Enantioselective acetylide addition

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. 

The key step in the synthesis of 23 is the enantioselective generation of its quaternary carbon center. This can be accomplished by adding to the protected ketoaniline precursor 24 the lithium acetylide 25 [Eq. (3)] [90]. Due to the high medical relevance of the final product efavirenz (23), this enantioselective organolithium addition has been intensively studied. These detailed investigations provide intriguing information on the nature of reactive intermediates and the origins of enantioselectivity. 

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

Scheme 11 Enantioselective zinc acetylide addition applied to efavirenz.

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. 

Even if hundreds of chiral catalysts have been developed to promote the enantioselective addition of alkylzinc reagents to aldehydes with enantioselectivities over 90% ee, the addition of organozinc reagents to aldehydes is not a solved problem. For example, only very few studies on the addition of vinyl groups or acetylides and even arylzinc reagents to aldehydes have been published, in spite of the fact that the products of these reactions, chiral allylic, propargylic and aryl alcohols, are valuable chiral building blocks. 

The free base 13 is obtained by stirring with sodium acetate in MTBE. Benzylation by treatment with a mild acid and p-methoxybenzyl alcohol provides 14 (Emert et al., 1977 Henneus et al., 1996). The initial conditions for the asymmetric addition of the lithium acetylide to the trifluoroketone appear in an earlier Merck paper (Thompson et al., 1993, 1996). Optimization of these conditions, which include some elaborate NMR studies (Thompson et al., 1998) and key scale-up experiments, provides a reliable and scaleable procedure to install the stereocenter in high yield, purity, and enantioselectivity (Scheme 6.3). n-Butyllithium (or w-hexyllithium, minimum four equivalents) is added to a solution of (lR,25)-A-pyrrolidinylnorephedrine (Corey and Cimrich, 1994) (two equivalents) and cyclopropylacetylene (two equivalents) at — 10°C and the reaction is allowed to warm to 0°C. These conditions are critical to establish the chiral complex that is responsible for the high enantioselectivity. This solution is cooled below — 50°C, and trifluoroketone 14 in THE is added and stirred for about 1 h at this temperature before... 

Methods for the enantioselective addition of metal acetylides to aldehydes can be divided into two categories ... 

R-(R, S )]-p-Methyl-a-phenyl-1-pyrrolidineethanol is an important chiral mediator for the enantioselective addition of an acetylide to a prochiral ketone.2 3 This reaction has been successfully applied to the synthesis of the reverse transcriptase inhibitor efavirenz (DMP-266) (Scheme 1).3.4 Preparation of the enantiomer, (1S,2R)-N-pyrrolidinylnorephedrine, has been reported.2 The method used potassium carbonate (K2CO3) as base, but the yield of the product was only 33%. The submitters have extensively studied the formation of the pyrrolidinyl ring under various conditions as summarized in Table I. Eventually they found that the reaction was extremely efficient when it was run in toluene using sodium bicarbonate (NaHCC>3) as base (entry 8, Table I),5 which gave [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol quantitatively. Enantioselective (up to 99% ee) addition of cyclopropylacetylene to the ketoaniline 1 is achieved when the solution of [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol is used as a chiral additive.3 In addition, this method is also applicable to the preparation of a variety of alkylated norephedrines and other amino alcohols in excellent yields as Illustrated in Table II. These amino alcohols are potentially useful in asymmetric syntheses. 

Enantioselective Addition of Alkynyllithium to Aldehydes. The enantioselective addition of alkynyllithium to aldehydes in the presence of (1) provides optically active propargylic alcohols. (5)-l-Phenyl-2-propyn-l-ol with 92% ee is obtained in 87% yield from the enantioselective addition of Lithium (Trimethylsi-lyl)acetylide to PhCHO in the presence of (1) and the subsequent removal of the MesSi group (eq 3). "... 

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. ... 

Thompson, A. Corley, E. G. Huntington, M. F. Grabowski, E. J. J. Remenar, J. F. Collum, D. B., Lithium Ephedrate-Mediated Addition of a Lithium Acetylide to a Ketone Solution Structures and Relative Reactivities of Mixed Aggregates Underlying the High Enantioselectivities. /. Am. Chem. Soc. 1998, 120,2028. 

Furthermore, optically active alkynyl alcohols, useful intermediates for the synthesis of several optically active natural products, were obtained by the asymmetric addition of lithium acetylides to aldehyde in the presence of chiral ligand 2a Enhanced enantioselectivity in this reaction depends apparently on the substituent group in the acetylene moiety. As shown in Table 8, use of trialkylsilylacetylides gave the best results Various optically active ethynyl alcohols were obtained by the reaction of lithium trimethylsilylacetylide with aliphatic aldehydes, as summarized in Table 9... 

In seeking an efficient, economic, and scaleable route to the new potent nonnucleoside HIV-1 reverse transcriptase inhibitor 16 (L-738,372) [2a], process chemists at the Merck Research Laboratories have significantly contributed to the field of asymmetric alkylation of imines. Huffman and co-workers have reported a very efficient asymmetric route to 16 via the addition of a lithium acetylide to the cyclic N-acylketimine 14 in the presence of the lithium alkoxide of the alkaloid quinine as a stoichiometric chiral additive (Scheme 9) [31aj the previous route to the inhibitor 16 included a resolution step [31bj. Whereas other types of chiral additives were screened (e.g., diamines, diethers), only P-ami-no alkoxides were enantioselective. The search for readily available amino alcohols was dictated by the necessity of developing a practical process. The commer-... 

Two equivalents of acetylide 25 and alkoxide 26 are required for full conversion of one equivalent of ketoaniline 24. Addition of ketone 24 to an equimolar alkynylation mixture of 25 and 26 (1 1 1 ratio) proceeds rapidly, but only up to 50% conversion at low temperature (-90°C). Further ketone addition at these temperatures gives rise to IR detectable carbonyl as well as NH functions of ketone 24, but no C-H signal of a protonated acetylene from 25 could be detected. Hence, 24 then coexists with a rather unreactive acetylide-alkoxide species, which neither alkynylates the CO function nor deprotonates the NH group in 24 at low temperatures (-90 °C) The completion of the reaction for this 1 1 1 stoichiometry proceeds at 0°C,but then even requires several hours and also shows significantly lower enantioselectivity for the last than for the first 50% conversion [88]. 

One of the most practical ways to achieve chiral propargyl alcohol is to add acetylene anion to a carbonyl group in an enantiofacial manner. This art was well demonstrated by Mukayama et al. in 1979 using (2S,2 S)-2-hydroxymethyl-l-[(l-methylpyrrolidine-2-yl)methyl]pyrrohdine as a chiral ligand. The addition of lithium trimethylsilyl acetylide to benzaldehyde afforded the corresponding alkynol in over 92% optical yield. It is noted that the enantioselectivity of the present reaction depended predominantly on the trialkylsilyl group of the acetylene. Scheme 21.7 confirms these observations. 

Scheme 2.7 Enantioselective addition of lithium(i) acetylides to ketones with the use of chiral lithium(i) binaphtholate.

The first example of the catalytic enantioselective addition of lithium acetylide to carbonyl compounds without the aid of other metal sources has been reported. Chiral lithium binaphtholate effectively catalysed such enantio-selective alkynylation of ketones with up to 93% ee. 

An optically active acetylenic alcohol is an useful starting material to prepare various chiral compounds, because it has two functional groups. However, the optical resolution of an acetylenic alcohol by the diastereomeric method for its phthalic acid half-ester is complicated and successful only in a few cases,1 Recently, the preparation of optically active secondary acetylenic alcohol by the enantioselective reduction of ethynyl ketone or by the enantioselective addition of lithium acetylide to aldehyde has been reported. However, these methods are not applicable to the preparation of optically active tertiary acetylenic alcohols. 

With the first three chiral auxiliaries, 8a-c, low to medium e.e.s of 7 were obtained, far from values needed to make the process operate on a large scale. Somewhat higher enantioselectivities were obtained when the reaction was performed at —40°C with an N-para-methoxybenzoyl (PMB)-protected substrate 9 (Scheme 13.3). Even more important for the research concept than just enhancement of e.e.s were the observations made in these experiments. First, 2 mol of the acetylide and 2 mol of the chiral auxiliary were needed for complete ketone alkynylation. Second, pyrolidino-ephedrine 8d proved to be the best auxiliary amino-alcohol. With this auxiliary, an e.e. of over 98% was achieved, with complete conversion of the ketone, but only when the acetylide-alkoxide solution was first warmed to 0°C then cooled down to —40°C before addition of the ketone 9 (Scheme 13.3). 

An enantioselective 1,2-addition of zinc acetylide to aryl aldehydes employing a catalytic amount of chiral BINOL ligand in combination with Ti(0/-Pr)4 is high yielding and allows as3mi-metric construction of chiral propargylic alcohols with excellent... 

More recently, the same group found that alkynyl aluminum reagents undergo conjugate addition to cyclic enones in the presence of chiral Ni-bisphosphine complexes [55]. They found that the use of binol-based phosphine L9 provides high yields and enantioselectivities (up to 90% ee) for a broad range of cyclic enones. Interestingly the scope of the reaction is not limited to TMS-protected acetylides but it can be extended to aryl-acetylides (Scheme 10). 

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