An aldol-based ‘build/couple/pair’ (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti- aldol reactions were performed to produce four stereoisomers of a Boc protected γ-amino acid. In addition both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes, namely: nucleophilic aromatic substitution (SNAr), Huisgen [3+2] cycloaddition and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on solid-phase to yield a 14,400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships (SSAR) was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.

[reaction: see text] The title technique is a convenient and powerful method for directly monitoring or assaying any reaction mixture or reagent solution. Examples of some common processes (Fischer esterification, lithiation, butyllithium/THF compatibility, olefin metathesis, and a quantification assay), each interrogated in its native solvent, are presented. The spectral data are easy to acquire, and the information content makes a compelling case for routine use of No-D NMR spectroscopy.

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The two-step functionalization of 30,000 SynPhase Polystyrene (PS) Lanterns in a 30-L glass process reactor is described. The first step involves bromination of the polystyrene backbone to afford an aryl bromide handle. Subsequent Suzuki cross coupling with the trialkylborane generated in situ from the reaction of allyldiisopropyl(4-methoxyphenyl)silane and 9-BBN provided an alkylsilyl linker ready for loading of various alcohols for solid-phase synthesis applications.

The concentration of reactive metal hydride (Met-H) reducing agents can be determined (in < or = 20 min) using No-D NMR spectroscopy. The method involves (i) reacting Met-H with an excess of p-methoxybenzaldehyde, (ii) quenching with excess acetic acid, (iii) recording the No-D NMR spectrum of this homogeneous mixture, and (iv) deducing the concentration of Met-H from the % conversion (as measured by integration). By a conceptually related method, the titer of the basic alkali metal hydrides KH and NaH can also be determined.

A procedure is described for the in situ generation of functional equivalents of glutaric, succinic, and malonic dialdehydes. DIBAL-H reduction of the corresponding 1,n-dioates followed by in situ addition of a nucleophilic trapping agent allows for one-pot, bidirectional homologation. Olefination and Grignard addition classes of reactions are specifically demonstrated.The two aldehyde groups in 1,n-dials, especially those of the succinic and glutaric families (1, Figure 1), are notorious for their tendencies to engage one another through intramolecular reaction. This phenomenon influences reactivity at the second aldehyde, a requirement for symmetrical chain elongation. Internal hydrate formation (see 2, Figure 1) or addition of a nucleophilic species (Nu -) to one of the free aldehydes and subsequent intramolecular adduct formation with the second (cf., 3, Figure 1) are common examples of this situation. One strategy for circumventing these problems is to expose the two aldehyde functional groups sequentially, rather than in parallel. While this is cumbersome and inefficient if it requires protecting group or oxidation-state differentiation of the two termini (i.e., multiple manipulations), a viable in situ release of each aldehyde in the presence of a suitable trapping nucleophile would not suffer from these drawbacks. Figure 1We recently encountered the need to chain extend, in a symmetrical fashion, various 3-oxygenated glutaraldehydes. With that and the above issues in mind, we considered whether a one-pot reduction-addition reaction sequence would provide a solution. In particular, we planned for an a,w-diester 4 to be treated sequentially and at low temperature first, with two equivalents of diisobutylaluminum hydride (DIBAL-H) and second, with an excess of a compatible trapping nucleophile (Nu-Met). Species 5 (Scheme 1) contains a pair of tetrahedral intermediates, which we envisioned collapsing to aldehydes, upon warming, at different moments in time. If each reactive aldehyde, once exposed, was rapidly trapped by NuMet, then species 7 would arise via 6 without the intervention of 1 or 2 (and the associated issues). Previous reports in which simple monoesters have been subjected to DIBAL-H/Horner-Emmons, 1 DIBAL-H/Mukaiyama aldol, 2 DIBAL-H/Grignard, 3 and LiBH 4 /Grignard 4 tandem reactions, provided precedent. Here we report results that demonstrate this strategy. Scheme 1We chose to study (Scheme 2) double Horner-Emmons (4 → 10) and double Grignard additions (4 → 11) using phosphonates 8 and allylmagnesium chloride (9) as representative trapping nucleophiles, Nu-Met. Scheme 2 R 1

The highly cytotoxic marine macrolide (+)-peloruside A (1) was isolated from the New Zealand sponge Mycale hentscheli by Northcote and co-workers. [1] It showed LD 50 values ranging from 6-18 nm toward H441, SH-SY5Y, and P388 cancer cell lines, [2] and has been additionally explored from a preclinical perspective. Like paclitaxel (Taxol), peloruside A is a microtubule stabilizer that arrests cells in the G2 M phase of the cell cycle, but it targets a different tubulin binding site relative to paclitaxel. [3] As a consequence peloruside A (1) is a candidate for use against paclitaxel-resistant cell lines. [4] The therapeutic potential, low natural abundance (3 mg/170 g wet sponge), and architectural complexity have generated significant interest in the development of chemical syntheses of 1. To date, four total syntheses of peloruside A have been reported by the research groups of De Brabander, Taylor, Ghosh, and Evans, [5][6][7][8] and related synthetic studies have been described. [9][10][11] Our interest in peloruside A (1) as a target was greatly heightened when we identified a plan that seemed ideally matched with strategies and technologies developed earlier in our group. In particular, it was attractive to apply a diastereoselective kinetic lactonization of a pseudosymmetric azelaic acid derivative [12] and to capitalize on the versatility of relay ring-closing metathesis (RRCM) [13] reactions.As summarized in Scheme 1 our plan for the synthesis was to effect a late-stage aldol coupling (path a) between the aldehyde acceptor 2 and methyl ketone donor 3 (or the complementary ketone/aldehyde pair 2'/3'). We planned to install the Z-trisubstituted and doubly allylically branched D 16,17 -alkene in 3 (or its aldehyde analogue 3') through RRCM (path b) of the silaketal [14] 5 a or ester [15] 5 b (peloruside A skeleton numbering is used throughout). We envisioned the main aldehyde fragment 2 (or its ketone analogue 2') to arise from the C 2 -symmetric azelaic ester precursor 4 (path c). As detailed below, reduction of the C5 ketone in 4 from either of its homotopic faces would give an alcohol that, through engagement of its pro-S rather than pro-R diastereotopic ester group, would selectively provide a valerolactone/monoester (i.e., 11 in Scheme 2). [16] Terminus differentiation and C9 À C10 bond formation would then provide access to 2 (or 2').The synthesis of fragment 2 is presented in Scheme 2. The main features are: 1) synthesis of the C 2 -symmetric ketodiester 4, 2) diastereoselective conversion, by desymmetrizing kinetic lactonization, of the derived alcohol 9 into the d-valerolactone 11, and 3) chemoselective elaboration (including prenylation) of the lactone versus ester carbonyl groups (C9 versus C1) in 11 to give fragment 2.The tetrol 7 was prepared from the ethylene ketal of dimethyl acetone dicarboxylate (6) [17] by utilizing a one-pot DIBAL-H reduction of both esters to give the intermediate 1,5-dialdehyde, and subsequent in situ double Horner-Wadsworth-Emmons homologation with (EtO) 2 P(O)CH-(Na)C...

A strategy has been developed in which mechanistically distinct lactonization reactions are used to prepare diastereomeric delta-lactones relevant to the C1-C9 fragment of (+)-peloruside A. Depending upon which of two reaction types is used, the central (C5) hydroxyl group can be directed to differentiate the C1 versus C9 termini of pseudosymmetric substrates to provide diastereomeric lactones. Thus, the 5-hydroxy-1,9-diester substrate 1 (an azelaic ester) cyclizes under classical (acid- or base-catalyzed) lactonization conditions to give a predominance of one diastereomer, whereas the 5-hydroxy-1,10-diene congener 2 provides the opposite sense of diastereoselectivity when subjected to ozonolytic lactonization (O3, MeOH, NaOH, at -78 degrees C). Thus, this under-utilized oxidative transformation is mechanistically orthogonal to the classical reaction.