Synthetic studies on the phorboxazoles: a short synthesis of an epi-C23 tetrahydropyran core

Studies on the synthesis of the anticancer natural products, the phorboxazoles have led to the synthesis of the C21-C32 penta-substituted tetrahydropyran core which is epimeric to the natural product at C23. The synthesis was achieved in only seven linear steps. The key steps were the use of a Masamune-Abiko anti-aldol reaction, the formation of a dihydropyran precursor molecule by the use of a new ‘Maitland-Japp-like’ cyclisation, and a highly diastereoselective reductive alkylation of the dihydropyran double bond, to generate the corresponding tetrahydropyran ring in an excellent yield.     

Total synthesis of bryostatins: the development of methodology for the atom-economic and stereoselective synthesis of the ring C subunit

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for the stereoselective assembly of the ring C subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the ring C subunit of bryostatins.     

A concise and practical synthesis of oseltamivir phosphate(Tamiflu) from d-mannose

A short and practical synthesis of oseltamivir phosphate was accomplished in 11 steps from inexpensive and abundant starting material, d-mannose. This synthetic route featured an intramolecular Horner–Wadsworth–Emmons reaction as the key step to furnish the cyclohexene ring product. The hydroxyl group was converted stereo specifically into an amino group by oxidation to the ketone and reductive amination whereas the second amino group was introduced by azide substitution of a hydroxyl group. This synthesis provided an economical and practical alternative for the synthesis of Tamiflu.     

Atom-economic and stereoselective syntheses of the ring a and B subunits of the bryostatins

This article describes chemoselective and atom-economic methods for the stereoselective assembly of the ring A and B subunits of bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition reaction was developed and applied to the synthesis of bryostatin ring B. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin ring A, although ring A was eventually furnished through an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of the northern bryostatin fragment containing both the ring A and B subunits.     

Stereocontrolled formal synthesis of (+/-)-platensimycin

The caged structure of platensimycin, known as Nicolaou's key intermediate for total synthesis of platensimycin, was synthesized stereoselectively by using the following key steps: (i) diastereoselective Diels-Alder reaction between gamma-benzoyloxy enone and tert-butyldimethylsiloxydiene, (ii) formation of a dihydropyran ring by intramolecular catalytic oxypalladation, and (iii) transannular radical cyclization of monothioacetal with tributyltin hydride and AIBN.     

Double intramolecular oxymercuration: the first stereoselective synthesis of the C10-C34 fragment of asimitrin

The first stereoselective synthesis of the C10-C34 fragment of asimitrin, a nonclassical acetogenin, has been achieved. A key feature of our approach is the application of stereoselective double intramolecular oxymercuration for the efficient preparation of a mono-hydroxylated unsymmetrical bis-THF ring with two flanking hydroxyl groups. A chelation-controlled Grignard reaction plays a pivotal role in the elaboration of a commercially available carbohydrate.     

Studies toward asymmetric synthesis of leiodelide A

An enantioselective route for oxazoline 4, a key fragment toward the asymmetric synthesis of leiodelide A, is described. We synthesized northern subunit 6 through a Julia–Lythgoe olefination and subsequent Sharpless asymmetric dihydroxylation. Moreover, a highly diastereoselective method using well-established Evans’ asymmetric aldol condensation was developed for preparation of southern fragment 5. The additional feature of this synthetic route is the formation of oxazoline 4 through DAST-promoted cyclization of the amidation product from subunits 5 and 6.     

Synthesis of the C(43)-C(67) fragment of amphidinol 3

[reaction: see text] A synthesis of the C(43)-C(67) fragment of amphidinol 3 (AM3) has been accomplished by a route that features the use of a double allylboration reaction for synthesis of 1,5-diol 4b, which serves as a precursor to dihydropyran 11.     

Total synthesis of amphidinolide X

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective formation of allenol 6 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 5 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 6 was then cyclized with the aid of Ag(I) to give dihydrofuran 7 containing the (R)-configured quarternary sp3 chiral center at C19 of the target. The anti-configured chiral centers at C10 and C11 were formed by the palladium-catalyzed, Et2Zn-promoted addition of propargyl mesylate 12 to the functionalized aldehyde 11. The key fragment coupling at the C13-C14 bond was achieved by the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction. Finally, the 16-membered macrodiolide ring was formed by a Yamaguchi esterification/lactonization strategy.     

Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of l-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.     

Total Synthesis of Pulvomycin D

A synthetic route to the pulvomycin class of natural products is presented, which culminated in the first synthesis of a pulvomycin, pulvomycin D. Key elements of the strategy include a pivotal aldol reaction which led to bond formation between the C24-C40 and the C8-C23 fragment. The remaining C1-C7 fragment was attached by a Yamaguchi esterification completing the assembly of the 40 carbon atoms within the main skeleton. Ring closure to the 22-membered lactone ring was achieved in the final stages of the synthesis by a Heck reaction. The completion of the synthesis required the removal of six silyl protecting groups in combination with olefin formation at C26-C27 by a Peterson elimination.     

Total synthesis of borrelidin

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is macrocyclization at C11-C12 for the construction of an 18-membered ring after esterification between two segments. A detailed examination of the macrocyclization led us to the samarium(II) iodide-mediated intramolecular Reformatsky-type reaction as the most efficient synthetic approach. The two key segments were synthesized through regioselective methylation, directed hydrogenation, stereoselective Reformatsky-type reaction, and MgBr2.Et2O-mediated chelation-controlled allylation.     

Formal synthesis of (+)-sorangicin A

The formal synthesis of (+)-sorangicin A was completed by two independent routes. Both approaches feature a cross metathesis reaction to form the C29-C30 bond to arrive at the bicyclic ether/tetrahydropyran fragment. Formation of the C15-C16 olefin to unite the dihydropyran fragment with the rest of the molecule was achieved by either a cross metathesis reaction or a Julia-Kocienski olefination.     

1,2-Diacetals in synthesis: total synthesis of a glycosylphosphatidylinositol anchor of Trypanosoma brucei

A full account on a total synthesis of GPI anchor 1 employing butanediacetal (BDA) groups and a chiral bis(dihydropyran) is presented. The reactivity of selenium and thio glycosides was tuned by the use of BDA groups. This allowed the assembly of an appropriately protected GPI anchor precursor 2 in just six steps from the six building blocks 5-10 including only one protecting group manipulation. myo-Inositol was desymmetrised with the bis(dihydropyran) derivative 15 and appropriately protected to give inositol acceptor 21 in nine steps and 17% overall yield. The use of common starting materials and BDA-protections give efficient access to building blocks 5, 6, 7 and 8. A new and improved synthesis of the glucosamine donor 28 is included. In summary, a highly convergent and efficient synthesis of GPI anchor 1, which is clearly adaptable to other GPI anchors, has been reported.     

Total synthesis of laulimalide: assembly of the fragments and completion of the synthesis of the natural product and a potent analogue

Herein, we present a full account of our efforts to couple the northern and the southern building blocks, the synthesis of which were described in the preceding paper, along with the modifications required to ultimately lead to a successful synthesis of laulimalide. Key highlights include an exceptionally efficient and atom-economical intramolecular ruthenium-catalyzed alkene-alkyne coupling to build the macrocycle, followed by a highly stereoselective 1,3-allylic isomerization promoted by a rhenium complex. Interestingly, the designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity. We also report a second generation route that provides a more concise synthesis of the natural product.     

Stereoselective synthesis of (+/-)-rocaglaol analogues

An intramolecular hydroxy epoxide opening was used to access the cyclopenta[b]benzofuran ring system of the natural product rocaglaol (2). Our route allowed the stereocontrolled preparation of the rocaglaol derivative (+/-)-(1S*,3S*,3aR*,8bS*)-3b. The synthesis of the (+/-)-(3R*)-epimer of 3b was also achieved. Our strategy is well-suited for the production of analogues with variation of the western ring. [reaction: see text]     

Bamford-Stevens reaction assisted synthesis of styrene C-glycosides

Modification of carbohydrates and their analogs is hindered due to multi-step synthetic methodologies involving selective protection and deprotection of multiple hydroxyl groups present in the molecule. A highly efficient route for the synthesis of 1-phenyl-2-(β-D-glycopyranosyl)ethenes has been developed from native sugars, which neither requires protection/deprotection of the hydroxyl groups nor use of any metal/metal ions. The key step of the developed methodology is the use of Bamford-Stevens reaction which led to the formation of the desired compounds in moderate to high yields in three steps only.     

Utility of the ammonia-free Birch reduction of electron-deficient pyrroles: total synthesis of the 20s proteasome inhibitor, clasto-lactacystin beta-lactone

A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.     

Synthesis of the bis-spiroacetal moiety of the shellfish toxins spirolides B and D using an iterative oxidative radical cyclization strategy

The enantioselective synthesis of the bis-spiroacetal fragment of the shellfish toxins, spirolides B 1 and D 2, is reported. The carbon framework was constructed via a Barbier reaction of dihydropyran 10 with aldehyde 11, followed by two oxidative radical cyclizations to construct the bis-spiroacetal ring system. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor 21. The initial unsaturated bis-spiroacetals 9a-d underwent equilibration during epoxidation to trans-epoxide 24 that was converted to tertiary alcohol 7.     

Stereoselective synthesis of (+)-IKD-8344

Total synthesis of IKD-8344 was accomplished via stepwise cyclodimerization of the monomeric seco acid under Yamaguchi conditions. In the synthesis of the monomeric seco acid, Wittig olefination reaction was employed for an efficient bond formation at C7-C8. The threo-trans oxolane unit for the rings a and c was prepared via intramolecular Williamson ether synthesis of the hydroxyl mesylate prepared via asymmetric aldol reaction. Radical cyclization of a β-alkoxymethacrylate intermediate furnished the threo-cis oxolane unit for the b ring fragment.