Lithium cyclopropylacetylide

The first generation of asymmetric addition of lithium-cyclopropylacetylide to 41. 

The First Generation of Asymmetric Addition of Lithium Cyclopropylacetylide to the Ketone 41... 

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... 

The above two quinazolinones were prepared as intermediates in the synthesis of the chiral nonnucleoside reverse transcriptase inhibitor DPC 961 441, although compounds of this type can also be formed directly by the addition of lithium cyclopropylacetylide to the N-unsubstituted 2(l//)-quinazolinone 440, in the presence of a chiral alkoxide moderator <20000L3119, 2004JA5427>. 

Addition of Acetylide to an Aromatic Ketone. The synthesis of efavirenz, a potent HIV transcriptase inhibitor, required tbe enantioselective addition of lithium cyclopropylacetylide to the carbonyl carbon of a trifluoroacetophenone (eq 3). Careful control of reaction conditions and the use of the lithium salt of the title ligand affords the desired alcohol in 91% yield and >99.5% ee. ... 

The structurally related product L-743,726 39 was similarly prepared by addition of lithium cyclopropylacetylide to ketone 37 in the presence of a /V,/V-disubstituted norephedrine derivative. This occurred in 98% e.e. at 0°C to give adduct 38 that was subsequently cyclized to afford 39. 

Figure 16. Stereoselective synthesis of L-738,372 and L-743,726. Reagents a, quinine, BuLi, then lithium 2-pyridylacetylide b, camphorsulfonic acid c, trifluoroacetic acid d, lithium cyclopropylacetylide, N-pyrrolidinyl norephedrine.

Exciting achievements have been reported in relation to the synthesis of the HIV-1 reverse transcriptase inhibitor Efavirenz. In the presence of a modified ephedrine, lithium cyclopropylacetylide adds onto 5-chloro-2-[7V-(4-methoxybenzyl)amino]phenyl trifluoromethyl ketone to provide the (5)-enantiomer 214 in 95% yield and 98% ee (Scheme 1-157). The success critically depends on the carefully controlled formation of the reagent/ligand 2 2 heteroaggregate. ... 

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