Menthyl glyoxalate

The magnesium bromide catalyzed cycloaddition of (7 )-menthyl glyoxalate (la) to 1-trimethyl-siloxy-1,3-butadiene (2) gives adducts in 14% yield and a d.r. 54,5 45.5 (for 3), (f )-8-Phenyl-menthyl glyoxalate (lb), under identical conditions, produces adducts with a d.r. 91 9 (for 3) but with only 5% yield32. 

With diazadienes derived from aromatic amines the dimer specificity can be raised to 95-99% while with diazadienes from (lR,3R,4.S )-4-menthan-3-amme up to 24% ee of (S -vinylcyclo-hexcne (glyoxal derivative) or 30 % ee of (S)-4-vinylcyclohexene (2-acetylpyridine derivative) are obtained. Higher asymmetric inductions (up to 62% ee) are obtained with diazadienes of the type pyridyl-CH=N-menthyl and 8-substituted derivatives 4 thereof61. 

More than 15 preparations described in patents are variations of the above synthetic schane. hi particular, to obtain optically pure Emtricitabine, lipase-catalyzed enzymatic resolution, as well as chiral stationary phase HPLC was used [143]. However, the most effective procedure included separation of menthyl derivatives. This method evolved significantly since the first publication (which in fact relied on separation of all the 4 possible diastereomers) [144] one of the recent multigram preparations is shown in the Scheme 37 [145]. The first step of the synthesis included formation of methyl ester 159 from glyoxalic acid and L-menthol. Reaction of 159 with 1,4-ditiane 154 gave 1,3-oxathiolane 160 as a mixture of cis diastereomers. 

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