Synthesis of 1-(allyloxycarbonyl)-methyl-3-(hydroxyethyl)-4-beta-naphthoxythiocarbony lthio-2-azetidinones and hydroxy protected analogs thereof

A multi-step stereospecific process for preparing (3S,4R,5R)-1-(allyloxycarbonyl)-methyl-3-(1-hydroxyethyl)-4-beta-naphthoxy thiocarbonylthio-2-azetidinones, stereoisomers thereof or hydroxy protected analogs thereof from anhydropenicillin. The azetidinones are intermediates useful for producing penems which are a known group of antibacterial compounds. The process involves protecting the hydroxy group of anhydropenicillin with a readily removable hydroxy protecting group, then converting the resulting compound by ozonolysis followed by reaction with a trialklyl phosphite, then hydrolysis to remove the methylidene group at the 2-position of anhydropenicillin. The resulting compound is converted to the unprotected 4-beta-naphthoxy thiocarbonylthio derivative by reaction with allyl alcohol and HCl followed by reaction with O-2-napththalenylcarbonochloridothioate, or to the protected compound by reaction with silver imidazolate and allyl alcohol followed by reaction with O-2-naphthalenylcarbonochloridothioate.

BACKGROUND 
This invention relates to an improvement in a multi-step stereospecific 
process for producing azetidinones which are useful as intermediates for 
preparing penems. More particularly this invention relates to an 
improvement in the stereospecific multi-step process in which 
anhydropenicillin, i.e., 
(5R,6S,8R)-3,7-dioxo-6-(1-hydroxyethyl)-2-(1-methylethylidene)-4-thia-1-az 
abicyclo[3.2.0]heptane, is converted to 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-(1-hydroxyethyl)-4-beta-naphthoxy( 
thiocarbonyl)thio-2-azetidinone or its hydroxy protected analog. 
In commonly assigned pending U.S. patent application Ser. No. 775,975, 
filed Sept. 13, 1985, the preparation of anhydropenicillin, designated as 
compound 1, is disclosed on pages 8-10 inclusive, which pages are 
incorporated by reference herein. The conversion of compound 1 to the 
hydroxy protected analog is disclosed in U.S. patent application Ser. No. 
775,975, filed Sept. 13, 1985, on page 14 last paragraph and page 15, 
first paragraph, which paragraphs are incorporated by reference herein. 
The anhydropenicillin is converted to azetidinones useful as intermediates 
for making penems by a multi-step process. 
The process of this invention does not require the removal and 
re-introduction of the sulfur atom which originates with 6-APA, the 
compound used to make anhydropenicillin (depicted below as compound 1). In 
addition, the process does not require the isolation of all the 
intermediates and is thus efficient and economical. The process utilizes 
and provides a means to prepare novel and known intermediates used 
ultimately in known processes for making penems. 
Nomenclature used herein for the various penem and azetidinone compounds is 
illustrated as follows, with the appropriate numbering system indicated 
and the stereoisomerism shown 
##STR1## 
(5R, 6S, 
8R)-3,7-dioxo-6-(1-hydroxyethyl)-2-(1-methylethylidene)-4-thia-1-azabicycl 
o[3.2.0]heptane refers to compound 1; and (3S,4R, 
5R)-1-(allyloxycarbonyl)methyl-3-(1-hydroxyethyl)-4-betanaphthoxy(thiocarb 
onyl)thio-2-azetidinone refers to compound N'. 
The preferred stereochemistry of the 1-hydroxyethyl side chain on compounds 
used in and prepared by the process of this invention is R as defined by 
the Cahn-Ingold-Prelog rules, as indicated by the R below carbon 5 in 
compound N' and carbon 8 in compound 1 and the remaining chiral centers 
are indicated by the appropriate R and S. 
SUMMARY OF THE INVENTION 
This invention provides an improved and novel stereospecific process for 
converting 
(5R,6S,8R)-3,7-dioxo-6-(1-hydroxyethyl)-2-(1-methylethylidene)-4-thia-1-az 
abicyclo[3.2.0]heptane into azetidinones useful in multi-step processes for 
producing penems. Penems are a known group of antibacterial compounds. 
More particularly, this invention provides the means to produce 
azetidinones represented by the following formula N 
##STR2## 
wherein P is hydrogen or a hydroxy protecting group; from a compound 
represented by the following formula 1 
##STR3## 
by protecting the hydroxy group with a readily removable hydroxy 
protecting group, then converting the resulting compound by ozonolysis 
followed by reaction with a trialkyl phosphite then hydrolysis into a 
compound represented by the following formula 5 
##STR4## 
wherein P is a hydroxy protecting group. 
Compound 5 is then converted to compound N is compound N i.e. compound N' 
wherein P is hydrogen by reaction with allyl alcohol and HCl followed by 
reaction with O-2-naphthalenylcarbonochloridothioate, or compound 5 can be 
converted to compound N i.e. compound N" werein P is a hydroxy protecting 
group, preferably t-butyldimethylsilyl, by reaction with silver 
imidazolate and allyl alcohol followed by reaction with 
O-2-naphthalenylcarbonochloridothioate. Compound N and its use in 
processes for preparing penems is disclosed in, e.g., U.S. Pat. Nos. 
4,503,064; 4,530,793; 4,559,333 and 4,584,133. 
In another aspect, this invention provides an improved stereospecific 
process for converting compound 1 into compound N' by first making the 
hydroxy protected analog of compound 1, heating it with oxygen and cuprous 
chloride, then reacting the resulting diazetidinone with ozone followed by 
ammonium hydroxide, then allyliodoacetate. The protecting group on the 
hydroxyl group of the resulting product is removed with acid and the 
disulfide bond is broken by means of zinc and acid. The resulting 
unisolated compound is then treated with 
O-2-naphthalenylcarbonochloridothioate to make compound N'. 
Novel compounds produced and used in this invention and which are a part 
thereof are compound 5 and the dimers of the following formula M 
##STR5## 
wherein P is hydrogen or a hydroxy protecting group and R and R.sup.1 are 
the same and are either 
##STR6## 
wherein R" is lower alkyl, preferably methyl, and R"' is a carboxy 
protecting group, perferably allyl. 
DETAILED DESCRIPTION 
In one aspect, the process of this invention comprises converting 
anhydropenicillin to a compound represented by formula N according to the 
following reaction Scheme A. The preferred stereoisomers are depicted for 
illustrative purposes in all reaction schemes which follow. Although the 
preferred stereochemistry of the reactants and intermediates in the 
process of this invention is as indicated in the various depicted 
structural formulas, it is to be understood that the process of this 
invention is operative for other stereoisomers and involves merely the 
selection of reactants having the desired stereochemical configuration and 
reaction conditions which result in the desired stereoisomers. 
##STR7## 
In Step A1 of Reaction Scheme A, the hydroxy group of compound 1 is 
protected by reaction of compound 1 in an organic base, e.g. 
triethylamine, and a suitable inert organic solvent, e.g., methylene 
chloride, under a dry, inert atmosphere, e.g., nitrogen, with a silylating 
agent, e.g., tertiary butyldimethylsilyl chloride or tertiary 
butyldimethylsilyltriflate in dimethylformamide (DMF) or in pyridine with 
a catalytic amount of 4-N,N-dimethylaminopyridine or without the catalyst 
to produce compound 2. 
In Step A2, compound 2 in an anhydrous inert, organic solvent, e.g., dry 
acetone, is treated with ozone at about -50.degree. to -85.degree. C. 
preferably about -78.degree. C. under an inert atmosphere, e.g. nitrogen, 
until the reaction is complete as evidenced by the formation of a blue 
colored reaction solution. The resulting compound 3 is not isolated but is 
used in the next step of the reaction, Step A3. 
In Step A3, compound 3 from Step A2 is treated with a 
triloweralkylphosphite, preferably triethylphosphite, and allowed to warm 
to room temperature (about 20.degree.-25.degree. C.). The reaction mixture 
is then treated with water until the reaction is complete, about 30 
minutes, and the product, compound 5, is recovered as a white solid. 
In Step A4, compound 5 is converted to compound N wherein P is hydrogen, in 
a two step reaction, first, by reaction with allyl alcohol in concentrated 
hydrochloric acid at room temperature until the reaction is complete, e.g. 
about 30 hours, and second, by reaction of the resulting product in an 
inert organic solvent, e.g. methylene chloride, at about -10.degree. C. to 
+10.degree. C., preferably 0.degree. C., with 
O-2-naththalenylcarbonochloridothioate, with or without an organic 
nitrogen base, then recovering the product, compound N wherein P is 
hydrogen. 
Compound 5 can also, in a more preferred embodiment, be converted to 
compound N wherein P is a hydroxy protecting group, according to the 
following Reaction Scheme B 
##STR8## 
In Step B1 of Reaction Scheme B, the penem ring of compound 5 is opened by 
reaction with allyl alcohol and silver imidazolate at room temperature 
until the reaction is completed in about 30 hours. The resulting product, 
compound 6, need not be isolated for use in the following Step B2. 
In Step B2, compound 6 is converted to compound N' wherein P is a hydroxy 
protecting group, e.g., tertiary butyldimethylsilyl, by reaction in an 
inert organic solvent, e.g., methylene chloride, with 
O-2-naphthalenylcarbonochloridothioate at room temperature until the 
reaction is completed in about one hour. The product, compound N" is then 
recovered in high yield. 
Compound N' wherein P is hydrogen can also be made from anhydropenicillin, 
compound 1, through its hydroxy protected analog, compound 2, by 
converting compound 2 into a dithiobisazetidinone as illustrated in the 
following Reaction Scheme C. 
##STR9## 
Step C1 of Reaction Scheme C is identical to Step A1 of Reaction Scheme A. 
In Step C2, compound 2 is converted to Compound 7 by reaction with oxygen 
and a copper salt, e.g. cupric acetate, cupric chloride and cuprous 
chloride, cuprous chloride is preferred, in a lower alkanol, preferably 
methanol. The reaction takes about one day at moderately elevated 
temperatures, e.g., about 40.degree. C. to 60.degree. C., preferably about 
50.degree. C. The product, compound 7, is recovered as a white solid. 
In Step C3, compound 7 is converted to compound 8 by treatment with ozone 
in an inert organic solvent, e.g. methylene chloride, at cold 
temperatures, e.g. about -78.degree. C. until a blue color is maintained, 
then treatment with dimethyl sulfide at room temperature. The resulting 
product, compound 8, is recovered as a white solid. 
In Step C4, the nitrogen of compound 8 is deprotected by reaction in an 
inert organic solvent, e.g. ethyl ether, with aqueous ammonium hydroxide 
at about -10.degree. C. to +10.degree. C. preferably 0.degree. C., the 
product, compound 9, is recovered as a white solid. 
In Step C5, the nitrogen of compound 9 is reacted with a 
halomethylallyloxycarbonyl, preferably allyliodoacetate, by reaction in an 
anhydrous inert organic solvent, e.g. tetrahydrofuran (THF), and an 
inorganic based such as sodium hydride or potassium carbonate, preferably 
sodium hydride, at cold temperatures of about 20.degree. C. to -40.degree. 
C., preferably -30.degree. C. for about one day. The product, compound 10, 
is recovered as a viscous oil. Other carboxy protecting groups can be used 
in place of allyl by replacing the halomethylallyl-oxycarbonyl reactant 
with appropriately protected halomethyl carboxylic acids, a typical 
suitable protecting moiety is paranitrobenzyl. Other protecting groups, 
particularly those which are readily removable and compatible with the 
reactants and products are known in the art. 
In Step C6, the hydroxy of compound 10 is deprotected by reaction in an 
inert organic solvent, e.g. THF, with hydrochloric acid at room 
temperature until the reaction is complete as evidenced by thin layer 
chromatography (tlc), resulting in compound 11 which is used in the next 
step without isolation. 
In Step C7, the disulfide bond of compound 11 is reduced by reaction with 
zinc and hydrochloric acid at room temperature until the reaction is 
completed as evidenced by tlc. Compound 12 is produced and is used in the 
next step without purification. Steps C6 and C7 are carried out 
successively in one pot. 
In Step C8, compound N' wherein P is hydrogen, is made from compound 12 by 
reaction of compound 12 with O-2-naphthalenylcarbonochloridothioate in an 
inert organic solvent, e.g. methylene chloride, with or without an organic 
nitrogen containing base, e.g., pyridine, anilines or lower alkyl amines, 
with triethylamine preferred, at about 0.degree. C. under an inert 
atmosphere, e.g. nitrogen, for about one hour. The product, compound N, is 
recovered as a white solid. 
Compound 11 can also be made from compound 13 as shown in Reaction Scheme 
C, Step C9 by reaction with iodine in an anhydrous inert organic solvent, 
e.g. toluene, at about 0.degree. C. The product, compound 11, is produced 
and need not be recovered for use in the next step. 
In Step C10, compound 13 is converted to compound 12 by reaction with zinc 
and methanolic hydrochloric acid in an inert organic solvent, e.g. THF, 
under an inert atmosphere, e.g. nitrogen, at about 0.degree. C. until the 
reaction is complete as evidence by tlc. The resulting product, compound 
12, can be converted to compound N' without purification. 
Compound 13 is a known compound and can be prepared from the disclosures of 
U.S. Pat. Nos. 4,503,064; 4,530,793 and 4,559,333. 
As used herein "hydroxy protecting group" means any group conventionally 
used for this purpose, with the only requirements being compatibility 
during protection and deprotection reactions with conventional reagents 
for this purpose which will not adversely affect the structure of the 
compounds. Typical of such groups are those listed in Green, "Protecting 
Groups in Organic Synthesis" John Wiley and Sons, New York, NY (1981), 
e.g., ethers such as methyl, methoxymethyl, methylthiomethyl, 
2-methoxyethoxymethyl, bis(2-chlorethoxy)methyl, tetrahydropyranyl, 
tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 
4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 
1-ethoxyethyl, 1-methyl-1-methoxyethyl, 2-(phenylselenyl)ethyl, t-butyl, 
allyl, benzyl, o-nitrobenzyl, triphenylmethyl, alpha naphthyl 
diphenylmethyl, para methoxyphenyldiphenylmethyl, 
9-(9-phenyl-10-oxo)anthryl, trimethylsilyl, isoamyldimethylsilyl, 
isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 
tribenzylsilyl, and triisopropylsilyl, as well as esters such as formate, 
acetate, trichloroacetate, phenoxyacetate, isobutyrate, pivaloate, 
adamantoate, benzoate, 2,4,5-trimethylbenzoate, methyl carbonate, 
2,2,2-trichloroethyl carbonate, allyl carbonate, paranitrophenyl 
carbonate, benzyl carbonate, paranitrobenzyl carbonate, S-benzyl 
thiocarbonate, N-phenylcarbonate, nitrate, 2,4-dinitrophenylsulfenate and 
the like. Most preferred for use in this invention are 
tertiarybutyldimethylsilyl ether. Others which are very suitable for use 
in this invention are 2,2,2-trichloroethoxycarbonyl ester, acetate ester, 
1-ethoxyethyl ether and isoamyldimethylsilyl ether. 
"Carboxy protecting group" means conventional carboxy protectors such as 
allyl, p-nitrobenzyl, benzyl or benzyhydryl, with allyl preferred. 
"Readily removable" means the group can be removed easily by relatively 
mild reaction conditions without adversely affecting the substrate. 
A "suitable inert organic solvent" means any organic solvent or combination 
of solvents that is unreactive in the reaction being conducted and is a 
solvent for the reactants. Such solvents used in the various reactions of 
this invention are identified in the discussion of the reaction schemes 
and in the examples. Typical suitable solvents are halogenated compounds 
such as chloroform or methylene chloride; heterocyclic compounds such as 
tetrahydrofuran (THF); dimethylformamide; mono or biphasic mixed or 
buffered solvents such as lower alkanols (C.sub.1 -C.sub.6 branched or 
straight chain alkanols) and ether or ammonium acetate dissolved in water, 
e.g., methanol and ammonium acetate dissolved in water, methanol and 
ether; lower alkanols such as methanol; lower alkyl carboxylic acids 
(C.sub.2 -C.sub.6 straight or branched chain alkyl carboxylic acids) such 
as acetic acid. 
"Mineral acid" means inorganic acids such as hydrochloric acid, nitric 
acid, sulfuric acid and phosphoric acid.

The following examples describe the process of the present invention. 
Throughout these examples "NMR" denotes nuclear magnetic resonance 
spectra, the spectra described, although in some cases incomplete, are 
sufficient to identify the compound involved; "mp" means melting point; 
"HPLC" means high pressure liquid chromatography; "ether" means 
diethylether; and the boiling range of the petroleum ether (pet ether) is 
35.degree. C. -60.degree. C. Chromatograph refers to flash chromatography 
on silica gel following the procedure of Still, et al., J. Organ. Chem., 
43, 2923 (1978). 
EXAMPLE 1 
(5R,6S,8R)-6-[1-(t-Butyldimethylsilyloxy)ethyl]3,7-dioxo-4-thia-1-azabicycl 
o[3.2.0]heptane 
Take 2.019 grams (0.0059 moles) 
(5R,6S,8R)-6-[1-(t-butyldimethylsilyloxy)ethyl]-3,7-dioxo-2-(1-methylethyl 
idene)-4-thia-1-azabicyclo-[3.2.0.]heptane, 25 ml dry acetone and add to a 
nitrogen-flushed 100 ml 3-necked flask. Cool to about -78.degree. C., 
bubble ozone through until the solution remains a blue color and stir for 
5 minutes, then bubble nitrogen through until the solution is colorless 
yielding 
(5R,6S,8R)-6-[1-(t-butyldimethylsilyloxy)ethyl]-4-thia-2,3,7-trioxo-1-azab 
icyclo [3.2.0]heptane which is not isolated during the reaction but is 
identified based on its .sup.13 C. NMR spectra. 
.sup.13 C. NMR: (CD.sub.3 COCD.sub.3, BB), .delta.=189.8, 164.2, 156.9, 
69.8, 65.0, 50.4, 25.9, 21.7, 18.4, -4.0, -5.5. 
Add 3.44 grams (0.0207 moles) freshly distilled triethylphosphite and let 
warm slowly to room temperature. Add 0.5 ml water after 4 hours, stir for 
30 minutes and concentrate using a rotary evaporator. Flash chromatograph 
the residue on silica gel (5-100% ethyl ether/pet ether) to yield the 
title product as a white solid. 
mp: 65.degree.-66.degree. C. (Recrystallized from ethyl ether/pet ether). 
.sup.1 H NMR: (CDCl.sub.3), .delta.=5.37 (s,1H), 4.37 (d,1H,J=16.8 Hz), 
4.30 (m,1H), 3.53 (dd,1H,J=1.5,4.4 Hz), 3.44 (dd,1H,J=0.9,16.8 Hz), 1.27 
(d,3H,J=6.2 Hz), 0.87 (s,9H), 0.08 (s,3H) 0.07 (s,3H). 
EXAMPLE 2 
(3S,4R,5R)-1-(Allyloxycarbonyl)methyl-3-[1-(t-butyldimethylsilyloxy)ethyl]4 
-.beta.- naphthoxy(thiocarbonyl)thio-2-azetidinone 
Take 0.317 grams (0.0011 moles) 
(5R,6S,8R)-6-[1-(t-butyldimethylsilyloxy)ethyl]-3,7-dioxo-4-thia-1-azabicy 
clo[3.2.0]heptane, 0.063 grams (0.0011 moles) allyl alcohol, 10 ml 
acetonitrile and add to a nitrogen-flushed 25 ml flask. Then add silver 
imidazolate (0.187 grams, 0.0011 moles), the flask protected from light 
with aluminum foil and the reaction mixture stirred at RT for 24 hours. 
Add another equivalent of allyl alcohol (0.063 grams, 0.0011 moles). After 
another 24 hours, add 25 ml methylene chloride, 25 ml brine and 10 ml 
water, separate the layers, extract the aqueous layer with 1.times.25 ml 
methylene chloride, dry the combined organic layers with Na.sub.2 SO.sub.4 
and concentrate using a rotary evaporator. Dissolve the crude solid in 20 
ml methylene chloride, cool to 0.degree. C., add 0.623 grams (0.0012 
moles) O-2-naphthalenylcarbonochloridothioate and stir the reaction 
mixture for 24 hours. Remove the solid formed by filtering through a pad 
of celite, wash the celite pad with 3.times.25 ml portions methylene 
chloride, then wash the combined organic layers with 1.times.25 ml 5% HCl, 
1.times.25 ml H.sub.2 O, 1.times.25 ml saturated NaHCO.sub.3, 1.times.25 
ml brine and dry (MgSO.sub.4). Flash chromatograph on silica gel (50% 
ethyl ether/pet ether) the residue obtained after concentration using a 
rotary evaporator to yield the product. 
.sup.1 H NMR: (CDCl.sub.3), .delta.=8.00-7.25 (br m,7H), 5.89 (d,1H,J=2.6 
Hz), 4.28 (d,1H,J=17.8 Hz), 3.96 (d,1H,J=17.8 Hz), 3.37 (dd,1H,J=2.5,6.0 
Hz), 1.34 (d,3H,J=6.1 Hz), 0.91 (s,9H), 0.12 (s,6H). 
EXAMPLE 3 
(3S,4R,5R)-1-(Allyloxycarbonyl)methyl-3-(1-hydroxyethyl)-4-8-naphthoxythioc 
arbonylthio-2-azetidinone 
Take 0.290 grams (0.0010 moles) 
(5R,6S,8R)-6-[1-(t-butyldimethylsilyloxy)ethyl]-3,7-dioxo-4-thia-1-azabicy 
clo[3.2.0]heptane, 3 ml allyl alcohol, 2 pipette drops concentrated HCl and 
add to a nitrogen-flushed 25 ml flask. After 30 hours stirring at room 
temperature, concentrate on a rotary evaporator, dissolve the residue in 
10 ml methylene chloride, cool to 0.degree. C. and add 0.250 grams (0.0011 
moles) O-2-naphthalenylcarbonochloridothioate. After 1 hour stirring at 
room temperature add 50 ml ethyl ether, 10 ml H.sub.2 O, separate, extract 
the aqueous layer with 1.times.25 ml ethyl ether, wash the combined 
organic layers with 2.times.20 ml 5% HCl, 1.times.20 ml brine, 1.times.20 
ml saturated NaHCO.sub.3, 1.times.20 ml brine and dry (MgSO.sub.4). 
Concentrate using a rotary evaporator and flash chromatograph the residue 
on silica gel (15-100% ethyl ether/pet ether) to yield the product. 
.sup.1 H NMR: (CDCl.sub.3), .delta.=7.93-7.21 (br m, 7H), 5.96 (d,1H,J=2.5 
Hz), 5.82 (m,1H), 4.37 (d,1H,J=18.1 Hz), 3.92 (d,1H,J=18.1 Hz), 3.47 
(dd,1H,J=2.5,5.4 Hz), 2.25 (d,1H,J=4.2 Hz), 1.41 (d,3H,J=6.4 Hz). 
EXAMPLE 4 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-Dithiobis-3-[1-butyldimethylsilyloxy)ethyl 
]-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone 
Take 25.1 grams (0.0735 moles) 
(5R,6S,8R)-6-[1-(t-butyldimethylsilyloxy)ethyl]-3,7-dioxo-2-(1-methylethyl 
idene)-4-thia-1-azabicyclo[3.2.0]heptane, 500 ml methanol and add to a 1-L 
flask. Bubble oxygen through for 5 minutes, place the flask in an oil bath 
at 50.degree. C. and add 4.05 grams (0.0412 moles) cuprous chloride. After 
3 hours bubble more oxygen through. Remove the oil bath after 22.5 hours, 
cool (ice bath) the reaction mixture, add 500 ml ethyl ether, 100 ml 5% 
HCl and filter the solution through a pad of celite. Wash the organic 
layer with 1.times.100 ml brine, 2.times.100 ml saturated NaHCO.sub.3, 
1.times.150 ml brine, dry (MgSO.sub.4) and concentrate using a rotary 
evaporator. Recrystallization of the residue (EtOH) yields the product as 
a white solid. 
mp: 124.degree.-125.degree. C. (recrystallized from EtOH). 
.sup.1 H NMR: (CDCl.sub.3, .delta.=5.14 (d,2H,J=2.2 Hz), 4.26 (m,2H) 3.72 
(s,6H), 3.40 (dd,2H,J=2.2,6.1 Hz), 2.21 (s,6H), 1.94 (s,6H), 1.33 
(d,6H,J=6.3 Hz), 0.88 (s,18H), 0.09 (s,6H), 0.07 (s,6H). 
A second, minor product is present in the mother liquors and was isolated 
and identified as 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-trithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl 
]-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone. 
.sup.1 H NMR: (CDCl.sub.3, .delta.=5.4 (d,2H,J=2.5 Hz), 4.29 (m,2H), 3.74 
(s,6H), 3.29 (dd,2H,J=2.5,3.9 Hz), 2.23 (s,6H), 1.94 (s,6H), 1.23 
(d,6H,J=6.3 Hz), 0.85 (s,18H), 0.07 (s,6H), 0.04 (s,6H). 
Add to a 250 ml flask the mother liquors from the recrystallization (8.20 
grams, approximately a 2:1 ratio of 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-trithiobis-3-[1-(t-butyldimethylsilyloxyethyl] 
-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone and 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl] 
-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone), 1.90 grams 
(0.0072 moles) triphenylphosphine and 50 ml acetonitrile. Stir for 3 
hours, then add 40 ml ethyl ether, filter off the white solid and 
concentrate the filtrate using a rotary evaporator. Flash chromatograph 
the crude product on silica gel (25-70% ethyl ether/pet ether) to yield 
additional 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl] 
-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone as a white solid. 
EXAMPLE 5 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-Dithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl]- 
1-(methoxycarbonyl) carbonyl-2-azetidinone 
Take 10.07 grams (0.0135 moles) 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-3-[1-(t-butyldimethylsilyloxy) 
ethyl]-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone, 60 ml 
methylene chloride and place in a 500 ml flask. Cool to -78.degree. C. 
(dry ice-acetone bath), bubble ozone through until the solution remains a 
blue color, stir 5 minutes, bubble nitrogen through until the solution is 
colorless, add 3.38 grams (0.0544 moles) dimethylsulfide and allow to warm 
to room temperature. After 3 hours concentrate the reaction mixture using 
a rotary evaporator to give a white solid. Dissolve the solid in 300 ml 
ethyl ether, wash with 1.times.50 ml brine, dry (MgSO.sub.4) and 
concentrate using a rotary evaporator. Recrystallize (ethyl ether/pet 
ether) the crude product to yield pure product as a white solid. 
mp: 147.5.degree.-148.5.degree. C. (recrystallized from ethyl ether/pet 
ether). 
.sup.1 H NMR: (CDCl.sub.3), .delta.=5.37 (d,2H,J=2.8 Hz , 4.36 (m,2H), 3.91 
(s,6H), 3.62 (t,2H,J=2.8 Hz), 1.25 (d,6H,J=6.4 Hz), 0.81 (s,18H), 0.06 
(s,6H), 0.01 (s,6H). 
EXAMPLE 6 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-Dithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl]- 
2-azetidinone 
Take 10.01 grams (0.0144 moles) 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl] 
-1-(methoxycarbonyl)carbonyl-2-azetidinone, 400 ml ethyl ether and place in 
a 1-L flask. Cool to 0.degree. C. (ice bath), add 150 ml 5% ammonium 
hydroxide solution and stir vigorously. After 3 hours, filter off the 
white precipitate, wash the solid with 400 ml ethyl ether, wash the 
combined organic layers with 2.times.100 ml brine, dry (MgSO.sub.4) and 
concentrate using a rotary evaporator. Flash chromatograph the residue on 
silica gel (50-100% ethyl ether/pet ether) to yield the product as a white 
solid. 
mp: 130.5.degree.-132.degree. C. (recrystallized from ethyl ether/pet 
ether) 
.sup.1 H NMR: (CDCl.sub.3), .delta.=6.52 (br s, 2H), 4.79 (d,2H,J=2.1 Hz), 
4.22 (m,2H), 3.29 (dd,2H,J=2.0,4.4 Hz.), 1.24 (d,6H,J=6.2 Hz), 0.86 
(s,18H), 0.064 (s,6H), 0.057 (s,6H). 
EXAMPLE 7 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-Dithiobis-1-(allyloxycarbonyl)methyl-3-[1-(t-bu 
tyldimethylsilvloxy)ethyl]-2-azetidinone 
Take 2.261 grams (0.0043 moles) 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-3-[1-(t-butyldimethylsilyloxy)ethyl] 
-2-azetidinone, 20 ml dry THF, 3.929 grams (0.0174 moles) allyliodoacetate 
and place in a nitrogen-flushed 250 ml flask. Cool the solution to 
-30.degree. C. (dry ice-acetone bath), add 0.428 grams (0.0107 moles, 60% 
oil dispersion) sodium hydride and stir at -30.degree. C. for 24 hours and 
then 1 hour under reduced pressure (20 torr). Add 200 ml ethyl ether and 
50 ml brine, filter off the precipitate formed, wash the organic layer 
with 2.times.50 ml brine, dry (MgSO.sub.4) and concentrate using a rotary 
evaporator. Flash chromatograph the residue on silica gel (0-5% ethyl 
acetate/methylene chloride) to yield the product as a viscous oil. 
.sup.1 H NMR: (CDCl.sub.3), .delta.=5.85 (m,2H), 5.04 (d,2H,J=1.9 Hz), 4.62 
(d,4H,J=6.0 Hz), 4.28 (d,2H,J=18.0 Hz), 3.78 (d,2H,J=18.0 Hz), 3.34 
(dd,2H,J=1.9,5.1 Hz), 1.27 (d,6H,J=6.4 Hz), 0.86 (s,18H), 0.08 (s,6H), 
0.05 (s,6H). 
EXAMPLE 8 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl -3-(1- 
hydroxyethyl)-4-sulfhydril-2-azetidinone 
To a solution of 0.70 g (1.44 mM) of 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-(1-hdyroxyethyl)-4-triphenylmethyl 
thio-2-azetidinone in 10 ml THF at 0.degree. under N.sub.2 atmosphere, add 
0.38 g (5.67 mM) of finely powdered zinc. Next, slowly add methanolic HCl 
[9 ml MeOH/1 ml conc. HCl] until all Zn dissolves. Repeat the steps of Zn 
followed by methanolic HCl addition until the reduction is complete as 
judged by tlc. Add 100 ml cold (0.degree.) CH.sub.2 Cl.sub.2 followed by 
ice and 5 ml sat. aq. NaCl. Separate the aqueous layer, re-extract the 
aqueous layer with CH.sub.2 Cl.sub.2, combine the organic phases and wash 
with cold (0.degree. C) sat. aq. NaCl soln. until the washes are neutral. 
Dry organic layer over anhyd. MgSO.sub.4 and concentrate in vacuo to give 
a white solid as a mixture of title compound and triphenylmethane suitable 
for further reaction without purification. 
NMR (CDCl.sub.3): .delta.1.35 (d,3H,J=7 Hz , 2.15 (d,1H,J=10 Hz), 2.6 
(br,1H), 3.17 (d of d,1H,J=2 Hz and 6 Hz), 3.77 and 4.2 (2d,2H,J=18 Hz), 
4.3 (m,1H), 4.6 (d,2H,J=7 Hz), 5.05 (d of d,1H,J=2 Hz and 10 Hz), 5.35 
(m,2H), 5.95 (m,1H). 
EXAMPLE 9 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-Dithiobis-1-(allyloxycarbonyl)methyl-3-(1-hydro 
xyethyl)-2-azetidinone 
To a solution of 0.125 g (0.256 mM) of 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-[1-hydroxyethyl]-4-triphenylmethyl 
thio-2-azetidinone in 5 ml dry toluene at 0.degree. C., add 0.033 g (0.256 
mM) I.sub.2. Stir the reaction mixture for 2 hr at 0.degree. C., dilute 
with CH.sub.2 Cl.sub.2, wash with 1:1 mixture of sat. aq. NaCl/H.sub.2 O 
containing traces of Na.sub.2 S.sub.2 O.sub.3 followed by distilled water, 
dry the organic layer over anhyd. Na.sub.2 SO.sub.4 and concentrate in 
vacuo to give a white solid as a mixture of the title compound and 
triphenylmethylcarbinol.sup.1, suitable for further reaction without 
purification. 
FNT .sup.1 Use of an alcohol, e.g. methanol, leads to ether, e.g. 
triphenylmethyl ether as a by product. 
NMR (CDCl.sub.3): .delta.1.38 (d,6H,J=7.5 Hz), 2.84 (br,2H), 3.4 (d of 
d,2H,J=3.5 Hz and 7 Hz), 3.8 and 4.3 (2d,4H,J=18 Hz), 4.25 (m,2H), 4.65 
(d,4H,J=7.5 Hz), 5.05 (d,2H,J=3 Hz), 5.3 (m,4H), 5.87 (m,2H). 
EXAMPLE 10 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-(1- 
hydroxyethyl)-4-sulfhydril-2-azetidinone 
To a stirred solution of 0.89 g (0.88 mM) of a mixture of 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-1-(allyloxycarbonyl)methyl-3-(1-hydr 
oxyethyl)-2-azetidinone and triphenylcarbinol in 10 ml THF containing 1 ml 
conc. HCl at 0.degree. C. under N.sub.2 atmosphere, slowly add finely 
powdered zinc over a 1 hr period until the disulfide reduction is 
complete. Stir the reaction mixture for an additional 0.5 hr, dilute with 
60 ml diethyl ether and wash with distilled water until the washes are 
neutral. Dry the ether layer with anhydrous Na.sub.2 SO.sub.4 and 
concentrate in vacuo to obtain a white solid as a mixture of the title 
compound and triphenylcarbinol, suitable for further reaction without 
purification. 
NMR: Identical to the NMR for the compound produced in Example 8. 
EXAMPLE 11 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-(1- 
hydroxyethyl)-4-sulfhydril-2-azetidinone 
To a solution of 0.43 g (0.6 mM) of 
(3S,4R,5R,3'S,4'R,5'R)-4,4'-dithiobis-1-(allyloxy-carbonyl)methyl-3-[1-(t- 
butyldimethylsilyloxy)ethyl]-2-azetidinone in 10 ml THF at room temperature 
add of 10N aq. HCl and stir the reaction mixture until desilylation is 
complete (2-4 hr) as judged by tlc. To this stirred solution of 
desilylated disulfide slowly add finely powdered Zn in small portions over 
4 Hr until the disulfide reduction is complete as judged by tlc. Dilute 
this reaction mixture with 100 ml ethyl acetate and wash with saturated 
aq. NaCl solution until the washes are neutral. Dry the organic phase over 
anhyd. Na.sub.2 SO.sub.4 and concentrate in vacuo at or below room 
temperature to obtain an oil consisting of the title compound and 
t-butyldimethylsilyl by products, suitable for further reaction without 
any purification. 
NMR: Identical to the NMR for the compound produced in Example 8. 
EXAMPLE 12 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-(1- 
hydroxyethyl)-4-.beta.-naphthoxythiocarbonylthio-2- azetidinone 
To a solution of 0.65 g (1.34 mM) of a mixture of 
(3S,4R,5R)-1-(allyloxycarbonyl)methyl-3-(1-hydroxyethyl)-4-sulfhydril-2-az 
etidinone and triphenylmethane.sup.1 in 18 ml CH.sub.2 Cl.sub.2 at 
0.degree. C. under N.sub.2 atmosphere add 0.32 g (1.44 mM) 
O-2-naphthalenyl- carbonochloridothioate (NCCT) followed by 0.2 ml (1.44 
mM) dry triethylamine. Stir the reaction mixture for 50 min. at 0.degree. 
C., dilute with CH.sub.2 Cl.sub.2 and wash with distilled water followed 
by a 1:1 mixture of aq. sat. NaCl:distilled water. Separate the organic 
phase, dry over anhydrous MgSO.sub.4 and concentrate in vacuo to give an 
off white solid. Chromatograph this solid (silica gel; CH.sub.2 Cl.sub.2 
followed by EtOAc/CH.sub.2 Cl.sub.2 (1:19) to obtain the title compound as 
a white solid, mp 76.degree.-78.degree. C. 
FNT .sup.1 The presence of triphenylcarbinol, triphenylmethyl ether, or 
t-butyldimethylsilyl by products in place of triphenylmethane does not 
alter the quality of the product. 
NMR (CDCl.sub.3): .delta.1.42 (d,3H,J=7 Hz), 2.25 (br,1H), 3.4 (d of d,1H, 
J=3 Hz and 6 Hz), 3.85 and 4.37 (J=18 Hz), 4.2-4.6 (m,3H), 5.17 (m,2H), 
5.75 (m,1H), 5.9 (d,1H, J=2 Hz), 7.1 to 7.9 (m,7H).