J . Org. Chem., Vol. 43, No. 21,1978 4183
8- and 13-Metnhylberbines
Stereospecific Cyclizations of Iminium Salts from a-Amino Acid Decarbonylation. Synthesis of 8- and 13-Methylberbines Richard T. Dean a n d Henry Rapoport* Department of Chemistry, University of California, B e r k e k v , California 94720 Received M a y 16,1978
Berbines containing methyl substituents at C-8 and C-13 have been synthesized by stereospecific cyclizations of iminium salts generated by a-amino acid decarbonylation. (8S,13aR)-(+)-8-Methyl-2,3,lO,ll-tetramethoxyberbine [( +)-0-methylcorytenchirine (5)] was synthesized starting from dihydroxyphenyl-L-alanine(7) via a previously described stereoselective introduction of the 1-methyl substituent to give (lS,3S)-(-)-1,2,3,4-tetrahydro-6,7dihydroxy-1-methyl-3-isoquinolinecarboxylicacid (8). This was efficiently converted to ethyl (lS,3S)-(-)-1,2,3,4tetrahydro-~,7-dimethoxy-l-methyl-3-isoquinolinecarboxylate (10) by esterification, N-formylation, methylation of the phenolic hydroxyls, and selective deformylation. Alkylation, hydrolysis, iminium salt formation, and cyclization then proceeded in high yield stereospecifically to give (+)-0-methylcorytenchirine ( 5 ) . P-Methyl(3,4-dimethoxypheny1)alanine was synthesized with the methyl substituent enantiomerically pure by resolving 3-(3,4-dimethoxypheny1)butyric acid and then aminating via the malonate derivative 31 using chloramine. Hydrolysis and decarboxylation of the optically active aminomalonate proceeded with little stereoselectivity. The resulting pmethyl(3,4-dimethoxyphenyl)alanine (19) was then converted to 2-[2-(3,4-dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-4-methyl-3-isoquinolinecarboxylic acid (23), decarbonylated to the iminium salt 1, and cy(2). Disproportionation clized stereospecifically to give racemic trans- 13-methyl-2,3,10-ll-tetramethoxyberbine was observed as a side reaction, and modified conditions are considered which decrease this disproportionation of the intermediate dihydroisoquinoline. T h e decarbonylation of a-tertiary amino acids has been demonstrated t o be a n efficient method for regiospecifically generating iminium sa1ts.l T h a t t h e starting material, a n a amino acid, also may be asymmetric suggests two additional potential advantages. Although t h e a-carbon asymmetry is lost on iminium salt generation, the chirality of the amino acid may be used t o induce asymmetry in earlier reactions introducing additional substituents. Secondly, enantiomerically pure products may be possible by prior resolution of t h e amino acid or amino acid precursors. T o address these questions, we chose to investigate the synthesis of 8- and 13-methylberbines, applying t h e general method for synthesis of berbines d e scribed in our earlier work.2 T h e synthesis of both classes of compounds presents a stereochemical question in the outcome of t h e cyclization s t e p since diastereomers are possible (Scheme I). 8-Methylberbines. Obligatory to the synthesis of berbines by the general method we have developed is a n intermediate 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid. A substituent at C-8 of t h e subsequently formed berbine requires a corresponding C-1 substituent in t h e tetrahydroisoquinoline. Such a compound has been described3 in t h e asymmetric synthesis of (lS,3S)-(-)-l,2,3,4-tetrahydro-6,7-dihydroxy1-methyl-3-isoquinolinecarboxylic acid (8) from dihydroxyphenyl-L-alanine (7)(Scheme 11).This reaction allows for the preparation of a n 8-methylberbine enantiomerically pure a t the 8 position. However, the phenolic secondary amine 8 must be N-alkylated a n d t h e phenolic hydroxyls converted t o methyl ethers t o realize t h e a-tertiary amino acid necessary for iminium salt generation. T h e simplest route t o t h e required dimethoxy tertiary amine would be t o selectively methylate t h e phenols and then N-alkylate. However, treatment of ethyl ester 9 with diazomethane gave mostly t h e permethylated compound 11 with a small amount of t h e selectively alkylated compound Applying a method which had previously5 been selective for the methylation of phenols, the phenolic amine 8 was treated b u t gave exclusively with N,N'-diisopropyl-0-methylisourea, t h e permethylated compound 11 with partial racemization. T h i s unexpected racemization foreshadowed difficulties in this seemingly simple conversion. Another scheme was t o protect t h e catechol portion of t h e molecule, alkylate the nitrogen, a n d t h e n deprotect a n d methylate t h e phenols. T h u s , 9 was treated with phenylbo-
ronic anhydride t o form t h e cyclic borate ester 12, which was N-alkylated t o give 13. T h e catechol was deprotected during Scheme I. Iminium Salt Cyclization to Diastereomeric 8- and. 13-Methyl-2,3,10,11-tetramethoxyberbines
I
OCH, 1
CH,O
+ OCH, OCH, n
3
CH $0
CH ,O
CH,O
CH ,O
OCH
OCH, I
OCH,; 4
0 1978 American Chemical Society 0022-3263/78/19~3-~183~Ql.QQIO
I
OCH3 6
4184 J . Org. Chem., 2/01, 43, No. 21, 1978
Dean a n d Rapoport
Scheme 11. Synthesis of 6,7-Dimethoxy-l-methyltetrahydro-3-isoquinolinecarboxylates with Partial Racemization
‘OZH
”*
HO
CH,CHO
HO
HO
7
12
10, R = H 11, R = CH,
cH’lw”Brl
CH,O
14, R,, R , = H ; R , = C,H, 15, R,, R , = CH,; R, = C,H, 1 6 , R,, R , = CH,; R , = H isolation by exchange with 1,3-propanediol, and the phenolic tertiary amine was methylated with N,N’-diisopropyl-0methylisourea to give 15 in 57% overall yield (Scheme 11).This ester was hydrolyzed, the acid 16 was decarbonylated, and the iminium salt 4 was cyclized to give t h e berbine. Ring closure took place exclusively to form isomer 5 with the 8-methyl and 13a-hydrogen cis as shown in Scheme I. T o our surprise, however, t h e optical rotation of the product indicated t h a t only 16% of the optical activity had been retained through this series of reactions. In considering where this substantial racemization might have occurred, we focused on the conversion of t h e catechol 14 t o t h e veratrole 15. Either t h e catechol or its monomethyl ether, with a free hydroxyl a t C-6, could lead t o racemization a t C - 1 of t h e tetrahydroisoquinoline through methide inter-
CH,
11
13
Scheme 111. Synthesis of Chirally Pure 6,7-Dimethoxy-lmethyltetrahydro-3-isoquinolinecarboxylates
8 (1) Ac,O/HCOOH ( 2 ) HC1/C,H,0H/H20
88%
CO,C,H-
HO
HOW
y
H CH
0
18
CH, 17
mediate 17. Racemizations of various tetrahydroisoquinolines analogous to ours have been observed.6 Thus, it became mandatory, for a chirally specific synthesis, 15, t h a t is, t o avoid to avoid conversions of t h e type 14 methylation of the phenolic tertiary amine. Actually, t h e desired transformation of the dihydroxytetrahydroisoquinoline 8 t o t h e dimethoxy secondary amine 10 has been accomplished4 with complete chiral integrity. However, the overall yield was poor (-6%). T h e transformation was effected by selectively protecting the amine as its acetyl derivative after esterification, b u t difficulties in removing t h e N-acetyl were responsible in part for t h e poor yield. We have modified this process a n d improved t h e overall yield t o 66%. A key change was t h e use of t h e formyl group t o protect the nitrogen. This allowed its facile selective removal in the presence of the ethyl ester a n d avoided t h e additional +
10
reesterification step. Also, a possible side reaction in t h e methylation step is conversion of the N-formyl group to methyl imidate salt. T h i s is accommodated by using a n alkaline isolation procedure a t this stage of t h e synthesis. T h e product, a mixture of amine a n d amide, was heated with HCl/CZHsOH t o remove all remaining formyl residues, a n d chirally p u r e ethyl (lS,3S)-(-)-l,2,3,4-tetrahydro-lmethyl-6,7-dimethoxy-3-isoquinolinecarboxylate (10) was isolated as its hydrochloride (Scheme 111). T o form berbine, ester hydrochloride 10 was then converted t o t h e free amine, alkylated with the phenylethyl bromide, hydrolyzed, decarbonylated, and cyclized in the usual manner to give 5 in high yield with a n optical rotation for t h e hydrochloride of [ a ]+136’ ~ (lit.4 [ a ]+148O), ~ corresponding to 94% retention of optical purity from isoquinoline 10. Ring closure of iminium salt 4 was stereospecific with less than 1%of isomer
J. Org. Chem., Vol. 43, No. 21,1978 4185
8- a n d 13-Methylberbines
Scheme V. Intermediates in t h e Synthesis of P-Methyl-3,4dimethoxyphenylalanine Enantiomerically Pure at the 0 Position
19
20, R = H 21, R = C,H,
24
25
+ 90%
CH,O
wOCH, 22, R = C,H, 23, R = H
6 as established by LC and GC. T h e product was identical with (+)-0-methylcorytenchirine (5) by comparison of its physical and spectral properties with those reported.7 T h u s , t h e optically active amino acid was able t o effect a stereospecific introduction of what ultimately became t h e 8-methyl group of t h e berbine. Even if t h e a carbon of t h e amino acid may have racemized in subsequent steps, its function of inducing asymmetry was complete and it need only serve t o create iminium salt regiospecifically by a self-destruction process. T h e methyl group, now of a single stereochemistry, directed a stereospecific ring closure t o a single, optically pure compound. Interestingly, t h e methyl group did this from a position relatively remote from the bond-forming site. This can be rationalized by assuming t h a t t h e methyl group influenced the conformation of the transition state and thus t h e mode of attack by t h e aromatic ring of t h e iminium salt. 13-Methylberbines. T h e complimentary substitution pattern with a 13-methyl substituent can be envisioned as being derived from a P-methylphenylalanine derivative (19; Scheme IV). Our plan was to resolve the asymmetry due to the methyl group a t some point in t h e scheme prior t o iminium salt cyclization. This should allow a chirally specific synthesis and the direct preparation of an optically active final product. 'rhus, we chose t o synthesize t h e P-methylphenylalanine 19 with the chirality a t the /3 carbon resolved. Since the carboxyl group would be lost in decarbonylation to form iminium salt, its stereochemistry was of no concern and we sought t h e diastereomeric pair with only t h e carbon configurationally pure. T h e synthetic options at this point were to prepare all four isomeric P-phenylalanines, separate diastereomers, and then resolve t o obtain a single compound. Alternatively, we could resolve only the asymmetry resulting from the P-methyl group by resolving 3-(3,4-dimethoxyphenyl)butyricacid (28) and then aminate to obtain t h e phenylalanine derivative. T h e former method has been reported,8 b u t is troublesome and inefficient. T h e target then became 28. Our synthesis (Scheme V) began with veratrole (24), which was converted t o acetoveratroneg (25) and thence in a carefully controlled Reformatsky reaction t o give, after dehydration, a mixture of t h e three isomeric unsaturated esters 26 in 90% yield. Catalytic reduction gave a single product, ethyl 3-(3,4-dimethoxypheny1)butyrate (27).This was hydrolyzed t o t h e free acid 28 for resolution. T h e resolution of 3-(3,4-dimethoxyphenyl)butyricacid (28), after a series of preliminary tests,1° was effected with d -aphenylethylamine in chloroform for t h e (-) isomer and quinine in acetone for t h e (t) isomer. In four recrystallizations, constant rotation (t)acid was obtained in 56% yield. Acid t h u s obtained was established as optically pure by quantita-
R = C,H,,99% R = H,92%
t
CH,O 27, R = C,H, 28, R = H
29, R = H 30,R = C,H,
31
32 tive amide formation using d-a-phenylethylamine-d and analysis for diastereomeric purity by GC. This classical resolution is quite efficient and superior to kinetic resolution available through optically active oxazolines.ll T h e comparable 3-phenylbutyric acid was obtained by the latter process in 50% yield, 13% optically pure. Conversion of (+)-3-(3,4-dimethoxyphenyl)butyricacid (29) t o t h e desired 6-methylphenylalanine (19) requires an cu-amination, which was attempted first through the a-bromo acid. T h e acid chloride was brominated with N-bromosuccinimide (NBS) in carbon tetrachloride,I2 using 2 equiv of NBS since ring bromination was more facile t h a n a-bromination. T h e a-bromo ester resulting from addition of methanol was treated with potassium phthalimide in DMF.13 Removal of the aromatic bromine by hydrogenolysis and hydrazinolysis-hydrolysis of t h e a-phthalimido ester give the desired amino acid 19; however, it was obtained in less t h a n 15% overall yield for seven steps. Amination of t h e acid was considered b u t dismissed since poor results have been reported.14 Amination of t h e ester by first forming t h e enolate with lithium diisopropylamide followed by treatment with chloramine yielded product, b u t again in less t h a n 15% yield. A possible reason for the poor amination yields of these strong bases with chloramine is t h a t chloramine has a pK, of 14 f Proton transfer could be occurring faster t h a n amination. On this basis, amination should be more successful on t h e anion of malonate 31, a weaker base. Indeed, when t h e anion of 31 was treated with chloramine in ether, an 85% yield of amino ester 32 was ob-
4186
J . Org. Chem., Val. 43, No. 21, 1978
Dean and Rapoport Scheme VI
23
38
37
T
1 c f \ l I~ bo d CH,O
R ' + 1
-
CHO , &;
\
fast
R+'
CH,O
36
\
+\R
CH30
(?)-l
CH,O
OCH,
YOCH, tained. Chloramine was conveniently prepared by adding a n NaOCl solution t o a cold N H 4 0 H solution buffered with NH4Cl and t h e n extracting into ether.16 This avoids decomposition caused by excess alkali and gives >90% yields of chloramine without t h e troublesome d i ~ t i 1 l a t i o n . T l ~h e malonate needed, 31, was prepared from ethyl ester 30 in 94% yield by forming t h e enolate with lithium diisopropylamide and treating with 150 mol % of ethyl chloroformate a t -78 OC.l* T h e aminomalonate 32 was then converted to amino acid 19 by hydrolysis followed by decarboxylation. Of interest was a reportlg t h a t aminomalonic acid 34 could be decarboxylated t o phenylalanine 35 sterospecifically. We were interested in applying this process to our aminomalonate
33
34
35 32 and thereby obtaining a single amino acid. No experimental details were given, and 35 was stated to be obtained in 47% yield from 33. We hydrolyzed 32 in refluxing 1 N HC1 t o produce amino acid 19 as a 4:3 mixture of diastereomers in 89%yield. When 32 was hydrolyzed with alkali, t h e dipotassium salt isolated, and this subjected t o decarboxylation in 1 N HC1, a 3:2 mixture of diastereomers was obtained. In t h e last case, our aminomalonic acid intermediate prior to decarboxylation should be identical (except for the two methoxyls) with the reportedlg example 34. One possible explanation for this apparent difference might be t h a t t h e reported reaction was not stereo-
specific but slightly stereoselective and t h a t only the erythro isomer was isolated (47% yield) by fractional crystallization. Indeed, in a similar report of t h e hydrolysis and decarboxylation of ethyl (f)-2-acetylamino-2-ethoxycarbonyl-3-phenylbutyrate to (f)-a-methylphenylalanine[(f)-35],the erythro isomer predominates (1.5-1.7:1), but is not exclusive, in t h e product.* T h e amino acid 19, enantiomerically pure at C-3 and mixed a t C-2, was converted to the 3-isoquinolinecarboxylic acid 20, and t h e ethyl ester 21 was formed in 79% overall yield. T h e secondary amine was then alkylated to give 22 in 76% yield. Hydrolysis proceeded in 89% yield to acid 23 (Scheme IV), now ready for iminium salt formation a n d ring closure. When 23 was subjected to the standard decarbonylation and cyclization conditions, a mixture of the desired berbine 2 and one of t h e dihydroisoquinoline disproportionation products, 2- [2-(3,4-dimethoxyphenyl)ethyl] -1,2,3,4-tetrahydro-4methylisoquinoline (37),was obtained. These two compounds were isolated as t h e only basic products from this reaction. Berbine 2 was established t o have the stereochemistry shown (Scheme VI) with the hydrogens a t C-13 and C-13a trans. This assignment is based on the N M R absorption, which for trans 13- and 13a-hydrogens shows a chemical shift for t h e 13methyl group of ca. 6 1.5 compared to ca. 6 1.0 for t h e case where the hydrogens are This is the expected mode of attack by t h e aromatic ring on an iminium salt with a substituted carbon adjacent t o the bond-forming site and provides synthetically based evidence corroborating earlier assignments. Finally, both products are racemic, indicating a loss of optical integrity a t t h e 4 position of t h e isoquinoline prior t o ring closure. Disproportionation of 4-alkyldihydroisoquinolines has been previously reported. For example, when 4-alkyl-1,2-dihydroisoquinolines were treated with acid in an a t t e m p t to obtain the iminium salt (i.e., the 1,4-dihydroisoquinolinium salt), disproportionation was reported as the exclusive r e s ~ l t . ~ ~ , ~ ~ T h e mechanism and conditions promoting this dispropor-
8- and 13-Methylberbines
J.Org. Chem., Vol. 43, No. 21, 1978
4187
base by addition to a saturated NazC03 solution, extraction with CHZClZ, drying, and evaporating to a residue which was a single spot by TLC (EtOAc; R f 0.16 compared to coralydine, Rj 0.27, and 0methylcorytenchirine, Rf 0.16, both prepared according to the literature7): NMR S 6.63,6.53 (4H, m), 4.37-3.97 (1H, m), 3.87 (12 H, s), 3.16 (1H, m), 2.90 (5 H, m), 1.40 (3 H, d, J = 7 Hz); MS mle (relative intensity) 369 (15), 354 (100). Ethyl (lS,3S)-(-)-1,2,3,4-Tetrahydr0-6,7-dihydroxy-lmethyl-3-isoquinolinecarboxylate Hydrochloride (9). Acid 8 (12.44 g, 56 mmol) in ethanol (100 mL) and saturated HCl/ethanol (50 mL) was refluxed for 6 h, the solvent evaporated, and the residue recrystallized from acetic acid to give ester 9 hydrochloride: 15.16 g (52.6 mmol, 94%); mp 220-221 "C dec (lit.3 mp 229-230 "C); [ a ] D -110.5" (C 1.2, CHsOH)]. Ethyl (lS,3S)-(+)-2-Formyl-l,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylate(18). To 9 (12.32 g, 42.8 mmol) was added 97% HCOzH (107 mL), HCOzK (3.96 g, 47 mmol), and then AczO (43 mL) dropwise over 5 min while maintaining the internal temperature a t 5 "C. The mixture was stirred a t room temperature for 3 h, and then ethanol (140 mL) was added, the solvent was evaporated, ethanol (200 mL) and 1 N HCl(4 mL) were added, and this mixture was stirred at room temperature for 14 h. The solvent was evaporated, and to the residue was added 1 N HCl(20 mL) and EtOAc (200 mL). The crystalline precipitate was washed with HzO (2 X 20 mL) and dried to give 5.42 g (19.5 mmol), mp 174.5-175 "C. The EtOAc layer was washed with saturated NaHC03 (2 X 20 mL) and saturated NaCl(50 mL), dried, and evaporated to give an additional 5 g (18mmol; total 37.5 mmol, 88%) of formyl derivative 18: mp 170-172 "C; single spot by TLC (CHC13/EtOH, 9:1), Rj 0.28; [ a ] ~ +6.0° (c 1, EtOH); NMR (MezSO-ds) 6 8.80 (2 H , s), 8.33 and 8.20 (2 H,s,s,1:1),6.66-6.56(2H,m),5.17-3.90(4H,m),3.11-2.87(2H,m), Experimental Section2' 1.55-0.94 (6H, m); IR 3320,2990,1738, 1656 cm-*. Ethyl (lS,3S)-(-)-1,2,3,4-Tetrahydr0-6,7-dimethoxy-lEthyl 2-[2-(3,4-Dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydromethyl-3-isoquinolinecarboxylateHydrochloride (10). Formyl 6,7-dimethoxy-l-methyl-3-isoquinolinecarboxylate ( 15a).27aTo ethyl (1S,3S)-(-)-1,2,3,4-tetrahydro-6,7-dihdroxy~l-methyl-3-iso- derivative 18 (3.90 g, 1 4 mmol), acetone (100 mL), KHC03 (12, g, 120 mmol), and (CH3)zSOd (5.3 mL, 56 mmol) were refluxed for 18.5 h, quinolinecarboxylate (9)4(3.24 g, 12.9 mmol) was added phenylbothe solvent was evaporated, and EtOAc (200 mL), saturated Na2C03 ronic anhydride (1.39 g, 4.5 mmol), benzene (60 mL), and DMF (10 (60 mL), and HzO (10 ml) added. After separation, the ethyl acetate mL), and this mixture was refluxed for 1 h, followed by distillation of 40 mL over 2.5 h. To the remaining mixture was added KzCO3 (3.82 was washed with saturated NaCl(100 mL), dried and evaporated, and excess (CH3)2SO4was removed by distillation at 50 "C (0.03 torr). The g, 26 mmol) and 1-(2-bromoethyl)-3,4-dimethoxybenzene (3.94 g, 1.6 residue, EtOH (50 mL), and saturated HCliEtOH (25 mL) were remmol), and the mixture was refluxed for 22 h and cooled. Ether (100 fluxed for 3 h. Evaporating to 20 mL and cooling gave crystals which mL), HzO (20 mL), 1,3-propanediol (0.3 mL, 40 mmol), and then 1 were washed with cold EtZOlEtOH (4:3) and then Et20 to yield 3.54 N HC1 (52 mL) were added; after 2 h, the ether layer was separated g (11.2 mmol, 80%) of ester hydrochloride 10: mp 213 "C (lit.4 mp and extracted with 1N HC1(50,25, and 25 mL). The acidic extracts 219-220'C); [ a ] -92.9" ~ (c 1, EtOH) [ l k 4[ a ]-95.8" ~ (c 1, EtOH)]; were neutralized to pH 8 with NaHC03, and extracted with CHC13 single spot by TLC (CHCl,/EtOH, 9:1),Rf 0.59, NMR 6 6.65 and 6.58 (50,2525, and 20 mL), and the dried CHC13 extracts were evaporated (2 H, s, s), 4.70 (1H, m), 4.22 (2 H, q), 4.20 (1H. m), 3.85 (6 H, s), 3.30 to give a crude residue (8.4 g). To this residue was added N,N'-di(2 H, m), 1.95 (2 H, d), 1.30 (3 H, t); IR 1750 cm-'. isopropyl-0-methylisourea (16.5 g, 104 mmol), and heating was ( 1S,3S)-2-[2-(3,4-Dimethoxyphenyl)ethyl]-1,2,3,4-tetrahymaintained at 100 "C for 26 h until all of the material was converted dro-6,7-dimethoxy-l-methyl-3-isoquinolinecarboxylic Acid to a single product by TLC (CHC13/MeOH,9:l; Rj 0.73). The mixture (16b).27bTo ester hydrochloride 10 (2.53 g. 8.0 mmol) was added was distilled, collecting ester 15a between 150-210 "C (0.01 torr), to saturated N a ~ C 0 3(50 mL), and this was extracted with CHC13 (3 X give3.25g(7.3mmol,57%):NMR66.8-6.5(5H,m),4.3-3.5(2H,m), 20 mL). The extracts were dried and evaporated. T o the residue was 4.1(2H,q),3.9(12H,s).3.0-2.7(6H,m),1.35(3H,d),l.l5(3H,t); added 1-(2-bromoethy1)-3,4-dimethoxybenzene IR 1728 cm-I; MS mle (relative intensity) 443 ( l ) 428 , (4), 370 (13), (2.45 g, 10 mmol), 292 (100). benzene (10 mL), DMF (10 mL), and K2CO3 (2.21 g, 16 mmol), and 2-[2-(3,4-Dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydro-6,7-di- this mixture was heated at 110 "C under reflux for 23 h. More 1-(2bromoethyl)-3,4-dimethoxybenzene(1 g, 4.1 mmol) was added, and methoxy- 1-methyl-3-isoquinolinecarboxylicAcid (16a). To ester reflux was continued for 8 h; this addition was repeated and reflux 15a (3.22 g, 7.3 mmol) was added ethanolic KOH (800 mg in 50 mL), continued for 13 h more. The mixture was cooled and added to H2O and the mixture was heated a t reflux for 3 h. The solvent was evapo(50 mL) and Et20 (100 mL), the aqueous layer was separated, saturated, water and decolorizing carbon were added, the mixture was rated NaCl(25 mL) was added, and the mixture was extracted with filtered, and the pH was adjusted to 6 with 6 N HC1. The filtered soEt20 (3 X 17 mL). The combined Et20 extracts were extracted with lution was extracted with CHC13 (3 X 20 mL) and the CHC13 evapo0.5 N HC1(50,25,and 25 mL), and the acid extracts were basified with rated to a residue, which was recrystallized from 15 mL of CH30H/ saturated Na2C03 (60 mL), extracted with CHzC:l:! (3 X 20 mL), dried, ether (1:2) to give 1.27 g (3.1 mmol, 42%) of acid 16a, mp 157-158 "C and evaporated. T o the residue was added EtOH (40 mL), H20 (10 with softening at 152 "C. A second crop of 328 mg was obtained, and mL), and KOH (18). The mixture was refluxed for 5.5 h. The solvent chromatography of the mother liquor gave 606 mg (80%total yield): was evaporated, H20 (40 mL) added followed by washing with Et20 NMR 6 6.64-6.30 (5 H, m), 4.47 (1 H, t), 3.84,3.81, and 3.75 (12 H , s, (20 mL), and then the aqueous phase adjusted to pH 6 with 6 N HC1 s, s), 4.10-3.54 (1 H, m), 3.54-2.84 (6 H, m), 1.64 (3 H, d); IR 1644 and stored in the cold overnight. The resulting mixture was filtered, N 66.5; O ~ :H, 7.0; N, 3.4. Found: C, cm-I. Anal. Calcd for C ~ ~ H ~ YC, the filtrate was extracted with CHC13 (3 X 17 mL), and the extracts 66.2; H, 7.0; N,3.3. were dried and evaporated to give 1.58 g (3.8 mmol, 48%).This tertiary 8-Methyl-2,3,10,11-tetramethoxyberbine(5a). Acid 16a (211 amino acid 16b was recrystallized from EtOH/Et20 (1:2):mp 167-158 mg, 0.51 mmol) and PO(& (1.0 mL, 11 mmol) were heated a t 70 "C "C dec; NMR and IR were identical with 16a. for 10 min. The mixture was cooled (ice bath) and HzO (11mL) added, (8S,13aR)-(+)-5,8,13,13a-Tetrahydro-2,3,lO,ll-tetramethand then it was heated at 100 "C for 1.25 h, cooled, extracted with oxy-8-methyl-6H-dibenzo[a,g]quinolizine [(8S,13aR)-(+)CHC13 (3 X 10 mL), saturated with NaCl, and extracted again with 8-Methyl-2,3,10,11-tetramethoxyberbine,(+)-0-MethylcorCHCln ( 5 mL). The dried extracts were evaporated to give 210 mg ytenchirine] (5b). Tertiary amino acid 16b (207 mg, 0.50 mmol) and which was chromatographed (after treatment with ethanolic HC1) POC13 (1 mL, 11 mmol) were heated a t 70 "C for 10 min and then on silica (1.1 X 11.5 cm) eluting with CHC13 (20 mL) and then acetone cooled (ice bath), and H20 (11 mL) was added. The mixture was (260 mL) to give 66 mg of an oily hydrochloride, [ a ] D +24" (c 1, heated a t 100 "C for 1.5 h, cooled, added to 2 N NaOH (30 mL), and CHC1:j) [lit.' [U]D +148O ti 1,CHCls)]. This was converted to the free
tionation are poorly understood. In an a t t e m p t t o evaluate some of the possible variables, t h e effect of conditions on t h e production of berbine 2 was briefly investigated. T h e factors studied were concentration, time, a n d temperature during both iminium salt formation and acid cyclization and acid strength in the latter. T h e results show t h a t 2 is favored over t h e disproportionation products under (1) minimum time, lower temperatures, and lower concentrations during decarbonylation in POC13 and (2) higher acidity in t h e aqueous cyclization step. Concentration of reactant in t h e aqueous medium appears unimportant. These data suggest that disporportionation is a bimolecular reaction a n d t h a t i t occurs primarily in t h e POC13 solution. Earlier studies showed that no cyclization occurs in the POC13 with this system, but takes place only in t h e subsequent aqueous acid treatment. T h e loss of optical activity in all products is explicable only if a rapid equilibrium between initially formed iminium salt 1 and enamine 36 is established prior t o cyclization and disproportionation. Scheme VI summarizes our observations and hypothesis. Our results are suggestive of additional steps now under investigation which might avoid disproportionation in this system such as formation of an activated acyl derivative under milder conditions and decarbonylation under strongly acidic or catalytic conditions.
4188 J . Org. Chem., Vol. 43, No. 21, 1978 extracted with CHZC12 (3 X 10 mL), and the extracts were dried and evaporated to give 169 mg (0.46 mmol, 92%) of crude oily base which was chromatographed (3 g of silica, eluting with EtOAc) and converted to hydrochloride by dissolving in hot Et20 and adding saturated HCl/EtOH (2 drops). The hydrochloride of 5b was recrystallized from isopropyl alcohol: 162 mg, 80% yield; mp 193-194 "C (lit.' mp 205-206 "c);[a]D+136" (c 0.35, CHC13) [lit.7 [ a ]+148" ~ (c 1,CHC13)I. The diastereomeric integrity was established by GC (5% Dexsil300 GC on Anachrom Q, He flow rate of 30 cm3/min, oven 262 "C, injection port 260-270 "C, detector 295 "C) using coralydine and O-methylcorytenchirine prepared according to the literature7 for comparison (Rt 47.2 and 51.6 min, respectively), by TLC (Brinkman HR, EtOAc; Rf 0.16) (coralydine, Rf 0.26), (coralydine, Rf 0.26), and by LC (
