Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes

F. Xu; R. A. Reamer; R. Tillyer; J. M. Cummins; E. J.J. Grabowski; P. J. Reider; D. B. Collum; J. C. Huffman

doi:10.1021/ja0022728

Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes

F. Xu, R. A. Reamer, R. Tillyer, J. M. Cummins, E. J.J. Grabowski, P. J. Reider, D. B. Collum, J. C. Huffman

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100 Scopus citations

Abstract

The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% enantioselectivity. Studies of acetylide-alkoxide complexes in solution by NMR spectroscopy and in the solid state by X-ray crystallography are described. Studies of the asymmetric addition reaction involving 2:2 tetramer 6 using low-temperature NMR spectroscopy provide conclusive evidence for formation of 2:1:1 tetramer 9 containing the product alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step.

Original language	English (US)
Pages (from-to)	11212-11218
Number of pages	7
Journal	Journal of the American Chemical Society
Volume	122
Issue number	45
DOIs	https://doi.org/10.1021/ja0022728
State	Published - Nov 15 2000
Externally published	Yes

All Science Journal Classification (ASJC) codes

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

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10.1021/ja0022728

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Xu, F., Reamer, R. A., Tillyer, R., Cummins, J. M., Grabowski, E. J. J., Reider, P. J., Collum, D. B., & Huffman, J. C. (2000). Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes. Journal of the American Chemical Society, 122(45), 11212-11218. https://doi.org/10.1021/ja0022728

@article{f2bd4a0a9ff0456a8bea0cb72c424891,

title = "Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes",

abstract = "The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% enantioselectivity. Studies of acetylide-alkoxide complexes in solution by NMR spectroscopy and in the solid state by X-ray crystallography are described. Studies of the asymmetric addition reaction involving 2:2 tetramer 6 using low-temperature NMR spectroscopy provide conclusive evidence for formation of 2:1:1 tetramer 9 containing the product alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step.",

author = "F. Xu and Reamer, {R. A.} and R. Tillyer and Cummins, {J. M.} and Grabowski, {E. J.J.} and Reider, {P. J.} and Collum, {D. B.} and Huffman, {J. C.}",

year = "2000",

month = nov,

day = "15",

doi = "10.1021/ja0022728",

language = "English (US)",

volume = "122",

pages = "11212--11218",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "45",

}

Xu, F, Reamer, RA, Tillyer, R, Cummins, JM, Grabowski, EJJ, Reider, PJ, Collum, DB & Huffman, JC 2000, 'Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes', Journal of the American Chemical Society, vol. 122, no. 45, pp. 11212-11218. https://doi.org/10.1021/ja0022728

Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes. / Xu, F.; Reamer, R. A.; Tillyer, R. et al.
In: Journal of the American Chemical Society, Vol. 122, No. 45, 15.11.2000, p. 11212-11218.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes

T2 - Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes

AU - Xu, F.

AU - Reamer, R. A.

AU - Tillyer, R.

AU - Cummins, J. M.

AU - Grabowski, E. J.J.

AU - Reider, P. J.

AU - Collum, D. B.

AU - Huffman, J. C.

PY - 2000/11/15

Y1 - 2000/11/15

N2 - The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% enantioselectivity. Studies of acetylide-alkoxide complexes in solution by NMR spectroscopy and in the solid state by X-ray crystallography are described. Studies of the asymmetric addition reaction involving 2:2 tetramer 6 using low-temperature NMR spectroscopy provide conclusive evidence for formation of 2:1:1 tetramer 9 containing the product alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step.

AB - The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% enantioselectivity. Studies of acetylide-alkoxide complexes in solution by NMR spectroscopy and in the solid state by X-ray crystallography are described. Studies of the asymmetric addition reaction involving 2:2 tetramer 6 using low-temperature NMR spectroscopy provide conclusive evidence for formation of 2:1:1 tetramer 9 containing the product alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step.

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Highly enantioselective 1,2-addition of lithium acetylide-ephedrate complexes: Spectroscopic evidence for reaction proceeding via a 2:2 tetramer, and X-ray characterization of related complexes

Abstract

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