Mechanism of formation of serine β-lactones by Mitsunobu cyclization: synthesis and use of L-serine stereospecifically labelled with deuterium at C-3

Abstract

. VEDERAS. Can. J. Chem. 64, 706 (1986).The ring closure of N-benzyloxycarbonyl-L-serine (1) under Mitsunobu conditions (Ph3P, dimethyl azodicarboxylate, -78°C) to give the corresponding p;lactone (2) is shown by deuterium and oxygen-18 labelling studies to proceed by hydroxy group activation, in contrast to analogous cyclizations of more hindered P-hydroxy acids, which usually occur by carboxy group activation. Samples of 1 stereospecifically labelled with deuterium at C-3 were prepared by hydrogenation of (2)-2-acetamido-3-methoxyacrylic acid (9) with deuterium, followed by selective Acylase I deacetylation of the 2 s isomer, removal of the protecting groups, and N-acylation of the resulting L-serine with benzyl chloroformate. Mitsunobu cyclizations of this 3R deuterated N-acyl serine, of the [hydroxy-'80] analog l g , and of the [ c a r b~x~- '~O ] derivative If show that lactonization occurs with inversion of configuration at C-3, loss of the hydroxy oxygen, and retention of the carboxy oxygens. Similar labelling experiments demonstrate that aqueous sodium hydroxide opens the p-lactone ring by exclusive attack at the carbonyl to regenerate 1 , whereas acidic hydrolysis proceeds primarily by attack of water at the C-3 methylene group of 2. This information allows interconversion of L-serines that are stereospecifically labelled at C-3 with hydrogen isotopes and affords access to other labelled P-substituted alanines. SHAWN E. RAMER, RICHARD N. MOORE et JOHN C. VEDERAS. Can. J. Chem. 64,706 (1986).Faisant appel a des etudes par marquage au deuterium et a l'oxygkne-18, on a dCmontrC que la cyclisation de la N-benzyloxycarbonyl L-strine (I), dans des conditions de Mitsunobu (Ph3P, azodicarboxylate de dimethyle, -7g°C), qui conduit h la formation de la p-lactone corespondante se produit par le biais d'une activation du groupement hydroxyle; ceci est en opposition avec ce qui se produit lors de cyclisations analogues d'acides P-hydroxyles plus empCchCs qui se produisent habituellement par le biais d'une activation du groupement carboxyle. On a prtpart des tchantillons de 1 marques sttr6os@cifiquement par du deuterium en C-3 en proctdant a une hydrogenation de l'acide acktamido-2 methyoxy-3 acryliques-(2) (9) avec du deuterium suivie d'une deacetylation stlective de l'isomkre 2-(S) par 1'Acylase I, de l'enlkvement des groupes protecteurs et finalement d'une N-acylation de la L-strine qui en rCsulte par du chloroformate de benzyle. Les cyclisations, selon Mitsunobu, de cette N-acyl sCrine deutkrte en 3(R), de son analogue l g portant un hydroxyle "0 et du derive lf portant un carboxyle ''0 demontrent que la lactonisation se produit avec une inversion de configuration en C-3, avec une perte d'oxygkne de l'hydroxyle et avec retention des oxygknes des groupements carboxyles. Des experiences semblables de marquage ont permis de dkmontrer que, sous l'influence de l'hydroxyde de sodium aqueux, le cycle de la p-lactone s'ouvre par une attaque qui se produit exclusivement au niveau du groupement carbonyle pour regentrer l...

Synthesis of new α, α′, β-trisubstituted β-lactones as monomers for hydrolyzable polyesters

“…Conceptually,¯-lactones can be prepared by activation of either the hydroxyl or carboxyl groups of monoesters Scheme 7. Reagents and conditions: (a) D1AD, TPP, THF, room temperature, 3 h. [16][17][18][19][20][21][22]. Among the different methods of lactonization of¯-hydroxyacids described in the literature, we chosen the Mitsunobu reaction [23,24].…”

“…The experiment was done with the monoester (9) (3 g, 13.7 mmol), PPh 3 (3.61 g) in THF (60 ml) and DIAD (2.72 ml) in THF (6 ml). After the puri cation, the lactone (16) (17). The experiment was realized with the monoester (10) (2.66 g, 12.2 mmol), PPh 3 (3.20 g) in THF (30 ml) and DIAD (2.40 ml) in THF (4 ml).…”

SAIL – stereo-array isotope labeling

“…Following a scheme developed by Arnold et al (Arnold et al 1985Ramer et al 1986 ;Williams, 1989), the synthesis of SAIL cystine ((2R,2kR,3S,3S)- [1,1k,2,2k,3,3k-13 C 6 ,2,2k-15 N 2 ; 3,3k-2 H 2 ]cystine) could be accomplished with a 35% overall yield, although potentially risky chemicals, such as dimethyl azodicarboxylate, were used. To avoid potentially hazardous reaction materials, a more easily accessible means to synthesize the stereoisomer at the b-position of SAIL cysteine was also examined (Fig.…”

Dual Modes of Modification of Hepatitis A Virus 3C Protease by a Serine-derived β-Lactone: Selective Crystallization and Formation of a Functional Catalytic Triad in the Active Site

“…19,20 "Soft" nucleophiles such as thiolate tend to attack the b-carbon whereas "hard" nucleophiles such as alkoxide or hydroxide target the carbonyl. 21 Nitrogen nucleophiles may attack at either site. 22 In previous studies, serine or threonine residues in proteins were shown to attack b-lactones at the carbonyl to give acylated products.…”