Two highly enantio- and diastereoselective one-pot procedures for the synthesis of epoxy alcohols with up to three contiguous stereocenters are reported. Route one involves asymmetric addition of an alkylzinc reagent to an enal followed by diastereoselective epoxidation. Route two entails asymmetric vinylation of an aldehyde with divinylzinc reagents and subsequent diastereoselective epoxidation. The oxidant for the epoxidation is generated by exposure of the allylic alkoxide intermediate and the remaining organozinc reagent to dioxygen. Upon addition of catalytic titanium tetraisopropoxide, the directed epoxidation yields the epoxy alcohols with good to excellent yields.

A regioselective intramolecular Huisgen cycloaddition was performed on various azido alkyne substrates giving rise to macrocyclic triazole rings. Using catalyst control, a common intermediate has been converted to two structurally unique macrocycles with either a 1,5-or a 1,4-triazole resulting in an n or n + 1 ring size. This is the first example of an intramolecular ruthenium-catalyzed Huisgen cycloaddition.The preparation and screening of small molecules constitutes a powerful strategy for the discovery of biological probes and pharmaceutical agents. 1-3 Diversity of structure within a particular compound collection is key to the discovery of hits over a wide range of biological areas. It has recently been shown that even large screening collections that lack diversity are insufficient to provide lead compounds against a range of antibacterial targets. 4 A current strategy for achieving diverse compound collections through diversity-oriented synthesis (DOS) focuses on the use of functional group pairing. 5,6 By using scaffolds with multiple functional group "handles" and joining them in a pairwise, intramolecular, and chemoselective fashion both skeletal diversity and rigidity are achieved. A complementary approach for generating structural diversity is known as "reagent-based" diversification. 7 This strategy involves the preparation of a singular scaffold that, when subjected to different reaction conditions, selectively yields different products. 1,8 To further develop this strategy, robust methodologies that allow for reagent-based differentiation must be developed.The Huisgen 1,3-dipolar cycloaddition is a widely utilized reaction in DOS. 9,10 This `click' reaction results from the ligation of azides and alkynes to give a triazole moiety. This reaction has been shown to be effective in the formation of a variety of macrocyclic rings. 11 A key point of interest for us was the regioselectivity of the cycloaddition. We surmised that a reagentbased diversity approach could be applied to generate both possible regioisomers from a common substrate as shown in Scheme 1. While many advances have been made in the formation of 1,4-triazoles using copper (I) catalysis, 9 the formation of 1,5-triazole rings using ruthenium (II) catalysis has only recently been reported and has been demonstrated in an intermolecular fashion and in a much more limited scope. 10,12 *E-mail: lisa@broad.mit.edu. Supporting Information Available Experimental procedures, compound characterization data and X-ray crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 June 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWith this in mind, we sought to expand the existing Huisgen methodology to make macrocyclic triazole rings regioselectively. This method is ideally suited to the preparation of smallmolecule libraries, because one compound can be converted int...

In this report, we outline a highly enantio- and diastereoselective one-pot method for the efficient synthesis of synthetically useful acyclic epoxy alcohols and allylic epoxy alcohols. Our method takes advantage of a highly enantioselective C-C bond-forming reaction to set the initial chirality. The resulting allylic zinc alkoxide intermediate is then epoxidized in situ using either dioxygen or TBHP in the presence of a titanium tetraalkoxide. Epoxy alcohols with up to three contiguous stereocenters are formed in one pot with excellent enantio- and diastereoselectivity. In cases where the zinc alkoxide intermediates contain two different allylic olefins, the more electron-rich double bond is chemoselectively epoxidized to afford an allylic epoxy alcohol. This method represents a highly efficient, stereoselective, and chemoselective approach to the synthesis of a wide range of useful epoxy alcohol and allylic epoxy alcohol products that were previously difficult to access.

Furans and pyrroles are important synthons in chemical synthesis and are commonly found in natural products, pharmaceutical agents, and materials. Introduced herein are three methods to prepare 2-substituted 3-furfurals starting from 3-furfural, 3-bromofuran, and 3-vinylfurans. Addition of a variety of organolithium, Grignard, and organozinc reagents (M-R) to 3-furfural provides 3-furyl alcohols in high yields. Treatment of these intermediates with NBS initiates a novel oxidative rearrangement that results in the installation of the R group in the 2 position of the 2-substituted 3-furfurals. Likewise, metalation of 3-bromofuran with n-BuLi and addition to benzaldehyde provides a furyl alcohol that is converted to 2-phenyl 3-furfural upon oxidative rearrangement. Enantioenriched disubstituted furans can be prepared starting with the Sharpless asymmetric dihydroxylation of 3-vinylfurans. The resulting enantioenriched diols undergo the oxidative rearrangement to furnish enantioenriched 2-substituted 3-furfurals with excellent transfer of asymmetry. This later method has been applied to the enantioselective preparation of an intermediate in Honda's synthesis of the natural product (-)-canadensolide. Mechanistic studies involving deuterium-labeled furyl alcohol suggest that the oxidative rearrangement proceeds through an unsaturated 1,4-dialdehyde intermediate. The alcohol then cyclizes onto an aldehyde, resulting in the elimination of water and rearomatization. On the basis of this proposed mechanism, we found that 3-furyl imines undergo the addition of organometallic reagents to provide furyl sulfonamides. Under the oxidative rearrangement conditions, 2-substituted 3-formyl pyrroles are formed, providing a novel route to these heterocycles. In contrast to the metalation of heterocycles, which often lead to mixtures of regioisomeric products, these new oxidative rearrangements of furyl alcohols and furyl sulfonamides generate only one regioisomer in each case.

Enantioenriched pyranones are important intermediates in the synthesis of natural products and the generation of compound libraries. A one-pot method for their synthesis is outlined. Catalytic asymmetric alkylation of 2-furfurals in the presence of catalytic (−)-MIB generates enantioenriched furyl zinc alkoxides. Addition of water/THF followed by NBS results in formation of pyranones with ee's >90% and yields between 46-77%.Advances in organic synthesis enable chemists to prepare most natural product targets. Even with state of the art methods, however, syntheses often require many synthetic manipulations and purifications, resulting in low overall yields and generation of large amounts of chemical waste. To address these issues, increasing synthetic efficiency and reducing E-factors (which is defined as the ratio of the mass of waste produced to the mass of product), are becoming more important in designing synthetic routes. 1 One approach to streamline organic synthesis is through tandem and sequential reactions that accomplish multiple steps in a single flask and minimize isolations, purifications, and solvent use.Herein, we present a one-pot method to prepare enantioenriched pyranones from 2-furfurals. Pyranones are valuable building blocks that have been extensively used in natural product 2, 3,4,5 and diversity oriented syntheses. 6 6-Hydroxy-(2H)-pyran-3-ones are typically prepared by the oxidative rearrangement of furyl alcohols in the Achmatowicz reaction. 7 Key intermediates in the Achmatowicz reaction are illustrated in Scheme 1. An example of the Achmatowicz reaction in the synthesis of (−)-8a-epi-swainsonine 2 by O'Doherty is shown in Scheme 2.The most popular approach to enantioenriched pyranones has relied on kinetic resolution (KR) of racemic furyl alcohols, 8 as illustrated in Fürstner's elegant synthesis of ipomoeassian E (Scheme 3). 9 Upon treatment of the racemic furyl alcohol under KR conditions with the Sharpless-Katsuki catalyst and TBHP, the matched enantiomer underwent the Achmatowicz reaction to generate the optically active pyranone. The unreacted enantiomerically enriched furyl alcohol was then isolated in 47% yield (>99% ee) and subjected to a second Achmatowicz reaction. 9Correspondence to: Patrick J. Walsh. Supporting Information Available Procedures and full characterization are available (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. In a KR, the product ee decreases with rising conversion while the starting material ee increases. 11 Thus, unless the KR selectivity factor (=k fast /k slow ) is very large, it is always the enantioenriched starting material that is carried forward. NIH Public AccessOur approach to enantioenriched pyranones is based on our enantioselective carbonyl addition/ epoxidation (Scheme 4). 12 These one-pot transformations generate epoxy alcohols with three contiguous stereogenic centers with high enantio-and diastereoselectivity. In applying this approach to the synthesis of enantioenriched pyranones, we fo...