Synthetic studies on the icetexones: Enantioselective formal syntheses of icetexone and epi-icetexone

Article abstract of DOI:10.1016/j.tet.2013.04.049

Two strategies for the synthesis of the icetexane diterpenoids icetexone and epi-icetexone that rely on Ga(III)-catalyzed cycloisomerization of alkynyl indene substrates to yield fused [6-7-6] tricycles have been explored. In the first approach, access to a tricycle bearing a gem-dimethyl group paved the way for explorations of C-H functionalization of one of the methyl groups in close proximity to a hydroxyl-directing group. This approach was ultimately unsuccessful and led only to ring cleaved products. In the second approach, an alkynyl indene substrate bearing a cyano substituent was utilized, which was effective in providing a functional handle to access the icetexone subclass of diterpenoids. A key epoxide opening/diazene rearrangement sequence was utilized to complete a formal synthesis of icetexone and epi-icetexone, which is discussed in detail. Furthermore, the cyano-containing substrate has been prepared in enantioenriched form using a Rh-catalyzed conjugate addition reaction, which now provides a route to the enantioselective synthesis of these natural products.

Full text of DOI:10.1016/j.tet.2013.04.049

Tetrahedron 69 (2013) 5665e5676
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Tetrahedron
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Synthetic studies on the icetexones: enantioselective formal
syntheses of icetexone and epi-icetexone
Felipe de Jesus Cortez, David Lapointe, Amy M. Hamlin, Eric M. Simmons,
*
Richmond Sarpong
Department of Chemistry, University of California, Berkeley, CA 94720, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two strategies for the synthesis of the icetexane diterpenoids icetexone and epi-icetexone that rely on
Ga(III)-catalyzed cycloisomerization of alkynyl indene substrates to yield fused [6-7-6] tricycles have
been explored. In the first approach, access to a tricycle bearing a gem-dimethyl group paved the way for
explorations of CeH functionalization of one of the methyl groups in close proximity to a hydroxyl-
directing group. This approach was ultimately unsuccessful and led only to ring cleaved products. In
the second approach, an alkynyl indene substrate bearing a cyano substituent was utilized, which was
effective in providing a functional handle to access the icetexone subclass of diterpenoids. A key epoxide
opening/diazene rearrangement sequence was utilized to complete a formal synthesis of icetexone and
epi-icetexone, which is discussed in detail. Furthermore, the cyano-containing substrate has been pre-
pared in enantioenriched form using a Rh-catalyzed conjugate addition reaction, which now provides
a route to the enantioselective synthesis of these natural products.
Received 23 February 2013
Received in revised form 8 April 2013
Accepted 11 April 2013
Available online 19 April 2013
Keywords:
Icetexanes
Total synthesis
Ga(III) cycloisomerization
Cycloheptadienes
Diterpenes
Enantioselective conjugate addition
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
9(10➔20)-abeo-abietane. Congeners vary by the level of oxidation
in each ring and the degree of oxygenation of the arene portion. In
The icetexane family of diterpenoids is a diverse group of natural
products that exhibit a unique structural skeleton and a wide range
of biological activity (see Fig.1). Members of this diterpenoid family
possess a [6-7-6] tricyclic motif, which has the systematic name
a recent review, a classification scheme was proposed that divided
this family into five groups on the basis of the oxygenation at the C3,
C11, C12, and C14 positions (see Fig. 1 for numbering).1 Of these
groups, the icetexones are the most complex, exhibiting oxygena-
tion at the C11, C12, and C14 positions, as well as possessing a lac-
tone or ether linkage between C19 and either the C10 or C6 position.
Members of the highly oxygenated icetexone subclass have been
isolated from different plants of the Salvia genus. Icetexone (1) was
the first compound in this family to be isolated and characterized
from the aerial parts of Salvia ballotaeflora Benth in 1976 along with
the ortho-quinone tautomer, romulogarzone (3).2 X-ray crystallo-
graphic analysis enabled a determination of the absolute configu-
ration of 1, the name of which has been used to represent this family
of natural products.3 Other members of the icetexone subclass,
such as 7,20-dihydroanastomosine (4), 19-deoxyisoicetexone (5),
and 19-deoxyicetexone (6) have subsequently been isolated from
the same source.4
In 2000, Nieto et al. reported the isolation of epi-icetexone (2)
from the aerial parts of Salvia gillessi Benth and later, Sanchez et al.
reported activity of this compound against Trypanosoma cruzi (IC50
Fig. 1. Selected icetexone natural products.
of 6.5ꢀ0.75
m
M).5 The trypanocidal activity of these diterpenoids
has been postulated to arise from a redox cycling process of the
quinone moiety, a structural motif that is shared with other try-
panocidal agents.6 Of note, in the account pertaining to the
* Corresponding author. Tel.: þ1 510 643 6312; fax: þ1 510 642 9675; e-mail
address: rsarpong@berkeley.edu (R. Sarpong).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.049

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F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
biological activity of 2, Sanchez et al. reported the spectral data for
isolated epi-icetexone, which matches the data for synthetic ice-
texone (and not synthetic epi-icetexone) reported by Majetich.7 As
such, the Nieto et al. report on the isolation of these compounds
may have switched the assignment of the two structures and
therefore the reported biological activity for epi-icetexone may in
fact be that of icetexone.
The biological activity and interesting structures of the ice-
texone subclass have garnered interest from the synthetic com-
munity. Majetich and Grove completed the first enantioselective
syntheses of icetexone, epi-icetexone, and 19-deoxyicetexone in
2009 using a ‘cyclialkylation’ strategy to form the [6-7-6] tricyclic
core.7 As noted above, the Majetich synthesis led to reassignment of
the spectral data reported in the literature for both icetexone and
epi-icetexone. In 2010, we reported formal syntheses of racemic
icetexone and epi-icetexone.8 In this full account, we present the
details of our studies that led to formal syntheses of icetexone and
epi-icetexone as well as the development of a route that accom-
plishes the formal enantioselective syntheses of these natural
products.
Our foray into the synthesis of the icetexone family began with
the development of a Ga(III)-catalyzed cycloisomerization reaction
of alkynyl indenes (e.g., 9, Scheme 1B) to form benzannulated
cycloheptadienes (e.g., 10). This transformation was inspired by
a report from Chatani and Murai on the Ga(III)-catalyzed skeletal
reorganization of enyne substrates that appeared in 2002 (Scheme
1A).9 By using an appropriate tether for our substrates, a [6-7-6]
tricyclic motif could be synthesized selectively and efficiently.
Other transition metal salts and complexes commonly utilized for
the cycloisomerization of enynes (e.g., PtCl2, PtCl4, [Ru(CO)3Cl]2,
[Rh(CO)2Cl]2)10 led to the competing formation of a [7-5-6] tricyclic
isomer (e.g., 11). These isomeric byproducts, as well as the starting
material, are difficult to separate from the desired products and so
it was important that the cycloisomerization reaction was highly
selective and proceeded to completion. This demanding criteria
was met by the Ga(III) salts that we employed as catalysts. Our
initial reports in this area demonstrated that various arene sub-
stitution patterns and a gem-dimethyl group on the alkyl tether
were well tolerated. The selectivity observed in the formation of the
benzannulated cycloheptadiene products utilizing substrates with
varying substitution on the benzenoid portion of the indene sub-
strate demonstrated that transposition of the indene double bond
(which would ultimately lead to isomeric products) was not a sig-
nificant competing process. This methodology was subsequently
applied to the total synthesis of several members of the icetexane
diterpenoid family.11
Scheme 2. Retrosynthetic analysis of icetexone (1).
2. Results and discussion
2.1. A first approach to icetexone and epi-icetexone
Retrosynthetically (Scheme 2), icetexone (1) could arise from
lactone 12 by a concluding oxidation of the hydroquinone moiety to
the corresponding quinone as well as cleavage of the lactone ring in
12 and a translactonization. Lactone 12 would be formed from
oxime 13 or the corresponding aldehyde, which could be oxidized
to the carboxylic acid. Specifically, lactone 12 would arise from the
acid derived from oxime 13 using a Mitsunobu displacement to
forge the lactone. The oxime (13) was envisioned to be accessible
from alcohol 14 using a Barton nitrite ester reaction.12a This clas-
sical and powerful CeH functionalization method has been used
previously for the functionalization of a range of remote CeH bonds
in complex molecule synthesis.12b The hydroxy group of alcohol 14
could be installed through an epoxidation of the tetrasubstituted
double bond of diene 15, isomerization to the corresponding
dihydrofuran, and hydroboration of the resulting alkene from the b-
face. Cycloheptadiene 15 could be obtained from 16 using the
Ga(III)-catalyzed cycloisomerization method.
To arrive at alkynyl indene 16, indanone 21 (Scheme 3) was first
prepared. This commenced with known alcohol 17,8,13 which was
converted to aldehyde 18 using ParikheDoering oxidation condi-
tions. Aldehyde 18 was subsequently subjected to Hor-
nereWadswortheEmmons conditions to provide a,b-unsaturated
ester 19. Hydrogenation of 19 (H2, Pd/C) followed by saponification
led to the formation of carboxylic acid 20 in 89% yield over the two
steps. Indanone 21 arose from an intramolecular FriedeleCrafts
acylation of the acid chloride derived from acid 20. The overall
sequence for the preparation of indanone 21 is robust and can be
scaled to prepare 5 g of 21 in one pass.
Scheme 1. Ga(III)-catalyzed cycloisomerization reaction.
As outlined in Scheme 2, with icetexone as the target, we
envisioned a similar strategy for the synthesis of the highly oxy-
genated icetexone subclass of the icetexane diterpenoids. This
reasoning led to our first approach to icetexone and epi-icetexone,
which would capitalize on substrates closely related to others that
we had prepared previously.
Scheme 3. Synthesis of indanone 21.

F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
5667
Formation of
b
-ketoester 22 (Scheme 4) was accomplished us-
epoxide to the dihydrofuran. Hydroboration of the resulting dihy-
drofuran double bond from the -face afforded hydroxy tetrahy-
ing NaHMDS and Mander’s reagent to favor the desired C-alkyl-
b
ation of indanone 21. Subsequent alkylation of
b
-ketoester 22 with
drofuran 26 in 73% yield over the two steps. Although we were able
to synthesize the nitrite ester of 26, an attempted Barton nitrite
ester functionalization14 upon irradiation led only to de-
composition products. A second attempt at remote functionaliza-
tion using a Norrish type II protocol was then undertaken. There
was cause for optimism with this procedure because of the existing
precedent of Jeger, who has demonstrated the formation of
a cyclobutanol product by functionalization of an angular methyl
group using a Norrish type II procedure.15 Synthesis of Norrish
substrate 27 was accomplished by oxidation of alcohol 26 to the
corresponding ketone followed by epimerization of the C5 stereo-
center. However, upon irradiation of ketone 27, the only identifiable
products appeared to arise from the fragmentation of the seven-
membered ring to form trace amounts of aldehyde 28.
alkyl iodide 2311a at 65 ꢁC led to adduct 24 in 66% yield over the two
steps.
2.2. A second, successful approach to icetexone
Scheme 4. Synthesis of adduct 24.
The myriad challenges encountered with the remote function-
alization strategy led us to devise a new plan to access the icetexone
core. We elected to pursue a pre-functionalization of the alkynyl
indene cycloisomerization substrate, which would provide a ben-
zannulated cycloheptadiene (e.g., 30, Scheme 7) already possessing
a functional handle at C19. Preliminary studies using a range of
alcohol derivatives proved futile, but eventually led to the identi-
fication of a cyano group as a masked carboxylic acid group that
was tolerated by our cycloisomerization conditions as well as
subsequent steps.
With b-ketoester 24 in hand, a saponification/decarboxylation
protocol was effected to afford indanone 25 (Scheme 5), which
underwent reduction using diisobutylaluminum hydride and
elimination of the resulting hydroxyl using methanesulfonic an-
hydride to generate the key alkylnyl indene (16) in 79% yield over
three steps. Utilizing the previously optimized conditions for
cycloisomerization established by our group (20 mol % GaCl3 and
4 A molecular sieves at 40 ꢁC), cycloheptadiene 15 was formed in
ꢀ
87% yield. With a route to 15 in place, we initiated a survey of
conditions to achieve the remote functionalization of one of the
geminal methyl groups (C19).
Scheme 7. Second generation retrosynthesis.
Scheme 5. Synthesis of cycloheptadiene 15.
In accord with this plan (Scheme 7), icetexone would arise from
primary amide 29 by oxygenation of the C10 position and sub-
sequent lactone formation. The amide group could form from hy-
drolysis of nitrile 30, which in turn could come from the Ga(III)-
cycloisomerization of alkynyl indene 31. This key substrate could
be synthesized by the alkylation of 32 with alkyl iodide 33. Im-
portantly, the use of a nitrile substrate would extend the scope of
the Ga(III)-catalyzed cycloisomerization chemistry to prepare [6-7-
6] ring systems. Finally, because 33 possesses a stereocenter that
would direct the installation of the two additional stereocenters in
1, the preparation of alkyl iodide 33 in enantioenriched form would
set the stage for an enantioselective synthesis of icetexone and epi-
icetexone.
Formation of the substrate for methyl group functionalization
(alcohol 26, Scheme 6) was initiated through selective epoxidation
of the tetrasubstituted double bond of diene 15 using m-chlor-
operbenzoic acid (m-CPBA), followed by isomerization of the vinyl
The synthesis of alkyl iodide 33 (Scheme 8) commenced with
commercially available 3-bromo-1-propanol (34). Protection of the
hydroxy group with triisopropylsilyl chloride and displacement of
the bromide with methyl cyanoacetate in the presence of K2CO3
gave 35 in 90% yield over the two steps. Formation of the quater-
nary center was accomplished using a standard methylation re-
action with methyl iodide and a subsequent chemoselective
reduction of the ester group in the presence of the nitrile group was
Scheme 6. Remote functionalization attempts.

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F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
Scheme 8. Synthesis of alkyl iodide 33.
achieved with an excess of sodium borohydride to provide alcohol
36. Oxidation of the alcohol group using Swern conditions followed
by an OhiraeBestmann homologation16 gave rise to alkyne 37 in
85% yield over the two steps. Finally, deprotection of the primary
alcohol followed by mesylation and displacement of the mesylate
with sodium iodide completed the synthesis of alkyl iodide 33.
Using this scalable sequence, 25 g of iodide 33 can be routinely
prepared in one pass.
Scheme 10. Lactone formation.
Table 1
Cycloisomerization optimization
Synthesis of the desired cycloisomerization substrate (31,
Scheme 9) commenced with a Claisen condensation of indanone 21
with diethyl carbonate to give ketoester 32.
b-Ketoester 32 un-
derwent alkylation with alkyl iodide 33 to give adduct 38 in 86%
yield over the two steps. A saponification/decarboxylation se-
quence gave rise to indanone 39, which was reduced with sodium
borohydride to afford the indanol as an inconsequential mixture of
alcohol diastereomers. Dehydration using KHSO4 completed the
synthesis of alkynyl indene 31 in 63% yield over the latter two steps.
Entry
Catalyst
Equiv
Temp (ꢁC)
Time (d)
Result (SM/Product)a
1
2
3
4
5
6
GaCl3
GaBr3
Gal3
Gal3
Gal3
0.2
0.2
0.2
0.5
0.25
0.25
40
40
40
2
2
2
4
4
2
1.36:1.0
1.29:1.0
0.63:1.0
Complete
Complete
Complete
65
80
GaCl3
100b
a
Conversion of substrate based on 1H NMR of crude product after aqueous
workup.
b
Reaction run in toluene.
catalyst loading could be decreased to 25 mol %, and complete
conversion was observed after 4 days (entry 5). Ultimately, it was
determined that the reaction time could be decreased to 2 days by
heating at 100 ꢁC in toluene (entry 6).
Using the optimized sequence, cycloisomerization of alkynyl
indene 31 proceeded in 91% isolated yield to afford cycloheptadiene
30 as the sole product (Scheme 9). Hydrolysis of the tertiary nitrile
group was initially attempted using standard acid and base-
mediated protocols. However, these proved to be ineffective and
either led to no reaction or the non-specific decomposition of the
starting material. Perusal of the literature brought to our attention
a platinum-based catalyst (see 40) developed by Ghaffar and Par-
kins,17 which accomplishes the conversion of nitrile groups to
primary carboxamides in excellent yields under mild conditions.
Gratifyingly, hydrolysis of nitrile 30 using Ghaffar and Parkins’
platinum complex (40) as a catalyst afforded amide 29 in 87% yield.
On the basis of our previous synthetic studies on the icetexane
diterpenoid salviasperanol,11a we anticipated that oxygenation at
the C10 position of diene 29 could occur through a chemoselective
epoxidation of the tetrasubstituted olefin. We were pleased to ob-
serve exclusive formation of vinyl oxirane 41 (as a single di-
astereomer) when diene 29 was treated with m-CPBA. Presumably,
epoxidation is directed by the amide functional group to the face
bearing the amide group. Initial attempts to open the vinyl epoxide
moiety of vinyl oxirane 41 included the use of DIBAL and Red-AlÒ,
as well as the use of Pd(0) catalysts in an attempt to form an
Scheme 9. Synthesis of cycloisomerization substrate 31.
With a route to the key alkynyl indene substrate in hand, several
cycloisomerization conditions were surveyed (Table 1). The stan-
dard conditions employed in our earlier cycloisomerization studies
(entry 1) yielded a mixture of starting material and the desired
product in a ratio of 1.36:1.0. It was gratifying to observe only trace
decomposition or isomeric byproducts. A study of other Ga(III) salts
under the same conditions yielded similar conversion ratios, with
GaI3 faring slightly better (compare entries 1e3). In one experi-
ment, complete conversion of alkynyl indene 31 to cycloheptadiene
30 was achieved using 50 mol % GaI3 with heating at 65 ꢁC over 4
days (entry 4). The temperature was then increased in an attempt
to decrease the catalyst loading and reaction time. At 80 ꢁC, the

F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
5669
intermediate
p
-allyl species. These efforts simply returned the
camphorsulfonic acid in the presence of tosyl hydrazide. Gratify-
ingly, lactone 44 was obtained (Scheme 12), albeit in low yield. This
observation eliminated the need to undergo the lengthy and low
yielding transposition sequence previously described (see Scheme
11). Furthermore, on the basis of the formation of 42 from a CSA-
catalyzed isomerization of epoxide 41, a one-pot epoxide ring-
opening followed by reductive transposition was proposed. Upon
subjecting vinyl epoxide 41 to the reaction conditions described
previously, a mixture of 44 and 45 (2.5:1 diastereomeric ratio) was
obtained, allowing access to both icetexone and epi-icetexone, re-
spectively. A brief optimization study established that this trans-
formation could be accomplished in a 42% combined yield of
lactones 44 and 45 from vinyl epoxide 41.
starting material. Also, on the basis of our previous studies, cam-
phorsulfonic acid was expected to effect an acid-catalyzed isom-
erization of the vinyl epoxide to the corresponding dihydrofuran,
but instead, lactone 42 was isolated. This unexpected, yet fortu-
itous, outcome could arise from opening of the vinyl epoxide under
acidic conditions, followed by trapping of an intermediate allylic
carbocation by adventitious water and lactonization with the pri-
mary amide.
Although lactone 42 was merely a deoxygenation away from
a per-methylated precursor to icetexone and epi-icetexone, all at-
tempts to directly remove the hydroxy group resident at C5 were
unsuccessful. For example, we were unable to transform the hy-
droxy group to a xanthate group in preparation for a Barton de-
oxygenation, presumably because of the high steric congestion at
C5. An attempted ionic reduction of the allylic alcohol with
BF3$OEt2 and triethylsilane led only to non-specific decomposition.
Because of the potential role of sterics in the lack of reactivity of the
hydroxy group of 42, transposition of the hydroxyl using chromium
reagents was attempted, but this also led to decomposition prod-
ucts. A stepwise transposition of the hydroxy group of 42 could be
achieved by first hydrogenating the double bond followed by
elimination using thionyl chloride, which yielded trisubstituted
alkene 43 (Scheme 11). Attempted isomerization of the tri-
substituted double bond in alkene 43 into conjugation with the
arene only returned starting material. Oxidation of the doubly ac-
tivated benzylic and allylic position of 43 with manganese tri-
acetate gave a stable peroxide intermediate that could be converted
to an alcohol (not shown) using an aluminum/mercury amalgam
procedure developed by Yu and Corey.18
Scheme 12. Formal synthesis of icetexone and epi-icetexone.
The variability in diastereomeric ratio of lactones 44 and 45
obtained from vinyl oxirane 41 (Scheme 12) as compared to that
obtained from allylic alcohol 42 (or alkene 43, Scheme 11) can be
rationalized by the following proposed mechanism (Scheme 13).
Acid-catalyzed opening of the vinyl epoxide likely leads to tertiary
carbocation 46, which can be stabilized by the styrenyl double
bond. Attack by tosyl hydrazide at the less sterically hindered
benzylic position from either face can give rise to intermediate 47.
From this intermediate, a tandem lactone formation and diazene
transposition yields lactones 44 and 45, wherein the stereochem-
istry at C5 is determined by which face nucleophilic attack occurs
from. For allylic alcohol 42 (or alkene 43), because the lactone is
formed prior to tosyl hydrazide attack, there is significant facial
control in the addition step.
Scheme 11. An initial formal synthesis of epi-icetexone.
Subjecting the alcohol generated from Mn(OAc)3/TBHP oxida-
tion of alkene 43 to Myers’ reductive allylic alcohol transposition
conditions19 only led to the recovery of the starting material.
However, it was reasoned that ionization of the allylic hydroxy
group could be possible since a doubly stabilized carbocation would
result. Thus, exposure of the alcohol intermediate to acidic condi-
tions in the presence of tosyl hydrazide at elevated temperatures
(ca. 80 ꢁC) led to diastereomeric lactones 44 and 45 (44 as the major
product, >10:1 dr). Presumably this occurs by the tosyl hydrazide
engaging the incipient carbocation followed by loss of sulfinic acid
and an ensuing diazene rearrangement. Comparison of the 1H NMR
and 13C NMR spectra of 44 to that reported in the literature by
Majetich confirmed its structure and thus a formal synthesis of epi-
icetexone was achieved.
Scheme 13. Proposed mechanism.
Although our access to 44 as described in Scheme 11 was ser-
viceable, several attempts were made to improve the synthetic
route. It was theorized that the ionization of tertiary alcohol 42
could lead directly to the same reactive carbocation intermediate
that was presumed to engage the tosyl hydrazide nucleophile.
To test this hypothesis, allylic alcohol 42 was exposed to
2.3. Enantioselective formal synthesis of icetexone and
epi-icetexone
It is evident from our retrosynthetic analysis of icetexone and
epi-icetexone (Scheme 7) that rendering the synthesis of alkyl

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F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
iodide 33 enantioselective would complete enantioselective for-
mal syntheses of these natural products given that the single
stereocenter in nitrile 33 controls the stereoselectivity during the
installation of all additional stereocenters. Our planned approach
to enantioenriched nitrile 33 sought to capitalize on the remark-
able enantioselective conjugate addition reaction of cyanopropi-
onates (e.g., 49, Scheme 14) to acrolein (50) using Rh(I)-2,20-bis[1-
(diarylphosphino)ethyl]-1,10-biferrocenes (ArylTRAP) complexes
(51) as first reported by Sawamura et al.20 In accordance with the
protocols developed by Sawamura et al., reacting cyanoester 49
(1 equiv) with acrolein (1.5 equiv) in benzene at 0 ꢁC yielded the
conjugate adduct, which was immediately reduced to provide
alcohol 52. The enantiomeric excess of quaternary cyanoester 52
(89% ee)21 was determined after its derivatization to the corre-
sponding p-nitro benzoate. To convert enantioenriched 52 to alkyl
iodide 33, the hydroxy group was protected with TIPSCl and, the
tert-butyl ester group could be reduced selectively to the corre-
sponding alcohol in the presence of the nitrile group using sodium
borohydride in EtOH/THF (4:1). Swern oxidation of the hydroxy
group and alkynylative homologation of the resulting aldehyde
using the OhiraeBestmann protocol gave enantioenriched 37 (not
shown in Scheme 14) in good yield. Unveiling the primary alcohol
of 37 (with TBAF) set the stage for its replacement with an iodide
group via the intermediacy of the mesylate. Enantioenriched 33
obtained in this way provided identical 1H and 13C NMR spectra as
the racemic material that we had prepared previously. Because we
began with the (S,S)-(R,R)-2,200-bis[1-(diphenylphosphino)ethyl]-
1,100-biferrocene complex (51), we wanted to ensure that the ab-
solute stereochemistry was as is depicted for naturally occurring
icetexone and epi-icetexone. Thus, using an analogous sequence as
described in Schemes 9 and 10, enantioenriched 33 was advanced
to tricyclic nitrile 30. Reduction of the nitrile group using LAH
proceeded without event to afford a primary amine, which was
derivatized with p-bromo benzoyl chloride to give amide de-
rivative 54. X-ray crystallographic analysis of 54 (see ORTEP in
Scheme 14) confirmed the C(4) stereocenter as R, consistent with
that found in the natural product, thus completing the formal
synthesis of icetexone and epi-icetexone.
3. Conclusion
In this article, formal syntheses of icetexone (1) and epi-ice-
texone (2) that rely on a Ga(III)-catalyzed cycloisomerization to
form 6-7-6 fused tricyclic carbocycles was presented. Two distinct
approaches were pursued. The first, which entailed attempts to
oxygenate the carbocyclic skeleton, involved a remote functional-
ization strategy that ultimately led to fragmentation of the seven-
membered ring. A pre-functionalization approach was then un-
dertaken, and the synthesis of a cyano group-containing tether
allowed for a successful Ga(III)-catalyzed alkynyl indene cyclo-
isomerization. Of note, this work served as the first demonstration
that a Ga(III)-catalyzed cycloisomerization is possible in the pres-
ence of a nitrile group. The presence of this functional handle was
exploited in achieving a formal synthesis of icetexone and epi-
icetexone through a tandem vinyl epoxide opening/diazene rear-
rangement sequence. Finally, using a Rh-catalyzed enantioselective
conjugate addition, the formal enantioselective syntheses of these
natural products was achieved.
4. Experimental section
4.1. General experimental details
All reagents were obtained from commercial chemical suppliers
and used without further purification unless otherwise noted. All
reactions were performed in round-bottomed flasks sealed with
rubber septa, under an atmosphere of N2, and stirred with a Tef-
lonÔ-coated magnetic stir bar unless otherwise noted. Tempera-
tures above 23 ꢁC were controlled by an IKAÒ temperature
modulator. Pre-dried tetrahydrofuran (THF), benzene, toluene,
acetonitrile (MeCN), methanol (MeOH), and triethylamine (Et3N),
were degassed with argon for 60 min and passed through activated
alumina columns. Dichloromethane (CH2Cl2) was distilled over
calcium hydride before use. Reactions were monitored by thin layer
chromatography (TLC) using Silicycle SiliaplateÔ glass backed TLC
ꢀ
plates (250
mm thickness, 60 A porosity, F-254 indicator) and vi-
sualized using UV (254 nm) and p-anisaldehyde stain or KMnO4
stain. Volatile solvents were removed using a rotary evaporator
under reduced pressure. Silica gel chromatography was performed
ꢀ
using Sorbent Technologies 60 A, 230ꢂ400 mesh silica gel
(40e63
m
m). 1H NMR and 13C NMR were obtained in CDCl3 on
Bruker 400, 500, or 600 MHz spectrometers with 13C operating
frequencies of 100, 126, or 151 MHz, respectively. Chemical shifts
are reported in parts per million (d) relative to residual chloroform
(7.26 ppm for 1H and 77.16 ppm for 13C). Data for 1H NMR spectra are
reported as follows: chemical shift (multiplicity, coupling constants,
number of hydrogens). Multiplicity is designated as s (singlet),
d (doublet), t (triplet), q (quartet), or m (multiplet). IR spectra were
obtained using a Nicolet MAGNA-IR 850 spectrometer as thin films
on NaCl plates and reported in frequency of absorption (cmꢃ1). High
resolution mass spectral (HRMS) data was obtained from the Mass
Spectral facility at the University of California, Berkeley.
4.1.1. 4-Isopropyl-2,3,5-trimethoxybenzaldehyde (18). To a solution
of 4-isopropyl-2,3,5-trimethoxybenzyl alcohol8,13 (17, 4.09 g,
17.0 mmol) in 4:1 CH2Cl2/DMSO (45 mL) at 0 ꢁC were added
SO3$pyr (4.73 g, 29.8 mmol) and Et3N (11.8 mL, 85 mmol). The
resulting mixture was stirred at 0 ꢁC and allowed to warm to rt over
18 h. The reaction mixture was poured into a mixture of saturated
aq NaHCO3 (25 mL) and water (25 mL), then extracted with Et2O
(3ꢂ100 mL). The combined organic layers were washed with sat-
urated aq NaHCO3 (100 mL), and brine (100 mL), dried over MgSO4,
and concentrated. The crude product was passed through a plug of
silica gel to give 3.49 g (14.6 mmol, 86%) of 18 as an orange oil. Rf
Scheme 14. Synthesis of an enantioenriched common intermediate.
0.66 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3)
d 10.28 (s, 1H),

F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
5671
6.99 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.52 (m, 1H), 1.26
1320, 1274, 1136, 1060, 1035 cmꢃ1; HRMS (EI) calcd for C15H21O4
(d, J¼7.2 Hz, 6H); 13C NMR (151 MHz, CDCl3)
d
189.2, 155.0, 152.0,
([M]þ): m/z 264.1366, found 264.1362.
151.5, 138.8, 127.3, 103.1, 62.3, 60.9, 55.6, 25.7, 20.7; IR (film) nmax
2959, 1688, 1595, 1465, 1414, 1384, 1348, 1273, 1235, 1208, 1136,
1063, 1024 cmꢃ1; HRMS (EI) calcd for C13H18O4 ([M]þ): m/z
238.1205, found 238.1205.
4.1.5. 2-(Carbomethoxy)-2-(40,40-dimethyl-50-hexynyl)-6-isopropyl-
4,5,7-trimethoxy-1-indanone (24). To a flask containing sodium
bis(trimethylsilyl)amide (1.0 M in THF, 6.06 mL, 6.06 mmol) in THF
(12 mL) under N2 at ꢃ78 ꢁC was added a solution of 21 (641 mg,
2.43 mmol) in THF (8 mL) over 2 min. After 45 min at ꢃ78 ꢁC, the
resulting bright orange solution was treated with methyl cyano-
formate (0.21 mL, 2.67 mmol). The mixture was stirred at ꢃ78 ꢁC for
15 min, then poured into water (30 mL) and extracted with EtOAc
(3ꢂ30 mL). The combined organic layers were washed with brine
(30 mL), dried over MgSO4, and concentrated to give a dark yellow
oil, which was used immediately without further purification. To
4.1.2. Ethyl(4-isopropyl-2,3,5-trimethoxy)cinnamate (19). Triethyl
phosphonoacetate (3.19 mL, 16.1 mmol) was added to a solution of
18 (3.49 g, 14.6 mmol) and LiCl (643 mg, 15.2 mmol) in CH3CN
(52 mL) under N2 at 0 ꢁC. After the addition of DBU (2.40 mL,
16.1 mmol), the resulting mixture was allowed to warm to rt and
was stirred for 13 h. The mixture was poured into water (100 mL)
and extracted with CHCl3 (3ꢂ50 mL). The combined organic layers
were washed with brine (100 mL), dried over MgSO4, and con-
centrated. Flash chromatography (9:1 hexanes/EtOAc) gave 3.95 g
(12.8 mmol, 88%) of 19 as a thick yellow oil. Rf 0.48 (4:1 hexanes/
a solution of the crude b-ketoester (22, 783 mg, 2.43 mmol) in
acetone (10 mL) in a Schlenk flask was added K2CO3 (1.01 g,
7.28 mmol), and the resulting suspension was stirred at rt for
15 min. A solution of 2311a (573 mg, 2.43 mmol) in acetone (6 mL)
was added, and the flask was evacuated and backfilled with N2
(3ꢂ). The flask was sealed and heated to 65 ꢁC for 40 h. After cooling
to rt, the mixture was diluted with water (30 mL) and extracted
with Et2O (3ꢂ30 mL). The combined organic layers were washed
with water (30 mL) and brine (30 mL), dried over MgSO4, and
concentrated. Flash chromatography (9:1 to 4:1 hexanes/EtOAc)
gave 689 mg (1.60 mmol, 66% over two steps) of 24 as a viscous pale
yellow syrup. Rf 0.59 (2:1 hexanes/EtOAc); 1H NMR (500 MHz,
EtOAc); 1H NMR (500 MHz, CDCl3)
d
7.92 (d, J¼16.1 Hz, 1H), 6.73 (s,
1H), 6.43 (d, J¼16.1 Hz, 1H), 4.24 (q, J¼7.1 Hz, 2H), 3.80 (s, 3H), 3.79
(s, 3H), 3.77 (s, 3H), 3.53e3.46 (m, 1H), 1.31 (t, J¼7.1 Hz, 3H), 1.28 (d,
J¼7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d 167.6, 155.1, 152.6, 147.5,
139.7, 134.1, 126.1, 118.7, 104.3, 61.6, 61.2, 60.7, 55.9, 25.8, 21.4, 14.7;
IR (film) nmax 2958, 1713, 1633, 1471, 1410, 1346, 1284, 1230, 1175,
1134, 1055, 1026 cmꢃ1; HRMS (ESI) calcd for C12H25O5 ([MþH]þ):
m/z 309.1697, found 309.1701.
4.1.3. 4-Isopropyl-2,3,5-trimethoxydihydrocinnamic acid (20). A
mixture of 19 (2.83 g, 9.18 mmol) and 10% Pd/C (283 mg) in EtOH
(95%, 30 mL) was placed under an atmosphere of H2 (balloon) and
stirred rapidly at rt for 12 h. The mixture was then filtered through
Celite and concentrated to give 2.53 g (8.15 mmol, 89%) of a light
yellow oil, which was used without further purification. To a solu-
tion of ethyl(4-isopropyl-2,3,5-trimethoxy)dihydrocinnamate
(3.96 g, 12.8 mmol) in 3:1 THF/water (60 mL) was added LiOH$H2O
(1.34 g, 31.9 mmol). The resulting mixture was stirred at rt for 18 h.
The mixture was acidified with 1 N HCl (50 mL) and extracted with
EtOAc (2ꢂ100 mL). The combined organic layers were washed with
brine (100 mL), dried over MgSO4, and concentrated to give 3.6 g
(12.8 mmol, 100%) of 20 as a thick yellow oil, which was used
without further purification. Rf 0.45 (2:1 hexanes/EtOAc); 1H NMR
CDCl3) d 3.93 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.60 (d,
J¼17.5 Hz, 1H), 3.48 (septet, J¼7.1 Hz, 1H), 2.95 (d, J¼17.5 Hz, 1H),
2.15e2.06 (m, 1H), 2.00 (s, 1H), 1.83e1.73 (m, 1H), 1.48e1.32 (m,
4H), 1.28 (d, J¼7.1 Hz, 6H), 1.14 (s, 3H), 1.12 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 198.3, 171.6, 158.6, 154.0, 145.3, 145.0, 134.8,
122.9, 91.4, 67.8, 62.3, 61.1, 60.6, 60.1, 52.6, 43.1, 35.2, 32.7, 30.9, 29.1,
29.0, 25.3, 21.6, 20.6; IR (film) nmax 3290, 2963, 2872, 1746, 1709,
1582,1471,1420,1323,1275,1200,1172,1136,1039 cmꢃ1; HRMS (EI)
calcd for C25H34O5 ([M]þ): m/z 430.2355, found 430.2351.
4.1.6. 2-(40,40-Dimethyl-50-hexynyl)-6-isopropyl-4,5,7-trimethoxyin
dene (16). To a solution of 24 (1.88 g, 4.37 mmol) in 3:1 THF/water
(20 mL) was added LiOH$H2O (916 mg, 21.8 mmol). The resulting
mixture was heated at 65 ꢁC for 16 h in a sealed tube under N2. After
cooling to rt, the reaction mixture was acidified with 1 N HCl
(40 mL) and extracted with Et2O (3ꢂ40 mL). The combined organic
layers were washed with brine (40 mL), dried over MgSO4, and
concentrated to give 25 as a light yellow oil, which was used
without further purification, Rf 0.64 (2:1 hexanes/EtOAc). To a so-
lution of the 25 (1.63 g, 4.37 mmol) in CH2Cl2 (35 mL) under N2 at
(500 MHz, CDCl3)
d 6.45 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.76 (s,
3H), 3.47 (m, 1H), 2.92 (t, J¼7.8 Hz, 2H), 2.68 (t, J¼7.8 Hz, 2H), 1.29
(d, J¼7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d 179.3, 154.4, 151.7,
145.3, 130.8, 128.9, 107.5, 60.6, 60.4, 55.7, 34.8, 25.5, 25.0, 21.2; IR
(film) nmax 2956, 2835, 1710, 1603, 1578, 1452, 1409, 1340, 1286,
1231, 1130, 1072, 1028 cmꢃ1; HRMS (EI) calcd for C15H22O5 ([M]þ):
m/z 282.1467, found 282.1463.
0
ꢁC was added diisobutylaluminum hydride (1.0 M in toluene,
5.28 mL, 5.28 mmol) dropwise over 5 min. The resulting solution
was stirred at 0 ꢁC for 30 min and then quenched by the addition of
an aq solution of Rochelle’s salt (4.47 g in 40 mL water). The
resulting biphasic mixture was allowed to warm to rt and stirred
vigorously for 1 h before it was diluted with water (40 mL) and
extracted with CH2Cl2 (3ꢂ40 mL). The combined organic layers
were washed with brine (40 mL), dried over MgSO4, and concen-
trated to give a pale yellow oil, which was used immediately
without further purification, Rf 0.40 (4:1 hexanes/EtOAc). To a so-
lution of the crude indanol (1.63 g, 4.37 mmol) and Et3N (1.84 mL,
13.2 mmol) in benzene (30 mL) was added methanesulfonic an-
hydride (1.53 g, 8.81 mmol). The resulting mixture was stirred at rt
for 35 min before it was poured onto water (40 mL) and extracted
with Et2O (3ꢂ40 mL). The combined organic layers were washed
with saturated aq NaHCO3 (40 mL), and brine (40 mL), dried over
MgSO4, and concentrated. Flash chromatography (20:1 hexanes/
EtOAc) to give 1.23 g (3.45 mmol, 79% over three steps) of 16 as
a viscous pale yellow oil. Rf 0.57 (4:1 hexanes/EtOAc); 1H NMR
4.1.4. 6-Isopropyl-4,5,7-trimethoxy-1-indanone (21). To
containing 20 (1.43 g, 5.06 mmol) in CH2Cl2 (16 mL) under N2 at
ꢁC was added oxalyl chloride (0.44 mL, 5.06 mmol), followed by
a
flask
0
DMF (3 drops) after 20 min. After stirring at 0 ꢁC for 2 h, the
resulting solution was warmed to rt. The resulting solution was
then added to a suspension of AlCl3 (1.35 g) in CH2Cl2 (8 mL) at 0 ꢁC
slowly via syringe. After stirring for 1 h, the mixture was poured
into ice-water in a separatory funnel and diluted with 1 N HCl
(25 mL) and CH2Cl2 (25 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2ꢂ25 mL). The combined
organic layers were washed with 1 N NaOH (25 mL), dried over
MgSO4, and concentrated to give 1.18 g (4.46 mmol, 88%) of 21 as
a thick light yellow syrup, which was used without further purifi-
cation. Rf 0.51 (2:1 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3)
d
3.94 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.52 (m, 1H), 3.06e2.99 (m,
2H), 2.68e2.60 (m, 2H), 1.31 (d, J¼7.1 Hz, 6H); 13C NMR (126 MHz,
CDCl3) d 203.5, 158.4, 153.7, 147.9, 146.1, 134.9, 125.5, 62.8, 61.1, 60.4,
37.3, 25.7, 22.5, 22.1; IR (film) nmax 2936, 1708, 1583, 1470, 1418,
(400 MHz, CDCl3) d 6.61 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.85 (s,

5672
F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
3H), 3.50 (septet, J¼7.1 Hz, 1H), 3.35 (s, 2H), 2.51 (t, J¼7.3 Hz, 2H),
2.11 (s, 1H), 1.86e1.73 (m, 2H), 1.51e1.43 (m, 2H), 1.37 (d, J¼7.1 Hz,
onto a 1:1 mixture of NH4Cl:water (15 mL) and extracted with
EtOAc (3 ꢂ 15 mL). The combined organic layers were washed with
brine (15 mL), dried over MgSO4, and concentrated to give 77 mg
(0.19 mmol, 100%) of crude alcohol 26 as a colorless oil, which was
used without further purification. Rf 0.16 (4:1 hexanes/EtOAc); 1H
6H), 1.24 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 148.5, 148.4, 146.9,
145.5, 133.9, 133.1, 133.0, 122.8, 91.7, 67.9, 61.8, 60.9, 59.6, 42.6, 38.7,
31.3, 30.9, 29.1, 25.7, 24.6, 22.1; IR (film) nmax 3288, 2963, 2937,
2870, 2831, 2107, 1467, 1419, 1338, 1278, 1213, 1121, 1058, 1042, 999,
980, 918, 834 cmꢃ1; HRMS (EI) calcd for C23H32O3 ([M]þ): m/z
356.2351, found 356.2350.
NMR (600 MHz, CDCl3)
d
5.04 (s, 1H), 3.99 (d, J¼7.3 Hz, 1H), 3.82 (s,
3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.37 (dd, J¼14.2, 7.1 Hz, 1H), 3.20 (d,
J¼18.3 Hz, 1H), 2.66 (d, J¼18.3 Hz, 1H), 2.03 (m, 1H), 1.81e1.74 (m,
2H), 1.74e1.70 (m, 2H), 1.70e1.65 (m, 2H), 1.56 (m, 1H), 1.33 (d,
J¼7.1 Hz, 3H), 1.31 (d, J¼7.1 Hz, 3H), 1.07 (s, 3H), 0.94 (s, 3H); 13C
4.1.7. 8-Isopropyl-6,7,9-trimethoxy-1,1-dimethyl-2,3,4,5-tetrahydro-
1H-dibenzo[a,d][7]annulene (15). In an N2 dry box, a Schlenk flask
NMR (151 MHz, CDCl3) d 151.2, 148.2, 147.3, 132.5, 128.2, 124.7, 82.1,
ꢀ
was charged with GaCl3 (122 mg, 0.69 mmol) and powdered 4 A
80.5, 79.3, 68.8, 62.7, 60.2, 59.5, 41.1, 40.8, 33.3, 33.1, 31.1, 25.7, 22.2,
22.0, 21.1, 20.2; IR (film) nmax 3422, 2938, 2870, 1646, 1456, 1415,
1360, 1341, 1284, 1173, 1123, 1071, 1042, 1013 cmꢃ1; HRMS (EI) calcd
for C23H34O5 ([M]þ): m/z 390.2406, found 390.2411.
molecular sieves (244 mg). The flask was removed from the dry box
and a solution of 16 (1.23 g, 3.45 mmol) in freshly distilled benzene
(85 mL) was added via syringe under N2 to give a dark red solution.
The flask was sealed and placed in an oil bath that was preheated to
40 ꢁC. After being stirred at 40 ꢁC for 24 h, the mixture was allowed
to cool to rt and the sieves were removed by filtration through
a plug of glass wool. The filtrate was poured onto a solution of
saturated aq NaHCO3 (50 mL) and extracted with Et2O (3ꢂ50 mL).
The combined organic layers were washed with brine (50 mL),
dried over MgSO4, and concentrated to give a viscous dark yellow
syrup. Flash chromatography (30:1 hexanes/EtOAc) gave 1.07 g
(3.00 mmol, 87%) of 15 as a viscous pale yellow oil, which crystal-
lized to a white solid on standing at rt. Rf 0.66 (4:1 hexanes/EtOAc);
4.1.9. 8-Isopropyl-6,7,9-trimethoxy-1,1-dimethyl-1,3,4,5,10,11a-hex-
ahydro-4a,10-epoxydibenzo[a,d][7]annulen-11(2H)-one
(27). To
a solution of the alcohol 26 (82 mg, 0.21 mmol) in CH2Cl2 (4.2 mL)
were added NaHCO3 (53 mg, 0.63 mmol) and DesseMartin peri-
odinane (106 mg, 0.25 mmol) at rt. After 1 h, the mixture was
poured onto saturated aq Na2SO3 (8 mL) and extracted with EtOAc
(3ꢂ16 mL). The combined organic layers were washed with satu-
rated aq NaHCO3 (2ꢂ16 mL) and brine (16 mL), dried over MgSO4,
and concentrated to give 62 mg (0.16 mmol, 76%) of a yellow oil. To
a solution of the crude cis-fused ketone (62 mg, 0.16 mmol) in 3:1
MeOH/CH2Cl2 (2.0 mL) was added sodium methoxide (9.6 mg,
0.18 mmol). The resulting pale yellow solution was stirred at rt for
21 h before it was poured onto a 1:1 mixture of water/saturated
aq NH4Cl (20 mL) and extracted with EtOAc (3ꢂ15 mL). The com-
bined organic layers were washed with brine (15 mL), dried over
MgSO4, and concentrated to give a colorless oil. Flash chromatog-
raphy (20:1 hexanes/EtOAc) gave 53 mg (0.14 mmol, 88%) of ketone
27 as a colorless oil. Rf 0.64 (2:1 hexanes/EtOAc); 1H NMR
mp 101.1e102.0 ꢁC; 1H NMR (500 MHz, CDCl3)
d
7.12 (d, J¼12.0 Hz,
1H), 6.66 (d, J¼12.0 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.69 (s, 3H),
3.49 (septet, J¼7.0 Hz, 1H), 2.97 (br s, 2H), 2.36 (t, J¼5.9 Hz, 2H),
1.69e1.59 (m, 2H), 1.51e1.42 (m, 2H), 1.37 (d, J¼7.1 Hz, 6H), 1.08 (s,
6H); 13C NMR (125 MHz, CDCl3)
d 152.4, 151.2, 145.4, 136.5, 132.5,
132.3, 131.5, 129.6, 126.6, 125.4, 61.6, 60.7, 60.3, 38.9, 33.4, 32.27,
32.26, 29.1, 25.6, 22.2, 19.6; IR (film) nmax 2933, 2868, 2827, 1580,
1454, 1400, 1341, 1315, 1120, 1101, 1061, 1047, 996, 969, 740 cmꢃ1
;
HRMS (EI) calcd for C23H32O3 ([M]þ): m/z 356.2351, found 356.2351.
(500 MHz, CDCl3) d 5.16 (s,1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H),
4.1.8. 8-Isopropyl-6,7,9-trimethoxy-1,1-dimethyl-1,2,3,4,5,10,11,11a-
octahydro-4a,10-epoxydibenzo[a,d][7]annulen-11-ol (26). A mixture
of cycloheptadiene 15 (229 mg, 0.64 mmol) and NaHCO3 (108 mg,
1.28 mmol) in CH2Cl2 (6.4 mL) at 0 ꢁC was treated with m-chlor-
operbenzoic acid (77%, 173 mg, 0.77 mmol). The resulting mixture
was stirred at 0 ꢁC for 1 h before it was quenched by the addition of
saturated aq. NaHSO3 (7 mL). The mixture was extracted with
CH2Cl2 (3 ꢂ 15 mL). The combined organic layers were washed with
saturated aq. NaHCO3 (2 ꢂ 15 mL), and brine (15 mL), dried over
MgSO4, and concentrated. Flash chromatography (20:1 hexanes/
EtOAc) gave 174 mg (0.47 mmol, 73%) of the dihydrofuran as a vis-
cous colorless oil. Rf 0.50 (4:1 hexanes/EtOAc); 1H NMR (500 MHz,
3.36 (m, 1H), 2.90 (d, J¼18.1 Hz, 1H), 2.43 (d, J¼18.0 Hz, 1H),
2.13e2.06 (m, 1H), 1.91e1.81 (m, 1H), 1.88 (s, 1H), 1.69e1.60 (m, 1H),
1.59e1.48 (m, 2H), 1.32 (d, J¼7.1 Hz, 3H), 1.29 (d, J¼7.1 Hz, 3H),
1.29e1.23 (m, 1H), 1.16 (s, 3H), 1.06 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 213.2,152.5,149.9,147.5,133.7,125.5,123.2, 79.7, 75.2, 63.5,
60.1, 59.4, 59.0, 40.0, 37.5, 35.1, 32.8, 31.8, 25.8, 22.8, 22.0, 21.9, 17.4;
IR (film) nmax 2952, 2872, 2838, 1749, 1459, 1414, 1345, 1271, 1250,
1174, 1121, 1067, 1040, 961, 836, 795, 737 cmꢃ1; HRMS (EI) calcd for
C23H32O5 ([M]þ): m/z 388.2250, found 388.2246.
4.1.10. Methyl 2-cyano-5-(triisopropylsilyloxy)pentanoate (35). To
a solution of 3-bromo-1-propanol (34, 20.0 mL, 230 mmol) in
CH2Cl2 (575 mL) were added imidazole (39.0 g, 575 mmol) and
triisopropylsilyl chloride (59.0 mL, 276 mmol). The cloudy reaction
mixture was stirred at rt for 12 h. The solution was poured into
water (500 mL) and extracted with CH2Cl2 (2ꢂ500 mL). The com-
bined organic layers were washed with brine (300 mL), dried over
MgSO4, and concentrated to give of a colorless oil that was used
without purification. To a solution of (3-bromopropoxy)triisopro-
pylsilane (67.5 g, 230 mmol) in DMF (460 mL) were added K2CO3
(95.0 g, 690 mmol) and methyl cyanoacetate (40 mL, 3460 mmol) at
rt. The flask was fitted with a reflux condenser, then heated to 65 ꢁC
for 1 h. After cooling to rt, the mixture was diluted with water
(500 mL) and extracted with Et2O (3ꢂ100 mL). The combined or-
ganic layers were washed with brine (1500 mL), dried over MgSO4,
and concentrated to give a thick yellow oil. Flash chromatography
(9:1 hexanes/EtOAc) gave 64.8 g (207 mmol, 90% over two steps) of
35 as a clear oil. Rf 0.68 (2:1 hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3)
d
6.06 (d, J ¼ 1.5 Hz, 1H), 5.47 (d, J ¼ 2.0 Hz, 1H), 3.81 (s, 3H),
3.73 (s, 3H), 3.70 (s, 3H), 3.33 (septet, J ¼ 7.1 Hz, 1H), 2.94 (d, J ¼ 17.3
Hz, 1H), 2.66 (d, J ¼ 17.3 Hz, 1H), 2.16-2.07 (m, 1H), 1.83-1.69 (m,
3H), 1.55-1.49 (m, 1H), 1.40-1.34 (m, 1H), 1.32 (d, J ¼ 7.1 Hz, 3H), 1.30
(d, J ¼ 7.1 Hz, 3H), 1.13 (s, 3H), 1.03 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 151.3, 150.3, 148.6, 148.5, 131.5, 127.82, 127.78, 125.8, 83.3,
74.8, 62.6, 60.2, 59.4, 40.0, 38.6, 33.8, 30.5, 29.8, 27.5, 25.6, 22.2,
22.0, 19.0; IR (film) nmax 2936, 2868, 1454, 1411, 1341, 1285, 1244,
1166, 1121, 1092, 1058, 1040, 1018, 1001, 965, 738 cm-1; HRMS (EI)
calcd for C23H32O4 ([M]þ): m/z 372.2301, found 372.2299. To a so-
lution of dihydrofuran (72 mg, 0.19 mmol) in THF (1.5 mL) under N2
was added a solution of BH3ꢄTHF (1.0 M in THF,1.54 mL,1.54 mmol).
The resulting solution was stirred at rt for 11 h. After cooling the
solution to 0 ꢁC, the excess borane was carefully quenched by slow,
dropwise addition of EtOH (0.54 mL). The resulting mixture was
then treated with a solution of NaOH (125 mg, 3.12 mmol) in water
(2.19 mL), followed by a solution of H2O2 (30% in water, 1.15 mL,10.2
mmol). After addition was complete, the mixture was allowed to
warm to rt and was stirred for 4 h. The reaction mixture was poured
CDCl3)
(m, 2H), 1.81e1.72 (m, 2H), 1.08 (m, 21H); 13C NMR (126 MHz,
CDCl3) 167.1, 116.9, 62.6, 37.6, 30.1, 18.4, 18.1, 12.7, 12.3; IR (film)
d
3.85 (s, 3H), 3.79 (m, 2H), 3.69 (dd, J¼8.4, 5.9 Hz, 1H), 2.12
d

F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
5673
nmax 2943, 2867, 1754, 1463, 1250, 1110, 1013 cmꢃ1; HRMS (ESI)
calcd for C16H32NO3Si ([MþH]þ): m/z 314.2146, found 314.2143.
chromatography (2:1 hexanes/EtOAc) gave 9.79 g (71 mmol, 76%) of
the alcohol as a colorless oil. To a solution of resulting alcohol
(9.79 g, 71 mmol) in CH2Cl2 (280 mL) was added methanesulfonyl
chloride (6.0 mL, 78 mmol) and Et3N (14.8 mL, 107 mmol) under N2
at 0 ꢁC. The resulting mixture was allowed to warm to rt. After
stirring for 2 h, the reaction mixture was washed with 1 N HCl
(150 mL), saturated aq NaHCO3 (150 mL), and brine (150 mL), dried
over MgSO4, and concentrated to give a light yellow oil that was
immediately used without further purification. The resulting
mesylate (15.2 g, 71 mmol) was added to a Schlenk flask with ac-
etone (280 mL). NaI (16.0 g, 107 mmol) was added and the flask was
sealed and placed in an oil bath preheated to 65 ꢁC. After stirring at
65 ꢁC for 15 h, the mixture was allowed to cool to rt and quenched
with water (280 mL). The reaction mixture was extracted with
pentane (3ꢂ300 mL) and the combined organic layers were washed
with brine (200 mL), dried over MgSO4, and concentrated to give
14.0 g (57 mmol, 80% over two steps) of 27 as a light yellow oil. Rf
4.1.11. 2-(Hydroxymethyl)-2-methyl-5-(triisopropylsilyloxy)pentane-
nitrile (36). To a solution of 35 (64.8 g, 207 mmol) in DMF (400 mL)
was added NaH (60% in mineral oil, 9.89 g, 248 mmol) portion-wise,
followed by methyl iodide (25.7 mL, 414 mmol) at rt. The reaction
mixture was stirred for 1 h, after which the reaction was quenched
with water (500 mL) then extracted with Et2O (3ꢂ500 mL). The
combined organic layers were washed with water (500 mL) and
brine (300 mL), dried over MgSO4, and concentrated to give 67.8 g
(207 mmol, 100%) of a clear oil, which was used without further
purification. Rf 0.54 (4:1 hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3)
d
3.81 (s, 3H), 3.71 (t, J¼5.9 Hz, 2H), 2.08e2.00 (m, 1H),
1.93e1.85 (m, 1H), 1.79e1.69 (m, 1H), 1.60 (s, 3H), 1.63e1.55 (m, 1H),
1.04 (m, 21H). To a solution of the ester (68.7 g, 207 mmol) in 14:1
THF/water (690 mL) was added NaBH4 (39.0 g, 1.03 mol) at rt. After
stirring for 3 h, saturated aq NH4Cl (300 mL) was added slowly at
0.62 (2:1 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3)
2.45 (s, 1H), 2.17 (m, 2H), 1.99e1.86 (m, 2H), 1.69 (s, 3H); 13C NMR
(126 MHz, CDCl3) 120.4, 80.8, 73.1, 42.1, 31.0, 29.7, 27.6, 5.0; IR
d 3.26 (m, 2H),
0
ꢁC. The mixture was stirred until gas evolution ceased. The re-
action mixture was extracted with Et2O (3ꢂ500 mL) and the
combined organic layers were washed with saturated aq NaHCO3
(300 mL), and brine (300 mL), dried over MgSO4, and concentrated
to give 62 g (207 mmol, 100%) of 36 as a colorless oil, which was
used immediately without purification. Rf 0.47 (2:1 hexanes/
d
(film) nmax 3290, 2939, 1451, 1382, 1294, 1253, 1185, 1148 cmꢃ1
;
HRMS (EI) calcd for C8H18NI ([M]þ): m/z 246.9858, found 246.9858.
4.1.14. Ethyl 2-(4-cyano-4-methylhex-5-yn-1-yl)-6-isopropyl-4,5,7-
trimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (38). To
a flask containing KOt-Bu (850 mg, 7.57 mmol) under N2 were
added 21 (1.00 g, 3.78 mmol) and diethyl carbonate (0.97 mL,
7.57 mmol) in THF (19 mL) at rt. The resulting mixture was heated
to 70 ꢁC in a flask fitted with a reflux condenser for 30 min. After
cooling to rt over 1 h, the mixture was diluted with EtOAc (40 mL)
and saturated aq NaHCO3 (40 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (2ꢂ40 mL). The
combined organic layers were washed with brine (40 mL), dried
over MgSO4, and concentrated to give 32 as a thick orange oil that
was used without further purification. Rf 0.43 (2:1 hexanes/
EtOAc). To a solution of the 32 (1.23 g, 3.78 mmol) in acetone
(20 mL) were added K2CO3 (1.56 g, 11.3 mmol) and 33 (933 mg,
3.78 mmol) in a Schlenk flask at rt. The flask was evacuated and
backfilled with N2 (3ꢂ), then sealed and heated at 65 ꢁC for 48 h.
After cooling to rt, the mixture was diluted with water (40 mL)
and extracted with Et2O (3ꢂ40 mL). The combined organic layers
were washed with brine (40 mL), dried over MgSO4, and con-
centrated. Flash chromatography (9:1 to 4:1 hexanes/EtOAc) gave
1.48 g (3.25 mmol, 86% over two steps) of 38 as a viscous dark
orange syrup. Rf 0.48 (2:1 hexanes/EtOAc); Mixture of di-
EtOAc); 1H NMR (500 MHz, CDCl3)
d
3.77 (t, J¼5.8 Hz, 2H), 3.67 (m,
2H), 2.04 (t, J¼6.7 Hz,1H), 1.90e1.76 (m,1H), 1.67e1.59 (m, 3H),1.38
(s, 3H), 1.09 (m, 21H); 13C NMR (151 MHz, CDCl3)
123.2, 68.0, 62.8,
d
39.4, 32.0, 28.0, 21.0, 18.0, 11.9; IR (film) nmax 3454, 2943, 2866,
1463, 1383, 1106, 1069 cmꢃ1; HRMS (ES) calcd for C13H26NO2Si
([MꢃC3H7]þ): m/z 256.1733, found 256.1737.
4.1.12. 2-Ethynyl-2-methyl-5-(triisopropylsilyloxy)pentanenitrile
(37). To a solution of anhydrous DMSO (31.0 mL, 436 mmol) in
CH2Cl2 (500 mL) was added oxalyl chloride (18.3 mL, 218 mmol)
under N2 at ꢃ78 ꢁC. After stirring for 120 min, a solution of 36
(32.5 g, 109 mmol) in CH2Cl2 (100 mL) was added at ꢃ78 ꢁC via
cannula. After an additional 4 h, Et3N (121 mL, 872 mmol) was
added at ꢃ78 ꢁC. The resulting mixture was allowed to warm to rt
and stirred for 12 h and then poured into a mixture of saturated
aq NH4Cl (300 mL) and water (300 mL). The layers were separated
and the aqueous layer was extracted with CH2Cl2 (3ꢂ500 mL). The
combined organic layers were washed with brine (300 mL), dried
over MgSO4, and concentrated to give a yellow oil, which was taken
on immediately without further purification. To a solution of the
crude aldehyde (32.4 g, 109 mmol) in MeOH (600 mL) were added
K2CO3 (30.1 g, 218 mmol) and the OhiraeBestmann reagent (23.0 g,
120 mmol) at 0 ꢁC. After stirring for 2 h, the reaction mixture was
poured into a mixture of saturated aq NaHCO3 (150 mL) and water
(150 mL), and extracted with Et2O (3ꢂ500 mL). The combined or-
ganic layers were washed with brine (300 mL), dried over MgSO4,
and concentrated to give a yellow oil. Flash chromatography (9:1
hexanes/EtOAc) gave 27.4 g (93 mmol, 85% over two steps) of 37 as
astereomers (1:1) 1H NMR (600 MHz, CDCl3)
d 4.20e4.07 (m, 4H),
3.93 (s, 6H), 3.84 (s, 6H), 3.84 (s, 6H), 3.60 (d, J¼17.4 Hz, 1H), 3.58
(d, J¼17.4 Hz, 1H), 3.52e3.45 (m, 2H), 2.93 (d, J¼17.4 Hz, 2H), 2.36
(s, 1H), 2.32 (s, 1H), 2.21e2.10 (m, 2H), 1.87e1.67 (m, 6H), 1.55 (m,
4H), 1.59 (s, 6H), 1.28 (d, J¼3.8 Hz, 12H), 1.20 (t, J¼7.1 Hz, 6H). 13C
NMR (151 MHz, CDCl3)
d 198.1, 198.0, 170.9, 170.8, 158.8, 154.1,
145.36, 145.35, 144.9, 135.0, 134.9, 122.9, 122.7, 120.1, 120.0, 80.7,
80.6, 72.24, 72.19, 62.3, 62.2, 61.61, 61.57, 60.9, 60.8, 60.6, 60.14,
60.12, 41.0, 34.0, 33.9, 32.7, 31.14, 31.13, 27.13, 27.09, 25.3, 21.6, 21.1,
21.0, 14.0; IR (film) nmax 3262, 2939, 2873, 1740, 1705, 1582, 1472,
1420, 1322, 1275, 1198, 1136, 1037 cmꢃ1; HRMS (ESI) calcd for
C26H33NO6 ([MþH]þ): m/z 456.2381, found 456.2396.
a light yellow oil. Rf 0.67 (EtOAc); 1H NMR (500 MHz, CDCl3)
(t, J¼5.5 Hz, 2H), 2.40 (s,1H), 1.99e1.81 (m, 4H), 1.68 (s, 3H),1.08 (m,
21H); 13C NMR (126 MHz, CDCl3)
120.8, 81.4, 72.4, 62.8, 38.2, 31.5,
d 3.79
d
29.4, 27.6, 18.4, 12.3; IR (film) nmax 3312, 2943, 2866, 1463, 1382,
1367, 1240, 1107, 1070, 1014 cmꢃ1; HRMS (ESI) calcd for C17H31NOSi
([MþH]þ): m/z 294.2248, found 294.2259.
4.1.15. 2-Ethynyl-5-(6-isopropyl-4,5,7-trimethoxy-1-oxo-2,3-
dihydro-1H-inden-2-yl)-2-methylpentanenitrile (39). To a solution
of 38 (1.04 g, 2.35 mmol) in 3:1 THF/water (12 mL) was added
LiOH$H2O (246 mg, 5.88 mmol). The resulting mixture was heated
at 65 ꢁC for 12 h in a sealed flask. After cooling to rt, the reaction
mixture was acidified with 1 N HCl (12 mL) and extracted with
EtOAc (3ꢂ12 mL). The combined organic layers were washed with
brine (12 mL), dried over MgSO4, and concentrated to give 774 mg
4.1.13. 2-Ethynyl-5-iodo-2-methylpentanenitrile (33). To a solution
of 37 (27.4 g, 93 mmol) in THF (370 mL) was added tert-buty-
lammonium fluoride (1.0 M in THF, 112 mL) at rt. After stirring for
12 h, the reaction mixture was poured into saturated aq NaHCO3
(300 mL) and extracted with Et2O (3ꢂ300 mL), the combined or-
ganic layers were washed with brine (200 mL), dried over MgSO4,
and concentrated to give
a
crude colorless oil. Flash

5674
F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
(2.01 mmol, 86%) of crude indanone 39 as a yellow oil, which was
used without further purification. Rf 0.48 (2:1 hexanes/EtOAc);
The vial was sealed and the reaction mixture was heated to 80 ꢁC.
After stirring for 4 days, the solvent was removed and CH2Cl2 (1 mL)
was added. The solution was filtered through a pad of Celite and
concentrated to give 260 mg (0.67 mmol, 87%) of 29 as a light
yellow oil that was used without further purification. Rf 0.25 (2:1
Mixture of diastereomers (1:1) 1H NMR (600 MHz, CDCl3)
d 3.95 (s,
6H), 3.92 (s, 6H), 3.88 (s, 6H), 3.57e3.49 (m, 2H), 3.31 (d, J¼8.0 Hz,
1H), 3.28 (d, J¼8.0 Hz, 1H), 2.73 (m, 1H), 2.70 (m, 1H), 2.68e2.58 (m,
2H), 2.43 (s, 1H), 2.41 (s, 1H), 2.08e1.97 (m, 2H), 1.91e1.78 (m, 8H),
1.68 (s, 6H), 1.58e1.45 (m, 2H), 1.34 (d, J¼7.1 Hz, 12H); 13C NMR
hexanes/EtOAc); 1H NMR (600 MHz, CDCl3)
d
7.18 (d, J¼11.9 Hz, 1H),
6.54 (d, J¼11.9 Hz, 1H), 5.36 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.64 (s,
3H), 3.45 (m, 1H), 3.13 (s, 1H), 2.94 (s, 1H), 2.44 (t, J¼5.9 Hz, 2H),
2.07e1.99 (m, 1H), 1.66 (m, 1H), 1.58e1.52 (m, 2H), 1.35 (s, 3H), 1.33
(151 MHz, CDCl3)
d 204.3, 158.2, 153.4, 145.7, 134.7, 124.6, 124.5,
120.3, 80.9, 72.2, 62.41, 62.39, 60.7, 60.1, 47.7, 47.5, 41.0, 40.9, 31.29,
31.26, 31.1, 31.0, 29.1, 29.0, 27.22, 27.18, 25.3, 23.8, 23.5, 21.6; IR
(film) nmax 3260, 2939, 2871, 1704, 1583, 1470, 1419, 1322, 1273,
1201, 1172, 1138, 1058, 1037 cmꢃ1; HRMS (ESI) calcd for C23H30NO4
([MþH]þ): m/z 384.2169, found 384.2188.
(d, J¼7.1 Hz, 6H); 13C NMR (151 MHz, CDCl3)
d 179.9, 153.2, 151.5,
145.6, 137.1, 132.3, 131.6, 131.1, 129.0, 128.1, 124.8, 61.9, 60.8, 60.3,
46.2, 36.3, 32.2, 31.8, 25.7, 24.2, 22.1, 22.0, 19.6; IR (film) nmax 3468,
3179, 2935, 2870, 1676, 1581, 1453, 1400, 1378, 1341, 1316, 1260,
1120, 1059, 1042 cmꢃ1; HRMS (ESI) calcd for C23H32NO4 ([MþH]þ):
m/z 386.2326, found 386.2336.
4.1.16. 2-Ethynyl-5-(5-isopropyl-4,6,7-trimethoxy-1H-inden-2-yl)-2-
methylpentanenitrile (31). To a solution of indanone 39 (748 mg,
1.95 mmol) in EtOH (10 mL) was added NaBH4 (74.0 mg, 1.95 mmol)
at rt in a water bath to maintain temperature. After 3 h, saturated
aq NH4Cl (30 mL) was added slowly at 0 ꢁC, along with Et2O
(30 mL). The reaction mixture was stirred until bubbling was no
longer observed. The layers were separated and the aqueous layer
was extracted with Et2O (2ꢂ30 mL). The combined organic layers
were washed with saturated aq NaHCO3 (30 mL) and brine (30 mL),
dried over MgSO4, and concentrated to give 563 mg (1.45 mmol) of
a clear oil, which was used immediately without purification. To
a solution of the crude indanol (543 mg, 1.45 mmol) in toluene
(7 mL) was added KHSO4 (191 mg, 1.45 mmol) in a sealed vial. The
reaction mixture was heated to 120 ꢁC and stirred for 4 h. After
cooling to rt, the reaction mixture was passed through a silica plug
with 2:1 hexanes/EtOAc to give 456 mg (1.24 mmol, 63% over two
steps) of 31 as a light yellow oil. Rf 0.63 (2:1 hexanes/EtOAc); 1H
4.1.19. 8-Isopropyl-6,7,9-trimethoxy-1-methyl-2,3,4,5-tetrahydro-
1H-4a,11a-epoxydibenzo[a,d][7]annulene-1-carboxamide (41). A
mixture of 29 (260 mg, 0.670 mmol) and NaHCO3 (113 mg,
0.81 mmol) in CH2Cl2 (7 mL) at 0 ꢁC was treated with m-chlor-
operbenzoic acid (70%,185 mg, 0.810 mmol). The resulting mixture
was stirred at 0 ꢁC for 15 min, and then warmed to rt. After stirring
for 3 h, the reaction mixture was quenched with saturated
aq NaHSO3 (5 mL). The solution was stirred for 1 h and then
extracted with Et2O (2ꢂ10 mL). The combined organic layers were
washed with saturated aq NaHCO3, (3ꢂ10 mL), and brine (10 mL),
dried over MgSO4, and concentrated to give 208 mg (0.52 mmol,
78%) of 41 as a clear oil. Rf 0.25 (2:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3)
d
6.82 (d, J¼11.6 Hz, 1H), 6.71 (s, 1H), 6.19 (d,
J¼11.6 Hz, 1H), 5.38 (s, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H),
3.56 (d, J¼13.2 Hz,1H), 3.47 (m,1H), 2.32 (d, J¼13.0 Hz,1H), 2.15 (m,
NMR (600 MHz, CDCl3)
d
6.64 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.86
2H), 2.06e1.98 (m, 2H),1.84 (m, 2H),
d
1.40 (d, J¼7.1 Hz, 3H),1.35 (d,
(s, 3H), 3.51 (m, 1H), 3.37 (s, 2H), 2.59 (t, J¼7.2 Hz, 2H), 2.43 (s, 1H),
J¼7.1 Hz, 3H), 1.09 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 178.7,153.2,
2.05e1.93 (m, 2H), 1.91e1.79 (m, 2H), 1.68 (s, 3H), 1.37 (d, J¼7.1 Hz,
152.2, 147.1, 133.6, 129.1, 128.5, 127.0, 125.5, 64.8, 62.4, 60.5, 60.4,
53.5, 45.2, 35.7, 32.5, 26.4, 25.7, 22.0, 19.9, 16.2; IR (film) nmax 3461,
2936, 1680, 1454, 1416, 1395, 1340, 1257, 1121, 1044 cmꢃ1; HRMS
(ESI) calcd for C23H32O5 ([MþH]þ): m/z 402.2275, found 402.2281.
6H); 13C NMR (151 MHz, CDCl3)
d 148.8, 147.1, 147.0, 145.6, 133.6,
133.2, 133.0, 123.6, 120.3, 80.9, 72.2, 62.0, 61.0, 59.8, 40.7, 38.7, 31.3,
30.5, 27.2, 25.7, 24.9, 22.2; IR (film) nmax 3275, 2937, 2832, 1460,
1418, 1337, 1278, 1218, 1121, 1057 cmꢃ1; HRMS (ESI) calcd for
C23H29NO3 ([MþH]þ): m/z 368.2220, found 368.2229.
4.1.20. 11a-Hydroxy-8-isopropyl-6,7,9-trimethoxy-1-methyl-1,2,3,4,
5,11a-hexahydro-4a,1-(epoxymethano)dibenzo[a,d][7]annulen-13-
one (42). To a solution of 41 (190 mg, 0.470 mmol) in CH2Cl2
(18 mL) was added camphorsulfonic acid (109 mg, 0.470 mmol) at
rt. After 2 h, the reaction mixture was quenched with saturated
aq NaHCO3 (20 mL) and extracted with Et2O (2ꢂ30 mL). The
combined organic layers were washed with brine (30 mL), dried
over MgSO4, and concentrated to give 163 mg (0.40 mmol, 86%) of
42 as a white foam that was used without further purification. Rf
4.1.17. 8-Isopropyl-6,7,9-trimethoxy-1-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[a,d][7]annulene-1-carbonitrile (30). In a N2 dry box,
a Schlenk flask was charged with GaCl3 (9 mg, 0.05 mmol) and
ꢀ
powdered 4 A molecular sieves (18 mg). The flask was removed
from the dry box and a solution of 31 (78 mg, 0.21 mmol) in freshly
distilled toluene (2.1 mL) was added via syringe under N2 to give
a dark brown solution. The flask was sealed and placed in an oil
bath that was preheated to 100 ꢁC. After stirring at 100 ꢁC for 48 h,
the mixture was allowed to cool to rt and the reaction mixture was
passed through a silica column with 4:1 hexanes/EtOAc to give
71 mg (0.19 mmol, 91%) of 30 as a viscous yellow oil. Rf 0.48 (4:1
0.33 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3)
d 7.15 (d,
J¼12.6 Hz,1H), 5.88 (d, J¼12.6 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.69
(d, J¼17.0 Hz, 1H), 3.65 (s, 3H), 3.45 (d, J¼17.0 Hz, 1H), 3.43 (m, 1H),
1.83e1.76 (m, 2H), 1.71e1.65 (m, 3H), 1.65e1.58 (m, 2H), 1.34 (d,
J¼6.7 Hz, 3H),1.32 (d, J¼6.7 Hz, 3H),1.30 (s, 3H); 13C NMR (151 MHz,
hexanes/EtOAc); 1H NMR (600 MHz, CDCl3)
d
7.27 (d, J¼11.9 Hz,1H),
6.66 (d, J¼11.9 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.70 (s, 3H),
CDCl3) d 179.0, 154.1, 154.0, 148.7, 133.6, 128.1, 127.7, 123.03, 122.96,
3.53e3.41 (m, 1H), 3.10 (s, 1H), 3.00 (s, 1H), 2.50e2.37 (m, 2H),
85.6, 80.1, 62.8, 60.4, 59.6, 51.9, 31.5, 30.8, 30.6, 26.1, 21.9, 21.8, 18.2,
14.0; IR (film) nmax 3466, 2932, 2874, 1781, 1653, 1570, 1558, 1507,
1455, 1416, 1397, 1341, 1256, 1123, 1092, 1035 cmꢃ1; HRMS (ESI)
calcd for C23H31O6 ([MþH]þ): m/z 403.2115, found 403.2118.
2.16e2.10 (m, 1H),1.85e1.78 (m,1H), 1.74 (m, 2H),1.49 (s, 3H), d 1.39
(d, J¼3.4 Hz, 3H), 1.38 (d, J¼3.4 Hz, 3H); 13C NMR (151 MHz, CDCl3)
d
153.3, 151.5, 145.7, 136.6, 132.4, 131.2, 129.0, 127.8, 127.3, 125.1,
124.6, 61.9, 60.8, 60.4, 35.6, 35.3, 32.1, 31.1, 26.3, 25.7, 22.09, 22.08,
19.1; IR (film) nmax 2937, 2870, 1453, 1417, 1400, 1342, 1316, 1260,
1121, 1060, 1043 cmꢃ1; HRMS (EI) calcd for C23H29NO3 ([M]þ): m/z
367.2147, found 367.2149.
4.1.21. 8-Isopropyl-6,7,9-trimethoxy-1-methyl-1,2,3,4,5,10-hexahydro-
4a,1-(epoxymethano)dibenzo[a,d][7]annulen-13-one (43). A mixture
of 42 (100 mg, 0.25 mmol) and10% Pd/C (40 mg) in EtOH (1.2 mL) was
placed under an atmosphere of H2 (balloon) and stirred rapidly at rt
for 12 h. The mixture was then filtered through Celite and concen-
trated to give 77 mg (0.19 mmol) of a yellow foam, which was used
without further purification. To a solution of the resulting alcohol
(77 mg, 0.19 mmol) in dry pyridine (1.6 mL) was added thionyl
4.1.18. 8-Isopropyl-6,7,9-trimethoxy-1-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[a,d][7]annulene-1-carboxamide (29). To a solution of
cycloheptadiene 30 (285 mg, 0.780 mmol) in 2:1 EtOH/water
(4 mL) was added Pt catalyst 4017 (11 mg, 0.03 mmol) in a vial at rt.

F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
5675
chloride (82
mL,1.14 mmol) at rt. The solution instantly turned yellow.
2.44e2.37 (m, 1H), 2.27 (s, 1H), 1.96e1.36 (m, 6H),
d
1.34 (d,
After 90 min, the reaction mixture was quenched with 1 N HCl (3 mL)
andextracted with Et2O (3ꢂ3 mL). The combined organic layers were
washed with brine (3 mL), dried MgSO4, and concentrated to give
45 mg (0.12 mmol, 47% over two steps) of 43 as a yellow oil that was
used without further purification. Rf 0.53 (2:1 hexanes/EtOAc); 1H
J¼2.9 Hz, 3H), 1.33 (d, J¼2.8 Hz, 3H), 1.27 (s, 3H); IR (film) nmax 2935,
1778, 1451, 1396, 1340, 1254, 1121, 1034 cmꢃ1; HRMS (ESI) calcd for
C23H31O5 ([MþH]þ): m/z 387.2166, found 387.2176.
4.1.24. (R)-tert-Butyl 2-cyano-2-methyl-5-(triisopropylsilyloxy)pen-
tanoate (53). A solution of tert-butyl 2-cyanopropanoate20d (49,
2.33 g, 15.0 mmol) in benzene (47 mL) was evacuated and backfilled
with N2 (3ꢂ). Acrolein (50, 90%, 0.5 mL, 7.5 mmol) was added to the
solution via syringe and the mixture was cooled to 0 ꢁC. In a separate
flask, Rh(acac)(CO)2 (128 mg, 0.15 mmol) and (S,S)-(R,R)-PhTRAP20b
(51, 128 mg, 0.16 mmol) were dissolved in 3 mL of benzene, when
the bubbling ceased the catalyst solution was added slowly to the
reaction mixture via syringe. The resulting mixture was stirred at 0 ꢁC
for a 2 h and monitored by TLC. Once the reaction was completed,
ethanol (99%, 10 mL) was added to the reaction mixture at 0 ꢁC,
NaBH4 (283 mg, 7.5 mmol) was then slowly added. The reaction was
warmed up to rt and stirred for w3 h. The reaction was quenched
with a saturated solution of NH4Cl (50 mL) and extracted with EtOAc
(4ꢂ30 mL). The combined organic layers were dried over MgSO4, and
concentrated. The crude product was used without further purifi-
NMR (600 MHz, CDCl3)
3H), 3.41 (m, 2H), 3.35 (m, 1H), 3.26 (m, 1H), 1.94 (m, 1H), 1.81e1.74
(m, 3H), 1.48e1.39 (m, 3H),
1.34 (d, J¼4.4 Hz, 3H), 1.33 (d, J¼4.4 Hz,
3H),1.19 (s, 3H); 13C NMR (151 MHz, CDCl3)
177.8,151.3,150.8,148.5,
d 5.50(m,1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.62 (s,
d
d
146.7, 133.5, 127.5, 113.3, 84.5, 62.3, 60.3, 60.2, 49.0, 37.0, 30.3, 32.5,
26.0, 24.1, 24.2, 22.2, 22.1, 19.3, 16.3; IR (film) nmax 2936, 2873, 1779,
1454,1414,1381,1341,1253,1122,1094,1043,1033; HRMS (ESI) calcd
for C23H30O5 ([MþH]þ): m/z 387.2166, found 387.2167.
4.1.22. 8-Isopropyl-6,7,9-trimethoxy-1-methyl-1,2,3,4,5,11a-hexahy-
dro-4a,1-(epoxymethano)dibenzo[a,d][7]annulen-13-one
from 43). To a solution of 43 (60 mg, 0.15 mmol) in EtOAc (1.5 mL)
were added tert-butyl hydrogen peroxide (0.15 mL) and 3 A molec-
(44þ45,
ꢀ
ular sieves (150 mg) at rt. After 30 min, Mn(OAc)3$H2O (5 mg,
0.02 mmol) was added at rt and kept in the dark for 18 h. The reaction
mixture was filtered through Celite to give 73 mg (0.15 mmol) as
a yellow oil that was used without further purification. To a solution
of the resulting peroxide (73 mg, 0.15 mmol) in Et2O (1.5 mL) was
added a freshly prepared amalgam from aluminum foil (150 mg) in
2% HgCl2 solution that was washed with water (1 mL), ethanol (1 mL),
and ether (1 mL). The reaction mixture was heated to 40 ꢁC. After 2 h,
the reaction mixture was filtered through Celite with Et2O and
concentrated to give 34 mg (0.085 mmol) of a clear oil that was used
without further purification. To a solution of the crude alcohol
(34.0 mg, 0.085 mmol) in 1,2 dichloroethane (8.5 mL) were added
tosyl hydrazide (79 mg) and camphorsulfonic acid (9.8 mg,
0.085 mmol) at rt. The reaction mixture was sealed and heated to
80 ꢁC for 12 h. The reaction mixture was cooled to rt and passed
through a pad of Celite. Flash chromatography (4:1 hexanes/EtOAc)
gave 10 mg (0.025 mmol, 17% over three steps) of a colorless oil. 1H
NMR analysis showed >10:1 dr with the intermediate leading to epi-
icetexone (44) as the major diastereomer. Rf 0.55 (2:1 hexanes/
cation. Rf 0.40 (6:4 hexanes/EtOAc); 1H NMR (300 MHz, CDCl3)
d 3.68
(t, J¼5.6 Hz, 2H), 2.07e1.96 (m, 1H), 1.87e1.73 (m, 2H), 1.73e1.61 (m,
1H),1.56 (s, 3H),1.50 (s, 9H),1.22e1.13 (m,1H). The crude alcohol (52)
was dissolved in CH2Cl2 (50 mL). Imidazole (2.25 g, 33 mmol) and
triisopropylsilyl chloride (3.5 mL,16.5 mmol) were added to the flask
and the reaction mixture was stir at rt. When the reaction was
complete by TLC (w4 h), saturated aq NH4Cl (30 mL) was added and
the aqueous layer was extracted with CH2Cl2 (3ꢂ30 mL). The com-
bined organic layers were washed with brine (30 mL), dried over
MgSO4, and concentrated. The crude material was purified via flash
chromatography (9:1 hexanes/EtOAc) to give 4.32 g (11.7 mmol, 78%)
of 53 as a clear oil. The desired product was often isolated along with
triisopropyl silanol and it was carried on as is in the following re-
action. Rf 0.66 (4:1 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3):
d 3.71
(t, J¼5.9 Hz, 2H), 1.99 (td, J¼12.9, 4.4 Hz, 1H), 1.82 (td, J¼13.0, 4.3 Hz,
1H), 1.78e1.69 (m, 1H), 1.64e1.57 (m, 1H), 1.54 (s, 3H), 1.48 (s, 9H),
1.09e1.02 (m, 21H); 13C NMR (126 MHz, CDCl3):
d 168.4, 120.5, 83.7,
EtOAc); 1H NMR (600 MHz, CDCl3)
d
6.97 (dd, J¼12.2, 2.8 Hz,1H), 5.68
62.5, 44.6, 35.2, 28.9, 27.8, 23.3, 18.1, 12.0; IR (film) nmax 2943, 2867,
(dd, J¼12.2, 3.1 Hz,1H), 3.88 (s, 3H), 3.73 (s, 3H), 3.64 (s, 3H), 3.58 (d,
J¼16.4 Hz,1H), 3.46e3.37 (m,1H), 3.13 (d, J¼16.4 Hz,1H), 2.87 (s,1H),
1739 cmꢃ1; HRMS (ESI) calcd for C20H39O3NNaSi ([MþNa]þ): m/z
392.2591, found 392.2594; [
a
]
21 ꢃ3.32 (c 1.17, CHCl3).
D
1.84e1.76 (m, 1H), 1.70e1.60 (m, 3H), 1.56e1.46 (m, 2H),
d 1.34 (d,
J¼2.6 Hz, 3H), 1.32 (d, J¼2.6 Hz, 3H), 1.23 (s, 3H); 13C NMR (151 MHz,
4.1.25. (R)-2-(Hydroxymethyl)-2-methyl-5-(triisopropylsilyloxy)pen-
tanenitrile (36). To a solution of 53 (4.32 g, 11.7 mmol) in a mixture
of ethanol(99%)/THF (4:1, 100 mL, 0.15 M) was added NaBH4 (2.84 g,
75 mmol). The resulting mixture was stirred at ambient tempera-
ture for 18 h. The reaction mixture was cooled to 0 ꢁC and then
quenched slowly by addition of a saturated aq NH4Cl (100 mL). The
aqueous layer was extracted with EtOAc (4ꢂ30 mL). The combined
organic layers were washed with brine (30 mL), dried over MgSO4,
and concentrated. The crude product was purified via flash chro-
matography (9:1 to 3:2 hexanes/EtOAc) to give 2.82 g (9.41 mmol,
80%) alcohol 36 as a clear oil. The alcohol 36 showed identical NMR
data to the previously reported data for the racemic alcohol. Rf 0.27
(8:2 hexanes/EtOAc).
CDCl3) d 180.1,153.0,148.6,133.6,127.0, 126.5,124.7, 122.1, 85.3, 62.3,
60.4, 59.9, 55.4, 47.0, 37.3, 27.4, 27.0, 26.0, 22.0, 21.9, 19.3, 18.9; IR
(film) nmax 2935,1778,1451,1396,1340,1254,1121,1034; HRMS (ESI)
calcd for C23H31O5 ([MþH]þ): m/z 387.2166, found 387.2176.
4.1.23. 8-Isopropyl-6,7,9-trimethoxy-1-methyl-1,2,3,4,5,11a-hexahy-
dro-4a,1-(epoxymethano)dibenzo[a,d][7]annulen-13-one
(44þ45,
from 41). To a solution of 41 (30 mg, 0.08 mmol) in benzene
(1.5 mL) were added tosyl hydrazide (74.5 mg, 0.400 mmol) and
camphorsulfonic acid (8.70 mg, 0.038 mmol) at rt. The reaction
vessel was sealed and brought to 80 ꢁC for 12 h. The reaction
mixture was cooled to rt and passed through a pad of Celite. Basic
alumina chromatography (4:1 hexanes/EtOAc) gave 12 mg
(0.031 mmol, 42%) of 44 and 45 as a colorless oil. 1H NMR analysis
showed 2.5:1 dr with the intermediate leading to epi-icetexone
(44) as the major diastereomer. Rf 0.53 (2:1 hexanes/EtOAc); Major
4.1.26. (S)-N-((8-Isopropyl-6,7,9-trimethoxy-1-methyl-2,3,4,5-tetra
hydro-1H-dibenzo[a,d][7]annulen-1-yl)methyl)-4-bromobenzamide
(54). To a flame dried Schlenk flask equipped with a stir bar and
under N2 atmosphere was added lithium aluminum hydride (38 mg,
1.0 mmol). Nitrile 30 (79 mg, 0.20 mmol) was added as a solution in
anhydrous THF (4 mL). The Schlenk flask was sealed and the reaction
was heated to 65 ꢁC for 2 h. The reaction mixture was cooled to rt and
slowly quenched by the addition of powdered Na2SO4$10H2O
(w200 mg). The solution was stirred overnight open to air, filter
through Celite, wash with EtOAc (50 mL), and concentrated to give
diastereomer: 1H NMR (500 MHz, CDCl3)
1H), 5.68 (m, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.64 (s, 3H), 3.59 (d,
d
6.97 (dd, J¼12.2, 3.0 Hz,
J¼16.4 Hz, 1H), 3.46e3.37 (m, 1H), 3.13 (d, J¼16.4 Hz, 1H), 2.87 (s,
1H), 1.88e1.74 (m, 2H), 1.64 (m, 4H),
d
1.34 (d, J¼2.9 Hz, 3H), 1.33 (d,
J¼2.8 Hz, 3H), 1.24 (s, 3H); Minor diastereomer: 1H NMR (500 MHz,
CDCl3) 6.79 (dd, J¼11.0, 2.4 Hz, 1H), 6.09 (dd, J¼11.0, 2.4 Hz, 1H),
3.87 (s, 3H), 3.79 (s, 3H), 3.66 (s, 3H), 3.42 (m, 1H), 2.72 (m, 1H),

5676
F. de J. Cortez et al. / Tetrahedron 69 (2013) 5665e5676
73 mg (0.20 mmol, 100%) of the amine that was used without further
References and notes
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(1.4 mL) and to the solution was added triethylamine (20
mL,
0.14 mmol) followed by the 4-bromobenzoyl chloride (23 mg,
0.11 mmol). The reaction was stirred at ambient temperature and
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to yield 27 mg (0.05 mmol, 71%) of 54 as a white solid. Slow diffusion
crystallization of hexanes into EtOAc provided X-ray quality crystals.
Rf 0.60 (2:1 hexanes/EtOAc); mp 148e157 ꢁC; 1H NMR (600 MHz,
CDCl3)
d
7.34 (d, J¼8.0 Hz, 2H), 7.22 (d, J¼11.9 Hz, 1H), 6.98 (s, 2H),
6.67 (d, J¼11.9 Hz, 1H), 5.45 (s, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 3.60 (dd,
J¼13.2, 8.7 Hz,1H), 3.52e3.31 (m, 5H), 3.08 (d, J¼12.7 Hz, 1H), 2.69 (s,
1H), 2.38 (t, J¼6.1 Hz, 2H), 1.70e1.60 (m, 2H), 1.47 (t, J¼5.2 Hz, 2H),
1.29 (d, J¼7.1 Hz, 3H), 1.28e1.24 (m, 6H); 13C NMR (126 MHz, CDCl3)
d
165.8, 153.4, 151.6, 145.8, 133.1, 132.7, 132.5, 132.0, 131.9, 128.9, 128.1,
128.0,126.0,124.8, 61.7, 61.1, 60.6, 49.4, 38.2, 34.1, 32.7, 32.5, 25.8, 24.1,
22.2, 22.2, 19.3; IR (film) nmax 3338, 3425, 2931, 2869, 1656, 1590,
1525 cmꢃ1; HRMS (ESI) calcd for C30H37O4N79Br ([MþH]þ): m/z
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€
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554.1900, found 554.1900; [
a
]
21 þ72.0 (c 0.65, CHCl3).
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D
Acknowledgements
The authors are grateful to the NIH (NIGMS RO1 086374 to R.S.
and F31GM089139-01 to F.C.) and Amgen for generous, unrestricted
financial support. D.L. thanks the FQRNTeCanada for a postdoctoral
fellowship. The authors thank Ms. Ariel Yeh (UC Berkeley) and Mr.
Christopher Marth (UC Berkeley) for their assistance in the prepa-
ration of starting material 31.
€
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Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.04.049.
21. Determined using a ChiralPak IC column. For details, see the Supplementary
data.