e.g. Filippa Pettersson or Cancer Res. 75(6) , 1102-12, (2015) or 10.1002/anie.201600521

The Journal of organic chemistry

Formal total synthesis of the potent renin inhibitor aliskiren: application of a SmI2-promoted acyl-like radical coupling

KB Lindsay, T Skrydstrup

Index: Lindsay, Karl B.; Skrydstrup, Troels Journal of Organic Chemistry, 2006 , vol. 71, # 13 p. 4766 - 4777

Full Text: HTML

Citation Number: 56

Abstract

A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thioester derivative of the amino acid representing the C5-C9 fragment of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted radical addition to n-butyl acrylate. ...

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

methyl (5S,7S)-5-(((benzyloxy)carbonyl)amino)-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-oxononanoate Structure

methyl (5S,7S)-...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

S-(pyridin-4-yl) (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanethioate Structure

S-(pyridin-4-yl...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

methyl (2S,4S)-2-amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate Structure

methyl (2S,4S)-...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

benzyl ((1S,3S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-((S)-5-oxo-4-(propan-2-ylidene)tetrahydrofuran-2-yl)pentyl)carbamate Structure

benzyl ((1S,3S)...

~%

tert-butyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S,4R)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Structure

tert-butyl N-[(...

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

methyl (5S,7S)-5-(((benzyloxy)carbonyl)amino)-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-oxononanoate Structure

methyl (5S,7S)-...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

S-(pyridin-4-yl) (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanethioate Structure

S-(pyridin-4-yl...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

methyl (2S,4S)-2-amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate Structure

methyl (2S,4S)-...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

benzyl ((1S,3S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-((S)-5-oxo-4-(propan-2-ylidene)tetrahydrofuran-2-yl)pentyl)carbamate Structure

benzyl ((1S,3S)...

~%

(3S,5S)-5-((1S,3S)-1-(BENZYLAMINO)-3-(4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL)-4-METHYLPENTYL)-3-ISOPROPYLDIHYDROFURAN-2(3H)-ONE Structure

(3S,5S)-5-((1S,...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

methyl (5S,7S)-5-(((benzyloxy)carbonyl)amino)-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-oxononanoate Structure

methyl (5S,7S)-...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

S-(pyridin-4-yl) (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanethioate Structure

S-(pyridin-4-yl...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

methyl (2S,4S)-2-amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate Structure

methyl (2S,4S)-...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

benzyl ((1S,3S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-((S)-5-oxo-4-(propan-2-ylidene)tetrahydrofuran-2-yl)pentyl)carbamate Structure

benzyl ((1S,3S)...

~%

tert-Butyl ((1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate Structure

tert-Butyl ((1S...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~94%

(R)-4-(2-(IODOMETHYL)-3-METHYLBUTYL)-1-METHOXY-2-(3-METHOXYPROPOXY)BENZENE Structure

(R)-4-(2-(IODOM...

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

~%

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~%

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

methyl (2S,4S)-2-amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate Structure

methyl (2S,4S)-...

~%

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

Benzyl chloroformate Structure

Benzyl chloroformate

methyl (2S,4S)-2-amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate Structure

methyl (2S,4S)-...

~91%

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~%

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

methyl (2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoate Structure

methyl (2S,4S)-...

~%

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

(2S,4S)-4-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-5-methyl-2-(phenylmethoxycarbonylamino)hexanoic acid Structure

(2S,4S)-4-[[4-m...

~%

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

S-(pyridin-4-yl) (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanethioate Structure

S-(pyridin-4-yl...

~%

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

methyl (2S,4S)-2-amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate Structure

methyl (2S,4S)-...

~%

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...

2-(3-Methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene) Structure

2-(3-Methoxypro...

~%

benzyl N-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2S)-5-oxooxolan-2-yl]pentyl]carbamate Structure

benzyl N-[(1S,3...