An approach toward the synthesis of PPAP natural product garsubellin A: Construction of the tricyclic core

Article abstract of DOI:10.1016/j.tet.2012.12.066

In a study directed toward the bioactive natural product garsubellin A, an expedient route to the bicyclo[3.3.1]nonan-9-one bearing tricyclic core, with a bridgehead anchored tetrahydrofuran ring, is delineated. The approach emanating from commercially av

Full text of DOI:10.1016/j.tet.2012.12.066

Tetrahedron 69 (2013) 1815e1821
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
An approach toward the synthesis of PPAP natural product
garsubellin A: construction of the tricyclic core
,
b
,
a,b
Goverdhan Mehta a , Mrinal K. Bera
*
a Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
b School of Chemistry, University of Hyderabad, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In a study directed toward the bioactive natural product garsubellin A, an expedient route to the bicyclo
[3.3.1]nonan-9-one bearing tricyclic core, with a bridgehead anchored tetrahydrofuran ring, is de-
lineated. The approach emanating from commercially available dimedone involved a DIBAL-H mediated
retro aldol/re-aldol cyclization cascade and a PCC mediated oxidative cyclization as the key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 18 December 2012
Accepted 27 December 2012
Available online 4 January 2013
Keywords:
Dimedone
PPAP natural product
Neurodegenerative disorder
Alzheimers’ disease
Aldol reaction
PCC oxidation
1. Introduction
like Alzheimers’, a disease condition that according to the cholin-
ergic hypothesis can be traced to the reduced synthesis of the
In recent years, particularly during the past decade, natural
products based on Polycyclic Polyprenylated Acyl Phloroglucin
(PPAP) framework have been encountered with increasing fre-
quency among diverse terrestrial plant species and their number
has now crossed a century mark. The diversity among PPAP natural
products manifests through a myriad of structural, functional group
and stereochemical variations. Thus, PPAPs may embody one or
more prenyl/geranyl groups at various biosynthetically ordained
locations on their bicyclo[3.3.1]nona-9-one framework embel-
lished with dense functionalization pattern.1,2 Among the more
prominent examples of the growing PPAP family with a generous
complement of prenyl groups are hyperforin 1, 2a,b papuaforin A 2,2e
garcinielliptone L 32c and nemorosone 42a,f,g to name a few (Fig. 1).
Apart from their structural complexity and varied functionalization
patterns, PPAP’s display wide range of biological activities that
range from enhancement of choline acetyltransferase (ChAT) acti-
vity,3e cytotoxicity,3b antidepressant activity,3c antibacterial,3d anti-
malarial3a and even anti-HIV activity.2b Among these bioactivity
attributes, the ability to upregulate choline acetyltransferase
(ChAT) activity has implications in neurodegenerative disorders
neurotransmitter acetylcholine (ACh).3e Thus, the inducers of the
enzyme choline acetyltransferase (ChAT), an enzyme responsible
for the biosynthesis of acetylcholine (ACh) can be regarded as
possible therapeutic lead compounds against Alzheimers’ disease.
In this context, garsubellin A 5,2h a complex PPAP natural product
reported by the group of Fukuyama in 1997 from the wood of
Garcinia subelliptica has received wide spread attention. It has been
reported by these authors through in vitro experiments that gar-
subellin A 5, enhanced the choline acetyltransferase (ChAT) activity
in P 10 rat septal neurons by 154% at 10 m
M concentration.2h This
was a significant observation and indicated a possible role for
garsubellin A 5 in Alzheimers’ therapeutics and this in turn trig-
gered a flurry of activity toward its synthesis. During the past de-
cade several total syntheses of garsubellin A 5 along with model
studies aimed at accessing its framework and analogs have surfaced
in the literature.4,5
As part of our continuing program5,6 toward the total synthesis of
PPAP natural products and convenient access to the diverse frame-
works present in them, we have explored the synthetic potential and
generality of a reconstructive aldol cyclization strategy to gain facile
entry into the bicyclo[3.3.1]nonanone framework from a conve-
niently accessible precursor as indicated in Scheme 1. The corner
stone of this strategy was the rapid construction of a bicyclic enol-
lactone moiety 6 and its rearrangement through retro-aldol, re-al-
dol steps to a bridged ketone 7 under thermodynamically controlled
* Corresponding author. Tel.: þ91 40 23010785; fax: þ91 40 23012460; e-mail
addresses: gmehta43@gmail.com, gm@orgchem.iisc.ernet.in, gmsc@uohyd.ernet.in
(G. Mehta).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.066

1816
G. Mehta, M.K. Bera / Tetrahedron 69 (2013) 1815e1821
O
O
O
O
O
O
OH
OH
O
OH
O
O
O
O
O
O
Ph
O
Hyperforin 1
Garcinielliptone L 3
Nemorosone 4
Papuaforin A 2
Fig. 1. Representative PPAP natural products.
reaction regime, Scheme 1. Herein, we outline an extension of the
reconstructive aldol protocol toward construction of the tricyclic
framework present in garsubellin A 5.
its enolic hydroxyl group on the neighboring prenyl group,
Scheme 2. -Hydroxyenone 8 embodies a versatile functional
b
motif ubiquitous1,2 among PPAPs and could be accessed through
functional group modifications in the bridged bicyclic precursor
9. Bicyclic 9 in turn was resourced through our previously tested
reconstructive aldol strategy from bicyclic enol lactone 10.5b The
enol lactone 10 could be prepared from precursor 11, which
harbored the quaternary center and the two prenyl arms in req-
uisite relative stereochemistry. Intermediate 11 was to be ob-
tained from the prenylated cyclohexenone 12, whose possible
origin could be traced to a versatile and readily available dime-
done 13, Scheme 2.
O
O
R
R
R
O
R
O
Redn.
O
O
R
R
6; R= H, Prenyl, Geranyl
To implement the synthetic strategy unraveled through the
retrosynthetic analysis, commercially sourced dimedone 13 was
transformed to 5,5-dimethyl-3-phenylthio-2-cyclohexenone 14
following a reported two step procedure.7 LDA mediated deproto-
nation in 14, under kinetically controlled conditions, and addition
of prenyl bromide led smoothly to the mono-prenylated product
15. The vinylogous thioether derivative 15 was reduced with LAH to
furnish epimeric allylic alcohols 16 and the mixture was used as
such for the next step involving HgCl2 mediated eliminative
unmasking of the carbonyl group8 to deliver the key cyclohexenone
building block 12, Scheme 3. The next objective was to regiose-
lectively reduce the enone double bond in 12 to obtain 17 and set-
up the key quaternary center through stereo- and regiocontrolled
tandem prenylation-Michael addition sequence. After some ex-
ploratory experiments using various conjugate enone reduction
protocols, chemoselective reduction of the enone double bond in 12
was successfully executed in the presence of nickelboride,9 gener-
ated in situ from NiCl2.6H2O and NaBH4, to afford the saturated
cyclohexanone derivative 17, Scheme 3.
O
HO
R
R
R
O
R
OH
O
O
R
R
7
Scheme 1. General strategy to access PPAP framework.
2. Results and discussion
In retrosynthetic terms, garsubellin A 5 framework, particu-
larly its bridgehead anchored tetrahydrofuran moiety, was sought
b-hydroxyenone 8
through oxidative tetrahydrofuran generating cyclization of
to be obtained from an advanced bicyclic
OH
O
O
O
18
OH
O
8
3
4
6
1
O
O
O
O
8
9
Garsubellin A 5
CO2Me
O
O
O
O
O
O
12
11
10
Dimedone 13
Scheme 2. Retrosynthetic consideration enroute garsubellin A 5.

G. Mehta, M.K. Bera / Tetrahedron 69 (2013) 1815e1821
1817
strategy. This was sought to be implemented through DIBAL-H
promoted retro-aldol/re-aldol reaction cascade. Toward this end,
enol-lactone 10 was reduced with DIBAL-10 to trigger the desired
structural reorganization and furnished the bicyclo[3.3.1]nonanone
derivative 20 as a mixture of C-1 hydroxy epimers. PCC oxidation in
20 readily furnished a single bicyclo[3.3.1]nonane based dione 9
embodying the bicyclic core of garsubellin A 5, Scheme 4.
O
O
O
a
b
SPh
O
SPh
Arrival at the bicyclo[3.3.1]nonanone derivative 9, with appro-
priate positioning of requisite substituents/functionalities at C-4
13
14
15
and C-8 paved the way for further elaboration toward b-hydrox-
c
yenone 8 as delineated in the retrosynthetic perspective (Scheme
2). This required installation of a 1,3-dicarbonyl moiety on to the
bicyclic framework to access 8. For this purpose, bicyclic dione 9
needed to be first transformed to the corresponding enone 21 and
this was accomplished following the Saegusa protocol11 involving
Pd-mediated eliminative dehydrosilylation. Thus, bicyclic ketone 9
was smoothly transformed to its TMS enol ether and Pdþ2 mediated
desilylation delivered the bicyclic enone 21, Scheme 5.
OH
d
e
O
O
SPh
Nucleophilic epoxidation in enone 21 in the presence of
H2O2eNaOH was straight forward and stereoselectively afforded
17
12
16
Scheme 3. Reagents and conditions: a) i) (COCl)2, DMF, 0 ꢀC / rt, 1 h, 97%; ii) PhSH,
NaOH, MeOH, rt, 6 h, 86%; b) LDA, prenyl bromide, THF, ꢁ78 ꢀC / 0 ꢀC, 12 h, 95%; c)
LAH, THF, 0 ꢀC / rt, 1 h; d) HgCl2, CH3CNeH2O (5:1), 60 ꢀC, 1 h, 64% (over two steps);
e) NiCl2$6H2O, NaBH4, MeOH, 0 ꢀC / rt, 1 h, 94%.
a,
b
-epoxy ketone 22 in good yield. After a few trials, it was found
that the epoxide moiety in -epoxy ketone 22 could be reduc-
tively cleaved in a regioselective manner employing the PhSeSePh-
NaBH4-EtOH milieu12 to furnish the
-hydroxy ketone 23, Scheme
5. It was expected that oxidation of 23 would generate the de-
sired 1,3-dicarbonyl precursor for implementing the oxy-
a,b
b
LDA promoted prenylation on 17 was first implemented and this
proceeded smoothly and regioselectively to deliver the mono-
prenylated product 18. Michael addition of methyl acrylate to
mono prenylated product 18 was effected in the presence of po-
tassium tert-butoxide to stereoselectively afford 11 as a single di-
astereomer, Scheme 4. Stereoselectivity during the Michael
addition step could be attributed to the 1,3-stereoinductive effect of
the bystander prenyl group at C-8 (garsubellin A 5 numbering).
Generation of the quaternary center in 11 through tandem
prenylation-Michael addition sequence resulted in the cis-dispo-
sition of the two prenyl groups, necessary for further evolution
toward the target. This also ensured the exo disposition of the C-8
prenyl arm on the bicyclo[3.3.1]nonanone framework of the natural
product. Ester group in 11 was routinely hydrolyzed to deliver the
carboxylic acid 19 and was transformed to the enol-lactone 10
following well established protocols, Scheme 4. Arrival of enol
lactone 10 set the stage for executing the reconstructive aldol
8
functionalization of the bridgehead C-4 prenyl side arm as envis-
aged in Scheme 2. However, this seemingly innocuous oxidation of
23 to 8 proved difficult despite recourse to a variety of reagents. In
the case of PCC-silica gel as the oxidant the outcome from 23 was
unexpected but prima facie interesting. Indeed, PCC oxidation of 23
delivered tricyclic compound 24, embodying a properly positioned
tetrahydrofuran ring, and this seemed to be a great bonus at first
sight and a fortuitous outcome as we were seeking the 1,3-
dicarbonyl compound 8 as a prelude to the generation of the tet-
rahydrofuran ring present in our target molecule. Although the
structure of 24 was clearly dictated from its spectral characteristics,
the data was not incisive enough to delineate the stereochemical
signature at the newly generated C-18 stereogenic center. Therefore
recourse was taken to single crystal X-ray structure de-
termination13 and an ORTEP representation is displayed in Fig. 2.
CO2H
CO2Me
a
b
c
8
8
O
O
O
O
17
18
11
19
d
O
O
8
8
f
e
1
O
O
O
OH
O
OH
9
20
10
Scheme 4. Reagents and conditions: a) LDA, prenyl bromide, THF, ꢁ78 ꢀC, 6 h, 72%; b) KOtBu, methyl acrylate, benzene, rt, 30 min, 71%; c) KOH, MeOH, H2O, 65 ꢀC, 2 h, 93%; d)
NaOAc, Ac2O, 140 ꢀC, 1 h, 79%; e) DIBAL-H, DCM, 0 ꢀC, 2 h, 67%; f) PCC, DCM, rt, 1 h, 95%.

1818
G. Mehta, M.K. Bera / Tetrahedron 69 (2013) 1815e1821
O
O
O
O
O
a
b
c
O
O
O
OTMS
9
22
21
d
OTMS
g
OTMS
OH
O
O
O
O
18
OH
O
O
O
f
e
O
OTMS
O
O
25
24
23
Scheme 5. Reagents and conditions: a) Et3N, DMAP, TMSOTf, DCM, 0 ꢀC, 1 h; b) Pd(OAc)2, CH3CN, 55 ꢀC, 6 h, 59% (over two steps); c) H2O2, NaOH, MeOH, 0 ꢀC, 1 h, 85%; d) PhSeSePh,
NaBH4, AcOH, EtOH, 0 ꢀC, 1 h, 71%; e) PCC, DCM, rt 1 h, 76%; f) Et3N, DMAP, TMSOTf, DCM, 0 ꢀC, 1 h; g) Pd(OAc)2, CH3CN, 55 ꢀC, 6h, 55% (over two steps).
and the stereochemical outcome for the formation of 24 is in-
dicated in Scheme 6 and has some precedence.14
Undeterred by the stereochemical truancy displayed by 23
during the oxidative cyclization, we decided to proceed further and
reinstall the C-2, C-3 double bond necessary for further progress
toward the natural product. Consequently, tricyclic ketone 24 was
subjected to Saegusa protocol11 via TMS enol ether formation and
palladium mediated eliminative dehydrosilylation to furnish enone
25 with concomitant protection of the tertiary hydroxyl group as
TMS-ether, Scheme 5.
Arrival at 25 signaled significant progress toward the synthesis
of garsubellin A as intermediates similar to it have been previously
subjected to a straight forward end game4 to deliver the natural
product. However, in our case the epimeric nature of the C-18
center prevented further march from 24 or 25 toward the target.
Nonetheless, the efficacy of our concise approach toward garsu-
Fig. 2. ORTEP diagram of compound 24.
While X-ray determination confirmed our assignment of gross
structure to 24, its stereochemistry at C-18 subdued our excitement
as it turned out to be epimeric with respect to that present in the
natural product, Scheme 5. Smooth formation of 24 during oxida-
tion with PCC indicated that the C-3 hydroxyl group is refractory to
oxidation and the oxidant PCC seem to induce a chromate ester
mediated stereoselective cyclization of 23 with the neighboring
prenyl participation to furnish 24, Scheme 6. A possible mechanism
bellin A core has been demonstrated and efforts are underway to
adapt its strategic elements to devise a synthesis of the natural
product.
3. Conclusion
In summary, we have demonstrated a concise and efficient
strategy to construct polyprenylated tricyclic core present in gar-
subellin
A 5 from commercially available dimedone. A re-
constructive aldol cyclization step and a fortuitous tetrahydrofuran
formation through oxidative prenyl cyclization were pivotal to the
success of our construction enroute garsubellin A. We believe that
a sound ground work has been laid in this effort to craft a synthesis
of this complex PPAP natural product.
O
O
O
O Cr
OH
OH
O
O
O
23
4. Experimental section
4.1. General information
O
O
OH
O
18
18
All reagents employed were purchased from commercial sour-
ces and used without further purification. Commercially available
Sisco Research Laboratories (SRL) silica gel (100e200 mesh particle
size) was used for column chromatography. The column was usu-
ally eluted with various combinations of ethyl acetateepetroleum
ether mixtures. Visualization of the spots on TLC plates was ach-
ieved under UV light or by exposure to iodine vapor or by
Cr
O
O
OH
O
O
O
24
Scheme 6. Plausible mechanism for formation of 24.

G. Mehta, M.K. Bera / Tetrahedron 69 (2013) 1815e1821
1819
employing ethanolic vanillin stain. Unless otherwise stated, all dry
and air sensitive reactions were performed in oven dried glassware
under argon/nitrogen atmosphere using standard syringe and
septum technique. Solvent, such as THF, was freshly distilled from
sodium benzophenone radical anion. Removal of solvents was
performed under reduced pressure using a rotary evaporator. 1H
and 13C NMR spectra were recorded on JEOL JNM-LA 300 or Bruker
AMX 400 instruments. 1H and 13C samples were generally made in
CDCl3 as solvent and TMS and CDCl3 were employed as an internal
reference for 1H and 13C NMR, respectively unless otherwise
mentioned.
a methanolic solution of enone 12 (3.47 g, 18.1 mmol) was trans-
ferred to it using a cannula. The cooling bath was removed imme-
diately after the addition and the reaction mixture was allowed to
stir at room temperature for 1 h. Reaction mixture was diluted with
ether (50 mL), the black mass was filtered off and the crude product
was purified on a silica gel column (eluent 5e10% ethyl acetate in
petroleum ether) to produce cyclohexanone 17 (3.30 g, 94%) as
a colorless oil. IR (Neat)
5.16 (m, 1H), 2.36e2.21 (m, 5H), 2.11e1.99 (m, 3H), 1.71 (s, 3H), 1.61
(s, 3H),1.54e1.42 (m,1H),1.05 (s, 3H), 0.81 (s, 3H); 13C NMR (75 MHz,
n ;
1716 cmꢁ1 1H NMR (300 MHz, CDCl3)
d
CDCl3) d 212.2,132.6, 123.5, 55.9, 46.1, 41.0, 38.6, 29.9, 27.9, 27.7, 25.8,
20.8, 17.8; HRMS (ESI) (m/z): found 217.1559 [MþNa]þ; calcd for
4.1.1. 5,5-Dimethyl-6-(3-methyl-2-butenyl)-3-(phenylsulfanyl)-2-
cyclohexen-1-one (15). To a THF solution of LDA (55 mL, 1.0 M, freshly
prepared from equimolar amount of DIPA and n-BuLi), kept at ꢁ78 ꢀC,
was added a THF (20 mL) solution of enone 14 (6.90 g, 29.7 mmol)
over a period of 10 min. The resulting solution was stirred for 1 h and
then prenyl bromide (10.3 mL, 89.2 mmol) was added to it. After
additional 1 h at ꢁ78 ꢀC, the reaction mixture was allowed to warm
up to 0 ꢀC and stirred for 12 h at the same temperature. Reaction was
quenched by adding 20 mL of satd NH4Cl solution and the product
was extracted with ether (3ꢂ100 mL). The combined ether extracts
were washed with water, brine and dried over anhydrous Na2SO4.
After evaporation of solvent, the resulting crude material was puri-
fied on a silica gel column (eluent 10e20% ethyl acetate in petroleum
C13H22ONa 217.1568.
4.1.4. Methyl 3-[(1R*,5S*)-4,4-dimethyl-1,5-di(3-methyl-2-butenyl)-2-
oxocyclohexyl] propanoate (11). To a THF solution of LDA (35 mL,
1.0 M, freshly prepared from equimolar amount of DIPA and n-BuLi),
kept at ꢁ78 ꢀC, was added a THF (10 mL) solution of cyclohexanone
derivative 17 (3.3 g, 17.0 mmol) over a period of 10 min. The resulting
solution was stirred for 1 h at the same temperature and then prenyl
bromide (3.93 mL, 34.0 mmol) was added to it and the resulting
mixture was stirred for 6 h at the same temperature. Reaction was
quenched by adding 15 mL of satd NH4Cl solution and the product
was extracted with ether (3ꢂ50 mL). The combined ether layer was
washed with water, brine solution and dried over anhydrous Na2SO4.
After evaporation of solvent, the crude material was purified on
a short silica gel column (eluent 5e15% ethyl acetate in petroleum
ether) to obtain di-prenylated cyclohexanone derivative 18 (3.2 g,
72%) as a light yellow oil, which was used directly for the next
reaction.
ether) to obtain 15 (8.47 g, 95%) as a light yellow oil. IR (Neat)
n 1660,
1590 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.49e7.40 (m, 5H), 5.42 (s,
1H), 5.16e5.11 (m, 1H), 2.49e2.30 (m, 2H), 2.24e2.19 (m, 2H),
2.06e2.02 (m, 1H), 1.65 (s, 3H), 1.57 (s, 3H), 1.08 (s, 3H), 1.01 (s, 3H);
13C NMR (75 MHz, CDCl3)
d 198.8,162.2, 135.4 (2C), 131.9, 130.0,129.8
(2C), 128.3, 122.8, 119.5, 57.9, 42.9, 36.9, 28.4, 25.7, 24.7, 24.3, 17.7;
HRMS (ESI) (m/z): found 301.1614 [MþH]þ; calcd for C19H24OS
301.1626.
Methyl acrylate (1.30 mL, 14.6 mmol) and KOtBu (1.59 g,
14.2 mmol) were added to a stirred solution of di-prenylated cy-
clohexane derivative 18 (3.2 g, 12.2 mmol) in dry benzene (30 mL)
at room temperature. After 30 min, the reaction mixture was di-
luted with ether (30 mL) and quenched with water (20 mL). The
organic phase was separated and the aqueous part was extracted
with ether (2ꢂ50 mL). The combined ether extract was washed
with water, brine and dried over Na2SO4. Removal of solvent pro-
duced a crude brown mass, which was purified by silica gel column
chromatography (10e20% ethyl acetate in petroleum ether) to ob-
4.1.2. 5,5-Dimethyl-4-(3-methyl-2-butenyl)-2-cyclohexen-1-one
(12). To a solution of the enone 15 (8.47 g, 28.2 mmol) in dry THF
(30 mL) was added LAH (1.07 g, 28.2 mmol) portion wise at 0 ꢀC and
the reaction mixture was stirred for 1 h at room temperature. Ex-
cess LAH was quenched with ethyl acetate and the reaction mixture
was then diluted with water (20 mL). The product was extracted
with ethyl acetate (3ꢂ100 mL) and the combined organic phase was
washed with brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the crude allylic alcohol
16 was used for next reaction without further purification.
tain 11 (3.0 g, 71%) as a colorless oil. IR (Neat)
NMR (300 MHz, CDCl3) 5.11e5.02 (m, 2H), 3.65 (s, 3H), 2.47e2.09
n
1741, 1704 cmꢁ1; 1H
d
(m, 8H), 1.98e1.88 (m, 2H), 1.79e1.65 (m, 2H), 1.72 (s, 3H), 1.70 (s,
3H), 1.59 (s, 6H), 1.42e1.33 (m, 1H), 1.04 (s, 3H), 0.73 (s, 3H); 13C
HgCl2 (15.33 g, 56.5 mmol) was added to a solution of crude
allylic alcohol 16 in 25 mL of acetonitrileewater (5:1) and the
resulting mixture was heated at 60 ꢀC for 1 h. Mercury salts were
filtered off and the organic solvent was removed under reduced
pressure. The product was extracted from the aqueous residue
with ether (3ꢂ50 mL). The crude product was purified on a short
silica gel column (eluent 10% ethyl acetate in petroleum ether) to
afford the corresponding enone 12 (3.47 g, 64%) as a light yellow
NMR (75 MHz, CDCl3) d 214.8, 173.9, 134.3, 132.5, 123.3, 119.3, 53.7,
51.7, 51.1, 42.0, 38.7(2C), 32.1, 31.0, 29.6, 28.7, 28.3, 26.0, 25.8, 19.9,
18.0, 17.9; HRMS (ESI) (m/z): found 371.3563 [MþNa]þ; calcd for
C22H36O3Na 371.3562.
4.1.5. 3-[(1R*,5S*)-4,4-Dimethyl-1,5-di(3-methyl-2-butenyl)-2-
oxocyclohexyl]propanoic acid (19). To a solution of ester 11 (3 g,
8.62 mmol) in 11 mL of methanolewater (10:1) was added KOH
(965 mg, 17.3 mmol) and the resulting mixture was heated at 65 ꢀC
(oil bath temperature) for 2 h. After completion of the reaction,
methanol was evaporated and the resulting residue was diluted
with 25 mL of ether and 25 mL of water. Both layers were separated.
The aqueous layer was carefully acidified to pH 1 (as indicated by
Litmus paper) with 6 N HCl and extracted with ethyl acetate
(3ꢂ50 mL). Combined ethyl acetate extract was washed with brine
and dried over Na2SO4. Removal of solvent in vacuo afforded car-
oil. IR (Neat)
n ; d 6.72 (dd,
1682 cmꢁ1 1H NMR (300 MHz, CDCl3)
J¼10.2, 2.7 Hz, 1H), 5.98 (dd, J¼10.2, 2.7 Hz, 1H), 5.17e5.14 (m,
1H), 2.28e2.19 (m, 4H), 1.99e1.84 (m, 1H), 1.74 (s, 3H), 1.63 (s,
3H), 1.09 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 200.0,
152.6, 134.1, 128.2, 122.0, 52.4, 47.3, 37.02, 28.9, 27.2, 25.8, 21.5,
17.9; HRMS (ESI) (m/z): found 193.1591 [MþH]þ; calcd for
C13H20O 193.1592.
4.1.3. 3,3-Dimethyl-4-(3-methyl-2-butenyl)cyclohexan-1-one
(17). NiCl2.6H2O (21.5 g, 90.4 mmol) was dissolved in 25 mL of dry
methanol. The resulting green colored solution was cooled to 0 ꢀC
and NaBH4 (3.43 g, 90.4 mmol) was added to it over a period of 5 min
with concurrent gas evolution. The resulting black suspension was
stirred at the same temperature for an additional 15 min and then
boxylic acid 19 (2.67 g, 93%) as colorless liquid. IR (Neat)
n 3189,
1707 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
5.11e5.02 (m, 2H),
2.46e2.41 (m, 1H), 2.37e2.05 (m, 5H), 2.02e1.87 (m, 2H), 1.75e1.64
(m, 2H), 1.72 (s, 3H), 1.70 (s, 3H), 1.59 (s, 6H), 1.44e1.22 (m, 3H), 1.04
(s, 3H), 0.74 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
214.9, 178.8, 134.5,
132.6, 123.3, 119.2, 53.7, 51.1, 42.1, 38.7, 38.6, 32.1, 30.7, 29.6, 28.7,

1820
G. Mehta, M.K. Bera / Tetrahedron 69 (2013) 1815e1821
28.3, 26.1, 25.9, 19.9, 18.0, 17.9; HRMS (ESI) (m/z): found 357.2406
[MþNa]þ; calcd for C21H34O3Na 357.2406.
petroleum ether) to obtain the pure enone 21 (278 mg, 59% over
two steps) as colorless liquid. IR (Neat)
1732, 1676 cmꢁ1; 1H NMR
(300 MHz, CDCl3)
n
d
6.82 (d, J¼9.7 Hz, 1H), 6.34 (d, J¼9.7 Hz, 1H),
4.1.6. (4aR*,6S*)-7,7-Dimethyl-4a,6-di(3-methyl-2-butenyl)-
3,4,4a,5,6,7-hexahydro-2H-2-chromenone (10). To a stirred solution
of carboxylic acid 19 (1.0 g, 2.99 mmol) in Ac2O (5 mL) was added
NaOAc (1.23 g, 14.9 mmol) and the resulting mixture was refluxed
at 140 ꢀC for 1 h under N2. Upon completion of the reaction, the
reaction mixture was cooled to 0 ꢀC and diluted with 15 mL of water
and 15 mL of ether. The acetic acid generated from Ac2O was
quenched by slowly adding solid NaHCO3. Layers were separated
and the aqueous phase was extracted with ether (2ꢂ50 mL) and
followed by usual work up. Ether was evaporated to give a residue,
which was purified on a silica gel column (eluent 5e10% ethyl ac-
etate in petroleum ether) to obtain 10 (747 mg, 79%) as a colorless
5.15e5.10 (m, 1H), 5.01e4.96 (m, 1H), 2.91 (s, 1H), 2.56e2.46 (m,
1H), 2.27e2.11 (m, 2H),1.87e1.81 (m,1H),1.79e1.62 (m, 2H),1.72 (s,
3H), 1.69 (s, 3H), 1.66 (s, 3H), 1.57 (s, 3H), 1.49e1.36 (m, 1H), 1.09 (s,
3H), 0.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 207.5, 197.8, 152.2,
135.3, 133.2, 131.6, 122.4, 118.4, 76.2, 53.4, 43.6, 40.1, 38.4, 32.1, 27.4,
26.6, 25.9, 25.8, 20.6, 18.0, 17.8; HRMS (ESI) (m/z): found 337.2139
[MþNa]þ; calcd for C21H30O2Na 337.2144.
4.1.9. (1R*,2R*,4R*,6R*,8S*)-7,7-Dimethyl-1,8-di(3-methyl-2-butenyl)-
3-oxatricyclo[4.3.1.02,4]decane-5,10-dione (22). To a methanolic solu-
tion (10 mL) of the enone 21 (278 mg, 0.89 mmol), kept at 0 ꢀC, was
added 50% aqueous solution of H2O2 (200 mL, 2.66 mmol) and an
oil. IR (Neat)
n
1765, 1683 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
5.29 (s,
aqueous solution of NaOH (35 mg, 0.89 mmol). After stirring for 1 h,
methanol was evaporated and the product was extracted with ether
(3ꢂ20 mL). Combined organic extract was washed by water, brine
and dried over anhydrous Na2SO4. After removal of solvent, the
crude residue was purified on a silica gel column (eluent 10e20%
ethyl acetate in petroleum ether) to obtain epoxy ketone 22 (248 mg,
1H), 5.07e5.04 (m, 2H), 2.68e2.55 (m, 3H), 2.17e2.05 (m, 4H),
1.92e1.78 (m, 1H), 1.71 (s, 6H), 1.60 (s, 6H), 1.54e1.43 (m, 2H),
1.30e1.24 (m, 1H), 1.04 (s, 3H), 0.86 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 170.5, 150.0, 134.8, 132.6, 123.4, 120.7, 119.3, 41.4, 37.6, 35.2,
35.1, 34.8, 29.7, 29.1, 28.1, 28.0, 25.9, 25.8, 22.0,18.1,17.9; HRMS (ESI)
(m/z): found 317.2484 [MþH]þ; calcd for C21H33O2 317.2480.
85%) as colorless oil. IR (Neat)
CDCl3) 5.28e5.23 (m, 1H), 5.10e5.00 (m, 1H), 3.49e3.47 (m, 1H),
n
1736, 1709 cmꢁ1; 1H NMR (300 MHz,
d
4.1.7. (1S*,5R*,7S*)-8,8-Dimethyl-5,7-di(3-methyl-2-butenyl) bicyclo
[3.3.1]nonane-2,9-dione (9). DIBAL-H (20% solution in toluene,
4.2 mL, 5.91 mmol) was added to a dichloromethane (20 mL) so-
lution of enol lactone 10 (747 mg, 2.36 mmol) at 0 ꢀC under N2 and
stirred for 2 h at the same temperature. Reaction was quenched by
adding 5% HCl solution (10 mL) and the product was extracted with
dichloromethane (3ꢂ50 mL). The combined organic layer was
washed with water, brine and dried over anhydrous Na2SO4. The
solvent was evaporated in rotary evaporator and the crude product
was purified on a silica gel column (eluent 30e50% ethyl acetate in
petroleum ether) to furnish 20 (503 mg, 67%) as a colorless oil.
To a dichloromethane (25 mL) solution of alcohol 20 (503 mg,
1.58 mmol), kept at room temperature, was added pre-dried PCC
(680 mg, 3.16 mmol) and silica gel (680 mg, 100e200 mesh) at
a time. The resulting orange colored suspension was stirred at the
same temperature for 1 h and then passed through a short silica gel
column (eluent 10% ethyl acetate in petroleum ether) to obtain
3.43e3.42 (m, 1H), 2.67 (s, 1H), 2.63e2.55 (m, 1H), 2.39e2.32 (m,
1H), 2.21e2.15 (m, 2H), 1.84e1.69 (m, 2H), 1.77 (s, 3H), 1.72 (s, 3H),
1.67 (s, 3H), 1.58 (s, 3H), 1.43e1.26 (m, 1H), 1.11 (s, 3H), 0.82 (s, 3H);
13C NMR (75 MHz, CDCl3)
d 205.7, 202.2, 136.3, 134.0, 122.6, 118.2,
72.9, 58.7, 55.9, 51.0, 46.7, 41.8, 37.4, 31.7, 28.5, 27.0, 26.5, 26.3, 21.2,
18.4, 18.3; HRMS (ESI) (m/z): found 353.1636 [MþNa]þ; calcd for
C21H30O3Na 353.1626.
4.1.10. (1S*,4S*,5R*,7S*)-4-Hydroxy-8,8-dimethyl-5,7-di(3-methyl-2-
butenyl)bicyclo[3.3.1]nonane-2,9-dione (23). Acetic acid (30
mL,
0.25 mmol) was added to an ethanolic solution of PhSeNa, prepared
by the reduction of PhSeSePh (470 mg, 1.50 mmol) with NaBH4
(114 mg, 3.01 mmol) in ethanol (6 mL), and the mixture was stirred
for 10 min at room temperature. The resulting solution was added
at once to a solution of epoxy ketone 22 (248 mg, 0.75 mmol) in
ethanol (4 mL) under N2 at ice cold condition. After being stirred for
1 h at the same temperature, the reaction mixture was diluted with
ethyl acetate and washed with brine. Removal of the solvent left the
residue, which was purified by silica gel column chromatography
bicyclic diketone 9 (475 mg, 95%) as colorless oil. IR (Neat)
n 1724,
1699 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
5.23e5.18 (m, 1H),
5.11e5.06 (m, 1H), 2.88 (s, 1H), 2.78e2.51 (m, 3H), 2.23e1.80 (m,
6H), 1.73 (s, 6H), 1.68e1.52 (m, 2H), 1.61 (s, 3H), 1.58 (s, 3H), 1.06 (s,
(eluent 30% ethyl acetate in petroleum ether) to give pure
droxy ketone 23 (177 mg, 71%) as an amorphous solid. IR (Thin film)
3420, 1726, 1700 cmꢁ1; 1H NMR (300 MHz, CDCl3)
5.27e5.22 (m,
b-hy-
3H), 0.85 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
210.6, 208.3, 134.5,
n
d
133.1, 122.7, 119.3, 79.4, 49.3, 45.6, 42.7, 42.4, 39.5, 35.3, 29.6, 29.5,
26.7, 26.1, 25.9, 21.2, 17.9(2C); HRMS (ESI) (m/z): found 339.2308
[MþNa]þ; calcd for C21H32O2Na 339.2300.
1H), 5.07e5.04 (m, 1H), 4.09 (br s, 1H), 3.02e2.57 (m, 4H), 2.89 (s,
1H), 2.25e2.13 (m, 5H), 1.74 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H), 1.58 (s,
3H), 1.51e1.34 (m, 1H), 1.04 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 208.7, 206.8, 135.8, 133.3, 122.3, 118.4, 79.1, 70.2, 54.3, 48.8,
4.1.8. (1S*,5R*,7S*)-8,8-Dimethyl-5,7-di(3-methyl-2-butenyl) bicyclo
[3.3.1]non-3-ene-2,9-dione (21). To a dichloromethane (10 mL) so-
lution of diketone 9 (475 mg, 1.50 mmol), kept at 0 ꢀC, was added
45.3, 42.4, 39.4, 31.4, 30.0, 26.9, 26.1, 25.9, 21.3, 18.0, 17.9; HRMS
(ESI) (m/z): found 355.2249 [MþNa]þ; calcd for C21H32O3Na
355.2249.
Et3N (525
mL, 3.76 mmol), DMAP (18 mg, 10 mol %) and TMSOTf
(545 L, 3.01 mmol) sequentially. After 1 h, reaction was quenched
m
4.1.11. (1S*,3R*,5S*,8S*,10S*)-3-(1-Hydroxy-1-methylethyl)-9,9-
by adding 10 mL of water. The organic phase was separated and the
aqueous phase was extracted with dichloromethane (2ꢂ30 mL).
Combined organic extract was washed with water, brine and dried
over anhydrous Na2SO4. Removal of solvent gave a crude TMS enol
ether (524 mg), which was thoroughly dried and directly used for
next reaction.
To a solution of TMS enol ether (524 mg, 1.35 mmol) in freshly
distilled acetonitrile (10 mL) was added Pd(OAc)2 (364 mg,
1.60 mmol) and the resulting mixture was heated at 55 ꢀC (oil bath
temperature) under N2 for 6 h. After completion of reaction, ace-
tonitrile was removed under reduced pressure and the black resi-
due was charged to a silica gel column (5e10% ethyl acetate in
dimethyl-10-(3-methyl-2-butenyl)-4-oxatricyclo [6.3.1.01,5
] dodec-
ane-7,12-dione (24). A mixture of pre-dried PCC (230 mg,
1.07 mmol) and silica gel (230 mg, 100e200 mesh) was added, at
a time, to a solution of b-hydroxy ketone 23 (177 mg, 0.53 mmol) in
dry dichloromethane (5 mL) at room temperature. After stirring for
1 h at the same temperature, the orange colored mixture was filtered
through a small silica gel column (eluent 30e40% ethyl acetate in
petroleum ether) to obtain 24 (141 mg, 76%) as a white solid. Mp.
113e115 ꢀC; IR (Thin film)
(300 MHz, CDCl3)
n ;
3516, 1727, 1704 cmꢁ1 1H NMR
5.04e5.01 (m, 1H), 4.22e4.19 (m, 1H), 3.79e3.75
d
(m, 1H), 2.92 (s, 1H), 2.84e2.82 (m, 2H), 2.66e2.59 (m, 1H),
2.17e2.05 (m, 3H),1.78e1.64 (m, 4H),1.72 (s, 3H),1.58 (s, 3H),1.22 (s,

G. Mehta, M.K. Bera / Tetrahedron 69 (2013) 1815e1821
1821
3H), 1.12 (s, 3H), 1.09 (s, 3H), 0.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
207.9, 205.8, 133.7, 122.2, 83.7, 79.9, 77.7, 71.8, 58.0, 46.0, 45.4, 42.8,
38.7, 33.3, 28.6, 27.4, 26.5, 25.9, 24.1, 21.3, 17.9; HRMS (ESI) (m/z):
found 371.2191 [MþNa]þ; calcd for C21H32O4Na 371.2198.
Singer, A.; Wonnenmann, M.; Hafner, U.; Rolli, M.; Schafer, C. Pharmacop-
sychiatry 1998, 31, 16e21; (e) Hefti, F. J. Neurobiol. 1994, 25, 1418e1435.
4. Lead references for synthetic approaches and total syntheses of PPAP natural
products: (a) McGrath, N. A.; Binner, J. R.; Markopolous, G.; Brichacek, M.;
Njardarson, J. T. Chem. Commun. 2011, 209e211; (b) Garnsey, M. R.; Matous, J.
A.; Kwiek, J. J.; Coltart, D. M. Bioorg. Med. Chem. Lett. 2011, 21, 2406e2409; (c)
Garnsey, M. R.; Lim, D.; Yost, J. M.; Coltart, D. M. Org. Lett. 2010, 12, 5234e5237;
(d) Uyeda, C.; Rotheli, A. R.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49,
9753e9756; (e) Zhang, Q.; Mitasev, B.; Qi, J.; Porco, J. A., Jr. J. Am. Chem. Soc.
2010, 132, 14212e14215; (f) Qi, J.; Beeler, B.; Zhang, Q.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2010, 132, 13642e13644; (g) Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai,
M.; Shibasaki, M. Angew. Chem., Int. Ed. 2010, 49, 1103e1106; (h) Shimizu, Y.;
Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron 2010, 66, 6569e6584;
(i) Abe, M.; Saito, A.; Nakada, M. Tetrahedron Lett. 2010, 51, 1298e1302; (j)
George, J. H.; Hesse, M. D.; Baldwin, J. E.; Adlington, R. M. Org. Lett. 2010, 12,
3532e3535; (k) Simpkins, N. S.; Taylor, J. D.; Weller, M. D.; Hayes, C. J. Synlett
2010, 639e643; (l) Tolon, B.; Delpech, B.; Marazano, C. Arkivok 2009, 13,
252e264; (m) Barabe, F.; Betournay, G.; Bellavance, G.; Barriault, L. Org. Lett.
2009, 11, 4236e4238; (n) Couladouros, E. A.; Dakanali, M.; Demadis, K. D.;
Vidali, V. P. Org. Lett. 2009, 11, 4430e4433; (o) Kraus, G. A.; Jeon, I. Tetrahedron
Lett. 2008, 49, 286e288; (p) Takagi, R.; Inoue, Y.; Ohkata, K. J. Org. Chem. 2008,
73, 9320e9325; (q) Ahmad, N. M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.;
Wilson, C. Org. Biomol. Chem. 2007, 5, 1924e1934; (r) Ahmad, N. M.; Rodeschini,
V.; Simpkins, N. S.; Ward, S. E.; Blake, A. J. J. Org. Chem. 2007, 72, 4803e4815; (s)
Nuhant, P.; Davis, M.; Pouplin, T.; Delpech, B.; Marazano, C. Org. Lett. 2007, 9,
287e289; (t) Pouplin, T.; Tolon, B.; Nuhant, P.; Delpech, B.; Marazano, C. Eur. J.
Org. Chem. 2007, 5117e5125; (u) Tsukano, C.; Siegel, D. R.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2007, 46, 8840e8844; (v) Qi, J.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2007, 129, 12682e12683; (w) Shimizu, Y.; Kuramochi, A.; Usuda, H.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 4173e4177; (x) Rodeschini, V.;
Simpkins, N. S.; Wilson, C. J. Org. Chem. 2007, 72, 4265e4267; (y) Abe, M.;
Nakada, M. Tetrahedron Lett. 2007, 48, 4873e4877; (z) Abe, M.; Nakada, M.
Tetrahedron Lett. 2006, 47, 6347e6351; (aa) Siegel, D. R.; Danishefsky, S. J. J. Am.
Chem. Soc. 2006, 128, 1048e1049; (ab) Rodeschini, V.; Ahmad, N. M.; Simpkins,
N. S. Org. Lett. 2006, 8, 5283e5285; (ac) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V.
Angew. Chem., Int. Ed. 2005, 44, 3895e3899; (ad) Kuramochi, A.; Usuda, H.;
Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
14200e14201; (ae) Takagi, R.; Nerio, T.; Miwa, Y.; Matsumura, S.; Ohkata, K.
Tetrahedron Lett. 2004, 45, 7401e7405; (af) Klein, A.; Miesch, M. Tetrahedron
Lett. 2003, 44, 4483e4485; (ag) Kraus, G. A.; Dneprovskaia, E.; Nguyen, T. H.;
Jeon, I. Tetrahedron 2003, 59, 8975e8978; (ah) Kraus, G. A.; Nguyen, T. H.; Jeon,
I. Tetrahedron Lett. 2003, 44, 659e661; (ai) Ciochina, R.; Grossman, R. B. Org.
Lett. 2003, 5, 4619e4621; (aj) Srikrishna, A.; Kumar, P. P.; Reddy, T. J. Arkivok
2003, 3, 55e66; (ak) Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002,
43, 3621e3624; (al) Usuda, H.; Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4,
859e862; (am) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943e1946; (an)
Young, D. G. J.; Zeng, D. Z. J. Org. Chem. 2002, 67, 3134e3147; (ao) Nicoloau, K.
C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am. Chem. Soc. 1999, 121, 4724e4725.
5. For earlier contributions towards the synthesis of garsubellin A from our group,
see: (a) Mehta, G.; Bera, M. K. Tetrahedron Lett. 2006, 47, 689e692; (b) Mehta,
G.; Bera, M. K. Tetrahedron Lett. 2004, 45, 1113e1116.
d
4.1.12. (1S*,3R*,8S*,10S*)-9,9-Dimethyl-10-(3-methyl-2-butenyl)-3-
1-methyl-1-[(1,1,1-trimethylsilyl)oxy]ethyl-4-oxatricyclo[6.3.1.01,5
]
dodec-5-ene-7,12-dione (25). To a dichloromethane (5 mL) solution
of diketone 24 (141 mg, 0.41 mmol), kept at 0 ꢀC, were added Et3N
(170 mL, 1.22 mmol), DMAP (5 mg, 10 mol %) and TMSOTf (145 mL,
0.81 mmol) sequentially and stirred for 1 h at the same tempera-
ture. Upon completion, the reaction was quenched by adding 5 mL
of water. Organic phase was separated and the aqueous phase was
extracted with dichloromethane (2ꢂ20 mL) followed by usual work
up. Removal of solvent gave a crude TMS enol ether (175 mg),
which was thoroughly dried and directly used for next reaction.
To a solution of TMS enol ether (175 mg, 0.36 mmol) in freshly
distilled acetonitrile (5 mL) was added Pd(OAc)2 (120 mg,
0.54 mmol) and the resulting mixture was heated at 55 ꢀC (oil bath
temperature) under N2 for 6 h. After completion of the reaction,
acetonitrile was removed under reduced pressure and the black
residue was charged on a silica gel column (eluent 5e10% ethyl
acetate in petroleum ether) to obtain the enone 25 (93 mg, 55% over
two steps) as colorless liquid. IR (Neat)
NMR (300 MHz, CDCl3) 5.78 (s, 1H), 5.05e5.01 (m, 1H), 4.19e4.14
n
1735, 1654, 1626 cmꢁ1; 1H
d
(m, 1H), 2.97e2.89 (m, 1H), 2.80 (s, 1H), 2.34e2.17 (m, 2H),
1.82e1.69 (m, 2H), 1.65 (s, 3H), 1.56 (s, 3H), 1.52e1.42 (m, 2H), 1.39
(s, 3H), 1.22 (s, 3H), 1.16 (s, 3H), 0.88 (s, 3H), 0.15 (s, 9H); 13C NMR
(75 MHz, CDCl3)
d 204.3, 194.5, 179.4, 133.0, 122.7, 105.4, 93.1, 73.4,
72.9, 59.7, 42.0, 41.3, 41.0, 27.5, 27.3, 27.0, 26.8, 26.3, 25.8, 20.4, 17.9,
2.5 (3C); HRMS (ESI) (m/z): found 419.2609 [MþNa]þ; calcd for
C24H38O4SiNa 419.2617.
Acknowledgements
One of us, M.K.B. thanks UGC for award of a research fellowship.
Single crystal X-ray diffraction data was collected at the CCD facility
of IISc, Bangalore. GM wishes to thank Eli Lilly and Jubilant Bhartia
Foundations for the current research support and the Government
of India for the award of National Research Professorship.
6. (a) Mehta, G.; Das, M.; Kundu, U. K. Tetrahedron Lett. 2012, 53, 4538e4542; (b)
Mehta, G.; Dhanbal, T.; Bera, M. K. Tetrahedron Lett. 2010, 51, 5302e5305; (c)
Mehta, G.; Bera, M. K. Tetrahedron Lett. 2009, 50, 3519e3522; (d) Mehta, G.;
Bera, M. K. Tetrahedron Lett. 2008, 49, 1417e1420; (e) Mehta, G.; Bera, M. K.;
Chatterjee, S. Tetrahedron Lett. 2008, 49, 1121e1124.
References and notes
7. (a) Mewshaw, R. E. Tetrahedron Lett. 1989, 30, 3753e3756; (b) Matoba, K.;
Tokizawa, M.; Morita, T.; Yamazaki, T. Chem. Pharm. Bull. 1985, 33, 368e372.
8. Trost, B. M.; Stanton, J. L. J. Am. Chem. Soc. 1975, 97, 4018e4025.
9. Gheorghe, A.; Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71, 2173e2176.
10. Mukai, C.; Kagayama, K.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1998,
3517e3518.
1. Recent reviewers: (a) Richard, J.-A.; Pouwer, R. H.; Chen, D. Y.-K. Angew. Chem.,
Int. Ed. 2012, 51, 2e28; (b) Njardarson, J. T. Tetrahedron 2011, 67, 7631e7666; (c)
Singh, I. P.; Sidana, J.; Bharate, S. B.; Foley, W. J. Nat. Prod. Rep. 2010, 27,
393e416; (d) Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963e3986.
2. (a) Hernandez, I. M.; Fernandez, M. C.; Cuesta-Rubio, O.; Piccinelli, A. N.;
Rastrelli, L. J. Nat. Prod. 2005, 68, 931e934; (b) Piccinelli, A. L.; Cuesta-Rubio, L.;
Chika, M. B.; Mahmood, N.; Pagano, B.; Pavone, M.; Barone, V.; Rastrelli, L. Tet-
rahedron 2005, 61, 8206e8211; (c) Weng, J.-R.; Tsao, L.-T.; Wang, J.-P.; Wu, R.-R.;
Lin, C.-N. J. Nat. Prod. 2004, 67, 1796e1799; (d) Savikin, F. K.; Aljancic, I.; Vajs, V.;
Menkovic, N.; Macura, S.; Gpjgic, G.; Milosavljevic, S. J. Nat. Prod. 2003, 66,
1236e1238; (e) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat.
Prod. 2001, 64, 701e706; (f) Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-Uribe,
B. A.; Cardenas, J. Phytochemistry 2001, 57, 279e283; (g) de Oliviera, C. M. A.;
Porto, A. L. M.; Bittrich, V.; Marsaioli, A. J. Phytochemistry 1999, 50, 1073e1079;
(h) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997, 45,
947e949; (i) de Oliveira, C. M. A.; Porto, A. M.; Bittrich, V.; Vencato, I.; Marsaioli,
A. J. Tetrahedron Lett. 1996, 37, 6427e6430; (j) Baystrov, N. S.; Chernov, B. K.;
Dobrynin, V. N.; Kolosov, M. N. Tetrahedron Lett. 1975, 16, 2791e2794.
11. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011e1013.
12. Miyashita, M.; Suzuki, T.; Yoshikoshi, A. Tetrahedron Lett. 1987, 28, 4293e4296.
13. Single crystal X-ray diffraction data of 24 was collected on a Bruker AXS SMART
APEX CCD diffractometer at 291 K. The X-ray generator was operated at 50 kV
and 35 mA using MoKa radiation. The data was collected with a
u scan width of
0.3ꢀ. A total of 606 frames per set were collected using SMART in three different
settings of 4 (0ꢀ, 90ꢀ and 180ꢀ) keeping the sample at a detector distance of 6.
062 cm and the 2
q
value fixed at ꢁ25ꢀ. The data was reduced by SAINTPLUS; an
empirical absorption correction was applied using the package SADABS, and
XPREP was used to determine the space group. The structure was solved using
SIR92 and refined using SHELXL97.Crystallographic data have been deposited
with the Cambridge Crystallographic data Centre, CCDC 846775. Crystal data for
ꢀ
compound 24: C21H32O4, M ¼ 348.48, triclinic, space group Pꢁ1, a¼6.681(6) A,
b¼11.084(9) A, c¼14.952(13) A,
a
¼71.602(14)ꢀ,
b
¼82.291(14)ꢀ,
g
¼73.374(14)ꢀ,
ꢀ
ꢀ
3. (a) Verotta, L.; Appendino, G.; Bombardelli, E.; Brun, R. Bioorg. Med. Chem. Lett.
2007, 17, 1544e1548; (b) Tanaka, N.; Takaishi, Y.; Shikishima, Y.; Nakanishi, Y.;
Basto, K.; Lee, K. H.; Honda, G.; Ito, M.; Akeda, Y.; Odzhimatov, O. K.;
Ashurmetov, A. J. Nat. Prod. 2004, 67, 1870e1875; (c) Adam, P.; Arigoni, D.;
Bacher, A.; Eisenreich, W. J. Med. Chem. 2002, 45, 4786e4793; (d) Muller, W. E.;
3
ꢀ
V¼1005.6(15) A . Z¼2, rcalcd¼1.151
g
cmꢁ3
,
F(000)¼380,
m
¼0.078 mmꢁ1
,
T¼291 K, number of l.s parameters¼298, R¼0.0543, Rw¼0.1260. GOF¼1.039.
14. Beihoffer, L. A.; Craven, R. A.; Knight, K. S.; Sisson, C. R.; Waddell, T. G. Trans.
Met. Chem. 2005, 30, 582e585.