Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids
(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configu...
| Main Authors: | , , , , |
|---|---|
| 格式: | Journal article |
| 出版: |
Beilstein-Institut
2019
|
| _version_ | 1826277326591098880 |
|---|---|
| author | Sintim, H Al Mamari, H Almohseni, H Fegheh-Hassanpour, Y Hodgson, D |
| author_facet | Sintim, H Al Mamari, H Almohseni, H Fegheh-Hassanpour, Y Hodgson, D |
| author_sort | Sintim, H |
| collection | OXFORD |
| description | (R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54–67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products. |
| first_indexed | 2024-03-06T23:27:13Z |
| format | Journal article |
| id | oxford-uuid:6ac7b66c-96fb-4ff9-a3c4-42a30e79d456 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:27:13Z |
| publishDate | 2019 |
| publisher | Beilstein-Institut |
| record_format | dspace |
| spelling | oxford-uuid:6ac7b66c-96fb-4ff9-a3c4-42a30e79d4562022-03-26T18:59:40ZAlkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acidsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6ac7b66c-96fb-4ff9-a3c4-42a30e79d456Symplectic Elements at OxfordBeilstein-Institut2019Sintim, HAl Mamari, HAlmohseni, HFegheh-Hassanpour, YHodgson, D(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54–67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products. |
| spellingShingle | Sintim, H Al Mamari, H Almohseni, H Fegheh-Hassanpour, Y Hodgson, D Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids |
| title | Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids |
| title_full | Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids |
| title_fullStr | Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids |
| title_full_unstemmed | Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids |
| title_short | Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids |
| title_sort | alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2 8 dioxabicyclo 3 2 1 octane core of squalestatins zaragozic acids |
| work_keys_str_mv | AT sintimh alkylationoflithiateddimethyltartrateacetonidewithunactivatedalkylhalidesandapplicationtoanasymmetricsynthesisofthe28dioxabicyclo321octanecoreofsqualestatinszaragozicacids AT almamarih alkylationoflithiateddimethyltartrateacetonidewithunactivatedalkylhalidesandapplicationtoanasymmetricsynthesisofthe28dioxabicyclo321octanecoreofsqualestatinszaragozicacids AT almohsenih alkylationoflithiateddimethyltartrateacetonidewithunactivatedalkylhalidesandapplicationtoanasymmetricsynthesisofthe28dioxabicyclo321octanecoreofsqualestatinszaragozicacids AT feghehhassanpoury alkylationoflithiateddimethyltartrateacetonidewithunactivatedalkylhalidesandapplicationtoanasymmetricsynthesisofthe28dioxabicyclo321octanecoreofsqualestatinszaragozicacids AT hodgsond alkylationoflithiateddimethyltartrateacetonidewithunactivatedalkylhalidesandapplicationtoanasymmetricsynthesisofthe28dioxabicyclo321octanecoreofsqualestatinszaragozicacids |