T H E PROAPORPHINE ALKALOIDS K. L. STUART Department of Chemistry, University of the West Indies, Kingston, Jamaica A N D M .P. CAVA
Department of Chemistry, Wayne State University, Detroit, Michigan @806 Received December 16, 1967 CONTENTS
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Chemistry and Stereochemistry of Proaporphinea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Chemistry of Reduced Proaporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Possible New Alkaloid Types Related to the Proaporphines.. . . . . . . . . . . . . . . . . . . . . . . . . . v. Spectroscopy. ......................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................................... VI. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . ........................................ VII. Pharmacology. . . . . . . . . . . . . . . . . . . . . . . . ........................................ VIII. Addendum, . . . . . . . . . . . . . . . . . . . . . . . . . . IX. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
321 322 327 330 330 335 337 337 338
I. INTRODUCTION In 1957, Barton and Cohen published a now classical analysis of the biogenetic aspects of phenol oxidation in the formation of a wide variety of natural product structures (2). I n considering logical mechanistic pathways for the formation of aporphine alkaloids from benzyltetrahydroisoquinolines, these anthors noted that aporphines having certain substitution patterns (e.g., I or 11) could be formed in the plant by direct oxidative coupling. On the other hand, they realized that aporphines having other substitution patterns (e.g., I11 or IV) could not be formed directly in this way, but that their formation could be rationalized within the general biogenetic scheme if dienones such as V were assumed to be intermediates in the process. Following known laboratory reactions, structure V should undergo an acid-catalyzed dienone-phenol rearrangement to I11: after reduction to the corresponding dienol VI, the molecule should undergo an acidcatalyzed dienol-phenol rearrangement to IV.
HO HO
v
VI
1““
Po
HO “QR
HO “
G
R
J y
HO
III
Iv
The hypothesis of Barton and Cohen received striking support in 1963 with the assignment of structures related to V to some naturally occurring alkaloids (15, 30). Dienone bases having the skeleton of V are now regarded as members of a new class of alkaloids designated as the proaporphines (19,52). At the time of the writing of this review, seven proaporphine alkaloids have been reported from natural sources, as well as eight alkaloids having a partially reduced proaporphine system. The numbering system indicated below will be used in this discussion. The absolute configuration of the proaporphines can correspond to either of the structures shown below, due to the asymmetry at C-6a.
I
OH
Jd
t)H I1
321
E(. L.
322
S T U A R T AND
In addition, the spirodienone ring is not symmetrical with respect to the rest of the molecule; when neces-
11.P.
CAV.4
I later in this review. Reduced proaporphine bases are discussed in a separate section. A.
sary, this asymmetry a t C-7a will be indicated by assigning the lower numbers (C-8 and (2-9) to the olefinic carbons which project from the plane of the paper when the structure is written so that the planar benzene ring is a t the upper left-hand corner.
O
U s 8
0
an L-proaporphine ((S) con@xation at G 6 a )
W8 9
a D-proaporphine ((R) configuration a t C-6a)
11. CHEMISTRY AND STEREOCHEMISTRY OF
PROAPORPHINES
I n this section, the reactions, stereochemistry, and synthesis of the individual proaporphine alkaloids will be considered. Trivial derivatives (e.g., salts, oximes, etc.) will not be included; these are referred to in Table
PRONUCIFERINE
Pronuciferine (1) undergoes the dienone-phenol rearrangement when heated with aqueous sulfuric acid to give (-)-1,2-dimethoxy-l0-hydroxyaporphine (2) (17). Reduction of pronuciferine with either lithium aluminum hydride or sodium borohydride affords a mixture of dienols 3 and 4, which undergo the dienolbenzene rearrangement on treatment with mineral acid to give (-)-nuciferine (5) (15, 17). The dienol mixture can be separated chromatographically into an oily isomer (3) and a crystalline isomer (4). The crystalline isomer is assigned structure 4 since it is reduced catalytically to the cyclohexanol derivative 6 , which is different from the hexahydropronuciferine (7) obtained by the direct catalytic reduction of pronuciferine using platinum oxide in acetic acid. The stereochemistry of alcohol 7, which is formed rapidly and almost stereospecifically, follows from the reasonable assumption that the carbonyl group of pronuciferine is reduced catalytically from the much less hindered lower side (17). Sodium in liquid ammonia effects a reductive cleavage of pronuciferine to give D-( -)-armepavine ( 8 ) . Since the absolute configuration of armepavine has been determined unambiguously (63) , this transformation establishes conclusively the D (or R) configura-
rl’HE ~’ROXPOIU’I1ISE
tion for natural (+)-pronuciferine. Given the absolute configuration of pronuciferine, it follows that its levorotatory aporphine transformation products 2 and 5 must also have the D (or R ) configiirntioii as nritteii (19,20).1 .I total synthesis of (*)-pronuciferine has been rcported in which the two lower rings are constructed one at a time using classical methods. Thus, homoveratrylamine (9) was converted (via the BischlerNapieralski synthesis) to the previously known ester 10. S-3lethylation of 10, followed by hydrolysis, yielded acid 11, which was cyclized by polyphosphoric acid to ketone 12. The reaction of 12 with methyl chloroacetate and sodium amide afforded the glycidic estrr 13. which iyas hydrolyzed and decarboxylated to give the aldehyde 14. The reaction of the latter aldehyde with methyl ethynyl ketone in the presence of a strong base (sodium hydride or pot:twiuni t-butoxidc) yiclded (k)-pronuciferine (14).
ALKALOIDS
323
give (-)-N-acetylriorarInep3virie (18) (19, 20). Natursl,lly occurring (+)-stepliartrine has the D (or R ) configuration, since it is methylated to (+)-pronuciferine (1) by formaldehyde and formic :tcid (19, 20). The reductive methylation of stepharirie by formaldehyde :md hydrogen in the presence of palladium yields tetrahydroproiiuciferirie (19) ; reduction of the dienonc system of stepharine a1)l)arentlytakes place at least as rapidly as N-methylation (20). C.
CHOTONOSISE
Crotonosine (20) undergoes the dienone-phenol rearrangement when liented with aqueous acid to give the aporphine Lase apocrotonosine (21) (27, 29). Rearrangement in niethariolic acid yielded the 10-0-methyl derivative of 21 (21b) (27). I n this as in similar proaporphine rearrangement>the other possible isomer 2 la was not obtained. llethylation of apocrotonosine with methyl iodide arid potassium cxrbonate yields a conipound which is idciitical with 0,N-dimethyltudiiranine methiodide (22) (29). CH30 Methylation of natural (+)-crotonosiiie with forinaldehyde and formic acid yields (+)-N-methylcrotono9 sine (23) ; sodium borohydride reduction of 23 yields a CHBO dienol mixture (24) which undergoes the dienol-benzene rearrangement with acid to give ( -)-1-methoxy-2c H 3 0 q H CH30 -+ CHjOq C H d hydroxyaporphine (25), identical with a naturally ocCH, YHz I curring alkaloid from Neluinbo nucifera Gaertn (29, 31). COOCiH:, COOH The orientatioii of the methoxyl arid hydroxyl suh10 11 stituents in crotonosiiic was proven by nmr-controlled deuterium exchange experiments, which were in accord with the 1-methoxy-2-hydroxy arrangement but not with the isomeric 1-hydroxy-2-methoxy pattern. By using alkaline deuterium oxide to exchange any hydro0 CH ;5“ gens ortho and para to phenolic groups, it was shown I 12 that apocrotonosine (2 1) contains three exchangeable COOCH, aromatic hydrogelis. Similarly, diacetyltetrahydro13 crotonosine (26) shows the exchange of one aromatic hydrogen when treated similarly and then reacetylated ; compound 26 can be prepared from crotonosine by acetylation, followed by catalytic reduction of the resulting 0,K-diacetylcrotonosine (27) (29, 31). CHO 0 J-J 14 Crotoiiosine has been assigned the D (or R ) configuration by correlation, via methiodide 22, with D-( +)The niethylatioii ol syiithetic ( *)-gluzioviiie ( ~ i d e pronuciferine (1) (29). This configuration is supported infra) constitutcs a second formal synthesis of (f)- also by circular dichroism studies (58). pronu c~iferine.
cH”opNHI -
-
D. B.
STEPHAILIXE
Stcphuriiie (15) undergoes the dienone-phenol r e arrangemelit when heated with aqueous acid to give (-)-tuduranine (16) (20), and it reacts with acetic anhydride to give K-acetylstepliarine (17), which is reductively cleaved by sodium in liquid ammonia to (1) The isolntion of L-(-)-pronuciferine ( i . e . . the S isomer) waa reported recently from Papave, persicum (47a) : see Iddonilum.
cry
HOMOLINEARISISE
The riaturitlly occurring base (-)-homolinearisine i b -)-N-niethylcrotonosine (28), since it is identical in all respects except optical rotation with D-(+)-Kmethylcrotonosine (23) (29, 31). Reduction of homolinearisine with sodium borohydride affords a mixture of dienols (29) which undergo the dienol-benzene rearrangement when treated with acid to give (+)-l-methoxy-2-hydroxyaporphine (30); L-(
324
cH'oyz: ):$?
I
N-METHYLOREOLINE
This phenolic alkaloid (83) was correlated to oreoline by N-methylation of the latter compound and was also shown to yield hexahydropronuciferine on O-methylation (41).
K. L. STUART AND M. P. CAVA
330
IV. POSSIBLE NEWALKALOID TYPES RELATED TO THE
PROAPORPHINES
Cularine (84) is the best known representative of a small group of alkaloids which differ from the aporphines in that the two aromatic rings are linked via an ether bridge rather than directly. The intermediacy of 1,Cdienones of the type 85 in the biogenesis of cularine and related alkaloids seems reasonable. Recently,
CH,O HOq N C H 3 CH2
K,Fe(CNh
I
(4%)
cH30T HO
OCH3
-
cH30w H+
?$
f$
CH30
0
OCHS
0CH3 87
0
0CH3
(45%)
85
84
a biogenetically patterned synthesis of a cularine-type base (86, not a natural alkaloid) was reported in which a derivative of 85 was isolated in low yield (3%) as an intermediate (36). The synthesis is outlined below.
RO
RP
0,
CHaO H+ c
CH30
-ed
HO
OCH3 86
The recent announcement of the discovery of a new class of alkaloids, the homoaporphines (typified by multifloramine (87),was coupled with the description of the synthesis of several of these bases using as the key step the oxidative coupling of a diphenol to a compound having the homoproaporphine skeleton (88) (7). The synthesis of multifloramine (87)is outlined below; the remarkably high yield (49%) in the formation of the dienone intermediate is worthy of note. It may be predicted with reasonable certainty that new types of alkaloids derived from the 1,Cdienone systems 85 and 88 will soon be isolated from natural sources (see Addendum). V. SPECTROSCOPY The use of physical tools, namely uv, ir, nmr, and maas spectroscopy can be of great value in the identification and structural elucidation of compounds of this
88
new group of alkaloids. The discussion in this section will be confined to the spectral characteristics of the proaporphines (see Table I for data on the reduced proaporphines) . The uv spectra of these compounds are consistent with that expected from the summation curves of homoveratrylamine and 4-methyl-4-allyl-cyclohex-2,5dien-1-one, and they usually show three absorption bands: -215 mfi (log E 4.40), -230 (4.4), and -285 (3.50), the latter sometimes appearing as a split peak. Circular dichroism studies have been used in assigning the 6a configuration to these compounds (58). The ir spectra of proaporphines have been determined in KBr, Nujol, and chloroform, and, although one usually notes small band shifts in the different media, most proaporphines show characteristic cyclohexadienone absorption bands at -1665, 1622, and 1605 cm-l. In the case of substituted cyclohexadienones (e.g., orientalinone), no significant changes are noted in this region of the ir spectrum. The absorption bands (-3200 cm-l) indicating the presence of a secondary amine can be clearly seen in the appropriate compounds: in some bases (e.g., crotonosine) containing a phenolic hydroxyl group, strong intermolecular hydrogen bonding involving this group can be observed. The nmr spectra of these compounds are not only characteristic of the 1,Cdienone structural type, but they also yield information on the location of the aromatic substituents. Part of the spectrum of crotonosine 20 (in DMSO) is reproduced in Figure 1to illustrate the location and coupling of the cyclohexadienone ring pro-
THEPROAPORPHINE ALKALOIDS
331 3.42
CH3O O H % :' 0
C HOP H 303 0 2 :
H@t I
I
Hal
I H,
1
CH30 0
0
47
20
tons and also the location of the C-3 proton. The olefinic pattern is greatly simplified in the case of orientalinone (47) showing the HAproton at r 4.08 ( J A=~ 2.5 cps) as a doublet, HX also as a doublet at T 3.67 (JBX = 10 cps), and HB appearing as a quartet centered a t r 3.21, being coupled by Hx and transannularly by HA. The position of the methoxyl group or groups in the nmr gives information of their location on the aromatic ring. The shielding by the cyclohexadienone ring on a methoxyl group at C-1 causes a shift from the normal r 6.18 position (e.g., at C-2) to -7 6.42 (29). Nmr control has also been very helpful in deuterium labeling experiments used in establishing the substitution pat-
M-l
__t
0
z
p
-
3.0
.
* . I . . . . L 4.0
(7)
q$ w
6 ,
Figure 1.-Partial
nmr spectrum of crotonosine.
This method depends on the deshielding effect of an acetoxyl group on the ortho proton at C-3.
SCHEME I
: Z F - C H 3
1 . .
1 .
C
H
3
M-29
cCHBO H 3 0 p - C H 3
0
m/e 311
m/e 310
m/e 282 t
re tro-Diels-Alder
odd-electron species stabilized by elimination of CH3or OCHB m/e 268
m/e 253
J
m/e 225
tern of crotonosine and glaziovine (29). By using suitable models, a comparison of the nmr spectra of phenolic proaporphines and their O-acetyl derivatives has also been successfully used in assisting with the assignment of the aromatic substitution pattern (26).
Two major mass spectrometric studies have been made of the proaporphine alkaloids (1, 60). I n all compounds and their derivatives (except O-ethylcrotonosine) the molecular peak was the base peak (1). Scheme I succinctly summarizes the major fragmenta-
K. L. STUART AND M. P. CAVA
332
TABLE I PHYSICAL PROPERTIBJS" Compound M ecam brine (f ugspsvine) , CisHnNOa
Derivatives and mp, OC 178-179
Optical rotation, deg [a]D -94 (CHCla)S' [ a b -116
Uv,mp (log Ago:H
231 (4.5): 294 (3.70)s'
NmrC a t 60 Mc/sec
Ir, cm-1
e)
Plant source Meconopais cambrica (L)
umax 1675 4:
Vig4tfS7
1667
Papaver fugaz Poir428" P . caucasicum MarschBieb.18 P . armeniacum (L) DC:a P . trindaefolium Boiss"?9 P . petsicum Lind L.:81:9 P . polychactum Schott et Kotechy:8,'9 P . dubium L.61 P . dubium sp. albifiorum (Boise) Dostad P . oueophilumsa
v g ~ ~ 1673, ''
1650, 1t330S6
Hydrochloride, 269-270 dec Picrate, 165 Semicarbazone. 237 Oxime, >285 2,4-DNP, >285 dec Hexahydrome[.ID -38.2" cambrine, 267269 Tetrahydromecambrine, 144146's Hexahydrome[.ID -47 cambrine-A, 186 (CHaOH)46 [ . I D -4446 *Hexahydromecambrine-B, 256
Crotonosine, CnHirNOa
197 dec, >30027
+180 (CHaOH)
[al*sD
hz:n 240 sh (3.64), 290 (3.58)
226 (4.30), 235 (4.33), 282 (3.37), 290
u:::'
(3.47)Z'
Methiodide, >250 dec N,O-Diacetyl deriv. 203-2052'
Croton linearis Jacq.9'
3220, 2600, 1664, 1622, 858*'
C. discolor Wild.28
umsl Nuiol 3333, 1667
vzt' 1775, 1670, 1640, 1628, 1258
-
3.43 (Cs-H), RB'2.96 (J$$' 2.5 cps) (8 lines) (Ja'o' 10 OPE), ea' 3.80 (Jam' = 1.5 cpa) (8 lines)
T~~~~
T
~ 7.82 ~ ~ (NCOCH:), 6.42 (OCH:), 7.71 (OCOCHa), 3.07 (Cs-H), 4.80 ( C a r H ) , 88' 2.95 (J$$' = 2.5 OPS), aa' 3.75 (Jaa' 1.6
cpa)
1760, 1715, 1630
N,O-Diacetyltetrahydrocrctonosine, 10610829
uZ:c1*
N-Methyltetra[a]% +59 hydrocrotoaosine, (CHsOH)Po 225-228 de0 N-Acetylcrotonosine, 20529 N-Acetyl-0-ethyl deriv, 170-17428 (+)-N,O-Di[ e ] 2 b +2.3 methyldesoxy(CHBOH)~~ hexahydrocrotonosine CHsI, 231-235
wmsX
Nuiol
1700
uzp' 3150, 1652, 1625
[rcDcls 7.80
(NCOCHs). 6.18 (OCH;), 7.55 (OCOCHs), 3.25 (C-3), 5.1 (C-6a) 1 x 9
'
~
THEPROAPORPHINE ALKALOIDS TABLE I (Continued) Compound Glaziovine, ClaHlgNO:
Derivatives and mp, OC
Optical rotation, deg
'""~7 HO
[ a b +7
235-237 de@
Uv, m p (log 4
I r , em-' v:?:'* 1657, 161Q96
XzAE 288 (3.57) X;\2H+KOH
(CHCla)
308 (3.74)
Picrate, 199-203 Tetrahydroglaziovine, 112-116
3520, 1699
aI : : :v
NmrC at 60 Mo/sec Plant source +CDCIa 7.6 (NCHa), Ocotea glariouii Mez.26 6.15 (OCHa), Papaver caucasicum 4.0 (OH), 3.35 Marsch-Bieb.4Ob ( C r H ) , 88' 3.40 + 3.75 aa' 2.7 + 3.328 7.65 (NCHd, 6.25 (OCHa), 4.7-5.5 (OH), 3.5 (CF H) 28
Methiodide, 25125326 Methochloride hydrate, 226-229
Pronuoiferine (base $1, CioHziNOs
127-129's
+9g (CHCls)" [a]% +105.8 (EtOH)?'
230 (4.41), 282 (3.49)
[uIz5D
v:::
":?:n
1656, 1634, 16131s 1656, 161816
3.42 ( C a H), 3.9 -* 3.5 and 3.3 2.9 (dienone), 7.59 (NCHa), 6.43 (OCHa), 6.22
7.CDC13
-
(ocH~)~~
Az':
Oxime HCI, >210, de@ Oxalate, 170-172 Methiodide, 244245 dec Hydrochloride, > 190 dec Hydriodide, 225227 dec Hydrobromide, 224-227 dec Dihydropronuciferine-I, 142-144 Hexahydropronuciferine-I HCI, 253-254 HexahydropronuciferineI1 HC1, 205-208
Stepharine, CisHieNOs CH,O
+u
0
CHJPl
L-( -)-N-Methylcrotono-
sine, CisHiaNOs H0
0 '
[a]foD
4-101.1
227 (4.40), 230 (4.41),280 (3.55),285 (3.35)21
Nelumbo nucifera Gaertn.'6%1a,a Croton Einearis Jacq.27 Stephania glabra Mierslo Papauer caucasicum Mars~h-Bieb.th"~
P. triniaefolium Boissa":g P . polychaetum Schott et KorschyaaJo P. fugaz Poir" P. peraium Lind,:s
vz$'1658, 16181 1605,1486"
229 (4.40). 278 (3.42)
287 (3.37)
Y:",
3I:::"
3155 3597
225 (3.95),
280 (3.29)
179-18119
IU']26D
+143 (CHCla)
180-18302
[a]% +158'*
N-Acetyl deriv,'$ 234-235, 22022162
[aI2'D
218-220 dec
[a]i6n -116.5
" : :A
213 (4.621, 231 (4.441,284 (3.48)49
vms. 166562
(N-H) exchangeable in DzO, 6.18 and 6.39 (20CHs)e2
rCDCla 8.00
Stepkani glabra Miersl@ S.rotunda Loureiro@,62 Pericampylus formosanusel
(CHCla) -801'
um8.
1660, 163002
(CHCla)
(CHaOH)
rCDC1'7.80
(NCOCHa). 6.13 and 6.35 (20CHa)eZ
x~~~~ 228 (4.29), 282 (3.18),288
(3.18)27
~2::"~1664, 162527
rDhLS0 6.48 (OCHg), Croton
3.37 (Cs-H), 2.85 (@B'-Hs) ( J 2.5 cps), 3-76(aa'-Hs) ( J a B = Ja'p' =s 10 0ps)Z'
-
linearis Jacq.l7 Papaver caucasicum Marsch.-Bieb.40
K. L. STUART AND M. P. CAVA
334
TABLE I (Continued) Compound Orientalinone, CiaHnNO4
Derivatives and mp, OC 230-232 dec'2
Optical rotation, deg [a]% -76'2 += 10 (CHCIa)
Uv,mr (log e) h z z o a 231 (4.30),
242 (4.14), 284 (3.77) '2
NmrC a t 60 Mc/aec
Ir, em-' v g z 1610, 1640, 1667" v:ZccIa 1605, 1630, 16658
CH,O
3.46 CJ-H
Plant source Papaver orientalee P . braeteatuna Lindl'z [(+ )-Orientalinone?l'*~J'
CH,O-H~ 0 4.08 and 3.57, H A ; JAB = 2.5 cps, Hx; JBX= 10 CP'J 3.21, H B coupled t o HA and H x ; JAX = -0
Data for Reduced Proaporphines Linearisine, CnHziNOi
219-22221
HO
cn30
w
HB
HA
XzE'
228 (4.30), 282 (3.19), 288 (3.22)27
~"2~ 1664, 1608,
rCDCLa 7.58
Croton linearis Jaoq.27 (NCHa), 6.30 (OCHs), 3.58 ( C s H ) , 3.16 (4unsaturated), 3.92 (ring D) ( J A B = 10 cps)2a
1600,1500,865, 685
"H Hydrochloride,
