Synthesis of (±)- and (+)-perovskone

Article abstract of DOI:10.1016/j.tet.2011.09.072

A biomimetic synthesis of the triterpene (±)-perovskone was achieved featuring a remarkable polycyclization process in which three rings, four bonds, and five stereocenters were created in a single operation in 82% yield. This convergent synthesis required 16 steps, starting from vanillin, and proceeded in 9% overall yield. A second route to prepare optically active quinone 2 took 15 steps in 36% overall yield and featured a palladium-catalyzed reductive allylic transposition to establish the C-5 chirality stereospecifically. Quinone (-)-2 was converted to (+)-perovskone (1) via a polycyclization cascade, which created four rings, five bonds, and six stereocenters in a single operation in 50% yield.

Full text of DOI:10.1016/j.tet.2011.09.072

Tetrahedron 67 (2011) 10129e10146
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (ꢀ)- and (þ)-perovskoneq
George Majetich , Yong Zhang, Xinrong Tian, Jonathan E. Britton , Yang Li , Ryan Phillips
y
z
*
Department of Chemistry, The University of Georgia, Athens, GA 30602, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2011
Received in revised form 15 September 2011
Accepted 16 September 2011
Available online 22 September 2011
A biomimetic synthesis of the triterpene (ꢀ)-perovskone was achieved featuring a remarkable poly-
cyclization process in which three rings, four bonds, and five stereocenters were created in a single
operation in 82% yield. This convergent synthesis required 16 steps, starting from vanillin, and proceeded
in 9% overall yield. A second route to prepare optically active quinone 2 took 15 steps in 36% overall yield
and featured a palladium-catalyzed reductive allylic transposition to establish the C-5 chirality stereo-
specifically. Quinone (ꢁ)-2 was converted to (þ)-perovskone (1) via a polycyclization cascade, which
created four rings, five bonds, and six stereocenters in a single operation in 50% yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Perovskone
Cyclialkylation
FriedeleCrafts alkylation
Cascade reaction
Pdepeallyl chemistry and one-pot reaction
1. Introduction
In 1992 Ahmad and co-workers isolated the triterpene per-
ovskone (1) from P. abrotanoides, Karel syn. P. artemisioides Boiss
Perovskia abrotanoides, a member of the plant family Lam-
iaceae,1 is a highly branched shrub found in Afghanistan, Baluchi-
stan, and in the Northwest Frontier provinces of Pakistan. This plant
is used locally in the Baluchistan area as a cooling medicine2 and as
a remedy for typhoid fever.3,4
(Labiatae) (Fig. 1).5 Perovskone contains a complex array of seven
fused and bridged rings as well as seven asymmetric centers, thus
posing a formidable challenge to total synthesis. Here we describe
in detail our syntheses of (ꢀ)- and (þ)-perovskone in which four of
the seven rings and six of the seven stereocenters are established in
a one-pot process.6,7
2. Results and discussion
The biosynthesis of perovskone, as proposed by Ahmad and
co-workers, involves the addition of geranyl pyrophosphate to an
icetexone precursor (Fig. 2).8 This prompted us to mimic nature by
using a DielseAlder addition9 of (E)-
b-ocimene (3) to p-quinone 2
Fig. 1. Structure of perovskone.
q
This article is part of a special issue honoring the many scientific contributions
of Professor Gilbert Stork and in celebration of his 90th birthday.
* Corresponding author. E-mail address: majetich@chem.uga.edu (G. Majetich).
y
Taken in part from the M.S. thesis of Jonathan E. Britton, University of Georgia
(2002).
z
Taken in part from the Ph.D. dissertation of Yang Li, University of Georgia
Fig. 2. Two conformations of quinone 2.
(2006).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.072

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G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
Table 1
to assemble the critical D-ring (Scheme 1). Inspection of Drieding
molecular models suggested that a diene would add to the -face of
Regioselective demethylation using bulky alkylthiolates
a
dienophile 2, creating the correct relative configurations at C-8, C-9,
and C-24. In addition, the use of ocimene as the diene component
Nucleophilic
reagent
Reaction
temperature (ꢂC)
Chemical
yield (%)
Product(s)
NaS-Et
NaS-Et
150
50
65
86
R¼R0¼H (1)
R¼H; R0¼CH3 (9a)
R¼CH3; R¼H (9b)
9a/9b¼3:2
NaS-i-Pr
NaS-t-Pr
L-Selectride
65
50
90
75
52
92
9a/9b¼3:2
9a/9b¼2:1
9a only
conditions developed by Feutrill and Mirrington12 were examined.
Complete demethylation of 8 was achieved upon treatment with
excess sodium ethylthiolate in DMF at 150 ꢂC. We speculated that
either lower reaction temperatures or the use of bulky alkylth-
iolates might result in the selective deprotection of the more ste-
rically accessible C-11 methoxy group; however, only modest
selectivity was observed at temperatures between 50 ꢂC and 60 ꢂC
with the sodium alkylthiolates studied (Table 1). In 1994, we re-
ported that L-Selectride efficiently deprotects aryl methyl ethers
and often exhibits a profound steric bias.13 Indeed, treatment of 8
with L-Selectride gave only phenol 9a in 92% yield. Unfortunately,
the oxidation of 9a to a p-quinone using mild oxidants like Fremy’s
salt,14a Rapoport’s conditions (AgO and nitric acid),14b or HgO14c
failed. Strong oxidants, such as H2O2,14d m-CPBA or CrO3,14e oxi-
dized the C-1,C-10 double bond instead. Extensive work established
that a p-quinone could be prepared from a barbatusol-derived
precursor if the phenol was the only oxidizable functional group
present (Scheme 3).
Scheme 1.
would subsequently permit ocimene the formation of the C-11,C-26
bond and the final carbocyclic ring (i.e., E) by an intramolecular
Prins reaction involving the C-11 ketone of cycloadduct 4. The acid-
catalyzed formation of the heterocyclic F- and G-rings completes
our perovskone retrosynthetic analysis (i.e., 4/5/6/1).
Recognition that the oxidation of barbatusol (7), for which we
had already developed an eight-step synthesis,10 would directly
afford p-quinone 2 greatly influenced our synthetic strategy
(Scheme 2). Unfortunately, the oxidation of barbatusol gave an
unstable o-quinone.11 Attempts to convert barbatusol methyl ether
(8) to quinone 2 produced enones corresponding to oxidation at
either C-20 or at C-1 arising from an allylic rearrangement.
Scheme 3.
These observations led us to prepare hydroquinone 10, which
should oxidize under mild conditions without compromising the
C-1,C-10 double bond (Scheme 4). Execution of this revised strategy
required the synthesis of dienone 12 possessing an additional
methoxy group at C-14.
Our synthesis of dienone 12 began with 1-bromo-2,3,5-
trimethoxybenzene (13), which is available from vanillin in three
steps in 63% overall yield.15 Treatment of 13 with tert-butyllithium,
followed by quenching the resultant carbanion with gaseous car-
bon dioxide, gave benzoic acid 14 in 89% yield (Scheme 5). An acid-
catalyzed FriedeleCrafts alkylation using 2-propanol introduced
the required isopropyl unit at C-13. Some cleavage of the C-11
methoxy group also occurred under these acidic conditions. Instead
of isolating phenolic acid 15, the crude mixture of benzoic acids 15
and 16 was treated with an excess of K2CO3 and iodomethane16 and
the resulting mixture was refluxed for 12 h. These conditions
achieved the esterification of the benzoic acid and the reprotection
of the C-11 hydroxyl group in nearly quantitative yield.
Scheme 2.
We were hopeful that selectively deprotecting the C-11 methoxy
group of 8 would permit the oxidation of C-14 under mild condi-
tions (Table 1). Traditional acidic demethylation conditions moved
the C-1,C-10 double bond into conjugation,11b so the nucleophilic

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10131
Scheme 4.
Ester 17 was converted into quinone 2 via the nine trans-
formations shown in Scheme 6. The reduction of 17 and the con-
version of benzylic alcohol 18 to benzylic bromide 19 were
straightforward. Alkylation of 4,4-dimethyl-1,3-cyclohexanedione
(20) with 19 furnished the mono-alkylated dione 21 in 68%
yield.17 Repeating this alkylation with recovered bromide provided
additional dione 21 for a combined yield of 89%. Treatment of dione
21 with sodium hydride in DMF and dimethyl sulfate generated
enol ether 22 in 99% yield. 1,2-Addition of vinylmagnesium bro-
mide to 22, followed by mild acid hydrolysis, produced the key
cyclization precursor 12. This Grignard reaction required activation
of the cyclohexenone carbonyl group by cerium chloride18 to sup-
press 1,4-addition and to overcome the steric influence of the gem-
dimethyl group. The cyclialkylation19 of 12 was accomplished in
96% yield using TiCl4 as catalyst.20
Scheme 6.
Fortunately, we realized that oxidation of catechol 24 would pro-
duce o-quinone 25, in which the C-14 methoxy group can be
regarded as part of a vinylogous ester. Hydrolysis of 25 with either
base or acid would therefore produce the deprotected o-quinone,
which could rearrange to a p-quinone.22 Treatment of 24 with
ammonium cerium(IV) nitrate23 gave o-benzoquinone 25 in situ;
addition of either sodium hydroxide or aqueous sulfuric acid to the
oxidation reaction mixture produced p-benzoquinone 2 in excel-
lent yield.24
Scheme 5.
Four transformations were needed to convert enone 11 into
quinone 2. The first step was a modified WolffeKishner reduction
of 11 that both reduced the C-1 carbonyl group and caused the
C-5,C-10 double bond to migrate to the C-1,C-10 position (cf. 23).21
Next, demethylation of two of the ether units was achieved in 75%
yield using sodium ethylthiolate. Catechol 24 resisted all attempts
at further deprotection. At first this seemed to be a setback.
Quinones are excellent dienophiles25,26 and we were confident
that quinone 2 would react in DielseAlder fashion. However, the
facial selectivity, which has important stereochemical

10132
G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
consequences, and the regioselectivity of the cycloaddition of qui-
none 2 with (E)- -ocimene presented unanswered concerns. We
b
expected that the preferred conformation of quinone 2 would be
cup-shaped, so that the diene would add to 2 from the more ac-
cessible convex a-face. This speculation was supported by both the
NMR studies of St. Jacques and Vaziri, which found that benzocy-
cloheptenes strongly favor a chair conformation,27 and by MM3
calculations,28 which indicate that the chair cycloheptene con-
former of 2 is >3.0 kcal/mol lower in steric energy than the boat
conformation (Fig. 3: i, 37.54 kcal/mol; ii, 40.78 kcal/mol). The
magnitude of this energy difference suggests that the equilibrium
between these conformers strongly favors the cup-shaped confor-
mation (i).
Fig. 3. Two conformations of quinone 2.
It was hoped that in the cycloaddition transition state the steric
interactions between the substituents of asymmetrically function-
alized dienes, such as (E)-b-ocimene (3), and the C-13 isopropyl
group would control the regiochemistry of the DielseAlder reaction
(Scheme 7). Unfortunately, (E)-b-ocimene (3) failed to react with 2
under avariety of thermal conditions.29 Common techniques used to
overcome a sluggish DielseAlder reaction are to carry out the cy-
cloaddition either in the presence of a Lewis acid catalyst30 or under
high pressure,31 or a combination of both conditions. Although (E)-
Scheme 7.
b
-ocimene is thermally stable,32 at temperatures above 50 ꢂC even
mild Lewis acids cause it to rearrange into its various allo-ocimene
isomers, which then react to form undesired products. This rapid
consumption of the (E)-
catalysis precluded the formation of a DielseAlder product. On the
other hand, substituting (E)- -ocimene (26) as the diene slowed the
rate of diene decomposition and gave a 30% yield of adduct 4 when
diethylaluminium chloride was used at rt to promote the cycload-
dition. It is important to note that under these conditions the
C-27,C-28 disubstituted double bond of the DielseAlder adduct
27 isomerized to the trisubstituted position (cf. C-26,C-27) after
the cycloaddition had taken place. A 79% yield of tetracycle 4
was obtained when 2 was treated in a sealed tube at 45 ꢂC for
b
-ocimene under thermal and Lewis acid-
necessary for the DielseAlder reaction to occur. Moreover, the res-
onance structure iv derived from iii governs the regioselectivity
observed.36 Finally, cycloadduct 28, which has the undesired ste-
reochemistry at the C-8 and C-9 quaternary centers, was produced
only when the Lewis acid-catalyzed DielseAlder reaction was
heated; hence the formation of this unwanted isomer could be
avoided.
a
24 h with (E)-a-ocimene in the presence of the mild Lewis acid tris-
(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)-euro-
pium [Eu(fod)3].33 This reaction also gave a low yield of an isomeric
C-8,C-9 DielseAlderadduct (28), the resultof addition of the diene to
the
b-face of quinone 2.
Several important observations were made in the course of
studying this DielseAlder reaction. First, the DielseAlder reaction
required at least 10 mol % of theLewisacid(relative tothequinone)at
either 0 ꢂC or rt. Stoichiometric quantities of theLewisacidprompted
rapid cycloaddition and migration of the C-22,C-23 double bond to
the tetrasubstituted position. While the isomerization of the
C-27,C-28double bonddafterthecycloadditionoccurreddcouldnot
be suppressed, we found that the undesired isomerization of the
C-22,C-23 double bond could be minimized if the reaction was
monitored. Further work showed that trienes 3 and 26 do not un-
dergo DielseAlder reactions, either thermally or with Lewis acid
catalysis, when the C-12 hydroxyl group is protected as either
a methyl ether, a trimethylsilyl ether, or as an acetate.34,35 These re-
Fig. 4. Lewis acid-activation of quinone 2.
With the DielseAlder adduct in hand, we next sought to
determine the conditions needed for the intramolecular ene
reaction to form the E-ring. In our retrosynthetic analysis we
assumed that formation of the E-, F-, and G-rings would require
separate steps. However, the need to use a Lewis acid to catalyze
the DielseAlder reaction suggested that these rings, complete with
the correct stereogenic centers, could be formed in a series of
tandem reactions (Scheme 8). Intermediates v/xi help to explain
the bond formations that occur during this proposed cascade as
well as the multiple functions of the catalyst. After the Lewis acid
sults suggest that complexation between the Lewis acid, the
a-hy-
droxy group and the C-11 carbonyl group of 2 (cf. chelate iii, Fig. 4) is

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10133
Scheme 8.
promotes the intermolecular DielseAlder reaction, it causes the
C-27,C-28 disubstituted double bond to isomerize (cf. v/vi). Since
ene reactions are facilitated by Lewis acids,37 the nucleophilic ad-
dition of the C-26,C-27 double bond to the C-11 carbonyl group
would also benefit from Lewis acid activation (cf. vi). Formation of
the C-11,C-26 bond generates a tertiary carbocation at C-27, which
is trapped by the C-12 hydroxyl group. This sequence, vi/vii/viii,
is best described as an intramolecular Lewis acid-catalyzed Prins
reaction. Formation of the heterocyclic F-ring would liberate the
proton needed to add to the C-1,C-10 double bond, and permits the
formation of the second tetrahydrofuran ring (cf. ix/x/xi/1).
Our quest became to discover the appropriate reaction condi-
tions needed to form the D-, E-, F-, and G-rings in a single step. We
decided to examine first the Prins reaction using AmberlystÒ 15
resin as a protic acid as catalyst (Scheme 9).38 We were delighted to
find that heating DielseAlder adduct 4 at 42 ꢂC for 12 h with this
acidic resin achieved both the desired Prins reaction and bis-
tetrahydrofuran formation (cf. 29). While the realization of the
polycyclization cascade was welcome, the migration of the C-22,C-
23 trisubstituted double bond to the C-23,C-24 position was not.
Perhaps one day triterpene 29 will be isolated from nature.39
Clearly, the use of a weaker acid catalyst than the AmberlystÒ 15
resin was needed to catalyze the Prins reaction and thereby initiate
the polycyclization cascade.
Brief reaction of alcohol 6 with AmberlystÒ 15 resin or with
pyridinium p-toluenesulfonate (PPTS)40 in DCM achieved the
final ring closure in high yield without the migration of the
C-22,C-23 trisubstituted double bond (Scheme 11). Our synthetic
Scheme 10.
(ꢀ)-perovskone displays 1H and 13C NMR, IR, and MS spectra that
are indistinguishable from those reported for the natural
material.5
Scheme 11.
Scheme 9.
Having achieved an efficient synthesis of racemic perovskone,
the siren call to find conditions whereby quinone 2 would produce
perovskone in a one-pot reaction was irresistible. Thus, a system-
atic study of the solvent, the choice of catalyst, and the reaction
temperatures required was undertaken (Table 2). While toluene
and DCM were suitable solvents, quinone 2 and triene 3 (or 26)
were insoluble in acetonitrile. When THF was used as the solvent,
only the DielseAlder reaction occurred. The use of weak Lewis
acids required heating in order to promote the DielseAlder and the
The next Lewis acid tested was the Eu(fod)3 reagent previously
used to achieve the DielseAlder reaction (Scheme 10). After heating
the Eu(fod)3-catalyzed DielseAlder reaction at 45 ꢂC for 24 h, the
reaction mixture had to be warmed to 110 ꢂC before consumption of
the DielseAlder adduct was observed. Heating the reaction mixture
at that temperature for an additional 48 h resulted in the isolation
of alcohol 6 in 82% yield.

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G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
Table 2
was based on the work of Sundberg and co-workers, who reported
Optimization of the cascade reaction
an efficient one-pot procedure for the synthesis of pentasubstituted
benzenes derived from 3043which selectively functionalized of the
3- and 6-positions with either identical or different electro-
philes.44,45 Given this, the introduction of an isopropyl group at the
3-position, followed by metalation of the 6-position and trapping
this anion (cf. 31) with formaldehyde, should produce benzyl al-
cohol 18. Previously, 4,4-dimethylcyclohexane-1,3-dione (20) was
C-alkylated with bromide 19 and then O-alkylated with iodo-
methane to give enone 22 in 67% yield. We can envision other
strategies to couple the A and C rings to give enone 22. The addition
of vinyllithium to enone 22, followed by cyclialkylation to form the
cycloheptane ring, produces key intermediate 11. For clarity’s sake,
our strategy for converting prochiral enone 11 into the required
enantiomer of 2 is postponed until after our second synthesis of 11
has been discussed.
Diene
Reaction conditions
Yield of 1 and/or 29
3
3
26
(a) 0 ꢂC (1.5 h)/50 ꢂC (10 h) in toluene
(b) 0 ꢂC (1.5 h)/50 ꢂC (7 h) in DCM
(c) 0 ꢂC (1.5 h)/50 ꢂC (10 h) in toluene
46%/26%
50%/15%
0%/71%
Prins reactions; unfortunately, these conditions would promote the
isomerization and hence decomposition of (E)- -ocimene (3). We
reasoned that the use of stronger Lewis acids at low temperatures
would produce only the cycloadduct derived from addition of the
b
diene to the a-face of the quinone and that short reaction times
would be required. Indeed, the use of nearly a stoichiometric
quantity of BF3$Et2O in toluene at 0 ꢂC allowed the DielseAlder
reaction of 2 with (E)-b-ocimene to be complete within 90 min;
lower reaction temperatures required longer reaction times.
Previous work had shown that the Prins reaction occurs at
a higher reaction temperature than the [4þ2]-cycloaddition. We
reasoned that the use of a strong Lewis acid would lower the re-
action temperature necessary to initiate the Prins reaction and that
shorter reaction times would be required. Indeed, warming the
crude DielseAlder reaction mixture to only 50 ꢂC caused the pol-
ycyclization cascade to occur; this temperature was maintained
overnight. Under these conditions a 46% yield of perovskone was
isolated along with a 26% yield of 29, in which the trisubstituted
double bond had isomerized to the tetrasubstituted position. Re-
peating this reaction using DCM as the solvent gave perovskone in
50% yield, while the yield of compound 29 was reduced to 14%.
Using BF3$Et2O as the catalyst and toluene as the solvent, (E)-a-
ocimene (26) rapidly formed the desired DielseAlder adduct;
however, isomerization of the C-22,C-23 trisubstituted double
bond of the adduct could not be avoided and occurred prior to
formation of the heterocyclic F- and G-rings. These conditions led
to the formation of 29 in 71% yield (unoptimized).
We explored other ideas to improve the cascade reaction. The
C-12 hydroxyl group of quinone 2 is also a vinylogous carboxylic
acid and could therefore serve as the only catalyst needed for the
DielseAlder and polycyclization cascade. However, simply heating
quinone 2 and (E)-b
-ocimene (26) together at 200 ꢂC gave only
a trace amount of the [4þ2]-adduct. Similar results were obtained
when 2 and 3 were kept at 12 kbar for 24 h. Grieco and co-workers
have established that lithium perchlorate in diethyl ether is
a powerful medium for promoting DielseAlder reactions.41 They
found that 2 and triene 26 in LiClO4$Et2O formed a 2:1 mixture of
adducts 4 and 28, respectively, in 50% yield using 5 M lithium
perchlorateediethyl ether as both catalyst and solvent. Finally,
we attempted to verify the proposed biosynthesis of perovskone
by treating geranyl pyrophosphate with quinone 2, our icete-
xone equivalent. Unfortunately, the geranyl pyrophosphate formed
a complex mixture of acyclic and cyclic terpenes without producing
any of the desired cycloaddition adduct.42
Scheme 12.
In 1984, Crowthers and co-workers found that treatment of
1,2,4-trimethoxybenzene (30) with n-butyllithium followed by
the addition of an electrophile affords only the 3-substituted
product.43 When that product is treated with a second equivalent
of n-butyllithium and TMEDA, metalation occurs selectively at the
6-position provided that the newly introduced C-3 substituent does
not react with the n-butyllithium used for deprotonation. Based on
Although our synthesis of (ꢀ)-perovskone from vanillin re-
quired only 16 steps and proceeded in 9% overall yield, a more ef-
ficient route was desired. Since the C-5 chiral center in 2 controls
the stereochemistry for each new chiral center produced in the
tandem polycyclizations leading to perovskone (cf. Scheme 1), the
ability to prepare quinone 2 in optically active form was essential
for us to prepare (þ)-perovskone.
these precedents,
a one-pot bis-functionalization of 30 was
attempted (Scheme 13). A 1:1 mixture of 30 and TMEDA was
treated with 1.1 equiv of n-butyllithium, followed by an equal of
acetone; a second equivalent of n-butyllithium was followed by the
addition of 1.1 equiv of DMF. Unfortunately, these conditions gave
a complex mixture of products.
The retrosynthetic analysis for a synthesis of optically active
quinone (2) is generalized in Scheme 12. Our selection of 1,2,4-
trimethoxybenzene (30) as a more attractive starting material

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10135
benzoate 35 in 96% yield. The addition of excess of methyl-
magnesium iodide to 35, followed by an acidic workup, gave ter-
tiary alcohol 32 in high yield. Hydrogenation of 32 in the presence
of HCl afforded tetrasubstituted benzene 34 in 93% yield.48 This
three-step reaction sequence was carried out on a scale of greater
than 50 g without isolation of the intermediates.
In our hands, metalation of 34 occurred at both the 6- and the
5-positions (Scheme 16), although significantly favoring the
6-position. Addition of excess DMF to the mixture of aryllithium
anions (xii) and (xiii) gave isomeric benzaldehydes 36 and 37 in
74% and 18% yield, respectively; these aldehydes were easily
separated by chromatography. Reduction of aldehyde 36 with
NaBH4 gave a nearly quantitative yield of alcohol 18. Alterna-
tively, anions (xii) and (xiii) could be trapped with gaseous
formaldehyde to produce alcohol 18 in 65% yield after chro-
matographic separation of the isomeric alcohol derived from
anion xiii. Alcohol 18 was then converted to bromide 19 in 92%
yield using PBr3.
Scheme 13.
Instead of functionalizing 30 at two sites in a one-pot process,
we decided to focus on introducing the isopropyl group at the
3-position before functionalizing the 6-position (Scheme 14). In
1993, we converted veratrole to isopropylveratrole in three steps
and a 50% overall yield.46 Thus, metalation of 30, followed by the
addition of acetone and quenching the reaction with acetic acid,
produced olefin 33 in 55% yield along with a 35% yield of recovered
30.47 Hydrogenation of 33 using 10% palladium on carbon at at-
mospheric pressure afforded tetrasubstituted benzene derivative
34 in 93% yield.
Scheme 14.
The introduction of an isopropyl group at the 3-position of 30
was significantly improved when ethyl chloroformate was used
instead of acetone (Scheme 15). Treatment of 30 with n-butyl-
lithium, followed by addition of ethyl chloroformate, produced
Scheme 16.
Enolates derived from enones alkylate with alkyl halides at the
a-position. In particular Smith and co-workers methylated
3-isobutoxy-6,6-dimethylcyclohexen-2-en-1-one at the a-position
in 61% yield using LDA and HMPA (Scheme 17).49 Since benzyl
halides are good electrophiles, we were confident that this alkyl-
ation would couple the A and C rings units.
Scheme 17.
Enone 39 was prepared in 82% yield by heating commercially
available dione 20 with methanol and TsOH with azeotropic
removal of water (Scheme 18); although column chromatography
Scheme 15.

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G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
separated 39 from isomer 40 their Rf values were very close.50 We
found that 39 could be prepared on a 20 g scale using the
StorkeDanheiser protocol51 by alkylating 3-methoxycyclohex-2-
en-1-one (38) twice with iodomethane in a 92% overall yield af-
ter distillation.
Scheme 18.
Enone 39 was treated with LDA using Smith’s conditions and the
resulting dienolate was treated with bromide 19. Surprisingly, al-
kylation product 22 was obtained in only 32% yield, along with >65%
of unreacted bromide 19 and recovered enone 39. This observation
caused us to carry out the alkylation using bromide 19 as the limiting
reagent. Indeed, 22 was prepared in 94% yield by using a threefold
excess of the dienolate relative to bromide 19; the excess 39 was
recovered via distillation. The conversion of bicyclic enone 22 to tri-
cyclic enone 11 used the same two steps worked out in our initial
synthesis. Thus, the preparation of enone 11 from 1,2,4-
trimethoxybenzene required nine steps [30/35/32/34/36/
18/19/22/12/11] and proceeded in 52% overall yield. While
enone 11 could be prepared using only seven transformations
[30/33/34/18/19/22/12/11], this shorter route gave only
a 29% overallyield. Nevertheless, bothsequencesareanimprovement
over our first route, which required 12 steps to convert vanillin into
enone 11 and proceeded in 15% overall yield.
Scheme 19.
their high selectivity for preparing chiral alcohols from ketones
and enones led us to utilize these reagents for the synthesis of
allylic alcohols (R)- and (S)-41 (Scheme 20). These reductions oc-
curred in high chemical yield (90%). The 19F NMR analysis of the
Mosher esters57 of alcohols (R)-41, (S)-41, and (ꢀ)-41 indicated
a 90% ee for (R)-41. We attempted to selectively hydrolyze only
one of the enantiomers of the acetate of (R)-41 using pig liver
esterase to enhance the enantiomeric purity of (R)-41.58 However,
this acetate exhibited severe solubility problems despite the large
variety of co-solvent systems studied. Fortunately, three re-
crystallizations of the 90% ee enriched (R)-41 gave material
We foresaw that quinone (S)-2 could be synthesized as sum-
marized in Scheme 19.52 Several methods now exist for the
asymmetric reduction of ketones53 including
a,b-disubstituted
cyclohex-2-en-1-ones.54 Access to allylic alcohol (R)-41 would
allow us to prepare (S)-2 via a modification of the one-pot Wolff-
Kisner reduction developed by Myers and Zheng.55 In the first step
of their modified process, an allylic alcohol is converted into a hy-
drazine derivative such as xiv using
a Mitsunobu reaction
(cf. 41/xiv/xv). The SN2 displacement of triphenylphosphine
oxide by nitrobenzenesulfonylhydrazine (NBSH)59 inverts the
configuration at C-1 and the base present converts intermediate xiv
into diazene xv. Once formed, diazene xv undergoes an intra-
molecular [1,5]-sigmatropic rearrangement to release a molecule of
nitrogen with the transfer of a hydride to C-5 and the movement of
the C-5,C-10 double bond to the C-1,C-10 position.56 The three
remaining transformations needed to convert (S)-23 to quinone
(S)-2 were developed in our synthesis of (ꢀ)-perovskone (1) and
occurred in high yield (cf. Scheme 6).
The commercial availability of (S)-methyl-CBS-oxaborolidine
[(S)-42] and (R)-methyl-CBS-oxaborolidine [(R)-42] coupled with
Scheme 20.

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10137
consisting of a single enantiomer of 99% ee based on the 19F NMR
analysis of its Mosher ester.
b-palladium formate xvii to produce cis-declin 46. We were hopeful
that this hydrogenolysis was applicable to the conversion of (R)-41
to (S)-23.
The addition of alcohol (R)-41 to the complex formed by treating
triphenylphosphine (TPP) with diethylazodicarboxylate (DEAD)
at ꢁ30 ꢂC, followed by the addition of NBSH, gave disappointing
yields of alkene (S)-23. Myers and Zheng observed that hindered
secondary alcohols required the use of a large excess of reagents in
a concentrated solution. Unfortunately, these conditions can also
result in elimination byproducts. They circumvented this problem
by using N-methyl morpholine (NMM) as solvent instead of THF.
The application of Myers’ reductive transposition to alcohol (R)-
41 was a demanding test of the generality of this procedure since
tetrasubstituted secondary allylic alcohols were not previously
studied. For a 100 mg scale reaction the best solvent system was
a 1:1 mixture of THF/NMM; less concentrated solutions resulted in
much lower yield. A threefold excess of TPP, DEAD, and NBSH at
a concentration of approximately 0.25 M with respect to the alcohol
gave the best yield (60%) of (S)-23. In general, the Mitsunobu in-
version of (R)-41 occurred at ꢁ10 ꢂC or 0 ꢂC but the overall yield of
the 1,3-transposition varied from 40% to 45% when more than 1 g of
alcohol (R)-41 was used.
As shown in Scheme 22, (R)-41 was treated with methyl chlor-
oformate and pyridine to generate carbonate (R)-47. The reaction of
carbonate 47 with 6 equiv of ammonium formate, 0.2 equiv of
Pd(OAc)2, and 0.2 equiv of PBu3 at rt in dry DMF gave optically pure
olefin (S)-23 in 98% yield. We found that a 1:1 ratio of the PBu3 to
the Pd(OAc)2 allowed the reaction to occur at rt overnight, whereas
higher ratios of PBu3 to the Pd(OAc)2 slowed down the reaction and
required heating, which resulted in lower overall yield. In general,
this transposition was carried out on 2e3 g scales in 98% yield.
The palladium-catalyzed hydrogenolysis of allylic acetates,
ethers, or carbonates by hydrides produces alkenes with trans-
position of the position of the double bond. In 1993, Mandai and
Tsuji used the palladium-catalyzed hydrogenolysis of allylic
formates to control the stereochemistry of ring junctions
(Scheme 21).60 In their study, allylic formate 43 gave trans-decalin
44, whereas allylic formate 45 produced cis-decalin 46. The initial
step of this transformation is the formation of a
peallylpalladium
complex, which occurs with inversion of the stereochemistry at the
allylic position. The subsequent migration of the hydride from the
a
-palladium formate xvi to the ring junction carbon occurred from
the -face to produce a trans-fused decalin. Similarly, the 3 -allylic
formate ( -face of the
a
a
a
-45) undergoes hydride transfer from the b
Scheme 22.
With tricycle (S)-23 in hand, all that remained to complete
a syntheses of quinone (S)-2 was to deprotect the C-11 and C-12
methyl ethers, and to oxidize the intermediate catechol to o-qui-
none 25 (Scheme 23). Treatment of 25 with either mild acid or mild
base isomerized o-quinone (S)-25 to p-quinone (S)-2. The reaction
Scheme 21.
Scheme 23.

10138
G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
of (S)-2 with (E)-
b
-ocimene (3) and BF3$Et2O using the optimized
9b¼0.74]. Analysis of the 1H NMR spectrum, particularly the set of
olefinic signals at 5.68 and 5.60 and the methoxy signals at 3.78 and
3.80, indicates that 9a and 9b were produced in a 3:2 ratio.
(b) Using NaS-i-Pr: The above procedure was repeated except
that isopropyl mercaptan (80 mL, 0.88 mmol) was added to sodium
hydride (29 mg, 0.70 mmol) in 2 mL of DMF. To this solution of
sodium isopropylthiolate was added 8 (29 mg, 0.09 mmol) and the
resulting mixture was heated at 65 ꢂC for 48 h. Standard ethereal
workup, followed by chromatography, gave 21 mg (75%) of phenols
9a and 9b as an inseparable 3:2 mixture, respectively. Analysis of
the 1H NMR spectrum, particularly the set of olefinic signals at 5.68
and 5.60 and the methoxy signals at 3.78 and 3.80, indicates that 9a
and 9b were produced in a 3:2 ratio.
(c) Using NaS-t-Bu: The above procedure was repeated except
that tert-butyl mercaptan (100 mL, 0.88 mmol) was added to
sodium hydride (29 mg, 0.70 mmol) in 2 mL of DMF. To this
solution of sodium tert-butylthiolate was added 8 (30 mg,
0.90 mmol) and the resulting mixture was heated at 50 ꢂC for
48 h. Standard ethereal workup, followed by chromatography,
gave 14.5 mg (52%) of phenols 9a and 9b as an inseparable 2:1
mixture, respectively. Analysis of the 1H NMR spectrum, partic-
ularly the set of olefinic signals at 5.68 and 5.60 and the methoxy
signals at 3.78 and 3.80, indicates that 9a and 9b were produced
in a 2:1 ratio.
conditions (Table 2) afforded (þ)-perovskone in 50% yield having
an ½a 2D3
ꢃ
of þ91.4, which compares favorably with the ½a D25
of þ94.0
ꢃ
reported by Ahmad and co-workers for natural perovskone.5
3. Conclusions
Sixteen transformations were needed to convert vanillin into
(ꢀ)-perovskone in a 9% overall yield. This synthesis featured a one-
pot reaction, which assembled three rings, four bonds, and five
stereocenters in 82% yield. The final step was an acid-catalyzed
olefin hydration, which occurred in 90% yield. In contrast, the
conversion of 1,2,4-trimethoxybenzene into (þ)-perovskone re-
quired fifteen steps and occurred in 18% overall yield. In this im-
proved synthesis, the polycyclization cascade created four rings,
five bonds, and six stereocenters in a one-pot reaction in 50% yield.
The chemistry discovered in the course of the synthesis of (ꢀ)- and
(þ)-perovskone has facilitated the synthesis of other complex ter-
penes,52 most recently a four-step synthesis of (þ)-salvadione-B,
a related pentacyclic triterpene.61 Additional applications of the
chemistry learned during this study are forthcoming.
4. Experimental section
4.1. General procedures
(d) Using L-Selectride: To a solution of bis-ether 8 (20 mg,
0.125 mmol) dissolved in 4.0 mL of dry glyme was added 375 mL of
L-Selectride (1.0 M, 3.75 mmol) and the resulting mixture was
refluxed (90 ꢂC) until TLC analysis indicated that the demethylation
was complete (24 h). The reaction mixture was cooled to 0 ꢂC and
diluted with 50 mL of ether. The resulting mixture was quenched
carefully with water. Standard ethereal workup, followed by chro-
matography (elution with H/E, 10:1) gave 17 mg of 9a (92%): 1H
All reactions were run under an atmosphere of nitrogen and
monitored by TLC analysis until the starting material was com-
pletely consumed. Unless otherwise indicated, all ethereal workups
consisted of the following procedure: the reaction was quenched at
rt with saturated aqueous ammonium chloride. The aqueous phase
organic solvent was removed under reduced pressure on a rotary
evaporator and the residue was taken up in ether, washed with
brine and dried over anhydrous MgSO4. Filtration, followed by
concentration at reduced pressure on a rotary evaporator and at
1 Torr to constant weight, afforded a crude residue, which was
purified by flash chromatography using NM silica gel 60
(230e400 mesh ASTM) and distilled reagent grade solvents.
1H and 13C NMR spectral data were obtained in CDCl3 on a Var-
ian AMX-400 or a Bruker AM-250 MHz spectrometer and were
NMR (250 MHz) d 6.66 (s, 1H), 5.60 (s, 1H), 3.78 (s, 3H), 3.20 (heptet,
1H, J¼7 Hz), 3.03 (d, 1H, J¼14.4 Hz), 2.7e2.8 (m, 2H), 1.9e2.15 (m,
3H), 1.79 (d, 1H, J¼12 Hz), 0.92e0.99 (m, 2H), 0.87 (s, 3H). This data
suggests that the following diagnostic data corresponds to isomer
9b: 1H NMR (250 MHz)
d 6.68 (s, 1H), 5.68 (s, 1H), 3.80 (s, 3H).
4.1.2. 2,3,5-Trimethoxybenzoic acid (14). 1-Bromo-2,3,5-trimetho-
xybenzene (13) (13.25 g, 53.60 mmol) was dissolved in 130 mL of
dry ether and was cooled to ꢁ78 ꢂC. t-Butyllithium (110 mmol,
65 mL of 1.7 M solution in pentane) was added and the resulting
solution was kept at ꢁ78 ꢂC over a 90-min period and then warmed
to ꢁ20 ꢂC. The reaction mixture was treated with solid CO2 (>5 g)
and stirred at ꢁ20 ꢂC for a 30-min period. The reaction was
quenched with water and the phases were separated. The aqueous
phase was acidified with 10% aqueous HCl, extracted with ether and
the combined ethereal extracts were dried over anhydrous MgSO4.
After filtration and evaporation of the solvent, the crude acid was
recrystallized from hexanes to afford 13.65 g (89%) of acid 14 as
white needles, which were homogeneous by TLC analysis (H/E, 1:1,
Rf 13¼0.69, Rf 14¼0.14): mp 101e101.5 ꢂC; 1H NMR (250 MHz)
calibrated using trace CHCl3 (d
7.27 and 77.23 ppm). 19F NMR
spectra were obtained in CDCl3 on a Bruker AMX-400 MHz spec-
trometer and were calibrated using trifluoroacetic acid as an ex-
ternal standard (0 ppm). Infrared spectra were obtained on
a PerkineElmer 1600 series FT-IR spectrometer and the absorption
frequencies are reported in wavenumbers (cmꢁ1). Mass spectra
were obtained on a PerkineElmer SCIEX API1 Plus spectrometer
using electrospray ionization. Microanalysis was performed by
Atlantic Microlab, Inc., Atlanta, GA.
The following abbreviations are used throughout this section:
hexanes (H), diethyl ether (E), and methyl tert-butyl ether (MTBE).
4.1.1. 11-Hydroxy-12-methoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraene (9a) and 12-hydroxy-11-methoxy-9(10/20)-
5aH-abeo-abieta-1(10),8,11,13-tetraene (9b). (a) Using NaSEt: Etha-
nethiol (16.80 g, 0.29 mol) was added dropwise to a cold solution
(0 ꢂC) of sodium hydride (3.20 g, 0.13 mol, 80% dispersion in oil)
suspended in 35 mL of freshly distilled DMF. The resulting mixture
was stirred at rt for a 2-h period, followed by the addition of a so-
lution of 1.60 g of barbatusol methyl ether (8) (4.47 mmol) dissolved
in 20 mL of dry DMF. The reaction mixture was heated to 50 ꢂC for
12 h, and then cooled to 0 ꢂC and cautiously neutralized with 2 N
aqueous HCl. Standard ethereal workup, followed by purification by
chromatography on silica gel (elution with H/E, 10:1/5:1), gave
1.26 g (86%) of phenols 9a and 9b as an inseparable 3:2 mixture,
which was homogeneous by TLC analysis [H/E, 5:1, Rf 8¼0.92, Rf 9a/
d
3.82 (s, 3H), 3.89 (s, 3H), 4.01 (s, 3H), 6.71 (d, 1H, J¼3.0 Hz), 7.16 (d,
1H, J¼3.0 Hz) [the carboxylic acid proton was not observed]; 13C
NMR (62.9 MHz) 165.3 (s), 156.4 (s), 152.8 (s), 142.5 (s), 121.8 (s),
106.3 (d), 104.6 (d), 62.3 (q), 56.1 (q), 55.8 (q) ppm; IR (Nujol) 1738,
1605 cmꢁ1; MS (m/z) 212 (100%), 197 (96%), 137 (67%). Elemental
analysis for C10H12O5. Calculated: C, 56.59%, H, 5.70%. Found: C,
56.63%, H, 5.71%.
4.1.3. 4-(1-Methylethyl)-2-hydroxy-3,5-dimethoxybenzoic acid (15)
and 4-(1-methylethyl)-2,3,5-trimethoxybenzoic acid (16). To a solu-
tion of 10.23 g of acid 14 (48.2 mmol) in 70 mL of 98% H2SO4 was
added 6.60 g of 2-propanol (0.11 mol) at rt. The resulting mixture
was heated to 45 ꢂC and an additional 116.8 mL of 2-propanol
(0.22 mol) was added to the reaction mixture in two portions

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10139
over a 30-min period. The resulting reaction mixture was held at
45 ꢂC for 2 h. Standard ethereal workup provided 12.18 g of a crude
residue that NMR analysis indicated consisted of 18% benzoic acid
15 and 55% yield of tris-ether 16. This crude mixture was used di-
rectly without further purification or characterization.
and concentrated. The crude residue was chromatographed (elu-
tion with H/E, 3:1) to afford 2.51 g (68%) of 21, which was homo-
geneous by TLC analysis (H/E, 4:1, Rf 21¼0.24): mp 81e83 ꢂC; 1H
NMR (250 MHz)
d
1.08 (s, 6H), 1.27 (d, 6H, J¼6.9 Hz), 1.75 (t, 2H,
J¼6.5 Hz), 2.40 (t, 2H, J¼6.5 Hz), 3.46 (heptet, 1H, J¼6.9 Hz), 3.49 (s,
2H), 3.73 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 6.66 (s, 1H); 13C NMR
(62.9 MHz) 202.7 (s), 170.4 (s), 155.5 (s), 150.8 (s), 142.3 (s), 131.1 (s),
128.5 (s), 112.6 (s), 108.2 (d), 61.6 (q), 61.0 (q), 55.6 (q), 39.5 (t), 35.2
(s), 34.1 (t), 25.7 (q), 25.0 (d), 24.9 (t), 21.1 (q) ppm; IR (film) 1734,
1705, 1603 cmꢁ1; Elemental analysis for C21H28O5. Calculated: C,
69.59%, H, 8.34%. Found: C, 69.32%, H, 8.41%.
4.1.4. Methyl 4-(1-Methylethyl)-2,3,5-trimethoxybenzoate (17). To
a solution of the above crude mixture (900 mg, 3.54 mmol) dis-
solved in ACS reagent grade acetone (6 mL) was added anhydrous
potassium carbonate (980 mg, 7.09 mmol) and iodomethane
(1.25 g, 8.80 mmol). The resulting heterogeneous mixture was
refluxed for 8 h, cooled to rt, and diluted with brine (10 mL).
Standard ethereal workup furnished 932 mg of a crude ester 17.
Chromatography (elution with H/E, 5:1) provided 920 mg (97%) of
ester 17, which was homogeneous by TLC analysis (H/E, 3:1, Rf
4.1.8. 3-Methoxy-6,6-dimethyl-2-[4-(1-methylethyl)-2,3,5-
trimethoxyphenylmethyl]-2-cyclohexenone (22). To a suspension of
degreased NaH (60%, 565 mg, 23.51 mmol) in 20 mL of dry DMF at
0 ꢂC was added dione 21 (7.13 g, 19.60 mmol) in 40 mL of DMF over
a 30-min period. The resulting solution was warmed to rt and then
stirred for 30 min. Dimethyl sulfate (2.70 g, 21.50 mmol) was then
added and the resulting mixture was stirred at rt for 12 h. The re-
action mixture was diluted with ether and quenched with water.
The resulting organic phase was washed sequentially with aqueous
10% HCl and saturated aqueous Na2CO3, dried over anhydrous
MgSO4, filtered, and concentrated. The crude residue was chro-
matographed (elution with H/E, 3:1) to give 7.30 g of 22 (99%),
which was homogeneous by TLC analysis (H/E, 2:1, Rf 21¼0.19, Rf
17¼0.75): 1H NMR (250 MHz)
1.30 (d, 6H, J¼6.9 Hz), 3.55 (heptet,
d
1H, J¼6.9 Hz), 3.80 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 7.02
(s, 1H); 13C NMR (62.9 MHz) 166.4 (s), 154.1 (s), 152.5 (s), 147.7 (s),
135.7 (s), 122.1 (s), 107.6 (d), 61.4 (q), 61.0 (q), 55.6 (q), 52.1 (q), 25.4
(d), 20.7 (q) ppm; IR (film) 1732 cmꢁ1; MS (m/z) 268 (88%), 221
(100%). Elemental analysis for C14H20O5. Calculated: C, 62.66%, H,
7.52%. Found: C, 62.50%, H, 7.56%.
4.1.5. 4-(1-Methylethyl)-2,3,5-trimethoxyphenylmethyl alcohol (18).
A suspension of LiAlH4 (1.56 g, 40.00 mmol) in 100 mL of anhydrous
ether was cooled to 0 ꢂC. A solution of ester 17 (10.00 g, 37.00 mmol)
in 50 mL of dry ether was added dropwise and the resulting mixture
was allowed to warm to rt over a 4-h period. Standard ethereal
workup afforded 9.67 g of a residue. Purification using chromatog-
raphy (elution with H/E, 3:1) gave 8.82 g (98%) of alcohol 18, which
was homogeneous by TLC analysis (H/E, 2:1, Rf 17¼0.47, Rf 18¼0.14):
22¼0.58): 1H NMR (250 MHz)
d
1.13 (s, 6H), 1.25 (d, 6H, J¼7.0 Hz),
1.88 (t, 2H J¼6.2 Hz), 2.64 (t, 2H, J¼6.2 Hz), 3.45 (heptet, 1H,
J¼7.0 Hz), 3.61 (s, 2H), 3.63 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.82 (s,
3H), 6.16 (s, 1H); 13C NMR (62.9 MHz) 202.7 (s), 170.6 (s), 154.1 (s),
151.3 (s), 145.1 (s), 131.9 (s), 127.2 (s), 115.7 (s), 106.1 (d), 60.7 (q),
60.1 (q), 55.4 (q), 54.8 (q), 39.4 (s), 34.3 (t), 24.9 (d), 24.5 (q), 22.0 (t),
21.4 (q), 21.3 (q) ppm; IR (film) 1615 cmꢁ1. Elemental analysis for
C22H32O5. Calculated: C, 70.17%, H, 8.57%. Found: C, 70.06%, H,
8.88%.
1H NMR (300 MHz)
d
1.29 (d, 6H, J¼7.0 Hz), 2.55 (br s, 1H), 3.48
(heptet, 1H, J¼7.0 Hz), 3.78 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 4.65 (s,
2H), 6.60 (s, 1H); 13C NMR (75.5 MHz) 154.6 (s), 151.5 (s), 144.8 (s),
131.5 (s), 130.1 (s), 106.3 (d), 61.3 (t), 60.7 (q), 60.7 (q) [note the
preceding signals overlap], 55.6 (q), 25.1 (d), 21.1 (q) ppm; IR (film)
3387 cmꢁ1; MS (m/z) 240 (Mþ). Elemental analysis for C13H20O4.
Calculated: C, 64.96%, H, 8.39%. Found: C, 65.00%, H, 8.42%.
4.1.9. 3-Ethenyl-4,4-dimethyl-2-[4-(1-methylethyl)-2,3,5-
trimethoxyphenylmethyl]-2-cyclohexenone (12). A solution of
7.50 g (20.00 mmol) of enone 22 and CeCl3 (161 mg, 0.66 mmol)
in 40 mL of ether at rt was treated dropwise with 70 mL
(70.00 mmol) of vinylmagnesium bromide (1.0 M in THF) over
a 30-min period. The reaction mixture was stirred at rt for 13 h.
The reaction mixture was quenched with ice and then diluted
with 100 mL of ether. The resulting mixture was placed in
a separatory funnel and the ethereal phase was shaken for a 5-
min period with 200 mL of a 10% aqueous HCl solution. Stan-
dard ethereal workup, followed by chromatography (elution with
H/E, 3:1), provided 6.93 g (95%) of conjugated dienone 12, which
was homogeneous by TLC analysis (H/E, 2:1, Rf 22¼0.15, Rf
4.1.6. 2-(1-Methylethyl)-1,3,4-trimethoxy-5-bromomethylbenzene
(19). To a cold solution (0 ꢂC) of 5.68 g of alcohol 18 (23.50 mmol)
in 50 mL of dry ether was carefully added phosphorus tribromide
(3.82 g, 14.11 mmol) and the mixture was stirred for 5 min. Stan-
dard ethereal workup, followed by chromatography (elution with
H/E, 10:1), gave 6.58 g (92%) of bromide 19, which was homoge-
neous by TLC analysis (H/E, 2:1, Rf 18¼0.17, Rf 19¼0.83): 1H NMR
(250 MHz)
d
1.83 (d, 6H, J¼7.2 Hz), 3.48 (heptet, 1H, J¼7.2 Hz), 3.78
(s, 3H), 3.81 (s, 3H), 3.90 (s, 3H), 4.54 (s, 2H), 6.58 (s, 1H); 13C NMR
(62.9 MHz) 154.5 (s), 151.8 (s), 145.6 (s), 131.7 (s), 128.5 (s), 107.7 (d),
60.6 (q), 60.6 (q) [note the preceding signals overlap], 55.6 (q), 28.7
(t), 25.2 (d), 21.0 (q) ppm; IR (film) 1601 cmꢁ1; MS (m/z) 304 (11%),
302 (11%), 223 (100%). Elemental analysis for C13H19O3Br. Calcu-
lated: C, 51.65%, H, 6.34%. Found: C, 51.33%, H, 6.27%.
12¼0.57): mp 104e105 ꢂC; 1H NMR (250 MHz)
d 1.23 (s, 6H), 1.26
(d, 6H, J¼7.2 Hz), 1.93 (t, 2H, J¼6.7 Hz), 2.55 (t, 2H, J¼6.7 Hz), 3.43
(heptet, 1H, J¼7.2 Hz), 3.66 (s, 3H), 3.68 (s, 2H), 3.81 (s, 6H), 5.15
(d, 1H, J¼17.9 Hz), 5.35 (d, 1H, J¼11.5 Hz), 6.13 (s, 1H), 6.36 (dd,
1H, J¼17.9, 11.5 Hz); 13C NMR (62.9 MHz) 195.4 (s), 163.5 (s),
154.0 (s), 151.5 (s), 144.9 (s), 133.4 (d), 132.3 (s), 131.7 (s), 127.6 (s),
119.7 (t), 106.1 (d), 60.7 (q), 59.9 (q), 55.4 (q), 37.3 (t), 35.5 (s),
34.4 (t), 27.2 (q), 26.2 (t), 24.9 (d), 21.2 (q) ppm; IR (film) 1670,
1600 cmꢁ1; MS (m/z) 372 (5%), 210 (100%), 195 (53%). Elemental
analysis for C23H32O4. Calculated: C, 74.15%, H, 8.66%. Found: C,
74.26%, H, 8.71%.
4.1.7. 4,4-Dimethyl-2-[4-(1-methylethyl)-2,3,5-trimethoxyphenyl-
methyl]-1,3-cyclohexanedione (21). 4,4-Dimethylcyclohexane-1,3-
dione (20) (2.78 g, 19.83 mmol, Aldrich), K2CO3 (1.37 g,
9.90 mmol), bromide 19 (3.00 g, 9.90 mmol), and KI (822 mg,
4.95 mmol) were dissolved in a mixture of 3 mL of water and 1.5 mL
of THF. The reaction mixture was stirred at rt for a 24-h period. The
aqueous solution was first extracted with ether (2ꢄ50 mL) and the
combined ethereal extracts were washed with 100 mL of saturated
aqueous NaHCO3. The resulting organic phase was extracted with
5% aqueous NaOH (2ꢄ50 mL) and the resulting aqueous solutions
were acidified with 10% aqueous HCl and extracted with ether
(3ꢄ50 mL). The ethereal extracts were dried over anhydrous MgSO4
4.1.10. 11,12,14-Trimethoxy-9(10/20)-5aH-abeo-abieta-
5(10),8,11,13-tetraen-1-one (11). To
a solution of 12 (3.00 g,
8.06 mmol) in 40 mL of dry DCM at ꢁ78 ꢂC was added 3.06 mL of
TiCl4 (16.12 mmol) and the reaction mixture was stirred at ꢁ78 ꢂ
C
for 20 min and then warmed to rt over a 30-min period. Standard
ethereal workup, followed by chromatography (elution H/E, 4:1),

10140
G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
provided 2.89 g (96%) of enone 11, which was homogeneous by TLC
analysis (H/E, 1:1, Rf 12¼0.43, Rf 11¼0.38): mp 120e121 ꢂC; 1H NMR
(q), 21.2 (q) [note: the two preceding signals overlap] ppm; IR (film)
3392 cmꢁ1. Elemental analysis for C21H30O3. Calculated: C, 76.33%,
H, 9.15%. Found: C, 72.69%, H, 9.20%.
(250 MHz)
d
1.16 (s, 6H), 1.32 (d, 6H, J¼7.2 Hz), 1.79 (t, 2H, J¼6.7 Hz),
2.49 (t, 2H, J¼6.7 Hz), 2.65 (br t, 2H, J¼6.4 Hz), 3.00 (br t, 2H,
J¼6.4 Hz), 3.37 (heptet, 1H, J¼7.2 Hz), 3.65 (s, 3H), 3.74 (s, 3H), 3.86
(s, 3H), 3.88 (s, 2H); 13C NMR (100.6 MHz) 20.5 (t), 22.3 (q), 24.2 (t),
26.1 (d), 26.9 (q), 29.5 (t), 34.5 (t), 36.6 (s), 37.3 (t), 60.6 (q), 60.8 (q),
62.0 (q), 129.0 (s), 131.9 (s) 131.9 (s) [note: the preceding signals
overlap], 132.8 (s) 132.8 (s) [note the preceding signals overlap],
147.5 (s), 151.2 (s), 165.4 (s), 197.7 (s) ppm; IR (film) 1664 cmꢁ1; MS
(m/z) 372 (Mþ). Elemental analysis for C23H32O4. Calculated: C,
74.15%, H, 8.66%. Found: C, 73.90%, H, 8.61%.
4.1.13 . ( ꢀ) - 12 - Hy d ro x y- 9 (10 /2 0 ) - 5 a H - a b e o - a b i e t a -
1(10),8(9),12(13)-trien-11,14-dione (2). (a) Via the in situ oxidation/
acid hydrolysis procedure: To a mixture of catechol 24 (740 mg,
2.24 mmol) and ammonium cerium nitrate (2.00 g, 3.65 mmol)
dissolved in 20 mL of a 1:1 mixture of water and ether was stirred
vigorously for a 1-h period at rt. The ethereal phase was separated
and concentrated to a residue. The crude residue was dissolved in
THF (10 mL) and 1 mL of 10% aqueous H2SO4 was added. The
resulting mixture was stirred vigorously at rt for a 5-h period.
Standard ethereal workup, followed by chromatography (elution
with H/E, 10:1), afforded 700 mg (99%) of quinone 2, which was
homogeneous by TLC analysis (H/E, 19:1, Rf 24¼0.64, Rf 2¼0.16):
4.1.11. 11,12,14-Trimethoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraene (23). A mixture of enone 11 (2.60 g,
6.99 mmol) and p-tosylhydrazine (1.43 g, 7.69 mmol) dissolved in
25 mL of absolute ethanol was stirred at rt for a 12-h period.
Evaporation of the solvent and elution of the residue through a plug
of silica gel afforded the crude hydrazone, which was used without
further purification or characterization (H/E, 1:1, Rf
hydrazone¼0.38, Rf 11¼0.34).
mp 158 ꢂC; 1H NMR (250 MHz)
d 0.86 (s, 3H), 0.90 (s, 3H),
1.08e1.47 (m, 9H), 1.21 (d, 6H, J¼7.2 Hz), 1.82 (br d, 1H, J¼10.9 Hz),
1.90e2.10 (m, 3H), 2.44e2.51 (m, 1H), 2.87 (d, 1H, J¼15.5 Hz),
3.00e3.10 (m, 1H), 3.20 (heptet, 1H, J¼7.2 Hz), 3.58 (d, 1H,
J¼15.5 Hz), 5.48 (s, 1H), 7.06 (s, 1H); 13C NMR (62.9 MHz) 183.6 (s),
166.7 (s), 149.9 (s), 146.8 (s), 138.9 (s), 134.7 (s), 124.6 (s), 122.8 (d),
50.3 (d), 33.7 (t), 32.2 (s), 31.4 (t), 27.1 (d), 27.1 (t), 26.4 (q), 24.6 (t)
[note: the two preceding signals overlap], 24.4 (q), 23.1 (t), 19.9
(q) ppm; IR (film) 3378, 1636 cmꢁ1. Elemental analysis for
C20H26O3. Calculated: C, 76.40%, H, 8.33%. Found: C, 76.08%, H,
8.22%.
(b) Via the in situ oxidation/saponification procedure: To a mix-
ture of catechol 24 (554 mg, 1.65 mmol) and ammonium cerium
nitrate (1.50 g, 2.73 mmol) dissolved in 20 mL of a 1:1 mixture of
water and ether was stirred vigorously for 1 h at rt. To the ethereal
phase were added 10 mL of aqueous 10% NaOH and 10 mL of THF.
The resulting homogeneous mixture was stirred vigorously at rt for
a 5-min period. Standard ethereal workup, followed by chroma-
tography (elution with H/E,10:1), afforded 520 mg (98%) of quinone
2, which was identical to that characterized above.
The above hydrazone was stirred in 10 mL of DMF and 10 mL of
sulfolane containing 10 mg of bromocresol green. The resulting
mixture was warmed to 90 ꢂC and sodium cyanoborohydride
(2.20 g, 350 mmol) was added, followed by sufficient 2 M aqueous
HCl to give a tan color. Heating was continued for 90 min during
which time several portions of 2 M aqueous HCl were added to
maintain the proper acidity, indicated by the tan color. The re-
action mixture was diluted with 25 mL of hexanes and the
resulting solution was refluxed for a 1-h period and then cooled.
Standard ethereal workup afforded 1.78 g of a crude residue.
Chromatography on silica gel (elution with H/E, 10:1) gave 1.61 g
(64%) of trisubstituted olefin 23, which was homogeneous by TLC
analysis (H/E, 1:1, Rf hydrazone¼0.32, Rf 23¼0.80): mp
101e103 ꢂC; 1H NMR (250 MHz)
d 0.89 (s, 3H), 0.93 (s, 3H),
1.05e1.42 (m, 9H), 1.33 (d, 3H, J¼7.1 Hz), 1.34 (d, 3H, J¼7.1 Hz),
1.75e1.83 (m, 1H), 1.92e2.15 (m, 3H), 2.35 (d, 1H, J¼15.0 Hz), 2.59
(ddd, 1H, J¼12.5, 8.7 Hz, 3.7 Hz), 3.05 (d, 1H, J¼15 Hz), 3.16 (ddd,
1H, J¼16.2, 8.7 Hz, 3.7 Hz), 3.41 (heptet, 1H, J¼7.1 Hz), 3.65 (s, 3H),
3.78 (s, 3H), 3.87 (s, 3H), 5.50 (br s, 1H); 13C NMR (62.9 MHz) 151.2
(s), 150.6 (s), 146.5 (s), 138.1 (s), 133.7 (s), 131.9 (s), 130.6 (s), 130.1
(s), 121.3 (d), 62.2 (q), 60.2 (q), 51.3 (q), 35.2 (t), 31.9 (s), 31.4 (t),
29.6 (t), 27.3 (d), 27.1 (d), 25.8 (q), 25.8 (q) [note: the two pre-
ceding signals overlap], 23.1 (t), 22.2 (q), 22.1 (q) ppm; IR (film)
2934 cmꢁ1. Elemental analysis for C23H34O3. Calculated: C, 77.04%,
H, 9.56%. Found: C, 77.15%, H, 9.66%.
4.1.14. EtAlCl2-catalyzed DielseAlder of 2 with (E)-
give DielseAlder adducts (4). A mixture of quinone 2 (450 mg,
1.43 mmol), (E)- -ocimene (1.50 g, 11.0 mmol), 50 mg of EtAlCl2,
a-ocimene (26) to
a
and 2.0 mL of dry benzene was stirred at rt for 12 h. The reaction
mixture was concentrated under vacuum and the residue was pu-
rified using silica gel chromatography (elution with H/E, 10:1) to
provide 168 mg (30%) of crystalline alcohol 4, which was homo-
geneous by TLC analysis (H/E, 10:1, Rf 2¼0.85, Rf 4¼0.60).
4.1.15. Eu(fod)3-catalyzed DielseAlder of 2 with (E)-
to give DielseAlder adducts (4) and isomer (28). A mixture of qui-
none 2 (450 mg, 1.43 mmol), (E)- -ocimene (1.50 g, 11.0 mmol),
50 mg of EtAlCl2, and 2.0 mL of dry benzene was stirred at rt for
12 h. Eventually the reaction mixture was heated at 45 ꢂC for 6 h.
The reaction mixture was concentrated under vacuum and the
residue was purified using silica gel chromatography (elution with
H/E, 10:1) to provide 517 mg (79%) of crystalline alcohol 4, which
was identical to that previously characterized.
a-ocimene (26)
4.1.12. 11,12-Dihydroxy-14-methoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraene (24). Ethanethiol (16.8 g, 0.29 mol) was
added dropwise to a cold solution (0 ꢂC) of sodium hydride (3.2 g,
0.13 mol, 80% dispersion in oil) suspended in 35 mL of freshly
distilled DMF. The resulting mixture was then stirred at rt for a 2-h
period, followed by the addition of a solution of 1.60 g of ether 23
(4.47 mmol) dissolved in 20 mL of dry DMF. The reaction mixture
was heated to 90 ꢂC for 24 h, and then cooled to 0 ꢂC and cautiously
neutralized with 2 M aqueous HCl. Standard ethereal workup, fol-
lowed by purification by chromatography on silica gel (elution with
H/E, 10:1/5:1), gave 1.26 g (86%) of catechol 24, which was ho-
mogeneous by TLC analysis [H/E, 5:1, Rf 23¼0.91, Rf 24¼0.30]: 1H
a
Continued elution afforded 59 mg (9%) of an isomeric alcohol
28, which was homogeneous by TLC analysis (H/E, Rf 28¼0.41): mp
145e146 ꢂC; 1H NMR (300 MHz)
d 0.87 (s, 3H), 0.88 (s, 3H), 0.99 (d,
3H, J¼7.1 Hz), 1.07 (d, 3H, J¼7.1 Hz), 1.05e1.17 (m, 1H), 1.38 (m, 1H),
1.47 (s, 3H), 1.61 (s, 3H), 1.62 (s, 3H), 1.60e2.11 (m, 9H), 2.22 (d, 1H,
J¼13.7 Hz), 2.31 (m, 1H), 2.82 (m, 1H), 2.91 (d, 1H, J¼13.7 Hz), 2.93
(heptet, 1H, J¼7.1 Hz), 5.24 (s, 1H), 5.45 (s, 1H); 13C NMR
(75.5 MHz) 203.8 (s), 172.0 (s), 138.7 (s), 137.3 (s), 125.5 (d), 120.9
(d), 120.0 (s), 90.3 (s), 88.4 (s), 52.9 (s), 52.5 (d), 52.1 (d), 51.8 (s),
44.1 (d), 43.4 (t), 34.9 (t), 33.6 (t), 31.8 (s), 31.4 (t), 28.0 (q), 27.2 (q),
26.9 (d), 25.4 (q), 24.7 (t), 24.2 (q), 23.9 (t), 23.7 (t), 21.0 (q), 19.6
NMR (300 MHz)
d 0.87 (s, 3H), 0.92 (s, 3H), 1.09e1.38 (m, 9H), 1.37
(d, 1H, J¼7.1 Hz), 1.38 (d, 1H, J¼7.1 Hz), 1.81 (dd, 1H, J¼13.8, 4.5 Hz),
1.93e2.11 (m, 3H), 2.55e2.65 (m, 1H), 3.05e3.15 (m, 2H), 3.44
(heptet, 1H, J¼7.1 Hz), 3.62 (d,1H, J¼12.4 Hz), 3.62 (s, 3H), 5.48 (br s,
1H); 13C NMR (75.5 MHz) 148.8 (s), 141.9 (s), 137.7 (s), 136.8 (s),
126.3 (s),125.9 (s),124.6 (s),121.2 (d), 62.5 (q), 50.6 (d), 35.4 (t), 32.0
(s), 31.4 (t), 29.9 (t), 27.2 (q), 27.2 (q), 25.5 (d), 25.3 (t), 23.1 (t), 21.2

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10141
(q), 19.0 (q) ppm; IR (film) 3414, 1668, 1609 cmꢁ1. Elemental
analysis for C30H42O3. Calculated: C, 79.94%, H, 9.40%. Found: C,
79.74%, H, 9.27%.
(q), 20.58 (t), 20.84 (q), 23.18 (d), 23.35 (q), 26.08 (q), 31.04 (q),
32.47 (t), 32.62 (s), 34.55 (t), 40.12 (t), 40.95 (t), 41.71 (t), 47.25 (s),
47.55 (d), 52.79 (d), 52.82 (d), 52.90 (s), 53.26 (t), 87.74 (s), 88.36 (s),
95.30 (s), 119.10 (d), 122.87 (s), 135.34 (s), 168.63 (s), 200.35
(s) ppm; IR (neat) 2922, 2852, 1628, 1460, 1368, 1265, 740,
703 cmꢁ1; Elemental analysis for C30H42O3. Calculated: C, 79.96%,
H, 9.39%. Found: C, 79.64%, H, 9.35%.
4.1.16. Europium-catalyzed DielseAlder reaction of 2 with (E)-
ocimene (26) to give alcohol 6. A mixture of quinone 2 (450 mg,
1.43 mmol), (E)- -ocimene (26) (1.50 g, 11.0 mmol), 50 mg of tris-
a-
a
(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)-euro-
pium, and 2.0 mL of dry benzene was stored at rt in a sealed tube for
3 days. The sealed reaction vessel was warmed to 45 ꢂC and heated
at that temperature for a 48-h period. Finally, the reaction mixture
was warmed to 100e110 ꢂC and heated at that temperature for an
additional 48 h. The reaction mixture was concentrated under
vacuum and the residue was purified using silica gel chromatog-
raphy (elution with H/E, 10:1) to provide 519 mg (82%) of crystalline
alcohol 6, which was homogeneous by TLC analysis (H/E, 10:1, Rf
4.1.18.1. (2)þ(3)/(1)þ(29) Using reaction conditions (a)
[Table 2]. BF3$Et2O (3
mL, 0.9 equiv) was added to a solution of
quinone 2 (40 mg, 0.13 mmol) and (E)-b-ocimene (3) (140 mg,
1.04 mmol) in freshly distilled dry toluene (0.50 mL) at 0 ꢂC. The
reaction mixture was stirred at 0 ꢂC for 90 min and then heated at
50 ꢂC for 10 h. The volatiles were removed in vacuo and the
resulting crude residue was directly chromatographed (elution
with H/E, 10:1) to give 27 mg (46%) of perovskone and 15 mg (26%)
of tetrasubstituted isomer 29.
2¼0.60, Rf 6¼0.40): mp 155e156 ꢂC; 1H NMR (250 MHz)
d 0.78 (s,
3H), 0.90 (s, 3H), 1.02 (d, 3H, J¼6.9 Hz), 1.08 (d, 3H, J¼6.9 Hz),
1.15e1.40 (m, 3H), 1.43 (s, 3H), 1.46e1.55 (m, 2H), 1.58 (s, 3H), 1.66
(s, 3H), 1.70e2.11 (m, 8H), 2.54e2.58 (m, 3H), 2.70 (d, 1H,
J¼14.6 Hz), 2.95 (heptet, 1H, J¼6.9 Hz), 3.95 (s, 1H), 3.36 (m, 1H),
5.85 (s, 1H); 13C NMR (62.7 MHz) 202.1 (s), 170.8 (s), 142.0 (s), 136.9
(s), 126.5 (d), 121.6 (d), 120.7 (s), 89.5 (s), 89.1 (s), 53.4 (d), 51.6 (s),
50.4 (s), 50.0 (d), 49.8 (d), 49.5 (t), 34.7 (t), 33.6 (t), 32.9 (s), 32.4 (t),
28.5 (q), 27.8 (q), 27.2 (t), 25.3 (q), 24.4 (q), 23.9 (t), 23.3 (d), 23.2 (t),
4.1.18.2. (2)þ(3)/(1)þ(29) Using reaction conditions (b) [Table 2].
BF3$Et2O (6
mL, 0.9 equiv) was added to a solution of quinone 2
(23 mg, 0.073 mmol) and (E)-b-ocimene (3) (71 mg, 0.52 mmol) in
freshly distilled dry DCM (0.50 mL) at 0 ꢂC. The reaction mixture was
stirred at 0 ꢂC for 90 min and then heated at 50 ꢂC for 7 h. The vol-
atiles were removed in vacuo and the resulting crude residue was
directly chromatographed (elution with H/E, 10:1) to give 16.5 mg
(50%) of perovskone and 5 mg (15%) of tetrasubstituted isomer 29.
20.7 (q), 20.1 (q), 19.7 (q) ppm; IR (film) 3500, 1627, 1607 cmꢁ1
.
Elemental analysis for C30H42O3. Calculated: C, 79.94%, H, 9.40%.
Found: C, 77.70%, H, 9.37%.
4.1.18.3. (2)þ(3)/(29) Using reaction conditions (c) [Table 2].
BF3$Et2O (10 mL, 0.9 equiv) was added to a solution of quinone 2
4.1.17. The Amberlyst reaction to give tetrasubstituted perovskone
isomer (29). To a solution of alcohol 4 (80 mg, 0.48 mmol) dis-
solved in 8 mL of freshly distilled CH2Cl2 was added 200 mg of
AmberlystÒ 15 resin. The resulting mixture was refluxed for 12 h,
cooled to rt, and filtered. The filtrate was concentrated and the
resulting residue was purified by chromatography (elution with H/
E, 10:1) to give 72 mg (90%) of crystalline 29, which was homo-
geneous by TLC analysis (H/E, Rf 4¼0.50, Rf 29¼0.50): mp
(26 mg, 0.082 mmol) and (E)-a-ocimene (29) (78 mg, 0.58 mmol) in
freshly distilled dry toluene (0.50 mL) at 0 ꢂC. The reaction mixture
was stirred at 0 ꢂC for 90 min and then heated at 50 ꢂC for 10 h. The
volatiles were removed in vacuo and the resulting crude residue was
directly chromatographed (elution with H/E, 10:1) to give 21 mg (71%)
of only 29, the tetrasubstituted C(23),C(24)-isomer of perovskone.
4.1.18.4. (2)þ(3)/No reaction. Quinone 2 (26 mg, 0.082 mmol)
and triene 29 (78 mg, 0.58 mmol) were placed in a sealed tube
(neat) and heated at 200 ꢂC for a 12-h period. 1H NMR and TLC
analysis of the crude reaction mixture indicated that only trace
amounts of DielseAlder adduct 4 had been produced.
153e154 ꢂC; 1H NMR (250 MHz)
d 0.79 (s, 3H), 0.82 (s, 3H), 0.85
(m, 1H), 1.01 (d, 3H, J¼7 Hz), 1.10 (d, 3H, J¼7 Hz), 1.12 (m, 1H), 1.24
(m, 1H) 1.30 (m, 1H,), 1.32 (m, 1H), 1.34 (s, 3H), 1.36 (m, 1H), 1.42
(m, 1H), 1.50 (s, 3H), 1.55 (m, 1H), 1.60 (m, 1H), 1.70 (m, 1H), 1.4 (m,
1H), 1.80 (m, 1H), 2.00 (m, 1H), 2.11 (m, 1H), 2.34 (m, 1H), 2.42 (br
t, 1H), 2.53 (d, 1H, J¼13.5 Hz), 2.72 (m, 1H), 3.08 (heptet, 1H,
J¼7 Hz), 5.32 (m, 1H); 13C NMR (62.7 MHz) 202.0 (s), 168.8 (s),
131.1 (s), 130.6 (s), 121.6 (s), 97.0 (s), 90.1 (s), 88.9 (s), 56.2 (s), 54.2
(d), 53.0 (d), 48.5 (s), 47.4 (t), 42.1 (t), 41.9 (t), 41.5 (t), 34.5 (t), 33.6
(s), 32.0 (d), 29.5 (q), 29.0 (t), 26.7 (t), 24.7 (q), 24.2 (q), 22.0 (q),
21.9 (t), 20.3 (q), 20.1 (q), 19.3 (t), 19.0 (q) ppm; IR (film)
1624 cmꢁ1. Elemental analysis for C30H42O3. Calculated: C, 79.84%,
H, 9.40%. Found: C, 79.84%, H, 9.04%.
4.1.18.5. (2)þ(26)þLiClO4/(4)þ(28). Quinone
2
(25 mg,
0.080 mmol) and (E)- -ocimene were dissolved in a 5 M solution of
b
LiClO4$Et2O. The resulting mixture was stirred at rt for a10-h pe-
riod. Standard ethereal workup produced a 2:1 mixture of Diel-
seAlder adducts 4 and 29, respectively.
4.1.18.6. (2)þ(29) at 12 kbar/No reaction. Quinone 2 (25 mg,
0.080 mmol) and (E)-b-ocimene were reacted at 12 kbar for 24 h.
Workup afford a low yield of the DielseAlder adducts 4 and 28, in
an undetermined ratio.
4.1.18. Cyclization of alcohol (6) to perovskone (1) using AmberlystÒ
15 resin. To a solution of alcohol 6 (80 mg, 0.48 mmol) dissolved in
8 mL of freshly distilled DCM was added 200 mg of AmberlystÒ 15
resin. The resulting mixture was refluxed for 25 min, cooled, and
filtered. The filtrate was concentrated and the resulting residue was
purified by chromatography (elution with H/E, 10:1) to give 72 mg
(90%) of crystalline (ꢀ)-perovskone (1), which was homogeneous
by TLC analysis (H/E, 10:1, Rf 6¼0.35, Rf 1¼0.42): mp 135e136 ꢂC; 1H
4.1.19. 3-(1-Methylethylenyl)-1,2,4-trimethoxybenzene (33). 1,2,4-
Trimethoxybenzene (30) (1.00 g, 5.95 mmol) was dissolved in an-
hydrous THF (30 mL) and the resulting solution cooled to 0 ꢂC.
n-Butyllithium (1.9 M, 3.4 mL, 6.55 mmol) was added dropwise
over a 5-min period and the reaction mixture was allowed to warm
to rt over a 30-min period. After 2 h, the mixture was cooled to 0 ꢂC
and anhydrous acetone (380 mg, 6.55 mmol) in THF (10 mL) was
added dropwise. The reaction mixture was refluxed for a 3-h pe-
riod, cooled to 0 ꢂC, and then quenched by the dropwise addition of
acetic acid (15 mL). Standard ethereal workup, followed by chro-
matography (elution with pet ether/E, 6:1), afforded 681 mg (55%)
of olefin 33 that was homogeneous by TLC analysis (pet ether/E, 6:1,
NMR (400 MHz)
d
0.81 (s, 3H), 0.84 (s, 3H), 1.03 (d, 3H, J¼7.2 Hz),
1.12 (d, 3H, J¼7.2 Hz), 1.24e1.34 (m, 4H), 1.36 (s, 3H), 1.39e1.48 (m,
3H), 1.52 (s, 3H), 1.56e1.66 (m, 5H), 1.67(s, 3H), 1.70e1.84 (m, 3H),
2.02 (dd, 1H, J¼13.6, 8.0 Hz), 2.13 (dt, 1H, J¼15.2, 7.2 Hz), 2.35 (dd,
1H, J¼12.4, 3.2 Hz), 2.42(br t, 1H, J¼8.8 Hz), 2.56 (d, 1H, J¼13.6 Hz),
2.73 (dd, 1H, J¼14.8, 7.2 Hz), 3.11 (heptet, 1H, J¼7.2 Hz), 5.34 (d, 1H,
J¼6.8 Hz); 13C NMR (400 MHz) 18.60 (t), 18.71 (q), 19.13 (q), 19.53
Rf 30¼0.31, Rf 33¼0.22): 1H NMR (400 MHz)
d 2.08 (s, 3H), 3.78 (s,

10142
G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
3H), 3.81 (s, 3H), 3.85 (s, 3H), 4.91 (s, 1H), 5.32 (s, 1H) 6.59 (d, 1H,
J¼8.9 Hz), 6.78 (d,1H, J¼8.9 Hz).
dropwise 25.0 mL of n-butyllithium (1.6 M, 40.0 mmol) at 0 ꢂC. The
reaction mixture was slowly warmed to rt, stirred for 30 min,
cooled to 0 ꢂC and then added via a cannula to a solution of an-
hydrous DMF (15 mL, 193.7 mmol) in MTBE (50 mL) and stirred at rt
for 6.5 h. Standard ethereal workup, followed by chromatography
(elution with H/E, 8:1), gave 6.31 g (74%) of 36, which was homo-
geneous by TLC analysis (H/E, 8:1, Rf 34¼0.50, Rf 36¼0.35): 1H NMR
4.1.20. 3-(1-Methylethyl)-1,2,4-trimethoxybenzene (34). Alkene 33
(681 mg, 3.27 mmol) and 10% Pd/C (50 mg) were dissolved in 5 mL
of ethanol and placed under an atmosphere of hydrogen for a 13-h
period at rt. Excess hydrogen gas was removed under a water as-
pirator and the palladium catalyst was removed by filtration
through Celite. Standard ethereal workup, followed by chroma-
tography (elution with pet ether/E, 6:1), gave 641 mg (93%) of 34
that was homogeneous by TLC analysis (pet ether/ether, 6:1, Rf
(250 MHz)
d
1.33 (d, 6H, J¼7.5 Hz), 3.57 (heptet, 1H, J¼7.6 Hz), 3.83
(s, 3H), 3.87 (s, 3H), 3.95 (s, 3H), 7.04 (s, 1H), 10.34 (s, 1H); 13C NMR
(62.9 MHz) 20.8 (q), 25.8 (d), 55.7 (q), 61.0 (q), 62.5 (q), 103.2 (d),
127.4 (s), 139.0 (s), 151.6 (s), 152.1 (s), 155.1 (s), 189.4 (d) ppm; IR
(film) 2991, 2957, 2871, 1688 cmꢁ1; MS (m/z) 239 (MHþ).
Continued elution (H/E, 8:1) afforded 1.50 g (18%) of the iso-
meric aldehyde 37, which was homogeneous by TLC analysis (H/E,
33¼0.67, Rf 34¼0.22): 1H NMR (400 MHz)
d
1.33 (d, 6H, J¼7.0 Hz),
3.55 (heptet, 1H, J¼7.1 Hz), 3.77 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H),
6.57 (d, 1H, J¼8.9 Hz), 6.70 (d, 1H, J¼8.9 Hz); 13C NMR (100.6 MHz)
21.4 (q), 25.4 (d), 56.0 (q), 56.3 (q), 61.2 (q), 106.4 (d), 109.6 (d), 131.0
(s), 147.5 (s), 148.0 (s), 153.0 (s) ppm; IR (film) 2985, 2952,
2832 cmꢁ1; MS (m/z) 210 (Mþ).
8:1, Rf 37¼0.23): 1H NMR (250 MHz)
d
1.36 (d, 6H, J¼7.5 Hz), 3.46
(heptet, 1H, J¼7.6 Hz), 3.85 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 7.25 (s,
1H), 10.28 (s, 1H); 13C NMR (62.9 MHz) 21.7 (q), 25.5 (d), 55.9 (q),
61.0 (q), 65.5 (q), 107.9 (d), 124.6 (s), 135.7 (s), 150.2 (s), 155.1 (s),
157.1 (s), 189.5 (d) ppm; IR (film) 2955, 2869, 1681 cmꢁ1; MS (m/z)
239 (MHþ).
4.1.21. Ethyl 2,3,6-trimethoxybenzoate (35). 1,2,4-Trimethoxybenzene
30 (82.30 g, 0.49 mol) was dissolved with mechanical stirring in
anhydrous THF (1.2 L) and then cooled to 0 ꢂC. n-Butyllithium
(210 mL, 2.5 M, 0.53 mol) was added dropwise over a 1-h period and
the reaction mixture was allowed to warm to rt. After 2 h, the mix-
ture was cooled to 0 ꢂC and then transferred via a cannula into
a solution of ethyl chloroformate (200 mL, 2.1 mol) in THF (500 mL).
The resulting mixture was stirred at rt for a 3-h period. Standard
ethereal workup, followed by chromatography (elution with H/E,
1:1), afforded 112.90 g (96%) of benzoate 35 that was homogeneous
by TLC analysis (H/E,1:1, Rf 30¼0.41, Rf 35¼0.22): 1H NMR (400 MHz)
4.1.25. 4-(1-Methylethyl)-2,3,5-trimethoxybenzyl alcohol (18). (a)
Via sodium borohydride reduction of benzaldehyde 36: Aldehyde 36
(2.00 g, 8.4 mmol) was dissolved in anhydrous ethanol (30 mL) and
cooled to 0 ꢂC. Sodium borohydride (381 mg, 10.1 mmol) was added
in small portions over a 30-min period, and the reaction mixture
was stirred at rt for 2 h. Water (10 mL) was added, and the ethanol
removed under reduced pressure. Treatment of the residue with
cold 5% aqueous HCl (20 mL), followed by standard ethereal
workup, provided 2.01 g (99%) of 18, which was homogeneous by
TLC analysis (H/E, 6:1, Rf 36¼0.63, Rf 18¼0.03) and was identical to
that characterized previously.
(b) Via metalation of 34 and reaction with formaldehyde:
n-Butyllithium (1.6 M, 3.3 mL, 5.2 mmol) was added to a mixture of
compound 34 (1.03 g, 4.76 mmol) and TMEDA (0.72 mL,
4.76 mmol) in anhydrous MTBE (40 mL) at 0 ꢂC. The reaction
mixture was then stirred for 2 h at rt. Gaseous formaldehyde,
generated by heating paraformaldehyde at 130 ꢂC, was then bub-
bled into the reaction mixture for a 5-min period. Water (10 mL)
was added, followed by 5% aqueous HCl (20 mL). Standard ethereal
workup, followed by chromatography (elution with H/E, 3:1),
afforded 767 mg (65%) of alcohol 18, which was homogeneous by
TLC analysis (H/E, 1:1, Rf 34¼0.85, Rf 18¼0.35) and identical to that
characterized previously.
d
1.38 (t, 3H, J¼7.1 Hz), 3.78 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 4.41 (q,
2H, J¼7.1 Hz), 6.60 (d,1H, J¼9.0 Hz), 6.88 (d, 1H, J¼9.0 Hz); 13C NMR
(100.6 MHz) 14.3 (q), 56.3 (q), 56.6 (q), 61.4 (t), 61.5 (q), 106.4 (d),
114.2 (d), 119.6 (s), 146.9 (s), 146.9 (s) [note: the preceding signals
overlap],150.5 (s),166.0 (s) ppm; IR (film) 2938, 2838, 1732 cmꢁ1; MS
(m/z) 240 (Mþ).
4.1.22. 3-(1-Methyl-1-hydroxyethyl)-1,2,4-trimethoxybenzene
(32). To a mechanically stirred solution of ester 35 (55.01 g,
0.23 mol) in anhydrous THF (700 mL) was added dropwise at 0 ꢂC
a solution of freshly prepared methylmagnesium iodide (0.81 mol)
in 300 mL of THF. The resulting mixture was stirred for 2 h at rt
and then quenched by the dropwise addition of water (100 mL),
followed by 100 mL of saturated aqueous NH4Cl. Standard ethereal
workup gave 37.5 g of alcohol 32 as a crude oil, which was ho-
mogeneous by TLC analysis and was used directly in the next re-
action without purification: 1H NMR (500 MHz)
d
1.64 (s, 6H), 3.80
4.1.26. 3-Methoxy-6,6-dimethylcyclohex-2-enone (39). 4,4-Dimeth-
ylcyclohexane-1,3-dione (20) (10.02 g, 71.3 mmol) and p-TsOH
(136 mg, 0.71 mmol) were refluxed in benzene (50 mL) and
methanol (10 mL) using a DeaneStark trap for a 20-h period. The
reaction mixture was cooled to rt and then quenched with 5%
Na2CO3 (50 mL). Standard ethereal workup, followed by chroma-
tography (elution with H/E, 3:2), provided 9.82 g (82%) of enone 39,
which was homogeneous by TLC analysis (H/E, 1:1, Rf 20¼0.35, Rf
(s, 6H), 3.82 (s, 3H), 5.92 (s, 1H), 6.62 (d, 1H, J¼8.9 Hz), 6.77 (d, 1H,
J¼8.9 Hz); 13C NMR (400 MHz) 151.4 (s), 148.0 (s), 147.3 (s), 129.9
(s), 110.5 (d), 107.3 (d), 74.2 (s), 61.3 (q), 56.2 (q), 56.15 (q), 31.2
(q) ppm.
4.1.23. 3-(1-Methylethyl)-1,2,4-trimethoxybenzene (34) from (32).
Tertiary alcohol 32 (37.50 g) and 10% Pd/C (2.40 g) were stirred in
a mixture of ethanol (200 mL) and 10% HCl (40 mL) under an at-
mosphere of hydrogen for a 48-h period at rt. Excess hydrogen gas
was removed under a water aspirator and the palladium catalyst
was removed by filtration through Celite. Standard ethereal
workup, followed by chromatography (elution with pet ether/E,
6:1), gave 35.60 g (93%) of 34 that was homogeneous by TLC
analysis (pet ether/E, 6:1, Rf 32¼0.67, Rf 34¼0.22), which was
identical to that previously characterized.
39¼0.52): 1H NMR (400 MHz)
d
1.13 (s, 6H), 1.37 (t, 3H, J¼7.0 Hz),
1.81 (t, 2H, J¼6.4 Hz), 2.44 (t, 2H, J¼6.4 Hz), 3.90 (q, 2H, J¼7.0 Hz),
5.30 (s, 1H); 13C NMR (100.6 MHz) 14.3 (q), 24.7 (q), 26.4 (q), 35.1
(t), 40.3 (s), 64.3 (t),101.1 (d),176.1 (s), 204.8 (s) ppm; IR (film) 2980,
2927, 2868, 1651, 1611 cmꢁ1; MS (m/z) 268 (Mþ). Continued elution
(H/E, 3:2) gave 2.15 g (18%) of enone 40.
4.1.27. 3-Methoxy-6,6-dimethyl-2-[4-(1-methylethyl)-2,3,5-
trimethoxyphenylmethyl]-2-cyclohexenone
(22)
from
enone
4.1.24. 3-(1-Methylethyl)-2,3,5-trimethoxybenzaldehyde (36) and
3-(1-methylethyl)-2,4,5-trimethoxybenzaldehyde (37). To com-
pound 34 (7.50 g, 35.7 mmol) and anhydrous TMEDA (5.4 mL,
35.8 mmol) dissolved in anhydrous MTBE (100 mL) was added
(39). Diisopropylamine (15.0 mL, 107 mmol) and freshly distilled
HMPA (19.2 mL, 110 mmol) were added to dry THF (250 mL). The
mixture was cooled to ꢁ78 ꢂC and n-butyllithium (2.5 M, 43.0 mL,
108 mmol) was added dropwise. After stirring for 30 min at ꢁ78 ꢂC,

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10143
enone 39 (18.02 g, 107 mmol) dissolved in THF (75 mL) was added
dropwise. The resulting mixture was stirred 8 h at ꢁ78 ꢂC and then
allowed to warm to 0 ꢂC over a 2-h period. Bromide 19 (10.52 g,
34.7 mmol) in THF (50 mL) was added portionwise, and the re-
action mixture was allowed to stir for a 12-h period at rt. Following
standard ethereal workup, the HMPA and excess enone were sep-
arated from the crude residue via distillation (100e120 ꢂC at
3 mmHg). The remaining residue was chromatographed (elution
with pet ether/ethyl acetate, 3:1) to afford 12.65 g (94%) of enone
22 that was homogeneous by TLC analysis (pet ether/EtOAc, 3:1, Rf
19¼1.00, Rf 22¼0.43) and was identical to that previously charac-
terized. The conversion of 22/12/11 is described above.
(100.6 MHz) 22.4 (q), 24.9 (t), 26.0 (d), 26.7 (q), 26.9 (t), 27.7 (t), 28.2
(q), 28.6 (t), 34.5 (t), 35.3 (s), 60.4 (q), 60.5 (q), 61.9 (q), 70.5 (d),
129.4 (s), 131.3 (s), 132.4 (s), 132.5 (s), 142.9 (s), 146.6 (s), 150.7 (s),
151.5 (s) ppm; MS (m/z) 374 (Mþ).
(S)-Methoxytrifluoromethylphenylacetyl chloride (50 mL,
0.27 mmol) was added to dry pyridine (0.5 mL), followed by the
addition of anhydrous DCM (0.8 mL). Alcohol (R)-41 (50 mg,
0.13 mmol) was added, and the resulting mixture was stirred for
a 72-h period at rt. After cooling to 0 ꢂC, the reaction mixture was
diluted with ether (25 mL) and washed successively with 10%
aqueous NH4Cl (2ꢄ10 mL), 5% aqueous NaHCO3 (2ꢄ10 mL), water
(10 mL), and brine (10 mL). The ethereal phase was then dried over
anhydrous Na2SO4 and filtered. Concentration under reduced
pressure afforded a crude ester that was examined directly by 19F
NMR spectroscopy. Chromatography (elution with pet ether/E,
10:1) afforded 77 mg (98%) of a Mosher ester that was homoge-
neous by TLC analysis (H/E, 10:1, Rf (R)-41¼0.08, Rf Mosher
4.1.28. (ꢀ)-11,12,14-Trimethoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraen-1-ol (41). Enone 11 (2.01 g, 5.35 mmol) dis-
solved in anhydrous THF (25 mL) was added dropwise to a sus-
pension of LiAlH4 in THF (75 mL) at 0 ꢂC. After stirring 30 min at
0
ꢂC, the reaction mixture was quenched by the successive drop-
ester¼0.83): 1H NMR (400 MHz)
d 0.99 (s, 3H), 1.02 (s, 3H),
wise addition of wet ether (50 mL), water (25 mL), and 1 M aqueous
HCl (50 mL). Standard ethereal workup, followed by chromatog-
raphy (elution with H/E, 3:1), afforded 1.78 g (89%) of alcohol
(ꢀ)-41 that was homogeneous by TLC analysis (H/E, 3:1, Rf 11¼0.31,
1.33e1.36 (m, 6H), 1.41e1.50 (m, 2H), 1.72e1.77 (m, 1H), 1.89e1.98
(m, 1H), 2.36e2.43 (m, 1H), 2.55e2.62 (m, 1H), 2.83e3.00 (m, 2H),
3.39 (heptet,1H, J¼7.0 Hz), 3.50 (br s, 2H), 3.60 (s, 3H), 3.66 (s, 3H),
3.71 (s, 3H), 3.84 (s, 3H), 5.53 (br t, 1H), 7.37e7.40 (m, 3H),
Rf 41¼0.23): 1H NMR (400 MHz)
d
1.00 (s, 3H), 1.03 (s, 3H), 1.33 (s,
7.58e7.60 (m, 2H). 19F NMR (400 MHz)
d 4.79 (90%) and 4.83 (10%).
3H), 1.35 (s, 3H), 1.57e1.64 (m, 1H), 1.68e1.74 (m, 1H), 1.83e1.89 (m,
2H), 2.39e2.51 (m, 2H), 2.91e3.00 (m, 2H), 3.38 (heptet, 1H,
J¼7.0 Hz), 3.58 (s, 1H), 3.60 (s, 1H), 3.66 (s, 3H), 3.80 (s, 3H), 3.86 (s,
3H) 4.05 (br t, 1H); 13C NMR (100.6 MHz) 22.4 (q), 24.9 (t), 26.1 (d),
26.7 (q), 27.0 (t), 27.7 (t), 28.3 (q), 28.6 (t), 34.5 (t), 35.3 (s), 60.5 (q),
60.6 (q), 61.9 (q), 70.6 (d), 129.4 (s), 131.3 (s), 132.4 (s), 132.5 (s),
143.0 (s), 146.6 (s), 150.7 (s), 151.6 (s) ppm; MS (m/z) 374 (Mþ).
(S)-Methoxytrifluoromethylphenylacetyl chloride (50 mL,
0.27 mmol) was added to dry pyridine (0.5 mL), followed by the
addition of anhydrous DCM (0.8 mL). Racemic alcohol 41 (50 mg,
0.13 mmol) was added, and the resulting mixture was stirred for
a 72-h period at rt. After cooling to 0 ꢂC, the reaction mixture was
diluted with ether (25 mL) and washed successively with 10%
aqueous NH4Cl (2ꢄ10 mL), 5% aqueous NaHCO3 (2ꢄ10 mL), water
(10 mL), and brine (10 mL). The ethereal phase was then dried over
anhydrous Na2SO4 and filtered. Concentration under reduced
pressure gave a crude ester that was purified by chromatography
(elution with pet ether/ether, 10:1) to afford 73 mg (93%) of the
Mosher esters derived from (R)-41 and (S)-41 (pet ether/E, 10:1, Rf
Recrystallization of the 90% enriched (R)-41 (3ꢄusing EtOAc/pet
ether) gave crystalline material, which was again converted into its
Mosher ester via the procedure described above. 19F NMR
(400 MHz)
d 4.79 (99%) and 4.83 (1%).
4.1.30. (S)-11,12,14-Trimethoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraen-1-ol [(S)-41]. (R)-Methyl-CBS-oxazaborolidine
[(R)-43] (1 M,1.1 mL,1.1 mmol) and borane-methyl sulfide (0.51 mL,
5.38 mmol) were dissolved in anhydrous THF (50 mL). Enone 11
(2.00 g, 5.38 mmol) was dissolved in THF (25 mL) and added
dropwise over a 1-h period at rt. The reaction mixture was stirred
for 4 h and then cooled to 0 ꢂC. Excess hydride was destroyed by the
slow, dropwise addition of cold methanol (25 mL). Following the
removal of the volatile components under reduced pressure, the
mixture was worked up using standard ethereal workup, except
two washes with 25 mL of 25% aqueous NH4Cl were included. Re-
crystallization from petroleum ether afforded 1.78 g (89%) of alco-
hol (S)-41 that was homogeneous by TLC analysis (H/E, 3:1, Rf
11¼0.31, Rf (S)-41¼0.23) and exhibited identical spectral data as for
alcohol (R)-41.
41¼0.08, Rf Mosher esters¼0.83): 19F NMR (400 MHz)
d 4.79 (49%)
and 4.83 (51%). This LAH reduction does not produce racemic ma-
terial as a 2% ee was observed!
(S)-Methoxytrifluoromethylphenylacetyl chloride (50 mL,
0.27 mmol) was added to dry pyridine (0.5 mL), followed by the
addition of anhydrous DCM (0.8 mL). Alcohol (S)-41 (50 mg,
0.13 mmol) was added, and the resulting mixture was stirred for
a 72-h period at rt. After cooling to 0 ꢂC, the reaction mixture was
diluted with ether (25 mL) and washed successively with 10%
aqueous NH4Cl (2ꢄ10 mL), 5% aqueous NaHCO3 (2ꢄ10 mL), water
(10 mL), and brine (10 mL). The ethereal phase was then dried
over anhydrous Na2SO4 and filtered. Concentration under re-
duced pressure afforded a crude ester that was examined directly
by 19F NMR spectroscopy. Chromatography (elution with H/E,
10:1) afforded 78 mg (99%) of a Mosher ester that was homo-
geneous by TLC analysis (H/E, 10:1, Rf (S)-41¼0.08, Rf ester¼0.83):
4.1.29. (R)-11,12,14-Trimethoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraen-1-ol [(R)-41]. (S)-Methyl-CBS-oxazaborolidine
[(S)-41] (1 M, 2.7 mL, 2.7 mmol) and borane-methyl sulfide (1.3 mL,
13.4 mmol) were dissolved in anhydrous THF (100 mL). Enone 11
(5.00 g, 13.4 mmol) was dissolved in anhydrous THF (50 mL) and
added dropwise over a 2-h period at rt. The reaction mixture was
stirred for 4 h and then cooled to 0 ꢂC. Excess hydride was
destroyed by the slow, dropwise addition of cold methanol (50 mL).
Following the removal of the volatile components under reduced
pressure, the reaction mixture was worked up using standard
ethereal workup, except that two washes with 75 mL of 25%
aqueous NH4Cl were included. The resulting ethereal extracts were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated to afford 4.53 g (90%) of alcohol (R)-41 that was ho-
mogeneous by TLC analysis (H/E, 3:1, Rf 9¼0.31, Rf (R)-41¼0.23):
1H NMR (400 MHz)
d 1.01 (s, 3H), 1.08 (s, 3H), 1.32e1.36 (m, 6H),
1.40e1.51 (m, 2H), 1.59e1.66 (m, 1H), 1.84e1.91 (m, 1H),
1.99e2.07 (m, 1H), 2.29e2.38 (m, 1H), 2.57e2.64 (m, 1H),
2.82e2.97 (m, 2H), 3.30 (d,1H, J¼8.6 Hz), 3.38 (heptet, 1H,
J¼7.0 Hz), 3.60 (s, 3H), 3.66 (s, 3H), 3.71 (s, 3H), 3.84 (s, 3H), 5.53
(br t, 1H), 7.38e7.45 (m, 3H), 7.63e7.65 (m, 2H). 19F NMR
½
a 2D4
ꢃ
þ33.3 (c 31.0 mg/ml, CHCl3). 1H NMR (400 MHz)
d 0.99 (s, 3H),
1.03 (s, 3H), 1.33 (s, 3H), 1.35 (s, 3H), 1.57e1.64 (m, 1H), 1.68e1.74
(m, 1H), 1.82e1.91 (m, 1H), 2.03 (br s, 1H), 2.39e2.51 (m, 2H),
2.91e2.97 (m, 2H), 3.38 (heptet, 1H, J¼7.0 Hz), 3.58 (s 1H), 3.60 (s,
1H), 3.65 (s, 3H), 3.79 (s, 3H), 3.86 (s, 3H) 4.05 (br t, 1H); 13C NMR
(400 MHz) d 4.79 (10%) and 4.83 (90%). Since alcohol (S)-41 was
prepared only to establish the enantiomeric purity of the (R)-41,
further enrichment of this material through recrystallization was
not carried out.

10144
G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
4.1.31. Acetylation of (ꢀ)-41. To (ꢀ)-alcohol 41 (280 mg,
0.67 mmol) dissolved in pyridine (0.8 mL) were added DMAP
(9 mg, 0.07 mmol, 0.09 equiv) and acetic anhydride (94 mL,
1.0 mmol, 1.5 equiv) at 0 ꢂC. After stirring for 1 h water (1 mL) was
added. The resulting mixture was stirred at rt for a 1-h period. The
crude reaction mixture was extracted with EtOAc and the organic
phase was washed with saturated aqueous CuSO4, saturated
aqueous NaHCO3, brine and dried over anhydrous Na2SO4. Con-
centration under reduced pressure afforded a crude oil, which was
chromatographed (elution with H/E, 9:1) to give 273 mg (98%) of
distilled DMF, placed under Argon, and stirred to dissolution. After
stirring for 5 min, n-Bu3P (23.0 mL, 0.092 mmol, 0.2 equiv) was
added and stirred for a 5-min period (or until the red color of the
solution darkens to almost black). At this point (R)-47 (200 mg,
0.462 mmol) dissolved in 2 mL of anhydrous DMF was added as
well as ammonium formate (175 mg, 2.77 mmol, 6 equiv) that had
been finely crushed with a mortar and pestle. The reaction was
allowed to stir overnight. Standard ethereal workup gave a crude
oil, which was purified by silica gel chromatography [elution with
pet ether/E, 4:1] to give (S)-23 (200 mg, 98% yield), which was
identical to that previously characterized.
the acetate of 41. 1H NMR (400 MHz)
d 1.02 (s, 3H), 1.04 (s, 3H),
1.32 (d, 3H, J¼6.8 Hz), 1.34 (d, 3H, J¼6.8 Hz), 1.55e1.62 (m, 1H),
1.68e1.74 (m, 1H), 1.85e1.94 (m, 1H), 2.09 (s, 3H), 2.47 (br s, 2H),
2.85e3.0 (m, 2H), 3.38 (heptet, 1H, J¼6.8 Hz), 3.4 (s, 2H), 3.66 (s,
3H), 3.72 (s, 3H), 3.86 (s, 3H), 5.26 (br s, 1H); 13C NMR (400 MHz)
171.4 (s), 151.2 (s), 150.6 (s), 146.7 (s), 145.4 (s), 132.4 (s), 131.9 (s),
129.5 (s), 127.1 (s), 72.8 (d), 61.8 (q), 60.3 (q), 60.2 (q), 35.1 (s), 34.5
(t), 28.0 (q), 27.2 (t), 26.5 (q), 25.9 (d), 25.6 (t), 24.7 (t), 22.3 (q),
22.1 (q), 21.5 (q) ppm.
4.1.33.2. (S)-23/(S)-24/(S)-25/(S)-2. To a solution of etha-
nethiol (7.5 mL, 101 mmol, 20.0 equiv) in 80 mL of DMF at 0 ꢂC was
added NaH (60% in mineral oil, 3.00 g, 75 mmol, 15 equiv) in five
portions under a N2 atmosphere. The reaction mixture bubbles vig-
orously after each addition of NaH and a viscous foam formed. The
resulting mixture was stirred at 0 ꢂC for 30 min until it became a clear
brown solution. Alkene (S)-23 (1.80 g, 5 mmol) was dissolved in DMF
(20 mL) and added to the NaSEt solution slowly. The resulting mix-
ture was heated for 4 days, at 90e95 ꢂC; temperatures >95 ꢂC caused
decomposition. TLC analysis revealed that the (S)-23 had been fully
deprotected. The reaction mixture was cooled to 0 ꢂC and aqueous
HCl (a 5% solution) was added to acidify the reaction mixture. It was
then extracted three times with EtOAc. The combined organic ex-
tracts were washed with water, brine, and dried over anhydrous
MgSO4. The organic phase was concentrated to give 1.89 g of a crude
foam, which was purified by column chromatography (elution with
pet ether/E, 4:1) to afford 1.46 g (88%) of hydroquinone (S)-24 as
4.1.32. (S)-11,12,14-Trimethoxy-9(10/20)-5aH-abeo-abieta-
1(10),8,11,13-tetraene [(S)-23] from (R)-41. To triphenylphosphine
(4.40 g,16.8 mmol) dissolved in anhydrous NMM (12 mL) was added
DEAD (2.4 mL, 15.2 mmol) at ꢁ30 ꢂC. After 10 min, alcohol (R)-41
(1.90 g, 5.08 mmol) dissolved in anhydrous THF (12 mL) was added
dropwise and the reaction mixture was stirred at ꢁ30 ꢂC for 15 min.
NBSH (3.31 g, 15.2 mmol) was added portionwise, and the mixture
was stirred at ꢁ30 ꢂC for a 2-h period. The temperature was slowly
increased to ꢁ20 ꢂC and stirred for a 2-h period. The temperature
was slowly increased to ꢁ10 ꢂC and stirred for a 1-h period. The
reaction mixture was then slowly warmed to rt and stirred over-
night. Standard ethereal workup, followed by chromatography
(elution with pet ether/E, 30:1) and recrystallization using hexane
afforded 891 mg (49%) of (S)-23 (TLC, pet ether/E, 10:1, Rf (R)-
a dark brown foam: ½a D24
ꢃ
ꢁ91.5 (c 6.4 mg/ml, benzene). The 1H NMR,
13C NMR, IR and MS for (S)-24 were the same as (ꢀ)-24.
To a solution of hydroquinone (S)-24 (1.46 g, 4.42 mmol) in
diethyl ether/water (40/40 mL) at rt was added ceric(IV) ammo-
nium nitrite (CAN) (4.85 g, 8.84 mmol, 2.0 equiv). The resulting
mixture was stirred for 4 h at rt. Water (10 mL) was then added and
the ether layer was separated. The aqueous layer was extracted
with ether (3ꢄ20 mL). The combined ethereal extracts were dried
over anhydrous MgSO4, filtered, and concentrated to afford 1.50 g of
(S)-25 as a red solid.
41¼0.08, Rf 23¼0.86): ½a D24
ꢃ
ꢁ87.1 (c 13.7 mg/ml, CHCl3); 1H NMR
(400 MHz)
d 0.95 (s, 3H), 0.99 (s, 3H), 1.06e1.29 (m, 2H), 1.39e1.44
(m, 6H), 1.82e2.17 (m, 4H), 2.60e2.68 (m, 1H), 3.08e3.18 (m, 2H),
3.45e3.51 (heptet, 1H, J¼7.0 Hz), 3.70 (s, 3H), 3.84 (s, 3H), 3.93 (s,
3H), 5.57 (br s,1H); 13C NMR (100.6 MHz) 22.4 (q), 22.4 (q) [note: the
preceding signals overlap], 23.4 (t), 26.1 (d), 27.4 (q), 27.7 (q), 29.8 (t),
31.6 (t), 32.2 (s), 35.4 (t), 51.6 (q), 60.5 (q), 62.5 (q),121.6 (d),130.3 (s),
132.1 (s), 136.9 (s), 136.9 (s) [note: the preceding signals overlap],
138.4 (s), 146.7 (s), 150.9 (s), 151.5 (s) ppm; MS (m/z) 359 (MHþ).
The above product was dissolved in THF (35 mL) and was treated
with 10% aqueous H2SO4 (15 mL) for 1 h. Diethyl ether (50 mL) was
added and the organic phase was separated. The aqueous layer was
extractedtwicewithether(20 mL)and thecombined organicextracts
were dried over anhydrous MgSO4 and concentrated to give 1.50 g of
a crude red solid. Column chromatography (elution with pet ether/E,
4.1.33. Preparation of carbonate (R)-47 from alcohol (R)-41. Alcohol
(R)-41 was dissolved in 3 mL of anhydrous DCM (200 mg,
0.534 mmol) at rt and placed under an atmosphere of Argon. The
solution was charged with methyl chloroformate (165 mL,
2.14 mmol), followed by the dropwise addition of pyridine (151 mL,
1.87 mmol). Gas evolution was observed during the addition of the
pyridine, as well as the formation of a white solid that soon dis-
solved back into solution. The reaction was monitored by TLC
analysis and upon completion was concentrated and purified by
silica gel chromatography without ethereal workup [pet ether/E,
4:1] to give a nearly quantitative yield of carbonate 47: 1H NMR
8:1) provided 1.32 g (95%) of p-quinone (S)-2 with ½a D24
ꢁ155.2 (c
ꢃ
0.0051 g/ml, CHCl3): 1H NMR (400 MHz)
d 0.87 (s, 3H), 0.91 (s, 3H),
1.11e1.21 (m, 2H),1.22 (d, 6H, J¼6.8 Hz),1.31e1.40 (m,1H),1.57 (d,1H,
J¼2.4 Hz), 1.82 (dd, 1H, J¼11.2, 4.0 Hz), 1.94e2.02 (m, 3H), 2.49 (ddd,
1H, J¼14.8, 9.6, 2.8 Hz), 2.98 (d, 1H, J¼16.0 Hz), 3.06 (ddd, 1H, J¼14.8,
8.0, 2.8Hz), 3.21(heptet,1H, J¼6.8 Hz), 3.59(d,1H, J¼15.6 Hz), 5.49 (br
t, 1H, J¼3.6 Hz), 7.06 (s, 1H); 13C NMR (400 MHz) 19.96 (q), 19.96 (q),
23.14 (t), 24.43 (d), 24.70 (t), 26.47 (q), 27.20 (t), 27.24 (q), 31.53 (t),
32.26 (s), 33.73 (t), 50.37 (d), 122.83 (d), 124/72 (s), 134.84 (s), 138.98
(s), 146.86 (s), 150.02 (s), 183.64 (s), 186.71 (s) ppm; HRMS: [MþH]þ
observed¼315.1956; [MþH]þ calculated¼315.1960; IR (neat) 3348,
(400 MHz)
d 5.12 (br t, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H),
3.65 (s, 3H), 3.51 (d, 2H, J¼16.4 Hz), 3.45 (d, 2H, J¼16.4 Hz), 3.38 (m,
2H), 3.01e2.84 (m, 3H), 2.46 (t, 2H, J¼5.6 Hz), 1.78 (m, 2H), 1.6 (m,
2H), 1.33 (d, 6H, J¼7.6 Hz), 1.04 (s, 3H), 1.01 (s, 3H); 13C NMR
(400 MHz) 156.3, 151.4, 150.9, 147.1, 146.6, 132.7, 131.9, 129.7, 126.6,
62.0, 60.6, 60.5, 54.7, 35.4, 34.4, 28.3, 27.8, 27.4, 26.4, 26.1, 25.7, 24.8,
22.4; IR (film) 1750, 1240 cmꢁ1; MS-HR (m/z calculated)¼432.2512,
(m/z observed)¼432.2421.
2961, 2934, 1872, 1638, 1391, 1321, 1287, 1128, 1038, 758 cmꢁ1
.
4.1.33.3. (S)-2/(S)-6/(S)-1. A mixture of p-quinone (S)-2
(45 mg, 0.143 mmol), E- -ocimene (26) (170 mg, 1.25 mmol,
b
8.7 equiv), and Eu(fod)3 (5 mg) in 1.3 mL of anhydrous benzene was
placed in a sealed tube reaction vessel. The tube was placed under
a nitrogen atmosphere and sealed. The resulting reaction mixture
was stirred at rt for 64 h, then stirred at 40 ꢂCe45 ꢂC for 69 h, and
then stirred at 100 ꢂCe110 ꢂC for an additional 48-h period. The
reaction mixture was cooled to rt and 3 mg of additional Eu(fod)3
4.1.33.1. (S)-23 from carbonate 47. Pd(OAc)2 (21 mg, 0.92 mmol)
was placed in a 10 mL round bottom flask containing 2 mL of freshly

G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
10145
was added. The mixture was sealed and heated at 100 ꢂC for an-
other 72-h period. The benzene was removed from the crude
mixture (via a pipette) and placed on a silica gel column. Elution
with pet ether/E (30:1 and then 20:1) afforded 51.6 mg (82%) of
for every sample we encountered. Thank you, Gilbert, for all the
fond memories and your mentoring!
Supplementary data
alcohol (S)-6: ½a D24
ꢃ
þ26.8 (c 0.37 mg/ml, benzene); 1H NMR
(400 MHz)
d
0.79 (s, 3H), 0.91(s, 3H), 1.02 (d, 3H, J¼7.2 Hz), 1.08 (d,
1H and 13C NMR spectra for the following have been provided:
compounds 30, 31, 18, 19, 22, 23, 33, 34, 35, 36, 37, 39, 41, and 25.
Tables of crystal data, atomic coordinates, bond lengths, angles, and
the ORTEP for byproduct 29, the isomer of perovskone are also
available. This material is available free of charge via the internet at
http://pubs.acs.org. Supplementary data associated with this article
can be found in the online version at doi:10.1016/j.tet.2011.09.072.
3H, J¼7.2 Hz), 1.20e1.28 (m, 1H), 1.32e1.40 (m, 1H), 1.43 (s, 3H),
1.48e1.56 (m, 3H), 1.59 (s, 3H), 1.67 (s, 3H), 1.76e1.86 (m, 1H),
1.88e1.98 (m, 2H), 1.98e2.14 (m, 4H), 2.37e2.56 (m, 4H), 2.70 (d,
1H, J¼14.4 Hz), 2.96 (heptet, 1H, J¼7.2 Hz), 3.95 (s, 1H), 5.07e5.08
(m, 1H), 5.85 (s, 1H); 13C NMR (400 MHZ) 19.90 (q), 20.31 (q), 20.92
(q), 23.51 (t), 23.60 (q), 24.18 (t), 24.62 (d), 25.58 (q), 27.47 (t), 50.09
(d), 50.25 (d), 50.71 (s), 51.88 (s), 53.69 (d), 89.71 (s), 89.73 (s),
120.91 (s), 121.90 (d), 127.06 (d), 137.10 (s), 142.26 (s), 171.00 (s),
202.32 (s) ppm; HRMS: [MþH]þ observed¼451.3226; [MþH]þ
calculated¼451.3212; IR (neat) 3473, 2957, 2870, 1670, 1629, 1456,
References and notes
1. Fujita, E.; Node, M. Prog. Chem. Org. Nat. Prod. 1986, 46, 77e157.
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Plants; Indian: Allahabad, 1918; p 1031.
3. Hasan, M.; Iqbal, R.; Ullah, I. Islamabad J. Sci. 1978, 5, 22e25.
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N. M.; Zamir, T.; Ahmad, V. U. J. Org. Chem. 1992, 57, 4339e4340.
6. Majetich, G.; Zhang, Y. J. Am. Chem. Soc. 1994, 116, 4979e4980.
7. For recent reviews of tandem reactions in organic synthesis, see: (a) Fustero, S.;
Sanchez-Rosello, M.; del Pozo, C. Pure Appl. Chem. 2010, 82, 669e677; (b)
Grondal, C.; Jeanty, M.; Ender, D. Nature Chem. 2010, 2, 167e178; (c) Li, X.-W.;
Wang, Z.-Y.; Zheng, L.-Y. Youji Huaxue 2006, 26, 1144e1149; (d) McCarrol, A. J.;
Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224e2248; (e) Tietze, L. F. Chem.
Rev. 1996, 96, 115e136; (f) Bunce, R. A. Tetrahedron 1995, 51, 13103e13159; (g)
Ho, T.-L. Tandem Organic Reactions; Wiley: New York, NY, 1992.
8. Watson, W. H.; Taira, Z. Tetrahedron Lett. 1976, 29, 2501e2504.
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445e448.
1386, 1275, 1192, 1119, 1035, 838 cmꢁ1
.
To a solution of alkene 6 (51.6 mg, 0.115 mmol) in DCM (10 mL)
was added 100 mg of AmberlystÒ 15 ion-exchange resin. The
resulting mixture was refluxed under a nitrogen atmosphere for
1 h. The AmerlystÒ 15 resin was removed by filtrations and the DCM
was concentrated under vacuum. Column chromatography of the
resulting residue (elution with pet ether/E, 8:1) gave 46.4 mg (90%)
of pure (þ)-perovskone: ½a D24
ꢃ
þ90.2 (c 0.0108 g/ml, CHCl3); 1H NMR
(400 MHz)
d
0.81 (s, 3H), 0.84 (s, 3H), 1.03 (d, 3H, J¼7.2 Hz), 1.12 (d,
3H, J¼7.2 Hz), 1.24e1.34 (m, 4H),1.36 (s, 3H), 1.39e1.48 (m, 3H),1.52
(s, 3H), 1.56e1.66 (m, 5H), 1.67(s, 3H), 1.70e1.84 (m, 3H), 2.02 (dd,
1H, J¼13.6, 8.0 Hz), 2.13 (dt, 1H, J¼15.2, 7.2 Hz), 2.35 (dd, 1H, J¼12.4,
3.2 Hz), 2.42(br t, 1H, J¼8.8 Hz), 2.56 (d,1H, J¼13.6 Hz), 2.73 (dd,1H,
J¼14.8, 7.2 Hz), 3.11 (heptet,1H, J¼7.2 Hz), 5.34 (d,1H, J¼6.8 Hz); 13C
NMR (400 MHz) 18.60 (t), 18.71 (q), 19.13 (q), 19.53 (q), 20.58 (t),
20.84 (q), 23.18 (d), 23.35 (q), 26.08 (q), 31.04 (q), 32.47 (t), 32.62
(s), 34.55 (t), 40.12 (t), 40.95 (t), 41.71 (t), 47.25 (s), 47.55 (d), 52.79
(d), 52.82 (d), 52.90 (s), 53.26 (t), 87.74 (s), 88.36 (s), 95.30 (s),119.10
(d), 122.87 (s), 135.34 (s), 168.63 (s), 200.35 (s) ppm; IR (neat)
2922, 2852, 1628, 1460, 1368, 1265, 740, 703 cmꢁ1; HRMS:
[MþH]þobserved¼451.3230, [MþH]þcalculated¼451.3212.
11. (a) Kelecom, A. Tetrahedron 1983, 39, 3603e3608; (b) Koft, E. R. Tetrahedron
1987, 43, 5775e5780.
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4.1.33.4. (S)-2/(S)-1. A solution of (S)-quinone 2 (64 mg,
0.203 mmol, 1.0 equiv), (E)-
a-ocimene (3) (222 mg, 1.63 mmol,
8 equiv), and freshly distilled BF3$Et2O (8.5 mg, 17.4
mL, 0.9 equiv)
was added to a solution of quinone (S)-2 (26 mg, 0.082 mmol) and
in freshly distilled dry DCM (1.00 mL) at 0 ꢂC. The reaction mixture
was stirred at 0 ꢂC for 90 min and then heated at 50 ꢂC for 10 h. The
volatiles were removed in vacuo and the resulting crude residue
was directly chromatographed (elution with H/E, 98:2 to 95:5) to
give 52 mg (57%) of (þ)-perovskone, which was identical to that
characterized via the two step sequence.
Acknowledgements
Appreciation is extended to the National Science Foundation
(CHE-0010128) for support of the (þ)-perovskone synthesis.
Thanks are extended to Scott Handy and Professor Paul Grieco
(Montana State University) for their study of the DielseAlder re-
action of quinone 2 and (E)-b-ocimene (3) with LiClO4$Et2O. The
efforts of Professor Takeshi Kitahara (University of Tokyo) to ex-
amine the same DielseAlder reaction at12 kbar are also gratefully
acknowledged.
The following Stork group members have greatly influenced my
scientific career: Patrick McCurry (undergraduate research), Paul
Grieco (doctoral research), Sam and Sarah Danishefsky, and Dick
Hill (my colleague at UGA since 1981). While at Columbia with
Professor Stork (1979e1981) I lived for those Saturday mornings
when Gilbert would ask me to help him clean out a refrigerator/
freezer and he would proceed to tell me the history and his dreams
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10146
G. Majetich et al. / Tetrahedron 67 (2011) 10129e10146
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