2- Butyne synthesis

A number of alternative multi-step procedures for the synthesis of a-tert-alkyl ketones are known, none of which possess wide generality. A previous synthesis of 2-tert-penty1cyclopentanone involved reaction of N-1-cyclopentenylpyrrol 1 dine with 3-chloro-3-methy1-l-butyne and reduction of the resulting acetylene (overall yield 46 ). However, all other enamines tested afford much lower yields. Cuprate addition to unsaturated ketones may be useful in certain cases. Other indirect methods have been briefly reviewed. ... 

The synthesis of the key intermediate aldehyde 68 is outlined in Schemes 19-21. The two hydroxyls of butyne-l,4-diol (74, Scheme 19), a cheap intermediate in the industrial synthesis of THF, can be protected as 4-methoxybenzyl (PMB) ethers in 94% yield. The triple bond is then m-hydrostannylated with tri-n-butyl-tin hydride and a catalytic amount of Pd(PPh3)2Cl238 to give the vinylstannane 76 in 98 % yield. Note that the stereospecific nature of the m-hydrostannylation absolutely guarantees the correct relative stereochemistry of C-3 and C-4 in the natural product. The other partner for the Stille coupling, vinyl iodide 78, is prepared by... 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

In contrast, synthesis of 3,4-diphosphorylthiophenes requires more elaboration because of low reactivity of 3,4-positions of thiophene and unavailability of 3,4-dihalo or dimetallated thiophenes. Minami et al. synthesized 3,4-diphosphoryl thiophenes 16 as shown in Scheme 24 [46], Bis(phosphoryl)butadiene 17 was synthesized from 2-butyne-l,4-diol. Double addition of sodium sulfide to 17 gave tetrahydrothiophene 18. Oxidation of 18 to the corresponding sulfoxide 19 followed by dehydration gave dihydrothiophene 20. Final oxidation of 20 afforded 3,4-diphosphorylthiophene 16. 3,4-Diphosphorylthiophene derivative 21 was also synthesized by Pd catalyzed phosphorylation of 2,5-disubstituted-3,4-dihalothiophene and converted to diphosphine ligand for Rh catalysts for asymmetric hydrogenation (Scheme 25) [47],... 

A more complex reaction is involved in the cooligomerization of acetylenes and tert-butyl isocyanide using nickel acetate as the catalyst (Scheme 20)43 the nature of intermediate complexes leading to the formation of 2-cyano-5-terf-butylaminopyrroles has not been established. Cocyclization of tert-butyl isocyanide with coordinated hexafluoro-2-butyne gives rise to coordinated cyclopentadienone anils for molybdenum systems,44 hence the nature of acetylene substitutents and of the organometallic catalyst play crucial roles in these processes. The pyrrole products from the former reaction can be decomposed by sulfuric acid and the overall sequence provides a simple synthesis of 5-amino-2-cyanopyrroles (Scheme 20). 

Synthesis of the dihydrothiophene derivatives was described by Flynn et al. [70] (depicted in Scheme 23) and involved the conversion of 3-butynol 92 to benzyl 3-butynal sulfide 93. Sonogashira coupling of the sulfide 93 with acetic acid 5-iodo-2-methoxyphenyl ester 94, produced the intermediate 95. Treatment of compound 95 with iodine resulted in a rapid and... 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

The stereospecific reduction of a 2-butyne-l, 4-diol derivative and silver( I)-mediated cyclization of the resulting allene were successively applied to a short total synthesis of (+)-furanomycin 165 (Scheme 4.42) [68], Stereoselective addition of lithium acetylide 161 to Garner s aldehyde in the presence of zinc bromide afforded 162 in 77% yield. The hydroxyl group-directed reduction of 162 with LiAlH4 in Et20 produced the allene 163 stereospecifically. Cyclization followed by subsequent functional group manipulations afforded (+)-furanomycin 165. 

An improved procedure for the synthesis of a-allenic alcohols in good yields and with approximately 90% e.e. was reported by Olsson and Claesson (56). (- )-(S)-3-Butyne-2-ol (25) was converted into the monotetrahydropyranyl derivatives 26a to c, which gave on reduction with LAH in ether or THF the chiral allenes 27a to c (Scheme 4). The absolute configurations of 27b and c were... 

As part of a study of the reactions of metallacyclic y-ketovinyl complexes of molybdenum and tungsten with acetylenes, directed toward the synthesis of complexed -/-lactones, Stone has reported92 the isolation of several vinyl-ketene complexes. When complex 72 was heated with 2-butyne, one molecule of the alkyne was incorporated into the complex with concomitant carbonylation. X-ray analysis of the product (73) has shown unequivocally that the C-l to C-4 vinylketene fragment is bonded in a planar, rj4-configu-ration. In contrast to the thermal reaction, ultraviolet irradiation of 72 or 74 in the presence of 2-butyne affords the complexes 75 and 76, respectively, where the lone carbonyl remaining after alkyne insertion had been replaced by a third molecule of the alkyne. 

Synthesis of the End-Capping Agent 4- (m-Hydroxyphenyl) -2-methyl-3-butyn-2-ol 1 ... 

In a formal total synthesis of matrine (116), Yamanaka and coworkers used the Sonogashira reaction of pyridyl halides as the means to form C—C bonds <86CPB2018>. For instance, bromonaphthyridinone 114 was coupled with 3-butyn-l-ol to furnish alkynylnaphthyridinone 115, an intermediate towards matrine (116). 

The synthesis of enantiomerically pure (S)-3-butyn-2-ol [(S)-24j was achieved via CPCR-catalyzed reduction by introducing a silyl group with an aromatic substituent into the substrate (compound 23c) [41]. 

A stereospecific synthesis for cw-3-hexen-l-ol starts with the ethylation of sodium acetylide to 1 -butyne, which is reacted with ethylene oxide to give 3-hexyn-l-ol. Selective hydrogenation of the triple bond in the presence of palladium catalysts yields cw-3-hexen-l-ol. Biotechnological processes have been developed for its synthesis as a natural flavor compound, e.g., [12]. 

Acetylenic precursors employed in the syntheses of sugars may be divided into three groups (a) aldehydes (usually in the form of acetals), (b) alkyl alkynyl ethers, and (c) alkynols or alkynediols. Some of them are commercially available (for example, 2-butyne-l,4-diol), and others are prepared by Grignard-type reactions between 1-alkynylmag-nesium halides or lithium alkynes and suitable aldehydes, ketones, or epoxides. In this way, the synthesis of substrates having the desired number of carbon atoms, as well as the necessary functional groups, can be achieved. The next step consists in partial saturation of the triple bond to afford the desired cis- or trans-alkene. ct.s-Alkene systems... 

Fraser and Raphael devised a synthesis of 2-deoxy-Di.-cn///irope n to se (2) starting from 2-butyne-l,4-diol. Monobenzov lation, followed by reaction with phosphorus tribromide, furnished l-(ben-zoyloxy)-4-bromo-2-butyne (151). Reaction of 151 with diethyl sodio-... 

The synthesis of llZ-retinal required the boronic-partner, which was prepared from 2-butyn-l-ol by addition of the tributylstannyl cuprate (83%), followed by protection of the alcohol with tBuMe2SiCl (TBDMSC1) (93%). The tributylstannyl group was substituted with boronic acid in three steps lithiation, quenching alkenyllithium with triisopropyl boronate and hydrolysis to the boronic acid. The Suzuki coupling of the C 6 tetraene with the boronic compound was carried out in THF at room temperature, in the presence of a catalytic amount of... 

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