Oxidative 1,2- and 1,3-alkyl shift processes: Developments and applications in synthesis

Article abstract of DOI:10.1021/jo300169k

Oxidative 1,2- and 1,3- alkyl shifts mediated by a hypervalent iodine reagent were performed on simple and inexpensive phenol derivatives. These transpositions enable rapid redesign of the main aromatic skeleton to generate good yields of highly functionalized scaffolds containing a prochiral dienone system, a quaternary carbon center connected to as many as four sp² centers, and a carbonyl functionality or precursor. An efficient enantioselective version of this process resulting in the formation of a challenging quaternary carbon center is also described. The products represent the central cores of several natural products having important bioactivities. As an illustration of the potential of this method, we describe the rapid synthesis of several functionalized polycyclic systems as well as a formal synthesis of acetylaspidoalbidine, a hexacyclic alkaloid belonging to the Aspidosperma family.

Full text of DOI:10.1021/jo300169k

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pubs.acs.org/joc
Oxidative 1,2- and 1,3-Alkyl Shift Processes: Developments and
Applications in Synthesis
Kimiaka C. Guerard, Amandine Guerinot, Cloe Bouchard-Aubin, Marc-Andre Menard, Mathieu Lepage,
́
́
́
́
́
Marc Andre Beaulieu, and Sylvain Canesi*
́
Laboratoire de Met
́
hodologie et Synthes
̀
e de Produits Naturels, Universite
́
du Queb
́
ec a
̀
Montrea
́
l, C.P. 8888, Succ. Centre-Ville,
Montreal, H3C 3P8 Quebec, Canada
́
S
* Supporting Information
ABSTRACT: Oxidative 1,2- and 1,3- alkyl shifts mediated by
a hypervalent iodine reagent were performed on simple and
inexpensive phenol derivatives. These transpositions enable
rapid redesign of the main aromatic skeleton to generate good
yields of highly functionalized scaffolds containing a prochiral
dienone system, a quaternary carbon center connected to as
many as four sp2 centers, and a carbonyl functionality or
precursor. An efficient enantioselective version of this process
resulting in the formation of a challenging quaternary carbon
center is also described. The products represent the central cores of several natural products having important bioactivities. As an
illustration of the potential of this method, we describe the rapid synthesis of several functionalized polycyclic systems as well as a
formal synthesis of acetylaspidoalbidine, a hexacyclic alkaloid belonging to the Aspidosperma family.
best performed in solvents such as hexafluoroisopropyl alcohol
(HFIP).8 An extension of the process to aromatic derivatives
would facilitate rapid redesign of simple and inexpensive cores,
such as phenols, into more complex spirodienone architectures.
In addition, this method is capable of transforming stable
aromatic ring structures into reactive dienone cores for use as
highly functionalized intermediates. Oxidative extensions of
cationic sigmatropic rearrangements via a 1,2-shift process or an
unprecedented 1,3 shift extension mediated by a concerted
mechanism involving a π-bond in a chairlike transition state
(contained in the substituent R3) would provide a rapid and
esthetically appealing route to complex structures, Figure 1.
INTRODUCTION
■
The sigmatropic rearrangement is one of the most impressive
transformations in organic synthesis. Processes of this type
permit rapid reconfiguration of simple skeletons into complex
architectures via 1,2-substituent shifts such as the Wagner−
Meerwein, pinacolic, and semipinacolic transpositions. Despite
being first described more than a century ago, these cationic
molecular transpositions1 still represent an appealing and
efficient route to complex molecular structures. The trans-
formations are generally performed on aliphatic substrates, and
an extension to aromatic scaffolds would open up several
applications in chemical synthesis. Our interest in oxidative
dearomatization of phenols2 mediated by hypervalent iodine
reagents3−5 led us to question whether an analogous process
could be initiated by oxidative activation. While electron-rich
aromatic systems normally react as nucleophiles, oxidative
activation converts them into highly electrophilic species, which
may then be intercepted with appropriate nucleophiles. If one
considers the behavior of the intermediate 2, this reversal of
reactivity may be thought of as involving “aromatic ring
umpolung”,2,3d an aromatic version of the umpolung concept,6
providing new strategic opportunities in synthesis by extending
several well-known aliphatic reactions to aromatic chemistry.
Such phenol dearomatization processes are generally mediated
by hypervalent iodine reagents such as iodobenzene diacetate
(DIB, an environmentally benign reagent), are well documented
in the literature, and have elicited substantial interest in the
synthetic arena. An indication of how the formation of the
corresponding phenoxonium ion 2 may be efficiently achieved
and sufficiently stabilized for nucleophilic trapping is apparent in
the work of Kita,7 who reported that such transformations are
Figure 1. Presumed course of oxidative 1,2- and 1,3-alkyl shifts.
Architectures generated by these methods are often present
in several natural products containing a quaternary carbon
center in a functionalized cyclohexanone subunit or its
derivative. Some examples include hamayne 7, a pentacyclic
core belonging to the Amaryllidaceae alkaloids,9 jiadifenin 8, a
Received: January 22, 2012
Published: February 14, 2012
© 2012 American Chemical Society
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Figure 2. Natural products containing a quaternary carbon center.
Table 1. Oxidative 1,2-Alkyl Shift Process
due to the complexity of generating a quaternary carbon center
connected to four sp2 centers in a single step. This most probably
occurs via the formation of an arenium intermediate. It should be
noted that a similar subunit is present in several natural products
such as hamayne and vindoline (Figures 2 and 3). As expected in
a normal pinacol process involving a 1,2-alkyl shift, migration of
the more electron-rich group predominates as well exemplified
by entry 3k, for which only a small amount of methyl migration
is observed (∼5%). In addition, the rearrangement may be
extended to bicyclic phenols 12, Table 2.
entry
R
R1
R2
yield (%)
a
b
c
d
e
f
H
Me
CH2CHCH2
CH2CHCH2
CH2CHCH2
CH2CHCH2
CH2C(Me)CH2
CHCH2
Ph
62
67
63
33
37
34
51
35
34
41
35
H
CH2CHCH2
Me
H
Me
CH2OTBS
Me
H
Table 2. Bicyclic System Contraction versus Migration
H
Me
g
h
i
H
Me
H
Et
Ph
Me
H
Me
Ph
j
n-Bu
Me
n-Bu
k
H
n-Bu
entry
X
R
n
yield 13 (%) yield 14 (%)
a
b
c
CH2
CH2
O
CH2CHCH2
2
2
1
2
43
novel majucin-type prezizaane isolated from the Illicium
jiadifengpi species of China,10 lycoflexine 9, an alkaloid
belonging to the lycopodium family,11 and (−)-platensimycin
10 and (−)-platencin 11, two exciting experimental antibiotics
acting as FabF inhibitors12 (Figure 2).
In this paper, we present an extension of our previous
oxidative alkyl shift processes2f to a large range of phenol
derivatives as well as an efficient enantioselective version of this
method. In addition, the formation of several advanced polycyclic
cores and a formal synthesis of acetylaspidoalbidine (an alkaloid
belonging to the Aspidosperma family) are described.
Ph
54
CH2CHCH2
43
d
CH2
Me
53
Another interesting example of this oxidative process is the
ring contraction observed in the tetralone derivative 12d,
leading to 13d in 53% yield. The process appears to occur as a
normal sigmatropic rearrangement and the rules applying to
conventional Wagner−Meerwein transpositions are observed.
One limitation results from the formation of phenol 16 as a side
product through a retro-Claisen process following nucleophilic
attack of species present in the medium (acetate, etc.) on
compound 3. Formation of this byproduct is increased if a
withdrawing substituent is present on the lateral chain (entry 1d),
which increases the electrophilicity of the ketone involved in
the retro-Claisen pathway if the reaction is not rapidly stopped
(Scheme 1).
RESULTS AND DISCUSSION
■
We decided to initially test the feasibility of oxidative 1,2-alkyl
shifts on phenol derivatives by oxidizing various benzylic
alcohol systems 1 readily obtained from various alkyl-Grignard
reagent additions to 4-hydroxyphenyl ketones. Oxidation of these
compounds promotes the desired rearrangement leading to the
products 3 in 33−67% yield. Several functional groups were in-
vestigated including allyl segments, which are known to be good
migrating group, as well as vinyl, phenyl, and simple alkyl groups.
A summary of representative experiments appears in Table 1.
An important aspect of this strategy is the ability to quickly
transform an inexpensive and simple phenol into a highly
functionalized core containing a prochiral dienone in the form of
a quaternary carbon center connected to several sp2 carbons.13
The reaction occurs in useful yields in the presence of allyl
groups (up to 67%) and is less efficient with vinyl, phenyl, or
alkyl groups. The migration of aryl groups to enable the
formation of compounds 3g−i represents a synthetic challenge
Scheme 1. Oxidative Ring Contraction and Retro-Claisen
Process
Protection of the alcohol moiety enabling the alkyl shift leads
to a corresponding acetal functionality 20 as an aldehyde
precursor in 57% yield. The formation of this compound results
from a direct attack by acetate ion released during the oxidative
process on oxonium species 19; the relative stability of this
carbocation enables it to react in a bimolecular mode with an
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external nucleophile despite the presence of a neighboring
silicon ether functionality, which could be explained by the
presence of HFIP as a non-nucleophilic and highly polar solvent.
This transformation appears to proceed through an oxidative
semipinacol/acetalization tandem process with the formation of
an intriguing and surprisingly stable acetal functionality. It
should be stressed that the formation of this acetal occurs only
with a protected secondary alcohol functionality, and no
corresponding ketal moiety has been observed with protected
tertiary alcohol derivatives, which would lead directly to a
ketone (Scheme 2).
process as outlined in Scheme 2. Under such conditions the
stable acetal functionality 27 is formed, avoiding further
transformation of the aldehyde functionality. In addition, this
tandem oxidative transposition−acetalization process may be
accomplished in an intramolecular mode with alcohol 28,
producing the acetal system 30 in 50% yield in one step via a
cascade transformation involving species 29. This tandem
process permits the rapid formation of a polyfunctionalized
compact core containing a dienone structure, a quaternary
carbon center, and two different aldehyde precursors on each
lateral chain (Scheme 3).
Scheme 2. Oxidative Pinacol-Acetalization Tandem Process
Scheme 3. Oxidative Transposition−Acetalization Tandem
Process
One limitation observed during this 1,3-shift process is the
formation of the side product dienone system 36, apparently
via oxidative Grob fragmentation14 from a direct sigmatropic
carbon−carbon bond cleavage on species 31 leading to methide
quinone 33, which is able to react with acetic acid released in
the medium during the umpolung activation in a 1,6 Michael
addition to produce phenol 34. A subsequent overoxidation of
34 with DIB leads to the side product 36, probably with the
assistance of the acetate 35 (Scheme 4).
The presence of an electron-rich substituent in the benzylic
position increases formation of methide quinone species (such
as 33), limiting the scope of this process when an allyl group is
used as a 1,3-migrating agent. As an example, oxidation of
compound 37 leads to the formation of two tricyclic systems,
one (pathway a) following π-bond attack of the allyl group
leading to the desired compound 39 and followed by Michael
addition to the hemiketal functionality leading to the tricyclic
system 41. A second route (pathway b) proceeds via direct σ
C−C bond cleavage from an apparent oxidative Grob process
to produce the phenol 40 after 1,6-Michael addition with acetic
acid released from a methide quinone species. Overoxidation
with DIB leads to the o-acetate system 42 resulting from attack
by the primary alcohol present on the lateral chain.
Compounds 41 and 42 have been obtained in 29% and 23%
yield, respectively (Scheme 5).
In order to explore the potential of this process, we envisaged
trapping the resulting phenoxonium ion with an intramolecular
homoallyl segment to produce a dienone core such as 23. This
unprecedented 1,3-allyl shift would be mediated by a concerted
mechanism involving a π-bond in a chairlike transition state 22
to produce the corresponding dienone 23. This novel extension
opens new avenues in chemical synthesis and may be extended
to several phenols 21. A summary of representative experiments
appears in Table 3.
Table 3. Oxidative 1,3-Allyl Shift Process
This process may also be applied to tetralone derivatives
containing the required homoallylic segment in the meta
position. However, in this case, the ortho positions must be
blocked with bromine atoms to force reaction of the allyl group
exclusively at the para position during oxidation. The migration
is otherwise mainly observed at the less hindered ortho position,
producing the substituted phenol 48 in 57% yield, Scheme 6.
The regioselectivity observed with bromine atoms may be
explained by considering that the first intermediate is a highly
delocalized carbonium ion, which can be represented by the
resonance structure 44. We believe that 44 rather than the ortho
mesomer 47 is the dominant resonance form because of the
presence of the electron-withdrawing bromine atoms. Con-
sequently, the reaction primarily occurs at the para position
As a rapid application of such a functionalized core, sub-
sequent treatment of 23c with Cs2CO3 led to a single
diastereomer of the bicyclic core 24 in 72% yield. It appears
that oxidation of a free secondary alcohol such as 21d leads to
aldehyde 23d in low (25%) yield, despite the fact that the crude
yields estimated from NMR results were reasonable. This is
because aldehyde 23d is not very stable, particularly on silica gel,
and yields were reduced during purification. The instability is due
to rapid Michael addition of the aldehyde to the dienone moiety,
resulting in formation of a hemiacetal in a manner similar to the
transformation described in Scheme 12. The problem may be
solved by using a protected alcohol to promote the 1,3-shift
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Scheme 4. Oxidative Grob Fragmentation as a Side Reaction
Scheme 5. 1,3-Allyl Shift versus Grob Fragmentation
Scheme 6. Ortho versus Para Attack
The oxidative 1,3-shift process is not restricted to allyl groups
and may be efficiently extended to alkynes to produce allenyl
systems such as 51. This aspect could be rationalized by the
linear geometry of the two sp carbon centers mediating a half
chair transition state 50, leading to 51 in good yield. In this
case, the side product 36 resulting from Grob fragmentation
was present in small amounts or not observed at all. Several 1,3-
alkyne promoters have been investigated, leading to the isolated
acetal 51 (Table 4).
The 1,3-alkyne shift process may also be extended to tertiary
alcohols such as 52 to furnish diallenic systems 53. The
additional allenyl Michael acceptor moiety present in 53 results
from rapid isomerization of the remaining alkyne that has not
intercepted the phenoxonium ion 50. Consequently, the yields
listed in Table 5 represent a tandem 1,3-alkyne shift-isomeri-
zation process. Migration of a single alkyne moiety occurs more
efficiently than allyl group migration (Tables 4 and 5 versus
Table 3), probably due to a favorable half-chair transition state
resulting from the less hindered geometry of the linear alkyne
moiety. This leads, in one step, to a polysubstituted and highly
functionalized core 53 containing a large number of unsatura-
tion sites. Furthermore, even when a substituted electron donor
group is present in the benzylic position, the undesired com-
petitive Grob fragmentation occurs only minimally (Scheme 5)
when bromine atoms shield the ortho positions through
stereoelectronic effects. The presence of a nucleophilic π-bond
in the meta position is in accordance with the results observed
when the transformation occurs through a bimolecular pathway,
and the same behavior was observed in the case of external
nucleophiles acting on phenoxonium species. Indeed, small
nucleophiles such as alcohols react at the para position, while
stereoelectronically stabilized carbonium species7 44 and
more hindered carbon-based nucleophiles react at the more
accessible ortho position 47.2g An added advantage is that the
bromine atoms could subsequently be used to introduce other
substituents through transition-metal chemistry (Scheme 6).
Table 4. Oxidative 1,3-Alkyne Shift Process
entry
R1
P
R
yield (%)
a
b
c
H
Br
H
Br
H
TBDMS
TBDMS
TIPS
H
H
H
H
64
76
61
70
55
d
e
TIPS
TBDMS
SiMe3
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Table 5. Diallenic Ketone System Formation
Scheme 8. Rapid Tetracyclic System Elaboration
entry
R
yield (%)
a
b
c
H
60
45
46
52
Me
CH2CHCH2
d
CH2CCH
to the aldehyde 64 in 55% yield and a very good 95% corrected
ee if we consider the optical purities of the starting material
(64%) and the final compound (61%). This could be explained
by the required minimal 1,3-allylic strain interactions between
the methyl group and the hydroxyl during the open transition
state 63. In addition, the presence of protic HFIP increases the
A value of the hydroxyl group (hydrogen bonds), favoring the
required equatorial position. The ee could be probably
improved by protecting the secondary alcohol moiety with a
bulky protecting group or reaction at lower temperature to
stabilize the required transition state. These observations
demonstrate the stereoselectivity of this process and its potential
applications in asymmetric synthesis (Scheme 9).
and the 1,3-alkyl shift process proceeds through one transition
state such as 50 remains the main pathway (entries 53b−d,
Table 5).
This method is also compatible with bicyclic phenols 54 and
56, yielding the desired dienones 55 and 57. It should be noted
that in the case of compound 56 and in contrast to the allyl
version 46 (Scheme 6), a free phenol 56a may be directly
oxidized to produce the dienone 57a without bromine atom
protection of the ortho positions. Indeed, due to the linear and
unhindered geometry of free alkynes, which are some of the
smallest carbon-based nucleophiles, direct addition of the alkyne
moiety at the stereoelectronically favored para position is
observed in 53% yield. However, in accordance with observations
of the more hindered sp2 allyl group in Scheme 6, this process is
more efficient with the dibromo tetralone derivative 56b, which
leads to 57b in 80% yield and avoids competitive pathways.
An important aspect enabling this transformation is the favored
axial position of the migrating substituent (allyl or propargyl
moiety), which is required to minimize 1,2 allylic strain with the
aryl moiety during the transition state and provide favorable π
overlap with the phenoxonium ion generated during the
umpolung activation. This leads to formation of a quaternary
carbon center with retention of configuration from the alcohol
stereocenter (Scheme 7).
Scheme 9. Enantioselective Route
An initial application of oxidative shift transposition is the
synthesis of the tricyclic core 72, which is a potential inter-
mediate for a plethora of natural products belonging to the
Aspidosperma family, including acetylaspidoalbidine 8016 iso-
lated from the Venezuelan tree species Aspidosperma fendleri
woodson and Aspidosperma rhombeosignatum markgraf, neblinine
81,17a vindoline 82,17b aspydophytine 83,18 a heptacyclic compound
isolated from Aspidosperma neblinae monachino, and beninine
84,19 isolated from Callichilia barteri isolated from Catharanthus
roseus. We employed the formal synthesis of acetylaspidoalbi-
dine as an example of this process in the production of complex
natural products such as those illustrated in Figure 3.
Scheme 7. Tetralone Derivatives
The Aspidosperma family is one of the most abundant indole
alkaloid families, containing more than 250 compounds from
several sources, many of which have important biological
activities. The core of these compounds is the pentacyclic subunit
named aspidospermidine.19 The synthesis of aspidospermine has
elicited substantial interest in the field of natural products
chemistry since the first and brilliant synthesis developed by Stork
and co-workers,20,21 who employed a Fischer indole strategy. The
oxidative 1,3-shift transposition described in this paper provides
an expeditious route to the various functionalities present in
several complex structures in the Aspidosperma family. The
tricyclic system 72 is a compact polyfunctionalized scaffold
containing a masked aldehyde functionality, an enone, and an
iodoalkene subunit. These groups are well positioned to produce
several congeners of this important alkaloid family. The key
tricyclic system 72 can be readily and efficiently obtained from an
inexpensive phenol and can be further transformed into
Interestingly, compound 57a may be rapidly elaborated into
a functionalized polycyclic system through an intramolecular
Diels−Alder process. Selective reduction of the dienone 57a
with zinc leads to an epimeric mixture of compound 58, which
is rapidly transformed into the most stable trans isomer in the
presence of DBU. Treatment of 58 with TBS-triflate generates
intermediate 59 which is slowly transformed into the tetracyclic
core 60; treatment with TBAF furnishes the ketones 61 in 70%
yield, Scheme 8.
Based on a hypothetical half-chair transition state, an enantio-
selective route enabling the formation of quaternary carbon
centers was developed beginning with the enantioenriched
alcohol 62 (64% ee), which may be obtained using a chiral and
user-friendly organoindium reagent.15 The enantiomeric excess
of 62 obtained from this practical asymmetric pathway has not
been optimized but was sufficient to demonstrate the stereo-
selectivity of the 1,3-shift process. Oxidation of phenol 62 leads
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Figure 3. Members of the Aspidosperma alkaloid family.
acetylaspidoalbidine 80 using conventional methodologies. The
global retrosynthetic pathway is presented in Figure 4.
Scheme 11. Concise Approach to the Tricyclic Core of
Aspidosperma Compounds
Figure 4. Retrosynthetic pathway to acetylaspidoalbidine.
The required phenol 49a may be easily obtained by protec-
tion of 4-allylphenol 65 with TBS-Cl, followed by epoxidation
with m-CPBA to afford compound 66 in 91% yield in two steps.
At this stage, the resulting epoxide is activated using BF3·OEt2
and captured by the anion of (TMS)-acetylene, quantitatively
producing compound 67. Protection of the secondary alcohol
with TBS-Cl followed by selective deprotection of the phenol
functionality under basic conditions leads to the required phenol
49a in 87% overall yield (Scheme 10).
stage, the tetracyclic main core of neblinine 81 may be
generated through a trans-acetalization process by treatment of
72 with methanol and potassium carbonate, proceeding through
formation of the intermediate 73 (Scheme 12).
Scheme 12. Formation of the Main Tetracyclic Core of
Neblinine
Scheme 10. Formation of the Phenolic Precursor 49a
Treatment of compound 72 with hydrogen over Pd/C se-
lectively reduced the iodo segment and the enone functionality,
quantitatively producing the ketone 75 (Scheme 13). At this
The dienone system 51a resulting from the oxidative shift
process (Table 4) represents an advanced intermediate. Mild
treatment of this allene with iodine resulted in a (Z/E) mixture
of the iodo substrate 68 in favor of the desired diastereoisomer.
Subsequent treatment with ethanolamine leads, via a SN2-
Michael tandem process, to bicyclic core 71 as well as the
undesired (Z)-secondary amine 70, depending on the former
configuration of the diiodo adduct 68 in 65% yield and in an
11/9 ratio in favor of the desired compound 71 (Scheme 11).
The SN2-Michael tandem process is a concise route to the
bicyclic system 71; we suspect that the preorganization of the
cis-double bond increases the feasibility of the 6-exo-trig Michael
process leading to 71. Further activation of the hydroxyl group
with mesyl chloride and treatment with potassium tert-butoxide
led to the tricyclic core 72 in 70% yield over two steps. At this
Scheme 13. Selective Hydrogenation
stage, we were pleased to observe an unexpected and efficient
selective reduction of the enone segment. It should be noted
that the remaining alkene moiety is present in several important
alkaloids possessing antitumor activity and belonging to the
same family, including vindoline and beninine. This method
appears to be an attractive approach to a wide array of alkaloids
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having a double bond at this position. The remaining double
bond may be hydrogenated by extending the reaction over
two days to produce the saturated tricyclic core 76 in excellent
yield from compound 72. Compounds 75 and 76 may be
incorporated into the synthesis of several alkaloids belonging to
the Aspidosperma family, as depicted in Figure 3.
EXPERIMENTAL SECTION
■
Unless otherwise indicated, 1H and 13C NMR spectra were recorded at
300 and 75 MHz, respectively, in CDCl3 solutions. Chemical shifts are
reported in ppm on the δ scale. Multiplicities are described as s
(singlet), d (doublet), dd, ddd, etc. (doublet of doublets, doublet of
doublets of doublets, etc.), t (triplet), q (quartet), quin (quintuplet), m
(multiplet), and further qualified as app (apparent), br (broad).
Coupling constants, J, are reported in Hz. IR spectra (cm−1) were
recorded from thin films. Mass spectra (m/e) were measured in the
electrospray (ESI) mode.
In order to rapidly demonstrate the synthetic applications
of this process, we focused on the hexacyclic core of acety-
laspidoalbidine 80, a fendleridine natural derivative.16 These
compounds have elicited substantial interest, and a number of
elegant syntheses have already been described by groups such as
Ban, Overman, and Boger.16 The mixed acetal moiety of 76 was
hydrolyzed in the presence of TFA and selectively reduced using
a hindered hydride to produce alcohol 77. The pentacyclic
skeleton was constructed using a Fischer indole process followed
by treatment with LiAlH4. This strategy led to a mixture of the
indoline core 78 and an undesired indole (depending on the
position of the enamine triggering the Claisen process), in a
2:1 ratio favoring the desired 78. A Schotten−Bauman protocol
selectively produced the known N-acetyl compound 79 in an
unoptimized 10% yield over four steps from compound 77.
Similar transformations are well described in the literature and
the present work describes only a single application to
demonstrate the potential of the oxidative 1,3-alkyl shift process.
Compound 79 has been employed as the final precursor of
acetylaspidoalbidine and may be transformed in one step into
acetylaspidoalbidine 80 by treatment with Hg(OAc)2 as first
demonstrated by Ban et al.16b and later described by Overman
and co-workers.16e This final intermediate leading to the
hexacyclic natural product has been obtained in 11 steps from
the key dienone system 51a (Scheme 14).
General Procedure for Oxidation of Phenols into Corre-
sponding Dienones. Method A: General Procedure for the
Oxidative (1,2-Alkyl Shift Process). To a stirred solution of phenol
(0.1 mmol) in HFIP (0.5 mL) at 0 °C was added DIB (38 mg,
0.11 mmol, 1.1 equiv) dissolved in HFIP (0.2 mL). The solution
was stirred for a further 1 min and then quenched by addition of
acetone (0.2 mL, the blue-green color disappears). The solution
was directly filtrated on a small pad of silica gel (washed with
ethyl acetate) and then concentrated under reduced pressure.
The crude product was purified by chromatography (n-hexane/
ethyl acetate) to afford the corresponding dienone. Note: as soon
as cold HFIP is introduced, the DIB solution has to be added
quickly. Indeed, some tertiary alcohol compounds are not very stable
in these acidic conditions and are transformed into an alkene via an
E1 reaction.
Method B: General Procedure for the Oxidative 1,3-Alkyl Shift
Process. To a stirred solution of phenol (0.1 mmol) in HFIP (0.6 mL)
at 0 °C was added DIB (38 mg, 0.11 mmol, 1.1 equiv) dissolved in
HFIP (0.2 mL) over 10 s. The solution was stirred for further 2 min
and then quenched by an addition of acetone (0.2 mL, the blue-green
color disappears). The solution was directly filtrated on a small pad of
silica gel (washed with ethyl acetate) and then concentrated under
reduced pressure. The crude product was purified by chromatography
(n-hexane/ethyl acetate) to afford the corresponding dienone.
4-Acetyl-4-allylcyclohexa-2,5-dienone (3a). Pale yellow oil: 0.062
1
mmol, 10.9 mg, 62% yield; H NMR (600 MHz, CDCl3) δ = 7.18
(d, 2H, J = 8.4 Hz), 7.00 (d, 2H, J = 8.4 Hz), 5.93 (m, 1H), 5.08 (d, 1H,
J = 8.0 Hz), 5.07 (d, 1H, J = 17.1 Hz), 3.37 (d, 2H, J = 6.7 Hz), 2.28
(s, 3H); 13C NMR (150 MHz, CDCl3) δ = 169.8, 149.1, 137.8, 137.3,
129.7, 121.6, 116.2, 39.7, 21.3. IR ν (cm−1) 2913, 1752, 1199; HRMS
calcd for C11H13O2 (M + H)+ 177.0910, found 177.0908.
Scheme 14. Formal Synthesis of Acetylaspidoalbidine
4-Allyl-4-(but-3-enoyl)cyclohexa-2,5-dienone (3b: Pale yellow oil:
1
0.067 mmol, 13.5 mg, 67% yield; H NMR (600 MHz, CDCl3) δ =
7.18 (d, 2H, J = 8.4 Hz), 7.00 (d, 2H, J = 8.4 Hz), 6.03 (m, 1H), 5.95,
(m, 1H), 5.28 (d, 1H, J = 18.2 Hz), 5.25 (d, 1H, J = 11.7 Hz), 5.09 (d,
1H, J = 8.2 Hz), 5.07 (d, 1H, J = 17.7 Hz), 3.37 (d, 2H, J = 6.5 Hz),
3.33 (d, 2H, J = 7.0 Hz); 13C NMR (150 MHz, CDCl3) δ = 170.0,
148.9, 137.6, 137.0, 129.6, 129.4, 121.3, 119.1, 116.0, 39.5, 39.1; IR ν
(cm−1) 2915, 1754, 1641, 1505, 1201; HRMS calcd for C13H15O2
(M + H)+ 203.1067, found 203.1063.
CONCLUSION
■
4-Acetyl-4-allyl-2-methylcyclohexa-2,5-dienone (3c). Pale yellow
oil: 0.063 mmol, 12.0 mg, 63% yield; 1H NMR (300 MHz, CDCl3) δ =
7.05 (s, 1H), 7.02 (d, 1H, J = 7.9 Hz), 6.92 (d, 1H, J = 7.9 Hz), 5.95
(m, 1H), 5.10 (d, 1H, J = 9.4 Hz), 5.80 (d, 1H, J = 17.1 Hz), 3.34 (d,
2H, J = 6.7 Hz), 2.31 (s, 3H), 2.51 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ = 169.3, 147.5, 137.7, 137.2, 131.2, 129.8, 126.9, 121.6,
115.8, 39.5, 20.7, 16.1; IR ν (cm−1) 2911, 1752, 1646, 1503, 1205;
HRMS calcd for C12H15O2 (M + H)+ 191.1067, found 191.1062.
4-Allyl-4-(2-((tert-butyldimethylsilyl)oxy)acetyl)cyclohexa-2,5-di-
We have developed an unprecedented synthetic method based
on oxidative 1,2- and 1,3-alkyl shift processes. This method
enables the stereoselective formation of polyfunctionalized and
polysubstituted compounds containing a quaternary carbon
center, a dienone system, and several other functionalities from
simple and inexpensive phenol derivatives in good yield. An
efficient enantiospecific version of this process enabling the
formation of a quaternary carbon center was also demonstrated.
The resulting structures are present in numerous natural
products possessing important biological activities. A rapid
approach to several polycyclic systems, including the main
tricyclic or tetracyclic systems of alkaloids belonging to the
Aspidosperma family and a new formal synthesis of
acetylaspidoalbidine were described. The results demonstrate
the potential of these oxidative transposition processes as well
as the utility of the “aromatic ring umpolung” concept.
1
enone (3d). Pale yellow oil: 0.033 mmol, 10.2 mg, 33% yield; H
NMR (600 MHz, CDCl3) δ = 7.95 (d, 2H, J = 7.7 Hz), 7.05 (d, 2H,
J = 7.7 Hz), 6.08 (m, 1H), 5.44 (s, 2H), 5. 02 (m, 2H), 3.73 (d, 2H,
J = 6.7 Hz), 0.88 (s, 9H), 0.12 (s, 6H); 13C NMR (150 MHz, CDCl3)
δ = 161.3, 131.4, 130.4, 118.4, 115.5, 87.5, 43.2, 25.7, 25.5, 17.8, −5.0;
IR ν (cm−1) 2929, 1725, 1679, 1508, 1255; HRMS calcd for
C17H27O3Si (M + H)+ 307.1724, found 307.1725.
4-Acetyl-4-(2-methylallyl)cyclohexa-2,5-dienone (3e). Pale yellow
oil: 0.037 mmol, 7.0 mg, 37% yield; 1H NMR (300 MHz, CDCl3) δ =
7.18 (d, 2H, J = 7.9 Hz), 7.00 (d, 2H, J = 7.9 Hz), 5.82 (s, 1H), 4.73
(s, 1H), 3.31 (s, 2H), 2.28 (s, 3H), 1.67 (s, 3H); 13C NMR (150 MHz,
2127
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Featured Article
CDCl3) δ = 169.5, 148.9, 144.7, 137.2, 129.7, 121.2, 112.1, 43.9, 22.0,
21.1; IR ν (cm−1) 1755; HRMS calcd for C12H15O2 (M + H)+
191.1067, found 191.1066.
187.3, 148.8, 136.7, 136.3, 133.1, 132.6, 128.6, 127.9, 37.6, 28.5, 22.0;
HRMS calcd for C16H15O2 (M + H)+ 239.1067, found 239.1057.
3-Allylbenzofuran-3,6(2H,3H)-dione (14c). Pale yellow oil: 0.043
1
4-Acetyl-4-vinylcyclohexa-2,5-dienone (3f). Pale yellow oil: 0.034
mmol, 8.2 mg, 43% yield; H NMR (600 MHz, CDCl3) δ = 6.54
1
mmol, 5.5 mg, 34% yield; H NMR (300 MHz, CDCl3) δ = 7.42 (d,
(d, 1H, J = 10.0 Hz), 6.49 (d, 1H, J = 10.0 Hz), 5.86 (s, 1H), 5.84
(m, 1H), 5.27 (d, 1H, J = 17.0 Hz), 5.26 (d, 1H, J = 10.4 Hz), 4.50 (d,
1H, J = 11.0 Hz), 4.30 (d, 1H, J = 11.0 Hz), 2.78 (m, 2H); 13C NMR
(150 MHz, CDCl3) δ = 186.9, 171.8, 137.2, 131.7, 130.1, 120.2, 105.4,
74.7, 72.5, 32.2; HRMS calcd for C11H10O3Na (M + Na)+ 213.0522,
found 213.0528.
2H, J = 8.2 Hz), 7.05 (d, 2H, J = 8.2 Hz), 6.70 (dd, 1H, J = 17.0;
10.4 Hz), 5.70 (d, 1H, J = 17.0 Hz), 5.52 (d, 1H, J = 10.4 Hz), 2.30
(s, 3H); 13C NMR (150 MHz, CDCl3) δ = 169.4, 150.1, 135.8, 135.3,
127.1, 121.5, 114.0, 21.1; IR ν (cm−1) 1647; HRMS calcd for
C10H10O2Na (M + Na)+ 185.0573, found 185.0571.
1-Acetyl[1,1′-biphenyl]-4(1H)-one (3g). Pale yellow oil: 0.051
(1-Allyl-3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-yl)((tert-
butyldimethylsilyl)oxy)methyl Acetate (20). Pale yellow oil: 0.057
mmol, 25.5 mg, 57% yield; 1H NMR (300 MHz, CDCl3) δ = 6.50 (d,
1H, J = 2.7 Hz), 6.46 (d, 1H, J = 2.7 Hz), 6.05 (s, 1H), 5.42 (m, 1H),
4.96 (m, 2H), 2.41 (m, 2H), 1.96 (s, 3H), 1.22 (s, 9H), 1.19 (s, 9H),
0.89 (s, 9H), 0.11 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ = 187.2, 170.0, 149.9, 149.8, 140.2, 140.1, 132.5, 130.5, 118.7, 94.1,
49.3, 39.3, 35.3, 29.8, 25.9, 21.4, 18.2, −4.2, −4.9; IR ν (cm−1) 2932,
2861, 1746, 1661, 1644, 1471, 1365, 1238, 1153, 839; HRMS (ESI)
calcd for C26H44O4SiNa (M + Na)+ 471.2901, found 471.2905
4-Allyl-4-(2-oxopent-4-en-1-yl)cyclohexa-2,5-dienone (23a). Pale
yellow oil: 0.042 mmol, 9.1 mg, 42% yield; 1H NMR (MHz, CDCl3) δ
= 6.94 (d, 2H, J = 10.0 Hz), 6.29 (d, 2H, J = 10.0 Hz), 5.84 (m, 1H),
5.56 (m,1H), 5.20 (d, 1H, J = 11.7 Hz), 5.12 (d, 1H, J = 17.0 Hz), 5.09
(d, 1H, J = 11.7 Hz), 5.06 (d, 1H, J = 17 Hz), 3.12 (d, 2H, J = 7.4 Hz),
2.71 (s, 2H), 2.47 (d, 2H, J = 7.4 Hz); 13C NMR (150 MHz, CDCl3) δ
= 204.8, 185.8, 152.3, 131.6, 129.6, 119.7, 119.5, 48.8, 48.6, 43.3, 42.0;
IR ν (cm−1) 2920, 1760, 1215, 1189; HRMS calcd for C14H16O2Na
(M + Na)+ 239.1043, found 239.1040.
1
mmol, 10.8 mg, 51% yield; H NMR (300 MHz, CDCl3) δ = 7.57
(d, 2H, J = 8.2 Hz), 7.55 (d, 2H, J = 8.2 Hz), 7.42 (t, 2H, J = 8.2 Hz),
7.14 (d, 2H, J = 8.2 Hz), 2.31 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
= 169.5, 150.0, 140.3, 138.9, 128.7, 128.1, 127.3, 127.1, 121.8, 21.1;
IR ν (cm−1) 1760, 1645, 1506, 1202; HRMS calcd for C14H12O2Na
(M + Na)+ 235.0730, found 235.0734.
1-Propionyl[1,1′-biphenyl]-4(1H)-one (3h). Pale yellow oil: 0.035
1
mmol, 7.9 mg, 35% yield; H NMR (300 MHz, CDCl3) δ = 7.59
(d, 2H, J = 8.2 Hz), 7.57 (d, 2H, J = 8.2 Hz), 7.44 (t, 2H, J = 8.2 Hz),
7.35 (t, 1H, J = 8.2 Hz), 7.16 (d, 2H, J = 8.2 Hz), 2.62 (q, 2H, J =
7.6 Hz), 1.29 (t, 3H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3) δ =
173.0, 150.1, 140.3, 138.8, 128.7, 127.2, 127.0, 121.7, 27.7, 9.0; IR
ν (cm−1) 1764, 1642; HRMS calcd for C15H15O2 (M + H)+ 227.1067,
found 227,1066.
1-Acetyl-3-methyl[1,1′-biphenyl]-4(1H)-one (3i). Pale yellow oil:
0.034 mmol, 7.7 mg, 34% yield; 1H NMR (600 MHz, CDCl3) δ = 7.54
(d, 2H, J = 8.2 Hz), 7.41 (m, 4H), 7.32 (t, 1H, J = 8.2 Hz), 7.07 (d,
1H, J = 8.2 Hz), 2.33 (s, 3H), 2.23 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ = 169.2, 148.8, 140.5, 139.2, 130.2, 129.9, 128.7, 127.1,
125.7, 122.1, 20.8, 16.3; IR ν (cm−1) 2923, 1760, 1641, 1505, 1202;
HRMS calcd for C15H15O2 (M + H)+ 227.1067, found 227.1062.
4-Butyl-4-pentanoylcyclohexa-2,5-dienone (3j). Pale yellow oil:
0.041 mmol, 9.6 mg, 41% yield; 1H NMR (600 MHz, CDCl3) δ = 7.16
(d, 2H, J = 8.2 Hz), 6.97 (d, 2H, J = 8.2 Hz), 2.59 (t, 2H, J = 7.6 Hz),
2.54 (t, 2H, J = 7.6 Hz), 1.74 (q, 2H, J = 7.6 Hz), 1.59 (q, 2H, J = 7.6
Hz), 1.44 (s, 2H, J = 7.6 Hz), 1.35 (sext, 2H, J = 7.6 Hz), 0.97 (t, 3H,
J = 7.6 Hz), 0.92 (t, 3H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3)
δ = 172.4, 148.6, 140.2, 129.2, 121.1, 35.0, 34.1, 33.5, 27.0, 22.2, 13.9,
13.7; HRMS calcd for C15H23O2 (M + H)+ 235.1693, found 235.1695.
4-Acetyl-4-butylcyclohexa-2,5-dienone (3k). Pale yellow oil: 0.035
4-Allyl-2,6-dibromo-4-(2-oxopent-4-en-1-yl)cyclohexa-2,5-dien-
1
one (23b). Pale yellow oil: 0.042 mmol, 9.1 mg, 42% yield; H NMR
(MHz, CDCl3) δ = 6.94 (d, 2H, J = 10.0 Hz), 6.29 (d, 2H, J = 10.0
Hz), 5.84 (m, 1H), 5.56 (m,1H), 5.20 (d, 1H, J = 11.7 Hz), 5.12 (d,
1H, J = 17.0 Hz), 5.09 (d, 1H, J = 11.7 Hz), 5.06 (d, 1H, J = 17 Hz),
3.12 (d, 2H, J = 7.4 Hz), 2.71 (s, 2H), 2.47 (d, 2H, J = 7.4 Hz); 13C
NMR (150 MHz, CDCl3) δ = 204.8, 185.8, 152.3, 131.6, 129.6, 119.7,
119.5, 48.8, 48.6, 43.3, 42.0; IR ν (cm−1) 2920, 1760, 1215, 1189;
HRMS calcd for C14H16O2Na (M + Na)+ 239.1043, found 239.1040.
4-Allyl-4-(3-(methylsulfonyl)-2-oxopropyl)cyclohexa-2,5-dienone
(23c). Pale yellow oil: 0.061 mmol, 22.8 mg, 61% yield; 1H NMR (600
MHz, CDCl3) δ = 7.43 (s, 2H), 5.84 (m, 1H), 5.56 (m, 1H), 5.24 (d,
1H, J = 10.0 Hz), 5.17 (d, 1H, J = 15.8 Hz), 5.16 (d, 1H, J = 10.0 Hz),
5.11 (d, 1H, J = 15.8 Hz), 3.14 (d, 2H, J = 7.0 Hz), 2.77 (s, 2H), 2.53
(d, 2H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3) δ 204.1, 172.8,
152.8, 130.8, 129.5, 122.7, 121.2, 120.2, 49.3, 48.7, 47.6, 41.4; HRMS
(ESI) calcd for C14H15O2Br2 (M + H)+ 374.9412, found 374.9407.
2-(1-Allyl-4-oxocyclohexa-2,5-dien-1-yl)acetaldehyde (23d). Pale
1
mmol, 6.8 mg, 35% yield; H NMR (600 MHz, CDCl3) δ = 7.17 (d,
2H, J = 8.2 Hz), 6.98 (d, 2H, J = 8.2 Hz), 2.60 (t, 2H, J = 7.6 Hz), 2.29
(s, 3H), 1.59 (q, 2H, J = 7.6 Hz), 1.35 (sext, 2H, J = 7.6 Hz), 0.92 (t,
3H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3) δ = 169.6, 148.5,
140.4, 129.2, 121.1, 35.0, 33.5, 22.2, 21.1, 13.9; HRMS calcd for
C12H16O2Na (M + Na)+ 215.1043, found 215.1041.
7-Acetyl-2,3-dihydro-1H-inden-5(7H)-one (13d). Pale yellow oil:
0.053 mmol, 9.3 mg, 53% yield; 1H NMR (600 MHz, CDCl3) δ = 6.76
(d, 1H, J = 10.0 Hz), 6.72 (d, 1H, J = 10.0 Hz), 6.58 (s, 1H), 2.51 (t,
2H, J = 7.6 Hz), 2.42 (t, 2H, J = 7.6 Hz), 2.15 (s, 3H), 1.79 (q, 2H, J =
7.6 Hz); 13C NMR (150 MHz, CDCl3) δ = 207.7, 187.5, 187.3, 148.7,
136.7, 136.3, 132.6, 42.6, 29.9, 28.3, 21.6; IR ν (cm−1) 2923, 1711,
1655, 1597, 1354, 1290, 904; HRMS calcd for C11H13O2 (M + H)+
177.0910, found 177.0909.
8-Allyl-3,4-dihydronaphthalene-1,6(2H,8H)-dione (14a). Pale yel-
low oil: 0.043 mmol, 8.7 mg, 43% yield; 1H NMR (600 MHz, CDCl3)
δ = 6.76 (d, 1H, J = 10.0 Hz), 6.71 (d, 1H, J = 10.0 Hz), 6.58 (s, 1H),
5.90 (m, 1H), 5.19 (d, 1H, J = 10.0 Hz), 5.15 (d, 1H, J = 17.0 Hz),
3.17 (d, 2H, J = 7.0 Hz), 2.52 (t, 2H, J = 7.6 Hz), 2.41 (t, 2H, J = 7.6
Hz), 1.80 (q, 2H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3) δ =
207.6, 187.5, 187.3, 148.7, 136.7, 136.3, 132.6, 130.3, 119.0, 47.8, 41.2,
28.3, 21.5; IR ν (cm−1) 2911, 1710, 1650, 1285, 1194; HRMS calcd for
C13H15O2 (M + H)+ 203.1067, found 203.1064.
1
yellow oil: 0.025 mmol, 4.4 mg, 25% yield; H NMR (600 MHz,
CDCl3) δ 9.51 (t, J = 2.1 Hz, 1H), 6.90 (d, J = 10.1 Hz, 2H), 6.37 (d,
J = 10.1 Hz, 2H), 5.59 (m, 1H), 5.11 (c, 2H), 2.66 (d, J = 2.1 Hz, 2H),
2.44 (d, J = 7.3 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 198.8, 185.4,
151.5, 130.9, 130.4, 120.2, 50.0, 43.1, 43.0; IR (cm−1) 2918, 2849,
1723, 1664, 1625, 1404; HRMS calcd for C11H12O2Na (M + Na)+
199.0730, found 199.0736.
7-Allyl-3-(methylsulfonyl)-3,4-dihydro-1H-indene-2,5(3H,7H)-
1
dione (24). Pale yellow oil: 8.5 mg, 72% yield; H NMR (600 MHz,
CDCl3) δ 6.52 (d, J = 10.0 Hz, 1H), 6.09 (d, J = 10.0 Hz, 1H), 5.83
(sext, J = 7.8 Hz, 1H), 5.26 (d, J = 9.4 Hz, 1H), 5.24 (d, J = 16.4 Hz,
1H), 3.42 (d, J = 9.4 Hz, 1H), 3.40 (m, 1H), 3.10 (s, 3H), 2.90 (s,
2H), 2.73 (d, J = 17.0 Hz, 1H), 2.61 (dd, J = 13.4, 7.6 Hz, 1H), 2.52
(dd, J = 13.4, 7.6 Hz, 1H), 2.48 (d, J = 17.0 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 203.6, 195.4, 167.3, 152.0, 131.3, 130.4, 120.8, 71.0,
51.1, 42.4, 41.8, 40.6, 39.0, 37.4; HRMS (ESI) calcd for C13H17O4S
(M + H)+ 269. 0842, found 269.0845.
8-Phenyl-3,4-dihydronaphthalene-1,6(2H,8H)-dione (14b). Pale
2-(1-Allyl-4-oxocyclohexa-2,5-dien-1-yl)-1-((tert-butyldimethylsilyl)-
1
oxy)ethyl Acetate (27). Pale yellow oil: 0.042 mmol, 14.7 mg, 42%
yellow oil: 0.054 mmol, 12.8 mg, 54% yield; H NMR (600 MHz,
1
yield; H NMR (300 MHz, CDCl3) δ = 6.80 (m, 2H), 6.27 (m, 2H),
CDCl3) δ = 7.94 (d, 2H, J = 8.2 Hz), 7.57 (t, 1H, J = 8.2 Hz), 7.47 (t,
2H, J = 8.2 Hz), 6.77 (d, 1H, J = 10.0 Hz), 6.72 (d, 1H, J = 10.0 Hz),
6.62 (s, 1H), 3.06 (t, 2H, J = 7.6 Hz), 2.52 (t, 2H, J = 7.6 Hz), 1.98 (q,
2H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3) δ = 199.1, 187.6,
5.78 (t, J = 5.1 Hz, 1H), 5.53 (m, 1H), 5.02 (c, 2H), 2.29 (d, J =
7.4 Hz, 2H), 2.13 (dd, J = 14.1, 4.8 Hz, 1H), 2.02 (c, 1H), 1.94 (s,
3H), 0.83 (s, 9H), −0.01 (s, 3H), −0.02 (s, 3H); 13C NMR (75 MHz,
2128
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Featured Article
CDCl3) δ 186.1, 169.5, 153.5, 153.4, 131.3, 129.5, 129.3, 119.6, 90.9,
46.1, 44.6, 43.5, 25.5, 21.3, 17.7, −4.5, −5.1; IR ν (cm−1) 2956, 1738,
1667, 1626, 1256; HRMS (ESI) calcd for C19H30NaO4Si (M + Na)+
373.1806, found 373.1805.
0.04 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 207.3, 172.5, 169.6,
152.5, 152.4, 121.1, 120.8, 91.4, 90.4, 80.6, 47.8, 45.1, 25.6, 21.2, 17.7,
−4.6, −5.0, HRMS (ESI) calcd for C19H26O4Br2SiNa (M + Na)+
528.9838, found 528.9835.
4-((1,3-Dioxolan-2-yl)methyl)-4-allylcyclohexa-2,5-dienone (30).
Pale yellow oil: 0.05 mmol, 11 mg, 50% yield; H NMR (300 MHz,
2-(4-Oxo-1-(propa-1,2-dien-1-yl)cyclohexa-2,5-dien-1-yl)-1-
1
((triisopropylsilyl)oxy)ethyl Acetate (51c). Pale yellow: 0.061 mmol,
1
23.8 mg, 61% yield; H NMR (600 MHz, CDCl3) δ = 6.91 (dd, 1H,
CDCl3) δ 6.82 (d, J = 10.2 Hz, 2H), 6.31 (d, J = 10.2 Hz, 2H), 5.57
(m, 1H), 5.05 (m, 2H), 4.65 (t, J = 4.5 Hz, 1H), 3.81 (c, 4H), 2.35 (d,
J = 7.3 Hz, 2H), 2.05 (d, J = 4.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 186.4, 153.7, 131.5, 129.3, 119.4, 101.7, 64.8, 44.1, 43.3,
42.9; IR ν (cm−1) 2921, 2886, 1661, 1622, 1406, 1138; HRMS (ESI)
calcd for C13H17O3 (M + H)+ 221.1172, found 221.1173.
J = 10.0; 3.1 Hz), 6.81 (dd, 2H, J = 10.0; 3.1 Hz), 6.26 (d, 1H, J = 10.0
Hz), 6.24 (d, 1H, J = 10.0 Hz), 6.03 (t, 1H, J = 4.7 Hz), 5.02 (t, 1H,
J = 6.0 Hz), 4.92 (d, 2H, J = 6.0 Hz), 2.26 (d, 1H, J = 14.6, 5.3 Hz),
2.14 (dd, 1H, J = 14.6, 5.3 Hz), 1.97 (s, 3H), 1.04 (m, 21H); 13C
NMR (150 MHz, CDCl3) δ 207.4, 185.7, 169.5, 152.1, 128.3, 128.0,
93.1, 91.1, 79.5, 46.0, 42.2, 21.3, 17.6, 17.8, 12.2; HRMS (ESI) calcd
for C22H34O4SiNa (M + Na)+ 413.2119, found 413.2117.
2-(3,5-Dibromo-4-oxo-1-(propa-1,2-dien-1-yl)cyclohexa-2,5-
dien-1-yl)-1-((triisopropylsilyl)oxy)ethyl Acetate (51d). Pale yellow
oil (this transformation has been done on 0.05 mmol): 0.035 mmol,
19.1 mg, 70% yield; 1H NMR (600 MHz, CDCl3) δ = 7.38 (d, 1H, J =
3.0 Hz), 7.24 (d, 1H, J = 3.0 Hz), 6.08 (t, 1H, J = 4.6 Hz), 5.00 (m,
3H), 2.32 (dd, 1H, J = 14.4, 4.4 Hz), 2.23 (dd, 1H, J = 14.4, 4.4 Hz),
2.03 1.04 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 207.4, 172.4,
169.6, 152.4, 152.3, 121.2, 120.8, 91.6, 90.8, 80.6, 47.8, 45.4, 21.2, 17.8,
17.7, 12.2; HRMS (ESI) calcd for C22H32O4SiNaBr2 (M + Na)+
571.0308, found 571.0312.
1-((tert-Butyldimethylsilyl)oxy)-2-(4-oxo-1-(1-(trimethylsilyl)-
propa-1,2-dien-1-yl)cyclohexa-2,5-dien-1-yl)ethyl Acetate (51e).
Pale yellow oil: 0.055 mmol, 23.1 mg, 55% yield; 1H NMR (600
MHz, CDCl3) δ = 6.88 (dd, 1H, J = 10.0, 3.0 Hz), 6.81 (dd, 1H, J =
10.0, 3.0 Hz), 6.28 (d, 1H, J = 10.0 Hz), 6.26 (d, 1H, J = 10.0 Hz),
5.90 (t, 1H, J = 5.3 Hz), 5.79 (t, 1H, J = 5.3 Hz), 4.62 (s, 2H), 2.33
(dd, 1H, J = 14.1, 4.8 Hz), 2.23 (dd, 1H, J = 14.1, 4.8 Hz), 1.96 (s,
3H), 0.85 (s, 9H), 0.07 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 185.9, 169.5, 153.7, 153.6, 128.7, 128.3, 97.7,
90.6, 73.4, 46.5, 44.6, 25.5, 21.3, 17.7, 0.5, −4.5, −5.0; HRMS (ESI)
calcd for C22H36O4Si2Na (M + Na)+ 443.2044, found 443.2040.
4-(2-Oxopenta-3,4-dien-1-yl)-4-(propa-1,2-dien-1-yl)cyclohexa-
2,5-dienone (53a). Pale yellow oil: 0.06 mmol, 12.7 mg, 60% yield; 1H
NMR (300 MHz, CDCl3) δ = 6.96 (d, 1H, J = 10.0 Hz), 6.26 (d, 1H,
J = 10.0 Hz), 5.76 (t, 1H, J = 6.4 Hz), 5.29 (d, 2H, J = 6.4 Hz), 5.21
(t, 1H, J = 6.4 Hz), 4.91 (d, 2H, J = 6.4 Hz), 2.98 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 217.0, 207.3, 195.8, 185.5, 151.3, 128.3, 97.5,
92.1, 79.3, 46.1, 42.4; HRMS (ESI) calcd for C14H13O2 (M + H)+
213.0910, found 213.0904.
(1-Hydroxy-4-oxocyclohexa-2,5-dienyl)methyl Acetate (36). 1H
NMR (300 MHz, CDCl3) δ 6.87 (d, J = 10.2 Hz, 2H), 6.27 (d, J =
10.2 Hz, 2H), 4.19 (s, 2H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 184.8, 170.6, 147.2, 129.7, 68.6, 68.1, 20.6; HRMS (ESI) calcd for
C9H10O4Na (M + Na)+ 205.0471, found 205.0474.
3b,8a-Diallyl-3,3a,3b,7,7a,8a-hexahydrofuro[2,3-b]benzofuran-
1
6(2H)-one (41). Pale yellow oil: 0.029 mmol, 7.5 mg, 29% yield; H
NMR (600 MHz, CDCl3) δ = 6.54 (d, 1H, J = 10.0 Hz), 6.03 (d, 1H,
J = 10.0 Hz), 5.85 (m, 1H), 5.64 (m, 1H), 5.10 (m, 4H), 4.28 (s, 1H),
4.15 (q, 2H, J = 7.6 Hz), 4.11 (q, 2H, J = 7.6 Hz), 2.72 (dd, 1H, J =
8.8, 5.3 Hz), 2.20 (s, 2H), 2.57 (dd, 1H, J = 14.1, 5.3 Hz), 2.28 (dd,
1H, J = 14.1, 7.6 Hz), 2.24−1.98 (m, 4H); 13C NMR (150 MHz,
CDCl3) δ 196.5, 146.8, 133.4, 128.3, 119.0, 118.5, 87.4, 83.4, 75.5,
71.6, 57.8, 44.0, 38.6, 38.2, 28.8; HRMS (ESI) calcd for C16H21O3
(M + H)+ 261.1485, found 261.1481.
1-Methyl-2,7,8-trioxaspiro[bicyclo[3.2.1]octane-6,1′-cyclohexa-
[2,5]dien]-4′-one (42). Pale yellow oil: 0.023 mmol, 5.6 mg, 23% yield;
1H NMR (600 MHz, CDCl3) δ = 7.18 (d, 1H, J = 10.0 Hz), 6.40 (d,
1H, J = 10.0 Hz), 6.22 (d, 1H, J = 10.0 Hz), 4.33 (m, 1H), 4.28 (dd,
1H, J = 11.7, 8.2 Hz), 2.40 (m, 2H), 1.69 (s, 3H), 1.64 (dd, 1H, J =
14.6, 4.7 Hz); 13C NMR (150 MHz, CDCl3) δ 184.5, 148.6, 141.4,
132.6, 128.1, 121.0, 79.8, 77.7, 58.7, 25.5, 23.3; HRMS (ESI) calcd for
C11H12NaO4 (M + Na)+ 231.0628, found 231.0630.
4-Allyl-6,8-dibromo-2,3,4,4a-tetrahydronaphthalene-1,7-dione
(45). Pale yellow oil: 0.05 mmol, 18.7 mg, 52% yield; 1H NMR
(300 MHz, CDCl3) δ = 7.24 (s, 1H), 5.45 (m, 1H), 5.13 (d, 1H, J =
10.4 Hz), 5.07 (d, 1H, J = 17.0 Hz), 2.74 (dm, 1H, J = 13.7 Hz), 2.51
(dd, 1H, J = 12.6; 7.2 Hz), 2.43 (t, 2H, J = 7.2 Hz), 2.29 (dd, 1H, J =
12.6; 7.2 Hz), 2.15 (m, 3H), 1.89 (m, 1H); 13C NMR (150 MHz,
CDCl3) δ = 200.5, 173.7, 172.8, 153.1, 129.3, 122.0, 121.2, 117.8, 53.7,
42.6, 38.8, 35.5, 20.2; IR ν (cm−1) 2922, 1716, 1673, 1200; HRMS
calcd for C13H13Br2O2 (M + H)+ 360.9262, found 360.9259.
4-(3-Oxohexa-4,5-dien-2-yl)-4-(propa-1,2-dien-1-yl)cyclohexa-
2,5-dienone (53b). Pale yellow oil: 0.045 mmol, 10.2 mg, 45% yield;
1H NMR (300 MHz, CDCl3) δ = 7.23 (dd, 1H, J = 10.2, 2.9 Hz), 6.75
8-Allyl-7-hydroxy-3,4-dihydronaphthalen-1(2H)-one (48). Pale
1
yellow oil: 0.057 mmol, 11.5 mg, 57% yield; H NMR (300 MHz,
(dd, 1H, J = 10.0, 2.9 Hz), 6.34 (dd, 1H, J = 10.0, 2.9 Hz), 6.30 (dd,
1H, J = 10.0, 2.9 Hz), 5.82 (t, 1H, J = 6.4 Hz), 5.32 (d, 2H, J = 6.4
Hz), 4.87 (dd, 1H, J = 11.2, 6.8 Hz), 4.82 (dd, 1H, J = 11.2, 6.8 Hz),
3.48 (q, 1H, J = 7.2 Hz), 1.02 (q, 3H, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 217.0, 207.4, 200.8, 185.7, 150.7, 150.0, 129.6, 129.3, 97.7,
91.2, 80.1, 78.8, 47.9, 46.2, 13.5; HRMS (ESI) calcd for C15H15O2
(M + H)+ 227.1067, found 227.1070.
4-(5-Oxoocta-1,6,7-trien-4-yl)-4-(propa-1,2-dien-1-yl)cyclohexa-
2,5-dienone (53c). Pale yellow oil: 0.046 mmol, 11.6 mg, 46% yield;
1H NMR (300 MHz, CDCl3) δ = 7.12 (dd, 1H, J = 10.6, 3.4 Hz), 6.78
CDCl3) δ = 7.05 (d, 1H, J = 8.2 Hz), 6.97 (d, 1H, J = 8.2 Hz), 5.12
(m, 3H), 3.89 (d, 1H, J = 6.0 Hz), 2.88 (t, 2H, J = 6.1 Hz), 2.63
(d, 2H, J = 6.1 Hz), 2.061 (q, 2H, J = 6.1 Hz); 13C NMR (150 MHz,
CDCl3) δ = 200.6, 153.7, 138.3, 136.6, 132.0, 127.8, 126.6, 120.7,
115.3, 40.8, 31.0, 30.3, 23.1; HRMS calcd for C13H15O2 (M + H)+
203.1067, found 203.1071.
1-((tert-Butyldimethylsilyl)oxy)-2-(4-oxo-1-(propa-1,2-dien-1-yl)-
cyclohexa-2,5-dien-1-yl)ethyl Acetate (51a). Pale yellow oil (this
transformation has been done on 1.80 mmol): 1.15 mmol, 0.4 g, 64%
1
yield; H NMR (600 MHz, CDCl3) δ = 6.88 (dd, 1H, J = 10.0; 3.0
(dd, 1H, J = 10.6, 3.4 Hz), 6.33 (d, 2H, J = 10.2 Hz), 5.88 (t, 1H, J =
6.6 Hz), 5.58 (m, 1H), 5.33 (d, 2H, J = 6.4 Hz), 5.18 (t, 1H, J = 6.6
Hz), 4.98 (d, 1H, J = 16.8 Hz), 4.97 (d, 1H, J = 10.3 Hz), 4.89 (dd,
1H, J = 11.2, 6.8 Hz), 4.84 (dd, 1H, J = 11.2, 6.8 Hz), 3.50 (dd, 1H, J =
11.3, 3.1 Hz), 2.31 (m, 1H), 2.13 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 218.0, 207.3, 199.9, 185.5, 150.2, 149.6, 134.2, 129.5, 129.6,
117.5, 99.6, 91.1, 80.3, 78.9, 52.9, 45.9, 33.0; HRMS (ESI) calcd for
C17H17O2 (M + H)+ 253.1223, found 253.1218.
Hz), 6.80 (dd, 1H, J = 10.0; 3.0 Hz), 6.26 (dd, 1H, J = 10.0; 3.0 Hz),
6.24 (dd, 1H, J = 10.0; 3.0 Hz), 5.90 (t, 1H, J = 5.3 Hz), 5.00 (t, 1H,
J = 7.0 Hz), 4.92 (d, 2H, J = 7.0 Hz), 2.21 (dd, 1H, J = 14.1, 4.8 Hz),
2.11 (dd, 1H, J = 14.1, 4.8 Hz), 1.98 (s, 3H), 0.86 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.3, 185.6, 169.5,
152.1, 128.3, 93.1, 90.7, 79.5, 45.6, 42.3, 25.5, 21.3, 17.7, −4.5, −5.1;
IR ν (cm−1) 2955, 1664, 1256; HRMS (ESI) calcd for C19H28NaO4Si
(M + Na)+ 371.1649, found 371.1650.
1-((tert-Butyldimethylsilyl)oxy)-2-(3,5-dibromo-4-oxo-1-(propa-
1,2-dien-1-yl)cyclohexa-2,5-dien-1-yl)ethyl Acetate (51b). Pale
yellow: 0.076 mmol, 38 mg, 76% yield; 1H NMR (600 MHz,
CDCl3) δ = 7.37 (d, 1H, J = 3.0 Hz), 7.25 (d, 1H, J = 3.0 Hz), 5.96 (t,
1H, J = 4.7 Hz), 5.00 (m, 3H), 2.26 (dd, 1H, J = 14.1, 4.1 Hz), 2.17
(dd, 1H, J = 14.1, 4.1 Hz), 2.02 (s, 3H), 0.87 (s, 9H), 0.05 (s, 3H),
4-(5-Oxoocta-6,7-dien-1-yn-4-yl)-4-(propa-1,2-dien-1-yl)-
cyclohexa-2,5-dienone (53d). Pale yellow oil: 0.052 mmol, 12.9 mg,
1
52% yield; H NMR (300 MHz, CDCl3) δ = 7.08 (dd, 1H, J = 10.6,
3.4 Hz), 6.75 (dd, 1H, J = 10.6, 3.4 Hz), 6.33 (d, 2H, J = 10.2 Hz),
5.97 (t, 1H, J = 6.6 Hz), 5.42 (dd, 1H, 11.2, 6.8 Hz), 5.36 (dd, 1H,
11.2, 6.8 Hz), 5.18 (t, 1H, J = 6.6 Hz), 4.90 (dd, 1H, J = 11.2, 6.8 Hz),
2129
dx.doi.org/10.1021/jo300169k | J. Org. Chem. 2012, 77, 2121−2133

The Journal of Organic Chemistry
Featured Article
1
4.86 (dd, 1H, J = 11.2, 6.8 Hz), 3.68 (dd, 1H, J = 11.3, 3.1 Hz), 2.44
(ddd, 1H, J = 16.5, 11.1, 2.6 Hz), 2.22 (dt, 1H, J = 16.5, 2.6 Hz), 1.95
(t, 1H, J = 2.6 Hz); 13C NMR (75 MHz, CDCl3) δ 218.3, 207.3, 198.8,
185.2, 149.5, 148.6, 129.9, 129.8, 99.5, 90.8, 80.6, 79.2, 70.5, 51.9, 45.5,
18.2; HRMS (ESI) calcd for C17H15O2 (M + H)+ 251.1067, found
251.1061.
oil: H NMR (300 MHz, CDCl3) δ = 4.98 (s, 1H), 4.96 (s, 1H), 3.67
(s, 1H), 2.62 (s, 1H), 2.60 (dd, 2H, J = 6.1, 3.5 Hz), 2.53 (m, 2H),
2.43−2.30 (m, 2H), 2.10 (m, 1H), 1.87 (d, 1H, J = 7.6 Hz), 1.80 (m,
1H), 1.48 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 206.1, 206.0, 144.0,
108.2, 57.8, 52.4, 41.2, 34.4, 33.5, 28.5, 27.9, 24.8, 19.5; HRMS (ESI)
calcd for C13H15O2 (M + H)+ 203.1067, found 203.1069.
6-Methyl-3-oxo-6-(propa-1,2-dienyl)cyclohexa-1,4-dienecarbal-
8-(Propa-1,2-dien-1-yl)-1,3,4,8-tetrahydronaphthalene-2,6-dione
1
1
dehyde (64). Pale yellow oil: 0.055 mmol, 9.6 mg, 55% yield; H
(55). Pale yellow oil: 0.043 mmol, 8.6 mg, 43% yield; H NMR (300
NMR (300 MHz, CDCl3) δ = 9.71 (s, 1H), 6.88 (d, 1H, J = 10.0 Hz),
6.82 (d, 1H, J = 1.8 Hz), 6.32 (dd, 1H, J = 10.0, 1.8 Hz), 5.40 (t, 1H,
J = 6.6 Hz), 4.89 (dd, 1H, J = 11.2, 6.6 Hz), 4.81 (dd, 1H, J = 11.2, 6.6
Hz), 1.55 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.5, 192.9, 186.3,
156.0, 155.7, 140.1, 126.6, 92.7, 78.7, 40.7, 23.9; HRMS (ESI) calcd
for C11H11O2 (M + H)+ 175.0754, found 175.0748.
MHz, CDCl3) δ = 6.66 (d, 1H, J = 10.0 Hz), 6.33 (d, 1H, J = 1.8 Hz),
6.26 (dd, 1H, J = 10.0, 1.8 Hz,), 5.03 (m, 2H), 4.87 (td, 1H, J = 6.6,
1.0 Hz), 2.97 (tdd, 1H, J = 13.5, 7.6, 1.7 Hz), 2.83 (dd, 1H, J = 14.7,
2.3 Hz), 2.72 (dd, 1H, J = 14.3, 7.2 Hz), 2.63 (ddt, 1H, J = 14.3, 6.3,
2.3 Hz), 2.45 (m, 1H), 2.36 (d, 1H, J = 14.7 Hz); 13C NMR (75 MHz,
CDCl3) δ 208.5, 205.3, 185.9, 159.6, 151.1, 127.2, 126.7, 92.6, 81.0,
48.2, 44.4, 39.7, 30.9; HRMS (ESI) calcd for C13H13O2 (M + H)+
201.0910, found 201.0917.
4-(Propa-1,2-dien-1-yl)-2,3,4,4-tetrahydronaphthalene-1,7-dione
(57a). Pale yellow oil: 0.053 mmol, 10.6 mg, 53% yield; 1H NMR (300
MHz, CDCl3) δ = 6.79 (d, 1H, J = 10.0 Hz), 6.49 (d, 1H, J = 1.8 Hz),
6.24 (dd, 1H, J = 10.0, 1.8 Hz,), 5.01 (t, 1H, J = 6.8 Hz), 4.87 (dd, 1H,
J = 11.7, 7.0 Hz), 4.82 (dd, 1H, J = 11.7, 7.0 Hz), 2.43−1.95 (m, 4H),
1.85 (td, 1H, J = 14.2, 5.2 Hz); 13C NMR (75 MHz, CDCl3) δ 208.1,
200.5, 186.1, 156.3, 152.1, 126.9, 91.4, 79.5, 46.1, 40.3, 34.2, 19.1;
HRMS (ESI) calcd for C13H13O2 (M + H)+ 201.0910, found
201.0907.
6,8-Dibromo-4-(propa-1,2-dien-1-yl)-2,3,4,4-tetrahydronaphtha-
lene-1,7-dione (57b). Pale yellow oil: 80% yield; 1H NMR (300 MHz,
CDCl3) δ = 7.26 (s, 1H), 4.97 (m, 3H), 2.72 (d, 1H, J = 15.6 Hz),
2.46 (m, 1H), 2.30−1.90 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
208.6, 199.1, 172.7, 155.5, 152.0, 120.3, 118.3, 88.6, 80.6, 52.8, 42.5,
36.3, 20.3; HRMS (ESI) calcd for C13H11O2Br2 (M + H)+ 358.9099,
found 358.9101.
tert-Butyldimethyl(4-(oxiran-2-ylmethyl)phenoxy)silane (66). To
a solution of 4-allylphenol (2.9 g, 21.6 mmol, 1 equiv) in DMF
(20 mL) at 0 °C were added imidazole (2.9 g, 43.2 mmol, 2 equiv) and
TBSCl (3.9 g, 26.0 mmol, 1.2 equiv). The reaction mixture was
allowed to warm to room temperature, and after 15 min, a saturated
aqueous solution of NaHCO3 (20 mL) was added. The phases were
separated, and the aqueous layer was extracted with Et2O (3 × 20 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel (hexanes/EtOAc 100/0 to 90/10) to give
5.16 g (96%) of the desired product as an oil. 4-(Allylphenoxy)(tert-
butyl)dimethylsilane: IR ν (cm−1) 3384, 2946, 1511, 1264; 1H NMR
(300 MHz, CDCl3) δ 7.03 (d, 2H, J = 8.2 Hz), 6.76 (d, 2H, J = 8.2
Hz), 5.95 (m, 1H), 5.09 (d, 1H, J = 15.8 Hz), 5.07 (d, 1H, J = 10.4 Hz),
3.32 (d, 2H, J = 6.6 Hz), 0.98 (s, 9H), 0.18 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 153.8, 137.8, 132.6, 129.4, 119.9, 115.3, 39.4, 25.6,
18.1, −4.4; HRMS (ESI) calcd for C15H25OSi (M + H)+ 249.1669,
found 249.1666. To a solution of the alkene (1.019 g, 4.11 mmol,
1 equiv) in CH2Cl2 (12 mL) at 0 °C was added m-CPBA (70% in water,
1.3 g, 5.34 mmol, 1.3 equiv). The reaction mixture was allowed to warm
to room temperature, and after 9 h, a saturated aqueous solution of
NaHCO3 was added. The phases were separated, and the aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried over Na2SO4 and filtered, and the solvent was evaporated
under vacuo. The residue was purified by flash chromatography on silica
gel (hexanes/EtOAc 100/0 to 95/5) to give the corresponding epoxide
(936 mg, 86%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.10
(d, 2H, J = 8.4 Hz), 6.79 (d, 2H, J = 8.4 Hz), 5.95 (m, 1H), 3.12
(m, 1H), 2.86 (dd, 1H, J = 14.6, 5.5 Hz), 2.78 (t, 2H, J = 5.0 Hz), 2.75
(dd, 1H, J = 14.6, 5.5 Hz), 2.53 (dd, 1H, J = 2.6, 5.0 Hz), 0.99 (s, 9H),
0.20 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 154.3, 129.8, 129.7, 120.0,
52.5, 46.7, 37.8, 25.6, 18.1, −4.4; HRMS (ESI) calcd for C15H25O2Si
(M + H)+ 265.1618, found 265.1626.
trans-4a-(Propa-1,2-dien-1-yl)-2,3,4,4a,8,8a-hexahydronaphtha-
lene-1,7-dione (58). Compound 57a (10.5 mg, 0.052 mmol) was
dissolved in MeOH (4 mL), and activated Zn (10.0 equiv) was added
followed by glacial acetic acid (5.0 equiv) at 0 °C. The resulting mixture
was stirred until no starting material was detected by TLC (∼1 h). The
mixture was directly filtered through a short pad of silica with a mixture
(1:1, ethyl acetate−hexane), and the filtrate was concentrated under
reduced pressure. The obtained residue was dissolved in DCM
(2.5 mL), and DBU (0.02 mmol) was added at 0 °C. The resulting
mixture was stirred during 1 h, and then a saturated solution of NH4Cl
was added (4 mL) as well as ethyl acetate (8 mL). The phases were
separated, and the aqueous layer was extracted with EtOAc (2 × 4 mL).
The combined organic layers were dried over Na2SO4 and filtered, and
the solvent was evaporated under vacuo. The residue was purified by
flash chromatography on silica gel (hexanes/EtOAc 7/3) to give 6.8 mg
1
(65%) of a yellow oil: H NMR (300 MHz, CDCl3) δ = 6.38 (d, 1H,
1-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-5-(trimethylsilyl)pent-4-
yn-2-ol (67). To a solution of trimethylsilylacetylene (4.0 mL,
28.1 mmol, 2.1 equiv) in dry THF (80 mL) at −78 °C was added
n-BuLi (2.5 M in hexanes, 10.2 mL, 25.5 mmol, 1.9 equiv). After 30
min at −78 °C, a solution of the previous epoxide (3.54 g, 13.4 mmol,
1 equiv) in dry THF (10 mL) and BF3·Et2O (2.0 mL, 16.1 mmol,
1.2 equiv) were successively added. The resulting mixture was stirred
at −78 °C for 30 min, and a saturated aqueous solution of NH4Cl was
added (50 mL). The phases were separated, and the aqueous layer was
extracted with EtOAc (3 × 50 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(hexanes/EtOAc 100/0 to 9/1) to yield 6 (4.84 g, quant) as a pale
yellow oil: IR ν (cm−1) 3350, 2942, 1509, 1254; 1H (300 MHz,
CDCl3) δ 7.08 (d, 2H, J = 8.4 Hz), 6.78 (d, 2H, J = 8.4 Hz), 3.92 (m,
1H), 2.84 (dd, 1H, J = 13.7, 5.8 Hz), 2.75 (dd, 1H, J = 13.7, 5.8 Hz),
2.44 (dd, 1H, J = 16.8, 5.8 Hz), 2.37 (dd, 1H, J = 16.8, 5.8 Hz), 1.99
(br, 1H), 0.98 (s, 9H), 0.19 (s, 6H), 0.17 (s, 9H); 13C NMR (150
MHz, CDCl3) δ 154.3, 130.3(*2), 120.0, 103.1, 87.8, 70.9, 41.6, 27.7,
25.6, 18.1, 0.0, −4.4; HRMS (ESI) calcd for C20H34O2Si2Na (M +
Na)+ 385.1990, found 385.1994.
J = 10.2 Hz), 5.95 (d, 1H, J = 10.2 Hz), 5.26 (t, 1H, J = 6.6 Hz), 4.87
(d, 1H, J = 6.6 Hz), 3.40 (m, 1H), 2.86 (m, 2H), 2.60−2.27 (m, 4H),
2.07−1.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 208.5, 207.1, 196.9,
150.9, 130.3, 95.7, 78.8, 53.4, 44.8, 40.4, 37.0, 34.6, 29.6, 22.4; HRMS
(ESI) calcd for C13H15O2 (M + H)+ 203.1067, found 203.1072.
9-Methylenehexahydro-1,4-methanocyclopropa[d]naphthalene-
3,5(1H,6H)-dione (61). To a solution of 58 (6.7 mg, 0.033 mmol) in
dry CH2Cl2 (1.5 mL) at 0 °C were added triethylamine (5 equiv) and
tert-butyldimetyl triflate (2.4 equiv) dropwise. The solution was stirred
for 1 h, the mixture was directly filtered through a short pad of silica
with a mixture of ethyl acetate−hexane (15:85), and the filtrate was
concentrated under reduced pressure. The crude product was dissolved
in toluene (5 mL) and stirred at 80 °C during 6 h, and the solvent was
evaporated under vacuo. At this stage, the corresponding dienol−ether
60 could be purified by chromatography (1:9, ethyl acetate−hexane) or
used as obtained for further transformation. The crude mixture was
dissolved in THF (2 mL), and TBAF (0.1 mmol, 3 equiv) was added at
0 °C. The solution was stirred for 1 h, the mixture was directly filtered
through a short pad of silica with a mixture (15:85, ethyl acetate−
hexane), and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(hexanes/EtOAc: 3/1) to give 4.7 mg (70% from 58) of a pale yellow
tert-Butyl(4-(2-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)-
pent-4-yn-1-yl)phenoxy)dimethylsilane (68). To a solution of
2130
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6 (4.88 g, 13.49 mmol, 1 equiv) in DMF (20 mL) at 0 °C were
successively added imidazole (2.7 g, 40.39 mmol, 3 equiv) and TBSCl
(3.0 g, 20.24 mmol, 1.5 equiv). The resulting mixture was allowed to
reach room temperature and stirred overnight. A saturated aqueous
solution of NaHCO3 (20 mL) and water (50 mL) was added. The
phases were separated, and the aqueous layer was extracted with Et2O
(3 × 50 mL). The organic layers were combined and dried over Na2SO4.
The solvents were evaporated in vacuum, and the crude product was
purified by flash chromatography on silica gel (hexanes/EtOAc:100/0 to
3.01 (d, J = 17.3 Hz, 1H), 2.77−2.33 (m, 5H), 2.00 (s, 3H), 1.90 (dd,
J = 14.2, 6.1 Hz, 1H), 0.81 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 198.6, 170.5, 152.7, 135.5, 128.2, 92.1, 91.7, 77.5, 59.0, 58.7,
57.5, 56.4, 46.1, 45.3, 33.0, 25.9 (3C), 21.7, 17.9, −4.4, −4.8; HRMS
(ESI) calcd for C21H35INO5Si (M + H)+ 536.1324, found 536.1311.
1-((tert-Butyldimethylsilyl)oxy)-2-(3-iodo-1-(2-((methylsulfonyl)-
oxy)ethyl)-7-oxo-1,2,4a,7,8,8a-hexahydroquinolin-4a-yl)ethyl Ace-
tate (72). To a solution of 71 (218 mg, 0.407 mmol, 1 equiv) in
CH2Cl2 (4 mL) at 0 °C were added Et3N (200 μL, 1.42 mmol, 3.5
equiv) and MsCl (56 μL, 0.710 mmol, 1.7 equiv). The reaction mixture
was allowed to warm to room temperature and after 2 h stirring, it was
directly purified by flash chromatography on silica gel (hexanes/EtOAc:
8/2 to 5/5) to give 224 mg (90%) of the corresponding mesylate
compound 1-((tert-butyldimethylsilyl)oxy)-2-(3-iodo-1-(2-((methyl-
sulfonyl)oxy)ethyl)-7-oxo-1,2,4a,7,8,8a-hexahydroquinolin-4a-yl)-
ethyl acetate as an oil: IR ν (cm−1) 2933, 2851, 1733, 1682, 1553, 1466,
1353, 1251, 1169; 1H NMR (300 MHz, CDCl3) δ 6.80 (d, J = 10.2 Hz,
1H), 6.15−6.04 (m, 2H), 5.94 (d, J = 10.2 Hz, 1H), 4.29 (t, J = 5.2 Hz,
2H), 3.50 (d, J = 10.2 Hz, 1H), 3.38 (dd, J = 12.4, 4.4 Hz, 1H), 3.20 (d,
J = 17.2 Hz, 1H), 3.04 (s, 3H), 2.97−2.77 (m, 2H), 2.62−2.29 (m, 3H),
2.18−1.97 (m, 1H), 1.97 (s, 3H), 0.86 (s, 9H), 0.06 (s, 6H); 13C NMR
(150 MHz, CDCl3) δ 198.6, 170.0, 152.0, 135.7, 128.4, 91.7, 91.5, 67.5,
58.7, 58.0, 46.1, 45.1, 37.7, 33.4, 31.8, 25.9 (3C), 21.8, 18.0, 4.2, 4.7;
HRMS (ESI) calcd for C22H37INO7SSi (M + H)+ 614.1099, found
614.1082. To a solution of the mesylate (82 mg, 0.133 mmol, 1 equiv) in
dry toluene (1.5 mL) at 0 °C was added t-BuOK (32 mg, 0.306 mmol,
2.3 equiv). The resulting mixture was allowed to reach room temperature,
and after 4 h, brine (1 mL) was added. The phases were separated, and
the aqueous layer was extracted with EtOAc (3 × 1 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (hexanes/EtOAc:9/1 to 7/3) to give 52 mg of 72 (75%): IR ν
(cm−1) 2943, 2912, 1733, 1671, 1246, 1143; 1H NMR (300 MHz,
CDCl3) δ 6.46 (m, 2H), 6.18 (t, J = 6.0 Hz, 1H), 5.93 (d, J = 10.2 Hz,
1H), 3.69 (d, J = 16.0 Hz, 1H), 3.16 (m, 1H), 3.01 (d, J = 16.5 Hz, 1H),
2.91−2.78 (m, 2H), 2.42−2.28 (m, 1H), 2.26−2.13 (m, 1H), 2.12−1.99
(m, 2H), 2.07 (s, 3H), 1.88 (dd, J = 14.4, 5.7 Hz, 1H), 0.90 (s, 9H), 0.12
(s, 3H), 0.10 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 199.0, 149.8,
138.2, 125.4, 91.0, 64.4, 63.0, 52.2, 46.0, 45.0, 44.0, 26.0 (3C), 25.2, 21.8,
18.1, 4.1, 4.7; HRMS (ESI) calcd for C21H33INO4Si (M + H)+ 518.1218,
found 518.1207.
1
9/1) to afford the desired product (5.8 g, 90%) as an oil: H NMR
(300 MHz, CDCl3) δ 7.08 (d, 2H, J = 8.2 Hz), 6.79 (d, 2H, J = 8.2 Hz),
3.95 (p, 1H, J = 6.1 Hz), 2.92 (dd, 1H, J = 13.5, 4.8 Hz), 2.70 (dd, 1H,
J = 13.5, 7.1 Hz), 2.37 (d, 2H, J = 6.1 Hz), 1.02 (s, 9H), 0.88 (s, 9H),
0.22 (s, 6H), 0.21 (s, 9H), 0.02 (s, 3H), −0.15 (s, 3H).; 13C NMR
(75 MHz, CDCl3) δ 154.0, 131.4, 130.7, 119.7, 104.6, 86.5, 72.7, 42.5,
28.5, 25.8, 25.7, 18.2, 18.0, 0.0, −4.4, −4.7, −4.9; HRMS (ESI) calcd for
C26H49O2Si3 (M + H)+ 477.3035, found 477.3030.
4-(2-((tert-Butyldimethylsilyl)oxy)pent-4-yn-1-yl)phenol (49a). To
a solution of the alkyne 49a (5.8 g, 12.18 mmol, 1 equiv) in MeOH
(100 mL) was added K2CO3 (3.3 g, 23.91 mmol, 2 equiv). The
resulting mixture was stirred overnight at room temperature, and water
was added (50 mL). The phases were separated, and the aqueous layer
was extracted with EtOAc (3 × 60 mL). The organic layers were
combined, dried over Na2SO4, filtered, and concentrated under vacuo.
The resulting crude product was purified by flash chromatography on
silica gel (hexanes/EtOAc 9/1 to 7/3) and 49 was isolated as an oil
1
(4.10 g, quant): IR ν (cm−1) 3384, 2946, 1511, 1264; H NMR (600
MHz, CDCl3) δ 7.08 (d, 2H, J = 8.2 Hz), 6.76 (d, 2H, J = 8.2 Hz), 3.93
(p, 1H, J = 5.3 Hz), 2.91 (dd, 1H, J = 14.1, 8.3 Hz), 2.70 (dd, 1H,
J = 13.5, 7.0 Hz), 2.30 (m, 2H), 2.05 (t, 1H, J = 2.3 Hz), 0.86 (s, 9H),
0.00 (s, 3H), −0.15 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 153.9,
130.9, 130.6, 115.0, 81.6, 72.3, 70.3, 42.0, 26.8, 25.7, 18.0, −4.8, −5.0;
HRMS (ESI) calcd for C17H27O2Si (M + H)+ 291.1775, found 291.1772.
(Z)-1-((tert-Butyldimethylsilyl)oxy)-2-(1-(3-((2-hydroxyethyl)-
amino)-2-iodoprop-1-en-1-yl)-4-oxocyclohexa-2,5-dien-1-yl)ethyl
Acetate (70) and 1-((tert-Butyldimethylsilyl)oxy)-2-(1-(2-hydrox-
yethyl)-3-iodo-7-oxo-1,2,4a,7,8,8a-hexahydroquinolin-4a-yl)ethyl
Acetate (71). To a solution of 51a (342 mg, 0.982 mmol, 1 equiv) in
CHCl3 (20 mL) were successively added NaHCO3 (1.2 g, 14.285 mmol,
15 equiv) and iodine (499 mg, 3.929 mmol, 2 equiv). The resulting
suspension was vigorously stirred at room temperature, and after 1 h, the
mixture was directly purified by flash chromatography on silica gel
(hexanes/EtOAc 100/0 and then 50/50) to afford 600 mg of 68
6-(2-Hydroxyethyl)-31,4,6a,7,8,9a-hexahydro-1H-pyrrolo[3,2,1-
ij]quinolin-9(2H)-one (75 Derivative). To a solution of 72 (99 mg,
0.191 mmol, 1 equiv) in EtOAc (100 μL) and EtOH (5 mL) was added
Pd/C (10%, 81 mg, 0.076 mmol, 0.4 equiv). The reaction mixture was
stirred at room temperature under an H2 atmosphere, and after 10 h,
it was filtered through a pad of Celite (EtOAc). The solvents were
evaporated to give 75 (80 mg, quant) which was used in the following
step without any further purification. To a stirred solution of the
compound 75 (80 mg, 0.191 mmol, 1 equiv) in CH2Cl2 (1.5 mL) at
0 °C was added TFA (50 μL, 0.650 mmol, 3.4 equiv). After 15 min at
0 °C and 10 min at room temperature, a saturated aqueous solution
of NaHCO3 (1 mL) was added. The two phases were separated, and
the aqueous layer was extracted with EtOAc (3 × 1 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was dissolved in dry THF (1.5 mL), and
LiAlH(O-t-Bu)3 (1 M in THF, 180 μL, 0.180 mmol, 0.94 equiv) was
added at 0 °C. The resulting mixture was stirred at 0 °C for 15 min
and quenched by addition of a saturated aqueous solution of NH4Cl
(1 mL). The phases were separated, and a saturated aqueous solution
of NaHCO3 (1 mL) was added to the aqueous layer. The aqueous
phase was extracted with EtOAc (3 × 1 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (CH2Cl2/MeOH 100/0 to 85/15), and an oil was obtained
1
(quant) as a 2/1 mixture of cis and trans diastereomers (see the H
NMR spectrum for ratio determination). This mixture of two
diastereomers was used without any further purification in the next
step, and to a stirred solution (600 mg, 0.982 mmol, 1 equiv) in dry
THF (40 mL) was added 1,2-aminoethanol (1.25 mL, 20.249 mmol, 20
equiv). The reaction mixture was stirred at room temperature for 1 h
and then directly filtered over silica gel (CH2Cl2/MeOH/Et3N 90/10/
1). The solvents were removed in vacuo, and the residue was purified by
flash chromatography on silica gel (hexanes/EtOAc 9/1 to 6/4 and then
CH2Cl2/MeOH 100/5 to 9/1) to yield 70 (157 mg) and 71 (178 mg)
in 64% yield overall from compound 51a. (Z)-1-((tert-
Butyldimethylsilyl)oxy)-2-(1-(3-((2-hydroxyethyl)amino)-2-iodo-
prop-1-en-1-yl)-4-oxocyclohexa-2,5-dien-1-yl)ethyl acetate (70): 1H
NMR (300 MHz, CDCl3) δ 6.85 (dt, J = 10.5, 3.3 Hz, 1H), 6.78 (dt, J =
10.5, 3.3 Hz, 1H), 6.36 (d, J = 10.1 Hz, 2H), 6.26 (s, 1H), 5.94 (t, J =
4.9 Hz, 1H), 3.68−3.56 (m, 2H), 3.46 (s, 1H), 2.63 (tapp, J = 6.0 Hz,
3H), 2.28 (dd, J = 14.0, 4.5 Hz, 1H), 2.18−2.10 (m, 2H), 2.14 (s, 3H),
0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
207.2, 186.1, 169.8, 149.8, 149.3, 133.1, 130.5, 130.3, 90.7, 62.5, 61.2,
49.0, 48.1, 45.2, 25.8 (3C), 21.6, 18.0, −4.2, −4.8; HRMS (ESI) calcd
for C21H35INO5Si (M + H)+ 536.1324, found 536.1314.
1-((tert-Butyldimethylsilyl)oxy)-2-(1-(2-hydroxyethyl)-3-iodo-7-
1
oxo-1,2,4a,7,8,8a-hexahydroquinolin-4a-yl)ethyl acetate (71): IR ν
(32 mg, 76% from 72): H NMR (300 MHz, CDCl3) δ 5.72 (dt, J =
1
(cm−1) 3487, 2933, 2851, 1733, 1682, 1471, 1379, 1256, 1148; H
10.1, 3.0 Hz, 1H), 5.53 (dt, J = 10.1, 2.2 Hz, 1H), 3.88−3.70 (m, 2H),
3.23−3.13(m, 1H), 3.10 (dd, J = 9.2, 2.4 Hz, 1H), 2.88−2.74 (m, 3H),
2.57−2.22 (m, 5H), 2.04−1.69 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 211.0, 131.6, 124.7, 68.6, 59.1, 53.8, 50.3, 48.3, 46.1, 40.3, 37.7, 36.5,
NMR (300 MHz, CDCl3) δ 6.67 (d, J = 10.2 Hz, 1H), 6.12 (t, J =
5.0 Hz, 1H), 6.02 (s, 1H), 5.88 (d, J = 10.1 Hz, 1H), 3.69−3.53
(m, 2H), 3.48 (d, J = 17.4 Hz, 1H), 3.35 (dd, J = 11.4, 5.4 Hz, 1H),
2131
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33.4, 21.1, 8.8; HRMS (ESI) calcd for C13H20NO2 (M + H)+ 222.1489,
found 222.1488.
(75 MHz, CDCl3) δ 168.7, 141.6, 138.1, 128.0, 124.6, 122.5, 118.6,
70.5, 68.1, 58.6, 53.9, 53.1, 52.6, 40.6, 39.7, 35.5, 35.3, 26.1, 24.4, 23.4,
21.7. HRMS (ESI) calcd for C21H29N2O2 (M + H)+ 341.2224, found
341.2225.
1-((tert-Butyldimethylsilyl)oxy)-2-(9-oxodecahydro-1H-pyrrolo-
[3,2,1-ij]quinolin-6a-yl)ethyl Acetate (76). To a solution of 75
(78 mg, 0.151 mmol, 1 equiv) in EtOAc (100 μL) and EtOH (5 mL)
was added by portions Pd/C (10%, 190 mg, 0.181 mmol, 1.2 equiv).
The reaction mixture was stirred at room temperature under an H2
atmosphere, and after 2 days, it was filtered through a pad of Celite
(EtOAc). The solvents were evaporated to give 76 (59 mg, quant)
which was used in the following step without any further purification:
1H NMR (300 MHz, CDCl3) δ 6.27 (t, J = 5.1 Hz, 1H), 3.12−2.99
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(m, 2H), 2.74−2.53 (m, 2H), 2.51−2.22 (m, 4H), 2.04 (s, 3H), 1.94−
1.29 (m, 10H), 0.91 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 210.7, 170.1, 91.6, 73.1, 53.2, 53.0, 48.3, 44.6, 37.0,
34.6, 34.2, 27.7, 25.9*3, 21.8, 21.4, 21.3, 18.1, −4.1, −4.7; HRMS
(ESI) calcd for C21H38NO4Si (M + H)+ 396.2565, found 396.2570.
6-(2-Hydroxyethyl)octahydro-1H-pyrrolo[3,2,1-ij]quinolin-9(2H)-
one (77). To a stirred solution of the compound 76 (53 mg,
0.134 mmol, 1 equiv) in CH2Cl2 (1 mL) at 0 °C was added TFA (35 μL,
0.456 mmol, 3.4 equiv). After 15 min at 0 °C and 10 min at room temp-
erature, a saturated aqueous solution of NaHCO3 (1 mL) was added.
The two phases were separated, and the aqueous layer was extracted
with EtOAc (3 × 1 mL). The organic layers were combined, dried over
Na2SO4, filtered, and concentrated under vacuum. The residue was
dissolved in dry THF (1 mL), and LiAlH(O-t-Bu)3 (1 M in THF,
120 μL, 0.120 mmol, 0.90 equiv) was added at 0 °C. The resulting
mixture was stirred at 0 °C for 15 min and quenched by addition of a
saturated aqueous solution of NH4Cl (1 mL). The phases were
separated, and a saturated aqueous solution of NaHCO3 (1 mL) was
added to the aqueous layer. The aqueous phase was extracted with
EtOAc (3 × 1 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (CH2Cl2/MeOH:
AUTHOR INFORMATION
Corresponding Author
*E-mail: canesi.sylvain@uqam.ca.
■
ACKNOWLEDGMENTS
We thank Dr. Alexandre Arnold (UQAM) for his help with 19
■
F
NMR. We are very grateful to the Natural Sciences and
Engineering Research Council of Canada (NSERC), the
Canada Foundation for Innovation (CFI), the provincial
government of Quebec (FQRNT and CCVC), and Boehringer
Ingelheim (Canada) Ltd. for financial support of this research.
K.C.G. and M.A.B. acknowledge the NSERC Vanier CGS and
the NSERC CGS-D programs, respectively.
REFERENCES
■
(1) (a) Fittig, R. Justus Liebigs Ann. Chem. 1860, 114, 54. (b) Wagner,
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1
100/0 to 85/15) to yield 77 (15 mg, 50%) as an oil: H (300 MHz,
CDCl3) δ 3.52 (t, J = 7.4 Hz, 2H), 3.06 (m, 3H), 2.74 (t, J = 6.2 Hz,
1H), 2.54 (dd, J = 15.3, 5.1 Hz, 1H), 2.54 (dd, J = 15.3, 5.1 Hz, 1H), 2.43
(dd, J = 15.3, 5.1 Hz, 1H), 2.36 (m, 3H), 2.2−1.84 (m, 5H), 1.83−1.56
(m, 3H), 1.50 (m, 1H), 1.31 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
211.1, 77.5, 73.4, 59.1, 53.8, 53.3, 48.5, 40.5, 37.1, 34.8, 34.1, 27.7, 21.5;
HRMS (ESI) calcd for C13H22NO2 (M + H)+ 224.1645, found 224.1651.
3-(2-Hydroxyethyl)-2,3,3a,4,5,5a,11,12-octahydro-1H-indolizino-
[8,1-cd]carbazol-6(3a-1H)-yl)ethanone (79). To a solution of ketone
77 (8 mg, 0.036 mmol, 1 equiv) in dry toluene (1 mL) was added
phenylhydrazine (6 μL, 0.054 mmol, 1.5 equiv), and the resulting
mixture was heated at 80 °C for 1 h 30. The mixture was then cooled
to room temperature, and the solvent was evaporated. The crude was
dissolved in dry toluene and solvent evaporated under reduced
pressure to remove residual water. The mixture was redissolved in dry
acetic acid (1 mL) and was heated under reflux. After 4 h, the mixture
was cooled to room temperature, the solvent was evaporated, and the
mixture was dissolved in THF (1 mL). LiAlH4 (14 mg, 0.360 mmol,
10 equiv) was added at 0 °C, and the mixture was stirred at room
temperature for 30 min. The mixture was cooled to 0 °C, water
(100 μL) was added, and the suspension was filtered through Celite
and washed with EtOAc. The resulting crude mixture was filtered over
silica gel (triethylamine/MeOH/CH2Cl2, 1/5/95) to give 78 together
with some inseparable impurities such as the unwanted indole
byproduct). This mixture was dissolved in a 1/1 mixture of CH2Cl2
and 2 M NaHCO3 (1.6 mL). AcCl (25 μL, 0.360 mmol, 10 equiv) and
the resulting solution were vigorously stirred at room temperature for
24 h. The phases were separated, the aqueous layer was extracted with
EtOAc (3 × 1 mL), the combined organic layers were dried over
Na2SO4 and filtered, and the solvent was evaporated in vacuo. The
crude product was purified by preparative TLC (AcOEt/Et3N 100/5)
to give 1.2 mg (∼10%) of 79 identical to the literature;16e see
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1
Overman’s formal synthesis: H NMR (300 MHz, CDCl3) δ 8.13 (d,
J = 7.7 Hz, 1H), 7.2 (d+t, J = 7.7 Hz, 2H), 4.07 (dd, J = 11.3, 6.3 Hz,
1H), 3.60 (m, 2H), 3.13 (td, J = 9.0, 3.2 Hz, 1H), 3.06 (d, J = 12.4 Hz,
1H), 2.38 (d, J = 13.2 Hz, 1H), 2.26 (m+s, 4H), 2.16 (s, 1H), 2.20−
1.88 (m, 4H), 1.84−1.462 (m, 6H), 1.35−1.10 (m, 2H); 13C NMR
Pouyseg
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u, L.; Oxoby, M.; Looney, M. A. Tetrahedron 2001, 57, 319.
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