An efficient synthesis of optically active trans-(3R,4R)-3-acetoxy-4-aryl- 1-(chrysen-6-yl)azetidin-2-ones using (+)-car-3-ene as a chiral auxiliary

Article abstract of DOI:10.1002/hlca.201100225

An efficient enantioselective synthesis of 3-acetoxy trans-β-lactams 7a and 7b via [2+2] cycloaddition reactions of imines 4a and 4b, derived from a polycyclic aromatic amine and bicyclic chiral acid obtained from (+)-car-3-ene, is described. The cycloadd

Full text of DOI:10.1002/hlca.201100225

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An Efficient Synthesis of Optically Active trans-(3R,4R)-3-Acetoxy-4-aryl-1-
(chrysen-6-yl)azetidin-2-ones Using (þ)-Car-3-ene as a Chiral Auxiliary
by Aarif L. Shaikh, Orlando Esparza, and Bimal K. Banik*
The University of Texas Pan American, Department of Chemistry, 1201 West University Drive,
Edinburg, Texas 78539, USA
(email: banik@utpa.edu)
An efficient enantioselective synthesis of 3-acetoxy trans-b-lactams 7a and 7b via [2 þ 2] cyclo-
addition reactions of imines 4a and 4b, derived from a polycyclic aromatic amine and bicyclic chiral acid
obtained from (þ)-car-3-ene, is described. The cycloaddition was found to be highly enantioselective,
producing only trans-(3R,4R)-N-azetidin-2-one in very good yields. This is the first report of the synthesis
of enantiomerically pure trans-b-lactams 7a and 7b with a polycyclic aromatic substituent at N(1) of the
azetidin ring.
Introduction. – The b-lactam skeleton is the key structural unit responsible for the
antibacterial property of the most widely employed antibiotics [1]. The resistance
developed by the microorganisms against the b-lactam drugs maintained the interest of
organic chemists for the development of new b-lactams with broader antibacterial
activity [2]. As a consequence, several synthetic methods for b-lactams are now
available, and the topic has been extensively reviewed [3]. The most convenient
procedure for the synthesis of the b-lactam ring skeleton is the [2 þ 2] cycloaddition of
ketenes to imines, known as the Staudinger cycloaddition [4]. In particular, this method
has provided useful and economical entries to b-lactams, mainly due to the ready
availability of both imines and ketenes; however, the subject still continues to be an
active area of research [5]. Over the past few years, asymmetric versions of this reaction
have been developed using a combination of either chiral ketenes and achiral imines, or
achiral ketenes and chiral imines, generally providing good diastereoselectivity [6].
In the diastereoselective synthesis of b-lactams, chiral starting materials such as
aldehydes, acids/acid halides, and amines have been widely used. High levels of
stereoselection were achieved, when the b-C-atom of the chiral aldehyde is attached to
a heteroatom [7]. In recent years, several researchers have studied different
approaches to optically pure b-lactams of predictable absolute configuration [8][9].
Deshmukh and co-workers [10] have reported that the reaction of an acid chloride (or
equivalent) with a Schiff base derived from an optically active aldehyde and an achiral
amine, in the presence of Et3N, leads to a very high level of diastereoselectivity. In some
cases, a single, optically pure, cis-b-lactam was obtained [10d][10e][10f]. We describe
here the synthesis of optically pure trans-b-lactams with a polyaromatic substituent at
N(1) of the azetidin-2-ones derived from (þ)-car-3-ene.
Results and Discussion. – In continuation of our endeavor for the synthesis and
biological evaluation of novel anticancer b-lactams, we have synthesized racemic trans-
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
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b-lactams from polycyclic aromatic imines and other imines [11]. A preliminary
structureꢀactivity study has revealed that trans-1-N-chrysenyl and 1-N-phenanthrenyl
3-acetoxy-4-arylazetidin-2-ones have potent, selective anticancer activities [11]. We
have also studied the diastereoselectivity of b-lactam formation with imines which have
N-polycyclic aromatic substituents. Our research has revealed that functionalized b-
lactams in racemic and optically active forms can be prepared by simple methods [11].
Therefore, we envision that enantiomerically pure trans-1-chrysenyl- and 1-phenan-
threnyl substituted 3-acetoxy-4-aryl-2-azetidinones would have higher anticancer
activities than their racemic forms. Also, there is no methodology reported to
synthesize chiral trans-b-lactams via a chiral ketene derived from a natural terpenoid.
With this background information, we have synthesized a bicyclic chiral acid 3 derived
from readily available and naturally abundant (þ)-car-3-ene (1) [12]. (þ)-Car-3-ene
(1), on reaction with NBS [13] in the presence of ethylene glycol, afforded bromo
alcohol 2 in moderate yield. Oxidation of 2 gave the bicyclic chiral acid 3 in excellent
yield (Scheme 1).
Scheme 1
i) N-Bromosuccinimide (NBS)/HOCH2CH2OH, 08, 4 h. ii) CrO3/acetone.
The Staudinger cycloaddition of 3 with imines 4a and 4b in the presence of Et3N and
Mukaiyamaꢂs reagent (2-chloro-1-methylpyridinium iodide) as an acid activator [14]
1
was performed. The progress of the reaction was monitored by TLC. The H-NMR
spectra of the crude products indicated the formation of trans-b-lactams 5a and 5b,
respectively, in good yield (Scheme 2). No trace of the cis-isomer was detected by
1H-NMR. The yield of the products was very good. The crude compounds were purified
by flash column chromatography to give pure trans-b-lactams 5a and 5b, respectively, as
white solids. The results described here are highly remarkable, as the preparation of a
single optically active trans-b-lactam starting from a ketene has so far been unknown.
The stereochemical outcome and structure of 5a was established by IR and NMR
spectroscopy. The pure diastereoisomer 5a showed a characteristic absorption band at
1766 cmꢀ1 for the b-lactam C¼O group. The 1H-NMR spectra showed doublets at 4.95
and 5.48 ppm for HꢀC(4) and HꢀC(3) of the b-lactam ring, respectively. The coupling
constant, J, of these two doublets is 1.95 Hz, which confirmed the trans-configuration
for the b-lactam ring of 5a. The signals in the aliphatic region at 0.67 – 2.48 ppm
confirmed the presence of the (þ)-car-3-ene moiety. The peak observed at 166.8 ppm in
the 13C-NMR spectra corresponds to the C¼O group.
The cleavage of the chiral auxiliary was accomplished by reacting pure diaster-
eoisomers 5a and 5b with Zn/AcOH under reflux for 12 – 15 h to give the corresponding

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Scheme 2
i) Dry Et3N, dry CH2Cl2, 2-chloro-1-methylpyridinium iodide, 08 to r.t., 15 h. ii) Zn/AcOH/MeOH,
reflux, 4 h. iii) AcCl, Et3N, anh. CH2Cl2, 08 to r.t., 15 h.
enantiomerically pure 3-hydroxy trans-b-lactams 6a and 6b, respectively, in excellent
yields (Scheme 2). Their formation was confirmed by their spectroscopic data (1H- and
13C-NMR). Further, 3-hydroxy trans-b-lactams 6a and 6b on reaction with AcCl and
Et3N gave 3-acetoxy trans-b-lactams 7a and 7b, respectively, again in excellent yield.
The structure 7a and 7b was established by spectroscopic and analytical data. The
absolute configuration of b-lactam 7a was assigned on the basis of its optical rotation
and melting point in comparison with those of an authentical sample of 7a, which was
prepared earlier in our laboratory by a different method [11h][11m]. The optical
rotation for 7a was [a]2D0:1 ¼ ꢀ39.62 (c ¼ 0.12, CHCl3). The absolute configuration of 7a
was also confirmed by a comparison with known trans-b-lactams described earlier with
respect to optical rotation and NMR data in the presence of a chiral shift reagent
[11h][11m][15].
In summary, we have synthesized enantiomerically pure 3-acetoxy trans-b-lactams
7a and 7b in excellent yield. This is the first protocol to synthesize 3-acetoxy trans-b-
lactams via (þ)-car-3-ene as a chiral precursor. Moreover, the resulting optically active
b-lactam should exhibit anticancer activity based on our previous work.

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Experimental Part
General. Anal. grade chemicals (SigmaꢀAldrich) were used. Silica gel (SiO2) was used for column
chromatography (CC). Deionized H2O was used for the preparation of all aq. solns. M.p.: Fisher
Scientific electrochemical Mel-Temp* manual melting point apparatus (Model 1001). Optical rotations:
Rudolph Polarimer. FT-IR Spectra: Bruker IFS 55 Equinox FT-IR spectrophotometer, as KBr discs. 1H-
(300 MHz) and 13C-NMR (75.4 MHz) spectra: at r.t., JEOL Eclipse-300 equipment with TMS as internal
standard and CDCl3 as solvent.
2-{[(1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]hept-3-yl]oxy}ethanol (2). To a stirred soln.
of (þ)-car-3-ene (1; 1.36 g, 10 mmol) and ethylene glycol (31 ml, 50 mmol) in CH2Cl2 (30 ml), powdered
NBS (2.23 g, 12.5 mmol) was added in small portions during 30 min at 08. The mixture was allowed to
warm to r.t. and stirred for a further 4 h. After completion of the reaction (TLC), cold H2O (50 ml) was
added to the mixture, which was extracted with CH2Cl2 (3 ꢁ 30 ml). The combined extracts were washed
with sat. NaHSO3 (15 ml), H2O (20 ml), and brine (15 ml), dried (anh. Na2SO4), and filtered. The
filterate was concentrated under reduced pressure, and the residue was purified by CC (SiO2, 120 mesh;
10% AcOEt/hexane) to give 1.24 g (45%) of 2. Pale-yellow liquid. [a]2D0 ¼ ꢀ33.45 (c ¼ 1.65, CHCl3).
1H-NMR (CDCl3): 0.65 – 0.90 (m, 2 H); 0.97 (s, 3 H); 1.00 (s, 3 H); 1.30 – 1.50 (m, 1 H); 1.35 (s, 3 H);
2.05 – 2.25 (m, 1 H); 2.40 – 2.50 (m, 2 H); 3.40 – 3.60 (m, 2 H); 3.65 – 3.75 (m, 2 H); 4.07 (t, J ¼ 8, 1 H).
13C-NMR (CDCl3): 15.48; 17.70; 18.32; 19.50; 21.63; 28.39; 29.97; 31.80; 59.92; 61.83; 62.04; 75.25.
2-{[(1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]hept-3-yl]oxy}acetic acid (3). To a stirred
soln. of 2 (276 mg, 1 mmol) in acetone (10 ml), Jones reagent was added dropwise at 08 until
decolorization of the reagent stopped. The mixture was further stirred for 3 h at r.t., the green precipitate
of the chromium salt was filtered off, and the excess reagent was destroyed by adding i-PrOH at 08. The
soln. was concentrated under vacuum, and the residue was extracted with Et2O (3 ꢁ 20 ml). The Et2O
extract was washed with brine and dried (Na2SO4). It was then filtered, and the filtrate, on concentration
under reduced pressure, afforded 3 (232 mg, 80%). Pure product was obtained by crystallization from
1
hexane/AcOEt to give 3 as white crystals. M.p. 858. [a]2D0 ¼ ꢀ72 (c ¼ 0.45, CHCl3). H-NMR (CDCl3):
0.65 – 0.90 (m, 2 H); 0.98, 1.00 (2s, 6 H); 1.40 (s, 3 H); 1.3 – 1.4 (m, 1 H); 2.20 (dd, J ¼ 5.5, 10, 1 H); 2.35 –
2.55 (m, 2 H); 4.00 (m, 1 H); 4.05 (d, J ¼ 18, 1 H); 4.10 (d, J ¼ 18, 1 H); 7.30 – 9.0 (br. s, 1 H). 13C-NMR
(CDCl3): 15.71; 17.34; 18.18; 19.55; 21.85; 28.57; 30.88; 31.99; 59.74; 59.89; 78.12; 160.00.
trans-b-Lactam 5a. To a stirred soln. of chrysene-1-imine 4a (0.434 g, 1.31 mmol), 3 (0.384 g,
1.31 mmol), and Et3N (0.54 ml, 3.93 mmol) in dry CH2Cl2 (20 ml), a soln. of 2-chloro-1-methylpyr-
idinium iodide (0.402 g, 1.57 mmol) in dry CH2Cl2 (20 ml) was added dropwise at 08 during 1 h. The
mixture was allowed to warm to r.t. and stirred overnight. The mixture was then diluted with CH2Cl2
(20 ml), and washed successively with H2O (30 ml), sat. NaHCO3 (30 ml), and brine (25 ml), and was
dried (anh. Na2SO4). The solvent was removed by distillation under reduced pressure, and CC (SiO2, 120
mesh; 10% AcOEt/hexane) of the residue gave 5a (0.560 g, 70%) as white solid. Following a similar
procedure, we have also obtained trans-b-lactam 5b (0.702 g, 65%).
(3R,4R)-3-{[(1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]hept-3-yl]oxy}-1-(chrysen-6-yl)-
4-phenylazetidin-2-one (5a). White solid. M.p. 209 – 2108. Rf (10% AcOEt/hexane) 0.55. [a]2D0:1 ¼ þ59.60
(c ¼ 0.33, CHCl3). IR (KBr): 1388, 1650, 1704, 1766. 1H-NMR (300 MHz, CDCl3): 0.67 – 0.97 (m, 2 H);
0.97 (s, 3 H); 1.5 (s, 3 H); 1.36 – 1.58 (m, 1 H); 2.22 – 2.43 (m, 1 H); 2.43 – 2.48 (m, 2 H); 4.01 – 4.05 (m,
4 H); 4.95 (d, J ¼ 1.95, HꢀC(4)); 5.48 (d, J ¼ 1.95, HꢀC(3)); 7.24 – 8.61 (m, 14 arom. H). 13C-NMR
(300 MHz, CDCl3): 18.0; 20.0; 21.3; 28.6; 32.0; 58.4; 66.8; 81.0; 114.2; 118.0; 120.0; 122.2; 123.4; 125.7;
126.8; 126.8; 127.5; 127.7; 131.5; 136.3; 166.9.
(3R,4R)-3-{[(1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]hept-3-yl]oxy}-1-(chrysen-6-yl)-
4-(4-methoxyphenyl)azetidin-2-one (5b). White solid. M.p. 208 – 2098. Rf (20% AcOEt/hexane) 0.48.
1H-NMR (300 MHz, CDCl3): 0.67 – 0.98 (m, 2 H); 0.99 (s, 6 H); 1.51 (s, 3 H); 1.26 – 1.59 (m, 1 H); 2.05 –
2.23 (m, 1 H); 2.44 – 2.47 (m, 2 H); 3.66 (s, 3 H); 4.06 – 4.16 (m, 4 H); 4.96 (d, J ¼ 1.90, HꢀC(4)); 5.43 (d,
J ¼ 1.90, HꢀC(3)); 6.77 – 8.72 (m, 13 arom. H). 13C-NMR (300 MHz, CDCl3): 18.1; 18.4; 20.0; 28.4; 28.7;
32.1; 55.1; 58.6; 66.0; 82.0; 114.3; 114.7; 121.0; 122.0; 126.7; 127.4; 127.6; 127.9; 128.1; 128.2; 159.9; 167.0.
(3R,4R)-1-(Chrysen-6-yl)-3-hydroxy-4-phenylazetidin-2-one (6a). To a soln. of 5a (0.189 g,
0.312 mmol) in MeOH (5 ml), activated Zn (0.248 g, 3.75 mmol), and glacial AcOH (1.0 ml) were

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added under stirring. The mixture was then heated to 808 with continuous removal of MeOH during 12 h.
Then, MeOH was distilled to recover (þ)-car-3-ene, and the residue was treated with CH2Cl2 (30 ml) and
filtered; the solid was washed with CH2Cl2 (3 ꢁ 20 ml). The combined filtrate was successively washed
with dil. HCl (5%, 10 ml), sat. NaHCO3 (2 ꢁ 15 ml), H2O (2 ꢁ 10 ml), brine (10 ml), and dried (anh.
Na2SO4). The removal of the solvent gave 6a (0.112 g, 93%). White solid. M.p.: 209 – 2108. Rf (30%
1
AcOEt/hexane) 0.33. IR (KBr): 1388, 1650, 1745, 3400. H-NMR (300 MHz, CDCl3): 4.98 (d, J ¼ 1.65,
HꢀC(4)); 5.44 (d, J ¼ 1.65, HꢀC(3)); 7.17 – 8.25 (m, 14 arom. H). 13C-NMR (300 MHz, CDCl3): 66.8;
82.0; 114.2; 118.0; 120.0; 122.2; 123.4; 125.7; 126.8; 126.8; 127.5; 127.7; 131.5; 136.3; 166.9.
(3R,4R)-1-(Chrysen-6-yl)-3-hydroxy-4-(4-methoxyphenyl)azetidin-2-one (6b). Pale yellow oil. Rf
1
(30% AcOEt /hexane) 0.25. H-NMR (300 MHz, CDCl3): 4.21 (s); 4.98 (d, J ¼ 1.65, HꢀC(4)); 5.39 (d,
J ¼ 1.65, HꢀC(3)); 6.72 – 8.22 (m, 13 arom. H). 13C-NMR (300 MHz, CDCl3): 55.1; 68.1; 68.2; 115.0;
119.5; 121.0; 128.6; 128.9; 130.7; 130.9; 131.1; 132.5; 148.0; 149.4; 161.5; 163.2; 167.8.
(3R,4R)-1-(Chrysen-6-yl)-2-oxo-4-phenylazetidin-3-yl Acetate (7a). To a soln. of 6a (0.073 g,
0.187 mmol) in CH2Cl2 (5 ml), Et3N (0.023 ml, 0.375 mmol) and AcCl (0.052 ml, 0.375 mmol) were
added at 08, and the mixture was kept at r.t. for 30 min. Then, the mixture was diluted with CH2Cl2, and
washed with sat. NaHCO3 and H2O to give a crude pale-yellow solid. The crude compound was purified
by flash CC (20% AcOEt/hexane) to give pure 7a (0.072 g, 90%). White solid. Recrystallization from
CH2Cl2/hexane gave white needles. M.p.: 262 – 2638. Rf (20% AcOEt/hexane) 0.54. [a]2D0:1 ¼ ꢀ39.62 (c ¼
0.12, CHCl3). IR (KBr): 1255, 1660, 1755. 1H-NMR (300 MHz, CDCl3): 2.28 (s); 5.53 (d, J ¼ 1.92,
HꢀC(4)); 5.76 (d, J ¼ 1.92, HꢀC(3)); 7.24 – 8.64 (m, 14 arom. H). 13C-NMR (300 MHz, CDCl3): 65.2;
68.6; 81.0; 115.7; 124.6; 127.4; 129.29; 129.8; 130.9; 138.8; 169.8; 182.3.
(2R,3R)-1-(Chrysen-6-yl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl Acetate (7b). Compound 7b was
prepared by the method as described for 7a. Recrystallization from CH2Cl2/hexane. White solid. M.p.
180 – 1818. Rf (20% AcOEt/hexane) 0.45. [a]2D0:1 ¼ ꢀ45.04 (c ¼ 0.10, CHCl3). 1H-NMR (300 MHz,
CDCl3): 2.29 (s); 3.68 (s); 5.48 (d, J ¼ 1.92, HꢀC(4)); 5.75 (d, J ¼ 1.92, HꢀC(3)); 6.78 – 8.63 (m, 13 arom.
H). 13C-NMR (300 MHz, CDCl3): 55.2; 65.6; 80.9; 114.3; 115.2; 117.3; 120.0; 122.2; 123.5; 124.7; 127.1;
128.0; 130.1; 132.3; 160.3; 163.3; 167.9; 170.2.
We gratefully acknowledge the funding support from the NIH-SCORE (Grant No. 2S06M008038-
37).
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Received June 2, 2011