A new construct of the cis-3a-aryloctahydroindole skeleton via the [4+2] cycloaddition of furanyl carbamates

Article abstract of DOI:10.3987/COM-02-S(M)12

Several 2-methylthio-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)-sulfonium tetrafluoroborate (DMTSF) with β-alkoxy-γ-dithiane amides. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridged cycloadducts underwent a subsequent rearrangement to form bicyclic lactams. Model studies were directed toward mesembrine as well as the core skeleton of the 3,4-benzoerythrinane skeleton. Using this cascade sequence, a formal synthesis of the alkaloid erysotrine was accomplished.

Full text of DOI:10.3987/COM-02-S(M)12

HETEROCYCLES, Vol. 58, 2002, pp. 227-242, Received, 12th February, 2002
A NEW CONSTRUCT OF THE CIS- 3a-ARYLOCTAHYDROINDOLE
SKELETON VIA THE [4+2] CYCLOADDITION OF FURANYL
‡
CARBAMATES
Albert Padwa,* Cheryl K. Eidell, and Stephen M. Lynch
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
*chemap@emory.edu
Abstract - Several 2-methylthio-5-amidofurans containing tethered
unsaturation were prepared via the reaction of dimethyl(methylthio)-
sulfonium tetrafluoroborate (DMTSF) with β-alkoxy-γ -dithiane amides.
Thermolysis of these furans resulted in an intramolecular Diels-Alder
reaction (IMDAF). The resulting oxa-bridged cycloadducts underwent a
subsequent rearrangement to form bicyclic lactams. Model studies were
directed toward mesembrine as well as the core skeleton of the 3,4-
benzoerythrinane skeleton. Using this cascade sequence, a formal
synthesis of the alkaloid erysotrine was accomplished.
The cis-3a-arylhydroindole skeleton (1) is a basic structural element of the Sceletium
1
2
alkaloids and is also a key subunit of the Erythrina family of alkaloids. These alkaloids
constitute a large family of natural products that have attracted considerable attention over
3
the years due to their diverse and interesting structures.
The Sceletium alkaloid
4
mesembrine (2) can be regarded as a structural prototype for the more complex members
of this family. The vast majority of naturally occurring Erythrina alkaloids possess the
5
tetracyclic framework and substitution pattern shown in structure (3).
The sterically
congested quaternary carbon centers represent a particular challenge toward the synthesis
of both these natural products. A number of creative strategies have emerged over the
OR
O
H
Me
H
OMe
Z
N
Me
N
N
OMe
OMe
2; mesembrine
Ar
X
H
1; cis-3a-arylocta-
hydroindole ring system
3; erythrine series
X or Z = O; R = Me

years to address this problem. Total syntheses of members of both classes of the above
6,7
families have been reported by many different groups,
as have a number of important
8
approaches to the characteristic core ring system. Despite the availability of many synthetic
methods, there still exists a need to develop procedures more efficient than those currently
in existence.
Several years ago we began a synthetic program designed to provide general access to
9
these alkaloids by [4+2] cycloaddition chemistry of furanyl carbamates. The plan for
assembling the requisite cis-3a-arylhydroindole skeleton was to take advantage of an
10
intramolecular Diels-Alder
reaction of an alkenyl-substituted 2-amidofuran derivative
(IMDAF), as had been outlined in earlier reports from these laboratories. Because initial
11
studies into the cycloaddition chemistry of these furans were promising, a more detailed
investigation has been conducted. The results of these inquiries are reported herein.
Results and Discussion
The convergency and stereochemical control associated with the IMDAF reaction sequence
of furanyl carbamates make it particularly suited for the assembly of natural product
scaffolds. Our preliminary studies were directed toward mesembrine (2) as well as the core
skeleton of the erythrina family (vide infra). The key step in our plan for mesembrine
involves the IMDAF reaction of furan (4) as outlined in Scheme 1. To pursue this approach,
Scheme 1
Me
Me
N
SMe
SMe
O
N
O
D
O
CH
2
O
Ar
Ar
5
4
Ar = C H (OMe)
2
6
3
O
SMe
H
Me
Me
O
N
O
N
OMe
Ar
6
OMe
2; mesembrine
we decided to first evaluate the scope and generality of the cascade sequence by carrying
out a model study using the simpler phenyl substituted system (12). The required furan (i.e.,
12) necessary for the intramolecular [4+2] cycloaddition studies was prepared by a
dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) induced cyclization of imido

12
dithioacetal (11) (vide infra).
This approach was devised by assuming that it should be
possible to induce cyclization of the imide carbonyl group onto the resulting thionium ion
formed from the DMTSF reaction of the dithioacetal. It is known that treatment of thioketals
13
14
with DMTSF causes the carbon-sulfur bond to become labile upon methylthiolation.
The resulting alkylthiosulfonium ion easily dissociates to produce a thionium ion and methyl
15
disulfide. Once the dihydrofuran ring has been forged, elimination of acetic acid (or its
equivalent) should proceed readily to furnish the 2-alkylthio-amidofuran. We found that
treating N-pivaloyl-N-methylacetamide (7) with LDA followed by reaction with
16
bis(methylsulfanyl)- acetaldehyde (8) furnished the cross-aldol intermediate (9), which
underwent a rapid N-O acyl transfer reaction to provide the secondary amide (10) upon
aqueous workup. Attempts to acylate this amide under basic conditions (i.e., Et N, DMAP,
3
etc.) resulted only in elimination of the pivolate. Using 4Å molecular sieves as a neutral acid
17
scavenger, however, resulted in the formation of imide (11) in good yield (Scheme 2).
Treatment of 1 1 with DMTSF produced the desired 2-alkylthio-5-amidofuran (1 2) in 60%
Scheme 2
SMe
O
O
O
OCOt-Bu
SMe
O
LDA
O
Me
SMe
Me
N
CH
3
N
H
N
-
O
O
SMe
SMe
Me
t-Bu
10
H
t-Bu
SMe
9
7
Ph
O
8
CH
O
Cl
2
SMe
O
Ph
O
OCOt-Bu
SMe
Me
N
SMe
Me
O
CH
N
2
N
DMTSF
D
O
CH
2
Me
SMe
O
Ph
Ph
11
13
12
o
yield. Heating a sample of 12 at 80 C for 8 h afforded the rearranged lactam (13) as a
single diastereomer in 61% yield. We then investigated the 1,2-carbonyl transposition of 13
so as to prepare the core skeleton of mesembrine. Ketone (13) was first reduced using
18
Luche conditions to the expected alcohol (14). Treatment of 14 with mesyl chloride and
triethylamine furnished dienyl sulfide (15) which was easily hydrolyzed to ketone (16)
19
using mercuric chloride in 3:1-acetonitrile/water in 62% yield (Scheme 3). The facility of
the cycloaddition/carbonyl transposition sequence using this model system provides a solid
basis for applying the method to mesembrine (2). Studies along these lines are currently
underway and will be reported in due course.
With a satisfactory method for the synthesis of the furan precursors in place, we became

Scheme 3
SMe
O
SMe
OH
Me
N
Me
O
CeCl3
N
NaBH4
O
Ph
Ph
13
14
MsCl
NEt3
O
SMe
Me
N
Me
O
HgCl2
N
MeCN/H2O
O
Ph
Ph
16
15
interested in evaluating the cycloaddition behavior of the closely related 2-methoxy-5-
amidofuranyl system. Incorporation of an electron-donating group onto the 2-position of
furan had been previously used as a means to enhance the reactivity of the 6π-
20
heteroaromatic nucleus.
MO calculations show that the presence of a methoxy group in
the 2-position of the furan ring increases its HOMO energy relative to that of the 2-thiomethyl
21
substituted furan. Consequently, one might expect that the 2-methoxy substituted system
Scheme 4
OAc
LDA
SMe
O
N
O
OMe
SMe
N
O
H
TMS
18
H
OMe
Ac O
19
17
2
O
Cl
CH
2
n
4 Å sieves
OAc
SMe
OMe
DMTSF
N
OMe
O
N
O
O
CH
2
O
n
n
CH
2
22; n = 1
23; n = 2
20; n = 1
21; n = 2

would exhibit higher reactivity in the IMDAF process, but would probably be less prone to
undergo a subsequent 1,2-methoxy shift. Accordingly, cyclization precursors (20) and (21)
were prepared by acylation of lactam (19) with the appropriate acid chlorides (Scheme 4).
Reaction of these substrates with DMTSF afforded the desired furans (22) and (23) in 65%
and 56% yield, respectively. Thermolysis of the furans furnished phenols (27) and (28) as
the only isolable products. Interestingly, formation of the tricyclic phenol (27) (48%)
required heating furan (22) at reflux in toluene, whereas the reaction of 23 to give 28
o
(30%) needed heating at 180 C in a sealed tube. Clearly, both furans react at a slower rate
than the 2-thiomethyl substituted system (i.e., 12), thereby suggesting that factors other than
simple MO considerations control the rate of cycloaddition. The higher temperature required
for the IMDAF reaction of furan (23) (vs. 22) is probably related to entropic factors which
diminish its rate of cycloaddition. Formation of the tricyclic phenols can be rationalized in
terms of an initial Diels-Alder cycloaddition that first produces an oxa-bridged cycloadduct
(i.e., 24), which was not detected since it readily underwent nitrogen-assisted ring opening
(Scheme 5). Methoxy group ejection followed by deprotonation most likely furnishes
cyclohexadienone (26) as a transient species which rapidly tautomerizes to the observed
products.
Scheme 5
N
OH
N
OMe
CH2
O
∆
O
O
n
n
27; n = 1
28; n = 2
22; n = 1
23; n = 2
-
O
N
OMe
+N
N
O
O
OMe
O
O
O
H
n
n
n
H
24
25
26
The potential of further employing this methodology for the synthesis of other alkaloids
prompted us to carry out a model study directed toward the 3,4-benzoerythrinane skeleton.
Construction of furan (31) was accomplished in two steps from amide (29). Thus, treatment
of 29 with butenoyl chloride followed by reaction with DMTSF provided the desired furan
(31) in 66% yield (Scheme 6). Heating a toluene solution of 31 at reflux for 3 h furnished
bicyclic lactam (32) in a respectable 63% yield. In this case, a 2:1-mixture of diastereomers
was obtained, probably as a result of epimerization at the α-position upon silica gel

chromatography. A prominent theme for elaborating the fully substituted carbon center at
the BC ring fusion of the benzoerythrinane skeleton has been the trapping of a N-
22
acyliminium ion intermediate with an adjacent electron rich aryl ring. With this in mind, we
treated bicyclic lactam (32) with DMTSF hoping that the thiomethylation reaction would
transform the thiomethyl substituent into a good leaving group thereby generating the
required N-acyliminium ion necessary for cyclization. Although the desired cationic
intermediate was indeed formed, preferential deprotonation followed by tautomerization
occurred to ultimately provide phenol (34) in 74% yield. To prevent aromatization, the
thiomethyl substituent was first removed by treatment with samarium diiodide affording
ketone (33) in 70% yield. Gratifyingly, the acid-catalyzed reaction of 33 furnished tetracycle
(35) in 74% yield. The conversion of 35 into erysotrine (36), the most common alkaloid
23
occurring in the Erythrina species, has already been reported by Haruna and Ito. .
Consequently, the sequence of reactions outlined in Scheme 6 constitutes a formal
synthesis of this particular erythrinan alkaloid.
Scheme 6
O
O
OCOt-Bu
SMe
O
OCOt-Bu
SMe
O
H
N
N
Cl
CH
2
SMe
SMe
Ar = C H (OMe)
6
3
2
29
30
Ar
Ar
DMTSF
R
Ar
∆
N
SMe
Ar
O
O
N
O
O
H
31
32; R = SMe
33; R = H
SmI
2
+
H
R = H
DMTSF
R = SMe
OMe
OMe
OMe
OMe
OMe
Ar
OH
N
O
N
N
O
34
O
H
36; erysotrine
35

In summary, a highly convergent synthesis of the cis-3a-arylhydroindole skeleton has been
devised using an IMDAF cycloaddition reaction of 2-methylthio-5-amidofurans. Application
of the methodology toward the construction of more complex alkaloids containing these
skeletons is currently in progress and will be reported at a later date.
EXPERIMENTAL
Melting points are uncorrected. MS spectra were determined at an ionizing voltage of 70eV.
Unless otherwise noted, all reactions were performed in flame dried glassware under an
atmosphere of dry argon. Solutions were evaporated under reduced pressure with a rotary
evaporator and the residue was chromatographed on a silica gel column using a 5% ethyl
acetate/hexane mixture as the eluent unless specified otherwise. All solids were
recrystallized from 3% ethyl acetate/hexane for analytical data.
1-Methyl-6-methylsulfanyl-3a-phenyl-1,3a,4,6-tetrahydro-3H-indole-2,5-dione
(13). To a solution containing 1.0 g (3.3 mmol) of 2,2-dimethylpropionic acid 1-
24
methylcarbamoylmethyl-2,2-bis-methylsulfanyl-ethyl ester (10) in 16 mL of CH Cl was
2
2
25
added 0.8 g (4.7 mmol) of 3-phenylbut-3-enoyl chloride followed by 3.3 g of powdered
molecular sieves. After stirring at rt overnight, the suspension was filtered through a pad of
silica gel and washed several times with ether. The filtrate was washed with a saturated
aqueous NaHCO solution, dried over MgSO , and concentrated under reduced pressure.
3
4
The crude reaction mixture was subjected to flash silica gel chromatography to give 1.1 g
(88%) of 2,2-dimethylpropionic acid 1-(bis-(methylsulfanylmethyl)-3-[methyl-(3-phenylbut-3-
enoyl)amino]-3-oxopropyl ester (11) as a yellow oil: IR (neat) 1729, 1696, 1146, and 1083
-1 1
cm ; H-NMR (400 MHz, CDCl ) δ 1.19 (s, 9H), 2.17 (s, 3H), 2.19 (s, 3H), 3.06 (dd, 1H, J =
3
17.2 and 7.2 Hz), 3.22 (s, 3H), 3.45 (dd, 1H, J = 17.2 and 5.4 Hz), 3.90 (d, 2H, J = 3.2 Hz),
3.94 (d, 1H, J = 4.4 Hz), 5.16 (s, 1H), 5.54-5.59 (m, 1H), 5.57 (s, 1H), and 7.27-7.42 (m,
13
5H); C-NMR (100 MHz, CDCl ) δ 14.4, 15.1, 27.3, 31.8, 39.0, 41.1, 44.9, 57.8, 71.5, 116.3,
3
125.9, 128.1, 128.7, 140.0, 141.4, 171.9, 172.9, and 173.9; HRMS Calcd for C H NO S :
22 31
4 2
437.1694. Found: 437.1693.
To a solution containing 2.7 g (6 mmol) of the above imide in 30 mL of MeCN was added
1.3 g (6.4 mmol) of DMTSF in one portion at -40 °C. The mixture was stirred for 1 h at -40 °C
and then 4 mL (31 mmol) of triethylamine was added. The solution was diluted with ether,
poured over a saturated aqueous NaHCO solution, extracted with ether, and dried over
3
K CO . The solvent was removed under reduced pressure and the crude residue was
2
3
subjected to flash silica gel chromatography to give 1.1 g (64%) of 3-phenylbutenoic acid
1
methyl-(5-methylsulfanylfuran-2-yl)amide (12) as a yellow oil: H-NMR (300 MHz, CDCl )
3
δ 2.40 (s, 3H), 3.19 (s, 3H), 3.46 (s, 2H), 5.07 (s, 1H), 5.45 (s, 1H), 6.05 (d, 1H, J = 4.4 Hz),
and 6.40 (d, 1H, J = 4.4 Hz). The furan was used for the next step without further purification.
A solution of 0.2 g (0.8 mmol) of the above furan in 10 mL of benzene was heated at reflux
overnight. Upon cooling, the reaction mixture was concentrated under reduced pressure
and the residue was subjected to silica gel chromatography to give 0.15 g (61%) of 13 as a

-1 1
white solid: mp 43-44 °C; IR (film) 1732, 1670, 1323, and 1117 cm ; H-NMR (400 MHz,
CDCl ) δ 2.08 (s, 3H), 2.84 (s, 2H), 2.94 (d, 1H, J = 12.8 Hz), 3.05 (s, 3H), 3.39 (d, 1H, J =
3
12.8 Hz), 3.48 (d, 1H, J = 2.8 Hz), 5.17 (d, 1H, J = 2.8 Hz), 7.13-7.21 (m, 3H), and 7.24-7.28
13
(m, 2H); C-NMR (100 MHz, CDCl ) δ 16.2, 26.6, 46.3, 47.5, 48.7, 49.2, 97.0, 125.8, 127.9,
3
129.3, 142.2, 147.2, 172.8, and 201.1; Anal. Calcd for C H NO S: C, 66.88; H, 5.97; N,
16 17
2
4.88. Found: C, 66.72; H, 5.81; N, 4.65.
1-Methyl-3a-phenyl-3,3a,4,5-tetrahydro-1H-indole-2,6-dione (16). To a solution
o
containing 0.6 g (2.1 mmol) of ketone (13) in 20 mL of MeOH at 0 C was added 0.8 g (2.3
mmol) of cerium chloride heptahydrate followed by 0.1 g (2.3 mmol) of sodium
18
borohydride . The mixture was stirred for 3 h and water was added. The reaction mixture
was concentrated under reduced pressure, and the residue was extracted with EtOAc. The
organic layers were combined and dried over MgSO . Silica gel chromatography of the
4
crude reaction mixture afforded 0.4 g (65%) of 5-hydroxy-1-methyl-6-methylsulfanyl-3a-
1
phenyl-1,3,3a,4,5,6-hexahydro-indol-2-one (14) as a yellow oil: H-NMR (400 MHz, CDCl )
3
δ 1.82-1.89 (m, 1H), 2.21 (s, 3H), 2.40 (dd, 1H, J = 16.2 and 4.2 Hz), 2.62-2.78 (m, 3H), 3.03
13
(s, 3H), 3.61-367 (m, 1H), 5.36 (d, 1H, J = 5.2 Hz), and 7.17-7.34 (m, 5H); C-NMR (100
MHz, CDCl ) δ 17.0, 2.64, 41.3, 46.8, 47.8, 51.1, 66.3, 100.2, 126.5, 127.3, 128.8, 144.6,
3
145.7, and 173.1. This alcohol was used for the next step without further purification.
To a solution containing 0.3 g (1.2 mmol) of the above alcohol in 12 mL of CH Cl was
2
2
added 0.2 mL (1.3 mmol) of triethylamine followed by 0.1 mL (1.3 mmol) of mesyl chloride.
The reaction mixture was stirred at rt overnight. Water was added, and the reaction mixture
was extracted with CH Cl . The organic layers were combined, dried over MgSO , and
2
2
4
concentrated under reduced pressure. The crude mixture was subjected to flash silica gel
chromatography to give 0.3 g (88%) of 1-methyl-6-methylsulfanyl-3a-phenyl-1,3,3a,4-
-1
1
tetrahydroindol-2-one (15) as a yellow oil: IR (neat) 1721, 1649, 1321, and 1096 cm ; H-
NMR (400 MHz, CDCl ) δ 2.10 (s, 3H), 2.62 (d, 1H, J = 16.0 Hz), 2.66 (dd, 1H, J = 15.2 and
3
3.6 Hz), 2.83 (d, 1H, J = 16.4 Hz), 2.85 (d, 1H, J = 16.0 Hz), 3.11 (s, 3H), 5.56 (d, 1H, J = 6.0
13
Hz), 5.69 (dd, 1H, J = 5.8 and 2.6 Hz), 7.18-7.23 (m, 3H), and 7.24-7.29 (m, 2H); C-NMR
(100 MHz, CDCl ) δ 15.0, 26.7, 42.7, 43.6, 47.5, 97.6, 116.3, 125.8, 127.4, 128.7, 130.2,
3
142.2, 143.9, and 174.1; HRMS Calcd for C H NOS: 271.1031. Found: 271.1028.
16 17
To a solution containing 0.4 g (1.6 mmol) of dienyl sulfide (15) in 20 mL of a 3:1 mixture of
acetonitrile/water was added 0.9 g (3.2 mmol) of mercuric chloride. The reaction mixture
was heated at reflux for 3 days. The orange suspension was filtered through Celite and
washed with ether. The filtrate was washed with a saturated NaHCO solution followed by
3
brine, and the organic layer was dried over MgSO and concentrated under reduced
4
pressure. Silica gel chromatography of the crude residue afforded 0.22 g (62%) of 16 as a
-1
1
yellow oil: IR (neat) 1726, 1680, 1321, and 1116 cm ; H-NMR (400 MHz, CDCl ) δ 2.69-
3
2.77 (m, 2H), 2.78-2.87 (m, 2H), 2.94 (dd, 1H, J = 18.6 and 5.8 Hz), 3.10 (s, 3H), 3.24 (d, 1H,
J = 15.2 Hz), 5.19 (dd, 1H, J = 5.8 and 2.2 Hz), 7.18-7.24 (m, 3H), and 7.27-7.31 (m, 2H);

13
C-NMR (100 MHz, CDCl ) δ 26.6, 37.9, 45.6, 46.8, 52.0, 94.3, 125.7, 127.8, 129.4, 142.1,
3
146.5, 173.1, and 207.8; Anal. Calcd for C H NO : C, 74.65; H, 6.27; N, 5.81. Found: C,
15 15
2
74.52; H, 6.09; N, 5.80.
8-Hydroxy-5,6-dihydro-1H,4H-pyrrolo[3,2,1-ij]quinolin-2-one (27). To a solution
containing 6.5 mL (46 mmol) of diisopropylamine in 150 mL of THF was added 30 mL (45
mmol) of a 1.6 M solution of n-butyllithium in hexane at -40 °C. After stirring for 1 h, the
26
reaction was cooled to -75 °C and 7.4 g (43 mmol) of 1-trimethylsilyl-2-piperidone in 25
mL of THF was added. The temperature was raised to -40 °C, and the reaction mixture was
stirred for 30 min. The temperature was lowered to -75 °C and 8.2 g (45 mmol) of
27
methoxy(phenylsulfanyl)acetaldehyde (18) in 40 mL of THF was added dropwise over
45 min. Following addition, the reaction mixture was stirred for an additional 30 min, and
then 4.5 mL (48 mmol) of acetic anhydride was added. The solution was slowly warmed to rt
overnight and poured into a saturated aqueous NaHCO solution and extracted with
3
CH Cl . The solvent was removed under reduced pressure and the crude residue was
2
2
subjected to flash silica gel chromatography to give 8.1 g (58%) of acetic acid 2-methoxy-2-
methylsulfanyl-1-(2-oxo-piperidin-3-yl)ethyl ester (19) as a yellow oil which consisted of a
complex mixture of diastereomers which was used in the next step without further
purification. For analytical purposes, the major two diastereomers were separated by HPLC:
-1
1
IR (neat) 1747, 1660, 1491, 1372, and 1229 cm ; H-NMR (400 MHz, CDCl ) (major
3
diastereomer) δ 1.64-1.93 (m, 4H), 2.06 (s, 3H), 3.22-3.28 (m, 3H), 3.47 (s, 3H), 5.20 (dd, 1H,
J = 10.8 and 3.6 Hz), 5.54 (d, 1H, J = 10.8 Hz), 5.92 (br s, 1H), 7.27-7.33 (m, 3H), and 7.46-
7.56 (m, 2H); (minor diastereomer) δ 1.64-1.93 (m, 4H), 2.08 (s, 3H), 2.93 (ddd, 1H, J = 14.7,
7.8 and 2.8 Hz), 3.22-3.28 (m, 2H), 3.53 (s, 3H), 5.15-5.19 (m, 1H), 5.43 (d, 1H, J = 12.0 Hz),
13
5.82 (br s, 1H), 7.27-7.33 (m, 3H), and 7.46-7.56 (m, 2H); C-NMR (100 MHz, CDCl ) δ
3
21.2, 21.4, 22.2, 22.3, 25.4, 42.0, 42.3, 45.1, 56.9, 74.6, 75.7, 91.1, 91.7, 127.7, 127.9, 128.9,
129.2, 132.9, 133.2, 133.4 133.7, 170.5, 170.8, 171.1, and 171.2; HRMS Calcd for
C H NO S: 323.1191. Found: 323.1190.
16 21
4
To a solution containing 0.6 g (1.8 mmol) of the above lactam in 9 mL of CH Cl was added
2
2
0.3 g (3.1 mmol) of 3-butenoyl chloride followed by 1.9 g of powdered molecular sieves.
After stirring at rt overnight, the suspension was filtered through a pad of silica and washed
several times with ether. The filtrate was washed with a saturated aqueous NaHCO
3
solution, dried over MgSO , and concentrated under reduced pressure. The crude reaction
4
mixture was subjected to flash silica gel chromatography to give 0.7 g (94%) of acetic acid
1-(1-but-3-enoyl-2-oxo-piperidin-3-yl)-2-methoxy-2-methylsulfanylethyl ester (20) as a
yellow oil which contained a complex mixture of diastereomers and was used in the next
step without further purification. For analytical purposes, the major two diastereomers were
-1 1
separated by HPLC: IR (neat) 1747, 1690, 1475, 1291, 1224, and 1163 cm ; H-NMR (400
MHz, CDCl ) (major diastereomer) δ 1.56-1.61 (m, 1H), 1.73-1.80 (m, 1H), 1.84-1.90 (m,
3
2H), 2.05 (s, 3H), 3.32-3.37 (m, 1H), 3.51 (s, 3H), 3.62-3.65 (m, 2H), 3.67-3.73 (m, 2H), 5.11-

5.17 (m, 2H), 5.26 (d, 1H, J = 7.2 Hz), 5.32 (dd, 1H, J = 7.2 and 3.6 Hz), 5.95-6.04 (m, 1H),
7.29-7.34 (m, 3H), and 7.50-7.52 (m, 2H); (minor diastereomer) δ 1.68-1.79 (m, 2H), 1.87-
1.93 (m, 1H), 2.01-2.08 (m, 1H), 2.07 (s, 3H), 3.02-3.07 (m, 1H), 3.47 (s, 3H), 3.62-3.68 (m,
2H), 3.74-3.79 (m, 2H), 4.88 (d, 1H, J = 6.8 Hz), 5.09-5.15 (m, 2H), 5.61 (dd, 1H, J = 6.8 and
13
3.4 Hz), 5.95-6.04 (m, 1H), 7.28-7.34 (m, 3H), and 7.48-7.53 (m, 2H); C-NMR (100 MHz,
CDCl ) (major diastereomer) δ 21.1, 21.7, 24.3, 43.7, 44.2, 45.3, 56.9, 75.0, 91.3, 118.3,
3
128.2, 129.3, 131.5, 132.8, 133.5, 170.5, 173.1, and 174.9; (minor diastereomer) δ 21.2,
21.8, 22.1, 43.7, 44.2, 45.6, 56.9, 73.4, 92.3, 118.3, 128.1, 129.3, 131.5, 132.5, 133.3, 133.6,
169.9, 173.6, and 175.0; HRMS Calcd for C H NO S: 391.1453. Found: 391.1452.
20 25
5
To a solution containing 0.5 g (1.4 mmol) of lactam (20) in 7 mL of CH Cl was added 0.3 g
2
2
(1.4 mmol) of DMTSF in one portion at -40 °C. The temperature was allowed to warm slowly
to 15 °C over 2 h and then 1 mL (6.8 mmol) of triethylamine was added. The reaction
mixture was diluted with ether, poured over a saturated aqueous NaHCO solution,
3
extracted with ether, and dried over K CO . The solvent was removed under reduced
2
3
pressure and the crude mixture was subjected to flash silica gel chromatography to give 0.2
g (65%) of 1-(2-methoxy-5,6-dihydro-4H-furo[2,3-b]pyridin-7-yl)but-3-en-1-one (22) as a
-1 1
yellow oil: IR (neat) 1752, 1670, 1603, and 1378 cm ; H-NMR (400 MHz, CDCl ) δ 1.86-
3
1.94 (m, 2H), 2.43 (t, 2H, J = 8.6 Hz), 3.46 (d, 2H, J = 8.6 Hz), 3.77-3.82 (m, 2H), 3.83 (s, 3H),
13
5.08 (s, 1H), 5.13-5.18 (m, 2H), and 5.94-6.06 (m, 1H); C-NMR (100 MHz, CDCl ) δ 21.0,
3
23.7, 40.6, 43.2, 58.3, 81.6, 92.3, 118.1, 131.5, 133.6, 157.3, and 174.9; HRMS Calcd for
C H NO : 221.1052. Found: 221.1054.
12 15
3
A solution containing 0.04 g (0.2 mmol) of furan (22) in 5 mL of toluene was heated at reflux
for 30 min. At the end of this time, the solvent was removed under reduced pressure and the
residue was subjected to flash silica gel chromatography to give 0.02 g (48%) of 27 as a
-1 1
white solid: mp 200-201 °C (hexane/ether); IR (film) 1654, 1629, 1480, and 1280 cm ; H-
NMR (400 MHz, CD OD) δ 1.92-1.98 (m, 2H), 2.67 (t, 2H, J = 6.0 Hz), 3.42 (s, 2H), 3.61-3.64
3
13
(m, 2H), 6.48 (br s, 1H), and 6.59 (br s, 1H); C-NMR (100 MHz, CD OD) δ 22.7, 25.4, 37.7,
3
40.2, 111.4, 114.0, 122.7, 125.9, 134.5, 154.8, and 176.2; Anal. Calcd for C H NO : C,
11 11
2
69.81; H, 5.86; N, 7.41. Found: C, 69.72; H, 5.69; N, 7.31.
9-Hydroxy-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (28). To
solution containing 0.9 g (2.9 mmol) of amide (19) in 15 mL of CH Cl was added 0.6 g (4.6
a
2
2
mmol) of pent-4-enoyl chloride followed by 3.0 g of powdered molecular sieves. After
stirring at rt overnight, the suspension was filtered through a pad of silica gel and washed
several times with ether. The filtrate was washed with a saturated aqueous NaHCO
3
solution, dried over MgSO , and concentrated under reduced pressure. The crude reaction
4
mixture was subjected to flash silica gel chromatography to give 0.9 g (76%) of acetic 2-
methoxy-2-methylsulfanyl-1-(2-oxo-1-pent-4-enoyl-piperidin-3-yl)ethyl ester (21) as a
yellow oil which contained a complex mixture of diastereomers and was used in the next
-1 1
step without further purification; IR (neat) 1752, 1696, 1373, 1224, and 1158 cm ; H-NMR

(400 MHz, CDCl ) (major diastereomer) δ 1.53-1.63 (m, 1H), 1.68-1.79 (m, 1H), 1.82-1.92
3
(m, 2H), 2.04 (s, 3H), 2.36-2.43 (m, 2H), 2.89-2.99 (m, 2H), 3.31-3.37 (m, 1H), 3.51 (s, 3H),
3.63-3.73 (m, 2H), 4.97-5.08 (m, 2H), 5.27 (d, 1H, J = 7.6 Hz), 5.32 (dd, 1H, J = 7.2 and 3.6
13
Hz), 5.79-5.89 (m, 1H), 7.27-7.34 (m, 3H), and 7.49-7.52 (m, 2H); C-NMR (100 MHz,
CDCl ) (major diastereomer) δ 21.1, 21.8, 24.4, 29.1, 38.8, 43.6, 45.3, 56.9, 75.1, 91.3,
3
115.4, 128.2, 129.3, 132.8, 133.4, 137.6, 170.5, 173.0, and 176.2; HRMS Calcd for
C H NO S: 405.1610. Found: 404.1608.
21 27
5
To a solution containing 0.1 g (0.3 mmol) of amide (21) in 2 mL of MeCN was added 0.1 g
(0.3 mmol) of DMTSF in one portion at -40 °C. The mixture was stirred for 1 h at -40 °C and
then 0.2 mL (1.5 mmol) of triethylamine was added. The reaction mixture was diluted with
ether, poured over a saturated aqueous NaHCO solution, extracted with ether, and dried
3
over K CO . The solvent was removed under reduced pressure and the crude residue was
2
3
subjected to flash silica gel chromatography to give 0.04 g (56%) of 1-(2-methoxy-5,6-
1
dihydro-4H-furo[2,3-b]pyridin-7-yl)pent-4-en-1-one (23) as a yellow oil: H-NMR (400 MHz,
CDCl ) δ 1.86-1.92 (m, 2H), 2.40-2.45 (m, 4H), 2.76 (t, 2H, J = 7.4 Hz), 3.77-3.81 (m, 2H),
3
3.82 (s, 3H), 4.96-5.08 (m, 2H), 5.07 (s, 1H), and 5.83-5.93 (m, 1H); HRMS Calcd for
C H NO : 235.1208. Found: 235.1213. The furan was used in the next step without
13 17
3
further purification.
A solution of 0.19 g (0.8 mmol) of furan (23) dissolved in toluene (5 mL) was heated in a
o
sealed tube at 180 C for 12 h. The solution was cooled to rt at which point a brown solid
precipitated from solution. The solid was collected by filtration and purified by
o
recrystallization from MeOH to provide 0.05 g (30%) of 28 as a white solid, mp 220-221 C;
-1
1
IR (film) 1727, 1632, 1393, 1180, and 1154 cm ; H-NMR (CD OD, 400 MHz) δ 1.82-1.85
3
(m, 2H), 2.50-2.54 (m, 2H), 2.67-2.70 (m, 2H), 2.73-2.77 (m, 2H), 3.75-3.77 (m, 2H), and
13
6.42-6.44 (m, 2H); C-NMR (CD OD, 100 MHz) δ 22.9, 26.2, 28.3, 32.5, 42.2, 114.1, 114.9,
3
128.4, 128.6, 129.2, 154.4, and 171.5; Anal. Calcd for C H NO : C, 70.90; H, 6.45; N,
12 13
2
6.89. Found: C, 70.82; H, 6.26; N, 6.80.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-6-methylsulfanyl-1,3a,4,6-tetrahydro-3H-
indole-2,5-dione (32). To a solution containing 13 g (60 mmol) of N-(3,4-dimethoxy-
benzyl)acetamide in 300 mL of CH Cl was added 13 mL (106 mmol) of pivalyl chloride
2
2
followed by 59 g of powdered molecular sieves. After stirring at rt overnight, the suspension
was filtered through a pad of silica and washed several times with ether. The filtrate was
washed with a saturated aqueous NaHCO solution, dried over MgSO , and concentrated
3
4
under reduced pressure. The crude residue was subjected to flash silica gel
chromatography to give 17 g (93%) of N-acetyl-N-[2-(3,4-dimethoxy-phenyl)ethyl]-2,2-
-1 1
dimethylpropionamide as a yellow oil: IR (neat) 1685, 1516, 1265, and 1029 cm ; H-NMR
(400 MHz, CDCl ) δ 1.29 (s, 9H), 2.17 (s, 3H), 2.79-2.83 (m, 2H), 3.76-3.80 (m, 2H), 3.86 (s,
3
13
3H), 3.88 (s, 3H), 6.72-6.74 (m, 2H), and 6.79-6.81 (m, 1H); C-NMR (100 MHz, CDCl )
3

δ 24.5, 28.5, 35.5, 43.1, 47.6, 56.1, 111.5, 112.4, 120.9, 130.9, 148.0, 149.2, 173.2, and
187.1; HRMS Calcd for C H NO : 307.1783. Found: 307.1782.
17 25
4
To a solution containing 3.4 mL (24 mmol) of diisopropylamine in 78 mL of THF was added
16 mL (23 mmol) of 1.4 M solution of n-butyllithium in hexane at 0°C. After stirring for 1 h,
the reaction mixture was cooled to -40 °C and 6.8 g (22 mmol) of the above imide in 12 mL
of THF was added and the solution was stirred for 1 h. The temperature was lowered to -
16
75 °C and 3.1 g (23 mmol) of 2,2-bis(methylsulfanyl)acetaldehyde in 23 mL of THF was
added dropwise over 3 h. Following the addition, the mixture was stirred for an additional
30 min and was quenched by the addition of a saturated aqueous NH Cl solution. The
4
mixture was slowly warmed to rt and extracted with CH Cl . The organic layer was dried
2
2
over MgSO and the solvent was removed under reduced pressure. Silica gel column
4
chromatography of the crude residue afforded 5.6 g (57%) of 2,2-dimethylpropionic acid 1-
{[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]methyl}-2,2-bismethylsulfanylethyl ester (29)
-1
1
as a yellow oil; IR (film) 1726, 1644, 1460, 1158, and 1024 cm ; H-NMR (400 MHz,
CDCl ) δ 1.18 (s, 9H), 2.16 (s, 3H), 2.18 (s, 3H), 2.55 (dd, 1H, J = 14.8 and 7.2 Hz), 2.74 (t,
3
2H, J = 7.2 Hz), 2.82 (dd, 1H, J = 14.8 and 5.8 Hz), 3.44-3.52 (m, 2H), 3.86 (s, 3H), 3.87 (s,
3H), 3.95 (d, 1H, J = 4.8 Hz), 5.41-5.45 (m, 1H), 5.66 (brt, 1H, J = 5.2 Hz), 6.71-6.73 (m, 2H),
13
and 6.79-6.81 (m, 1H); C-NMR (100 MHz, CDCl ) δ 14.5, 15.1, 27.3, 35.4, 38.7, 39.1, 40.9,
3
56.0, 56.1, 57.6, 72.1, 111.6, 112.0, 120.8, 131.3, 147.9, 149.3, 169.2, and 177.7; HRMS
Calcd for C H NO S : 443.1800. Found: 443.1798.
21 33
5 2
To a solution containing 13 g (29 mmol) of the above amide in 140 mL of CH Cl was
2
2
added 5.1 g (48 mmol) of 3-butenoyl chloride followed by 28 g of powdered molecular
sieves. After stirring at rt overnight, the suspension was filtered through a pad of silica and
washed several times with ether. The filtrate was washed with a saturated aqueous
NaHCO solution, dried over MgSO , and concentrated under reduced pressure. The crude
3
4
residue was subjected to flash silica gel chromatography to give 11.9 g (81%) of 2,2-
dimethylpropionic acid 1-(bis-methylsulfanylmethyl)-3-{but-3-enoyl-[2-(3,4-dimethoxy-
phenyl)ethyl]amino}3-oxopropyl ester (30) as a pale yellow oil: IR (neat) 1726, 1705,
-1 1
1378, and 1029 cm ; H-NMR (400 MHz, CDCl ) δ 1.12 (s, 9H), 2.11 (s, 3H), 2.12 (s, 3H),
3
2.74 (t, 2H, J = 7.2 Hz), 2.97 (dd, 1H, J = 16.8 and 8.0 Hz), 3.22-3.25 (m, 2H), 3.26 (dd, 1H, J
= 16.8 and 4.8 Hz), 3.75-3.78 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 3.87 (d, 1H, J = 4.8 Hz),
4.99 (dd, 1H, J = 17.2 and 1.2 Hz), 5.09 (dd, 1H, J = 10.2 and 1.2 Hz), 5.49-5.53 (m, 1H),
13
5.78-5.89 (m, 1H), 6.65-6.67 (m, 2H), and 6.73-6.75 (m, 1H); C-NMR (100 MHz, CDCl )
3
δ 14.1, 14.8, 27.0, 31.5, 34.7, 38.7, 40.4, 42.4, 46.2, 55.8, 57.5, 71.2, 111.3, 112.0, 118.6,
120.8, 130.5, 130.6, 147.8, 149.0, 172.5, 174.1, and 177.3; Anal. Calcd for C H NO S :
25 37
6 2
C, 58.68; H, 7.29; N, 2.74. Found: C, 58.54; H, 7.08; N, 2.63.
To a solution containing 8.8 g (17 mmol) of the above amide in 80 mL of MeCN was added
3.6 g (18 mmol) of DMTSF in one portion at -40 °C. The mixture was stirred for 1 h at -40 °C
and 12 mL (86 mmol) of triethyl amine was added. The mixture was diluted with ether,

poured over a saturated aqueous NaHCO solution, extracted with ether, and dried over
3
K CO . The solvent was removed under reduced pressure and the crude residue was
2
3
subjected to flash silica gel chromatography to give 4.2 g (66%) of but-3-enoic acid [2-(3,4-
1
dimethoxy-phenyl)ethyl]-(5-methyl-sulfanyl-furan-2-yl)-amide (31) as a yellow oil: H-NMR
(400 MHz, CDCl ) δ 2.39 (s, 3H), 2.81 (t, 2H, J = 7.8 Hz), 3.78-3.82 (m, 2H), 3.83 (s, 3H),
3
3.84 (s, 3H), 3.84-3.86 (m, 2H), 4.97-5.08 (m, 2H), 5.81-5.91 (m, 1H), 5.87 (d, 1H, J = 3.2 Hz),
and 6.38 (d, 1H, J = 3.2 Hz); HRMS Calcd for C H NO S: 361.1348. Found: 361.1341.
19 23
4
The furan was used for the next step without further purification.
A solution of 0.1 g (0.2 mmol) of furan (31) in 2 mL of toluene was heated at reflux for 3 h.
Upon cooling, the reaction mixture was concentrated under reduced pressure and the
residue was subjected to silica gel chromatography to give 0.06 g (63%) of 32 as a pale
yellow oil which contained a 2:1-mixture of diastereomers: IR (neat) 1716, 1669, 1321, and
-1 1
1029 cm ; H-NMR (400 MHz, CDCl ) (major diastereomer) δ 2.10 (s, 3H), 2.16-2.23 (m,
3
2H), 2.73 (dd, 1H, J = 17.4 and 9.8 Hz), 2.80 (t, 2H, J = 7.8 Hz), 3.03 (dd, 1H, J = 11.6 and
6.4 Hz), 3.52-3.57 (m, 2H), 3.63 (d, 1H, J = 6.8 Hz), 3.74-3.83 (m, 1H), 3.84 (s, 3H), 3.87 (s,
3H), 5.04 (dd, 1H, J = 6.8 and 2.4 Hz), 6.70-6.74 (m, 2H), and 6.77 (s, 1H); (minor
diastereomer) δ 2.13 (s, 3H), 2.24-2.32 (m, 2H), 2.56-2.69 (m, 1H), 2.77-2.82 (m, 2H), 3.05-
3.07 (m, 1H), 3.50-3.60 (m, 3H), 3.73-3.83 (m, 1H), 3.84 (s, 3H), 3.87 (s, 3H), 4.87 (t, 1H, J =
13
2.6 Hz), 6.70-6.74 (m, 2H), and 6.79 (s, 1H); C-NMR (100 MHz, CDCl ) δ 16.1, 16.4, 30.0,
3
32.4, 32.6, 35.4, 36.2, 36.4, 39.1, 41.5, 41.6, 41.7, 49.0, 49.9, 56.0, 56.1, 91.6, 94.4, 111.4,
112.0, 120.9, 130.4, 130.5, 144.4, 147.9, 148.1, 149.1, 173.8, 174.3, 200.8, and 202.0;
HRMS Calcd for C H NO S: 361.1348. Found: 361.1346.
19 23
4
1-[2-(3,4-Dimethoxyphenyl)ethyl]-1,3a,4,6-tetrahydro-3H-indole-2,5-dione
(33). To a solution containing 2.5 mL (0.3 mmol) of a 0.1 M solution of SmI in THF was
2
added dropwise 0.04 g (0.1 mmol) of sulfide (32) in a 3:1 THF/MeOH mixture at -78 °C. The
temperature was allowed to rise to 0 °C and the reaction mixture was stirred for an
additional 10 min. The mixture was poured into a saturated K CO solution, extracted with
2
3
ether, dried over MgSO , and concentrated under reduced pressure. The crude residue
4
was subjected to silica gel chromatography to give 0.03 g (70%) of 33 as a yellow oil: IR
-1 1
(neat) 1721, 1675, 1408, and 1019 cm ; H-NMR (400 MHz, CDCl ) δ 2.26 (dd, 1H, J =
3
17.2 and 8.8 Hz), 2.35 (dd, 1H, J = 15.4 and 12.6 Hz), 2.71-2.84 (m, 4H), 2.99-3.01 (m, 2H),
3.06-3.16 (m, 1H), 3.53-3.61 (m, 1H), 3.77-3.86 (m, 1H), 3.85 (s, 3H), 3.87 (s, 3H), 4.93-4.96
13
(m, 1H), and 6.73-6.80 (m, 3H); C-NMR (100 MHz, CDCl ) δ 32.0, 32.7, 36.4, 38.3, 41.6,
3
44.4, 56.0, 56.1, 92.2, 111.4, 112.1, 120.9, 130.8, 143.1, 147.9, 149.1, 174.0, and 208.5;
Anal. Calcd for C H NO : C, 68.54; H, 6.72; N, 4.44. Found: C, 68.37; H, 6.69; N, 4.28.
18 19
4
1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-hydroxy-1,3-dihydro-indol-2-one (34). To
a solution containing 0.3 g (0.9 mmol) of 32 in 5 mL of MeCN was added 0.2 g (0.9 mmol)
of DMTSF in one portion at -40 °C. The mixture was stirred for 10 min at -40 °C and then 0.6
mL (4.3 mmol) of triethylamine was added. The mixture was diluted with ether, poured over

a saturated aqueous NaHCO solution, extracted with ether, and dried over K CO . The
3
2
3
solvent was removed under reduced pressure and the crude residue was subjected to flash
silica gel chromatography to give 0.2 g (74%) of 34 as a pale yellow oil; IR (neat) 1675,
-1 1
1516, 1260, and 1019 cm ; H-NMR (400 MHz, CDCl ) δ 2.87-2.92 (m, 2H), 3.47 (s, 2H),
3
3.83 (s, 3H), 3.85 (s, 3H), 3.86-3.90 (m, 2H), 5.33 (br s, 1H), 6.63 (d, 1H, J = 8.0 Hz), and
13
6.72-6.82 (m, 5H); C-NMR (100 MHz, CDCl ) δ 33.5, 36.3, 42.0, 56.0, 56.1, 108.9, 111.5,
3
112.2, 113.1, 114.1, 120.9, 126.2, 130.9, 138.0, 147.9, 149.2, 151.8, and 174.8; Anal. Calcd
for C H NO : C, 68.98; H, 6.12; N, 4.47. Found: C, 68.83; H, 6.09; N, 4.33.
18 19
4
11,12-Dimethoxy-1,2,4a,5,8,9-hexahydro-4H-indolo[1a, 7a]isoquinoline-3,6-
dione (35). To 0.3 g (1 mmol) of lactam (33) in 10 mL of toluene was added a catalytic
amount of camphorsulfonic acid, and the reaction mixture was stirred overnight at rt. The
solution was poured over a saturated aqueous NaHCO and extracted with CH Cl . The
3
2
2
organic phase was dried over MgSO , and the solvent was removed under reduced
4
pressure. The residue was purified by silica gel chromatography to give 0.25 g (74%) of 35
-1
as a white solid: mp 165-166 °C (hexane/ether); IR (film) 1716, 1680, 1419, and 1260 cm ;
1
H-NMR (400 MHz, CDCl ) δ 2.09-2.15 (m, 1H), 2.23-2.44 (m, 4H), 2.58-2.75 (m, 3H), 2.93-
3
3.12 (m, 4H), 3.85 (s, 3H), 3.87 (s, 3H), 4.34-4.39 (m, 1H), 6.56 (s, 1H), and 6.67 (s,
13
1H); C-NMR (100 MHz, CDCl ) δ 27.7, 33.7, 34.9, 35.4, 37.6, 37.9, 43.4, 56.1, 56.5, 62.6,
3
107.4, 111.9, 125.7, 134.5, 148.4, 148.6, 172.3, and 210.3; Anal. Calcd for C H NO : C,
18 21
4
68.55; H, 6.71; N, 4.44. Found: C, 68.44; H, 6.67; N, 4.39.
ACKNOWLEDGMENT
We gratefully acknowledge the National Institutes of Health GM59384 and GM60003 for
generous support of this work.
REFERENCES AND NOTES
‡
Dedicated to Albert I. Meyers on the occasion of his 70th birthday and for his many
contributions to the field of heterocyclic chemistry.
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