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A solid-phase synthesis of saframycin analogs

Record Type:	Electronic resources : Monograph/item
Title/Author:	A solid-phase synthesis of saframycin analogs
Author:	Lanman, Brian A.
Description:	416 p.
Notes:	Adviser: Andrew G. Myers.
Notes:	Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2420.
Contained By:	Dissertation Abstracts International65-05B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3131892
ISBN:	049679132X

A solid-phase synthesis of saframycin analogs
Lanman, Brian A.

A solid-phase synthesis of saframycin analogs [electronic resource] - 416 p.

Adviser: Andrew G. Myers.

Thesis (Ph.D.)--Harvard University, 2004.

The (S)-configured morpholino nitrile substrate, ( S)-47, was found to transform with at least five-fold greater efficiency than the corresponding (R)-configured substrate in the solid-phase synthesis. Accordingly, methods were developed for the stereoselective synthesis of the (S)-morpholino nitrile linkage. To this end, three enantiopure trans-2,5-disubstituted morpholine derivatives (82, 90, and 91) were prepared and employed as substrates in diastereoselective Strecker condensations with cyanohydrins 42 and 99. The condensation of morpholine derivative 82 with cyanohydrin 99 was found to provide C-protected alpha-amino aldehyde 100 as a 31:1 mixture of ( S)- and (R)-morpholino nitrile diastereomers [without epimerization of the alpha-amino aldehyde-derived alpha-carbon (C10)]. C-Protected alpha-amino aldehyde 100 was subsequently successfully employed in a second-generation solid-phase synthesis of two saframycin analogs, 15 and 57, which were obtained in 33% and 43% yield, respectively, over a 9-step solid-phase sequence.

ISBN: 049679132XSubjects--Topical Terms:

193634
Chemistry, Organic.

A solid-phase synthesis of saframycin analogs
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245 1 2 $a A solid-phase synthesis of saframycin analogs $h [electronic resource]
300 $a 416 p.
500 $a Adviser: Andrew G. Myers.
500 $a Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2420.
502 $a Thesis (Ph.D.)--Harvard University, 2004.
520 # $a The (S)-configured morpholino nitrile substrate, ( S)-47, was found to transform with at least five-fold greater efficiency than the corresponding (R)-configured substrate in the solid-phase synthesis. Accordingly, methods were developed for the stereoselective synthesis of the (S)-morpholino nitrile linkage. To this end, three enantiopure trans-2,5-disubstituted morpholine derivatives (82, 90, and 91) were prepared and employed as substrates in diastereoselective Strecker condensations with cyanohydrins 42 and 99. The condensation of morpholine derivative 82 with cyanohydrin 99 was found to provide C-protected alpha-amino aldehyde 100 as a 31:1 mixture of ( S)- and (R)-morpholino nitrile diastereomers [without epimerization of the alpha-amino aldehyde-derived alpha-carbon (C10)]. C-Protected alpha-amino aldehyde 100 was subsequently successfully employed in a second-generation solid-phase synthesis of two saframycin analogs, 15 and 57, which were obtained in 33% and 43% yield, respectively, over a 9-step solid-phase sequence.
520 # $a The solid-phase synthesis of 23 analogs (15 and 52--73) of the antiproliferative agent saframycin A (1) is described. The synthetic route, which bears analogy to solidphase peptide synthesis, involved the sequential condensation of a resin-immobilized C protected alpha-amino aldehyde (47) with a series of alpha-amino aldehyde and aldehyde reactants. A "dual-linker" construct, comprising both silyl ether and morpholino nitrile linker groups, was used to tether the C-protected alpha-amino aldehyde to the resin support (see compound 47). Condensation of resin 47 with N-protected alpha-amino aldehyde 9, followed by Pictet-Spengler cyclization of the resulting imine, afforded the first of two tetrahydroisoquinoline ring systems of the saframycin analogs (see resin 48); repetition of the condensation-cyclization sequence with a second aldehyde reactant (after N-alkylation and deprotection of 48) then afforded the second tetrahydroisoquinoline ring system of the analogs (e.g., resin 50). Analogs 15 and 52--73 were cleaved from the resulting bis(tetrahydroisoquinoline) resins (e.g., 50) by a diastereospecific cyclorelease mechanism wherein substrates derived from the cis product of the first Pictet-Spengler cyclization of the synthetic sequence were simultaneously cyclized and cleaved from the resin support. Using this method, saframycin analogs 15 and 52--73 were obtained in 9--58% yield over a 10-step, solid-phase sequence.
590 $a School code: 0084.
650 # 0 $a Chemistry, Organic. $3 193634
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