Matthew Brichacek

Creative approaches towards the synthesis of 2,5-dihydro- furans, thiophenes, and pyrroles. One method does not fit all!

A single method is never sufficient, which is why there is a great need for developing many diverse and creative approaches towards every chemical substrate class. This statement is supported by the contents of this perspective in addition to providing the reader with a helpful synthetic roadmap for selecting a suitable method for the building blocks being discussed. Detailed in this review are eight different synthetic approaches that provide access to valuable 2,5-dihydro- furan, thiophene and pyrrole building blocks. Each approach is briefly presented and its limits discussed. The strengths and weaknesses of each approach are further highlighted with a graphical table summary at the end. This summary clearly drives home the point that for every chemical substrate class we need many good methods in order to provide access to every member of each class.

Lewis Acid Catalyzed [1,3]-Sigmatropic Rearrangement of Vinyl Aziridines

This paper details the copper-catalyzed ring expansion of vinyl aziridines to 3-pyrrolines. Broad substrate scope (24 examples) using tosyl- and phthalimide-protected vinyl aziridine substrates is observed. Cu(hfacac)2 was determined to be superior to all other catalysts tested.

Stereospecific Ring Expansion of Chiral Vinyl Aziridines

In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis- or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.

Stereoselective ring expansion of vinyl oxiranes: mechanistic insights and natural product total synthesis.

The central part of our research program is the development of broadly applicable atom-efficient synthetic methods to generate structural complexity. We recently reported a new copper-catalyzed ring expansion of vinyl oxiranes using commercially available, structurally simple, and air-stable copper(II) catalysts. These studies demonstrated the success of this reaction for a broad range of substrates. Missing from these early studies were experiments focused on assessing the stereoselective potential of the ring expansion. The studies presented herein are aimed at addressing this point to learn if the oxirane C O bond, which is broken during the ring expansion, could be stereoselectively transferred to the olefin terminus. Moreover, an added benefit to the proposed studies would be critical mechanistic insights that could shed additional light on the exact mechanism of this unique catalytic ring-expansion reaction. If vinyl oxiranes can indeed be stereoselectively ring expanded using copper catalysts then the practical benefits of this new reaction would be significantly expanded. Also this transformation would rival existing methods to stereoselectively access 2,5-dihydrofurans in terms of efficiency and scope. Our studies have focused on disubstituted vinyl oxirane substrates (Scheme 1), which depending on their stereochemistry and olefin geometry could serve as precursors for accessing either a 2,5-cisor a 2,5-trans-substituted 2,5dihydrofuran product. In the case of a stereoselective ring expansion, vinyl oxiranes 3 and 4 would be expected to afford the cis product 1. whereas 5 and 6 should afford the trans product 2. When these substrates are ranked with respect to steric crowding during formation of the new C O bond, vinyl oxiranes 3 and 5 emerge as more suitable precursors for accessing the 2,5-cisand 2,5-trans-dihydrofuran products, respectively. Therefore we synthesized vinyl oxiranes 7 and 8, which differ only in the oxirane stereochemistry (transor cissubstituted oxiranes). Ring expansion of these two substrates afforded the symmetrically substituted cisand trans-dihydrofurans 9 and 10 (Table 1). Under the standard reaction conditions used in our previous paper (Table 1, entries 2 and

Synthesis of Dimeric Adp-Ribose and its Structure with Human Poly(Adp-Ribose) Glycohydrolase.

Poly(ADP-ribosyl)ation is a common post-translational modification that mediates a wide variety of cellular processes including DNA damage repair, chromatin regulation, transcription, and apoptosis. The difficulty associated with accessing poly(ADP-ribose) (PAR) in a homogeneous form has been an impediment to understanding the interactions of PAR with poly(ADP-ribose) glycohydrolase (PARG) and other binding proteins. Here we describe the chemical synthesis of the ADP-ribose dimer, and we use this compound to obtain the first human PARG substrate-enzyme cocrystal structure. Chemical synthesis of PAR is an attractive alternative to traditional enzymatic synthesis and fractionation, allowing access to products such as dimeric ADP-ribose, which has been detected but never isolated from natural sources. Additionally, we describe the synthesis of an alkynylated dimer and demonstrate that this compound can be used to synthesize PAR probes including biotin and fluorophore-labeled compounds. The fluorescently labeled ADP-ribose dimer was then utilized in a general fluorescence polarization-based PAR-protein binding assay. Finally, we use intermediates of our synthesis to access various PAR fragments, and evaluation of these compounds as substrates for PARG reveals the minimal features for substrate recognition and enzymatic cleavage. Homogeneous PAR oligomers and unnatural variants produced from chemical synthesis will allow for further detailed structural and biochemical studies on the interaction of PAR with its many protein binding partners.

An Efficient Substrate‐Controlled Approach Towards Hypoestoxide, a Member of a Family of Diterpenoid Natural Products with an Inside‐Out [9.3.1]Bicyclic Core

for generations, to treat various skin rashes and infections. Hypoestoxide has been shown in recent studies to exhibit promising anticancer, antimalarial, and anti-inflammatory activity. Our interest stems primarily from encouraging antiangiogenic activities, in which hypoestoxide was shown to inhibit the growth of a number of human and murine tumor cell lines in vivo. In terms of angiogenesis, hypoestoxide inhibited vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Hypoestoxide is a bicyclo[9.3.1]pentadecane diterpenoid containing a rigid “inside–outside” ring system decorated with an exocyclic enone, two epoxide moieties, and an acetate group. This rare ring system has also been described for the verticillanes, of which verticillol (3, Scheme 1) is the most well known. As a more oxygenated variant of verticillol, it is tempting to propose that hypoestoxide is formed from the same common cationic precursor (5) as both verticillol and taxol (4), which in turn originates from consecutive cyclizations of geranylgeranyl pyrophosphate. In the case of verticillol, the cation 5 is trapped with water, whereas, for taxol and hypoestoxide, it undergoes endocyclic and exocyclic eliminations, followed by oxygenations and cyclizations. As part of our efforts to evaluate the molecular mechanisms of promising natural product anticancer agents we have focused our investigations on hypoestoxide and the verticillanes. Several factors needed to be considered before beginning our synthetic efforts. First, for a trans-[9.3.1]bicyclic framework, two different atropisomers are possible. Calculations (B3LYP/6-311 + G(d,p)) indicated that hypoestoxide is 4.1 kcalmol 1 more stable than the atropisomer (2). Therefore, we imagined that any such macrocyclization would preferentially form the naturally occurring atropisomer. In addition, the energy change attributed to the process of interconverting hypoestoxide and the atropisomer was estimated to be 65 kcal mol . Diene 6 seemed an ideal target because it allows access to all known verticillanes, and we attempted its synthesis using a conformationally controlled ring-closing metathesis (Scheme 2). This diene provides four

An efficient oxidative dearomatization–radical cyclization approach to symmetrically substituted bicyclic guttiferone natural products

Detailed in this communication is an efficient synthetic approach towards the guttiferone family of natural products. Oxidatively unraveling a para-quinone monoketal followed by consecutive 5-exo radical cyclizations provides the bicyclic core. An additional strength of this approach is a late stage asymmetric desymmetrization of an advanced symmetric intermediate.

Efficient Synthesis of Thiopyrans Using a Sulfur‐Enabled Anionic Cascade

Sulfur is the fifth most important element, following carbon, hydrogen, oxygen, and nitrogen, in the context of biological significance and representation in important natural and nonnatural constructs. Its unique properties also make it one of the most chemically versatile of the early elements. For example, sulfur compounds are: 1) great nucleophiles; 2) readily reduced and oxidized; 3) good at stabilizing carbanions and carbocations; 4) a source of useful ylide and umpolung chemistry; 5) of great utility in radical chemistry; 6) able to be chiral at sulfur; 7) found in the cores of important chiral auxiliaries, and 8) the key enabling element for more than twenty name reactions in organic chemistry. In terms of pharmaceuticals, sulfur is solidly the most significant and successful element following the four key elements of life (C, H, N, and O), with seven of the ten bestselling pharmaceuticals worldwide containing sulfur. As a part of our program focused on the development of new useful synthetic transformations involving sulfur as the central element, we report a new anionic cascade that provides convergent access to thiopyran products in a single pot from simple starting materials (Scheme 1). The inspiration for the design of this new reaction originated from a desire to extend our ring expansion investigations to include vinyl thietanes, which we envisioned could be converted into a thiopyran upon treatment with a metal catalyst. Intrigued by the simple and convergent thiirane synthetic approach we had utilized for our formal synthesis of biotin, we postulated that the thiopyran constructs could possibly be accessed in a single step from an appropriately functionalized carbonyl construct containing a thiol group at the b position instead of a ring expansion path. This new one-pot anionic cascade would be initiated upon addition of a vinyl nucleophile to the carbonyl group, at which point the substitutent on sulfur migrates to the newly formed alkoxide, thus forming a new leaving group and a thiolate nucleophile. Ketones and esters were expected to be the most suitable substrates for this new anionic cascade. Tertiary substitution of the alkoxide, formed by coupling the two carbon fragments together, was expected to ensure preference for the desired 6-endo cyclization pathway over the competing 4-exo pathway. The most critical part of the reaction design was the nature of the thiol substitutent (XYZ; Scheme 1). A suitable substitutent would be required to 1) survive the addition of the carbon nucleophile, 2) readily transfer from sulfur to the alkoxide, and 3) transform the alkoxide into a good leaving group. Literature precedents suggested three structural frameworks that might fit our criteria: 1) thiocarbonateor xanthate-type acyl groups, 2) thio-substituted heterocycles, or 3) phosphates. Phosphates were chosen as the group to study the feasibility of the anionic cascade because of their ease of substrate synthesis, stability toward carbon nucleophiles, and leaving group ability (Z = P, Y= OR and X = O or S; Scheme 1). To test our hypothesis, we chose to explore the addition of vinyl nucleophiles to the aryl ketone thiophosphate 1 (Table 1). The addition product would afford a tertiary alkoxide, which would then undergo a migration of the thiophosphate to form a thiolate nucleophile, which we expected would favor the 6-endo cyclization pathway. Vinyl Grignard addition to the aryl ketone 1 proceeded well to form 2 without interference from the thiophosphate group. Interestingly, in tetrahydrofuran with magnesium as the alkoxide counterion, the expected in situ anionic cascade to form 3 or 4 did not take place. Instead, the corresponding alcohol was isolated (entry 1). Presumably the magnesium counterion impedes thiophosphate transfer to the alkoxide. However, treatment of the corresponding alcohol with an alkoxide base or sodium hydride resulted in a facile cyclization, which afforded the thiopyran 3 as the major product following an acidic workup. We postulated that an alkali metal alkoxide additive might exchange out the magnesium in situ and allow the proposed anionic cascade to proceed in one pot (Table 1, entries 2–13). After screening lithium, sodium, and potassium alkoxides in methanol, ethanol, 2-propanol, or tertbutanol, it became clear that adding potassium tert-butoxide Scheme 1. One-pot anionic cascade route to thiopyrans.

Dihydropyran as a Template for Lactone Synthesis

Abstract 3,4‐Dihydro‐2H‐pyran (DHP) was efficiently transformed into 4‐thiophenyl‐3,4‐dihydro‐2H‐pyran. This intermediate was converted to the corresponding 1,3‐O,S‐allylic carbanion with t‐butyllithium and selectively alkylated at the carbon α to the sulfur with alkyl halides, an epoxide, and an aldehyde. An one‐pot oxidative elimination of the sulfur fragment using vanadium pentoxide generates the desired β‐substituted α,β‐unsaturated δ‐valero lactone.