CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence
Enantioenriched molecules bearing indole-substituted stereocenters form a class of privileged compounds in biological, medicinal, and organic chemistry. Thus, the development of methods for asymmetric indole alkylation is highly valuable in organic synthesis. Traditionally, achieving N-selectivity i...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Chemical Society (ACS)
2020
|
| Online Access: | https://hdl.handle.net/1721.1/126070 |
| _version_ | 1826189971049938944 |
|---|---|
| author | Ye, Yuxuan Kim, Seoung-Tae Jeong, Jinhoon Baik, Mu-Hyun Buchwald, Stephen Leffler |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Ye, Yuxuan Kim, Seoung-Tae Jeong, Jinhoon Baik, Mu-Hyun Buchwald, Stephen Leffler |
| author_sort | Ye, Yuxuan |
| collection | MIT |
| description | Enantioenriched molecules bearing indole-substituted stereocenters form a class of privileged compounds in biological, medicinal, and organic chemistry. Thus, the development of methods for asymmetric indole alkylation is highly valuable in organic synthesis. Traditionally, achieving N-selectivity in indole alkylation reactions is a significant challenge, since there is an intrinsic preference for alkylation at C3, the most nucleophilic position. Furthermore, selective and predictable access to either N- or C3-alkylated chiral indoles using catalyst control has been a long-standing goal in indole functionalization. Herein, we report a ligand-controlled regiodivergent synthesis of N- and C3-alkylated chiral indoles that relies on a polarity reversal strategy. In contrast to conventional alkylation reactions in which indoles are employed as nucleophiles, this transformation employs electrophilic indole derivatives, N-(benzoyloxy)indoles, as coupling partners. N- or C3-alkylated indoles are prepared with high levels of regio- and enantioselectivity using a copper hydride catalyst. The regioselectivity is governed by the use of either DTBM-SEGPHOS or Ph-BPE as the supporting ligand. Density functional theory (DFT) calculations are conducted to elucidate the origin of the ligand-controlled regiodivergence. |
| first_indexed | 2024-09-23T08:33:02Z |
| format | Article |
| id | mit-1721.1/126070 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:33:02Z |
| publishDate | 2020 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1260702022-09-30T09:29:38Z CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence Ye, Yuxuan Kim, Seoung-Tae Jeong, Jinhoon Baik, Mu-Hyun Buchwald, Stephen Leffler Massachusetts Institute of Technology. Department of Chemistry Enantioenriched molecules bearing indole-substituted stereocenters form a class of privileged compounds in biological, medicinal, and organic chemistry. Thus, the development of methods for asymmetric indole alkylation is highly valuable in organic synthesis. Traditionally, achieving N-selectivity in indole alkylation reactions is a significant challenge, since there is an intrinsic preference for alkylation at C3, the most nucleophilic position. Furthermore, selective and predictable access to either N- or C3-alkylated chiral indoles using catalyst control has been a long-standing goal in indole functionalization. Herein, we report a ligand-controlled regiodivergent synthesis of N- and C3-alkylated chiral indoles that relies on a polarity reversal strategy. In contrast to conventional alkylation reactions in which indoles are employed as nucleophiles, this transformation employs electrophilic indole derivatives, N-(benzoyloxy)indoles, as coupling partners. N- or C3-alkylated indoles are prepared with high levels of regio- and enantioselectivity using a copper hydride catalyst. The regioselectivity is governed by the use of either DTBM-SEGPHOS or Ph-BPE as the supporting ligand. Density functional theory (DFT) calculations are conducted to elucidate the origin of the ligand-controlled regiodivergence. National Institutes of Health (Award R35-GM122483) 2020-07-07T17:42:54Z 2020-07-07T17:42:54Z 2019-01 2018-11 2020-03-17T16:29:38Z Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 https://hdl.handle.net/1721.1/126070 Ye, Yuxuan et al. "CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence." Journal of the American Chemical Society 141, 9 (January 2019): 3901–3909 © 2019 American Chemical Society en http://dx.doi.org/10.1021/jacs.8b11838 Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Ye, Yuxuan Kim, Seoung-Tae Jeong, Jinhoon Baik, Mu-Hyun Buchwald, Stephen Leffler CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence |
| title | CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence |
| title_full | CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence |
| title_fullStr | CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence |
| title_full_unstemmed | CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence |
| title_short | CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence |
| title_sort | cuh catalyzed enantioselective alkylation of indole derivatives with ligand controlled regiodivergence |
| url | https://hdl.handle.net/1721.1/126070 |
| work_keys_str_mv | AT yeyuxuan cuhcatalyzedenantioselectivealkylationofindolederivativeswithligandcontrolledregiodivergence AT kimseoungtae cuhcatalyzedenantioselectivealkylationofindolederivativeswithligandcontrolledregiodivergence AT jeongjinhoon cuhcatalyzedenantioselectivealkylationofindolederivativeswithligandcontrolledregiodivergence AT baikmuhyun cuhcatalyzedenantioselectivealkylationofindolederivativeswithligandcontrolledregiodivergence AT buchwaldstephenleffler cuhcatalyzedenantioselectivealkylationofindolederivativeswithligandcontrolledregiodivergence |