GB2270072A - Tetrahydropyran compounds - Google Patents

Abstract

Compounds of the formula: <IMAGE> wherein X is an amino of the formulae <IMAGE> R<1> is hydrogen, methyl, C1-10 alkoxycarbonyl or arylsulfonyl when X is CH3CH2CHNH2 and R<1> is additionally aralkoxycarbonyl when X is NH2; one of R<2> and R<3> is hydrogen and the other is OH, NHR<1> or NMeR<1>, R<4> is hydrogen or C1-10 alkyl when X is CH3CH2CHNH2 and is additionally aralkyl when X is NH2; R<5> is hydrogen or C1-3 alkyl when X is CH3CH2CHNH2; R<5> is hydrogen when X is NH2; and one of R<6> and R<7> is hydrogen and the other is methyl except when X is CH3CH2CHNH2 and R<5> is hydrogen, in which case R<6> is Me and R<7> is H, are useful as intermediates in the synthesis of azalide antibiotics. <IMAGE>

Description

TITLE OF THE INVENTION AMINE-CONTAINING FRAGMENTS OF AZALIDE ANTIBIOTICS TITE OF THE INVENTION AMINE -CONTAINING FRAGMENTS OF AZALIDE ANTIBIOTICS BACKGROUND OF THE INVENTION The present invention relates to novel compounds that are intermediates useful in the synthesis of azalide antibiotics. Azalide antibiotics are useful in the therapy of bacterial infections in mammals.

The novel compounds are of the structural formula

wherein X is an amine of the formulae

R1 is hydrogen, methyl, C1-10 alkoxycarbonyl or arylsulfonyl when X is CH3CH2CHNH2 and R1 is additionally aralkoxycarbonyl when X is NH2; one of R2 and R3 is hydrogen and the other is OH, NHR1 or NMeR1 where R1 is as defined above; R4 is hydrogen or C1-10 alkyl when X is CH3CH2CHNH2 and is additionally aralkyl when X is NH2; R5 is hydrogen or C1-3 alkyl when X is CH3CH2CHNH2; R5 is hydrogen when X is NH2; and one of R6 and R7 is hydrogen and the other is methyl except when X is CH3CH2CHNH2 and R5 is hydrogen, in which case R6 is Me and R7 is H.

The compounds of the invention are synthesized by a method that begins with the well known antibiotic macrocycle erythromycin A (Ia).

Erythromycin A (la) Erythromycin A is cleaved to form an "eastern fragment" which.

consists of carbons 1 through 10 of the macrocycle.

The eastern fragment exists as an equilibrium mixture of ketone (IIa) and hemiketal (rib) forms as shown:

Erythromycin eastern fragments The prototypical erythromycin fragment(s) are converted into a fragment (hereinafter referred to as the 8a-aza fragment) which is structurally homologous to the azalide antibiotic 9-deoxo-8a-aza-8ahomoerythromycin A, or alternatively into a fragment (hereinafter called the 9a-aza fragment) which is structurally homologous to the azalide antibiotic 9-deoxo-9a-aza-9a-homoerythromycin A.This homology is exact in the case of the 8a-aza fragment and 9-deoxo-8aaza-8a-homoerythromycin A, and nearly exact in the case of the 9a-aza fragment and 9-deoxo-9a-aza-9a-homoerythromycin A (differing only in the presence of an ethyl group at C9 of the 9a-aza fragment) as can be seen in the formulae which follow::

8a-aza fragment (era) 9-deoxo-8a-aza-8a-homoerythromycin A

9a-aza fragment (IVa) 9-deoxo-9a-aza-9a-homoerythromycin A These amine fragments ma and IVa are useful intermediates in the synthesis of azalide antibiotics which have high structural homology to 9-deoxo-8a-aza-8a-homoerythromycin A and 9-deoxo-9a-aza-9ahomoerythromycin A in their "eastern" sides, but which are free to diverge in structure by an arbitrary amount in their "western" sides (western side shall be understood to be any portion of the macrocyclic ring not part of the eastern side, as eastern is defined above). SUMMARY OF THE INVENTION The invention comprises compounds of the formula::

wherein X is an amine of the formulae

R1 is hydrogen, methyl, Cl 1o alkoxycarbonyl or arylsulfonyl when X is CH3CH2CHNH2 and R1 is additionally aralkoxycarbonyl when X is NH2; one of R2 and R3 is hydrogen and the other is OH, NHR1 or NMeR1 where R1 is as defined above; R4 is hydrogen or C1-10 alkyl when X is CH3CH2CHNH2 and is additionally aralkyl when X is NH2; R5 is hydrogen or C1-3 alkyl when X is CH3CH2CHNH2; R5 is hydrogen when X is NH2; and one of R6 and R7 is hydrogen and the other is methyl except when X is CH3CH2CHNH2 and R5 is hydrogen, in which case R6 is Me andR7isH.

A more preferred group of compounds are those 9a-aza fragments of the formula

wherein R1 is hydrogen, methyl, Cl 1o alkoxycarbonyl or phenylsulfonyl; one of R2 and R3 is hydrogen and the other is NHR, NMeR or OH where R is hydrogen, methyl, C1-10 alkoxycarbonyl or phenylsulfonyl; R4 is hydrogen or Cl 1o alkyl; R5 is hydrogen or C1-3 alkyl; one of R6 and R7 is hydrogen and the other is methyl when R5 is C1-3alkyl ; and R6 is methyl and R7 is hydrogen when R5 is hydrogen.

The most preferred of the 9a-aza fragments are those compounds of the formula

wherein R5 is hydrogen or methyl; one of R6 and R7 is hydrogen and the other is methyl when R5 is methyl; and R6 is methyl and R7 is hydrogen when R5 is hydrogen.

Preferred 8a-aza fragments are those compounds of the formulae

wherein R1 is hydrogen, methyl, C1-10 alkoxycarbonyl or phenylsulfonyl, one of R2 and R3 is hydrogen and the other is OH, NHR or NMeR where R is hydrogen, C1-10 alkyl or phenalkyl, and R4 is hydrogen, Cl 1o alkyl or phenalkyl Most preferred 8a-aza fragments are those compounds of the formulae

With respect to compound IV, reduction of the oxime produces the 9a-aza fragment (IV) directly.

where R1 through R7 are as defined above for X = CH3CH2CHNH2.

With respect to compound m, subjection of the oxime to a Beckmann rearrangement with intramolecular trapping of the intermediate cation by the C6 hydroxy group yields an imino ether that can be reductively cleaved to yield the 8a-aza fragment (m).

where R1 through R4, R6 and R7 are as defined above for when X is NH2.

The products m and IV can be readily prepared according to the following flow charts, detailed descriptions, examples, and modifications thereof, using readily available starting materials, reagents and conventional synthesis techniques. The overall process is illustrated in the following flow sheet. In these reactions it is also possible to use variants that are themselves known to those of ordinary skill in this art, but which are not mentioned in greater detail.

These flow charts and details likewise serve to illustrate the utility of the 8a-aza and 9a-aza fragments in subseequent synthesis to azalide antibiotics.

In flow charts 1 and 2, it will be seen that X, R1, R2, R3, R4, R5, R6 and R7 are as defined previously; R8 is hydrogen, arylsulfonyl, Cm 10 alkyl or fluoroalkyl; Y is O, NR1 or CH2; A is a chain of 2-7 carbon atoms which may contain unsaturation or be interrupted by a heteroatom or a heterocycle or aromatic ring and which may bear a combination of the following substituents: hydrogen, aLkyl, aryl, aralkyl, OR9 (where R9 is hydrogen, alkyl, aryl, aralkyl or trialkylsilyl), SR10 (where R10 is hydrogen, alkyl, aryl, aralkyl or acyl), or NR10R11 (where R10 and R11 are individually hydrogen, alkyl, aryl, aralkyl or acyl), oxo, nitro, cyano or halogen.

FLOW CHART 1

FLOW CHART 2

DETAILED DESCRIPTION OF THE INVENTION The compounds m and IV can be prepared readily according to the following detailed descriptions and accompanying examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures.

Appropriate starting materials for the fragmentation reaction include erythromycin and a large subset of its derivatives. The fragmentation is a retro-aldol process and requires the hydroxy function at position 11 and the ketone function (or other a-anion stabilizing function including but not limited to oximino, imino, hydrazono, etc.) at position 9. Modification of erytliromycin at other sites should in general not affect the course of the fragmentation reaction.

Although not intending to be limited by a single theory of the invention, the fragmentation reaction is believed to occur by initial retro-aldol rupture of the C10-C11 bond and subsequent saponification of the ester function at carbon 1. The smaller fragment, comprised of carbons 11-13, can retroaldol further and/or polymerize under the reaction conditions, and is normally not isolated. The larger fragment, a carboxylate salt comprised of carbons 1-10 of the macrocycle, is essentially the sole isolated product of the reaction.

The retroaldol reaction is a well known base catalyzed reaction, and can in general be carried out with a large number of bases under a variety of reaction conditions. For derivatives of erythromycin the situation is complicated by the fact that several pathways for base catalyzed reaction exist. Most combinations of alkali and alkaline earth metal hydroxides and alkoxides in protic solvents give predominantly or exclusively another style of reaction and little or no retroaldol style reaction.

Preferably the retroaldol reaction is done in a polar aprotic solvent (most preferably ThF but including and not limited to DMF, DMSO, DME, etc.) with a strong base which has good solubility in the chosen solvent (most preferably KOTMS but including and not limited to KOH, NaOH, LDA, etc.). Preferably the fragmentation reaction is carried out at a concentration of 0.01 to 0.10 M, with 0.02 M most preferred. The amount of base used is preferably from 1 to 10 equivalents based on starting material, with 5 to 6 equivalents most preferred. The reaction is usually run at a temperature of from 0 to 50 C, preferably at 22250 C. The reaction can be allowed to run from 2 hours to 35 days, but is preferably carried out over 6-18 hours.

The immediate product of the fragmentation reaction is a carboxylate salt, which is generally not isolated or purified but subjected immediately to conditions which form an ester at position 1.

Esterification of a carboxylate can be accomplished in a very large number of ways, including but not limited to acid catalyzed condensation with alcohols and nucleophilic displacement on electrophilic alkyl species by the carboxylate ion. Acid catalyzed condensation is not preferrred for derivatives of erythromycin due to the potential labile nature of the attached carbohydrates under acid conditions, but if carefully optimized these methods could be used.

Nucleophilic displacement by carboxylate on species of the general form R-X where R is a suitable alkyl group and X is a leaving group (including but not limited to Cl, Br, I, N2, triflate, methanesulfonate, benzenesulfonate, tosylate, etc.) is the preferred method of esterification, and reaction with diazomethane is the most preferred of these methods. Because diazomethane must be protonated to form the active methyl diazonium species, the reaction mixture must be neutralized prior to reaction with diazomethane. For most other R-X species the derivatization can be carried out without prior neutralization.

Preferably the diazomethane reaction is done in an aprotic solvent (most preferably methylene chloride but including and not limited to DMF, DMSO, DME, ether, etc.) in which the neutralized (presumably zwitterionic) crude product of the fragmentation reaction is dissolved to a concentration of between 0.01 M and 0.25 M with 0.07 M most preferred. A crude solution of diazomethane in a suitable solvent (preferably ether) is dripped in until the yellow color persists, and then after being allowed to stir from 5 minutes to one hour the excess diazomethane is quenched with a suitable carboxylic acid (preferably acetic acid). The reaction is usually run at a temperature of from 0 C to 250 C, preferably at 22-25" C.

Example A Preparation of an equilibrium mixture of 11, 12, 12a, 13, 14, 15hexanorerythromycin A seco acid methyl ester and the two C-9 diasteriomeric 11, 12, 12a,13, 14, 15-hexanorerythromycin A-6, 9hemiketal seco acid methyl esters

To a 2 L flask was introduced 10 g of erythromycin A (ca. 13.6 mmol, ca. 95%.pure, available from Aldrich Chemical Company, Milwaukee, WI) and 10 g of tech. potassium trimethysilanoate (70 mmol, ca. 90% pure, available from-Aldrich Chemical Company, Milwaukee, WI). The two powdery compounds were thoroughly mixed by agitation, and then 800 ml of Aldrich Sure-Seal tetrahydrofuran was poured quickly into the flask with shaking to insure rapid mixing.The reaction was allowed to stir at room temperature for three hours, during which time the color changed from clear to greenish yellow, and a bit of fine precipitate formed and clung to the walls of the flask. At this time the reaction was judged to be complete by thin layer chromatography (silica plates, 93:7:1 CH2C12:MeOH:aq. NH3 as eluent, p-anisaldehyde stain). The tetrahydrofuran was removed under vacuum and the residue was dried further under high vacuum at room temperature for 30 minutes. Next, 300 ml of water was added to the residue and the pH was adjusted to 7.0 using 2N HCl and monitoring continuously with a pH meter. The water was then removed under high vacuum.The residue was then triturated repeatedly with CH2Cl2, each time decanting the organic from the gummy salts (centrifugation can be used here if necessary.) When it was judged that all of the compound had been removed from the salts, the methylene chloride solution was dried with MgSO4 and concentrated to about 250 ml.

Diazomethane was prepared from 4 g N-nitroso-N-methylurea, 12 ml 40% KOH and 100 ml ether in the manner described in Org.

Syn. Coll, Vol, 2 165 (1943). This ether solution of diazomethane was poured into the methylene chloride solution of the carboxylic acid from above, and allowed to stir for 5 minutes, after which time acetic acid was added until the excess diazomethane was decomposed (as judged by the disappearance of the yellow color). TLC (silica plates, 93:7.1 CH2Cl2:MeOH:aq. NH3 as eluent, p-anisaldehyde stain) at this point showed a major spot with an Rf of approximately 0.6, along with a substantial baseline spot. Extraction with water effectively removed the baseline material, which could be reneutralized and subjected again to the diazomethane reaction. The organic layer was extracted with sat.

aq. NaHCO3,. dried over MgSO4, and rotovapped to yield 5.8 g of crude hemiketal. The product of this reaction was sufficiently pure to be used in a subsequent step, but could be further purified by flash chromatography on silica gel, eluting with 92:8:1 CH2C12:MeOH: aq, NH3. NMR shows predominantly the hemiketal form of the product.

Selected spectral data: 1H NMR (400 MHz, CDCl3) 8 4.54 (d, H-1"), 4.47 (d, H-1'), 4.15 (dd, H-3), 3.96 (dq, H-5"), 3.63 (s, COOCH3), 3.49 (m, H-5'), 3.26 (dd, H2'), 3.24 (s, OCH3), 2.93 (d, H-4"), 2.73 (dq, H-2), 2.50 (m, H-3'), 2.27 (s, N(CH3)2), 1.43 (d, H-2" ax), 1.08 (d), 0.89 (t, CH3-11), 13C NMR (CDCl3) # 176.6, 107.1, 102.6.

Synthesis of the 9a-Aza Fragment (TV) The overall process for the synthesis of compound IV is shown as follows:

where R1 is hydrogen, methyl, C1-10 alkoxycarbonyl or arylsulfonyl or additionally aralkoxycarbonyl prior to the conversion step that yields product IV; one of R2 and R3 is hydrogen and the other is OH, NHR1 or NMeR1 where R1 is hydrogen, methyl, Cl 1o alkoxycarbonyl, arylsulfonyl or aralkoxycarbonyl;R4 is hydrogen or C1-10 alkyl or additionally aralkyl prior to the conversion step that yields product IV; R5 is hydrogen or C1-3 alkyl; when R5 is hydrogen, then R6 is methyl and R7 is hydrogen and the two structures for the starting material IIc and IId exist in equilibrium with each other; when R5 is C1-3 alkyl, then one of R6 and R7 is hydrogen and the other is methyl and the starting material exists only as structure IIc.

The starting material for the sequence is the C1-C10 fragment (II) derived from erythromycin or one of its simple derivatives. When R5 is alkyl, this fragment has a ketone function at C9 (IIc); when R5 is hydrogen, this compound exists as an equilibrium mixture of the ketone (inc) and the diastereomeric 6,9-hemiketal forms (lid). In general, the hemiketal form predominates in the mixture. Many derivatives of the ketone. however, are readily prepared from this mixture because the ketone is present in a finite, if small, amount and is constantly replenished as it is drained away.

The first step of the sequence involves preparation of the oxime from the ketone or ketone/hemiketal mixture. The conversion of ketones to oximes is an old and well known reaction and is not the invention as claimed below, but is rather one component of the invention. Although it has many variations in its details, it essentially involves exposing the ketone to hydroxylamine hydrochloride and a suitable base in a suitable solvent. The reaction is exothermic and proceeds readily. Preferably the reaction is carried out in pyridine, which acts as both the solvent and the base, but the combination of ethanol and an amine base such as triethylamine is also suitable. The concentration of starting material is preferably 0.01 to 0.5 M with 0.1 M most preferred.Preferably from 1 to 10 equivalents of hydroxylamine hydrochloride is used in the reaction, with 5 equivalents most preferred. The reaction is usually run at a temperature of from 22"C to 50 C, with 250C most preferred. The reaction can be allowed to run from 5 hours to several days, but is usually complete within 6-18 hours.

The second step of the sequence involves reducing the oxime to the corresponding amine. This can be accomplished in a variety of ways. The preferred means is a high pressure catalytic hydrogenation (1000 psi H2) using PtO2 catalyst and acetic acid as solvent. The concentration of starting material is preferably 0.01 to 0.5 M with 0.1 M most preferred. Preferably from 0.1 to 1 weight equivalents of platinum oxide catalyst is used in the reaction, with 1 equivalent most preferred. The reaction is usually run at a temperature of from 22"C to 50 C, with 250C most preferred. The reaction can be allowed to run from 16 to 48 hours, but is usually complete within 24 hours.In general, benzyl and substituted benzyl protecting groups for the carboxyl function as well as the benzyloxycarbonyl protecting group for the amines will be lost under the catalytic hydrogenation conditions required to reduce the oxime to a ketone.

A A good alternative method for accomplishing this reduction is the combination of TiCl3 and NaH3BCN described by Kirst and Leeds in Synthetic Communications, 18(8), 777 (1988), the disclosure of which is incorporated herein by reference. Still other means of carrying out this reduction include catalytic hydrogenation with other catalysts (particularly Pd/C or Raney Ni), dissolving metal reduction (particularly using Na, Na-Hg, or Al-Hg), or metal hydride reducing agents (NaBH4/TiCl4 or NaBH4/NiC12.) Synthesis of the 8a-Aza Fragment (m) The overall process for the synthesis of amine fragment'III is shown in flow charts 3,4 and 5 (where R1, R2, R3, and R4 are as defined before) and begins with a Beckmann rearrangement of the oxime (prepared as described above.).

FLOW CHART 3

FLOW CHART 4

FLOW CHART 5

In general, the Beckmann rearrangement of ketoximes leads to carboxamides. The mechanism involves initial conversion of the amine hydroxyl group to a leaving group which is lost with concommitant migration of the oxime carbon substituent that is situated anti to the leaving group. In aqueous media, the intermediate nitrilium cation thus formed usually is trapped by water to afford the amide product. The nitrilium intermediate can also be trapped by other nucleophiles, including intramolecular trapping by hydroxyl groups located elsewhere in the molecule.

Spectral data indicate that the oxime starting material V is predominantly a single stereoisomer, which based on simple steric arguments is presumably the E isomer. Beckmann rearrangement of the E isomer of V with trapping of the intermediate cation by the 6-OH gives rise to the major product, the cyclic iminoether VI. The C-8 epimeric iminoether VII presumably arises from initial epimerization of the E-oxime under the mild acidic conditions of the rearrangement as it is normally practiced. The mixture of C-8 epimeric lactones VIII presumbly arises from Beckmann rearrangement of the minor Z-oxime to form an unstable exocyclic iminoether, which hydrolyzes to the lactone during aqueous workup.

There are many ways to accomplish the Beckmann rearrangement under acidic, neutral or basic conditions (see "Comprehensive Organic Chemistry", I. O. Sutherland (ed.), Pergamon Press, New York, 1979, Vol. 2, pgs. 398-400 & 967-968). The. most acidic conditions (which include concentrated sulfuric acid, polyphosphoric acid, thionyl chloride, phosphorus pentachloride, sulfur dioxide, and formic acid) are of little value here due to the sensitivity of the macrolide fragment (particularly the cladinose residue) to strong acid.

A preferred method for effecting the Beckmann rearrangement involves intial O-acylation of the oxime group with an alkylsulfonyl halide, arylsulfonyl halide, or arylsuffonic anhydride. The intermediate oxime sulfonate thus formed can be isolated or, as more commonly practiced, converted in situ to the rearranged products. The acylation and rearrangement reactions are generally performed in the presence of an organic or inorganic base.

Preferred acylating reagents for effecting the rearrangement of the oxime A include methanesulfonyl chloride, benzenesulfonyl chloride, 4-acetamidobenzene-sulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride.

The reaction can be carried out in the presence of an inorganic base (such as sodium bicarbonate or potassium carbonate) or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, or N,Ndiisopropylethylamine. Suitable solvents include anhydrous organic solvents such as dichloromethane, chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, toluene, acetonitrile, and pyridine. Mixtures of organic solvents, especially those containing pyridine, are very useful; Aqueous mixtures such as aqueous acetone or aqueous dioxane are unsuitable because they favor formation of the amide XI. The reaction is generally performed using 1-5 molar equivalents of the acylating reagent and one or more molar equivalents of base at -10 "C to 60 C.

Pyridine can be used as both the solvent and the base.

The distribution of products resulting from the Beckmann rearrangement of oxime V depends on the particular reaction conditions employed. In general, treating a 0.05 to 0.1 M solution of the oxime in pyridine with one equivalent of activating reagent (such as ptoluenesulfonyl chloride or p-toluenesulfonic anhydride) at room temperature leads to incomplete conversion of starting material to desired imino ether VI. If the reaction is conducted at 600C it proceeds essentially to completion, but with substantial formation of the lactone by-products VIII (along with a smaller amount of the epimeric byproduct VII).Conducting the reaction at room temperature with 5 equivalents of the activating reagent also forces the reaction to near completion, but with substantial formation of epimeric by-product VII (along with smaller amounts of Vm.) The most preferred conditions for effecting this reaction involve treating a 1.3 to 1.5 M solution of the oxime in pyridine with 1.1 equivalents of p-toluenesulfonyl chloride.

At this greater concentration the reaction proceeds to very near completion with minimum formation of by-products.

It should be noted that the epimeric iminoether by-product VII is easily separated from iminoether VI by silica chromatography and is useful for the synthesis of the 8-S amino fragment md. To this end, the oxime can be initially epimerized with p-toluenesulfonic acid (or virtually any other acid) in pyridine, after which Beckmann rearrangement yields approximately a 50/50 mixture of VI and VII.

Conversion of iminoether VI into amine fragment fflc (note that everything in the following discussion applies equally well to the conversion of iminoether VII to the amine fragment md) is not readily accomplished by simple acid hydrolysis, as this leads almost exclusively to the amide XI. Most methods of reduction similarly fail to provide the aminal IX or the amine mc. Catalytic hydrogenation (1000 psi H2 with PtO2 catalyst in acetic acid) furnishes the propylamine XII in good yield as the only product. Reduction of iminoether V with sodium borohydride at room temperature or at pH < 6 also furnishes predominantly the propylamine XII.

The preferred means of reducing the iminoether VI to the aminal IX essentially follows the method developed by Myers et al and described in J. Org. Chem., Vol. 38, No. 1, p. 36, 1973. This preferred method involves cooling a solution of the iminoether VI (0.005 M to 0.5 M) in a 1:1 mixture of tetrahydrofuran and 95% ethanol to between -35 C and -450C, and then treating this solution with from 1 to 5 mole equivalents (3 most preferred) of sodium borohydride in a small amount of water. To this solution is then added 850 ml of 2N HCl for each millimole of sodium borohydride used. This produces a solution which "tests" as pH 6 to 7 when applied to damp pH paper.The reaction is allowed to stir for 4 to 24 hours at a temperature of between -35 and -45 C. Any lactone contaminant in the starting material is unaffected by this reaction.

The aminal 1X produced in this manner is a single stereoisomer of uncertain configuration at the aminal carbon. The aminal can be isolated by silica chromatography as long as ammonia is a component of the eluent: otherwise it decomposes on silica to the amine fragment mc. Normally the aminal is not isolated, however, but is directly hydrolyzed to the amine fragment mc. This hydrolysis can be accomplished by exposing the aminal to virtually any mild acid in the presence of water. A preferred method of accomplishing this hydrolysis involves exposing the aminal to a mixture of THF, ethanol, and pH 4 aqueous acetic acid at room temperature.. The reaction is allowed to proceed for between 5 and 48 hours, with 16 hours preferred.

Example 1 Preparation of 11,12,12a,13,14,15-hexanor-9-deoxo-9-hydroxyimino erythromycin A seco acid methyl ester (Va)

To the 6.0 g of the hemiketaUketone starting material (IIa/Hb) was added 120 ml pyridine and 3.4 g hydroxylamine hydrochloride, and the mixture was allowed to stir at room temperature for 16 hours. The reaction was then concentrated almost to dryness under reduced pressure, and the residue was partitioned between 500 ml CH2C12 and 200 ml sat. aq. NaHCO3. The aqueous layer was extracted twice with 100 ml CH2Cl2, and the combined organics were dried over MgSO4 and rotovapped to a foamy solid. This solid was chromatograped on silica eluting with 93:7:1 CH2Cl2: MeOH: aq. NH3 to yield 4.5 g of pure oxime Va.

There is no obvious doubling of peaks in the proton NMR spectrum, but doubling of some peaks can be seen in the carbon NMR spectrum. From rough integration it seems that the minor oxime isomer (presumably Z) accounts for 10-20% of the product mixture.

Selected spectral data for Va: 1H NMR (400 MHz, CDC13) 3 4.51 (d, H-t"), 4.27 (d, H1'), 4.02 (dd, H-3), 3.95 (dq, H-5"), 3.49 (m, H-5'), 3.40 (d, H-5), 3.25 (dd, H-2'), 3.56 (s, COOCH3), 3.17 (s, OCH3), 2.21 (s, N(CH3)2), 2.80 (dq, H-2), 2.49 (dt, H-3'), 2.19 (d, H-2" eq), 1.61 (d, H-4'), 1.37 (dd, H-2" as) 13C NMR of major isomer (CDC13) 6 176.23, 166.81, 104.46, 96.40, 85.95, 80.31, 77.81, 74.39, 72.75, 70.60, 69.47, 65.43, 64.78, 51.67, 50.20, 49.28, 41.67, 40.37, 37.86, 35.13, 34.33, 29.48, 23.73, 21.44, 20.98, 20.68, 20.21, 17.69, 10.73, 10.64, 10.38 13C NMR of minor isomer (CDCl3) 6 176.13, 166.26, 104.57, 86.02, 80.25, 70.48, 69.65, 65.50, 64.68 FAB MS: 655 (M + Li+), 649 (M + H+) Example 2 Preparation of 11,12,1 2a, 13,14, 15-hexanor-6-O-methyl-9-deoxo-9- hydroxyimino-erythromycin A seco acid methyl ester as a mixture of C8 epimers (Vb)

To the 1.61 g of the ketone starting material IIe was added 30 ml pyridine and 0.9 g hydroxylamine hydrochloride, and the mixture was allowed to stir at room temperature for 16 hours. The reaction was then concentrated almost to dryness under reduced pressure, and the residue was partitioned between 500 ml CH2C12 and 200 ml sat. aq.

NaHCO3. The aqueous layer was extracted twice with 100 ml CH2C12, and the combined organics were dried over MgSO4 and evaporated under reduced pressure to give a foamy solid. This solid was chromatograped on silica eluting with 95:5:0.5 CH2Cl2 : MeOH: aq.

NH3 to yield 1.6 g of pure oxime Vb.

The product of this reaction is in theory a mixture of four compounds: the 8-R E-oxime, the 8-S E-oxime, the 8-R Z-oxime, and the 8-S Z-oxime. The product mix can be separated into two fractions using careful silica chromatography: one fraction presumably corresponds to the 8-R compounds and the other to the 8-S, but this is unproven.

Selected spectral data for Vb: 1H NMR of higher Rf fraction (400 MHz, CDCl3) 6 4.62 (d, H1"), 4.39 (d, H-1'), 3.95 (m, H-5" & H-3), 3.62 (s, COOCH3), 3.29 (s, 5'-OCH3), 3.05 (s, 6-OCH3), 2.28 (s, N(CH3)2) 1H NMR of lower Rf fraction (400 MHz, CDCl3) 6 4.62 (d, H1"), 4.39 (d, H-t'), 3.95 (m, H-5" & H-3), 3.60 (s, COOCH3), 3.30 (s, 5'-OCH3), 3.19 (s, 6-OCH3), 2.28 (s, N(CH3)2) FAB MS of higher Rf fraction: 670 (M + Li+) FAB MS of lower Rf fraction: 670 (M + Li+) Example 3 A General Procedure for the Preparation of Oxime Fragments V

Using the procedure taught in examples 1 and 2, an erythromycin fragment starting material (IIc/IId)is converted into an oxime fragment V, which in general is a mixture of the E and Z forms at the oxime with E predominating.In the above diagram R1 is hydrogen, methyl, Ct-to alkoxycarbonyl, aralkoxycarbonyl or arylsulfonyl; one of R2 and R3 is hydrogen, the other is OH, NHR1 or NMeRt where R1 is as defined before; R4 is hydrogen, Ct-t0 alkyl, or aralkyl; R5 is hydrogen or Ct 3 alkyl; if R5 is hydrogen, then R6 is methyl and R7 is hydrogen and the two structures for the erythromycin starting material exist in equilibrium with each other; if R5 is alkyl, then one of R6 and R7 is hydrogen and the other is methyl and the erythromycin starting material exists only as the structure on the left.A representative but nonlimiting sampling of the compounds which may be produced in this manner include those in the following table wherein it is understood that the oxime products are species of oxime genus V, the generic structure of which is given above.

Table for Example 3 Substituent Oxime Products

R R R R4 R5 R6 R7 V1 Me H NH2 Me H Me H V2 Me NH2 H Me H Me H H V3 Me OH H Me n-Pr Me H H V4 Me OH H H Me Me H H V5 PhSO2 OH H Me Me Me H H V6 Me OH H Bn Me Me H H V7 t-BOC OH H Me Me Me H H V8 Cbz OH H Me Me Me H H Ph = phenyl t-BOC = t-butyloxycarbonyl Cbz = benzyloxycarbonyl n-Pr = n-propyl Bn = benzyl Example 4 Preparation of 11,12,12a,13,14, 15-iexanor-9-deoxo-9-amino- erythromycin A seco acid methyl ester as a mixture of C-9 epimers (IVa)

A hydrogenation vessel was charged with 3.7 g of the oxime starting material (Va), along with 60 ml of AcOH and 3.7 g of PtO2.

This was subjected to 1000 psi of H2 for 24 hours. The solution was then filtered carefully through a medium glass frit under an inert atmosphere (to prevent ignition of the platinum) and the platinum was washed three times with AcOH. The AcOH was removed under vacuum, and the residue was partitioned between 300l CH2Cl2 and 100 ml sat. aq. NaHCO3. The aqueous layer was washed twice with 50 ml CH2C12 and the combined organics were dried over MgSO4 and rotovapped to a foamy solid. This solid ways chromatograped on silica, eluting with 88:12:1 CH2Cl2 : MeOH: aq. NH3 to yield 2.85 g of pure amine IVa, as an approximately 1:1 mixture of diastereomers at C9.

Peak doublings are mostly not seen in the proton NMR, but may be seen in the carbon NMR.

Selected spectral data: 1H NMR of diastereomeric mixture (400 MHz, CDC13) 6 4.61 (d, H-1"), 4.36 (d, H-1"), 4.11 (dd, H-3), 4.02 (dq, H-5), 3.62 (s, COOCH3), 3.55 (m, H-5'), 3.50 (d, H-5), 3.30 (dd, H-2'), 3.25 (s, OCH3), 3.95 (d, H-4"), 2.81 (m, H-2), 2.50 (dt, H-3'), 2.28 (s, N(CH3)2), 2.26 (m, H-2'), 2.05 (m, H-4), 1.67 (d, H-4') 13C NMR of diastereomeric mixture (CDCl3) # 176.31, 104.63, 104.50, 96.17, 96.08, 86.56, 86.25, 80.29, 77.85, 74.22, 73.78, 72.73, 70.52, 70.44, 69.56, 65.38, 65.11, 51.65, 49.31, 42.67, 40.35, 37.65, 37.56, 35.13, 28.92, 24.25, 23.92, 21.55, 21.12, 17.75, 10.97, 10.41 FARMS: 635 (M + H+) Example 5 Preparation of 11,12,12a,13,14,15-hexanor-6-O-methyl-9-deoxo-9amino-erythromycin A seco acid methyl ester as a mixture of C-8 and C-9 epimers (IVb)

A hydrogenation vessel was charged with 1.6 g of the oxime Vb along with 15 ml of AcOH and 1.7 g of Pt02. This was subjected to 1000 psi of H2 for 48 hours. The solution was then filtered carefully through a medium glass frit under an inert atmosphere (to prevent ignition of the platinum) and the platinum was washed three times with AcOH. The AcOH was removed under vacuum, and the residue was partitioned between 300 ml CH2Cl2 and 100 ml sat. aq. NaHCO3. The aqueous layer was washed twice with 50 ml (CH2C12 and the combined organics were dried over MgSO4 and rotovapped to a foamy solid.

This solid was chromatograped on silica, eluting with 90:10:1 CH2Cl2: MeOH: aq. NH3 to yield 1.27 g of pure amine mixture IVb. Rough integration of the quadrupled resonance around 6 95 in the carbon NMR indicates that the product mixture is composed of approximately equal amounts of the four possible diastereomers.

Selected spectral data: 1H NMR of four component diastereomeric mixture (400 MHz, CDCl3) 8 4.63 (m, H-i"), 4.40 (m, H-l'), 3.98 (m, H-3 & H-5"), 3.65 (d, H-5), 3.61 (s, COOCH3), 3.45 (m, H-5'), 3.25 (s, 3"-OCH3), 3.15 (s, 6-OCH3), 2.94 (d, H-4"), 2.23 (s, N(CH3)2), 2.26 (m, H-2'), 1.61 (d, H-4') 13C NMR of four component diastereomeric mixture (CDCl3) 8 176.19, 176.11, 102.71, 102.48, 102.42, 95.16, 95.07, 94.99, 94.92, 79.97, 79.89, 79.76, 79.73, 79.39, 79.32, 79.19, 78.85, 77.98, 72.73, 70.88, 70.81, 68.92, 65.27, 58.34, 51.62, 51.59, 50.23, 50.12, 49.98, 49.33, 41.62, 41.42, 41.39, 40.36, 37.77, 37.60, 37.37, 36.87, 36.78, 36.36, 35.09, 33.00, 29.03, 28.94, 28.82, 27.61, 27.19, 21.58, 21.24, 21.04, 20.97, 20.83, 20.47, 18.03, 17.63, 16.88, 14.79, 14.74, 14.12, 11.44, 11.40, 11.21, 11.14, 10.96, 10.89, 10.83, 10.79, 10.67 FARMS: 656 (M + Li+) Example 6 A General Procedure for the Preparation of 9a-Aza Fragments IV

Using the procedure taught in examples 4 and 5, an oxime fragment V is converted into a 9a-aza fragment IV, which in general is a mixture of the R and S forms at C9.In the above diagram R1 is hydrogen, methyl, Ct-10 alkoxycarbonyl, aralkoxycarbonyl or arylsulfonyl; one of R2 and R3 is hydrogen, the other is OH, NHR1 or NMeR1 where R1 is as defined before; R5ishydrogenorC1-3 alkyl; if R5 is hydrogen, then R6 is methyl and R7 is hydrogen; if R5 is alkyl, then one of R6 and R7 is hydrogen and the other is methyl; R4 is hydrogen, C1-10 alkyl, or aralkyl.

A representative but nonlimiting sampling of the compounds which may be produced in this manner include those in the following tables wherein it is to be understood that the starting materials are species of the oxime genus V and the products are species of the 9a-aza genus IV, whose generic structures are given above.

Table for Example 6 Substituent Amine Product Compounds

R1 R2 R3 R4 R5 R6 R7 IV1 Me H NH2 Me H Me H IV2 Me NH2 H Me H Me H IV3 Me OH H Me n-Pr Me H IV4 Me OH H H Me Me H IV5 PhSO2 OH H Me Me Me H IV6 t-BOC OH H Me Me Me H IV7 Cbz OH H Me Me Me H Ph = phenyl t-BOC = t-butoxycarbonyl Cbz = benzyloxycarbonyl n-pr = n-propyl Bn = benzyl Example 7 Preparation of 11,12,1 2a,1 3,14, 15-hexanor-8a-aza-9-deoxo-8a,9- didehydro-6,9-epoxyerythromycin A seco acid methyl ester, 11,12,12a,13,14,15-hexanor-8a-aza-9-deoxo-18a,9-didehydro-6,9epoxy-8-epierythromycin A seco acid methyl ester, 10,10a,11,12,12a,13,14,15-octanor-6,9-epoxyerythromycin A seco acid methyl ester, and 10,10a,l 1.12,12a,13,14.15-octanor-6,9-epoxy-8- epierythromycin A seco acid methyl ester

Method 1: To a 50 ml flask was introduced 5.45 g of oxime Va and 1.5 g of tosyl chloride, and 5 ml of dry pyridine. The reaction was stirred at room temperature for 18 hours. Approximately 100 ml of methylene chloride was added to the reaction, and the organic layer was extracted twice with 0.1 M NaOH. The organic layer was separated, dried over MgSO4, and the solvent was removed under reduced pressure.The resulting residue was chromatographed on silica eluting with 94:6:1 CH2C12 : MeOH: aq. NH3 to yield 3.06 g of product VIa (contaminated with approximately 5% of lactone by-product Villa, which does not interfere in subsequent reactions), and 1.72 g of a mixture of product VIa, 8-epimeric product VIIa, and starting material. If desired, a second careful chromatography can provide pure samples of Viva, VIIa and Villa: In the 94:6:1 CH2Cl2: MeOH: aq. NH3 solvent system the lactones Vma elute first followed closely by the desired iminoether VIa and it is difficult to separate the two. Next eluting but relatively easy to separate from the higher Rf compounds is the epi-iminoether VIIa, followed closely by unreacted starting material.

Selected spectral data for 11,12,12a,13,14,15-hexanor-8a-aza-9- deoxo-8a,9-didehydro-6,9-epoxyerythromycin A seco acid methyl ester VIa: 1H NMR (400 MHz, CDCl3) # 4.61 (d, H-1"), 4.41 (d, H-1'), 4.09 (dd, H-3), 3.99 (dq, H-5"), 3.72 (d, H-5), 3.64 (s, COOCH3), 3.49 (m, H-5'), 3.34 (m, H-8), 3.26 (s, OCH3), 3.21 (m, H-2'), 2.95 (d, H4"), 2.78 (m, H-2), 2.48 (d, H-3'), 2.25 (s, N(CH3)2), 2.25 (m, H-2"), 2.11 (q, H-10), 2.01 (dt, H-4), 1.80 (d, H-7), 1.65 (d, H-4'), 1.45 (dd, H-2" ax), 1.32 (s, 6-Me), 1.28 (d, H-7), 1.18 (d, H-4'), 1.08 (d, 2-Me + 4-Me), 1.05 (t, H-ll), 13C NMR (CDC13) 8 176.29, 159.76, 103.02, 95.48, 80.35, 80.00, 78.84, 77.97, 72.75, 70.62, 69.46, 65.57, 65.44, 65.28, 51.75, 49.37, 44.56, 41.29, 40.34, 36.77, 35.14, 33.72, 28.90, 28.75, 24.14, 23,26,21,62, 21.20, 17.94, 11.38, 10.94, 10.29 FAB MS: 637 (M + Li+) Selected spectral data for 11,12,12A,13,14,15-hexanor-8a-aza-9-deoxo- 8a,9-didehydro-6,9-epoxy-8-epierythromycin A seco acid methyl ester VIIa: 1H NMR (400 MHz, CDCL3) 6 4.59 (d, H-l"), 4.39 (d, H-1'), 4.02 (dd, H-3), 3.92 (dq, H-5"), 3.71 (d, H-5), 3.63 (s, COOCH3), 3.45 (m, H-5'), 3.45 (m, H-8), 3.27 (m, H-2'), 3.24 (s, OCH3), 2.93 (d, H4"), 2.70 (m, H-2), 2.45 (d, H-3'), 2.25 (s, N(CH3)2), 2.25 (m, H-2"), 2.18 (q, H-10), 2.12 (d, H-7), 1.92 (dt, H-4), 1.63 (d, H-4'), 1.45 (dd, H-2" ax), 1.30 (s, 6-Me), 1.18 (dd, H-4'), 1.15 (d, H-7), 1.06 (d, 2-Me + 4-Me), 1.06 (tj H-ll), FAB MS: 637 (M + Li+) Selected spectral data for the mixture of 10,10a,11,12,12a,13,14,15- octanor-6,9-epoxyerythromycin A seco acid methyl ester and 10,10a,11,12,12a,13,14,15-octanor-6,9-epoxy-8-epierythromycin A seco acid methyl ester VIIIa: 1H NMR (400 MHz, CDCL3) 8 4.71 & 4.65 (d, H-1"), 4.45 & BR< 4.41 (d, H-1'), 4.02 (m, H-3), 3.95 (dq, H-5"), 3.64 & 3.62 (s, COOCH3), 3.49 (m, H-8), 3.26 (s, OCH3), 3.15 (dd, H-2'), 2.95 (d, H4"), 2.71 (m, H-2), 2.45 (d, H-3'), 2.27 (s, N(CH3)2), 1.66 (d, H-4'), 1.45 (dd, H-2" ax), 1.30 (s, 6-Me), 1.18 (dd, H-4'), 1.15 (d, H-7), 1.06 (d, 2-Me + 4-Me), 1.06 (t, H-ll), FARMS: 605 (M + H+) IR: 1762, 1730, 1665 cm-1 Example 8 A General Procedure for the Preparation of Iminoethers VI and VII

Using the procedure taught in example 7, an-oxime fragment V is converted into a mixture of iminoethers VI and VII and lactones VIII, with the iminoether VI being the major product of the reaction. In the above diagram R1 is hydrogen, methyl, Ct-to alkoxycarbonyl, aralkoxycarbonyl or arylsulfonyl; one of R2 and R3 is hydrogen, the other is OH, NHR1 or NMeR1 where R1 is as defined before; R4 is hydrogen, Ct-io alkyl, or aralkyl.

A representative but nonlimiting sampling of the compounds which may be produced in this manner include those in the following table where it is to be understood that the starting oxime compounds are species of the oxime genus V and the desired products are iminoethers of the genera VI and VII, whose generic structure is given above.

Table for Example 8 Substituent Iminoether Products

R R R R4 VI-1, VII-1 Me H NH2 Me VI-2, VII-2 Me NH2 H Me VI-3, VII-3 Me OH H Me VI-4, VII-4 Me OH H H VI-5, VII-5 PhSO2 OH H Me VI-6, VII-6 Me OH H Bn VI-7, VII-7 t-BOC OH H Me VI-8, VII-8 Cbz OH H Me Ph = phenyl t-BOC = t-butyloxycarbonyl Cbz = benzyloxycarbonyl n-Pr = n-propyl Bn = benzyl Example 9 Preparation of 11,12,12a,13,14,15-hexanor-8a-aza-9-deoxo-6,9epoxyerythromycin A seco acid methyl ester (single diastereomer of uncertain configuration at C-9) (lea) and 9,10,10a,11,12,12a,13,14,15- nonanor-8a-azaerythromycin A seco acid methyl ester (IIIa)

To a 2 1 flask was introduced 1.94 g of iminoether starting material VIa (contaminated with approximately 5% lactones (Villa, see example 7) and 500 ml of 1:1 : 1 95% EtOH: THF.The reaction was stirred and cooled to -40 OC. A solution of 360 mg NaBH4 in 3 ml H2O was prepared and added dropwise to the stirred, chilled reaction. The "pH" of the solution was checked by applying a drop of the solution to wet pH paper, and the initial "pH" was 9 to 10. At this point, 8.1 ml of 2 N HCl was added, after which the "pH" was approximately 7. The reaction was allowed to stir at -40 to -45 C for 16 hours, at which time about two-thirds of the solvent was removed under reduced pressure without warming above 10 "C. Normally the aminal IXa was not isolated, but was hydrolyzed directly to the amine ma. About 800 ml of water was added to the solution, and the pH was adjusted to 4 using AcOH and monitoring with a pH meter.The solution was stirred at room temperature for 16 to 24 hours; and then basified to pH 14 with 5 N NaOH. The aqueous solution was extracted four times with 200 ml of methylene chloride, and this organic solution was dried over MgSO4 and rotovapped. The crude white foam was chromatographed on silica eluting with 90:10:1 CH2Cl2 MeOH: aq. NH3 to yield 567 mg of higher Rf material (lactone impurity in the starting material plus some aminal), and 1.25 g of pure amine ffia.

Selected spectral data for 11,12,12a,13,14,15-hexanor-8a-aza-9 deoxo-6,9-epoxyerythromycin A seco acid methyl ester (single diastereomer of uncertain configuration at C-9)(IXa): 1H NMR (400 MHz, CDCL3) 6 4.61 (d, H-1"), 4.40 (d, H-1'), 4.22 (dd, H-9), 4.12 (dd, H-3), 4.01 (dq, H-5"), 3.58 (d, H-5), 3.63 (s, COOCH3), 3.50 (m, H-5'), 3.27 (s, OCH3), 3.21 (m, H-2'), 2.99 (d, H4"), 2.82 (m, H-2), 2.47 (d, H-3'?, 2.25 (s, N(CH3)2), 2.25 (m, H-2"), 1.64 (d, H-4'), 0.87 (t, H-11), 13C NMR (CDCL3) 6 176.74, 102.89, 95.13, 82.25, 81.18, 80.31, 78.05, 77.39, 70.69, 69.32, 65.56, 65.12, 51.59, 49.39, 45.66, 40.85, 40.33, 38.99, 37.50, 36.02, 35.18, 29.34, 28.85, 22.85, 21.63, 21.18, 20.87, 17.91, 11.66, 10.20, 9.71 FARMS: 639(M+Lit) Selected spectral data for 9,10,10a,11,12,12a,13,14,15-nonanor- 8a-azaerythromycin A seco acid methyl ester (IIIa) : 1H NMR (400 MHz, CDCL3) 6 4.60 (d, H-1"), 4.33 (d, H-1'), 4.10 (dd, H-3), 4.00 (dq, H-5"), 3.63 (s, COOCH3), 3.53 (m, H-5'), 3.48 (d, H-5), 3.28 (dd, H-2'), 3.25 (s, OCH3), 3.25 (m, H-8), 2.95 (d, H-4"), 2.79 (dq, H-2), 2.49 (m, H-3'), 2.27 (s, N(CH3)2), 2.26 (dd, H2"), 2.04 (m, H-4), 2.49 (dt, H-3'), 1.64 (br d, H-4'), 1.45 (dd, H-2" ax), 1.45 (m, H-7), 1.35 (m, H-7), 1.24 (s, H-6Me), 1.21 (m, H-6' or 6"), 1.21 (m, H-4'), 1.20 (s, H-6' or 6"), 1.16 (s, H-3"Me), 1.09 (d, H2Me), 1.09 (d, H-8Me), 1.04 (d, H-4Me).

13C NMR (CDCL3) 6 176.35 (C-1), 104.37 (C-1'), 95.98 (Ci"), 85.70 (C-5), 80.33 (C-3), 77.79 (C-4"), 75.01 (C-6), 72.66 (C-3"), 70.39 (C-2'), 69.57 (C-5'), 65.30 (C-5"), 65.11 (C-3'), 51.65 (C-ester Me), 49.34 (C-3"-OMe), 44.16 (C-7), 43.96 (C-8), 41.24 (C-2), 35.11 (C-2"), 28.81 (C-4'), 26.51 (C-8Me or 2Me), 24.39 (C-6Me), 21.50 (C3"Me), 21.05 (C-6'), 17.73 (C-6"), 11.00 (C-4Me), 10.08 (C-8Me or 2Me).

FAB MS: 594 (M + H+) Example 10 A General Procedure for the Preparation of Aminals IX and X and 8a Aza Fragments IIIc and IIId

Using the procedure taught in example 9, an iminoether fragment VI or VII is converted into an aminal IX or X, respectively, which is hydrolyzed to an 8a-aza fragment me or IIId, respectively. In the above diagram R is hydrogen, methyl, C1-10 alkoxycarbonyl, aralkoxycarbonyl or arylsulfonyl; one of R2 and R3 is hydrogen, the other is OH, NHR1 or NMeR1 where R1 is as defined before; R4 is hydrogen, C1-10 alkyl, or aralkyl.A representative but nonlimiting sampling of the compounds which may be produced in this manner include those in the following table wherein it is to be understood that the product compounds are species of the genus of 8a-aza fragments Ilic or md, whose generic structure is given above.

Table for Example to Substituent Product Compound

R1 R2 R3 R4 R6 R7 III-1 Me OH H Me H Me III-2 Me H NH2 Me Me H III-3 Me NH2 H Me Me H III-4 Me OH H Me Me H III-5 Me OH H H Me H III-6 PhSO2 OH H Me Me H III-7 Me OH H Bn Me H III-8 t-BOC OH H Me Me H III-9 cbz OH H Me Me H III-10 Me H NH2 Me H Me rn-ti Me NH2 H Me H Me III-12 Me OH H Me H Me III-13 Me OH H H H Me III-14 PhSO2 OH H Me H Me III-15 Me OH H Bn H Me

E-16 t-BOC OH H Me H Me E-17 Cbz OH H Me Me H Cbz = benzyloxycarbonyl t-BOC = tert-butyloxycarbonyl Ph = phenyl Bn = benzyl While the invention has been described, exemplified 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 possible.

Claims (4)

1. WHAT IS CLAIMED IS:

   i. A compound of the formula:

   wherein X is an amine of the formulae

   R1 is hydrogen, methyl, Cm leo alkoxycarbonyl or arylsulfonyl when X is CH3CH2CHNH2 and R1 is additionally aralkoxycarbonyl when X is NH2; one of R2 and R3 is hydrogen and the other is OH, NHR1 or NMeR where R1 is as defined above; R4 is hydrogen or C1-10 alkyl when X is CH3CH2CHNH2 and is additionally aralkyl when X is NH2 ; R5 is hydrogen or C1-3 alkyl when X is CH3CH2CHNH2; R5 is hydrogen when X is NH2; and one of R6 and R7 is hydrogen and the other is methyl except when X is CH3CH2CHNH2 and R5 is hydrogen, in which case R6 is Me and R7 is H.
2. 2. A compound of the formula

   wherein R is hydrogen, methyl, C1-10 alkoxycarbonyl or phenylsulfonyl ; one of R2 and R3 is hydrogen and the other is NHR, NMeR or OH where R is hydrogen, methyl C1-10 alkoxycarbonyl or phenylsulfonyl; R4 is hydrogen or Ct-to alkyl; R5 is hydrogen or C1-3 alkyl; one of R6 and R7 is hydrogen and the other is methyl when R5 is C1-3 alkyl ; and R6 is methyl and R7 is hydrogen when R5 is hydrogen.
3. 3. A compound of the formula

   wherein R5 is hydrogen or methyl; one of R6 and R7 is hydrogen and the other is methyl when R5 is methyl; and R6 is methyl and R7 is hydrogen when R5 is hydrogen.
4. 4. A compound of the formulae

   wherein R1 is hydrogen, methyl, C1-10 alkoxycarbonyl or phenylsulfonyl; one of R2 and R3 is hydrogen and the other is OH, NHR or NMeR where R is hydrogen, C1-10 alkyl or phenalkyl ; and R4 is hydrogen, C1-10 alkyl or phenalkyl.

   5 A compound of the formulae