[reaction: see text] A new total synthesis of (-)-agelastatin A (1) has been achieved from the chiral oxazolidinone (-)-3. Although enone transposition was problematic when the Michael ring closure of 2 was attempted with strong base, the desired cyclization could be effected with Hunig's base after the pyrrole nucleus was brominated. Subsequent reduction and monobromination afforded synthetic (-)-agelastatin A (1).

[reaction: see text] An enantiospecific total synthesis of Weinreb's advanced intermediate 2 for (-)-agelastatin A has been achieved from the Hough-Richardson aziridine 8. Noteworthy reactions in our sequence include the highly regioselective trans-diaxial ring-opening of 8 with azide ion to set up the vicinal diamido functionality present within (-)-2 and the Grubbs-Hoveyda ring-closing metathesis (RCM) reaction that was used to construct its cyclopentene core.

Three brominated analogues of the highly mutagenic drinking water micropollutant 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) have been synthesized from MX by halogen exchange reaction.

Highly selective reaction of methyl tetra-O-pivaloyl-beta-D-glucopyranuronate 2 with iodotrimethylsilane or (Me3Si)(2) and I-2 affords, in excellent yield, the 'disarmed' glycosyl iodide 1 which has good stability at 20 degreesC and excellent stability at 0 degreesC; the X-ray crystal structure of 1 is described, along with a comparison of its utility as a glycosyl donor to that of the corresponding bromide.

AbstractFor Abstract see ChemInform Abstract in Full Text.

(R)- and (S)-Methadones and levo-alpha-acetylmethadol (LAAM) have been synthesised starting from lipase-catalysed acylation of dimethylaminopropan-2-ol. An approach to the synthesis of (R)-bufuralol is also presented. (C) 2003 Elsevier Science Ltd. All rights reserved.

A number of analogues of morphine-6-glucuronide 1 have been prepared and evaluated as potential analgesic agents by competitive mu-receptor binding assay and in vivo antinociceptive activity. The analogues show variation in the nature of the carbohydrate residue, the N-substituent, the O(3)-substituent and saturation of the 7,8-double bond compared to 1. In general, only the 6beta-glucoside or beta-glucuronide carbohydrate residues showed potent agonism; other modified carbohydrates were less active or exhibited potential antagonism. Variations in N-substituent led to either reduced agonism (N-H) or potential antagonism [N-allyl, N-(cyclopropyl)methyl]; a polar N-substituent, carboxymethyl, failed to bind. Saturation of the 7,8-double bond led to increased agonism compared to the parent compound in all three examples studied.

New and greatly improved preparations of the 12 alpha ,1 ' beta- (5) and 12 beta ,1 ' beta- (6) glucuronides of dihydroartemisinin (DHA, 2) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12 alpha -epimer 5.

Following regioselective protection of the estrogen receptor downregulator fulvestrant (ICI 182,780) 1 as its 17-acetate 2 or 3-benzoate 4, the 3-sulfate 5 and 3- and 17-glucuronide conjugates 8 and 12 were prepared. Satisfactory preparation of 12 required use of the tri-O-isobutyryl imidate derivative 10 in conjunction with an inverse-addition technique not previously employed in glucuronidation. The value of this method for simpler aglycones is discussed together with a study of variations in donor acyl substituent and catalyst. Another putative metabolite, the 17-ketone 19, was prepared by direct oxidation of 1.

The 3-sulfate 4 and 3- and 17-glucuronide conjugates 5 and 6 of the pure anti-estrogenic steroid ICI 182,780 1, which is expected to be an effective agent for the treatment of breast cancer, have been prepared. The synthesis of 6 could only be satisfactorily achieved using an inverse addition technique, not previously employed in the glucuronic acid series: the value of this technique for some other aglycones is discussed.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A convenient two-step synthesis of morphine-3,6-di-β-d-glucuronide in fair yield from morphine and methyl 2,3,4-tri-O-isobutyryl-1-O-trichloroacetimidoyl-α-d-glucopyranuronate is reported.

We have devised an asymmetric synthesis of chiral artemisinin analogues (+)- 4a and (−)- 4a that retain the tricyclic ring system found in the natural product. The key step in the preparation of (+)- 4a involves an asymmetric MgCl 2 promoted Michael addition of the ( R )-(−)pyrrolidinemethanol-derived enamine 8 to acrylonitrile. This gives the corresponding ketone 9 in 50% yield (>95% ee). Subsequent elaboration of 9 provides the trioxane target (+)- 4a in greater than 85% ee. Enantiomeric trioxane (−)- 4a was prepared in a similar manner using ( S )-(+)-pyrrolidinemethanol in the first step of the sequence.

The selective enzymatic glucuronidation of the 6-position of morphine was probed by the glucuronidation of a series of 3-O-protected morphine derivatives. 3-O-Benzylmorphine 5 was converted to the corresponding 3-O-benzylmorphine-6-glucuronide 8 by human liver microsomes. The identity of 8 was confirmed by independent chemical synthesis. The glucuronide 8 was subsequently converted to 7,8-dihydromorphine-6-glucuronide.

The combination of TMSOTf and AgClO4 promotes the efficient C-10 phenoxylation of dihydroartemisinin (3) in good chemical yield and excellent stereoselectivity. In contrast to previous reports on other phenoxyglycoside derivatives, the phenoxy derivatives (5a–11b) of dihydroartemisinin do not undergo O to C rearrangement to the corresponding C-10-aryl derivatives. All of the new derivatives had potent in vitro antimalarial activity.