Lactams of the general structural formula: ##STR1## wherein R is hydrogen or C.sub.1-10 alkyl. These compounds are macrolides useful as antibiotics and as intermediates for the synthesis of other macrolide antibiotics.

BACKGROUND OF THE INVENTION 
The present invention relates to a novel group of chemical compounds having 
antibacterial activity, which are useful in the therapy of bacterial 
infections in mammals. The compounds themselves are also useful as 
intermediates in the synthesis of other antibacterial compounds. More 
specifically, the invention relates to derivatives of the well-known 
macrolide antibiotic, erythromycin A, the compound of the structure: 
##STR2## 
Even more specifically, the invention relates to the compounds of the 
structure: 
##STR3## 
wherein R is hydrogen or C.sub.1-10 alkyl. 
The present invention also provides for novel pharmaceutical compositions 
and methods of their use as antibiotic agents. 
SUMMARY OF THE INVENTION 
The present invention relates to novel compounds, cyclic lactams of 15 
membered macrolide antibiotics having the formula. 
##STR4## 
where R is hydrogen or C.sub.1-10 alkyl. 
The invention includes the pharmaceutically acceptable salts and esters of 
the compounds shown above. Such salts are generally prepared as acid 
addition salts by combining the compound of formula II with a 
stoichiometric amount of an appropriate acid in an inert solvent. The salt 
is then recovered by solvent evaporation or by filtration if the salt 
precipitates spontaneously, or by precipitation using a co-solvent or 
non-polar co-solvent followed by filtration. 
Representative salts and esters include the following: 
______________________________________ 
Acetate Isothionate 
Benzenesulfonate Lactate 
Benzoate Lactobionate 
Bicarbonate Laurate 
Bisulfate Malate 
Bitartrate Maleate 
Borate Mandelate 
Bromide Mesylate 
Calcium Edetate Methylsulfate 
Camsylate Mucate 
Carbonate Napsylate 
Chloride Nitrate 
Clavulanate Oleate 
Citrate Oxalate 
Edetate Pamoate (Embonate) 
Edisylate Palmitate 
Estolate Pantothenate 
Esylate Phosphate/diphosphate 
Ethylsuccinate Polygalacturonate 
Fumarate Salicylate 
Gluceptate Stearate 
Glucoheptonate Subacetate 
Gluconate Succinate 
Glutamate Tannate 
Glycollylarsanilate 
Tartrate 
Hexylresorcinate Teoclate 
Hydrabamine Tosylate 
Hydrobromide Triethiodode 
Hydrochloride Valerate 
Iodide 
______________________________________

DETAILED DESCRIPTION OF THE INVENTION 
The term "pharmacologically effective amount" shall mean that amount of a 
drug or pharmaceutical agent that will elicit the biological or medical 
response of a tissue, system or animal that is being sought by a 
researcher or clinician. 
The term "antibiotically effective amount" shall mean that amount of an 
antibiotic compound that will achieve a level of antibacterial activity at 
the site of infection that is sufficient to inhibit the bacteria in a 
manner that allows the host organism to overcome the infection. 
The term "alkyl" shall mean cyclic or linear straight or branched chain 
alkane of one to ten carbon atoms, or cyclic or linear straight or 
branched chain alkene of two to ten carbon atoms with one or more degrees 
of unsaturation. 
The compounds of formula II can be prepared readily according to the 
following detailed descriptions and examples or modifications thereof 
using readily available starting materials, reagents and conventional 
synthesis procedures. The overall process is illustrated in flow sheet I 
wherein the steps leading to (II) are explicitly described below. In these 
reactions, it is also possible to make use of variants which are 
themselves known to those of ordinary skill in this art, but which are not 
mentioned in greater detail. 
##STR5## 
Isomerization of (9E)-9-Deoxo-9-hydroxyiminoery-thromycin A to the (9Z) 
isomer 
In a single step procedure, (9Z)-9-deoxo-9-hydroxyimininoerythromycin A of 
the structure: 
##STR6## 
is obtained by reacting a (9E)-9-deoxo-9-hydroxyiminoerythromycin A of the 
structure: 
##STR7## 
with a base in the presence of a protic or an aprotic solvent. Preferably, 
the base is an alkali metal hydroxide and the solvent is an alcohol. Most 
preferably, the base is lithium hydroxide (as the monohydrate) and the 
solvent is ethanol. 
Optimization of the method of the isomerization step requires a base 
sufficient to substantially deprotonate the hydroxyimino group of (IV). 
Furthermore, the oxime anion must be reasonably stable under the reaction 
conditions for the time period required to complete the isomerization 
process. 
Upon addition of the base to (IV), an equilibrium condition is created as 
shown in the following equation: 
##STR8## 
The workup performed on the anions includes protonation of the oxime anions 
to give the neutral oxime product mixture from which the desired Z-isomer 
is isolated by crystallization or by chromatography followed by 
crystallization. 
The relative amounts of E and Z oxime anions (and neutral oximes after the 
workup) in the equilibrium mixture can be controlled and depends on a 
number of factors. These include (a) the strength and quantity of the base 
reagent, (b) the size and polarizability of the counterion .sup.+ M, (c) 
the reaction solvent, and (d) the reaction temperature. 
Suitable bases include hydroxides, alkoxides, carbonates, metal amides, 
amines and metal hydrides. 
The following list of reagents is given to illustrate suitable bases and 
solvents, although the list is not to be taken as exhaustive and other 
bases and solvents known to those of ordinary skill in the art are not 
excluded. Preferred bases and solvents are indicated by an asterisk and 
most preferred bases are indicated by a dagger. 
______________________________________ 
Bases 
______________________________________ 
1. Hydroxides 
* LiOH lithium hydroxide 
* NaOH sodium hydroxide 
*KOH potassium hydroxide 
CsOH cesium hydroxide 
Ca(OH).sub.2 calcium hydroxide 
Mg(OH).sub.2 magnesium hydroxide 
*Me.sub.4 NOH tetramethylammonium hydroxide 
BnMe.sub.3 NOH 
benzyltrimethylammonium 
hydroxide 
Et.sub.4 NOH tetraethylammonium hydroxide 
Bu.sub.4 NOH tetrabutylammonium hydroxide 
2. Alkoxides 
* LiOMe lithium methoxide 
* LiOEt lithium ethoxide 
LiOiPr lithium isopropoxide 
LiOnBu lithium n-butoxide 
LiOsBu lithium sec-butoxide 
* NaOMe sodium methoxide 
* NaOEt sodium ethoxide 
NaOPr sodium n-propoxide 
NaOiPr sodium iso-propoxide 
NaOnBu sodium n-butoxide 
NaOsBu sodium sec-butoxide 
NaOtBu sodium tert-butoxide 
NaOSiMe.sub.3 sodium trimethylsilanoate 
KOMe potassium methoxide 
*KOEt potassium ethoxide 
KOtBu potassium tert-butoxide 
KOSiMe.sub.3 potassium trimethylsilanoate 
KOsBu potassium sec-butoxide 
CsOtBu cesium tert-butoxide 
Ca(OMe).sub.2 calcium methoxide 
*Mg(OEt).sub.2 
magnesium ethoxide 
Ti(OEt).sub.4 titanium (IV) ethoxide 
Ti(OiPr).sub.4 
titanium (IV) isopropoxide 
BnMe.sub.3 NOMe 
benzyltrimethylammonium- 
methoxide 
3. Carbonates 
K.sub.2 CO.sub.3 
potassium carbonate 
*Cs.sub.2 CO.sub.3 
cesium carbonate 
Na.sub. 2 CO.sub.3 
sodium carbonate 
4. Amides (for use in aprotic solvents) 
LiNH.sub.2 lithium amide 
LiNMe.sub.2 lithium dimethylamide 
*LiNiPr.sub.2 lithium diisopropylamide 
LiN(C.sub.6 H.sub.11).sub.2 
lithium dicyclohexylamide 
LiN(SiMe.sub.3).sub.2 
lithium bis(trimethylsilyl) 
amide 
NaNH.sub.2 sodium amide 
KN(SiMe.sub.3).sub.2 
potassium bis(trimethylsilyl) 
amide 
5. Amines 
*TMG 1,1,3,3-tetramethyl guanidine 
DBU 1,8-diazabicyclo[5.4.0] 
undec-7-ene 
proton sponge 1,8-bis(dimethylamino)- 
naphthalene 
6. Hydrides (for use in aprotic solvents) 
LiH lithium hydride 
*NaH sodium hydride 
KH potassium hydride 
7. Solvents 
a. Protic 
H.sub.2 O (generally used in combination 
with an alcohol solvent) 
* MeOH methanol 
* EtOH ethanol 
* iPrOH isopropanol 
n-BuOH normal-butanol 
s-BuOH sec-butanol 
t-BuOH tert-butanol 
b. Aprotic 
i. Nonpolar (as a group, these are generally 
used in combination with a 
protic or polar solvent) 
Et.sub.2 O diethyl ether 
THF tetrahydrofuran 
DME dimethoxyethane 
PhMe toluene 
CH.sub.2 Cl.sub.2 
dichloromethane 
CHCl.sub.3 chloroform 
ii. Polar 
*DMF dimethylformamide 
DMAC dimethylacetamide 
DMI 1,3-dimethyl-2-imidazolidinone 
*NEP 1-ethyl-2-pyrrolidinone 
*NMP 1-methyl-2-pyrrolidinone 
HMPA hexamethylphosphoramide 
MeNO.sub.2 nitromethane 
*MeCN acetonitrile 
dioxane 
pyridine 
DMSO dimethyl sulfoxide 
______________________________________ 
Preferably, the isomerization reaction is carried out at a concentration of 
1-25% w/v of E-oxime to solvent, and most preferably at 10% w/v. The 
amount of base used is preferably 1.0-10.0 molar equivalents based on the 
amount of starting E-oxime, more preferably 1.0-3.0 molar equivalents, and 
most preferably 2.0 molar equivalents. The reaction is generally run at a 
temperature of from 0.degree. C. to 80.degree. C., and more preferably at 
22.degree.-25.degree. C. The reaction can be allowed to run for 0.5 hour 
to 20 days, but most preferably is carried out over 20-24 hours. 
Beckmann Rearrangement of (9Z)-9-Deoxo-9 hydroxyiminoerythromycin A 
##STR9## 
The conversion of (9Z)-9-deoxo-9-hydroxyiminoerythromycin A (III) to the 
8a-aza-8a-homoerythromycin products (II), (V) and (VI) is accomplished by 
means of the Beckmann rearrangement (see "Comprehensive Organic 
Chemistry", I. O. Sutherland (Ed.), Pergamon Press, N.Y. 1979, Vol. 2, 
pgs. 398-400 and 967-968). In general, the Beckmann rearrangement of 
ketoximes leads to carboxamides and, of particular relevance in cyclic 
systems, to ring expanded lactams. The mechanism of the rearrangement 
involves initial conversion of the oxime hydroxyl group to a leaving group 
which is then lost with concomitant migration of the oxime carbon 
substituent that is situated anti to the leaving group. In aqueous media, 
the intermediate nitrilium cation thus formed usually reacts with water to 
afford the amide product. The nitrilium intermediate can also be trapped 
by other suitable nucleophiles thereby leading to imino products such as 
imidates and amidines. 
The Beckmann rearrangement has been accomplished under a variety of acidic, 
neutral and basic conditions. Common acidic reagents that promote the 
transformation include concentrated sulfuric acid, polyphosphoric acid, 
thionyl chloride, phosphorous pentachloride, sulfur dioxide, and formic 
acid. These reagents are generally not applicable to the rearrangement of 
oxime (III) due to the sensitivity of the macrolide molecule, and 
especially the cladinose sugar residue, to acidic conditions. Efficient 
Beckmann rearrangement also occurs by heating the oxime with silica gel in 
xylene or under mildly basic conditions by heating the oxime in 
hexamethylphosphoramide. These conditions are not particularly valuable 
for the conversion of (III) to products (II), (V) and (VI) due to 
competing isomerization of the oxime function under the reaction 
conditions. 
A preferred method for effecting the Beckmann rearrangement involves 
initial O-sulfonylation of the oxime group with an alkylsulfonyl halide, 
arylsulfonyl halide or arylsulfonic anhydride. The intermediate oxime 
sulfonate thus formed can be isolated or, as more commonly practiced, 
converted in situ to the rearranged products. The sulfonylation and 
rearrangement reactions are generally performed in the presence of an 
organic or inorganic base. This method is particularly valuable for the 
conversion of oxime (III) to the rearranged products (II), (V), and (VI). 
Preferred sulfonylating reagents for effecting the rearrangement of oxime 
(III) include methanesulfonyl chloride, benzenesulfonyl chloride, 
4-acetamidobenzenesulfonyl chloride, p-toluenesulfonyl chloride, 
benzenesulfonic anhydride, and p-toluenesulfonic anhydride. The reaction 
is carried out in the presence of an inorganic base such as sodium 
bicarbonate or potassium carbonate, or in the presence of an organic base 
such as pyridine, 4-dimethylaminopyridine, triethylamine, or 
N,N-disopropylethylamine. Suitable solvents include aqueous mixtures such 
as aqueous acetone or aqueous dioxane and organic solvents such as 
dichloromethane, chloroform, ethyl acetate, diethyl ether, 
tetrahydrofuran, toluene, acetonitrile, and pyridine. Mixtures of organic 
solvents, especially those containing pyridine, are highly useful. The 
reaction is generally performed using 1-3 molar equivalents of the 
sulfonylating agent and one or more molar equivalents of base at a 
reaction temperature of -20.degree. C. to 50.degree. C. Pyridine is often 
used as both solvent and base. 
The distribution of products resulting from Beckmann rearrangement of oxime 
(III) depends on the particular reaction conditions employed. For example, 
when the rearrangement is effected with p-toluenesulfonyl chloride and 
sodium bicarbonate in aqueous acetone, the major products are the lactam 
(II) and the 6,9-bridged iminoether (V). When the reaction is conducted 
under anhydrous conditions such as p-toluenesulfonyl chloride in pyridine, 
the major products are the 6,9-bridged and 9,12-bridged iminoethers (V) 
and (VI). 
The products of the Beckmann rearrangement of oxime (III) are conveniently 
purified by chromatographic methods. For example, the lactam (II) is 
easily separated from iminoether (V) using column chromatography on silica 
gel or by reverse phase, high-pressure liquid chromatography. Products (V) 
and (VI) can also be separated by chromatographic methods, and the (VI) 
thus obtained can be further purified by crystallization from 
nitromethane. 
As previously noted, Beckmann rearrangement of oxime (III) under anhydrous 
conditions leads to a product mixture comprised of the 6,9- and 
9,12-bridged iminoethers (V) and (VI). The 9,12-bridged product, which is 
formed by internal trapping of the intermediate nitrilium species by the 
hydroxyl group at C-12, is initially isolated as a mixture of major and 
minor forms. The initial mixture of isomers equilibrates at room 
temperature, both in solution or on storing as a crude foam, to 
approximately a 1:1 mixture of isomers. The first-formed, major isomer can 
be isolated from the mixture by crystallization from nitromethane 
solution. 
##STR10## 
The compounds of formula (II) wherein R is a 1-10 carbon alkyl substituent 
are readily prepared by the methods outlined in Flow Sheets II, III, and 
IV. 
In Flow Sheet II, the unsubstituted lactam (II, R=H) is first silylated in 
order to protect the hydroxyl groups in the subsequent alkylation step. 
O-Silylation is readily accomplished with a variety of reagents and 
generally leads to products in which three to five of the available 
hydroxyl groups are covered. The degree of silylation depends on the exact 
conditions employed and on the quantity of silylating agent used. For 
example, using excess trimethylsilyl trifluoromethanesulfonate in 
dichloromethane containing 2,6-lutidine or using excess 
bis(trimethylsilyl) trifluoroacetamide (BSTFA) in pyridine provides the 
persilylated intermediate (VII). 
N-Alkylating is accomplished by treating the slylated intermediate (VII) 
with a strong base and an alkylating agent. Suitable bases include, but 
are not limited to, potassium hydroxide, sodium hydroxide, sodium hydride 
and lithium diisopropylamide. The alkylating agent is of the form RX 
wherein X represents a leaving group such as bromide, iodide, 
methanesulfonate (OMs), p-toluenesulfonate (OTs) or 
trifluormethanesulfonate (OTf). The alkylation reaction is usually carried 
out in a nonaqueous solvent such as tetrahydrofuran, diethyl ether, 
toluene, dimethylsulfoxide, dimethylformamide, dimethoxyethane, or 
mixtures thereof. A particularly preferred alkylation method uses sodium 
hydride in dimethylformamide to deprotonate the lactam group followed by 
addition of an alkyl iodide or bromide to introduce the desired alkyl 
substituent. 
The resulting N-alkylated, O-silylated intermediate (VII) is then 
desilylated using any one of a number of well known techniques. 
Representative methods include hydrolysis in aqueous acetic acid or the 
use of fluoride based reagents such as hydrogen fluoride in pyridine or, 
preferably, tetrabutylammonium fluoride in tetrahydrofuran. The resulting 
final products (II) are conveniently purified by chromatography on silica 
gel, by direct crystallization, or by a combination of chromatography and 
crystallization. 
An alternative method of introducing alkyl substitution at position 8a of 
the aglycone ring is illustrated in Flow Sheets III and IV. The overall 
chemistry, which involves 1) protection of the desosamine dimethlyamino 
group by conversion to its oxide, 2) N-alkylation of the imidate group, 3) 
hydrolysis of the alkylated imidate to a lactam group, and 4) 
deoxygenation of the sugar N-oxide, is identical in the two schemes. The 
schemes differ only as to the specific structure of the starting 
iminoether; that is, whether the 9,12-bridged intermediate (VI) or the 
6,9-bridged intermediate (V) is used. Since the reactions are equivalent 
in both schemes, the discussion below is limited to Flow Sheet III, with 
the understanding that the discussion also applies to the transformations 
illustrated in Flow Sheet IV. 
The initial step in Flow Sheet III involves the protection of the 
desosamine dimethylamino group to alkylation by its conversion to the 
corresponding N-oxide derivative (IX). This transformation is readily 
accomplished using oxidizing agents such as m-chloroperbenzoic acid in 
dichloromethane or aqueous hydrogen peroxide in methanol. The imidate 
group of the resulting product is N-alkylated using a powerful alkylating 
agent in an inert organic solvent. Suitable combinations include alkyl 
iodides, alkyl trifluoromethanesulfonates and trialkyloxonium salts in 
solvents such as dichloromethane, acetonitrile and nitromethane. The 
resulting quaternized imidate (X) is easily hydrolyzed under basic 
conditions to the N-substituted lactam intermediate (XI). Representative 
reagents for the (X) to (XI) conversion include concentrated aqueous 
ammonia or sodium hydroxide in aqueous ethanol. The final step of Flow 
Sheet III involves the deoxygenation of the desosaminyl N-oxide group. 
This transformation is accomplished using a deoxygenating reagent such as 
triphenylphosphine or by hydrogenation in the presence of a palladium or 
platinum catalyst. As noted before, the final products (II) can be 
purified by chromatography or by crystallization. 
As antibiotics, the compounds of formula (II) can be administered in such 
oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, 
tinctures, suspensions, syrups and emulsions. Likewise, they may also be 
administered in intravenous, intraperitoneal, subcutaneous or 
intramuscular form, all using forms well known to those of ordinary skill 
in the pharmaceutical arts. In general, the preferred form of 
administration is oral. An effective but non-toxic amount of the compound 
can be employed as a mammalian antibiotic. 
The dosage regimen utilizing the compounds of formula (II) is selected in 
accordance with a variety of factors including type, species, age, weight, 
sex and medical condition of the patient; the severity of the condition to 
be treated; the route of administration; the renal and hepatic function of 
the patient; and the particular compound or salt thereof employed. An 
ordinarily skilled physician or veterinarian can readily determine and 
prescribe the effective amount of the drug required to prevent, counter or 
arrest the progress of the condition. 
Dosages of the compounds of formula (II), when used for the indicated 
effects, will range between about 0.2 mg per kg of body weight per day 
(mg/kg/day) to about 120 mg/kg/day and preferably 4-50 mg/kg/day. 
Advantageously, the compound may be administered in a single daily dose, 
or the total daily dosage may be administered in divided doses of two, 
three or four times daily. 
Furthermore, the compounds of formula (II) can be administered in topical, 
otic or ophthalmic form via use of suitable vehicles. 
In the methods of using the compounds (II), they can form the active 
ingredient, and are typically administered in admixture with suitable 
pharmaceutical diluents, excipients or carriers (collectively referred to 
herein as "carrier" materials) suitably selected with respect to the 
intended form of administration, that is, oral tablets, capsules, elixirs, 
syrups, and the like, and consistent with conventional pharmaceutical 
practices. 
For instance, for oral administration in the form of a tablet or capsule, 
the active drug component can be combined with an oral, non-toxic, 
pharmaceutically acceptable, inert carrier such as lactose, starch, 
sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium 
phosphate, calcium sulfate, mannitol, sorbitol, and the like; for oral 
administration in liquid form, the oral drug components can be combined 
with any oral, non-toxic, pharmaceutically acceptable inert carrier such 
as ethanol, glycerol, water, and the like. Moreover, when desired or 
necessary, suitable binders, lubricants, disintegrating agents and 
coloring agents can also be incorporated into the mixture. Suitable 
binders include starch, gelatin, natural sugars such as glucose or 
beta-lactose, corn sweetners, natural and synthetic gums such as acacia, 
tragacanth or sodium alginate, carboxymethylcellulose, polyethylene 
glycol, waxes, and the like. Disintegrators include, without limitation, 
starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. 
The compounds of formula (II) can also be administered in the form of 
liposome delivery systems, such as small unilamellar vesicles, large 
unilamellar vesicles and multilamellar vesicles. Liposomes can be formed 
from a variety of phospholipids, such as cholesterol, stearylamine or 
phosphatidylcholines. 
The compounds of formula (II) may also be coupled with soluble polymers as 
targetable drug carriers. Such polymers can include polyvinylpyrrolidone, 
pyran copolymer, polyhydroxypropylmethacrylamide phenyl, 
polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine 
substituted with palmitoyl residues. Furthermore, the compounds of formula 
(II) may be coupled to a class of biodegradable polymers useful in 
achieving controlled release of a drug, for example, polylactic acid, 
polyglycolic acid, copolymers of polylactic and polyglycolic acid, 
polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 
polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or 
amphipathic block copolymers of hydrogels. 
The following examples further illustrate details for the practice of the 
invention. Those skilled in the art will readily understand that known 
variations, when taken with the alternative bases and solvents taught 
above, can be used. 
EXAMPLE 1 
##STR11## 
Preparation of (9E)-9-Deoxo-9-hydroxyiminoerythromycin A 
Hydroxylamine hydrochloride (224 g, 3.23 mol) was added to a solution of 
erythromycin A (100 g, ca. 95% pure, 0.129 mol, available from Aldrich 
Chemical, Inc., Milwaukee, Wis.) in pyridine (500 mL). The resulting 
mixture was stirred at room temperature for 27 hours, and then 
concentrated under vacuum at ca. 40.degree. C. The semi-solid residue was 
kept under high vacuum overnight, then stirred with ethanol (600 mL) for 
15 minutes and filtered. The collected solids were washed with hot 
(50.degree. C.) ethanol. The combined filtrate and washing was evaporated 
under vacuum to a pale blue foam. The foam was shaken with water (850 mL) 
to give a thick emulsion which was stirred rapidly at room temperature for 
2.5 hours to give a filterable precipitate. The precipitate was collected, 
washed with water (150 mL), and dried under vacuum to give a white solid 
(117.7 g). 
The crude oxime hydrochloride was suspended in 5% aqueous sodium 
bicarbonate (1000 mL) and methylene chloride (1000 mL), and the mixture 
was stirred while the pH was adjusted to 9.5 by addition of 5N aqueous 
sodium hydroxide. The layers were separated and the aqueous portion was 
extracted with ethyl acetate (500 mL) and ethyl ether (500 mL). The 
combined organic layer and extracts were dried over sodium sulfate, 
filtered, and evaporated under vacuum to a white solid (92.3 g). The solid 
was dissolved in hot ethyl acetate (250 mL), and the solution diluted with 
hot hexanes (400 mL) and left overnight in a refrigerator. The crystals of 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A were collected, washed with 
ice-cold hexane (250 mL), and dried under vacuum to afford a white solid 
(88.5 g). 
IR (CH.sub.2 Cl.sub.2) 3560, 3400 (br), 2980, 2950, 1735, 1460, 1389, 1165, 
1110, 1085, 1050, and 1010 cm.sup.-1. 
.sup.1 H NMR (CDCl.sub.3) .delta. 5.05 (dd, H-13), 4.90 (d, H-1"), 4.38 (d, 
H-1'), 4.01 (m, H-5"), 3.99 (d, H-3), 3.74 (m, H-8), 3.66 (s, H-11), 3.54 
(d, H-5), 3.45 (m, H-5'), 3.28 (s, OCH.sub.3), 3.23 (dd, H-2'), 2.96 (t, 
H-4"), 2.87 (m, H-2), 2.64 (q, H-10), 2.43 (m, H-3'), 2.32 (d, H-2"eq), 
2.27 (s, N(CH.sub.3).sub.2), 1.98 (m, H-4), 1.87 (m, H-14a), 1.63 (m, 
H-4'eq), and 1.46 (s, 6-CH.sub.3). 
.sup.1 H NMR (CD.sub.3 OD) .delta. 5.19 (dd, H-13), 4.48 (d, H-1'), 4.15 
(dq, H-5"), 3.98 (d, H-3), 3.76 (m, H-8), 3.70 (m, H-5'), 3.67 (s, H-11), 
3.58 (d, H-5), 3.33 (s, OCH.sub.3), 3.23 (dd, H-2'), 3.01 (d, H-4"), 2.92 
(m, H-2), 2.72 (m, H-10), 2.70 (m, H-3'), 2.43 (d, H-2"eq), 2.33 (s, 
N(CH.sub.3).sub.2), 2.01 (m, H-4), 1.88 (m, H-14a), 1.72 (m, H-4'eq), 1.58 
(dd, H-2"b), 1.48 (m, H-14ax), 1.45 (s, 6-CH.sub.3), 1.26 (d, 
5"-CH.sub.3), 1.23 (s, 3"-CH.sub.3), 1.14 (s, 12-CH.sub.3), 1.10 (d, 
4-CH.sub.3), 1.05 (d, 8-CH.sub.3), and 0.84 (t, CH.sub.2 CH.sub.3). 
.sup.13 C NMR (CDCl.sub.3) .delta. 175.3, 171.3, 103.1, 96.3, 83.5, 80.3, 
78.1, 77.1, 75.1, 74.3, 72.6, 71.2, 70.9, 68.8, 65.4, 65.3, 49.4, 44.6, 
40.3, 38.8, 37.8, 35.1, 32.6, 29.2, 27.0, 25.4, 21.5, 21.3, 18.7, 18.6, 
16.3, 14.3, 10.6, and 9.3. 
.sup.13 C NMR (CD.sub.3 OD) .delta. 177.5, 171.6, 104.0, 98.0, 84.2, 81.2, 
79.3, 78.3, 76.3, 74.2, 72.9, 72.2, 69.0, 66.7, 65.2, 50.0, 46.3, 40.7, 
39.3, 36.2, 32.0, 27.4, 26.7, 22.3, 22.0, 21.6, 19.3, 19.1, 17.3, 16.6, 
14.8, 11.2, and 10.2. 
EI Mass Spectrum, m/z 748, 590, 574, 462, 431, 416, 398, 174, 159, 158, and 
116. 
##STR12## 
Conversion of (9E)-9-Deoxo-9-hydroxyiminoerythromycin A to 
(9Z)-9-Deoxo-9-hydroximinoerythromycin A 
Method 1 
(9E)-9-Deoxo-9-hydroxyiminoerythromycin A (20.0 g, 26.7 mmol) was added to 
a stirred solution of lithium hydroxide monohydrate (2.25 g, 53.5 mMol) in 
absolute ethanol (200 mL). The solution was blanketed with nitrogen and 
stirred overnight at room temperature. The solvents were evaporated under 
vacuum and the residue was partitioned between ethyl acetate (200 mL) and 
brine (120 mL). The pH of the mixture was adjusted from 11 to 9.3 with 2N 
hydrochloric acid. The ethyl acetate was removed and the brine was 
re-extracted with more ethyl acetate (2.times.200 mL). The combined ethyl 
acetate extracts were washed with brine (100 mL), dried with anhydrous 
magnesium sulfate, filtered and evaporated under vacuum to a foam (ca. 20 
g). 
The crude oxime mixture was dissolved in methylene chloride (220 mL) and 
stirred for 1 hour at room temperature to give a filterable, white solid 
(18.7 g). This material was dissolved in ethyl acetate (100 mL), diluted 
with nitromethane (100 mL), and 50 mL of solvent was evaporated under 
vacuum. Additional nitromethane (50 mL) was added and 80 mL of solvent was 
evaporated under vacuum. The solution was seeded with the (9Z)-isomer and 
stirred at room temperature for 3 hours. The resulting suspension was 
filtered and the solids were rinsed with nitromethane (20 mL) and dried 
under a stream of nitrogen to afford 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A (14.8 g, 74% yield) as a white 
solid. 
MP 157.degree.-164.degree. C. 
IR (CHCl.sub.3) 3680, 3435 (br), 2970, 2940, 1725, 1455, 1375, 1345, 1165, 
1105, 1085, 1045, 1005, and 950 cm.sup.-1. 
.sup.1 H NMR (CDCl.sub.3) .delta. 5.01 (dd, H-13), 4.87 (d, H-1"). 4.40 (d, 
H-1'), 3.98 (m, H-3 and H-5"), 3.80 (s, H-11), 3.49 (m, H-5 and H-5'), 
3.27 (s, OCH.sub.3), 3.21 (dd, H-2'), 2.99 (m, H-4"), 2.8 (m, H-8, H-2 and 
H-10), 2.74 (m, H-10), 2.43 (m, H-3'), 2.32 (d, H-2"eq), 2.27 (s, 
N(CH.sub.3).sub.2), 1.91 (m, H-4), 1.87 (m, H-14a), 1.63 (m, H-4'eq), 1.51 
(m, H-2"b and H-7), 1.42 (m, H-14ax), 1.37 (s, 6-CH.sub.3), 1.28 (d, 
10-CH.sub.3), 1.24 (d, 5"-CH.sub.3), 1.19 (s, 3"-CH.sub.3), 1.18 (d, 
5'-CH.sub.3), 1.12 (d, 2-CH.sub.3), 1.11 (s, 12-CH.sub.3), 1.08 (d, 
8-CH.sub.3), 1.04 (d, 4-CH.sub.3), and 0.79 (t, CH.sub.2 CH.sub.3). 
.sup.1 H NMR (CD.sub.3 OD) .delta. 5.20 (br d, H-13), 4.50 (br d, H-1'), 
4.16 (dq, H-5"), 4.02 (d, H-3), 3.70 (m, H-5'), 3.56 (br d, H-5), 3.34 (s, 
OCH.sub.3), 3.25 (dd, H-2'), 3.03 (d, H-4"), 2.87 (m, H-8), 2.84 (m, H-2), 
2.73 (m, H-3'), 2.44 (d, H-2"eq), 2.33 (s, N(CH.sub.3).sub.2), 1.97 (m, 
H-4), 1.88 (m, H-14a), 1.73 (m, H-4'eq), 1.64 (m, H-7), 1.59 (dd, H-2"b), 
1.47 (m, H-14ax), 1.36 (br s, 6-CH.sub.3), 1.28 (d, 5"-CH.sub.3), 1.24 (s, 
3"-CH.sub.3), 1.18 (m, 5' -CH.sub.3, 2-CH.sub.3, 8-CH.sub.3 and 
10-CH.sub.3)), 1.13 (s, 12-CH.sub.3), 1.08 (d, 4-CH.sub.3), and 0.86 (t, 
CH.sub.2 CH.sub.3). 
.sup.13 C NMR (CDCl.sub.3) .delta. 176.2, 168.2, 102.8, 95.9, 83.6 (br), 
79.3 (br), 77.9, 77.3, 75.2, 75.1, 72.7, 71.0, 70.9, 68.8, 65.5, 65.3, 
49.4, 40.2, 39.9 (br), 37.8 (br), 35.7 (br), 34.9, 34.1 (br), 28.9, 26.0 
(br), 21.4, 21.3, 19.8 (br), 18.4, 16.8, 15.3 (br), 10.7, and 9.2. 
.sup.13 C NMR (CD.sub.3 OD) .delta. 177.7, 170.0, 103.9, 97.7, 84.3 (br), 
80.7, 79.2, 78.1, 77.0 (br), 76.1, 74.1, 72.8, 71.7 (br), 69.2, 66.7, 
65.1, 49.9, 46.2 (br), 41.8 (br), 40.8, 40.5 (br), 36.0, 33.8 (br), 31.9, 
26.7 (br), 22.8, 21.8, 21.7 (br), 21.6, 19.1, 17.5, 15.8 (br), 12.2 (br), 
11.3, and 10.1. 
FAB mass spectrum, m/z 749, 591, 416, 398, 174, 159, 158, and 116. 
Elemental Analysis Calculated for C.sub.37 H.sub.68 N.sub.2 O.sub.13 : C, 
59.34; H, 9.15; N, 3.74. Found: C, 59.12; H, 8.80; N, 3.82. 
Method 2: 1.0 LiOH in EtOH 
(9E)-9-Deoxo-9-hydroxyiminoerythromycin A (255 mg, 0.34 mmol) was added to 
a solution of lithium hydroxide monohydrate (14.3 mg, 0.34 mmol) in 
absolute ethanol (2.55 mL). The resulting solution was stirred at room 
temperature for 25 hours, and then stored in a freezer at -20.degree. C. 
for 68 hours. After warming to room temperature, the solution was 
evaporated under reduced pressure to remove the solvent. The residue was 
stirred with saturated aqueous sodium chloride (5 mL) and ethyl acetate (5 
mL) while the pH was adjusted to 9.2 by addition of dilute hydrochloric 
acid. After shaking, the phases were separated and the aqueous portion 
extracted with more ethyl acetate (2.times. 2.5 mL). The combined ethyl 
acetate extracts were washed with saturated sodium chloride solution (4 
mL), dried over magnesium sulfate, filtered and evaporated at reduced 
pressure to afford a white foam (263 mg). Examination of this material by 
.sup.1 H NMR spectroscopy revealed a 31:69 mixture of 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A. 
Method 3: 2.0 LiOH in EtOH 
(9E)-9-Deoxo-9-hydroxyiminoerythromycin A (291 mg, 0.333 mmol) was added to 
a solution of lithium hydroxide monohydrate (32.6 mg, 0.776 mmol) in 
absolute ethanol (2.9 mL). The resulting solution was stirred at room 
temperature under a nitrogen atmosphere for 22.5 hours. The solvent was 
evaporated at reduced pressure and the residue stirred with ethyl acetate 
(5 mL) and saturated aqueous sodium chloride (5 mL) while adjusting the pH 
to 9 by addition of 2N hydrochloric acid. The mixture was shaken, the 
phases separated, and the aqueous portion extracted with more ethyl 
acetate (2.times.2.5 mL). The combined ethyl acetate extracts were washed 
with saturated sodium chloride solution (4 mL), dried with magnesium 
sulfate, filtered and evaporated under vacuum to a white foam (299 mg). 
This material was shown by .sup.1 H NMR to be a 21:79 mixture of 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A. 
Method 4: 3.0 LiOH in EtOH 
(9E)-9-Deoxo-9-hydroxyiminoerythromycin A (239 mg, 0.319 mmol) was was 
added to a mixture of lithium hydroxide monohydrate (40.2 mg, 0.957 mmol) 
in absolute ethanol (2.4 mL), and the resulting solution was stirred at 
room temperature under a nitrogen atmosphere for 21.7 hours. Workup as 
described in method 3 afforded a white foam (236 mg) shown by .sup.1 H NMR 
to consist of a 19:81 mixture of (9E)-9-deoxo-9-hydroxyiminoerythromycin A 
and (9Z)-9-deoxo-9-hydroxyiminoerythromycin A. 
Method 5: 2.0 NaOEt in EtOH 
Freshly cut sodium metal (48 mg, 2.087 mmol) was dissolved in absolute 
ethanol (7.8 mL) under a nitrogen atmosphere. 
9-Deoxo-9(E)-hydroxyiminoerythromycin A (782 mg, 1.043 mmol) was added and 
the resulting solution was stirred at room temperature. A crystalline 
precipitate, identified as the starting oxime by thin layer 
chromatography, appeared after a few hours. After stirring overnight, the 
mixture was once again a clear solution. After 54 hours, approximately 
half (3.9 mL) of the reaction mixture was removed and evaporated under 
reduced pressure. The gummy residue was stirred with ethyl acetate (5 mL) 
and saturated aqueous sodium chloride (5 mL) while the pH was adjusted to 
9.2 by addition of dilute hydrochloric acid (2N and 0.2N solutions). The 
mixture was shaken, the layers separated, and the aqueous portion 
extracted with more ethyl acetate (2.times.2.5 mL). The combined ethyl 
acetate solution was washed with saturated brine (5 mL), dried with 
magnesium sulfate, filtered and evaporated under reduced pressure to a 
white foam (361 mg). This material was shown by .sup.1 H NMR spectroscopy 
to consist of a 22:78 mixture of the 9(E) and 9(Z) isomers of 
9-deoxo-9-hydroxyiminoerythromycin A. 
Method 6: 2.0 NaOH in EtOH 
The remaining half of the reaction mixture from method 5 was treated with 
water (0.0188 mL, 1.04 mmol) to give a solution effectively consisting of 
sodium hydroxide and oxime in ethanol. The solution was stirred at room 
temperature for 23 hours, then worked up as described in method 5 to give 
a white foam (402 mg). This material was shown by .sup.1 H NMR to consist 
of a 24:76 mixture of the (9E) and (9Z) isomers of 
9-deoxy-9-hydroxyiminoerythromycin A. 
Method 7: 2.0 LiOH in MeOH 
A solution of lithium hydroxide monohydrate (37 mg, 0.88 mmol), 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A (330 mg, 0.44 mmol), and 
methanol (3.3 mL) was stirred at room temperature for 65.5 hours. The 
solution was then stored at -20.degree. C. for 13 days before warming to 
room temperature and evaporating the solvent at reduced pressure. The 
residue was stirred with ethyl acetate (5 mL) and brine (5 mL) while 
adjusting the pH to 9.2 by addition of dilute hydrochloric acid. The 
mixture was shaken, the layers separated and the aqueous portion extracted 
with more ethyl acetate (2.times.2.5 mL). The combined ethyl acetate 
solution was washed with brine (5 mL), dried with magnesium sulfate, and 
evaporated under vacuum to provide a white foam (324 mg). NMR analysis of 
this material indicated a 45:55 ratio of (9E) to (9Z) 
9-deoxo-9-hydroxyiminoerythromycin A products. 
Method 8: 2.0 NaOMe in MeOH 
A solution of (9E)-9-deoxo-9-hydroxyiminoerythromycin A (375 mg, 0.5 mmol) 
in anhydrous methanol (3.5 mL) was cooled in an ice bath and stirred under 
a nitrogen atmosphere while methanolic sodium methoxide (0.23 mL of a 25 
wt % solution, 1.01 mmol) was added by syringe. The cooling bath was 
removed and the solution was stirred at room temperature and under a 
nitrogen atmosphere for 66 hours. The solution was then stored at 
-20.degree. C. for 13.3 days before being processed to a white foam (329 
mg) as described in method 7. The product consisted of a 35:65 mixture of 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A as determined by .sup.1 H NMR 
spectroscopy. 
Method 9: 10.0 NaOMe in MeOH 
A solution of (9E)-9-deoxo-9-hydroxyiminoerythromycin A (100 mg, 0.134 
mmol) in anhydrous methanol (4.70 mL) was treated with sodium methoxide 
(0.305 mL of a 25 wt % solution in methanol, 1.335 mmol) and stirred at 
room temperature for 74.5 hours. The solvent was evaporated under reduced 
pressure and the residue stirred with ethyl acetate (5 mL) and saturated 
brine (5 mL) while adjusting the pH of the aqueous layer to 9.4 with 2N 
hydrochloric acid. The mixture was shaken, the layers separated and the 
aqueous portion extracted with more ethyl acetate (2.times.2.5 mL). The 
combined ethyl acetate solution was washed with brine (5 mL), dried with 
magnesium sulfate, filtered and evaporated at reduced pressure to afford a 
white foam (102 mg). This material was shown by .sup.1 H NMR spectroscopy 
to consist of a 26:74 mixture of the (9E) and (9Z) isomers of 
9-deoxo-9-hydroxyiminoerythromycin A. 
Method 10: 2.0 LiOH in iPrOH 
(9E)-9-Deoxo-9-hydroxyiminoerythromycin A (279 mg, 0.361 mmol) was added to 
a partial solution of lithium hydroxide monohydrate (30.3 mg, 0.721 mmol) 
in isopropanol (2.7 mL), and the mixture was stirred at room temperature 
in a capped flask. A fine white precipitate formed in a few minutes and, 
after stiring overnight, the mixture was a hazy suspension. After 21 
hours, the mixture was transferred to a freezer at -20.degree. C. and 
stored there for 15 days. After warming to room temperature, the solvent 
was evaporated under vacuum and the residue stirred with ethyl acetate (5 
mL) and brine (5 mL) while adjusting the pH to 9.2 with dilute 
hydrochloric acid. The mixture was shaken, the layers separated, and the 
aqueous phase extracted with more ethyl acetate (2.times.2.5 ml). The 
combined ethyl acetate solution was washed with brine (4 mL), dried with 
magnesium sulfate, filtered and evaporated under vacuum to afford a white 
foam (249 mg). The product consisted of a 26:74 mixture of 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A as determined by .sup.1 H NMR 
spectroscopy. 
Method 11: 1.0 LiOH in MeCN 
A mixture of (9E)-9-deoxo-9-hydroxyiminoerythromycin A (500 mg, 0.668 
mmol), lithium hydroxide monohydrate (28 mg, 0.668 mmol), and absolute 
ethanol (5 mL) was stirred at room temperature for 10 minutes to give a 
solution. The solution was evaporated under reduced pressure to afford a 
residue that was twice diluted with ethanol (10 mL) and evaporated at 
reduced pressure and then suspended in anhydrous acetonitrile (5 mL) and 
evaporated at reduced pressure. The solid residue was suspended in 
anhydrous acetonitrile (5 mL) and the mixture was stirred at room 
temperature for 18 days. The solvent was evaporated under reduced pressure 
and the residue was stirred with ethyl acetate (5 mL) and saturated 
aqueous sodium chloride solution (5 mL) while adjusting the pH of the 
aqueous phase to 9.5 by addition of dilute hydrochloric acid. The mixture 
was shaken, the layers separated, and the aqueous portion was extracted 
with additional ethyl acetate (2.times.2.5 mL). The combined ethyl acetate 
solution was washed with brine (5 mL), dried over magnesium sulfate, 
filtered and evaporated under reduced pressure to afford a foam (442 mg). 
This material was shown by .sup.1 H NMR spectroscopy to consist of a 44:56 
mixture of the (9E) and (9Z) isomers of 9-deoxo-9-hydroxyiminoerythromycin 
A. 
Method 12: 1.0 LiOH in DMF 
A mixture of (9E)-9-deoxo-9-hydroxyiminoerythromycin A (500 mg, 0.668 
mmol), lithium hydroxide monohydrate (28 mg), and dimethylformamide (5 mL) 
was stirred at room temperature in a capped flask. After a few hours, the 
initial suspension gave way to a solution. After stirring for 18 days and 
18 hours, the solution was evaporated under reduced pressure and the 
residue was processed as described in method 11 to afford a foam (402 mg). 
Analysis of this material by .sup.1 H NMR spectroscopy indicated a 62:38 
mixture of the (9E) and (9Z) isomers of 9-deoxo-9-hydroxyimioerythromycin 
A. 
Method 13: 1.2 LiN(SiMe.sub.3).sub.2 in MeCN 
A suspension of (9E)-9-deoxo-9-hydroxyiminoerythromycin (500 mg, 0.668 
mmol) in anhydrous acetonitrile (4 mL) was treated with lithium 
hexamethyldisilazide (0.80 mL of a 1M solution in hexane, 0.80 mmol). The 
resulting suspension rapidly gave way to a solution which reformed a 
suspension after stirring several days at room temperature. After 18 days 
and 19 hours, the reaction mixture was worked up as described in method 11 
to afford a foam (423 mg). This material was shown by .sup.1 H NMR 
spectroscopy to be a 50:50 mixture of 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A. 
EXAMPLE 3 
Crystallization of (9Z)-9-Deoxo-9-hydroxyiminoerythromycin A 
A 3:1 mixture (30.0 g) of (9Z)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A was added over 2 minutes to well 
stirred ethyl acetate (60 mL). After obtaining a solution, methylene 
chloride (120 mL) was rapidly added and the resulting suspension was 
stirred in an ice bath for one hour. The precipitate was filtered off, 
washed with methylene chloride (60 mL), and dried under a stream of 
nitrogen to afford an 86:14 mixture (26.5 g) of 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A. 
A solution of the above solid in ethyl acetate (60 mL) was diluted with 
methylene chloride (120 mL). The resulting suspension was cooled in an ice 
bath for one hour and then filtered. The collected solid was rinsed with 
methylene chloride (60 mL) and dried under a stream of nitrogen to afford 
a 95:5 mixture (23.4 g) of (9Z)-9-deoxo-9-hydroxyiminoerythromycin A and 
(9E)-9-deoxo-9-hydroxyiminoerythromycin A. 
EXAMPLE 4 
##STR13## 
Synthesis of 8a-Aza-8a-homoerythromycin A and 
9-Deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A by 
the Beckmann Rearrangement of 9-Deoxo-9(Z)-hydroxyiminoerythromycin A 
Method 1 
(9Z)-9-Deoxo-9-hydroxyiminoerythromycin A (200 mg, 0.27 mmol) was dissolved 
in acetone (2 mL) and the resulting solution was cooled in an ice-bath and 
stirred under a nitrogen atmosphere. A solution of sodium bicarbonate (84 
mg, 1.0 mmol) in water (2 mL) was added followed by the dropwise addition 
of an acetone solution (2 mL) of p-toluenesulfonyl chloride (100 mg, 0.53 
mmol) over 5 minutes. 
After stirring for 1.5 hours at 0.degree.-5.degree. C., the mixture was 
diluted with dichloromethane (10 mL) and water (5 mL), and the pH was 
adjusted from 10 to 5.5 with 2N HCl. The dichloromethane layer was 
discarded and the aqueous layer was washed with additional dichloromethane 
(2.times.10 mL) which was also discarded. Dichloromethane (10 mL) was 
added to the aqueous layer and the pH was adjusted to 8.5 with 2.5N NaOH. 
The dichloromethane layer was removed and the aqueous layer was extracted 
with more dichloromethane (2.times.20 mL). The combined dichloromethane 
extracts were dried over anhydrous magnesium sulfate, filtered and 
evaporated under vacuum to give a mixture of the title compounds as a foam 
(150 mg). 
The above mixture was purified by preparative layer chromatography (two 0.1 
mm.times.20.times.20 cm Analtech silica gel GF plates, developing and 
eluting with 60:10:1 dichloromethane-methanol concentrated ammonium 
hydroxide) to afford 8a-aza-8a-homoerythromycin A (95 mg) and 
9-deoxo-6-deoxy-6, 9-epoxy-8a, 9-didehydro-8a-aza-8a-homoerythromycin A 
(33 mg). 
Method 2: 
A solution of p-toluenesulfonyl chloride (1.00 g, 5.2 mmol) in acetone (20 
mL) was added to a solution of sodium bicarbonate (0.90 g, 10.7 mmol) in 
water (20 mL). The resulting suspension was cooled in a -10.degree. C. 
bath and stirred while a solution of 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A (2.00 g, 2.7 mmol) in acetone 
(20 mL) was added slowly over 75 minutes. The mixture was stirred at 
-10.degree. C. for 5 hours, then warmed to 0.degree. C. over 10 minutes 
and stirred at 0.degree.-5.degree. C. for 30 minutes. The mixture was 
evaporated under vacuum to remove the acetone. The aqueous residue was 
diluted with water (40 mL) and dichloromethane (60 mL) and stirred while 
the pH was adjusted to 5.5 with dilute hydrochloric acid. The aqueous 
layer was separated, washed with dichloromethane (60 mL), layered with 
dichloromethane (60 mL), and stirred while the pH was brought to 9 with 
dilute aqueous sodium hydroxide. The layers were separated and the aqueous 
portion extracted with more dichloromethane (2.times.50 mL). The combined 
pH 9 extracts were dried over magnesium sulfate, filtered and evaporated 
under reduced pressure to afford a gum (1.97 g) which was shown by .sup.1 
H NMR spectroscopy to be a 1:1 mixture of 8a-aza-8a-homoerythromycin A and 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
The crude product mixture was dissolved in 120:10:1 
dichloromethane-methanol-conc. aqueous ammonium hydroxide (5 mL) and 
loaded onto a column of silica gel (4.times.16 cm). The column was eluted 
with 120:10:1 dichloromethane-methanol-ammonium hydroxide. After a 150 mL 
forerun, 15 mL fractions were collected. Fractions 9-13 were combined and 
evaporated under vacuum to afford 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A (ca. 
500 mg) and fractions 22-26 were combined and evaporated to afford 
8a-aza-8a-homoerythromycin A (ca. 500 mg). The latter product was 
crystallized from ether to give the amide (ca. 130 mg) as a white solid. 
Physical data for 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
IR (CHCl.sub.3) 3550, 3440 (br), 2970, 2940, 2880, 1725, 1665, 1455, 1375, 
1345, 1325, 1240, 1170, 1105, 1080, 1050, 1015, 995, and 955 cm-1. 
.sup.1 H NMR (CDCl.sub.3) .delta. 5.02 (d, H-1"), 4.90 (dd, H-13), 4.48 (d, 
H-1"), 4.09 (dq, H-5"), 4.02 (t, H-3), 3.81 (d, H-5), 3.53 (m, H-5'), 3.49 
(d, H-11), 3.43 (m, H-8), 3.35 (s, OCH.sub.3), 3.20 (dd, H-2'), 3.07 (t, 
H-4"), 2.75 (dq, H-2), 2.68 (dq, H-10), 2.52 (ddd, H-3'), 2.43 (d, 
H-2"eq), 2.28 (s, N(CH.sub.3)2), 1.98 (ddq, H-4), 1.91 (m, H-14a), 1.90 
(dd, H-7a), 1.68 (ddd, H-4'eq), 1.62 (dd, H-2"ax), 1.46 (m, H-14b), 1.39 
(s, 6-CH.sub.3), 1.32 (d, 5"-CH.sub.3), 1.27 (s, 3"-CH.sub.3), 1.24 (m, 
H-7b), 1.22 (d, 5'-CH.sub.3), 1.21 (m, H-4'ax), 1.16 (d, 10-CH.sub.3), 
1.15 (d, 8-CH.sub.3), 1.15 (s, 12-CH.sub.3), 1.14 (d, 2-CH.sub.3), 1.08 
(d, 4-CH.sub.3), and 0.87 (t, CH.sub.2 CH.sub.3). 
.sup.13 C NMR (CDCl.sub.3) .delta. 177.6, 160.6, 102.4, 94.6, 80.1, 78.9, 
77.9, 77.4, 76.5, 75.7, 73.0, 70.6, 70.0, 68.8, 65.8, 65.6, 49.4, 44.9, 
44.0, 42.3, 42.1, 40.3, 34.5, 32.0, 28.5, 23.8, 22.4, 21.5, 21.3, 21.0, 
18.2, 17.0, 16.4, 12.5, 10.8, and 8.4. 
FAB mass spectrum, m/z 731, 713, 602, 573, 555, 398, 159, 158, and 116. 
Physical data for 8a-aza-8a-homoerythromycin A 
MP 170.degree.-176.degree. C. 
IR (CHCl.sub.3) 3500 (br), 3430, 3320, 2970, 2935, 2880, 1730, 1630, 1560, 
1525, 1455, 1375, 1325, 1280, 1170, 1160, 1105, 1085, 1045, 1010 and 995 
cm.sup.-1. 
.sup.1 H NMR (CDCl.sub.3) .delta. 5.89 (br d, NH), 5.07 (d, H-1"), 4.92 
(dd, H-13), 4.43 (d, H-1'), 4.35 (d, H-3), 4.21 (m, H-8), 4.01 (dq, H-5"), 
3.58 (d, H-5), 3.50 (m, H-5'), 3.50 (s, H-11), 3.32 (s, OCH.sub.3), 3.21 
(dd, H-2'), 3.03 (t, H-4"), 2.62 (dq, H-2), 2.54 (m, H-3'), 2.35 (m, 
H-10), 2.35 (s, N(CH.sub.3).sub.2), 2.31 (d, H-2"eq), 1.90 (m, H-4), 1.89 
(m, H-14a), 1.75 (br d, H-4'eq), 1.57 (dd, H-2"ax), 1.51 (m, H-7a and 
H-7b), 1.44 (m, H-14b), 1.43 (s, 6-CH.sub.3), 1.30 (d, 5"-CH.sub.3), 1.24 
(s, 3"-CH.sub.3), 1.23 (m, H-4'ax), 1.23 (d, 5'-CH.sub.3), 1.20 (d, 
8-CH.sub.3), 1.19 (d, 10-CH.sub.3), 1.18 (d, 2-CH.sub.3), 1.09 (s, 
12-CH.sub.3), 1.05 (d, 4-CH.sub.3), and 0.89 (t, CH.sub.2 CH.sub.3). 
.sup.13 C NMR (CDCl.sub.3) .delta. 177.6, 176.6, 102.7, 94.2, 83.0, 77.9, 
77.0, 76.6, 74.6, 73.7, 72.9, 70.0, 69.8, 68.8, 65.8, 65.2, 49.2, 45.8, 
43.2, 42.4, 41.0, 40.4, 40.1, 34.5, 28.3, 27.6, 23.1, 21.7, 21.5, 21.2, 
18.0, 16.1, 14.6, 11.2, 10.0, and 9.1. 
Mass Spectrum, m/z 749, 731, 591, 589, 573, 416, 174, 159, 158 and 117. 
Elemental Analysis: Calculated for C.sub.37 H.sub.68 N.sub.2 O.sub.13 : C, 
59.34; H, 9.15; N, 3.74. Found: C, 59.24; H, 9.15; N, 3.44. 
Loss on drying at 120.degree. C., 3.11%. 
EXAMPLE 5 
Synthesis of 
9-Deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A and 
9-Deoxo-12-deoxy-9,12-epoxy-8a, 9-didehydro-8a-aza-8a-homoerythromycin A 
by Beckmann Rearrangement of (9Z)-9-Deoxo-9-hydroximinoerythromycin A 
##STR14## 
Method 1 
A solution of p-toluenesulfonyl chloride (15.0 g, 0.079 mol) in diethyl 
ether (50 mL) was added dropwise over 8 minutes to an ice-cold, stirring 
solution of (9Z)-9-deoxo-9-hydroxyiminoery thromycin A (23.2 g, 0.031 mol) 
in pyridine (180 mL). the resulting solution was stirred at 
0.degree.-5.degree. C. for 2.5 hours, then diluted with dichloromethane 
(400 mL) and water (500 mL) and basified to pH 9.5 by addition of 5N 
sodium hydroxide. The layers were separated and the aqueous portion 
extracted with more dichloromethane (200 mL, 100 mL). The combined 
dichloromethane extracts were dried over magnesium sulfate, filtered, and 
evaporated under vacuum to afford an oil. Residual pyridine was removed by 
twice taking the product up in toluene (100 mL) and evaporating the 
solvent under vacuum. The resulting foam (21.4 g) was shown by .sup.1 H 
NMR spectroscopy to be a 26:74 mixture of 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A and 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
Method 2 
A solution of p-toluenesulfonyl chloride (160 mg, 0.84 mmol) in diethyl 
ether (0.5 mL) was added rapidly to an ice-cold solution of 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A (250 mg, 0.33 mmol) in pyridine 
(2.0 mL). The resulting solution was stirred at 0.degree.-5.degree. C. for 
1.5 hours, then diluted with dichloromethane (4 mL) and water (4 mL) and 
basified to pH 9.5 by addition of 5N sodium hydroxide. The layers were 
separated and the aqueous portion extracted with more dichloromethane 
(2.times.4 mL). The combined dichloromethane extracts were dried over 
magnesium sulfate, filtered, evaporated under vacuum and stripped with 
hexane (4.times.15 mL) to afford a yellow solid (260 mg). This material 
was shown by 1H NMR spectroscopy to be a 25:75 mixture of 
9-deoxo-6-deoxy-6,9-epoxy- and 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-dide-hydro-8a-aza-8a-homoerythromycin A. 
Method 3 
A solution of p-toluenesulfonyl chloride (160 mg, 0.84 mmol) in 
acetonitrile (0.5 mL) was added rapidly to an ice-cold solution of 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A (250 mg, 0.33 mmol) in pyridine 
(2.0 mL). The resulting solution was stirred at 0.degree.-5.degree. C. for 
80 minutes, then diluted with dichloromethane (4 mL) and water (5 mL) and 
basified to pH 9.5 by addition of 5N sodium hydroxide. The layers were 
separated and the aqueous portion extracted with more dichloromethane 
(2.times.4 mL). The combined dichloromethane extracts were dried over 
magnesium sulfate, filtered, and evaporated under vacuum to a foam which 
was stripped with toluene (2.times.10 mL) and hexanes (10 mL) to afford a 
solid (230 mg). This material was shown by 1H NMR spectroscopy to be a 
33:67 mixture of 9-deoxo-6-deoxy-6,9-epoxy-and 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
Method 4 
A solution of p-toluenesulfonyl chloride (160 mg, 0.84 mmol) in toluene 
(0.5 mL) was added rapidly to an ice-cold solution of 
(9Z)-9-deoxo-9-hydroxyiminoerythromycin A (250 mg, 0.33 mmol) in pyridine 
(2.0 mL). The resulting solution was stirred at 0.degree.-5.degree. C. for 
90 minutes, then diluted with dichloromethane (4 mL) and water (4 mL) and 
basified to pH 9.5 by addition of 1N sodium hydroxide. The layers were 
separated and the aqueous portion extracted with more dichloromethane 
(3.times.4 mL). The combined dichloromethane extracts were dried over 
magnesium sulfate, filtered, and evaporated under vacuum to a solid (250 
mg). This material was shown by 1H NMR spectroscopy to be a 27:73 mixture 
of 9-deoxo-6-deoxy-6,9-epoxy- and 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
Method 5 
Benezenesulfonyl chloride (0.107 mL, 0.84 mmol) was added by syringe to an 
ice-cold solution of (9Z)-9-deoxo-9-hydroxyiminoerythromycin A (250 mg, 
0.33 mmol) in pyridine (2.0 mL). The resulting solution was stirred at 
0.degree.-5.degree. C. for 75 minutes, then processed as described above 
to afford a yellow solid (240 mg). This material was shown by 1H NMR 
spectroscopy to be a 31:69 mixture of 9-deoxo-6-deoxy-6,9-epoxy- and 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
Method 6 
Methanesulfonyl chloride (0.065 mL, 0.84 mmol) was added by syringe to an 
ice-cold solution of (9Z)-9-deoxo-9-hydroxyiminoerythromycin A (250 mg, 
0.33 mmol) in pyridine (2.0 mL). The resulting solution was stirred at 
0.degree.-5.degree. C. for 2 hours, then processed as described above to 
afford an off-white solid (246 mg). This material was shown by .sup.1 H 
NMR spectroscopy to be a 25:70:5 mixture of 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A, 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A, 
and 
9-deoxy-9,12-epoxy-4"-0-methanesulfonyl-8a,9-didehydro-8a-aza-8a-homoeryth 
romycin A. 
Method 7 
A solution of (9Z)-9-deoxo-9-hydroxy-iminoerythromycin A (250 mg, 0.33 
mmol) in pyridine (2.0 mL) was cooled in a -20.degree. C. bath and treated 
with methanesulfonyl chloride (0.071 mL, 0.92 mmol). The resulting hazy 
solution was stirred at -10.degree. to -20.degree. C. for 90 minutes, then 
processed as described above to afford a yellow solid (254 mg). This 
material was shown by 1H NMR spectroscopy to be a 88:12 mixture of 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A and 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
Method 8 
A mixture of (9Z)-9-deoxo-9-hydroxyiminoerythromycin A (0.50 g, 0.67 mmol), 
p-toluenesulfonyl chloride (318 mg, 1.67 mmol) and pyridine (0.162 mL, 2.0 
mmol) in dichloromethane (5.0 mL) was stirred at room temperature for 1.5 
hours. The mixture was diluted with water and stirred rapidly while 
adjusting the pH to 11 with 5N sodium hydroxide. The organic phase was 
separated, dried with magnesium sulfate, filtered and evaporated under 
reduced pressure to afford a yellow solid (570 mg). Analysis of the crude 
product by .sup.1 H NMR spectroscopy revealed a 80:20 mixture of 
9-deoxo-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A and 
9-deoxo-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
Purification of 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A by 
Column Chromatography 
The following procedure illustrates the purification process for 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A. 
The crude products from methods 3 and 4 above were combined, dissolved in 
94:5:1 dichloromethane-methanol-triethylamine, and loaded onto a column of 
silica gel (230-400 mesh, 2.5.times.24.5 cm, wet packed under 94:5:1 
dichloromethane-methanol-triethylamine). The column was eluted with 94:5:1 
dichloromethane-methanol-triethylamine, collecting 6 mL fractions. 
Fractions 15-18 were combined, evaporated under reduced pressure, and the 
residue twice stripped with toluene to provide 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
(190 mg) as a foam. The product is a mixture of major and minor forms as 
ascertained by .sup.1 H and .sup.13 C NMR spectroscopy. 
IR (CHCl.sub.3) 3550, 3390 (br), 2975, 2940, 2880, 1735, 1690, 1455, 1375, 
1240, 1165, 1085, 1045, 1010, and 970 cm.sup.-1. 
FAB mass spectrum, m/z 731, 713, 602, 573, 556, and 158. 
Chromatographic Separation of 
9-Deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A and 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
and Crystallization of 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerthromycin A 
A sample (4.0 g) of the crude product mixture obtained as described in 
method 1 was dissolved in 60:10:1 dichloromethane-methanol-conc. aqueous 
ammonium hydroxide (6 mL) and the solution was loaded onto a column of EM 
silica gel 60 (4.5.times.18 cm, 230-400 mesh, wet packed under 60:10:1 
dichloromethane-methanol-conc. ammonium hydroxide). The column was eluted 
with 60:10:1 dichloromethane-methanol-conc. aqueous ammonium hydroxide. 
The fractions collected from 150 mL to 165 mL of eluant were evaporated 
under vacuum to afford 
9-deoxo-6-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
(0.34 g) as a foam. The fractions collected from 185 mL to 285 mL of 
eluant were combined and evaporated under reduced pressure to afford a 
mixture of the two isomeric forms of 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
(1.36 g) as a foam. 
A solution of the mixture of 9,12-epoxy isomers in nitromethane (2 mL) 
deposited a large, crystalline mass on standing at room temperature for 
several days. The mixture was diluted with nitromethane (10 mL) and 
filtered to remove the solid portion, which was washed with nitromethane 
(2 mL) and dried under high vacuum. The white solid thus obtained (0.9 g) 
was shown by .sup.1 H NMR spectroscopy to be the major 9,12-epoxy isomer 
which is initially formed in the Beckmann rearrangement reaction. While 
stable in the solid state, solutions of the crystalline isomer in 
chloroform-d equilibrate at room temperature in several hours to a 1:1 
mixture of the two isomers of 
9-deoxo-12-deoxy-6,9-epoxy-8a,9-didehydro-8a-aza-8a-homoerthromycin A. 
Physical data for 
9-deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A: 
Isomer A (crystalline isomer) 
MP 124.degree.-130.degree. C. (slowly softens). 
IR (CHCl.sub.3) 3350, 3380 (br), 2970, 2935, 2875, 1735, 1695, 1560, 1460, 
1375, 1250, 1165, 1115, 1085, 1045, 1015, and 975 cm.sup.-1. 
.sup.1 H NMR (CDCl.sub.3) .delta. 5.17 (dd, H-13), 4.73 (d, H-1"), 4.47 (d, 
H-1"), 4.15 (dq, H-5"), 4.09 (dd, H-3), 3.99 (br s, H-5), 3.81 (t, H-11), 
3.68 (m, H-8), 3.65 (m, H-5'), 3.40 (ddd, H-2'), 3.23 (s, OCH.sub.3), 2.96 
(t, H-4"), 2.70 (p, H-10), 2.68 (m, H-3'), 2.57 (br d, 11-OH), 2.45 (p, 
H-2), 2.31 (s, N(CH.sub.3).sub.2), 2.28 (d, H-2"eq), 2.20 (d, 4"-OH), 2.07 
(ddq, H-14a), 1.90 (br d, H-7a), 1.75 (dd, H-7b), 1.74 (m, H-4), 1.70 (m, 
H-4'eq), 1.69 (m, H-14b), 1.46 (dd, H-2"ax), 1.40 (s, 6-CH.sub.3), 1.29 
(m, H-4'ax), 1.27 (d, 10-CH.sub.3), 1.27 (d, 5"-CH.sub.3), 1.25 (d, 
2-CH.sub.3), 1.24 (d, 5'-CH.sub.3), 1.21 (s, 3"-CH.sub.3), 1.18 (s, 
12-CH.sub.3), 1.07 (d, 8-CH.sub.3), 1.01 (d, 4-CH.sub.3), and 0.86 (t, 
CH.sub.2 CH.sub.3). 
.sup.13 C NMR (CDCl.sub.3) .delta. 174.2, 161.3, 106.7, 98.3, 85.4, 84.2, 
80.5, 79.8, 77.4, 75.0, 72.3, 70.3, 69.4, 66.3, 63.8, 49.4, 49.2, 49.0, 
47.1, 45.4, 43.2, 40.4, 35.0, 29.3, 27.5, 24.6, 24.4, 23.3, 21.4, 21.0, 
17.6, 17.2, 16.9, 11.3, and 11.2. 
Elemental Analysis Calculated for C.sub.37 H.sub.66 N.sub.2 O.sub.12 : C, 
60.80; H, 9.10; N, 3.83. Found: C, 60.71; H, 9.38; N, 3.78. 
Loss on drying at 120.degree. C., 2.82%. 
Isomer B 
.sup.1 H NMR (CDCl.sub.3) .delta. 5.20 (dd, H-13), 4.74 (d, H-1"), 4.48 (d, 
H-1'), 4.17 (t, H-3), 4.15 (m, H-5"), 4.11 (dd, H-11), 3.97 (m, H-8), 3.71 
(d, H-4), 3.62 (m, H-5'), 3.30 (br dd, H-2'), 3.23 (s, OCH.sub.3), 2.97 
(t, H-4"), 2.88 (d, 11-OH), 2.85 (p, H-10), 2.60 (m, H-3'), 2.46 (p, H-2), 
2.28 (s, N(CH.sub.3).sub.2), 2.27 (d, H-2"eq), 2.23 (d, 4"-OH), 1.98 (ddq, 
H-14a), 1.84 (dd, H-7a), 1.77 (m, H-4), 1.76 (m, H-14b), 1.66 (m, 
H-4'eq), 1.64 (dd, H-7b), 1.49 (dd, H-2"ax), 1.29 (s, 6-CH.sub.3), 1.27 
(d, 5"-CH.sub.3), 1.24 (d, 2-CH.sub.3), 1.22 (d, 5'-CH.sub.3), 1.19 (d, 
10-CH.sub.3), 1.19 (s, 3"-CH.sub.3), 1.14 (s, 12-CH.sub.3), 1.09 (d, 
8-CH.sub.3), 1.09 (d, 4-CH.sub.3), and 0.94 (t, CH.sub.2 Ce,uns/H/ 
.sub.3). 
.sup.13 C NMR (CDCl.sub.3) .delta. 174.4, 160.5, 104.6, 97.0, 86.2, 79.1, 
78.6, 77.7, 77.4, 75.1, 70.5, 69.4, 66.0, 64.7, 49.4, 48.2, 47.7, 47.4, 
42.3, 40.4, 34.9, 29.1, 25.6, 24.0, 23.6, 22.9, 21.5, 21.0, 15.8, 11.7, 
10.7, and 9.6. 
EXAMPLE 6 
Synthesis of 8a-Aza-8a-allyl-8a-homoerythromycin A 
##STR15## 
Step 1: 
2'-0.4"-0.6-0.11-0.12-0-Penta(trimethylsilyl)-8a-aza-8a-homoerythromycin A 
8a-Aza-8a-homoerythromycin A (748 mg, 1 mmol) is added to a mixture of 
pyridine (2 mL, 24.7 mmol) and bis(trimethylsilyl) trifluoroacetamide (2 
mL, 7.5 mmol) and the resulting solution is stirred at room temperature 
for 48 hours. The mixture is evaporated under vacuum and the residue is 
three times diluted with toluene (40 mL each) and evaporated under vacuum. 
The residue is dissolved in 1:1 hexane-diethylether (1 mL) and loaded onto 
a column of EM silica gel 60 (2.5.times.24 cm, 230-400 mesh, wet packed 
with 1:1 hexane-diethylether). The column is eluted with 1:1 
hexane-diethylether, collecting 10 mL fractions. The appropriate fractions 
are combined and evaporated under vacuum. The residue is lyophilized from 
benzene to afford the title compound. 
Step 2: 
2'-0.4"-0.6-0.11-0.12-0-Penta(trimethylsilyl)-8a-aza-ally-8a-homoerythromy 
cin A 
2'-0,4"-0,6-0,11-0,12-0-Penta(trimethylsilyl)-8a-aza-8a-homoerythromycin A 
(200 mg, 0.18 mmol) is dissolved in anhydrous dimethylformamide (0.5 mL) 
and the solution is treated with sodium hydride (5.5 mg of a 80% 
dispersion in mineral oil, 0.184 mmol). The suspension is blanketed with 
nitrogen and stirred at room temperature for 2 hours. The reaction mixture 
is cooled in an ice bath and treated with allyl bromide (0.016 mL, 0.18 
mmol). After stirring for two hours, the reaction mixture is removed from 
the ice-bath and is allowed to warm to room temperature. After stirring an 
additional two hours, the solution is evaporated under vacuum and the 
residue is partitioned between methylene chloride (5 mL) and water (5 mL). 
The aqueous layer is re-extracted and the combined methylene chloride 
extracts are dried with magnesium sulfate, filtered and evaporated to give 
the crude product. The title compound is purified by column chromatography 
on EM silica gel 60 (2.5.times.24 cm, 230-400 mesh, wet packed with 1:1 
hexane-diethylether). The column is eluted with 1:1 hexanediethylether, 
collecting 10 mL fractions. The appropriate fractions are combined, 
evaporated and lyophilized from benzene to afford the title compound. 
Step 3: 8a-Aza-8a-allyl-8a-homoerythromycin A 
2'-0,4"-0,6-0,11-0,12-0-Penta(trimethylsilyl)-8a-aza-8a-allyl-8a-homoerythr 
omycin A (200 mg, 0.17 mmol) is dissolved in anhydrous tetrahydrofuran (1 
mL) and the resulting solution is treated with tetrabutylammonium fluoride 
(0.5 mL of a 3.4M solution in THF, 1.7 mmol). The solution is blanketed 
with nitrogen and stirred 18 hours at room temperature. The solution is 
added to a well stirred mixture of methylene chloride (5 mL) and water (5 
mL), and the pH is adjusted to 4 with 2N hydrochloric acid. The methylene 
chloride layer is removed and the aqueous layer is washed with additional 
methylene chloride (3.times.5 mL). Methylene chloride (5 mL) is added to 
the aqueous phase and the mixture is stirred rapidly while the pH is 
adjusted to 10 with 2N sodium hydroxide. The methylene chloride layer is 
separated and the aqueous layer is re-extracted with additional methylene 
chloride (3.times.5 mL). The combined pH 10 methylene chloride extracts 
are dried with magnesium sulfate, filtered and evaporated under vacuum to 
afford the title compound. 
EXAMPLE 7 
Synthesis of 8a-Aza-8a-methyl-8a-homoerythromycin A 
##STR16## 
Step 1: 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
3'-N-oxide 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
(3.0 g, 4.1 mmol) in methanol (24 mL) is treated with 30% aqueous hydrogen 
peroxide (1.9 mL, 18.6 mmol) and the mixture is stirred at room 
temperature for 6 hours. The solution is added to an ice cooled mixture of 
water (100 mL) and dichloromethane (100 mL) and the excess oxidant is 
destroyed by the careful addition of a saturated aqueous solution of 
sodium sulfite. The phases are separated and the aqueous layer is 
re-extracted with more dichloromethane (25 mL). The combined extracts are 
dried with magnesium sulfate, filtered, and evaporated under vacuum to 
give the title compound. 
Step 2: 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-methyl-8a-homoerythro 
mycin A 3'-N-oxide trifluoromethanesulphonate 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A 
3'-N-oxide (1.0 g, 1.34 mmol) is dissolved in anhydrous dichloromethane 
(10 mL) and the solution is treated with methyl trifluoromethanesulfonate 
(0.158 mL, 1.4 mmol) over 5 minutes. After stirring two hours at room 
temperature, the solvent is evaporated under vacuum to afford the title 
compound. 
Step 3: 8a-Aza-8a-methyl-8a-homoerythromycin A 3'-N-oxide 
9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-methyl-8a-homoerythrom 
ycin A 3'-N-oxide trifluoromethanesulphonate (455 mg, 0.5 mmol) is added to 
a stirred solution of sodium hydroxide (22 mg, 0.55 mmol) in 50% aqueous 
ethanol (5 mL). The solution is blanketed with nitrogen and stirred 
overnight at room temperature. The reaction mixture is evaporated under 
vacuum and the residue is partitioned between water (10 mL) and 
dichloromethane (10 mL). The dichloromethane portion is dried with 
magnesium sulfate, filtered and evaporated under vacuum to give the title 
compound. 
Step 4: 8a-Aza-8a-methyl-8a-homoerythromycin A 
8a-Aza-8a-methyl-8a-homoerythromycin A 3'-N-oxide (100 mg, 0.11 mmol) is 
dissolved in ethanol (5 mL) and the mixture is hydrogenated for 2 hours at 
40 psi in the presence of 10% palladium on carbon (100 mg). The suspension 
is filtered and the filtrate is evaporated under reduced pressure. The 
residue is dissolved in 90:10:1 dichloromethane-methanol-concentrated 
ammonium hydroxide (1 mL) and loaded onto a column of EM silica gel 60 
(230-400 mesh, 2.5.times.24 cm, wet packed with 90:10:1 
dichloromethane-methanol-concentrated ammonium hyroxide). The column is 
eluted with 90:10:1 dichloromethane-methanol-concentrated ammonium 
hydroxide, collecting 6 mL fractions. The product containing fractions are 
located by thin layer chromatography, combined and evaporated under vacuum 
to afford the title compound. 
The test procedures employed to measure the activity of the compounds of 
the invention are described below. 
EXAMPLE 8 
The compounds of formula (II) will show antibacterial activity against a 
range of aerobic Gram positive and negative bacteria as shown in the 
following Table. The assay employs a liquid turbidimetric microtiter 
method for determination of the minimum inhibitory concentration (MIC) in 
broth media. The MIC endpoint in mcg/ml is defined as the lowest 
concentration of test compound that completely inhibits the growth 
(absence of detectable turbidity) of bacteria. The MIC is generally not an 
absolute value but rather a concentration range that falls within a 
two-fold dilution limit. Generally, twelve two-fold dilutions of the test 
compound are employed with the initial concentration set at 128 mcg/ml. 
TABLE I 
______________________________________ 
In vitro Activity 
MIC Values 
Microorganism (mcg/ml) 
______________________________________ 
Enterococcus faecalis 
MB 5407 16 
Enterococcus faecium 
MB 5416 .ltoreq.0.06 
Streptococcus agalactiae 
CL 1343 0.25 
Staphylococcus aureus 
MB 2865 1 
Staphylococcus epidermidis 
MB 5414 2 
Staphylococcus haemolyticus 
MB 5412 2 
Steptococcus pneumoniae 
CL 2883 .ltoreq.0.06 
Streptococcus pyogenes 
MB 2874 .ltoreq.0.06 
Streptococcus pyogenes 
MB 5406 128 
Streptococcus viridans 
CL 2943 4 
Escherichia coli MB 2884 32 
Escherichia coli MB 4926 4 
Klebsiella pneumoniae 
MB 4005 64 
Yersinia enterocoltica 
CL 1598 64 
Pseudomonas stutzeri 
MB 1231 0.12 
______________________________________ 
Values given are for 8aaza-8a-homoerythromycin A, the product of Example 
4. 
The compounds of formula (II) are useful as antibacterial agents both in 
vitro and in vivo, and their spectrum of activity is similar to that of 
erythromycin A. Consequently, they can be used for the same purposes, and, 
in the same manner, as erythromycin A. In general, the antibacterial 
compounds of formula II and salts thereof, exhibit in vitro activity 
against a variety of Gram-positive microorganisms, e.g. Streptococcus 
pyogenes and Staphylococcus aureaus, and against certain Gram-negative 
microorganisms such as those of spherical or ellipsoidal shape (cocci). 
Their activity is readily demonstrated by in vitro tests against various 
microorganisms. Their in vitro activity renders them useful for topical 
application; for sterilization purposes, e.g., sick-room utensils; and as 
industrial antimicrobials, for example, in water treatment, slime control, 
and preservation of paint and wood. The extrapolation of such in vitro 
tests to support for such utilities for macrolide compounds is taught in 
U.S. Pat. No. 4,518,590. For in vitro use for topical application, it will 
usually be convenient to prepare pharmaceutical composition, in which a 
compound is combined with a pharamaceutically acceptable carrier or 
diluent, for example, in the form of ointments and creams. Appropriate 
carriers and diluents for these purposes include mineral oils and 
vegetable oils, and solvents such as water, alcohols, and glycols, and 
mixtures thereof. Such a pharmaceutical composition will normally contain 
the pharmaceutically-acceptable carrier and a compound of formula II in a 
weight ratio in the range from 1:4 to 1:200. 
Additionally, the antibacterial compounds of formula II and the 
pharmaceutically-acceptable salts thereof are active in vivo versus a 
variety of Gram-positive microorganisms, e.g. Streptococcus pyogenes and 
Staphylococcus aureaus, and also certain Gram-negative microorganisms, via 
the oral and parenteral routes of administration in animals, including 
man. Their in vivo activity is more limited than their in vitro activity 
as regards susceptible organisms, and it is determined by the usual 
procedure which comprises infecting mice of substantially uniform weight 
with the test organism and subsequently treating them orally or 
subcutaneously with the test compound. Extrapolation of such in vivo tests 
to support for human utility for macrolide compounds is likewise taught in 
U.S. Pat. No. 4,518,590, cited above. 
While the invention has been described and illustrated in reference to 
certain preferred embodiments thereof, those skilled in the art will 
appreciate that various changes, modifications and substitutions can be 
made therein without departing from the spirit and scope of the invention. 
It is intended, therefore, that the invention be limited only by the scope 
of the claims which follow and that such claims be interpreted as broadly 
as is reasonable.