Stereoselective synthesis of N-phenylsulfonyl substituted spiro-β- lactams

Article abstract of DOI:10.1016/S0957-4166(99)00096-8

A stereoselective synthesis of N-phenylsulfonyl substituted spiro-β- lactams obtained from the N-(phenylmethylene)benzenesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds derived from 4- hydroxy substituted N-acyl-L-prolines

Full text of DOI:10.1016/S0957-4166(99)00096-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1193–1199
Stereoselective synthesis of N-phenylsulfonyl substituted
spiro-β-lactams
Piero Dalla Croce a and Concetta La Rosa b,∗
aDipartimento di Chimica Organica e Industriale and Centro C.N.R., V. Venezian 21, I-20133 Milano, Italy
bIstituto di Chimica Organica, Facoltà di Farmacia, V. Venezian 21, I-20133 Milano, Italy
Received 23 February 1999; accepted 12 March 1999
Abstract
A stereoselective synthesis of N-phenylsulfonyl substituted spiro-β-lactams obtained from the N-
(phenylmethylene)benzenesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds
derived from 4-hydroxy substituted N-acyl-L-prolines in the presence of acetic anhydride as the dehydrating agent
is presented. The reaction of (2S,4R)-4-acetyloxy or benzoyloxy-N-acyl-proline with the above imine afforded a
mixture of two diastereoisomeric spiro-β-lactams with complete stereoselectivity for the spiro carbon. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
In previous communications, we have reported on the reactivity of cyclic N-acyl-α-aminoacids to-
wards imines such as N-(phenylmethylene)aniline1 and N-(phenylmethylene)benzenesulfonamide,1,2 in
the presence of a dehydrating agent such as N,N0-dicyclohexylcarbodiimide or acetic anhydride. The
reaction of the N-acyl-α-aminoacids 1–4 with N-(phenylmethylene)benzenesulfonamide 5 in toluene
solution at 80°C using 3 mols of acetic anhydride led to a mixture of diastereoisomeric N-phenylsulfonyl
substituted spiro-β-lactams 6 and 7, and/or bicyclic imidazole 8, depending on the experimental condi-
tions and the nature of the R and X groups2 (Scheme 1).
The cyclodehydration of N-acyl-α-aminoacids 1–4 leads to the bicyclic mesoionic compound 9, and
this, or its ketene valence tautomer 10, undergoes nucleophilic attack by the imine nitrogen onto the
carbonyl carbon to give the zwitterionic intermediate 11 which, after ring closure, affords 6 and 7
(Scheme 2).
The phenyl group on the imine carbon can stabilize the positive charge so that the zwitterionic inter-
mediate 11 can isomerize its double C_N bond to the cis-form, thus affording the thermodynamically
∗
Corresponding author. E-mail: mabuck@icil64.cilea.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00096-8

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P. Dalla Croce, C. La Rosa / Tetrahedron: Asymmetry 10 (1999) 1193–1199
Scheme 1.
Scheme 2.
more stable β-lactam 6;3 in fact the ratio of products 6:7 is always in favor of the β-lactam 6, which has
the C-phenyl and the N-acyl groups trans to each other (ratio 6:7=3:1).
These results prompted us to plan a stereoselective synthesis of the spiro-β-lactams 6 and 7 starting
from one of the two reagents (α-aminoacid or imine) containing a stereocenter in a suitable position.
Given the growing interest in the stereoselective synthesis of β-lactam antibiotics or natural products
having β-lactams as chiral starting materials, the asymmetric synthesis of β-lactams has received much
attention over recent years,4 in particular, the asymmetric Staudinger reaction (a [2+2] cycloaddition
between a ketene and an imine) has been extensively and successfully studied.5–7 However, to the best
of our knowledge, no study regarding the stereoselective synthesis of β-lactams through the Staudinger
reaction of imines and ketenes derived from bicyclic mesoionic compounds 1,3-oxazolium-5-one has
ever been published.
2. Results and discussion
Asymmetric induction in the Staudinger reaction can be achieved by introducing a chiral auxiliary in
the precursor of the ketene (normally an acid chloride) or in the C- or N-substituent of imine.5–7 In our
case, we could have placed it on the C- or N-substituent of the imine, on the α-aminoacid ring or on the
N-acyl residue (Fig. 1).
It is worth noting that, although the α-aminoacids 1–4 contain a stereocenter in position 2, this is
lost during the formation of the mesoionic compound and is therefore irrelevant to the stereochemical
course of the reaction. We excluded possibilities (B) and (D) because the stereocenter would have been
too far from the newly forming C3–C4 bond in the zwitterionic intermediate; between (A) and (C), we

P. Dalla Croce, C. La Rosa / Tetrahedron: Asymmetry 10 (1999) 1193–1199
1195
Figure 1.
chose the latter on the basis of synthetic considerations and the commercial availability of the reagent
precursors. N-Benzoyl-L-proline was chosen as the cyclic α-aminoacid on the basis of our previous
results.1,2 Position 3 of the ring proved to be the most promising as it is nearest to the reaction centers of
the intermediate, but the commercial availability of the inexpensive (2S,4R)-4-hydroxy-proline initially
prompted us to evaluate the effect of the stereocenter in position 4 on the stereochemical course of the
reaction. The presence of an acidic hydrogen (such as that of a hydroxyl group) might interfere with
mesoionic formation, and so we decided to acylate the hydroxyl group and also evaluate the influence
of the acylating group size. Therefore we studied the stereochemical course of the reactions between the
imine 5 and the prolines 12 and 13 shown in Fig. 2.
Figure 2.
Product 12 was previously unknown. As shown in Scheme 3, the best experimental conditions under
which to introduce the benzoyl on the N- and acetyl groups on the O-atoms of the commercial (2S,4R)-
4-hydroxy-proline were: (1) benzoyl chloride and sodium hydroxide at 5°C, and (2) acetic anhydride in
pyridine at room temperature. In this way the (2S,4R)-4-acetyloxy-N-benzoyl-proline 12 was obtained
with a total yield of 81%. Similarly, the commercially available N-acetyl-4-hydroxy-L-proline was
benzoylated with benzoyl chloride in pyridine and afforded the (2S,4R)-N-acetyl-4-benzoyloxy-proline
13 with a yield of 75% (Scheme 3).
Scheme 3.
The reactions of 12 and 13 with imine 5 were performed in toluene solution at 80°C using 3 mols of
acetic anhydride as the dehydrating agent. The crude reaction mixtures were analyzed by means of 1H
NMR in order to identify all the obtained stereoisomers. The product mixtures were separated by means
of column chromatography and further purified by crystallization.
The reaction between 12 and 5 gave a mixture of three products (Scheme 4), similar to those observed
in the reaction of N-benzoyl-L-proline and 5.2

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P. Dalla Croce, C. La Rosa / Tetrahedron: Asymmetry 10 (1999) 1193–1199
Scheme 4.
Spiro-β-lactams 15 and 16 were obtained with a total yield of 61% and a ratio of 60:40, respectively.
The bicyclic imidazole 17 (deriving from the 1,3-dipolar cycloaddition between 5 and the mesoionic
1
intermediate 9) was obtained with a yield of 20%. The spiro-β-lactams are diastereoisomers: their H
NMR spectra show some differences in the chemical shifts (from 0.05 to 0.5 ppm) and, sometimes,
1
in the multiplicity of the main signals. Unlike previous examples,1,2 their H NMR spectra did not
allow them to be assigned the cis- or trans-relative configuration because the difference between the
chemical shift values (5.55 and 5.60 δ) of the two benzylic protons was too small to determine what
hydrogen is in the deshielding cone of the N-benzoyl carbonyl group. Consequently, a single crystal X-
ray analysis was performed to assign the absolute configuration to the new stereocenters C3 and C4.8
The relative trans-configuration was assigned to the more abundant product and cis to the other, with the
absolute configurations of, respectively, 3S,4S,7R and 3R,4S,7R. The two spiro-β-lactams thus had the
same absolute configuration S to the spiranic carbon C4 and differed in that of the benzylic carbon C3.
The formation of the same configuration for C4 is the result of the stereochemical induction of the
stereocenter on the proline ring during the course of the reaction. This induction takes place at the level
of the ring closure of the zwitterionic intermediate to β-lactam: the presence of the acetyloxy group favors
this closure from the less hindered opposite side of the proline ring and leads to the S-configuration of
C4. Such a high degree of induction was not observed for the stereocenter C3: the formation of both
diastereoisomers 15 and 16 with a ratio of 1.5:1 derives from the trans–cis isomerization of the C_N
double bond of the imine in the zwitterionic intermediate;3 the presence of the stereocenter in the proline
ring seems to be irrelevant to this isomerization. On the contrary, the energy difference between the two
products 15 and 16 seems to decrease as their ratio tends to one.
We subsequently verified the effect on stereocenter formation of a more bulky acyl group on the
hydroxyl of the 4-hydroxy-L-proline: product 13 was reacted with imine 5 in the presence of acetic
anhydride at 80°C (Scheme 5).
Scheme 5.
This reaction afforded a mixture of spiro-β-lactams 18 and 19, which were obtained with a total yield
of 65% and a ratio of 63:37. As in the case of N-acetyl-L-proline,2 no 1,3-dipolar cycloaddition product
was formed. The difference between the chemical shift values of the benzylic protons of β-lactams 18 and

P. Dalla Croce, C. La Rosa / Tetrahedron: Asymmetry 10 (1999) 1193–1199
1197
19 (5.51 and 5.58 δ) was too small to assign their relative configuration. Assuming that the reaction was
totally stereoselective for the spiranic carbon C4, and therefore obtained with the same S-configuration
in both products, we analyzed the more abundant β-lactam by means of homonuclear NOE difference
spectra in order to evaluate the spatial proximity between the ortho-protons of C3-phenyl and C8-protons
(β-lactam 18) or between the C3-H and C8-protons (β-lactam 19).
The NOE experiment allowed structure 18 to be assigned to the predominant spiro-β-lactam and
structure 19 to the other. The obtained products therefore have the same 3S,4S,7R and 3R,4S,7R absolute
configurations even with a more bulky acyl group on the stereocenter of the proline ring. It is worth
noting that the size of the acyl group does not have any appreciable effect on the stereoselectivity of the
benzylic carbon C3: the two β-lactams were obtained with almost the same ratio regardless of whether
the acetyl or benzoyl group was used.
3. Conclusion
The present paper describes the first example of a stereoselective synthesis of spiro-β-lactams by
means of a reaction between imines and chiral ketenes deriving from bicyclic mesoionic compounds.
The presence of a stereocenter in position 4 of the cyclic aminoacid is sufficient to ensure complete
stereoselectivity on the spiranic carbon C4, but is almost irrelevant to C3. The possibility of obtaining
this new class of enantiomerically pure diastereoisomeric spiro-β-lactams, with the desired absolute
configuration of C4 and in good yields, makes this reaction worthy of the further studies that are currently
ongoing.
4. Experimental
Melting points were determined using a Büchi apparatus and are uncorrected. All the 1H NMR spectra
were recorded in CDCl3 solution by means of a Bruker AC 300 spectrometer. Chemical shifts (δ) are
given in ppm relative to TMS; all coupling constants (J) are in hertz. Optical rotations were measured
using a Perkin–Elmer 241 spectropolarimeter. The X-ray crystallographic analyzes8 were carried out on
single crystals obtained by precipitation from ethyl acetate 15 and acetone 16. Compounds 59 and 14
were prepared according to the method of Jennings10 and Portoghese,11 respectively.
4.1. (2S,4R)-4-Acetyloxy-N-benzoyl-proline 12
A mixture of (2S,4R)-N-benzoyl-4-hydroxy-proline 14 (1 g, 4.25 mmol), acetic anhydride (3 ml) and
pyridine (0.04 ml, 0.487 mmol) was stirred at room temperature for 24 h. After evaporation of the solvent,
the residue was taken up in dichloromethane and the solution was washed with water. The organic phase
was dried (Na2SO4) and the solvent evaporated off. The residue was purified by column chromatography
over silica gel (EtOH) affording 12 as colorless solid (1.06 g, 90% yield); mp 172–173°C; [α]20 −41.1
D
(c 1.03, CHCl3); 1H NMR (CDCl3) (mixture of two conformers) δ 1.98, 2.05 (3H, s, CH3), 2.48 (2H, m,
H3), 3.63 (1H, AB syst. J=10.4, H5), 3.85 (1H, AB syst. J=10.4 and 2.2, H5), 4.85, 4.91 (1H, t, H2), 5.2,
5.3 (1H, m, H4), 7.3–7.6 (5H, m, Ar), 7.8 (1H, broad, COOH). Anal. calcd for C14H15NO5: C, 60.65; H,
5.42; N, 5.05. Found: C, 60.38; H, 5.12; N, 5.00.

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P. Dalla Croce, C. La Rosa / Tetrahedron: Asymmetry 10 (1999) 1193–1199
4.2. (2S,4R)-N-Acetyl-4-benzoyloxy-proline 13
A mixture of N-acetyl-4-hydroxy-L-proline (0.5 g, 2.89 mmol), pyridine (2 ml) and benzoyl chloride
(0.37 ml, 3.17 mmol) was stirred at room temperature for 2 h. After evaporation of the solvent, the residue
was taken up in dichloromethane and the solution was washed with water. The organic phase was dried
(Na2SO4) and the solvent evaporated off. Recrystallization from H2O:EtOH gave 13 as a colorless solid
(0.6 g, 75% yield); mp 180–181°C (lit.12 185–186°C); [α]20 −28.8 (c 1, H2O); 1H NMR (D2O) (mixture
D
of two conformers) δ 2.08, 2.13 (3H, s, CH3), 2.30, 2.40 (1H, m, H3), 2.67, 2.80 (1H, m, H3), 3.75 (1H,
AB syst. J=15.7 and 3.1, H5), 4.03 (1H, AB syst. J=15.7, H5), 4.49, 4.60 (1H, t, H2), 5.58, 5.65 (1H, m,
H4), 7.55 (2H, t, Ar), 7.70 (1H, t, Ar), 8.05 (2H, d, Ar).
4.3. General procedure for reactions of 12 and 13 with 5
Acetic anhydride (30 mmol) was added dropwise, under nitrogen, to a stirred solution of 12 and 13 (10
mmol) in toluene (20 ml). The mixture was heated at 80°C for 1 h, and then a solution of 5 (10 mmol)
in toluene (10 ml) was added dropwise and the heating continued for 24–30 h. After evaporation of the
solvent, the residue was taken up in dichloromethane (50 ml) and the solution was washed with 10%
sodium bicarbonate and water. The organic phase was dried (Na2SO4) and the solvent evaporated off.
The crude mixture was separated by means of column chromatography (silica gel, toluene:ethyl acetate,
90:10). The products were recrystallized and identified by means of analytical and spectroscopic data.
4.4. (3S,4S,7R)-7-Acetyloxy-5-benzoyl-3-phenyl-2-(phenylsulfonyl)-2,5-diazaspiro[3.4]octan-1-one 15
Mp 165–167°C (iPrOH); [α]20 −51.46 (c 0.93, CHCl3); H NMR (CDCl3) δ 1.65 (1H, AB syst.
1
D
J=15.8 and 6.3, H8), 2.02 (3H, s, CH3), 2.25 (1H, AB syst. J=15.8 and 2.1, H8), 3.58 (1H, AB syst.
J=13.2, H6), 3.71 (1H, AB syst. J=13.2 and 5.3, H6), 4.87 (1H, m, H7), 5.55 (1H, s, H3), 7.1–7.7 (13H,
m, Ar), 8.05 (2H, d, Ar). Anal. calcd for C27H24N2O6S: C, 64.28; H, 4.76; N, 5.55. Found: C, 63.96; H,
4.55; N, 5.25.
4.5. (3R,4S,7R)-7-Acetyloxy-5-benzoyl-3-phenyl-2-(phenylsulfonyl)-2,5-diazaspiro[3.4]octan-1-one 16
Mp 186–187°C (iPrOH); [α]20 −4.67 (c 0.92, CHCl3); 1H NMR (CDCl3) δ 1.72 (3H, s, CH3), 2.07
D
(1H, AB syst. J=15.8 and 5.2, H8), 2.4 (1H, AB syst. J=15.8 and 7.3, H8), 3.5 (1H, AB syst. J=14.2 and
4.2, H6), 3.78 (1H, AB syst. J=14.2 and 6.8, H6), 5.03 (1H, m, H7), 5.60 (1H, s, H3), 7.3–7.7 (13H, m,
Ar), 7.98 (2H, d, Ar). Anal. calcd for C27H24N2O6S: C, 64.28; H, 4.76; N, 5.55. Found: C, 64.10; H,
4.65; N, 5.35.
4.6. (6R)-6-Acetyloxy-1,3-diphenyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole 17
Mp 183–184°C (iPrOH); [α]20 +9.38 (c 0.41, CHCl3); H NMR (CDCl3) δ 2.1 (3H, s, CH3), 3.22
1
D
(1H, AB syst. J=11.0, H7), 3.54 (1H, AB syst. J=11.0 and 5.9, H7), 4.23 (1H, AB syst. J=9.2, H5), 4.58
(1H, AB syst. J=9.2 and 3.7, H5), 5.9 (1H, m, H6), 7.2–7.6 (6H, m, Ar), 7.78 (2H, d, Ar), 7.87 (2H, d,
Ar). Anal. calcd for C20H18N2O2: C, 75.47; H, 5.66; N, 8.81. Found: C, 75.21; H, 5.55; N, 8.78.

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4.7. (3S,4S,7R)-5-Acetyl-7-benzoyloxy-3-phenyl-2-(phenylsulfonyl)-2,5-diazaspiro[3.4]octan-1-one 18
Mp 164–165°C (iPrOH); [α]20 +2.09 (c 0.67, CHCl3); H NMR (CDCl3) δ 2.1 (3H, s, CH3), 2.49
1
D
(2H, d, J=3.57, H8), 3.72 (1H, AB syst. J=11.73, H6), 3.92 (1H, AB syst. J=11.73 and 6.1, H6), 5.26 (1H,
m, H7), 5.51 (1H, s, H3), 7.0–7.7 (13H, m, Ar), 7.98 (2H, d, Ar). Anal. calcd for C27H24N2O6S: C, 64.28;
H, 4.76; N, 5.55. Found: C, 64.08; H, 4.73, N, 5.48.
4.8. (3R,4S,7R)-5-Acetyl-7-benzoyloxy-3-phenyl-2-(phenylsulfonyl)-2,5-diazaspiro[3.4]octan-1-one 19
Mp 205–207°C (iPrOH); [α]20 +88.98 (c .59, CHCl3); H NMR (CDCl3) δ 1.84 (1H, AB syst.
1
D
J=14.73 and 5.13, H8), 2.04 (3H, s, CH3), 2.34 (1H, AB syst. J=14.73 and 3.2, H8), 3.69 (1H, AB syst.
J=11.5 and 1.87, H6), 3.79 (1H, AB syst. J=11.5 and 4.5, H6), 5.18 (1H, m, H7), 5.58 (1H, s, H3), 7.3–7.7
(11H, m, Ar), 8.08 (2H, d, Ar), 8.13 (2H, d, Ar). Anal. calcd for C27H24N2O6S: C, 64.28; H, 4.76; N,
5.55. Found: C, 64.15; H, 4.68, N, 5.50.
Acknowledgements
The authors thank Dr. Alessandra Forni for the X-ray crystallography analyzes and Dr. Emanuela
Capaldi for her helpful technical assistance.
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