprenylated phloroglucinol natural products
bearing densely functionalized bicyclo[3.3.1]nonane-1,3,5-trione
core structures have been reported from plant sources (Figure 1).2
These include clusianone 1 and its C7 epimer 2,3 isolated from the
floral resins of Clusia species, nemorosone 3,4 a regioisomer of 1,
and the adamantane-containing polyprenylated phloroglucinol hy-
peribone K 4.5 In light of the challenging structures and promising
biological activities of these compounds, a number of synthetic
efforts have been reported.6 Recently, impressive syntheses of (()-
Figure 1. Polyisoprenylated phloroglucinol natural products.
garsubellin A7 and (+)-clusianone 18 have been accomplished,
further underscoring interest in this target class. In this Communica-
Scheme 1. Synthetic Plan for Clusianone
tion, we report our initial studies on the synthesis of polyprenylated
phloroglucinols employing a tandem alkylative dearomatization-
annulation process to rapidly construct the bicyclo[3.3.1]nonane-
1,3,5-trione core.
Our approach to clusianone (Figure 1, 1) and related polypre-
nylated phloroglucinols was inspired by biosynthetic considerations4
as well as the facile alkylative dearomatization observed for
clusiaphenone B 59 (Scheme 1). Prenylation of 5 (prenyl bromide,
aq KOH) afforded 6 (40% yield),10 presumably through the
intermediacy of grandone 7.11 This transformation underscored the
propensity for sequential bisalkylation of the phloroglucinol core
and suggested a concise approach to clusianone and related targets
involving alkylative dearomatization-annulation. Recent reports12
Scheme 2. Model Studies
have described sequential Michael-elimination reactions of enolates
with acrylates to prepare bicyclo[3.3.1]nonane core structures. On
the basis of the alkylation sequence 5 f 7 f 6, we considered
whether an anionic species 8 derived from clusiaphenone B 5 may
participate in conjugate addition with a Michael acceptor such as
9 to afford dearomatized product 10. Intramolecular conjugate
addition completes the synthesis of 11 which possesses the
clusianone framework.
The synthesis of the polyisoprenylated benzophenone clusiaphe-
none B 5 commenced with C-prenylation13 of acylphloroglucinol
12 (Scheme 2).14 After considerable experimentation, we found that
treatment of 5 with LiHMDS (3 equiv) followed by the addition
of R-acetoxymethyl acrylate 1312a (2 equiv) at 0 °C led to an
efficient, highly diastereoselective dearomatization-annulation
process in which an additional Michael-elimination event had
unexpectedly occurred to afford 14 (70% yield). The backbone
structure of 14 was suggested by computational-assisted structure
both equivalents of the Michael acceptor and base led to the
production of 20 (41% yield) after enol methylation (entry 2). This
result supports the lower reactivity of acrylonitriles as Michael
acceptors in comparison to acrylate 13. Using the more sterically
hindered R-acetoxymethyl acceptor 910 (entry 3), annulation and
enol methylation were found to proceed cleanly to afford the
clusianone-type compound 21 and its epimer 22 (dr ) 4:1). The
stereochemical assignment of 21 and 22 were based on NOE
experiments and comparison to coupling constants reported for 1
and 2.16 Reactions of the electron deficient Michael acceptors
trifluoroethyl ester 2310 (entry 4) and sulfone 2510 (entry 5) afforded
products 24 and 26 leading us to suspect epimerization of the C7
stereocenter during the tandem process (vide infra).
elucidation based on H, 13C, H-1H COSY, HMQC, and HMBC
data.10 The relative stereochemistry of 14 was determined by
acylation and X-ray crystal structure analysis of the derived
p-bromobenzoate ester 15. The stereochemistry of the final Michael-
elimination event is likely dictated by the approach of 13 from the
convex face of the enolate intermediate 16 which has been observed
for transformations in related compounds.7b
1
1
To evaluate the scope of the dearomatization-annulation process,
we examined the reaction of substituted phloroglucinols with a
variety of substituted R-acetoxyacrylates (Table 1). Phloroglucinol
17 bearing an alkyl-aryl ketone reacted with 13 in a similar manner
to 5 (LiHMDS, THF, 0 °C) to afford the bicyclo[3.3.1]nonane
derivative 18 (entry 1). Reaction of acrylonitrile 1915 with 5 under
similar conditions afforded a mixture of products. Reduction of
To access clusianone, we considered use of R-acetoxy enal 2710
in the annulation process to install an aldehyde handle for prenyl
installation (Scheme 3). Accordingly, treatment of 5 with KHMDS
9
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10.1021/ja0762339 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Access to an Adamantane Framework
Table 1. Alkylative Dearomatization-Annulation
Table 1) and establish a possible route to adamantane-containing
polyprenylated phloroglucinols including hyperibone K (4, Figure
1).
In summary, we have developed a concise approach to the
bicyclo[3.3.1]nonane framework of the polyprenylated phloroglu-
cinol natural products utilizing alkylative dearomatization-annu-
lation. A related approach has been used to access an adamantane
structure with four all carbon quaternary centers formed in one step
from a phloroglucinol precursor. Further applications of the
methodology to the synthesis of additional polyprenylated phloro-
glucinol natural products are currently in progress and will be
reported in due course.
Acknowledgment. We thank the National Institutes of Health
(Grant GM-62842), the Novartis Institutes for BioMedical Research,
and Merck Research Laboratories for research support and Mr. Ang
Li (The Scripps Research Institute) and Drs. Jianglong Zhu and
Shun Su (Boston University) for helpful discussions.
a Yield after enol methylation using TMSCHN2 (2 equiv) and iPr2EtN
(1.5 equiv). b Mixture of enol ether isomers produced, one shown for clarity.
Scheme 3. Synthesis of (()-Clusianone
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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