Lithium acetylide, addition

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. 

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... 

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. 

Similarly, Paquette s stereoselective synthesis of a marine sesquiterpene from the capnellene family utilizes this addition/rearrangement protocol/ Alcohol 50, produced by lithium acetylide addition to 49, underwent smooth rearrangement to provide 51 in excellent yield. 

Phenolic acetylenes (183) are prepared by lithium acetylide addition to quinones followed by reduction oxidation yields the corresponding phenoxyl radicals (184). Some of the spin density is shown by e.s.r. to reside on the acetylenic carbon and this is reflected in the nature of the dimeric product (185) isolated.i ... 

Scheme 10 Efaverinz and understanding enantioselective lithium alkoxide-mediated lithium acetylide additions.

A mixture of 0.40 mol of propargyl chloride and 150ml of dry diethyl ether was cooled at -90°C (liquid nitrogen bath) and a solution of 0.40 mol of ethyl-lithium (note 1) in about 350 ml of diethyl ether (see Exp. 1) was added with vigorous stirring and occasional cooling (note 2). The temperature of the reaction mixture was kept between -70 and -90°C. The formation of the lithium derivative proceeded almost instantaneously, so that the solution obtained could be used directly after the addition of the ethyl 1ithium, which was carried out in 15-20 min. This lithium acetylide solution is very unstable and must be kept below -60°C. 

Hove 1. The procedure described in Ref. 1 was modified. To a solution of 2.0 mol of lithium acetylide in 1.2 1 of liquid ammonia in a 4-1 round-bottomed, three-necked flask (see Fig. 2) was added 1.5 mol of freshly distilled benzaldehyde with cooling at about -45°C. After an additional 30 min finely powdered ammonium chloride (2 mol) was introduced in 15 min. The ammonia was allowed to evaporate, then water (1.1 1) was added and the product was extracted with diethyl ether. After drying over magnesium sulfate the extract was concentrated in a water-pump vacuum. High-vacuum distillation,... 

The 2-alken-4-ynylamine analogues (A. Stiitz, 1987) are best synthesized by Grignard-type additions of lithium acetylides to propenal and either... 

The addition of lithium acetylides can also be carried out enantioselectively in the presence of 22-24 ]vjucieophiiic addition of the unsubstituted lithium acetylide led to the alkynyl alcohol with lower enantioselectivity than the addition ofsilyl-substituted acetylides. The trimethylsilyl substituted acetylides gave the best results. 

The monolithium salt of 4-hydroxy-4-(phenylethynyl)-2.5-cyclohexadienone (12), prepared in situ by the addition of lithium acetylide to /7-benzoquinone, was treated with methylmagnesium chloride in l HF-TMEDA or in THF —DMPU. The syn-, 4-addition adduct 13, derived from intramolecular delivery of the carbon nucleophile by the hydroxy oxygen, as well as the <7s-1,4-diol 14, obtained via intermolecular 1,2-addition, were obtained in varying amounts depending on the conditions. The selectivity on 1,4- to 1,2-addition increased by the addition of cation chelating agents such as DMPU, TMEDA, and 15-crown-5. Although the 1,4 to 1,2... 

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. 

A classical chiral resolution method was established, prior to investigation of the asymmetric addition of lithium acetylide to the ketimine 5. 

The scope and limitations were briefly studied. Unfortunately the scope of the reaction was rather narrow, as shown in Table 1.4. The Emit of generality may originate from differences in aggregation of each individual lithium acetylide. For instance, changing 2-pyridyl to 3-pyridyl, the ee dropped to 36%. Furthermore, changing to 4-pyridyl, the ee further decreased to 13%. Fortunately, asymmetric addition of a TMS protected acetylide provided the desired adduct in 82% ee. Since... 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

We came up with the idea of using a dummy ligand, as shown in Scheme 1.23 [34]. Reaction of dimethylzinc with our chiral modifier (amino-alcohol) 46 provided the methylzinc complex 62, which was subsequently reacted with 1 equiv of MeOH, to form chiral zinc alkoxide 63, generating a total of 2 moles of methane. Addition of lithium acetylide to 63 would generate an ate complex 64. The ate complex 64 should exist in equilibrium with the monomeric zincate 65 and the dimer 66. However, we expected that the monomer ate complex 64 and the mono-... 

On the other hand, asymmetric addition of lithium acetylide in the presence of the ephedrine derivative 46 is a homogeneous reaction and reveals great detail about the reaction mechanism. 

Aging a mixture of lithium acetylide and the lithium alkoxide of 46 at higher temperature (-10 to 0°C) prior to addition of ketone 41 is needed to obtain constantly high enantiomeric excess. 

Modifying the reaction medium to involve liquid ammonia with metallic lithium, f-butyl alcohol, and white phosphorus, to which is added the haloalkane, is reported to provide the primary alkylphos-phine derived from the haloalkane.19 Similar results are reported for the reaction of red phosphorus with sodium acetylides20 and by treatment of red phosphorus with sodium metal in an organic medium followed by the addition of two equivalents of f-butyl alcohol and the haloalkane.21 The latter approach is noteworthy in that moderate yields (45%) are obtained for primary phosphines derived from secondary haloalkanes (Figure 2.6). Mixtures of tertiary phosphines bearing one or two acetylenic linkages are produced in low yield ( 15%) by the reaction of lithium acetylides with white phosphorus in liquid ammonia followed by addition of a haloalkane.22... 

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. 

Whereas deprotonation and halogen-lithium exchange represent the most common methods to access allenic and propargylic lithium intermediates, several less direct routes to more functionalized analogues have also been reported. Additions of various lithium acetylides to acylsilanes followed by Mel or EtI afforded alkylated allenyl silyl ethers (Table 9.4) [10]. The adducts were analyzed after hydrolysis to the related enones. 

In 1991, Park reported123 the first synthesis of iron alkynylcarbene complexes (184), involving the nucleophilic attack of a lithium acetylide on pentacarbonyl iron, followed by electrophilic quench. With such compounds in hand, he proceeded to investigate their reactivity123,124 and found that upon addition of cyclopentadiene to the alkynylcarbene complexes 184, the products formed were 774-vinylketene complexes (185). During column chromatography, some of these products (185.a and 185.b) were transformed into the tricarbonyl(norbornadiene)iron derivatives 186. Others (185.C and 185.d, not shown) were hydrolyzed as part of the workup procedure, to afford pure samples of the norbornadiene complexes 186.C and... 

A multi-step reaction sequence was then realized to prepare the precursor (178) for the pivotal macrocyclization reaction. Alternate stepwise chain elongations were achieved according to Schemes 28 and 29. Reaction of the tosylate prepared from the alcohol 162 with lithium acetylide afforded the alkyne 174 (Scheme 28). Following the introduction of a tosylate at the upper branch, a one-carbon chain elongation of the terminal alkyne afforded the methyl alkynoate 175. A methyl cuprate 1,4-addition was used to construct the tri-substituted C double bond stereoselectively. For this purpose, the alkynoate 175 was initially transformed into the Z-configured a,/ -unsat-... 

A. 1 -Phenyl-3-butyh-1 -ol (1) (Note 1). A 1000-mL, oven-dried, three-necked, round-bottomed flask is equipped with a magnetic stir bar and pressure-equalizing addition funnel, fitted with a rubber septum, and placed under an argon atmosphere. The flask is charged with lithium acetylide-ethylenediamine complex (50 g, 543 mmol) (Note 2), which is dissolved in anhydrous dimethyl sulfoxide (360 mL) (Note 3) with stirring. The flask is placed in a room temperature water bath (Note 4), the addition funnel is charged with styrene oxide (42.0 mL, 368 mmol) (Note 5), and styrene oxide is added dropwise over a period of approximately 5 min. The reaction mixture is stirred for 2 hr and quenched by... 

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