Total synthesis of the elastin crosslinker (+)-desmopyridine

Desmopyridine, isolated from the acid hydrolysates of bovine ligamentum nuchae, is an elastin crosslinker and an amino acid that has a 3,4,5-trisubstituted pyridine skeleton. Herein we report the first total synthesis of (+)-desmopyridine in 10% yield over six steps starting from 4-aminopyridine via chemo- and regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions.

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2-(S)-((tert-Butoxycarbonyl)amino)-3-hydroxypropionic acidC8H15NO5[α]D20=+1.2 (c 1.0, MeOH)Source of chirality: the precursorAbsolute configuration: (S)

tert-Butyl 2-(S)-((tert-butoxycarbonyl)amino)-3-hydroxypropanoateC12H23NO5[α]D25=-20.8 (c 1.6, EtOH)Source of chirality: the precursorAbsolute configuration: (S)

tert-Butyl 2-(S)-((tert-butoxycarbonyl)amino)-3-iodopropanoateC12H22INO4[α]D25=-11.5 (c 1.0, MeOH)Source of chirality: the precursorAbsolute configuration: (S)

tert-Butyl 2-(S)-((tert-butoxycarbonyl)amino)-5-(trimethylsilyl)pent-4-ynoateC17H31NO4Si[α]D25=+54.0 (c 0.1, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)

tert-Butyl 2-(S)-((tert-butoxycarbonyl)amino)pent-4-ynoateC14H23NO4[α]D25=+44.7 (c 0.1, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)

(S)-tert-Butyl 2-(tert-butoxycarbonylamino)-5-(3,5-dibromopyridin-4-yl)pent-4-ynoateC19H24Br2N2O4[α]D20=+25.6 (c 0.1, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)

(2S,2′S)-Benzyl 4,4′-(4-((S)-5-(tert-butoxy)-4-(tert-butoxycarbonylamino)-5-oxopent-1-ynyl)pyridine-3,5-diyl)bis(2-(tert-butoxycarbonylamino)butanoate))C51H68N4O12[α]D20=+32.1 (c 0.1, CHCl3)Source of chirality: the precursorAbsolute configuration: (S), (S), (S)

DesmopyridineC18H28N4O6[α]D20=+10.2 (c 0.1, H2O)Source of chirality: the precursorAbsolute configuration: (S), (S), (S)