Oxazolium-derived azomethine ylides. External oxazole activation and internal dipole trapping in the synthesis of an aziridinomitosene

Article abstract of DOI:10.1021/jo0001277

Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO₂CH₂CH₂OTf is possible despite the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts with BnNMe₃(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33. Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b. The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15 with tert-butyl chloroacetate.

Full text of DOI:10.1021/jo0001277

5498
J . Org. Chem. 2000, 65, 5498-5505
Oxa zoliu m -Der ived Azom eth in e Ylid es. Exter n a l Oxa zole
Activa tion a n d In ter n a l Dip ole Tr a p p in g in th e Syn th esis of a n
Azir id in om itosen e
Edwin Vedejs,*,† David W. Piotrowski, and Fabio C. Tucci
Chemistry Department, University of Wisconsin, Madison, Wisconsin 52706
edved@umich.edu
Received J anuary 31, 2000
Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO2CH2CH2OTf is possible despite
the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts
with BnNMe3(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an
oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced
cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33.
Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b.
The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15
with tert-butyl chloroacetate.
Prior work in our laboratory has demonstrated the
bond is responsible for the DNA cross-linking properties
of the mitomycin antibiotics. This reactivity complicates
synthetic strategies that target derivatives of 8, and so
far there is only one total synthesis of a natural aziridi-
nomitosene (8 with R ) H and X ) OCH3).7 Several
simpler analogues related to 8 have also been prepared
in the course of synthetic studies,8 including a C(10) ester
9a .8b A similar structure 9b was selected as our initial
target to determine whether the ylide cycloaddition
approach of Scheme 1 would tolerate an aziridinyl
substituent as the R′′ group. Assuming that the aziridinyl
analogue of ylides 4a or 4b can be trapped internally by
[2 + 3] cycloaddition, it should be possible to prepare the
hydroxymethyl aziridine 10, a logical precursor of 9b,
starting from a derivative of 1 where R′′ is a suitably
protected 2-aziridinyl substituent.
There was little reason to expect that the N-benzyl
group in 9b might serve as a removable protecting group
in aziridinomitosene synthesis, given the sensitivity of
the ring system.9 On the other hand, the N-benzyl
environment should allow a realistic test for the surviv-
ability of the aziridine group through the oxazolium salt
activation and azomethine ylide generation sequence.
Furthermore, the related N-benzyl aziridinomitosene 9a
is already known,8b and NMR and UV comparisons would
feasibility of pyrrole synthesis by intramolecular cycload-
dition of azomethine ylides starting from oxazole precur-
sors.1-3 The key dipole intermediates 4a or 4b were
generated from oxazolium salts 2 by nucleophilic activa-
tion using a hydride source (path a) or cyanide ion (path
b). Both reactions proceed via a transient 4-oxazoline
intermediate corresponding to 3a or 3b, and internal [2
+ 3] cycloaddition results in the initial formation of
dihydropyrroles 5a or 5b. Compared to the alternative
method for generation of carbonyl-stabilized azomethine
ylides from aziridines,4 the oxazole approach has the
advantage of considerably lower temperatures and greater
tolerance for alkyl substituents on the ylide carbons.
In our initial studies, path a was more promising.2 The
resulting dihydropyrroles 5a were difficult to purify due
to facile double bond migration and aromatization, but
isolation of the stable pyrrole 6 obtained by DDQ oxida-
tion was relatively easy. Eventually, it was found that
path b works better if an organic-soluble cyanide source,
BnNMe3(+) CN(-), is used as the nucleophile.3 This
procedure has the advantage that conversion from 5b to
6 occurs spontaneously.1,3,5 Both methods a and b have
been used to prepare indoloquinones of general structure
7, resulting from the DDQ oxidation of 6.
The goal of the work described below was to explore
an extension of the oxazolium salt activation method for
the synthesis of indoloquinones belonging to the aziridi-
nomitosene family.6 Typical members of this series
consist of a tetracyclic skeleton 8 with X ) OCH3 or NH2
and contain a sensitive aziridine ring with R ) H or CH3.
The high solvolytic reactivity of the aziridine C(1)-N
(6) (a) Patrick, J . B.; Williams, R. P.; Meyer, W. E.; Fulmor, W.;
Cosulich, D. B.; Broschard, R. W.; Webb, J . S. J . Am. Chem. Soc. 1964,
86, 1889. (b) Reviews: Remers, W. A. In The Chemistry of Antitumor
Antibiotics; Wiley: New York, 1979; Vol. 1, pp 221-276. Tisler, M. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic:
New York, 1988; Vol. 45, pp 38-150. Tomasz, M. Chem. Biol. 1995, 2,
575.
(7) Dong, W.; J imenez, L. S. J . Org. Chem. 1999, 64, 2520.
(8) (a) Review: Danishefsky, S. J .; Schkeryantz, J . M. Synlett 1995,
475. (b) Shaw, K. J .; Luly, J . R.; Rapoport, H. J . Org. Chem. 1985, 50,
4515. (c) Lee, S.; Lee, W. M.; Sulikowski, G. A. J . Org. Chem. 1999,
64, 4224. Edstrom, E. D.; Yu, T. Tetrahedron 1997, 53, 4549. Wang,
Z.; J imenez, L. S. J . Org. Chem. 1996, 61, 816. Danishefsky, S. J .;
Egbertson, M. J . Am. Chem. Soc. 1986, 108, 4648. Iyenger, B. S.;
Remers, W. A.; Bradner, W. T. J . Med. Chem. 1986, 29, 1864. Cory, R.
M.; Ritchie, B. M. J . Chem. Soc., Chem. Commun. 1983, 1244. Suita,
G. J .; Franck, R. W.; Kempton, R. J . J . Org. Chem. 1974, 39, 3739.
Hirata, H.; Yamada, Y.; Matsui, M. Tetrahedron Lett. 1969, 19. Hirata,
H.; Yamada, Y.; Matsui, M. Tetrahedron Lett. 1969, 4107.
(9) Han, I.; Kohn, H. J . Org. Chem. 1991, 56, 4648.
† Current address: Department of Chemistry, University of Michi-
gan, Ann Arbor, MI 48109.
(1) (a) Vedejs, E.; Grissom, J . W. J . Am. Chem. Soc. 1988, 110, 3238.
(b) Vedejs, E.; Dax, S. L. Tetrahedron Lett. 1989, 30, 2627.
(2) Vedejs, E.; Piotrowski, D. W. J . Org. Chem. 1993, 58, 1341.
(3) Vedejs, E.; Monahan, S. D. J . Org. Chem. 1997, 62, 4763.
(4) Lown, J . W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Chapter 6.
(5) Hassner, A.; Fischer, B. Tetrahedron Lett. 1990, 31, 7213.
Hassner, A.; Fischer, B. J . Org. Chem. 1992, 57, 3070.
10.1021/jo0001277 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/09/2000

Oxazolium-Derived Azomethine Ylides
J . Org. Chem., Vol. 65, No. 18, 2000 5499
Sch em e 1
Sch em e 2
imines,10b but the oxazole derivative 11b gave a cis:trans
mixture (1.5:1 12c-cis:12c-tr a n s in THF, 79% isolated
after hydrolytic cleavage of the unstable N-trimethylsi-
lylaziridines 12b-cis/tr a n s) in the reaction with tert-
butyl chloroacetate/LiHMDS. On the other hand, the
analogous N-benzyl imine 11d 11a afforded a single dias-
tereomer according to NMR assay. Although the yield
after chromatography was modest (70%), an evaluation
of NMR data confirmed that the major product was the
cis-diastereomer 12d -cis: J (2,3) ) 6.6 Hz. A similar
result was observed starting from the benzylimine of
pyridine-2-carbaldehyde11b (13-cis formed as the sole
isomer detected by NMR assay, J (2,3) ) 7.0 Hz), sug-
gesting that this may be a general pattern of stereose-
lectivity for the aza-Darzens reaction of N-benzyl imines
derived from heteroaromatic aldehydes.
On the basis of the encouraging model study, the same
aza-Darzens procedure was used to prepare the starting
materials required to test azomethine ylide cycloaddition
methodology. Thus, the 5-substituted 2-formyloxazole
1412 was converted to the N-benzyl imine 15. Treatment
with tert-butyl chloroacetate and lithium hexamethyl-
disilazide gave a single major aziridine 16 after chroma-
tography. According to NMR analysis, J (2,3) ) 6.6 Hz,
16 is the desired cis-disubstituted aziridine.
help to establish structures for related aziridinomitosenes
such as 9b. The N-benzyl series was therefore adopted
for the feasibility study as described below.
Another reason for selecting the N-benzyl target 9b
was that the N-alkyl environment allowed relatively easy
access to cis-disubstituted aziridines using an aza-
Darzens approach.10 Wartskii had already shown that the
enolate of tert-butyl chloroacetate converts PhNdCHPh
into the cis-disubstituted aziridine if a lithium base is
used for enolate generation.10a However, we found that
the corresponding oxazole imine 11a (prepared from
2-formyl-5-phenyloxazole;11a Scheme 2) produces a 1:1.7
cis:trans mixture, 12a -cis and 12a -tr a n s (90%), under
the Wartskii conditions. In the course of optimization
studies, it was found that solvent changes could increase
the proportion of the undesired trans isomer (cis:trans
ratios toluene, 1:2.8; ether, 1:3.1; dimethoxyethane, 1:5.6)
while a reaction in THF-HMPA produced a 1:1 isomer
ratio. Changes in the aza-Darzens leaving group (bromo-
vs chloroacetate) had no effect, so the effort to achieve
better cis selectivity focused on changing the imine
nitrogen substituent. Cainelli et al. have reported cis-
selective aza-Darzens reactions using N-trimethylsilyl
Conversion of 16 into the benzoate ester 17 was
accomplished after some difficulty by reduction (NaEt3-
BH/THF) and treatment with benzoyl chloride. Lithium-
based reducing agents were not suitable for this reduc-
tion, apparently due to competing aziridine ring opening.
Deprotection of the silyl ether and Swern oxidation
occurred without complications and allowed the prepara-
tion of a key aldehyde 18. Following precedents from ear-
lier model studies,2 18 was then treated with the cerium-
(10) (a) Wartski, L. J . Chem. Soc., Chem. Commun. 1977, 602. (b)
Cainelli, G.; Panunzio, M.; Giacomini, D. Tetrahedron Lett. 1991, 32,
121.
(11) (a) Pridgen, L. N.; Shilcrat, S. C. Synthesis 1984, 1048. (b)
Quast, H.; von der Saal, W.; Stawitz, J . Angew. Chem. Int. Ed. Engl.
1981, 20, 588.

5500 J . Org. Chem., Vol. 65, No. 18, 2000
Vedejs et al.
Sch em e 3
the same hybridization effect that decreases the basicity
of aziridines compared to acyclic amines.13 Furthermore,
the cis-disubstituted aziridine ring should force the
N-benzyl group into the less hindered orientation away
from the C(2), C(3) substituents. This would place the
unshared electron pair cis to the C(2), C(3) substituents,
resulting in steric hindrance for aziridine N-alkylation.
The combination of hybridization and steric factors might
allow the direct N-alkylation of the oxazole nitrogen in
20 as required for oxazole activation.
Ultimately, it would be necessary to remove the N-
alkyl group used to activate the oxazole because the
unsubstituted nitrogen is required for eventual cycliza-
tion of ring C via closure of the C(3), N(4) bond. The
initial experiments were therefore performed using tri-
flate 21 (from the alcohol and triflic anhydride/pyridine,
86%) as a reagent that would introduce the potentially
removable PhSO2(CH2)2 group14,15 at oxazole and, eventu-
ally, at pyrrole nitrogen. Reaction of 20 with 21 occurred
at a reasonable rate in acetonitrile at room temperature
and a promising downfield chemical shift was seen in the
oxazole C-4 proton, suggesting that 22 may have been
formed. However, the salt could not be purified to confirm
the desired selectivity for oxazole rather than aziridine
N-alkylation, or to prove that oxazole nitrogen had been
alkylated rather than protonated. This structural uncer-
tainty raised concerns when numerous attempts failed
to convert the presumed oxazolium salt 22 into the
desired cycloadducts 25a or 26 (Scheme 3) via the
reductive activation procedure of Scheme 1, path a.
The only hint of success using reductive activation
came in an experiment where the salts obtained from 20
and 21 were reacted with NaBH4 as the hydride source.
The complex product mixture was treated with Bu4NF
to deprotect the alcohol, followed by DDQ oxidation to
force conversion of the presumably unstable 25a into the
quinone 27. Numerous products were detected by TLC
assay, but one of the minor spots was relatively easy to
separate, and its characteristic yellow color attracted
closer scrutiny. The NMR and UV characteristics were
those expected for an indoloquinone 27, but the yield was
only 2%!
An attempt was made to improve the efficiency of ylide
trapping by increasing the electron demand in the
dipolarophile. Thus, alcohol 19 was converted into the
sensitive keto ester 28 by Dess-Martin oxidation (48%).
Alkylation with PhSO2(CH2)2OTf in acetonitrile was
performed as before, but reduction of the presumed
oxazolium salt was carried out with the PhSiH3/CsF
reagent in the hope that it might be more tolerant of the
presence of the acetylenic ketone, but the resulting
mixture of products was again highly complex. The crude
material was therefore treated with DDQ, and the
product was assayed by TLC. This time, the reaction
produced the yellow quinone 27 (3-5%), together with a
second minor product that had a striking purple color.
This proved to be a mixture of two diastereomers
tentatively assigned the structure 31 (3-5%). The color
as well as the UV spectrum (λmax 534) is characteristic
of an amino quinone of this type, and there is precedent
in our model studies for the sequence of events leading
modified ethyl propiolate anion followed by O-silylation
of the alcohol 19 to give 20 (62% from 18). Structure 20
contains the substituents required to evaluate azome-
thine ylide generation, as described in Scheme 3.
The intended conversions from 20 to a pyrrole 25
involve several challenging stages starting with the
selective N-alkylation of oxazole nitrogen in the presence
of aziridine nitrogen. Initially, we had imagined that this
alkylation might be quite difficult because 20 contains a
potentially nucleophilic aziridine nitrogen. On the other
hand, the strained ring is expected to reduce the nucleo-
philic reactivity of the aziridine N-electron pair due to
(12) Oxazole 14 was prepared from i and acrylonitrile via ii and iii
following methods described in ref 2 for the corresponding sequence
from i and acetonitrile.
(13) Alder, R. W. Chem. Rev. 1989, 89, 1215.
(14) Gonzalez, C.; Greenhouse, R.; Tallabs, R.; Muchowski, J . Can.
J . Chem. 1983, 61, 1697.
(15) Balgobin, N.; J osephson, S.; Chattopadhyaya, J . B. Tetrahedron
Lett. 1981, 22, 1915.

Oxazolium-Derived Azomethine Ylides
J . Org. Chem., Vol. 65, No. 18, 2000 5501
Sch em e 4
Su m m a r y
The experiments described above establish that inter-
molecular alkylation is selective for an oxazole nitrogen
in the presence of an N-benzyl aziridine, and that the
aziridine can survive the conditions required for azome-
thine ylide generation via a 4-oxazoline intermediate with
subsequent intramolecular trapping by [2 + 3] cycload-
dition. The 66% yield of 26 defines the lower limit for
the selectivity for oxazole vs aziridine N-alkylation and
reflects the combined influence of aziridine hybridization
and substituent steric effects on nitrogen nucleophilicity
in the three-membered ring.13,16a A convenient triflate
reagent 21 for oxazole alkylation was developed in the
course of this study. The crystalline triflate is easy to
make and to store, and it should be useful for applications
in nitrogen protection chemistry, judging from prior work
with the less reactive phenylsulfonylethyl bromide.14
Recent studies show that a variation of the azomethine
ylide approach is possible where the oxazolium salt is
formed via intramolecular alkylation.16b Further develop-
ment of the azomethine ylide methodology for aziridi-
nomitosene synthesis17 will be reported in due course.
Exp er im en ta l Section
5-P h en yloxa zole-2-ca r b oxa ld eh yd e N-p h en ylim in e
(11a ). 2-Formyl-5-phenyloxazole11a (382 mg, 2.2 mmol) was
dissolved in 8 mL of dichloromethane. Excess magnesium
sulfate (ca. 2 g) was added followed by aniline (202 µL, 2.2
mmol). After 24 h, the reaction was filtered through a pad of
Celite and the solvent was removed (aspirator) to give 544 mg
(99%) of imine 11a as a yellow solid. Examination of the crude
to the purple quinone.3 Presumably, 31 is formed from
the cycloadduct 30 by initial double bond migration into
the six-membered ring and subsequent oxidation, while
27 arises via initial aromatization to the pyrrole 26,
followed by oxidation of the six-membered ring.
1
material by 200 MHz H NMR showed exclusive formation of
the imine. The crude material was sufficiently pure for further
use. A sample of pure material was obtained by crystallization
from hexane: mp 100-101.2 °C; HRMS 248.0965 (calcd for
C
16H12N2O 248.09500); IR (CCl4, cm-1) 1620 (CdN); 200 MHz
The uncertainty regarding selective oxazole N-alkyla-
tion was resolved when improved conditions for oxazo-
lium ion activation were developed using the crystalline,
organic soluble cyanide source BnNMe3(+)CN(-) corre-
sponding to path b, Scheme 1.3 Formation of 22 in
acetonitrile as before, followed by addition of a large
excess of BnNMe3(+)CN(-) at room temperature resulted
in the formation of a new product in 66% yield that
proved to be the previously elusive pyrrole 26 (Scheme
4). Confirmation of the structure was obtained by treating
26 with Bu4NF/DDQ to give the same yellow quinone 27
that had been isolated in low yield from the reductive
activation experiments of Scheme 3. None of the purple
quinone 31 was formed, as expected if the sequence from
22 to the dihydropyrrole 25b is followed by spontaneous
aromatization to 26.3 These observations also confirm
that the ylide 24b has been generated from 22 via an
unstable 4-oxazoline 23b (Scheme 4).
The overall yield of 26 (66% based on 20) was suf-
ficiently high to investigate further transformations to
the aziridinomitosene skeleton. Saponification of the
benzoate ester followed by base-induced cleavage of the
PhSO2(CH2)2 protecting group14 gave the pyrrole alcohol
10. Subsequent mesylate formation with CH3SO2Cl/Et3N
afforded 32 and base-induced cyclization produced the
tetracyclic 33. Finally, deprotection and DDQ oxidation
gave the racemic aziridinomitosene 9b, and the structure
was established by comparison of UV and NMR charac-
teristics with the closely related aziridinomitosene 9a
reported by Rapoport et al.8b
NMR (CDCl3, ppm) δ 8.42 (1H, s), 7.84-7.79 (2H, m), 7.58 (1H,
s), 7.51-7.31 (8H, m).
ter t-Bu tyl cis- a n d tr a n s-2-(5-P h en yloxa zol-2-yl)-N-
p h en yla zir id in eca r boxyla te (12a -cis a n d 12a -tr a n s). Bu-
tyllithium (0.27 mL, 1.71 M in hexanes) was added dropwise
to a solution of hexamethyldisilazane (98 µL, 0.47 mmol,
Aldrich, distilled) in 5 mL of THF at -78 °C. After warming
to room temperature over 15 min, the solution was re-cooled
to -78 °C, and tert-butyl bromoacetate (63 µL, 0.39 mmol,
Aldrich, neat) was added dropwise. After 15 min of stirring at
-78 °C, a solution of oxazole N-phenylimine 11a (39 mg, 0.16
mmol) in THF was added dropwise. The reaction was quenched
at -78 °C with saturated ammonium chloride solution after
10 min, warmed to room temperature, diluted with water,
extracted with dichloromethane, dried (MgSO4), and filtered.
After concentration (aspirator), the crude reaction mixture was
analyzed by 200 MHz 1H NMR to reveal a 1.8:1 trans:cis ratio.
The residue was purified by flash chromatography on silica
(16) (a) The role of the N-benzyl group in the selective N-alkylation
has been probed using analogues of 20 where Bn is replaced by H and
OBz by iodide (see ref 16b for methodology to access the deprotected
aziridines). Treatment of the NH aziridine with MeOTf in the presence
of 2,6-di-tert-butyl-4-methylpyridine in deuterated aceonitrile gave ca.
25% of the N-methylaziridine as well as recovered starting material
and decomposition products. Characteristic NMR shifts for oxazolium
protons were also observed, indicating that the rates of oxazole and
aziridine alkylation are similar in the absence of the N-benzyl
substituent. (b) Vedejs, E.; Klapars, A.; Naidu, B. N.; Piotrowski, D.
W. Tucci, F. C. J . Am. Chem. Soc. 2000, 122, 5401.
(17) For studies dealing with azomethine ylide approaches to
mitosenes, see: Hershenson, F. M. J . Org. Chem. 1975, 40, 1260.
Rebek, J .; Shabar, S. H.; Shue, Y.-K.; Gehret, J .-C.; Zimmerman, S. J .
Org. Chem. 1984, 49, 5164. Rebek, J .; Shaber, S. H. Heterocycles 1981,
16, 1173. Rebek, J .; Gehret, J .-C. E. Tetrahedron Lett. 1977, 19, 3027.
Anderson, W. K.; Corey, P. F. J . Org. Chem. 1977, 42, 559.

5502 J . Org. Chem., Vol. 65, No. 18, 2000
Vedejs et al.
gel (13 mm × 30 cm), 1:4 EtOAc/hexane eluent to afford 32
mg (58%) of trans-aziridine and 18 mg (32%) of cis-aziri-
dine. 12a -tr a n s: analytical TLC on silica gel, 1:4 EtOAc/
hexane, Rf ) 0.32; HRMS 362.1616 (calcd for C22H22N2O3
362.16306); IR (neat, cm-1) 1730 (CdO), 200 MHz NMR
(CDCl3, ppm) δ 7.50-7.18 (8H, m), 7.01-6.94 (3H, m), 4.03
(1H, d, J ) 2.5 Hz), 3.65 (1H, d, J ) 2.5 Hz), 1.39 (9H, s).
12a -cis: analytical TLC on silica gel, 1:4 EtOAc/hexane, Rf )
0.22; HRMS 362.1626 (calcd for C22H22N2O3 362.16306), base
peak ) 261 amu; IR (neat, cm-1) 1750 (CdO), 1150 (C-O);
200 MHz NMR (CDCl3, ppm) δ 7.70-7.66 (2H, m), 7.44-7.07
(9H, m), 3.62 (1H, d, J ) 6.5 Hz), 3.20 (1H, d, J ) 6.5 Hz),
1.37 (9H, s).
ter t-Bu tyl cis- a n d tr a n s-2-(5-P h en yloxa zol-2-yl)a zir i-
d in eca r boxyla te (12c-cis a n d 12c-tr a n s). Butyllithium (2.0
mL, 1.68 M in hexanes) was added dropwise to a solution of
hexamethyldisilazane (0.7 mL, 3.33 mmol, Aldrich, distilled)
in 5 mL of THF at -78 °C. After warming to room temperature
over 15 min, the solution was cooled to 0 °C, and a solution of
2-formyl-5-phenyloxazole (524 mg, 3.03 mmol) in 1.5 mL of
THF was added. The solution was allowed to warm to room
temperature over 1 h to form 11b. In a separate flask,
butyllithium (5.4 mL, 1.68 M in hexanes) was added dropwise
to a solution of hexamethyldisilazane (1.9 mL, 9.08 mmol) in
20 mL of THF at -78 °C. After warming to room temperature
over 15 min, tert-butyl chloroacetate (1.3 mL, 9.08 mmol,
Aldrich, neat) was added dropwise. After 15 min of stirring at
-78 °C, the previously prepared solution of N-TMS imine 11b
was added dropwise. The reaction was warmed to room
temperature after 1 h, quenched with water, extracted with
ether, dried (MgSO4), and filtered. After removal of solvent
(aspirator), the residue was purified by flash chromatography
on silica gel 1:2 EtOAc/hexane eluent, to afford 357 mg (41%)
cis-aziridine and 162 mg (19%) trans-aziridine. 12c-cis: ana-
lytical TLC on silica gel, 3:2 EtOAc/hexane, Rf ) 0.32; HRMS
286.1317 (calcd for C16H18N2O3 286.13174); 200 MHz NMR
(CDCl3, ppm) δ 7.72-7.32 (5H, m), 7.28 (1H, s), 3.34 (1H, dd,
J ) 5.9, 8.4 Hz), 2.90 (1H, dd, J ) 5.9, 9.1 Hz), 2.10 (1H, dd,
J ) 8.4, 9.1 Hz), 1.33 (9H, s). 12c-tr a n s: analytical TLC on
silica gel, 3:2 EtOAc/hexane, Rf ) 0.57; 200 MHz NMR (CDCl3,
ppm) δ 7.72-7.31 (5H, m), 7.27 (1H, s), 3.41 (1H, dd, J ) 2.4,
9.8 Hz), 3.05 (1H, dd, J ) 2.42.4, 8.4 Hz), 1.90 (1H, dd, J )
8.4, 9.8 Hz), 1.51 (9H, s).
obtained by crystallization from hexane: mp 112.5-113.5 °C;
HRMS 376.1778 (calcd for C23H24N2O3 376.17871), base peak
) 275 amu; IR (CCl4, cm-1) 1753 (CdO), 1715 (CdO), 1170
(C-O); 200 MHz NMR (CDCl3, ppm) δ 7.65-7.50 (2H, m),
7.46-7.27 (9H, m), 3.92 (1H, d, J ) 15.8 Hz), 3.83 (1H, d, J )
15.8 Hz), 3.06 (1H, d, J ) 6.6 Hz), 2.63 (1H, d, J ) 6.6 Hz),
1.32 (9H, s).
ter t-Bu tyl cis-2-(2-P yr id yl)-N-ben zyla zir id in eca r boxy-
la te (13-cis). Butyllithium (1.7 mL, 1.64 M in hexanes) was
added dropwise to a solution of hexamethyldisilazane (574 µL,
2.72 mmol, Aldrich, distilled) in 10 mL of THF at -78 °C. After
warming to room temperature over 15 min, the solution was
re-cooled to -78 °C, and tert-butyl chloroacetate (389 µL, 2.72
mmol, Aldrich, neat) was added dropwise. After 15 min of
stirring at -78 °C, a solution of 2-pyridine carbaldehyde11b
N-benzylimine (178 mg, 0.91 mmol) in THF was added
dropwise. The reaction was warmed to room temperature after
30 min, quenched with water, extracted with dichloromethane,
dried (MgSO4), and filtered. After removal of solvent (aspira-
tor), the residue was purified by flash chromatography on silica
gel, 1:2 EtOAc/hexane eluent, to afford 140 mg (50%) of the
cis-aziridine 13-cis as a solid: analytical TLC on silica gel,
1:2 EtOAc/hexane, Rf ) 0.14. Pure material was obtained by
crystallization from hexane: mp 67.5-68.5 °C; HRMS 311.1778
(calcd for C19H22N2O2, M + 1); base peak ) 209 amu; IR (CCl4,
cm-1) 1745 (CdO); 200 MHz NMR (CDCl3, ppm) δ 8.48-8.45
(1H, m), 7.65-7.09 (8H, m), 3.99 (1H, d, J ) 13.7 Hz), 3.61
(1H, d, J ) 13.7 Hz), 3.18 (1H, d, J ) 7.0 Hz), 2.65 (1H, d, J
) 7.0 Hz), 1.20 (9H, s).
Syn th esis of 2-F or m yl-5-(3′-ter t-bu tyld im eth ylsiloxy-
p r op yl)oxa zole (14). 2-Vinyl-5-(3′-chloropropyl)oxazole was
prepared following the procedure for 2-methyl-5-(3′-chloropro-
pyl)oxazole reported in ref 2, substituting acrylonitrile for
acetonitrile. The product was purified by distillation to afford
80% of 2-vinyl-5-(3′-chloropropyl)oxazole as a clear liquid: bp
70-73 °C, 1.0 mmHg, short path; HRMS 171.0447 (calcd
for C8H10ClNO), base peak ) 108 amu; IR (neat, cm-1) 1600
(CdN); 200 MHz NMR (CDCl3, ppm) δ 6.82 (1H, s), 6.55 (1H,
dd, J ) 11.2, 17.7 Hz), 6.10 (1H, dd, J ) 1.1, 17.7 Hz), 5.58
(1H, dd, J ) 1.1, 11.2 Hz), 3.59 (2H, t, J ) 6.3 Hz), 2.86 (2H,
t, J ) 7.1 Hz), 2.20-2.06 (2H, m).
2-Vinyl-5-(3′-acetoxypropyl)oxazole: Sodium acetate (5.67
g, 68.4 mmol), sodium iodide (3.18 g, 21.2 mmol), and 2-vinyl-
5-(3′-chloropropyl)oxazole (5.87 g, 34.2 mmol) were mixed in
44 mL 1:1 HMPA/THF, and the suspension was heated at 65
°C. After 36 h, water was added. The solution was extracted
with ether and with ethyl acetate. The combined organic layers
were washed with water and brine, dried (MgSO4), and
filtered. After removal of solvent (aspirator), the residue was
purified by flash chromatography on silica gel, EtOAc/hexane
(gradient 0:1-1:2) eluent, to afford 5.07 g (76%) of 2-vinyl-5-
(3′acetoxypropyl)oxazole as an oil: analytical TLC on silica gel,
1:2 EtOAc/hexane, Rf ) 0.25; M+ calcd for C10H13NO3 195.08952,
found 195.0896, error ) 0 ppm, base peak ) 135 amu; IR (neat,
cm-1) 1745 (CdO), 1600 (CdN), 1240 (C-O); 200 MHz NMR
(CDCl3, ppm) δ 6.69 (1H, t, J ) 0.9 Hz), 6.55 (1H, dd, J )
11.2, 17.7 Hz), 6.09 (1H, dd, J ) 1.1, 17.7 Hz), 5.56 (1H, dd, J
) 1.1, 11.1 Hz), 4.14 (2H, t, J ) 6.3 Hz), 2.76 (2H, dt, J ) 0.8,
6.8 Hz), 2.08-1.94 (5H, overlapping m and s).
5-P h en yloxazole-2-car boxaldeh yde N-ben zylim in e (11d).
2-Formyl-5-phenyloxazole (322 mg, 1.86 mmol) was dissolved
in 8 mL of dichloromethane. Excess magnesium sulfate (ca. 2
g) was added to the solution followed by the addition of
benzylamine (203 µL, 1.86 mmol). After 24 h, the reaction was
filtered through a pad of Celite, and the solvent was removed
(aspirator) to give 483 mg (99%) of imine 11d as a yellow solid.
Examination of the crude material by 200 MHz 1H NMR
showed exclusive formation of the imine. The crude material
was sufficiently pure for further use. Pure material was
obtained as yellow needles by crystallization from ethyl
acetate/hexane: mp 91-92 °C; HRMS 262.1107 (calcd for
C
17H14N2O 262.11063), base peak ) 91 amu; IR (CCl4, cm-1
)
1630 (CdN); 200 MHz NMR (CDCl3, ppm) δ 8.25 (1H, t, J )
1.5 Hz), 7.78-7.73 (2H, m), 7.49-7.33 (9H, m), 4.94 (2H, d, J
) 1.5 Hz).
ter t-Bu tyl cis-2-(5-P h en yloxa zol-2-yl)-N-ben zyla zir i-
d in eca r boxyla te (12d -cis). Butyllithium (0.44 mL, 1.7 M in
hexanes) was added dropwise to a solution of hexamethyld-
isilazane (156 µL, 0.74 mmol, Aldrich, distilled) in 5 mL of
THF at -78 °C. After warming to room temperature over 15
min, the solution was re-cooled to -78 °C, and tert-butyl
chloroacetate (106 µL, 0.74 mmol, Aldrich, neat) was added
dropwise. After 15 min of stirring at -78 °C, a solution of
N-benzylimine 11d (65 mg, 0.25 mmol) in THF was added
dropwise. The reaction was warmed to room temperature after
10 min, quenched with water, extracted with dichloromethane,
dried (MgSO4), and filtered. After removal of solvent (aspira-
tor), the residue was purified by flash chromatography on silica
gel (15 mm × 40 cm), 1:2 EtOAc/hexane eluent, to afford 65
mg (70%) of aziridine 12d -cis as an oil: analytical TLC on
silica gel, 1:2 EtOAc/hexane, Rf ) 0.24. Pure material was
2-Vinyl-5-(3′-hydroxypropyl)oxazole: Potassium carbonate
(3.10 g, 22.3 mmol) was added to a solution of 2-vinyl-5-(3′-
acetoxypropyl)oxazole (3.96 g, 20.3 mmol) in 100 mL of
methanol and 5 mL of water. After 1 h, the solution was
concentrated and then extracted with ethyl acetate, dried
(MgSO4), and filtered. After removal of solvent (aspirator), the
residue was purified by flash chromatography on silica gel,
EtOAc/hexane (0:1-1:1) eluent, to afford 1.86 g (60%) of the
title alcohol as an oil: analytical TLC on silica gel, 1:1 EtOAc/
hexane, Rf ) 0.15; HRMS 153.0800 (calcd for C8H11NO2
153.07898), base peak ) 108 amu; IR (neat, cm-1) 3400
(O-H), 1600 (CdN); 200 MHz NMR (CDCl3, ppm) δ 6.78 (1H,
t, J ) 1.0 Hz), 6.56 (1H, dd, J ) 11.2, 17.7 Hz), 6.09 (1H, dd,
J ) 1.1, 17.7 Hz), 5.56 (1H, dd, J ) 1.1, 11.2 Hz), 3.72 (2H, t,
J
) 6.3 Hz), 2.79 (2H, t, J ) 7.4 Hz), 1.99-1.86 (3H,
overlapping m and br s).

Oxazolium-Derived Azomethine Ylides
J . Org. Chem., Vol. 65, No. 18, 2000 5503
2-Formyl-5-(3′-tert-butyldimethylsiloxypropyl)oxazole (14):
tert-Butyldimethylsilyl chloride (0.83 g, 5.52 mmol) was added
to a solution of 2-vinyl-5-(3′-hydroxypropyl)oxazole (0.77 g, 5.02
mmol), triethylamine (0.84 mL, 6.02 mmol), and a catalytic
amount of DMAP (approximately 15 mg) in dichloromethane
at 0 °C. After warming to room temperature, the reaction was
stirred for 24 h. The reaction mixture was poured into water,
extracted with dichloromethane, dried (MgSO4), and filtered.
After removal of solvent (aspirator), the residue was purified
by flash chromatography on silica gel, EtOAc/hexane (0:1-1:
4) eluent, to afford 1.30 g (97%) of 2-vinyl-5-(3′-tert-butyldi-
methyl-siloxypropyl)oxazole, sufficiently pure for use in the
next step.
A catalytic amount of osmium tetroxide (30 mg, Merck) was
added to a solution of 2-vinyl-5-(3′-tert-butyldimethylsiloxy-
propyl)oxazole (1.30 g, 4.86 mmol) in 20 mL of THF and 15
mL water. After 5 min, sodium metaperiodate (2.34 g, 10.94
mmol, Aldrich) was added portionwise over 1 h. After 24 h,
the mixture was diluted with water, extracted with ethyl
acetate, dried (MgSO4), and filtered. After removal of solvent
(aspirator), the residue was purified by flash chromatography
on silica gel (15 mm × 35 cm), EtOAc/hexane (gradient; 0:1-
1:4) eluent, to afford 976 mg (75%) of 14 as an oil: analytical
TLC on silica gel, 1:4 EtOAc/hexane, Rf ) 0.20; HRMS
269.1463 (calcd for C13H23NO3Si 269.14471), base peak ) 212
amu; IR (neat, cm-1) 1711 (CdO); 200 MHz NMR (CDCl3, ppm)
δ 9.66 (1H, s), 7.07 (1H, s), 3.65 (2H, t, J ) 5.8 Hz), 2.85 (2H,
t, J ) 8.1 Hz), 1.97-1.86 (2H, m), 0.87 (9H, s), 0.03 (6H, s).
ter t-Bu tyl cis-3-[5-(3′-ter t-bu tyld im eth ylsiloxyp r op yl)-
oxa zol-2-yl]-N-ben zyla zir id in e-2-ca r boxyla te (16). The
2-formyloxazole TBS ether 14 (2.26 g, 8.39 mmol) was dis-
solved in 50 mL of dichloromethane. Excess MgSO4 (ap-
proximately 4 g) was added followed by the addition of
benzylamine (0.93 mL, 8.47 mmol, Aldrich, distilled). After 24
h, the mixture was filtered through a pad of Celite and
concentrated (aspirator). Residual solvent and benzylamine
were removed in vacuo (1 mmHg) to give 2.92 g (97%) of
N-benzylimine 15 as an oil. The crude material was sufficiently
pure for use in the next step.
7.26 (5H, m), 6.64 (1H, s), 4.00-3.80 (1H, m), 3.88 (1H, d, J )
13.5 Hz), 3.65-3.50 (1H, m), 3.64 (2H, t, J ) 6.0 Hz), 3.60
(1H, br s), 3.56 (1H, d, J ) 13.4 Hz), 2.75-2.67 (3H, d,
overlapping d and t, J ) 6.4 Hz and J ) 7.8 Hz), 2.36-2.27
(1H, m), 1.90-1.80 (2H, m), 0.90 (9H, s), 0.05 (6H, s).
Benzoyl chloride (139 µL, 1.25 mmol, Mallinckrodt) was
added to a solution of the aziridine alcohol from the preceding
step (420 mg, 1.04 mmol), triethylamine (218 µL, 1.56 mmol),
and a catalytic amount of DMAP (ca. 10 mg) in 20 mL of
dichloromethane at 0 °C. After slowly warming to room
temperature over 2 h, the solution was stirred for an additional
10 h. The reaction was quenched with water, extracted with
dichloromethane, dried (MgSO4), and filtered. After removal
of solvent (aspirator), the residue was purified by flash
chromatography on silica gel (15 mm × 40 cm), 1:2 EtOAc/
hexane eluent, to afford 459 mg (87%) of the aziridinemethanol
benzoate 17 as an oil: analytical TLC on silica gel, 1:2 EtOAc/
hexane, Rf ) 0.29; HRMS 506.2590 (calcd for C29H38N2O4Si
506.26007), base peak ) 105 amu; IR (neat, cm-1) 1725 (Cd
O), 1240 (C-O); 200 MHz NMR (CDCl3, ppm) δ 7.89-7.81 (2H,
m), 7.57-7.22 (8H, m), 6.70 (1H, s), 4.57 (1H, dd, J ) 5.2, 11.8
Hz), 4.47 (1H, dd, J ) 7.5, 11.8 Hz), 4.07 (1H, d, J ) 13.4 Hz),
3.62 (2H, t, J ) 6.0 Hz), 3.41 (1H, d, J ) 13.4 Hz), 2.95 (1H,
d, J ) 6.4 Hz), 2.71 (2H, t, J ) 7.5 Hz), 2.52-2.43 (1H, m),
1.89-1.76 (2H, m), 0.89 (9H, s), 0.04 (6H, s).
Con ver sion of 17 to th e Ald eh yd e 18. A solution of
tetrabutylammonium fluoride (0.88 mL, 1.0 M in THF, Pe-
trarch) was added dropwise to a solution of oxazole aziridine
17 (444 mg, 0.88 mmol) in 20 mL of THF. After 1 h, the
reaction was diluted with ethyl acetate and water, extracted
with ethyl acetate, dried (MgSO4), and filtered. After removal
of solvent (aspirator), the residue was purified by flash
chromatography on silica gel (15 mm × 40 cm), EtOAc eluent,
to afford 303 mg (88%) of deprotected alcohol as an oil:
analytical TLC on silica gel, EtOAc, Rf ) 0.30; HRMS 392.1725
(calcd for C23H24N2O4 392.17358), base peak ) 105 amu; IR
(neat, cm-1) 3400 (O-H), 1718 (CdO); 200 MHz NMR
(CDCl3, ppm) δ 7.85-7.81 (2H, m), 7.57-7.23 (8H, m), 6.72
(1H, s), 4.56 (1H, dd, J ) 5.4, 11.8 Hz), 4.45 (1H, dd, J ) 7.4,
11.8 Hz), 4.07 (1H, d, J ) 13.4 Hz), 3.65 (2H, t, J ) 5.4 Hz),
3.43 (1H, d, J ) 13.3 Hz), 2.97 (1H, d, J ) 6.4 Hz), 2.74 (2H,
t, J ) 7.4 Hz), 2.53-2.44 (1H, m), 1.95-1.81 (2H, m), 1.65 (1H,
br s).
DMSO (1.2 mL, 16.6 mmol) was added dropwise to a
solution of oxalyl chloride (760 µL, 8.7 mmol) in 50 mL of
dichloromethane at -78 °C. After 20 min, a solution of
deprotected alcohol, prepared as described above, (1.31 g, 3.33
mmol) in 20 mL of dichloromethane was added, dropwise via
cannula. After 40 min, triethylamine (1.9 mL, 13.3 mmol) was
added and the solution was warmed to room temperature. The
reaction was quenched with water, extracted with dichlo-
romethane, dried (MgSO4), and filtered. After removal of
solvent (aspirator), the residue was purified by flash chroma-
tography on silica gel (17 mm × 35 cm), 1:1 EtOAc/hexane
eluent, to afford 1.10 g (85%) of oxazole aldehyde 18 as an
amorphous solid: analytical TLC on silica gel, EtOAc, Rf )
0.48; HRMS 390.1580 (calcd for C23H22N2O4 390.15796), base
peak ) 105 amu; IR (CCl4, cm-1) 2820 (aldehyde C-H), 2715
(aldehyde C-H), 1725 (CdO); 200 MHz NMR (CDCl3, ppm) δ
9.79 (1H, s), 7.85-7.81 (2H, m), 7.58-7.20 (8H, m), 6.73 (1H,
s), 4.56 (1H, dd, J ) 5.4, 11.8 Hz), 4.43 (1H, dd, J ) 7.4, 11.8
Hz), 4.06 (1H, d, J ) 13.3 Hz), 3.44 (1H, d, J ) 13.3 Hz), 3.01-
2.94 (3H, m), 2.76 (2H, t, J ) 6.6 Hz), 2.54-2.44 (1H, m).
Alk yn oa te Alcoh ol TBS Eth er 20. Ceric chloride, 3.53 g
(9.0 mmol) (CeCl3‚7H2O ground to a powder and dried (1 mm)
and 140 °C for 5 h), was suspended in 45 mL of dry THF under
nitrogen at 0 °C and stirred 15 h at room temperature to make
a slurry. In a separate flask, butyllithium (3.3 mL, 2.42 M in
hexane) was added dropwise to a solution of hexamethyldisi-
lazane (1.31 g, 8.1 mmol) in 30 mL of THF at - 78 °C. The
resulting LiHMDS solution was warmed to room temperature
over 15 min. Ethyl propiolate (Aldrich, 0.780 g, was then added
dropwise by syringe to the previously prepared CeCl3/THF
suspension at -78 °C, followed by dropwise cannula transfer
of the LiHMDS solution. The resulting yellow mixture was and
Butyllithium (4.94 mL, 1.51 M in hexanes) was added
dropwise to a solution of hexamethyldisilazane (1.20 g, 7.46
mmol, Aldrich, distilled) in 60 mL of dry THF at -78 °C. After
warming to room temperature over 15 min, the solution was
re-cooled to -78 °C, and a solution of tert-butyl chloroacetate
(1.123 g, 7.46 mmol, Aldrich) in 10 mL of THF was added
dropwise. After 30 min of stirring at -78 °C, a solution of
N-benzylimine 15 (0.889 g, 2.48 mmol) in 15 mL of THF was
added dropwise. The orange reaction mixture was warmed to
room temperature after 35 min, and the resulting yellow
solution was quenched with water, extracted with ether, dried
(MgSO4), and filtered. After removal of solvent (aspirator), the
residue was purified by flash chromatography on silica gel (15
mm × 35 cm), 1:2 EtOAc/hexane eluent, to afford a forerun of
byproducts (ca. 0.5 g) followed by a more polar fraction, 0.725
g (62%) of cis-aziridine 16 as an oil: analytical TLC on silica
gel, 1:2 EtOAc/hexane, Rf ) 0.26; HRMS 472.2754 (calcd for
C
26H40N2O4Si 472.27560); IR (neat, cm-1) 1745 (CdO), 1725
(CdO); 200 MHz NMR (CDCl3, ppm) δ 7.45-7.27 (5H, m), 6.68
(1H, t, J ) 1.0 Hz), 3.89 (1H, d, J ) 14.1 Hz), 3.77 (1H, d, J )
13.9 Hz), 3.63 (2H, t, J ) 6.1 Hz), 2.98 (1H, d, J ) 6.6 Hz),
2.71 (2H, t, J ) 7.5 Hz), 2.55 (1H, d, J ) 6.6 Hz), 1.89-1.76
(2H, m), 1.37 (9H, s), 0.89 (9H, s), 0.04 (6H, s).
Oxa zolyl Azir id in e Ben zoa te Ester 17. cis-3-[5-(3′-tert-
Butyldimethylsiloxypropyl)oxazol-2-yl]-N-benzylaziridine-2-
methanol: A solution of sodium triethylborohydride (1.7 mL,
1.0 M in THF, Aldrich) was added dropwise to a solution of
oxazole aziridine ester 16 (319 mg, 0.68 mmol) in 15 mL of
THF at -78 °C. After warming to room temperature over 20
min, the reaction was quenched with methanol (2 mL). After
evaporation (aspirator), the residue was purified by flash
chromatography on silica gel (15 mm × 40 cm), EtOAc/hexane
(0:1-1:0) eluent, to afford 226 mg (83%) of the aziridine alcohol
as an oil: analytical TLC on silica gel, 1:1 EtOAc/hexane, Rf
) 0.21; HRMS 403.2407 (calcd for C22H34N2O3Si, M + 1); IR
(neat, cm-1) 3400 (O-H); 200 MHz NMR (CDCl3, ppm) δ 7.40-

5504 J . Org. Chem., Vol. 65, No. 18, 2000
Vedejs et al.
stirred 0.5 h at -78 °C. A solution of aldehyde 18 (0.837 g,
2.15 mmol) in 20 mL of THF was then added dropwise via
cannula and stirred for 0.5 h. The reaction was quenched with
water, extracted with ethyl acetate, washed with brine, dried
(MgSO4), and filtered. After removal of solvent (aspirator), the
crude alcohol 19 was obtained as an oil (1.05 g).
Hz), 3.04 (1H, d, J ) 13.1 Hz), 2.52-2.46 (1H, m), 1.35 (3H, t,
J ) 7.2 Hz).
Yn on e Ester 28. Dess-Martin periodinane19 (579 mg, 1.37
mmol) was added to a solution of oxazole alkynol 19 (214 mg,
0.44 mmol) in 25 mL of dichloromethane. After 30 min,
saturated aqueous NaHCO3 and excess Na2S2O3 were added
to the reaction mixture. After the solids were dissolved the
mixture was extracted with dichloromethane. The combined
organic layers were washed with saturated aqueous NaHCO3,
dried (MgSO4), and filtered. After removal of solvent (aspira-
tor), the residue was purified by flash chromatography on silica
gel (13 mm × 20 cm), 2:3 EtOAc/hexane eluent, to afford 102
mg (48%) of 28 as an oil: analytical TLC on silica gel, 1:1
EtOAc/hexane, Rf ) 0.26; HRMS 368.1135 (calcd C28H26N2O6
- C8H8N), base peak ) 105 amu; IR (CCl4, cm-1) 1724 (CdO),
1695 (CdO); 200 MHz NMR (CDCl3, ppm) δ 7.86-7.81 (2H,
m), 7.58-7.22 (8H, m), 6.75 (1H, s), 4.56 (1H, dd, J ) 5.4, 11.8
Hz), 4.42 (1H, dd, J ) 7.4, 11.8 Hz), 4.30 (2H, q, J ) 7.2 Hz),
4.07 (1H, d, J ) 13.3 Hz), 3.43 (1H, d, J ) 13.3 Hz), 3.04-
2.99 (4H, m), 2.95 (1H, d, J ) 6.4 Hz), 2.54-2.44 (1H, m), 1.33
(3H, t, J ) 7.1 Hz).
tert-Butyldimethylsilyl chloride (0.486 g, 3.23 mmol, Pe-
trarch) was added to a solution of the crude alkynol 19 (1.05
g) from above and imidazole (0.366 g, 5.38 mmol) in 15 mL of
DMF at room temperature. After 12 h, the mixture was poured
into water, extracted with ethyl acetate, dried (MgSO4), and
evaporated (aspirator). The residue was purified by flash
chromatography on silica gel (13 mm × 20 cm) using 1:2
EtOAc/hexane to afford 0.80 g of 20 as an oil (62% from 18):
analytical TLC on silica gel, 1:1 EtOAc/hexane, Rf ) 0.50;
HRMS 602.2806 (calcd for C34H42N2O6Si 602.28119), base peak
) 105 amu; IR (CCl4, cm-1) 2238 (CdC), 1723 (CdO); 200 MHz
NMR (CDCl3, ppm) δ 7.89-7.81 (2H, m), 7.57-7.22 (8H, m),
6.72 (1H, s), 4.61-4.38 (3H, m), 4.24 (2H, q, J ) 7.1 Hz), 4.07
(1H, d, J ) 13.2 Hz), 3.42 (1H, d, J ) 13.4 Hz), 2.95 (1H, d, J
) 6.4 Hz), 2.81 (2H, t, J ) 7.7 Hz), 2.53-2.43 (1H, m), 2.10-
1.99 (2H, m), 1.31 (3H, t, J ) 7.1 Hz), 0.91 (9H, s), 0.16 (3H,
s), 0.11 (3H, s).
2-(P h en ylsu lfon yl)eth yl tr iflu or om eth an esu lfon ate (21).
Triflic anhydride (551 µL, 3.27 mmol, Aldrich) was added
dropwise to a solution of pyridine (287 µL, 3.55 mmol) in 20
mL of dichloromethane at -20 °C to give a white suspension.
After 10 min, a solution of 2-(phenylsulfonyl)ethanol18 (508 mg,
2.73 mmol) in dichloromethane was added dropwise to the
above suspension. The mixture was warmed to room temper-
ature over 30 min, filtered through a plug of coarse silica gel
(25 mm × 15 cm) with ether, and concentrated (aspirator).
Pure material was obtained by crystallization from carbon
tetrachloride to afford 749 mg (86%) of 2-(phenylsulfonyl)ethyl
triflate 21 as white needles: mp 63-64 °C; HRMS 317.9845
(calcd for C9H9F3O5S2 317.98431), base peak ) 125 amu; IR
(CHCl3, cm-1) 1330 (SO2), 1145 (SO2); 200 MHz NMR (CDCl3,
ppm) δ 7.97-7.92 (2H, m), 7.74-7.59 (3H, m), 4.83 (2H, t, J
) 6.2 Hz), 3.61 (2H, t, J ) 6.2 Hz).
Azir id in yl In d oloqu in on e via Bor oh yd r id e Ylid e Gen -
er a tion (27). Oxazole 20 (89 mg, 0.15 mmol) and 2-(phenyl-
sulfonyl)ethyl triflate (21) (52 mg, 0.16 mmol) were dissolved
in 5 mL of dry acetonitrile and stirred at room temperature
for 34 h. Solid sodium borohydride (11 mg, 0.28 mmol, Aldrich)
was added to give a yellow solution. After 1 h of stirring at
room temperature, the reaction was diluted with ethyl acetate
and water, extracted with ethyl acetate, dried (MgSO4),
filtered, and concentrated (aspirator) to give a white foam. The
foam was purified by plug filtration chromatography on silica
gel, 2:5 EtOAc/hexane eluent, to give 68 mg of a mixture that
was dissolved in 5 mL of THF and treated with excess TBAF
(0.3 mL, 1.0 mL in THF, Petrarch). After 12 h, water was
added, and the solution was extracted with ethyl acetate, dried
(MgSO4), filtered, and concentrated (aspirator). Residual
solvent was removed in vacuo (1 mm) to give a brown foam.
The brown foam was dissolved in 5 mL of THF along with
DDQ (101 mg, 0.45 mmol) and refluxed for 1.5 h. After removal
of solvent (aspirator), the residue was purified by flash
chromatography on silica gel (13 mm × 30 cm), 1:1 EtOAc/
hexane eluent, to afford 8 mg of impure yellow quinone 27.
Repurification by preparative thin-layer chromatography on
silica gel; 1:1 EtOAc/hexane eluent (two elutions) afforded 2
mg (2%) of quinone 27 as a yellow amorphous solid: analytical
TLC on silica gel, 1:1 EtOAc/hexane, Rf ) 0.36; HRMS
561.1350 (calcd for C36H32N2O8S -C7H7), base peak ) 125 amu;
IR (CCl4, cm-1) 1727, CdO; 1670, CdO; 1654, CdO; UV
(MeOH, λmax (nm)) 288 (ꢀ ) 10 400), 220 (ꢀ ) 27 860),
broadened shoulder 400; 200 MHz NMR (CDCl3, ppm) δ 7.84-
7.79 (2H, m), 7.70-7.24 (13H, m), 6.54 (1H, d, J ) 10.4 Hz),
6.45 (1H, d, J ) 10.3 Hz), 5.10-4.90 (1H, m), 4.76-4.68 (1H,
m), 4.67 (1H, d, J ) 13.0 Hz), 4.40-4.25 (2H, m), 4.13 (1H,
dd, J ) 5.0, 12.0 Hz), 3.95-3.65 (3H, m), 3.20 (1H, d, J ) 6.2
P u r p le Qu in on e (31). Alkynyl ketone 28 (102 mg, 0.21
mmol) and 2-(phenylsulfonyl)ethyl triflate (21) (75 mg, 0.23
mmol) were dissolved in 6 mL of dry acetonitrile and stirred
at room temperature for 48 h. Phenyl silane (39 µL, 0.31 mmol)
was added to the solution of the crude oxazolium salt, and then
the solution was added via cannula to flame-dried CsF
(approximately 60 mg) in 2 mL of dry acetonitrile. After 15 h
of stirring at room temperature, the reaction was filtered
through a plug of Celite and concentrated (aspirator). The
crude oil was dissolved in 8 mL of THF along with DDQ (63
mg, 0.28 mmol) and refluxed for 1 h. After removal of solvent
(aspirator), the residue was purified by flash chromatography
on silica gel (13 mm × 20 cm), 1:1 EtOAc/hexane eluent, to
afford 12 mg of a yellow zone containing 27 and 12 mg of a
purple zone containing product 31. The products were purified
further by preparative thin-layer chromatography on silica gel,
1:1 EtOAc/hexane, to afford 27 (analytical TLC on silica gel,
1:1 EtOAc/hexane, Rf ) 0.36, identical to material prepared
from oxazole 20) and the purple quinone 31 (analytical TLC
on silica gel, 1:1 EtOAc/hexane, Rf ) 0.29; UV (MeOH, λmax
(nm)) 534 (ꢀ ) 470), 272 (ꢀ ) 5650), 220 (ꢀ ) 17 064); partial
270 MHz NMR (CDCl3, ppm) δ 6.53 (1H, d, J ) 10.1 Hz), 6.37
(1H, d, 10.1 Hz), 4.44 (1H, dd, J ) 5.6, 11.7 Hz), 4.31 (1H, dd,
J ) 7.1, 11.7 Hz), 3.78 (1H, d, J ) 12.7 Hz), 3.38 (1H, d, J )
12.7 Hz), 2.33-2.24 (1H, m).
In ter n a l Azom eth in e Ylid e Cycloa d d ition to F or m 26.
To a solution of aziridinyl oxazole 20 (527 mg, 0.88 mmol) in
dry acetonitrile (25 mL) was added 21 (318 mg, 1.00 mmol),
and this mixture was stirred at room temperature under N2
for 48 h. Then, a solution of BnMe3NCN (385 mg, 2.19 mmol)
in dry acetonitrile (15 mL) was slowly added via cannula. The
resulting yellow gold solution was stirred for 1 h at room
temperature and then poured into an aqueous 1% NaHCO3
solution. The mixture was extracted with ethyl acetate (50
mL), the organic layer was separated and washed succesively
with H2O and brine. After drying over MgSO4, the solution
was filtered, and the solvent was removed (aspirator). The
residue was chromatographed on silica gel with 2:1 hexane:
ethyl acetate to yield 446 mg (66%) of 26 as a white foam: 1:1
mixture of diastereomers; Rf ) 0.56 (2:1 hexane/ethyl acetate);
1H NMR (CDCl3, 300 MHz, ppm) δ 7.95-7.85 (2H, m); 7.65-
7.46 (8H, m), 7.35-7.22 (5H, m), 5.46-5.43 (1H, m), 5.28-
5.08 (1H, m), 4.87 (0.5H, d, J ) 12.0 Hz), 4.86 (0.5H, d, J )
12.6 Hz), 4.63-4.78 (1H, m), 4.46-4.16 (3H, m), 4.09-3.83
(1H, m), 3.70-3.51 (1.5H, m), 3.39 (0.5H, dd, J ) 11.5, 8.4
Hz), 3.16 (0.5 H, d, J ) 6.3 Hz), 3.11 (0.5H, d, J ) 6.3 Hz),
3.01-2.88 (2H, m), 2.52-2.45 (1H, m), 2.35-2.26 (1H, m),
2.25-2.03 (2H, m), 1.38 (1.5H, t, J ) 7.3 Hz), 1.39 (1.5H, t, J
) 7.3 Hz), 0.84 (4.5H, s), 0.79 (4.5H, s), 0.16 (1.5H, s), 0.14
(1.5H, s), 0.02 (1.5H, s), -0.06 (1.5H, s); IR (neat, cm-1) 2949,
1703, 1667; HRMS 770.3029 (calcd for C42H50N2O8SSi 770.3057).
(18) Hartung, W. H.; Simonoff, R. Org. React. 1953, 7, 263.
(19) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156.

Oxazolium-Derived Azomethine Ylides
J . Org. Chem., Vol. 65, No. 18, 2000 5505
Con ver sion of 26 to Tetr a cyclic Keton e 32. Sodium (14
mg) was added to a flask containing absolute ethanol (15 mL),
at room temperature and under N2. The mixture was stirred
until all sodium had been dissolved. A solution of 26 (200 mg,
0.26 mmol) in absolute ethanol (5 mL) was added, and the
resulting mixture was stirred for 8 h. The reaction was then
diluted with H2O and extracted with ethyl acetate. The organic
phase was washed with brine and dried (MgSO4). After
filtration and evaporation (aspirator) the residue was chro-
matographed on silica gel with 2:1 hexane:ethyl acetate to yield
the saponified alcohol, 148 mg (86%), as a white foam,
consisting of a 1:1 mixture of diastereomers: Rf ) 0.35 (2:1
hexane/ethyl acetate); IR (neat, cm-1) 3467, 1716, 1663; HRMS
666.2794 (calcd for C35H46N2O7SSi 666.2795); 300 MHz NMR
(CDCl3, ppm) δ 7.98-7.89 (2H, m), 7.69-7.30 (8H, m), 5.45-
5.40 (1H, m), 5.30-5.00 (1H, br) 4.85-4.63 (2H, m), 4.47-4.35
(1H, m), 4.28-4.16 (1H, m), 3.96-3.59 (2H, m), 3.43-3.35 (1H,
m), 3.21-3.14 (1H, m), 3.09-2.85 (3H, m), 2.33-2.26 (2H, m),
2.07-2.04 (2H, m), 1.80-1.55 (1H, m), 1.37 (1.5H, t, J ) 6.2
Hz), 1.35 (1.5H, t, J ) 6.2 Hz), 0.83 (4.5H, s), 0.78 (4.5H, s),
0.15 (1.5H, s), 0.10 (1.5H, s), 0.02 (1.5H, s), -0.09 (1.5H, s).
Sodium hydride (18 mg of a 60% suspension in oil; 0.43
mmol) was placed in a 10-mL round-bottomed flask fitted with
a rubber septum under N2. Dry hexane (2 mL) was added via
syringe, and the suspension was stirred for 15 min. Stirring
was stopped, and the solids were allowed to settle. The
supernatant liquid was carefully removed with a syringe, and
dry hexane (2 mL) was again added via syringe. This operation
was repeated once more. To the washed solid, dry DMF (5 mL)
was added, and the resulting suspension was cooled to 0 °C.
A solution of the saponification product from above (140 mg,
0.21 mmol) in DMF (1 mL) was slowly added via cannula. The
resulting mixture was stirred for 1 h at 0 °C. H2O (5 mL) was
slowly added via syringe followed by ethyl acetate (20 mL).
The organic layer was then successively washed with H2O and
brine, dried (MgSO4), and evaporated (aspirator). The residue
was chromatographed on silica gel with 2:1 hexane:ethyl
acetate, yielding 74 mg (70%) of alcohol 10 as a white foam,
1:1 mixture of diastereomers, Rf ) 0.48 (1:1 hexane/ethyl
acetate), sufficiently pure for the next step.
tetracyclic 33 as a 1:1 mixture of diastereomers: Rf ) 0.41
(2:1 hexane/ethyl acetate); IR (neat, cm-1) 2936, 1716, 1663;
HRMS 480.2414 (calcd for C27H36O4N2Si 480.2444); 300 MHz
NMR (CDCl3, ppm) δ 7.36-7.26 (5H, m), 5.43 (0.5H, t, J )
2.7 Hz), 5.41 (0.5H, t, J ) 2.7 Hz), 4.44 (0.5H, d, J ) 13.8 Hz),
4.40 (0.5H, d, J ) 13.2 Hz), 4.36-4.11 (3H, m), 3.65 (1H, s),
3.66 (1H, AB q J ) 13.8 Hz), 3.45 (0.5H, d, J ) 4.8 Hz), 3.41
(0.5H, d, J ) 4.5 Hz), 3.11 (t, J ) 4.5 Hz), 3.03-2.89 (1H, m),
2.33 (0.5H, t, J ) 3.0 Hz), 2.28 (0.5H, t, J ) 3.0 Hz), 2.14-
2.10 (2H, m), 1.28-1.22 (3H, m), 0.85 (9H, s), 0.20 (1.5H, s),
0.05 (1.5H, s), 0.04 (1.5H, s), 0.01 (1.5H, s).
Dep r otection of 33 a n d DDQ Oxid a tion to 9b. A solution
of 33 (53 mg, 0.11 mmol) in THF (6 mL) under N2 was
prepared, and tetrabutylammonium fluoride (500 µL of a 1.0
M solution in THF; 0.50 mmol) was added via syringe. The
resulting mixture was stirred at room temperature for 2 h,
and water (10 mL) was added. The reaction mixture was
extracted with ethyl acetate, and the organic layer was washed
with H2O and brine, dried (MgSO4), and evaporated (aspira-
tor). The residue was chromatographed on silica gel with 1:1
hexane/ethyl acetate to yield 35 mg (87%) of the desilylated
alcohol as an oil: 1:1 diastereomeric mixture; Rf ) 0.19 (1:1
hexane/ethyl acetate); IR (neat, cm-1) 3405, 3006, 1662; HRMS
366.1577 (calcd for C21H22N2O4 366.1579); 300 MHz NMR
(CDCl3, ppm) δ 7.35-7.26 (5H, m), 5.52 (1H, s), 5.13-5.09 (1H,
m), 4.44 (1H, d, J ) 13.5 Hz), 4.30-4.19 (2H, m), 4.20 (1H,
dd, J ) 13.8, 3.9 Hz), 3.82 (1H, d, J ) 13.5 Hz), 3.65 (2H, AB
q, J ) 13.8 Hz), 3.37 (1H, d, J ) 4.8) 3.14 (1H, t, J ) 4.8 Hz),
2.64-2.57 (1H, m), 2.48-2.37 (2H, m), 2.10-2.06 (1H, m), 1.19
(1.5H, t, J ) 7.2 Hz), 1.21 (0.5H, t, J ) 7.2 Hz).
The alcohol from above (5.6 mg, 0.015 mmol) was dissolved
in benzene (400 µL), under N2 with stirring. DDQ (10 mg, 0.046
mmol) was then added, and the mixture was refluxed for 1 h
and then cooled to room temperature. The solvent was removed
(aspirator), and the residue was filtered through a short
column of silica gel with ethyl acetate. After solvent removal,
4.4 mg (80%) of 9b was obtained as a yellow amorphous solid:
Rf ) 0.38 (1:1 hexane/ethyl acetate); 300 MHz NMR (CDCl3,
ppm) δ 7.40-7.25 (5H, m), 6.63 (1H, d, J ) 9.9 Hz), 6.53 (1H,
d, J ) 9.9 Hz), 4.47 (1H, d, J ) 14.1 Hz), 4.35-4.22 (3H, m),
3.69 (2H, s), 3.51 (1H, d, J ) 4.2 Hz), 3.21 (1H, t, J ) 4.2 Hz),
1.26 (3H, t, J ) 6.9 Hz); IR (neat, cm-1) 2936, 1716, 1663;
HRMS 362.1250 (calcd for C21H18N2O4 362.1267); UV (MeOH,
λmax (nm)) ) 250 (ꢀ ) 11 400), 406 (ꢀ ) 1340).
To a solution containing 10 (105 mg, 0.21 mmol) and
triethylamine (49 µL, 0.35 mmol) in CH2Cl2 (10 mL), under
N2 and at 0 °C, was added mesyl chloride (23 µL, 0.30 mmol).
The resulting mixture was stirred for 2 h at 0 °C, then diluted
with ethyl ether, and washed with H2O and brine. The organic
layer was dried (MgSO4) and evaporated (aspirator) to yield
121 mg of the mesylate 32 as a yellow oil.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (CA17918).
The mesylate 32 (121 mg) was dissolved in THF (40 mL),
and potassium tert-butoxide (30 mg, 0.25 mmol) was added.
This mixture was stirred for 2 h under N2, and then partitioned
between ethyl acetate and brine. The organic phase was
washed with H2 and brine, dried (MgSO4), and evaporated
(aspirator). The residue was chromatographed on silica gel
with 2:1 hexane/ethyl acetate to yield 93 mg (93% from 10) of
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0001277