Synthesis of optically active imidazolines, azapenams, dioxocyclams, and bis-dioxocyclams

Article abstract of DOI:10.1021/jo962343e

Optically active 4-methyl-4-carbomethoxy-Δ²-imidazoline was efficiently synthesized on a multigram scale. Photolysis with (methoxymethylcarbene)chromium complex produced the optically active azapenam in good yield and with high stereoselectivity. Acid-catalyzed dimerization followed by reduction produced the corresponding optically active dioxocyclam in good yield. Using a bis-carbene complex, an optically active bis-dioxocyclam was produced in excellent yield.

Full text of DOI:10.1021/jo962343e

3586
J . Org. Chem. 1997, 62, 3586-3591
Syn th esis of Op tica lly Active Im id a zolin es, Aza p en a m s,
Dioxocycla m s, a n d Bis-d ioxocycla m s
Yi Hsiao and Louis S. Hegedus*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received December 13, 1996X
Optically active 4-methyl-4-carbomethoxy-∆2-imidazoline was efficiently synthesized on a multigram
scale. Photolysis with (methoxymethylcarbene)chromium complex produced the optically active
azapenam in good yield and with high stereoselectivity. Acid-catalyzed dimerization followed by
reduction produced the corresponding optically active dioxocyclam in good yield. Using a bis-carbene
complex, an optically active bis-dioxocyclam was produced in excellent yield.
In tr od u ction
about the mechanism of this process, and less about the
structural requirements of the various cyclam agents for
anti-HIV activity.
Cyclams constitute a class of 14-membered tetraaza-
macrocycles that form very stable, kinetically inert
complexes with a range of metals, particularly first-row
transition metals, with the potential for wide-ranging
biological activity,1 including proton and metal ion trans-
port, oxygen complexation and activation,2 and super-
oxide dismutase activity.3 Dioxocyclams are a subgroup
of this class, structurally intermediate between oligopep-
tides and polyamines, which have also been extensively
studied.4 Nickel complexes of dioxocyclams catalyze olefin
epoxidation,4,5 while closely related nickel macrocycles
effect selective oxidative cleavage of exposed guanine
residues in nucleic acids.6 Nickel(II) complexes of bis-
tetraazamacrocycles containing rigid spacers catalyzed
phosphate ester hydrolysis more effectively than mono-
nuclear nickel(II) complexes.7 This process has potential
application for the nonoxidative cleavage of the phos-
phate diester backbone of DNA.8 Cyclams and dioxo-
cyclams are exceptional ligands for technecium-99m, and
these complexes provide a new class of renal imaging
agents,9 while cyclam tetraacetates form lanthanide
complexes of use in magnetic resonance imaging.10 Fi-
nally, bis-cyclams11 and related bis-nickel complexes12
have potent anti-HIV activity, inhibiting replication and
interrupting the viral uncoating event. Little is known
Optically active cyclams or dioxocyclams, bearing
chirality on the carbon skeleton, are considerably less
common and have only recently been synthesized, al-
though in low (7-12%) yield.4 Recently, novel ap-
proaches to optically active nonracemic dioxocyclams via
optically active imidazolines13 and racemic bis-dioxo-
cyclams via achiral imidazolines14 have been reported
from these laboratories. For a number of planned
biological applications, from the above list, it became
important to be able to stereospecifically synthesize
single enantiomers of optically active mono- and bis-
dioxocyclams having peripheral functionality to provide
the desired selectivity and solubility for the planned
studies. The results of efforts addressing this problem
are presented below.
Resu lts a n d Discu ssion
Initial studies centered on the synthesis of optically
active dioxocyclams from monosubstituted imidazolines,
prepared from optically active amino acids as shown in
Scheme 1. This route, used to prepare isopropyl 6a and
its corresponding dioxocyclam in the original work,5 was
extended to the methyl (6b) and phenyl (6c) analogs,
from (S)-alanine and (S)-phenylglycine respectively. The
results for the gem-dimethyl analog 6d , from com-
mercially available diamine 3d , are shown for purposes
of comparison. This reaction sequence was reasonably
efficient in all four cases up to the unprotected imidazo-
lines 4, all of which were quite stable and easily purified
by distillation. Surprisingly, monoalkylimidazolines 4a-c
underwent protection in poor yield, and the protected
heterocycles 5a and 5b were quite thermally unstable,
decomposing on standing over the course of a few days.
This was in marked contrast to gem-dimethylimidazoline
(4d ), which underwent protection in good yield and
produced a quite stable 5d . The photochemical cyclo-
addition (5a -c f 6a -c) also went in poor yield, probably
because of thermal decomposition of the imidazolines,
and produced azapenams 6 contaminated with many
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) For reviews see: (a) Kimura, E. Tetrahedron 1992, 48, 6175-
6217. (b) Kimura, E. J . Coord. Chem. 1986, 15, 1-28. (c) Busch, D. H.
Acct. Chem. Res. 1978, 11, 392-400. (d) Parker, D. Tailoring Macro-
cycles for Medical Applications. In Crown Compounds Towards Future
Applications; Copper, S. R., Ed.; VCH: New York, 1992; pp 51-67.
(2) Busch, D. H.; Alcock, N. W. Chem. Rev. 1994, 94, 585-623.
(3) Kimura, E.; Sakonaka, A.; Nakamoto, M. Biochim. Biophys. Acta
1981, 678, 172-179.
(4) Wagler, T. R.; Fang, Y.; Burrows, C. J . J . Org. Chem. 1989, 54,
1584-1589 and references therein.
(5) Nam, W.; Ho, R.; Valentine, J . S. J . Am. Chem. Soc. 1991, 113,
7052-7054.
(6) Burrows, C. J .; Rokita, S. E. Acc. Chem. Res. 1994, 27, 295-
301.
(7) Crane, C. G.; Burrows, C. J . J . Inorg. Biochem. 1991, 43, 661.
For a comprehensive review see: Halcrow, M. A.; Christou, G. Chem.
Rev. 1994, 94, 2421-2482.
(8) (a) For an example using Ce(III) see: Takasaki, B. K.; Chin, J .
J . Am. Chem. Soc. 1994, 116, 1121-1122. (b) For a recent example of
bimetallic catalysis see: Tsubouchi, A.; Bruice, T. C. J . Am. Chem.
Soc. 1994, 116, 11614-11615.
(9) (a) Herzog, K. M.; Deutsch, E.; Deutsch, K.; Silberstein, E. B.;
Saragarajan, R.; Cacini, W. J . Nucl. Med. 1992, 33, 2190-2195. (b)
Riche, F.; Pasqualini, R.; Duatte, A.; Vidal, M. Appl. Radiat. Isot. 1992,
43, 437-442.
(10) (a) Dischino, D. D.; Delany, E. J .; Emswiler, J . E.; Gaughan,
G. T.; Prasad, J . S.; Srivastava, S. K.; Tweedle, M. F. Inorg. Chem.
1991, 30, 1265-1269. (b) Kodama, M.; Koike, T.; Mahatma, A. B.;
Kimura, E. Inorg. Chem. 1991, 30, 1270-1273.
(11) DeClerq, E.; Yamamoto, N.; Pauwels, R.; Baba, M.; Schols, D.;
Nakashima, H.; Balzarini, J .; Debyser, Z.; Murrer, B. A.; Schwartz,
D.; Thornton, D.; Bridger, G.; Fricker, S.; Henson, G.; Abrams, M.;
Picker, D. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5286-5290.
(12) Inoue, Y.; Kanamori, T.; Yoshida, T.; Bu, X.; Shionoya, M.;
Koike, T.; Kimura, E. Biol. Pharm. Bull. 1994, 17, 243-250.
(13) Betschart, C.; Hegedus, L. S. J . Am. Chem. Soc. 1992, 114, 5010.
(14) Dumas, S.; Lastra, E.; Hegedus, L. S. J . Am. Chem. Soc. 1995,
117, 3368.
S0022-3263(96)02343-2 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Optically Active Imidazolines
J . Org. Chem., Vol. 62, No. 11, 1997 3587
Sch em e 1
Sch em e 2
by conversion to the desired protected imidazoline 10
proceeded uneventfully, completing the synthesis. (A
related method of Davies18 was briefly examined but
proved less convenient in this particular instance.)
Photolysis of imidazoline 10 with the (methoxymethyl-
carbene)chromium complex under standard conditions
(500 W Hanovia medium pressure Hg lamp, 30 °C, Pyrex)
gave variable, low yields of the desired azapenam 11 with
the chromium pentacarbonyl imidazoline complex from
decomposition of the carbene complex as the major
byproduct. Optimum photochemical conditions were
found to require the use of four 500 W quartz/halogen
lamps as the light source and control of the reaction
temperature to 70 °C. Under these conditions reproduc-
ibly good yields of a single diastereoisomer of the â-lactam
on multigram scales were readily obtained (eq 1).
unidentified byproducts, again in contrast to the disub-
stituted case 5d f 6d . With yields in the 8-21% range
over the last two steps, and the expectation that these
low-yield problems would only be amplified when applied
to bis-dioxocyclam synthesis, these monosubstituted,
optically active imidazolines were deemed unsuitable for
further study.
The observation that gem-disubstituted imidazoline 5d
suffered neither from protection problems nor low yields
in the photochemical step, along with a desire to intro-
duce additional functionality into the ultimate macro-
cycles led to the choice of imidazoline 10 as the next
target. This was efficiently synthesized on a large scale
in good yield with high optical purity using oxazolidinone
chemistry developed by Seebach and Fadel,15 to produce
the desired diamine by the procedures of J ones16 and
Gilbert17 (Scheme 2). Initially, both (S)-alanine and (S)-
phenylglycine were used as sources of the chiral center.
However, the oxazolidinone from phenylglycine produced
an inseparable mixture of diastereoisomers 7b, while that
from alanine gave a 58% yield of optically pure 7a on a
20-50 g scale after only two recrystallizations. Alkyl-
ation of 7a with N-(bromomethyl)phthalimide produced
8 in 74% yield as a single diastereoisomer, after one
recrystallization. Hydrolysis to the diamine 9 followed
The absolute configuration of azapenam 11 was deter-
mined by X-ray crystallography19 and is as shown. The
stereochemical outcome of the photocyclization to form
11 was not easily predicted. Previous studies20 of reac-
tions between alkoxycarbene complexes and imines sug-
gested that the stereochemical outcome of these reactions
was contrasteric, arising from the sterically more crowded
transition state, and being driven by electronic effects
(15) (a) Seebach, D.; Fadel, A. Helv. Chim. Acta 1985, 68, 1243. (b)
Fadel, A.; Salaun, J . Tetrahedron Lett. 1987, 28, 2243.
(16) J ones, R. C. F.; Crockett, A. K.; Rees, D. C.; Gilbert, I. H.
Tetrahedron: Asymmetry 1994, 5, 1661.
(17) Gilbert, I. H.; Rees, D. C.; Crockett, A. K.; J ones, C. F.
Tetrahedron 1995, 51, 6315.
(18) Alonso, F.; Davies, S. G. Tetrahedron: Asymmetry 1995, 6, 353.
(19) We thank Melissa Hellman for carrying out the X-ray diffraction
studies.
(20) Dumas, S.; Hegedus, L. S. J . Org. Chem. 1994, 59, 4967.

3588 J . Org. Chem., Vol. 62, No. 11, 1997
Hsiao and Hegedus
Sch em e 3
good yield and as a single diastereoisomer. Acid-
catalyzed dimerization to give 15 followed by reduction
gave optically active bis-dioxocyclam 16 in very good yield
(40% overall from 10 and 31% overall from diamine 9).
The structure and absolute stereochemistry of bis-
dioxocyclam 16 was again confirmed by X-ray crystal-
lography. Despite the fact that the bis-azapenam pre-
cursor 14 had an [R]D of -177° and the monocyclam
analog 12 had an [R]D of +25°, bis-dioxocyclam 15 had
an [R]D of just -0.4°, notwithstanding the presence of
eight chiral centers of S configuration! Only modest
rotation was observed at shorter wavelengths with a
maximum [R]436 of -5.4° (c 4.0 CH2Cl2) in spite of the
fact that the compound is optically pure. The chiroptical
properties of this unusual macrocycle and nickel com-
plexes thereof are under current study.
In summary, an efficient synthesis of optically active
mono- and bis-dioxocyclams having peripheral ester
groups suitable for appending additional functional
groups has been developed, making this class of com-
pounds accessible for the study of biological properties.
The chemistry developed should be suitable for alkyl
groups other than methyl at the quaternary carbon in
imidazoline 10 (Scheme 2) since oxazolidinones 8 having
n-butyl,16,17 isopropyl,15b benzyl,15b and CH3SCH2CH2-
15b
groups have been synthesized in good yield and high
optical purity. Its use in the development of biologically
active dioxocyclams is under current study.
Exp er im en ta l Section
Gen er a l Meth od s. If not otherwise stated, melting points
were taken on a MelTemp apparatus and are uncorrected. All
NMR spectra were recorded in CDCl3 at 300 MHz for 1H and
75.5 MHz for 13C. Chemical shifts are given in δ ppm relative
to (CH3)4Si (δ 0.00, 1H) or CDCl3 (δ 77.0, 13C). IR spectra were
recorded on a Perkin-Elmer 1600 series FTIR.
Ether and THF was distilled from sodium/benzophenone
under an atomosphere of nitrogen. CH2Cl2 and triethylamine
were distilled from CaH2.
The following chemicals were prepared according to litera-
ture procedures: pentacarbonyl(methoxymethylcarbene)-
chromium,21 bis-chromium alkoxycarbene complex (13),14 ox-
azolidinone (7a ).15b
that dramatically lowered the barrier for cyclization from
this less stable transition state. Those arguments pre-
dicted that the larger group on the imidazoline (the
methyl group) should end up on the same face of the
â-lactam as the methoxy group. This was not the case
with 11, and the ester group must exert some as yet
unexplained electronic bias on the stereochemical out-
come of the reaction. The important point is that the
reaction is highly stereoselective.
(S)-2-[(Ben zyloxyca r bon yl)a m in o]p r op a n -1-yl Mesyl
Ester (2b). Lithium aluminum hydride (17.0 g, 0.43 mol) was
suspended in 600 mL of THF at 0 °C. (S)-alanine (20.0 g, 0.22
mol) was added slowly in small portions. The reaction mixture
was heated at reflux overnight and then cooled to room
temperature. Saturated K2CO3 was added slowly. Filtration
and evaporation of solvent gave a colorless oil. Distillation
(76-78 °C/∼20 mmHg) of the crude oil gave (S)-2-aminopro-
pan-1-ol as a light yellowish oil (15.9 g, 95%): 1H NMR δ 0.99
(d, J ) 6.2 Hz, 3H), 2.51 (brs, 3H), 2.92-3.01 (m, 1H), 3.18
(dd, J ) 7.7, 10.7 Hz), 3.48 (dd, J ) 3.5, 10.2 Hz).
(S)-2-Aminopropan-1-ol was dissolved in dichloromethane
(350 mL) and 5% NaHCO3 (350 mL). Benzyl chloroformate
(42.0 g, 234 mmol) was then added. The reaction mixture was
stirred at 20 °C for 16 h. The organic layer was separated
from the aqueous layer, and the aqueous layer was extracted
with dichloromethane (150 mL). The combined organic layers
were dried over MgSO4, and the solvent was evaporated. The
residue was recrystallized from hexane and ethyl acetate (3:
1) to give a white solid (37.3 g, 84%): 1H NMR δ 1.15 (d, J )
6.7 Hz, 3H), 2.08 (brs, 1H), 3.51 (dd, J ) 5.9, 11.0 Hz, 1H),
3.65 (dd, J ) 3.5, 10.8 Hz, 1H), 3.82 (brs, 1H), 4.86 (brs, 1H),
5.08 (s, 2H), 7.29-7.35 (m, 5H).
The acid-catalyzed dimerization of azapenam 11 pro-
duced, after reduction of the imine moieties, dioxocyclam
12 in excellent yield and, as expected, as a single
diastereoisomer. (Note that dimerization of racemic 11
produced two diastereoisomers of 12, so any lack of
stereoselectivity during the reaction sequence in Scheme
1
2 would have been easily detected by H NMR spectros-
copy at this stage.) An X-ray crystal structure19 again
confirmed the assigned stereochemistry and indicated
that the ester groups and methoxy groups were on the
same face of the macrocycle.
The use of optically active imidazoline 10, having a
quaternary chiral center, allowed at least a 4-fold in-
crease in yield (from the diamine) over those having a
tertiary chiral center (Scheme 1), making optically active
dioxocyclams more easily accessible. More importantly,
this efficiency was also observed in the synthesis of bis-
dioxocyclams (Scheme 3), for which imidazolines 5a -c
had proven unacceptably inefficient. Photolysis of imid-
azoline 10 with bis-carbene complex 13 followed by
deprotection gave optically active bis-azapenam 14 in
(21) Bao, J .; Wulff, W. D.; Doming, J . B.; Fumo, M. J .; Grant, E. B.;
Rob, A. C.; Whitcomb, M. C.; Yeung, S-i.; Ostrander, R. L.; Rheingold,
A. L. J . Am. Chem. Soc. 1996, 118, 3392.

Synthesis of Optically Active Imidazolines
J . Org. Chem., Vol. 62, No. 11, 1997 3589
(S)-2-[(Benzyloxycarbonyl)amino]propan-1-ol (37.0 g, 177
mmol) was dissolved in dichloromethane (300 mL) and tri-
ethylamine (20 g, 198 mmol). This solution was cooled to 0
°C, and then mesyl chloride (15 mL, 195 mmol) was added.
After 20 min of stirring at 20 °C, the solution was washed with
1 N HCl (100 mL), 5% Na2CO3 (100 mL), and brine (100 mL),
and then it was dried over Na2SO4. After evaporation of the
solvent, recrystallization of the residue from ethyl acetate and
hexane (1:5) gave white crystals of (S)-2-[(benzyloxycarbonyl)-
(MeOH:ether 1:5) of the residue gave yellowish crystals of (S)-
1,2-propanediamine‚2HCl (8.1 g, 55.1 mmol, 79%). To these
dried crystals, a powder of sodium hydroxide (18.0 g, 450
mmol) was added. Distillation of the mixture gave a colorless
oil. This oil was dried over CaH2 and distilled, giving a
colorless oil (3.87 g, 95%). This material was identical in all
respects to the same compounds reported in the literature.22
(S)-2-P h en yl-1,2-eth a n ed ia m in e (3c). (S)-N-(Benzyloxy-
carbonyl)-R-phenylglycinol mesyl ester (20.0 g, 57.2 mmol) was
dissolved in toluene (150 mL) and water (130 mL). Sodium
amino]propan-1-yl mesyl ester (49.3 g, 97%): mp 101-103 °C;
1
[R]21 -20.9° (c 1.05, CH2Cl2); H NMR δ 1.22 (d, J ) 6.9 Hz,
nBu) NBr (2.0 g, 6.2 mmol) were
azide (29.8 g, 458 mmol) and (
D
4
3H), 2.93 (s, 3H), 4.01 (m, 1H), 4.12 (m, 1H), 4.18 (m, 1H),
4.98 (brs, 1H), 5.07 (s, 2H), 7.28-7.34 (m, 5H); 13C NMR δ
17.0, 37.2, 46.0, 66.8, 71.7, 128.1, 128.2, 128.5, 136.2, 155.5;
IR (KBr plate) ν 3372, 3035, 1693, 1524, 1459, 1345 cm-1. Anal.
Calcd for C12H17NO5S: C, 50.16; H, 5.96; N, 4.87. Found: C,
50.40; H, 6.17; N, 4.90.
(S)-N-(Ben zyloxyca r bon yl)-r-p h en ylglycin ol Mesyl Es-
ter (2c). Lithium aluminum hydride (11.0 g, 257 mmol) was
suspended in 500 mL of THF at 0 °C. (S)-Phenylglycine (20.0
g, 132 mmol) was added slowly in small portions. The reaction
mixture was then heated at reflux overnight and then cooled
to room temperature. Saturated K2CO3 was added slowly.
Filtration and evaporation of solvent gave a yellow solid. The
residue was recrystallized from hexanes and ethyl acetate (3:
1) to give (S)-R-phenylglycinol as a yellow solid (17.7 g, 97%):
1H NMR δ 2.33 (brs, 3H), 3.53 (dd, J ) 8.3, 10.8 Hz, 1H), 3.71
(dd, J ) 4.4, 10.8 Hz, 1H), 4.02 (dd, J ) 4.3, 8.3 Hz, 1H), 7.2-
7.4 (m, 5H).
(S)-R-Phenylglycinol (15.0 g, 0.11 mol) was dissolved in
dichloromethane (170 mL) and 5% NaHCO3 (200 mL). Benzyl
chloroformate (21.6g, 0.12 mol) was then added. The reaction
mixture was stirred at 20 °C overnight. The layers were
separated, and the aqueous layer was extracted with dichloro-
methane (150 mL). The combined organic layers were dried
over MgSO4, and the solvent was evaporated. The residue was
recrystallized from hexane and ethyl acetate (∼3:1) to give
white needles of (S)-N-(benzyloxycarbonyl)-R-phenylglycinol
(26.8 g, 90%): 1H NMR δ 1.24 (brs, 1H), 3.85 (brm, 2H), 4.83
(brm, 1H), 5.08 (m, 2H), 5.48 (brs, 1H), 7.26-7.37 (m, 5H).
(S)-N-(Benzyloxycarbonyl)-2-phenylglycinol (20.0 g, 73.7
mmol) was dissolved in dichloromethane (250 mL) and tri-
ethylamine (11.7 mL, 84 mmol). This solution was cooled to
0 °C, and then mesyl chloride (6.3 mL, 81 mmol) was added.
After 20 min of stirring at 20 °C, the solution was washed with
1 N HCl (100 mL), 5% Na2CO3 (100 mL), and brine (100 mL),
and then it was dried over Na2SO4. After evaporation of the
solvent, recrystallization of the residue from ethyl acetate and
hexane (∼1:3) gave white crystals of (S)-N-(benzyloxycarbonyl)-
R-phenylglycinol mesyl ester (25.7 g, 98%): mp 132-134 °C;
[R]21D +17.7° (c 1.42, CH2Cl2); 1H NMR δ 2.82 (s, 3H), 4.4-4.5
(m, 1H), 5.0-5.1 (m, 3H), 5.42 (brs, 1H), 7.30-7.39 (m, 10H);
13C NMR δ 37.3, 54.1, 67.1, 70.8, 126.6, 128.2, 128.5, 128.9,
136.0, 155.7; IR (KBr plate) ν 3337, 1690, 1542, 1342, 1285,
1254 cm-1. Anal. Calcd for C17H19NO5S: C, 58.44; H, 5.48;
N, 4.01. Found: C, 58.66; H, 5.43; N, 3.96.
(S)-1,2-P r op a n ed ia m in e (3b). (S)-2-[(Benzyloxycarbonyl)-
amino]propan-1-yl mesyl ester (22.5 g, 78.3 mmol) was dis-
solved in toluene (150 mL) and water (200 mL). Sodium azide
(40.7 g, 626 mmol) and (nBu)4NBr (2.8 g) were added. The
reaction mixture was then heated overnight at 85-90 °C. After
the reaction mixture was cooled to room temperature, the
aqueous layer was separated, and the organic layer was
washed with phosphate buffer (pH ∼5.4, 0.5 M, 60 mL × 2)
and brine (60 mL) and dried over MgSO4. Evaporation of the
solvent gave (S)-2-[(benzyloxycarbonyl)amino]propan-1-yl azide
as a yellowish oil (16.2 g, 88%). This azide was used for the
next step without further purification: 1H NMR δ 1.19 (d, J
) 6.8 Hz, 3H), 3.29-3.50 (m, 2H), 3.91 (brs, 1H), 4.78 (brs,
1H), 5.09 (brs, 2H), 7.29-7.35 (m, 5H); 13C NMR δ 18.1, 46.6,
55.8, 66.7, 128.0, 128.1, 128.4, 136.3, 155.5.
added. The reaction mixture was then heated overnight at
85-90 °C. After the reaction mixture was cooled to room
temperature, the layers were separated, and the organic layer
was washed with phosphate buffer (pH ∼5.4, 0.5 M, 60 mL ×
2) and brine (60 mL) and dried over MgSO4. The solvent was
evaporated, and the residue was chromatographed on silica
gel (Et2O:hexane 1:10), giving a yellowish oil of (S)-2-[(benzyl-
oxycarbonyl)amino]-2-phenyl ethyl azide (12.0 g, 78%): 1H
NMR δ 3.63 (brm, 2H), 4.92 (brm, 1H), 5.10 (m, 2H), 5.33 (brm,
1H), 7.27-7.39 (m, 5H).
The azide (10 g, 37.1 mmol) was hydrogenated using
MeOH-HCl (∼3 M, 65 mL) as solvent and Pd/C (10%, 2.0 g)
as catalyst under 90 psi of hydrogen. After the mixture was
stirred at room temperature for 48 h, the catalyst was removed
by filtration, and the solvent was evaporated. Recrystalliza-
tion (MeOH:ether 1:3) of the residue gave yellowish crystals
of (S)-2-phenyl-1,2-ethanediamine‚2HCl (4.0 g, 78%). To these
dried crystals was added a powder of sodium hydroxide (18.0
g, 450 mmol). Distillation of the mixture gave a colorless oil.
This oil was dried over CaH2 and distilled (oven 55-60 °C/0.1
mmHg), and a colorless oil was obtained (3.87 g, 95%): 1H
NMR (D2O) δ 2.83 (d, J ) 6.7 Hz, 2H), 3.87 (t, J ) 6.7 Hz,
1H), 7.34-7.49 (m, 5H); 13C NMR (D2O) δ 51.2, 60.0, 129.7,
130.5, 131.8, 146.2.
(S)-4-Meth yl-∆2-im id a zolin e (4b). The mixture of (S)-1,2-
propanediamine (3.87 g, 52.2 mmol) and dimethylformamide
dimethyl acetal (6.7 g, 52.9 mmol) was heated under argon at
60-65 °C overnight. The resulting yellowish oil was distilled
(60-61/∼0.1 mmHg) to give a colorless oil of (S)-4-methyl-∆2-
imidazoline (3.91 g, 89%): 1H NMR δ 1.14 (d, J ) 6.4 Hz, 3H),
3.09 (dd, J ) 7.4, 11.5 Hz, 1H), 3.63 (t, J ) 10.2 Hz, 1H), 3.8-
4.0 (m, 1H), 4.61 (brs, 1H), 6.96 (s, 1H); 13C NMR δ 21.6, 55.4,
56.2, 135.5.
(S)-4-P h en yl-∆2-im id a zolin e (4c). The mixture of (S)-2-
phenyl-1,2-ethanediamine (2.0 g, 15.0 mmol) and dimethyl-
formamide dimethyl acetal (1.9 g, 15.0 mmol) was heated
under argon at 60-65 °C overnight. A yellowish oil was
obtained (2.2 g) and used for the next step without future
purification: 1H NMR δ 3.40 (ddd, J ) 0.98, 8.7, 12.2 Hz, 1H),
3.95 (dd, 1H, J ) 1.1, 11.0 Hz), 4.79 (dd, J ) 8.7, 10.9 Hz,
1H), 5.01 (brs, 1H), 7.07 (s, 1H), 7.1-7.3 (m, 5H); 13C NMR δ
58.4, 63.0, 126.1, 127.2, 128.5, 143.6, 154.3.
(S)-N-(Ben zyloxyca r b on yl)-4-m et h yl-∆2-im id a zolin e
(5b). (S)-4-Methyl-∆2-imidazoline (3.5 g, 41.6 mmol) was
dissolved in dichloromethane (60 mL) and triethylamine (5.0
g, 49.4 mmol). This reaction mixture was cooled to 0 °C, and
then benzyl chloroformate (8.5 g, 47.3 mmol) was added. After
being stirred at room temperature overnight, the solution was
washed with 1 N HCl (30 mL), 5% Na2CO3 (30 mL), and brine
(30 mL) and dried over Na2SO4. Evaporation of the solvent
gave a yellow oil that was chromatographed on silica gel
(hexane/EtOAc 1:1) to give an unstable colorless oil (4.0 g,
44%): 1H NMR δ 1.27 (d, J ) 6.8 Hz, 3H), 3.22 (dd, J ) 7.2,
10.3 Hz, 1H), 3.78 (t, J ) 10.0 Hz, 1H), 4.23 (m, 1H), 5.20 (m,
2H), 7.31-7.37 (m, 5H), 7.48 (brs, 1H).
(S)-N-(Ben zyloxyca r b on yl)-4-p h en yl-∆2-im id a zolin e
(5c). (S)-4-Phenyl-∆2-imidazoline (2.2 g, 14.7 mmol) was
dissolved in dichloromethane (30 mL) and triethylamine (1.7
g, 16.7 mmol). This reaction mixture was cooled to 0 °C, and
then benzyl chloroformate (3.0 g, 16.7 mmol) was added. After
being stirred at room temperature overnight, the solution was
washed with 1 N HCl (30 mL), 5% Na2CO3 (30 mL), and brine
The azide (16.2 g, 69.2 mmol) was hydrogenated using
MeOH-HCl (∼3 M, 300 mL) as solvent and Pd/C (10%, 4.0 g)
as catalyst under 90 psi of hydrogen. After the mixture was
stirred at room temperature for 24 h, the catalyst was removed
by filtration and the solvent was evaporated. Recrystallization
(22) Reihler, H.; Weinbrenner, E.; v. Hessling, G. Ann. Chem. 1932,
494, 43.

3590 J . Org. Chem., Vol. 62, No. 11, 1997
Hsiao and Hegedus
(30 mL) and dried over Na2SO4. Evaporation of the solvent
gave a yellow oil that was chromatographed on silica gel
(hexane/EtOAc 1:1) to give a colorless oil (2.5 g, 61% from
(S)-2-phenyl-1,2-ethanediamine): [R]21D -112.7° (c 1.85, CH2Cl2);
1H NMR δ 3.58 (brt, J ) 8.6 Hz, 1H), 4.11 (t, J ) 10.7 Hz,
1H), 5.22 (s, 2H), 5.30 (brt, J ) 9.1 Hz, 1H), 7.06-7.37 (m,
5H), 7.73 (brs, 1H); 13C NMR δ 50.9, 67.8, 126.3, 127.4, 128.1,
128.4, 128.5, 128.6, 135.2, 141.2; IR (KBr) ν 1722, 1619, 1405,
1348, 1278, 1219, 1125 cm-1. Anal. Calcd for C17H16N2O2: C,
72.84; H, 5.75; N, 9.99. Found: C, 73.00; H, 5.92; N, 10.04.
2,6-Dim eth yl-6-m eth oxyl-1,4-diazabicyclo[3.2.0]h eptan -
7-on e (6b). Pentacarbonyl(methoxymethylcarbene)chromium(0)
(680 mg, 2.7 mmol) and (S)-N-(benzyloxycarbonyl)-4-methyl-
∆2-imidazoline (5b) (590 mg, 2.7 mmol), were dissolved in
CH2Cl2 (20 mL) under argon in a Pyrex pressure tube. After
three freeze-thaw degassings, the resulting red brown solution
was irradiated with a 4 × 500 W halogen lamp under 90 psi
of CO pressure at 70 °C. The progress of the reaction was
indicated by the fading of the color. After the reaction, the
solvent was evaporated. The residue was triturated with
MeOH and kept for a few hours at -20 °C. Filtration of
chromium hexacarbonyl, evaporation of MeOH, and purifica-
tion by chromatography on silica gel gave the N-(benzyloxy-
carbonyl)azapenam (190 mg, 23%): 1H-NMR δ 1.16, 1.18, (2d,
J ) 3.3 Hz, 3H), 1.55, 1.57 (2s, 3H), 3.46 (brs, 3H), 3.3-3.5
(m, 1H), 3.95-4.15 (m, 1H), 5.0-5.3 (m, 3H), 7.2-7.4 (m, 5H).
Because of the low yield this material was not further studied.
6-Meth oxy-6-m eth yl-2-p h en yl-1,4-d ia za bicyclo[3.2.0]-
h ep ta n -7-on e (6c). Pentacarbonyl(methoxymethylcarbene)-
chromium(0) (270 mg, 1.1 mmol) and (S)-N-(benzyloxycarbonyl)-
4-phenyl-∆2-imidazoline (5c) (300 mg, 1.1 mmol) were dissolved
in CH2Cl2 (20 mL) under argon in a Pyrex pressure tube. After
three freeze-thaw degassings, the resulting red brown solution
was irradiated with a mercury lamp under 90 psi of CO
pressure at 30 °C. The progress of the reaction was indicated
by the fading of the color. After the reaction, the solvent was
evaporated. The residue was triturated with MeOH and kept
for a few hours at -20 °C. Filtration of chromium hexacar-
bonyl, evaporation of MeOH, and purification by chromatog-
raphy on silica gel gave the crude N-(benzyloxycarbonyl)-
azapenam in 35% yield (137 mg). This material was impure
and because of the low yield was not further studied.
(2S,4S)-3-Ben zoyl-4-m eth yl-2-p h en yl-1,3-oxa zolid in -5-
on e (7a ).15b (S)-Alanine (32.9 g, 370 mmol) was added into a
solution of NaOH (15.1 g, 370 mmol) in H2O (50 mL), and
methanol (250 mL) was added to this solution. The solution
was heated until the solid dissolved, and then the solvent was
evaporated until precipitation began (∼30 mL). The residue
was dissolved in ethanol (250 mL), and benzaldehyde (59 g,
556 mmol) was added. This mixture was stirred at room
temperature for 3 h. The ethanol and most of water was
removed under vacuum, and the residue was dissolved in
ethanol (200 mL) and dried over 4 Å molecular sieves.
Filtration and evaporation of the solvent gave a white solid
that was dried in vacuo overnight. This solid was suspended
in dichloromethane (500 mL), and a solution of benzoyl
chloride (52.0 g, 370 mmol) in dichloromethane (100 mL) was
added dropwise at 0 °C. After 3 h, the reaction mixture was
allowed to stir at room temperature overnight. This turbid
mixture was washed with H2O, 5% NaHCO3, 5% of NaHSO3,
and H2O again and then dried over Na2SO4. Evaporation of
the solvent gave a white solid. Fractional recrystallizations
of this solid from CH2Cl2 and ether (1:2) gave white crystals
of (2S,4S)-3-benzoyl-4-methyl-2-phenyl-1,3-oxazolidin-4-one (60
g, 58%): [R]21D +225° (lit15b [R]21D +225.0°). This material was
identical in all respects to the same compound reported in the
literature.
red brown solution was stirred at this temperature for 3 h. A
solution of N-(bromomethyl)phthalimide (22.2 g, 92.5 mmol)
in THF (200 mL) was then added dropwise. The reaction
mixture was allowed to warm to 20 °C in 4 h and stirred at
this temperature overnight. The solvent was evaporated. The
residue was dissolved in 10% NH4Cl (250 mL) and extracted
with CH2Cl2. The organic phase was dried over Na2SO4 and
evaporated. Recrystallization from CH2Cl2 and ether (1:4)
gave a white crystal (23 g, 74%) of (2S,4S)-3-benzoyl-4-
methyl-4-(phthalimidomethyl)-2-phenyl-1,3-oxazolidin-5-
one: mp 204-205 °C; [R]21 +220° (c 1.12, CHCl3); 1H NMR δ
D
2.21 (s, 3H), 4.32 (d, J ) 14.3 Hz, 1H), 4.78 (d, J ) 14.4 Hz,
1H), 6.45 (s, 1H), 6.85 (s, 1H), 6.87 (s, 1H), 7.0-7.3 (m, 8H),
7.76-7.79 (m, 2H), 7.90-7.95 (m, 2H); 13C NMR δ 23.3, 42.1,
63.1, 90.4, 123.8, 126.1, 126.8, 128.3, 128.5, 129.7, 129.8, 131.7,
134.4, 136.0, 136.2, 168.0, 169.4, 172.2; IR (KBr plate) ν 1799,
1720, 1657, 1394, 1356, 1227, 1175 cm-1
. Anal. Calcd for
C26H20N2O5: C, 70.90; H, 4.58; N, 6.36. Found: C, 71.09; H,
4.50; N, 6.43. From the mother liquor, (2S,4R)-3-benzoyl-4-
methyl-4-(phthalimidomethyl)-2-phenyl-1,3-oxazolidin-5-one was
obtained (3g, 9.4%).
(S)-r-Am in om eth yla la n in e Meth yl Ester (9). A solution
of (2S,4S)-3-benzoyl-4-methyl-4-(phthalimidomethyl)-2-phenyl-
1,3-oxazolidin-5-one (8) (21 g, 0.5 mol) in 48% of HBr (200 mL)
was heated at reflux (120 °C oil bath) overnight. After being
washed with dichloromethane, the solution was evaporated to
give a brownish white crystalline material (14.5 g) of crude
diamino acid dihydrobromide salt.
Thionyl chloride (60 g, 0.50 mmol) was added to methanol
(130 mL) at -10 °C slowly, and then the solution was stirred
at room temperature for 30 min. Diamino acid dihydrobromide
salt was added, and the solution was heated at reflux
overnight. Evaporation of the solvent followed by drying under
vacuum gave a yellowish foam. This residue was dissolved in
CH2Cl2 (50 mL), and triethylamine (30 mL) was added. The
solvent was evaporated, and the residue was dissolved in THF
(100 mL). Filtration and evaporation gave a red yellow oil
that was distilled rapidly. The colorless distillate was dis-
solved in CH2Cl2 (15 mL) and dried over CaH2. Evaporation
of solvent and distillation gave a colorless oil (4.9 g, 77%). It
is essential that this diamine be absolutely dry to ensure good
yields in the next step. Dryness was assessed by comparing
the integration of the OMe peak at 3.73 with the NH2 peak at
1.5, which also contained H2O peaks. If this ratio exceeded
4:3, the product was redried and redistilled: bp 58-61 °C/
1
vacuum (0.05-0.01 mmHg); [R]21 -6.4° (c 1.12, CHCl3); H
D
NMR δ 1.27 (s, 3H), 1.52 (s, 4H), 2.64 (d, 1H, J ) 5.6 Hz),
3.01 (d, 1H, J ) 5.6 Hz), 3.73 (s, 3H); 13C NMR δ 24.2, 51.0,
52.2, 59.3, 177.6; IR(KBr) ν 3294, 2953, 1731, 1592, 1458, 1212
cm-1
.
(S)-N-(Ben zyloxyca r bon yl)-4-m eth yl-4-ca r bom eth oxy-
∆2-im id a zolin e (10). As solution of CH2Cl2 (50 mL), (S)-R-
aminomethylalaninemethyl ester (9) (4.1 g, 31 mmol) and
dimethylformamide dimethyl acetal (3.9 g, 31 mmol) was
heated at reflux under argon at 55-60 °C for 6 h. Evaporation
of solvent gave a yellowish oil of 4-(methoxycarbonyl)-4-phenyl-
∆2-imidazoline (crude ∼6 g), which was used for the next step
without purification.
4-Methyl-4-carbomethoxy-∆2-imidazoline was dissolved in
dichloromethane (50 mL) and triethylamine (16 g, 0.15 mol).
This reaction mixture was cooled to 0 °C, and then benzyl
chloroformate (6.1 g, 34 mmol) was added slowly. After being
stirred 1 h at 0 °C and 4 h at room temperature, the solution
was washed with 1 N HCl, 5% Na2CO3, and brine and dried
over Na2SO4. Evaporation of the solvent gave a yellow oil that
was chromatographed on silica gel (hexane/Et2O 1:1) to give
a yellowish oil (6.1 g, 70%): [R]21 -115° (c 1.05, ether); 1H
D
NMR δ 1.53 (s, 3H), 3.51(d, J ) 4.8 Hz, 1H), 3.76 (s, 3H), 4.17
(d, J ) 4.8 Hz, 1H), 5.22 (s, 2H), 7.29-7.38 (m, 5H), 7.57 (brs,
1H); 13C NMR δ 25.5, 52.3, 52.7, 68.0, 128.3, 128.4, 128.5,
128.5, 134.9, 172.8; IR (KBr) ν 1729, 1617, 1407 cm-1. Anal.
Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
60.60; H, 5.59; N, 9.94.
(2S,5R,6S)-2,6-Dim et h yl-6-m et h oxy-2-ca r b om et h oxy-
1,4-d ia za bicyclo[3.2.0]-h ep ta n -7-on e (11). Pentacarbonyl-
(methoxymethylcarbene)chromium(0) (360 mg, 1.4 mmol) and
(2S,4S)-3-Ben zoyl-4-m eth yl-4-(p h th a lim id om eth yl)-2-
p h en yl-1,3-oxa zolid in -5-on e (8). Into a solution of hexa-
methyldisilazane (17.5 g, 106 mmol) in THF (100 mL) was
added n-butyllithium (1.58 M in hexane, 50 mL, 78.5 mmol)
-78 °C. After 5 min at -78 °C, the solution was allowed to
warm to 0 °C for 30 min and then cooled to -78 °C again. A
solution of (2S,4S)-3-benzoyl-4-methyl-2-phenyl-1,3-oxazolidin-
5-one (dried overnight in vacuo before using, 20 g, 71 mmol)
in THF (250 mL) was added slowly under argon, and the dark

Synthesis of Optically Active Imidazolines
J . Org. Chem., Vol. 62, No. 11, 1997 3591
(S)-N-(benzyloxycarbonyl)-4-(methoxycarbonyl)-4-methyl-∆2-
imidazoline (10) (360 mg, 1.3 mmol) were dissolved in CH2Cl2
(20 mL) under argon in a Pyrex pressure tube. After three
freeze-thaw degassings, the resulting red brown solution was
irradiated with 4 × 500-W halogen lamps (work lamps, Ace
Hardware, Fort Collins, CO) under 90 psi of CO pressure at
70 °C. The progress of the reaction was indicated by the fading
of the color. After the reaction, the solvent was evaporated.
The residue was triturated with MeOH and kept for a few
hours at -20 °C. Filtration of chromium hexacarbonyl,
evaporation of MeOH, and purification by chromatography on
silica gel gave the N-(benzyloxycarbonyl)azapenam as a single
diastereomer (354 mg, 75%): 1H-NMR δ 1.22, 1.33 (2s, 3H),
1.80 (s, 3H), 3.25 (d, J ) 5.1 Hz, 1H), 3.40,3.51 (2s, 3H), 3.73
(s, 3H), 4.37 (d, J ) 5.1 Hz, 1H), 5.10-5.30 (m, 3H), 7.46 (s,
at -20 °C. Filtration of chromium hexacarbonyl, evaporation
of MeOH, and purification by radial layer chromatography
(ether:hexane 1:1) gave the N-(benzyloxycarbonyl)bisazapenam
as a single diastereomer (1.4 g, 75%): 1H-NMR δ 1.22, 1.33
(2s, 3H), 1.80 (s, 3H), 3.25 (d, J ) 5.1 Hz, 1H), 3.40, 3.51 (2s,
3H), 3.73 (s, 3H), 4.37 (d, J ) 5.1 Hz, 1H), 5.10-5.30 (m, 3H),
7.46 (s, 5H); IR (KBr) ν 1782, 1741, 1714, 1411 cm-1
.
The N-(benzyloxycarbonyl)bisazapenam (1.0 g, 1.36 mmol)
was dissolved in methanol (20 mL) and triethylamine (5 mL).
Hydrogenation with palladium on carbon (300 mg) at 80 psi
for 3 h, filtration through washed Celite, and evaporation of
the solvent gave the corresponding bisazapenam (14) (605 mg,
1
95%): [R]21 -177° (c 1.01, CH2Cl2); H NMR δ 1.19 (s, 3H),
D
1.63 (s, 3H), 1.76 (brt, 2H), 2.43 (brs, 2H), 2.55 (d, J ) 5.3 Hz,
2H), 3.63 (s, 3H), 3.45-3.75 (m, 6H), 4.78 (s, 2H); 13C NMR δ
14.4, 17.1, 29.9, 52.5, 60.52, 61.7, 66.0, 79.8, 89.6, 171.9, 175.3;
5H); IR (KBr) ν 1782, 1741, 1714, 1411 cm-1
.
IR (KBr) ν 3352, 2951, 1759, 1742 cm-1
. Anal. Calcd for
The N-(benzyloxycarbonyl)azapenam (260 mg, 0.72 mmol)
was dissolved in methanol (10 mL) and triethylamine (2 mL).
Hydrogenation with palladium on carbon(100 mg) at 80 psi
for 3 h, filtration through washed Celite, and evaporation of
C21H32N4O8: C, 53.84; H, 6.88; N, 11.96. Found: C, 53.65; H,
6.70; N, 11.76.
Bis-d ioxocycla m (16). The bisazapenam (14) (400 mg,
0.85 mmol) and a catalytic amount (10 mg) of racemic
camphorsulfonic acid in CH2Cl2 (50 mL) were stirred for 2 h
at 80 °C. The solution was washed with 5% NaHCO3 and dried
over Na2SO4. Evaporation of the solvent gave the bis-cyclic
diimine (15) (270 mg, 67%). The bis-cyclic diimine, NaBH3-
CN (220 mg, 3.5 mmol), and a small amount of bromocresol
green were dissolved in MeOH (20 mL)/CH2Cl2 (20 mL) at 0
°C. HCl (1 N)/MeOH was added dropwise until a yellow-green
color remained, and the resulting solution was warmed to room
temperature and stirred overnight. Excess NaBH3CN was
neutralized with 1 N HCl/MeOH. Aqueous NaOH (5%) was
added to adjust the pH to 9-10, and the aqueous layer was
extracted with CH2Cl2. The organic layer was dried over
K2CO3 and was evaporated to give a white solid of bis-
dioxocyclam, which was purified by radial layer chromatog-
the solvent gave the corresponding azapenam (155 mg, 95%):
1
[R]21 -211° (c 1.09, CH2Cl2); H NMR δ 1.27 (s, 3H), 1.73 (s,
D
3H), 2.32 (brs, 1H), 2.65 (d, J ) 5.3 Hz, 1H), 3.46 (s, 3H), 3.64
(d, J ) 5.3 Hz, 1H), 3.72 (s, 3H), 4.85 (s, 2H); 13C NMR δ 14.0,
16.9, 52.3, 53.0, 60.3, 65.8, 79.0, 90.1, 171.7, 174.9; IR (KBr
plate) ν 3374, 1738, 1666 cm-1. Anal. Calcd for C10H16N2O4:
C, 52.62; H, 7.07; N, 12.27. Found: C, 52.44; H, 7.25; N, 12.14.
(2S,6S,9S,13S)-6,13-Dim et h oxy-2,6,9,13-t et r a m et h yl-
2,9-d ica r bom et h oxy-1,4,8,11-t et r a a za cyclot et r a d eca n e-
5,12-d ion e (12). The azapenams 11 (100 mg) and a catalytic
amount (10 mg) of racemic camphorsulfonic acid in CH2Cl2
(10 mL) were stirred 2 h at 80 °C. The solution washed with
5% NaHCO3 and dried over Na2SO4. Evaporation of the
solvent gave the cyclic diimines. The cyclic diimine, NaBH3-
CN (30 mg, 0.48 mmol), and a small amount of bromocresol
green were dissolved in MeOH (15 mL)/CH2Cl2 (15 mL) at 0
°C. HCl (1 N)/MeOH was added dropwise until a yellow-green
color remained, and the resulting solution was warmed to room
temperature and stirred overnight. Excess NaBH3CN was
neutralized with 1 N HCl/MeOH. Aqueous NaOH (5%) was
added to adjust the pH to 9-10, and the aqueous layer was
extracted with CH2Cl2. The organic layer was dried over
K2CO3 and was evaporated to give a white solid of dioxocyclam
that was purified by radial layer chromatography (Si gel, 1:1
ether/ethyl acetate) (85 mg, 85%): mp 173-174 °C; [R]21D +25°
(c 0.5, CH2Cl2); 1H NMR δ 1.27 (s, 6H), 1.59 (s, 6H), 2.60-
2.81 (m, 8H), 3.25(s, 6H), 3.81 (s, 6H), 7.90 (brs, 2H); 13C NMR
δ 18.3, 21.2, 50.0, 52.8, 53.0, 54.8, 61.3, 79.9, 172.0, 174.5; IR
(KBr) ν 2958, 2835, 1738, 1681, 1520, 1454, 1262 cm-1. Anal.
Calcd for C20H36N4O8: C, 52.16; H, 7.88; N, 12.17. Found: C,
52.25; H, 8.09; N, 12.21.
raphy (Si gel, 1:1 ether/ethyl acetate) (230 mg, 85%): mp 245
1
°C dec; [R]21 -0.4° (c 4.8, CH2Cl2); H NMR δ 1.26 (s, 12H),
D
1.57 (s, 12H), 1.65 (s, 4H), 1.96 (quint, J ) 3.2 Hz, 4H), 1.7-
2.9 (m, 12H), 3.28 (dd, J ) 3.2, 5.2 Hz, 4H), 3.35-3.55 (m,
8H), 3.78 (s, 12H), 8.35 (s, 4H); 13C NMR δ 19.5, 20.3, 31.6,
52.9, 53.7, 54.9, 59.9, 60.8, 79.6, 172.4, 174.4; IR (KBr) ν 3391,
2950, 1738, 1676, 1519, 1451 cm-1
.
Anal. Calcd for
C42H72N8O16: C, 53.38; H, 7.68; N, 11.86. Found: C, 53.32;
H, 7.48; N, 12.02.
Ack n ow led gm en t. Support for this research under
Grant No. GM26178 from the National Institutes of
General Medical Sciences (Public Health Service) is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation Grant No. GM49631.
Bisa za p en a m (14). Bis-chromium alkoxycarbene complex
(13)14 (1.9 g, 2.6 mmol) and (S)-N-(benzyloxycarbonyl)-4-
(methoxycarbonyl)-4-methyl-∆2-imidazoline (10) (1.5 g, 5.4
mmol) were dissolved in CH2Cl2 (110 mL) under argon in a
Pyrex pressure tube. After three freeze-thaw degassings, the
resulting red brown solution was irradiated with 4 × 500W
halogen lamps under 90 psi of CO pressure at 70 °C. The
progress of the reaction was indicated by the fading of the
color. After the reaction, the solvent was evaporated. The
residue was triturated with MeOH, and kept for a few hours
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds not characterized by elemental analyses
(12 pages). This material is contained in libraries on micro-
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of the journal, and can be ordered from the ACS; see any
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J O962343E