(S)-Nyasol was selected as the target to demonstrate the efficiency of the copper-catalyzed substitution of secondary propargylic phosphates. The key phosphate (R)-TBDPSO(CH2)2CH(C≡CC6H4OTBS)-(OP(O)(OEt)2) was synthesized from TBDPSO(CH2)2CO2H in four steps. The substitution of the phosphate with TBSOC6H4MgBr in the presence of CuBr·Me2S as a catalyst in THF/DME proceeded with both stereo- and regioselectivity at the propargylic position. All the silyl groups in the propargylic product, TBDPSO(CH2)2CH(C≡CC6H4OTBS)(C6H4OTBS), were removed, and the acetylene bond was reduced using active Zn to produce the cis olefin. Finally, the HO(CH2)2 moiety was converted to CH2=CH-, thus producing (S)-nyasol with 97% cis selectivity, 94.5% ee, and >99% es. Similarly, dihydro-nyasol was synthesized via hydrogenation of the substitution product followed by construction of the terminal olefin.
trans-2,6-Disubstituted cyclohexanones were synthesized with high regio- and stereoselectivity by allylic substitution followed by ozonolysis. Both alkyl and aryl groups were successfully installed to the cyclohexane ring. The stereochemistry of the SN2' products was determined to be controlled by the pre-existing chirality on the ring. The present method is highlighted by the synthesis of enantiomerically enriched cyclohexanones.
The substitution of secondary propargylic phosphates ROP(O)(OEt)2 where R = [Ph(CH2)2]C(H)(C≡CTMS)] Ph(CH2)2CH(OP(O)(OEt)2)(C≡CTMS) with copper reagents derived from PhLi and copper salts such as CuCl, CuCN, and Cu(acac)2 was studied to establish an ArLi-based reagent system. Among the reagents prepared, PhLi/CuCl (2:1) showed 98% α regioselectivity (rs), while PhLi/Cu(acac)2 was γ selective (>99% rs). PhLi prepared in situ from PhI and PhBr by Li-halogen exchange with t-BuLi was also used for the α selective substitution. A study using the (S)-phosphate disclosed 99% enantiospecificity (es) and the inversion of the stereochemistry. The substitution of five phosphates with substituted aryl reagents produced the corresponding propargylic products with high rs and es values. Similar reactivity and selectivity were observed with 2-furyl and 2-thienyl reagents, which were prepared via direct lithiation with n-BuLi.
Synthesis of trans-2,6-Disubstituted Cyclohexanones Through Allylic Substitution. -trans-2,6-Disubstituted cyclohexanones (IV) are synthesized with high regioand stereoselectivity by allylic substitution followed by ozonolysis. Both aryl and alkyl groups are successfully installed to the cyclohexane ring. The stereochemistry of the S N2' products is determined to be controlled by the pre-existing chirality on the ring. The present method is highlighted by the synthesis of enantiomerically enriched cyclohexanones like (VIII). -(KOBAYASHI*, Y.; FENG, C.; IKOMA, A.; OGAWA, N.; HIROTSU, T.; Org. Lett. 16 (2014) 3, 760-763, http://dx.doi.org/10.1021/ol403472y ; Dep. Bioeng., Tokyo Inst. Technol., Yokohama 226, Japan; Eng.) -H. Haber 26-064
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