Donald D. Johnson

Collagen cross-links: Synthesis of pyridinoline, deoxypyridinoline and their analogues

Abstract An efficient chiral synthesis of (S,S)-(−)-3g, a key intermediate for the preparation of collagen cross-links pyridinoline (Pyd, 1) and deoxypyridinoline (Dpd, 2) was achieved from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (21b). Quaternization of (S,S)-(−)-3g with iodide (2S,5R)-(+)-4a followed by hydrolysis provided a first chiral synthesis of natural (+)-Pyd (1). 1-(2S)-(+)-Pyd (1) was also synthesized from (S,S)-(−)-3g and iodide (2S,5S)-(+)-4a. Similarly, quaternization of (S,S)-(−)-3g with iodide (2S)-(−)-4b, which was prepared from (2S)-(−)-6-amino-2-[(tert-butoxycarbonyl)amino]hexanoic acid (31) in three steps, followed by hydrolysis afforded natural (+)-Dpd (2) in 5.3% overall yield. Also, the synthesis of racemic Dpd [(±)-2] and a variety of its analogues is presented.

TOTAL SYNTHESIS OF (+)-DEOXYPYRROLOLINE : A POTENTIAL BIOCHEMICAL MARKER FOR DIAGNOSIS OF OSTEOPOROSIS

The collagen cross-link (+)-deoxypyrrololine (Dpl, 1), a potential biochemical marker for diagnosis of osteoporosis, has been obtained by a general and convergent total synthesis. The key synthetic features involve utilization of a L-glutamic acid derivative as a source for all three chiral centers in (+)-1, and construction of the pyrrole ring by condensation of an alpha-acetoxynitro compound with benzyl isocyanoacetate.

Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

Abstract An efficient synthesis of tert -butyl-(2 S )-2-[( tert -butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate ( 5 ), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1 ) and (+)-deoxypyridinoline (Dpd, 2 ) was described from (4 S )-5-( tert -butoxy)-4-[( tert -butoxycarbonyl)amino]-5-oxopentanoic acid ( 6 ) in six steps. Also, an improved synthesis of iodide (2 S )-(−)- 4b was presented.

Evaluation of chemiluminescent estradiol conjugates by using a surface plasmon resonance detector.

A series of chemiluminescent 17beta-estradiol probes were synthesized. Relative equilibrium dissociation constants (K(D)) for the interaction of an anti-E(2) Fab fragment for the probes in solution were evaluated using a single E(2)-analog biosensor surface on a BIAcore surface plasmon resonance instrument. The results show the antibody fragment binds all chemiluminescent conjugates tested with high affinity showing only minor preferences for site of substitution (C6 versus C7), stereochemistry (alpha versus beta), or linker moiety.

Bone collagen cross-links: an efficient one-pot synthesis of (+)-pyridinoline and (+)-dexoypyridinoline

Abstract A one-pot reaction of (2 S ,5 R )-(−)- tert -butyl-[(2- tert -butoxycarbonyl)amino]-5-hydroxy-6-aminohexanoate 2b or ( S )-(−)- tert -butyl-[(2- tert -butoxycarbonyl)amino]-6-aminohexanoate 2c with ( S )-(−)- tert -butyl-6-bromo-[bis-(2- tert -butoxycarbonyl)amino]-5-oxohexanoate 5 in the presence of K 2 CO 3 in MeCN–MeOH followed by hydrolysis gave bone collagen cross-links, (+)-Pyd 1b or (+)-Dpd 1c , in 42–48% yield, respectively.

A CONVENIENT METHOD FOR THE PREPARATION OF α-KETOACETALS

ABSTRACT A convenient method for the preparation of α-ketoacetal derivatives 2a–g was developed by addition of Grignard reagent (1a–g) to commercially available ethyl diethoxyacetate (3) in 60–96% yield.

A concise synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine

Abstract A convergent synthesis of ( S )-(−)-3-(2-carboxy-4-pyrrolyl)-alanine (CPA) 1 , a non-proteinogenic amino acid is described starting from a commercially available dimethyl l -aspartate 2 in good overall yield.

A stereoselective synthesis of 1α-(3′-Carboxypropyl)-4-androsten-17β-ol-3-one: Preparation of immunoreagents for quantification of testosterone by fluorescence polarization immunoassay

Abstract 1α(3′-Carboxypropyl)-4-androsten-17β-ol-3-one (2), a novel hapten, was prepared from boldenone (3) via addition of 4-pentenyl magnesium bromide in the presence of CuBr, as a key step in >95% epimeric excess and 13.8% overall yield. Two immunogens (7,8) and three fluorescent tracers (11,18,19) were prepared from acid (2) for the development of an immunoassay for testosterone (1).

A stereoselective synthesis of 7α-(3′-carboxypropyl)estradiol from a noncontrolled substance

Abstract Alkylation of 3,17β-bis(2-trimethylsilyl)ethoxymethyl-1,3,5(10) estratriene-6-one (2) with 5-bromo-1-pentene using NaHMDS in THF afforded 3,17β-bis(2-trimethylsilyl)ethoxymethyl-7-α-(4′-pentenyl)-1,3,5(10)estratriene-6-one (3) in excellent stereoselectivity (>95% epimeric excess). Functionalization of the side chain in compound 3 was accomplished via ozonolysis, oxidation and esterification to give 5 in 72% yield. The reduction of ester (5) using NaBH4 in MeOH afforded the corresponding 6α-hydroxy compound (6) as a single isomer in 72% yield. The hydroxyl group in 6 was removed by converting to the corresponding xanthate (7) followed by reduction using n-Bu3SnH to afford 8 in good yield. Finally, the SEM protective groups in 8 were removed, after which the ester function was hydrolyzed with LiOH to give 7α-(3′-carboxypropyl)estradiol (10), in 10.6% overall yield from 3.

Totalsynthese von (+)‐Desoxypyrrololin: ein potentieller biochemischer Marker zur Diagnose der Osteoporose

Der Kollagen-Quervernetzer (+)-Desoxypyrrololin (Dpl) 1, ein potentieller biochemischer Marker fur die Diagnostik der Osteoporose, wurde in einer allgemein anwendbaren und konvergenten Totalsynthese hergestellt. Die Verwendung eines L-Glutaminsaure-Derivates als Quelle fur alle drei chiralen Zentren von (+)-1 ist neben dem Aufbau des Pyrrolrings durch Kondensation einer α-Acetoxynitroverbindung mit Isocyanessigsaurebenzylester ein Schlusselschritt der Synthese.