Benzylic quaternary centers

In a series of studies, Shibasaki examined the formation of chiral benzylic quaternary centers by using asymmetric intramolecular Heck reactions. The effect of double-bond stereochemistry was examined in the cyclization of aryl Inflates 9.1 and 9.3 (Scheme 8G.9) [22], As is commonly... 

Scheme 6-30 Asymmetric Heck cyclizations to form benzylic quaternary centers.

There is of course a sound reason for the synthetic challenge morphine contains nearly completely dissonant1 arrangement of carbon atoms, a benzylic quaternary center at C13, and its skeleton is prone to a number of fascinating rearrangements thus limiting the methods by which it might become accessible. 

The synthesis of benzylic quaternary centers by an AHR has also been reported by Shibasaki and co-workers in connection with syntheses of (-)-eptazocine and of hale-naquinone and halenaquinol As in Sect. E.i, the key steps in both syntheses... 

Asymmetric 1,4-addition to alkylidene Meldrum s acids creates benzylic quaternary centers, using the catalytic combination of Cu(OTf)2/R2Zn in DME. Phosphoramidite ligand 128 (10 mol%) controlled the sense of chiral induction, and in most cases examined, with ee s in the 75-95% range. Alkylzinc reagents (Me, Et, -Bu) gave the best results both yield and ee-wise. 

R348 J. L. Garcia Ruano, A. M. Martin Castro, E. Torrente and A. M. Poveda, Diastereodivergent Synthesis of Benzylic Quaternary Centers Mediated by a Remote Sulfinyl Group Spectroscopic Evidence of the Structure of the Carbanionic Intermediates , Phosphorus, Sulfur Silicon Relat. Elem., [online computer file], 2011, 186, 1119. 

In 1998, Buchwald and coworkers reported the first example of the direct catalytic asymmetric a-arylation of ketone enolates using (S)-BINAP/Pd2(dba)3 as the catalyst [54]. Since then, the transition-metal-catalyzed enantioselective a-arylation of carbonyl compoimds has emerged as a simple and robust method for the construction of chiral benzylic quaternary centers [55]. 

T. Takemoto, M. Sodeoka, H. Sasai, M. Shibasaki Catalytic Asymmetric Synthesis of Benzylic Quaternary Carbon Centers. An Efficient Synthesis of (-)-Eptazocine , J. Am. Chem. Soc 1993,115, 8477-8478. 

Carbon-carbon ternary centers can also be assembled by nucleophilic addition. Manfred Braun of the Universitat Diisseldorf has devised (Angew. Chem. bit. Ed. 2004,43,514) the Lewis acidic Ti complex 8. Exposure of a racemic benzylic silyl ether such as 7 to allyltrimethylsilane in the presence of the catalyst 8 leads to the alkylated product 9. Racemic tertiary benzylic ethers are also converted to the alkylated quaternary centers in > 90% . 

As Shibasaki and co-workers demonstrated, tetralin derivatives of type 55 (with a quaternary benzylic carbon center) can also be enantioselec-tively prepared by an intramolecular Heck reaction (Scheme 14) [19]. 

Chiral imidazolines such as 4, obtained by condensation of iminoether hydrochlorides with (15,25)-1,2-diaminocyclohexane, may be metalated and alkylated with high stereoselectivity. This process is highly efficient for the stereoselective synthesis of quaternary benzylic stereogenic centers, and has been applied to a total synthesis of mesembrine (eq 6). (15,25)-1,2-Diaminocyclohexane here again gives higher diastereomeric excesses than 1,2-diphenyl ethylenediamine in this reaction. 

Further advances in the series are compounds that combine a substituent in the benzylic position of the tetrahydronaphthalene, which triggers the agonist activity with these MBO replacements. In cases of larger substituents at the quaternary center, like cyclopentyl this results in compounds with a dissociated profile the aryl pyrazole motif is responsible for good GR selectivity (Figure 9.11). 

Takemoto, T., Sodeoka, M., Sasai, H. and Shibasaki, M. (1993) Catalytic asymmetric s3mthesis of benzylic quaternary carbon centers. An efficient synthesis of (—)-eptazocine. J. Am. Chem. Soc., 115, 8477-8. 

While the focus of this chapter is on hydroamination with amines, impressive recent advances in the hydroamidation and hydrocarbamation of allenes have been disclosed. Espinet showed that acyclic carbenes can be used as ligands for Au(I) to realize intramolecular hydrocarbamation [240], while Widenhoefer has used the commercially available l,3-bis[(2,6-diisopropylphenyl)imidazole-2-ylidine] (IPr) NHC in combination with cationic Au(I) to realize regioselective intermolecular hydroamination of 1,1-disubstituted allenes with benzyl carbamate to access allylamines with quaternary centers adjacent to N. This same catalyst can also accommodate 1,3-disubstituted allenes and even tetrasubstituted allenes (Table 15.19) [241]. Interestingly, these products are in contrast to the preferred products accessed with related Au(I)-phosphine complexes in combination with aniline substrates (Table 15.18) [239]. Hydroureation has been achieved intramolecularly [242, 243] and will be later discussed (Section 15.3.6). 

Asymmetric intramolecular addition/ring opening reaction of 3-(2-borylphenyljcyclobutanones afforded 1-indanones having chiral benzylic quaternary carbon centers by enantioselective P-carbon elimination (Scheme 3.18) [30]. 

We will now move away from biomimetic synthesis and examine a perhydrophenanthrene-based approach reported by Mulzer. The plan was to prepare tetrahydrophenanthrene 89, use conjugate addition chemistry to set the quaternary center, and use the indicated benzylic position as a handle for construction of the same C-N bond central to the Gates, Fuchs and Parker syntheses. Tetralone 90 will serve as our point of departure. 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

Asakawa K, Noguchi N, Takashima S, Nakada M. Preparation of a new chiral building block containing a benzylic quaternary stereogenic center and a formal total synthesis of (—)-physostigmine. Tetrahedron Asymm. 2008 19 2304— 2309. 

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