Total synthesis and absolute configuration assignment of MRSA active garcinol and isogarcinol

Article abstract of DOI:10.1002/chem.201406077

A short total synthesis of (±)-garcinol and (±)-isogarcinol, two endo-type B PPAPs with reported activity against methiciline resistant Staphylococcus aureus (MRSA), is presented. The separation of framework-constructing from framework-decorating steps and the application of two highly regio- and stereoselective Pd-catalysed allylations, that is, the Pd-catalysed decarboxylative Tsuji-Trost allylation and the diastereoselective Pd-catalysed allyl-allyl cross-coupling, are key elements that allowed the total synthesis to be accomplished within 13 steps starting from acetylacetone. After separation of the enantiomers the absolute configurations of the four natural products (i.e., (-)-garcinol, (+)-guttiferone E (i.e., ent-garcinol), (-)-isogarcinol, and (+)-isoxanthochymol (i.e., ent-isogarcinol)) were assigned based on ECD spectroscopy.

Full text of DOI:10.1002/chem.201406077

DOI: 10.1002/chem.201406077
Full Paper
&
Natural Products
Total Synthesis and Absolute Configuration Assignment of MRSA
Active Garcinol and Isogarcinol
Cecilia Socolsky[a] and Bernd Plietker*[b]
Abstract: A short total synthesis of (ꢀ)-garcinol and (ꢀ)-
isogarcinol, two endo-type B PPAPs with reported activity
against methiciline resistant Staphylococcus aureus (MRSA), is
presented. The separation of framework-constructing from
framework-decorating steps and the application of two
highly regio- and stereoselective Pd-catalysed allylations,
that is, the Pd-catalysed decarboxylative Tsuji–Trost allylation
and the diastereoselective Pd-catalysed allyl–allyl cross-cou-
pling, are key elements that allowed the total synthesis to
be accomplished within 13 steps starting from acetylace-
tone. After separation of the enantiomers the absolute con-
figurations of the four natural products (i.e., (ꢁ)-garcinol,
(+)-guttiferone E (i.e., ent-garcinol), (ꢁ)-isogarcinol, and
(+)-isoxanthochymol (i.e., ent-isogarcinol)) were assigned
based on ECD spectroscopy.
Introduction
The PPAPs (polyprenylated polycyclic acylphloroglucinols) are
a growing family of natural products that consists of more
than 200 members.[1] The majority of PPAPs possess a character-
istic perprenylated bicyclo[3.3.1]nonatrione core and interest-
ing biological activities that alter depending on the nature of
the side-chain or position of the exocyclic acyl group within
the core. Within recent years a number of sophisticated syn-
thetic approaches toward type A and type B PPAPs have been
reported by the groups of Simpkins, Marazano, Shibasaki, Dani-
shefsky, Shair, Coltart, Porco, and most recently Barriault.[1,2] In
2009 our group reported a general strategy toward endo-
type B PPAPs in which the separation of framework-construct-
ing from framework-decorating steps allowed the access of
various PPAPs without altering the overall synthetic strategy.[3]
Based on this platform we were subsequently able to elabo-
rate methods that allowed either a site-selective oxidation of
one out of three different prenyl-type side-chains or to intro-
duce another quarternary stereocentre at C7 within the bicyclic
framework.[4] Amongst the plethora of PPAPs reported to date
a significant number possess isogeranyl side-chains. Some ex-
amples worth mentioning, besides garcinol, are guttiferone F,
14-deoxygarcinol and 7-epi-isogarcinol (Figure 1). Guttiferone F,
an epimer of garcinol at C-30, shows antiprotozal activity
against Leishmania donovani with an IC50 lower than miltefo-
sine, used as reference.[5] The other two mentioned natural
Figure 1. Bioactive natural products structurally related to garcinol.
products are also closely related to garcinol and display anti-
plasmodial effects against Plasmodium falciparum (Figure 1).[6]
Both garcinol (1) and isogarcinol (3) show interesting biolog-
ical activities. Garcinol suppresses colonic aberrant crypt foci
(ACF) formation, acts as a histone acetyltransferase (HATs) in-
hibitor,[7] and induces apoptosis through cytochrome c release
and activation of caspase in human leukemia HL-60 cells.[8]
More recently, they were shown to have anti-inflammatory and
anticarcinogenic properties.[9,10] These compounds are reported
to inhibit the NF-kB activation and COX-2 expression, and to
decrease iNOS expression and NO release from LPS-stimulated
macrophages by inhibition of the signal transducer and activa-
tor of transcription-1 (STAT-1).[10,11] Further biological studies in-
dicated both compounds to have interesting antiulcer and in
[a] Dr. C. Socolsky
INQUINOA-CONICET, Ayacucho 471, 4000 Tucumꢀn (Argentina)
[b] Prof. Dr. B. Plietker
Institut fꢁr Organische Chemie, Universitꢂt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: bernd.plietker@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406077.
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particular antibiotic activities against methiciline-resistant
Staphylococcus aureus (MRSA).[12,13] Interestingly, the reported
activities are comparable to that of vancomycine, which serves
as a second-defense-line antibiotic.[14] The growing problem of
MRSA, the reported mode of action of garcinol in cancer thera-
py and, from a chemical point of view, the interesting question
on how to create an all-carbon stereocentre in an exocyclic iso-
geranyl side-chain as it is found in many PPAPs, spurred our in-
terest in developing a short total synthetic approach toward
garcinol.
Herein we report the successful realisation of this synthetic
venture by employing two consecutive substrate controlled,
highly diastereo- and regioselective Pd-catalysed allyl-transfer
reactions at a late stage of the synthesis, that is, a decarboxyla-
tive Tsuji–Trost allylation to generate a quarternary stereocen-
tre and a allyl–allyl cross-coupling to establish the isogarcinol-
type side-chain (Figure 2). The regioselective cyclization of gar-
cinol into isogarcinol, the separation of the enantiomers and
the assignment of the absolute configuration of the natural
products by ECD spectroscopy are also reported herein.
Scheme 1. Diastereoselective synthesis of the allyl–allyl cross coupling pre-
cursor 11.
densation, and 1,2-addition afforded cyclohexenone 6 in good
overall yield (Scheme 1).
Since preliminary studies aiming to introduce the isogeranyl
side-chain by a-alkylation of 6 with lavandulyl bromide met
with failure we envisioned a Pd-catalysed allyl–allyl cross-cou-
pling to be a promising strategy to build up the isogeranyl
motif on a late stage of the total synthesis. This cross-coupling
reaction has been investigated by the groups of Echavarren
and more recently by Morken, amongst others.[14,15] However, it
has not been applied within a complex natural product synthe-
sis. Apart from the question of whether the catalytic conditions
for this particular type of cross-coupling reaction are compati-
ble with a densely functionalized core structure, the allyl–allyl
cross-coupling precursor needed to be stable against an 1,4-
addition with organocopper reagents and unreactive under
the conditions of a Pd-catalysed decarboxylative Tsuji–Trost al-
lylation. We decided to introduce an acetoxylated prenyl-type
side-chain due to the comparably low leaving group tendency
of this functional group under various substitution conditions.
Fortunately, the introduction of 4-acetoxylated prenylchlor-
ide 7 led to the allylation product 8 in good yield and high
trans-diastereoselectivity. Subsequent 1,4-addition of MeCu fur-
nished cyclohexanone 9. A competing SN-type reaction be-
Figure 2. Pd-catalysed allyl transfer reactions as key steps in the synthesis of
garcinol.
Results and Discussion
Total synthesis of garcinol and isogarcinol
Our synthesis started from acetylacetone 5. Following the liter-
ature reported sequence of isoprenylation, decarboxylative
aldol-condensation, domino Michael-addition-Dieckmann con-
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tween the exocyclic allylacetate and the organocopper species
was not observed. Finally, cyclohexanone 9 was transferred
into a mixture of two regioisomeric allyl vinyl carbonates 10a
and 10b in order to set the stage for the decarboxlative Tsuji–
Trost allylation (Scheme 1). Both regioisomers were subse-
quently subjected to a decarboxylative Tsuji–Trost allylation
using catalytic amounts of [Pd2dba3]/(p-tol)3P.[4] The desired C-
allylated cyclohexenone 11 was obtained in good yields and
excellent diastereoselectivity. No attack of the Pd-catalyst at
the exocyclic allylic acetate was observed. The diastereoselec-
tive course of the CꢁC bond formation is most likely directed
by steric repulsion between the allyl-Pd moiety and an axially
oriented methyl group on the one side and the carboxylate
moiety on the other side (Scheme 1).
a clean formation of 12 with full control of regio- and stereose-
lectivity (entry 12, Table 1). We did not observe the formation
of another diastereoisomer in either of the catalytic cross-cou-
plings. The CꢁC bond was formed with exclusive stereoselec-
tivity. We were pleased to obtain a crystal structure of 12,
which allowed us to confirm unambiguously the correct rela-
tive configuration of the newly formed exocyclic stereocentre
(Figure 3).[16] The stereochemical course can be explained by
transition state II (Figure 3), in which the Pd-catalyst is coordi-
nated to the carbonyl group with formation of a rigid allyl–Pd
complex. The subsequent metal-to-ligand allyl transfer sets the
observed configuration of the exocyclic stereocentre.
With key intermediate 11 in hand, we set out to develop the
allyl–allyl cross-coupling (Table 1).
Table 1. Development of the diastereoselective Pd-catalysed allyl–allyl
cross-coupling.
Entry[a] Ligand
Solvent
T
Stoichiometry Yield
[8C] (borane/CsF)
12/13 [%][b]
[equiv]
2
3
4
5
6
7
8
9
10
11
12
13[c]
dppm
dppe
dppp
THF
THF
THF
60
60
60
60
4:3
4:3
4:3
4:3
4:3
4:3
4:3
4:3
4:3
8:3
8:4
4:2
0:58
50:34
6:40
34:23
25:28
33:41
26:18
30:8
10:34
19:32
54:22
45:22
Figure 3. Stereochemical model for the Pd-catalysed allyl–allyl cross-cou-
pling; X-ray structure of 12.
dpp-benzene THF
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
heptane 60
toluene
CH3CN
DMF
DMF
DMF
60
60
60
80
60
60
60
With this piece of information in hand, the stereoselective
course of the cross-coupling might be rationalized by assum-
ing that the trajectory of the incoming Pd-catalysts is directed
through coordination of the carbonyl oxygen atoms within the
cyclohexanone core. Through ionization p-allyl–Pd complex II
is formed which undergoes a transmetallation with the fluo-
ride-activated allylboronate. CꢁC bond formation under SN2’-
type conditions via metal-to-ligand transfer furnishes the de-
sired product in a highly diastereoselective manner (Figure 3).
Compound 12 allowed for the completion of the total syn-
thesis of (ꢀ)-garcinol through a base-mediated intramolecular
Claisen cyclization to construct the bicyclo[3.3.1]nonatrione
core 14 followed by cross-metathesis to install the prenyl side-
chains and acylation to give, after deprotection, the desired
natural product (Scheme 2).
DMF
DMF
[a] All reactions were performed on a 0.1 mmol scale in the appropriate
solvent (0.3 mL) under a N2 atmosphere. [b] Isolated yields. [c] Pd(OAc)2
(10 mol%) was used as the catalyst under otherwise identical reaction con-
ditions.
Attempts to introduce an allyl side-chain by using organo-
copper chemistry met with failure. However, the Pd-catalysed
cross-coupling using allyl boronate was successful. Depending
on the nature of the Pd-precatalyst, solvent, and in particular
the ligand, significant amounts of diene 13 were formed prob-
ably by a competing b-hydride elimination pathway (Table 1).
Whereas variation of the stoichiometries and the solvent led to
a slight improvement, the ligand bite angle proved to be the
key parameter. The use of bis-diphenylphosphinoethane
(dppe) as a ligand and addition of CsF as activator led to
In total we were able to synthesize (ꢀ)-garcinol in 13 steps
starting from acetylacetone in an overall yield of 4%. This nat-
ural product was subsequently treated with conc. HCl solution
to furnish the tricyclic natural product (ꢀ)-isogarcinol in 87%
yield as a single regioisomer (Scheme 2).
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Figure 4. Lowest energy conformer of isogarcinol optimized at PBE0/def2-
SVPD.
graphical interface TmoleX 3.4.[18]. Solvent effects were consid-
ered through the conductor-like screening model (COSMO),
a continuum solvation model.
Time dependent density functional theory (TD-DFT) was
used to calculate the excitation energies and rotatory
strengths of the 40 lowest spin allowed excited states, with
the same combination of method and basis set at the opti-
mized geometries. Conversion of these data into simulated
electronic circular dichroism spectra gave theoretical curves
that were compared with those derived experimentally for
both synthetic natural products (isogarcinol and isoxanthochy-
mol). The calculated spectrum of the enantiomer with S config-
uration at C-30 showed diagnostic positive and negative
Cotton effects around 220 and 265 nm, respectively. This simu-
lated CD spectrum was in good agreement with that experi-
mentally derived for synthetic isogarcinol (Figure 5), indicating
this enantiomer represented the actual structure of the natural
product.[16] The theoretical ECD spectrum of the enantiomer
with R configuration at C-30 showed opposite sign bands
when compared with that of isogarcinol. This simulated spec-
trum was in good agreement with the experimental CD spec-
trum of isoxanthochymol. Hence, based on these theoretical
and experimental data, the absolute configurations of 1–4
were unambiguously assigned as depicted (Figure 2).
Scheme 2. Final steps in the total synthesis of (ꢀ)-garcinol and (ꢀ)-isogarci-
nol.
Assignment of absolute configuration
Both enantiomeric forms of garcinol and isogarcinol were iso-
lated from natural sources and were given different names:
(ꢁ)-garcinol (or camboginol); (+)-garcinol (which was named
guttiferone E); (+)-isogarcinol (which was named isoxantho-
chymol); and (ꢁ)-isogarcinol (or cambogin). The various names
for the same natural product plus the discrepancies in the op-
tical rotation between two enantiomers encouraged us to
assign the absolute configuration of the respective natural
products by means of ECD spectroscopy and quantum me-
chanical calculations. Both enantiomers of racemic isogarcinol
were separated by means of preparative chiral HPLC to give
the respective enantiomerically pure natural products (ꢁ)-iso-
garcinol and (+)-isoxanthochymol. Optical rotations were
measured and compared to that of (ꢁ)-isogarcinol prepared
from commercial (ꢁ)-garcinol by acid-catalysed cyclization
(Scheme 2). The absolute configuration of these two synthetic
natural products was unambiguously assigned by CD spectros-
copy in combination with a computational method.
Conclusions
Herein we report a short concise total synthesis of (ꢀ)-garcinol
and (ꢀ)-isogarcinol within 13 and 14 steps, respectively, start-
ing from acetylacetone. Two consecutive highly diastereoselec-
tive Pd-catalysed allyl transfer reaction, that is, a decarboxyla-
tive Tsuji–Trost allylation and an allyl–allyl cross-coupling, were
used in order to build up the correct relative configurations.
Whereas the appropriate choice of leaving groups set the
stage for the high chemoselectivity, the diastereoselectivity is
orchestrated by the set of chiral centres present in the respec-
tive substrate. Acid treatment of garcinol led to the regioselec-
tive tetrahydropyrane formation in isogarcinol which was sepa-
rated in its enantiomers by means of chiral HPLC. The absolute
configuration was unambiguously assigned by combining in
silico and experimental ECD spectroscopy and comparing the
In the lowest energy conformer of isogarcinol the aromatic
ring lies perpendicular to the diketone system, as was previ-
ously observed in an X-ray crystallographic analysis of this
compound (Figure 4).[16] The tetrahydropyran ring has a twist-
boat-like conformation to allow the bulky isoprenyl substituent
to be equatorial, whereas the cyclohexanone lies in a chair-like
conformation. The structure of the lowest energy conformer of
each enantiomer was used as a starting point for a geometry
optimization in methanol solution at the PBE0/def2-SVPD level
of theory, using TURBOMOLE 6.5[17] in combination with the
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Figure 5. Comparison of calculated and experimental ECD spectra in MeOH for both enantiomers of isogarcinol.
0.1 mmol, 1 equiv), allylpinacolborane (67 mg, 0.4 mmol, 4 equiv)
and CsF (45.6 mg, 0.3 mmol, 3 equiv) were added successively. The
reaction mixture was stirred at 608C, overnight, diluted with Et2O
and transferred to a separation funnel. The mixture was washed
with NaHCO3 (sat.) and brine and dried with Na2SO4. The solvent
was removed and the desired product was purified by column
chromatography and HPLC (petroleum ether/EtOAc, 7:1).
results to those of an authentic sample. By these means, the
absolute configurations of garcinol and its enantiomer guttifer-
one E, as well as those of isogarcinol and its enantiomer iso-
xanthochymol were unambiguously assigned for the first time.
Experimental Section
General remarks
General procedure for the acid catalysed cyclization (GP-II)
All reactions and manipulation of substances which are sensitive to
air or moisture were performed under dry nitrogen by using stan-
dard Schlenk techniques. Solvents were purified prior to use.
Chemicals were purchased from Acros Organics, Sigma Aldrich,
Alfa Aesar or Enzo Life Sciences. Reactions were monitored by thin
layer chromatography on 0.20 mm Macherey–Nagel Alugram Xtra
Sil silica gel plates. Purification by semipreparative HPLC was car-
ried out on a Knauer System, pump K-501 and RI detector K-2400,
using a Nucleodur 100-5 Si or a Chiralpak AD CPS column
(250 mmꢁ20 mm i.d.). NMR spectra were recorded at 300 MHz
(1H NMR) and 75 MHz (13C NMR) on a Burker Avance 300 spectrom-
eter or at 500 MHz (1H NMR) and 125.6 MHz (13C NMR) on a Bruker
To a solution of garcinol (10 mg, 0.3 mmol, 1 equiv) in toluene
(10 mL), HCl (37% solution, 50 mL) was added under N2. The mix-
ture was refluxed for 2 h and then transferred to a separation
funnel. The water phase was removed and the organic layer was
washed twice with water, once with brine and dried with Na2SO4.
The solvent was removed at reduced pressure. The residue was
processed by column chromatography over silica gel (petroleum
ether/EtOAc, 1:1).
Cyclohexenone 8
Diester 6[3] (2.94 g, 10 mmol, 1 equiv) was dissolved in THF (30 mL)
and cooled to 08C. Then, NaH (60% in mineral oil, 440 mg,
11 mmol, 1.1 equiv) was added portion wise. After stirring for 1 h
at this temperature, methyllithium (1.6m in THF, 14.4 mL, 23 mmol,
2.3 equiv) was added dropwise and the mixture was further stirred
for 3 h at 08C. The solution was hydrolysed with sat. NH4Cl (3 mL)
and extracted with ethyl acetate (3ꢁ25 mL). The combined organic
layers were washed with brine, dried over Na2SO4, filtered and con-
centrated at reduced pressure. The crude product was used with-
out further purification. The crude product (10 mmol, 1 equiv) was
dissolved in THF (30 mL). The solution was cooled to 08C and NaH
(60% in mineral oil, 440 mg, 11 mmol, 1.1 equiv) was added por-
tion wise followed by 18-crown-6 (264 mg, 1 mmol, 0.1 equiv).
After being stirred at this temperature for 1 h, 7 (53%, 6.1 g,
20 mmol, 2 equiv) and NaI (150 mg, 1 mmol, 0.1 equiv) were added
successively. The reaction mixture was allowed to warm to room
temperature and was further stirred for 48 h. Then, the reaction
was quenched by adding NH4Cl (sat.) and was extracted three
times with EtOAc. The combined organic layers were washed with
1
Avance 500 spectrometer. H chemical shifts are expressed in ppm,
using a residual solvent signal as reference (CDCl3, d=7.26 ppm;
[D6]acetone, d=2.05ppm, [D5]pyridine, d=7.62 ppm), with multi-
plicity (s=singlet, d=doublet, t=triplet, dd=doublet of doublets,
m=multiplet) and coupling constants (J) in Hz. 13C chemical shifts
are reported as chemical shifts (d) with residual chloroform (d=
77.16 ppm) as internal reference. IR spectra were recorded on a FT-
IR spectrometer, Vektor 22 from Bruker, in an ATR mode. Mass
spectra were measured using electrospray ionization (ESI) or elec-
tron impact (EI) on a Bruker Micro-TOF-Q or a Finnigan MAT 95
spectrometer, respectively. ECD spectra were registered on
a JASCO J-815 spectropolarimeter, using MeOH as solvent.
General procedure for allyl–allyl cross coupling (GP-I)[15]
The solvent (0.3 mL) was freeze dried and then the Pd catalyst
(10 mol%) and the ligand (20 mol%) were added. The resulting
slurry was stirred for 90 min at RT. Then, the substrate (46 mg,
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brine, dried with Na2SO4, and the solvent was removed at reduced
pressure. The resulting orange oil was purified by column chroma-
tography over silica gel using petroleum ether/EtOAc (7:1!3:1).
The desired product was further purified via HPLC (petroleum
ether/EtOAc, 3:1) to yield 2.14 g of a yellow oil (53% yield after
1.1 equiv) was added portion-wise. The mixture was stirred for 1 h
at this temperature and then, allylchloroformiate (2.6 mL,
24.9 mmol, 2.5 equiv) was added dropwise. The mixture was al-
lowed to warm to room temperature and was further stirred, over-
night. The reaction was hydrolysed with NH4Cl (sat.) and extracted
with ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo. The
product was purified by flash chromatography to afford a colourless
oil (4.7 g, 94% yield) as a mixture of regioisomers (a/b, 1:2.8).
1
two steps). H NMR (500 MHz, CDCl3): d=5.34 (brt, J=7.2 Hz, 1H),
5.05 (brt, J=7.0 Hz, 1H), 4.61 (d, J=12.2 Hz, 1H), 4.54 (d, J=
12.2 Hz, 1H), 3.72 (s, 3H), 2.66 (dd, J=14.8, 7.2 Hz, 1H), 2.56 (dd,
J=14.8, 7.5, Hz, 1H), 2.44–2.36 (overlapping signals, 2H), 2.27 (dd,
J=13.8, 7.4 Hz, 1H), 2.28 (s, 3H), 2.08–2.02 (overlapping signals,
2H), 2.05 (s, 3H), 1.93 (s, 3H), 1.74 (brs, 3H), 1.72 (brs, 3H),
1.61 ppm (brs, 3H); 13C NMR (125 MHz, CDCl3): d=204.0, 194.4,
172.7, 171.1, 160.8, 139.0, 135.0, 133.7, 124.7, 120.6, 63.0. 56.1, 52.7,
38.5, 33.3, 31.41, 31.39, 30.5, 26.0, 21.8, 21.0, 19.6, 18.1 ppm; IR
(film): n˜ =1733 (s), 1704 (m), 1659 (m), 1377 (w), 1356 (w),
1225 cmꢁ1 (s); ESI-HR-MS calcd for [C23H32O6Na]+: 427.2104, found:
427.2097.
1
Regioisomer 10a: H NMR (500 MHz, CDCl3): d=5.87 (tdd, J=17.0,
10.2, 5.8 Hz, 1H), 5.33 (dd, J=17.0, 1.0 Hz, 1H), 5.26 (brd, J=10.2,
1.2 Hz, 1H), 5.25 (t, J=ND, 1H), 4.99 (brt, J=7.1 Hz, 1H), 4.61–4.51
(overlapping signals, 4H), 3.63 (s, 3H), 2.86 (dd, J=14.8, 6.7 Hz,
1H), 2.46 (dd, J=14.8, 8.5, Hz, 1H), 2.27 (s, 3H), 2.12 (brd, J=
13.8 Hz, 1H), 2.05 (s, 3H), 2.03 (t, J=13.4 Hz, 1H), 1.76 (dd, J=ND,
2.8 Hz, 1H), 1.74 (brs, 3H), 1.73–1.64 (overlapping signal, 1H), 1.69
(brs, 3H), 1.58 (brs, 3H), 1.40 (ddt, J=13.0, 10.8, 2.4 Hz, 1H), 1.15
(s, 3H), 1.07 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=203.8,
172.9, 171.1, 152.5, 143.8, 140.8, 133.46, 133.36, 131.1, 125.2, 122.9,
119.5, 69.4, 63.2, 52.8, 50.4, 40.9, 38.1, 33.5, 32.4, 30.5, 27.7, 26.0,
25.2, 21.8, 21.1, 21.0, 18.0 ppm; IR (film): n˜ =1767 (m), 1735 (s),
1698 (m), 1386 (w), 1367 (w), 1223 (s), 1171 cmꢁ1 (m); ESI-HR-MS
calcd for [C28H40O8Na]+: 527.2621, found: 527.2624. ND: not deter-
mined due to overlapping signals.
Cyclohexanones 9a/9b
LiCl (416 mg, 9.8 mmol, 2.05 equiv) was heated at 808C for 3 h
under vacuo (1 mbar). THF (40 mL) and CuI (1.82 g, 9.54 mmol,
2 equiv) were added at room temperature. After being stirred for
5 min at this temperature the suspension was cooled to ꢁ788C
and methylmagnesium bromide (3m in THF, 3.2 mL, 9.54 mmol,
2 equiv), TMSCl (1.2 mL, 9.54 mmol, 2 equiv) and a solution of 8
(1.93 g, 4.77 mmol, 1 equiv) in THF (30 mL) were successively
added. The resulting mixture was stirred at ꢁ788C for 5 h. The re-
action was hydrolysed with NH4Cl/2N HCl (1:1, 100 mL) and extract-
ed with ethyl acetate (3ꢁ100 mL). The combined organic layers
were washed with NH4Cl/NH3 (1:1, until the organic layer was col-
ourless) and brine, and then dried over Na2SO4 filtered and con-
centrated in vacuo. The crude product was purified by flash chro-
matography to yield 1.71 g of a slightly yellow oil as a mixture of
diastereomers (85% yield, a/b, 1:3).
1
Regioisomer 10b: H NMR (500 MHz, CDCl3): d=5.94 (tdd, J=17.0,
10.3, 5.8 Hz, 1H), 5.39 (dd, J=17.0, 1.2 Hz, 1H), 5.30 (dd, J=10.3,
1.2 Hz, 1H), 5.29 (t, J=7.6 Hz, 1H), 4.99 (brt, J=7.0 Hz, 1H), 4.67 (d,
J=6.0 Hz, 2H), 4.60 (d, J=12.4 Hz, 1H), 4.57 (d, J=12.4 Hz, 1H),
3.59 (s, 3H), 2.66 (dd, J=14.5, 7.6 Hz, 1H), 2.59 (dd, J=14.5, 7.6,
Hz, 1H), 2.36 (dd, J=14.2, 13.4 Hz, 1H), 2.10 (brd, J=14.2 Hz, 1H),
2.05 (s, 3H), 1.96 (s, 3H), 1.78 (dd, J=14.5, 3.2 Hz, 1H), 1.74 (brs,
3H), 1.72–1.65 (overlapping signal, 1H), 1.69 (brs, 3H), 1.58 (brs,
3H),1.21–1.14 (overlapping signal, 1H) 1.19 (s, 3H), 1.14 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=202.3, 171.9, 171.1, 151.9,
150.5, 135.2, 133.9, 133.4, 131.2, 124.4, 122.8, 119.7, 69.2, 63.0, 60.1,
52.7, 44.2, 41.8, 32.9, 32.6, 27.5, 26.6, 26.0, 21.8, 21.0, 19.1, 18.5,
18.0 ppm; IR (film in CH2Cl2): n˜ =1763 (m), 1738 (s), 1701 (m), 1384
(w), 1367 (w), 1230 (s), 1172 cmꢁ1 (m); ESI-HR-MS calcd for
[C28H40O8Na]+: 527.2621, found: 527.2614.
1
Diastereomer 9a: H NMR (500 MHz, CDCl3): d=5.29 (t, J=7.4 Hz,
1H), 5.11 (t, J=6.6 Hz, 1H), 4.58 (d, J=12.3 Hz, 1H), 4.51 (d, J=
12.3 Hz, 1H), 3.71 (s, 1H), 3.70 (s, 3H), 2.48 (td, J=14.6, 7.8 Hz, 1H),
2.47 (td, J=14.6, 7.0, Hz, 1H), 2.26 (brdd, J=13.8, 4.6 Hz, 1H), 2.20
(dd, J=14.4, 7.6 Hz, 1H), 2.14 (s, 3H), 2.04 (s, 3H), 1.87 (dd, J=
14.4, 4.4 Hz, 1H), 1.83–1.76 (m, 1H), 1.75–1.67 (overlapping signal,
1H), 1.70 (brs, 6H), 1.57 (brs, 3H), 1.06 (s, 3H), 0.99 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=204.7, 204.0, 173.1, 171.1, 133.7,
133.2, 124.6, 122.9, 70.9, 63.0, 60.2, 52.6, 42.0, 41.1, 34.0, 32.6, 32.3,
26.8, 25.9, 24.9, 24.4, 21.6, 21.0, 18.0 ppm; IR (film): n˜ =1722 (s),
1688 (m), 1387 (w), 1355 (w), 1225 cmꢁ1 (s); EI-HR-MS calcd for
[C24H36O6]+: 420.2512, found: 420.2505.
Cyclohexanone 11
Tris(dibenzylideneacetone)dipalladium(0)
(108 mg,
0.12 mmol,
0.025 equiv) and tri(p-tolyl)phosphine (86 mg, 0.28 mmol,
0.06 equiv) were dissolved in toluene (60 mL) and stirred for
30 min at RT. Then, a solution of the substrate (2.37 g, 4.7 mmol,
1 equiv) in toluene (25 mL) was added slowly. The resulting mix-
ture was stirred at 608C, overnight, and then filtered through
a plug of silica gel using petroleum ether/ethyl acetate (7:1). The
desired product was purified by HPLC (petroleum ether/EtOAc, 7:1)
to yield 1.88 g of a white solid (87% yield). 1H NMR (500 MHz,
CDCl3): d=5.42 (brt, J=7.2 Hz, 1H), 5.31 (dddd, J=17.8, 12.5, 8.9,
5.2 Hz, 1H), 5.01 (brt, J=7.8 Hz, 1H), 4.94 (d, J=4.2 Hz, 1H), 4.91
(s, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.56 (d, J=12.3, Hz, 1H), 3.18
(brdd, J=14.2, 5.1 Hz, 1H), 3.75 (s, 3H), 2.59–2.47 (m, 2H), 2.27 (dd,
J=14.5, 9.0 Hz, 1H), 2.21–2.14 (m, 1H), 2.12 (s, 3H), 2.08–2.00
(overlapping signals, 2H), 2.06 (s, 3H), 1.93 (dd, J=14.5, 2.6 Hz,
1H), 1.82–1.70 (overlapping signal, 1H), 1.78 (s, 3H), 1.71 (s, 3H),
1.60 (s, 3H), 1.06 (s, 3H), 0.99 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3): d=209.0, 206.3, 173.0, 171.0, 134.0, 133.7, 133.6, 125.6,
122.8, 117.6, 73.7, 63.0, 59.8, 52.7, 40.6, 37.8, 37.4, 32.9, 32.4, 31.7,
27.5, 26.0, 22.2, 21.9, 21.8, 21.0, 18.1 ppm; IR (film): n˜ =1736 (s),
1
Diastereomer 9b: H NMR (500 MHz, CDCl3): d=5.30 (t, J=6.8 Hz,
1H), 5.02 (brt, J=7.4 Hz, 1H), 4.82 (d, J=12.2 Hz, 1H), 4.42 (d, J=
12.2 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 1H), 2.85 (dd, J=15.1, 8.0 Hz,
1H), 2.67 (dd, J=15.1, 5.8, Hz, 1H), 2.22 (dd, J=13.6, 5.0 Hz, 1H),
2.07 (t, J=13.2 Hz, 1H), 2.04 (s, 3H), 1.99 (s, 3H), 1.87 (dd, J=14.5,
3.6 Hz, 1H), 1.75–1.61 (overlapping signals, 2H), 1.72 (brs, 3H), 1.68
(brs, 3H), 1.57 (brs, 3H), 1.08 (s, 3H), 1.07 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=206.6, 204.7, 172.2, 171.0, 133.6, 133.4, 124.6,
122.7, 69.4, 62.8, 61.6, 52.5, 43.9, 43.0, 35.2, 32.7, 31.9, 27.1, 26.2,
25.9. 21.6, 21.0, 18.0, 16.0 ppm; IR (film): n˜ =1723 (s), 1700 (m),
1387 (w), 1355 (w), 1229 cmꢁ1 (s); EI-HR-MS calcd for [C24H36O6]+:
420.2512, found: 420.2509.
Allylvinylcarbonates 10a/10b
To a solution of the starting material (4.18 g, 9.94 mmol, 1 equiv) in
DMF at 08C, NaH (60% in mineral oil, 398 mg, 10.9 mmol,
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Full Paper
1701 (m), 1686 (s), 1372 (w), 1354 (w), 1220 (s), 1165 cmꢁ1 (m); ESI-
HR-MS calcd for [C27H40O6Na]+: 483.2723, found: 483.2729.
3H); 13C NMR (125 MHz, CDCl3): d=210.7, 202.6, 202.5, 148.8,
136.8, 133.9, 132.5, 122.5, 120.5, 115.9,114.2, 71.6, 64.0, 63.0, 52.5,
46.8, 44.7, 43.3, 39.0, 37.6, 32.2, 29.1, 26.5, 25.9, 23.4, 18.1,
16.9 ppm; IR (solid): n˜ =3076 (w), 2663 (br), 2609 (br), 2532 (br),
1722 (m), 1641 (w), 1605 (m), 1586 (m), 1520 (s), 1231 (s), 911 (m),
890 cmꢁ1 (m); ESI-HR-MS calcd for [C27H38O3Na]+: 433.2719, found:
433.2696.
Cyclohexanone 12[15]
DMF (0.3 mL) was freeze dried and then tris(dibenzylideneacetone)-
dipalladium(0) (9.2 mg, 10 mol%) and 1,2-bis(diphenylphosphino)-
ethane (8 mg, 20 mol%) were added. The resulting solution was
stirred for 90 min at RT. Then, the substrate (46 mg, 0.1 mmol,
1 equiv), pinacol allylboronate (134 mg, 0.8 mmol, 8 equiv) and CsF
(61 mg, 0.4 mmol, 4 equiv) were added successively. The reaction
mixture was stirred at 608C for 17 h. After cooling the mixture to
room temperature, the mixture was diluted with Et2O and trans-
ferred to a separation funnel. It was then washed with NaHCO3
(sat.) and brine. The organic layer was dried with Na2SO4 and the
solvent was removed at reduced pressure. The desired product
was purified by HPLC (petroleum ether/EtOAc, 7:1) to yield 24 mg
of the cross coupling product 12 (54% yield) and 9 mg of the elim-
Bicyclo[2.2.1]nonatrione 15[4]
To a solution of the starting material (63 mg, 0.15 mmol, 1 equiv)
in CH2Cl2 (1.6 mL), the catalyst (6.4 mg, 5 mol%) and amylene
(1.6 mL, 15 mmol, 100 equiv) were added successively under N2.
The Schlenk was capped and heated to 508C for 6 h. The reaction
mixture was filtered through a plug of silica gel and processed by
normal phase HPLC (petroleum ether/EtOAc, 7:1) to yield an oil.
1H NMR (300 MHz, CDCl3): d=5.03 (brt, J=6.7 Hz, 1H), 4.92 (brt,
J=7.3 Hz, 1H), 4.82 (brt, J=6.1 Hz, 1H), 4.53 (s, 2H), 3.55 (d, J=
17.1 Hz, 1H), 3.47 (d, J=17.1 Hz, 1H), 2.92 (m,1H), 2.56 (d, J=
7.3 Hz, 2H), 2.28 (dd, J=13.8, 0.9 Hz, 1H), 2.14 (brd, J=ND, 1H),
2.07–1.80 (overlapping signals, 4H), 1.73 (dd, J=14.0, 3.7 Hz, 1H),
1.68 (brs, 3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.61 (s, 6H), 1.50 (s, 3H),
1.46 (s, 3H), 1.37 (dd, J=13.9, 7.0 Hz, 1H), 1.30 (m, 1H), 1.24 (s,
3H), 0.97 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=211.0, 203.2,
202.9, 149.4, 136.2, 133.8, 132.3, 122.7, 122.5, 118.0, 113.9, 71.1,
63.8, 63.0, 52.4, 46.8, 44.9, 43.6, 38.0, 33.0, 29.1, 27.0, 26.6, 26.1,
25.9(2C), 23.5, 18.1 (2C), 18.0, 17.0 ppm; IR (CHCl3): n˜ =3048 (w),
1705 (s), 1599 (m), 1394 (w), 1375 cmꢁ1 (m); EI-HR-MS calcd for
[C31H46O3]+: 466.3447, found: 466.3443. ND: not determined due to
overlapping signals.
1
ination product 13 (22% yield). H NMR (500 MHz, CDCl3): d=5.64
(ddt, J=16.8, 10.4, 7.1 Hz, 1H), 5.32 (dddd, J=17.2, 10.0, 8.9,
5.1 Hz, 1H), 5.10 (brt, J=7.0 Hz, 1H), 4.96 (d, J=17.2 Hz, 1H), 4.94
(d, J=10.0 Hz, 1H), 4.92 (d, J=10.4 Hz, 1H), 4.88 (d, J=16.8, Hz,
1H), 4.80 (brs, 1H), 4.75 (s, 1H), 3.75 (s, 3H), 3.17 (brdd, J=14.5,
5.0 Hz, 1H), 2.31 (m, 1H), 2.25–2.16 (overlapping signals, 2H), 2.10
(s, 3H), 2.16–2.02 (overlapping signals, 4H), 1.85–1.76 (overlapping
signals, 4H), 1.72 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.04 (s, 3H),
0.96 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=208.9, 206.5, 173.3,
147.3, 136.7, 134.1, 133.1, 122.9, 117.4, 115.9, 112.4, 73.9, 60.7, 52.5,
43.7, 40.5, 39.3, 37.9, 37.5, 36.4, 33.0, 31.0, 28.1, 26.2, 22.3, 21.8,
20.0, 18.0 ppm; IR (CHCl3): n˜ =3075 (w), 1748 (s), 1726 (m), 1699 (s),
1688 (s), 1641 (w), 1375 (w), 1220 (s), 1168 (s), 1109 (s), 911 cmꢁ1
(m); ESI-HR-MS calcd for [C28H42O4Na]+: 465.2975, found: 465.2978.
(ꢀ)-Garcinol[3,4]
1
13: H NMR (300 MHz, CDCl3): d=6.29 (d, J=16.2 Hz, 1H), 5.56 (d,
The crude product 15 (0.15 mmol, 1 equiv) was dissolved in dry
THF (4.5 mL) and the solution was cooled to 08C. KOtBu (168 mg,
1.5 mmol, 10 equiv) was added. The mixture was stirred at this
temperature for 45 min and then cyanide (927 mg, 3.75 mmol,
25 equiv) was added portion wise. The reaction mixture was al-
lowed to warm to room temperature and was further stirred for
48 h and then MeOH (4.5 mL) and K2CO3 (1.14 g, 55 equiv) were
added. After being stirred for 2.5 h, the reaction was quenched
with NH4Cl (sat.) and extracted three times with EtOAc. The com-
bined organic layers were washed with brine, dried with Na2SO4
and the solvent was removed. The residue was processed by
column chromatography and the product was purified by HPLC
(petroleum ether/EtOAc, 1:1) to afford 39.1 mg of a yellow oil (43%
yield after 3 steps). 1H NMR (500 MHz, CDCl3): d=6.98–6.96 (over-
lapping signals, 2H), 6.72 (d, J=9.0 Hz, 1H), 5.10 (brs, 1H), 5.04
(brt, J=6.5 Hz, 1H), 4.92 (brt, J=7.0 Hz, 1H), 4.42 (s, 1H), 4.37 (s,
1H), 2.80–2.72 (overlapping signals, 2H), 2.58 (brd, J=13.5 Hz, 1H),
2.36 (d, J=14.0 Hz, 1H), 2.22–1.40 (overlapping signals, 6H), 2.14
(dd, J=13.5, 10.0 Hz, 1H), 1.90 (dd, J=13.5, 3.8 Hz, 1H), 1.80 (s,
3H), 1.75 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.54 (s, 6H),
J=16.2 Hz, 1H), 5.34–5.18 (overlapping signals, 2H), 5.06 (brs, 1H),
4.97 (brs, 1H), 4.88 (dt, J=10.1, 1.7 Hz, 1H), 4.74 (brd, J=16.7 Hz,
1H), 3.76 (s, 3H), 3.03 (ddt, J=14.0, 4.9, 1.6 Hz, 1H), 2.37 (dd, J=
14.6, 3.4 Hz, 1H), 2.39–2.19 (overlapping signals, 2H), 2.17 (s, 3H),
2.06 (dd, J=14.1, 8.8 Hz, 1H), 1.96 (tt, J=10.9, 2.7 Hz, 1H), 1.89–
1.76 (overlapping signal, 1H), 1.83 (brs, 3H), 1.78 (brs, 3H), 1.66
(brs, 3H), 1.09 (s, 3H), 0.97 ppm (s, 3H); IR (CHCl3): n˜ =1734 (s),
1694 (s), 1375 (m), 1355 (m), 1241 (s), 1223 cmꢁ1 (s); ESI-HR-MS
calcd for [C25H36O4Na]+: 423.2511, found: 423.2508.
Bicyclo[2.2.1]nonatrione 14[3,4]
The starting material (71.6 mg, 0.16 mmol, 1 equiv) was dissolved
in dry THF (4.5 mL) and cooled to 08C. Then, KOtBu (36.3 mg,
0.32 mmol, 2 equiv) was added under N2. After stirring for 15 min
at this temperature, the reaction was quenched by adding NH4Cl
(sat.). The mixture was poured into a separation funnel and was ex-
tracted three times with EtOAc. The combined organic layers were
washed with brine and dried with Na2SO4. The solvent was then re-
moved at reduced pressure. The product was purified by column
chromatography (petroleum ether/EtOAc, 7:1) to afford 63 mg of
1
1.17 (s, 3H), 1.02 ppm (s, 3H); H NMR (500 MHz, [D5]pyridine): d=
1
a white solid (94% yield). H NMR (500 MHz, CDCl3): d=5.71 (ddt,
7.93 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.3, 2.0 Hz, 1H), 7.24 (d, J=ND,
1H), 5.61 (brt, J=6.0 Hz, 1H), 5.31 (brt, J=6.6 Hz, 1H), 5.08 (brt, J=
6.9 Hz, 1H), 4.94 (d, J=2.4 Hz, 1H), 4.80 (brs, 1H), 3.16 (m, 1H),
3.04 (dd, J=13.2, 8.5 Hz, 1H), 2.92 (dd, J=13.4, 4.8 Hz, 1H), 2.70
(m, 1H), 2.51 (d, J=13.9 Hz, 1H), 2.50–2.37 (overlapping signals,
2H), 2.32 (dd, J=13.8, 8.3 Hz, 1H), 2.33–2.21 (overlapping signals,
2H), 2.20 (dd, J=14.3, 7.1 Hz, 1H), 1.87 (s, 3H), 1.85 (s, 3H), 1.80 (s,
3H), 1.71 (s, 3H), 1.69 (s, 3H), 1.68 (s, 3H), 1.66 (s, 3H), 1.59 (m,
1H), 1.40 (s, 3H), 1.26 (m, 1H), 1.14 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=209.2, 199.0, 195.4, 194.0, 149.8, 148.2, 143.8,
J=17.2, 10.0, 7.0 Hz, 1H), 5.64 (dddd, J=16.5, 10.0, 9.0, 5.5 Hz, 1H),
5.09 (d, J=17.2 Hz, 1H), 5.04 (dd, J=10.0, 2.0 Hz, 1H), 5.03 (dd, J=
17.0, 2.0 Hz, 1H), 4.98 (dd, J=10.0, 2.0 Hz, 1H), 4.83 (brt, J=6.5 Hz,
1H), 4.53 (s, 2H), 3.57 (d, J=17.0 Hz, 1H), 2.94 (m, 1H), 2.76 (dd,
J=12.5, 6.0 Hz, 1H), 2.47 (dd, J=12.5, 9.0 Hz, 1H), 2.31 (dd, J=
13.5, 1.0 Hz, 1H), 2.14 (brd, J=15.5 Hz, 1H), 2.09–2.02 (overlapping
signals, 3H), 1.98 (dd, J=14.0, 6.0 Hz, 1H), 1.72 (dd, J=14.0, 3.0 Hz,
1H), 1.66 (s, 3H), 1.51 (s, 3H), 1.47 (s, 3H), 1.39 (dd, J=14.5, 7.5 Hz,
1H), 1.35–1.23 (overlapping signals, 2H), 1.22 (s, 3H), 0.98 ppm (s,
Chem. Eur. J. 2014, 20, 1 – 10
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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135.4, 133.1, 132.2, 128.0, 124.2, 124.0, 122.7, 120.2, 116.6, 116.0,
114.7, 112.9, 69.9, 58.0, 49.8, 46.9, 43.7, 42.7, 36.3, 32.8, 29.0, 27.2,
26.2, 26.0, 25.9, 22.9,18.3, 18.1, 18.0, 17.8 ppm; IR (in CHCl3): n˜ =
3363 (broad), 3074 (w), 1728 (m), 1644 (m), 1596 (s), 1374 (s),
1290 cmꢁ1 (s); ESI-HR-MS calcd for [C38H50O6Na]+: 625.3607, found:
625.3493. ND: not determined due to overlapping signals.
lnRn
ꢂ 1040
pffiffiffi
De ¼
22:94 pDl
where Den is the peak intensity of the nth transition in
Lmolꢁ1 cmꢁ1, ln is the wavelength of this transition in cm, Rn is the
rotatory strength, and Dln is the width at 1/e of the peak maxi-
mum.
Preparation of racemic isogarcinol
According to GP-II racemic garcinol (12 mg, 0.02 mmol, 1 equiv) in
toluene (12 mL) was treated with HCl (37% solution, 60 mL) to
afford 10 mg of a yellow solid. Enantiomers were separated by
chiral HPLC (Chiralpak AD CPS column, n-heptane/isopropanol, 9:1)
to afford isogarcinol 3 (3.5 mg, tR =16 min) and isoxanthochymol 4
(3.2 mg, tR =41 min).
Dln ¼ ln2Dn,
Dn was considered equal to 2500 cmꢁ1 in this particular case:
ꢂ ꢀ
ꢁ ꢃ
2
X
l ꢁ ln
Isogarcinol 3: [a]D =ꢁ206 (MeOH, 258C); 1H NMR (500 MHz,
CDCl3): d=7.45 (d, J=1.8 Hz, 1H), 7.03 (dd, J=8.2, 1.8 Hz, 1H),
6.68 (d, J=8.2 Hz, 1H), 5.11 (brt, J=6.3 Hz, 1H), 4.92 (brt, J=
7.2 Hz, 1H), 4.87 (brt, J=6.2 Hz, 1H), 3.05 (dd, J=14.3, 3.7 Hz, 1H),
2.71–2–59 (overlapping signals, 2H), 2.46 (dd, J=13.6, 4.8 Hz, 1H),
2.29 (d, J=14.4 Hz, 1H), 2.20 (brd, J=14.1 Hz, 1H), 2.05–1.94 (over-
lapping signals, 2H), 1.77 (m, 1H), 1.71 (s, 3H), 1.67 (s, 3H), 1.64 (s,
3H), 1.58 (s, 9H), 1.49–1.36 (overlapping signals, 3H), 1.24 (s, 3H),
1.16 (s, 3H), 0.99 (s, 3H), 0.92 ppm (s, 3H); 1H NMR (500 MHz,
[D6]acetone): d=8.62 (brs, 1H), 8.40 (brs, 1H), 7.36 (d, J=2.0 Hz,
1H),7.12 (dd, J=8.2, 2.0 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 5.20 (brt,
J=6.3 Hz, 1H), 4.95 (brs, 2H), 3.02 (dd, J=14.1, 3.6 Hz, 1H), 2.76
(ddd, J=14.3, 11.2, 9.0 Hz, 1H), 2.63 (dd, J=13.5, 8.4 Hz, 1H), 2.41
(dd, J=13.6, 5.0 Hz, 1H), 2.29 (d, J=14.6 Hz, 1H), 2.15–2.07 (over-
lapping signals, 2H), 2.04 (dd, J=14.6, 7.7 Hz, 1H), 1.86 (m, 1H),
1.76 (s, 3H), 1.69 (s, 3H), 1.68 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.54
(s, 3H), 1.54–1.49 (overlapping signal, 1H), 1.44 (ddt, J=13.2, 10.0,
3.6 Hz, 1H), 1.27 (s, 3H), 1.14 (s, 3H), 1.07 (t, J=13.4 Hz, 1H), 0.98
(s, 3H), 0.93 ppm (s, 3H); 13C NMR (125 MHz, CDCl3/CD3OD, 5:1):
d=207.2, 194.6, 193.2, 171.7, 150.6, 144.7, 134.6, 133.6, 133.0,
129.8, 125.1, 124.8, 123.8, 121.3, 119.6, 114.4, 114.3, 86.7, 68.2, 51.2,
46.2, 46.1, 42.8, 39.3, 29.5, 29.2, 28.5, 28.2, 26.6, 25.9, 25.7, 25.6,
25.4, 22.3, 21.1, 17.9, 17.82, 17.80 ppm; IR (solid): n˜ =3463 (w),
3359 (broad), 1718 (m), 1678 (m), 1638 (m), 1602 (s), 1364 (s), 1350
(s), 1296 cmꢁ1 (s); ESI-HR-MS calcd for [C38H50O6Na]+: 625.3505,
found: 625.3480.
DeðlÞ ¼
De exp ꢁ
Dln
n
A scale factor (0.2) was used to fit the calculated molar circular di-
chroism to the experimental CD spectra.
Acknowledgements
Financial support by the Alexander von Humbold Foundation
(Georg-Foster fellowship for C.S.) is gratefully acknowledged.
Keywords: allylation · antibiotics · catalysis · cross-coupling ·
natural products
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Received: November 13, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 10
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9
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
&
Natural Products
C. Socolsky, B. Plietker*
&& – &&
Total Synthesis and Absolute
Configuration Assignment of MRSA
Active Garcinol and Isogarcinol
A quick fix: A short total synthesis of
(ꢀ)-garcinol and (ꢀ)-isogarcinol, two
endo-type B PPAPs with reported activi-
ty against methiciline resistant Staphylo-
coccus aureus (MRSA), is presented. The
stereo- and regioselective Pd-catalysed
decarboxylative Tsuji–Trost allylation/
allyl–allyl cross-coupling are key ele-
ments that allowed the total synthesis
to be accomplished within 13 steps
starting from acetylacetone (see
scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
10
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!