Total Synthesis of the Norhasubanan Alkaloid Stephadiamine.

(+)-Stephadiamine is an unusual alkaloid isolated from the vine Stephania japonica. It features a norhasubanan skeleton, and contains two adjacent α-tertiary amines, which renders it an attractive synthetic target. Here, we present the first total synthesis of stephadiamine, which hinges on an efficient cascade reaction to implement the aza[4.3.3]propellane core of the alkaloid. The α-aminolactone moiety in a highly hindered position was installed via Tollens reaction and Curtius rearrangement. Useful building blocks for the asymmetric synthesis of morphine and (nor)hasubanan alkaloids are introduced.

Total Synthesis of (-)-Morphine.

Asymmetric total synthesis of (-)-morphine has been accomplished in 18 steps from commercially available 7-methoxy-2-tetralone. Our synthesis features a simple transformation from a readily prepared chiral intermediate, construction of the E-ring by acid-mediated cyclization, and singlet oxygen-mediated manipulation of the C-ring. Transformation of the final stage involves construction of the morphinan skeleton by means of 1,6-addition of in situ generated secondary amine.

The quest for a practical synthesis of morphine alkaloids and their derivatives by chemoenzymatic methods.

We became interested in approaches to morphine in the early 1990s following our immersion into the new program on the enzymatic dihydroxylation of aromatics. Larry Kwart, a former classmate of one of us at Rice University, who worked with our group at Virginia Tech in the mid-1980s, introduced to us the use of blocked mutants of Pseudomonas putida (Pp39D) for the production of arene-cis-dihydrodiols. Larry had gained expertise in microbiology from a postdoctoral stay with David Gibson, who discovered this unique enzymatic transformation, and he helped us to establish a strong program in chemoenzymatic synthesis that continues to this day. Without his pioneering effort, none of our accomplishments in chemoenzymatic synthesis, including the various approaches to morphine, would have materialized. Here we trace the evolution of our approaches to morphine alkaloids and some commercial opiate-derived medicinal agents. The design features and chronology of our approaches are discussed in a way that allows the reader to appreciate a number of errors that were made in conception as well as in execution. Experience acquired from many failed or less-than-effective attempts has finally led to an "almost reasonable" total synthesis, the key concept being based on our very first but unsuccessful attempt more than two decades ago. The irony of this accomplishment has not been lost on us. Each section of this Account presents a summary of distinctly different approaches to morphine alkaloids. Each ends with a short and philosophical lesson that was (or should have been) learned in the process. We intend for this Account to offer more than the history of a search for the perfect design solution to a synthetic problem. In today's era of rapid and often careless publication of results, it should serve also as a reminder that the success and the integrity of synthetic ventures depends on perseverance, adjustment of strategy, improvements of previous attempts, and serious attention to the quality of experimental data. Although somewhat satisfied with our latest accomplishment in morphinan synthesis, we plan to improve our design in the hope that a six-step synthesis is no longer in the realm of fantasy. With more than 20 years of effort in this area, our continuing involvement may qualify as obsession.

Total Synthesis of Codeine.

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system.

Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products.

The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products.

Gram-scale enantioselective formal synthesis of morphine through an ortho-para oxidative phenolic coupling strategy.

A gram-scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho-para oxidative phenolic coupling and a highly diastereoselective "desymmetrization" of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.

Synthesis of (-)-morphine: application of sequential Claisen/Claisen rearrangement of an allylic vicinal diol.

A detailed exploration of the synthesis of (-)-morphine based on sequential [3,3]-sigmatropic rearrangements is described. The sequential Claisen/Claisen rearrangements of an allylic vicinal diol resulted in the stereoselective formation of the two contiguous carbon centers, including a sterically encumbered quaternary carbon, in a single operation. The two ethyl esters generated in this reaction were successfully differentiated during a subsequent Friedel-Crafts-type cyclization. The (-)-morphine double bond was introduced at a late stage in our first-generation synthesis, but was formed at an earlier stage in the second-generation synthesis, resulting in a more efficient route to the end product.

Synthesis and bioanalytical evaluation of morphine-3-O-sulfate and morphine-6-O-sulfate in human urine and plasma using LC-MS/MS.

The aim of this work was to synthesize morphine-3-O-sulfate and morphine-6-O-sulfate for use as reference substances, and to determine the sulfate conjugates as possible heroin and morphine metabolites in plasma and urine by a validated LC-MS/MS method. Morphine-6-O-sulfate and morphine-3-O-sulfate were prepared as dihydrates from morphine hydrochloride, in overall yields of 41 and 39% with product purities of >99.5% and >98%, respectively. For bioanalysis, the chromatographic system consisted of a reversed-phase column and gradient elution. The tandem mass spectrometer was operated in the positive electrospray mode using selected reaction monitoring, of transition m/z 366.15 to 286.40. The measuring range was 5-500 ng/mL for morphine-3-O-sulfate and 4.5-454 ng/mL for morphine-6-O-sulfate in plasma. In urine, the measuring range was 50-5000 ng/mL for morphine-3-O-sulfate and 45.4-4544 ng/mL for morphine-6-O-sulfate. The intra-assay and total imprecision (coefficient of variation) was below 11% for both analytes in urine and plasma. Quantifiable levels of morphine-3-O-sulfate in authentic urine and plasma samples were found. Only one authentic urine sample contained a detectable level of morphine-6-O-sulfate, while no detectable morphine-6-O-sulfate was found in plasma samples.

Recent advances in the synthesis of morphine and related alkaloids.

Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system.

Total syntheses of the morphine alkaloids are described that use a direct stereoselective formation of the phenanthrofuran system via an intramolecular 4 + 2 cycloaddition of a diene tethered to the 4-position of a 7-methoxybenzofuran-3-carboxylic acid ester.

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues.

Design, synthesis, and evaluation of biotinylated opioid derivatives as novel probes to study opioid pharmacology.

A generally applicable strategy of chemically labeling (-)-morphine (1) is described. The synthesis starts from commercially available starting materials and can be completed in two steps with an overall yield of 23%. In silico simulation and NMR results show that the binding of (-)-morphine to one of its molecular targets, toll-like receptor 4 (TLR4), was not affected by the modification. Secreted embryonic alkaline phosphatase (SEAP) reporter assay results demonstrate that C(3) biotinylated and unmodified (-)-morphine show similar biological activities in live cells. To our knowledge, these studies provide the first practical and concise method to label various opioid derivatives, a group of important therapeutics in pain management, for biochemical/pharmacological studies.

Cycloaddition across the benzofuran ring as an approach to the morphine alkaloids.

The intramolecular Diels-Alder reaction of several amidofurans tethered onto a benzofuran ring was examined as a strategy for the synthesis of morphine. Bromo substitution on the furan ring did not provide sufficient activation to allow the cycloaddition to take place across the aromatic benzofuran. However, the presence of a large o-methylbenzyl group on the amido nitrogen atom causes the reactive s-trans conformation of the amidofuran to be highly populated, thereby facilitating its Diels-Alder cycloaddition across a tethered benzofuran.

The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis.

Evidence of human use of opium dates back as far as the sixth millennium BCE. Ancient societies through the Renaissance period created a variety of opium products, proliferating its common use and subsequent addiction. Because the active moiety was not known at this time, the potency of these opium concoctions could neither be predicted nor controlled. The first step in identifying opium's active ingredient, morphine, was its chemical isolation in the early 1800s by Wilhelm Sertürner. The subsequent elucidation of morphine's chemical formula and Sir Robert Robinson's derivation of morphine's structural formula, which won him the 1947 Nobel Prize in Chemistry, round out 150 years of the incremental advances in our chemical understanding of morphine. Nevertheless, our attempts to synthesize morphine, despite our advanced knowledge in synthetic chemistry, are still no match for the plant-based extraction of morphine from the poppy plant. The status quo remains problematic socially, economically, and politically; the relationships between the countries laboriously growing poppy plants to extract morphine and those countries importing these painkillers are unstable at best. In this study, we contrast the cumulative scientific discoveries that have led to our current chemical knowledge of morphine with the centuries-old natural method of morphine production that still dominates the opioid market today.

Total synthesis of (+/-)-morphine.

[Structure: see text] The morphinan skeleton was effectively synthesized by an intramolecular Mannich-type reaction. Further transformation led to total synthesis of morphine.

Underexplored Opportunities for Natural Products in Drug Discovery.

The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity.

Encapsulation of an intrathecal catheter.

A 47-year-old patient with cancer pain underwent implantation of an intrathecal drug delivery device. When the patient suffered from an infection with fever, pain on injection into the catheter and an elevated number of granulocytes in the cerebrospinal fluid 7 weeks later, radiologic examination showed an encapsulation of the catheter tip. Concentrations of morphine and morphine-6-glucuronide in the cerebrospinal fluid suggested transport of morphine into the systemic circulation via the vascularisation of the encapsulating membrane. After antibiotic therapy and removal of the catheter, morphine was administered intravenously with a one to one conversion ratio.

A rapid, high-yield conversion of codeine to morphine.

Brief treatment of codeine (1) in chloroform with boron tribromide has consiste-tly given morphine (2) in 90-91% yield after a simple isolation procedure. The yield and simplicity of operation in this method are vastly superior to those previously reported for this transformation.

An improved method for O-demethylation of codeine.

The O-demethylation of codeine was effected by sodium propylmercaptide in dimethylformamide at 125 degrees C to afford morphine in 80% yield. Similar treatment of thebaine was unrewarding.