Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

Synthesis of new ligands for targeting the S1P1 receptor

“…The synthesis of the 3-deoxysphingosine analogues (Scheme 1) was based on preceding works by Marhold et al 15 The fluorinated allylic alcohol 7 was prepared according to our well-established three step sequence involving bromofluorination of hexadec-1-ene, HBr-elimination and SeO 2 -mediated allylic oxidation. 16 The non-fluorinated allylic alcohol 6 was prepared by direct SeO 2 -mediated allylic oxidation of hexadec-1-ene (4).…”

“…17 After esterification with Boc-glycine the chelate ester enolate Claisen rearrangement proceeded with complete chirality transfer from C-3 of the allylic esters 8 and 9 to C-2 of the amino acids 10 and 11 due to the preferred lowest energy chair-like, six-membered transition state. 15 Thus, starting from the (R)-alcohols, the amino function is obtained in the correct configuration as compared to sphingosine.…”

“…The fluorinated glycine allylic ester 9 has been synthesized from hexadec-1-ene as described by Marhold et al 15 The synthesis of cfluorinated c,d-unsaturated a-amino acids by chelate ester enolate Claisen rearrangement is also described in the publication mentioned above. For the synthesis of the c,d-unsaturated a-amino acids 10 and 11 the published reaction conditions 15 were changed slightly as described below.…”

“…The corresponding non-fluorinated glycine allylic ester 8 and its precursors were prepared according to the described procedures. Similarly to the described procedure, 15 dry diisopropylamine (0.36 mL, 250 mg, 2.50 mmol, 2.5 equiv) was dissolved in abs diethyl ether (4.0 mL). The solution was cooled to 0°C and n-butyllithium (1.6 M solution in hexane, 1.6 mL, 2.50 mmol, 2.5 equiv) was added dropwise.…”

“…(2R)-(4Z)-2-tert-Butoxycarbonylamino-4-fluorooctadec-4-ene-1-ol (R-13)The fluorinated amino acid (R)-1115 (723 mg, 1.74 mmol) was reduced according to the general procedure described above. The product was purified by flash…”