A- tetrahydroisoquinolines

A common modification of the Bischler-Napieralski reaction involves reduction of the dihydroisoquinoline product 2 to provide a tetrahydroisoquinoline derivative 19. A variety of different reducing agents have been employed, with NaBHi used with the greatest frequency. In many cases the reduction is carried out on the crude product of the Bischler-Napieralski reaction purification of the dihydroisoquinoline prior to reduction is usually not necessary. 

Marsden BJ, Nguyen TM-D, Schiller PW. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Peptide Protein Res 1993 41 313-316. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

This strategy normally involves the generation of an iminium species from a tetrahydroisoquinoline and formaldehyde, followed by its Pictet-Spengler cyclization. It can be exemplified by the preparation of the berberine derivative 330 from tetrahydroisoquinoline 329 (Scheme 72) <2001JOC3495>. 

Trabectedin (36 Yondelis, ecteinascidin-743, ET-743 Zelfia and Johnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid produced hy the ascidian Ecteinascidia turbinate,received approval for its sale in Europe, Russia and South Korea by Zelfia and Johnson and Johnson under the brand name YondelisT for the treatment of advanced soft tissue sarcoma (STS). Trabectedin (36) binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle. 

Arizonine (282), a tetrahydroisoquinoline alcaloid, has been recently synthesized in 35% yield from isovanilline, using a photochemical rearrangement like that depicted in Scheme 71. The yield of the photochemical step is 55%, and other byproducts (not shown in Scheme 71) are also formed [200]. The same authors reported the synthesis of caseadine following an analogous procedure. 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

This class of compounds can be divided into three types the Et-743 type (1, 63-67) with a tris(tetrahydroisoquinoline) skeleton, the Et-736 type (68 and 69) in which a tetrahydroisoquinoline is substituted by a tetrahydrocarboline unit, and finally the Et s 597, 583, 594, and 596 (70-73), which are characterized by the presence of just two tetrahydroisoquinoline units. 

A stereoselective 6-exo selenoamination to form a tetrahydroisoquinoline ring system is probably a result of the specific substitution pattern.252 Selenocyclizations which generate piperidine systems by 6-endo cyclization give products predicted by reaction through the more stable chair conformation (equation 116).41 158c 216e,232a... 

The oxidative cyclization process is analogous to the formation of a methylenedioxy group (see page 27), whilst the mechanism of cyclization is exactly the same as that invoked in formation of a tetrahydroisoquinoline ring, i.e. a Mannich-like... 

Kong, F., Harper, M. K., and Faulkner, D. J., Fuscusine, a tetrahydroisoquinoline alkaloid from the sea star Perknaster fuscus antarcticus, Nat. Prod. Lett., 1, 71, 1992. 

Although these compounds are all anticancer agents, they act through different mechanisms. Bryostatin 1, a cyclic macrolide, inhibits protein kinase C tumor promotion while aplidine is a protein synthesis inhibitor. Dolastatin 10, a linear peptide, and ET743, a tetrahydroisoquinoline... 

The knowledge of the emetine fragmentation pattern proved very helpful in the structure elucidation of the unknown alkaloid tubulo-sine.85 Mass spectrometry aided very much in solving the structural problem of rhoeadine, first thought to be a tetrahydroisoquinoline alkaloid but now shown to be a representative of a new alkaloid... 

An oxygen function in the 4-position of a tetrahydroisoquinoline is benzylic and in a ring. On the basis of its electronic and steric situation, it should be, and is, readily replaced by nucleophiles. The nucleophiles which have been found to be effective thus far are activated (by oxygen) aromatic rings and alcohols. In a related reaction, 4,7-diacetoxytetra-hydroisoquinolines have been shown to undergo a number of base-catalyzed nucleophilic reactions. 

The second route involves the oxidation of a tetrahydroisoquinoline to the 3,4-dihydro derivative and the addition of a Grignard reagent [Eq. (40)].82,87 It would appear that a general route through Eqs. (13), (7), and (29) may now provide a simpler sequence. 

Tetrahydroprotoberberines.1 A novel entry into this ring synthesis involves the cobalt-catalyzed cocyclization of a tetrahydroisoquinoline such as 1 with trimethylsilyl-methoxyethyne (2). The reaction proceeds regioselectively in favor of the more hindered isomer (3). In the absence of the trimethylsilyl group of 1, the condensation results in two isomers in a 1 1 ratio. 

Aromatic amino acids that originate from the shikimate pathway also act as precursors to many alkaloids. Alkaloids that contain a phenylethylamine moiety are derived from L-tyrosine or its oxidation product L-dihydroxyphenylalanine (L-DOPA). Mescaline (N7) originating from the latter amino acid is known to occur in several cacti and is responsible for the hallucinogenic activity of peyote (Lophophora williamsii, Cactaceae). Lophocerine is a tetrahydroisoquinoline alkaloid derived from L-dopamine and found to occur in a different Lophophora species, L. schotti. 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

Seebach also compared the same pivaloylisoquinoline to a tetrahydroisoquinoline formamidine to evaluate die face-selectivity in the addition of die metalated derivatives to aldehydes. 2,i63 cases, the organolithium showed significantly lower diastereoselectivity than the Grignard obtained by transmetalation with MgBr2-Et20, as shown by the examples in Scheme 47. The transmetalation protocol was used to prepare a number of racemic isoquinoline alkaloids. 

A new approach to the morphine skeleton was demonstrated by the total synthesis of (+)-desoxycodeine-D by C.-Y. Cheng and co-workers." " The key step was the formation of the B ring by the Stevens rearrangement of a tetrahydroisoquinoline-derived quaternary ammonium salt upon treatment with phenyllithium. 

M. Yamato, K. Hashigaki, N. Qais, S. Ishikawa, Asymmetric synthesis of 1-alkytetrahydroisoqui-nolines using chiral oxazolo[2,3-a]tetrahydroisoquinolines. Tetrahedron 46 (1990) 5909. 

The yield of the lithiation, in case of benzylamine, is again good only when the amine is tertiary. This then leads to the quaternary salt in the cyclisation reaction. The dehydrogenation of quaternary salt does not proceed in synthetically useful yield. For this reason the method is not suitable for the synthesis of isoquinolines themselves. However, when the desired product is a tetrahydroisoquinoline the method can be of some value as in a synthesis of tetrahydropalmatine (vide infra). 

Gitto R, Caruso R, Pagano B et al (2006) Novel potent anticonvulsant agent containing a tetrahydroisoquinoline skeleton. J Med Chem 49 5618-5622... 

With its 2-carbon bridge across the middle, maprotiline (Fig. 12-26) is technically a tetracyclic compound, yet it behaves as a secondary amine TCA (i.e., a relatively selective NE reuptake). The drug s second-generation standing is purely chronological. It has been in the U.S. market since 1981. Amoxapine, which was marketed the same year, is, of course, the N4-demethylated antipsychotic loxapine (Fig. 12-26). It has been suggested the cumulation of the 8-OH metabolite may be responsible for the inhibition of NE uptake and account for the antidepressant effect. Nomifensine, which is a tetrahydroisoquinoline with potential as an inhibitor of NE and DA, but not 5-HT, was withdrawn in 1987 for toxicity reasons. 

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