To demonstrate the scope of the reaction, a series of ( E )-alkenyl bromides were cross-coupled with NHP ester 31 , affording the corresponding products in uniformly good yield and high ee (Table 4.3). Perfect chemoselectivity for cross-coupling of the NHP ester over the primary alkyl chloride is observed. This highlights an advantage of the NHP ester for certain C(sp3) electrophiles, as the corresponding α-chloroether substrate is unstable and difficult to work with.
Further studies of the mechanism are ongoing; it is currently unclear whether the absolute stereochemistry is set during the oxidative addition or reductive elimination steps18. The chloroalkyl moiety is thought to be important for proteasome inhibition and the presence of hydroxyl groups at C1 and C14 contributes to binding. Macrocycle 229 would result from Ni-catalyzed double asymmetric reductive cross-coupling of bis-electrophile 227 , in which the key C6–C7 and C19–C20 bonds would be formed while setting the C7/C20 stereogenic centers.
This strategic application of an asymmetric reductive cross-coupling has since become particularly suitable for the preparation of the macrocyclic cylindrocyclophanes. In addition, research on the main reductive alkenylation will expand the scope and deepen our understanding of these new and underutilized reductive cross-coupling transformations.
Preliminary studies
Based on this previous work, we proposed to prepare the cylindrocyclophane F macrocycle by a Ni-catalyzed asymmetric reductive dimerization/macrocyclization of NHP ester 227 (Scheme 4.5). Although the asymmetric reductive coupling of NHP esters tolerates electron-rich substrates, the o,o dissubstitution on the arene of the required substrate was expected to challenge the established conditions and require further reaction development. To first investigate the feasibility of the intermolecular reductive cross-coupling, model substrates 231 and 232 were synthesized (Scheme 4.7).
The benzyl ester substrate NHP 231 was chosen over the corresponding benzyl chloride due to its improved stability;. A mixture of 231 and 232 was subjected to conditions previously developed for the asymmetric reductive alkenylation of NHP esters: NiBr2 (diglyme) as catalyst, cPro-indaBOX (L4) as ligand, TDAE as stoichiometric reducing agent, and TMSBr as an activating agent; however, no product formation was observed under these conditions. In contrast, when Mn0 was used as the stoichiometric reductant, the product was formed in 15% yield.
Although the homo-dimer derived from 231 was not isolated, the NHP ester 231 was consumed under these conditions. This suggests that increasing the concentration of the carbon-centered radical increases productive cross-coupling.
Further development of substrate scope
It is possible that adjusting the redox potential of the ester could improve the yield; therefore, we will also investigate whether other redox-active esters provide improved reactivity (Figure 4.3). In addition to tuning the redox potential of the ester, we will investigate whether substitution in the para-position of the arene (e.g., 238, X substituent) can be used to tune the stability of the radical; having a handle at the para position would also be useful as we ultimately need to functionalize the arene here for deepening to 227 (Figure 4.3). Similarly, different protecting groups in the ortho position will be evaluated for their effect on yield and selectivity (eg 239 , Y-substituent).
Given the promising levels of enantioselectivity obtained using 4-HeptylBiOX (L6) under the initial screening conditions, we are confident that suitable conditions to deliver the product with high yield and enantioselectivity can be identified. Of particular interest is the improved reactivity with other NHP (or related) esters bearing o-substitution (240), or bulky substituents at the benzylic position (241) (Figure 4.4). In addition, we will investigate whether the newly identified conditions allow the cross-coupling of Z- and tri-substituted alkenyl bromides (242 and 243), substrates that fail to cross under our first-generation conditions.
Thus, in addition to solving the specific synthetic challenge presented by cylindrocyclophanes, these studies will also serve to improve the generality of these asymmetric reductive alkenylation reactions.
Synthesis of cylindrocyclophane F
Ester 248 is then subjected to Ir-catalyzed C–H borylation conditions, 34–36 and the resulting aryl pinacol boronate is formed in 87% yield. This pinacol boronate will then be coupled to alkyl iodide 250 using the Ni-catalyzed conditions developed by Fu and co-workers.37,38 Preliminary experiments show that we can couple a simple alkyl iodide to 249 in good yield ( not shown), demonstrating the feasibility of this transformation. Alkyne 250 can be prepared from commercially available hex-5-ynoic acid according to a protocol developed by Paquette.39 Finally, alkyne 251 will be converted to alkenyl bromide and the ester will be transesterified to give bis-electrophile 227 .
The bis-electrophile 227 will undergo Ni-catalyzed reductive alkenylation conditions developed in the model system (Scheme 4.9). A range of reaction concentrations will be explored to favor the formation of macrocycle 229 over competing linear dimerization reactions.
Alternative strategies
Conversion of the alkyne to the alkenyl bromide, and conversion of the methyl ester to the NHP ester, would allow a second Ni-catalyzed reductive coupling to form the macrocycle and intercept diene 229 . The second backup strategy will prepare the key fragment, 229, using a Ni-catalyzed asymmetric reductive alkenylation of NHP ester 238 (Scheme 4.11). Exposure of 257 to the CM/RCM conditions developed by Smith and co-workers should lead to macrocycle formation, and hydrogenation and demethylation will complete the synthesis of 220F.
This route could prove necessary if our optimization studies of the Ni-catalyzed alkenylation show that electronic modulation of the NHP ester by p-substitution is required.
CONCLUSION
EXPERIMENTAL SECTION .1 Materials and methods
Substrate Preparation .1 NHP Ester Synthesis
The crude reaction was concentrated to give a thick oil, which was purified by column chromatography (silica, EtOAc/hexane or CH2Cl2) to give the desired product. The crude residue was purified by filtration through a plug of silica with CH2Cl2 as eluent to give 8.7 g (88% yield) of 259 as a white solid. The crude residue was purified by filtration through a plug of silica with 30% EtOAc/hexane as eluent to give 671 mg (74% yield) of 260 as a white solid.
The crude residue was purified by filtration through a plug of silica using 30% EtOAc/hexane as eluent to provide 290 mg (87% yield) of 261 as a yellow solid. The crude residue was purified by filtration through a plug of silica using 20% EtOAc/hexane as eluent to afford 511 mg (48% yield) of 262 as a pale yellow solid. The crude residue was purified by filtration through a plug of silica using 20% EtOAc/hexane as eluent to afford 590 mg (63% yield) of 263 as a white solid.
Prepared from 2-(4-(dimethylamino)phenyl)propanoic acid (392 mg, 2.02 mmol) according to general procedure 1, except without DMAP. Prepared from 2-(3,4-dichlorophenyl)propanoic acid (231 mg, 1.05 mmol) according to general procedure 1, except without DMAP. This crude material was used in an esterification step without purification, which was carried out according to General Procedure 1.
The crude residue was purified by column chromatography and dried under high vacuum (silica, 0 to 20% EtOAc/hexane) to give 664 mg (31% yield) of 269 as a colorless oil. The crude residue was purified by filtration through a plug of silica to give 6.2 g (77% yield) of 272 as a white solid. The crude residue was purified by column chromatography (silica, ether/hexanes) to afford vinyl bromide.
The crude residue was purified by column chromatography (silica gel, hexane) to afford 186 (37 mg, 88% yield) in 96% ee as a colorless oil. The crude residue was purified by column chromatography (silica gel, hexane) to afford 189 (29 mg, 69% yield) in 91% ee as a colorless oil. The crude residue was purified by column chromatography (silica gel, hexane) to afford 190 (31 mg, 72% yield) in 94% ee as a colorless oil.
The crude residue was purified by column chromatography (Florisil, hexane to 1% Et 2 O/hexane) to afford 191 (33 mg, 66% yield) as a colorless oil. The crude residue was purified by column chromatography (silica gel, hexane) to give 193 (28 mg, 68% yield) in 97% ee as a colorless oil.
Radical Clock Investigation
NOTES AND REFERENCES
