Model studies directed toward the alkaloid mersicarpine utilizing a Rh(II)-catalyzed insertion/cycloaddition sequence

Article abstract of DOI:10.1021/jo4026622

Model studies dealing with the rhodium(II)-catalyzed carbenoid insertion/cyclization/cycloaddition cascade of several α-diazo dihydroindolinones have been carried out as an approach to the alkaloid mersicarpine. The cascade reaction of α-diazo dihydroindolinone 21 proceeded in high yield with excellent diastereoselectivity to give cycloadduct 22, which possesses the required stereochemistry of the two adjacent quaternary carbon centers present in mersicarpine. The overall reaction enabled the rapid assemblage of a polycyclic ring system that contains three new stereocenters and three continuous quaternary carbons in a single operation in high yield with excellent diastereoselectivity. The 3-indolinone derivative 36 was eventually formed from cycloadduct 22 by an acid-induced hydrolysis of 22 to give 23, which was subsequently converted in several steps to 36. The synthesis of this compound constitutes a successful construction of the tricyclic core of mersicarpine. Reduction of the nitrile group of 36 followed by a subsequent reductive cyclization/ring-opening aromatization cascade, as was found to occur with the related compound 29, will be employed for an eventual synthesis of demethylmersicarpine.

Full text of DOI:10.1021/jo4026622

Article
pubs.acs.org/joc
Model Studies Directed toward the Alkaloid Mersicarpine Utilizing a
Rh(II)-Catalyzed Insertion/Cycloaddition Sequence
Hao Li, Sara A. Bonderoff, Bo Cheng, and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: Model studies dealing with the rhodium(II)-catalyzed carbenoid insertion/cyclization/cycloaddition cascade of
several α-diazo dihydroindolinones have been carried out as an approach to the alkaloid mersicarpine. The cascade reaction of α-
diazo dihydroindolinone 21 proceeded in high yield with excellent diastereoselectivity to give cycloadduct 22, which possesses
the required stereochemistry of the two adjacent quaternary carbon centers present in mersicarpine. The overall reaction enabled
the rapid assemblage of a polycyclic ring system that contains three new stereocenters and three continuous quaternary carbons
in a single operation in high yield with excellent diastereoselectivity. The 3-indolinone derivative 36 was eventually formed from
cycloadduct 22 by an acid-induced hydrolysis of 22 to give 23, which was subsequently converted in several steps to 36. The
synthesis of this compound constitutes a successful construction of the tricyclic core of mersicarpine. Reduction of the nitrile
group of 36 followed by a subsequent reductive cyclization/ring-opening aromatization cascade, as was found to occur with the
related compound 29, will be employed for an eventual synthesis of demethylmersicarpine.
The synthetic plan that we have in mind for a mersicarpine
synthesis highlights an entirely different approach to this
alkaloid and involves a Rh(II)-catalyzed cascade reaction of
bis(diazo) imide 1.8−10 Over a period of years, our research
group has made extensive use of the rhodium(II)-catalyzed
reaction of α-diazo carbonyl compounds as a method to
generate various aza-containing carbonyl ylide dipoles such as
INTRODUCTION
■
Mersicarpine (4) is a structurally unique alkaloid that was
isolated from the Kopsia species of plants by Kam and co-
workers in 2004.1 It contains a seven-membered cyclic imine
and an intricately oxidized indole moiety centered in the
tetracyclic ring system with two quarternary carbons (C20 and
C21)1 arranged adjacent to the imine moiety. The first total
synthesis of mersicarpine was accomplished by Kerr and co-
workers in 2008 using a Mn(III)-mediated malonic radical
cyclization.2 Somewhat later, a formal synthesis of mersicarpine
was reported by Zard, who employed an intermolecular radical
addition/cyclization cascade.3 In addition to these two radical
approaches, application of a Lewis acid-catalyzed allylic
substitution of a tertiary alcohol for a formal synthesis of
mersicarpine was demonstrated by Han and co-workers.4 In
2010, Fukuyama and co-workers reported the first enantiose-
lective synthesis of mersicarpine employing a combination of a
Sonogashira coupling reaction with a gold(III)-catalyzed
cyclization.5 More recently, Tokuyama and co-workers applied
a DIBAL-H-mediated reductive ring-expansion reaction in their
enantioselective synthesis of mersicarpine, and this approach
constitutes the most concise synthesis of this alkaloid to date.6
Another interesting and rapid access to the core of mersicarpine
was developed by Liang in 2013 and features an initial aldol
reaction followed by a Beckmann rearrangement for the
synthesis of a δ-lactam intermediate.7 A subsequent intra-
molecular nucleophilic aromatic substitution (SNAr) was then
used for indoxyl formation, and this was followed by a final
autoxidation reaction.
isomunchnones.11 A subsequent intramolecular dipolar cyclo-
̈
addition was then employed to assemble the azapolycyclic
framework of many different classes of alkaloids.12 Should the
reaction of bis(diazo) imide 1 with 4-methylenehexan-1-amine
proceed in the manner that was encountered with several
alkenyl substituted alcohols10 (vide infra), compound 2 would
be formed. Treatment of either 2 or an N-protected derivative
with a Rh(II) catalyst was expected to give rise to cycloadduct 3
(Scheme 1). We believed that it would be possible to convert 3
to mersicarpine (4) following along the synthetic lines we had
already worked out in our laboratory for an aspidophytine
synthesis.13 With this in mind, we set out to examine a number
of related model systems to probe whether this sequence of
reactions could be employed for an eventual synthesis of
mersicarpine.
RESULTS AND DISCUSSION
Our initial set of model studies involved the use of alkenyl
alcohols in order to establish the desired insertion/cyclo-
■
Received: December 2, 2013
Published: December 13, 2013
© 2013 American Chemical Society
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Scheme 1
addition cascade sequence. The reaction of 1 with but-3-en-1-ol
in the presence of catalytic Rh2(OPiv)4 afforded the expected
OH-insertion product 5 (n = 2) in 64% yield. When the same
reaction was carried out in refluxing benzene, cycloadduct 8 was
isolated in 61% yield, and its formation involves generation of
Scheme 3
the transient isomunchnone 7 from 5 followed by a subsequent
̈
intramolecular dipolar cycloaddition of this reactive 1,3-dipole
(Scheme 2). We were pleased to note that the same sequence
Scheme 2
unfavorable entropic factors in the transition state of the
cycloaddition reaction results in a preferred proton exchange of
the 1,3-dipole, giving rise to compound 12. The difference in
the Rh(II)-catalyzed behavior of ether 6, which results in the
formation of the seven-membered cycloadduct 9, versus amine
11, which affords 12, is rather subtle and requires additional
study in order to determine the reactivity disparity.
With the knowledge that the reaction of α-diazo amide 1
with N-allylaniline results in a facile Rh(II)-catalyzed
cyclization/intramolecular dipolar cycloaddition cascade, we
subsequently found that a 3-amino substituted α-diazo
dihydroindolinone such as 13 also undergoes a related
Rh(II)-catalyzed cyclization/cycloaddition cascade to furnish
the azapolycyclic ring system 14 in 83% yield as a 8:5 mixture
of diastereomeric cycloadducts (Scheme 4).14 Although we did
of reactions occurred when bis(diazo) compound 1 was treated
with pent-4-en-1-ol in refluxing benzene in the presence of the
rhodium(II) catalyst. In this case, the seven-membered
cycloadduct 9 was isolated in 44% yield, thereby establishing
the feasibility of the desired cascade sequence that we hoped to
use for an eventual synthesis of mersicarpine (4).
In order to further expand the scope of the Rh(II)-catalyzed
insertion/cycloaddition cascade, an analogous sequence was
carried out using N-allylaniline for the initial insertion reaction
with bis(diazo) imide 1. Since this particular Rh(II)-catalyzed
reaction was carried out in refluxing benzene, the expected
amine derived from insertion of the rhodium carbenoid into the
NH bond was not detected. Instead, the initially formed
insertion product simply underwent a very rapid cyclization/
cycloaddition cascade to produce cycloadduct 10 in 74%
isolated yield (Scheme 3). An analogous reaction was also
carried out at room temperature using N-(pent-4-en-1-
yl)aniline for the initial insertion with bis(diazo) imide 1.
Under these conditions, the amino-substituted diazo indolinone
11 was obtained in 48% yield. However, when 11 was heated at
reflux in benzene in the presence of Rh2(OPiv)4, the only
product (56%) that was isolated corresponded to oxazolo[3,2-
a]indol-3(2H)-one 12. All of our efforts to detect or isolate an
intramolecular cycloadduct analogous to 9 or 10 failed, as there
was no indication of its presence in the crude reaction mixture.
Most likely a low rate of intramolecular cycloaddition due to
Scheme 4
not probe the further chemistry of the resulting cycloadduct
mixture, we assume that it should be possible to induce the loss
of HCN and thereby generate the key imino group that is
present in the alkaloid mersicarpine (4).
Since α-diazo-substituted dihydroindolinone 13 underwent
such a smooth Rh(II)-catalyzed cycloaddition, we embarked on
a further study of this type of reaction using α-amino nitrile 17
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as the key substrate for the Rh(II)-catalyzed cascade with the
hope of assembling all of the critical rings of mersicarpine in a
one-pot procedure (Scheme 5). The preparation of 17 started
Scheme 7
Scheme 5
ol; this was followed by acylation with 16 to deliver 21, now
containing a disubstituted alkenyl tethered side chain. We were
please to find that when 21 was treated with the rhodium(II)
acetate catalyst, the pentacyclic cycloadduct 22 was isolated in
92% yield (Scheme 7). Most importantly, cycloadduct 22
possesses the required stereochemistry of the two adjacent
quaternary carbon centers present in mersicarpine. Notably,
this particular cascade reaction enabled the rapid assemblage of
a polycyclic ring system containing three new stereocenters and
three continuous quaternary carbons in a single operation in
high yield with excellent diastereoselectivity.
with the generation of a transient imine formed by a reaction
between isatin and the known 4-methylenehexan-1-amine.15
Trapping of the initially formed imine with KCN followed by
acylation with ethyl 2-diazomalonyl chloride (16)16 delivered
the desired α-diazo dihydroindolinone 17 in 50% yield.
Unfortunately, the reaction of 17 with a variety of rhodium(II)
catalysts did not produce the desired cycloaddition adduct 18.
Once again it would seem that formation of the seven-
membered ring required for the dipolar cycloaddition reaction
is entropically disfavored in the transition state and other
competitive reactions occur instead.
In order to promote the Rh(II)-catalyzed cyclization/
cycloaddition cascade, α-diazo dihydroindolinone 19 contain-
ing a smaller alkenyl side chain was prepared with the
expectation that the involvement of a six-membered-ring
transition state for the intramolecular cycloaddition would be
more likely to occur because of conformational factors. Our
hope was that the resulting ketal functionality present in
cycloadduct 20 would serve as a handle for the eventual
introduction of the imino group that is necessary for a
mersicarpine synthesis. Indeed, compound 19 was easily
prepared by the reaction of isatin with but-3-en-1-ol followed
by an acylation with 16. Most satisfactorily, exposure of 19 to
catalytic amounts of rhodium(II) acetate in benzene at 80 °C
for 1 h afforded the desired cycloaddition product 20 in nearly
quantitative yield as a single diastereomer (Scheme 6).
With cycloaddition product 22 in hand, we next examined its
hydrolysis, which was found to furnish the primary alcohol 23
in 78% yield (Scheme 8). A Lewis acid-mediated oxabicyclic
Scheme 8
Scheme 6
ring cleavage was then carried out using BF3·Et2O under
refluxing conditions to afford α-hydroxy ester 24. This reaction
presumably involves an initial oxabicyclic ring opening to
generate a transient iminium ion intermediate, which then
reacts with the neighboring primary alcohol to give 24. α-
Hydroxy ester 24 was subsequently converted into the
corresponding secondary alcohol 25 as a 2:1 mixture of
inseparable diastereomers in 84% yield. This base-mediated
reaction proceeds by an α-hydroxy ester rearrangement/
hydrolysis cascade.17,18 The mixture of diastereomeric alcohols
25 was easily converted to xanthate 26, and this was followed
by a facile Barton−McCombie deoxygenation19 to produce
tetracyclic 3-indolinone derivative 27, which contains the
tricyclic core of mersicarpine (Scheme 8). Most unfortunately,
all of our efforts to induce opening of the tetrahydrofuran ring
of 27 under either reductive or acidic conditions led to the
complete decomposition of the starting material without a trace
of the desired ring-opened alcohol 28.
One of the key synthetic challenges that must be solved for a
synthesis of mersicarpine lies in the construction of the two
adjacent quaternary carbon centers (C20 and C21),1 and
whichever method is used should also proceed with high
diastereoselectivity. In order to probe the feasibility of using the
Rh(II)-catalyzed cascade sequence for a stereoselective syn-
thesis of the C20 and C21 quaternary carbon centers of
mersicarpine, α-diazo dihydroindolinone 21 was chosen as
another model substrate (Scheme 7). Treatment of isatin with
acid in MeOH provided the expected dimethyl ketal, which was
then submitted to a ketal exchange using 3-methylbut-3-en-1-
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Intramolecular reductive cyclizations represent a powerful
tool for the synthesis of heterocycles and natural products.20
With this type of cyclization reaction in mind, we treated
TBDMS-protected alcohol 29 derived from 23 with BF3·Et2O/
Et3SiH at room temperature to produce a 1:1 mixture of
products: in addition to the reductive cyclization product 30
(40%), indole 31 was also isolated in 40% yield (Scheme 9).
Our attempted synthesis of nitrile 36 commenced by a
standard bromination of alcohol 23 making use of the Appel
reaction.21 Unfortunately, exposure of the resulting bromide 37
to KCN did not provide the desired nitrile 38. Instead, the
unexpected cyclization product 39 was isolated in 68% yield
(Scheme 11). The formation of 39 presumably proceeds by an
Scheme 11
Scheme 9
initial nucleophilic addition of cyanide anion to the reactive
carbonyl group of 37 to form an alkoxy anion that reacts further
by an SN2 displacement of the tethered alkyl bromide to furnish
the tetrahydropyran ring present in structure 39.
To inhibit this undesired reaction, alcohol 23 was first
converted into the cyclic ketal 40 under acidic conditions in
63% yield (Scheme 12). Mesylation of 40 with MsCl and Et3N
Scheme 12
We believe that tetrahydropyran derivative 30 arises by
fluoride-mediated deprotection of TBDMS ether 29 followed
by an intramolecular cyclization to eventually deliver the cyclic
oxonium ion intermediate 32, which is then reduced by Et3SiH.
The formation of indole 31 most likely occurs by a Lewis acid-
mediated oxabicyclic ring cleavage of 30 to afford transient
iminium intermediate 33, which undergoes subsequent
aromatization by loss of a proton.
Inspired by the reductive cyclization/ring-opening aromati-
zation cascade of 29, we envisioned that a demethylated
derivative of mersicarpine (i.e., 34) could be obtained from α-
hydroxy indolyl ester 35 and that this approach would serve as
a model system for an eventual synthesis of mersicarpine. In
principle, indole 35 could be prepared by the reduction of
nitrile 36 to a primary amine followed by a similar sequence of
reactions as outlined in Scheme 9. We expected that compound
36 would be quickly assembled from alcohol 23 by conversion
of the OH group into a nitrile, and this would be followed by
reduction of the cyano group and further transformation to give
compound 35 (Scheme 10).
followed by an SN2 displacement reaction of the resulting
mesylate 41 with NaI furnished iodide 42. Subsequent
cyanation of 42 using NaCN delivered 36 in 85% yield. With
the key intermediate 36 in hand, our plan is to carry out a
reduction of the nitrile group and then apply the reductive
cyclization/ring-opening aromatization cascade (Scheme 9)
toward an eventual synthesis of demethylmersicarpine 34.
CONCLUSION
■
Model studies dealing with a rhodium(II)-catalyzed carbenoid
cyclization/cycloaddition cascade of α-diazo dihydroindoli-
nones have been carried out as an approach to the alkaloid
mersicarpine. The model cascade sequence proceeds in high
yield with excellent diastereoselectivity to afford intramolecular
cycloadducts. The 3-indolinone derivative 36 was eventually
formed from cycloadduct 22 by an acid-induced hydrolysis of
22 to give 23, which was subsequently converted in several
steps to 36. The synthesis of this compound constitutes a
successful construction of the tricyclic core of mersicarpine.
Reduction of the nitrile group of 36 followed by a reductive
cyclization/ring-opening aromatization cascade, as was found to
occur with the related compound 29, will be employed for an
eventual synthesis of demethylmersicarpine.
Scheme 10
EXPERIMENTAL SECTION
General Procedures. Melting points are uncorrected. Mass
spectra were obtained at an ionizing voltage of 70 eV. Unless
■
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1
otherwise noted, reactions were performed in flame-dried glassware
under an atmosphere of either dry nitrogen or argon. All solvents were
distilled prior to use. Solutions were evaporated under reduced
pressure with a rotary evaporator, and the residue was chromato-
graphed on a silica gel column (0.04−0.062 mm) using an ethyl
acetate/hexane mixture as the eluent unless specified otherwise. All
solids were recrystallized from ethyl acetate/hexane for analytical data.
Yields refer to isolated, spectroscopically pure compounds.
1466 cm−1; H NMR (400 MHz, CDCl3) δ 1.35 (t, 3H, J = 7.1 Hz),
1.75−1.92 (m, 5H), 2.74 (dd, 1H, J = 12.8 and 8.1 Hz), 2.77−2.83 (m,
1H), 3.68 (td, 1H, J = 12.0 and 1.7 Hz), 4.32−4.42 (m, 3H), 5.30 (s,
1H), 7.17 (td, 1H, J = 7.5 and 1.1 Hz), 7.34−7.37 (m, 1H), 7.41 (d,
1H, J = 7.9 Hz), and 7.45 (d, 1H, J = 7.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 14.4, 31.5, 34.8, 35.9, 45.2, 62.6, 75.4, 83.6, 88.0, 108.5,
114.2, 125.2, 126.9, 130.5, 130.8, 139.8, 165.1, and 169.7; HRMS calcd
for [C18H19NO5 + H]+ 330.1336, found 330.1334.
1-(Ethyl diazomalonyl)-3-diazoindolin-2-one (1). A sample of
3-diazoindolin-2-one22 (1.2 g, 7.55 mmol) was dissolved in THF (38
mL), and the solution was cooled in an ice/water bath. A sample of
NaH (604 mg, 60% dispersion in mineral oil, 15.1 mmol) was added in
one portion, and the resulting suspension was allowed to stir for 10
min. Ethyl 2-diazomalonyl chloride (16)16 (2.0 g, 11 mmol) was then
added, and the mixture was allowed to stir for 30 min. The solution
was concentrated under reduced pressure, and the combined extracts
were washed with water followed by brine. The solution was dried
over anhydrous magnesium sulfate, filtered, and concentrated to give
an orange solid. The crude product was purified by crystallization to
furnish 1.68 g (74% yield) of the title compound as orange crystals.
Mp 117−118 °C; IR (film) 2983, 2140, 2105, 1713, 1663, 1605, and
(2aR,2a1R,4R,10bS)-Ethyl 5-Oxo-1-phenyl-2,2a,3,4,5,10b-
hexahydro-1H-2a1,4-epoxybenzo-[b]pyrrolo[4,3,2-hi]-
indolizine-4-carboxylate (10). A catalytic amount (0.6 mg) of
Rh2(OPiv)4, benzene (1.0 mL), and N-allylaniline (13 mg, 0.10 mmol)
were added sequentially to a 10 mL flask with a side arm (which was
stoppered with a septum) and equipped with a condenser. The
resulting solution was heated at reflux, and a solution of bis(diazo)
compound 1 (30 mg, 0.10 mmol) in benzene (1.0 mL) was added
through the side arm over a 1 h period using a syringe pump. Stirring
was continued at this temperature for an additional 3 h, and the
solution was then concentrated under reduced pressure. Purification
by flash column chromatography gave 28 mg (74% yield) of the title
compound 10 as an off-white solid. Mp 196−198 °C; IR (film) 2982,
2845, 1728, 1602, 1502, and 1466 cm−1; 1H NMR (600 MHz, CDCl3)
δ 1.40 (t, 3H, J = 7.2 Hz), 2.36 (dd, 1H, J = 12.7 and 5.5 Hz), 2.61
(dd, 1H, J = 12.7 and 8.2 Hz), 2.80−2.86 (m, 1H), 3.09 (dd, 1H, J =
11.1 and 9.0 Hz), 3.97 (t, 1H, J = 8.1 Hz), 4.42 (q, 2H, J = 7.2 Hz),
6.85−6.92 (m, 3H), 7.15 (t, 1H, J = 7.6 Hz), 7.34 (t, 2H, J = 7.7 Hz),
7.34 (t, 1H, J = 7.8 Hz), and 7.63 (d, 1H, J = 7.7 Hz); 13C NMR (150
MHz, CDCl3) δ 14.4, 33.0, 46.2, 53.0, 60.2, 62.8, 96.2, 108.8, 113.1,
114.7, 118.7, 125.7, 127.9, 129.9, 130.4, 134.6, 135.3, 148.1, 161.8, and
164.5; HRMS calcd for [C22H20N2O4 + H]+ 377.1496, found
377.1508.
1
1464 cm−1; H NMR (400 MHz, CDCl3) δ 1.31 (t, 3H, J = 7.2 Hz),
4.30 (q, 2H, J = 7.2 Hz), 7.17−7.25 (m, 3H), and 7.63−7.69 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 14.5, 62.3, 62.8, 72.3, 114.7, 116.6,
118.1, 125.1, 126.4, 130.6, 160.0, 160.7, and 165.1; HRMS calcd for
[C13H9N5O4 + Na]+ 322.0547, found 322.0547.
3-(But-3-en-1-oxy)-1-(ethyl diazomalonyl)indolin-2-one (5).
Bis(diazo) compound 1 (100 mg, 0.33 mmol), dichloromethane (6.7
mL), 3-buten-1-ol (86 μL, 1.0 mmol), and Rh2(OPiv)4 (1 mg, 0.002
mmol) were added sequentially to a 25 mL flask. The resulting orange
solution was allowed to stir at rt under a nitrogen atmosphere for 30
min. The yellow solution was concentrated under reduced pressure,
and the residue was purified by flash column chromatography to give
73 mg (64% yield) of the title compound 5 as a pale-yellow oil. IR
Ethyl 2-Diazo-3-oxo-3-(2-oxo-3-(pent-4-en-1-yl(phenyl)-
amino)indolin-1-yl)propanoate (11). Rh2(OAc)4 (3 mg, 0.007
mmol), benzene (2.8 mL), and N-(pent-4-en-1-yl)aniline (45 mg, 0.28
mmol) were added sequentially to a flask, and a solution of bis(diazo)
compound 1 (75 mg, 0.28 mmol) in benzene (2.8 mL) at rt was added
over 1 h using a syringe pump. Following the addition, the solution
was concentrated under reduced pressure. Purification by flash column
chromatography gave 59 mg (48% yield) of the title compound 11 as a
pale-brown oil. IR (neat) 2934, 2139, 1701, 1652, 1601, 1581, 1505,
1
(neat) 2980, 2139, 1766, 1724, 1659, 1609, 1480, and 1466 cm−1; H
NMR (400 MHz, CDCl3) δ 1.31 (t, 3H, J = 7.1 Hz), 2.38−2.45 (m,
2H), 3.68 (dt, 1H, J = 8.9 and 6.6 Hz), 3.87 (dt, 1H, J = 8.9 and 6.6
Hz), 4.24−4.33 (m, 2H), 5.05−5.17 (m, 2H), 5.11 (s, 1H), 5.84 (ddt,
1H, J = 17.1, 10.3, and 6.7 Hz), 7.21 (t, 1H, J = 7.5 Hz), 7.37 (t, 1H, J
= 8.0 Hz), 7.44 (d, 1H, J = 7.5 Hz), and 7.62 (d, 1H, J = 8.1 Hz); 13C
NMR (150 MHz, CDCl3) δ 14.5, 34.4, 62.3, 68.8, 76.2, 114.5, 117.0,
124.8, 125.3, 125.5, 130.4, 134.9, 140.0, 160.2, 160.5, and 174.0;
HRMS calcd for [C17H17N3O5 + H]+ 344.1241, found 344.1248.
(3aS,3a1R,5R)-Ethyl 6-Oxo-3,3a,4,5,6,11b-hexahydro-2H-
3a1,5-epoxybenzo[b]pyrano[4,3,2-hi]indolizine-5-carboxylate
(8). Bis(diazo) compound 1 (30 mg, 0.1 mmol) was dissolved in
benzene (2.0 mL), and homoallyl alcohol (8.6 μL, 0.10 mmol)
followed by Rh2(OPiv)4 (0.3 mg) was added. The resulting orange
solution was heated to reflux for 2 h, and the yellow solution was
allowed to cool to rt and concentrated under reduced pressure.
Purification by flash column chromatography gave 20 mg (61% yield)
of the title compound 8 as a pale-yellow oil. IR (CDCl3 film) 2980,
1
and 1448 cm−1; H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J = 7.2
Hz), 1.61−1.76 (m, 2H), 2.02 (q, 2H, J = 7.1 Hz), 3.11−3.34 (m, 2H),
4.27 (q, 2H, J = 7.2 Hz), 4.90−4.98 (m, 2H), 5.47 (s, 1H), 5.73 (ddt,
1H, J = 17.0, 10.3, and 6.6 Hz), 6.78−6.84 (m, 3H), 7.17 (t, 1H, J =
7.4 Hz), 7.20−7.25 (m, 2H), 7.31 (d, 1H, J = 7.4 Hz), 7.36 (t, 1H, J =
8.1 Hz), and 7.67 (d, 1H, J = 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ
14.5, 27.3, 31.2, 49.4, 62.2, 64.7, 114.6, 115.3, 115.4, 119.1, 124.8,
125.2, 126.0, 129.5, 129.6, 138.0, 139.3, 147.9, 160.39, 160.41, and
174.4; HRMS calcd for [C24H24N4O4 + H]+ 433.1870, found
433.1871.
Ethyl 3-Oxo-9-(pent-4-en-1-yl(phenyl)amino)-2,3-
dihydrooxazolo[3,2-a]indole-2-carboxylate (12). Bis(diazo)
compound 1 (30 mg, 0.10 mmol) was dissolved in benzene (2.0
mL), and N-(pent-4-en-1-yl)aniline (18 mg, 1.1 mmol) followed by
Rh2(OPiv)4 (0.6 mg) was added. The resulting solution was heated to
reflux, and after 5 h the solution was allowed to cool to rt and
concentrated under reduced pressure. Purification by flash column
chromatography gave 23 mg (56% yield) of the title compound 12 as a
pale-yellow solid. Mp 109−111 °C; IR (neat) 2926, 1753, 1664, 1596,
1
2871, 1733, 1607, 1467, 1479, and 1306 cm−1; H NMR (400 MHz,
CDCl3) δ 1.37 (t, 1H, J = 7.1 Hz), 1.59−1.70 (m, 1H), 2.01 (dd, J =
12.8 and 4.0 Hz), 2.09−2.19 (m, 1H), 2.46−2.55 (m, 1H), 2.65 (dd,
1H, J = 12.8 and 8.1 Hz), 3.84−4.00 (m, 2H), 4.34−4.46 (m, 2H),
5.38 (s, 1H), 7.16 (t, 1H, J = 7.4 Hz), 7.36 (t, 1H, J = 7.5 Hz), 7.41 (d,
1H, J = 7.7 Hz), and 7.46 (d, 1H, J = 7.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 14.4, 27.1, 34.5, 36.2, 62.7, 62.8, 75.6, 90.8, 101.5, 114.1,
125.3, 127.0, 130.86, 130.93, 137.7, 165.0, and 165.2; HRMS calcd for
[C17H17NO5 + H]+ 316.1180, found 316.1178.
1
and 1498 cm−1; H NMR (600 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.1
Hz), 1.84 (pent, 2H, J = 7.5 Hz), 2.14 (q, 2H, J = 7.1 Hz), 3.69 (ABX2,
2H, ΔδAB = 0.03, JAB = 14.5 Hz, JAX = JBX = 7.4 Hz), 4.37 (ABX3, 2H,
ΔδAB = 0.02, JAB = 10.7 Hz, JAX = JBX = 7.1 Hz), 4.96 (d, 1H, J = 10.2
Hz), 5.00 (d, 1H, J = 17.1 Hz), 5.58 (s, 1H), 5.82 (ddt, 1H, J = 17.1,
10.2, and 6.6 Hz), 6.75−6.81 (m, 3H), 7.11 (d, 2H, J = 7.6 Hz), 7.18−
7.22 (m, 2H), 7.24 (t, 1H, J = 7.8 Hz), and 7.85 (d, 1H, J = 7.7 Hz);
13C NMR (100 MHz, CDCl3) δ 14.3, 27.3, 31.3, 51.0, 63.6, 84.8,
100.0, 113.7, 113.9, 115.3, 118.1, 119.7, 123.3, 124.7, 125.6, 129.4,
133.3, 138.2, 147.5, 149.3, 159.3, and 163.4; HRMS calcd for
[C24H24N2O4 + H]+ 405.1809, found 405.1804.
(4aS,4a1R,6R)-Ethyl 7-Oxo-2,3,4,4a,5,6,7,12b-octahydro-
4a1,6-epoxybenzo[b]oxepino-[4,3,2-hi]indolizine-6-carboxy-
late (9). Bis(diazo) compound 1 (75 mg, 0.25 mmol) was dissolved in
benzene (5.0 mL), and 4-penten-1-ol (26 μL, 0.25 mmol) followed by
Rh2(OPiv)4 (0.8 mg) was added. The resulting solution was heated to
reflux for 3 h, and the solution was allowed to cool to rt and
concentrated under reduced pressure. Purification by flash column
chromatography gave 36 mg (44% yield) of the title compound 9 as a
white solid. Mp 121−123 °C; IR (film) 2925, 1747, 1607, 1482, and
396
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Article
Ethyl 3-(3-Cyano-3-((4-methylenehexyl)amino)-2-oxoindo-
lin-1-yl)-2-diazo-3-oxopropanoate (17). To a 50 mL round-
bottom flask charged with a solution of isatin (15) (1.65 g, 11.3 mmol)
in ethanol (22.6 mL) were sequentially added 4-methylenehexan-1-
amine15 (1.40 g, 12.4 mmol) and two drops of glacial acetic acid. The
mixture was stirred for 24 h at 25 °C. After removal of the solvent
under reduced pressure, ether (20 mL) was added, and the yellow
precipitate that formed was collected by filtration to furnish 1.90 g of
(Z)-3-((4-methylenehexyl)imino)indolin-2-one, which was used with-
out further purification. To a 10 mL round-bottom flask charged with
a solution of the above imine (242 mg, 1.0 mmol) in methanol (5 mL)
at 25 °C were sequentially added KCN (68 mg, 1.05 mmol) and HCl
(1.25 M in methanol, 1.6 mL, 2.0 mmol). After 5 h of stirring, the
mixture was quenched with aqueous NaOH (1 N, 2 mL) and extracted
with CH2Cl2. The combined organic layers were washed with water
and brine and dried over MgSO4. After removal of the solvent under
reduced pressure, the residue was subjected to flash silica gel
chromatography to furnish 153 mg (50% yield) of 3-((4-
methylenehexyl)amino)-2-oxoindoline-3-carbonitrile as a pale-yellow
mixture was heated at 80 °C for 1 h. After cooling to rt, the reaction
mixture was concentrated under reduced pressure and subjected to
flash silica gel chromatography to furnish 23 mg (98% yield) of the
title compound 20 as a colorless oil. IR (thin film) 2947, 1732, 1607,
1
and 1481 cm−1; H NMR (400 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.2
Hz), 1.67−1.75 (m, 1H), 2.06 (dd, 1H, J = 12.8 and 7.6 Hz), 2.12−
2.21 (m, 1H), 2.37−2.46 (m, 3H), 2.64 (dd, 1H, J = 12.8 and 8.0 Hz),
3.73−3.93 (m, 3H), 4.12−4.18 (m, 1H), 4.31−4.45 (m, 2H), 5.02−
5.05 (m, 1H), 5.07−5.13 (m, 1H), 5.77−5.87 (m, 1H), 7.15 (td, 1H, J
= 7.6 and 1.2 Hz), 7.40 (td, 1H, J = 7.6 and 1.2 Hz), 7.45 (d, 1H, J =
8.0 Hz), and 7.48 (d, 1H, J = 8.0 Hz); 13C NMR (150 MHz, CDCl3) δ
14.3, 26.0, 34.3, 35.1, 36.7, 59.5, 62.6. 63.1, 90.4, 99.8, 99.9, 114.5,
117.1, 124.6, 125.8, 130.8, 131.5, 134.7, 136.3, 164.8, and 164.9;
HRMS calcd for [C21H23NO6 + Na]+ 408.1417, found 408.1419.
Ethyl 3-(3,3-Bis(3-methylbut-3-en-1-yloxy)-2-oxoindolin-1-
yl)-2-diazo-3-oxopropanoate (21). To a 250 mL round-bottom
flask charged with a solution of 3,3-dimethoxyindolin-2-one (6.30 g,
32.6 mmol) in 3-methylbut-3-en-1-ol (66 mL, 652 mmol) was added
anhydrous PTSA (561 mg, 3.26 mmol). The mixture was stirred for 24
h at 25 °C, filtered through a short plug of silica gel to remove PTSA,
and concentrated under reduced pressure. The resulting residue
containing 3,3-bis(3-methylbut-3-en-1-yloxy)indolin-2-one was taken
up in CH2Cl2 (50 mL), and DMAP (9.54 g, 78.2 mmol) and ethyl 2-
diazomalonyl chloride (8.63 g, 48.9 mmol) were sequentially added.
The mixture was stirred for 12 h at 25 °C. After removal of the solvent
under reduced pressure, the residue was subjected to flash silica gel
chromatography to furnish 8.91 g (62% yield over two steps) of the
title compound 21 as a colorless oil. IR (thin film) 2969, 2139, 1772,
1704, and 1662 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.30 (t, 3H, J =
7.2 Hz), 1.73 (s, 6H), 2.31 (t, 4H, J = 7.2 Hz), 3.81−3.87 (m, 4H),
4.29 (q, 2H, J = 7.2 Hz), 4.72 (s, 2H), 4.77 (s, 2H), 7.22 (t, 1H, J = 7.8
Hz), 7.40 (t, 1H, J = 7.8 Hz), 7.45 (d, 1H, J = 7.8 Hz), and 7.65 (d,
1H, J = 8.4 Hz); 13C NMR (150 MHz, CDCl3) δ 14.4, 22.9, 37.9, 62.2,
62.4, 112.1, 114.8, 125.0, 125.1, 125.3, 131.0, 139.3, 142.4, 159.9,
160.3, 169.8, and 173.2; HRMS calcd for [C23H27N3O6 + H]+
442.1972, found 442.1975.
1
oil. IR (thin film) 2928, 1730, 1625, and 1480 cm−1; H NMR (400
MHz, CDCl3) δ 1.00 (t, 3H, J = 7.6 Hz), 1.65 (p, 2H, J = 7.6 Hz), 1.99
(q, 2H, J = 7.6 Hz), 2.08 (t, 2H, J = 7.6 Hz), 2.79−2.93 (m, 2H), 4.68
(s, 1H), 4.71 (s, 1H), 6.95 (d, 1H, J = 7.6 Hz), 7.16 (t, 1H, J = 7.6
Hz), 7.38 (t, 1H, J = 7.2 Hz), 7.47 (d, 1H, J = 8.0 Hz), and 7.78 (br s,
1H). This material was used in the next step without further
purification.
To a 50 mL round-bottom flask charged with a solution of the
above compound (128 mg, 0.47 mmol) in CH2Cl2 (10 mL) were
sequentially added DMAP (115 mg, 0.94 mmol) and ethyl 2-
diazomalonyl chloride (126 mg, 0.71 mmol). The mixture was stirred
for 20 min at 25 °C. After removal of the solvent under reduced
pressure, the residue was subjected to flash silica gel chromatography
to furnish 127 mg (82% yield) of the title compound 17 as a colorless
1
oil. IR (thin film) 2964, 2144, 1766, 1728, 1668, and 1480 cm−1; H
NMR (400 MHz, CDCl3) δ 1.00 (t, 3H, J = 7.6 Hz), 1.31 (t, 3H, J =
7.2 Hz), 1.65 (p, 2H, J = 7.6 Hz), 2.00 (q, 2H, J = 7.6 Hz), 2.08 (t, 2H,
J = 7.6 Hz), 2.84−2.89 (m, 2H), 4.26−4.32 (m, 2H), 4.69 (s, 1H),
4.72 (s, 1H), 7.28 (t, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.55 (d,
1H, J = 8.0 Hz), and 7.62 (d, 1H, J = 8.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 12.4, 14.5, 28.0, 28.7, 33.6, 44.0, 60.5, 62.4, 108.2, 114.7,
115.2, 124.0, 125.2, 125.9, 131.6, 139.3, 150.5, 159.8, 159.9, and 168.2;
HRMS calcd for [C21H23N5O4 + H]+ 410.1822, found 410.1824.
Ethyl 3-(3,3-Bis(but-3-en-1-yloxy)-2-oxoindolin-1-yl)-2-
diazo-3-oxopropanoate (19). To a 10 mL round-bottom flask
charged with a solution of isatin (147 mg, 1.0 mmol) in but-3-en-1-ol
(2 mL, 23.4 mmol) was added anhydrous p-toluenesulfonic acid
(PTSA) (35 mg, 0.2 mmol). The mixture was stirred for 20 h at 80 °C.
After removal of the excess alcohol under reduced pressure, the
resulting solution was filtered through a short plug of silica gel and
concentrated under reduced pressure. The resulting residue containing
3,3-bis(but-3-en-1-yloxy)indolin-2-one was taken up in CH2Cl2 (6
mL), and DMAP (244 mg, 2.0 mmol) and ethyl 2-diazomalonyl
chloride (265 mg, 1.5 mmol) were sequentially added. The mixture
was stirred for 12 h at 25 °C. After removal of the solvent under
reduced pressure at 20 °C, the residue was subjected to flash silica gel
chromatography to furnish 149 mg (36% yield over two steps) of the
title compound 19 as a colorless oil. IR (thin film) 2924, 2143, 1772,
Ethyl 3a-Methyl-11b-(3-methylbut-3-en-1-yloxy)-6-oxo-
3,3a,4,5,6,11b-hexahydro-2H-3a1,5-epoxybenzo[b]pyrano-
[4,3,2-hi]indolizine-5-carboxylate (22). To a 350 mL pressure
tube charged with a solution of the above diazo compound 21 (5.47 g,
12.4 mmol) in benzene (100 mL) was added Rh2(OAc)4 (273 mg,
0.62 mmol). The mixture was heated at 80 °C for 2 h. After cooling to
rt, the reaction mixture was concentrated under reduced pressure and
subjected to flash silica gel chromatography to furnish 4.71 g (92%
yield) of the title compound 22 as a colorless oil. IR (thin film) 2939,
1
1735, 1607, and 1481 cm−1; H NMR (600 MHz, CDCl3) δ 1.17 (s,
3H), 1.35 (t, 3H, J = 7.2 Hz), 1.74 (s, 3H), 2.01 (t, 2H, J = 7.2 Hz),
2.15 (d, 1H, J = 12.6 Hz), 2.31 (d, 1H, J = 13.2 Hz), 2.32−2.39 (m,
2H), 3.77 (td, 1H, J = 8.4 and 5.4 Hz), 3.86 (td, 1H, J = 9.0 and 6.6
Hz), 3.96 (dt, 1H, J = 11.4 and 8.4 Hz), 3.96 (dt, 1H, J = 12.0 and 6.6
Hz), 4.30−4.41 (m, 2H), 4.72 (s, 1H), 4.77 (s, 1H), 7.14 (t, 1H, J =
7.8 Hz), 7.40 (t, 1H, J = 7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), and 7.49 (d,
1H, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 14.2, 23.1, 23.2, 31.6,
37.8, 41.5, 43.7, 58.4, 62.0, 62.6. 89.7, 99.3, 101.3, 112.0, 114.1, 124.5,
125.6, 131.4, 131.5, 136.9, 142.6, 164.4, and 164.9; HRMS calcd for
[C23H27NO6 + H]+ 414.1911, found 414.1913.
Ethyl 9-(2-Hydroxyethyl)-9-methyl-6,10-dioxo-7,8,9,10-tet-
rahydro-6H-7,9a-epoxypyrido[1,2-a]indole-7-carboxylate (23).
To a 350 mL pressure tube charged with a solution of cycloadduct 22
(3.0 g, 7.26 mmol) in acetone (150 mL) was added PTSA·H2O (2.76
g, 14.52 mmol). The mixture was heated at 70 °C for 1 h. After
cooling to rt, the reaction mixture was quenched with 100 mL of a
saturated aqueous NaHCO3 solution and extracted with ether. The
combined organic layers were washed with water and brine and dried
over MgSO4. After removal of the solvent under reduced pressure, the
residue was subjected to flash silica gel chromatography to furnish 1.94
g (78% yield) of the title compound 23 as a white foam. IR (thin film)
3496, 2979, 1720, 1602, and 1467 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.19 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz), 2.12 (t, 2H, J = 6.4 Hz), 2.20
(d, 1H, J = 13.2 Hz), 2.74 (d, 1H, J = 13.2 Hz), 3.89 (t, 2H, J = 6.8
1
1733, 1668, and 1465 cm−1; H NMR (400 MHz, CDCl3) δ 1.30 (t,
3H, J = 7.2 Hz), 2.36 (q, 4H, J = 6.8 Hz), 3.73−3.86 (m, 4H), 4.29 (q,
2H, J = 7.2 Hz), 5.04 (d, 2H, J = 9.6 Hz), 5.09 (dd, 2H, J = 17.2 and
1.6 Hz), 5.75−5.86 (m, 2H), 7.22 (t, 1H, J = 7.2 Hz), 7.41 (t, 1H, J =
8.0 Hz), 7.45 (d, 1H, J = 7.2 Hz), and 7.65 (d, 1H, J = 8.4 Hz); 13C
NMR (100 MHz, CDCl3) δ 14.4, 34.3, 62.3, 63.1, 96.8, 114.8, 117.0,
125.1, 131.1, 134.8, 139.3, 153.7, 159.9, 160.4, 169.7, and 177.2;
HRMS calcd for [C21H23N3O6 + Na]+ 436.1479, found 436.1480.
Ethyl 11b-(But-3-en-1-yloxy)-6-oxo-3,3a,4,5,6,11b-hexahy-
dro-2H-3a1,5-epoxybenzo[b]pyrano[4,3,2-hi]indolizine-5-car-
boxylate (20). To a 10 mL pressure tube charged with a solution
containing the above diazo compound 19 (24 mg, 0.06 mmol) in
benzene (2 mL) was added Rh2(OAc)4 (2.6 mg, 0.006 mmol). The
397
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Article
Hz), 4.37 (q, 2H, J = 7.2 Hz), 7.28 (t, 1H, J = 7.2 Hz), 7.69 (t, 1H, J =
8.0 Hz), 7.74 (d, 1H, J = 8.4 Hz), and 7.77 (d, 1H, J = 7.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 14.2, 21.0, 38.5, 41.0, 47.9, 59.7, 62.8,
90.1, 98.5, 115.5, 125.4, 125.6, 131.3, 138.5, 148.5, 164.1, 165.8, and
189.7; HRMS calcd for [C18H19NO6 + H]+ 346.1285, found 346.1287.
Ethyl 5-Hydroxy-3a-methyl-6,12-dioxo-3,3a,4,5,6,12-hexa-
hydro-2H-furo[2′,3′:2,3]pyrido[1,2-a]indole-5-carboxylate
(24). To a 350 mL pressure tube charged with a solution of the above
alcohol 23 (570 mg, 1.65 mmol) in CH2Cl2 (62 mL) was added BF3·
OEt2 (1.1 mL, 8.66 mmol). The mixture was heated at 60 °C for 18 h.
After cooling to rt, the mixture was quenched with 50 mL of a
saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The
combined organic layers were washed with water and brine and dried
over MgSO4. After removal of the solvent under reduced pressure, the
residue was subjected to flash silica gel chromatography to furnish 455
mg (80% yield) of the title compound 24 as a colorless oil. IR (thin
195.8, and 216.0; HRMS calcd for [C17H17NO4S2 + H]+ 364.0682,
found 364.0679.
3a-Methyl-3,3a,4,5-tetrahydro-2H-furo[2′,3′:2,3]pyrido[1,2-
a]indole-6,12-dione (27). To a 10 mL pressure tube charged with a
solution of xanthate 26 (13 mg, 0.04 mmol) in benzene (2 mL) were
sequentially added AIBN (4 mg, 0.02 mmol) and n-Bu3SnH (53 μL,
0.2 mmol). The reaction mixture was heated at 80 °C for 4 h under
argon. After the mixture was cooled to rt, the solvent was removed
under reduced pressure, and the residue was subjected to flash silica
gel chromatography to furnish 8 mg (75% yield) of the title compound
27 as a colorless oil. IR (thin film) 2965, 1748, 1604, and 1480 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.18 (s, 3H), 1.75−1.83 (m, 1H),
2.01−2.06 (m, 1H), 2.07−2.13 (m, 1H), 2.53 (dt, 1H, J = 16.4 and 4.8
Hz), 2.68−2.77 (m, 2H), 4.14 (app q, 1H, J = 8.4 Hz), 4.22 (td, 1H, J
= 8.4 and 3.6 Hz), 7.21 (t, 1H, J = 7.6 Hz), 7.65 (t, 1H, J = 8.0 Hz),
7.70 (d, 1H, J = 7.6 Hz), and 8.41 (d, 1H, J = 8.0 Hz); 13C NMR (100
MHz, CDCl3) δ 22.1, 28.5, 32.0, 35.4, 41.7, 65.8. 76.1, 97.0, 118.1,
121.8, 124.8, 125.5, 137.7, 151.8, 166.7, 171.7, and 196.6; HRMS calcd
for [C15H15NO3 + H]+ 258.1124, found 258.1127.
1
film) 3434, 2931, 1729, 1684, and 1603 cm−1; H NMR (600 MHz,
CDCl3) δ 1.28 (s, 3H), 1.30 (t, 3H, J = 7.2 Hz), 2.21 (ddd, 1H, J =
12.0, 7.8, and 4.2 Hz), 2.28 (d, 1H, J = 15.0 Hz), 2.48 (d, 1H, J = 14.4
Hz), 2.70 (dt, 1H, J = 12.0 and 8.4 Hz), 4.19 (td, 1H, J = 8.4 and 3.6
Hz), 4.29−4.34 (m, 4H), 7.27 (t, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.8
Hz), 7.74 (d, 1H, J = 7.8 Hz), and 8.40 (d, 1H, J = 7.8 Hz); 13C NMR
(150 MHz, CDCl3) δ 14.1, 22.1, 40.1, 40.4, 44.7, 63.2, 65.2. 76.1, 97.0,
118.1, 121.8, 124.8, 125.5, 137.7, 151.8, 166.7, 171.7, and 195.1;
HRMS calcd for [C18H19NO6 + Na]+ 368.1104, found 368.1108.
5-Hydroxy-3a-methyl-3,3a,4,5-tetrahydro-2H-furo[2′,3′:2,3]-
pyrido[1,2-a]indole-6,12-dione (25). To a 50 mL pressure tube
charged with a solution of the above tertiary alcohol 24 (158 mg, 0.46
mmol) in CH3CN (10 mL) were sequentially added Cs2CO3 (899 mg,
2.76 mmol) and distilled water (1 mL). The mixture was heated at 80
°C for 1 h. After cooling to rt, the mixture was quenched with 10 mL
of a saturated aqueous NH4Cl solution and extracted with ether. The
combined organic layers were washed with water and brine and dried
over MgSO4. After removal of the solvent under reduced pressure, the
residue was subjected to flash silica gel chromatography to furnish 105
mg (84% yield) of the title compound 25 as a colorless oil consisting
of a 2:1 mixture of inseparable diastereomers. IR (thin film) 3337,
2951, 2897, 1726, 1681, and 1602 cm−1; 1H NMR (600 MHz, CDCl3)
major isomer δ 1.29 (s, 3H), 2.04−2.12 (m, 2H), 2.26 (t, 1H, J = 12.6
Hz), 2.82 (q, 1H, J = 10.2 Hz), 3.39 (br s, 1H), 4.12 (td, 1H, J = 10.2
and 2.4 Hz), 4.24 (q, 1H, J = 8.4 Hz), 4.37 (dd, 1H, J = 12.0 and 6.0
Hz), 7.26 (t, 1H, J = 7.2 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.73 (d, 1H, J =
7.8 Hz), and 8.37 (d, 1H, J = 8.4 Hz); 13C NMR (150 MHz, CDCl3)
major isomer δ 18.2, 38.1, 40.0, 45.2, 64.6, 66.9. 97.0, 117.9, 122.3,
124.8, 125.4, 137.4, 151.6, 170.6, and 194.6; HRMS calcd for
[C15H15NO4 + H]+ 274.1073, found 274.1072.
Ethyl 9-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-9-methyl-
6,10-dioxo-7,8,9,10-tetrahydro-6H-7,9a-epoxypyrido[1,2-a]-
indole-7-carboxylate (29). To a 10 mL round-bottom flask charged
with a solution of alcohol 23 (50 mg, 0.15 mmol) in CH2Cl2 (3 mL)
were sequentially added imidazole (21 mg, 0.3 mmol) and TBSCl (25
mg, 0.17 mmol). The mixture was stirred at 25 °C for 1.5 h. After
removal of the solvent under reduced pressure, the residue was
subjected to flash silica gel chromatography to furnish 53 mg (77%
yield) of the title compound 29 as a colorless oil. IR (thin film) 2981,
1
1722, 1610, and 1474 cm−1; H NMR (600 MHz, CDCl3) δ 0.07 (s,
6H), 0.89 (s, 9H), 1.18 (s, 3H), 1.34 (t, 3H, J = 7.2 Hz), 2.09 (dt, 1H,
J = 15.0 and 6.0 Hz), 2.12 (dt, 1H, J = 14.4 and 6.6 Hz), 2.15 (d, 1H, J
= 13.2 Hz), 2.90 (d, 1H, J = 13.2 Hz), 3.85 (t, 2H, J = 6.0 Hz), 4.33−
4.40 (m, 2H), 7.27 (t, 1H, J = 7.2 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.72
(t, 1H, J = 7.8 Hz), and 7.76 (d, 1H, J = 7.8 Hz); 13C NMR (150
MHz, CDCl3) δ −5.24, 14.3, 18.2, 20.5, 26.0, 38.0, 41.0, 48.1, 60.1,
62.7. 90.4, 98.6, 115.5, 125.4, 125.6, 126.5, 138.4, 148.6, 164.2, 166.1,
and 189.8; HRMS calcd for [C24H33NO6Si + H]+ 460.2157, found
460.2158.
Ethyl 3a-Methyl-6-oxo-3,3a,4,5,6,11b-hexahydro-2H-3a1,5-
epoxybenzo[b]pyrano[4,3,2-hi]indolizine-5-carboxylate (30)
and Ethyl 5-Hydroxy-3a-methyl-6-oxo-2,3,3a,4,5,6-
hexahydrobenzo[b]pyrano[4,3,2-hi]indolizine-5-carboxylate
(31). To a 10 mL round-bottom flask charged with a solution of the
above TBDMS compound 29 (25 mg, 0.05 mmol) in CH2Cl2 (2 mL)
were sequentially added Et3SiH (45 μL, 0.28 mmol) and BF3·OEt2 (36
μL, 0.28 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred
at this temperature for 30 min. The reaction mixture was quenched
with 2 mL of a saturated aqueous NaHCO3 solution and extracted
with CH2Cl2. The combined organic layers were washed with water
and brine and dried over MgSO4. After removal of the solvent under
reduced pressure, the residue was subjected to flash silica gel
chromatography to furnish 7 mg (40% yield) of compound 30 and
7 mg (40% yield) of compound 31.
S-Methyl O-(3a-Methyl-6,12-dioxo-3,3a,4,5,6,12-hexahydro-
2H-furo[2′,3′:2,3]pyrido[1,2-a]indol-5-yl) Carbonodithioate
(26). To a 10 mL round-bottom flask charged with a solution of the
above alcohol mixture 25 (22 mg, 0.08 mmol) in THF (2 mL) was
added NaH (60% dispersion in mineral oil, 16 mg, 0.4 mmol) at 0 °C.
The solution was warmed to 25 °C and stirred at this temperature for
0.5 h. This was followed by the dropwise addition of CS2 (24 μL, 0.4
mmol), and the solution was kept at 25 °C for 1 h. To this mixture was
slowly added MeI (25 μL, 0.4 mmol). After 1 h of stirring, the mixture
was quenched with 2 mL of a saturated aqueous NH4Cl solution and
warmed to rt. The solution was then extracted with ether, and the
combined organic phases were washed with water and brine and dried
over anhydrous MgSO4. After removal of the solvent under reduced
pressure, the residue was subjected to flash silica gel chromatography
to furnish 13 mg (45% yield) of the title compound 26 as a colorless
Compound 30 was obtained as a colorless oil. IR (thin film) 2978,
1
2873, 1734, 1607, and 1479 cm−1; H NMR (600 MHz, CDCl3) δ
1.30 (s, 3H), 1.36 (t, 3H, J = 7.2 Hz), 1.95−1.98 (m, 1H), 2.07 (ddd,
1H, J = 13.2, 9.6, and 4.8 Hz), 2.17 (d, 1H, J = 12.6 Hz), 2.27 (d, 1H, J
= 13.2 Hz), 3.90−3.95 (m, 1H), 4.08−4.13 (m, 1H), 4.35−4.40 (m,
2H), 5.30 (s, 1H), 7.16 (t, 1H, J = 7.2 Hz), 7.37 (t, 1H, J = 7.2 Hz),
7.45 (d, 1H, J = 7.2 Hz), and 7.46 (d, 1H, J = 7.2 Hz); 13C NMR (100
MHz, CDCl3) δ 14.3, 23.8, 32.6, 40.5, 43.7, 62.0, 62.7. 76.3, 90.0,
103.5, 113.8, 125.1, 127.0, 130.8, 131.2, 139.0, 165.2, and 165.4;
HRMS calcd for [C18H19NO5 + H]+ 330.1336, found 330.1336.
The structure of the second fraction isolated from the column was
assigned as 31, which was obtained as a colorless oil. IR (thin film)
1
oil. IR (thin film) 2938, 1750, 1604, and 1526 cm−1; H NMR (400
MHz, CDCl3) δ 1.21 (s, 3H), 2.07 (app t, 1H, J = 12.8 Hz), 2.24 (ddd,
1H, J = 12.4, 6.0, and 3.6 Hz), 2.43 (dd, 1H, J = 13.6 and 6.0 Hz), 2.66
(s, 3H), 2.77 (dt, 1H, J = 12.4 and 9.6 Hz), 4.31−4.35 (m, 2H), 6.54
(dd, 1H, J = 13.2 and 6.0 Hz), 7.24 (td, 1H, J = 7.6 and 0.8 Hz), 7.68
(td, 1H, J = 7.6 and 1.2 Hz), 7.72 (d, 1H, J = 7.2 Hz), and 8.40 (d, 1H,
J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 19.5, 23.4, 40.7, 41.5,
42.3, 66.6, 75.3, 96.7, 117.4, 121.5, 124.8, 125.1, 138.2, 151.6, 165.7,
1
3430, 2923, 2852, 1732, 1686, and 1483 cm−1; H NMR (600 MHz,
CDCl3) δ 1.34 (t, 3H, J = 7.2 Hz), 1.37 (s, 3H), 1.84−1.92 (m, 2H),
2.03 (d, 1H, J = 13.2 Hz), 2.92 (d, 1H, J = 13.2 Hz), 4.28−4.36 (m,
2H), 4.34 (s, 1H), 4.42 (td, 1H, J = 12.0 and 3.6 Hz), 4.53 (ddd, 1H, J
= 12.0, 4.2, and 1.8 Hz), 7.32 (t, 1H, J = 7.8 Hz), 7.37 (t, 1H, J = 7.2
398
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Article
Hz), 7.49 (d, 1H, J = 7.8 Hz), and 8.36 (d, 1H, J = 8.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 14.1, 26.2, 28.1, 37.0, 46.5, 62.9, 64.4, 76.3,
117.3, 117.5, 119.4, 124.0, 125.0, 125.7, 133.6, 137.2, 167.5, and 171.5;
HRMS calcd for [C18H19NO5 + Na]+ 352.1153, found 352.1158.
Ethyl 9-(2-Bromoethyl)-9-methyl-6,10-dioxo-7,8,9,10-tetra-
hydro-6H-7,9a-epoxypyrido[1,2-a]indole-7-carboxylate (37).
To a 50 mL round-bottom flask charged with a solution of alcohol
23 (100 mg, 0.29 mmol) in THF (4 mL) were sequentially added
PPh3 (304 mg, 1.16 mmol) and CBr4 (385 mg, 1.16 mmol) at 0 °C.
The mixture was stirred at 25 °C for 12 h. After removal of the solvent
under reduced pressure, the residue was subjected to flash silica gel
chromatography to furnish 100 mg (85% yield) of the title compound
37 as a colorless oil. IR (thin film) 2964, 1718, 1606, and 1480 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.19 (s, 3H), 1.36 (t, 3H, J = 7.2 Hz),
2.24 (d, 1H, J = 12.8 Hz), 2.41−2.45 (m, 2H), 2.57 (d, 1H, J = 12.8
Hz), 3.41−3.48 (m, 1H), 3.61−3.67 (m, 1H), 4.38 (t, 2H, J = 7.2 Hz),
7.30 (t, 1H, J = 7.2 Hz), 7.68 (d, 1H, J = 8.4 Hz), 7.74 (t, 1H, J = 7.6
Hz), and 7.78 (d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ
14.3, 21.1, 28.5, 40.1, 40.6, 49.2, 63.0, 90.0, 98.2, 115.6, 125.6, 125.8,
126.3, 138.7, 148.6, 163.8, 165.8, and 189.3; HRMS calcd for
[C18H18NO5Br + H]+ 408.0441, found 408.0444.
10.4, 5.6, and 2.8 Hz), 3.98−4.13 (m, 2H), 4.15−4.22 (m, 1H), 4.31−
4.39 (m, 2H), 4.42 (dd, 1H, J = 6.0 and 2.8 Hz), 4.48 (ddd, 1H, J =
12.0, 5.6, and 2.8 Hz), 7.17 (t, 1H, J = 8.0 Hz), 7.42−7.46 (m, 2H),
and 7.51 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 14.3,
23.1, 31.6, 37.9, 41.4, 43.8, 58.7, 60.6. 62.5, 69.3, 89.6, 99.3, 100.9,
114.3, 124.7, 125.3, 130.8, 131.8, 136.8, 164.1, and 164.7; HRMS calcd
for [C21H25NO9S] 467.1244, found 467.1246.
Ethyl 9-(2-Iodoethyl)-9-methyl-6-oxo-6,7, 8, 9-
tetrahydrospiro[7,9a-epoxypyrido[1,2-a]indole-10,2′-[1,3]-
dioxolane]-7-carboxylate (42). To a 150 mL pressure tube charged
with a solution of mesylate 41 (785 mg, 1.68 mmol) in acetone (20
mL) was added NaI (277 mg, 1.85 mmol) at 25 °C. The mixture was
heated at 80 °C for 24 h. After cooling to rt, the reaction mixture was
quenched with 20 mL of a saturated aqueous NaHCO3 solution and
extracted with ethyl acetate. The combined organic layers were washed
with water and brine and dried over MgSO4. After removal of the
solvent under reduced pressure, the residue was subjected to flash
silica gel chromatography to furnish 788 mg (94% yield) of the title
compound 42 as a white solid. Mp 183−184 °C; IR (thin film) 2978,
1
1732, 1606, and 1481 cm−1; H NMR (600 MHz, CDCl3) δ 1.16 (s,
3H), 1.36 (t, 3H, J = 7.2 Hz), 2.02−2.05 (m, 2H), 2.16 (d, 1H, J =
12.6 Hz), 2.32 (d, 1H, J = 12.6 Hz), 3.22−3.32 (m, 2H), 3.94−4.02
(m, 3H), 4.27−4.32 (m, 1H), 4.33−4.41 (m, 2H), 7.16 (t, 1H, J = 7.8
Hz), 7.42 (t, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 7.8 Hz), and 7.50 (d,
1H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 2.1, 14.3, 23.1, 31.4,
41.4, 43.6, 58.8, 62.5, 64.2, 89.7, 99.3, 101.0, 114.1, 124.6, 125.3, 131.1,
131.6, 136.9, 164.2, and 164.7; HRMS calcd for [C20H22NO6I + H]+
500.0564, found 500.0565.
Ethyl 11b-Cyano-3a-methyl-6-oxo-3,3a,4,5,6,11b-hexahy-
dro-2H-3a1,5-epoxybenzo[b]pyrano[4,3,2-hi]indolizine-5-car-
boxylate (39). To a 10 mL round-bottom flask charged with a
solution of the above bromide 37 (22 mg, 0.05 mmol) in CH3CN (1
mL) were sequentially added 18-crown-6 (37 mg, 0.14 mmol) and
KCN (4 mg, 0.06 mmol). The mixture was heated at 60 °C for 30 min
and then cooled to rt. After removal of the solvent under reduced
pressure, the residue was subjected to flash silica gel chromatography
to furnish 13 mg (68% yield) of the title compound 39 as a white solid.
Mp 155−156 °C; IR (thin film) 2982, 2884, 1747, 1604, and 1477
cm−1; 1H NMR (600 MHz, CDCl3) δ 1.30 (s, 3H), 1.35 (t, 3H, J = 7.2
Hz), 2.10−2.14 (m, 2H), 2.19 (d, 1H, J = 13.2 Hz), 2.38 (d, 1H, J =
12.6 Hz), 4.17 (dt, 1H, J = 11.4 and 9.0 Hz), 4.29 (ddd, 1H, J = 11.4,
8.4, and 3.6 Hz), 4.33−4.40 (m, 2H), 7.26 (td, 1H, J = 7.2 and 3.0
Hz), 7.48−7.51 (m, 2H), and 7.61 (d, 1H, J = 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 14.2, 22.8, 31.0, 41.2, 43.1, 61.4, 62.9. 75.2, 90.0, 96.0,
102.0, 114.3, 125.9, 126.8, 128.8, 132.9, 138.7, 164.1, and 164.8;
HRMS calcd for [C19H18N2O5 + H]+ 355.1288, found 355.1289.
Ethyl 9-Methyl-9-(2-((methylsulfonyl)oxy)ethyl)-6-oxo-
6,7,8,9-tetrahydrospiro[7,9a-epoxypyrido[1,2-a]indole-10,2′-
[1,3]dioxolane]-7-carboxylate (41). To a 250 mL round-bottom
flask charged with a solution of alcohol 23 (1.37 g, 4.0 mmol) in
ethylene glycol (75 mL) was added anhydrous PTSA (688 mg, 4.0
mmol) at 25 °C. The mixture was stirred at 80 °C for 1 h. After
cooling to rt, the reaction mixture was quenched with 75 mL of a
saturated aqueous NaHCO3 solution and extracted with ethyl acetate.
The combined organic layers were washed with water and brine and
dried over MgSO4. After removal of the solvent under reduced
pressure, the residue was subjected to flash silica gel chromatography
to furnish 974 mg (63% yield) of ethyl 9-(2-hydroxyethyl)-9-methyl-6-
oxo-6,7,8,9-tetrahydrospiro[7,9a-epoxypyrido[1,2-a]indole-10,2′-[1,3]-
dioxolane]-7-carboxylate (40) as a colorless oil. IR (thin film) 3485,
Ethyl 9-(2-Cyanoethyl)-9-methyl-6-oxo-6,7,8,9-
tetrahydrospiro[7,9a-epoxypyrido[1,2-a]indole-10,2′-[1,3]-
dioxolane]-7-carboxylate (36). To a 100 mL round-bottom flask
charged with a solution of iodide 42 (550 mg, 1.10 mmol) in DMSO
(20 mL) was added NaCN (61 mg, 1.24 mmol) at 25 °C. The mixture
was stirred at 25 °C for 20 h, quenched with 20 mL of distilled water,
and extracted with ethyl acetate. The combined organic layers were
washed with water and brine and dried over MgSO4. After removal of
the solvent under reduced pressure, the residue was subjected to flash
silica gel chromatography to furnish 374 mg (85% yield) of the title
compound 36 a colorless oil. IR (thin film) 2979, 2899, 2158, 1751,
1
1607, and 1482 cm−1; H NMR (600 MHz, CDCl3) δ 1.17 (s, 3H),
1.36 (t, 3H, J = 7.2 Hz), 2.03−2.08 (m, 2H), 2.17 (d, 1H, J = 12.6 Hz),
2.32 (d, 1H, J = 13.8 Hz), 2.63 (dt, 1H, J = 16.8 and 6.0 Hz), 2.71−
2.77 (m, 1H), 3.83−3.86 (m, 1H), 3.98−4.04 (m, 2H), 4.29−4.40 (m,
3H), 7.16 (t, 1H, J = 7.2 Hz), 7.42−7.45 (m, 2H), and 7.51 (d, 1H, J =
7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 14.3, 18.9, 22.9, 31.3, 41.4,
43.6, 58.4, 59.0, 62.6, 89.7, 99.6, 100.9, 114.2, 117.9, 124.7, 125.3,
130.5, 131.8, 137.0, 164.3, and 164.7; HRMS calcd for [C21H22N2O6 +
Na]+ 421.1370, found 421.1379.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data of various key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
2970, 1731, 1604, and 1485 cm−1; H NMR (600 MHz, CDCl3) δ
1.18 (s, 3H), 1.36 (t, 3H, J = 7.2 Hz), 2.01−2.06 (m, 2H), 2.18 (d, 1H,
J = 13.2 Hz), 2.31 (d, 1H, J = 12.6 Hz), 3.75−3.82 (m, 3H), 3.91−3.94
(m, 1H), 4.00 (dt, 1H, J = 11.4 and 7.8 Hz), 4.21−4.25 (m, 1H),
4.32−4.41 (m, 2H), 7.15 (t, 1H, J = 7.8 Hz), 7.41 (t, 1H, J = 7.8 Hz),
7.48 (d, 1H, J = 8.4 Hz), and 7.50 (d, 1H, J = 8.4 Hz). This compound
was used in the next step without further purification.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chemap@emory.edu.
Notes
To a 250 mL round-bottom flask charged with a solution of the
above alcohol 40 (529 mg, 1.36 mmol) in CH2Cl2 (50 mL) were
sequentially added Et3N (0.57 mL, 4.08 mmol) and MsCl (0.12 mL,
1.50 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C. After
removal of the solvent under reduced pressure, the residue was
subjected to flash silica gel chromatography to furnish 603 mg (95%
yield) of the title compound 41 as a colorless oil. IR (thin film) 2941,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly appreciate the financial support provided by the
National Science Foundation (CHE-1057350) and the Alfred
B. Heilbrun Jr. Award from the Emory Emeritus Foundation.
Elena Villhauer is acknowledged for her help in the preparation
of α-diazo amide 21.
1
1751, 1607, and 1481 cm−1; H NMR (400 MHz, CDCl3) δ 1.16 (s,
3H), 1.35 (t, 3H, J = 6.8 Hz), 2.01−2.06 (m, 2H), 2.18 (d, 1H, J =
12.4 Hz), 2.31 (d, 1H, J = 12.8 Hz), 3.09 (s, 3H), 3.91 (ddd, 1H, J =
399
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Article
REFERENCES
■
(1) Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M.
Tetrahedron Lett. 2004, 45, 5995.
(2) Magolan, J.; Carson, B. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437.
(3) Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11, 2800.
(4) Zhong, X.; Li, Y.; Han, F.-S. Chem.Eur. J. 2012, 18, 9784.
(5) Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2010, 132, 1236.
(6) (a) Iwama, Y.; Okano, K.; Sugimoto, K.; Tokuyama, H. Org. Lett.
2012, 14, 2320. (b) Iwama, Y.; Okano, K.; Sugimoto, K.; Tokuyama,
H. Chem.Eur. J. 2013, 19, 9325.
(7) Li, Z.; Liang, G. Tetrahedron Lett. 2013, 54, 242.
(8) (a) Padwa, A. Tetrahedron 2011, 67, 8057. (b) Padwa, A. Chem.
Soc. Rev. 2009, 38, 3072.
(9) Burrell, A. J. M.; Coldham, I. Curr. Org. Synth. 2010, 7, 312.
(10) Bonderoff, S. A.; Padwa, A. Org. Lett. 2013, 15, 4114.
(11) (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(b) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(c) Padwa, A. Top. Curr. Chem. 1997, 189, 121. (d) Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds; John Wiley and Sons: New York, 1998.
(e) Padwa, A. Helv. Chim. Acta 2005, 88, 1357. (f) Padwa, A.; Marino,
J. P., Jr.; Osterhout, M. H. J. Org. Chem. 1995, 60, 2704. (g) Padwa, A.;
Marino, J. P., Jr.; Osterhout, M. H.; Price, A. T.; Semones, M. A. J. Org.
Chem. 1994, 59, 5518. (h) Hertzog, D. L.; Nadler, W. R.; Osterhout,
M. H.; Price, A. T.; Padwa, A. J. Org. Chem. 1994, 59, 1418.
(12) (a) England, D. B.; Padwa, A. Org. Lett. 2007, 9, 3249.
(b) England, D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792.
(13) Mejia-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275.
(14) Li, H.; Cheng, B.; Boonnak, N.; Padwa, A. Tetrahedron 2011, 67,
9829.
(15) McCaffery, E. L.; Shalaby, S. W. J. Organomet. Chem. 1967, 8,
17.
(16) Marino, J. P., Jr.; Osterhout, M. H.; Price, A. T.; Sheehan, S. M.;
Padwa, A. Tetrahedron Lett. 1994, 35, 849.
(17) For a review of dealkoxycarbonylations, see: Krapcho, A. P.
Synthesis 1982, 805.
(18) (a) Rubin, M. B.; Inbar, S. Tetrahedron Lett. 1977, 18, 1037.
(b) Davis, F. A.; Clark, C.; Kumar, A.; Chen, B.-C. J. Org. Chem. 1994,
59, 1184.
(19) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574.
(20) (a) Yoda, H.; Yamazaki, H.; Kawauchi, M.; Takabe, K.
Tetrahedron: Asymmetry 1995, 6, 2669. (b) Yoda, H.; Yamazaki, H.;
Takabe, K. Tetrahedron: Asymmetry 1996, 7, 373. (c) Amorde, S. M.;
Jewett, I. T.; Martin, S. F. Tetrahedron 2009, 65, 3222. (d) Rudolph, A.
C.; Machauer, R.; Martin, S. F. Tetrahedron Lett. 2004, 45, 4895.
(21) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(22) Song, H.; Yang, J.; Chen, W.; Qin, Y. Org. Lett. 2006, 8, 6011.
400
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