Asymmetric synthesis of tetrahydropalmatine via tandem 1,2-addition/ cyclization

Article abstract of DOI:10.1021/jo051554t

The enantioselective synthesis of both enantiomers of tetrahydropalmatine (2) (ee = 98%), a natural alkaloid belonging to the tetrahydroprotoberberine family, is described. The key step of this total synthesis is based on our tandem 1,2-addition/ring-closure methodology employing lithiated methylbenzamide and benzaldehyde SAMP or RAMP hydrazones as substrates. An initial route was investigated for the formation of N- and 3-substituted dihydroisoquinolones starting from 2-substituted benzaldehyde SAMP hydrazones, but although high diastereoselectivity was achieved, only disappointing yields were obtained. In our subsequent synthetic strategy, 2,3-dimethoxy-6-methylbenzamide 6 and 3,4-dimethoxybenzaldehyde SAMP or RAMP hydrazone 19 gave the dihydroisoquinolones 20 in high diastereomeric purity (de ≥ 96%) and reasonable yield (54-55%), taking into account the complex functionalities established in one step. Cleavage of the N-N bond of the chiral auxiliary and reduction of the carbonyl group of the amide moiety were performed in the same step, and the resulting tetrahydroisoquinolines 22 (ee = 99%) were N-functionalized by treatment with various electrophiles to investigate the ring closure by Pummerer, Friedel-Crafts, and Pomeranz-Fritsch reactions. The Pummerer cyclization led to the formation of (S)-(-)-2 with slight racemization (ee = 89%), whereas the Friedel-Crafts reaction proved to be unsuccessful. Finally, Pomeranz-Fritsch-type cyclization afforded the desired title compound (R)-(+)-2 in excellent enantioselectivity in 9% overall yield over seven steps and after optimization of the last step (S)-(-)-2 in 17% overall yield.

Full text of DOI:10.1021/jo051554t

Asymmetric Synthesis of Tetrahydropalmatine via Tandem
1,2-Addition/Cyclization
Marine Boudou and Dieter Enders*
Institut fu¨r Organische Chemie, RWTH Aachen, Landoltweg 1, D-52074 Aachen, Germany
enders@rwth-aachen.de
Received July 26, 2005
The enantioselective synthesis of both enantiomers of tetrahydropalmatine (2) (ee ) 98%), a natural
alkaloid belonging to the tetrahydroprotoberberine family, is described. The key step of this total
synthesis is based on our tandem 1,2-addition/ring-closure methodology employing lithiated
methylbenzamide and benzaldehyde SAMP or RAMP hydrazones as substrates. An initial route
was investigated for the formation of N- and 3-substituted dihydroisoquinolones starting from
2-substituted benzaldehyde SAMP hydrazones, but although high diastereoselectivity was achieved,
only disappointing yields were obtained. In our subsequent synthetic strategy, 2,3-dimethoxy-6-
methylbenzamide 6 and 3,4-dimethoxybenzaldehyde SAMP or RAMP hydrazone 19 gave the
dihydroisoquinolones 20 in high diastereomeric purity (de g 96%) and reasonable yield (54-55%),
taking into account the complex functionalities established in one step. Cleavage of the N-N bond
of the chiral auxiliary and reduction of the carbonyl group of the amide moiety were performed in
the same step, and the resulting tetrahydroisoquinolines 22 (ee ) 99%) were N-functionalized by
treatment with various electrophiles to investigate the ring closure by Pummerer, Friedel-Crafts,
and Pomeranz-Fritsch reactions. The Pummerer cyclization led to the formation of (S)-(-)-2 with
slight racemization (ee ) 89%), whereas the Friedel-Crafts reaction proved to be unsuccessful.
Finally, Pomeranz-Fritsch-type cyclization afforded the desired title compound (R)-(+)-2 in excellent
enantioselectivity in 9% overall yield over seven steps and after optimization of the last step
(S)-(-)-2 in 17% overall yield.
Introduction
families, are characterized by a tetracyclic skeleton
containing an isoquinoline core.1 Alkoxy or hydroxy
substituents of the A ring are always situated at the same
positions, whereas the substitution pattern of the D ring
can slightly vary. In addition to their stereogenic center
in C-14, these alkaloids can possess alkyl or hydroxy
substitution at the C-13 position.3
The protoberberines, a large class of naturally occur-
ring alkaloids, possess antitumor, antimicrobial, and
other biological activities.1,2 The tetrahydroprotober-
berines 1, a subclass occurring in at least eight botanical
(1) (a) Bhakuni, D. S.; Jain, S. In The Alkaloids: Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1986; Vol.
28, p 95. (b) Sˇantavy´, F. In The Alkaloids: Chemistry and Physiology;
Manske, R. H. F., Rodrigo, R. G. A., Eds.; Academic Press: New York,
1979; Vol. 17, 385. (c) Sˇantavy´, F. In The Alkaloids: Chemistry and
Physiology; Manske, R. H. F., Ed.; Academic Press: New York, 1970;
Vol. 12, p 333. (d) Jeffs, P. W. In The Alkaloids: Chemistry and
Physiology; Manske, R. H. F., Ed.; Academic Press: New York, 1967;
Vol. 9, p 41. (e) Manske, R. H. F.; Ashford, W. R. In The Alkaloids:
Chemistry and Physiology; Manske, R. H. F., Holmes, H. L., Eds.;
Academic Press: New York, 1954. Vol. 4, p 78.
(2) (a) Memetzidis, G.; Stambach, J. F.; Jung, L.; Schott, C.; Heitz,
C.; Stoclet, J. C. Eur. J. Med. Chem. 1991, 26, 605. (b) Suffnees, M.;
Cordell, A. C. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, FL, 1985; Vol. 25, p 3. (c) Cushman, M.; Dekow, F. W.;
Jacobsen, L. B. J. Med. Chem. 1979, 22, 331. (d) Wilson, W. D.; Gough,
A. N.; Doyle, J. J.; Davison, M. W. J. Med. Chem. 1976, 19, 1261. (e)
Zee-Cheng, R. K. Y.; Cheng, C. C. J. Med. Chem. 1976, 19, 882.
(3) Ro¨mpp-Lexikon Naturstoffe; Fugmann, B., Ed.; Thieme: Stut-
tgart, 1997; pp 519-520.
10.1021/jo051554t CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/14/2005
9486
J. Org. Chem. 2005, 70, 9486-9494

Asymmetric Synthesis of Tetrahydropalmatine
SCHEME 1
Among the different strategies described for the con-
struction of the tetrahydroprotoberberine core, the clas-
sical Pictet-Spengler4 or Bischler-Napieralski/reduc-
tion5 procedures occupy a prominent position. Unfortu-
nately, the use of these heterocyclization procedures to
effect the final ring closure between the isoquinoline core,
containing rings A and D, has strong limitations. Indeed,
the electronic requirements of the cyclization restrict the
scope of the substitution pattern at the aromatic ring of
the tetrahydroprotoberberine skeleton. Those methods
are unsuitable for the synthesis of 9,10-disubstituted
derivatives as for example tetrahydropalmatine (2).
Several approaches have been developed to overcome
these difficulties, but currently, the three described
asymmetric syntheses of tetrahydropalmatine have not
been fully selective.6
Very recently, we reported the asymmetric synthesis
of 3-substituted dihydro-2H-isoquinolin-1-ones, dihydro-
and tetrahydroisoquinolines via a tandem 1,2-addition/
ring-closure sequence7 employing lithiated N,N-diethyl-
2-methylbenzamides and aromatic hydrazones derived
from enantiomerically pure hydrazines SAMP or RAMP
((S)- or (R)-1-amino-2-(methoxymethyl)pyrrolidine).8 We
were hoping that an application of this methodology to
the asymmetric total synthesis of 9,10-disubstituted
tetrahydroprotoberberines, and more particularly tet-
rahydropalmatine, should prove the validity of our
synthetic strategy.
Both enantiomers of 2 as well as the racemate are
present in nature. Although (R)-(+)-tetrahydropalmatine
seems to have been isolated as early as 1903,9 it was not
before 1923 that the structure elucidation of this alkaloid
was accomplished after its isolation from tubers of
Corydalis cava.10 Among the biological activities at-
tributed to tetrahydropalmatine, the racemic form was
shown to possess an insecticidal activity against larvae
and adults of Drosophila melanogaster,11 whereas the (S)-
(-) enantiomer might be valuable as an antitumor
promoter (inhibitory effect on Epstein-Barr virus).12 The
(R)-(+) enantiomer was shown to inhibit the activity of
GABA-T by 46%, this irreversible inhibition being the
basic action mechanism of drugs used in the treatment
of convulsive disorders.13
(4) For a review on Pictet-Spengler cyclization, see: Cox, E. D.;
Cook, J. M. Chem. Rev. 1995, 95, 1797. For examples, see: (a)
Munchoff, M. J.; Meyers, A. I. J. Org. Chem. 1996, 61, 4607. (b) Miller,
R. B.; Tsang, T. Tetrahedron Lett. 1988, 29, 6715. (c) Meyers, A. I.;
Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095. (d) Meyers, A.
I.; Boes, M.; Dickman, D. A. Angew. Chem., Int. Ed. Engl. 1984, 23,
458. (e) McMurtrey, K. D.; Meyerson, L. R.; Cashaw, J. L.; Davis, V.
E. J. Org. Chem. 1984, 49, 947. (f) Kametani, T.; Nakano, K.; Shishido,
K.; Fukumoto, K. J. Chem. Soc. C 1971, 3350.
The target molecules (R)-(+)- and (S)-(-)-tetrahydro-
palmatine (2) should either be obtained after ozonolysis,
deprotection, and reductive amination of precursor 3
(Scheme 1, route I) or should result from the ring closure
of tetrahydroisoquinoline 4 employing a Friedel-Crafts,
(5) See, for example: (a) Venkov, A. P.; Ivanov, I. I. Tetrahedron
1996, 52, 12299. (b) Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis,
P.; Grabowski, E. J. J.; Reider, P. J.; Shinkai, I. J. Org. Chem. 1991,
56, 6034. (c) Pandey, G. D.; Tiwari, K. P. Heterocycles 1980, 14, 59. (d)
Patra, A.; Mukhopadhyay; Mitra, A. K. Indian J. Chem., Sect. B 1980,
19, 561. (e) Pai, B. R.; Natarajan, S.; Manikumar, G.; Rajaraman, R.;
Suguna, H. J. Org. Chem. 1978, 43, 1992. (f) Rajaraman, R.; Pai, B.
R.; Premila, M. S.; Suguna, H. Indian J. Chem., Sect. B 1977, 15, 876.
(6) (a) Cutter, P. S.; Miller, R. B.; Schore N. E. Tetrahedron 2002,
58, 1471. (b) Matulenko, M. A.; Meyers, A. I. J. Org. Chem. 1996, 61,
573. (c) Pyne, S. G.; Dikic, B. J. Org. Chem. 1990, 55, 1932.
(7) Enders, D.; Braig, V.; Boudou, M.; Raabe, G. Synthesis 2004,
2980.
(10) Spa¨th, E.; Mosettig, E.; Tro¨thandl, O. Chem. Ber. 1923, 56, 875.
(11) Miyazawa, M.; Yoshio, K.; Ishikawa, Y.; Kameoka, H. J. Agric.
Food Chem. 1998, 46, 1914.
(12) Ito, C.; Itoigawa, M.; Tokuda, H.; Kuchide, M.; Nishino, H.;
Furukawa, H. Planta Med. 2001, 67, 473.
(8) (a) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173.
(b) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933.
(9) Heyl, G. Arch. Pharm. (Weinheim, Ger.) 1903, 241, 318.
(13) Choi, S. Y.; Bang, M.-H.; Lee, E. J.; Kwon, O.-S.; Kang, T.-C.;
Lee, Y.-H.; Rho, Y.-D.; Baek, N.-I. Agric. Chem. Biotechnol. 2003, 46,
67 and references cited therein.
J. Org. Chem, Vol. 70, No. 23, 2005 9487

Boudou and Enders
SCHEME 2a
SCHEME 3a
a Reagents and conditions: (a) SAMP or RAMP, MS 4 Å, Et2O,
0 °C to room temperature, 18-21 h.
amount of LDA at -78 °C to minimize the risk of self-
condensation.16 The lithiated species was then reacted
with 2-substituted benzaldehyde SAMP hydrazones (S)-
11, (S)-12, or (S)-13 previously complexed to AlMe3 at
-40 °C. However, instead of dihydroisoquinolinone (R,S)-
15, a complex mixture of products was isolated containing
(S)-11 together with its isomer, namely (2E)-2-propenyl
benzaldehyde SAMP hydrazone. For the bromide-substi-
tuted SAMP hydrazone (S)-12, only 11% of dihydroiso-
quinolone (R,S)-16 could be isolated with an excellent
diastereoselectivity of 96%. A comparison with the 65%
yield previously reported for para-bromobenzaldehyde
SAMP hydrazone indicated a strong steric hindrance for
this ortho-equivalent.7 In fact, a slight increase in the
yield of this reaction was observed by switching from the
bromide to the methyl substituent. This time the tandem
1,2-addition/ring closure between 2-methylbenzamide 14
and 2-methylbenzaldehyde SAMP hydrazone (S)-13 gave
27% of the desired dihydroisoquinolone (R,S)-17 with a
diastereomeric excess g96% (Scheme 2).
This series of reactions showed that ortho-substitution
on the benzaldehyde SAMP hydrazone was poorly toler-
ated by our system. It should be mentioned that the
Meyers route to tetrahydropalmatine6b was also thwarted
by the ortho-substitution in one of the reaction compo-
nents. Therefore, a second strategy (route II) was inves-
tigated where the ring closure of the tetrahydropalmatine
core does not require the help of an ortho-substituent on
the phenyl ring of our 3-substituted dihydroisoquinolone
system.
a Reagents and conditions: (a) SAMP, MS 4 Å, Et2O, 0 °C to
room temperature, 20-25 h. (b) LDA (7.0 equiv), THF, -78 °C
then (S)-11, (S)-12 or (S)-13, AlMe3 (1.1 equiv), THF, -40 °C, 16-
20 h.
a Pummerer, or a Pomeranz-Fritsch reaction (route II).
Both routes should ensure the correct methoxy substitu-
tion pattern present in ring A of 2 during the ring closure.
In addition, the formation of tetrahydroisoquinolines 3
or 4, containing the D ring with the correct substitution
pattern, gives then access to the 9,10-disubstituted
derivatives. Both tetrahydroisoquinolines could be de-
rived from a common precursor, namely N-substituted
3-phenyl-substituted dihydroisoquinolinone 5, after N-N
cleavage of the chiral auxiliary, reduction of the amide
functionality, and protection or functionalization of the
resulting free amine. However, to introduce the allyl
chain in 3, the protected bromide or methyl-substituted
amines derived from 5 would have to be submitted to
further functionalization. The generation of 5 was envis-
aged by our tandem 1,2-addition/ring-closure methodol-
ogy7 starting from 2,3-dimethoxy-6-methylbenzamide 6
and 3,4-dimethoxy benzaldehyde SAMP or RAMP hy-
drazone 7, respectively (Scheme 1).
3,4-Dimethoxybenzaldehyde SAMP or RAMP hydra-
zones 19 were obtained in virtually quantitative yield by
condensation of commercial 3,4-dimethoxybenzaldehyde
(18) and SAMP or RAMP, respectively, under the condi-
tions described above (Scheme 3).
The deprotonation of 2,3-dimethoxy-6-methylbenza-
mide (6), prepared in 92% yield over two steps starting
from commercially available 2,3-dimethoxybenzoic acid,17,18
Results and Discussion
As the tandem reaction had never been performed with
a 2-substituted SAMP hydrazone before, first a model
system of route I was investigated. Indeed, a reaction of
simple 2-methylbenzamide 14 with 2-substituted ben-
zaldehyde SAMP hydrazones (S)-11, (S)-12, or (S)-13
should function as a guide in terms of the possible yield
and diastereoselectivity offered by this tandem process
(Scheme 2).
The syntheses of SAMP hydrazones (S)-11, (S)-12, and
(S)-13 were achieved in excellent yields by condensation
of SAMP with the corresponding benzaldehydes 8,14 9,
and 10 in Et2O using molecular sieves to remove the
water formed during the reaction.15 Following the condi-
tions developed for our methodology,7 7 equiv of 2-me-
thylbenzamide 14 were deprotonated using an equimolar
(15) For recent reviews on the SAMP/RAMP-hydrazone method,
see: (a) Enders, D.; Voith, M.; Lenzen, A. Angew. Chem. 2005, 117,
1330; Angew. Chem., Int. Ed. 2005, 44, 1304. (b) Enders, D.; Boudou,
M.; Gries, J. In New Methods for the Asymmetric Synthesis of Nitrogen
Heterocycles; Vicario, J. L., Bad´ıa, D., Carillo, L., Eds.; Research
Signpost: Trivandrum, India, 2005; p 1. (c) Job, A.; Janeck, C. F.;
Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253.
(16) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
(17) Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Egbertson,
M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.; Hazuda, D. J.; Felock,
P. J.; Wolfe, A. L.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif,
W. A.; Gabryelski, L. J.; Leonard, Y. M.; Lynch, J. J., Jr.; Michelson,
S. R.; Young, S. D. J. Med. Chem. 2003, 46, 453.
(18) de Silva, S. O.; Ahmad, I.; Snieckus, V. Can. J. Chem. 1979,
57, 1598.
(14) Kampmeier, J. A.; Harris, S. H.; Mergelsberg, I. J. Org. Chem.
1984, 49, 621.
9488 J. Org. Chem., Vol. 70, No. 23, 2005

Asymmetric Synthesis of Tetrahydropalmatine
SCHEME 4a
BH3‚THF complex (20 equiv) was used to cleave the
N-N bond of the chiral auxiliary of dihydroisoquinoli-
none (R,S)-20 and to reduce the carbonyl group of the
amide moiety in the same step (Scheme 6). After hy-
drolysis of the borane using a 1 N aqueous solution of
HCl and a basic workup, we obtained tetrahydroiso-
quinoline (R)-22 in an excellent yield of 82% and with
an enantiomeric excess of 99% (determined by chiral
stationary phase HPLC). Analogously, (S)-22 was ob-
tained in the same enantiomeric purity and a reproduc-
ible yield of 83%.
The synthesis of (S)-(-)-tetrahydropalmatine was then
attempted by ring closure via Pummerer reaction. The
generation of Pummerer precursor (S)-23 was easily
carried out by a Michael reaction of tetrahydroisoquino-
line (S)-22 with phenyl vinyl sulfoxide in refluxing
methanol. A diastereoisomeric mixture of (S)-23 (ratio
of 64/36 determined by HPLC) was obtained in 94% yield.
The Pummerer reaction was realized by subjecting (S)-
23 to 3 equiv of TFAA and 6 equiv of TFA in refluxing
toluene.21 Phenylsulfanyl tetrahydrodibenzoquinolizine
(S)-24 was passed through silica gel and then directly
subjected to the next step. We were pleased to see that,
after reductive desulfurization with Raney nickel, 31%
yield of (S)-(-)-tetrahydropalmatine (2) could be obtained
over two steps (Scheme 7). However, slight racemization
occurred during this sequence (ee ) 89% determined by
chiral stationary phase HPLC), which may have to do
with the harsh TFA conditions necessary for this trans-
formation.
The possibility to synthesize (S)-(-)-tetrahydropalma-
tine by Friedel-Crafts reaction was subsequently inves-
tigated. After reflux of a solution of tetrahydroisoquin-
oline (S)-22 and iodoethanol in MeCN in the presence of
NaHCO3, the alcohol (S)-25 was obtained in 80% yield.
The conversion of the primary alcohol into the corre-
sponding chloride was performed after mesylation and
nucleophilic attack of the intermediate anion in the
presence of four additional equivalents of LiCl.22 A yield
of 70% of the desired chloroethyl tetrahydroisoquinoline
(S)-26 was achieved. A cyclization experiment was con-
ducted with only 1.1 equiv of AlCl3 to prevent possible
demethylation of the methoxy substituents,23 but only
starting material was recovered. Because demethylation
had obviously not taken place and assuming that AlCl3
might complex with the methoxy substituents, four more
equivalents of AlCl3 were added to the reaction mixture.
Unfortunately, after 7 h reflux 2 could not be observed
by NMR analysis of the crude mixture, and it seemed
that the main products were starting material and a
phenol derivative (Scheme 8).
a Reagents and conditions: (a) TMEDA (7.0 equiv)/s-BuLi (6.5
equiv), Et2O/THF (5/1), -78 °C then (S)-19 or (R)-19, AlMe3 (3.1
equiv), Et2O, -40 °C, 17 h.
was first attempted with LDA. To our surprise, the
solution did not turn burgundy red, a typical color for
lithiated species of 2-methylbenzamide derivatives. As
there is a literature precedence for the deprotonation of
2 equiv of 2,4-dimethoxy-6-methylbenzamide with 3 equiv
of LDA19 and assuming that LDA probably forms a
chelate with the methoxy groups of the aromatic ring and
the amide group, an additional experiment was per-
formed using 3 equiv of LDA compared to the benzamide.
The reaction mixture turned bright orange, but no
product could be isolated. We then turned to the use of 7
equiv of an equimolar mixture of s-BuLi and TMEDA. A
small amount of THF had to be used to maintain a good
solubility of the lithiated species when deprotonating 2,3-
dimethoxy-6-methylbenzamide 6 in Et2O.20 Taking into
account that the methoxy substituents can play an
important role in this reaction, we increased the amount
of AlMe3 to 3.1 equiv for the complexation with hydrazone
20. Finally, cyclized product (R,S)-20 was obtained with
excellent diastereoselectivity and in reasonable yield
(55%), taking into account the complex functionalities set
up in one step (Scheme 4).
The absolute configuration of the generated stereogenic
center could be assigned as (R) based on our previous
work.7 The high diastereoselectivity of the reaction may
be explained through complexation between one molecule
of lithiated 2-methylbenzamide 6 and the methoxymeth-
ylpyrrolidine moiety of the auxiliary. Another equivalent
of lithiated 2-methylbenzamide would then add to the CN
double bond of hydrazone 19 on the less hindered Re face,
activated by complexation to 1 equiv of AlMe3. The
resulting intermediate 21 possessing (R) configuration
at the new stereocenter would then cyclize to (R,S)-20
(Scheme 5). This proposed mechanism is supported by
the fact that in our previously reported model reaction
with 2-methylbenzamide 14 and benzaldehyde SAMP
hydrazone,7 one untouched equivalent of 14 could always
be isolated after the 1,2-addition/ring-closure process
independent of the time of the reaction and despite the
self-condensation.
Because the final ring closure might as well be effected
by a Pomeranz-Fritsch reaction, the respective precur-
sors were prepared. First, the synthesis of diethyl acetal
(R)-27 was attempted starting from (R)-22 in the pres-
ence of bromoacetaldehyde diethyl acetal and K2CO3 in
refluxing MeCN. Unfortunately, only 33% of the desired
Analogously, (S,R)-20 could also be obtained in a
similar yield, demonstrating the reproducibility of the
reaction.
(21) Takano, S.; Iida, H.; Inomata, K.; Ogasawara, K. Heterocycles
1993, 35, 47.
(22) In a model reaction, it was found that 61% of (S)-2-(2-
(19) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y.
M. Org. Lett. 2000, 2, 3901.
(20) A further optimization of the model tandem reaction of meth-
ylbenzamide 14 with benzaldehyde SAMP-hydrazone was realized by
switching the solvent of the reaction from THF to Et2O. This resulted
in an increase of the yield from 70 to 80%.
chloroethyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline could be obtained
by addition of 1.1 equiv of Et3N and 1.1 equiv of MsCl to a solution of
2-((S)-3-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanol in absence of
LiCl.
(23) Hudlicky, T.; Butora, G. U.S. Patent 5912347, 1999.
J. Org. Chem, Vol. 70, No. 23, 2005 9489

Boudou and Enders
SCHEME 5
SCHEME 6a
SCHEME 8 a
a Reagents and conditions: (a) BH3‚THF (20 equiv), THF, ∆, 2
h then 1 N aq. HCl, -5 °C to ∆, 15 min.
SCHEME 7a
a Reagents and conditions: (a) NaHCO3, 2-iodoethanol, MeCN,
reflux, 24 h. (b) Et3N, MsCl, LiCl, CH2Cl2, 0 °C to room temper-
ature, 5 h.
Fritsch-type cyclization. Each quinolizin-5-ol 28 was
obtained in very good yield as a mixture of diastereoiso-
mers (ratio determined by chiral stationary phase HPLC).
The deoxygenation of alcohols 28 still had to be ac-
complished to obtain both enantiomers of the target
molecule tetrahydropalmatine (2), and to our knowledge
no examples other than dehydration reactions are re-
ported in the literature for the removal of the hydroxy
group.25
First, a combination of 2.5 equiv of BF3‚OEt2 and Et3-
SiH was applied on the diastereoisomeric mixture of
quinolizin-5-ol (R)-28 for 2 h at -78 °C. The choice of
these smooth conditions proved to be appropriate because
(R)-(+)-tetrahydropalmatine (2) was obtained in excellent
enantiomeric purity, although in a low yield (Scheme 9).
Possible reasons could be either that the number of
equivalents of both reagents had to be higher, as often
employed in the literature for this combination, or that
the Lewis acid promoted the demethylation of the meth-
oxy substituents. Because no traces of phenol could be
detected in the NMR spectra of the crude mixture,
another attempt was made with 5 equiv of both reagents
a Reagents and conditions: (a) phenyl vinyl sulfoxide, MeOH,
reflux, 22 h. (b) TFAA (3 equiv), TFA (6 equiv), PhMe, reflux, 15
h. (c) Ra Ni, H2, EtOH, reflux, 22 h.
Pomeranz-Fritsch precursor could be obtained. In a
second attempt, a stoichiometric amount of KI was
employed to perform a bromide-iodide exchange in situ
before the nucleophilic attack, and indeed the yield of
(R)-27 could be increased to 75% (Scheme 9). When this
reaction was repeated under the same conditions for the
other enantiomer, 63% of (S)-27 were obtained. The
enantiomeric excess for both enantiomers of 27 remained
excellent (ee ) 99% determined by chiral stationary
phase HPLC).
(24) Carillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Anakabe, E.; Osante, I.;
Tellitu, I.; Vicario, J. L. J. Org. Chem. 1999, 64, 1115.
(25) (a) Bad´ıa, D.; Dom´ınguez, E.; Iriondo, C. J. Heterocycl. Chem.
1986, 23, 1599. (b) Tellitu, I.; Bad´ıa, D.; Dom´ınguez, E.; Carillo, L.
Heterocycles 1996, 43, 2099.
Slightly modifying a protocol described in the litera-
ture,24 we exposed the diethyl acetals 27 to concentrated
HCl in acetone overnight to perform the Pomeranz-
9490 J. Org. Chem., Vol. 70, No. 23, 2005

Asymmetric Synthesis of Tetrahydropalmatine
SCHEME 9a
(16), 130 (13), 129 (33), 116 (12), 115 (17), 114 (10), 85 (22), 70
(44); IR (in CHCl3) ν 3062, 2974, 2880, 2827, 1636, 1580, 1552,
1477, 1450, 1382, 1342, 1305, 1285, 1248, 1197, 1119, 995, 975,
911, 756 cm-1; Anal. Calcd for C16H22N2O: C, 74.38; H, 8.58;
N, 10.84. Found: C, 74.14; H, 8.09; N, 11.18.
[1-(2-Bromophenyl)-meth-(1E)-ylidene]-((2S)-2-meth-
oxymethylpyrrolidin-1-yl)-amine [(S)-12]. According to the
general procedure described for the synthesis of hydrazones,
2-bromobenzaldehyde (1.17 mL, 10.0 mmol) and SAMP (1.658
g, 12.0 mmol, 94% purity (GC)) were reacted overnight. After
distillation under high vacuum, 2.743 g (92%) of (S)-12 was
obtained as a yellow liquid; bp 115-122 °C/0.04 mbar; [R]25
D
1
-132.6 (c 2.47, CHCl3); H NMR (400 MHz, CDCl3) δ 1.85-
2.11 (m, 4H), 3.11-3.17 (m, 1H), 3.40 (s, 3H), 3.45-3.52 (m,
1H), 3.53 (dd, J ) 6.6 Hz, J ) 9.3 Hz, 1H), 3.67 (dd, J ) 3.9
Hz, J ) 9.3 Hz, 1H), 3.70-3.77 (m, 1H), 6.99-7.05 (m, 1H),
7.21-7.26 (m, 1H), 7.42 (s, 1H), 7.48 (dd, J ) 1.1 Hz, J ) 8.0
Hz, 1H), 7.89 (dd, J ) 1.7 Hz, J ) 8.0 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 22.2, 26.9, 48.8 (CH2), 59.2 (CH3), 62.9
(CH), 74.4 (CH2), 121.9 (C), 125.7, 127.0, 127.6, 130.2, 132.5
(CH), 135.7 (C) ppm; MS (EI) m/z (%) 298 (M+, 10), 296 (M+,
13), 254 (12), 253 (100), 251 (98), 70 (37); IR (capillary) ν 2972,
2924, 2878, 2826, 1568, 1544, 1463, 1436, 1375, 1342, 1308,
1284, 1248, 1197, 1156, 1114, 1019, 974, 870, 851, 753 cm-1
;
Anal. Calcd for C13H17BrN2O: C, 52.54; H, 5.77; N, 9.43.
Found: C, 52.10; H, 6.16; N, 9.92.
a Reagents and conditions: (a) bromoacetaldehyde diethyl acetal
(1.2 equiv), KI (1.2 equiv), K2CO3 (1.1 equiv), DMF, 110 °C, 24 h.
(b) Concentrated HCl, acetone, 0 °C to room temperature, 16-18
h. (c) BF3‚OEt2 (2.5 equiv), Et3SiH (2.5 equiv), CH2Cl2, -78 °C, 2
h. (d) BF3‚OEt2 (5 equiv), Et3SiH (5 equiv), CH2Cl2, -78 °C to room
temperature, 19 h.
((2S)-2-Methoxymethylpyrrolidin-1-yl)-[1-o-tolylmeth-
(1E)-ylidene]-amine [(S)-13]. According to the general pro-
cedure described for the synthesis of hydrazones, 2-methyl-
benzaldehyde (1.39 mL, 12.0 mmol) and SAMP (1.382 g, 10.0
mmol, 94% purity (GC)) were reacted overnight. After distil-
lation under high vacuum with the help of a microdistillation
slowly warming up to room temperature overnight. The
isolated yield for (S)-(-)-tetrahydropalmatine (2) im-
proved to 92%, and the enantiopurity remained excellent
(determined by chiral stationary phase HPLC) (Scheme
9).
apparatus, 2.088 g (90%) of (S)-13 was obtained as a yellow
1
liquid; bp 84 °C/0.02 mbar; [R]25 -158.9 (c 1.23, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 1.84-2.09 (m, 4H), 2.39 (s, 3H),
2.99-3.07 (m, 1H), 3.40 (s, 3H), 3.45-3.58 (m, 2H), 3.64-3.71
(m, 2H), 7.09-7.18 (m, 3H), 7.38 (s, 1H), 7.75 (d, J ) 7.4 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 19.7 (CH3), 22.2, 26.8,
49.0 (CH2), 59.2 (CH3), 63.1 (CH), 74.5 (CH2), 124.6, 125.8,
126.6, 130.26, 130.9 (CH), 134.2, 134.9 (C) ppm; MS (EI)
m/z (%) 232 (M+, 13), 188 (12), 187 (100), 70 (34); IR (capillary)
ν 3057, 2879, 1697, 1579, 1553, 1458, 1379, 1342, 1248,
1198, 1154, 1120, 973, 879, 755, 719 cm-1; Anal. Calcd for
C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.74; H,
9.20; N, 12.55.
Conclusion
Our tandem 1,2-addition/ring-closure methodology
proved to be applicable to the synthesis of tetrahydro-
protoberberines. Indeed, the enantioselective synthesis
of both enantiomers of tetrahydropalmatine was achieved
in seven steps (including the synthesis of the 2,3-
dimethoxy-6-methylbenzamide (6)). The overall yield was
9% (not optimized) for (R)-(+)-tetrahydropalmatine (ee
) 98%) and after optimization 17% for (S)-(-)-tetrahy-
dropalmatine (ee ) 98%). This total synthesis compares
favorably in terms of yield and enantioselectivity with
the previous asymmetric syntheses of 2.6
[1-(3,4-Dimethoxyphenyl)-meth-(1E)-ylidene]-((2S)-2-
methoxymethylpyrrolidin-1-yl)-amine [(S)-19]. According
to the general procedure described for the synthesis of hydra-
zones, 3,4-dimethoxybenzaldehyde (3.988 g, 24.0 mmol) and
SAMP (2.791 g, 20.0 mmol, 93% purity (GC)) were reacted
overnight. After distillation under high vacuum using a
microdistillation apparatus, 5.466 g (98%) of (S)-19 was
obtained as an orange syrup; bp 136 °C/0.03 mbar; [R]25
D
1
-114.7 (c 0.89, CHCl3); H NMR (300 MHz, CDCl3) δ 1.78-
Experimental Section
2.08 (m, 4H), 2.94-3.05 (m, 1H), 3.40 (s, 3H), 3.42-3.53 (m,
2H), 3.59-3.72 (m, 2H), 3.86 (s, 3H), 3.92 (s, 3H), 6.80 (d, J )
8.2 Hz, 1H), 6.96 (dd, J ) 1.8 Hz, J ) 8.2 Hz, 1H), 7.20 (s,
1H), 7.25 (d, J ) 1.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
δ 22.2, 26.8, 49.4 (CH2), 55.8, 55.9, 59.3, 63.2 (CH3), 74.8, 107.2,
110.0, 119.0 (CH), 130.6 (C), 133.0 (CH), 148.6, 149.2 (C) ppm;
MS (EI) m/z (%) 278 (M+, 32), 234 (16), 233 (100), 70 (18); IR
(capillary) ν 2933, 2833, 1597, 1563, 1513, 1461, 1416, 1379,
1342, 1268, 1118, 1028, 973, 885, 807, 758 cm-1; HRMS m/z
calcd for C15H22N2O3 (M+): 278.1630. Found: 278.1630.
[1-(3,4-Dimethoxyphenyl)-meth-(1E)-ylidene]-((2R)-2-
methoxymethylpyrrolidin-1-yl)-amine [(R)-19]. According
to the general procedure described for the synthesis of hydra-
zones, 3,4-dimethoxybenzaldehyde (3.988 g, 24.0 mmol) and
RAMP (3.493 g, 20.0 mmol, 75% purity (GC)) were reacted
overnight. After distillation under high vacuum using a
microdistillation apparatus, 5.539 g (quant.) of (R)-19 was
collected as a pale yellow syrup; [R]28D +114.1 (c 1.27, CHCl3).
[1-(2-Allylphenyl)-meth-(1E)-ylidene]-((2S)-2-methoxy-
methylpyrrolidin-1-yl)-amine [(S)-11]. According to the
general procedure described for the synthesis of hydrazones,
2-allylbenzaldehyde (8) (1.038 g, 7.10 mmol) and SAMP (1.079
g, 7.81 mmol, 94% purity (GC)) were reacted overnight. After
purification by column chromatography (n-pentane/Et2O )
20/1 to 3/1 + 2% Et3N), 1.747 g (95%) of (S)-11 was obtained
as a pale yellow liquid; [R]24.5D -156.2 (c 1.84, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 1.84-2.09 (m, 4H), 2.98-3.06 (m, 1H),
3.40 (s, 3H), 3.41-3.56 (m, 4H), 3.64-3.70 (m, 2H), 4.99 (dq,
J ) 1.7 Hz, J ) 17.0 Hz, 1H), 5.05 (dq, J ) 1.7 Hz, J ) 10.1
Hz, 1H), 5.92 (tdd, J ) 6.0 Hz, J ) 10.1 Hz, J ) 17.0 Hz, 1H),
7.10-7.22 (m, 3H), 7.39 (s, 1H), 7.81 (dd, J ) 1.4 Hz, J ) 7.7
Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 22.2, 26.8, 37.5,
49.0 (CH2), 59.2 (CH3), 63.1 (CH), 74.5, 115.4 (CH2), 124.9,
126.3, 126.8, 129.8, 130.7 (CH), 134.8, 135.9 (C), 137.0 (CH)
ppm; MS (EI) m/z (%) 258 (M+, 17), 214 (17), 213 (100), 144
J. Org. Chem, Vol. 70, No. 23, 2005 9491

Boudou and Enders
(3R)-3-(2-Bromophenyl)-2-((2S)-2-methoxymethylpyr-
rolidin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one [(R,S)-16].
In a 250-mL Schlenk flask under argon, n-BuLi (6.6 mL, 10.50
mmol, 1.59 M in hexane) was added to a solution of (i-Pr)2NH
(1.5 mL, 10.50 mmol) in abs. THF (50 mL) at 0 °C. The solution
was stirred at 0 °C for 15 min and cooled to -78 °C before a
solution of N,N-diethyl-2-methylbenzamide (14) (10.50 mmol)
in abs. THF (10 mL) was added dropwise. The temperature
was raised to -40 °C, and a solution of the SAMP hydrazone
(S)-12 (1.50 mmol) in abs. THF (6 mL), previously complexed
to AlMe3 (0.83 mL, 1.65 mmol, 2 M in heptane) for at least 1
h, was added dropwise over 30 min. The reaction mixture was
stirred overnight (∼18 h) at -40 °C. The reaction was
quenched with 10% aqueous potassium and sodium tartrate
(5 mL) and sat. aqueous NH4Cl (10 mL). After warming to
room temperature and phase separation, the aqueous layer
was extracted 3 times with Et2O (30 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated under reduced pressure. After purification by column
chromatography (n-pentane/Et2O ) 8/1 to 1/3), 0.066 g (11%)
of (R,S)-16 was obtained as a yellow syrup: de g 96% (1H
NMR); [R]27D +62.3 (c 0.83, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 1.37-1.47 (m, 1H), 1.57-1.68 (m, 1H), 1.92-2.02 (m, 1H),
2.05-2.14 (m, 1H), 2.78-2.85 (dt, J ) 4.4 Hz, J ) 7.7 Hz, 1H),
3.05 (dd, J ) 1.7 Hz, J ) 15.9 Hz, 1H), 3.40-3.47 (m, 2H),
3.42 (s, 3H), 3.69-3.78 (m, 2H), 4.00-4.10 (m, 1H), 5.53 (dd,
J ) 1.7 Hz, J ) 7.4 Hz, 1H), 6.93-6.98 (m, 2H), 7.01-7.06
(m, 2H), 7.29-7.34 (m, 2H), 7.51-7.56 (m, 1H), 8.05-8.11 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 23.2, 27.0, 34.2, 51.6
(CH2), 58.9 (CH3), 60.7, 65.0 (CH), 77.3 (CH2), 122.5 (C), 126.8,
126.9, 127.1, 127.5, 127.7, 128.6 (CH), 130.1 (C), 131.8, 133.0
19 (0.418 g, 1.50 mmol) in abs. Et2O (6 mL), previously
complexed to AlMe3 (2.3 mL, 4.65 mmol, 2 M in heptane) for
at least 1 h, was added dropwise over 45 min. The reaction
mixture was stirred overnight (17 h) at -40 °C. The reaction
was quenched with 10% aqueous potassium and sodium
tartrate (10 mL) and sat. aqueous NH4Cl (10 mL). After phase
separation, the aqueous layer was extracted 4 times with Et2O
(30 mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
mixture was purified by column chromatography (n-pentane/
AcOEt ) 1/2) to yield 0.375 g (55%) of (R,S)-20 as a pale yellow
syrup: de g 96% (1H NMR); [R]24D +21.18 (c 1.67, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 1.40-1.53 (m, 1H), 1.56-1.72 (m,
1H), 1.88-2.02 (m, 1H), 2.06-2.20 (m, 1H), 2.83 (dd, J ) 2.2
Hz, J ) 15.3 Hz, 1H), 2.95 (dt, J ) 3.7 Hz, J ) 7.7 Hz, 1H),
3.40 (s, 3H), 3.38-3.50 (m, 2H), 3.65-3.91 (m, 2H), 3.73 (s,
3H), 3.78 (s, 3H), 3.81 (s, 3H), 3.98 (s, 3H), 4.10-4.22 (br, 1H),
4.98 (dd, J ) 2.2 Hz, J ) 6.2 Hz, 1H), 6.62-6.69 (m, 4H), 6.84
(d, J ) 8.4 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 22.9,
26.8, 37.0, 51.7 (CH2), 55.7, 55.8, 56.1, 58.9 (CH3), 59.9 (CH),
61.6 (CH3), 65.8 (CH), 77.2 (CH2), 109.8, 110.8, 115.3, 118.7,
122.8 (CH), 124.6, 128.9, 133.4, 147.6, 148.5, 149.8, 152.7,
161.8 (C) ppm; MS (EI) m/z (%) 456 (M+, 1), 412 (24), 411 (87),
344 (24), 343 (100), 342 (14), 327 (15), 325 (18), 324 (12), 312
(17), 205 (15), 192 (10), 178 (11), 166 (11), 151 (46); IR (in
CHCl3) ν 3001, 2937, 2876, 2836, 1653, 1581, 1516, 1484, 1455,
1419, 1389, 1302, 1265, 1140, 1102, 1064, 1033, 1002, 792, 755
cm-1; HRMS m/z calcd for C23H27N2O5 (M+-C2H5O): 411.1920.
Found: 411.1920.
(3S)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-2-((2R)-2-
methoxymethylpyrrolidin-1-yl)-3,4-dihydro-2H-isoquin-
olin-1-one [(S,R)-20]. In the same manner as described for
the synthesis of (R,S)-20, s-BuLi (7.5 mL, 9.75 mmol, 1.3 M
in hexane), TMEDA (1.59 mL, 10.50 mmol), 2,3-dimethoxy-6-
methylbenzamide 6 (2.639 g, 10.50 mmol), RAMP hydrazone
(R)-19 (0.418 g, 1.50 mmol), and trimethylaluminum (2.3 mL,
4.65 mmol, 2 M in heptane) were reacted overnight (17 h). The
crude mixture was purified twice by column chromatography
(pure Et2O) to yield 0.371 g (54%) of (S,R)-20 as a pale yellow
(CH), 134.6, 139.5, 163.5 (C) ppm; MS (EI) m/z (%) 417 (M+
+
1, 5), 415 (M+ + 1, 6), 372 (20), 371 (100), 370 (24), 369 (99),
304 (14), 303 (16), 302 (16), 206 (25), 178 (13), 114 (72), 113
(18), 68 (10); IR (in CHCl3) ν 2925, 2875, 1653, 1604, 1462,
1406, 1329, 1249, 1102, 1025, 754 cm-1; Anal. Calcd for C21H23-
BrN2O2: C, 60.73; H, 5.58; N, 6.74. Found: C, 60.27; H, 5.42;
N, 7.06.
(3R)-2-((2S)-2-Methoxymethylpyrrolidin-1-yl)-3-o-tolyl-
3,4-dihydro-2H-isoquinolin-1-one [(R,S)-17]. According to
the procedure described for the synthesis of (S,R)-16, 2-me-
thylbenzamide 14 and SAMP-hydrazone (S)-13 were reacted
overnight in abs. THF. After purification by column chroma-
tography (n-pentane/Et2O ) 4/1), 0.142 g (27%) of (R,S)-17 was
obtained as a pale pink crystalline solid: de g 96% (1H NMR);
syrup: de g 96% (1H NMR); [R]30 -20.76 (c 0.79, CHCl3).
D
(3R)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline [(R)-22]. In a Schlenk flask under
argon fitted with a reflux condenser, BH3‚THF (5.5 mL, 5.52
mmol, 1 M in THF) was added to a solution of dihydroiso-
quinolinone (R,S)-20 (0.126 g, 0.28 mmol) in abs. THF (11 mL),
and the reaction mixture was heated at reflux for 4 h. After
cooling the solution to 5 °C, we cautiously added 1 N aqueous
HCl (2.2 mL). After 1 min reflux, the solvent and most of the
water were evaporated under reduced pressure and sat.
aqueous NaHCO3 was added to the residue until no evolution
of gas could be observed any more. The mixture was extracted
3 times with Et2O. The combined organic phases were dried
over MgSO4, filtered, and evaporated under reduced pressure.
After purification by column chromatography (n-hexane/
acetone ) 1/1), 0.075 g (82%) of (R)-22 was obtained as a
champagne-beige solid: ee ) 99% (Chiralpak AD; n-heptane/
i-PrOH ) 65/35; Rt ) 14.96 min; λ ) 214 nm); mp 103-104
°C; [R]30D +81.6 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.99 (br, 1H), 2.86-2.96 (m, 2H), 3.83-3.91 (m, 1H), 3.84 (s,
3H), 3.85 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H), 4.10 (d, J ) 16.4
Hz, 1H), 4.36 (d, J ) 16.4 Hz, 1H), 6.78 (d, J ) 8.5 Hz, 1H),
6.82 (d, J ) 8.5 Hz, 1H), 6.85 (d, J ) 8.2 Hz, 1H), 6.95 (dd, J
) 1.9 Hz, J ) 8.2 Hz, 1H), 7.02 (d, J ) 1.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 37.3, 44.8 (CH2), 55.8, 55.9 (CH3), 58.2
(CH), 60.0 (CH3), 109.4, 110.7, 110.9, 118.5, 123.9 (CH), 128.0,
128.7, 136.9, 145.1, 148.0, 148.9, 150.1 (C) ppm; MS (EI) m/z
(%) 330 (M+ + 1, 10), 329 (M+, 49), 328 (11), 165 (14), 164
(100), 149 (40); IR (KBr) ν 3976, 3459, 3330, 3236, 2990, 2936,
2831, 1596, 1515, 1492, 1461, 1421, 1323, 1272, 1228, 1157,
1080, 1030, 869, 800, 758 cm-1; Anal. Calcd for C19H23NO4:
C, 69.28; H, 7.04; N, 4.25. Found: C, 69.48; H, 7.36; N, 4.38.
mp 88 °C; [R]21 +7.7 (c 0.65, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 1.36-1.48 (m, 1H), 1.54-1.64 (m, 1H), 1.87-2.01 (m,
1H), 2.04-2.16 (m, 1H), 2.44 (s, 3H), 2.73 (dt, J ) 4.2 Hz, J )
7.9 Hz, 1H), 2.86 (dd, J ) 1.7 Hz, J ) 15.6 Hz, 1H), 3.39-3.43
(m, 2H), 3.40 (s, 3H), 3.66 (dt, J ) 7.9 Hz, J ) 7.9 Hz, 1H),
3.77 (ddd, J ) 0.7 Hz, J ) 7.7 Hz, J ) 15.6 Hz, 1H), 4.01-
4.12 (m, 1H), 5.38 (dd, J ) 1.7 Hz, J ) 7.7 Hz, 1H), 6.85-6.98
(m, 3H), 7.07 (td, J ) 1.7 Hz, J ) 7.0 Hz, 1H), 7.11-7.16 (m,
1H), 7.29-7.36 (m, 2H), 8.06-8.13 (m, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 19.3 (CH3), 23.3, 27.0, 34.6, 51.6 (CH2), 58.9
(CH3), 60.4, 62.0 (CH), 77.5 (CH2), 125.7, 126.0, 127.0, 127.0,
127.3, 127.6 (CH), 130.5 (C), 130.7, 131.9 (CH), 134.6, 135.1,
139.2, 163.6 (C) ppm; MS (EI) m/z (%) 351 (M+ + 1, 0.4), 306
(24), 305 (100), 221 (16), 178 (13), 158 (10), 114 (83), 91 (10),
84 (11); IR (KBr) ν 3449, 2923, 2875, 2838, 1648, 1602, 1488,
1458, 1410, 1385, 1331, 1255, 1128, 1105, 1041, 753, 731 cm-1
;
Anal. Calcd for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99.
Found: C, 75.00; H, 7.14; N; 7.78.
(3R)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-2-((2S)-2-
methoxymethylpyrrolidin-1-yl)-3,4-dihydro-2H-isoquin-
olin-1-one [(R,S)-20]. In a 250-mL Schlenk flask under argon,
s-BuLi (7.5 mL, 9.75 mmol, 1.3 M in hexane) was added to a
solution of TMEDA (1.59 mL, 10.50 mmol) in abs. THF (10
mL) and abs. Et2O (50 mL) at -78 °C. After 15 min, a solution
of 2,3-dimethoxy-6-methylbenzamide 6 (2.639 g, 10.50 mmol)
in abs. Et2O (10 mL) was added dropwise. The temperature
was raised to -40 °C, and a solution of SAMP hydrazone (S)-
9492 J. Org. Chem., Vol. 70, No. 23, 2005

Asymmetric Synthesis of Tetrahydropalmatine
(3S)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline [(S)-22]. (S)-22 was prepared in the
same manner as described for the synthesis of (R)-22 using
dihydroisoquinolinone (S,R)-20 (0.300 g, 0.66 mmol) and BH3‚
THF (13.1 mL, 13.14 mmol, 1 M in THF). After purification
by column chromatography (Et2O/MeOH ) 20/1), 0.182 g (83%)
of (S)-22 was obtained as a champagne-beige solid: ee ) 99%
(Chiralpak AD; n-heptane/i-PrOH ) 65/35; Rt ) 11.47 min; λ
3.61 (d, J ) 16.5 Hz, 1H), 3.71-3.78 (m, 2H), 3.83 (s, 3H),
3.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 4.17 (d, J ) 16.5 Hz,
1H), 6.79-6.88 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3) δ
35.6, 48.8, 54.7 (CH2), 55.7, 55.8, 55.8 (CH3), 58.3 (CH2), 60.1
(CH3), 63.1, 110.9, 110.8, 110.9, 120.0, 123.2 (CH), 127.3, 127.9,
134.1, 145.1, 148.1, 148.9, 150.1 (C) ppm; MS (EI) m/z (%) 373
(M+, 10), 343 (23), 342 (100), 314 (11), 313 (49), 282 (13), 175
(12), 164 (16), 151 (12), 149 (16); IR (in CHCl3) ν 3563, 3536,
3379, 3314, 3012, 2936, 2836, 1596, 1497, 1461, 1423, 1373,
1263, 1233, 1145, 1087, 1030, 986, 877, 756, 667 cm-1; HRMS
m/z calcd for C21H27NO5 (M+): 373.1889. Found: 373.1890.
) 214 nm); [R]27 -84.8 (c 0.70, CHCl3).
D
(3S)-2-(2-Phenylsulfinylethyl)-3-(3,4-dimethoxyphenyl)-
7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline [(S)-23]. In
a 10-mL flask under argon, a solution of tetrahydroisoquinoline
(S)-22 (0.109 g, 0.33 mmol) and phenyl vinyl sulfoxide (66 µL,
0.50 mmol) in abs. MeOH (2 mL) was heated at reflux for 22
h. The solvent was evaporated under reduced pressure, and
the residue was purified by column chromatography (pure
Et2O then Et2O/MeOH ) 20/1) to give 0.150 g (94%) of (S)-23
as a yellow syrup: dr ) 64/36 (spherical silica; n-heptane/i-
PrOH ) 9/1; Rt ) 21.82 min; Rt ) 27.90 min; λ ) 254 nm); 1H
NMR (400 MHz, CDCl3, mixture of diastereomers) δ 2.46-
2.54 (m, 1H), 2.73-3.18 (m, 11H), 3.55 (d, J ) 16.1 Hz, 1H),
3.58-3.75 (m, 3H), 3.78 (s, 3H), 3.83 (s, 6H), 3.85 (s, 9H), 3.88
(s, 3H), 3.89 (s, 3H), 4.06 (d, J ) 16.2 Hz, 1H), 4.18 (d, J )
16.1 Hz, 1H), 6.75-6.84 (m, 9H), 6.91 (s, 1H), 7.43-7.49 (m,
8H), 7.51-7.55 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3,
mixture of diastereomers) δ 36.1, 36.7, 47.1, 49.4, 49.5, 54.8,
55.3 (CH2), 55.7, 55.8, 55.8, 60.1, 60.2 (CH3), 63.0, 63.6, 110.4,
110.5, 110.6, 111.0, 119.9, 120.0, 123.1, 123.7 (CH), 127.2,
127.3, 127.7, 127.9 (C), 128.9, 128.9, 130.6 (CH), 133.8, 134.1,
143.5, 144.0, 145.0, 148.1, 148.2, 148.8, 149.0, 150.0 (C) ppm;
MS (EI) m/z (%) 466 (10), 465 (31), 464 (M+ - OH, 100), 355
(10), 354 (12), 313 (17), 164 (27), 149 (11), 137 (25); IR (in
CHCl3) ν 3013, 2962, 2935, 1513, 1497, 1461, 1263, 1219, 1143,
1083, 1032, 758, 667 cm-1; HRMS m/z calcd for C27H30NO4S
(M+ - OH): 464.1896. Found: 464.1896.
(3S)-2-(2-Chloroethyl)-3-(3,4-dimethoxyphenyl)-7,8-
dimethoxy-1,2,3,4-tetrahydroisoquinoline [(S)-26]. In a
25-mL Schlenk flask under argon, a solution of the alcohol (S)-
25 (0.135 g, 0.36 mmol) in abs. CH2Cl2 (12 mL) was cooled to
0 °C. Et3N (55 µL, 0.40 mmol), methanesulfonyl chloride (31
µL, 0.40 mmol), and LiCl (0.061 g, 1.45 mmol) were succes-
sively added, and the temperature was increased to room
temperature. After 5 h the reaction was diluted with CH2Cl2,
and the organic phase was washed twice with sat. aqueous
NaHCO3 and twice with H2O. After drying over MgSO4,
filtration, and concentration under reduced pressure, the
residue was purified by column chromatography (n-pentane/
Et2O ) 1/1) to yield 0.097 g (70%) of (S)-26 as a colorless solid;
1
mp 113-115 °C; H NMR (300 MHz, CDCl3) δ 2.51-2.62 (m,
1H), 2.88-3.11 (m, 3H), 3.53-3.68 (m, 4H), 3.85 (s, 3H), 3.85
(s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.26 (d, J ) 16.1 Hz, 1H),
6.85-6.88 (m, 4H), 6.97 (d, J ) 1.2 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 36.6, 41.8, 50.2, 55.5 (CH2), 55.9, 55.9, 60.2
(CH3), 63.8, 110.5, 110.8, 111.1, 120.1, 123.3 (CH), 127.5, 128.0,
134.9, 145.2, 148.4, 149.2, 150.3 (C) ppm; MS (EI) m/z (%) 393
(M+, 22), 392 (18), 391 (M+, 61), 390 (11), 343 (13), 342 (68),
328 (19), 313 (46), 312 (24), 165 (13), 164 (100), 149 (36); IR
(KBr) ν 2999, 2931, 2831, 2362, 1596, 1512, 1458, 1373, 1325,
1263, 1234, 1153, 1081, 1030, 980, 878, 807, 761, 741 cm-1
;
HRMS m/z calcd for C21H26ClNO4 (M+): 391.1550. Found:
(13aS)-2,3,9,10-Tetramethoxy-5-phenylsulfanyl-
5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine [(S)-
24]. In a 25-mL flask under argon, a solution of sulfoxide (S)-
23 (0.124 g, 0.26 mmol), TFAA (0.11 mL, 0.77 mmol), and TFA
(0.12 mL, 1.55 mmol) in abs. toluene (12 mL) was heated at
reflux for 15 h. The volatiles were removed under reduced
pressure, and a part of the resulting crude mixture was
purified by preparative TLC (Et2O/MeOH ) 20/1) for analysis
whereas the rest was passed through silica (Et2O/MeOH ) 20/
1). The combined products were then used for the next step
391.1551.
(3R)-2-(2,2-Diethoxyethyl)-3-(3,4-dimethoxyphenyl)-
7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline [(R)-27]. In
a 10-mL flask, bromoacetaldehyde diethyl acetal (72 µL, 0.48
mmol) was added to a suspension of tetrahydroisoquinoline
(R)-22 (0.132 g, 0.40 mmol), K2CO3 (0.061 g, 0.44 mmol), and
KI (0.080 g, 0.48 mmol) in anhydrous DMF (5 mL). The
reaction mixture was heated at 110 °C for 24 h and diluted
with H2O. The organic phase was kept, and the aqueous phase
was extracted 4 times with Et2O. The combined organic phases
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting crude mixture was purified
by column chromatography (n-pentane/Et2O ) 1/3) to yield
0.135 g (75%) of (R)-27 as a yellow syrup: ee ) 99% (Chiralpak
AD; n-heptane/i-PrOH ) 9/1; Rt ) 15.54 min; λ ) 230.1 nm);
[R]24D +46.8 (c 1.10, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.15
(t, J ) 7.2 Hz, 3H), 1.19 (t, J ) 7.2 Hz, 3H), 2.39 (dd, J ) 5.2
Hz, J ) 13.4 Hz, 1H), 2.76 (dd, J ) 5.2 Hz, J ) 13.4 Hz, 1H),
2.95 (dd, J ) 4.7 Hz, J ) 16.3 Hz, 1H), 3.05 (dd, J ) 9.2 Hz,
J ) 16.3 Hz, 1H), 3.38-3.72 (m, 6H), 3.84 (s, 3H), 3.85 (s, 6H),
3.87 (s, 3H), 4.38 (d, J ) 16.6 Hz, 1H), 4.64 (t, J ) 5.2 Hz,
1H), 6.74 (m, 3H), 6.86 (dd, J ) 1.7 Hz, J ) 8.4 Hz, 1H), 6.96
(d, J ) 1.7 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 15.3
(CH3), 36.2, 50.8 (CH2), 55.8, 55.9 (CH3), 56.3 (CH2), 60.2 (CH3),
61.5, 62.2 (CH2), 63.6, 102.4, 110.8, 120.3, 123.3 (CH), 127.7,
128.9, 135.3, 145.3, 148.2, 149.0, 150.3 (C) ppm; MS (EI) m/z
(%) 445 (M+, 6), 400 (12), 399 (11), 343 (32), 342 (100), 329
(13), 314 (20), 313 (50); IR (in CHCl3) ν 2973, 2933, 2903, 2835,
1594, 1497, 1460, 1423, 1373, 1265, 1236, 1138, 1085, 1058,
1030, 988, 803, 757 cm-1; Anal. Calcd for C25H35NO6: C, 67.39;
H, 7.92; N, 3.14. Found: C, 67.22; H, 7.90; N, 2.94.
1
without any further purification. H NMR (400 MHz, CDCl3,
mixture of diastereomers) δ 2.71-3.00 (m, 4H), 3.18-3.40 (m,
4H), 3.42-3.71 (m, 4H), 3.78 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H),
3.86 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s,
3H), 4.15 (d, J ) 15.9 Hz, 1H), 4.21 (d, J ) 15.9 Hz, 1H), 4.36
(s, 1H), 4.72 (dd, J ) 5.2 Hz, J ) 9.9 Hz, 1H), 6.64 (s, 1H),
6.73 (s, 1H), 6.75-6.90 (m, 4H), 7.24-7.35 (m, 8H), 7.42-7.52
(m, 4H) ppm; 13C NMR (100 MHz, CDCl3, mixture of diaster-
eomers) δ 35.8, 36.1 (CH2), 45.9, 47.7 (CH), 53.0, 53.3 (CH2),
55.8, 55.8, 56.0 (CH3), 57.7 (CH2), 58.9, 59.1 (CH), 60.8 (CH3),
108.0, 108.2, 110.7, 110.8, 110.9, 111.7, 123.6 (CH), 126.2 (C),
127.0 (CH), 128.0 (C), 128.7, 128.9 (CH), 130.8 (C), 131.6 (CH),
132.3, 134.5, 144.9, 147.4, 148.0, 150.1 (C) ppm.
2-[(3S)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-3,4-di-
hydro-1H-isoquinolin-2-yl]-ethanol [(S)-25]. In a flask
under argon, a suspension of tetrahydroisoquinoline (S)-22
(0.097 g, 0.30 mmol), anhydrous MeCN (3 mL), 2-iodoethanol
(25 µL, 0.32 mmol), and NaHCO3 (0.027 g, 0.32 mmol) was
heated to reflux overnight (24 h). After cooling to room
temperature, the reaction mixture was filtered with CH2Cl2,
and the volatiles were evaporated under reduced pressure. The
resulting crude mixture was purified by column chromatog-
raphy (Et2O/MeOH ) 80/1 to 20/1) providing 0.089 g (80%) of
(3S)-2-(2,2-Diethoxyethyl)-3-(3,4-dimethoxyphenyl)-
7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline [(S)-27]. (S)-
27 was prepared in the same manner as described for the
synthesis of (R)-27 using bromoacetaldehyde diethyl acetal (71
µL, 0.47 mmol), tetrahydroisoquinoline (S)-22 (0.129 g, 0.39
1
(S)-25 as a pale yellow foam; [R]25 -36.9 (c 0.45, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 2.38 (dt, J ) 4.7 Hz, J ) 12.9 Hz,
1H), 2.59 (br, 1H), 2.80 (ddd, J ) 4.7 Hz, J ) 12.9 Hz, 1H),
2.99-3.12 (m, 2H), 3.55 (dt, J ) 4.7 Hz, J ) 11.0 Hz, 1H),
J. Org. Chem, Vol. 70, No. 23, 2005 9493

Boudou and Enders
mmol), K2CO3 (0.060 g, 0.43 mmol), and KI (0.078 g, 0.47
mmol). The resulting crude mixture was purified by column
chromatography (n-pentane/Et2O ) 1/3) to give 0.111 g (64%)
of (S)-27 as a yellow syrup: ee ) 99% (Chiralpak AD;
was purified by column chromatography (n-pentane/Et2O )
1/1 + 5% Et3N) to yield 16 mg (38%) of (R)-2 as a light yellow
solid: ee ) 98% (Chiralpak AD; n-heptane/i-PrOH ) 8/2; Rt
) 9.81 min; λ ) 230 nm); 1H NMR (400 MHz, CDCl3) δ 2.61-
2.71 (m, 2H), 2.83 (dd, J ) 11.4 Hz, J ) 15.8 Hz, 1H), 3.10-
3.24 (m, 2H), 3.27 (dd, J ) 3.7 Hz, J ) 15.8 Hz, 1H), 3.51-
3.58 (m, 2H), 3.56 (s, 6H), 3.87 (s, 3H), 3.89 (s, 3H), 4.25 (d, J
) 15.9 Hz, 1H), 6.62 (s, 1H), 6.74 (s, 1H), 6.79 (d, J ) 8.2 Hz,
1H), 6.88 (d, J ) 8.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 29.1, 36.3, 51.5, 54.0 (CH2), 55.8, 55.8, 56.0 (CH3), 59.3 (CH),
60.1 (CH3), 108.4, 110.8, 111.2, 123.7 (CH), 126.6, 127.6, 128.5,
129.5, 144.9, 147.2, 147.3, 150.1 (C) ppm. All analytical data
correspond to those reported in the literature.26
(13aS)-2,3,9,10-Tetramethoxy-5,8,13,13a-tetrahydro-
6H-dibenzo[a,g]quinolizine; (S)-(-)-Tetrahydropalma-
tine [(S)-(-)-2]. Method A. In a 25-mL flask under argon,
Raney nickel W2 (two spatulas) was added to a solution of
crude sulfide (S)-24 (max. 0.26 mmol) in anhydrous EtOH (10
mL). The argon atmosphere was removed under high vacuum
until the EtOH started to bubble, and hydrogen gas was added.
This operation was repeated twice, and the reaction mixture
was heated at reflux for 22 h. The suspension was then filtered
with CH2Cl2 over a pad of Celite. After evaporation of the
solvents, the residue was purified by column chromatography
(n-pentane/Et2O ) 1/2 to 1/1 + 5% Et3N) to give 0.029 g (31%
over two steps) of (S)-2 as a light yellow solid: ee ) 90%
(Chiralpak AD; n-heptane/i-PrOH ) 8/2; Rt ) 13.74 min; λ )
230 nm).
n-heptane/i-PrOH ) 9/1; Rt ) 14.13 min; λ ) 230.1 nm); [R]23.5
D
-47.1 (c 0.64, CHCl3).
(13aR)-2,3,9,10-Tetramethoxy-5,8,13,13a-tetrahydro-
6H-dibenzo[a,g]-quinolizin-5-ol [(R)-28]. In a 10-mL flask,
a solution of acetal (R)-27 (0.105 g, 0.24 mmol) in acetone (2.6
mL) was cooled to 0 °C. Concentrated aqueous HCl (86 µL)
was added dropwise, and the temperature was slowly in-
creased to room temperature. After 2 h and 30 min, the cooling
bath was removed, and the reaction mixture was stirred for
an additional 14 h. The temperature was decreased to 0 °C,
and 1 N aqueous NaOH was carefully added until pH 10 was
reached. The reaction mixture was extracted 4 times with CH2-
Cl2, and the combined organic phases were dried over MgSO4,
filtered, and concentrated under reduced pressure. The result-
ing crude mixture was purified by column chromatography
(Et2O/MeOH ) 60/1) providing 0.077 g (88%) of (R)-28 as a
yellow solid: dr ) 44/56 (Chiralcel OD; n-heptane/i-PrOH )
1
8/2; Rt ) 18.33 min; Rt ) 23.72 min; λ ) 230 nm); H NMR
(400 MHz, CDCl3, mixture of diastereomers) δ 2.49 (dd, J )
8.1 Hz, J ) 11.0 Hz, 1H), 2.72-2.85 (m, 3H), 3.12 (dd, J ) 4.0
Hz, J ) 16.1 Hz, 1H), 3.24-3.30 (m, 2H), 3.33 (dd, J ) 4.9
Hz, J ) 11.0 Hz, 1H), 3.52 (dd, J ) 3.9 Hz, J ) 11.2 Hz, 1H),
3.58 (d, J ) 15.9 Hz, 1H), 3.64 (dd, J ) 4.0 Hz, J ) 11.8 Hz,
1H), 3.69 (d, J ) 16.8 Hz, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 3.86
(s, 3H), 3.87 (s, 6H), 3.89 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H),
4.15 (d, J ) 16.5 Hz, 1H), 4.19 (d, J ) 16.8 Hz, 1H), 4.53 (s,
1H), 4.86 (dd, J ) 4.9 Hz, J ) 8.1 Hz, 1H), 6.69 (s, 1H), 6.74
(s, 1H), 6.78 (d, J ) 8.2 Hz, 1H), 6.81 (d, J ) 8.5 Hz, 1H), 6.84
(d, J ) 8.5 Hz, 1H), 6.87 (d, J ) 8.2 Hz, 1H), 6.89 (s, 1H), 7.06
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3, mixture of diaster-
eomers) δ 34.6, 36.2, 53.0, 53.5 (CH2), 55.8, 55.8, 56.0 (CH3),
58.0 (CH2), 58.5 (CH), 58.7 (CH2), 59.0 (CH), 60.1 (CH3), 66.5,
107.8, 109.1, 110.8, 111.0, 111.7, 123.6, 123.7 (CH), 127.0,
127.1, 127.9, 128.2, 128.7, 129.8, 130.0, 130.1, 144.8, 145.0,
147.8, 148.2, 148.8, 150.1, 150.2 (C) ppm; MS (EI) m/z (%) 371
(M+, 41), 370 (13), 355 (10), 354 (47), 165 (32), 164 (100), 163
(16), 150 (13), 149 (69), 121 (11); IR (in CHCl3) ν 1514, 1497,
1460, 1278, 1261, 1218, 1148, 755 cm-1; HRMS m/z calcd for
C21H25NO5 (M+): 371.1733. Found: 371.1733.
Method B. In a 5-mL flask, a solution of alcohol (S)-28 (60
mg, 0.162 mmol) in abs. CH2Cl2 (3 mL) was cooled to -78 °C.
BF3‚OEt2 (0.10 mL, 0.808 mmol) and Et3SiH (0.13 mL, 0.808
mmol) were successively added. After 1 h at -78 °C the
temperature was increased to room temperature, and the
reaction mixture was stirred for an additional 18 h. The
solution was then neutralized with sat. aqueous NaHCO3
(∼1-2 mL). The organic phase was kept, and the aqueous
phase was extracted 4 times with CH2Cl2. The combined
organic phases were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The resulting crude mixture
was purified by column chromatography (n-pentane/Et2O )
1/1 + 5% Et3N) to provide 53 mg (92%) of (S)-2 as a light yellow
solid: ee ) 98% (Chiralpak AD; n-heptane/i-PrOH ) 8/2; Rt
) 13.74 min; λ ) 230 nm); mp 138 °C (Lit.27 140 °C); [R]24.5
D
(13aS)-2,3,9,10-Tetramethoxy-5,8,13,13a-tetrahydro-
6H-dibenzo[a,g]-quinolizin-5-ol [(S)-28]. According to the
procedure described for the synthesis of (R)-28, acetal (S)-27
(0.105 g, 0.24 mmol) was converted into (S)-28 using concen-
trated aqueous HCl (86 µL). The resulting crude mixture was
purified by column chromatography (Et2O/MeOH ) 60/1) to
yield 0.076 g (83%) of (S)-28 as a yellow solid; dr ) 63/37
(Chiralcel OD; n-heptane/i-PrOH ) 8/2; Rt ) 18.33 min; Rt )
23.72 min; λ ) 230 nm).
(13aR)-2,3,9,10-Tetramethoxy-5,8,13,13a-tetrahydro-
6H-dibenzo[a,g]quinolizine; (R)-(+)-Tetrahydropalma-
tine [(R)-(+)-2]. In a 5-mL flask under argon, a solution of
alcohol (R)-28 (43 mg, 0.116 mmol) in abs. CH2Cl2 (1.5 mL)
was cooled to -78 °C. BF3‚OEt2 (37 µL, 0.289 mmol) and Et3-
SiH (46 µL, 0.289 mmol) were successively added. After 2 h
at -78 °C the temperature was increased to room temperature,
and the reaction mixture was stirred for an additional 5 h.
The solution was then neutralized with sat. aqueous NaHCO3
(∼0.5-1 mL). The organic phase was kept, and the aqueous
phase was extracted 4 times with CH2Cl2. The combined
organic phases were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The resulting crude mixture
-268.5 (c 0.8, CHCl3, ee ) 98%) (Lit.28 [R]20 -269 (c 0.8,
D
CHCl3)).
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Sonderforschungs-
bereich 380, Graduiertenkolleg 440, scholarship to M.B.)
and the Fond der Chemischen Industrie. We thank
Bayer AG, BASF AG, and Degussa AG for the donation
of chemicals.
Supporting Information Available: Chiral HPLC data
for 22, 27, and 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO051554T
(26) (a) Blanchfield, J. T.; Sands, D. P. A.; Kennard, C. H. L.; Byriel,
K. A.; Kitching, W. Phytochemistry 2003, 63, 711. (b) Miyazawa, M.;
Yoshio, K.; Ishikawa, Y.; Kameoka, H. J. Agric. Food Chem. 1998, 46,
1914.
(27) Bhakuni, D. S.; Jain, S.; Gupta, S. Tetrahedron 1984, 40, 1591.
(28) Halbsguth, C.; Meissner, O.; Haeberlein, H. Planta Med. 2003,
69, 305.
9494 J. Org. Chem., Vol. 70, No. 23, 2005