Conformationally Constrained β-Amino Acid Derivatives by Intramolecular [2 + 2]-Photocycloaddition of a Tetronic Acid Amide and Subsequent Lactone Ring Opening
2005-11-25T00:00:00Z (GMT) by
The <i>N</i>-Boc-protected <i>N</i>-3-alkenyltetronic acid amides <b>9</b> and <b>12</b> were prepared from tetronic acid bromide (<b>7</b>) and the corresponding amines <b>6</b> and <b>10</b> by nucleophilic substitution and subsequent acylation in 71% and 39% overall yield. They underwent an intramolecular [2 + 2]-photocycloaddition upon direct irradiation (λ = 254 nm) to yield diastereoselectively the strained lactones <b>15</b> (76%) and <b>16</b> (91%) with a 2-azabicyclo[3.2.0]heptane core. In attempts to defunctionalize the 1-hydroxymethyl substituent of the 2-azabicyclo[3.2.0]heptane skeleton, lactone <b>15</b> was converted into mesylate <b>18</b> (74% overall yield). Intermolecular substitution reactions on this mesylate, however, proceeded sluggishly or failed completely. Lactone <b>15</b> could be opened reductively (Dibal-H) or by substitution with benzylamine to the <i>N</i>-Boc-protected 2-azabicyclo[3.2.0]heptanes <b>21</b> (71%) and <b>22</b> (81%). Conformationally constrained β-amino acid derivatives were obtained by quantitative <i>N</i>-Boc deprotection of photocycloaddition product <b>15</b>, followed by <i>N</i>-functionalization and subsequent lactone ring opening. The <i>N</i>-functionalization was conducted by acylation (to <b>24</b>−<b>26</b>), alkylation (to <b>27</b>), tosylation (to <b>28</b>), and isocyanate addition (to <b>30</b>). The reactions proceeded in yields of 70−84%. Lactone ring opening reactions were conducted with amines to establish the suitability of this process for library synthesis. As an example, the tripeptide <b>38</b> was obtained from photocycloaddition product <b>15</b> in an overall yield of 51%.
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