Asymmetric alkynylide additions to carbonyls have emerged as a useful tool in organic synthesis.[1] Several different stoichiometric and catalytic versions of additions to aldehydes have been documented for the preparation of secondary propargylic alcohols in high enantiomeric purity.[2] By contrast, enantioselective alkynylation of ketones towards the formation of tertiary alcohols has enjoyed only limited success with respect to both scope and selectivity.[3] Unquestionably, the most prominent example of zinc-mediated asymmetric alkynylation of ketones was described by Tan and co-workers at Merck for the manufacture of efavirenz [4] (Sustiva, Stocrin), a key drug for the treatment of HIV. [5a,b] This landmark chemical process prescribes the use of stoichiometric quantities of diethylzinc, metalated acetylene, chiral amino alcohol ligand, and trifluoroethanol additive to furnish the key intermediate (S)-2 in 99.3 % ee and 95 % yield (Scheme 1).[5c] Herein, we disclose a catalytic, enantioselective process, which involves the use of a cocktail including substoichiometric quantities of the ligand (1R,2S)-N-pyrrolidinylnorephedrine (4), [6] Et 2 Zn, and substoichiometric amounts of the product (S)-2 at the outset of the reaction. [7] The catalytic reaction benefits from the presence of product as an autocatalyst, resulting in a more atom-economical route to efavirenz in 79(67) % yield and 99.6(99.5 %) % ee. [8] Beyond the economic relevance, this process showcases the first example that employs autocatalysis in the synthesis of a pharmaceutical agent which may be conducted on large scale (Scheme 2).[9]We have been interested in the chemistry of terminal acetylenes in catalytic, enantioselective synthesis.[2j-n] Because of the global importance of efavirenz for human health, we turned our attention to its synthesis. The current large-scale production of the key intermediate (S)-2 proceeds through a chiral zincate, requiring excess quantities of the chiralityinducing ligand 4 (1.5 equiv), 1.2 equiv of Et 2 Zn, and 0.9 equiv of trifluoroethanol (Scheme 1).[10] We set out to carefully examine this process with the aim of establishing a cost-effective protocol that would employ substoichiometric amounts of these components, namely a catalytic enantioselective process. [11] Given the regulatory and financial issues involved in registering a new protocol for an existing drug, we set out to craft a catalytic, enantioselective process that would parallel the current stoichiometric one. We thus focused our efforts on the screening of reaction parameters, such as base, temperature, concentration, solvent polarity, order of addition of the various components, and relative proportions of the components. In our initial studies the most promising result was achieved with 0.3 equiv of (1R,2S)-4, 0.24 equiv of Et 2 Zn, 0.18 equiv of CF 3 CH 2 OH, 0.8 equiv of LiOtBu as the base, and 1.1 equiv of cyclopropyl acetylene 3. Under these conditions the desired tertiary alkynol (S)-2 was formed with 97.4 % ee and 40.4 % yield, based on...
Treatment of Cp2ZrBu2 with enol ether containing a remote double bond lead to conjugated metalated diene as single isomer via a tandem isomerization-elimination sequence. 2-Arylsulfonyl 1,3-dienes can also be used as a source of dienyl zirconocene derivatives, and the stereochemistry of the diene is dependent on the transmetalation reaction.
Several dienyl zirconocene derivatives were easily prepared, as unique geometrical isomers, from simple non-conjugated unsaturated enol ethers with (1-butene)ZrCp2 complexes. This new methodology is based on a tandem allylic C-H bond activation-elimination sequence and the mechanism has been mapped out by deuterium labeling experiments. The stereochemical outcome of this process was determined by addition of several electrophiles. Moreover, when the organometallic derivative is vinylic as well as allylic such as in 44-47Zr, an unexpected reversal of the stereochemistry has been found during the zirconium to copper transmetalation step.
From A to Z: Allylzirconocenes have been easily prepared in a one‐pot procedure through a tandem allylic CH activation–β‐elimination reaction from unsaturated fatty alcohol and ether starting materials (see scheme). The reaction proceeds rapidly under mild condition and is insensitive to the length of the carbon tether between the double bond and the alcohol moiety.
The one-pot preparation of allyl-and dienyl-zirconocene derivatives can be easily achieved via a tandem allylic C-H-activation-b-elimination reaction from unsaturated fatty alcohol and enol ether derivatives, respectively. The reaction proceeds rapidly, under mild conditions, and is insensitive to the length of the carbon tether between the double bond and the leaving group moiety.
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