Trisubstituted macrocyclic

As recently demonstrated by Furstner and Langemann, higher yields of the disubstituted olefin 83 can be obtained under high dilution conditions using la as the catalyst. Our experiments clearly illustrate that synthesis of trisubstituted macrocyclic alkenes is more complicated than that of their disubstituted analogues. See Furstner A, Langemann K (1996) J Org Chem 61 3942... 

A methodology to access trisubstituted macrocyclic ( )- and (Z)-alkenes from ring-closing metathesis (RCM) has been described. The strategy employs a substrate controlled RCM reaction of linear vinylsiloxanes to generate macrocyclic ( )-alkenyl siloxanes selectively. Conditions were developed to convert the alkenyl siloxane products into alkenyl halides with retention or inversion of configuration of the alkene geometry. 

Based on information accrued during the stereochemical elucidation, macrolactone 85 was identified as a viable synthetic intermediate (Scheme 12). The authors were cognizant of the potential challenges that could arise. First, the required formation of a trisubstituted alkene in a projected Horner-Emmons macrocyclization was without strong precedent. Also, this strategy would necessitate a stereoselective reduction of the Cl5 ketone, which was predicted to be feasible based on MM2 calculations. 

The acid-catalyzed addition of aliphatic ketones to 2,3,4- or 2,3,5-trisubstituted pyrroles generally produces bispyrrolylalkanes, analogous in structure to the products of the corresponding reactions with aldehydes, whereas 2,5-disubstituted pyrroles react with acetone to form a 2 3 adduct (113). Pyrrole and 3,4-disubstituted pyrroles react with aliphatic ketones to give porphyrinogens (114), which, unlike the macrocycles obtained from the... 

Confalone and Ko have reported formation of the macrocyclic INOC product (104) in 30% yield from cyclization of an aryl-bridged nitrotriene containing a 17-atom intervening bridge.48 Cyclization to the conjugated diene system did not occur, presumably because of geometric constraints and the fact that the more accessible double bond is trisubstituted. Isoxazoline (104) is a potential maytansine precursor. 

The polyhomologation of 1-boraadamantane THF by dimethylsulfoxonium methylide formed a series of new macrocyclic trialkylboranes 24, oxidation generated a three-armed star polymethylenic polymer, based on a c/s,m-l,3,5-trisubstituted cyclohexane core <03JA12179>. 

Amythiamicin D was the first in the family to be synthesized. The 2,3,6-trisubstituted pyridine core was synthesized from serine-derived l-alkoxy-2-azadienes and thiazoyl enamide dienophiles ultilizing a biosynthesis-inspired hetero-Diels-Alder route under MW irradiation. After successive incorporation of glycine and bis-thiazole fragments, amythismicin D was obtained by macrocyclization <2005JA15644, 2004CC946>. 

GE2270A 394 is an antibiotic produced by Planobispora rosea ATCC 537731. It inhibits Gram-positive bacteria and anaerobes by acting on the protein synthesis elongation factor (EF) <1991JAN693, 1995T4867>. It contains proline, serine, glycine, two thiazolyl amino acids, and a heterocyclic centerpiece of a trisubstituted pyridine, all in a macrocyclic array. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

One of the analogues of FK506, rapamycin (sirolimus) produced by Strepto-myces hygroscopicus, is a 31-membered macrocyclic lactone that contains a masked a- and P-diketo amide L-pipecolic acid residue similar to that found in FK506, and a unique triene segment including a distinctive shikimic acid-derived trisubstituted cyclohexane moiety (Fig. 1) [19]. It was originally isolated as an... 

The possibility of using 2,6-disubstituted pyridines and 2,6,7-trisubstituted quinuclidines, where the substituents feature remote atoms with lone pairs to stabilize the hydrogen upon protonation, are proposed snperbases that have been explored by computational approaches. There is interest in synthesizing macrocyclic proton chelaters as catalytically active organic snperbases,and a new strnctnral motif for snperbases featuring caged secondary amines has been reported. The alkali metal hydroxides, of eqnal basicity in aqueous solution, have proton affinities in the order LiOH (1000 kJ/mol) < NaOH < KOH < CsOH (1118 kJ/mol). This order matches the increasing ionic character of the alkah metal-hydroxide bonds. 

Several features of this reaction are worth further consideration. First, one should recognize that although the then-available ruthenium alkylidenes such as 12 and 13 have a level of functional group tolerance compatible with 23, their reactivity as metathesis catalysts has, in general, proven too low for them to effect the formation of macrocyclic trisubstituted olefins. Accordingly, at the... 

This idea is presented more formally in Scheme 5 with the thought that five of the six rings of the target molecule and seven of its stereocenters (as expressed in 34) could arise from a polyunsaturated precursor (30) through a series of two cycloaddition reactions and a macrocyclization event. For instance, if 30 initially participated in a Type I intramolecular Diels—Alder reaction with endo selectivity to afford 32, a subsequent intramolecular condensation of the Knoe-venagel type could then provide 33, a substrate poised for an intramolecular transannular hetero-Diels—Alder reaction between its electron-poor enone system and the proximal trisubstituted double... 

The retrosynthetic analysis is outlined in Scheme 22. The amide was introduced by the Curtius rearrangement, and the macrolide 117 was formed by Horner-Emmons macrocyclization at the C2-C3 bond. The C17-C18 bond was constructed by the ring-opening of epoxide 118. 119 was formed via the Kocienski-Julia olefination at the C8-C9 bond. The cis-2,6-disubstituted tetrahydropyran in 120 was constructed by the Petasis-Ferrier rearrangement. The C4-C5 (Z)-trisubstituted alkene in 121 was formed by carbomet-allation to an alkyne. 

Thomas et al. [90] prepared two 17-membered macrocyclic tetraenes that are possible precursors of the natural product lankacidin C in this case, a trisubstituted vinyl iodide was involved, and the amount of Pdjdbaj required was relatively high (30%). Toshima et al. [91] reported a highly stereoselective total synthesis of the macrolide antibiotic concanamycin F again, intermolecular and intramolecular vinyl-vinyl couphngs were used. WhUe liCl was used as an additive in the former, it was replaced by DIPEA in the latter. In a recent pubUcation [49], Toshima et al. 

When several cationic moieties were organized in the conformationally regulated non-macrocycle to match the shape of a guest, the electrostatic interactions operated in the specific binding of the anionic guests. 1,3,5-Trisubstituted benzene provided an effective scaffold to arrange three func-... 

In 2008, Donohoe and coworkers reported the total synthesis of (—)-(Z)-deoxpukalide (1) [30], a complex marine natural product with an intriguing 14-membered carbon macrocyclic skeleton containing a trisubstituted furan moiety (Fig. 1). The key features in the synthesis involve a selective alkene RCM/aromati-zation protocol to prepare the disubstituted furan methyl ester (3) as well as a late stage RCM to furnish the butenolide moiety. Since the five-membered ring formation is more favored, the marked exomethylene functionality was intact under the alkene RCM conditions. 

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