Acetylide addition

Acetylide addition in the racemic version Originally, 4equiv of lithium 2-pyridylacetylide (6) in THF/hexane was added to a mixture of 5 and 4equiv of Mg(OTf)2 in Et20 at room temperature. Precoordination with Mg(OTf)2 and 5 was reported to be essential to prevent reduction of the carbon-nitrogen double bond in 5 [2]. However, it turned out that precoordination was unnecessary for this reaction, as shown in Scheme 1.4, and racemic adduct 7 was obtained in 86% yield by treatment with 1.3 equiv of 6 at -15 °C in THF without Mg(OTf)2. 

Naturally, we thought our novel asymmetric acetylide addition on ketenimine 5 (Scheme 1.6) could also be applicable in the preparation of Efavirenz . The structure of 36 in Scheme 1.14 is somewhat misleading. We should expect that one of... 

In the second half of this section, we will discuss the mechanistic understanding of this chiral addition with lithium acetylide, the cornerstone of the first manufacturing process. Based on the mechanism of asymmetric lithium acetylide addition, we will turn our attention toward the novel highly efficient zincate chemistry. This is an excellent example in which mechanistic studies paid off handsomely. 

Initially, preparation of 41 was not an easy task and it very unexpectedly seems to be more difficult than the following key asymmetric acetylide addition. N-Mono alkylation of 36 with pMBCl 42 under various standard reaction conditions did not proceed as expected. It was found that the desired 41 was formed when 36 and chloride 42 were co-spotted on the TLC. So we turned our attention to reaction of... 

Scheme 1.16 Alternative installation of pMB on 36, followed by acetylide addition.

It would be ideal if the asymmetric addition could be done without a protecting group for ketone 36 and if the required amount of acetylene 37 would be closer to 1 equiv. Uthium acetylide is too basic for using the non-protected ketone 36, we need to reduce the nucleophile s basicity to accommodate the acidity of aniline protons in 36. At the same time, we started to understand the mechanism of lithium acetylide addition. As we will discuss in detail later, formation of the cubic dimer of the 1 1 complex of lithium cyclopropylacetylide and lithium alkoxide of the chiral modifier3 was the reason for the high enantiomeric excess. However, due to the nature of the stable and rigid dimeric complex, 2 equiv of lithium acetylide and 2 equiv of the lithium salt of chiral modifier were required for the high enantiomeric excess. Therefore, our requirements for a suitable metal were to provide (i) suitable nucleophilicity (ii) weaker basicity, which would be... 

Here, we will discuss the reaction mechanism of the asymmetric lithium acetylide addition to pMB protected amino ketone 41. Then we will discuss some speculation about the asymmetric addition via the novel zinc acetylide addition. 

Reaction Mechanism for the Lithium Acetylide Addition to pMB Protected Amino Ketone 41... 

Reaction Mechanism for the Zinc Acetylide Addition to Amino Ketone 36... 

A new domino lithium acetylide addition/rearrangement procedure on trans-1,2-dibenzoyl-3,5-cyclohexadiene furnished 3-alkylidene-2,3-dihydrofurans via an intriguing mechanism involving three bond formations and two bond cleavages in one single operation <06SL1230>. The reaction of dimedone with meso-diacetoxycyclohexene in the presence of a palladium catalyst led to the formation of the tricyclic product as depicted below <06S865>. 

Various catalytic or stoichiometric asymmetric syntheses and resolutions offer excellent approaches to the chiral co-side chain. Among these methods, kinetic resolution by Sharpless epoxidation,14 amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde,15 lithium acetylide addition to an alkanal,16 reduction of the corresponding prochiral ketones,17 and BINAL-H reduction18 are all worth mentioning. 

The relative configuration at the allene unit of 2, obtained from 1 (see p 424), was unknown. For assignment, 2 was prepared independently from 3 via 4, 5, and 6. On condition that the rearrangement 5 - 6 occurs suprafacially and the desulfurization 6 -> 2 with retention of configuration (see p 473), the configurational assignment of 2 rests solely on the stereochemistry of step 3 - 4. Based on literature precedent the acetylide addition to 3 was assumed to occur from the a-direction to yield 4148. 

A highly efficient, enantioselective industrial synthesis of the HIV reverse transcriptase inhibitor efavirenz is made available for the manufacture of this important compound. A novel, chiral Zn-alkoxide-mediated, enantioselective acetylide addition reaction is used to establish the chiral center in the target with a remarkable level of stereocontrol. The synthesis provides analytically pure efavirenz in an overall yield of 75 % in five steps from 4-chloroaniline. 

In 2007, Betzer, Ardisson and co-workers reported their synthesis of discodermo-lide [64] following the Marshall disconnection strategy of C7-C8 acetylide addition and Suzuki cross-coupling at C14-05 (Scheme 32) [53, 54], The synthesis of the key subunits 160 (C1-C7), 161 (C8-C14) and 162 (C15-C24) demonstrated the versatility of the Hoppe crotyltitanation reaction [166-169] in the synthesis of polypropionate motifs, using the incorporated (Z)-0-enecarbamate to configure the requisite alkene substitution patterns [170, 171],... 

Air-stable palladium(0) catalyst, [(Cy3P)2Pd(H)(H20)]BF4, catalyses carbonylation of propargylic alcohols to generate dienoic acids and esters (equation 167). Since propar-gyl alcohols are obtained from carbonyl compounds by acetylide addition reactions, this sequence constitutes a three-carbon homologation. a-Allenic alcohols are converted to a-vinylacrylic acids under similar conditions (equation 168). ... 

Ring closure of ortfto-aminoaryl-alkynyl-carbinols, readily available by acetylide addition to an aryl-ketone or -aldehyde, can be achieved with copper or palladium catalysis. Comparable ort/io-nitroaryl-carbinols undergo nitro group reduction and ring closure simply by treatment with a metal/acid combination. ... 

In addition, the linear approach was represented by sequential dithiane coupling [21] of the epoxides for the necessary fragments to either side of the ketone function at C21. Another approach uses microbial reduction (baker s yeast) to set the stereocenter at C25 before elaboration of that fragment into a methyl acetylenic ketone [89]. This acetylenic ketone was condensed with the aldehyde partner representing Cl5-19 to give the aldol adduct which was cyclized in acid to afford a precursor similar to those obtained from acetylide addition to lactone B 3. Yet another linear assembly pathway involves the alkylation of the portion containing C23-27 of 22,23-dihydroavermectin B to the dianion of 2,4-pentanedione followed by another condensation to 3-be-nzyloxypropanal [108]. Subsequent acidic cyclization and standard chemistry provided the thermodynamic spiroketal. 

By the judicious choice of reaction conditions, it is possible to control the regioselectivity and stereoselectivity of acetylide addition to a keto group. For instance, the reaction of the diketone 14 with lithium acetylide in THF at low temperatures gives the C(9)-acetylenic alcohol 75 (Scheme 4) [10], and a stereospecific synthesis of the acetylenic triol 16 is achieved by the condensation of the lithium reagent 77 derived from the isopropenylmethyl (IPM) ether of ( j-3-methylpent-2-en-4-yn-l-ol (18) with the optically active ketone 19, followed by acid-catalysed removal of the protecting groups [11]. Only 3% of the C(6)-diastereoisomer of 16 was detected (Scheme 5). The preparation of 16 is described in Worked Example 2. Table 1 lists a selection of a-hydroxyalkynes that have been prepared from metal acetylides. 

Diketone anions of 1-aryl-4,4,4-trifluorobutane-l,3-dione (85) undergo nucleophilic addition of sodium acetylide to give tertiary 1,4-alkynediols (86). Double cyclization gives a 2,2 -bifuran. While the mechanism of acetylide addition has not been proved, a likely first step is the formal reaction of two carbanions to give a C-C bond. °... 

A two-step protocol, employing acetylide addition followed by catalytic Meyer-Schuster rearrangement has been reported for the olefination of l,4-pentadien-3-ones to give [3]dendralenes (Scheme 94). ... 

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