In the past two decades, alkene metathesis has risen in prominence to become a significant synthetic strategy for alkene formation. Many total syntheses of natural products have used this transformation. We review the use, from 2003 to 2015, of ring-closing alkene metathesis (RCM) for the generation of dihydrofurans or -pyrans in natural product synthesis. The strategies used to assemble the RCM precursors and the subsequent use of the newly formed unsaturation will also be highlighted and placed in context.

Redox reactions catalyzed by highly selective nicotinamide-dependent oxidoreductases are rising to prominence in industry. The cost of nicotinamide adenine dinucleotide coenzymes has led to the use of well-established elaborate regeneration systems and more recently alternative synthetic biomimetic cofactors. These biomimetics are highly attractive to use with ketoreductases for asymmetric catalysis. In this work, we show that the commonly studied cofactor analogue 1-benzyl-1,4-dihydronicotinamide (BNAH) can be used with alcohol dehydrogenases (ADHs) under certain conditions. First, we carried out the rhodium-catalyzed recycling of BNAH with horse liver ADH (HLADH), observing enantioenriched product only with unpurified enzyme. Then, a series of cell-free extracts and purified ketoreductases were screened with BNAH. The use of unpurified enzyme led to product formation, whereas upon dialysis or further purification no product was observed. Several other biomimetics were screened with various ADHs and showed no or very low activity, but also no inhibition. BNAH as a hydride source was shown to directly reduce nicotinamide adenine dinucleotide (NAD) to NADH. A formate dehydrogenase could also mediate the reduction of NAD from BNAH. BNAH was established to show no or very low activity with ADHs and could be used as a hydride donor to recycle NADH.Catalysts 2019, 9, 207 2 of 11 or aldehydes to the corresponding (enantioenriched) alcohols through the use of one equivalent of nicotinamide adenine dinucleotide cofactor NAD(P). ADHs are known to be specific to either the phosphorylated NADP or non-phosphorylated NAD, although a few have been found to accept both [1-3]. These cofactors act as hydride acceptor and donor intermediates between the substrate and product.Enzyme recognition of NAD(P), usually by a cofactor (binding) motif such as the Rossmann fold, is important for cellular processes, however when using in vitro systems, the adenine dinucleotide moiety of the cofactor becomes obsolete and disadvantageous, being prone to hydrolysis [4]. Synthetic nicotinamide coenzyme biomimetics (NCBs) have been shown to replace NAD(P)H in flavin-dependent enzymes such as nitroreductase and NAD(P)H quinone oxidoreductase [5-7], a cytochrome P450 BM3 variant [8], ene-reductases [9][10][11][12][13][14][15][16], and styrene monooxygenase [17]. In all cases described, a flavin was involved as an electron mediator [18][19][20][21][22].Jones pioneered the use of synthetic cofactor analogues with horse liver ADH (HLADH) [23][24][25][26], followed by Fish [27] and others [28,29]. A dehydrogenase from the aldo-reductase superfamily from Pyrococcus furiosus (AdhD) was engineered to increase catalytic efficiency towards nicotinamide mononucleotide (NMN, Figure 1A) [30,31]. Acyclic analogues of NAD ( Figure 1B) were shown not only to be used with HLADH, but also to alter the substrate specificity of the enzyme [32]. More recently, the group of Sieber showed the use of synthetic NCBs with an NADH oxidase [33,34], and a glucose dehydrogenase...

The sodium salts E-15 and Z-15 of the originally proposed dihydropyran acid structure of aruncin B (1) were prepared through ring-closing alkene metathesis (RCM) and ethoxyselenation-selenoxide elimination, but acid sensitivity of these salts, together with inconsistencies in the spectral data, suggested a significant structural misassignment. A β-iodo Morita-Baylis-Hillman reaction to give Z-iodo ester 24, followed by Sonogashira cross-coupling-5-exo-dig lactonization, provided concise access to a Z-γ-alkylidenebutenolide 18, which possessed data corresponding to those originally reported for aruncin B.

Herein, we describe a stereodivergent route to (±)-batzelladine D (2), (+)-batzelladine D (2), (−)-batzelladine D (2), and a series of stereochemical analogues and explore their antimicrobial activity for the first time. The concise synthetic approach enables access to the natural products in a sequence of 8–12 steps from readily available building blocks. Highlights of the synthetic strategy include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton, and a modular strategy that enables analogue generation. A key bicyclic β-lactam intermediate not only serves as the key controlling element for pyrrolidine stereochemistry but also serves as a preactivated coupling partner to install the ester side chain. The stereocontrolled synthesis allowed for the investigation of the antimicrobial activity of batzelladine D, demonstrating promising activity that is more potent for non-natural stereoisomers.