Additions of lithiated alkoxyallenes to D-glyceraldehydebased nitrones 1 and 2 did not provide the expected hydroxylamine derivatives. Instead, a novel [3+3] cyclization process furnished 4-alkoxy-3,6-dihydro-2H-1,2-oxazines 9-14 with excellent syn selectivities and in moderate to good yields. Through precomplexation of the nitrones the corresponding anti-configured 1,2-oxazines 9, 10 and 13 could be obtained with high stereoselectivity. The reactions of nitrones 3-6, derived from D-erythrose or D-threose, generally proceeded less diastereoselectively, but reasonable yields of anti-configured 1,2-oxazines such as anti-17 and anti-19 could be obtained under Lewis acid promotion conditions. This was also the case for reactions of the D-arabinose-derived nitrone 7, which provided the anti-1,2-oxazines 23 and
Several methods are
presented for the enantioselective synthesis
of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a
dual orexin receptor antagonist. Initial clinical supplies were secured
by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori
ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity
eroded upon scale-up. A broad screening exercise identified TaniaPhos
as ligand for the iridium-catalyzed asymmetric hydrogenation with
a dedicated catalyst pretreatment protocol, culminating in the manufacture
of more than 6 t of the acetate salt of the tetrahydroisoquinoline.
The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline
substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH
was later successfully reduced to practice, delivering several hundreds
of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst
cost contribution significantly. The two methods are compared with
regard to green and efficiency metrics.
Ozonolysis and subsequent in situ acylation/base treatment converted the enantiopure carbohydrate-derived 1,2-oxazines 1, 5, 8 (either syn-or anti-configured) and anti-11 into the highly functionalized α-amino-β-hydroxy esters 2, 6, 9 and 12 in moderate to good yields. Ketals of 5-hydroxylated 1,2-oxazines (e.g., syn-3) were formed as side products in most cases; the reactions of precursors syn-and anti-8 even provided the ketals syn-or anti-10 as major components. The
Oxazine derivatives R 0595 Stereodivergent Syntheses of Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines by Addition of Lithiated Alkoxyallenes to Carbohydrate-Derived Aldonitrones. -Addition of lithiated alkoxyallenes (II) towards carbohydrate-based nitrones [cf. (I)] directly provides access to the [3 + 3] cycloadducts without isolation of the intermediate hydroxylamines. The reaction proceeds with moderate to excellent syn-selectivity depending on the nature of auxiliary carbohydrate. The selectivity can, however, be altered in favor of the anti-diastereomer when the nitrone is precomplexed with a Lewis acid like Et2AlCl [cf. (IV)]. -(HELMS, M.; SCHADE, W.; PULZ, R.; WATANABE, T.; AL-HARRASI, A.; FISERA, L.; HLOBILOVA, I.; ZAHN, G.; REISSIG*, H.-U.; Eur.
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