Design, total synthesis, and evaluation of novel open-chain epothilone analogues

[structure: see text] The design, total synthesis, and biological evaluation of two open-chain analogues of epothilone incorporating the critical C1-C8 fragment and the aromatic side chain held together by a small molecular scaffold have been achieved. Biological evaluation revealed that further restraint between the flexible C1-C8 region and the molecular scaffold may be necessary for potent inhibition of cell proliferation.     

Total synthesis of hypermodified epothilone analogs with potent in vitro antitumor activity

The convergent total synthesis of hypermodified epothilone analogs 1 and 2 has been achieved with the stereoselective cyclopropanation of allylic alcohol 17 and ring-closing olefin metathesis with diene 22 as the key steps. In spite of significant structural differences between these analogs and the natural epothilone scaffold, 1 and 2 are potent inducers of tubulin polymerization and inhibit the growth of human cancer cells in vitro with sub-nM IC50 values.     

High-yielding macrocyclization conditions used in the synthesis of novel Sansalvamide A derivatives

Described are the syntheses of nine Sansalvamide A derivatives using new, high-yielding, in situ deprotection-cyclization conditions that are general for this series of macrocycles, 55% average for both steps. This is 10-fold greater than previously reported yields.     

Highly concise routes to epothilones: the total synthesis and evaluation of epothilone 490

A concise modular laboratory construction of the epothilone class of promising antitumor agents has been accomplished. For the first time in the epothilone area, the new synthesis exploits the power of ring-closing olefin metathesis (RCM) in a stereospecific way. Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by complete lack of stereocontrol in the generation of the desired 12,13-olefin geometry in the products. The isolation of epothilone 490 (3) prompted us to reevaluate the utility of the RCM procedure for fashioning the 10,11-olefin, with the Z-12,13-olefin geometry already in place. Olefin metathesis of the triene substrate 12 afforded the product diene macrolide in stereoselective fashion. For purposes of greater synthetic convergency, the C3-(S)-alcohol was fashioned late in the synthesis, using chiral titanium-mediated aldol conditions with the entire O-alkyl fragment as a C15 acetate as the enolate component. Examination of the effects of protecting groups on the RCM process showed that deprotection of the C7 alcohol has a beneficial effect on the reaction yield. Performing the RCM as the last synthetic step in the sequence afforded a 64% yield of only the desired E-olefin. Selective diimide reduction of the new 10,11-olefin yielded 12,13-desoxyepothilone B, our current clinical candidate, demonstrating the utility of this new RCM-reduction protocol in efficiently generating the epothilone framework. Furthermore, the new olefin was selectively funtionalized to demonstrate the advantage conferred by this route for the construction of new analogues for SAR studies, in cytoxicity and microtubule affinity screens. Also described is the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promising in vitro data. This disappointing outcome was traced to unfavorable pharmacokinetic features of the drug in murine plasma. By the pharmacokinetic criteria, the prognosis for the effectiveness of 3 in humans is, in principle, much more promising.     

Alkyne metathesis: development of a novel molybdenum-based catalyst system and its application to the total synthesis of epothilone A and C

Sterically hindered molybdenum(III) amido complexes of the general type [Mo[(tBu)(Ar)N]3] (1), upon treatment with CH2Cl2 or other halogen donors, have been converted into highly effective catalysts for all kinds of alkyne metathesis reactions. Although the actual nature of the propagating species formed in situ is still elusive, halogen transfer to the Mo center of 1 plays a decisive role in the activation of such precatalysts. It was possible to isolate and characterize by X-ray crystallography some of the resulting molybdenum halide derivatives such as 15, 16 and 20 which themselves were shown to be catalytically active. Numerous applications illustrate the performance of the catalytic system 1/CH2Cl2 which operates under mild conditions and tolerates an array of polar functional groups. The wide scope allows the method to be implemented into the total synthesis of sensitive and polyfunctional natural products. Most notable among them is a concise entry into the potent anticancer agents epothilone A (86) and C (88). The macrolide core of these targets is forged by ring closing alkyne metathesis (RCAM) of diyne 113, followed by Lindlar hydrogenation of cycloalkyne 114 thus formed. Since this strategy opens a stereoselective entry into (Z)-alkene 115, the approach is inherently more efficient than previous syntheses based on conventional RCM.     

Multi-step application of immobilized reagents and scavengers: a total synthesis of epothilone C

The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.     

First total synthesis of piperodione and analogs

Piperodione (3), a secondary metabolite previously isolated from the Javanese pepper plant Piper retrofractum in 0.0002% isolated yield was synthesized in a convergent strategy utilizing a Mannich and a Stetter reaction. An over-all yield of 76% could be achieved. Several analogs were prepared by this synthetic sequence. None of the compounds showed a significant cytotoxicity for human tumor cells (photometric sulforhodamine B assay).     

Homolytic macrocyclization in the synthesis of thiacrown ethers

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, PP. 2663–2664, November, 1990.     

First total synthesis of versicotide D and analogs

The first total synthesis of cyclotetrapeptide versicotide D has been achieved in 21% overall yield using solid phase peptide synthesis and solution cyclization. In addition, in the search for candidates of antimalarial new drugs, one cyclic tetrapeptide analog which differs in the sequence, and four cyclic pentapeptide containing N-methyl amino acids, were prepared. The obtained compounds were evaluated against P. falciparum 3D7. Versicotide D showed low micromolar antiplasmodial activity.     

Formal total synthesis of oximidine II via a Suzuki-type cross-coupling macrocyclization employing potassium organotrifluoroborates

A formal total synthesis of oximidine II has been achieved, employing a Suzuki-type coupling approach to construct the highly strained, polyunsaturated 12-membered macrolactone. To achieve this goal, benefit was derived from the stability of potassium alkenyltrifluoroborates to establish conditions for the macrocyclization. The stereocontrolled formation of the cis-1,2-diol subunit was accomplished using a diastereoselective, reagent controlled addition to a chiral aldehyde utilizing the Carreira protocol. Advantage was taken of the Snieckus hydroborating reagent to gain access to the key trifluoroborate needed for the macrocyclization.     

First efficient synthesis of novel oxophenyl-arcyriaflavin analogs

New oxophenylarcyriaflavins were synthesized in a few efficient steps. The key steps involved at first a palladium cross-coupling between the 3-bromo-4-(1H-indol-3-yl)1-methylpyrrole-2,5-dione and the 2-formylphenylboronic acid or a methyl 2-trialkylstannylbenzoate, followed by an intramolecular acylation in a C-2 indolic position. All the sequence was carried out without any indolic protective group.     

Design and synthesis of novel dinucleotide analogs

Syntheses of dinucleotide analogs, (S,R) cis-(4-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-1,3-dioxolan-2-yl)methyl (2R,3R,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl hydrogen phosphate (5a) and (S,R) cis-(5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-1,3-oxathiolan-2-yl)methyl (2R,3R,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl hydrogen phosphate (5b), were accomplished by the use of a new strategy. The use of phenyldichlorophosphate (Method A) as the coupling reagent was shown to possess superiority relative to the reported use of di(1H-benzo[d][1,2,3]triazol-1-yl)phenyl phosphonate (Method B).     

Exploring azide-enolate cycloaddition in the synthesis of novel Rufinamide analogs

The exploration of azide-enolate cycloaddition in the synthesis of novel Rufinamide analogs is reported for the first time. A very simple procedure involving the use of β-ketonitriles as dipolarophiles afforded 5-aril/heteroayl Rufinamide derivatives in two steps.     

Studies towards the synthesis of neopeltolide: synthesis of a ring-closing metathesis macrocyclization precursor

An advanced ring-closing metathesis precursor for the synthesis of the marine macrolide neopeltolide is prepared in a stereocontrolled manner by the coupling of the C2-C10 and C11-C16 subunits. The metathesis reaction of 4 with Grubbs’ II or Nolan’s indenylidene catalyst led to the unexpected formation of cycloheptene 18.     

Expedient total synthesis of pyrrothine natural products and analogs

This paper describes an expedient and straightforward total synthesis of the two pyrrothine natural products holomycin (7 steps, 11% overall) and xenorhabdin I (7 steps, 11% overall) and analogs thereof via a common late-stage intermediate. The pathway proceeds via the pyrrothine hydrochloride intermediate (6 steps, 17% overall) which also gave access to very fast synthesis of analogs as demonstrated by the synthesis of , and (7 steps, 11-12% overall).     

Combined coinage metal catalysis in natural product synthesis: total synthesis of (+)-varitriol and seven analogs

A modular total synthesis of the natural product (+)-varitriol (1) and seven analogs was achieved by using combined coinage metal catalysis. Starting from enynol 13, reagent-controlled introduction of stereogenic centers and efficient center-to-axis-to-center chirality transfer viaα-hydroxyallene 5 afforded (+)-varitriol with 6.4% yield over 10 steps.     

Total synthesis of epothilone a through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C

The total synthesis of epothilone A is described by the coupling four segments 4-7 a. Three of the segments, 4, 5 and 7 a, have only one chiral center; all other chiral centers were introduced by simple asymmetric catalytic reactions. The key steps are the ring opening of epoxide 5 with acetylide 8 for the construction of the C12-C13 cis double bond and a practical hydrolytic kinetic resolution (HKR) developed by Jacobsen group for the introduction the chiral center at C3. Especially, the stereospecific epoxidation of 3-O-PMB epothilone C 3 b through long-range effect of 3-O-PMB protecting group gave high yields of the C12-C13 alpha-epoxide for the synthesis of target molecule.     

Studies towards the synthesis of epothilone A via organoboranes

Studies towards the synthesis of epothilone A via organoboranes have been described. A modified procedure for the large-scale preparation of B-gamma,gamma-dimethylallyldiisopinocampheylborane from prenyl alcohol has been developed. This reagent, upon reaction with various aldehydes, provides the corresponding alpha,alpha-dimethylhomoallylic alcohols in high enantioselectivities. The application of this reagent for the synthesis of the C1-C6 subunit of epothilone has been demonstrated. Alternatively, inter- and intramolecular asymmetric reduction protocols have also been utilized for the synthesis of the C1-C6 subunit of epothilone A. The synthesis of the C7-C21 fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using alpha-pinene-derived reagents has also been described.