Synthesis of protoberberines using a silyl-directed Pictet-Spengler cyclization

Article abstract of DOI:10.1016/S0040-4020(02)00010-8

Five naturally-occurring protoberberines have been synthesized in enantioenriched form by alkylation by two different 2-trimethylsilylbenzyl chlorides of four tetrahydroisoquinolines, derivatized with Meyers' formamidine valinol methyl ether chiral auxiliary. Silyl-directed Pictet-Spengler cyclization of the ensuing 3,4-dimethoxy-2-trimethylsilylbenzyl tetrahydroisoquinolines leads to four of the target protoberberines in excellent yield and complete regioselectivity. In the fifth case, the 3,4-methylenedioxy analog gives a mixture of protoberberine and a product of ring closure at C6 of the benzyl moiety in a 3:4 ratio.

Full text of DOI:10.1016/S0040-4020(02)00010-8

TETRAHEDRON
Pergamon
Tetrahedron 58 92002) 1471±1478
Synthesis of protoberberines using a silyl-directed
Pictet±Spengler cyclization
²
Paul S. Cutter, R. Bryan Miller and Neil E. Schorep
Department of Chemistry, University of California, Davis, CA 95616, USA
Received 11 October 2001; accepted 17 December 2001
AbstractÐFive naturally-occurring protoberberines have been synthesized in enantioenriched form by alkylation by two different
2-trimethylsilylbenzyl chlorides of four tetrahydroisoquinolines, derivatized with Meyers' formamidine valinol methyl ether chiral auxiliary.
Silyl-directed Pictet±Spengler cyclization of the ensuing 3,4-dimethoxy-2-trimethylsilylbenzyl tetrahydroisoquinolines leads to four of the
target protoberberines in excellent yield and complete regioselectivity. In the ®fth case, the 3,4-methylenedioxy analog gives a mixture of
protoberberine and a product of ring closure at C6 of the benzyl moiety in a 3:4 ratio. q 2002 Published by Elsevier Science Ltd.
1. Introduction
isoquinolines. The Pictet±Spengler sequence4 produces
the 1,2,3,4-tetrahydroisoquinoline system found within the
structure of most natural protoberberines. It involves the
addition of formaldehyde to a phenylethylamine to form
an iminium ion. This electrophile is suitable for aromatic
substitution and ring-closure 9Fig. 2).
Protoberberines are naturally occurring tetracyclic iso-
quinoline alkaloids. Protoberberines commonly bear sub-
stituents at positions 2, 3, 9, and 10, and a single
stereocenter at carbon 14 with the 9S) con®guration.
Examples include sinactine and corypalmine 9Fig. 1).1
A complication of the Pictet±Spengler synthesis of proto-
berberines is regiochemical control in the closure of ring C
when activating substituents are present on the D ring.
Experimentally, Pictet±Spengler reactions performed on
benzylisoquinolines of the 30,40-disubstitution type yield
predominantly or exclusively the 10,11-disubstitution
Several approaches exist for the synthesis of proto-
berberines and other isoquinoline alkaloids, all of which
are variants of the Friedel±Crafts reaction. The Pomeranz±
Fritsch reaction2 produces fully aromatic isoquinolines, and
the Bischler±Napieralski process3 affords 1,2-dihydro-
Figure 1. Representative protoberberines and the protoberberine numbering scheme.
Figure 2. The Pictet±Spengler reaction sequence.
Keywords: enantioselective; ipso-substitution; Pictet±Spengler reaction; protoberberine; regioselectivity; silyl-direction.
Corresponding author. Tel.: 11-530-752-6263; fax: 11-530-754-7610; e-mail: neschore@ucdavis.edu
Deceased October 29, 1998.
p
²
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020902)00010-8

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P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
Figure 3. Regiochemistry of the Pictet±Spengler ring-closure.
Figure 4. Ring-closure using trimethylsilyl ipso-direction.
product, rather than the 9,10-disubstitution pattern present
in the majority of naturally occurring protoberberines5
9Fig. 3).
of trimethylsilyl direction of ring closure with several
substitution patterns. These preparations also make use of
an appropriate chiral auxiliary to evaluate the degree to
which this methodology affords enantiomerically enriched
products.
Several approaches have been used to overcome this
problem. One has been to block the 60 position 9para to
substituent `Y') with bromine, which is removed after
cyclization to give the desired isomer. While this sequence
has been used successfully by Kametani,6 it lowers the yield
of the Pictet±Spengler reaction as well as adding two more
steps to the synthesis. Our solution was to induce 9,10-
disubstitution by ipso-direction at the 20 position using a
trimethylsilyl group. Miller and Tsang demonstrated the
®rst successful use of ipso direction for protoberberine
ring-closure in systems such as the one shown in Fig. 4.7
2. Results and discussion
2.1. Synthesis overview
Our convergent pathway to the construction of proto-
berberines involved four steps: 91) normal Pictet±Spengler-
based construction of appropriately substituted tetrahydro-
isoquinolines 9for rings A and B), 92) preparation of the
2-trimethylsilyl-3,4-dialkoxybenzyl chloride alkylating
agents 9ring D), 93) enantioselective coupling to give
914S)-benzylisoquinolines using Meyers' formamidine
methodology,8±11and 94) trimethylsilyl-directed Pictet±
Spengler reaction to close the C ring and produce the ®nal
products 9Fig. 5).
They found that unsubstituted benzylisoquinolines are
unreactive under Pictet±Spengler conditions: apparently
the ring is insuf®ciently activated for electrophilic aromatic
substitution to occur. However, 20-trimethylsilylbenzyl-
isoquinoline gives a 27% yield of unsubstituted proto-
berberine, suggesting that the TMS groupis
ipso-
activating. The example in Fig. 4 illustrates the dramatic
combined directing and activating effects of trimethylsilyl
substitution on reaction of a 30-methoxybenzylisoquinoline,
suggesting that this approach may have general synthetic
utility. In this paper we demonstrate that this is indeed the
case: we describe syntheses of ®ve naturally-occurring
protoberberines, canadine, sinactine, tetrahydropalmatine,
corypalmine, and isocorypalmine, evaluating the ef®cacy
2.2. Tetrahydropalmatine, canadine, and sinactine
To begin the syntheses of these protoberberines the
appropriate benzaldehyde was subjected to Henry conden-
sation and the resulting nitrostyrene reduced to the
corresponding 3,4-dialkoxyphenylethylamine with lithium
aluminum hydride.12 Pictet±Spengler cyclization using
paraformaldehyde in formic acid gave the initial
Figure 5. Overview of the synthetic route.

P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
1473
Scheme 1. 9a) CH3NO2, HOAc, NH4OAc, D, 1.5 h; 9b) LiAlH4, THF, D, 12 h; 9c) 9CH2O)n, HCO2H, D, 12 h.
Scheme 2. 9a) 9CH3)2NH, NaBH3CN, ZnCl2, 1 h; 9b) n-BuLi, THF, 08C, 4 h; 9c) 9CH3)3SiCl, 2788C to rt, 4 h, 9d) ClCO2Et, 2788C to rt, 12 h.
tetrahydroisoquinolines 1 and 2 in overall yields of nearly
70%. N-Methylation was not observed provided that a 1:1
ratio of phenylethylamine and paraformaldehyde was
maintained 9Scheme 1).
with 5 followed by Pictet±Spengler cyclization. The cycli-
zation itself proceeded in excellent yield, with complete
ipso regioselectivity: no trace of products with any other
D-ring substitution pattern was found. However, the optical
rotation of the product revealed it to possess an optical
purity of only 55%, corresponding to a 77:23 diastereo-
selectivity in the alkylation step. This is considerably poorer
than that obtained using benzyl halides lacking ortho substi-
tution, but somewhat better than the 32% ee obtained by
Meyers using an analog of 5 containing a carboethoxy group
instead of trimethylsilyl. Similarly, alkylation of the forma-
The alkylating agents 5 and 6 were formed from the same
starting benzaldehydes, via a sequence of reductive
amination using N,N-dimethylamine, doubly ortho-directed
lithiation at C2, trimethylsilylation, and replacement of the
dimethylamino groupby Cl using ethyl chloroformate.
Overall yields of about 40% were realized 9Scheme 2).
midine-derivatized tetrahydroisoquinoline
2
with
5
Enantioselective alkylation of the tetrahydroisoquinolines 1
and 2 by the substituted benzyl chlorides 5 and 6 to form
predominantly the natural 914S) protoberberine precursors
utilized the valinol methyl ether-derived formamidine
9±CHvNVME) as a chiral auxiliary.9,13 The forma-
midine-derivatized precursors were prepared in essentially
identical optical purity 9$97%) to that described by Meyers.
Finally, each TMS-substituted benzyl tetrahydroisoquino-
line was subjected to Pictet±Spengler conditions, giving
rise to the corresponding protoberberine. Thus 9S)-92)-
tetrahydropalmatine was obtained in 46% overall yield
from the chiral formamidine derivative of 1 by alkylation
followed by cyclization afforded 9S)-92)-canadine in 51%
overall yield and 58% optical purity 9Scheme 3).
In Meyers' carboethoxy system the lone pairs on the sub-
stitutent were positioned to interfere with the desired stereo-
directing lithium chelation. The origin of the stereochemical
problem in our system is less clear. Perhaps the electron-
releasing effect of the silyl substituent increases the Lewis
basicity of one of the methoxy groups enough to partially
interfere with chelation. This is pure speculation, however,
for which we have no independent evidence. The excep-
tional regioselectivity, however, may be contrasted to the
Scheme 3. 9a) 9S)-i-Pr9CH3OCH2)CHNvCHNMe2, 9NH4)2SO4, toluene, 1118C, 18 h; 9b) n-BuLi, THF, 2788C, 0.5 h; 9c) 5, THF, 21058C, 0.5 h, then HOAc,
NH2NH2, 08C to rt, 12 h; 9d) HCl, CH2O, EtOH, 858C, 12 h.

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P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
Scheme 4. 9a) n-BuLi, THF, 2788C, 0.5 h; 9b) 6, THF, 21058C, 0.5 h, then HOAc, NH2NH2, 08C to rt, 12 h; 9c) HCl, CH2O, EtOH, 858C, 12 h.
results of Haworth and Perkin.5b In an attempt to prepare
canadine, they carried out Pictet±Spengler cyclization on
the analog of 8 lacking silyl substitution. The sole product
obtained was the undesired 10,11-dimethoxy regioisomer,
in 60% yield; thus, use of a silyl substitution strategy in this
case leads to a signi®cantly improved yield and a complete
reversal of regioselectivity.
92,3-methylenedioxy-substituted A ring) gave a similar
mixture containing 40% of a para-cyclized silicon-contain-
ing product and 29% of the natural product stylopine.14 Thus
it is clear that the stereoelectronic enhancement of the acti-
vating and directing power of the methylenedioxy group on
the D-ring, relative to two freely rotating methoxy groups, is
such that it overcomes the ipso-directing capability of the
silyl substituent.15 As a result, we abandoned work with
methylenedioxy-substituted D-ring precursors.
We next investigated the synthesis of sinactine, a proto-
berberine with 9,10-methylenedioxy substitution on the
D-ring, using the same approach. The required precursor 9
was prepared from formamidine-derivatized 1 by alkylation
with 6 in 50% yield. In this case, however, the ®nal
cyclization no longer displayed selective trimethylsilyl-
directed ipso-substitution. We obtained a 31% yield of
9S)-92)-sinactine, but 39% of a product that retained
the silyl groupand was derived from cyclization at
C6 9para to the oxygen at C3) of the alkylating agent
9Scheme 4).
2.3. Corypalmine and isocorypalmine
These protoberberines were accessed from the two regio-
isomeric methoxybenzyloxytetrahydroisoquinolines 10 and
11, prepared in the manner described in Scheme 1. Both
syntheses proceeded uneventfully. After debenzylation
using HCl in aqueous EtOH, 9S)-92)-corypalmine was
obtained in 46% yield and 59% optical purity from the
formamidine derivative of 10, and 9S)-92)-isocorypalmine
was similarly obtained from derivatized 11 in 57% yield and
57% optical purity 9Scheme 5).
In other, contemporaneous work from our laboratory,
Taylor found that the analogous system derived from 2
Scheme 5. 9a) 9S)-i-Pr9CH3OCH2)CHNvCHNMe2, 9NH4)2SO4, toluene, 1118C, 18 h; 9b) n-BuLi, THF, 2788C, 0.5 h; 9c) 5, THF, 21058C, 0.5 h, then HOAc,
NH2NH2, 08C to rt, 12 h; 9d), HCl, CH2O, EtOH, 858C, 12 h; 9e) conc. HCl, EtOH, 1008C, 2 h.

P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
1475
3. Conclusions
6.89 9d, 1H, Jˆ7.8 Hz), 4.65 9s, 2H), 3.85 9s, 3H), 3.84 9s,
3H), 0.42 9s, 9H). 13C NMR d 153.2, 146.2, 139.5, 130.2,
121.9, 111.5, 89.2, 81.1, 46.3, 0.7. IR 9®lm): 2081, 1982,
1857, 1589, 1568, 1468, 1388, 1296, 1246, 1159, 1047,
.
258.0838, found 258.0844.
Five protoberberines have been synthesized via a silyl-
mediated Pictet±Spengler reactions. Cyclizations to give
9,10-dimethoxy-substituted systems proceed with complete
silyl-directed ipso-regioselectivity. However, the analogous
9,10-methylenedioxy system does not form selectively and
is not best accessed in this way. Even though the optical
purities of the formamidine precursors matched those in the
literature, the optical purities of the ®nal alkaloids measured
only in the 55±60% range, apparently a consequence of low
stereoselectivity in the chiral-auxiliary-mediated alkylation
step.
858 cm21
HRMS for C12H19ClO2Si 9M1): calcd
4.1.3. 1-0Dimethylamino)methyl-3,4-methylenedioxy-2-
trimethylsilylbenzene 04). In a manner similar to the
preparation of 3, 1-9dimethylamino)methyl-3,4-methylene-
dioxybenzene
9a-dimethylamino-3,4-methylenedioxy-
toluene) 93.10 g, 17.29 mmol) was converted into 4 by
successive treatment with n-butyllithium 92.37 M,
10.73 mL, 24.42 mmol) and chlorotrimethylsilane 93.23
mL, 25.42 mmol) in THF. After work-upand puri®cation
1
4 was isolated as a light yellow oil 92.99 g, 69% yield). H
4. Experimental
4.1. General
NMR d 6.80 9d, 1H, Jˆ8.1 Hz), 6.72 9d, 1H, Jˆ7.8 Hz),
5.89 9s, 2H), 3.35 9s, 2H), 2.14 9s, 6H), 0.35 9s, 9H). 13C
NMR d 153.2, 145.0, 138.2, 122.9, 118.9, 108.2, 99.8, 64.4,
45.0, 1.2. IR 9®lm): 1583, 1412, 1367, 1279, 1228, 1147,
1057, 1024, 897, 843, 767 cm21. HRMS for C13H22NO2Si
9MH1): calcd 252.1419, found 252.1414.
Solvents were puri®ed and dried according to standard
procedures. All reactions were carried out under an
atmosphere of dry N2, unless indicated otherwise. All
NMR spectra were recorded at 298 K in CDCl3 at
300 MHz 91H) or 75 MHz 913C). High-resolution mass
spectra were obtained on a VG 7070 mass spectrometer at
the UC Riverside mass spectrometry lab in Riverside, CA
and were performed by Mary Young. Optical rotations were
measured on a Jasco DIP-370 digital polarimeter at UC
Davis. Preparations of known compounds are detailed in
Supplementary Materials.
4.1.4. 1-Chloromethyl-3,4-methylenedioxy-2-trimethyl-
silylbenzene 06). In a manner similar to the preparation of
5, amine 4 92.72 g, 10.82 mmol) was converted into 6 by
reaction with K2CO3 92.24 g, 16.23 mmol) and ethyl chloro-
formate 91.55 mL, 16.23 mmol) in THF. Work-upand puri-
®cation produced 6 as a pale yellow liquid 91.95 g, 74%
1
yield). H NMR d 6.88 9d, 1H, Jˆ8.1 Hz), 6.76 9d, 1H,
Jˆ7.8 Hz), 5.93 9s, 2H), 4.62 9s, 2H), 0.42 9s, 9H). 13C
NMR d 153.2, 146.2, 135.7, 124.8, 119.2, 109.1, 100.3,
47.7, 0.8. IR 9®lm): 2081, 1982, 1857, 1589, 1568, 1468,
1388, 1296, 1246, 1159, 1047, 858 cm21. HRMS for
C11H15ClO2Si 9M1): calcd 242.0526, found 242.0522.
4.1.1.
3,4-Dimethoxy-1-0dimethylamino)methyl-2-tri-
methylsilylbenzene 03). To a solution of 3,4-dimethoxy-
1-9dimethylamino)methylbenzene 9a-dimethylamino-3,4-
dimethoxytoluene) 94.96 g, 25.40 mmol) in THF 930 mL)
at 2788C was added n-butyllithium 92.37 M, 17.17 mL,
39.07 mmol) dropwise. The mixture was than warmed to
08C, stirred 4 h, and recooled to 2788C. Chlorotrimethyl-
silane 95.17 mL, 40.67 mmol) was cooled to 2788C, diluted
with 6 mL of tetrahydrofuran and then added to the amine
via cannula. The mixture was then warmed to rt and stirred
an additional 4 h. The reaction mixture was quenched with
water and extracted 3£ with CH2Cl2. The combined organic
layers were dried 9Na2SO4), evaporated, and the residue
chromatographed 9SiO2, 9:1:1 hexane/EtOAc/Et3N) to
4.1.5. 0S)-1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[[01-
0methoxymethyl)-2-methylpropyl)imino]methyl]iso-
quinoline 01-formamidine).13 To a solution of 1,2,3,4-
tetrahydro-6,7-dimethoxyisoquinoline
1
91.44 g, 7.45
mmol) and Meyers' 9S)-92)-formamidine chiral auxiliary
91.93 g, 11.18 mmol) in toluene 910 mL) was added
9NH4)2SO4 90.10 g, 0.77 mmol), and the mixture was heated
to re¯ux for 18 h open to the air. After cooling to rt and
evaporation of the solvent the crude product was chromato-
graphed 9SiO2, 6:3:1 EtOAc/hexane/Et3N) to give the
formamidine-derivatized isoquinoline 91-formamidine) as
1
give 3 as a light yellow oil 94.78 g, 70% yield). H NMR
d 7.04 9d, 1H, Jˆ8.1 Hz), 6.84 9d, 1H, Jˆ7.8 Hz), 3.84 9s,
3H), 3.81 9s, 3H), 2.13 9s, 6H), 0.35 9s, 9H). 13C NMR d
162.7, 159.0, 138.2, 122.9, 118.9, 108.2, 74.3, 72.8, 63.3,
45.7, 1.2. IR 9®lm): 1583, 1412, 1367, 1279, 1228, 1147,
1057, 1024, 897, 843, 767 cm21. HRMS for C14H25NO2Si
9M1): calcd 267.1648, found 267.1660.
25
a yellow oil 91.74 g, 73% yield); [a]D ˆ27.48 9c 2.46,
THF), lit13: [a]D ˆ27.46 9c 2.59, THF). H NMR d 7.40
9s, 1H), 6.63 9s, 1H), 6.60 9s, 1H), 4.50 9d, 1H, Jˆ16.5 Hz),
4.40 9d, 1H, Jˆ16.8 Hz), 3.85 9s, 3H), 3.83 9s, 3H), 3.53±
3.49 9m, 4H), 3.34 9s, 3H), 2.78 9m, 3H), 1.74 9sept, 1H,
Jˆ6.6 Hz), 0.85 9t, 6H, Jˆ6.3 Hz). 13C NMR d 153.6,
147.6, 147.4, 126.5, 125.5, 111.5, 109.2, 76.1, 71.4, 59.0,
55.9, 46.4, 44.4, 30.8, 28.7, 20.1, 18.7. IR 9®lm): 1662,
25
1
4.1.2. 1-Chloromethyl-3,4-dimethoxy-2-trimethylsilyl-
benzene 05). To a slurry of 3 94.08 g, 15.26 mmol) and
K2CO3 93.36 g, 24.35 mmol) in THF 933 mL) at 2788C
was added ethyl chloroformate 92.33 mL, 24.35 mmol).
The reaction was warmed to rt and stirred for 12 h. The
resulting slurry was quenched with water and extracted 3£
with EtOAc. The combined organic layers were dried
9Na2SO4), evaporated, and the residue chromatographed
9SiO2, 19:1 hexane/EtOAc) to give 5 as a pale yellow liquid
1488, 1382, 1380, 1252, 1105 cm21
.
4.1.6. 0S)-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-[03,4-
dimethoxy-2-trimethylsilylphenyl)methyl]isoquinoline
07). The 1-formamidine 90.850 g, 2.65 mmol) was weighed
into a ¯ame-dried ¯ask, placed under high vacuum, and
gently warmed with a heat gun while N2 was introduced.
The evacuation-warming cycle was repeated ®ve times.
1
92.93 g, 74% yield). H NMR d 7.08 9d, 1H, Jˆ8.1 Hz),

1476
P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
THF 930 mL) was introduced under N2 and the solution
cooled to 2788C. N-Butyllithium 91.25 M in hexanes,
3.08 mL, 3.83 mmol) was added until a yellow color
persisted, whereupon the remainder was added dropwise.
After 0.5 h, the deepred solution was cooled to 21058C,
and a solution of 5 90.720 g, 2.78 mmol) in THF 930 mL)
was added dropwise. After 0.5 h, the light yellow mixture
was warmed to rt, quenched with 4 mL sat'd NH4Cl,
followed by the addition of water and EtOAc. The aqueous
layer was extracted 2£ with CH2Cl2, and then the combined
organic layers dried 9Na2SO4) and evaporated to yield crude
alkylated formamidine derivative as a yellow oil. This
material was directly subjected to hydrazinolysis in order
to remove the auxiliary, as follows.
mmol) was converted into 2-formamidine by reaction with
the Meyers auxiliary 92.81 g, 15.83 mmol). The product was
25
obtained as a yellow oil 92.28 g, 71%); [a]D ˆ254.2 9c
3.07, CDCl3), lit13 [a]D ˆ255.6 9c 1.21, CDCl3). 1H
25
NMR d 7.38 9s, 1H), 6.59 9s, 1H), 6.57 9s, 1H), 5.89 9s,
2H), 4.45 9d, 1H, Jˆ16.5 Hz), 4.36 9d, 1H, Jˆ16.8 Hz),
3.54±3.35 9m, 4H), 3.33 9s, 3H), 2.82 9m, 1H), 2.75 9t,
2H, Jˆ6.0 Hz), 1.74 9sept, 1H, Jˆ6.6 Hz), 0.85 9t, 6H,
Jˆ6.3 Hz). 13C NMR d 153.6, 146.00, 145.98, 127.7,
126.6, 108.6, 106.3, 100.7, 76.3, 71.5, 59.0, 46.8, 44.4,
30.9, 29.2, 20.1, 18.7. IR 9®lm): 1653, 1487, 1387, 1248,
1200, 1113, 1039, 928, 856, 756 cm21
.
4.1.9. 0S)-1,2,3,4-Tetrahydro-1-[03,4-dimethoxy-2-tri-
methylsilylphenyl)methyl]-6,7-methylenedioxyisoquino-
line 08). In a manner similar to that described for 7,
2-formamidine 91.78 g, 5.82 mmol) was alkylated with 5
to produce 3.08 g of crude benzyl tetrahydroisoquinoline
formamidine derivative as a yellow oil. This material was
directly subjected to hydrazinolysis to yield after puri®ca-
tion the benzyl tetrahydroisoquinoline 8 as a yellow oil
Crude alkylated formamidine 91.44 g, based on 2.65 mmol
of precursor) was taken up in EtOH 995%, 3.5 mL), cooled
to 08C, and treated with HOAc 90.43 mL) followed by
hydrazine monohydrate 90.86 mL). The solution was then
warmed to rt, stirred for 12 h, and then partitioned between
water and CH2Cl2. The aqueous layer was extracted 2£ with
CH2Cl2. The organic layers were then dried 9Na2SO4) and
evaporated. The residue was chromatographed 9SiO2, 6:2:1
hexane/EtOAc/Et3N) to give 7 as a yellow oil 90.573 g, 52%
25
1
91.31 g, 56% yield); [a]D ˆ251.7 9c 3.17, CDCl3). H
NMR d 6.96 9d, 1H, Jˆ8.1 Hz), 6.89 9d, 1H, Jˆ8.4 Hz),
6.57 9s, 1H), 6.56 9s, 1H), 5.88 9s, 2H), 3.96 9m, 1H), 3.85 9s,
6H), 3.39 9dd, 1H, Jˆ13.5, 5.1 Hz), 3.19±3.11 9m, 1H),
2.87±2.68 9m, 4H), 1.68 9bs, 1H), 0.35 9s, 9H). 13C NMR
d 154.5, 150.2, 145.7, 145.4, 136.6, 132.3, 131.7, 128.3,
126.4, 113.5, 108.8, 106.1, 100.5, 60.6, 57.5, 55.4, 41.5,
41.4, 30.1, 2.9. IR 9nujol): 1485, 1246, 1156, 1046,
25
yield); [a]D ˆ251.7 9c 3.17, CDCl3). 1H NMR d 6.90 9d,
1H, Jˆ8.1 Hz), 6.89 9d, 1H, Jˆ8.4 Hz), 6.58 9s, 1H), 6.42
9s, 1H), 4.10 9m, 1H), 3.86 9s, 6H), 3.81 9s, 3H), 3.70 9s, 3H),
3.37 9dd, 1H, Jˆ13.5, 5.1 Hz), 3.21 9m, 1H), 2.98±2.80 9m,
4H), 1.62 9bs, 1H), 0.36 9s, 9H). 13C NMR d 155.0, 150.3,
147.3, 146.6, 136.9, 132.3, 130.4, 127.2, 126.7, 113.5,
111.8, 109.5, 60.7, 57.2, 56.1, 55.8, 55.5, 41.7, 41.3, 29.5,
2.9. IR 9nujol): 1510, 1463, 1381, 1258, 1220 cm21. HRMS
for C23H34NO4Si 9MH1): calcd 416.2258, found 416.2263.
860 cm21
.
400.1944, found 400.1941.
HRMS for C22H30NO4Si 9MH1): calcd
4.1.10. 0S)-02)-Canadine. Pictet±Spengler cyclization was
carried out as described for the preparation of tetrahydro-
palmatine earlier, to convert benzyl tetrahydroisoquinoline
8 90.188 g, 0.471 mmol) into 9S)-92)-canadine, isolated
after puri®cation as a yellow solid 90.146 g, 91% yield);
synthetic mpˆ142±1458C; natural19 mpˆ1328C. Synthetic
4.1.7. 0S)-02)-Tetrahydropalmatine. A mixture of EtOH
92.1 mL) and aq. formaldehyde 90.9 mL, 37%), which had
been acidi®ed with 10% HCl, was added to 7 90.235 g,
0.565 mmol), and suf®cient additional dilute HCl was
added after dissolution to adjust the mixture to pH 6. The
mixture was heated to 858C overnight, open to the air, then
cooled and basi®ed with 1N aq. NaOH. The mixture was
extracted with CH2Cl2. The organic layer was washed
successively with water and brine, dried 9Na2SO4), and
evaporated. The resulting yellow solid was chromato-
graphed 9SiO2, 9:1 hexane/EtOAc) to give 9S)-92)-tetra-
hydropalmatine as a yellow solid 90.179 g, 89% yield);
synthetic mpˆ142±1458C; natural16 mpˆ1438C. Synthetic
25
15
[a]D ˆ2174 9c 2.88, CDCl3). Natural [a]D ˆ2299
9CDCl3). H NMR17 d 6.87 9d, 1H, Jˆ8.4 Hz), 6.78 9d,
1
1H, Jˆ8.1 Hz), 6.73 9s, 1H), 6.59 9s, 1H), 5.92 9s 2H),
4.24 9d, 1H, Jˆ15.9 Hz), 3.85 9s, 6H), 3.53 9d, 1H,
Jˆ15.6 Hz), 3.53 9m, 1H), 3.26±3.07 9m, 3H), 2.81 9dd,
1H, Jˆ15.9, 11.4 Hz), 2.70±2.59 9m, 2H). 13C NMR18
d
150.3, 146.1, 145.9, 145.0, 130.8, 128.6, 127.8, 127.7,
123.9, 110.9, 108.4, 105.5, 100.8, 60.2, 59.6, 55.9, 53.9,
51.4, 36.5, 29.6.
25
20
[a]D ˆ2160 9c 2.73, CDCl3). Natural [a]D ˆ2291
9EtOH). H NMR17 d 6.88 9d, 1H, Jˆ8.0 Hz), 6.80 9d, 1H,
4.1.11. 0S)-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-[03,4-
methylenedioxy-2-trimethylsilylphenyl)methyl]iso-
quinoline 09). In a manner similar to that described for 7,
1-formamidine 90.876 g, 2.73 mmol) was alkylated with 6
to produce 1.43 g of crude benzyl tetrahydroisoquinoline
formamidine derivative as a yellow oil. This material was
directly subjected to hydrazinolysis to yield after puri®ca-
tion the benzyl tetrahydroisoquinoline 9 as a yellow oil
1
Jˆ8.0 Hz), 6.74 9s, 1H), 6.63 9s, 1H), 4.25 9d 1H,
Jˆ15.7 Hz), 3.90 9s, 3H), 3.88 9s, 3H), 3.86 9s, 6H), 3.54
9d, 1H, Jˆ15.7 Hz), 3.49 9dd, 1H, Jˆ12.2, 4.0 Hz), 3.27 9dd,
1H, Jˆ15.8, 4.0 Hz), 3.23 9m, 1H), 3.10 9m, 1H), 2.91 9dd,
1H, Jˆ15.8, 12.2 Hz), 2.68 9m, 1H), 2.65 9m, 1H). 13C
NMR18 d 150.2, 147.5, 147.3, 145.0, 129.6, 128.6, 127.7,
126.7, 123.8, 111.2, 110.8, 108.5, 60.1, 59.3, 56.0, 55.8,
55.7, 54.0, 51.5, 36.3, 29.1.
25
1
90.546 g, 50% yield); [a]D ˆ246.8 9c 2.84, CHCl3). H
NMR d 6.77 9d, 1H, Jˆ8.1 Hz), 6.71 9d, 1H, Jˆ8.1 Hz),
6.60 9s, 1H), 6.56 9s, 1H), 5.93 9s, 2H), 4.01 9m, 1H), 3.82 9s,
3H), 3.76 9s, 3H), 3.31 9dd, 1H, Jˆ13.5, 5.1 Hz), 3.16 9m,
1H), 2.86±2.66 9m, 4H), 1.74 9bs, 1H), 0.36 9s, 9H). 13C
NMR d 154.2, 149.8, 149.7, 147.1, 136.9, 129.2, 128.9,
126.0, 119.3, 114.7, 111.6, 100.6, 59.5, 59.4, 56.4, 45.8,
4.1.8. 0S)-1,2,3,4-Tetrahydro-2-[[01-0methoxymethyl)-2-
methylpropyl)imino]methyl]-6,7-methylenedioxyiso-
quinoline 02-formamidine).13 In manner similar to that
used for the preparation of 1-formamidine, 1,2,3,4-tetra-
hydro-6,7-methylenedioxyisoquinoline 2 91.87 g, 10.55

P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
1477
44.2, 31.5, 2.9. IR 9nujol): 1493, 1454, 1331, 1275 cm21
.
hydroisoquinoline 12 as a yellow oil 90.802 g, 53% yield
25
HRMS for C22H30NO4Si 9MH1): calcd 400.1944, found
400.1951.
overall from the corresponding formamidine); [a]D
ˆ
244.3 9c 2.32, CDCl3). 1H NMR d 6.96 9d, 1H,
Jˆ8.1 Hz), 6.89 9d, 1H, Jˆ8.4 Hz), 6.57 9s, 1H), 6.56 9s,
1H), 5.88 9s, 2H), 3.95 9m, 1H), 3.86 9s, 6H), 3.80 9s, 3H),
3.39 9dd, 1H, Jˆ13.5, 5.1 Hz), 1.35±3.18 9m, 1H), 2.91±
2.70 9m, 4H), 1.67 9bs, 1H), 0.32 9s, 9H). 13C NMR d 156.4,
152.2, 143.7, 142.5, 138.7, 135.2, 134.8, 134.4, 128.0,
125.9, 123.8, 123.1, 121.2, 119.5, 117.5, 117.8, 72.7, 64.2,
58.7, 54.3, 53.8, 46.2, 27.7, 2.6. IR 9nujol): 1490, 1466,
1326, 1280 cm21. HRMS for C29H38NO4Si 9MH1): calcd
492.2571, found 492.2563.
4.1.12. 0S)-02)-Sinactine and 0S)-02)-2,3-dimethoxy-
10,11-methylenedioxy-12-trimethylsilylprotoberberine.
Pictet±Spengler cyclization was carried out as described for
the preparations of tetrahydropalmatine and canadine
earlier, on benzyl tetrahydroisoquinoline 9 90.181 g,
0.236 mmol). After separation and puri®cation of the result-
ing crude product mixture as previously described, two
products were obtained: the 60 ring-closure product,
9S)-92)-2,3-dimethoxy-10,11-methylenedioxy-12-trimethyl-
silylprotoberberine, a yellow solid 90.073 g, 39% yield), and
the 20 ring-closure product, 9S)-92)-sinactine, also a yellow
solid 90.048 g, 31% yield).
4.1.14. 0S)-02)-Corypalmine. Pictet±Spengler cyclization
was carried out as described for the preparation of tetra-
hydropalmatine earlier, to convert benzyl tetraisoquinoline
12 90.225 g, 0.458 mmol) into 9S)-92)-corypalmine, a
yellow solid 90.145 g, 86% yield); synthetic mpˆ210±
#S)-#2)-2,3-Dimethoxy-10,11-methylenedioxy-12-trimethyl-
2158C; natural21 mpˆ235±2368C. Synthetic [a]D ˆ2166
25
silylprotoberberine: mpˆ81±848C; [a]D ˆ299.6 9c 0.45
25
1
CHCl3). H NMR d 6.68 9s, 1H), 6.59 9s, 1H), 6.52 9s,
16
9c 2.13, CDCl3). Natural [a]D ˆ2280 9CHCl3). 1H NMR d
1H), 5.93 9s, 2H), 3.89 9d, 1H, Jˆ14.4 Hz), 3.85 9s, 3H),
3.79 9s, 3H), 3.63 9d, 1H, Jˆ14.4 Hz), 3.47 9dd, 1H, Jˆ10.8,
3.3 Hz), 3.31 9dd, 1H, Jˆ15.6, 3.0 Hz), 3.16±3.08 9m, 2H),
2.78 9dd, 1H, Jˆ15.0, 11.1 Hz), 2.67±2.50 9m, 2H), 0.36 9s,
9H). 13C NMR d 151.6, 146.2, 145.9, 144.5, 142.2, 131.6,
130.9, 127.8, 127.0, 117.7, 108.5, 107.0, 105.1, 100.7, 99.7,
60.1, 59.3, 51.2, 38.5, 29.5, 1.4. HRMS for C23H30NO4Si
9MH1): calcd 412.1945, found 412.1954.
6.86 9d, 1H, Jˆ8.4 Hz), 6.78 9d, 1H, Jˆ8.4 Hz), 6.70 9s,
1H), 6.65 9s, 1H), 6.14 91H, bs), 4.27 9d, 1H, Jˆ15.6),
3.89 9s, 3H), 3.85 9s, 3H), 3.84 9s, 3H), 3.55 9d, 1H,
Jˆ15.6 Hz), 3.46 9dd, 1H, Jˆ12.0, 4.0 Hz), 3.25 9dd, 1H,
Jˆ15.6, 4.0 Hz), 3.18 9m, 1H), 3.10 9m, 1H), 2.88 9dd, 1H,
Jˆ15.6, 11.8 Hz), 2.66 9m, 1H), 2.64 9m, 1H). 13C NMR d
150.2, 147.1, 147.0, 145.0, 129.1, 128.6, 127.6, 127.4,
123.8, 114.2, 110.8, 107.7, 60.2, 59.3, 56.0, 55.8, 53.9,
51.5, 36.4, 28.8.
#S)-#2)-Sinactine: synthetic mpˆ170±1738C; natural20
25
mpˆ1758C. Synthetic [a]D ˆ2187 9c 3.17, CHCl3).
4.1.15. 0S)-7-Benzyloxy-1,2,3,4-tetrahydro-6-methoxy-1-
[03,4-dimethoxy-2-trimethylsilylphenyl)methyl]iso-
quinoline 013). Reaction of 7-benzyloxy-6-methoxy-
1,2,3,4-tetrahydroisoquinoline 911) 91.20 g, 4.46 mmol)
and the Meyers auxiliary 91.19 g, 6.69 mmol) was carried
out in the manner described for 1-formamidine. After
workup and silica gel chromatography the corresponding
formamidine was obtained as a yellow oil 91.05 g, 59%
25
1
Natural [a]D ˆ2312 90.37 CHCl3). H NMR d 6.73 9s,
1H), 6.67 9AB pattern, 2H), 6.62 9s, 1H), 5.90 9s, 2H),
4.08 9d, 1H, Jˆ16.0 Hz), 3.85 9s, 3H), 3.83 9s, 3H), 3.52
9d, 1H, Jˆ16.0 Hz), 2.42±3.24 9m, 7H). 13C NMR d 150.3,
146.1, 145.9, 145.0, 130.8, 128.6, 127.8, 127.7, 123.9,
110.9, 108.4, 105.5, 100.8, 60.7, 59.6, 55.9, 53.9, 51.4,
36.5, 29.6.
25
1
yield); [a]D ˆ247.2 9c 2.12, CDCl3). H NMR d 7.43±
7.28 9m, 5H), 6.63 9s, 1H), 6.62 9s, 1H), 5.11 9s, 2H), 4.41 9d,
1H, Jˆ16.5 Hz), 4.32 9d, 1H, Jˆ16.8 Hz), 3.86 9s, 2H),
3.54±3.45 9m, 4H), 3.33 9s, 3H), 2.79 9m, 1H), 2.77 9t,
2H, Jˆ6.0 Hz), 1.76 9sept, 1H, Jˆ6.6 Hz), 0.85 9t, 6H,
Jˆ6.3 Hz). 13C NMR d 157.6, 154.2, 146.2, 137.9, 128.4,
127.5, 126.3, 125.8, 114.0, 104.3, 103.6, 76.6, 72.1, 59.6,
56.3, 47.6, 45.9, 32.9, 28.7, 20.4, 18.1. IR 9®lm): 1650,
4.1.13. 0S)-6-Benzyloxy-1,2,3,4-tetrahydro-7-methoxy-1-
[03,4-dimethoxy-2-trimethylsilylphenyl)methyl]iso-
quinoline 012). Reaction of 6-benzyloxy-7-methoxy-
1,2,3,4-tetrahydroisoquinoline 910) 91.49 g, 5.03 mmol)
and the Meyers auxiliary 91.34 g, 7.55 mmol) was carried
out in the manner described for 1-formamidine. After
workup and silica gel chromatography the corresponding
formamidine was obtained as a yellow oil 91.24 g, 62%
1509, 1387, 1251 cm21
.
25
1
yield); [a]D ˆ245.2 9c 3.04, CDCl3). H NMR d 7.43±
7.26 9m, 5H), 6.63 9s, 1H), 6.62 9s, 1H), 5.11 9s, 2H), 4.41 9d,
1H, Jˆ16.5 Hz), 4.32 9d, 1H, Jˆ16.8 Hz), 3.86 9s, 3H),
3.54±3.41 9m, 4H), 3.33 9s, 3H), 2.78 9t, 2H, Jˆ6.0 Hz),
2.51 9m, 1H), 1.74 9sept, 1H, Jˆ6.6 Hz), 0.86 9t, 6H,
Jˆ6.3 Hz). 13C NMR d 154.0, 148.5, 147.1, 137.5, 128.9,
128.1, 127.5, 125.9, 112.6, 112.0, 76.7, 71.8, 71.5, 59.3,
56.4, 46.7, 44.9, 31.2, 29.1, 20.4, 19.1. IR 9®lm): 1642,
Without further puri®cation this formamidine 91.05 g,
2.65 mmol) was subjected to alkylation by 5 90.892 g,
3.45 mmol) in the manner described for the preparation of
7. The crude alkylated material 91.64 g, based on 2.65 mmol
of precursor) was directly subjected to hydrazinolysis to
yield after puri®cation the benzyl tetrahydroisoquinoline
13 as a yellow oil 90.807 g, 62% yield overall from the
1514, 1454, 1381, 1255 cm21
.
corresponding formamidine); [a]D ˆ249.6 9c 2.14,
25
1
CDCl3). H NMR d 7.41 9m, 5H), 6.91 9d, 1H, Jˆ8.0 Hz),
Without further puri®cation this formamidine 91.22 g,
3.08 mmol) was subjected to alkylation by 5 91.04 g,
4.00 mmol) in the manner described for the preparation of
7. The crude alkylated material 91.90 g, based on
0.685 mmol of precursor) was directly subjected to
hydrazinolysis to yield after puri®cation the benzyl tetra-
6.89 9d, 1H, Jˆ8.0 Hz), 6.62 9s, 1H), 6.45 9s, 1H), 5.10 9s,
2H), 4.10 9m, 1H), 3.86 9s, 3H), 3.82 9s, 3H), 3.70 9s, 3H),
3.41 9dd, 1H, Jˆ13.5, 5.1 Hz), 3.18 9m, 1H), 2.89±2.64 9m,
4H), 1.51 9bs, 1H), 0.37 9s, 9H). 13C NMR d 154.5, 150.1,
147.2, 146.5, 137.2, 136.9, 132.1, 131.6, 128.3, 127.3,
127.6, 126.8, 126.3, 114.7, 113.5, 110.2, 71.0, 60.5, 57.2,

1478
P. S. Cutter et al. /Tetrahedron 58 #2002) 1471±1478
1686. 9c) Buck, J. S.; Perkin, W. H. J. Chem. Soc. 1924, 125,
1675.
55.7, 55.4, 41.6, 41.2, 29.4, 2.8. IR 9nujol): 1494, 1470,
1332, 1290 cm21. HRMS for C29H38NO4Si 9MH1): calcd
492.2571, found 492.2567.
6. Kametani, T.; Nakano, K.; Shishido, K.; Fukumoto, K.
J. Chem. Soc. #C) 1971, 3350.
7. Miller, R. B.; Tsang, T. Tetrahedron Lett. 1988, 29, 6715.
8. Early achiral studies: 9a) Meyers, A. I.; Hellring, S.; Hoeve, T.
Tetrahedron Lett. 1981, 22, 5115. 9b) Meyers, A. I.; Edwards,
P. D.; Rieker, W. F.; Bailey, T. R. J. Am. Chem. Soc. 1984,
106, 3270.
4.1.16. 0S)-02)-Isocorypalmine. Pictet±Spengler cycliza-
tion was carried out as described for the preparation of
tetrahydropalmatine earlier, to convert benzyl tetraiso-
quinoline 13 90.201 g, 0.409 mmol) into 9S)-92)-iso-
corypalmine,
a yellow solid 90.128 g, 92% yield);
synthetic mpˆ228±2358C; natural22 mpˆ241±2428C.
9. Chiral tetrahydroisoquinoline studies: 9a) Meyers, A. I.;
Fuentes, L. M.; Kubota, Y. Tetrahedron 1984, 40, 1361.
9b) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron
1987, 43, 5095. 9c) Meyers, A. I.; Du, B.; Gonzalez, M. A.
J. Org. Chem. 1990, 55, 4218. 9d) Meyers, A. I.; Gottlieb, L.
J. Org. Chem. 1990, 55, 5659. 9e) Meyers, A. I.; Gonzalez,
M. A.; Struzka, V.; Akahane, A.; Guiles, J.; Warmus, J. S.
Tetrahedron Lett. 1991, 32, 5501. For related work with
carbonyl electrophiles, see Gawley, R.E.; Zhang, P. J. Org.
Chem. 1996, 61, 8103 and references therein. We are grateful
to one of the reviewers for pointing out this work to us.
10. Mechanistic studies: 9a) Meyers, A. I.; Dickman, D. A. J. Am.
Chem. Soc. 1987, 109, 1263. 9b) Meyers, A. I.; Warmus, J. S.;
Rodkin, M. A.; Barkley, R. Chem. Commun. 1993, 1357.
11. Reviews: 9a) Meyers, A. I. Aldrichimica Acta 1985, 18, 59.
9b) Meyers, A. I. Tetrahedron 1992, 48, 2589.
25
Synthetic [a]D ˆ2173 9c 2.44, CDCl3). Natural
[a]D ˆ2303 9CHCl3). 1H NMR
d
6.87 9d, 1H,
25
Jˆ8.4 Hz), 6.78 9d, 1H, Jˆ8.1 Hz), 6.71 9s, 1H), 6.68 9s,
1H), 5.88 9bs, 1H), 4.24 9d, 1H, Jˆ15.9 Hz), 3.90 9s, 3H),
3.87 9s, 6H), 3.53 9d, 1H, Jˆ15.6 Hz), 3.53 9m, 1H), 3.26±
3.07 9m, 3H), 2.81 9dd, 1H, Jˆ15.9, 11.4 Hz), 2.70±2.59
9m, 2H). 13C NMR d 150.4, 145.9, 145.3, 144.2, 129.4,
128.7, 124.3, 124.0, 123.7, 114.3, 111.3, 108.1, 60.1, 59.4,
56.9, 56.0, 54.0, 51.5, 36.5, 29.0.
Acknowledgements
We thank the University of California, Davis, Committee on
Research and the National Science Foundation 9Grants
CHE-9710286 and CHE-0078191) for support of this
research.
12. Cf. Kohno, M.; Sasao, S.; Murahashi, S. Bull. Chem. Soc. Jpn
1990, 63, 1252.
13. Matulenko, M. A.; Meyers, A. I. J. Org. Chem. 1996, 61, 573.
14. Taylor, C.B. Dissertation, UC Davis, 1997.
15. Baffeley, G.; Smith, N. H. P.; Vickars, M. A. J. Chem. Soc.
1956, 2455.
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