1,3-Dipolar cycloaddition of 2-dialkylaminothioisomuenchnones with aliphatic aldehydes: Synthesis of β-lactams and thiiranes, structure elucidation, and rationale for chemoselective fragmentation of cycloadducts

Article abstract of DOI:10.1021/jo034188r

A series of highly funtionalized β-lactams and thiiranes can be generated on treatment of 1,3-thiazolium-4-olates (thioisomuenchnones) with aliphatic aldehydes. Although in some cases a variety of products have been obtained, the present paper now provides a mechanistic rationale to explain the product distribution based on stereoelectronic effects. Thus, ring fragmentation of the initial [3+2] cycloadduct is essentially dictated by the electronic character of the aryl substituent on the nitrogen atom of the parent thioisomuenchnone. However, further evolution of such cycloadducts into β-lactams or thiiranes is governed by steric effects to a large extent. Evidence for such interactions has been obtained by computing PM3-optimized diastereomeric transition structures in the reaction of a thioisomuenchnone with a chiral aliphatic aldehyde.

Full text of DOI:10.1021/jo034188r

1,3-Dip ola r Cycloa d d ition of 2-Dia lk yla m in oth ioisom u1 n ch n on es
w ith Alip h a tic Ald eh yd es: Syn th esis of â-La cta m s a n d Th iir a n es,
Str u ctu r e Elu cid a tion , a n d Ra tion a le for Ch em oselective
F r a gm en ta tion of Cycloa d d u cts†
Martin Avalos, Reyes Babiano, Pedro Cintas, Fernando R. Clemente, Ruth Gordillo,
J ose´ L. J ime´nez,* and J uan C. Palacios
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Extremadura,
E-06071 Badajoz, Spain
requejo@unex.es
Received February 11, 2003
A series of highly funtionalized â-lactams and thiiranes can be generated on treatment of 1,3-
thiazolium-4-olates (thioisomu¨nchnones) with aliphatic aldehydes. Although in some cases a variety
of products have been obtained, the present paper now provides a mechanistic rationale to explain
the product distribution based on stereoelectronic effects. Thus, ring fragmentation of the initial
[3+2] cycloadduct is essentially dictated by the electronic character of the aryl substituent on the
nitrogen atom of the parent thioisomu¨nchnone. However, further evolution of such cycloadducts
into â-lactams or thiiranes is governed by steric effects to a large extent. Evidence for such
interactions has been obtained by computing PM3-optimized diastereomeric transition structures
in the reaction of a thioisomu¨nchnone with a chiral aliphatic aldehyde.
In tr od u ction
by reaction of mesoionics 1a -c with aromatic aldehydes
(2a -c) (Scheme 1).
The performance of mesoionic dipoles as substrates for
1,3-dipolar cycloadditions was well-established more than
two decades ago.1 Still, a few classes of mesoionicsssuch
as isomu¨nchnones and thioisomu¨nchnonesshave been
incorporated into the common repertory of synthetic
protocols owing to their versatility for the expeditious
construction of heterocyclic systems.2 However, most
cycloadditions lead to stable cycloadducts which may
undergo subsequent ring cleavage to yield a rather
narrow range of five- and six-membered heterocycles.
In these reactions we were gratifyingly amazed by the
fact that thioisomu¨nchnones 1a and 1b led to â-lactams
(4),6 whereas 1c gave rise to thiiranes (5) under the same
reaction conditions, no matter which aldehyde 2 one
chooses as the reaction partner. This transformation
represented a novel and stoichiometric entry7 to this
important family of constrained amides. Such findings
would suggest that the cleavage of the nonisolated
intermediate cycloadduct (3) and its further evolution
could be governed by electronic factors. Our group then
recognized that an analysis of the stereoelectronic effects
controlling this rather capricious behavior was required.
In addition, single-point energy calculations at the
B3LYP/6-31G* level also confirmed the preferential exo
route to â-lactams.8
Our next target involved the preparation of optically
active â-lactams by reaction of mesoionics 1a -c with a
chiral building aldehyde (6) from D-arabinose. In stark
contrast with the preceding results, no â-lactams could
be detected at all, but thiiranes 8a -c were detected in
modest to low yields. Sometimes and depending on the
reaction conditions, alkenes 9a -c, arising from thiiranes
In the early nineties, we came to cycloaddition chem-
istry of thioisomu¨nchnones (the common and worldwide
accepted jargon for anhydro-4-hydroxy-1,3-thiazolium
hydroxides). N,N-Dialkylamino-substituted thioisomu¨nch-
nones, which can easily be generated from N,N-dialkyl-
thioureas, not only exhibited an enhanced reactivity with
respect to similar masked dipoles, but also afforded
products hitherto unknown in these 1,3-dipolar cycloaddi-
tions.3-5 It was especially notable the results obtained
* Corresponding author. Phone: +34-924-289380. Fax: +34-924-
271149.
† In loving memory of Prof. Francisco J . Higes: a good scientist, but
most of all a close friend.
(5) Areces, P.; Avalos, M.; Babiano, R.; Gonza´lez, L.; J ime´nez, J . L.;
Me´ndez, M. M.; Palacios, J . C. Tetrahedron Lett. 1993, 34, 2999-3002.
(6) Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; J ime´nez,
J . L.; Light, M. E.; Lo´pez, I.; Palacios, J . C. Chem. Commun. 1999,
1589-1590.
(7) A series of catalytic approaches to the preparation of â-lactams
has been recently envisaged. For a brief and timely revision see:
Magriotis, P. A. Angew. Chem. 2001, 113, 4507-4509; Angew. Chem.,
Int. Ed. 2001, 40, 4377-4379.
(8) Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; J ime´nez,
J . L.; Light, M. E.; Lo´pez, I.; Palacios, J . C.; Silvero, G. Chem. Eur. J .
2001, 7, 3033-3042.
(1) (a) Newton, C. G.; Ramsden, C. A. Tetrahedron 1982, 38, 2965-
3011. (b) Potts, K. T. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, 1984; Vol. 2, pp 1-82.
(2) (a) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994,
123-141. (b) Padwa, A. Top. Curr. Chem. 1997, 189, 121-158.
(3) Areces, P.; Avalos, M.; Babiano, R.; Cintas, P.; Gonza´lez, L.;
Hursthouse, M. B.; J ime´nez, J . L.; Light, M. E.; Lo´pez, I.; Palacios, J .
C.; Silvero, G. Eur. J . Org. Chem. 2001, 2135-2144.
(4) Are´valo, M. J .; Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse,
M. B.; J ime´nez, J . L.; Light, M. E.; Lo´pez, I.; Palacios, J . C. Tetrahedron
Lett. 1999, 40, 8675-8678.
10.1021/jo034188r CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/12/2003
6338
J . Org. Chem. 2003, 68, 6338-6348

Cycloaddition of 2-Dialkylaminothioisomu¨nchnones
SCHEME 1
CHART 1. Alip h a tic Ald eh yd es Used in th e Cycloa d d ition Rea ction s
8 by sulfur extrusion, could also be isolated. One could
then conclude that cycloadduct 7, structurally related to
3, evolves into three-membered rings owing to steric,
rather than electronic, factors and this surmise has
recently been the subject of a preliminary communica-
tion.9
Described below is a full account of our logical exten-
sion to diversely substituted aliphatic compounds (Chart
1), including the chiral sugar aldehyde 6. The synthetic
procedure is presented together with a mechanistic
analysis that satisfactorily accounts for the full set of
experimental data.
dichloromethane at reflux. Similar results were obtained
in both solvents, although the starting mesoionic was less
prone to decomposition in benzene (reactions proceeded
faster). Nevertheless, alkenes are often formed in this
hydrocarbon solvent. Reactions of 1a -c with aldehydes
10, 12, and 13 were run in refluxing benzene, whereas
isobutyraldehyde itself (11, bp ) 63 °C) served as the
medium in its cycloaddition reactions. Reactions based
on acetaldehyde (14, bp ) 21 °C) were accomplished in
CH2Cl2 at room temperature. Although these transfor-
mations were monitored by thin-layer chromatography,
the end point could easily be determined by color dis-
charge because the absence of the typical orange color of
mesoionic species was clearly visible to the naked eye.
Up to four compounds may be obtained on treatment
of 2,3,4,5-tetra-O-acetyl-D-arabinose (6) with mesoionic
heterocycles 1a -c (Chart 2). In each case, such sub-
stances could be separated by flash chromatography and
Resu lts
Syn th eses a n d Str u ctu r e. Reactions of mesoionics
1a -c10 with aldehyde 6 were conducted in benzene or
(9) Preliminary communication: Avalos, M.; Babiano, R.; Cintas,
P.; Clemente, F. R.; Gordillo, R.; Hursthouse, M. B.; J ime´nez, J . L.;
Light, M. E.; Palacios, J . C. Tetrahedron: Asymmetry 2001, 12, 2265-
2268.
(10) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; Higes, F.
J .; J ime´nez, J . L.; Palacios, J . C. J . Org. Chem. 1996, 61, 3738-3748.
J . Org. Chem, Vol. 68, No. 16, 2003 6339

Avalos et al.
CHART 2
TABLE 1. P r od u ct Distr ibu tion s in th e Rea ction s of 1a -c w ith 6 a n d 11-14
a
Not isolated, detected by NMR spectroscopy.
1
identified as chiral thiiranes 15-26. H NMR spectra of
crude mixtures recorded at 400 MHz allowed us to
determine the complete product distribution (Table 1).
Suspecting that the bulky, though flexible, chiral chain
of 6 might have exerted a major effect on the steric
course, we embarked on an exploration of aldehyde 10.
Results were disappointing as only decomposition of the
starting thioisomu¨nchnones was observed after longer
reaction times.
Assignments were also facilitated by the fact that the
heterocyclic moieties of 15-17 and 18-20 (and likewise
21-23 and 24-26) bear an enantiomeric relationship.
This conclusion was immediately supported by the for-
mation of alkene 55 after heating an equimolar mixture
of 17 and 20 in DMSO at 100 °C. Similarly, a mixture of
thiiranes 23 and 26 led to the same alkene 56 after sulfur
elimination (Chart 4). Compound 54 could be isolated
from the reaction mixture of 1a and 6 and, in addition,
the 1H NMR spectrum (400 MHz) of a diastereomeric
mixture of 15 and 18 registered in DMSO-d6 at 87 °C
revealed the formation of the (E)-alkene 54.
Table 1 sumarizes clearly the product of each reaction
and their structures are collectively grouped in Charts 2
and 3.
Previous ambiguities as to the actual structure of the
three-membered heterocycles could be ruled out by a full
analysis of the X-ray crystallographic data of compounds
17 and 22.9 NMR data of these substances were used to
correlate such structures with those of the chiral thi-
iranes formed on treatment of 6 with thioisomu¨nchnones
1a -c.
NMR data also reveal that the H-3 resonance of (Z)-
thiiranes is invariably more shielded than that of their
(E)-configured counterparts. A similar trend for that
signal may be observed between (Z)- and (E)-alkenes.
Furthermore, most of the chemical shifts attributed to
C-2 are observed at a lower field than the signals for the
C-3 atoms. Likewise, the C-2 resonances for the (Z)-
6340 J . Org. Chem., Vol. 68, No. 16, 2003

Cycloaddition of 2-Dialkylaminothioisomu¨nchnones
CHART 3. Str u ctu r es of th e P r od u cts Obta in ed in th e Rea ction s of Mesoion ic Heter ocycles 1a -c w ith
Ach ir a l Ald eh yd es 11-14
CHART 4
SCHEME 2
thiiranes were found to be more deshielded than those
for the alternative (E)-configured structures.
Since the formation of only one â-lactam could be
detected, except for the reaction of heterocycle 1a with
acetaldehyde (14), it was not possible to establish an
unequivocal configuration for compounds 27-36 by means
of their NMR data. Nevertheless, spectroscopic data of
(Z)-â-lactams 27-35 are very similar, and the H4 proton
appears in the range δ 4.93-5.49. This signal is much
more deshielded than the H3 signal in thiiranes 15-26
and 37-44 (δ 2.49-4.40) and, in addition, more deshield-
ed than the H4 signal in (E)-â-lactam 36 (δ 4.56).
Moreover, both analytical and spectroscopic data for the
â-lactams 27-36 are equally consistent with those of
analogous systems described previously.8 All these ex-
perimental data, together with the known tendency of
aldehydes to react with thioisomu¨nchnones adopting an
endo disposition,8 allowed us to assign a Z configuration
to â-lactams 27-35 and an E configuration to â-lactam
36.
lection may be rationalized in terms of the endo and exo
approaches (respective of the aldehyde substituent) to
any enantiotopic face of the heterocyclic dipole. Such
orientations involve either the Re or Si faces of the
prochiral aldehydes (Scheme 2).
The ease with which these cycloadducts undergo ring
cleavage should be ascribed to the existence of several
heteroatoms capable of stabilizing, to a great extent,
complete or partial charges after heterolytic scission of
their bonds. Moreover, fragmentation to five- or six-
membered monocyclic structures having arisen from
C-N or C-S bond scission, respectively, relieves the
strain. In both cases, the resulting zwitterionic structures
contain a powerful nucleophile (S- or ArN-) and a still
better leaving group (an oxonium ion).12 A facile intramo-
lecular nucleophilic substitution yields either â-lactams
or thiiranes (Scheme 3).
Discu ssion
Having established that the cycloaddition reaction of
1,3-thiazolium-4-olates with aldehydes proceeds with
complete regioselectivity,8 the critical issue of stereose-
(11) Potts, K. T.; Chen, S. J .; Kane, J .; Marshall, J . L. J . Org. Chem.
1977, 42, 1633-1638.
J . Org. Chem, Vol. 68, No. 16, 2003 6341

Avalos et al.
SCHEME 3
SCHEME 4
The observed stereospecificity of this ring opening is
consistent with a concerted SN2-like mechanism. Thus,
exo cycloadducts only give rise to (E)-â-lactams and/or
(Z)-thiiranes, while, conversely, endo isomers give (Z)-
â-lactams and/or (E)-thiiranes.
We may then ask which factors are involved in the
preferential formation of â-lactams or thiiranes. As to this
question, the electronic effect of substituents on the
N-aryl group should largely affect the chemical outcome.
Electron-withdrawing substituents decrease the energy
of the transition state by spreading the negative charge,
thereby facilitating C-N bond breaking that leads to
â-lactams. On the contrary, electron-donating groups
concentrate the charge making less stable the zwitter-
ionic intermediates 59 and 60, while favoring the forma-
tion of 1,3-oxazinium-5-thiolate ions (57 and 58).
The electronic effect alone, however, does not account
for the rest of the experimental evidence and an ad-
ditional effect on the reactivity should almost certainly
be steric at any stage of the synthesis. Thus, the thio-
isomu¨nchnone 1a reacts with aldehydes 11 and 12 to give
exclusively a â-lactam (27 and 28, respectively), whereas
the chiral aldehyde 6 leads to the four possible thiiranes
with no trace of â-lactam formation. Inspection of mo-
lecular models reveals the origin of this abnormal be-
havior. The intramolecular attack by ArN at the first
stereogenic center of the sugar chain is about as sterically
hindered as attack at the analogous carbon atom of
isobutyraldehyde. Accordingly, the absence of â-lactams
in the case of 6 does not correlate with the ability of the
N-aryl group to effect the intramolecular displacement.
Severe steric strain caused by the polyacetylated side
chain takes place in the initial conformation change going
from cycloadducts to zwitterionic intermediates, and
crowding is especially relevant in the case of 60 in which
the sugar adopts an endo orientation in the cycloadduct.
The exclusive formation of thiiranes could also be
explained by the reaction mechanism outlined in Scheme
4. This pathway involves the participation of the vicinal
acetyl group in the initial cycloadduct cleavage. In fact,
to test this hypothesis the aldehyde 13 was also evalu-
ated. Nevertheless, isolation of â-lactams 30 and 33 from
cycloaddition reactions of aldehyde 13 with thioiso-
mu¨nchnones 1a and 1b allowed us to discard this
reaction pathway, and therefore the influence of steric
hindrance produced by the polyacetylated moiety in the
nature of the final compound was fully confirmed.
The lack of reactivity exhibited by aldehyde 10 should
reasonably be attributed to the steric congestion of the
bimolecular transition state, irrespective of whether
sulfur or nitrogen nucleophiles are involved.
Another key feature of these [3+2] cycloadditions,
evidenced after conducting the synthesis with chiral
aldehydes, is the absence of facial selectivity exhibited
by 6. The full sets of diastereomeric thiiranes (15-17,
18-20, 21-23, and 24-26) were formed in essentially
the same proportion. The stereochemical outcome shown
in Scheme 5 indicates that (E)-configured thiiranes (15-
17 as well as 18-20) stem from endo approach of 6 to
both faces of the heterocyclic dipole, while exo approaches
of reactants lead to (Z)-thiiranes.
(12) (a) Perst, H. Oxonium Ions in Organic Chemistry; Verlag
Chemie: Deerfield Beach, FL, 1971; p 100. (b) Perst, H. In Carbonium
Ions; Olah, G., Schleyer, P. v. R., Eds.; Wiley: New York, 1976; Vol. 5,
p 1961.
6342 J . Org. Chem., Vol. 68, No. 16, 2003

Cycloaddition of 2-Dialkylaminothioisomu¨nchnones
SCHEME 5
absence of diastereoselectivity is likely to be associated
with the high degree of pyramidalization of the carbonyl
carbon in all the transition structures. Because that
carbon is near-sp3 hybridized, the steric factor caused by
crowding of substituents, and otherwise responsible for
facial discrimination, is considerably alleviated when the
transition state is reached. This is why the approach to
the less hindered Si face of the aldehyde, which would
produce the preferential formation of thiiranes 18-23,
has not been observed.
Con clu sion s
This study provides a foundation for understanding the
synthetic processes to form either â-lactams or thiiranes
by means of thioisomu¨nchnone-aldehyde cycloadditions.
Syntheses may also be tailored to efficiently generate
three- or four-membered rings with a particular config-
uration. We have identified the structural motifs and
stereoelectronic factors that determine cycloadduct open-
ing. Manipulation of these influences will allow a higher
degree of selectivity to be achieved.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
capillary apparatus and are uncorrected. Optical rotations
were measured at the sodium line at 18 ( 2 °C. Analytical
and preparative TLC were performed on silica gel with
monitoring by means of UV light at 254 and 360 nm and iodine
vapors. Flash chromatography15 was performed with silica gel
(400-230 mesh). IR spectra were recorded in a MIDAC
Corporation FTIR spectrometer on KBr pellets or as a thin
film on NaCl. Nuclear magnetic resonance spectra were
recorded at 400 MHz for 1H and 100 MHz for 13C nuclei with
toluene-d8 or DMSO-d6. Chemical shifts are reported in ppm
(δ) with Me4Si as internal standard. High-resolution mass
spectra (HRMS/CI+) were obtained by the Servicio de Espec-
trometr´ıa de Masas at the Universidad de Co´rdoba, Spain.
Microanalyses were obtained in a LECO CHNS-932 microana-
lyzer. Compounds 5,16 9,17 and 11-1310 were prepared accord-
ing to literature procedures.
The loss of facial diastereoselection with respect of the
chiral aldehyde 6 is somewhat surprising assuming that
the first stereocenter of its acyclic chain is adjacent to
one of the reaction sites. Furthermore, the similar
distribution of (E)- and (Z)-thiiranes clearly suggests that,
although the bulkiness of the carbohydrate moiety should
not be underestimated, it does not govern the approxima-
tion of reactants.
We have sought to identify why this chiral version
proceeds with little or no face selectivity. Reasoning that
the answer might lie in the nature of the transition
states, we have located such structures leading to cy-
cloadducts which, after cleavage, form the cyclized prod-
ucts 16, 19, 22, and 25 (Figure 1). Given the large
number of heavy atoms involved, the computational cost
could be reduced by using semiempirical PM3 calcula-
tions13 implemented on the Gaussian98 package.14
In agreement with experimental results, the gas-phase
energies found for structures TS16, TS19, TS22, and
TS25 (Table 2) suggest that there should be no preference
for a particular set of diastereomers. A further analysis
of geometries reveals that the main reason for the
Gen er a l P r oced u r e for th e Syn th esis of (2R,3R)-,
(2S,3S)-, (2R,3S)-, a n d (2S,3R)-3-(1′,2′,3′,4′-Tetr a -O-a cetyl-
D-a r a bin o-tetr itol-1′-yl)-2-[4-ben zyl-2-(4-n itr op h en yl)-1,3-
d ioxo-2,4-d ia za p en tyl]-2-p h en yllth iir a n es (15, 18, 21, a n d
24) a n d (E)-N-(N′-Ben zyl-N′-m eth ylca r ba m oyl)-N-(4-n i-
tr op h en yl)-2,3-d id eoxy-2-p h en yl-4,5,6,7-tetr a -O-a cetyl-D-
a r a bin o-h ep t-2-en a m id e (54). To a suspension of 1a (0.52
g, 1.3 mmol) in benzene (20 mL) was added 6 (0.40 g, 1.3
mmol). The reaction mixture was refluxed until observance of
decolorization of the solution (30 min). TLC analysis (diethyl
ether-n-hexane, 5:1) revealed the appearance of four new
compounds (Rf 0.4, 0.3, 0.2, and 0.1) which could be separated
by column flash cromatography (diethyl ether-n-hexane, 5:1)
and further purification by preparative TLC (acetonitrile-
1
(13) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220.
(14) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
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.; Baboul, A. G.; 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.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian 98, Revision A.7;
Gaussian, Inc.: Pittsburgh, PA, 1998.
benzene, 1:10). The H NMR spectrum of a compound having
Rf 0.4 revealed the existence of a diastereomeric mixture of
compounds 21 and 24 (ratio 6.4:1) (0.12 g, 12%). Compounds
15 (Rf 0.3) (0.05 g, 5%), 18 (Rf 0.2) (0.02 g, 2%), and 54 (Rf 0.1)
(0.02 g, 2%) could be obtained diastereomerically pure and
crystallized from diethyl ether-n-hexane as colorless solids.
(15) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(16) Wolfrom, M. L.; Weisblat, D. I.; Zophy, W. H.; Waisbrot, S. W.
J . Am. Chem. Soc. 1941, 63, 201-203 and references therein.
(17) Shiao, M. J .; Yang, C. Y.; Lee, S. H.; Wu, T. C. Synth. Commun.
1988, 18, 359-366.
J . Org. Chem, Vol. 68, No. 16, 2003 6343

Avalos et al.
F IGURE 1. PM3-optimized diastereomeric transition structures for the 1,3-dipolar cycloaddition of 3 with 5.
TABLE 2. Ca lcu la ted En er gies (in k ca l/m ol, P M3 level)
for Str u ctu r es TS16, TS29, TS22, a n d TS25 (F igu r e 1)
Com p ou n d 18: mp 85 °C; [R]D -170.6 (c 0.8, CHCl3); IR
1
(KBr) 1745, 1690, 1680 cm-1; H NMR (400 MHz, toluene-d8,
350 K) δ 7.60 (d, J ) 8.8 Hz, 2H), 7.19-6.91 (m, 12H), 5.58
(dd, J ) 8.2, 3.0 Hz, 1H), 5.08 (m, 1H), 4.47 (dd, J ) 9.4, 2.9
Hz, 1H), 4.35 (d, J ) 9.4 Hz, 1H), 4.29 (dd, J ) 12.3, 2.3 Hz,
1H), 4.12 (m, 3H), 2.34 (s, 3H), 1.76 (s, 3H), 1.74 (s, 3H), 1.67
(s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz, toluene-d8, 350 K) δ
170.7, 170.0, 168.5, 155.8, 148.3, 141.3, 136.9, 133.3, 130.5,
129.9, 129.7, 129.4, 128.9, 124.7, 73.0, 71.9, 70.4, 62.7, 54.3,
54.2, 43.5, 35.5, 21.0, 20.8, 20.7. Anal. Calcd for C36H37N3-
energy
TS16
TS19
TS22
TS25
-237.3
-235.7
-236.7
-236.1
P r oced u r e b for th e Syn th esis of 15, 18, 21, a n d 24. A
solution of 1a (0.29 g, 0.9 mmol) and 6 (0.38 g, 0.9 mmol) in
CH2Cl2 (20 mL) was refluxed until observance of decolorization
of the solution (3 h). TLC analysis (diethyl ether-n-hexane,
5:1) of the reaction mixture revealed the formation of three
new compounds (Rf 0.4, 0.3, and 0.2) which could be separated
by preparative TLC (diethyl ether-n-hexane, 5:1). The 1H
NMR spectrum of a compound having Rf 0.4 revealed the
existence of a diastereomeric mixture of compounds 21 and
24 (ratio 4.6:1) (0.13 g, 19%). Compounds 15 (Rf 0.3) (0.22 g,
33%) and 18 (Rf 0.2) (0.04 g, 6%) could be obtained diastereo-
merically pure and crystallized from diethyl ether-n-hexane
as colorless solids.
O
12S: C, 58.77; H, 5.07; N, 5.71; S, 4.36. Found: C, 58.70; H,
5.37; N, 5.62; S, 4.04.
Dia ster eom er ic m ixtu r e of 21 a n d 24: 1H NMR (400
MHz, toluene-d8, 350 K) δ 7.85-6.94 (m, 28H), 6.35 (d, J )
8.1 Hz, 2H), 5.81 (m, 2H), 5.43 (m, 2H), 5.31 (m, 1H), 4.49-
4.13 (m, 8H), 3.46 (d, J ) 9.6 Hz, 1H), 3.20 (d, J ) 8.1 Hz,
1H), 2.56 (br s, 3H), 2.47 (s, 3H), 2.04 (s, 3H), 1.84-1.61 (m,
21H).
Com p ou n d 54: mp 71 °C, [R]D -18.5 (c 0.1, CHCl3); IR
(KBr) 1750, 1740, 1730, 1695, 1680 cm-1; 1H NMR (400 MHz,
toluene-d8, 350 K) δ 7.73 (d, J ) 8.8 Hz, 2H), 7.57 (d, J ) 7.3
Hz, 2H), 7.08-6.89 (m, 10H), 6.45 (d, J ) 8.4 Hz, 1H), 5.80
(dd, J ) 8.4, 3.5 Hz, 1H), 5.38 (dd, J ) 7.8, 3.7 Hz, 1H), 5.26
(m, 1H), 4.18 (m, 2H), 4.07 (m, 2H), 2.27 (br s, 3H), 1.88 (s,
3H), 1.71 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H); 1H NMR (400 MHz,
DMSO-d6, 360 K) δ 8.15 (d, J ) 9.1 Hz, 2H), 7.37-7.14 (m,
12H), 6.25 (d, J ) 8.3 Hz, 1H), 5.49 (dd, J ) 8.5, 3.7 Hz, 1H),
5.13 (dd, J ) 7.0, 3.9 Hz, 1H), 5.03 (m, 1H), 4.39 (s, 2H), 4.11
(dd, J ) 12.3, 3.1 Hz, 1H), 4.03 (dd, J ) 12.3, 5.9 Hz, 1H),
2.63 (s, 3H), 2.08 (s, 3H), 1.96 (s, 3H), 1.89 (s, 3H), 1.87 (s,
3H); 13C NMR (100 MHz, toluene-d8, 350 K) δ 170.3, 169.9,
160.8, 156.3, 148.0, 147.0, 135.1, 134.2, 130.7, 130.0, 129.7,
129.4, 129.3, 127.5, 125.2, 72.5, 70.3, 70.1, 62.9, 54.4, 35.7, 20.8.
Com p ou n d 15: mp 85 °C; [R]D +165.6 (c 0.4, CHCl3); IR
(KBr) 1745, 1670, 1665 cm-1; H NMR (400 MHz, toluene-d8,
1
350 K) δ 7.57 (m, 4H), 7.08-6.85 (m, 10H), 5.15 (dd, J ) 9.2,
1.9 Hz, 1H), 5.01 (m, 1H), 4.63 (dd, J ) 9.6, 1.9 Hz, 1H), 4.36
(d, J ) 9.6 Hz, 1H), 4.13 (m, 2H), 3.97 (m, 1H), 3.92 (dd, J )
12.5, 4.9 Hz, 1H), 2.30 (br s, 3H), 1.99 (s, 3H), 1.77 (s, 3H),
1.73 (s, 3H), 1.58 (s, 3H); 13C NMR (100 MHz, toluene-d8, 350
K) δ 170.4, 170.0, 169.6, 169.5, 161.0, 155.3, 147.7, 144.1,
136.9, 133.2, 131.1, 129.5, 129.1, 128.8, 128.6, 124.6, 71.7, 70.5,
69.3, 62.7, 54.1, 53.5, 44.5, 35.5, 20.8, 20.7. Anal. Calcd for
C
36H37N3O12S: C, 58.77; H, 5.07; N, 5.71; S, 4.36. Found: C,
58.60; H, 4.89; N, 5.83; S, 4.05.
6344 J . Org. Chem., Vol. 68, No. 16, 2003

Cycloaddition of 2-Dialkylaminothioisomu¨nchnones
Anal. Calcd for C36H37N3O12 C, 61.45; H, 5.30; N, 5.97.
:
Com p ou n d 20: mp 69 °C; [R]D -88.3 (c 0.4, CHCl3); IR
(KBr) 1740, 1680 cm-1 1H NMR (400 MHz, toluene-d8, 350
Found: C, 61.19; H, 5.23; N, 5.79.
;
K) δ 7.20-6.93 (m, 12H), 6.46 (d, J ) 8.6 Hz, 2H), 5.59 (dd,
J ) 8.1, 2.6 Hz, 1H), 5.07 (m, 1H), 4.47 (dd, J ) 9.5, 2.4 Hz,
1H), 4.32 (m, 4H), 4.13 (dd, J ) 12.4, 5.0 Hz, 1H), 3.35 (s, 3H),
2.62 (s, 3H), 1.78 (s, 3H), 1.74 (s, 3H), 1.68 (s, 3H), 1.64 (s,
3H); 13C NMR (100 MHz, toluene-d8, 350 K) δ 170.4, 170.2,
170.0, 168.3, 160.5, 155.2, 137.7, 133.8, 131.5, 130.1, 129.6,
129.3, 129.1, 128.9, 128.4, 115.1, 72.9, 72.1, 70.4, 62.7, 55.9,
54.3, 54.1, 43.4, 35.3, 21.1, 20.8, 20.7. Anal. Calcd for
Syn th esis of (2R,3R)-, (2S,3S)-, a n d (2R,3S)-3-(1′,2′,3′,4′-
Tetr a -O-a cetyl-D-a r a bin o-tetr itol-1′-yl)-2-[4-ben zyl-1,3-d i-
oxo-2-p h en yl-2,4-d ia za p en tyl]-2-p h en ylth iir a n es (16, 19,
a n d 22). These substances were obtained from 1b (0.47 g, 1.3
mmol) and 6 (0.40 g, 1.3 mmol) according to the general
procedure b described above. The reaction mixture was re-
fluxed until observance of decolorization of the solution (1 h):
22 (Rf 0.4.), 16 (Rf 0.3), and 19 (Rf 0.2). Purification by
preparative TLC (diethyl ether-n-hexane, 5:1) gave 16 (0.24
g, 28%) and 19 (0.06 g, 7%) and as colorless solids.
C
37H40N2O11S: C, 61.65; H, 5.59; N, 3.88; S, 4.44. Found: C,
61.20; H, 5.35; N, 3.40; S, 4.30.
Dia ster eom er ic m ixtu r e of 23 a n d 26: 1H NMR (400
MHz, toluene-d8, 350 K) δ 7.81 (d, J ) 7.6 Hz, 2H), 7.64 (br s,
2H), 7.24 (d, J ) 8.8 Hz, 2H), 7.10-6.98 (m, 18H), 6.62 (d,
J ) 9.0 Hz, 2H), 6.55 (d, J ) 8.5 Hz, 2H), 6.42 (dd, J ) 8.1,
4.0 Hz, 1H), 5.82 (m, 2H), 5.48 (dd, J ) 9.5, 2.5 Hz, 1H), 5.41
(m, 1H), 5.31 (m, 1H), 4.47 (dd, J ) 12.4, 2.7 Hz, 1H), 4.38 (m,
5H), 4.26 (dd, J ) 12.6, 5.2 Hz, 1H), 4.18 (dd, J ) 12.3, 5.8
Hz, 1H), 3.37 (d, J ) 9.5 Hz, 1H), 3.30 (br s, 6H), 3.10 (d, J )
8.8 Hz, 1H), 2.78 (br s, 3H), 2.64 (s, 3H), 2.02 (s, 3H), 1.85-
1.59 (m, 21H); 13C NMR (100 MHz, toluene-d8, 350 K) 170.7,
170.5, 170.4, 170.3, 170.1, 169.9, 169.4, 160.6, 160.3, 157.9,
157.2, 140.0, 138.3, 137.5, 132.1, 131.7, 130.9, 130.6, 130.0,
129.7, 129.5, 129.3, 129.1, 129.0, 128.5, 128.4, 115.4, 115.2,
74.1, 73.3, 73.0, 71.2, 70.7, 63.4, 62.8, 56.6, 56.2, 55.8, 54.5,
46.5, 45.5, 35.9, 21.5, 21.4, 21.3, 21.2, 21.0, 20.9, 20.6. Anal.
Calcd for C37H40N2O11S: C, 61.65; H, 5.59; N, 3.88; S, 4.44.
Found: C, 61.44; H, 5.62; N, 3.51; S, 4.01.
Syn th esis of (E)-N-(N′-Ben zyl-N′-m eth ylca r ba m oyl)-N-
(4-m eth oxyp h en yl)-2,3-d id eoxy-2-p h en yl-4,5,6,7-tetr a -O-
a cetyl-D-a r a bin o-h ep t-2-en a m id e (55) fr om 17 a n d 20. A
solution of a diastereomeric mixture of 17 and 20 (0.10 g, 0.1
mmol) in DMSO (1 mL) was heated for 1 h at 100 °C. Following
workup, the solution was diluted with 5 mL of distilled water
and extracted with diethyl ether to remove DMSO, the
combined ethereal layers were dried with anhydrous magne-
sium sulfate, and the solvent was evaporated. TLC analysis
(diethyl ether-n-hexane, 5:1) revealed the complete disap-
pearance of 17 and the appearance of 55 (Rf 0.1), which
crystallized form diethyl ether-n-hexane as a colorless solid
(0.03 g, 37%).
Com p ou n d 55: mp 55.8 °C, [R]D +11.2 (c 0.3, CHCl3); IR
(KBr) 1749, 1683 cm-1; 1H NMR (400 MHz, DMSO-d6, 360 K)
δ 7.34-7.25 (m, 6H), 7.14 (m, 4H), 6.97 (d, J ) 6.9 Hz, 2H),
6.85 (d, J ) 8.8 Hz, 2H), 6.09 (d, J ) 8.7 Hz, 1H), 5.45 (dd,
J ) 8.7, 3.8 Hz, 1H), 5.11 (dd, J ) 6.9, 4.0 Hz, 1H), 5.01 (m,
1H), 4.42 (s, 2H), 4.08 (dd, J ) 12.3, 3.3 Hz, 1H), 4.03 (dd,
J ) 12.3, 5.9 Hz, 1H), 3.76 (s, 3H), 2.70 (s, 3H), 2.06 (s, 3H),
1.95 (s, 3H), 1.89 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz,
DMSO-d6, 360 K) δ 169.3, 168.8, 168.2, 158.3, 155.5, 141.2,
136.0, 133.3, 130.6, 129.6, 128.2, 128.0, 127.8, 127.6, 127.3,
127.0, 114.2, 70.7, 68.4, 67.6, 61.2, 55.2, 52.2, 34.6, 19.8. Anal.
Calcd for C37H40N2O11: C, 64.52; H, 5.85; N, 4.07. Found: C,
64.13; H, 6.16; N, 4.05.
Syn th esis of (Z)-N-(N′-Ben zyl-N′-m eth ylca r ba m oyl)-N-
(4-m eth oxyp h en yl)-2,3-d id eoxy-2-p h en yl-4,5,6,7-tetr a -O-
a cetyl-D-a r a bin o-h ep t-2-en a m id e (56) fr om 23 a n d 26. A
solution of a diastereomeric mixture of 23 and 26 (0.10 g, 0.1
mmol) in DMSO (1 mL) was heated for 1 h at 100 °C. Following
workup, the solution was diluted with 5 mL of distilled water
and extracted with diethyl ether to remove DMSO, the
combined ethereal layers were dried with anhydrous magne-
sium sulfate, and the solvent was evaporated. TLC analysis
(diethyl ether-n-hexane, 5:1) revealed the complete disap-
pearance of 23 and 26 and the appearance of 56 (Rf 0.3), which
crystallized form diethyl ether-n-hexane as a colorless solid
(0.04 g, 37%).
Com p ou n d 16: mp 72 °C; [R]D +140.9 (c 0.5, CHCl3); IR
(KBr) 1749, 1689 cm-1 1H NMR (400 MHz, toluene-d8, 350
;
K) δ 7.5 (br s, 2H), 7.09-6.85 (m, 13H), 5.16 (d, J ) 8.9 Hz,
1H), 5.03 (m, 1H), 4.65 (d, J ) 9.7 Hz, 1H), 4.37 (dd, J ) 9.8,
1.5 Hz, 1H), 4.16 (m, 3H), 3.90 (dd, J ) 12.4, 4.9 Hz, 1H), 2.48
(br s, 3H), 2.00 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.58 (s, 3H);
13C NMR (100 MHz, toluene-d8, 350 K) δ 170.4, 170.2, 169.8,
169.6, 156.4, 139.1, 137.6, 133.9, 131.0, 129.9, 129.5, 129.1,
128.4, 72.1, 70.7, 69.6, 62.9, 54.2, 53.9, 44.7, 35.5, 21.0. Anal.
Calcd for C36H38N2O10S: C, 62.60; H, 5.54; N, 4.05; S, 4.64.
Found: C, 62.20; H, 5.43; N, 4.31; S, 4.73.
Com p ou n d 19: mp 74 °C; [R]D -162.4 (c 0.2, CHCl3); IR
(KBr) 1751, 1689 cm-1 1H NMR (400 MHz, toluene-d8, 350
;
K) δ 7.21 (br s, 2H), 7.10-6.72 (m, 13H), 5.62 (d, J ) 8.1, 2.2
Hz, 1H), 5.07 (m, 1H), 4.47 (dd, J ) 9.3, 2.7 Hz, 1H), 4.32 (m,
3H), 4.15 (m, 2H), 2.50 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H), 1.67
(s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz, toluene-d8, 350 K) δ
170.4, 170.0, 168.3, 155.5, 138.9, 137.5, 130.4, 130.0, 129.6,
129.3, 129.2, 129.0, 128.5, 73.0, 72.1, 70.4, 62.8, 54.2, 43.4, 35.3,
21.1, 20.8, 20.7. Anal. Calcd for C36H38N2O10S: C, 62.60; H,
5.54; N, 4.05; S, 4.64. Found: C, 62.43; H, 5.64; N, 4.21; S,
4.68.
Com p ou n d 22: mp 161 °C; [R]D -176.3 (c 1.0, CHCl3); IR
1
(KBr) 1751, 1692, 1655 cm-1; H NMR (400 MHz, toluene-d8,
350 K) δ 7.85 (d, J ) 7.2 Hz, 2H), 7.35 (d, J ) 7.5 Hz, 2H),
7.13-6.91 (m, 11H), 5.83 (dd, J ) 7.4, 2.1 Hz, 1H), 5.49 (dd,
J ) 9.5, 2.2 Hz, 1H), 5.31 (m, 1H), 4.44 (m, 2H), 4.26 (m, 2H),
3.42 (d, J ) 9.5 Hz, 1H), 2.59 (s, 3H), 2.02 (s, 3H), 1.82 (s,
3H), 1.73 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, toluene-
d8, 350 K) δ 170.5, 170.4, 170.1, 169.9, 169.3, 157.5, 140.0,
139.5, 137.4, 130.7, 129.8, 129.5, 129.4, 128.9, 128.6, 128.2,
74.1, 73.1, 71.2, 62.8, 56.5, 54.5, 46.5, 35.8, 21.4, 21.2, 20.8,
20.6. Anal. Calcd for C36H38N2O10S: C, 62.60; H, 5.54; N, 4.05;
S, 4.64. Found: C, 62.20; H, 5.61; N, 4.19; S, 4.88.
Syn th esis of (2R,3R)-, (2S,3S)-, (2R,3S)-, a n d (2S,3R)-
3-(1′,2′,3′,4′-Tet r a -O-a cet yl-D-a r a bin o-t et r it ol-1′-yl)-2-[4-
ben zyl-2-(4-m eth oxyp h en yl)-1,3-d ioxo-2,4-d ia za p en tyl]-
2-p h en ylth iir a n es (17, 20, 23, a n d 26). These substances
were obtained from 1c (0.51 g, 1.3 mmol) and 6 (0.40 g, 1.3
mmol) according to the general procedure b described above.
The reaction mixture was refluxed until observance of decol-
orization of the solution (1 h): diastereomeric mixture of 23
and 26 (Rf 0.4), 17 (Rf 0.3), and 20 (Rf 0.2). Purification by
preparative TLC (diethyl ether-n-hexane 5:1) gave 17 (Rf 0.3)
(0.39 g, 43%), 20 (Rf 0.2) (0.08 g, 8%), and a diastereomeric
mixture of 23 and 26 (ratio 1:1.3) (0.13 g, 15%).
Com p ou n d 17: mp 140 °C; [R]D +110.1 (c 1.2, CHCl3); IR
1
(KBr) 2940, 1740, 1670 cm-1; H NMR (400 MHz, toluene-d8,
350 K) δ 7.48 (br s, 2H), 7.12-6.95 (m, 10H), 6.44 (d, J ) 8.5
Hz, 2H), 5.19 (dd, J ) 8.9, 1.7 Hz, 1H), 5.08 (m, 1H), 4.69 (dd,
J ) 9.5, 1.8 Hz, 1H), 4.40 (d, J ) 9.7 Hz, 1H), 4.32 (br s, 2H),
4.17 (dd, J ) 12.4, 2.3 Hz, 1H), 3.93 (dd, J ) 12.4, 5.1 Hz,
1H), 3.32 (s, 3H), 2.63 (br s, 3H), 2.05 (s, 3H), 1.79 (s, 3H),
1.75 (s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz, toluene-d8, 350
K) δ 170.4, 170.2, 169.8, 169.6, 160.4, 156.7, 137.7, 134.0,
131.5, 130.7, 129.9, 129.5, 129.2, 129.1, 129.0, 128.4, 115.0,
72.2, 70.6, 69.5, 62.9, 55.8, 54.2, 54.0, 44.8, 35.4, 21.0, 20.9.
Anal. Calcd for C37H40N2O11S: C, 61.65; H, 5.59; N, 3.88; S,
4.44. Found: C, 61.79; H, 5.34; N, 3.66; S, 4.19.
Com p ou n d 56: mp 61 °C, [R]D -167.6 (c 0.3, CHCl3); IR
(KBr) 1749, 1693 cm-1; 1H NMR (400 MHz, DMSO-d6, 360 K)
δ 7.31-7.14 (m, 10H), 7.01 (d, J ) 8.5 Hz, 2H), 6.74 (d, J )
8.3 Hz, 2H), 6.01 (dd, J ) 8.7, 3.9 Hz, 1H), 5.87 (d, J ) 8.8 Hz,
J . Org. Chem, Vol. 68, No. 16, 2003 6345

Avalos et al.
1H), 5.9 (dd, J ) 6.6, 4.0 Hz, 1H), 5.20 (m, 1H), 4.43 (br s,
2H), 4.31 (dd, J ) 12.3, 3.0 Hz, 1H), 4.16 (dd, J ) 12.1, 6.1
Hz, 1H), 3.71 (s, 3H), 2.77 (br s, 3H), 2.08 (s, 3H), 2.06 (s, 3H),
1.99 (s, 3H), 1.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 360
K) δ 169.5, 169.0, 168.9, 166.9, 158.4, 154.8, 140.9, 135.8,
135.4, 129.5, 128.0, 127.7, 127.2, 126.9, 125.9, 113.9, 71.4, 68.6,
68.3, 61.4, 55.2, 52.2, 34.4, 20.2, 19.9. Anal. Calcd for
1H), 4.26 (d, J ) 15.0 Hz, 1H), 3.75 (d, J ) 9.2 Hz, 1H), 3.25
(s, 3H), 2.64 (s, 3H), 0.85 (d, J ) 6.2 Hz, 3H), 0.74 (m, 4H); 13
C
NMR (100 MHz, toluene-d8, 400 K) δ 170.8, 156.9, 137.8, 135.3,
131.8, 130.4, 129.5, 128.9, 128.7, 128.5, 128.3, 114.8, 55.8, 55.7,
54.4, 54.1, 35.3, 31.3, 24.0, 20.8. Anal. Calcd for C28H30N2O3S:
C, 70.86; H, 6.37; N, 5.90; S, 6.75. Found: C, 70.55; H, 6.62;
N, 5.75; S, 6.39.
C
37H40N2O11: C, 64.52; H, 5.85; N, 4.07. Found: C, 64.48; H,
Com p ou n d 43: mp 123 °C; IR (KBr) 3046, 2955, 1676,
1605, 1508 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.70
(d, J ) 7.1 Hz, 2H), 7.11-6.98 (m, 10H), 6.53 (d, J ) 9.0 Hz,
2H), 4.37 (s, 2H), 3.28 (s, 3H), 2.61 (s, 3H), 2.49 (d, J ) 9.8
Hz, 1H), 1.95 (m, 1H), 1.37 (d, J ) 6.4 Hz, 3H), 1.06 (d, J )
6.7 Hz, 3H); 13C NMR (100 MHz, toluene-d8, 400 K) δ 170.2,
160.2, 157.5, 140.6, 137.7, 132.2, 130.4, 129.9, 129.7, 129.5,
129.2, 129.0, 128.5, 115.2, 58.7, 57.1, 55.7, 54.3, 35.5, 34.3, 24.3,
22.1. HRMS (CI+) calcd for C28H30N2O3S + H+ 475.2055, found
475.2032.
Syn th esis of (3R,4R)- a n d (3S,4S)-4-Ben zyl-3-(N-ben -
zyl-N-m eth ylca r ba m oylth io)-3-p h en yl-1-(4-n itr op h en yl)-
a zetid in -2-on e (28). To a suspension of 1a (0.50 g, 1.2 mmol)
in benzene (5 mL) was added 0.2 mL (1.7 mmol) of phenylac-
etaldehyde (12). The reaction mixture was refluxed and
instantaneous decolorization of the solution was observed. TLC
analysis (diethyl ether-n-hexane, 1:1) revealed the appearance
of a new compound 28 (Rf 0.3). Purification by flash chroma-
tography (diethyl ether-n-hexane, 1:1) gave 28 (0.48 g, 74%)
as a yellow pale solid.
5.89; N, 4.03.
Syn th esis of (3R,4R)- a n d (3S,4S)-3-(N-Ben zyl-N-m eth -
ylca r ba m oylth io)-4-isop r op yl-1-(4-n itr op h en yl)-3-p h en -
yla zetid in -2-on e (27). A suspension of 1a (0.50 g, 1.2 mmol)
in 5 mL of redistilled isobutyraldehyde (11) was refluxed under
Argon atmosphere and decolorization of the solution was
instantaneouly observed. TLC analysis (diethyl ether-n-
hexane, 1:1) revealed the appearance of a new product 27 (Rf
0.3). Purification by flash chromatography (diethyl ether-n-
hexane, 1:1) gave 27 (0.44 g, 76%) as a yellow pale solid.
Com p ou n d 27: mp 63 °C; IR (KBr) 2965, 2922, 1767, 1657,
1593, 1516, 1497 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K)
δ 7.88 (d, J ) 9.0 Hz, 2H), 7.77 (m, 2H), 7.40 (d, J ) 9.1 Hz,
2H), 7.09 (m, 8H), 4.95 (d, J ) 4.8 Hz, 1H), 4.15 (m, 2H), 2.48
(s, 3H), 2.07 (m, 1H), 0.90 (d, J ) 6.9 Hz, 3H), 0.55 (d, J ) 6.9
Hz, 3H); 13C NMR (100 MHz, toluene-d8, 400 K) δ 167.7, 166.6,
145.3, 145.1, 137.2, 136.2, 129.9, 129.7, 129.2, 128.6, 125.6,
125.4, 120.2, 119.9, 72.6, 68.9, 53.8, 34.9, 30.7, 22.3, 19.2.
HRMS (CI+) calcd for C27H27N3O4S + H+ 490.1801, found
490.1814.
Syn th esis of (3R,4R)- a n d (3S,4S)-3-(N-Ben zyl-N-m eth -
ylca r b a m oylt h io)-4-isop r op yl-1,3-d ip h en yla zet id in -2-
on e (31) a n d (2R,3R)- a n d (2S,3S)-2-(4-Ben zyl-1,3-d ioxo-
2-p h en yl-2,4-d ia za p en tyl)-3-isop r op yl-2-p h en ylth iir a n e
(37). A suspension of 1b (0.50 g, 1.3 mmol) in 5 mL of
redistilled isobutyraldehyde (11) was refluxed under Argon
atmosphere until observance of decolorization of the solution
(10 min). TLC analysis (diethyl ether-n-hexane, 1:1) revealed
the appearance of two new compounds 37 (Rf 0.5) and 31 (Rf
0.4). Purification by preparative TLC (diethyl ether-n-hexane,
1:1) gave 31 (0.06 g, 10%) as a colorless oil and 37 (0.04 g, 7%)
as a colorless solid.
Com p ou n d 28: mp 79 °C; IR (KBr) 3077, 2924, 1767, 1555,
1
1514 cm-1; H NMR (400 MHz, toluene-d8, 340 K) δ 7.33 (m,
4H), 7.18-6.93 (m, 15H), 5.42 (m, 1H), 4.17 (s, 2H), 2.98 (dd,
J ) 15.1, 5.3 Hz, 1H), 2.58 (dd, J ) 15.1, 7.5 Hz, 1H), 2.48 (s,
3H); 13C NMR (100 MHz, toluene-d8, 400 K) δ 167.0, 166.1,
144.9, 144.15, 138.7, 137.2, 135.7, 130.3, 129.8, 128.7, 127.9,
125.4, 119.2, 69.4, 68.3, 53.9, 39.1, 35.0. Anal. Calcd for
C
31H27N3O4S: C, 69.25; H, 5.06; N, 7.82; S, 5.96. Found: C,
69.5; H, 5.10; N, 7.32; S, 5.49.
Syn th esis of (3R,4R)- a n d (3S,4S)-4-Ben zyl-3-(N-ben -
zyl-N -m e t h ylca r b a m oylt h io)-1,3-d ip h e n yla ze t id in -2-
on e (32) an d (E)-N-(N′-Ben zyl-N′-m eth ylcar bam oyl)-N,2,4-
tr ip h en ylen a m id e (46). To a suspension of 1b (0.50 g, 1.3
mmol) in benzene (5 mL) was added 0.2 mL (1.7 mmol) of
phenylacetaldehyde (12). The reaction mixture was refluxed
until observance of decolorization of the solution (30 min). TLC
analysis (diethyl ether-n-hexane, 1:1) revealed the appearance
of two new compounds 32 (Rf 0.5) and 46 (Rf 0.4). Purification
by preparative TLC (ethyl ether-n-hexane, 1:1) gave 32 as a
colorless solid (0.13 g, 19%) and 46 (0.15 g, 28%) as a colorless
oil.
Com p ou n d 31: IR (NaCl) 2965, 1757, 1659, 1599, 1495
cm-1; 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.54 (d, J ) 8.2
Hz, 2H), 7.16-6.86 (m, 11H), 5.04 (d, J ) 4.5 Hz, 1H), 4.17
(m, 2H), 2.45 (s, 3H), 2.17 (m, 1H), 0.95 (dd, J ) 7.0, 0.7 Hz,
3H), 0.58 (dd, J ) 7.0, 0.8 Hz, 3H); 13C NMR (100 MHz,
toluene-d8, 400 K) δ 167.2, 165.6, 140.2, 137.7, 129.8, 129.6,
129.4, 129.2, 128.7, 128.5, 125.6, 121.4, 72.2, 68.3, 53.8, 34.9,
30.8, 22.7, 18.8. HRMS (CI+) calcd for C27H28N2O2S + H+
445.1950, found 445.1975.
Com p ou n d 32: mp 133 °C; IR (KBr) 3061, 3027, 2915,
Com p ou n d 37: mp 51 °C; IR (KBr) 3069, 3034, 2961, 2922,
1742, 1653, 1597, 1495, 1454 cm-1 1H NMR (400 MHz,
;
2870, 1686, 1593, 1491, 1452 cm-1
;
1H NMR (400 MHz,
toluene-d8, 340 K) δ 7.83 (d, J ) 8.4 Hz, 2H), 7.33 (d, J ) 7.7
Hz, 2H), 7.18-6.98 (m, 15H), 6.82 (m, 1H), 5.49 (m, 1H), 4.19
(s, 2H), 3.06 (dd, J ) 15.1, 5.4 Hz, 1H), 2.71 (dd, J ) 15.1, 7.1
Hz), 2.48 (s, 3H); 13C NMR (100 MHz, toluene-d8, 340 K) δ
167.4, 165.0, 139.5, 139.3, 137.5, 137.5, 136.9, 130.4, 130.0,
129.6, 129.5, 129.4, 128.7, 128.5, 127.4, 125.0, 120.0, 69.0, 67.8,
53.9, 39.0, 34.9. Anal. Calcd for C31H28N2O2S: C, 75.58; H, 5.73;
N, 5.69; S, 6.51. Found: C, 75.39; H, 5.67; N, 5.78; S, 6.73.
Com p ou n d 46: IR (NaCl) 3050, 3020, 1690, 1685, 1655,
1590, 1485, 1440 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K)
δ 7.40 (m, 2H), 7.12-6.91 (m, 18H), 6.52 (t, J ) 7.7 Hz, 1H),
toluene-d8, 340 K) δ 7.25-6.84 (m, 15H), 4.30 (m, 2H), 3.79
(d, J ) 8.9 Hz, 1H), 2.59 (s, 3H), 0.89 (d, J ) 5.9 Hz, 3H), 0.78
(m, 4H); 13C NMR (100 MHz, toluene-d8, 400 K) δ 170.5, 156.6,
137.6, 135.2, 130.6, 129.5, 129.3, 128.9, 128.7, 128.3, 55.6, 54.3,
54.1, 35.2, 31.3, 24.0, 20.8. HRMS (CI+) calcd for C27H28N2O2-
S + H+ 445.1950, found 445.1963.
Syn t h esis of (2R,3R)- a n d (2S,3S)-2-[4-Ben zyl-2-(4-
m eth oxyp h en yl)-1,3-d ioxo-2,4-d ia za p en tyl]-3-isop r op yl-
2-p h en ylt h iir a n e (39) a n d (2R,3S)- a n d (2S,3R)-2-[4-
Ben zyl-2-(4-m eth oxyp h en yl)-1,3-d ioxo-2,4-d ia za p en tyl]-
3-isop r op yl-2-p h en ylth iir a n e (43). A suspension of 1c (0.50
g, 1.22 mmol) in 5 mL of redistilled isobutyraldehyde (11) was
refluxed under Argon atmosphere until observance of decol-
orization of the solution (20 min). TLC analysis (diethyl ether-
n-hexane, 1:1) revealed the appearance of two new compounds
43 (Rf 0.5) and 39 (Rf 0.4). Purification by preparative TLC
(diethyl ether-n-hexane 1:1) gave 39 (0.35 g, 59%) and 43 (0.01
g, 2%) as colorless solids.
1
4.29 (s, 2H), 3.30 (d, J ) 7.7 Hz, 2H), 2.38 (s, 3H); H NMR
(400 MHz, DMSO-d6, 360 K) δ 7.37-7.03 (m, 20H), 6.44 (t,
J ) 7.7 Hz, 1H), 4.37 (s, 2H), 3.38 (d, J ) 7.6 Hz, 2H), 2.64 (s,
3H); 13C NMR (100 MHz, toluene-d8, 340 K) δ 171.4, 157.9,
140.7, 140.6, 137.7, 136.8, 136.6, 130.8, 129.9, 129.6, 129.5,
129.2, 129.0, 128.6, 128.4, 127.9, 127.6, 127.2, 54.2, 35.8, 35.5.
HRMS (CI+) calcd for C31H28N2O2 460.2151, found 460.2151.
Syn th esis of (3R,4R)- a n d (3S,4S)-4-Ben zyl-3-(N-ben -
zyl-N -m e t h ylca r b a m oylt h io)-1-(4-m e t h oxyp h e n yl)-3-
p h en yla zetid in -2-on e (35), (2R,3R)- a n d (2S,3S)-3-Ben zyl-
2-[4-ben zyl-2-(4-m eth oxyp h en yl)-1,3-d ioxo-2,4-d ia za p en -
Com p ou n d 39: mp 55 °C; IR (KBr) 2963, 1696, 1605, 1593,
1495 cm-1 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.21-
;
6.87 (m, 12H), 6.38 (d, J ) 8.8 Hz, 2H), 4.41 (d, J ) 13.2 Hz,
6346 J . Org. Chem., Vol. 68, No. 16, 2003

Cycloaddition of 2-Dialkylaminothioisomu¨nchnones
tyl]-2-p h en ylth iir a n e (40), a n d (E)-N-(N′-Ben zyl-N′-m eth -
ylcar bam oyl)-N-(4-m eth oxyph en yl)-2,4-diph en ylbu t-2-en -
a m id e (49). To a suspension of 1c (0.50 g, 1.2 mmol) in
benzene (5 mL) was added 0.2 mL (1.7 mmol) of phenylac-
etaldehyde (12). The reaction mixture was refluxed until
observance of decolorization of the solution (30 min). TLC
analysis (diethyl ether-n-hexane, 1:1) revealed the appearance
of three new compounds 40 (Rf 0.3), 35 (Rf 0.2), and 49 (Rf
0.1) which could be separated by flash chromatography (diethyl
ether-n-hexane, 1:1) and further purification by preparative
TLC (diethyl ether-n-hexane, 1:1). Compounds 35 (0.09 g,
14%) and 40 (0.31 g, 49%) crystallized from diethyl ether-n-
hexane as colorless solids and 49 (0.03 g, 4%) was obtained as
a colorless oil.
Com p ou n d 35: mp 57 °C; IR (KBr) 2918, 2357, 1753, 1653,
1512 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.86 (dd,
J ) 8.4, 1.6 Hz, 2H), 7.25-6.99 (m, 15H), 6.58 (m, 2H), 5.45
(m, 1H), 4.20 (s, 2H), 3.31 (s, 3H), 3.10 (dd, J ) 15.0, 5.2 Hz,
1H), 2.69 (dd, J ) 14.9, 7.2 Hz, 1H), 2.49 (s, 3H); 13C NMR
(100 MHz, toluene-d8, 340 K) δ 167.9, 164.6, 157.9, 139.7,
137.2, 132.7, 130.5, 130.1, 130.0, 129.7, 129.5, 129.4, 129.0,
128.8, 128.6, 127.4, 121.8, 115.3, 69.0, 68.1, 55.7, 54.1, 39.2,
35.0. HRMS (CI+) calcd for C32H30N2O3S 522.1977, found
522.1991.
0.8 mmol) in benzene (5 mL) was added 2-acetoxypropanal (13)
(0.25 g, 2.5 mmol) solved in benzene (5 mL). The reaction
mixture was refluxed until observance of decolorization of the
solution (10 min). TLC analysis (diethyl ether-n-hexane, 3:2)
revealed the appearance of three new compounds 33 (Rf 0.3),
51 (Rf 0.2), and 47 (Rf 0.1) which could be purified by
preparative TLC (diethyl ether-n-hexane, 3:2). Compounds
33 (0.08 g, 20%), 47 (0.09 g, 24%), and 51 (0.06, 18%) were
obtained as colorless oils.
Com p ou n d 33: IR (NaCl) 3034, 2941, 1746, 1657, 1597,
1501, 1447, 1377 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K)
δ 7.92 (m, 2H), 7.70 (m, 2H), 7.17-6.90 (m, 11H), 5.27 (t, J )
4.8 Hz, 1H), 4.40 (dd, J ) 12.5, 4.4 Hz, 1H), 4.20-4.14 (m,
3H), 2.44 (s, 3H), 1.54 (s, 3H); 13C NMR (100 MHz, toluene-
d8, 340 K) δ 170.0, 167.0, 164.5, 139.4, 137.4, 136.6, 130.0,
129.9, 129.7, 129.5, 129.3, 129.0, 128.7, 128.6, 125.3, 119.5,
67.7, 64.2, 62.8, 53.8, 34.0, 20.6. HRMS (CI+) calcd for
C
27H26N2O4S + H+ 475.1695, found 475.1684.
Com p ou n d 47: IR (NaCl) 3055, 2930, 1742, 1682, 1595,
1493, 1396 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.28
(dd, J ) 8.2, 1.4 Hz, 2H), 7.09-6.91 (m, 13H), 6.44 (t, J ) 6.5
Hz, 1H), 4.53 (d, J ) 6.5 Hz, 2H), 4.21 (s, 2H), 2.40 (s, 3H),
1.64 (s, 3H); 13C NMR (100 MHz, toluene-d8, 340 K) δ 170.6,
170.3, 157.5, 142.7, 140.2, 137.6, 135.7, 132.0, 130.4, 129.9,
129.5, 129.2, 129.1, 129.0, 128.6, 128.5, 127.8, 127.7, 120.7,
61.9, 54.1, 35.5, 20.9. HRMS (CI+) calcd for C27H26N2O4
442.1893, found 442.1888.
Com p ou n d 40: mp 59 °C; IR (KBr) 3043, 2953, 2948, 2835,
1
1685, 1603, 1508, 1496 cm-1; H NMR (400 MHz, toluene-d8,
340 K) δ 7.22 (d, J ) 6.1 Hz, 2H), 7.10-6.93 (m, 15H), 6.45 (d,
J ) 8.7 Hz, 2H), 4.32 (m, 3H), 3.30 (s, 3H), 2.59 (m, 4H), 2.15
(dd, J ) 15.0, 8.5 Hz, 1H); 13C NMR (100 MHz, toluene-d8,
400 K) δ 170.7, 160.4, 156.9, 140.2, 137.8, 135.5, 131.8, 131.5,
130.4, 129.9, 129.5, 129.3, 128.9, 128.8, 128.6, 128.3, 127.4,
114.9, 55.8, 55.3, 54.1, 47.1, 38.9, 34.9. Anal. Calcd for
Com p ou n d 51: IR (NaCl) 3032, 2945, 1738, 1688, 1595,
1491, 1364 cm-1 1H NMR (400 MHz, toluene-d8, 340 K) δ
;
7.24-7.20 (m, 4H), 7.11-6.86 (m, 11H), 5.84 (t, J ) 6.5 Hz,
1H), 4.99 (d, J ) 6.5 Hz, 2H), 4.22 (s, 2H), 2.49 (s, 3H), 1.75
(s, 3H); 13C NMR (100 MHz, toluene-d8, 340 K) δ 170.5, 168.7
156.6, 141.7, 139.3, 138.0, 137.5, 129.9, 129.7, 129.5, 129.4,
129.0, 128.5, 128.1, 127.9, 127.8, 63.0, 54.2, 35.4, 21.0. HRMS
(CI+) calcd for C27H26N2O4 442.1893, found 442.1889.
Syn th esis of (E)-4-Acetoxy-N-(N′-ben zyl-N′-m eth ylca r -
bam oyl)-N-(4-m eth oxyph en yl)-2-ph en ylbu t-2-en am ide (50)
a n d (Z)-4-Acetoxy-N-(N′-ben zyl-N′-m eth ylca r ba m oyl)-N-
(4-m eth oxyp h en yl)-2-p h en ylbu t-2-en a m id e (53). To a sus-
pension of 1c (0.30 g, 0.7 mmol) in benzene (5 mL) was added
2-acetoxypropanal (13) (0.25 g, 2.5 mmol) dissolved in benzene
(5 mL). The reaction mixture was refluxed until observance
of decolorization of the solution (30 min). TLC analysis (diethyl
ether-n-hexane, 8:5) revealed the appearance of two new
compounds 53 (Rf 0.2) and 50 (Rf 0.1) which could be purified
by preparative TLC (diethyl ether-n-hexane, 3:2). Compounds
50 (0.19 g, 55%) and 53 (0.10, 28%) were obtained as colorless
oils.
C
32H30N2O3S: C, 73.54; H, 5.79; N, 5.36; S, 6.14. Found: C,
73.38; H, 5.91; N, 5.44; S, 5.72.
Com p ou n d 49: IR (NaCl) 3059, 2926, 2852, 1680, 1510
1
cm-1; H NMR (400 MHz, toluene-d8, 340 K) δ 5.89 (m, 2H),
7.14-6.95 (m, 15H), 6.59 (d, J ) 8.8 Hz, 2H), 6.49 (t, J ) 7.7
Hz, 1H), 4.26 (s, 2H), 3.39 (s, 3H), 3.29 (d, J ) 7.7 Hz, 2H),
2.48 (s, 3H); 1H NMR (400 MHz, DMSO-d6, 360 K) δ 7.36-
7.20 (m, 14H), 7.03 (m, 4H), 6.87 (m, 2H), 6.40 (t, J ) 7.6 Hz,
1H), 4.38 (s, 2H), 3.77 (s, 3H), 3.36 (d, J ) 7.7 Hz, 2H), 2.68
(s, 3H); 13C NMR (100 MHz, toluene-d8, 340 K) δ 171.5, 159.9,
158.1, 140.7, 140.6, 137.9, 136.8, 136.4, 136.5, 130.7, 129.5,
129.1, 129.0, 128.6, 128.4, 127.2, 115.4, 55.8, 54.2, 35.8, 35.5.
HRMS (CI+) calcd for C32H30N2O3 490.2256, found 490.2268.
Syn th esis of (3R,4R)- a n d (3S,4S)-4-(1′-Acetoxym eth yl)-
3-(N-ben zyl-N-m eth ylca r ba m oylth io)-1-(4-n itr op h en yl)-
3-p h en yla zetid in -2-on e (29). To a suspension of 1a (0.60 g,
1.4 mmol) in benzene (10 mL) was added 2-acetoxypropanal
(13) (0.50 g, 4.9 mmol) dissolved in benzene (10 mL). The
reaction mixture was refluxed and instantaneous decoloriza-
tion of the solution was observed. TLC analysis (diethyl ether-
n-hexane, 2:1) revealed the appearance of a new compound
29 (Rf 0.3). Purification by flash chromatography (diethyl
ether-n-hexane, 1:1) gave 29 (0.24 g, 32%) as a yellow pale
solid.
Com p ou n d 29: mp 55 °C; IR (KBr) 2930, 1771, 1655, 1593,
1516, 1449 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.91
(dd, J ) 9.0, 1.8 Hz, 2H), 7.76 (d, J ) 8.5 Hz, 2H), 7.54 (d,
J ) 9.1 Hz, 2H), 7.18-6.96 (m, 8H), 5.18 (t, J ) 4.9 Hz, 1H),
4.21-4.09 (m, 4H), 2.45 (s, 3H), 1.56 (s, 3H); 13C NMR (100
MHz, toluene-d8, 340 K) δ 170.0, 166.7, 156.6, 145.3, 144.1,
137.1, 135.1, 130.0, 129.7, 129.1, 128.8, 128.7, 126.0, 118.8,
68.3, 64.8, 62.7, 53.8, 34.9, 20.7. Anal. Calcd for C27H25N3O6S:
C, 62.41; H, 4.85; N, 8.09; S, 6.17. Found: C, 62.65; H, 5.19;
N, 7.97; S, 5.78.
Com p ou n d 50: IR (NaCl) 2963, 1737, 1682, 1510, 1443,
1
1396 cm-1; H NMR (400 MHz, toluene-d8, 340 K) δ 7.27 (d,
J ) 6.9 Hz, 2H), 7.08-6.96 (m, 10H), 6.58 (d, J ) 8.8 Hz, 2H),
6.42 (t, J ) 6.6 Hz, 1H), 4.53 (d, J ) 6.6 Hz, 2H), 4.27 (s, 2H),
3.32 (s, 3H), 2.49 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz,
toluene-d8, 340 K) δ 170.8, 170.2, 160.0, 157.7, 142.8, 137.8,
135.9, 132.9, 131.6, 130.3, 129.9, 129.6, 129.5, 129.1, 129.0,
128.9, 128.5, 126.2, 115.4, 61.9, 55.8, 54.2, 35.4, 20.9. HRMS
(CI+) calcd for C28H28N2O5 472.1998, found 472.2002.
Com p ou n d 53: IR (NaCl) 2938, 2847, 1694, 1510, 1365
1
cm-1; H NMR (400 MHz, toluene-d8, 340 K) δ 7.23-7.01 (m,
12H), 6.54 (m, 2H), 5.83 (t, J ) 6.5 Hz, 1H), 5.01 (d, J ) 6.5
Hz, 2H), 4.35 (s, 2H), 3.31 (s, 3H), 2.62 (s, 3H), 1.78 (s, 3H);
13C NMR (100 MHz, toluene-d8, 340 K) δ 170.5, 169.0 160.3,
156.9, 142.0, 138.1, 137.6, 132.0, 129.9, 129.6, 129.5, 129.4,
129.2, 129.0, 128.4, 127.7, 115.2, 63.1, 55.8, 54.2, 35.5, 21.0.
HRMS (CI+) calcd for C28H28N2O5 472.1998, found 472.2001.
Syn th esis of (3R,4R)- a n d (3S,4S)-3-(N-Ben zyl-N-m eth -
ylca r b a m oylt h io)-4-m et h yl-1-(4-n it r op h en yl)-3-p h en yl-
a zetid in -2-on e (30), (3R,4S)- a n d (3S,4R)-3-(N-Ben zyl-N-
m e t h ylca r b a m oylt h io)-4-m e t h yl-1-(4-n it r op h e n yl)-3-
p h en yla zetid in -2-on e (36), a n d (E)-N-(N′-Ben zyl-N′-m eth -
ylca r ba m oyl)-N-(4-n itr op h en yl)-2-p h en ylbu t-2-en a m id e
(45). To a solution of 1a (0.50 g, 1.2 mmol) in CH2Cl2 (3 mL)
Syn th esis of (3R,4R)- a n d (3S,4S)-4-(1′-Acetoxym eth yl)-
3-(N-ben zyl-N-m eth ylca r ba m oylth io)-1,3-d ip h en yla zeti-
d in -2-on e (33), (E)-4-Acetoxy-N-(N′-ben zyl-N′-m eth ylca r -
b a m oyl)-N,2-d ip h en ylb u t -2-en a m id e (47), a n d (Z)-4-
Ac e t o x y -N -(N ′-b e n z y l -N ′-m e t h y l c a r b a m o y l )-N ,2 -
d ip h en ylbu t-2-en a m id e (51). To a suspension of 1b (0.30 g,
J . Org. Chem, Vol. 68, No. 16, 2003 6347

Avalos et al.
was added acetaldehyde (14) (0.1 mL, 1.8 mmol). The solution
(s, 3H), 2.63 (s, 3H), 0.85 (d, J ) 6.1 Hz, 3H); 13C NMR (100
MHz, toluene-d8, 340 K) δ 170.9, 159.2 157.0, 137.8, 135.6,
131.7, 130.4, 129.5, 129.4, 129.3, 128.8, 128.5, 128.4, 115.0,
was stirred until observance of decolorization of the solution
1
(20 min). H NMR analysis of the reaction mixture revealed
that compounds 30, 36, and 45 were formed in a 6.6:3.8:1.0
ratio.
55.7, 55.1, 54.1, 41.3, 35.3, 54.2, 17.9. Anal. Calcd for C26H26
N2O3S: C, 69.9; H, 5.87; N, 6.27; S, 7.18. Found: C, 69.9; H,
6.11; N, 6.47; S, 6.84.
-
Syn th esis of (3R,4R)- a n d (3S,4S)-3-(N-Ben zyl-N-m eth -
ylca r b a m oylt h io)-4-m et h yl-1,3-d ip h en yla zet id in -2-on e
(34), (2R,3R)- a n d (2S,3S)-2-(4-Ben zyl-2-p h en yl-1,3-d ioxo-
2,4-d ia za p en tyl)-3-m eth yl-2-p h en ylth iir a n e (38), (2R,3S)-
a n d (2S,3R)-2-(4-Ben zyl-2-p h en yl-1,3-d ioxo-2,4-d ia za p en -
tyl)-3-m eth yl-2-p h en ylth iir a n e (42), (E)-N-(N′-Ben zyl-N′-
m eth ylca r ba m oyl)-N,2-d ip h en ylbu t-2-en a m id e (48), a n d
(Z)-N-(N′-Ben zyl-N′-m eth ylca r ba m oyl)-N,2-d ip h en ylbu t-
2-en a m id e (52). To a solution of 1b (0.50 g, 1.3 mmol) in CH2-
Cl2 (3 mL) was added acetaldehyde (14) (0.1 mL, 1.8 mmol).
The solution was stirred until observance of decolorization of
the solution (40 min). 1H NMR of the reaction mixture revealed
that compounds 34, 38, 42, 48, and 52 were formed in a 1:3.5:
3.5:10.6:2.3 ratio.
Syn t h esis of (2R,3R)- a n d (2S,3S)-2-[4-Ben zyl-2-(4-
m et h oxyp h en yl)-1,3-d ioxo-2,4-d ia za p en t yl]-3-m et h yl-2-
p h en ylth iir a n e (41) a n d (2R,3S)- a n d (2S,3R)-2-[4-Ben zyl-
2-(4-m eth oxyph en yl)-1,3-dioxo-2,4-diazapen tyl]-3-m eth yl-
2-p h en ylth iir a n e (44). To a solution of 1c (0.50 g, 1.2 mmol)
in CH2Cl2 (3 mL) was added acetaldehyde (14) (0.1 mL, 1.8
mmol). The solution was stirred until observance of decolori-
zation of the solution (1 h). TLC analysis (diethyl ether-n-
hexane, 1:1) revealed the appearance of two new compounds
44 (Rf 0.4) and 41 (Rf 0.3) which could be purified by
preparative TLC (benzene-acetonitrile, 30:1). 1H NMR of the
reaction mixture revealed that compounds 41 and 44 were
formed in a 2:1 ratio. Compounds 41 (0.12 g, 22%) and 44 (0.04,
7%) were obtained as colorless solids.
Com p ou n d 44: mp 110 °C; IR (KBr) 2967, 1682, 1607,
1508, 1449, 1395 cm-1; 1H NMR (400 MHz, toluene-d8, 340 K)
δ 7.66 (d, J ) 7.4 Hz, 2H), 7.11-7.00 (m, 10H), 6.57 (m, 2H),
4.33 (s, 2H), 3.30 (s, 3H), 2.80 (c, J ) 6.0 Hz, 1H), 2.55 (s, 3H),
2.63 (s, 3H), 1.72 (d, J ) 6.0 Hz, 3H); 13C NMR (100 MHz,
toluene-d8, 340 K) δ 169.8, 160.2 157.5, 140.6, 137.7, 132.3,
130.2, 129.9, 129.6, 129.5, 129.2, 129.0, 128.5, 115.2, 56.1, 55.7,
54.3, 45.4, 35.5, 21.0. Anal. Calcd for C26H26N2O3S: C, 69.9;
H, 5.87; N, 6.27; S, 7.18. Found: C, 70.0; H, 6.14; N, 5.95; S,
6.66.
Ack n ow led gm en t. Financial support from the Min-
istry of Science and Technology (Projects PB98-0997 and
BQU2000-0248) and the J unta de Extremadura-Fondo
Social Europeo (Grants IPR00-C021, IPR00-C047, and
IPR98-A065) is gratefully acknowledged. R.G. thanks
the J unta de Extremadura for a predoctoral scholarship.
We thank Professor J ose´ Luis Garc´ıa Ruano for helpful
discussions and suggestions.
Su p p or tin g In for m a tion Ava ila ble: Cartesian coordi-
nates of transition structures TS16, TS19, TS22, and TS25
with their computed total energies; 1H NMR spectra of
diastereomeric mixtures of compounds 21 and 24, and 23 and
1
26; H NMR spectra of compounds 27, 31, 33, 35, 37, 43, 46,
Com p ou n d 41: mp 52 °C; IR (KBr) 2932, 1686, 1508, 1445,
47, 49, 50, 51, and 53. This material is available free of charge
via the Internet at http://pubs.acs.org.
1397 cm-1 1H NMR (400 MHz, toluene-d8, 340 K) δ 7.16-
;
6.92 (m, 12H), 6.45 (d, J ) 8.8 Hz, 2H), 4.39 (d, J ) 15.0 Hz,
1H), 4.30 (d, J ) 15.0 Hz, 1H), 4.05 (q, J ) 6.0 Hz, 1H), 3.30
J O034188R
6348 J . Org. Chem., Vol. 68, No. 16, 2003