Studies directed towards the total synthesis of anthracycline antibiotics

At present anthracycline antibiotics have proven to be the most exciting agents in cancer chemotherapy. Both adriamycin and daunomycin are proven to be effective against a variety of human tumour cells, despite their cardiotoxicity. However, some synthetic analogues, such as 4-demethoxydaunomycin, are shown to be better therapeutic ratios compared to adriamycin or daunomycin. Various approaches have been successfully made for the total synthesis of (±) 4-demethoxydaunomycinone, the aglycone of (±) 4=demethoxydaunomycin, starting from benzoquinone, napthalene or anthraquinone precursors. Finally an elegant approach for the stereoconvergent synthesis of (+) 4-demethoxydaunomycinone has been worked out. New methods involving both Diels-Alder and Friedal-Crafts acylation, have been developed for the total synthesis of daunomycinone and 11-deoxydaunomycinone. The synthesis of L-daunosamine, the amino sugar unit present in the antitumor anthracyclines has been successfully elaborated starting either from D-glucose or D-glucosamine.     

Studies directed towards the total synthesis of morphine alkaloids

Application of metallated enamines to the synthesis of morphine related congeners is reported. A formal total synthesis of (±)-morphine has been completed.     

Studies directed towards the total synthesis of clavosolides: synthesis of an isomer of clavosolide A

The total synthesis of clavosolide A, employing a radical-mediated route to build its substituted tetrahydropyran unit, a Yamaguchi reaction to construct the diolide aglycon and the Schmidt method for the final glycosidation step, revealed that the reported structure is an isomer of the natural product.     

Studies directed towards the total synthesis of koshikalide: stereoselective synthesis of the macrocyclic core

The stereoselective synthesis of the macrolactone core of the natural product koshikalide is described. Starting with readily available 1,4-butanediol and malic acid as synthons, our synthetic strategy involved the reiterative application of Gilman’s reaction, Swern oxidation and Sharpless asymmetric epoxidation to establish the required stereocentres. Other key steps in the synthesis include Negishi cross coupling and Horner–Wadsworth–Emmons (HWE) reactions for construction of the main fragments. The 14-membered lactone ring was prepared by a selective Mitsunobu macrolactonization approach.     

Studies directed towards asymmetric synthesis of levobupivacaine

We report herein the first catalytic asymmetric synthesis of levobupivacaine. The key step involves the asymmetric alkylation of N-benzylimine glycinamide (2b).     

Studies directed towards the synthesis of taxane diterpenes: A remarkable rearrangement

Acid-catalyzed fragmentation of the intramolecular dioxolenone photocycloaddition product 9 leads not to 10, the desired taxane skeleton, but instead to the remarkable rearrangement product 11.     

Studies towards the total synthesis of batzelladine A

Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction. An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the particular compounds required for this target.     

Stereocontrol in organic synthesis using silicon-containing compounds. Studies directed towards the synthesis of ebelactone A

Several approaches to the synthesis of ebelactone A 2 are described, culminating in the synthesis of the benzenesulfonate of 2-epi-ebelactone A 161. All the approaches were based on three fragments A, B and C, originally defined in general terms in, but eventually used as the aldehyde 72, the allenylsilane 3 and the aldehyde 139, respectively. They were joined, first B with C, and then B+C with A. In the main routes to fragments A and C, the relative stereochemistry was controlled by highly stereoselective enolate methylations 67-->67, 68-->69, and 135-->136, in each case anti to an adjacent silyl group, and by a highly stereoselective hydroboration of an allylsilane 137-->138, also anti to the silyl group. The hydroxyl groups destined to be on C-3 and C-11 were unmasked by silyl-to-hydroxy conversions 69-->70 and 138-->139 with retention of configuration. The stereochemistry created in the coupling of fragment B to C was controlled by the stereospecifically anti S(E)2' reaction between the enantiomerically enriched allenylsilane 3 and the aldehyde 139. The double bond geometry was controlled by syn stereospecific silylcupration 148-->151, and preserved by iododesilylation 151-->152 of the vinylsilane with retention of configuration, and Nozaki-Hiyama-Kishi coupling with the aldehyde 72 gave the whole carbon skeleton 153 of ebelactone A with the correct relative configuration, all of which had been controlled by organosilicon chemistry. In the steps to remove the superfluous allylic hydroxyl, an intermediate allyllithium species 156 abstracted the proton on C-2, and its reprotonation inverted the configuration at that atom. Other routes to the fragments A and C were also explored, both successful and unsuccessful, both silicon-based and conventional, and a number of unexpected side reactions were investigated.     

Studies towards the stereoselective total synthesis of Gliomasolide A

The first synthetic approach towards the Gliomasolide A is described in 15 linear steps with 4% overall yield. The key steps in this approach are RCM protocol for the construction of 14-member macrolide, a Sharpless kinetic resolution, Keck and Brown’s allylations for the installation of desired stereocenters.     

Studies towards the total synthesis of contignasterol

The (17R,20S,22S,24S) C₂₀-C₂₉ segment of contignasterol has been stereoselectively prepared in 8 steps and 40% overall yield from (S)-carvone. Synthetic studies towards contignasterol's C/D ring functionalization/isomerization are also reported.     

Studies towards the total synthesis of Phostriecin

A synthetic approach toward the phostriecin, an antitumor natural product is described. The key features of the present synthesis are Wittig reaction, synthesis of homoallylic alcohol using Brown’s protocol (alkoxyallylboration) and RCM for the creation of unsaturated lactone moiety of phostriecin.     

Studies towards the total synthesis of hygrocins A and B

The western segment of hygrocins A–B has been synthesized through the coupling of a chiral C5–C13 synthon with the sterically demanding hexasubstituted naphthalenic core. The C5–C13 chiral fragment has been assembled via a stereoselective Johnson orthoester rearrangement of an optically pure allylic alcohol derived from d-glucose. Our studies lay the platform for the determination of the absolute configuration of the unassigned C8-stereocenter of the title compounds in addition to the completion of the total synthesis of the unique ansamacrolides hygrocins A and B.     

Studies directed towards the stereoselective total synthesis of ilexlactone via a tandem ring-closing enyne metathesis protocol

Studies directed towards the stereoselective total synthesis of ilexlactone resulted in the synthesis of bicyclic systems 1a, 1b and ent-1a through tandem ring-closing enyne metathesis using Grubbs’ catalyst. The structures of synthetic 1a, 1b and ent-1a revealed that the proposed structure for ilexlactone is incorrect.     

Studies towards a total synthesis of kainic acid

The preparation of the fused bicycle 14 is reported together with its photocyclisation to the dioxinone 2. Base induced fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by Wittig methylenation gave the kainoid derivative 18.     

Studies directed toward total synthesis of rhodocomatulins: A regioselective synthesis of brominated hydroxyanthraquinones by anionic annulations

In this work, brominated hydroxyanthraquinones, which are the core structural motif of naturally occurring bromorhodocomatulins, were successfully synthesized using Hauser annulation reaction as the key step. When brominated Michael acceptors (brominated p-quinone monoketals) and cyanophthalides or bromocyanophthalides (Hauser donors) were reacted under the annulation conditions, brominated anthraquinones were obtained with 81–87% yields for four examples. On acidic quenching, products were obtained as solid which were separated by filtration and purified by recrystallization in acetone. No chromatography was required.     

Studies directed towards the total synthesis of botcinic acid, the revised structure of botcinolide: synthesis of the highly substituted tetrahydropyran moiety

Synthesis of the highly substituted polyoxygenated tetrahydropyran ring of botcinic acid, the revised structure of botcinolide is achieved using, as key steps, a highly stereoselective aldol reaction of the titanium enolate from a lactate-derived chiral ketone and a stereoselective dihydroxylation.     

Studies directed towards the synthesis of botcinolides: synthesis of the nonalactone ring of 2-epibotcinolide

Synthesis of the polyoxygenated nonalactone ring of 2-epibotcinolide was achieved using a highly stereoselective aldol reaction of the titanium enolate from a lactate-derived chiral ketone, a stereoselective dihydroxylation and a Yamaguchi macrolactonization reaction.