Almost half of prescription medications are metabolized by cytochrome P450 3A4 and 3A5. CYP3A4 and 3A5 have significant substrate overlap, and there is currently no way to selectively monitor the activity of these two enzymes, which has led to the erroneous habit of attributing the cumulative activity to CYP3A4. While CYP3A4 expression is ubiquitous, CYP3A5 expression is polymorphic, with large individual differences in CYP3A5 expression level. The CYP3A5 genotype has been shown to alter the pharmacokinetics of drugs in clinical trials. We report the first tool compound capable of determining CYP3A5 activity in biologic samples containing both enzymes. Oxidation of T-5 by CYP3A5 yields an N-oxide metabolite that is over 100-fold selective over CYP3A4. Formation of T-5 N-oxide highly correlates with the CYP3A5 genotype and CYP3A5 expression levels in human liver microsomes and human hepatocytes.

Hyperforin [1] (1) and perforatumone [2] (2) are two secondary metabolites with unique molecular architectures and were isolated from Hypericum perforatum (St. Johns wort), [3] famous for its antidepressant properties. Despite their relatively small size, these structures constitute thorny synthetic challenges and remain to this day defiant to chemical synthesis.[4] As part of our efforts to develop synthetic routes to these and other natural and designed polyprenylated phloroglucinol derivatives, we sought a general method of entry into bridged medium-sized rings reminiscent of this class of compounds. Herein we report a novel synthetic sequence to such polyfunctional systems from simple cyclic ketones that involves a series of cascade reactions and delivers model systems of both hyperforin and perforatumone in a stereoselective manner.Scheme 1 depicts the hypothetical strategy devised for reaching bridged medium (and potentially large)-sized rings of type III, IV, and V from simple building blocks such as disubstituted cyclic ketones I and a,b-unsaturated aldehydes II. Implementation of this strategy would require annulation of cyclic ketone I with the a,b-unsaturated aldehyde II to

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C–C bonds, one C–H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti–alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.

The first total synthesis of tovophyllin B (2), an antimicrobial xanthone derived from mangosteen, has been accomplished through a convergent strategy from building blocks 6 and 7 involving lithiummediated coupling, dehydrative cyclization, and 6π electrocyclization as key steps.Tovophyllin B, a prenylated pentacyclic xanthone, was first isolated in 1972 from the wood of Tovomita macrophylla by de Oliveira et al. 1 The originally proposed structure (1 ; Figure 1) was corrected in 1975 on the basis of chemical and spectroscopic data to the currently accepted structure (2 , Figure 1) in which one of the phenolic groups is H-bonded to the carbonyl moiety of the molecule. 2 Recent investigations of the antituberculosis potential of the fruit hulls of mangosteen (Garcinia mangostana), traditionally used in Thai folk medicine for alleviation of a number of maladies, led to re-isolation of this natural product and revealed that tovophyllin B (2) possesses a significant inhibitory activity against Mycobacterium tuberculosis (MIC = 25 μg/mL). 3 Therefore, as a lead compound for drug discovery, the total synthesis of tovophyllin B and its analogs is deemed important. In this letter we report a short and efficient total synthesis of this molecule that may also serve to prepare designed analogs.Scheme 1 shows the retrosynthetic analysis of the molecule of tovophyllin B (2) in which a 6π electrocyclization (a) plays the role of casting the final heterocyclic ring in the synthetic direction (3→2). An aldol/dehydration sequence (b) then traces 3, expected to be a transient intermediate, back to xanthone 4 and prenal (4′). Disconnection of the indicated carbon-oxygen bond within xanthone 4 through a retro dehydrative cyclization leads to bisaryl ketone 5, whose disassembly through a retro lithium-mediated coupling as shown reveals benzaldehyde 6 and benzopyran derivative 7 as the required building blocks for the projected synthesis.Scheme 2 summarizes the synthesis of advanced intermediate bisaryl ketone 5. Thus, Opropargylation 4 of the readily available phenol 8 (prepared from 2,4-dihydroxybenzaldehyde in three steps) 5 with methyl 2-methyl-3-yn-2-yl carbonate (9) in the presence of DBU and catalytic amounts of CuCl 2 proceeded smoothly to afford 1,1-dimethylpropargyl ether 10, which, upon heating in toluene at 140 °C, underwent Claisen rearrangement, leading to 2,2-dimethylchromene 11, in 74% overall yield for the two steps. 6 Regioselective lithiation of 11 facilitated by the two OMOM groups (nBuLi, THF, 25 °C), followed by quenching of the resulting lithiated species with prenyl bromide furnished Correspondence to: K.C. Nicolaou. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may...

One is not like the other: The title approach proceeds by stepwise coupling of three relatively simple substrates. Three natural product‐inspired agents are described, one of which has natural product‐like toxicity for HeLa and MCF7 cells. It is isoform‐selective, thus targeting Hsp90α/β over Grp94, and adopts a conformation similar to that of geldanamycin when complexed with Hsp90.

The total synthesis of anticancer marine natural product lehualide B is described. Overall, the synthesis proceeds in just eight steps from a simple γ-pyrone, does not require the use of protecting groups, and delivers each nonconjugated trisubstituted alkene with high levels of stereoselection. The challenging C12-C16 bis-trisubstituted 1,4-diene was installed with a complex reductive cross-coupling reaction between a preformed Ti-alkyne complex and a pyronecontaining allylic alcohol.The lehualides (Figure 1) are a family of pyrone-containing marine natural products recently isolated from an undescribed Hawaiian Plakortis sp. that have been shown to possess anticancer properties in a focused evaluation of ovarian (IGROV-ET) and leukemia (K562) cell lines.1 Interestingly, subtle differences in pyrone substitution apparently lead to dramatic differences in biological properties, as lehualide B (2) serves as a nanomolar inhibitor of IGROV-ET cell proliferation, while its isomer lehualide A was not found to have significant growth inhibitory effects in either IGROV-ET or K562 cells. This differential biological profile is interesting, especially in light of the close structural homology between the pyrone ring of lehualide B and the pyridine subunit shared by the piericidins (3) -potent inhibitors of the mitochondrial electron transport chain protein NADH-ubiquinone reductase (Complex I).2 While lehaulide does not possess a single chiral center, the stereochemistry and substitution of the polyunsaturated tail represents a significant challenge to modern synthetic organic chemistry. Perhaps the most complex stereochemical feature is the C12-C16 skipped diene that is composed of two trisubstituted alkenes of (E)-and (Z)-stereochemistry. The synthesis of such stereodefined architecture would be difficult with modern synthetic methods based on carbonyl olefination or transition metal-catalyzed cross-coupling. While methods based on carbonyl olefination would inevitably be plagued by challenges associated with the control of stereochemistry in the establishment of the trisubstituted alkenes from ketones, and difficulties associated with advancing unstable β,γ-unsaturated systems, transition metal-catalyzed coupling would be similarly complex owing to the multistep nature of micalizio@scripps.edu . Supporting Information Available: Experimental procedures and tabulated spectroscopic data for new compounds (PDF) are available free of charge via the Internet at http://pubs.acs.org/paragonplus/submission/jacsat/. synthetic pathways to the required stereodefined coupling partners, and the associated problems with regio-and stereocontrol in the reaction of intermediate π-allyl complexes. In addition to these difficulties, each alkene present in the system (from C8-C16) is separated from at least one other unsaturation by a methylene -a structural feature that both decreases stability and further complicates any attempted synthesis. Here, we describe the first total synthesis of any member of the lehualide class of mar...

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.

We report a concise and convergent laboratory synthesis of the rare marine natural product lehualide B that has led to the discovery that: (1) this compound has low nanomolar activity against human multiple myeloma cells, and (2) the anti-cancer effects of lehualide B and its analogs are selective (i.e., they are ~ two to three orders of magnitude less toxic to human breast cancer cells). Synthetic lehualide B is shown to be an effective inhibitor of complex I of the mitochondrial electron transport chain, with potency similar to that observed for the terrestrial natural products piericidin A1 and rotenone – an observation that led to the discovery that piericidin A1 is also selectively cytotoxic toward human multiple myeloma cells. Interestingly, synthetic derivatives of lehualide B that resemble verticipyrone (an established complex I inhibitor composed of a γ-pyrone and a simple mono-unsaturated hydrophobic chain) lack the potent anti-myeloma activity of the natural product. Finally, the synthesis and evaluation of a collection of lehualide-inspired analogs led to the elucidation of structure-activity relationships for this rare natural product that established important roles for the substituted γ-pyrone head group and the skipped polyene side chain.