STEREOCHEMICAL PROBLEMS IN MACROLIDE .STEREOCHEMICAL PROBLEMS IN MACROLIDE ANTIBIOTICS W. D. CELMER

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  • STEREOCHEMICAL PROBLEMS INMACROLIDE ANTIBIOTICS

    W. D. CELMER

    Medical Research Laboratories, Pfizer, Inc., Groton, Connecticut 06340, USA

    ABSTRACTSince 1950, well over fifty macrolides have been derived from variousActinomycetes in screening laboratories located at many corners of the world.Among the most intensely studied macrolides are those produced on a com-mercial scale (erythromycin, oleandomycin, tylosin, leucomycin and spira-mycin) as well as examples of particular historical/scientific importance(Magnamycin, pikromycin, narbomycin, methymycin). As a result of chemicalstudies by numerous investigators, many macrolides are now structurallydefined. Their overall constitutional structures reveal an unusual wealth ofstereochemical features involving numerous asymmetric centres and conforma-tional possibilities among 12-, 14- or 16-membered lactone rings containingan array of substituents including one, two or three glycoside units.

    Fruitful approaches to the special macrolide sugar problems have followedclassical carbohydrate stereochemistry while numerous aglycone asymmetriccentres have been successfully defined through localization in a variety ofdiagnostic fragments. X-ray studies are now complete on three macrolidederivatives. Total absolute configurations are ascribed to oleandomycin,erythromycin, Magnamycins, leucomycins, spiramycins, methymycin andpikromycin. Moreover, considerable configurational data are available on theaglycones of narbomycin, neomethymycin, lankamycin and chalcomycin.

    Recent structural revisions have greatly simplified the overall stereochemicalproblem by bringing 'into line' certain biogenetically 'out-of-step' proposalsthat have involved unusual 17-, 18- and 22-membered rings as well as misplacedsugars. Growing stereochemical knowledge has largely confirmed an earlierbiogenetically-based hypothesis that all antibacterial macrolides can beviewed as following the same configurational model regardless of ring size ordegree of carbon branching in the aglycone chain. Application of the modelto specific macrolides in need of further configurational definition affordslikely insight to the chirality at many experimentally unprobed asymmetriccentres. Recent conformational analyses of the 14-membered ring system inerythromycin aglycones using 100 MHz nuclear magnetic resonance and circu-lar dichroism techniques indicate that the shape of the molecule in solutionis relatively stable and similar to that in the crystal. The conformation mostevident for erythronolide B is a modification of the diamond-lattice sectionmodel, taken from the geometry of cyclotetradecane. Available evidencesuggests that 'isosteric' macrolides (erythromycin, lankamycin and oleando-mycin) have similar conformations.

    Although the configurational and conformational models for macrolideantibiotics are still undergoing further refinements, they have proven usefulduring the entire course of their development in testing certain biogeneticand physico-chemical theories. At present, they are finding increasing applica-

    413

  • W. D. CELMER

    tions as aids in explaining and/or predicting a wide variety of macrolidephenomenology involving stereospecificity in biosynthesis, chemical modifica-

    tions, mode of action and mechanism of drug resistance.

    INTRODUCTIONOur work on oleandomycin led us to take an active interest in the structures

    and stereochemistry of related macrolide antibiotics 121 Typical of themacrolide group22 under discussion is the growing number of structurally-defined members listed in Table 1. All of the examples possess, in common, a

    Table 1. Macrolides of defined constitutional structure

    Examples Year of definition and referencesMethymycin (1956)69Erythromycin At & B (1957)8081Erythromycin C (1957) (Revised, 1962)48Magnamycin A & B (Carbomycins A & B) (1957) (Revised, 1965)' 52Pikromycin (1957)72 (Revised, 1968)'Neomethymycin (1958)Oleandomycint (196O)Narbomycin (1962)71Niddamycin (1962)Chalcomycin (1964)41Spiramycinst (1964)56 (Revised, 1965) (Re-revised,

    1969)Lankamycin (1964)58 (Revised, 1970)Leucomycins (Kitasamycins)t (1967) ci Josamycint (1970)Neutramycin (1969)42Cirramycin A1 (1969)Megalomicin A (1969)Kujimycin A (1969)60B-58941 (1970)25Tylosint (1970)O-Demethyloleandomycin (1971)20

    t Produced in various geographical areas on a commercial scale for application in human and/or veterinary medicine.

    glycosidically substituted large ring lactone, Actinomycetes origins, as wellas distinctive activity against bacteria (chiefly Gram-positive) and myco-plasma. Many such macrolides are produced commercially as the free base,various salts, and/or as certain semi-synthetic ester derivatives. There is acontinued search for new macrolide products among fermentations, bychemical modifications and through directed biosynthesis.

    The recent influx of new and revised structural determinations of variousmacrolides is indicative of widespread chemical interest in the field. Thepresent survey of macrolide constitutional structures (illustrated in Figure 1)calls attention to a gradual gradation of molecular features among 12-,14-. and 16-membered rings and varying degrees of carbon branching,oxygenation, unsaturation and glycoside substitution. Recent revisions tomore conventional structures of certain incorrect proposals (some involving'unorthodox' 17- or 22-membered rings or 'misplaced' sugars) now permit

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  • STEREOCHEMICAL PROBLEMS IN MACROLIDE ANTIBIOTICS

    Table 2. Macrolide D-sugar moieties

    Name Stereo-structure Macrolide origin

    D-MycaminoseMagnamycinsCH3 0Leucomycins

    O Cirramycin A1(CH - TylosinNiddamycin

    D-Desosamine CH3 o MethymycinsErythromycins

    (CH3)2. Oleandomycin0 PikromycinNarbomycinMegalomicin AO-Demethyloleando-

    mycinCH3 o

    D-Forosamine (CH

    0Spiramycins

    D-Rhodosamine HO/ CH30

    (CH3) Megalomicin A

    D-Chalcose CH3(Lankavose) CH3. ChalcomycinO Lankamycin

    OH Neutramycin

    D-Mycinose CH3 oChalcomycin

    o NeutramycinCH3

    TylosinOCH3

    D-Aldgarose

    Aidgamycin E

    0

    415

  • Met

    hym

    ycin

    :

    Neo

    met

    hym

    ycin

    CH

    3 C

    H3

    CH

    3

    o_4#

    L O

    H

    o_41

    4L..4

    11 O

    H

    o..1

    L%

    OH

    H

    3C

    OH

    o

    H b4

    r,'I

    Rho

    do

    H r#

    E

    1 sa

    min

    e D

    esos

    amin

    e A

    cO

    Cha

    lcos

    e

    H3C

    H

    3C

    HO

    D

    esos

    amin

    e H

    O

    Des

    osam

    in'e

    H

    3C

    HC

    H

    O

    CH

    3 H

    O

    CH

    R

    C

    H

    Cla

    dino

    se

    Myc

    aros

    e M

    ycar

    ose

    H3C

    - I Ar

    cano

    sc

    CH

    3 C

    H3

    CH

    3 '1

    13

    CH

    3 C

    H3

    'r

    0 R

    0

    0 H

    3C

    OH

    0 C

    H3I

    Ery

    thro

    myc

    in A

    : O

    H

    Ery

    thro

    myc

    in B

    : H

    CH

    3

    Des

    osam

    ine

    0 H

    3C

    R1

    R2

    OH

    H

    H

    O

    H

    .

    R

    H3C

    Nar

    bom

    ycin

    : Pi

    krom

    ycin

    : O

    H

    O.

    H3C

    J L

    -CH

    3 D

    esos

    amin

    e H

    O

    Des

    osam

    ine

    H3C

    C

    H3

    H3C

    O

    livos

    e

    CH

    3 0

    O-D

    emet

    hyl-

    olea

    ndom

    ycin

    rn

    Ery

    thro

    myc

    in C

    M

    egal

    omic

    in A

    R

    Lan

    kam

    ycin

    : A

    IyI

    Kuj

    imyc

    in A

    : H

  • Figu

    re 1.

    Mac

    rolid

    e con

    stitu

    tiona

    l st

    ruct

    ures

    Isov

    aler

    yl

    Myc

    aros

    e

    Myc

    amin

    ose

    CH

    3

    0 M

    agna

    myc

    in A

    R2

    Myc

    aros

    e

    Myc

    amin

    ose

    R

    Mag

    nam

    ycin

    B:

    Afy

    l Sp

    iram

    ycin

    s N

    idda

    myc

    in:

    11

    R

    1:

    H

    11:

    Ace

    tyl

    Leu

    com

    ycin

    s R

    1 R

    2

    111:

    Pr

    opio

    nyl

    Cl-

    I3

    A1:

    H

    5A

    3:

    Ace

    tyl

    A4:

    A

    cety

    l A

    5:

    H

    A6:

    Ace

    tyl

    CH

    O

    A7:

    H

    M

    ycar

    ose

    A8:

    A

    cety

    l A

    9:

    H

    Myc

    inos

    e C

    halc

    omyc

    in:

    CH

    3

    Isov

    aler

    yl

    Isov

    aler

    yl

    n-B

    utyr

    yl

    n-B

    utyr

    yl

    Prop

    iony

    l Pr

    opio

    nyl

    Ace

    tyl

    Ace

    tyl

    R

    Myc

    ami n

    ose C

    H2

    R

    Myc

    inos

    e

    CM

    H

    rn 0 (J

    rn 0 tn CM 0 rn z H 0 H (-) CM

    Neu

    tram

    ycin

    H

    * Jo

    sam

    ycin

    Cirr

    amyc

    in A

    1:

    0!-!

    B

    589

    41:

    (Cin

    erul

    ose

    A)

    H3C

    T

    ylos

    in

  • W. D. CELMER

    Table 3. Macrolide L-sugar moieties

    Name Stereo-structure Macrolide origin

    L-Oleandrose

    L-Cladinose

    L-Mycarose

    L-Arcanose

    2,3,6Trideoxy-hexopyranos-4-ulose

    (cf. L-Cinerulose A)

    L-Oliose(L-2-Deoxyfucose)

    HO