Synthesis of azapolycyclic systems via the intramolecular [4 + 2] cycloaddition chemistry of 2-(alkylthio)-5-amidofurans.

Article abstract of DOI:10.1021/jo0111816

A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with beta-alkoxy-gamma-dithiane amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.

Full text of DOI:10.1021/jo0111816

3
412
J . Org. Chem. 2002, 67, 3412-3424
Syn th esis of Aza p olycyclic System s via th e In tr a m olecu la r [4 + 2]
Cycloa d d ition Ch em istr y of 2-(Alk ylth io)-5-a m id ofu r a n s
†
Albert Padwa,* J ohn D. Ginn, Scott K. Bur, Cheryl K. Eidell, and Stephen M. Lynch
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received December 26, 2001
A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the
reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with â-alkoxy-γ-dithiane
amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intra-
molecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged
cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic
lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether
allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen
in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the
dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary
for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction
at or below room temperature. To identify structural features that promote the IMDAF reaction,
a computational study was undertaken. Ground-state and transition-state energies were calculated
for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G* model. The theoretical results were in
good agreement with those observed. The results indicate that the incorporation of an amide carbonyl
as part of the tether system works to place the dienophile in closer proximity to the furan ring,
thereby lowering the activation energy needed to reach the transition state.
It is well-known that aromatic heterocycles, such as
involves cleavage of the oxygen bridge to produce func-
tionalized cyclohexene derivatives.1
7-22
furans, thiophenes, and pyrroles, can undergo Diels-
Alder reactions as 4π diene components despite their
aromaticity and hence expected decreased reactivity.1-3
In fact, the proclivity of furans to undergo [4 + 2]
cycloaddition with various π-bonds has attracted the
attention of many research groups, as it allows for the
rapid construction of valuable synthetic intermediates.4
The initial cycloaddition gives rise to a substituted
While the intramolecular Diels-Alder reaction of
6
furans (IMDAF) has been the subject of many reports,
much less is known regarding the intramolecular cy-
cloaddition behavior of furan Diels-Alder systems that
contain heteroatoms attached directly to the furan
-6
23-25
ring.
Recent work in our laboratory has shown that
7
-oxabicyclo[2.2.1]hept-5-ene (7-oxanorbornene) that can
(16) Smith, A. B.; Liverton, N. J .; Hrib, N. J .; Sivaramakrishnan,
H.; Winzenberg, K. J . Org. Chem. 1985, 50, 3239. Smith, A. B.;
Liverton, N. J .; Hrib, N. J .; Sivaramakrishnan, H.; Winzenberg, K. J .
Am. Chem. Soc. 1986, 108, 3040. Best, W. M.; Wege, D. Tetrahedron
Lett. 1981, 22, 4877.
be manipulated with impressive selectivity, leading to a
variety of interesting target molecules.7-16 A crucial
synthetic transformation employing these intermediates
(17) Le Drian, C.; Vieira, E.; Vogel, P. Helv. Chim. Acta 1989, 72,
3
38. Takahashi, T.; Lyobe, A.; Arai, Y.; Koizumi, T. Synthesis 1989,
†
NIH postdoctoral Fellow; Grant No. GM20666.
189. Guildford, A. J .; Turner, R. W. J . Chem. Soc., Chem. Commun.
1983, 466. Yang, W.; Koreeda, M. J . Org. Chem. 1992, 57, 3836.
(18) Suami, T. Pure Appl. Chem. 1987, 59, 1509. Harwood, L. M.;
J ackson, B.; Prout, K.; Witt, F. J . Tetrahedron Lett. 1990, 31, 1885.
Koreeda, M.; J ung, K.-Y.; Hirota, M. J . Am. Chem. Soc. 1990, 112,
7413. Reynard, E.; Reymond, J .-L.; Vogel, P. Synlett 1991, 469. Ogawa,
S.; Yoshikawa, M.; Taki, T. J . Chem. Soc., Chem. Commun. 1992, 406.
(19) J ung, M. E.; Street, L. Y. J . Am. Chem. Soc. 1984, 106, 8327.
Mirsadeghi, S.; Rickborn, B. J . Org. Chem. 1985, 50, 4340.
(20) Grieco, P. A.; Lis, R.; Zelle, R. E.; Finn, J . J . Am. Chem. Soc.
1986, 108, 5908.
(
1) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
(2) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J . Am. Chem. Soc.
1
988, 110, 7188.
3) Woo, S.; Keay, B. A. Synthesis 1996, 669. Lautens, M.; Fillion,
E. J . Org. Chem. 1996, 61, 7994.
(
(
4) Dean, F. M. Adv. Heterocycl. Chem. 1981, 30, 168.
(5) Sargent, M. V. Furans and Their Benzo Derivatives. In Com-
prehensive Heterocyclic Chemistry; Bird, C. W., Cheesman, G. W. H.,
Eds.; Pergamon Press: London, 1984; Vol. 4, pp 599-656.
(6) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
1
4179.
(21) Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett. 1986,
27, 5509. Hanessian, S.; Beaulieu, P.; Dube, D. Tetrahedron Lett. 1986,
27, 5071.
(22) Arjona, O.; de Dios, A.; dela Pradilla, R. F.; Plumet, J .; Viso, A.
J . Org. Chem. 1994, 59, 3906.
(7) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett 1990,
1
5
73. Reymond, J . L.; Pinkerton, A. A.; Vogel, P. J . Org. Chem. 1991,
6, 2128.
(8) Renaud, P.; Vionnet, J . P. J . Org. Chem. 1993, 58, 5895.
(
9) Eggelte, T. A.; de Koning, H.; Huisman, H. O. J . Chem. Soc.,
(23) Padwa, A.; Kappe, C. O.; Cochran, J . E.; Snyder, J . P. J . Org.
Chem. 1997, 62, 2786. Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu,
T. J . Org. Chem. 1997, 62, 4088.
Perkin Trans. 1 1978, 980.
10) Ogawa, S.; Iwasawa, Y.; Nose, T.; Suami, T.; Ohba, S.; Ito, M.;
Saito, Y. J . Chem. Soc., Perkin Trans. 1 1985, 903.
(
(24) 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 . Organo-
metallics 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. Vaidya, N. A.; Nixon,
W. J .; Fatmi, A. A.; Dewitt-Blanton, C. J . Org. Chem. 1982, 47, 2483.
(
11) Lautens, M.; Ma, S. Tetrahedron Lett. 1996, 37, 1727.
(12) Murai, A.; Takahashi, K.; Taketsuru, H.; Masamune, T. J .
Chem. Soc., Chem. Commun. 1981, 221.
(
(
(
13) Kotsuki, H.; Nishizawa, H. Heterocycles 1981, 16, 1287.
14) Cox, P. J .; Simpkins, N. S. Synlett 1991, 321.
15) Van Royen, L. A.; Mjingheer, R.; De Clercq, P. J . Tetrahedron
Lett. 1983, 24, 3145.
1
0.1021/jo0111816 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

Synthesis of Azapolycyclic Systems
J . Org. Chem., Vol. 67, No. 10, 2002 3413
Sch em e 1
Sch em e 2
the IMDAF reaction of 2-amido-substituted furans rep-
resents an effective route to indolines and tetrahydro-
quinolines.26 This methodology has also been utilized for
the synthesis of the hexahydroindolinone skeleton found
in numerous natural products.27 The interesting biologi-
cal activity associated with alkaloids in the structurally
ant azabicycle 3 (R * H), or else aromatic products (i.e.,
2
4) were formed.26 In an effort to circumvent this aroma-
diverse aspidosperma,28 erythrina, and stemona fami-
lies has also made the perhydroindole core of these
alkaloids an important preparative target for which many
synthetic strategies have been devised.31 Because cy-
cloaddition reactions such as the Diels-Alder reaction
can achieve high levels of both regio- and stereoselectiv-
29
30
tization, we sought to incorporate an alternate reaction
pathway, such as a rearrangement, through which to
alleviate the charge in the reactive intermediate (e.g. 7).
For example, a 2-(methylthio)-5-amidofuran with an
appropriately tethered olefin (e.g. 5) should undergo the
cycloaddition-nitrogen-assisted ring-opening cascade
(Scheme 2). Rather than lose a proton to quench the
iminium ion, the ring-opened intermediate 7 could un-
dergo a 1,2-alkylthio shift to provide 8. Because initial
studies into the cycloaddition chemistry of these furans
were promising,37 a more detailed investigation has been
conducted. The results of these inquiries are reported
herein.
3
2
ity, especially the intramolecular Diels-Alder reac-
tion,33 a synthetic approach based upon this methodology
could allow for a concise construction of the perhydro-
indole skeleton. As part of our program designed to
explore the synthetic utility of the intramolecular cy-
cloaddition chemistry of amido-substituted furans, we
have used this methodology for the preparation of hip-
padine,34 (()-dendrobine, and (()-lycorane. This ap-
proach, demonstrated by the cyclization of 1 to the
intermediate oxabicycle 2 (Scheme 1), was limited to
systems containing an angular substituent in the result-
35
36
Resu lts a n d Discu ssion
The required 2-(methylthio)-5-amidofurans necessary
for the intramolecular [4 + 2] cycloaddition studies were
prepared by a dimethyl(methylthio)sulfonium tetrafluo-
roborate (DMTSF) induced cyclization of various amido
dithioacetals.38 This approach was devised by the as-
sumption that it should be possible to induce cyclization
of the amide carbonyl group onto the resulting thionium
ion formed from the DMTSF reaction of the dithioacetal.
(
25) Schlessinger, R. H.; Bergstrom, C. P. Tetrahedron Lett. 1996,
3
7, 2133. Schlessinger, R. H.; Wu, X. H.; Pettus, T. R. R. Synlett 1995,
5
36. 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.
(
26) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem.
998, 63, 3986.
27) Padwa, A.; Brodney, M. A.; Dimitroff, M. J . Org. Chem. 1998,
3, 5304.
28) Boekelheide, V. Alkaloids 1960, 7, 201. Hill, R. K. In The
1
(
6
39
It is known that treatment of thioketals with DMTSF
(
causes the carbon-sulfur bond to become labile upon
methylthiolation.40 The resulting (alkylthio)sulfonium ion
easily dissociates to produce a thionium ion and methyl
disulfide.41 Once the dihydrofuran ring has been forged,
elimination of acetic acid (or its equivalent) should
proceed readily to furnish the 2-(alkylthio)amidofuran.
Indeed, this protocol worked well and led to the formation
of various (alkylthio)amidofurans in good yield. Thus,
we found that treating N-pivaloyl-N-methylacetamide (9)
with LDA followed by reaction with bis(methylsulfanyl)-
acetaldehyde (10)43 furnished the crossed-aldol interme-
Alkaloids; Manske, R., Ed.; Acedemic Press: New York, 1967; Vol. 9,
p 483. Dyke, S.; Quessy, S. In The Alkaloids; Rodrigo, R., Ed.; Academic
Press: New York, 1981; Vol. 18, p 1. Saxton, J . E. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, p 1.
(29) Chawla, A.; Kapoor, V. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Elsevier Science: New York, 1994;
Vol. 9, p 85.
(30) Gotz, M.; Strunz, G. Tuberostemonine and Related Com-
pounds: The Chemistry of Stemona Alkaloids; Butterworths: London:,
4
2
1
1
975; Vol. 9. Pilli, R. A.; de Oliveira, M. C. F. Nat. Prod. Rep. 2000,
7, 117.
(
31) Banwell, M. G.; Wu, A. W. J . Chem. Soc., Perkin Trans. 1 1994,
2
671. Grothjahn, D.; Vollhardt, K. Synthesis 1993, 579. Pearson, W.
H.; Schkeryantz, J . M. J . Org. Chem. 1992, 57, 6783. Backvall, J . E.;
Andersson, P. G.; Stone, G. B.; Gogoll, A. J . Org. Chem. 1991, 56, 2988.
J olly, R. S.; Livinghouse, T. J . Am. Chem. Soc. 1988, 110, 7536. Stork,
G.; Mah, R. Heterocycles 1989, 28, 723. Rigby, J . H.; Laurent, S.;
Cavezza, A.; Heeg, M. J . J . Org. Chem. 1998, 63, 5587.
(37) Ginn, J . D.; Lynch, S. M.; Padwa, A. Tetrahedron Lett. 2000,
41, 9387.
(
32) Tokoroyama, T. Synthesis 2000, 611.
(38) Padwa, A.; Ginn, J . D.; McClure, M. S. Org. Lett. 1999, 1, 1559.
(39) Trost, B. M.; Murayama, E. J . Am. Chem. Soc. 1981, 103, 6529.
Trost, B. M.; Sato, T. J . Am. Chem. Soc. 1985, 107, 719. Commercially
available from Aldrich Chemical Co.
(33) Roush, W. In Comprehensive Organic Synthesis; Trost, B., Ed.;
Pergamon Press: Elmsford, NY, 1991; Vol. 5, p 513. Roush, W. In
Advances in Cycloaddition; Curran, D. P., Ed.; J AI: Greenwich, CT,
1
990; Vol. 2, pp 91-146. Fallis, A. G. Can. J . Chem. 1984, 62, 183.
Craig, D. Chem. Soc. Rev. 1987, 16, 187.
34) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J . Org.
Chem. 1999, 64, 3595.
35) Padwa, A.; Brodney, M. A.; Dimitroff, M.; Liu, B.; Wu, T. J .
Org. Chem. 2001, 66, 3119.
36) Padwa, A.; Brodney, M. A.; Lynch, S. M. J . Org. Chem. 2001,
6, 1716.
(40) Kice, J . L.; Favstritsky, N. A. J . Am. Chem. Soc. 1969, 91, 1751.
Smallcombe, S. H.; Caserio, M. C. J . Am. Chem. Soc. 1971, 93, 5826.
Kim, J . K.; Pau, J . K.; Caserio, M. C. J . Org. Chem. 1979, 44, 1544.
(41) Braish, T. F.; Saddler, J . C.; Fuchs, P. L. J . Org. Chem. 1988,
53, 3648. Gr a´ cia, J .; Casamitjana, N.; Bonjoch, J .; Bosch, J . J . Org.
Chem. 1994, 59, 3939.
(
(
(
(42) Padwa, A.; Eidell, C. K.; Ginn, J . D.; McClure, M. S. J . Org.
Chem., in press.
6

3
414 J . Org. Chem., Vol. 67, No. 10, 2002
Padwa et al.
Sch em e 3
Sch em e 4
lactam products 21-23 were isolated (after silica gel
chromatography) as mixtures (1:1) that were diastereo-
meric about the C(6) stereocenter. However, examination
diate 11, which underwent a rapid N-/O-acyl transfer
reaction to provide the secondary amide 12 upon aqueous
workup. Attempts to acylate this amide under basic
1
of the H NMR spectra of the crude reaction mixtures
indicated that only one diastereomer was initially pro-
duced in each reaction. Thus, it appears that the dia-
stereomeric ratios obtained upon isolation are the result
of a facile epimerization of the C(6) center on silica gel
separation and are not kinetically derived (vide infra).
Encouraged by both the success of the cycloaddition-
rearrangement cascade and the apparent generality of
the amido(thioalkyl)furan synthesis, more complex cy-
clization systems, wherein the furan was fused to a
nitrogen heterocycle, were examined. Accordingly, cy-
clization precursors 33-38 were prepared by the sequen-
tial acylation of lactams 25 or 26 with an appropriate
acid chloride and reaction of the resulting diimides 27-
3
conditions (i.e., Et N, DMAP, etc.) resulted only in
elimination of the pivalate. Using 4 Å molecular sieves
as a neutral acid scavenger,44 however, resulted in the
formation of imides 13-16 in good yield (60-90%)
(Scheme 3). These imides were then treated with DMTSF
to produce the 2-(alkylthio)-5-amidofurans 17-20 in 40-
7
0% yield.
With a satisfactory method for the synthesis of the
cycloaddition precursors in place, we became interested
in evaluating the facility with which these (thioalkyl)-
amidofuranyl systems would undergo cycloaddition. We
noted that in the case of imide 15 (R ) CO Me; n ) 1),
2
3
2 with DMTSF (Scheme 4). Formation of tricyclic
the furan (i.e., 19) could not be isolated from the DMTSF
reaction. Rather, lactam 23 was obtained in 68% isolated
yield. Several of the other amidofuran substrates also
spontaneously underwent [4 + 2] cycloaddition at room
temperature (ca. 15 h) to produce bicyclic lactams,
although heating accelerated the cascade. For conven-
ience, therefore, furans 17, 18, and 20 were not purified;
the crude products were immediately thermolyzed to
provide the bicyclic lactams. In a typical example, heating
a toluene solution of crude furan 17 (R ) H; n ) 1) at
reflux for 2 h produced 21 in 72% yield. In stark contrast,
furan 20 (R ) H, n ) 2)45 failed to produce 24 even when
heated at 200 °C in a sealed tube. In all cases, the bicyclic
lactams 39 (92%) and 40 (61%) required heating the
requisite furan at reflux in toluene, whereas the reaction
of 36 to give 42 (76% yield) needed to be carried out at
1
50 °C in a sealed tube. Furan 38 (R ) H, m ) n ) 2)
also required 150 °C to effect the Diels-Alder reaction,
but tricyclic lactam 44 was not formed. Rather, the
remarkably robust oxabicycle 45 was isolated in 75%
2
yield (Scheme 5). Amido(thioalkyl)furans 35 (R ) CO -
Me; m ) n ) 1) and 37 (R ) H; m ) 1, n ) 2) could not
be isolated because the Diels-Alder cycloaddition occurs
under the conditions of their formation. While 37 pro-
ceeds directly to the tricyclic lactam 43 in 64% yield,
furan 35 provided oxabicycle 46 in 77% yield. Heating a
benzene solution of this cycloadduct at reflux provided
the tricyclic lactam 41 in 77% yield. The relative stereo-
chemistry of 46 was secured by a single-crystal X-ray
analysis.
(43) Nakane, M.; Hutchinson, C. J . Org. Chem. 1978, 43, 3922.
Barbero, M.; Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R. J . Org.
Chem. 1995, 60, 6017.
(44) Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski, A. M.;
Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M. Tetrahedron
Lett. 1975, 16, 3979.
To further illustrate the viability of the cycloaddition/
rearrangement cascade as a practical strategy for the
synthesis of complex polyazacyclic systems, we studied
(45) Experimental details for the preparation of 20 and 66 and their
spectroscopic properties are given in the Supporting Information.

Synthesis of Azapolycyclic Systems
J . Org. Chem., Vol. 67, No. 10, 2002 3415
Sch em e 5
Sch em e 7
the IMDAF behavior of the related amidofuran 47. We
were gratified to find that heating 47 at 110 °C for 2 h
gave the rearranged amide 48 as a single diastereomer
in 80% yield. The relative stereochemistry of 48 was
unequivocally established by X-ray crystallographic analy-
sis.
As described above, a majority of the bicyclic lactams
were isolated as mixtures of diastereomers. However,
monitoring the thermolysis by 1H NMR spectroscopy
showed that only one diastereomer was present in the
crude reaction mixture prior to silica gel chromatography.
Because the stereogenic center adjacent to the ketone
moiety is readily epimerized, the relative stereochemistry
of the kinetically formed products could not be easily
assigned. A mechanistic probe wherein the final product
lacks the easily epimerizable center would allow for the
isolation of the kinetic product. To this end, furan 56 was
synthesized from amide 54 via acylation with vinyl acetic
acid chloride followed by exposure of the resulting imide
55 to DMTSF and p-TsOH42 (Scheme 7). Thermolysis of
56 in toluene at 110 °C for 1 h produced the tricyclic
lactam 57 in 70% yield as a single diastereomer whose
relative stereochemistry was established by X-ray analy-
sis.
In addition to the simple substituted alkenes shown
in Scheme 4, tethered alkynes also participate in the
cycloaddition cascade, although at a much slower rate.
For example, when furan 49 was heated to 160 °C for 2
days, a 1:1 mixture of 52 and 53 was isolated in nearly
quantitative yield (Scheme 6). From the oxa-bridged
cycloadduct 50, two possible 1,2-alkylthio shifts can occur
to alleviate the charge on the transient N-acyl iminium
ion 51. Indeed, both rearrangement pathways occurred
to an equal extent, providing a 1:1 mixture of the isomeric
phenols.
The X-ray crystal structure of oxabicycle 46 reveals a
preferred exo orientation of the tether in the Diels-Alder
adduct. This stereochemical result is consistent with that
reported by others for related furanyl systems possessing
short tethers.4
6,47
The ring-opened lactams (i.e., 39-43)
are derived from an IMDAF cycloaddition where the
sidearm of the tethered alkenyl group is oriented syn
Sch em e 6
(exo) with respect to the oxygen bridge. Products result-
ing from an endo sidearm transition state were neither
detected nor isolated. This result is not so surprising
since, in these mobile cycloaddition equilibria, the exo
adducts are expected to be thermodynamically more
favored. It should also be noted that bicyclic lactam 57
possesses a configuration in which the methylthio group
and the angular hydrogen are on the same face. This
feature, combined with the exclusive formation of one
diastereomer in the thermolysis of 56, suggest a con-
certed 1,2-shift of the methylthio group. While a stepwise
elimination-stereoselective addition of the methylthio
substituent is possible, the lack of stereodirecting fea-
tures within these systems is inconsistent with the
observed degree of stereoselectivity. It should be noted
that a somewhat related methylthio group migration was
(46) Woo, S.; Keay, B. A. Tetrahedron: Asymmetry 1994, 5, 1411.
Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477. Rogers, C.;
Keay, B. A. Synlett 1991, 353. Rogers, C.; Keay, B. A. Can. J . Chem.
1
992, 70, 2929.
47) De Clercq, P. J .; Van Royen, L. A. Synth. Commun. 1979, 9,
71. Van Royen, L. A.; Mijngher, R.; De Clercq, P. J . Bull. Soc. Chim.
(
7
Belg. 1984, 93, 1019. Fischer, K.; Hunig, S. J . Org. Chem. 1987, 52,
64.
5

3
416 J . Org. Chem., Vol. 67, No. 10, 2002
Padwa et al.
Sch em e 8
Sch em e 9
reported by Wu and co-workers48 in their studies of the
intramolecular Diels-Alder reaction of a furan contain-
ing a tethered allenyl ether dienophile (Scheme 8). The
initially formed cycloadduct 60 was proposed to undergo
ring opening of the bridged oxygen atom to produce
zwitterion 61, which underwent a subsequent 1,4-meth-
ylthio shift to eventually give phenol 63. In contrast to
our studies, the alkylthio shift encountered with 60 was
proposed to proceed via a tight ion pair.
One of the more striking features of the intramolecular
Diels-Alder cascade reactions outlined in the above
schemes is the variable reactivity of structurally similar
substrates. Previous work from this laboratory, for
example, demonstrated that amidofuran 64 required
heating to 165 °C to undergo a cascade that furnished
the effects of amide- and ester-linked tethers on the
diastereoselectivity of intramolecular Diels-Alder reac-
tions have been attributed to relative transition state
stabilities.50 J ung and Gervay, however, reported data
for intramolecular Diels-Alder reactions which suggest
that substitution on the tether results in an increase in
the population of reactive rotamers.51 Thus, the rate
enhancement was suggested to originate from a restricted
rotation, producing a lowest energy ground state con-
former that is more energetically similar to the reactive
conformer.
6
5 (Scheme 9). In stark contrast, 2-(alkylthio)-5-amid-
ofuran 17 produced 21 when left at room temperature
for 12 h (vide supra). Likewise, the amidofuran 33, in
which the furan is fused to a six-membered ring, required
heating to 110 °C to afford 39. However, furan 37, in
which the heteroaromatic ring is fused to a seven-
membered ring, could not be isolated, as 43 was produced
under the reaction conditions used to form the furan.
Interestingly, systems that differed from furan 33 only
in the placement or deletion of the amide carbonyl group
would not undergo the initial Diels-Alder reaction. For
example, furans 66 and 67 resisted cyclization even at
temperatures up to 200 °C.
The primary structural differences between 64 and 17
are the presence of a methylthio group on the furan and
the location of the amide carbonyl in 17. That alkylthio
substituents are known to have little effect on the facility
of Diels-Alder reactions combined with the lack of
reactivity in 66 and 67 implicates the placement of the
carbonyl center within the dienophilic tether as the more
important structural change.
Because there was no clear precedent regarding whether
the origin of the rate differences resided either in ground-
state conformational effects or in relative strain within
the transition states, we investigated the ground-state
conformations of 64, 17, 33, and 37 as well as the
transition states through which these reactants must
pass to obtain the corresponding oxabicycles. Initial
attempts to explore the conformational space of these
molecules using MM2* and MMFF force fields were
inconclusive because of the inadequate parametrization
5
2
of the force fields for these amidofuran systems. Density
functional methods were therefore employed for the
Dramatic effects originating from the placement of a
carbonyl group on the tether have previously been noted.
In one example involving an intramolecular dipolar
cycloaddition, a severe steric interaction was found in the
transition state, while no such interaction was identifi-
able in either the starting material or product ground
states.49 Introduction of a carbonyl group on the tethered
dipolarophile relieved the source of the strain. Similarly,
(
50) For examples see: (a) Oppolzer, W.; Fr o¨ stl, W. Helv. Chim. Acta
1
975, 58, 590. (b) Oppolzer, W.; Fr o¨ stl, W.; Weber, H. P. Helv. Chim.
Acta 1975, 58, 593. (c) White, J . D.; Demnitz, F. W. J .; Oda, H.; Hassler,
C.; Snyder, J . P. Org. Lett. 2000, 2, 3313. (d) Turner, C. I.; Williamson,
R. M.; Paddon-Row, M. N. J . Org. Chem. 2001, 66, 3963. (e) Tantillo,
D. J .; Houk, K. N.; J ung, M. E. J . Org. Chem. 2001, 66, 1938.
(51) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224. See
also: (b) Sternbach, D. D.; Rossana, D. M.; Onan, D. D. Tetrahedron
Lett. 1985, 26, 591. Giessner-Prettre, C.; H u¨ kel, S.; Maddaluno, J .;
J ung, M. E. J . Org. Chem. 1997, 62, 1439.
(52) For MMFF parameters see: Halgren, T. A. J . Comput. Chem.
1999, 20, 730. For a comparison of parameters see: Gundertofte, K.;
Liljefors, T.; Norrby, P. O.; Petersson, I. J . Comput. Chem. 1996, 17,
429.
(
48) Wu, H. J .; Shao, W. D.; Ying, F. H. Tetrahedron Lett. 1994, 35,
29. Wu, H. J .; Ying, F. H.; Shao, W. D. J . Org. Chem. 1995, 60, 6168.
Wu, H. J .; Yen, C. H.; Chuang, C. T. J . Org. Chem. 1998, 63, 5064.
49) Weingarten, M. D.; Prein, M.; Price, A. T.; Snyder, J . P.; Padwa,
A. J . Org. Chem. 1997, 62, 2001.
7
(

Synthesis of Azapolycyclic Systems
J . Org. Chem., Vol. 67, No. 10, 2002 3417
conformational search. Using the B3LYP/3-21G* model53,54
as implemented by Gaussian 98,55 ground-state confor-
mations were explored by optimizing structures with, for
example, various gauche and anti comformations about
rotatable bonds. Transition states for each of the Diels-
Alder reactions were also located (Figure 1).56
Initial results from B3LYP/3-21G* optimizations showed
relative activation energies that were consistent with
experimental observations. Single-point calculations us-
ing the 6-31G* basis set, however, predicted a relative
energy of activation for the conversion of 64a to A that
was much lower than expected. Reoptimization of the
structures in Figure 1 using the 6-31G* basis set con-
firmed the single-point energy calculations without sig-
nificantly altering the optimized geometry. Because
density functional theory is known to overemphasize the
resonance stabilization of aromatic compounds,5 single-
point MP2/6-311+G*//B3LYP/6-31G* calculations were
performed. These results also predict a lower energy of
activation for the conversion of 64a to A than was
experimentally observed (vide infra).
7,58
Examination of the optimized transition states A-D
revealed no obvious strain or large steric interactions.
The ground-state conformations, however, contained two
features that may explain the observed differences in
reactivity. The first feature involves the conformation
that the carbonyl enforces within the tether. In compound
6
4a , for example, the substituents on the adjacent
methylene carbons C(3′) and C(4′) prefer an anti confor-
mation that projects the olefin away from the furan. A
gauche conformation is required for the reaction to
proceed. In compound 17a , however, the C(3′)-C(4′) bond
has a nearly synclinal orientation with respect to the
amide carbonyl (O-C(4′)-C(3′)-C(2′) ) -100.8°),59 and
this conformation places the olefin in much closer prox-
imity to the furan than the conformation of 64a .
The energy differences associated with a single bond
rotation cannot account for the larger differences in
activation barrier, but a second conformational feature
appears to place 17a closer to a reactive conformation
than 64a . The C(3)-C(2)-N-C(4′) dihedral angle in 64a
F igu r e 1. (a) B3LYP/6-31G* optimized ground-state confor-
mations. (b) Calculated relative energies of activation in kcal/
mol at B3LYP/3-21G*, B3LYP/6-31G* (in bodlface), and MP2/
(
53) For Becke’s three-parameter exchange functional see: Becke,
A. D. J . Chem. Phys 1993, 98, 5648.
54) For the LYP correlation functional see: Lee, C.; Yang, W.; Parr,
R. Phys. Rev. B 1988, 37, 785.
55) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
6
-311+G*//B3LYP/6-31G (in italics). (c) Corresponding transition
(
states with transitional bond lengths in angstroms as opti-
mized at B3LYP/3-21G* and B3LYP/6-31G* (in boldface) levels
of theory.
(
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.7; Gaussian, Inc.: Pittsburgh, PA,
was calculated to be 172.5°, while the same angle in 17a
was 131.7°. The C(3)-C(2)-N-C(4′) dihedral angle in
A was calculated to be 123.4°, while the same torsional
angles in B-D were calculated to be approximately 130°.
Thus, the rotation about the C(2)-N bond appears to be
biased toward a reactive conformer in 17a . Conformer
17b, which is similar to the low-energy conformation 64a ,
was calculated to be less than 0.1 kcal/mol higher in
energy than 17a due to an A1 interaction between the
methyl substituent on the nitrogen and the protons on
C(3′) (Figure 2). The oxygen in the carbamate moiety of
64 does not produce this destabilizing interaction.
Preferred ring conformations dictate the C(3)-C(2)-
N-C(4) dihedral angle in 33a and 37a . The six-mem-
bered ring annealed to the furan in 33a adopts a half-
chair conformation in which the C(3)-C(2)-N-C(4)
dihedral angle is 156.0°. The seven-membered ring
annealed to the furan in 37a adopts a low-energy
1
998.
56) Transition state structures were characterized by one imaginary
,3
(
vibrational frequency (Nimag ) 1) corresponding to the bonding event.
No zero-point energy corrections were applied to any of the calculated
structures.
(57) Plattner, D. A.; Houk, K. N. J . Am. Chem. Soc. 1995, 117, 4405.
Chesnut, D. B.; Davis, K. M. J . Comput. Chem. 1996, 18, 584. Sulzbach,
H. M.; Schaefer, H. F., III. J . Am. Chem. Soc. 1996, 118, 3519.
(58) Nendel, M.; Houk, K. N.; Tolbert, L. M.; Vogel, E.; J iao, H.;
Schleyer, P. v. R. Angew. Chem., Int. Ed. 1997, 36, 748. King, R. A.;
Crawford, D.; Stanton, J . F.; Schaefer, H. F., III. J . Am. Chem. Soc.
1
999, 121, 10788.
59) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p 617.
(

3
418 J . Org. Chem., Vol. 67, No. 10, 2002
Padwa et al.
molecules undergo intramolecular Diels-Alder cyclo-
additions. Application of this methodology toward the
construction of more complex alkaloids containing these
skeletons is currently in progress in our laboratory and
will be reported at a later date.
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 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 other-
wise. All solids were recrystallized from 3% ethyl acetate/
hexane for analytical data.
F igu r e 2. Second low-energy conformations of 17 and 37.
2
,2-Dim et h ylp r op ion ic Acid 1-(Bis((m et h ylsu lfa n yl)-
m eth yl)-3-(bu t-3-en oylm eth yla m in o)-3-oxop r op yl Ester
(13). To a solution containing 0.4 g (1.4 mmol) of amide 12
4
2
conformation that imparts a 119.7° angle, but a simple
ring flip provides a conformation (37b) in which the angle
increases to 132.7° (Figure 2). The rapid interconversion
of 37a and 37b (a calculated 2.2 kcal/mol energy differ-
ence) allows 37 to adopt a reactive conformation more
easily than 64 or 33. The differences in reactivity among
furans 64, 17, 33, and 37, therefore, appear to correlate
with a bias in the rotation about the C(2)-N bond.
While the effects attributed to the placement of the
carbonyl and the effects that stem from the rotational
bias about the C(2)-N bond appear to be localized to the
ground state, some of the structural features may desta-
bilize the transition states. For example, the geometry
of furan 33 that is required to reach a transition state is
difficult for a cyclohexene-like ring to achieve. Significant
ring strain may, therefore, account for the higher calcu-
lated activation energy. The correlation between ground-
state conformational preferences and reactivity is, how-
ever, significant.
2 2
in 8 mL of CH Cl was added 0.3 g (2.7 mmol) of 3-butenoyl
chloride60 followed by 1.5 g of powdered molecular sieves. After
it was stirred at room temperature overnight, the suspension
was filtered through a pad of silica and washed several times
with diethyl ether. The filtrate was washed with a saturated
3 4
aqueous NaHCO solution, dried over MgSO , and concen-
trated under reduced pressure. The crude reaction mixture was
subjected to flash silica gel chromatography to give 0.5 g (87%)
of 13 as a yellow oil: IR (neat) 1731, 1700, 1639, 1152, and
-
1 1
1075 cm ; H NMR (400 MHz, CDCl
3
3
3
) δ 1.16 (s, 9H), 2.16 (s,
H), 2.17 (s, 3H), 3.09 (dd, 1H, J ) 17.2 and 7.6 Hz), 3.19 (s,
H), 3.41-3.47 (m, 3H), 3.94 (d, 1H, J ) 4.4 Hz), 5.11-5.20
1
3
(
m, 2H), 5.52-5.57 (m, 1H), and 5.89-5.99 (m, 1H); C NMR
100 MHz, CDCl ) δ 14.3, 15.0, 27.2, 31.4, 38.9, 40.9, 42.8, 57.7,
1.4, 118.9, 130.5, 172.8, 174.1, and 177.6; HRMS calcd for
361.1381, found 361.1380.
2,2-Dim eth ylp r op ion ic Acid 1-([Meth yl(3-m eth ylbu t-
(
3
7
16 4 2
C H27NO S
3-en oyl)ca r ba m oyl]m eth yl)-2,2-Bis(m eth ylsu lfa n yl) Eth -
yl Ester (14). To a solution containing 1.0 g (3.5 mmol) of
amide 12 in 18 mL of CH
2
Cl
2
6
was added 0.7 g (5.9 mmol) of
1
3
-methylbut-3-enoyl chloride followed by 3.5 g of powdered
The small difference in calculated activation energies
between the conversion of 64 to 65 and 33 to 39 caused
us to reexamine the conditions under which these cy-
cloadditions occur. It was discovered that the intramo-
lecular Diels-Alder reaction of 64 proceeded at 130 °C
molecular sieves. After it was stirred at room temperature
overnight, the suspension was filtered through a pad of silica
and washed several times with diethyl ether. The filtrate was
3
washed with a saturated aqueous NaHCO solution, dried over
4
MgSO , and concentrated under reduced pressure. The crude
reaction mixture was subjected to flash silica gel chromatog-
(35 °C lower than previously observed) to produce a
raphy to give 0.5 g (41%) of 14 as a yellow oil: IR (neat) 1731,
mixture (3:2) of enamino ketones 68a ,b in 64% yield. At
lower temperatures (e.g. 110 °C), however, decomposition
pathways were faster than cycloaddition, and a lower
limit could not be determined.
-
1 1
1
(
480, 1275, and 1153 cm ; H NMR (400 MHz, CDCl
3
) δ 1.19
s, 9H), 1.81 (s, 3H), 2.19 (s, 3H), 2.20 (s, 3H), 3.13 (dd, 1H, J
)
17.0 and 7.2 Hz), 3.20 (s, 3H), 3.37 (s, 2H), 3.50 (dd, 1H, J
17.0 and 5.0 Hz), 3.96 (d, 1H, J ) 5.0 Hz), 4.79 (s, 1H), 4.96-
)
4
.97 (m, 1H), and 5.56-5.60 (m, 1H); 13C NMR (100 MHz,
CDCl
14.9, 138.9, 172.9, 173.8, and 177.8; HRMS calcd for C17
NO 375.1538, found 373.1537.
3
) δ 14.4, 15.1, 22.9, 27.3, 31.7, 39.0, 41.3, 46.9, 57.8, 71.5,
1
29
H -
4
S
2
N-[3-((2,2-Dim et h ylp r op ion yl)oxy)-4,4-b is(m et h ylsu l-
fa n yl)bu tyr yl]-N-m eth yl-2-m eth ylen e Su ccin a m ic Acid
Meth yl Ester (15). To a solution containing 0.3 g (1.0 mmol)
of amide 12 in 5 mL of CH
2 2
Cl was added 0.2 g (1.4 mmol) of
6
2
3
-(methoxycarbonyl)but-3-enoyl chloride followed by 1.0 g of
In summary, a highly convergent synthesis of hexa-
hydropyrroloquinolinone derivatives has been devised
using an IMDAF cycloaddition reaction of 2-(methylthio)-
powdered molecular sieves. After it was stirred at room
temperature overnight, the suspension was filtered through
a pad of silica and washed several times with diethyl ether.
5
-amidofurans. Conformational effects that have a dra-
The filtrate was washed with a saturated aqueous NaHCO
3
matic impact on the relative reaction rates were identi-
fied in the low-energy ground-state conformations of
furans 64, 17, 33, and 37. Specifically, the placement of
a carbonyl in the tether caused the molecules to adopt
conformations that were much closer to the reactive
conformations than molecules that lacked this tether
carbonyl. A bias in the rotation about the C(2)-N bond
was also found to correlate with the rates at which these
solution, dried over MgSO , and concentrated under reduced
4
pressure. The crude reaction mixture was subjected to flash
silica gel chromatography to give 0.3 g (66%) of 15 as a yellow
-1 1
oil: IR (neat) 1726, 1695, 1209, 1152, and 1086 cm ; H NMR
(60) Knapp, S.; Levorse, A. T. J . Org. Chem. 1988, 53, 4006.
(61) Parham, W. E.; Boykin, D. W. J . Org. Chem. 1977, 42, 260.
(62) Achiwa, K.; Chaloner, P.; Parker, D. J . Organomet. Chem. 1981,
218, 249.

Synthesis of Azapolycyclic Systems
J . Org. Chem., Vol. 67, No. 10, 2002 3419
(
2
400 MHz, CDCl
.99 (dd, 1H, J ) 17.0 and 7.4 Hz), 3.14 (s, 3H), 3.34 (dd, 1H,
J ) 17.0 and 4.8 Hz), 3.61 (s, 2H), 3.65 (s, 3H), 3.85 (d, 1H, J
4.8 Hz), 5.44-5.49 (m, 1H), 5.56 (s, 1H), and 6.22 (s, 1H);
3
) δ 1.09 (s, 9H), 2.08 (s, 3H), 2.09 (s, 3H),
1-Meth yl-6-(m eth ylsu fan yl)-2,5-dioxo-1,2,3,4,5,6-h exah y-
d r oin d ole-3a -ca r boxylic Acid Meth yl Ester (23). To a
solution containing 0.6 g (1.4 mmol) of imide 15 in 7 mL of
)
3
CH CN was added 0.3 g (1.4 mmol) of DMTSF in one portion
1
3
C NMR (100 MHz, CDCl
1.6, 52.0, 57.5, 71.1, 128.2, 134.2, 166.6, 172.5, 173.2, and
77.3. Anal. Calcd for C18 : C, 51.53; H, 6.97; N, 3.34.
3
) δ 14.1, 14.8, 27.0, 31.2, 38.7, 40.5,
at -40 °C. The mixture was stirred for 1 h at -40 °C, and 1
mL (7 mmol) of triethylamine was added. The reaction mixture
was diluted with diethyl ether, poured over a saturated
4
1
H
6 2
29NO S
Found: C, 51.42; H, 6.85; N, 3.22.
Bu t-3-en oic Acid Meth yl(5-(m eth ylsu lfa n yl)fu r a n -2-
yl)a m id e (17). To a solution containing 0.9 g (2.4 mmol) of
aqueous NaHCO
dried over K CO
pressure, and the crude mixture was subjected to flash silica
3
solution, extracted with diethyl ether, and
. The solvent was removed under reduced
2
3
gel chromatography to give 0.3 g (68%) of 23 as a yellow oil:
amide 13 in 12 mL of CH
DMTSF in one portion at -40 °C. The mixture was stirred for
h at -40 °C, and 1.7 mL (12 mmol) of triethylamine was
added. The reaction mixture was diluted with diethyl ether,
poured over a saturated aqueous NaHCO solution, extracted
with diethyl ether, and dried over K CO . The solvent was
3
CN was added 0.5 g (2.4 mmol) of
-1 1
IR (neat) 1731, 1675, 1388, and 1224 cm ; H NMR (400 MHz,
CDCl ) (major diastereomer) δ 2.16 (s, 3H), 2.44 (d, 1H, J )
7.6 Hz), 2.74-2.77 (m, 1H), 2.78 (d, 1H, J ) 14.4 Hz), 2.93
s, 1H), 3.06 (d, 1H, J ) 16.4 Hz), 3.63 (s, 3H), 3.66-3.70 (m,
1
3
1
(
3
1
1
(
2
H), and 4.98 (d, 1H, J ) 3.2 Hz); H NMR (400 MHz, CDCl
minor diastereomer) δ 2.11 (s, 3H), 2.49 (d, 1H, J ) 17.6 Hz),
.74-2.79 (m, 1H), 2.97 (d, 1H, J ) 14.4 Hz), 2.98 (s, 3H),
3.50 (d, 1H, J ) 17.6 Hz), 3.64-3.69 (m, 1H), 3.65 (s, 3H), and
3
)
2
3
removed under reduced pressure, and the crude mixture was
subjected to flash silica gel chromatography to give 0.2 g (39%)
1
of 17 as a yellow oil: H NMR (400 MHz, CDCl
3
) δ 2.42 (s,
5
1
4
2
5
.11 (d, 1H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl
) δ 16.4,
3
3
5
3
H), 2.99-3.01 (m, 2H), 3.19 (s, 3H), 4.99-5.11 (m, 2H), 5.83-
6.5, 26.6, 26.8, 39.8, 42.0, 42.4, 45.0, 45.9, 46.2, 47.9, 48.2,
9.9, 53.5, 94.7, 97.6, 142.7, 145.9, 171.7, 172.2, 172.5, 172.6,
00.2, and 200.9. Anal. Calcd for C12H15NO S: C, 53.51; H,
4
.91 (m, 1H), 6.06 (d, 1H, J ) 3.2 Hz), and 6.42 (d, 1H, J )
.2 Hz). As a consequence of its lability, the furan was used
in the next step without further purification.
-Meth ylbu t-3-en oic Acid Meth yl(5-(m eth ylsu lfa n yl)-
fu r a n -2-yl)a m id e (18). To a solution containing 0.5 g (1.4
mmol) of amide 14 in 7 mL of CH CN was added 0.3 g (1.4
.62; N, 5.20. Found: C, 53.42; H, 5.51; N, 5.15.
3
Acetic Acid 1-(1-Bu t-3-en oyl-2-oxop ip er id in -3-yl)-2,2-
bis(m eth ylsu lfa n yl) Eth yl Ester (27). To a 2.1 g (7.6 mmol)
sample of 25 dissolved in CH Cl (40 mL) was added 7.6 g of
oven-dried 4 Å powdered molecular sieves followed by 1.3 g
13 mmol) of but-3-enoyl chloride.60 The reaction mixture was
3
2
2
mmol) of DMTSF in one portion at -40 °C. The mixture was
stirred for 1 h at -40 °C, and 1.0 mL (7.0 mmol) of triethy-
lamine was added. The mixture was diluted with diethyl ether,
poured over a saturated aqueous NaHCO
with diethyl ether, and dried over K CO
(
stirred at 25 °C for 15 h and then filtered through a silica gel
column and washed with ether. The organic phase was washed
with a saturated aqueous NaHCO
anhydrous MgSO . The solvent was removed under reduced
3
solution, extracted
3
. The solvent was
2
3
solution and dried over
removed under reduced pressure, and the crude mixture was
4
subjected to flash silica gel chromatography to give 0.2 g (62%)
pressure, and the crude mixture was subjected to flash silica
gel chromatography to give 2.5 g (94%) of the title compound
as a yellow oil which contained a 1:1 mixture of diastereomers.
For analytical purposes, the diastereomers were separated by
1
of 18 as a yellow oil: H NMR (400 MHz, CDCl
3
) δ 1.72 (s,
3
H), 2.41 (s, 3H), 2.99 (s, 3H), 3.20 (s, 2H), 4.63 (s, 1H), 4.83
(
s, 1H), 6.05 (d, 1H, J ) 3.2 Hz), and 6.40 (d, 1H, J ) 3.2 Hz).
As a consequence of its lability, the furan was used in the next
step without further purification.
HPLC: IR (neat) 1751, 1689, 1425, and 1238 cm- ; H NMR
1
1
(
1
400 MHz, CDCl
.98 (m, 1H), 2.03-2.10 (m, 1H), 2.08 (s, 3H), 2.15 (s, 3H), 2.20
3
) (diastereomer A) δ 1.68-1.85 (m, 2H), 1.92-
1
-Meth yl-6-(m eth ylsu lfa n yl)-1,3a ,4,6-tetr a h yd r o-3H-in -
d ole-2,5-d ion e (21). A solution of 0.08 g (0.4 mmol) of furan
7 in 6 mL of toluene was heated at reflux for 2 h. After it
(
3
s, 3H), 3.23-3.30 (m, 1H), 3.66 (dd, 2H, J ) 6.8 and 0.8 Hz),
1
.72-3.77 (m, 2H), 3.90 (d, 1H, J ) 8.0 Hz), 5.10-5.16 (m,
H), 5.70 (dd, 1H, J ) 8.0 and 4.2 Hz), and 5.94-6.04 (m, 1H);
was cooled to room temperature, the reaction mixture was
concentrated under reduced pressure and subjected to silica
gel chromatography to give 0.06 g (72%) of 21 as a yellow oil:
2
1
H NMR (400 MHz, CDCl ) (diastereomer B) δ 1.60-1.80 (m,
3
2
3
3
H), 1.94-2.07 (m, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H),
-
1 1
IR (film) 1731, 1669, 1429, 1316, and 1260 cm ; H NMR (400
MHz, CDCl ) major diastereomer δ 2.07 (s, 3H), 2.16-2.33 (m,
.15 (m, 1H), 3.57-3.64 (m, 1H), 3.66-3.69 (m, 2H), 3.82-
3
.89 (m, 1H), 4.22 (d, 1H, J ) 9.6 Hz), 5.11-5.17 (m, 2H), 5.40
2
1
6
H), 2.76 (dd, 1H, J ) 17.4 and 9.8 Hz), 2.93 (s, 3H), 3.02 (dd,
13
(
(
dd, 1H, J ) 9.6 and 3.2 Hz), and 5.97-6.07 (m, 1H); C NMR
H, J ) 18.4 and 6.4 Hz), 3.55-3.59 (m, 1H), 3.62 (d, 1H, J )
100 MHz, CDCl
3
) (diastereomer A) δ 13.2, 14.0, 21.0, 21.7,
1
.8 Hz), and 5.00 (dd, 1H, J ) 6.6 and 2.6 Hz); H NMR (400
4
1
1
1
3.6, 44.2, 46.0, 56.8, 72.1, 118.4, 131.4, 169.8, 173.7, and
MHz, CDCl
3
) (minor diastereomer) δ 2.10 (s, 3H), 2.24-2.33
13
74.8; C NMR (100 MHz, CDCl
3.6, 21.2, 21.9, 23.7, 43.9, 44.3, 46.3, 56.4, 73.6, 118.3, 131.6,
70.3, 172.4, and 175.1; HRMS calcd for C15 : 345.1068,
3
)(diastereomer B) δ 12.9,
(
1
m, 1H), 2.55 (dd, 1H, J ) 12.2 and 4.2 Hz), 2.68 (dd, 1H, J )
6.8 and 8.4 Hz), 2.93 (s, 3H), 3.02-3.12 (m, 1H), 3.53-3.61
H
4 2
23NO S
13
(
m, 2H), and 4.84 (t, 1H, J ) 2.8 Hz); C NMR (100 MHz,
CDCl ) δ 16.0, 16.3, 26.3, 26.4, 29.8, 35.0, 36.2, 36.4, 39.0, 41.5,
9.0, 49.9, 91.3, 94.1, 145.6, 149.3, 173.9, 174.4, 200.8, and
02.1. Anal. Calcd for C10 S: C, 56.85; H, 6.21; N, 6.63.
found 345.1071.
Acetic Acid 1-[1-(3-Meth yl-bu t-3-en oyl)-2-oxop ip er i-
d in -3-yl]-2,2-bis(m eth ylsu lfa n yl) Eth yl Ester (28). To a 1.6
g (5.6 mmol) sample of lactam 25
added 6 g of oven-dried 4 Å powdered molecular sieves and
1.0 g (8.4 mmol) of 3-methylbut-3-enoyl chloride.61 The mixture
was stirred at room temperature for 15 h, followed by filtration
through a plug of silica with diethyl ether. The filtrate was
3
4
2
H
13NO
2
142
2 2
in CH Cl (50 mL) was
Found: C, 56.72; H, 6.11; N, 6.45.
,3a -Dim eth yl-6-(m eth ylsu lfa n yl)-1,3a ,4,6-tetr a h yd r o-
H-in d ole-2,5-d ion e (22). A solution of 0.2 g (0.9 mmol) of
1
3
furan 18 in 5 mL of toluene was heated at reflux for 3 h. After
it was cooled, the reaction mixture was concentrated under
reduced pressure and subjected to silica gel chromatography
to give 0.1 g (42%) of 22 as a pale yellow oil: IR (neat) 1731,
washed with a saturated aqueous NaHCO
over MgSO , and the solvent was removed under reduced
3
solution and dried
4
pressure. The residue was purified by flash silica gel chroma-
tography to give 1.3 g (64%) of 28 as a colorless oil consisting
of a 1:1 mixture of diastereomers. For analytical purposes the
diastereomers were separated by HPLC: IR (neat) 1748, 1652,
-
1 1
1
670, 1327, and 1111 cm ; H NMR (400 MHz, CDCl
diastereomer) δ 1.12 (s, 3H), 2.12 (s, 3H), 2.31-2.51 (m, 3H),
.94 (s, 3H), 3.14 (d, 1H, J ) 12.4 Hz), 3.57 (d, 1H, J ) 3.2
3
) (major
2
1
-1 1
Hz), and 4.78 (d, 1H, J ) 3.2 Hz); H NMR (400 MHz, CDCl
3
)
3
1476, and 1424 cm ; H NMR (400 MHz, CDCl ) (diastereomer
(
(
2
minor diastereomer) δ 1.40 (s, 3H), 2.27 (s, 3H), 2.31-2.41
m, 2H), 2.58 (d, 1H, J ) 17.0 Hz), 2.82 (d, 1H, J ) 17.0 Hz),
.96 (s, 3H), 3.73 (d, 1H, J ) 5.6 Hz), and 4.98 (d, 1H, J ) 5.6
A) δ 1.75 (m, 3H), 1.79 (s, 3H), 1.95 (m, 1H), 2.08 (s, 3H), 2.15
(s, 3H), 2.20 (s, 3H), 3.25 (m, 1H), 3.61 (s, 2H), 3.76 (m, 2H),
3.90 (d, 1H, J ) 8.0 Hz), 4.72 (m, 1H), 4.89 (m, 1H), and 5.69
1
3
(dd, 1H, J ) 7.6 and 4.4 Hz); 1H NMR (400 MHz, CDCl
Hz); C NMR (100 MHz, CDCl
3
) δ 16.3, 17.1, 26.5, 26.6, 27.6,
9.2, 37.4, 40.2, 44.5, 45.6, 45.7, 48.2, 49.4, 50.8, 150.3, 151.4,
73.4, 202.4, and 205.1. Anal. Calcd for C11 S: C, 58.65;
3
)
2
1
(diastereomer B) δ 1.69 (m, 2H), 1.79 (s, 3H), 2.01 (m, 2H),
2.11 (s, 3H), 2.12 (s, 3H), 2.14 (s, 3H), 3.17 (m, 1H), 3.60 (s,
1H), 3.61 (m, 1H), 3.63 (s, 1H), 3.85 (m, 1H), 4.22 (d, 1H, J )
H
15NO
2
H, 6.72; N, 6.22. Found: C, 58.59; H, 6.81; N, 6.14.

3
420 J . Org. Chem., Vol. 67, No. 10, 2002
Padwa et al.
9
.2 Hz), 4.74 (s, 1H), 4.90 (s, 1H), and 5.39 (dd, 1H, J ) 9.4
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography to give
2.0 g (85%) of 31 as a yellow oil consisting of a 4:1 mixture of
diastereomers. For analytical purposes the diastereomers were
separated by HPLC: IR (neat) 1748, 1694, 1179, and 1143
1
3
and 3.4 Hz); C NMR (100 MHz, CDCl ) (diastereomer A) δ
3
1
3.3, 14.1, 21.0, 21.1, 21.7, 23.1, 43.6, 46.0, 47.8, 56.9, 72.2,
14.2, 140.1, 140.1, 169.8, 173.6, and 174.5; 13C NMR (100
) (diastereomer B) δ 13.0, 13.7, 21.2, 22.0, 23.1,
3.9, 43.9, 46.3, 47.9, 56.5, 73.7, 114.3, 140.1, 170.3, 172.4, and
74.7; HRMS calcd for C16 359.1225, found 359.1236.
-(2-[3-(1-Acet oxy-2,2-b is(m et h ylsu lfa n yl)et h yl)-2-ox-
op ip er id in -1-yl]-2-oxoeth yl) Acr ylic Acid Meth yl Ester
29). To a 0.5 g (1.8 mmol) sample of lactam 25 in CH Cl (10
1
MHz, CDCl
3
-1 1
2
1
cm ; H NMR (400 MHz, CDCl
1.55 (m, 2H), 1.58-1.65 (m, 1H), 1.82-1.95 (m, 3H), 2.14 (s,
H), 2.17 (s, 3H), 2.20 (s, 3H), 3.20-3.26 (m, 1H), 3.48-3.53
m, 1H), 3.65 (m, 2H), 4.04 (d, 1H, J ) 4.4 Hz), 4.70-4.75 (m,
H), 5.11-5.17 (m, 2H), 5.65 (dd, 1H, J ) 8.0 and 4.4 Hz),
3
) (major diastereomer) δ 1.24-
H
4 2
25NO S
3
(
2
1
(
2
2
1
3
and 5.93-6.03 (m, 1H); H NMR (400 MHz, CDCl ) (minor
diastereomer) δ 1.37-1.55 (m, 2H), 1.60-1.69 (m, 1H), 1.83-
1.97 (m, 3H), 2.11 (s, 3H), 2.12 (s, 3H), 2.14 (s, 3H), 3.15-3.21
mL) was added 1.8 g of oven-dried powdered 4 Å molecular
sieves and 0.44 g (2.7 mmol) of 3-(methoxycarbonyl)but-3-enoyl
6
2
chloride. The mixture was stirred at room temperature for
5 h, followed by filtration through a plug of silica with diethyl
ether. The filtrate was washed with a saturated aqueous
NaHCO solution and dried over MgSO , and the solvent was
(
m, 1H), 3.44-3.48 (m, 1H), 3.58-3.73 (m, 2H), 4.19 (d, 1H, J
1
)
7.2 Hz), 4.69-4.74 (m, 1H), 5.35-5.38 (m, 1H), 5.09-5.14
13
(
m, 2H), 5.36 (t, 1H, J ) 6.6 Hz), and 5.94-6.04 (m, 1H);
C
3
4
NMR (100 MHz, CDCl ) (major diastereomer) δ 14.3, 15.1,
3
removed under reduced pressure. The residue was purified by
flash silica gel chromatography to give 0.6 g (90%) of 29 as a
pale wax which consisted of a 1:1 mixture of diastereomers:
2
1
1.1, 26.5, 27.7, 27.8, 42.6, 44.4, 48.5, 57.0, 73.6, 118.4, 131.5,
70.4, 174.5, and 177.0; 13C NMR (100 MHz, CDCl
) (minor
3
-1
1
diastereomer) δ 12.7, 14.6, 21.2, 27.2, 27.6, 27.6, 42.4, 44.3,
8.2, 56.5, 73.7, 118.2, 131.6, 170.7, 174.5, and 176.0. Anal.
Calcd for C16 : C, 53.45; H, 7.01; N, 3.90. Found: C,
3.60; H, 7.12; N, 3.93.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-1-p en t-4-
en oyla zep a n -3-yl) Eth yl Ester (32). To a 1.0 g (3.6 mmol)
sample of 26 in CH Cl (20 mL) was added 3.6 g of oven-dried
4 Å powdered molecular sieves and 0.6 g (5.2 mmol) of pent-
-enoyl chloride.63 The mixture was stirred at room temper-
IR (neat) 1744, 1699, 1371, and 1149 cm ; H NMR (400 MHz,
CDCl ) δ 1.63-1.83 (m, 4H), 1.92-2.00 (m, 2H), 2.08 (s, 3H),
.11 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.14 (s, 3H), 2.19 (s,
4
3
H
4 2
25NO S
2
3
3
1
2
3
1
4
1
5
H), 2.16-2.22 (m, 1H), 2.33-2.89 (m, 1H), 2.55-3.62 (m, 1H),
.62-3.78 (m, 4H), 3.73 (s, 6H), 3.85-3.88 (m, 6H), 4.22 (d,
H, J ) 9.6 Hz), 5.39 (dd, 1H, J ) 9.6 and 3.2 Hz), 5.69 (m,
H), 5.70 (dd, 1H, J ) 8.4 and 4.0 Hz), and 5.26 (dd, 2H, J )
2
2
1
3
.2 and 1.2 Hz); C NMR (100 MHz, CDCl ) δ 12.9, 13.1, 13.5,
3
4
3.9, 20.9, 21.0, 21.1, 21.6, 21.8, 23.7, 43.4, 43.5, 43.7, 44.1,
6.0, 46.3, 52.2, 56.5, 56.7, 72.0, 73.6, 127.9, 128.0, 135.1, 135.2,
67.1, 169.8, 170.3, 172.5, 173.7, 174.0, and 174.2. Anal. Calcd
ature for 15 h, followed by filtration through a plug of silica
with diethyl ether. The filtrate was washed with a saturated
aqueous NaHCO solution and dried over MgSO , and the
3 4
for C17
6 2
H25NO S : C, 50.60; H, 6.24; N, 3.47. Found: C, 50.33;
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to give 0.9 g (69%)
of 32 as a yellow oil consisting of a 4:1 mixture of diastereo-
mers. For analytical purposes a sample of the diastereomers
was separated by HPLC: IR (neat) 1747, 1696, 1369, and 1143
H, 6.19; N, 3.56.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-1-p en t-4-
en oylp ip er id in -3-yl) Eth yl Ester (30). To a 2.1 g (7.5 mmol)
2 2
sample of lactam 25 in CH Cl (40 mL) was added 7.5 g of
oven-dried 4 Å powdered molecular sieves and 1.3 g (11 mmol)
-1 1
of pent-4-enoyl chloride.63 The mixture was stirred at room
cm ; H NMR (400 MHz, CDCl
1
3
3
) (major diastereomer) δ 1.35-
.55 (m, 2H), 1.58-1.69 (m, 1H), 1.82-1.96 (m, 3H), 2.11 (s,
H), 2.12 (s, 3H), 2.14 (s, 3H), 2.35-2.41 (m, 2H), 2.88-3.06
temperature for 15 h, followed by filtration through a plug of
silica with diethyl ether. The filtrate was washed with a
saturated aqueous NaHCO solution and dried over MgSO ,
3 4
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography to give
(
1
(
1
1
3
m, 2H), 3.16 (dd, 1H, J ) 14.8 and 11.6 Hz), 3.43-3.47 (m,
H), 4.19 (d, 1H, J ) 7.6 Hz), 4.69-4.75 (m, 1H), 4.95-5.06
m, 2H), 5.36 (dd, 1H, J ) 7.6 and 6.0 Hz), and 5.78-5.88 (m,
1
3
H); H NMR (400 MHz, CDCl ) (minor diastereomer) δ 1.40-
2
.5 g (92%) of 30 as a yellow oil consisting of a 1:1 mixture of
.52 (m, 2H), 1.58-1.64 (m, 1H), 1.81-1.94 (m, 3H), 2.13 (s,
H), 2.16 (s, 3H), 2.19 (s, 3H), 2.39 (dd, 2H, J ) 13.6 and 7.2
diastereomers. For analytical purposes the diastereomers were
separated by HPLC: IR (neat) 1745, 1688, 1368, and 1289
-
1
1
Hz), 2.87-3.03 (m, 2H), 3.21 (dd, 1H, J 14.8 and 11.6 Hz),
3
1
cm ; H NMR (400 MHz, CDCl
1
3
(
)
3
) (diastereomer A) δ 1.67-
.84 (m, 2H), 1.94-1.97 (m, 1H), 2.02-2.10 (m, 1H), 2.07 (s,
H), 2.14 (s, 3H), 2.19 (s, 3H), 2.34-2.40 (m, 2H), 2.95-3.00
.47-3.51 (m, 1H), 4.05 (d, 1H, J ) 4.4 Hz), 4.69-4.74 (m,
H), 4.97-5.07 (m, 2H), 5.64 (dd, 1H, J ) 8.0 and 4.4 Hz),
1
3
3
and 5.79-5.89 (m, 1H); C NMR (100 MHz, CDCl ) (major
m, 2H), 3.22-3.27 (m, 1H), 3.72-3.75 (m, 2H), 3.90 (d, 1H, J
diastereomer) δ 12.7, 14.6, 21.2, 27.3, 27.7, 27.7, 29.4, 39.0,
8.0 Hz), 4.95-5.07 (m, 2H), 5.69 (dd, 1H, J ) 8.0 and 4.0
1
42.4, 48.3, 56.5, 73.8, 115.4, 137.6, 170.8, 175.9, and 176.0;
Hz), and 5.78-5.88 (m, 1H); H NMR (400 MHz, CDCl
3
)
1
3
C NMR (100 MHz, CDCl
3
) (minor diastereomer) δ 14.3, 15.2,
(
(
3
(
diastereomer B) δ 1.59-1.79 (m, 2H), 1.93-2.06 (m, 2H), 2.10
s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.37-2.42 (m, 2H), 2.97-
2
1
3
1.0, 26.5, 27.7, 27.8, 29.3, 39.1, 42.5, 48.5, 57.1, 73.7, 115.5,
37.5, 170.4, 175.8, and 177.0; HRMS calcd for C16
73.1381, found 373.1379.
4 2
H25NO S
.01 (m, 2H), 3.17 (ddd, 1H, J ) 11.4, 6.6, and 3.2 Hz), 3.60
ddd, 1H, J ) 13.6, 9.6, and 4.2 Hz), 3.81-3.87 (m, 1H), 4.33
d, 1H, J ) 9.6 Hz), 4.96-5.08 (m, 2H), 5.39 (dd, 1H, J ) 9.6
N-(2-(Met h ylsu lfa n yl)-5,6-d ih yd r o-4H -fu r o[2,3-b]p y-
r id in e)bu t-3-en a m id e (33). To a 0.6 g (1.9 mmol) sample of
7 in CH Cl (10 mL) was added 0.5 g (2.4 mmol) of DMTSF
(
1
3
and 3.2 Hz), and 5.79-5.90 (m, 1H); C NMR (100 MHz,
2
2
2
CDCl
3
) (diastereomer A) δ 13.2, 14.0, 21.0, 21.0, 21.7, 29.1,
in one portion at -40 °C. Following the general procedure,
flash silica gel chromatography of the crude reaction mixture
gave 0.3 g (68%) of furan 33 as a clear oil: IR (neat) 1673,
3
1
1
1
9.0, 43.4, 46.0, 56.8, 72.1, 115.5, 137.5, 169.8, 173.6, and
1
3
76.2; C NMR (100 MHz, CDCl
3.6, 21.2, 21.9, 23.8, 29.1, 39.0, 43.8, 46.3, 56.5, 73.6, 115.4,
4 2
37.6, 170.3, 172.3, and 176.4. Anal. Calcd for C16 25NO S :
3
) (diastereomer B) δ 12.9,
-
1 1
1
1
624, 1510, and 1368 cm ; H NMR (400 MHz, CDCl
3
) δ 1.85-
H
.91 (m, 2H), 2.44 (t, 2H, J ) 6.4 Hz), 3.55 (d, 2H, J ) 7.2
Hz), 3.80-3.83 (m, 2H), 5.14-5.20 (m, 2H), 6.94-6.05 (m, 1H),
C, 53.46; H, 7.02; N, 3.90. Found: C, 53.17; H, 7.05; N, 3.88.
Acetic Acid 1-(1-Bu t-3-en oyl-2-oxoa zep a n -3-yl)-2,2-bis-
13
and 6.36 (s, 1H); C NMR (100 MHz, CDCl
1.0, 43.1, 105.3, 117.8, 118.3, 131.5, 141.0, 146.2, and 169.0.
Anal. Calcd for C12 S: C, 60.74; H, 6.38; N, 5.91.
Found: C, 60.69; H, 6.07; N, 6.08.
-Met h yl-N-(2-(m et h ylsu lfa n yl)-5,6-d ih yd r o-4H -fu r o-
2,3-b]p yr id in -7-yl)bu t-3-en a m id e (34). To a 1.0 g (2.8
mmol) sample of 28 in CH CN (15 mL) at -40 °C was added
.6 g (3.0 mmol) of DMTSF. The reaction mixture was stirred
3
) δ 20.2, 20.6, 23.1,
(
m eth ylsu lfa n yl) Eth yl Ester (31). To a 1.9 g (6.4 mmol)
sample of lactam 25 in CH Cl (35 mL) was added 6.4 g of
oven-dried 4 Å powdered molecular sieves and 1.0 g (9.5 mmol)
4
2
2
H
15NO
2
6
0
of but-3-enoyl chloride. The mixture was stirred at room
temperature for 15 h, followed by filtration through a plug of
silica with diethyl ether. The filtrate was washed with a
3
[
3
3 4
saturated aqueous NaHCO solution and dried over MgSO ,
0
at -40 °C for 3 h, and then 2.1 mL (15 mmol) of triethylamine
was added. The mixture was diluted with diethyl ether, and
(63) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R., J r.
Tetrahedron 2000, 56, 5735.
3
poured into a saturated aqueous NaHCO solution. The organic

Synthesis of Azapolycyclic Systems
J . Org. Chem., Vol. 67, No. 10, 2002 3421
phase was separated, and the aqueous phase was washed with
diethyl ether. The combined organic layer was dried over
chromatography to provide 0.06 g (61%) of 40 as a orange oil
which consisted of a 1:1 mixture of inseparable diastereo-
-
1
1
anhydrous K
2
CO
3
, and the solvent was removed under reduced
mers: IR (neat) 1732, 1689, 1601, 1275, and 1204 cm ; H
NMR (400 MHz, CDCl ) δ 1.13 (s, 3H), 1.38 (s, 3H), 1.62-
pressure. The residue was purified by flash silica gel chroma-
3
tography to give 0.5 g (66%) of furan 34 as a clear oil: IR (neat)
2.03 (m, 6H), 2.10 (s, 3H), 2.24 (s, 3H), 2.29-2.57 (m, 6H), 2.83
(d, 1H, J ) 16.8 Hz), 3.17 (d, 1H, J ) 12.4 Hz), 3.26-3.30 (m,
1H), 3.31-3.41 (m, 1H), 3.42 (s, 1H), 3.48 (s, 1H), 3.59-3.65
1
1
766, 1672, 1512, 1425, and 1145 cm-1; H NMR (400 MHz,
CDCl
3
) δ 1.83 (s, 3H), 1.86-1.92 (m, 2H), 2.37 (s, 3H), 2.45 (t,
2
H, J ) 6.4 Hz), 3.83-3.86 (m, 2H), 4.78 (s, 1H), 4.88 (s, 1H),
(m, 1H), and 3.74-3.80 (m, 1H); 13C NMR (100 MHz, CDCl
3
)
1
3
and 6.37 (s, 1H); C NMR (100 MHz, CDCl
3
) δ 20.2, 20.7, 23.1,
3.2, 43.2, 44.9, 105.2, 113.7, 118.0, 139.8, 140.9, 146.4, and
68.8. Anal. Calcd for C13 S: C, 62.13; H, 6.82; N, 5.58.
δ 16.0, 16.9, 21.1, 22.7, 24.0, 27.5, 28.6, 36.5, 38.8, 39.0, 39.1,
2
1
45.2, 46.2, 46.3, 50.8, 52.7, 53.5, 102.7, 103.4, 142.6, 143.5,
H
17NO
2
2
172.4, 172.6, 201.6, and 204.9. Anal. Calcd for C13H17NO S:
Found: C, 62.08; H, 6.63; N, 5.44.
N-(2-(Meth ylsu lfa n yl)-5,6-d ih yd r o-4H-fu r o[2,3-b]p yr i-
d in -7-yl)p en t-4-en a m id e (36). To a 0.9 g (2.4 mmol) sample
C, 62.13; H, 6.82; N, 5.58. Found: C, 62.01; H, 6.59; N, 5.53.
7-(Me t h ylsu lfa n yl)-2,8-d ioxo-1,2,5,6,8,9-h e xa h yd r o-
4H,7H-pyr r olo[3,2,1-ij]qu in olin e-9a -car boxylic Acid Meth -
yl Ester (41). A solution of 0.5 g (1.3 mmol) of cycloadduct 46
(vide infra) dissolved in benzene (7 mL) was heated at reflux
for 1 h. The reaction mixture was cooled to room temperature,
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography to
provide 0.3 g (77%) of 41 as a pale yellow oil consisting of a
1:1 mixture of diastereomers: IR (neat) 1732, 1435, 1201, and
of 30 in CH CN (12 mL) at -40 °C was added 0.5 g (2.4 mmol)
3
of DMTSF. The reaction mixture was stirred at -40 °C for 3
h, and then 1.7 mL (12 mmol) of triethylamine was added.
The mixture was diluted with diethyl ether and poured into a
3
saturated aqueous NaHCO solution. The organic phase was
separated, and the aqueous phase was washed with diethyl
ether. The combined organic layer was dried over anhydrous
-
1
1
K
2
CO
3
, and the solvent was removed under reduced pressure.
3
1172 cm ; H NMR (400 MHz, CDCl ) δ 1.75-2.10 (m, 4H),
The residue was purified by flash silica gel chromatography
to give 0.4 g (61%) of furan 36 as a clear oil: IR (neat) 1621,
2.11 (s, 3H), 2.13 (s, 3H), 2.35-2.52 (m, 4H), 2.77-2.81 (m,
2H), 3.05 (s, 1H), 3.09 (d, 1H, J ) 2.0 Hz), 3.35-3.48 (m, 2H),
3.43 (s, 1H), 3.52-3.60 (m, 2H), 3.53 (s, 1H), 3.65 (s, 3H), 3.68
-
1 1
1
(
508, and 1381 cm ; H NMR (400 MHz, CDCl
m, 2H), 2.37 (s, 3H), 2.42-2.47 (m, 2H), 2.45 (t, 2H, J ) 6.4
Hz), 2.86 (t, 2H, J ) 7.8 Hz), 3.81-3.84 (m, 2H), 4.98-5.11
3
) δ 1.86-1.92
(s, 3H), and 3.71-3.78 (m, 4H); 13C NMR (100 MHz, CDCl
) δ
3
16.1, 16.4, 20.7, 20.7, 23.4, 24.1, 39.0, 39.3, 40.6, 42.4, 42.7,
45.3, 45.6, 49.2, 52.3, 52.4, 53.5, 105.6, 107.0, 135.6, 137.8,
171.2, 171.7, 172.0, 172.6, 199.0, and 201.2. Anal. Calcd for
1
3
(
m, 2H), 5.85-5.95 (m, 1H), and 6.37 (s, 1H); C NMR (100
MHz, CDCl ) δ 20.1, 20.7, 23.3, 29.4, 35.4, 43.1, 105.2, 115.3,
17.8, 137.7, 140.9, 146.5, and 170.5. Anal. Calcd for C13
3
1
H
17
-
14 4
C H17NO S: C, 56.93; H, 5.81; N, 4.75. Found: C, 56.77; H,
NO
2
S: C, 62.13; H, 6.82; N, 5.58. Found: C, 62.09; H, 6.72;
5.69; N, 4.72.
N, 5.49.
N-(2-(Met h ylsu lfa n yl)-4,5,6,7-t et r a h yd r ofu r o[2,3-b]a -
zep in -8-yl)p en t-4-en a m id e (38). To a 0.7 g (1.9 mmol)
sample of 32 in CH
8-(Meth ylsu lfa n yl)-1,2,6,7,10,10a -h exa h yd r o-5H,8H-p y-
r id o[3,2,1-ij]qu in olin e-3,9-d ion e (42). To an oven-dried,
heavy-walled, high-pressure tube equipped with a magnetic
stirring bar and rubber septum was added a solution of 0.1 g
(0.4 mmol) of furan 36 in toluene (4 mL). Argon was bubbled
through the solution for 15 min, and the septum was replaced
with a threaded Teflon cap containing a rubber O-ring seal.
The vessel was heated at 150 °C behind a protective shield
for 15 h. The mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. The residue
was purified by flash silica gel chromatography to give 0.08 g
(76%) of 42 as a clear oil consisting of a 3:2 mixture of
3
CN (10 mL) at -40 °C was added 0.4 g
1.9 mmol) of DMTSF. The reaction mixture was stirred at
(
-
40 °C for 3 h, and then 1.3 mL (9 mmol) of triethylamine
was added. The mixture was diluted with diethyl ether and
3
poured into a saturated aqueous NaHCO solution. The organic
phase was separated, and the aqueous phase was washed with
diethyl ether. The combined organic layer was dried over
anhydrous K CO , and the solvent was removed under reduced
2 3
pressure. The residue was purified by flash silica gel chroma-
-1 1
tography to give 0.25 g (49%) of furan 38 as a colorless oil: IR
diastereomers: IR (neat) 1716, 1669, 1297, and 1197 cm ; H
NMR (400 MHz, CDCl ) δ 1.51 (qd, 1H, J ) 13.2 and 4.0 Hz,
-
1
1
(
neat) 1685, 1441, 1295, and 1163 cm ; H NMR (400 MHz,
CDCl ) δ 1.58-1.64 (m, 2H), 1.76-1.81 (m, 2H), 2.33-2.42 (m,
H), 2.38 (s, 3H), 3.63-3.65 (m, 2H), 4.94-5.02 (m, 2H), and
.74-5.84 (m, 1H); 13C NMR (100 MHz, CDCl
) δ 19.5, 24.8,
5.9, 29.4, 30.7, 33.9, 45.7, 99.5, 115.3, 117.6, 118.3, 137.5,
423, and 172.9. Anal. Calcd for C14 S: C, 63.37; H,
.22; N, 5.28. Found: C, 63.19; H, 7.11; N, 5.06.
-(Meth ylsu lfa n yl)-5,6,9,9a -tetr a h yd r o-1H,4H,7H-p yr -
3
3
minor diastereomer), 1.68 (qd, 1H, J ) 13.2 and 5.0 Hz, major
diastereomer), 1.75-2.03 (m, 4H), 2.08 (s, 3H, minor diaste-
reomer), 2.11 (s, 3H, major diastereomer), 2.17-2.67 (m, 4H),
2.89 (dd, 1H, J ) 18.4 and 5.6 Hz, minor diastereomer), 3.16
(t, 1H, J ) 12.6 Hz, major diastereomer), 3.26 (s, 1H, minor
6
5
2
1
7
3
H
19NO
2
1
3
diastereomer), 3.35-3.48 (m, 2H), and 3.97-4.08 (m, 1H);
C
7
NMR (100 MHz, CDCl ) δ 16.0, 16.4, 21.1, 21.3, 26.2, 26.3,
3
r olo[3,2,1-ij]qu in olin e-2,8-d ion e (39). A 0.7 g (3.0 mmol)
sample of furan 33 dissolved in toluene (15 mL) was heated
at reflux for 1 h at 110 °C. The reaction mixture was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The crude residue was purified by flash silica
gel chromatography to provide 0.6 g (92%) of 39 as a yellow
oil which consisted of a 1.4:1 mixture of diastereomers: IR
27.5, 31.8, 32.4, 32.5, 36.5, 40.1, 40.5, 40.8, 42.5, 54.4, 55.1,
108.9, 109.5, 134.3, 136.0, 168.2, 168.5, 201.9, and 202.4. Anal.
Calcd for C13H17NO S: C, 62.13; H, 6.82; N, 5.58. Found: C,
2
62.06; H, 6.67; N, 5.33.
Further heating of 42 at 200 °C gave 0.13 g (82%) of
9-hydroxy-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-
one as a white solid: mp 220-221 °C; IR (film) 1727, 1632,
-
1
1
-1
1
(
neat) 1716, 1682, 1420, and 1197 cm ; H NMR (400 MHz,
CDCl ) δ 1.84-1.94 (m, 4H), 1.99-2.07 (m, 2H), 2.10 (s, 3H),
.12 (s, 3H), 2.16-2.32 (m, 4H), 2.32-2.47 (m, 1H), 2.58-2.60
m, 1H), 2.67 (dd, 1H, J ) 16.4 and 8.4 Hz), 2.76 (dd, 1H, J )
1180, and 1154 cm ; H NMR (400 MHz, CD
3
OD) δ 1.82-
3
1.85 (m, 2H), 2.50-2.54 (m, 2H), 2.67-2.70 (m, 2H), 2.73-
1
3
2
(
1
3
2
4
2.77 (m, 2H), 3.75-3.77 (m, 2H), and 6.42-6.44 (m, 2H);
NMR (100 MHz, CD OD) δ 22.9, 26.2, 28.3, 32.5, 42.2, 114.1,
114.9, 128.4, 128.6, 129.2, 154.4, and 171.5. Anal. Calcd for
12 2
C H13NO : C, 70.90; H, 6.45; N, 6.89. Found: C, 70.78; H,
C
3
7.2 and 10 Hz), 3.02-3.08 (m, 3H), 3.35-3.46 (m, 5H), and
) δ 15.9, 16.1,
.59-3.69 (m, 2H); 13C NMR (100 MHz, CDCl
3
1.1, 21.2, 22.8, 23.6, 29.3, 34.0, 37.1, 37.2, 38.8, 39.1, 39.5,
2.1, 52.9, 54.0, 102.4, 103.7, 138.3, 140.7, 173.2, 173.3, 201.2,
6.32; N, 6.66.
8-(Meth ylsu lfan yl)-4,5,6,7,10,10a -h exah ydr o-1H,8H-aze-
p in o[3,2,1-h i]in d ole-2,9-d ion e (43). To a 0.5 g (1.4 mmol)
sample of 31 dissolved in CH CN (10 mL) at -40 °C was added
3
0.3 g (1.4 mmol) of DMTSF. The reaction mixture was stirred
at -40 °C for 3 h, and then 1.0 mL (7.1 mmol) of triethylamine
was added. The mixture was diluted with diethyl ether and
poured into a saturated aqueous NaHCO solution. The organic
3
phase was separated, and the aqueous phase was washed with
diethyl ether. The combined organic layer was dried over
and 201.4. Anal. Calcd for C12
5
9
H
15NO
2
S: C, 60.74; H, 6.38; N,
.91. Found: C, 60.51; H, 6.27; N, 5.74.
a -Me t h yl-7-(m e t h ylsu lfa n yl)-5,6,9,9a -t e t r a h yd r o-
H,4H,7H-p yr r olo[3,2,1-ij]qu in olin e-2,8-d ion e (40). A so-
1
lution of 0.1 g (0.4 mmol) of furan 34 in toluene (2 mL) was
heated at reflux for 7 h. The reaction mixture was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was purified by flash silica gel

3
422 J . Org. Chem., Vol. 67, No. 10, 2002
Padwa et al.
anhydrous K CO , and the solvent was removed under reduced
2
3
1H), 2.27-2.42 (m, 2H), 2.58-2.67 (m, 1H), 2.91 (br s, 1H),
3.75 (d, 3H, J ) 2.0 Hz), 5.03-5.06 (m, 1H), and 6.88-6.90
pressure. The residue was purified by flash silica gel chroma-
tography to give 0.2 g (64%) of 43 as a yellow oil consisting of
a 3:2 mixture of diastereomers: IR (neat) 1716, 1669, 1284,
(m, 1H); 13C NMR (CDCl
, 100 MHz) δ 31.1, 32.1, 51.8, 75.6,
3
137.9, 146.9, and 165.6; HRMS calcd for C
found 142.0633.
7 10 3
H O 142.0630,
-
1
1
and 1197 cm ; H NMR (300 MHz, CDCl
1
3
) δ 1.64-2.00 (m,
0H), 2.06 (s, 3H, minor diastereomer), 2.09 (s, 3H, major
5-Acetoxycyclop en t-1-en eca r boxylic Acid Meth yl Es-
ter . To 3.3 g (23 mmol) of the above alcohol in 40 mL of CH
Cl at 0 °C was consecutively added 2.8 mL (34.8 mmol) of
diastereomer), 2.14-2.66 (m, 10H), 3.05-3.08 (m, 1H, minor
diastereomer), 3.10-3.19 (m, 1H, major diastereomer), 3.24
2
-
2
(
s, 1H, major diastereomer), 3.20-3.47 (m, 1H, major diaste-
pyridine, 4.6 mL (48.7 mmol) of acetic anhydride, and 0.3 g
(2.3 mmol) of DMAP. The mixture was stirred at 0 °C for 2 h
and then diluted with diethyl ether and washed with 10%
reomer), 3.33 (s, 1H, minor diastereomer), and 3.94-4.08 (m,
1
3
2
2
5
2
3
H); C NMR (75 MHz, CDCl ) δ 16.0, 16.4, 21.1, 21.3, 26.0,
6.1, 26.2, 27.4, 31.7, 32.4, 32.4, 36.5, 40.0, 40.4, 40.8, 42.5,
4.4, 55.1, 108.8, 109.3, 134.3, 136.0, 168.1, 168.4, 201.9, and
4 4
CuSO . The organic layer was dried over MgSO and concen-
trated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 3.4 g (80%) of
the title compound as a colorless oil: IR (neat) 1731, 1639,
2
02.3. Anal. Calcd for C13H17NO S: C, 62.12; H, 6.82; N, 5.57.
Found: C, 62.00; H, 6.87; N, 5.40.
,3,4,5,6,9,10,11-Octa h yd r o-2-(m eth ylth io)-6-oxo-8H-2,-
2-m eth en o-3a H-fu r o[2,3-k]p yr id o[1,2-a ]a zep in e (45). To
-
1 1
2
3
1240, and 1040 cm ; H NMR (CDCl , 400 MHz) δ 1.84-1.91
1
(m, 1H), 2.00 (s, 3H), 2.32-2.49 (m, 2H), 2.60-2.69 (m, 1H),
3.71 (s, 3H), 5.93-5.96 (m, 1H), and 7.08 (t, 1H, J ) 2.4 Hz);
an oven-dried, heavy-walled, high-pressure tube equipped with
a magnetic stirring bar and rubber septum was added a
solution of 0.1 g (0.4 mmol) of furan 38 in toluene (4 mL).
Argon was bubbled through the solution for 15 min, and the
septum was replaced with a threaded Teflon cap containing a
rubber O-ring seal. The vessel was heated at 150 °C behind a
protective shield for 4 h. The reaction mixture was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was purified by flash silica gel
chromatography to give 0.08 g (75%) of 45 as a white solid:
1
3
C NMR (CDCl , 100 MHz) δ 21.3, 31.3, 31.5, 51.7, 77.5, 134.9,
3
150.3, 164.2, and 170.8; HRMS calcd for C
found 184.0737.
9 12 4
H O 184.0736,
5-((ter t-Bu t oxyca r b on yl)m et h yl)cyclop en t -1-en eca r -
boxylic Acid Meth yl Ester . A solution of LDA was prepared
by the addition of 2.8 mL (5.5 mmol) of n-BuLi (2.0 M in
hexane) to a solution of 0.8 mL (5.7 mmol) of diisopropylamine
in 10 mL of THF at -78 °C. The solution was warmed to 0 °C
for 30 min and then cooled to -30 °C, and 0.7 mL (5.3 mmol)
of tert-butyl acetate in 5 mL of THF was added. After it was
stirred for 30 min, the solution was cooled to -78 °C and 0.75
g (4.1 mmol) of the above cyclopentenyl acetate in 5 mL of THF
was added dropwise. After it was stirred for 1.5 h, the solution
was warmed to room temperature, quenched with a saturated
-
1 1
mp 97-98 °C; IR (KBr) 1666, 1410, 1339, and 1176 cm ; H
NMR (400 MHz, CDCl
2
2
3
) δ 1.28-1.38 (m, 1H), 1.48-1.70 (m,
H), 1.72-1.95 (m, 7H), 2.18 (s, 3H), 2.27-2.36 (m, 1H), 2.36-
.52 (m, 2H), 2.82 (t, 1H, J ) 12.8 Hz), 4.30 (dd, 1H, J ) 14.2
1
3
and 4.6 Hz), and 5.89 (s, 1H); C NMR (100 MHz, CDCl
3
) δ
2.2, 25.7, 26.8, 29.1, 29.8, 32.5, 38.1, 42.0, 44.4, 90.1, 99.3,
32.0, 151.7, and 170.4. Anal. Calcd for C14 S: C, 63.37;
1
1
aqueous NH
organic extracts were dried over MgSO
4
Cl solution, and extracted with EtOAc. The
and concentrated
H
19NO
2
4
H, 7.22; N, 5.28. Found: C, 63.24; H, 7.09; N, 5.14.
,3,4,5,8,9-Hexa h ydr o-2-(m eth ylth io)-5-oxo-7H-2,10-m e-
th en o-3a H-fu r o[2,3-i]in dolizin e-3a -car boxylic Acid Meth -
yl Ester (46). To a 0.5 g (1.3 mmol) sample of 29 in CH Cl
15 mL) at -40 °C was added 0.3 g (1.3 mmol) of DMTSF. The
mixture was stirred at -40 °C for 30 min before warming to
°C. After the mixture was stirred for 3 h at 0 °C, 0.9 mL (6.4
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 0.84 g (87%) of the title
compound as a colorless oil: IR (neat) 2980, 1726, 1367, and
2
-
1
1
1
1
2
3
147 cm ; H NMR (CDCl , 400 MHz) δ 1.43 (s, 9H), 1.70-
2
2
.78 (m, 1H), 2.17-2.27 (m, 2H), 2.36-2.56 (m, 2H), 2.70-
.78 (m, 1H), 3.26-3.34 (m, 1H), 3.72 (s, 3H), and 6.78-6.80
(
(
m, 1H); 13C NMR (CDCl
3
, 100 MHz) δ 28.3, 29.7, 31.7, 39.8,
0
4
1.3, 51.6, 80.4, 138.3, 145.2, 165.5, and 172.3; HRMS calcd
240.1362, found 240.1368.
-(Ca r b oxym et h yl)cyclop en t -1-en eca r b oxylic
Meth yl Ester . The above diester was stirred with 10 mL of a
0% TFA solution of CH Cl at room temperature for 3 h. The
mmol) of triethylamine was added. The mixture was diluted
with diethyl ether and poured into a saturated aqueous
for C13
20 4
H O
5
Acid
NaHCO
aqueous phase was washed with diethyl ether. The combined
organic layer was dried over anhydrous K CO , and the solvent
was removed under reduced pressure. The residue was purified
by recrystallization from hexane/CH Cl to provide 0.3 g (77%)
of 46 as a colorless solid: mp 95-96 °C; IR (film) 1729, 1482,
3
solution. The organic phase was separated, and the
1
2
2
2
3
solvent was evaporated under reduced pressure, and the crude
residue was subjected to flash silica gel chromatography to
afford 0.4 g (67%) of the title compound as a colorless oil: IR
2
2
-
1 1
-
1
1
3
(neat) 3508 (br), 1710, 1629, and 1439 cm ; H NMR (CDCl ,
1
(
3
306, and 1160 cm ; H NMR (400 MHz, CDCl ) δ 1.82-1.90
4
00 MHz) δ 1.70-1.78 (m, 1H), 2.23-2.34 (m, 2H), 2.39-2.58
m, 2H), 2.14-2.20 (m, 1H), 2.24 (s, 3H), 2.25 (d, 1H, J ) 11.6
(
(
m, 2H), 2.93 (ddd, 1H, J ) 16.0, 4.0, and 1.2 Hz), 3.31-3.40
Hz), 2.50-2.56 (m, 1H), 2.59 (d, 1H, J ) 11.6 Hz), 2.76 (d, 1H,
1
3
m, 1H), 3.73 (d, 3H, J ) 0.8 Hz), and 6.84-6.86 (m, 1H);
C
J ) 15.6 Hz), 2.82 (d, 1H, J ) 15.6 Hz), 3.34-3.40 (m, 1H),
NMR (CDCl
3
, 100 MHz) δ 30.1, 31.7, 38.5, 40.8, 51.7, 137.8,
3
1
4
1
.66 (s, 3H), 3.68-3.75 (m, 1H), and 6.05 (dd, 1H, J ) 2.8 and
13
146.1, 165.6, and 179.3; HRMS calcd for C
found 184.0734.
9 12 4
H O 184.0736,
.2 Hz); C NMR (100 MHz, CDCl
1.2, 42.5, 52.8, 58.3, 92.7, 100.5, 130.7, 144.5, 172.5, and
78.0. Anal. Calcd for C14 S: C, 56.93; H, 5.80; N, 4.74.
3
) δ 12.1, 21.8, 21.9, 39.9,
5
-(2-[3-(1-Acet oxy-2,2-b is(m et h ylsu lfa n yl)et h yl)-2-ox-
H
17NO
4
op ip er id in -1-yl]-2-oxoet h yl)cyclop en t -1-en eca r b oxylic
Acid Meth yl Ester . To a 0.34 g (1.8 mmol) sample of the
above acid in 10 mL of CH Cl was added 0.2 mL (2.2 mmol)
2 2
of oxalyl chloride followed by 1 drop of DMF. The reaction
mixture was stirred at room temperature for 1 h and then
concentrated under reduced pressure to give the corresponding
acid chloride as a yellow oil. The acid chloride was immediately
Found: C, 56.82; H, 5.75; N, 4.82.
5
-Hyd r oxycyclop en t-1-en eca r boxylic Acid Meth yl Es-
6
4
ter . A modification of the procedure of Ogasawara was used
to prepare this ester. A mixture containing 13.0 mL (100 mmol)
of 2,5-dimethoxytetrahydrofuran and 80 mL of 0.6 N HCl was
stirred at 70 °C for 3 h. After it was cooled to 0 °C, the mixture
was neutralized with a 10% KHCO
mmol) of trimethyl phosphonoacetate and 32 mL (200 mmol)
of a 6.4 M aqueous solution of K CO were added. The mixture
3
solution and 16.4 mL (100
taken up in 3 mL of CH
containing 0.3 g (1.0 mmol) of lactam 25 and 1.0 g of 4 Å
powdered molecular sieves in 10 mL of CH Cl . The reaction
2 2
Cl and slowly added to a solution
2
3
2
2
was stirred at room temperature for 48 h and then extracted
with EtOAc. The extracts were washed with brine, dried over
MgSO , and concentrated under reduced pressure. The residue
4
mixture was vigorously stirred at room temperature for 12 h
and then filtered over a pad of Celite. The filtrate was washed
with a saturated NaHCO solution, dried over MgSO , and
3 4
was distilled under high vacuum to furnish 7.6 g (54%) of the
title compound as a colorless oil: IR (neat) 3447, 1721, 1634,
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to afford 0.42 g (96%)
of the title compound as a mixture of two major diastereo-
-
1
1
and 1296 cm ; H NMR (CDCl
3
, 400 MHz) δ 1.81-1.88 (m,
-
1
1
mers: IR (neat) 1751, 1716, 1690, 1623, and 1372 cm ; H
NMR (CDCl , 400 MHz) (diastereomer A) δ 1.55-1.65 (m, 1H),
(64) Yamane, T.; Takahashi, M.; Ogasawara, K. Synthesis 1995, 444.
3

Synthesis of Azapolycyclic Systems
.67-1.80 (m, 2H), 1.89-1.95 (m, 1H), 2.03-2.10 (m, 1H), 2.05
J . Org. Chem., Vol. 67, No. 10, 2002 3423
1
2.14 (s, 6H), 2.19 (s, 3H), 2.49-2.62 (m, 8H), 3.11-3.19 (m,
5H), 3.20-3.28 (m, 1H), 3.58-3.64 (m, 1H), 3.73-3.80 (m, 2H),
3.86-3.90 (m, 1H), 3.89 (d, 1H, J ) 8.0 Hz), 4.21 (d, 1H, J )
9.6 Hz), 5.40 (dd, 1H, J ) 9.2 and 3.2 Hz), and 5.69 (dd, 1H,
(s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.21-2.29 (m, 1H), 2.37-
2
3
2
.49 (m, 2H), 2.91 (ddd, 1H, J ) 18.0, 14.0, and 10.4 Hz), 3.18-
.27 (m, 2H), 3.36-3.41 (m, 1H), 3.68 (s, 3H), 3.66-3.79 (m,
J ) 8.0 and 4.2 Hz); 13C NMR (100 MHz, CDCl
) δ 12.9, 13.1,
H), 3.86 (dd, 1H, J ) 8.0 and 1.6 Hz), 5.65 (dt, 1H, J ) 8.0
3
1
and 4.0 Hz), and 6.75-6.80 (m, 1H); H NMR (CDCl
MHz) (diastereomer B) δ 1.56-1.65 (m, 1H), 1.67-1.77 (m,
3
, 400
13.6, 14.0, 14.4, 14.5, 20.9, 21.0, 21.2, 21.7, 21.9, 23.7, 38.8,
38.9, 43.5, 43.9, 45.0, 46.3, 56.4, 56.8, 68.8, 69.3, 72.1, 73.6,
83.5, 83.6, 169.9, 170.3, 172.4, 173.7, 174.8, and 175.0; HRMS
1
2
1
4
3
9
H), 1.91-2.06 (m, 3H), 2.07 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H),
.23-2.30 (m, 1H), 2.35-2.48 (m, 2H), 2.91 (ddd, 1H, J ) 18.0,
3.2, 10.4 Hz), 3.11-3.17 (m, 1H), 3.28 (dt, 1H, J ) 18.0 and
.0 Hz), 3.38-3.46 (m, 1H), 3.59-3.66 (m, 1H), 3.69 (s, 3H),
.79-3.84 (m, 1H), 4.20 (t, 1H, J ) 9.6 Hz), 5.36 (dt, 1H, J )
+
calcd for C H NO S [M - AcOH] 297.0857, found 297.0857.
1
4
19
2
2
N-(2-(Meth ylsu lfa n yl)-5,6-d ih yd r o-4H-fu r o[2,3-b]p yr i-
d in -7-yl)p en t-4-yn a m id e (49). To a 0.5 g (1.4 mmol) sample
of the above compound in CH
.4 g (1.8 mmol) of DMTSF. The mixture was stirred at -40
C for 30 min before warming to 0 °C. After the mixture was
2 2
Cl (10 mL) at -40 °C was added
.6 and 3.2 Hz), and 6.77-6.79 (m, 1H); 13C NMR (CDCl
, 100
3
0
°
MHz) (diastereomer A) δ 13.1, 13.9, 20.9, 21.6, 30.6, 31.6, 40.6,
4
1
3.2, 43.8, 43.9, 45.8, 51.4, 56.7, 71.9, 138.5, 145.0, 165.4, 169.8,
stirred for 3 h at 0 °C, 1.0 mL (7 mmol) of triethylamine was
added. The mixture was diluted with diethyl ether and poured
into a saturated aqueous NaHCO solution. The organic phase
3
was separated, and the aqueous phase was washed with
diethyl ether. The combined organic layer was dried over
2 3
anhydrous K CO , and the solvent was removed under reduced
1
3
3
73.5, and 175.7; C NMR (CDCl , 100 MHz) (diastereomer
B) δ 13.0, 13.4, 21.9, 23.7, 28.2, 30.7, 31.6, 40.7, 43.6, 43.9,
4
1
6.2, 51.5, 56.4, 73.6, 138.6, 145.1, 165.4, 170.3, 172.2, and
76.0; HRMS calcd for C18 [M - CH COO] 383.1225,
H
26NO
4
S
2
3
found 383.1210.
5
-[2-(2-(Meth ylsu lfa n yl)-5,6-d ih yd r o-4H-fu r o[2,3-b]p y-
pressure. The residue was purified by flash silica gel chroma-
r id in -7-yl)-2-oxoet h yl]cyclop en t -1-en eca r b oxylic Acid
Meth yl Ester (47). To a solution of 0.11 g (0.24 mmol) of the
tography to give 0.15 g (42%) of furan 49 as a clear oil: IR
-1
1
(
neat) 2115, 1666, 1510, and 1344 cm ; H NMR (400 MHz,
CDCl ) δ 1.87-1.93 (m, 2H), 1.97 (t, 1H, J ) 2.8 Hz), 2.38 (s,
H), 2.45 (t, 2H, J ) 6.4 Hz), 2.57-2.61 (m, 2H), 3.02 (t, 2H,
above mixture of diastereomers in 8 mL of CH CN at -40 °C
3
3
was added 0.05 g (0.24 mmol) of DMTSF. The reaction mixture
3
was stirred at -40 °C for 1 h and then quenched with 5 equiv
of Et N and diluted with diethyl ether. The organic layer was
3
washed with a saturated NaHCO solution, dried over K CO ,
3 2 3
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 0.05 g
13
J ) 7.4 Hz), 3.83-3.86 (m, 2H), and 6.37 (s, 1H); C NMR
(
1
100 MHz, CDCl
3
) δ 14.5, 20.1, 20.6, 23.2, 35.2, 43.2, 68.8, 83.7,
15
05.3, 117.7, 141.1, 146.2, and 169.0. Anal. Calcd for C13H -
2
NO S: C, 62.63; H, 6.07; N, 5.62. Found: C, 62.55; H, 5.91;
N, 5.55.
(
1
1
62%) of 47 as a colorless oil: IR (neat) 1710, 1664, 1618, and
9
-H yd r oxy-8-(m et h ylsu lfa n yl)-1,2,6,7-t et r a h yd r o-5H -
-
1
1
511 cm ; H NMR (CDCl
.84-1.90 (m, 2H), 2.24-2.39 (m, 2H), 2.32 (s, 3H), 2.41-2.44
3
, 400 MHz) δ 1.68-1.76 (m, 1H),
p yr id o[3,2,1-ij]qu in olin -3-on e (52). To an oven-dried, heavy-
walled, high-pressure tube equipped with a magnetic stirring
bar and rubber septum was added a solution of 0.05 g (0.18
mmol) of furan 49 in toluene (2 mL). Argon was bubbled
through the solution for 15 min, and the septum was replaced
with a threaded Teflon cap containing a rubber O-ring seal.
The vessel was heated at 170 °C behind a protective shield
for 2 days. The reaction mixture was cooled, and the solvent
was removed under reduced pressure. The residue was purified
by flash silica gel chromatography to give 0.05 g (100%) of a
tan solid consisting of a 1:1 mixture of thiomethyl isomers 52
and 53. Compound 52 was obtained as a pale yellow oil: IR
(
m, 2H), 2.48-2.58 (m, 1H), 2.72-2.79 (m, 1H), 3.23 (dt, 1H,
J ) 16.8 and 3.2 Hz), 3.40-3.48 (m, 1H), 3.70 (s, 3H), 3.72-
3
1
2
1
.78 (m, 1H), 3.83-3.89 (m, 1H), 6.33 (s, 1H), and 6.82 (dd,
13
H, J ) 4.0 and 2.4 Hz); C NMR (CDCl
0.6, 23.3, 30.5, 31.7, 39.9, 41.0, 43.0, 51.5, 105.2, 117.6, 138.6,
40.8, 145.4, 146.5, 165.5, and 170.2. Anal. Calcd for C17
S: C, 60.87; H, 6.31; N, 4.18. Found: C, 60.53; H, 6.09;
N, 4.11.
-(Meth ylsu lfan yl)-4,9-dioxo-1,2,2a ,3,4,6,7,8,9,9a -decah y-
3
, 100 MHz) δ 20.0,
21
H -
NO
4
8
d r o-5H -4a -a za cyclop en t a [cd ]p h en a len e-9b-ca r b oxylic
Acid Meth yl Ester (48). A solution of 0.9 g (0.25 mmol) of
furan 47 in 4 mL of toluene was heated at 110 °C for 2 h. The
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to afford 0.7
g (80%) of 48 as a pale yellow solid: mp 134-135 °C; IR (neat)
-
1
1
(
film) 1727, 1632, 1393, 1180, and 1154 cm ; H NMR (400
MHz, CDCl ) δ 1.92-1.98 (m, 2H), 2.20 (s, 3H), 2.59-2.63 (m,
H), 2.82-2.85 (m, 2H), 3.02 (t, 2H, J ) 6.2 Hz), 3.84-3.87
m, 2H), 6.73 (s, 1H), and 6.84 (s, 1H); 13C NMR (100 MHz,
CDCl ) δ 18.6, 21.8, 25.9, 26.4, 31.5, 40.4, 112.0, 118.0, 129.4,
29.8, 130.1, 152.6, and 169.2. Anal. Calcd for C13 S:
C, 62.63; H, 6.07; N, 5.62. Found: C, 62.69; H, 6.12; N, 5.48.
-Hyd r oxy-10-(m eth ylsu lfa n yl)-1,2,6,7-tetr a h yd r o-5H-
3
2
(
726, 1701, 1665, 1639, and 1383 cm-1; 1H NMR (CDCl
, 400
3
1
3
1
H15NO
2
MHz) δ 1.40-1.50 (m, 1H), 1.80-1.90 (m, 3H), 1.91-2.00 (m,
1
2
H), 2.07 (s, 3H), 2.08-2.14 (m, 1H), 2.34-2.40 (m, 1H), 2.42-
.54 (m, 4H), 3.35 (s, 1H), 3.55-3.61 (m, 1H), 3.71 (s, 3H), 3.80
9
1
3
p yr id o[3,2,1-ij]qu in olin -3-on e (53). Extensive silica gel
chromatography of the above mixture gave the isomeric phenol
3 as a clear oil: IR (film) 1727, 1632, 1393, 1180, and 1154
(
dd, 1H, J ) 11.6 and 7.6 Hz), and 4.02-4.08 (m, 1H); C NMR
(
CDCl
2.5, 53.3, 53.9, 54.5, 112.6, 132.2, 166.2, 174.5, and 203.0.
Anal. Calcd for C17 S: C, 60.87; H, 6.31; N, 4.18.
3
, 100 MHz) δ 16.4, 21.3, 27.1, 28.5, 30.4, 32.4, 40.9, 42.9,
5
5
-
1
1
cm ; H NMR (400 MHz, CDCl
s, 3H), 2.58-2.63 (m, 2H), 2.73-2.76 (m, 2H), 3.13-3.18 (m,
3
) δ 1.87-1.96 (m, 2H), 2.17
H
21NO
4
(
2
(
1
Found: C, 60.58; H, 6.30; N, 4.08.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-1-p en t-4-
yn oylp ip er id in -3-yl) Eth yl Ester . To a 1.0 g (3.7 mmol)
1
3
H), 3.82-3.85 (m, 2H), 6.68 (s, 1H) and 6.88 (s, 1H); C NMR
) δ 18.9, 21.6, 23.7, 27.7, 31.3, 40.8, 113.0,
17.3, 128.7, 129.3, 130.4 152.5, and 169.0. Anal. Calcd for
S: C, 62.63; H, 6.07; N, 5.62. Found: C, 62.48; H,
100 MHz, CDCl
3
sample of 25 in CH
2
Cl
2
(18 mL) was added 3.6 g of oven-dried
13 2
C H15NO
5.89; N, 5.37.
4
4
Å powdered molecular sieves and 0.85 g (7.3 mmol) of pent-
-ynoyl chloride. The mixture was stirred at room temper-
6
5
ature for 15 h, followed by filtration through a plug of silica
with diethyl ether. The filtrate was washed with a saturated
aqueous NaHCO solution and dried over MgSO , and the
3 4
3-[1-(Bis(m eth ylsu lfa n yl)m eth yl)-1-h yd r oxyp r op yl]p i-
p er id in -2-on e (54). To a solution of 9.8 mL (70 mmol) of
diisopropylamine in THF (150 mL) at 0 °C was added n-
butyllithium (70 mmol, 46 mL of a 1.5 M solution in hexane).
The reaction mixture was stirred at 0 °C for 30 min, and 13.5
g (70 mmol) of 1-(trimethylsilanyl)piperidin-2-one in THF
(100 mL) was added dropwise. The mixture was stirred at 0
°C for an additional 30 min and then cooled to -78 °C. A
solution of 12 g (70 mmol) of 1,1-bis(methylsulfanyl)butan-2-
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to give 0.8 g (59%)
of the title compound as a yellow oil consisting of a 1:1 mixture
6
6
-
1
of diastereomers: IR (neat) 1744, 1687, 1369, and 1156 cm
;
1
H NMR (400 MHz, CDCl
3
) δ 1.64-1.81 (m, 4H), 1.95 (t, 1H,
J ) 2.6 Hz), 2.00 (t, 1H, J ) 2.6 Hz), 2.08 (s, 3H), 2.11 (s, 6H),
(
65) Wulff, W.; McCallum, J .; Kunng, F. J . Am. Chem. Soc. 1988,
(66) Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo,
A. A. J . Org. Chem. 1990, 55, 3682.
1
10, 7419.

3
424 J . Org. Chem., Vol. 67, No. 10, 2002
Padwa et al.
one67 dissolved in THF (100 mL) was added dropwise. After
the addition was complete, the reaction mixture was stirred
for an additional 30 min before being poured into a saturated
(1.5 mmol) of DMTSF. The reaction mixture was stirred at
-40 °C for 3 h, and then 1.0 mL (7 mmol) of triethylamine
was added. The mixture was diluted with diethyl ether and
aqueous solution of NH
and the aqueous phase was washed with EtOAc. The combined
organic layers were dried over anhydrous MgSO , and the
4
Cl. The organic phase was separated,
3
poured into a saturated aqueous NaHCO solution. The organic
phase was separated, and the aqueous phase was washed with
diethyl ether. The combined organic layer was dried over
4
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to yield 13 g (65%)
of 54 as a yellow oil consisting of a 5:1 mixture of inseparable
2 3
anhydrous K CO , and the solvent was removed under reduced
pressure. The residue was purified by flash silica gel chroma-
tography to give 0.2 g (60%) of furan 56 as a colorless oil: IR
-1
1
-1
1
diastereomers: IR (neat) 1641, 1488, 1442, and 1409 cm ; H
NMR (400 MHz, CDCl ) δ 0.91 (t, 3H, J ) 7.6 Hz, minor
(film) 1673, 1625, 1373, 1308, and 1175 cm ; H NMR (400
MHz, CDCl ) δ 1.13 (t, 3H, J ) 7.4 Hz), 1.88-1.94 (m, 2H),
2.30 (s, 3H), 2.41-2.49 (m, 4H), 3.56-3.58 (m, 2H), 3.82-3.84
3
3
diastereomer), 0.94 (t, 3H, J ) 7.6 Hz, major diastereomer),
1
3
1
1
.34-1.43 (m, 1H), 1.57-1.70 (m, 2H), 1.82-1.89 (m, 1H),
.94-2.01 (m, 1H), 2.03-2.09 (m, 1H), 2.18 (s, 6H, minor
(m, 2H), 5.15-5.22 (m, 2H), and 5.96-6.07 (m, 1H); C NMR
(100 MHz, CDCl ) δ 14.7, 18.5, 19.8, 20.5, 23.1, 41.2, 43.0,
105.1, 118.3, 131.7, 133.3, 136.6, 145.6, and 169.1. Anal. Calcd
for C14 S: C, 63.36; H, 7.22; N, 5.28. Found: C, 63.17;
3
diastereomer), 2.22 (s, 3H, major diastereomer), 2.23 (s, 3H,
major diastereomer), 3.19-3.33 (m, 3H), 3.51 (s, 1H, major
diastereomer), 3.67 (s, 1H, minor diastereomer), 6.74 (s, 1H,
major diastereomer), 6.95 (s, 1H, minor diastereomer), and
H
19NO
2
H, 7.08; N, 5.13.
7-E t h y l-7-(m e t h y ls u lfa n y l)-5,6,9,9a -t e t r a h y d r o -
1H,4H,7H-p yr r olo[3,2,1-ij]qu in olin e-2,8-d ion e (57). A so-
lution of 0.2 g (0.9 mmol) of furan 56 in toluene (5 mL) was
heated at reflux for 1 h. The reaction mixture was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was purified by flash silica gel
chromatography to give 0.2 g (70%) of 57 as a white solid: mp
1
3
7
3
.18 (s, 1H); C NMR (100 MHz, CDCl ) (major diastereomer)
δ 8.6, 15.6, 16.7, 22.5, 23.1, 30.0, 42.2, 47.0, 64.1, 64.1, 81.6,
and 176.9; (minor diastereomer) δ 8.2, 13.7, 15.2, 23.2, 30.3,
4
2.1, 44.1, 64.8, 82.7, and 176.9. Anal. Calcd for C11
NO : C, 50.15; H, 8.04; N, 5.32. Found: C, 50.26; H, 8.07;
N, 5.24.
-[1-(Bis(m eth ylsu lfa n yl)m eth yl)-1-h yd r oxyp r op yl]-1-
bu t-3-en oylp ip er id in -2-on e (55). To a 9.5 g (36 mmol)
sample of 54 in CH Cl (200 mL) was added 36 g of oven-dried
Å powdered molecular sieves and 5.6 g (54 mmol) of but-3-
21
H -
2
S
2
-
1
1
3
117-118 °C; IR (film) 1729, 1682, 1351, and 1180 cm ; H
NMR (400 MHz, CDCl ) δ 0.75 (t, 3H, J ) 7.5 Hz), 1.62-1.70
3
2
2
(m, 1H), 1.79-1.88 (m, 1H), 1.91 (s, 3H), 1.93-1.99 (m, 1H),
2.06-2.31 (m, 5H), 2.72 (dd, 1H, J ) 17.1 and 9.2 Hz), 3.02
(dd, 1H, J ) 17.1 and 5.8 Hz), 3.30-3.45 (m, 2H), and 3.55-
4
6
0
enoyl chloride. The mixture was stirred at room temperature
for 15 h, followed by filtration through a plug of silica with
diethyl ether. The filtrate was washed with a saturated
3.60 (m, 1H); 13C NMR (100 MHz, CDCl
) δ 10.1, 13.1, 20.5,
21.4, 25.2, 29.9, 37.2, 38.8, 44.0, 56.7, 105.0, 141.6, 173.2, and
201.6. Anal. Calcd for C14 S: C, 63.36; H, 7.22; N, 5.28.
3
aqueous NaHCO
3
solution and dried over MgSO
4
, and the
H19NO
2
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to give 10 g (86%)
of 55 as a yellow oil consisting of a single diastereomer: IR
Found: C, 63.08; H, 7.15; N, 5.24.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (Grant Nos. GM59384 and
GM60003) for generous support of this work. We wish
to thank Dr. J ames P. Snyder for discussions on the
application of density functional theory to the modeling
of organic systems.
-
1 1
3
(neat) 1808, 1701, and 1384 cm ; H NMR (400 MHz, CDCl )
δ 0.97 (t, 3H, J ) 7.6 Hz), 1.53 (qd, 1H, J ) 11.8 and 4.2 Hz),
1
3
.66-1.76 (m, 1H), 1.73 (hept, 1H, J ) 7.4 Hz), 1.94-2.12 (m,
H), 2.27 (s, 3H), 2.28 (s, 3H), 3.47 (dd, 1H, J ) 11.8 and 7.0
Hz), 3.50 (m, 1H), 3.63-3.70 (m, 2H), 3.72 (d, 1H, J ) 0.8 Hz),
3
.88-3.94 (m, 1H), 5.11-5.18 (m, 3H), and 5.95-6.05 (m, 1H);
1
3
C NMR (100 MHz, CDCl
4.5, 50.5, 64.6, 81.9, 118.5, 131.3, 174.9, and 178.3. Anal.
: C, 54.36; H, 7.61; N, 4.23. Found: C,
4.19; H, 7.55; N, 4.09.
N-(3-Eth yl-2-(m eth ylsu lfa n yl)-5,6-d ih yd r o-4H-fu r o[2,3-
b]p yr id in -7-yl)bu t-3-en a m id e (56). To a 0.5 g (1.5 mmol)
sample of 55 in CH CN (10 mL) at -40 °C was added 0.3 g
3
) δ 8.9, 16.2, 16.9, 22.1, 23.1, 30.0,
1
Su p p or tin g In for m a tion Ava ila ble: Figures giving H
4
13
and C NMR spectra for new compounds lacking elemental
3 2
Calcd for C15H25NO S
analyses together with ORTEP drawings for structures 46, 48,
and 57 and text giving experimental details for the preparation
of 20 and 66 and their spectroscopic properties. This material
is available free of charge via the Internet at http://pubs.ac-
s.org. The authors have deposited atomic coordinates for these
structures with the Cambridge Crystallographic Data Centre.
5
3
(67) Solladie, G.; Boeffel, D.; Maignan, J . Tetrahedron 1996, 52,
2
065.
J O0111816