A rapid acquisition of the bicyclo[3.3.1]nonan-9-one core present in garsubellin A and related phloroglucins

Article abstract of DOI:10.1016/j.tetlet.2005.11.120

An exceptionally concise and stereoselective route to the prenylated bicyclo[3.3.1]nonan-9-one core present in garsubellin A and related phloroglucin natural products from the readily available precursor dimedone is delineated.

Full text of DOI:10.1016/j.tetlet.2005.11.120

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 689–692
A rapid acquisition of the bicyclo[3.3.1]nonan-9-one core present
in garsubellin A and related phloroglucins
Goverdhan Mehta* and Mrinal K. Bera
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 26 September 2005; revised 15 November 2005; accepted 23 November 2005
Abstract—An exceptionally concise and stereoselective route to the prenylated bicyclo[3.3.1]nonan-9-one core present in garsubellin
A and related phloroglucin natural products from the readily available precursor dimedone is delineated.
ꢀ 2005 Elsevier Ltd. All rights reserved.
A range of polyisoprenylated phloroglucinol derivatives
(phloroglucins) with increasing levels of structural com-
plexity are often being reported in the contemporary lit-
erature from diverse plant sources.1 Typical examples of
this growing family of natural products, based on bicy-
clo[3.3.1]nonane framework and generously embodying
isoprene derived fragments and a dense oxygenation
pattern, are garsubellin A 1,1b nemorosone 2,1e,r propo-
lone D 31r and enervosanone 41s to name but a few.
Besides their complex, enchanting framework and func-
tionalization pattern, these pholoroglucinol derived nat-
ural products exhibit wide ranging biological activity
profiles, which include cytotoxicity against several hu-
man cancer cell lines and antibacterial activity.1 Among
these pholoroglucins, garsubellin A 1, isolated by the
group of Fukuyama1b in 1997 from the wood of Garci-
nia subelliptica (Guttiferae) holds special appeal. These
authors also made an important observation that 1 en-
hanced in vitro choline acetyltransferase (ChAT) activ-
ity in P10 rat septal neuron cultures by 154% at 10 lM
concentration.1b This finding is of much significance as
a deficiency in the levels of the neurotransmitter acetyl-
choline (ACh) has been implicated in several neurode-
generative disorders such as AlzheimerÕs disease. Thus,
inducers of the enzyme (ChAT), which is involved in
the biosynthesis of ACh have implications in developing
Alzheimer therapeutics. Such a potential has evoked a
great deal of synthetic interest in garsubellin A 1, which,
in addition, is endowed with a very challenging molecu-
lar architecture and several groups have entered the
fray. These synthetic efforts have understandably
focused on the synthesis of bicyclo[3.3.1]nonane core
with varying degrees of functionalization for further
elaboration to the natural product and several innova-
tive strategies have been devised in this context.2 We
too have recently delineated an enantiospecific approach
to 1 emanating from monoterpene a-pinene 5 that has
resulted in the synthesis of the bicyclic core 6, Scheme
1.3 Concurrently, we have also been exploring an alter-
native synthetic approach that could provide a short
access to the core structure present in phloroglucins.
In this letter, we disclose an exceptionally short and
simple acquisition of the prenylated bicyclo[3.3.1]-
nonane fragment from the readily available dimedone
7, setting the stage for further elaboration to the natural
product garsubellin A 1 and for generating diversity
based on this scaffold.
OH
O
O
5
O
OH
4
8
7
2
O
O
O
O
Ph
Garsubellin A (1)
Nemorosone (2)
OH
O
O
O
O
O
O
O
Ph
*
Corresponding author. Tel.: +91 8023 600367; fax: +91 8023
600283; e-mail: gm@orgchem.iisc.ernet.in
Propolone D (3)
Enervosanone (4)
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.120

690
G. Mehta, M. K. Bera / Tetrahedron Letters 47 (2006) 689–692
O
O
O
HO
O
AcO
AcO
ref. 3
(i)
AcO
H
AcO
H
H
H
5
6
15
16
Scheme 1.
O
O
HO
Sequential addition of methyl acrylate and prenyl bro-
mide to dimedone 7 in the presence of DBU led to the
formation of 8 in a single-pot operation.4,5 Hydrolysis
of 8 to lactone carboxylic acid 94 and enol-lactonization
furnished d-lactone 104 in excellent yield, Scheme 2.
Quenching the kinetic enolate derived from 10 with pre-
nyl bromide introduced the second prenyl group and
stereoselectively delivered 11.4 DIBAL-H reduction of
11 led to the desired structural reconstitution along with
the concomitant stereoselective reduction of the bystan-
der carbonyl group and directly furnished the bicyclic
exo,exo-diol 144 through the intermediacy of the initially
formed lactol anion 12 and aldol cyclization product 13,
Scheme 2. Interestingly, exo,exo-keto-diol 14 was ob-
tained as a single diastereomer during the aldolization
process and was further regioselectively converted into
the crystalline monoacetate 15. An X-ray crystal struc-
(ii)
HO
AcO
H
14
18
(iii)
O
O
AcO
(iv)
HO
H
O
17
19
Scheme 3. Reagents and conditions: (i) PCC, DCM, rt, 1 h, 95%; (ii)
Ac2O, Et3N, DMAP, rt, 12 h, 85%; (iii) K2CO3, MeOH, rt, 1 h, 70%;
(iv) PCC, DCM, rt, 1 h, 94%.
Scheme 2. Reagents and conditions: (i) (a) CH2@CHCO2Me, DBU, THF, rt, 3 h, (b) Me2C@CHCH2Br, DBU, THF, rt, 3 h, 70% over two steps; (ii)
H2SO4, acetone–water (5:1), reflux, 12 h, 87%; (iii) CH3COONa (1.2 equiv), Ac2O, reflux, 2 h, 92%; (iv) Me2C@CHCH2Br, LHMDS, THF, À78 ꢁC,
1 h, 62%; (v) DIBAL-H (2.5 equiv), DCM, 0 ꢁC, 3 h, 52%; (vi) Ac2O, Et3N, DMAP, DCM, rt, 3 h, 92%.

G. Mehta, M. K. Bera / Tetrahedron Letters 47 (2006) 689–692
691
2005, 68, 354; (q) Massoit, G.; Long, C.; David, B.;
Serrano, M. J.; Daubie, F.; Alby, F.; Ausseil, F.; Knibieh-
ler, M.; Moretti, C.; Hoffmann, J. S.; Cazaux, C.; Lavaud,
C. J. Nat. Prod. 2005, 68, 979; (r) Hernandez, I. M.;
Fernandez, M. C.; Cuesta-Rubio, O.; Piccinelli, A. N.;
Rastrelli, L. J. Nat. Prod. 2005, 68, 931; (s) Taher, M.; Idris,
M. S.; Ahmad, F.; Arbain, D. Phytochemistry 2005, 66,
723.
ture determination of 15 secured its formulation and the
ORTEP diagram with 50% thermal ellipsoidal probabil-
ity is shown in Scheme 2 (hydrogen atoms not shown for
clarity).6
In 14, two of the three prenyl units present in the
phloroglucins were in place and all the three bridges of
bicyclo[3.3.1]nonane moiety had functionality and in
routine transformations it was further shown that the
carbonyl group, required for further elaboration could
be positioned on either of the two bridges (Scheme 3)
to furnish either of diketones 16 and 17. While 16 was
prepared from keto-diol 14 through regioselective
monoacetate 15 and PCC oxidation, the diketone 17
was obtained from 14 by conversion to diacetate 18, reg-
ioselective hydrolysis to 194 and oxidation with PCC,
Scheme 3.
2. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X.
J. Am. Chem. Soc. 1999, 121, 4724; (b) Usuda, H.; Kanai,
M.; Shibasaki, M. Org. Lett. 2002, 4, 859; (c) Usuda, H.;
Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 3621;
(d) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943; (e)
Young, D. G. J.; Zeng, D. J. Org. Chem. 2002, 67, 3134; (f)
Kraus, G. A.; Nguyen, T. H.; Jeon, I. Tetrahedron Lett.
2003, 44, 659; (g) Takagi, R.; Nerio, T.; Miwa, Y.;
Matsumura, S.; Ohkata, K. Tetrahedron Lett. 2004, 45,
7401.
3. Mehta, G.; Bera, M. K. Tetrahedron Lett. 2004, 45, 1113.
4. All new compounds were fully characterized on the basis of
their IR, 1H NMR, 13C NMR and mass spectral data.
Selected spectral data for key compounds: 8: IR (neat): mmax
1738, 1693 cmÀ1; 1H NMR (300 MHz, CDCl3): d 4.89–4.84
(1H, m), 3.64 (3H, s), 2.65 (2H, d, J = 14.7 Hz), 2.49–2.38
(4H, m), 2.21–2.15 (2H, m), 2.09–2.03 (2H, m), 1.65 (3H, s),
1.59 (3H, s), 1.06 (3H, s), 0.89 (3H, s). 13C NMR (75 MHz,
CDCl3): d 208.9 (2C), 173.4, 136.4, 116.9, 67.9, 51.6 (3C),
35.9, 30.6, 29.7, 29.3, 27.5, 26.7, 25.9, 17.9. HRMS
(ES): m/z calculated for C17H26O4Na: 317.1729 (M+Na)+,
found: 317.1729. Compound 9: IR (neat): mmax 1714,
In summary, we have described a very concise (five
steps, 18% overall yield) and promising synthetic strat-
egy for the rapid acquisition of the polyprenylated bicy-
clo[3.3.1] nonan-9-one core, present in phloroglucin
natural products, from the commercially available di-
ketone dimedone.7
Acknowledgements
1693 cmÀ1 1H NMR (300 MHz, CDCl3): d 4.90–4.85
;
(1H, m), 2.72–2.64 (2H, m), 2.49–2.44 (4H, m), 2.26–2.21
(2H, m), 2.09–2.04 (2H, m), 1.68 (3H, s), 1.60 (3H, s), 1.08
(3H, s), 0.89 (3H, s). 13C NMR (75 MHz, CDCl3): d 208.9
(2C), 178.4, 136.6, 117.6, 67.9, 51.5 (2C), 36.2, 30.6, 29.8,
29.2, 27.4, 26.1, 25.9, 18.0. HRMS (ES): m/z calculated for
C16H24O4Na: 303.1572 (M+Na)+, found: 303.1572. Com-
pound 10: IR (neat): mmax 1766, 1718, 1678 cmÀ1; 1H NMR
(300 MHz, CDCl3): d 5.46 (1H, s), 4.99–4.94 (1H, m), 2.68–
2.49 (4H, m), 2.38–2.27 (2H, m), 2.02–1.89 (2H, m), 1.68
(3H, m), 1.58 (3H, s), 1.15 (3H, s), 1.02 (3H, s). 13C NMR
(75 MHz, CDCl3): d 208.6, 168.1, 148.2, 136.4, 118.4, 118.3,
117.4, 50.6, 48.8, 33.5, 33.2, 30.2, 27.4, 25.8, 24.9, 17.9.
HRMS (ES): m/z calculated for C16H22O3Na: 285.1467
(M+Na)+, found: 285.1460. Compound 11: IR (neat): mmax
1764, 1715 cmÀ1; 1H NMR (300 MHz, CDCl3): d 5.40 (1H,
s), 5.07–4.94 (2H, m), 2.78–2.68 (1H, m), 2.59–2.52 (3H, m),
2.38–2.26 (3H, m), 2.20–2.13 (1H, dd, J = 13.8, 7.5 Hz),
1.68 (6H, s), 1.61 (3H, s), 1.57 (3H, s), 1.51 (1H, dd,
J = 13.8, 10.8 Hz), 1.15 (3H, s), 1.03 (3H, s). 13C NMR
(75 MHz, CDCl3): d 208.9, 170.1, 148.4, 136.3, 135.3, 119.6,
117.5, 116.8, 50.6, 48.8, 38.5, 33.2, 32.8, 31.0, 30.9, 30.3,
30.2, 25.8 (2C), 17.9 (2C). HRMS (ES): m/z calculated for
C21H30O3Na: 353.2093 (M+Na)+, found: 353.2094. Com-
One of us, M.K.B., thanks UGC for the award of a re-
search fellowship. We thank the CCD facility at IISc for
the single crystal X-ray diffraction data.
References and notes
1. (a) Karanjgoakar, C. G.; Rama Rao, A. V.; Venkataraman,
K.; Palmer, K. J. Tetrahedron Lett. 1973, 14, 4977; (b)
Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm.
Bull. 1997, 45, 947; (c) Fukuyama, Y.; Minami, H.;
Kuwayama, A. Phytochemistry 1998, 49, 853; (d) de
Oliveira, C. M. A.; Porto, A. L. M.; Bittrich, V.; Marsaioli,
A. J. Phytochemistry 1999, 50, 1073; (e) Cuesta-Rubio, O.;
´
Velez-Castro, H.; Frontana-Uribe, B. A.; Cardenas, J.
Phytochemistry 2001, 57, 279; (f) Shan, M. D.; Hu, L. H.;
Chen, Z. L. J. Nat. Prod. 2001, 64, 127; (g) Winkelmann,
K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat.
Prod. 2001, 64, 701; (h) Cuesta-Rubio, O.; Frontana-Uribe,
´
´
B. A.; Ramırez-Apan, T.; Cardenas, J. Z. Naturforsch.
2002, 57c, 372; (i) Wu, J.; Cheng, X.-F.; Harrison, L. J.;
Goh, S.-H.; Sim, K.-Y. Tetrahedron Lett. 2004, 45, 9657; (j)
Verotta, L.; Lovaglio, E.; Sterner, O.; Appendino, G.;
1
pound 14: IR (thin film): mmax 3437, 1699 cmÀ1; H NMR
ˇ
Bombardelli, E. J. Org. Chem. 2004, 69, 7869; (k) Savikin-
(300 MHz,CDCl3):d 5.18–5.06 (2H, m), 3.95 (1H, bs), 3.76–
3.73 (1H, m), 2.43–2.35 (2H, m), 2.21–2.14 (1H, m), 2.07
(1H, t, J = 1.8 Hz), 2.03–1.96 (1H, m), 1.91–1.81 (1H, m),
1.77–1.76 (1H, m), 1.73 (3H, s), 1.70 (3H, s), 1.65 (3H, s),
1.62 (3H, s), 1.51–1.50 (1H, m), 1.26–1.19 (2H, m), 1.15
(6H, s). 13C NMR (75 MHz, CDCl3): d 215.5, 135.1, 133.9,
121.4, 118.7, 78.4, 75.0, 68.3, 51.7, 41.0, 39.3, 37.8, 34.9,
30.9, 30.2, 29.4, 27.9, 26.1, 25.9, 17.9 (2C). HRMS (ES):
m/z calculated for C21H34O3Na: 357.2406 (M+Na)+,
found: 357.2410.
´
´
Fodulovic, K.; Aljancic, I.; Vajs, V.; Menkovic, N.;
ˇ ´
´
´
Macura, S.; Gojgic, G.; Milosavljevic, S. J. Nat. Prod.
2003, 66, 1236; (l) Weng, J.-R.; Tsao, L.-T.; Wang, J.-P.;
Wu, R.-R.; Lin, C.-N. J. Nat. Prod. 2004, 67, 1796; (m) Wu,
C.-C.; Weng, J.-R.; Won, S.-J.; Lin, C.-N. J. Nat. Prod.
2005, 68, 1125; (n) Gartner, M.; Muller, T.; Simon, J. C.;
¨
Giannis, A.; Sleeman, J. P. ChemBioChem 2005, 6, 171; (o)
Herath, K.; Jayasuriya, H.; Ondeyka, J. G.; Guan, Z.;
Borris, R. P.; Stijfhoorn, E.; Stevenson, D.; Wang, J.;
Sharma, N.; Macnaul, K.; Menke, J. G.; Ali, A.; Schulman,
M. J.; Singh, S. B. J. Nat. Prod. 2005, 68, 617; (p) Baggett,
S.; Protiva, P.; Mazzola, E. P.; Yang, H.; Ressler, E. T.;
Basile, M. J.; Weinstein, I. B.; Kennelly, E. J. J. Nat. Prod.
5. To a solution of dimedone (1.0 g, 7.1 mmol) in dry THF
(15 mL) was added DBU (3.4 mL, 21.4 mmol) at room
temperature and the mixture was allowed to stir for 15 min.
Then methyl acrylate (1.0 mL, 10.7 mmol) was added and

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G. Mehta, M. K. Bera / Tetrahedron Letters 47 (2006) 689–692
the reaction mixture was stirred for 3 h. When the starting
reduced by SAINTPLUS; an empirical absorption correc-
tion was applied using the package SADABS, and XPREP
was used to determine the space group. The structures were
solved using SIR92 and refined using SHELXL97. Crystal data
for compound 15: C23H36O4, M = 376.52, monoclinic,
material was fully consumed, prenyl bromide (1.3 mL,
10.7 mmol) was added at rt and after an additional 3 h, the
reaction was quenched with water (5 mL) and the product
extracted with EtOAc (30 · 3 mL). The combined organic
extract was washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent produced a yellow oil,
which was filtered through a silica gel column to furnish
˚
˚
space group P21/c, a = 12.8517(17) A, b = 15.222(2) A,
3
˚
c = 11.8734(16), b = 108.021(2)ꢁ, V = 2208.9(5) A , Z = 4,
q
calcd = 1.132 g cmÀ3
,
F(000) = 824, l = 0.076 mmÀ1
,
1
pure 8 (1.47 g, 70%). For the IR, H NMR, 13C NMR and
number of l.s. parameters = 252, R = 0.0670, Rw =
0.1437, GOF = 1.108 for 3889 reflections with I > 2r(I).
The CIF file has been submitted to the Cambridge
Crystallographic Data Centre and assigned the correspond-
ing depository number (CCDC 286618).
mass spectral data of 8, see Ref. 4.
6. Single crystal X-ray diffraction data were collected on a
Bruker AXS SMART APEX CCD diffractometer at 292 K.
The X-ray generator was operated at 50 kV and 35 mA
using Mo Ka radiation. The data was collected with a x
scan width of 0.3ꢁ. A total of 606 frames per set were
collected using SMART in three different settings of u (0ꢁ,
90ꢁ and 180ꢁ) keeping the sample detector distance at
6.062 cm and the 2h value fixed at À25ꢁ. The data were
7. While this manuscript was being reviewed, a total synthesis
of garsubellin A 1 by the group of Shibasaki came to our
attention (Kuramochi, A.; Usuda, H.; Yamatsugu, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
ASAP).