[104173-34-4] · C9H15NO3 · (R)-Methyl 2-t-Butyl-3(2H)-oxazolecarboxylate · (MW 185.25)
(chiral oxazoline with highly reactive double bond;1-3 chiral derivative of a-hydroxy- or a-aminoacetaldehyde; reactions with acylating reagents,1a,2 with carbenes,1a,3 and with electron-poor alkenes;1a,3 cycloadditions;1a,3 building block for the synthesis of amino alcohols and aminohydroxy carboxylic acid derivatives1 -3)
Physical Data: bp 70 °C/0.02 mmHg; [a]
Solubility: sol all common nonprotic organic solvents.
Preparative Method: the acetal from serine methyl ester and pivaladehyde is N-methoxycarbonylated and saponified to give the cis-half ester (2) (61% yield). Oxidative decarboxylation by electrolysis in AcOH (1:3 by weight) in the presence of 5% Et3N affords (3) (87%), which upon heating with NH4Br in toluene yields the title oxazoline (1) (75% after distillation in vacuo) (eq 1).4
Handling, Storage, and Precautions: stable over many months in a freezer under inert atmosphere (N2 or Ar). Use in a fume hood.
The oxazoline (1) can be metalated on the double bond carbon atom next to the ester group, and the resulting Li derivative coupled with electrophiles (eq 2).2
Vilsmeier and Friedel-Crafts reactions lead to 5-acyl derivatives (eq 3),2 which can be further elaborated3 as indicated in eq 4; a single enantiopure diastereoisomer of the anhydride (4) is formed. Seebach and co-workers3 erroneously assigned (4) as arising from an exo rather than the endo addition.
[2 + 1], [2 + 2], and [4 + 2] cycloadditions with electrophilic reactants such as carbenes (eq 5), tetracyanoethylene (eq 6), and a-keto-b,g-unsaturated nitriles5 (eq 7) lead to interesting products which are all enantiopure; see, for instance, the 5-amino-6-hydroxy-2-keto acid (5).
Table 1 shows oxazolines and thiazolines also prepared from amino acids (serine, threonine, or cysteine), with or without decarboxylation; common to all of them is the conversion of the original stereogenic center to a trigonal center, and chirality due to a t-butyl-substituted acetal carbon in the ring (see Table 1).1-4,6,7 The structure and reactivity of such acetals has been discussed.8,9
The photochemistry (Paterno-Büchi reactions) of the achiral oxazoline (7) has been studied.10 The analogous urethane (8), which is chiral by attachment of an apocamphanoyl group, shows an intriguing stereoselectivity pattern in its reaction with electrophiles.11 For another case of an oxidative decarboxylation as a key step in the application of the SRSC (self-regeneration of stereogenic centers) principle, see the preparation of the dihydropyrimidone (9) from aspartic acid.12
Joachim Podlech & Dieter Seebach
Eidgenössische Technische Hochschule Zürich, Switzerland