A General Methodology for the Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids

a Starting from tricyclic lactam 2 , which is easily accessible by cyclocondensation of d -oxoester 1 with ( R )-phenylglycinol, a three-step synthetic route to enantiopure 1-substituted tetrahydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyl-tetrahydroisoquinoline alkaloids as well as the tricyclic alkaloid (–)-crispine A, has been developed. The key step is a stereoselective a -amidoalkylation reaction using the appropriate Grignard reagent.


Introduction
The tetrahydroisoquinoline ring system is present in numerous structurally diverse natural products exhibiting a wide range of biological and pharmacological activities. [1] In particular, simple 1substituted tetrahydroisoquinolines are of great interest not only as alkaloids themselves but also as useful key intermediates in the synthesis of more complex alkaloids. This has stimulated the development of a number of methodologies aimed at the enantioselective synthesis of 1-substituted tetrahydroisoquinoline derivatives [2] (Figure 1). Figure 1. Selected 1-substituted tetrahydroisoquinoline alkaloids. In previous work we have demonstrated that phenylglycinolderived oxazolopiperidone lactams are versatile scaffolds that allow the regio-and stereocontrolled introduction of substituents at the different positions of the piperidine ring, thus providing access to enantiopure substituted piperidines bearing virtually any type of substitution pattern, as well as to quinolizidine, indolizidine, decahydroquinoline, and complex piperidine-containing indole alkaloids [3] (Scheme 1). Scheme 1. Natural and bioactive products prepared from phenylglycinolderived lactams.

Results and Discussion
To further expand the synthetic potential of phenylglycinolderived oxazolopiperidone lactams, we report here a general methodology for the enantioselective synthesis of 1-substituted tetrahydroisoquinoline alkaloids. The application of our enantiomeric scaffolding strategy [4] would simply require starting from an appropriate benzo-fused oxazolopiperidone lactam and the subsequent stereocontrolled introduction of the substituent at the 1position of the tetrahydroisoquinoline ring by an asymmetric αamidoalkylation reaction. [5] Tricyclic lactam 2 was envisaged as the pivotal intermediate of our synthesis. It was prepared in 52% yield by cyclocondensation of aldehyde ester 1 [6] with (R)-phenylglycinol in refluxing toluene in the presence of a catalytic amount of p-TsOH (Scheme 2). The absolute configuration of lactam 2 was unambiguously determined by X-ray crystallographic analysis. [7] Minor amounts (6%) of the lactam epi-2, epimeric at the 2-position of the oxazolidine ring, were also formed. Scheme 2. Preparation of the key tricyclic lactam 2.
In contrast with related cis-oxazolopiperidone lactams, [8] the minor cis lactam epi-2 did not undergo epimerization under acidic conditions (1.2 N HCl,MeOH,r.t), isoquinolone 3 and trace amounts of dimer 4 being formed instead. This dimer was formed in 49% yield after a prolonged acidic treatment (1.2 N HCl,MeOH,reflux,66 h) of isoquinolone 3. Initial attempts to carry out the α-amidoalkylation reaction with a higher order cyanocuprate [Me 2 Cu(CN) Li 2 ] in the presence of BF 3 .Et 2 O [9] resulted in failure, leading exclusively to isoquinolone 3. However, treatment of lactam 2 with an excess (3 equiv.) of methylmagnesium chloride at 5 ºC stereoselectively led to the expected 1-substituted tetrahydroisoquinolone 5a in 61% yield (Table 1). [10] Isoquinolone 3 was formed as a by-product (17%). Higher temperatures resulted in the formation of increasing amounts of 3, whereas when the reaction was carried out at a lower temperature the starting lactam was recovered to a considerable extent.
The observed retention of the configuration of the reactive methine carbon can be rationalized by considering that the Grignard reagent coordinates with the oxygen atom of the oxazolidine ring and that the subsequent intramolecular delivery of the alkyl group occurs on the same face of the C-O bond of the incipient acyl iminium salt ( Figure 2). [11] Figure 2. Stereochemical outcome of the α-amidoalkylation reaction.
Removal of the phenylethanol moiety from lactam 5a was accomplished in excellent yield with sodium in liquid ammonia to give the N-unsubstituted lactam 6a. A subsequent reduction with borane generated in situ from NaBH 4 and iodine completed the enantioselective synthesis of (-)-salsolidine 7a. [13] Taking into account previous correlations, this synthesis also constitutes a formal synthesis of the alkaloid (-)-carnegine. [14] The above protocol provides general access to 1-alkyl substituted tetrahydroisoquinolines. Thus, reaction of lactam 2 with ethylmagnesium bromide stereoselectively afforded (82% yield) lactam 5b, which was then debenzylated and converted to (S)- 1ethyl-1,2,3,4-tetrahydroisoquinoline 7b in good overall yield, as in the above methyl series. With the aim of demonstrating the potential of the methodology for the synthesis of 1-aryl-, 1-benzyl-, and 1-phenethyl tetrahydroisoquinoline alkaloids, we applied the above three-step sequence from lactam 2 using a variety of aryl-, benzyl-, and phenethylmagnesium halides. The results are summarized in Table  1 (entries c-g). In all cases the α-amidoalkylation reaction took place stereoselectively to give a single 1-substituted tetrahydroisoquinolone derivative (5c-g). [15] Although the reductive cleavage of the exocyclic benzylic C-N bond of the 2-phenyl derivative 5c with Na/liq. NH 3 occurred with concomitant cleavage of the doubly benzylic endocyclic C-N bond to give 2-benzyl-4,5-dimethoxyphenylacetamide (8), a similar reduction from the methoxyphenyl substituted tetrahydroisoquinolones 5d and 5e satisfactorily led to the respective N-unsusbtituted lactams 6d and 6e in excellent yield. A subsequent reduction of the lactam carbonyl of 6d led to (-)norcryptostyline II (7d), which constitutes a formal synthesis of the alkaloid (+)-cryptostyline II. [16] Similarly, lactam 6e was converted to (-)-norcryptostyline III (7e), a known precursor of the alkaloid (+)-cryptostyline III. [17] The same set of sequential reductions (Na/liq. NH 3 and then NaBH 4 -I 2 ) was used to convert 2-benzyl Odimethylcoclaurine (7f). [18] Taking into account previous transformations, this synthesis also constitutes a formal synthesis of the alkaloids (+)- O-methylarmepavine, [18a,b] zanoxyline, [19] and Similarly, the usefulness of this methodology in the synthesis of 1-phenethyltetrahydroisoquinolines was demonstrated by the preparation of 7g [20] from the α-amidoalkylation product 5g.
The procedure allows the preparation of tetrahydroisoquinolines and tetrahydroisoquinolones bearing a functionalized C-1 substituent, for instance allyl [21] or 2-(1,3-dioxan-2-yl)ethyl (Table  1, entries h, i), [22] which can open access to more complex tetrahydroisoquinoline alkaloids embodying an additional ring. This was exemplified with the synthesis of the pyrrolo[2, 1g]isoquinoline alkaloid crispine A. The three-carbon fragment required to assemble the pyrrolidine ring was incorporated in the α-amidoalkylation step by reaction of lactam 2 with the Grignard reagent derived from 2-(2-bromoethyl)-1,  to give 5i. In this synthesis, the lactam carbonyl was reduced prior to debenzylation to give tetrahydroisoquinoline 9 in excellent yield. A subsequent catalytic hydrogenation under acidic conditions brought about the hydrogenolysis of the exocyclic benzylic C-N bond, deprotection of the acetal function, and closure of the pyrrolidine ring by reductive amination, directly leading to crispine A [23] in 74% yield. Scheme 3. Enantioselective synthesis of (-)-crispine A.

Conclusions
Tricyclic (R)-phenylglycinol-derived lactam 2 has proven to be a useful scaffold that provides general access to enantiopure 1substituted tetrahydroisoquinoline derivatives, including 1-alkyl-, 1-aryl-, and 1-benzyltetrahydroisoquinoline alkaloids as well as more complex alkaloids bearing the tetrahydroisoquinoline moiety (Scheme 4). The enantioselective synthesis of 1benzyltetrahydroisoquinolines is of particular interest because these derivatives not only play a pivotal role in the biosynthesis of numerous alkaloids with a variety of skeletal types (e.g. aporphines, cularines, protoberberines, and pavines) but have also been used as key synthetic precursors of such alkaloids. [24] Scheme 4. Enantiopure 1-substituted tetrahydroisoquinolines prepared from the common scaffold 2.