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Erythroxan diterpenes from Fagonia species
Pergamoa
Phymhmtimy. Vol.36, No. 6 pp; 1431-1433.1991 Copyright 0 I!394Elwiet Sacna Ltd Printed III Great Bntin All ri&u IUCIV~~ 0031~Q422/94 S7.00+0.00
ERYTHROXAN MAGED
Department
DITERPENES
FROM
FAGONIA SPECIES
S. AEDEL-KADER, ABDALLAHA. OMAR, NABIL A. ABDEL-SALAMand
of Pharmacognosy,
FRANK R. SrErm-rz*t
Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; *Department Colorado State University, Fort Collins, Colorado 80523, U.S.A.
of Chemistry,
(Received in revised form 3 January 1994)
Key Word Index-Fagonia bruguieri; F. glutinosa; Zygophyllaceae; erythroxan diterpenes; fagonone; fagonene; 7-/I-hydroxyfagonene; 2,7-dioxofagonenes; S-epifagonenes.
Abstract-Aerial parts of Fagonia bruguieri afforded a new erythroxan-type diterpene: 15,16dihydroxy-7+hydroxycis-enterythrox3ene (7-b-hydroxyfagonene). Aerial parts of F. glutinosa yielded a series of additional new related erythroxans, most based upon a 15,16-dihydroxy-cis-em-erythrox-3ene structure, trivially named fagonene. These isolations extend the recently discovered presence of diterpenes in the Zygophyllaceae and provide additional examples in the ent-erythroxane diterpene series.
INTRODUCTION
The isolation and structural characterization of fagonone (1) and 160-acetylfagonone (2) from Fagoniu bruguieri
DC. [l] was the first report of diterpenes from the Zygophyllaceae and the first reported diterpenes with an ent-erythroxan structure. In the current work, an additional new diterpene from F. bruguieri and other new related diterpenes from F. glutinosa Del. are described. To simplify discussion and to emphasize the relationships among the compounds, structure 3 is designated as fagonene. Fagonone (1) for example, then becomes 7oxofagonene. Although the major isolated components all had the typical structure 3, minor isolates varied slightly in stereochemistry at some positions.
1: R,.R2--0;R3-Ft=H 2: R,.R~--O;R,-H;F~=~ 3: R,-R~=R~-R,-H 3; ;,-R,-Ft-H;%=OH
,=OH;RZ=R~=R,-H
RESULTS AND DISCUSSION
All the isolated diterpenes had the fagonene side chain at C-13 containing either free hydroxyl groups or acetylated hydroxyls, as well as the tricyclic formulation with four quatemary methyl groups and a C-3, C-4 double bond. Molecular formulae were established from the nominal molecular weight from mass spectra, combined with ‘%NMR spectra (including DEPT 135 and DEPT 90). These data, along with the ‘HNMR spectra, were compared to similar data [l] for 1 and 2, the latter of which had also yielded an X-ray crystal structure [ 11. Final structure assignments rested on some chemical interconversions and more detailed spectral interpretations, the discussion of which will, in each case, focus only on specific differences caused by functional group variance. Complete t3C NMR and selected ‘H NMR data are given in Tables 1 and 2, with additional ‘H NMR data in the Experimental. tAuthor to whom correspondence should he addressed.
7-/LHydroxyfagonene
(4) C2,,H340J,
was similar to 1,
but lacked the carbonyl carbon resonance of 1 and instead had a 668.5 carbon resonance for a CHOH group. The proton NMR resonance for the CHOH group (63.15) was coupled (HETCOR) to part of a CH2 resonance (62.32). An HMBC spectrum showed two-bond correlations for the 62.32 proton to 6 37.0 and 68.5 carbon resonances and three-bond correlations to the S 33.7,48.7, 52.7 and 140.1 carbon resonances. Such an array of correlations would only be possible if the hydroxyl group in 4 was at C-7. Hydride reduction of fagonone (1) yielded an alcohol, 5, whose NMR spectra were very similar to, but different from those of 4. The X-ray structure for 2 and a molecular model of 1 showed that the carbonyl of 1 was only accessible to hydride from the B face since the 01 face of the carbonyl was blocked by the C-20 methyl.
1431
M. S.
1432 Table 1. “CNMR 4
C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 co
ABDEL-KADER er al.
spectral data for compounds 4-10 5
6
17.8 18.9 35.7 36.5 38.7 200.5 124.0 122.7 128.3 140.1 142.0 170 37.0 37.0 30.7 47.7 44.3 50.9 68.5 73.0 213 48.7 44.7 53.4 39.6 38.6 46.3 52.7 54.0 55.3 24.6 25.3 27.9 30.0 30.5 29.5 38.5 37.9 44.7 29.6 34.4 34.2 82.3 82.8 82.0 63.2 63.5 63.4 19.6 19.4 19.1 20.4 21.6 21.5 33.7 35.0 32.9 13.4 15.9 16.1 --
COk&
7
IO
9
8
34.6 197.4 127.6 166.2 35.7 50.2 209.7 52.5 44.7 54.4 26.5 28.0 43.2 33.0 77.8 65.6 18.2 21.2 32.3 15.4 171.3
34.8 197.1 127.9 165.7 35.5 50.3 209.1 52.6 44.7 54.7 26.3 28.0 43.3 32.6 78.1 62.7 19.3 21.3 32.6 15.5 170.4 170.8 20.7 20.7 20.8
34.3 34.4’ 199.7 200.7 125.5 125.5 170.8 172.6 36.0 36.4 41.7 35.7 70.4 34.1’ 45.5 41.3 40.6 36.7b 52.3 52.9 29.5 25.5 28.5 29.0 37.6 42.1 34.3 36.1b 80.7 81.0 62.4 62.5 18.8 18.8 19.0 18.9 19.9 19.1 13.2 12.1 170.8 -21.3
--
**“These assignments may be interchanged.
Table 2. Selected ‘H NMR spectral data for compounds 4-108 H 3 17 18 19 20
4
5
6
7
8
9
10
5.25 0.87 1.71 1.08 0.87
5.29 1.07 1.78 1.07 0.88
5.78 0.84 1.94 1.42 0.51
5.77 0.88 1.94 1.42 0.51
5.78 0.95 1.94 1.42 0.51
5.68 0.88 1.86 1.21 0.89
5.67 0.88 1.86 1.10 0.80
*Resonances are singlets or broad singlets 18, d, J= 1.0 Hz) and 9 (C-18, d. J= 1.0 Hz),
except
for 4 (C-
Hence 5 must possess the z-configuration at C-7 and 4 the p-configuration. These stereochemical assignments were confirmed when a NOE enhancement in the H-7 resonance was seen for 4, but not 5, upon irradiation of the C18 methyl, which lies under ring B. As a final proof of the basic structure, 4, yielded 1 after oxidation of the diolblocked derivative and removal of the blocking group. As a result of the HMBC experiment on 4 and a reexamination of the ‘H NMR spectrum of 1 at 500 MHz, the following reassignments of resonances given previously for 1 [l] were made: C-2 (634.8), C-6 (650.4), C-8 (652.6), C-10 (653.0), C-14 (627.3). H-2 (al.35 and 1.71, 2H, m), H-6 (62.16 and 2.70, 2H, d, J= 14.8 Hz), H-8 (62.41, lH,dd, 5=12, 3.9 Hz), H-lO(S1.71, lH,m), H-14 (61.38 and 1.42, 2H, dd, J= 19.4, 3.2 Hz). 2,7_Dioxofagonene (6) CIoH,,O,, when compared to I, lacked one CH, group and had an additional carbonyl (6200.5; UV absorption at 238 nm; IR absorptions at
1657 and 1713 cm-‘). The “%ZNMR resonances for C-3 and C-4 were at 6 128.3 and 170 as compared to b 123.1 and 138.9 for 1. These data indicated the presence of an a&unsaturated carbonyl system and further NMR analysis in comparison to 1 established structure 6. 16-O-Acetyl-2,7_dioxofagonene (7) C22H3205, and l&16-di-0-acetyl-2,7-dioxofagonene (8) C24H3406, were characterized as the mono- and diacetyl derivatives of 6 from their mass, UV, IR. and NMR spectra which closely corresponded to those for 6 with the expected exceptions resulting from the acetylated side chain. Thus, the acetyl group for 7 was placed on OH-16 since the C-16 proton resonances for 7 were shifted downfield from those in 1 and 6 and were virtually identical with those observed for 2. For the diacetate 8, the H-l 5 resonance was at 63.98 as compared to 63.41 for 7. In the mass spectra, 6,7 and 8 all gave relatively intense m/z 273 ions, which resulted from the side chain cleavage and hence show that all had the same tricyclic component. Hydrolysis of 7 and 8 with 0.1 N aq. NaOH resulted in formation of 6, while acetylation of 6 and 7 gave 8, thus confirming the structure assignments. 7-fl-0-Acetyl-2-oxo-S-epi-fagonene (9) C,,H 34O5, had IR, UV and 13C NMR spectra which showed it to have an a&unsaturated carbonyl system in ring A as did 6. The spectral resonances for the remainder of the molecule were similar to those for 4, with important exceptions. An acetoxy group, lacking in 4, was present and this was assigned to C-7 from the change in the H-7 resonance from 63.15 in 4 to 64.86 in 9. In addition, the ‘-‘C resonance for C-19 was at 6 19.9 rather than in the 630 region as it is in all the cis-ent-fagonene structures. Such a resonance is diagnostic for a C-5 methyl in an A/B transfused structure [2, 33 and suggested structure 9. The structure was confirmed by the following NOE experiments. Irradiation of H-7 at 64.86 resulted in an enhancement of resonances for the C-19 and C-20 methyls at iil.21 and 0.89, respectively. Similarly, irradiation of the C-19 methyl resonance at 61.21 resulted in enhancements of resonances for H-7 (64.86), the C-20 methyl (60.89) and the C-18 methyl (6 1.86). 2-Oxo-5-epi-fagonene (10) C,,H,,O,, was isomeric with 1. The NMR spectra and the UV spectrum were those expected for an a&unsaturated carbonyl system and hence the carbonyl must be at C-2 rather than at C-7 as in 1. The remaining resonances were those of a fagonene structure, expect for C-19 (b 19.1) which, as in 9, was diagnostic for a C-5 sl-configuration. This resulted in assignment of structure 10 to the isolate. EXPERIMENTAL
Mps: uncorr. IR spectra were recorded in KBr disks. NMR spectra were in CDCI, (‘H 300 MHz; ref. 67.24 and 13C 75 MHz; ref. 677.0). ‘H resonances not described in Table 2 or below were parts of unresolved multiplets. The HMBC spectrum (500 MHz) was measured (CL Harris, Merck Sharp & Dohme, Rahway, New Jersey) with J=7.3 Hz. Mass spectra were obtained at 70 eV, with NH, in the CI mode.
Phymhmtimy. Vol.36, No. 6 pp; 1431-1433.1991 Copyright 0 I!394Elwiet Sacna Ltd Printed III Great Bntin All ri&u IUCIV~~ 0031~Q422/94 S7.00+0.00
ERYTHROXAN MAGED
Department
DITERPENES
FROM
FAGONIA SPECIES
S. AEDEL-KADER, ABDALLAHA. OMAR, NABIL A. ABDEL-SALAMand
of Pharmacognosy,
FRANK R. SrErm-rz*t
Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; *Department Colorado State University, Fort Collins, Colorado 80523, U.S.A.
of Chemistry,
(Received in revised form 3 January 1994)
Key Word Index-Fagonia bruguieri; F. glutinosa; Zygophyllaceae; erythroxan diterpenes; fagonone; fagonene; 7-/I-hydroxyfagonene; 2,7-dioxofagonenes; S-epifagonenes.
Abstract-Aerial parts of Fagonia bruguieri afforded a new erythroxan-type diterpene: 15,16dihydroxy-7+hydroxycis-enterythrox3ene (7-b-hydroxyfagonene). Aerial parts of F. glutinosa yielded a series of additional new related erythroxans, most based upon a 15,16-dihydroxy-cis-em-erythrox-3ene structure, trivially named fagonene. These isolations extend the recently discovered presence of diterpenes in the Zygophyllaceae and provide additional examples in the ent-erythroxane diterpene series.
INTRODUCTION
The isolation and structural characterization of fagonone (1) and 160-acetylfagonone (2) from Fagoniu bruguieri
DC. [l] was the first report of diterpenes from the Zygophyllaceae and the first reported diterpenes with an ent-erythroxan structure. In the current work, an additional new diterpene from F. bruguieri and other new related diterpenes from F. glutinosa Del. are described. To simplify discussion and to emphasize the relationships among the compounds, structure 3 is designated as fagonene. Fagonone (1) for example, then becomes 7oxofagonene. Although the major isolated components all had the typical structure 3, minor isolates varied slightly in stereochemistry at some positions.
1: R,.R2--0;R3-Ft=H 2: R,.R~--O;R,-H;F~=~ 3: R,-R~=R~-R,-H 3; ;,-R,-Ft-H;%=OH
,=OH;RZ=R~=R,-H
RESULTS AND DISCUSSION
All the isolated diterpenes had the fagonene side chain at C-13 containing either free hydroxyl groups or acetylated hydroxyls, as well as the tricyclic formulation with four quatemary methyl groups and a C-3, C-4 double bond. Molecular formulae were established from the nominal molecular weight from mass spectra, combined with ‘%NMR spectra (including DEPT 135 and DEPT 90). These data, along with the ‘HNMR spectra, were compared to similar data [l] for 1 and 2, the latter of which had also yielded an X-ray crystal structure [ 11. Final structure assignments rested on some chemical interconversions and more detailed spectral interpretations, the discussion of which will, in each case, focus only on specific differences caused by functional group variance. Complete t3C NMR and selected ‘H NMR data are given in Tables 1 and 2, with additional ‘H NMR data in the Experimental. tAuthor to whom correspondence should he addressed.
7-/LHydroxyfagonene
(4) C2,,H340J,
was similar to 1,
but lacked the carbonyl carbon resonance of 1 and instead had a 668.5 carbon resonance for a CHOH group. The proton NMR resonance for the CHOH group (63.15) was coupled (HETCOR) to part of a CH2 resonance (62.32). An HMBC spectrum showed two-bond correlations for the 62.32 proton to 6 37.0 and 68.5 carbon resonances and three-bond correlations to the S 33.7,48.7, 52.7 and 140.1 carbon resonances. Such an array of correlations would only be possible if the hydroxyl group in 4 was at C-7. Hydride reduction of fagonone (1) yielded an alcohol, 5, whose NMR spectra were very similar to, but different from those of 4. The X-ray structure for 2 and a molecular model of 1 showed that the carbonyl of 1 was only accessible to hydride from the B face since the 01 face of the carbonyl was blocked by the C-20 methyl.
1431
M. S.
1432 Table 1. “CNMR 4
C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 co
ABDEL-KADER er al.
spectral data for compounds 4-10 5
6
17.8 18.9 35.7 36.5 38.7 200.5 124.0 122.7 128.3 140.1 142.0 170 37.0 37.0 30.7 47.7 44.3 50.9 68.5 73.0 213 48.7 44.7 53.4 39.6 38.6 46.3 52.7 54.0 55.3 24.6 25.3 27.9 30.0 30.5 29.5 38.5 37.9 44.7 29.6 34.4 34.2 82.3 82.8 82.0 63.2 63.5 63.4 19.6 19.4 19.1 20.4 21.6 21.5 33.7 35.0 32.9 13.4 15.9 16.1 --
COk&
7
IO
9
8
34.6 197.4 127.6 166.2 35.7 50.2 209.7 52.5 44.7 54.4 26.5 28.0 43.2 33.0 77.8 65.6 18.2 21.2 32.3 15.4 171.3
34.8 197.1 127.9 165.7 35.5 50.3 209.1 52.6 44.7 54.7 26.3 28.0 43.3 32.6 78.1 62.7 19.3 21.3 32.6 15.5 170.4 170.8 20.7 20.7 20.8
34.3 34.4’ 199.7 200.7 125.5 125.5 170.8 172.6 36.0 36.4 41.7 35.7 70.4 34.1’ 45.5 41.3 40.6 36.7b 52.3 52.9 29.5 25.5 28.5 29.0 37.6 42.1 34.3 36.1b 80.7 81.0 62.4 62.5 18.8 18.8 19.0 18.9 19.9 19.1 13.2 12.1 170.8 -21.3
--
**“These assignments may be interchanged.
Table 2. Selected ‘H NMR spectral data for compounds 4-108 H 3 17 18 19 20
4
5
6
7
8
9
10
5.25 0.87 1.71 1.08 0.87
5.29 1.07 1.78 1.07 0.88
5.78 0.84 1.94 1.42 0.51
5.77 0.88 1.94 1.42 0.51
5.78 0.95 1.94 1.42 0.51
5.68 0.88 1.86 1.21 0.89
5.67 0.88 1.86 1.10 0.80
*Resonances are singlets or broad singlets 18, d, J= 1.0 Hz) and 9 (C-18, d. J= 1.0 Hz),
except
for 4 (C-
Hence 5 must possess the z-configuration at C-7 and 4 the p-configuration. These stereochemical assignments were confirmed when a NOE enhancement in the H-7 resonance was seen for 4, but not 5, upon irradiation of the C18 methyl, which lies under ring B. As a final proof of the basic structure, 4, yielded 1 after oxidation of the diolblocked derivative and removal of the blocking group. As a result of the HMBC experiment on 4 and a reexamination of the ‘H NMR spectrum of 1 at 500 MHz, the following reassignments of resonances given previously for 1 [l] were made: C-2 (634.8), C-6 (650.4), C-8 (652.6), C-10 (653.0), C-14 (627.3). H-2 (al.35 and 1.71, 2H, m), H-6 (62.16 and 2.70, 2H, d, J= 14.8 Hz), H-8 (62.41, lH,dd, 5=12, 3.9 Hz), H-lO(S1.71, lH,m), H-14 (61.38 and 1.42, 2H, dd, J= 19.4, 3.2 Hz). 2,7_Dioxofagonene (6) CIoH,,O,, when compared to I, lacked one CH, group and had an additional carbonyl (6200.5; UV absorption at 238 nm; IR absorptions at
1657 and 1713 cm-‘). The “%ZNMR resonances for C-3 and C-4 were at 6 128.3 and 170 as compared to b 123.1 and 138.9 for 1. These data indicated the presence of an a&unsaturated carbonyl system and further NMR analysis in comparison to 1 established structure 6. 16-O-Acetyl-2,7_dioxofagonene (7) C22H3205, and l&16-di-0-acetyl-2,7-dioxofagonene (8) C24H3406, were characterized as the mono- and diacetyl derivatives of 6 from their mass, UV, IR. and NMR spectra which closely corresponded to those for 6 with the expected exceptions resulting from the acetylated side chain. Thus, the acetyl group for 7 was placed on OH-16 since the C-16 proton resonances for 7 were shifted downfield from those in 1 and 6 and were virtually identical with those observed for 2. For the diacetate 8, the H-l 5 resonance was at 63.98 as compared to 63.41 for 7. In the mass spectra, 6,7 and 8 all gave relatively intense m/z 273 ions, which resulted from the side chain cleavage and hence show that all had the same tricyclic component. Hydrolysis of 7 and 8 with 0.1 N aq. NaOH resulted in formation of 6, while acetylation of 6 and 7 gave 8, thus confirming the structure assignments. 7-fl-0-Acetyl-2-oxo-S-epi-fagonene (9) C,,H 34O5, had IR, UV and 13C NMR spectra which showed it to have an a&unsaturated carbonyl system in ring A as did 6. The spectral resonances for the remainder of the molecule were similar to those for 4, with important exceptions. An acetoxy group, lacking in 4, was present and this was assigned to C-7 from the change in the H-7 resonance from 63.15 in 4 to 64.86 in 9. In addition, the ‘-‘C resonance for C-19 was at 6 19.9 rather than in the 630 region as it is in all the cis-ent-fagonene structures. Such a resonance is diagnostic for a C-5 methyl in an A/B transfused structure [2, 33 and suggested structure 9. The structure was confirmed by the following NOE experiments. Irradiation of H-7 at 64.86 resulted in an enhancement of resonances for the C-19 and C-20 methyls at iil.21 and 0.89, respectively. Similarly, irradiation of the C-19 methyl resonance at 61.21 resulted in enhancements of resonances for H-7 (64.86), the C-20 methyl (60.89) and the C-18 methyl (6 1.86). 2-Oxo-5-epi-fagonene (10) C,,H,,O,, was isomeric with 1. The NMR spectra and the UV spectrum were those expected for an a&unsaturated carbonyl system and hence the carbonyl must be at C-2 rather than at C-7 as in 1. The remaining resonances were those of a fagonene structure, expect for C-19 (b 19.1) which, as in 9, was diagnostic for a C-5 sl-configuration. This resulted in assignment of structure 10 to the isolate. EXPERIMENTAL
Mps: uncorr. IR spectra were recorded in KBr disks. NMR spectra were in CDCI, (‘H 300 MHz; ref. 67.24 and 13C 75 MHz; ref. 677.0). ‘H resonances not described in Table 2 or below were parts of unresolved multiplets. The HMBC spectrum (500 MHz) was measured (CL Harris, Merck Sharp & Dohme, Rahway, New Jersey) with J=7.3 Hz. Mass spectra were obtained at 70 eV, with NH, in the CI mode.