Enantioselective modification of the Pomeranz-Fritsch-Bobbitt synthesis of tetrahydroisoquinoline alkaloids synthesis of (-)-salsolidine and (-)-carnegine

Article abstract of DOI:10.1016/S0957-4166(00)00196-8

(-)-Salsolidine 7 and (-)-carnegine 8 were prepared in 46 and 36% e.e., respectively, by enantioselective addition of methyllithium to the Pomeranz-Fritsch imine 13 in the presence of ligands 9-12, followed by acid-catalyzed cyclization and hydrogenolysis

Full text of DOI:10.1016/S0957-4166(00)00196-8

Tetrahedron: Asymmetry 11 (2000) 2359±2366
Enantioselective modi®cation of the Pomeranz±Fritsch±
Bobbitt synthesis of tetrahydroisoquinoline alkaloids:
synthesis of (^)-salsolidine and (^)-carnegine
Agata G•uszynska and Maria D. Rozwadowska*
Faculty of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznan, Poland
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Received 30 March 2000; accepted 16 May 2000
Abstract
(^)-Salsolidine 7 and (^)-carnegine 8 were prepared in 46 and 36% e.e., respectively, by enantioselective
addition of methyllithium to the Pomeranz±Fritsch imine 13 in the presence of ligands 9±12, followed by
acid-catalyzed cyclization and hydrogenolysis. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The Bobbitt modi®cation1 of the traditional Pomeranz±Fritsch isoquinoline synthesis,2 which
enables the synthesis of 1,2,3,4-tetrahydroisoquinoline derivatives, involves benzylaminoacet-
aldehyde acetal 2 as the key intermediate (Scheme 1). This aminoacetal 2 is usually prepared from
the classic Pomeranz±Fritsch imine 1 by in situ catalytic hydrogenation of the imine CˆN double
bond1 or by addition of Grignard reagents.3 6 Recently, this type of benzylaminoacetal
intermediate 2 has been prepared from the corresponding benzyl alcohol on reaction with
aminoacetaldehyde derivatives,7 10 or by N-alkylation of benzylamine with bromoacetaldehyde
acetal.6
Scheme 1.
* Corresponding author. E-mail: wzantk@main.amu.edu.pl
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00196-8

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In the next step, intermediate 2 is cyclized in acidic solution to give unstable 1,2-dihydro-
isoquinoline, which may be reduced in situ to 1,2,3,4-tetrahydroisoquinoline (the Bobbitt
modi®cation1), or dehydrogenated, preferably via an N-tosyl derivative, to a fully aromatic system
(the Jackson modi®cation11).
Only a few examples of stereochemical modi®cation of the Pomeranz±Fritsch±Bobbitt
cyclization resulting in chiral non-racemic isoquinoline alkaloids have been repeorted.6,8,9 This
approach has been investigated much less frequently then the two other classic syntheses, the
Bischler±Napieralski and the Pictet±Spengler ones, which have made important contributions to
the many strategies available for stereoselective synthesis of isoquinoline alkaloids.12
In the published stereoselective Pomeranz±Fritsch±Bobbitt syntheses a source of the C-1
stereogenic center has already been present in the precursors of amine 2. Thus, in the synthesis of
(+)- and (^)-reticuline, Hirsenkorn8 used alternatively optically active hydrobenzoin 3 or epoxide
4 and converted each into type 2 amines by aminolysis with N-methyl aminoacetaldehyde acetal.
In Kaufman's9 synthesis of (^)-salsolidine 7, non-racemic benzyl alcohol 5 was treated with N-
tosyl-aminoacetaldehyde acetal under Mitsunobu reaction conditions to give N-tosylated amine
type 2. Several optically active benzylamines, type 6, alkylated with bromoacetaldehyde acetal,
have been applied by Badia et al.6 for the synthesis of a series of isopavine alkaloids (Scheme 2).
Scheme 2.
2. Results and discussion
Herein we report the enantioselective synthesis of isoquinoline alkaloids performed according
to the Pomeranz±Fritsch±Bobbitt methodology based on the enantioselective addition of
methyllithium to type 1 imines induced by ligands 9±12, prior to isoquinoline cyclization. It
should be mentioned that enantioselective addition of carbon nucleophiles to imines, recently
reviewed by Denmark and Nicaise13 and Enders and Reinhold,14 has not been studied as inten-
sively as that of the analogous reaction involving prochiral carbonyl compounds.
To achieve enantioselectivity in the addition step for the two isoquinoline alkaloids, salsolidine
7 and carnegine 8, we have used non-racemic oxazolines 9±12. These compounds were chosen not
only because of the well-known eciency of oxazolines in stereoselective transformations, both in
the reactions based on chiral auxiliary and in asymmetric catalysis,15 17 but also because they
could be obtained from (1S,2S)-2-amino-1-aryl-1,3-propandiols (industrial waste products) which
we have used successfully as a source and/or promoter of stereochemistry in many types of
organic synthesis.18,19

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2361
The starting Schi€ base 13 was obtained in good yield, as a single isomer, by condensation of
veratraldehyde with aminoacetaldehyde dimethyl acetal in the usual manner.18b The E-con-
®guration of 13 was established by 1H NMR spectroscopy on the basis of NOESY spectrum, which
showed through space interaction between H-1 and both the H-3 and OCH3 group protons.
Ligands 10 and 12 were synthesized from the known (4S,5S)-oxazolines 9 and 11, prepared
easily from (+)-thiomicamine or (1S,2S)-2-amino-1-phenyl-1,3-propandiol, respectively, in reaction
with benzonitrile, according to a known procedure.18a Compounds 9 and 11 were O-methylated
with CH3I±NaH in DMF to give O-methyl derivatives (4S,5S)-10 and 12,20 respectively, in a
satisfactory yield (Scheme 3).
Scheme 3.
In order to optimize the reaction conditions of the key step, the enantioselective addition of
MeLi to imine 13, we have undertaken initial studies with the use of ligand 10 as a promoter
(Table 1). Before addition of methyllithium the imine 13 was allowed to react with the catalyst for
30 min to 1 h (data in parentheses, Table 1). It was found that 2.5 equiv. of MeLi and 2.5±3.5 h
reaction time (TLC monitoring) were necessary for conversion of imine 13 to amine 14. Imine 13
was essentially unreactive toward MeLi at low temperatures in the absence of the ligands, indi-
cating the catalytic activity of the latter compounds. Toluene, a solvent with a low coordination
ability for organolithium reagents, was found to be superior to ethyl ether and THF (entries 5,
10, 11). The in¯uence of temperature on enantioselectivity was also evaluated. The results in
Table 1 show that the selectivity successively increased with lowering temperature from rt to
^65ꢀC (entries 13, 12, 7, 6, 5), while at ^90ꢀC no further increase was observed (entry 8). In the
reactions carried out with substoichiometric quantities of 10 (0.1±0.5 equiv., entries 1 and 2),
enantioselectivity was much lower than that in which 1.0±2.0 equiv. were used (entries 3 and 4);
however, the best results (49% e.e.) were obtained in the presence of 2.6 equiv. of 10 (entry 5), a
quantity applied by Tomioka et al.,21 which was even better than with 3.0 equiv. (entry 9).
As a result of the above experiments we conclude that the optimum conditions for the addition
step involve the use of: 2.5 equiv. of MeLi, toluene as a solvent, ±65ꢀC as the reaction temperature,
2.6 equiv. of the ligand and 1 h of interaction of the imine with the catalyst. The optimized
conditions were applied in further studies in which other ligands 9, 11 and 12 were used. Poor
asymmetric induction (1±9%) was achieved with the use of ligands 9 and 11; however, in the case
of 12 the enantioselectivity reached 40%.
The enantiomeric excess of amine 14 was determined by integrating absorption bands of the
1
acetal methoxy group protons split into two singlets at 3.31 and 3.36 ppm in the H NMR
spectrum recorded in the presence of 3 equiv. of TADDOL,22 used as a solvating agent. Its (S)-
con®guration was established in the course of subsequent transformation of a sample of optically
active amine 14 into (1S)-(^)-salsolidine 7 of known absolute stereochemistry.23

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Table 1
Addition of methyllithium to imine 13 in the presence of ligand 10
For the synthesis of salsolidine 7, amine 14 of 49% e.e. in 6N hydrochloric acid was subject to
catalytic hydrogenolysis in the presence of 5% palladium on carbon at rt to a€ord levorotatory
1
salsolidine 723 in 57% yield and with 46% enantioselectivity (Scheme 4). In its H NMR
spectrum, recorded in the presence of 2 equiv. of TADDOL, the doublet of CH3 group protons
was split into two doublets from which the lower-®eld one (1.26 ppm), which was dominant,
represented the (S)-(^)-enantiomer, since the other one (1.21 ppm) was earlier identi®ed as
belonging to the (R)-(+)-salsolidine.18b
In another series of experiments amine 14 showing 38% e.e. was ®rst N-methylated with the
HCOH/CH3COOH±NaBH4 system to give N-methyl derivative (^)-15 in 86% yield and with
38% e.e., before it was cyclized in the conditions employed for the synthesis of 7 to give (^)-
carnegine 8 of known (S)-con®guration23 in 79% yield and 36% e.e. (Scheme 4).
3. Conclusion
The ®rst enantioselective modi®cation of the known Pomeranz±Fritsch±Bobbitt synthesis of
tetrahydroisoquinoline alkaloids has been achieved. The concept of the synthesis is built upon
enantioselective addition of organometallic reagents to the Pomeranz±Fritsch imine 13 prior to

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A. G•uszynska, M. D. Rozwadowska / Tetrahedron: Asymmetry 11 (2000) 2359±2366
2363
Scheme 4. Reagents and conditions: (i) CH3Li, toluene, ^65ꢀC, ligands 9±12; (ii) HCHO, CH3COOH/NaBH4, EtOH;
(iii) 6N HCl, 1 day, H2/Pd±C; (iv) 6N HCl, 2 days, H2/Pd±C
cyclization of the heterocyclic ring. The steric course of the addition step is controlled by
oxazolines 9±12 used as external ligands. The most important points of the strategy employed are
that the C-1 stereogenic center of the alkaloids is formed at an early stage of the synthesis, and no
covalently bonded chiral auxiliary is involved. The enantiomeric excess achieved in the addition
step leading to amine 14 was not lost during the synthesis of the alkaloids (^)-salsolidine 7 and
(^)-carnegine 8.
4. Experimental
4.1. General
Melting points: determined on a Ko‚er block and are uncorrected. IR spectra: Perkin±Elmer
180 in KBr pellets. NMR spectra: Varian Gemini 300, in CDCl3, with TMS as internal standard.
Mass spectra (EI): Joel D-100, 75 eV. Speci®c rotation: Perkin±Elmer polarimeter 243B at 20ꢀC.
Merck Kieselgel 60 (70±230 mesh) was used for column chromatography and Merck DC-Alufolien
Kieselgel 60254 for TLC.
4.2. O-Methylation of oxazoline 9
To oxazoline 918a (13.16 g, 44 mmol) in DMF (128 ml), NaH (1.32 g, 55 mmol) was added
portionwise at ice-bath temperature. The mixture was stirred at this temperature for 1 h before
CH3I (3.5 ml, 56 mmol) was introduced. The whole mixture was stirred at rt for 17 h, then poured
onto ice and after rt was reached the solid was ®ltered o€. It was washed with water and air-dried
to give crude oxazoline 10. An additional amount of 10 was obtained from the ®ltrate by

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A. G•uszynska, M. D. Rozwadowska / Tetrahedron: Asymmetry 11 (2000) 2359±2366
2364
extraction with ethyl ether until the Dragendor€ test was negative. The two bunches of the
product were combined and recrystallized from ethyl ether to give 12.5 g (91%) of enantiomerically
pure (4S,5S)-oxazoline 10; m.p. 85.5±86.5oC; [ꢀ]D=+60.5 (c 0.5, CH2Cl2). IR cm^1: 1645 (CˆN);
1H NMR ꢁ: 2.47 (s, 3H, SCH3), 3.43 (s, 3H, OCH3), 3.60 (dd, J=6.6, 9.6 Hz, 1H, CHHOCH3),
3.73 (dd, J=4.7, 9.6 Hz, 1H, CHHOCH3), 4.31 (ddd, J=6.9, 6.6, 4.7 Hz, 1H, CHN), 5.45 (d,
J=7.1 Hz, 1H, CHPh), 7.23±7.54 (m, 7H, ArH), 8.01±8.05 (m, 2H, ArH); MS m/z (%): 313 (M+,
37), 268 (70), 192 (73), 165 (100), 105 (50); found: C, 68.92; H, 6.06; N, 4.49. C18H19NO2S
(313.11) requires: C, 68.98; H, 6.11; N, 4.47.
4.3. Addition of CH3Li to imine 13. A typical procedure
A mixture of imine 1318b (0.127 g, 0.5 mmol) and ligand 10 (0.407 g, 1.3 mmol) in toluene (30
ml) was stirred under an argon atmosphere at ^65ꢀC for 1 h. CH3Li (1.6 M solution in ether, 0.78
ml, 1.25 mmol) was then added and stirring was continued until the end of the reaction (ca. 2 h,
TLC). The reaction mixture was quenched with 20% NH4Cl at ^65ꢀC and, after rt was reached,
phases were separated and the aqueous one was extracted with ethyl ether until the Dragendor€
test was negative. The combined organic extracts were dried and the solvent was evaporated
under reduced pressure. The residue was dissolved in methanol from which ligand 10 precipitated
overnight at 0ꢀC. It was ®ltered o€, the ®ltrate was concentrated in vacuo, and the e.e. of the
1
crude product was determined by H NMR spectrum measured in the presence of 2 equiv. of
TADDOL22 by integration peaks at 3.31 and 3.36 ppm.
For further transformation the crude amine 14 was puri®ed by column chromatography (crude
14:silica gel, 1:10; toluene:ethyl ether, 99:1). TLC comparison with an authentic sample of
racemic 14 and spectral characteristics of the oily base 14, obtained in 92% yield, corresponded to
the literature data.18b
4.4. (S)-(^)-(2,2-Dimethoxyethyl)-[1-(3,4-dimethoxyphenyl)ethyl]-N-methylamine 15
To a mixture composed of amine 14 (1.32 g, 4.91 mmol), glacial acetic acid (0.46 ml, 8 mmol)
and aqueous formaldehyde (37%, 1.18 ml, 15.9 mmol) in ethanol (10 ml), sodium borohydride
(1.26 g, 33.3 mmol) was added in portions over a 40 min period at ice-bath temperature. The
solvent was then evaporated under reduced pressure and water was added, followed by extraction
with ethyl ether until the Dragendor€ test was negative. The organic extracts were dried and the
solvent was evaporated to a€ord crude amine 15. It was puri®ed by column chromatography
(crude 15:silica gel, 1:10; toluene:ethyl ether, 9:1) to give 1.19 g yellow oil (86%); [ꢀ]D=ca. ^6.0
(c 0.7, CH2Cl2); 1H NMR ꢁ: 1.35 (d, J=7.0 Hz, 3H, CCH3), 2.30 (s, 3H, NCH3), 2.38 (dd, J=5.1,
13.2 Hz, 1H, CHHN), 2.60 (dd, J=5.5, 13.2 Hz, 1H, CHHN), 3.28, 3.29 (2s, 3H each, OCH3),
3.56 (q, J=7.0 Hz, 1H, CH), 3.87, 3.89 (2s, 3H each, OCH3), 4.44 (dd, J=5.1, 5.5 Hz, 1H, CH),
6.78±6.94 (m, 3H, ArH); MS m/z (%): 283 (M+, 4), 252 (3), 165 (100), 75 (5), 28 (9); HRMS
found: 283.1783; calcd for C15H25NO4: 283.1782.
4.5. (S)-(^)-Salsolidine 7
Amine 14 (0.269 g, 1 mmol) (49% e.e.) was dissolved in 6N hydrochloric acid (5 ml) and the
solution was stirred at rt for 26 h. It was then hydrogenated with hydrogen at 0.3 MPa in the
presence of 5% palladium on carbon (0.27 g). When no more starting material was present in the

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2365
reaction mixture (TLC, 21 h) the catalyst was removed by ®ltration through a pad of Celite, the
®ltrate was basi®ed with 20% NaOH and extracted with CHCl3. After work-up the crude
reaction product was puri®ed by column chromatography (crude 7:silica gel, 1:10; dichloro-
methane:methanol, 100:1) to give pure (^)-salsolidine 7 in 57% yield, identical with an authentic
sample by TLC and spectral data comparison.18b,23 Enantioselectivity (46%) was established by
1
integration of absorption bands at 1.21 and 1.26 ppm in the H NMR spectrum recorded in the
presence of 2 equiv. of TADDOL.22
4.6. (S)-(^)-Carnegine 8
Amine 15 (0.283 g, 1 mmol) (prepared from amine 14 showing 38% e.e.) was dissolved in 6N
hydrochloric acid (10 ml) and stirred at rt for 48 h, then hydrogenated with hydrogen at 0.3 MPa
in the presence of 5% palladium on carbon (0.28 g) (TLC, 20 h) and worked up as described
above. After column chromatography (crude 8:silica gel, 1:20; dichloromethane) pure (^)-
carnegine 8 was obtained with 79% yield and 36% e.e. Enantiomeric composition was established
1
by integration of absorption bands at 2.25 and 2.27 ppm in the H NMR spectrum recorded in
the presence of 2 equiv. of TADDOL.22 It was identical with natural (^)-carnegine23 in terms of
spectral data and TLC comparison.
Acknowledgements
This work was ®nancially supported by KBN grant no. 3 T09A 027 17 and 3 T09A 145 18.
References
1. Bobbitt, J. M.; McNew Kiely, J.; Khanna, K. L.; Eberman, R. J. Org. Chem. 1965, 30, 2247±2250.
2. (a) Shamma, M. The Isoquinoline Alkaloids, Chemistry and Pharmacology; Academic Press: New York, 1972. (b)
Shamma, M.; Moniot, L. Isoquinoline Alkaloid Research 1972±1977; Plenum Press: New York, 1978.
3. Bobbitt, J. M.; Steinfeld, A. S.; Weisgraber, K. H.; Dutta, S. J. Org. Chem. 1969, 34, 2478±2479.
4. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1974, 2190±2194.
5. Yamada, K.; Takeda, M.; Itoh, N.; Ohtsuka, H.; Tsunashima, A.; Iwakuma, T. Chem. Pharm. Bull. 1982, 30,
3197±3201.
6. Carillo, L.; Badia, D.; Dominguez, E.; Vicario, J.; Tellitu, I. J. Org. Chem. 1997, 62, 6716±6721.
7. (a) Garcia, A.; Castedo, L.; Dominguez, D. Synlett 1993, 271±272. (b) Garcia, A.; Castedo, L.; Dominguez, D.
Tetrahedron Lett. 1993, 34, 1797±1798.
8. (a) Hirsenkorn, R. Tetrahedron Lett. 1990, 31, 7591±7594. (b) Hirsenkorn, R. Tetrahedron Lett. 1991, 32, 1775±
1779.
9. Ponzo, V. L.; Kaufman, T. S. Tetrahedron Lett. 1995, 36, 9105±9108.
10. Kaufman, T. S. Synth. Commun. 1993, 23, 473±476.
11. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1974, 2185±2190.
12. Rozwadowska, M. D. Heterocycles 1994, 39, 903±931.
13. Denmark, S. E.; Nicaise, O. J. C. J. Chem. Soc., Chem. Commun. 1996, 999±1004.
14. Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895±1946.
15. Gant, T. G.; Meyers, A. I. Tetrahedron 1997, 50, 2297±2360.
16. Meyers, A. I. J. Heterocyclic Chem. 1998, 35, 991±1002.
17. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 859±875.
18. (a) Rozwadowska, M. D. Tetrahedron: Asymmetry 1998, 9, 1615±1618. (b) Brozda, D.; Chrzanowska, M.;
G•uszynska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 1999, 10, 4791±4796.

Â
A. G•uszynska, M. D. Rozwadowska / Tetrahedron: Asymmetry 11 (2000) 2359±2366
2366
19. (a) Rozwadowska, M. D. Tetrahedron: Asymmetry 1993, 4, 1619±1624. (b) Fiedorow, P.; Ratajczak-Sitarz, M.;
Rozwadowska, M. D.; Rozwadowski, Z. J. Mol. Struct. 1998, 442, 65±70.
20. Kamata, K.; Agata, I. J. Org. Chem. 1998, 63, 3113±3116.
21. (a) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1991, 32, 3095±3098. (b) Inoue, I.; Shindo,
M.; Koga, K.; Tomioka, K. Tetrahedron 1994, 50, 4429±4438.
22. Bussche-Hunnefeld, C.; Beck, A. K.; Seebach, D. Helv. Chim. Acta 1992, 75, 438±441.
23. Battersby, A. R.; Edwards, T. P. J. Chem. Soc. 1960, 1214±1221.