Synthesis of (±)-14-epi-hydroxydolasta-1(15),7,9-triene and (±)-7-epi -acetoxy-14-epi-hydroxydolasta-1(15),8-diene

Article abstract of DOI:10.1139/v11-116

1,3-Dimethyl-2-nitrobenzene was converted to the key intramolecular Friedel-Crafts intermediate 24 in ten steps. Treatment of 24 with TiCl ₄ produced tricyclic enone 25 in 61%-75% yield, having the requisite trans relationship of the two angular methyl groups and many of the salient features of the dolastane diterpenes. The structure of enone 25 was verified by X-ray crystallography analysis. Cyclization product 25 permitted the facile synthesis of (±)-14-epi-hydroxydolasta-1(15),7,9-triene and (±)-7-epi-acetoxy-14-epi-hydroxydolasta-1(15),8-diene, which are detailed in this article.

Full text of DOI:10.1139/v11-116

75
Synthesis of ( )-14-epi-hydroxydolasta-1(15),7,9-
triene and ( )-7-epi-acetoxy-14-epi-
hydroxydolasta-1(15),8-diene*
George Majetich and Jianhua Yu
Abstract: 1,3-Dimethyl-2-nitrobenzene was converted to the key intramolecular Friedel–Crafts intermediate 24 in ten steps.
Treatment of 24 with TiCl4 produced tricyclic enone 25 in 61%–75% yield, having the requisite trans relationship of the
two angular methyl groups and many of the salient features of the dolastane diterpenes. The structure of enone 25 was veri-
fied by X-ray crystallography analysis. Cyclization product 25 permitted the facile synthesis of ( )-14-epi-hydroxydolasta-1
(15),7,9-triene and ( )-7-epi-acetoxy-14-epi-hydroxydolasta-1(15),8-diene, which are detailed in this article.
Key words: dolastanes, cyclialkylation, intramolecular Friedel–Crafts reactions, conformational biasing, regiospecific reduc-
tions.
Résumé : On a effectué la transformation en dix étapes du 1,3-diméthyl-3-nitrobenzène en composé 24, l’intermédiaire clé
d’une réaction de Friedel–Crafts intramoléculaire. Le traitement du produit 24 par du TiCl4 à conduit avec un rendement de
61 à 75 % à formation de l’énone tricyclique 25 comportant la relation trans requise entre les deux groupes méthyles angu-
laires ainsi que plusieurs des caractéristiques principales des diterpènes du dolastane. La structure de l’énone 25 par diffrac-
tion des rayons-X. La cyclisation du produit 25 a permis de réaliser facilement la synthèse du ( )-14-épi-hydroxydolasta-1
(15),7,9-triène et du ( )-7-épi-acétoxy-14-épi-hydroxydolasta-1(15),8-diène. Veuillez noter la cyclialkylation dans le texte.
Mots‐clés : dolastanes, cycloalkylation, réactions de Friedel–Crafts intramoléculaires, biais conformationnel, réductions
régiospécifiques.
[Traduit par la Rédaction]
The research groups of Pattenden,7 Piers,8 Mehta,9
Introduction
Paquette,10 Williams,11 and Majetich12 have completed total
syntheses of various dolastanes. The first dolastane synthe-
sized was ( )-amijiol (2) by Pattenden and co-workers in
1986.7 Their strategy for introducing the trans angular methyl
groups is shown in Chart 1. The alkylation of hydroazule-
none 5, produced in seven steps from cyclopentanone, gave
exclusively the a–epimer 6 because of the steric influence of
the C-16 angular methyl group. The C-ring was formed with
the requisite C-14 stereochemistry, using an intramolecular
reductive coupling of ketone 6 with the alkyne; an allylic ox-
idation of alkene 7 introduced the C-2 hydroxyl group, albeit
in low yield. In their synthesis of 3 from ketone 8, Piers and
Friesen used a similar alkylation strategy to introduce the C-
12 and C-5 chirality (cf. 9 → 10).8 Vinylstannane 10 was
converted into a Grignard reagent, which added to the C-14
carbonyl group to complete the synthesis. In 1987 Mehta
and Krishnamurthy used a similar A+B→AB+C→ABC
strategy to prepare 10, using Pattenden’s strategy, to install
the C–14 hydroxyl group and create the C-ring.9 The synthe-
sis of the non-natural ( )-4ab,10b-doladiol acetate (4) was
achieved by Paquette et. al.10 Instead of using the C-12
Fifty years ago, the diterpenoids were rare components of
the marine environment. However, there are now more than
1900 diterpenoids known,1 including twenty-five dolastanes.
Dolatriol (1), the first dolastane isolated, was obtained from
extracts of the digestive gland of the poisonous Indian Ocean
sea hare Dolabella auricularia (Scheme 1)2–5 and was very
cytotoxic. Further work, however, established that dolatriol
was actually produced by a brown algae genus Dictyota and
only concentrated by Dolabella auricularia through its diet.
All dolastanes have a distinctive 5,7,6-linear fused tricyclic
framework. Their structural diversity rests on the following
features: (i) the number and the position(s) of the hydroxyl
group and double bond(s) (cf. 3); (ii) the trans configuration
of the two angular methyl groups at C-5 and C-12; (iii) the
BC-ring system is usually trans fused; and (iv) many of the
relative stereochemical configurations have been assigned
based on X-ray crystal structure analysis or NMR studies. Fi-
nally, isoamijiol (2) has antimicrobial activity against Mucor
mucedo and Staphylococcus aureus, and several dolastanes
exhibit promising biological activity.6
Received 2 May 2011. Accepted 10 July 2011. Published at www.nrcresearchpress.com/cjc on 1 November 2011.
G. Majetich and J. Yu. Department of Chemistry, University of Georgia, Athens, Georgia, 30602, USA.
Corresponding author: George Majetich (e-mail: Majetich@uga.edu).
This article is part of a Special Issue dedicated to Professor Tak-Hang Chan.
*Taken in part from the Ph.D. dissertation of Jianhua Yu, University of Georgia, Athens, Georgia, USA, 2009.
Can. J. Chem. 90: 75–84 (2012)
doi:10.1139/V11-116
Published by NRC Research Press

76
Can. J. Chem. Vol. 90, 2012
Scheme 1.
are comparable. We have observed that when the ortho and
para positions are both substituted with identical groups (H,
CH3, or Cl), cyclization occurs at the para position relative
to the electron donating substitutent (cf. ii). Thus, ring clo-
sure via conformer ii would produce the central cyclohexane
ring and a trans relationship between the C-12 and C-5 angu-
lar methyl groups. If so, the functionality present in the A-
and C-rings of enone 25 makes it an attractive precursor for
the synthesis of several dolastanes. Herein, we report the syn-
thesis of tricyclic enone 25 and its conversion into ( )-14-
epi-hydroxydolasta-1(15),7,9-triene (3) and ( )-7-epi-acetoxy-
14-epi-hydroxydolasta-1(15),8-diene (4).
15
1
16
OH
HO
HO
11
10
2
3
14
6
12
5
4
8
9
HO
20
7
17
OH
18
19
isoamijiol
3
dolatriol
1 2
2
( )
( )
Our study began with the preparation of the A- and C-
rings. The A-ring was synthesized from 4-methylpentan-2-
one (26), using our published procedure (Scheme 3);12 com-
mercially available 1,3-dimethyl-2-nitrobenzene (29) was our
starting material for the C-ring synthesis (Scheme 4).
HO
HO
Monobromination of 29 followed by nucleophilic aromatic
substitution gave anisole derivative 30 in 83% yield.15 Zinc
metal reduction of the nitro group provided aniline com-
pound 31.16 The next step, a Sandmeyer reaction,17 gave an
inseparable mixture of mono- and di-bromination products
32 and 35, respectively. Fortunately, the reaction of the orga-
nolithium reagents derived from 32 and 35 with DMF pro-
duced aldehyde 33 and dialdehyde 36, which were easily
separated. Reduction of aldehyde 33 to an alcohol with LAH
was followed by the conversion of the benzylic alcohol to the
corresponding benzyl bromide 34 by treatment with PBr3.
With the A- and C-rings in hand, we set out to prepare di-
enone 24, the key cyclization precursor. Coupling of 19 with
34 gave adduct 37 in excellent yield (Scheme 5). Addition of
vinyllithium to ketone 37, followed by acidic work-up, gave
dienone 24 in high yield. There are two facial-selective prod-
ucts possible from the cyclization of dienone 24 (cf. 25 and
25a) and two possible regioisomers (cf. 25b and 25c). In
each case, cyclialkylation would produce a C-ring dienone,
since the newly created quaternary carbon center (either at
C-5 or at C-1) precludes re-aromatization. In a related cy-
clialkylation,18 we found that under Lewis acid catalysis, di-
enone 38 produces tricycle 39 having an angularly fused
quaternary carbon center (Scheme 6). We were pleased to
find that treatment of dienone 24 with TiCl4 at –60 °C for
30 min produced only enone 25, albeit the isolated yield var-
ied between 61% and 75%. An X-ray crystal structure analy-
sis of 25 verified the trans configuration of the two angular
methyl groups.
OAc
14-hydroxydolasta-
1(15),7,9-triene (3 4
7-epi-acetoxy-14-epi-
)
hydroxydolasta-1(15),8-
4 5
diene ( )
methyl group to create the C-5 stereocenter, the alkylation of
decalenone 11 produced alkylated product 12, using the C-5
angular methyl group to create the C-12 stereochemistry.
This synthesis featured a photochemical rearrangement to
isomerize the 6,6,6-tricyclic a,b-epoxy ketone 13 into a
5,7,6-tricyclic dolastane skeleton. Six additional steps were
needed to convert enone 14 into the 7,14-epimers of natural
dolastane 4. Williams and co-workers synthesized (–)-clavulara-
1(15),17-dien-3,4-diol (18) from (+)-9,10-dibromocamphor
15, which fragmented to form acid 16 upon exposure to
NaOH.11 Thirty-four transformations were required to trans-
form 16 into macrocyclic epoxide 17. An acid-catalyzed
transannular epoxide opening of 17 created the C-ring with
the required C-5 stereogenic center in 38% yield. In contrast
to these strategies, Majetich and co-workers used an A
+C→AC→ABC strategy to synthesize natural ( )-1(15),8-
dolastadien-2-ol ( )-23 (also called 14-deoxyisoamijiol).12
In this synthesis, a functionalized A-ring (cf. 19) was
coupled with a C-ring containing an allylsilane (cf. 20), fol-
lowed by the addition of vinyllithium to the C-8 carbonyl
group to produce dienone 21. An intramolecular 1,6-addition
of the allylsilane to the dienone 21 produced the dolastane
skeleton with the trans relationship of the C-5 and C-12 an-
gular methyl groups (cf. 22). Nine steps were needed to in-
troduce the C-1,C-15 double bond and the b-oriented C-2
hydroxyl group of 23.
Several of the dolastanes have a b-hydroxyl group at C-2
and a C-1, C-15 exocyclic double bond, or a C-14 b-hydroxyl
group, or a hydroxyl group or an acetate at C-4 (Scheme 7).
To achieve a synthesis of ( )-7,14-epi-1(15),8-dolastadiene-
7,14-diol 7-acetate (4), we needed to selectively reduce the
C-2 and C-10 carbonyl groups and the C-3,C-4 double
bond of enone 25, as well as selectively introduce an ace-
tate at C-7 and an a-oriented hydroxyl group at C-14 (cf.
4). We were confident that the A-ring enone moiety would
permit the introduction of the C-7,C-9 diene (cf. 40)
thereby facilitating a synthesis of 10.
We have found that intramolecular Friedel–Crafts reac-
tions, or cyclialkylations,13 of conjugated dienones represent
a powerful strategy to assemble various tricyclic frame-
works.14 We speculated that conformational biasing prior to
ring formation would also create stereogenic centers
(Scheme 2). However, the examination of a Dreiding model
of 24 suggests that steric interactions between the C-16 and
C-20 methyl groups in conformer i, and the steric interactions
between the C-16 and C-15 methyl groups in conformer ii
The C-2 carbonyl group, which is conjugated to two dou-
ble bonds, has more resonance contributors with a negative
charge on oxygen, thereby making it less reactive than the
C-10 carbonyl group (Scheme 8). Indeed, treatment of enone
Published by NRC Research Press

Majetich and Yu
77
Chart 1.
H
O
Pattenden's Synthesis
of amijiol (2):7
i-Pr3-Si
O
16
16
HO
1) NaH, CH3I
2) TBAF
O
H
seven
Na
12
5
steps
(29%)
(58% over
two steps)
20
5
6
7
SeO2
20% yield
2
( )-
Piers's Synthesis of 10:8
(CH3)3Sn
(CH3)3Sn
16
16
HO
O
O
H
O
1) I2
2) Mg
KO-t-Bu,
CH3I
14
12
5
(60% over
two steps)
steps
(68%)
20
O
O
9
10
8
3
Paquette's Synthesis of 4:10
Cl
H
1) hv
NaN(TMS)2
CH3I (94%)
12
four steps
12
2) Ac2O
5
5
Cl
O
(64% over-
all yield)
(64% overall
yield)
O
O
13
O
O
OAc
12
14
11
six steps
( )-4
(64% overall yield)
11
18
Williams's Synthesis of
:
Br
H
NaOH
Br
OH
in wet
DMSO
(94%)
O
OH
COOH
16
34 steps
OH
CSA
H
(38%)
O
OH
H
15
17
H
H 18
Majetich's Synthesis of 14-deoxyisoamijiol (23):12
1) LDA,
C6H5(CH3)2Si
OH
C6H5(CH3)2Si
H
EtO
nine
steps
12
(20) Br
5
O
O
2) Et2AlCl
(94%)
O
2) vinyllithium
19
22
21
23
(96% over
two steps)
25 with sodium borohydride in the presence of TFA in di-
chloromethane selectivity reduced the C-10 carbonyl group
to a methylene unit.19 If, however, we first reduced the C-3,
C-4 double bond (cf. 42), the C-2 carbonyl group was found
to be more reactive, presumably a result of the steric hin-
drance by the isopropyl group. Note that under the reaction
conditions, enone 43 is rapidly reduced to produce diene 44.
In their synthesis of 4, Paquette et al. found that singlet oxy-
gen migrated the C-1,C-14 double bond to the C-1,C-15 po-
sition and introduced an a-oriented alcohol at C-14.10a
Reaction of enone 43 with singlet oxygen, followed by reduc-
tion of the intermediate allylic peroxide, introduced an alco-
hol from the a-face because of the steric effect of the C-16
methyl, which added in Michael fashion to the A-ring enone
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78
Can. J. Chem. Vol. 90, 2012
Scheme 2.
Scheme 4.
20
NO2
OCH3
NO2
1) FeBr3, Br2, Fe
16
OCH3
2) NaOCH3, CuBr
(83% over
two steps)
OCH3
15
O
30
29
O
(i)
3) NH4Cl, Zn
MeOH, H2O
(76%)
24
OCH3
O
15
CHO
NH2
Friedel–
Crafts
reaction
OCH3
CHO
OCH3
O
O
20
31
(8% over
two steps)
36
(ii)
25
4) HBr, LiBr
NaNO2,
CuBr
5) t-BuLi
DMF
Scheme 3.
O
four steps
O
Br
O
Br
(31% yield)12
26
+
27
OCH3
OCH3
Br
32
EtOH,
H+ (95%)
35
5) t-BuLi
DMF
(37% over
two steps)
LDA, CH3I
(78%)
EtO
O
EtO
O
Br
CHO
28
19
6) LAH
7) PBr3
to form tetrahydrofuran 45 in 92% yield. This result indicated
that the C-10 carbonyl group had to be removed, or pro-
tected, before the C-14 a-hydroxyl group is introduced.
Another way to introduce the C-14 a-allylic alcohol was
by opening a C-1,C-14 a-epoxide. However, because of the
steric influence of the C-16 methyl group, the epoxidation of
43 gave only epoxide 46 (Scheme 9). The reduction of the C-
10 carbonyl group with LAH gave an allylic alcohol, which
rapidly dehydrated to form diene 47. Treatment of 47 with
LDA at 50 °C overnight gave alcohol 48 in 93% yield; this
compound is epimeric at C-14 to natural dolastane 10. A tra-
ditional way to prepare an epimeric epoxide is to make the
bromohydrin from the alkene and then treat it with base.
Since the C-16 methyl blocks the b-face of the C-1,C-14
double bond, bromonium ion formation must occur from the
a-face so that the addition of water to the bromonium ion
generated in situ must add from the b-face to provide the b-
epoxide. However, when 43 was treated with NBS in wet
acetone, allylic oxidation at C-2 produced dienone 42 in
71% yield.
OCH3
(92% over
two steps)
OCH3
34
33
diene 44 in 73% yield. The reaction of diene 44 with sele-
nium dioxide and t-butylhydroperoxide produced alcohol 49
in 45% yield and triene 50 in 40% yield; all efforts to prevent
the in situ dehydration of 49 failed. Allylic alcohol 49 was
oxidized using freshly activated MnO2 to enone 51, which
Paquette and co-workers converted to 4 using the three trans-
formations shown in 64% overall yield.10c
In summary, 1,3-dimethyl-2-nitrobenzene was converted in
ten steps into tricyclic dienone 25. In the key reaction, diene
24 was cyclized to produce the central seven-membered ring
and created the required stereochemistry of the C-5 and C-12
quaternary carbon atoms. Changing the oxidation states at C-3,
C-4, C-10, C-14, and C-15 required six transformations and
produced ( )-14-epi-hydroxydolasta-1(15),7,9-triene (48),
which is epimeric at C-14 to the natural dolastane. Diene
44, at first an unwanted side product in the reduction of di-
enone 42, was optimized and then converted in two steps
into enone 51, an intermediate in Paquette’s synthesis of
Scheme 10 presents a formal synthesis of 4 from diene 44.
Longer reaction time in the reduction of enone 42 produced
Published by NRC Research Press

Majetich and Yu
79
Scheme 5.
Scheme 8.
15
20
O
O
OCH3
10
O
2
NaBH4,
8) LDA,
34
EtO
12
TFA, DCM
(62%)
EtO
O
25
41
O
(97%)
19
37
11) H2, Pd/C
EtOAc (99%)
9) vinyl-
lithium
(91%)
CH3
O
O
10
O
O
1
12) NaBH4,
TFA, DCM
12
5
O
O
10) TiCl4
(61%)
42
44
30 min (30%) or
12 h (73%)
24
25
+
16
5
O
1
O
O
1
O
13) O2,h?
5
O
O
rose bengal,
P(OEt)3
(92%)
R
O
43
30 min
(55%)
45
25b
R = ?-CH3
= ?-CH3
(
)
25a
25c
(
)
Scheme 9.
Scheme 6.
16
1
2
CH3O
O
O
14
10
O
O
O
O
14) m-CPBA
TiCl4
DCM (95%)
43
46
(86%)
NBS, H2O
42
15) LAH, H3O+
(80%)
38
39
Scheme 7.
HO
14
O
15
1
16
8
HO
14
O
10
O
16) LDA,
2
50 ºC
(93%)
5
9
7
4
48
47
25
OAc
4
( )-7-epi-acetoxy-14-epi-hydroxydolasta-1(15),8-diene
(4).
We are confident that dienone 25,, or a derivative thereof,
will permit the efficient synthesis of the more oxygenated
naturally occurring dolastanes.
O
HO
Experimental section
General procedures
All reactions were run under a nitrogen atmosphere and
monitored by TLC analysis. Unless otherwise indicated, all
ethereal work-ups consisted of the following procedure. The
10
40
Published by NRC Research Press

80
Can. J. Chem. Vol. 90, 2012
Scheme 10.
This crude bromide was used in the next reaction without pu-
rification.
A solution of sodium methoxide was prepared by adding
small pieces of sodium metal (21.0 g, 0.913 mol) to anhy-
drous methanol (300 mL). After the complete consumption
of the sodium, a solution of the above bromide (70.0 g,
304 mmol) in anhydrous DMF (300 mL) was added, fol-
lowed by the addition of CuBr (4.0, 28.0 mmol). The reac-
tion mixture was heated at 110 °C for 12 h, then cooled to
RT, and water (100 mL) was added dropwise to quench the
reaction. Standard ethereal work-up gave 46.8 g (85%) of ni-
trobenzene 30 as a crude red solid, which was recrystallized
(benzene) to give white crystals. Mp 48.7–49.0 °C. IR (film)
14) SeO2
HO
44
49 (45%)
15) MnO2
+
16) 1O2 ,
P(OEt)3
1
lmax: 2930, 1524, 1263, 810 cm–1. H (400 MHz) d: 7.06 (d,
17) DIBAL
4
( )-
J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 2.23
(s, 3H), 2.14 (s, 3H). 13C NMR (100 MHz) d: 181.1 (s),
156.4 (s), 128.9 (d), 120.6 (s), 118.7 (s), 111.8 (d), 56.2 (q),
18) Ac2O
(64% over
three steps)
16.7 (q), 10.9 (q) ppm. HR-MS: [M]+obs = 181.0741, [M]+
181.0739.
=
O
calcd
51
50
(40%)
3-Methoxy-2,6-dimethylaniline (31)
reaction was quenched at RT (RT) with water. The organic
solvent was removed under reduced pressure on a rotary
evaporator, and the residue was extracted with diethyl ether
twice. The combined organic layer was washed with water,
brine, and dried over anhydrous magnesium sulfate. Filtra-
tion, followed by concentration at reduced pressure on a ro-
tary evaporator and at 1 torr (1 torr = 133.322 4 Pa) to
constant weight, afforded a crude residue that was purified
by flash chromatography using silica gel 60 (230–400 mesh
ASTM) eluted with distilled reagent grade petroleum ether
and diethyl ether. Melting points were recorded on a Labora-
To a solution of anisole 30 (30.0 g, 166 mmol) in MeOH
(270 mL) and H2O (30 mL) was added NH4Cl (26.0 g,
486 mmol), followed by Zn powder (110 g, 1.68 mol) in
small portions. The reaction mixture was stirred at RT for
2 h, followed by standard ethereal work-up, to give 19.0 g
(76.0%) of aniline 31 as a crude red oil which was used in
the next step without purification. IR (film) lmax: 3393,
2910, 1626, 1496, 1262, 791 cm–1. H (400 MHz) d: 6.89
1
(d, J = 8.4 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H),
2.15 (s, 3H), 2.09 (s, 3H). 13C NMR (100 MHz) d: 156.7 (s),
143.8 (s), 127.6 (d), 115.1 (s), 110.9 (s), 101.0 (d), 55.9 (q),
1
tory Devices Mel–Temp 3.0. H and 13C NMR spectra were
17.4 (q), 9.4 (q) ppm. HR-MS: [M]+obs = 152.1074, [M]+
152.1075.
=
calcd
recorded on Bruker AVB–400 and DRX–500 MHz spectrom-
eters with 13C operating frequencies of 100 and 125 MHz, re-
spectively. 1H NMR spectra were obtained in CDCl3 and
were calibrated using trace CHCl3 present (d 7.27) as an in-
ternal reference. 13C NMR spectra were obtained in CDCl3
and were calibrated using trace CHCl3 present (d 77.23) as
an internal reference. The IR spectra were obtained using an
Avatar 360FT-IR spectrophotometer and are reported in fre-
quency of absorption (cm–1). Only selected IR absorbances
are reported. High-resolution MS spectra were taken using a
LCT Premier mass spectrometer from Waters.
2-Bromo-4-methoxy-1,3-dimethylbenzene (32) and 1,4-
dibromo-2-methoxy-3,5-dimethylbenzene (35)
A round bottom flask at 0 °C was charged with HBr
(4.67 g, 27.7 mmol), THF (60 mL), LiBr (1.14 g,
13.1 mmol), NaNO2 (1.0 g, 14.5 mmol), and CuBr (2.26 g,
15.8 mmol). The ice bath was removed, and aniline 31
(3.0 g, 2.00 mmol) in THF (15 mL) was added dropwise.
The reaction mixture was stirred at RT for an additional 1 h,
followed by standard ethereal work-up, to give 3.43 g of a
black oil which was predominantly bromide 32 along with
dibromide 35, which could not be separated. Albeit a mix-
ture, the following data is for bromide 32, the major compo-
1-Methoxy-2,4-dimethyl-3-nitrobenzene (30)
To a solution of 1,3-dimethyl-2-nitrobenzene (29) (50.0 g,
331 mmol) in freshly distilled DCM (150 mL) was added
FeBr3 (2.0 g, 6.8 mmol) and Fe (5.0 g, 89 mmol). Molecular
bromine (18.6 mL, 361 mmol) was added dropwise, and
100 mL of DCM was added to the mixture. The reaction
mixture was refluxed for 8 h. The reaction mixture was
cooled to RT, followed by standard ethereal work-up. The or-
ganic layer was dried over anhydrous MgSO4, filtered, and
then concentrated under vacuum using rotary evaporator to
give 74.3 g (98.0%) of the bromide as a crude red oil. IR
1
nent. H (400 MHz) d: 7.08 (d, J = 8.3 Hz, 1H), 6.75 (d, J =
8.3 Hz, 1H), 3.80 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H).
3-Methoxy-2,6-dimethylbenzaldehyde (33) and 2-methoxy-
3,5-dimethylterephthalaldehyde (36)
To a solution of 32 and 35 (34 g) in THF (250 mL)
at –78 °C was slowly added t-BuLi (180 mL, 306 mmol).
This mixture was stirred at –78 °C for 2 h, followed by
the addition of DMF (40 mL). The reaction mixture was
warmed to RT and stirred overnight. Water (10 mL) was
added slowly to quench the reaction, followed by standard
ethereal work-up. Column chromatography (elution with
pet. ether/EtOAc, 10:1) gave 1.22 g (37% over two steps)
of aldehyde 33 (hexane/EtOAc, 4:1, Rf 33 = 0.66) as a
1
(film): lmax: 2927, 1517, 1370, 815 cm–1. H (400 MHz)
d: 7.55 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 2.35
(s, 3H), 2.26 (s, 3H). 13C NMR (100 MHz) d: 134.0 (d),
129.9 (d), 129.6 (s), 128.7 (s), 123.2 (s), 18.3 (q), 17.3 (q)
ppm. HR-MS: [M]+ = 228.9738, [M]+
= 228.9738.
obs
calcd
Published by NRC Research Press

Majetich and Yu
81
white solid. IR (film) lmax: 2939, 1691, 1262 cm–1. 1H
(400 MHz) d: 10.6 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.93
(d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 2.51 (s, 3H), 2.46 (s,
3H). 13C NMR (125 MHz) d: 194.5 (d), 156.4 (s), 133.8
(s), 132.1 (s), 129.8 (s), 129.6 (d), 115.0 (d), 56.1 (q), 20.1
then raised to –63 °C. A solution of bromide 34 (2.94 g,
17.2 mmol) in THF (10 mL) was cannulated into the reaction
mixture over a 2 min period, and the resulting mixture was
stirred overnight. Standard ethereal work-up, followed by col-
umn chromatography (elution with pet ether/EtOAc, 10:1),
afforded 4.2 g (97%) of adduct 37 as a light yellow oil (hex-
ane/EtOAc, 4:1, Rf 137 = 0.47). IR (film) lmax: 2981, 1622,
1342, 1253 cm–1. H (400 MHz) d: 6.94 (d, J = 8.4 Hz,
1H), 6.64 (d, J = 8.4 Hz, 1H), 3.99 (m, 1H), 3.87 (m, 1H),
3.79 (s, 3H), 3.28 (d, J = 14.8 Hz, 1H), 3.74 (d, J =
14.8 Hz, 1H), 2.71 (septet, J = 7.2 Hz, 1H), 2.38 (d, J =
17.2 Hz, 1H), 2.18 (s, 3H), 2.16 (d, J = 17.2 Hz, 1H), 2.10
(s, 3H), 1.28 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H), 1.10 (d, J =
6.8 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz)
d: 209.3 (s), 181.9 (s), 156.3 (s), 137.9 (s), 129.7 (s), 128.0
(d), 126.4 (s), 122.9 (s), 108.5 (d), 64.9 (t), 55.8 (q), 46.9
(s), 36.8 (t), 36.4 (t), 27.9 (q), 23.0 (d), 21.0 (q), 20.3 (q),
(q), 11.5 (q) ppm. HR-MS: [M]+ = 164.0840, [M]+
=
obs
164.0837. Further elution gave 0.31 g (8.1% over two csatlcedps)
of bis-aldehyde 36 as a white solid (hexane/EtOAc, 4:1, Rf
36 = 0.45). Mp = 82.0–82.3 °C. IR (film) lmax: 2930,
1691, 1409, 1232 cm–1. 1H (400 MHz) d: 10.6 (s, 1H),
10.4 (s, 1H), 7.54 (s, 1H), 3.85 (s, 3H), 2.55 (s, 3H), 2.52
(s, 3H). 13C NMR (100 MHz) d: 193.7 (d), 190.1 (d), 160.4
(s), 138.8 (s), 136.2 (s), 134.9 (s), 131.4 (s), 128.9 (d), 63.8
(q), 19.9 (q), 11.8 (q) ppm. HR-MS: [M]+ = 192.0790,
obs
[M]+
= 192.0786.
calcd
2-(Bromomethyl)-4-methoxy-1,3-dimethylbenzene (34)
A solution of aldehyde 33 (10.0 g, 61.0 mol) in Et2O
(150 mL) was cooled to 0 °C and LAH (2.55 g, 67.1 mmol)
was added portion-wise. The ice bath was removed and the
solution was stirred at RT for 1 h. The solution was poured
into a 2 L Erlenmeyer flask containing Na2SO4 (20 g) and
EtOAc (300 mL). Water was added slowly until the heteroge-
neous mixture turned to white. Standard ethereal work-up,
followed by column chromatography (elution with pet ether/
EtOAc = 4:1), afforded 9.60 g (95%) (3-methoxy-2,6-dime-
thylphenyl)methanol as a white solid (hexane/EtOAc, 4:1, Rf
alcohol = 0.25). IR (film) lmax: 3396, 2957, 1464, 1258 cm–1.
20.3 (q), 15.1 (q), 13.5 (q) ppm. HR-MS: [M+H]+
=
obs
331.2266, [M+H]+
= 331.2273.
calcd
2-Isopropyl-4-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-3-
vinylcyclopent-2-en-1-one (24)
To a solution of vinyl bromide (3.2 mL, 45 mmol) in
freshly distilled Et2O (60 mL) at –78 °C, t-butyllithium
(54 mL, 1.7 mol/L, 91 mmol) was added over a 15 min pe-
riod. After stirring 2.5 h at RT, the vinyllithium mixture was
cannulated into 37 (2.00 g, 6.1 mmol) in THF (60 mL) solu-
tion at –78 °C. The resulting mixture was warmed to RT and
stirred for an additional 8 h. Hydrochloric acid (20.0 mL, 1.0
mol/L) was added dropwise at 0 °C, and the resulting mix-
ture was stirred for 30 min. Standard ethereal work-up, fol-
lowed by column chromatography (elution with pet ether/
EtOAc, 8:1), gave 1.76 g (91%) of conjugated dienone 24 as
a light yellow oil (hexane/EtOAc, 2:1, Rf1 24 = 0.75). IR
(film) lmax: 2960, 1693, 1258, 1102 cm–1. H (400 MHz) d:
6.96 (d, J = 8.0 Hz, 1H), 6.90 (dd, J1 = 11.2 Hz, J2 =
17.6 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.63 (d, J =
17.6 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 3.79 (s, 3H), 3.43
(m, 1H), 3.08 (dd, J1 = 6.4 Hz, J2 = 14.0 Hz, 1H), 2.93
(septet, J = 7.2 Hz, 1H), 2.57 (dd, J1 = 10.0 Hz, J2 =
14.0 Hz, 1H), 2.28 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.28
(s, 3H), 1.26 (d, J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 1H).
1H (400 MHz) d: 7.02 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.0 Hz,
1H), 4.75 (s, 2H), 3.82 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H). 13
C
NMR (125 MHz) d: 156.4 (s), 137.8 (s), 129.2 (s), 128.4 (d),
126.4 (s), 110.4 (d), 59.8 (t), 55.9 (q), 19.2 (q), 11.6 (q) ppm.
HR-MS: [M]+obs = 166.0999, [M]+calcd = 166.0994.
A solution of the above alcohol (5.00 g, 30.1 mmol) in
Et2O (150 mL) was cooled to 0 °C and PBr3 (3.1 mL,
33.1 mmol) was added dropwise. The resulting solution was
removed from the ice bath and stirred at RT for 1 h. The re-
sulting solution was cooled to 0 °C, and brine (30 mL) was
added slowly. The aqueous phase was removed and the or-
ganic layer was dried over anhydrous magnesium sulfate. Fil-
tration, followed by concentration at reduced pressure, and
column chromatography (elution with pet ether/EtOAc, 15:1)
afforded 6.69 g (97%) of bromide 34 as a white solid (hex-
ane/EtOAc, 4:1, Rf 34 = 0.80). Mp = 62.3–62.5 °C. IR
13C NMR (125 MHz) d: 208.3 (s), 166.9 (s), 156.4 (s), 145.0
(s), 138.1 (s), 130.4 (d), 128.4 (s), 128.3 (d), 125.2 (), 121.5
(t), 108.4 (d), 55.5 (q), 41.1 (t), 36.8 (d), 35.8 (t), 20.9 (q),
20.6 (q), 20.5 (q), 15.1 (q), 12.8 (q) ppm.
1
(film) lmax: 3000, 2833, 1486, 1261 cm–1. H (400 MHz) d:
7.03 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.60 (s,
2H), 3.83 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H). 13C NMR
(125 MHz) d: 156.4 (s), 135.3 (s), 129.3 (s), 128.4 (d),
126.5 (s), 111.0 (d), 55.9 (q), 29.9 (t), 19.0 (q), 11.4 (q)
(3aS,8aR)-1-Isopropyl-3a,5,8a-trimethyl-3a,4,9,10-
tetrahydrobenzo[f]azulene-2,6(3H,8aH)-dione (25)
ppm. HR-MS: [M+H]+
228.0150.
= 228.0140, [M+H]+
=
To a solution of conjugated dienone 24 (200 mg,
0.641 mmol) in fresh distilled DCM (2 mL) at –78 °C was
added TiCl4 (10 mL, 0.91 mmol). The resulting mixture was
stirred at –78 °C for 1 h, and the temperature was raised
to –60 °C, then stirred for an additional 0.5 h. Water
(5 mL) was added dropwise to quench the reaction, fol-
lowed by standard ethereal work-up. Column chromatogra-
phy (elution with pet ether/EtOAc, 4:1) afforded 115 mg
(61%) of tricyclic enone 25 as a white solid (hexane/EtOAc,
2:1, Rf 25 = 0.41). IR (film) lmax: 2963, 1738, 1693, 1658,
obs
calcd
3-Ethoxy-2-isopropyl-5-(3-methoxy-2,6-dimethylbenzyl)-5-
methylcyclopent-2-en-1-one (37)
To a solution of diisopropylamine (2.40 mL, 17 mmol) in
THF (20 mL) at –78 °C was added n-butyllithium (6.30 mL,
16 mmol) over a 5 min period. The resulting mixture was
stirred at RT for 10 min then cooled to –78 °C. A solution
of enone 19 (2.60 g, 14.3 mmol) and HMPA (2.60 g,
14.3 mmol) in THF (10 mL) was cannulated over a 5 min
period. The resulting solution was stirred for 1 h at –78 °C
1
1627, 1379 cm–1. H (500 MHz) d: 6.81 (d, J = 9.5 Hz,
1H), 6.31 (d, J = 9.5 Hz, 1H), 3.03 (d, J = 13.5 Hz, 1H),
Published by NRC Research Press

82
Can. J. Chem. Vol. 90, 2012
2.74 (m, 1H), 2.67 (septet, J = 7.0 Hz, 1H), 2.35 (m, 3H),
2.17 (m, 1H), 1.96 (s, 3H), 1.71 (m, 1H), 1.59 (m, 1H),
1.22 (s, 3H), 1.13 (m, 6H), 1.09 (s, 3H). 13C NMR
(125 MHz) d: 207.4 (s), 186.2 (s), 179.3 (s), 158.0 (s),
157.7 (d), 140.9 (s), 136.0 (s), 128.2 (d), 52.0 (t), 45.6 (t),
45.1 (s), 40.0 (t), 38.4 (t), 29.9 (q), 25.7 (q), 24.7 (d), 23.9
ard ethereal work-up. Column chromatography (elution with
pet ether/EtOAc, 10:1) gave 44 mg (30%) of diene 44 as a
light yellow oil (hexane/EtOAc, 4:1, Rf 44 = 0.90). IR (film)
1
lmax: 2933, 1464, 1372 cm–1. H (400 MHz) d: 1.70–2.35
(m, 17H), 1.67 (s, 3H), 1.13–1.19 (m, 6H), 1.10 (s, 3H),
0.98 (s, 3H). 13C NMR (100 MHz) d: 208.6 (s), 182.5 (s),
139.7 (s), 132.9 (s), 131.9 (s), 52.0 (t), 44.9 (s), 41.7 (t),
38.3 (s), 37.9 (t), 37.2 (t), 32.3 (t), 28.4 (q), 25.7 (q), 24.6 (d),
(t), 20.8 (q), 20.7 (q), 13.8 (q) ppm. HR-MS: [M+H]+
=
obs
299.2010, [M+H]+
= 299.2011.
calcd
22.9 (t), 21.8 (q), 20.9 (q), 19.3 (t) ppm. HR-MS: [M]+
=
obs
(3aR,8aR)-1-Isopropyl-3a,5,8a-trimethyl-2,3,3a,4,9,10-
hexahydrobenzo[f]azulen-6(8aH)-one (41)
286.2295, [M]+
= 286.2297. Further elution gave
calcd
76 mg (55%) of enone 43 as a light yellow oil (hexane/
EtOAc, 4:1, Rf 43 = 0.55). 1H (400 MHz) d: 2.58–2.74
(m, 3H), 2.30 (d, J = 18.4 Hz, 1H), 2.20 (d, J = 18.0 Hz,
1H), 2.12 (m, 1H), 1.95 (m, 3H), 1.68–1.84 (m, 3H), 1.67
(s, 3H), 1.25–1.44 (m, 3H), 1.15 (m, 6H), 1.10 (s, 3H),
0.98 (s, 3H). 13C NMR (100 MHz) d: 208.6 (s), 182.5 (s),
139.7 (s), 132.9 (s), 131.9 (s), 52.0 (t), 44.9 (s), 41.7 (t),
38.3 (s), 37.9 (t), 37.2 (t), 32.3 (t), 28.4 (q), 25.7 (q), 24.6
(d), 22.9 (t), 21.8 (q), 20.9 (q), 19.3 (t) ppm. HR-MS:
To a solution of tricycle 25 (100 mg, 0.336 mmol) in
freshly distilled DCM (10 mL) was added 10% TFA in
DCM solution (5 mL), followed by NaBH4 (64 mg,
1.7 mmol). The resulting mixture was stirred for 0.5 h. Water
(5 mL) was added to quench the reaction, followed by stand-
ard ethereal work-up. Column chromatography (elution with
pet ether/EtOAc, 10:1) gave 64 mg (67%) of dienone 41 as a
light yellow oil (hexane/EtOAc, 4:1, Rf 41 = 0.55). IR (film)
[M+H]+ = 287.2376, [M+H]+
= 287.2375. Note: Al-
1
lmax: 2963, 1658, 1462, 1151 cm–1. H (500 MHz) d: 6.81
obs
calcd
lowing the reduction to proceed overnight (12 h) gave diene
(d, J = 9.5 Hz, 1H), 6.31 (d, J = 9.5 Hz, 1H), 2.67 (septet,
J = 7.0 Hz, 1H), 2.15–1.5 (m, 11H), 1.96 (s, 3H), 1.22 (s,
44 in 73% yield.
3H), 1.13 (m, 6H), 1.09 (s, 3H). HR-MS: [M+H]+
=
obs
285.2222, [M+H]+
= 285.2218.
(1S,3aS,8aS)-1-Isopropyl-3a,8a-dimethyl-5-
calcd
methylenedecahydro-4a,10a-epoxybenzo[f]azulen-2(1H)-
one (45)
(3aR,8aR)-1-Isopropyl-3a,5,8a-trimethyl-2,3,3a,4,8,8a,9,10-
octahydrobenzo[f]azulen-6(7H)-one (42)
A solution of 43 (10 mg, 0.034 mmol) and rose bengal
(2.0 mg) in 5 mL of a solution of methanol/dichloromethane
(1:9) was irradiated at –5 °C with a 500 W tungsten lamp,
while oxygen was bubbled through the reaction mixture.
After 40 min, the reaction mixture was treated with triethyl
phosphite (0.3 mL) at RT for 1 h with vigorous stirring.
After concentration, standard ethereal work-up provided a
crude residue, which was purified by column chromatogra-
phy (elution with pet ether: EtOAc, 10:1) and gave 9.9 mg
(92%) of furan 45 (hexane: EtOAc, 4:1, Rf 45 = 0.45) as a
colorless oil. IR (film) lmax: 2933, 1740, 1075, 895 cm–1.
To a dry 20-mL round-bottomed flask was added tricycle
25 (100 mg, 0.336 mmol) under nitrogen atmosphere, fol-
lowed by addition of anhydrous EtOAc (5 mL) and 5% of
Pd/C (10 mg, 10% in weight). The nitrogen in the reaction
flask was removed by bubbling H2 into the reaction medium
for a 5 min period. A balloon filled with H2 was connected to
the round-bottomed flask and the resulting mixture was
stirred under H2 for 2 h. The H2 balloon was disconnected
and the residue H2 gas was removed by bubbling N2 into the
reaction mixture, followed by filtration through a short pad of
silica gel to remove the catalyst. Standard ethereal work-up,
followed by column chromatography (elution with pet ether/
EtOAc, 4:1), gave 100 mg (99%) of bis-enone 42 as a white
solid (hexane/EtOAc, 2:1, Rf 42 = 0.40). Mp = 147.0–
147.2 °C. IR (film) lmax: 3376, 2959, 1697, 1460, 1379,
1H (400 MHz) d: 4.76 (s, 1H), 4.66 (s, 1H), 2.93 (d, J =
17.6 Hz, 1H), 2.61–2.74 (m, 2H), 2.08–2.41 (m, 6H), 1.72–
1.80 (m, 1H), 1.58–1.69 (m, 4H), 1.25–1.40 (m, 2H), 1.20
(m, 6H), 1.12 (s, 3H), 0.83 (s, 3H). 13C NMR (100 MHz) d:
217.0 (s), 148.7 (s), 103.1 (t), 90.9 (s), 86.6 (s), 59.2 (d),
54.6 (t), 46.6 (t), 44.9 (q), 36.2 (s), 35.8 (t), 32.8 (t), 31.4
(t), 25.7 (d), 24.4 (t), 21.9 (q), 21.2 (t), 19.9 (q), 18.8 (q),
1
1118 cm–1. H (400 MHz) d: 2.87 (d, J = 13.2 Hz, 1H),
2.52–2.79 (m, 4H), 2.39 (d, J = 18.0 Hz, 1H), 2.30 (d, J =
18.8 Hz, 1H), 2.21 (m, 2H), 2.04 (m, 1H), 1.85 (s, 3H), 1.79
(m, 1H), 1.58 (m, 2H), 1.17 (m, 9H), 1.13 (s, 3H). 13C NMR
(100 MHz) d: 207.3 (s), 198.5 (s), 179.5 (s), 160.6 (s), 140.6
(s), 135.3 (s), 52.0 (t), 44.5 (s), 41.0 (t), 40.1 (t), 34.9 (t),
34.4 (t), 26.6 (q), 25.5 (q), 24.7 (d), 22.5 (t), 20.9 (q), 20.8
18.1 (q) ppm. HR-MS: [M+H]+obs = 303.2316, [M+H]+
303.2324.
=
calcd
(1aR,4aS,9aS,10aS)-7-Isopropyl-1a,4a,9a-trimethyl-
2,3,4,4a,5,6,9a,10-octahydro-1aH-azuleno[5′,6′:1,6]benzo
(q), 13.7 (q) ppm. HR-MS: [M+H]+ = 301.2167, [M+H]
obs
[1,2-b]oxiren-8(9H)-one (46)
+
= 301.2168.
calcd
To a solution of diene 43 (35 mg, 0.12 mmol) in freshly
distilled DCM (4 mL) under nitrogen atmosphere was added
m-CPBA (77%, 33 mg, 0.15 mmol, 1.2 equiv.). The resulting
mixture was stirred at RT for 1 h. Standard ethereal work-up,
followed by column chromatography (elution with pet ether/
EtOAc, 5:1), afforded 35.0 mg (95%) of epoxide 46 as a
white foam (hexane/EtOAc, 2:1, Rf 46 = 0.49). IR (film)
(3aS,8aS)-1-Isopropyl-3a,5,8a-trimethyl-3a,4,6,7,8,8a,9,10-
octahydrobenzo[f]azulen-2(3H)-one (43) and (3aR,8aS)-1-
isopropyl-3a,5,8a-trimethyl-2,3,3a,4,6,7,8,8a,9,10-
decahydrobenzo[f]azulene (44)
To a solution of bis-enone 42 (153 mg, 0.510 mmol) in
fresh distilled DCM (15 mL) was added 10% TFA in DCM
solution (10 mL), followed by NaBH4 (97 mg, 2.6 mmol).
The resulting mixture was stirred for 0.5 h at RT. Water
(5 mL) was added to quench the reaction, followed by stand-
1
lmax: 3006, 2918, 1717, 1364, 1224 cm–1. H (400 MHz) d:
2.87 (m, 1H), 2.73 (septet, J = 7.2 Hz, 1H), 2.42 (m, 1H),
2.22 (d, J = 8.8 Hz, 2H), 1.90–2.12 (m, 3H), 1.64–1.83 (m,
3H), 1.39–1.52 (m, 3H), 1.37 (s, 3H), 1.29 (s, 3H), 1.20–
Published by NRC Research Press

Majetich and Yu
83
1.25 (m, 1H), 1.18 (s, 3H), 1.16 (s, 3H) 0.97 (s, 3H). 13C
NMR (100 MHz) d: 207.3 (s), 179.4 (s), 141.2 (s), 68.6 (s),
65.3 (s), 53.3 (t), 42.8 (s), 42.2 (t), 37.7 (s), 36.8 (t), 36.7 (t),
31.4 (t), 25.9 (q), 24.8 (d), 24.2 t), 23.4 (q), 23.0 (q), 20.4
(3aS,8aR)-1-Isopropyl-3a,5,8a-trimethyl-3a,4,8,8a,9,10-
hexahydrobenzo[f]azulene-2,6(3H,7H)-dione (42) from
enone (43)
To a solution of enone 43 (10 mg, 0.035 mmol) in acetone
(2 mL) and H2O (1 mL) was added N-bromosuccinimide
(8.1 mg, 0.046 mmol, 1.3 equiv.) in one portion. The result-
ing mixture was stirred at RT for 5 min and was quenched
with water (2 mL). Acetone was removed under vacuum us-
ing a rotary evaporator, followed by standard ethereal work-
up. Column chromatographic purification (elution with pet
ether/EtOAc, 4:1) gave 7.4 mg (71%) of bis-enone 42 (hex-
ane/EtOAc, 2:1, Rf 42 = 0.40) as a white solid, which was
identical to that previously characterized (i.e., the reduction
of 25 to give 42).
(q), 20.3 (q), 16.6 (q) ppm. HR-MS: [M]+ = 302.2243,
obs
+
[M]
= 302.2246.
calcd
(1aR,4aS,9aR,10aS)-7-Isopropyl-1a,4a,9a-trimethyl-
2,3,4,4a,5,9,9a,10-octahydro-1aH-azuleno[5′,6′:1,6]benzo
[1,2-b]oxirene (47)
To a solution of enone 46 (60 mg, 0.20 mmol) in freshly
distilled Et2O (10 mL) at 0 °C under nitrogen atmosphere
was added LAH (7.6 mg, 0.20 mmol). The resulting reaction
mixture was stirred for 1 h at RT. Water (4 mL) was slowly
added to quench the reaction, followed by standard ethereal
work-up. Concentration of the filtered organic phase afforded
yellow oil. Silica gel was added to the bottle, and the result-
ing mixture was allowed to sit on the bench overnight. Col-
umn chromatography (elution with pet ether/EtOAc, 15:1)
afforded 45.5 mg (80%) of diene 47 (hexane/EtOAc, 8:1, Rf
47 = 0.50) as a colorless oil. IR (film) lmax: 3247, 2952,
(3aR,8aS,10S)-1-Isopropyl-3a,5,8a-trimethyl-
2,3,3a,4,6,7,8,8a,9,10-decahydrobenzo[f]azulen-10-ol (49)
To a solution of SeO2 (9.1 mg, 0.089 mmol) in freshly dis-
tilled DCM (0.50 mL) was added t-BuOOH (37 mL,
0.36 mmol). The resulting mixture was stirred for 25 min at
RT. Diene 44 (48 mg, 0.18 mmol) in DCM (0.50 mL) was
added dropwise. The resulting mixture was stirred at RT for
8 h, followed by standard ethereal work-up. Column chroma-
tography (elution with pet ether/EtOAc, 10:1) afforded 19 mg
(40%) of triene 50 as a light yellow oil (hexane/EtOAc, 4:1,
Rf 50 = 0.95). Further elution gave 23 mg (45%) of allylic
alcohol 49 as a light yellow oil (hexane/EtOAc, 4:1, Rf 49 =
0.39).
1
1660, 1359, 1010 cm–1. H (500 MHz) d: 5.60 (s, 1H), 5.45
(m, 1H), 2.90 (d, J = 15.0 Hz, 1H), 2.41 (m, 1H), 2.14–2.33
(m, 3H), 1.70–1.98 (m, 4H), 0.80–1.62 (m, 4H), 1.39 (s,
3H), 1.18 (s, 3H), 1.07–1.13 (m, 6H), 1.03 (s, 3H). 13C
NMR 154.5 (s), 149.5 (s), 125.6 (d), 113.6 (d), 70.4 (s),
65.8 (s), 49.6 (t), 43.5 (s), 39.2 (t), 37.9 (s), 37.2 (t), 34.8
(t), 30.1 (t), 25.7 (d), 24.0 (q), 23.7 (q), 23.3 (q), 22.3 (q),
(3aR,8aS)-1-Isopropyl-3a,5,8a-trimethyl-2,3,3a,4,7,8,8a,9-
octahydrobenzo[f]azulen-10(6H)-one (51)
22.3 (q), 16.7 (t) ppm. HR-MS: [M]+
= 286.2297,
obs
[M]+
= 286.2297.
calcd
To a solution of allylic alcohol 49 (5.2 mg, 0.018 mmol)
in CCl4 (0.5 mL) was added MnO2 (16 mg, 0.18 mmol).
The resulting mixture was heated at 60 °C for 6 h. Standard
ethereal work-up, followed by column chromatography (elu-
tion with pet ether/EtOAc, 12:1), gave 3.4 mg (65%) of
enone 51 as a light yellow oil (hexane/EtOAc, 4:1, Rf 51 =
(3aR,4aR,8aS)-1-Isopropyl-3a,8a-dimethyl-5-methylene-
3,3a,4,4a,5,6,7,8,8a,9-decahydrobenzo[f]azulen-4a-ol (48)
To a solution of diisopropylamine (0.70 mL, 5.0 mmol) in
freshly distilled Et2O (10 mL) at 0 °C was added n-butyl-
lithium (2 mL, 5 mmol). The resulting mixture was stirred at
RT for 10 min. Epoxide 47 (8.0 mg, 0.028 mmol) was trans-
ferred into a sealed tube, and 2 mL of the above LDA solu-
tion was added. The reaction vessel was closed, and it was
heated to 50 °C and kept at this temperature for 36 h. Water
(2 mL) was added to quench the reaction followed by stand-
ard ethereal work-up. Column chromatography (elution with
pet ether/EtOAc, 15:1) afforded 7.4 mg (93%) of allylic alco-
hol 48 (hexane/EtOAc, 8:1, Rf 48 = 0.81) as a colorless oil.
1
0.75). H (400 MHz) d: 3.34 (heptet, J = 7.2 Hz, 1H), 2.85
(d, J = 14.8 Hz, 1H), 2.57 (d, J = 14.0 Hz, 1H), 2.40 (t, J =
7.2 Hz, 2H), 2.22 (d, J = 14.8 Hz, 1H), 2.16 (d, J =
14.0 Hz, 1H), 2.01 (bs, 2H), 1.67 (s, 3H), 1.46–1.75 (m,
6H), 1.08 (s, 3H), 0.98–1.04 (m, 9H). 13C NMR (125 MHz)
d: 202.7, 161.7, 142.9, 133.7, 129.0, 58.0, 48.7, 42.0, 40.8,
39.6, 36.1, 33.4, 29.1, 27.9, 25.6, 23.0, 20.9, 20.7, 20.7,
19.1 ppm.
Supplementary data
1
IR (film) lmax: 3556, 2923, 1466, 1115 cm–1. H (500 MHz)
d: 5.74 (t, J = 7.0 Hz, 1H), 5.70 (s, 1H), 5.02 (s, 1H), 4.69
(s, 1H), 3.01 (s, 1H), 2.61 (d, J = 17.0 Hz, 1H), 2.44 (septet,
J = 7.0 Hz, 1H), 2.36 (m, 2H), 2.27 (m, 1H), 2.12 (dd, J1 =
3.0 Hz, J2 = 16.5 Hz, 1H), 2.03 (dt, J1 = 12.5 Hz, J2 =
5 Hz, 1H), 1.83 (m, 2H), 1.40–1.62 (m, 3H), 1.44 (s, 3H),
1.13 (d, J = 7.0 Hz, 3H), 1.11 (s, 3H), 1.04 (d, J = 7.0 Hz,
3H), 0.96 (s, 3H). 13C NMR (125 MHz) d: 157.5 (s), 153.6
(s), 148.6 (s), 128.3 (d), 125.8 (d), 107.1 (t), 79.2 (s), 50.5
(t), 45.4 (t), 44.4 (s), 41.7 (t), 39.0 (t), 34.7 (t), 30.6 (q),
28.4 (q), 25.9 (d), 23.6 (t), 79.2 (s), 50.5 (t), 45.4 (t), 44.4
(s), 41.7 (t), 39.0 (t), 34.7 (t), 30.6 (q), 28.4 (q), 25.9 (d),
Supplementary data for this article are available on the
journal Web site (www.nrcresearchpress.com/doi/suppl/
10.1139/v11-116). The X-ray data for key intermediate 25,
CCDC 835868, has also been deposited with the Cambridge
Crystallographic Data Centre. These data can be obtained,
free of charge, via www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi (or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1Ez, UK; fax +44 1223 336033; or e-
mail deposit@ccdc.cam.ac.uk).
Acknowledgments
23.6 (t), 22.2 (q), 21.7 (q), 21.3 (q) ppm. HR-MS: [M]+
=
Appreciation is extended to the NSF for partial support of
this research (CHE-05064846) and to Dr. Pinrong Wang
obs
286.2300, [M]+
= 286.2297.
calcd
Published by NRC Research Press

84
Can. J. Chem. Vol. 90, 2012
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