Asymmetric synthesis of anti-α-alkyl-β-amino acids

Abstract

An investigation into the asymmetric induction accompanying alkylations of enolates derived from the highly diastereoselective conjugate addition of lithium (R) -N-benzyl-N-a-methylbenzylamide (R)-1 to crotonate and cinnamate esters has been performed. The access to different enolate geometries afforded by the conjugate addition process and subsequent enolate regeneration by deprotonation of the p-amino ester conjugate adducts enabled two disparate sets of selectivity data to be compiled. Although both approaches furnished predominantly anti-a-alkyl-P-amino esters, the two-step procedure proved to be considerably more selective. Several factors which play a major role in determining the alkylation selectivity are identified, including the cooperative influence of the a-methylbenzylamino stereocentre. Since debenzylation and hydrolysis of the alkylated products was straightforward, this methodology provides a direct route to anti-a-alkyl-p-amino acids in homochiral form.The conjugate addition of a nucleophile to a polarized n-system is an invaluable synthetic tool, particularly when followed by the tandem capture of the conjugate adduct intermediates with electrophiles. We have previously demonstrated that lithium (R)-N-benzyl-N-a-methylbenzylamide (R)-1 shows a very high degree of diastereoselection in its conjugate addition to a$-unsaturated esters where the intermediate enolates are simply protonated. Since the conjugate addition products are easily hydrolysed and debenzylated, this constitutes a general route for the synthesis of homochiral p-amino acids which contain only a P-stereogenic centre (Scheme 1). I Th PhLi (rn-1 Scheme 1With the aim of extending this methodology to include aalkyl-P-amino acids, we have surveyed the alkylation selectivities elicited by quenching with alkyl halides the p-amino enolates generated by the conjugate addition of (R)-1 to crotonate and cinnamate esters, and describe herein this approach to the asymmetric synthesis of anti-a-alkyl-P-amino acids. Part of this work has been previously communicated.2In addition to their incorporation into p-lactam antibiotics such as thienamycin and ( +)-(PS)-5,4 a-alkyl-&amino acids can be found as components of several biologically interesting natural p r o d~c t s ,~ and may also exhibit significant bacteriological and fungicidal properties in themselves.6 However, few general approaches to their enantioselective synthesis have been reported, with the most successful strategies based on diastereoselective enolate-imine condensations or alkylations of cyclic p-amino acid synthetic equivalents.8 Results and DiscussionThe first set of alkylation selectivity data was obtained from the tandem addition-alkylation of (R)-1 with the methyl and rertbutyl esters of crotonic and cinnamic acids (Schemes 2-5). The conjugate additions were performed in THF at -78 O C , iiH+orRX ' UIW R R 6 R = H 75% syn anti 7 R = Me 7:8 = 1.2:l 50% 8 R = Me 9 R = B n 9:10=3:1 54% 10 R = B n scheme2 R R anfi =Yn 11 R = H 75% 12 R=Me 12:13 =1.36:1 60% 13 R=Me 14 R = B n 14...

Development of an Efficient Therapeutic Agent for Alzheimer's Disease: Design and Synthesis of Dual Inhibitors of Acetylcholinesterase and Serotonin Transporter

“…This is consistent with the fact that only a slight difference was observed for the IC 50 values of the isomers of 5j. On the other hand, the interaction energy of the most stable model of (R)-33a was about 6 kcal/mol more stable than that of (S)-33a, which is consistent with the observed potencies of the isomers of 33a, i.e., (R)-33a is around 40 times more potent than (S)-33a.…”

Isolation and Structure Determination of Lyngbyastatin 3, a Lyngbyastatin 1 Homologue from the Marine Cyanobacterium Lyngbya majuscula. Determination of the Configuration of the 4-Amino-2,2-dimethyl-3-oxopentanoic Acid Unit in Majusculamide C, Dolastatin 12, Lyngbyastatin 1, and Lyngbyastatin 3 from Cyanobacteria

“…As shown in Table 1, the reduction of the samples of 1•3 produced adducts that contained Adhpa units in which the configuration of C-4 was derived from both R-and S-Ibu, and in all three cases, the minor products (24,26,28) had the configuration of C-4 in Adhpa derived from S-Ibu. On the other hand, the reduction of majusculamide C (4) produced a sample (29) that contained an Adhpa unit derived from only S-Ibu.…”

“…Synthetic standards of the Amha unit were prepared following Davies' procedure for anti-a-alkyl-/3-amino acids. 24 The Michael addition of (R)-(+)-N-benzyl-A7-a-methylbenzylamine to ethyl hex-2(E)-enoate afforded the enantiomerically pure adduct 15 in 50% yield (Scheme 1). Treatment of 15 with potassium hexamethyldisilazane (KHMDS) and an excess of iodomethane gave 16, which was then hydrogenated and hydrolyzed to afford a mixture of (2S,3R)-and (2R,3R)-17.…”

“…)-17 as expected from synthesis. 24 Derivatization of the remaining amount of 17 with DL-FDLA and subsequent HPLC separation produced standards equivalent to (2R,3S)-and (2S,3S)-17. 232627 Comparison by LC-MS of these standards with the L-FDLA-derivatized hydrolysate established the 2S,3i?…”

Ulongapeptin, a Cytotoxic Cyclic Depsipeptide from a Palauan Marine Cyanobacterium Lyngbya sp.

“…)-enoate (3). This a,/3-unsaturated ester was then treated according to Davies' procedure 13 except the diastereomers were not separated after methylation with KHMDS and iodomethane. The C-2 diastereomers were separated after deprotection as their FDLA derivatives in the manner previously described.…”