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Hydromethylation of Unactivated Olefins.

Dao HT, Li C, Michaudel Q, Maxwell BD, Baran PS - J. Am. Chem. Soc. (2015)

Bottom Line: This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents.This mild protocol can be used to simplify the synthesis of a specific target or to directly "edit" complex natural products and other advanced materials.The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.

View Article: PubMed Central - PubMed

Affiliation: †Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
A solution to the classic unsolved problem of olefin hydromethylation is presented. This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents. An array of olefins, including mono-, di-, and trisubstituted olefins, are all smoothly hydromethylated. This mild protocol can be used to simplify the synthesis of a specific target or to directly "edit" complex natural products and other advanced materials. The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.

No MeSH data available.


Applicationin synthesis of stable and radioactive labeled compounds.
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fig4: Applicationin synthesis of stable and radioactive labeled compounds.

Mentions: Another striking use of the current methodology is in thecontextof isotopic labeling. In theory, since formaldehyde is readily availablein a myriad of radioactive and stable labeled forms, it can be usedto prepare methyl groups with many permutations of 14CHn, 13CHn, 12CDn, 13CDn, and 12CTn. As a proof of concept, l-Fmoc-allylglycine-OMe (1y) was converted into l-Fmoc-leucine-OMe (CH3) and stable labeled derivatives containing CDH2 (2y-d1), CD2H (2y-d2), and CD3 (2y-d3) in >40% isolatedyield without erosion of enantiopurity (Figure 4). Deuterium incorporation was >99% in the case of 2y-d2 and >75% in the other two cases;presumably this is due to incomplete deuteration of the intermediatealkylhydrazide. The divergent synthesis of leucine derivatives shownhere may find use in the stereo-array isotope labeling technique15 and carbon–deuterium probes in vibrationalspectroscopy.16 In an application in thesynthesis of labeled drugs, (R,S)-Fmoc-pregabalin-OtBu-d2 (2z) was smoothlylabeled from simple precursor 1z. As a final showcaseof the utility of this method, a radioactive methyl group (14CH3) was installed to rotenone (1t) usingcommercially available [14C]formaldehyde solution.


Hydromethylation of Unactivated Olefins.

Dao HT, Li C, Michaudel Q, Maxwell BD, Baran PS - J. Am. Chem. Soc. (2015)

Applicationin synthesis of stable and radioactive labeled compounds.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490774&req=5

fig4: Applicationin synthesis of stable and radioactive labeled compounds.
Mentions: Another striking use of the current methodology is in thecontextof isotopic labeling. In theory, since formaldehyde is readily availablein a myriad of radioactive and stable labeled forms, it can be usedto prepare methyl groups with many permutations of 14CHn, 13CHn, 12CDn, 13CDn, and 12CTn. As a proof of concept, l-Fmoc-allylglycine-OMe (1y) was converted into l-Fmoc-leucine-OMe (CH3) and stable labeled derivatives containing CDH2 (2y-d1), CD2H (2y-d2), and CD3 (2y-d3) in >40% isolatedyield without erosion of enantiopurity (Figure 4). Deuterium incorporation was >99% in the case of 2y-d2 and >75% in the other two cases;presumably this is due to incomplete deuteration of the intermediatealkylhydrazide. The divergent synthesis of leucine derivatives shownhere may find use in the stereo-array isotope labeling technique15 and carbon–deuterium probes in vibrationalspectroscopy.16 In an application in thesynthesis of labeled drugs, (R,S)-Fmoc-pregabalin-OtBu-d2 (2z) was smoothlylabeled from simple precursor 1z. As a final showcaseof the utility of this method, a radioactive methyl group (14CH3) was installed to rotenone (1t) usingcommercially available [14C]formaldehyde solution.

Bottom Line: This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents.This mild protocol can be used to simplify the synthesis of a specific target or to directly "edit" complex natural products and other advanced materials.The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.

View Article: PubMed Central - PubMed

Affiliation: †Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
A solution to the classic unsolved problem of olefin hydromethylation is presented. This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents. An array of olefins, including mono-, di-, and trisubstituted olefins, are all smoothly hydromethylated. This mild protocol can be used to simplify the synthesis of a specific target or to directly "edit" complex natural products and other advanced materials. The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.

No MeSH data available.