Rapid access with diversity to enantiopure flexible PNA monomers following asymmetric orthogonal strategies

Different synthetic procedures are described in the rapid elaboration of flexible PNA monomers based on the 6-amino-8-base-octanoate and 5-amino-7-base-heptanoate scaffolds. Asymmetric Aza-Michael monoaddition is successfully applied to starting materials derived from sebacic/azelaic long-chain diacids and 6-membered oxacyclohexane commercial derivatives. Chain length, orthogonality of the ester functionalities, and Z/E isomerism of these prime substrates yielded high-valuable multifunctional intermediates through this asymmetric conjugate addition. Key features are the diversity toward PNA monomer synthesis, orthogonal chemoselective transformations, and Mitsunobu nucleobase substitution as an exceptional approach to introduce nucleobases in the final step.

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(R,E)-7-(Benzyl((R)-1-phenylethyl)amino)-9-methoxy-9-oxonon-2-enoic acidC25H31NO4[α]D20 = +4.6 (c 1.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (7R,E,αR)

Methyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-oxoheptanoateC23H29NO3[α]D20 = +12.5 (c 0.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

C23H29NO4(R)-5-(Benzyl((R)-1-phenylethyl)amino)-7-methoxy-7-oxoheptanoic acid[α]D20 = +2.1 (c 3.36, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R,αR)

7-(tert-Butyl) 1-methyl (R)-3-(benzyl((R)-1-phenylethyl)amino)heptanedioateC27H37NO4[α]D20 = +9.8 (c 0.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

7-(tert-Butyl) 1-methyl (R)-3-((tert-butoxycarbonyl)amino)heptanedioateC17H31NO6[α]D20 = +15.3 (c 1.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-hydroxyheptanoateC16H31NO5[α]D20 = +9.8 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-((methylsulfonyl)oxy)heptanoateC17H33NSO7[α]D20 = −1.0 (c 2.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Methyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-hydroxyheptanoateC23H31NO3[α]D20 = +8.1 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-(6-chloro-9H-purin-9-yl)heptanoateC21H32ClN5O4[α]D20 = −10.5 (c 1.4, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-7-(2-amino-6-chloro-9H-purin-9-yl)-5-((tert-butoxycarbonyl)amino)heptanoateC21H33ClN6O4[α]D20 = −15.7 (c 1.2, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-7-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-((tert-butoxycarbonyl)amino)heptanoateC28H39N3O7[α]D20 = −16.8 (c 1.0, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)heptanoateC21H35N3O6[α]D20 = −15.4 (c 0.7, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Ethyl (R)-5-((tert-butoxycarbonyl)amino)-7-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)heptanoateC19H31N3O6[α]D20 = −11.2 (c 0.24, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Di(pentan-3-yl) (R,E)-8-(benzyl((R)-1-phenylethyl)amino)dec-3-enedioateC35H51NO4[α]D20 = +6.9 (c 0.93, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (8R,E,αR)

Di(pentan-3-yl) (R,E)-8-(benzyl((R)-1-phenylethyl)amino)dec-2-enedioateC35H51NO4[α]D20 = +6.2 (c 2.62, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (8R,E,αR)

Ppentan-3-yl (R)-3-(benzyl((R)-1-phenylethyl)amino)-8-oxooctanoateC28H39NO3[α]D20 = +6.8 (c 1.28, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Pentan-3-yl (R)-3-(benzyl((R)-1-phenylethyl)amino)-6-(1,3-dioxolan-2-yl)hexanoateC29H41NO4[α]D20 = +11.9 (c 0.7 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Pentan-3-yl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-(1,3-dioxolan-2-yl)heptanoateC30H43NO4[α]D20 = +9.0 (c 1.30 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Pentan-3-yl (R)-3-((tert-butoxycarbonyl)amino)-6-(1,3-dioxolan-2-yl)hexanoateC19H35NO6[α]D20 = +11.2 (c 1.2 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

Pentan-3-yl (R)-3-((tert-butoxycarbonyl)amino)-7-(1,3-dioxolan-2-yl)heptanoateC20H37NO6[α]D20 = +10.4 (c 1.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-(6-(1,3-dioxolan-2-yl)-1-hydroxyhexan-3-yl)carbamateC14H27NO5[α]D20 = −2.1 (c 1.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-(7-(1,3-dioxolan-2-yl)-1-hydroxyheptan-3-yl)carbamateC15H29NO5[α]D20 = −1.8 (c 0.91, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-(1-bromo-7-(1,3-dioxolan-2-yl)heptan-3-yl)carbamateC15H28NBrO4[α]D20 = −8.7 (c 1.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)