C-Secomeliacins. This is a large and important group containing the most complex compounds
and as mentioned above, is specifically confined to neem and Persian lilac (Melia azedarach).
There are three important sub-groups viz. nimbin, salannin and azadirachtin. Currently, 22
members of nimbin and salannin group have been isolated from neem (Table 7). Nimbolin¬B41
(81) and nimbilin11 (82) contain C-7 cinnamoyloxy moiety instead of the commonly noticed
acetoxy substituent. The C-ring has apparently undergone expansion probably due to Baeyer
Villiger type oxidation of the likely precursor, nimbidinin (72) to a lactone, ohchinolide B57 (83) or
lactols 81 and 82. Following the structural analogy of salannin (85) with nimbin (90), the
elucidation and establishment of stereo chemical structure of 85 became possible. Extensive
chemical modification studies60 of 85 led to conversion of salannin to its desacetyl derivative (86)
and nimbidic acid (84) which were later isolated from neem. The occurrence of other analogues,
87-89 indicates the versatility of neem in esterifying the two hydroxyl groups present in salannin.
and as mentioned above, is specifically confined to neem and Persian lilac (Melia azedarach).
There are three important sub-groups viz. nimbin, salannin and azadirachtin. Currently, 22
members of nimbin and salannin group have been isolated from neem (Table 7). Nimbolin¬B41
(81) and nimbilin11 (82) contain C-7 cinnamoyloxy moiety instead of the commonly noticed
acetoxy substituent. The C-ring has apparently undergone expansion probably due to Baeyer
Villiger type oxidation of the likely precursor, nimbidinin (72) to a lactone, ohchinolide B57 (83) or
lactols 81 and 82. Following the structural analogy of salannin (85) with nimbin (90), the
elucidation and establishment of stereo chemical structure of 85 became possible. Extensive
chemical modification studies60 of 85 led to conversion of salannin to its desacetyl derivative (86)
and nimbidic acid (84) which were later isolated from neem. The occurrence of other analogues,
87-89 indicates the versatility of neem in esterifying the two hydroxyl groups present in salannin.
| Table 7. C-secomeliacins –salannin group |
Stru- Name Substituents Molecular m.p. Isolated Ref.
ture R1 R2 R3 Formula Weight (*C) from No.
No.
81. Nimbolin B - - - C39H46O10 674 243-5 Trunk wood 41
82. Nimbilin - - - C32H50O10 714 149-50 Root bark 11
83. Ohchinolide B - - - C35H44O10 624 211-12 Seed kernels 57
84. Nimbidic acid H H H C26H34O7 458 230 99
85. Salannin Tg Ac Me C34H44O9 596 168 Seed oil 60
86. 3-Desacetyl salannin Tg H Me C32H42O8 554 214-5 Seed 70
87. Salannol CO1Bu H Me C32H44O8 556 208 Seed oil 70
88. 2’3’-Dehydro-salannol COCH:Cme2 H Me C32H42O8 554 52
89. Salannol acetate CO1Bu Ac Me C34H36O9 598 Gummy Seed 116
ture R1 R2 R3 Formula Weight (*C) from No.
No.
81. Nimbolin B - - - C39H46O10 674 243-5 Trunk wood 41
82. Nimbilin - - - C32H50O10 714 149-50 Root bark 11
83. Ohchinolide B - - - C35H44O10 624 211-12 Seed kernels 57
84. Nimbidic acid H H H C26H34O7 458 230 99
85. Salannin Tg Ac Me C34H44O9 596 168 Seed oil 60
86. 3-Desacetyl salannin Tg H Me C32H42O8 554 214-5 Seed 70
87. Salannol CO1Bu H Me C32H44O8 556 208 Seed oil 70
88. 2’3’-Dehydro-salannol COCH:Cme2 H Me C32H42O8 554 52
89. Salannol acetate CO1Bu Ac Me C34H36O9 598 Gummy Seed 116
Table 7B. C-secomeliacins – nimbin group
Stru- Name Substituents Molecular m.p. Isolated Ref.
ture R1 R2 R3 Formula Weight (*C) from No.
No.
90. Nimbin α-COOMe Ac Me C30H36O9 540 205 Seed oil 59,103,126
91. 6-Desacetyl nim. α-COOMe H Me C28H34O8 498 208 Seed oil 104
92. 4-Epinimbin β-COOMe Ac Me C30H36O9 540 196-7 Seed oil 135
93. Nimbanal α-CHO Ac Me C29H34O8 510 195-7 Seed oil 116
94. 6-Desacetyl nim. α-CHO H Me C27H32O7 468 Amorph. 25
95. Nimbinol α-CH2OH H Me C29H36O8 512 Amorph 25
96. Dihydro nimbic ac. α-COOH H H Leaves 39
(2,3-dihydro)
97. Nimbolide C27H30O7 466 245-7 Leaves 39
98. 28-Dexonimbolide C27H32O6 452 170 Leaves 25
99. Nimbinene C28H34O7 482 134 Seed 71
100. 6-Desacetyl nimbinene C26H32O6 440 141 Seed oil 71
101. Nimbandiol C26H32O7 456 121 All parts 71
102. 6-0-Acetyl nimbandiol C28H34O8 498 178 All parts 71
ture R1 R2 R3 Formula Weight (*C) from No.
No.
90. Nimbin α-COOMe Ac Me C30H36O9 540 205 Seed oil 59,103,126
91. 6-Desacetyl nim. α-COOMe H Me C28H34O8 498 208 Seed oil 104
92. 4-Epinimbin β-COOMe Ac Me C30H36O9 540 196-7 Seed oil 135
93. Nimbanal α-CHO Ac Me C29H34O8 510 195-7 Seed oil 116
94. 6-Desacetyl nim. α-CHO H Me C27H32O7 468 Amorph. 25
95. Nimbinol α-CH2OH H Me C29H36O8 512 Amorph 25
96. Dihydro nimbic ac. α-COOH H H Leaves 39
(2,3-dihydro)
97. Nimbolide C27H30O7 466 245-7 Leaves 39
98. 28-Dexonimbolide C27H32O6 452 170 Leaves 25
99. Nimbinene C28H34O7 482 134 Seed 71
100. 6-Desacetyl nimbinene C26H32O6 440 141 Seed oil 71
101. Nimbandiol C26H32O7 456 121 All parts 71
102. 6-0-Acetyl nimbandiol C28H34O8 498 178 All parts 71
The isolation of nimbin (90) in 1942 marked the beginning of the chemistry of neem meliacins.126 Structure elucidation of nimbin posed
formidable challenges as there was no structural precedence to lean on, at a time when, the nmr technique was at its infancy and engaged
at least four schools of chemists59.lo3.164 and all the classical methods of structural elucidation were imposed on this molecule34.64.
Extensive chemical modification studies were carried out on nimbin and several derivatives were obtained which included among others,
nimbic acid, nimbinic acid, i.e. the partial methyl ester of nimbic acid, desacetylnimbin, dihydro and hexahydronimbin etc. 59 Pyrolysis of
nimbic acid gave a dienol-lactone (C-l enol linked to C-12 carboxylic acid) called pyronimbic acid by concerted decarboxylation of C-28,
enolisation of C-l carbonyl and dehydration. The correct molecular formula of nimbin was also computed by high-resolution mass
spectrometry. On the basis of above-mentioned hydrolytic and pyrolytic products, constitution of rings A and B was proposed.
Independently, on the basis of biogenetic proposition supported with other chemical data, NarayananlO3 could assign the complete
constitution of nimbin. Later, the structure of nimbinic acid was also established. An attempt to acetylate hydroxy-dicarboxylic acid of
hexahydronimbin gave a dilactone, which luckily enabled the elucidation of configuration at C-4 in nimbin. The stereochemistry of nimbin
was later confirmed on the basis of double resonance NMR spectra59. The 1,3-diequatorial configuration of C-28 and C-6 ester groups
was also implied by means of difference in the rate of hydrolysis of nimbin and desacetyl nimbin. Similarly, chemical evidence was
submitted for the stereochemistry at C-15 and C-17. The absolute stereochemistry of A-B ring fusion was established on the basis of
ORD/CD measurement using pyronimbic acidl64. Thus, the decade, 1959-1968 was a landmark period, culminating in the structure
elucidation of the premier neem meliacin, nimbin but also the first limonoid, limonin.
formidable challenges as there was no structural precedence to lean on, at a time when, the nmr technique was at its infancy and engaged
at least four schools of chemists59.lo3.164 and all the classical methods of structural elucidation were imposed on this molecule34.64.
Extensive chemical modification studies were carried out on nimbin and several derivatives were obtained which included among others,
nimbic acid, nimbinic acid, i.e. the partial methyl ester of nimbic acid, desacetylnimbin, dihydro and hexahydronimbin etc. 59 Pyrolysis of
nimbic acid gave a dienol-lactone (C-l enol linked to C-12 carboxylic acid) called pyronimbic acid by concerted decarboxylation of C-28,
enolisation of C-l carbonyl and dehydration. The correct molecular formula of nimbin was also computed by high-resolution mass
spectrometry. On the basis of above-mentioned hydrolytic and pyrolytic products, constitution of rings A and B was proposed.
Independently, on the basis of biogenetic proposition supported with other chemical data, NarayananlO3 could assign the complete
constitution of nimbin. Later, the structure of nimbinic acid was also established. An attempt to acetylate hydroxy-dicarboxylic acid of
hexahydronimbin gave a dilactone, which luckily enabled the elucidation of configuration at C-4 in nimbin. The stereochemistry of nimbin
was later confirmed on the basis of double resonance NMR spectra59. The 1,3-diequatorial configuration of C-28 and C-6 ester groups
was also implied by means of difference in the rate of hydrolysis of nimbin and desacetyl nimbin. Similarly, chemical evidence was
submitted for the stereochemistry at C-15 and C-17. The absolute stereochemistry of A-B ring fusion was established on the basis of
ORD/CD measurement using pyronimbic acidl64. Thus, the decade, 1959-1968 was a landmark period, culminating in the structure
elucidation of the premier neem meliacin, nimbin but also the first limonoid, limonin.
Once the structure of nimbin became known, assignment of structures for its analogues became fairly easy. Thus, appeared reports on the
occurrence of desacetylnimbin104 (91), 2,3-dihydronimbic acid39 (96) and nimbolide39 (97). Recent addition to nimbin group of meliacins
are the novel 4-epinimbin35 (92), the C-28 formyl analogues, nimbanal16 (93) and 6-desacetylnimbinal (94), the C-28 carbinol, nimbinol
(95), 28-deoxonimbolide25.66 (98) and the four pentanortriterpenoids71 viz. nimbinene (99), 6-desacetylnimbinene (100), nimbandiol
(101) and 6-0-acetylnimbandiol (102). The conversions of 90-92 to nimbolide (97) and nimbinenes (99-100) have been recently reported37
.
occurrence of desacetylnimbin104 (91), 2,3-dihydronimbic acid39 (96) and nimbolide39 (97). Recent addition to nimbin group of meliacins
are the novel 4-epinimbin35 (92), the C-28 formyl analogues, nimbanal16 (93) and 6-desacetylnimbinal (94), the C-28 carbinol, nimbinol
(95), 28-deoxonimbolide25.66 (98) and the four pentanortriterpenoids71 viz. nimbinene (99), 6-desacetylnimbinene (100), nimbandiol
(101) and 6-0-acetylnimbandiol (102). The conversions of 90-92 to nimbolide (97) and nimbinenes (99-100) have been recently reported37
.
C-secomeliacins with a Modified Side Chain
So far, seven C-secomeliacins containing a γ-Hydroxybutenolide as the side chain in place of furan ring have been isolated from neem
(Table 8). Salannolide51 (103), a salannin analogue has been found to occur in seeds and seems to be synonymous with photosalannin.
163 Its occurrence in trunk bark was earlier inferred.41 Isoazadirolide (104) isolated from fresh leavesl39 is the side chain analogue of 2',3'-
dehydrosalannol (88), wherein the stereochemistry at C-23 is not yet established. Salannolactam I and II (104 and 105) are the only
nitrogen-containing meliacins known.74 Margocinolidel35 (106) has structure intermediate between azadirone (42) and salannolide (103).
Thus, it has its A ring similar to 42 with a difference of only ether bridge between C-28 and C-6, as in 103. The other congeners of 107 in
green twigs were .its 23-oxo isomer (108) and the two isomeric desacetylnimbinolidesl38 (109 and 110). Isonimbinolide (111) was found
in neem bark.6 there is no report of the occurrence of azadirolide and nimbinolide.
So far, seven C-secomeliacins containing a γ-Hydroxybutenolide as the side chain in place of furan ring have been isolated from neem
(Table 8). Salannolide51 (103), a salannin analogue has been found to occur in seeds and seems to be synonymous with photosalannin.
163 Its occurrence in trunk bark was earlier inferred.41 Isoazadirolide (104) isolated from fresh leavesl39 is the side chain analogue of 2',3'-
dehydrosalannol (88), wherein the stereochemistry at C-23 is not yet established. Salannolactam I and II (104 and 105) are the only
nitrogen-containing meliacins known.74 Margocinolidel35 (106) has structure intermediate between azadirone (42) and salannolide (103).
Thus, it has its A ring similar to 42 with a difference of only ether bridge between C-28 and C-6, as in 103. The other congeners of 107 in
green twigs were .its 23-oxo isomer (108) and the two isomeric desacetylnimbinolidesl38 (109 and 110). Isonimbinolide (111) was found
in neem bark.6 there is no report of the occurrence of azadirolide and nimbinolide.
Table 8. C-seco-limonoids containing γ-Hydroxybutenolide (except 105, 106) side chain
Stru- Name Molecular m.p. Isolated form Ref.
ture Formula Weight (*C) No.
No.
103. Salannolide C28H36O7 628 .320 Seed 51
104. Isoazadirolide 576.27 130 Fresh leaves 139
105. Salannolactam-I 611.31 213 Seed kernels 74
106. Salannolactam-II 611.31 - Seed kernels 74
107. Margosinolide 484.21 130 Fresh green twigs 135
108. Isomargosinolide 484.21 125 Fresh green twigs 135
109. Desacetyl nimbinolide 530.22 196 Fresh green twigs 138
110. Desacetyl Isonimbinolide 530.00 180 Fresh green twigs 138
111. Isonimbinolide 572 114 Stem bark 6
ture Formula Weight (*C) No.
No.
103. Salannolide C28H36O7 628 .320 Seed 51
104. Isoazadirolide 576.27 130 Fresh leaves 139
105. Salannolactam-I 611.31 213 Seed kernels 74
106. Salannolactam-II 611.31 - Seed kernels 74
107. Margosinolide 484.21 130 Fresh green twigs 135
108. Isomargosinolide 484.21 125 Fresh green twigs 135
109. Desacetyl nimbinolide 530.22 196 Fresh green twigs 138
110. Desacetyl Isonimbinolide 530.00 180 Fresh green twigs 138
111. Isonimbinolide 572 114 Stem bark 6
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