Total synthesis

About: Total synthesis is a research topic. Over the lifetime, 25578 publications have been published within this topic receiving 489319 citations.

Total Synthesis of Merrilactone A

Abstract: Merrilactone A (1) has been shown to possess neurotrophic activity and thus is expected to hold therapeutic potential in the treatment of neurodegeneration diseases. In this paper, we report the total synthesis of (±)-1, employing, as key steps, a novel desymmetrization protocol of meso-diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1 (3 → 2) and a radical cyclization to install the highly congested C9-quaternary carbon (16 → 17).

Total synthesis of sarcodictyins A and B: Solid- and solution-phase synthesis and biological evaluation of combinatorial sarcodictyin libraries

Abstract: Isolated from certain species of soft corals, the sarcodictyins, eleutherobin, and eleuthosides have become important synthetic targets due the their novel molecular architectures, important biological activities, and potential in medicine. Of particular interest is their Taxol-like mechanism of action involving disturbance of the tubulin−microtubule interplay resulting in tumor cell death. Their scarcity and biological profile prompted us to initiate a program directed at exploring their chemical synthesis and chemical biology. Herein we report (a) the first total synthesis of sarcodictyins A (7) and B (8) by a combination of solution and solid-phase methods through the attachment of the common precursors 18 or 20 on solid support, thus generating conjugates 23 and 24, followed by standard chemical manipulations; (b) the construction of a combinatorial library of sarcodictyins by solution and solid-phase chemistry modifying the C-8 ester, C-15 ester, and C-4 ketal functionalities, and, therefore, produci...

Total Synthesis of (+)-Lactacystin from (R)-Glutamate

Abstract: The discovery by dmura' of (+)-lactacystin (1) in Streptomycessp. OM-65 19 and the finding that it possesses neurotrophic activity have created much excitement, since the role of neurotrophic proteins, such as nerve growth factors (NGFs), in diseases is the center of much current interest.2 This substance consists of two a-amino acids, (R)-N-acetylcysteine and a novel pyroglutamic acid derivative 2. The combination of biological activity and the unique structure of lactacystin encouraged us to develop a synthesis which could permit variations of both the substituents and their stereochemistry. During the course of our work two elegant syntheses were r e p ~ r t e d , ~ . ~ which are strategically different from our route. The key reaction in our synthesis involves the stereoselective aldol reaction of a siloxypyrrole, readily available from pyroglutamate, with an aldehyde, thereby assembling the quaternary center and secondary alcohol in the correct stereochemical form, Scheme 1. The bicyclic oxazolidine 3 was prepared from (R)-glutamic acid in three steps (57%)5 and was elaborated to the unsaturated derivative 4 by sequential methylation6 and selenenylation/ozonolysis (65%, Scheme 2). The key siloxypyrrole 5 was obtained as a crystalline solid (89%) by treatment with TBSOTf and 2,6-lutidine.' The aldol reaction of 5 with isobutyraldehyde was achieved at -78 OC in ether in the presence of 2 equiv of SnC14 to afford 68 and its secondary alcohol epimers in the ratio 9: 1. The major isomer 6 was obtained as a crystalline solid after chromatography (55% yield). The surprising *-facial selectivity observed here, i.e., addition to the same face as the phenyl substituent, was revealed by X-ray crystallography of thep-bromobenzoate derivative of er1t-6.~ Use of other Lewis acids and solvents led to the formation of other isomers at the quaternary and secondary alcohol centers,1° thereby permitting access to these substances. Following acetylation 7 was converted to the diol 8 as a single isomer (87%) by osmylation (OsO,, N-methylmorpholine N-oxide). The tertiary hydroxyl group was removed via the cyclic thiocarbonate with Bu3SnH in

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families.

Abstract: Indolosesquiterpenoids are a growing class of natural products that exhibit a wide range of biological activities. Here, we report the total syntheses of xiamycin A and oridamycins A and B, indolosesquiterpenoids isolated from Streptomyces. Two parallel strategies were exploited to forge the carbazole core: 6π-electrocyclization/aromatization and indole C2-H bond activation/Heck annulation. The construction of their trans-decalin motifs relied on two diastereochemically complementary radical cyclization reactions mediated by Ti(III) and Mn(III), respectively. The C23 hydroxyl of oridamycin B was introduced by an sp(3) C-H bond oxidation at a late stage. On the basis of the chemistry developed, the dimeric congener dixiamycin C has been synthesized for the first time. Evaluation of the antiviral activity of these compounds revealed that xiamycin A is a potent agent against herpes simplex virus-1 (HSV-1) in vitro.