biogenesis of limonoids - biogenesis of limonoids: the main features of triterpene biogenesis are...

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  • 20

    Biogenesis of limonoids:

    The main features of triterpene biogenesis are

    now v;ell established and are summarised in scheme "1, The

    limonoids are def̂ raded triterpenes and constitute a group

    which derives its name from limonin, the bitter principle

    3 9 present m most citrus species '•". Determination of the

    structure'of this principle was a magor problem in the mid

    fifties v/hich v;as solved through the efforts of several

    10-12 internationally reno\̂ med chemists , Since NPIR

    spectroscopy had not yet arrived on the scene, the structure

    was deduced largely from chemical transformations of the

    molecule. X-ray analysis clarified such doubts as still

    existed and established besides the relative stereochemistry,

    The absolute configuration of limonin and other members

    of the group was assumed on the basis of biogenetic

    relationship to the tetracyclic triterî ene tirucallol/euphol

    which had been previously related to compounds of known

    absolute configuration. Further confirmation v̂ as soon

    1^ available through apolication of ORD -''.

    Evolution of the limonin carbcai skeleton from

    euDhol (3) involves elimin&tion of four carbon atoms of the

  • 21

    side chain, cleavage of Gp-C., bond of ring A, migration of

    C^^ methyl to G^ and modification of ring D. The limonin

    nucleus emerges through oxidative cyclisation leading to

    tv;o 5 membered and tv/o 5 membered heterocyclic rings. The

    changes can be represented diagrammatically as shovm in

    scheme - I.

    [ SCHB\/!E I ]

    Scission of r ing A as "oostulated in the 'blorcr.etlc

    schene v/as o r i g i n a l l y observed in dammarenolic acid and

    • 1 5 i s of v;ide occurrence among t r i t e r p e n e s e .g . shoreic acio - ,

  • 22

    . . 16 putranjivic acid and migration of the methyl group occurs

    with introduction of double bond between C^^ and C.̂ - during

    oxidation of butyrospermyl acetate (5) to the 7-keto

    compound (5) , Conversion of ring D to the 6 membered lactone

    can occur through an in vivo enuivalent of the Baeyer -

    Villiger oxidation. Many compounds have been isolated in the

    intervening years which lie either on the pathv/ay to limonin

    from euphol, or have resulted through scission and modifi-

    cation of other ring. '\

    NZO'^'

    H

    ACO

    (5) (6)

    In the scheme that follows limonoids or their

    immediate precursors have been so arranged as to place the

    more primitive, and therefore siiapler ones, before the

  • 23

    structurally more complex. Protolimoaoids are compounds in

    which structural changes of the precursor triterpene moiety

    are confined to the side chain. Thus flindissol (7)

    turraeanthin (8) aphanamixin (9) melianone (10) contain all

    the carbon atoms of tirucallol/euphoi but cyclisation of

    AcO

    R = H r OH

    (9)

    do;

    Lhe side chain to the Cdiurabcd furan has already occurred.

  • 24

    Cedrelone (11) and grandifolone (12) are representative of

    compounds in v/hich methyl migration is accompanied by loss

    of 4-carbon atoms from the side chain. Gedunine (13) type

    t

  • and ichangin (17) must be its immediate precursor.

    25

    (14) (15)

    O^^'

    ;i6} (17

    Also regarded as members of the limonoid group

    arc andirobin (18) and methyl angolensate (19) in v/tiich

  • 26

    ring B undergoes scission and ring A remains intact, v/hereas

    in nimbin (20) both rings A and B survi\-e and it is ring C

    that is modified. Though more complex structurally

    swietenolide (21) and mexicanolide (22) are readily accommo-

    dated in the scheme as products formed through cyclisation of

    ring A with the methylene resulting fron scission of ring C,

    ^ COOCH

    US) [19)

  • CH OC 2 II O

    20) 21

    COXI^

    ^

    27

    2 2 )

  • 28

    Structure elucidation of Limonoids;

    NMR opectroscQ-py:

    The structural problem of liraonin, as already

    pointed out, v/as resolved largely through chemical trans-

    formations and PMR spectroscopy, applied at a later stage

    of the work, served only to confirm the number of methyls.

    The published data was meagre and only resonances of the

    furanoid protons v;ere assigned. The first comprehensive

    18 study of PI'IE spectra of limonoids was made by D,L.Dryer ,

    vjho also employed it in confirming the structures assigned

    to products resulting from deep-seated rearrangement of the

    molecule.

    In spite of the comparatively poor resolving

    pov;er of the 60 KHz instruments, the spectra of limonin

    and its derivatives reported by him are fa.irly clear, a

    consequence of the wide difference in chemical shifts of

    structurally significant protons and presence of but fev;

    contiguous methylonos. It was thus possible to make

    assignments with some certainty, the important ones being

    of (a) methyl resonances (b) epoxidic protons (c) the C-1

    and C-19 methine and methylene (d) furfuryl proton and (e)

  • 90

    the furanoid protons.

    Methyl Resonance:

    The C-8 methyl bei.ng farthest av;ay from deshielding

    influences resonates at highest field followed by the

    gem-dimethyls which are B to the ether ox;}'-gen and the / • — • ' '

    18-methyl v/hich is in proximity to the luran ring. That the

    resonance of the C-8 methyl is correctly identified follows

    from the fact that it is the one most affected by reduction

    01 carbonyl or its conversion to oxime. Similarly in obacunone

    methyl assignments could be made on the basis of shifts

  • 30

    produced by opening of the 7-niembered lactone ring.

    Protons under oxygen:

    Of these there are five and of the five only the

    one at C-1 is further coupled. The 0-19 methylene gives

    rise to a singlet In some compounds and in others to AB

    doublets. The singlet of the epoxide profcons v;as found to

    overlap in some limonoids v/ith the mulfciplet of the C-1

    proton but there is no ambig\,iity about the furfuryl proton

    as, apart from its being on a carbon under oxygen, it is

    further deshielded by the adjacent furan ring.

    The epoxide proton appears at much lov;er field

    than in similar compounds, because of uhe 0-7 carbonyl group.

    The effect is similar to that observed, in case of 0-1

    hydrogen in 11-ketosteroids '̂ nd 0-7 hydrogen in some

    diterpenes e.g. fibleucin (23). Reduction of the 0-7 carbonyl

    23)

  • 31

    gives two compounds, liraonol and epilimonol v/hich are

    epimeric at C-7. The position of the epo;.dde proton

    differs by about 40 Hz in the two compounds, Spilimonol,

    the reduction product in which the epoxide hydrogen appears

    at lower field, has been assigned equatorial [̂ OH as in

    this case the hydroxy group ojid epoxide proton are in

    proximity and the latter is thus exposed to the deshielding

    influence of C-0 bond. An interesting fact that emerges

    from a study of different limonoids is that the epoxidic

    proton in compounds in which ring A is 7-Kiembored e.g.

    obacunone (15) is at higher field than in limonin. Besides

    serving to distinguish compounds of the two tj'~oes this

    provides evidence of conformational changes in ring B on

    expansion of ring A. Further the epoxidic ring also

    influences the environment of the C-7 hydrogen in C-7

    alcohol causing it to resonate at lovier field when it is

    equatorial, as in limonolo Models shov/ that the epoxide

    ring is also close tc the fu.riuryl proton and excercises

    a deshielding influence on it too, for in dooxylimonin the

    proton is shifted upfield hy about 20-30 Hz.

    The stereochemistry at C-I7 was established

    through recourse to Klyne's modification of Hudson's

  • 32

    19 lactone rule , The axial i.e. orientation of the

    -fupfuryl proton is clearly discernible in columbin by the

    larger coupling constant with the axial proton of the

    adjacent methylene in columbin (24-) 20

    24

  • 33

    Sfcructure of Janfpraolide:

    The defatted bark of Jlacourtia cataphracta v;as

    extracted v̂ ich ethariol and acetone :..nd from the extract after

    the usual purification a v.'hite cry£i:alline solid v/as

    isolated. It had sharp melting poini; and initially appeared

    pure on tic but the mass spectrum vras not very clear about

    the position of M ' and the HMR too seemed to belong to a

    mixture. The NHR spectrum shov/ed 8 t art-methyls atj high

    field which suggested that the compound was a triterpene but

    the mass spectrum had its most prominent ion at 5'J-8 with

    peaks of very lov/ intensity only at higher mass values. It

    was therefore presumed that the isolated solid was a mixture

    of tv/o diterpenes. The IR spectrum (?ig-I) shov/ed a broad

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