Total synthesis of (-)- and (+)-dysibetaine.

Glycidamides 6R and 6S were elaborated to (R,R)- and (S,S)-dysibetaines (1R and 1S) by intramolecular alkylation and functional group modification in 23% overall yield. The absolute stereochemistry of natural dysibetaine was established as S,S by comparison of the optical rotation of the natural product with that of the synthetic materials.

Total synthesis of (-)-salicylihalamide A.

[see structure]. A 16-step synthesis of the novel cytotoxin salicylihalamide A (1E) has been achieved in 3.3% overall yield using ring closing metathesis to generate the macrolide and addition of (1Z,3Z)-hexadienylcuprate (2), which was generated in situ from ethylcuprate and acetylene, to alkenyl isocyanate 3 to form the side chain.

Synthesis of the hydroazulene ring system of guanacastepene.

[reaction: see text] A 12-step synthesis of 26, the functionalized hydroazulenone ring of guanacastepene (1), has been completed using the EtAlCl(2)-initiated cyclization of gamma,delta-unsaturated ketone 13 to construct 2,2,3-trisubstituted cyclopentanone 14, the palladium-catalyzed coupling of vinylmagnesium bromide with enol triflate 17 to prepare triene 21, and olefin metathesis of triene 21 to form the key hydroazulene 20.

Total synthesis of (+/-)-martinellic acid.

A 14-step synthesis of martinellic acid (1) that proceeds in 3% overall yield has been completed using the reaction of aniline 11 with Meldrum's acid-activated vinylcyclopropane 4 to give vinyl pyrrolidinone 12, condensation of aldehyde 13 with N-benzylglycine to form an azomethine ylide that cyclizes to give 14, selective reduction of 14 to amino alcohol 16 with LiBH(4) and MeOH, and guanidine formation by reaction of a cyanamide with 3-methyl-2-buten-1-amine in hexafluoro-2-propanol at 120 degrees C as key steps. [structure: see text]

Total synthesis of (+/-)-deoxypenostatin A. Approaches to the syntheses of penostatins A and B.

A short synthesis of (+/-)-deoxypenostatin A (28) has been carried out using the convergent coupling of dienal 11, epoxide 13, and methylenetriphenylphosphorane (17) to prepare trienol 19 in only two steps. The key step is the Yb(OTf)(3)-catalyzed intramolecular Diels-Alder reaction of hydrated trienyl glyoxylate 23, which gives lactone 24 stereoselectively. Elaboration of lactone 24 to enone 27 by an intramolecular Horner-Emmons Wittig reaction and epimerization completes the synthesis of 28. Modest yields of Diels-Alder adducts 45a and 46a could be prepared analogously from MEM ether 44c, but the sensitivity of several of the intermediates precluded the elaboration of 45a to penostatin A (1).

Total syntheses of (-)-fumiquinazolines A, B, and I.

[structure] The first total syntheses of (-)-fumiquinazolines A, B, and I have been accomplished efficiently using the Pd-catalyzed cyclization of an iodoindole carbamate to construct the imidazoindolone moiety and the dehydrative cyclization of a diamide followed by rearrangement through an amidine to construct the quinazolone moiety.

Total syntheses of (+/-)-anchinopeptolide D and (+/-)-cycloanchinopeptolide D.

The first synthesis of (+/-)-anchinopeptolide D (4) has been accomplished in seven steps in 10% overall yield from octopamine hydrochloride (17), N-(Boc)glycine (16), and 5-amino-2-hydroxypentanoic acid (22). The key step is the aldol dimerization and hemiaminal formation of alpha-keto amide 26, which gives primarily protected anchinopeptolide D 27 under kinetically controlled conditions. Cycloanchinopeptolide D (31) has been prepared by the unprecedented head-to-head photodimerization of the two hydroxystyrylamides of 4 using the hydrophobic effect in water to force the two side chains into close proximity so that [2 + 2] cycloaddition is faster than trans to cis double bond isomerization. Coupling of amine 21 with pyroglutamic acid affords the naturally occurring tripeptide 35, which had been assigned glutamic acid structure 34.

Synthesis of the N-((1E)-alkenyl)-(2Z,4Z)-heptadienamide side chain of salicylihalamide A and apicularens A and B.

[reaction: see text] The unstable N-((1E)-alkenyl)-(2Z,4Z)-heptadienamide side chain of salicylihalamide A (1) and apicularens A and B (3 and 4) has been prepared in one pot by the addition of (1Z,3Z)-hexadienylcuprate, prepared in situ from EtLi, CuBr.SMe2, and acetylene, to a (1 E)-alkenyl isocyanate.

Synthesis of (-)-dysiherbaine.

[reaction: see text] The first synthesis of (-)-dysiherbaine has been accomplished using intramolecular SN2 substitutions of a carbamate anion on an epoxide and an alkoxide on a secondary mesylate to efficiently construct the bicyclic skeleton stereospecifically from xylose. A general sequence has been developed to introduce an allyl group and convert it to the alanine side chain that should be useful for the construction of dysiherbaine analogues.

Biomimetic total syntheses of (-)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D.

[reaction: see text] The muscarinic antagonists (-)-TAN1251A (1), (+)-TAN1251B (2), (+)-TAN1251C (3), and (+)-TAN1251D (4) have been synthesized biomimetically by enamine formation from an amino aldehyde to give TAN1251C ketal 18. Oxidation and reduction lead to TAN1251A (1), which has been hydroxylated to give TAN1251B (2). Stereospecific reduction of TAN1251C ketal 18 leads to TAN1251D (4).

Revision of the stereochemistry of batzelladine F. Approaches to the tricyclic hydroxyguanidine moiety of batzelladines G, H, and I.

The polycyclic guanidine alkaloids batzelladines F-I isolated from a Jamaican sponge of the genus Batzella in 1997 are of potential value for the treatment of AIDS because they induce p56lck-CD4 dissociation at micromolar concentrations. Comparison of the spectral data for both the synthetic syn and anti tricyclic left-hand portions of batzelladine F establishes that the natural product has the syn rather than the anti stereochemistry originally assigned. Approaches to the tricyclic hydroxyguanidine moiety of batzelladines G-I are described.

Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa.

Two different mutations of the active-site Lys-296 in rhodopsin, K296E and K296M, have been found to cause autosomal dominant retinitis pigmentosa (ADRP). In vitro studies have shown that both mutations result in constitutive activation of the protein, suggesting that the activated state of the receptor may be responsible for retinal degeneration in patients with these mutations. Previous work has highlighted the potential of retinylamine analogs as active-site directed inactivators of constitutively active mutants of rhodopsin with the idea that these or related compounds might be used therapeutically for cases of ADRP involving mutations of the active-site Lys. Unfortunately, however, amine derivatives of 11-cis-retinal, although highly effective against a K296G mutant of rhodopsin, were without affect on the two naturally occurring ADRP mutants, presumably because of the greater steric bulk of Glu and Met side chains in comparison to Gly. For this reason we synthesized a retinylamine analog one carbon shorter than the parent 11-cis-retinal and show that this compound is indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19 retinylamine analog 1 inhibits constitutive activation of transducin by these mutants and their constitutive phosphorylation by rhodopsin kinase, and it does so in the presence of continuous illumination from room lights.

Cytotoxicity of synthetic racemic ptilocaulin: a novel cyclic guanidine.

(+)-Ptilocaulin, a novel cyclic guanidine extracted from the Caribbean sponge Ptilocaulis aff. P. Spiculifer, is reported to have broad spectrum antimicrobial activity in vitro as well as in vitro activity against L1210 murine leukemia. To more fully evaluate this compound as an anticancer agent, the in vitro cell growth inhibitory potencies of synthetic racemic ptilocaulin and ten clinical anticancer drugs were determined and compared in 16 different normal and transformed human and murine cell populations. Potency, expressed as the 50% inhibitory concentration (IC50), was determined by a tetrazolium reduction (MTT) assay. Ptilocaulin showed a fairly broad spectrum of in vitro activity against colon and mammary adenocarcinomas, melanomas, leukemias, transformed fibroblasts and normal lymphoid cells (IC50s 0.05- greater than 10 micrograms/ml). This activity was comparable to that of many of the clinical drugs, including vinca alkyloids, antibiotics, alkylators and antimetabolites. Cell viability was affected only after a 72 hr exposure to the compound. In a clonogenic assay, cytocidal effects were observed after 24-72 hr exposures to 10 x IC50 concentrations of ptilocaulin, as evidenced by failure of cells to resume growth after removal of the compound. Cytostatic effects were observed at less than or equal to IC50 concentrations, as evidenced by resumption of growth to near-control levels after removal of the compound. Ptilocaulin was toxic at 50 and 25 mg/kg in an in vivo L1210 tumor model and was ineffective at lower concentrations (T/Cs 100-112%). In vivo studies in a more sensitive tumor system are recommended but are limited by the lack of availability of sufficient quantities of the compound.