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Pennsylvanine and pennsylvanamine, two new dimeric isoquinoline alkaloids
TetrahedronLetters No. 26, pp 2291 - 2294, 1974.
PRNNSYLVANINH AND PENNSVLVANAMINE,
Perwon
RWWJ.
Printed in Crest Britain.
TWO NEW DIMERIC ISCQUINOLINE ALKALOIDS1
hi. Shamma and J.L. Moniot, Department
of
Chemistry,
The
Pennsylvania State University,
University Park, Pennsylvania
16802
(Received in USA 21 March 1974; received in OK for publication20 May 1974)
The -in viva tumor inhibitory activity of thalicarplne prompts us to report the characterization and pennsylvanamine
of two new potential tumor inhibitors pennsylvanlne
is endemic throughout Pennsylvania.
(11, C,,,H1sN208, [aI; +131° (c = 0.7, MeOH), a major alkaloid of the plant, was
obtained as crystals mp 112-113O (ether).
The uv spectrum, Aiz
4.18 and 4.051, was reminiscent of that for thalicarpine and a bathochromic
(1)
(21, phenolic analogs of 3, obtained from the giant meadow rue, Thalictrum
polygamum Muhl. (Ranunculaceae),which Pennsylvanine
(3)2,3 now chosen for clinical trial,
shift to imax MeCH-CH
284, 304 and 320sh nm (log a 4.26,
(3) and showed both a hyperchromic effect
284, 311 and 32Osh nm (log B 4.32, 4.29 and 4.151.
The major
fragments in the mass spectrum of l_, m/e 682 CM+), 476 (M+ - xl, 340 (M+ - yl, 324 (M+ - 21, and 206 (x+, base), were identical with those in the spectrum of the related monophenolic benzylisoqulnoline pine (3).
dimer thalidoxlne
(4).
4
Diazomethane 0-methylation
Assignment of the phenolic function of pennsylvanlne
of 1 afforded (+)-thalicar-
(1) to C-5" in the benzyl ring was
confirmed by analysis of the nmr data for pennsylvanine acetate (51, Cd2H18N209, obtained by treatment of 1 with AcZO in pyridine.
aporphine-
mp
137-13~3~ (ether),
Whereas acetylation of the C-4" phenol in thali-
doxine (4) gave rise to a 0.1-0.2 ppm upfield shift of the C-8 aporphine aromatic proton due to shielding by the.acetate carbonyl,
5
no such upfield shift was observable in the spectrum of 5.
The second alkaloid, pennsylvanamlne
(21, CSeH.,INZOg, [crl: = +119O (c = 0.94, MeOH), was
obtained as fine needles, mp 128-129° (acetone-ether), trum, A:: bathochromic
or prisms,
mp
107-lOSo (ether).
The uv spec-
276sh, 284, 297sh and 312sh nm (log C 4.07, 4.17, 4.11 and 4.061, showed a pronounced shift to "Ez"-
C-l phenolic aporphine.6
292, 315 and 352 nm (log c 4.10, 3.98 and 3.821, suggestive of a
The mass spectrum of pennsylvanamine
(21, m/e 668 CM+), 462 (M+ - xl, 326
(M+ - ~1, 325 (M+ - y - H), 309 CM+ - z - H) and 206 (x+, base), indicated an aporphine-benzylisoquinoline dimer with s phenolic hydroxyl on the benzyl ring and another phenolic function on the aporphine.
The aporphine phenol must be at C-l because of the absence of a high field methoxyl
signal near 63.70 in the nmr spectrum.
4
2291
3.67 3.71 3.70 -
3.54 3.58 3.58 -
2.61
2.50
2.57
2.46
Thalmelatine acetate (11)
-
2.52
,!.-'
2.49
-
2.48
2.42 3.71
3.72
-
3.59
2.53
2.52
2.51
Thalictrogamine 2.49 diacetate (13) PennsylvanaZne((2) 2.47
2.50
-
3.60
2.52
(12) 2.49
Pennsylvanamine diacetate (6) Thalmelatin& (10)
-
-
2.53
2.50
Pennsylvanine acetate (5) Thalictrc&W
Thalidoxine acetate (9, Pennsylvanine (9
3.70
3.57
2.48
2.47
3.80
3.79
3.70
3.80
3.80
3.83
3.71
3.79
-
-
3.78
3.78
C-4"
3.76
3.79
3.83
3.83
3.76
3.83
3.83
3.82
3.84
3.78
3.82
3.82
C-6'
3.90
3.88
3.86
3.92
3.84
3.92
3.88
3.90
3.86
3.88
3.84
3.88
C-2
6.58
6.55
6.57
6.55
6.53
6.58
6.57
6.56
6.54
6.50
6.53
6.55
6.59 6.60 6.57 6.60 6.62 6.63 6.58 6.62 6.58 6.68 6.60 6.61
6.55 6.55 6.50 6.54 6.59 6.61 6.58 6.62 6.58 6.61 6.60 6.61
6.65
6.68
6.90
6.80
6.66
6.77
6.87
6.76
6.87
6.77
6.63
6.67
_ -
_ -
2.33 2.28
-
_ 2.34
2.29
_
-
_ -
2.25
-
-
2.34
RZ=CRS
11. RISkIS. R11=Ck13C0
10. RI=CRS, RZ=H
8. R,=CR$O,
2.19
-
-
2.19
-
-
-
-
-
-
-
-
7. R,=H, R2=CIQ
8.19
8.16
7.63
8.20
7.60
8.18
8.20
8.18
8.14
8.15
7.60
8.18
c-7'
C-l -
13. RI=RZ=CRJCO
6.54
6.52
6.53
6.55
6.51
6.53
6.51
6.52
6.40
6.50
6.50
6.55
c-11
12. R,=RRZzII
6.45
6.43
6.25
6.26
6.43
6.40
6.23
6.22
6.13
6.23
6.18
6.20
C-8'
Acetate Methyl
(6)
9. RI=R3=CRS, RZ=CR3C0
3.92
3.95
3.88
3.94
3.91
3.96
3.91
3.92
3.90
3.90
3.92
3.92
c-10
Aromatic protons
6. RI=R3=CRSOD, R2=CRS
5. R,=R2=CRlr RJ=CRSCO
3.80
3.79
-
-
3.80
3.79
-
-
3.70
3.75
3.78
-
3.58
2.47
2.45
3.78
-
3.58
Thalictropine acetate (4) Thalidoxine (4)
2.50
2.47
Thalictropine (1)
C-5"
C-7' C-l --_-----
Methoxyl Groups
NMR Spectral Data for Phenolic Analogs of Thalicarpine and their Acetate Derivatives
N-Methyls
Table 1.
.3 %
w \o Iu
Treatment of pennsylsanamlne mp 147-14S" (ether).
(2) with Ac20 in pyrldine afforded the diacetate 5, CISH,aNZOIO,
The signal for the aporphine C-11 proton was now shifted upfield to 67.63,
consonant with the presence of a C-l acetate function.
7
No other aromatic proton had undergone an
upfield shift so that the phenolic function on the beneyl ring of pennsylvanamine situated at C-5". (+)-thalicarpine
Diazomethane O-methylation (21 and (+)-thalictroplne
(2) must be
of 2 yielded an easily separable 1:l mixture of
(z).7
The structural assignment for any new phenollc analog of (+)-thallcarpine can now be derived from the combination of uv, nmr and mass spectral data for the alkaloid and its acetate.
Mass
spectroscopy will readily detect the phenol(s) on any of the three large moieties of the alkaloid: aporphlne, isoqulnoline and benxyl ring.
The relevant nmr chemical shifts have been summarized In
Table 1, and some of the more useful generalizations
for specifically locating the phenollc
function(s) have been listed In Table 2. An interesting recent development has been the Isolation in this Laboratory of two other dimerlc alkaloids, pennsylpavlne
(14) and pennsylpavollne
(=I.
These are the first aporphlne-
pavlne dlmers known, and it Is tempting to speculate that in the plant pennsylvanlne pennsylvanamlne
(2) may act as precursors to 14 and 2,
Table 2. Phenol at C-l
a, 4
c-2
:: 4 c-10
respectively.
(1) and
10
Diagnostic Spectral Features for Phenollc Analogs of Thalicarplne
Observed Data for Parent Phenol
Observed Data for Acetate Derivative
C-l methoxyl signal at 83.71 absent. Strong bathochromlc 8 shift In uv spectrum with base.
Aporphine H-11 signal shifted upfield to w 67.60. Acetate methyl signal at w 62.34.
A single methoxyl signal will appear below 63.85 assignable to c-10.9
C-l methoxyl signal originally near 63.71 will be shifted to slightly higher field. No slgnlflcant shift of aporphlne H-11 signal.9
A single methoxyl signal will appear below 63.85 assignable to c-2.9
Aporphlne H-11 signal will be shifted downfield to n 88.30. Acetate methyl signal near 52.20.D
Hlghfield C-7' methoxyl signal at = 63.58. H-8' signal at -66.23. Hlghfleld C-7' methoxyl signal at ~63.58 absent, H-8' signal at -66.4 rather than 66.2.
H-S' signal near 66.4 essentially unchanged. Acetate methyl signal at 62.19.
Aromatic proton at .W 66.80. H-8' signal near 66.23. No distinct bathochromlc shift In uv spectrum with base.
Lowest field aromatic proton at w 66.90. Aporphlne H-8 Signal at w 66.23 unchanged. signal shifted upfield to CII66.40. One methoxyl signal shifted upfleld to cu 63.70.
Aromatic proton at M 66.80. H-8' signal near 66.23. Bathochromlc shift in uv spectrum with base.
Lowest field aromatic proton at w 66.90. No upfleld shift of aromatic proton signals. One methoxyl signal shifted upfleld tow63.76.
2294
NO. 26
14. R=c!IQ 15. R=H
References
1.
This work was supported by grant HL-12971 from the National Institutes of Health. spectra are In CDClg at 60 MHz. mass spectroscopy.
FOT
Nmr.
All compounds were analyzed by means of high resolution
a recent review on the aporphine-benzylisoquinoline
dimers see P.
Isoquinoline Alkaloids", Academic Press, New York (19721, p. 232. Shamma, "The 2.
S.M. Kupchan and A.I. Liepa, -Chem. Commun., 599 (1971); and J.L. Hartwell and B.J. Abbott, Advances in Pharmacology and Chemotherapy, --
3.
Vol. 7, Academic Press, New York (1969), P. 117.
The known alkaloids homoaromoline, 0-methylrepandine, and thaliglucinone
thalidasine, thalmelatine, hernandaline
have also been isolated from T. polygamum in this Laboratory.
4.
M. Shamma, S.S. Salgar and J.L. Moniot, Tetrahedron LeLe., 1859 (1973).
5.
L.M. Jackman and S. Sternhell, "Applications -of Nuclear Resonance Spectroscopy -in Organic Chemistry", 2nd ed., Pergamon Press, Oxford (19691, p. 68.
6.
M. Shsmma, S.Y. Yao, B.R. Pai and R. Charubala, 2. Org. Qlem., 36, 3253 (1971). -
7.
M. Shamma and J.L. Moniot, Tetrahedron
8.
This spectral pattern is also observed for the related dimer fetidine: K. Wskisaka, Tetrahedron e.,
9.
E.,
775 (1973). M.P. Cava and
2309 (1972).
The expected data for the C-10 phenol was extrapolated from that observed for monomeric aporphines and for the pakistanine series of aporphine-benzylisoquinoline
alkaloids,
M. Shamma, J.L. Moniot, S.Y. Yao, G.A. Miana and M. Ikrsm, J. Amer. Chem. %., -. -
95, 5742
(1973). 10. The chemistry of -14 and 5
will be described in a separate paper.
Conclusive proof
regarding the biogenesis of 14 and 15 can come only from -in viva experiments using labeled nrecursors.
PRNNSYLVANINH AND PENNSVLVANAMINE,
Perwon
RWWJ.
Printed in Crest Britain.
TWO NEW DIMERIC ISCQUINOLINE ALKALOIDS1
hi. Shamma and J.L. Moniot, Department
of
Chemistry,
The
Pennsylvania State University,
University Park, Pennsylvania
16802
(Received in USA 21 March 1974; received in OK for publication20 May 1974)
The -in viva tumor inhibitory activity of thalicarplne prompts us to report the characterization and pennsylvanamine
of two new potential tumor inhibitors pennsylvanlne
is endemic throughout Pennsylvania.
(11, C,,,H1sN208, [aI; +131° (c = 0.7, MeOH), a major alkaloid of the plant, was
obtained as crystals mp 112-113O (ether).
The uv spectrum, Aiz
4.18 and 4.051, was reminiscent of that for thalicarpine and a bathochromic
(1)
(21, phenolic analogs of 3, obtained from the giant meadow rue, Thalictrum
polygamum Muhl. (Ranunculaceae),which Pennsylvanine
(3)2,3 now chosen for clinical trial,
shift to imax MeCH-CH
284, 304 and 320sh nm (log a 4.26,
(3) and showed both a hyperchromic effect
284, 311 and 32Osh nm (log B 4.32, 4.29 and 4.151.
The major
fragments in the mass spectrum of l_, m/e 682 CM+), 476 (M+ - xl, 340 (M+ - yl, 324 (M+ - 21, and 206 (x+, base), were identical with those in the spectrum of the related monophenolic benzylisoqulnoline pine (3).
dimer thalidoxlne
(4).
4
Diazomethane 0-methylation
Assignment of the phenolic function of pennsylvanlne
of 1 afforded (+)-thalicar-
(1) to C-5" in the benzyl ring was
confirmed by analysis of the nmr data for pennsylvanine acetate (51, Cd2H18N209, obtained by treatment of 1 with AcZO in pyridine.
aporphine-
mp
137-13~3~ (ether),
Whereas acetylation of the C-4" phenol in thali-
doxine (4) gave rise to a 0.1-0.2 ppm upfield shift of the C-8 aporphine aromatic proton due to shielding by the.acetate carbonyl,
5
no such upfield shift was observable in the spectrum of 5.
The second alkaloid, pennsylvanamlne
(21, CSeH.,INZOg, [crl: = +119O (c = 0.94, MeOH), was
obtained as fine needles, mp 128-129° (acetone-ether), trum, A:: bathochromic
or prisms,
mp
107-lOSo (ether).
The uv spec-
276sh, 284, 297sh and 312sh nm (log C 4.07, 4.17, 4.11 and 4.061, showed a pronounced shift to "Ez"-
C-l phenolic aporphine.6
292, 315 and 352 nm (log c 4.10, 3.98 and 3.821, suggestive of a
The mass spectrum of pennsylvanamine
(21, m/e 668 CM+), 462 (M+ - xl, 326
(M+ - ~1, 325 (M+ - y - H), 309 CM+ - z - H) and 206 (x+, base), indicated an aporphine-benzylisoquinoline dimer with s phenolic hydroxyl on the benzyl ring and another phenolic function on the aporphine.
The aporphine phenol must be at C-l because of the absence of a high field methoxyl
signal near 63.70 in the nmr spectrum.
4
2291
3.67 3.71 3.70 -
3.54 3.58 3.58 -
2.61
2.50
2.57
2.46
Thalmelatine acetate (11)
-
2.52
,!.-'
2.49
-
2.48
2.42 3.71
3.72
-
3.59
2.53
2.52
2.51
Thalictrogamine 2.49 diacetate (13) PennsylvanaZne((2) 2.47
2.50
-
3.60
2.52
(12) 2.49
Pennsylvanamine diacetate (6) Thalmelatin& (10)
-
-
2.53
2.50
Pennsylvanine acetate (5) Thalictrc&W
Thalidoxine acetate (9, Pennsylvanine (9
3.70
3.57
2.48
2.47
3.80
3.79
3.70
3.80
3.80
3.83
3.71
3.79
-
-
3.78
3.78
C-4"
3.76
3.79
3.83
3.83
3.76
3.83
3.83
3.82
3.84
3.78
3.82
3.82
C-6'
3.90
3.88
3.86
3.92
3.84
3.92
3.88
3.90
3.86
3.88
3.84
3.88
C-2
6.58
6.55
6.57
6.55
6.53
6.58
6.57
6.56
6.54
6.50
6.53
6.55
6.59 6.60 6.57 6.60 6.62 6.63 6.58 6.62 6.58 6.68 6.60 6.61
6.55 6.55 6.50 6.54 6.59 6.61 6.58 6.62 6.58 6.61 6.60 6.61
6.65
6.68
6.90
6.80
6.66
6.77
6.87
6.76
6.87
6.77
6.63
6.67
_ -
_ -
2.33 2.28
-
_ 2.34
2.29
_
-
_ -
2.25
-
-
2.34
RZ=CRS
11. RISkIS. R11=Ck13C0
10. RI=CRS, RZ=H
8. R,=CR$O,
2.19
-
-
2.19
-
-
-
-
-
-
-
-
7. R,=H, R2=CIQ
8.19
8.16
7.63
8.20
7.60
8.18
8.20
8.18
8.14
8.15
7.60
8.18
c-7'
C-l -
13. RI=RZ=CRJCO
6.54
6.52
6.53
6.55
6.51
6.53
6.51
6.52
6.40
6.50
6.50
6.55
c-11
12. R,=RRZzII
6.45
6.43
6.25
6.26
6.43
6.40
6.23
6.22
6.13
6.23
6.18
6.20
C-8'
Acetate Methyl
(6)
9. RI=R3=CRS, RZ=CR3C0
3.92
3.95
3.88
3.94
3.91
3.96
3.91
3.92
3.90
3.90
3.92
3.92
c-10
Aromatic protons
6. RI=R3=CRSOD, R2=CRS
5. R,=R2=CRlr RJ=CRSCO
3.80
3.79
-
-
3.80
3.79
-
-
3.70
3.75
3.78
-
3.58
2.47
2.45
3.78
-
3.58
Thalictropine acetate (4) Thalidoxine (4)
2.50
2.47
Thalictropine (1)
C-5"
C-7' C-l --_-----
Methoxyl Groups
NMR Spectral Data for Phenolic Analogs of Thalicarpine and their Acetate Derivatives
N-Methyls
Table 1.
.3 %
w \o Iu
Treatment of pennsylsanamlne mp 147-14S" (ether).
(2) with Ac20 in pyrldine afforded the diacetate 5, CISH,aNZOIO,
The signal for the aporphine C-11 proton was now shifted upfield to 67.63,
consonant with the presence of a C-l acetate function.
7
No other aromatic proton had undergone an
upfield shift so that the phenolic function on the beneyl ring of pennsylvanamine situated at C-5". (+)-thalicarpine
Diazomethane O-methylation (21 and (+)-thalictroplne
(2) must be
of 2 yielded an easily separable 1:l mixture of
(z).7
The structural assignment for any new phenollc analog of (+)-thallcarpine can now be derived from the combination of uv, nmr and mass spectral data for the alkaloid and its acetate.
Mass
spectroscopy will readily detect the phenol(s) on any of the three large moieties of the alkaloid: aporphlne, isoqulnoline and benxyl ring.
The relevant nmr chemical shifts have been summarized In
Table 1, and some of the more useful generalizations
for specifically locating the phenollc
function(s) have been listed In Table 2. An interesting recent development has been the Isolation in this Laboratory of two other dimerlc alkaloids, pennsylpavlne
(14) and pennsylpavollne
(=I.
These are the first aporphlne-
pavlne dlmers known, and it Is tempting to speculate that in the plant pennsylvanlne pennsylvanamlne
(2) may act as precursors to 14 and 2,
Table 2. Phenol at C-l
a, 4
c-2
:: 4 c-10
respectively.
(1) and
10
Diagnostic Spectral Features for Phenollc Analogs of Thalicarplne
Observed Data for Parent Phenol
Observed Data for Acetate Derivative
C-l methoxyl signal at 83.71 absent. Strong bathochromlc 8 shift In uv spectrum with base.
Aporphine H-11 signal shifted upfield to w 67.60. Acetate methyl signal at w 62.34.
A single methoxyl signal will appear below 63.85 assignable to c-10.9
C-l methoxyl signal originally near 63.71 will be shifted to slightly higher field. No slgnlflcant shift of aporphlne H-11 signal.9
A single methoxyl signal will appear below 63.85 assignable to c-2.9
Aporphlne H-11 signal will be shifted downfield to n 88.30. Acetate methyl signal near 52.20.D
Hlghfield C-7' methoxyl signal at = 63.58. H-8' signal at -66.23. Hlghfleld C-7' methoxyl signal at ~63.58 absent, H-8' signal at -66.4 rather than 66.2.
H-S' signal near 66.4 essentially unchanged. Acetate methyl signal at 62.19.
Aromatic proton at .W 66.80. H-8' signal near 66.23. No distinct bathochromlc shift In uv spectrum with base.
Lowest field aromatic proton at w 66.90. Aporphlne H-8 Signal at w 66.23 unchanged. signal shifted upfield to CII66.40. One methoxyl signal shifted upfleld to cu 63.70.
Aromatic proton at M 66.80. H-8' signal near 66.23. Bathochromlc shift in uv spectrum with base.
Lowest field aromatic proton at w 66.90. No upfleld shift of aromatic proton signals. One methoxyl signal shifted upfleld tow63.76.
2294
NO. 26
14. R=c!IQ 15. R=H
References
1.
This work was supported by grant HL-12971 from the National Institutes of Health. spectra are In CDClg at 60 MHz. mass spectroscopy.
FOT
Nmr.
All compounds were analyzed by means of high resolution
a recent review on the aporphine-benzylisoquinoline
dimers see P.
Isoquinoline Alkaloids", Academic Press, New York (19721, p. 232. Shamma, "The 2.
S.M. Kupchan and A.I. Liepa, -Chem. Commun., 599 (1971); and J.L. Hartwell and B.J. Abbott, Advances in Pharmacology and Chemotherapy, --
3.
Vol. 7, Academic Press, New York (1969), P. 117.
The known alkaloids homoaromoline, 0-methylrepandine, and thaliglucinone
thalidasine, thalmelatine, hernandaline
have also been isolated from T. polygamum in this Laboratory.
4.
M. Shamma, S.S. Salgar and J.L. Moniot, Tetrahedron LeLe., 1859 (1973).
5.
L.M. Jackman and S. Sternhell, "Applications -of Nuclear Resonance Spectroscopy -in Organic Chemistry", 2nd ed., Pergamon Press, Oxford (19691, p. 68.
6.
M. Shsmma, S.Y. Yao, B.R. Pai and R. Charubala, 2. Org. Qlem., 36, 3253 (1971). -
7.
M. Shamma and J.L. Moniot, Tetrahedron
8.
This spectral pattern is also observed for the related dimer fetidine: K. Wskisaka, Tetrahedron e.,
9.
E.,
775 (1973). M.P. Cava and
2309 (1972).
The expected data for the C-10 phenol was extrapolated from that observed for monomeric aporphines and for the pakistanine series of aporphine-benzylisoquinoline
alkaloids,
M. Shamma, J.L. Moniot, S.Y. Yao, G.A. Miana and M. Ikrsm, J. Amer. Chem. %., -. -
95, 5742
(1973). 10. The chemistry of -14 and 5
will be described in a separate paper.
Conclusive proof
regarding the biogenesis of 14 and 15 can come only from -in viva experiments using labeled nrecursors.