Polyhydroxy amino acid derivatives via β-lactams using enantiospecific approaches and microwave techniques

Article abstract of DOI:10.1016/S0040-4020(00)00410-5

Enantiospecific synthesis has been developed for α-hydroxy β-lactams of predictable absolute configuration starting with readily available carbohydrates. Stereospecific approaches and microwave assisted chemical reactions have been utilized for the prepar

Full text of DOI:10.1016/S0040-4020(00)00410-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5603±5619
Polyhydroxy Amino Acid Derivatives via b-Lactams Using
Enantiospeci®c Approaches and Microwave Techniques1
²,
Ajay K. Bose, Bimal K. Banik, Chandra Mathur, Dilip R. Wagle and Maghar S. Manhas
*
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology, Hoboken, NJ 07030, USA
Received 6 December 1999; accepted 2 February 2000
AbstractÐEnantiospeci®c synthesis has been developed for a-hydroxy b-lactams of predictable absolute con®guration starting with readily
available carbohydrates. Stereospeci®c approaches and microwave assisted chemical reactions have been utilized for the preparation of these
3-hydroxy-2-azetidinones and their conversion to natural or non-natural enantiomeric forms of intermediates for gentosamine, 6-epi-
lincosamine, g-hydroxythreonine, and polyoxamic acid. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
tuted-2-azetidinones (3a or 3b) by the condensation of an
acid chloride (1 or equivalent) with a Schiff base 2 in
presence of triethylamine (Scheme 1). This annulation reac-
tion can lead to four stereoisomers (cis and trans dl-pairs).
The last few decades have witnessed a remarkable growth in
the ®eld of b-lactam chemistry. The discovery of a succes-
sion of b-lactams in nature with antimicrobial activity has
led to the synthesis of a variety of monocyclic and fused
bicyclic b-lactams for the development of many life-saving
antibiotics.2 A recent report3 discloses the potential of some
b-lactams to serve as therapeutic agents for lowering plasma
cholesterol. Undoubtedly, the search will continue for
clinically useful b-lactams that are not antibiotics.
The degree of diastereoselectivity achieved in the b-lactam
forming reaction determines the proportion of unwanted
isomers obtained which would become chemical waste. It
is essential to have an easy access to optically pure products
of the desired absolute con®guration; the mirror image of
these products may also become chemical waste unless they
can be recycled. The increasing need for reducing pollution
at the source for achieving more eco-friendly chemical
synthesis is thus providing a strong incentive for practicing
`atom economy'.7 It is becoming very important, therefore,
to plan for higher stereocontrol of reactions, greater yield of
target compounds, and the possibility of one-pot reactions
that combine two or more synthetic steps. In recent years,
we have found microwave-assisted8 reactions to be often
more eco-friendly than conventional synthesis.
For natural products chemists, b-lactams hold a special
attraction: these four membered, chiral heterocycles have
been shown to be versatile synthons for a wide variety
of natural products.4 Synthetic approaches have been devel-
oped for preparing homochiral b-lactams with diverse
substituents with the desired stereochemistry.5 Therefore,
many natural products are available in optically active
form with the natural or non-natural absolute con®guration
via synthetic b-lactams.
We wish to describe here an enantiospeci®c approach to
polyhydroxy a-amino acid derivatives using both conven-
tional and microwave-assisted reactions.9 Optically active
In the course of our continuing studies6 on lactams, we have
been interested in the stereocontrolled synthesis of 3-substi-
Scheme 1.
Keywords: annulation; azetidinones; enantiospeci®c; amino sugars; amino acids; microwave irradiation.
* Corresponding author. Tel.: 1713-792-7749; fax: 1713-792-5940; e-mail: banik@mdanderson.org
Present address: The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
²
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00410-5

5604
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
Scheme 2.
a-hydroxy-2-azetidinones were the synthons for our target
compounds. Recently, 3-hydroxy-2-azetidinones of type 4
have attracted attention because the semisynthesis of the
anti-tumor drug paclitaxel (Taxole) and its analog
docetaxel (Taxoteree) utilizes optically active forms of
410 (Scheme 2).
Since both d- and l-threonine are equally available, access
to either 7 (or analog) or its antipode 8 can be obtained
conveniently.
From the point of view of atom economy7 a more desirable
approach to homochiral b-lactam synthons is the com-
pletely enantiospeci®c synthesis of a-amino b-lactam
derivatives (for example, 10) achieved by two labora-
tories12±14 working independently. The key step was the
reaction of azidoacetyl chloride (5) (or equivalent) and
triethylamine with a Schiff base 9 derived from an optically
active aldehyde and an achiral amine (Scheme 4).
Stereocontrolled a-substituted b-lactam formation
In previous publications11 we have reported varying levels
of high diastereoselectivity during b-lactam formation by
the reaction of azidoacetyl chloride (5) with Schiff bases 6
derived from threonine esters and an achiral aldehyde (such
as cinnamaldehyde). High diastereoselectivity (7:8ˆ95:5)
was achieved when the hydroxy group of threonine was
converted to a very bulky group, for example by the for-
mation of triphenylsilyl ether as in 6 (RˆPNB, RˆSiPh3,
Scheme 3).
Scientists at Hoffmann-La Roche Laboratories12 had used
l-glyceraldehyde acetonide prepared from l-ascorbic acid
and determined the absolute con®guration of the b-lactam
formed by single crystal X-ray diffraction. Our initial
work14 was conducted with 9 (RˆMe) derived in several
steps from d-threonine and the absolute con®guration of 10
(RˆMe) was deduced from X-ray diffraction data. Subse-
quent studies involved d-glyceraldehyde acetonide and also
aldehydes derived from various sugars leading to a variety
Separation of the major diastereomer (or a derivative) from
this reaction as an optically pure compound was found to be
easy by column chromatography and/or crystallization.
Scheme 3.

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5605
acetyl chloride 11 (RˆMe or COCH3) with 12 produces a
single, optically pure cis-b-lactam 13a or 13c (Scheme 5).
The absolute con®guration of the a-hydroxy b-lactams 13d
was established by chemical correlation with a-azido
b-lactam 10 (Qˆp-anisyl, RˆH) of known absolute con-
®guration. The same chirality was induced at C3 and C4 of
the a-azido b-lactam 10 (Qˆp-anisyl, RˆH) as for the
a-hydroxy b-lactam 13d. Thus, the cis a-acetoxy b-lactam
13c was hydrolyzed15 under mild conditions to the cis
a-hydroxy b-lactam 13d (Scheme 6) and then mesylated
to give the cis a-mesyloxy b-lactam 13e. The mesyloxy
group was replaced by an azido group to obtain a trans
a-azido b-lactam 14 via Sn2 displacement at C3. Reduction
of the azido group and subsequent reaction with Nefkens
reagent (16) produced a trans a-phthalimido b-lactam (see
below) which was identical with the compound 18 in all
respects (Scheme 6). This optically pure trans b-lactam
18 had been prepared earlier from 10 of known stereo-
chemistry. When the cis a-azido b-lactam 10 was converted
Scheme 4.
of Schiff bases. It appeared that the absolute con®guration of
the b-lactam obtained depended only on the chiral center
next to the aldehyde group (Scheme 5).
The strategy for a-hydroxy-b-lactams
We15 have found that the reaction of methoxy-, or acetoxy-
Scheme 5.
Scheme 6.

5606
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
Scheme 7.
to a cis a-phthalimido b-lactam 17 via 15 and then epimer-
ized at C3 (Scheme 6), the trans b-lactam 18 of established
absolute con®guration was obtained.
method was in agreement with the absolute con®guration
of 13.
Reduction of the g-lactone 19 by a known method (reaction
with diisobutylaluminum hydride) led to the pyranose
derivative, the stereostructure of which is represented by
20. This amino sugar is a derivative of the natural enantio-
mer of gentosamine (21) which is a 3-amino sugar present in
the antibiotic complex gentamicin-A
Preparation of an amino sugar lactone
Appropriately substituted b-lactams are known to undergo
rearrangement4 to generate a variety of heterocycles. When
the a-methoxy b-lactam 13g was heated under re¯ux with
90% tri¯uoroacetic acid, molecular rearrangement with
b-lactam cleavage occurred. The product was a single
g-lactone 19 in 68% yield (Scheme 7). Since this g-lactone
19 was dextrorotatory, the absolute con®guration at C4 of
the sugar could be deduced by using Hudson's lactone rule.
The stereochemical assignment of C4 determined by this
a-Hydroxy b-lactams with multiple chiral centers
To obtain information on the chirality induced by aldehydes
with several asymmetric centers, b-lactams were prepared
from imines derived from appropriately protected sugars.
Scheme 8.

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5607
Scheme 9.
Also arylalkyl amines (such as benzylamine) were used in
place of aryl amines for the synthesis of Schiff bases.
linked through an amide bond to a proline derivative)
(Fig. 1).
Commercially available methyl 2,3-O-isopropylidene-b-d-
ribofuranoside (22) was oxidized with pyridinium chloro-
chromate to obtain the aldehyde 23. The Schiff base 24
prepared from 23 and benzylamine was treated with meth-
oxyacetyl chloride and triethylamine; a single cis b-lactam
25 was obtained in about 30% yield (Scheme 8).
Reduction of 30 with lithium aluminium hydride led to an
eight-carbon amino sugar derivative 34. Treatment of 30a
with sodium methoxide in methanol provided the ester 35
which was found to be a more convenient intermediate than
34 for the preparation of an amino sugar that was related to
33 (Scheme 10). Benzylation of 35 led to a crystalline
product 36 which was reduced with lithium aluminum
hydride to a primary alcohol 37 in good yield. Unexpectedly
a chloro compound 38 was formed instead of a mesylate
when 37 was treated with mesyl chloride and pyridine at
08C. After some experimentation it was possible to obtain
crystalline 39 by the reduction of 38 with an excess of a
clear solution of lithium aluminum hydride in ether. Single
crystal X-ray diffraction study of 39 con®rmed the absolute
con®guration and the structure of this 6-epi-lincosamine
derivative.18
Following a published method16 the acetonide group in 25
was hydrolyzed with 1% solution of iodine in methanol to
obtain 26a. This b-lactam was oxidized with ruthenium
tetraxide (RuCl31NaIO4) to convert the sugar moiety to a
carboxy group which was converted to the methyl ester by
treatment with diazomethane. The cis b-lactam 27a so
obtained was the mirror image of the same b-lactam 27b
prepared from 26b via 13h and 13g of known absolute
con®guration (Scheme 8).
Strategy for homochiral hydroxy amino acids
A similar set of reactions (Scheme 9) was conducted with
28aÐthe diacetonide of d-galalactose and the correspond-
ing aldehyde 28b. The Schiff base 29 from 28b and benzyl-
amine were converted to the cis b-lactam 30a which was
obtained as a single product in the cycloaddition reaction.
The 1-benzyl-3-methoxy-4-carbomethoxy-2-azetidinone
(31) that was prepared from the b-lactam 30a through 30b
was identical in all respects (including speci®c rotation)
with 27a for which the absolute con®guration had been
determined earlier (Scheme 8). Again, the chirality induced
in the b-lactam 30a, was dependent on the absolute con®g-
uration of the aldehyde-bearing carbon alone and was
predictable.
Easy access to densely substituted b-lactams of predictable
absolute con®guration led to a convenient strategy for the
preparation of various substituted amino acids and their
derivatives. Thus, with the multiple hydroxy groups (for
example, in 30a) in a suitable protected form, the b-lactam
Preparation of a 6-epi-lincosamine derivative
The a-methoxy b-lactam 30a, synthesized from a d-galac-
tose derivative 28, provided access to an epimer of linco-
samine17Ðan eight-carbon amino sugar found in nature.
Lincomycin (32) is a potent antibiotic which consists of a
carbohydrate (lincosamine-a 6-amino-octopyranoside, 33
Figure 1.

5608
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
Scheme 12.
3-hydroxy-2-azetidinones could then lead to different
types of target compounds. Commercially available
d-mannitol was selected as one of the starting materials.
d-mannitol was utilized in two different ways:
(a) In the form of the symmetrical diacetonide 45 which
was cleaved with sodium periodate to provide d-glycer-
aldehyde acetonide (46).19
Scheme 10.
(b) In the form of the triacetonide 47 which was selec-
tively hydrolyzed to the diacetonide 48 and then cleaved
with periodic acid to the known aldehyde 49 (d-arabinose
diacetonide)20 (Scheme 12).
can be hyrolyzed to obtain a b-amino acid derivative (such
as in 35); or, the b-lactam amide can be reduced with
lithium aluminum hydride to provide a b-amino alcohol
derivative (for example 34) which can lead to a variety of
new compounds. Such homochiral b-amino diols 40 are of
special interest as they can lead to a-amino acids 42 and 44
of either enantiomeric form starting with a single inter-
mediate (Scheme 11).
It was demonstrated that the same d-mannitol could be used
for generating derivatives of antipodal forms of a-hydroxy
b-lactams by starting with either 46 or 49 for the preparation
of Schiff bases.
Some of these strategies are illustrated here by the prepar-
ation of optically active forms of a dihydroxy amino acid
and a trihydroxy amino acid. At the inception of this
research, it was decided to utilize a readily available
economically priced, optically pure sugar derivative that
would be compatible with easy protection and deprotecion
of speci®c hydroxy groups. An aldehyde from such a sugar
derivative would permit the synthesis of a-hydroxy
b-lactams of predictable absolute con®guration. These
Enantiospeci®c synthesis of (2)-2S, 3S-2-amino-3,4-
dihydroxybutyric acid
This unusual amino acid, also known as l-g-hydroxythreo-
nine, has received considerable attention because of the
claim by Klenk and Diebold21, that it is one of the oxidative
cleavage products of sphingosine. Since then several synth-
eses of this compound have been reported.22
Scheme 11.

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5609
Scheme 13.
The starting material for our synthesis (Scheme 13) was d-
glyceraldehyde acetonide (46) which was allowed to react
with benzyl amine to form the Schiff base 50. Treatment of
50 with benzyloxyacetyl chloride and triethyl amine
produced a single cis-b-lactam 51 for which the absolute
con®guration could be predicted.23
compound 54 which was converted to t-butoxycarbonyl
derivative 55 using standard reaction conditions.
It was decided to prepare an l-amino acid. Therefore, the
diol (acetonide) was left undisturbed and a carboxy group
was generated by ruthenium tetraxide oxidation of the
unprotected diol 55. The amino acid derivative 56 obtained
in this manner was treated with tri¯uoroacetic acid to
remove the protective groups when the levorotatory
(natural) form of g-hydroxy threomine, the desired amino
acid 57, was obtained.
Microwave assisted catalytic transfer hydrogenation24 of 51
was conducted at about 1308C with ammonium formate25as
the source of hydrogen and 10% Pd/C as the catalyst. Selec-
tive hydrogenolysis to 52 was observed: the benzyloxy
group was converted to a hydroxy group but the N-benzyl
group was unaffected. Lithium aluminum hydride reduction
of 52 cleaved the b-lactam ring and led to the vicinal diol
53. After some experimentation it was discovered that
protection of the amino group was necessary before
conducting the planned oxidation step.
Synthesis of (2)-polyoxamic acid
Polyoxins26 constitute a group of unusual nucleosides which
acts against the pathogenic fungus that causes the sheath
blight disease of the rice plant. They incorporate carbamoyl-
ated dipeptides attached to the sugar moiety. Controlled
alkaline hydrolysis of polyoxins (58) results in several
products, one of which has been ideni®ed as (1)-(2S, 3S,
Microwave-assisted catalytic transfer hydrogenation of 53
removed the N-benzyl group to give the primary amino
Figure 2.

5610
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
Scheme 14.
4S)-2-amino-3,4,5-trihydroxypentanoic acid (polyoxamic
acid, 59) (Fig. 2). This polyhydroxyamino acid and its
mirror image 60 have been the target of synthesis in several
laboratories.27 We describe here enantiospeci®c reactions
leading to 60Ðthe mirror image of the natural form of
polyoxamic acid (59) (Scheme 14).
of one of the acetonide protective groups in 62 could be
achieved by mild hydrolysis with aqueous acetic acid.30
The diol 63 that was obtained was treated successively
with sodium periodate and sodium borohydride to remove
one of the carbons and obtain 64b. At this stage catalytic
transfer hydrogenation of 64b was carried out to convert the
benzyloxy group to a hydroxy group, as in 65a. Reaction
with trityl chloride and triethylamine gave selective protec-
tion to the primary hydroxyl group in 65a and led to 65b.
Since the target was a d-amino acid, the aldehyde 49
prepared from the triacetonide 47 of d-mannitol was the
starting material. The Schiff base 61 obtained by the
condensation of 49 with benzylamine was allowed to react
with benzyloxyacetyl chloride and triethylamine; a single
optically active b-lactam 62 was the product.28 Based on the
absolute con®guration of the chiral center next to the alde-
hyde group in 49, it was possible to predict the absolute
con®guration29 of this cis b-lactam to be as shown in 62.
Lithium aluminum hydride reduction of this a-hydroxy b-
lactam 65b produced the vicinal diol 66 with a free benzyl-
amino group. In preparation for an oxidation reaction, the
N-benzyl group was removed by microwave-assisted cata-
lytic transfer hydrogenation with ammonium formate and
Pd/C catalyst. The primary amine 67a so obtained was
converted to a t-Boc derivative 67b which was then
oxidized with ruthenium trichloride±sodium periodate.
After initial studies it was found that the selective removal

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5611
Cleavage of the diol produced an a-amino acid 68 with
protected hydroxyl groups.
b-lactams are formed at all levels of microwave irradiation.
On a few grams scale, optically active cis b-lactams 51 and
62 are obtained in high yield after about 3 min of irradiation
in a 800 W microwave oven.
All the protection groups in 68 were removed simul-
taneously by treatment with tri¯uoroacetic acid in methanol.
The optically active polyoxamic acid (60) that was formed
was converted to the stable lactone 69 by reaction with
acetic anhydride. The optical rotation27c of 60 clearly
demonstrated that the non-natural enantiomer of poly-
oxamic acid (59) had been synthesized. The prediction of
the absolute con®guration of the b-lactam 62 was thereby
shown to be correct.
Recent work in our laboratory has shown that the Schiff base
formation step can be conducted as a solventless or `dry'
reaction under microwave irradiation. Following the
method of Varma et al.32 we have used Montmorillonite
clay as a catalyst in this reaction. The next step, which is
the b-lactam forming reaction, can be carried out as a one-
pot reaction in combination with the ®rst step. It is not
necessary to remove the clay in the reaction mixture for
the successful completion of the second step.
Microwave-assisted eco-friendly synthetic steps
A major advantage of MORE chemistry techniques is the
reduced amount of solvents used. A slurry at room tempera-
ture allows enough reactants to go into solution at the
comparatively high temperatures reached in a microwave
oven in 1 or 2 min. Reduction in the use of solvents as
reaction media and lowered amounts of by-products formed,
reduce pollution at the source and ensure high levels of
`atom economy'.
During the course of our studies on the synthesis of
b-lactams and other heterocycles we have found it con-
venient to conduct several types of synthetic steps under
microwave irradiation. We8 have developed `Microwave-
induced Organic Reaction Enhancement (MORE)' chemis-
try techniques for using nontraditional methods for rapid,
safe and environment friendly reactions. These reactions are
performed in unmodi®ed domestic microwave ovens in a
matter of minutes using very limited amounts of high
boiling solvents (such as DMF and ethylene glycol) or no
solvents if one of the reactants is a suitable liquid.
Another advantage of MORE chemistry techniques is the
lowered energy consumption compared to conventional
reactions conducted under re¯ux requiring input of latent
heat of vaporization. Since, the reaction mixture under
irradiation is not allowed to come to the boiling point,
there is little vaporization and therefore little expenditure
of latent heat of vaporization of liquids. Also, microwave
assisted reactionsÐeven on several hundred grams scaleÐ
require only 10±15 min of irradiation in a domestic micro-
wave oven of 800±1000 W rating.
Domestic microwave ovens use radiation of 2450 MHz
frequency which is directed into the oven. The level of the
energy is controlled by an on±off cycle that can be adjusted
for various levels of energy. Microwaves are non-ionizing
radiation that are absorbed by ions in solution and
compounds with dipoles. Glass and many polymeric
materials are nearly transparent to microwaves. Advantage
is taken of this property of microwaves to sharply reduce the
amount of organic solvents used as the reaction medium or
microwave energy transfer agent. Upon irradiating a
reaction mixture in an open glass vessel (a large beaker or
Erlenmyer ¯ask with a loose cover), microwave energy is
transferred to the reactants directly without the necessity for
heating the glass vessel and setting up convection currents.
The energy input is controlled so that the solvent and/or the
reaction mixture is not allowed to approach the boiling point
too closely. Thereby the amount of vaporization is kept low
and no re¯ux condenser is needed. Stirrers are not required
if the reaction mixture is placed as a comparatively thin
layer in the glass vessel used so that microwaves can
penetrate the entire reaction mixture. The usual reaction
time is a few minutes even on a few hundred grams
scale.
Recently commercial microwave ovens are being designed
for kilogram scale preparative reactions. The availability of
such equipment would certainly lead to the use of MORE
chemistry techniques for process development research.
There is little doubt that in coming decades microwave
enhanced chemical synthesis will play an important role
for the manufacture of speciality pharmaceuticals such as
peptides, steroids, alkaloids and their analogs.
Concluding Remarks
Our studies on Schiff bases derived from chiral aldehydes
and achiral amines showed that b-lactam formation was
stereospeci®c. In all cases a single b-lactam was formed
through an enantiospeci®c reaction. The absolute con®gura-
tion of the b-lactam could be predicted based solely on the
absolute con®guration of the chiral center next to the imino
group. This approach to versatile b-lactam synthons
coupled with microwave assisted chemistry can lead to
high levels of atom economy.
It is not clear yet whether microwaves alter the transition
state parameters of reactions. But, many laboratories
(including our own) have reported that microwave-assisted
reactions are much faster, comparatively free of by-products
and sometimes susceptible to steric control. Thus, we31 have
shown that the reaction of acetoxyacetyl chloride and
N-methylmorpholine with a Schiff base such as 2
(YˆQˆaromatic) gives mostly cis b-lactams 3a at low
levels of microwave irradiation but at higher energy levels
producing higher temperaturesÐmore that 90% of the
b-lactam formed may be the trans isomer 3b. Interestingly,
with Schiff bases of type 12, 24, 29, 50, and 61 the cis
Experimental
Melting points were determined with a mel-temp. apparatus
and are uncorrected. IR spectra were recorded on a Perkin±
1
Elmer model 1310 instrument. H and 13C NMR spectra

5612
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
were recorded on a Bruker Al-200 spectrometer using TMS
as an internal standard and CDCl3 as the solvent unless
speci®ed and all the chemical shifts were recorded in d-
scale. Chemical ionization mass spectra were recorded on
a Biospect instrument either CH4 or ammonia as the reagent
gas. Thin-layer chromatography was performed with What-
mann plates, and the spots were detected in a UV viewing
chamber. Optical rotations were measured on Rudolph
Polarimeter. All organic solvents were dried by standard
procedure. All the extracts after work-up were dried by
anhydrous sodium sulfate. Microanalyses were performed
by Schwarzkopf Microanalytical Laboratory, New York.
room temperature, washed with saturated sodium bicarbo-
nate solution (50 mL), brine (50 mL), dried and evaporated
to give the crude product which was puri®ed by column
chromatography over silica gel.
Mixed anhydride method using cyanuric chloride
(Method B). To a stirred solution of the potassium salt of
the acid (0.02 mol), triethyl amine (0.04 mol) and Schiff
base (0.01 mol) in dry dichloromethane (100 mL) main-
tained at 2208C under nitrogen, was added, a solution of
cyanuric chloride (0.02 mol) in dichloromethane (100 mL)
over a 30 min period. The mixture was left overnight,
washed with saturated sodium bicarbonate solution
(3£30 mL), brine (30 mL) and dried. Evaporation of the
solvent afforded the crude b-lactam which was puri®ed by
column chromatography.
Methyl 2,3-O-isopropylidene-b-d-ribopentodialdo-1,4-
furanoside (23). To a solution of commercially available
methyl 1, 2:3, 4-di-O-isopropylidene-b-d-galactopyranose
(22) (2.6 g, 10 mmol) in dry dichloromethane (200 mL)
Ê
was added powdered molecular sieves (4 g, 4 A) and pyri-
Microwave-assisted synthesis (Method C). To a solution
of the Schiff base (10 mmol) in 1,2-dichloroethane (20 mL)
in a 500 mL Erlenmyer ¯ask was added triethylamine
(30 mmol) followed by acid chloride (12 mmol). The ¯ask
vas capped with a glass funnel and placed in a microwave
oven (G. E. model, 1450 W). A 500 mL beaker containing
150 mL of water was placed in the oven next to the reaction
¯ask to serve as a heat sink. The mixture was irradiated for
3 min. After the usual work-up, the b-lactam was isolated
(60±70% yield).
dinium chlorochromate (4.3 g, 19 mmol). The mixture was
stirred overnight at room temperature. The dichloromethane
layer was passed through ¯orisil and eluted with dichloro-
methane. Evaporation of the solution gave the aldehyde 23
(1.8 g, 70%; bp 1028C/0.5 mmHg) which was used directly
in the next step; mp 598C; IR (neat): 1670 cm21; CIMS
(NH3) m/e 203 (M1H)1.
1,2:3,4-Di-O-isoprylidene-a-d-galactohexodialdo-1,5-
pyranose (28b). By following the above procedure, 28a was
oxidized, yield 70%; bp 1028C/0.5 mmHg; IR (neat)
cis-1-Benzyl-4[-(3aaH,8baH)-tetrahydro-2,2,7,7-tetra-
hydro-2,2,7,7-tetramethyl-5H-bis[1,3]dioxolo [4,5-b:40,50-
d]pyran-5-yl]-3-methoxy-azetidin-2-one (30a). Prepared
by following Methods A and B; yield 55%, mp 89±
908C:[a]2D6ˆ274.3 (cˆ0.6, MeOH); IR (Nujol):
1
1670 cm21; H NMR: 9.57 (s, 1H), 5.62 (d, Jˆ4.8 Hz,
1H), 4.6±4.17 (m, 4H), 1.5 (s, 3H), 1.44 (s, 3H), 1.32 (s,
6H).
1
General method for the synthesis of the Schiff base. A
solution of the amine (50 mmol) in dichloromethane
Ê
(100 mL) was cooled at 08C, molecular sieves (20 g, 4 A)
was added and the mixture was stirred. The aldehyde
(50 mmol) in dichloromethane (50 mL) was added dropwise
to it. After being stirred for 1 h at room temperature, it was
®ltered, dried and evaporated to give the crude Schiff base
which was used directly without puri®cation.
1750 cm21; H NMR: 7.30 (s, 5H), 5.61 (d, 1H), 4.80 (d,
2H), 4.62 (m, 1H), 4.51 (d, 1H), 4.35 (m, 2H), 4.30 (d, 2H),
4.13 (d, 1H), 3.81 (m, 1H), 3.62 (s, 3H), 1.55 (s, 3H), 1.37 (s,
6H), 1.30 (s, 3H); 13C NMR: 167.46, 136.05, 128.76,
128.43, 127.36, 109.49, 108.89, 96.10, 83.09,70.69, 70.67,
70.29, 69.69, 59.12, 55.62, 45.11, 26.01, 25.89, 24.96,
24.73; CIMS (NH3) m/e 437 (M1NH4)1; Anal. Calcd for
C22H29NO7: C, 63.00, H, 7.0, N, 3.3. Found: C, 62.78, H,
7.11, N, 3.15.
N-(Benzyl)-4-(methyl-2,3-O-isopropylidene-b-d-ribo-
pento-1,4 furanoside)-methylene-imine (24). 24 was
prepared by condensing 23 and benzylamine in quantitative
yield; CIMS (NH3) m/e 292 (M1H)1.
cis-1-(Benzyl)-3-methoxy-4-(methyl-2,3-O-isopropylidene-
b-D-ribopento-1,4-furanoside)-azetidin-2-one (25). b-
Lactam 25 was prepared by following Methods A and B;
yield, 0.8 g (30%), mp 97±988C; [a]2D6ˆ237.2 (cˆ0.576,
1
N-Benzyl-4-[1, 2:3, 4-di-O-isopropylidine-a-d-galacto-
hexo-1,5-pyranose]-methylene-imine (29). 29 was
prepared by condensing 28b with benzylamine in quantita-
tive yield; CIMS (NH3) m/e 365 (M1NH4)1.
MeOH), IR (Nujol): 1755 cm21; H NMR: 7.25 (m, 5H),
4.95 (d, 1H), 4.85 (d, 1H), 4.65 (d, 1H), 4.61 (d, 1H), 4.50
(d, 1H), 4.45 (m, 1H), 4.35 (d, 1H), 3.81 (m, 1H), 3.65 (s,
3H), 3.0 (s, 3H), 1.52 (s, 3H), 1.31 (s, 3H); 13C NMR: 168.0,
136.5,128.6, 128.5, 127.4, 127.2, 112.5, 110.3, 88.6,
84.6,83.3, 81.9, 59.4, 59.2, 55.3, 44.4, 26.5, 25.1; CIMS
(NH3) m/e 381 (M1NH4)1; Anal. Calcd for C, 62.8; H,
6.88; N, 3.85;. Found: C, 62.79; N, 3.53; H, 7.11.
General procedure for the synthesis of b-lactams. The b-
lactams were prepared by one of the following three
methods. The yields of the b-lactams by each of these
three methods were comparable.
cis-1-Benzyl-4-[(3aaH,8baH)-tetrahydro-2,2,7,7-tetra-
hydro-2,2,7,7-tetramethyl-5H-bis(1,3)dioxolo (4,5-b:
40,50-d)pyran-5-yl)]-3-methoxy-2-azetidinone (30a). b-
Lactam 30a was prepared by following methods A and B;
yield (55%), mp 89±908C: [a]2D6ˆ274.3 (cˆ0.6, MeOH);
IR (Nujol): 1750 cm21; 1H NMR: 7.31 (s, 5H), 5.62 (d, 1H),
4.80 (d, 2H), 4.61 (m, 1H), 4.55 (d, 1H), 4.35 (m, 2H), 4.30
Acid chloride-imine method (Method A). A solution
consisting of an acid chloride (0.015 mol) in dry dichloro-
methane (50 mL) was added dropwise to a stirred solution
containing Schiff base (0.013 mol) and distilled triethyl-
amine (0.03 mol) in dry dichloromethane (100 mL) at
2208C. The reaction mixture was stirred overnight at

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5613
(d, 2H), 4.11 (d, 1H), 3.82 (m, 1H), 3.65 (s, 3H), 1.55 (s,
3H), 1.37 (s, 6H), 1.32 (s, 3H); 13C NMR: 167.46, 136.05,
128.76, 128.43, 127.36, 109.49, 108.89, 96.10, 83.09, 70.69,
70.67, 70.29, 69.69, 59.12, 55.62, 45.11, 26.01, 25.89,
24.96, 24.73; CIMS (NH4) m/e 437 (M1NH4)1. Anal.
Calcd for C22H29 NO7: C, 63.00; H, 7.0; N, 3.3. Found: C,
62.78; H, 7.11; N, 3.15.
160.69, 156.93, 129.85, 119.72, 114.33, 110.72, 74.62,
65.11, 65.02, 61.51, 55.40, 26.53, 24.60; CIMS (NH3
reagent gas) m/e 336 (M1NH4)1; Anal. Calcd for C15H18
N4O4: C, 56.60; H, 5.66; N, 17.61. Found: C, 56.80; H, 5.96;
N, 17.47.
cis-1-(p-Anisyl)-3-amino-4-[(S)2,2-dimethyl-1,3-dioxalan-
4-yl]azetidin-2-one (15). Hydrogen sul®de gas was bubbled
through a solution containing 13f (0.5 g, 1.6 mmol) in dry
dichloromethane (50 mL) at 08C for 20 min. The reaction
mixture was quenched with triethylamine (0.6 mL,
4.3 mmol) in dichloromethane (5 mL). It was stirred for
l h at 08C, evaporated, the solid residue triturated with
benzene (10 mL) and ®ltered. The ®ltrate upon evaporation
at reduced pressure gave a residue of crude amine which
was crystallized from ethyl acetate±hexanes to afford pure
amine 15 in 95% yield (0.44 g); mp 1698C; [a]2D6ˆ281.90
cis-1-Benzyl-3S-benzyloxy-4R-[l0R,20S,30R,40-di-O-iso-
propylidene]butyl-azetidin-2-one (62) b-Lactam 62 was
prepared by following Methods A, B, and C, as described
above; yield: 70±75%; mp 1148C, IR (Nujol): 3050, 2950,
2900, 1740, 1600, 1480, 1450, 1440 cm21; 1H NMR: 7.38±
7.21 (m, 10H), 4.98 (d, Jˆ11.4 Hz, 1H), 4.90 (d,
Jˆ14.8 Hz, 1H), 4.7 (d, Jˆ11.4 Hz, 1H), 4.62 (d,
Jˆ5.16 Hz, 1H), 4.15 (d, Jˆ14.8 Hz, 1H), 4.10 (m, 1H),
4.05 (d, Jˆ7.04 Hz), 3.8 (m, 1H), 3.79 (m, 3H), 3.71 (dd,
J1ˆ5.09 Hz, J2ˆ6.76 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 3H),
1.21 (s, 6H); 13C NMR: 167.48, 136.95, 135.68, 128.76,
128.72, 128.69, 128.54, 127.69, 110.08, 109.36, 81.02,
79.33, 78.39, 75.74, 73.13, 65.69, 57.84, 45.12, 27.50,
26.21, 25.31; CIMS m/e 468 (M1H)1; Anal. Calcd for
C27H33NO6: C, 69.36; H, 7.11; N, 2.99. Found: C, 69.01;
H, 6.73; N, 3.08.
1
(cˆ0.48, MeOH); IR (Nujol) 3420, 1730 cm21; H NMR:
7.58±6.88 (dd, 4H), 4.4±4.15 (m, 4H), 3.91 (m, 1H), 3.82 (s,
3H), 1.80 (s,2H), 1.44 (s, 3H), 1.47 (s, 3H); 13C NMR:
168.60, 156.85, 131.62, 120.16, 114.46, 110.00, 77.00,
67.28, 61.77, 60.99, 55.79, 26.62, 25.50; CIMS (NH3
reagent) m/e: 310 (M1NH4)1; Anal. Calcd for
C15H20N2O4 C, 61.64; H, 6.85; N, 9.59. Found: C, 61.38;
H, 7.00; N, 9.20.
(3R,4S)-cis-1-(p-Anisyl)-3-mesyloxy-4-(S)-20,20-dimethyl-
10,30-dioxalan-4-yl)-azetidin-2-one (13e). A mixture of
hydroxy b-lactam (13d) (2.93 g, 10 mmol), triethylamine
(4.04 g, 40 mmol) and 4-dimethylaminopyridine (310 mg,
2.5 mmol) in dry dichloromethane (100 mL) was cooled
to 08C and methane sulfonyl chloride (2.28 g, 20 mmol) in
dichloromethane (10 mL) was added dropwise with stirring
under nitrogen atmosphere. The reaction mixture was stirred
at room temperature overnight. It was washed with dilute
hydrochloric acid (2£50 mL), brine (1£50 mL), dried, and
evaporated to give the crude mesylate 13e which was
puri®ed by ¯ash chromatography (silica gel, 230±400
mesh, hexane±ethyl acetate 7:3); yield: 3.5 g (95%); mp
1338C; [a]2D6ˆ297.4 (cˆ0.3, MeOH); IR (Nujol)
cis-l-(p-Anisyl)-3-phthalimido-4-[(S)2,2-dimethyl-1,3-
dioxalan-4-yl]azetidin-2-one (17). A solution of (15)
(0.4 g, 1.4 mmol) was taken in tetrahydrofuran (25 mL)
and treated with a saturated sodium carbonate solution
(5 mL) followed by Nefken's reagent (16) (0.5 g,
2.2 mmol). The reaction mixture was stirred at room
temperature for a period of 45 min, extracted with ethyl
acetate and dried. The organic layer upon evaporation
yielded the crude b-lactam which was puri®ed by column
chromatography using 1:1 ethyl acetate±petroleum ether to
give the bright yellow crystalline b-lactam 17 in 70% yield
(0.41 g); mp 1748C; [a]2D6ˆ233.2 (cˆ0.52, MeOH); IR
(Nujol) 1750, 1710 cm21 1H NMR: 8.0±7.7 (aromatic
;
1
1740 cm21; H NMR: 7.6±6.9 (dd, 4H), 5.65 (d, Jˆ5 Hz,
protons, 6H), 6.91 (d, aromatic, 2H), 5.50 (d, Jˆ6 Hz,
1H), 4.61±4.32 (m, 2H), 3.75 (m, 1H), 3.55 (t, 1H), 1.52
(s, 3H), 1.29 (s, 3H); 13C NMR: 166.63, 161.17, 156.96,
134.88, 131.20, 130.58, 123.69, 120.29, 114.33, 110.09,
75.89, 65.91, 60.66, 55.45, 55.36, 26.56, 24.93; CIMS
(CH4 reagent gas) m/e 423 (M1H)1; Anal. Calcd for
C23H22N2O6: C, 65.4; H, 5.21; N, 6.63. Found: C, 65.3; H,
5.28; N, 6.54.
1H), 4.37 (m, 3H), 3.85 (m, 1H), 3.7 (s, 3H), 3.3 (s, 3H),
1.55 (s, 3H), 1.35 (s, 3H); 13C NMR: 160.27, 157.13,
119.91, 114.11, 110.39, 77.93, 76.30, 66.61, 61.54, 55.47,
39.40, 26.58, 24.77; CIMS (NH3 reagent gas) m/e 389
(M1NH4)1; Anal. Calcd for C16H21NO7S: C, 51.75; H,
5.66; N, 3.77; S, 8.63. Found: C, 51.06; H, 5.36; N, 3.72;
S, 8.69.
(3S,4R)-trans-l-(p-Anisyl)-3-azido-4-[(S)20,20-dimethyl-
10,30-dioxalan-40-yl)]-azetidin-2-one (14). Lithium azide
(2.45 g, 50 mmol) was added to a solution of the mesylate
(13e) (3.5 g, 9.4 mmol) in dry N,N-dimethylformamide
(20 mL) and the resultant mixture was heated at 808C.
When TLC indicated the absence of the starting material,
it was poured onto ice water and extracted several times
with dichloromethane. The organic layer was washed with
water (5£100 mL), dried, and evaporated to give the title
compound as an oil which was puri®ed by ¯ash chroma-
tography (silica gel, 230±400 mesh, hexane±ethyl acetate,
1:1); yield: 2.59 g (91%); mp 96±988C; [a]2D6ˆ2119.8
trans-1-(p-Anisyl)-3-phthalimido-4-[4(S)2,2-dimethyl-1,3-
dioxalan-4-yl]azetidin-2-one (18). A mixture of 17 (50 mg,
0.12 mmol) in dry benzene (9 mL) and 1,5-diazadibicyclo
[4.3.0] non-5-ene (DBN) (14.7 mg, 0.12 mmol) was heated
under re¯ux in a nitrogen atmosphere. The solvent was
evaporated in vacuo and the crude product was chromato-
graphed over ¯orisil. Elution with 2:8 ethyl acetate±hexane
afforded 18 as a white crystalline solid in 75% isolated yield
(35 mg); mp 1278C; [a]2D6ˆ111.6 (cˆ0.5, MeOH); IR
1
(Nujol) 1745, 1720 cm21; H NMR (C6D6): 7.85±6.8 (dd,
AB pattern, 4H), 7.45±7.2 (m, 4H), 5.2 (d, Jˆ3 Hz, 1H),
4.56 (dd, 1H), 4.2 (q, 1H), 3.95 (m, 1H), 3.7 (m, 1H), 3.45 (s,
3H), 1.45 (s, 3H), 1.25 (s, 3H); 13C NMR: 166.70, 161.36,
157.00, 134.56, 132.55, 131.71, 123.80, 120.32, 114.37,
110.94, 75.90, 65.48, 60.73, 55.51, 55.38, 26.52, 24.98;
1
(cˆ0.5, MeOH); IR (Nujol) 2120, 1750 cm21; H NMR:
7.45±6.8 (dd, 4H), 4.5 (m, 2H), 4.05 (m, 2H), 3.85 (m,
1H), 3.81 (s, 3H), 1.52 (s, 3H), 1.42 (s, 3H); 13C NMR:

5614
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
EIMS m/e 423 (M)1; Anal. Calcd for C23H22N2O6: C, 65.4;
H, 5.21; N, 6.63. Found: C, 65.66; H, 5.54; N, 6.56.
tetrahydrofuran and water (30 mL) and re¯uxed for 48 h.
The reaction mixture was diluted with methylene chloride
(200 mL) and washed with saturated sodium bicarbonate
solution (3£50 mL) and water (2£50 mL), dried and
evaporation of the solvent gave a white solid 13h in quanti-
Synthesis of b-lactams 26a and 30b. To the b-lactam 25
(2 g, 5.5 mmol) or 30a, (4 g, 9.5 mmol) in a round bottom
¯ask was added a 1% solution of iodine in methanol
(20 mL) and (40 mL) respectively. The mixture was
re¯uxed for 4 h and at the end of that period methanol
was evaporated and the solid was taken in ethyl acetate
(1 L), washed with sodium thiosulphate solution (5%,
3£30 mL), brine (50 mL) and dried. Evaporation of the
solvent afforded the crude b-lactam 26a or 30b, respec-
tively. The b-lactams 26a or 30b were recrystallized from
methanol±ethyl acetate±hexane to yield 0.63 g, (35%) of
1
tative yield. IR (Nujol): 3400, 1735 cm21; H NMR: 7.25
(m, 5H), 4.84 (d, 1H), 4.45 (d, 1H), 4.25 (d, 1H), 4.0 (m,
1H), 3.65 (m, 3H), 3.6 (s, 3H), 3.30 (bs, 1H).
2-Methoxy-3(40-benzylamine)-5-hydroxy-pentano-g-lac-
tone (19). The b-lactam 13h (0.5 g, 1.7 mmol) was re¯uxed
in 90% tri¯uoro acetic acid (10 mL), cooled to 08C and
neutralized with solid NaHCO3. The resulting mixture was
extracted with ethyl acetate (3£15 mL), dried, ®ltered and
evaporated to afford crude lactone 19, which was puri®ed by
column chromatography using 3:7 ethyl acetate±hexane as
solvent; yield (0.3 g, 70%), mp 79±808C; [a]2D6ˆ167.4
pure 26a, mp 1188C; IR (Nujol): 3350±3500, 1730 cm21
;
1H NMR: 7.31 (m, 5H), 5.42 (d, 2H), 4.73 (d, 1H), 4.25 (m,
1H), 4.2 (m, 1H), 4.05 (d, 1H), 3.85 (d, 1H), 3.75 (s, 3H),
3.65 (m, 1H), 3.1 (s, 3H), 3.0 (brs, 1H); 13C NMR: 166.5,
135.6, 128.5, 127.9, 127.5, 108.8, 84.1, 83.4, 74.6, 72.6,
60.5, 59.0, 54.9, 44.6; CIMS (NH3) m/e 341 (M1NH4)1
and 1.26 g (37.5%) of pure 30b, mp 1678C; IR (CHC13):
1
(cˆ0.51, CHCl3); IR (Nujol) 3300, 1760 cm21; H NMR:
7.4 (brs, 1H), 7.35 (s, 5H), 4.5 (d, Jˆ7.81 Hz, 1H), 4.26 (m,
1H), 3.91 (m, 4H), 3.75 (m, 1H), 3.65 (s, 3H), 2.6 (brs, 1H);
CIMS (NH3) m/e 252 (M1H)1. Anal. Calcd for C13H17NO4:
C, 62.15; H, 6.77; N, 5.57. Found: C, 61.75; H, 6.51; N,
5.83.
3400, 3340,1725 cm21
;
1H NMR (CDC1311 drop
MeOH):7.30 (m, 5H), 4.81 (d, 2H), 4.52 (d, 2H), 4.31 (d,
1H), 4.09 (m, 4H), 3.72 (brs, 2H), 3.64 (s, 3H), 3.35 (s, 3H);
CIMS (NH3) m/e 371 (M1NH4)1; Anal. Calcd for
C17H23NO7: C, 57.8; H, 6.6; N, 4.0. Found: C, 57.93; H,
6.25; N, 3.84.
cis-1-(Benzyl)-3-methoxy-4-aldehydo-azetidin-2-one (26b).
To a stirred solution of the cis-methoxy b-lactam 13h (2.5 g,
10 mmol) in dry benzene (50 mL) was added lead tetra-
acetate (3.7 g, 8.4 mmol) at room temperature under nitro-
gen. The reaction mixture was stirred for 45 min and then
®ltered. The ®ltrate was puri®ed through ¯orisil column
eluting with dichloromethane. Evaporation of the solvent
yielded an oil 26b in quantitative yield (2 g), IR (neat):
1750, 1730 cm21; 1H NMR: 9.42 (d, Jˆ2.93 Hz, 1H), 7.35
(m, 5H), 4.75 (d, Jˆ4.88 Hz, 1H), 4.61 (d, Jˆ14.65 Hz,
1H), 4.52 (d, Jˆ14.6 Hz, 1H), 4.05 (m, 1H), 3.5 (s, 3H);
13C NMR: 198.48, 165.61, 134.27, 129.02, 128.62, 128.31,
85.81, 63.22, 59.15, 45.71; CIMS (NH3) m/e: 237
(M1NH4)1.
cis-1-(Benzyl)-3-methoxy-4-carbomethoxyazetidin-2-one
(27a and 31). To a solution of b-lactam 26a, (0.45 g,
1.4 mmol) or 30b (0.5 g, 1.4 mmol) in carbon tetrachloride,
acetonitrile and water (8 mL:8 mL:12 mL) was added
sodium metaperiodate (1.2 g, 5.6 mmol) and ruthenium
trichloride (5.7 mg, 0.028 mmol) and the mixture was
re¯uxed for 30 h. Dichloromethane (20 mL) was added
and the inorganic phase separated and extracted with
dichloromethane (3£10 mL). The combined dichloro-
methane extracts were dried and evaporated to yield a
crude b-lactam acid, (0.11 g, 37%) which was used as
such in the next step. It was found that the b-lactam acid
derived from either 26a or 30b showed exactly identical IR,
NMR and mass spectral data; IR (neat): 3400, 1750,
cis-1-(Benzyl)-3-methoxy-4-carbomethoxy-azetidin-2-one
(27b). To a solution of b-lactam 26b (0.11 g, 0.5 mmol) in
acetone (20 mL) was added Jones reagent (CrO3, 1.35 g,
13.6 mmol), conc. H2SO4, (0.12 mL), water, (0.5 mL) and
the mixture stirred at room temperature for 2 h. Ethyl
acetate (25 mL) was added to it, washed with water
(3£15 mL) and dried. Evaporation of the solvent yielded a
1
1730 cm21; H NMR: 8.1 (brs, 1H), 7.32 (m, 5H), 4.91 (d,
1H), 4.70 (d, 1H), 4.15 (d, 1H) 4.10 (d, 1H), 3.52 (s, 3H);
CIMS (NH3) m/e 267 (M1NH4)1.
A solution of the crude b-lactam acid (0.5 g, 2 mmol),
obtained from 30b was esteri®ed with diazomethane to
b-lactam (0.11 g, 91%); IR (neat): 3420, 1750, 1730 cm21
;
1H NMR: 7.3 (m, 5H), 6.3 (brs, 1H), 4.90 (d, 1H), 4.7 (d,
1H), 4.15 (d, 1H), 4.1 (d, 1H), 3.5 (s, 3H); CIMS (NH3) m/e
267 (M1NH4)1.
afford 31 as
a light yellow oil; (0.44 g, 85%);
[a]2D6ˆ243.28 (cˆ0.24, MeOH); IR (neat): 1760 cm21; H
NMR: 7.32 (m, 5H), 4.91 (d, Jˆ14.65 Hz, 1H), 4.74 (d,
Jˆ5 Hz, 1H), 4.15 (m, 2H), 3.83 (s, 3H), 3.5 (s, 3H); 13C
NMR: 168.46, 165.63, 134.3, 128.81, 128.43, 127.96, 85.09,
59.27, 58.11, 52.22, 44.94; CIMS (NH3) m/e 267
(M1NH4)1.
1
A solution of the above b-lactam (0.5 g, 2 mmol) was
dissolved in methanol (5 mL), cooled to 08C, and to this
was added crude diazomethane in anhydrous ether
(200 mL) [generated from N-nitroso methyl urea (1 g,
9.7 mmol) and 50% aqueous potassium hydroxide
(15 mL)]. After usual work-up the resulting oil was puri®ed
on silica gel column and eluted with 3:7 ethyl acetate±hex-
ane to yield 27b, (0.47 g, 90%); [a]2D6ˆ138.98 (cˆ0.26,
Similarly the oil 27a obtained from 26a was puri®ed and it
was found to be identical with 31.
cis-1-(Benzyl)-3-methoxy-4-[(S)20,20-dimethyl-10,30-dioxa-
lan-40-yl]azetidin-2-one (13h). The cis-methoxy-b-lactam
13g (2.91 g, 10 mmol) and p-toluene sulfonic acid mono-
hydrate (0.19 g, 1 mmol) were taken up in a (1:1) mixture of
1
MeOH); IR (neat) 1760 cm21; H NMR: 7.31 (m, 5H),
4.92 (d, Jˆ14.69 Hz, 1H), 4.75 (d, Jˆ4.9 Hz, 1H) 4.15
(m, 2H), 3.8 (s, 3H), 3.55 (s, 3H), 13C NMR: 168.4, 165.5,

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5615
134.2, 128.75, 128.33, 127.9, 85.04, 59.2, 58.09, 52.15,
44.79; CIMS (NH3) m/e 267 (M1NH4)1.
57.68, 26.15, 25.74, 25.05, 24.79; CIMS (NH3) m/e 533
(M1H)1 with characteristic chlorine isotope peak.
Synthesis of 35. A mixture of the b-lactam 30a, (2 g,
4.8 mmol), and sodium methoxide (0.27 g, 5 mmol) in abso-
lute methanol (25 mL) was re¯uxed under nitrogen atmos-
phere. At the end of 4 h a further amount of sodium
methoxide (0.1 g, 1.8 mmol) was added and the mixture
re¯uxed for additional 8 h. At the end of this period metha-
nol was evaporated and the product was dissolved in ethyl
acetate (75 mL) and washed with cold water (3£30 mL)
until the water washings were neutral and then it was
dried. The crude mixture obtained was passed through silica
gel column and eluted with ethyl acetate±hexanes (2:8) to
afford 35 as a white crystalline solid, 0.39 g (35%), mp
Synthesis of 34. To a solution of 30a (0.3 g, 0.69 mmol) in
anhydrous ether (20 mL) was added lithium aluminum
hydride (13 mg, 0.35 mmol) at room temperature under
nitrogen and the mixture re¯uxed for 1 h. It was then cooled
to 08C and to this a saturated solution of sodium sulfate was
added. The contents were allowed to warm to room
temperature (2 h) and ®ltered. The residue was washed
with ether (3£20 mL) and the combined ether layer was
dried and evaporated to yield 34 (0.18 g, 60%) as a white
solid; mp 99±1008C; IR (CHC13): 3600±3100 (b),
1
3340 cm21; H NMR: 7.3(m, 5H), 5.6 (d, 1H), 4.6 (q, 1H),
4.3 (m, 1H), 4.25±4.1 (m, 3H), 4.05 (m, 2H), 3.9 (d, 1H),
3.75 (m, 1H), 3.4 (brs, 1H), 3.35 (s, 3H), 3.2 (m, 1H), 1.6 (s,
3H), 1.4 (s, 3H),1.3 (s, 6H); 13C NMR: 140.12, 128.76,
128.35,126.98, 109.26, 108.79, 96.74, 77.51, 72.44, 71.19,
70.66, 67.26, 62.16, 60.35, 56.61, 52.51, 26.03, 25.84,
25.05, 24.44; CIMS (NH3) m/e 424 (M1H)1.
1
1238C; IR (Nujol): 3320, 1740 cm21; H NMR: 7.21 (m,
5H), 5.64 (d, 1H), 4.65 (q, 1H), 4.35 (d, 1H), 4.15 (d, 1H),
4.07 (m, 2H), 4.02 (d, 1H), 3.75 (d, 1H), 3.73, (s, 3H), 3.45
(s, 3H), 3.35 (q, 1H), 1.65 (bs, 1H), 1.5 (s, 3H), 1.45 (s, 3H),
1.3 (s, 6H); 13C NMR: 171.36, 141.54, 128.44, 127.94,
126.4, 109.48, 108.67, 96.72, 81.84, 71.53, 71.30, 70.59,
66.65, 58.85, 58.50, 51.97, 51.47, 26.09, 25.86, 25.05,
24.71; CIMS (NH3) m/e 452 (M1H)1; Anal. Calcd for
C23H33NO8: C, 61.2; H, 7.4; N, 3.1. Found: C, 61.06; H,
7.34; N, 2.93.
Synthesis of 37. 36 was reduced as described earlier to yield
pure 37, (94%) as a crystalline solid, mp 149±1508C; IR
(neat): 3550, 3440 cm21; [a]2D6ˆ291.87 (cˆ0.443, MeOH);
1H NMR: 7.30 (m, 10H), 5.75 (d, 1H), 5.51 (d, 1H), 4.65 (m,
3H), 4.42 (q, 1H), 4.15 (d, 1H), 3.9 (d, 4H), 3.45 (s, 3H),
1.65 (s, 3H), 1.5 (s, 3H), 1.4 (s, 3H), 1.3 (s, 3H); 13C NMR:
139.6, 130.0, 128.1, 128.0, 127.8, 126.8, 109.1, 108.6, 96.6,
79.4, 71.8, 71.1, 70.1, 67.9, 61.5, 58.5, 56.5, 26.0, 25.6,
24.9, 24.5; CIMS (NH3) m/e 515 (M1H)1. Anal. Calcd
for C29H39NO7: C, 67.84; H, 7.7; N, 2.73. Found: C,
67.73, H, 7.57, N, 2.85.
Synthesis of 36. A stirred solution of 35, (0.42 g, 0.9 mmol)
in acetonitrile (25 mL) containing dimethyl amino pyridine,
(0.88 g, 7.2 mmol) was re¯uxed under nitrogen with the
dropwise addition of benzyl bromide (0.6 g, 3.6 mmol). At
the disappearance of the starting material, acetonitrile was
evaporated. The solid residue was taken in ethyl acetate
(30 mL), washed with water (5£20 mL) and dried. Column
chromatography on silica gel with ethyl acetate±hexane
(1:4) yielded pure 36 (80%, 0.41 g) as a crystalline solid;
Synthesis of 39. To a solution of 38 (600 mg, l mmol), in
dry THF (10 mL) was added a clear solution of LiAlH4 in
THF (1 mol, 1 mL, 1 mmol). The mixture was allowed to
re¯ux under nitrogen for 24 h. It was cooled to 08C and the
excess LiAlH4 was quenched by the addition of ice-cold
water, ®ltered, washed with THF, evaporated most of the
THF, extracted with ethyl acetate (3£25 mL), washed with
brine (25 mL), dried and evaporated. The crude product was
puri®ed by chromatography (ethyl acetate±hexaneˆ1:8)
and pure 39 was obtained as a white solid (0.52 g, 92%);
mp 1488C; IR (Nujol): no characteristic absorption except
1
mp 1678C; IR (CHCl3): 1740 cm21; H NMR: 7.21 (m,
10H), 5.73 (d, 1H), 4.71 (q, 1H), 4.55 (d, 1H), 4.4 (m,
1H), 4.10 (d, 1H), 4.0 (m, 1H), 3.85 (d, 4H), 3.55 (dd,
1H), 3.4 (s, 3H), 3.3 (s, 3H), 1.65 (s, 3H), 1.55 (s,
3H), 1.45 (s, 3H), 1.35 (s, 3H); 13C NMR: 170.5,
140.8, 130.0, 127.7, 126.3, 109.6, 108.9, 96.6,
83.3,72.1, 71.5, 70.4, 67.9, 59.0, 57.1, 56.3, 51.3,
26.3,25.8, 25.1, 24.9; CIMS (NH3) m/e 543 (M1H)1.
Synthesis of 38. To an ice cold solution containing
methanesulfonyl chloride (0.2 g, 1.75 mmol) in anhydrous
pyridine (1.5 mL), and a catalytic amount of DMAP
(0.21 mg, 0.001 mmol) was added dropwise, the substrate
37 (0.35 g, 0.69 mmol) in dry dichloromethane (25 mL)
under a nitrogen atmosphere. The reaction was allowed to
warm up to room temperature. When the starting material
disappeared, pyridine was evaporated, water was added
(20 mL), and the product was extracted with dichloro-
methane (2£30 mL) and washed with brine (30 mL). The
crude product was puri®ed by chromatography (1:7 ethyl
acetate±hexanes to yield pure 38 as an oil (0.196 g, 63%);
IR (neat): no characteristic absorption except in the ®nger-
print region; 1H NMR: 7.20 (m, 10H), 5.72 (d, 1H), 4.72 (m,
1H), 4.50 (m, 1H), 4.41 (m, 1H), 4.23 (m, 2H), 3.91 (d, 2H),
3.80 (m, 1H), 3.53 (d, 2H), 3.47 (s, 3H), 3.33 (m, 1H), 3.16
(m, 1H), 1.62 (s, 3H), 1.50 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H);
13C NMR: 140.12, 129.58, 128.14, 126.85, 109.25, 108.50,
96.61, 83.08, 79.04, 71.9, 71.04, 70.18, 67.96, 61.33, 58.71,
1480 cm21
, adjacent to nujol absorption at 1440,
1
1360 cm21; [a]D26ˆ276.14 (cˆ0.346, CHC13); H NMR:
7.32 (m, 10H), 5.72 (d, 1H), 4.65 (m, 1H), 4.54 (m, 1H),
4.37 (m, 1H), 4.16 (m, 1H), 3.90 (d, 4H), 3.43 (m, 1H), 3.17
(s, 3H), 2.85 (m, 1H), 1.64 (s, 1H), 1.44 (s, 3H), 1.36 (s, 3H),
1.3 (s, 3H), 1.05 (d, 3H); 13C NMR: 141.58, 129.76,129.35,
127.74, 126.38, 109.16, 108.7, 96.79 ` 77.95, 72.27, 71.29,
70.31, 68.84, 58.45, 56.32, 56.09, 26.21, 25.77, 25.17,
24.97, 15.97; CIMS (NH3) m/e 499 (M1H)1; Anal. Calcd
for C29H39NO6: C, 70.02; H, 7.85; N, 2.82. Found: C, 69.3;
H, 7.93; N, 2.79. The structure and stereochemistry were
con®rmed by single crystal X-ray diffraction study.
1-Benzyl-3S-benzyloxy-4R-[10R,20S-O-isopropylidene-30R,
40-dihydroxy]butyl azetidine-2-one (63). To a solution of
b-lactam 62 (8 g, 17.16 mmol) in methanol (32 mL) was
added water (40 mL) followed by glacial acetic acid
(48 mL). The reaction mixture was stirred at room
temperate for 60 h. The acid was neutralized by careful

5616
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
addition of sodium carbonate solution (10%) and the
mixture was extracted with ethyl acetate (4£50 mL),
washed with brine, dried and evaporated. The pure product
63 was isolated after crystallization from ethyl acatate±
hexanes: 5.84 g (80%); mp 1008C; IR (Nujol): 3400,
Pd-C (3.5 g) and the mixture was heated under re¯ux for
30 min. Catalyst was ®ltered off and ethanol was evaporated
under reduced pressure. The residue was taken in ethyl ace-
tate (150 mL) and washed with brine (2£25 mL), dried and
evaporated. The semisolid residue on crystallization from
ethyl acetate±hexanes gave the pure b-lactam diol 65a
(2.43 g, 90%), mp 1098C; IR (Nujol): 3300, 3050, 2950,
1
3500, 2950, 1738, 1620 cm-l, H NMR: 7.36±7.23 (m,
10H), 5.06 (d, Jˆ11. 24 Hz, 1H), 4.9 (d, Jˆ14.16 Hz,
1H), 4.75 (d, Jˆ11. 24 Hz, 1H), 4.63 (d, Jˆ4.92 Hz, 1H),
4.3 (dd, J1ˆ5.67 Hz, J2ˆ9.05 Hz, 1H), 4.2 (d, Jˆ4.16 Hz,
1H), 3.6 (m, 5H), 1.34 (s, 3H), 1.27 (s, 3H); 13C NMR:
163.38 135.52, 135.33, 128.85, 128.82, 128.79, 128.69,
109.85, 80.50, 79.63, 73.11, 72.04, 63.67, 58.05, 45.37,
27.29; CIMS m/e: 428 (M1H)1; Anal. Calcd for
C24H29NO6: C, 67.43, H, 6.83, N, 3.27. Found: C, 67.62;
H, 6.49; N, 3.33.
1
2900, 1730, 1580, 1400 cm21; H NMR: 7.68±7.14 (m,
5H), 4.84 (d, Jˆ4.63 Hz, IH), 4.78 (d, Jˆ14.61 Hz, 1H),
4.21 (d, Jˆ14.6 Hz, 1H), 4.2 (dd, J1ˆ9 Hz, J2ˆ2.25 Hz,
1H), 3.8 (m, 3H), 3.6 (dd, J1ˆ4.6 Hz, J2ˆ9 Hz, 1H), 1.38
(s, 3H), 1.30 (s, 3H); 13C NMR: 168.96, 135.26, 128.62,
128.53, 128.50, 127.47, 109.35, 79.82, 78.84, 74.98,
62.42, 60.0, 45.21, 26.95; CIMS m/e: 308 (M1H)1 Anal.
Calcd for C16H21NO5: C, 62.53; H, 6.88; N, 4.55. Found: C,
62.35; H, 6.67; N, 4.63.
1-Benzyl-3S-benzyloxy-4R-[l0R,20S-O-isopropylidene-3-
oxo]propyl-azetidin-2-one (64a). To a mixture of b-lactam
diol 63 (5 g, 11.7 mmol) in methanol (15 mL) and water
(25 mL) was added a solution of sodium periodate (2.67 g,
12.5 mmol) in water (60 mL) at 0±58C within 15 min with
stirring. The stirring was continued at 0±58C for additional
1 h. The aldehyde 64a was isolated after extraction with
ethyl acetate (4£40 mL) and drying, as a gummy solid
Microwave-assisted catalytic transfer hydrogenation
The standard method in our laboratory now for reduction or
hydrogenolysis25 is to use high temperature (100±1508C)
catalytic transfer hydrogenation with ammonium formate
as the hydrogen source, Pd/C as the catalyst, and ethylene
glycol (bp 1988C) as the reaction medium. Microwave
irradiation in a beaker or a conical ¯ask for 2±3 min is
adequate to raise the temperature of the reaction mixture
to 120±1308C and the reduction or hydrogenolysis step is
complete in near quantitative yield in another 2 or 3 min.
4.3l g (90%); IR (Nujol): 1735, 1720, 1610 cm21 1H
;
NMR: 9.49 (d, Jˆ2.23 Hz, 1H), 7.39±7.21 (m, 1H), 4.98
(d, Jˆ11.51 Hz, 1H), 4.83 (d, Jˆ14.4 Hz, 1H), 4.69 (d,
Jˆ11.68 Hz, 1H), 4.63 (d, Jˆ5.14 Hz, 1H), 4.25 (d,
Jˆ14.4 Hz, IH), 4.56 (dd, J1ˆ6.21 Hz, J2ˆ8.80 Hz, 1H),
4.01 (dd, J1ˆ2.7 Hz, J2ˆ6.14 Hz, 1H), 3.67 (dd,
J1ˆ5.13 Hz, J2ˆ8.81 Hz, 1H), 1.42 (s, 3H), 1.34 (s, 3H);
13C NMR: 196.67, 166.63, 135.93, 135.23, 128.31, 128.19,
127.95, 127.42, 111.77, 82.16, 79.74, 77.12, 72.57, 58.31,
44.67, 26.64, 26.21; CIMS m/e: 410 (M1H)1; Anal. Calcd
for C23H25NO5: C, 69,86; H, 6.37; N, 3.54. Found: C, 70.12;
H, 6.61; N, 3.42.
We23 used the above technique to convert the a-benzyloxy
b-lactam 51 to the a-hydroxy b-lactam 52 in excellent
yield. We prepared 25 g of 52 in only one day starting
with mannitol diacetonide (45). Fortunately the N-benzyl
group of a b-lactam is unaffected under these conditions.
But the N-benzyl group can be successfully removed from
the open amines as shown by the conversion of 53 to 54, and
66 to 67a. However, an aryl group at C4 leads to the scission
of the C4±N bond a shown by Ojima et al.33 Selective reduc-
tion has been achieved without b-lactam scission by using
Ra±Ni catalyst in place of Pd/C catalyst.25
1-Benzyl-3S-benzyloxy-4R-[10R,20S-O-isopropylidene-30-
hydroxy]propyl-azetidin-2-one (64b). Sodium boro-
hydride (383 mg, 10.12 mmol) was added to a stirred
solution of the aldehyde 64a (4 g, 10.12 mmol) in methanol
(100 mL) at 0±58C and then the mixture was stirred at the
same temperature for 1 h. Water (25 mL) was added and
most of the methanol was evaporated under reduced
pressure. The residue was extracted with ethyl acetate
(4£40 mL), washed with brine (2£20 mL) and evaporated.
The crude product on crystallization from ethyl acetate±
hexanes gave the pure alcohol (64b, 3.49 g, 90%), mp
818C; IR (Nujol): 3400, 3020, 2950, 2900, 1735, 1595,
General procedure for hydrogenation in a microwave
oven. A detailed experimental procedure and safety prin-
ciple for catalytic transfer hydrogenation experiment is
described in our earlier publication.25b To 10 mL of ethylene
glycol (or 1,3-propanediol) in an Erlenmeyer ¯ask were
added b-lactam (2.72 mmol), ammonium formate
(10.84 mmol) and 10% Pd-C (1 g). This reaction mixture
was irradiated in a microwave oven for 3 min, at low
power setting and ®ltered. The ®ltrate was diluted with
water (50 mL) and extracted with ethyl acetate
(3£20 mL). Evaporation of the solvent gave the product in
90% yield. b-Lactam 65a was prepared following the
microwave irradiation method in 90% yield.
;
1490 cm21 1H NMR: 7.71±7.20 (m, 10H), 4.98 (d,
Jˆ11.4 Hz, 1H), 4.60 (d, Jˆ5.09 Hz, 1H), 4.7 (d, Jˆ
11.4 Hz, 1H), 4.22 (dd, J1ˆ6.45 Hz, J2ˆ9.1 Hz, 1H), 4.20
(d, Jˆ14.55 Hz, 1H), 3.84 (m, 1H), 1.40 (s, 3H), 1.23 (s,
3H); 13C NMR: 166.78, 135.99, 135.57, 128.48, 128.42,
128,39, 128.2, 127.47, 109.61, 80.21, 79.99, 78.47, 72.75,
62.61, 58.6, 44.99, 27.19; CIMS m/e: 398 (M1H)1; Anal.
Calcd for C23H27NO5: C, 69.50; H, 6.84; N, 3.52. Found: C,
69.62; H, 6.66, N, 3.62.
1-Benzyl-3S-hydroxy-4R-[10R,20R-O-isopropylidene-30-
triphenylmethoxy]propyl azetidin-2-one (65b). Trityl
chloride (2.44 g, 8.79 mmol) in dry dichloromethane
(50 mL) was added dropwise to a stirred solution of the
b-lactam diol 65a (2.7 g, 8.79 mmol) in dry dichloro-
methane (100 mL) and triethylamine (2.66 g, 26.38 mmol)
at 2308C. Stirring at this temperature was continued for 2 h
and then the mixture was kept at 08C for 24 h. The reactants
1-Benzyl-3S-hydroxy-4R-[10R,20R-O-isopropylidene-30-
hydroxy]propylazetidin-2-one (65a). To a solution of the
b-lactam alcohol 64b (3.5 g, 8.81 mmol) in absolute ethanol
(120 mL) was added ammonium formate (3.5 g) and 10%

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5617
were washed with dilute hydrochloric acid (2%, 4£l0 mL),
water (2£25 mL), sodium bicarbonate solution (5%,
2£25 mL), brine, dried and evaporated. The crude product
on crystallization from ethyl acetate gave the pure trityl
b-lactam 65b (3.86 g, 80%); mp 2108C; IR (Nujol): 3800,
3020, 1735, 1620 cm21; 1H NMR: 7.34±7.22 (m, 20H), 4.88
(d, Jˆ14.74 Hz, 1H), 4.81 (dd, J1ˆ4.57 Hz, J2ˆ8.86 Hz),
4.14 (d, Jˆ14.74 Hz, 1H), 4.04±3.98 (m, 2H), 3.69±3.65
(m, 1H), 3.34 (d, Jˆ9.15 Hz, 1H), 3.41±3.39 (m, 1H), 3.1±
3.08 (m, 1H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR (DM SO):
169.14, 136.52 128.45, 127.76, 126.97, 117.92, 109.95,
78.00, 77.2, 74.81, 63.9, 60.0, 43.92, 27.5, 27.15; CIMS
m/e: 551 (M1H)1, Anal. Calcd for C35H35NO5: C, 76.48;
H, 6.42; N, 2.54. Found; C, 76.02; H, 5.95; N, 2.65.
5H), 3.58 (brs, 1H), 3.44±3.23 (m, 3H), 2.82 (brs, 1H),
1.44 (s, 3H); 13C NMR: 157.00, 143.54, 128.91, 128.75,
128.56, 128.51, 127.07, 126.93, 109.74, 87.09, 80.49,
80.21, 74.22, 63.71, 62.62, 49.58, 28.22, 28.02; CIMS
m/e: 565 (M1H)1. Anal. Calcd for C33H41NO7: C, 70.32; H,
7.33; N, 2.48. Found: C, 70.30; H, 7.21; N, 2.47.
Synthesis of the t-Boc derivative 55. The compound 55
was prepared by conventional and microwave-assisted
method in a similar way from 54 in 50% yield as described
1
for 66; yield 60%, IR (Nujol): 3450, 1690, 1600 cm21; H
NMR: 5.14 (d, Jˆ9.60 Hz, 1H), 4.43±4.37 (m, 1H), 4.12±
4.05 (m, 1H), 3.94±3.42 (m, 5H), 3.15 (brs, 2H), 1. 46 (s,
12H),1.37 (s, 3H); 13C NMR: 110.18, 80.78, 74.19, 66.91,
63.16, 5 1.00, 28.67, 26.61, 25.44; CIMS m/e: 292 (M1H)1.
Anal. Calcd for C13H25O6N: C, 53.60; H, 8.65; N, 4.80.
Found: C, 53.60; H, 8.57; N, 4.69.
(2R,3R-O-Isopropylidene-4S-) (N-benzylamino)-5R,6-di-
hydroxyhexyl-triphenylmethyl ether (66). To a solution
of the trityl b-lactam 65b (2.4 g, 4.37 mmol) in dry tetra-
hydrofuran (60 mL) was added LiAlH4 (332 mg,
8.74 mmol) and the mixture was re¯uxed for 3 h. After
usual work-up as described for 39, the crude product on
¯ash chromatography afforded the pure amino alcohol 66
(1.93 g, 80%); IR (Nujol): 3350, 3050, 2900, 1590 cm21; 1H
NMR: 7.44±7.11 (m, 20H), 4.21±3.85 (m, 4H), 3.61 (s, 2H),
3.34±3.27 (m, 2H), 2.90±2.84 (m, 2H), 1.40 (s, 3H), 1.34 (s,
3H); 13C NMR: 143.71, 139.72, 128.65, 128.5, 128.17,
127.86, 127.25, 127.09, 108.91, 79.27, 77.65, 70.68, 64.4,
58.31, 53.68, 27.22, 26.98; CIMS m/e: 555(M1H)1 Anal.
Calcd for C35H39NO5: C, 75.92, H, 7.10; N, 2.53. Found: C,
75.71; H, 6.99; N, 2.50.
Oxidation of diol 67b to the carboxylic acid 68. To a
solution of diol 67b (1.52 g, 2.66 mmol) in carbon tetra-
chloride (16 mL), acetonitrile (16 mL) and water (24 mL)
was added sodium periodate (3.42 g, 16 mmol) and the
mixture was stirred. After 5 min, RuCl3 (25 mg) was
added and the stirring was continued at room temperature
for 6 h. The mixture was ®ltered and the residue was washed
with ethyl acetate (50 mL), washed with brine (2£25 mL),
dried and evaporated. The residue after chromatographic
puri®cation over silica gel with ethyl acetate±hexanes
(1:1) as eluent gave the pure acid 68 (1.2 g, 83%); mp
1728C; IR (Nujol): 3350, 3050, 2950, 1720, 1695,
1
1600 cm21; H NMR: 9.35 (brs, 1H), 7.56±7.23 (m, 15H),
Synthesis of the amino-alcohol 53. Amino-alcohol 53 was
prepared in a similar way as described for 66, yield 80%, IR
5.36 (d, 1H), 4.6±4.52 (m, 2H), 4.15±4.02 (m, 1H), 3.47±
3.29 (m, 2H); 13C NMR: 176.0, 156.05, 143.6, 129.72,
127.85, 127.07, 110.0, 87.02, 80.05, 63.8, 53.2, 28.25,
26.87; CIMS m/e: 549 (M 1H) 1; Anal. Calcd for
C32H37NO7: C, 70.18, H, 6. 81; N, 2.55. Found: C, 69.99,
H, 6.51, N, 2.47.
1
(Nujol) 3400, 3020, 1590 cm21; H NMR: 7.35 (brs, 5H),
4.26 (d, Jˆ6.38 Hz, 1H), 4.08 (dd, Jˆ6.44, 8.26 Hz, 1H),
3.91 (d, Jˆ1 2.74 Hz, 2H), 3.77 (dd, Jˆ6.77, 8.16 Hz, 1H),
3.67 (m, 2H), 2.77 (dd, J1ˆ3.9 Hz, J2ˆ6.05 Hz, 1H), 1.43
(s, 3H), 1.36 (s, 3H), 13C NMR: 139.71, 128.60, 128.44,
127.27, 109.20, 76.41, 70.29, 67.09, 64.86, 60.80, 53.42,
26.57, 25.22; CIMS m/e: 282 (M1H)1. Anal. Calcd for
C15H23NO4: C, 64.04, H, 8.24; N, 4.97. Found: C, 63.81;
H, 8.27; N, 4.95.
Oxidation of diol 55 to the carboxylic acid 56. Carboxylic
acid 56 was prepared in a similar way as described for 67b,
yield 80%, mp 1668C; IR (Nujol) 3340, 1715, 1695 cm21
;
1H NMR: 5.23 (d, Jˆ8.99 Hz, 1H), 4.67±464 (m, 1H),
4.46±4.41 (m, 1H), 4.17±4.09 (m, 1H) 3.86±3.79 (m,
1H), 1.47 (s, 12H), 1.36 (s, 3H); CIMS m/e: 276
(M1H)1; Anal. Calcd for C12H21NO6: C, 52.36; H, 7.69;
N, 5.08. Found: C, 52.97; H, 8.24; N, 4.74; CIMS m/e: 276
(M1H)1.
Synthesis of the t-Boc derivative 67b. To a solution of the
alcohol 66 (4 g, 7.23 mmol) in dry ethanol (150 mL) was
added ammonium formate (2.28 g, 36.16 mmol) followed
by Pd-C (10%, 2.28 g). This mixture was heated under
re¯ux for 10 min. After usual work-up 67a was obtained
as an oil (3.1 g, 93%) which was used as such for the next
step without puri®cation. 67a was also prepared by follow-
ing the microwave irradiation method in 95% yield.
(2)-Polyoxamic acid (60). To the acid 68 (330 mg,
0.6 mmol) was added cold methanol and TFA mixture
(1:10, 12 mL) and the mixture was kept at room temperature
for 1.5 h. Dry ether (120 mL) was added to it, cooled for 2 h,
®ltered, the residue washed with dry ether and the white
amorphous solid subjected to ion-exchange chromatography
(AG50W-X8H1 column, aqueous ammonia as the eluent) to
afford pure 60 (90 mg), mp 165±1728C (dec); [a]2D5ˆ25.18
(cˆ1. 0, H20); IR (KBr): 3400, 2950, 1687, 1500 cm21; 1H
NMR (D20):4.86 (m, 1H), 4.53 (d, Jˆ3.1 Hz, 1H), 4.39±
4.29 (m, lH), 4.16±4.01 (m, 2H).
A soluton of di-tert-butyldicarbonate (1.41 g, 65 mmol) in
dioxane (10 mL) was added to a solution of the amino
alcohol 67a (2 g, 6.03 mmol) in NaOH solution (l N,
9 mL) at 0±58C. Stirring at this temperature was done for
1 h and continued for 3 h at room temperature. The reaction
mixture was extracted with ethyl acetate (5£25 mL),
washed with brine (2£25 mL), dried and evaporated. The
crude product was puri®ed by ¯ash chromatography over
silica gel to afford the pure 67b (2 g, 83%); IR (Nujol):
Synthesis of l-g-hydroxythreonine (57). 57 was prepared
in a similar way as described for 60; mp 200±2108C (dec.);
[a]2D6ˆ2108 (cˆ1.0, H20); IR (Nujol) 3380, 1690,
3400, 3050, 2950, 2900, 1695, 1590, 1480 cm21 1H
;
NMR: 7.48±7.18 (m, 15H), 5.24 (d, 1H), 4.08±3.85 (m,

5618
A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
1500 cm21; 1H NMR (D20): 4.21±4.14 (m, 1H), 3.85±3.79
(m, 1H), 3.73±3.71 (m, 2H).
Chiang, J.; Bose, A. K. Heterocycles 1988, 27, 1755. (c) Ojima,
I. Acc. Chem. Res. 1995, 28, 383.
5. For the recent synthesis of some homochiral b-lactams, see: (a)
Srirajan, V.; Deshmukh, A. R. A. S.; Bhawl, B. M. Tetrahedron
1996, 52, 5585. (b) Palomo, C.; Oiarbide, M.; Esnal, A.; Landa, A.;
Miranda, J. D.; Linden, A. J. Org. Chem. 1998, 63, 5838; and
references cited therein.
Synthesis of the lactone 69. To the amino acid 60 (70 mg,
0.42 mmol) was added dry methanol (8 mL) followed by
distilled acetic anhydride (0.4 mL) and stirred vigorously
for 24 h. After evaporation of the solvent and excess reagent
under reduced pressure, the residue was chromatographed
over silica gel using methanol±ethyl acetate as eluent to
afford the lactone 69 (56 mg, 70%); mp 1488C; IR (KBr):
3510, 3283, 3056, 2929, 2843, 1769, 1748, 1652, 1642,
6. For example, see (a) Banik, B. K.; Newaz, S. N.; Manhas. M. S.;
Bose, A. K. Synlett 1993, 897. (b) Banik, B. K.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1994, 59, 4714. (c) Banik, B. K.;
Subbaraju, G. V.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett.
1996, 37, 1363. (d) Banik, B. K.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1997, 38, 5077. (e) Banik, B. K.; Zegrocka,
O.; Manhas, M. S.; Bose, A. K. Heterocycles 1997, 46, 173.
7. Trost, B. M. Science 1991, 254, 1471.
1535 cm21
;
IR (CHC13): 3500±3400, 2950, 1765,
1650 cm21; H NMR (CDC13, 1 trace of DMSO): 8.34
(d, 1H), 5.53 (d, Jˆ5.01 Hz, 1H), 4.81 (t, Jˆ5.64 Hz, IH),
4.60±4.50 (m, 3H), 3.88±3.82 (m, 1H), 1.98 (s, 3H); 13C
NMR (CDC13 1 trace of DMSO): 173.08, 168.0, 78.2, 71.0,
58.5, 57.0, 21.9; HRMS for C7Hl1NO5: Calculated:
190.07155 (M1H)1. Found: 190.07155 (M1H)1.
1
8. (a) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei,
K.; Urbanczyk-Lipkowsa, Z. Heterocycles 1990, 30, 741. (b) Bose,
A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.; Bari, S. S.;
Newaz, S. N.; Banik, B. K.; Chaudhury, A. G.; Barakat, K. J.
J. Org. Chem. 1991, 56, 6968. (c) Bari, S. S.; Bose, A. K.;
Chaudhury, A. G.; Manhas, M. S.; Raju, V. S.; Robb, E. W.
J. Chem. Edn. 1992, 69, 938. (d) Banik, B. K.; Newaz, S. N.;
Manhas, M. S.; Bose, A. K. Bioorg. Med. Chem. Lett. 1993, 3,
2363. (e) Bose, A. K.; Manhas, M. S.; Banik, B. K.; Robb, E. W.
Res. Chem. Intermed. 1994, 20, 1. (f) Banik, B. K.; Jayaraman, M.;
Srirajan V.; Manhas, M. S.; Bose, A. K. J. Indian Chem. Soc. 1997,
74, 951. (g) Banik, B. K.; Manhas, M. S.; Robb. E. W.; Bose, A. K.
Heterocycles 1997, 44, 405.
Acknowledgements
We are grateful to the Stevens Institute of Technology for
research facilities and a teaching assistantship to one of us
(C. M.). Thanks are due to the Howard Hughes Medical
Institute for partial support in the early stages of this project.
We are very thankful to George Barasch and the New York
Cardiac Center for the support of several undergraduate
participants in our research project. We wish to thank Ann
Randy, Linda Hackfeld, Anju Sharma, Sochanchingwung
Rumthao, Unmesh Shah and Indrani Banik for technical
help in the preparation of this manuscript.
9. For reviews on microwave chemistry, see: (a) Abramovich,
R. A. Org. Prep. Proc. Int., 1991, 23, 683. (b) Mingos, D. M.;
Baghurst, D. R. Chem Soc. Rev. 1991, 20, 1. (c) Whittaker,
A. G.; Mingos, D.M.P. J. Microwave Power, Electromagnetic
Energy 1994, 29, 195. (d) Majetich, G.; Hicks, R. J. Microwave
Power Electromagnetic Energy 1995, 30, 27. (e) Caddick, S.
Tetrahedron 1995, 51, 1040. (f) Strauss, C. R.; Trainor, R. W.
Aust. J. Chem. 1995, 48, 1665. (g) Langa, F.; Cruz, P. D. I.;
Hoz, A. D. L.; Diaz-Ortiz, A.; Diez-barra, E. Contemp. Org.
Synthesis 1997, 74, 951. (h) Bose, A. K.; Banik, B. K.; Lavlinskaia,
L.; Jayaraman, M.; Manhas, M. S. Chemtech 1997, 27, 18.
10. Suffness, M. Taxolw Science and Applications, CRC Press:
Boca Raton, FL, 1995.
References
1. Studies in Lactams, part 108. Microwave-induced Organic
Reaction Enhancement (MORE) chemistry, part 15. Studies in
Lactams, for part 107 and MORE chemistry, for part 14, see:
Manhas, M. S.; Banik, B. K.; Mathur, A.; Vincent, J. E.; Bose,
A. K. Tetrahedron, Symposium in Print, 2000, 56, 5587±5601.
MORE chemistry, for part 13, see: Banik, B. K.; Barakat, K. J.;
Wagle, D. R.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1999, 64,
5746. Studies in Lactams, for part 106, see: Jayaraman, M.;
Batista, M. T.; Manhas, M. S.; Bose, A. K. Heterocycles 1998,
49, 97.
11 Bose, A. K.; Manhas, M. S.; van der Veen, J. M.; Bari, S. S.;
Wagle, D. R. Tetrahedron 1992, 48, 4831.
12 (a) Hubscwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66,
2206. (b) Hubscwerlen, C. Synthesis 1986, 962.
13 (a) Bose, A. K.; Manhas, M. S.; van der Veen, J. M.; Bari, S. S.;
Wagle, D. R.; Hegde, V. R.; Krishnan, L. Tetrahedron Lett. 1985,
26, 33. (b) Bose, A. K.; Hegde, V. R.; Wagle, D. R.; Bari, S. S.;
Manhas, M. S. J. Chem Soc., Chem. Commun. 1986, 16.
14 (a) Bose, A. K.; Manhas, M. S.; van der Veen, J. M.; Bari, S. S.;
Wagle, D. R.; Hegde, V. R.; Krishnan, L. Tetrahedron Lett. 1985,
26, 33. (b) Bose, A. K.; Manhas, M. S., van der Veen, J. M.; Bari,
S. S.; Wagle, D. R.; Hegde, V. R. In Third International Sym-
posium on Recent Advances in the Chemistry of b-Lactam Anti-
biotics, Spec. Publ. No. 52; The Royal Society of Chemistry, 1985,
p 387.
2. For some recent examples, see: (a) Southgate, R.; Brach, C.;
Coulton, S.; Hunt, E. In Recent progress in the Chemical Synthesis
of Antibiotics and Related Microbial Products; Lukacs, G., Ed.;
Berlin: Springer, 1993; Vol. 2, p 621. (b) Southgate, R. Contemp.
Org. Synthesis 1994, 1, 417. (c) Georg, G. I. In The Organic
Chemistry of b-Lactams; VCH Publishers: New York, 1992. (d)
Bose, A. K.; Manhas, M. S.; Banik, B. K.; Srirajan, V. In The
Amide Linkage: Selected Structural Aspects in Chemistry,
Biochemistry, and Material Science; Greenberg, A., Breneman,
C. M., Liebman, J. F., Eds.; Wiley±Interscience: New York,
2000; p 157, Chapter 7 (b-Lactams: Cyclic Amides of Distinc-
tion).
15. Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys,
B. E.; Strohmeyer, T. W.; Hegde, V. R.; Manhas, M. S.; Bose, A. K.
J. Org. Chem. 1988, 53, 4227.
3. Burnett, D. A.; Caplen, M. A.; Darris Jr., H. R.; Burrier, R. E.;
Clader, J. W. J. Med. Chem. 1994, 37, 1733.
16. Szarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R.
Tetrahedron Lett. 1986, 27, 3827.
4. For example: (a) Manhas, M. S.; Amin, S. G.; Bose, A. K.
Heterocycles 1976, 5, 699. (b) Manhas, M. S.; Wagle, D. R.;
17. (a) Howorth, G. B.; Lance, D. G.; Szarek, W.A.; Jones, J. K. N.
J. Chem. Soc., Chem. Commun. 1969, 47, 75. (b) Danishefsky,

A. K. Bose et al. / Tetrahedron 56 (2000) 5603±5619
5619
S. M.; Larson, E.; Springer, J. P. J. Am. Chem. Soc. 1985, 107,
1274; and references cited therein.
245. (c) Saksena, A. K.; Lovey, R. G.; Girijavallabhan, V. M.;
Ganguly, A. K. J. Org. Chem. 1986, 51, 5024. (d) Hirama, H.;
Hioku, H.; Ito, S. Tetrahedron Lett. 1988, 29, 3125. (e) Garner,
P.; Park, J. M. J. Org. Chem. 1988, 53, 2979. (f) Savage, I.;
Thomas, E. J. J. Chem. Soc., Chem. Commun. 1989, 717. (g)
Dureault, A.; Carreaux, F.; Depezay, J. C. Synthesis 1990, 46,
265. (h) Paz, M. M.; Sardina, F. J. J. Org. Chem. 1993, 58,
6990. (i) Dondini, A.; Franco, S.; Merchan, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1993, 34, 5479. (j) Matsura, F.;
Hamada, Y.; Shioroi, T. Tetrahedron Lett. 1994, 35, 733. (k)
Marshall, J. A.; Seletsky, B. M.; Coan, P. S. J. Org. Chem. 1994,
59, 5139. (l) Jackson, R. F. W.; Palmer, N. J.; Wythes, M. J.; Clegg,
W.; Elsegood, M. R. J. Org. Chem. 1995, 60, 6431. (m) Kang,
S. H.; Choi, H. W. Chem Commun. 1996, 1521. (n) Trost, B. M.;
Krueger, A. C.; Bunt, R. C., Zombrano, J. J. Am. Chem. Soc. 1996,
118, 6520. (o) Bandini, E.; Martelli, G.; Spunta, G.; Borgini, A.;
Panuzio, M.; Piersanti, G. Tetrahedron: Asymmetry 1997, 8, 3717.
(p) Veeresa, G.; Dutta, A. Tetrahedron Lett. 1998, 39, 119.
28. Banik, B. K.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1993,
58, 307.
18. Bose, A. K.; Mathur, C.; Wagle, D. R.; Naqvi, R.; Manhas,
M. S. Heterocycles 1994, 39, 491.
19. Baer, E.; Fishcher, H. O. L. J. Biol. Chem. 1939, 128, 463.
20. Bonner, W. A. J. Am. Chem Soc. 1951, 73, 3126.
21. Klerk, E.; Diebold, W. Z. Physiol. Chem. 1931, 198, 25.
22. For the earlier synthesis, see: (a) Hamel, E. E.; Painter, E. P.
J. Am. Chem. Soc. 1953, 75, 1362. (b) Okawa, K.; Hori, K.; Hirose,
H.; Nakagawa, Y. Nippon Kagaku Zasshi 1968, 89, 998. (c)
Hirama, M.; Hioki, H.; Ito, S. Tetrahedron Lett. 1988, 29,
3125. (d) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A.
Tetrahedron Lett. 1995, 36, 2859.
23. Banik, B. K.; Manhas, M. S.; Kaluza, Z.; Barakat, K. J.; Bose,
A. K. Tetrahedron Lett. 1992, 33, 3603.
24. For the recent examples of catalytic transfer hydrogenation,
see: (a) Wiener, H.; Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56,
4481. (b) Rajagopal, S.; Spatola, A. F. J. Org. Chem. 1995, 60,
1347.
25. (a) Bose, A. K.; Banik, B. K.; Barakat, K. J.; Manhas, M. S.
Synlett 1993, 575. (b) Banik, B. K.; Barakat, K. J.; Wagle, D. R.;
Manhas, M. S.; Bose, A. K. J. Org. Chem. 1999, 64, 5746. For the
use of ammonium formate in catalytic transfer hydrogenation
method, see: (a) Anwar, M. K.; Spatola, A. F. Synthesis 1980,
929. (b) Carpino, L.; Tunga, A. J. Org. Chem. 1986, 51, 1930.
(c) Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745.
(d) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91.
29. The structure and stereochemistry were con®rmed by single
crystal X-ray diffraction study of a related b-lactam. For example,
see: Pain, S.; Biswas, G.; Bose, A.K.; Banerjee, A. Acta Cryst.
1992, C48, 666.
30. Huber, R.; Vasella, A. Tetrahedron 1990, 46, 33.
31. Bose, A. K.; Banik, B. K.; Manhas, M. S. Tetrahedron Lett.
1995, 36, 213. Also see: Bose, A. K.; Jayaraman, M.; Okawa, A.;
Bari, S. S.; Robb, E. W. Tetrahedron Lett. 1996, 37, 6989.
32. Varma, R. S.; Dahiya, R.; Kumar, S. Tetrahedron Lett. 1997,
38, 2039.
26. Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91,
7499.
27. For the synthesis of natural and unnatural polyoxamic acid,
see: (a) Kuzuhara, H.; Emoto, S. Tetrahedron Lett. 1973, 5051. (b)
Kuzuhara, H.; Kimura, M.; Emoto, S. Carbohydr. Res. 1975, 45,
33. Ojima, I.; Suga, S.; Abe, R. Chem. Lett. 1980, 853.