Iodine-mediated ring-closing iodoamination with concomitant N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidines

Treatment of a range of homochiral unsaturated β-amino esters (containing a cis-dioxolane unit) with iodine promotes a novel ring-closing alkene iodoamination reaction which proceeds with concomitant N-debenzylation, providing a simple and stereoselective route to iodomethyl pyrrolidines. Functional group interconversion of the resulting iodomethyl pyrrolidines upon treatment with AgOAc proceeds via the corresponding aziridinium ion, with subsequent deprotection giving access to polyhydroxylated pyrrolidines.

A novel ring-closing alkene iodoamination with concomitant N-debenzylation protocol provides a direct route for the asymmetric synthesis of polyhydroxylated pyrrolidines from homochiral β-amino esters.Figure optionsDownload as PowerPoint slide

(2S,3R,4S,5S)-N(1)-Benzyl-2-iodomethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC21H30INO4[α]D24=+2.1 (c 0.8 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2S,3R,4S,5S)

(2R,3R,4S,5S)-N(1)-Benzyl-2-iodomethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC21H30INO4[α]D25=+52.8 (c 0.9 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3R,4S,5S)

tert-Butyl (3S,4S,5R,αR)-3-[N-benzyl-N-(α-methyl-4′-methoxybenzyl)amino]-4,5-O-isopropylidene-hepta-6-enoateC30H41NO5[α]D24=+12.1 (c 0.9 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (3S,4S,5R,αR)

tert-Butyl (3S,4S,5R,αR)-3-[N-(4′-methoxybenzyl)-N-(α-methylbenzyl)amino]-4,5-O-isopropylidene-hept-6-enoateC30H41NO5[α]D25=+11.4 (c 1.25 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (3S,4S,5R,αR)

(2S,3R,4S,5S)-N(1)-(4′-Methoxybenzyl)-2-iodomethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC22H32INO5[α]D25=-2.9 (c 1.0 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2S,3R,4S,5S)

(2R,3R,4S,5R)-N(1)-Benzyl-2-iodomethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC21H30INO4[α]D25=+4.5 (c 0.4 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3R,4S,5R)

tert-Butyl (2R,3S,4S,5R,αR)-2-hydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]-4,5-O-isopropylidene-hept-6-enoateC29H39NO5[α]D24=+20.7 (c 0.8 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3S,4S,5R,αR)

tert-Butyl (2R,3R,4S,5R,αR)-2-acetoxy-3-[N-benzyl-N-(α-methylbenzyl)amino]-4,5-O-isopropylidene-hepta-6-enoateC31H41NO6[α]D27=+37.9 (c 1.0 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3R,4S,5R,αR)

tert-Butyl (2R,2′R,3′R,4′S,5′R)-2-acetoxy-2-(N(1′)-benzyl-2′-iodomethyl-3′,4′-O-isopropylidene-pyrrolidin-5′-yl)acetateC23H32INO6[α]D24=+66.6 (c 0.9 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,2′R,3′R,4′S,5′R)

tert-Butyl (2R,2′S,3′R,4′S,5′R)-2-acetoxy-2-(N(1′)-benzyl-2′-iodomethyl-3′,4′-O-isopropylidene-pyrrolidin-5′-yl)acetateC23H32INO6[α]D21=-10.4 (c 0.65 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,2′S,3′R,4′S,5′R)

tert-Butyl (2R,2′R,3′R,4′S,5′R)-2-hydroxy-2-(N(1′)-benzyl-2′-iodomethyl-3′,4′-O-isopropylidene-pyrrolidin-5′-yl)acetateC21H30INO5[α]D22=+66.8 (c 1.2 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,2′R,3′R,4′S,5′S)

(1S,2S,3S,4R,5R)-N(1)-Benzyl-2-(tert-butoxycarbonylmethyl)-3,4-O-isopropylidene-1-azoniabicyclo[3.1.0]hexane tetrafluoroborate[C21H30NO4][BF4][α]D26=-15.1 (c 1.6 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (1S,2S,3S,4R,5R)

(2R,3R,4S,5S)-N(1)-Benzyl-2-acetoxymethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC23H33NO6[α]D26=+10.3 (c 0.6 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3R,4S,5S)

(1R,2S,3S,4R,5S)-N(1)-Benzyl-2-(tert-butoxycarbonylmethyl)-3,4-O-isopropylidene-1-azoniabicyclo[3.1.0]hexane tetrafluoroborate[C21H30NO4][BF4][α]D22=-8.4 (c 1.4 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (1R,2S,3S,4R,5S)

(2S,3R,4S,5R)-N(1)-Benzyl-2-acetoxymethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC23H33NO6[α]D25=+10.1 (c 0.5 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2S,3R,4S,5R)

(2R,3S,4R,5R)-N(1)-benzyl-2-(tert-butoxycarbonylmethyl)-3,4-O-isopropylidene-5-acetoxy-piperidineC23H33NO6[α]D24=-11.1 (c 0.7 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3S,4R,5R)

(2R,3R,4S,5S)-2-Acetoxymethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC16H27NO6[α]D24=-19.2 (c 1.0 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3R,4S,5S)

(2R,3R,4S,5S)-2-Hydroxymethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC14H25NO5[α]D22=-37.2 (c 1.6 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2R,3R,4S,5S)

(2′R,3′R,4′S,5′S)-(2′-Hydroxymethyl-3′,4′-dihydroxy-pyrrolidin-5′-yl)ethanoic acidC7H13NO5[α]D24=+20.3 (c 0.9 in H2O)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2′R,3′R,4′S,5′S)

(2S,3R,4S,5R)-2-Acetoxymethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC16H27NO6[α]D25=+4.0 (c 1.0 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2S,3R,4S,5R)

(2S,3R,4S,5R)-2-Hydroxymethyl-3,4-O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidineC14H25NO5[α]D25=-12.8 (c 1.0 in CHCl3)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2S,3R,4S,5R)

(2′S,3′R,4′S,5′R)-(2′-Hydroxymethyl-3′,4′-dihydroxy-pyrrolidin-5′-yl)ethanoic acidC7H13NO5[α]D23=-30.3 (c 0.8 in H2O)Source of chirality: d-ribose/asymmetric synthesisAbsolute configuration: (2′S,3′R,4′S,5′R)