Chiral formamidines

Deprotonation of chiral formamidines of 6,7-dimethoxy- and 6,7-methylenedioxytetra-hydroisoquinolines, followed by alkylation affords 1-substituted tetrahydroisoquinolyl... 

Chiral formamidines, derivatives of N-heterocycles in asymmetric synthesis 92T2589. 

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. 

Preparative Methods easily prepared from (5 )-valinol in a high yielding four-step procedure (eq 1). Other chiral formamidines can be prepared and used successfully in the methodology outlined here (eq 2). ... 

Upon heating the title formamidine with a secondary amine, dimethylamine is extruded, affording a chiral formamidine derivative of the original amine (eq 3). ... 

See the previous procedure for preparation of this chiral formamidine Org. Synth. 1988, S7, 52. 

Two asymmetric syntheses of phenethylisoquinolines have been reported. Simple exchange between isoquinoline 125 and imine 126 gave the chiral formamidine 127. Methylation of 127 with /ert-butyllithium gave the lithiated formamidine, which was alkylated with 3,4-dimethoxyphenethyl iodide and hydrazinolyzed to give the (S)-(-)-isoquinoline 128 in 95% enantiomeric excess (e.e.) (74). The e.e. of 128 was determined by chiral-column HPLC analysis, as developed by Pirkle and applied to chiral N-heterocycles and other amines (75). 

Formula 175 represents the incorrect planar structure proposed by Brindley and Pyman 147) in 1927 for emetine (1). In this connection, Harada et al. 148) synthesized the four stereoisomers possible for ( )-C-noremetine Pyman [( )-176] and isolated them in the form of hydrobromide salts. Takacs and Boito 149) synthesized the (-)-tricyclic alcohol 177, a one-carbon homolog of the Alangium alkaloid (-)-protoemetinol (34), from the chiral formamidine 117 in 36% overall yield via a five-step route proceeding through the stereoselective iron-catalyzed cyclization of the key intermediate 178. 

Chiral formamidines 1.115 have been developed by Meyers and cowoikers [388-392], These reagents are prepared from HC(NMe2XOMe)2 d a-aminoethers 1.60 (R = Me or ferf-Bu) [393], Once again, (5)-valinol and (S)-terf-leudnol derivatives 1.115 (R = /-Pr or tert-Bu) are the most effective chiral auxiliaries. The main applications of these reagents are enantioselective alkylations of tetrahydroquinolines, and the products of these alkylations are very useful in alkaloid synthesis [343, 391, 394], The chiral auxiliaiy is regenerated by treating the products with hydrazine. 

Chiral cyclic allylic amines have also been utilized in lithiation-substitution reactions to access substitution a to nitrogen. Meyers and coworkers have demonstrated that lithiation of chiral formamidine-protected pyrroline 135 and tet-rahydropyridine 136 followed by substitution with electrophiles provides both the a and y-substituted heterocycles (Scheme 43) [97]. 

The formation of the chiral formamidine 1658 from octahydroisoquinoline 1656 and the isocyanide 1657 derived from valinol tert-butyl ester gives an intermediate with high chirality-inducing potential, which, through further reaction steps, allows an asymmetric synthesis of (+)-morphinane with high enantiomeric purity (>98% ee in the decisive asymmetric reaction step) [1229]. The isocyanide 1657 is obtained in 85% yield by dehydration of the corresponding formamide with thionyl chloride. 

The method has also proved to be applicable to isoquinoline alkaloid synthesis as illustrated by the example of die two enantiomers of tetrahy opapaverine (75) shown below. It is instructive to compare this fourth-generation approach with the second-generation method using chiral formamidines (section 5.3.4). 

Recently a novel chiral ferrocene-based amidinato ligand and its rhodium complexes have been described. The chiral N,N -bis(ferrocenyl)-substituted formamidine (N,N -bis[(S)-2- (lR)-l-(diphenylphosphino)ethyl ferrocen-l-yl]for-mamidine was prepared from commercially available (IR)-l-(dimethylamino) ethyl ferrocene by a multistep procedure in an overall yield of 29%. Deprotonation of the ligand with -butyllithium followed by addition of [RhCl2(COD)2] as illustrated in Scheme 167 yielded the corresponding (formamidinato)rhodium(l)... 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

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. ° ... 

The mechanism of this sequence is enlightening when contrasted with the mechanism of the formamidine auxiliary (Scheme 56). Scheme 59a illustrates the results of some deprotonation-alkylation experiments on deuteriated diastereomers. ° ° Two features of the product of these experiments were examined the diastereomer ratio and the percent deuterium incorporation. The deuterium incorporation in the product reveals that there is a preference for removal of the -proton. When deuterium is in the -position, this selectivity is opposed by the isotope effect, and the product has about half the original deuterium remaining. When deuterium is in the a-position, the selectivity for the -proton (imposed by the chiral auxiliary) and the isotope effect act in concert, and virtually all the... 

Meyers, A. I. Milot, G. a-Alkylation and stereochemistry of cis- and trans-decahydroqui-nolines mediated by the formamidine and Boc activating groups. Synthesis of pumiliotoxin C.J. Am. Chem. Soc. 1993, 335, 6652-6660. Elworthy, T. R. Meyers, A. I. The configurational stability of chiral lithio a-amino carbanions. The effect of Li-O vs Li-N complexa-tion. Tetrahedron 1994, 50, 6089-6096. 

Formamidines also activate secondary centres towards lithiation, and have been used extensively in the synthesis of the benzylisoquinolines, where the lithiation takes place at a benzylic position. Formamidines bearing chiral substituents (for example the serine-derived 85) allow the introduction of asymmetry at such centres.58... 

Meyers, A. I., Miller, D. B and White, K H Chiral and achiral formamidine in synthesis. The first asymmetric route to (—)-yohirabone and an efficient total synthesis of ( )-yohim-bone, J. Am. Chem Soc., 110,4778, 1988. 

Reaction of dimethylformamide dimethyl acetal or formamidine with chiral 1,2-diamines provides optically active imidazolines <1997JOC3586, 1997JMC2931, 20040L43> (Scheme 311). In these examples, the 2-position in the imidazolines is unsubstituted. 

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