Total synthesis of piericidin A1 and B1 and key analogues

Full details of the total synthesis of piericidin A1 and B1 and its extension to the preparation of a series of key analogues are described including ent-piericidin A1 (ent-1), 4'-deshydroxypiericidin A1 (58), 5'-desmethylpiericidin A1 (73), 4'-deshydroxy-5'-desmethylpiericidin A1 (75), and the corresponding analogues 51, 59, 76, and 77 bearing a simplified farnesyl side chain. The evaluation of these key analogues, along with those derived from their further functionalizations, permitted a scan of the key structural features providing new insights into the role of the substituents found in both the pyridyl core as well as the side chain. A strategic late stage heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain permitted ready access to the analogues in which each half of the molecule could be systematically and divergently modified. The pyridyl cores were assembled enlisting inverse electron demand Diels-Alder reactions of N-sulfonyl-1-azabutadienes, while key elements of side chain syntheses include an anti selective asymmetric aldol to install the C9 and C10 relative and absolute stereochemistry (for natural and ent-1) and a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chains.     

Isolation, biological significance, synthesis, and cytotoxic evaluation of new natural parathiosteroids A-C and analogues from the soft coral Paragorgia sp

Three unusual new steroid thioesters, parathiosteroids A-C (1a-3a), were isolated from the 2-propanol extract of the soft coral Paragorgia sp. collected in Madagascar. Their structures, determined by detailed spectroscopic analysis, were confirmed by synthesis and represent the first isolation of natural steroids bearing a C22 thioester in their side chain. These compounds displayed cytotoxicity against a panel of three human tumor cell lines at the micromolar level. The preparation of several analogues revealed structure/activity relationships in this type of steroids, for example, that the XCH2CH2NHCOCH3 moiety (X = S, O, NH) in the side chain is essential for the antiproliferative activity, and a low degree of oxidation in the A-ring results in higher bioactivity. These natural products could be biosynthetic intermediates in the steroid side chain degradation pathway involving activation with CoA and beta-oxidations.     

Synthesis and conformational analysis of 17alpha,21-cyclo-22-unsaturated analogues of calcitriol

Six new calcitriol analogues, conformationally restricted at their side chain by the introduction of both a cyclopropane ring at C17-C20 and a double or triple bond at C22, were synthesized using the Wittig-Horner approach to construct the triene system. The six CD-ring and side-chain bearing fragments were prepared from ketone 14 by a divergent route to generate both series of epimers at C20, followed by stereoselective cyclopropanation. The (E)-alkenyl side chain was synthesized by means of a Wittig reaction. The alkynyl side chain was prepared by Corey-Fuchs homologation, followed by alkylation. The (Z)-alkenyl side chain was prepared from the previous alkyne by partial hydrogenation. The 20-epi analogues bind more strongly to VDR than the corresponding analogues with the C20 natural stereochemistry. These results can be reasoned by conformational analysis and hydrophobic interactions with the VDR ligand-binding domain.     

Total syntheses of furaquinocin A, B, and E

A modular approach to the total synthesis of furaquinocins culminated in the total syntheses of furaquinocin A, B, and E. A Pd-catalyzed dynamic kinetic asymmetric transformation (DYKAT) on carbonates derived from Baylis-Hillman adducts, followed by a reductive Heck cyclization allows the enantio- and diastereoselective construction of dihydrobenzofuran 32. Introduction of a double unsatured side chain via Horner-Wadsworth-Emmons reaction and assembly of the naphthoquinone with squaric acid based methodology leads to furaquinocin E. The use of differentially substituted squaric acid derivatives allows the synthesis of three analogues of furaquinocin E. The additional stereocenters in furaquinocin A and B can be introduced with a diastereoselective Sakurai allylation. The stereoselective elongation of the side chain is possible using cross metathesis or ring closing metathesis. The obtained late-stage intermediates were successfully transformed to furaquinocin A and B.     

Structure-activity relationship studies of gymnocin-A

The structural elements required for cytotoxicity of gymnocin-A, a polycyclic ether isolated from the red tide-forming dinoflagellate, Karenia mikimotoi, were investigated by the total synthesis and evaluation of the structural analogues. The results of the structure-activity relationship studies indicated that the α,β-unsaturated aldehyde functionality of the side chain as well as the molecular length were needed for exhibiting the cytotoxicity of gymnocin-A.     

Lobatamide C: total synthesis,stereochemical assignment,preparation of simplified analogues,and V-ATPase inhibition studies

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.     

Synthesis and biological evaluation of neopeltolide and analogs

The synthesis of neopeltolide analogues that contain variations in the oxazole-containing side chain and in the macrolide core are reported along with the GI(50) values for these compounds against MCF-7, HCT-116, and p53 knockout HCT-116 cell lines. Although biological activity is sensitive to changes in the macrocycle and the side chain, several analogues displayed GI(50) values of <25 nM. Neopeltolide and several of the more potent analogues were significantly less potent against p53 knockout cells, suggesting that p53 plays an auxiliary role in the activity of these compounds.     

Function Oriented Synthesis: Preparation and Initial Biological Evaluation of New A-Ring-Modified Bryologs

The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7-2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A-ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function.     

Synthesis of new 18-substituted analogues of calcitriol using a photochemical remote functionalization

A novel convergent synthetic approach to new analogues of calcitriol modified at the C-18 position is reported. The key step in the synthesis is the 20-hydroxyl-directed photochemical iodination of the 18-methyl group in the presence of (diacetoxyiodo)benzene. Using this methodology, two new analogues of calcitriol were prepared: the first contains a hydroxylated alkyl side chain attached at C-18 with the natural side chain replaced by an isopropylidene group; the second is a conformationally locked analogue due to an extra oxacycle between the C-18 and C-20 positions.     

Parallel synthesis of prostaglandin E1 analogues

The first demonstration of the rapid parallel synthesis of diverse prostaglandin derivatives is reported. Upper (alpha-) side chain diversity was introduced to core 1 via the parallel Suzuki coupling of hydroborated alkenes. Conversion to the enones 3 and 9 was followed by the addition of the lower (omega-) side chains as higher-order cuprates 4. Upper side chains incorporating an N-acylsulfonamide protecting group were further transformed into prostaglandin amide analogues. Cleavage from support with HF/pyridine followed by scavenging provided 26 prostaglandin E1 analogues in high purity.     

Development of analogues of 1alpha,25-dihydroxyvitamin D3 with biased side chain orientation: methylated des-C,D-homo analogues

The discovery that 1alpha,25-dihydroxyvitamin D3 is effective in the inhibition of cellular proliferation and in the induction of cellular differentiation has led to a search for analogues in which these activities and the classical calcemic activity of this hormone are separated. In this context, the synthesis and biological evaluation are reported of the three stereoisomeric CD-ring modified structural analogues in order to enforce a particular and different orientation of the 25-hydroxylated side chain. Comparison of the results of the biological evaluation and conformational analysis of the side chain suggests one defined and "active" geometry.     

Parallel synthesis of a vitamin D(3) library in the solid-phase.

A highly efficient synthesis of the vitamin D(3) system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D(3) were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D(3) system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu(I)-catalyzed Grignard reagent. Parallel synthesis of the vitamin D(3) analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks.     

Alkylation of 2‐pyridinones: Synthesis of novel acyclonucleosides

This paper presents the synthesis of some novel acyclonucleosides containing 2‐pyridinones and 2‐hydroxyethoxymethyl, 2,3‐dihydroxy‐propyl side chain. The tosylate of these nucleosides analogues could be modified to azido derivatives. Also, acyclonucleosides with 1‐ethoxymethyl, 1‐benzyloxymethyl, 1‐methylthiomethy 1 and 2‐hydroxyethyl side chains have been investigated. The O‐alkylated pyridine derivatives were obtained during most reactions.     

Asymmetric Total Synthesis of Propindilactone G,Part 1: Initial Attempts towards the Synthesis of Schiartanes

Our first‐generation synthetic study towards the total synthesis of propindilactone G ( 1 ) and its analogues is reported. The key synthetic steps were an intramolecular Pauson–Khand reaction (PKR) and a vinylogous Mukaiyama reaction (VMAR). The stereoselective synthesis of the CDE ring moiety with an all‐carbon quaternary center through a PKR was difficult, whilst a VMAR afforded a product with the opposite stereochemistry at the C20 position on the side chain. These results led us to redesign our synthetic strategy for the total synthesis of compound 1 .     

Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy

An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.     

Synthesis of new aromatic (C17-C20)-locked side-chain analogues of calcitriol (1alpha,25-dihydroxyvitamin D(3))

The synthesis of four new analogues of calcitriol (1alpha, 25-(OH)(2)-D(3)) possessing aromatic and conjugated double bond units at the side chain are described. The triene system is introduced using the Lythgoe-Hoffmann La Roche convergent Wittig-Horner approach. The key steps in the preparation of the requisite upper fragments are the introduction of the side chain with the E-conjugated aromatic system and its photochemical conversion to the Z counterpart.     

Inversion of the Side‐Chain Stereochemistry of Indvidual Thr or Ile Residues in a Protein Molecule: Impact on the Folding,Stability, and Structure of the ShK Toxin

ShK toxin is a cysteine‐rich 35‐residue protein ion‐channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side‐chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo‐Thr or an allo‐Ile residue. The three allo‐Thr or allo‐Ile‐containing ShK polypeptides were able to fold into defined protein products, but with different folding propensities. Their relative thermal stabilities were measured and were consistent with the MD simulation data. Structures of the three ShK analogue proteins were determined by quasi‐racemic X‐ray crystallography and were similar to wild‐type ShK. All three ShK analogues retained ion‐channel blocking activity.     

A novel methodology for the synthesis of 1-desoxy-Δ-tetrahydrocannabinol (THC) analogues

A versatile and efficient sequence was developed for the synthesis of 1-desoxy-Δ⁸-THC analogues and is demonstrated by the synthesis of sulfonamide analogues with an acetylene group at the C-2^′ position in the side chain. In this procedure the 1-desoxy-Δ⁸- THC ring structure is built first and the synthesis of the side chain is then developed.     

Inversion of the Side‐Chain Stereochemistry of Indvidual Thr or Ile Residues in a Protein Molecule: Impact on the Folding,Stability, and Structure of the ShK Toxin

ShK toxin is a cysteine‐rich 35‐residue protein ion‐channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side‐chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo‐Thr or an allo‐Ile residue. The three allo‐Thr or allo‐Ile‐containing ShK polypeptides were able to fold into defined protein products, but with different folding propensities. Their relative thermal stabilities were measured and were consistent with the MD simulation data. Structures of the three ShK analogue proteins were determined by quasi‐racemic X‐ray crystallography and were similar to wild‐type ShK. All three ShK analogues retained ion‐channel blocking activity.     

Synthesis of 4-phenylethoxyquinazoline Fungicides/Insecticides

Recently, 4-phenylethoxyquinzoline and its analogues have been found to have both fungicidal and insecticidal activities. The synthesis of these compounds involves the construction of the quinazoline ring, preparation of the side chain, and coupling the side chain with 4-chloroquinazoline and its analogs.