Seebach protocol

Deprotonation at an activated 4-position has been employed extensively in asymmetric synthesis, which is the key step in the Seebach protocol for the preparation of a-alkyl amino acids.The existing alkyl group at the 5-position acts as a directing group for the alkylation and is oriented trans to the new alkyl group (Scheme 8.118). This reaction provides an efficient methodology for normally difficult stereoselective construction of a quaternary chiral center. 

Preparative Method the title compound can be prepared in multigram scale from (5)-phenylalanine methyl ester using a modified Seebach protocol (eq 1) the ester of the amino acid, or the corresponding HCl salt, is converted to iV-methylamide with excess of ethanolic MeNH2, which, in turn, is condensed with pivalaldehyde in the presence of a catalytic amount of FeCls (20mol%) and molecular sieves. Under these conditions the Schiff base intermediate undergoes cyclization and forms a mixture of cis- and frans-imidazolidinones. After addition of 0.5 M equiv of HCl (IN in ether), the undesired tran -isomer-HCl can he filtered off and the residue recrystallized to provide the cw-(25,55)-isomer as a crystalline solid. The frans-isomer can he converted to the cw-isomer by partial epimerization in THF solution in the presence of FeCls. 

Seebach and co-workers have developed complementary protocols for stereocontrol of the Henry reaction (Scheme 3.12).18,19... 

Seebach et al. (154) showed that a 0-isopropylidene-2,3-dihydroxy-l, 1,4,4-tetraphenyl-l,4-diol (TADDOL)-derived aminothiolate serves as a moderately effective ligand for the catalyzed conjugate addition of Grignard reagents to cyclic enones. The catalyst, synthesized from the lithiothiolate and CuCl, exhibits optimal selectivities under a slow addition protocol (2 h), Eq. 124. 

Seebach and co-workers 383 have demonstrated that the coupling of (3-amino acids can be achieved in a solid-phase protocol with the use of Fmoc-protected (3-amino acids 58 linked to a chlorotrityl resin (Scheme 18). They demonstrated that while 33-amino acids can be coupled in a straightforward manner, the analogous 32-amino acids are a little more problematic, with HPLC analysis of the products showing some impurities. 

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. 

P-Amino acid oligomers (P-peptides) present a unique class of peptides. In contrast to their natural a-amino acid counterparts, P-peptides require relatively few residues to form secondary structures like turns, helices, or sheets (Seebach et al. 1996, 2001, 2004 Cheng et al. 2001). However, these secondary structures can also severely hamper the synthesis of these compounds (Murray and Gellman 2005 Lelais et al. 2006). To increase the synthetic efficiency of helical P-peptides, microwave-assisted solid phase peptide synthesis (SPPS) protocols have also been applied (Murray and Gellman 2005 Lelais et al. 2006 Erddlyi and Gogoll 2002). 

Rieder E, Kasimir MT, Silberhumer G, Seebacher G, Wolner E, Simon P, et al. Decellu-larization protocols of porcine heart valves differ importantly in efficiency of cell removal and susceptibility of tbe matrix to receUularization with human vascular cells. J Thorac Cardiovasc Surg 2004 127(2) 399-405. 

Herein, we describe an efficient enantiospecific synthesis of BIRT-377 (1) based on a modification of Seebach s strategy in which we extend the original protocol to achieve complete (>99.9%) overall diastereoselectivity. 

There are several methods to prepare oxazolidinones from a-amino acids, for the use as templates in alkylation reactions. [3] Our early investigations focused on the protocol by Seebach based on acylation of imine salts of amino acids, [5] but we encountered problems associated with the heterogeneous formation of imine salts on larger scale. A method was then developed by which commercially available (i)-W-Cbz-alanine (24) is reacted with benzaldehyde dimethylacetal(25) in the presence of SOCI2 and ZnCl2 to provide the oxazolidinone 26 with a predominant cw-relationship cis trans ca. 5-15 1) between the phenyl group and the a-methyl group, as shown in Scheme 7.[2i]... 

In the research groups of Seebach [67, 153] and Tidwell [154], alkyl and aryl lithium compounds were found to add readily to ketenes 153 that are accessible by various methods, as, for example, treatment of acid chlorides with triethy-lamine or acid bromides with zinc. As a result, ketone enolates 154 are formed. Due to the high reactivity of the ketenes, the protocol permits to access even sterically hindered trisubstituted enolates, the configuration of which depends on the steric demand of the substituents and R. Thus, alkyllithium reagents add from the sterically less hindered side, so that enolates 154 form with high diastereoselectivity. Of course, the ketone enolates thus generated are pure regioisomers. 

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