1 - -1,2,3,4-tetrahydroisoquinolines chiral synthesis

A novel asymmetric synthesis of l-aryl-l,2,3,4-tetrahydroisoquinolines is based on the addition of chiral phenylacetaldehyde acetals to acyUmines <95TL(36)8003>. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

An additional indication of the mildness of the cyclization is provided by the synthesis of the chiral tetrahydroisoquinoline-3-carboxylic acid (294) (72HCA15) in the presence of hydrogen and palladium-on-charcoal the jV-methyl derivative was obtained. Acetaldehyde gave a mixture of diastereoisomers in which the cis isomer (295) predominated (95 5). Unstable aldehydes can sometimes be generated in situ, as when the phenylglycidate (296) replaces the much less stable phenylacetaldehyde (66T(S8)129) acetals, enol ethers and chloromethyl methyl ethers have also been used. The mild conditions also allow the isolation of 4-hydroxytetrahydroisoquinolines (297) (75H(3)311). A review is available listing syntheses of 4-oxytetrahydroisoquinolines (73AHC(15)99). 

Consistently high levels of asymmetric induction have been achieved in the alkylation of tetrahydroisoquinolines using this methodology, as is demonstrated in the synthesis of chiral isoquinolinium alkaloids, e.g., (-)-salsolidine (61% yield, 95% ee)13, ( + )-homolaudanosine (48% yield, 96% op)14, ( —)-norcoralydine (37% yield, 98.5% op)15, some ben-zo[ ]quinolizidines (>99%ee), precursors of natural emetine16, corynantheine alkaloids17 and some azasteroids (93% ee)18. 

Benzylated 1,2,3,4-tetrahydroisoquinolines possess important physiological properties and, as illustrated in Scheme 20, also serve as common intermediates for synthesis of naturally ubiquitous isoquinoline alkaloids with different skeletons. Because some natural products have the 1/ configuration while the others possess the IS configuration, the synthesis must be chirally flexible. 

The catalytic and chiral efficiency of (S,S)-le was also appreciated in the asymmetric synthesis of isoquinoline derivatives, which are important conformationally constrained a-amino acids. Treatment of 2 with a,a -dibromo-o-xylene under liquid-liquid phase-transfer conditions in the presence of (S,S)-le showed complete consumption ofthe starting Schiffbase. Imine hydrolysis and subsequent treatment with an excess amount of NaHCOs facilitated intramolecular ring closure to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 38 in 82% yield with 98% ee. A variety of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives possessing different aromatic substituents, such as 39 and 40, can be conveniently prepared in a similar manner, with excellent enantioselectivity (Scheme 5.20) [25]. 

Efficient and rapid synthesis of chiral (S)-6-hydroxy-tetrahydroisoquinoline-3-carboxylic acid with a yield of 30% has been reported [126]. The route starts with separation of (A)-m-tyrosine from the (/ ,S)-racemate by resolution with... 

Chirality can be induced at the C-l position by the cyclization of o-vinylphenethylamine in the presence of a chiral selenium reagent (Equation 68) <1998S162>. Removal of the selenide gives the 2-methyltetrahydroisoquinoline. The use of the Pictet-Spengler reaction in the asymmetric synthesis of tetrahydroisoquinolines remains active. Therefore the intramolecular reaction of /3-iminosulfoxide 33 yields the chiral product 34 (Equation 69) <1998EJ0435>. 

The asymmetric syntheses of tetrahydroisoquinoline derivatives were also reported. Optically pure 3,4-disubstituted tetrahydroisoquinolines such as 78 were prepared by Friedel-Crafts cyclization of amino alcohols 77 <02TL1885>. Enantioselective syntheses of dihydropyrrolo[2,l-a]isoquinolines via a highly diastereoselective, chiral auxiliary assisted N-acyliminium cyclization was disclosed <02SL593>. The enantioselective synthesis (-)-tejedine, a seco-bisbenzyltetrahydroisoquinoline was also reported. One key step in this synthesis involved a chiral auxiliary-assisted diastereoselective Bischler-Napieralski cyclization <02OL2675>. Additionally, an asymmetric Bischler-Napieralski was reported for the preparation of 1,3,4-trisubstituted 1,2,3,4-tetrahydroisoquinolines <02JCS(P1)116>. 

Metallation-alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquin-oline provides optically active 1-alkyl-1.2,3,4-tetrahydroisoquinolines. The formam-idines of 10 optically active amino alcohols have been examined as the chiral auxiliaries and of these, the bistrimethylsilyl ether 2 (S.S-BISPAD) of 1 proved to be the mc>st efficient as well as consistent (equation II). The configuration (S) was established by synthesis of the benzoquinolizine (S)-5, a degradation product of an alkaloid. 

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." ... 

The Noyori asymmetric transfer hydrogenation was utilized in the synthesis of the chiral 1,2,3,4-tetrahydroisoquinolines by R.A. Sheldon et al. These compounds are important intermediates in the Rice and Beyerman routes to morphine. The "Rice imine" was exposed to a series of chiral Ru " complexes, which was prepared from r -arene-Ru " chloride dimeric complexes and A/-sulfonated 1,2-diphenylethylenediamines along with the azeotropic mixture of HCOOH/NEts. With the best catalyst the desired tetrahydroisoquinoline was isolated in 73% yield and the enantiomeric excess was 99%. 

Gluszynska, A., Rozwadowska, M. D. Enantioselective addition of methyllithium to a prochiral imine-the substrate in the Pomeranz-Fritsch-Bobbitt synthesis of tetrahydroisoquinoline derivatives mediated by chiral monooxazolines. Tetrahedron Asymmetry 20M, 15, 3289-3295. 

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. 

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

Chirality in the /V-acyl substituent can also induce stereoselectivity in the iminium addition process (equation 86). The chiral auxiliary in (115) appears to be one of the best chiral inductors and reacts with the silyl enol ether from acetophenone in 90% diastereoselectivity. It is argued that the A -acylim-inium intermediate in this reaction adopts the s-trans conformation. Similar methodology is used for the asymmetric synthesis of tetrahydroisoquinolines (equation 87). The reactive intermediate is generated through hydride abstraction from the amide by using the triphenylmethane cation. 

A chiral Ir(I) catalyst derived from the amino-(2,2 -biphenoxy)phosphine 37 promotes the synthesis of optically active 3-amino-l-alkenes from 2-alkenols, which are activated by (Eto)5Nb/ l-Vinyl-l,2,3,4-tetrahydroisoquinolines are obtained in good yields in the Pd-catalyzed process. Enantioselectivity is induced by the atropisomeric 38. ... 

Bringman et al. have described a synthesis of the unusual isoquinoline alkaloid ancistrocladine (82) starting from the chiral tetrahydroisoquinoline (79). Conversion of (79) to the ester (80), followed by a palladium catalysed coupling reaction led to the helicene-type lactone (81) which was then easily converted to (82). In a new route to the morphine ring system, Ludwig and Schafer have developed the intramolecular Lewis acid catalysed coupling of the tetrahydroisoquinoline (83) to (84) as a key step.26 The tetracycle... 

New modifications of the traditional approach to isoquinoline synthesis via carbocation intermediates continue to be reported. Abnormal products of the Bischler-Napieralski reaction were observed <97JCS(P1)2217>. A stereoselective introduction of a quaternary carbon center in the A-acyliminium cyclization (Scheme 14) of the chiral enamide 46 affords an asymmetric synthesis of tetrahydroisoquinolines <97T2449,3045>. An asymmetric Pictet-Spengler reaction has been developed mediated by the chiral urethane 47 <97T16327>. A Pummerer reaction of A-acyl-A-(aryl)methyl-2-(phenylsulfinyl)ethylamine allows cyclization to the 4-phenylthio-... 

The asymmetric synthesis of l-subsliluted-l,23,4-tetrahydroisoquinolines received much attention as well. The Pictet-Spengler reaction of iV-sulfinyl amines such as 77 afforded 1-substituted-l,23,4-tetrahydroisoquinolines (78) with diastereomeric ratios as high as 96 4. The chiral auxiliary can be removed with HCl in ElOH <01TL8885>. A similar method was used... 

The deprotonation of a stereogenic carbon in chiral non-racemic substrates with KHMDS has been used as a first step of sequences relying on the memory of chirality for asymmetric synthesis of organic products. The treatment of Al-Boc-protected amino esters featuring a Michael acceptor group with KHMDS in DMF-THF (1 1) at —78°C for 30 min provided trisubstituted pyrrolidines, piperidines and tetrahydroisoquinolines, and in good yields (65-74%) and diastereoselectivities (4 1 for pyrrolidine, and 1 0 for piperidines and tetrahydroisoquinoline) and excellent enantiomeric excesses (91-98% ee) (eqs 66 and 67). ... 

It has been found that in aqueous solution HCl and trifluoroacetic acid are superior to CH3COOH, HCOOH, CSA, and TCA. Current studies of this reaction focus on the diastereoselective and enantioselective synthesis of tetrahydroisoquinolines via chirality transfer from the auxiliary group of either the arylethylamine or the carbonyl component,or the application of chiral Lewis acid. °° ... 

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