Biomedical subjects
Publications and source records attributed to Philip L Fuchs.
The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.
Synthesis of the South 7 hemisphere of cephalostatin 7 is described applying a second-generation synthetic strategy, which retains all the existing carbons in hecogenin acetate 1. TFAT (trifluoroacetyl trifluoromethanesulfonate)-assisted E-ring opening yields the key D-ring cyclopentadiene. A facially selective [4 + 2] cycloaddition between a series of steroidal D-ring dienes and singlet oxygen was conformationally directed by the C21-Me stereochemistry of the side chain. Sharpless asymmetric dihydroxylation of the terminal olefin provides (S)-C25-OH. An acid-catalyzed SN2' intramolecular alkylation of an acetal oxygen was followed by a one-pot sequence of beta-elimination and spiroketalization. The new route provides a practical 16-operation synthesis of the South 7 hemisphere (20% overall), as well as a model for construction of the crucial North 1 hemisphere.
3,3,3-Trichloropropyl-1-triphenylphosphonium chloride is conveniently prepared from 2-chloroethanol, triphenylphosphine, and trichloroacetic acid. Deprotonation of this reagent generates 3,3,3-trichloropropyl-1-triphenylphosphorane, which reacts with aldehydes to give trichloromethylated (Z)-olefins, which are useful for the synthesis of (Z)-1,3-enynes, (Z,Z)-1-chloro-1,3-dienes, and 1,3-diynes in high yields and stereospecificities.
[reaction: see text] Various C-16 hydroxy steroids have been prepared with the aid of CrO(3)/Bu(4)NIO(4). Out of the two possible reaction courses, transition state B is favored because of less steric interference between substrate and CrO(4). Thus, C-H bonds at C-16 are oxidized selectively.
A three-operation conjunctive strategy is available for the synthesis of EE, EZ, and ET dienes. This protocol employs a sequential Wadsworth-Emmons reaction using a GAPPS reagent followed by alkylation of an allylic sulfone anion, and finally ligand-mediated, palladium-catalyzed desulfonylation.
[reaction: see text]. Polyphosphoric acid trimethylsilyl ester (PPSE)-promoted intramolecular Friedel-Crafts reactions on a nonaromatic carboxylic acid system have been investigated. Studies led to the synthesis of C-18 functionalized steroidal compounds 5 and 9a-d with strict retention of the spiroketals. Isomerization of spiroketal 9e was studied.
[reaction: see text] Ring opening of steroidal spiroketals under exceptionally mild conditions is smoothly achieved via reaction with trifluoroacetyl trifluoromethanesulfonate (TFAT). The new spiroketal ring-opening protocol provides omega-trifluoroacetyl vinyl ethers in good yield and avoids difficulties that attended previously employed vigorous reaction conditions.
[reaction: see text] Methods for functionalization of the D ring of diene 1 were investigated. This study led to efficient syntheses of 3 and the subsequent 23'-deoxy,17'alpha-hydroxy cephalostatin 1 analog (4). The bioactivity data of 2 and 4 are in the low nanomolar range for a 10-cell-line minipanel.
[reaction: see text] Dioxiranes made in situ from the commercially available tetrafluoroacetophenones (7, 8) and pentafluoroacetophenone (9) are reported for highly efficient epoxidation of olefins for the first time. Studies showed that ketone 7, 8, or 9 can be used in catalytic amount (0.2 equiv) with only 0.6 equiv of Oxone (equal to 1.2 equiv of peroxymonosulfate) to selectively oxidize diene 1 to epoxide 2. The epoxidation reactions of dioxiranes of fluoroacetophenones are compared with the recently described complementary aliphatic acyclic fluorinated ketones.
Dimethyldioxirane (DMDO) C-H oxidation of ketone 17 to hemiketal 18 (82%), bis-dehydration to vinyl ether 21 (77%), and DMDO again provides C-23 axial alcohol 23 (99%). Routine processing, including a double-stereoselective Sharpless AD reaction (de >98%), gives alcohols 7 and 32. C-23 deoxy substrate 7 undergoes Suarez hypoiodite oxidative cyclization to (natural) beta spiroketal 34, but compound 32, bearing a C-23 silyl ether, generates unnatural spiroketal 33. [reaction: see text]
[reaction: see text] Two methods have been developed for the synthesis of epoxide 36. The first uses (+)-pulegone 25 as an enantiopure starting material and introduces the requisite intricacy of target 22 in 12 operations. The second method employs an enantiospecific catalytic Jacobsen epoxidation of 1a and is five operations shorter. The second sequence features an oxygen-directed alkylative oxidation reaction that re-establishes the dienyl sulfone functionality with concomitant 1,3-transposition of the sulfone moiety.
Enantiopure epoxyvinyl sulfones SS-9a, SS-9b, produced from Jacobsen epoxidation of 2-phenylsulfonyl 1,3-cyclohexa- and cycloheptadiene, are used as a template for the construction of substituted cycloalkenones and as chiral synthetic equivalents of enones a and b. The addition of carbon nucleophiles to SS-9a, SS-9b is high yielding and stereospecific. Enantiopure alpha,beta- and gamma-substituted cycloalkenones are easily constructed using a variety of methods.
Hecogenin acetate was converted to ritterazine M in 16 operations with an average yield per opearation of 87%. The overall linear yield was 12%. This confirmed 1 as the corrected structure for ritterazine M by total synthesis.
The structure of the North spiroketal moiety of ritterazine M has been corrected from 1a to 1b. This was accomplished by comparison of published spectra of the natural product with five synthetic spiroketal-alcohols. Synthesis of these models was efficiently accomplished by reductive cleavage of the spiroketal and Sharpless asymmetric dihydroxylation of an isopentyl, methyl 1,1-disubstituted olefin, followed by Suarez iodine[III] oxidative spirocyclization of monoprotected 1 degree,3 degree 1,2 diols.
A large-scale and inexpensive synthesis of dienes 1 and 2 has been developed via a four-step procedure starting with benzenethiol and the corresponding cyclic ketone. No chromatography is required.
Prostacyclin is an endogenous mediator that shows potent platelet inhibitory activity and powerful relaxation of peripheral resistance vessels. Prostacyclin receptor agonists are valuable drugs in the treatment of various vascular diseases spanning primary pulmonary hypertension to Raynaud's syndrome. Although agonists from various structural classes were synthesized, a common pharmacophore was never defined. Therefore, an attempt was made to integrate the different agonists into a single model. A dataset of structurally diverse prostacyclin receptor agonists was tested for its affinity to the human platelet prostacyclin receptor. The dataset included prostanoid and nonprostanoid ligands comprising iloprost, cicaprost, and BMY45778. Extensive conformational analyses were performed for both classes of compounds because of the absence of rigid templates. The search and superimposition procedure yielded a pharmacophore that aligns the essential carboxylate group of the agonists as well as demonstrates that different functional groups in prostanoid and nonprostanoid agonists can be arranged in a uniform conformation. A three-dimensional quantitative structure-activity relationship study was performed using the programs GRID and GOLPE. This analysis yielded a cross-validated correlation coefficient of 0.77. With this model, it is possible to predict the affinity of untested compounds.