Enantioselective total syntheses of [6R,7R] and [6S,7S] tricyclic β-lactams

Article abstract of DOI:10.1021/jo951651u

The reaction of Ox-glycyl chloride with a chiral imine derived from the combination of D-(R)-glyceraldehyde acetonide and protected D-threonine afforded optically active, highly functionalized cis-substituted β-lactams 11 and 12. These β-lactams provide versatile intermediates for the syntheses of biologically important carbacephalosporins, isooxacephems, and other multicyclic β-lactams. Desilylation and oxidation of 12 with Dess-Martin periodinane followed by intramolecular cyclization produced a novel tricyclic β-lactam 17 and a 1-(hydroxymethyl)-O-2-isocephem 18 with [6R,7R] absolute configuration. Removal of the Ox protecting group and acylation of 17 in a one-pot reaction followed by saponification furnished the target salt 24. Alternatively, reaction of phthaloylglycyl chloride with the chiral imine derived from the combination of L-(S)-glyceraldehyde acetonide and protected D-threonine gave only one enantiomeric azetidinone 27 in high yield. Further manipulation of 27 provided a new tricyclic β-lactam 39 with [6S,7S] absolute configuration which satisfies the stereochemistry typically required for antibacterial activity. This synthetic procedure provides a short, versatile and enantioselective method of preparing polycyclic β-lactams. Biological testing of these tricyclic β-lactams indicated that salt 39 has potential inhibitory activity against four typical strains of bacteria.

Full text of DOI:10.1021/jo951651u

1014
J . Org. Chem. 1996, 61, 1014-1022
En a n tioselective Tota l Syn th eses of [6R,7R] a n d [6S,7S] Tr icyclic
â-La cta m s
Chuansheng Niu, Teresia Pettersson,† and Marvin J . Miller*
Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556
Received September 8, 1995X
The reaction of Ox-glycyl chloride with a chiral imine derived from the combination of D-(R)-
glyceraldehyde acetonide and protected D-threonine afforded optically active, highly functionalized
cis-substituted â-lactams 11 and 12. These â-lactams provide versatile intermediates for the
syntheses of biologically important carbacephalosporins, isooxacephems, and other multicyclic
â-lactams. Desilylation and oxidation of 12 with Dess-Martin periodinane followed by intramo-
lecular cyclization produced a novel tricyclic â-lactam 17 and a 1-(hydroxymethyl)-O-2-isocephem
18 with [6R,7R] absolute configuration. Removal of the Ox protecting group and acylation of 17 in
a one-pot reaction followed by saponification furnished the target salt 24. Alternatively, reaction
of phthaloylglycyl chloride with the chiral imine derived from the combination of L-(S)-glyceraldehyde
acetonide and protected D-threonine gave only one enantiomeric azetidinone 27 in high yield.
Further manipulation of 27 provided a new tricyclic â-lactam 39 with [6S,7S] absolute configuration
which satisfies the stereochemistry typically required for antibacterial activity. This synthetic
procedure provides a short, versatile and enantioselective method of preparing polycyclic â-lactams.
Biological testing of these tricyclic â-lactams indicated that salt 39 has potential inhibitory activity
against four typical strains of bacteria.
In tr od u ction
associated with a single enantiomer. Therefore, enan-
tioselective synthesis of â-lactams is of great interest to
organic and medicinal chemists. During the course of
design, syntheses, and study of novel â-lactams in our
laboratory, we sought to investigate approaches for
asymmetric syntheses of biologically important carba-
cephalosporins, isooxacephems, and other multicyclic
â-lactams in few overall steps. This paper describes a
short, versatile, and enantioselective method for synthe-
ses of polycyclic â-lactams and as a demonstration, we
report herein the asymmetric synthesis of two novel
tricyclic â-lactams.
For many years, the efforts of the organic synthetic
community have been directed toward searching for new
â-lactam antibiotics to meet the challenges of bacterial
resistance to existing drugs. O-2-Isocephems,1 a par-
ticular class of nuclear analogues of the cephalosporins,
are but one group of the many structural types of
â-lactams derived from extensive investigations. Struc-
ture-activity relationship studies of a series of O-2-
isocephems have revealed promise for this class as orally
absorbed antibiotics that exhibit comparable or better
activity against some common pathogenic bacteria rela-
tive to the analogous cephalosporins. Additionally, the
development of methodology for the preparation of mul-
ticyclic â-lactams has attracted considerable interest as
the syntheses of a number of novel multicyclic â-lactams
have been reported recently2 and some of these com-
pounds have potent biological activity.2,3
Resu lts a n d Discu ssion
One of the most direct routes to the â-lactam nucleus
involves the Staudinger (ketene + imine) reaction.4 The
Ox group (4,5-diphenyl-1-oxazolin-2-one) is a versatile
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J . Chem. Soc., Chem. Commun. 1994, 441. (b) Elliott, R. L.; Takle, A.
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Chem. Pharm. Bull. 1993, 41, 1885. (e) Schmidt, G.; Schro¨ck, W.;
Endermann, R. Bioorg. Med. Chem. Lett. 1993, 3, 2193. (f) Pitlik, J .;
Gunda, T. E.; Batta, G.; J eko, J . Bioorg. Med. Chem. Lett. 1993, 3,
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(3) For other biologically active tricyclic analogs, see: (a) Branch,
C. L.; Finch, S. C.; Pearson, M. J . J . Chem. Soc., Perkin Trans. 1 1985,
1491. (b) Pearson, M. J . J . Chem. Soc., Perkin Trans. 1 1981, 2544. (c)
Lammert, S. R.; Kukolja, S. J . Am. Chem. Soc. 1975, 97, 5583.
(4) (a) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; Chapter 6. (b)
Holden, K. G. In Chemistry and Biology of â-Lactam Antibiotics; Morin,
R. B., Gorman, M., Eds.; Academic: New York, 1982; Vol. 2, Chapter
2.
It is well-known that the biological activity of â-lactam
antibiotics and â-lactamase inhibitors most often is
† Visiting undergraduate research participant, Department of Chem-
istry, The Royal Institute of Technology, Stockholm, Sweden.
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) (a) Ishikawa, H.; Tsubouchi, H.; Yasumura, K. Bioorg. Med.
Chem. Lett. 1994, 4, 1147. (b) Tsubouchi, H.; Tsuji, K.; Yasumura, K.;
Tada, N.; Nishitani, S.; Minamikawa, J .; Ishikawa, H. Tetrahedron
Asymmetry 1994, 5, 441. (c) Nitta, H.; Hatanaka, M.; Ueda, I. J . Chem.
Soc., Perkin Trans. 1 1990, 432. (d) Mastalerz, H.; Menard, M.; Vinet,
V.; Desiderio, J .; Fung-Tomc, J .; Kessler, R.; Tsai, Y. J . Med. Chem.
1988, 31, 1190. (e) Natta, H.; Hatanaka, M.; Ishimaru, T. J . Chem.
Soc., Chem. Commun. 1987, 51. (f) Mastalerz, H.; Vinet, V. J . Chem.
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Chem. 1980, 58, 1605.
0022-3263/96/1961-1014$12.00/0 © 1996 American Chemical Society

Enantioselective Total Syntheses of Tricyclic â-Lactams
J . Org. Chem., Vol. 61, No. 3, 1996 1015
Sch em e 1
Sch em e 2
and convenient protecting group.5 It is very stable
toward hydrolysis under general acidic or basic condi-
tions, and Ox protected compounds tend to be crystalline,
highly fluorescent solids. Thus, Ox-glycyl chloride was
first chosen as the “ketene” component in this synthesis,
and its preparation is shown in Scheme 1. Reaction of
tetramethylammonium glycinate (1) with cyclic carbonate
2 gave Ox-glycine (3) in 60% yield.6 Treatment of 3 with
phosphorus pentachloride provided Ox-glycyl chloride 4
as a white crystalline solid in 89% yield.
D-(R)-Glyceraldehyde acetonide 6 has been extensively
used in the synthesis of natural products. Many of the
known methods7 for the preparation of D-(R)-glyceralde-
hyde acetonide (6) suffer from the use of hazardous
reagents [Pb(OAc)4], low yields, or inconvenient proce-
dures. We investigated the process and found that
oxidation of 1,2,5,6-di-O-isopropylidene-D-mannitol (5)
with 1.25-1.3 equiv of NaIO4 in a 3:1 mixture of
methylene chloride and buffer (0.05 M potassium phos-
phate monobasic-sodium hydroxide buffer, pH 7) for 20
min afforded the desired aldehyde 6 in 92% yield. This
solvent system (CH2Cl2 + buffer) is a key factor for the
successful oxidation, and other solvents led only to
diminished yields. The reaction has been performed
several times, reproducibly providing 6 cleanly and in
high yields (eq 1).
reaction with increased diastereoselectivity when the size
of the protecting group on the threonine hydroxyl group
was increased.9 We anticipated that by combining both
chiral threonine and D-(R)-glyceraldehyde in a single
imine, the Staudinger reaction would provide optically
active cis-â-lactams with high functionality. As illus-
trated in Scheme 2, acid-catalyzed esterification of D-
threonine (7) in methanol gave D-threonine methyl ester
hydrochloride (8)10 quantitatively. Silylation11 of 8 with
tert-butyldimethylsilyl chloride and imidazole in N,N-
dimethylformamide afforded O-silyl ether 9 in 94% yield.
Formation of chiral imine 10 was accomplished by
treatment of a mixture of 9 and D-(R)-glyceraldehyde
acetonide 6 with anhydrous magnesium sulfate. Subse-
quent annulation of 10 with Ox-glycyl chloride (4) in the
presence of triethylamine provided a 1:2.9 mixture of
diastereomeric â-lactams 11 and 12 in 61% yield, along
with amide 13 as a byproduct in 21% yield.12 Separation
of 11 and 12 by flash column chromatography or pre-
parative TLC was difficult. However, each pure enan-
tiomer 11 or 12 could be obtained by recrystallization
from a mixture of methylene chloride and hexanes. By
carefully adjusting the ratio of methylene chloride and
hexanes, â-lactam 12 was selectively crystallized.
Use of imines derived from D-(R)-glyceraldehyde in the
Staudinger reaction generally provides cis-â-lactams with
good diastereoselectivity.8 Threonine-derived imines also
have been shown to give cis-â-lactams in the Staudinger
Upon examination of the proton NMR, the stereochem-
istry of each diastereomer (11 and 12) was found to be
(8) (a) Palomo, C.; Cossio, F. P.; Ontoria, J . M.; Odriozola, J . M.
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K.; Manhas, M. S.; Van der Veen, J . M.; Bari, S. S.; Wagle, D. R.;
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1601. (b) See refs 1b and 1l. (c) Also see ref 8c. (d) Bose, A. K.; Manhas,
M. S.; Vincent, J . E.; Gala, K.; Fernandez, I. F. J . Org. Chem. 1982,
47, 4075.
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5b.
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L.; Prather, D. E.; Schantz, R. E.; Sear, N. L.; Vianco, C. S. J . Org.
Chem. 1991, 56, 4056. (b) Hertel, L. W.; Grossman, C. S.; Kroin, J . S.
Synth. Commun. 1991, 21, 151. (c) J ackson, D. Y. Synth. Commun.
1988, 18, 337. (d) Mikkilineni, A. B.; Kumar, P.; Abushanab, E. J . Org.
Chem. 1988, 53, 6005. (e) For a review, see: J urczak, J .; Pikul, S.;
Bauer, T. Tetrahedron 1986, 42, 447. (f) Schreiber, S. L.; Satake, K.
Tetrahedron Lett. 1986, 27, 2575. (g) Kierstead, R. W.; Faraone, A.;
Mennona, F.; Mullin, J .; Guthrie, R. W.; Crowley, H.; Simko, B.; Blaber,
L. C. J . Med. Chem. 1983, 26, 1561. (h) Barton, D. H. R.; Godfrey, C.
R. A.; Morzycki, J . W.; Motherwell, W. B.; Stobie, A. Tetrahedron Lett.
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42, 355.
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G.; van der Gen, A. J . Org. Chem. 1993, 58, 4315. (b) Corey, E. J .;
Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94, 6190.
(12) Niu, C. S.; Miller, M. J . Tetrahedron Lett. 1995, 36, 497.

1016 J . Org. Chem., Vol. 61, No. 3, 1996
Niu et al.
Sch em e 3
two unsaturated carbon peaks at 100.06 and 178.02 ppm.
This data indicates that compound 15 exists primarily
in the enolic form. Hydrolysis of 15 with dilute aqueous
hydrochloric acid in tetrahydrofuran afforded glycol 16
in 84% yield. Attempted cyclization of 16 by a Mitsunobu
reaction18 or TPP/I2 was unsuccessful. However, re-
19
fluxing 16 with p-toluenesulfonic acid in dry benzene for
1 h produced tricyclic â-lactam 17 in 31% yield. Fur-
thermore, refluxing acetonide 15 with 1 equiv of ferric
chloride20 in dry benzene for 20 min provided the same
product, tricyclic â-lactam 17, in 40% yield, along with a
bicyclic â-lactam, 1-(hydroxymethyl)-O-2-isocephem 18,
in 17% yield.
For antibacterial activity with â-lactam antibiotics, an
acylated amino function R to the â-lactam carbonyl and
a free carboxylic acid on the carbon atom adjacent to the
azetidinone nitrogen are required.21 To complete the
total synthesis of a tricyclic â-lactam suitable for biologi-
cal testing, our efforts at this point focused on removal
of the Ox protecting group, followed by acylation to
incorporate a biologically acceptable side chain and
finally hydrolysis of the methyl ester to produce a free
carboxylic acid or its sodium or potassium salt. It is
known that the Ox group can be removed by reductive,
oxidative, or photolytic processes.5b,22 These methods
have not been applied to highly functionalized â-lactams;
therefore, model studies were performed to explore
deprotection conditions. As outlined in Scheme 4, ir-
radiation of 12 in methanol (Pyrex flask) with a 275-W
sunlamp for 20 h gave a new compound. Its mass
spectrum showed m/e 634 as the molecular weight
corresponding to C34H42N2O8Si. Relative to the parent
compound 12 (C34H44N2O8Si), two protons were lost. The
proton NMR indicated that four aromatic protons had
shifted downfield. Thus, the compound was assigned
structure 19. Catalytic hydrogenolysis of 11 was then
tried using several catalysts, including 10% Pd/C, Pd
black, 10% Pt/C, or 20% Pd(OH)2/C23 in tetrahydrofuran,
methanol, ethyl acetate, or chloroform. The desired
deprotected product 20 was obtained in good yield by
hydrogenolysis over 10% Pd/C at 44 psi of hydrogen
pressure in methanol containing acetic acid. Subsequent
acylation of 20 with benzyl chloroformate, as a model
acylating agent, and sodium bicarbonate as base provided
compound 21.
cis with identical 5.4 Hz coupling constants for the C3-
C4 protons. The absolute configuration of each diaste-
reomer was determined by X-ray crystal structural
analysis and chemical degradation.12 These optically
active monocyclic â-lactams containing functionality at
both the â-lactam nitrogen and C-4 could be versatile
precursors to many classes of fused-ring â-lactams.
Although the stereochemistry about the â-lactam is
opposite that usually observed in biologically active
antibiotics, we initially intended to utilize the major
product 12 to demonstrate the utility of such highly
functionalized, yet readily available â-lactams, for the
asymmetric syntheses of the corresponding O-2-iso-
cephem derivatives.
As shown in Scheme 3, desilylation of 12 with 3 equiv
of trifluoroacetic acid in methylene chloride gave â-hy-
droxy ester 14 in 92% yield after column chromatogra-
phy. The oxidation of 14 to 15 proved to be troublesome.
Swern oxidation13 resulted in only recovery of the starting
material. Oxidation of 14 with PCC in methylene
chloride or with Brown’s oxidant14 was equally unsuc-
cessful. J ones oxidation15 gave the desired product 15
in low yields (10-19%). The problem was finally solved
by using Dess-Martin periodinane.16 Thus, â-hydroxy
ester 14 was treated with 1.4 equiv of Dess-Martin
periodinane in dry methylene chloride for 2 h, providing
15 in 72% yield.17 The proton NMR spectrum of 15
showed a broad peak at 12.27 ppm corresponding to an
enol hydroxy group, and its 13C NMR spectrum showed
(17) In this synthesis, Dess-Martin periodinane was prepared by
following the original procedure16a with improvement: Reaction of
potassium bromate (3.841 g, 0.023 mmol) with 2-iodobenzoic acid (4.216
g, 0.017 mol) gave 4.316 g (91%) of 1-hydroxy-1,2-benzodioxol-3(1H)-
one 1-oxide, which was suspended in Ac2O (14.776 g, 0.145 mol) and
glacial HOAc (11.876 g, 0.198 mol) and stirred at 85 °C. After 10 min,
the reaction mixture became homogeneous. The reaction was continued
for another 2.5 h at 85 °C and allowed to stand then stood overnight
at rt under N2, and the periodinane was crystallized. Filtration under
N2 and washing the crystals with anhydrous ether (3 × 7 mL) afforded
5.596 g (86%) of Dess-Martin periodinane: mp 132-134 °C (lit.16a mp
133-134 °C).
(18) (a) Hughes, D. L. Org. React. 1992, 42, 335. (b) Mitsunobu, O.
Synthesis 1981, 1.
(19) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604.
(20) Experiments and Techniques in Organic Chemistry; Pasto, D.
J ., J ohnson, C. R., Miller, M. J ., Eds.; Prentice-Hall: Englewood Cliffs,
NJ , 1992; p 504.
(13) For a review, see: Mancuso, A. J .; Swern, D. Synthesis 1981,
165.
(14) Brown, H. C.; Garg, C. P.; Liu, K.-T. J . Org. Chem. 1971, 36,
387.
(21) (a) Christensen, B. G.; Ratcliffe, R. W. Annu. Rep. Med. Chem.
1976, 11, 271. (b) Doyle, T. W.; Belleau, B.; Luh, B.-Y.; Ferrari, C. F.;
Cunningham, M. P. Can. J . Chem. 1977, 55, 468.
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Chem. Soc. 1953, 2548. (b) Bowden, K.; Heilbron, I. M.; J ones, E. R.
H.; Weedon, B. C. L. J . Chem. Soc. 1946, 39.
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R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(22) (a) Guziec, F. S., J r.; Tewes, E. T. J . Heterocycl. Chem. 1980,
17, 1807. (b) Miller, M. J .; Mattingly, P. G. Tetrahedron 1983, 39, 2563.
(c) Salituro, G. M.; Townsend, C. A. J . Am. Chem. Soc. 1990, 112, 760.
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M. Heterocycles 1988, 27, 1167.

Enantioselective Total Syntheses of Tricyclic â-Lactams
J . Org. Chem., Vol. 61, No. 3, 1996 1017
Sch em e 4
Sch em e 6
Sch em e 5
The model experiments revealed that use of methanol
containing a weak acid as solvent was necessary to effect
hydrogenolytic removal of the Ox group from a highly
functionalized â-lactam. Application of the same condi-
tions described above to tricyclic â-lactam 17 was at-
tempted but thwarted by solubility problems in methanol.
Further study of the solvents used in the deprotection
revealed that hydrogenolysis of 17 over 10% Pd/C in a
1:1:0.1 mixture of methanol/tetrahydrofuran/5% acetic
acid at 52 psi hydrogen pressure smoothly afforded 22.
Subsequent Schotten-Baumann acylation24 of crude 22
with phenylacetyl chloride gave the desired phenylac-
etamido compound 23 in 55% overall yield. Hydrolysis
of 23 with 1 equiv of potassium hydroxide in a 1:1
mixture of tetrahydrofuran and water provided the
corresponding potassium salt 24, with [6R,7R] absolute
configuration, in 81% yield (Scheme 5).
which has the correct absolute configuration usually
required for antibacterial activity.
The synthesis of chiral â-lactams with complete dias-
tereoselectivity has been achieved by the cycloaddition
of acid chlorides with imines derived from L-(S)-glycer-
aldehyde and cis â-lactams with [3S,4S] absolute con-
figuration were obtained in high optical yields by the
Roche group.25 Therefore, L-(S)-glyceraldehyde ace-
tonide26 in our synthetic strategy was chosen as the chiral
aldehyde component to prepare the imine and phtha-
loylglycyl chloride27 was used as the ketene precursor to
determine if it would have any advantages over the use
of the Ox-protected glycine derivative 4. As shown in
Scheme 6, starting from protected D-threonine 9 and
L-(S)-glyceraldehyde acetonide 25, chiral imine 26 was
synthesized in quantitative yield. Subsequent reaction
of imine 26 with N-phthaloylglycyl chloride derived from
N-phthaloylglycine in the presence of triethylamine gave
Based on the successful synthesis of [6R,7R]-tricyclic
â-lactam 24 described above, we next turned our atten-
tion to the synthesis of the [6S,7S]-tricyclic â-lactam 39
(25) (a) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66,
2206. (b) Hubschwerlen, C.; Specklin, J .-L. Org. Synth. 1993, 72, 14.
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W. J . Org. Chem. 1971, 36, 1259.

1018 J . Org. Chem., Vol. 61, No. 3, 1996
Niu et al.
Sch em e 7
desired cis â-lactam 27 in 90% yield, along with amide
28 as a minor byproduct in 8% yield. The excellent yield
of 27 as a single diastereomer represented a significant
improvement over the related reaction of 4 with 10 which
gave a lower yield of a mixture of diastereomers 11 and
12. Desilylation of 27 with TBAF led to decomposition
of the starting material, and no desired product could be
detected. Treatment of 27 with 3 equiv of trifluoroacetic
acid smoothly gave free hydroxy compound 29. This
deprotection was sensitive to the temperature of the
reaction. When the reaction was carried out at rt for 1
h, desired product 29, contaminated with the deacetonide
byproduct, was isolated in a ratio of 3.6:1 as determined
by proton NMR. Reducing the temperature to 0 °C and
increasing the reaction time to 8 h gave the mixture in
nearly the same ratio. However, when the reaction was
run at 14 °C, desilylation gave 29 in 87% yield along with
a trace of byproduct. Conversion of 29 to enol ester 30
was accomplished in 90% yield by oxidation of 29 with
1.7 equiv of Dess-Martin periodinane in dry methylene
chloride. Deprotection of acetonide 30 with 1 N HCl in
THF gave glycol 31 in 50% yield. TLC analysis showed
the existence of decomposed material on the baseline.
Alternatively, refluxing acetonide 30 with p-toluene-
sulfonic acid in a 1:1 mixture of THF and H2O enhanced
the yield of 31 from 50% to 87%.
Sch em e 8
To construct the fused-ring â-lactams, the previous
procedure described for the preparation of 17 and 18 was
first followed. Acetonide 30 was refluxed with p-tolu-
enesulfonic acid in benzene leading to decomposition. Use
of ferric chloride instead of p-toluenesulfonic acid gave
tricyclic â-lactam 32 in only 12% yield and 1-hydroxy-
O-2-isocephem 33 in 4% yield. To improve the yields,
we then chose glycol 31 as the substrate, and the
cyclization was attempted under a variety of reaction
conditions. Refluxing 31 with 1 equiv of p-toluenesulfonic
acid and excess silica gel (EM Science, 230-400 mesh
ASTM, SiO2/31 ) 6/1) as a dehydration agent in dry
benzene produced â-lactams 32 and 33 in 48% and 17%
yield, respectively. It is worth noting that both compound
32 and 33 decomposed partly on silica gel during at-
tempted standard flash chromatographic separation;
therefore, it was necessary to use a short column for the
isolation in order to minimize decomposition and obtain
good yields.
With tricyclic â-lactam 32 in hand, it was possible at
this point to attempt the removal of the phthalimido
protecting group and attach a biologically active side
chain. Ing-Manske’s hydrazinolysis28 of N-substituted
phthalimides is often effective for removal of the phthal-
imido protecting groups and is used extensively in organic
synthesis, but sometimes it was ineffective with phthal-
imido-containing penicillins and ∆3-cephalosporins29 due
to the lack of selectivity. To observe the competitive
effect of hydrazine on a highly functionalized â-lactam,
a model study, shown in Scheme 7, was performed to
explore the deprotection conditions. Interestingly, treat-
ment of monocyclic â-lactam 27 with 1 equiv of hydrazine
in methanol for 4 h at rt and then in methylene chloride
for several days released the free amino compound 34
without destruction of the methyl ester or azetidinone
ring. This deprotection selectivity might be attributed
to the steric effect of the O-TBDMS function. Subsequent
Schotten-Baumann acylation of crude 34 with phenyl-
acetyl chloride produced the desired phenylacetamido
product 35 in 52% overall yield. Hydrolysis of methyl
ester 35 with 1 equiv of potassium hydroxide provided a
new product. Proton NMR analysis showed that the
O-silyl functional group was eliminated, and an olefin
proton appeared as a quartet at 6.53 ppm. High resolu-
tion mass spectral analysis gave m/e 426 as the molecular
ion corresponding to C20H23N2O6K allowing assignment
of the new product as structure 36.
Application of the model deprotection conditions to
tricyclic â-lactam 32 is outlined in Scheme 8. The free
amino compound 37 was prepared by treatment of
tricyclic â-lactam 32 with 1 equiv of hydrazine in a 1:1
mixture of methanol and methylene chloride at rt for 3
h, followed by refluxing in methylene chloride for 48 h
and stirring for an additional 48 h at rt. Acylation of 37
in situ with phenylacetyl chloride and sodium bicarbon-
ate gave 7-phenylacetamido tricyclic â-lactam 38 in 60%
overall yield. Subsequent hydrolysis of 38 with 1 equiv
of potassium hydroxide in a mixture of tetrahydrofuran
and water provided target compound 39 in 93% yield.
St er eoch em ist r y of Tr icyclic â-La ct a m s 17 a n d
32. The configuration at C-3 and C-4 of tricyclic â-lac-
1
tams 17 and 32 was determined by H NMR and NOE
experiments (Figure 1). When H6 of 17 was irradiated,
H7, H1, and H2a were enhanced ca. 23%, 7%, and 12%,
respectively, but no enhancement of H4 could be observed.
The R-orientation of H4 was therefore determined. The
same orientation of the methyl group on C-3 was unam-
biguously determined, since ca. 29% enhancement was
observed for H4 when the methyl was irradiated. There-
fore, 17 possesses the 1S,3R,4S,6R,7R configuration.
(28) Ing, H. R.; Manske, R. H. F. J . Chem. Soc. 1926, 2348.
(29) (a) Sheehan, J . C.; Cruickshank, P. A. J . Am. Chem. Soc. 1956,
78, 3677, 3680, 3683. (b) Spry, D. O. J . Am. Chem. Soc. 1970, 92, 5006.
(c) Lammert, S. R.; Kukolja, S. J . Am. Chem. Soc. 1975, 97, 5582.

Enantioselective Total Syntheses of Tricyclic â-Lactams
J . Org. Chem., Vol. 61, No. 3, 1996 1019
crude solid, which was recrystallized from benzene and hex-
anes to yield 3.343 g (89%) of 4 as a crystalline solid: mp 108-
110 °C; IR (KBr) 1792, 1760, 1600, 1500, 1375 cm-1; 1H NMR
(CDCl3) δ 4.57 (s, 2H), 7.1-7.6 (m, 10H); 13C NMR (CDCl3) δ
51.7, 122.0, 124.4, 125.7, 126.9, 128.1, 128.4, 129.8, 130.2,
130.7, 135.3, 153.7, 169.5; MS(CI) m/z 314 (MH+).
2,3-O-Isop r op ylid en e-D-glycer a ld eh yd e (6). To a solu-
tion of 1,2,5,6-di-O-isopropylidene-D-mannitol (5) (1.049 g, 4
mmol) in CH2Cl2 (6 mL) was added dropwise a suspension of
NaIO4 (1.07 g, 5 mmol) in 2 mL of buffer solution (0.05 M Na2-
HPO3-NaOH, pH 7) over a period of 10 min. The mixture
was stirred for an additional 10 min at rt under N2. TLC
analysis indicated the reaction was complete. Na2SO4 was
added and filtered, and the slurry residue was washed several
times with CH2Cl2. The combined filtrate and washes were
dried over anhydrous Na2SO4. Filtration and evaporation of
the solvent gave 0.953 g (92%) of clean product 6 as a colorless
oil: [R]23 +54.5° (c 2.7, C6H6) [lit.7c [R]23 +63.3° (c 1.25,
F igu r e 1.
Also, irradiation of H6 of 32 enhanced H7 and H1 ca. 30%
and 7%, respectively, but no enhancement was observed
for H4. The â-orientation of H4 was then determined.
Irradiating the methyl on C-3 led to a 28% enhancement
of H4, which indicated that the methyl on C-3 has the
same orientation as H4. Hence 32 possesses the 1R,3S,
4R,6S,7S configuration.
Biologica l Activity of 39. Monocyclic â-lactam 36
and enantiomeric tricyclic â-lactams 24 and 39 were
tested for their antibacterial activity in vitro. Of these
compounds, 39 exhibited significant inhibitory activity
against Streptococcus pneumoniae (MIC 0.25 µg/mL) and
moderate inhibitory activity against Streptococcus pyo-
genes (MIC 2 µg/mL), Moraxella catarrhalis (MIC 8 µg/
mL), and Staphylococcus aureus (MIC 32 µg/mL). As
expected, 24, the “unnatural” enantiomer of 39, was
inactive against the same organisms.
D
D
C6H6)]; IR (neat) 2805, 1735 cm-1; 1H NMR (CDCl3) δ 1.43 (s,
3H), 1.49 (s, 3H), 4.15 (m, 2H), 4.39 (m, 1H), 9.73 (d, 1H, J )
1.9 Hz); HRMS(CI) calcd for C6H11O3 131.0708, found 131.0707.
O-(ter t-Bu tyld im eth ylsilyl)-D-th r eon in e Meth yl Ester
(9). To a mixture of D-threonine methyl ester hydrochloride
(8) (7.10 g, 0.042 mol)10 and imidazole (9.395 g, 0.138 mol) in
dry DMF (30 mL) cooled to 0 °C was added TBDMSCl (6.981
g, 0.045 mol). The mixture was stirred for 30 min at 0 °C
under N2 and then allowed to warm to rt overnight. To this
was added water (200 mL), and the mixture was extracted with
ether (4 × 40 mL). The combined extracts were washed with
H2O (2 × 40 mL) and brine (40 mL) and dried over anhydrous
Na2SO4. After filtration and evaporation of the solvent, the
residue was purified by flash column chromatography on silica
gel, eluting with CH2Cl2-EtOAc (3:1) to give 9.829 g (94%) of
9 as a pale yellow oil: [R]23 +18.5° (c 1.3, CHCl3); IR (neat)
D
3390, 3320, 1740, 1250, 1075, 835 cm-1; H NMR (CDCl3) δ
1
Con clu sion
0.01 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H), 1.26 (d, 3H, J ) 6.3
Hz), 1.62 (br, 2H), 3.29 (d, 1H, J ) 2.7 Hz), 3.72 (s, 3H), 4.35
(dq, 1H, J ) 2.7, 6.3 Hz); 13C NMR (CDCl3) δ -5.7, -4.8, 17.4,
A short, efficient, and enantioselective method of
preparing multicyclic â-lactams has been developed. The
synthetic procedure described here has successfully
produced two enantiomeric tricyclic â-lactams. Starting
from the Staudinger [2 + 2] cycloaddition of Ox-glycyl
chloride with D-(R)-glyceraldehyde-derived imine or of
phthaloylglycyl chloride with an optically active imine
derived from a combination of L-(S)-glyceraldehyde and
a D-threonine derivative, the asymmetric total syntheses
of novel tricyclic â-lactams 24 and 39 were accomplished
in only six and seven steps, respectively. Through the
use of the versatile intermediates 11, 12, and 27 which
have multiple functional groups attached to both the
â-lactam nitrogen atom and the C-4 position, a number
of bicyclic and polycyclic â-lactams may be created in
relatively few steps. In addition, biological testing for
these tricyclic â-lactams has demonstrated the potential
possibility for this class as new members of the â-lactam
antibiotic family.
20.4, 25.2, 51.4, 60.1, 69.0, 174.3; HRMS(CI) calcd for C11H26
NO3Si 248.1682, found 248.1678.
-
Im in e 10. A stirred solution of 9 (5.930 g, 0.024 mol) in
dry CH2Cl2 (100 mL) was treated with MgSO4 (9.268 g, 0.077
mol) at 0 °C under N2. To this was added dropwise a solution
of D-glyceraldehyde acetonide (6) (3.120 g, 0.024 mol) in dry
CH2Cl2 (15 mL). The reaction mixture was stirred for 4 h at
0 °C and then filtered, and the solvent was removed to give
crude imine 10, which was used in next step without further
purification.
(3S,4S)- a n d (3R,4R)-1-[1(R)-(Meth oxyca r bon yl)-2(S)-
O-[(ter t-bu tyldim eth ylsilyl)oxy]pr opyl]-3-(2-oxo-4,5-diph e-
n yl-1-oxa zolin yl)-4-[(S)-2,2-d im et h yl-1,3-d ioxola n -4-yl]-
a zetid in -2-on e (11 a n d 12). To a solution of 10 (6.821 g,
0.019 mol) in dry CH2Cl2 (170 mL) at -18 °C was added TEA
(2.327 g, 0.023 mol), followed by a solution of Ox-glycyl chloride
(4) (5.347 g, 0.017 mol) in dry CH2Cl2 (30 mL) over a period of
20 min under N2. The mixture was stirred for 2 h at the same
temperature and then allowed to warm to 0 °C for 30 min.
The reaction mixture was then washed with 5% citric acid
solution (2 × 50 mL), saturated NaHCO3 solution (50 mL),
H2O (50 mL), and brine (50 mL), dried (Na2SO4), filtered, and
concentrated. Isolation by flash column chromatography on
silica gel (CH2Cl2-EtOAc, 20:1) gave a mixture of 11 and 12
(6.598 g, 61%). Recrystallization of the mixture from CH2Cl2/
hexanes afforded separate crops of pure 11 and 12 in a ratio
Exp er im en ta l Section
Gen er a l Meth od s. Instruments and standard methods
used have been described previously.30 Solvents used in
synthetic work were dried, when necessary, by standard
methods.31 Flash column chromatography was conducted on
silica gel 60 (EM Science, 230-400 mesh ASTM). Analytical
and preparative TLC was performed using commercially
available aluminum-backed 0.2-mm silica gel 60 F254 plates
(EM SEPARATIONS).
of about 1:2.9. 11: mp 71-73 °C; [R]21 -10.7° (c 1.0, CH2-
D
1
Cl2); IR (KBr) 1775, 1765, 1600, 1500 cm-1; H NMR (CDCl3)
δ 0.05 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 1.26 (s, 3H), 1.40 (d,
3H, J ) 7.5 Hz), 1.42 (s, 3H), 3.73 (s, 3H), 3.95 (dd, 1H, J )
6.0, 8.8 Hz), 4.25 (dd, 1H, J ) 6.0, 8.8 Hz), 4.48 (dd, 1H, J )
Ox-glycyl Ch lor id e (4). Ox-glycine (3)6 (3.540 g, 0.012
mol) and PCl5 (2.499 g, 0.012 mol) in dry benzene (24 mL) were
heated for 2 h at 65 °C (bath temperature) with stirring. The
solvent was then removed under reduced pressure to give a
5.4, 9.3 Hz), 4.53 (m, 2H), 4.71 (m, 2H), 7.2-7.6 (m, 10H); 13
C
NMR (CDCl3) δ -4.6, -4.5, 18.2, 20.6, 24.9, 26.0, 26.7, 52.2,
60.0, 60.8, 63.2, 68.9, 69.9, 74.7, 109.0, 123.5, 124.5, 126.5,
127.7, 127.8, 128.4, 129.4, 130.2, 130.8, 134.9, 154.0, 165.8,
168.9; HRMS(FAB) calcd for C34H45N2O8Si 637.2945, found
(30) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548.
(31) Purification of Laboratory Chemicals, 2nd ed.; Perrin, D. D.,
Armarego, W. L. F., Perrin, D. R., Eds.; Pergamon: New York, 1980.
637.2925. 12: mp 198-199 °C; [R]21 +5.1° (c 1.0, CH2Cl2);
D
IR (KBr) 1785, 1770, 1750, 1600, 1500, 1145, 1060 cm-1; H
1

1020 J . Org. Chem., Vol. 61, No. 3, 1996
Niu et al.
NMR (CDCl3) δ 0.00 (s, 3H), 0.06 (s, 3H), 0.81 (s, 9H), 1.29 (s,
3H), 1.30 (d, 3H, J ) 6.3 Hz), 1.34 (s, 3H), 3.64 (dd, 1H, J )
6.8, 8.3 Hz), 3.71 (s, 3H), 3.86 (dd, 1H, J ) 5.6, 8.5 Hz), 3.97
(dd, 1H, J ) 6.8, 8.3 Hz), 4.31 (d, 1H, J ) 5.1 Hz), 4.51 (m,
1H), 4.67 (d, 1H, J ) 5.4 Hz), 4.79 (m, 1H), 7.1-7.6 (m, 10H);
13C NMR (CDCl3) δ -5.1, -4.1, 17.7, 21.1, 24.7, 25.5, 26.3, 52.1,
57.8, 62.4, 65.7, 67.3, 74.6, 109.5, 122.5, 124.5, 125.8, 127.0,
128.2, 128.4, 129.9, 130.6, 130.6, 135.7, 153.0, 162.3, 168.8;
HRMS(FAB) calcd for C34H45N2O8Si 637.2945, found 637.2940.
Anal. Calcd for C34H44N2O8Si: C, 64.12; H, 6.97; N, 4.40.
Found: C, 63.95; H, 6.91; N, 4.29.
was refluxed for 1 h using a Dean-Stark apparatus. The
reaction mixture was then cooled to 0 °C, and saturated
NaHCO3 solution (2 mL) was added. After the mixture was
stirred for 5 min, EtOAc (8 mL) was added. The organic layer
was separated and washed with saturated NaHCO3 (3 mL),
H2O (3 mL), and brine (3 mL), dried (Na2SO4), filtered, and
concentrated. Isolation by preparative TLC (CH2Cl2-acetone,
20:0.8) gave 10 mg (31%) of 17 as a white solid: mp 271-273
°C. Anal. Calcd for C25H22N2O7: C, 64.92; H, 4.80; N, 6.06.
Found: C, 65.05; H, 4.70; N, 6.06.
Meth od B. A mixture of acetonide 15 (104 mg, 0.2 mmol)
and ferric chloride (33 mg, 0.2 mmol) in dry benzene (4 mL)
was refluxed for 20 min under argon and then cooled to 0 °C,
and 10% aqueous NaHCO3 solution (2 mL) was added. After
stirring for 3 min, the organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined
organic layers were washed with H2O and brine, dried over
anhydrous Na2SO4, filtered, and concentrated. Isolation by
flash column chromatography on silica gel (CH2Cl2-THF, 20:
0.5) gave 37 mg (40%) of 17 as a white solid and 16 mg (17%)
(3R,4R)-1-[1(R)-(Met h oxyca r b on yl)-2(S)-h yd r oxyp r o-
pyl]-3-(2-oxo-4,5-diph en yl-1-oxazolin yl)-4-[(S)-2,2-dim eth yl-
1,3-d ioxola n -4-yl]a zetid in -2-on e (14). To a solution of 12
(636 mg, 1 mmol) in of CH2Cl2 (14 mL) was added trifluoro-
acetic acid (342 mg, 3 mmol). The solution was stirred for 1.5
h at rt and then diluted with CH2Cl2 (10 mL), washed with
10% aqueous NaHCO3 solution (2 × 8 mL) and brine (10 mL),
dried (Na2SO4), filtered, and concentrated. Isolation by flash
column chromatography on silica gel (CH2Cl2-EtOAc, 19:1)
gave 480 mg (92%) of 14 as a white solid: mp 162-163 °C;
of 18 as a pale yellow solid. 17: mp 273-275 °C; [R]23
D
[R]23 -3.8° (c 0.5, CH2Cl2); IR (KBr) 3400, 1765, 1600, 1500,
-130.7° (c 0.45, CHCl3); IR (KBr) 1780, 1770, 1735 cm-1; H
1
D
1065 cm-1; H NMR (CDCl3) δ 1.32 (s, 3H), 1.37 (s, 3H), 1.49
NMR (CDCl3) δ 1.75 (s, 3H,), 3.61 (d, 1H, J ) 5.0 Hz), 3.73 (s,
3H), 3.81 (d, 1H, J ) 7.5 Hz), 3.89 (dd, 1H, J ) 4.4, 7.5 Hz),
4.62 (s, 1H), 4.76 (d, 1H, J ) 4.4 Hz), 4.94 (d, 1H, J ) 5.0 Hz),
7.2-7.6 (m, 10H); 13C NMR (CDCl3) δ 23.1, 52.5, 55.3, 61.2,
63.2, 69.5, 70.4, 105.1, 122.7, 124.6, 126.3, 127.1, 128.3, 128.5,
129.9, 130.6, 130.7, 135.6, 152.3, 165.8, 167.8; HRMS(FAB)
calcd for C25H23N2O7 463.1505, found 463.1484. 18: mp 125-
127 °C; [R]23D -57.6° (c 0.5, CHCl3); IR (KBr) 3450, 1760, 1720,
1
(d, 3H, J ) 6.3 Hz), 3.51 (dd, 1H, J ) 6.4, 8.2 Hz), 3.72 (dd,
1H, J ) 5.4, 9.4 Hz), 3.77 (s, 3H), 3.99 (dd, 1H, J ) 6.5, 8.2
Hz), 4.32 (d, 1H, J ) 3.0 Hz), 4.45 (m, 1H), 4.74 (m, 1H), 4.80
(d, 1H, J ) 5.3 Hz), 7.2-7.7 (m, 10 H); 13C NMR (CDCl3) δ
20.3, 25.1, 26.7, 52.8, 56.6, 61.70 65.7, 66.1, 67.3, 75.2, 110.1,
122.2, 124.6, 125.5, 126.8, 128.4, 128.6, 130.2, 130.5, 131.0,
136.1, 153.2, 163.9, 169.1; HRMS(FAB) calcd for C28H31N2O8
523.2080, found 523.2090. Anal. Calcd for C28H30N2O8: C,
64.34; H, 5.79; N, 5.36. Found: C, 64.15; H, 5.90; N, 5.33.
(3R,4R)-1-[1(R)-(Meth oxyca r bon yl)-2(S)-h yd r oxyp r op -
1-en yl]-3-(2-oxo-4,5-d ip h en yl-1-oxa zolin yl)-4-[(S)-2,2-d i-
m eth yl-1,3-d ioxola n -4-yl]a zetid in -2-on e (15). A solution
of 14 (347 mg, 0.66 mmol) in dry CH2Cl2 (3 mL) was added to
a stirred solution of Dess-Martin reagent16,17 (381 mg, 0.9
mmol) in dry CH2Cl2 (7 mL). The reaction mixture was stirred
for 2 h at rt under N2 and then added to CH2Cl2 (10 mL) and
a saturated NaHCO3 (5 mL) solution containing saturated
Na2S2O3 (1 mL) solution. The mixture was stirred for 5 min.
The organic layer was separated and washed with H2O (5 mL)
and brine (5 mL), dried (Na2SO4), filtered, and concentrated.
Isolation by flash column chromatography on silica gel (CH2-
Cl2-EtOAc, 19:1) gave 250 mg (72%) of 15 as a white solid:
1620, 1500 cm-1 1H NMR (CDCl3) δ 2.29 (s, 3H), 3.73 (dd,
;
1H, J ) 5.1, 8.8 Hz), 3.80 (s, 3H), 3.93 (m, 2H), 4.86 (m, 1H),
5.02 (d, 1H, J ) 5.1 Hz), 7.2-7.6 (m, 10H); 13C NMR (CDCl3)
δ 18.0, 51.2, 51.9, 61.2, 61.9, 75.0, 106.0, 123.1, 124.6, 126.1,
127.1, 128.3, 128.6, 130.0, 130.6, 130.7, 135.8, 153.8, 156.2,
160.5, 163.1; HRMS(FAB) calcd for C25H23N2O7 463.1505,
found 463.1506.
P h otooxid a tion of Com p ou n d 12. A methanolic (1 mL)
solution of 12 (10 mg, 0.016 mmol) in a Pyrex flask was
irradiated with a 275-W sunlamp for 20 h. The solvent was
removed, and the residue was purified by preparative TLC
(hexanes-EtOAc, 6:4) to give 4 mg (40%) of 19 as a yellowish,
viscous oil: IR (neat) 1780, 1750 cm-1; 1H NMR (CDCl3) δ 0.16
(s, 3H), 0.18 (s, 3H), 0.95 (s, 9H), 1.17 (s, 3H), 1.22 (s, 3H),
1.45 (d, 3H, J ) 6.0 Hz), 3.69 (m, 2H), 3.81 (s, 3H), 4.42 (dd,
1H, J ) 5.4, 8.4 Hz), 4.52 (d, 1H, J ) 5.0 Hz), 4.74 (m, 2H),
5.88 (d, 1H, J ) 5.3 Hz), 7.72 (m, 4H), 8.03 (m, 1H), 8.13 (m,
1H), 8.70 (m, 1H), 8.85 (m, 1H); 13C NMR (CDCl3) δ -4.8, -4.0,
17.9, 21.4, 24.4, 25.8, 26.1, 52.3, 60.9, 61.9, 62.4, 65.6, 67.6,
75.0, 109.6, 119.6, 120.3, 120.3, 120.6, 123.2, 124.8, 126.0,
126.5, 127.6, 127.7, 128.0, 128.6, 128.8, 136.2, 153.9, 161.8,
169.0; HRMS(FAB) calcd for C34H43N2O8Si 635.2789, found
635.2752.
(3S,4S)-1-[1(R )-(Me t h oxyca r b on yl)-2(S)-O-[(t er t -b u -
tyld im eth ylsilyl)oxy]p r op yl]-3-[N-(ca r boben zyloxy)a m i-
n o]-4-[(S)-2,2-d im et h yl-1,3-d ioxola n -4-yl]a zet id in -2-on e
(21). â-Lactam 11 (10 mg, 0.016 mmol) was dissolved in
methanol (1 mL) containing 1 drop of glacial HOAc and
hydrogenated over 10% Pd/C (3 mg) at 44 psi hydrogen
pressure for 24 h. The reaction mixture was filtered through
Celite and the solvent removed. The crude products containing
20 and bibenzyl were used directly in the following acylation
step without further purification.
mp 95-97 °C; [R]23 +16.2° (c 0.45, CH2Cl2); IR (KBr) 3420,
D
1785, 1765, 1655, 1620, 1500 cm-1; H NMR (CDCl3) δ 1.29
1
(s, 3H), 1.32 (s, 3H), 2.33 (s, 3H), 3.53 (dd, 1H, J ) 5.9, 8.2
Hz), 3.73 (s, 3H), 3.91 (dd, 1H, J ) 5.6, 9.4 Hz), 3.99 (dd, 1H,
J ) 6.4, 8.2 Hz), 4.72 (d, 1H, J ) 5.6 Hz), 4.78 (m, 1H), 7.2-
7.7 (m, 10H), 12.27 (br, 1H); 13C NMR (CDCl3) δ 18.5, 25.1,
26.7, 52.0, 57.9, 63.5, 66.3, 74.6, 100.1, 110.0, 122.3, 124.6,
125.7, 126.8, 128.4, 128.6, 130.1, 130.7, 130.9, 136.2, 153.4,
163.0, 169.6, 178.0; HRMS(EI) calcd for C28H28N2O8 520.1845,
found 520.1832.
(3R,4R)-1-[1(R)-(Meth oxyca r bon yl)-2(S)-h yd r oxyp r op -
1-en yl]-3-(2-oxo-4,5-d ip h en yl-1-oxa zolin yl)-4-[(S)-1,2-d i-
h yd r oxyeth yl]a zetid in -2-on e (16). To a solution of 15 (80
mg, 0.154 mmol) in THF (3 mL) was added 1 N HCl (3 mL).
The mixture was stirred for 3 d at rt under N2. The solvent
was then removed under reduced pressure, and the residue
was isolated by flash column chromatography on silica gel
(CH2Cl2-CH3OH, 20:1) to yield 62 mg (84%) of 16 as a white
solid: mp 109-111 °C; [R]23D +25.1° (c 0.33, CHCl3); IR (KBr)
3450, 1760, 1655, 1500 cm-1; 1H NMR (CDCl3) δ 2.34 (s, 3H),
3.55 (dd, 1H, J ) 5.3, 11.4 Hz), 3.69 (dd, 1H, J ) 3.5, 11.4
Hz), 3.75 (s, 3H), 4.19 (t, 1H, J ) 5.6 Hz), 4.27 (m, 1H), 4.73
(d, 1H, J ) 5.6 Hz), 7.2-7.6 (m, 10H), 12.24 (br, 1H); 13C NMR
(CDCl3) δ 18.8, 52.2, 58.7, 61.6, 64.6, 69.4, 100.5, 123.0, 124.7,
125.7, 126.8, 128.5, 128.6, 130.0, 130.6, 130.8, 136.3, 154.3,
163.0, 169.6, 177.3; HRMS(FAB) calcd for C25H25N2O8 481.1611,
found 481,1606.
To a solution of the crude product 20 prepared above in THF
(0.5 mL) and H2O (0.4 mL) was added solid NaHCO3 (2 mg,
0.023 mmol) followed by addition of benzyl chloroformate (3.5
µL, 0.023 mmol). The mixture was stirred in an ice bath for
30 min. H2O (1 mL) was added and extracted with CH2Cl2 (3
× 1 mL). The combined organic layers were washed with brine
(1 mL), dried (Na2SO4), filtered, and concentrated. Isolation
by preparative TLC (CH2Cl2-acetone, 20:0.8) gave 2 mg (23%)
1
of 21: IR (neat) 1780, 1740 cm-1; H NMR (CDCl3) δ 0.05 (s,
[1S,3R,4S,6R,7R]-Tr icyclic â-La cta m (17) a n d (1S,6R,
7R)-1-(Hyd r oxym eth yl)-O-2-isocep h em (18). Meth od A.
A solution of 16 (33 mg, 0.069 mmol) and p-toluenesulfonic
acid monohydrate (11 mg, 0.058 mmol) in dry benzene (3 mL)
3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.25 (s, 3H), 1.33 (d, 3H, J )
6.5 Hz), 1.51 (s, 3H), 3.61 (dd, 1H, J ) 7.9, 9.1 Hz), 3.73 (s,
3H), 3.91 (t, 1H, J ) 7.6 Hz), 4.33 (dd, 1H, J ) 1.4, 5.6 Hz),
4.52 (d, 1H, J ) 2.4 Hz), 4.55 (m, 1H), 5.11 (m, 1H), 5.14 (s,

Enantioselective Total Syntheses of Tricyclic â-Lactams
J . Org. Chem., Vol. 61, No. 3, 1996 1021
2H), 5.48 (dd, 1H, J ) 5.6, 10.7 Hz), 5.94 (d, 1H, J ) 10.7 Hz),
7.33 (m, 5H); MS(FAB) m/z 551 (MH+), 493, 360, 159, 149, 91
(100%); HRMS(FAB) calcd for C27H43N2O8Si 551.2789, found
551.2787.
with H2O (70 mL), 10% NaHCO3 solution (70 mL), and brine
(70 mL), dried (Na2SO4), filtered, and concentrated. Isolation
by flash column chromatography on silica gel (CH2Cl2-THF,
20:1) gave 1.503 g (87%) of 29 as a white solid: mp 72-73 °C;
[R]22D -7.0° (c 1.0, CHCl3); IR (KBr) 1770, 1720 cm-1; 1H NMR
(CDCl3) δ 1.29 (s, 3H), 1.42 (s, 3H), 1.44 (d, 3H, J ) 6.6 Hz),
3.51 (dd, 1H, J ) 5.8, 8.6 Hz), 3.73 (dd, 1H, J ) 6.2, 8.6 Hz),
3.83 (s, 3H), 4.55 (m, 5H), 5.57 (d, 1H, J ) 5.3 Hz), 7.7-8.0
(m, 4H); 13C NMR (CDCl3) δ 20.2, 25.1, 26.3, 52.5, 54.8, 62.7,
63.0, 66.0, 67.3, 75.5, 110.5, 124.1, 131.2, 134.9, 166.2, 167.0,
169.2; HRMS(FAB) calcd for C21H24N2O8 433.1611, found
433.1609.
[1S,3R,4S,6R,7R]-7-P h en yla ceta m id o Tr icyclic â-La c-
ta m 23. Compound 17 (51 mg, 0.11 mmol) was dissolved in a
mixture of CH3OH-THF-5% HOAc (8 mL, 1:1:0.1) and
hydrogenated over 10% Pd/C (20 mg) at 52 psi hydrogen
pressure for 10 h. The reaction mixture was filtered through
Celite and the solvent was removed under reduced pressure.
The residual crude 22 was dissolved in acetone-H2O (3 mL,
1:1). To this was added phenylacetyl chloride (16 µL, 0.12
mmol) followed by the addition of solid NaHCO3 (10 mg, 0.12
mmol). The reaction mixture was stirred for 50 min in an ice
bath. Water (2 mL) was added, and the mixture was extracted
with CH2Cl2 several times. The combined organic layers were
washed with brine, dried (Na2SO4), filtered, and concentrated.
Isolation by flash column chromatography on silica gel (CH2-
Cl2-THF, 20:1) gave 22 mg (55%) of 23 as a white solid: mp
59-61 °C; [R]22D -122.0° (c 0.1, CHCl3); IR (CHCl3) 1775, 1755,
(3S,4S)-1-[1(R)-(Meth oxyca r bon yl)-2(S)-h yd r oxyp r op -
1-en yl]-3-p h th a lim id o-4-[(R)-2,2-d im eth yl-1,3-d ioxola n -4-
yl]a zetid in -2-on e (30). A suspension of 29 (0.877 g, 2.03
mmol) and Dess-Martin periodinane (1.463 g, 3.45 mmol) in
dry CH2Cl2 (35 mL) was stirred for 2.5 h at rt under argon.
Saturated NaHCO3 solution (20 mL) and saturated Na2S2O3
solution (10 mL) was added, and the reaction mixture was
stirred vigorously for 5 min. The organic layer was separated
and washed with H2O (30 mL) and brine (30 mL), dried (Na2-
SO4), filtered, and concentrated. Isolation by flash column
chromatography on silica gel (CH2Cl2-THF, 20:1) gave 0.785
1
1678 cm-1; H NMR (CDCl3) δ 1.66 (s, 3H), 3.64 (dd, AB, 2H,
J ) 15.7 Hz), 3.77 (s, 3H), 3.85 (m, 3H), 4.35 (dd, 1H, J ) 0.8,
5.3 Hz), 4.55 (s, 1H), 5.40 (dd, 1H, J ) 4.6, 7.2 Hz), 6.09 (d,
1H, J ) 7.2 Hz), 7.36 (m, 5H); 13C NMR (CDCl3) δ 23.3, 43.3,
52.5, 55.9, 59.3, 63.6, 68.6, 70.8, 105.0, 127.7, 129.2, 133.9,
167.8, 171.3, 171.9; HRMS(EI) calcd for C18H20N2O6 360.1321,
found 360.1330.
g (90%) of 30 as a white solid: mp 180-181 °C; [R]22 -17.7
D
(c 3.3, CHCl3); IR (KBr) 1780, 1770, 1715, 1655, 1615 cm-1
;
1H NMR (CDCl3) δ 1.23 (s, 3H), 1.33 (s, 3H), 2.39 (s, 3H), 3.48
(dd, 1H, J ) 8.5, 5.6 Hz), 3.72 (dd, 1H, J ) 8.5, 6.4 Hz), 3.84
(s, 3H), 4.17 (dd, 1H, J ) 9.5, 5.6 Hz), 4.39 (m, 1H), 5.44 (d,
1H, J ) 5.6 Hz), 7.7-7.9 (m, 4H); 13C NMR (CDCl3) δ 18.5,
25.2, 26.8, 52.2, 54.5, 62.9, 66.0, 75.4, 100.4, 109.9, 124.0, 131.2,
134.9, 163.9, 167.2, 169.7, 177.6; HRMS (EI) calcd for
C21H22N2O8 430.1376, found 430.1360.
P ota ssiu m Sa lt 24. Potassium hydroxide (5.6 mg, 0.1
mmol) was dissolved in H2O (1 mL). To a solution of 23 (7.2
mg, 0.02 mmol) in THF (0.2 mL) was added the KOH solution
(0.2 mL, 0.02 mmol). The reaction mixture was stirred for 40
min at rt, diluted with H2O (0.2 mL), and extracted with ether
(3 × 0.5 mL) and EtOAc (0.5 mL). Removal of H2O under
reduced pressure gave 6.2 mg (81%) of 24 as a white solid:
mp 186-190 °C; [R]22D -170.3° (c 0.35, CH3OH); IR (KBr) 1755,
1655, 1605, 1380 cm-1; 1H NMR (CD3OD) δ 1.69 (s, 3H), 3.64
(dd, 2H, J ) 14.3 Hz), 3.75 (dd, 1H, J ) 5.1, 7.4 Hz), 3.82 (m,
2H), 4.33 (s, 1H), 4.34 (d, 1H, J ) 4.8 Hz), 5.31 (d, 1H, J ) 4.6
Hz), 7.30 (m, 5H); 13C NMR (CD3OD) δ 24.4, 43.1, 57.4, 59.6,
67.2, 70.0, 72.1, 106.9, 128.0, 129.6, 130.2, 136.8, 174.0, 174.6,
174.7; HRMS(FAB) calcd for C17H17N2O6K2 423.0361, found
423.0357.
(3S,4S)-1-[1(R)-(Meth oxyca r bon yl)-2(S)-h yd r oxyp r op -
1-en yl]-3-ph th alim ido-4-[(R)-1,2-dih ydr oxyeth yl]azetidin -
2-on e (31). A solution of 30 (215 mg, 0.5 mmol) and
p-toluenesulfonic acid (71 mg, 0.4 mmol) dissolved in THF (5
mL) and H2O (5 mL) was refluxed for 18 h, and the solvent
was then removed under reduced pressure. The residue was
subjected to flash column chromatography on silica gel, eluting
with 1:1 CH2Cl2-THF, affording 170 mg (87%) of 31 as a white
solid: mp 186-188 °C; [R]22 -15.8 (c 0.4, CHCl3); IR (KBr)
D
3400, 1785, 1750, 1710, 1685, 1600 cm-1; H NMR (CDCl3) δ
1
1.90 (br, 1H), 2.41 (s, 3H), 2.67 (d, 1H, J ) 3.8 Hz), 3.45 (m,
2H), 3.84 (s, 3H), 4.05 (m, 1H), 4.30 (dd, 1H, J ) 7.3, 5.7 Hz),
5.49 (d, 1H, J ) 5.7 Hz), 7.7-8.0 (m, 4H); 13C NMR (CDCl3) δ
18.7, 52.3, 54.9, 61.0, 64.0, 70.4, 100.8, 124.0, 131.4, 134.9,
164.3, 167.6, 177.4; HRMS (FAB) calcd for C18H19N2O8 391.1141,
found 391.1142.
(3S,4S)-1-[1(R )-(Me t h oxyca r b on yl)-2(S)-O-[(t er t -b u -
t yld im et h ylsilyl)oxy]p r op yl]-3-p h t h a lim id o-4-[(R)-2,2-
d im eth yl-1,3-d ioxola n -4-yl]a zetid in -2-on e (27). Imine 26
was prepared by the reaction of protected D-threonine 9 (4.997
g, 0.02 mol) and L-(S)-glyceraldehyde acetonide 25 (2.630 g,
0.02 mol) in the presence of MgSO4 (7.310 g, 0.06 mol)
following the same procedure for the preparation of imine 10.
To a solution of imine 26 in dry CH2Cl2 (50 mL) cooled in an
ice bath was added dropwise TEA (3.036 g, 0.03 mol) followed
by addition of a solution of phthaloylglycyl chloride (5.575 g,
0.025 mol) in dry CH2Cl2 (20 mL) under argon. The reaction
mixture was then stirred for 3 h, diluted with CH2Cl2 (80 mL),
and washed with H2O (100 mL), 1 N HCl (100 mL), saturated
NaHCO3 solution (100 mL), H2O (100 mL), and brine (100 mL),
dried (Na2SO4), filtered, and concentrated. Isolation by flash
column chromatography on silica gel (CH2Cl2-EtOAc, 20:1)
[1R,3S,4R,6S,7S]-Tr icyclic â-La cta m (32) a n d 1-(Hy-
d r oxym eth yl)-O-2-isocep h em (33). A mixture of glycol 31
(78 mg, 0.2 mmol), p-TsOH (34 mg, 0.2 mmol), and silica gel
(468 mg) in dry benzene (5 mL) was refluxed for 25 min. The
solid was filtered and washed with EtOAc several times. The
combined organic solvents were washed with 10% aqueous
NaHCO3 solution twice and brine, dried (Na2SO4), filtered, and
concentrated. Isolation by flash column chromatography on
silica gel (CH2Cl2-THF, 20:1) gave 36 mg (48%) of 32 and 13
mg (17%) of 33 both as white solids. 32: mp 235-236 °C;
[R]22D +163.6° (c 0.75, CHCl3); IR (KBr) 1790, 1770, 1725, 1385
gave 9.902 g (90%) of 27 as a white solid: mp 55-57 °C; [R]22
D
1
+34.1° (c 3.7, CHCl3); IR (KBr) 1775, 1745, 1725, 1382 cm-1
;
cm-1; H NMR (CDCl3) δ 1.81 (s, 3H), 3.80 (s, 3H), 3.81 (m,
1H NMR (CDCl3) δ 0.10 (s, 3H), 0.12 (s, 3H), 0.91 (s, 9H), 1.24
(s, 3H), 1.28 (d, 3H, J ) 6.2 Hz), 1.33 (s, 3H), 3.60 (dd, 1H, J
) 5.9, 8.6 Hz), 3.71 (dd, 1H, J ) 6.8, 8.6 Hz), 3.85 (s, 3H), 4.13
(dd, overlap with the peaks at 4.15 ppm, 1H, J ) 5.5 Hz), 4.15
(d, 1H, J ) 6.6 Hz), 4.53 (dt, 1H, J ) 6.1, 6.6 Hz), 4.71 (p, 1H,
J ) 6.3 Hz), 5.36 (d, 1H, J ) 5.4 Hz), 7.7-7.9 (m, 4H); 13C
NMR (CDCl3) δ -4.8, -4.5, 17.8, 21.5, 24.8, 25.7, 26.4, 52.3,
54.6, 62.6, 64.3, 65.2, 67.2, 75.2, 109.6, 123.8, 131.4, 134.6,
163.2, 166.9, 168.6; HRMS (FAB) calcd for C27H39N2O8Si
547.2476, found 547.2490.
(3S,4S)-1-[1(R)-(Meth oxycar bon yl)-2(S)-h ydr oxypr opyl]-
3-p h th a lim id o-4-[(R)-2,2-d im eth yl-1,3-d ioxola n -4-yl]a ze-
tid in -2-on e (29). To a solution of â-lactam 27 (2.184 g, 0.004
mol) in dry CH2Cl2 (50 mL) was added TFA (0.92 mL, 0.012
mol) dropwise at 14 °C under N2. The solution was stirred
for 4 h at 14 °C and then diluted with CH2Cl2 (70 mL), washed
2H), 3.90 (d, 1H, J ) 5.0 Hz), 4.51 (d, 1H, J ) 3.9 Hz), 4.73 (s,
1H), 5.71 (d, 1H, J ) 5.0 Hz), 7.7-8.0 (m, 4H); 13C NMR
(CDCl3) δ 23.2, 52.6, 54.90, 57.5, 63.1, 69.6, 70.7, 105.2, 124.0,
131.4, 134.7, 166.5, 167.2, 167.8; HRMS(FAB) calcd for
C18H17N2O7 373.1036, found 373.1015. 33: mp 114-117 °C;
[R]22 +50.1° (c 1.0, CHCl3); IR (KBr) 3450, 1790, 1770, 1720,
D
1615, 1385 cm-1; 1H NMR (CDCl3) δ 2.29 (s, 3H), 3.69 (d, 2H,
J ) 4.9 Hz), 3.77 (dd, 1H, J ) 8.9, 5.0 Hz), 3.84 (s, 3H), 4.47
(dt, 1H, J ) 8.9, 5.0 Hz), 5.83 (d, 1H, J ) 5.2 Hz), 7.7-7.9 (m,
4H); 13C NMR (CDCl3) δ 18.0, 51.1, 52.0, 57.6, 61.9, 75.1, 106.2,
123.9, 131.4, 134.7, 155.7, 161.6, 163.3, 167.4; HRMS (FAB)
calcd for C18H17N2O7 373.1036, found 373.1041.
(3S,4S)-1-[1(R )-(Me t h oxyca r b on yl)-2(S)-O-[(t er t -b u -
tyld im eth ylsilyl)oxy]p r op yl]-3-p h en yla ceta m id o-4-[(R)-
2,2-d im eth yl-1,3-d ioxola n -4-yl]a zetid in -2-on e (35). To a
solution of 27 (218 mg, 0.4 mmol) in CH3OH (8 mL) was added

1022 J . Org. Chem., Vol. 61, No. 3, 1996
Niu et al.
hydrazine monohydrate (22 mg, 0.44 mmol), and the mixture
was stirred for 4 h at rt. The solvent was removed, and the
residue was redissolved in of CH2Cl2 (8 mL). The solution was
refluxed for 20 h and then stirred at rt for 5 d. The solid was
filtered off, and the solvent was removed to give crude 34
which was then dissolved in a 1:1 mixture of acetone and H2O
(10 mL). To this was added phenylacetyl chloride (77 mg, 0.5
mmol) followed by addition of solid NaHCO3 (42 mg, 0.5 mmol).
The reaction mixture was stirred overnight at rt and then
extracted with CH2Cl2 (4 × 5 mL). The combined extracts
were washed with brine (8 mL), dried (Na2SO4), filtered, and
concentrated. Isolation by flash column chromatography (CH2-
Cl2-THF, 20:1) gave 112 mg (52%) of 35 as a white solid: mp
was dissolved in CH2Cl2 (5 mL). Refluxing for 48 h and
stirring for an additional 48 h at rt gave crude 37. The same
procedure for acylation of 34 was then followed, using phenyl-
acetyl chloride (39 mg, 0.25 mmol) and solid NaHCO3 (21 mg,
0.25 mmol) in a 1:1 mixture of acetone and H2O (5 mL). The
crude product was purified by flash column chromatography
on silica gel (CH2Cl2-EtOAc-CH3OH, 3:1:0.1) affording 43 mg
(60%) of 38 as a white solid: mp 64-65 °C; [R]22 +139.7° (c
D
1
0.8, CHCl3); IR (KBr) 3300, 1775, 1755, 1655 cm-1; H NMR
(CDCl3) δ 1.65 (s, 3H), 3.64 (dd, AB, J ) 15.3 Hz), 3.76 (s,
3H), 3.83 (m, 3H), 4.35 (d, 1H, J ) 4.9 Hz), 4.55 (s, 1H), 5.39
(dd, 1H, J ) 4.6, 7.2 Hz), 6.25 (d, 1H, J ) 7.2 Hz), 7.32 (m,
5H); 13C NMR (CDCl3) δ 23.3, 43.3, 52.5, 55.9, 59.3, 63.6, 68.6,
70.8, 105.0, 127.6, 129.1, 134.0, 167.8, 171.3, 171.9; HRMS-
(FAB) calcd for C18H21N2O6 361.1400, found 361.1409.
93-95 °C; [R]22 +35.7° (c 1.5, CHCl3); IR (KBr) 3270, 1780,
D
1
1755, 1655, 1555 cm-1; H NMR (CDCl3) δ 0.05 (s, 3H), 0.07
(s, 3H), 0.86 (s, 9H), 1.18 (d, 3H, J ) 6.2 Hz), 1.20 (s, 3H),
1.37 (s, 3H), 3.57 (dd, AB, 2H, J ) 15.1 Hz), 3.63 (m, 2H), 3.72
(s, 3H), 3.81 (dd, 1H, J ) 5.0, 7.5 Hz), 3.91 (d, 1H, J ) 7.4
Hz), 3.95 (m, 1H), 4.62 (dq, 1H, J ) 7.2, 6.2 Hz), 5.26 (dd, 1H,
J ) 5.2, 8.1 Hz), 6.48 (d, 1H, J ) 8.1 Hz), 7.31 (m, 5H); 13C
NMR (CDCl3) δ -4.8, -4.3, 17.8, 21.5, 24.7, 25.7, 26.4, 43.5,
52.2, 56.6, 61.8, 65.3, 65.9, 67.2, 75.5, 109.5, 127.5, 129.1, 129.2,
134.1, 166.1, 169.0, 171.1; HRMS(FAB) calcd for C27H43N2O7-
Si 535.2840, found 535.2857.
Sa lt 39. Following the same procedure for preparation of
36, hydrolysis of 38 (7 mg, 0.02 mmol) in THF (0.2 mL) with
0.1 M KOH solution (0.2 mL, 0.02 mmol) gave 7 mg (93%) of
39 as a white solid: mp 185-187 °C; [R]22 +124.8° (c 0.25,
D
CH3OH); IR (KBr) 1755, 1655, 1605 cm-1; 1H NMR (CDCl3) δ
1.69 (s, 3H), 3.62 (dd, AB, 2H, J ) 14.2 Hz), 3.75 (dd, 1H, J )
5.4, 7.3 Hz), 3.82 (d, 1H, J ) 7.3 Hz), 3.83 (d, 1H, J ) 4.4 Hz),
4.33 (s, 1H), 4.34 (d, 1H, J ) 4.9 Hz), 5.31 (d, 1H, J ) 4.8 Hz),
7.31 (m, 5H); 13C NMR (CDCl3) δ 24.4, 43.2, 57.4, 59.6, 67.3,
69.9, 72.1, 106.9, 128.0, 129.6, 130.2, 136.8, 174.0, 174.5;
HRMS(FAB) calcd for C17H18N2O6K 385.0802, found 385.0827.
Sa lt 36. To a solution of 35 (10 mg, 0.02 mmol) in THF
(0.2 mL) was added 0.1 M KOH solution (0.2 mL, 0.02 mmol),
and the mixture was stirred for 45 min at rt and extracted
with ether (4 × 0.4 mL) and EtOAc (0.4 mL). Removal of water
under reduced pressure gave 4 mg (50%) of 36 as a white
solid: mp 171-174 °C; [R]22D +41.5° (c 0.2, CH3OH); IR (KBr)
Ack n ow led gm en t. We gratefully acknowledge the
NIH and Eli Lilly and Co. for providing financial
support for this research and Eli Lilly and Co. for
biological testing. We sincerely appreciate the use of
the NMR facilities provided by the Lizzadro Magnetic
Research Center at the University of Notre Dame.
1
1750, 1655, 1578 cm-1; H NMR (CDCl3) δ 1.15 (s, 3H), 1.27
(s, 3H), 1.85 (d, 3H, J ) 7.1 Hz), 3.38 (dd, 1H, J ) 6.3, 8.5
Hz), 3.50 (dd, 1H, J ) 6.6, 8.6 Hz), 3.56 (dd, AB, 2H, J ) 14.0
Hz), 4.07 (m, 1H), 4.37 (dd, 1H, J ) 5.4, 7.2 Hz), 5.23 (d, 1H,
J ) 5.4 Hz), 6.62 (q, 1H, J ) 7.1 Hz), 7.33 (m, 5H); 13C NMR
(CDCl3) δ 14.7, 25.5, 26.9, 43.8, 57.5, 62.5, 67.0, 76.7, 110.8,
128.2, 129.8, 130.2, 130.3, 133.1, 136.4, 167.5, 174.3; HRMS-
(FAB) calcd for C20H24N2O6K 427.1271, found 427.1270.
[1R,3S,4R,6S,7S]-7-P h en yla ceta m id o Tr icyclic â-La c-
ta m (38). To a solution of 32 (74 mg, 0.2 mmol) in CH3OH-
CH2Cl2 (5 mL 1:1) was added hydrazine monohydrate (11 mg,
0.22 mmol), and the mixture was stirred at rt for 3 h. The
solvent was removed under reduced pressure, and the residue
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 11, 12, 15, 17, 18, 23, 24, 27, 29-33, 35, 36, 38,
and 39 (35 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O951651U