Pan,"Direct Stereoselective Total Synthesis of (±)-Seychellene,"

Given the efficiency of the ARC Type II multi-component process employing linchpins (-)-66, 80, 81, and 86 in conjunction with the iterative use of these linchpins, we are confident that this protocol will find extensive use in diversity-oriented synthesis (DOS) of a wide variety of “natural product-like” chemical entities (vide infra).

Choe,"Total Synthesis of Cyclophellitol and(1

Chem. 2004, 116, 4623-4626;

Strychnine total synthesis in chemistry ..

To illustrate the Type II ARC tactic in complex molecule synthesis, we first took on a modest challenge, the construction of a gorgonian sesquiterpene (-)-111 (), that possesses modest cytotoxicity against a variety of human cancer cell lines [IC50 values (mg/mL): 5.0 for A-549 (human lung carcinoma, 5.0 for HT-29 (human colon carcinoma, and 5.0 for MEL-28 (human melanoma)]. At the time the absolute configuration of (-)-111 had not been defined. Particularly attractive was the possibility of assembling the complete carbon skeleton of the sesquiterpene in a single Type II multi-component ARC reaction.

Rearrangements in Total Synthesis 3 1.1 ..

We have recently validated the power of the Type II multi-component ARC tactic both in complex molecule synthesis and in diversity oriented synthesis. Two synthetic and one DOS example from our laboratory will be presented.

Su, "Total Synthesis of Bao Gong Teng A, aNatural Antiglaucoma Compound,"
Fahr, "TotalSynthesis of the Cytotoxic MarineNatural Product, Aplysiapyranoid C,"

Enantioselective Total Synthesis of Convolutamydines B and E , ..

Related multi-component relay tactics, employing 2-trimethylsilyl-1,3-dithiane (4) as a progenitor of anionic linchpins, were disclosed independently in 1994 by the Tietze and Schaumann groups (). In the first example, one equivalent of 4 with 2.2 equivalents of enantiopure epoxide (-)-2a (R=Ph or Me) efficiently furnished homocoupled 1,5-diols (-)-6 and (+)-7 in 65 and 89% yield, respectively. Timing of the Brook rearrangement however proved elusive. As a result only C2 symmetric (i.e., homocoupled) products were possible. This limitation restricts the utility of the Tietze reaction in multi-component sequences to symmetrical systems (vide infra). Schaumann elegantly implemented a dual-functionalized epoxide coupling partner (7) that upon nucleophilic addition by linchpin 4, promoted silicon migration and concominant ring closure to provide cyclopentanol 8 in good yield.

Li, "Total Synthesisof the Epoxy Isoprostane Phospholipids PEIPC and PECPC,"

5C404 : Synthesis of natural and bioactive products ..

The introduction of iversity-riented ynthesis (DOS) during the past decade has provided the biology and biomedical communities with access to libraries of structurally diverse compounds for high-throughput screening (HTS) campaigns to define lead structures for both the development of biologically useful probe molecules and lead structures in drug development. However, many of the libraries employed today, both in academia and the pharmaceutical industry, do not incorporate compounds with the rich, three dimensional shape characteristics of most natural products, in spite of the fact that greater than 70% of the currently marketed drugs have their origins in natural products. It is here that we believe multi-component anion relay chemistry may hold the greatest potential, especially employing the iterative manifold. The ability to readily construct highly functionalized three dimensional carbon scaffolds in an efficient manner, exploiting the Type I and II ARC protocols, presents the chemist with great potential to enhance both the large high throughput screening and smaller focused libraries. That is, by rational design of the individual nucleophiles, linchpins and electrophile (), hosting a wider variety of reactive functional groups, such as well positioned carboxylic acids, hydroxy or amino groups, and/or olefins, capable of activation and further elaboration (i.e., macrolactonization, macrolactamization, RCM, etc.) should permit access to a diverse supply of architecturally interesting “natural product-like” compounds.

Total Synthesis of L-threo Sphingosine and Safingol,”  2012, , 4216-4220.

Short Enantioselective Total Synthesis of Tatanan A and 3 ..

The ARC Type II multi-component process proceeded as anticipated. For example, reaction of (+)-66 with a variety of alkyl- and phenyl trialkylsilyldithiane anions as initiating nucleophiles, followed by Brook rearrangement (O→sp3 migration) and capture of the resultant anion with a series of primary epoxides, as well as reactive alkyl, allyl and benzyl halides furnished tri-component adducts 67-71 in good to excellent yields. Particularly interesting was use of epichlorohydrin as the second eletrophile to furnish 68 (; Entry 3), possessing a new electrophilic epoxide site for potential further diversification with a variety of nucleophiles.