Total synthesis of plukenetione A

Article abstract of DOI:10.1021/ja105784s

We describe an alkylative dearomatization/acid-mediated adamantane annulation sequence that allows facile access to type A polyprenylated acylphloroglucinol natural products including plukenetione A. Introduction of the 2-methyl-1-propenyl moiety was achieved via stereodivergent S_N2 and S_N1 cyclizations of allylic alcohol substrates.

Full text of DOI:10.1021/ja105784s

Published on Web 09/15/2010
Total Synthesis of Plukenetione A
Qiang Zhang, Branko Mitasev, 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 June 30, 2010; E-mail: porco@bu.edu
Abstract: We describe an alkylative dearomatization/acid-mediated adamantane annulation sequence that
allows facile access to type A polyprenylated acylphloroglucinol natural products including plukenetione A.
Introduction of the 2-methyl-1-propenyl moiety was achieved via stereodivergent SN2 and SN1 cyclizations
of allylic alcohol substrates.
Introduction
The polycyclic polyprenylated acylphloroglucinol (PPAP)
plukenetione A (1, Figure 1)1 was isolated by Jacobs and co-
workers in 19962 from Clusia plukenetii (Guttiferae) and is the
first natural product bearing an adamantane framework isolated
from plant sources. In addition to its unique structure, 1 has
been found to inhibit the enzymatic activities of both topoi-
somerase I and DNA polymerase.3 Plukenetione A may be
biogenetically derived from oxidation of 7-epi-nemorosone
(3).4,5 Further oxidation of 1 may also lead to the densely
functionalized derivatives 66 and 7.5 Compounds 1-3 and
related derivatives7 are described as type A PPAPs.8 Clusianone
(4), its C7 epimer 5,9 and the adamantane hyperibone K (8)10
are categorized as isomeric type B PPAPs. In light of their
challenging structures and promising biological activities, the
synthetic chemistry community has shown significant attention
to the PPAP family, with a number of chemical synthesis efforts
reported to date,11 including a recent synthesis of the plukene-
tione core.11i
Figure 1. Polycyclic polyprenylated acylphloroglucinol (PPAP) natural
products.
Scheme 1. Synthesis of the Type B Adamantane Core
We have previously reported the synthesis of the type B PPAP
clusianone (4) employing a tandem alkylative dearomatization-
annulation process (Scheme 1).12 During these studies, we found
that treatment of the acylphloroglucinol clusiaphenone B (9)
with R-acetoxy enal 10 under basic conditions led to the
production of adamantane 11 via a tandem Michael addition-eli-
mination-Michael aldol sequence proceeding through anionic
(1) Presented in part at the 238rd American Chemical Society National
Meeting, Aug 18-23, 2009, Washington DC, ; abstract ORGN 595.
(2) Henry, G. E.; Jacobs, H.; Sean Carrington, C. M.; McLean, S.;
Reynolds, W. F. Tetrahedron Lett. 1996, 37, 8663.
(3) Diaz-Carballo, D.; Malak, S.; Bardenheuer, W.; Freistuehler, M.; Peter,
R. Bioorg. Med. Chem. 2008, 16, 9635.
(4) de Oliveira, C. M. A.; Porto, A. L. M.; Bittrich, V.; Marsaioli, A. J.
Phytochemistry 1999, 50, 1073.
(5) Hu, L.; Sim, K. Tetrahedron 2000, 56, 1379.
intermediates 12 and 13. In subsequent work, we developed an
enantioselective variant of this transformation employing chiral
phase-transfer catalysis and applied the methodology to the
enantioselective synthesis of hyperibone K (8).13 For acylphlo-
roglucinol substrate 9, alkylative dearomatization-annulation
occurred chemoselectively at carbons 1 and 3. In the present
work, we considered whether a protected acylphloroglucinol
such as clusiaphenone methyl ether (14) may block initial
(6) Christian, O. E.; Henry, G. E.; Jacobs, H.; McLean, S.; Reynolds,
W. F. J. Nat. Prod. 2001, 64, 23.
(7) Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-Uribe, B.; Cardenas, J.
Phytochemistry 2001, 57, 279.
(8) Ciochina, R.; Grossman, R. Chem. ReV. 2006, 106, 3963.
(9) Piccinelli, A.; Cuesta-Rubio, O.; Chica, M.; Mahmood, N.; Pagano,
B.; Pavone, M.; Barone, V.; Rastrelli, L. Tetrahedron 2005, 61, 8206.
(10) Tanaka, N.; Takaishi, Y.; Shikishima, Y.; Nakanishi, Y.; Bastow, K.;
Lee, K. H.; Honda, G.; Ito, M.; Takeda, Y.; Kodzhimatov, O. K.;
Ashurmetov, O. J. Nat. Prod. 2004, 67, 1870.
9
14212 J. AM. CHEM. SOC. 2010, 132, 14212–14215
10.1021/ja105784s  2010 American Chemical Society

Total Synthesis of Plukenetione A
A R T I C L E S
Scheme 3. Silylative Cyclization to the Bicyclo[3.3.1] Ring System
Figure 2. Alkylative dearomatization approach to type A PPAPs.
Scheme 2. Attempted Alkylative Dearomatization-Annulation
a C9 stereochemistry unassigned. See Supporting Information.
Scheme 4. Unexpected Production of the Type B Adamantane
Core
alkylative dearomatization at C1 and redirect annulation to C3
and C5 (Figure 2). Successful achievement of this approach
would afford the type A PPAP framework 15 which may be
further elaborated to 1 and related natural products. In this
article, we report development of methodology along these lines
to access the isomeric type A PPAPs, leading to the total
synthesis of the complex adamantane plukenetione A (1).
ethylamine (DIEA)16 yielded the cyclized products 19 and 20 as
a 3:1 mixture of structural isomers (Scheme 3). On the basis of
this result, we proceeded to evaluate cyclizations of 19 and 20 under
demethylation conditions to access an adamantane structure
(Scheme 4). Interestingly, treatment of silyl ether 20 using
conditions reported by Krapcho and co-workers17 unexpectedly led
to the formation of the type B adamantane 21. In this case, the
chloride ion may remove the silyl protecting group, thereby
triggering retro-aldol fragmentation and formation of ring-opened
aldehyde 16. Further nucleophilic demethylation, followed by
intramolecular Michael addition, provides aldehyde 22 which
participates in intramolecular aldol cyclization to 21. In order to
further probe the proposed mechanism, treatment of dearomatized
substrate 16 under identical reaction conditions led to clean
formation of adamantane alcohol 21 as a single product.
Results and Discussion
We initiated our investigation by examining alkylative
dearomatization of 14 (prepared in two steps from 5-methoxy-
resorcinol)14 with R-acetoxy enal 1012 (Scheme 2) under basic
conditions.15 In initial studies, we found that the desired
annulation product 15 was not observed, and only mono-
dearomatized adduct 16 was obtained. The inability of enolate
intermediate 17 to further cyclize to a bicyclo[3.3.1] ring system
under basic conditions as previously observed in the type B
series (cf. Scheme 1) is likely related to facile and reversible
retro-Michael addition of 18 due to the high thermodynamic
stability of enolate 17.
In an effort to identify irreversible cyclization conditions,
silylative cyclization of 16 with TBSOTf and N,N-diisopropyl-
We also evaluated chlorinative cyclization18 of silyl enol ether
19 with the expectation that this reaction mode would allow us to
directly access an adamantane framework (Scheme 5). To our
delight, treatment of 19 with N-chlorosuccinimide (NCS)18 in the
presence of LiCl to promote demethylation17 (DMA, 60 °C) led
to the formation of chloroadamantane 23 as a single diastereomer,
likely through cyclization of silyloxonium (siloxycarbinyl cation)19
24. Unfortunately, chloroadamantane derivative 23 was found to
be resilient to desilylation and led to either no reaction or formation
of byproducts under either acidic or basic fluoride-mediated reaction
conditions.
(11) For select syntheses of type A PPAPs, see: (a) Spessard, S. J.; Stoltz,
B. M. Org. Lett. 2002, 4, 1943. (b) Ciochina, R.; Grossman, R. B.
Org. Lett. 2003, 5, 4619. (c) Kraus, G. A.; Nguyen, T. H.; Jeon, I.
Tetrahedron Lett. 2003, 44, 659. (d) Kuramochi, A.; Usuda, H.;
Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005,
127, 14200. (e) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V. Angew.
Chem., Int. Ed. 2005, 44, 3895. (f) Siegel, D. R.; Danishefsky, S. J.
J. Am. Chem. Soc. 2006, 128, 1048. (g) Tsukano, C.; Siegel, D. R.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 8840. (h) Ahmad,
N. M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.; Blake, A. J. J.
Org. Chem. 2007, 72, 4803. (i) Takagi, R.; Inoue, Y.; Ohkata, K. J.
Org. Chem. 2008, 73, 9320. (j) Couladouros, E. A.; Dakanali, M.;
Demadis, K. D.; Vidali, V. P. Org. Lett. 2009, 11, 4430. (k) Shimizu,
Y.; Shi, S.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int.
Ed. 2010, 49, 1103. (l) Simpkins, N.; Taylor, J.; Weller, M.; Hayes,
C. Synlett 2010, 4, 639. (m) Abe, M.; Saito, A.; Nakada, M.
Tetrahedron Lett. 2010, 51, 1298.
(16) Kozikowski, A. P.; Jung, S. J. Org. Chem. 1986, 51, 3400.
(17) Krapcho, A.; Weimaster, J.; Eldridge, J.; Jahngen, E.; Lovey, A.;
Stephens, W. J. Org. Chem. 1978, 43, 138.
(12) Qi, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 12682.
(13) Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A., Jr. J. Am. Chem. Soc.
2010, 132, xxxx.
(18) For a review of NCS-mediated reactions, see: Golebiewski, W. M.;
Gucma, M. Synthesis 2007, 23, 3599.
(19) (a) Hambly, G. F.; Chan, T. H. Tetrahedron Lett. 1986, 27, 2563. (b)
Ohkata, K.; Mase, M.; Akiba, K. J. Chem. Soc., Chem. Commun. 1987,
22, 1727.
(14) Mitasev, B.; Porco, J. A., Jr. Org. Lett. 2009, 11, 2285.
(15) See Supporting Information for complete experimental details.
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A R T I C L E S
Zhang et al.
Scheme 5. Synthesis of the Type A Adamantane Framework
Figure 3. Possible reaction mechanisms for adamantane formation.
Scheme 7. Retro-Aldol/Organocerium Addition
Scheme 6. Direct Access to the Adamantane Core of 1
derivative 32 which may undergo final demethylative aldol
cyclization22 to afford adamantane 25.23
We next investigated whether adamantane alcohol 25 could
be converted to plukenetione A using the retro-aldol/alkenyl
metal addition protocol employed in our hyperibone K synthe-
sis.13 Unexpectedly, exposure of 25 to LDA followed by
addition of 2-methyl-1-propenyl magnesium bromide led to
fragmentation to provide the clusianone (type B PPAP) aldehyde
33 after enol methylation of the crude product (Scheme 7). This
cascade process likely occurs by deprotonation of derived
aldehyde 34, followed by retro-Michael reaction to intermediate
35, which may undergo subsequent intramolecular Michael
addition. The structure of 33 was further confirmed by treatment
with Sc(OTf)3 in CH3NO2 to afford the type B PPAP adaman-
tane derivative 21.13,15 After surveying a number of base/
nucleophile combinations, the fragmentation process was cir-
cumvented by cerium(III) chloride-promoted reaction of the
alkenyl Grignard reagent,24 which cleanly afforded the desired
adduct 36 without noticeable side reactions. Interestingly,
quenching of the organocerium reaction with 1 N HCl led to
the production of adamantanes 37 and 38 as a 1:6 mixture of
isomers, favoring the undesired stereoisomer 38.
On the basis of these results, we continued to probe the reaction
mechanism leading to adamantanes 37 and 38 and the possibility
to reverse the selectivity. We found that quenching of organocerium
addition with pH 7 buffer led to formation of an enol intermediate,
39, which was acylated directly with p-bromobenzoyl chloride to
provide enol ester 40 (Scheme 8) along with its enol ester isomer.
The structure of 40 was confirmed by single X-ray crystal structure
analysis (Figure 4).15 Inspection of this structure indicates that the
configuration at C6 of the allylic alcohol of 36 may be derived
from long-range chelation between Ce(III) (or Mg (II)) of the enol/
The latter observation led us to reevaluate the possibility for
protonation/cyclization of 19 to directly access the adamantane core
of plukenetione A. Subjection of silyl enol ether 19 to conventional
desilylation conditions and Lewis and Brønsted acids (e.g., TFA
and AcOH) generally led to formation of ring-opened product 16
or the rearomatized acylphloroglucinol 14 (Scheme 3).20 After a
survey of conditions, we found that exposure of 19 to concentrated
HCl in THF (4 equiv) led to the production of adamantane alcohol
25 in 69% yield as a single diastereomer (cf. Scheme 5). As we
suspected hydrolysis of 19 to enal 16 under the reaction conditions,
we found that treatment of 16 or its bis-prenylated variant 26 with
concentrated HCl in THF led directly to adamantanes 25 and 27
(Scheme 6),21 enabling rapid construction of the plukenetione A
core in two steps from acylphloroglucinol 14. The structure of
adamantane 27 was confirmed by acylation to p-bromobenzoate
28 and X-ray crystal structure analysis.15
Two possible pathways for the acid-mediated adamantane
cyclization are shown in Figure 3. In pathway a, the protonated
aldehyde 29 may undergo demethylative aldol cyclization22 to 30
which may be followed by protonation of the tetrasubstituted alkene
and cationic cyclization11i to afford 25. In pathway b, the allylic
cation resonance structure 31 derived from 29 may participate in
cationic cyclization,11i leading to the production of bicyclo[3.3.1]
(20) For rearomatization of dearomatized acylphloroglucinols, see: Raikar,
S.; Nuhant, P.; Delpech, B.; Marazano, C. Eur. J. Org. Chem. 2008,
8, 1358.
(23) According to the insightful recommendation of a reviewer, demethyl-
ation of intermediates 29 and 32 may also occur by hydrolysis of
oxonium intermediates produced after cyclization.
(24) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(21) Anhydrous HCl was also examined with substrates 16 and 19 at room
temperature, leading to recovery of starting materials after 2 days.
(22) For demethylative aldol reactions, see: Murakami, M.; Minamikawa,
H.; Mukaiyama, T. Chem. Lett. 1987, 1051.
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Total Synthesis of Plukenetione A
A R T I C L E S
Scheme 10. Completion of the Synthesis of Plukenetione Aa
Scheme 8. Proposal for Diastereoselectivity in the Grignard
Addition
a For 44, one enol ether isomer shown for clarity.
Scheme 9. Rationale for Stereoselectivity
Figure 4. X-ray structure of enol ester 40.
plukenetione A (1) in 74% yield. Spectral data for 1 (1H NMR, 13
C
NMR, mass spectrum) were in full agreement with data reported for
the natural product.2,15
ketone25 moiety and the aldehyde, followed by facially selective
addition of the alkenyl metal reagent to the face away from the
gem-dimethyl moiety.
Conclusion
In summary, we have developed an expedient approach to the type
A PPAP natural products including plukenetione A (1). The strategy
relies on introduction of an ether blocking group on an acylphloro-
glucinol substrate to direct the regiochemistry for alkylative
dearomatization-annulation and acid-mediated cyclization to construct
the adamantane core. Introduction of the 2-methyl-1-propenyl moiety
of 1 was achieved via stereodivergent SN2 and SN1 cyclizations of
allylic alcohol substrates. Studies to further probe the mechanism of
the acid-mediated adamantane cyclization as well as the synthesis and
biological evaluation of other type A PPAP natural product targets
are currently underway and will be reported in due course.
On the basis of the cyclization results and the observed stereo-
chemistry at C6, we propose a rationale for stereoselectivity of the
adamantane cyclization as shown in Scheme 9. Quenching of
intermediate 36 with 1 N HCl should lead to protonated enol 41, which
is properly situated for SN2 cyclization26 leading to formation of the
C6-epi derivative 38. Alternatively, ionization of allylic alcohol 41
should afford allylic cation 42 which may undergo cationic (SN1)
cyclization leading to 37.13
Given the high reactivity of the free enol/allylic alcohol 39/43, we
proceeded to methylate the crude enols 39/43 in an effort to lower its
nucleophilicity in the form of vinylogous ester 44 and access an SN1
cyclization mode (Scheme 10). Gratifyingly, treatment of 44 with TFA
(10 equiv) in hexafluoroisopropanol (HFIP)27 as solvent led to selective
formation of adamantane derivative 37. Other cyclization conditions
were also attempted on substrate 44, including use of Sc(OTf)3 and
the cation-stabilizing solvent nitromethane (MeNO2), which afforded
37 and 38 in a 1:3 ratio. Olefin cross-metathesis of 37 using isobutylene
in the presence of the Grubbs II28 metathesis catalyst afforded
Acknowledgment. We thank the National Institutes of Health
(GM-073855) and the National Science Foundation (0848082) for
research support and Profs. Gary Molander (University of Pennsyl-
vania) and Aaron Beeler (Boston University) for helpful discussions.
We also thank Prof. Helen Jacobs (University of West Indies, Kingston,
Jamaica) for providing NMR spectra of natural plukenetione A.
Note Added after ASAP Publication. Schemes 1 and 6
contained errors in the version published ASAP September 15,
2010; the correct version reposted September 20, 2010.
(25) For eight -membered-ring chelation using Sm(III), see: (a) Molander,
G.; McKie, J. J. Am. Chem. Soc. 1993, 115, 5821. Using Mg(II): (b)
Chung, K.; Chu, C.; Chang, M. Bull. Korean Chem. Soc. 2004, 25, 417.
(26) For SN1 vs SN2 reactivity in metal triflate-catalyzed alkylations, see:
Noji, M.; Konno, Y.; Ishii, Y. J. Org. Chem. 2007, 72, 5161.
(27) For solvolytic reactions in fluorinated alcohols, see: (a) Bentley, T. W.;
Llewellyn, G.; Ryu, Z. J. Org. Chem. 1998, 63, 4654. For a review
on fluorinated solvents, see: (b) Shuklov, I. A.; Dubrovina, N. V.;
Bo¨rner, A. Synthesis 2007, 2925.
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.
(28) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4, 1939.
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