A triple cascade sequence as a strategy for the construction of the erythrinane skeleton

Article abstract of DOI:10.1021/jo9716183

α-Thiocarbocations generated from Pummerer reactions of several o- imido sulfoxides were intercepted by adjacent carbonyl groups to produce α- amido-substituted isobenzofurans as transient intermediates. When an olefinic tether was present, intramolecular Diels-Alder cycloaddition occurred followed by a ring-opening-elimination sequence that produced an N- acyliminium ion. Deprotonation of the iminium ion led to oxindole derivatives in good yields. When the iminium ion contained both a blocking substituent, such as a carbomethoxy group, as well as an activated aromatic π-tether, the N-acyliminium ion intermediate underwent stereoselective spirocyclization to afford cis-3,4-benzoerythrinane or homerythrinane derivatives in good yield. The overall triple cascade sequence represents an efficient one-pot approach toward the erythrina skeleton in which the spirocyclic ABC skeleton is assembled in a single operation. The scope and limitations of the triple cascade were explored by varying both the olefinic and nucleophilic tethers. The required sulfoxide precursors for these Pummerer-induced transformations were easily synthesized starting from 2-[(ethylthio)methyl]benzoic acid. The tandem Pummerer/Diels-Alder/N-acyliminium ion cyclization was used for the synthesis of indoloisoquinoline 38. Since compound 38 was converted to 47 which, in turn, was transformed into erysotramidine (2), its preparation represents an extraordinarily facile, formal synthesis of this member of the Erythrina alkaloid family.

Full text of DOI:10.1021/jo9716183

1144
J . Org. Chem. 1998, 63, 1144-1155
A Tr ip le Ca sca d e Sequ en ce a s a Str a tegy for th e Con str u ction of
th e Er yth r in a n e Sk eleton
Albert Padwa,* Rudiger Hennig, C. Oliver Kappe, and Thomas S. Reger
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received September 2, 1997
R-Thiocarbocations generated from Pummerer reactions of several o-imido sulfoxides were
intercepted by adjacent carbonyl groups to produce R-amido-substituted isobenzofurans as transient
intermediates. When an olefinic tether was present, intramolecular Diels-Alder cycloaddition
occurred followed by a ring-opening-elimination sequence that produced an N-acyliminium ion.
Deprotonation of the iminium ion led to oxindole derivatives in good yields. When the iminium
ion contained both a blocking substituent, such as a carbomethoxy group, as well as an activated
aromatic π-tether, the N-acyliminium ion intermediate underwent stereoselective spirocyclization
to afford cis-3,4-benzoerythrinane or homoerythrinane derivatives in good yield. The overall triple
cascade sequence represents an efficient one-pot approach toward the erythrina skeleton in which
the spirocyclic ABC skeleton is assembled in a single operation. The scope and limitations of the
triple cascade were explored by varying both the olefinic and nucleophilic tethers. The required
sulfoxide precursors for these Pummerer-induced transformations were easily synthesized starting
from 2-[(ethylthio)methyl]benzoic acid. The tandem Pummerer/Diels-Alder/N-acyliminium ion
cyclization was used for the synthesis of indoloisoquinoline 38. Since compound 38 was converted
to 47 which, in turn, was transformed into erysotramidine (2), its preparation represents an
extraordinarily facile, formal synthesis of this member of the Erythrina alkaloid family.
The Erythrina alkaloids are a widely distributed family
rich aryl rings.6 It appeared to us to be highly desirable
of structurally interesting and biologically active natural
products.1-5 Many members of this family possess
curare-like activity, and the alkaloidal extracts have been
used in indigenous medicine.3 A variety of pharmaco-
logical effects, including sedative, hypotensive, neuro-
muscular blocking, and CNS depressant properties are
associated with the erythrinane skeleton.1-3 The vast
majority of naturally occurring Erythrina alkaloids pos-
sess the tetracyclic framework and substitution pattern
shown in structure 1. Numerous synthetic approaches
into the Erythrina ring system have been developed4,5
and a prominent theme for elaborating the fully substi-
tuted carbon center at the BC ring fusion has been
trapping of N-acylimium ion intermediates with electron-
to design a new, easily tunable strategy for the Erythrina
alkaloids, that relied on a multicascade sequence of
reactions. Tandem or cascade processes belong to a
growing family of reactions that allow the regio- and
stereocontrolled formation of several carbon-carbon
bonds and/or ring systems in a single operation.7 Im-
portant contributions to this area have been realized
utilizing a combination of cationic, anionic, radical,
carbenoid, or pericyclic processes.8 Few reactions can
compete with the Diels-Alder cycloaddition with respect
to the degree of complexity that can be accomplished in
a single synthetic step.9 Carbon-carbon bond forming
reactions involving N-acyliminium ions play an equally
important role in the synthesis of nitrogen heterocycles
(1) Boekelheide, V. Alkaloids 1960, 7, 201. Hill, R. K. In The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967;
Vol. 9, p 483. Dyke, S. F.; Quessy, S. N. In The Alkaloids; Rodrigo, R.
G. A., Ed.; Academic Press: New York, 1981; Vol. 18, p 1. J ackson, A.
H. In The Chemistry and Biology of Isoquinoline Alkaloids; Phillipson,
J . D., Roberts, M. F., Zenk, M. H., Eds.; Springer: Berlin, 1985; p 62.
(2) Chawla, A. S.; J ackson, A. H. Nat. Prod. Rep. 1984, 371. Ibid.
1986, 355. Ibid. 1989, 55. Ibid. 1990, 565. Bentley, K. W. Nat. Prod.
Rep. 1991, 339. Ibid. 1992, 365. Ibid. 1993, 449. Ibid. 1994, 555. Ibid.
1995, 419.
(3) Deulofeu, V.; In Curare and Curarelike Agents; Bovet, D., Bovet-
Nitti, F., Marini-Bettolo, G. B., Eds; Elsevier: Amsterdam, 1959; p
163. Williams, M.; Robinson, J . L. J . Neurosci. 1984, 4, 2906. Decker,
M. W.; Anderson, D. J .; Brioni, J . D.; Donnelly-Roberts, D. L.; Kang,
C. H.; O’Neill, A. B.; Piattoni-Kaplan, M.; Swanson, S.; Sullivan, J . P.
Eur. J . Pharmacol. 1995, 280, 79.
(4) Mondon, A. Chem. Ber. 1959, 92, 1461. Ibid. 1959, 92, 1472.
Mondon, A.; Hansen, K. F. Tetrahedron Lett. 1960, 5. Mondon, A.;
Nestler, H. J . Angew. Chem., Int. Ed. Engl. 1964, 3, 588. Sano, T.;
Toda, J .; Kashiwaba, N.; Oshima, T.; Tsuda, Y. Chem. Pharm. Bull.
1987, 35, 479. Sano, T. J . Org. Chem. 1985, 50, 5667. Ahmad-Schofiel,
R.; Mariano, P. S. J . Org. Chem. 1987, 52, 1478. Ishibashi, H.; Sato,
T.; Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 2787.
(5) Belleau, B. Can. J . Chem. 1957, 35, 651. Prelog, V.; Langemann,
A.; Rodig, O.; Ternmah, M. Helv. Chim. Acta 1959, 42, 1301. Sugasawa,
S.; Yoshikawa, H. Chem. Pharm. Bull. 1960, 8, 290. Mu¨ller, M.;
Grossnickle, T. T.; Boekelheide, V. J . Am. Chem. Soc. 1959, 81, 3959.
(6) Tsuda, Y.; Sano, T. In Studies in Natural Products Chemistry;
Rahman, A. U., Ed.; Elsevier: Amsterdam, 1989; Vol. 3, Part B, p 455.
(7) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
Waldmann, H. In Domino Reaction in Organic Synthesis Highlights;
Waldmann, H., Ed.; VCH: Weinheim, 1995; pp 193-202. Wender, P.
A., Ed. Frontiers in Organic Synthesis. Chem. Rev. 1996, 96, 1-600.
(8) For
a recent classification of cascade/domino reactions, see:
Tietze, L. F. Chem. Rev. (Washington, D.C.) 1996, 96, 115.
(9) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10.
Oppolzer, W. Synthesis 1978, 793. Brieger, G.; Bennet, J . N. Chem.
Rev. (Washington, D.C.) 1980, 80, 63. Ciganek, E. Org. React. 1984,
32, 1. Fallis, A. G. Can. J . Chem. 1984, 62, 183. Funk, R. L.; Vollhardt,
S0022-3263(97)01618-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/04/1998

Construction of the Erythrinane Skeleton
J . Org. Chem., Vol. 63, No. 4, 1998 1145
Sch em e 1
due to the inaccessibility and inherent instability of the
2-aminofuran ring system.15-17 Recently, we reported on
the Pummerer-induced cyclization of keto sulfoxides18 as
a method to prepare thio-substituted isobenzofurans of
type 8.19 The R-thiocarbocation generated from the
Pummerer reaction of an o-benzoyl-substituted sulfoxide
(7a ) was intercepted by the adjacent keto group to
produce isobenzofuran 820 as a transient intermediate
which undergoes a subsequent Diels-Alder cycloaddition
with an added dienophile. The resulting cycloadduct was
subsequently converted to several types of arylnaphtha-
lene lignans such as Taiwanin E (9).21
and alkaloidal target molecules.10 A sequential combina-
tion of these two powerful synthetic methods would allow
for the rapid, stereocontrolled synthesis of a variety of
azapolycyclic products.
The retrosynthetic analysis to which we were attracted
involved disconnection of the strategic bonds indicated
by the wavy lines in Scheme 1. Disassembly of 3 in this
fashion was expected to allow for a highly convergent
synthesis of the Erythrina alkaloid ring system. The
central feature of this approach involves using 2-amino-
substituted furans such as 6 which contain both a
suitable leaving group (LG) and an olefinic tether to allow
for an intramolecular Diels-Alder reaction. The result-
ing cycloadduct 5 is expected to readily undergo ring-
opening to generate a vinylogous C-acyliminium ion of
type 4. This sequence of reactions allows for a rapid
entry into the erythrinane skeleton 3, where the key ABC
ring system is assembled in a single operation (6 f 3),
and which also allows the oxygen functionality to be
placed in the appropriate position. Reported herein are
the complete details of our synthetic approach which
culminated in a very concise, formal total synthesis of
the Erythrina alkaloid, (()-erysotramidine (2).11
We also found that o-amido-substituted sulfoxides (i.e.,
7b) can be used as precursors for generating 2-amino-
substituted isobenzofurans (8; R2dNR3R4) as reactive
intermediates.22 To test the viability of this pathway as
an entry into the 3,4-benzoerythrinane skeleton, we
decided to examine the Pummerer-induced reaction of
o-imido sulfoxide 11 (Scheme 2). The construction of 11
was accomplished in four steps from the known carboxylic
acid 10.22 Thus, treatment of 10 with thionyl chloride
at 25 °C followed by reaction of the crude acid chloride
with 3,4-dimethoxyphenethylamine provided the ex-
pected amide. Subsequent acylation with but-3-enoyl
chloride followed by oxidation with sodium periodate
furnished 11 in 69% overall yield. Slow addition of
sulfoxide 11 to a refluxing mixture of p-xylene, acetic
anhydride (10 equiv), and p-toluene sulfonic acid (5 mol
(13) Kappe, C. O.; Cochran, J . E.; Padwa, A. Tetrahedron Lett. 1995,
36, 9285. Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org.
Chem. 1997, 62, 4088. Cochran, J . E.; Wu, T.; Padwa, A. Tetrahedron
Lett. 1996, 37, 2903.
Resu lts a n d Discu ssion
(14) Schlessinger, R. H.; Bergstrom, C. P. Tetrahedron Lett. 1996,
37, 2133. Schlessinger, R. H.; Wu, X. H.; Pettus, T. R. R. Synlett 1995,
536. Schlessinger, R. H.; Pettus, T. R. R.; Springer, J . P.; Hoogsteen,
K. J . Org. Chem. 1994, 59, 3246. Schlessinger, R. H.; Bergstrom, C. P.
J . Org. Chem. 1995, 60, 16.
There are only a few cases in the literature where
Diels-Alder cycloadditions of 2-aminofurans have been
described.12-14 The paucity of examples is undoubtedly
(15) Dunlop, A. P.; Peters, F. N.; In The Furans; Reinhold: New
York, 1953; pp 170-192. Dean, F. M. Adv. Heterocycl. Chem. 1982,
31, 237. McClenaghan, I.; Ramsden, C. A. J . Heterocycl. Chem. 1993,
30, 113.
(16) Bite, P.; Ramonczai, J .; Vargha, L. J . Am. Chem. Soc. 1948,
70, 371. Edwards, W. R., J r.; Singleton, H. M. J . Am. Chem. Soc. 1938,
60, 540. Marquis, R. Ann. Chim. Phys. 1905, 4, 196.
(17) Freure, B. T.; J ohnson, J . R. J . Am. Chem. Soc. 1931, 53, 3,
1142.
(18) For a review of the Pummerer reaction and different triggering
methods, see: DeLucchi, O.; Miotti, U.; Modena, G. Organic Reactions;
Paquette, L. A., Ed.; J ohn Wiley: 1991; Chapter 3, pp 157-184.
(19) Cochran, J . E.; Padwa, A. Tetrahedron Lett. 1995, 36, 3495.
(20) For a review on isobenzofurans, see: Friedrichsen, W. Adv.
Heterocycl. Chem. 1980, 26, 135. Rickborn, B. Advances in Theoretical
Interesting Molecules; Thummel, R. P., Ed.; J AI Press: Greenwich, CT,
1989; Vol. 1, p 1. Friedrichsen, W.; In Houben-Weyl, Methoden der
Organischen Chemie; Kreher, R., Ed.; Thieme Verlag: Stuttgart, 1994;
Vol. E6b, pp 163-216.
(21) Cochran, J . E.; Padwa, A. J . Org. Chem. 1995, 60, 3938. Padwa,
A.; Cochran, J . E.; Kappe, C. O. J . Org. Chem. 1996, 61, 3706.
(22) Padwa, A.; Kappe, C. O.; Cochran, J . E.; Snyder, J . P. J . Org.
Chem. 1997, 62, 2786.
K. P. C. Chem. Soc. Rev. 1980, 9, 41. Craig, D. Chem. Soc. Rev. 1987,
16, 187. Taber, D. F. Intramolecular Diels-Alder and Alder-Ene
Reactions; Springer: Berlin, 1984. Roush, W. R.; In Advances in
Cycloaddition; Curran, D. P., Ed.; J AI Press: Greenwich, CT, 1990;
Vol. 2, p 91.
(10) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, pp 1047-1082. Speckamp, W. N.; Hiemstra, H. Tetrahedron
1985, 41, 4367. Hiemstra, H.; Speckamp, W. N. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1988; Vol. 32, p 271. Hart,
D. J . In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed; Wiley: New York, 1988; Vol. 6, p 227.
(11) For a preliminary report, see: Padwa, A.; Kappe, C. O.; Reger,
T. S. J . Org. Chem. 1996, 61, 4888. Reger, T.; Padwa, A. Abstracts of
the 16th ISHC meeting, Bozeman, Mt., 1997.
(12) Gewald, K. Chem. Ber. 1966, 99, 1002. Boyd, G. V.; Heather-
ington, K. J . Chem. Soc., Perkin Trans. 1 1973, 2523. Nixon, W. J .;
Garland, J . T.; DeWitt-Blanton, C. Synthesis 1980, 56. Aran, V. J .;
Soto, J . L. Synthesis 1982, 513. Semmelhack, M. F.; Park, J . Orga-
nomet. 1986, 5, 2550. Chatani, N.; Hanafusa, T. J . Org. Chem. 1987,
52, 4408. Cutler, S. J .; El-Kabbani, F.; Keane, C.; Fisher-Shore, S. L.;
DeWitt-Blanton, C. Heterocycles 1990, 31, 651.

1146 J . Org. Chem., Vol. 63, No. 4, 1998
Padwa et al.
Sch em e 2
Sch em e 3
rier relative to the corresponding amine.22 Indeed, we
found that benzodihydroindole 17 was formed in 78%
yield when 16 was subjected to the standard Pummerer
conditions. Once again, deprotonation of the initially
formed iminium ion proved much faster than spirocy-
clization.
%)23 did not lead to the desired benzoerythrinane deriva-
tive, but instead gave oxindole 15 in 76% yield. The
isolation of 15 supports the proposed cyclization-cy-
cloaddition/ring opening/elimination sequence 11 f 12
f 13 f 14 f 15. With this system, the initially formed
iminium ion 14 undergoes deprotonation followed by
O-acetylation to afford the isolated oxindole 15 rather
than the spirocyclization product. The driving force
associated with the rapid deprotonation undoubtedly
involves formation of the conjugated aromatic system
present in 15.
For comparison purposes, we have also investigated
the chemistry of the closely related imido sulfoxide 16
where the carbonyl group has been switched from “inside”
the tether to the “outside” position. In an earlier study
we noted that incorporation of a CdO group R to nitrogen,
either internal or external to the tether, promotes the
intramolecular [4 + 2]-cycloaddition reaction of the
isobenzofuran derivative across the tethered π-bond.22
Removal of the CdO functionality significantly sup-
pressed the Diels-Alder cycloaddition reaction. Density
functional theory (DFT)24 calculations suggested that the
presence of an amido tether raises the energy of the
intermediate isobenzofuran ground state and thereby
reduces the intramolecular Diels-Alder activation bar-
To avoid the deprotonation step, we prepared sulf-
oxides 18 and 19, each possessing a carbomethoxy group
attached to the olefin tether. This substituent was
selected not only to prevent deprotonation, but also
because the presence of an electron-withdrawing group
on the double bond was expected to enhance the rate of
intramolecular [4 + 2]-cycloaddition based on FMO
considerations.25 Subjection of 18 to the standard Pum-
merer conditions provided a 2:1 mixture of the N,S- and
N,O-ketals 21 and 22, respectively. These products are
derived from bimolecular trapping of iminium ion 20 with
a nucleophilic species present in the reaction medium
(i.e., EtS-; AcO-/HO-) (Scheme 3). Both ketals can be
independently converted to the desired benzoerythrinane
derivative 23 by heating each in toluene which contained
1.1 equiv of p-TsOH. We found it to be more convenient,
however, to carry out the triple cascade sequence (18 f
23) in a one-pot fashion by first subjecting sulfoxide 18
to the Ac2O/p-TsOH conditions, followed by treatment of
the crude reaction mixture (after evaporation of the
solvent and excess Ac2O) with an additional quantity (1.1
equiv) of p-TsOH in refluxing toluene. By using this one-
pot protocol, 3,4-benzoerythrinane 23 was obtained as a
single diastereomer in 65-70% yield from sulfoxide 18.
(23) Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kuma-
moto, T. Bull. Chem. Soc. J pn. 1981, 54, 817.
(24) Becke, A. D. J . Chem. Phys. 1993, 98, 5648. Stevens, P. J .;
Devlin, F. F.; Chablowski, C. F.; Frisch, M. J . J . Chem. Phys. 1994,
99, 11623. Wiest, O.; Black, K. A.; Houk, K. N. J . Am. Chem. Soc. 1994,
116, 10336.
(25) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.

Construction of the Erythrinane Skeleton
J . Org. Chem., Vol. 63, No. 4, 1998 1147
Sch em e 4
Alternatively, the tandem sequence could also be trig-
gered at 0 °C by utilizing the more electrophilic trifluo-
roacetic anhydride as the Pummerer promoter (CH2Cl2,
2 equiv of Et3N).23 In this case, the isobenzofuran
cycloadduct (i.e., 13; RdCO2Me) was isolated and was
converted to 23 (70% overall) by exposure to p-TsOH (1.1
equiv) in refluxing toluene. The cis-stereochemistry of
the A/B ring system of 23 is supported by a number of
related iminium ion cyclizations reported in the litera-
1
ture4,26 and by the distinct H-chemical shift of the methyl
ester.27 Semiempirical calculations (AM1 or PM3) show
that the ground-state energy of the cis A/B ring fusion
present in 23 is ca. 15-18 kcal lower than the trans
diastereomer and presumably some of this thermody-
namic energy difference is reflected in the transition state
for cyclization.
A similar one-pot sequence was successfully employed
for the conversion of the homologous sulfoxide 19 to the
homoerythrina analogue 25 in 66% yield. The triple
cascade sequence of 19 was also carried out using
trifluoroacetic anhydride at 0 °C with 2 equiv of triethyl-
amine. Under these conditions, cycloadduct 24 was
isolated and was subsequently transformed into 25 (65%)
by exposure to 1.1 equiv of p-TsOH in refluxing toluene.
a C-acyliminium ion onto a highly activated aromatic
π-bond. So that a cross section of additional information
could be obtained in regard to the facility of the cycliza-
tion step, we needed to evaluate a series of amido
sulfoxides containing different aromatic π-bonds. Com-
pounds ranging from unsubstituted aromatics to indoles
to simple alkenyl-tethered systems were considered.
Ultimately, substrates 26 and 29 were studied as they
contain a range of synthetically interesting and easily
attainable functionalities.
The Pummerer-induced reaction of imido sulfoxide 26
using trifluoroacetic anhydride proceeded uneventfully
and provided the expected isobenzofuran cycloadduct 27
The versatility of acyliminium ions for the synthesis
of a wide variety of nitrogenous materials underscores
the need to find new methods for their preparation.28
These reactive intermediates readily react with a wide
assortment of π-nucleophiles to effect an overall R-amido
alkylation.29 The last step of our Pummerer-induced
triple cascade reaction involves a Mannich cyclization of
(26) Wilkens, H. J .; Traxler, F. Helv. Chim. Acta 1975, 58, 1512.
(27) The high field chemical shift of the methyl ester (3.21 ppm for
23 vs 3.83 for sulfoxide 18) is due to the fact that the ester functionality
present in cis-23 is situated directly above the plane of the aromatic
D-ring of the erythrina skeleton. This particular stereochemical
relationship is only realized in the cis-erythrina series and has been
previously utilized to distinguish between the cis- and trans-ring fusion
in erythrina derivatives.26
(28) Speckamp, W. N. Rec. Trav. Chim. Pays-Bas 1981, 100, 345.
Maryanoff, B. E.; Rebarchak, M. C. Synthesis 1992, 1245.
(29) For representative examples of π-nucleophiles, see: Heaney,
H.; Shuhaibar, K. F. Synlett 1995, 47. Lee, Y. S.; Kang, D. W.; Lee, S.
J .; Park, H. J . Org. Chem. 1995, 60, 7149. Li, W. H.; Hanau, C. E.;
Davignon, A.; Moeller, K. D. J . Org. Chem. 1995, 60, 8155. Logers,
M.; Overman, L. E.; Welmalker, G. S. J . Am. Chem. Soc. 1995, 117,
9139. Marson, C. M.; Pink, J . H.; Smith, C. Tetrahedron Lett. 1995,
36, 8107. Rigo, B.; Elghammarti, S.; Couturier, D. Tetrahedron Lett.
1996, 37, 485. Yamada, H.; Aoyagi, S.; Kibayashi, C. J . Am. Chem.
Soc. 1996, 118, 1054.
in 59% yield. When acetic anhydride was used as the
Pummerer promoter, hydroxy lactam 28 was the only
product (35%) isolated from the reaction mixture. All of
our attempts to induce a further reaction of 27 or 28
using a variety of Lewis acids failed to give any charac-
terizable products. The anticipated product of electro-
philic aromatic substitution was not observed, thereby
(30) J ones, G. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 2, p 438.

1148 J . Org. Chem., Vol. 63, No. 4, 1998
Padwa et al.
Sch em e 5
suggesting that only highly activated aromatic rings are
capable of undergoing the Mannich cyclization reaction.30
The synthesis of indoles bearing substituents at the
2- and 3-positions has been of interest for many years
due to the large number of biologically active natural
products having this substitution pattern.31 Conse-
quently, we decided to investigate the Pummerer reaction
of imido sulfoxide 29 where an indolyl tether has been
placed on the amide nitrogen as a method for generating
highly functionalized indoles. Surprisingly, subjection of
29 to the standard Pummerer conditions failed to provide
any product derived from an intramolecular cycloaddition
across the acrylate π-bond. Instead, a 5:1-mixture of the
unexpected tetracyclic fused indoles 31 (58%) and 32
(11%) was obtained. Indole 31 was readily converted to
32 upon heating in the presence of acetic anhydride. The
mechanism of this unusual reaction has not been un-
equivocally established, but one possibility involves
formation of the expected isobenzofuran derivative which
undergoes preferential [4 + 2]-cycloaddition across the
indole π-bond to give 30. Cycloadduct 30 proceeds on to
give 31/32 via oxabicyclic ring opening as outlined in
Scheme 4. There are a few examples reported in the
literature where the indole ring can function as a
dienophile in intramolecular Diels-Alder chemistry,32,33
thereby providing some precedent for the key step in this
cycloaddition.
Interestingly, when the corresponding N-tosyl imido
sulfoxide 33 was exposed to TMSOTf/NEt3, cycloadduct
34 derived from the more traditional cyclization-cy-
cloaddition pathway was isolated in 71% yield. The
Pummerer reaction of 33 using Ac2O/p-TsOH, however,
led to a complex mixture of products which resisted
characterization. All of our attempts to convert 34 into
a benzoerythrinane derivative were unsuccessful, and we
abandoned further work with this system. At the mo-
ment, we have no satisfactory explanation to account for
why the isobenzofuran derived from the NH-indole 29
prefers to react across the indole π-bond whereas the
related N-tosyl amide 33 undergoes cycloaddition across
(31) Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London, 1981.
(32) Kraus, G. A.; Raggon, J .; Thomas, P. J .; Bougie, D. Tetrahedron
Lett. 1988, 29, 5605. Kraus, G. A.; Bougie, D.; J acobsen, R. A.; Su, Y.
J . Org. Chem. 1989, 54, 2425. Benson, S. C.; Li, J . H.; Snyder, J . K. J .
Org. Chem. 1992, 57, 5285.
(33) Corsico Coda, A.; Gru¨nanger, P.; Vernesi, G. Tetrahedron Lett.
1966, 2911. Caramella, P.; Cellerino, G.; Corsico Coda, A.; Invernizzi,
A. G.; Gru¨nanger, P.; Houk, K. N.; Albini, F. M. J . Org. Chem. 1976,
41, 3349. Caramella, P. Tetrahedron Lett. 1968, 743. Caramella, P.;
Cellerino, G.; Gru¨nanger, P.; Albini, F. M.; Cellerino, M. R. Tetrahedron
1978, 34, 3545. Caramella, P.; Cellerino, G.; Houk, K. N.; Albini, F.
M.; Santiago, C. J . Org. Chem. 1978, 43, 3006. Caramella, P.; Corsico
Coda, A.; Corsaro, A.; Monte, D. D.; Albini, F. M. Tetrahedron 1982,
38, 173. Hassner, A.; Murthy, K. S. K.; Padwa, A.; Chiacchio, U.; Dean,
D. C.; Schoffstall, A. M. J . Org. Chem. 1989, 54, 5277. Dehaen, W.;
Hassner, A. J . Org. Chem. 1991, 56, 896. Yin, H.; Franck, R. W.; Chen,
S. L.; Quigley, G. J .; Todaro, L. J . Org. Chem. 1992, 57, 644.

Construction of the Erythrinane Skeleton
J . Org. Chem., Vol. 63, No. 4, 1998 1149
the acrylate π-bond. The insight gained from these
experiments is that the last step of the triple cascade
process is markedly dependent on the nature of the
π-aromatic tethered onto the amide nitrogen atom.
At this point, we decided to undertake a synthesis of
(()-erysotramidine (2)1 in order to test the viability of
the triple cascade process as an entry into the erythri-
nane alkaloid family. The requisite starting imido sul-
foxide 37, possessing both a dienophilic and diactivated
aromatic π-tether, was efficiently synthesized from the
known allylic bromide 35.34 Displacement of the bromide
with ethanethiol/KOH followed by ester hydrolysis and
subsequent conversion of the resulting acid to amide 36
was accomplished in 54% overall yield. Standard acyl-
ation and oxidation steps furnished the desired sulfoxide
37 in 82% yield. We found it most effective to trigger
the cyclization reaction by adding trifluoroacetic anhy-
dride to a solution of sulfoxide 37 and 2 equiv of
triethylamine at -78 °C. The starting sulfoxide was
consumed immediately upon addition of the Pummerer
promoter. After addition of 3 equiv of BF3‚OEt2 and
gradual warming of the reaction to reflux, compound 38
was obtained as a single diastereomer in 83% yield. The
cis A/B ring fusion present in 38 was unequivocally
established by an X-ray crystallographic analysis35 and
is identical to the stereochemical relationship found in
the naturally occurring Erythrina alkaloids.26
assisted ring opening of the oxabicyclic bridge results in
the formation of zwitterionic intermediate 42 which
undergoes a 1,2-thioethyl shift followed by methoxide ion
ejection. Cyclization of the diactivated aromatic tether
onto N-acyliminium ion 44 ultimately provides the tet-
racyclic amide 38. By carrying out the reaction for
shorter periods of time, it was possible to isolate N,O-
ketal 45. This compound arises by addition of water to
iminium ion 44 and was independently converted to 38
when treated with BF3‚OEt2.
With a supply of 38 in hand, this enone was converted
into the corresponding vinyl triflate36 which, in turn, was
subjected to a palladium-catalyzed formate reduction to
furnish diene 46.37 This thio-substituted diene was
subsequently transformed into ketone 47 via a titanium-
mediated hydrolysis.38 The present sequence constitutes
a formal synthesis of (()-erysotramidine (2) based on the
successful conversion of 47 into 2 by Tsuda and co-
workers.39
In conclusion, the ready conversion of imido sulfoxide
37 into the azapolyheterocycle 38 represents an efficient
and novel approach toward the erythrinane skeleton in
which the spirocyclic ABC ring skeleton is assembled in
a single operation. The key step in this transformation
involves the generation of a vinylogous C-acyliminium
ion intermediate by fragmentation of a suitable Diels-
Alder cycloadduct. This triple cascade process is ap-
plicable toward the preparation of ring homologues of the
Erythrina skeleton by simply varying the tether length
of the starting sulfoxides. Further work in this area and
the application of this methodology to other furano
systems is in progress and will be reported at a later date.
The conversion of 37 into 38 is believed to follow the
pathway outlined in Scheme 5. The initially formed
R-thiocarbocation intermediate generated from the Pum-
merer reaction of 37 is intercepted by the adjacent imido
carbonyl to produce the R-amido substituted furan 40.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
This transient intermediate undergoes a subsequent
intramolecular Diels-Alder cycloaddition across the
tethered π-bond to furnish cycloadduct 41. Nitrogen-
(34) J ones, R. C. F.; Bates, A. D. Tetrahedron Lett. 1986, 27, 5285.
(35) The authors have deposited coordinates for structure 38 with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U. K.
(36) McCague, R. Tetrahedron: Asymmetry 1990, 1, 97.
(37) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 42,
4821.
(38) Mukaiyama, T.; Kamio, K.; Kobayashi, S.; Takei, H. Bull. Chem.
Soc. J pn. 1972, 45, 3723.

1150 J . Org. Chem., Vol. 63, No. 4, 1998
Padwa et al.
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 2.99 (t, 2H, J ) 8.0
Hz), 3.56 (s, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.41 (t, 2H, J ) 8.0
Hz), 6.74-6.82 (m, 3H), 7.21 (s, 1H), 7.51-7.60 (m, 2H), 7.88
(dd, 1H, J ) 8.0 and 1.0 Hz), 8.29 (dd, 1H, J ) 8.0 and 1.0
Hz); 13C NMR (75 MHz, CDCl3) δ 20.7, 34.5, 36.0, 43.4, 55.5,
55.6, 111.2, 111.8, 115.0, 119.9, 120.5, 120.9, 121.1, 122.3,
125.6, 126.2, 126.7, 130.0, 136.8, 141.8, 147.6, 148.7, 169.5,
175.8. Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72; N, 3.45.
Found: C, 71.09; H, 5.71; N, 3.43.
Gen er a l P r oced u r e for th e Ta n d em P u m m er er Cy-
cliza tion Diels-Ald er Cycloa d d ition Sequ en ce. A mix-
ture containing 10 mL of xylene, 0.5 mL of acetic anhydride,
and 5 mg of p-toluenesulfonic acid was heated at reflux under
argon. To this mixture was added dropwise a solution of 0.5
mmol of the appropriate sulfoxide in 3 mL of solvent via
syringe over a 20 min period. After the addition was complete,
the solution was heated at reflux for an additional 10 min until
no sulfoxide was detected by TLC. The mixture was concen-
trated under reduced pressure, and the crude residue was
purified by flash silica gel chromatography.
N-Bu t -3-en yl-2-[(et h ylt h io)m et h yl]b en za m id e. To a
stirred suspension containing 4.9 g (25 mmol) of 2-[(ethylthio)-
methyl]benzoic acid (10) in 50 mL of benzene was added 6.0 g
(50 mmol) of thionyl chloride. After stirring at rt for 1 h, the
solution was concentrated under reduced pressure. The crude
acid chloride was dissolved in 20 mL of CH2Cl2, and this
mixture was added dropwise to a solution containing 5.3 g (75
mmol) of but-3-enylamine in 50 mL of CH2Cl2 at 0 °C under
argon. After stirring at rt for 2 h, the mixture was washed
successively with 5% HCl, a saturated NaHCO3 solution, and
brine. The organic layer was dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified by
flash silica gel chromatography and recrystallized from ethyl
acetate/hexane to give 4.7 g (76%) of N-but-3-enyl-2-[(ethyl-
thio)methyl]benzamide as a colorless solid, mp 48-49 °C; IR
N -(3,4-Dim e t h oxyp h e n e t h yl)-2-[(e t h ylt h io)m e t h yl]-
ben za m id e. To a stirred suspension containing 4.9 g (25
mmol) of 2-[(ethylthio)methyl]benzoic acid (10) in 50 mL of
benzene was added 6.0 g (50 mmol) of thionyl chloride. After
stirring at rt for 1 h, the solution was concentrated under
reduced pressure. The resulting oil was dissolved in 20 mL
of CH2Cl2, and this mixture was added dropwise to a solution
containing 13.6 g (75 mmol) of 3,4-dimethoxyphenylethylamine
in 50 mL of CH2Cl2 at 0 °C under argon. After stirring at rt
for 2 h, the mixture was washed successively with 5% HCl, a
saturated NaHCO3 solution, and brine. The organic layer was
dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash silica gel chromatography
and recrystallized from ethyl acetate/hexane to give 7.8 g (88%)
of N-(3,4-dimethoxyphenethyl)-2-[(ethylthio)methyl]benzamide
as a colorless solid, mp 96-97 °C; IR (KBr) 3317, 1633, 1543,
1
(KBr) 3291, 1637, 1537, 1317, 701 cm-1; H NMR (300 MHz,
CDCl3) δ 1.26 (t, 3H, J ) 7.5 Hz), 2.39 (dt, 2H, J ) 7.0 and 7.0
Hz), 2.52 (q, 2H, J ) 7.0 Hz), 3.54 (dt, 2H, J ) 7.0 and 7.0
Hz), 3.92 (s, 2H), 5.09-5.19 (m, 2H), 5.78-5.91 (m, 1H), 6.53
(brs, 1H), 7.25-7.49 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.3,
25.8, 33.5, 33.6, 38.9, 117.0, 127.0, 128.1, 129.6, 130.4, 135.2,
135.7, 136.4, 169.2. Anal. Calcd for C14H19NOS: C, 67.43;
H, 7.68; N, 5.62. Found: C, 67.51; H, 7.75; N, 5.61.
1
1515, 1262 cm-1; H NMR (300 MHz, CDCl3) δ 1.22 (t, 3H, J
) 7.5 Hz), 2.42 (q, 2H, J ) 7.5 Hz), 2.91 (t, 2H, J ) 7.0 Hz),
3.70 (dt, 2H, J ) 7.0 and 7.0 Hz), 3.85 (s, 8H), 6.56 (brs, 1H),
6.79-6.83 (m, 3H), 7.23-7.44 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 14.3, 25.8, 33.5, 35.0, 41.0, 55.7, 55.8, 111.3, 111.9,
120.6, 127.1, 128.1, 129.7, 130.5, 131.3, 135.8, 136.3, 147.5,
148.9, 169.2. Anal. Calcd for C20H25NO3S: C, 66.82; H, 7.01;
N, 3.90. Found: C, 66.68; H, 6.97; N, 3.84.
N-Bu t -3-en yl-N-(3,4-d im et h oxyp h en yla cet yl)-2-[(et h -
ylth io)m eth yl]ben za m id e. A mixture of 1.3 g (5 mmol) of
the above amide, 1.6 g (7.5 mmol) of 3,4-dimethoxyphenyl-
acetyl chloride, and 4.0 g of powdered molecular sieves (4 Å)
in 30 mL of CH2Cl2 was stirred at rt for 24 h. The reaction
mixture was filtered through a pad of silica gel, the solvent
was removed under reduced pressure, and the resulting crude
oil was purified by flash silica gel chromatography to give 1.8
g (84%) of N-but-3-enyl-N-(3,4-dimethoxyphenylacetyl)-2-[(eth-
ylthio)methyl]benzamide as a colorless oil; IR (neat) 1691,
N-Bu t -3-en oyl-N-(3,4-d im et h oxyp h en et h yl)-2-[(et h yl-
th io)m eth yl]ben za m id e. A mixture containing 1.8 g (5
mmol) of the above amide, 0.78 g (7.5 mmol) of but-3-enoyl
chloride, and 4.0 g of powdered molecular sieves (4 Å) in 30
mL of CH2Cl2 was stirred at rt for 24 h. The reaction mixture
was filtered through a pad of silica gel, the solvent was
removed under reduced pressure, and the resulting oil was
purified by flash silica gel chromatography to give 1.8 g (82%)
of N-but-3-enoyl-N-(3,4-dimethoxyphenethyl)-2-[(ethylthio)-
methyl]benzamide as a colorless oil; IR (neat) 1691, 1654, 1515,
1651, 1590, 1509, 1448 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.21 (t, 3H, J ) 7.5 Hz), 2.31 (dt, 2H, J ) 7.0 and 7.0 Hz),
2.45 (q, 2H, J ) 7.5 Hz), 3.72 (t, 2H, J ) 7.0 Hz), 3.83 (s, 2H),
3.85 (s, 6H), 3.92 (s, 2H), 4.97-5.03 (m, 2H), 5.60-5.74 (m,
1H), 6.70 (d, 1H, J ) 8.0 Hz), 6.72 (s, 1H), 6.81 (d, 1H, J ) 8.0
Hz), 7.15-7.42 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.3, 25.9,
32.9, 33.0, 44.3, 45.8, 55.8, 55.9, 111.1, 112.6, 117.2, 121.6,
127.1, 127.9, 130.7, 130.9, 134.7, 135.4, 137.7, 148.0, 148.8,
173.4, 175.2; HRMS (FAB) Calcd for C24H29NO4S: 427.1817.
Found: 427.1809.
1
1354, 1258, 1141 cm-1; H NMR (300 MHz, CDCl3) δ 1.20 (t,
3H, J ) 7.5 Hz), 2.42 (q, 2H, J ) 7.5 Hz), 2.86 (t, 2H, J ) 7.0
Hz), 3.31 (d, 2H, J ) 7.0 Hz), 3.79 (s, 3H), 3.83 (s, 3H), 3.83-
3.89 (m, 2H), 3.86 (s, 2H), 5.02-5.16 (m, 2H), 5.88-6.01 (m,
1H), 6.56-6.76 (m, 3H), 7.13-7.42 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 13.9, 25.6, 32.8, 34.1, 42.9, 47.8, 55.4, 55.5, 110.9,
111.7, 118.0, 120.6, 126.8, 127.5, 130.3, 130.5, 130.7, 135.1,
136.9, 147.3, 148.5, 172.9, 174.4; HRMS (FAB) Calcd for
N-Bu t-3-en yl-N-(3,4-d im eth oxyp h en yla cetyl)-2-[(eth yl-
su lfin yl)m eth yl]ben za m id e (16). To a solution containing
a 1.7 g (4 mmol) sample of the above sulfide in 20 mL of
methanol was added 0.95 g (4.4 mmol) of sodium periodate at
0 °C. To this mixture was added 3 mL of water, and the
solution was stirred for 5 h at rt. After the addition of water,
the aqueous layer was extracted with CH2Cl2, and the com-
bined organic layer was washed with water, dried over MgSO4,
and concentrated under reduced pressure. The crude residue
was purified by flash silica gel chromatography to give 1.7 g
(95%) of sulfoxide 16 as a colorless oil; IR (neat) 1684, 1651,
C
24H30NO4S (M + H) 428.1896. Found: 428.1887.
N-Bu t -3-en oyl-N-(3,4-d im et h oxyp h en et h yl)-2-[(et h yl-
su lfin yl)m eth yl]ben za m id e (11). A 1.7 g (4 mmol) sample
of the above sulfide was oxidized in the manner outlined
previously21 to give 1.8 g of sulfoxide 11 (95%) as a colorless
oil; IR (neat) 1686, 1654, 1509, 1451, 1349, 1023 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.33 (t, 3H, J ) 7.5 Hz), 2.60-2.92 (m,
4H), 3.38 (d, 2H, J ) 7.0 Hz), 3.80 (s, 3H), 3.84 (s, 3H), 3.82-
3.99 (m, 4H), 5.04-5.17 (m, 2H), 5.86-5.97 (m, 1H), 6.57-
6.77 (m, 3H), 7.22-7.52 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
6.5, 34.2, 42.7, 45.4, 48.1, 55.0, 55.5, 55.6, 111.0, 112.0, 118.5,
120.8, 127.8, 127.9, 130.4, 130.7, 131.2, 132.2, 135.1, 147.7,
148.6, 172.8, 174.3; HRMS (FAB) Calcd for C24H30NO5S (M +
H): 444.1845. Found: 444.1863.
1
1511, 1445, 1259 cm-1; H NMR (300 MHz, CDCl3) δ 1.36 (t,
3H, J ) 7.5 Hz), 2.34 (dt, 2H, J ) 7.0 and 7.0 Hz), 2.61-2.85
(m, 2H), 3.72-3.79 (m, 2H), 3.82 (s, 3H), 3.83 (s, 2H), 3.85 (s,
3H), 3.99 (d, 1H, J ) 13.0 Hz), 4.20 (d, 1H, 13.0 Hz), 4.99-
5.05 (m, 2H), 5.61-5.74 (m, 1H), 6.67-6.79 (m, 3H), 7.17 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 6.8, 33.2, 44.3, 45.7, 45.9,
55.3, 55.8, 55.9, 111.1, 112.4, 117.5, 121.4, 126.6, 128.2, 128.3,
130.8, 131.6, 132.6, 134.5, 135.6, 148.1, 148.9, 173.3, 175.1;
HRMS (FAB) Calcd for C24H30NO5S (M + H): 444.1845.
Found: 444.1845.
5-Acetoxy-1-(3,4-d im eth oxyp h en eth yl)-2,3-d ih yd r o-1H-
ben zo[g]in d ol-2-on e (15) was obtained from 217 mg (0.5
mmol) of sulfoxide 11 in 76% yield as a white solid, mp 168-
5-Acetoxy-1-(3,4-d im eth oxyp h en yla cetyl)-2,3-d ih yd r o-
1H -b en zo[g]in d ole (17) was obtained from 217 mg (0.5
169 °C (ethanol); IR (KBr) 1760, 1698, 1513, 1199, 1158 cm-1
;

Construction of the Erythrinane Skeleton
J . Org. Chem., Vol. 63, No. 4, 1998 1151
mmol) of sulfoxide 16 in 78% yield as a white solid upon
treatment with Ac2O, mp 178-179 °C (ethanol); IR (KBr) 1758,
N,O-Ketal 22: white solid, mp 168-169 °C (ethanol); IR
(KBr) 3360, 1740, 1698, 1685, 1515, 1397, 1256 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.33-2.42 (m, 2H), 2.57 (d, 1H, J ) 16.5
Hz), 2.97 (d, 1H, J ) 16.5 Hz), 3.30-3.43 (m, 2H), 3.61 (s, 3H),
3.72 (s, 3H), 3.61-3.67 (m, 2H), 3.79 (s, 3H), 4.51 (s, 1H,
exchangeable with D2O), 6.29 (s, 1H), 6.30 (d, 1H, J ) 8.0 Hz),
6.56 (d, 1H, J ) 8.0 Hz), 7.54 (dd, 1H, J ) 7.5 and 7.0 Hz),
7.72 (dd, 1H, J ) 7.5 and 7.0 Hz), 7.94-8.00 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 34.0, 39.4, 40.6, 45.0, 53.0, 54.4, 55.5, 55.7,
88.6, 110.9, 111.4, 120.5, 126.8, 127.8, 129.6, 130.3, 130.9,
133.8, 138.8, 147.4, 148.5, 172.0, 173.4, 192.5. Anal. Calcd
for C24H25NO7: C, 65.59; H, 5.73; N, 3.19. Found: C, 65.43;
H, 5.86; N, 3.15.
1653, 1509, 1397, 1201 cm-1 1H NMR (300 MHz, CDCl3) δ
;
2.45 (s, 3H), 3.11 (brs, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 3.91 (s,
2H), 4.25 (brs, 2H), 6.78-6.98 (m, 3H), 7.16 (s, 1H), 7.42-
7.55 (m, 2H), 7.82-7.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
21.0, 30.6, 43.2, 51.7, 55.9, 111.3, 111.8, 115.1, 120.9, 121.5,
125.3, 125.8, 125.9, 126.5, 127.3, 131.2, 136.6, 144.8, 148.0,
149.2, 169.6. Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72;
N, 3.45. Found: C, 70.84; H, 5.75; N, 3.40.
N-(3,4-Dim eth oxyp h en eth yl)-N-[3-(m eth oxyca r bon yl)-
bu t-3-en oyl]-2-[(eth ylth io)m eth yl]ben za m id e. A mixture
containing 1.8 g (5.0 mmol) of N-(3,4-dimethoxyphenethyl)-2-
[(ethylthio)methyl]benzamide, 1.2 g (7.5 mmol) of 3-(methoxy-
carbonyl)but-3-enoyl chloride (prepared from the corresponding
carboxylic acid),40 and 4.0 g of powdered molecular sieves (4
Å) in 30 mL of CH2Cl2 was stirred at rt for 24 h. The reaction
mixture was filtered through a pad of silica gel, and the filtrate
was washed with an aqueous NaHCO3 solution. The organic
layer was dried over Na2SO4 and was concentrated under
reduced pressure. The crude oil was purified by flash silica
gel chromatography to give 2.0 g (83%) of N-(3,4-dimethoxy-
phenethyl)-N-[3-(methoxycarbonyl)but-3-enoyl]-2-[(ethyl-
thio)methyl]benzamide as a colorless oil; IR (neat) 1718, 1691,
Met h yl 15,16-Dim et h oxy-2,8-d ioxo-3,4-b en zoer yt h r i-
n a n e-6-ca r boxyla te (23). A mixture containing 10 mL of
toluene, 0.5 mL of acetic anhydride, and 1 mg of p-toluene-
sulfonic acid was heated at reflux under argon. To this
mixture was added dropwise a solution of 251 mg (0.5 mmol)
of sulfoxide 18 in 3 mL of toluene via syringe over a 15 min
period. After the addition was complete, the solution was
heated at reflux for an additional 5 min until no sulfoxide was
detected by TLC. The mixture was concentrated under
reduced pressure, and the residue was dissolved in 10 mL of
toluene. To this solution was added 94 mg (0.55 mol) of
p-TsOH, and the mixture was heated at reflux for 15 min.
After removal of the solvent under reduced pressure, the crude
residue was purified by flash silica gel chromatography and
recrystallized from CH2Cl2/hexane to give 147 mg (70%) of 23
as a white solid; mp 257-258 °C; IR (KBr) 1730, 1697, 1690,
1659, 1515, 1440, 1349 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.20 (t, 3H, J ) 7.5 Hz), 2.44 (q, 2H, J ) 7.5 Hz), 2.84 (t, 2H,
J ) 8.0 Hz), 3.72 (s, 2H), 3.78 (s, 6H), 3.81-3.88 (m, 2H), 3.83
(s, 3H), 3.85 (s, 2H), 5.67 (s, 1H), 6.32 (s, 1H), 6.54 (s, 1H),
6.58 (d, 1H, J ) 8.0 Hz), 6.73 (d, 1H, J ) 8.0 Hz), 7.20-7.42
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.2, 25.9, 33.0, 34.2,
42.1, 48.4, 52.0, 55.7, 55.8, 111.1, 112.0, 120.8, 127.0, 127.6,
128.2, 130.5, 130.7, 130.8, 134.7, 135.1, 137.1, 147.5, 148.8,
166.6, 173.4, 173.7; HRMS (FAB) Calcd for C26H31NO6S:
485.1872. Found: 485.1865.
1592, 1515, 1413, 1248 cm-1 1H NMR (300 MHz, CDCl3) δ
;
2.54 (d, 1H, J ) 16.5 Hz), 2.71-2.93 (m, 3H), 2.99 (d, 1H, J )
16.5 Hz), 3.21 (s, 3H), 3.28-3.40 (m, 1H), 3.61-3.65 (m, 1H),
3.64 (s, 3H), 3.87 (s, 3H), 4.52-4.59 (m, 1H), 6.30 (s, 1H), 6.65
(s, 1H), 7.22 (dd, 1H, J ) 8.0 and 1.0 Hz), 7.43 (t, 1H, J ) 8.0
Hz), 7.54 (t, 1H, J ) 8.0 Hz), 8.06 (dd, 1H, J ) 8.0 and 1.0
Hz); 13C NMR (75 MHz, CDCl3) δ 27.6, 36.2, 40.4, 41.1, 52.0,
53.5, 55.6, 56.0, 66.3, 110.6, 111.1, 125.9, 126.7, 127.2, 128.2,
128.8, 129.9, 134.9, 145.0, 147.8, 148.5, 171.0, 171.2, 194.8.
Anal. Calcd for C24H23NO6: C, 68.40; H, 5.50; N, 3.32.
Found: C, 68.28; H, 5.58; N, 3.30.
N-(3,4-Dim eth oxyp h en eth yl)-N-[3-(m eth oxyca r bon yl)-
bu t-3-en oyl]-2-[(eth ylsu lfin yl)m eth yl]ben za m id e (18). A
1.9 g (4 mmol) sample of the above sulfide was oxidized in the
manner previously outlined21 to give sulfoxide 18 (93%) as a
colorless oil; IR (neat) 1714, 1684, 1656, 1512, 1351, 1260, 1149
cm-1 1H NMR (300 MHz, CDCl3) δ 1.35 (t, 3H), 2.65-2.89
;
(m, 4H), 3.63 (s, 2H), 3.77 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H),
3.81-3.92 (m, 4H), 5.70 (s, 1H), 6.32 (s, 1H), 6.56 (s, 1H), 6.59
(d, 1H, J ) 8.0 Hz), 6.74 (d, 1H, J ) 8.0 Hz), 7.28-7.53 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 6.6, 34.3, 41.8, 45.5, 48.6,
51.9, 54.9, 55.6, 55.7, 111.1, 112.1, 120.9, 128.0, 128.1, 128.4,
130.5, 130.6, 131.3, 132.2, 134.4, 135.1, 147.6, 148.8, 166.6,
173.2, 173.6; HRMS (FAB) Calcd for C26H32NO7S (M + H):
502.1899. Found: 502.1892.
Meth yl 1-(3,4-Dim eth oxyp h en eth yl)-2,5-d ioxo-9b-(eth -
ylth io)-1,2,3,4,5,9b-h exa h yd r oben zo[g]in d ole-3a -ca r box-
yla te (21). The reaction of 251 mg (0.5 mmol) of sulfoxide 18
with acetic anhydride following the general procedure21 af-
forded a 2:1-mixture of 21 and methyl 1-(3,4-dimethoxyphen-
ethyl)-2,5-dioxo-9b-hydroxy-1,2,3,4,5,9b-hexahydrobenzo[g]in-
dole-3a-carboxylate (22). The crude mixture was separated
by flash silica gel chromatography to furnish 113 mg (47%) of
N,S-ketal 21 and 50 mg (23%) of N,O-ketal 22.
N,S-Ketal 21: white solid, mp 149-150 °C (ethanol); IR
(KBr) 1740, 1709, 1697, 1593, 1575, 1262 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.08 (t, 3H, J ) 7.5 Hz), 2.08-2.41 (m, 4H),
2.63 (d, 1H, J ) 16.5 Hz), 2.73 (d, 1H, J ) 16.5 Hz), 3.31-
3.52 (m, 2H), 3.57 (s, 3H), 3.73 (s, 3H), 3.77 (s, 3H), 3.78-3.89
(m, 2H), 6.24 (d, 1H, J ) 8.0 Hz), 6.31 (s, 1H), 6.55 (d, 1H, J
) 8.0 Hz), 7.55 (t, 1H, J ) 7.5 Hz), 7.71 (t, 1H, J ) 7.5 Hz),
8.11 (dd, 1H, J ) 7.5 and 1.0 Hz), 8.22 (dd, 1H, J ) 7.5 and
1.0 Hz); 13C NMR (75 MHz, CDCl3) δ 13.6, 25.8, 33.8, 40.0,
41.0, 44.5, 52.7, 55.5, 55.8, 56.9, 76.4, 110.8, 111.5, 120.6, 127.2,
129.7, 130.1, 131.2, 132.6, 133.3, 135.5, 147.5, 148.5, 170.4,
171.9, 192.5. Anal. Calcd for C26H29NO6S: C, 64.58; H, 6.04;
N, 2.90. Found: C, 64.68; H, 6.07; N, 2.87.
The cyclization of 18 was also carried out using trifluoro-
acetic anhydride. To a solution of 250 mg (0.5 mmol) of
sulfoxide 18 and 101 mg (1.0 mmol) of triethylamine in 20 mL
of CH2Cl2 was added dropwise 116 mg (0.55 mmol) of trifluo-
roacetic anhydride at 0 °C. After stirring at rt for 10 min, the
mixture was filtered through a plug of silica gel, and the
solvent was removed under reduced pressure. The crude
product was dissolved in 10 mL of toluene, and after addition
of 94 mg (0.55 mmol) of p-TsOH, the solution was heated at
reflux for 1 h. Removal of the solvent under reduced pressure
followed by flash silica gel chromatography provided 147 mg
(70%) of 23. In addition, cycloadduct 13 (RdCO2Me) was
isolated as a colorless oil; IR (KBr) 1726, 1515, 1461, 1400,
1
1264, 1237 cm-1; H NMR (300 MHz, CDCl3) δ 1.29 (t, 3H, J
) 7.5 Hz), 2.31 (d, 1H, J ) 12.0 Hz), 2.64-3.07 (m, 7H), 3.31
(s, 3H), 3.57-3.67 (m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 3.91-
4.01 (m, 1H), 6.72-6.80 (m, 3H), 6.98 (dd, 1H, J ) 8.0 and 1.0
Hz), 7.27 (t, 1H, J ) 8.0 Hz), 7.40 (t, 1H, J ) 8.0 Hz), 7.45
(dd, 1H, J ) 8.0 and 1.0 Hz); 13C NMR (75 MHz, CDCl3) δ
15.1, 24.1, 34.4, 40.8, 43.8, 44.4, 52.3, 55.7, 55.8, 56.7, 92.3,
105.0, 111.1, 112.1, 119.2, 120.7, 121.3, 127.6, 128.8, 131.2,
138.0, 144.3, 147.5, 148.7, 171.2, 176.1; HRMS (FAB) Calcd
for C26H29NO6SLi (M + Li): 490.1876. Found: 490.1879.
N-(3,4-Dim eth oxyp h en eth yl)-N-[4-(m eth oxyca r bon yl)-
p en t-4-en oyl]-2-[(eth ylth io)m eth yl]ben za m id e. A mixture
of 2.2 g (6.0 mmol) of N-(3,4-dimethoxyphenethyl)-2-[(ethyl-
thio)methyl]benzamide, 1.6 g (9.0 mmol) of 4-(methoxycar-
bonyl)pent-4-enoyl chloride (prepared from the corresponding
acid),41 and 6.0 g of powdered molecular sieves (4 Å) in 40 mL
of CH2Cl2 was stirred at rt for 24 h. The reaction mixture
was filtered through a pad of silica gel, and the filtrate was
washed with an aqueous NaHCO3 solution. The organic layer
(39) Tsuda, Y.; Hosoi, S.; Nakai, A.; Sakai, Y.; Abe, T.; Ishi, Y.;
Kiuchi, F.; Sano, T. Chem. Pharm. Bull. 1991, 39, 1365.
(40) Achiwa, K.; Chaloner, P. A.; Parker, D. J . Organomet. Chem.
1987, 218, 249.
(41) Foote, C. S.; Kwon, B. M. J . Org. Chem. 1989, 54, 3878.

1152 J . Org. Chem., Vol. 63, No. 4, 1998
Padwa et al.
was dried over Na2SO4 and was concentrated under reduced
pressure. The crude residue was purified by flash silica gel
chromatography to 2.3 g (76%) of N-(3,4-dimethoxyphenethyl)-
N-[4-(methoxycarbonyl)pent-4-enoyl]-2-[(ethylthio)methyl]ben-
zamide as a colorless oil; IR (neat) 1714, 1691, 1652, 1510,
171.7; HRMS (FAB) Calcd for C27H31NO6SLi (M + Li):
504.2032. Found: 504.2049.
N-P h en et h yl-2-[(et h ylt h io)m et h yl]b en za m id e. To a
stirred suspension containing 3.0 g (15.2 mmol) of 2-[(eth-
ylthio)methyl]benzoic acid (10)22 in 30 mL of benzene was
added 5.4 g (45.4 mmol) of thionyl chloride. After stirring at
rt for 2 h, the solution was concentrated under reduced
pressure. The crude acid chloride was dissolved in 25 mL of
CH2Cl2, and 3.86 g (31.9 mmol) of phenethylamine was added
to the solution at 0 °C over a 10 min period. After stirring at
rt for 2 h, the mixture was poured into water and extracted
with CH2Cl2. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was puri-
fied by flash silica gel chromatography and recrystallized from
ethyl acetate/hexane to give 3.9 g (86%) of N-phenethyl-2-
[(ethylthio)methyl]benzamide as a white solid, mp 79-80 °C;
1
1438, 1348 cm-1; H NMR (300 MHz, CDCl3) δ 1.20 (t, 3H, J
) 7.5 Hz), 2.44 (q, 2H, J ) 7.5 Hz), 2.64 (q, 2H, J ) 7.2 Hz),
2.78-2.88 (m, 4H), 3.73 (s, 2H), 3.80 (s, 3H), 3.81-3.88 (m,
2H), 3.84 (s, 6H), 5.52 (s, 1H), 6.12 (s, 1H), 6.57-6.63 (m, 2H),
6.75 (d, 1H, J ) 8.1 Hz), 7.14-7.43 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 14.2, 25.9, 27.4, 33.0, 34.4, 37.4, 48.0, 51.7, 55.7, 55.8,
111.1, 111.9, 120.8, 125.7, 127.0, 127.6, 130.4, 130.7, 130.8,
135.5, 137.1, 138.9, 147.5, 148.8, 167.0, 173.2, 175.5; HRMS
Calcd for C27H33NO6S: 499.2028. Found: 499.2027.
N-(3,4-Dim eth oxyp h en eth yl)-N-[4-(m eth oxyca r bon yl)-
p en t-4-en oyl]-2-[(eth ylsu lfin yl)m eth yl]ben za m id e (19). A
1.7 g (3.4 mmol) sample of the above sulfide was oxidized in
the standard manner21 to give sulfoxide 19 (90%) as a colorless
oil; IR (neat) 1713, 1691, 1656, 1512, 1445, 1351 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.34 (t, 3H, J ) 7.5 Hz), 2.61-2.89 (m,
8H), 3.74 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 3.86-3.96 (m, 4H),
5.56 (s, 1H), 6.17 (s, 1H), 6.58-6.64 (m, 2H), 6.75 (d, 1H, J )
8.1 Hz), 7.21-7.49 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 6.6,
27.6, 34.5, 37.1, 45.5, 48.2, 51.8, 55.2, 55.7, 55.8, 111.1, 112.1,
121.0, 126.0, 127.8, 128.0, 130.5, 130.6, 131.2, 132.3, 135.5,
138.7, 147.7, 148.8, 167.0, 173.0, 175.4; HRMS (FAB) Calcd
for C27H33NO7SLi (M + Li): 522.2138. Found: 522.2159.
IR (neat) 3296, 1631, 1538, 1445, 1311 cm-1 1H NMR (300
;
MHz, CDCl3) δ 1.21 (t, 3H, J ) 7.5 Hz), 2.43 (q, 2H, J ) 7.5
Hz), 2.96 (t, 2H, J ) 6.9 Hz), 3.72 (q, 2H, J ) 6.9 Hz), 3.84 (s,
2H), 6.55 (brs, 1H), 7.21-7.42 (m, 9H); 13C NMR (75 MHz,
CDCl3) δ 14.4, 25.9, 33.6, 35.5, 41.0, 126.4, 127.2, 128.2, 128.5,
128.7, 129.8, 130.6, 135.8, 136.3, 138.8, 169.9. Anal. Calcd
for C18H21NOS: C, 72.21; H, 7.08; N, 4.68. Found: C, 72.21;
H, 7.09; N, 4.73.
N-P h en et h yl-N-[3-(m et h oxyca r b on yl)b u t -3-en oyl]-2-
[(eth ylth io)m eth yl]ben za m id e. A mixture of 2.1 g (7.0
mmol) of the above amide, 1.7 g (10.5 mmol) of 3-(methoxy-
carbonyl)but-3-enoyl chloride,40 and 5.5 g of powdered molec-
ular sieves (4 Å) in 40 mL of CH2Cl2 was stirred at rt for 24 h.
The reaction mixture was filtered through a pad of silica gel,
and the filtrate was washed twice with an aqueous NaHCO3
solution. The organic layer was dried over MgSO4 and was
concentrated under reduced pressure to give 2.1 g (69%) of
N-phenethyl-N-[3-(methoxycarbonyl)but-3-enoyl]-2-[(ethyl-
thio)methyl]benzamide as a colorless oil; IR (neat) 1721, 1692,
P u m m er er -In d u ced Rea ction of Su lfoxid e 19. A mix-
ture of 10 mL of toluene and 0.5 mL of acetic anhydride
containing 5 mg of p-toluenesulfonic acid was heated at reflux
under argon. To this solution was added dropwise a solution
of 257 mg (0.5 mmol) of sulfoxide 19 in 3 mL of toluene via
syringe over a 10 min period. After the addition was complete,
the solution was heated at reflux for an additional 5 min until
no sulfoxide was detected by TLC. The mixture was concen-
trated under reduced pressure, and the residue was dissolved
in 10 mL of toluene and, after addition of 85 mg (0.5 mmol) of
p-TsOH, was heated at reflux for 30 min. After evaporation
of the solvent under reduced pressure, the crude residue was
purified by flash silica gel chromatography and recrystallized
from CH2Cl2/hexane to give 144 mg (66%) of 25 as a white
solid, mp 170-171 °C; IR (neat) 1727, 1687, 1656, 1512, 1410,
1660, 1441, 1350, 1207 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.19 (t, 3H, J ) 7.5 Hz), 2.42 (q, 2H, J ) 7.5 Hz), 2.91 (t, 2H,
J ) 7.2 Hz), 3.71 (s, 2H), 3.77 (s, 3H), 3.81-3.85 (m, 4H), 5.66
(s, 1H), 6.32 (s, 1H), 7.05 (d, 2H, J ) 6.6 Hz), 7.17-7.43 (m,
7H); 13C NMR (75 MHz, CDCl3) δ 14.2, 25.9, 33.0, 34.7, 42.1,
48.2, 52.0, 126.4, 127.1, 127.6, 128.2, 128.4, 128.8, 130.6, 130.7,
134.7, 135.1, 137.2, 138.3, 166.7, 173.4, 173.7; HRMS Calcd
for C24H27NO4S: 425.1661. Found: 425.1659.
1
1262 cm-1; H NMR (300 MHz, CDCl3) δ 1.76 (t, 2H, J ) 7.5
N-P h en et h yl-N-[3-(m et h oxyca r b on yl)b u t -3-en oyl]-2-
[(eth ylsu lfin yl)m eth yl]ben za m id e (26). A 1.7 g (4.0 mmol)
sample of the above sulfide was oxidized in the standard
manner21 to give sulfoxide 26 (91%) as a colorless oil; IR (neat)
1718, 1690, 1658, 1442, 1351, 1268 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.34 (t, 3H, J ) 7.5 Hz), 2.62-2.96 (m, 4H), 3.62 (s,
2H), 3.76 (s, 3H), 3.81-3.96 (m, 4H), 5.69 (s, 1H), 6.32 (s, 1H),
7.06 (d, 2H, J ) 7.8 Hz), 7.19-7.50 (m, 7H); 13C NMR (75 MHz,
CDCl3) δ 6.7, 34.7, 41.8, 45.5, 48.4, 52.0, 55.0, 126.5, 128.0,
128.1, 128.5, 128.6, 129.0, 130.4, 131.3, 132.2, 134.4, 135.2,
138.1, 166.6, 173.2, 173.6; HRMS (FAB) Calcd for C24H27NO5-
SLi (M + Li): 448.1770. Found: 448.1790.
Hz), 2.45-2.64 (m, 3H), 2.71 (d, 1H, J ) 18.6 Hz), 2.75-2.84
(m, 1H), 3.03-3.12 (m, 1H), 3.49 (s, 3H), 3.52 (s, 3H), 3.53 (d,
1H, J ) 18.6 Hz), 3.86 (s, 3H), 5.32-5.39 (m, 1H), 6.16 (s, 1H),
6.66 (s, 1H). 7.31 (dd, 1H, J ) 7.8 and 0.9 Hz), 7.48 (t, 1H, J
) 7.8 Hz), 7.67 (t, 1H, J ) 7.8 Hz), 8.15 (dd, 1H, J ) 7.8 and
0.9 Hz); 13C NMR (75 MHz, CDCl3) δ 28.7, 29.1, 29.9, 40.8,
45.2, 52.4, 52.5, 55.8, 55.9, 66.1, 111.5, 113.0, 125.4, 125.9,
126.2, 128.5, 130.3, 131.9, 136.0, 145.8, 146.8, 148.2, 171.3,
172.1, 195.4. Anal. Calcd for C25H25NO6: C, 68.95; H, 5.79;
N, 3.22. Found: C, 69.00; H, 5.76; N, 3.16.
The Pummerer reaction of 19 was also carried out using
trifluoroacetic anhydride. To a solution of 257 mg (0.5 mmol)
of sulfoxide 19 and 0.1 g (1.0 mmol) of triethylamine in 10 mL
of CH2Cl2 was added dropwise 146 mg (0.7 mmol) of trifluo-
roacetic anyhydride at 0 °C. After stirring at rt for 5 min, the
mixture was filtered through a plug of silica gel, and the
solvent removed under reduced pressure. The crude product
was dissolved in 10 mL of toluene, and, after addition of 85
mg (0.5 mmol) of p-TsOH, the solution was heated at reflux
for 1 h. Evaporation of the solvent under reduced pressure
followed by flash silica gel chromatography provided 139 mg
(64%) of 25. In addition, cycloadduct 24 was isolated as a
P u m m er er -In d u ced Rea ction of Su lfoxid e 26. A mix-
ture of 10 mL of toluene and 0.5 mL of acetic anhydride
containing 5 mg of p-toluenesulfonic acid was heated to reflux
under argon. To this mixture was added dropwise a solution
of 0.21 g (0.47 mmol) of sulfoxide 26 in 3 mL of toluene via
syringe over a 10 min period. After the addition was complete,
the solution was heated at reflux for an additional 10 min until
no sulfoxide was detected by TLC. The mixture was concen-
trated under reduced pressure, and the crude residue was
purified by flash silica gel chromatography and recrystallized
from CH2Cl2/hexane to afford 65 mg (36%) of N,O-ketal 28 as
a white solid, mp 134-135 °C; IR (neat) 3322, 1741, 1688,
colorless oil; IR (neat) 1734, 1668, 1515, 1461, 1397, 1345 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J ) 7.5 Hz), 2.18 (d,
1H, J ) 12 Hz), 2.20-2.58 (m, 2H), 2.47 (d, 1H, J ) 12 Hz),
2.63-2.88 (m, 5H), 3.07 (dt, 1H, J ) 12 and 5.1 Hz), 3.39 (dt,
1H, J ) 12 and 5.1 Hz), 3.45 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H),
1
1403, 1291, 1205 cm-1; H NMR (300 MHz, CDCl3) δ 2.40 (d,
1H, J ) 16.5 Hz), 2.41-2.60 (m, 2H), 2.61 (d, 1H, J ) 17.1
Hz), 3.01 (d, 1H, J ) 17.1 Hz), 3.30 (d, 1H, J ) 16.5 Hz), 3.41-
3.65 (m, 2H), 3.66 (s, 3H), 4.20 (s, 1H), 6.84-6.87 (m, 2H),
7.11-7.13 (m, 3H), 7.56 (t, 1H, J ) 7.8 Hz), 7.78 (t, 1H, J )
7.8 Hz), 7.98-8.05 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 34.5,
39.5, 40.7, 45.0, 53.2, 54.3, 88.6, 126.4, 127.1, 127.9, 128.4,
128.5, 129.8, 130.9, 134.2, 138.0, 139.0, 172.4, 173.2, 192.5.
4.09-4.19 (m, 1H), 6.62-6.74 (m, 3H), 7.20-7.37 (m, 4H); 13
C
NMR (75 MHz, CDCl3) δ 15.4, 24.1, 29.4, 30.2, 34.5, 47.2, 48.4,
51.9, 53.9, 55.6, 55.7, 89.9, 99.4, 111.0, 111.9, 119.7, 120.4,
122.4, 127.1, 128.4, 132.0, 140.1, 144.8, 147.2, 148.6, 170.8,

Construction of the Erythrinane Skeleton
J . Org. Chem., Vol. 63, No. 4, 1998 1153
Anal. Calcd for C22H21NO5: C, 69.65; H, 5.58; N, 3.69.
Found: C, 69.48; H, 5.61; N, 3.63.
134.5, 134.8, 136.2, 166.7, 173.2, 173.7; HRMS (FAB) Calcd
for C26H28N2O5SLi (M + Li): 487.1879. Found: 487.1895.
2-[[[2-[6-(E t h ylt h io)-11-oxo-5,11-d ih yd r ob en zo[b]ca r -
ba zol-11a -yl]eth yl]ca r ba m oyl]m eth yl]a cr ylic Acid Meth -
yl Ester (31). The reaction of 190 mg (0.4 mmol) of sulfoxide
29 with acetic anhydride following the general procedure21
gave rise to a 5:1 mixture of 31 and 2-[[[2-(5-acetyl-6-(eth-
ylthio)-11-oxo-5,11-dihydrobenzo[b]carbazol-11a-yl)ethyl]car-
bamoyl]methyl]acrylic acid methyl ester (32) which were
separated by silica gel chromatography.
The cyclization of 26 was also carried out using trifluoro-
acetic anhydride. To a solution of 255 mg (0.58 mmol) of
sulfoxide 26 and 117 mg (1.16 mmol) of triethylamine in 10
mL of CH2Cl2 was added dropwise 180 mg (0.85 mmol) of
trifluoroacetic anyhdride at 0 °C. After stirring at rt for 5 min,
the solution was concentrated under reduced pressure. The
crude residue was purified by flash silica gel chromatography
and recrystallized from CH2Cl2/hexane to give 144 mg (59%)
of cycloadduct 27 as a pale yellow solid, mp 86-87 °C; IR (neat)
1725, 1458, 1393, 1302, 1198 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.29 (t, 3H, J ) 7.5 Hz), 2.30 (d, 1H, J ) 12.0 Hz), 2.66 (d,
1H, J ) 12.0 Hz), 2.67-2.80 (m, 2H), 2.73 (d, 1H, J ) 16.5
Hz), 2.98 (d, 1H, J ) 16.5 Hz), 3.00-3.11 (m, 2H), 3.33 (s, 3H),
3.59-3.69 (m, 1H), 3.89-4.00 (m, 1H), 6.88 (d, 1H, J ) 7.2
Hz), 7.20-7.45 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 15.2, 24.2,
34.9, 40.9, 43.8, 49.6, 52.4, 56.8, 92.4, 105.1, 119.3, 121.4, 126.4,
127.8, 128.4, 128.5, 128.9, 138.0, 138.8, 144.3, 171.4, 176.3.
Anal. Calcd for C24H25NO4S: C, 68.06; H, 5.95; N, 3.31.
Found: C, 67.95; H, 5.94; N, 3.37.
Cycloadduct 31 (58%): IR (neat) 3318, 1721, 1676, 1456,
1
1331, 1213 cm-1; H NMR (300 MHz, CDCl3) δ 1.20 (t, 3H, J
) 7.5 Hz), 2.05 (q, 2H, J ) 7.5 Hz), 2.61 (t, 2H, J ) 7.2 Hz),
3.00 (s, 2H), 3.06-3.10 (m, 1H), 3.28-3.35 (m, 1H), 3.71 (s,
3H), 5.70 (s, 1H), 5.76 (brs, 1H, exchangeable with D2O), 6.24
(s, 1H), 6.87 (d, 1H, J ) 7.8 Hz), 7.00 (t, 1H, J ) 7.8 Hz), 7.16-
7.24 (m, 2H), 7.32 (brs, 1H), 7.56 (dt, 1H, J ) 8.1 and 1.2 Hz),
7.76 (d, 1H, J ) 8.1 Hz), 7.84 (d, 1H, J ) 7.5 Hz), 7.90 (dd,
1H, J ) 7.5 and 1.2 Hz); 13C NMR (75 MHz, CDCl3) δ 14.9,
28.0, 35.4, 39.8, 42.3, 52.1, 60.4, 93.4, 109.4, 120.8, 124.2, 124.7,
125.6, 126.0, 127.4, 128.5, 128.6, 129.0, 133.8, 134.8, 140.6,
144.3, 160.3, 167.0, 169.3, 199.4; HRMS (FAB) Calcd for
C26H26N2O4SLi (M + Li): 469.1773. Found: 469.1795.
Cycloadduct 32 (11%): IR (neat) 3310, 1717, 1681, 1654,
N-[2-(1H -In d ol-3-yl)et h yl]-2-[(et h ylt h io)m et h yl]b en z-
a m id e. To a stirred suspension containing 1.12 g (5.7 mmol)
of 2-[(ethylthio)methyl]benzoic acid (10) in 20 mL of dry
benzene was added 1.47 g (12 mmol) of thionyl chloride. After
stirring at rt for 2 h, the solution was concentrated under
reduced pressure. The crude acid chloride was dissolved in
20 mL of CH2Cl2, and 2.01 g (12.5 mmol) of tryptamine was
added over a 10 min period at 0 °C. After stirring at rt for 2
h, the mixture was poured into water and extracted with CH2-
Cl2. The organic layer was dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography and recrystallized from ethyl acetate/
hexane to give 1.45 g (76%) of N-[2-(1H-indol-3-yl)ethyl]-2-
[(ethylthio)methyl]benzamide as a white solid, mp 68-69 °C;
1
1453, 1332, 1268 cm-1; H NMR (300 MHz, CDCl3) δ 0.93 (t,
3H, J ) 7.5 Hz), 1.99-2.05 (m, 2H), 2.41 (q, 2H, J ) 7.5 Hz),
2.49 (s, 3H), 3.02 (s, 2H), 3.08-3.16 (m, 2H), 3.72 (s, 3H), 5.72
(s, 1H), 5.84 (brs, 1H, exchangeable with D2O), 6.25 (s, 1H),
7.20 (t, 1H, J ) 7.2 Hz), 7.33 (t, 1H, J ) 7.8 Hz), 7.43 (t, 1H,
J ) 7.2 Hz), 7.71 (t, 1H, J ) 7.8 Hz), 7.95-8.03 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 14.1, 25.0, 28.0, 35.3, 39.9, 40.0, 52.2,
58.2, 116.3, 124.6, 125.1, 127.4, 127.6, 128.2, 128.5, 128.9,
129.1, 133.7, 135.0, 136.7, 143.2, 167.1, 169.4, 169.7, 197.6;
HRMS Calcd for C28H28N2O5S: 504.1719. Found: 504.1741.
N-[2-(N-Tosylin d ol-3-yl)et h yl]-2-[(et h ylt h io)m et h yl]-
ben za m id e. To a stirred solution of 0.5 g (1.5 mmol) of amide
N-[2-(1H-indol-3-yl)ethyl]-2-[(ethylthio)methyl]benzamide and
51 mg (0.15 mmol) of tetrabutylammonium hydrogen sulfate
in 15 mL of benzene was added 5 mL of a 50% aqueous NaOH
solution. After stirring for 5 min, a solution of 0.35 g (1.84
mmol) of p-toluenesulfonyl chloride in 8 mL of benzene was
added dropwise over a 10 min period. The mixture was stirred
at rt for 1 h and washed with water, and the aqueous phase
was extracted with benzene. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The crude
residue was purified by flash silica gel chromatography to give
0.66 g (90%) of N-[2-(N-tosylindol-3-yl)ethyl]-2-[(ethylthio)-
methyl]benzamide as a colorless oil; IR (neat) 3296, 1649, 1529,
1
IR (neat) 3404, 3296, 1640, 1528, 1457, 1309 cm-1; H NMR
(300 MHz, CDCl3) δ 1.15 (t, 3H, J ) 7.5 Hz), 2.36 (q, 2H, J )
7.5 Hz), 3.09 (t, 2H, J ) 6.6 Hz), 3.79 (q, 2H, J ) 6.6 Hz), 3.83
(s, 2H), 6.61 (brs, 1H), 7.02-7.64 (m, 9H), 8.36 (brs, 1H); 13C
NMR (75 MHz, CDCl3) δ 14.4, 25.2, 26.0, 33.6, 40.1, 111.2,
112.7, 118.6, 119.3, 122.0, 122.2, 127.2, 127.3, 128.2, 129.8,
130.6, 135.8, 136.4, 169.4. Anal. Calcd for C20H22N2OS: C,
70.97; H, 6.55; N, 8.28. Found: C, 70.86; H, 6.62; N, 8.27.
N-[2-(1H-In d ol-3-yl)eth yl]-N-[(m eth oxyca r bon yl)bu t-3-
en oyl]-2-[(eth ylth io)m eth yl]ben za m id e. A mixture of 2.96
g (8.8 mmol) of the above amide, 2.15 g (13.2 mmol) of
3-(methoxycarbonyl)but-3-enoyl chloride,40 and 8.5 g of pow-
dered molecular sieves (4 Å) in 60 mL of CH2Cl2 was stirred
at rt for 24 h. The reaction mixture was filtered through a
pad of silica gel, and the filtrate was washed with an aqueous
NaHCO3 solution. The organic layer was dried over MgSO4
and was concentrated under reduced pressure. The crude
residue was purified by flash silica gel chromatography to give
2.54 g (63%) of N-[2-(1H-indol-3-yl)ethyl]-N-[(methoxycarbo-
nyl)but-3-enoyl]-2-[(ethylthio)methyl]benzamide as a colorless
1
1448, 1367, 1173 cm-1; H NMR (300 MHz, CDCl3) δ 1.17 (t,
3H, J ) 7.5 Hz), 2.27 (s, 3H), 2.39 (q, 2H, J ) 7.5 Hz), 3.01 (t,
2H, J ) 6.9 Hz), 3.24 (q, 2H, J ) 6.9 Hz), 3.82 (s, 2H), 6.68
(brs, 1H), 7.07 (d, 2H, J ) 8.1 Hz), 7.20-7.42 (m, 6H), 7.46 (s,
1H), 7.53-7.71 (m, 3H), 7.98 (d, 1H, J ) 8.1 Hz); 13C NMR
(75 MHz, CDCl3) δ 14.3, 21.4, 25.0, 25.9, 33.6, 39.1, 113.7,
119.4, 119.7, 123.1, 123.5, 124.8, 126.6, 127.2, 128.3, 129.7,
129.8, 130.5, 130.6, 135.0, 135.2, 135.9, 136.1, 144.7, 169.4;
HRMS (FAB) Calcd for C27H29N2O3S2 (M + H): 493.1620.
Found: 493.1622.
oil; IR (neat) 3396, 1711, 1697, 1654, 1439, 1352, 1209 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.15 (t, 3H, J ) 7.5 Hz), 2.38 (q,
2H, J ) 7.5 Hz), 3.05 (t, 2H, J ) 7.2 Hz), 3.76 (s, 3H), 3.77 (s,
4H), 3.87 (t, 2H, J ) 7.2 Hz), 5.66 (s, 1H), 6.33 (s, 1H), 6.90-
7.41 (m, 9H), 8.15 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2,
24.4, 25.8, 32.9, 42.2, 47.4, 52.0, 111.0, 112.2, 118.6, 119.2,
121.9, 122.4, 127.1, 127.2, 127.7, 128.3, 130.5, 130.7, 134.8,
135.1, 136.1, 137.1, 166.8, 173.7, 173.9; HRMS Calcd for
N-[2-(N-Tosylin d ol-3-yl)et h yl]-N-[3-(m et h oxyca r b on -
yl)bu t-3-en oyl]-2-[(eth ylth io)m eth yl]ben za m id e. A mix-
ture of 1.3 g (2.6 mmol) of the above amide, 0.64 g (3.9 mmol)
of 3-(methoxycarbonyl)but-3-enoyl chloride,40 and 3.1 g of
powdered molecular sieves (4 Å) in 20 mL of CH2Cl2 was
stirred for 24 h at rt. The reaction mixture was filtered
through a pad of silica gel, and the filtrate was washed with
an aqueous NaHCO3 solution. The organic layer was dried
over MgSO4 and was concentrated under reduced pressure.
The resulting crude oil was purified by flash silica gel
chromatography to give 1.3 g (77%) of N-[2-(N-tosylindol-3-
yl)ethyl]-N-[3-(methoxycarbonyl)but-3-enoyl]-2-[(ethylthio)m-
ethyl]benzamide as a colorless oil; IR (neat) 1718, 1696, 1656,
1438, 1359, 1169 cm -1; 1H NMR (300 MHz, CDCl3) δ 1.15 (t,
3H, J ) 7.5 Hz), 2.31 (s, 3H), 2.38 (q, 2H, J ) 7.5 Hz), 2.98 (t,
2H, J ) 7.2 Hz), 3.70 (s, 2H), 3.78 (s, 3H), 3.81-3.86 (m, 4H),
5.68 (s, 1H), 6.33 (s, 1H), 7.10-7.42 (m, 10H), 7.70 (d, 2H, J )
C
26H28N2O4S: 464.1770. Found: 464.1774.
N-[2-(1H-In d ol-3-yl)eth yl]-N-[3-(m eth oxyca r bon yl)bu t-
3-en oyl]-2-[(eth ylsu lfin yl)m eth yl]ben za m id e (29). A 2.44
g (5.3 mmol) sample of the above sulfide was oxidized in the
standard manner21 to afford sulfoxide 29 (74%) as a clear oil:
1
IR (neat) 3385, 1709, 1680, 1651, 1439, 1353, 1209 cm-1; H
NMR (300 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.5 Hz), 2.52-2.70
(m, 2H), 2.99-3.11 (m, 2H), 3.50 (brs, 2H), 3.67 (s, 2H), 3.75
(s, 3H), 3.82-4.00 (m, 2H), 5.66 (s, 1H), 6.31 (s, 1H), 6.86-
7.43 (m, 9H), 8.79 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 6.7,
24.4, 41.7, 45.2, 47.8, 52.0, 54.8, 111.2, 111.5, 118.3, 119.2,
121.7, 123.0, 127.0, 127.9, 128.0, 128.5, 130.5, 131.1, 132.0,

1154 J . Org. Chem., Vol. 63, No. 4, 1998
Padwa et al.
8.1 Hz), 7.92 (d, 1H, J ) 8.1 Hz); 13C NMR (75 MHz, CDCl3)
δ 14.4, 21.6, 24.3, 26.1, 33.2, 42.4, 46.5, 52.2, 113.7, 119.3,
119.7, 123.2, 123.8, 124.8, 126.9, 127.4, 127.8, 128.5, 129.9,
130.7, 130.8, 131.0, 134.9, 135.1, 135.2, 135.3, 137.6, 144.9,
166.9, 173.6, 174.1; HRMS (FAB) Calcd for C33H35N2O6S2 (M
+ H): 619.1937. Found: 619.1930.
separated, dried over MgSO4, and concentrated under reduced
pressure. The crude amide was purified by flash silica gel
chromatography and recrystallized from CH2Cl2/hexane to give
2.9 g (68%) of amide 36 as a white solid, mp 72-73 °C; IR
(neat) 3302, 1654, 1517, 1452, 1256, 1146 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.21 (t, 3H, J ) 7.5 Hz), 2.52 (q, 2H, J )
7.5 Hz), 2.75 (t, 2H, J ) 6.9 Hz), 3.39 (s, 2H), 3.49 (q, 2H, J )
6.9 Hz), 3.54 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 5.12 (s, 1H),
5.85 (brs, 1H), 6.71-6.82 (m, 3H); 13C NMR (75 MHz, CDCl3)
δ 14.5, 29.5, 35.1, 39.9, 40.7, 55.1, 55.8, 55.9, 92.9, 111.3, 111.9,
120.6, 131.3, 147.6, 148.9, 157.7, 168.4. Anal. Calcd for
N-[2-(N-Tosylin d ol-3-yl)eth yl]-N-[3-(m eth oxyca r bon yl-
)bu t-3-en oyl]-2-[(eth ylsu lfin yl)m eth yl]ben za m id e (33). A
0.93 g (1.50 mmol) sample of the above sulfide was oxidized
in the standard manner21 to give sulfoxide 33 as a colorless
oil (78%); IR (neat) 1719, 1684, 1648, 1452, 1347, 1262 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J ) 7.5 Hz), 2.31 (s,
3H), 2.62-3.08 (m, 4H), 3.62 (s, 2H), 3.78 (s, 3H), 3.81-4.00
(m, 4H), 5.71 (s, 1H), 6.33 (s, 1H), 7.10-7.51 (m, 10H), 7.72
(d, 2H, J ) 8.1 Hz), 7.94 (d, 1H, J ) 8.1 Hz); 13C NMR (75
MHz, CDCl3) δ 7.0, 21.7, 24.4, 42.2, 45.9, 46.9, 52.3, 55.0, 113.8,
119.0, 119.6, 123.4, 124.2, 124.9, 127.0, 128.3, 128.4, 128.9,
130.1, 130.6, 131.0, 131.7, 132.7, 134.7, 135.0, 135.2, 135.3,
145.1, 166.9, 173.4, 174.1; HRMS (FAB) Calcd for C33H35N2O7S2
(M + H): 635.1886. Found: 635.1914.
C17H25NO4S: C, 60.15; H, 7.42; N, 4.13. Found: C, 59.93; H,
7.36; N, 4.22.
Met h yl 2-[2-[N-[2-(3,4-Dim et h oxyp h en et h yl)-4-(et h -
ylth io)-3-m eth oxybu t-2-en oyl]a m in o]-2-oxoeth yl]p r op -2-
en oa te. A mixture containing 730 mg (2.15 mmol) of amide
36, 525 mg (3.23 mmol) of 3-(methoxycarbonyl)but-3-enoyl
chloride,40 and 25 mL of benzene was heated at reflux for 24
h. After cooling, the reaction mixture was washed with a 10%
NaOH solution, and the organic layer was separated, dried
over MgSO4, and concentrated under reduced pressure. The
crude oil was purified by flash silica gel chromatography to
give 902 mg (90%) of methyl 2-[2-[N-[2-(3,4-dimethoxyphen-
ethyl)-4-(ethylthio)-3-methoxybut-2-enoyl]amino]-2-oxoethyl]-
prop-2-enoate as a yellow oil; IR (neat) 1717, 1681, 1645, 1595,
P u m m er er -In d u ced Rea ction of Su lfoxid e 33. To a
solution of 120 mg (0.19 mmol) of sulfoxide 33 and 60 µL (0.43
mmol) of triethylamine in 10 mL of CH2Cl2 was added
dropwise 52 µL (0.29 mmol) of trimethylsilyl trifluoromethane-
sulfonate at 0 °C. After stirring at rt for 5 min, the solution
was concentrated under reduced pressure. The residue was
purified by flash silica gel chromatography to give 83 mg (71%)
1
1509, 1258 cm-1; H NMR (CDCl3, 300 MHz) δ 1.26 (t, 3H, J
) 7.5 Hz), 2.63 (q, 2H, J ) 7.5 Hz), 2.86 (t, 2H, J ) 7.2 Hz),
3.59 (s, 3H), 3.69 (s, 2H), 3.72 (s, 2H), 3.76 (s, 3H), 3.85 (s,
3H), 3.87 (s, 3H), 3.91 (t, 2H, J ) 7.2 Hz), 5.30 (s, 1H), 5.66 (s,
1H), 6.32 (s, 1H), 6.76-6.84 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 14.6, 26.6, 31.5, 34.4, 41.8, 47.2, 51.9, 55.6, 55.7, 55.8,
94.1, 111.3, 112.3, 120.8, 128.0, 131.3, 134.9, 147.6, 149.0,
166.8, 169.5, 173.4, 174.1; HRMS (FAB) Calcd for C23H31NO7-
SLi (M + Li): 472.1981. Found: 472.2001.
1
of cycloadduct 34; IR (neat) 1726, 1441, 1362, 1171 cm-1; H
NMR (300 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.5 Hz), 2.30 (s,
3H), 2.64-2.78 (m, 4H), 2.70 (d, 1H, J ) 16.5 Hz), 2.95 (d,
1H, J ) 16.5 Hz), 2.98-3.10 (m, 2H), 3.31 (s, 3H), 3.58-3.68
(m, 1H), 4.03-4.13 (m, 1H), 7.02 (d, 1H, J ) 7.5 Hz), 7.13-
7.45 (m, 9H), 7.71 (d, 2H, J ) 8.1 Hz), 7.93 (d, 1H, J ) 8.1
Hz); 13C NMR (75 MHz, CDCl3) δ 15.2, 21.5, 24.2, 24.3, 40.9,
41.4, 44.4, 52.4, 56.8, 92.5, 104.9, 113.6, 119.2, 119.4, 119.5,
121.5, 123.0, 123.2, 124.7, 126.7, 127.8, 129.0, 129.8, 130.6,
135.1, 135.2, 137.8, 144.3, 144.7, 171.3, 176.2; HRMS (FAB)
Calcd for C33H33N2O6S2 (M + H): 617.1776. Found: 617.1780.
N-[2-(3,4-Dim eth oxyp h en eth yl)]-4-(eth ylth io)-3-m eth -
oxy-2-bu ten a m id e (36). To a solution containing 14.0 g (0.25
mol) of KOH in 60 mL of water was added 15 mL (0.20 mol) of
ethanethiol at 0 °C. After stirring for 10 min, a solution of
37.6 g (0.18 mol) of methyl 4-bromo-3-methoxybut-2-enoate
(35)34 in 40 mL of ether was added, and the biphasic mixture
was warmed to rt. After stirring vigorously at rt for 20 h, the
organic layer was separated, dried over MgSO4, and concen-
trated under reduced pressure. The crude product was
distilled to give 30.4 g (89%) of methyl 4-(ethylthio)-3-methoxy-
2-butenoate as a colorless liquid, bp 88-90 °C (0.2 mm); IR
Meth yl 2-[2-[N-[2-(3,4-Dim eth oxyp h en eth yl)-4-(eth yl-
su lfin yl)-3-m eth oxybu t-2-en oyl]a m in o]-2-oxoeth yl]p r op -
2-en oa te (37). A 698 mg (1.50 mmol) sample of the above
sulfide was oxidized in the standard manner21 to give sulfoxide
37 (92%) as a colorless oil; IR (neat) 1720, 1675, 1642, 1597,
1
1512, 1447 cm-1; H NMR (CDCl3, 300 MHz) δ 1.38 (t, 3H, J
) 7.5 Hz), 2.79-2.89 (m, 4H), 3.61 (s, 3H), 3.67 (s, 2H), 3.77
(s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.92 (d, 1H, J ) 12 Hz), 3.93
(m, 2H), 4.16 (d, 1H, J ) 12 Hz), 5.55 (s, 1H), 5.66 (s, 1H),
6.33 (s, 1H), 6.76-6.84 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
6.5, 34.5, 41.8, 46.4, 47.2, 52.0, 55.1, 55.8, 55.9, 56.2, 97.6,
111.4, 112.4, 120.9, 128.3, 131.2, 134.7, 147.7, 149.0, 166.6,
166.8, 169.4, 173.5; HRMS (FAB) Calcd for C23H31NO8SLi (M
+ Li): 488.1950. Found: 488.1930.
Meth yl 11-(Eth ylth io)-7,8-dim eth oxy-2,12-dioxo-1,4,5,12,
13,13a-h exah ydr o-2H-in dolo[7a,1-a ]isoqu in olin e-13a-car -
boxyla te (38). To a solution of 286 mg (0.59 mmol) of
sulfoxide 37 and 120 mg (1.18 mmol) of triethylamine in 10
mL of CH2Cl2 was added dropwise 186 mg (0.89 mmol) of
trifluoroacetic anhydride at -78 °C. After stirring for 10 min,
254 mg (1.79 mmol) of boron trifluoride etherate was added,
and the mixture was warmed to rt. After stirring for 30 min
at rt, the solution was heated to reflux for an additional 20 h.
The reaction mixture was poured into water and extracted
with CH2Cl2. The combined organic layer was dried over
MgSO4 and concentrated under reduced pressure, and the
crude product was purified by flash silica gel chromatography
and recrystallized from CH2Cl2/hexane to give 211 mg (83%)
of 38 as a white solid, mp 187-188 °C; IR (neat) 1730, 1687,
1
(neat) 1713, 1623 cm-1; H NMR (CDCl3, 300 MHz) δ 1.27 (t,
3H, J ) 7.5 Hz), 2.63 (q, 2H, J ) 7.5 Hz), 3.69 (s, 6H), 3.85 (s,
2H), 5.08 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.6, 26.3, 30.6,
50.9, 55.7, 91.1, 167.5, 172.7; HRMS Calcd for C8H1403S:
190.0664. Found: 190.0662.
A mixture containing 12.0 g (63 mmol) of the above ester,
9.3 g (65 mmol) of potassium trimethylsilanolate (ca. 90%
purity, Aldrich), and 150 mL of ether was stirred for 16 h at
rt. The white precipitate that formed was filtered, dissolved
in 20 mL of water, and acidified with 2 N HCl. The aqueous
solution was extracted with chloroform, and the organic layer
was separated, dried over MgSO4, and concentrated under
reduced pressure to give 4-(ethylthio)-3-methoxy-2-butenoic
acid as a yellow liquid which was used without purification in
the next step; IR (neat) 1712, 1614 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.23 (t, 3H, J ) 7.5 Hz), 2.55 (q, 2H, J ) 7.5 Hz), 3.59
(s, 2H), 3.63 (s, 3H), 5.21 (s, 1H), 10.6 (brs, 1H); 13C NMR (75
MHz, CDCl3) δ 14.5, 29.5, 37.3, 55.2, 92.9, 156.9, 176.2; HRMS
Calcd for C7H12O3S: 176.0507. Found: 176.0508.
To a solution containing 2.18 g (12.4 mmol) of the above
carboxylic acid and 30 mL of CH2Cl2 was added 2.54 g (15.7
mmol) of 1,1′-carbonyldiimidazole. After stirring for 2 h at
rt, 4.4 mL (26.0 mmol) of 3,4-dimethoxyphenethylamine was
added, and the mixture was stirred for an additional 3 h. The
solution was poured into water, washed with saturated NH4-
Cl, and extracted with chloroform. The organic layer was
1
1509, 1346, 1260 cm-1; H NMR (CDCl3, 300 MHz) δ 1.28 (t,
3H, J ) 7.5 Hz), 2.54 (d, 1H, J ) 16.5 Hz), 2.61-2.70 (m, 3H),
2.77 (d, 1H, J ) 16.5 Hz), 2.81-2.85 (m, 1H), 2.92 (d, 1H, J )
17.7 Hz), 2.99-3.07 (m, 1H), 3.29 (s, 3H), 3.58 (d, 1H, J )
17.7 Hz), 3.82 (s, 3H), 3.87 (s, 3H), 4.46-4.52 (m, 1H), 6.15 (s,
1H), 6.59 (s, 1H), 6.63 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
12.9, 24.5, 28.1, 35.6, 40.7, 41.0, 52.2, 52.7, 55.9, 56.3, 64.8,
109.6, 111.9, 124.0, 127.7, 135.0, 135.2, 148.0, 149.0, 170.3,
171.0, 192.3. Anal. Calcd for C22H25NO6S: C, 61.24; H, 5.84;
N, 3.25. Found: C, 60.98; H, 5.86; N, 3.10.
When the above reaction was quenched before heating at
reflux for 20 h, N,O-ketal 45 was isolated in 51% yield as a

Construction of the Erythrinane Skeleton
J . Org. Chem., Vol. 63, No. 4, 1998 1155
white solid, mp 158-159 °C (CH2Cl2/hexane); IR (neat), 1738,
300 MHz) δ 1.26 (t, 3H, J ) 7.5 Hz), 2.56-3.09 (m, 7H), 3.22
(s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 4.39-4.45 (m, 1H), 5.45 (s,
1H), 5.97 (d, 1H, J ) 10.2 Hz), 6.33 (d, 1H, J ) 10.2 Hz), 6.51
(s, 1H), 6.79 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 13.7, 25.2,
27.9, 35.5, 43.9, 51.8, 53.6, 55.8, 56.0, 66.4, 109.3, 110.8, 121.2,
123.3, 125.7, 127.0, 127.5, 128.7, 147.7, 148.6, 171.0, 172.2;
HRMS Calcd for C22H25NO5S: 415.1453. Found: 415.1440.
Meth yl 7,8-Dim eth oxy-2,11-dioxo-1,4,5,10,11,13a-h exah y-
d r o-2H-in d olo[7a ,1-a ]isoqu in olin e-13a -ca r boxyla te (47).
To a solution containing 20 µL (0.18 mmol) of TiCl4 in 3 mL of
acetic acid was added 35 mg (0.08 mmol) of vinyl sulfide 46 in
1 mL of acetic acid. After stirring for 30 min at rt, 3 mL of
water was added, and the mixture was stirred for an additional
24 h. The solution was washed with a saturated NaHCO3
solution and extracted with ethyl acetate. The organic layer
was dried over MgSO4 and concentrated under reduced pres-
sure, and the crude product was purified by flash silica gel
chromatography to furnish 17 mg (54%) of 47 as a white solid,
mp 203-204 °C (ethanol) (lit.39 mp 206-207 °C); IR (neat)
1734, 1700, 1686, 1512, 1415, 1252 cm-1; 1H NMR (CDCl3, 300
MHz) δ 2.63-2.67 (m, 1H), 2.80 (d, 1H, J ) 16.4 Hz), 2.81-
2.83 (m, 1H), 2.86 (d, 1H, J ) 15.6 Hz), 3.01 (d, 1H, J ) 16.4
Hz), 3.04-3.07 (m, 1H), 3.16 (d, 1H, J ) 15.6 Hz), 3.26 (s, 3H),
3.69 (s, 3H), 3.84 (s, 3H), 4.39-4.43 (m, 1H), 6.40 (d, 1H, J )
10.4 Hz), 6.50 (s, 1H), 6.56 (s, 1H), 7.25 (d, 1H, J ) 10.4 Hz);
13C NMR (75 MHz, CDCl3) δ 28.0, 35.2, 41.7, 50.2, 52.3, 53.1,
55.7, 55.8, 66.4, 107.7, 111.6, 126.1, 127.7, 127.8, 147.2, 147.5,
148.4, 168.6, 171.2, 194.9.
1
1672, 1510, 1260 cm-1; H NMR (CDCl3, 300 MHz) δ 1.35 (t,
3H, J ) 7.5 Hz), 2.32 (d, 1H, J ) 17.1 Hz), 2.51 (d, 1H, J )
16.2 Hz), 2.61-2.94 (m, 5H), 3.15 (d, 1H, J ) 17.1 Hz), 3.48-
3.69 (m, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.92 (s,
1H, exchangeable with D2O), 6.02 (s, 1H), 6.70-6.77 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 12.7, 24.4, 29.9, 34.8, 39.0, 41.2,
43.7, 53.2, 53.3, 55.8, 87.7, 111.2, 111.9, 120.7, 129.7, 130.7,
140.0, 147.8, 148.9, 171.7, 171.9, 191.1. Anal. Calcd for
C
22H27NO7S: C, 58.78; H, 6.05; N, 3.12. Found: C, 58.72; H,
6.11; N, 3.07.
Met h yl 11-(E t h ylt h io)-7,8-d im et h oxy-2-oxo-12-[[(t r i-
flu or om e t h yl)su lfon yl]oxy]-1,4,5,13a -t e t r a h yd r o-2H -
in d olo[7a ,1-a ]isoqu in olin e-13a -ca r boxyla te. To a solution
of 100 mg (0.88 mmol) of KH (35% dispersion in mineral oil)
in 5 mL of THF was added 187 mg (0.43 mmol) of enone 38 in
5 mL of THF at rt. After stirring for 20 min, a solution
containing 315 mg (0.88 mmol) of N-phenyltrifluoromethane-
sulfonimide in 5 mL of THF was added, and stirring was
continued for an additional 30 min. Water (3 mL) was added
slowly to the mixture, and the aqueous layer was extracted
with chloroform. The combined organic layer was dried over
MgSO4 and concentrated under reduced pressure, the crude
product was purified by flash silica gel chromatography to yield
107 mg (70%) of methyl 11-(ethylthio)-7,8-dimethoxy-2-oxo-
12-[[(trifluoromethyl)sulfonyl]oxy]-1,4,5,13a-tetrahydro-2H-in-
dolo-[7a,1-a]isoquinoline-13a-carboxylate; IR (neat) 1733, 1698,
1
1510, 1420, 1211 cm-1; H NMR (CDCl3, 300 MHz) δ 1.28 (t,
3H, J ) 7.5 Hz), 2.55-3.08 (m, 7H), 3.25 (s, 3H), 3.80 (s, 3H),
3.84 (s, 3H), 4.42-4.48 (m, 1H), 5.70 (s, 1H), 6.35 (s, 1H), 6.53
(s, 1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 13.2, 26.5,
27.8, 35.7, 43.2, 52.3, 54.1, 55.7, 56.0, 66.1, 108.6, 111.0, 118.7,
125.0, 125.2, 125.8, 128.0, 143.8, 148.2, 149.0, 170.1, 170.5.
Anal. Calcd for C23H24F3NO8S2: C, 49.02; H, 4.29; N, 2.49.
Found: C, 49.05; H, 4.33; N, 2.43.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26750), DHEW, for gen-
erous support of this work. C.O.K. wishes to acknowl-
edge the Austrian Science Foundation (FWF) for an
Erwin-Schro¨dinger Postdoctoral Fellowship. Use of
high-field NMR spectrometer used in these studies was
made possible through equipment grants from the NIH
and NSF. We thank Chris Straub for determining the
X-ray structure of 38.
Meth yl 11-(Eth ylth io)-7,8-d im eth oxy-2-oxo-1,4,5,13a -
tetr a h yd r o-2H-in d olo[7a ,1-a ]isoqu in olin e-13a -ca r boxy-
la te (46). To a solution containing 94 mg (0.17 mmol) of the
above triflate and 2 mL of DMF were added sequentially 51
mg (0.50 mmol) of triethylamine, 12 mg (0.017 mmol) of bis-
(triphenylphosphine)palladium(II) chloride, and 40 mg (0.87
mmol) of formic acid at rt. After heating the mixture at 60 °C
for 15 min, ethyl acetate and water were added to the solution.
The mixture was washed with water, and the organic layer
was dried over MgSO4 and concentrated under reduced pres-
sure. The crude product was purified by flash silica gel
chromatography to give 64 mg (91%) of 46 as a clear oil; IR
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking analyses together
with an ORTEP drawing for structure 38 (27 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
(neat) 1731, 1693, 1513, 1431, 1260 cm-1
;
1H NMR (CDCl3,
J O9716183