From serine to functionalized enantiopure tetrahydroisoquinolines

Article abstract of DOI:10.1016/S0040-4039(00)00765-6

The reaction of γ-amino-α,β-unsaturated esters prepared from L-serine with diversely substituted arylcuprates affords the corresponding syn- adducts. Transformation of the amino group to an isocyanate, followed by Friedel-Crafts intramolecular condensatio

Full text of DOI:10.1016/S0040-4039(00)00765-6

Tetrahedron Letters 41 (2000) 4999±5003
From serine to functionalized enantiopure
tetrahydroisoquinolines
Stephen Hanessian,* Emmanuel Demont and Willem A. L. van Otterlo
  Â
Department of Chemistry, Universite de Montreal, C.P. 6128, Succursale Centre-ville, Montreal,
Â
Quebec H3C 3J7, Canada
Received 22 March 2000; accepted 10 May 2000
Abstract
The reaction of g-amino-a,b-unsaturated esters prepared from l-serine with diversely substituted aryl-
cuprates a€ords the corresponding syn-adducts. Transformation of the amino group to an isocyanate,
followed by Friedel±Crafts intramolecular condensation, leads to enantiopure 3,4-disubstituted tetrahydro-
isoquinolin-1-ones, which can be reduced to the corresponding tetrahydroisoquinolines. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Friedel±Crafts; organocuprate; conjugate addition.
Isoquinoline alkaloids have been a cornerstone in the large collection of naturally occurring
substances belonging to the alkaloid family and they ®gure prominently in the arsenal of phar-
macologically active compounds.1 Tetrahydroisoquinolines are traditionally synthesized from the
ring closure of iminium intermediates via the well-known Pictet±Spengler2 or Bischler±Napieralski3
reactions. Other methods are also known for the synthesis of 1-substituted 1,2,3,4-tetrahydro-
isoquinolines in racemic and enantiopure forms.1
In contrast, there are fewer methods for the stereocontrolled synthesis of 3- or 3,4-substituted
congeners.4 A recent claim to 3-substituted tetrahydroisoquinolines from N,N-dibenzylamino
alcohols,5 has been repudiated after careful experimentation by another group.6 Such compounds
could be viewed as versatile sca€olds on which to attach pharmacophore-like groups through the
chemical elaboration of existing functionality of the tetrahydroisoquinoline nucleus. An assembly
protocol that also allows for the incorporation of substituents on the aromatic portion would
greatly enhance the versatility of these molecules as potential pharmacologically important
agents, or as probes to study interactions with biological receptors, enzymes, etc.
We report herein a method for the stereocontrolled synthesis of 3,4-disubstituted tetrahydro-
isoquinolin-1-ones and tetrahydroisoquinolines in enantiopure form starting with l-serine7 as seen
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00765-6

5000
in Scheme 1. The method consists in the stereocontrolled conjugate addition of diarylmagnesio-
cuprates to a readily available a,b-unsaturated ester.8 10 After transformation of the amino group
to the corresponding isocyanate, the products are subjected to a Friedel±Crafts intramolecular
cyclization11 to provide tetrahydroisoquinolin-1-ones.
Scheme 1.
Thus, l-serine was converted to the a,b-unsaturated ester8 10 2, which is known to react with
organocuprate reagents in the presence of trimethylsilyl chloride to give predominantly syn-
adducts8 10,12 (Scheme 2).
Scheme 2.

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Extension of this reaction to a variety of o-, m-, and p-substituted diarylmagnesiocuprates led
to the corresponding b-aryl adducts 3 in excellent yields, and diastereoselectivities exceeding 8:1
in favor of the syn-isomer.10 The rationale for the observed stereoselectivity has been discussed in
a previous paper from our group.10 In order to carry out the intramolecular cyclizations en route
to the desired tetrahydroisoquinolin-1-ones 6, it was necessary to introduce functionality and
protective groups that would be compatible with the use of aluminum chloride under Friedel±
Crafts conditions. The adducts 3 were transformed to the bis-pivaloyl esters of generic structure
4 in good overall yields. Removal of the N-Boc group with tri¯uoroacetic acid in the presence of
resorcinol,13 followed by treatment with triphosgene14 led to the corresponding isocyanates15 5.
In general, the Friedel±Crafts reaction gave single products in good to excellent yields (Fig. 1).
In the case of the m-methyl isomer corresponding to 5, the reaction a€orded a 2.2:1 mixture of
the o- and p-methyl cyclization products 17a and 17b which were separable by column chroma-
tography. The corresponding methoxy analog gave the product of p-substitution 19, only, no
doubt due to the activating e€ect of the methoxy group. Interestingly, the m-¯uoro isocyanate
corresponding to 5 also gave the p-substituted product 20 only (Fig. 1).16
b
Figure 1. aYields of chromatographically pure product over three steps as in Scheme 2; [ꢀ]D reported in CHCl3 with
c
1
concentration in brackets; all products were adequately characterized by H, 13C and HRMS
In order to further demonstrate the utility of these compounds, we explored reactions taking the
p-methyl analog as a prototype (Scheme 2). Hydrolysis of the pivalate esters, gave the corresponding
diol 7 which was transformed to a diastereomeric mixture of 2-phenyl-1,3-oxazolidine derivatives
8, thus allowing for further elaboration of the distal hydroxyethyl group. In a typical example,
displacement of the mesylate 9 with azide gave the corresponding azido derivative 10. The phenylthio
ether 11 was also prepared from 8 following known precedents.17 Acid hydrolysis of 10 and 11
a€orded the selectively functionalized azido and phenylthio derivatives 12 and 13, respectively,
in enantiopure form. A prototypical tetrahydroisoquinoline 14 was prepared by reduction of the
diol 7 with LiAlH4.
The methodology reported in this paper provides access to diversely functionalized enantiopure
3,4-disubstituted tetrahydroisoquinolines with di€erent aromatic substituents. The azido and
phenylthio derivatives 12 and 13 can be subjected to further orthogonally directed chemical
manipulations, thus expanding the versatility of this class of heterocycles not only as sca€olds for
the deployment of pharmacophores, but also as potential bioactive compounds. In this regard,

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recent reports concerning the synthesis of polysubstituted tetrahydroisoquinolines and related
compounds on solid-support and by parallel array are noteworthy.18,19
Acknowledgements
We thank NSERCC for ®nancial assistance through the Medicinal Chemistry Chair Program.
References
1. Rozwadowska, M. D. Heterocycles 1994, 39, 903, and references cited therein; Herbert, R. B. In The Chemistry
and Biology of Isoquinoline Alkaloids; Philipson, J. D.; Roberts, M. F.; Zenk, M. H., Eds.; Springer-Verlag: Berlin,
1985; p. 213; Shamma, M. In Isoquinoline Alkaloids, Chemistry and Pharmacology; Academic: New York, 1972.
2. Cox, A. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
3. For a recent example, see: Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183.
4. For leading references, see: Vicario, J. L.; Badõa, D.; Domõnguez, E.; Carrillo, L. J. Org. Chem. 1999, 64, 4610;
Monsees, A.; Laschat, S.; Dix, I. J. Org. Chem. 1998, 63, 10018.
5. Chandrasekhar, S.; Mohanty, P. K.; Harikishan, K.; Sasmal, P. K. Org. Lett. 1999, 1, 877.
6. Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647.
7. For the synthesis of heterocycles from amino acids, see: Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825;
for early seminal work in asymmetric synthesis, see: Meyers, A. I.; Fuentes, L. M. J. Am. Chem. Soc. 1983, 105,
117.
8. Hanessian, S.; Wang, W.; Gai, Y. Tetrahedron Lett. 1996, 37, 7477.
9. Jako, I.; Uiber, P.; Mann, A.; Taddei, M.; Wermuth, C.-G. Tetrahedron Lett. 1990, 31, 1011.
10. Hanessian, S.; Sumi, K. Synthesis 1991, 1083.
11. E€enberger, F.; Gleiter, R. Chem. Ber. 1964, 97, 472.
12. For a review on a-amino acid aldehydes, their derivatives, and further transformations, see: Reetz, M. T.; Rohrig,
D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1706; Reetz, M. T. Chem. Rev. 1999, 99, 1121.
13. Wunsch, E.; Jaeger, E.; Kisfaludy, L.; Low, M. Angew. Chem., Int. Ed. Engl. 1977, 16, 317; Schmidt, U.;
Lieberknecht, A.; Bokens, H.; Griesser, H. J. Org. Chem. 1983, 48, 2680.
14. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894.
15. Nowick, J. S.; Powell, N. A.; Nguyen, T. M.; Noronha, G. J. Org. Chem. 1992, 57, 7364.
16. Typical procedure for cuprate addition: A suspension of magnesium chips (535 mg, 22 mmol, 1.1 equiv.) with a
trace of iodine in 6 mL of THF was heated at re¯ux until colorless. After cooling to room temperature, 2-bromo-
toluene (3.4 g, 20 mmol), in 34 mL of THF was added dropwise over 30 min so that the temperature was kept
below 40ꢀC. Stirring was maintained for 30 min and after 12 h the supernatant was cannulated into a ¯ask,
a€ording a 0.5 M solution of the Grignard reagent. To a suspension of CuI (1.9 g, 10 mmol) in 10 mL of THF at
^78ꢀC was added dropwise 40 mL of the preceding solution of Grignard reagent (0.5 M in THF, 20 mmol). The
resulting mixture was allowed to warm to ^20ꢀC over 1 h, then recooled to ^78ꢀC. To the reaction mixture were
added trimethylsilyl chloride (3 mL, 22 mmol) and a solution of 2 (712 mg, 2.5 mmol) in 5 mL of THF dropwise.
The resulting mixture was stirred at this temperature for 12 h, then quenched with 30 mL of a saturated aqueous
NH4Cl solution. After dilution with AcOEt, the layers were separated. The aqueous layer was extracted twice with
AcOEt and the combined organic phases were washed twice with NH4OH (5% in solution), brine, dried over
Na2SO4 and concentrated in vacuo to give after ¯ash chromatography on silica gel (petroleum ether:AcOEt, 9:1
then 8:2) 760 mg (81%) of 3 as a pale yellow oil. Typical procedure for the Friedel±Crafts cyclization: To a solution
of 4 (680 mg, 1.42 mmol) and resorcinol (157 mg, 1.42 mmol) in 5 mL of toluene at 0ꢀC was added 1 mL of
CF3COOH. The resulting mixture was stirred at this temperature for 6 h, then concentrated in vacuo. The resulting
material was diluted in AcOEt, washed twice with 1 M NaOH, brine, dried over Na2SO4 and concentrated in
vacuo to give 5 (520 mg, 97%) as a pale yellow oil which was used in the next reaction without puri®cation. To a
solution of triphosgene (143 mg, 0.48 mmol) in 5 mL of CH2Cl2 at 0ꢀC was added dropwise by cannula a solution
of 4 (520 mg, 1.38 mmol) and pyridine (280 ml, 3.45 mmol) in 5 mL of CH2Cl2. The resulting yellow solution was

5003
stirred at this temperature for 2 h, diluted in AcOEt and washed rapidly with water (pH 3). The aqueous layer was
extracted with AcOEt and the combined organic phases washed rapidly with a saturated aqueous NaHCO3
solution, brine, then dried over Na2SO4 and concentrated in vacuo to give isocyanate 5 (520 mg, 93%) as a brown
oil which was used in the next reaction without puri®cation. To a suspension of AlCl3 (860 mg, 6.45 mmol) in 5
mL of CH2Cl2 at 0ꢀC was added a solution of 5 (520 mg, 1.29 mmol) in 3 mL of CH2Cl2. The mixture was allowed
to warm to room temperature and stirred overnight, then partitioned between AcOEt and 10% aqueous HCl. The
layers were separated and the aqueous layer was extracted with AcOEt. The combined organic phases were
washed with a saturated aqueous NaHCO3 solution, brine, then dried over Na2SO4 and concentrated in vacuo to
give after ¯ash chromatography (petroleum ether:AcOEt. 3:1 then 1:1) 370 mg (72%) of 6 as a colorless oil.
17. See, for example: Hanessian, S.; Tyler, P. C.; Demailly, G.; Chapleur, Y. J. Am. Chem. Soc. 1981, 103, 6243;
Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409.
18. Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977.
19. Baudelle, R.; Melnyk, P.; Deprez, B.; Tartar, A. Tetrahedron 1998, 54, 4125.