Asperdiol synthesis

Allylic bromides can also serve as progenitors for nucleophilic organochromium reagents. An elegant example is found in Still and Mobilio s synthesis of the 14-membered cembranoid asperdiol (4) (see Scheme 2).7 In the key step, reduction of the carbon-bromine bond in 2 with chromium(n) chloride in THF is attended by intramolecular carbonyl addition, affording a 4 1 mixture of cembranoid diastereoisomers in favor of the desired isomer 3. Reductive cleav-... 

Diastereoselective macrocycUzation. A ke> step in a synthesis of the 14-membered cembranoid asperdiol (4) involves intramolecular ( yclization of the aldehydo allylic bromide (1) with chromium(II) chloride. The intermolccular version of this reaction is known to be anf/-selective (8,112). Treatment of racemic 1 with CrCl, (5 equiv., THF) results in a 4 1 mixture of the two anti-diastereomers 2 and 3 in 64% combined yield. The stereochemistry of this cyclization is evidently controlled by the remote epoxide group. The natural product was obtained by deprotection of 2 (Na/NH, 51% yield). 

The intramolecular variant of the chromium(U) ion mediated Barbier-Grignard-type addition reaction was first described by Still and Mobilio in an elegant synthesis of ( )-Asperdiol (122 R = H). Qm>-mium(II)-mediated cyclization of (121 R = Bn) provided a 4 1 mixture of (122) and (123) in 64% yield (equation 50). The relative topicity of the process is ik. This result is in accord with a synclinal chair transition structure (124) in which both hydrocarbon chains diverge from the reacting centers pseudo-... 

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

As a final example of ring-closing allylation in natural product synthesis. Still and co-workers demonstrated that the crotylchromium species derived in situ from the allylbromide 191 undergoes intramolecular allylation to give a 4 1 ratio of adducts 192 and 193, where the major adduct 192 was subsequently converted to asperdiol (Scheme 11-8) [102]. 

Aold, M., Tooyama, Y, Uyehara, T., and Kato, T. (1983) Synthesis of ( )-asperdiol, a marine anticancer cembrenoid. Tetrahedron Lett., 24, 2267-2270. 

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