An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired β-anomer from the glycosylation step.
Compound (1) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed, along with operational improvements and extensive safety evaluations of potentially hazardous reactions.
A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).
A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.
A serious outbreak of hepatoenteritis in 1979 on Palm Island (Queensland, Australia) requiring the hospitalization of about 100 people was found to be due to drinking water in which the cyanobacterium (blue-green alga) Cylindrospermopsin raciborskii was growing. 1 It was discovered that this freshwater alga produces a toxic substance causing hepatotoxicity symptoms in mice identical to those that afflicted the human victims. In 1992, Moore and co-workers 2 described the isolation of the toxin, which was named cylindrospermopsin, and using extensive NMR evidence proposed the tetracyclic structure and stereochemistry shown in 1 for this metabolite. More recently, the same hepatotoxin was isolated from the alga Umezakia natans collected in Lake Mikata (Fukui, Japan) 3 and from Aphanizomenon oValisporum found in Lake Kinneret in Israel. 4 The latter cyanobacterium was also found to coproduce a minor metabolite 7-epicylindrospermopsin, formulated as 2, which was reported to be as toxic as 1. 5 A key premise in the assignment of stereochemistry at C-7 for 1 and 2 is that the molecules exist in the rigid conformations shown, enforced by a hydrogen bond between an enolic uracil D-ring tautomer and the guanidine C-ring. Such a conformation was used to rationalize the observed C-7,8 proton coupling constants in the two isomers. A third metabolite in the series, 7-deoxycylindrospermopsin (3), was also recently isolated from C. raciborskii. 6 Interestingly, this latter compound proved to be nontoxic. Cylindrospermopsin continues to be a serious public health problem, particularly in tropical areas, and has recently been traced to the deaths of livestock in Australia. 7 On the basis of work reported by Runnegar and co-workers it appears that cylindrospermopsin exerts its toxic effects by inhibiting biosynthesis of cell-reduced glutathione. 8 We 9 and others 10 have described studies on the synthesis of cylindrospermopsin, and the Snider group has recently reported a total synthesis of this structurally unique natural product. 10c In this paper we disclose a synthesis which completely controls the six stereogenic centers of the proposed cylindrospermopsin structure 1 and which now proves that the stereochemical assignments at C-7 in fact have been reversed in cylindrospermopsin and the 7-epi compound. Thus, cylindrospermopsin has the constitution shown in 2 and 7-epicylindrospermopsin is 1 (vide infra). Our approach utilizes a novel stereospecific intramolecular [4 + 2]-cycloaddition of an N-sulfinylurea heterodienophile 11 and application of our new efficient uracil synthesis 9c as key strategic steps.Construction of the requisite Diels-Alder precursor 12 with the attendant four stereogenic centers contained in the piperidine A-ring was effected as outlined in Scheme 1. Using the methodology of Comins, 12 an efficient high-yield sequence was developed for preparation of vinylogous urethane 4 involving N-acylation of 4-methoxypyridine with benzyl chloroformate, followed by addition of (allyldimethylsilyl)methylmagnesium bromid...
A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic resolution of a racemic cyclopropanol acetate. Process safety considerations surrounding the use of 5 were examined, and an improved procedure is described which was safely demonstrated at multikilogram scale.
The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.
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