A Rh(II)-catalyzed cycloaddition approach toward the synthesis of komaroviquinone

Article abstract of DOI:10.1016/j.tet.2008.01.129

Using a rhodium(II)-catalyzed cyclization/cycloaddition sequence as the key reaction step, the icetexane core of komaroviquinone was constructed by an intramolecular dipolar-cycloaddition of a carbonyl ylide dipole across a tethered π-bond. The ylide was arrived at by cyclization of a rhodium carbenoid intermediate onto a proximal ester group. Efforts toward the preparation of the required precursor for elaboration to the natural product are discussed.

Full text of DOI:10.1016/j.tet.2008.01.129

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4758e4767
www.elsevier.com/locate/tet
A Rh(II)-catalyzed cycloaddition approach toward the synthesis
of komaroviquinone
*
Albert Padwa , Majid J. Chughtai, Jutatip Boonsombat, Paitoon Rashatasakhon
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Received 30 August 2007; received in revised form 23 October 2007; accepted 23 October 2007
Available online 6 February 2008
Abstract
Using a rhodium(II)-catalyzed cyclization/cycloaddition sequence as the key reaction step, the icetexane core of komaroviquinone was con-
structed by an intramolecular dipolar-cycloaddition of a carbonyl ylide dipole across a tethered p-bond. The ylide was arrived at by cyclization
of a rhodium carbenoid intermediate onto a proximal ester group. Efforts toward the preparation of the required precursor for elaboration to the
natural product are discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Diterpene; Icetexane; Komaroviquinone; Diazo carbonyl; Rhodium(II); Catalyst; Carbonyl ylide; Intramolecular; Dipolar-cycloaddition
O
O
O
1. Introduction
O
OMe
biogenetically
OH
O
Me
Me
Me transformed
Me
Me
Dried whole plants of a perennial semishrub that is referred
to as ‘buzbosh’ (Dracocephalum komarovi) in Uzbekistan
were extracted and fractionated to give several icetexane diter-
penes whose structures were elucidated by extensive analysis
of their NMR data.1,2 The major fraction isolated from the
plant was assigned structure 1 and was named komaroviqui-
none. This compound showed strong in vitro trypanocidal
activity against epimastigotes of Trypanosoma cruzi, the caus-
ative agent of Chagas’ disease in Central and South America.3
In addition to compound 1, a minor diterpene 2 was also iso-
lated from the same plant, which possesses a novel spiro-octa-
hydroindene skeleton and was named komarovispirone (2).4a
Biogenetically, komarovispirone (2) may be derived from
komaroviquinone (1) through a novel ring-contraction se-
quence as outlined in Scheme 1.4b The stereochemistry of 2
was tentatively assigned as indicated in the scheme.
Me
Me
H
H
Me
O
O
OMe
H
1; komaroviquinone
2; komarovispirone
Scheme 1.
the basic skeleton mainly through acid-catalyzed cyclialkyl-
ation reactions.8 More recently, the first total synthesis of (ꢀ)-
komaroviquinone (1) was reported by Banerjee and co-workers
in 20059a and more recently by Majetich and co-workers.9b
Construction of the critical trans-10-hydroxy-1,1-dimethyl-
octahydrodibenzo[a,d]cyclohepten-7-one core was achieved
by employing an intramolecular Heck reaction for the crucial
carbonecarbon bond forming step.10 Thus, cyclization of the
olefinic intermediate 3 with Pd(OAc)2, K2CO3, and PPh3 in
acetonitrile under reflux was followed by oxidation of the
methylene group to produce ketone 5, which was found to
be in equilibrium with the hemiketal form 6 in solution. Fur-
ther oxidation of the equilibrating mixture with silver oxide
in dilute HNO3 afforded (ꢀ)-komaroviquinone (1) as the
major product in 68% yield for this last step (Scheme 2).
The total syntheses of several related diterpenes, which
incorporate a functionalized 6-7-6 fused tricyclic framework
have appeared in the literature5e7 and involve generation of
* Corresponding author. Tel.: þ1 404 727 0283; fax: þ1 404 727 6629.
E-mail address: chemap@emory.edu (A. Padwa).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.129

A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
4759
OH
Another approach involves the condensation of an aldehyde
with an a-diazoketone and the resulting aldol product is then
subjected to a metal-catalyzed decomposition.19 In order to
test the feasibility of the retrosynthetic strategy outlined in
Scheme 3, our initial efforts were focused on several model
substrates. According to our design, we hoped to employ a tan-
dem cyclization/cycloaddition reaction of a rhodium carbenoid
intermediate to rapidly generate the 9,10-benzo-12-oxa-tri-
cyclo[6.3.1.00,0]dodecane-dione skeleton from a relatively
simple precursor (i.e., 13).
OH
OMe
OMe
OMe
Me
OMe
Me
Pd(OAc)2
PPh3
Me
Me
Me
Me
Br
CH2
H
H
OMeMe
OMe
Me
X
4; X = CH2
5; X = O
3
oxidation
OMe
O
O
OMe
Me
OMe
Me
Me
O
O
Our synthesis of the key diazo-dione 13 commenced with
o-carbomethoxy diazoketone 11, which is readily available
in high yield from phthalic acid monomethyl ester. We antic-
ipated that under suitable reaction conditions, 11 would react
with hex-5-enal to give diketone 12 following a protocol de-
veloped by Holmquist and Roskamp for b-keto esters.20 These
authors have found that aldehydes can be converted into
b-keto esters by the addition of ethyl diazoacetate in the pres-
ence of tin(II) chloride. In our hands, a modest (but unopti-
mized) yield of 12 (ca. 40%) was obtained from the reaction
of 11 with hex-5-enal. A subsequent Regitz diazo transfer
reaction21 using nosyl azide and Et3N furnished diazo-dione
13 in 98% yield. Treating a sample of 13 with Rh2(OAc)4 in
benzene at 80 ꢁC afforded cycloadduct 16 in 75% yield
(Scheme 4). Interestingly, when the Rh(II)-catalyzed reaction
was carried out at room temperature, the major product iso-
lated corresponded to epoxy-indanone 15 (71%) with only
a small amount (<10%) of cycloadduct 16 being formed.
Heating a sample of 15 at 80 ꢁC in benzene gave 16 in 78%
isolated yield. This reaction presumably occurs via thermal
CeC bond cleavage of the epoxide ring to generate dipole
14, which undergoes a subsequent intramolecular [3þ2]-
cycloaddition to give 16. Most noteworthy, when a sample
of the methoxy substituted cycloadduct 16 was treated with
aqueous acid it was smoothly converted into the corresponding
oxidation Me
Me
Me
Me
H
H
Me
OMe
OH
OH
6
1; komaroviquinone
Scheme 2.
Based on prior work in our laboratory using the intramole-
cular dipolar-cycloaddition reaction of carbonyl ylides for the
synthesis of various natural products,11e14 we felt that the
Rh(II)-catalyzed reaction of a diazo-dione precursor (i.e., 7)
might allow for a facile entry to the icetexane core of komaro-
viquinone (1). The eventual formation of the oxatricyclo-
[6.3.1.00,0]dodecane skeleton of 1 was envisioned to come
about from cyclization of the rhodium carbenoid intermediate
8 with the adjacent carbomethoxy group.13 The ensuing dipole
9 was expected to undergo an intramolecular [3þ2]-cycloaddi-
tion across the tethered p-bond. The resulting cycloadduct 10
would then be converted to (ꢀ)-komaroviquinone in several
steps via sequential reduction of the keto groups, oxidation
to the benzoquinone core, and acid hydrolysis of the ketal
moiety (Scheme 3).15
O
O
OMe
O
OMe
Me
OMe
Me
O
Me
Me
Me
Me
H
H
Me
Me
CO2Me
OMe
O
MeO
10
OH
CO2Me
CHN2
CHO
SnCl2
1; komaroviquinone
41%
OH
O
O
12
OMe
Me
Me
OMe
OMe
11
Me
Me
OMe
OMe
O
nosyl azide
Et3N
MeO2C
98%
Me
+
Me
X
Me Me
O
-
OMe
CO2Me
N2
OMe
O
O
+
O
OMe
Rh(II)
25 °C
O
-
9
7; X = N2
8; X = Rh
O
O
O
O
13
14
Scheme 3.
Rh(II)
80 °C
25 °C
71%
80 °C
75%
heat
2. Results and discussion
OMe
O
OR
O
H
1,3-Dicarbonyl compounds represent a basic building block
in organic chemistry and consequently many procedures have
been developed for their synthesis.16 Among these methods,
the condensation of ethyl diazoacetate with aldehydes employ-
ing a variety of Lewis and Bronsted acids as catalysts17 repre-
sents a facile and efficient way to prepare 1,3-diones.18
80 °C
78%
O
O
O
O
15
16; R = Me
17; R = H
Scheme 4.

4760
A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
O
hemiketal 17. We assume that the hydrolytic conversion of 16
to 17 occurs by oxabicyclic ring opening under the acidic con-
ditions to produce a hydroxy-tricarbonyl as a transient species,
which subsequently cyclizes to hemiketal 17.
O
9-BBN then
NaOH, H2O2
EtO
EtO
OH
EtO
55%
19
18
95% TBSCl
O
Many studies support the intermediacy of carbonyl ylides in
reactions involving the interaction of a metallo-carbenoid with
a carbonyl oxygen.22 The great majority of literature reports on
carbonyl ylides are dominated by 1,3-dipolar-cycloaddition re-
actions rather than cyclization of the dipole to produce the oxi-
rane ring system.11e14 Huisgen was the first to report the
formation of an epoxide from the reaction of dimethyl diazo-
malonate with benzaldehyde, but only in 7% yield when the re-
action was carried out at 125 ꢁC in the presence of 1 mol % of
Cu(acac)2.23 More recently, the Doyle24 and Davies25 groups
have reported on stereospecific epoxide formation by
Rh2(OAc)4 catalyzed reactions of aryl, heteroaryl, and vinyl di-
azoacetates with a,b-unsaturated aldehydes or ketones. Later,
a similar epoxidation process was used to prepare spiro-indo-
loxiranes with cyclic diazoamides by the Mathusamy group.26
When dimethyl diazomalonate was used as the carbenoid
source, a competition between dioxolane and epoxide forma-
tion was noted. Doyle was able to direct the decomposition
of the diazomalonate system to produce either epoxide or dioxo-
lane by influencing the stability of the intermediate carbonyl
ylide dipole.27 When the electron rich p-anisaldehyde was
used as the trapping reagent, only epoxide formation was ob-
served. Stabilization of the intermediate ylide was suggested
to account for its diminished reactivity toward cycloaddition
with a second molecule of the added aldehyde. The fact that
we were able to isolate epoxide 15 in 71% yield from the cycli-
zation of dipole 14 is perfectly consistent with the Doyle obser-
vations (Scheme 4). Thus, stabilization of the positive center of
the dipole by interaction with the adjacent methoxy group di-
minishes the rate of the dipolar-cycloaddition reaction and pro-
motes cyclization of the ylide to the epoxide ring.
1. LiAlH4
2. PCC
O
H
OTBS
OTBS
70%
21
20
MePPh3I,n-BuLi
80%
O
H
1. TBAF
2. PCC
80%
OTBS
23
22
CO2Me
N2
11
20%
O
CO2Me
N2
NsN3,
Et3N
38%
CO2Me
( )
( )
2
2
O
O
O
OH
24
25
Scheme 5.
OR
Me
Me
CO2Me
N2
H
Me
Me
Rh(II)
80 °C
O
O
O
O
O
25
26; R = Me, 92%
27; R = H
Scheme 6.
this method suggests that a similar approach could be used
in our planned synthesis of komaroviquinone (1).
The Rh(II)-catalyzed reaction of the related dimethyl
substituted diazo ester 25 was also studied since this system
contained the required substituent groups needed for the even-
tual synthesis of komaroviquinone (1). The rate of an intramo-
lecular reaction is often increased when alkyl groups are
placed on a chain between the two reacting centers.28 This
is known as the gem-dialkyl effect and is often exploited to
promote difficult cyclization reactions.29
The required side chain for the Rh(II)-catalyzed reaction
was prepared using standard chemistry starting from ethyl
2,2-dimethylpent-4-enoate 18 (Scheme 5). Hydroboratione
oxidation followed by protection of the resulting hydroxyl
group gave ester 20. Adjustment of the oxidation state was fol-
lowed by Wittig methylenation in 80% yield. The hydroxyl
group was unmasked and oxidized to give aldehyde 23, which
was coupled with a-diazoketone 11 and further elaborated to
diazo-dione 25 as before to give the key substrate needed
for the cyclization/cycloaddition sequence. Indeed, the reac-
tion of diazo-dione 25 with a Rh(II) catalyst gave cycloadduct
26 in 92% yield, Scheme 6. Most importantly, when 26 was
treated with aqueous acid it was readily converted to 27 in
essentially quantitative yield. The conversion of 25 to 27 via
Accordingly, we set out to prepare the diazo dicarbonyl pre-
cursor 7, which is essential for our planned synthetic route.
After the cycloaddition chemistry, oxidation of the aromatic
portion would be expected to provide the para-benzoquinone
moiety found in the natural product. Thus, the challenge
became the preparation of a hexa-substituted aromatic carboxy-
lic acid (i.e., 30), which could be coupled via a-diazoketone
29 to a suitable olefinic tether to give the necessary diazo
dicarbonyl precursor 7 (Scheme 7).
Our approach toward carboxylic acid 30 initially centered
on the thermal rearrangement of cyclobutenones.30 Moore
and co-workers have shown this to be an expedient route for
the preparation of phenols.31 Starting from squaric acid (31),
methylation with diazomethane gave dimethyl squarate
(Scheme 8).32 Treatment with isopropyl magnesium bromide
at ꢂ78 ꢁC followed by hydrolysis produced cyclobutenedione
32 in 89% yield. The thermal rearrangement precursor was
formed by addition of 2-lithiopropene to a solution of 32 in
THF at ꢂ78 ꢁC followed by trapping with methyl triflate.
The mixture was then heated at reflux in hexane to give phenol
33 as the only isolable product in 45% yield. The addition of
the organo lithium reagent to dione 32 was completely

A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
4761
OMe
OMe
using methanol as the solvent, the brominated derivative 35
was obtained in 67% yield. Both lithiumehalogen exchange
and carbonyl insertion chemistry were examined without suc-
cess. We suspect that steric crowding around the carbon atom
bearing the bromo atom is responsible for the difficulty in con-
verting the aryl bromide into the corresponding carbomethoxy
group.
Me
Me
OMe
OMe
OMe
Me
Me
OMe
MeO2C
N2
MeO2C
Me
Me
Me
Me
O
O
O
O
7
28
Despite the congestion about the aromatic scaffold, we
decided to develop another approach toward the synthesis of
carboxylic acid 30. Introduction of a primary alcohol in place
of the methyl group should result in a better directing group
for the subsequent ortho-lithiation reaction since an electron
lone pair on the oxygen atom would coordinate to the lithium
ion thereby enhancing the stability of the complex. The cyclo-
butanone/thermolysis chemistry still appeared worth carrying
out since the use of lithiopropynes had been reported earlier.31
With this in mind, the tetrahydropyranyl protected propargyl
alcohol 37 was treated with n-BuLi followed by reaction
with cyclobutenedione 32 in a manner analogous to that de-
scribed above, Scheme 9. Disappointingly, the expected phenol
39 could not be observed in the crude reaction mixture after
heating in toluene. Therefore, we embarked on an alternative
strategy for the synthesis of the related alcohol 44 starting
from 1,2,4-trimethoxybenzene (see Scheme 10). Treatment
of this compound with n-BuLi at ꢂ78 ꢁC resulted in the selec-
tive lithiation at the 3-position of the aromatic ring by virtue of
OMe
Me
Me
OMe
OMe
Me
Me
OMe
MeO2C
MeO2C
Me
Me
and
H
HO
O
N2
23
OMe
29
O
O
OMe
30
Scheme 7.
regioselective and resulted in the formation of only one of the
two possible regiomeric phenols. The identification of phenol
33 was confirmed by NMR spectroscopy studies and is consis-
tent with reports made elsewhere.31
Me
HO
HO
O
O
O
O
Me
1. Diazald, KOH, 74%
2. i-PrMgBr, -78 °C
then TFAA, 0 °C, 89%
MeO
32
31
Br
1.
, n-BuLi, -78 °C
then MeOTf
2. hexane, Δ
45%
Me
Me
OTHP
n-BuLi,
O
O
O
H
Me
Me
OTHP
Me OMe
37
Me OH
NaH, THF 0 °C
then MeOTf
then MeOTf
29%
MeO
MeO
OMe
Me
MeO
Me
MeO
38
32
Me
90%
Me
OMe
34
toluene, Δ
OMe
33
Me OH
67% KBr, Oxone
Me
MeO
OTHP
1.n-BuLi
OMe
39
Me OMe
Br
Me OMe O
O
Me
MeO
Me
MeO
OMe
Me
Cl
OMe
2.
Scheme 9.
Me
OMe
35
OMe
36
1. n-BuLi, -78 °C
OMe
Me
OH OMe
OMe
OMe
O
Scheme 8.
Me
Me
MeO
Me
then
Cl
OMe
H2SO4
H2, Pd/C
2. MeMgBr
MeO
MeO
Prior to elaboration of the 2-H position of phenol 33, pro-
tection of the phenolic hydroxy group was carried out using
sodium hydride/methyl triflate in 90% yield. Our initial at-
tempts to introduce functionality into this position employing
lithiation chemistry were unsuccessful. ortho-Lithiation under
a range of conditions (n-BuLi, n-BuLi/TMEDA, s-BuLi/
TMEDA) at a variety of temperatures followed by quenching
with methyl chloroformate resulted only in recovered starting
material. We next turned our attention to a mild bromination
protocol developed by Kulkarni and co-workers.33 They re-
ported on the use of KBr/oxoneÒ as a facile method for the
bromination of a variety of aromatic compounds. In our hands
OMe
OMe
41
40
42
NBS,
MeCN
Me
Me
OMe
OMe
1. n-BuLi then DMF
Br
Me
Me
MeO
OH
2. NaBH4, MeOH
78%
MeO
OMe
OMe
43
44
Scheme 10.

4762
A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
Me
O
OH
lithiate coordination with the adjacent methoxy groups.
Quenching with methyl chloroformate followed by methyl
Grignard addition afforded tertiary alcohol 41, which was sub-
sequently dehydrated and hydrogenated in a one pot procedure
to give 42.34 This compound was then subjected to a regio-
Me
Me
1. SOCl2, MeOH
2. MeMgBr
Me
MeO
51
HO
MeO
H3PO4
H2, Pd/C
OMe 65%
MeO
89%
OMe
OMe
49
50
specific bromination by following a procedure described by
~
n-BuLi
then DMF
35
Carreno, which resulted in the formation of compound 43 in
82%
excellent yield. Next, lithiumehalogen exchange followed by
reaction with N,N0-dimethylformamide provided the expected
aldehyde, which was readily reduced with sodium borohydride
to furnish alcohol 44 in 78% over the final two steps.
At this point we anticipated that lithiation at the remaining
aromatic ring position would provide a nucleophilic site,
which could be subsequently treated with a suitable electro-
phile to supply ester 46 (see Scheme 11). Unfortunately, this
could not be borne out in practice as the steric congestion
around the local environment proved prohibitory.
Me
Me
1.
Me2N HNMe
n-BuLi
CO2Me
H
Me
MeO
Me
MeO
H
OMeO
52
O
OMeO
55
2.
MeO Cl
1. NaBH4
2.MOMCl,
iPr2NEt
85%
Me
Me
Br
Me
Me
MeO
NBS
24%
Me OMe
MeO
CH2OMOM
OMe
OMeOMOM
OH
1. NaH
2. n-BuLi
Me
Me OMe
Me OMe
Me
MeO
53
O-Na+
54
Me
MeO
MeO
OH
OMe
Scheme 13.
Li
CO2Me
OMe
44
OMe
45
46
respective NOE’s of the aromatic proton. A minor improve-
ment in the regiomeric ratio could be obtained by changing
the reaction conditions, but at the expense of a lower overall
reaction yield. The rather low yield of the desired bromide
led to the abandonment of this particular route. Further ap-
proaches toward the necessary aromatic framework are cur-
rently under investigation.
In conclusion, the Rh(II)-catalyzed intramolecular dipolar-
cycloaddition described herein allows for a facile access to the
icetexane core of komaroviquinone. Completion of the synthe-
sis of the natural product requires the preparation of a highly
substituted aromatic system, which has thus far proved elusive.
Efforts are currently underway to address this issue in order to
enable the completion of the synthesis.
Scheme 11.
Consequently, we turned our attention to still another ap-
proach designed to alleviate the steric crowding by preparing
a penta-substituted aromatic ring with the expectation that
the final substituent could be introduced by an oxidation reac-
tion to give the desired para-quinone (see Scheme 12).
Starting from 2,3-dimethoxybenzoic acid (49), methyl esteri-
fication followed by Grignard addition of methyl magnesium
bromide delivered alcohol 50 in 89% for the two step sequence
(Scheme 13). Once again, the dehydrationehydrogenation
protocol proceeded uneventfully to give isopropyl veratrole 51
in 65% yield. This compound was subsequently treated with
n-BuLi followed by reaction with N,N0-dimethylformamide to
give aldehyde 52 in 82% yield.36,37
3. Experimental
Further functionalization of the aromatic framework was
not possible using either Comins’38 lithiation chemistry or by
electrophilic substitution chemistry. Therefore, the aldehydic
carbonyl group was reduced with sodium borohydride and
protected as its MOM ether derivative 53. Lithiation of 53 re-
turned only starting material and so instead, 53 was exposed to
N-bromosuccinimide, which successfully delivered the bromo
compound 54, albeit as a mixture of regioisomers and with the
desired aryl bromide 54 being formed in only 24% yield. The
two regioisomeric bromides could be distinguished from the
3.1. General
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. All solids were recrystallized
from ethyl acetate/hexane for analytical data.
3.1.1. o-Methoxycarbonyl-a-diazoacetophenone (11)
To a 5.0 g (28 mmol) sample of phthalic acid monomethyl
ester was added 24 mL (0.28 mol) of thionyl chloride at rt.
The mixture was stirred at 25 ꢁC for 3 h and then the excess thi-
onyl chloride was removed under reduced pressure. The crude
residue dissolved in 200 mL of Et2O and an etheral solution of
diazomethane, prepared by the addition of 32 g (0.15 mol) of
diazald (N-methyl-N-nitroso-p-toluenesulfonamide) in 60 mL
Me
O
Me
CO2R2
CO2R1
CO2R2
CO2R1
Me
MeO
Me
MeO
OMe
O
47
48
Scheme 12.

A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
4763
of Et2O to 7.7 g (0.14 mol) of potassium hydroxide in 12 mL
3.1.4. 8-Methoxy-12-oxatricyclo[6.3.1.0.0,0]octahydro-
of water and 37 mL of ethanol, was added to the above
acid chloride solution at 0 ꢁC. After the addition was com-
plete, the reaction mixture was allowed to warm to room
temperature. Excess silica gel was added, the mixture was
stirred for 5 min, filtered, and the solvent was removed under
reduced pressure. The crude residue was purified by flash
silica gel column chromatography using a 40% EtOAc/
hexane mixture as the eluent to provide 5.1 g (99%) of
the titled compound as a yellow solid: mp 61e62 ꢁC (lit.39
mp 62e63 ꢁC); IR (neat) 3094, 2100, 1726, 1619, and
dibenzo-[a,d]-4,11-dione (16)
To a solution containing 0.13 g (0.43 mmol) of the above
diazo-dione in 5 mL of benzene was added 0.01 g
(0.02 mmol) of Rh2(OAc)4 at room temperature. The mixture
was heated for 30 min at 80 ꢁC, cooled to room temperature
and the solvent was removed under reduced pressure. The
crude residue was purified by flash silica gel column chroma-
tography using a 50% EtOAc/hexane mixture as the eluent to
provide 0.03 g (75%) of the titled compound as a pale yellow
solid: mp 165e166 ꢁC; IR (neat) 3025, 2910, 1726, 1693,
1352 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 3.88 (s, 3H),
1600, 1305, and 1281 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
5.58 (br s, 1H), 7.39 (dd, 1H, J¼7.2 and 2.0 Hz), 7.44e
7.52 (m, 2H), and 7.80 (br s, 1H); 13C NMR (100 MHz,
CDCl3) d 52.5, 56.1, 126.8, 129.8, 130.3, 130.8, 131.5,
139.6, 167.4, and 188.7.
d 1.39e1.52 (m, 1H), 1.92e2.12 (m, 4H), 2.32 (dd, 1H,
J¼12.4 and 5.6 Hz), 2.51e2.63 (m, 2H), 2.84e2.95 (m, 1H),
3.50 (s, 3H), 7.42e7.50 (m, 2H), 7.63 (td, 1H, J¼7.3 and
1.3 Hz), and 7.99 (dd, 1H, J¼8.3 and 1.3 Hz); 13C NMR
(100 MHz, CDCl3) d 21.7, 28.4, 37.2, 41.9, 42.0, 52.8, 90.1,
106.5, 123.5, 127.5, 128.9, 129.9, 134.5, 144.7, 193.0, and
205.8; Anal. Calcd for C16H16O4: C, 70.56; H, 5.93. Found:
C, 70.13; H, 5.74.
3.1.2. Methyl 2-(3-oxo-oct-7-enoyl)benzoate (12)
To a solution containing 0.09 g (0.88 mmol) of hex-5-enal
and 0.01 g of SnCl2 (0.1 mmol) in 1 mL of CH2Cl2 was added
0.15 g (0.74 mmol) of the above diazoketone 11 in 2 mL of
CH2Cl2. The mixture was stirred at room temperature for
1 h, diluted with CH2Cl2, and washed with water. The organic
phase was dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude residue was purified
by flash silica gel column chromatography using a 30%
EtOAc/hexane mixture as the eluent to provide 0.04 g
(41%) of the titled compound as a yellow oil, which exists
predominantly in the enol form: IR (neat) 1734, 1727, 1545,
3.1.5. 6a-Hex-5-enoyl-1a-methoxy-1a,6a-dihydro-1-oxa-
cyclo-propa[a]inden-6-one (15)
To a solution containing 0.1 g (0.33 mmol) of the above di-
azo-dione in 3 mL of benzene was added 0.01 g (0.02 mmol)
of Rh2(OAc)4 at room temperature. The mixture was stirred
at room temperature for 30 min, the solvent was removed un-
der reduced pressure and the crude residue was purified by
flash silica gel column chromatography to provide 0.054 g
(71%) of the titled compound as a pale yellow solid, mp
113e115 ꢁC; IR (neat) 1737, 1724, 1541, 1290, and
1396, 1292, and 1063 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d 1.81e1.90 (m, 2H), 2.15 (q, 2H, J¼6.7 Hz), 2.62 (q,
2H, J¼7.6 Hz), 3.87 (s, 3H), 5.00e5.08 (m, 2H), 5.70e5.82
(m, 1H), 6.28 (s, 1H), 7.57e7.66 (m, 3H), 7.82e7.86
(m, 1H), and 15.6 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 32.9, 37.2, 53.0, 100.2, 116.3, 129.0, 130.4,
131.4, 132.2, 132.8, 133.3, 136.9, 167.2, 186.4, and
196.8; HRMS Calcd for [(C16H18O4)þHþ]: 275.1278. Found:
275.1274.
1061 cmꢂ1 1H NMR (400 MHz, CDCl3) d 1.67e1.87 (m,
;
2H), 2.05e2.20 (m, 2H), 2.80e2.99 (m, 2H), 3.42 (s, 3H),
4.94e5.08 (m, 2H), 5.76e5.88 (m, 1H), 7.28 (td, 1H, J¼7.9
and 1.3 Hz), 7.41 (ddd, 2H, J¼15.9, 7.9 and 1.0 Hz), and
7.58 (td, 1H, J¼7.9 and 1.3 Hz); 13C NMR (100 MHz,
CDCl3) d 23.0, 33.0, 40.3, 51.9, 90.3, 99.5, 115.0, 125.6,
127.2, 129.5, 130.1, 134.7, 137.4, 138.3, 187.0, and 197.8;
Anal. Calcd for C16H16O4: C, 70.56; H, 5.93. Found: C,
69.96; H, 5.95.
In addition, 0.009 g (10%) of cycloadduct 16 was also iso-
lated from the chromatographic column. Heating a sample of
epoxide 15 in benzene at 100 ꢁC for 2 h afforded cycloadduct
16 in 78% yield.
3.1.3. Methyl 2-(2-diazo-3-oxo-oct-7-enoyl)benzoate (13)
To a solution containing 0.09 g (0.33 mmol) of the above
1,3-dione 12 in 3.0 mL of CH3CN were added 0.14 mL
(0.98 mmol) of Et3N and 0.07 g (0.39 mmol) of p-nitrobenz-
enesulfonyl azide40 at room temperature. The mixture was
stirred at rt for 1 h. The solvent was removed under reduced
pressure and the crude residue was purified by flash silica
gel column chromatography using a 10% EtOAc/hexane mix-
ture as the eluent to provide 0.1 g (98%) of the titled com-
pound as a pale yellow oil: IR (neat) 2120, 1721, 1656, and
3.1.6. 8-Hydroxy-12-oxa-tricyclo[6.3.1.0.0,0]octahydro-
dibenzo[a,d]-4,11-dione (17)
To a solution containing 0.1 g of cycloadduct 16 in a 1:2:1
mixture of THF/MeOH/H2O (2 mL) was added 0.5 mL of
concd HCl. The mixture was heated at reflux for 6 h, cooled
to rt and extracted with EtOAc. The combined organic layer
was dried over MgSO4, the solvent was removed under
reduced pressure, and the crude mixture was purified by flash
silica gel column chromatography using a 50% EtOAc/hexane
mixture as the eluent to provide 0.08 g (84%) of the titled
compound as a yellow solid: mp 156e158 ꢁC; IR (KBr)
1195 cmꢂ1 1H NMR (400 MHz, CDCl3) d 1.71e1.77 (m,
;
2H), 2.09 (q, 2H, J¼6.7 Hz), 2.83 (br s, 2H), 3.87 (s, 3H),
4.95 (d, 1H, J¼10.5 Hz), 5.00 (d, 1H, J¼17.1 Hz), 5.71e
5.81 (m, 1H), 7.34 (d, 1H, J¼7.6 Hz), 7.54 (td, 1H, J¼7.6
and 1.0 Hz), 7.62 (td, 1H, J¼7.6 and 1.0 Hz), and 8.03 (d,
1H, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3) d 23.1, 33.0,
40.2, 52.6, 85.8, 115.2, 126.3, 127.6, 130.1, 130.6, 132.9,
137.6, 140.5, 165.8, 186.4, and 191.8.
1
3425, 2939, 1721, 1692, and 1289 cmꢂ1; H NMR (400 MHz,

4764
A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
CDCl3) d 1.32 (qd, 1H, J¼12.7 and 4.8 Hz), 1.86e2.06 (m,
3H), 1.96 (dd, 1H, J¼12.0 and 6.7 Hz), 2.32 (dd, 1H, J¼
12.0 and 8.6 Hz), 2.38e2.47 (m, 1H), 2.53 (ddd, 1H,
J¼16.8, 9.5, and 6.0 Hz), 2.85 (ddd, 1H, J¼16.8, 11.1, and
4.8 Hz), 5.79 (s, 1H), 7.28 (td, 1H, J¼7.6 and 1.0 Hz), and
7.43e7.55 (m, 3H); 13C NMR (100 MHz, CDCl3) d 21.8,
28.1, 36.7, 41.9, 43.2, 90.6, 103.6, 123.1, 127.1, 127.5,
128.4, 134.8, 146.7, 192.6, and 207.2; Anal. Calcd for
C15H14O4: C, 69.74; H, 5.47. Found: C, 69.70; H, 5.34.
Et2O, the solvent was dried and then removed under reduced
pressure and the crude alcohol was taken up in 15 mL of
CH2Cl2. This solution was added to a stirred solution of
1.1 g (4.5 mmol) of pyridinium chlorochromate in 10 mL
of CH2Cl2 at room temperature. The mixture was stirred over-
night, filtered, and the solvent was removed under reduced
pressure. The crude residue was purified by flash silica gel col-
umn chromatography using a 10% EtOAc/hexane mixture as
the eluent to provide 0.59 g (70%) of the titled compound as
a clear oil:15,42 IR (neat) 2960, 2925, 1726, 1701, 1470, and
3.1.7. Ethyl 5-hydroxy-2,2-dimethylpentanoate (19)
1255 cmꢂ1 1H NMR (400 MHz, CDCl3) d 0.04 (s, 6H),
;
To a stirred solution of 24 mL (12.0 mmol) of 9-BBN
(0.5 M in THF) was added a solution of 2.0 g (12.0 mmol)
of 2,2-dimethyl-pent-4-enoic acid ethyl ester41 in 6 mL of
THF at rt. After stirring for 2 h, the reaction was cooled to
0 ꢁC and 8 mL of ethanol, 2.4 mL of 6 M aqueous NaOH
solution, and 4.8 mL of 30% aqueous H2O2 were added con-
secutively. The mixture was heated at 50 ꢁC for 1 h, cooled
to room temperature and extracted with EtOAc. The combined
organic layer was dried over MgSO4 and the solvent was re-
moved under reduced pressure. The crude residue was purified
by flash silica gel column chromatography using a 8% EtOAc/
hexane mixture as the eluent to provide 1.2 g (55%) of the ti-
tled compound as a clear oil:15,42 IR (neat) 3437, 2971, and
0.85 (s, 9H), 1.15 (s, 6H), 1.35e1.50 (m, 4H), 3.60 (t, 2H,
J¼6.0 Hz), and 9.40 (s, 1H); 13C NMR (100 MHz, CDCl3)
d ꢂ5.4, 18.3, 21.2, 25.9, 27.6, 33.3, 45.4, 63.1, and 206.2.
3.1.10. tert-Butyl-4,4-dimethylhex-5-enyloxyldimethylsilane
(22)
To a stirred solution of 0.48 g (1.2 mmol) of methyltriphe-
nylphosphonium iodide in 5 mL of THF at 0 ꢁC was slowly
added 0.6 mL (1.2 mmol) of n-BuLi (2.1 M in THF). After
stirring for 30 min, the solution was warmed to rt and was
stirred for an additional 1 h. The mixture was then cooled to
0 ꢁC and a solution of 0.29 g (1.1 mmol) of the above alde-
hyde 21 in 2 mL of THF was added dropwise and the mixture
was allowed to warm to rt and was stirred overnight. The re-
action mixture was quenched with H2O and extracted with
Et2O. The combined organic layer was dried over MgSO4
and the solvent was removed under reduced pressure. The
crude residue was purified by flash silica gel column chroma-
tography using a 6% EtOAc/hexane mixture as the eluent to
provide 0.23 g (80%) of the titled compound as a clear
oil:15,42 IR (neat) 3083, 2960, 2930, 2852, 1634, and
1634 cmꢂ1 1H NMR (400 MHz, CDCl3) d 1.15 (s, 6H),
;
1.22 (t, 3H, J¼7.2 Hz), 1.50e1.65 (m, 4H), 3.60 (br t, 2H,
J¼6.0 Hz), and 4.15 (q, 2H, J¼7.2 Hz); 13C NMR
(100 MHz, CDCl3) d 13.9, 24.8, 27.9, 36.4, 41.6, 60.1, 62.4,
and 177.9.
3.1.8. Ethyl 5-(tert-butyldimethylsilyloxy)-2,2-dimethyl-
pentanoate (20)
To a solution containing 0.75 g (4.0 mmol) of the above
alcohol 19 in 2 mL of DMF was added 0.77 g (10.7 mmol)
of imidazole and a crystal of 4-dimethylaminopyridine. The
mixture was cooled to 0 ꢁC for 15 min and then 0.77 g
(5.0 mmol) of tert-butyl-dimethylsilyl chloride was added in
one portion. The reaction was stirred for 2 h, quenched with
H2O and extracted with Et2O. The combined organic layer
was dried over MgSO4 and the crude residue was purified
by flash silica gel column chromatography using a 10%
EtOAc/hexane mixture as the eluent to provide 1.0 g (95%)
of the titled compound as a clear oil:15,42 IR (neat) 2650,
1096 cmꢂ1 1H NMR (400 MHz, CDCl3) d 0.04 (s, 6H),
;
0.08 (s, 9H), 0.99 (s, 6H), 1.23e1.29 (m, 2H), 1.40e1.48
(m, 2H), 3.47 (t, 2H, J¼6.8 Hz), 4.88 (dd, 1H, J¼4.8 and
1.2 Hz), 4.92 (q, 1H, J¼1.2 Hz), and 5.76 (dd, 1H, J¼17.6
and 10.4 Hz); 13C NMR (100 MHz, CDCl3) d ꢂ5.3, 18.3,
26.0, 26.7, 28.1, 36.1, 38.6, 63.9, 110.3, and 148.4.
3.1.11. 4,4-Dimethylhex-5-enal (23)
To a solution containing 0.45 g (1.9 mmol) of the above
alkene 22 in 8 mL of THF was added 2.3 mL (2.3 mmol) of
tetra-butyl ammonium fluoride (1.0 M in THF) at 0 ꢁC. The
reaction mixture was stirred for 2 h after which a 1:1-mixture
of H2O and Et2O was added to the solution. The aqueous layer
was extracted with Et2O and the combined organic layer was
dried over MgSO4. The solvent was removed under reduced
pressure and the crude alcohol was redissolved in 3 mL of
CH2Cl2. The mixture was added to a stirred solution of 0.6 g
(2.7 mmol) of pyridinium chlorochromate in 2 mL of CH2Cl2
at room temperature. The solution was stirred overnight, fil-
tered, and the solvent was removed under reduced pressure.
The crude residue was purified by flash silica gel column chro-
matography using a 6% EtOAc/hexane mixture as the eluent to
provide 0.19 g (80%) of the titled compound15,42 as a clear oil:
2925, 2889, 2848, and 1726 cmꢂ1 1H NMR (400 MHz,
;
CDCl3) d 0.05 (s, 6H), 0.84 (s, 9H), 1.12 (s, 6H), 1.20 (t,
3H, J¼7.4 Hz), 1.40e1.47 (m, 2H), 1.49e1.54 (m, 2H),
3.54 (t, 2H, J¼6.2 Hz), and 4.08 (q, 2H, J¼7.4 Hz); 13C
NMR (100 MHz, CDCl3) d ꢂ5.3, 14.2, 18.3, 25.1, 25.9,
28.4, 36.8, 41.8, 60.2, 63.4, and 177.9.
3.1.9. 5-(tert-Butyldimethylsilyloxy)-2,2-dimethylpentanal
(21)
To a suspension of 0.13 g (3.0 mmol) of lithium aluminum
hydride in 25 mL of Et2O at 0 ꢁC was added 0.99 g (3.0 mmol)
of the above ester 20 in 10 mL of Et2O. After stirring for
30 min at 0 ꢁC, the reaction was quenched by the slow addi-
tion of 30 mL of H2O. The aqueous layer was extracted with
IR (neat) 3084, 2955, 2852, 2807, 2709, 1726, and 1639 cmꢂ1
1H NMR (400 MHz, CDCl3) d 0.96 (s, 6H), 1.60 (t, 2H,
;

A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
4765
J¼8.0 Hz), 2.34 (td, 2H, J¼8.0 and 1.6 Hz), 4.91 (dd, 1H,
J¼17.2 and 1.2 Hz), 4.95 (dd, 1H, J¼10.8 and 1.2 Hz), 5.68
(dd, 1H, J¼17.2 and 10.8 Hz), and 9.74 (t, 1H, J¼1.6 Hz);
13C NMR (100 MHz, CDCl3) d 26.5, 33.9, 36.0, 39.8, 111.6,
147.0, and 202.8.
IR (neat) 2955, 1721, 1690, and 1270 cmꢂ1
;
1H NMR
(400 MHz, CDCl3) d 0.93 (s, 3H), 0.95 (s, 3H), 1.81 (ddd,
1H, J¼14.0, 9.2, and 1.6 Hz), 1.93 (dt, 1H, J¼14.0 and
9.6 Hz), 2.03e2.22 (m, 2H), 2.40 (t, 1H, J¼8.8 Hz), 2.65
(dt, 1H, J¼18.8 and 9.6 Hz), 2.81 (ddd, 1H, J¼19.2, 9.6,
and 1.6 Hz), 3.49 (s, 3H), 7.48 (d, 2H, J¼7.6 Hz), 7.63 (td,
1H, J¼7.6 and 1.2 Hz), and 7.98 (dd, 1H, J¼8.4 and
1.2 Hz); 13C NMR (100 MHz, CDCl3) d 20.3, 29.8, 32.9,
35.7, 36.1, 36.5, 51.5, 52.7, 88.7, 106.5, 123.6, 127.5, 128.9,
129.6, 134.4, 144.6, 193.1, and 206.7; HRMS (FAB) Calcd
for [(C18H20O4)þLiþ]: 300.1361. Found: 300.1373.
3.1.12. Methyl 2-(6,6-dimethyl-3-oxo-oct-7-enyl)benzoate
(24)
To a solution containing 0.34 g (1.6 mmol) of diazoketone
11 and 0.03 g (0.16 mmol) of anhydrous SnCl2 in 4 mL of
CH2Cl2 was added a solution of 0.25 g (1.9 mmol) of the
above aldehyde 23 in 4 mL of CH2Cl2 and the mixture was
stirred at rt for 18 h. The solution was quenched with H2O
and extracted with Et2O. The combined organic layer was
dried over MgSO4 and the crude residue was purified by flash
silica gel column chromatography using a 20% EtOAc/hexane
mixture as the eluent to provide 1.0 g (20%) of the titled com-
pound as a clear oil,15 which exists primarily in the enol form:
3.1.15. 2-Isopropyl-1,3,4-trimethoxy-5-methyl-benzene (34)
To a solution of 1.2 g (5.7 mmol) sample of the penta-
substituted arene 3331 in 30 mL of THF at ꢂ78 ꢁC was added
1.52 g (23 mmol) of NaH (60% in mineral oil) in one portion.
The mixture was warmed to 0 ꢁC and stirred for 30 min. At the
end of this time, the solution was cooled to ꢂ78 ꢁC, and
0.97 mL (8.6 mmol) of MeOTf was added dropwise. The solu-
tion was warmed to rt, stirred for an additional 2 h, and then
quenched with H2O and extracted with Et2O. The combined
organic layer was dried over Na2SO4 and the crude residue
was purified by flash silica gel column chromatography using
a 10% EtOAc/hexane mixture as the eluent to provide 1.15 g
(90%) of the titled compound as a pale yellow solid: mp
26e27 ꢁC; IR (neat) 1582, 1455, 1403, 1231, 1135, 1073,
1
IR (neat) 3500, 1721, 1701, 1588, and 1265 cmꢂ1; H NMR
(400 MHz, CDCl3) d 1.02 (s, 6H), 1.62e1.70 (m, 2H),
2.28e2.35 (m, 2H), 3.83 (s, 3H), 4.90e5.00 (m, 2H), 5.75
(dd, 1H, J¼17.6 and 10.8 Hz), 5.84 (s, 1H), 7.47e7.53 (m,
3H), and 7.72e7.77 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 26.5, 34.0, 36.4, 38.0, 52.5, 99.0, 111.5, 127.9, 129.5,
130.5, 131.0, 131.1, 137.5, 147.1, 168.4, 188.4, and 194.4;
HRMS Calcd for [(C18H22O4)þHþ]: 303.1591. Found:
303.1591.
1
and 840 cmꢂ1; H NMR (400 MHz, CDCl3) d 1.29 (d, 6H,
J¼7.2 Hz), 2.24 (s, 3H), 3.47 (sept, 1H, J¼7.2 Hz), 3.76 (s,
3H), 3.77 (s, 3H), 3.82 (s, 3H), 6.20 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 15.9, 21.3, 25.0, 55.6, 60.1, 60.9,
108.5, 127.9, 128.9, 145.5, 151.6, and 154.2; HRMS Calcd
for [(C13H20O3)þHþ]: 225.1491. Found: 225.1487.
3.1.13. Methyl 2-(2-diazo-6,6-dimethyl-3-oxooct-7-enyl)-
benzoate (25)
To a solution containing 1.0 g (0.32 mmol) of the above
diketo-ester 24 and 0.11 g (0.44 mmol) of p-nitrobenzene-
sulfonyl azide40 in 3 mL of CH3CN at 0 ꢁC was added
0.09 g (0.65 mmol) of Et3N. The reaction mixture was stirred
for 3 h, the solvent was removed under reduced pressure and
the crude residue was purified by flash silica gel column chro-
matography using a 50% EtOAc/hexane mixture as the eluent
to provide 0.4 g (38%) of the titled compound as a clear oil: IR
3.1.16. 1-Bromo-3-isopropyl-2,4,5-trimethoxy-6-methyl-
benzene (35)
To a solution of 0.09 g (0.4 mmol) of the above penta-
substituted arene 34 in 4 mL of THF at rt was added 0.05 g
(0.44 mmol) of KBr followed by 0.27 g (0.44 mmol) of ox-
oneÒ. The reaction mixture was allowed to stir at rt for 1 h.
The mixture was then passed through a filter funnel and the
filtrate was concentrated under reduced pressure. The crude
residue was purified by flash silica gel column chromato-
graphy using a 10% EtOAc/hexane mixture as the eluent to
provide 0.08 g (67%) of the titled compound as a yellow oil:
(neat) 3078, 2955, 2120, 1716, 1650, and 1280 cmꢂ1 1H
;
NMR (400 MHz, CDCl3) d 0.95 (s, 6H), 1.55e1.65 (m, 2H),
2.65 (br s, 2H), 3.85 (s, 3H), 4.87 (dd, 1H, J¼17.2 and
1.2 Hz), 5.69 (dd, 1H, J¼17.2 and 10.8 Hz), 7.33 (dd, 1H,
J¼7.6 and 0.8 Hz), 7.53 (td, 1H, 8.0 and 0.8 Hz), 7.62 (td,
1H, J¼8.0 and 1.6 Hz), and 8.03 (dd, 1H, J¼7.6 and
0.8 Hz); 13C NMR (100 MHz, CDCl3) d 26.5, 36.0, 36.2,
36.9, 52.6, 86.1, 111.3, 126.4, 127.7, 130.1, 130.6, 133.0,
140.7, 147.2, 165.8, 186.5, and 192.2.
IR (neat) 2935, 1454, 1398, 1231, 1120, and 1030 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 1.32 (d, 6H, J¼7.2 Hz), 2.30
(s, 3H), 3.43 (sept, 1H, J¼7.2 Hz), 3.72 (s, 3H), 3.73 (s,
3H), and 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) d 16.3,
22.1, 26.7, 60.1, 60.5, 61.4, 114.7, 130.5, 133.6, 148.5,
151.0, and 151.9.
3.1.14. 1,1-Dimethyl-8-methoxy-12-oxa-tricyclo-
[6.3.1.0.0,0]-octahydrodibenzo[a,d]-4,11-dione (26)
To a solution containing 0.04 g (0.12 mmol) of diazo-dione
25 in 1 mL of benzene was added 0.004 g (0.01 mmol) of
Rh2(OAc)4. The mixture was heated at 80 ꢁC for 18 h, filtered,
and the solvent was removed under reduced pressure. The
crude residue was purified by flash silica gel column chroma-
tography using a 6% EtOAc/hexane mixture as the eluent to
provide 0.012 g (92%) of the titled compound as a clear oil:
3.1.17. 2-Isopropyl-3,4-dimethoxy-4-[3-(tetrahydro-pyran-
2-yloxy)-prop-1-ynyl]-cyclobut-2-enone (38)
To a solution of 0.25 mL (1.8 mmol) of 2-[(propyl-2-yn-
1yl)oxy]-tetrahydropyran in 3 mL of THF at ꢂ78 ꢁC was
added 0.84 mL (2.1 mmol) of n-BuLi (2.5 M in hexane) drop-
wise. The solution was stirred for 1 h at ꢂ78 ꢁC and

4766
A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
transferred to a ꢂ78 ꢁC solution of 0.25 g (1.6 mmol) of 3-iso-
propyl-4-methoxy-cyclobut-3-ene-1,2-dione (31)31 in 3 mL of
THF via cannula, followed by the addition of 0.24 mL
(2.1 mmol) of MeOTf. The solution was warmed to 0 ꢁC
and was stirred for additional 30 min. After quenching with
aqueous NH4Cl, the solution was extracted with Et2O. The
combined organic layer was dried over Na2SO4 and the sol-
vent was removed under reduced pressure. The crude residue
was purified by silica gel flash chromatography using a 10%
EtOAc/hexane mixture as the eluent to provide 0.14 g (29%)
of the titled compound as an orange oil: 1H NMR
(400 MHz, CDCl3) d 1.07 (d, 6H, J¼7.2 Hz), 1.40e1.80 (m,
6H), 2.43 (sept, 1H, J¼7.2 Hz), 3.50 (s, 3H), 3.45e3.50 (m,
1H), 3.72e3.79 (m, 1H), 4.05 (s, 3H), 4.30 (dd, 2H, J¼3.0
and 1.2 Hz), and 4.72 (t, 1H, J¼2.0 Hz); 13C NMR
(100 MHz, CDCl3) d 18.8, 19.9, 23.9, 25.2, 30.0, 54.1, 54.2,
59.4, 61.8, 78.3, 87.6, 96.8, 135.6, 177.4, and 184.3.
of chlorotrimethylsilane at 0 ꢁC and the mixture was stirred for
12 h at room temperature. The solvent was removed under
reduced pressure to afford 9.3 g (95%) of the titled ester as
a white solid; mp 47e48 ꢁC (Et2O) [lit. 47 ꢁC];43 1H NMR
(400 MHz, CDCl3) d 3.88 (s, 3H), 3.91 (s, 6H), 7.05e7.11
(m, 2H), and 7.31e7.33 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 52.4, 56.3, 61.7, 116.0, 122.4, 124.0, 126.3, 149.3,
153.4, and 167.0.
To a solution of 9.3 g (47.5 mmol) of the above ester in
100 mL of THF at 0 ꢁC was slowly added 50 mL (3.0 M) of
methyl magnesium bromide. The solution was heated at reflux
for 6 h. After cooling to 0 ꢁC, the reaction mixture was
quenched by the cautious addition of 50 mL of 1 M HCl and
was then extracted with ether. The organic phase was washed
successively with water and brine, dried, filtered, and concen-
trated under reduced pressure. The residue was purified by
flash silica gel chromatography using a 20% EtOAc/hexane
mixture as the eluent to provide 8.75 g (94%) of the titled
compound36 as a clear oil: 1H NMR (400 MHz, CDCl3)
d 1.61 (s, 6H), 3.88 (s, 3H), 4.00 (s, 3H), 4.30 (s, 1H), 6.86
(dd, 1H, J¼8.0 and 2.0 Hz), 6.94 (dd, 1H, J¼8.0 and
2.0 Hz), and 7.02 (t, 1H, J¼8.0 Hz); 13C NMR (100 MHz,
CDCl3) d 31.0, 56.0, 61.2, 73.0, 111.8, 118.2, 123.9, 141.4,
147.0, and 152.9.
3.1.18. (3-Isopropyl-2,4,5-trimethoxy-phenyl)-methanol (44)
To a solution of 4.0 g (13.8 mmol) of 1-bromo-3-isopropyl-
2,4,5-trimethoxybenzene (43)34,35 in 55 mL of THF at ꢂ78 ꢁC
was added 6.1 mL (15.2 mmol) of n-BuLi (2.5 M in hexane)
dropwise. The solution was stirred for 1 h, then 1.3 mL
(17.3 mmol) of DMF was slowly added to the reaction flask.
After stirring the mixture at ꢂ78 ꢁC for 2 h, aqueous NH4Cl
was added. The mixture was extracted with EtOAc, dried
over Na2SO4, and the solvent was removed under reduced
pressure. The residue was then purified by flash silica gel chro-
matography using a 20% EtOAc/hexane mixture as the eluent
to provide 2.9 g (87%) of 3-isopropyl-2,4,5-trimethoxybenzal-
dehyde as a white solid: mp 45e47 ꢁC; IR (neat) 2955, 2842,
3.1.20. 1-Isopropyl-2,3-dimethoxy-4-((methoxy-methoxy)
methyl)benzene (53)
To a solution of 2.2 g (10.1 mmol) of (4-isopropyl-2,3-di-
methoxyphenyl)methanol5c in 50 mL of CH2Cl2 was added
5.3 mL (30 mmol) of Hunig’s base. To this mixture was slowly
¨
added 1.5 mL (20 mmol) of chloromethyl methyl ether at 0 ꢁC
and the reaction mixture was allowed to warm to room temper-
ature and was stirred for 15 h. The reaction was then quenched
by the addition of a saturated NH4Cl solution and was ex-
tracted with CH2Cl2. The organic phase was washed with
brine, dried over Na2SO4, filtered, and concentrated under re-
duced pressure to afford a pale yellow residue. Purification by
flash silca gel column chromatography using a 90% EtOAc/
hexane mixture as the eluent afforded 1.3 g (90%) of the titled
1685, 1583, and 1083 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d 1.33 (d, 6H, J¼7.1 Hz), 3.43 (sept, 1H, J¼7.1 Hz), 3.81
(s, 3H), 3.85 (s, 3H), 3.91 (s, 3H), 7.22 (s, 1H), and 10.24
(s, 1H); 13C NMR (100 MHz, CDCl3) d 21.6, 25.4, 55.8,
60.8, 65.4, 107.7, 124.4, 135.4, 150.0, 154.8, 156.8, and 189.1.
To a solution of 2.6 g (10.9 mmol) of the above aldehyde in
MeOH at 0 ꢁC was added 0.5 g (13 mmol) of NaBH4 in por-
tions. The mixture was stirred for 1 h at 0 ꢁC and then water
was added. The MeOH was removed under reduced pressure
and the residue was extracted with EtOAc. The combined
organic layer was dried over Na2SO4 and the solvent was re-
moved under reduced pressure. The crude residue was purified
by flash silica gel chromatography using a 25% EtOAc/hexane
mixture as the eluent to provide 2.4 g (90%) of the titled com-
pound as a yellow oil: IR (neat) 3416, 2955, 1598, 1480, 1224,
1107, and 1040 cmꢂ1; 1H NMR (400 MHz, CDCl3) d 1.35 (d,
6H, J¼7.1 Hz), 2.13 (t, 1H, J¼5.7 Hz), 3.40 (sept, 1H, J¼
7.1 Hz), 3.71 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.68 (d, 2H,
J¼5.7 Hz), and 6.79 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 21.8, 25.8, 55.7, 60.6, 61.0, 62.3, 110.0, 128.7, 135.0,
148.2, 149.3, and 149.6; HRMS Calcd for [(C13H20O4)þHþ]:
241.1440. Found: 241.1438.
1
compound as a clear liquid: IR (thin film) 2961 cmꢂ1; H
NMR (400 MHz, CDCl3) d 1.22 (d, 6H, J¼7.0 Hz), 3.33
(sept, 1H, J¼7.0 Hz), 3.44 (s, 3H), 3.86 (s, 3H), 3.89 (s,
3H), 4.60 (s, 2H), 4.74 (s, 2H), 6.98 (d, 1H, J¼8.0 Hz), and
7.09 (d, 1H, J¼8.0 Hz); 13C NMR (100 MHz) 23.7, 27.0,
55.5, 60.9, 61.0, 64.5, 96.0, 121.5, 125.0, 129.4, 143.2,
150.5, and 151.5; HRMS Calcd for [(C14H22O4)þHþ]:
255.1596. Found: 255.1598.
3.1.21. 1-Bromo-5-isopropyl-3,4-dimethoxy-2-((methoxy-
methoxy)methyl)benzene (54)
To a stirred solution of 0.5 g (2.0 mmol) of 1-isopropyl-2,3-
dimethoxy-4-((methoxy-methoxy)methyl)benzene (53) in 5 mL
of DMF was added 0.35 g (2.0 mmol) of N-bromosuccinimide
at room temperature. After stirring for 12 h at rt, the reaction
mixture was quenched by the addition of NaHCO3 and was
extracted with Et2O. The combined organic layer was washed
with brine, dried over Na2SO4, filtered and concentrated under
3.1.19. 2-(2,3-Dimethoxyphenyl)propan-2-ol (50)
To a solution of 9.1 g (50 mmol) of 2,3-dimethoxybenzoic
acid in 100 mL methanol was slowly added 6.3 mL (50 mmol)

A. Padwa et al. / Tetrahedron 64 (2008) 4758e4767
4767
13. (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263; (b) Padwa, A.;
Weingarten, M. D. Chem. Rev. 1996, 96, 223; (c) Padwa, A. Top. Curr.
Chem. 1997, 189, 121.
reduced pressure. The crude product was purified by flash
silica gel column chromatography using a 66% CH2Cl2/
hexane mixture as the eluent to afford 0.16 g (24%) of the
14. (a) Padwa, A.; Sandanayaka, V. P.; Curtis, E. A. J. Am. Chem. Soc. 1994,
116, 2667; (b) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem.
1996, 61, 73.
1
titled compound as a clear oil: IR (thin film) 2962 cmꢂ1; H
NMR (600 MHz, CDCl3) d 1.29 (d, 6H, J¼6.7 Hz), 3.28
(sept, 1H, J¼6.7 Hz), 3.47 (s, 3H), 3.83 (s, 3H), 3.89 (s,
3H), 4.70 (s, 2H), 4.77 (s, 2H), and 7.21 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 23.4, 27.1, 55.7, 60.8, 61.5, 64.3, 96.6,
120.0, 126.0, 129.1, 145.0, 150.2, and 153.4.
15. Padwa, A.; Boonsombat, J.; Rashatasakhon, P.; Willis, J. Org. Lett. 2005,
7, 3725.
16. Milan, M.; Viktor, M.; Rudolf, K.; Dusan, I. Curr. Org. Chem. 2004, 8,
695.
17. (a) Dhavale, D. D.; Patil, P. N.; Mali, R. S. J. Chem. Res., Synop. 1994,
152; (b) Balaji, B. S.; Chanda, B. M. Tetrahedron 1998, 54, 13237; (c)
Bandgar, B. P.; Pandit, S. S.; Sadavarte, V. S. Green Chem. 2001, 3,
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Chem. 2004, 69, 7599; (e) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah,
B.; Reddy, P. N. Tetrahedron 2005, 61, 875.
Acknowledgements
We greatly appreciate the financial support provided by
the National Science Foundation (CHE-0450779). We thank
Dr. Jerremey Willis for some experimental assistance.
18. Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
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~
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