Mitsunobu reaction with serine

Cherney, R. J. Wang, L. Efficient Mitsunobu reactions with N-phenylfluorenyl or N-trityl serine esters./. Org. Chem. 1996, 63, 2544— 2546. 

As the structure of the side chain of the pyrimidine moiety remained uncertain until the very final stage of the structure elucidation, we proceeded to synthesize the most probable candidate for the structure of this moiety to compare with the natural sample. Relevant methodology was required to acquire the skeleton of BLM and we found a new synthon diethoxyacetamidine (8) for the efficient preparation of multifunctional pyrimidine (9), which was readily converted into the key aldehyde (10) (Fig. 10) [37]. The p-aminoalanin-amide moiety (7) was synthesized by Mitsunobu reaction of serine derivative (6)... 

Ring closure of (3-hydroxy-a-amino acids with sulfuryl chloride/triethylamine 68 is accompanied by formation of (3-chloroalanine,16 1 whereas cyclization of urethane-protected serine and threonine by the Mitsunobu reaction 54 69 70 leads to oxazoline and dehydroalanine formation as side products. 47,71 Formation of dehydroalanine can be prevented by bulky carboxy protecting groups such as tert-butyl esters. 69 ... 

A further chemical synthesis (93) (Scheme 22) relied on catalytic cis reduction of the (Z)-olefin 81, yielding the protected serine 82. This was resolved using hog renal acylase (EC 3.5.1.4), and BBrj treatment gave (2S, 3/ )-[2,3- H2]serine 60e contaminated with (2S)-[2,3,3- H3]serine. The (2S, 3S)-isomer could be obtained by a Mitsunobu reaction (93). 

The strategy was chosen to (1) link the amino acid derivative to a polystyrene-supported hydroxylamine, (2) carry out the cyclization under Mitsunobu conditions, and (3) assemble a short peptide on the free amino group present in the ring. This approach has been shown to be suitable particularly for solid-phase synthesis, as the supported (3-lactam could be easily separated from the by-products of the Mitsunobu reaction. The linker employed was a polystyrene resin carrying 0-trityl-hydroxylamine linker, prepared according to the literature procedure [151]. After the deprotection of Fmoc group carried out with 20% piperidine in DMF, the L-cbz-serine (or L-cbz-threonine) was coupled using (4,6-Dimethoxy-[l, 3, 5]-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) [152] in M-methylpyrrolidone (NMP) in the presence of M,M-diisopropylethylamine (DIPEA) (Schemes 42 45). 

Amino acid synthesis.1 Optically pure amino acids can be prepared in two steps from serine, readily available as either the d- or L-enantiomer. Reaction of N-benzylserine (or of N-benzyl-N-Boc-serine) with the preformed Mitsunobu reagent in CH3CN at -55° provides the protected serine (J-lactone (2) in almost quantitative yield. The lactone reacts with lithium organocuprates (R2CuLi) to... 

---