Oxocene synthesis

One year after the total synthesis of (-l-)-laurencin, Crimmins disclosed total syntheses of (-l-)-prelaureatin 232 and (-f)-laurallene 233, applying a similar strategy (Scheme 43). The critical RCM reaction was undertaken with precursor 230, anticipating that the gauche effect of the C6 and C7 oxygens would accelerate the ring closure. Exposure of 230 (0.005 M in dichloromethane) to catalyst B proceeded smoothly to provide the key A -oxocene 231 in 95% yield with no detectable dimerization. 

C2H5)jSiH/BF3- 0(C2H5)2. The presence of a c/r-double bond is an essential for this cyclization. Another limitation is that yields are low when extended to synthesis of a nine-membered oxocene. 

The intramolecular allylboration of an aldehyde function leads selectively to cir-disubstituted cyclic ethers. It has been shown that both the reactive aldehyde and the allylboronate moiety can be initially generated in situ in a masked form and then liberated simultaneously by hydrolysis of the precursor functions <1997JA7499>. This methodology was successfully applied to the one-pot synthesis of the oxocene 82, a precursor of (-l-)-laurencin (Scheme 13). A DIBAL reduction of the Weinreb amide 80, metalation with r f-butyllithium, borylation with the pinacol borate ester, and, finally, liberation of both the aldehyde and the allylboronate function by aqueous pH 7 buffer solution generated the reactive 81, which cyclized in 38% overall yield to the oxocene 82. Only the all-cis-diastereomer is formed, which means that the cyclization proceeds under high asymmetric induction from the resident stereogenic center present in 80. 

An impressive application is the highly stereocontrolled and enandoselective synthesis of (-)-laure-nyne (113 Scheme 54). The key step is the cyclization of the mixed acetal (110) to give the oxocene (112), with the required endocyclic unsaturation at the correct position. The formation of this eight-mem-bered cyclic ether, instead of the corresponding seven-membered ring with an exocyclic double bond, may be rationalized by an intramolecular ene-type reaction of the intermediate oxocarbenium ion (111). 

The first enantioselective total synthesis of (+)-prelaureatin was achieved by M.T. Crimmins et al. The oxocene core of the natural product was constructed in high yield by a RCM reaction using the first generation Grubbs catalyst. 

Eight- and nine-membered cyclic ethers are also generated via type-III reactions by treating the 5-hexen-l-ol acetals with Lewis acids. 8-endo Cyclization of 5-hexenyl methoxyethoxymethyl ether in the presence of two equivalents of tin(IV) chloride forms a 2 1 mixture of chlorinated and unsaturated 1 -oxycyclooctanes 11 and 1232. Vinylsilane undergoes an 8-endo Prins cyclization. After O-desilylation, oxocene 13, which is used as a precursor in a laurenyne synthesis, is obtained in 37% yield33. 

Overman has also shown that eight- and nine-membered cyclic ethers can be prepared by type 111 cy-clizations.136 Treatment of (257) with 2 equiv. of SnCL for 13 h at -20 C gives (258), which cyclizes to give a 2 1 mixture of (259) and (260) in 83% yield.137 Cleaner reaction mixtures have been obtained using vinylsilanes, as in the synthesis of laurenyne.138 SnCU-mediated cyclization of acetal (261) in CH2CI2 at 0 C, followed by 0-desilylation produces oxocene (262) in 37% yield as the sole cyclic ether (Scheme 38). 

The high level of induced and simple diaslereoselectivity was also maintained on ring closure to a civS-oxocene-ring 39 bearing a hydroxy and vinyl function. This ring closure was the key step in our partial synthesis of (+)-laurencin 40. This time, the aldehyde function was pregenerated in protected form by reduction of a Weinreb-amide 38. (/5)... 

---